PMID- 23724465 TI - Posterolateral rotatory instability from multiple steroids injections for tennis elbow: a case report. AB - This article reports the complication (lateral collateral ligament rupture) arising from improper numbers of steroids injections for the chronic lateral elbow pain (tennis elbow). Clinical sign and investigation with MRI confirmed a diagnosis of LCL rupture. In the present report, we describe the successful outcome of one year results in surgical debridement and lateral collateral ligament (LCL) reconstruction. A discussion of the proper conservative role for the chronic lateral epicondyalgia and the surgical decision to resolve this complication is also included. PMID- 23724466 TI - Minimally invasive palatal surgery for obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is a common condition in Thai population characterized by recurrent episodes of apnea during sleep. Patients may have detrimental consequences and the management of OSA is complex and challenging. Many patients respond to medical treatments including weight loss, body position training, oral appliances and continuous positive airway pressure (CPAP). Although medical intervention fails, surgical procedure is the alternative options to improve the upper airway patency Many palatal surgical procedures have been introduced to alleviate upper airway obstruction. However most procedures are invasive, destructive, painful, also associated with significant morbidity. Recently, minimally invasive surgery also achieves the same results as the invasive procedures with less postoperative risks. The treatment outcomes have now been validated by many centers in appropriately selected patients. The types, results and complications of the procedures are reviewed. PMID- 23724467 TI - Judgement Day: the Hospital Corporation of America decision. PMID- 23724468 TI - MSMA goes to Washington. PMID- 23724469 TI - Kansas City Metropolitan Physician Association: An alternative for independent physicians in Kansas City. PMID- 23724470 TI - Physicians of the future. PMID- 23724471 TI - Headed for a fall: over the Social Security disability fiscal cliff. PMID- 23724472 TI - The tragedy of mental health law. PMID- 23724473 TI - Off-label, not off-limits: the FDA needs to create a safe harbor for off-label drug use. PMID- 23724474 TI - FDA approvals are a matter of life and death. PMID- 23724475 TI - All hat no cattle. PMID- 23724476 TI - Drivers of health care costs. A Physicians Foundation white paper - second of a three-part series. PMID- 23724477 TI - Should ophthalmologists test hearing & sell hearing aids? Con. PMID- 23724478 TI - Should ophthalmologists test hearing & sell hearing aids? Con. PMID- 23724479 TI - Should ophthalmologists test hearing & sell hearing aids? Con. PMID- 23724480 TI - Should ophthalmologists test hearing & sell hearing aids? Con. PMID- 23724481 TI - Mary Jane still dulls the pain. PMID- 23724482 TI - The use of simulation in medical and surgical education. PMID- 23724483 TI - Task training and simulation in the pre-hospital environment. AB - The increasing popularity of standardized patients is helping Emergency Medical Services (EMS) educators to develop (and reinforce) good professional behaviors among EMS students before they hit the streets to serve our communities. PMID- 23724484 TI - Simulation in internal medicine training. AB - Simulation is a growing safe format to train learners on different skills and procedures in the field of Internal Medicine. This article will provide an overview of Simulation in Internal Medicine training as well as a description of different procedures and competencies. The goal of this review is to provide clinician educators and learners specific information on how they can implement simulation training in their clinical setting. PMID- 23724485 TI - No longer waiting for an accident to happen: Simulation in emergency medicine. AB - The practice of emergency medicine (EM) requires proficient and expert skills in multiple high risk procedures. The emergency physician in-training needs a safe and realistic environment in which to practice and perfect the skills necessary to care for patients ranging from the critically ill to the patient with difficult intravenous access. Undergraduate medical, education overall has a need for training that enables students to develop the knowledge, skills and attitudes to practice in a variety of specialties. This article provides an overview of simulation in a three-year emergency medicine residency at Truman Medical Center, in a required final year clerkship for all medical students at the University of Missouri-Kansas City, and discusses national trends for the use of simulation in emergency medicine. PMID- 23724486 TI - Simulation in anesthesiology: A key element in the new recertification process. AB - The training of anesthesiologists has long utilized simulation based on the need to achieve maximum patient safety. The value of this type of training is that it can provide a real life experience and instruction in the complex dynamic environment of the operating room or intensive care unit through the use of didactic sessions, group or team-based exercises, and computer or servo mechanical simulator training with post-simulation debriefings. This type of training is becoming more important in the formal training of anesthesiologists and will become part of the ongoing evaluation and certification of providers in the future. PMID- 23724487 TI - Simulation in surgery. PMID- 23724488 TI - Simulation in obstetrics & gynecology. PMID- 23724489 TI - Simulation in pediatrics. PMID- 23724490 TI - Simulation in orthopaedics. PMID- 23724491 TI - Simulation in ophthalmology. PMID- 23724492 TI - Modern cardiac rehabilitation: Integrating the best measures to reduce a second cardiac event. AB - Patients with established cardiovascular disease are at high risk for future myocardial infarction, stroke, and death. Interventions that may reduce recurrent cardiovascular events serve a critical role in improving both long-term morbidity and mortality. Cardiac rehabilitation following a cardiac event has been modernized with the integration of coronary risk factor reduction programs in addition to its traditional role of early graded mobilization of the patient and has been shown to significantly benefit men and women with coronary heart disease. PMID- 23724493 TI - The interrelationship of sleep, biologic clocks, neurotransmitters, gonadotropins and pubertal development. AB - PURPOSE: To evaluate the influence of sleep on early pre-pubertal and pubertal development and to explore the importance of circadian rhythms and gonadotropin secretion. METHODS: Mechanisms of suppression and turning on of the hypothalamic gonadotropin releasing hormone (GnRH) pulse generator at different times in development are evaluated. Furthermore, the influence of neurotransmitters in controlling pubertal development is also considered. RESULTS: By the end of the first year, certain genes are activated that cause marked sensitivity of the GnRH pulse generator to negative feedback of circulating sex steroid. Furthermore, a central nervous system mechanism contributes greatly to the juvenile pause. Biologic clocks help to turn on the gonadostat and loss of negative feedback to sex steroid. This occurs during the sleeping hours. Equally important is to neutralize the neurotransmitter gamma amino butyric acid (GABA) which is the main central nervous system inhibitor. CONCLUSIONS: Pubertal development is a complex process requiring the activation of certain genes which activate biologic clocks. This results in the increased secretion of certain neurotransmitters, for example, leptin and kisspeptin, which are very important in awakening the GnRH pulse generator. Suppression of the inhibitory neurotransmitter GABA is equally important. PMID- 23724494 TI - Isolating sperm by selecting those with normal nuclear morphology prior to intracytoplasmic sperm injection (ICSI) does not provide better pregnancy rates compared to conventional ICSI in women with repeated conception failure with in vitro fertilization. AB - PURPOSE: To determine if isolation of sperm by nuclear characteristics using high magnification offers any advantage over the normal morphologic methods when performing intracytoplasmic sperm injection (ICSI) in refractory cases in which the male partner had an abnormal DNA fragmentation index. MATERIALS AND METHODS: Women aged < or = 39 with failure to have a successful conception after three consecutive embryo transfers whose male partner had a DNA fragmentation index > 30% were randomly assigned to isolation of sperm for ICSI by a new high magnification procedure to evaluate nuclear morphology and the usual method with normal magnification where nuclear characteristics were not seen. Women 40-43 were not randomized and were given the option after hearing pros and cons. RESULTS: Overall the live delivered pregnancy rates were similar in the high vs normal magnification groups (33.3% vs 36.3%). CONCLUSIONS: Isolation of sperm with normal nuclei with high magnification does not offer any advantage over conventional IVF for refractory cases where the male partner has a high DNA fragmentation index. PMID- 23724495 TI - Intracytoplasmic sperm injection allows normal pregnancy rates for males 40 with low hypoosmotic swelling test scores even when complicated by very low motility percentage. AB - PURPOSE: To determine if the additional burden of low percentage motility reduces the chance that sperm with low hypoosmotic swelling (HOS) test scores will achieve a pregnancy following in vitro fertilization (IVF) with intracytoplasmic sperm injections (ICSI). METHODS: Couples undergoing IVF-embryo transfer (ET) and ICSI for low HOS tests (< 50%) were retrospectively identified. The percentage motility was divided into deciles. Pregnancy rates were determined according to the deciles of motility. RESULTS: No differences in clinical or live delivered pregnancy rates per transfer were found in even the very lowest percent motility category. CONCLUSIONS: The added complicating factor of low percentage motility added to sperm with low HOS test scores does not reduce the effectiveness of IVF with ICSI. PMID- 23724496 TI - Pregnancy rates following the exclusive transfer of twice frozen twice thawed embryos using a modified slow cool cryopreservation technique. AB - PURPOSE: To determine the pregnancy rate following the exclusive transfer of twice frozen twice thawed embryos. MATERIALS AND METHODS: All day 3 transfers of exclusive twice frozen-twice thawed embryos were retrospectively identified over a 13-year time-period. The cryopreservation technique used a simplified slow cool freezing protocol. Embryos could have been originally cryopreserved at the 2 pronuclear or multi-cell stage. RESULTS: Survival rates were 83.3%. The live delivered pregnancy rate was 18.1% (15/83). The implantation rate was 13.1% (22/168). CONCLUSIONS: These data suggest that twice frozen twice thawed embryos should not be discarded but either transferred alone if they are the only embryos left, or mixed with frozen embryos that have never been thawed. Though the live delivered pregnancy rates are inferior to fresh embryo transfer the marked reduction in cost and avoidance of the risk of ovarian hyperstimulation justifies their transfer. PMID- 23724497 TI - Embryo apoptosis may be a significant contributing factor in addition to aneuploidy inhibiting live deliveries once a woman reaches age 45. AB - PURPOSE: To determine the relative role of aneuploidy vs embryo apoptosis as the etiologic factor of poor pregnancy rates with advancing age. MATERIALS AND METHODS: A retrospective review of chemical vs clinical vs live delivery pregnancy rates in women aged 40-42, 43-45, and > or = 45 years is reported. The data were further stratified according to oocyte reserve based on day 3 serum follicle-stimulating hormone (FSH) < or = 11 mIU/ml vs >12 mIU/ml. RESULTS: For women aged 40-42 years there were no differences in live delivery pregnancy rates in women with normal vs decreased egg reserve (DOR). There were no differences in live delivery pregnancy rates in women aged 40-42 years vs 43-44 years with normal oocyte reserve; however despite no differences in clinical pregnancy rates in women aged 43-44 years with normal vs DOR, the live delivery pregnancy rates were markedly lower in the group with DOR. In contrast, there were very low chemical pregnancy rates in women aged > or = 45 years. CONCLUSIONS: As seen in younger women, there does not appear to be any increased risk of meiosis errors in women aged 40-42 years with DOR compared to women of the same age with normal reserve. Low pregnancy rates in women aged 43-44 years with DOR is related to meiosis errors. In contrast the very low chemical pregnancy rates found in women aged > or = 45 years despite embryo transfer (ET) suggest embryo apoptosis is mostly responsible for poor pregnancy rates in this very advanced reproductive age group. PMID- 23724498 TI - Adding luteinizing hormone to follicle stimulating hormone from day 3-5 improves pregnancy outcome in normal but not poor responders using gonadotropin releasing hormone antagonists. AB - PURPOSE: To determine if the addition of luteinizing hormone (LH) to follicle stimulating hormone (FSH) stimulation for controlled ovarian hyperstimulation (COH) protocols using gonadotropin releasing hormone (GnRH) antagonists improves pregnancy rates following in vitro fertilization-embryo transfer (IVF-ET). MATERIALS AND METHODS: All IVF-ET cycles using a GnRH antagonist were evaluated according to whether FSH was used exclusively or if LH was added. The cycles were further stratified according to age (< or = 39 and 40-42 years) and according to good responders (> or = five oocytes retrieved) or poor responders (< or = four oocytes). RESULTS: Combining all data, a significantly higher clinical and live delivered pregnancy rates were found in those adding LH (34.7% and 32.3%) vs those taking all FSH (33.4% and 25.8%). The only subgroup not showing this effect was the women aged 40-42 years with diminished oocyte reserve. CONCLUSIONS: LH should be added not only to COH protocols using GnRH agonists but also those using GnRH antagonists. PMID- 23724499 TI - The effect of diminished oocyte reserve in younger women (age < or = 37) on pregnancy rates in natural cycles. AB - PURPOSE: To determine the relative confounding effect of diminished oocyte reserve on the chance of successful pregnancy in non-in vitro fertilization embryo transfer (IVF-ET) cycles. MATERIALS AND METHODS: Matched controlled study comparing pregnancy outcome in women aged < or = 37 years with severely decreased oocyte reserve as manifested by a day 3 serum follicle stimulating hormone (FSH) > or = 15 mIU/ml compared to women with normal oocyte reserve (serum FSH < or = 8 mIU/ml). Couples were excluded if they did not have tubal patency or a semen analysis that required IVF-ET. Only couples that tried at least three natural cycles (unless pregnancy occurred first) were included. RESULTS: The live delivered pregnancy rates within a maximum of five cycles of luteal phase support with progesterone (P) or at most mild FSH stimulation, or intrauterine insemination for mild male factor or cervical factor was 33.3% (8/24) with increased day 3 FSH and 62.5% (16/24) for the normal group (p = 0.08, Fisher's exact test). CONCLUSION: Women with marked oocyte depletion are half as likely to conceive with assisted reproductive techniques compared to women with normal oocyte reserve. PMID- 23724500 TI - Younger women with diminished oocyte reserve are not more prone to meiosis errors leading to spontaneous abortion than their age peers with normal oocyte reserve. AB - PURPOSE: To determine the relative effect of age vs ovarian oocyte reserve on miscarriage rates. MATERIALS AND METHODS: Miscarriage rates (loss of pregnancy established by ultrasound) from pregnancies achieved through in vitro fertilization-embryo transfer (IVF-ET) were evaluated according to four age groups (< or = 35, 36-39, 40-42, and 43-44 years) and four day 3 serum follicle stimulating hormone (FSH) groups (< or = 11, 12-14, 15-17, and > 17 mIU/ml). All cycles were supplemented with progesterone in the luteal phase. RESULTS: With each advancing age group irrespective of the FSH levels, there was a progressive increase in miscarriage rates. In contrast, no difference in miscarriage rates were seen as FSH levels increased (and thus ovarian reserve decreased) in women up to 42 years of age. Only in the group aged 43-44 years was there an association with diminished oocyte reserve and miscarriage. CONCLUSIONS: Since low FSH stimulation protocols were purposely used for the group with diminished oocyte reserve, the data are consistent that the conclusion regarding poor oocyte quality in women with diminished oocyte reserve was mostly iatrogenic and related to the use of high-dosage FSH stimulation trying to create more oocytes for retrieval. PMID- 23724501 TI - Intrauterine insemination (IUI) does not improve pregnancy rates in infertile couples where semen parameters are normal and postcoital tests are adequate. AB - PURPOSE: To determine if intrauterine insemination (IUI) improves pregnancy rates in couples with a correctable ovulatory defect but a male partner with an apparent normal semen analysis and a normal postcoital test. MATERIALS AND METHODS: A prospective evaluation of clinical live delivered pregnancy rates following the first cycle where follicular maturation was demonstrated naturally or with a follicle maturing drug. The couples were given the option of IUI. RESULTS: The live delivered pregnancy rates per IUI cycle were similar with intercourse only vs addition of IUI (18.7% vs 21.4%). CONCLUSIONS: There is no evidence to support the notion that IUI improves pregnancy rates in circumstances where the semen analysis and postcoital tests are normal. PMID- 23724502 TI - Low hypo-osmotic swelling tests correlate with low percent motility and age of the male. AB - PURPOSE: To determine if sperm motility and hypo-osmotic swelling (HOS) test scores are associated. Furthermore the study would determine if the chance of having a subnormal HOS test increases as motility levels decrease. Finally the study would determine if age, motility, and HOS test scores are independent factors or if they interact. MATERIALS AND METHODS: A retrospective analysis of males of all ages with a normal sperm concentration of > 20 x 10(6)/ml is presented. Males were evaluated separately according to age (< 40 vs > or = 40 years) for percent progressive motility and HOS test scores. The percent motility was assessed according to percentage in deciles. RESULTS: A significantly higher percentage of males with low motility have low (< 50%) HOS test scores irrespective of age. The odds ratio of males < 40 years having an abnormal HOS test score is 6.73 times higher and is 8.23 times higher for males > or = 40 years. As age increases, there is a significantly larger proportion of males with abnormal HOS test scores (6% to 13%). CONCLUSIONS: Factors that cause an abnormality in the functional integrity of the sperm membrane, as evidenced by a low HOS test score, can also have a negative effect on motility. PMID- 23724503 TI - Effect of triple line vs isoechogenic endometrial texture on pregnancy outcome following embryo transfer according to use of controlled ovarian stimulation (COH) or estrogen/progesterone replacement. AB - PURPOSE: To determine if pregnancy rates following embryo transfer are reduced if the endometrial echo pattern in the late proliferative phase is isoechogenic (IE) vs triple line (TL). METHODS: Pregnancy and implantation rates were compared according to TL vs IE pattern in the late proliferative phase in women having in vitro fertilization-embryo transfer (IVF-ET), frozen ET, and transfer of embryos derived from donor oocytes. RESULTS: There was no difference in pregnancy rates with IE vs TL pattern with fresh or frozen ET or in donor egg recipients. The degree of ovarian reserve did not affect the pregnancy rates according to endometrial echo pattern. CONCLUSIONS: The presence of an IE pattern in the late proliferative phase should not influence the treating physician to either cancel the cycle and withhold human chorionic gonadotropin (hCG) injection or freeze all embryos and defer transfer. PMID- 23724504 TI - Frequency of endometriosis and adenomyosis in patients with leiomyomas, gynecologic premalignant, and malignant neoplasias. AB - OBJECTIVE: This study investigated the association between gynecological neoplasms, endometriosis, and adenomyosis in women who underwent surgical treatment for gynecological cancer and uterine leiomyoma during reproductive years or after menopause. MATERIALS AND METHODS: Information was collected from patient records from the Hospital's database from 1985 to 2007. The study included 502 women, of which 375 were premenopausal and 132 were postmenopausal. RESULTS: A significant association was observed between the occurrence of adenomyosis in cancer in women with four or more pregnancies, and in women aged over 40 years (p < 0.0001). The frequency of adenomyosis was significantly higher than the frequency of endometriosis for cancer in two sites (p = 0.0419) or for leiomyomas (p < 0.0001). CONCLUSION: Therefore adenomyosis is more frequently found than endometriosis in women with leiomyomas or cancer in two sites in premenopausal women, and clinicians need to be aware of patients with adenomyosis and the risk of cancer. PMID- 23724505 TI - Placental apoptosis in preeclampsia, intrauterine growth retardation, and HELLP syndrome: an immunohistochemical study with caspase-3 and bcl-2. AB - OBJECTIVE: To examine the placental expression of caspase-3 and bcl-2 in pregnancies complicated by preeclampsia, IUGR, and HELLP syndrome. MATERIALS AND METHODS: A prospective case-control study was conducted on 50 pregnant women between December 2006 and August 2007 at Dr. Zekai Tahir Burak Women Health Research and Education Hospital, Ankara, Turkey. Placental tissue samples were obtained from 15 pregnancies complicated by preeclampsia, 15 pregnancies with normotensive IUGR, five pregnancies with HELLP syndrome, and 15 gestational age matched normotensive pregnancies without intrauterine infection as a control group. The placental expression of caspase-3 and bcl-2 has been investigated by immunohistochemical staining. RESULTS: Caspase-3 immunostaining score was significantly higher in each group when compared with the control group (p = 0.002). However there was no statistically signifant difference with bcl-2 immunostaining in each group when compared with the control group. CONCLUSIONS: Apoptotic marker caspase-3 is significantly increased in the villous trophoblasts of patients with preeclampsia, HELLP syndrome, and IUGR indicating increased placental apoptosis. PMID- 23724506 TI - Obstetric outcome in adolescence: a single centre experience over seven years. AB - PURPOSE OF INVESTIGATION: The aim of this study was to compare the obstetric outcome of adolescent pregnant women (aged < or = 18) with the outcome of adult pregnant women who delivered in a tertiary university hospital. MATERIALS AND METHODS: Delivery files from 2004 to 2011 were reviewed concerning age of the pregnant women, parity, gestational age, mode of delivery and birth weight of the neonates. RESULTS: During the study period 119 (0.94%) out of 10,483 deliveries were performed in adolescent women. Caesarean section was the mode of delivery in 41 adolescent patients (34.45%), while the corresponding rate was 53.6% (5,556 cases) in adult pregnant women. The preterm labour rate in the adolescent group was 13.44% (16 cases) while in the adult group it was 21% (2,201 cases). The most frequent indication of caesarean section in the adults was previous caesarean section (21%). DISCUSSION: In adolescent pregnancies the caesarean section rate was lower than in adult pregnancies. As far as the prevalent cause of caesarean section is concerned, it was repeat caesarean section for adults while in adolescents it was failure of labour to progress. PMID- 23724507 TI - The impact of socio-economic, lifestyle habits, and obesity in developing of pregnancy-induced hypertension in fast-growing country: global comparisons. AB - OBJECTIVE: The aim of the study was to determine the prevalence and associated risk factors of pregnancy-induced hypertension (PIH) in the third trimester of Arab women and their neonatal outcome. DESIGN: A prospective study. SETTING: Women's Hospital and Maternity Clinics. SUBJECTS AND METHODS: The study was based on pregnant women in third trimester from the first week of January 2010 to April 2011. A total of 2,056 pregnant women, who had any kind of maternal complications, were approached and 1,608 women (78.2%) expressed their consent to participate in the study. A questionnaire covered variables related to socio demographic factors, family history, medical history, maternal complications, and neonatal outcome. Multiple logistic regressions were used to describe the relationship between socio-demographic factors and PIH. RESULTS: Pregnant women with Qatari nationality were 30% more likely to have PIH (Adj. OR 0.7; 95% CI 0.5 0.9, p = 0.03). Those living in villas were 50% more likely than those living in apartments (Adj. OR 0.5; 95% CI 0.3-0.9) and 40% more likely than those living in traditional houses (Adj. OR 0.6; 95% CI 0.4-0.8) to have PIH. The odds of PIH linearly increases with each decrease of 5,000 QAR in monthly income from > 20,000 to 10-15,000 (Adj. OR 1.2; 95% CI 0.7-2.1, Adj. OR 1.9; 95% CI 1.1-3.2, respectively) and then it starts decreasing from 10,000 to < 5,000 monthly income (Adj. OR 1.8;95% CI 1.1-3.1 and Adj. OR 1.3; 95% CI 0.7-2.7 respectively). The odds of PIH linearly increase with each five years increase in age among pregnant women from 30 to 45 years of age. A 10-fold increase in PIH odds was observed when body mass index (BMI) increased above > or = 30 (obese) (Adj. OR 10.0; 95% CI 6.4-15.6). Pregnant women who had no history of previous abortion were 60% less likely than those who had positive history of previous abortion (Adj. OR 1.6; 95% CI 1.1-1.2; p = 0.007) to have PIH. The odds of PIH increases by 50% when women do not receive antenatal care (Adj. OR 1.5; 95% CI 1.1-2.1; p = 0.040). CONCLUSION: Qatar has a high prevalence of PIH compared to both regional and global rates. Maternal age > 30, increased BMI, previous abortion, lack of antenatal care, and physical activity were found to be significantly associated with increased risk of PIH in Arab women and could be potentially modifiable risk factors. PMID- 23724508 TI - Arterial hypertension and female sexual dysfunction in postmenopausal women. AB - PURPOSE: To evaluate female sexual dysfunction in hypertensive postmenopausal women and the effects of antihypertensive therapy. MATERIALS AND METHODS: Female sexual dysfunction was assessed by the Female Sexual Function Index (FSFI) in three groups of postmenopausal patients: normotensive women (group A: 240 women), hypertensive women without therapy (group B: 220 women), hypertensive women on therapy (group C: 80 women). RESULTS: The incidence of female sexual dysfunction was increased in group B compared to groups A and C. Healthy patients showed higher FSFI scores compared to hypertensive patients (groups B and C). Hypertensive-treated patients accounted for higher scores in all items compared to hypertensive patients without therapy. CONCLUSIONS: Essential hypertension significantly affects female sexual function. Physicians should recognize and properly manage FSD in hypertensive women. PMID- 23724509 TI - Gestational hypertension risk evaluation based on epidemiological, biochemical, and hemodynamic factors. AB - PURPOSE: Gestational hypertension (GH) is a serious health hazard for pregnant women and fetuses. The incidence of GH involves many epidemiological, biochemical, and hemodynamic factors. METHODS: The current study investigated the GH risk under the influence of epidemiological, biochemical, and hemodynamic factors, and designed corresponding GH risk evaluation methods and apparatus. RESULTS: The evaluation method has 74.15% sensitivity and 81.84% specificity. The ROC area under the curve is 0.841. The apparatus automatically imports epidemiological, biochemical, and hemodynamic factors, and then expresses the GH risk as numbers, bar codes, and colors through logic array analysis. CONCLUSION: The GH risk value can effectively give the risk level of GH. The GH risk barcode can improve the degree of automation of information storage, transmission, and identification in GH monitoring. The GH risk color can also improve the GH macro description. PMID- 23724510 TI - Relevance of anti-Mullerian hormone on in vitro fertilization outcome. AB - PURPOSE: The aim of this study was to investigate the relevance of serum and follicular anti-Mullerian hormone (AMH) concentrations on ovarian reserve and clinical pregnancy. MATERIALS AND METHODS: Thirty patients were prospectively included in this study. Serum AMH levels were quantitatively measured on the follicle aspiration day. Retrieving less than five oocytes was defined as poor response. Eleven days after embryo transfer, beta-human chorionic gonadotropin (beta-hCG) level in the blood was measured. Two weeks after the beta-hCG test, a clinical pregnancy was confirmed by transvaginal ultrasound (TVUS). RESULTS: There was a statistically significant correlation between serum AMH and number of retrieved oocytes (p = 0.024). There was a correlation between the number of retrieved oocytes and baseline antral follicle count (AFC), between ovarian reserve and baseline follicle-stimulating hormone (FSH), and between ovarian reserve and serum AMH (p < 0.05). Serum AMH cut-off value for the normal ovarian reserve was calculated as 0.37ng/ml (sensitivity 71.43%, specificity 66.67%, positive prediction 83.33%, negative prediction 50%). CONCLUSION: Increasing use of serum AMH will be of considerable benefit. Consequently, the observed positive correlation between serum AMH and ovarian reserve will require larger sampling to refine the role of AMH. PMID- 23724511 TI - Doppler parameters of maternal renal blood flow in normal pregnancy. AB - The purpose of this investigation was to evaluate changes in maternal renal arterial blood flow during pregnancy. MATERIALS AND METHODS: The study included 40 non-pregnant, 200 pregnant, and 30 women after delivery. The authors measured pulsatility index (Pi) and resistance index (Ri) in the right and left renal arteries in the hilus. The authors compared the values between non-pregnant and women during first, second, and third trimester and post-partum period and tested correlation with gestational age. RESULTS: The authors did not find a statistical difference in Pi and Ri between the right and left kidneys. There was no difference in Pi and Ri in pregnancy trimester compared to the non-pregnant state. There was no correlation between the values of Pi and Ri and gestational weeks. CONCLUSION: During pregnancy there are no changes in the values of maternal renal Pi and renal Ri. Unchanged total vascular resistance may result from physiological changes of the glomerular filtration rate. PMID- 23724512 TI - Comparison of transvaginal 3D sonohysterography with outpatient hysteroscopy in the evaluation of abnormal uterine bleeding. AB - OBJECTIVE: To compare transvaginal three-dimensional sonohysterography (3D SHSG) and outpatient hysteroscopy with regards to diagnostic accuracy, procedure time, and patient discomfort with a prospective randomized controlled cohort study in a teaching hospital in London. The study included a population group of 49 women with abnormal uterine bleeding from varied ethnic backgrounds, of which 44 completed the study. Subjects with pregnancies, pelvic infections, large uteruses, suspicious or diagnosed pelvic malignancies, and who did not meet the criteria for day surgery, were excluded. MATERIALS AND METHODS: Patients were randomized into two groups: group 1 had hysteroscopy followed by SHSG while group 2 had SHSG followed by hysteroscopy. Diagnostic accuracy, procedure time, and patient discomfort of SHSG in comparison to hysteroscopy were studied. RESULTS: A total of 44 patients completed the study. The average age of the study population was 44.8 years and the mean parity was 1.8. Nulliparas represented 34.03% of the study population and the average duration of symptoms was 14.8 months. CONCLUSION: In the investigation of women with abnormal bleeding in an outpatient setting, both hysteroscopy and SHSG are comparable in the diagnosis of intracavity lesions, pain rating, and procedure time. However patient acceptability of SHSG was significantly more when compared to outpatient hysteroscopy. PMID- 23724513 TI - Factors affecting completion of laparoscopic myomectomy. AB - PURPOSES: This study aimed to elucidate the factors affecting completion of laparoscopic myomectomy without unintended surgery. MATERIALS AND METHODS: The medical records of 143 patients who underwent laparoscopic myomectomy desiring to retain their uterus were retrospectively reviewed. Unintended surgery was defined as the need for conversion to other surgical methods including laparotomy or laparoscopic hysterectomy at any time during the procedures. All variables associated with completion of laparoscopic myomectomy in the univariate analysis were selected at the threshold ofp < 0.25 and then tested in a multiple-logistic regression model. RESULTS: The rate of unintended surgery was 13.3%. Univariate analysis revealed that age, previous abdomino-pelvic surgery, current medical disease, transfusion, > five myomas, myoma size > 8.2 cm, posterior wall location of myoma, intramural type of myoma, and the presence of adenomyosis were statistically significant risk factors for unintended surgery. Multivariate logistic regression analysis demonstrated that completion of laparoscopic myomectomy was significantly influenced by a history of previous abdomino-pelvic surgery (odds ratio; 6.46, 95% CI, 0.03-0.41; p value 0.04). CONCLUSION: The risk of unintended surgery during laparoscopic myomectomy is associated with a history of previous abdomino-pelvic surgery. PMID- 23724514 TI - How to prevent the complications caused by the changes of pelvic anatomical relationship after gynecological surgery? AB - Gynecological surgery may bring about a series of corresponding diseases, because the excision of certain organs will have changed the pelvic anatomical relationship. The gynecologist must be well aware of the surgical indications for various diseases and select the proper method, range, and approach to achieve the optimal therapeutic effects with minimal injuries. This paper discusses some diseases caused by changes of pelvic anatomical relationship after gynecological surgeries, as well as their prevention and treatment. PMID- 23724515 TI - Bilateral hypogastric artery ligation in emergency setting for intractable postpartum hemorrhage: a secondary care center experience. AB - OBJECTIVE: To report the authors' experience in bilateral hypogastric (internal iliac) artery ligation which was performed for controlling intractable postpartum hemorrhage in a secondary care center. MATERIALS AND METHODS: The patients that required bilateral hypogastric artery ligation for severe intractable postpartum hemorrhage from November 2007 to August 2009 were included in this retrospective study. Data were retrieved from patients' hospital records. RESULTS: A total of 26 cases required hypogastric artery ligation during the study period. Causes of postpartum hemorrhage included uterine atony, placental abruption, uterine rupture, and placenta accreta. Hemorrhage was effectively controlled in 20 of 26 cases (76.9%) and hysterectomy was avoided. Iliac vein injury occurred in one patient (3.8%) as an operative complication. There was one maternal death. CONCLUSION: Hypogastric artery ligation is an effective therapeutic option for severe postpartum hemorrhage and should be kept in mind during obstetric emergency conditions. PMID- 23724516 TI - Loss of heterozygosity in the fragile histidine triad (FHIT) locus and expression analysis of FHIT protein in patients with breast disorders. AB - PURPOSE OF INVESTIGATION: The fragile histidine triad (FHIT) gene is a tumor suppressor frequently inactivated in various types of tumors. The authors evaluated the occurrence of loss of heterozygosity (LOH) in the FHIT locus and FHIT protein changes in breast tissue. MATERIALS AND METHODS: Blood and breast tissue samples were obtained from 35 women with mammary disorders. The occurrence of LOH in FHIT locus was assayed by polymerase chain reaction (PCR), and the results obtained from blood and breast tissues from each patient were compared. FHIT protein expression was evaluated by immunohistochemistry. RESULTS: LOH in the FHIT gene occurred in 48.6% (17/35) of patients with mammary disorder. Among patients with malignant breast disorders, 59.1% (13/22) presented LOH in the FHIT gene in comparison with patients with benign breast lumps, in which the LOH was observed in 30.8% (4/13) of women, suggesting that changes in this gene occur prior to the process of mammary carcinogenesis. The changes in the locus of the FHIT gene occur with greater frequency in the coded region of the gene, principally near exons 5 and 8, where the FRA3B site and the histidine triad respectively are found. Changes in FHIT did not modify protein expression. The association between menopause and LOH in the FHIT gene was evident. CONCLUSIONS: LOH in the FHIT gene may be related to menopause in women with breast disorders. PMID- 23724517 TI - The value of negative Chlamydia trachomatis antibody in prediction of normal tubes in infertile women. AB - OBJECTIVE: To evaluate the value of Chlamydia trachomatis antibody testing in prediction of at least one normal tube in infertile women. MATERIALS AND METHODS: Eighty infertile women without any history of abdominal or pelvic surgery, pelvic inflammatory disease, and endometriosis were recruited in this cross-sectional study from 2009 to 2010. The patients underwent hysterosalpingography, laparoscopy, and anti Chlamydia trachomatis IgG antibody (CAT) testing. We compared laparoscopy findings and CAT regarding sensitivity, specificity, accuracy, and predicting value of tubal conditions. RESULTS: The CAT was positive in 50 patients (62.5%) and laparoscopy was positive in 32 patients (40%). The CAT was significantly higher in women with tubal disease (1.88 +/- 0.34) versus in women with normal tubes (1.21 +/- 0.28) (p = 0.003). Five out of 30 sero-negative women had unilateral tubal abnormality and none of them had bilateral tubal obstruction or severe pelvic adhesion. The sensitivity, specificity, positive and negative predictive value, and accuracy of the CAT in prediction of one normal tube were 100%, 42.25%, 18%, 100%, and 48.75%, respectively. CONCLUSION: The negative predictive value of CAT to predict at least one normal tube in infertile women without history of abdominal or pelvic surgery, pelvic inflammatory disease, and endometriosis was 100%. PMID- 23724518 TI - Evaluation of low-dose letrozole addition to ovulation induction in IVF. AB - PURPOSE: The aim was to investigate the impact of low-dose letrozole usage along with gonadotropin treatment in vitro fertilization (IVF) cycles in comparison to gonadotropin treatment alone. MATERIALS AND METHODS: Fifty patients were prospectively included in this randomized study and were divided into two groups. Age, demographic features, causes, and period of infertility were adjusted and matched for both groups. Group 1 included 25 patients who received gonadotropin treatment and letrozole along with gonadotropin-releasing hormone (GnRH) antagonist protocol; group 2 included 25 patients who received gonadotropin treatment along with GnRH antagonist protocol. RESULTS: Total follicle stimulating hormone (FSH) and daily FSH doses were lower in group 1, although not statistically significant (p > 0.05). The period of ovulation induction was significantly shorter in group 2. While numbers of retrieved oocytes and transferred embryos were lower in group 1, they were not statistically significant (p > 0.05). Number of clinical pregnancies per embryo transfer, number of clinical pregnancies per cycle, and number of ongoing pregnancies (> 16 gestational weeks) were similar in both groups (p > 0.05). CONCLUSIONS: Addition of low-dose letrozole to gonadotropin treatment in GnRH antagonist protocols may result in a lower dose of gonadotropin administration. However, routine clinical practice remains questionable due to no evident positive effect on pregnancy rates. PMID- 23724519 TI - Lentivirus vectors mediated eGFP transfected into rat ovary in vivo. AB - PURPOSE: To evaluate the optimum dosage and time-effect relationship of lentivirus vectors mediated enhanced green fluorescence protein gene (lenti-eGFP) transfection into the rat ovary in vivo. MATERIALS AND METHODS: Lenti-eGFP was microinjected into rats' ovaries with different dosage (2 x 10(6) TU and 10 x 10(6) TU virosome respectively, n = 5 rats). The expression of eGFP was examined by the fluorescence microscope at injection at five days. The fluorescence intensity of different dose groups was calculated and determined the optimum dosage. The authors observed the expression of eGFP in ovaries and others tissues at days 5, 15, 30, 45, 60, and 75 after the rats' ovaries were microinjected with the optimum dosage of lenti-eGFP. Reserve transcription-polymerase chain reaction (RT-PCR) and RT-quantitative (q) PCR (RT-qPCR) were used to qualitative and quantitative analyze the expression of eGFP in different tissues and organs of transfected rats. RESULTS: The expression of eGFP in both ovaries of every rat was seen at five days of transfection. Semi-quantitative assessment of green fluorescence for the two-dosage group was 0.2311 +/- 0.0203 and 0.2307 +/- 0.0199, respectively. There was no significant difference in both groups (p = 0.976). The expression of eGFP enhanced with transfection time prolongation and continued with 75 days of transfection (the fluorescence density in different time was 0.2307 +/- 0.0199, 0.3119 +/- 0.0213, 0.3462 +/- 0.0264, 0.3568 +/- 0.0127, 0.3496 +/- 0.0133, and 0.3513 +/- 0.0172, respectively). Furthermore, there were efficient and durable expressions of eGFP in other tissues and organs of rats. RT-PCR and RT-qPCR proved these results. CONCLUSION: Lenti-eGFP may successfully transfect ovary tissues and other organs in vivo simultaneously, the expression of eGFP is highly efficient and durable. PMID- 23724520 TI - Practical biometric ratios of first-trimester screening. AB - PURPOSE: The authors aimed to determine some practical contributive biometry ratios of the first trimester screening in order to note more accurate measurements and recognize abnormal/mistaken measurements. MATERIALS AND METHODS: All medical records of singleton pregnancies whose first-trimester screening that was performed between the years of 2004-2010, were evaluated retrospectively. Singleton pregnancies with detected/suspicious anatomical or genetic fetal anomalies, any systemic disease, and familial genetic diseases were excluded. The following ratios were calculated and compared: measurements of biparietal diameter [BPD], head circumference [HC], abdominal circumference [AC], femur length [FL], and crown rump length [CRL] of included fetuses, to each other were calculated. Mean and standard deviations of the ratios were determined for each gestational weeks of 11(0-6), 12(0-6), and 13(0-6). RESULTS: A total of 1,615 singleton pregnancies were included in the data analyses according to exclusion and inclusion criteria. Mean maternal age was 29.5 +/- 4.6 years. Mean gestational age of the fetuses was 12.6 +/- 0.6 weeks. Mean and standard deviation of the ratios were as follows; CRL/BPD: 3.0 +/- 0.2; AC/BPD: 3.0 +/- 0.2; CRL/AC: 1.0 +/- 0.1; CRL/HC: 0.8 +/- 0.1; CRL/FL: 8.8 +/- 1.6; BPD/FL: 2.9 +/- 0.6; AC/FL: 8.9 +/- 1.6; HC/FL: 11.1 +/- 2.2, and HC/AC: 1.3 +/- 0.1. Among these ratios the standard deviation was small in the ratios of CRL/BPD, AC/BPD, CRL/AC, CRL/HC, and HC/AC. The equations of these ratios were derived from linear regression analyses. The AC/BPD, and CRL/AC ratios had lower R2 values than others, indicating a rather constant ratio. CONCLUSIONS: The ratios of CRL/BPD, AC/BPD, and CRL/AC seem more practical to be used in the first-trimester fetal ultrasonography practice. PMID- 23724521 TI - Immunohistochemical study of inhibin A and B expression in placentas from normal and pathological gestations. AB - OBJECTIVE: The aim of the study was to examine, by an immunohistochemical method, the distribution of Inhibin-A and -B, in placentas from normal and pathological gestations. MATERIALS AND METHODS: Sixty-two specimens of placental tissue were examined: i) ten cases from early gestations, ii) 28 cases from mature placentas, iii) six cases associated with intrauterine growth restriction, iv) four cases associated with diabetes mellitus and v) 14 placentas from gestations with fetal chromosome abnormalities. The expression of Inhibin A and B was studied by automatic Ventana method. RESULTS: i) Early gestation specimens: Inhibin A (+) immunoreaction was observed in the syncytiotrophoblast (8/10 cases) and in the intermediate trophoblast (6/10 cases). Inhibin B (+) immunoreaction was observed in the syncytiotrophoblast (10/10 cases) and in the intermediate trophoblast (4/10 cases), ii) Normal mature placentas: Inhibin A (+) immunostain was observed in 2/28 cases in the syncytiotrophoblast and in 7/28 cases in the intermediate trophoblast. Inhibin B (+) immunostain was observed in 28/28 cases in the syncytiotrophoblast and in 18/28 cases in the intermediate trophoblast. iii) Placentas associated with intrauterine growth restriction: Inhibin A (+) immunostain was observed in the intermediate trophoblast in 2/6 cases. Inhibin B (+) immunostain was observed in 5/6 cases in the syncytiotrophoblast and in 4/6 cases in the intermediate trophoblast. iv) Placentas associated with gestational diabetes mellitus: Inhibin A (+) immunostain was observed in 2/4 cases in the intermediate trophoblast. Inhibin B (+) immunostain was observed in 2/4 cases in the syncytiotrophoblast. v) Placentas from gestations with fetal chromosome abnormalities: no Inhibin A immunoreaction was observed. Inhibin B (+) immunostain was observed in 13/14 cases in the syncytiotrophoblast and in 9/14 cases in the intermediate trophoblast. The cytotrophoblast, the umbilical cord, and the membranes do not participate in the production of Inhibins. DISCUSSION: Inhibin A and B are located in the syncytiotrophoblast and the intermediate trophoblast of the placenta, during early pregnancy (Inhibin A) and present throughout pregnancy (Inhibin B). No remarkable findings in placentas of pathological gestations support the evidence that Inhibins do not participate in processes that affect the development of the placenta or the fetus, but may participate in,the mechanism of labor. PMID- 23724522 TI - Ultrasound parameters and L/S ratio in prediction of perinatal outcome in term growth restricted newborns. AB - AIM: The relation between biophysical profile (BPP), cerebroplacental (C/P) ratio, and lecithin/sphingomyelin (L/S) ratio as a predictor perinatal outcome in term intrauterine growth restricted (IUGR) neonates was evaluated. MATERIALS AND METHODS: A retrospective study of the perinatal outcome of 77 term monofetal pregnancies complicated with IUGR fetuses (< 10 percentile) who were terminated by cesarean section in 2010 was performed at the Institute of Gynecology and Obstetrics, Belgrade. RESULTS: The most frequent early neonatal complication was asphyxia. The authors found a strong correlation between the L/S ratio and birth weight (BW) r = 0.609, as well as between BPP and Apgar score 5 r = 0.583. Significant negative correlation was found between asphyxia and BPP r = -0.398, as well as between asphyxia and C/P ratio r = -0.379. CONCLUSION: In serous IUGR neonates, low values of BPP and L/S ratios predicted asphyxia. PMID- 23724523 TI - Symptomatic Shigella sonnei urinary tract infection in pregnancy. AB - PURPOSE OF INVESTIGATION: This report describes a case of urinary tract infection (UTI) due to Shigella sonnei during pregnancy. METHODS: A 31-year-old pregnant woman was admitted complaining of left-flank tenderness, dysuria, and fever. RESULTS: Following examination, significant laboratory data were collected including increased leukocyte count (10,800/ul with 86% neutrophils) and C reactive protein (9.6 mg/dl). Urinalysis revealed 30 to 50 leukocytes per high power field while from the quantitative urine culture Shigella sonnei was recovered after 24 h incubation at 37 degrees C. After a two-week course with 750 mg cefuroxime every 8 h, the patient experienced gradual resolution of all symptoms and urinary cultures were negative two weeks and one month, respectively, after completing the therapy. The gestational course was uneventful and the patient delivered a healthy baby girl at term. CONCLUSION: Shigella sonnei can be responsible for UTI during pregnancy even when no predisposing factors or an apparent source of infection can be identified. PMID- 23724524 TI - Single dose epidural morphine instead of patient-controlled epidural analgesia in the second day of cesarean section; an easy method for the pain relief of a new mother. AB - PURPOSE: Pain management has a particular importance after Cesarean section. This study was undertaken in order to document the efficacy and side-effects of epidural morphine instead of patient-controlled analgesia technique used for the control of post-cesarean pain during postoperative 24-48 hours. MATERIALS AND METHODS: This study was performed as a retrospective review of patient charts who had received combined spinal-epidural anaesthesia. Post-cesarean analgesia was performed with epidural technique either by using (Group 1) patient-controlled epidural analgesia for 48 hours, or (Group 2) patient-controlled epidural analgesia for the first 24 hours and then single dose of 3 mg epidural morphine for the second 24 hours. RESULTS: Incidences of side-effects were similar in both groups. None of the patients experienced respiratory depression. Additional analgesia was used on an as-required basis in nine of 39 (23%) patients in Group 1 and six of 39 (13%) in Group 2. CONCLUSION: Small doses of epidural morphine provides up to 24 hours of pain relief from a single injection and could obviate the need for an indwelling epidural catheter on the second day of postcesarean section, thus reducing the potential for catheter-related complications. PMID- 23724525 TI - The efficacy of intrauterine versus oral progestin for the treatment of endometrial hyperplasia. A prospective randomized comparative study. AB - OBJECTIVES: This study compared the efficacy of the levonorgestrel-releasing intrauterine device (LNG-IUD) to oral medroxyprogesterone acetate (MPA) applied for the same length of time for the management of endometrial hyperplasia without atypia. STUDY DESIGN: This was single-center, open, randomized, and clinical trial. One hundred four patients aged between 30-50 years and diagnosed with endometrial hyperplasia without atypia by endometrial biopsy, were randomized to receive LNG-IUD or MPA. Both groups were further divided into two groups as three month and six-month treatment subgroups. The primary objective was to compare the complete regression rates of hyperplasia, and the secondary objective was to determine the minimum duration of time required for the achievement of regression. RESULTS: At two-year follow-up, the success rates of LNG-IUD treatment and oral MPA for three months therapy were 84% and 50%, respectively. While the regression rate was 100% in the six-month LNG-IUD group, it was 64% in the oral MPA group. LNG-IUD appeared to have a significantly higher success rate (p = 0.0001). CONCLUSION: It is believed that by this study LNG-IUD applications may be a reliable preference for younger patients who wish to preserve their uterus and especially for non-atypical cases, and if the patient demands fertility, even a six-month application will provide effective treatment. PMID- 23724526 TI - Ondansetrone or metoclopromide? Which is more effective in severe nausea and vomiting of pregnancy? A randomized trial double-blind study. AB - BACKGROUND: Nausea and vomiting of pregnancy (NVP) are seen in 50-80% of pregnancies. However, in severe NVP, called hypermesis gravidarum (HG), medical therapy to reduce nausea and vomiting is inevitable and ondansetron (OND) as an effective drug has recently been proposed. This study evaluated the effectiveness of OND versus metoclopramide (MET) in the treatment of HG. METHODS: In this clinical trial study, 83 pregnant women with HG were enrolled in 2011-2012 and randomly divided in two groups. The first group received oral administration of MET and the second group was treated with OND for two weeks. Severity of nausea and vomiting were evaluated according to visual analogue scale (VAS) criteria. Data analysis was done by chi2, Fisher exact test and Student's t-test. RESULTS: Comparison of the trend of change of vomiting in the two groups during the 14-day treatment showed the OND group had significantly lower vomiting scores versus the MET group (p = 0.042), while there was no significant difference in the trend of nausea. CONCLUSION: OND has a more favorable effect in controlling severe vomiting. PMID- 23724527 TI - Liquid based cytology and HPV DNA testing in a Greek population compared to colposcopy and histology. AB - Screening for cervical cancer in Greece is still unorganised and based on self- motivation. The purpose of this study was to evaluate the accuracy of cytological findings from a large observational population sample, originating from Western Athens, in association with reflex DNA test, colposcopic estimation, and final histologic diagnosis. The rate of invasive carcinoma, both squamous cell and adenocarcinoma, is indicative of a largely unscreened population. In this study, the estimated overall prevalence of human papilloma virus (HPV) was 41.1%, with HPV positivity at 37.4% of cytologically normal women. HPV testing did not seem to improve sensitivity of cytology for atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LGSIL) cases in identifying CIN 2+ lesions, but outperformed cytology in detecting CIN3+ for cytological high-grade squamous intraepithelial lesion (HGSIL) cases. For HGSIL cases sensitivity of colposcopy for detecting CIN3+ was comparable to cytology. PMID- 23724528 TI - The role of mini laparotomy in patients with uterine myomas. AB - AIM: The aim of this study was to evaluate the therapeutic effectiveness of myomectomy by mini laparotomy in patients with subserosal and/or intramural uterine myomas. MATERIALS AND METHODS: Between January 2002 and December 2008, 83 women with symptomatic uterine myomas were referred to the Second Department of Gynecology of St. Savvas Anticancer--Oncologic Hospital of Athens. The study included women with subserosal and/or intramural uterine myomas with a maximum diameter of ten cm. All patients underwent myomectomy by mini laparotomy. RESULTS: The median age of the patients was 36.8 years (range 19-43). The median number of the removed uterine myomas was 3.1 (range 1-12) and the median operative time was 98 minutes (range 47-170). All patients were mobilized within the first 24 hours and the median time of postoperative ileus was 1.6 days (range 1-3). The median hospital stay was 44 hours (range 30-120). There were no serious intraoperative or early postoperative complications. Conversion to laparotomy was performed only in four cases (4.82%), but none of the patients underwent emergency hysterectomy. During a mean follow up of 38 months, no recurrences of uterine myomas in the study population were observed. CONCLUSION: Mini laparotomic myomectomy is a safe and effective minimally invasive method alternative to laparoscopic myomectomy for patients with subserosal and/or intramural uterine myomas. PMID- 23724529 TI - Ankaferd blood stopper in episiotomy repair. AB - BACKGROUND AND OBJECTIVE: Ankaferd blood stopper (ABS) is a new hemostatic agent that is licensed for external hemorrhages. ABS comprises of a standard mixture of Thymus vulgaris, Glycyrrhiza glabra, Vitis vinifera, Alpinia officinarum, and Urtica dioica which has also been approved in Turkey for the management of bleeding. The authors, aim was to evaluate the efficacy of ABS spray in terms of blood loss during episiotomy repair. MATERIALS AND METHODS: The authors included pregnant women with a term singleton fetus (37-40 wks) in a vertex position, who were at least 18-years-old, had delivered vaginally, and required a mediolateral episiotomy. The patients were randomly assigned to one of the two approaches: 20 (Group 1) to ABS and 20 (Group 2) to isotonic saline solution (0.9% NaCl). The authors applied 4 ml ABS spray solution (1 ml/puff X 4) or isotonic saline solution (0.9% NaCl) (4 ml) topically on a sponge applied on the episiotomy. The sponge was weighed before and after the episiotomy repair to determine the amount of bleeding. Hemoglobin values were also recorded on admission and 12 hours after delivery. RESULTS: Both groups were similar in terms of maternal age, parity, body mass index and gestational age. The sponges weighed heavier in Group 2. Baseline hemoglobin values measured on admission showed no significant differences between the groups. Hemoglobin on the first postpartum day was significantly higher in the ABS group (p < 0.05). The operative time for episiotomy repair for the two groups was also statistically insignificant. No major immediate or delayed complications were observed in either group. CONCLUSION: In this study group, the application of 4 ml of ABS instead of isotonic saline solution lessened bleeding. PMID- 23724530 TI - Type of delivery and self-reported postpartum symptoms among Iranian women. AB - The aim of the present study was to examine the association between mode of delivery and self-reported postpartum among women eight weeks postpartum. A cross sectional study was conducted on postpartum women with symptoms. A total of 300 individuals over 16 years (155 with normal vaginal delivery and 145 with elective cesarean section) from ten primary healthcare centers in an urban area of Amol, Mazandaran, Iran were selected using a clustering random sampling technique. A standard questionnaire named Edinburgh postnatal depression scale (EPDS) was used to assess depressive symptom. Most women (98.3%) reported at least one postpartum symptom at eight weeks postpartum. The most prevalent postpartum symptoms were excessive tiredness or fatigue (72.2%), pain (65.7%) and backache (61.3%). There was a decrease in percentage of occurrence of sexual problems (p = 0.009) with elective cesarean section at postpartum was founded. Compared with women having vaginal delivery, cesarean delivery women were more likely to report headaches (OR = 2.5; CI = 1.493, 4.289) and less to report sexual problems (OR = 0.594; CI = 0.362, 0.975) during postpartum. It would be useful to provide a defined standard for postpartum care and apply regular postpartum visits in primary health care centers, hospital, and home visits and restricting mediolateral episiotomy. PMID- 23724531 TI - Comparison of HbA1c levels in obese and non-obese polycystic ovarian patients. AB - AIM: To compare obese and non-obese polycystic ovary syndrome (PCOS) patients with respect to lipid profile, hormone profiles, and hemoglobin A1c (HbA1c) values indicating chronic hyperglicemia. MATERIALS AND METHODS: Thirty PCOS patients with a body mass index (BMI) > 25 and 35 non-obese PCOS patients with BMI < 25 were compared with regard to basal luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), estradiol (E2), fasting blood sugar (FBS), low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol (TCOL), triglyceride (TG), and HbA1c values. RESULTS: HDL value (p = 0.005) was significantly higher in non-obese group while TG (p = 0.001) was higher in the obese group. No significant difference was found between other values. CONCLUSION: Lipid metabolism impairment seems to be more marked in obese PCOS patients. Moreover, it is obvious that insulin resistance is higher in obese group. The absent difference between obese and non-obese groups in terms of HbA1c values suggests that insulin resistance occurring in the obese group may also be important in the non-obese group. In this context, cardiovascular risks may increase in non-obese PCOS patients. PMID- 23724532 TI - Administration of lopinavir/ritonavir association during rat pregnancy: maternal and fetal effects. AB - PURPOSE: To evaluate the effects of the association of lopinavir and ritonavir administered during the whole period of rat pregnancy. METHODS: 62 Wistar rats of the EPM-1 variant weighing about 200 g were randomly divided into five groups: two controls (Ctrl = stress control, n = 10; and Ctr2 = drug vehicle control, n = 10) and three experimental ones which were treated with an oral solution of lopinavir/ritonavir (Exp1 = 12.8/3.2 mg/kg b.w., n = 14; Exp2 = 38.4/9.6 mg/kg b.w., n = 14; Exp3 = 115.2/28.8 mg/kg b.w., n = 14) from 'day 0' up to the 20th day of pregnancy. Maternal body weight was recorded at the start of the experiment and on the 7th, 14th and 20th day thereafter. At term (20th day), upon laparotomy and hysterotomy, the rats were anesthetized and the amount of implantations, reabsorptions, living fetuses, placentae and intrauterine deaths were recorded. The collected fetuses and placentae were weighed and the concepts were examined under a stereoscope microscope for external malformations. RESULTS: An apparent dose-unrelated lethal effect of the antiviral association on the pregnant rats was observed; notwithstanding, the body weight gain of the surviving rats had no changes, independent of the considered group. It was noted that the quantitative and qualitative intrauterine content of living term rats was indistinguishable from that of the controls. CONCLUSION: There was some degree of deleterious effects of the administration of the lopinavir/ritonavir association on pregnant rats; such effects eventually led to maternal death. However, neither the surviving rats showed toxicity nor did their concepts present any detectable change which could be related to the drug association. PMID- 23724533 TI - Surgical repair of a complicated urethro-vaginal fistula: case report and review of the literature. AB - BACKGROUND: Urethro-vaginal fistulae (UVF) occur usually as infrequent complications of a variety of gynecological surgical procedures. The aim of this study was to present an interesting case of a complicated UVF diagnosed after gynaecological surgery. CASE: A 61-year-old gravida-2, para-2, post-menopausal woman was referred with a complaint of urine loss through the vagina. She had undergone anterior and posterior vaginal wall repair due to cystocele and stress urinary incontinence (SUI). Transvaginal repair was performed 20 weeks after primary surgery. However, a second transvaginal reconstructive surgery using Martius-flap originating from the bulbocavernosus muscle was necessary due to persistent urine leakage in the vagina. Thirty-two months after successful urethro-vaginal treatment, the patient self-referred for persistent SUI. Burch colposuspension was performed and at 16 months follow-up the patient remains continent. DISCUSSION: Surgical repair of complicated UVF seems to be more successful with Martius flap interposition than with no interposition. PMID- 23724534 TI - Misoprostol for labor induction in the second trimester in a woman with previous three cesarean deliveries and an intrauterine death of an anencephaly. AB - Termination of pregnancy in the second trimester for an intrauterine death of a fetus with anencephaly in a woman with previous three cesarean sections is a difficult clinical dilemma. A 34-year-old, gravida 4, para 3 woman was admitted at 20 weeks gestation for termination of pregnancy due to intrauterine death of a fetus with anencephaly. She had had three previous cesarean sections. She received two doses of 200 mcg misoprostol tablets vaginally 12 hours apart. Then two doses of 400 mcg misoprostol tablets were given vaginally 12 hours apart. There were no uterine contractions or cervical changes. Finally, she received five doses of 400 mcg misoprostol tablets vaginally every eight hours. The patient responded after the last dose and the fetus with the placenta aborted completely without complications. The estimated blood loss was 200 ml. CONCLUSION: Misoprostol can avoid hysterotomy for termination of pregnancy in the second trimester with history of previous three cesarean sections and an intrauterine death of a fetus with anencephaly. PMID- 23724535 TI - Repeated term pregnancies in a young patient with pelvic organ prolapse. AB - Pregnancy complicated with pelvic organ prolapse is a rare event; pregnancy in a patient with prolapse existing before the pregnancy is even less common. The authors report two consecutive term pregnancies in a young woman with pelvic organ prolapse. A 24-year-old pregnant woman, gravida 4, para 3, was admitted to the hospital at 38 2/7 weeks gestation with uterine contractions and severe cervical prolapse. She was conservatively treated during the antenatal period. On admission, an edematous and gangrenous totally prolapsed cervix was seen protruding outside the introitus and cesarean section was then performed. A healthy female infant with a birth weight of 2,920 g was delivered. On postpartum second day examination, uterine cervix was reduced. Stage 2 pelvic organ prolapse quantification system (POPQ) was observed during the follow-up examination at sixth weeks postpartum. Conservative approach during pregnancy followed by cesarean section may be the appropriate management in these cases. PMID- 23724536 TI - Ultrasound diagnosis of recurring Jeune's syndrome: a case report. AB - Jeune's Syndrome or asphyxiating thoracic dystrophy (ATD) is a rare autosomal recessive skeletal dysplasia syndrome characterized by a small and narrow chest, short extremities, and often polydactyly associated with multiple organ manifestations. The severity of complications ranges from mild to lethal. This is a report of two cases of ATD diagnosed in successive pregnancies of a nonconsanguineous couple. The contribution of sonography in prenatal diagnosis of the syndrome is highlighted. PMID- 23724537 TI - Benign pelvic metastatic leiomyoma: case report. AB - Benign metastasizing leiomyoma is a rare condition characterized by benign soft tissue tumors most frequently involving the lung, and is usually associated with a benign leiomyoma or intravenous leiomyomatosis of the uterus. We present a case of a 58-year-old female patient with abdominal pain and symptoms of urinary tract infection four years after hysterectomy due to uterine fibroid. The results of CT revealed a pelvic mass. Pathological examination confirmed that it was a metastatic pelvic benign metastasizing leiomyoma (BML). BML only involving the pelvis is extremely rare. The patient underwent surgical resection and recovered well. PMID- 23724538 TI - Pyomyoma after dilatation and curettage for missed abortion. AB - Infection of a leiomyoma is a very rare clinical entity called pyomyoma. Pathology may be encountered during the reproductive period, pregnancy, and even postmenopausal period. In this report, we present a case of pyomyoma which developed after dilatation and curettage managed by broad spectrum antibiotics and myomectomy to preserve the fertility in a 31-year-old patient. PMID- 23724539 TI - The management of fusion of the labia minora pudendi in adult women using a radiosurgical knife. AB - Fusion of the labia minora is a rare event in adult women and rarely seen as a clinical entity. We present a case of a 30-year-old woman with labial fusion, unmarried, a virgin, and sexually inactive with the complaint of discomfort during menstruation and difficulty in micturition since her puberty. The labia minora were fused in the midline with a pinpoint aperture for draining urine, while the clitoris could not be visualized. Previous history regarding a causal factor was perineal trauma in childhood. Effective surgical resection to separate the fusion was done by a radio frequency surgical knife. After the surgical separation, it was possible to expose the normal hymen behind the previously fused labia. We have shown that the separation of labial fusion in adult women with a radio frequency surgical knife, associated with topical application of estrogen cream, prevents re-fusion of the labia and leads to healing without scarring of the vulva. PMID- 23724540 TI - Spontaneous rupture of uterine varices in third trimester pregnancy: an unexpected cause of hemoperitoneum. A case report and literature review. AB - The authors report a case of spontaneous rupture of uterine varices occurring in the third trimester of pregnancy. It was responsible for a collapse in breast hemoperitoneum. The patient, whose pregnancy was a simple, suddenly felt symptoms of preterm labor. There was a rapid onset of maternal collapse with acute fetal distress. Only emergency exploratory laparotomy allowed for etiological diagnosis and treatment. PMID- 23724541 TI - Laparoscopic myomectomy of a giant myoma. AB - We present the case of an infertile woman with a giant myoma which was laparoscopically removed. A 34-year-old patient was referred to our department with a large abdominal mass. Ultrasound revealed an 18 cm uterine myoma. Diagnostic laparoscopy showed a giant uterine myoma and with the help of a bent angle camera we started myoma enucleation. The myoma was totally enucleated and removed without disturbing the endometrial cavity. The uterine defect was closed with an absorbable suture in two layers. The myoma was removed using a PK (Gyrus) morcelator, without tissue or blood spillage in the abdomen. The operation time was 165 minutes and the myoma's weight was 1,200 g. The patient recovered uneventfully. Laparoscopic myomectomy can be an option even for giant myomas, with the condition of an expert surgeon and appropriate surgical instruments. PMID- 23724542 TI - Depth profile analysis of non-specific fluorescence and color of tooth tissues after peroxide bleaching. AB - PURPOSE: To examine laboratory changes of endogenous non-specific fluorescence and color throughout subsurface of tooth structures prior to and following peroxide bleaching. METHODS: Extracted human teeth were cross sectioned and mounted on glass slides. Cross sections were examined for internal color (digital camera) and nonspecific fluorescence (microRaman spectroscopy) throughout the tooth structure at specified locations. Surfaces of sections were then saturation bleached for 70 hours with a gel containing 6% hydrogen peroxide. Cross sections were reexamined for color and non-specific fluorescence changes. RESULTS: Unbleached enamel, dentin-enamel junction and dentin exhibit different CIELab color and non-specific fluorescence properties. Bleaching of teeth produced significant changes in color of internal cross sections and substantial reductions of non-specific fluorescence levels within enamel dentin and DEJ. Enamel and dentin non-specific fluorescence were reduced to common values with bleaching with enamel and the DEJ showing larger reductions than dentin. PMID- 23724543 TI - Dentin hypersensitivity after teeth bleaching with in-office systems. Randomized clinical trial. AB - PURPOSE: To comparatively and prospectively compare in a randomized clinical trial, dentin hypersensitivity after treatment with three in-office bleaching systems, based on hydrogen peroxide at different concentrations, with and without light source activation. METHODS: 88 individuals were included according to inclusion and exclusion criteria. Subjects were randomly divided into the following three treatment groups: Group 1 was treated with three 15-minute applications of hydrogen peroxide at 15% with titanium dioxide (Lase Peroxide Lite) that was light-activated (Light Plus Whitening Lase) with five cycles of 1 minute and 30 seconds each cycle, giving a total treatment time of 45 minutes; Group 2 was treated with three 10-minute applications of hydrogen peroxide at 35% (Lase Peroxide Sensy), activated by light (LPWL) same activation cycles than Group 1, with a total treatment time of 30 minutes; Group 3 was treated with only one application for 45 minutes of hydrogen peroxide at 35% (Whitegold Office) without light activation. Each subject underwent one session of bleaching on the anterior teeth according to the manufacturers' instructions. Dentin sensitivity was recorded with a visual analogue scale (VAS) at baseline, immediately after, and at 7 and 30 days after treatment using a stimulus of an evaporative blowing triple syringe for 3 seconds on the upper central incisors from a distance of 1 cm. A Kruskal-Wallis test followed by Mann-Whitney test was performed for statistical analysis. RESULTS: All groups showed increased sensitivity immediately after treatment. Group 1 displayed less changes relative to baseline with no significant differences (P = 0.104). At 7 and 30 days after treatment, a comparison of VAS values indicated no significant differences between all groups (P = 0.598 and 0.489, respectively). PMID- 23724544 TI - In situ evaluation of a low fluoride concentration gel with sodium trimetaphosphate in enamel remineralization. AB - PURPOSE: To evaluate the capability of gels with low fluoride (F) concentration and supplemented with sodium trimetaphosphate (TMP) to promote in situ enamel remineralization. METHODS: Bovine enamel blocks were selected on the basis of their surface hardness after demineralization, and divided into five groups: gel without F or TMP (placebo); gel with 4,500 ppm F (4,500); gel with 4,500 ppm F + 5% TMP (4,500 5% TMP); gel with 9,000 ppm F (9,000) and gel with 12,300 ppm F (12,300). The study design was blind and cross-over: 12 subjects used palatal devices with four demineralized enamel blocks for 3 days, after topical fluoride application (TFA). Two blocks were removed immediately for analysis of the loosely bound fluoride (CaF2) and firmly bound fluoride (F) after TFA in enamel. In the remaining blocks, the percentage of surface hardness recovery (% SH), cross-sectional hardness (deltaKHN) and CaF2 and F were determined after remineralization. The results were subjected to ANOVA and Bonferroni tests (P < 0.05). RESULTS: The groups 4,500 5% TMP, 9,000, and 12,300 showed the best results with regard to % SH (P < 0.05). Lower deltaKHN values were observed in the 4,500 5% TMP and 12,300 gel groups (P < 0.05). Higher concentrations of CaF2 and F were observed in the 12,300 group, followed by the 4,500 5% TMP and 9,000 groups (P > 0.05). It was concluded that it is possible to promote enamel remineralization using gels with low fluoride concentration supplemented with TMP. PMID- 23724545 TI - The prevalence of tooth hypersensitivity following periodontal therapy with special reference to root scaling. A systematic review of the literature. AB - PURPOSE: To provide a current status of the art, answering the question whether a certain procedure of periodontal treatment is more reliable than another and where innovative developments could improve on the incidence of hypersensitivity by a systematic literature review. METHODS: Pubmed, Embase and Cochrane library were considered for the study. 2,656 articles of the PubMed search were found, from the beginning of 1945 until April 2011. 99 articles from PubMed were evaluated for this review. From Embase, 60 articles were selected and one was included in this review. From the Cochrane library, 182 were found, of which two contributed to the review. Included were all studies dealing with periodontal treatment followed by hypersensitivity and all studies dealing with the loss of attachment, followed by hypersensitivity. Excluded were any treatments of tooth hypersensitivity with pathogenesis not related to dentin exposure, genetically caused disorders, and fractures. Ultimately, 102 papers were evaluated, included and referred to in the review. RESULTS: The term "tooth hypersensitivity" is most often used. Common causes of loss of hard substance are listed and updated. Mechanical loss of hard tissue formed one group of etiological factors; gingival recession and loss of attachment another. Surgical interventions, scaling and root planing were considered and in most cases performed as combined procedures. The different methods were evaluated and critically discussed. There were no properly randomized studies in the literature. The weak point of all epidemiological studies is the lack of any objective measurement. With respect to periodontal therapy, further research and developmental work on medical devices is needed, as well as ongoing applied research with laser technologies, continuing education and training programs for professionals. PMID- 23724546 TI - Four-year clinical evaluation of two self-etching dentin adhesives of different pH values used to restore non-retentive cervical lesions. AB - PURPOSE: To evaluate the clinical performance of two self-etching adhesives of different pH values when used to restore non-retentive cervical lesions. METHODS: 84 paired non-retentive class 5 restorations were originally placed in 21 subjects in need of 2, 4 or 6 restorations in incisors, canines and premolars. The retention of the placed restorations relied on the two adhesives only, which were iBOND NG plus B (iB), now marketed as iBOND Self Etch, and Clearfil SE (CB). Lesions were restored with a micro-hybrid composite (Venus). Following a baseline evaluation, the subjects were recalled and evaluated after 3 months, 1 year, 2 years and 4 years. RESULTS: At the 4-year evaluation, 17 subjects remained who had originally received 66 restorations (33 of each adhesive). Eight of these 66 restorations had dropped out during the 4 years (4 iB and 4 CB) for different reasons. Two of the drop-outs (one iB and one CB) had fractured in the same patient, leaving a large piece of the composite still bonded to the dentin. Two other drop outs (both material iB) were not available for evaluation because they had been crowned (one after endodontic treatment and one after cusp fracture), while the remaining drop-out iB restoration had debonded. Regarding material CB, except for the fractured and partly retained drop-out restoration, the remaining three drop-outs had debonded. Pair-wise comparison of the evaluated parameters using Fishers Exact Test revealed no statistically significant (P < 0.05) differences between the two materials. PMID- 23724547 TI - Randomized controlled trial of the 2-year clinical performance of a silorane based resin composite in class 1 posterior restorations. AB - PURPOSE: To compare the 2-year clinical performance of a silorane-based resin composite with that of an established nanoceramic resin composite for class 1 posterior restorations. METHODS: In this randomized controlled study, 100 class 1 molar cavities were prepared in 50 subjects. Each subject received a restoration with Filtek Silorane and Ceram.X Duo in different quadrants. The restorations were evaluated using the modified USPHS criteria at baseline and 6, 12, and 24 months. Parametric changes over the 2-year period were assessed with the Friedman test. The baseline and recall scores were compared by using the Wilcoxon signed rank test (P < 0.05). RESULTS: No subject developed secondary caries or postoperative sensitivity. Further, the resin composites showed no significant differences in all the evaluated parameters over 2 years (P > 0.05). At 2 years, four Filtek Silorane and seven Ceram.X Duo restorations had Bravo scores for anatomic form, marginal adaptation, and surface texture (P < 0.05); however, these changes were mainly the effect of scoring shifts from Alfa to Bravo. Overall, both materials showed good clinical results with predominantly Alfa scores. PMID- 23724548 TI - Shear resistance of fiber-reinforced composite and metal dentin pins. AB - PURPOSE: To assess whether dentin pins increase shear resistance of extensive composite restorations and to compare performance of mini fiber-reinforced composite (FRC) anchors with metal dentin pins in the laboratory. METHODS: 30 extracted sound molars were randomly divided into three groups. Occlusal surfaces were ground flat with a standard surface area and resin composite restorations were made in Group A. In Groups B and C similar restorations were made, with additionally four metal pins placed in Group B and four FRC pins in Group C. Specimens were statically loaded until failure occurred. Failure modes were characterized as intact remaining tooth substrate (adhesive or cohesive failure of restoration) or fractured remaining tooth substrate. RESULTS: Mean failure stresses were 6.5 MPa (SD 3.2 MPa) for Group A, 9.7 MPa (SD 2.6 MPa) for Group B and 9.2 MPa (SD 2.6 MPa) for Group C. Difference in mean failure stresses between Group A and Groups B and C was statistically significant (P = 0.01), while the difference between Groups B and C was not (P = 0.63). Failures of the restoration without fracture of tooth substrate were seen for 80% of specimens in Group A and 20% in Groups B and C (P = 0.04). PMID- 23724549 TI - Microtensile bond strengths for six 2-step and two 1-step self-etch adhesive systems to enamel and dentin. AB - PURPOSE: To examine the microtensile bond strengths (microTBS) of six 1-step and one 2-step self-etch systems to dentin and ground enamel. METHODS: Resin composite buildups were bonded to buccal and lingual ground enamel surfaces, and to occlusal dentin of third molars using the following 1-step adhesives: Xeno IV (XE), GBond (GB), Clearfil S3 Bond (CS3); Adper Prompt L-Pop (AD); Go (GO) and All Bond SE (1-step; ABSE), in comparison to the 2-steps (All Bond SE; (2-step ABSE) and Clearfil SE Bond (CSE). After storage in water (24 hour/37 degrees C), the bonded specimens were sectioned into beams approximately 0.9 mm2. These beams were tested until failure at a crosshead speed of 0.5 mm/minute. Data were subjected to appropriate statistical analysis (alpha = 0.05). RESULTS: The total number of specimens/premature debonding specimens (PDS) for each adhesive were, respectively, in enamel: XE (59/36), GB (63/33), CS3 (62/29), AD (47/19), GO (53/14), 1-step ABSE (61/29), 2-step ABSE (57/14) and CSE (58/13); and in dentin: XE (51/24), GB (50/7), CS3 (53/13), ADP (51/1), GO (43/8), 1-step ABSE (59/2), 1 step ABSE (56/0) and CSE (47/0). The fracture pattern was predominantly adhesive/mixture for all adhesives in dentin (51.5 to 99%) and in enamel (34.8 to 75.4%), however XE (61.2) and GB (52.5) had more than 50% PDS. For ground enamel, no significant difference was detected among materials in the same subgroup (with or without PDS). However, there was a significant difference for all adhesives when subgroups (with and without PDS, respectively) were tested against each other: XE (7.9/10.5 double dagger 19.7/5.5), GB (8.6/10.5 double dagger 17.2/7.4), CS3 (8.8/10.3 double dagger 15.7/5.6), AD (13.0/12.0 = 20.3/8.9), Go (18.2/13.8 = 25.1/10.0), 1-step ABSE (15.9/11.4 = 16.2/5.4), 2-step ABSE (8.4/9.1 double dagger 25.3/7.9) and CSE (17.6/16.3 = 19.9/7.8). For dentin, no difference was found when subgroups for the same adhesive were tested against each other (with or without PDS). However, significantly higher resin-dentin bond strength was observed for adhesives in the following order: CSE (38.5/6.5 = 38.5/6.5) > or = 2-step ABSE (41.4/16.3 double dagger 42.4/19.3) = 1-step ABSE (43.9/17.7 = 44.2/17.1) = AD (34.4/14.2 = 35.2/13.3) < or = CS3 (31.9/19.4 = 40.1/13.4) double dagger GB (14.3/6.3 = 16.3/5.9) = Go (14.2/13.9 = 22.4/12.6) double dagger XE (7.1/5.4 = 9.5/5.1), respectively for with PDS and without PDS. All materials showed similar performance on ground enamel. The performance of one-step self etch systems to dentin appears to be material-dependent. Adper Prompt L-Pop, Clearfil S3 Bond and the 1-step All Bond SE had microTBS similar to Clearfil SE Bond and the 2-step All Bond SE, while Xeno IV and GBond had significantly lower microTBS values. Go had an intermediate performance. PMID- 23724550 TI - Effect of polishing and finishing procedures on the surface integrity of restorative ceramics. AB - PURPOSE: To investigate the effect of surface polishing and finishing methods on the surface roughness of restorative ceramics. METHODS: Disk specimens were prepared from feldspar-based, lithium disilicate-based, fluorapatite leucite based and zirconia ceramics. Four kinds of surface polishing/finishing methods evaluated were: Group 1: CONTROL: carborundum points (CP); Group 2: silicon points (SP); Group 3: diamond paste (DP); Group 4: glazing (GZ). Surface roughness was measured using an interferometer and the parameters of Sa (average height deviation of the surface) and St (maximum peak-to-valley height of the surface) were evaluated. Data were statistically analyzed using two-way ANOVA (P < 0.05) followed by post-hoc test. The mean values were also compared by Student's t-test. Specimen surfaces were evaluated by 3-D images using an interferometer. RESULTS: The zirconia showed the least surface roughness (Sa and St) values after grinding with carborundum points. The significantly lowest Sa values and St values were obtained for lithium disilicate and zirconia ceramics surfaces finished with DP and GZ. The fluorapatite leucite ceramic showed significantly reduced Sa and St values from DP to GZ. The feldspathic porcelain showed the highest surface roughness values among all types of ceramics after all of the polishing/finishing procedures. PMID- 23724551 TI - Fluoride dentifrice containing xylitol: in vitro root caries formation. AB - PURPOSE: To evaluate the effects of experimental xylitol dentifrices with and without fluoride on in vitro root caries formation. METHODS: Root surfaces from caries-free human permanent teeth (n = 10) underwent debridement and a fluoride free prophylaxis. The tooth roots were sectioned into quarters, and acid resistant varnish was placed with two sound root surface windows exposed on each tooth quarter. Each quarter from a single tooth was assigned to a treatment group: (1) No treatment control; (2) Aquafresh Advanced (0.15% F = 1,150 ppm F); (3) Experimental xylitol dentifrice without fluoride (0.45% xylitol); and (4) Diamynt fluoride dentifrice with xylitol (0.83% sodium monofluorophosphate = 1,100 ppm F and 0.20% xylitol). Tooth root quarters were treated with fresh dentifrice twice daily (3 minutes) followed by fresh synthetic saliva rinsing over a 7-day period. Controls were exposed twice daily to fresh synthetic saliva rinsing daily over a 7-day period. In vitro root caries were created using an acidified gel (pH 4.25, 21 days). Longitudinal sections (three sections/tooth quarter, 60/group) were evaluated for mean lesion depths (water inhibition, polarized light, ANOVA, DMR). RESULTS: Mean lesion depths were 359 +/- 37 microm for the control Group; 280 +/- 28 microm for Aquafresh Advanced; 342 +/- 41 microm for the experimental xylitol dentifrice without fluoride; and 261 +/- 34 microm for Diamynt. Aquafresh Advanced and Diamynt had mean lesion depths significantly less than those for the no treatment control and the experimental xylitol without fluoride dentifrice (P< 0.05). There were minimal non-significant differences in mean lesion depths between Aquafresh Advanced and Diamynt (P > 0.05). PMID- 23724552 TI - Compounding can be confounding. PMID- 23724553 TI - A career in nursing has its ups and downs. PMID- 23724554 TI - The power of the IOL checklist. A safety initiative for the cataract patient. PMID- 23724555 TI - Adaptation of WHO safe surgery checklist to ophthalmic surgery. PMID- 23724556 TI - Killing the amoebae. PMID- 23724557 TI - Zen techniques in reducing pain and anxiety in periorbital cosmetic injections. PMID- 23724558 TI - Intraocular foreign body? PMID- 23724559 TI - Advanced practice in nursing, a United Kingdom (UK) and international perspective. PMID- 23724561 TI - Small steps to a healthier you. PMID- 23724560 TI - Use of ophthalmic lidocaine gel as an anesthetic for intravitreal injections. PMID- 23724562 TI - ANA nurses stand with Obama in calling for healthcare reform now; nation's "most trusted profession" adds to momentum at White House event. PMID- 23724563 TI - Milagros Colon De Lopez: A world class ophthalmic nursing leader. PMID- 23724564 TI - Packing for camp. PMID- 23724565 TI - The diabetes belt. PMID- 23724566 TI - Leading lady. PMID- 23724567 TI - Where's the fat? PMID- 23724568 TI - Focused suggestion with somatic anchoring technique: rapid self-hypnosis for pain management. AB - This article details a self-hypnosis technique designed to teach patients how to manage acute or chronic pain through directed focus. The focused suggestion with somatic anchoring technique has been used with various types of pain, including somatic pain (arthritis, post-injury pain from bone breaks, or muscle tears), visceral pain (related to irritable bowel disease), and neuropathic pain (related to multiple sclerosis). This technique combines cognitive restructuring and mindfulness meditation with indirect and direct suggestions during hypnosis. The case examples demonstrate how the focused suggestion with somatic anchoring technique is used with both acute and chronic pain conditions when use of long term medication has been relatively ineffective. PMID- 23724569 TI - Therapeutic hypnosis, psychotherapy, and the digital humanities: the narratives and culturomics of hypnosis, 1800-2008. AB - Culturomics is a new scientific discipline of the digital humanities-the use of computer algorithms to search for meaning in large databases of text and media. This new digital discipline is used to explore 200 years of the history of hypnosis and psychotherapy in over five million digitized books from more than 40 university libraries around the world. It graphically compares the frequencies of English words about hypnosis, hypnotherapy, psychoanalysis, psychotherapy, and their founders from 1800 to 2008. This new perspective explore issues such as: Who were the major innovators in the history of therapeutic hypnosis, psychoanalysis, and psychotherapy? How well does this new digital approach to the humanities correspond to traditional histories of hypnosis and psychotherapy? PMID- 23724570 TI - Deficits of encoding in hypnosis: a result of altered state of awareness. AB - Because no studies have examined learning in hypnosis in an academic setting, the current study tested whether learning in hypnosis impacts test performance. Participants (N = 43) were randomly assigned into a hypnosis or a control group. Participants listened to an academic lecture, answered questions about their hypnotic depth, and completed a quiz based on the lecture. The data was analyzed using multilevel modeling predicting test performance from group placement. Learning in the hypnosis predicted significantly worse performance compared to the control group. This relationship was significantly mediated by attention, which had a positive relationship to test performance. However, the altered state of awareness produced by the hypnosis condition was associated with a more significant decrease in test performance. PMID- 23724571 TI - Ethical considerations of therapeutic hypnosis and children. AB - Historically, therapeutic hypnosis has been met with skepticism within some fields, although acceptance has expanded in recent decades. Development and application of ethical standards and principles has contributed to increased acceptance of hypnosis with children. The Ethics Code of the American Psychological Association (APA, 2002) and the Code of Conduct of the American Society of Clinical Hypnosis (ASCH, 2000) serve as guides to ethical considerations when treating children. From a developmental and practical perspective, children have limited decision-making capacities, therefore special attention should be paid to their rights and welfare. Important ethical considerations relevant to children and hypnosis have emerged, including competence, supervision, informed consent, confidentiality, and boundaries. Considerations are reviewed from a normal and abnormal child development perspective. PMID- 23724572 TI - Hypnosis versus diazepam for embryo transfer: a randomized controlled study. AB - Levitas et al. (2006) showed in a cohort study that hypnosis during embryo transfer (ET) increased pregnancy ratio by 76%. In order to evaluate hypnosis during ET in a general population, the authors performed a randomized prospective controlled study comparing diazepam (usual premedication) administered before ET plus muscle relaxation versus hypnosis plus placebo in 94 patients. Additionally, the authors studied anxiety pre and post ET. Anxiety scores were not different in the two groups before and after ET. No difference in pregnancy and birth ratio was found in the two groups. Hypnosis during ET is as effective as diazepam in terms of pregnancy ratio and anxiolytic effects, but with fewer side effects and should be routinely available. PMID- 23724573 TI - Language and social work: are we really communicating effectively? PMID- 23724574 TI - Mental health issues in recently returning women veterans: implications for practice. AB - Increasing numbers of women are found in the military, and they are now performing roles very similar to those of male service members. More returning servicewomen and veterans have been exposed to stressful and traumatic experiences, such as combat and difficult living circumstances, and military sexual trauma is common. These experiences have been found to be associated with adverse mental health outcomes, posttraumatic stress disorder, depression, and substance abuse in particular. Comorbidity rates are also high. In addition, more veterans are returning with injuries, including traumatic brain injuries. Although more women veterans of Operation Enduring Freedom and Operation Iraqi Freedom are seeking health services at Veterans Administration facilities, many are not. Thus, community-based social workers need to be familiar with the needs of this growing population to serve them effectively. Use of empirically supported assessment instruments and screening for military sexual trauma are recommended. Recommended interventions include the use of evidence-supported practices, such as cognitive-behavioral treatment, and offering assistance to enhance social support among women veterans. PMID- 23724575 TI - Grassroots responsiveness to human rights abuse: history of the Washtenaw Interfaith Coalition for Immigrant Rights. AB - The purpose of this article is to discuss how a community agency based in Washtenaw County, the Washtenaw Interfaith Coalition for Immigration Rights (WICIR), emerged in response to increasing punitive immigration practices and human rights abuses toward the Latino community. The article discusses how WICIR is engaged in advocacy, community education on immigration issues, and political action toward a more humane immigration reform. Detailed examples of human rights abuses and the WICIR activities described in response to the abuses serve as illustrations of social work advocacy, education, and policy formulation that affect the general public, policymakers, and law enforcement officials. PMID- 23724576 TI - Stepfamily functioning and closeness: children's views on second marriages and stepfather relationships. AB - Current research on stepfamily well-being often overlooks the perspective of children, and deals primarily with factors as reported by the adults involved. The authors examine a number of family role characteristics, parental subsystem characteristics, and resources that might influence how children perceive the quality of their stepfamily relationships. A sample of 1,088 children in households with a mother and stepfather, ages 10 to 16 years, in the National Longitudinal Survey of Youth, 1979 cohort-Children and Young Adult Sample, is used for the analyses. Results indicate that open communication between children and their mothers, low amounts of arguing between mothers and stepfathers, along with agreement on parenting, and gender, all affect the closeness children report having with their stepfathers. Conclusions, limitations, and clinical implications are discussed. PMID- 23724577 TI - The value of a college degree for foster care alumni: comparisons with general population samples. AB - Higher education is associated with substantial adult life benefits, including higher income and improved quality of life, among others. The current study compared adult outcomes of 250 foster care alumni college graduates with two samples of general population graduates to explore the role higher education plays in these young adults' lives. Outcomes compared include employment, income, housing, public assistance, physical and mental health, happiness, and other outcomes that are often found to be related to educational attainment. Foster care alumni college graduates were very similar to general population college graduates for individual income and rate of employment. However, foster care alumni graduates were behind general population graduates on factors such as self reported job security, household earnings, health, mental health, financial satisfaction, home ownership, happiness, and public assistance usage. Results have implications for policy and practice regarding the most effective means of supporting postcollege stability of youths with foster care experience. PMID- 23724578 TI - Factors affecting social workers' inclusion of animals in practice. AB - Experts suggest that social work practitioners can improve their client service with a more thorough understanding of the impact of other animals on individuals and families. Studies indicate that some social work practitioners are including animals in their practices through assessment and interventions. Little is known about what factors contribute to this inclusion, especially because there is a lack of attention in social work education and research to animal-human relationships. This study used logistical regression to examine the impact of certain demographic, knowledge, and practice variables on the inclusion of animals in social work practice. Findings include that knowing other social workers who include animals in practice and primary client population served were significant for inclusion of animals in assessment, animal-assisted intervention, and treating clients for animal abuse or loss of an animal. Although practitioners' having a companion animal was positively related to including animals in interventions and treating clients for loss of an animal, contributing to animal welfare through volunteering at shelters or financially contributing to animal groups did not have an effect on inclusion of animals in practice. Implications for these and other findings are discussed, and recommendations for social work research, education, and practice are offered. PMID- 23724579 TI - Social work in a digital age: ethical and risk management challenges. AB - Digital, online, and other electronic technology has transformed the nature of social work practice. Contemporary social workers can provide services to clients by using online counseling, telephone counseling, video counseling, cybertherapy (avatar therapy), self-guided Web-based interventions, electronic social networks, e-mail, and text messages. The introduction of diverse digital, online, and other forms of electronic social services has created a wide range of complex ethical and related risk management issues. This article provides an overview of current digital, online, and electronic social work services; identifies compelling ethical issues related to practitioner competence, client privacy and confidentiality, informed consent, conflicts of interest, boundaries and dual relationships, consultation and client referral, termination and interruption of services, documentation, and research evidence; and offers practical risk management strategies designed to protect clients and social workers. The author identifies relevant standards from the NASW Code of Ethics and other resources designed to guide practice. PMID- 23724580 TI - Technology use among emerging adult homeless in two U.S. cities. PMID- 23724581 TI - One hypothesis about the decline and fall of ACORN. PMID- 23724582 TI - "The best health care system in the World"? PMID- 23724583 TI - Virtual boundaries: ethical considerations for use of social media in social work. AB - In real life, we often use physical cues to help us identify our role and put the appropriate boundaries in place, but online it is more difficult to determine where our boundaries lie. This article provides and overview of various social media tools and uses along with personal and professional considerations to help in guiding the ethical use of social media tools. As the use of social media continues to grow, the importance of virtual boundaries will also rise. Therefore, proactive considerations that include policies and guidelines that encourage responsible and ethical use of social media are needed to help social workers mediate personal and professional boundaries. PMID- 23724584 TI - Clinical practice with suicidal clients. PMID- 23724585 TI - Requiring continuing education units on interpersonal violence. PMID- 23724586 TI - Women being battered is terrible but can be stopped! PMID- 23724587 TI - The Porter Fellowships: A major contributor to my professional success. PMID- 23724588 TI - APS urges NIH to revisit chimpanzee recommendations. PMID- 23724589 TI - Workplace dynamics: understanding how to work together in research environments. PMID- 23724590 TI - Letter to Margaret Anderson. PMID- 23724591 TI - Letter to Phil Posner. PMID- 23724592 TI - Focus on research. PMID- 23724593 TI - There is power in the school nurse recommendation to immunize. PMID- 23724594 TI - Addressing diabetes and depression in the school setting; the role of school nurses. AB - What Can School Nurses Do to Address Diabetes and Depression in the School Setting? 1. Remember that depression and diabetes are common comorbidities. If you see signs of depression, remember to obtain the appropriate consent and approvals for students under the age of 18 before screening. 2. Remember that depression can interfere with self-management skills and may make diabetes worse- so connect students to community resources to help them reduce the risk of complications. 3. Remember that depression and risk-taking behaviors are common in adolescents with diabetes. Have educational materials ready and available to help students in need. PMID- 23724595 TI - Effective partnership: how school nurses and physical education teachers can combat childhood obesity. AB - School systems face many challenges in attempting to address the childhood overweight and obesity epidemic. Given the accumulated nature of the required physical activity and the likelihood that only one meal will be delivered while on school grounds, the potential for impactful change in obese or overweight children through school policy is limited. From this vantage point, it is easy to see that physical education programs alone cannot ensure that children participate in 60 minutes of daily physical activity. The necessary multifaceted approach requires opportunities for physical activity to be obtained throughout the school day. The school nurse and physical education teachers are the school personnel most likely to be involved in efforts to curtail the childhood overweight and obesity epidemic at the school level. These individuals are in critical roles of assisting both parents and children when it comes to understanding the devastating effects of being overweight and obese and in helping children identify positive health behaviors that may help reverse this condition. The purpose of this article is to describe the ways in which the school nurse and physical education teacher can work collaboratively to better address the childhood overweight and obesity epidemic. PMID- 23724596 TI - School nurses as gatekeepers to plan, prepare, and prevent child and youth suicide: new SOS signs of suicide online module. PMID- 23724597 TI - An innovative program to address learning barriers in small schools: Washington State School Nurse Corps. AB - While all schools in Washington State have had to deal with shrinking financial resources, small, rural school districts, with fewer than 2,000 students, face unique circumstances that further challenge their ability to meet rising student health needs. This article will explore how small districts utilize the services of the Washington State School Nurse Corps (SNC), an innovative program that supports student health and safety while reducing barriers to learning. Through direct registered nursing services and regional nurse administrative consultation and technical assistance, the SNC strengthens rural school districts' capacity to provide a safe and healthy learning environment. In addition, we will examine current research that links health and learning to discover how the SNC model is successful in addressing health risks as barriers to learning. Lastly, as resources continue to dwindle, partnerships between schools, the SNC, and state and local health and education organizations will be critical in maintaining health services and learning support to small, rural schools. PMID- 23724598 TI - Using evidence-based practice in the school health room. AB - School nurses should be engaging in evidence-based practice (EBP) in their health room settings as supported by the initiatives of the Institute of Medicine. EBP is a set of skills that health professionals can use in order to ensure high quality and current clinical care is provided. School nurses are faced with a diverse and complex population of children and often work in isolation from nursing peers, which can lead to limited professional peer discussions about recent changes or outdated clinical practices. EBP combines the use of evidence from the literature, expert guidelines, clinician expertise and client preferences in order to provide optimum care. This article leads the school nurse through the process and use of EBP in the school setting. PMID- 23724599 TI - Health considerations for children with congenital heart disease in school. Part 2. AB - School participation for children with congenital heart disease (CHD) can be challenging. Despite advances in treatment that have increased survival to adulthood and decreased morbidity, concerns remain about the health and safety of these students in the school environment. This article, the second in a series, discusses recent research on the increased incidence of neurodevelopmental disabilities that can impact academic performance in children with CHD. Exercise and sports participation is also addressed. School nurses are in a unique position to advocate for the child's health needs in the school setting and facilitate communication with the health care team and school personnel. PMID- 23724600 TI - The case for school nursing: review of the literature. PMID- 23724601 TI - Epinephrine: the drug of choice for anaphylaxis. PMID- 23724602 TI - Tennis. PMID- 23724603 TI - Professional tennis players' serve: correlation between segmental angular momentums and ball velocity. AB - The purpose of the study was to identify the relationships between segmental angular momentum and ball velocity between the following events: ball toss, maximal elbow flexion (MEF), racket lowest point (RLP), maximal shoulder external rotation (MER), and ball impact (BI). Ten tennis players performed serves recorded with a real-time motion capture. Mean angular momentums of the trunk, upper arm, forearm, and the hand-racket were calculated. The anteroposterior axis angular momentum of the trunk was significantly related with ball velocity during the MEF-RLP, RLP-MER, and MER-BI phases. The strongest relationships between the transverse-axis angular momentums and ball velocity followed a proximal-to-distal timing sequence that allows the transfer of angular momentum from the trunk (MEF RLP and RLP-MER phases) to the upper arm (RLP-MER phase), forearm (RLP-MER and MER-BI phases), and the hand-racket (MER-BI phase). Since sequence is crucial for ball velocity, players should increase angular momentums of the trunk during MEF MER, upper arm during RLP-MER, forearm during RLP-BI, and the hand-racket during MER-BI. PMID- 23724604 TI - Effect of a common task constraint on the body, racket, and ball kinematics of the elite junior tennis serve. AB - The development of a powerful and accurate serve is a priority for most tennis players. Various drills are proposed to enhance characteristics of the serve such as ball speed and spin, yet research has failed to address their efficacy. The aim of this study was therefore to compare the kinematics of a flat serve with that of a service drill, where the player serves from the knees in an endeavour to promote specific changes in trunk, arm, racket, and ball motion. A 22-camera 250 Hz VICON MX motion analysis system captured the trunk, arm, racket, and ball kinematics of eight high-performance junior players hitting flat serves and knee serves. Paired t-tests assessed within-group kinematic differences between the two serve conditions. Changes in ball toss, trunk, arm, and racket kinematics were a manifestation of the constraints presented by the knee serve. These changes effected an increased angle of attack of the racket but without greater frontal plane trunk rotation, which represented primary objectives of the knee serve. In sum, partial support was offered to the use of the knee serve as an intervention that promotes immediate, specific changes in trunk and racket kinematics in the service actions of elite junior players. PMID- 23724605 TI - Ball spin in the tennis serve: spin rate and axis of rotation. AB - The purpose of this study was to describe three-dimensional ball kinematics including spin axis and spin rate for the flat, slice, and kick serves executed by elite male tennis players. Trajectories of three retro-reflective markers attached to the surface of the ball were measured using a Vicon MX motion analysis system. The local coordinate system of the ball enabled the ball's angular velocity vector to be determined. Mean (+/- SD) spin rates recorded were 127.4 (+/- 56.3), 232.1 (+/- 34.8), and 336.5 (+/- 51.5) rad/s for the flat, slice, and kick serves, respectively. The resultant horizontal velocities of the ball were 52.0 (+/- 2.9), 46.4 (+/- 3.4), and 40.8 (+/- 2.8) m/s, respectively, and a clear tradeoff existed between the development of ball spin rate and horizontal ball velocity. [corrected]. The spin axis and ball velocity vector were close to perpendicular regardless of serve type. Mean angles between the spin axis and the horizontal plane (elevation angles) were 65.68 (+/- 10.28), 68.48 (+/- 6.98), and 54.58 (+/- 8.48) for the flat, slice, and kick serves, respectively. [corrected]. PMID- 23724606 TI - Association between body height and serve speed in elite tennis players. AB - The purpose of this study was to determine the association between the body height (BH) of elite tennis players and their serve speeds: SF (fastest serve in a match), S1 (average speed of the first serve in a match), and S2 (average speed of the second serve in a match). Data were collected from the world's best tennis players who participated in all four Grand Slam tournaments in 2008 (men, n = 78 84, BH = 1.85 +/- 0.07 m; women, n = 70-78, BH = 1.73 +/- 0.07 m). Statistically significant correlations (r) between BH and serve speed were found in all 24 statistical analyses (p < 0.01). The correlation coefficients were similar in men and women. The correlation coefficients of BH with SF and S1 ranged 0.48-0.64 for men and 0.48-0.59 for women. The correlations between BH and S2 were weaker and more variable (r = 0.20-0.50 for men and 0.24-0.42 for women). The BH of the men explained 27%, 30%, and 14% of the variance of SF, S1, and S2, respectively, with corresponding values for female players of 27%, 27%, and 12%. PMID- 23724607 TI - Supination control increases performance in sideward cutting movements in tennis. AB - The objective of this study was to explore the effects of tennis shoe characteristics on performance during sideward cutting movements followed by direction changes. Five tennis players (age = 21.5 +/- 0.8 years, mass = 75.2 +/- 2.8 kg, and height = 1.78 +/- 0.05 m) participated in the study and 10 tennis shoes were tested. Several footwear mechanical parameters were analyzed: Shore A hardness, longitudinal and transverse flexibility, midsole height at heel, presence of heel counters, and weight. A force plate was used to measure the kinetic variables, and two video cameras were used to perform a three-dimensional photogrammetric analysis. Results revealed that subject-footwear interaction was statistically not significant (p > 0.05) for the kinetic and kinematic variables. Only contact time (p = 0.008) and supination movement (p = 0.009) were footwear dependent. Positive correlations between contact time and first supination peak (r = 0.783, p = 0.007) and second supination peak (r = 0.730, p = 0.016) were observed. Impulse was not changed, which means shoes limiting supination allowed tennis players to perform faster sideward cutting movements. PMID- 23724608 TI - The interaction between the tennis court and the player: how does surface affect leg stiffness? AB - An adequate level of leg stiffness is necessary for an optimal tennis performance and leg stiffness should be adapted to frequently changing surfaces as tennis players usually play on different courts. The aim of this study was to evaluate leg stiffness in competitive tennis players on different court surfaces. Ten healthy competitive tennis players (nine men and one woman; mean age = 17.6 +/- 3.2 years) underwent leg stiffness testing by modeling the vertical ground reaction force using an optical system. Flight time and contact time were determined during hopping on two different tennis court surfaces (clay and acrylic). No significant difference was found in the flight time, contact time, and jump height between the surfaces. No significant difference in leg stiffness was found between the surfaces (18.25 +/- 5.8 and 19.27 +/- 4.9 kN/m for clay and acrylic, respectively; p = 0.28). This study demonstrated that contact time and flight time as well as leg stiffness of tennis players remained unchanged when hopping on two different tennis surfaces. Results of this research provide objective data regarding the tennis-specific loading of the locomotor system and proper mechanical adaptation of the player on different surfaces, which may be useful for testing protocols and planning training programs. PMID- 23724609 TI - The hypertrophy of the lateral abdominal wall and quadratus lumborum is sport specific: an MRI segmental study in professional tennis and soccer players. AB - The aim was to determine the volume and degree of asymmetry of quadratus lumborum (QL), obliques, and transversus abdominis; the last two considered conjointly (OT), in tennis and soccer players. The volume of QL and OT was determined using magnetic resonance imaging in professional tennis and soccer players, and in non active controls (n = 8, 14, and 6, respectively). In tennis players the hypertrophy of OT was limited to proximal segments (cephalic segments), while in soccer players it was similar along longitudinal axis. In tennis players the hypertrophy was asymmetric (18% greater volume in the non-dominant than in the dominant OT, p = 0.001), while in soccer players and controls both sides had similar volumes (p > 0.05). In controls, the non-dominant QL was 15% greater than that of the dominant (p = 0.049). Tennis and soccer players had similar volumes in both sides of QL. Tennis alters the dominant-to-non-dominant balance in the muscle volume of the lateral abdominal wall. In tennis the hypertrophy is limited to proximal segments and is greater in the non-dominant side. Soccer, however, is associated to a symmetric hypertrophy of the lateral abdominal wall. Tennis and soccer elicit an asymmetric hypertrophy of QL. PMID- 23724610 TI - Diagnostic characteristics and application of alcohol biomarkers. AB - Alcohol biomarkers play a significant role in the early diagnosis of alcohol intoxication/abuse, alcohol-related organ damages, assessment of alcoholism therapy outcomes, and in forensic medicine. Laboratory detection of excessive alcohol consumption can be carried out by direct measuring of the ethanol and/or metabolites in biological samples which is of particular importance in the cases of acute ethanol intoxication/controlling and/or monitoring of alcohol consumption, or indirectly, by using biomarkers. Preferred diagnostic characteristics of alcohol biomarkers, specificity and sensitivity dependent on the particular demands such as: prevention and treatment of alcoholism in primary and social care, criminal justice, workplace health and safety screening, trafficking control, etc. Alcohol biomarkers traditionally used in clinical practice [blood alcohol concentration (BAC), gamma-glutamyl transferase (GGT), carbohydrate-deficient transferrin (CDT), the ratio GGT/CDT, alanine aminotransferase (ALT), aspartate aminotransferase (AST), the rati. AST/ALT, mean cbrpuscular volume (MCV), phosphatidylethanol (PEth)] are well validated. They are used as screening/monitoring markers of acute/chronic excessive alcohol intake, alcoholism in pregnancy, and other disorders/conditions related to alcohol abuse. Numerous potential alcohol biomarkers have been discovered, but few are validated. Potential alcohol biomarkers (ethanol and serotonin metabolites, sialic acids, etc.) have good diagnostic characteristics, but their application in clinical practice is limited due to the costly equipment necessary for their measurement. Significant progress has been made in the development of sensitive and practical alcohol transdermal devices that can instantly/continuously measure BAC through human skin. Transdermal sensing of alcohol may become a valuable method for monitoring abstinence. A special aspect of alcoholism is genetic predisposition to alcohol abuse and alcoholism, or alcohol-related organ damage. Recent genome-wide association studies (GWASs) have proposed several susceptibility loci for alcohol dependence. PMID- 23724611 TI - Evaluation of chromium, cobalt and manganese in biological samples (scalp hair, blood, and urine) of Pakistani viral hepatitis (A-E) patients and controls. AB - BACKGROUND: The aim of the present study was to compare the level of chromium (Cr), cobalt (Co), and manganese (Mn) in biological samples (blood, urine, and scalp hair) of patients suffering from different types of viral hepatitis (A, B, C, D, and E; n = 521) of both genders, ages ranging from 31 - 45 years. For comparative study, 255 age-matched control subjects of both genders residing in the same city were selected as referents. METHODS: The digests of all biological samples were analysed for Cr, Co, and Mn by electrothermal atomic absorption spectrometry (ETAAS). The validity and accuracy of the methodology was checked by using certified reference materials (CRMs) and compared with those values obtained by conventional wet acid digestion method on same CRMs. RESULTS: The results of this study showed that the mean values of Cr, Co, and Mn were higher in blood and scalp hair samples of hepatitis patients than in age-matched control subjects. The urinary levels of these elements were found to be higher in the hepatitis patients than in the age-matched healthy controls (p <0.001). CONCLUSIONS: These results are consistent with literature-reported data, confirming that the overload of these trace elements can directly cause lipid peroxidation and eventually hepatic damage. PMID- 23724612 TI - Obese subjects have significantly higher serum prooxidantantioxidant balance values compared to normal-weight subjects. AB - BACKGROUND: It has been reported that obesity is associated with higher levels of oxidative stress. We aimed to evaluate the hypothesis that pro-oxidant antioxidant balance (PAB) values could be affected by adiposity and to assess the association between PAB levels and indices of obesity. METHODS: Subjects (n = 733) were recruited and tlen were divided into 3 groups of normal-weight (BMI < 25, n = 207), overweight (25 < BMI < 30, n = 375), and obese (BMI > 30, n = 151). PAB values were measured in all participants. RESULTS: There was a significant association between PAB values and weight when the correlation was determined for all subjects (p < 0.05). Obese subject had significantly higher levels of PAB values [40.8 (34.3 - 51.1) HK unit] compared with overweight [37.5 (29.7 - 47.3) HK unit] and normal-weight subjects [37.2 (29.6 - 45.2) HK unit] (p < 0.05 in each case). However, there was no significant difference in PAB values between normal and over-weight subjects (p > 0.05). On performing the analysis of covariance, low-density lipoprotein-cholesterol (LDL-C) was found to have a significant independent association with PAB values (j = 0.046, p = 0.04). CONCLUSIONS: The high levels of PAB values in obese subjects without overt signs/symptoms of cardiovascular disease may be related to a heightened state of oxidative stress associated with obesity. PMID- 23724613 TI - Short-time variation in serum uric acid concentrations in post-myocardial infarction patients. AB - BACKGROUND: Studies on SUA temporal profile in relation to acute myocardial infarction (AMI) are controversial. The aim of this study was to evaluate the SUA level variations following myocardial infarction. METHODS: We studied 222 patients more than 18 years old diagnosed with AMI. SUA was measured at baseline and on day 2 to 4 and day 5 to 8 after AMI. Within and between person variability of SUA following an AMI was estimated using intraclass correlation coefficients (ICC). The change in SUA between each assessment point was analyzed by repeated measures one-way analysis of variance. To evaluated.SUA variation post-myocardial infarction and its predictors we used generalized linear mixed-effects models. RESULTS: The mean plasma concentration of SUA was lower at baseline (58.5 +/- 18.9 mg/L). The ICC across the three time points was 0.75 (95% CI 0.70 - 0.80). SUA levels increased 1.33 mg/L per day after AMI (2.3 mg/L/day in women and 1.0 mg/L/day in men). Normouricemic patients had a 1.6 fold increase risk to change to hyperuricemic status per day after AMI (OR = 1.60, 95% CI: 1.27 - 2.00). CONCLUSIONS: Serum uric acid concentration is relatively stable over an eight-day post-myocardial infarction period. However, even a small increase of SUA per day after AMI is associated with a high probability of changing the classification of hyperuricemic status. PMID- 23724614 TI - Emergence of norovirus GII/4 2006a and 2006b variants in hospitalized children with acute gastroenteritis in Thailand. AB - BACKGROUND: Norovirus (NoV) is recognized as a significant cause of acute gastroenteritis in infants and young children worldwide. This study investigated the prevalence of NoV infection in hospitalized children with gastroenteritis in Chiang Mai, Thailand in 2006. METHODS: A total of 156 fecal specimens were collected from children with diarrhea admitted to McCormick Hospital in 2006. All fecal specimens were examinedffor NoV by RT-PCR and the genotypes were identified by sequence analysis. RESULTS: A high prevalence of NoV infection was detected (20.5%, 32/156). NoV GII/4 was the most predominant genotype with a prevalence of 87.5% (28/32), while GII/3, GII/6, GII/12, and GII/15 were less common (3.1% each). Among GII/4 strains, 2006b variant (75%, 21/28) emerged as the leading strain and dominated over the Hunter'04-like variant, which was the most common strain in the previous season of 2005. In addition, the 2003, 2004, and 2006a variants were also detected. NoV infections were most commonly observed in the rainy season in Thailand. CONCLUSIONS: This study demonstrated the emergence of GII/4 2006b variants as the major pathogen causing acute gastroenteritis among infants and children at the age of less than 5 years old who admitted to hospital in Chiang Mai, Thailand in 2006. Additionally, other GII/4 variants of 2003, 2004, and 2006a were also reported. PMID- 23724615 TI - The impact of topical calcipotriol and betamethasone on human beta-defensin 2 expression and serum level in psoriatic patients. AB - BACKGROUND: As defensins are dysregulated in psoriasis, the present work is aimed at the assessment of the impact of topical betamethasone with and without calcipotriol on human beta-defensin 2 (hBD-2) expression and serum level in a cohort Egyptian psoriatic patients. METHODS: A biopsy was performed at the site of psoriatic plaque for all patients participating in the study before application of any treatment. The first group of patients (n = 25) used an ointment containing a combination of calcipotriol and betamethasone dipropionate for 4 weeks while the second group (n = 25) used an ointment containing betamethasone valerate for the same period. For all patients, human beta defensin 2 expression and serum level was assayed before and after either treatment course. RESULTS: No statistically significant difference way detected between both groups as regards PASI score, hBD-2 expression or serum level before application of either treatment regimen, while those who used the combined regimen showed lower expression and serum level of hBD-2 associated with lower PASI score on comparison with those who followed the mono-therapy. CONCLUSIONS: Psoriasis treatment using the combined calcipotriol and betamethasone therapy is superior in effect to monotherapy using betamethasone alone. In addition, serum hBD-2 might be a useful marker for disease activity in psoriasis that can help assess the patient's clinical condition. PMID- 23724616 TI - Detection of antinuclear antibodies (ANA), antibodies to double stranded DNA (anti-dsDNA) and antibodies to extractable nuclear antigens (anti-ENA) in Greek patients. AB - BACKGROUND: The diagnosis of autoimmune diseases depends on clinical history, physical examination, and laboratory detection of specific autoantibodies directed against nuclear or cytoplasmic antigens. The aim of this study was to investigate the types and prevalence of serum ANA, anti-dsDNA, and anti-ENA antibodies in a population examined at the Immunology Laboratory of the Naval Hospital of Athens and their correlation with patient age and gender. METHODS: We evaluated the sera of 3000 patients, both male and female, aged between 18 and 75 years old, born in different parts of Greece. All requests for ANA detection were performed by enzyme linked immunoassay (ELI SA). All ELISA borderline, weak positive and pbsitive results were run on the indirect immunofluorescence assay (IFA) on Hep-2 cells. Anti-dsDNA antibodies were detected by IFA on Crithidia luciliae substrate slides. Antibodies to Sm, RNP, SS-A(Ro), SS-B(La), Jo-1, and Scl-70 were determined by an immunodot qualitative test. RESULTS: 206 patients were positive for ANA, representing a prevalence of 6.87%. The positive samples demonstrated the expected variety of titers and reactivity patterns. 9 samples (4.37%) presented anti-dsDNA positive result and 44 (21.36%) presented reactivity to various ENA autoantibodies. All the examined autoantibodies presented a higher prevalence among women. CONCLUSIONS: In this study we estimated the prevalence of ANA, anti-dsDNA, and anti-ENA antibodies in samples of 3000 sera. We followed the strategy of performing immunofluorescence testing in order to confirm positive ELISA results, proposed by many scientists. We also evaluated autoantibody titers and fluorescence patterns, and we examined the correlation of autoantibody presence with patient age and gender. PMID- 23724617 TI - Contribution of specific anti-hydatid IgG subclasses in the diagnosis of echinococcosis primary infection and relapses. AB - BACKGROUND: Serological diagnosis of hydatid disease still faces problems of sensitivity, limiting its use to either diagnosis or post-surgical monitoring. The use of IgG subclasses seems to overcome these difficulties. The contribution of IgG subclasses was evaluated in the diagnosis of primary infested and hydatid cyst relapse patients. METHODS: A group of patients (n = 34) diagnosed for the first time with liver cystic echinococcosis (CE) and a group of patients with CE surgical recurrence were included. Enzyme-linked immunosorbent assay anti-hydatid antigens (HA) specific IgG1, 2, 3, and 4 subclasses were analyzed by ROC curves. RESULTS: ROC curve analyses demonstrated that IgG4 had the ability to discriminate between primary infested and relapsed groups whereas IgG2 was not discriminatory. The sensitivity of IgG4 was statistically higher in the relapsed cases group (97.1% versus 70.6%, p = 0.008). CONCLUSIONS: anti-HA specific IgG2 was the best marker of primary infestation whereas IgG4 was the best marker of relapse. PMID- 23724618 TI - Atorvastatin therapy is not associated with slowing the progression of aortic stenosis: findings of a randomized controlled trial. AB - BACKGROUND: Aortic stenosis (AS) is the most common type of valvular cardiac disorders. AS has many risk factors in common with atherosclerosis. Hypercholesterolemia is an important pathomechanism for AS. However, the impact of statin drugs on slowing AS progression has not yet been well established. OBJECTIVE: To investigate the impact of statin therapy on slowing AS progression. METHODS: This was a randomized double-blind placebo-controlled trial in which 75 patients with mild to moderate AS were randomized to receive either simvastatin (20 mg/day) or placebo for a period of one year. Serum lipid profile, C-reactive protein (CRP), and echocardiographic parameters were evaluated at baseline as well as at the end of trial. RESULTS: Treatment with atorvastatin was associated with significant decreases in total cholesterol, triglycerides, and LDL-C and an elevation of HDL-C. None of the lipid profile parameters changed in the placebo group. Serum CRP was not significantly altered in any of the groups. Left ventricular end-systolic volume was significantly increased by the end of trial in the statin group (p = 0.012). In the placebo group, significant increases were observed for aortic valve mean (p = 0.017) and peak (p < 0.001) gradient. Other echocardiographic measures remained statistically unchanged in the statin and placebo groups. The number of patients whose disease progressed into severe stage was comparable between the groups and post-trial echocardiographic assessment did not reveal any significant change in the severity of AS between atorvastatin and placebo (p > 0.05). CONCLUSIONS: The findings of the present randomized trial did not support a beneficial effect of statin therapy (20 mg/day) against AS progression in Iranian patients with mild to moderate disease. PMID- 23724619 TI - Clinical evaluation of a new creatine kinase MB activity reagent abrogating the effect of mitochondrial creatine kinase. AB - BACKGROUND: Measuring creatine kinase (CK) MB activity using the immunoinhibition method remains useful in clinical laboratories. CK-MB activity is abnormally high when macro CK type 2 (mitochondrial creatine kinase, MtCK) is present in patient serum. In order to improve the accuracy of the CK-MB activity assay, we developed a new CK-MB activity method using highly specific anti-MtCK antibodies. We evaluated the clinical performance of the new method, which abrogates the effect of MtCK activity. METHODS: Receiver operating characteristic analysis, CK-MB activity range, cut-off, and CK-MB to CK activity ratio were investigated. RESULTS: Mean CK-MB activity in normal human serum was 2.5 U/L by our method, in contrast to 12.0 U/L by the current method. Approximately 80% of CK-MB activity determined using the current kit corresponds to MtCK activity, and ubiquitous mitochondrial creatine kinase activity constitutes approximately 90% of MtCK activity. The cut-off and CK-MB activity ratio of our method were 12 U/L and 3 to 20%, respectively, in contrast to 22 U/L and 5 to 23%, respectively, using the current CK-MB method. The areas under the curve of our method, current CK-MB, electrophoresis, and CK-MB mass were 0.976, 0.928, 0.967, and 0.991, respectively. Our new method was superior to the electrophoresis and CK-MB mass as well as the conventional method due to jts promptness, simplification, and low cost. CONCLUSIONS: The new kit will improve the clinical diagnosis of acute myocardial infarction. CK-MB activity assay was considered as a suitable alternative to conventional cardiac markers due to its superior diagnostic validity. PMID- 23724620 TI - Evaluation of urinary human telomerase reverse transcriptase mRNA and scatter factor protein as urine markers for diagnosis of bladder cancer. AB - BACKGROUND: Expression of the human telomerase reverse transcriptase (hTERT) gene, which codes for the catalytic subunit of telomerase is considered an important tumor marker used for bladder cancer detection being found in the majority of cancer cells. Scatter Factor (SF) is a secretory protein produced by fibroblasts and smooth muscles and induces scattering of the epithelial cells. The aim of the current study was to evaluate the potential usefulness of hTERT and SF measurement as urinary markers for bladder cancer diagnosis. METHODS: Voided urine specimens were collected from patients with histologically confirmed bladder urothelial carcinoma (malignant group: n = 60), urological patients without urothelial carcinoma (benign group: n = 25), and healthy volunteers (control group: n = 20). All cases underwent urine cytology, serological schistosomiasis antibody assay and detection of urinary hTERT mRNA using RT-PCR and SF using ELISA. RESULTS: Positivity rate of hTERT mRNA was markedly higher in malignant versus benign or control cases (86.67%, 8%, and 0%, respectively, p value < 0.001). Combining hTERT and cytology increased the sensitivity of cytology to 95%. According to a cut-off value of urinary SF (> or = 410 ng/mg protein), 57 (95%) of the patients with bladder carcinoma, 10 (40%) with benign lesions, and non of the control individuals were positive and the difference between the 3 groups was statistically significant (p < 0.001). The sensitivity of cytology was increased to 98.33% when combined with the SF assay. When associating the two urinary markers with different clinicopathological factors of the bladder cancer group, only SF exerted a significantly higher positivity rate at the invasive stage (100%) than the superficial stage (88.46%) as well as in transitional cell carcinoma (100% thansquamous cell carcinoma type (87.5%). CONCLUSIONS: hTERT and SF can be considered potential useful markers for detection of bladder cancer. PMID- 23724621 TI - Evaluating appropriateness of digoxin, carbamazepine, valproic acid, and phenytoin usage by therapeutic drug monitoring. AB - BACKGROUND: Therapeutic drug monitoring (TDM) is a useful tool for the optimization of drug therapy. The aim of this retrospective study was to evaluate the appropriateness of carbamazepine, phenytoin, valproic acid, and digoxin therapy by using TDM data. METHODS: We evaluated the appropriateness of drug usage in 325 patients who received carbamazepine, valproic acid, phenytoin, or digoxin in a large teaching hospital during the period from March 2010 to January 2011. The serum drug levels were measured by cloned enzyme donor immunoassay (CEDIA). RESULTS: A total of 325 TDM tests were performed in this period. In our TDM unit, valproic acid was the most evaluated test among the samples obtained. In 100 valproic acid-treated patients, serum levels in 58 patients (58%) were within the therapeutic range. While 11 patients (11%) had serum levels in the above-therapeutic range, 31 patients (31%) had sub-therapeutic levels of valproic acid: The results of TDM were mostly found in the therapeutic range for carbamazepine. A total of 91 request forms were collected. The overall data show that 64 patients (70.3%) had serum carbamazepine levels within the therapeutic range. In the phenytoin assays, the mean plasma concentrations generally did not reach the therapeutic range. Among the total of 49 blood samples, the highest number of sub-therapeutic levels (65.3%) were detected for phenytoin. Similarly, inappropriate levels of digoxin were established in about half of all cases. CONCLUSIONS: This study gives information about the inappropriate usage of digoxin and phenytoin in respect to the results of our TDM practice. Our results suggest that there is a need for interventions to improve the appropriate use of digoxin and phenytoin in patients treated with these drugs. PMID- 23724622 TI - Upper reference limits of high-sensitivity cardiac troponin T in a general population: comparison with those of sensitive cardiac troponin I. AB - BACKGROUND: Upper reference limits (97.5th, 99th percentiles) of high-sensitivity and sensitive cardiac troponins (hs-cTn and s-cTn) can be influenced by several factors. Our aim was to study: (1) the ability of hs-cTnT and s-cTnI to detect circulating cTn in a general community population, and (2) the effects of age, renal function, and gender on their 97.5th - 99th percentile values. METHODS: Hs cTnT and s-cTnI values were measured in 177 subjects. RESULTS: Thirty-six subjects (20%) presented hs-cTnT values above the limit of detection (LoD), whereas no subjects presented detectable s-cTnI values. Men presented more frequently than women with detectable hs-cTnT levels (37% vs. 11%; p = 0.0001). Hs-cTnT was more frequently found in older (> or = 70 years) than in younger subjects (57 vs. 14%; p < 0.0001). Subjects with low estimated glomerular filtration rates (eGFR < 60 mL/min1/ 1.73m2) presented more frequently with detectable hs-cTnT levels than subjects with higher eGFR (71% vs. 17%; p < 0.0001). Hs-cTnT 97.5th - 99th percentiles varied according to selection by age, renal function, and gender; percentile values of s-cTnI were below the LoD of the assay. CONCLUSIONS: Hs-cTnT is more often quantified than s-cTnI in healthy subjects. Age, gender, and eGFR values influence 97.5th - 99th hs-cTnT percentile values. PMID- 23724623 TI - Laboratory features throughout the disease course of influenza A (H1N1) virus infection. AB - BACKGROUND: Influenza has emerged every year but a complete profile of laboratory indices throughout the disease course remains unknown. METHODS: Clinical data was collected from 28 confirmed cases of the pandemic influenza H1N1 2009. The levels of serum iron (Fe), carbon dioxide combining power (CO2-CP), total complement hemolytic activity (CH50), C-reactive protein (CRP), and white blood cell (WBC) and differential count were analyzed. RESULTS: Major laboratory abnormalities recokled for patients upon admission were lymphopenia (96.4%), eosinopenia (50.0%), hypoferremia (92.9%), decreased levels of serum CO2-CP (60.7%), increased levels of serum CRP (84.6%) and serum CH50 (71.4%). The serum iron and CO2-CP concentration and the counts for lymphocytes, eosinophils, and basophils were significantly increased four days after sickness was noticed compared with the first three days of illness (p < 0.05). The total WBC and neutrophil counts were significantly decreased four days after onset of illness compared with the counts over the first three days (p < 0.05). The monocyte count and CRP concentration was significantly decreased 7 days after onset of illness compared with first 3 days after illness onset (p < 0.05). The serum CH50 concentrations were higher than the normal range during disease course and significantly elevated 7 days after onset of illness compared with the first 6 days after illness onset (p < 0.05). CONCLUSIONS: The serum levels of iron, CO2-CP, CH50, CRP, and WBC and differential count Were significantly varied during the whole pandemic influenza (H1N1) 2009. The development of WBC count in patients with influenza may be an effective predictor for severity of illness. PMID- 23724624 TI - Mutations of the connexin 37 and 40 gap-junction genes in patients with acute myocardial infarction. AB - BACKGROUND: There is evidence showing the association between connexin 37 (Cx37) C1019T polymorphism and acute myocardial infarction (AMI). Since there has been no study that takes the polymorphisms of Cx37 and connexin 40 (Cx40) into consideration at the same time, we investigated the association between AMI and the polymorphism gene of two gap junction proteins Cx 37 and Cx40 which are important in the electrical coupling between arterial myocytes. METHODS: 200 patients with acute myocardial infarction (AMI) and 185 healthy controls were included in this study. Cx37 and Cx40 genotypes were determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: We identified that single nucleotide polymorphism (SNP) of Cx37 was significantly associated with AMI disease. Significant differences between cases and controls were observed for Cx37 genotype frequencies (p < 0.001, Chi2 = 16.528). The T allele of Cx37 had more frequency in the AMI group compared to the control group. (53.75% vs. 40%; p < 0.05). Subsequent analysis identified that, in contrast to the previous studies, there is a significant difference in women (p < 0.01) but not in men. We also found that the SNP of Cx40 was not significantly associated with AMI disease (p > 0.05). Our study showed that the 44A allele and -44AA genotype were not significantly different in the AMI and control groups (p > 0.05). CONCLUSIONS: It is suggested that the polymorphism in the Cx37 gene (but not Cx40 gene) potentially plays a significant role in the manifestation of AMI disease in Iranian population. PMID- 23724625 TI - Quantitative changes in p53, Bcl-2 and apoptosis in blood and urine of bladder cancer patients. AB - BACKGROUND: While current pathological and clinical parameters provide important prognostic information, they still have a limited ability to predict the true malignant potential of most bladder tumors. Therefore, the present study was carried out to investigate the levels of anti-apoptotic proteins such as p53 and Bcl-2, and of apoptosis itself as reflected by the increase in sub-G1 peak staining, in the blood and urine of bladder cancer patients, and to thus determine the usefulness of these parameters as tools for early and accurate prediction of tumor growth and development of metastases, in order to assess treatment benefit potential. METHODS: A total of 80 bladder cancer patients and 50 healthy controls without malignancies were enrolled in this study. The levels of p53, Bcl-2 and apoptosis (sub-G1 peak) were evaluated by flow cytometry in the urine and blood of patients and controls. RESULTS: Levels of p53, Bcl-2 and apoptosis were significantly higher in the urine sediment than in the blood. Moreover, p53 levels in the blood and urine of bladder cancer patients were significantly higher than in controls, and were significantly increased during the development of tumor grades and in association with positive parameters of urine analysis. In contrast, Bcl-2 and apoptosis levels in the blood and urine of bladder cancer patients were significantly lower than in samples from controls, and were significantly decreased during the development of tumor grades and in association with positive parameters of urine analysis. Apoptosis levels were positively correlated with Bcl-2 levels but negatively correlated with p53 levels. CONCLUSIONS: These findings suggest that quantitative analysis of p53, Bcl-2 and apoptosis, especially in the urine sediment, may be a useful tool in the diagnosis of bladder cancer. PMID- 23724626 TI - Annexin A5 as independent predictive biomarker for subclinical atherosclerosis and endothelial dysfunction in systemic lupus erythematosus patients. AB - BACKGROUND: Increased atherosclerosis prevalence in patients with systemic lupus erythematosus (SLE) is an epidemiological certainty. SLE patients are linked to endothelial immune conflict, chronic inflammation antiphospholipid antibodies, and high serum annexin A5 levels. Many of these factors belong to the inflammatory cascade which is common to both SLE and ATS. Therefore, there is an overlap between traditional and nontraditional atherosclerosis risk factors in SLE patients. The purpose of the study was to determine the association of conventional cardiovascular risk factors and atherosclerosis characteristics with biomarkers that are known to be implied in atherogenesis in SLE patients. METHODS: In this study subclinical atheroscler is was evaluated by'carotid intima medial thickness (IMT) and endothelial dysfunction by flow mediated dilation (FMD) in both SLE patients and controls. 132 SLE patients were recruited: 32 patients were assigned to the atherosclerosis group (ASLE, mean age +/- standard deviation 42.16 +/-9.18 years) and 100 were assigned to non-atherosclerosis group (nASLE, mean age 41.54 +/- 11.79 years). 50 healthy controls were enrolled (control group, mean age 41.4 +/- 11 years). Annexin A5 levels, anti phosphatidyl serine, and anti oxidized LDL antibodies were measured by enzyme-linked immunosorbent assay in both patients and healthy controls. RESULTS: Mean IMT in all SLE patients (0.83 - 0.11 mm) was significantly higher when compared to controls (0.66 +/- 0.04 mm, p < 0.05); mean FMD was significantly smaller in SLE patients (2.98 +/- 1.58%) when compared to controls (10.83 +/- 2.02%, p < 0.05). When all SLE patients and controls were considered together, SLIC presence, body mass index, serum annexin A5 levels, history of hypertension, and age were found to be independent predictors for abnormal IMT. In the SLE group only age and serum annexin A5 levels were found to be independent predictors for IMT. When all SLE patients were considered together, serum annexin A5 and age were found as independent predictors of FMD. In both ASLE and nASLE groups, age and serum annexin A5 levels were found to be independent predictive variables for endothelial dysfunction. CONCLUSIONS: This study confirms the presence of both endothelial dysfunction and subclinical atherosclerosis in SLE patients and suggests serum annexin A5 as predictive biomarker for subclinical atherosclerosis in SLE patients. PMID- 23724627 TI - Serum neurotrophic factor levels in patients with type 2 diabetes mellitus: relationship to metabolic syndrome components. AB - BACKGROUND: It has been thought that neurotrophins have metabotrophic effects and take part in the carbohydrate and lipid metabolism. The aim of the present study is to examine the levels of neurotrophins in type 2 diabetes mellitus (T2DM) and whether the levels are linked to the components of metabolic syndrome. METHODS: 90 patients and 35 healthy controls were enrolled in this study. The brain derived neurotrophic factor, nerve growth factor, and neurotrophin-3 were measured using an enzyme-linked immunosorbent assay. Plasma glucose, insulin, systolic blood pressure, diastolic blood pressure, and body mass index were measured, and, for each subject, the homeostasis model assessment of insulin resistance was calculated as the index of metabolic syndrome. RESULTS: The serum levels of brain-derived neurotrophic factor and neurotrophin-3 levels were higher, nerve growth factor lower in the T2DM patients than those of healthy controls (p < 0.001, p < 0. 001, and p < 0.001, respectively). The neurotrophic factor levels did not display any difference with respect to gender. The brain derived neurotrophic factor was correlated with neurotrophin-3 level in female T2DM patients. In the male patients, brain-derived neurotrophic factor was correlated positively with plasma insulin and the homeostasis model assessment of insulin resistance; neurotrophin-3 was correlated positively with both systolic blood pressure and diastolic blood pressure, and nerve growth factor was correlated negatively with plasma glucose. CONCLUSIONS: We thought that the changes in the serum neurotrophic factor levels were associated with metabolic syndrome components in T2DM. PMID- 23724628 TI - Endothelial cell protein C receptor (EPCR) is expressed by lung carcinoma and correlated with clinical parameters. AB - BACKGROUND: Endothelial cell protein C receptor (EPCR) is a cellular receptor for protein C and activated protein C (APC). In view of convincing evidence, it seems that EPCR, beyond its effects on coagulation and inflammation, could interfere with carcinogenesis. METHODS: In the present study, we investigated EPCR expression in 60 lung carcinoma tissues and 37 para-carcinoma tissues, and analyzed the relationship between EPCR expression and histopathological parameters, clinical parameters, and vascular density. RESULTS: In vitro, culturing lung cancer cell lines constitutively expressed EPCR at the level of mRNA and protein. The pathologic results clearly demonstrated that EPCR expression, including membranous and cytoplasmic staining, was significantly higher in carcinoma than that in the para-carcinoma tissues. The EPCR expression was therefore related to tumor size, lymph node metastasis as well as TNM stage. The expression of EPCR was also significantly correlated with microvessel density (MVD). CONCLUSIONS: These observations provide evidence that EPCR may be involved in the carcinogenesis of lung cancer. It is suggested that EPCR may be a useful biomarker for evaluating the clinical status of lung cancer. PMID- 23724629 TI - Multiple resistance to betalactam antibiotics, azithromycin or moxifloxacin in implant associated bacteria. AB - BACKGROUND: Antibiotics are more and more frequently prescribed in dentistry for prevention and treatment of oral diseases. Bacterial resistance to these agents is clearly increasing, including even previously susceptible micro-organisms and true pathogens. The aim of the present investigation was to examine resistant bacterial strains with respect to possible multiple antibiotic resistance. METHODS: In a previous investigation, implant-associated bacteria were tested first as mixed cultures and again as pure isolates (n = 138) for resistance to one of five antibiotics (ampicillin/AM, ampicillin + sulbactam/AB, azithromycin/AZ, penicillin/PG, moxifloxacin/MX) using the Etest. The resistance of most of the pure isolates was lower than in mixed culture, but 31.2% had retained their original resistance. Subsequently, all 138 isolates were tested for resistance or susceptibility to the other four antibiotics, again using the Etest. RESULTS: 27.6% (38/138) of the isolates retained their original antibiotic resistance and were resistant to at least one other antibiotic (MIC > or = 128 microg/mL for AB, AM or AZ, > or = 32 microg/mL PG, > or = 24 microg/mL MX). 2.2% (3/138) strains had lost their original antibiotic resistance, but were resistant to at least one other antibiotic (MIC > 128 microg/mL for AB, AM, or AZ, > or = 32 microg/mL PG, > or = 24 microg/mL MX). CONCLUSIONS: Some of the isolates belonging to the implant-associated microflora were multi-resistant, even though the patients had not received any antibiotics six weeks prior to the sampling. The exact mechanisms that lead to multiple resistance need to be examined in further studies. PMID- 23724630 TI - Evaluation of multiple myeloma cell apoptosis in primary bone marrow samples. AB - BACKGROUND: Although different approaches have been proposed to selectively determine multiple myeloma (MM) cells in a heterogeneous population of bone marrow (BM) cells, studies on plasma cells from primary samples of MM patients are still challenging. This is partially due to difficulties in obtaining a suitable amount of sample, but even more due to uneven infiltration of BM by MM cells. When the apoptotic effect of different agents on MM plasma cells is studied, evaluation is additionally complicated by morphological changes induced by apoptosis. We introduce a modified gating approach combining specific antibodies and exclusion of cellular interferences. METHODS: The extent of apoptosis induced by arsenic trioxide and camptothecin was evaluated by flow cytometry using annexin V and propidium iodide (PI) after selective labelling of plasma cells with CD38 and CD138 antibodies. We selectively analysed MM plasma cell apoptosis combining CD38/CD138-positivity and exclusion of cellular interferences. RESULTS: Thirty BM samples from newly diagnosed MM patients were analysed. We compared the proportion of cells in different phases of apoptosis obtained by gating on a CD38/CD138-positive population only and by the novel approach. The proportion of cells in early apoptosis evaluated by the modified gating technique was significantly higher for both inductors. CONCLUSIONS: The introduced gating approach can increase the reliability of selective evaluation of MM plasma cell apoptosis in primary samples. The modified method can further be implemented for the analysis of various processes in plasma cells by flow cytometry. PMID- 23724631 TI - Four automated 25-OH total vitamin D immunoassays and commercial liquid chromatography tandem-mass spectrometry in Finnish population. AB - BACKGROUND: Comparing four fully automated 25-OH-D immunoassays to a commercially available liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with human serum samples from Finnish population. METHODS: 400 samples were analyzed with the Liaison Total Vitamin D, the IDS-iSYS 25-Hydroxy Vitamin D, the ARCHITECT 25-OH Vitamin D, the ADVIA Centaur Vitamin D Total, and a commercially available LC-MS/MS 25-OH D (PerkinElmer) method. RESULTS: The Liaison method mean value (95% confidence intervals) was 65.6 nmol/L (62.6 - 68.6); the IDS-iSYS mean was 70.3 nmol/L (67.4 - 73.1); the ARCHITECT mean was 69.0 nmol/L (65.5 - 72.5); ADVIA Centaur mean was 71.6 nmol/L (68.9 - 74.3), and the LC-MS/MS mean was 82.8 nmol/L (79.4 - 86.2). The regression coefficients (r) between the LC-MS/MS and immunoassays were 0.650 for Liaison, 0.757 for IDS-iSYS, 0.721 for ARCHITECT and 0.684 for ADVIA Centaur. With the Passing-Bablok analysis, none of the immunoassays gave results equivalent to LC-MS/MS. Two of the four automated 25-OH vitamin D assays (IDS-iSYS, ADVIA Centaur) were overall in good clinical agreement with LC-MS/MS, even though the results obtained with all compared methods were not equivalent. CONCLUSIONS: In conclusion, in routine clinical laboratory both immunoassays and LC-MS/MS are useful for measuring 25-OH-vitamin D provided that these methods are correctly standardized and especially sample pretreatment is carefully performed. PMID- 23724632 TI - Vitamin D status in female students and its relation to calcium metabolism markers, lifestyles, and polymorphism in vitamin D receptor. AB - BACKGROUND: Vitamin D is essential for maintiiining bone health and growth throughout life. Vitamin D deficiency not only leads to bone metabolic diseases in children and adults but may increase the risk of many chronic diseases. The aim of this study was to evaluate the prevalence of vitamin D deficiency and its relation with vitamin D receptor (VDR) gene polymorphism. In addition the study included the evaluation of known risk factors and their correlation to the vitamin D status among girls aged 11 - 17 years in Rafsanjan during the winter of 2009. METHODS: In a cross-sectional study, 250 healthy female students (age range, 11 - 17 years) were selected by random sampling method. Fasting blood samples were collected and the concentration of serum 25 (OH) vitamin D3, PTH, ionized Ca, P, ALP, and VDR gene polymorphism (exon 9) were evaluated. Values of 20 nmol/L were considered severe, 20.1 - 37.5 nmol/L moderate, 37.6 - 50 nmol/L mild deficiency, and 25 (OH) vitamin D3 levels higher than 50 nmol/L were considered normal. RESULTS: The results showed 59.6% of students suffered from vitamin D deficiency (14.4% severe, 24.4% moderate, and 20.8% mild deficiency). There was a significant relationship between serum levels of vitamin D with ionized Ca, PTH, ALP, type of clothing, and egg consumption, while no significant relationship was found between serum levels of vitamin D with age, residency, menstruation status, skin color, sun light exposure, body mass index, waist to hip ratio, exercise, physical activity, fish consumption, and polymorphisms in exon 9 of VDR gene. CONCLUSIONS: This study indicated a high prevalence of vitamin D deficiency in female students in a sunny city, Rafsanjan in winter. Low sun light exposure, coverage especially veil, and low intake vitamin D are important factors in vitamin D deficiency in studied subjects. PMID- 23724633 TI - Donor exposures in recipients of pooled platelet concentrates: a case-study in arithmetic, logic, "expert opinion", and the "peer review" process. AB - Advocacy for single-donor (rather than pooled) platelets has been based on the absolute increase in the risk of transfusion-transmitted infections (TTIs) from pooled (rather than single-donor) platelets in the population of platelet transfusion recipients. A recent study published in a prestigious medical journal advocated for pooled (rather than single-donor) platelets based on the relative increase in the risk of TTIs from pooled (rather than single-donor) platelets in patients transfused with any blood component. If this policy recommendation for use of pooled (rather than single-donor) platelets were followed in the US, there would be an annual increase in the risk of TTIs by 15-20 recipient infections for hepatitis B virus, 85-113 recipient infections for the next "West-Nile-virus like" pathogen, and 528-704 recipient infections for the next "human immunodeficiency-virus-like" pathogen to emerge in the future. We present the calculation of the increased risk and discuss the stark contrast between simple arithmetic and logic versus the end result of a process of "expert opinion" and "peer review". PMID- 23724634 TI - A case of hereditary spherocytosis misdiagnosed as pyruvate kinase deficient hemolytic anemia. AB - BACKGROUND: Hereditary spherocytosis (HS) and pyruvate kinase (PK) deficiency are the most common causes of congenital hemolytic anemia. We describe a case of HS with defective PK activity initially misdiagnosed as PK deficiency. METHODS: Hematologic investigation, SDS-PAGE analysis of red cell membrane proteins and sequencing of the PKLR gene were performed. RESULTS: The molecular characterization of the PKLR gene showed a heterozygous mutation 994G > A (Gly332Ser) associated with the promoter substitution -148C > T, whose role in the pathophysiology of PK deficiency is debated. Further investigations revealed spectrin deficiency; the family study demonstrated that the hemolysis was exclusively attributable to HS. CONCLUSIONS: The present case pinpoints to the need for extensive family investigations to correctly diagnose chronic hemolytic anemia, in particular when molecular characterization does not fully explain the clinical phenotype. PMID- 23724635 TI - Visceral leishmaniasis with massive hematemesis and peripheral blood involvement. AB - BACKGROUND: Visceral leishmaniasis can create some unusual clinical manifestations such as hematemesis and also, in rare cases, with peripheral blood involvement. Therefore, these manifestations can be considered in early diagnosis of the disease. CASE PRESENTATION: A 9 year-old boy was admitted to Imam Reza teaching hospital in Mashhad, Iran in 2010 with fever, sweating, abdominal distention, massive hematemesis, weight loss, huge splenomegaly and hepatomegaly. Peripheral blood smears and also bone marrow aspiration (BMA) and biopsy showed leishman bodies in monocytes/macophges. CONCLUSIONS: Although the sensitivity of blood smears for diagnosis of the parasite is low, it is an easy and accessible test we advise to perform for all patients suspected to visceral leishmaniasis in endemic area. We also suggest screening tests for visceral leishmaniasis to be considered in blood donors in the endemic areas. PMID- 23724636 TI - Imbalance of circulating T-lymphocyte subpopulation in gastric cancer patients correlated with performance status. AB - BACKGROUND: Performance status is an attempt to quantify cancer patients' general well-being. This measure is used to determine whether they can receive chemotherapy. This study was to determine the expression of T-lymphocyte subpopulation in patients with gastric cancer and the relationship between T lymphocyte subpopulation expression and patient performance status. METHODS: Flow cytometry was used to detect the T-lymphocyte subsets presented in peripheral blood in untreated patients with gastric cancer (n = 57) and healthy controls (n = 27). The gastric cancer patients were assessed with ECOG score and divided into two groups by score > 2 (n = 8) and score < or = 2 (n = 16). Spearman's rank correlation was used to determine the relationship between the proportion of T lymphocytes and ECOG score. In addition, the clinical data of gastric cancer patients were Analyzed. RESULTS: The percentage of CD8+ and CD4+ T-cells among lymphocytes was higher and lower, respectively, in advanced gastric cancer patients than that in early gastric cancer patients (p < 0.05). Furthermore, the percentage of CD8+ and CD4+ cells among lymphocytes was higher and lower in advanced gastric cancer patients with PS > 2 and PS < or = 2, respectively (p < 0.05). However, no significant difference of CD8+ and CD4+ lymphocytes was found among the advanced gastric cancer patients with PS < or = 2, early gastric cancer patients, and healthy controls. CONCLUSIONS: Our results show that the determinants of the T-lymphocyte subpopulation in gastric cancer patients were of value in assessing performance status. We considered CD4+ and CD8+ T-lymphocytes to be a representative and stable parameter in quantifying cancer patients' general well-being, which could be used to determine whether they can receive chemotherapy and/or whether dose adjustment is necessary. PMID- 23724637 TI - Relationship between serum bilirubin and remnant lipoprotein cholesterol level. AB - BACKGROUND: Bilirubin has antioxidant properties and is known to have a role in the prevention of cardiovascular disease. Bilirubin is known to be negatively associated with serum parameters related to atherosclerosis. Triglyceride-rich lipoprotein is known to play an important role in the progression of atherosclerosis. The aim of the present study was to elucidate the relationship between serum bilirubin and serum remnant lipoprotein cholesterol (RLP-c). METHODS: We examined 270 Japanese males (mean age 64.8 years) without liver dysfunction and anemia from the Outpatient Clinic of Kinki University Hospital. Serum bilirubin, cholesterol, LDL cholesterol, HDL cholesterol, triglyceride and RLP-c levels were measured. RESULTS: Serum RLP-c level was significantly lower in patients in the high bilirubin group than those in the low bilirubin group. CONCLUSIONS: The findings of this study show that serum bilirubin within physiological levels may affect the serum RLP-c and suggest bilirubin may have a role in preventing atherosclerosis. PMID- 23724638 TI - Determination of levamisole in the plasma of patients with falciparum malaria using high-performance liquid chromatography. AB - BACKGROUND: The oral antihelmintic drug levamisole reduces sequestration of late stage parasites in falciparum malaria. Levamisole has been also identified as a cocaine adulterant. In the present study, authors developed a sensitive and selective HPLC-assay for the determination of levamisole in the plasma from patients with falciparum malaria. METHODS: Chromatographic separation was achieved by using a C18 column and with an isocratic elution system comprising phosphate buffer and acetonitrile. The eluate was monitored at 235 nm by diode array detection. RESULTS: The calibration curve for levamisole was linear in the range from 50 to 2000 ng/mL (r2 > 0.999). The limit of quantification was 28 ng/mL and the inter- and intraday coefficients of variation were less than 7%. No interference from commonly prescribed malaria treatments was observed. CONCLUSIONS: The HPLC method is simple, rapid, and robust and is suited for monitoring levamisole patients in routine or toxicological studies. PMID- 23724639 TI - Laboratory tools for oligo-secretory myeloma diagnosis: capillary electrophoresis versus free light chain assay. AB - BACKGROUND: To investigate how capillary electrophoresis (CE) works in oligo secretory myeloma (OSM), we report a case here of OSM using multiple diagnostic methods including gel electrophoresis (GE), CE, and free light chain assay (sFLC). Also, we provide a brief review of laboratory methods to compare their diagnostic utilities in OSM. METHODS: A 72 year-old Korean male suffering from low back pain during the past 6 months was transferred to the department of neurosurgery in order to evaluate abnormal findings in an imaging study, suggesting plasma cell myeloma (PCM) with multiple bone metastasis. CE showed no suspicious M-component; however, it showed increased Kappa components and skewing Kappa/Lambda ratio (K/L). Bone marrow examination revealed plasma cells observed up to 70%, which were compatible with sFLC results. RESULTS: Based on these results, the diagnosis turned out to be OSM with multiple bone metastases. Thereafter, the patient started the first cycle of chemotherapy accompanied by palliative radiation therapy. CONCLUSIONS: In our case, sFLC showed abnormal Kappa and K/L results from both serum and urine specimen. Therefore, it seems to be more sensitive and appropriate than both GE and CE to diagnose OSM. PMID- 23724640 TI - [Strategy for keeping efficient expression and pharmacodynamics in reducing rAAV gene medicine immune response based on the decrease of vector dosage]. AB - How to reduce immune response is an unprecedented challenge for rAAV gene medicine. Recent studies suggested that lowering dosage of the vector used could reduce immune response caused by rAAV gene medicine. Nevertheless, it would also decrease the transgene expression, leading to failure of gene treatment. It is therefore important to take appropriate steps to maintain high gene expression level and pharmacodynamic, while the dosage of rAAV used is reduced. Here, steps to enhancing gene therapy, such as optimization of the administration, reconstruction of the viral vector and selection of the promoter, are discussed in order to achieve maximum outcome. PMID- 23724641 TI - [Targeting the substrate binding domain of polo-like kinase 1: advances in the study of PBD1 inhibitors]. AB - Polo-box domain 1 (PBD1) is a characteristic domain of polo-like kinase 1 (PLK1), which locates in C-terminal and can influence the catalytic activity and specific subcellular locations of PLK1. At present, most PLK1 inhibitors are developed to occupy the ATP pocket or its close sites. However, this kind of PLK1 inhibitors is difficult to pursue target selectivity and may encounter cross drug resistance with other kinase inhibitors due to the conserved sequence of ATP pocket. Recently, PBD1, with aberrant specificity in sequence and structure, has attracted enormous interests as the alternative target to the discovery of corresponding inhibitors for anti-tumor drugs. The structure and function of PBD1 as well as the advances of its inhibitors are reviewed in this paper. PMID- 23724642 TI - [Chemistry and biological activities of Viburnum odoratissimum]. AB - Viburnum odoratissimum is a folk medicinal plant, it can dredge the meridian passage and contains mainly diterpenes, triterpenes, flavonoids, sesquiterpenes, lignans, coumarin glycosides, etc. Vibsanin-type diterpenoids are the characteristic compounds of V. odoratissimum, and are divided into eleven membered ring, seven-membered ring, and rearrangement-type. Vibsanin B, vibsanin C and neovibsanin A are the representative compounds of the three subtypes of vibsanin-type diterpenoids respectively. V. odoratissimum has cytotoxic activity, antibacterial activity, fish piscicidal activity and activity of inhibiting the growth of plants, Cytotoxic activity is the main biological activity. PMID- 23724643 TI - [Research progress of transgenic Drosophila model of Alzheimer disease]. AB - Alzheimer disease (AD) is a common neurodegenerative disease. Drosophila has been regard as one of the ideal models for Alzheimer because of its unique advantage on genetic manipulation. AD transgenic drosophila models not only help to elucidate the pathogenesis of Alzheimer disease, but also provide potential screening models for drugs to treat the disease. In this review, we summarize the recent research progress using AD transgenic drosophila. PMID- 23724644 TI - [Bibenzyl from Dendrobium inhibits angiogenesis and its underlying mechanism]. AB - Bibenzyl is a type of active compounds abundant in Dendrobium. In the present study, we investigated the inhibitory effects of six bibenzyls isolated from Dendrobium species on vascular endothelial growth factor (VEGF)-induced tube formation in human umbilical vascular endothelial cells (HUVECs). All those bibenzyls inhibited VEGF-induced tube formation at 10 micromol x L(-1) except tristin, and of which moscatilin was found to have the strongest activity at the same concentration. The lowest effective concentration of moscatilin was 1 micromol x L(-1). Further results showed that moscatilin inhibited VEGF-induced capillary-like tube formation on HUVECs in a concentration-dependent manner. Western blotting results showed that moscatilin also inhibited VEGF-induced phosphorylation of VEGFR2 (Flk-1/KDR) and extracellular signal-regulated kinase 1/2 (ERK1/2). Further results showed that moscatilin inhibited VEGF-induced activation of c-Raf and MEK1/2, which are both upstream signals of ERK1/2. Taken together, results presented here demonstrated that moscatilin inhibited angiogenesis via blocking the activation of VEGFR2 (Flk-1/KDR) and c-Raf-MEK1/2 ERK1/2 signals. PMID- 23724645 TI - [Establishment of EV71 animal models with 2-week-old BALB/c mice]. AB - Animal model is very important for anti-EV71 (enterovirus 71) drug and vaccine development. 1-day-old suckling EV71 mouse model is the main in vivo model used in China. 1-day-old suckling EV71 mouse is too small to perform antiviral experiment. And the route of administration and dosage capacity are also restricted. A strong virulence EV71 virus strain was selected after screening from five EV71 strains with 1-day-old suckling mice. A mouse-adapted EV71 strain with increased virulence in 12-day-old suckling mice, EV71-M5, was generated after five serial passages of the parental EV71 strain in mice. Virus titers of EV71 infected mice heart, liver, spleen, lung, kidney, small intestine, brain and muscle tissue were determined by cytopathic effect (CPE) assay. The virus used in this model is the first isolated EV71 strain in China. And 2-week-old suckling mice were used in this model. This is a supplement for the EV71 animal model in China. Establishment of this EV71 model will provide an attractive platform for anti-EV71 vaccine and drug development. PMID- 23724646 TI - [Inhibitory effect of 8-prenylnaringenin on osteoclastogensis of bone marrow cells and bone resorption activity]. AB - This study is to investigate the effect of 8-prenylnaringenin (8-PNG) on osteoclastogensis of bone marrow cells and bone resorption activity of osteoclasts. Osteoclasts were separated from long bone marrow of newborn rabbits and cultured in alpha-MEM containing 10% FBS. 8-PNG was added into culture media at 1 x 10(-7), 1 x 10(-6), 1 x 10(-5) mol xL(-1), separately. 17beta-Estradiol (E2, 1 x 10(-7) mol x L(-7)) was used as positive control. T RAP staining and TRAP activity measurement were performed after 5 days, and the bone resorption pits were analyzed after 7 days. Annexin V staining for the detection of apoptotic osteoclasts was performed after 2, 4, 8, 12, 24, 36 and 48 h separately. The mRNA expression level of TRAP and cathepsin K (CTSK) was measured by real-time RT-PCR. 8-PNG significantly reduced the number of osteoclasts which was TRAP staining positive and with more than three nucleus, the area and number of bone resorption pits decreased obviously in 8-PNG-supplemented groups. The apoptosis rate peaked earlier in the 8-PNG-supplemented groups and the mRNA expression level of TRAP and CTSK decreased significantly. All these inhibitory effects were in a dose dependent manner, the highest effect was obtained by 1 x 10(-5) mol x L(-1) 8-PNG. 8-PNG inhibits bone resorption activity of osteoclasts by inducing osteoclast apoptosis and inhibiting the gene expression and enzyme activity including TRAP and CTSK, and restrains bone marrow cells to osteoclast differentiation. PMID- 23724647 TI - [The long lasting effect of the murine fibroblast growth factor-21 on blood glucose control of diabetic animals]. AB - Insulin is the most common medicine used for diabetic patients, unfortunately, its effective time is short, even the long-acting insulin cannot obtain a satisfactory effect. Fibroblast growth factor (FGF)-21 is a recently discovered glucose mediator and expected to be a potential anti-diabetic drug that does not rely on insulin. In this study, db/db mice were used as the type 2 diabetic model to examine whether mFGF-21 has the long-term blood lowering effect on the animal model. The results showed that mFGF-21 could stably maintain the blood glucose at normal level for a long-term in a dose-dependent manner. Administration of mFGF 21 once a day with three doses (0.125, 0.25 and 0.5 mg x kg(-1)) could maintain blood glucose of the model animals at normal level for at least 24 h. Administration of mFGF-21 every two days with the same doses could maintain blood glucose of the model animals at normal level for at least 48 h, although it took longer time for blood glucose to reach to normal level depending on doses used (twenty injections for 0.125 mg x kg(-1) and 0.25 mg x kg(-1) doses, ten injections for 0.5 mg x kg(-1) dose). Surprisingly, the blood glucose of the treated model animals still maintained at normal level for 24 h after the experiment terminated. Glycosylated hemoglobin level of the animals treated with mFGF-21, which represented long-term glucose status, decreased significantly compared to the control group and the insulin group. The results suggest that FGF 21 has potential to become a long-acting and potent anti-diabetic drug. PMID- 23724648 TI - [Plasmid-mediated expression of kallistatin and its biological activity in lung cancer related cells]. AB - This study is to investigate whether naked plasmid DNA can effectively transfect lung cancer related cells and express human kallistatin, an endogenous protein that inhibits angiogenesis and tumor growth, and to explore the biological activity of the low-level expressed kallistatin to lung cancer in vitro and in vivo. The plasmids were delivered with Lipofectamine 2000 to transfect various lung cancer related cells. Kal expression was determined by ELISA. The biological effects of Kal expression on proliferation, migration and apoptosis rate of the cells were examined. In subcutaneous NCI-H446 xenograft model, pKal was injected directly into tumors, the changes of CD34, Ki-67 and E-cadherin expression were detected with immunohistochemical assay, the tumor apoptosis was analyzed with TUNEL assay. Both the endothelial cell and lung cancer cells could express kallistatin after plasmid transfection. The proliferation and migration of human umbilical vein endothelial cells were inhibited, but the apoptosis rate was not affected. The proliferation rates of all the three tested lung cancer cells, such as NCI-H446, NCI-H460 and A549, were inhibited, and their apoptosis rates were enhanced, but different cells behaved differently. In subcutaneous NCI-H446 xenograft model, intratumor injection of pKal inhibited the growth of lung cancer by reducing angiogenesis and proliferation of tumor cells. In conclusion, this study demonstrated the efficacy of plasmid-mediated expression of kallistatin to lung cancer related cells, thus providing a basis for their clinical application in the treatment of lung cancer. PMID- 23724649 TI - [Molecular design, structural analysis and bactericidal activity of derivatives of antimicrobial peptide buforin II]. AB - A novel peptide, named BF2-X, was designed based on the structure-activity analysis of an analogue of Buforin II, named BF2-A. The BF2-X was a hybrid peptide containing the N-terminal residues 5 to 13 of BF2-A and three repeats of the C-terminal regular alpha-helical motif RLLR, and the residues 8 valine were replaced by leucine. The results of bioinformatics analysis had showed that compared with BF2-A, the helicity, positive charge, hydrophobicity rate and C terminal amphipathy of BF2-X had remarkably enhanced. Both peptides showed a random coil structure in an aqueous solution, while displaying a typical alpha helical structure in 50% trifluoroethanol solution (a membrane mimic condition). BF2-X exhibited higher alpha-helical contents than BF2-A in hydrophobic environment. BF2-X displayed potent antimicrobial activities against a broad spectrum of microorganisms. And BF2-X showed stronger antimicrobial activities against bacteria tested than parent peptide BF2-A. These results suggest that the alpha-helical content was directly correlated with the enhanced antibacterial activity. Both peptides had no hemolytic action on mouse erythrocyte. PMID- 23724650 TI - [Synthesis and biological evaluation of novel diphenyl methane sulfinyl and diphenylthio-acetamide derivatives]. AB - According to the structure-activity relationships (SARs) of modafinil, a therapeutic drug of hypnolepsy, we designed and synthesized two series of compounds 2-[(diphenylmethane)sulfinyl] acetamides and 2-[(diphenylmethyl)thio] acetamides, and measured their biological activities. The target compounds (6a 6o) were synthesized beginning with diphenyl carbinol by substitution, oxidation, acylation and so on. Their structures were confirmed by ESI-MS, 1H NMR and elemental analysis. The central stimulatory effects of the target compounds were determined by the independent activity assay on mice. Compounds 6c, 6f and 6n have considerable activities, while the central stimulative effect of 6h is slightly better than the positive control modafinil. PMID- 23724651 TI - [Phenolic constituents from Lysimachia patungensis]. AB - To study the chemical constituents of Lysimachia patungensis Hand.-Mazz., silica gel column chromatography, reverse phase ODS column chromatography, MCI and Sephadex LH-20, were used to separate the 95% EtOH extract of the whole plant of Lysimachia patungensis Hand.-Mazz.. The structures of the isolated compounds have been established on the basis of chemical and NMR spectroscopic evidence as well as ESI-MS in some cases. Twelve phenolic compounds were obtained and identified as quercetin-3, 3'-di- O-alpha-L-rhamnoside (1), myricetrin (2), quercitrin (3), rutin (4), 2-hydroxynaringenin-4'-O-glucopyranoside (5), naringenin 7-O glucopyranoside (6), liquiritin apioside (7), licochalcone B (8), tetrahydroxymethoxy chalcone (9), methyl-p-coumarate (10), 2, 4, 6-trihydroxy acetophenone-2-O-glucopyranoside (11) and vaccihein A (12). Among them, compound 1 is a new compound, and compounds 5, 11 and 12 are isolated from the genus Lysimachia L. for the first time, and the others are isolated from the plant for the first time. PMID- 23724652 TI - [In vitro metabolism of forscolin isolated from Coleus forskohlii]. AB - This paper is to report the study of the metabolism of forscolin in plasma and liver microsomes for guiding clinical therapy. Forscolin was quantified by HPLC MS/MS. The metabolic stability of forscolin in rat, Beagle dog, monkey and human plasma and liver microsomes, mediated enzymes of forscolin and its inhibition on cytochrome P450 isoforms in human liver microsomes were studied. Results showed that forscolin was not metabolized in plasma of the four species but metabolized in liver microsomes of the four species. The t1/2 of forscolin in rat, Beagle dog, monkey and human liver microsomes were (52.0 +/- 15.0), (51.2 +/- 5.9), (6.0 +/- 0.2) and (11.9 +/- 1.8) min; CL(int) were (75.6 +/- 18.7), (60.9 +/- 6.8), (513.8 +/- 14.3) and (176.2 +/- 25.6) mL x min(-1) x kg(-1); CL were (34.8 +/- 4.5), (23.3 +/- 1.0), (40.3 +/- 0.5) and (17.9 +/- 0.3) mL x min(-1) x kg(-1), respectively. Forscolin was metabolized by CYP3A4 in human liver microsomes. There was definite inhibition on CYP3A4 at the concentrations of forscolin between 0.1 ng x mL(-1) and 5 microg x mL(-1). Therefore, forscolin is rapidly excreted from liver microsomes. Attention should be paid to the drug interaction when forscolin was used along with other drugs metabolized by CYP3A4 in clinics. PMID- 23724653 TI - [Pharmacokinetics of tenofovir in Beagle dogs after oral dosing of tenofovir dipivoxil fumarate using HPLC-MS/MS analysis]. AB - A simple, rapid and sensitive method was developed for the quantification of tenofovir in plasma of Beagle dogs using HPLC-MS/MS analysis. The analytes tenofovir and internal standard (IS) adefovir were separated on a Zorbax SB-C18 column (3.5 microm, 100 mm x 2.1 mm, Agilent, USA) with mobile phase of methanol/water containing 0.3% formic acid using a gradient elution mode at a flow rate of 0.2 mL x min(-1). The plasma sample preparation was a simple deproteinization by the addition of 20% trichloroacetic acid followed by centrifugation. The detection was performed in positive selected reaction monitoring (SRM) mode with an electrospray ionization (ESI) source. The reactions monitored were m/z 288.1-176.2 for tenofovir and m/z 274.1-162.2 for adefovir (IS). Linear detection responses were obtained for tenofovir ranging from 10 to 5 000 ng x mL(-1). The intra- and inter-day precisions (RSD%) was no more than 6.3% with high recovery and good stability for the quantification, indicating the present method was specific, fast, accurate and reliable. The method was successfully applied to the pharmacokinetic study of two tenofovir agents. Tenofovir dipivoxil fumarate (BP0018, test agent) and tenofovir disoproxil fumarate (reference agent) were orally administrated to 8 Beagle dogs according to the 2 x 2 crossover design. Comparing with the reference agent, the longer MRT and t1/2 were obtained in the group of BP0018, while no significant difference was observed in AUC(0-t), AUC(0-infinity), C(max) and t(max) between them, suggesting that tenofovir dipivoxil fumarate was bioequivalent to the tenofovir disoproxil fumarate in Beagle dogs. PMID- 23724654 TI - [Simultaneous determination of erdosteine and its active metabolite in human plasma by liquid chromatography-tandem mass spectrometry with pre-column derivatization]. AB - A sensitive, rapid and accurate liquid chromatography-tandem mass spectrometric (LC-MS/MS) method with pre-column derivatization was developed for the simultaneous determination of erdosteine and its thiol-containing active metabolite in human plasma. Paracetamol and captopril were chosen as the internal standard of erdosteine and its active metabolite, respectively. Aliquots of 100 microL plasma sample were derivatized by 2-bromine-3'-methoxy acetophenone, then separated on an Agilent XDB-C18 (50 mm x 4.6 mm ID, 1.8 microm) column using 0.1% formic acid methanol--0.1% formic acid 5 mmol x L(-1) ammonium acetate as mobile phase, in a gradient mode. Detection of erdosteine and its active metabolite were achieved by ESI MS/MS in the positive ion mode. The linear calibration curves for erdosteine and its active metabolite were obtained in the concentration ranges of 5-3 000 ng x mL(-1) and 5-10 000 ng x mL(-1), respectively. The lower limit of quantification of erdosteine and its active metabolite were both 5.00 ng x mL( 1). The pharmacokinetic results of erdosteine and its thiol-containing active metabolite showed that the area under curve (AUC) of the thiol-containing active metabolite was 6.2 times of that of erdosteine after a single oral dose of 600 mg erdosteine tables in 32 healthy volunteers, The mean residence time (MRT) of the thiol-containing active metabolite was (7.51 +/- 0.788) h, which provided a pharmacokinetic basis for the rational dosage regimen. PMID- 23724655 TI - [Identification of the related substances in fasudil hydrochloride with hyphenated techniques]. AB - The study aims to identify the related substances in fasudil hydrochloride by hyphenated techniques. A WondaSil C18 (250 mm x 4.6 mm, 5 microm) column was used for the separation of the related substances with a mixture of methanol and ammonium acetate buffer solution as the mobile phase by gradient elution. The structures of the related substances were speculated by electrospray positive ionization LC-TOF/MS accurate ion mass and MS/MS determination and elucidation, and verified further through synthesis and spectroscopic analysis. Fasudil hydrochloride and the related substances were separated under the established HPLC condition. Three related substances in fasudil hydrochloride were characterized by hyphenated techniques. The hyphenated LC-MS method is useful for the identification of related substances in fasudil hydrochloride and the results obtained are valuable for its manufacturing process and quality control. PMID- 23724656 TI - [Pharmacokinetics of tramadol hydrochloride in the extracellular fluid of mouse frontal cortex studied by in vivo microdialysis]. AB - The paper aims to explore the studying method for the pharmacokinetics of drugs in target organs, the pharmacokinetic process of tramadol hydrochloride in the extracellular fluid of frontal cortex (FrCx) of mice was investigated. Six male mice (Kunming strain) were anaesthetized (urethane, 1.8 g x kg(-1), ip) and secured on a stereotaxic frame. A microdialysis probe was implanted into the FrCx and perfused with artificial cerebrospinal fluid at a flow rate of 2 microL x min(-1). One hour later, mice were administrated (ip) with tramadol hydrochloride (50 mg x kg(-1)) and dialysates were collected continuously at 12-min intervals (24 microL each) for 6 h. The tramadol concentration in dialysates was determined by HPLC-Ultraviolet detection method, and the concentration-time curve and pharmacokinetic parameters of tramadol were calculated with DAS software. The results showed that the pharmacokinetic process of tramadol in the FrCx extracellular fluid of mice was fitted to a two-compartment open model, and the main pharmacokinetic parameters t1/2alpha, t1/2beta, t(max), C(max) and AUC(0 infinity) were (0.27 +/- 0.05) h, (2.72 +/- 0.24) h, (0.50 +/- 0.10) h, (2 110.37 +/- 291.22) microg x L(-1) and (4 474.51 +/- 441.79) microg x L(-1) x h, respectively. In conclusion, a studying method for pharmacokinetics of drugs in the target organ is established, which is simple and feasible. Tramadol hydrochloride shows a two-compartment model in the extracellular fluid of the mouse FrCx, and the distribution- and elimination half-life are 0.5 h and 2.7 h, respectively. PMID- 23724657 TI - [Polybasic research on the biopharmaceutical characteristics of 20 (S) protopanaxadiol]. AB - In this study, the biopharmaceutical properties of 20 (S)-protopanaxadiol (PPD) were studied. Firstly, the equilibrium solubility and apparent oil/water partition coefficient of PPD were used to predict the absorption in vivo. Meanwhile the membrane permeability and absorption window were studied by Caco-2 cell model and single-pass intestinal perfusion model. Furthermore, the bioavailability and metabolism were combined to study the absorption properties and metabolic properties in vivo. All of them were used to provide theoretical and practical foundation for designing PPD preparation. The results showed that PPD is poorly water-soluble, and the equilibrium solubility in water is only 35.24 mg x L(-1). The oil-water partition coefficient is 46.21 (logP = 1.66). By Caco-2 cell model, the results showed PPD uptake in general, and it also has efflux. By in situ intestinal perfusion model, the results showed that the absorption of PPD in the intestine is good, and the effective permeability coefficient were duodenum > jejunum > ileum > colon. The oral bioavailability of PPD was 29.39%. It was not well. Metabolic studies showed PPD in vivo presented a wide spread metabolism. So the main factors that restricted oral bioavailability of PPD were the poor solubility and first-pass effect. PMID- 23724658 TI - [Cellular toxicity and anti-tumor efficacy of iRGD modified doxorubixin loaded sterically stabilized liposomes]. AB - iRGD-modified sterically stabilized liposomes loaded doxorubicin (iRGD-SSL-DOX) were prepared and their cellular toxicity and anti-tumor efficacy were evaluated, comparing to doxorubixin loaded sterically stabilized liposomes (SSL-DOX) and RGD modified doxorubixin loaded sterically stabilized liposomes (RGD-SSL-DOX). The iRGD peptide, with both tumor targeting and cell penetrating functions, was conjugated to DSPE-PEG-NHS and DSPE-PEG-iRGD was obtained. DSPE-PEG-RGD was gained in the same way. iRGD-SSL-DOX, RGD-SSL-DOX and SSL-DOX were prepared by ammonium sulfate gradient method. The size and zeta potential of the liposomes were characterized by dynamic laser light scattering. The cellular toxicity study was done on B16 melanoma cell line and the anti-tumor efficacy study was carried on B16 cell line bearing C57BL/6 mice. The results showed that the particle sizes of liposomes were all around 90-100 nm. DOX entrapment efficiency was above 95%. The formulations were with good preparation reproducibility. iRGD-SSL-DOX showed no significant difference in B16 cellular toxicity with SSL-DOX and RGD-SSL-DOX, but the anti-tumor efficacy on B16 melanoma bearing C57BL/6 mice was significantly better than that of SSL-DOX, similar as that of RGD-SSL-DOX. Therefore, iRGD modified liposomes loaded DOX would be a promising drug delivery system for tumor therapy. PMID- 23724659 TI - [Intestinal absorption kinetics of flurbiprofen in rats]. AB - To study the in situ intestinal absorption kinetics of flrubiprofen in rats, the absorption of flurbiprofen in small intestine (duodenum, jejunum and ileum) and colon of rats was investigated using in situ single-pass perfusion method and the drug content was measured by HPLC. The effects of drug concentration on the intestinal absorption were investigated. The K(a) and P(app) values of flurbiprofen in the small intestine and colon had no significant difference (P > 0.05). Drug concentration (4.0, 10.0 and 16.0 mg x L(-1)) had no significant influence on the K(a) values (P > 0.05). However, when concentration was 4.0 mg x L(-1) and 10.0 mg x L(-1), significant effect on the P(app) values (P < 0.05) was found, but significant effect on the P(app) values was not shown between 10.0 mg x L(-1) and 16.0 mg x L(-1) (P > 0.05). The K(a) and P(app) values of flurbiprofen on the perfusion flow rate had significant difference (P < 0.05). Flurbiprofen could be absorbed at all segments of the intestine in rats and had no special absorption window. The absorption of flurbiprofen complies with the facilitated diffusion in the general intestinal segments, and accompany with the cytopsistransport mechanism probably. The perfusion flow rate had significant effect on the K(a) and P(app). PMID- 23724660 TI - [Macroscopic and microscopic characteristics of Chinese caterpillar fungus]. AB - Chinese Caterpillar Fungus (CCF) is one of the rare Chinese traditional drugs. As the resource is reducing sharply, the price is rising higher and higher, and there have been much more adulterants in the markets, but until now we don't have a scientific and accurate research on the identification study for this drug. On the basis of resource investigation, during the study of the samples collected by ourselves and the specimens stored in the museum, using the macroscopic and microscopic methods, referring to the literatures of entomology, emphasizing on the characteristics of polypide part, we have studied this species in detail of the macroscopic characters such as the insertion position of the stroma part, the annulations and segments of the caterpillar, the abdominal leg, the pinaculum, and the microscopic characters of the body wall; firstly added the microscopic character of the crotchets on the planta of abdominal leg. The result turned out that the characters which we have studied are regular and stable, and it have laid the foundation for the powder products and patent medicines which have used the crude drug of CCF. PMID- 23724661 TI - [Effect of rhGH on JAK2-STAT3 signal pathway after GHR was down-regulated by siRNA in gastric cancer cell]. AB - To investigate the effect of recombinant human growth hormone (rhGH) on JAK2 STAT3 pathway and the growth of gastric cancer cell lines at different GHR expression status, the eukaryotic expression vector targeting human GHR (pGPU6/GFP/Neo-shGHR and pGPU6/GFP/Neo-scramble) was constructed and transfected into MGC803 cells by Lipofectamine 2000. Stable expressive cell lines were obtained by G418 screening. The expression of GHR was analyzed by Western blotting. After being stimulated with rhGH, cell growth was detected by MTT assay. Cell cycle and apoptosis were examined by flow cytometry. The components of JAK2/STAT3 signaling pathway were detected by Western blotting. There is no significant difference of GHR expression between MGC803 and pGPU6/GFP/Neo scramble-transfected cells (named as MGC803-NC) (P > 0.05). Compared with MGC803, the GHR expression in pGPU6/GFP/Neo-shGHR-transfected cells (named as MGC803 shGHR) decreased significantly (protein decreased 50%). The cells were treated with rhGH at 0, 150 and 300 ng x mL(-1), the growth rate of MGC803 and MGC803-NC increased significantly, PI and the number of G2/M phase cells all increased significantly, and apoptosis decreased significantly. Western blotting revealed that the expression of pJAK2 and pSTAT3 was up-regulated after being treated with rhGH in MGC803 and MGC803-NC cells. In contrast, similar change was not observed in MGC803-shGHR cells. Knockdown of GHR gene may decrease the sensitivity of gastric cancer cells to rhGH, and down-regulating of components of the expression of JAK2/STAT3 signaling pathway may be the potential mechanisms. PMID- 23724662 TI - [Exploration of one-step preparation of Ganoderma lucidum multicomponent microemulsion]. AB - To explore one-step method for the preparation of Ganoderma lucidum multicomponent microemulsion, according to the dissolution characteristics of triterpenes and polysaccharides in Ganoderma lucidum, formulation of the microemulsion was optimized. The optimal blank microemulsion was used as a solvent to sonicate the Ganoderma lucidum powder to prepare the multicomponent microemulsion, besides, its physicochemical properties were compared with the microemulsion made by conventional method. The results showed that the multicomponent microemulsion was characterized as (43.32 +/- 6.82) nm in size, 0.173 +/- 0.025 in polydispersity index (PDI) and -(3.98 +/- 0.82) mV in zeta potential. The contents of Ganoderma lucidum triterpenes and polysaccharides were (5.95 +/- 0.32) and (7.58 +/- 0.44) mg x mL(-1), respectively. Sonicating Ganoderma lucidum powder by blank microemulsion could prepare the multicomponent microemulsion. Compared with the conventional method, this method is simple and low cost, which is suitable for industrial production. PMID- 23724663 TI - [Project design and implementation of the fourth national survey Chinese matiera medica resources]. AB - The planning of the fourth national survey on Chinese materia medica resources shall follow the requirement of "carrying out the national survey on Chinese materia medica resources, strengthening the construction of Chinese materia medica resources monitoring and information network" which is according to the document issued by the State Council. Based on the responsibilities of State Administration of Traditional Chinese Medicine which is "organizing the survey, promoting the resource-protection, keeping development and rational utilization", combined with the key problems that need to be solved in current medicinal industry, the related instructions issued by central leadership and the recommendations from NPC delegates, CPPCC members and experts, the planning shall make overall plans and top-level design for the new round of national survey on Chinese materia medica resources. PMID- 23724664 TI - [Pharmaceutical study on multi-component traditional Chinese medicines]. AB - Due to the limitation of science and technology in ancient times, traditional Chinese medicines (TCMs) could have prepared only in traditional dosage forms, such as pills, powders, ointments and pellets. Though studies on multi-component TCMs have become one of major development orientations of TCM, the druggability of their preparations has always been neglected. On the basis of two key difficulties--the integration of studies on multi-component TCMs and TCM theory as well as the evaluation on their druggability, the essay proposes methods and technologies that can be adopted in studies on multi-component TCM preparations, including the characteristic physicochemical property of multi-component TCMs and its correlation with forming process, the release-modified micro pill preparation technology based on prescription-symptom-dosage, and the evaluation technology on release of release-modified micro pill components based on mathematical set model. PMID- 23724665 TI - [New technologies used for Panax genus research]. AB - The authors reviewed the new technologies used for Panax genus research, including molecular identification technologies (especially for DNA barcoding), modern biotechnologies (e. g. the first generation and second generation sequencing technologies), and gene cloning and identification in this paper. These technologies have been successfully applied to species identification, transcriptome analysis, secondary metabolite biosynthetic pathway and the key enzyme function identification, indicating that the application of modern biotechnologies provide guarantee for the molecular identification of Panax genus. The application of modern biotechnologies also reveals the genetic information of transcriptome and functional genomics, and promotes the design of Panax plants genomic map. In summary, the application of the new technologies lay the foundation for clarifying the molecular mechanisms of ginsenoside biosynthesis and enforcing the in vitro synthesis of important natural products and new drugs in future. PMID- 23724666 TI - [Advance and prospect of studies on bioactivity and mechanism of Cordyceps fungi]. AB - Cordyceps is a precious medical fungi resource, with diverse metabolites and bioactive. There is huge prospect for its applicaiton in functional food and biomedicine fields. Cordyceps has abundant species resources, particularly Cordyceps sinensis is one of three most precious traditional Chinese restoratives in China. The essay summarizes the latest studies on bioactivity and mechanism of Cordyceps and its metabolites, and analyzes problems during R&D of the resources, in order to bring forth new ideas to future development. PMID- 23724667 TI - [Regulative mechanisms of tubular epithelial to mesenchymal transition and interventional effects of Chinese herbal medicine]. AB - Epithelial to mesenchymal transition (EMT) has been proposed as a key role leading to the progressive tubulo-interstitial fibrosis (TIF). The tubular EMT is an highly regulated process involving four key steps including: loss of epithelial cell adhesion, de novo smooth muscle actin expression and actin reorganization, disruption of tubular basement membrane,and enhanced cell migration and invasion. These crucial processes are closely connected to the relative actions on many signaling pathways in EMT. Additionally, increasing evidences suggest that some Chinese herbal medicines and their extracts, such as Astragali Radix, Cordyceps, Salvia miltiorrhiza, as well as Chinese. herbal prescriptions including Astragalus Angelica mixture and Supplementing Qi and activating blood circulation decoction, could intervene the related events controlling EMT both in vitro and in vivo. Chinese herbal medicines could ameliorate TIF by intervening the course of EMT. PMID- 23724668 TI - [Advance of studies on effect of resveratrol on activity of cytochrome P450]. AB - Resveratrol is a natural antioxidant, with such effects of anti-tumor, anti inflammation, and relief and prevention of cardiovascular disease. Studies on the effect of resveratrol on the activity of cytochrome P450 are of positive significance to combined clinical administration of resveratrol and other drugs. As there are many in vivo and in vitro experiments proving the effect of resveratrol on the activity of cytochrome P450 at present, the essay summarizes relevant studies in recent years. PMID- 23724669 TI - [Advance of studies on application of hapten antibodies]. AB - Hapten antibodies are active components of traditional Chinese medicines, have been widely applied in all of study fields of traditional Chinese medicine. First, hapten monoclonal antibodies could be designed into ELISA kits for quantitative analysis on the content of effective components in plant crude extracts or biological samples, which be applied for quality control and studies on pharmacokenetics of traditional Chinese medicines. Second, hapten monoclonal antibodies could be coupled with solid-phase carriers to generate immunoaffinity chromatography column, which could be used for knock-out extract preparation or pre-treatment of complicated sampless. Finally, a single-chain variable fragment antibody (scFV) gene segment of effective components of hapten monoclonal antibodies could be transformed into relative plant cells to gain new varieties with high-enrichment effective components, and thus achieve the molecular breeding of medicinal plants. PMID- 23724670 TI - [Analysis on codon usage of chloroplast genome of Eleutherococcus senticosus]. AB - OBJECTIVE: To analyze the codon usage of chloroplast genome and the influencing factor in Eleutherococcus senticosus. METHOD: Codon of 52 genes, which were selected from the chloroplast genome sequence of E. senticosus, was multivariate statistical and correspondence analyzed using CodonW and SPSS software. RESULT: GC content at the three position of codons by turns was 46.46%, 38.26%, 29.88%, whereas GC1 and GC2 had a significant correlation coefficient (P < 0.01). The correlation coefficient with GC12, and GC3 was 0.205 and was not significant correlated. There were 30 codons which relative synonymous codon usage was greater than 1 and 29 codons end with A and T. In the corresponding analysis, the first axis shows 10.35% variation. And there was significant correlation coefficient between ENC and GC3. The correlation coefficients with GC3 and ENC were -0.288 and 0.353, respectively. We defined 16 codons from 16 amino acids as the major preference codons in chloroplast genome of E. senticosus. CONCLUSION: The third positions for all codon are preferred to ending with A and T. The codon usage bias is formed under effect of mutation and selection, as well as other factors. But the selection will have a far greater impact than others. PMID- 23724671 TI - [Effects of bionic glue on experimental population dynamics of Paratrioza sinica and its natural enemies]. AB - OBJECTIVE: To find out whether and how the newly invented technique-bionic glue affects the main pest of wolf berry-Paratrioza sinica and its natural enemies Tamarixia lyciumi and Chrysopa septempunctata. METHOD: Spraying bionic glue in field when wolf berry just geminated, investigated the adults and nymphs of P. sinica and it's natural enemies: adults of T. lyciumi and eggs of C. septempunctata. RESULT AND CONCLUSION: Bionic glue can significantly reduce the population number of P. sinica, but with little impacts on its natural enemies of T. lyciumi and C. septempunctata, and more experiments are need for further research. PMID- 23724672 TI - [Interspecific association of companion species in Artemisia annua community in southwest of China]. AB - The interspecific association of companion species in Artemisia annua community in 48 region of southwest China was analyzed by variance analysis, chi2-test and association indices. The total related variance ratio among species in A. annua community was 2.05. Among 45 species pairs of 10 main species in the community, only 4 pairs showed significant negative correlations. Chi2 test, PC, OI, DI and AC values indicated pairs 1-8 (A. annua- A. lactiflora), 1-9 (A. annua- Setaria viridis) and 1-10 (A. annua- Bidens pilosa) showed a high correlations, and common utilization to non-restrictive resources. The results indicated that there was a significant positive correlation among species,and the community was at a stable stage, showed strong ability to human interference. PMID- 23724673 TI - [Content comparison of buddleoside and pectolinarin in Cirsium japonicum, C. leo and C. leducei]. AB - OBJECTIVE: To compare Cirsium japonicum characteristics with C. leo and C. leducei, along with the content of buddleoside and pectolinarin, and lay the foundation for the quality control of C. japonicum. METHOD: Samples were collected and the relevant drugs were bought. The samples were divided into root, stem, leaf and flower, and the content of buddleoside and pectolinarin was determine by the HPLC. Chromatographic column: Waters XBridge C18 (4.6 mm x 250 mm), mobile phase: methanol-water (45: 55), measurement wavelength: 326 nm, flow rate: 0.8 mL x min(-1), column temperature: 30 degrees C. RESULT AND CONDUSION: Standard curve equation of buddleoside: Y = 74 064X-47 748, R2 = 0.991. Standard curve equation of pectolinarin: Y = 1 711 64X - 180 707, R2 = 0.999. The content of buddleoside: C. japonicum leaf was 1.987 3%, C. leo leaf 1.412 2%, C. leducei leaf 0.149 2%. The content of buddleoside was lower in root and stem. Pectolinarin was not detected in the C. japonicum and C. leo. The pectolinarin content was 0.069 0% in C. leducei leaf. PMID- 23724674 TI - [Study on effective constituents extracted from fibrous roots of Salvia miltiorrhiza with degrading multi-enzymes from taishan Ganoderma lucidum]. AB - OBJECTIVE: To study the application of degrading multi-enzymes from Ganoderma lucidum in extracting effective constituents from fibrous roots of Salvia miltiorrhiza. METHOD: Effective constituents were extracted from fibrous roots by degrading multi-enzymes of wood fiber. The enzymatic parameters were optimized by the orthogonal design. RESULT: The extraction efficiencies of total tanshinones and total salvianolic acids in the extracts of fibrous roots of S. miltiorrhiza was obtained using optimum enzymolysis process reached 11.923%, 12.465%, respectively, which were 62.794%, 56.086% more than that by conventional non enzymatic hydrolysis. CONCLUSION: Degrading multi-enzymes of wood fiber can be used to fully extract effective constituents from fibrous roots of S. miltiorrhiza, which provides a new approach for recycling wastes of traditional Chinese medicines. PMID- 23724675 TI - [Quality evaluation of polysaccharide of ginseng injections from different manufacturers]. AB - OBJECTIVE: To evaluate injections of ginseng polysaccharide from 4 different manufacturers of 5 batches on the market. METHOD: Based on quality analysis, normal examinations were investigated, and monosaccharide composition and the molecular weight of polysaccharide in ginseng injections were performed. RESULT: Products from 4 different manufacturers were in line with the requirements of quality standard and Chinese Pharmacopeia (2010 edition). But there were great differences in molecular weight and monosaccharide composition. CONCLUSION: It is suggested to enhance the quality standard to ensure the medication safety use. PMID- 23724676 TI - [Simultaneous determination of ephedrine hydrochloride, D-pseudoephedrine and amygdalin in xiao'er pingchuan qutan granule by HPLC]. AB - OBJECTIVE: To establish an HPLC method for the determination of ephedrine hydrochloride, D-pseudo-ephedrine and amygdalin in Xiao'er Pingchuan Qutan granule. METHOD: Pheny ether chromatographic column (4.6 mm x 250 mm, 5 microm) was adopted, with acetonitrile-0.1% phosphoric acid (containing 0.1% three ethylamine) (3:97) as the mobile phase. The UV detection wavelength was at 210 nm, with the flow rate of 1 mL x min(-1), and column temperature was at 35 degrees C. RESULT: The linearity of ephedrine hydrochloride, D-pseudo-ephedrine and amygdalin ranged between 0.078 60-3.144 microg (r = 1.000 0), 0.103 4-2.068 microg (r = 0.999 7) and 0.430 5-3.157 microg (r = 0.999 8), respectively. Their average recoveries were 98.46% (RSD 1.1%), 103.0% (RSD 1.5%) and 97.15% (RSD 2.1%), respectively. CONCLUSION: The method is simple, stable and reliable that it can be used to determine the content of ephedrine hydrochloride, D-pseudo ephedrine and amygdalin in Xiao'er Pingchuan Qutan granule. PMID- 23724677 TI - [Determination of chlorogenic acid and baicalin in Yinhuang film-coated tablets by HPLC isocratic elution]. AB - OBJECTIVE: To establish an HPLC method for determination of chlorogenic acid and baicalin in Yinhuang film-coated tablets. METHOD: HPLC isocratic elution was adopted, with the C18 column (4.6 mm x 250 mm, 5 microm) as the chromatographic column, methanol-water-phosphoric acid (45: 55: 0.2) as the mobile phase. The flow rate was set at 1.0 mL x min(-1), and column temperature was set at 30 degrees C. The detection wavelength was 328 nm, and the sample size was 20 microL. RESULT: At concentrations ranging between 2.200-44.00, 24.20-242.0 mg x L(-1), peak area of chlorogenic acid and baicalin showed good linear relationship, the average recoveries were 99.63% (RSD 1.8%, n = 9) and 99.72% (RSD 1.9%, n = 9), respectively. CONCLUSION: The method is simple that it can accurately measure the content of chlorogenic acid and baicalin in Yinhuang film coated tablets. PMID- 23724678 TI - [Study on determination of anthraquinones in dachengqi tang residues of Magnolia officinalis and Citrus aurantium removed in decoction process]. AB - OBJECTIVE: The traditional decoction method of Dachengqi Tang is that "First boiling Magnolia officinalis and Citrus aurantium with a pipeful of water, taking out five litres from the decoction, removing residues, adding rheum officinale, boiling again, taking out two litres from it, removing residues, adding mirabilite, boiling it with low fire". According to it, residues of M. officinalis and C. aurantium should be removed after decocting. This essay aims to study the content of anthraquinones, in order to proof whether the removal of residues of M. officinalis and C. aurantium is scientific. METHOD: The traditional method was adopted to prepare Dachengqi Tang. Decoction A (original method) was obtained by removing residues of M. officinalis and C. aurantium, whereas decoction B was obtained without removing residues of M. officinalis and C. aurantium. The content of anthraquinones of both methods was determined with HPLC. RESULT: The content of both combined and free anthraquinones in decoction A was higher than that of decoction B. The content of total anthraquinones in residues of decoction A was lower than that of residue B. CONCLUSION: The traditional decoction method of removing residues of M. officinalis and C. aurantium from Dachengqi Tang is scientific, because it improves the dissolution rate of effective ingredients, which provides a theoretical basis for effective substances of the drug. PMID- 23724679 TI - New hydrolysable tannin from Cibotium barometz. AB - OBJECTIVE: To study the chemical constituents from Cibotium batometz. METHOD: Column chromatograph and HPLC were used to isolate and purify the compound, and the structure was elucidated on the basis of MS and NMR spectroscopic methods. RESULT: A new phenolic compound, 4-O-caffeoyl-D-glucopyranose, has been isolated from the rhizome of C. barometz. The structure of the new compound was elucidated on the basis of chemical and spectroscopic methods, including intensive 1D, 2D NMR and ESI-MS data analysis. CONCLUSION: 4-O-caffeoyl-D-glucopyranose was a new phenolic compound. PMID- 23724680 TI - [Chemical constituents from leaves of Nelumbo nucifera]. AB - To study the chemical constituents, twenty-seven compounds were isolated from the 70% ethanol extract from leaves of Nelumbo nucifera by modern chromatographic techniques. Their structures were identified as 10-octacosanol (1), beta sitosterol (2), 1-undecanol (3), 1-eicosanol (4), daucosterol (5), 6'-hydroxy 4,4'-dimethoxychalcone (6), 3,7,8-trimethoxy-1-hydroxy-xanthone (7), rhamnetin-3 O-beta-D-glucopyranoside (8), chrysoeriol-7-O-beta-D-glucoside (9), quercetin-3-O beta-D-glucopyranoside (10), quercetin-3-O-alpha-L-rhamnopyranosyl (11), hyperoside (12), quercetin-3-O-rutinoside (13), astragalin (14), isorhamnetin-3-O alpha-L-rhamnopyranosyl-(1--> 6)-[alpha-D-lyxopyranosyl-(1 --> 2) -beta-D glucopyranoside] (15), isorhamnetin-3-O-alpha-D-lyxopyranosyl-(1 --> 2) -beta-D glucopyranoside (16), isorhamnetin-3-O-beta-D-glucopyranoside (17), isorhamnetin 3-O-alpha-L-rhamnopyranosyl-(1 --> 6)-beta-D-glucopyranoside (18), quercetin (19), kaempferol (20), dehydronuciferine (21), roemerine (22), stigmast-7-en-3-O beta-D-glucopyranoside (23), stigmast-7-en-3beta-ol (24), and benzene-1,2-diol (25) on the basis of spectral data analysis. Compounds 1, 6, 7, 8, 24 and 25 were isolated from this plant for the first time, and compounds 15-18 were isolated from the leaves for the first time. Compounds 6, 8, 10, 11, 13 and 15 showed inhibitory activities against beta amyloid (1-42) by A-beta aggregation method with inhibition rates of (63.99 +/- 24.29)%, (79.61 +/- 4.49)%, (49.96 +/- 12.61)%, (101.19 +/- 8.19)%, (88.41+/-6.76)% and (72.48 +/- 8.97)%, respectively. PMID- 23724681 TI - [Chemical constituents from Hydrangea macrophylla]. AB - OBJECTIVE: To investigate chemical constituents from Chinese herbal medicine Hydrangea macrophylla. METHOD: The compounds were separated and purified by column chromatography over silica gel, ODS, and preparative HPLC. Their structures were identified by spectral methods including 1H, 13C-NMR and MS. RESULT: Eleven compounds were isolated and identified as zeorin, hopane-6, 22 diol (1), botulin (2), betulinic acid (3), 2-ethyl-3-methyl-maleimide-N-beta-D glucopyranoside (4), uridine (5), thymidine (6), adenosine (7), nicotinamide (8), methyl pyroglutamate (9), hydrangenol (10) and hydrangenol-4'-O-beta-D glucopyranoside (11), respectively. CONCLUSION: Compounds 14 and 7-9 were obtained from the genus Hydrangea for the first time. PMID- 23724682 TI - [Peptides analysis in digested edible bird's nest by HPLC-MS]. AB - Edible bird's nest contains lots of glycoproteins. The glycosylation inhomogeneity for glycoprotein often results in wide range of molecular weight and the difficulty for protein separation and charaterization. In this paper, proteins in the edible bird's nest were extracted using multiple extractions, and then digested by PNgase F and trypsin. The digest mixture was separated with HPLC, and peptides were identified based on MS/MS data searching. The results indicated that the extracted proteins were amount to 79.7% of total protein in the edible bird's nest. More than 20 species of peptides in the digested mixture were identified. The sequences of these peptides showed similarity with some proteins from Swiss-prot. The research indicated that deglycosylation, tryptic digestion coupled with HPLC-MS/MS is a proper strategy for characterization of proteins in the edible bird's nest. PMID- 23724683 TI - [Determination of rhynchophylline and isorhynchophylline in Uncaria rhynchophylla by HPLC]. AB - OBJECTIVE: To explore an HPLC method for determination of rhnchophylline and isorhnchophylline in Uncaria rhnchophylla. METHOD: An HPLC method has been developed for determination of rhnchophylline and isorhnchophylline. The transformation of rhnchophylline and isorhnchophylline after heating was also studied by HPLC-ESI-MS. RESULT: Good linearities of rhynchophylline and isorhynchophylline were 0.064-5.100, 0.064-5.110 mg, respectively. The average recoveries were from 87.51% to 88.83% for rhynchophylline and from 107.9% to 113.9% for isorhynchophylline. The recoveries of rhynchophylline and isorhnchophylline reference solutions after extraction were 12.60% and 40.00% in the reflux extraction procedure, respectively. While in the ultrasonic extraction procedure, the average recoveries of rhynchophylline and isorhynchophylline was from 99.48% to 103.2% and from 97.00% to 99.59%, resepectively. The recoveries of rhynchophylline and isorhnchophylline reference solutions after extraction were 47.08% and 51.03%, respectively. The unqualified recovery could be elucidated by HPLC-ESI-MS analysis, indicating that trhynchophylline could be transformed mostly into isorhynchophylline and a little amount of unkown composition, while isorhynchophylline could be transformed into rhynchophylline isocorynoxeine, corynoxeine and 22-O-beta-D-glucopyranosyl isocorynoxeinic acid during the extraction procedure. CONCLUSION: Ultrasonic extraction procedure was more sutble for HPLC determination of the content of rhynchophylline and isorhynchophylline in U. rhnchophylla, however, the recovery problems should be paid attention to when it comes to the determination. PMID- 23724684 TI - [Protective effect and mechanism of astragaloside IV on oxidative stress injury of mesangial cells]. AB - OBJECTIVE: To study the protective effect of astragaloside IV (AS IV) on H2O2 induced human mesangial cells (HMC), and further explore its molecular mechanism. METHOD: The cultured mesangial cells were divided into 5 groups: the normal control group, the H2O2 model group, the AS IV (12.5, 100 nmol x L(-1)) group and the Tempol (1 x 10(5) nmol x L(-1)) group. The MTT method was used to observe cell viability. Hoechst 33258 staining was used to observe the HMC apoptosis and DHE staining was used to detect the generation of reactive oxygen species (ROS). The flow cytometry was used to detect the changes in cell cycle. Western blot was used to detect the expression of Cyclin D1, CyclinA, p38, and T-p38. RESULT: H2O2 (1 x 10(5), 2 x 10(5), 3 x 10(5), and 4 x 10(5) nmol x L(-1)) could induce HMC oxidative stress injury, with significant decrease in the cell survival rate. AS IV (100 nmol x L(-1)) could significantly inhibit HMC oxidative stress injury induced by H2O2 (3 x 10(5) nmol x L(-1)), increase the survival rate of HMC cells, inhibit cell apoptosis, and decrease intracellular ROS production. AS IV could also increase the expression of Cyclin D1, recover normal cell proliferation, and decrease the expression of p38. CONCLUSION: AS IV can protect H2O2 induced oxidative stress injury in mesangial cells. Its mechanisms may be related to inhibiting the p38/MAPK signaling pathway, increasing the expression of Cyclin D1 and decreasing the intracellular ROS oxidative stress injury. PMID- 23724685 TI - [Effect of combination of sub-MIC sodium houttuyfonate and erythromycin on biofilm of Staphylococcus epidermidis]. AB - OBJECTIVE: To observe the effect of the combination of sub-MIC sodium houttuyfonate and erythromycin on biofilm of Staphylococcus epidermidis. METHOD: The serial dilution method was adopted to determine MIC of the combination of sodium houttuyfonate and erythromycin on S. epidermidis; the checkerboard method was used to evaluate the combination of sodium houttuyfonate and erythromycin on suspended bacteria of S. epidermidis; S. epidermidis biofilm was built in vitro, and XTT reduction assay was used to evaluate the effect of the combination of sub MIC sodium houttuyfonate and erythromycin on the adhesion of S. epidermidis and bacterial metabolism inside the biofilm. Microscope was applied to observe the impact the single administration and combination of the two medicines under sub MIC on biofilm morphology of S. epidermidis. RESULT: The MIC of sodium houttuyfonate and erythromycin were 62.5, 7.812 5 mg x L(-1), respectively. The combination of 1/8MIC sodium houttuyfonate and 1/2MIC erythronmycin showed a synergistic effect on S. epidermidis. Sodium houttuyfonate, erythromycin and their combination had an inhibitory effect on the adhesion and metabolism of S. epidermidis biofilm bacteria, and made impact on the morphology of S. epidermidis biofilm. CONCLUSION: The sub-MIC sodium houttuyfonate and erythromycin have an inhibitory effect on S. epidermidis biofilm. The combination of sodium houttuyfonate and erythromycin shows a synergistic effect in inhibiting suspended bacteria and biofilm of S. epidermidis, particularly in inhibiting the metabolism of S. epidermidis biofilm bacteria and impacting the morphology of biofilm. PMID- 23724686 TI - [Study on efficacy and mechanism of weiyangning pills against experimental gastric ulcer]. AB - OBJECTIVE: To study the efficacy and mechanism of Weiyangning pills against experimental gastric ulcer. METHOD: The gastric ulcer model were established by acetic acid, water-immersion stress, aspirin induction, pyloric ligation in rats, in order to observe the effect of Weiyangning pills against experimental gastric ulcer and study its effect on the content of nitric oxide (NO) and epidermal growth factor (EGF), gastric mucosal blood flow, the content of PGE2, gastric secretion, gastric acid content and the activity of pepsin. RESULT: Weiyangning pills markedly reduced index of gastric ulcers of various types, increased the content of NO, EGF, PGE2 and gastric mucosal blood flow, inhibited gastric secretion and gastric acid content, and decreased the activity of pepsin. CONCLUSION: Weiyangning pills has a significant effect against experimental gastric ulcer, which is related to the reduction of gastric mucosa damage factors (gastric acid and pepsin) and the increase in gastric mucosa's function as a barrier and its recovery effects, such as NO, EGF, PGE2 and gastric mucosal blood flow. PMID- 23724687 TI - [Pharmacokinetics of ferulic acid in transdermal delivery]. AB - OBJECTIVE: To study the pharmacokinetics of ferulic acid in transdermal delivery; the influence factors such as temperature, flow rate, and drug concentration on the probe recovery are also investigated to obtain accurate data. METHOD: The stability of in vitro and in vivo recovery was determined by loss but the influence factor on the recovery was determined by gain. Appling dermal microdialysis to ferulic acid analytes, the concentration of ferulic acid in the dialysate was detected by HPLC. RESULT: There is a significant effect on the probe recovery for the in vitro recovery is much bigger at a higher temperature. When the flow rate rises, the in vitro recovery is down at index rate instead. Within the measuring rage, the drug concentration doesn't have effect on the recovery. The steady and reproduce of recovery is well within the measuring time, and the average recovery of in vitro is (24.82 +/- 1.01)% without temperature control and in vivo is (16.50 +/- 1.92)%. The C(max) of ferulic acid is 86 min and MRT is 291 min after dermal administration. CONCLUSION: Dermal microdialyis can be used in the ferulic acid study. For the ferulic acid can permeate the corneum quciky, it is practical to develop a transdermal delivery. PMID- 23724688 TI - [Determination of endogenous amino acids in brain tissues after cerebral ischemia by RRLC-QQQ]. AB - OBJECTIVE: To establish a method to determine underivatized endogenous amino acids in brain tissues after cerebral ischemia based on RRLC-QQQ. METHOD: Diamonsil chromatographic column C18 (4.6 mm x 250 mm, 5 microm) was adopted to determine 12 amino acids in 15 min, with acetonitrile-0.1% formic acid for gradient elution. The flow rate was set at 0.5 mL x min(-1). With ESI as the ion source, positive ion scanning mode was adopted for multi-reaction monitoring. RESULT: Each amino acid standard curve (AAs) showed good linear relationship within the detection range (r > 0.996), with the limit of detection of less than 11%, the limit of quantitation of less than 3.09 microg x L(-1). The RSD of intra and inter-day precisions at high, middle and low concentrations were less than 11%. CONCLUSION: The determination results of actual samples showed that compared with the levels of AAs of the sham operation group, all of the remaining amino acids apart from N-acetyl-aspartate increased in brain tissues. Some amino acids showed significant changes in a time-dependent manner after the operation. The method is so simple, rapid and sensitive that it can be used for finding biological metabolite markers of cerebral ischemia, and exploring cerebral ischemia molecular mechanisms and synergistic mechanism of combined administration of multi-component traditional Chinese medicines. PMID- 23724689 TI - [Determination of theacrine in rat plasma by RP-HPLC]. AB - OBJECTIVE: To establish a method for the determination of theacrine in rat plasma after ig. administration of theacrine. METHOD: Blood sample was taken timely from the eyes canthus of rats. Plasma was isolated and the protein was precipitated by ethyl acetate. Then the plasma concentration of theacrine was determined with RP HPLC. Caffeine was used as the internal standard. The chromatographic conditions were as follows: Phenomenex Luna C18 (4.6 mm x 250 mm, 5 microm) at 25 degrees C, a mixture of methanol-water (25: 75) as the mobile phase, at the flow rate of 1.0 mL x min(-1) and the detection wavelength of 290 nm. RESULT: The linear range of theacrine was 0.5-100 mg x L(-1) (R2 = 0.998 9). The lower limit of quantification was 0.5 mg x L(-1). The intra-day RSD was 1.49% 4.40% and inter day RSD was 0.80% -10.27%. The average extraction recoveries of theacrine were 90.3% -95.8% at concentrations of 0.5, 5.0, 50 mg x L(-1). The main pharmacokinetic parameters after ig. administration of theacrine at concentration of 30 mg x kg(-1) were as follow: C(max) (35.45 +/- 30 2.68) mg x L(-1), t(max) (0.51 +/- 0.13) h, t1/2 (3.13 +/- 1.37) h, AUC(0-infinity) (2.65.39 +/- 94.71) mg x L(-1) x h. CONCLUSION: The method has been confirmed to be simple, stable, reproducible and with high specificity, and can be used for the pharmacokinetic study of theacrine in rats. PMID- 23724690 TI - [Study on TLC identification of Dida commonly used in Tibetan medicine from different species]. AB - OBJECTIVE: To establish a method of TLC identification for Dida commonly used in Tibetan medicine from different species. METHOD: With silica gel G as the stationary phase, and chloroform-methanol (40: 1) as mobile phase, oleanolic acid from different species of Dida was separated and identified. RESULT: Oleanolic acid was detected in 70 kinds of Dida derived from the Gentianaceae Swertia, Halenia, Gentianopsis, Lomatogonium, and Saxifragaceae saxifrage, except for the saxifrage, there are some differences among different genera or subjection. CONCLUSION: This TLC method can be used for identification of oleanolic acid in Dida from different species except saxifrage. PMID- 23724691 TI - [Research on quality standards of zhuang medicine Lonicerae dasystylae flos]. AB - OBJECTIVE: To establish quality standard of Zhuang medicine Lonicera dasystyla, and provide scientific basis for the quality control of L. dasystyla. METHOD: Characteristics of materia medica, microscopic features, TLC indentification, inspection, extractum and determination of chlorogenic acid, macranthoidin B, dipsacoside B were carried out through the experience, microscopic, physical and chemical methods, respectively. The standard of quality control was formulated thereafter. RESULT: The characteristics of materia medica, microscopic features, TLC indentification were specified, the average contents of water, total ash, acid-insoluble ash, alcohol-soluble extracts, chlorogenic acid were 11.6%, 6.6%, 0.2% , 24.4%, 1.16%, respectively, the total amount of macranthoidin B and dipsacoside B was 3.13%. Quality standard of L. dasystyla was proposed according to experimental results. CONCLUSION: The quality of L. dasystyla can be controlled effectively with the quality standard. PMID- 23724692 TI - [Introduction of U.S. FDA mini-sentinel program]. AB - In China, all of traditional Chinese medicine injections should pass clinical trials I, II and III for their safety and effectiveness before coming into the market. However, these clinical tests are mostly restricted to standard treatment for specific groups, and conducted in strict accordance with clinical trial protocols. In the real world, as there are more changes in the post-market clinical application of traditional Chinese medicine injections than in the experiment environment, regulatory bodies set stricter requirements for the post market re-assessment on traditional Chinese medicine injections. Early-stage studies could only provide the most fundamental and restricted data of efficacy and safety of traditional Chinese medicine injections. In this essay, mini sentinel program of U. S. FDA is introduced in order to provide reference for large-sample-size post-market clinical safety monitoring studies for traditional Chinese medicine injections. PMID- 23724693 TI - [Application of network analysis in diseases and drug studies]. AB - A disease is rarely caused by a single virulence gene, but by an imbalanced regulatory network arising from dysfunction of multiple genes or their products. However, drugs intervene the occurrence and development of a disease by acting on multiple target points in the disease network and making a synergy effect on each target point, in order to achieve the therapeutic effect. Unlike traditional approaches focusing on a single molecule or pathway, network analysis with high throughput data provides a new perspective for studying disease pathobiology and pharmacological mechanisms, and brings forth new ideas for multi-component and multi-target-point pharmacologic mechanisms of traditional Chinese medicines, in three aspects-establishment of relevant disease and drug network, network decomposition, and biological significant of sub-network. PMID- 23724694 TI - [Chemoinformatics study on antibacterial activity of traditional Chinese medicine compounds]. AB - OBJECTIVE: The structure-activity relationship between traditional Chinese medicine (TCM) compounds and antibacterial activity was studied by chemoinformatics approach. METHOD: Cytoscape and its plug-in ChemViz were applied to compute the 2D chemical structure similarity and topological parameter TPSA (topological molecular polar surface area), which measures cell permeability of chemicals, between TCM compounds and clinical antibacterials. The overall degree of structure similarity was then calculated and represented by E-value for the eight categories of TCM compounds and the known antibacterials. RESULT: Our results indicated that flavonoids showed good structural similarity with antibacterials and appropriate cell permeability, compared with those of the TCM compounds of the other categories. As flavonoids were featured by good drug safety, it suggested that they can be regarded as the preferred lead compounds skeleton structure source for further antibacterials synthesis. CONCLUSION: The application of chemoinformatics helps explore the structure-activity relationship between TCM compounds and the antibacterial activity and search for suitable antibacterial lead compounds skeleton structure source. PMID- 23724695 TI - The effect of acupuncture on high blood pressure of patients using antihypertensive drugs. AB - Blood pressure control is an important component of cardiovascular disease prevention. Despite the advances in the treatment of hypertension; effective management remains poor. The combined use of multiple drug strategies fail to regulate blood pressure and chronic use of those agents cause severe side effects. New strategies are required to control high blood pressure. We aim in our study to research the effects of acupuncture treatment on blood pressure of hypertensive patients who have already been exposed to antihypertensive drug therapy for at least 24 months. Each patient was using 1-3 antihypertensive drug of a heterogeneous pharmacological group ranging from ACE inhibitors, diuretics, and beta blockers and the most common complaint of those patients were fatigue, dizziness, weakness, headache and joint pain, sleeping problems, cold hands and feet, edema, depression. We did not alter patients' diet (salt intake), physical activity or use of antihypertensive drugs. The study includes 24 male and 10 female patients. Ki 3 (Taixi), Liv 3 (Taichong), Sp 9 (Yinlingquan), L.I. 4 (Hegu), Ht 7 (Shenmen), St 36 (Zusanli), Sp 6 (Sanyinjiao), Ki 7 (Fulio), Lu 9 acupuncture points were needled. After being treated with acupuncture for one month in every two days for a total of 15 sessions, we found significant reductions (p ? 001) in both systolic (from 163.14 +/- 19.33 to 129.49 +/- 18.52) and diastolic (from 94.37 +/- 19.70 to 79.31 +/- 7.87) blood pressures of these patients. The aim here is not to compare the effectiveness of acupuncture and drug therapy on blood pressure, but to simply report that on patients currently using antihypertensive medication, acupuncture facilitated a significant reduction in blood pressure and reduced the patients complaints. We therefore conclude that our data strongly suggest that acupuncture should be in the hypertension treatment guidelines and widely used for blood pressure regulation. PMID- 23724696 TI - Treating angina pectoris by acupuncture therapy. AB - Acupuncture therapy on PC 6 (Neiguan) has a therapeutic effect on cardiac and chest ailments including angina pectoris. Additional beneficial acupuncture points are PC 4 (Ximen), HT 7 (Shenmen point), PC 7 (Daling point), PC 5 (Jianshi point), PC 3 (Quze point), CV 17 (Danzhong point), CV 6 (Qihai point), BL 15 (Xinshu point), L 20 (Pishu point), BL 17 (Geshu point), BL23 (Shenshu point), BL18 (Ganshu point), HT 5 (Tongli point), and ST36 (Zusanli point). Acupuncture not only quickly relieve the symptoms of acute angina pectoris, but also improve nitroglycerine's therapeutic effects. Therefore, it is an efficient simple therapeutic method used for emergency and for regular angina treatment. Review of studies on acupuncture therapy has shown effectiveness were between 80% to 96.2% that are almost as effective as conventional drug regimen. When compared with conventional medical treatment, the acupuncture therapy shows the obvious advantage of lacking, adverse side effects commonly associated with the Western anti-anginal drugs such as 1) Nitroglycerine (headache--63% with nitroglycerine patch and 50% with spray; syncope--4%; and dizziness--8% with patch; hypotension- 4% with patch; and increased angina 2% with patch). 2) Isosorbide mononitrate (dizziness--3 to 5%; nausea/vomiting--2 to 4% and other reactions including hypotension, and syncope even with small doses). 3) Propranolol (bradycardia, chest pain, hypotension, worsening of AV conduction disturbance, Raynaud's syndrome, mental depression, hyperglycemia, etc.). Many conventional anti-anginal medications cause inter-drug reactions with other medications the patients taking for other diseases. Whereas, acupuncture therapy does not pose such an interference with patient's medications. Nevertheless, surgery is still the treatment of choice when acupuncture or conventional drug therapy fails. Combination of conventional drug therapy and acupuncture would considerably decrease the frequency and the required dosage of drug taking, thereby decreasing the unpleasant side effects of the drug therapy. PMID- 23724697 TI - Factors significantly increasing or inhibiting early stages of malignant melanoma (M.M.) and non-invasive evaluation of new treatment by ingestion and external application of optimal doses of the most effective anti-M.M. substances: haritaki, cilantro, vitamin D3, nori, EPA with DHA, & application of special (+) solar energy stored paper, which reduced the M.M. active area & asbestos rapidly. AB - Sterilizing the pre-cancer skin of malignant melanoma (M.M.) with 70% Isopropyl alcohol intensified malignancy & the malignant response extended to surrounding normal looking skin, while sterilizing with 80% (vodka) or 12% (plum wine) ethyl alcohol completely inhibited M.M. in the area (both effects lasted for about 90 minutes initially). Burnt food (bread, vegetables, meat, and fish), a variety of smoked & non-smoked fish-skin, many animal's skin, pepper, Vitamin C over 75 mg, mango, pineapple, coconut, almond, sugars, Saccharine & Aspartame, garlic, onion, etc & Electromagnetic field from cellular phones worsened M.M. & induced abnormal M.M. response of surrounding skin. We found the following factors inhibit early stage of M.M. significantly: 1) Increasing normal cell telomere, by taking 500 mg Haritaki, often reached between 400-1150 ng& gradually diminished, but the M.M. response was completely inhibited until normal cell telomeres are reduced to 150 ng, which takes 6-8 hours. More than 70 mg Vitamin C, Orange Juice, & other high Vitamin C containing substances shouldn't be taken because they completely inhibit the effects of Haritaki. 2) We found Chrysotile asbestos & Tremolite asbestos (% of the Chrysotile amount) coexist. A special Cilantro tablet was used to remove asbestos & some toxic metals. 3) Vitamin D3 400 I.U. has a maximum inhibiting effect on M.M. but 800 I.U. or higher promotes malignancy. 4) Noricontaining Iodine, etc., was used. 5) EPA 180 mm with DHA 120 mg was most effectively used after metastasis to the surrounding skin was eliminated. When we combined 1 Cilantro tablet & Vitamin D3 400 I.U. withsmall Nori pieces & EPA with DHA, the effect of complete inhibition of M.M. lasted 9-11 hours. When these anti M.M.substances (Haritaki, Vitamin D3, Cilantro, Nori, EPA. with DHA) were taken together, the effect lasted 12-14 hoursand M.M. involvement in surrounding normal looking skin disappeared rapidly & original dark brown or black are as satisfying "ABCD" of M.M. completely fell off. Both oral & frequent external application of mixed solution of plum wine & the same combination of anti-M.M. substances can be used as very effective treatment by taking 2-3 times daily. Additional application of special (+) Solar Energy Stored Paper reduced asbestos & accelerated reduction of M.M. positive area rapidly. This method with individualized optimal doses has also been successfully applied to treat several other types of malignancies. PMID- 23724698 TI - Influence of I-ching (Yijing, or The Book Of Changes) on Chinese medicine, philosophy and science. AB - I-Ching or Yi-Jing ([see text] also known as The Book of Changes) is the earliest classic in China. It simply explained the formation of the universe and the relationship of man to the universe. Most, if not all, branches of various knowledge, including traditional Chinese medicine, can be traced back its origin to this Book in which Fu Shi ([see text] 2852 B.C.) theorized how the universe was formed, through his keen observation of environment and orbits of sun, moon and stars. He used symbols to represent his views. The essence of I-Ching is basically the expression and function of Yang symbolized as "--" (from <---->) and Yin symbolized "- -" (from --><--), and [see text] Yin and Yang as interaction and circulation of Yang and Yin. Both Yin and Yang were derived from the same origin, Tai-Chi. Fu Shi believed Yin and Yang were the two opposite background force and energy that make the universe as what it is. Yang and Yin manifest in great variety of phenomena such as mind and body, masculine and feminine, sun and moon, hot and cold, heaven and earth, positive and negative electricity etc. The entire theory of Chinese medicine is based on the theories of Yin and Yang as well as that of 5 Element Cycles which are also related to the orderly arrangement of 8 trigrams ([see text]) by King Wen ([see text]1099-1050 B.C.). The 5 Elements Theory explains the "check and balance" mechanism created by the background force of Yin and Yang Qi and illustrated the relationships that are either strengthened or weakened by "acting and controlling" among the 5 elements. I-Ching has exerted profound influences on some well- known European philosophers and scientists, notably Leibnitz and Hegel. Between I-Ching and modern cosmology and the physics of sub-atomic particles, there are some basic theories in common. PMID- 23724699 TI - Name-valence and physical attractiveness in Facebook: their compensatory effects on friendship acceptance. AB - Name-valence and physical attractiveness have been shown to be associated with how people respond toward others, in that people judge and behave more positively toward individuals with positive names and individuals who are physically attractive. The present research examined whether Facebook users are more likely to accept friendship requests from other Facebook users with positive (relative to negative) names and who are physically attractive (relative to being moderately attractive). In fact, both name-valence and physical attractiveness affected friendship acceptance. Moreover, results revealed that name-valence can be compensated by physical attractiveness (and vice versa). Acceptance rates of requests from users with positive names who are moderately attractive, as well as requests from users with negative names who are attractive did not significantly differ from those with positive names who are attractive. PMID- 23724700 TI - Customer emotion regulation in the service interactions: its relationship to employee ingratiation, satisfaction and loyalty intentions. AB - Many studies have explored emotional regulation on the part of service employees, and its antecedents. However, customers' emotional regulation in general, and how it is affected by service employee behavior in particular, have received only scant attention. The present article explores a model suggesting that service employees' ingratiatory behavior relates to customer emotion regulation strategies, which in turn are related to customer satisfaction and loyalty. The model was tested with 131 service employee-customer dyads. The results show that service employee ingratiation was positively related to customers' deep acting but not related to surface acting. Customers' deep acting was positively related to their satisfaction. A positive relationship was found between customer satisfaction and loyalty. PMID- 23724701 TI - Attachment styles, relationship satisfaction, and well-being in working women. AB - We propose and test a model connecting women's attachment styles, intimate relationship quality, workplace supervisor relationships, and well-being. The factors that lead to women's successful interaction patterns at home with a partner are suggested to be similar to successful interactions at work and are suggested to be related to well-being. A model was tested with data from 209 working women across various U.S. organizations. Women with an avoidance attachment style tended to have intimate relationships that were low in satisfaction and cohesion as well as low-quality relationships with their supervisors. Women in cohesive intimate relationships were likely to be satisfied with their job, experience low conflict at work, and report few physical symptoms. Women who had quality relationships with their superiors also had low conflict at work and were satisfied with their jobs. Results show important associations among social relationships at home and work related to quality of life. PMID- 23724702 TI - Exploring the moderating role of context on the mathematics performance of females under stereotype threat: a meta-analysis. AB - The current meta-analysis synthesized 17 years of research on stereotype threat (ST). Specifically, it examined the moderating effect of contextual factors on ST. Findings revealed that, on average, females in ST conditions performed less well on mathematics tests than their control counterparts (d =|10.24|). Results also showed that females did not benefit more from female-only testing situations, or testing contexts where they formed the majority. Nevertheless, the trend in ST effects differed by broader contextual factors like geography and level of education, with females in countries with small gender-gaps showing better performance under ST conditions, and ST effects being greater for students in middle and high school compared to college students. PMID- 23724703 TI - Corralling the ingroup: deviant derogation and perception of group variability. AB - Two experiments investigated the relationship between the evaluation of a deviant group member and the perceived group variability among participants with varying degrees of ingroup identification. In Experiment 1 (N = 79) ingroup identification was negatively associated with perceived ingroup variability following the presentation of a deviant ingroup member. This relationship was mediated by ratings of the deviant: the stronger the identification, the more negatively the deviant was evaluated, and the more homogeneous the ingroup was perceived. These effects were replicated in Experiment 2 (N = 169), which also showed that there was no association between ingroup identification and the representation of the outgroup following exposure to a deviant outgroup member. The findings suggest that deviant derogation may serve to isolate undesirable members from the rest of the ingroup and protect the group's identity. PMID- 23724704 TI - Implicit and explicit attitudes toward gay males and lesbians among heterosexual males and females. AB - In this article, we examined explicit and implicit attitudes toward gay males and lesbians using the Single Category IAT (SC-IAT). In Study 1, we examined attitudes toward gay people in general. Participants reported positive explicit attitudes and neutral implicit attitudes toward gay people. In Study 2, we examined implicit and explicit attitudes toward gay men and lesbians separately. Participants rated gay men and lesbians positively on explicit attitude measures. Analysis of SC-IAT scores revealed neutral associations with gay men and positive associations with lesbians. As a secondary goal, we also tested the Balanced Identity Theory in both studies and did not find evidence of balance between implicit sexual orientation attitudes, implicit sexual identity, and implicit self-esteem using the SC-IAT. PMID- 23724705 TI - The value of outside support for male and female politicians involved in a political sex scandal. AB - This research examined how third party statements impact the evaluation of male and female politicians caught in a scandal (i.e., extramarital affair). Governor's sex was crossed with three types of support statements: third party supportive (TPS), third party non-supportive (TPNS), and governor self-supportive (GSS). In Experiment 1, a female politician was evaluated more positively than a male politician. The TPS and the GSS conditions were both evaluated more positively than the TPNS condition. Experiment 2's design was similar to Experiment l's, except it involved multiple affairs. In Experiment 2, participants used the third party's statements as an information source and thus reduced their use of gender stereotypes in the TPS and TPNS conditions compared to the GSS condition. We also found that male respondents gave more negative evaluations of the female governor than female respondents. Implications for the gender stereotype and social influence literatures are discussed. PMID- 23724706 TI - [Incidental finding on the hand. A rudimentary finger? A ganglion]. PMID- 23724707 TI - [A young man on very distinctive feet. So far he has no symptoms]. PMID- 23724708 TI - [Beginning of the quarter. Caution with requested transfers!]. PMID- 23724709 TI - [Fees conflict concluded, concerns of psychotherapists. Will psychotherapy be in short supply?]. PMID- 23724710 TI - [Galenus von Pergamon Prize 2012. Excellent research and innovation]. PMID- 23724711 TI - [New heart attack guideline. What is new and where the biggest deficits are]. PMID- 23724712 TI - [Control measures for the new allergy wave. Can ambrosia still be stopped?]. PMID- 23724713 TI - [Phytotherapy. Which plant extracts for the common cold?]. PMID- 23724718 TI - [Transient hemiplegia, neurologically unremarkable. Should I continue to investigate?]. PMID- 23724719 TI - [Preventive screening in general practice. What examined and how reliable is it?]. PMID- 23724720 TI - [The general practitioner as an expert for vaccinations]. PMID- 23724721 TI - [When does the thyroid need a therapy?]. PMID- 23724722 TI - [Insulin therapy of type 2 diabetes: from simple to flexible--three strategies are available]. PMID- 23724723 TI - [Rheumatoid arthritis: early diagnosis and early therapy are essential]. PMID- 23724724 TI - [Diagnosis and therapy of deep vein thrombosis]. PMID- 23724725 TI - [Medical management of coronary artery disease]. PMID- 23724726 TI - [Tumor associated pain in GP's office]. PMID- 23724727 TI - [Chronic wounds: supplementation for better healing of ulcers]. PMID- 23724728 TI - A synthesis of our current knowledge of philometrid nematodes, a group of increasingly important fish parasites. AB - Members of the Philometridae represent the most important group of dracunculoid nematodes parasitizing fishes. In his monograph treating the Dracunculoidea, Moravec (2006) reported a total of 11 genera and 105 species of philometrids parasitizing freshwater, brackish-water and marine fishes. However, during the last six years (2007-2012), an additional 42 new species of Philometridae have been described, representing a 40% increase of the number of nominal species. Most of these species (30) belong to Philometra Costa, 1845, mainly represented by parasites of marine fishes, a few others (8) to Philometroides Yamaguti, 1935, and a single one to each of the following genera: Caranginema Moravec, Montoya Mendoza et Salgado-Maldonado, 2008, Dentiphilometra Moravec et Wang, 2002, Dentirumai Quiazon et Moravec, 2013* and Spirophilometra Parukhin, 1971. Moreover, three new genera, Afrophilometra Moravec, Charo-Karisa et Jirku, 2009, Caranginema and Dentirumai, were erected. Representatives of seven genera, Afrophilometra, Buckleyella Rasheed, 1963, Caranginema, Dentiphilometra, Dentirumai, Paraphilometroides Moravec et Shaharom-Harrison, 1989 and Rumai Travassos, 1960, were studied using scanning electron microscopy (SEM) for the first time. Thirteen known but poorly described philometrid species were redescribed and, in some species of Caranginema and Philometra, previously unknown conspecific males were discovered and described. The male surface ultrastructure studied by SEM provided new taxonomically important features for species distinction. Gene sequencing was used in several recent studies and advanced our understanding of phylogenetic interrelationships among representatives of seven genera (Afrophilometra, Alinema Rasheed, 1963, Caranginema, Nilonema Khalil, 1960, Philometra, Philometroides and Rumai) and of the extent of the biodiversity of philometrids. New data were obtained on the biology and pathogenicity of several species of Nilonema, Philometra, Philometroides and Rumai. The need to carry out surveys in order to find males and to use SEM and gene sequencing to identify philometrids is emphasized. Appropriate quantitative methods to determine the impact of philometrids in ovarian tissue on host fecundity are recommended. Further detailed studies on philometrids would be significant not only from the theoretical viewpoint, but also because of their practical implications. A list of philometrid nematode species by continents is provided. PMID- 23724729 TI - Calodium hepaticum (Nematoda: Capillaridae) in a red fox (Vulpes vulpes) in Italy with scanning electron microscopy of the eggs. AB - Calodium hepaticum (Bancroft, 1893) Moravec, 1982 (syn. Capillaria hepatica) is a cosmopolitan capillariid nematode, infecting mainly rodents and occasionally other mammals, including humans. Reports of C. hepaticum in canids are rare and the present one is, to the best of our knowledge, the first reported case in a red fox (Vulpes vulpes Linnaeus) in Italy. Scanning electron microscopy (SEM) examination of the eggs of C. hepaticum allowed a precise description of the egg morphology, which is one of the most relevant specific characteristics of capillariid nematodes. The egg shell showed a fibrous beam-like network which differs from that of the eggs of closely related trichinelloid species. This characteristic can be useful especially in case of spurious infection, when misdiagnosis among different trichinelloids species can occur. PMID- 23724730 TI - Gonad-infecting philometrids (Nematoda: Philometridae) including four new species from marine fishes off the eastern coast of India. AB - Based on light and scanning electron microscopical studies, the following five gonad-infecting species of the Philometridae (Nematoda: Dracunculoidea) are described from marine perciform fishes off the eastern coast of India (Bay of Bengal): Philometra sphyraenae sp. n. (males and females) from the pickhandle barracuda Sphyraena jello Cuvier (Sphyraenidae), Philometra gerrei sp. n. (males and females) from the whipfin silver-biddy Gerres filamentosus Cuvier (Gerreidae), Philometra otolithi sp. n. (single female) from the tigertooth croaker Otolithes ruber (Bloch et Schneider) (Sciaenidae), Philometra sp. (females) from the Belanger's croaker Johnius belangerii (Cuvier) (Sciaenidae), and Philometroides eleutheronemae sp. n. (females) from the fourfinger threadfin Eleutheronema tetradactylum (Shaw) (Polynemidae). All new species are distinguished from their congeners parasitizing gonads of marine fishes by morphological (mainly the gubernaculum structure in males and the shape and structure of the cephalic and caudal ends and of the oesophagus in females) and biometrical features. Philometra rajani Mukherjee, 1963 is considered a species inquirenda. PMID- 23724732 TI - Pseudocapillaria (Pseudocapillaria) moraveci sp. n. (Nematoda: Capillariidae) from the stomach of Gobius paganellus (Perciformes: Gobiidae) from Vigo estuary (NW Spain). AB - Pseudocapillaria moraveci sp. n. (Nematoda, Capillariidae) is described from the stomach of Gobius paganellus Linnaeus (Perciformes, Gobiidae) from rocky shores of the Vigo estuary (Northwest Atlantic coast of Spain). Scanning electron microscopy reveals the absence of a dorsal cuticular membrane interconnecting the caudal lobes of male, thus confirming the assignment of this new species to the nominotypical subgenus Pseudocapillaria Freitas, 1959. Pseudocapillaria moraveci can be easily differentiated from other marine congeneric species belonging to subgenera Pseudocapillaria and Ichthyocapillaria Moravec, 1982 by its muscular oesophagus, which is distinctly thickened at the distal third, the terminal or almost terminal anus in female, the presence of a basal internal papilla on each ventrolateral caudal lobe in male, and its exclusive site preference for the stomach. In addition, the spicule, which measures 0.180-0.292 mm in length (4.9 7.9% of body length) and possesses a proximal end expanded and oblique in lateral view, a narrowed middle part, and a distal end almost pointed, also distinguishes this species. Pseudocapillaria moraveci is, together with P. tomentosa (Dujardin, 1843) Moravec, 1987, the only species in the genus Pseudocapillaria that has been reported to infect members of the family Gobiidae. PMID- 23724731 TI - Global assessment of molecularly identified Anisakis Dujardin, 1845 (Nematoda: Anisakidae) in their teleost intermediate hosts. AB - Here, we present the ITS ribosomal DNA (rDNA) sequence data on 330 larvae of nematodes of the genus Anisakis Dujardin, 1845 collected from 26 different bony fish species from 21 sampling locations and different climatic zones. New host records are provided for Anisakis simplex (Rudolphi, 1809) sensu stricto (s.s.) and A. pegreffli Campana-Rouget et Biocca, 1955 from Anoplopoma fimbria (Pallas) (Santa Barbara, East Pacific), A. typica (Diesing, 1860) from Caesio cuning (Bloch), Lepturacanthus savala (Cuvier) and Katsuwonus pelamis (Linnaeus) (Indonesia, West Pacific), A. simplex s.s. from Cololabis saira (Brevoort) (Hawaii, Central Pacific), A. simplex C of Nascetti et al. (1986) from Sebastolobus alascanus Bean (Santa Barbara, East Pacific) and A. physeteris Baylis, 1923 from Synaphobranchus kaupii Johnson (Namibia, East Atlantic). Comparison with host records from 60 previous molecular studies of Anisakis species reveals the teleost host range so far recorded for the genus. Perciform (57 species) and gadiform (21) fishes were the most frequently infected orders, followed by pleuronectiforms (15) and scorpaeniforms (15). Most commonly infected fish families were Scombridae (12), Gadidae (10), Carangidae (8) and Clupeidae (7), with Merluccius merluccius (Linnaeus) alone harbouring eight Anisakis species. Different intermediate host compositions implicate differing life cycles for the so far molecularly identified Anisakis sibling species. PMID- 23724733 TI - Khawia abbottinae sp. n. (Cestoda: Caryophyllidea) from the Chinese false gudgeon Abbottina rivularis (Cyprinidae: Gobioninae) in China: morphological and molecular data. AB - Khawia abbottinae sp. n. is described from the Chinese false gudgeon, Abbottina rivularis (Basilewsky) (Cyprinidae: Gobioninae), from the Yangtze River basin in China. The new species can be distinguished from the congeneric species mainly by the arrangements of the testes, which form two longitudinal bands (other congeneric species have the testes irregularly scattered throughout the testicular region) and their number (at maximum 85 testes versus at least 160 in the other Khawia spp.), and the morphology of the scolex, which varies from cuneiform to widely bulbate scolex, being separated from the remaining body by a short neck and possessing a smooth, blunt or rounded anterior margin. Other typical features of K. abbottinae are its small size (total length less than 1.5 cm) and body shape, with the maximum width at its first third. The distinct status of the new species was confirmed by molecular data (ssrDNA and ITS1 sequences). Phylogenetic analyses revealed a close relationship of the new species with K. rossittensis (Szidat, 1937) and K. parva (Zmeev, 1936), parasites of crucian carp and goldfish (Carassius spp.), but both species markedly differ from K. abbottinae in their morphology. Until now, five valid species of Khawia (K. abbottinae, K. japonensis, K. rossittensis, K. saurogobii and K. sinensis) have been reported from China. PMID- 23724734 TI - A parvicapsulid (Myxozoa) infecting Sprattus sprattus and Clupea harengus (Clupeidae) in the Northeast Atlantic uses Hydroides norvegicus (Serpulidae) as invertebrate host. AB - A myxosporean producing actinospores of the tetractinomyxon type in Hydroides norvegicus Gunnerus (Serpulidae) in Denmark was identified as a member of the family Parvicapsulidae based on small-subunit ribosomal DNA (SSU rDNA) sequences. Myxosporean samples from various Danish and Norwegian marine fishes were examined with primers that detect the novel myxosporean. Sprattus sprattus (Linnaeus) and Clupea harengus Linnaeus (Teleostei, Clupeidae) were found to be infected. The sequences of this parvicapsulid from these hosts were consistently slightly different (0.8% divergence), but both these genotypes were found in H. norvegicus. Disporic trophozoites and minute spores of a novel myxosporean type were observed in the renal tubules of some of the hosts found infected through PCR. The spores appear most similar to those of species of Gadimyxa Koie, Karlsbakk et Nylund, 2007, but are much smaller. The actinospores of the tetractinomyxon type from H. norvegicus have been described previously. In GenBank, the SSU rDNA sequences of Parvicapsulidae gen. sp. show highest identity (82%) with Parvicapsula minibicornis Kent, Whitaker et Dawe, 1997 infecting salmonids (Oncorhynchus spp.) in fresh water in the western North America. A phylogenetic analysis places P. minibicornis and Parvicapsulidae gen. sp. in a sister clade to the other parvicapsulids (Parvicapsula spp. and Gadimyxa spp.). PMID- 23724735 TI - Genetic diversity of Clonorchis sinensis (Trematoda: Opisthorchiidae) in the Russian southern Far East based on mtDNA cox1 sequence variation. AB - We examined the phylogeography and the variation of the mitochondrial DNA (mtDNA) cytochrome c oxidase subunit 1 gene (cox1) of the Chinese liver fluke Clonorchis sinensis (Cobbold, 1875) in two geographic localities in the Russian southern Far East and compared them with those from different geographical regions (China, Korea, Japan and Vietnam). The Russian samples differed from those of the other regions in haplotype frequencies, haplotype and nucleotide diversities, and AT/GC ratios. Only 4 of the 18 haplotypes were common to Russian and Chinese samples, and two haplotypes were common to Russia and other regions. The intraspecific genetic distances ranged from 0 to 1.58% for the entire dataset studied and from 0 to 1.25% among the samples from Russia. Phylogenetic trees revealed no significant genealogical clades of samples corresponding to sampling localities and no strong isolation by distance was estimated with Mantel test. Neutrality test analysis suggested a relatively recent population expansion for C. sinensis, whereas goodness-of-fit tests indicated deviation from the strict model of uniform expansion. Therefore, the sequences of the mtDNA cox1 gene provide useful genetic markers for evaluating intraspecific diversity and generating phylogeographic reconstructions for this fish-borne trematode. PMID- 23724736 TI - Metacercariae of Clinostomum schizothoraxi Kaw, 1950 (Digenea: Clinostomatidae) in Carassius carassius (Linnaeus) under different environmental conditions. AB - This report addresses the possible impacts of local habitat characteristics on the metacercariae of Clinostomum schizothoraxi Kaw, 1950 infecting crucian carp, Carassius carassius (Linnaeus), from three lakes in Kashmir. The lakes chosen encompass an extremely wide gradient in trophic status--Manasbal (less polluted and mesotrophic), Dal (moderately polluted and eutrophic) and Anchar (strongly polluted and hypertrophic). The results indicate that infrapopulation-level descriptors of abundance of C. schizothoraxi in fish differed between the three lakes and revealed that the infection levels were greater at Anchar Lake. Furthermore, the prevalence, mean abundance and mean intensity of infection also changed during the period of investigation along the seasonal gradient of water temperature. The fact that the abundance patterns of the parasite differed in different populations of the same host provided a unique opportunity for a comparative study on the temporal variations in infection patterns attained during different seasons. In particular, the lake environments showed a high degree of variability in the density profiles of mollusc intermediate hosts and, thus, the differences in the infection status of crucian carp were derived on the basis of intermediate host population size which, in turn, was influenced by the trophic characteristics of the three lakes. PMID- 23724737 TI - Redescription of cystacanths of Corynosoma pseudohamanni Zdzitowiecki, 1984 (Acanthocephala: Polymorphidae) from paratenic fish hosts. AB - Cystacanths of Corynosoma pseudohamanni Zdzitowiecki, 1984 (Palaeacanthocephala: Polymorphidae) are redescribed on the basis of specimens recovered from three species of Antarctic notothenioid fish, Trematomus bernacchii Boulenger, Gobionotothen gibberifrons (Lonnberg) and Notothenia coriiceps Richardson, collected from the Prince Gustav Channel, Antarctica. The cystacanths' morphometry and their internal anatomy including trunk muscles were studied using light and scanning electron microscopy (SEM). The characteristic features of this species such as the length of proboscis and the number of hooks (i.e. 260 hooks arranged in 20 rows with 13 hooks each, including two basal hooks) were confirmed and the intraspecific variability was evaluated. Sexual dimorphism was manifested in the shape of the hindtrunk, and the distribution and extent of the somatic armature only. SEM observations of internal anatomy revealed the detailed organization of trunk musculature. PMID- 23724738 TI - Occurrence of Diplostomum pseudospathaceum Niewiadomska, 1984 and D. mergi Dubois, 1932 (Digenea: Diplostomidae) in Danish freshwater snails: ecological and molecular data. AB - Freshwater pulmonate snails from three locations in Lake Fureso north of Copenhagen were screened for infection with furcocercariae (by shedding in the laboratory) and recovered parasite larvae were diagnosed by molecular methods (by performing PCR of rDNA and sequencing the internal transcribed spacer [ITS] region). Overall prevalence of infection in snails was 2%. Recovered cercariae from Lymnaea stagnalis (Linnaeus) were diagnosed as Diplostomum pseudospathaceum Niewiadomska, 1984 (prevalence 4%) and cercariae from Radix balthica (Linnaeus) as D. mergi (Dubois, 1932) (prevalence 2%). Pathogen-free rainbow trout were then exposed to isolated cercariae and infection success and site location of metacercariae in these fish were determined. Infection experiments confirmed that both species could infect rainbow trout with the eye lens as infection site for the metacercarial stage although infection success differed. Combination of molecular and biological assays may contribute to improvement of our knowledge on diagnosis, distribution and biology of diplostomids in fish. PMID- 23724739 TI - Preface. Array clinical laboratory. PMID- 23724740 TI - Folate and B12 in prostate cancer. AB - Mechanisms postulated to link folate and B12 metabolism with cancer, including genome-wide hypomethylation, gene-specific promoter hypermethylation, and DNA uracil misincorporation, have been observed in prostate tumor cells. However, epidemiological studies of prostate cancer risk, based on dietary intakes and blood levels of folate and vitamin B12 and on folate-pathway gene variants, have generated contradictory findings. In a meta-analysis, circulating concentrations of B12 (seven studies, OR = 1.10; 95% CI 1.01, 1.19; P = 0.002) and (in cohort studies) folate (five studies, OR = 1.18; 95% CI 1.00, 1.40; P = 0.02) were positively associated with an increased risk of prostate cancer. Homocysteine was not associated with risk of prostate cancer (four studies, OR = 0.91; 95% CI 0.69, 1.19; P = 0.5). In a meta-analysis of folate-pathway polymorphisms, MTR 2756A > G (eight studies, OR = 1.06; 95% CI 1.00, 1.12; P = 0.06) and SHMT1 1420C > T (two studies, OR = 1.11; 95% CI 1.00, 1.22; P = 0.05) were positively associated with prostate cancer risk. There were no effects due to any other polymorphisms, including MTHFR 677C > T (12 studies, OR = 1.04; 95% CI 0.97, 1.12; P = 0.3). The positive association of circulating B12 with an increased risk of prostate cancer could be explained by reverse causality. However, given current controversies over mandatory B12 fortification, further research to eliminate a causal role of B12 in prostate cancer initiation and/or progression is required. Meta-analysis does not entirely rule out a positive association of circulating folate with increased prostate cancer risk. As with B12, even a weak positive association would be a significant public health issue, given the high prevalence of prostate cancer and concerns about the potential harms versus benefits of mandatory folic acid fortification. PMID- 23724741 TI - Mismatch repair proteins in recurrent prostate cancer. AB - Normal cell function requires strict control over the repair of DNA damage, which prevents excessive mutagenesis. An enhanced accumulation of mutations results in the multistep process generally known as carcinogenesis. Defects in repair pathways fuel such mutagenesis by allowing reiterative cycles of mutation, selection, and clonal expansion that drive cancer progression. The repair of mismatches is an important mechanism in the prevention of such genetic instability. In addition, proteins of this pathway have the unique ability to function in DNA damage response by inducing apoptosis when irreparable damage is encountered. Though originally identified primarily in association with a predisposition to hereditary colon cancer, mismatch repair defects have been identified in many other cancer types, including prostate cancer. From the first discovery of microsatellite instability in prostate cancer cell lines and tumor samples, variations in protein levels and a possible association with recurrence and aggression of disease have been described. Current results suggest that the involvement of mismatch repair proteins in prostate cancer may differ from that found in colorectal cancer, in the type of proteins and protein defects involved and the type of causative mutations. Additional work is clearly needed to investigate this involvement and the possibility that such defects may affect treatment response and androgen independence. PMID- 23724742 TI - Protein antioxidants in thalassemia. AB - It is common knowledge that thalassemic patients are under significant oxidative stress. Chronic hemolysis, frequent blood transfusion, and increased intestinal absorption of iron are the main factors that result in iron overload with its subsequent pathophysiologic complications. Iron overload frequently associates with the generation of redox-reactive labile iron, which in turn promotes the production of other reactive oxygen species (ROS). If not neutralized, uncontrolled production of ROS often leads to damage of various intra- and extracellular components such as DNA, proteins, lipids, and small antioxidant molecules among others. A number of endogenous and exogenous defense mechanisms can neutralize and counteract the damaging effects of labile iron and the reactive substances associated with it. Endogenous antioxidant enzymes, such as superoxide dismutase, catalase, glutathione peroxidase, and ferroxidase, may directly or sequentially terminate the activities of ROS. Nonenzymatic endogenous defense mechanisms include metal binding proteins (ceruloplasmin, haptoglobin, albumin, and others) and endogenously produced free radical scavengers (glutathione (GSH), ubiquinols, and uric acid). Exogenous agents that are known to function as antioxidants (vitamins C and E, selenium, and zinc) are mostly diet-derived. In this review, we explore recent findings related to various antioxidative mechanisms operative in thalassemic patients with special emphasis on protein antioxidants. PMID- 23724743 TI - Immune complexome analysis. AB - Immune complexes (ICs) are produced during an immune response and may reflect some aspects of an ongoing immune response. Therefore, the identity of antigens incorporated into ICs provides the information that in the future may aid in the development of diagnosis and treatment strategies for autoimmune diseases, infection, cancer, and transplantation therapy, and this information might be more relevant than the information on free antigens. Because ICs may contain many antigens, comprehensive identification and profiling of such antigens are more effective than immunoblotting detection. Here, we introduced mass spectrometry (MS)-based two approaches (immunoproteomics and immune complexome analysis) to comprehensively identify the antigens. Immunoproteomics is a concept to identify disease-associated antigens that elicit immune responses by combining protein separation (two-dimensional electrophoresis, gel-free separation), immunological detection (Western blotting), and MS or by combining immunocapture and MS. Immune complexome analysis is designed for identifying antigens in circulating ICs and consists of ICs separation from serum and direct tryptic digestion followed by nano-liquid chromatography-tandem MS. PMID- 23724744 TI - Genetics of gallstone disease. AB - Gallstone disease (GSD) is one of the most common biliary tract disorders worldwide. The prevalence, however, varies from 5.9-21.9% in Western society to 3.1-10.7% in Asia. Most gallstones (75%) are silent. Approximately half of symptomatic gallstone carriers experience a second episode of biliary pain within 1 year. These individuals are at increased risk of developing acute cholecystitis, acute cholangitis, and biliary pancreatitis. As can be expected, these complications burden health care systems because of their invasive nature and surgical cost. Factors that contribute to gallstone formation include supersaturation of cholesterol in bile, gallbladder hypomotility, destabilization of bile by kinetic protein factors, and abnormal mucins. Epidemiologic studies have implicated multiple environmental factors and some common genetic elements in gallstone formation. Genetic factors that influence gallstone formation have been elaborated from linkage studies of twins, families, and ethnicities. Accumulating evidence suggests that genetic factors play a role in GSD. PMID- 23724745 TI - Glycoprotein 2 antibodies in Crohn's disease. AB - The pathogenesis of Crohn's disease (CrD) and ulcerative colitis (UC), the two major inflammatory bowel diseases (IBD), remains poorly understood. Autoimmunity is considered to be involved in the triggering and perpetuation of inflammatory processes leading to overt disease. Approximately 30% of CrD patients and less than 8% of UC patients show evidence of humoral autoimmunity to exocrine pancreas, detected by indirect immunofluorescence. Pancreatic autoantibodies (PAB) were described for the first time in 1984, but the autoantigenic target(s) of PABs were identified only in 2009. Utilizing immunoblotting and matrix assisted laser desorption ionization time-of-flight mass spectrometry, the major zymogen granule membrane glycoprotein 2 (GP2) has been discovered as the main PAB autoantigen. The expression of GP2 has been demonstrated at the site of intestinal inflammation, explaining the previously unaddressed contradiction of pancreatic autoimmunity and intestinal inflammation. Recent data demonstrate GP2 to be a specific receptor on microfold (M) cells of intestinal Peyer's patches, which are considered to be the original site of inflammation in CrD. Novel ELISAs, employing recombinant GP2 as the solid phase antigen, have confirmed the presence of IgA and IgG anti-GP2 PABs in CrD patients and revealed an association of anti-GP2 IgA as well as IgG levels with a specific clinical phenotype in CrD. Also, GP2 plays an important role in modulating innate and acquired intestinal immunity. Its urinary homologue, Tamm-Horsfall protein or uromodulin, has a similar effect in the urinary tract, further indicating that GP2 is not just an epiphenomenon of intestinal destruction. This review discusses the role of anti GP2 autoantibodies as novel CrD-specific markers, the quantification of which provides the basis for further stratification of IBD patients. Given the association with a disease phenotype and the immunomodulating properties of GP2 itself, an important role for GP2 in the immunopathogenesis of IBD cannot be excluded. PMID- 23724746 TI - Is baldness a risk factor for coronary heart disease? PMID- 23724747 TI - Advances in the treatment of metastatic prostate cancer. AB - Prostate cancer is the most common cancer in men in the UK. It accounts for nearly a quarter of all male cancer diagnoses and is the second most common cause of male cancer death. Despite a large increase in prostate cancer incidence, mortality rates have remained relatively constant through improvements in survival. Most patients present with localised disease, but there are still many who present with metastatic disease. Prostate cancers are driven by androgens, such as testosterone. Androgen deprivation therapy (ADT), which is still the mainstay of systemic treatment, effectively reduces intraprostatic androgen levels resulting in reduced androgen receptor (AR) stimulation and increased apoptosis. Medical castration using LHRH analogues has become the gold standard in managing both locally advanced prostate cancer, in ombination with radiotherapy, and metastatic disease. Eventually most men with advanced prostate cancer become resistant to ADT. This is now called castrate refractory prostate cancer (CRPC), and is associated with a poor prognosis. There is now hope for patients who progress after chemotherapy with the emergence of several new agents that have been shown to benefit patients. The first AR-targeted drug to show a definite clinical benefit is abiraterone. It markedly decreases levels of androgens in CRPC and initial trials showed promising activity. Enzalutamide has a high affinity and selectivity for AR binding, blocks nuclear translocation and reduces recruitment of co-activators. Abiraterone, enzalutamide and other AR targeted drugs are being studied in clinical trials for patients earlier in their disease, e.g. in addition to ADT at first presentation of metastatic disease, where it is likely that greater benefits will be seen. PMID- 23724748 TI - Managing epididymo-orchitis in general practice. AB - Epididymitis and orchitis normally co-exist with isolated epididymitis being more common than an isolated orchitis. Epididymo-orchitis (EO) can be acute (less than 6 weeks' duration), sub-acute, or chronic if persisting for more than three months and typically presents with testicular pain and swelling. Sexually transmitted infection (STI) is the most common cause in younger men and urinary tract pathogens are the more common culprits in older men. The most common pathogens in the under 35s are N gonorrhoeae and C trachomatis and E coli is the most common cause of acute epididymitis in the over 35s. Acute testicular torsion is the most important differential diagnosis of acute testicular pain especially in younger men. If there is any suspicion of testicular torsion, the patient should be referred to secondary care immediately as surgery is required within four to six hours. Patients who are in severe pain or systemically unwell should be referred for analgesia, IV antibiotics and hydration. Examination of a patient with acute EO classically reveals a swollen, tender testis with swelling of the epididymis which starts at the lower pole and moves up towards the head of the epididymis at the upper pole of the testes. UTI in men is often associated with bladder outflow obstruction. So it is important to examine the bdomen for a palpable bladder and to perform a digital rectal exam to check for BPH, prostate cancer, constipation and prostatitis which can also cause EO. PMID- 23724749 TI - Can my patient with CVD travel to high altitude? AB - Patients with borderline health should consult a physican before travelling to altitude. The physician will need to know the duration of the trip, ascent profile and how much exercise the patient plans to undertake. The presence of comorbid diseases which reduce oxygenation and ventilation should also be taken into account. Every patient must be assessed on an individual basis, there are no clinical investigations which reliably predict outcome at altitude. Complex cases may require advice from the patient's cardiologist. Travelling from sea level to an altitude of 2,500 m causes a 20% reduction in the partial pressure of inspired oxygen. There is an initial net increase in myocardial oxygen consumption during the first 3-5 days, this then falls as cardiac output on exercise is reduced. During this time patients with angina pectoris may become symptomatic at a lower level of exercise than at sea level and should be advised to reduce their activity. After five days at 2,500 m, the exertion threshold returns to sea level values. Patients should not travel to high altitude immediately after an acute coronary syndrome. Most patients with stable coronary artery disease with a sufficiently high exercise capacity at sea level can go as high as 3,000-3,500 m with only a minimally increased risk. Patients with heart failure have a greater reduction in exercise performance than healthy people at altitude. Patients with mild to moderately impaired systolic LVF and mild symptoms may travel up to 3,000 3,500 m for a day trip. Patients with poorly controlled hypertension should not travel to high altitude. Those with controlled hypertension should consider taking their own blood pressure during a stay at altitude. PMID- 23724750 TI - Papulosquamous disorders. PMID- 23724751 TI - Blue brains (or peripheral stasis). 1913. PMID- 23724752 TI - Looking at cases through the retrospectoscope. PMID- 23724753 TI - Education and learning: the new era. PMID- 23724754 TI - Hunt response to Francis report: HCA regulation 'too bureaucratic'. PMID- 23724755 TI - School Nurse 121 Campaign. PMID- 23724756 TI - Too much too young. PMID- 23724757 TI - Coping with cuts. Interview by Louise Naughton. PMID- 23724758 TI - Improving smoking cessation data collection via a health visitor community of practice. AB - A Collaborations for Leadership in Applied Health Research and Care (CLAHRC) funded study engaged health visitors in investigating the ways in which routinely collected data were captured, stored, transferred, analysed and then used to inform clinical practice. This report focuses on the establishment of a community of practice (CoP) to support these activities and then presents the outcome of the CoP's investigations into the collection and use of data on one key area of concern; maternal smoking behaviour. Evidence-based recommendations for clinical practice made by the CoP ranged from simple changes to the daily working practices of health visitors to ensure accurate data collection and dissemination of information, to major changes to processes and procedures relating to data quality and data sharing. The findings of the CoP emphasised the importance of cross-discipline communication and collaboration. PMID- 23724759 TI - A service evaluation of the Solihull Approach training and practice. AB - The Solihull Approach (SA) is a conceptual framework concerned with parent-child relationships. Across the UK, training in the SA expanded from health visitors (HVs) to various practitioners in health, social care, education and voluntary sectors. A substantial amount of research had provided evidence for the effectiveness of the SA with HVs. The present study developed Ottmann's themes into an 18-item questionnaire. This measure was then administered to a large and varied sample of SA-trained professionals. Scores were compared across HVs and family support workers. The two groups described the SA training as useful to their work with clients as well as within their multidisciplinary teams. Participants identified the crucial role of managerial support, supervision and consultation in implementing the training in practice. Results are discussed with relation to the SA theory. PMID- 23724760 TI - My Time, My Space (an arts-based group for women with postnatal depression): a project report. AB - This paper will describe an innovative method of treatment for women with postnatal depression that has been used in the south west of England since 2004 and has now been successfully piloted in other areas of the UK. My Time My Space is an arts-based group for women with postnatal depression that aims to improve mood by reducing social isolation and using creativity to improve self-esteem. Results of the programme will be shared, in addition to the ways in which the project has been implemented using collaborative working with children's centres and building community capacity by engaging local charities. The qualitative results have been collected from participants (n = 30) over the last two years using post-course evaluation forms with open questions to elicit participants' views. The quantitative results of a small pilot study (n = 8) based on pre- and post-group Edinburgh Postnatal Depression Scale scores (EPDS) are also reported. The findings suggest My Time My Space has a positive effect on women's mood and perceived social support, and provides an effective alternative or additional method of treatment for postnatal depression. PMID- 23724761 TI - The role of the Unite health sector representative. PMID- 23724762 TI - Identifying victims of human trafficking. PMID- 23724764 TI - Change is in the air. PMID- 23724763 TI - Evidence-based portion sizes for children aged 1-4 years. AB - Existing guidelines on how to feed preschool children have left parents and carers unsure about how to offer a diet that will provide their young children with adequate nutrition but prevent excess weight gain. The consequences of malnutrition, such as iron deficiency anaemia and obesity, remain prevalent in this age group and giving parents more specific guidance will help address this. The evidence-based portion sizes from the Infant & Toddler Forum for 1-4-year-old children have been calculated to meet, but not exceed, their energy requirements and provide all their nutrients, with the exception of vitamin D for which they need a daily supplement. These portion size ranges can be used as serving guides by parents, carers and staff in early years settings. Their use will both reassure parents who worry their preschool children are not eating enough and will help address excess energy intake by toddlers, which is the main cause of obesity. PMID- 23724765 TI - Brave new world. PMID- 23724766 TI - Picture article: Congenital melanocytic naevus. PMID- 23724767 TI - Management of infantile colic: an update. PMID- 23724768 TI - Supporting neonates with prolonged jaundice in the community. PMID- 23724769 TI - Skin care for infants: an evidence-based review. PMID- 23724770 TI - ImPact test-retest reliability: reliably unreliable? AB - CONTEXT: Computerized neuropsychological testing is commonly used in the assessment and management of sport-related concussion. Even though computerized testing is widespread, psychometric evidence for test-retest reliability is somewhat limited. Additional evidence for test-retest reliability is needed to optimize clinical decision making after concussion. OBJECTIVE: To document test retest reliability for a commercially available computerized neuropsychological test battery (ImPACT) using 2 different clinically relevant time intervals. DESIGN: Cross-sectional study. SETTING: Two research laboratories. PATIENTS OR OTHER PARTICIPANTS: Group 1 (n = 46) consisted of 25 men and 21 women (age = 22.4 +/- 1.89 years). Group 2 (n = 45) consisted of 17 men and 28 women (age = 20.9 +/ 1.72 years). INTERVENTION(S): Both groups completed ImPACT forms 1, 2, and 3, which were delivered sequentially either at 1-week intervals (group 1) or at baseline, day 45, and day 50 (group 2). Group 2 also completed the Green Word Memory Test (WMT) as a measure of effort. MAIN OUTCOME MEASURES: Intraclass correlation coefficients (ICCs) were calculated for the composite scores of ImPACT between time points. Repeated-measures analysis of variance was used to evaluate changes in ImPACT and WMT results over time. RESULTS: The ICC values for group 1 ranged from 0.26 to 0.88 for the 4 ImPACT composite scores. The ICC values for group 2 ranged from 0.37 to 0.76. In group 1, ImPACT classified 37.0% and 46.0% of healthy participants as impaired at time points 2 and 3, respectively. In group 2, ImPACT classified 22.2% and 28.9% of healthy participants as impaired at time points 2 and 3, respectively. CONCLUSIONS: We found variable test-retest reliability for ImPACT metrics. Visual motor speed and reaction time demonstrated greater reliability than verbal and visual memory. Our current data support a multifaceted approach to concussion assessment using clinical examinations, symptom reports, cognitive testing, and balance assessment. PMID- 23724771 TI - Two- and 3-dimensional knee valgus are reduced after an exercise intervention in young adults with demonstrable valgus during squatting. AB - CONTEXT: Two-dimensional (or medial knee displacement [MKD]) and 3-dimensional (3D) knee valgus are theorized to contribute to anterior cruciate ligament injuries. However, whether these displacements can be improved in the double legged squat (DLS) after an exercise intervention is unclear. OBJECTIVE: To determine if MKD and 3D knee valgus are improved in a DLS after an exercise intervention. DESIGN: Randomized controlled clinical trial. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 32 participants were enrolled in this study and were randomly assigned to the control (n = 16) or intervention (n = 16) group. During a DLS, all participants demonstrated knee valgus that was corrected with a heel lift. INTERVENTION(S): The intervention group completed 10 sessions of directed exercise that focused on hip and ankle strength and flexibility over a 2- to 3-week period. MAIN OUTCOME MEASURE(S): We assessed MKD and 3D knee valgus during the DLS using an electromagnetic tracking system. Hip strength and ankle-dorsiflexion range of motion were measured. Change scores were calculated for MKD and 3D valgus at 0%, 10%, 20%, 30%, 40%, and 50% phases, and group (2 levels)-by phase (6 levels) repeated-measures analyses of variance were conducted. Independent t tests were used to compare change scores in other variables (alpha < .05). RESULTS: The MKD decreased from 20% to 50% of the DLS (P = .02) and 3D knee valgus improved from 30% to 50% of the squat phase (P = .001). Ankle-dorsiflexion range of motion (knee extended) increased in the intervention group (P = .009). No other significant findings were observed (P > .05). CONCLUSIONS: The intervention reduced MKD and 3D knee valgus during a DLS. The intervention also increased ankle range of motion. Our inclusion criteria might have limited our ability to observe changes in hip strength. PMID- 23724772 TI - Psychosocial aspects of athletic injuries as perceived by athletic trainers. AB - CONTEXT: Despite the Psychosocial Strategies and Referral content area, athletic trainers (ATs) generally lack confidence in their ability to use this information. OBJECTIVE: The current study's primary purpose was to determine (a) perceived psychological responses and coping behaviors athletes may present to ATs, (b) psychosocial strategies ATs currently use with their athletes, (c) psychosocial strategies ATs deem important to learn more about, and (d) ATs' current practices in referring athletes to counseling or sport psychology services. DESIGN: Mixed-methods study. SETTING: Online survey containing both quantitative and qualitative items. PATIENTS OR OTHER PARTICIPANTS: A total of 215 ATs (86 male, 129 female), representing a response rate of 22.50%. MAIN OUTCOME MEASURE(S): The Athletic Training and Sport Psychology Questionnaire. RESULTS: Stress/anxiety (4.24 +/- 0.82), anger (3.70 +/- 0.96), and treatment adherence problems (3.62 +/- 0.94) were rated as the primary psychological responses athletes may present upon injury. Adherence and having a positive attitude were identified as key determinants in defining athletes' successful coping with their injuries. The top 3 selected psychosocial strategies were keeping the athlete involved with the team (4.57 +/- 0.73), using short-term goals (4.45 +/- 0.67), and creating variety in rehabilitation exercises (4.32 +/- 0.75). The top 3 rated psychosocial strategies ATs deem important to learn more about were understanding motivation (4.29 +/- 0.89), using effective communication (4.24 +/- 0.91), and setting realistic goals (4.22 +/- 0.97). Of the sample, only 59 (27.44%) ATs reported referring an athlete for counseling services, and 37 (84.09%) of those who had access to a sport psychologist (n = 44) reported referring for sport psychology services. CONCLUSIONS: These results not only highlight ATs' current use of psychosocial strategies but also their desires to increase their current knowledge and understanding of these strategies while caring for injured athletes. PMID- 23724773 TI - Evidence for added value of baseline testing in computer-based cognitive assessment. AB - CONTEXT: Large-scale baseline cognitive assessment for individuals at risk for concussion is a common part of the protocol for concussion-surveillance programs, particularly in sports. Baseline cognitive testing is also being conducted in US military service members before deployment. Recently, the incremental validity of large-scale baseline cognitive assessment has been questioned. OBJECTIVE: To examine the added value of baseline cognitive testing in computer-based neuropsychological assessment by comparing 2 methods of classifying atypical performance in a presumed healthy sample. DESIGN: Cross-sectional study. SETTING: Military base. PATIENTS OR OTHER PARTICIPANTS: Military service members who took the Automated Neuropsychological Assessment Matrix (ANAM) before and after deployment (n = 8002). MAIN OUTCOME MEASURE(S): Rates of atypical performance in this healthy, active-duty sample were determined first by comparing postdeployment scores with a military normative database and then with each individual's personal baseline performance using a reliable change index. RESULTS: Overall rates of atypical performance were comparable across these 2 methods. However, these methods were highly discordant in terms of which individuals were classified as atypical. When norm-referenced methods were used, 2.6% of individuals classified as normal actually demonstrated declines from baseline. Further, 65.7% of individuals classified as atypical using norm referenced scores showed no change from baseline (ie, potential false-positive findings). CONCLUSIONS: Knowing an individual's baseline performance is important for minimizing potential false-positive errors and reducing the risks and stresses of misdiagnosis. PMID- 23724774 TI - Customized noise-stimulation intensity for bipedal stability and unipedal balance deficits associated with functional ankle instability. AB - CONTEXT: Stochastic resonance stimulation (SRS) administered at an optimal intensity could maximize the effects of treatment on balance. OBJECTIVE: To determine if a customized optimal SRS intensity is better than a traditional SRS protocol (applying the same percentage sensory threshold intensity for all participants) for improving double- and single-legged balance in participants with or without functional ankle instability (FAI). DESIGN: Case-control study with an embedded crossover design. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Twelve healthy participants (6 men, 6 women; age = 22 +/- 2 years, height = 170 +/- 7 cm, mass = 64 +/- 10 kg) and 12 participants (6 men, 6 women; age = 23 +/- 3 years, height = 174 +/- 8 cm, mass = 69 +/- 10 kg) with FAI. INTERVENTION(S): The SRS optimal intensity level was determined by finding the intensity from 4 experimental intensities at the percentage sensory threshold (25% [SRS25], 50% [SRS50], 75% [SRS75], 90% [SRS90]) that produced the greatest improvement in resultant center-of-pressure velocity (R-COPV) over a control condition (SRS0) during double-legged balance. We examined double- and single legged balance tests, comparing optimal SRS (SRS(opt1)) and SRS0 using a battery of center-of-pressure measures in the frontal and sagittal planes. MAIN OUTCOME MEASURE(S): Anterior-posterior (A-P) and medial-lateral (M-L) center-of-pressure velocity (COPV) and center-of-pressure excursion (COPE), R-COPV, and 95th percentile center-of-pressure area ellipse (COPA-95). RESULTS: Data were organized into bins that represented optimal (SRS(opt1)), second (SRS(opt2)), third (SRS(opt3)), and fourth (SRS(opt4)) improvement over SRS0. The SRS(opt1) enhanced R-COPV (P <= .05) over SRS0 and other SRS conditions (SRS0 = 0.94 +/- 0.32 cm/s, SRS(opt1) = 0.80 +/- 0.19 cm/s, SRS(opt2) = 0.88 +/- 0.24 cm/s, SRS(opt3) = 0.94 +/- 0.25 cm/s, SRS(opt4) = 1.00 +/- 0.28 cm/s). However, SRS did not improve R-COPV over SRS0 when data were categorized by sensory threshold. Furthermore, SRS(opt1) improved double-legged balance over SRS0 from 11% to 25% in all participants for the center-of-pressure frontal- and sagittal-plane assessments (P <= .05). The SRS(opt1) also improved single-legged balance over SRS0 from 10% to 17% in participants with FAI for the center-of-pressure frontal- and sagittal-plane assessments (P <= .05). The SRS(opt1) did not improve single legged balance in participants with stable ankles. CONCLUSIONS: The SRS(opt1) improved double-legged balance and transfers to enhancing single-legged balance deficits associated with FAI. PMID- 23724775 TI - Should athletes return to activity after cryotherapy? AB - REFERENCE/CITATION: Bleakley CM, Costello JT, Glasgow PD. Should athletes return to sport after applying ice? A systematic review of the effect of local cooling on functional performance. Sports Med. 2012; 42(1):69-87. CLINICAL QUESTION: Does local tissue cooling affect immediate functional performance outcomes in a sport situation? DATA SOURCES: Studies were identified by searching MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE, each from the earliest available record through April 2011. Combinations of 18 medical subheadings or key words were used to complete the search. Study Selection : This systematic review included only randomized controlled trials and crossover studies published in English that examined human participants who were treated with a local cooling intervention. At least 1 functional performance outcome that was measured before and after a cooling intervention had to be reported. Excluded were studies using whole-body cryotherapy or cold-water immersion above the waist and studies that measured strength or force production during evoked muscle contraction. DATA EXTRACTION: Data were extracted by 2 authors using a customized form to evaluate relevant data on study design, eligibility criteria, detailed characteristics of cooling protocols, comparisons, and outcome measures. Disagreement was resolved by consensus or third-party adjudication. To perform an intent-to-treat analysis when possible, data were extracted according to the original allocation groups, and losses to follow-up were noted. The review authors were not blinded to the study author, institution, or journal. For each study, mean differences or standardized mean differences and 95% confidence intervals were calculated for continuous outcomes using RevMan (version 5.1; The Nordic Cochrane Centre, Copenhagen, Denmark). Treatment effects were based on between-groups comparisons (cryotherapy versus control) using postintervention outcomes or within-group comparisons (precryotherapy versus postcryotherapy). If continuous data were missing standard deviations, other statistics including confidence intervals, standard error, t values, P values, or F values were used to calculate the standard deviation. The Cochrane risk-of-bias tool was used to assess the methodologic quality of included studies. Each study was evaluated for sequence generation, allocation concealment, assessor blinding, and incomplete outcome data. Studies were graded as low or high based on the criteria met, but the risk of bias across the studies was consistently high, so meaningful subgroup classifications were not possible. Differences in study quality and intervention details, including duration of cryotherapy interventions and time periods after intervention before follow-up, were potential sources of bias and considered for a subgroup analysis. MAIN RESULTS: Using the search criteria, the authors originally identified 1449 studies. Of these, after title and abstract review, 99 studies were deemed potentially relevant and kept for further analysis (1350 studies were excluded). Of the 99 potentially relevant studies, 35 were included in the final review (64 studies were excluded), with relevant outcomes of strength, power, vertical jump, endurance, agility, speed, performance accuracy, and dexterity reported. The 64 excluded studies were rejected due to intervention relevancy, outcome relevancy, and non-English language. In the 35 studies meeting the inclusion criteria, 665 healthy participants were assessed. Muscle strength (using an isokinetic dynamometer, cable tensiometer, strain-gauge device, or load cell) was assessed in 25 studies, whole-body exercise (vertical jump height, power, timed hop test, sprint time, and time taken to complete running-based agility tests, including carioca runs, shuttle sprints, T-shuttle, and cocontraction tests) was assessed in 6, performance accuracy (throwing or shooting) was assessed in 2, and hand dexterity was assessed in 2. Outcomes before and immediately after cryotherapy intervention were reported in all studies; additional outcome assessments at times ranging from 5 to 180 minutes postintervention were recorded in 11 studies. The review authors reported a high risk of bias: selection bias (poor randomization and concealment of group allocation), performance and detection bias (poor blinding of assessors), and attrition bias (incomplete data). Because of the diversity of studies, particularly with respect to cryotherapy protocols and the potential for rewarming before the posttest, the effects of cryotherapy on functional performance were mixed. From the included studies, the authors concluded that cryotherapy treatment reduced upper and lower extremity muscle strength immediately after cryotherapy. However, increases in force output after cryotherapy were reported in 5 studies. Regardless of the effect of cryotherapy on strength, the clinical meaningfulness of most of the data may not be important due to variability and small effects. Studies reporting outcomes of muscle endurance resulted in conflicting evidence: endurance increased immediately after cryotherapy in 6, whereas muscle endurance decreased in 3 . These conflicting results limit the ability to draw clinically relevant conclusions about the effect of cryotherapy on muscle endurance. The majority of studies evaluating whole-body exercise demonstrated decreases in performance after cryotherapy; these outcomes included vertical jump, sprint, and agility, even when cryotherapy was applied only to a body part. Additionally, cryotherapy appeared to decrease hand dexterity and throwing accuracy immediately after intervention, although an increase in shooting performance postintervention was reported in 1 study . CONCLUSIONS: The authors suggested that the available evidence indicates that athletic performance may be adversely affected when athletes return to play immediately after cryotherapy treatments. Many of the included studies used variable cooling protocols, reflecting differences in time, temperature, and mode of cryotherapy. The majority of the included studies used cryotherapy for at least 20 minutes. However, when considering an immediate return to activity, this cooling duration may not be clinically relevant because cryotherapy applications during practice and competitions usually last less than 20 minutes. When immediate return to activity occurs after cryotherapy, short-duration cold applications or progressive warm-ups should be implemented to prevent a deleterious effect on functional performance. PMID- 23724776 TI - Solution nuclear magnetic resonance structure of the GATase subunit and structural basis of the interaction between GATase and ATPPase subunits in a two subunit-type GMPS from Methanocaldococcus jannaschii. AB - The solution structure of the monomeric glutamine amidotransferase (GATase) subunit of the Methanocaldococcus janaschii (Mj) guanosine monophosphate synthetase (GMPS) has been determined using high-resolution nuclear magnetic resonance methods. Gel filtration chromatography and 15N backbone relaxation studies have shown that the Mj GATase subunit is present in solution as a 21 kDa (188-residue) monomer. The ensemble of 20 lowest-energy structures showed root mean-square deviations of 0.35 +/- 0.06 A for backbone atoms and 0.8 +/- 0.06 A for all heavy atoms. Furthermore, 99.4% of the backbone dihedral angles are present in the allowed region of the Ramachandran map, indicating the stereochemical quality of the structure. The core of the tertiary structure of the GATase is composed of a seven-stranded mixed beta-sheet that is fenced by five alpha-helices. The Mj GATase is similar in structure to the Pyrococcus horikoshi (Ph) GATase subunit. Nuclear magnetic resonance (NMR) chemical shift perturbations and changes in line width were monitored to identify residues on GATase that were responsible for interaction with magnesium and the ATPPase subunit, respectively. These interaction studies showed that a common surface exists for the metal ion binding as well as for the protein-protein interaction. The dissociation constant for the GATase-Mg(2+) interaction has been found to be ~1 mM, which implies that interaction is very weak and falls in the fast chemical exchange regime. The GATase-ATPPase interaction, on the other hand, falls in the intermediate chemical exchange regime on the NMR time scale. The implication of this interaction in terms of the regulation of the GATase activity of holo GMPS is discussed. PMID- 23724778 TI - Role of propagule pressure in colonization success: disentangling the relative importance of demographic, genetic and habitat effects. AB - High propagule pressure is arguably the only consistent predictor of colonization success. More individuals enhance colonization success because they aid in overcoming demographic consequences of small population size (e.g. stochasticity and Allee effects). The number of founders can also have direct genetic effects: with fewer individuals, more inbreeding and thus inbreeding depression will occur, whereas more individuals typically harbour greater genetic variation. Thus, the demographic and genetic components of propagule pressure are interrelated, making it difficult to understand which mechanisms are most important in determining colonization success. We experimentally disentangled the demographic and genetic components of propagule pressure by manipulating the number of founders (fewer or more), and genetic background (inbred or outbred) of individuals released in a series of three complementary experiments. We used Bemisia whiteflies and released them onto either their natal host (benign) or a novel host (challenging). Our experiments revealed that having more founding individuals and those individuals being outbred both increased the number of adults produced, but that only genetic background consistently shaped net reproductive rate of experimental populations. Environment was also important and interacted with propagule size to determine the number of adults produced. Quality of the environment interacted also with genetic background to determine establishment success, with a more pronounced effect of inbreeding depression in harsh environments. This interaction did not hold for the net reproductive rate. These data show that the positive effect of propagule pressure on founding success can be driven as much by underlying genetic processes as by demographics. Genetic effects can be immediate and have sizable effects on fitness. PMID- 23724777 TI - Pan-genome analysis of the emerging foodborne pathogen Cronobacter spp. suggests a species-level bidirectional divergence driven by niche adaptation. AB - BACKGROUND: Members of the genus Cronobacter are causes of rare but severe illness in neonates and preterm infants following the ingestion of contaminated infant formula. Seven species have been described and two of the species genomes were subsequently published. In this study, we performed comparative genomics on eight strains of Cronobacter, including six that we sequenced (representing six of the seven species) and two previously published, closed genomes. RESULTS: We identified and characterized the features associated with the core and pan genome of the genus Cronobacter in an attempt to understand the evolution of these bacteria and the genetic content of each species. We identified 84 genomic regions that are present in two or more Cronobacter genomes, along with 45 unique genomic regions. Many potentially horizontally transferred genes, such as lysogenic prophages, were also identified. Most notable among these were several type six secretion system gene clusters, transposons that carried tellurium, copper and/or silver resistance genes, and a novel integrative conjugative element. CONCLUSIONS: Cronobacter have diverged into two clusters, one consisting of C. dublinensis and C. muytjensii (Cdub-Cmuy) and the other comprised of C. sakazakii, C. malonaticus, C. universalis, and C. turicensis, (Csak-Cmal-Cuni Ctur) from the most recent common ancestral species. While several genetic determinants for plant-association and human virulence could be found in the core genome of Cronobacter, the four Cdub-Cmuy clade genomes contained several accessory genomic regions important for survival in a plant-associated environmental niche, while the Csak-Cmal-Cuni-Ctur clade genomes harbored numerous virulence-related genetic traits. PMID- 23724779 TI - Pearson's principle inspired generalized strategy for the fabrication of metal hydroxide and oxide nanocages. AB - Designing a general route for rational synthesis of a series or families of nanomaterials for emerging applications has become more and more fascinating and vital in the view of nanoscience and nanotechnology. Herein, we explore a general strategy for fabricating uniform nanocages of metal hydroxides (MHs) and metal oxides (MOs). A template-assisted route inspired by Pearson's hard and soft acid base (HSAB) principle was employed for synthesizing MH nanocages via meticulous selection of the coordinating etchant as well as optimization of the reaction conditions. The concept of "coordinating etching" is successfully achieved in this work. This unique route shows potential in designing well-defined and high quality MH nanocages with varying components, shell thicknesses, shapes, and sizes at room temperature. Consequently, porous MO nanocages can be obtained readily just through appropriate thermal treament of the respective MH nanocages. The overall strategy present in this work extends the application of the HSAB principle in nanoscience and offers a unqiue clue for rational fabrication of hollow (porous) and/or amorphous structures on the nanoscale, where these nanocages may present promising potential for various applications. PMID- 23724781 TI - Crystal structure and local structure of Mg(2-x)Pr(x)Ni4 (x = 0.6 and 1.0) deuteride using in situ neutron total scattering. AB - We studied crystal structure and local structure of Mg(2-x)Pr(x)Ni4 (x = 0.6 and 1.0) and their deuterides using in situ neutron total scattering and first principles calculations. The total scattering data were analyzed using Rietveld refinement and pair distribution function analysis (PDF). The crystal structure of Mg(2-x)Pr(x)Ni4 before deuterium absorption was C15b in space group F43m. No difference between the crystal and local (PDF) structures was observed. The crystal structure of Mg1.0Pr1.0Ni4D(~4) was found to be orthorhombic in space group Pmn2(1), with three deuterium occupation sites: PrNi3 and two types of bipyramidal Pr2MgNi2 that have a plane of symmetry composed of MgNi2. There is no significant difference between the crystal structure and the local structure of Mg1.0Pr1.0Ni4D(~4). On the other hand, the average crystal structure of the Mg rich Mg1.4Pr0.6Ni4D(~3.6) was C15b with two deuterium occupation sites: PrNi3 and MgPrNi2 suggesting that the deuterium occupation shifts away from the Pr2MgNi2 bipyramid. First-principles relaxed structures also showed the shift of the hydrogen occupation site toward the Pr atom of the bipyramid, when induced by Mg substitution for the opposing Pr, resulting in hydrogen occupation in the MgPrNi2 tetrahedral site. The PDF pattern of Mg1.4Pr0.6Ni4D(~3.6) cannot be refined below 7.2 A in atomic distances using the C15b structure which was obtained from Rietveld refinement but can be done using an orthorhombic structure. It suggests that Mg1.4Pr0.6Ni4D(~3.6) was locally distorted to the orthorhombic. PMID- 23724780 TI - U1 adaptors for the therapeutic knockdown of the oncogene pim-1 kinase in glioblastoma. AB - U1 small nuclear interference (U1i) has recently been described as a novel gene silencing mechanism. U1i employs short oligonucleotides, so-called U1 adaptors, for specific gene knockdown, expanding the field of current silencing strategies that are primarily based on RNA interference (RNAi) or antisense. Despite the potential of U1 adaptors as therapeutic agents, their in vivo application has not yet been studied. Here we explore U1i by analyzing U1 adaptor-mediated silencing of the oncogene Pim-1 in glioblastoma cells. We have generated Pim-1-specific U1 adaptors comprising DNA, locked nucleic acids (LNA), and 2'-O-Methyl RNA and demonstrate their ability to induce a Pim-1 knockdown, leading to antiproliferative and pro-apoptotic effects. For the therapeutic in vivo application of U1 adaptors, we establish their complexation with branched low molecular weight polyethylenimine (PEI). Upon injection of nanoscale PEI/adaptor complexes into subcutaneous glioblastoma xenografts in mice, we observed the knockdown of Pim-1 that resulted in the suppression of tumor growth. The absence of hepatotoxicity and immune stimulation also demonstrates the biocompatibility of PEI/adaptor complexes. We conclude that U1i represents an alternative to RNAi for the therapeutic silencing of pathologically upregulated genes and demonstrate the functional relevance of Pim-1 oncogene knockdown in glioblastoma. We furthermore introduce nanoscale PEI/adaptor complexes as efficient and safe for in vivo application, thus offering novel therapeutic approaches based on U1i mediated gene knockdown. PMID- 23724782 TI - Pulmonary lipoma in a dog. AB - An eight-year-old, neutered, male German short-haired pointer was presented for a chronic cough and an intrathoracic mass. Computed tomography revealed a mass with low attenuation in the right caudal lung lobe that invaded the principal bronchi. The mass was removed by right caudal and accessory lung lobectomy. The histopathological diagnosis was pulmonary lipoma. The clinical signs resolved following surgery. There was no evidence of recurrence or de novo lesions on computed tomography performed 12 months post-surgery. To the authors' knowledge, this is the first report of a pulmonary lipoma in a dog. PMID- 23724783 TI - Oxide heterostructure resistive memory. AB - Resistive switching devices are widely believed as a promising candidate for future memory and logic applications. Here we show that by using multilayer oxide heterostructures the switching characteristics can be systematically controlled, ranging from unipolar switching to complementary switching and bipolar switching with linear and nonlinear on-states and high endurance. Each layer can be tailed for a specific function during resistance switching, thus greatly improving the degree of control and flexibility for optimized device performance. PMID- 23724784 TI - Intra-operative correction of acidosis, coagulopathy and hypothermia in combat casualties with severe haemorrhagic shock. AB - We assessed acidosis, coagulopathy and hypothermia, before and after surgery in 51 combat troops operated on for severe blast injury. Patients were transfused a median (IQR [range]) of 27 (17-38 [5-84]) units of red cell concentrate, 27 (16 38 [4-83]) units of plasma, 2.0 (0.5-3.5 [0-13.0]) units of cryoprecipitate and 4 (2-6 [0-17]) pools of platelets. The pH, base excess, prothrombin time and temperature increased: from 7.19 (7.10-7.29 [6.50-7.49]) to 7.45 (7.40-7.51 [7.15 7.62]); from -9.0 (-13.5 to -4.5 [-28 to -2]) mmol.l-1 to 4.5 (1.0-8.0 [-7 to +11]) mmol.l-1; from 18 (15-21 [9-24]) s to 14 (11-18 [9-21]) s; and from 36.1 (35.1-37.1 [33.0-38.1]) degrees C to 37.4 (37.0-37.9 [36.0-38.0]) degrees C, respectively. Contemporary intra-operative resuscitation strategies can normalise the physiological derangements caused by haemorrhagic shock. PMID- 23724785 TI - Local atopy is more relevant than serum sIgE in reflecting allergy in childhood adenotonsillar hypertrophy. AB - BACKGROUND: There was a lack of convincing evidence supporting the influence of allergy on the adenotonsillar hypertrophy (ATH). We investigated the presence of specific IgE (sIgE) in the serum and adenotonsillar tissues in children with ATH. METHODS: A Pharmacia ImmunoCAP system was used to test sIgE against 31 allergens in the serum in 83 children with ATH before adenotonsillectomy. sIgE against 15 representative allergens were detected in adenotonsillar tissues from 20 of those children. RESULTS: A total of 51 (61.45%) children had positive serum sIgE. 20 children with ATH had positive sIgE to more than two allergens at both tonsils and adenoids, although half of them were serum sIgE negative. The percentage of subjects with positive sIgE expression in adenoids and tonsils was 50.0% and 42.9%, respectively, among the subjects with positive serum sIgE expression. Of subjects with negative serum sIgE expression, local sIgE was detected in 36.0% of adenoids and 43.8% of tonsils, respectively. The rate of sIgE presence in local tissue (adenoids or tonsils) was significantly higher than that seen in the serum. CONCLUSION: This study provided evidence that there was an important role for allergic inflammation in the ATH. The inconsistency in sIgE expression between adenotonsillar and serum suggests a role of local atopy in childhood ATH. PMID- 23724787 TI - WU polyomavirus detected in respiratory tract specimens from young children in Japan. AB - Polyomaviruses (PyV) WU and KI are reportedly associated with respiratory tract disease (RTD) worldwide but their incidence is unclear in Japan. In a 2 year prospective study, WU/KIPyV were detected in 48 (13.9%) and in five (1.4%) of 345 children hospitalized with lower RTD, respectively. The seasonal distribution was observed in spring and early summer. Other respiratory viruses were co-detected in 51% of PyV-positive patients, but eight (2.3%) of the WUPyV-positive patients were negative for other known pathogens. PMID- 23724786 TI - Evaluation of multifunctional polysaccharide hydrogels with varying stiffness for bone tissue engineering. AB - The use of hydrogels for bone regeneration has been limited due to their inherent low modulus to support cell adhesion and proliferation as well as their susceptibility to bacterial infections at the wound site. To overcome these limitations, we evaluated multifunctional polysaccharide hydrogels of varying stiffness to obtain the optimum stiffness at which the gels (1) induce proliferation of human dermal fibroblasts, human umbilical vascular endothelial cells (HUVECs), and murine preosteoblasts (MC3T3-E1), (2) induce osteoblast differentiation and mineralization, and (3) exhibit an antibacterial activity. Rheological studies demonstrated that the stiffness of hydrogels made of a polysaccharide blend of methylcellulose, chitosan, and agarose was increased by crosslinking the chitosan component to different extents with increasing amounts of genipin. The gelation time decreased (from 210 to 60 min) with increasing genipin concentrations. Proliferation of HUVECs decreased by 10.7 times with increasing gel stiffness, in contrast to fibroblasts and osteoblasts, where it increased with gel stiffness by 6.37 and 7.8 times, respectively. At day 14 up to day 24, osteoblast expression of differentiation markers-osteocalcin, osteopontin and early mineralization marker-alkaline phosphatase, were significantly enhanced in the 0.5% (w/v) crosslinked gel, which also demonstrated enhanced mineralization by day 25. The antibacterial efficacy of the hydrogels decreased with the increasing degree of crosslinking as demonstrated by biofilm formation experiments, but gels crosslinked with 0.5% (w/v) genipin still demonstrated significant bacterial inhibition. Based on these results, gels crosslinked with 0.5% (w/v) genipin, where 33% of available groups on chitosan were crosslinked, exhibited a stiffness of 502+/-64.5 Pa and demonstrated the optimal characteristics to support bone regeneration. PMID- 23724788 TI - Outcome of mitral valve plasty or replacement: atrial fibrillation an effect modifier. AB - BACKGROUND: Advances in the understanding of mitral valve pathology have laid to mitral valve plasty (MPL) as the procedure of choice of all the mitral intervention as compared to mitral valve replacement (MVR). MATERIAL AND METHODS: A cohort of 355 patients with mitral valve disease operated between January 1993 to January 2007 with closing date first of mars 2011. There were 214 MPL and 141 MVR at the Hospital discharge. This retrospective cohort had the design of exposed (MPL) versus non-exposed (MVR) with outcome total mortality and reoperation during follow up. Also echocardiography follow-up was undertaken to estimate the true long-term failure rate of repair. RESULTS: The mean follow up was 5.3 years SE (3.82) maximum follow up was 14.1 years. Considering the patient time model the association between repair/replacement and total mortality RR = 0.43 95% (0.28-074) p = 0.002 controlling for the confounding effect of 3-vessels disease. Those results were confirmed by propensity score analysis. CONCLUSION: In a cohort of patient with mitral valve disease undergoing MPL/MVR was examined. MPL was associated with better survival, and lower reoperation rate for patients without AF but same rate for patients with AF. We advocate more attention in controlling risk factors of AF in the clinical management of mitral disease. Long term failure rate of MPL was low during follow up time. A replication of our results by a randomized clinical trial is mandatory. PMID- 23724789 TI - The effect of carbohydrate and marine peptide hydrolysate co-ingestion on endurance exercise metabolism and performance. AB - BACKGROUND: The purpose of this study was to examine the efficacy of introducing a fish protein hydrolysate (PEP) concurrently with carbohydrate (CHO) and whey protein (PRO) on endurance exercise metabolism and performance. METHODS: In a randomised, double blind crossover design, 12 male volunteers completed an initial familiarisation followed by three experimental trials. The trials consisted of a 90 min cycle task corresponding to 50% of predetermined maximum power output, followed by a 5 km time trial (TT). At 15 min intervals during the 90 min cycle task, participants consumed 180 ml of CHO (67 g(.)hr(-1) of maltodextrin), CHO-PRO (53.1 g(.)hr of CHO, 13.6 g(.)hr(-1) of whey protein) or CHO-PRO-PEP (53.1 g(.)hr(-1) of CHO, 11 g(.)hr(-1) of whey protein and 2.4 g(.)hr(-1)of hydrolyzed marine peptides). RESULTS AND CONCLUSIONS: During the 90 min cycle task, the respiratory exchange ratio (RER) in the CHO-PRO condition was significantly higher than CHO (p < 0.001) and CHO-PRO-PEP (p < 0.001). Additionally, mean heart rate for the CHO condition was significantly lower than that for CHO-PRO (p = 0.021). Time-to-complete the 5 km TT was not significantly different between conditions (m +/- SD: 456 +/- 16, 456 +/- 18 and 455 +/- 21 sec for CHO, CHO-PRO and CHO-PRO-PEP respectively, p = 0.98). Although the addition of hydrolyzed marine peptides appeared to influence metabolism during endurance exercise in the current study, it did not provide an ergogenic benefit as assessed by 5 km TT performance. PMID- 23724790 TI - Apigenin promotes apoptosis, inhibits invasion and induces cell cycle arrest of T24 human bladder cancer cells. AB - BACKGROUND: Apigenin (4',5,7-trihydroxyflavone) was recently shown effective in inhibiting several cancers. The aim of this study was to investigate the effect and mechanism of apigenin in the human bladder cancer cell line T24 for the first time. METHODS: T24 cells were treated with varying concentrations and time of apigenin. Cell viability was evaluated by MTT assay. Cell motility and invasiveness were assayed by Matrigel migration and invasion assay. Flow cytometry and western blot analysis were used to detect cell apoptosis, cell cycle and signaling pathway. RESULTS: The results demonstrated that apigenin suppressed proliferation and inhibited the migration and invasion potential of T24 bladder cancer cells in a dose- and time-dependent manner, which was associated with induced G2/M Phase cell cycle arrest and apoptosis. The mechanism of action is like to involve PI3K/Akt pathway and Bcl-2 family proteins. Apigenin increased caspase-3 activity and PARP cleavage, indicating that apigenin induced apoptosis in a caspase-dependent way. CONCLUSIONS: These findings suggest that apigenin may be an effective way for treating human bladder cancer. PMID- 23724791 TI - Evaluation of the effectiveness of sugammadex for verapamil intoxication. AB - Previous studies have shown that medications from the cyclodextrin family bind to verapamil. The aim of our study was to determine whether sugammadex could bind to verapamil and prevent the cardiovascular toxicity of that drug. Twenty-eight sedated Wistar rats were infused with verapamil at 37.5 mg/kg/h. Five minutes after the start of infusion, the animals were treated with a bolus of either 16 mg/kg, 100 mg/kg or 1000 mg/kg sugammadex. The control group was treated with an infusion without sugammadex. The heart rate and respiratory rate were monitored, and an electrocardiogram was recorded. The primary end-point was the time to asystole. The verapamil infusion continued until the animals arrested. The asystole time for the S16 group was significantly longer compared to those for the control and S1000 groups (p < 0.05). The asystole time for the S1000 group was significantly shorter than those for all of the other groups (p < 0.05). Reflecting these data, there was a near doubling of the mean lethal dose of verapamil from 13.57 mg/kg (S.D. +/-8.1) in the saline-treated rats to 22.42 mg/kg (S.D. +/-9.9) in the sugammadex 16 group (p < 0.05). However, for the sugammadex 1000 group, the mean lethal dose was found to be 6.28 +/- 1.11 mg/kg. This dose is significantly lower than those for all of the other groups (p < 0.05). We found that treatment with 16 mg/kg sugammadex delayed verapamil cardiotoxicity in rats. However, 1000 mg/kg sugammadex accelerated verapamil cardiotoxicity in rats. Further studies must be conducted to investigate the interaction between verapamil and sugammadex. PMID- 23724792 TI - Should psychomotor disturbance be an essential criterion for a DSM-5 diagnosis of melancholia? AB - BACKGROUND: The CORE measure has proved useful in rating observed psychomotor disturbance (PMD), which has been held to be a key feature of melancholic depression. However, studies have shown a substantial percentage of subjects fulfilling DSM criteria for melancholia do not have observable PMD. METHODS: A semi-structured interview schedule was used in assessing and diagnosing depressed older patients. DSM-IV diagnoses were made, and the CORE measure was used to rate PMD. Comparisons were made between melancholia inpatients who scored low and those scoring high on the CORE in relation to presentation and pattern of symptoms. RESULTS: Of 32 inpatients with melancholia, 10 scored 0-7, 8 scored 8 10, and 14 scored 15 or more on the CORE. Thirty-two inpatients with psychotic depression scored 13 or more. High-CORE participants manifested unvarying depression more often than did low-CORE participants, and were less likely to state that stress precipitated their depressive episode. CONCLUSIONS: High-CORE melancholia cases appear to have more in common with psychotic depression than do low-CORE cases. Designation of observable PMD as an essential criterion in making a diagnosis of melancholia could increase the utility of the DSM classification in relation to treatment planning. PMID- 23724793 TI - Positron emission tomography computed tomography in large cell transformation of mycosis fungoides. PMID- 23724794 TI - Tissue-specific DNA methylation profiles in newborns. AB - BACKGROUND: Epidemiological studies demonstrate that foetal growth restriction and low birth weight affect long-term health. Derangements in tissue-specific epigenetic programming of foetal and placental tissues are a suggested underlying mechanism of which DNA methylation is best understood. DNA methylation has been mostly investigated in DNA from white blood cells. To improve baseline understanding of tissue-specific DNA methylation, we examined variation in DNA methylation profiles of the imprinted foetal growth genes IGF2 and H19 in three different tissues from the same newborn obtained at the same time. FINDINGS: We obtained DNA from umbilical cord blood mononuclear cells (MNC; CD34+ and CD34-, n = 6), foetal side of the placenta (n = 5) and umbilical cord Wharton jelly (n = 5). DNA methylation of the IGF2 differentially methylated region (DMR) and H19 DMR was measured using quantitative mass spectrometry. Analysis of variance testing showed no statistical difference between total mean methylation of CD34+ and CD34- MNC. Further comparisons were made with the pooled total MNC fraction. Mean IGF2 DMR methylation of Wharton jelly was 1.3 times higher (P = 0.001) than mean methylation of the pooled MNC. Placental mean methylation was 0.8 times lower (P <0.001) and Wharton jelly 0.9 times lower (P <0.001) than the pooled MNC of H19 DMR. CONCLUSION: The total MNC fraction is a rather homogeneous cell population for methylation studies of imprinted genes in umbilical cord blood white blood cells, but may not always reflect the methylation levels of IGF2 and H19 in other organs. PMID- 23724795 TI - Pilot study of perioperative accidental durotomy: does the period of postoperative bed rest reduce the incidence of complication? AB - INTRODUCTION: An accidental durotomy is a recognised and not infrequent complication of lumbar spine surgery, and may lead to postoperative low-pressure headaches, pseudomeningocele and CSF leak. Conventional postoperative management involves a period of flat bed rest. There is no agreement as to the need for and duration of postoperative bed rest. This study aims to determine whether the duration of flat bed rest alters the rate of these complications. MATERIALS AND METHODS: This is a retrospective study. All patients who underwent surgery for degenerative spinal disease between May 2010 and May 2011 were reviewed. All patients who incurred an accidental durotomy and who were repaired using fibrin glue were included in this study. Their notes were reviewed for evidence of complications for a minimum of 12 months after surgery. The following complications were identified: postural headache, pseudomeningocele, CSF leak wound infection, subdural haematoma. RESULTS: Eight hundred and eighty-nine patients underwent lumbar spine surgery. Sixty-one (6.8%) patients suffered an accidental durotomy and were repaired with fibrin glue. Twenty-six patients were mobilised on the first postoperative day, 9 patients on the second, and a further 26 patients were mobilised on the third postoperative day or later. The overall incidence of complications related to the durotomy was 18%. There was no statistical significance between the day of mobilisation and the rate of complication (p = 0.433). CONCLUSION: A longer period of mandatory bed rest does not decrease the rate of complications. Patients should be mobilised as soon as they can. This could potentially reduce the length of hospital stay and the cost of aftercare. PMID- 23724796 TI - The effect of differing intensities of acute cycling on preadolescent academic achievement. AB - The present study examined the effects of differing intensity levels of acute exercise on preadolescent academic ability. In a repeated measures design, 18 preadolescent participants (mean age+/-S.D.= 9.8+/-1.4 years: 9 male and 9 female) completed the Wide Range Achievement Test (WRAT 4) following 20 minutes of rest, 20-minutes on a cycling ergometer at 50% maximal heart rate reserve (HRR), and 20-minutes on a cycling ergometer at 75% HRR on separate days. Exercise was found to improve spelling irrespective of intensity level. Moderate levels of exercise improved reading although the effect of high levels of intensity is less clear. Both intensity levels impaired arithmetic, whilst sentence comprehension was unaffected. These findings further support the past research that indicates acute bouts of exercise can selectively improve cognition in preadolescent children. However, the present study finds no support for the notion that increasing the intensity of exercise accentuates benefits. PMID- 23724797 TI - Combinatorial neural codes from a mathematical coding theory perspective. AB - Shannon's seminal 1948 work gave rise to two distinct areas of research: information theory and mathematical coding theory. While information theory has had a strong influence on theoretical neuroscience, ideas from mathematical coding theory have received considerably less attention. Here we take a new look at combinatorial neural codes from a mathematical coding theory perspective, examining the error correction capabilities of familiar receptive field codes (RF codes). We find, perhaps surprisingly, that the high levels of redundancy present in these codes do not support accurate error correction, although the error correcting performance of receptive field codes catches up to that of random comparison codes when a small tolerance to error is introduced. However, receptive field codes are good at reflecting distances between represented stimuli, while the random comparison codes are not. We suggest that a compromise in error-correcting capability may be a necessary price to pay for a neural code whose structure serves not only error correction, but must also reflect relationships between stimuli. PMID- 23724798 TI - Invasive candidiasis: update on current pharmacotherapy options and future perspectives. AB - INTRODUCTION: Invasive candidiasis (IC), mainly candidemia, is a leading cause of morbidity and mortality among immunocompromised patients and those admitted to intensive care units. Despite the recognition of risk factors and advances in disease prevention, Candida-related hospitalizations and mortality continue to rise. For treatment, four classes of older and newer antifungal agents are currently available. Adjunctive immunotherapies and a monoclonal antibody against heat shock protein 90 (efungumab) are promising novel therapeutic approaches. AREAS COVERED: In this article, approaches and therapeutic agents for candidemia and other forms of IC are reviewed. EXPERT OPINION: The thorough understanding of the available antifungal agents in combination with the increasing knowledge of the mechanisms that underlie the pathogenesis of Candida infections and the development of newer approaches such as efungumab and immunotherapy with adjunctive cytokines may improve the prognosis of patients with life-threatening invasive Candida infections. PMID- 23724800 TI - Prospective assessment of dynamic CT and MR cholangiography in functional biliary pain. AB - OBJECTIVE: The objectives of our study were to assess the feasibility of dynamic CT and MR cholangiography during gallbladder stimulation, to compare CT and MR cholangiography with biliary scintigraphy, and to identify morphologic differences between patients with functional biliary pain and healthy control subjects. SUBJECTS AND METHODS: In this prospective study, 30 patients with functional biliary pain underwent biliary scintigraphy, CT cholangiography, and MR cholangiography before and during 45-minute sincalide infusions. Thirty healthy control subjects also underwent MR cholangiography with sincalide infusion. IV contrast agents (iodipamide meglumine or gadobenate dimeglumine) were administered before scanning. CT and MR images were qualitatively and quantitatively analyzed. RESULTS: Diagnostic images were obtained of all participants. There was good agreement for gallbladder ejection fraction (EF) at 40 minutes by all three methods (Lin's concordance correlation coefficient >= 0.6). Gallbladder contraction and refilling occurred more promptly by CT and MR cholangiography than scintigraphy. CT and MR cholangiography showed previously undiagnosed gallstones in two patients (7%). Gallbladder shape was categorized as straight, curved, or folded; a folded gallbladder was present in 37% and 23% of patients at baseline and 40 minutes, respectively, versus in 3% of control subjects at both times (p <= 0.004). Asymmetric patterns of gallbladder contraction occurred in 10 patients (33%) and four control subjects (13%) (p = 0.13). CONCLUSION: Dynamic CT cholangiography and MR cholangiography performed during pharmacologic stimulation accurately measure gallbladder EFs and detect missed gallstones. Gallbladder shape before and during contraction differs between patients with functional biliary pain and healthy control subjects. Dynamic CT cholangiography and MR cholangiography are promising techniques that might improve selection of patients to undergo cholecystectomy for functional biliary pain. PMID- 23724801 TI - Nanoscale patterning of metal nanoparticle distribution in glasses. AB - : We show that electric field imprinting technique allows for patterning of metal nanoparticles in the glass matrix at the subwavelength scale. The formation of glass-metal nanocomposite strips with a width down to 150 nm is demonstrated. The results of near-field microscopy of imprinted patterns are in good agreement with the performed numerical modeling. Atomic force microscopy reveals that imprinting also results in the formation of nanoscale surface profile with the height going down with the decrease of the strip width. The experiments prove the applicability of this technique for the fabrication of nanoscale plasmonic components. PMID- 23724803 TI - Preparation of a homologous series of tetraalkylammonium graphite intercalation compounds. AB - Graphite intercalation compounds (GICs) of a series of symmetric or asymmetric tetraalkylammonium (TAA) intercalates are obtained from stage-1 [Na(en)1.0]C15 via cation exchange. The prepared dull-black TAA-GICs contain either flattened monolayer or bilayer galleries, with significant cointercalation of the dimethylsulfoxide (DMSO) solvent in the bilayer galleries. The TAA-GIC products obtained are characterized by X-ray diffraction and related structural modeling, compositional analyses, and Raman spectroscopy. [(C4H9)4N]C43 is obtained as a pure stage-1 GIC with the flattened monolayer structure. The larger symmetric TAA cations, (C6H13)4N, (C7H15)4N, (C8H17)4N, and the asymmetric TAA cations, (C12H25)(CH3)3N, (C18H37)(CH3)3N, (C18H37)2(CH3)2N, all form pure stage-1 GICs with flattened bilayer conformations. Thermogravimetric analyses combined with mass spectrometry and elemental analyses indicate the presence of ~1-2 DMSO cointercalates per bilayer cation. The intercalate layers in these TAA-GICs have expansions along the stacking direction of ~0.40 nm. Raman data confirm the low graphene sheet charge densities in the obtained TAA-GICs. PMID- 23724802 TI - Can temperature explain the latitudinal gradient of ulcerative colitis? Cohort of Norway. AB - BACKGROUND: Incidence and prevalence of ulcerative colitis follow a north-south (latitudinal) gradient and increases northwards at the northern hemisphere or southwards at the southern hemisphere. The disease has increased during the last decades. The temporal trend has been explained by the hygiene hypothesis, but few parallel explanations exist for the spatial variability. Many factors are linked to latitude such as climate. Our purpose was to investigate the association between variables governing the climate and prospectively identified patients. METHODS: In this study, we used a subset of the population-based Cohort of Norway (n = 80412) where 370 prevalent cases of ulcerative colitis were identified through self-reported medication. The meteorological and climatic variables temperature, precipitation, and altitude were recorded from weather stations of the Norwegian Meteorological Institute. Summer temperature was used to capture environmental temperature. RESULTS: Summer temperature was significantly related to the prevalence of ulcerative colitis. For each one-degree increase in temperature the odds for ulcerative colitis decreased with about 9% (95% CI: 3% 15%). None of the other climatic factors were significantly associated to the risk of ulcerative colitis. Contextual variables did not change the association to the prevalence of ulcerative colitis. CONCLUSIONS: The present results show that the prevalence of ulcerative colitis is associated to summer temperature. Our speculation is that summer temperature works as an instrumental variable for the effect of microbial species richness on the development of ulcerative colitis. Environmental temperature is one of the main forces governing microbial species richness and the microbial composition of the commensal gut flora is known to be an important part in the process leading to ulcerative colitis. PMID- 23724804 TI - Dairy cows welfare quality in tie-stall housing system with or without access to exercise. AB - BACKGROUND: Tie-stall housing of dairy cows is used extensively worldwide, despite of the welfare concerns regarding the restriction of voluntary movement and limitation of expression of the cows' natural behaviour. The aim of this study was to compare the welfare quality of dairy cows kept in two types of tie stall housing systems: with regular outdoor exercise and without access to exercise. In addition, the study investigated the relationship between different welfare measures of dairy cows kept in tie-stalls. METHODS: 3,192 lactating cows were assessed using the Welfare Quality(r) assessment protocol for cattle in 80 commercial dairy farms, half of the farms providing outdoor access for the animals to exercise. The descriptive statistical indicators were determined for the assessed measures and for the welfare criteria and principle scores. The data obtained in the two housing types were compared and the correlation coefficients were calculated between the different welfare measures. RESULTS: The significant differences found between the two housing systems for the majority of the animal based measures indicate the positive effect of exercise on the welfare of tethered cows. Many of the animal welfare parameters correlated with each other. For the farms allowing the cows' turnout in a paddock, pasture or both, the mean scores for the welfare criteria and principles were higher than for the farms with permanent tethering of the cows, except the criteria absence of prolonged hunger and expression of social behaviours. The lowest scores were obtained for the criterion positive emotional state, in both housing systems. With regard to the overall classification, none of the farms were considered excellent. In the not classified category were only farms with all-year-round tethering of the animals and in the enhanced category only farms where the cows had outdoor access. CONCLUSIONS: The welfare quality of the investigated dairy cows was significantly better in the tie-stall farms which allow exercise for cows (paddocks, pasture or both) than in those which do not. In the light of our results we consider that dairy cattle welfare is not necessarily poor in tie stall housing systems, its quality depending on the management practices. PMID- 23724806 TI - Effect of cephalograms on decisions for early orthodontic treatment. AB - OBJECTIVE: To assess the extent to which cephalograms modify therapeutic decisions related to early orthodontic treatment. MATERIALS AND METHODS: Diagnostic records of six patients requiring early treatment were digitized for this purpose. A total of 234 orthodontists were then asked to select therapeutic measures on a treatment-planning sheet at two different times (T1 and T2). Three groups of orthodontists were formed and were provided with case-specific records either including or not including cephalograms and the appended tracing values. Forty-seven orthodontists completed all phases of the questions. RESULTS: Statistical analysis revealed only two statistically significant differences between the first (T1) and second (T2) treatment plans, both concerning options of transverse treatment. None of the other results showed any significant changes from T1 to T2 treatment planning. CONCLUSION: It follows that cephalograms did not influence therapeutic decisions for early orthodontic treatment and should not be routinely used in very young patients. PMID- 23724805 TI - Are patients with inflammatory eye disease treated with systemic immunosuppressive therapy at increased risk of malignancy? AB - The purpose of this study is to review the literature on the risk of malignancy in patients with inflammatory eye disease (IED) treated with systemic immunosuppressive (IS) therapy. Relevant databases in transplant medicine, autoimmune diseases and literature regarding uveitis and scleritis were reviewed. Literature with regards systemic IS therapy in transplant recipients and patients with autoimmune diseases revealed a significant increase in malignancies, especially non-melanocytic skin cancers and lymphomas. Studies of patients with IED were limited in number and scope, with no studies adequately evaluating the incidence of malignancy in these patients. Difficulties associated with the evaluation of the risk of malignancy associated with IS therapy in patients with IED include the heterogeneity of the disease and treatment regimens as well as the low frequency of IED, its variable severity and the lack of adequate long term follow-up studies. Systemic IS therapy is an important therapeutic option in the treatment of patients with severe IED. A well-designed, comprehensive, multi centre long-term follow-up study is required to evaluate the risk of malignancy in patients with specific IED diseases treated with defined systemic IS therapy. Until such evidence is available, we recommend the adoption of preventative strategies to help minimise the risk of malignancy in such patients. PMID- 23724807 TI - Phosphorus flame retardants in indoor dust and their relation to asthma and allergies of inhabitants. AB - Organophosphate esters are used as additives in flame retardants and plasticizers, and they are ubiquitous in the indoor environment. Phosphorus flame retardants (PFRs) are present in residential dust, but few epidemiological studies have assessed their impact on human health. We measured the levels of 11 PFRs in indoor floor dust and multi-surface dust in 182 single-family dwellings in Japan. We evaluated their correlations with asthma and allergies of the inhabitants. Tris(2-butoxyethyl) phosphate was detected in all samples (median value: 580 MUg/g in floor dust, 111 MUg/g in multi-surface dust). Tris(2-chloro iso-propyl) phosphate (TCIPP) was detected at 8.69 MUg/g in floor dust and 25.8 MUg/g in multi-surface dust. After adjustment for potential confounders, significant associations were found between the prevalence of atopic dermatitis and the presence of TCIPP and tris(1,3-dichloro-2-propyl) phosphate in floor dust [per log10 -unit, odds ratio (OR): 2.43 and 1.84, respectively]. Tributyl phosphate was significantly associated with the prevalence of asthma (OR: 2.85 in floor dust, 5.34 in multi-surface dust) and allergic rhinitis (OR: 2.55 in multi surface dust). PFR levels in Japan were high compared with values reported previously for Europe, Asia-Pacific, and the USA. Higher levels of PFRs in house dust were related to the inhabitants' health status. PMID- 23724809 TI - Quantitative determination of paralytic shellfish toxins in cultured toxic algae by LC-MS/MS. AB - We developed a sample preparation and LC-MS/MS method for the determination of saxitoxins in toxic algae. Paralytic shellfish toxins (PSTs) were successfully separated by gradient elution on an amide column with the hydrophilic interaction mode and quantified with multiple reaction monitoring (MRM) detection in the positive ion mode. This method showed good performance in the summed LODs and LOQs for all 12 toxins, 25 and 84 nM, respectively. Next, extracts of cultured strains of a toxic dinoflagellate Alexandrium tamarense and a freshwater cyanobacteria Anabaena circinalis were treated in a short column of basic alumina and the toxic fractions were analysed by our LC-MS/MS method and by HPLC with fluorescence detection. Comparison of the results obtained by the two methods demonstrated that approximately equivalent results were obtained for both the dinoflagellate and the cyanobacteria. In addition, the retention time of the toxins showed acceptable shifts. Therefore, the clean-up of the toxic algal extracts by using the basic alumina column controlled unwanted chromatographic behaviour and variable ionisation efficiency during MS detection. LC-MS/MS for saxitoxins has great potential as a rapid analytical method for determining all primary saxitoxins in cultured algae. PMID- 23724808 TI - Clinical and bacteriological evaluation of adapalene 0.1% gel plus nadifloxacin 1% cream versus adapalene 0.1% gel in patients with acne vulgaris. AB - This multicenter, randomized parallel group study investigated the efficacy and tolerability of adapalene 0.1% gel plus nadifloxacin 1% cream (combination therapy) compared with adapalene gel (monotherapy) during 12-week treatment of acne vulgaris. A total of 184 Japanese patients aged above 12 years with moderate to severe acne as indicated by the Japanese severity grading criteria were randomized to combination therapy (n = 84) and monotherapy (n = 100) groups, both having comparable demographic and baseline characteristics. Adapalene was applied only to inflammatory acne lesions in order to minimize skin irritation and ensure the treatment results. Efficacy and safety evaluations, treatment compliance and satisfaction with drug application were periodically monitored. The combination therapy provided a significantly greater efficacy than adapalene in decrement of inflammatory papulopustular lesions at 4 weeks and thereafter (P = 0.0056). The overall judgment of the therapeutic efficacy by the physician at the end of study revealed a significant difference (P = 0.02496) between the groups in favor of combination therapy. Dryness was reported in a greater proportion of patients undergoing monotherapy than combination therapy at weeks 2 and 4 (P = 0.04652). The patient self-assessment in satisfaction with the drug application at the end of study revealed a significant difference (P = 0.00268) between the groups in favor of combination therapy. Among 76 strains of Propionibacterium acnes isolated from 87 patients, no strain was resistant to nadifloxacin. Thus, the simultaneous use of adapalene and nadifloxacin may provide an additive and complementary effect, resulting in clinical superiority and greater patient adherence compared to adapalene monotherapy. PMID- 23724810 TI - Female education. PMID- 23724811 TI - Congenital diaphragmatic hernia in Northern Queensland. AB - AIMS: To investigate the survival of non-syndromic live born infants diagnosed in Northern Queensland with congenital diaphragmatic hernia (CDH). METHOD: Case note audit was completed of all live born newborns with a diagnosis of CDH admitted between February 1987 and December 2010. Demographic and clinical data were extracted. RESULTS: Overall survival to time of discharge for all infants was 67.3% (n = 35/52). For infants born before 2003 survival was 59.5% and for those born in 2003 and onwards was 86.7% (P = 0.10, OR 4.4, 95% confidence interval (CI) 0.87-22.55). Infants born prior to 2003, compared to those born from 2003 onwards, were less likely to survive with an isolated defect (P = 0.04, OR 8.0, 95% CI 0.93-68.62). Isolated congenital diaphragmatic hernia survival since 2003 was 92.3%. A significant difference was found in the time to surgery with those born in 2003 onwards having surgery significantly later, median 134 h, compared to the earlier cohorts median time to surgery of 83 h (P < 0.005, 95% CI 32.61 167.09). Premature infants had poorer survival (46.7%) compared to term infants (75.7%) (P < 0.0001 OR 3.6, 95% CI 1.99-6.68). Univariate analysis identified low birthweight was associated with poorer survival. CONCLUSIONS: Survival to discharge in our cohort equals other reported rates in Australia and around the world, including centres with tertiary paediatric services. The current management strategies used for these infants have seen a significant improvement in outcomes over time. PMID- 23724812 TI - White pinhead-like eruptions on the back of a 10-year-old. This 10-year-old boy has lichen nitidus. PMID- 23724813 TI - Differentiating abusive from accidental fractures. PMID- 23724814 TI - Computerised tomographic brain scans increase the risk of brain tumour or leukaemia. PMID- 23724815 TI - Dogs and cats can seriously improve your child's health. PMID- 23724816 TI - Cerebral proliferative angiopathy: a rare form of vascular malformation. PMID- 23724817 TI - Poverty is the problem, not colour. PMID- 23724819 TI - Recurrent anaphylaxis caused by topical povidone-iodine (Betadine). PMID- 23724818 TI - Multiple magnet ingestion in children: near-fatal attractions. PMID- 23724820 TI - Paediatric assessment in a general metropolitan emergency department. PMID- 23724823 TI - Surface modification of a polyimide gate insulator with an yttrium oxide interlayer for aqueous-solution-processed ZnO thin-film transistors. AB - We report a simple approach to modify the surface of a polyimide gate insulator with an yttrium oxide interlayer for aqueous-solution-processed ZnO thin-film transistors. It is expected that the yttrium oxide interlayer will provide a surface that is more chemically compatible with the ZnO semiconductor than is bare polyimde. The field-effect mobility and the on/off current ratio of the ZnO TFT with the YOx/polyimide gate insulator were 0.456 cm(2)/V.s and 2.12 * 10(6), respectively, whereas the ZnO TFT with the polyimide gate insulator was inactive. PMID- 23724822 TI - Structural basis of multisite single-stranded DNA recognition and ACTA2 repression by purine-rich element binding protein B (Purbeta). AB - A hallmark of dysfunctional fibroblast to myofibroblast differentiation associated with fibrotic disorders is persistent expression of ACTA2, the gene encoding the cyto-contractile protein smooth muscle alpha-actin. In this study, a PURB-specific gene knockdown approach was used in conjunction with biochemical analyses of protein subdomain structure and function to reveal the mechanism by which purine-rich element binding protein B (Purbeta) restricts ACTA2 expression in mouse embryo fibroblasts (MEFs). Consistent with the hypothesized role of Purbeta as a suppressor of myofibroblast differentiation, stable short hairpin RNA-mediated knockdown of Purbeta in cultured MEFs promoted changes in cell morphology, actin isoform expression, and cell migration indicative of conversion to a myofibroblast-like phenotype. Promoter-reporter assays in transfected Purbeta knockdown MEFs confirmed that these changes were attributable, in part, to derepression of ACTA2 transcription. To map the domains in Purbeta responsible for ACTA2 repression, several recombinant truncation mutants were generated and analyzed based on hypothetical, computationally derived models of the tertiary and quaternary structure of Purbeta. Discrete subdomains mediating sequence- and strand-specific cis-element binding, protein-protein interaction, and inhibition of a composite ACTA2 enhancer were identified using a combination of biochemical, biophysical, and cell-based assays. Our results indicate that the Purbeta homodimer possesses three separate but unequal single-stranded DNA-binding modules formed by subdomain-specific inter- and intramolecular interactions. This structural arrangement suggests that the cooperative assembly of the dimeric Purbeta repressor on the sense strand of the ACTA2 enhancer is dictated by the association of each subdomain with distinct purine-rich binding sites within the enhancer. PMID- 23724824 TI - Asymmetric synthesis of druglike six-membered spirooxindoles through an amino enyne catalysis. AB - An effective reflexive-Michael (r-M) reaction has been disclosed to access drug like six-membered spirooxindoles in good yields and excellent enantioselectivities by using an aminoenyne-catalysis. PMID- 23724826 TI - A revisit to sample size and power calculations for testing odds ratio in two independent binomials. AB - We reexamine the subject of sample size determination (SSD) when testing logarithm of odds ratio (OR) against zero in two independent binomials. Four common approaches are considered: a closed-form SS formula based on the Wald test (nW), closed-form formulas that meet SS requirement by score and exact tests respectively (nS and nE), and a numerical approach to calculating SS based on likelihood ratio (LR) tests (nL). Several practically useful findings are presented. First, nW is a strictly convex function of OR for OR >1 and OR <1, respectively, implying that SS calculated by nW does not necessarily decrease as OR gets further away from 1. However, minimum SS often occurs at OR values that are deemed relatively extreme and rare in real life. nS, nE, and nL decrease monotonically as OR diverges from 1. Secondly, the optimal sampling ratio (OSR) between two independent binomials that yields maximum power for a given total SS is not always 1:1 but depends on the odds of outcome in each arm. nW benefits the most from the application of OSR in that total SS can be significantly reduced as compared to the commonly used 1:1 sampling ratio. Savings in SS by OSR in nS, nL and nE are relatively immaterial from a practical perspective. Finally, we use simulation studies to examine the power loyalty of each SS approach and explore penalized likelihood as a remedy for undermined power loyalty. PMID- 23724825 TI - Sensitive and specific detection of mosaic chromosomal abnormalities using the Parent-of-Origin-based Detection (POD) method. AB - BACKGROUND: Mosaic somatic alterations are present in all multi-cellular organisms, but the physiological effects of low-level mosaicism are largely unknown. Most mosaic alterations remain undetectable with current analytical approaches, although the presence of such alterations is increasingly implicated as causative for disease. RESULTS: Here, we present the Parent-of-Origin-based Detection (POD) method for chromosomal abnormality detection in trio-based SNP microarray data. Our software implementation, triPOD, was benchmarked using a simulated dataset, outperformed comparable software for sensitivity of abnormality detection, and displayed substantial improvement in the detection of low-level mosaicism while maintaining comparable specificity. Examples of low level mosaic abnormalities from a large autism dataset demonstrate the benefits of the increased sensitivity provided by triPOD. The triPOD analyses showed robustness across multiple types of Illumina microarray chips. Two large, clinically-relevant datasets were characterized and compared. CONCLUSIONS: Our method and software provide a significant advancement in the ability to detect low-level mosaic abnormalities, thereby opening new avenues for research into the implications of mosaicism in pathogenic and non-pathogenic processes. PMID- 23724827 TI - Application of partial directed coherence to the analysis of resting-state EEG fMRI data. AB - The simultaneous acquisition of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) data potentially allows measurement of brain signals with both high spatial and temporal resolution. Partial directed coherence (PDC) is a Granger causality measure in the frequency domain, which is often used to infer the intensity of information flow over the brain from EEG data. In the current study, we propose a new approach to investigate functional connectivity in resting-state (RS) EEG-fMRI data by combining time-varying PDC with the analysis of blood oxygenation level-dependent (BOLD) signal fluctuations. Basically, we aim to identify brain circuits that are more active when the information flow is increased between distinct remote neuronal modules. The usefulness of the proposed method is illustrated by application to simultaneously recorded EEG-fMRI data from healthy subjects at rest. Using this approach, we decomposed the nodes of RS networks in fMRI data according to the frequency band and directed flow of information provided from EEG. This approach therefore has the potential to inform our understanding of the regional characteristics of oscillatory processes in the human brain. PMID- 23724828 TI - Surface control of alkyl chain conformations and 2D chiral amplification. AB - Trioctyl-functionalized triazatriangulenium (trioctyl-TATA) deposited on Au(111) and Ag(111) surfaces by electrospray ionization was investigated using low temperature scanning tunneling microscopy. The molecule surprisingly adsorbs with gauche rather than anti conformations of the octyl groups. We observed chiral amplification in the islands. Only one of the eight possible configurations of the octyl groups was found in homochiral hexagonal networks. Quantum-chemical calculations confirmed and explained the preference for the gauche conformations of adsorbed trioctyl-TATA. PMID- 23724829 TI - Hour-specific nomogram for transcutaneous bilirubin in Japanese neonates. AB - BACKGROUND: The measurement of transcutaneous bilirubin (TcB) is very important to screen for hyperbilirubinemia in newborns. Until now, however, there has been no hour-specific, percentile-based TcB nomogram during the early neonatal period in Japanese neonates. The aim of this study was to develop a TcB nomogram within 72 h of birth in Japanese neonates. METHODS: A total of 3152 TcB measurements for 181 healthy Japanese neonates (gestational age >=36 weeks, birthweight >=2300 g) were obtained within 72 h of birth. All measurements were performed with a Konica Minolta jaundice meter, the JM-103. A nomogram curve was plotted to show the trend of TcB level over time. RESULTS: The nomogram curves rose almost linearly for all percentiles until 72 h after birth. CONCLUSION: An hour-specific, percentile-based TcB nomogram during the first 72 h after birth in Japanese neonates was successfully developed. Because Japanese neonates have higher and later peak bilirubin, an original hour-specific 97.5th percentile-based TcB nomogram may be needed to identify early-onset jaundice and manage neonatal hyperbilirubinemia. PMID- 23724830 TI - Musculoskeletal physiotherapists' perceptions of non-responsiveness to treatment for cervicogenic headache. AB - Cervicogenic headache (CH) is a debilitating pain problem, estimated to affect 13 17% of the population with chronic headache. Physiotherapy can improve this condition in 75% of patients but the remaining 25% are unresponsive to treatment, and to date researchers have been unable to identify predictors of non responsiveness. The aim of this study was to seek both consensus and alternative accounts by examining the perceptions of experienced musculoskeletal physiotherapists regarding the features associated with non-responsiveness to treatment in adults and children with CH. A cross-sectional study was conducted (response rate 74%) in which 90 physiotherapists were asked about factors influencing non-responsiveness, using both written responses and Visual Analog Scale ratings, ranging from 0 (strongly disagree) to100 (strongly agree). The means for features in adult CH that physiotherapists rated as being most related to non-responsiveness were: history of severe trauma, 60 SD 27; genetic history of CH or other headache types, 55 SD 24; neural sensitivity, 49 SD 21; minimal presence of upper cervical neck pain and impairment, 55 SD 26; immunological comorbidities, 51 SD 26; and latency of response to treatment, 50 SD 26. These same features were considered to be associated with CH in children, but without the non-responsiveness of adults. PMID- 23724831 TI - Reliability and validity of the Performance Recorder 1 for measuring isometric knee flexor and extensor strength. AB - BACKGROUND: Muscular strength is a key parameter of rehabilitation programs and a strong predictor of functional capacity. Traditional methods to measure strength, such as manual muscle testing (MMT) and hand-held dynamometry (HHD), are limited by the strength and experience of the tester. The Performance Recorder 1 (PR1) is a strength assessment tool attached to resistance training equipment and may be a time- and cost-effective tool to measure strength in clinical practice that overcomes some limitations of MMT and HHD. However, reliability and validity of the PR1 have not been reported. METHODS: Test-retest and inter-rater reliability was assessed using the PR1 in healthy adults (n = 15) during isometric knee flexion and extension. Criterion-related validity was assessed through comparison of values obtained from the PR1 and Biodex(r) isokinetic dynamometer. RESULTS: Test-retest reliability was excellent for peak knee flexion (intra-class correlation coefficient [ICC] of 0.96, 95% CI: 0.85, 0.99) and knee extension (ICC = 0.96, 95% CI: 0.87, 0.99). Inter-rater reliability was also excellent for peak knee flexion (ICC = 0.95, 95% CI: 0.85, 0.99) and peak knee extension (ICC = 0.97, 95% CI: 0.91, 0.99). Validity was moderate for peak knee flexion (ICC = 0.75, 95% CI: 0.38, 0.92) but poor for peak knee extension (ICC = 0.37, 95% CI: 0, 0.73). CONCLUSIONS: The PR1 provides a reliable measure of isometric knee flexor and extensor strength in healthy adults that could be used in the clinical setting, but absolute values may not be comparable to strength assessment by gold-standard measures. PMID- 23724832 TI - Soluble adhesion molecules correlate with surface expression in an in vitro model of endothelial activation. AB - Endothelial activation is a pivotal event in the development and progression of inflammation. Central to endothelial activation is the up-regulation of cellular adhesion molecules (CAMs) including E-selectin (CD62E), ICAM-1 (CD54), VCAM-1 (CD106) and PECAM-1 (CD31). These CAMs are also found in soluble forms (sCAMs). In this in vitro study of endothelial activation, we examined whether the levels of sCAMs correlate with the endothelial surface expression of CAMs in a dose dependent and time-dependent manner. Such a correlation would support the use of sCAMs as surrogate markers for endothelial activation in inflammatory conditions. Human umbilical vein endothelial cells (HUVEC) were cultured with various concentrations of TNF-alpha for 8 hr and at a fixed concentration of TNF-alpha for various durations. The levels of soluble and surface-bound E-selectin, ICAM 1, VCAM-1 and PECAM-1 were quantified by flow cytometry. TNF-alpha stimulation increased CAM and sCAM expression in a dose-dependent and time-dependent manner. There was a significant positive correlation between the levels of ICAM-1 and sICAM-1 and between the levels of VCAM and sVCAM-1 in both the dose-response and time-response experiments. A positive correlation between the levels of E selectin and sE-selectin was observed in the time-response experiment. This study supports the use of sCAMs as potential biomarkers of endothelial activation. In particular, the use of sICAM-1, sVCAM-1 and sE-selectin seems promising. PMID- 23724833 TI - Seizure control after subtotal lesional resection. AB - Reports on seizure outcomes following surgery for lesional epilepsy consistently cite extent of resection as a significant predictor of outcome. Unfortunately, gross-total resection is not technically feasible in all cases of medically refractory tumor-associated epilepsy. Here, the authors present the case of a 4 year-old girl whose epilepsy was medically controlled after 1-stage electrocorticography-guided subtotal resection (STR) of a large diffuse protoplasmic astrocytoma. They also review the modern literature on epilepsy associated with brain tumors. Outcomes are compared with those following surgical treatment of focal cortical dysplasia and vascular lesions. Gross-total lesional resection shows significant superiority across pathologies and anatomical regions. Despite a considerable number of STRs yielding seizure freedom, other favorable treatment factors have not been defined. Although gross-total lesional resection, if possible, is clearly superior, tailored surgery may still offer patients a significant opportunity for a good outcome. Treatment factors yielding successful seizure control following STR remain to be fully elucidated. PMID- 23724834 TI - Disconnective surgery in posterior quadrantic epilepsy: experience in a consecutive series of 10 patients. AB - OBJECT: Outcomes following functional hemispherotomy in patients with drug resistant epilepsy have been well described. However, studies reporting long-term longitudinal outcomes after subhemispheric disconnective epilepsy surgery are still limited. METHODS: The authors conducted a retrospective review of prospectively collected data of 10 children who underwent temporoparietooccipital (TPO) disconnective surgery at the Vienna Pediatric Epilepsy Center. RESULTS: There were 3 males and 7 females (median age 8.7 years; range 4.2-22.1 years). The affected hemisphere was the left in 3 patients and the right in 7. The patients' median age at seizure onset was 3.0 years (range 0.2-8.3 years). The median duration of epilepsy before surgery was 5.2 years (range 1.3-17.2 years). The underlying pathology was TPO malformation of cortical development in 5 patients, and venous infarction, posterior hemispheric quadrant atrophy, Sturge Weber syndrome, cortical involvement of a systemic lupus erythematosus, and gliosis after cerebral tumor treatment in 1 each. In 6 children, a pure TPO disconnection was performed; in 2 patients, the temporal lobe was resected and parietooccipital disconnection was performed. The 2 remaining patients had had previous epilepsy surgery that was extended to a TPO disconnection: disconnection of the occipital lobe (n = 1) and resection of the temporal lobe (n = 1). The authors encountered no complications while performing surgery. No patient needed blood replacement therapy. No patient developed CSF disturbances that warranted treatment. Nine of 10 patients are currently seizure free since surgery (Wieser Class 1a) at a median follow-up time of 2.1 years (range 4 months to 8.1 years). CONCLUSIONS: Temporoparietooccipital disconnection is a safe and effective motor sparing epilepsy surgery in selected cases. Technical adjuncts facilitate a better intraoperative visualization and orientation, thereby enabling a less invasive approach than previously suggested. PMID- 23724835 TI - Hemispherectomy: historical review and recent technical advances. AB - The surgical options available for intractable hemispheric epilepsy have evolved since their initial description in the early 20th century. Surgical techniques have advanced, as has the ability to predict good surgical outcomes with noninvasive diagnostics. The authors review the history of hemispherectomy and detail the novel imaging and surgical strategies used to confer seizure freedom. PMID- 23724836 TI - Complications after mesial temporal lobe surgery via inferiortemporal gyrus approach. AB - OBJECT: The purpose of this study was to identify the complications associated with the inferior temporal gyrus approach to anterior mesial temporal lobe resection for temporal lobe epilepsy. METHODS: This retrospective study examined complications experienced by 483 patients during the 3 months after surgery. All surgeries were performed during 1998-2012 by the senior author (F.L.V.). RESULTS: A total of 13 complications (2.7%) were reported. Complications were 8 delayed subdural hematomas (1.6%), 2 superficial wound infections (0.4%), 1 delayed intracranial hemorrhage (0.2%), 1 small lacunar stroke (0.2%), and 1 transient frontalis nerve palsy (0.2%). Three patients with subdural hematoma (0.6%) required readmission and surgical intervention. One patient (0.2%) with delayed intracranial hemorrhage required readmission to the neuroscience intensive care unit for observation. No deaths or severe neurological impairments were reported. Among the 8 patients with subdural hematoma, 7 were older than 40 years (87.5%); however, this finding was not statistically significant (p = 0.198). CONCLUSIONS: The inferior temporal gyrus approach to mesial temporal lobe resection is a safe and effective method for treating temporal lobe epilepsy. Morbidity and mortality rates associated with this procedure are lower than those associated with other neurosurgical procedures. The finding that surgical complications seem to be more common among older patients emphasizes the need for early surgical referral of patients with medically refractory epilepsy. PMID- 23724837 TI - Stereoelectroencephalography for continuous two-dimensional cursor control in a brain-machine interface. AB - Stereoelectroencephalography (SEEG) is becoming more prevalent as a planning tool for surgical treatment of intractable epilepsy. Stereoelectroencephalography uses long, thin, cylindrical "depth" electrodes containing multiple recording contacts along each electrode's length. Each lead is inserted into the brain percutaneously. The advantage of SEEG is that the electrodes can easily target deeper brain structures that are inaccessible with subdural grid electrodes, and SEEG does not require a craniotomy. Brain-machine interface (BMI) research is also becoming more common in the Epilepsy Monitoring Unit. A brain-machine interface decodes a person's desired movement or action from the recorded brain activity and then uses the decoded brain activity to control an assistive device in real time. Although BMIs are primarily being developed for use by severely paralyzed individuals, epilepsy patients undergoing invasive brain monitoring provide an opportunity to test the effectiveness of different invasive recording electrodes for use in BMI systems. This study investigated the ability to use SEEG electrodes for control of 2D cursor velocity in a BMI. Two patients who were undergoing SEEG for intractable epilepsy participated in this study. Participants were instructed to wiggle or rest the hand contralateral to their SEEG electrodes to control the horizontal velocity of a cursor on a screen. Simultaneously they were instructed to wiggle or rest their feet to control the vertical component of cursor velocity. The BMI system was designed to detect power spectral changes associated with hand and foot activity and translate those spectral changes into horizontal and vertical cursor movements in real time. During testing, participants used their decoded SEEG signals to move the brain-controlled cursor to radial targets that appeared on the screen. Although power spectral information from 28 to 32 electrode contacts were used for cursor control during the experiment, post hoc analysis indicated that better control may have been possible using only a single SEEG depth electrode containing multiple recording contacts in both hand and foot cortical areas. These results suggest that the advantages of using SEEG for epilepsy monitoring may also apply to using SEEG electrodes in BMI systems. Specifically, SEEG electrodes can target deeper brain structures, such as foot motor cortex, and both hand and foot areas can be targeted with a single SEEG electrode implanted percutaneously. Therefore, SEEG electrodes may be an attractive option for simple BMI systems that use power spectral modulation in hand and foot cortex for independent control of 2 degrees of freedom. PMID- 23724838 TI - Optogenetics in epilepsy. AB - Optogenetics, the use of light to stimulate or inhibit neural circuits via viral transduction of protein channels, has emerged as a possible method of treating epilepsy. By introducing viral vectors carrying algal-derived cation or anion channels, known as opsins, neurons that initiate or propagate seizures may be silenced. To date, studies using this technique have been performed in animal models, and current efforts are moving toward more sophisticated nonhuman primate models. In this paper, the authors present a brief overview of the development of optogenetics and review recent studies investigating optogenetic modification of circuits involved in seizures. Further developments in the field are explored, with an emphasis on how optogenetics may influence future neurosurgical interventions. PMID- 23724839 TI - Successful surgical treatment of an inflammatory lesion associated with new-onset refractory status epilepticus. AB - New-onset refractory status epilepticus (NORSE) has high morbidity and mortality. The authors describe the successful surgical treatment of a 56-year-old man presenting with NORSE. Magnetic resonance imaging showed a left temporal lobe lesion suspicious for a low-grade tumor, while PET imaging with the alpha[(11)C]methyl-L-tryptophan (AMT) radiotracer showed increased cortical uptake extending beyond this lesion and partly overlapping with epileptogenic cortex mapped by chronic intracranial electroencephalographic monitoring. Resection of the epileptic focus resulted in long-term seizure freedom, and the nonresected portion of the PET-documented abnormality normalized. Histopathology showed reactive gliosis and inflammatory markers in the AMT-PET-positive cortex. Molecular imaging of neuroinflammation can be instrumental in the management of NORSE by guiding placement of intracranial electrodes or assessing the extent and severity of inflammation for antiinflammatory interventions. PMID- 23724840 TI - Hypothalamic hamartomas. Part 1. Clinical, neuroimaging, and neurophysiological characteristics. AB - Hypothalamic hamartomas are uncommon but well-recognized developmental malformations that are classically associated with gelastic seizures and other refractory seizure types. The clinical course is often progressive and, in addition to the catastrophic epileptic syndrome, patients commonly exhibit debilitating cognitive, behavioral, and psychiatric disturbances. Over the past decade, investigators have gained considerable knowledge into the pathobiological and neurophysiological properties of these rare lesions. In this review, the authors examine the causes and molecular biology of hypothalamic hamartomas as well as the principal clinical features, neuroimaging findings, and electrophysiological characteristics. The diverse surgical modalities and strategies used to manage these difficult lesions are outlined in the second article of this 2-part review. PMID- 23724841 TI - Hypothalamic hamartomas. Part 2. Surgical considerations and outcome. AB - Hypothalamic hamartomas are uncommon developmental heterotopic masses composed of an intermixed array of neurons, glia, and myelinated fibers closely associated with the mammillary bodies. Gelastic seizures, the hallmark feature of hypothalamic hamartomas, commonly present in early childhood. However, patients usually also display a disabling clinical syndrome, which may include various other types of refractory seizures with secondary generalization together with progressive cognitive, behavioral, and psychiatric dysfunction. The hamartoma itself has been unequivocally shown to be intrinsically epileptogenic. Over the past 2 decades there has been considerable effort to develop neurosurgical techniques to treat the epileptic syndrome effectively as well as to improve the neurocognitive and behavioral outcome. PMID- 23724842 TI - Tissue localization during resective epilepsy surgery. AB - OBJECT: Imaging-guided surgery (IGS) systems are widely used in neurosurgical practice. During epilepsy surgery, the authors routinely use IGS landmarks to localize intracranial electrodes and/or specific brain regions. The authors have developed a technique to coregister these landmarks with pre- and postoperative scans and the Montreal Neurological Institute (MNI) standard space brain MRI to allow 1) localization and identification of tissue anatomy; and 2) identification of Brodmann areas (BAs) of the tissue resected during epilepsy surgery. Tracking tissue in this fashion allows for better correlation of patient outcome to clinical factors, functional neuroimaging findings, and pathological characteristics and molecular studies of resected tissue. METHODS: Tissue samples were collected in 21 patients. Coordinates from intraoperative tissue localization were downloaded from the IGS system and transformed into patient space, as defined by preoperative high-resolution T1-weighted MRI volume. Tissue landmarks in patient space were then transformed into MNI standard space for identification of the BAs of the tissue samples. RESULTS: Anatomical locations of resected tissue were identified from the intraoperative resection landmarks. The BAs were identified for 17 of the 21 patients. The remaining patients had abnormal brain anatomy that could not be meaningfully coregistered with the MNI standard brain without causing extensive distortion. CONCLUSIONS: This coregistration and landmark tracking technique allows localization of tissue that is resected from patients with epilepsy and identification of the BAs for each resected region. The ability to perform tissue localization allows investigators to relate preoperative, intraoperative, and postoperative functional and anatomical brain imaging to better understand patient outcomes, improve patient safety, and aid in research. PMID- 23724843 TI - Correlation between magnetoencephalography-based "clusterectomy" and postoperative seizure freedom. AB - OBJECT: During the presurgical evaluation of patients with medically intractable focal epilepsy, a variety of noninvasive studies are performed to localize the hypothetical epileptogenic zone and guide the resection. Magnetoencephalography (MEG) is becoming increasingly used in the clinical realm for this purpose. No investigators have previously reported on coregisteration of MEG clusters with postoperative resection cavities to evaluate whether complete "clusterectomy" (resection of the area associated with MEG clusters) was performed or to compare these findings with postoperative seizure-free outcomes. METHODS: The authors retrospectively reviewed the charts and imaging studies of 65 patients undergoing MEG followed by resective epilepsy surgery from 2009 until 2012 at the Cleveland Clinic. Preoperative MEG studies were fused with postoperative MRI studies to evaluate whether clusters were within the resected area. These data were then correlated with postoperative seizure freedom. RESULTS: Sixty-five patients were included in this study. The average duration of follow-up was 13.9 months, the mean age at surgery was 23.1 years, and the mean duration of epilepsy was 13.7 years. In 30 patients, the main cluster was located completely within the resection cavity, in 28 it was completely outside the resection cavity, and in 7 it was partially within the resection cavity. Seventy-four percent of patients were seizure free at 12 months after surgery, and this rate decreased to 60% at 24 months. Improved likelihood of seizure freedom was seen with complete clusterectomy in patients with localization outside the temporal lobe (extra temporal lobe epilepsy) (p = 0.04). CONCLUSIONS: In patients with preoperative MEG studies that show clusters in surgically accessible areas outside the temporal lobe, we suggest aggressive resection to improve the chances for seizure freedom. When the cluster is found within the temporal lobe, further diagnostic testing may be required to better localize the epileptogenic zone. PMID- 23724844 TI - Epilepsy surgery. PMID- 23724845 TI - Unique mechanical properties of nanostructured transparent MgAl2O4 ceramics. AB - Nanoindentation tests were performed on nanostructured transparent magnesium aluminate (MgAl2O4) ceramics to determine their mechanical properties. These tests were carried out on samples at different applied loads ranging from 300 to 9,000 MUN. The elastic recovery for nanostructured transparent MgAl2O4 ceramics at different applied loads was derived from the force-depth data. The results reveal a remarkable enhancement in plastic deformation as the applied load increases from 300 to 9,000 MUN. After the nanoindetation tests, scanning probe microscope images show no cracking in nanostructured transparent MgAl2O4 ceramics, which confirms the absence of any cracks and fractures around the indentation. Interestingly, the flow of the material along the edges of indent impressions is clearly presented, which is attributed to the dislocation introduced. High-resolution transmission electron microscopy observation indicates the presence of dislocations along the grain boundary, suggesting that the generation and interaction of dislocations play an important role in the plastic deformation of nanostructured transparent ceramics. Finally, the experimentally measured hardness and Young's modulus, as derived from the load displacement data, are as high as 31.7 and 314 GPa, respectively. PMID- 23724846 TI - Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. AB - BACKGROUND: The programmed death 1 (PD-1) receptor is a negative regulator of T cell effector mechanisms that limits immune responses against cancer. We tested the anti-PD-1 antibody lambrolizumab (previously known as MK-3475) in patients with advanced melanoma. METHODS: We administered lambrolizumab intravenously at a dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor responses were assessed every 12 weeks. RESULTS: A total of 135 patients with advanced melanoma were treated. Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. The confirmed response rate across all dose cohorts, evaluated by central radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was 38% (95% confidence interval [CI], 25 to 44), with the highest confirmed response rate observed in the cohort that received 10 mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively). Responses were durable in the majority of patients (median follow-up, 11 months among patients who had a response); 81% of the patients who had a response (42 of 52) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months. CONCLUSIONS: In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. (Funded by Merck Sharp and Dohme; ClinicalTrials.gov number, NCT01295827.). PMID- 23724848 TI - Deoxygenation of sulfoxides to sulfides with thionyl chloride and triphenylphosphine: competition with the pummerer reaction. AB - Although a number of methods have been developed to reduce sulfoxides to sulfides, many of these processes are limited by side reactions, low yields, poorly available reagents, or harsh reaction conditions. We recently studied the reaction of various sulfoxides with SOCl2 and Ph3P. We were able to obtain the corresponding sulfides in excellent yields (>90%) when aliphatic and aromatic sulfoxides were treated with SOCl2 as a catalyst and Ph3P in THF at room temperature. PMID- 23724849 TI - Three-phase electroextraction: a new (online) sample purification and enrichment method for bioanalysis. AB - The migration and at the same time enrichment of analytes from a liquid aqueous sample donor phase through an immiscible organic solvent layer acting as a filter phase into a liquid aqueous acceptor phase is enabled by the application of an electric field between the donor and acceptor phase. The organic filter phase acts as a purification filter, which prevents, for example, proteins from migrating into the acceptor phase. Moreover, the composition of the organic filter phase influences the selectivity of the extraction. We show that analytes can be rapidly enriched from a 50 MUL donor phase at the bottom of a sample vial, via an immiscible organic filter phase, into a 2 MUL acceptor phase which consists of a droplet that is hanging from a (conductive) pipet tip in the organic filter phase. Acylcarnitines spiked to human plasma as a donor phase were extracted reproducibly with good linearity and a 10-fold improved limit of detection and, importantly, resulted in a stable, protein-free nanoelectrospray signal. Finally, a proof of principle toward the online integration in an automated nanoelectrospray-direct infusion-mass spectrometry platform has been realized. This makes 3-phase electroextraction (3-phase EE) a novel sample purification and enrichment method, with straightforward online integration possibility. We envision that 3-phase EE will enable new possibilities using electrokinetic sample pretreatment for fully automated, high-throughput bioanalysis purposes. PMID- 23724847 TI - Marine algal natural products with anti-oxidative, anti-inflammatory, and anti cancer properties. AB - For their various bioactivities, biomaterials derived from marine algae are important ingredients in many products, such as cosmetics and drugs for treating cancer and other diseases. This mini-review comprehensively compares the bioactivities and biological functions of biomaterials from red, green, brown, and blue-green algae. The anti-oxidative effects and bioactivities of several different crude extracts of algae have been evaluated both in vitro and in vivo. Natural products derived from marine algae protect cells by modulating the effects of oxidative stress. Because oxidative stress plays important roles in inflammatory reactions and in carcinogenesis, marine algal natural products have potential for use in anti-cancer and anti-inflammatory drugs. PMID- 23724850 TI - Trends in incidence and costs of injuries to the shoulder, arm and wrist in The Netherlands between 1986 and 2008. AB - BACKGROUND: Upper extremity injuries account for a large proportion of attendances to the Emergency Department. The aim of this study was to assess population-based trends in the incidence of upper extremity injuries in the Dutch population between 1986 and 2008, and to give a detailed overview of the associated health care costs. METHODS: Age-standardized incidence rates of upper extremity injuries were calculated for each year between 1986 and 2008. The average number of people in each of the 5-year age classes for each year of the study was calculated and used as the standard (reference) population. Injury cases were extracted from the National Injury Surveillance System (non hospitalized patients) and the National Medical Registration (hospitalized patients). An incidence-based cost model was applied in order to estimate associated direct health care costs in 2007. RESULTS: The overall age-adjusted incidence of upper extremity injuries increased from 970 to 1,098 per 100,000 persons (13%). The highest incidence was seen in young persons and elderly women. Total annual costs for all injuries were 290 million euro, of which 190 million euro were paid for injuries sustained by women. Wrist fractures were the most expensive injuries (83 million euro) due to high incidence, whereas upper arm fractures were the most expensive injuries per case (4,440 euro). Major cost peaks were observed for fractures in elderly women due to high incidence and costs per patient. CONCLUSIONS: The overall incidence of upper extremity injury in the Netherlands increased by 13% in the period 1986-2008. Females with upper extremity fractures and especially elderly women with wrist fractures accounted for a substantial share of total costs. PMID- 23724852 TI - Synthesis, structural characterization, and photophysical, spectroelectrochemical, and anion-sensing studies of heteroleptic ruthenium(II) complexes derived from 4'-polyaromatic-substituted terpyridine derivatives and 2,6-bis(benzimidazol-2-yl)pyridine. AB - Heteroleptic bis-tridentate ruthenium(II) complexes of composition [(H2pbbzim)Ru(tpy-Ar)](ClO4)2, where H2pbbzim = 2,6-bis(benzimidazol-2 yl)pyridine and tpy-Ar = 4'-substituted terpyridine ligands with Ar = phenyl (2), 2-naphthyl (3), 9-anthryl (4), and 1-pyrenyl (5) groups, have been synthesized and characterized by using standard analytical and spectroscopic techniques. The X-ray crystal structures of the complexes [(H2pbbzim)Ru(tpy-Naph)](ClO4)2 (3), [(pbbzim)Ru(tpy-Naph)].(CH3)2CO.H2O (3a), and [(H2pbbzim)Ru(tpy-Py)](ClO4)2 (5) have been determined. The absorption, steady-state, and time-resolved luminescence spectral properties of the complexes were thoroughly investigated in dichloromethane. The compounds display strong luminescence at room temperature with lifetimes (tau2) in the range of 5.5-62 ns, depending upon the nature of the polycyclic aromatic moiety as well as the solvents. The complexes are found to undergo one reversible oxidation in the positive potential window (0 to +1.5 V) and four successive quasi-reversible reductions in the negative potential window (0 to -2.4 V). The anion-sensing properties of the receptors were thoroughly investigated in acetonitrile/dichloromethane (1/9 v/v) solutions (2 * 10(-5) M) using absorption, steady-state, and time-resolved emission spectroscopic studies. (1)H NMR titration experiments, on the other hand, were carried out in either CD3CN or DMSO-d6. The anion-sensing studies revealed that the receptors act as sensors for F(-), CN(-), AcO(-), and SO4(2-) and to some extent for HSO4(-) and H2PO4(-). It is evident that, in the presence of excess anions, deprotonation of the imidazole N-H fragments of the receptors occurs, which is signaled by the change of color from yellow-orange to violet visible with the naked eye. From the absorption and emission titration studies the binding/equilibrium constants of the receptors with the anions have also been determined. Anion-induced lifetime quenching and/or enhancement make the receptors suitable lifetime-based sensors for selective anions. Cyclic voltammetric (CV) measurements of the compounds carried out in acetonitrile have provided evidence in favor of anion-dependent electrochemical responses with F(-) and AcO(-) ions. Spectroelectrochemical studies have also been carried out for both the protonated and deprotonated forms of the complexes in the range of 300-1200 nm. With successive oxidation of the Ru(II) center, replacement of MLCT bands by LMCT bands occurs gradually with observation of sharp isosbestic points in all cases. PMID- 23724851 TI - Region growing by sector analysis for detection of blue-gray ovoids in basal cell carcinoma. AB - Blue-gray ovoids (B-GOs) are critical dermoscopic structures in basal cell carcinomas (BCCs) that pose a challenge for automatic detection. Due to variation in size and color, B-GOs can be easily mistaken for similar structures in benign lesions. Analysis of these structures could help further accomplish the goal of automatic BCC detection. This study introduces an efficient sector-based method for segmenting B-GOs. Four modifications of conventional region-growing techniques are presented: (i) employing a seed area rather than a seed point, (ii) utilizing fixed control limits determined from the seed area to eliminate re calculations of previously-added regions, (iii) determining region growing criteria using logistic regression, and (iv) area analysis and expansion by sectors. Contact dermoscopy images of 68 confirmed BCCs having B-GOs were obtained. A total of 24 color features were analyzed for all B-GO seed areas. Logistic regression analysis determined blue chromaticity, followed by red variance, were the best features for discriminating B-GO edges from surrounding areas. Segmentation of malignant structures obtained an average Pratt's figure of merit of 0.397. The techniques presented here provide a non-recursive, sector based, region-growing method applicable to any colored structure appearing in digital images. Further research using these techniques could lead to automatic detection of B-GOs in BCCs. PMID- 23724853 TI - Does lavender aromatherapy alleviate premenstrual emotional symptoms?: a randomized crossover trial. AB - BACKGROUND: A majority of reproductive-age women experience a constellation of various symptoms in the premenstrual phase, commonly known as premenstrual syndrome (PMS). Despite its prevalence, however, no single treatment is universally recognized as effective, and many women turn to alternative approaches, including aromatherapy, a holistic mind and body treatment. The present study investigated the soothing effects of aromatherapy on premenstrual symptoms using lavender (Lavandula angustifolia), a relaxing essential oil, from the perspective of autonomic nervous system function. METHODS: Seventeen women (20.6 +/- 0.2 years) with mild to moderate subjective premenstrual symptoms participated in a randomized crossover study. Subjects were examined on two separate occasions (aroma and control trials) in the late-luteal phases. Two kinds of aromatic stimulation (lavender and water as a control) were used. This experiment measured heart rate variability (HRV) reflecting autonomic nerve activity and the Profile of Mood States (POMS) as a psychological index before and after the aromatic stimulation. RESULTS: Only a 10-min inhalation of the lavender scent significantly increased the high frequency (HF) power reflecting parasympathetic nervous system activity in comparison with water (aroma effect: F = 4.50, p = 0.050; time effect: F = 5.59, p = 0.017; aroma x time effect: F = 3.17, p = 0.047). The rate of increase in HF power was greater at 10-15 min (p = 0.051) and 20-25 min (p = 0.023) in the lavender trial than in the control trial with water. In addition, POMS tests revealed that inhalation of the aromatic lavender oil significantly decreased two POMS subscales-depression-dejection (p = 0.045) and confusion (p = 0.049)-common premenstrual symptoms, in the late-luteal phase, as long as 35 min after the aroma stimulation. CONCLUSIONS: The present study indicated that lavender aromatherapy as a potential therapeutic modality could alleviate premenstrual emotional symptoms, which, at least in part, is attributable to the improvement of parasympathetic nervous system activity. This study further implies that HRV could evaluate the efficacy of aromatherapy using various fragrances to relieve premenstrual symptoms, and ultimately, support the mind and body health of women. PMID- 23724854 TI - Observational case series on a group of psoriasis patients who failed to respond to any TNF blockers. AB - INTRODUCTION: Data that can identify the patients who will not respond to anti TNF agents are sparse. Therefore, the authors wished to describe specific clinical factors that could be associated with a non-response to any available TNF blockers in patients with psoriasis. METHODS: A retrospective observational study was performed through the mailing of a questionnaire to five departments of Dermatology. Only psoriasis patients who were not responsive to all available anti-TNF agents (etanercept, infliximab and adalimumab), whatever the chronology of their use, were included. RESULTS: Twenty-two patients were included. Forty patients (64%) did not work at the time of the study and 12 (55%) qualified for Social Security Disability Allowance. Forty patients (64%) were considered as "overweight". Fifty-nine percent of patients were smokers. Antinuclear antibodies were positive in 9 out of 16 patients tested (56%) at the time of non-response. Ustekinumab, which was further introduced in 19 patients, led to PASI 75 in all (94%) but one patient. CONCLUSION: The data identified different clinical factors associated with a non-response to any available TNF blockers. Furthermore, non responder patients were highly responsive to ustekinumab suggesting that in few psoriasis patients, TNF blockade is not the best target and other TNF-independent signaling pathway should be considered. PMID- 23724855 TI - Fixed eruption due to quinine in tonic water: a case report with high-performance liquid chromatography and ultraviolet A analyses. AB - Fixed drug eruption is a common cutaneous adverse reaction in young patients with a characteristic clinical appearance. However, the diagnosis and identification of the substance may be difficult if food or food additives provoke the fixed eruption. A 26-year-old man had a history of two episodes of cutaneous erythema with residual pigmentation. Close examination of the history including his diet in addition to an oral challenge test and patch testing led to the diagnosis of fixed eruption secondary to quinine in tonic water. We examined for the presence of quinine in commercially available brands of tonic water using ultraviolet A and irradiation and high-performance liquid chromatography. Both Schweppes and CANADA DRY brands of tonic water emitted fluorescent light upon ultraviolet A irradiation, and contained quinine at concentrations of 67.9 and 61.3 mg/L, respectively. Quinine contained in some tonic waters may trigger fixed eruption. PMID- 23724856 TI - Sympathetic ophthalmia: to the twenty-first century and beyond. AB - Sympathetic ophthalmia is a rare bilateral granulomatous inflammation that follows accidental or surgical insult to the uvea of one eye. Onset of sympathetic ophthalmia can be insidious or acute, with recurrent periods of exacerbation. Clinical presentation shows mutton-fat keratic precipitates, choroidal infiltrations, and Dalen-Fuchs nodules. Histopathology reveals diffuse or nodular granulomatous inflammation of the uvea. Prevention and treatment strategies for sympathetic ophthalmia are currently limited to two modalities, enucleation of the injured eye and immunosuppressive therapy, aimed at controlling inflammation. The etiology and pathophysiology of the disease is still unclear but is largely thought to be autoimmune in nature. Recent insight on the molecular pathology of the disease as well as developments in imaging technology have furthered both the understanding on the autoimmune process in sympathetic ophthalmia and the targeting of prevention and treatment strategies for the future. PMID- 23724857 TI - Synthesis of ABCBA penta stereoblock polylactide copolymers by two-step ring opening polymerization of L- and D-lactides with poly(3-methyl-1,5-pentylene succinate) as macroinitiator (C): development of flexible stereocomplexed polylactide materials. AB - BCB triblock copolymers consisting of poly-L-lactide (PLLA: B) and poly(3-methy 1,5-pentylene succinate) (SA/MPD: C) were first synthesized by ring-opening polymerization (ROP) of L-lactide by using a dihydroxyl-terminated SA/MPD (Mn~20k) and tin octoate as the macroinitiator and catalyst, respectively. The telechelic dihydroxyl-terminated SA/MPD was readily synthesized by the controlled melt-polycondensation of succinic acid and 3-methyl-1,5-pentandiol (MPD). The resultant triblock copolymers, dihydroxyl-terminated, were subsequently utilized as the macroinitiators in the second-step ROP of D-lactide to obtain ABCBA penta block copolymers (penta-sb-PLA) consisting of poly-D-lactide (PDLA), PLLA, and SA/MPD as the A, B, and C blocks, respectively. The weight-average molecular weights of the resultant penta-sb-PLAs became higher than 150 kDa. The cast films of these penta-sb-PLAs exhibited flexible nature due to the presence of the SA/MPD soft block as well as excellent heat-stability owing to the easy stereocomplex formation of the neighboring enantiomeric PLLA and PDLA blocks. PMID- 23724858 TI - A two-component histidine kinase Shk1 controls stress response, sclerotial formation and fungicide resistance in Sclerotinia sclerotiorum. AB - Fungal histidine kinases (HKs) are involved in osmotic and oxidative stress responses, hyphal development, fungicide sensitivity and virulence. Members of HK class III are known to signal through the high-osmolarity glycerol mitogen activated protein kinase (HOG MAPK). In this study, we characterized the Shk1 gene (SS1G_12694.3), which encodes a putative class III HK, from the plant pathogen Sclerotinia sclerotiorum. Disruption of Shk1 resulted in resistance to phenylpyrrole and dicarboximide fungicides and increased sensitivity to hyperosmotic stress and H2 O2 -induced oxidative stress. The Shk1 mutant showed a significant reduction in vegetative hyphal growth and was unable to produce sclerotia. Quantitative real-time polymerase chain reaction (qRT-PCR and glycerol determination assays showed that the expression of SsHOG1 (the last kinase of the Hog pathway) and glycerol accumulation were regulated by the Shk1 gene, but PAK (p21-activated kinase) was not. In addition, the Shk1 mutant showed no change in virulence. All the defects were restored by genetic complementation of the Shk1 deletion mutant with the wild-type Shk1 gene. These findings indicate that Shk1 is involved in vegetative differentiation, sclerotial formation, glycerol accumulation and adaption to hyperosmotic and oxidative stresses, and to fungicides, in S. sclerotiorum. Taken together, our results demonstrate, for the first time, the role of two-component HKs in Sclerotinia. PMID- 23724859 TI - Effect of quercetin on the toxicokinetics of ochratoxin A in rats. AB - Previous studies indicate that the intestinal absorption of the nephrotoxic mycotoxin ochratoxin A (OTA) occurs mainly through passive diffusion of the undissociated form. However, several in vitro studies have shown that OTA is partly re-secreted into the intestinal lumen by the multi-drug resistance associated protein (MRP2) and breast cancer resistance protein (BRCP). In vitro studies using Caco-2 cells have shown that some polyphenols (quercetin, genistein, resveratrol) may impair OTA efflux through competitive inhibition of MRP2, possibly resulting in an increased systemic availability of OTA. Among the tested polyphenols, quercetin showed the highest potential as efflux pump inhibitor; therefore, the aim of the present in vivo study was to investigate possible effects of quercetin on the toxicokinetics of OTA in rats. Eighteen growing male F344 Fisher rats (body weight: 200 g) were allocated to two dietary treatments consisting of (1) a commercial, flavonoid-free balanced diet containing 10 mg OTA/kg derived from inoculated wheat and (2) the same diet supplemented with 100 mg quercetin/kg. The animals were fed restrictively (~0.7 of ad libitum intake, 13 g/d) to avoid differences in OTA intake. Animals were kept in metabolism cages to facilitate total urine and faeces collection. After 6 days on trial, rats were euthanised and blood, liver, kidney, muscle and brain samples were taken from each animal. Faeces, urine and tissue samples were analysed for OTA and its main metabolite ochratoxin alpha by high-performance liquid chromatography using fluorescence detection. Quercetin supplementation had no effect (P > 0.05) on feed consumption, OTA-intake, water intake and body weight gain. Faecal and urinary excretion of OTA and ochratoxin alpha and concentrations of OTA in all tissues were not affected by quercetin supplementation. Based on the total excretion and tissue concentrations of OTA, it is concluded that the polyphenol quercetin has no impact on the toxicokinetics of OTA in vivo. PMID- 23724861 TI - Mollolide A, a diterpenoid with a new 1,10:2,3-disecograyanane skeleton from the roots of Rhododendron molle. AB - Mollolide A (1), a diterpenoid featuring a new 1,10:2,3-disecograyanane skeleton, was isolated from the roots of Rhododendron molle. Its structure was elucidated through extensive MS, IR, and NMR spectroscopy analyses. The absolute configuration was determined by single-crystal X-ray diffraction of its p bromobenzoate derivative (1b). Compound 1 exhibits a significant analgesic effect at a dose of 20 mg/kg and antiviral activity against the Coxsackie B3 virus with an IC50 value of 27.7 MUM. PMID- 23724860 TI - The genomic architecture and association genetics of adaptive characters using a candidate SNP approach in boreal black spruce. AB - BACKGROUND: The genomic architecture of adaptive traits remains poorly understood in non-model plants. Various approaches can be used to bridge this gap, including the mapping of quantitative trait loci (QTL) in pedigrees, and genetic association studies in non-structured populations. Here we present results on the genomic architecture of adaptive traits in black spruce, which is a widely distributed conifer of the North American boreal forest. As an alternative to the usual candidate gene approach, a candidate SNP approach was developed for association testing. RESULTS: A genetic map containing 231 gene loci was used to identify QTL that were related to budset timing and to tree height assessed over multiple years and sites. Twenty-two unique genomic regions were identified, including 20 that were related to budset timing and 6 that were related to tree height. From results of outlier detection and bulk segregant analysis for adaptive traits using DNA pool sequencing of 434 genes, 52 candidate SNPs were identified and subsequently tested in genetic association studies for budset timing and tree height assessed over multiple years and sites. A total of 34 (65%) SNPs were significantly associated with budset timing, or tree height, or both. Although the percentages of explained variance (PVE) by individual SNPs were small, several significant SNPs were shared between sites and among years. CONCLUSIONS: The sharing of genomic regions and significant SNPs between budset timing and tree height indicates pleiotropic effects. Significant QTLs and SNPs differed quite greatly among years, suggesting that different sets of genes for the same characters are involved at different stages in the tree's life history. The functional diversity of genes carrying significant SNPs and low observed PVE further indicated that a large number of polymorphisms are involved in adaptive genetic variation. Accordingly, for undomesticated species such as black spruce with natural populations of large effective size and low linkage disequilibrium, efficient marker systems that are predictive of adaptation should require the survey of large numbers of SNPs. Candidate SNP approaches like the one developed in the present study could contribute to reducing these numbers. PMID- 23724862 TI - Bridging conditional and marginal inference for spatially referenced binary data. AB - Spatially referenced binary data are common in epidemiology and public health. Owing to its elegant log-odds interpretation of the regression coefficients, a natural model for these data is logistic regression. To account for missing confounding variables that might exhibit a spatial pattern (say, socioeconomic, biological, or environmental conditions), it is customary to include a Gaussian spatial random effect. Conditioned on the spatial random effect, the coefficients may be interpreted as log odds ratios. However, marginally over the random effects, the coefficients no longer preserve the log-odds interpretation, and the estimates are hard to interpret and generalize to other spatial regions. To resolve this issue, we propose a new spatial random effect distribution through a copula framework which ensures that the regression coefficients maintain the log odds interpretation both conditional on and marginally over the spatial random effects. We present simulations to assess the robustness of our approach to various random effects, and apply it to an interesting dataset assessing periodontal health of Gullah-speaking African Americans. The proposed methodology is flexible enough to handle areal or geo-statistical datasets, and hierarchical models with multiple random intercepts. PMID- 23724863 TI - Higher prevalence of obesity in Greek children living in rural areas despite increased levels of physical activity. AB - AIM: The purpose of the present study was to evaluate whether levels of physical activity (PA) and sedentary behaviours could explain observed differences in the prevalence of childhood obesity in a sample of Greek children. METHODS: Epidemiological study. PA and sedentary behaviours were assessed by a self administrated PA checklist. Body mass index (BMI) was calculated from measured weight and height. A representative sample of Greek children aged 10-12 years attending fifth and sixth grade (n = 3195), living in rural and urban areas, were enrolled. Maturation status was not evaluated due to technical reasons. RESULTS: Prevalence of obesity was higher among children living in rural areas as compared with urban areas (12.1% vs. 10.7%, P < 0.01). Surprisingly, children living in rural areas had higher levels of self-reported PA (P < 0.001) and met current PA guidelines to a greater extent than their urban counterparts (P < 0.05). Furthermore, boys had higher levels of total, low-to-moderate intensity and vigorous intensity physical activity, as well as sedentary behaviours, than girls (all P-values <0.05). Stratified analysis by BMI category revealed that normal weight boys and girls had higher levels of total PA and vigorous intensity physical activity compared with overweight and obese boys from the same type of setting (all P-values <0.05). CONCLUSIONS: Children living in rural areas have higher levels of PA and more frequently met PA guidelines than their urban counterparts, despite a higher prevalence of obesity. PMID- 23724864 TI - Factors affecting subject-specific finite element models of implant-fitted rat bone specimens: critical analysis of a technical protocol. AB - The authors propose a protocol to derive finite element (FE) models from micro computer tomography scans of implanted rat bone. A semi-automatic procedure allows segmenting the images using specimen-specific bone mineral density (BMD) thresholds. An open-source FE model generator processes the segmented images to a quality tetrahedral mesh. The material properties assigned to each element are integrated from the BMD field. Piecewise, threshold-dependent density-elasticity relationships are implemented to limit the effects of metal artefacts. A detailed sensitivity study highlights the coherence of the generated models and quantifies the influence of the modelling parameters on the results. Two applications of the protocol are proposed. The stiffness of bare and implanted rat tibiae specimens is predicted by simulating three-point bending and inter-implant displacement, respectively. Results are compared with experimental tests. The mean value and the variability between the specimens are well captured in both tests. PMID- 23724865 TI - Electrochemical synthesis of ZnO branched submicrorods on carbon fibers and their feasibility for environmental applications. AB - We investigated the structural and optical properties of the hierarchically integrated zinc oxide (ZnO) branched submicrorods on carbon fibers (ZOCF) by scanning/transmission electron microscopy, X-ray diffraction, and photoluminescence (PL) measurements. The ZnO submicrorods were facilely synthesized by an electrochemical deposition method on polyacrylonitrile-based carbon fiber sheets used as a substrate. After coating the ZnO seed layer on the surface of the carbon fibers, ZnO submicrorods were densely grown on the nuclei sites of the seed layer. The prepared ZOCF samples exhibited high crystallinity and good PL properties. A feasibility for environmental application in Pb(II) removal from aqueous solutions was also studied. The ZOCF adsorbent exhibited an excellent maximum adsorption capacity of 245.07 mg g-1, which could be practically used in Pb(II) removal from water. These fabricated ZOCFs are potentially useful for multifunctional and environmental devices. PMID- 23724866 TI - Combination checkpoint blockade--taking melanoma immunotherapy to the next level. PMID- 23724867 TI - Nivolumab plus ipilimumab in advanced melanoma. AB - BACKGROUND: In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma. METHODS: We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses. RESULTS: A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for >=24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%. CONCLUSIONS: Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.). PMID- 23724868 TI - Alterations of N-3 polyunsaturated fatty acid-activated K2P channels in hypoxia induced pulmonary hypertension. AB - Polyunsaturated fatty acid (PUFA)-activated two-pore domain potassium channels (K2P ) have been proposed to be expressed in the pulmonary vasculature. However, their physiological or pathophysiological roles are poorly defined. Here, we tested the hypothesis that PUFA-activated K2P are involved in pulmonary vasorelaxation and that alterations of channel expression are pathophysiologically linked to pulmonary hypertension. Expression of PUFA activated K2P in the murine lung was investigated by quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), by patch clamp (PC) and myography. K2P -gene expression was examined in chronic hypoxic mice. qRT-PCR showed that the K2P 2.1 and K2P 6.1 were the predominantly expressed K2P in the murine lung. IHC revealed protein expression of K2P 2.1 and K2P 6.1 in the endothelium of pulmonary arteries and of K2P 6.1 in bronchial epithelium. PC showed pimozide-sensitive K2P -like K(+) -current activated by docosahexaenoic acid (DHA) in freshly isolated endothelial cells as well as DHA induced membrane hyperpolarization. Myography on pulmonary arteries showed that DHA induced concentration-dependent instantaneous relaxations that were resistant to endothelial removal and inhibition of NO and prostacyclin synthesis and to a cocktail of blockers of calcium-activated K(+) channels but were abolished by high extracellular (30 mM) K(+) -concentration. Gene expression and protein of K2P 2.1 were not altered in chronic hypoxic mice, while K2P 6.1 was up-regulated by fourfold. In conclusion, the PUFA-activated K2P 2.1 and K2P 6.1 are expressed in murine lung and functional K2P -like channels contribute to endothelium hyperpolarization and pulmonary artery relaxation. The increased K2P 6.1-gene expression may represent a novel counter-regulatory mechanism in pulmonary hypertension and suggest that arterial K2P 2.1 and K2P 6.1 could be novel therapeutic targets. PMID- 23724869 TI - Hyperendemic malaria transmission in areas of occupation-related travel in the Peruvian Amazon. AB - BACKGROUND: Plasmodium vivax and Plasmodium falciparum cause a significant illness burden in Peru. Anopheline indices for populated communities in the peri Iquitos region of Loreto have been reported to be remarkably low, with entomological inoculation rates (EIR) estimated at one to 30 infective bites per year based on a few studies in close proximity to the urban centre of Iquitos and surrounding deforested areas. Local reports suggest that a large number of the reported cases are contracted outside of populated communities in undeveloped riverine areas frequented by loggers and fishermen. METHODS: To better understand vectorial capacity in suspected high malaria transmission zones in a rural district near Iquitos, Peru, mosquito collections were conducted at different points in the seasonality of malaria transmission in 21 sites frequented by occupational labourers. Prevalence of Plasmodium spp in vectors was determined by circumsporozoite protein ELISA on individual mosquitoes. Slide surveillance was performed for humans encountered in the zone. RESULTS: In total, of 8,365 adult female mosquitoes examined, 98.5% were identified as Anopheles darlingi and 117 (1.4%) tested positive for sporozoites (P. falciparum, P. vivax VK210 or P. vivax VK247). Measured human biting rates at these sites ranged from 0.102 to 41.13 bites per person per hour, with EIR values as high as 5.3 infective bites per person per night. Six percent of the 284 blood films were positive for P. vivax or P. falciparum; however, 88% of the individuals found to be positive were asymptomatic at the time of sampling. CONCLUSIONS: The results of this study provide key missing indices of prominent spatial and temporal heterogeneity of vectorial capacity in the Amazon Basin of Peru. The identification of a target human subpopulation as a principal reservoir and dispersion source of Plasmodium species has important implications for vaccine development and the delivery of effective targeted malaria control strategies. PMID- 23724870 TI - Clinicopathological features of mycosis fungoides in patients exposed to Agent Orange during the Vietnam War. AB - There are no reports on the clinicopathological features of mycosis fungoides (MF) among veterans exposed to Agent Orange, one of the herbicides used during the Vietnam War. To evaluate the clinical, histopathological and genotypic findings of Vietnam War veterans with MF and a positive history of exposure to Agent Orange, we performed a comparative clinicopathological study between MF patients with a history of Agent Orange exposure and those without a history of Agent Orange exposure. Twelve Vietnam War veterans with MF were identified. The mean interval from Agent Orange exposure to diagnosis was 24.5 years (range, 9 35). Skin lesions were significantly present on exposed and unexposed areas. Most patients (75%) experienced pruritus (mean visual analog scale score of 6.7). MF was manifested by plaques in 10 patients and by lichenification in five. Histopathological features of most cases were consistent with MF. Biopsy specimens also demonstrated irregular acanthosis (66.7%). In the comparative study, MF patients with a history of Agent Orange exposure differed significantly from those without exposure to Agent Orange in demographic and clinical characteristics. In addition, patients with exposure had an increased tendency for lesions in the exposed area. Notably, our patients showed a higher frequency (33.3%) of mycosis fungoides palmaris et plantaris than in previous studies. Histologically, irregular acanthosis was more frequently observed than ordinary MF. Our results indicate that dermatologists should pay close attention to these clinicopathological differences. Careful assessment of history of exposure to defoliants is warranted in some cases suspicious for MF. PMID- 23724871 TI - An improvement of the diffusion model for assessment of drought stress in plant tissues. AB - The article discusses an improvement of a previously developed method for assessment of ion leakage from plant tissues as a gauge of membrane and cell wall performance under stressful environment. It employs conductometric measurements of the ion efflux from leaves and their quantitative interpretation by a theoretical model based on the laws of diffusion. Experimental data are readily fit with the model and results are in accordance with relative water content of dehydrated barley (Hordeum vulgare) seedlings of two distinct cultivars. Some new parameters obtained from fitting are proposed as reliable indicators of the leaf status. They appear to be helpful in further distinguishing the behavior of two separate cellular structures with respect to their electrolyte permeability. It is concluded that the established method based on the kinetics of ion leakage is adequate for evaluation of contrasting genotypes under normal and stress conditions. Furthermore, it could be used as a simple and powerful tool for routine analysis and screening for drought tolerance in crops. PMID- 23724873 TI - Dissociative fugue symptoms in a 28-year-old male Nigerian medical student: a case report. AB - INTRODUCTION: Dissociative fugue is a psychiatric disorder characterized by amnesia coupled with sudden unexpected travel away from the individual's usual surroundings and denial of all memory of his or her whereabouts during the period of wandering. Dissociative fugue is a rare disorder that is infrequently reported. Before now, no case of it had been reported in a medical student. CASE PRESENTATION: This article focuses on the report of a case of dissociative fugue symptoms in a 28-year-old male Nigerian medical student. CONCLUSION: The observation in this case report brings to the fore that dissociative fugue is often related to stressful life events and can comorbid with a depressive disorder. PMID- 23724872 TI - Can negative life events and coping style help explain socioeconomic differences in perceived stress among adolescents? A cross-sectional study based on the West Jutland cohort study. AB - BACKGROUND: Previous research suggests that perceived stress in adolescence is socially patterned, but that this relationship may depend on the measure of socioeconomic status (SES) used. This study examines if social gradients in perceived stress, negative life events, and coping exist amongst Danish adolescents, and, if life events and coping strategies can partly account for an association between SES and perceived stress. These relationships are studied separately for two different measures of SES. METHODS: Questionnaire data were collected from 3054 14-15 year old youths (83% response rate) during baseline measurement in the West Jutland birth cohort study. Parents were identified via the Central Office of Civil Registration in which the respondents are linked to their parents or guardians via their CPR-number, a personal identification number given to everyone in Denmark. The study employs data from two independent sources, adolescent self-report data (stress, life events and coping) and national registers (parental educational level, household income and confounder variables). Ordinary Least Squares regression estimated the effects of parental SES, negative life events and coping on perceived stress. Analyses were stratified by gender. RESULTS: Girls reported more perceived stress than boys. SES accounted for a small but significant amount of the variance in perceived stress. Lower parental education and lower household income were associated with higher stress levels irrespective of gender, but the social gradient was strongest amongst girls when parents' education was used to measure SES, and strongest for boys when income was used. Life events and coping were also found to be associated with SES and both mediated part of the SES-perceived stress relationship. In general, the social gradient in perceived stress was accounted for by the study variables to a higher degree among girls than among boys. CONCLUSIONS: Lower parental education and household income are associated with higher levels of perceived stress amongst Danish adolescents. Furthermore, both life events and coping appear to mediate this relation. Gender differences in the ways SES and stress are related may exist. PMID- 23724874 TI - Impaired insulin-stimulated glucose transport in ATM-deficient mouse skeletal muscle. AB - There are reports that ataxia telangiectasia mutated (ATM) plays a role in insulin-stimulated Akt phosphorylation, although this is not the case in some cell types. Because Akt plays a key role in insulin signaling, which leads to glucose transport in skeletal muscle, the predominant tissue in insulin stimulated glucose disposal, we examined whether insulin-stimulated Akt phosphorylation and (or) glucose transport would be decreased in skeletal muscle of mice lacking functional ATM, compared with muscle from wild-type mice. We found that in vitro insulin-stimulated Akt phosphorylation was normal in soleus muscle from mice with 1 nonfunctional allele of ATM (ATM+/-) and from mice with 2 nonfunctional alleles (ATM-/-). However, insulin did not stimulate glucose transport or the phosphorylation of AS160 in ATM-/- soleus. ATM protein level was markedly higher in wild-type extensor digitorum longus (EDL) than in wild-type soleus. In EDL from ATM-/- mice, insulin did not stimulate glucose transport. However, in contrast to findings for soleus, insulin-stimulated Akt phosphorylation was blunted in ATM-/- EDL, concomitant with a tendency for insulin-stimulated phosphatidylinositol 3-kinase activity to be decreased. Together, the findings suggest that ATM plays a role in insulin-stimulated glucose transport at the level of AS160 in muscle comprised of slow and fast oxidative-glycolytic fibers (soleus) and at the level of Akt in muscle containing fast glycolytic fibers (EDL). PMID- 23724875 TI - Coingestion of carbohydrate and protein during training reduces training stress and enhances subsequent exercise performance. AB - Researchers have focused primarily on investigating the effects of coingesting carbohydrate (CHO) and protein (PRO) during recovery and, as such, there is limited research investigating the benefits of CHO+PRO coingestion during exercise for enhancing subsequent exercise performance. The aim of this study was to investigate whether coingestion of CHO+PRO during endurance training would enhance recovery and subsequent exercise performance. Ten well-trained male cyclists (aged 29.7 +/- 7.5 years; maximal oxygen uptake, 66.2 +/- 6 mL.kg( 1).min(-1)) took part in a randomized, double-blind, cross-over trial. Each trial consisted of a 2.5-h morning training bout during which the cyclists ingested a CHO+PRO or energy-matched CHO beverage followed by a 4-h recovery period and a subsequent performance time trial (total work, 7 kJ.kg(-1)). Blood was collected before and after exercise. Time-trial performance was 1.8% faster in the CHO+PRO trial compared with the CHO trial (p = 0.149; 95% CI, -13 to 87 s; 75.8% likelihood of benefit). The increase in myoglobin level from before the training bout to after the training bout was lower in the CHO+PRO trial (0.74 nmol.L(-1); 95% CI, 0.3-1.17 nmol.L(-1)) compared with the CHO trial (1.16 nmol.L(-1); 95% CI, 0.6-1.71 nmol.L(-1)) (p = 0.018). Additionally, the decrease in neutrophil count over the recovery period was greater in the CHO+PRO trial (p = 0.034), and heart rate (p < 0.022) and rating of perceived exertion (RPE) (p < 0.01) were lower during training in the CHO+PRO trial compared with the CHO trial. Ingesting PRO, in addition to CHO, during strenuous training lowered exercise stress, as indicated by reduced heart rate, RPE, and muscle damage, when compared with CHO alone. CHO+PRO ingestion during training is also likely to enhance recovery, providing a worthwhile improvement in subsequent cycling time-trial performance. PMID- 23724876 TI - Extracellular hyperosmotic stress stimulates glucose uptake in incubated fast twitch rat skeletal muscle. AB - The influence of hyperosmotic stress on glucose uptake, handling, and signaling processes remains unclear in mammalian skeletal muscle. Thus, the purpose of this study was to investigate alterations in glucose uptake and handling during extracellular hyperosmotic stress in isolated fast-twitch mammalian skeletal muscle. Using an established in vitro isolated whole-muscle model, extensor digitorum longus (EDL) muscles were dissected from male rats (4-6 weeks of age) and incubated (30-60 min) in an organ bath, containing Sigma Medium-199 with 8 mmol.L(-1) D-glucose, and mannitol was added to the targeted osmolalities (ISO, iso-osmotic, 290 mmol.kg(-1); HYPER, hyperosmotic, 400 mmol.kg(-1)). Results demonstrate that relative water content decreased in HYPER. HYPER resulted in significant alterations in muscle metabolite concentrations (lower glycogen, elevated lactate, and glucose-6-phosphate), suggesting a decrease in energy charge. Glucose uptake was also found to be higher in HYPER, and AS160 (implicated in insulin- and contraction-mediated glucose uptake) was found to be significantly more phosphorylated in HYPER than in ISO after 30 min. In conclusion, glucose uptake and handling is altered with hyperosmotic extracellular stress in the fast-twitch EDL. The increases in glucose uptake might be facilitated through alterations in AS160 signaling after 30 to 60 min of osmotic stress. PMID- 23724877 TI - The effect of the ALAnerv nutritional supplement on some oxidative stress markers in postacute stroke patients undergoing rehabilitation. AB - Stroke is a pathologic condition associated with redox imbalance. This pilot study was designed to evaluate the effect of the consumption of the nutritional supplement ALAnerv on some oxidative stress markers in postacute stroke patients undergoing rehabilitation. To achieve this goal, we assigned 28 patients to 2 study groups: (-)ALA and (+)ALA. Patients in both groups participated in the same rehabilitation program and received comparable standard medications; however, patients in the (+)ALA group received ALAnerv for 2 weeks (2 pills per day). We assessed total and nonproteic thiols, protein carbonyls, ceruloplasmin, oxidized low-density lipoprotein (LDL) particles, lipid hydroperoxide concentrations, gamma-glutamyl transpeptidase activity, and total antioxidant capacity. Regression analysis indicated that supplementation with ALAnerv was responsible for the significant decrease in glucose (p = 0.002) and oxidized LDL particles (p < 0.001) during the study period. For both parameters, the variation in the percent of concentration between the 2 groups during the study period reached statistical significance (p = 0.012 and p < 0.001, respectively). Moreover, Barthel Index values at discharge were significantly influenced by ALAnerv treatment. These preliminary results indicate that ALAnerv might be helpful because it rapidly corrects plasma fasting glucose and corrects serum oxidized LDL particle concentrations, suggesting the need for longer treatment with 2 pills or more per day. PMID- 23724878 TI - Hydration status of Greco-Roman wrestlers in an authentic precompetition situation. AB - We assessed the urinary indexes of hydration status of Greco-Roman wrestlers in an authentic precompetition situation at the time of official weigh-in (OWI). A total of 51 of 89 wrestlers competing in the Estonian Championship in 2009 donated a urine sample. Questionnaire responses revealed that 27 wrestlers (body mass losers (BMLs)) reduced body mass before the competition, whereas 24 wrestlers (those who do not lose body mass (n-BMLs)) did not. In 42 wrestlers, values of urine specific gravity >=1.020 and urine osmolality >=700 mOsmol.kg(-1) revealed a hypohydrated status. The prevalence of hypohydration in the BMLs (96%) was higher than in the n-BMLs (67%) (chi(2) = 7.68; p < 0.05). The prevalence of serious hypohydration (urine specific gravity >1.030) was 5.3 times greater (chi(2) = 8.32; p < 0.05) in the BMLs than in the n-BMLs. In the BMLs, the extent of body mass gain during the 16-h recovery (2.5 +/- 1.2 kg) was associated (r = 0.764; p < 0.05) with self-reported precompetition body mass loss (4.3 +/- 2.0 kg) and exceeded the body mass gain observed in the n-BMLs (0.7 +/- 1.2 kg; p < 0.05). We conclude that hypohydration is prevalent among Greco-Roman wrestlers at the time of OWI. The prevalence of hypohydration and serious hypohydration is especially high among wrestlers who are accustomed to reducing body mass before competition. These results suggest that an effective rehydration strategy is needed for Olympic-style wrestlers, and that changes in wrestling rules should be considered to reduce the prevalence of harmful body mass management behaviours. PMID- 23724879 TI - Total body water and its compartments are not affected by ingesting a moderate dose of caffeine in healthy young adult males. AB - Acute and chronic caffeine intakes have no impact on hydration status (R.J. Maughan and J. Griffin, J. Hum. Nutr. Diet. 16(6): 411-420, 2003), although no research has been conducted to analyze the effects using dilution techniques on total-body water (TBW) and its compartments. Therefore, the aim of this study was to investigate the effects of a moderate dose of caffeine on TBW, extracellular water (ECW), and intracellular water (ICW) during a 4-day period in active males. Thirty men, nonsmokers and low caffeine users (<100 mg.day(-1)), aged 20-39 years, participated in this double-blind, randomized, crossover trial (ClinicalTrials.gov: No. NCT01477294). The study included 2 conditions (5 mg.kg( 1).day(-1) of caffeine and placebo (malt-dextrin)) of 4 days each, with a 3-day washout period. TBW and ECW were assessed by deuterium oxide and sodium bromide dilution, respectively, whereas ICW was calculated as TBW minus ECW. Body composition was assessed by dual-energy X-ray absorptiometry. Physical activity (PA) was assessed by accelerometry and water intake was assessed by dietary records. Repeated-measures analysis of variance (ANOVA) was used to test main effects. No changes in TBW, ECW, or ICW and no interaction between the randomly assigned order of treatment and time were observed (p > 0.05). TBW, ECW, and ICW were unrelated to fat-free mass, water ingestion, and PA (p > 0.05). These findings indicate that a moderate caffeine dose, equivalent to approximately 5 espresso cups of coffee or 7 servings of tea, does not alter TBW and fluid distribution in healthy men, regardless of body composition, PA, or daily water ingestion. PMID- 23724880 TI - Effects of caffeine and carbohydrate mouth rinses on repeated sprint performance. AB - Our purpose was to examine the effectiveness of carbohydrate and caffeine mouth rinses in enhancing repeated sprint ability. Previously, studies have shown that a carbohydrate mouth rinse (without ingestion) has beneficial effects on endurance performance that are related to changes in brain activity. Caffeine ingestion has also demonstrated positive effects on sprint performance. However, the effects of carbohydrate or caffeine mouth rinses on intermittent sprints have not been examined previously. Twelve males performed 5 * 6-s sprints interspersed with 24 s of active recovery on a cycle ergometer. Twenty-five milliliters of either a noncaloric placebo, a 6% glucose, or a 1.2% caffeine solution was rinsed in the mouth for 5 s prior to each sprint in a double-blinded and balanced cross over design. Postexercise maximal heart rate and perceived exertion were recorded, along with power measures. A second experiment compared a combined caffeine-carbohydrate rinse with carbohydrate only. Compared with the placebo mouth rinse, carbohydrate substantially increased peak power in sprint 1 (22.1 +/ 19.5 W; Cohen's effect size (ES), 0.81), and both caffeine (26.9 +/- 26.9 W; ES, 0.71) and carbohydrate (39.1 +/- 25.8 W; ES, 1.08) improved mean power in sprint 1. Experiment 2 demonstrated that a combination of caffeine and carbohydrate improved sprint 1 power production compared with carbohydrate alone (36.0 +/- 37.3 W; ES, 0.81). We conclude that carbohydrate and (or) caffeine mouth rinses may rapidly enhance power production, which could have benefits for specific short sprint exercise performance. The ability of a mouth-rinse intervention to rapidly improve maximal exercise performance in the absence of fatigue suggests a central mechanism. PMID- 23724881 TI - Combined food intake and exercise unmask different hormonal responses in lean and obese children. AB - Our purpose was to investigate the effect of obesity in prepubertal children on the hormonal response to exercise performed under different conditions of nutrient availability. Prepubertal obese (age, 10.3 +/- 1.8 years; %body fat, 36.1 +/- 6.1; n = 9) and lean (age, 9.2 +/- 1.6 years; %body fat, 22.2 +/- 4.1; n = 7) children completed 2 experimental sessions in which they performed a 30 min of cycling exercise at 50% of their maximal aerobic power either 1 h (T1h) or 3 h (T3h) after a standardized breakfast. Plasma insulin-like growth factor 1 (IGF 1), IGF binding protein 1 (IGFBP-1), and IGFBP-3 levels were assessed at baseline and after exercise. Urine was collected during the sessions, and catecholamine and glucocorticoid excretions were analyzed. A significant time effect was observed for IGFBP-1; postexercise levels decreased in lean and obese children (p <= 0.001). IGF-1 and IGFBP-3 were not affected by obesity or food intake combined with exercise. In lean children, urinary excretion rates of epinephrine, norepinephrine, cortisol, and cortisone were significantly higher during the sessions than during the overnight resting period; in obese children, only epinephrine in T1h was significantly increased (p <= 0.05 for all). Our study indicates that the activity of the hypothalamic-pituitary-adrenal axis and sympathetic adrenal medullary axis was similar in lean and obese children, based on measurement under resting conditions, but response to exercise performed in postprandial conditions was altered in obese children for both axes. In addition, exercise in the postprandial state elicited a decrease in IGFBP-1 plasma levels, whereas IGF-1 and IGFBP-3 levels were not significantly altered. PMID- 23724882 TI - Heart rate recovery and heart rate variability are unchanged in patients with coronary artery disease following 12 weeks of high-intensity interval and moderate-intensity endurance exercise training. AB - Decreased heart rate variability and attenuated heart rate recovery following exercise are associated with an increased risk of mortality in cardiac patients. This study investigated the effects of 12 weeks of moderate-intensity endurance exercise (END) and a novel low-volume high-intensity interval exercise protocol (HIT) on measures of heart rate recovery and heart rate variability in patients with coronary artery disease (CAD). Fourteen males with CAD participated in 12 weeks of END or HIT training, each consisting of 2 supervised exercise sessions per week. END consisted of 30-50 min of continuous cycling at 60% peak power output (PPO). HIT involved ten 1-min intervals at 88% PPO separated by 1-min intervals at 10% PPO. Heart rate recovery at 1 min and 2 min was measured before and after training (pre- and post-training, respectively) using a submaximal exercise bout. Resting time and spectral and nonlinear domain measures of heart rate variability were calculated. Following 12 weeks of END and HIT, there was no change in heart rate recovery at 1 min (END, 40 +/- 12 beats.min(-1) vs. 37 +/- 19 beats.min(-1); HIT, 31 +/- 8 beats.min(-1) vs. 35 +/- 8 beats.min(-1); p >= 0.05 for pre- vs. post-training) or 2 min (END, 44 +/- 18 beats.min(-1) vs. 43 +/ 19 beats.min(-1); HIT, 42 +/- 10 beats.min(-1) vs. 50 +/- 6 beats.min(-1); p >= 0.05 for pre- vs. post-training). All heart rate variability indices were unchanged following END and HIT training. In conclusion, neither END nor HIT exercise programs elicited training-induced improvements in cardiac autonomic function in patients with CAD. The absence of improvements with training may be attributed to the optimal medical management and normative pretraining state of our sample. PMID- 23724883 TI - The effects of strength training and endurance training order on running economy and performance. AB - This study examined the acute effect of strength and endurance training sequence on running economy (RE) at 70% and 90% ventilatory threshold (VT) and on running time to exhaustion (TTE) at 110% VT the following day. Fourteen trained and moderately trained male runners performed strength training prior to running sessions (SR) and running prior to strength training sessions (RS) with each mode of training session separated by 6 h. RE tests were conducted at baseline (Base RE) and the day following each sequence to examine cost of running (CR), TTE, and lower extremity kinematics. Maximal isometric knee extensor torque was measured prior to and following each training session and the RE tests. Results showed that CR at 70% and 90% VT for SR-RE (0.76 +/- 0.10 and 0.77 +/- 0.07 mL.kg( 0.75).m(-1)) was significantly greater than Base-RE (0.72 +/- 0.10 and 0.70 +/- 0.11 mL.kg(-0.75).m(-1)) and RS-RE (0.73 +/- 0.09 and 0.72 +/- 0.09 mL.kg( 0.75).m(-1)) (P < 0.05). TTE was significantly less for SR-RE (237.8 +/- 67.4 s) and RS-RE (275.3 +/- 68.0 s) compared with Base-RE (335.4 +/- 92.1 s) (P < 0.01). The torque during the SR sequence was significantly reduced for every time point following the strength training session (P < 0.05). However, no significant differences were found in torque following the running session (P > 0.05), although it was significantly reduced following the strength training session (P < 0.05) during the RS sequence. These findings show that running performance is impaired to a greater degree the day following the SR sequence compared with the RS sequence. PMID- 23724884 TI - Influence of hormone replacement therapy and aerobic exercise training on oxygen uptake kinetics in postmenopausal women. AB - The purpose of this study was to determine the effects of aerobic exercise training on the adjustment of pulmonary oxygen (O2) uptake (VO2p) kinetics in postmenopausal women in 2 groups: those using hormone replacement therapy (HRT) (HRT group) (n = 7, aged 56 +/- 4 years) and those not using HRT (nonHRT group) (n = 8, aged 60 +/- 5 years). The influence of training (cycle-ergometer 3 times per week for 6 weeks) on step transitions to both moderate-intensity (80% of the gas exchange threshold) and heavy-intensity (Delta50) cycling exercise was studied. Breath-by-breath VO2p data were collected using a mass spectrometer. There were no differences in baseline characteristics between the HRT and nonHRT groups. Moderate-intensity exercise VO2p kinetics were significantly speeded (p < 0.05) with the tauVO2p decreasing from 46 +/- 8 s before training to 32 +/- 4 s after training. Similarly, during the heavy-intensity exercise, on-transient phase 2 tauVO2p was reduced from before training (48 +/- 7 s) to after training (38 +/- 6 s). The use of HRT did not influence the effect of the endurance exercise training on tauVO2p during moderate or heavy exercise in healthy postmenopausal women. To provide insight into the mechanism of adjustment, knee extension exercise was studied, and the VO2p kinetics were significantly speeded (p < 0.05), with the tauVO2p of the knee extension exercise decreasing from 62.2 +/- 18.3 s before training to 48.0 +/- 16.2 s after training. Thus, 6 weeks of exercise training resulted in appreciably faster cycling phase 2 VO2p kinetics during moderate and heavy exercise in older women, independent of HRT use. PMID- 23724885 TI - Nutrition marketing on processed food packages in Canada: 2010 Food Label Information Program. AB - The current study describes the frequency of use of different forms of nutrition marketing in Canada and the nutrients and conditions that are the focus of nutrition marketing messages. Prepackaged foods with a Nutrition Facts table (N = 10,487) were collected between March 2010 and April 2011 from outlets of the 3 largest grocery chains in Canada and 1 major western Canadian grocery retailer. The nutrition marketing information collected included nutrient content claims, disease risk reduction claims, and front-of-pack nutrition rating systems (FOPS). We found that nutrition marketing was present on 48.1% of Canadian food packages, with nutrient content claims being the most common information (45.5%), followed by FOPS on 18.9% of packages. Disease risk reduction claims were made least frequently (1.7%). The marketing messages used most often related to total fat and trans fat (15.6% and 15.5% of nutrient content claims, respectively). Limiting total and trans fats is a current public health priority, as recommended by Health Canada and the World Health Organization. However, other nutrients that are also recommended to be limited, including saturated fats, sodium, and added sugars, were not nearly as prominent on food labels. Thus, greater emphasis should be placed by the food industry on these other important nutrients. Repeated data collection in the coming years will allow us to track longitudinal changes in nutrition marketing messages over time as food marketing, public health, and consumer priorities evolve. PMID- 23724886 TI - Cardiovascular re-adjustments and baroreflex response during clinical reambulation procedure at the end of 35-day bed rest in humans. AB - During the reambulation procedure after 35-day head-down tilt bed rest (HDTBR) for 9 men, we recorded for the first time heart rate (HR; with electrocardiogram) and arterial pressure profiles (fingertip plethysmography) for 5 min in HDTBR and horizontal (SUP) positions, followed by 12 min in standing position, during which 4 subjects fainted (intolerant, INT) and were laid horizontal again (Recovery). We computed: mean arterial pressure (P; pressure profiles integral mean), stroke volume (SV; obtained with Modelflow method), and cardiac output (Q; SV * HR). All cardiovascular data remained stable in HDTBR and SUP for both groups (EXP). Taking the upright posture, EXP showed a decrease in SV and an increase in HR, becoming significantly different from SUP within 1 min. Further evolution of these parameters kept Q stable in both groups until the second minute of standing. Afterward, in INT, P precipitated without further HR increases: SV stopped being corrected and Q reached 2.9 +/- 0.4 L.min(-1) at the last 15 s of standing. Sudden drop in P allowed identification of a low-pressure threshold in INT (70.7 +/- 12.9 mm Hg), after which syncope occurred within 80 s. During Recovery, baroreflex curves showed a flat phase (P increase, HR stable), followed by a steep phase (P increased, HR decreased, starting when P was 84.5 +/- 12.5 mm Hg and Q was 9.6 +/- 1.5 L.min(-1)). INT, in contrast with tolerant subjects, did not sustain standing because HR was unable to correct for the P drop. These results indicate a major role for impaired arterial baroreflexes in the onset of orthostatic intolerance. PMID- 23724887 TI - Consumption of sucrose and high-fructose corn syrup does not increase liver fat or ectopic fat deposition in muscles. AB - It has been postulated that fructose-induced triglyceride synthesis is augmented when accompanied by glucose. Chronic elevations could lead to excess fat accumulation in the liver and ectopic fat deposition in muscles, which in turn could contribute to the induction of abnormalities in glucose homeostasis, insulin resistance, and the subsequent development of type 2 diabetes. Our objective was to evaluate the effect of the addition of commonly consumed fructose- and (or) glucose-containing sugars in the usual diet on liver fat content and intramuscular adipose tissue. For 10 weeks, 64 individuals (mean age, 42.16 +/- 11.66 years) consumed low-fat milk sweetened with either high-fructose corn syrup (HFCS) or sucrose; the added sugar matched consumption levels of fructose in the 25th, 50th, and 90th percentiles of the population. The fat content of the liver was measured with unenhanced computed tomography imaging, and the fat content of muscle was assessed with magnetic resonance imaging. When the 6 HFCS and sucrose groups were averaged, there was no change over the course of 10 weeks in the fat content of the liver (13.32% +/- 10.49% vs. 13.21% +/- 10.75%; p > 0.05), vastus lateralis muscle (3.07 +/- 0.74 g per 100 mL vs. 3.15 +/- 0.84 g per 100 mL; p > 0.05), or gluteus maximus muscle (4.08 +/- 1.50 g per 100 mL vs. 4.24 +/- 1.42 g per 100 mL; p > 0.05). Group assignment did not affect the result (interaction > 0.05). These data suggest that when fructose is consumed as part of a typical diet in normally consumed sweeteners, such as sucrose or HFCS, ectopic fat storage in the liver or muscles is not promoted. PMID- 23724888 TI - Effects of different levels of physical inactivity on plasma visfatin in healthy normal-weight men. AB - We tested whether physical inactivity (PI) is an independent predictor of plasma visfatin, a newly discovered adipokine likely involved in the relationship between obesity-associated low-grade inflammation and insulin resistance. PI was induced in healthy men (Body Mass Index = 23.4 +/- 0.6 kg.m(-2)) by 10 days of confinement (n = 8), 1 month of detraining (n = 10), and 3 months of bed rest with (n = 7) and without exercise (n = 8). Visfatin was negatively associated with activity energy expenditure (p = 0.03). No relationship was observed with insulin sensitivity. This suggested that PI itself increases visfatin concentrations. PMID- 23724889 TI - Leucine supplementation increases serum insulin-like growth factor 1 concentration and liver protein/RNA ratio in rats after a period of nutritional recovery. AB - This study evaluated the effect of leucine on the protein status of rats submitted to 50% food restriction for 1 week, followed by 2 weeks of nutritional recovery. A significant increase of serum insulin-like growth factor 1 and protein/RNA ratio in the liver was observed in leucine-supplemented rats. There was no change in carcass, liver, or gastrocnemius protein content when compared with control animals. The supplementation tested did not favor protein status, although it improved some indicators of an anabolic state. PMID- 23724893 TI - Local frustration determines molecular and macroscopic helix structures. AB - Decorative domains force amyloid fibers to adopt spiral ribbon morphologies, as opposed to the more common twisted ribbon. We model the effect of decorating domains as a perturbation to the relative orientation of beta strands in a bilayered extended beta-sheet. The model consists of minimal energy assemblies of rigid building blocks containing two anisotropic interacting ellipsoids. The relative orientation of the ellipsoids dictates the morphology of the resulting assembly. Amyloid structures derived from experiment are consistent with our model, and we use magnets to demonstrate that the frustration principle is scale and system independent. In contrast to other models of amyloid, our model isolates the effect of frustration from the fundamental interactions between building blocks to reveal the frustration rather than dependence of morphology on the physical interactions. Consequently, amyloid is viewed as a discrete molecular version of the more general macroscopic frustrated bilayer that is exemplified by Bauhinia seedpods. The model supports the idea that the interactions arising from an arbitrary peptide sequence can support an amyloid structure if a bilayer can form first, which suggests that supplementary protein sequences, such as chaperones or decorative domains, could play a significant role in stabilizing such bilayers and therefore in selecting morphology during nucleation. Our model provides a foundation for exploring the effects of frustration on higher-order superstructural polymorphic assemblies that may exhibit complex functional behavior. Two outstanding examples are the systematic kinking of decorated fibers and the nested frustration of the Bauhinia seedpod. PMID- 23724892 TI - Comparison of Validated Assessment Scales and 3D digital fringe projection method to assess lifetime development of wrinkles in men. AB - BACKGROUND: The assessment of wrinkle severity is an important evaluation criterion to determine the efficacy of aesthetic treatments. Aim of the present study was to compare Validated Assessment Scales (VAS) and 3D fringe projection (PRIMOS((r)) ) for the evaluation of facial wrinkles in men and to determine standard values for each level of the VAS. METHODS: 150 male subjects (20 to 70 years) were selected following strict criteria. Wrinkle severity at periorbital, glabella and forehead lines was evaluated using the 3D fringe projection and 5 point photonumeric VAS. The results of both methods were matched by determining quantitative values for each level of the clinical rating scale. RESULTS: High average correlation with age was found for VAS, Wd, maxWd, lWd, Wv, aWa and pWa. With a Wd of 60 to 70MUm crow's feet and forehead lines are pronounced first, whereas glabella lines develop in subject's mid-forties, by an Wd of 180MUm. Wrinkle severity increases at all locations every 10 years of age by one level of the VAS. This increase corresponds to an increase of Wd about 100 MUm at glabella and forehead lines, and about 50 MUm at crow's feet. CONCLUSION: The presented reference values for the Validated Assessment Scale are an important step towards an optimized assessment of skin aging and aesthetic dermatological treatments. The data helps to combine the precession of a biophysical measurement with the practical relevance of a clinical rating. PMID- 23724894 TI - Highly conductive and flexible nylon-6 nonwoven fiber mats formed using tungsten atomic layer deposition. AB - Low-temperature vapor-phase tungsten atomic layer deposition (ALD) using WF6 and dilute silane (SiH4, 2% in Ar) can yield highly conductive coatings on nylon-6 microfiber mats, producing flexible and supple nonwovens with conductivity of ~1000 S/cm. We find that an alumina nucleation layer, reactant exposure, and deposition temperature all influence the rate of W mass uptake on 3D fibers, and film growth rate is calibrated using high surface area anodic aluminum oxide. Transmission electron microscopy (TEM) reveals highly conformal tungsten coatings on nylon fibers with complex "winged" cross-section. Using reactant gas "hold" sequences during the ALD process, we conclude that reactant species can transport readily to reactive sites throughout the fiber mat, consistent with conformal uniform coverage observed by TEM. The conductivity of 1000 S/cm for the W-coated nylon is much larger than found in other conductive nonwovens. We also find that the nylon mats maintain 90% of their conductivity after being flexed around cylinders with radii as small as 0.3 cm. Metal ALD coatings on nonwovens make possible the solvent-free functionalization of textiles for electronic applications. PMID- 23724895 TI - Protein expression profiling of nuclear membrane protein reveals potential biomarker of human hepatocellular carcinoma. AB - BACKGROUND: Complex molecular events lead to development and progression of liver cirrhosis to HCC. Differentially expressed nuclear membrane associated proteins are responsible for the functional and structural alteration during the progression from cirrhosis to carcinoma. Although alterations/ post translational modifications in protein expression have been extensively quantified, complementary analysis of nuclear membrane proteome changes have been limited. Deciphering the molecular mechanism that differentiate between normal and disease state may lead to identification of biomarkers for carcinoma. RESULTS: Many proteins displayed differential expression when nuclear membrane proteome of hepatocellular carcinoma (HCC), fibrotic liver, and HepG2 cell line were assessed using 2-DE and ESI-Q-TOF MS/MS. From the down regulated set in HCC, we have identified for the first time a 15 KDa cytochrome b5A (CYB5A), ATP synthase subunit delta (ATPD) and Hemoglobin subunit beta (HBB) with 11, 5 and 22 peptide matches respectively. Furthermore, nitrosylation studies with S-nitrosocysteine followed by immunoblotting with anti SNO-cysteine demonstrated a novel and biologically relevant post translational modification of thiols of CYB5A in HCC specimens only. Immunofluorescence images demonstrated increased protein S nitrosylation signals in the tumor cells and fibrotic region of HCC tissues. The two other nuclear membrane proteins which were only found to be nitrosylated in case of HCC were up regulated ATP synthase subunit beta (ATPB) and down regulated HBB. The decrease in expression of CYB5A in HCC suggests their possible role in disease progression. Further insight of the functional association of the identified proteins was obtained through KEGG/ REACTOME pathway analysis databases. String 8.3 interaction network shows strong interactions with proteins at high confidence score, which is helpful in characterization of functional abnormalities that may be a causative factor of liver pathology. CONCLUSION: These findings may have broader implications for understanding the mechanism of development of carcinoma. However, large scale studies will be required for further verification of their critical role in development and progression of HCC. PMID- 23724896 TI - Effects of ammonium bicarbonate on the electrospray mass spectra of proteins: evidence for bubble-induced unfolding. AB - Many protein investigations by electrospray ionization (ESI) mass spectrometry (MS) strive to ensure a "native" solvent environment, i.e., nondenaturing conditions up to the point of gas-phase ion formation. Ideally, these studies would employ a volatile pH buffer to mitigate changes in H(+) concentration that can occur during ESI. Ammonium acetate is a commonly used additive, despite its low buffering capacity at pH 7. Ammonium bicarbonate provides greatly improved pH stabilization, thus offering an interesting alternative. Surprisingly, protein analyses in bicarbonate at pH 7 tend to result in the formation of very high charge states, similar to those obtained when electrospraying unfolded proteins in a denaturing solvent. This effect has been reported previously (Sterling, H. J.; Cassou, C. A.; Susa, A. C.; Williams, E. R. Anal. Chem. 2012, 84, 3795), but its exact mechanistic origin remains unclear. ESI-mediated unfolding does not take place in acetate under otherwise identical conditions. We demonstrate that heating of protein-containing bicarbonate solutions results in extensive foaming, caused by CO2 outgassing. In contrast, acetate solutions do not generate foam. Protein denaturation caused by gas bubbles is a well-known phenomenon. Adsorption to the gas/liquid interface is accompanied by major conformational changes that allow the protein to act as a surfactant. The foaming of beer is a manifestation of this effect. Bubble formation in bicarbonate during ESI is facilitated by collisional and blackbody droplet heating. Our data imply that heat and bubbles act synergistically to cause unfolding during the electrospray process, while proteins reside in ESI droplets. Because of this effect we advise against the use of ammonium bicarbonate for native ESI-MS. Ammonium acetate represents a gentler droplet environment, despite its low buffering capacity. PMID- 23724897 TI - Receptivity and preferences of pancreatic cancer family members for participating in lifestyle programs to reduce cancer risk. AB - BACKGROUND: Cancer is a shared family experience that might provide an opportunity for lifestyle change among at-risk family members. The purpose of this study was to assess receptivity and preferences for cancer risk reduction programs among at-risk family members with two or more relatives affected with pancreas cancer. METHODS: We surveyed 401 at-risk family members in an existing pancreatic cancer family registry. Participants completed a mailed survey which examined demographic, medical, and psychosocial correlates of willingness to participate in lifestyle cancer risk reduction programs. Multivariable generalized estimating equation approaches were used to model preferences. RESULTS: Overall, 85% (n = 342) of at-risk family members were receptive to lifestyle cancer risk reduction programs. Participant preferred programs focused on nutrition (36%, n = 116) and weight management (33%, n = 108), with Web/Internet (46%, n = 157) being the most preferred delivery channel. Most respondents preferred to participate in programs with their family or friends (74%, n = 182), rather than alone (25%, n = 85). In multivariable analysis, younger age (p = 0.008) and higher perceived likelihood of developing cancer (p = 0.03) were associated with willingness to participate in lifestyle programs. CONCLUSIONS: Family members of those with pancreatic cancer are receptive to cancer risk reduction programs focusing on nutrition and weight management delivered via the internet. Further research is indicated to determine how to best incorporate a family-based approach when designing lifestyle intervention programs. PMID- 23724898 TI - "Soft" liquid-phase adsorption for the fabrication of solution processable organic material films on wettability-patterned surfaces. AB - We discuss a "soft" liquid-phase adsorption (SLPA) technique for the fabrication of organic films on wettability-patterned templates by using methanol/hexane and toluene/water emulsions. The emulsions are stable for several hours at room temperature, and the diameters of the dispersed phase are estimated to be several micrometers using dynamic light scattering. The templates are fabricated by exposing self-assembled monolayers to an ultraviolet/ozone atmosphere through a shadow mask. Fluorescent dye and semiconductor polymer films are formed selectively on the hydrophilic region of the substrates and the hydrophobic region of the self-assembled monolayer, respectively. The thickness is significantly larger than those of the films fabricated by conventional film forming techniques such as spin-coating and dip-coating, respectively. These patterned films serve as photoluminescent films. These results demonstrate that the SLPA technique allows for the fabrication of organic films on wettability patterned templates using solution-processable materials. This technique will find application to the fabrication of electronic and photonic devices with small material consumption and few film-forming processes. PMID- 23724899 TI - Quantitative trait loci for partial resistance to Pseudomonas syringae pv. maculicola in Arabidopsis thaliana. AB - Segregation of partial resistance to Pseudomonas syringae pv. maculicola (Psm) ES4326 was studied in the recombinant inbred population created from accessions (ecotypes) Columbia (Col-4), the more susceptible parent, and Landsberg (Ler-0). Plants were spray inoculated with lux-transformed bacteria in experiments to measure susceptibility. The amount of disease produced on a range of Col * Ler lines by spray inoculation was highly correlated with that produced by pressure infiltration of bacteria into the apoplast. Quantitative trait locus (QTL) analysis identified four loci that contributed to partial resistance: QRpsJIC 1.1, QRpsJIC-2.1, QRpsJIC-3.1 and QRpsJIC-5.1 on chromosomes 1, 2, 3 and 5, respectively. QRpsJIC-3.1, located 8.45 cM from the top of the consensus genetic map of chromosome 3, had a large, approximately additive effect on partial resistance, explaining 50% of the genetic variation in this population. Fine mapping narrowed the region within which this QTL was located to 62 genes. A list of candidate genes included several major classes of resistance gene. PMID- 23724900 TI - Absence of differences in urinary iodine excretion and thyroid function tests in operating room staff members using or not using iodine-containing antiseptic solutions. PMID- 23724901 TI - Stationarity tests for spatial point processes using discrepancies. AB - For testing stationarity of a given spatial point pattern, Guan (2008) proposed a model-free statistic, based on the deviations between observed and expected counts of points in expanding regions within the sampling window. This article extends his method to a general class of statistics by incorporating also such information when points are projected to the axes and by allowing different ways to construct regions in which the deviations are considered. The limiting distributions of the new statistics can be expressed in terms of integrals of a Brownian sheet and hence asymptotic critical values can be approximated. A simulation study shows that the new tests are always more powerful than that of Guan. When applied to the longleaf pine data where Guan's test gave an inconclusive answer, the new tests indicate a clear rejection of the stationarity hypothesis. PMID- 23724902 TI - A reference line on temporomandibular joint MRI. AB - PURPOSE: The aim of this study was to establish a reference line and the 12 o'clock position on sagittal MRI images of the temporomandibular joint (TMJ) for close observation of early changes in disk position. MATERIALS AND METHODS: The study included 106 joints of 53 consecutive male and female patients (mean age 13.3 years) with available MRI and limited cone-beam computed tomography (LCBCT) images, from a pool of postorthodontic patients who had finished phase I or phase II orthodontic treatment between March 2006 and March 2008 in a private orthodontic office. High-resolution (0.1 pixel) LCBCT images taken in natural head position in the same time period and adjusted to the same magnification were superimposed on corresponding MRI images. The true horizontal line (THL) determined by natural head position on the LCBCT image was transferred to the MRI image. A clinically easy-to-use reference line (RL) approximating THL was drawn by connecting two readily locatable anatomical landmarks, the most inferior point of the articular eminence and the center of the auditory canal, and correspondence between THL and RL was assessed. RESULTS: The mean angle formed by THL and RL on the MRI images of the TMJs studied was 2.2 degrees (SD 2.8 degrees ) clockwise around the center of the auditory canal, and the angulations of THL and RL on MRI images of the TMJs studied demonstrated a high positive correlation (r = 0.84). CONCLUSIONS: THL can be established directly on MRI images using the THL-RL angle obtained by this study in patients without advanced disk displacement resulting in bony changes of the joint. The deepest point on the glenoid fossa that meets the THL can be used as the 12 o'clock position for evaluation of incipient disk position change. PMID- 23724904 TI - The power of meta-analysis in genome-wide association studies. AB - Meta-analysis of multiple genome-wide association (GWA) studies has become common practice over the past few years. The main advantage of this technique is the maximization of power to detect subtle genetic effects for common traits. Moreover, one can use meta-analysis to probe and identify heterogeneity in the effect sizes across the combined studies. In this review, we systematically appraise and evaluate the characteristics of GWA meta-analyses with 10,000 or more subjects published up to June 2012. We provide an overview of the current landscape of variants discovered by GWA meta-analyses, and we discuss and assess with extrapolations from empirical data the value of larger meta-analyses for the discovery of additional genetic associations and new biology in the future. Finally, we discuss some emerging logistical and practical issues related to the conduct of meta-analysis of GWA studies. PMID- 23724903 TI - The genetic theory of infectious diseases: a brief history and selected illustrations. AB - Until the mid-nineteenth century, life expectancy at birth averaged 20 years worldwide, owing mostly to childhood fevers. The germ theory of diseases then gradually overcame the belief that diseases were intrinsic. However, around the turn of the twentieth century, asymptomatic infection was discovered to be much more common than clinical disease. Paradoxically, this observation barely challenged the newly developed notion that infectious diseases were fundamentally extrinsic. Moreover, interindividual variability in the course of infection was typically explained by the emerging immunological (or somatic) theory of infectious diseases, best illustrated by the impact of vaccination. This powerful explanation is, however, best applicable to reactivation and secondary infections, particularly in adults; it can less easily account for interindividual variability in the course of primary infection during childhood. Population and clinical geneticists soon proposed a complementary hypothesis, a germline genetic theory of infectious diseases. Over the past century, this idea has gained some support, particularly among clinicians and geneticists, but has also encountered resistance, particularly among microbiologists and immunologists. We present here the genetic theory of infectious diseases and briefly discuss its history and the challenges encountered during its emergence in the context of the apparently competing but actually complementary microbiological and immunological theories. We also illustrate its recent achievements by highlighting inborn errors of immunity underlying eight life threatening infectious diseases of children and young adults. Finally, we consider the far-reaching biological and clinical implications of the ongoing human genetic dissection of severe infectious diseases. PMID- 23724905 TI - Cascade cyclizations of acyclic and macrocyclic alkynones: studies toward the synthesis of phomactin A. AB - A study of the reactivity and diastereoselectivity of the Lewis acid promoted cascade cyclizations of both acyclic and macrocyclic alkynones is described. In these reactions, a beta-iodoallenolate intermediate is generated via conjugate addition of iodide to an alkynone followed by an intramolecular aldol reaction with a tethered aldehyde to afford a cyclohexenyl alcohol. The Lewis acid magnesium iodide (MgI2) was found to promote irreversible ring closure, while cyclizations using BF3.OEt2 as promoter occurred reversibly. For both acyclic and macrocyclic alkynones, high diastereoselectivity was observed in the intramolecular aldol reaction. The MgI2 protocol for cyclization was applied to the synthesis of advanced intermediates relevant to the synthesis of phomactin natural products, during which a novel transannular cation-olefin cyclization was observed. DFT calculations were conducted to analyze the mechanism of this unusual MgI2-promoted process. PMID- 23724906 TI - Plasma progranulin levels in cortical dementia phenotypes with asymmetric perisylvian atrophy. AB - BACKGROUND AND PURPOSE: Decreased plasma progranulin levels are a very specific marker for the diagnosis of frontotemporal lobar degeneration (FTLD) caused by mutations in the progranulin gene (GRN). A frequent neuroimaging pattern in this type of dementia is asymmetric cortical atrophy. The aim of this study was to screen for GRN-linked FTLD in cases with different cortical dementia phenotypes and asymmetric perisylvian atrophy. METHODS: Progranulin plasma levels were analyzed in a variety of FTLD phenotypes (n = 71), dementia of the Alzheimer type (DAT) (n = 22) and probable Lewy body dementia (n = 8), both latter groups presented with asymmetric perisylvian atrophy. A group of elderly controls (n = 29) and DAT cases with symmetric atrophy (n = 33) were also analyzed. The GRN gene was sequenced in cases with lower plasma levels. RESULTS: Four cases with clinical FTLD phenotypes and plasma levels below 70 ng/ml were found to carry different GRN mutations: M1?, C139R, a point mutation in the splice donor site of intron 3 (A89VfsX41), and a deletion in exon 9 (A303AfsX57), this latter one being a new mutation. Thirteen cases with levels between 72 and 85 ng/ml did not show pathogenic changes in the GRN gene. None of the cases with asymmetric atrophy and clinical phenotypes other than FTLD had GRN mutations. CONCLUSIONS: Asymmetric perisylvian atrophy is not likely to predict progranulin-linked FTLD unless it is associated with a consistent FTLD clinical phenotype. PMID- 23724908 TI - An empirical test of the information-motivation-behavioral skills model of ART adherence in a sample of HIV-positive persons primarily in out-of-HIV-care settings. AB - The current body of evidence supporting the Information-Motivation-Behavioral Skills (IMB) model of antiretroviral therapy (ART) adherence rests exclusively on data collected from people living with HIV (PLWH) at point-of-HIV-care services. The aims of this study were to: (1) determine if the IMB model is a useful predictive model of ART adherence among PLWH who were primarily recruited in out of-HIV-care settings; and (2) assess whether the theorized associations between IMB model constructs and adherence persist in the presence of depression and current drug use. PLWH (n = 312) responding to a one-time online survey completed the Life Windows IMB-ART-Adherence Questionnaire, and demographic, depression (CES-D 10), and drug use items. Path models were used to assess the fit of a saturated versus fully mediated IMB model of adherence and examined for moderating effects of depression and current drug use. Participants were on average 43 years of age, had been living with HIV for 9 or more years, and mostly male (84.0%), Caucasian (68.8%), and gay-identified (74.8%). The a priori measurement models for information and behavioral skills did not have acceptable fit to the data and were modified accordingly. Using the revised IMB scales, IMB constructs were associated with adherence as predicted by the theory in all but one model (i.e., the IMB model operated as predicted among nondrug users and those with and without depression). Among drug users, information exerted a direct effect on adherence but was not significantly associated with behavioral skills. Results of this study suggest that the fully or partially mediated IMB model is supported for use with samples of PLWH recruited primarily out-of-HIV care service settings and is robust in the presence of depression and drug use. PMID- 23724907 TI - Variability of antibiotic prescribing in patients with chronic obstructive pulmonary disease exacerbations: a cohort study. AB - BACKGROUND: The role of antibiotics in treating mild or moderate exacerbations in patients with acute chronic obstructive pulmonary disease (COPD) is unclear. The aims were to: (i) describe patient characteristics associated with acute exacerbations amongst a representative COPD population, (ii) explore the relationship between COPD severity and outcomes amongst patients with exacerbations, and (iii) quantify variability by general practice in prescribing of antibiotics for COPD exacerbations. METHOD: A cohort of 62,747 patients with COPD was identified from primary care general practices (GP) in England, and linked to hospital admission and death certificate data. Exacerbation cases were matched to three controls and characteristics compared using conditional logistic regression. Outcomes were compared using incidence rates and Cox regression, stratified by disease severity. Variability of prescribing at the GP level was evaluated graphically and by using multilevel models. RESULTS: COPD severity was found to be associated with exacerbation and subsequent mortality (very severe vs. mild, odds ratio for exacerbation 2.12 [95%CI 19.5-2.32]), hazard ratio for mortality 2.14 [95%CI 1.59-2.88]). Whilst 61% of exacerbation cases were prescribed antibiotics, this proportion varied considerably between GP practices (interquartile range, 48-73%). This variation is greater than can be explained by patient characteristics alone. CONCLUSIONS: There is significant variability between GP practices in the prescribing of antibiotics to COPD patients experiencing exacerbations. Combined with a lack of evidence on the effects of treatment, this supports the need and opportunity for a large scale pragmatic randomised trial of the prescribing of antibiotics for COPD patients with exacerbations, in order to clarify their effectiveness and long term outcomes whilst ensuring the representativeness of subjects. PMID- 23724909 TI - Genetic association of OPR genes with resistance to Hessian fly in hexaploid wheat. AB - BACKGROUND: Hessian fly (Mayetiola destructor) is one of the most destructive pests of wheat. The genes encoding 12-oxo-phytodienoic acid reductase (OPR) and lipoxygenase (LOX) play critical roles in insect resistance pathways in higher plants, but little is known about genes controlling resistance to Hessian fly in wheat. RESULTS: In this study, 154 F6:8 recombinant inbred lines (RILs) generated from a cross between two cultivars, 'Jagger' and '2174' of hexaploid wheat (2n = 6 * =42; AABBDD), were used to map genes associated with resistance to Hessian fly. Two QTLs were identified. The first one was a major QTL on chromosome 1A (QHf.osu-1A), which explained 70% of the total phenotypic variation. The resistant allele at this locus in cultivar 2174 could be orthologous to one or more of the previously mapped resistance genes (H9, H10, H11, H16, and H17) in tetraploid wheat. The second QTL was a minor QTL on chromosome 2A (QHf.osu-2A), which accounted for 18% of the total phenotypic variation. The resistant allele at this locus in 2174 is collinear to an Yr17-containing-fragment translocated from chromosome 2N of Triticum ventricosum (2n = 4 * =28; DDNN) in Jagger. Genetic mapping results showed that two OPR genes, TaOPR1-A and TaOPR2-A, were tightly associated with QHf.osu-1A and QHf.osu-2A, respectively. Another OPR gene and three LOX genes were mapped but not associated with Hessian fly resistance in the segregating population. CONCLUSIONS: This study has located two major QTLs/genes in bread wheat that can be directly used in wheat breeding programs and has also provided insights for the genetic association and disassociation of Hessian fly resistance with OPR and LOX genes in wheat. PMID- 23724910 TI - A palladium-catalyzed carbo-oxygenation: the bielschowskysin case. AB - An asymmetric synthesis of an advanced tetracyclic intermediate toward the synthesis of bielschowskysin (1) is described. A biomimetic [2 + 2] photocyclization was used to establish the cyclobutane core of bielschowskysin. Macrocyclization under Heck conditions led to an unprecedented carbo-oxygenation of a 1,1-disubstituted double bond. PMID- 23724911 TI - Chronic exposure by ingestion of environmentally relevant doses of (226)Ra leads to transient growth perturbations in fathead minnow (Pimephales promelas, Rafinesque, 1820). AB - PURPOSE: To assess the impact of environmentally relevant levels of ingested (226)Ra on a common freshwater fish species. METHODS: Fathead minnow (Pimephales promelas, Rafinesque) were obtained at the first feeding stage and established on a commercial fish food diet containing (226)Ra in the activity range 10 mBq/g( 1), -10,000 mBq/g(-1). They remained on this diet for 24 months and were sampled invasively at 1,6,18 and 24 months to assess growth, biochemical indices and accumulated dose and non-invasively also at 12 and 15 months to assess growth. RESULTS: Fish fed 10 and 100 mBq/g(-1) diet showed a small transitory deregulation of growth at 6 and 12 months. Fish fed higher activities showed less significant or insignificant effects. There was a trend at 18 months which was stronger at 24 months for the population distribution to change in all of the (226)Ra fed groups so that smaller fish were smaller and bigger fish were bigger than the controls. There were also significant differences in the ratios of protein:DNA at 24 months which were seen as a trend but were not significant at earlier time points. CONCLUSIONS: Fish fed a radium diet for 2 years show a small and transitory growth dysregulation at 6 and 12 months. The effects predominate at the lower activities suggesting hormetic or homeostatic adjustments. There was no effect on growth of exposure to the high activities (226)Ra. This suggests that radium does not have a serious impact on the ecology of the system and the level of radium that would be transferred to humans is very low. The results may be important in the assessment of long-term environmental impacts of (226)Ra exposure. PMID- 23724912 TI - Case of neuro-Behcet's disease successfully maintained a remission using infliximab for 2 years. AB - Behcet's disease is a systemic inflammatory disorder with chronic remissions and relapses. Involvement of the central nervous system, called neuro-Behcet's disease (NBD), is a serious complication. Although corticosteroids and immunosuppressive agents are used, there is no definite standard of treatment with long term-effects for NBD. Here, we report a female case with NBD successfully treated by infliximab and corticosteroids for 2 years. Our report suggests treatment with infliximab may be effective for long-term remission of NBD. PMID- 23724913 TI - Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. AB - BACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.). PMID- 23724915 TI - Cu2+ in layered compounds: origin of the compressed geometry in the model system K2ZnF4:Cu2+. AB - Many relevant properties (including superconductivity and colossal magnetoresistance) of layered materials containing Cu(2+), Ag(2+), or Mn(3+) ions are commonly related to the Jahn-Teller instability. Along this line, the properties of the CuF6(4-) complex in the K2ZnF4 layered perovskite have recently been analyzed using a parametrized Jahn-Teller model with an imposed strain [Reinen, D. Inorg. Chem.2012, 51, 4458]. Here, we present results of ab initio periodic supercell and cluster calculations on K2ZnF4:Cu(2+), showing unequivocally that the actual origin of the unusual compressed geometry of the CuF6(4-) complex along the crystal c axis in that tetragonal lattice is due to the presence of an electric field due to the crystal surrounding the impurity. Our calculations closely reproduce the experimental optical spectrum. The calculated values of the equilibrium equatorial and axial Cu(2+)-F(-) distances are, respectively, R(ax) = 193 pm and R(eq) = 204 pm, and so the calculated distortion R(ax) - R(eq) = 11 pm is three times smaller than the estimated through the parametrized Jahn-Teller model. As a salient feature, we find that if the CuF6(4-) complex would assume a perfect octahedral geometry (R(ax) = R(eq) = 203 pm) the antibonding a(1g)*(~3z(2) - r(2)) orbital is placed above b(1g)*(~x(2) - y(2)) with a transition energy E((2)A(1g) -> (2)B(1g)) = 0.34 eV. This surprising fact stresses that about half the experimental value E((2)A(1g) > (2)B(1g)) = 0.70 eV is not due to the small shortening of the axial Cu(2+)-F(-) distance, but it comes from the electric field, E(R)(r), created by the rest of the lattice ions on the CuF6(4-) complex. This internal field, displaying tetragonal symmetry, is thus responsible for the compressed geometry in K2ZnF4:Cu(2+) and the lack of symmetry breaking behind the ligand relaxation. Moreover, we show that the electronic energy gain in this process comes from bonding orbitals and not from antibonding ones. The present results underline the key role played by ab initio calculations for unveiling all the complexity behind the properties of the model system K2ZnF4:Cu(2+), opening at the same time a window for improving our knowledge on d(9), d(7), or d(4) ions in other layered compounds. PMID- 23724914 TI - Acquired resistance to crizotinib from a mutation in CD74-ROS1. AB - Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), has also recently shown efficacy in the treatment of lung cancers with ROS1 translocations. Resistance to crizotinib developed in a patient with metastatic lung adenocarcinoma harboring a CD74-ROS1 rearrangement who had initially shown a dramatic response to treatment. We performed a biopsy of a resistant tumor and identified an acquired mutation leading to a glycine-to-arginine substitution at codon 2032 in the ROS1 kinase domain. Although this mutation does not lie at the gatekeeper residue, it confers resistance to ROS1 kinase inhibition through steric interference with drug binding. The same resistance mutation was observed at all the metastatic sites that were examined at autopsy, suggesting that this mutation was an early event in the clonal evolution of resistance. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.). PMID- 23724916 TI - A novel morphological response of maize (Zea mays) adult roots to heterogeneous nitrate supply revealed by a split-root experiment. AB - Approximately 35-55% of total nitrogen (N) in maize plants is taken up by the root at the reproductive stage. Little is known about how the root of an adult plant responds to heterogeneous nutrient supply. In this study, root morphological and physiological adaptations to nitrate-rich and nitrate-poor patches and corresponding gene expression of ZmNrt2.1 and ZmNrt2.2 of maize seedlings and adult plants were characterized. Local high nitrate (LoHN) supply increased both lateral root length (LRL) and density of the treated nodal roots of adult maize plants, but only increased LRL of the treated primary roots of seedlings. LoHN also increased plant total N acquisition but not N influx rate of the treated roots, when expressed as per unit of root length. Furthermore, LoHN markedly increased specific root length (m g(-1)) of the treated roots but significantly inhibited the growth of the lateral roots outside of the nitrate rich patches, suggesting a systemic carbon saving strategy within a whole root system. Surprisingly, local low nitrate (LoLN) supply stimulated nodal root growth of adult plants although LoLN inhibited growth of primary roots of seedlings. LoLN inhibited the N influx rate of the treated roots and did not change plant total N content. The gene expression of ZmNrt2.1 and ZmNrt2.2 of the treated roots of seedlings and adult plants was inhibited by LoHN but enhanced by LoLN. In conclusion, maize adult roots responded to nitrate-rich and nitrate-poor patches by adaptive morphological alterations and displayed carbon saving strategies in response to heterogeneous nitrate supply. PMID- 23724918 TI - Posterior reversible encephalopathy syndrome in a survivor of valproate-induced acute liver failure: a case report. AB - INTRODUCTION: Posterior reversible encephalopathy syndrome is an extremely rare radiological diagnosis that has not been reported previously in association with acute liver failure. CASE PRESENTATION: A 6-year-old Sri Lankan girl developed acute liver failure with severe hepatic encephalopathy due to sodium valproate. She was successfully treated medically with N-acetylcysteine and L-carnitine. During recovery she again developed features of encephalopathy and had repeated convulsions associated with moderate hypertension. The diagnosis of posterior reversible encephalopathy syndrome was made on clinical and radiological grounds and she showed a gradual improvement with control of blood pressure. CONCLUSIONS: This report adds to the evidence behind treatment of valproate-induced acute liver failure with N-acetylcysteine and L-carnitine and illustrates a rare but interesting association between acute liver failure and posterior reversible encephalopathy syndrome. PMID- 23724919 TI - HLA-A, -B and -DRB1 polymorphism in Koreans defined by sequence-based typing of 4128 cord blood units. AB - Human leucocyte antigen (HLA) alleles and haplotypes differ significantly among different ethnic groups, and high-resolution typing methods allow for the detection of a wider spectrum of HLA variations. In this study, HLA-A, -B and DRB1 genotypes were analysed in 4128 cord blood units obtained from Korean women using the sequence-based typing method. A total of 44 HLA-A, 67 HLA-B and 48 HLA DRB1 most probable alleles were identified. Of these, high-frequency alleles found at a frequency of >=5% were 6 HLA-A (A*02:01, A*02:06, A*11:01, A*24:02, A*31:01, A*33:03), 5 HLA-B (B*15:01, B*44:03, B*51:01, B*54:01, B*58:01) and 7 HLA-DRB1 (DRB1*01:01, DRB1*04:05, DRB1*07:01, DRB1*08:03, DRB1*09:01, DRB1*13:02, DRB1*15:01) alleles. At each locus, A*02, B*15 and DRB1*04 generic groups were most diverse at allelic level, consisting of 8, 11 and 10 different alleles, respectively. Two- and three-locus haplotypes estimated by the maximum likelihood method revealed 73 A-B, 74 B-DRB1 and 42 A-B-DRB1 haplotypes with frequencies of >=0.3%. A total of 193 A-B-DRB1 haplotypes found at a frequency of >=0.1% were presented, and the six most common haplotypes were A*33:03-B*44:03-DRB1*13:02 (4.6%), A*33:03-B*58:01-DRB1*13:02 (3.0%), A*24:02-B*07:02-DRB1*01:01 (2.7%), A*33:03-B*44:03-DRB1*07:01 (2.5%), A*30:01-B*13:02-DRB1*07:01 (2.2%) and A*24:02 B*52:01-DRB1*15:02 (2.1%). Compared with previous smaller scale studies, this study further delineated the allelic and haplotypic diversity in Koreans including low-frequency alleles and haplotypes. Information obtained in this study will be useful for the search for unrelated bone marrow donors and for anthropologic and disease association studies. PMID- 23724917 TI - Venous hemodynamics in neurological disorders: an analytical review with hydrodynamic analysis. AB - Venous abnormalities contribute to the pathophysiology of several neurological conditions. This paper reviews the literature regarding venous abnormalities in multiple sclerosis (MS), leukoaraiosis, and normal-pressure hydrocephalus (NPH). The review is supplemented with hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.CCSVI-like venous anomalies seem unlikely to account for reduced CBF in patients with MS, thus other mechanisms must be at work, which increase the hydraulic resistance of the cerebral vascular bed in MS. Similarly, hydrodynamic changes appear to be responsible for reduced CBF in leukoaraiosis. The hydrodynamic properties of the periventricular veins make these vessels particularly vulnerable to ischemia and plaque formation.Venous hypertension in the dural sinuses can alter intracranial compliance. Consequently, venous hypertension may change the CSF dynamics, affecting the intracranial windkessel mechanism. MS and NPH appear to share some similar characteristics, with both conditions exhibiting increased CSF pulsatility in the aqueduct of Sylvius.CCSVI appears to be a real phenomenon associated with MS, which causes venous hypertension in the dural sinuses. However, the role of CCSVI in the pathophysiology of MS remains unclear. PMID- 23724920 TI - Eating habits of a population undergoing a rapid dietary transition: portion sizes of traditional and non-traditional foods and beverages consumed by Inuit adults in Nunavut, Canada. AB - BACKGROUND: To determine the portion sizes of traditional and non-traditional foods being consumed by Inuit adults in three remote communities in Nunavut, Canada. METHODS: A cross-sectional study was carried out between June and October, 2008. Trained field workers collected dietary data using a culturally appropriate, validated quantitative food frequency questionnaire (QFFQ) developed specifically for the study population. RESULTS: Caribou, muktuk (whale blubber and skin) and Arctic char (salmon family), were the most commonly consumed traditional foods; mean portion sizes for traditional foods ranged from 10 g for fermented seal fat to 424 g for fried caribou. Fried bannock and white bread were consumed by >85% of participants; mean portion sizes for these foods were 189 g and 70 g, respectively. Sugar-sweetened beverages and energy-dense, nutrient-poor foods were also widely consumed. Mean portion sizes for regular pop and sweetened juices with added sugar were 663 g and 572 g, respectively. Mean portion sizes for potato chips, pilot biscuits, cakes, chocolate and cookies were 59 g, 59 g, 106 g, 59 g, and 46 g, respectively. CONCLUSIONS: The present study provides further evidence of the nutrition transition that is occurring among Inuit in the Canadian Arctic. It also highlights a number of foods and beverages that could be targeted in future nutritional intervention programs aimed at obesity and diet related chronic disease prevention in these and other Inuit communities. PMID- 23724922 TI - Hamartomatous polyposis syndromes. AB - Hamartomas are tumour-like malformations, consisting of disorganized normal tissues, typical of the site of tumour manifestation. Familial manifestation of hamartomatous polyps can be noted in juvenile polyposis syndrome (JPS), Peutz Jeghers' syndrome (PJS), hereditary mixed polyposis syndrome (HMPS) and PTEN hamartoma tumour syndrome (PHTS). All the aforementioned syndromes are inherited in an autosomal dominant manner and form a rather heterogenous group both in respect to the number and localization of polyps and the risk of cancer development in the alimentary tract and other organs. Individual syndromes of hamartomatous polyposis frequently manifest similar symptoms, particularly during the early stage of the diseases when in several cases their clinical pictures do not allow for differential diagnosis. The correct diagnosis of the disease using molecular methods allows treatment to be implemented earlier and therefore more effectively since it is followed by a strict monitoring of organs that manifest a predisposition for neoplastic transformation. PMID- 23724923 TI - JPEG vs. JPEG2000: benchmarking with dermatological images. AB - BACKGROUND: Despite the importance of images in the discipline and the diffusion of digital imaging devices, the issue of image compression in dermatology was discussed only in few studies, which yielded results often not comparable, and left some unanswered questions. OBJECTIVE: To evaluate and compare the performance of the JPEG and JPEG2000 algorithms for compression of dermatological images. METHODS: Nineteen macroscopic and fifteen videomicroscopic images of skin lesions were compressed with JPEG and JPEG2000 at 18 different compression rates, from 90% to 99.5%. Compressed images were shown, next to uncompressed versions, to three dermatologists with different experience, who judged quality and suitability for educational/scientific and diagnostic purposes. Moreover, alterations and quality were evaluated by calculation of mean 'distance' of pixel colors between compressed and original images and by peak signal-to-noise ratio, respectively. RESULTS: JPEG2000 was qualitatively better than JPEG at all compression rates, particularly highest ones, as shown by dermatologists' ratings and objective parameters. Agreement between raters was high, but with some differences in specific cases, showing that different professional experience can influence judgement on images. CONCLUSION: In consideration of its high qualitative performance and wide diffusion, JPEG2000 represents an optimal solution for the compression of digital dermatological images. PMID- 23724924 TI - Thermochemistry of paddle wheel MOFs: Cu-HKUST-1 and Zn-HKUST-1. AB - Metal-organic framework (MOF) porosity relies upon robust metal-organic bonds to retain structural rigidity upon solvent removal. Both the as-synthesized and activated Cu and Zn polymorphs of HKUST-1 were studied by room temperature acid solution calorimetry. Their enthalpies of formation from dense assemblages (metal oxide (ZnO or CuO), trimesic acid (TMA), and N,N-dimethylformamide (DMF)) were calculated from the calorimetric data. The enthalpy of formation (DeltaHf) of the as-synthesized Cu-HKUST-H2O ([Cu3TMA2.3H2O].5DMF) is -52.70 +/- 0.34 kJ per mole of Cu. The DeltaHf for Zn-HKUST-DMF ([Zn3TMA2.3DMF].2DMF) is -54.22 +/- 0.57 kJ per mole of Zn. The desolvated Cu-HKUST-dg [Cu3TMA2] has a DeltaHf of 16.66 +/- 0.51 kJ/mol per mole Cu. The DeltaHf for Zn-HKUST-amorph [Zn3TMA2.2DMF] is -3.57 +/- 0.21 kJ per mole of Zn. Solvent stabilizes the Cu-HKUST-H2O by -69.4 kJ per mole of Cu and Zn-HKUST-DMF by at least -50.7 kJ per mole of Zn. Such strong chemisorption of solvent is similar in magnitude to the strongly exothermic binding at low coverage for chemisorbed H2O on transition metal oxide nanoparticle surfaces. The strongly exothermic solvent-framework interaction suggests that solvent can play a critical role in obtaining a specific secondary building unit (SBU) topology. PMID- 23724926 TI - Weighted least-squares method for right-censored data in accelerated failure time model. AB - The classical accelerated failure time (AFT) model has been extensively investigated due to its direct interpretation of the covariate effects on the mean survival time in survival analysis. However, this classical AFT model and its associated methodologies are built on the fundamental assumption of data homoscedasticity. Consequently, when the homoscedasticity assumption is violated as often seen in the real applications, the estimators lose efficiency and the associated inference is not reliable. Furthermore, none of the existing methods can estimate the intercept consistently. To overcome these drawbacks, we propose a semiparametric approach in this article for both homoscedastic and heteroscedastic data. This approach utilizes a weighted least-squares equation with synthetic observations weighted by square root of their variances where the variances are estimated via the local polynomial regression. We establish the limiting distributions of the resulting coefficient estimators and prove that both slope parameters and the intercept can be consistently estimated. We evaluate the finite sample performance of the proposed approach through simulation studies and demonstrate its superiority through real example on its efficiency and reliability over the existing methods when the data is heteroscedastic. PMID- 23724925 TI - Disease control priorities for neglected tropical diseases: lessons from priority ranking based on the quality of evidence, cost effectiveness, severity of disease, catastrophic health expenditures, and loss of productivity. AB - BACKGROUND: In the context of limited health care budgets in countries where Neglected Tropical Diseases (NTDs) are endemic, scaling up disease control interventions entails the setting of priorities. However, solutions based solely on cost-effectiveness analyses may lead to biased and insufficiently justified priorities. OBJECTIVES: The objectives of this paper are to 1) demonstrate how a range of equity concerns can be used to identify feasible priority setting criteria, 2) show how these criteria can be fed into a multi-criteria decision making matrix, and 3) discuss the conditions under which this decision-making procedure should be carried out in a real-world decision-making context. METHODS: This paper draws on elements from theories of decision analysis and ethical theories of fair resource allocation. We explore six typical NTD interventions by employing a modified multi-criteria decision analysis model with predefined criteria, drawn from a priority setting guide under development by the WHO. To identify relevant evidence for the six chosen interventions, we searched the PubMed and Cochrane databases. DISCUSSION: Our in vitro multi-criteria decision analysis suggested that case management for visceral leishmaniasis should be given a higher priority than mass campaigns to prevent soil-transmitted helminthic infections. This seems to contradict current health care priorities and recommendations in the literature. We also consider procedural conditions that should be met in a contextualised decision-making process and we stress the limitations of this study exercise. CONCLUSION: By exploring how several criteria relevant to the multi-facetted characteristics of NTDs can be taken into account simultaneously, we are able to suggest how improved priority settings among NTDs can be realised. PMID- 23724927 TI - Evaluation of therapeutics in three-dimensional cell culture systems by MALDI imaging mass spectrometry. AB - Drug penetration into solid tumors is critical for the effectiveness of clinical chemotherapy. Failing to consider the efficiency of drug penetration can lead to fatal recurrence in many cancers. Three-dimensional (3D) cell cultures have served as an important model system and have contributed to valuable assays in drug discovery studies. However, limited methodologies result in incomplete evaluation of the distribution of many anticancer drugs. As a proof-of-concept study, we have applied matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) in HCT 116 colon carcinoma multicellular spheroids to assess the distribution of the anticancer drug, irinotecan. The time dependent penetration of irinotecan was visualized and the localization of three metabolites as well as the parent drug in treated spheroids was mapped. To validate the identities of the metabolites, we analyzed extracts from drug treated spheroids using nanoflow liquid chromatography-tandem mass spectrometry (nLC-MS/MS). Ten metabolites were identified with nLC-MS/MS, including those detected by MALDI IMS. This novel approach allows the measurement of drug penetration and distribution in 3D culture mimics and provides a more cost and time-effective approach for the testing of new pharmaceuticals compared to animal models. PMID- 23724928 TI - p.E66Q mutation in the GLA gene is associated with a high risk of cerebral small vessel occlusion in elderly Japanese males. AB - BACKGROUND AND PURPOSE: GLA is the causative gene of Fabry disease, an X-linked lysosomal storage disorder resulting from alpha-galactosidase A (alpha-GAL) deficiency. Stroke is an important manifestation of Fabry disease, and recent epidemiological studies have indicated that up to 4.9% of young male cryptogenic stroke patients have GLA mutations. To determine the importance of GLA mutations in the general stroke population, the frequency of GLA mutations in Japanese male ischaemic stroke (IS) patients with various risk factors and ages was measured. METHODS: A total of 475 male IS patients (mean age 69.7 +/- 12.5 years), were enrolled in this study. A blood sample was obtained to produce blood spots for measurement of alpha-GAL activity. Blood samples with decreased enzymatic activity were reassayed and the entire GLA gene was analyzed by direct DNA sequencing if alpha-Gal A activity was consistently low. RESULTS: alpha-Gal A activity was decreased in 10 men, five of whom (1.1%) had the GLA gene mutation, p.E66Q. All IS patients with p.E66Q mutation had substantial residual alpha-Gal A activity, in contrast to patients with classic-type Fabry disease. Clinically, all patients with p.E66Q mutation were > 50 years old and had multiple small vessel occlusions (lacunar infarctions). Statistical analysis using Fisher's exact test showed the allele frequency of GLA p.E66Q in patients with small vessel occlusion to be significantly higher than that in the general Japanese population [odds ratio (OR) = 3.34, P = 0.025). CONCLUSIONS: GLA p.E66Q mutation is a genetic risk factor for cerebral small-vessel occlusion in elderly Japanese males. PMID- 23724929 TI - Quantitative relationship between rate constants and molecular structure descriptors for the gas phase hydrogen abstraction reactions. AB - The abstraction of hydrogen by general radicals has a wide role in environmental and also in technological processes because it results in reactive free radicals that play a vital role in atmospheric chemistry and also in biochemical processes. In addition to experimental studies, the theoretical modelling of this elementary reaction has been important for understanding and predicting respective rate constants. In this paper, molecular descriptors in the context of a QSAR approach are used to codify the relationship between molecular structure and rate constants. Unique experimental data is collected from the literature for the reaction R(i)* + R(j)H -> R(i)H + R(j)*, where R(i)* = H* and R(j)* are diverse radicals. The four-parameter QSAR model (n = 34, r(2) = 0.81, r(2)(CV) = 0.74, r(2)(scr) = 0.12, s(2) = 0.19) is presented for the bimolecular rate constants, accompanied with model diagnostics and analysis of descriptors in the model. PMID- 23724931 TI - Transannular reductive rearrangement of alpha-amino ketones: construction of aza tricyclic frameworks of several alkaloids. AB - Transannular reductive rearrangement of bridged cyclic alpha-amino ketones led to the aza-tricyclic frameworks azepinoindole, hydrolulolidine, and hydrojulolidine of the typical alkaloids of Stemona, Aspidosperma, and Lycopodium, respectively. This facile approach demonstrates the potential applicability of the Clemmensen Clemo-Prelog-Leonard reductive rearrangement of tricyclic alpha-amino ketones for the aza-heterocycle synthesis. PMID- 23724930 TI - Fatigue behavior of the resinous cement to zirconia bond. AB - PURPOSE: Resinous cements are widely used for luting zirconia restorations. Adhesive failures have occurred at the cement/zirconia interface, rather than at the cement/dentin interface, suggesting that the cement/zirconia bond may lack durability; however, few comprehensive, comparative evaluations of fatigue effects have been reported. The rate of fatigue-induced loss of bond strength may be a more important predictor of long-term success than a single snapshot of bond strength after an arbitrary number of thermocycles. Previous studies have failed to identify trends by investigating bond strengths at several different numbers of cycles. This may result in invalid conclusions about which cements have superior bond strengths. The purpose of this study was to investigate the effects of artificial aging by thermocycling and resinous cement type on bond strengths to zirconia. MATERIALS AND METHODS: The effect of the number of thermocycles (0, 1, 10, 100, 1000, and 10,000) on the bond strengths of five resinous cements, two of which were used with and without a primer, and an oxygen-inhibiting gel, was studied. Specimens were randomly assigned to thermocycle number/cement-type test groups. Because zirconia has a very low thermal diffusivity, exceptionally long thermocycle dwell times were used. Cylinders of zirconia were bonded end-to-end. One end of each bonded specimen was insulated, specimens were thermocycled and tested in shear, and bond strengths were calculated and analyzed. RESULTS: Two way ANOVA revealed that the effects of cement type, the number of thermocycles, and their interaction all significantly affected bond strength (p < 0.0001). By 10,000 cycles, most cements had lost at least half of their initial bond strengths, and two cements effectively recorded zero bond strengths. Failure modes were cement specific, but adhesive modes predominated. Fatigue resistance of two cements was greatly improved by use of a primer and an oxygen-inhibiting gel, as recommended by their respective manufacturers. CONCLUSIONS: Both the type of resin cement and the number of thermocycles influenced bond strength. Fatigue through thermocycling affected different cement types in different ways. Some materials displayed more rapid loss of bond strength than others. Cements differed in their failure modes. PMID- 23724932 TI - Challenges to the involvement of people living with HIV in community-based HIV/AIDS organizations in Ontario, Canada. AB - The Greater Involvement of People Living with HIV/AIDS Principle (GIPA) has been a core commitment for many people involved in the community-based HIV/AIDS movement. GIPA refers to the inclusion of people living with HIV/AIDS in service delivery and decision-making processes that affect their lives. Despite its central importance to the movement, it has received little attention in the academic literature. Drawing on focus group discussions among staff members and volunteers of AIDS service organizations, activists, and community members, we explore challenges to the implementation of the GIPA principle in community-based HIV/AIDS organizations in Ontario, Canada. Our findings reveal ways in which implementing GIPA has become more complicated over recent years. Challenges relating to health, stigma and disclosure, evolving HIV/AIDS organizations, and GIPA-related tensions are identified. This paper considers our findings in light of previous research, and suggests some implications for practice. PMID- 23724934 TI - Chemical cystitis due to crystal violet dye: a case report. AB - INTRODUCTION: Crystal violet was commonly used for the treatment of oral and vaginal candidiasis or for sterilization during operations up to the 1960s. Because crystal violet is potentially toxic to mucosal membranes, it has been replaced with other disinfectants, and crystal violet is rarely used. We report a case of chemical cystitis due to intravesical instillation of crystal violet dye. CASE PRESENTATION: Crystal violet dye was instilled into the bladder of a 47-year old Japanese woman to confirm the presence of a vesicovaginal fistula. Our patient developed symptoms of gross hematuria, frequent urination and lower abdominal pain. Computed tomography showed thickening of her whole bladder wall with spotted high-density lesions. Cystoscopy demonstrated desquamated epithelial cells and a hemorrhagic bladder wall. We treated our patient conservatively with nonsteroidal anti-inflammatory drugs and glucocorticoids. During follow-up, magnetic resonance images showed that the detrusor muscle of her bladder was normal. Our patient's symptoms gradually improved and she completely recovered within six months. CONCLUSION: Considering the severe side effect of crystal violet, it would be better not to use this dye to examine conditions such as a vesicovaginal fistula. Magnetic resonance imaging may help to evaluate the level of damage in the bladder wall of patients with chemical cystitis. PMID- 23724933 TI - A new genomic tool, ultra-frequently cleaving TaqII/sinefungin endonuclease with a combined 2.9-bp recognition site, applied to the construction of horse DNA libraries. AB - BACKGROUND: Genomics and metagenomics are currently leading research areas, with DNA sequences accumulating at an exponential rate. Although enormous advances in DNA sequencing technologies are taking place, progress is frequently limited by factors such as genomic contig assembly and generation of representative libraries. A number of DNA fragmentation methods, such as hydrodynamic sharing, sonication or DNase I fragmentation, have various drawbacks, including DNA damage, poor fragmentation control, irreproducibility and non-overlapping DNA segment representation. Improvements in these limited DNA scission methods are consequently needed. An alternative method for obtaining higher quality DNA fragments involves partial digestion with restriction endonucleases (REases). RESULTS: We constructed a horse genomic library and a deletion derivative library of the butyrylcholinesterase cDNA coding region using a novel method, based on TaqII, Thermus sp. family bifunctional enzyme exhibiting cofactor analogue specificity relaxation. We used sinefungin (SIN) - an S-adenosylmethionine (SAM) analogue with reversed charge pattern, and dimethylsulfoxide (DMSO), to convert the 6-bp recognition site TaqII (5'-GACCGA-3' [11/9]) into a theoretical 2.9-bp REase, with 70 shortened variants of the canonical recognition sequence detected. Because partial DNA cleavage is an inherent feature of the Thermus sp. enzyme family, this modified TaqII is uniquely suited to quasi-random library generation. CONCLUSIONS: In the presence of SIN/DMSO, TaqII REase is transformed from cleaving every 4096 bp on average to cleaving every 58 bp. TaqII SIN/DMSO thus extends the palette of available REase prototype specificities. This phenomenon, employed under partial digestion conditions, was applied to quasi random DNA fragmentation. Further applications include high sensitivity probe generation and metagenomic DNA amplification. PMID- 23724935 TI - Metastatic basosquamous carcinoma detected by sentinel lymph node biopsy. AB - We describe a rare case of basosquamous carcinoma (BSC) in a 69-year-old man. He had noticed a pigmented nodule on his left thigh. Dermoscopic examination showed ulceration at the center and non-typical leaf-like areas at the periphery. Linear irregular vessels were also seen. He underwent tumor excision in addition to sentinel lymph node biopsy (SLNB). Histopathological examination revealed both features of basal cell carcinoma (BCC) and squamous cell carcinoma. The sentinel lymph node was positive for tumor cells. Immunostaining for Ber-EP4 was focally positive for invasive tumor cells. Although complete inguinal lymphadenectomy had been performed, multiple in-transit metastases around the primary lesion and left iliac lymph node metastasis developed after the operation. It is considered that BSC has a worse prognosis than BCC with a potential for metastasis. Based on the findings of previously reported cases and our case, SLNB may be applied for certain high-risk cases including BSC larger than 3 cm in size and careful follow up is recommended for patients with BSC. PMID- 23724936 TI - Response of the airways and autonomic nervous system to acid perfusion of the esophagus in patients with asthma: a laboratory study. AB - BACKGROUND: Gastro-esophageal reflux disease (GERD) predisposes to airway disease through a vagally-mediated esophago-bronchial reflex. This study investigates this vagal response to esophageal acid perfusion. METHODS: 40 asthmatics with mild stable asthma participated. Each subject underwent spirometry and autonomic function testing (valsalva maneuver, heart rate response to deep breathing and to standing from supine position) four times: a) before intubation, b) after intubation, and then immediately after perfusion with, in random order, c) concentrated lime juice solution (pH 2-3) and d) 0.9% saline. Subjects were blinded to the solution perfused. RESULTS: Asthmatics were of mean (SD) age 34.3 years (1.3), and 67.5% of them were females. pH monitoring demonstrated that 20 subjects had abnormal reflux and 20 did not. In each group 10 subjects had a positive GERD symptom score. Following perfusion with acid compared to saline, all subjects showed significant decreases in FEV1 and PEFR and significant increases in the mean valsalva ratio and heart rate difference on deep breathing from baseline values, but no changes in FVC or heart rate ratio on standing. There were no significant differences in any of the parameters between subjects with and without reflux. CONCLUSIONS: Acid stimulation of the distal esophagus results in increased parasympathetic activity and concomitant broncho constriction in asthmatics irrespective of their reflux state. This strengthens the hypothesis that GER triggers asthma-like symptoms through a vagally mediated esophago-bronchial reflex and encourages a possible role for anti-cholinergic drugs in the treatment of reflux-associated asthma. PMID- 23724938 TI - Substituent effects on "hyperconjugative" aromaticity and antiaromaticity in planar cyclopolyenes. AB - Computed aromatic stabilization energies (ASEs) and dissected nucleus independent chemical shifts (NICSpizz) quantify the effect of hyperconjugation on the (anti)aromaticities of the planar conformations of three, five, seven, and nine membered (CnHn)CR2 (R = H, SiH3, F) rings. CH2 and especially C(SiH3)2 groups supply two "pseudo" pi electrons hyperconjugatively along with the olefinic pi electrons in the ring, whereas a CF2 group acts like a partially vacant p orbital. Following the Huckel rule, compounds with 4n+2 (or 4n) pseudo pi electrons are "hyperconjugatively" aromatic (or antiaromatic). PMID- 23724937 TI - Tumor necrosis factor receptor superfamily 10B (TNFRSF10B): an insight from structure modeling to virtual screening for designing drug against head and neck cancer. AB - BACKGROUND: Head and neck cancer (HNC) belongs to a group of heterogeneous disease with distinct patterns of behavior and presentation. TNFRSF10B, a tumor suppressor gene mapped on chromosome 8. Mutation in candidate gene is responsible for the loss of chromosome p arm which is frequently observed in head and neck tumors. TNFRSF10B inhibits tumor formation through apoptosis but deregulation encourages metastasis, migration and invasion of tumor cell tissues. RESULTS: Structural modeling was performed by employing MODELLER (9v10). A suitable template [2ZB9] was retrieved from protein databank with query coverage and sequence identity of 84% and 30% respectively. Predicted Model evaluation form Rampage revealed 93.2% residues in favoured region, 5.7% in allowed region while only 1 residue is in outlier region. ERRAT and ProSA demonstrated 51.85% overall quality with a -1.08 Z-score of predicted model. Molecular Evolutionary Genetics Analysis (MEGA 5) tool was executed to infer an evolutionary history of TNFRSF10B candidate gene. Orthologs and paralogs [TNFRSF10A & TNFRSF10D] protein sequences of TNFRSF10B gene were retrieved for developed ancestral relationship. Topology of tree presenting TNFRSF10A gene considered as outgroup. Human and gorilla shared more than 90% similarities with conserved amino acid sequence. Virtual screening approach was appliedfor identification of novel inhibitors. Library (Mcule) was screened for novel inhibitors and utilized the scrutinized lead compounds for protein ligand docking. Screened lead compounds were further investigated for molecular docking studies. STRING server was employed to explore protein-protein interactions of TNFRSF10B target protein. TNFSF10 protein showed highest 0.999 confidence score and selected protein-protein docking by utilizing GRAMM-X server. In-silico docking results revealed I-58, S-90 and A-62 as most active interacting residues of TNFRSF10B receptor protein with R-130, S-156 and R 130 of TNFSF10B ligand protein. CONCLUSION: Current research may provide a backbone for understanding structural and functional insights of TNFRSF10B protein. The designed novel inhibitors and predicted interactions might serve to inhibit the disease. Effective in-vitro potent ligands are required which will be helpful in future to design a drug to against Head and neck cancer disease. There is an urgent need for affective drug designing of head and neck cancer and computational tools for examining candidate genes more efficiently and accurately are required. PMID- 23724939 TI - Crowded bis-(M-salphen) [M = Pt(II), Zn(II)] coordination architectures: luminescent properties and ion-selective responses. AB - For binuclear luminescent host systems, cooperativity between metal-organic moieties becomes feasible with regards to photophysical properties and sensing behavior. A new class of conformationally rigid binuclear platinum(II) and zinc(II) complexes bearing tetradentate aromatic Schiff base (salphen) ligands with limited rotational freedom has been prepared and characterized, and the molecular structure of a (Pt-salphen)2 derivative has been determined by X-ray crystallography. Their UV-vis absorption and emission properties have been investigated and are tentatively ascribed to different excited states depending on the metal and the extent of intramolecular pi-stacking interactions. Colorimetric and phosphorescent responses by the bis-Pt(II) complexes in the presence of selected metal ions have been observed. The nature of the host-guest interactions has been examined by quantitative binding studies, mass spectrometry and DFT calculations, and through comparisons with control complexes. PMID- 23724940 TI - The effects of leg crossing and applied tension on blood donor return. AB - BACKGROUND AND OBJECTIVES: Repeated isometric muscle tension (applied tension) during blood donation reduces vasovagal symptoms in many donors. Experiencing vasovagal symptoms has been found to reduce blood donor return. However, does practicing applied tension improve blood donor return? Follow-up results from a randomized controlled trial are presented. METHODS: Data were collected in mobile clinics held in several colleges and universities. During the baseline donation, participants either (1) practiced 'standard' applied tension consisting of repeated 5 s cycles of whole-body isometric muscle tension in the donation chair (N = 133), (2) practiced tension with legs crossed (N = 131), or (3) gave blood as usual (N = 140). Subsequent blood donations in the following 2 years were determined. RESULTS: Applied tension had no effect on immediate (at the end of the baseline blood donation) rating of intention to give blood or the dichotomous measure of whether or not the participant gave blood again in the following 2 years. However, men asked to practice applied tension with legs crossed gave approximately one unit more during the follow-up period compared with men in the control group (F1,106 = 5.32, P = 0.023). This was associated significantly with adherence - men assigned to the applied tension with legs crossed condition who did not practice as instructed were no more likely to return than controls. CONCLUSION: The results provide modest support for the idea that applied tension may increase subsequent blood donation though the results were limited to men who practiced the technique as instructed. PMID- 23724941 TI - Oriented film growth of Ba(1-x)Sr(x)TiO3 dielectrics on glass substrates using 2D nanosheet seed layer. AB - An approach to fabricate Ba0.5Sr0.5TiO3 (BST) films with a preferred orientation on a glass substrate by pulsed laser deposition was developed. To ensure a preferred crystallographic orientation, we utilized a molecularly thin Ca2Nb3O10 perovskite nanosheet as a seed layer and successfully fabricated BST films with a nearly perfect (100)-axis orientation. The 100 nm films after annealing at 450 degrees C in air showed a good dielectric performance (epsilon(r) > 400), which was comparable to the epsilon(r) value of epitaxially grown films with the same thickness. These results indicate that the nanosheet seed layer plays a crucial role in controlled film growth, realizing a nearly intrinsic performance of BST. PMID- 23724942 TI - A novel scheme to design the filter for CT reconstruction using FBP algorithm. AB - BACKGROUND: The Filtered Back-Projection (FBP) algorithm is the most important technique for computerized tomographic (CT) imaging, in which the ramp filter plays a key role. FBP algorithm had been derived using the continuous system model. However, it has to be discretized in practical applications, which necessarily produces distortion in the reconstructed images. METHODS: A novel scheme is proposed to design the filters to substitute the standard ramp filter to improve the reconstruction performance for parallel beam tomography. The design scheme is presented under the discrete image model and discrete projection environment. The designs are achieved by constrained optimization procedures. The designed filter can be regarded as the optimal filter for the corresponding parameters in some ways. RESULTS: Some filters under given parameters (such as image size and scanning angles) have been designed. The performance evaluation of CT reconstruction shows that the designed filters are better than the ramp filter in term of some general criteria. CONCLUSIONS: The 2-D or 3-D FBP algorithms for fan beam tomography used in most CT systems, are obtained by modifying the FBP algorithm for parallel beam tomography. Therefore, the designed filters can be used for fan beam tomography and have potential applications in practical CT systems. PMID- 23724943 TI - Advancing sex and gender competency in medicine: sex & gender women's health collaborative. AB - Research conducted to date has deepened our understanding of sex and gender differences in the etiology, diagnosis, treatment, and outcomes for many conditions that affect both women and men. The Sex and Gender Women's Health Collaborative (SGWHC) is supported by the coordinated efforts of our founding partners: the American Medical Women's Association, the American College of Women's Health Physicians and Society for Women's Health Research to address the gaps in medical education with regard to sex and gender competency in the care of women. The SGWHC initiated and continues to build a novel digital resource library of sex and gender specific materials to be adopted and adapted into medical education and clinical practice, residing @ http://www.sgwhc.org. This article presents a case for the inclusion of sex and gender focused content into medical curricula and describes a means for students, faculty, and practitioners to access a centralized, interactive repository for these resources. PMID- 23724944 TI - Colorimetric response of dithizone product and hexadecyl trimethyl ammonium bromide modified gold nanoparticle dispersion to 10 types of heavy metal ions: understanding the involved molecules from experiment to simulation. AB - A new kind of analytical reagent, hexadecyl trimethyl ammonium bromide (CTAB), and dithizone product-modified gold nanoparticle dispersion, is developed for colorimetric response to 10 types of heavy metal ions (M(n+)), including Cr(VI), Cr(3+), Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+), and Pb(2+). The color change of the modified gold nanoparticle dispersion is instantaneous and distinct for Mn(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+), and Pb(2+). The color change results from the multiple reasons, such as electronic transitions, cation-pi interactions, formation of coordination bonds, and M(n+) induced aggregation of gold nanoparticles (AuNPs). The different combining capacity of heavy metal ions to modifiers results in the different broadening and red-shifting of the plasmon peak of modified AuNPs. In addition, Cr(VI), Cu(2+), Co(2+), Ni(2+), and Mn(2+) cause the new UV-vis absorption peaks in the region of 360-460 nm. The interactions between the modifiers and AuNPs, and between the modifiers and M(n+), are investigated by using Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The results confirm that AuNPs are modified by CTAB and dithizone products through electrostatic interactions and Au-S bonds, respectively, and the M(n+)-N bonds form between M(n+) and dithizone products. Furthermore, the experimental and density functional theory calculated IR spectra prove that dithizone reacts with NaOH to produce C6H5O(-) and [SCH2N4](2-). The validation of this method is carried out by analysis of heavy metal ions in tap water. PMID- 23724945 TI - Collaborative international research: ethical and regulatory issues pertaining to human biological materials at a South African institutional research ethics committee. AB - Human Biological Materials (HBMs) are an invaluable resource in biomedical research. OBJECTIVE: To determine if researchers and a Research Ethics Committee (REC) at a South African institution addressed ethical issues pertaining to HBMs in collaborative research with developed countries. STUDY DESIGN: Ethically approved retrospective cross-sectional descriptive audit. RESULTS: Of the 1305 protocols audited, 151 (11.57%) fulfilled the study's inclusion criteria. Compared to other developed countries, a majority of sponsors (90) were from the USA (p = 0.0001). The principle investigators (PIs) in all 151 protocols informed the REC of their intent to store HBMs. Only 132 protocols informed research participants (P < 0.0001). In 148 protocols informed consent (IC) was obtained from research participants, 116 protocols (76.8%) solicited broad consent compared to specific consent (32; 21.2%) [p < 0.0001]. In 105 cases a code was used to maintain confidentiality. HBMs were anonymised in 14 protocols [p < 0.0001]. More protocols informed the REC (90) than the research participants (67) that HBMs would be exported (p = 0.011). Export permits (EPs) and Material Transfer Agreements (MTAs) were not available in 109 and 143 protocols, respectively. CONCLUSIONS: Researchers and the REC did not adequately address the inter-related ethical and regulatory issues pertaining to HBMs. There was a lack of congruence between the ethical guidelines of developed countries and their actions which are central to the access to HBMs in collaborative research. HBMs may be leaving South Africa without EPs and MTAs during the process of international collaborative research. PMID- 23724946 TI - A group-specific sequencing approach to investigate the presence of atypical human leucocyte antigen alleles. AB - Accurate human leucocyte antigen (HLA) typing results are essential in determining the degree of compatibility between donor and recipient in both solid organ (SO) and hematopoietic stem cell (HSC) transplantation. Current HLA typing methodologies can generate ambiguous results which may need resolving. This group specific sequencing approach allowed investigation into the presence of the low expressor HLA-A*24:02:01:02L allele and the rare HLA-A*02:64 allele in a SO transplant recipient and a HSC transplant recipient, respectively. Locus-specific amplification of HLA-A was performed. Exons 2 and 3 were sequenced in both directions followed by group-specific sequencing to resolve ambiguities. Hemizygous sequence data of intron 2 generated from the HLA-A*24 allele indicated the presence of the HLA-A*24:02:01:01 allele. HLA-A*02:64 was identified by sequencing the allele in isolation over exons 2 and 3 and allowed confirmation of this allele sequence with the IMGT/HLA database (Accession number AY297166). This approach is cost efficient and can be modified to sequence alleles at other HLA loci. It has also been adapted to characterize the novel HLA-DQB1*06:48 allele (Accession number HE647646) as well as the non-HLA gene, UGT2B17, making it a useful tool to augment existing typing methodologies. PMID- 23724947 TI - Pharmacologic agents for type 2 diabetes therapy and regulation of adipogenesis. AB - The close link between type 2 diabetes and excess body weight highlights the need to consider the effects on weight of different treatments used for correction of hyperglycaemia. Indeed, specific currently available diabetes therapies can cause weight gain, including insulin and its analogues, sulphonylureas, and thiazolidinediones, while others, such as metformin and the GLP-1 receptor agonists, can promote weight loss. Excess body weight in patients with diabetes is largely due to expansion of adipose tissue, and these drugs could interfere with the mechanisms underlying the expansion and differentiation of adipocyte precursors. Almost all anti-diabetes drugs could also potentially affect adipocyte metabolism directly, by modulating lipogenesis, lipolysis, and fat oxidation. This review will examine the available evidence for specific effects of various anti-diabetes drugs on adipose tissue development and function with the ultimate goal of increasing our understanding of how pharmacological agents can modulate energy balance and body fat. PMID- 23724948 TI - GEE for multinomial responses using a local odds ratios parameterization. AB - In this article, we propose a generalized estimating equations (GEE) approach for correlated ordinal or nominal multinomial responses using a local odds ratios parameterization. Our motivation lies upon observing that: (i) modeling the dependence between correlated multinomial responses via the local odds ratios is meaningful both for ordinal and nominal response scales and (ii) ordinary GEE methods might not ensure the joint existence of the estimates of the marginal regression parameters and of the dependence structure. To avoid (ii), we treat the so-called "working" association vector alpha as a "nuisance" parameter vector that defines the local odds ratios structure at the marginalized contingency tables after tabulating the responses without a covariate adjustment at each time pair. To estimate alpha and simultaneously approximate adequately possible underlying dependence structures, we employ the family of association models proposed by Goodman. In simulations, the parameter estimators with the proposed GEE method for a marginal cumulative probit model appear to be less biased and more efficient than those with the independence "working" model, especially for studies having time-varying covariates and strong correlation. PMID- 23724951 TI - Sexual behaviour among HIV-infected new mothers in South Africa 3-12 months after delivery. AB - The aim of this study was to assess sexual activity, condom use and disclosure of HIV infection status among HIV-infected women 3-12 months after delivery and to identify factors associated with unsafe sex. A cross-sectional study was carried out on 480 HIV-positive sexually active new mothers in 48 primary health care clinics in Nkangala District. Post-natal women were recruited by systematic sampling (every consecutive patient over a period of 2 months) and responded to a questionnaire. Overall, 31.9% reported unsafe sex with an HIV-uninfected of unknown-status partner. In multivariate regression analysis, not having disclosed their HIV status, having experienced physical partner violence, lack of male involvement and not having attended a support group were associated with unsafe sex. Several risk factors for unsafe sex post-natally have been identified and can be utilised in post-partum sexual health education programmes. PMID- 23724952 TI - On the use of electronic descriptors for QSAR modelling of PCDDs, PCDFs and dioxin-like PCBs. AB - The electronic properties of 29 polychlorinated dibenzo-p-dioxins and dibenzofurans and dioxin-like polychlorinated biphenyls that have been included in the toxic equivalency factor system have been investigated and used to derive quantum mechanical (QM) chemical descriptors for QSAR modelling. Their utility in this context was investigated alongside descriptors based on ultraviolet absorption data and traditional 2D descriptors including log K(ow), polarizability, molecular surface properties, van der Waals volume and selected connectivity indices. The QM descriptors were calculated using the semi-empirical AM1 method and the density functional theory method B3-LYP/6-31G**. Atom-specific and molecular quantum chemical descriptors were calculated to compare the electronic properties of dioxin-like compounds regardless of their chemical class, with particular emphasis on the lateral positions. Multivariate analysis revealed differences between the chemical classes in terms of their electronic properties and also highlighted differences between congeners. The results obtained demonstrated the importance of considering molecular orbital energies, but also indicated that the ratios of the coefficients of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) at the lateral carbons were important. In addition, the digitalized UV spectra contained chemical information that provided crucial insights into dioxin-like activity. PMID- 23724953 TI - Label-free cancer cell separation from human whole blood using inertial microfluidics at low shear stress. AB - We report a contraction-expansion array (CEA) microchannel device that performs label-free high-throughput separation of cancer cells from whole blood at low Reynolds number (Re). The CEA microfluidic device utilizes hydrodynamic field effect for cancer cell separation, two kinds of inertial effects: (1) inertial lift force and (2) Dean flow, which results in label-free size-based separation with high throughput. To avoid cell damages potentially caused by high shear stress in conventional inertial separation techniques, the CEA microfluidic device isolates the cells with low operational Re, maintaining high-throughput separation, using nondiluted whole blood samples (hematocrit ~45%). We characterized inertial particle migration and investigated the migration of blood cells and various cancer cells (MCF-7, SK-BR-3, and HCC70) in the CEA microchannel. The separation of cancer cells from whole blood was demonstrated with a cancer cell recovery rate of 99.1%, a blood cell rejection ratio of 88.9%, and a throughput of 1.1 * 10(8) cells/min. In addition, the blood cell rejection ratio was further improved to 97.3% by a two-step filtration process with two devices connected in series. PMID- 23724954 TI - Ipsilateral distal femoral and proximal tibial epiphyseal growth plate injury: a case report. AB - INTRODUCTION: Both the isolated distal femoral epiphysiolysis and the isolated proximal tibial epiphysiolysis are the least common epiphyseal injuries. Even though they are uncommon, they have a high incidence rate of complications. CASE PRESENTATION: We present a case with Gustilo-Anderson grade 3b open and Salter Harris type 1 epiphysiolysis of the distal femur and proximal tibia caused by a farm machinery accident. The patient was a 10-year-old boy, treated by open reduction and internal fixation. CONCLUSION: Although distal femoral and proximal tibial growth plate injuries are rarely seen benign fractures, their management requires meticulous care. Anatomic reduction is important, especially to minimize the risk of growth arrest and the development of degenerative arthritis. However, there is a high incidence of growth arrest and neurovascular injury with these type of fractures. PMID- 23724955 TI - Adult attachment interviews of women from low-risk, poverty, and maltreatment risk samples: comparisons between the hostile/helpless and traditional AAI coding systems. AB - The main aim of this study was to investigate the correlates of a Hostile Helpless (HH) state of mind among 67 women belonging to a community sample and two different at-risk samples matched on socio-economic indicators, including 20 women from low-SES population (poverty sample) and 15 women at risk for maltreatment being monitored by the social services for the protection of juveniles (maltreatment risk sample). The Adult Attachment Interview (AAI) protocols were reliably coded blind to the samples' group status. The rates of HH classification increased in relation to the risk status of the three samples, ranging from 9% for the low-risk sample to 60% for the maltreatment risk sample to 75% for mothers in the maltreatment risk sample who actually maltreated their infants. In terms of the traditional AAI classification system, 88% of the interviews from the maltreating mothers were classified Unresolved/Cannot Classify (38%) or Preoccupied (50%). Partial overlapping between the 2 AAI coding systems was found, and discussion concerns the relevant contributions of each AAI coding system to understanding of the intergenerational transmission of maltreatment. PMID- 23724956 TI - Useful theories should apply to individuals. PMID- 23724957 TI - Thermal stability and molecular microstructure of heat-induced cereal grains, revealed with Raman molecular microspectroscopy and differential scanning calorimetry. AB - The objectives of the present study were to use Raman molecular microspectroscopy and differential scanning calorimetry (DSC) to reveal molecular thermal stability and thermal degradation behavior of heat-induced cereal grains and reveal the molecular chemistry of the protein structures of cereal grain tissues affected by heat processing and to quantify the protein secondary structures using multicomponent peak modeling Gaussian and Lorentzian methods. Hierarchical cluster analysis (CLA) and principal components analysis (PCA) were also conducted to identify molecular differences in the Raman spectra. Three cereal grain seeds, wheat, triticale, and corn, were used as the model for feed protein in the experiment. The specimens were autoclaved (moist heating) and dry-heated (roasted) at 121 degrees C for 80 min, respectively. Raman spectroscopy results revealed that there are marked differences in the secondary structures of the proteins subjected to various heating treatments of different cereals. The sensitivity of cereals to moist heating was much higher than the sensitivity to dry heating. The multivariate analyses (CLA and PCA) showed that heat treatment was significantly isolated between the different Raman raw spectra. The DSC study revealed that the thermal degradation behavior of cereals was significantly changed after moist- and dry-heat treatments. The position of the major endothermic peak of dry-heated cereals shifted toward a higher temperature, from 131.7 to 134.0 degrees C, suggesting the high thermal stability of dry-heated cereals. In contrast, the endothermic peak position was slightly decreased to 132.1 degrees C in the case of moist autoclaved heating. The digestive behavior and nutritive value of rumen-undegradable protein in animals may be related to the changes of the protein secondary molecular structure and thermal stability of the cereal grain materials, which is attributed by Raman microspectroscopy and DSC endotherm profiles. PMID- 23724958 TI - Efficacy of spray administration of formalin-killed Streptococcus agalactiae in hybrid Red Tilapia. AB - An initial evaluation of spray vaccination was carried out with 60 hybrid Red Tilapia Oreochromis spp., divided into three groups that consisted of 10 fish per group with duplicates. The formalin-killed cells (FKCs) of Streptococcus agalactiae were administered once to group 1 by spray and once daily for five consecutive days to group 2. Group 3 remained as the untreated control group and was sprayed with normal saline. A booster was given twice to all the groups, once at the second week and again at the fourth week after the first vaccination. After this initial evaluation, a challenge study was conducted with 40 tilapia divided into two groups that consisted of 10 fish per group with duplicates. Group 1 was vaccinated with FKCs of S. agalactiae by a single spray administration while group 2 remained as the untreated control group. A booster was given twice using the same protocol as in the initial evaluation. After 6 weeks, fish from one of the duplicate tanks from each of groups 1 and 2 were challenged with pathogenic S. agalactiae by intraperitoneal (IP) injection, while fish in another tank were challenged through immersion. Based on the observations, serum immunoglobulin M (IgM) levels were significantly higher (P < 0.05) in the challenged fish than in the either the preexposed fish or the control group 1 week after the initial exposure. However, no significant differences (P > 0.05) were noted between challenged groups 1 and 2. In addition, no significant differences (P > 0.05) were observed between the frequencies of exposure. The mucus IgM level, however, remained high after each booster until the end of the 8-week study period. Meanwhile, serum IgM levels decreased after the challenge. A higher percentage of survival was noted for fish challenged through immersion (80%) compared with IP injection (70%). These results suggested that single spray exposure was able to induce IgM, which gave moderate to high protection during the challenge study. PMID- 23724960 TI - Highly stereocontrolled total synthesis of beta-D-mannosyl phosphomycoketide: a natural product from Mycobacterium tuberculosis. AB - beta-D-mannosyl phosphomycoketide (C32-MPM), a naturally occurring glycolipid found in the cell walls of Mycobacterium tuberculosis, acts as a potent antigen to activate T-cells upon presentation by CD1c protein. The lipid portion of C32 MPM contains a C32-mycoketide, consisting of a saturated oligoisoprenoid chain with five chiral methyl branches. Here we develop several stereocontrolled approaches to assemble the oligoisoprenoid chain with high stereopurity (>96%) using Julia-Kocienski olefinations followed by diimide reduction. By careful choice of olefination sites, we could derive all chirality from a single commercial compound, methyl (2S)-3-hydroxy-2-methylpropionate (>99% ee). Our approach is the first highly stereocontrolled method to prepare C32-MPM molecule with >96% stereopurity from a single >99% ee starting material. We anticipate that our methods will facilitate the highly stereocontrolled synthesis of a variety of other natural products containing chiral oligoisoprenoid-like chains, including vitamins, phytol, insect pheromones, and archaeal lipids. PMID- 23724959 TI - Microarray and deep sequencing cross-platform analysis of the mirRNome and isomiR variation in response to epidermal growth factor. AB - BACKGROUND: Epidermal Growth Factor (EGF) plays an important function in the regulation of cell growth, proliferation, and differentiation by binding to its receptor (EGFR) and providing cancer cells with increased survival responsiveness. Signal transduction carried out by EGF has been extensively studied at both transcriptional and post-transcriptional levels. Little is known about the involvement of microRNAs (miRNAs) in the EGF signaling pathway. miRNAs have emerged as major players in the complex networks of gene regulation, and cancer miRNA expression studies have evidenced a direct involvement of miRNAs in cancer progression. RESULTS: In this study, we have used an integrative high content analysis approach to identify the specific miRNAs implicated in EGF signaling in HeLa cells as potential mediators of cancer mediated functions. We have used microarray and deep-sequencing technologies in order to obtain a global view of the EGF miRNA transcriptome with a robust experimental cross-validation. By applying a procedure based on Rankprod tests, we have delimited a solid set of EGF-regulated miRNAs. After validating regulated miRNAs by reverse transcription quantitative PCR, we have derived protein networks and biological functions from the predicted targets of the regulated miRNAs to gain insight into the potential role of miRNAs in EGF-treated cells. In addition, we have analyzed sequence heterogeneity due to editing relative to the reference sequence (isomiRs) among regulated miRNAs. CONCLUSIONS: We propose that the use of global genomic miRNA cross-validation derived from high throughput technologies can be used to generate more reliable datasets inferring more robust networks of co-regulated predicted miRNA target genes. PMID- 23724962 TI - Microleakage of teeth restored with different adhesive dowel systems: an in vitro study. AB - PURPOSE: Commercial fiber-reinforced dowel systems are marketed as having better adhesion and sealing ability than conventional metallic dowel systems. The aim of this in vitro study was to evaluate the microleakage of teeth restored with nine dowel systems. MATERIALS AND METHODS: Ninety mandibular second premolar teeth were decoronated, and nine homogenous groups were composed of ten teeth each. Root canal and dowel space preparations were made, and eight fiber-reinforced composite dowel systems and one stainless steel dowel system were used to fabricate dowel restorations. Microleakage measurements of the restored teeth were made with a modified fluid filtration method, and data were collected. One sample Kolmogorov-Smirnov, one-way ANOVA, and Tukey-HSD tests were performed on the relative microleakage data of the groups. RESULTS: Microleakage values were reported relative to those for teeth with unfilled canals. The highest and lowest relative microleakage values were recorded for the metallic Parapost (7.06 * 10( 4) %) and fiber-reinforced Everstick (3.55 * 10(-4) %) groups, respectively. Significant differences in relative microleakage between the fiber-reinforced dowels and stainless steel dowels were observed. Significant differences among the fiber-reinforced dowel groups were observed as well. CONCLUSIONS: The sealing ability of all fiber-reinforced composite dowels is not better than that of stainless steel dowels, and there are significant differences among different fiber-reinforced dowel systems as well. Differences among commercial dowel systems must be taken into consideration when making a selection. PMID- 23724963 TI - Bilateral apical vertebral derotation technique by vertebral column manipulation compared with vertebral coplanar alignment technique in the correction of Lenke type 1 idiopathic scoliosis. AB - BACKGROUND: Widely used rod rotation and translation techniques for idiopathic scoliosis (IS) are effective in correcting spinal coronal deformity. Bilateral apical vertebral derotation technique by vertebral column manipulation (VCM) and vertebral coplanar alignment (VCA) technique are two strategies for three dimensional (3D) correction for IS. The purpose of this study is to compare the post-surgical results and technical features of the bilateral apical vertebral derotation technique by VCM against the VCA technique in patients with Lenke type 1 IS. METHODS: Forty-eight patients with Lenke type 1 IS were enrolled in the present prospective clinical assay. They were divided into groups A (bilateral apical vertebral derotation technique by VCM, n=24) and B (VCA technique, n=24). Radiographic parameters measured before and after surgery included the Cobb angle, thoracic kyphosis, and apical vertebral rotation. Scoliosis Research Society (SRS)-22 scores were evaluated during the final follow-up. The differences in the demographics, surgical details, and radiographic measurements between the two groups were determined using a T test. The Mann-Whitney U test was used to evaluate the differences in the SRS-22 scores. A value of P<0.05 was considered statistically significant. RESULTS: In the coronal plane, a significant difference was found in the correction rate of the major curve (group A: 84.8%, group B: 78.4%; P=0.045) and in the Cincinnati Correction Index between two groups (group A: 2.21, group B: 1.98; P=0.047). In the sagittal plane, no difference was found in the postoperative thoracic kyphosis between the two groups (P=0.328). In the transverse plane, no difference was found between the two groups in the correction rates of the rotation angle sagittal (P=0.298), rib hump (P=0.934), apical vertebral body-to-rib ratio (P=0.988), or apical rib spread difference (P=0.184). Patients underwent follow up for an average of 21.9 and 22.2 months in groups A and B, respectively. Results obtained at the final follow-up indicated no significant loss of correction. No differences were found in the SRS-22 scores between the two groups. No aortic or neurological complications were observed. CONCLUSIONS: The 3D deformity of the spine was effectively corrected using the bilateral apical vertebral derotation technique by VCM and the VCA technique, and encouraging post-surgical results were obtained for patients with Lenke type 1 IS. The two techniques were effective in allowing 3D correctional force that was applied in different ways. PMID- 23724964 TI - Rh[III]-catalyzed C-H amidation using aroyloxycarbamates to give N-Boc protected arylamines. AB - The Rh(III)-catalyzed amidation of C(sp(2))-H bonds by the use of electron deficient aroyloxycarbamates as efficient electrophilic amidation partners is reported. The reaction proceeded under mild conditions with broad functional group tolerance, and pyridine and O-methyl hydroxamic acids serve as efficient directing groups, giving access to valuable N-Boc protected arylamines (also Fmoc and Cbz). Preliminary mechanistic experiments are discussed. PMID- 23724961 TI - Viruses and neurodegeneration. AB - Neurodegenerative diseases (NDs) are chronic degenerative diseases of the central nervous system (CNS), which affect 37 million people worldwide. As the lifespan increases, the NDs are the fourth leading cause of death in the developed countries and becoming increasingly prevalent in developing countries. Despite considerable research, the underlying mechanisms remain poorly understood. Although the large majority of studies do not show support for the involvement of pathogenic aetiology in classical NDs, a number of emerging studies show support for possible association of viruses with classical neurodegenerative diseases in humans. Space does not permit for extensive details to be discussed here on non viral-induced neurodegenerative diseases in humans, as they are well described in literature.Viruses induce alterations and degenerations of neurons both directly and indirectly. Their ability to attack the host immune system, regions of nervous tissue implies that they can interfere with the same pathways involved in classical NDs in humans. Supporting this, many similarities between classical NDs and virus-mediated neurodegeneration (non-classical) have been shown at the anatomic, sub-cellular, genomic and proteomic levels suggesting that viruses can explain neurodegenerative disorders mechanistically. The main objective of this review is to provide readers a detailed snapshot of similarities viral and non viral neurodegenerative diseases share, so that mechanistic pathways of neurodegeneration in human NDs can be clearly understood. Viruses can guide us to unveil these pathways in human NDs. This will further stimulate the birth of new concepts in the biological research, which is needed for gaining deeper insights into the treatment of human NDs and delineate mechanisms underlying neurodegeneration. PMID- 23724966 TI - A synthetic route to a molecular galloxane dihydroxide and its group 4 heterobimetallic compounds. AB - Controlled hydrolysis of (Me)LGaCl2 ((Me)L = HC[(CMe)N(2,4,6-Me3C6H2)]2(-)) (1) in the presence of a N-heterocyclic carbene, as a HCl acceptor, led to the unprecedented molecular galloxane dihydroxide [{(Me)LGa(OH)}2(MU-O)] (2) in high yield. Compound 2 was used in the assembly of the heterobimetallic galloxanes with group 4 metals [{((Me)LGa)2(MU-O)}(MU-O)2{M(NR2)2}] (M = Ti, R = Me (6); M = Zr (7), Hf (8), R = Et). PMID- 23724965 TI - Prenatal exposure to polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) may influence birth weight among infants in a Swedish cohort with background exposure: a cross-sectional study. AB - BACKGROUND: Prenatal exposure to persistent organic pollutants, e.g. polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) has been suggested to negatively affect birth weight although epidemiological evidence is still inconclusive. We investigated if prenatal exposure to PCBs and PBDEs is related to birth weight in a Swedish population with background exposure. METHODS: Breast milk was sampled during the third week after delivery from first-time mothers in Uppsala county, Sweden 1996-2010 (POPUP cohort) (N = 413). Samples were analysed for di-ortho PCBs (CB-138, 153, 180) and tetra- to hexa- brominated PBDEs (BDE-47, 99, 100, 153). Simple and multiple linear regression models were used to investigate associations between lipid-adjusted, ln-transformed PCB and PBDE concentrations, and birth weight. Covariates included in the multivariate regression model were PCB and PBDE exposure, maternal age, pre-pregnancy BMI, weight gain during pregnancy, education, smoking, gender of the infant and gestational length. The effect of including fish consumption was also investigated. RESULTS: In the multivariate model, prenatal exposure to di ortho PCBs was significantly associated with increased birth weight (beta = 137; p = 0.02). The result did not change when gestational length was added to the model. An inverse association between PBDE(4) (sum of BDE-47, -99, -100 and -153) and birth weight was observed in the multivariate model including gestational length (beta = -106; p = 0.04). Maternal pre-pregnancy BMI and weight gain during pregnancy were important confounders of the association between di-ortho PCBs and birth weight. The associations were not alleviated after adjustment for fish consumption, a major source of PCB and PBDE exposure. The observed associations were stronger for boys than for girls. CONCLUSIONS: Our results indicate that prenatal exposure to di-ortho PCBs and PBDE(4) may influence birth weight in different directions, i.e. PCB exposure was associated with higher birth weight and PBDE exposure with lower birth weight. Maternal pre-pregnancy BMI and weight gain during pregnancy were important confounders that may hide positive association between di-ortho PCB exposure and birth weight if they are not included in the statistical model. We speculate that even small PCB- and PBDE induced shifts in the distribution of birth weight may influence future public health in populations with background exposure. PMID- 23724967 TI - Protein co-expression network analysis (ProCoNA). AB - BACKGROUND: Biological networks are important for elucidating disease etiology due to their ability to model complex high dimensional data and biological systems. Proteomics provides a critical data source for such models, but currently lacks robust de novo methods for network construction, which could bring important insights in systems biology. RESULTS: We have evaluated the construction of network models using methods derived from weighted gene co expression network analysis (WGCNA). We show that approximately scale-free peptide networks, composed of statistically significant modules, are feasible and biologically meaningful using two mouse lung experiments and one human plasma experiment. Within each network, peptides derived from the same protein are shown to have a statistically higher topological overlap and concordance in abundance, which is potentially important for inferring protein abundance. The module representatives, called eigenpeptides, correlate significantly with biological phenotypes. Furthermore, within modules, we find significant enrichment for biological function and known interactions (gene ontology and protein-protein interactions). CONCLUSIONS: Biological networks are important tools in the analysis of complex systems. In this paper we evaluate the application of weighted co-expression network analysis to quantitative proteomics data. Protein co-expression networks allow novel approaches for biological interpretation, quality control, inference of protein abundance, a framework for potentially resolving degenerate peptide-protein mappings, and a biomarker signature discovery. PMID- 23724968 TI - Pearls are self-organized natural ratchets. AB - Pearls, the most flawless and highly prized of them, are perhaps the most perfectly spherical macroscopic bodies in the biological world. How are they so round? Why are other pearls solids of revolution (off-round, drop, ringed pearl), and yet others have no symmetry (baroque pearls)? We observe that with a spherical pearl the growth fronts of nacre are spirals and target patterns distributed across its surface, and that this is true for a baroque pearl, too, but that in pearls with rotational symmetry spirals and target patterns are found only in the vicinity of the poles; elsewhere the growth fronts are arrayed in ratchet fashion around the equator. We argue that pearl rotation is a self organized phenomenon caused and sustained by physical forces from the growth fronts, and that rotating pearls are an example--perhaps unique--of a natural ratchet. PMID- 23724969 TI - A distinctive colour associated with high iodine content in malignant pleural effusion from metastatic papillary thyroid cancer: a case report. AB - INTRODUCTION: Pleural effusions are a common clinical problem and affect about one million people in the United States and United Kingdom each year. Over 60 causes of pleural effusion have been identified; establishing the definitive aetiology can be difficult, and often requires invasive procedures. Guidelines state that macroscopic examination of the fluid should be the first step in determining the aetiology of a pleural effusion. Papillary thyroid carcinoma is an uncommon cause of malignant pleural effusion, with only 10 cases reported in the literature, their physical characteristics and composition having been rarely described. We describe for the first time a distinctive brown colour of the malignant effusion (despite centrifugation) from a rare case of metastatic papillary thyroid cancer to the pleura, associated with a high pleural fluid iodine content. Such a characteristic may be useful in expediting diagnosis of a malignant pleural effusion in the appropriate clinical context. CASE PRESENTATION: We present the case of a 71-year-old Caucasian man with metastatic papillary thyroid cancer; a large, long-standing, right-sided pleural effusion and a 83-fold higher pleural thyroglobulin level compared to corresponding serum, supporting this malignancy as the cause of the patient's effusion. The pleural fluid had a distinctive pigmentation similar to iodine-containing antiseptic preparations. Biopsy during medical thoracoscopy confirmed metastatic papillary thyroid carcinoma. Analysis of pleural fluid showed a pleural thyroglobulin level over 80 times that of serum levels (29,000MUg/L versus 350ug/L). Pleural fluid iodine content was 23,000ug/L and may account for the fluid's distinctive pigment, as iodine is an essential component in thyroglobulin and thyroid hormone synthesis. CONCLUSIONS: Pleural fluid pigmentation may aid diagnosis in the appropriate clinical setting. A distinctive iodine-like brown colour of pleural fluid may represent elevated iodine content and should raise consideration of metastatic thyroid cancer as a cause for a pleural effusion. PMID- 23724970 TI - Treatment of scabies with oral ivermectin in 15 infants: a retrospective study on tolerance and efficacy. AB - BACKGROUND: The incidence of scabies is increasing in Europe, and it often affects children and infants. Although numerous topical treatments have been approved for treatment of scabies in adults, they are often poorly tolerated in infants. One treatment, ivermectin, remains off label for infants weighing < 15 kg. OBJECTIVES: To report our experience on the safety and efficacy of oral ivermectin in refractory scabies in infants. METHODS: A retrospective study was performed in the dermatology and paediatrics departments of Rouen University Hospital between January 2009 and October 2012. Infants diagnosed with scabies were identified, and the data for those fulfilling the inclusion criteria were analysed. RESULTS: Of 219 infants identified, 15 had received oral ivermectin and had been followed up for at least 3 months. All 15 patients were given two doses of ivermectin, 200 MUg kg(-1), at baseline and 14 days later. Of 14 patients contacted 1 month after treatment, 12 had achieved healing. The other two were treated with ivermectin or benzyl benzoate; both healed. Overall, 3 months after the first ivermectin treatment, 13/14 patients had healed and only one had active disease. CONCLUSIONS: Ivermectin is generally well tolerated in infants. The 80% rate of healing observed in infants who had failed to respond to at least two other topical treatments suggests that ivermectin could be considered for treatment of infants with recalcitrant or relapsing scabies. PMID- 23724971 TI - Vaccination against seasonal influenza is effective in Japanese patients with rheumatoid arthritis enrolled in a large observational cohort. AB - OBJECTIVE: To investigate the effectiveness of influenza vaccination in patients with rheumatoid arthritis (RA) from a large practice-based cohort. METHOD: Patients with RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort completed self-administered questionnaires as part of the April IORRA surveys of 2001, 2002, 2003, and 2007, which included their influenza vaccination status and occurrence of an actual influenza attack. Vaccine coverage rate and attack rates were calculated in each season. Relative risks (RRs) of vaccination for an actual influenza attack were evaluated and risk factors for influenza infection were determined by multiple logistic regression analysis. RESULTS: Data from 3529, 4518, 4816, and 4872 patients in the 2000/01, 2001/02, 2002/03, and 2006/07 seasons, respectively, were analysed. Coverage rates were increased from 12.2% in the 2000/01 season to 38.7% in the 2006/07 season. For each season, the attack rates in vaccinated patients trended lower than the rates in unvaccinated patients but the differences were not significant; however, by combining these four seasonal results, the attack rate was significantly lower for vaccinated patients [RR 0.83, 95% confidence interval (CI) 0.71-0.95, p < 0.01]. Male gender [odds ratio (OR) 1.48, 95% CI 1.25-1.76, p < 0.001] was associated with increased risk whereas vaccination was associated with reduced risk for influenza attack (OR 0.76, 95% CI 0.63-0.91, p < 0.01). There were no associations between influenza attacks and RA disease activity, treatment with methotrexate (MTX) or corticosteroids. CONCLUSION: Influenza vaccination was effective in patients with RA regardless of disease activity or treatment. PMID- 23724972 TI - Coexistence of left ventricular noncompaction and aortic interruption. PMID- 23724973 TI - Diagnostic advantage of S1 foramen-evoked H-reflex for S1 radiculopathy in patients with diabetes mellitus. AB - Hoffmann reflex to tibial nerve stimulation at the popliteal fossa (tibial H reflex) is routinely used to evaluate S1 radiculopathy. However, it lacks sensitivity because other lesions along this reflex circuit affect the H-reflex bilaterally. This study was undertaken to determine whether the H-reflex evoked by stimulating proximally at the S1 foramen (S1 foramen H-reflex) could improve S1 root lesion evaluation sensitivity in patients with diabetes mellitus. A randomized paired study was designed to evaluate tibial and S1 foramen H reflexes; bilateral H-M interval (HMI) and H-reflex latency were compared in 22 diabetic patients with unilateral S1 radiculopathy. Other electrophysiological evaluations included standard tibial conduction studies, sural conduction studies and needle electromyography (EMG). The S1 foramen H-reflex had a significantly higher sensitivity (91.0%, 20 of 22) in evaluating S1 radiculopathy than the conventional tibial H-reflex (63.6%, 14 of 22, p < 0.05). Bilateral tibial compound muscle action potential amplitudes were reduced in 3 patients, and sural sensory nerve action potential amplitudes decreased in 7 patients. Needle EMG revealed denervation restricted to the paraspinal muscle and myotomes supplied by the S1 nerve root on the ipsilateral side in 18 patients, and multiple lumbosacral nerve roots were involved bilaterally in the other 4 patients. Our results demonstrate that the S1 foramen H-reflex is a more sensitive assessment of S1 compressive radiculopathy in patients with diabetes mellitus. PMID- 23724974 TI - Prediction of immobilised artificial membrane chromatography retention factors using theoretical molecular fragments and structural features. AB - Many in silico alternatives to aquatic toxicity tests rely on hydrophobicity based quantitative structure-activity relationships (QSARs). Hydrophobicity is often estimated as log P, where P is the octanol-water partition coefficient. Immobilised artificial membrane (IAM) high performance liquid chromatography (HPLC) may be a more biologically relevant alternative to log P. The aim of this study was to investigate the applicability of a theoretical structural fragment and feature-based method to predict log k IAM (the logarithm of the retention index determined by IAM-HPLC) values. This will allow the prediction of log k IAM based on chemical structure alone. The use of structural fragment values to predict log P was first proposed in the 1970s. The application of a similar method using fragment values to predict log k IAM is a novel approach. Values of log k IAM were determined for 22 aliphatic and 42 aromatic compounds using an optimised and robust IAM-HPLC assay. The method developed shows good predictive performance using leave-one-out cross validation and application to an external validation set not seen a priori by the training set also generated good predictive values. The ability to predict log k IAM without the need for practical measurement will allow for the increased use of QSARs based on this descriptor. PMID- 23724976 TI - Experimental comparison of pathogenic potential of two sibling species Anisakis simplex s.s. and Anisakis pegreffii in Wistar rat. AB - OBJECTIVES: There are little data available on the pathology caused by the sibling species Anisakis simplex s.s. and Anisakis pegreffii. The differences shown in their ability to penetrate the muscle of fish may also be manifested in humans. The purpose of this study is to confirm possible differences in pathogenicity between A. simplex s.s. and A. pegreffii using an experimental model which simulates infection in humans. METHODS: Female Wistar rats were infected with 190 Anisakis type I L3 larvae from the Iberian coastline. After the animal was sacrificed, these L3 larvae were then recovered and identified via PCR RFLP of the ITS1-5.8S-ITS2. A logistic regression analysis was performed searching for association between experimental pathogenic potential and species. RESULTS: The distribution of A. simplex s.s. and A. pegreffii between Atlantic and Mediterranean waters of the Iberian Peninsula showed statistically significant differences (P < 0.001) which were not observed in the hybrid genotypes (P > 0.3). 21.6% showed pathogenic potential, interpreted as the capacity of the larvae to cause lesions, stick to the gastrointestinal wall or penetrate it. The species variable showed association with the pathogenic role of the larva (P = 0.008). Taking A. simplex s.s. as our reference, the OR for A. pegreffii is 0.351 (P = 0.028). CONCLUSIONS: Despite this difference, A. pegreffii is also capable of causing anisakiasis, being responsible for 14.3% of the penetrations of the gastric mucosa found in rats, which justifies both species being considered aetiologic agents of this parasitic disorder. PMID- 23724977 TI - Does high sensitive CRP improve cardiovascular risk prediction in metabolic syndrome among the aged? AB - OBJECTIVES: To analyze whether an elevated level of high hsCRP has an additive effect on metabolic syndrome (MetS) in predicting future cardiovascular events (CVEs) as well as on all-cause mortality among the aged subjects. DESIGN: A prospective, population-based study with a 9-year follow-up. The study population consisted of persons aged 64 and above in 1998-99 without vascular disease and CRP less than 10 mg/l at baseline (n = 733). Adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs) for CVEs and all-cause mortality predicted by baseline MetS (defined by both International Diabetes Federation (IDF) and World Health Organization (WHO)) and hsCRP-level were estimated. RESULTS: During the 9-year follow-up, a total of 142 CVEs and 206 deaths occurred. After multivariable adjustment, no significant interactions were found between hsCRP and MetS in CVEs (IDF: p = 0.828; WHO: p = 0.572) or in all-cause mortality (IDF: p = 0.113; WHO: p = 0.374). HsCRP was not associated with the occurrence of CVEs (IDF: HR = 1.10, 95% CI = 0.92-1.32, p = 0.281; WHO: HR = 1.10, 95% CI = 0.93 1.32, p = 0.247) or with all-cause mortality (IDF: HR = 1.12, 95% CI = 0.97-1.29, p = 0.134; WHO: HR = 1.11, 95% CI = 0.96-1.28, p = 0.146). CONCLUSIONS: It seems that hsCRP does not give any extra value in evaluation of CVE risk or all-cause mortality of older subjects with MetS. PMID- 23724978 TI - Ethical use of antiretroviral resources for HIV prevention in resource poor settings. AB - The effectiveness of antiretroviral regimes (ARVs) to reduce risk of HIV transmission from mother to child and as post-exposure prophylaxis has been known for almost two decades. Recent research indicates ARVs can also reduce the risk of HIV transmission via sexual intercourse in two other ways. With pre-exposure prophylaxis (PrEP), ARVs are used to reduce risk of HIV acquisition among persons who are HIV negative and significantly exposed to the virus. With treatment as prevention (TasP), ARVs are used to reduce risk of HIV transmission from persons who are already HIV positive. The development of these new prevention strategies raises a rationing problem: given the chronic shortage of ARVs for HIV-infected persons in need of treatment, is it ethically justified to allocate ARVs for PrEP and/or TasP? This article examines the intuitively appealing view that allocation of ARVs for treatment should be the highest priority, the use of ARVs for TasP should be a secondary priority, and that utilizing ARVs for PrEP would be unethical. I will argue that selective, evidence-based allocation of ARVs for prevention in certain cases could be ethically justified even when there is insufficient anti-retroviral access for all those needing it for treatment. PMID- 23724979 TI - Modifying dielectrophoretic response of nonviable yeast cells by ionic surfactant treatment. AB - Nonviable cells are essential biosystems, due to the functionalities they offer and their effects on viable cells. Therefore, the separation and immobilization of nonviable cells separately or in the vicinity of viable cells is of great importance for many fundamentals investigations in cell biology. However, most nonviable cells become less polarizable than the surrounding medium at conductivities above 0.01 S/m. This means that in such a medium, dielectrophoresis, despite its great versatilities for manipulation of cells, cannot be employed for immobilizing nonviable cells. Here, we present a novel approach to change the dielectrophoretic (DEP) response of nonviable yeast cells by treating them with low concentrations of ionic surfactants such as sodium dodecyl sulfate. After this treatment, they exhibit a strong positive DEP response, even at high medium conductivities. The capability of this treatment is demonstrated in two proof-of-concept experiments. First, we show the sorting and immobilization of viable and nonviable yeast cells, along consecutive microelectrode arrays. Second, we demonstrate the immobilization of viable and nonviable cells in the vicinity of each other along the same microelectrode array. The proposed technique allows DEP platforms to be utilized for the immobilization and subsequent postanalysis of both viable and nonviable cells with and without the presence of each other. PMID- 23724980 TI - Intraoperative diagnosis. PMID- 23724981 TI - Attenuation of neurological injury with early baicalein treatment following subarachnoid hemorrhage in rats. AB - OBJECT: Baicalein has been shown to offer neuroprotection in the ischemic brain, but its effect in subarachnoid hemorrhage (SAH) is unknown. The authors used a double-hemorrhage model to study the role of early baicalein treatment in SAH. METHODS: Subarachnoid hemorrhage was induced in male Wistar rats through a repeat injection of autologous blood at a 48-hour interval. Rats subjected or not subjected to SAH received a 30-mg/kg baicalein injection 3 hours after SAH and daily for 6 consecutive days, and results were compared with those obtained in vehicle-treated control rats. Mortality of the rats was recorded. Neurological outcome was assessed daily. Cerebrospinal fluid dialysates were collected and examined for glutamate concentrations. Cerebral vasospasm (CVS), brain water content, neuron variability, expression of glutamate transporter-1 (GLT-1), immunoreactivity of astrocyte, and level of malondialdehyde, activities of superoxide dismutase (SOD), and catalase in brain tissues content were determined on post-SAH Day 7. RESULTS: Mortality rate, neuronal degeneration, brain water content, and CVS were decreased and neurological function improved in the baicalein-treated rats. Baicalein increased astrocyte activity and preserved GLT 1, which attenuated the glutamate surge after SAH. Baicalein also provided antioxidative stress by preserving activities of SOD and catalase and decreased malondialdehydelevel after SAH. The glutamate, body weight, neurological scores, and glial fibrillary acidic protein activity were significantly correlated. The CVS was correlated with neuronal degeneration, and GLT-1 was correlated with oxidative stress. CONCLUSIONS: Early baicalein treatment attenuated CVS and limited neurological injury following SAH. These data may indicate clinical utility for baicalein as an adjunct therapy to reduce brain injury and improve patient outcomes. PMID- 23724982 TI - Subarachnoid hemorrhage and outcome. PMID- 23724983 TI - Time course of recovery following poor-grade SAH: the incidence of delayed improvement and implications for SAH outcome study design. AB - OBJECT: Data regarding the time course of recovery after poor-grade subarachnoid hemorrhage (SAH) is lacking. Most SAH studies assess outcome at a single time point, often as early as 3 or 6 months following SAH. The authors hypothesized that recovery following poor-grade SAH is a dynamic process and that early outcomes may not always approximate long-term outcomes. To test this hypothesis, they analyzed long-term outcome data from a cohort of patients with poor-grade aneurysmal SAH to determine the incidence and predictors of early and delayed neurological improvement. METHODS: The authors reviewed outcome data from 88 poor grade SAH patients enrolled in a prospective SAH treatment trial (the Barrow Ruptured Aneurysm Trial). They assessed modified Rankin Scale (mRS) scores at discharge, 6 months, 12 months, and 36 months after treatment to determine the incidence and predictors of neurological improvement during each interval. RESULTS: The mean aggregate mRS scores at 6 months (3.31 +/- 2.1), 12 months (3.28 +/- 2.2), and 36 months (3.17 +/- 2.3) improved significantly compared with the mean score at hospital discharge (4.33 +/- 1.3, p < 0.001), but they did not differ significantly among themselves. Between discharge and 6 months, 61% of patients improved on the mRS. The incidence of improvement between 6-12 months and 12-36 months was 18% and 19%, respectively. Hunt and Hess Grade IV versus V (OR 6.20, 95% CI 2.11-18.25, p < 0.001) and the absence of large (> 4 cm) (OR 2.76, 95% CI 1.02-7.55, p = 0.05) or eloquent (OR 5.17, 95% CI 1.89-14.10, p < 0.01) stroke were associated with improvement up to 6 months. Age <= 65 years (OR 5.56, 95% CI 1.17-26.42, p = 0.02), Hunt and Hess Grade IV versus V (OR 4.17, 95% CI 1.10-15.85, p = 0.03), and absence of a large (OR 8.97, 95% CI 2.65-30.40, p < 0.001) or eloquent (OR 4.54, 95% CI 1.46-14.08, p = 0.01) stroke were associated with improvement beyond 6 months. Improvement beyond 1 year was most strongly predicted by the absence of a large stroke (OR 7.62, 95% CI 1.55-37.30, p < 0.01). CONCLUSIONS: A substantial minority of poor-grade SAH patients will experience delayed recovery beyond the point at which most studies assess outcome. Younger patients, those presenting in better clinical condition, and those without CT evidence of large or eloquent stroke demonstrated the highest capacity for delayed recovery. PMID- 23724984 TI - Hypoglossal canal dural arteriovenous fistula: incidence and the relationship between symptoms and drainage pattern. AB - OBJECT: The purpose of this study was to evaluate the incidence, radiographic findings, relationship between presenting symptoms for treatment and drainage pattern, and treatment outcomes of hypoglossal canal dural arteriovenous fistula (HC-dAVF). METHODS: During a 16-year period, 238 patients underwent endovascular treatment for cranial dAVF at a single center. The incidence, radiographic findings, relationship between presenting symptoms for treatment and drainage pattern, and treatment outcomes of HC-dAVF were retrospectively evaluated. RESULTS: The incidence of HC-dAVF was 4.2% (n = 10). Initial symptoms were tinnitus with headache (n = 6), tinnitus only (n = 1), ocular symptoms (n = 1), otalgia (n = 1), and congestive myelopathy (n = 1). Presenting symptoms requiring treatment included ocular symptoms (n = 4), hypoglossal nerve palsy (n = 4), aggravation of myelopathy (n = 1), and aggravation of tinnitus with headache (n = 1). While the affected HC was widened in 4 of 10 patients, hypersignal intensity on source images was conspicuous in all 7 patients who underwent MR angiography (MRA). All ocular symptoms and congestive myelopathy were associated with predominant drainage to superior ophthalmic or perimedullary veins due to antegrade drainage restriction. All patients who underwent transvenous coil embolization (n = 8) or transarterial N-butyl cyanoacrylate (NBCA) embolization (n = 1) improved without recurrence. One patient who underwent transarterial particle embolization had a recurrence 12 months posttreatment and was retreated with transvenous embolization. CONCLUSIONS: The incidence of HC-dAVF was 4.2% of all cranial dAVF patients who underwent endovascular treatment. Source images of MRA helped to accurately diagnose HC-dAVF. More aggressive symptoms may develop as a result of a change in the predominant drainage route due to the development of venous stenosis or obstruction over time. Transvenous coil embolization appears to be the first treatment of choice. PMID- 23724985 TI - Case-specific protocol to reduce cerebrospinal fluid leakage after endonasal endoscopic surgery. AB - OBJECT: Endoscopic transsphenoidal surgery is expanding in acceptance, yet postoperative CSF leak rates remain a concern. This study presents the Cornell closure protocol, which has yielded significantly lower postoperative CSF leak rates compared with prior reports, as an algorithm that can be used by centers having difficulty with CSF leak. METHODS: A single closure algorithm for endoscopic surgery has been used since January 2010 at Weill Cornell Medical College. A prospective database noting intraoperative CSF leak, closure technique, and postoperative CSF leak was reviewed. The authors used a MEDLINE search to identify similar studies and compared CSF leak rates to those of patients treated using the Cornell algorithm. RESULTS: The retrospective study of a prospectively acquired database included 209 consecutive patients. In 84 patients (40%) there was no intraoperative CSF leak and no postoperative CSF leak. In the 125 patients (60%) with an intraoperative CSF leak, 35 of them with high-flow leaks, there were 0 (0%) postoperative CSF leaks. CONCLUSIONS: It is possible to achieve a CSF leak rate of 0% by using this closure protocol. With proper experience, endoscopic skull base surgery should not be considered to have a higher CSF leak rate than open transcranial or microscopic transsphenoidal surgery. PMID- 23724986 TI - Accuracy of deep brain stimulation electrode placement using intraoperative computed tomography without microelectrode recording. AB - OBJECT: In this prospective study the authors' objective was to evaluate the accuracy of deep brain stimulation (DBS) electrode placement using image guidance for direct anatomical targeting with intraoperative CT. METHODS: Preoperative 3-T MR images were merged with intraoperative CT images for planning. Electrode targets were anatomical, based on the MR images. A skull-mounted NexFrame system was used for electrode placement, and all procedures were performed under general anesthesia. After electrode placement, intraoperative CT images were merged with trajectory planning images to calculate accuracy. Accuracy was assessed by both vector error and deviation off the planned trajectory. RESULTS: Sixty patients (33 with Parkinson disease, 26 with essential tremor, and 1 with dystonia) underwent the procedure. Patient's mean age was 64 +/- 9.5 years. Over an 18 month period, 119 electrodes were placed (all bilateral, except one). Electrode implant locations were the ventral intermediate nucleus (VIM), globus pallidus internus (GPI), and subthalamic nucleus (STN) in 25, 23, and 12 patients, respectively. Target accuracy measurements were as follows: mean vector error 1.59 +/- 1.11 mm and mean deviation off trajectory 1.24 +/- 0.87 mm. There was no statistically significant difference between the accuracy of left and right brain electrodes. There was a statistically significant (negative) correlation between the distance of the closest approach of the electrode trajectory to the ventricular wall of the lateral ventricle and vector error (r(2) = -0.339, p < 0.05, n = 76), and the deviation from the planned trajectory (r(2) = -0.325, p < 0.05, n = 77). Furthermore, when the distance from the electrode trajectory and the ventricular wall was < 4 mm, the correlation of the ventricular distance to the deviation from the planned trajectory was stronger (r(2) = -0.419, p = 0.05, n = 19). Electrodes placed in the GPI were significantly more accurate than those placed in the VIM (p < 0.05). Only 1 of 119 electrodes required intraoperative replacement due to a vector error > 3 mm. In this series there was one infection and no intraparenchymal hemorrhages. CONCLUSIONS: Placement of DBS electrodes using an intraoperative CT scanner and the NexFrame achieves an accuracy that is at least comparable to other methods. PMID- 23724987 TI - Contribution of estrogen receptors alpha and beta in the brain response to traumatic brain injury. AB - OBJECT: Although there is evidence that estradiol has neuroprotective effects after traumatic brain injury (TBI) in female rats, it is unclear which estrogen receptor (ER) subtype, ERalpha or ERbeta, mediates this effect. The authors therefore examined the roles of the different ERs in this effect. Here the authors used the ERalpha selective agonist propyl pyrazole triol (PPT) and the ERbeta selective agonist diarylpropionitrile (DPN) alone and in combination in female rats to investigate this question. METHODS: Before the ovariectomized animals were injured using the Marmarou TBI technique, they were randomly divided into the following 9 groups: control, sham, TBI, vehicle, E1 (physiological dose of 17-beta estradiol), E2 (pharmacological dose of 17-beta estradiol), PPT, DPN, and PPT+DPN. Levels of blood-brain barrier (BBB) disruption (5 hours) and water content (24 hours) were evaluated after TBI. In groups receiving drugs or vehicle, treatment was administered as a single dose intraperitoneally 30 minutes after induction of TBI. RESULTS: Results showed that brain edema or brain water content after TBI was lower (p < 0.001) in the E2, PPT, DPN, and PPT+DPN groups than it was in the vehicle group. After trauma, the Evans blue dye content or BBB permeability was significantly higher in the TBI and vehicle groups (p < 0.001) than in the E2, PPT, DPN, and PPT+DPN groups. The inhibitory effects of PPT+DPN on brain water content, neurological scores, and Evans blue dye content were the highest for all groups. Although both PPT and DPN increased neurological scores after TBI, PPT appears to be more effective in increasing neurological scores. CONCLUSIONS: Neuroprotective effects of estradiol on brain edema, BBB permeability, and neurological scores are mediated through both ERalpha and ERbeta. This may suggest a therapeutic potential in the brain trauma for ER specific agonists. PMID- 23724988 TI - Distinct transcriptome profiles identified in normal human bronchial epithelial cells after exposure to gamma-rays and different elemental particles of high Z and energy. AB - BACKGROUND: Ionizing radiation composed of accelerated ions of high atomic number (Z) and energy (HZE) deposits energy and creates damage in cells in a discrete manner as compared to the random deposition of energy and damage seen with low energy radiations such as gamma- or x-rays. Such radiations can be highly effective at cell killing, transformation, and oncogenesis, all of which are concerns for the manned space program and for the burgeoning field of HZE particle radiotherapy for cancer. Furthermore, there are differences in the extent to which cells or tissues respond to such exposures that may be unrelated to absorbed dose. Therefore, we asked whether the energy deposition patterns produced by different radiation types would cause different molecular responses. We performed transcriptome profiling using human bronchial epithelial cells (HBECs) after exposure to gamma-rays and to two different HZE particles (28Si and 56Fe) with different energy transfer properties to characterize the molecular response to HZE particles and gamma-rays as a function of dose, energy deposition pattern, and time post-irradiation. RESULTS: Clonogenic assay indicated that the relative biological effectiveness (RBE) for 56Fe was 3.91 and for 28Si was 1.38 at 34% cell survival. Unsupervised clustering analysis of gene expression segregated samples according to the radiation species followed by the time after irradiation, whereas dose was not a significant parameter for segregation of radiation response. While a subset of genes associated with p53-signaling, such as CDKN1A, TRIM22 and BTG2 showed very similar responses to all radiation qualities, distinct expression changes were associated with the different radiation species. Gene enrichment analysis categorized the differentially expressed genes into functional groups related to cell death and cell cycle regulation for all radiation types, while gene pathway analysis revealed that the pro-inflammatory Acute Phase Response Signaling was specifically induced after HZE particle irradiation. A 73 gene signature capable of predicting with 96% accuracy the radiation species to which cells were exposed, was developed. CONCLUSIONS: These data suggest that the molecular response to the radiation species used here is a function of the energy deposition characteristics of the radiation species. This novel molecular response to HZE particles may have implications for radiotherapy including particle selection for therapy and risk for second cancers, risk for cancers from diagnostic radiation exposures, as well as NASA's efforts to develop more accurate lung cancer risk estimates for astronaut safety. Lastly, irrespective of the source of radiation, the gene expression changes observed set the stage for functional studies of initiation or progression of radiation-induced lung carcinogenesis. PMID- 23724989 TI - Indoor secondary organic aerosol formation initiated from reactions between ozone and surface-sorbed D-limonene. AB - Reactions between ozone and terpenoids produce numerous products, some of which may form secondary organic aerosol (SOA). This work investigated the contribution to gas-phase SOA formation of ozone reactions with surface-sorbed D-limonene, which is common indoors. A model framework was developed to predict SOA mass formation because of ozone/terpenoid surface reactions, and it was used with steady state experiments in a 283 L chamber to determine the aerosol mass fraction of SOA resulting from surface reactions, xis (the ratio of mass of SOA formed and mass of ozone consumed by ozone/terpenoid surface reactions), for ozone/D-limonene reactions on stainless steel. The xis = 0.70-0.91, with lower relative humidity leading to both higher mass and number formation. Also, surface reactions promoted nucleation more than gas-phase reactions, and number formation due to surface reactions and gas-phase reactions were 126-339 and 51.1-60.2 no./cm(3) per MUg/m(3) of formed SOA, respectively. We also used the model framework to predict that indoor spaces in which ozone/D-limonene surface reactions would likely lead to meaningful gas-phase SOA formation are those with surfaces that have low original reactivity with ozone, such as glass, sealed materials, or smooth metals. PMID- 23724990 TI - Benign dermoscopic features in melanoma. AB - BACKGROUND: Various dermoscopic features are usually associated with benign melanocytic lesions. Our objective was to determine frequency and extension of benign dermoscopic features (BDF) in melanoma. METHODS: Retrospective review of dermoscopic images of a consecutive series of 516 histopathologically proven melanomas collected in 6 years in Graz. Correlation of BDF with mean Breslow thickness, with presence/absence of associated benign nevus component and with the pre-operative clinico-dermoscopic diagnosis, as reported on the original histopathologic reports. RESULTS: In addition to melanoma specific criteria, 42% of melanomas showed BDF. In 12.3% cases, the benign features occupied more than the half of the lesion. The BDF typical pigment network, homogeneous pattern and regular globules/cobblestone pattern had the highest frequency. BDF were associated with relatively thinner melanomas (mean Breslow thickness of 0.51 mm). The presence of BDF was observed in 67.1% of histopathologically documented nevus associated melanoma and in 35.7% of melanoma de novo. A pre-operative clinico dermoscopic diagnosis of melanoma was achieved in only 54.1% of cases displaying BDF. CONCLUSION: A significant proportion of melanomas may exhibit BDF. Clinicians should be aware of the presence of BDF in melanoma as possible diagnostic pitfall. PMID- 23724991 TI - Plasticity of melanoma in vivo: murine lesions resulting from Trp53, but not Cdk4 or Arf deregulation, display neural transdifferentiation. AB - We previously noted that melanomas developing in Cdk4(R24C/R24C) ::Tyr-NRAS, Arf( /-) ::Tyr-NRAS and Trp53(F/F) ::Tyr-Cre(ER)::Tyr-NRAS mice exhibited differences in behaviour in vivo. We investigated this phenomenon using global gene expression profiling of lesions from the respective genotypes. While those from the Cdk4- and Arf-mutant mice exhibited similar profiles, the Trp53(F/F) ::Tyr Cre(ER)::Tyr-NRAS melanomas were strikingly different, showing relative down regulation of melanocyte-related genes, and up-regulation of genes related to neural differentiation. Specifically, they highly expressed genes representative of the myelin-producing peripheral oligodendrite (Schwann cell) lineage, although histopathologically the lesions did not exhibit the classical features of schwannoma. As Schwann cell precursors can be a cellular origin of melanocytes, it is unsurprising that plasticity with respect to melanocyte-neural differentiation can occur in melanoma. What is surprising is the genotype proclivity. Comparison of gene expression signatures revealed that melanomas from the Trp53-mutant mice show significant similarities with a subset of aggressive human melanomas with relatively low levels of MITF. PMID- 23724992 TI - Increased rate of cholecystectomies performed with doubtful or no indications after laparoscopy introduction: a single center experience. AB - BACKGROUND: During recent years laparoscopic cholecystectomy has dramatically increased, sometimes resulting in overtreatment. Aim of this work was to retrospectively analyze all laparoscopic cholecystectomies performed in a single center in order to find the percentage of patients whose surgical treatment may be explained with this general trend, and to speculate about the possible causes. METHODS: 831 patients who underwent a laparoscopic cholecystectomy from 1999 to 2008 were retrospectively analyzed. RESULTS: At discharge, 43.08% of patients were operated on because of at least one previous episode of biliary colic before the one at admission; 14.08% of patients presented with acute lithiasic cholecystitis; 14.68% were operated on because of an increase in bilirubin level; 1.56% were operated on because of a previous episode of jaundice with normal bilirubin at admission; 0.72% had gallbladder adenomas, 0.72% had cholangitis, 0.36% had biliodigestive fistula and one patient (0.12%) had acalculous cholecystitis. By excluding all these patients, 21.18% were operated on without indications. CONCLUSIONS: The broadening of indications for laparoscopic cholecystectomy is undisputed and can be considered a consequence of new technologies that have been introduced, increased demand from patients, and the need for practice by inexperienced surgeons. If not prevented, this trend could continue indefinitely. PMID- 23724993 TI - Modeling the spatial distribution of Chagas disease vectors using environmental variables and people's knowledge. AB - BACKGROUND: Chagas disease is caused by the protozoan Trypanosoma cruzi, which is transmitted to mammal hosts by triatomine insect vectors. The goal of this study was to model the spatial distribution of triatomine species in an endemic area. METHODS: Vector's locations were obtained with a rural householders' survey. This information was combined with environmental data obtained from remote sensors, land use maps and topographic SRTM data, using the machine learning algorithm Random Forests to model species distribution. We analysed the combination of variables on three scales: 10 km, 5 km and 2.5 km cell size grids. RESULTS: The best estimation, explaining 46.2% of the triatomines spatial distribution, was obtained for 5 km of spatial resolution. Presence probability distribution increases from central Chile towards the north, tending to cover the central coastal region and avoiding areas of the Andes range. CONCLUSIONS: The methodology presented here was useful to model the distribution of triatomines in an endemic area; it is best explained using 5 km of spatial resolution, and their presence increases in the northern part of the study area. This study's methodology can be replicated in other countries with Chagas disease or other vectorial transmitted diseases, and be used to locate high risk areas and to optimize resource allocation, for prevention and control of vectorial diseases. PMID- 23724994 TI - Synthesis of triazole-linked oligonucleotides with high affinity to DNA complements and an analysis of their compatibility with biosystems. AB - New oligonucleotide analogues with triazole internucleotide linkages were synthesized, and their hybridization properties were studied. The analogues demonstrated DNA binding affinities similar to those of unmodified oligonucleotides. The modification was shown to protect the oligonucleotides from nuclease hydrolysis. The modified oligonucleotides were tested as PCR primers. Modifications remote from the 3'-terminus were tolerated by polymerases. Our results suggest that these new oligonucleotide analogues are among the most promising triazole DNA mimics characterized to date. PMID- 23724995 TI - Gene therapy for blindness. AB - Sight-restoring therapy for the visually impaired and blind is a major unmet medical need. Ocular gene therapy is a rational choice for restoring vision or preventing the loss of vision because most blinding diseases originate in cellular components of the eye, a compartment that is optimally suited for the delivery of genes, and many of these diseases have a genetic origin or genetic component. In recent years we have witnessed major advances in the field of ocular gene therapy, and proof-of-concept studies are under way to evaluate the safety and efficacy of human gene therapies. Here we discuss the concepts and recent advances in gene therapy in the retina. Our review discusses traditional approaches such as gene replacement and neuroprotection and also new avenues such as optogenetic therapies. We conjecture that advances in gene therapy in the retina will pave the way for gene therapies in other parts of the brain. PMID- 23724996 TI - Transformation of visual signals by inhibitory interneurons in retinal circuits. AB - One of the largest mysteries of the brain lies in understanding how higher-level computations are implemented by lower-level operations in neurons and synapses. In particular, in many brain regions inhibitory interneurons represent a diverse class of cells, the individual functional roles of which are unknown. We discuss here how the operations of inhibitory interneurons influence the behavior of a circuit, focusing on recent results in the vertebrate retina. A key role in this understanding is played by a common representation of the visual stimulus that can be applied at different stages. By considering how this stimulus representation changes at each location in the circuit, we can understand how neuron-level operations such as thresholds and inhibition yield circuit-level computations such as how stimulus selectivity and gain are controlled by local and peripheral visual stimuli. PMID- 23724997 TI - Electrical compartmentalization in dendritic spines. AB - Most excitatory inputs in the CNS contact dendritic spines, avoiding dendritic shafts, so spines must play a key role for neurons. Recent data suggest that, in addition to enhancing connectivity and isolating synaptic biochemistry, spines can behave as electrical compartments independent from their parent dendrites. It is becoming clear that, although spines experience voltages similar to those of dendrites during action potentials (APs), spines must sustain higher depolarizations than do dendritic shafts during excitatory postsynaptic potentials (EPSPs). Synaptic potentials are likely amplified at the spine head and then reduced as they invade the dendrite through the spine neck. These electrical changes, probably due to a combination of passive and active mechanisms, may prevent the saturation of dendrites by the joint activation of many inputs, influence dendritic integration, and contribute to rapid synaptic plasticity. The electrical properties of spines could enable neural circuits to harness a high connectivity, implementing a "synaptic democracy," where each input can be individually integrated, tallied, and modified in order to generate emergent functional states. PMID- 23724998 TI - Mechanisms and functions of theta rhythms. AB - The theta rhythm is one of the largest and most sinusoidal activity patterns in the brain. Here I survey progress in the field of theta rhythms research. I present arguments supporting the hypothesis that theta rhythms emerge owing to intrinsic cellular properties yet can be entrained by several theta oscillators throughout the brain. I review behavioral correlates of theta rhythms and consider how these correlates inform our understanding of theta rhythms' functions. I discuss recent work suggesting that one function of theta is to package related information within individual theta cycles for more efficient spatial memory processing. Studies examining the role of theta phase precession in spatial memory, particularly sequence retrieval, are also summarized. Additionally, I discuss how interregional coupling of theta rhythms facilitates communication across brain regions. Finally, I conclude by summarizing how theta rhythms may support cognitive operations in the brain, including learning. PMID- 23725000 TI - Neural basis of the perception and estimation of time. AB - Understanding how sensory and motor processes are temporally integrated to control behavior in the hundredths of milliseconds-to-minutes range is a fascinating problem given that the basic electrophysiological properties of neurons operate on a millisecond timescale. Single-unit recording studies in monkeys have identified localized timing circuits, whereas neuropsychological studies of humans who have damage to the basal ganglia have indicated that core structures, such as the cortico-thalamic-basal ganglia circuit, play an important role in timing and time perception. Taken together, these data suggest that a core timing mechanism interacts with context-dependent areas. This idea of a temporal hub with a distributed network is used to investigate the abstract properties of interval tuning as well as temporal illusions and intersensory timing. We conclude by proposing that the interconnections built into this core timing mechanism are designed to provide a form of degeneracy as protection against injury, disease, or age-related decline. PMID- 23725001 TI - Cortical control of arm movements: a dynamical systems perspective. AB - Our ability to move is central to everyday life. Investigating the neural control of movement in general, and the cortical control of volitional arm movements in particular, has been a major research focus in recent decades. Studies have involved primarily either attempts to account for single-neuron responses in terms of tuning for movement parameters or attempts to decode movement parameters from populations of tuned neurons. Even though this focus on encoding and decoding has led to many seminal advances, it has not produced an agreed-upon conceptual framework. Interest in understanding the underlying neural dynamics has recently increased, leading to questions such as how does the current population response determine the future population response, and to what purpose? We review how a dynamical systems perspective may help us understand why neural activity evolves the way it does, how neural activity relates to movement parameters, and how a unified conceptual framework may result. PMID- 23725002 TI - Neuronal computations in the olfactory system of zebrafish. AB - The main olfactory system encodes information about molecules in a combinatorial fashion by distributed spatiotemporal activity patterns. As activity propagates from sensory neurons to the olfactory bulb and to higher brain areas, odor information is processed by multiple transformations of these activity patterns. This review discusses neuronal computations associated with such transformations in the olfactory system of zebrafish, a small vertebrate that offers advantages for the quantitative analysis and manipulation of neuronal activity in the intact brain. The review focuses on pattern decorrelation in the olfactory bulb and on the readout of multiplexed sensory representations in the telencephalic area Dp, the homolog of the olfactory cortex. These computations are difficult to study in larger species and may provide insights into general information-processing strategies in the brain. PMID- 23724999 TI - The genetics of hair cell development and regeneration. AB - Sensory hair cells are exquisitely sensitive vertebrate mechanoreceptors that mediate the senses of hearing and balance. Understanding the factors that regulate the development of these cells is important, not only to increase our understanding of ear development and its functional physiology but also to shed light on how these cells may be replaced therapeutically. In this review, we describe the signals and molecular mechanisms that initiate hair cell development in vertebrates, with particular emphasis on the transcription factor Atoh1, which is both necessary and sufficient for hair cell development. We then discuss recent findings on how microRNAs may modulate the formation and maturation of hair cells. Last, we review recent work on how hair cells are regenerated in many vertebrate groups and the factors that conspire to prevent this regeneration in mammals. PMID- 23725003 TI - Evolution of polyvinylidene fluoride (PVDF) hierarchical morphology during slow gelation process and its superhydrophobicity. AB - In the paper, we proposed an evolution process of polyvinylidene fluoride (PVDF) macromolecular aggregation in a mixed solvent through the simple and slow gelation process at room temperature. The mixed solvent is prepared with a room temperature solvent and a high-temperature solvent. The evolution process can be terminated by quenching and exchanging with nonsolvent in a nonsolvent coagulation bath properly, and then the vivid petal-like nanostructure and microspherulite is formed simultaneously. This hierarchical morphology endows PVDF with superhydrophobic and self-cleaning properties, which is useful to PVDF coating and membrane materials. The evolution processes are investigated through the measurements of differential scanning calorimetry (DSC), X-ray diffraction (XRD). In addition, the rheological properties of solution, dry gel and wet gel, are explored. PMID- 23725004 TI - Novel birch pollen specific immunotherapy formulation based on contiguous overlapping peptides. AB - BACKGROUND: Synthetic contiguous overlapping peptides (COPs) may represent an alternative to allergen extracts or recombinant allergens for allergen specific immunotherapy. In combination, COPs encompass the entire allergen sequence, providing all potential T cell epitopes, while preventing IgE conformational epitopes of the native allergen. METHODS: Individual COPs were derived from the sequence of Bet v 1, the major allergen of birch pollen, and its known crystal structure, and designed to avoid IgE binding. Three sets of COPs were tested in vitro in competition ELISA and basophil degranulation assays. Their in vivo reactivity was determined by intraperitoneal challenge in rBet v 1 sensitized mice as well as by skin prick tests in volunteers with allergic rhinoconjunctivitis to birch pollen. RESULTS: The combination, named AllerT, of three COPs selected for undetectable IgE binding in competition assays and for the absence of basophil activation in vitro was unable to induce anaphylaxis in sensitized mice in contrast to rBet v 1. In addition no positive reactivity to AllerT was observed in skin prick tests in human volunteers allergic to birch pollen. In contrast, a second set of COPs, AllerT4-T5 displayed some residual IgE binding in competition ELISA and a weak subliminal reactivity to skin prick testing. CONCLUSIONS: The hypoallergenicity of contiguous overlapping peptides was confirmed by low, if any, IgE binding activity in vitro, by the absence of basophil activation and the absence of in vivo induction of allergic reactions in mouse and human. TRIAL REGISTRATION: ClinicalTrials.gov NCT01719133. PMID- 23725005 TI - Refusal of treatment for acute leukemia in pregnancy: a case report. AB - INTRODUCTION: Acute leukemia is rare in pregnancy. The importance of promptly diagnosing and treating this disease in pregnancy stems from its life-threatening potential, both to the mother and fetus. CASE PRESENTATION: We report a case of relapse of acute myeloid leukemia at 23 weeks of pregnancy in a 24-year-old Albanian woman. Our patient categorically refused chemotherapy treatment, and in her 35th week of gestation, severe hemorrhagic diathesis rapidly developed. The manifestation and course of this life-threatening complication posed therapeutic challenges for the attending medical team. CONCLUSION: Based both on our experience and the results of other gynecological studies, there exists a strong indication that the earlier a patient's chemotherapy treatment begins, the better the maternal outcome. We support chemotherapy for patients who are pregnant presenting with such illness. The present case report testifies that refusal of chemotherapy by such patients is a high-risk decision. PMID- 23725006 TI - High intensity interval training vs. high-volume running training during pre season conditioning in high-level youth football: a cross-over trial. AB - We aimed at comparing the endurance effects of high-intensity interval training (HIIT) with high-volume running training (HVT) during pre-season conditioning in 20 high-level youth football players (15.9 (s 0.8) years). Players either conducted HVT or HIIT during the summer preparation period. During winter preparation they performed the other training programme. Before and after each training period several fitness tests were conducted: multi-stage running test (to assess the individual anaerobic threshold (IAT) and maximal running velocity (Vmax)), vertical jumping height, and straight sprinting. A significant increase from pre- to post-test was observed in IAT velocity (P < 0.001) with a greater increase after HVT (+0.8 km . h(-1) vs. +0.5 km . h(-1) after HIIT, P = 0.04). Maximal velocity during the incremental exercise test also slightly increased with time (P = 0.09). Forty per cent (HIIT) and 15% (HVT) of all players did not improve IAT beyond baseline variability. The players who did not respond to HIIT were significantly slower during 30 m sprinting than responders (P = 0.02). No further significant differences between responders and non-responders were observed. Jump heights deteriorated significantly after both training periods (P < 0.003). Both training programmes seem to be promising means to improve endurance capacity in high-level youth football players during pre-season conditioning. PMID- 23725007 TI - Utilization of genetic testing prior to subspecialist referral for cerebellar ataxia. AB - OBJECTIVE: To evaluate the utilization of laboratory testing in the diagnosis of cerebellar ataxia, including the completeness of initial standard testing for acquired causes, the early use of genetic testing, and associated clinical and nonclinical factors, among a cohort referred for subspecialty consultation. METHODS: Data were abstracted from records of 95 consecutive ataxia patients referred to one neurogenetics subspecialist from 2006-2010 and linked to publicly available data on characteristics of referral clinicians. Multivariable logistic and linear regression models were used to analyze unique associations of clinical and nonclinical factors with laboratory investigation of acquired causes and with early genetic testing prior to referral. RESULTS: At referral, 27 of 95 patients lacked evidence of any of 14 laboratory studies suggested for initial work-up of an acquired cause for ataxia (average number of tests=4.5). In contrast, 92% of patients had undergone brain magnetic resonance imaging prior to referral. Overall, 41.1% (n=39) had genetic testing prior to referral; there was no association between family history of ataxia and obtaining genetic testing prior to referral (p=0.39). The level of early genetic testing was 31.6%, primarily due to genetic testing despite an incomplete laboratory evaluation for acquired causes and no family history. A positive family history was consistently associated with less extensive laboratory testing (p=0.004), and referral by a neurologist was associated with higher levels of early genetic testing. CONCLUSIONS: Among consecutive referrals to a single center, a substantial proportion of sporadic cases had genetic testing without evidence of a work-up for acquired causes. Better strategies to guide decision making and subspecialty referrals in rare neurologic disorders are needed, given the cost and consequences of genetic testing. PMID- 23725008 TI - Association between cytotoxic T-lymphocyte-associated antigen 4 +49A/G polymorphism and persistent hepatitis B virus infection in the Asian population: evidence from the current studies. AB - AIMS: A number of studies assessed the association between cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) +49A/G polymorphism and persistent hepatitis B virus (HBV) infection risk. However, the results are quite contradictory. In order to obtain a more precise estimation of the relationship, a meta-analysis was performed. METHODS: Pubmed, ISI Web of Knowledge, HuGE Navigator, Wanfang Database, and China National Knowledge Infrastructure were searched. Crude odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated to estimate the strength of this association. RESULTS: Six publications were included in the final meta-analysis with 1075 cases and 1321 controls for CTLA-4 +49A/G polymorphism according to our inclusion and exclusion criteria. We observed that the CTLA-4 +49A/G polymorphism was significantly correlated with chronic HBV infection risk (the homozygote codominant model: OR 1.67, 95% CI 1.30-2.15; the dominant model: OR 1.34, 95% CI 1.01-1.78; the recessive model: OR 1.56, 95% CI 1.24-1.96; the allele contrast model: OR 1.32, 95% CI 1.10-1.59). No publication bias was observed in this study according to Begg's funnel plot and Egger's test. CONCLUSION: CTLA-4 +49A/G polymorphism is assumed to confer a higher risk for persistent HBV infection in the Asian population. PMID- 23725009 TI - An electromyographic analysis of orbicularis oris and buccinator muscle activity in patients with complete dentures fabricated using two neutral zone techniques- a pilot study. AB - PURPOSE: Several studies have evaluated electromyographic (EMG) activity of perioral muscles in patients using unsatisfactory old complete dentures and after the insertion of new clinically acceptable dentures; however, studies evaluating EMG activity of orbicularis oris (OO) and buccinator (BUC) muscles in patients wearing complete dentures fabricated using swallowing (SNZ) and phonetic neutral zone (PNZ) techniques are lacking in the literature. The purpose of this study was to evaluate differences in muscle activity of the superior orbicularis oris (SOO), inferior orbicularis oris (IOO) and BUC muscle during the use of unsatisfactory old complete dentures, in comparison with the satisfactory dentures fabricated using the two neutral zone techniques. MATERIALS AND METHODS: Ten completely edentulous participants dissatisfied with their existing mandibular complete dentures participated in the study. Each patient received two sets of new dentures fabricated using the SNZ and PNZ techniques. Surface EMG activity of the OO and BUC muscles was recorded using a 4-channel Medelec premier plus electromyography machine while the patients still used their old dentures (group A) and with the SNZ (group B) and PNZ (group C) dentures. On the basis of participation in the study, five participants first received the SNZ dentures and five the PNZ type. After having worn the prosthesis for a minimum of 2 months, EMG recordings were repeated for the first set of dentures. The prostheses were then changed and the procedures repeated. The activity of OO and BUC muscles was recorded at rest, while pursing and laughing, and during pronunciation of various syllables. Results are expressed as mean +/- SD and as absolute numbers and percentage. ANOVA with appropriate correction (Bonferroni or Tamhane) and Student's t-test were used for statistical analysis. A p-value < 0.05 was taken to indicate a significant difference. RESULTS: There was no statistically significant difference in the mean EMG activity of SOO, IOO, and BUC muscles at rest, or during pursing or laughing among the three groups. No significant difference was observed in the mean EMG activity of SOO and BUC muscle among the groups for all the syllables pronounced. For IOO, a statistically significant difference was observed among the groups for the words "baby" and "cheese." Within-group comparisons of the mean EMG activities of SOO and IOO during pronunciation and pursing showed no significant difference; however, at rest a statistically significant difference was observed in group B. CONCLUSION: OO and BUC muscle activities did not significantly differ, irrespective of the technique used for fabrication of complete dentures. PMID- 23725010 TI - Vertical profiles of community and activity of methanotrophs in landfill cover soils of different age. AB - AIM: Aerobic CH4 oxidation is an important process controlling CH4 release from landfills to the atmosphere. The aim of this study was to investigate the link between CH4 oxidation activity and methanotrophs abundance and diversity in landfill cover soils of different age. METHODS AND RESULTS: Among the three investigated sites, the highest CH4 emission occurred at the active landfill area with the range of 1371-2242 mg m(-2) day. The CH4 oxidation activities of landfill cover soils were 1.07-1.21 MUmol g(-1) h(-1) in the landfill area of 7 16 years, which was 7-17 times higher than those in the active landfill area. The relative abundance of methanotrophs assessed by quantification of pmoA gene was about 1.7 * 10(6) -2.4 * 10(7) copies g(-1) in the landfill cover soils. The CH4 oxidation activity was positively correlated with pmoA copy number in the landfill cover soil of each site, respectively. Type II methanotrophs (Methylocystis) and type I methanotrophs including Methylosoma, Methylocaldum and Methylococcus were all present in the landfill cover soils. Compared to type I methanotroph, type II methanotroph, Methylocystis, was more abundant in the acidic landfill cover soils. CONCLUSIONS: Oxidation activity and community structure of methanotrophs varied with depth and age of landfill cover soils. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings provide new fundamental information regarding the activity and diversity of methanotrophs in landfill cover soils of different age that may aid predicting and modelling CH4 flux from landfills. PMID- 23725011 TI - Energetic high-nitrogen compounds: 5-(trinitromethyl)-2H-tetrazole and tetrazolates, preparation, characterization, and conversion into 5 (dinitromethyl)tetrazoles. AB - A convenient access to 5-(trinitromethyl)-2H-tetrazole (HTNTz) has been developed, based on the exhaustive nitration of 1H-tetrazole-5-acetic acid, which was prepared from ethyl cyanoacetate and HN3 in a 1,3-dipolar cycloaddition reaction, followed by basic hydrolysis. HTNTz was converted into the ammonium, guanidinium, rubidium, cesium, copper, and silver 5-(trinitromethyl)-2H tetrazolates. In addition, the ammonia adducts of the copper and silver salts were isolated. The reaction of HTNTz with hydrazine and hydroxylamine resulted in the formation of hydrazinium 5-(dinitromethyl)tetrazolate and hydroxylammonium 5 (dinitromethyl)-1H-tetrazolate, respectively. Acid treatment of both 5 (dinitromethyl)tetrazolates resulted in the isolation of 5-(dinitromethylene)-4,5 dihydro-1H-tetrazole, which was converted into potassium 5-(dinitromethyl)-1H tetrazolate by reaction with K2CO3. All prepared compounds were fully characterized by (1)H, (13)C, (14)N, and (15)N NMR spectroscopy and X-ray crystal structure determination. Initial safety testing (impact, friction, and electrostatic sensitivity) and thermal stability measurements (differential thermal analysis, DTA) were also carried out. The 5-(trinitromethyl) and 5 (dinitromethyl)tetrazoles are highly energetic materials that explode upon impact or heating. PMID- 23725012 TI - Paper analytical devices for fast field screening of beta lactam antibiotics and antituberculosis pharmaceuticals. AB - Reports of low-quality pharmaceuticals have been on the rise in the past decade, with the greatest prevalence of substandard medicines in developing countries, where lapses in manufacturing quality control or breaches in the supply chain allow substandard medicines to reach the marketplace. Here, we describe inexpensive test cards for fast field screening of pharmaceutical dosage forms containing beta lactam antibiotics or combinations of the four first-line antituberculosis (TB) drugs. The devices detect the active pharmaceutical ingredients (APIs) ampicillin, amoxicillin, rifampicin, isoniazid, ethambutol, and pyrazinamide and also screen for substitute pharmaceuticals, such as acetaminophen and chloroquine that may be found in counterfeit pharmaceuticals. The tests can detect binders and fillers such as chalk, talc, and starch not revealed by traditional chromatographic methods. These paper devices contain 12 lanes, separated by hydrophobic barriers, with different reagents deposited in the lanes. The user rubs some of the solid pharmaceutical across the lanes and dips the edge of the paper into water. As water climbs up the lanes by capillary action, it triggers a library of different chemical tests and a timer to indicate when the tests are completed. The reactions in each lane generate colors to form a "color bar code" which can be analyzed visually by comparison with standard outcomes. Although quantification of the APIs is poor compared with conventional analytical methods, the sensitivity and selectivity for the analytes is high enough to pick out suspicious formulations containing no API or a substitute API as well as formulations containing APIs that have been "cut" with inactive ingredients. PMID- 23725013 TI - Melatonin induces apoptosis through a caspase-dependent but reactive oxygen species-independent mechanism in human leukemia Molt-3 cells. AB - Melatonin is a naturally occurring indoleamine synthesized in the pineal gland that exhibits an extensive repertoire of biological activities. An increasing number of studies indicate that melatonin protects normal cells, while it reducing cancer cell proliferation. In this study, we investigated the effect of melatonin on the growth of the human leukemia cells and found that it efficiently reduced the number of cells in a concentration- and time-dependent manner. Thus, incubation with the indoleamine increased the percentage of cells with a hypodiploid DNA content, augmented the number of annexin V-positive cells, and also provoked ultrastructural changes that are features of apoptotic cell death. Evaluation of caspases revealed that caspase-3, caspase-6, caspase-7, and caspase 9, but not caspase-8 and caspase-2, were quickly activated (3-6 hr). The increase in the activity of these proteases was associated with up-regulation of the pro apoptotic factor Bax and also with the release of cytochrome c from mitochondria. Pretreatment of the cells with the general caspase inhibitor z-VAD-fmk, reduced melatonin-induced apoptosis, but it did not block cell death suggesting that melatonin activates an alternative cell death modality in the absence of caspase activity. Thus, the activation of caspases was preceded by a fast (<30 min) increase in reactive oxygen species (ROS). Rotenone and antimycin A reduced the levels of ROS stimulated by melatonin, indicating that the complex I and the complex III of the mitochondrial electron transport chain are important sources of these chemical species. However, the role of ROS in melatonin-induced cell death remains elusive because anti-oxidants that were shown to decrease ROS levels (glutathione, N-acetyl-l-cysteine and Trolox) were unable to abrogate melatonin-induced cell death. PMID- 23725014 TI - Ruthenium-catalyzed self-coupling of primary and secondary alcohols with the liberation of dihydrogen. AB - The dehydrogenative self-condensation of primary and secondary alcohols has been studied in the presence of RuCl2(IiPr)(p-cymene). The conversion of primary alcohols into esters has been further optimized by using magnesium nitride as an additive, which allows the reaction to take place at a temperature and catalyst loading lower than those described previously. Secondary alcohols were dimerized into racemic ketones by a dehydrogenative Guerbet reaction with potassium hydroxide as the additive. The transformation gave good yields of the ketone dimers with a range of alkan-2-ols, whereas more substituted secondary alcohols were unreactive. The reaction proceeds by dehydrogenation to the ketone, followed by an aldol reaction and hydrogenation of the resulting enone. PMID- 23725015 TI - The genome and transcriptome of the pine saprophyte Ophiostoma piceae, and a comparison with the bark beetle-associated pine pathogen Grosmannia clavigera. AB - BACKGROUND: Ophiostoma piceae is a wood-staining fungus that grows in the sapwood of conifer logs and lumber. We sequenced its genome and analyzed its transcriptomes under a range of growth conditions. A comparison with the genome and transcriptomes of the mountain pine beetle-associated pathogen Grosmannia clavigera highlights differences between a pathogen that colonizes and kills living pine trees and a saprophyte that colonizes wood and the inner bark of dead trees. RESULTS: We assembled a 33 Mbp genome in 45 scaffolds, and predicted approximately 8,884 genes. The genome size and gene content were similar to those of other ascomycetes. Despite having similar ecological niches, O. piceae and G. clavigera showed no large-scale synteny. We identified O. piceae genes involved in the biosynthesis of melanin, which causes wood discoloration and reduces the commercial value of wood products. We also identified genes and pathways involved in growth on simple carbon sources and in sapwood, O. piceae's natural substrate. Like the pathogen, the saprophyte is able to tolerate terpenes, which are a major class of pine tree defense compounds; unlike the pathogen, it cannot utilize monoterpenes as a carbon source. CONCLUSIONS: This work makes available the second annotated genome of a softwood ophiostomatoid fungus, and suggests that O. piceae's tolerance to terpenes may be due in part to these chemicals being removed from the cells by an ABC transporter that is highly induced by terpenes. The data generated will provide the research community with resources for work on host-vector-fungus interactions for wood-inhabiting, beetle-associated saprophytes and pathogens. PMID- 23725016 TI - E-cadherin autoantibody profile in patients with pemphigus vulgaris. AB - BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune skin blistering disease. The main targets of autoantibodies are the desmosomal proteins desmoglein (Dsg)3 and Dsg1. Anti-E-cadherin antibody is the second most frequent antibody found in pemphigus foliaceus (fogo selvagem), but the frequency in PV is unknown. OBJECTIVES: To determine the anti-E-cadherin antibody profile in the two major subtypes of PV: mucosal PV (mPV) and mucocutaneous PV (mcPV). METHODS: Sera from 80 patients with PV and 80 controls were tested. Patients with PV were subdivided into mPV (n = 18) and mcPV (n = 62). Samples were tested by E-cadherin, Dsg1 and Dsg3 enzyme-linked immunosorbent assays (ELISAs), and immunoprecipitation coupled with Western blotting (IP-WB). RESULTS: Both mPV and mcPV sera have antibodies against E-cadherin as demonstrated by ELISA and IP-WB. Both subtypes of PV have low levels of anti-E-cadherin antibodies, but significantly higher levels than healthy controls by ELISA (P < 0.0001). No difference exists in antibody levels between subgroups (P = 0.82). By IP-WB, 78% of mcPV sera reacted to E-cadherin, vs. 33% of mPV sera tested. Correlation analysis suggests a moderate correlation between anti-E-cadherin antibodies and Dsg1 antibodies (average r = 0.61), but no correlation with Dsg3 antibodies (average r = 0.19). Patients with mPV can have lower levels of Dsg1 antibodies compared with controls by ELISA (P < 0.0001). A few mPV sera also reacted to Dsg1 protein by IP-WB (17%). CONCLUSIONS: Anti-E cadherin antibodies are present in both major subtypes of PV. A moderate correlation exists between E-cadherin and Dsg1 antibodies. Patients with mPV can have low levels of both E-cadherin and Dsg1 antibodies. PMID- 23725017 TI - Poor reporting of randomized controlled trials in solid organ transplantation is indicative of a wider problem in surgery. PMID- 23725019 TI - Structural and water-holding characteristics of untreated and ensiled chicory root pulp. AB - Cell wall polysaccharides (CWPs) from chicory root pulp (CRP) and the effect of ensiling on CWP structure to reduce the water-holding capacity (WHC) were studied. Sequential extractions of CRP showed that hot water extraction solubilized arabinan-rich pectin and inulin, each representing 6% of all CRP sugars. A significant amount of pectic sugars (46%) rich in uronic acid from CRP was solubilized by chelating agents. Both dilute alkali extraction, which solubilized branched pectin (14% from CRP), and concentrated alkali extraction, which solubilized hemicellulose dominant in xyloglucans (2.5%) mostly of the XXXG type and mannan (0.9%), from CRP CWPs seemed to influence the WHC of CRP. Alkali insoluble residue (39% of CRP sugars) mainly comprised cellulose and some branched pectin (17% from CRP). Ensiling reduced the methyl esterification of pectin, caused degradation of homogalacturonan and rhamnogalacturonan, and possibly modified the xyloglucan, mannan, and glucan network, reducing the WHC from 6 mL/g to 3.4 mL/g. PMID- 23725018 TI - Ceramide mediates acute oxygen sensing in vascular tissues. AB - AIMS: A variety of vessels, such as resistance pulmonary arteries (PA) and fetoplacental arteries and the ductus arteriosus (DA) are specialized in sensing and responding to changes in oxygen tension. Despite opposite stimuli, normoxic DA contraction and hypoxic fetoplacental and PA vasoconstriction share some mechanistic features. Activation of neutral sphingomyelinase (nSMase) and subsequent ceramide production has been involved in hypoxic pulmonary vasoconstriction (HPV). Herein we aimed to study the possible role of nSMase derived ceramide as a common factor in the acute oxygen-sensing function of specialized vascular tissues. RESULTS: The nSMase inhibitor GW4869 and an anticeramide antibody reduced the hypoxic vasoconstriction in chicken PA and chorioallantoic arteries (CA) and the normoxic contraction of chicken DA. Incubation with interference RNA targeted to SMPD3 also inhibited HPV. Moreover, ceramide and reactive oxygen species production were increased by hypoxia in PA and by normoxia in DA. Either bacterial sphingomyelinase or ceramide mimicked the contractile responses of hypoxia in PA and CA and those of normoxia in the DA. Furthermore, ceramide inhibited voltage-gated potassium currents present in smooth muscle cells from PA and DA. Finally, the role of nSMase in acute oxygen sensing was also observed in human PA and DA. INNOVATION: These data provide evidence for the proposal that nSMase-derived ceramide is a critical player in acute oxygen-sensing in specialized vascular tissues. CONCLUSION: Our results indicate that an increase in ceramide generation is involved in the vasoconstrictor responses induced by two opposite stimuli, such as hypoxia (in PA and CA) and normoxia (in DA). PMID- 23725020 TI - Synthesis of indolines via Pd(II)-catalyzed amination of C-H bonds using PhI(OAc)2 as the bystanding oxidant. AB - The Pd(II)-catalyzed intramolecular C-H amination of 2-pyridinesulfonyl-protected phenethylamine derivatives has been achieved using PhI(OAc)2 as a bystanding oxidant, providing access to a variety of substituted indoline derivatives in good yields. The use of the 2-pyridinesulfonyl protecting group allows for facile deprotection following C-H functionalization. PMID- 23725021 TI - Last resort or roll of the die? Exploring the role of metaphors in cancer clinical trials education among medically underserved populations. AB - Improving communication about cancer clinical trials may help increase patients' understanding of medical research and their interest in participating. It is unfortunate that there is little empirical research to provide guidance on how to adapt clinical trial messages to maximize cultural sensitivity. This study examines (a) how medically underserved women conceptualize clinical trials by examining the language they use to describe them and (b) how this audience interprets metaphorical language used to explain randomization in the context of Phase III cancer clinical trials. The author conducted in-depth interviews and focus groups with 41 rural, low-income older women who either had been diagnosed with cancer or were caregivers for a person with cancer. The most commonly used lay metaphors for clinical trials had strong negative connotations and included treatment by trial and error, patients are guinea pigs, and treatment of last resort. Participants also expressed strong, unfavorable responses to conventional metaphors that equate randomization with the roll of a die or use other gambling language. Low-literacy definition approaches were unexpectedly problematic, suggesting the potential effectiveness of culturally grounded metaphors for communicating about clinical trials. Ethical implications of these findings for cancer communication are discussed. PMID- 23725022 TI - Pulsed ultrasound promotes melanoblast migration through upregulation of macrophage colony-stimulating factor/focal adhesion kinase autocrine signaling and paracrine mechanisms. AB - Repigmentation of vitiliginous lesions relies on the proliferation and migration of melanoblasts from hair follicles to the epidermis. Pulsed ultrasound has been demonstrated to have stimulatory effects on cell proliferation and migration and has been applied clinically to enhance tissue repair. To clarify the biologic effects and signaling mechanisms of pulsed ultrasound on melanoblast proliferation and migration, two melanoblast cell lines, the undifferentiated NCCmelb4 cells and the differentiated NCCmelan5 cells, were examined. We demonstrated that pulsed ultrasound increased cell migration in a dose-dependent manner without altering cell proliferation. Pulsed ultrasound enhanced autocrine secretion of macrophage colony-stimulating factor (M-CSF), which subsequently activated the focal adhesion kinase (FAK) pathway to promote melanoblast migration. Furthermore, conditioned medium from mouse embryonic fibroblasts NIH 3T3 and primary human keratinocytes treated with pulsed ultrasound could stimulate melanoblast migration through a paracrine effect. Our results provide a novel mechanism to promote migration of melanoblasts by pulsed ultrasound stimulation. PMID- 23725023 TI - X-ray photoemission spectroscopy investigation of the interaction between 4 mercaptopyridine and the anatase TiO2 surface. AB - In polymer-metal oxide hybrid solar cells, an extremely careful engineering of the interface is required to ensure good device performances. Recently, very promising results have been obtained by functionalizing titanium dioxide (TiO2) by means of 4-mercaptopyridine (4-MPy) molecules, showing the beneficial effect of these molecules on the interface morphology. This study investigates the nature of the interaction of 4-MPy molecules with the TiO2 surface by means of X ray photoemission spectroscopy. In order to mimic the device processing conditions, our analysis is carried out on molecules adsorbed from solution on a nanocrystalline surface. According to our analysis, 4-MPy molecules (C5H5NS) are likely bound with the oxide through the nitrogen atom. The bonding precedes either via a covalent interaction with Lewis surface sites, or via hydrogen mediation, possibly in the form of hydrogen bonds. Interestingly, in the latter case, we also observe strong changes in the spectroscopic features attributed to the thiol group. PMID- 23725024 TI - A one step real-time RT-PCR assay for the quantitation of Wheat yellow mosaic virus (WYMV). AB - BACKGROUND: Wheat yellow mosaic virus (WYMV) is an important pathogen in China and other countries. It is the member of the genus Bymovirus and transmitted primarily by Polymyxa graminis. The incidence of wheat infections in endemic areas has risen in recent years. Prompt and dependable identification of WYMV is a critical component of response to suspect cases. METHODS: In this study, a one step real-time RT-PCR, followed by standard curve analysis for the detection and identification of WYMV, was developed. Two reference genes, 18s RNA and beta actin were selected in order to adjust the veracity of the real-time RT-PCR assay. RESULTS: We developed a one-step Taqman-based real-time quantitative RT PCR (RT-qPCR) assay targeting the conserved region of the 879 bp long full-length WYMV coat protein gene. The accuracy of normalized data was analyzed along with appropriate internal control genes: beta-actin and 18s rRNA which were included in detecting of WYMV-infected wheat leaf tissues. The detectable end point sensitivity in RT-qPCR assay was reaching the minimum limit of the quantitative assay and the measurable copy numbers were about 30 at 106-fold dilution of total RNA. This value was close to 104-fold more sensitive than that of indirect enzyme linked immunosorbent assay. More positive samples were detected by RT-qPCR assay than gel-based RT-PCR when detecting the suspected samples collected from 8 regions of China. Based on presented results, RT-qPCR will provide a valuable method for the quantitative detection of WYMV. CONCLUSIONS: The Taqman-based RT qPCR assay is a faster, simpler, more sensitive and less expensive procedure for detection and quantification of WYMV than other currently used methods. PMID- 23725025 TI - The integrity of social psychology turns on the free will dilemma: reply to Baumeister, Vonasch, and Bargh. AB - The observation that while Roy Baumeister does not accept that there is a strong link between belief in free choice and malign effects on the weak and unlucky, the Baumeister and Vonasch study newly evidences discrimination against the poor and unlucky through belief in free choice. Baumeister also acknowledges that institutional-level injustice is exacerbated by belief in free will. Bargh seems to acknowledge Baumeister's inconsistency, but introduces a different fallacy when he suggests the debate is not really about freedom of choice. Miles argues that even for a self-styled 'compatibilist' like John Bargh, this debate is all about free choice. PMID- 23725026 TI - Evaluation of healing following tooth extraction with ridge preservation using cortical versus cancellous freeze-dried bone allograft. AB - BACKGROUND: The objective of this study is to compare histologic and clinical healing following tooth extraction and ridge preservation with either cortical or cancellous freeze-dried bone allograft (FDBA) in non-molar extraction sockets. METHODS: Forty patients requiring implant placement were enrolled, with 20 patients randomly assigned to each group (cortical versus cancellous FDBA). All of the allograft materials were obtained from the same donor to control for variability between donors and processing. Patients returned after 17 to 21 weeks (average: 18.2 weeks), and a 2-mm-diameter core biopsy was obtained before implant placement. Histomorphometric analysis was performed to determine percentage of new bone formation, residual graft material, and non-mineralized connective tissue (CT)/other material. Clinical measurements of ridge dimensions were taken at the time of tooth extraction and again at implant placement. RESULTS: There was no significant difference in new bone formation between the cortical and cancellous FDBA groups (P = 0.857). A significantly greater percentage of residual graft material was detected in the cortical FDBA group compared with the cancellous FDBA group (P = 0.019). A significantly greater percentage of non-mineralized CT/other material was found in the cancellous FDBA group compared with the cortical FDBA group (P = 0.040). The only significant clinical difference between groups was a greater loss of lingual ridge height in the cancellous group. CONCLUSIONS: This is the first reported study to compare the histologic changes following tooth extraction with ridge preservation in humans using cortical versus cancellous FDBA. There were no differences in the percentage of new bone formation between the groups. PMID- 23725027 TI - The role of smoking and gingival crevicular fluid markers on coronally advanced flap outcomes. AB - BACKGROUND: This study evaluates possible effects of smoking on the following: 1) biochemical content in gingival crevicular fluid (GCF) samples from sites of gingival recession and saliva; and 2) clinical outcomes of coronally advanced flap (CAF) for root coverage. METHODS: Eighteen defects in 15 patients were included in each of the smoker and non-smoker groups. Baseline cotinine, basic fibroblast growth factor, vascular endothelial growth factor, platelet-derived growth factor, interleukin (IL)-8, IL-10, IL-12, tumor necrosis factor-alpha, matrix metalloproteinase (MMP)-8, MMP-9, and plasminogen activator inhibitor-1 levels were determined in GCF and saliva samples. CAF with microsurgery technique was applied. Plaque index, papilla bleeding index, recession depth (RD), recession width (RW), and root surface area were evaluated at baseline and postoperative months 1, 3, and 6. Probing depth, clinical attachment level (CAL), and keratinized gingival width (KGW) was recorded at baseline and month 6. Percentage of root coverage and complete root coverage were calculated at postoperative months 1, 3, and 6. RESULTS: All biochemical parameters were similar in the two groups apart from the definite difference in salivary cotinine concentrations (P = 0.000). Compared with the baseline values, RD, RW, CAL, and root surface area decreased, and KGW increased, with no significant difference between the study groups. CAL gain, percentage of root coverage, and complete root-coverage rates were similar in the study groups. CONCLUSION: Similar baseline biochemical data and comparably high success rates of root coverage with CAF in systemically and periodontally healthy smokers versus non-smokers suggest lack of adverse effects of smoking on clinical outcomes. PMID- 23725028 TI - An evidenced-based scoring index to determine the periodontal prognosis on molars. AB - BACKGROUND: This retrospective study evaluates and assigns scores to six prognostic factors and derives a quantitative scoring index used to determine the periodontal prognosis on molar teeth. METHODS: Data were gathered on 816 molars in 102 patients with moderate-to-severe periodontitis. The six factors evaluated (age, probing depth, mobility, furcation involvement, smoking, and molar type) were assigned a numeric score based on statistical analysis. The sum of the scores for all factors was used to determine the prognosis score for each molar. Only patients with all first and second molars at the initial examination qualified for the study. All patients were evaluated a minimum of 15 years after treatment. RESULTS: The post-treatment time ranged from 15 to 40 years and averaged 24 years. When the study was completed, 639 molars survived (78%), and, of those surviving molars, 588 survived and were periodontally healthy (92%). In molars with lower scores (scores 1-3), the 15-year survival rates ranged from 98% to 96%. In molars with middle scores (scores 4-6), the 15-year survival rates ranged from 95% to 90%, and, for molars with higher scores (scores 7-10), the survival rates ranged from 86% to 67%. CONCLUSION: The present results indicate that the periodontal prognosis of molars diagnosed with moderate-to-severe periodontitis can be calculated using an evidence-based scoring index. PMID- 23725029 TI - Serum antibody responses to periodontal microbiota in chronic and aggressive periodontitis: a postulate revisited. AB - BACKGROUND: The authors revisited the 1999 International Workshop postulate of robust serum antibody responses to infecting agents in localized aggressive periodontitis (LAgP) and weak responses in generalized aggressive periodontitis (GAgP). Antibody responses were further examined in localized and generalized chronic periodontitis (LCP and GCP). METHODS: The study includes 119 patients (60 males and 59 females, aged 11 to 76 years), 18 with LAgP, 37 with GAgP, 37 with LCP, and 27 with GCP. Multiple subgingival plaque samples/patient (1,057 in total) were analyzed with respect to 11 bacterial species using checkerboard DNA DNA hybridizations, and serum immunoglobulin (Ig)G levels were measured against the same bacteria using checkerboard immunoblotting. Further, infection ratios (antibody level over the average bacterial colonization by the homologous species) were computed for each patient. Comparisons of bacterial colonization, serum IgG levels, and infection ratios were made across the diagnostic categories using multivariable linear regression models adjusting for age and race/ethnicity. RESULTS: There were no statistically significant differences in serum IgG levels to Aggregatibacter actinomycetemcomitans among the four diagnostic categories. IgG levels to several species, including Porphyromonas gingivalis, Treponema denticola, and Campylobacter rectus, were highest in patients with GAgP and significantly different from LCP and GCP, but not from LAgP. Comparisons based on infection ratios showed no statistically significant differences for any species between GAgP and LAgP. CONCLUSION: This study provides evidence against the 1999 Workshop's postulate of weak serum antibody responses in patients with GAgP and shows that serum IgG responses in GAgP are comparable to those in LAgP, but higher than in GCP or LCP for several species. PMID- 23725030 TI - Periodontitis in patients with coronary artery disease: an 8-year follow-up. AB - BACKGROUND: This study examines whether preceding assessment of periodontal status in patients with established coronary artery disease (CAD) can predict future CAD endpoints (myocardial infarction, new revascularization procedure, or CAD-related death) during 8-year follow-up and whether the changes in periodontal status over time differ in patients with CAD compared with healthy controls. METHODS: In 2003, periodontal status was examined in 161 patients with CAD who underwent percutaneous coronary intervention or coronary artery bypass graft due to significant stenosis in the coronary arteries and 162 controls without CAD. Eight years later, 126 patients with CAD (102 males and 24 females, mean age: 68 +/- 8.9 years) and 121 controls (101 males and 20 females, mean age: 69 +/- 9.0 years) were reexamined periodontally. A standard classification of periodontal disease in three groups (mild, moderate, and severe) was used. CAD endpoints during follow-up were obtained by review of medical records. CAD as cause of death was confirmed from the Swedish Cause of Death Register. RESULTS: No significant differences were found among patients with CAD, with or without CAD related endpoints at 8-year follow-up, and severity of periodontitis at baseline (P = 0.7). CAD did not influence the incidence or severity of periodontitis. Significant differences were found at the final examination in periodontitis prevalence and severity (P = 0.001), number of teeth (P = 0.006), probing depth 4 to 6 mm (P = 0.016), bleeding on probing (P = 0.001), and radiographic bone level (P = 0.042) between CAD patients and controls, all in favor of controls. CONCLUSIONS: The study results did not show a significant association during 8 years among CAD endpoints and periodontal status at baseline. The progression of periodontitis was low in both groups, although the higher proportion of individuals with severe periodontitis among patients with CAD compared with controls remained unchanged over the 8-year follow-up. Further long-term prospective studies are needed to show whether periodontitis can be considered a risk or prognostic factor for CAD, in terms of endpoints including myocardial infarction, new revascularization procedure, and CAD-related death. PMID- 23725031 TI - A prospective evaluation of the temporal matrix metalloproteinase response after severe traumatic brain injury in humans. AB - Abstract Accumulating pre-clinical data suggests that matrix metalloproteinase (MMP) expression plays a critical role in the pathophysiology of secondary brain injury. We conducted a prospective multimodal monitoring study in order to characterize the temporal MMP response after severe traumatic brain injury (TBI) in eight critically ill humans and its relationship with outcomes. High-cutoff, cerebral microdialysis (n=8); external ventricular drainage (n=3); and arterial and jugular venous bulb catheters were used to collect microdialysate, cerebrospinal fluid, and arterial and jugular bulb blood over 6 days. Levels of MMP-8 and -9 were initially high in microdialysate and then gradually declined over time. After these MMPs decreased, a spike in the microdialysate levels of MMP-2 and -3 occurred, followed by a gradual rise in the microdialysate concentration of MMP-7. Use of generalized estimating equations suggested that MMP-8 concentration in microdialysate was associated with mortality (p=0.019) and neurological outcome at hospital discharge (p=0.013). Moreover, the mean microdialysate concentration of MMP-8 was 2.4-fold higher among those who died after severe TBI than in those who survived. Mean microdialysate levels of MMP-8 also rose with increasing intracranial pressure (ICP), whereas those of MMP-7 decreased with increasing cerebral perfusion pressure (CPP). Significant changes in the mean microdialysate concentrations of MMP-1, -2, -3, and -9 and MMP-1, -2, -3, -7, and -9 also occurred with increases in microdialysate glucose and the lactate/pyruvate ratio, respectively. These results imply that monitoring of MMPs following severe TBI in humans is feasible, and that their expression may be associated with clinical outcomes, ICP, CPP, and cerebral metabolism. PMID- 23725032 TI - Signal transducer and activator of transcription (STAT)-3 regulates microRNA gene expression in chronic lymphocytic leukemia cells. AB - BACKGROUNDS: Approximately 1,000 microRNAs (miRs) are present in the human genome; however, little is known about the regulation of miR transcription. Because miR levels are deregulated in chronic lymphocytic leukemia (CLL) and signal transducer and activator of transcription (STAT)-3 is constitutively activated in CLL, we sought to determine whether STAT3 affects the transcription of miR genes in CLL cells. METHODS: We used publically available data from the ENCODE project to identify putative STAT3 binding sites in the promoters of miR genes. Then we transfected CLL cells with STAT3-shRNA or with an empty vector, and to determine which miRs are differentially expressed, we used a miR microarray approach followed by validation of the microarray results for 6 miRs using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: We identified putative STAT3 binding sites in 160 promoter regions of 200 miRs, including miR-21, miR-29, and miR-155, whose levels have been reported to be upregulated in CLL. Levels of 72 miRs were downregulated (n = 63) or upregulated (n = 9). qRT-PCR confirmed the array data in 5 of 6 miRs. CONCLUSIONS: The presence of activated STAT3 has a profound effect on miR expression in CLL cells. PMID- 23725033 TI - Mediated electrochemistry of nitrate reductase from Arabidopsis thaliana. AB - Herein we report the mediated electrocatalytic voltammetry of the plant molybdoenzyme nitrate reductase (NR) from Arabidopsis thaliana using the established truncated molybdenum-heme fragment at a glassy carbon (GC) electrode. Methyl viologen (MV), benzyl viologen (BV), and anthraquinone-2-sulfonic acid (AQ) are employed as effective artificial electron transfer partners for NR, differing in redox potential over a range of about 220 mV and delivering different reductive driving forces to the enzyme. Nitrate is reduced at the Mo active site of NR, yielding the oxidized form of the enzyme, which is reactivated by the electro-reduced form of the mediator. Digital simulation was performed using a single set of enzyme dependent parameters for all catalytic voltammetry obtained under different sweep rates and various substrate or mediator concentrations. The kinetic constants from digital simulation provide new insight into the kinetics of the NR catalytic mechanism. PMID- 23725034 TI - Prosthetic rehabilitation of a cleidocranial dysplasia patient with vertical maxillofacial deficiency: a clinical report. AB - Cleidocranial dysplasia (CCD) is a rare congenital disorder characterized by skeletal and dental anomalies. This clinical report describes the prosthodontic approach to treating a CCD patient who presented with decreased facial height and relative mandibular protrusion due to maxillary hypoplasia after orthodontic treatment. Functional and esthetic rehabilitation was achieved using telescopic detachable prostheses in the maxilla and osseointegrated implants and metal ceramic fixed dental prostheses in the mandible. These treatment approaches precluded the need for orthognathic surgical correction and presented a favorable prognosis during the 5-year observation period. PMID- 23725036 TI - Early antibiotic exposure and body mass index in children born small for gestational age. PMID- 23725035 TI - Expression and efficient secretion of a functional chitinase from Chromobacterium violaceum in Escherichia coli. AB - BACKGROUND: Chromobacterium violaceum is a free-living beta-proteobacterium found in tropical and subtropical regions. The genomic sequencing of C. violaceum ATCC 12472 has revealed many genes that underpin its adaptability to diverse ecosystems. Moreover, C. violaceum genes with potential applications in industry, medicine and agriculture have also been identified, such as those encoding chitinases. However, none of the chitinase genes of the ATCC 12472 strain have been subjected to experimental validation. Chitinases (EC 3.2.1.14) hydrolyze the beta-(1,4) linkages in chitin, an abundant biopolymer found in arthropods, mollusks and fungi. These enzymes are of great biotechnological interest as potential biocontrol agents against pests and pathogens. This work aimed to experimentally validate one of the chitinases from C. violaceum. RESULTS: The open reading frame (ORF) CV2935 of C. violaceum ATCC 12472 encodes a protein (439 residues) that is composed of a signal peptide, a chitin-binding domain, a linker region, and a C-terminal catalytic domain belonging to family 18 of the glycoside hydrolases. The ORF was amplified by PCR and cloned into the expression vector pET303/CT-His. High levels of chitinolytic activity were detected in the cell free culture supernatant of E. coli BL21(DE3) cells harboring the recombinant plasmid and induced with IPTG. The secreted recombinant protein was purified by affinity chromatography on a chitin matrix and showed an apparent molecular mass of 43.8 kDa, as estimated by denaturing polyacrylamide gel electrophoresis. N terminal sequencing confirmed the proper removal of the native signal peptide during the secretion of the recombinant product. The enzyme was able to hydrolyze colloidal chitin and the synthetic substrates p-nitrophenyl-beta-D-N,N' diacetylchitobiose and p-nitrophenyl-beta-D-N,N',N"-triacetylchitotriose. The optimum pH for its activity was 5.0, and the enzyme retained ~32% of its activity when heated to 60 degrees C for 30 min. CONCLUSIONS: A C. violaceum chitinase was expressed in E. coli and purified by affinity chromatography on a chitin matrix. The secretion of the recombinant protein into the culture medium was directed by its native signal peptide. The mature enzyme was able to hydrolyze colloidal chitin and synthetic substrates. This newly identified signal peptide is a promising secretion factor that should be further investigated in future studies, aiming to demonstrate its usefulness as an alternative tool for the extracellular production of recombinant proteins in E. coli. PMID- 23725037 TI - Polymorphism in the HMOX1 gene is associated with high levels of fetal hemoglobin in Brazilian patients with sickle cell anemia. AB - The aim of this study was to investigate the association between three polymorphisms involved in the oxidative stress pathway and fetal hemoglobin (Hb F) levels in patients with sickle cell anemia in a Brazilian population. One hundred and seven patients with sickle cell anemia were recruited for genomic DNA extraction. The levels of Hb F, sex and age were evaluated. Three polymorphisms, rs4673:T>C and rs9932581:G>A in the CYBA gene and rs2071746:A>T in the HMOX1 gene, were identified through direct sequencing. Hb F levels were not associated with sex, age, or the polymorphisms rs4673:T>C and rs9932581:G>A. However, the TT genotype of the rs2071746:A>T polymorphism was associated with increased levels of Hb F (p value = 0.0131). We observed an association between the TT genotype of the rs2071746:A>T polymorphism, present in the HMOX1 gene, and increased levels of Hb F, indicating the presence of a new marker related to Hb F levels in sickle cell anemia patients. PMID- 23725038 TI - Cationic gemini surfactant-assisted synthesis of hollow Au nanostructures by stepwise reductions. AB - A novel synthetic approach was developed for creating versatile hollow Au nanostructures by stepwise reductions of Au(III) upon the use of cationic gemini surfactant hexamethylene-1,6-bis(dodecyl dimethylammonium bromide) (C12C6C12Br2) as a template agent. It was observed that the Au(I) ions obtained from the reduction of Au(III) by ascorbic acid can assist the gemini surfactant to form vesicles, capsule-like, and tube-like aggregates that subsequently act as soft templates for hollow Au nanostructures upon further reduction of Au(I) to Au(0) by NaBH4. It was demonstrated that the combination of C12C6C12Br2 and Au(I) plays a key role in regulating the structure of the hollow precursors not only because C12C6C12Br2 has a stronger aggregation ability in comparison with its single chain counterpart but also because the electrostatic repulsion between head groups of C12C6C12Br2 is greatly weakened after Au(III) is converted to Au(I), which is in favor of the construction of vesicles, capsule-like, and tube-like aggregates. Compared with solid Au nanospheres, the resultant hollow nanostructures exhibit enhanced electrocatalytic activities in methanol oxidation, following the order of elongated nanocapsule > nanocapsule > nanosphere. Benefiting from balanced interactions between the gemini surfactant and Au(I), this soft-template method may present a facile and versatile approach for the controlled synthesis of Au nanostructures potentially useful for fuel cells and other Au nanodevices. PMID- 23725039 TI - Primary hypothyroidism with growth failure and pituitary pseudotumor in a 13-year old female: a case report. AB - INTRODUCTION: Primary hypothyroidism is a well-known cause of poor linear growth in children. A rare finding with profound or long-standing disease is anterior pituitary enlargement (pituitary pseudotumor). This case highlights this uncommon finding, discusses clinical situations in which gradual dose escalation of levothyroxine may be advisable and reviews adjuvant therapies that have been previously attempted to improve final height in the setting of profound hypothyroidism. CASE PRESENTATION: We report the case of a 13-year-old Hispanic girl initially evaluated for poor linear growth and delayed puberty, and found to have pituitary enlargement secondary to profound primary hypothyroidism. Treatment with progressive doses of levothyroxine normalized her symptoms and led to complete resolution of her pituitary findings, but she then rapidly progressed through puberty, achieving an adult height of only 142cm, significantly below her calculated mid-parental height. CONCLUSIONS: In cases of severe primary hypothyroidism with prolonged elevation of thyroid-stimulating hormone and pituitary pseudotumor, gradual replacement of thyroid hormone with slowly escalating doses of levothyroxine may be beneficial to prevent complications of therapy. Early recognition and treatment of hypothyroidism during childhood is essential for normal growth, as final height is invariably compromised in children with prolonged disease. Additional study is needed to determine the potential beneficial effects of gonadotropin-releasing hormone agonist and recombinant human growth hormone treatment in this setting. PMID- 23725040 TI - High-throughput genotyping of wheat-barley amphiploids utilising diversity array technology (DArT). AB - BACKGROUND: Hordeum chilense, a native South American diploid wild barley, is one of the species of the genus Hordeum with a high potential for cereal breeding purposes, given its high crossability with other members of the Triticeae tribe. Hexaploid tritordeum (*Tritordeum Ascherson et Graebner, 2n=6*=42, AABBH(ch)H(ch)) is the fertile amphiploid obtained after chromosome doubling of hybrids between Hordeum chilense and durum wheat. Approaches used in the improvement of this crop have included crosses with hexaploid wheat to promote D/H(ch) chromosome substitutions. While this approach has been successful as was the case with triticale, it has also complicated the genetic composition of the breeding materials. Until now tritordeum lines were analyzed based on molecular cytogenetic techniques and screening with a small set of DNA markers. However, the recent development of DArT markers in H. chilense offers new possibilities to screen large number of accessions more efficiently. RESULTS: Here, we have applied DArT markers to genotype composition in forty-six accessions of hexaploid tritordeum originating from different stages of tritordeum breeding program and to H. chilense-wheat chromosome addition lines to allow their physical mapping. Diversity analyses were conducted including dendrogram construction, principal component analysis and structure inference. Euploid and substituted tritordeums were clearly discriminated independently of the method used. However, dendrogram and Structure analyses allowed the clearest discrimination among substituted tritordeums. The physically mapped markers allowed identifying these groups as substituted tritordeums carrying the following disomic substitutions (DS): DS1D (1H(ch)), DS2D (2H(ch)), DS5D (5H(ch)), DS6D (6H(ch)) and the double substitution DS2D (2H(ch)), DS5D (5H(ch)). These results were validated using chromosome specific EST and SSR markers and GISH analysis. CONCLUSION: In conclusion, DArT markers have proved to be very useful to detect chromosome substitutions in the tritordeum breeding program and thus they are expected to be equally useful to detect translocations both in the tritordeum breeding program and in the transference of H. chilense genetic material in wheat breeding programs. PMID- 23725041 TI - Dynamic analysis of global copper flows. Global stocks, postconsumer material flows, recycling indicators, and uncertainty evaluation. AB - We present a dynamic model of global copper stocks and flows which allows a detailed analysis of recycling efficiencies, copper stocks in use, and dissipated and landfilled copper. The model is based on historical mining and refined copper production data (1910-2010) enhanced by a unique data set of recent global semifinished goods production and copper end-use sectors provided by the copper industry. To enable the consistency of the simulated copper life cycle in terms of a closed mass balance, particularly the matching of recycled metal flows to reported historical annual production data, a method was developed to estimate the yearly global collection rates of end-of-life (postconsumer) scrap. Based on this method, we provide estimates of 8 different recycling indicators over time. The main indicator for the efficiency of global copper recycling from end-of-life (EoL) scrap--the EoL recycling rate--was estimated to be 45% on average, +/- 5% (one standard deviation) due to uncertainty and variability over time in the period 2000-2010. As uncertainties of specific input data--mainly concerning assumptions on end-use lifetimes and their distribution--are high, a sensitivity analysis with regard to the effect of uncertainties in the input data on the calculated recycling indicators was performed. The sensitivity analysis included a stochastic (Monte Carlo) uncertainty evaluation with 10(5) simulation runs. PMID- 23725042 TI - Biological parameters determining the clinical outcome of autologous cultures of limbal stem cells. AB - AIM: Limbal cultures restore the corneal epithelium in patients with ocular burns. We investigated the biological parameters instrumental for their clinical success. METHODS: We report a long-term multicenter prospective study on 152 patients carrying corneal destruction due to severe ocular burns, treated with autologous limbal cells cultured on fibrin and clinical-grade 3T3-J2 feeder cells. Clinical results were statistically evaluated both by parametric and nonparametric methods. RESULTS: Clinical outcomes were scored as full success, partial success and failure in 66.05, 19.14 and 14.81% of eyes, respectively. The total number of clonogenic cells, colony size, growth rate and presence of conjunctival cells could not predict clinical results. Instead, the clinical data provided conclusive evidence that graft quality and likelihood of a successful outcome rely on an accurate evaluation of the number of stem cells detected before transplantation as holoclones expressing high levels of the p63 transcription factor. No adverse effects related to the feeder layer have been observed and the regenerated epithelium was completely devoid of any 3T3-J2 contamination. CONCLUSION: Cultures of limbal stem cells can be safely used to successfully treat massive destruction of the human cornea. We emphasize the importance of a discipline for defining the suitability and the quality of cultured epithelial grafts, which are relevant to the future clinical use of any cultured cell type. PMID- 23725043 TI - Macrophages and angiogenesis in rheumatic diseases. AB - Angiogenesis plays a key role in several rheumatic diseases, including rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, systemic sclerosis, systemic lupus erythematosus, and vasculitides. An imbalance between angiogenic inducers and inhibitors seems to be a critical factor in pathogenesis of these diseases. Macrophages promote angiogenesis during rheumatoid arthritis. In addition, macrophages can produce a variety of pro-angiogenic factors that have been associated with the angiogenic response occurring during other rheumatic diseases. Lastly, macrophages could be a target in the treatment of rheumatoid arthritis and other rheumatic diseases. Nevertheless, further studies are needed to better elucidate the exact role of macrophage in angiogenesis in these diseases. PMID- 23725045 TI - Temporary intraoperative porto-caval shunt: a more complete set of data is needed. PMID- 23725044 TI - Presence of acyl-homoserine lactones in 57 members of the Vibrionaceae family. AB - AIMS: The aim of this study was to use a sensitive method to screen and quantify 57 Vibrionaceae strains for the production of acyl-homoserine lactones (AHLs) and map the resulting AHL profiles onto a host phylogeny. METHODS AND RESULTS: We used a high-performance liquid chromatography-tandem mass spectrometry (HPLC MS/MS) protocol to measure AHLs in spent media after bacterial growth. First, the presence/absence of AHLs (qualitative analysis) was measured to choose internal standard for subsequent quantitative AHL measurements. We screened 57 strains from three genera (Aliivibrio, Photobacterium and Vibrio) of the same family (i.e. Vibrionaceae). Our results show that about half of the isolates produced multiple AHLs, typically at 25-5000 nmol l(-1) . CONCLUSIONS: This work shows that production of AHL quorum sensing signals is found widespread among Vibrionaceae bacteria and that closely related strains typically produce similar AHL profiles. SIGNIFICANCE AND IMPACT OF THE STUDY: The AHL detection protocol presented in this study can be applied to a broad range of bacterial samples and may contribute to a wider mapping of AHL production in bacteria, for example, in clinically relevant strains. PMID- 23725046 TI - Fasting induces nuclear factor E2-related factor 2 and ATP-binding Cassette transporters via protein kinase A and Sirtuin-1 in mouse and human. AB - AIMS: The purpose of this study was to determine whether 3'-5'-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and Sirtuin-1 (SIRT1) dependent mechanisms modulate ATP-binding Cassette (ABC) transport protein expression. ABC transport proteins (ABCC2-4) are essential for chemical elimination from hepatocytes and biliary excretion. Nuclear factor-E2 related-factor 2 (NRF2) is a transcription factor that mediates ABCC induction in response to chemical inducers and liver injury. However, a role for NRF2 in the regulation of transporter expression in nonchemical models of liver perturbation is largely undescribed. RESULTS: Here we show that fasting increased NRF2 target gene expression through NRF2- and SIRT1-dependent mechanisms. In intact mouse liver, fasting induces NRF2 target gene expression by at least 1.5 to 5-fold. In mouse and human hepatocytes, treatment with 8-Bromoadenosine-cAMP, a cAMP analogue, increased NRF2 target gene expression and antioxidant response element activity, which was decreased by the PKA inhibitor, H-89. Moreover, fasting induced NRF2 target gene expression was decreased in liver and hepatocytes of SIRT1 liver specific null mice and NRF2-null mice. Lastly, NRF2 and SIRT1 were recruited to MAREs and Antioxidant Response Elements (AREs) in the human ABCC2 promoter. INNOVATION: Oxidative stress mediated NRF2 activation is well described, yet the influence of basic metabolic processes on NRF2 activation is just emerging. CONCLUSION: The current data point toward a novel role of nutrient status in regulation of NRF2 activity and the antioxidant response, and indicates that cAMP/PKA and SIRT1 are upstream regulators for fasting-induced activation of the NRF2-ARE pathway. PMID- 23725047 TI - Chikungunya virus with E1-A226V mutation causing two outbreaks in 2010, Guangdong, China. AB - BACKGROUND: CHIKV is a mosquito-borne emerging pathogen that has a major health impact in humans in tropical zones around the globe. A new variant of the virus, E1-A226V caused a large outbreak in the Indian Ocean islands and India from 2004 2007. CHIKV outbreak was initially reported in Dongguan region of Guangdong in 2010 in China, another smaller CHIKV outbreak was found in Yangjiang region of Guangdong two weeks later. The viral agent causing the two outbreaks was inferred to be the new E1-A226V variant and Yangjiang CHIKV might be introduced from Dongguan. To confirm the hypothesis and determine the origin of CHIKV causing the outbreaks, we described Yangjiang outbreak in this study, and the molecular characterization of CHIKV from Yangjiang and Dongguang outbreaks were analyzed. RESULTS: 27 clinical cases of CHIK fever were reported in outbreak in Yangjiang region. Sera sample from 12 clinical cases were collected from the outbreak, and nucleic acid and antibody tests for CHIKV were performed using Real-time RT-PCR and indirect immunofluorescence. Positive samples of Real-time RT-PCR were subjected to viral isolation. The results showed 3/12 samples positive for Real time RT-PCR. 7/12 and 4/12 samples were positive for IgM and IgG against CHIKV respectively, two virus strains were isolated. Four viral genomes from Dongguan and Yangjiang were sequenced, characterized and phylogeneticly analyzed. Phylogenetic analysis revealed that the four seqeunced viruses had the closest relationship (99.4~99.6% identify) with the Singapore 2008 isolate belonging to the Indian ocean clade. A common mutation at the site of the E1-A226V was observed among four viruses. Four and three aa substitutions were detected in the CHIKV sequence from the Dongguan and Yangjiang outbreak strains respectively. CONCLUSION: CHIKV with an E1-A226V mutation that originated from Southeast Asia isolates caused two outbreaks in China in 2010, and originated from two different infectious sources. PMID- 23725048 TI - Mitogen-activated protein kinase pathways in osteoblasts. AB - Mitogen-activated protein kinases (MAPKs) are ancient signal transducers well characterized as mediators of inflammation and neoplastic transformation. Recent work has expanded our understanding of their developmental functions, particularly in the regulation of bone mass via control of osteoblast differentiation. Here, we review the functions of MAPK pathways in osteoblasts, including a consideration of MAPK substrates. In particular, MAPKs function to regulate the key transcriptional mediators of osteoblast differentiation, with ERK and p38 MAPKs phosphorylating RUNX2, the master regulator of osteoblast differentiation. ERK also activates RSK2, which in turn phosphorylates ATF4, a transcriptional regulator of late-stage osteoblast synthetic functions. The MAP3Ks and MAP2Ks upstream of MAPKs have also been investigated, and significant differences have been found in the wiring of MAPK pathways in osteoblasts relative to other tissues. Thus, the investigation of MAPKs in osteoblasts has both revealed critical mechanisms for the maintenance of bone mass and added to our understanding of how the individual components of MAPK pathways function in concert in a complex in vivo system. PMID- 23725049 TI - Kinetic study of hydroxytyrosol oxidation and its related compounds by Red Globe grape polyphenol oxidase. AB - Red Globe grape polyphenol oxidase, partially purified using phase partitioning with Triton-X114, was used to study the oxidation of hydroxytytosol (HT) and its related compounds tyrosol (TS), tyrosol acetate (TSA), and hydroxytyrosol acetate (HTA). The enzyme showed activity toward both monophenols (monophenolase activity) and o-diphenols (diphenolase activity) with a pH optimum (pH 6.5) that was independent of the phenol used. However, the optimal temperature for diphenolase activity was substrate-dependent, with a broad optimum of 25-65 degrees C for HT, compared with the maximum obtained for HTA (40 degrees C). Monophenolase activity showed the typical lag period, which was modulated by pH, substrate and enzyme concentrations, and the presence of catalytic amounts of o diphenols. When the catalytic power (Vmax/K(M)) was determined for both activities, higher values were observed for o-diphenols than for monophenols: 9 fold higher for the HT/TS pair and 4-fold higher for HTA/TSA pair. Surprisingly, this ratio was equally higher for TSA (2.2-fold) compared with that of TS, whereas no such effect was observed for o-diphenols. This higher efficiency of TSA could be related to its greater hydrophobicity. Acetyl modification of these phenols not only changes the kinetic parameters of the enzyme but also affects their antioxidant activity (ORAC-FL assays), which is lower in HTA than in HT. PMID- 23725050 TI - Immunologic hypo- or non-responder in natural dengue virus infection. AB - Serologically defined primary dengue virus infection and/or subsequent homologous serotype infection is known to be associated with less severe disease as compared with secondary subsequent heterologous serotype infection. In geographical locales of high dengue endemicity, almost all individuals in the population are infected at some point in time and should therefore are at high risk of secondary infection. Interestingly, dengue viremia in healthy blood donors whose sera apparently lack detectable levels of specific antibody to dengue viral antigens has been reported. The incidence rate of potential immunologic hypo- or non responders following natural primary dengue virus infection in dengue endemic regions, who do become immune responders only after repeated exposure, has not been described. These are the patients who may be diagnosed as primary infection in the subsequent infection, but actually are secondary infection. This concept has important implications with regards to the hypothesis of immunological enhancement of dengue pathogenesis, which has largely been advanced based on empirical observations and/or from in vitro experimental assays. The fact that dengue naive travelers can suffer from severe dengue upon primary exposure while visiting dengue endemic countries underscores one of the major problems in explaining the role of immune enhancement in the pathogenesis of severe dengue virus infection. This evidence suggests that the mechanism(s) leading to severe dengue may not be associated with pre-existing enhancing antibody. Consequently, we propose a new paradigm for dengue virus infection classification. These include a) patients with naive primary infection, b) those that are serologically defined primary in dengue endemic zones and c) those who are serologically defined secondary dengue virus infection. We submit that clarity with regards to such definitions may help facilitate the delineation of the potential mechanisms of severe dengue virus infection. PMID- 23725051 TI - Perceived message sensation value and psychological reactance: a test of the dominant thought disruption hypothesis. AB - The present study tests to see whether perceived message sensation value reduces psychological reactance within the context of anti-marijuana ads for television. After controlling for sensation seeking, biological sex, and marijuana use, the results indicate that message novelty is negatively associated with a freedom threat, whereas dramatic impact and emotional arousal were not associated with the antecedent to reactance. Results support the use of novel messages in future ads while at the same time offer an explanation to the challenges involved in creating effective anti-marijuana ads. Overall, the results provide partial support for the dominant thought disruption hypothesis and are discussed with an emphasis on the theoretical and practical implications for health communication researchers and practitioners. PMID- 23725052 TI - A simple way to intrude overerupted upper second molars with miniscrews. AB - Various methods of using skeletal anchorage for the intrusion of overerupted maxillary molars have been reported; however, it is difficult to intrude the overerupted upper second molars because of the low bone density in the region of the tuberosity. This article illustrates a new treatment method using partial fixed edgewise appliances and miniscrews to intrude the overerupted upper second molars. The miniscrews were applied to reinforce the anchorage of the upper first molar. The intrusive force was generated by the Ni-Ti wire. The clinical results showed a significant intrusion effect without root resorption or periodontal problems. This report demonstrates that the combination of partial conventional fixed appliances with miniscrews is a simple and effective treatment option to intrude overerupted upper second molars, especially in situations where miniscrews cannot be inserted directly next to the second molar. PMID- 23725053 TI - Detection of histone modification by chromatin immunoprecipitation combined zinc finger luciferase-based bioluminescence resonance energy transfer assay. AB - Epigenetic modification such as DNA methylation and histone modification have important roles in gene regulation. Epigenetic modification can be altered by environmental influences and are related to diseases. Therefore, epigenetic modifications may serve as biomarkers. In this study, we developed a convenient histone modification detection system by combining a chromatin immunoprecipitation (ChIP) and bioluminescence resonance energy transfer (BRET) based homogeneous PCR product detection system using zinc finger fused to luciferase (ZF-luciferase) with DNA intercalating dye (ChIP-ZF-BRET assay). The ChIP-ZF-BRET assay comprises the following 3 steps: (1) ChIP, (2) PCR amplification of the target genomic region, which includes a zinc-finger recognition site, and (3) homogeneous detection of the PCR product by BRET using ZF-luciferase and fluorescent DNA intercalating dye. Using this system, we conveniently and accurately detected target histone modification at the androgen receptor gene promoter region in LNCaP and Du145 cells. The system can be applicable to DNA methylation detection using a methyl-CpG-binding domain protein or methylcytidine antibody instead of histone modification antibodies. Therefore, it may be useful and convenient for simultaneous detection of histone modification and DNA methylation in clinical diagnoses. PMID- 23725054 TI - Electrospun acetalated dextran scaffolds for temporal release of therapeutics. AB - Electrospun acetalated dextran (Ac-DEX) scaffolds were fabricated to encapsulate resiquimod, an immunomodulatory toll-like-receptor (TLR) agonist. Ac-DEX has been used to fabricate scaffolds for sustained and temporal delivery of therapeutics because it has tunable degradation rates that are dependent on its synthesis reaction time or the molecular weight of dextran. Additionally, as opposed to commonly electrospun polyesters that shift the local pH upon degradation, the degradation products of Ac-DEX are pH-neutral: dextran, an alcohol, and the metabolic byproduct acetone. Formulations of Ac-DEX with two different degradation rates were used in this study. The effects of electrospinning conditions on the scaffold size and morphology were examined as well as fibroblast adhesion as imaged with fluorescence microcopy and scanning electron microscopy. Macrophage (MPhi) viability further indicates that the scaffolds are cytocompatible. Also, the controlled release profiles of resiquimod from loaded scaffolds and nitric oxide (NO) production by MPhi incubated with these scaffolds show the potential for Ac-DEX scaffolds to be used to temporally and efficiently deliver therapeutics. Overall, we present a novel scaffold that can have tunable and unique drug release rates for tissue engineering, drug delivery, immunomodulation, and wound healing applications. PMID- 23725055 TI - Ethical tradeoffs in trial design: case study of an HPV vaccine trial in HIV infected adolescent girls in lower income settings. AB - The Declaration of Helsinki and the Council of the International Organization of Medical Sciences provide guidance on standards of care and prevention in clinical trials. In the current and increasingly challenging research environment, the ethical status of a trial design depends not only on protection of participants, but also on social value, feasibility, and scientific validity. Using the example of a study assessing efficacy of a vaccine to prevent human papilloma virus in HIV-1 infected adolescent girls in low resource countries without access to the vaccine, we compare several trial designs which rank lower on some criteria and higher on others, giving rise to difficult trade-offs. This case demonstrates the need for developing more nuanced guidance documents to help researchers balance these often conflicting criteria. PMID- 23725056 TI - Feeding the normal newborn: whose art is it? PMID- 23725057 TI - Drug reaction with eosinophilia and systemic symptoms and thyroiditis: human herpesvirus-6, the possible common link. PMID- 23725058 TI - Progress in developing common data elements for traumatic brain injury research: version two--the end of the beginning. AB - To accelerate data sharing and research on traumatic brain injury (TBI), several federal agencies have been collaborating to support the development and implementation of common data elements (CDEs). The first recommendations for CDEs were made in 2010, and were well suited for hospital-based studies of acute TBI in adults. To broaden the utility of the TBI CDEs, experts were asked to update the recommendations to make them relevant to all ages, levels of injury severity, and phases of recovery. The second version of the TBI CDEs (v.2) was organized around four major study types: 1) epidemiological research; 2) studies on acute, hospitalized patients; 3) studies of the rehabilitation for moderate/severe TBI; and 4) mild TBI/concussion research. Given the heterogeneity of TBI, only a small set of core CDEs were found to be relevant across all study types. However, within groups, a much larger set of highly relevant CDEs were identified, and these were called basic CDEs. In addition, an expanded number of supplemental CDEs were specified and recommended for use depending upon the study goals. Version 2 provides a rich data dictionary for TBI research with about 900 CDEs. Many of the CDEs overlap across the study types, which will facilitate comparisons and meta-analysis across studies. Further modifications of the CDEs should be based on evaluation of their usefulness following implementation across a range of studies. PMID- 23725059 TI - MutS homologue hMSH4: interaction with eIF3f and a role in NHEJ-mediated DSB repair. AB - BACKGROUND: DNA mismatch repair proteins participate in diverse cellular functions including DNA damage response and repair. As a member of this protein family, the molecular mechanisms of hMSH4 in mitotic cells are poorly defined. It is known that hMSH4 is promiscuous, and among various interactions the hMSH4 hMSH5 interaction is involved in recognizing DNA intermediate structures arising from homologous recombination (HR). RESULTS: We identified a new hMSH4 interacting protein eIF3f--a protein that functions not only in translation but also in the regulation of apoptosis and tumorigenesis in humans. Our studies have demonstrated that hMSH4-eIF3f interaction is mediated through the N-terminal regions of both proteins. The interaction with eIF3f fosters hMSH4 protein stabilization, which in turn sustains gamma-H2AX foci and compromises cell survival in response to ionizing radiation (IR)-induced DNA damage. These effects can be, at least partially, attributed to the down-regulation of NHEJ activity by hMSH4. Furthermore, the interplay between hMSH4 and eIF3f inhibits IR-induced AKT activation, and hMSH4 promotes eIF3f-mediated bypass of S phase arrest, and ultimately enhancing an early G2/M arrest in response to IR treatment. CONCLUSION: Our current study has revealed a role for hMSH4 in the maintenance of genomic stability by suppressing NHEJ-mediated DSB repair. PMID- 23725060 TI - Metabolic evolution of Corynebacterium glutamicum for increased production of L ornithine. AB - BACKGROUND: L-ornithine is effective in the treatment of liver diseases and helps strengthen the heart. The commercial applications mean that efficient biotechnological production of L-ornithine has become increasingly necessary. Adaptive evolution strategies have been proven a feasible and efficient technique to achieve improved cellular properties without requiring metabolic or regulatory details of the strain. The evolved strains can be further optimised by metabolic engineering. Thus, metabolic evolution strategy was used for engineering Corynebacterium glutamicum to enhance L-ornithine production. RESULTS: A C. glutamicum strain was engineered by using a combination of gene deletions and adaptive evolution with 70 passages of growth-based selection. The metabolically evolved C. glutamicum strain, named DeltaAPE6937R42, produced 24.1 g/L of L ornithine in a 5-L bioreactor. The mechanism used by C. glutamicum DeltaAPE6937R42 to produce L-ornithine was investigated by analysing transcriptional levels of select genes and NADPH contents. The upregulation of the transcription levels of genes involved in the upstream pathway of glutamate biosynthesis and the elevated NADPH concentration caused by the upregulation of the transcriptional level of the ppnK gene promoted L-ornithine production in C. glutamicum DeltaAPE6937R42. CONCLUSIONS: The availability of NADPH plays an important role in L-ornithine production in C. glutamicum. Our results demonstrated that the combination of growth-coupled evolution with analysis of transcript abundances provides a strategy to engineer microbial strains for improving production of target compounds. PMID- 23725061 TI - Production of melanin pigment from Pseudomonas stutzeri isolated from red seaweed Hypnea musciformis. AB - Hypnea musciformis red seaweed is popularly known to produce carrageenan was collected from the Gulf of Mannar, India. Strain HMGM-7 [MTCC 11712] was isolated from the surface of this seaweed, which was capable of producing an extracellular black-coloured polymeric pigment. Based on phenotypic characterization and 16S rDNA sequencing, the strain HMGM-7 was identified as Pseudomonas stutzeri. Biophysical characterization by UV-visible, FT-IR, EPR and XRD spectroscopic studies confirmed the pigment as melanin. Further chemical characterization showed that it was acid-resistant, alkali-soluble and alkali-insoluble in most of the organic solvents and distilled water. To our knowledge, this is a first report on a marine Pseudomonas stutzeri strain producing significant amounts of melanin of about 6.7 g l(-1) without L-tyrosine supplementation in the sea-water production medium. SIGNIFICANCE AND IMPACT OF THE STUDY: This investigation reports a marine Pseudomonas stutzeri strain HMGM-7 [MTCC 11712] that produces significant quantities of melanin (6.7 g l(-1) ) in sea-water medium without the supplementation of L-tyrosine. The confirmation of the produced melanin was carried out by various chemical and physical characterization studies. The isolated melanin may find potential application for use in cosmetic and/or pharmaceutical industries. PMID- 23725062 TI - Reactive ground-state pathways are not ubiquitous in red/green cyanobacteriochromes. AB - Recent characterization of the red/green cyanobacteriochrome (CBCR) NpR6012g4 revealed a high quantum yield for its forward photoreaction [J. Am. Chem. Soc. 2012, 134, 130-133] that was ascribed to the activity of hidden, productive ground-state intermediates. The dynamics of the pathways involving these ground state intermediates was resolved with femtosecond dispersed pump-dump-probe spectroscopy, the first such study reported for any CBCR. To address the ubiquity of such second-chance initiation dynamics (SCID) in CBCRs, we examined the closely related red/green CBCR NpF2164g6 from Nostoc punctiforme. Both NpF2164g6 and NpR6012g4 use phycocyanobilin as the chromophore precursor and exhibit similar excited-state dynamics. However, NpF2164g6 exhibits a lower quantum yield of 32% for the generation of the isomerized Lumi-R primary photoproduct, compared to 40% for NpR6012g4. This difference arises from significantly different ground state dynamics between the two proteins, with the SCID mechanism deactivated in NpF2164g6. We present an integrated inhomogeneous target model that self consistently fits the pump-probe and pump-dump-probe signals for both forward and reverse photoreactions in both proteins. This work demonstrates that reactive ground-state intermediates are not ubiquitous phenomena in CBCRs. PMID- 23725063 TI - Marked increase in the incidence rate of esophageal adenocarcinoma in a high-risk area for esophageal cancer. AB - BACKGROUND: Esophageal cancer (EC) is the eighth common cancer worldwide. Esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAD) are the most common histologic types of EC. Many recent reports showed an increasing trend in EAD and a decreasing trend in ESCC in many Western countries. Golestan Province in northeastern Iran has been known as a high-risk area for EC. The aim of this study was to describe the time trend of EAD in this area between 2000-2009. METHODS: Data on cancer cases were obtained from Golestan Population-based Cancer Registry. Analysis was done using Joinpoint software. To examine the incidence trends, the annual percent change was calculated. The possibilities of anatomic and histologic misclassification were considered by assessing the trend of ESCC and gastric adenocarcinoma. RESULTS: A total number of 1186 histologically confirmed EC cases were recruited. The incidence rate of EAD showed a significant increasing trend. There was no significant trend in the incidence of ESCC during the study period. A significant increase in the incidence rate of gastric adenocarcinoma was observed during the period of 2000-2005, followed by a plateau during the period of 2005-2009. CONCLUSIONS: We found a significant increasing trend in the incidence rate of EAD. We find no evidence to support an alternative explanation including anatomic and histologic misclassification. So, the observed rise in the incidence of EAD seems to be real. Therefore, designing and implementation of control programs, including control of preventable risk factors of EAD, should be considered in this high- risk area. PMID- 23725064 TI - A case-control study of the relationship between gastric cancer and meat consumption in Iran. AB - BACKGROUND: Despite the descending trends of gastric cancer in many parts of the world, its mortality rate has still remained high globally. Meat, red and processed meat in particular, may induce gastric carcinogenesis through potential mechanisms. However, the role of this dietary aspect in the risk of gastric cancer has not well been investigated so far. Therefore, we designed a study to assess the relation between meat consumption and the risk of gastric cancer in Golestan Province, a high- risk area for gastric malignancies in Iran. METHODS: Subjects of this population-based case-control study included 190 histologically confirmed cases of gastric cancer and 647 controls. Meat consumption was evaluated using a 116-item semi-quantitative food frequency questionnaire. A lifestyle questionnaire also collected data concerning demographic features, anthropometric measures, and other known risk factors of gastric cancer. We estimated crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the relation between meat intake and gastric cancer. RESULTS: After being adjusted for potential confounders, red meat intake was positively associated with gastric cancer which reached statistical significance (OR = 1.87, 95% CI: 1.01-3.47, Ptrend = 0.073). On the other hand, individuals in the highest quartile of white meat consumption had a statistically significant reduced risk of gastric cancer compared to those in the lowest quartile (OR = 0.36, 95% CI: 0.19-0.68, Ptrend = 0.005). CONCLUSIONS: We observed a positive association between red meat consumption and the risk of gastric cancer, and a reverse relationship regarding white meat intake and the risk of this malignancy. PMID- 23725065 TI - Helicobacter pylori vacA d1/-i1 genotypes and geographic differentiation between high and low incidence areas of gastric cancer in Iran. AB - BACKGROUND: Helicobacter pylori (H. pylori)-specific genotypes have been closely correlated with an increased risk of gastric cancer (GC). The present study aimed to determine the distribution of H. pylori pathogenic genotypes amongst Iranians infected with strains representing European ancestry in areas with different GC incidence. METHODS: A total of 138 H. pylori isolates from ten districts in Iran were used for genotyping. RESULTS: The following genotypic frequency was observed: vacA s1 (94.9%), s2 (5.1%), m1 (24.6%), m2 (75.4%), d1 (39.9%), d2 (60.1%), i1 (40.6%), i2 (59.4%), iceA1 (76.8%), iceA2 (52.9%), iceA1/2 (29.7%), babA2 (40.6%), and cagA (65.9%). Hierarchical analyses of molecular variance (AMOVA) for the vacA d1, d2, i1, and i2 alleles and iceA1 and iceA1/2 genes found significant levels of genetic differentiation among populations (P < 0.05). Prevalence of the vacA d1, i1, and iceA1/2 (but not iceA1) genes and vacA d1/i1, vacA d1/iceA1, vacA d1/iceA1/2, vacA d1/cagA+, vacA i1/iceA1, vacA i1/iceA1/2, and vacA i1/cagA+ genotypes were significantly higher (>2- or 3-fold) among H. pylori isolates from high incidence GC areas that had age-standardized rates (ASRs) of >20/105 (max. 51.8/105) when compared with those from low incidence (ASRs <10/105) GC areas (P < 0.005, for the latter, P = 0.016). In contrast, the vacA d2/i2, m2/d2, and m2/i2 genotypes were significantly more prevalent in low compared to high incidence GC areas (P < 0.005). The results of Mantel's test only showed a low correlation between genetic and geographic distances for the iceA1 and iceA1/2 (but not vacA alleles, iceA2, babA2, and cagA) genes among ten districts of Iran (r = 0.098 and 0.074, respectively, P < 0.05). CONCLUSIONS: We propose that the H. pylori vacA d1/-i1 genotypes, which are new determinants of GC, have tremendous potential for differentiating H. pylori strains from high and low incidence GC areas in Iran. PMID- 23725066 TI - Prognostic significance of preoperative CA72-4 in patients with esophageal squamous cell carcinoma. AB - BACKGROUND: Carbohydrate antigen 72-4 (CA72-4) is a tumor marker for gastric cancer however its role in esophageal cancer (EC) is still controversial. The aim of this study is to determine the prognostic value of CA72-4 in patients with esophageal squamous cell carcinoma (ESCC). METHODS: From January 2006 to December 2007 we conducted a retrospective analysis of 192 consecutive patients with ESCC. A receiver operating characteristic (ROC) curve for survival prediction was plotted to verify the optimum cut-off point for CA72-4. Univariate and multivariate analyses were performed to evaluate the prognostic parameters. RESULTS: The positive rate for CA 72-4 in our study was 18.8% (36/192). The ROC curve for survival prediction showed the optimum cut-off point for CA 72-4 to be 3.95 U/mL. Patients with CA 72-4 <=3.95 U/mL had a significantly better five-year overall survival (51.4% vs. 13.6%; P<0.001) and relapse-free survival (49.5% vs. 19.8%; P < 0.001) than those with CA 72-4 levels >3.95 U/mL. Multivariate analyses showed that CA 72-4 was a significant predictor of both overall survival and relapse-free survival. CA 72-4 levels >3.95 U/mL had a hazard ratio (HR) of 2.129 [95% confidence interval (CI): 1.436-3.155; P < 0.001] for overall survival and 2.151 (95% CI: 1.449-3.192; P < 0.001) for relapse-free survival. CONCLUSIONS: CA 72-4 is an independent predictive factor for long-term survival in ESCC. We conclude that 3.95 U/mL may be the optimum cut-off point for CA72-4 in predicting survival in ESCC. Although CA 72-4 shows significant association with poorer prognosis, its low sensitivity limits clinical application. PMID- 23725067 TI - Gastric cancer mortality in a high incidence area: long-term follow-up of Helicobacter pylori-related precancerous lesions in the general population. AB - BACKGROUND: Due to a lack of clear criteria for recognizing subjects at risk of progression to gastric cancer (GC), this cohort study seeks to identify predictors of GC death in a high-risk population. METHODS: During 2000-2001, 1011 randomly selected residents of Ardabil, Iran without a history of gastrointestinal diseases, underwent upper endoscopy with targeted biopsy sampling. Until 2013, cancer mortality data were obtained using cancer and death registry data and verbal autopsy reports. Cox regression was used to estimate hazard ratios (HR). RESULTS: A total of 3.95% of the participants [mean age: 53.1 +/- 9.9 years, 49.8% males, and 88.2% Helicobacter pylori (H. pylori-positive)] died of GC. In the multivariate model, precancerous lesions at the beginning of follow-up were associated with increased GC mortality. The HR [95% confidence interval (CI)] was 7.4 (1.6-33.8) for atrophic gastritis (AG) and 23.6 (5.5 102.3) for intestinal metaplasia (IM). Age over 50 (HR = 4.4; 1.3-14.2), family history of GC (HR = 6.8; 3.3-13.8), smoking (HR = 7.4; 3.2-17.3), and endoscopically confirmed gastric ulcer (GU, HR = 6.5; 2.5-16.4) were independently associated with GC mortality. The concomitant presence of a precancerous lesion increased the HR to 46.5 (10.8-198.6) for a family history of GC, 27.6 (6.5-116.4) for smoking, and 25.1 (6.3-105.3) for age >50 years. CONCLUSIONS: In this population with a high rate of H. pylori infection, age over 50 years, smoking, family history of GC, IM, AG, and in particular, an undiagnosed GU were significant independent risk factors for mortality due to GC. The assessment of a combination of these risk factors might identify individuals at risk of GC who could possibly benefit from regular surveillance. PMID- 23725068 TI - Hepatocellular carcinoma in explanted livers of patients with genotype d HBV cirrhosis: report of the first experience from Iran. AB - BACKGROUND: This study was conducted to determine the impact of hepatitis B virus (HBV) as a cause of hepatocellular carcinoma (HCC) in a single liver transplant center in Iran. METHODS: We included all hepatectomy specimens from patients with HBV-related cirrhosis who underwent transplants from May 1993 until January 2012 in this study. From these, we determined the number that had HBV-induced HCC. Nested PCR results were used to determine the HBV genotype from sections of the hepatectomy pathology specimens. RESULTS: During this time period there were 1361 cirrhotic livers transplanted in our center. Of these, 249 were attributed to HBV cirrhosis. Overall, HCC was detected in 40 (2.9%) subjects, of which 29 (1.2%) had HBV-related HCC. Genotype D was only genotype observed in all HBV subjects. CONCLUSIONS: The results revealed that although HBV-related cirrhosis was the most frequent single cause for liver transplant, the frequency of HBV induced HCC was very low among transplant recipients. Out of 1361 transplant recipients, only 29 (2.1%) were diagnosed with HBV-related HCC. All HBV subjects had genotype D. PMID- 23725069 TI - Endoscopic screening for esophageal squamous cell carcinoma. AB - Esophageal cancer (EC) is the eighth common cancer and the sixth most common cause of death from cancer worldwide. Esophageal squamous cell carcinoma (ESCC) remains the most common type of EC in the developing world and an important health problem in high-risk areas. Most of ESCC cases present in late stages, resulting in delayed diagnosis and poor prognosis. Prevention is the most effective strategy to control ESCC. Primary and secondary preventive methods may be considered for ESCC. In primary prevention, we try to avoid known risk factors. The aim of the secondary preventive method (ESCC screening programs) is to detect and eliminate premalignant precursor lesion of ESCC, preventing its progression into advanced stages. Similar to all population-based screening programs, any screening for early detection of ESCC must be cost-effective; otherwise, screening may not be indicated in that population. Endoscopy with iodine staining has been accepted as a population-level ESCC screening program in some high-risk areas including parts of China. This method may be too expensive and invasive in other high-risk communities. Nonendoscopic methods may be more applicable in these populations for population-based screenings. The limitations (questionable validity and costs) of new endoscopic imaging modalities, including narrow-band imaging (NBI), made them inappropriate to be used in population-level ESCC screening programs. Low-cost, less-invasive endoscopic imaging methods with acceptable diagnostic performance may make screening of ESCC in high-risk areas cost-effective. PMID- 23725070 TI - Environmental and lifestyle risk factors of gastric cancer. AB - Effective prevention and early diagnostic strategies are the most important public health interventions in gastric cancer, which remains a common malignancy worldwide. Preventive strategies require identification and understanding of environmental risk factors that lead to carcinogenesis. Helicobacter pylori (H. pylori) is the primary carcinogen as this ancient bacterium has a complex ability to interact with its human host. Smoking and salt are strong independent risk factors for gastric cancer whereas alcohol is only a risk when it is heavily consumed. Red meat and high fat increase the risk of gastric cancer however fresh fruits, vegetables (allium family) and certain micronutrients (selenium, vitamin C) reduce the risk, with evidence lacking for fish, coffee and tea. Foods that inhibit H. pylori viability, colonization and infection may reduce cancer risk. Obesity is increasingly recognized as a contributory factor in gastric cardia carcinogenesis. Therefore, modest daily physical activities can be protective against cancer. Foundry workers are at risk for developing gastric cancer with dust iron being an important cause. Other risk factors include Epstein-Barr virus (EBV), possibly JC virus and radiation but the effects of these are likely to remain small. PMID- 23725071 TI - Mucinous subtype of invasive ductal carcinoma arising within a fibroadenoma. AB - Fibroadenoma is a common benign tumor observed during the second and third decades of life. Malignancy transformation in the epithelial component of a fibroadenoma is rare and can occur 20 years after its diagnosis. Mammographic findings in this phenomenon include indistinct margins and microcalcifications. Here we present a 58-year-old woman with a mobile, lateral upper quadrant mass that was rather firm when palpated. The mammography showed a lobulated mass without calcification suggestive of a benign process, most probably fibroadenoma. However the excisional biopsy contained both an intracanalicular fibroadenoma and invasive ductal carcinoma with mucinous components. PMID- 23725072 TI - Squamous cell carcinoma of the pancreas. AB - Squamous cell carcinoma (SCC) of the pancreas is a controversial entity of uncertain origin, as the pancreas is entirely devoid of squamous cells. Cases of pancreatic carcinomas that exhibit primary squamous morphology are rarely described in the literature. We report a case of primary SCC of the pancreas in a 66-year-old woman with complaints of epigastric pain of five months duration. Imaging studies demonstrated a solid tumor in the body of the pancreas that invaded the superior mesenteric (SMA) and celiac arteries, as well as regional lymph nodes. Cytological examination of an endosonography-guided fine needle aspiration (EUS-FNA) specimen confirmed the diagnosis of well-differentiated SCC of the pancreas. On the basis of diagnosis and examinations prior to chemotherapy, we did not detect any SCC lesions that might have metastasized to the pancreas. Primary SCC of the pancreas is a rare entity that comprises 0.05% of all exocrine pancreatic carcinomas. The clinical profile and biological behavior of pancreas SCC are similar to typical pancreatic ductal adenocarcinomas. PMID- 23725073 TI - Photoclinic. PMID- 23725074 TI - The Persian legend of ophthalmology: Ali Asghar Khodadoust and his everlasting lines. AB - This is a brief celebratory overview of the fruitful life and scientific endeavors of Professor Ali Asghar Khodadoust (b.1935), a world renowned ophthalmologist, Persian icon of modern ophthalmology and an international pioneer of eye research. The global reputation of Dr. Khodadoust is rooted in his extensive studies on corneal diseases and transplantation biology. As a result of his truly deserved world renown, several famous American ophthalmologists have recognized him as the world's best corneal graft surgeon. Due to his exceptionally impressive achievements in this field, a clinical finding has been named in his honor, the "Khodadoust rejection line", a sign indicative of a chronic focal transplant reaction. PMID- 23725075 TI - Two similar near-infrared (IR) absorbing benzannulated aza-BODIPY dyes as near-IR sensitizers for ternary solar cells. AB - Ternary composite inverted organic solar cells based on poly(3-hexylthiophen-2,5 diyl) (P3HT) and phenyl-C61-butyric acid methyl ester (PCBM) blended with two different near-infrared absorbing benzannulated aza-BODIPY dyes, difluoro-bora bis-(1-phenyl-indoyl)-azamethine (1) or difluoro-bora-bis-(1-(5-methylthiophen) indoyl)-azamethine (2), were constructed and characterized. The amount of these two aza-BODIPY dyes, within the P3HT and PCBM matrix, was systematically varied, and the characteristics of the respective devices were recorded. Although the addition of both aza-BODIPY dyes enhanced the absorption of the blends, only the addition of 1 improved the overall power conversion efficiency (PCE) in the near infrared (IR) region. The present work paves the way for the integration of near infrared absorbing aza-BODIPY derivatives as sensitizers in ternary composite solar cells. PMID- 23725076 TI - Are there financial savings associated with supplementing current diagnostic practice for preeclampsia with a novel test? Learnings from a modeling analysis from a German payer perspective. AB - OBJECTIVE: To quantify the financial impact of adding a novel serum test to the current diagnostic toolkit for preeclampsia (PE) detection in Germany. METHODS: A decision-analytic model was created to quantify the economic impact of adding a recently developed novel diagnostic test for PE (Roche Diagnostics, Rotkreuz, Switzerland) to current diagnostic practice in Germany. The model simulated a cohort of 1000 pregnant patients receiving obstetric care and quantified the budget impact of adding the novel test to current German PE detection and management practices. RESULTS: The model estimates that the costs associated with managing a typical pregnancy in Germany are ?941 when the novel test is used versus ?1579 with standard practice. This represents savings of ?637 per pregnant woman, even when the test is used as a supplementary diagnostic tool. The savings are attributed to the novel test's ability to better classify patients relative to current practice, specifically, its ability to reduce false negatives by 67% and false positives by 71%. CONCLUSION: The novel PE test has the potential to provide substantial cost savings to German healthcare payers, even when used as an addition to standard practice. Better classification of patients at risk for developing PE and declassification of those that are not compared to current practice leads to economic savings for the healthcare system. Furthermore, by reducing the rates of false-positive and false-negative classification relative to current standard of care, the test helps better target healthcare spending and lowers overall costs associated with PE care. PMID- 23725077 TI - Increase of placental sensitivity to melatonin and the alteration to its local synthesis in hypertensive syndromes in pregnancy. AB - OBJECTIVE: To evaluate the relation between hypertensive syndromes and melatonin, and its possible protective role against lesions due to hypertension. METHODS: Placentas were classified into gestational hypertension (GH), chronic hypertension (CH), pre-eclampsia (PE) and pre-eclampsia superimposed on chronic hypertension, and morphologically examined by hematoxylin-eosin and periodic acid Schiff methods. Immunohistochemistry was performed to detect tryptophan hydroxylase (TH) and melatonin receptor 1A (MR-1A). RESULTS: MR-1A expression was higher in all types of hypertensive syndromes in pregnancy (HSP), mainly in cases with GH, in Caesarean section delivery, preterm placentas and in the cases with alterations in the placental morphology, particularly those presenting inflammation. The expression of TH was higher in cases with CH when compared with the control. This expression was lower in primigestas, in the cases of inflammation and with PE. CONCLUSIONS: HSP therapies should be considered and studied, especially in the cases of HSP associated with PE, in which the placenta is more sensitive as it has more receptors, but its synthesis ability is reduced. As for GH and CH, the possible benefits should be evaluated, since the local placental ability to produce melatonin still exists. PMID- 23725078 TI - Endothelial function progressively deteriorates during normal pregnancy. AB - OBJECTIVE: To elucidate changes in endothelial function throughout the gestational period in normal pregnancy and its relationship with plasma soluble fms-like tyrosine kinase-1 (sFlt-1) levels. METHODS: Endothelial function was evaluated by reactive hyperemia index (RHI) using Endo-PAT2000 and plasma sFlt-1 levels were measured simultaneously by ELISA. RESULTS: RHI gradually deteriorated with increasing gestational age. Plasma sFlt-1 levels exhibited a gradual increase at late pregnancy and were inversely correlated with RHI. CONCLUSION: Maternal endothelial function gradually deteriorates with increasing gestational age and there is an inverse correlation between endothelial function and plasma sFlt-1 levels in normal pregnancy. PMID- 23725079 TI - Predictive value of 3+ spot urinary protein value measured by dipstick in hypertensive pregnant patients. AB - OBJECTIVE: To evaluate whether the spot urinary protein (SUP) level has predictive value on pregnancy outcomes in hypertensive pregnant patients. METHODS: Retrospective case-control study of 109 pregnant patients with hypertension and spot urinary proteinuria measured by dipstick. RESULTS: Presence of 24 h proteinuria was higher in patients with 3+ SUP. Gestational age at delivery was significantly lower in patients with 3+ SUP when compared with patients with <=2+ SUP (p = 0.009). Rate of SGA babies was higher in patients with 3+ SUP when compared with patients with <=2+ SUP (p < 0.001). CONCLUSION: Although it cannot replace 24 h urinary protein determination, 3+ proteinuria with dipstick may have a prognostic value, particularly in emergency cases. PMID- 23725080 TI - Nutritional status of women with gestational hypertension compared with normal pregnant women. AB - BACKGROUND: Some evidence indicated the role of nutrition in the development of hypertensive disorders of pregnancy. METHODS: This case-control study was conducted on 113 women with gestational hypertension and 150 healthy pregnant women referred to Shahid Akbarabadi Hospital in Tehran. A demographic questionnaire was filled out for all participants. A validated semi-quantitative food frequency questionnaire was used to assess the dietary intakes of the study subjects. All nutrients were adjusted for total energy intake. Logistic regression was used to find the association of energy and nutrient intakes with gestational hypertension. RESULTS: We found that higher intakes of energy (OR, 1.33; 95% CI: 1.17-1.52), monounsaturated fatty acids (OR, 1.34; 95% CI: 1.03 1.74) and polyunsaturated fatty acids (OR, 1.26; 95% CI: 1.00-1.54) were positively associated with the risk of gestational hypertension after adjustment for confounders. We also observed decreased odds of gestational hypertension with increased intakes of vitamin C (OR, 0.87; 95% CI: 0.81-0.94), potassium (OR, 0.45; 95% CI: 0.28-0.71) and magnesium (OR, 0.68; 95% CI: 0.51-0.89). CONCLUSION: This study demonstrates higher intakes of energy, monounsaturated fatty acids and polyunsaturated fatty acids as well as lower intakes of vitamin C, potassium and magnesium are positively correlated with the risk of developing gestational hypertension. PMID- 23725081 TI - The expression of immediate early response gene X-1 in preeclampsia placenta and its pro-apoptotic role in preeclampsia. AB - The stress-inducible immediate early response gene X-1 (IEX-1) regulates cell proliferation and apoptosis in a cell type and stimulus-dependent manner. The aim of this study was to investigate IEX-1 expression in preeclampsia placenta and human umbilical vein endothelial cells (HUVECs) cultured in the serum isolated from preeclampsia patients, to explore its relationship with the pathogenesis of preeclampsia. Thirty preeclampsia patients with 10 cases in the moderate group, 20 cases in the severe group (PE group) and 20 cases of normal pregnant women (control group) were randomly obtained. Reverse transcriptase-polymerase chain reaction and immunohistochemistry showed that IEX-1 expression was significantly higher in preeclampsia patients than in normal pregnant women (p < 0.05). There was also a significant difference between moderate and severe preeclampsia (p < 0.05). IEX-1 protein was mainly present in cytoplasm of placental trophoblast cells and decidual cells. Compared with the normal pregnancy group, IEX-1 in the preeclampsia group was colored more obviously, and the color was strengthened in correlation with the severity of the disease using immunocytochemial method. Flow cytometry and MTT revealed that the serum isolated from preeclampsia patients appeared to promote IEX-1 expression in cytoplasm of HUVECs, inhibited the proliferation and promoted the apoptosis of HUVECs when compared to the serum of normal pregnant women. Our study demonstrates a correlation of IEX-1 expression levels with the severity of preeclampsia. Given a well-known function of IEX-1 in regulation of apoptosis, IEX-1 may be important in the pathogenesis of preeclampsia by regulating placental villous trophoblast and decidual cell apoptosis as well as participation in endothelial cell injury process. PMID- 23725082 TI - Hypertensive disease of pregnancy is associated with decreased risk for respiratory distress syndrome in moderate preterm neonates. AB - OBJECTIVE: To examine the effect of hypertensive disease of pregnancy (HDP) on the development of respiratory distress syndrome (RDS) in preterm neonates. DESIGN: A retrospective cohort study. SETTING: All neonatal intensive care units in New South Wales and the Australian Capital Territory. PATIENTS: A total of 18,845 preterm neonates aged between 24 and 36 weeks gestation admitted to the units from 1998 to 2006 were included for study purpose. Exclusion criteria were multiple pregnancies, chorioamnionitis, antepartum hemorrhage and neonates who developed respiratory diagnoses other than RDS. OUTCOME MEASURES: Effect of HDP on the development of RDS was measured. RESULTS: A total of 1093 neonates from hypertensive and 2274 from normotensive pregnancies with complete datasets were included. The association between HDP and the development of RDS was modified by gestational age (HDP-by-gestational age interaction p value <0.0001). Therefore the cohort was divided into extreme (24-28 weeks gestation, n = 752), severe (29 32 weeks gestation, n = 1448) and moderate (33-36 weeks gestation, n = 1167) preterm groups. HDP was associated with a decreased risk of RDS in the moderate preterm group (OR: 0.68; 95% CI: 0.48-0.98, p = 0.04) and a non-significant change in risk for the severe preterm group. Almost all neonates in the extreme preterm group experienced RDS. CONCLUSION: HDP is associated with a lower risk of developing RDS in moderate preterm neonates. This could have clinical implications in terms of risk stratification for this group of neonates. PMID- 23725083 TI - The effects of magnesium sulfate on placental vascular endothelial growth factor expression in preeclampsia. AB - OBJECTIVE: To evaluate the effect of magnesium sulfate (MgSO(4)) on placental expression levels of vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: Cotyledons of term normotensive and preeclamptic placentas were dually perfused for 6 h, with MgSO(4) (6-7 mg%) in the maternal reservoir [normotensive (n = 3); preeclamptic (n = 4)] and with the control medium (without MgSO(4)) [normotensive (n = 3); preeclamptic (n = 6)]. After perfusion, placental tissue samples were collected from four different placental compartments (amnion, chorion, placental villous and decidua). The collected placental tissues were homogenized and examined for VEGF by ELISA. Statistical significance was determined using a two-way analysis of variance. RESULTS: After perfusion with control medium, significantly lower levels of VEGF were detected in the chorion and placental villous compartments of preeclamptic placentas (70 +/- 24 pg/g protein and 29 +/- 11 pg/g protein; respectively), as compared with normotensive placentas (172 +/- 80 pg/g protein and 51 +/- 17 pg/g protein; respectively; p < 0.05). Exposure of preeclamptic placentas to MgSO(4) resulted in decreased VEGF levels by the amnion (57 +/- 26 pg/g protein), as compared with the control group (153 +/- 62 pg/g protein) (p < 0.05). On the other hand, MgSO(4) significantly increased VEGF levels by the placental villous and the decidua (58 +/- 15 pg/g protein, 70 +/- 29 pg/g protein; respectively), as compared with the control group (29 +/- 11 pg/g protein, 33 +/- 14 pg/g protein; respectively) (p < 0.01, p < 0.05; respectively). Exposure to MgSO(4) did not affect VEGF levels in normotensive placentas. CONCLUSION: Reduced levels of VEGF are expressed by some placental compartments in preeclampsia compared with normotensive pregnancy. Perfusion with MgSO(4) affects VEGF expression differently by preeclamptic and normotensive placentas. Increased production of placental VEGF in preeclampsia may play a role in the therapeutic action of MgSO(4). PMID- 23725085 TI - Interactions between exogenous FGF-2 and sulfonic groups: in situ characterization and impact on the morphology of human adipose-derived stem cells. AB - FGF-2 is often used as a supplement to stem cells culture medium aiming at preserving their self-renewal capacity and plasticity through the passages. However, little is known on the influence of the underlying substrate in these interactions. In this study, we have used mixed self-assembled monolayers with different ratios of -SO3H and -OH tail groups to investigate the influence of substrate properties (e.g., charge) on the FGF-2 adsorption and activity. QCM-D data demonstrated that, in the presence of -OH groups, the quantity of the adsorbed FGF-2 is proportional to the percentage of surface -SO3H groups. The bioactivity of the adsorbed FGF-2 follows the same tendency as demonstrated by its interactions with anti-FGF-2. Surprisingly, the adlayer of FGF-2 formed on the surface containing only SO3H-tailed SAMs was similar to the surface with 25% of -SO3H groups, demonstrating that FGF-2 adsorption is not solely driven by electrostatic interactions. We related these results with changes in the morphology of adipose-derived stem cells (ASCs) cultured on the same surfaces. PMID- 23725084 TI - Clinical characterization and outcomes of preeclampsia with normal angiogenic profile. AB - OBJECTIVE: To compare the clinical characteristics and outcomes of preeclamptic women presenting with a normal plasma angiogenic profile with those subjects who are characterized by an abnormal angiogenic profile. METHODS: This was a secondary analysis of a prospective cohort study in women presenting to obstetrical triage at <37 weeks of gestation and diagnosed with preeclampsia within 2 weeks of enrollment and in whom angiogenic factors (sFlt1 and PlGF) measurements were available. Patients were divided into two groups based on their circulating levels of these factors described as a ratio; the sFlt1/PlGF ratio, non-angiogenic preeclampsia (sFlt1/PlGF ratio <85) and angiogenic preeclampsia (sFlt1/PlGF ratio >=85). The data are presented by sFlt1/PlGF category using median and quartile 1-quartile 3 for continuous variables and by frequency and sample sizes for categorical variables. RESULTS: In our cohort, the patients with non-angiogenic preeclampsia (N = 46) were more obese [BMI: 35.2 (31.6, 38.7) versus 31.1 (28.0, 39.0), p = 0.04], more likely to have preexisting diabetes (21.7% versus 2.0%, p = 0.002) and presented at a later gestational age [35 (32, 37) versus 32 (29, 34) weeks, p < 0.0001] as compared with women with angiogenic preeclampsia (N = 51). Women with non-angiogenic preeclampsia had no serious adverse outcomes (elevated liver function tests/low platelets: 0% versus 23.5%, abruption: 0% versus 9.8%, pulmonary edema: 0% versus 3.9%, eclampsia: 0% versus 2.0 %, small for gestational age: 0% versus 17.7% and fetal/neonatal death: 0% versus 5.9%) as compared with women with angiogenic preeclampsia. The rate of preterm delivery <34 weeks was 8.7% in non-angiogenic preeclampsia compared with 64.7% in angiogenic preeclampsia (p < 0.0001). Interestingly, delivery between 34 and 37 weeks and resource utilization (hospital admission days) were similar in the two groups. CONCLUSION: In contrast to the angiogenic form, the non angiogenic form of preeclampsia is characterized by little to no risk of preeclampsia-related adverse outcomes, other than iatrogenic prematurity. Incorporation of angiogenic biomarkers in the evaluation of preeclampsia may allow accurate and early identification of severe disease. PMID- 23725087 TI - Camel milk-associated infection risk perception and knowledge in French Hajj pilgrims. AB - Cases of brucellosis have been recently reported in Hajj pilgrims following camel milk consumption. With the aim of evaluating French pilgrim's potential risk for raw camel milk-associated diseases, we conducted a knowledge, attitude, and practice study among 331 pilgrims departing to the 2011 Hajj. A proportion of 8.2% have drunk camel milk before, mostly in North Africa (62.9%) and Saudi Arabia (18.5%). A proportion of 13.9% declared they knew that drinking raw camel milk could cause diseases and 40.6% said that they would drink it if offered during the pilgrimage. Given that camel milk consumption in the Middle East is associated with several zoonotic infections in man, we recommend that Hajj pilgrims be cautioned against consuming unpasteurized dairy products. PMID- 23725086 TI - Effects of increase in fish oil intake on intestinal eicosanoids and inflammation in a mouse model of colitis. AB - BACKGROUND: Inflammatory bowel diseases (IBD) are chronic intestinal inflammatory diseases affecting about 1% of western populations. New eating behaviors might contribute to the global emergence of IBD. Although the immunoregulatory effects of omega-3 fatty acids have been well characterized in vitro, their role in IBD is controversial. METHODS: The aim of this study was to assess the impact of increased fish oil intake on colonic gene expression, eicosanoid metabolism and development of colitis in a mouse model of IBD. Rag-2 deficient mice were fed fish oil (FO) enriched in omega-3 fatty acids i.e. EPA and DHA or control diet for 4 weeks before colitis induction by adoptive transfer of naive T cells and maintained in the same diet for 4 additional weeks. Onset of colitis was monitored by colonoscopy and further confirmed by immunological examinations. Whole genome expression profiling was made and eicosanoids were measured by HPLC MS/MS in colonic samples. RESULTS: A significant reduction of colonic proinflammatory eicosanoids in FO fed mice compared to control was observed. However, neither alteration of colonic gene expression signature nor reduction in IBD scores was observed under FO diet. CONCLUSION: Thus, increased intake of dietary FO did not prevent experimental colitis. PMID- 23725088 TI - Engaging diverse social and cultural worlds: perspectives on benefits in international clinical research from South african communities. AB - The issue of benefits in international clinical research is highly controversial. Against the background of wide recognition of the need to share benefits of research, the nature of benefits remains strongly contested. Little is known about the perspectives of research populations on this issue and the extent to which research ethics discourses and guidelines are salient to the expectations and aspirations existing on the ground. This exploratory study contributes to filling this void by examining perspectives of people in low-income South African communities on benefits in international clinical research. Twenty-four individuals with and without experience of being involved in clinical research participated in in-depth interviews. Respondents felt that ancillary care should be provided to clinical research participants, while a clinical study conducted in particular community should bring better health to its members through post trial benefits. Respondents' perspectives were grounded in the perception that the ultimate goal of international clinical research is to improve local health. We argue that perspectives and understandings of the respondents are shaped by local moral traditions rather than clinical research specificities and require attention as valid moral claims. It is necessary to acknowledge such claims and cultural worlds from which they emerge, thus building the foundation for equal and embracing dialogue to bridge different perspectives and handle contradicting expectations. PMID- 23725089 TI - Evidence of the syndrome of rapid onset end-stage renal disease (SORO-ESRD) in the acute kidney injury (AKI) literature--preventable causes of AKI and SORO-ESRD -a call for re-engineering of nephrology practice paradigms. AB - INTRODUCTION: We described the previously unrecognized syndrome of rapid-onset end-stage renal disease (SORO-ESRD) in 2010, in the journal Renal Failure, as distinct from the classic CKD-ESRD progression of a methodical, linear, time dependent and predictable progression from CKD through CKD stages I-V, ending in ESRD requiring renal replacement therapy (RRT). It remains unclear to what extent this syndrome may have been identified in the past without acknowledging its uniqueness. METHODS: We reviewed AKI reports and ascertained cases of SORO-ESRD as defined by patients with a priori stable kidney function who subsequently exhibited unanticipated and irreversible ESRD requiring RRT following new AKI episodes. RESULTS: Fifteen AKI reports demonstrating SORO-ESRD were analyzed. The reports span most regions of the world. The 15 studies with 20 to 1095 AKI patients each, mean age 39-65 years, published between 1975 and 2010, demonstrated SORO-ESRD rates from 1% to 85% of the AKI series. AKI was caused by hypovolemia/hypotension, infections/sepsis and exposure to nephrotoxics especially radiocontrast, NSAIDs, aminoglycosides and RAAS blocking agents, ACEIs and ARBs. DISCUSSION: Irreversible ESRD following AKI, consistent with our recent description of a new and unrecognized syndrome has been sporadically reported in the AKI literature, without a clear mandate as a syndrome, potentially distinct from the classic ESRD. The contribution of SORO-ESRD to the global ESRD pandemic, the impact of SORO-ESRD on AV-Fistula planning, any differential behavior of SORO ESRD versus classic ESRD in terms of mortality outcomes and any predisposing factors to SORO-ESRD as advanced age and nephrotoxic exposure all call for serious research study. PMID- 23725090 TI - In vitro performance of Class I and II composite restorations: a literature review on nondestructive laboratory trials--part II. AB - A literature review was conducted on adhesive Class I and II restorations and nondestructive in vitro tests using the PubMed/Medline database for the 1995-2010 period. The first part of this review has presented and critically appraised selected literature dealing with the quality and in vitro behavior of adhesive Class II restorations using photoelasticity, finite element analysis, and microleakage study protocols. This second part reviews additional parameters, which are deformation and fracture resistance to cyclic loading, shrinkage stress and tooth deformation following restoration placement, bond strength (microtensile, tensile, and shear tests), and marginal and internal adaptation. In addition, a "relevance score" has been proposed that aims to classify the different study protocols according, firstly, to the resulting quality, quantity, and consistency of the evidence and then, secondly, to their potential clinical relevance, as estimated by their ability to simulate oral and biomechanical strains. The highest clinical relevance was attributed to marginal and internal adaptation studies, following cyclic loading in a moist environement. However, a combination of in vitro protocols will have an even greater predictive potential and has to be considered as a crucial preclinical research approach with which to investigate the numerous restorative configurations that cannot be efficiently and rapidly tested in vivo. PMID- 23725091 TI - Effects of carbohydrates on the oNPG converting activity of beta-galactosidases. AB - The effects of high concentrations of carbohydrates on the o-nitrophenyl beta-d galactopyranoside (oNPG) converting activity of beta-galactosidase from Bacillus circulans are studied to get a better understanding of the enzyme behavior in concentrated and complicated systems in which enzymatic synthesis of galacto oligosaccharides is usually performed. The components that were tested were glucose, galactose, lactose, sucrose, trehalose, raffinose, Vivinal GOS, dextran 6000, dextran-70,000, and sarcosine. Small carbohydrates act as acceptors in the reaction. This speeds up the limiting step, which is binding of the galactose residue with the acceptor and release of the product. Simultaneously, both inert and reacting additives seem to cause some molecular crowding, which results in a higher enzyme affinity for the substrate. The effect of molecular crowding on the enzyme activity is small compared to the effect of carbohydrates acting in the reactions as acceptors. The effects of reactants on beta-galactosidases from B. circulans, A. oryzae, and K. lactis are compared. PMID- 23725092 TI - Comparing the effectiveness of two cardiovascular prevention programmes for highly educated professionals in general practice: a randomised clinical trial. AB - BACKGROUND: Cardiovascular disease is a major cause of mortality and morbidity and its prevalence is set to increase. While the benefits of medical and lifestyle interventions are established, the effectiveness of interventions which seek to improve the way preventive care is delivered in general practice is less so. The aim was to study and to compare the effectiveness of 2 intervention programmes for reducing cardiovascular risk factors within general practice. METHODS: A randomised controlled trial was conducted in Belgium between 2007-2010 with 314 highly educated and mainly healthy professionals allocated to a medical (MP) or a medical + lifestyle (MLP) programme. The MP consisted of medical assessments (screening and follow-up) and the MLP added a tailored lifestyle change programme (web-based and individual coaching) to the MP. Primary outcomes were total cholesterol, blood pressure, and body mass index (BMI). The secondary outcomes were smoking status, fitness-score, and total cardiovascular risk. RESULTS: The mean age was 41 years, 95 (32%) participants were female, 7 had a personal cardiovascular event in their medical history and 3 had diabetes. There were no significant differences found between MP and MLP in primary or secondary outcomes. In both study conditions decreases of cholesterol, systolic blood pressure, and diastolic blood pressure were found. Unfavourable increases were found for BMI (p < .05). A significant decrease of the overall cardiovascular risk was reported (p < .001). CONCLUSIONS: Both interventions are effective in reducing cardiovascular risk. In our population the combined medical and lifestyle programme was not superior to the medical programme. TRIAL REGISTRATION: ISRCTN23940498. PMID- 23725093 TI - Antibiotic content of selective culture media for isolation of Capnocytophaga species from oral polymicrobial samples. AB - In oral microbiome, because of the abundance of commensal competitive flora, selective media with antibiotics are necessary for the recovery of fastidious Capnocytophaga species. The performances of six culture media (blood agar, chocolate blood agar, VCAT medium, CAPE medium, bacitracin chocolate blood agar and VK medium) were compared with literature data concerning five other media (FAA, LB, TSBV, CapR and TBBP media). To understand variable growth on selective media, the MICs of each antimicrobial agent contained in this different media (colistin, kanamycin, trimethoprim, trimethoprim-sulfamethoxazole, vancomycin, aztreonam and bacitracin) were determined for all Capnocytophaga species. Overall, VCAT medium (Columbia, 10% cooked horse blood, polyvitaminic supplement, 3.75 mg l(-1) of colistin, 1.5 mg l(-1) of trimethoprim, 1 mg l(-1) of vancomycin and 0.5 mg l(-1) of amphotericin B, Oxoid, France) was the more efficient selective medium, with regard to the detection of Capnocytophaga species from oral samples (P < 0.001) and the elimination of commensal clinical species (P < 0.001). The demonstrated superiority of VCAT medium, related to its antibiotic content, made its use indispensable for the optimal isolation of Capnocytophaga species from polymicrobial samples. SIGNIFICANCE AND IMPACT OF THE STUDY: Isolation of Capnocytophaga species is important for the proper diagnosis and treatment of the systemic infections they cause and for epidemiological studies of periodontal flora. We showed that in pure culture, a simple blood agar allowed the growth of all Capnocytophaga species. Nonetheless, in oral samples, because of the abundance of commensal competitive flora, selective media with antibiotics are necessary for the recovery of Capnocytophaga species. The demonstrated superiority of VCAT medium made its use essential for the optimal detection of this bacterial genus. This work showed that extreme caution should be exercised when reporting the isolation of Capnocytophaga species from oral polymicrobial samples, because the culture medium is a determining factor. PMID- 23725094 TI - The effect of different restorative and abutment materials on marginal and internal adaptation of three-unit cantilever implant-supported fixed partial dentures: an in vitro study. AB - PURPOSE: Passive fit is generally assumed to be a significant prerequisite for long-term implant success. The aim of this study was to evaluate the precision fit of three-unit implant-supported fixed partial dentures with different restorative and abutment materials on two implant systems: the Straumann and Astra Tech. MATERIALS AND METHODS: Two mandibular epoxy resin models (one for each implant system) were fabricated, and two implants were inserted at the first and second molar region. Poly(vinyl siloxane) impression material was used to make the dental impression. For each implant system, fifteen models were fabricated, and each group was divided into three subgroups (group 1: titanium abutment with metal framework, group 2: titanium abutment with zirconium framework, group 3: zirconium abutment with zirconium framework). The replica technique was used to examine the marginal and internal gap values. For each restoration, 20 measurements were performed, totaling 1200 measurements for all groups. Data were evaluated statistically using ANOVA and LSD post hoc test (p < 0.05). RESULTS: The highest values at internal adaptation measurements were found at the occlusal surface for all groups. When the mean values of the marginal measurements were assessed, the lowest measurements were found in group 3 (51.416 MUm), and the highest values were found in group 1 (79.394 MUm). There were statistically significant differences between subgroups for marginal measurements (p < 0.05). CONCLUSIONS: As included in our study, marginal measurement values were found to be 46 to 87 MUm. The marginal discrepancy of the tested materials could be considered clinically acceptable. PMID- 23725095 TI - Differential modulation of nociceptive versus non-nociceptive synapses by endocannabinoids. AB - BACKGROUND: Although a number of clinical and preclinical studies have demonstrated analgesic effects of cannabinoid treatments, there are also instances when cannabinoids have had no effect or even exacerbated pain. The observed pro-nociceptive effects appear to be due to cannabinoid-induced disinhibition of afferent synaptic input to nociceptive circuits. To better understand how cannabinoid-mediated plasticity can have both pro- and anti nociceptive effects, we examined the possibility that cannabinoids differentially modulate nociceptive vs. non-nociceptive synapses onto a shared postsynaptic target. These experiments were carried out in the central nervous system (CNS) of the medicinal leech, in which it is possible to intracellularly record from presynaptic nociceptive (N-cell) or pressure-sensitive (P-cell) neurons and their shared postsynaptic targets. RESULTS: The endocannabinoid 2-arachidonoyl glycerol (2AG) elicited significant long-lasting depression in nociceptive (N-cell) synapses. However, non-nociceptive (P-cell) synapses were potentiated following 2AG treatment. 2AG-induced potentiation of non-nociceptive synapses was blocked by the TRPV antagonist SB366791, suggesting involvement of the same TRPV-like receptor that has already been shown to mediate endocannabinoid-dependent depression in nociceptive inputs. Treatment with the GABA receptor antagonist bicuculline also blocked 2AG-induced potentiation, consistent with the idea that increased synaptic signaling was the result of endocannabinoid-mediated disinhibition. Interestingly, while bicuculline by itself increased non nociceptive synaptic transmission, nociceptive synapses were depressed by this GABA receptor antagonist indicating that nociceptive synapses were actually excited by GABAergic input. Consistent with these observations, GABA application depolarized the nociceptive afferent and hyperpolarized the non-nociceptive afferent. CONCLUSIONS: These findings show that endocannabinoids can differentially modulate nociceptive vs. non-nociceptive synapses and that GABAergic regulation of these synapses plays an important role in determining whether endocannabinoids have a potentiating or depressing effect. PMID- 23725096 TI - COPD and disease-specific health status in a working population. AB - BACKGROUND: It has been debated whether treatment should be started early in subjects with mild to moderate COPD. An impaired health status score was associated with a higher probability of being diagnosed with COPD as compared with undiagnosed COPD. PURPOSE: To investigate the health status in a healthy working population, to determine reference scores for healthy non-smoking subjects, and to investigate the relationship between their health status and airflow limitation. METHODS: A total of 1333 healthy industrial workers aged >=40 years performed spirometry and completed the St. George's Respiratory Questionnaire (SGRQ) and the COPD Assessment Test (CAT). RESULTS: The prevalence of COPD defined by the fixed ratio of the forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) was 10.9%, and the prevalence defined by the Lower Limit of Normal was 5.0%. All SGRQ and CAT scores were skewed to the milder end. In 512 non-smoking subjects with normal spirometry, the mean SGRQ score was 5.7, and the mean CAT score was 5.8. In 145 people with COPD defined by the fixed ratio, the mean SGRQ score was 7.9, with a zero score in 6.9% of the subjects. Using the CAT, the mean score was 7.3, with 7.6% of the scores being zero. The scores in patients identified using the Lower Limit of Normal approach were: SGRQ 8.4 (13.4% had a score of zero) and CAT 7.4 (13.4% had a score of zero). Although the 95th percentiles of the Total, Symptoms, Activity, and Impact scores of the SGRQ and CAT sores were 13.8, 34.0, 23.4, 7.2 and 13.6 in the 512 healthy non smoking subjects, respectively, they were also distributed under their upper limits in over 80% of the COPD subjects. CONCLUSION: The COPD-specific health status scores in a working population were good, even in those with spirometrically diagnosed COPD. All scores were widely distributed in both healthy non-smoking subjects and in subjects with COPD, and the score distribution overlapped remarkably between these two groups. This suggests that symptom-based methods are not suitable screening tools in a healthy general population. PMID- 23725097 TI - An effective protein extraction method for two-dimensional electrophoresis in the anticancer herb Andrographis paniculata Nees. AB - Proteomic analysis of plants relies on high yields of pure protein. In plants, protein extraction and purification present a great challenge due to accumulation of a large amount of interfering substances, including polysaccharides, polyphenols, and secondary metabolites. Therefore, it is necessary to modify the extraction protocols. A study was conducted to compare four protein extraction and precipitation methods for proteomic analysis. The results showed significant differences in protein content among the four methods. The chloroform trichloroacetic acid-acetone method using 4-(2-hydroxyethyl)-1 piperazineethanesulfonic acid (HEPES) buffer provided the best results in terms of protein content, pellets, spot resolution, and intensity of unique spots detected. An overall of 83 qualitative or quantitative significant differential spots were found among the four methods. Based on the 2-DE gel map, the method is expected to benefit the development of high-level proteomic and biochemical studies of Andrographis paniculata, which may also be applied to other recalcitrant medicinal plant tissues. PMID- 23725098 TI - Incorporation of ubiquinone in supported lipid bilayers on ITO. AB - Ubiquinone (UQ) is one of the main electron and proton shuttle molecules in biological systems, and dipalmitoylphosphatidylcholine (DPPC) is one of the most used model lipids. Supported planar bilayers (SPBs) are extensively accepted as biological model membranes. In this study, SPBs have been deposited on ITO, which is a semiconductor with good electrical and optical features. Specifically, topographic atomic force microscopy (AFM) images and force curves have been performed on SPBs with several DPPC:UQ ratios to study the location and the interaction of UQ in the SPB. Additionally, cyclic voltammetry has been used to understand the electrochemical behavior of DPPC:UQ SPBs. Obtained results show that, in our case, UQ is placed in two main different positions in SPBs. First, between the DPPC hydrophobic chains, fact that originates a decrease in the breakthrough force of the bilayer, and the second between the two leaflets that form the SPBs. This second position occurs when increasing the UQ content, fact that eventually forms UQ aggregates at high concentrations. The formation of aggregates produces an expansion of the SPB average height and a bimodal distribution of the breakthrough force. The voltammetric response of UQ depends on its position on the bilayer. PMID- 23725099 TI - Aberrant cortical neuroplasticity in the OSA patient (Commentary on Opie et al.). PMID- 23725101 TI - A 72-year-old woman with an uncorrected tetralogy of Fallot presenting with possible pulmonary endocarditis: a case report. AB - INTRODUCTION: Tetralogy of Fallot is one of the most common forms of cyanotic congenital heart disease and in the absence of surgical correction it has an elevated early mortality, with most patients dying in childhood.The authors reported this case because of the unusual course of an uncorrected tetralogy of Fallot. There are only a few reports of patients with an uncorrected tetralogy of Fallot who reach an advanced age and to the best of our knowledge this is the first case report of a possible endocarditis in a patient with an uncorrected tetralogy of Fallot who is older than 70 years. CASE PRESENTATION: The authors present a case of a 72-year-old Caucasian woman with uncorrected tetralogy of Fallot who was admitted with fever and heart failure to our Cardiology Department with possible infective endocarditis. CONCLUSIONS: The longevity of this patient is probably due to the association between a large ventricular septal defect, a balanced subpulmonary stenosis and to the presence of systemic hypertension. After empiric antibiotic therapy, the patient was discharged and no surgical intervention was performed due to her previous benign evolution. PMID- 23725100 TI - Early, but not late onset estrogen replacement therapy prevents oxidative stress and metabolic alterations caused by ovariectomy. AB - AIMS: The usefulness of estrogen replacement therapy (ERT) in preventing oxidative stress associated with menopause is controversial. We aimed to study if there is a critical time window for effective treatment of the effects of ovariectomy with estrogens at the molecular, metabolic, and cellular level. RESULTS: Our main finding is that early, but not late onset of ERT prevents an ovariectomy-associated increase in mitochondrial hydrogen peroxide levels, oxidative damage to lipids and proteins, and a decrease in glutathione peroxidase and catalase activity in rats. This may be due to a change in the estrogen receptor (ER) expression profile: ovariectomy increases the ER alpha/beta ratio and immediate estrogen replacement prevents it. Positron emission tomography analysis shows that ovariectomy decreases the brain glucose uptake in vivo and that estrogen administration is beneficial, but only if administered immediately after deprivation. Ovariectomy decreases GLUT-1 and 3 glucose transporters in the brain, and only early onset estrogen administration prevents it. Plasma from rats treated with estrogens immediately after ovariectomy show similar metabolomics profiles as controls. INNOVATION: We provide molecular basis for the recommendation of early onset ERT and explain its lack of effectiveness if a significant time period elapses after ovariectomy and probably after the onset of menopause. CONCLUSION: Only early, but not late onset administration of estrogens after ovariectomy has beneficial effects at molecular levels on oxidative stress, brain glucose uptake, and metabolomic profiles. PMID- 23725102 TI - Enterocin TW21, a novel bacteriocin from dochi-isolated Enterococcus faecium D081821. AB - AIMS: Purification and characterization of a novel bacteriocin produced by strain Enterococcus faecium D081821. METHODS AND RESULTS: Enterococcus faecium D081821, isolated from the traditional Taiwanese fermented food dochi (fermented black beans), was previously found to produce a bacteriocin against Listeria monocytogenes and some Gram-positive bacteria. This bacteriocin, termed enterocin TW21, was purified from culture supernatant by ammonium sulfate precipitation, Sep-Pak C18 cartridge, ion-exchange and gel filtration chromatography. Mass spectrometry analysis showed the mass of the peptide to be approximately 5300.6 Da. The N-terminal amino acid sequencing yielded a partial sequence NH2 ATYYGNGVYxNTQK by Edman degradation, and it contains the consensus class IIa bacteriocin motif YGNGV in the N-terminal region. The open reading frame (ORF) encoding the bacteriocin was identified from the draft genome sequence of Enterococcus faecium D081821, and sequence analysis of this peptide indicated that enterocin TW21 is a novel bacteriocin. CONCLUSIONS: Enterococcus faecium D081821 produced a bacteriocin named enterocin TW21, the molecular weight and amino acid sequence both revealed it to be a novel bacteriocin. SIGNIFICANT AND IMPACT OF STUDY: A new member of class IIa bacteriocin was identified. This bacteriocin shows great inhibitory ability against L. monocytogenes and could be applied as a natural food preservative. PMID- 23725103 TI - Effects of perceived parental attitudes on children's views of smoking. AB - BACKGROUND: The aim of this study was to examine the effects of perceived parental attitudes on children's discernment of cigarettes. MATERIALS AND METHODS: The study sample consisted of 250 children attending grades 6, 7 and 8. Data were collected via a socio-demographic survey questionnaire, the Parental Attitude Scale (PAS) and the Decisional Balance Scale (DBS). Data analysis covered percentages, medians, one-way analysis of variance (ANOVA) and post-hoc tests using a statistical package. RESULTS: There were 250 participants; 117 were male, 133 were female. The mean age was 13.1 +/- 0.98 for the females and 13.3 +/ 0.88 for the males. A statistically significant difference was found in the children's mean scores for 'pros' subscale on the Decisional Balance Scale (DBS) according to perceived parental attitudes (F=3.172, p=0.025). There were no statistically significant differences in the DBS 'cons' subscale scores by perceived parental attitudes. CONCLUSIONS: It was determined that while perceived parental attitudes affect children's views on advantages of smoking, they have no effect on children's views on its disadvantages. PMID- 23725104 TI - Update on the APJCP and the APOCP in 2013 - what is going to be achieved in the future? AB - The history of the APOCP/APJCP goes back to 1999 when a number of interested scientists joined together to form the organization and to launch a new journal to support cancer prevention research in the Asian-Pacific area. Since the initial Founding Conference, some six General Assemblies (GAs) and ten Regional Conferences (RCs) and Special Study Sessions have been organized. Already the decisions have been made for two further GAs and at least three RCs. As of the April issue of 2013, a total of nearly 3,700 papers have already been published in regular issues of the APJCP or special supplements. With support of the Korean National Cancer Center, housing the Chief Editorial Office, the journal is now including approximately 100 papers a month. Although it experienced a set-back by reduction in the Impact Factor (IF) from 1.29 in 2010 to 0.67 in 2011, there are good grounds to expect an improvement in 2012. However, the future of the APOCP/APJCP will continue to depend on its membership, making continuous efforts to attend our conferences and submit good quality manuscripts. It is particularly important to cite papers in the APJCP wherever possible, if the wish is for an IF commensurate with our long term aims. In that sense it is up to all authors, since the journal will continue to have a very positive policy towards accepting papers from all countries within the Asian-Pacific, with its very varied levels of resources. The editorial team looks forward to your considered support. The APOCP also hopes to see you in person at future meeetings, so that you have a more active voice in deciding the best way forward in our cooperative enterprise. PMID- 23725105 TI - Global controversies and advances in skin cancer. AB - Advances and controversies of skin cancer prevention in the Asian-Pacific region are to be examined the world's first Global Controversies and Advances in Skin Cancer Conference to be held in Brisbane, Australia this November. APOCP Members are cordially invited to register early for the opportunity to contribute to the debate on a cancer which continues to be a prominent issue in the Asia Pacific and indeed worldwide. We need answers to the questions of why a cancer that is so preventable and easily detectable is still shrouded in controversy. Primary focuses will be on issues like viral involvement, vaccines and novel clinical approaches. PMID- 23725106 TI - Roles of cancer registries in enhancing oncology drug access in the Asia-Pacific region. AB - Cancer registries help to establish and maintain cancer incidence reporting systems, serve as a resource for investigation of cancer and its causes, and provide information for planning and evaluation of preventive and control programs. However, their wider role in directly enhancing oncology drug access has not been fully explored. We examined the value of cancer registries in oncology drug access in the Asia-Pacific region on three levels: (1) specific registry variable types; (2) macroscopic strategies on the national level; and (3) a regional cancer registry network. Using literature search and proceedings from an expert forum, this paper covers recent cancer registry developments in eight economies in the Asia-Pacific region - Australia, China, Hong Kong, Malaysia, Singapore, South Korea, Taiwan, and Thailand - and the ways they can contribute to oncology drug access. Specific registry variables relating to demographics, tumor characteristics, initial treatment plans, prognostic markers, risk factors, and mortality help to anticipate drug needs, identify high-priority research area and design access programs. On a national level, linking registry data with clinical, drug safety, financial, or drug utilization databases allows analyses of associations between utilization and outcomes. Concurrent efforts should also be channeled into developing and implementing data integrity and stewardship policies, and providing clear avenues to make data available. Less mature registry systems can employ modeling techniques and ad-hoc surveys while increasing coverage. Beyond local settings, a cancer registry network for the Asia-Pacific region would offer cross-learning and research opportunities that can exert leverage through the experiences and capabilities of a highly diverse region. PMID- 23725107 TI - Lung cancer detection by screening - presenting circulating miRNAs as a promising next generation biomarker breakthrough. AB - Lung cancer remains a major cause of morbidity and mortality worldwide, accounting for more deaths than any other cause. All the clinical practice guidelines recommended against routine screening for lung cancer have cited lack of robust evidence, at least until a few years back. However, the potential to screen lung cancers has received renewed interest due to superior performance of low dose CT (LD-CT) in detecting early stage cancers. The incremental costs and risks involved due to the invasive procedures in the screened population due to a high false positivity rate questions the use of LD-CT scan as a reliable community based screening tool. There is therefore an urgent need to find a less invasive and a more reliable biomarker that is crucial to increase the probability of early lung cancer detection. This can truly make a difference in lung cancer survival and at the same time be more cost and resource utilization effective. Sampling blood serum being minimally invasive, low risk and providing an easy to obtain biofluid, needs to be explored for potential biomarkers. This review discusses the use of circulatory miRNAs that have been able to discriminate lung cancer patients from disease free controls. Several studies conducted recently suggest that circulating miRNAs may have promising future applications for screening and early detection of lung cancer. PMID- 23725108 TI - Power and promise of ubiquitin carboxyl-terminal hydrolase 37 as a target of cancer therapy. AB - Ubiquitin carboxyl-terminal hydrolase 37 (UCH37, also called UCHL5), a member of the deubiquitinating enzymes, can suppress protein degradation through disassembling polyubiquitin from the distal subunit of the chain. It has been proved that UCH37 can be activated by proteasome ubiqutin chain receptor Rpn13 and incorporation into the 19S complex. UCH37, which has been reported to assist in the mental development of mice, may play an important role in oncogenesis, tumor invasion and migration. Further studies will allow a better understanding of roles in cell physiology and pathology, embryonic development and tumor formation, hopefully providing support for the idea that UCH37 may constitute a new interesting target for the development of anticancer drugs. PMID- 23725109 TI - Review of selenium and prostate cancer prevention. AB - Prostate cancer is the most common malignancy in men in the United States. Surgery or radiation are sometimes unsatisfactory treatments because of the complications such as incontinence or erectile dysfunction. Selenium was found to be effective to prevent prostate cancer in the Nutritional Prevention of Cancer Trial (NPC), which motivated two other clinical trials: the Selenium and Vitamin E Cancer Prevention Trial (SELECT) and a Phase III trial of selenium to prevent prostate cancer in men with high-grade prostatic intraepithelial neoplasia. However, these two trials failed to confirm the results of the NPC trial and indicated that the selenium may not be preventive of prostate cancer. In this article we review the three clinical trials and discuss some different points which might be potential factors underlying variation in results obtained. PMID- 23725110 TI - Potential therapeutic targets for the primary gallbladder carcinoma: estrogen receptors. AB - Gallbladder carcinoma, the most frequent malignant neoplasm of the biliary tract system, has always been considered to feature late clinical presentation and diagnosis, limited treatment options and an extremely poor prognosis. In recent years, while the incidence of gallbladder cancer has appeared to be on the increase, the available treatment methods have not greatly improved survival of the affected patients. Thus, exploring new therapeutic targets for this devastating disease is an urgent matter at present. Epidemical studies have demonstrated that the incidence of gallbladder carcinoma exhibits a distinct gender bias, affecting females two to three times more than males, pointing to crucial roles of estrogen. It is well known that estrogen acts on target tissues by binding to estrogen receptors (ERs), which are mainly divided into three subtypes, ERalpha, ERbeta and ERgamma. ERalpha and ERbeta appear to have overlapping but also unique even opposite biological effects. As important pathogenic mediators, ERs have been considered to relate to several kinds of tumors. In gallbladder carcinoma tissue, ERs have been shown to be positively expressed, and ERs expression levels are associated with differentiation and prognosis of this cancer. Nevertheless, the exact mechanisms of estrogen inducing growth of gallbladder carcinoma remain poorly understood. On the base of the current investigations, we deduce that estrogen participates in promotion of gallbladder carcinoma by influencing the formation of gallstones, stimulating angiogenesis, and promoting abnormal proliferation. Since ERs mediate the carcinogenic actions of estrogen in gallbladder, and therapy targeting ERs may provide new directions for gallbladder carcinoma. Therefore, it should be stressed that ERs are potential therapeutic targets for gallbladder carcinoma. PMID- 23725111 TI - Equol, adiponectin, insulin levels and risk of breast cancer. AB - Breast cancer is one of the most frequently diagnosed cancers and the leading cause of cancer death among women. Soy isoflavones have been widely studied and among all isoflavones equol has been gaining interest with regard to its relationship with breast cancer risk. Obesity has been revealed as one of the breast cancer risk factors, known to be associated with high levels of circulating insulin and decreased levels of adiponectin. Hence there have been many studies investigating relationships between insulin and adiponectin levels and breast cancer risk. Additionally recent findings have suggested that insulin and adiponectin themselves may have influence on breast cancer development, independent of obesity. In the present review, we discuss the relationships between breast cancer risk and equol, insulin and adiponectin levels, which are three important factors in our ongoing hospital-based case-control study. Herein these factors are reviewed not only from the clinical viewpoint but also from possible chemical and biological points of view which may explain clinical observations. PMID- 23725112 TI - Potential targets for prevention of colorectal cancer: a focus on PI3K/Akt/mTOR and Wnt pathways. AB - Colorectal cancer (CRC) is one of the most common cancers in many parts of the world. Its development is a multi-step process involving three distinct stages, initiation that alters the molecular message of a normal cell, followed by promotion and progression that ultimately generates a phenotypically altered transformed malignant cell. Reports have suggested an association of the phosphoinositide-3-kinase (PI3K)/Akt pathway with colon tumorigenesis. Activation of Akt signaling and impaired expression of phosphatase and tensin homolog (PTEN) (a negative regulator of Akt) has been reported in 60-70% of human colon cancers and inhibitors of PI3K/Akt signaling have been suggested as potential therapeutic agents. Around 80% of human colon tumors possess mutations in the APC gene and half of the remainder feature beta-catenin gene mutations which affect downstream signaling of the PI3K/Akt pathway. In recent years, there has been a great focus in targeting these signaling pathways, with natural and synthetic drugs reducing the tumor burden in different experiment models. In this review we survey the role of PI3K/Akt/mTOR and Wnt signaling in CRC. PMID- 23725113 TI - Mechanics behind breast cancer prevention - focus on obesity, exercise and dietary fat. AB - Cancer prevention is rapidly emerging as a major strategy to reduce cancer mortality. In the field of breast cancer, significant strides have recently been made in the understanding of underlying preventive mechanisms. Currently, three major strategies have been linked to an increase in breast cancer risk: obesity, lack of physical exercise, and high levels of saturated dietary fat. As a result, prevention strategies for breast cancer are usually centered on these lifestyle factors. Unfortunately, there remains controversy regarding epidemiological studies that seek to determine the benefit of these lifestyle changes. We have identified crucial mechanisms that may help clarify these conflicting studies. For example, recent reports with olive oil have demonstrated that it may influence crucial transcription factors and reduce breast tumor aggressiveness by targeting HER2. Similarly, physical exercise reduces sex hormone levels, which may help protect against breast cancer. Obesity promotes tumor cell growth and cell survival through upregulation of leptin and insulin-like growth factors. This review seeks to discuss these underlying mechanisms, and more behind the three major prevention strategies, as a means of understanding how breast cancer can be prevented. PMID- 23725114 TI - Anti-cancer mechanism and possibility of nano-suspension formulations for a marine algae product fucoxanthin. AB - Recently, use of natural products available from marine sources, and especially algae products, are receiving more attention. Scientific evidence for claimed nutraceutical and therapeutical effects of one such marine algae product, fucoxanthin, is discussed in this paper with a summary of the currently available literature regarding its antioxidant, anti-obesity and anticancer activities. It is safe for use in humans, but as it has poor solubility a nano-suspension mode of delivery may be adopted to improve efficacy of supplements. We conclude from our literature review that the marine algae product fucoxanthin has significant antioxidant, anti-obesity and anticancer activity with established mechanisms of action. PMID- 23725115 TI - Evaluation of levels of knowledge about etiology and symptoms of oral cancer in southern Iran. AB - BACKGROUND: Knowledge regarding risk factors and primary signs of oral cancer in the general population can help them to avoid risky behaviour and seek timely advice from a physician. The aim of this study was to survey adult knowledge about risk factors and signs of oral cancer in Shiraz Dental University. MATERIALS AND METHODS: In this descriptive cross-sectional study using an investigator-made questionnaire, 783 adults who were referred to Shiraz Dental University participated. Questionnaire data were analyzed by ANOVA and T-test. RESULTS: The results showed that 32.3% of participants were aware of oral cancer and gained their knowledge from the media. The risk factors mentioned by these participants was as follows: sunlight 30.8%, hot and peppery food 40.7%, alcoholic drinks 47.4% and smoking 73.6% (there was significant relationship for drinking alcohol and gender, education and times of using dental service, p<0.05). They also mentioned the primary signs of oral cancer as follows: red patch without pain 27.8%, white patch without pain 13.5% and prolong scarring without pain 56.7% (there was significant relationship between these three signs and education and times of using dental service, p<0.05). The mean knowledge about the risk factors and signs of oral cancer were 1.94 from 5 with 1.14 standard deviation and 0.96 from 3 with 0.93 standard deviation. CONCLUSIONS: The observed low level of knowledge of people regarding both risk factors and signs of oral cancer emphasizes the need for more efforts to be made about the above mentioned issues by the media. PMID- 23725116 TI - Deletion of GSTM1 and T1 genes as a risk factor for development of acute leukemia. AB - The glutathione S-transferases (GSTs) are a family of enzymes involved in the detoxification of a wide range of chemicals, including important environmental carcinogens, as well as chemotherapeutic agents. In the present study 294 acute leukemia cases, comprising 152 of acute lymphocytic leukemia (ALL) and 142 of acute myeloid leukemia, and 251 control samples were analyzed for GSTM1 and GSTT1 polymorphisms through multiplex PCR methods. Significantly increased frequencies of GSTM1 null genotype (M0), GSTT1 null genotype (T0) and GST double null genotype (T0M0) were observed in the both ALL and AML cases as compared to controls. When data were analyzed with respect to clinical variables, increased mean levels of WBC, Blast %, LDH and significant reduction in DFS were observed in both ALL and AML cases with T0 genotype. In conclusion, absence of both GST M and GST T might confer increased risk of developing ALL or AML. The absence of GST enzyme might lead to oxidative stress and subsequent DNA damage resulting in genomic instability, a hallmark of acute leukemia. The GST enzyme deficiency might also exert impact on clinical prognosis leading to poorer DFS. Hence GST genotyping can be made mandatory in management of acute leukemia so that more aggressive therapy such as allogenic stem cell transplantation may be planned in the case of patients with a null genotype. PMID- 23725117 TI - Effects of obesity on presentation of breast cancer, lymph node metastasis and patient survival: a retrospective review. AB - BACKGROUND: As data on the relation between obesity and lymph node ratio are missing in the literature, we here aimed to assess the impact of obesity on this parameter and other clinicopathological features of breast cancer cases and patient survival. MATERIALS AND METHODS: Medical data of 646 patients, all referred to two centers in Tehran, Iran, were reviewed. Factors that showed significant association on univariate analysis were entered in a regression model. Kaplan-Meier and Cox-regression were employed for survival analysis. RESULTS: Obesity was correlated with the expression of estrogen and progesterone receptor (p=0.004 and p=0.039, respectively), metastasis to axillary lymph nodes (p=0.017), higher lymph node rate (p<0.001) and larger tumor size (p<0.001). The effect of obesity was stronger in premenopausal women. There was no association between obesity and expression of human epidermal growth factor receptor. Three factors showed independent association with BMI on multivariate analysis; tumor size, estrogen receptor and lymph node ratio. Obesity was predictive of shorter disease-free survival with a hazard ratio of 3.324 (95%CI: 1.225-9.017) after controlling for the above-mentioned variables. CONCLUSIONS: The findings of this study support the idea that obese women experience more advanced disease with higher axillary lymph node ratio, and therefore higher stage at the time of diagnosis. Furthermore, obesity was associated with poorer survival independent of lymph node rate. PMID- 23725118 TI - Her-2/neu status: a neglected marker of prognostication and management of breast cancer patients in India. AB - BACKGROUND: Categorizing breast tumors based on the ER, PR and HER/Neu 2 receptor status is necessary in order to predict outcome and assist in management of breast cancer. Herfe we assessed this question in South Indian patients. MATERIALS AND METHODS: A total of 619 formalin fixed paraffin embedded breast tumor tissues were collected from pathology archives after receipt of ethical clearance. With the help of primary and secondary conjugated antibodies, expression status of ER, PR and HER2/neu was determined. All the experimental data were assessed for correlations with histopathological features of tumors and clinical presentation of the subjects. RESULTS: In the present study, the ages ranged from 20-87 years with a mean of 50.0+/-12.q years, and majority of the tumors (84%) were of infiltrating duct cell carcinoma type. Assessment of ER, PR and Her-2/neu expression showed that 46% were triple negative. Interestingly, an inverse relation between ER, PR and HER-2/neu was apparent in 41.2% (p<0.0001) of the tumors, of which 24.5% (p<0.0001) were ER and PR co-negative but HER-2 positive. CONCLUSIONS: ER and PR positive tumors are less common (i.e<30%) compared to HER-2/neu positive tumors (i.e>50%) in Indian breast cancer patients, underlining the need for effective diagnostic screening and specific therapeutic managements in order to improve the survival rate of patients in low resource countries such as India. PMID- 23725119 TI - Impact of applied progressive deep muscle relaxation training on the level of depression, anxiety and stress among prostate cancer patients: a quasi experimental study. AB - BACKGROUND: The aim of this study was to determine the impact of applied progressive muscle relaxation training on the levels of depression, anxiety and stress among prostate cancer patients. MATERIALS AND METHODS: A quasi experimental study was conducted at the University Malaya Medical Centre (UMMC) and Universiti Kebangsaan Malaysia Medical Centre (UKMMC) over six months. Prostate cancer patients from UMMC received the intervention and patients from UKMMC were taken as controls. The level of depression, anxiety and stress were measured using Depression, Anxiety Stress Scales - 21 (DASS-21). RESULTS: A total of 77 patients from the UMMC and 78 patients from the UKMMC participated. At the end of the study, 90.9% and 87.2% of patients from the UMMC and UKMMC groups completed the study respectively. There were significant improvements in anxiety (p<0.001, partial ?2=0.198) and stress (p<0.001, partial ?2=0.103) at the end of the study in those receiving muscle training. However, there was no improvement in depression (p=0.956). CONCLUSIONS: The improvement in anxiety and stress showed the potential of APMRT in the management of prostate cancer patients. Future studies should be carried out over a longer duration to provide stronger evidence for the introduction of relaxation therapy among prostate cancer patients as a coping strategy to improve their anxiety and stress. PMID- 23725120 TI - Dose planning study of target volume coverage with intensity- modulated radiotherapy for nasopharyngeal carcinoma: Penang General Hospital experience. AB - BACKGROUND: To compare the dosimetric coverage of target volumes and organs at risk in the radical treatment of nasopharyngeal carcinoma (NPC) between intensity modulated radiotherapy (IMRT) and three- dimensional conformal radiotherapy (3DCRT). MATERIALS AND METHODS: Data from 10 consecutive patients treated with IMRT from June-October 2011 in Penang General Hospital were collected retrospectively for analysis. For each patient, dose volume histograms were generated for both the IMRT and 3DCRT plans using a total dose of 70Gy. Comparison of the plans was accomplished by comparing the target volume coverage (5 measures) and sparing of organs at risk (17 organs) for each patient using both IMRT and 3DCRT. The means of each comparison target volume coverage measures and organs at risk measures were obtained and tested for statistical significance using the paired Student t-test. RESULTS: All 5 measures for target volume coverage showed marked dosimetric superiority of IMRT over 3DCRT. V70 and V66.5 for PTV70 showed an absolute improvement of 39.3% and 24.1% respectively. V59.4 and V56.4 for PTV59.4 showed advantages of 18.4% and 16.4%. Moreover, the mean PTV70 dose revealed a 5.1 Gy higher dose with IMRT. Only 4 out of 17 organs at risk showed statistically significant difference in their means which were clinically meaningful between the IMRT and 3DCRT techniques. IMRT was superior in sparing the spinal cord (less 5.8Gy), V30 of right parotid (less 14.3%) and V30 of the left parotid (less 13.1%). The V55 of the left cochlea was lower with 3DCRT (less 44.3%). CONCLUSIONS: IMRT is superior to 3DCRT due to its dosimetric advantage in target volume coverage while delivering acceptable doses to organs at risk. A total dose of 70Gy with IMRT should be considered as a standard of care for radical treatment of NPC. PMID- 23725121 TI - Inhibitory effects of Tualang Honey on experimental breast cancer in rats: a preliminary study. AB - The study was conducted to determine the effect of Malaysian jungle Tualang Honey (TH) on development of breast cancer induced by the carcinogen 7,12 dimethylbenz(alpha)anthracene (DMBA) in rats. Forty nulliparous female Sprague Dawley rats were given 80 mg/kg DMBA then randomly divided into four groups: Group 1 served as a Control while Groups 2, 3 and 4 received 0.2, 1.0 or 2.0 g/kg bodyweight/day of TH, respectively, for 150 days. Results showed that breast cancers in the TH-treated groups had slower size increment and smaller mean tumor size (<= 2 cm3) compared to Controls (<= 8 cm3). The number of cancers developing in TH-treated groups was also significantly fewer (P<0.05). Histological grading showed majority of TH-treated group cancers to be of grade 1 and 2 compared to grade 3 in controls. There was an increasing trend of apoptotic index (AI) seen in TH-treated groups with increasing dosage of Tualang Honey, however, the mean AI values of all TH-treated groups were not significantly different from the Control value (p>0.05). In conclusion, Tualang Honey exerted positive modulation effects on DMBA-induced breast cancers in rats in this preliminary study. PMID- 23725122 TI - Acetylation of retinoblastoma like protein2 (Rb2/p130) in tumor tissues. AB - The activity of Rb proteins is controlled by post-translational modifications, especially through phosphorylation. Acetylation of Rb2/p130 was reported recently in NIH3T3 cells but its physiological relevance in cell cycle control and tumorigenesis is still unknown. Efforts are underway to investigate possible interplay between Rb2/p130 phosphorylation and acetylation. Here we hypothesized that Rb2/p130 acetylation, like p53 acetylation, may play a role in development of the tumor phenotype. The proposed hypothesis regarding acetylation of Rb2/p130 in tumor VS normal cells was found to be true in our case study of 36 tumor samples. Statistical analysis of results suggest strong correlation among Rb2/p130 acetylation and cancer phenotype. PMID- 23725123 TI - Lack of health insurance increases all cause and all cancer mortality in adults: an analysis of National Health and Nutrition Examination Survey (NHANES III) data. AB - BACKGROUND: Public use National Health and Nutrition Examination Survey (NHANES III) and NHANES III linked mortality data were here applied to investigate the association between health insurance coverage and all cause and all cancer mortality in adults. PATIENTS AND METHODS: NHANES III household adult, laboratory and mortality data were merged. Only patients examined in the mobile examination center (MEC) were included in this study. The sampling weight employed was WTPFEX6, SDPPSU6 being used for the probability sampling unit and SDPSTRA6 to designate the strata for the survey analysis. All cause and all cancer mortalities were used as binary outcomes. The effect of health insurance coverage status on all cause and all cancer mortalities were analyzed with potential socioeconomic, behavioral and health status confounders. RESULTS: There were 2398 sample persons included in this study. The mean age was 40 years and the mean (S.E.) follow up was 171.85 (3.12) person months from the MEC examination. For all cause mortality, the odds ratios (significant p-values) of the covariates were: age, 1.0095 (0.000); no health insurance coverage (using subjects with health insurance), 1.71 (0.092); black race (using non-Hispanic white subjects as the reference group) 1.43, (0.083); Mexican-Americans, 0.60 (0.089); DMPPIR, 0.82, (0.000); and drinking hard liquor, 1.014 (0.007). For all cancer mortality, the odds ratio (significant p-values) of the covariates were: age, 1.0072 (0.00); no health insurance coverage, using with health coverage as the reference group, 2.91 (0.002); black race, using non-Hispanic whites as the reference group, 1.64 (0.047); Mexican Americans, 0.33 (0.008) and smoking, 1.017 (0.118). CONCLUSION: There was a 70% increase in risk of all cause death and almost 300% of all cancer death for people without any health insurance coverage. PMID- 23725124 TI - Complex regulatory network of microRNAs, transcription factors, gene alterations in adrenocortical cancer. AB - Several lines of evidence indicate that cancer is a multistep process. To survey the mechanisms involving gene alteration and miRNAs in adrenocortical cancer, we focused on transcriptional factors as a point of penetration to build a regulatory network. We derived three level networks: differentially expressed; related; and global. A topology network ws then set up for development of adrenocortical cancer. In this network, we found that some pathways with differentially expressed elements (genetic and miRNA) showed some self-adaption relations, such as EGFR. The differentially expressed elements partially uncovered mechanistic changes for adrenocortical cancer which should guide medical researchers to further achieve pertinent research. PMID- 23725125 TI - Current evidence on associations between the MMP-7 (-181A>G) polymorphism and digestive system cancer risk. AB - Matrix metalloproteinases (MMPs) degrade various components of the extracellular matrix and functional polymorphisms in encoding genes may contribute to genetic susceptibility to many cancers. Up to now, associations between MMP-7 (-181A>G) and digestive system cancer risk have remained inconclusive. To better understand the role of the MMP-7 (-181A>G) genotype in digestive cancer development, we conducted this comprehensive meta-analysis encompassing 3,518 cases and 4,596 controls. Overall, the MMP-7 (-181A>G) polymorphism was associated with higher digestive system cancer risk on homozygote comparison (GG vs. AA, OR=1.21, 95% CI = 1.12-1.60) and in a dominant model (GG/GA vs. AA, OR=1.16, 95% CI =1.03-1.46). On subgroup analysis, this polymorphism was significantly linked to higher risks for gastric cancer (GG vs. AA, OR=1.22, 95% CI = 1.02- 1.46; GA vs. AA, OR=1.82, 95% CI =1.16-2.87; GG/GA vs. AA, OR=1.13, 95% CI =1.01-1.27; GG vs. GA/AA, OR= 1.25, 95% CI = 1.06-2.39. We also observed increased susceptibility to colorectal cancer and esophageal SCC in both homozygote (OR = 1.13, 95% CI = 1.06-1.26) and heterozygote comparisons (OR = 1.45, 95% CI = 1.11-1.91). In the stratified analysis by controls, significant effects were only observed in population-based studies (GA vs. AA, OR=1.16, 95% CI=1.08-1.50; GA/AA vs. GG, OR=1.10, 95% CI=1.01 1.72). According to the source of ethnicity, a significantly increased risk was found among Asian populations in the homozygote model (GG vs. AA, OR=1.40, 95% CI=1.12-1.69), heterozygote model (GA vs. AA, OR=1.26, 95% CI=1.02-1.51), and dominant model (GG/GA vs. AA, OR=1.18, 95% CI=1.08-1.55). Our findings suggest that the MMP-7 (-181A>G) polymorphism may be a risk factor for digestive system cancer, especially among Asian populations. PMID- 23725126 TI - Proteomic profiling of serum from stage I lung squamous cell carcinoma patients. AB - OBJECTIVES: This study employed proteomic profiling to identify specific tumor markers that might improve early diagnosis of lung squamous cell carcinoma. METHODS: Serum samples were isolated from 30 patients with stage I lung squamous cell carcinoma and 30 age-and gender-matched healthy controls, and proteomic profiles were obtained by matrix-assisted laser desorption ionization time of flight mass spectrometry. RESULTS: Three highly expressed potential tumor markers were identified in the sera of stage I lung squamous cell carcinoma patients, with molecular weights of 3261.69, 3192.07, and 2556.92 Da. One protein peak with molecular weight 3261.69 Da was chosen as the candidate biomarker and identified as a fibrinogen alpha chain through a search of the IPI, NCBI or SWISS-PROT protein databases. CONCLUSION: As a potential tumor biomarker, fibrinogen alpha chain may be applicable for the early diagnosis and prognosis of lung squamous cell carcinoma patients. PMID- 23725127 TI - Effects of age, breast density and volume on breast cancer diagnosis: a retrospective comparison of sensitivity of mammography and ultrasonography in China's rural areas. AB - PURPOSE: Mammography has been confirmed as the only effective mode to improve the prognosis of patients with breast cancer in Western developed countries, but might not be a good choice in other areas of the world. One of the major challenges in China is to determine an optimal imaging modality for breast cancer screening. This study was designed to clarify the sensitivity of ultrasonography compared with that of mammography in rural China. METHODS: We retrospectively studied the sensitivity of mammography and ultrasonography based on 306 breast cancer patients detected by the program of "screening for cervical cancer and breast cancer" performed in Chinese rural areas between January 2009 and December 2011, and analyzed the effects of age, breast density and volume on the sensitivity. RESULTS: Stratified analysis showed that the sensitivity of breast ultrasonography was significantly higher than that of mammography in premenopausal patients (81.4% vs. 61.1%, p=0.02), in women <= 55 years of age (82.2% vs. 63.4%, p<0.01), in the high breast density group (American College of Radiology [ACR] levels 3-4) (85.9% vs. 60.6%, p<0.01) and in the small breast volume group (<= 400 ml) (87.1% vs. 66.7%, p<0.01). Age had a significant effect on sensitivity of mammography (breast density and volume-adjusted odds ratio, 6.39; 95% confidence interval, 2.8-14.4 in age group > 55 compared to age group <= 45), but not that of ultrasonography. Neither breast density nor volume had significant effect on sensitivity of mammography or ultrasonography. CONCLUSIONS: Ultrasonography is more sensitive than mammography in detecting breast cancer in women under 55 year-old Chinese, especially in those with high-density and relatively small breasts. PMID- 23725129 TI - Aberrant expression of miR-20a and miR-203 in cervical cancer. AB - MicroRNAs (miRNAs) are small, non-coding RNAs that are critical regulators of various diseases. MicroRNA- 20a (miR-20a) and microRNA-203 (miR-203) have previously shown significant alteration in a range of cancers. In this study, the expression levels of miR-20a and miR-203 in 100 cervical cancer tissues were detected by qRT-PCR and compared to patient matched-nontumor cervical tissues. Correlations between expression level and clinicopathologic characteristics of cervical cancer were also analyzed. Finally, we studied the effect of miR- 20a and miR-203 on cell proliferation in cervical cancer cell lines by MTT. We found that the expression level of miR-20a (P<0.001) was significantly higher in cervical cancer patients than in healthy controls, while that of miR-203 (P<0.001) was lower. Aberrant expression of miR-20a was correlated with lymph node metastasis (LNM), histological grade and tumor diameter, but down-regulated miR-203 was correlated with LNM only. Furthermore, we found that over-expression of miR-203 decreased cell proliferation, while reduction of miR- 20a also prevented tumor progression. Our results support the involvement of miR-20a and miR-203 in cervical tumorigenesis. We propose that miRNAs might be used as therapeutic agents for cervical cancer. PMID- 23725128 TI - XELIRI plus bevacizumab compared with FOLFIRI plus bevacizumab as first-line setting in patients with metastatic colorectal cancer: experiences at two institutions. AB - BACKGROUND: Efficacy of chemotherapy plus bevacizumab has been shown in patients with metastatic colorectal cancer (mCRC) compared with chemotherapy alone. The aim of the present study was to evaluate the efficacy and safety of FOLFIRI or XELIRI regimens in combination with bevacizumab for mCRC patients in a first-line setting. MATERIALS AND METHODS: A total of 132 patients with previously untreated and histologically confirmed mCRC were included. They were treated with either FOLFIRI-Bevacizumab (Bev) or XELIRI-Bev according to physician preference. The efficacy and safety of the two regimens were compared. RESULTS: Between 2006 and 2010, 68 patients were treated with the XELIRI-Bev regimen, while the remaining 64 patients received the FOLFIRI-Bev regimen. The median age was 58.5 years (53.6 years in the FOLFIRI-Bev and 59.7 years in the XELIRI-Bev arm, p=0.01). Objective response rate was 51.6% for FOLFIRI-Bev versus 41.2% for XELIRI-Bev (p=0.38). At the median follow-up of 24.5 months, the median progression-free survival (PFS) was not different between two groups (14.2 months in FOLFIRI-Bev vs. not reached in the XELIRI-Bev, p=0.30). However, median overall survival time for the FOLFIRI Bev arm was better than that for patients treated with XELIRI- Bev, but these differences was not statistically significant (37.8 months vs. 28.7 months, respectively, p=0.58). Most commonly reported grade 3-4 toxicities (FOLFIRI-Bev vs XELIRI-Bev) were nausea/vomiting (7.8% vs. 14.7%, p=0.27), diarrhea (10.9% vs 22.1%, p=0.10), hand-foot syndrome (0% vs 8.8%, p=0.02) and neutropenia (18.7% vs 27.9%, p=0.22). CONCLUSION: Our results showed that FOLFIRI-Bev and XELIRI-Bev regimens were similarly effective treatments in a first-line setting for patients with untreated mCRC, with manageable adverse event profiles. PMID- 23725130 TI - Caveolin-1, through its ability to negatively regulate TLR4, is a crucial determinant of MAPK activation in LPS-challenged mammary epithelial cells. AB - BACKGROUND: To explore the role of caveolin-1(CAV-1) gene silencing on MAPK activation in lipopolysaccharide (LPS)-challenged human mammary epithelial cells. METHODS: We established a MCF-10ACE of CAV-1 gene silencing from human mammary epithelial cell line MCF-10A by RNAi technology. DNA Microarray were used to detect the expression of inflammation-associated genes in MCF-10ACE. Western blotting was used to examine the activation of MAPK in lipopolysaccharide(LPS) challenged MCF-10A and MCF-10ACE. Moreover, immunofluorescence and Western bloting were performed to detect the co-localization of CAV-1 and toll-like receptor 4 (TLR4) in human mammary epithelial cells. RESULTS: MCF-10ACE exhibited significant increases in inflammation-associated gene expression, especially IL-6 (~7-fold) and IL6R (~17-fold). In addition, LPS-induced p38 MAPK and JNK MAPK activation was significantly increased in MCF-10ACE. Furthermore, CAV-1 co- localized with TLR4 and appeared a negative correlation trend. CONCLUSION: CAV-1 gene silencing promotes MAPK activation via TLR4 signaling in human mammary epithelial cells response to LPS. PMID- 23725131 TI - Isolation of a quinone-rich fraction from Ardisia crispa roots and its attenuating effects on murine skin tumorigenesis. AB - Ardisia crispa (Family: Myrsinaceae) is an evergreen, fruiting shrub that has been traditionally used as folklore medicine. Despite a scarcity of research publications, we have succeeded in showing suppressive effects on murine skin papillomagenesis. In extension, the present research was aimed at determining the effect of a quinone-rich fraction (QRF) isolated from the same root hexane extract on both initiation and promotion stages of carcinogenesis, at the selected dose of 30 mg/kg. Mice (groups I-IV) were initiated with a single dose of 7,12-dimethylbenz(alpha)anthracene (DMBA, 100 MUg/100 MUl) followed by repeated promotion of croton oil (1%) twice weekly for 20 weeks. In addition, group I (anti-initiation) received QRF 7 days before and after DMBA; group II (anti-promotion) received QRF 30 minutes before each croton oil application; group III (anti-initiation/ promotion) was treated with QRF as a combination of group I and II. A further two groups served as vehicle control (group V) and treated control (group VI). As carcinogen control, group IV showed the highest tumor volume (8.79+/-5.44) and tumor burden (3.60+/-1.17). Comparatively, group III revealed only 20% of tumor incidence, tumor burden (3.00+/-1.00) and tumor volume (2.40+/-1.12), which were significantly different from group IV. Group II also showed significant reduction of tumor volume (3.11), tumor burden (3.00) and tumor incidence (11.11%), along with prominent increase of latency period of tumor formation (week 12). Group I, nonetheless, demonstrated marked increment of tumor incidence by 40% with prompted latency period of tumor formation (week 7). No tumor formation was observed in groups V and VI. This study provided clear evidence of inhibitory effects of QRF during promotion period which was in agreement with our previous findings. The mechanism(s) underlying such effects have yet to be elucidated. PMID- 23725132 TI - Enhanced antitumor effect of curcumin liposomes with local hyperthermia in the LL/2 model. AB - Curcumin previously was proven to inhibit angiogenesis and display potent antitumor activity in vivo and in vitro. In the present study, we investigated whether a combination curcumin with hyperthermia would have a synergistic antitumor effect in the LL/2 model. The results indicated that combination therapy significantly inhibited cell proliferation of MS-1 and LL/2 in vitro. LL/2 experiment model also demonstrated that the combination therapy inhibited tumor growth and prolonged the life span in vivo. Furthermore, combination therapy reduced angiogenesis and increased tumor apoptosis. Our findings suggest that the combination therapy exerted synergistic antitumor effects, providing a new perspective fpr clinical tumor therapy. PMID- 23725133 TI - Down-regulation of long non-coding RNA TUG1 inhibits osteosarcoma cell proliferation and promotes apoptosis. AB - OBJECTIVE: To investigate the expression level of TUG1 and one of its transcript variants (n377360) in osteosarcoma cells and assess the role of TUG1 in proliferation and apoptosis in the U2OS cell line. METHODS: TUG1 and n377360 expression levels in patients with osteosarcomas and the U2OS human osteosarcoma cell line were evaluated using real-time quantitative PCR. U2OS cells were transected with TUG1 and n377360 siRNA or non-targeting siRNA. MTS was performed to assess the cell proliferation and flow cytometry was applied to analyze apoptosis. RESULTS: We found significantly higher TUG1 and n377360 expression levels in osteosarcoma tissues compared with matched non-tumorous tissues. In line with this, suppression of TUG1 and n377360 expression by siRNA significantly impaired the cell proliferation potential of osteosarcoma cells. Furthermore, inhibition of TUG1 expression significantly promoted osteosarcoma cell apoptosis. CONCLUSIONS: The overexpression of TUG1 and n377360 in osteosarcoma specimens and the functional role of TUG1 and n377360 regarding cell proliferation and apoptosis in an osteosarcoma cell line provided evidence that the use of TUG1 or n377360 may be a viable but an as yet unexplored therapeutic strategy in tumors that over express these factors. PMID- 23725134 TI - Testing the transtheoretical model in predicting smoking relapse among Malaysian adult smokers receiving assistance in quitting. AB - The role of The Transtheoretical Model (TTM) in predicting relapse is limited. We aimed to assess whether this model can be utilised to predict relapse during the action stage. The participants included 120 smokers who had abstained from smoking for at least 24 hours following two Malaysian universities' smoking cessation programme. The smokers who relapsed perceived significantly greater advantages related to smoking and increasing doubt in their ability to quit. In contrast, former smokers with greater self-liberation and determination to abstain were less likely to relapse. The findings suggest that TTM can be used to predict relapse among quitting smokers. PMID- 23725135 TI - Plumbagin from Plumbago Zeylanica L induces apoptosis in human non-small cell lung cancer cell lines through NF- kappaB inactivation. AB - OBJECTIVE: To detect effects of plumbagin on proliferation and apoptosis in non small cell lung cancer cell lines, and investigate the underlying mechanisms. MATERIALS AND METHODS: Human non-small cell lung cancer cell lines A549, H292 and H460 were treated with various concentrations of plumbagin. Cell proliferation rates was determined using both cell counting kit-8 (CCK-8) and clonogenic assays. Apoptosis was detected by annexin V/propidium iodide double-labeled flow cytometry and TUNEL assay. The levels of reactive oxygen species (ROS) were detected by flow cytometry. Activity of NF-kappaB was examined by electrophoretic mobility shift assay (EMSA) and luciferase reporter assay. Western blotting was used to assess the expression of both NF-kappaB regulated apoptotic-related gene and activation of p65 and IkappaBkappa. RESULTS: Plumbagin dose-dependently inhibited proliferation of the lung cancer cells. The IC50 values of plumbagin in A549, H292, and H460 cells were 10.3 MUmol/L, 7.3 MUmol/L, and 6.1 MUmol/L for 12 hours, respectively. The compound concentration-dependently induced apoptosis of the three cell lines. Treatment with plumbagin increased the intracellular level of ROS, and inhibited the activation of NK-kappaB. In addition to inhibition of NF-kappaB/p65 nuclear translocation, the compound also suppressed the degradation of IkappaBkappa. ROS scavenger NAC highly reversed the effect of plumbagin on apoptosis and inactivation of NK-kappaB in H460 cell line. Treatment with plumbagin also increased the activity of caspase-9 and caspase-3, downregulated the expression of Bcl-2, upregulated the expression of Bax, Bak, and CytC. CONCLUSIONS: Plumbagin inhibits cell growth and induces apoptosis in human lung cancer cells through an NF-kappaB-regulated mitochondrial-mediated pathway, involving activation of ROS. PMID- 23725136 TI - Epidemiology of leukemia and multiple myeloma in Golestan, Iran. AB - BACKGROUND: The aim of this paper was to present the incidence rates of leukemia and multiple myeloma (MM) in Golestan province located in northeastern Iran during 2004-2009. MATERIALS AND METHODS: This was a descriptive cross-sectional study. Data on newly diagnosed (incident) leukemia and MM cases were obtained from collected from Golestan population-based cancer registry. Data was entered into CanReg-4 software. Age standardized incidence rates (ASR) (per 100000 person years) for leukemia and MM were calculated. Data on Golestan population was obtained from the data of Iranian national census in 2006. RESULTS: Totally, 11036 new cancer cases were registered in GPRC from 2004-2009. Leukemia and MM accounted for 693 and 124 of cases, respectively. The mean age in patients with leukemia and MM was 43.8 and 62.4 years, respectively. The ASRs for leukemia among men and women were 10.4 and 7.8, respectively (p<0.001). The ASRs for MM were 2.1 and 2 in men and women, respectively (p=0.93). The rate of leukemia was significantly higher in rural areas (p=0.02) whereas the incidence of MM was higher in urban areas (p<0.001). CONCLUSIONS: Our results showed a high incidence rate of leukemia in Golestan province of Iran. The incidence of leukemia was significantly higher in males and residents of rural areas. High exposure to pesticides and other agricultural related products may be a possible explanation for epidemiological pattern of leukemia in this area. Determining and controlling important risk factors, especially environmental factors, of leukemia may lead to decrease in its burden in Golestan province of Iran. PMID- 23725137 TI - Association of mir-499 and mir-149 polymorphisms with cancer risk in the Chinese population: evidence from published studies. AB - Meta-analyses have shown that microRNA polymorphisms have variable effects in different population. Yet, no meta-analysis investigated the association of two common polymorphisms of miRNA, mir-499 rs3746444 polymorphism and mir-149 rs2292832 polymorphism, with cancer risk in the Chinese population. We searched the PubMed, Web of Knowledge, MEDLINE, CNKI databases, as well as Cochrane library, updated on December 31, 2012 for assays regarding cancer risk association with these two common polymorphisms in the present meta-analysis. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to explore the strength of associations. The results showed that rs3746444 polymorphism was associated with increased cancer risk (dominant model: GG/AG vs. AA: OR = 1.43, 95% CI: 1.14-1.80; recessive model: GG vs. AG/AA: OR = 1.54, 95% CI: 1.04-2.30; homozygote model: GG vs. AA: OR = 1.69, 95% CI: 1.10-2.60; heterozygote model: AG vs. AA: OR = 1. 35, 95% CI: 1.09-1.67), and rs3746444 was associated with liver cancer in the subgroup of cancer types. For the rs2292832 polymorphism, the results showed no significant risk association in both overall pooled analysis and subgroup of cancer types, smoking status, gender and tea drinking status in the Chinese population. This meta-analysis suggested that the rs3746444 GG genotype is associated with increased cancer risk, especially liver cancer, while the rs2292832 polymorphism showed no association with cancer risk in Chinese. PMID- 23725138 TI - Effects of celecoxib on cycle kinetics of gastric cancer cells and protein expression of cytochrome C and caspase-9. AB - OBJECTIVE: This investigation aimed to determine effects of celecoxib on the cell cycle kinetics of the gastric cancer cell line MGC803 and the mechanisms involved by assessing expression of cytochrome C and caspase-9 at the protein level. METHODS: Cell proliferation of MGC803 was determined by MTT assay after treatment with celecoxib. Apoptosis was assessed using fluorescence staining and cell cycle kinetics by flow cytometry. Western blotting was used to detect the expression of caspase-9 protein and of cytochrome C protein in cell cytosol and mitochondria. RESULTS: Celecoxib was able to restrain proliferation and induce apoptosis in a dose- and time- dependent manner, inducing G0/G1 cell cycle arrest, release of cytochrome C into the cytosol, and cleavage of pro-caspase-9 into its active form. CONCLUSION: Celecoxib can induce apoptosis in MGC803 cells through a mechanism involving cell cycle arrest, mitochondrial cytochrome C release and caspase activation. PMID- 23725139 TI - NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T gene polymorphism association with digestive tract cancer: a meta-analysis. AB - NAD(P)H: quinone oxidoreductase 1 (NQO1) C609T gene polymorphisms have been reported to influence the risk for digestive tract cancer (DTC) in many studies; however, the results remain controversial and ambiguous. We therefore carried out a meta-analysis of published case-control studies to derive a more precise estimation of any associations. Electronic searches were conducted on links between this variant and DTC in several databases through April 2012. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to estimate the strength of associations in fixed or random effect models. Heterogeneity and publication bias were also assessed. A total of 21 case-control studies were identified, including 6,198 cases and 7,583 controls. Overall, there was a statistically significant association between the NQO1 C609T polymorphism and DTC risk (TT vs. CC: OR=1.224, 95%CI=1.055-1.421; TT/CT vs. CC: OR=1.195, 95%CI=1.073 1.330; TT vs. CT/CC: OR=1.183, 95%CI=1.029-1.359; T vs. C: OR=1.180, 95%CI=1.080 1.290). When stratified for tumor location, the results based on all studies showed the variant allele 609T might have a significantly increased risk of upper digest tract cancer (UGIC), but not colorectal cancer. In the subgroup analysis by ethnicity, we observed a significantly risk for DTC in Caucasians. For esophageal and gastric cancer, a significantly risk was found in both populations, and for colorectal, a weak risk was observed in Caucasians, but not Asians. This meta-analysis suggested that the NQO1 C609T polymorphism may increase the risk of DTC, especially in the upper gastric tract. PMID- 23725140 TI - Preliminary study on human papillomavirus frequency and specific type distribution in vulva cancer from Thai women. AB - Vulva cancer is rare among all gynecological cancer worldwide, including Thailand, and mainly affects older women. Persistent high risk type infection of human papillomavirus (HPV) is the one important factor for developing cancer. In this study, we focused on HPV DNA investigation and type-specific distribution of HPV in 25 formalin-fixed paraffin-embedded (FFPE) samples collected from Thai women with vulva cancer histologically confirmed by the National Cancer Institute, Thailand, during 2003-2011. HPV DNA detection and genotyping were undertaken with polymerase-chain reaction and enzyme-immunoassay using GP5+/bio6+ consensus specific primers and digoxigenin-labeled specific oligoprobes, respectively. Human beta-globin genes was used as the internal control. Our results showed that 44% (11/25) of all vulva cancer samples were HPV-positive. All of them are high risk HPV type infection, detected as single (63.64%, 7/11) and/or double infections (4/11, 36.36%). HPV 16 was the most common type identified in vulva cancer, followed by HPV 35, 33, 18 and 58. In conclusion, this study presented that HPV-16 is observed at the highest frequency in this cancer, similar to cervical cancer, with HPV 18 being less frequent. Although the sample size was small and could not represent overall incidence and prevalence in Thai women, these preliminary data for vulva cancer are of interest since they reinforce the necessity for HPV screening or vaccination in Thailand. PMID- 23725141 TI - Effects of miR-155 antisense oligonucleotide on breast carcinoma cell line MDA-MB 157 and implanted tumors. AB - Diverse studies have shown that miR-155 is overexpressed in different tumor types. However, the precise molecular mechanism of the ectopic expression of miR 155 in breast cancer is still poorly understood. To further explore the role of miR-155 in breast tumorigenesis, we here assessed the influence of miR-155 antisense oligonucleotide (miR-155 ASO) on MDA-MB-157 cell viability and apoptosis in vitro. Furthermore, the effects of inhibitory effects of miR-155 on the growth of xenograft tumors in vivo were determined with performance of immunohistochemistry to detect expression of caspase-3, a pivotal apoptosis regulatory factor, in xenografts. Transfection efficiency detected by laser confocal microscope was higher than 80%. The level of miR-155 expression was significantly decreased (P<0.05) in the cells transfected with miR-155 ASO, compared with that in cells transfected with a negative control. After being transfected with miR-155 ASO, the viability of MDA-MB-157 cells was reduced greatly (P<0.05) and the number of apoptotic cells was increased significantly. Additionally, miR-155 ASO inhibited the growth of transplanted tumor in vivo and significantly increased the expression of caspase-3. Taken together, our study revealed that miR-155 ASO can induce cell apoptosis and inhibit cell proliferation in vitro. Moreover, miR-155 ASO could significantly repress tumor growth in vivo, presumably by inducing apoptosis via caspase-3 up-regulation. These findings provide experimental evidence for using miR-155 as a therapeutic target of breast carcinoma. PMID- 23725142 TI - Preventive effects of resveratrol against azoxymethane induced damage in rat liver. AB - BACKGROUND: In recent years, due to modern lifestyles and exposure to chemical carcinogens, cancer cases are steadily increasing. From this standpoint, azoxymethane (AOM), a chemical carcinogen which causes de novo liver damage, and resveratrol, which is an antioxidant found in foods and protects against oxidative stress damage, are of interest. We here aimed to evaluate whether resveratrol could protect the liver tissues from the effects of AOM. MATERIALS AND METHODS: The study was conducted in 4 groups, each consisting of seven rats, the first receiving only AOM (2 times per week, 5 mg/kg), group 2 AOM and resveratrol (2 times a week, 20 mg/kg), group 3 assessed only as a control and group 4 administered only resveratrol. At the end of the seventh week, the rats were sacrificed. Rat liver MDA, NO, GSH levels were analyzed biochemically, as well as the tissues being evaluated histopathologically. RESULTS: MDA and NO increased in AOM group as signs of increased oxidative stress. The group concomitantly administered resveratrol was been found to be significantly decreased in MDA and NO levels and increased in GSH activity. However, there were no significant findings on histopathological evaluation. CONCLUSIONS: In the light of these results, resveratrol appears to exert protective effect on oxidative stress in the liver tissue due to deleterious effects of chemical carcinogens. PMID- 23725143 TI - Prediction and analysis of ligands against estrogen related receptor alpha. AB - Breast cancer is one of the most common malignancies in women around the world. Among the various hormonal types of breast cancer, those that are estrogen receptor (ER) positive account for the majority. Among the estrogen related receptors, estrogen related receptor alpha is known to have a potential role in breast cancer and is one of the therapeutic target. Hence, prediction of novel ligands interact with estrogen related receptor alpha is therapeutically important. The present study, aims at prediction and analysis of ligands from the KEGG COMPOUND database (containing 10,739 entries) able to interact against estrogen receptor alpha using a similarity search and molecular docking approach. PMID- 23725144 TI - Comparison of clinical efficacy of three different neoadjuvant approaches (chemotherapy combined vaginal intracavitary irradiation, neoadjuvant chemotherapy alone or radiotherapy) combined with surgery for patients with stage Ib2 and IIa2 cervical cancer. AB - A total of 285 patients with stage Ib2 and IIa2 cervical cancer were categorized into three groups, and received preoperative neoadjuvant chemotherapy combined with vaginal intracavitary irradiation, neoadjuvant chemotherapy alone or radiotherapy, respectively. The effective rate of 70.6 % in group 1 was much higher than 41.4% in group 2 (P=0.000) and 46.9 % in group 3 (P=0.000); The percentage of patients receiving postoperative adjuvant therapy was 44.1% in group 1, much lower than 67.8% in group 2 (P=0.001) and 64.6% in group 3 (P=0.004); The percentage of patients with no postoperative risk factor in group 1 was 52.0%, much higher than 32.2% in group 2 (P=0.006) and 35.4% in group 3 (P=0.019); The occurrence rate of surgery-related complications in groups 1, 2 and 3 were 29.4%, 28.7%, and 33.3%, respectively, with no statistical differences among the groups (P=0.981). Regarding preoperative neoadjuvant complications, none were obvious in group 3, while occurrence rates of myelosuppression in groups 1 and 2 were 89.1% and 86.6%, of nausea and vomitting were 78.4% and 78.2%, but without significant differences (all P>0.05). Among 166 patients who received postoperative adjuvant therapy in the three groups, the occurrence rates were: 65.4%, 64.3% and 61.1% respectively for myelosuppression; 42.3%, 38.1%, and 38.9% for nausea and vomiting; 9.6%, 9.5% and 9.7% for urocystitis; and 63.5%, 69.0% and 65.3% enteritis and rectitis. There were no statistically significant differences among them (all P>0.05). The five-year disease-free survival rates (DFS) in groups 1, 2, 3 were 78.3%, 75.1%, 80.9%, respectively; the five-year overall survival rates (OS) were 81.4%, 78.2%, and 81.1%, respectively. The five year OS of 166 patients receiving postoperative in the three groups were 72.4%, 69.5%, and 71.8%, respectively, with no significant variation (all P>0.05). Although there were no differences among three groups in DFS and OS, preoperative neoadjuvant chemotherapy combined with intracavitary radiotherapy may increase the effective rate and the percentage of patients with no postoperative risk factors and decrease the percentage of patients receiving postoperative adjuvant therapy, thereby decreasing complications indirectly and increasing quality of life. PMID- 23725145 TI - Soluble expression of recombinant human SMP30 for detecting serum SMP30 antibody levels in hepatocellular carcinoma patients. AB - Senescence marker protein 30 (SMP30), a hepatocellular carcinoma (HCC) associated antigen, was earlier shown by our research group to be highly expressed in HCC paracancerous tissues, but have low levels in HCC tissues. In order to detect anti-SMP30 antibody in serum of HCC patients, we established pET30a-SMP30 and pColdIII-SMP30 expression systems in Escherichia coli. However, the expression product was mainly in the form of inclusion bodies. In this research, we used several combinations of chaperones, four molecular chaperone plasmids with pET30a SMP30 and five molecular chaperone plasmids with pColdIII-SMP30 to increase the amount of soluble protein. Results showed that co-expression of HIS-SMP30 with pTf16, combined with the addition of osmosis-regulator, and a two-step expression resulted in the highest enhancement of solubility. A total of 175 cases of HCC serum were studied by ELISA to detect anti- SMP30 antibody with recombinant SMP30 protein. Some 22 were positive and x2 two-sided tests all showed P>0.05, although it remained unclear whether there was a relationship between positive cases and clinical diagnostic data. PMID- 23725146 TI - Effect of Bcl-2 on apoptosis and transcription factor NF-kappaB activation induced by adriamycin in bladder carcinoma BIU87 cells. AB - Resistance to apoptosis is a major obstacle preventing effective therapy for malignancies. Bcl-2 plays a significant role in inhibiting apoptosis. We reconstructed a stable human Bcl-2 transfected cell line, BIU87- Bcl-2, that was derived from the transfection of human bladder carcinoma cell line BIU87 with a plasmid vector containing recombinant Bcl-2 [pcDNA3.1(+)-Bcl-2]. A cell line transfected with the plasmid alone [pcDNA3.1(+)- neo] was also established as a control. BIU87 and BIU87-neo proved sensitive to adriamycin induced apoptosis, while BIU87-Bcl-2 was more resistant. In view of the growing evidence that NF kappaB may play an important role in regulating apoptosis, we determined whether Bcl-2 could modulate the activity of NF-kappaB in bladder carcinoma cells. Stimulation of BIU87, BIU87-neo and BIU87-Bcl-2 with ADR resulted in an increase expression of NF-kappaB (p<0.001). The expression of NF-kappaB in BIU87-Bcl-2 was higher than in the other two cases, with a concomitant reduction in the IkappaBkappa?protein level. These results suggest that the overexpression of Bcl 2 renders human bladder carcinoma cells resistant to adriamycin -induced cytotoxicity and there is a link between Bcl-2 and the NF-kappaB signaling pathway in the suppression of apoptosis. PMID- 23725147 TI - Mitochondrial genome microsatellite instability and copy number alteration in lung carcinomas. AB - OBJECTIVE: Mitochondrial DNA (mtDNA) is considered a hotspot of mutations in various tumors. However, the relationship between microsatellite instability (MSI) and mtDNA copy number alterations in lung cancer has yet to be fully clarifieds. In the current study, we investigated the copy number and MSI of mitochondrial genome in lung carcinomas, as well as their significance for cancer development. METHODS: The copy number and MSI of mtDNA in 37 matched lung carcinoma/adjacent histological normal lung tissue samples were examined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assays for sequence variation, followed by sequence analysis and fluorogenic 5' nuclease real-time PCR. Student's t test and linear regression analyses were employed to analyze the association between mtDNA copy number alterations and mitochondrial MSI (mtMSI). RESULTS: The mean copy number of mtDNA in lung carcinoma tissue samples was significantly lower than that of the adjacent histologically normal lung tissue samples (p < 0.001). mtMSI was detected in 32.4% (12/37) of lung carcinoma samples. The average copy number of mtDNA in lung carcinoma samples containing mtMSI was significantly lower than that in the other lung carcinoma samples (P < 0.05). CONCLUSIONS: Results suggest that mtMSI may be an early and important event in the progression of lung carcinogenesis, particularly in association with variation in mtDNA copy number. PMID- 23725148 TI - Predictive factors determining neoadjuvant chemotherapy outcomes in breast cancer - a single center experience. AB - From January 1, 2008 to March 31, 2010, 101 patients with stage II-III breast cancer were enrolled in this study and subjected to an anthracycline-based neoadjuvant chemotherapy regimen with or without docetaxel. Surgery was performed after 2-6 cycles of chemotherapy, and the clinical response was determined by pathological and histochemical assessments. The clinical response rate, as indicated by complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD), were 6.9, 52.5, 36.6, and 4.0%, respectively. A multivariable correlation analysis indicated that the overall clinical response rate correlated with the number of metastatic lymph nodes, number of chemotherapy cycles, and vessel invasion status. Importantly, the CR rate was only associated with the number of chemotherapy cycles. Nonparametric tests failed to detect a correlation between HER2 or Topo IIalpha status and clinical response to neoadjuvant chemotherapy in these patients. When they were stratified by HER2 or HR status, for HER2-positive patients the CR rate was associated with vessel invasion and Topo IIalpha status. Based on our findings, we propose that HR, HER 2 and Topo IIalpha are not putative predictive biomarkers of chemotherapy outcome for breast cancer patients. Topo IIalpha expression level was only inversely correlated with CR rate among HR-positive patients. Importantly, the achievement of CR was largely related to the number of chemotherapy cycles. PMID- 23725149 TI - Post-diagnosis soy food intake and breast cancer survival: a meta-analysis of cohort studies. AB - BACKGROUND AND OBJECTIVES: Data on associations between soy food intake after cancer diagnosis with breast cancer survival are conflicting, so we conducted this meta-analysis for more accurate evaluation. METHODS: Comprehensive searches were conducted to find cohort studies of the relationship between soy food intake after cancer diagnosis and breast cancer survival. Data were analyzed with comprehensive meta-analysis software. RESULTS: Five cohort studies (11,206 patients) were included. Pooling all comparisons, soy food intake after diagnosis was associated with reduced mortality (HR 0.85, 95%CI 0.77 0.93) and recurrence (HR 0.79, 95%CI 0.72 0.87). Pooling the comparisons of highest vs. lowest dose, soy food intake after diagnosis was again associated with reduced mortality (HR 0.84, 95%CI 0.71 0.99) and recurrence (HR 0.74, 95%CI 0.64 0.85). Subgroup analysis of ER status showed that soy food intake was associated with reduced mortality in both ER negative (highest vs. lowest: HR 0.75, 95%CI 0.64 0.88) and ER positive patients (highest vs. lowest: HR 0.72, 95%CI 0.61 0.84), and both premenopausal (highest vs. lowest: HR 0.78, 95%CI 0.69 0.88) and postmenopausal patients (highest vs. lowest: HR 0.81, 95%CI 0.73 0.91). In additioin, soy food intake was associated with reduced recurrence in ER negative (highest vs. lowest: HR 0.64, 95%CI 0.44 0.94) and ER+/PR+ (highest vs. lowest: HR 0.65, 95%CI 0.49 0.86), and postmenopausal patients (highest vs. lowest: HR 0.67, 95%CI 0.56 0.80). CONCLUSION: Our meta- analysis showed that soy food intake might be associated with better survival, especially for ER negative, ER+/ PR+, and postmenopausal patients. PMID- 23725150 TI - Epidermal growth factor receptor tyrosine kinase inhibitor versus placebo as maintenance therapy for advanced non- small-cell lung cancer: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Use of epidermal growth factor receptor inhibitors (EGFR-TKIs ) is now standard for non- small-cell lung cancer (NSCLC). However, the effects of EGFR-TKIs in maintenance therapy for advanced NSCLC patients are still unclear. The preent meta-analysis was performed to examine pooled data of randomized control trials (RCT) where EGFR-TKIs were compared against placebo in maintenance regimens for patients with advanced NCSLC to quantify potential benefits and determine safety. METHODS: Several data bases were searched, including PubMed, EMBASE and CENTRAL, and we performed an internet search of conference literature. The endpoints were objective response rates (ORR), progression-free survival (PFS) and overall survival (OS). We performed a meta-analysis of the published data, using Comprehensive Meta Analysis software (Version 2.0). with a fixed effects model and an additional random effects model, when applicable. The results of the meta-analysis are expressed as hazard ratios (HRs) or risk ratios (RRs), with their corresponding 95% confidence intervals (95%CIs). RESULTS: The final analysis included six trials, covering 3,758 patients. Compared with placebo, EGFR-TKIs maintenance therapy improved ORR and PFS for patients with advanced NSCLC, the difference being statistically significant (P<0.05), but proved unable to prolong patients' OS. The main adverse reactions were diarrhea and rashes. CONCLUSION: EGFR-TKIs demonstrated encouraging efficacy, safety and survival when delivered as maintenance therapy for patients with advanced NSCLC after first-line chemotherapy, especially for the patients who had adenocarcinomas, were female, non-smokers and patients with EGFR gene mutations. PMID- 23725151 TI - Treatment outcomes of paclitaxel for refractory or recurrent epithelial ovarian cancer patients in Thailand. AB - BACKGROUND: To study the response rate, toxicity profiles, and survival of refractory or recurrent epithelial ovarian cancer (EOC) patients treated with paclitaxel. MATERIALS AND METHODS: Patients with refractory or recurrent EOC who were treated with paclitaxel between January 2002 and December 2011 at the Department of Obstetrics and Gynecology, Faculty of Medicine, Vajira Hospital were identified. Clinicopathological features of the patients including detailed data of paclitaxel treatment were collected. RESULTS: During the study period, a total of 44 patients were identified, with a mean age of 52.9+/-8.2 years. Some 13.6% (six patients) had refractory cancer to first-line chemotherapy while 86.4% (38 patients) had recurrent cancer. Among these, 35 (79.6%) and 9 (20.4%) patients were considered as platinum-sensitive and platinum-resistant, respectively. Three patients (6.8%) received fewer than 2 cycles of paclitaxel due to loss to follow-up, leaving 41 patients evaluable for response. The overall response rate observed in all 41 patients was 41.5% (17 patients; 12 complete and five partial responses): 12.5% or 1/8 patients with refractory or platinum resistant cancer and 48.5% or 16/33 patients with platinum-sensitive disease. Stable disease was demonstrated in 17.0% (seven patients) while progressive disease was apparent in 41.5% (17 patients). Median time to progress was 4.5 months (range, 0.67- 58.6 months). Median progression-free survival was not reached while median overall survival was 16.3 months (95% confidence interval, 11.0 months -21.6 months). Common toxicities were neutropenia, neuropathy, and alopecia. CONCLUSIONS: Paclitaxel is an active agent for refractory or recurrent EOC. Neutropenia, neuropathy and alopecia are common side effects. PMID- 23725152 TI - Epidemiology of esophageal cancer in Yanting - regional report of a national screening programme in China. AB - BACKGROUND AND OBJECTIVES: Yanting in Sichuan Province is one of the highest risk areas of esophageal cancer (EC) in the world. We here summarize the epidemiology of EC in Yanting using data from the national screening programme during 2006 2011. METHODS: Random cluster sampling was used to select a proportion of natural villages from six towns in Yanting, and residents aged 40-69 years old were invited for screening. Participants were screened using endoscopy with iodine staining and then confirmed by histological examinations. RESULTS: The overall detection rates of low-grade hyperplasia (LH), moderate hyperplasia (MH), high grade hyperplasia (HH), carcinoma in situ (CIS), intramucosal carcinoma (IC) and invasive carcinoma (INC) were 5.33%, 1.28%, 0.68% , 0.15% , 0.06% and 0.29%, respectively. The detection rates of LH, MH, HH and INC increased with age, reaching the peak among those aged 60-65 years, and the prevalences of LH and MH were higher among men than among women. In addition, the detection rates of hyperplasia were much higher in mountainous than in hilly areas. CONCLUSIONS: Among the high risk population, there are a great number of people with early stage EC or precancerous conditions who do not have presenting symptoms. In particular, the elderly, men, or those living in mountainous areas are the most vulnerable population. It is therefore important to reinforce health education and screening services among such high risk populations. PMID- 23725153 TI - Vascular endothelial growth factor (VEGF) gene polymorphisms and breast cancer risk in a Chinese population. AB - Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis and thereby involved in the development and progression of solid tumours. Associations between three VEGF gene polymorphisms (-634 G/C, +936 C/T, and +1612 G/A) and breast cancer risk have been extensively studied, but the currently available results are inconclusive. Our aim was to investigate associations between three VEGF gene polymorphisms and breast cancer risk in Chinese Han patients. We performed a hospital-based case-control study including 680 female incident breast cancer patients and 680 female age-matched healthy control subjects. Polymerase chain reaction restriction fragment length polymorphism (PCR RFLP) analysis was performed to detect the three VEGF gene polymorphisms. We observed that women carriers of +936 TT genotypes [odds ratio (OR) =0.46, 95% confidence interval (CI) = 0.28, 0.76; P=0.002] or 936 T-allele (OR=0.81, 95% CI= 0.68, 0.98; P=0.03) had a protective effect concerning the disease. Our study suggested that the +1612G/A polymorphism was unlikely to be associated with breast cancer risk. The -634CC genotype was significantly associated with high tumor aggressiveness [large tumor size (OR=2.63, 95% CI=1.15, 6.02; P=0.02) and high histologic grade (OR=1.47, 95% CI= 1.06, 2.03; P=0.02)]. The genotypes were not related with other tumor characteristics such as regional or distant metastasis, stage at diagnosis, or estrogen or progesterone receptor status. Our study revealed that the VEGF -634 G/C and +936 C/T gene polymorphisms may be associated with breast cancer in Chinese Han patients. PMID- 23725154 TI - Associations of IL-10 gene polymorphisms with acute myeloid leukemia in Hunan, China. AB - We investigated the possible association of interleukin-10 (IL-10) single nucleotide polymorphisms (SNPs) and susceptibility to acute myeloid leukemia (AML) in 115 patients and 137 healthy controls. Genetic analysis of IL-10 SNPs at -819 and -592 was carried out with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. The IL-10 mRNA expression of AML patients and controls with different genotype was detected by real-time quantitative polymerase chain reaction (RT-PCR). Genetic analysis of IL-10 revealed that the -819AA genotype frequencies and the -819A allele frequencies in the AML group were higher than in the controls (59.1% vs 40.9%; 75.6% vs 63.9%, respectively); there were remarkable differences in -819T/C and -592A/C gene distribution (P<0.05) and the TA haploid frequencies were higher in the AML group (75.6% vs 63.9%, P<0.05). IL-10 mRNA expression in incipient AML patients was obvious higher than the non- tumor group and the remission group (7.78?10-3 vs 2.43?10-3, 3.64?10-3, P<0.05).The study suggested that the haploid TA and genotype TA/TA may be associated with AML in Han people in Hunan province.The IL 10 SNPs at -819 and -592 sites were associated with AML and may affect IL-10 mRNA expression in AML patients. PMID- 23725155 TI - Utility of VEGF and sVEGFR-1 in bronchoalveolar lavage fluid for differential diagnosis of primary lung cancer. AB - Published data have shown that the levels of vascular endothelial growth factor (VEGF) and soluble VEGF receptor-1 (sVEGFR-1) in plasma and pleural effusion might be usefulness for lung cancer diagnosis. Here, we performed a prospective study to investigate the utility of VEGF and sVEGFR-1 in bronchoalveolar lavage fluid (BALF) for differential diagnosis of primary lung cancer. A total of 56 patients with solitary pulmonary massed by chest radiograph or CT screening were enrolled in this study. BALF and plasma samples were obtained from all patients and analyzed for VEGF and sVEGFR-1 using a commercially available sandwich ELISA kit. The results showed that the levels of VEGF in BALF were significantly higher in patients with a malignant pulmonary mass compared with patients with a benign mass (P < 0.001). However, no significant difference of sVEGFR-1 in BALF was found between malignant and non-malignant groups (P = 0.43). With a cut-off value of 214 pg/ml, VEGF showed a sensitivity and specificity of 81.8% and 84.2%, respectively, in predicting the malignant nature of a solitary pulmonary mass. Our study suggests that VEGF is significantly increased in BALF among patients with lung cancer than in benign diseases. Measurement of VEGF in BALF might be helpful for differential diagnosis of primary lung cancer. PMID- 23725156 TI - Inhibition by imatinib of expression of O-glycan-related glycosyltransferases and tumor-associated carbohydrate antigens in the K562 human leukemia cell line. AB - OBJECTIVE: To study changes of tumor associated carbohydrate antigen (TACAs) expression and mRNA levels for tumor associated glycosyltransferases, and assess subcellular localizations of N-acetyl galactosyltransferases (GalNAc-Ts) in the K562 leukemia cell line after imatinib treatment. METHODS: RT-PCR was performed to analyze the expression of glycosyltransferases which synthesize O-glycan in tumor-associated carbohydrate antigens (TCTAs). The expression of Tn antigen, T antigen and sialyl T antigen on K562 cell membranes was measured by flow cytometry after treatment with different concentrations of imatinib. Co localization of GalNAc-Ts and ER (endoplasmic reticulum) was determined by confocal laser scanning microcopy. RESULTS: Transcript expression levels of several glycosyltransferases related to TCTAs were decreased after imatinib (0 0.3MUM) treatment. Expression of Tn antigen and T antigen was increased while that of sialyl T antigen was decreased. Co-localization of GalNAc-Ts and ER was reduced by 0.2MUM of imatinib. CONCLUSION: Imatinib inhibited the expression of O glycan related TACAs and several related glycosyltransferases, while decreasing the co-localization of GalNAc-Ts and ER and normalizing O-glycosylation in the K562 human leukemia cell. PMID- 23725157 TI - Risk of serious neutropenic events in cancer patients treated with bevacizumab: a meta-analysis. AB - Bevacizumab has been approved for use in combination with chemotherapy to treat many types of cancer but associated neutropenic events, including febrile neutropenia, have been reported. To estimate the incidence and relative risk of neutropenic events in cancer patients treated with bevacizumab combination therapy, we searched PubMed, EMBASE, and Web of Science literature databases, as well as abstracts presented at the American Society of Clinical Oncology conferences, to identify relevant studies published from January 1966 to December 2011. Studies that compared bevacizumab plus chemotherapy or biological therapy with chemotherapy or biological therapy alone, and that had adequate safety data profiles, were selected for analysis. Statistical analyses were conducted to calculate the summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) using fixed- or random-effects models. A total of 22 clinical trials involving 15,056 patients were included in the analysis. The summary incidences of high-grade neutropenia (HGN) and high-grade febrile neutropenia (HGFN) in patients receiving bevacizumab was 27.3% (95% CI: 26.4%-28.3%) and 3.91% (95% CI: 3.51%-4.37%), respectively. The risks of HGN (RR=1.10; 95% CI: 1.02-1.19; P=0.02) and HGFN (RR=1.31; 95% CI: 1.08-1.59; P=0.005) were significantly increased in bevacizumab-treated patients, compared to those who did not receive bevacizumab. The RR of bevacizumab-associated HGN, but not HGFN, varied significantly with tumor types (P=0.005). The increased risk of bevacizumab-associated neutropenic events was dose-dependent, as the RR was greater at a dose of 5 mg/kg/week than at 2.5 mg/kg/week. Our findings suggest that bevacizumab addition to cancer therapy significantly increases the risk of serious neutropenic events, and this risk may be dose-dependent. PMID- 23725158 TI - Estimation of gas-particle partitioning coefficients (Kp) of carcinogenic polycyclic aromatic hydrocarbons in carbonaceous aerosols collected at Chiang Mai, Bangkok and Hat-Yai, Thailand. AB - To assess environmental contamination with carcinogens, carbonaceous compounds, water-soluble ionic species and trace gaseous species were identified and quantified every three hours for three days at three different atmospheric layers at the heart of Chiang-Mai, Bangkok and Hat-Yai from December 2006 to February 2007. A DRI Model 2001 Thermal/Optical Carbon Analyzer with the IMPROVE thermal/optical reflectance (TOR) protocol was used to quantify the organic carbon (OC) and elemental carbon (EC) contents in PM10. Diurnal and vertical variability was also carefully investigated. In general, OC and EC mass concentration showed the highest values at the monitoring period of 21.00-00.00 as consequences of human activities at night bazaar coupled with reduction of mixing layer, decreased wind speed and termination of photolysis at nighttime. Morning peaks of carbonaceous compounds were observed during the sampling period of 06:00-09:00, emphasizing the main contribution of traffic emission in the three cities. The estimation of incremental lifetime particulate matter exposure (ILPE) raises concern of high risk of carbonaceous accumulation over workers and residents living close to the observatory sites. The average values of incremental lifetime particulate matter exposure (ILPE) of total carbon at Baiyoke Suit Hotel and Baiyoke Sky Hotel are approximately ten times higher than those air samples collected at Prince of Songkla University Hat-Yai campus corpse incinerator and fish-can manufacturing factory but only slightly higher than those of rice straw burning in Songkla province. This indicates a high risk of developing lung cancer and other respiratory diseases across workers and residents living in high buildings located in Pratunam area. Using knowledge of carbonaceous fractions in PM10, one can estimate the gas-particle partitioning of polycyclic aromatic hydrocarbons (PAHs). Dachs-Eisenreich model highlights the crucial role of adsorption in gas-particle partitioning of low molecular weight PAHs, whereas both absorption and adsorption tend to account for gas-particle partitioning of high molecular weight PAHs in urban residential zones of Thailand. Interestingly, the absorption mode alone plays a minor role in gas particle partitioning of PAHs in Chiang-Mai, Bangkok and Hat-Yai. PMID- 23725159 TI - Prognostic significance of 18F-fluorodeoxyglucose positron emission tomography (PET)-based parameters in neoadjuvant chemoradiation treatment of esophageal carcinoma. AB - AIMS AND BACKGROUND: The purpose of the research was to study the prognostic value of tumor 18F-FDG PET-based parameters in neoadjuvant chemoradiation for patients with squamous esophageal carcinoma. METHODS: Sixty patients received chemoradiation therapy followed by esophagectomy and two 18FDG-PET examinations at pre- and post-radiation therapy. PET-based metabolic-response parameters were calculated based on histopathologic response. Linear regression correlation and Cox proportional hazards models were used to determine prognostic value of all PET-based parameters with reference to overall survival. RESULTS: Sensitivity (88.2%) and specificity (86.5%) of a percentage decrease of SUVmax were better than other PET- based parameters for prediction of histopathologic response. Only percentage decrease of SUVmax and tumor length correlated with overall survival time (linear regression coefficient beta: 0.704 and 0.684, P<0.05). The Cox proportional hazards model indicated higher hazard ratio (HR=0.897, P=0.002) with decrease of SUVmax compared with decrease of tumor size (HR=0.813, P=0.009). CONCLUSION: Decrease of SUVmax and tumor size are significant prognostic factors in chemoradiation of esophageal carcinoma. PMID- 23725160 TI - Survey on knowledge and attitudes related to the relation between tobacco, alcohol abuse and cancer in the northern state of Sudan. AB - BACKGROUND: The aim of this study was to determine the epidemiology of tobacco smoking, toombak dipping and alcohol consumption as risk factors for cancer in the adult population of the northern state of Sudan. MATERIALS AND METHODS: A cross-sectional survey from March to April 2010, covering 963 adults, was performed. RESULT: Only 207 had responded, and the male female prevalence was 20.8% and 0.73%. Out of 207 respondents, 29.5% had smoked tobacco in their lifetime, 38% were toombak dippers, while 14% were consumers of alcoholic beverages. CONCLUSIONS: The prevalence of toombak dipping was higher than tobacco smoking among the adult population in the northern state of Sudan. Female participation in tobacco and alcohol related studies was found to suffer from major obstacles since these habits are considered as social stigma. Appreciation of the full impact of smoking on population health will definitely make a major contribution to improvement of the poor public health situation in Sudan. PMID- 23725161 TI - Genotoxicity and interference with cell cycle activities by an ethanolic extract from Thai Plumbago indica roots in human lymphocytes in vitro. AB - In Thai traditional medicine, Plumbago indica or Jetamul-Pleung-Dang in Thai is known to have health benefit especially for anti-inflammatory, antibacterial, and antitumor activities. However, the mechanisms of its action are still uncertain. One of which might be genotoxic effects. In the present study, we investigated the genotoxicity of an ethanolic extract of Plumbago indica root (EEPIR) by sister chromatid exchange (SCE) assay in human lymphocytes. Results have shown that all treatments with EEPIR (12.5-100 MUg/ml) could induce cell cycle delay as shown by significant increase in the number of metaphase cells in the first cell cycle but neither in the second nor the third cell cycle. Only at concentrations of 25, 50, and 100 MUg/ml were SCE levels significantly increased above that of the control (p<0.05) . EEPIR at a concentration of 500 MUg/ml induced cell death as few mitotic cells were shown. Accordingly, EEPIR (25-100 MUg/ml) is genotoxic in human lymphocytes and cytotoxic at concentrations of >= 500 MUg/ml in vitro. Therefore, these activities of the EEPIR could serve its potential therapeutic effects, especially as an anticancer agent. Further study of EEPIR in vivo is now needed to support this in vitro evidence. PMID- 23725162 TI - Three treatment methods via the hepatic artery for hepatocellular carcinoma - a retrospective study. AB - BACKGROUND: To evaluate the relative effectiveness of different treatments of hepatocellular carcinoma (HCC) via the hepatic artery. MATERIALS AND METHODS: The study sample group consisted of 418 patients who were randomly selected from 2008 to 2012 with a first diagnosis of HCC and treated with transcatheter arterial chemoembolization (TACE) or without (TAE) chemotherapy or transcatheter arterial infusion (TAI). We collected data including tumor size preoperative and one month thereafter to compare change in areas across the three groups, along with various laboratory indexes for comparison. RESULTS: The overall average change of areas was 240.8 +/- 72.1 mm2. In the three groups it was 265.0 +/- 58.0 mm2 vs. 250.5 +/- 51.9 mm2 vs. 123.7 +/- 26.2 mm2. In groups TACE and TAE values were larger than in group TAI (p<0.01), but the difference between the two was not statistically significant (p= 0.191). Additionally, U/L change of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in groups TACE and TAE was greater than in the TAI cases (24.0 +/- 13.5 vs. 20. 9+/- 12.1 vs. 5.47 +/- 8.20 and 25.6 +/- 13.5 vs.23.2 +/- 12.28 vs.5.48 +/- 14.3) on the preoperative day and two days thereafter (p<0.01). Between the two groups there was no significant cariation (p= 0.320 and p= 0.609). However, the AST and ALT recovered to normal levels one month later on therapy with liver protecting drugs. CONCLUSION: The groups TACE and TAE demonstrated more effective reduction of tumor size than group TAI. While lipiodol caused acute liver function damage, this proved reversible. PMID- 23725163 TI - Dietary fat and physical activity in relation to breast cancer among Polish women. AB - BACKGROUND: Dietary fat has been inconsistently associated with the risk of breast cancer. The purpose of this study was to examine the relationship between meat and animal and plant fat intake and breast cancer risk in subgroups by total lifetime physical activity, using data from a case-control study conducted in the Region of Western Pomerania, Poland. MATERIALS AND METHODS: The study included 858 women with histological confirmed breast cancer and 1,085 controls, free of any cancer diagnosis. The study was based on a self-administered questionnaire including questions about socio-demographic characteristics, current weight and height, reproductive factors, family history of breast cancer and lifestyle habits. Unconditional logistic regression was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: High animal fat intake significantly increased OR from 1.7 times (OR=1.66, 95%CI=1.07-3.59) to 2.9 times (OR=2.9, 95%CI=1.37- 6.14) independent of physical activity level, comparing the third versus the lowest quartile. Women with a high intake of red meat or processed meat and low physical activity showed increased risk of breast cancer: OR=2.70, 95%CI=1.21-6.03 and 1.78, 95%CI=1.04-3.59, respectively. The plant fat dietary pattern was negatively associated with breast cancer in sedentary women (OR=0.57, 95%CI=0.32-0.99). CONCLUSIONS: These results indicated that a diet characterized by a high consumption of animal fat is associated with a higher breast cancer risk in sedentary women, while consumption of plant fat products may reduce risk in the same group. PMID- 23725164 TI - Histone deacetylases and their inhibitors as potential therapeutic drugs for cholangiocarcinoma - cell line findings. AB - Histone deacetylation mediated by histone deacetylases (HDACs) has been reported as one of the epigenetic mechanisms associated with tumorigenesis. The poor responsiveness of anticancer drugs found with cholangiocarcinoma (CCA) leads to short survival rate. We aimed to investigate mRNA expression of HDACs class I and II, and the effect of HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA), in CCA in vitro. Expression of HDACs was studied in CCA cell lines (M213, M214 and KKU-100) and an immortal cholangiocyte (MMNK1) by semi quantitative reverse transcription-PCR. SAHA and VPA, as well as a classical chemotherapeutic drug 5-fluorouracil (5-FU) were used in this study. Cell proliferation was determined by sulforhodamine assay. IC50 and IC20 were then analyzed for each agent and cell line. Moreover, synergistic potential of VPA or SAHA in combination with 5-FU at subtoxic dose (IC20) of each agent was also evaluated. Statistic difference of HDACs expression or cell proliferation in each experimental condition was analyzed by Student's t-test. The result demonstrated that HDACs were expressed in all studied cell types. Both SAHA and VPA inhibited cell proliferation in a dose-dependent manner. Interestingly, KKU-100 which was less sensitive to classical chemotherapeutic 5-FU was highly sensitive to HDAC inhibitors. Simultaneous combination of subtoxic doses of HDAC inhibitors and 5 FU significantly inhibited cell proliferation in CCA cell lines compared to single agent treatment (P <= 0.01), while sequentially combined treatments were less effective. The present study showed inhibitory effects of HDACIs on cell proliferation in CCA cell lines, with synergistic antitumor potential demonstrated by simultaneous combination of VPA or SAHA with 5-FU, suggesting a novel alternative therapeutic strategy in effective treatment of CCA. PMID- 23725165 TI - Predictive factors for supraclavicular lymph node recurrence in N1 breast cancer patients. AB - BACKGROUND: The purpose of this study was to identify predictive factors for supraclavicular lymph node recurrence (SCLR) in N1 breast cancer patients and define a high-risk subgroup who might benefit from supraclavicular nodal radiotherapy (RT). MATERIALS AND METHODS: From January 1995 to December 2009, 113 breast cancer patients with 1 to 3 positive axillary lymph nodes were enrolled in this study. All patients underwent breast-conserving surgery (BCS) or modified radical mastectomy (MRM). RT was given to all patients who received BCS. Among the patients given MRM, those with breast tumors >5 cm in size received RT. Regional nodal irradiation was not applied. Systemic chemotherapy was given to 105 patients (92.9%). Patient data were retrospectively reviewed and analyzed to identify predictive factors for SCLR. RESULTS: The median follow-up duration was 6.5 years, with 5- and 10-year actuarial SCLR rates of 9.3% and 11.2%, respectively. Factors associated with SCLR on univariate analysis included histologic grade, number of dissected axillary lymph nodes, lymphovascular invasion, extracapsular extension (ECE), and adjuvant chemotherapy. On multivariate analysis, histologic grade and ECE remained significant. The patient group with grade 3 and ECE had a significantly higher rate of SCLR compared with the remainder (5-year SCLR rate; 71.4% vs. 4.0%, p<0.001). CONCLUSIONS: Histologic grade and ECE status are significant predictive factors for SCLR. Supraclavicular nodal RT is necessary in N1 breast cancer patients featuring histologic grade 3 and ECE. PMID- 23725166 TI - Total laparoscopic hysterectomy versus total abdominal hysterectomy for endometrial cancer: a meta-analysis. AB - The standard surgery for early-stage endometrial cancer is total abdominal hysterectomy (TAH), while total laparoscopic hysterectomy (TLH) is less invasive and assumed to be associated with lower morbidity. This meta- analysis was performed to investigate the effects of TLH versus TAH in women with early-stage endometrial cancer. We searched the PubMed, EMBASE, CBM and Cochrane Review databases for randomized trials assessing the effects of TLH versus TAH in women with early-stage endometrial cancer. The relative risks (RR) with 95% confidence intervals (CIs) from each study were pooled using meta-analysis. In our study, 9 randomized trials with a total of 1,263 patients were included. Meta-analyses showed that TLH was associated with lower risks of major complications (RR = 0.53, 95%CI 0.29-0.98, P = 0.042), total complications (RR = 0.59, 95%CI 0.42 0.82, P = 0.002) and postoperative complications (RR = 0.57, 95%CI 0.40-0.83, P = 0.003). However, there were no obvious differences in risks of intra-operative complications (RR = 0.98, 95%CI 0.62-1.55, P = 0.919) and mortality (RR = 0.96, 95%CI 0.66-1.40, P = 0.835). In conclusion, our results provide new evidence of a benefit for TLH over TAH in terms of major complications, total complications and postoperative complications in endometrial cancer patients. PMID- 23725167 TI - BRAF mutations in Iranian patients with papillary thyroid carcinoma. AB - BACKGROUND: Papillary thyroid cancer or papillary thyroid carcinoma (PTC) is the most common thyroid cancer. The fact that it occasionally occurs in women aged 30 40 years old suggests that genetic alterations are involved its genesis. Recently, activator mutations in BRAF gene have been relatively frequently discovered. MATERIALS AND METHODS: In this study, we tested 63 DNA samples from PTC patients to identify the V600E mutation frequency in the Ahvaz population. DNA was isolated from formalin fixed paraffin-embedded (FFPE) PTC tumor tissues. Genotyping was performed by PCR-RFLP and confirmed by direct DNA sequencing of a subset of PCR products. PCR-RFLP data were reported as genotype frequencies and percentages. RESULTS: Forty nine out of 63 patients (77.8%) had a mutated heterozygote form while 14 (22.2%) showed normal genotype but none demonstrated a mutant homozygote genotype. The frequency of V600E mutation was significantly high in PTC patients. CONCLUSIONS: These findings support involvement of V600E mutations in PTC occurrence in Iran. Assessment of correlations between BRAF V600E mutations and papillary thyroid cancer progression needs to be performed. PMID- 23725168 TI - Growth and differentiation effects of Homer3 on a leukemia cell line. AB - The Homer protein family, also known as the family of cytoplasmic scaffolding proteins, which include three subtypes (Homer1, Homer2, Homer3). Homer3 can regulate transcription and play a very important role in the differentiation and development for some tissues (e.g. muscle and nervous systems). The current studies showed that Homer3 abnormal expression changes in acute myeloid leukemia (AML). Forced expression of Homer3 in transfected K562 cells inhibited proliferation, influenced the cell cycle profile, affected apoptosis induced by As2O3 through inhibition of Bcl2 expression, and also promoted cell differentiation induced by 12-O-tetra decanoylphorbol-acetate (TPA). These results showed that Homer3 is a novel gene which plays a certain role in the occurrence and development of AML. PMID- 23725169 TI - Characteristics of gynecologic oncology patients in King Chulalongkorn Memorial Hospital - complications and outcome of pelvic exenteration. AB - BACKGROUND: Pelvic exenteration is a procedure which includes enbloc resection of pelvic organs followed by surgical reconstruction. Aims include both cure and palliation but data for pelvic exenteration in Thailand are very limited. OBJECTIVE: This study was conducted to evaluate characteristics of patients, operative procedure outcomes and complications. MATERIALS AND METHODS: This retrospective review covered all of the charts of exenteration patients during January 2002 to December 2011. Baseline characteristic of the patients were collected as well as details of clinical results. RESULTS: A total of 13 cases of pelvic exenteration were included. Most underwent total pelvic exenteration (9 cases) and the remainder posterior and anterior exenteration. Their primary cancers were ovarian, cervical and vulva. Mean operative time was 532 minutes (SD 160.2, range 270- 750) and estimated blood loss was 2830 ml (1850, 1000-8000). Mean tumor size was 7.33 cm (3.75, 4-15). Mean hospital stay was 35.2 days (29.8, 13-109). The most common post operative complication was urinary tract infection. Overall disease free survival with a negative surgical margin was significantly better than in positive surgical margin patients (p=0.014). CONCLUSIONS: Surgical margin was the most significant prognostic factor for disease free survival, in line with earlier studies. PMID- 23725170 TI - Cost-effectiveness outcomes of the national gastric cancer screening program in South Korea. AB - BACKGROUND: Although screening is necessary where gastric cancer is particularly common in Asia, the performance outcomes of mass screening programs have remained unclear. This study was conducted to evaluate cost-effectiveness outcomes of the national cancer screening program (NCSP) for gastric cancer in South Korea. MATERIALS AND METHODS: People aged 40 years or over during 2002-2003 (baseline) were the target population. Screening recipients and patients diagnosed with gastric cancers were identified using the NCSP and Korea Central Cancer Registry databases. Clinical outcomes were measured in terms of mortality and life-years saved (LYS) of gastric cancer patients during 7 years based on merged data from the Korean National Health Insurance Corporation and National Statistical Office. We considered direct, indirect, and productivity-loss costs associated with screening attendance. Incremental cost-effectiveness ratio (ICER) estimates were produced according to screening method, sex, and age group compared to non screening. RESULTS: The age-adjusted ICER for survival was 260,201,000 371,011,000 Korean Won (KW; 1USD=1,088 KW) for the upper-gastrointestinal (UGI) tract over non-screening. Endoscopy ICERs were lower (119,099,000-178,700,000 KW/survival) than UGI. To increase 1 life-year, additional costs of approximately 14,466,000-15,014,000 KW and 8,817,000-9,755,000 KW were required for UGI and endoscopy, respectively. Endoscopy was the most cost-effective strategy for males and females. With regard to sensitivity analyses varying based on the upper age limit, endoscopy NCSP was dominant for both males and females. For males, an upper limit of age 75 or 80 years could be considered. ICER estimates for LYS indicate that the gastric cancer screening program in Korea is cost-effective. CONCLUSION: Endoscopy should be recommended as a first-line method in Korea because it is beneficial among the Korean population. PMID- 23725171 TI - For which cancer types can neuron-specific enolase be clinically helpful in Turkish patients? AB - BACKGROUND: The aim of the present study was to evaluate the serum neuron specific enolase (NSE) levels in patients with prostate cancer, Hodgkin lymphoma, lung cancer and peripheral nerve tumors. MATERIALS AND METHODS: NSE levels were determined by ELISA in the sera of 100 prostate cancer, 47 Hodgkin lymphoma, 35 lung cancer and 35 peripheral nerve tumor patients and also in 132 healthy controls. RESULTS: The median levels of serum NSE were elevated in patients with lung cancer (p=0.018) and peripheral nerve tumors (p=0.008). NSE levels in prostate cancer and Hodgkin lymphoma patients were higher than the controls but there was no statistically significant difference (p>0.05). CONCLUSIONS: We conclude that NSE may be applied in routine to gain insight about the clinical statuses of various cancer patients, but more studies are needed to determine the organ specificity. PMID- 23725172 TI - Knowledge and views of secondary school students in Kuala Lumpur on cervical cancer and its prevention. AB - Cervical cancer is one of the most frequent cancers in women worldwide. Persistent infection with a human papillomavirus (HPV) is the main cause for cervical cancer. Vaccination and Pap smear screening are the best methods for prevention of the disease. The objective of this cross-sectional study was to assess the knowledge and views of upper secondary school female students in Kuala Lumpur, Malaysia, toward prevention of cervical cancer. This study was conducted from April 2009 to September 2009 in 8 schools in Kuala Lumpur area using pre tested and validated questionnaires. Results indicated that the respondents had low knowledge of cervical cancer and its prevention although the majority of students (80.4%) had heard about the disease. The level of knowledge of cervical cancr and its prevention was significantly higher among students from the science stream (p<0.001) compared to students from the art stream. Most students (69.3%) agreed to take the vaccination if the service was available in schools. A high percentage of students (82.2%) agreed that the vaccination should be compulsory to the students. In conclusion, most students had low knowledge of cervical cancer and its prevention but they had positive attitude toward vaccination and agreed that vaccination should be compulsory. Therefore, suitable educational programmes should be developed to improve the knowledge of secondary school students on the prevention of cervical cancer. PMID- 23725173 TI - Physical activity and quality of life of cancer survivors: a lack of focus for lifestyle redesign. AB - BACKGROUND: Physical activity is a component of lifestyle activity and one that has been increasingly seen as 'the medicine' to cure chronic diseases, including certain types of cancer. Physical activity has potent impact on mortality but only if it is well incorporated as lifestyle activity may it allow a better outcome of the quality of life of cancer survivors. This paper presents a review on the evidence of physical activity being actively promoted as lifestyle activity amongst cancer survivors, for the last five years. MATERIALS AND METHODS: Electronic databases were systematically searched for randomized controlled trials incorporated as lifestyle activity through MEDLINE with the associated terms "physical activity or exercise", "quality of life" and "cancer survivor or people with cancer", 'lifestyle' and 'randomised controlled trial'. The period of search was confined to publication within January 2008 till December 2012 and further limits were to full text, peer reviewed, abstract available and English language. RESULTS: Based on inclusion criteria, 45 articles were retrieved. Of these, 41 were excluded after examining the full paper. Four final articles on randomized controlled trials were studied to determine the effectiveness of PA to improve the quality of life in post treatment cancer survivors and positive associations were found. CONCLUSIONS: Physical activity is related to better quality of life of cancer survivors. Only one paper had characteristics of lifestyle incorporation for a lifestyle redesign, but none overtly or actively promoting exercise interventions as an essential lifestyle activity. With increasing survivorship, the benefits of physical activity must be aggressively and overtly promoted to optimize its positive impact. PMID- 23725174 TI - Efficacy and safety of concomitant chemoradiotherapy with cisplatin and docetaxel in patients with locally advanced squamous cell head and neck cancers. AB - BACKGROUND: Chemoradiation (CRT) using cisplatin-based regimens has become the standard of care in the treatment of squamous cell head and neck cancers (SCHNC). The impact of taxanes as radiosensitizing agents with concurrent CRT regimens is unknown. We therefore retrospectively evaluated the efficacy and tolerability of a weekly cisplatin+docetaxel combination with CRT in locally advanced SCHNC. METHODS: Sixty-six patients with locally advanced SCHNC (39.4% stage IV, 53% stage III, and 7.6% stage II) were assessed retrospectively. Total radiation dose to the PTV of gross disease (primary and/or node) was 70 Gy/ 35 fractions, 5 fractions per week. Minimum doses of 60 Gy and 50 Gy were administered to PTVs of elective high risk and low risk disease, respectively. Chemotherapy (CT) consisted of weekly cisplatin (20 mg/m2) +docetaxel (20 mg/m2) concurrently with RT. RESULTS: The median age of the patients was 58 years (range, 32-77). Objective response rate was 83.3%. The 2-year progression-free survival (PFS) and overall survival (OS) were 75.7% and 78.3%, respectively. The most common grade 3 and 4 toxicities were mucositis (36.4%), nausea and vomiting (12.1%), neutropenia (4.5%). CONCLUSION: Weekly cisplatin and docetaxel concurrent with RT for locally advanced SCHNC was found tolerable with high efficacy. PMID- 23725175 TI - Serum IL-33 as a diagnostic and prognostic marker in non- small cell lung cancer. AB - BACKGROUND: Interleukin-33 (IL-33) has recently been implicated in tumor immunity. The aim of this study was to explore the clinical role of serum IL-33 in patients with non-small-cell lung cancer (NSCLC). METHODS: Sera collected from 250 healthy volunteers (HV), 256 patients with benign lung diseases (BLD) and 262 NSCLC cases were subjected to IL-33 ELISA and relationships between serum IL-33 and clinical characteristics were evaluated. RESULTS: Circulating IL-33 levels were higher in the NSCLC group in comparison with the HV and BLD groups (p<0.001). Using a cut-off level 68 pg/ml (95% specificity in the HV group), IL 33 showed a good diagnostic performance for NSCLC. Multivariate survival analysis indicated that serum IL-33 was an independent prognostic factor in the entire NSCLC group [hazards ratio (HR) = 0.64 for low versus high IL-33 levels, 95% confidence interval (CI) 0.50-0.82; p<0.001] and in 165 selected patients with locally advanced or metastatic disease receiving chemoradiotherapy or chemotherapy (HR 0.70, 95% CI 0.52-0.94; p=0.013). CONCLUSIONS: IL-33 is a promising potential diagnostic and prognostic marker in NSCLC, independent of the therapeutic intervention. PMID- 23725176 TI - African American race and low income neighborhoods decrease cause specific survival of endometrial cancer: a SEER analysis. AB - BACKGROUND: This study analyzed Surveillance, Epidemiology and End Results (SEER) data to assess if socio- economic factors (SEFs) impact on endometrial cancer survival. MATERIALS AND METHODS: Endometrial cancer patients treated from 2004 2007 were included in this study. SEER cause specific survival (CSS) data were used as end points. The areas under the receiver operating characteristic (ROC) curve were computed for predictors. Time to event data were analyzed with Kaplan Meier method. Univariate and multivariate analyses were used to identify independent risk factors. RESULTS: This study included 64,710 patients. The mean follow up time (S.D.) was 28.2 (20.8) months. SEER staging (ROC area of 0.81) was the best pretreatment predictor of CSS. Histology, grade, race/ethnicity and county level family income were also significant pretreatment predictors. African American race and low income neighborhoods decreased the CSS by 20% and 3% respectively at 5 years. CONCLUSIONS: This study has found significant endometrial survival disparities due to SEFs. Future studies should focus on eliminating socio-economic barriers to good outcomes. PMID- 23725177 TI - AKT1 inhibitory DNAzymes inhibit cell proliferation and migration of thyroid cancer cells. AB - AKT1 is a member of the serine/threoine AGC protein kinase family involved in thyroid cancer metabolism, growth, proliferation and survival. It is overexpressed in thyroid tumors. In this study, we designed two AKT1 specific DNAzymes (DRz1 and DRz2) that target AKT1 mRNA. The results showed that DRz1 could decrease the expression of AKT1 by 58%. Furthermore, DRz1 significantly inhibited cell proliferation, induced apoptosis and inhibited invasion in SW597 cells. In addition, down-regulation of survivin expression was associated with decreased caspase-3, VEGF and MMP2 in SW597 cells after 24 h. In our study, the efficacy of DRz1 in decreasing AKT1 protein levels were better than DRz2. AKT1 DRz1 might have anti-tumorigenic activity and may provide the basis for a novel therapeutic intervention in thyroid cancer treatment. PMID- 23725178 TI - Interleukin-10 gene promoter polymorphisms and risk of gastric cancer in a Chinese population: single nucleotide and haplotype analyses. AB - OBJECTIVES: Interleukin (IL) -10 is a potent cytokine with a dual ability to immunosuppress or immunostimulate. We aimed to explore the association of IL10 promoter polymorphisms with risk of gastric cancer (GC) in a Han population in Southwestern China. METHODS: We enrolled 308 pairs of GC and control subjects from four hospitals and a community between October 2010 and August 2011 in a 1:1 matched case-control design. Demographic information was collected using a designed questionnaire. IL10-592 A>C and IL10-1082 A>G polymorphisms were determined by Sequenom MassARRAY analysis. RESULTS: Patients with GC reported statistically higher proportions of family history of cancer (29.9% versus 10.7%, P<0.01) and alcohol drinking (54.6% versus 43.2%, P<0.01) than did controls. Similar results were observed in comparison between non-cardia GC patients and controls (P<0.01 and P=0.03). Variant genotypes of IL10-592 A>C and IL10-1082 A>G were not associated with overall GC risk (adjusted OR, 0.94, 95% CI, 0.66-1.33; adjusted OR, 1.00, 95% CI, 0.62-1.60). Sub-analysis showed that the IL10-592 AC/CC variant genotype was associated with decreased non-cardia GC risk (adjusted OR, 0.58; 95% CI, 0.36-0.95). No association was found between any of the IL10 haplotypes established from two polymorphisms and risk of non-cardia GC. CONCLUSIONS: In conclusion, our data do not link the two SNPs of IL10-592 and IL10-1082 with overall GC risk. We demonstrate that IL10-592 polymorphism is associated with protective effect against non-cardia GC. Our findings may offer insight into risk associated with the development of GC in this region. PMID- 23725179 TI - Diabetes mellitus increases the risk of bladder cancer: an updated meta-analysis. AB - PURPOSE: Studies have indicated that diabetes mellitus (DM) is a risk factor for bladder cancer; however, not all evidence supports this conclusion. The aim of this meta-analysis was to collate and evaluate all primary observational studies investigating the risk of bladder cancer associated with DM. METHODS: The PubMed and Google Scholar databases were searched to identify studies that estimated the association of DM and bladder cancer. Summary effect estimates were derived using a random-effects meta-analysis model. RESULTS: A total of 23 studies (8 case control studies, 15 cohort studies) including 643,683 DM and 4,819,656 non-DM cases were identified. Analysis of all studies showed that DM was associated with an increased risk of bladder cancer compared with non-DM overall (OR=1.68, 95% CI 1.32-2.13). Analysis of subgroups demonstrated this to be the case in both case control studies (OR=1.59, 95% CI 1.28-1.97, I2=58%) and cohort studies (RR=1.70, 95% CI 1.23-2.33, I2=96%). There was no gender difference in DM-associated bladder cancer risk. Bladder cancer risk was increased in Asia and the North America region, but not in Europe. Furthermore, DM-associated bladder cancer risk was obviously higher in Asia than North America and Europe or in those with Caucasian ethnicity. With extension of follow-up time, the bladder cancer risk was not increased for the patients with DM. CONCLUSIONS: This meta-analysis provided further evidence supporting the DM association with a significantly higher risk of bladder cancer obtained from observational studies. PMID- 23725180 TI - Clinical comparison between paclitaxel liposome (Lipusu(r)) and paclitaxel for treatment of patients with metastatic gastric cancer. AB - AIM: To compare the efficacy and safety of paclitaxel liposome (Lipusu(r)) with paclitaxel in combination with tegafur and oxaliplatin in treating patients with advanced gastric cancer. MATERIALS AND METHODS: Patients with advanced gastric cancer receiving chemotherapy were retrospectively collected, and divided into two groups. Patients in group A received paclitaxel liposomes at a dose of 135 mg/m2 on day 1 of each cycle, and patients in group B were given paclitaxel at the same dose with the same timing. All patients received tegafur at a dose of 500 mg mg/m2 on days 1-5, and oxaliplatin at a dose of 80-100 mg/m2 on day 1 for 2 cycles (each cycle was 21 d in total). RESULTS: Fifty-eight patients could be evaluated for efficacy. The overall response rate was 47% in group A (14/30), and 46% in group B (13/28). Disease control rate was 73% in group A (22/30), and 71% in group B (20/28) (P>0.05). No significant differences were detected in hematologic and neurologic toxicities between the two groups (P>0.05). However, nausea, vomiting and hypersensitive reactions were significantly lower in group A than in group B (P<0.05). CONCLUSION: Paclitaxel liposomes are as effective as paclitaxel when combined with tegafur and oxaliplation in treating patients with advanced gastric cancer, but adverse reactions with paclitaxel liposomes are less common. PMID- 23725181 TI - Prostate cancer: a hospital-based survival study from Mumbai, India. AB - BACKGROUND: Prostate cancer is common in elderly men, especially in western countries, and incidences are rising in low-risk populations as well. In India, the age-standardized rates vary between registries. Under these circumstances we have estimated the survival of prostate cancer patients based on age, family history, diabetes, hypertension, tobacco habit, clinical extent of disease (risk group) and treatment received. MATERIALS AND METHODS: The present retrospective study was carried out at the Tata Memorial Hospital (TMH), Mumbai, India. During years 1999-2002, some 850 prostate cancer cases, including 371 new cases, treated in TMH were considered as eligible entrants for the study. Five-year survival rates using actuarial and loss-adjusted (LAR) method were estimated. RESULTS: The patient population was distributed uniformly over the three age groups. A larger proportion of the patients were diagnosed at 'metastatic stage' and hormone treatment was most common. 20% patients had history of diabetes and 40% with hypertension. The 5-year overall survival rate was 64%. Survival was 55%, 74% and 52% for ' <59 years', '60-69 years' and ' >70 years' respectively. Non-diabetic (70%), hypertensive (74%), with family history (80%) of cancer, with localized disease (91%) and treated with surgery, either alone or in combination, (91%) had better survival. CONCLUSIONS: The present study showed that prostate cancer patients with localized disease at diagnosis experience a better outcome. Local treatment with either surgery or radiation achieves a reasonable outcome in prostate cancer patients. A detailed study will help in understanding the prognostic indicators for survival especially with the newer treatment technologies available now. PMID- 23725182 TI - Immunostimulating effect of a well-known Thai folkloric remedy in breast cancer patients. AB - The study aimed to evaluate immune-stimulating effects of a well-known Thai folkloric remedy when used for adjuvant therapy with conventional chemotherapeutics for treatment of breast cancer. Immunostimulating influence of the remedy (215 mg/kg body weight per day) on NK cell activity and TNF-alpha release from the monocytes/macrophages were investigated in a total of 15 healthy women and 13 female patients with breast cancer (Group 1). The effect of breast tumor surgery on NK cell activity was further investigated in 18 female patients with breast cancer (Group 2). NK cell cytotoxic activity was determined by chromium release cytotoxic assay using K562, an erythroleukemic cell line. TNF alpha release from monocytes/macrophages separated from blood samples was determined through a biological assay using actinomycin D-treated L929 mouse fibroblast cells in the presence and absence of LPS. Baseline NK cell activity of the monocytes/macrophages separated from Group 2 patients expressed as %cytotoxicity was significantly lower than in the healthy subjects at E:T ratios of 100:1 and 25:1. In healthy subjects, there was no change in NK cell cytotoxic activity (%cytotoxicity or LU) following 1 and 2 weeks of treatment with the remedy compared with the baseline at various E:T ratios but the binding activity (%binding) was significantly increased after 2 weeks of treatment. The addition of one or two conventional chemotherapeutic regimens did not significantly reduce the NK cytotoxic activity but did affect release of TNF-alpha in both unstimulated and LPS-stimulated samples. Surgery produced a significant suppressive effect on NK cell activity. The use of the remedy as an adjunct therapy may improve therapeutic efficacy and safety profiles of conventional chemotherapeutic regimens through stimulation of the immune system in cancer patients. PMID- 23725183 TI - Inhibitory effect of benzyl isothiocyanate on proliferation in vitro of human glioma cells. AB - Malignant glioma, also known as brain cancer, is the most common intracranial tumor, having an extremely high mortality and recurrence rate. The survival rate of the affected patients is very low and treatment is difficult. Hence, growth inhibition of glioma has become a hot topic in the study of brain cancer treatment. Among the various isothiocyanate compounds, it has been confirmed that benzyl isothiocyanate (BITC) can inhibit the growth of a variety of tumors, including leukemia, glioma and lung cancer, both inside and outside the body. This study explored inhibitory effects of BITC on human glioma U87MG cells, as well as potential mechanisms. It was found that BITC could inhibit proliferation, induce apoptosis and arrest cell cycling of U87MG cells. In addition, it inhibited the expression of SOD and GSH, and caused oxidative stress to tumor cells. Therefore, it is believed that BITC can inhibit the growth of U87MG cells outside the body. Its mechanism may be related to the fact that BITC can cause oxidative stress to tumor cells. PMID- 23725184 TI - Intrapleural or intraperitoneal lobaplatin for treatment of patients with malignant pleural effusion or ascites. AB - AIMS: To explore efficacy and side effects of intrapleural or intraperitoneal lobaplatin for treating patients with malignant pleural or peritoneal effusions. METHODS: Patients in Jiangsu Cancer Hospital and Research Institute with cytologically confirmed solid tumors complicated with malignant pleural effusion or ascites were enrolled into this study. Lobaplatin (20-30 mg/m2) was intrapleurally or intraperitoneally infused for patients with malignant pleural effusion or ascites. RESULTS: From 2012 to 2013, intrapleural or intraperitonea lobaplatin was administered for patients with colorectal or uterus cancer who were previous treated for malignant pleural effusion or ascites. Partial response was achieved for them. Main side effects were nausea/vomiting, and bone marrow suppression. No treatment related deaths occurred. CONCLUSION: Intrapleural or intraperitoneal infusion of lobaplatin is a safe treatment for patients with malignant pleural effusion or ascites, and the treatment efficacy is encouraging. PMID- 23725185 TI - Systematic review of research into the psychological aspects of prostate cancer in Asia: what do we know? AB - BACKGROUND: To review the peer reviewed literature on the psychological aspects of the prostate cancer experience of men in Asia. MATERIALS AND METHODS: Medline and PsycINFO, CINAHL, ProQuest, and Web of Science (1999 - November Week 4, 2012) were searched. Inclusion criteria were: included men with prostate cancer and/or their partners or caregivers who identify as Asian recruited in an Asian country; and assessed health-related quality of life, psychological and social adjustment relating to prostate cancer and published in English after 1st January 1999 and prior to 30th November, 2012. Study aims; design; quality; level of evidence, and key results were assessed. RESULTS: 43 articles met all inclusion criteria and were retained for initial review. Of these most focussed on health-related QOL with only five evidence Level IV studies from Japan and Taiwan including a specific psychological focus. Of these, one was a cross-sectional case control study; three were cross- sectional descriptive quantitative designs; one was a cross-sectional descriptive qualitative study. From the data available, a substantive sub group of men with prostate cancer (approximately one third) in these countries experience clinically high psychological distress and decision regret. CONCLUSIONS: Research on the psychological needs of men with the increasingly prevalent condition of prostate cancer in Asian countries is scant with only a small number of low level evidence descriptive studies identified. Future research to underpin the development and evaluation of effective and culturally relevant psychological and supportive care interventions for such men is urgently needed. PMID- 23725186 TI - Ovarian masses: is multi-detector computed tomography a reliable imaging modality? AB - BACKGROUND: Ovarian cancer continues to pose a major challenge to physicians and radiologists. It is the third most common gynecologic malignancy and estimated to be fifth leading cancer cause of death in women, constituting 23% of all gynecological malignancies. Multi-detector computed tomography (MDCT) appears to offer an excellent modality in diagnosing ovarian cancer based on combination of its availability, meticulous technique, efficacy and familiarity of radiologists and physicians. The aim of this study was to compute sensitivity, specificity, positive and negative predictive values and diagnostic accuracy of 64- slice MDCT in classifying ovarian masses; 95% confidence intervals were reported. MATERIALS AND METHODS: We prospectively designed a cross-sectional analytical study to collect data from July 2010 to August 2011 from a tertiary care hospital in Karachi, Pakistan. A sample of 105 women aged between 15-80 years referred for 64 MDCT of abdomen and pelvis with clinical suspicion of malignant ovarian cancer, irrespective of stage of disease, were enrolled by non- probability purposive sampling. All patients who were already known cases of histologically proven ovarian carcinoma and having some contraindication to radiation or iodinated contrast media were excluded. RESULTS: Our prospective study reports sensitivity, specificity; positive and negative predictive values with 95%CI and accuracy were computed. Kappa was calculated to report agreement among the two radiologists. For reader A, MDCT was found to have 92% (0.83, 0.97) sensitivity and 86.7% (0.68, 0.96) specificity, while PPV and NPV were 94.5% (0.86, 0.98) and 86.7% (0.63, 0.92), respectively. Accuracy reported by reader A was 90.5%. For reader B, sensitivity, specificity, PPV and NPV were 94.6% (0.86, 0.98) 90% (0.72, 0.97) 96% (0.88, 0.99) and 87.1% (0.69, 0.95) respectively. Accuracy computed by reader B was 93.3%. Excellent agreement was found between the two radiologists with a significant kappa value of 0.887. CONCLUSION: Based on our study results, we conclude MDCT is a reliable imaging modality in diagnosis of ovarian masses accurately with insignificant interobserver variability. PMID- 23725187 TI - Incidence and trends of malignant and benign pancreatic lesions in Yazd, Iran between 2001 and 2011. AB - BACKGROUND: Despite recent valuable steps in initiating a cancer registry in Iran, data depicting prevalence, incidence, and clinical picture of pancreatic tumors in the country are exceedinglyly sparse. With the aim of filling this knowledge gap, we reviewed cases in the pathology archive of Shahid Sadoughi hospital (Yazd, Iran), between 2001 and 2011. MATERIALS AND METHODS: Medical records of 177 patients are reported in the present study. In cases for which paraffin-embedded blocks were available, the specimens were evaluated by two independent pathologists blinded to the primary diagnosis. We extrapolated the frequency of malignant lesions in our study to the population of Yazd province, derived from national census data, to generate cancer incidence rates. RESULTS: Final diagnosis of malignancy was made in 117 cases (66.1%), and the remainder (60 lesions, 33.9%) were classified as benign. Adenecarcinoma and neuroendocrine tumors were the two most common histological types of malignancy identified in 88 (75.2%) and 11 (9.4%) specimens, respectively. Crude annual incidence of pancreatic cancer was 0.55 per 100,000 person in 2001 and increased to 1.68 in 2011. Age standardized incidence rates in 2001 and 2011 were 0.75 and 2.68, respectively. A significant increasing trend in cancer incidence was observed during the 11 years of the study period (r =+0.856, p=0.009). Sex-stratified analysis, confirmed the observed trend in men (r=+0.728, p=0.034), but not women (r=+0.635, p=0.083). CONCLUSIONS: Over the past decade, incidence of pancreas malignancies has risen steadily in Yazd, Iran. Nevertheless, these figures are still substantially lower than those prevalent in developed nations. PMID- 23725188 TI - 6,8-dihydroxy-7-methoxy-1-methyl-azafluorenone induces caspase-8- and -9-mediated apoptosis in human cancer cells. AB - 6,8-dihydroxy-7-methoxy-1-methyl-azafluorenone (DMMA), a purified compound from Polyalthia cerasoides roots, is cytotoxic to various cancer cell lines. The aims of this study were to demonstrate the type of cancer cell death and the mechanism(s) involved. DMMA inhibited cell growth and induced apoptotic death in human leukemic cells (HL-60, U937, MOLT-4), human breast cancer MDA-MB231 cells and human hepatocellular carcinoma HepG2 cells in a dose dependent manner, with IC50 values ranging between 20-55 muM DMMA also decreased cell viability of human peripheral blood mononuclear cells. The morphology of cancer cells induced by the compound after staining with propidium iodide and examined under a fluorescence microscope was condensed nuclei and apoptotic bodies. Mitochondrial transmembrane potential (MTP) was decreased after 24h exposure in all five types of cancer cells. DMMA-induced caspase-3, -8, and -9 activity was strongly induced in human leukemic HL-60 and MOLT-4 cells, while in U937-, MDA-MB231- and HepG2-treated cells there was partial induction of caspase. In conclusion, DMMA-induced activation of caspase-8 and -9 resulted in execution of apoptotic cell death in human leukemic HL-60 and MOLT-4 cell lines via extrinsic and intrinsic pathways. PMID- 23725189 TI - Association between smoking and mortality: Khon Kaen cohort study, Thailand. AB - BACKGROUND: Despite anti-smoking campaigns, smoking prevalence among Thai males aged 30 or older is high, at around 50%. The purpose of this study was to determine the relationship between smoking and mortality in a rural Thai community. MATERIALS AND METHODS: Subjects enrolled into the Khon Kaen cohort study between 1990 and 2001 were followed up for their vital status until 16th March 2012. The death resource was from the Bureau of Policy and Strategy, Ministry of Interior, Thailand. A Cox proportional hazards model was used to analyse the association between smoking and death, controlling for age, education level and alcohol drinking, and confidence intervals were calculated using the floating risk method. RESULTS: The study recruited 5,962 male subjects, of whom 1,396 died during a median 13.5 years of follow-up. Current smokers were more likely to die than never smokers after controlling for age, education level and alcohol drinking (HR, 95%CI: 1.41, 1.32- 1.51), and the excess mortality was greatest for lung cancer (HR, 95%CI: 3.51, 2.65-4.66). However, there was no increased risk with increasing dose of tobacco, and no difference in risk between smokers of yamuan (hand- rolled cigarettes) and manufactured tobacco. CONCLUSION: Mortality from cancer, particularly lung cancer, and from all causes combined is dependent on smoking status among men in rural Thailand, but the relative risks are lower than have been reported from studies in high income countries, where the tobacco epidemic is more established. PMID- 23725190 TI - Prevalence of depression in breast cancer survivors: a systematic review of observational studies. AB - BACKGROUND: Depression is common in breast cancer patients. The aim of this paper was to make a systematic review of its prevalence and associated factors oin breast cancer survivors. MATERIALS AND METHODS: An extensive systematic electronic review (PUBMED, CINAHL, PsyINFO and Ovid) and handsearch were carried out to retrieve published articles up to November 2012, using Depression OR Dysthymia AND (Cancer OR Tumor OR Neoplasms as the keywords. Information about the design of the studies, measuring scale, characteristics of the participants, prevalence of depression and its associated factors from the included studies were extracted and summarized. RESULTS: We identified 32 eligible studies that recruited 10,826 breast cancer survivors. Most were cross-sectional or prospective designed. The most frequent instrument used to screen depression was the Center for Epidemiological Studies for Depression (CES-D, n=11 studies) followed by the Beck Depression Inventory (BDI, n=6 studies) and the Hospital Anxiety and Depression Scale (HADS, n=6 studies). CES-D returned about similar prevalence of depression (median=22%, range=13-56%) with BDI (median=22%, range=17-48%) but higher than HADS (median=10%, range=1-22%). Depression was associated with several socio-demographic variables, cancer-related factors, treatment-related factors, subject psychological factors, lifestyle factors, social support and quality of life. CONCLUSIONS: Breast cancer survivors are at risk for depression so that detection of associated factors is important in clinical practice. PMID- 23725191 TI - Accuracy of frozen section analysis of sentinel lymph nodes for the detection of Asian breast cancer micrometastasis - experience from Pakistan. AB - BACKGROUND: Intraoperative sentinel lymph node biopsy has now become the standard of care for patients with clinically node negative breast cancer for diagnosis and also in order to determine the need for immediate axillary clearance. Several large scale studies confirmed the diagnostic reliability of this method. However, micrometastases are frequently missed on frozen sections. Recent studies showed that both disease free interval and overall survival are significantly affected by the presence of micrometastatic disease. The aim of this study was to determine the sensitivity and specificity of intraoperative frozen section analysis of sentinel lymph nodes (SLNs) for the detection of breast cancer micrometastasis and to evaluate the status of non-sentinel lymph nodes (non-SLNs) in those patients subjected to further axillary sampling. MATERIALS AND METHODS: We performed a retrospective study on 154 patients who underwent SLN biopsy from January 2008 till October 2011. The SLNs were sectioned at 2 mm intervals and submitted entirely for frozen sections. Three levels of each section submitted are examined and the results were compared with further levels on paraffin sections. RESULTS: Overall 40% of patients (62/154) were found to be SLN positive on final (paraffin section) histology, out of which 44 demonstrated macrometastases (>2mm) and 18 micrometastases (<2mm). The overall sensitivity and specificity of frozen section analysis of SLN for the detection of macrometastasis was found to be 100% while those for micrometastasis were 33.3% and 100%, respectively. Moreover 20% of patients who had micrometastases in SLN had positive non-SLNs on final histology. CONCLUSIONS: Frozen section analysis of SLNs lacks sufficient accuracy to rule out micrometastasis by current protocols. Therefore these need to be revised in order to pick up micrometastasis which appears to have clinical significance. We suggest that this can be achieved by examining more step sections of blocks. PMID- 23725192 TI - Chemotherapy and late course three dimensional conformal radiotherapy for treatment of patients with stage III non- small cell lung cancer. AB - OBJECTIVE: To compare the efficacy and complications of chemotherapy and late course three-dimensional conformal radiotherapy (3DCRT) in treating patients with stage III non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: All patients were divided into two groups: to receive chemotherapy and late course 3DCRT (3DCRT group), or chemotherapy and conventional fraction radiation (control group). In the 3DCRT-group, patients were given 6~15 MV X-rays with a total dose of 40 Gy, followed by 3DCRT, 2.5 Gy~3.0 Gy per fraction, 1 fraction/ every day, total 68 Gy~70 Gy; in the control group, with conventional fraction radiation the total dose was 64~66 Gy. The chemotherapy regimen in both cases was EP (VP-16 and DDP). RESULTS: Sixty four patients with stage III NSCLC were divided into two groups: 32 patients into 3DCRT, 32 into the control group. One and 2-year survival rates in 3DCRT and control group were 87.5%, 56.3%mad 65.6%, 34.4%, respectively (P<0.05); local control rates were 90.6%, 81.3% and 65.6%, 53.1%, respectively (P<0.05). CONCLUSION: Chemotherapy and late course 3DCRT is associated with improved survival rate in patients with stage III NSCLC with good tolerability. PMID- 23725193 TI - Histopathology analysis of benign colorectal diseases and colorectal cancer in Hatyai Hospital, Songkhla, Thailand. AB - BACKGROUND: Colorectal cancer (CRC) is a major cause of morbidity and mortality in the western world and also ranks as the fifth-leading malignancy and death in Thailand. This study aimed to provide a present outlook of colorectal diseases among Thai patients with special emphasis on CRC in Hatyai, Songkhla, southern Thailand. MATERIALS AND METHODS: This retrospective study covered ten year data of CRC, benign colorectal tumors and non-colorectal tumors from the Department of Pathology in Hatyai Hospital, Songkhla, Thailand, between years 2003-2012. Incidence rates based on age, gender, ten year incidence trends, and distribution of histopathological characteristics of patients were calculated and demonstrated. RESULTS: Out of 730 biopsies, 100 cases were benign colorectal tumors, 336 were CRC and 294 were non-colorectal tumors. Colorectal tumors (both benign and CRC) (60.1%) were more common than non-colorectal tumors (39.9%). CRC (77.1%) were more common than benign colorectal tumors (32.9%). Colorectal tumors were mainly found in patients aged over sixty whereas non-colorectal and benign colorectal tumors were found in those under sixty (P=0.01). sAmong CRC, adenocarcinoma contributed about 97.3% of all cases with well differentiated tumors being the most frequent (56.9%). Both benign colorectal tumors and CRC were more commonly found in males (63%) than females (37%). The incidence trend of CRC demonstrated increase from 2003-2012. CONCLUSIONS: The incidence of CRC increased in Hatyai from 2003-2012. CRC tends to be more common in people older than sixty, thus, screening programs, cost-effective analysis of treatment modalities, and treatment protocols for the elderly should be examined. Proper implementation of preventive measures such as changing lifestyle factors might enhance control of colorectal disease. PMID- 23725194 TI - Role of dental institutions in tobacco cessation in India: current status and future prospects. AB - Tobacco abuse is a major preventable cause of premature death and disease, including various cancers. The Global Adult Tobacco Survey India (GATS) 2009-10 revealed that more than one-third of adults use tobacco in one form or the other. Nearly two in five smokers and smokeless tobacco users made attempts to quit the habit in the past 12 months. Tobacco dependence is a chronic condition characterized by susceptibility of relapse over years. It can be well handled by sustained professional support from health care providers mainly through behavioral counseling and pharmacotherapy. Dental professionals can play a pivotal role in diagnosing and effectively managing tobacco dependence. Dental Institutions have rapidly grown in last two decades across the country and so has the curriculum been adapted to improve student competencies to accommodate changing disease patterns and technological advances, but not in regard to tobacco cessation. Untapped dental manpower like undergraduates, dental hygienists and other paramedical staff need effective training to be more penetrative. The present review paper explores the potential role of dental training institutions and recommends various approaches to counter public health jeopardy of tobacco related diseases. PMID- 23725195 TI - Cervical cancer: is vaccination necessary in India? AB - In India, cervical cancer is the most common woman-related cancer, followed by breast cancer. The rate of cervical cancer in India is fourth worldwide. Two vaccines, Gardasil and Cervarix, both targeting HPV-16 and 18 which account for 70% of invasive cervical carcinomas, are licensed in the United States and numerous countries worldwide. Both vaccine formulations have shown excellent efficacy with minimal toxicity in active female population but numerous questions arise in vaccinating like cost effectiveness, lack of proven efficacy against other HPV strains, social acceptance of HPV vaccination and other ethical issues. The main objective of this study is to emphasis the advantages and disadvantages of the vaccination in India. PMID- 23725196 TI - Comparison of apples with their parts: rethinking a metaanalysis on the association between cooking and uveal melanoma risk. PMID- 23725197 TI - Note of clarification of data in the meta-analysis of XPC 939A>C and 499C>T polymorphisms in skin cancer. PMID- 23725198 TI - Younger adult type 2 diabetic patients have poorer glycaemic control: a cross sectional study in a primary care setting in Singapore. AB - BACKGROUND: The aim was to study the glycaemic control of type 2 diabetic patients, and to identify factors associated with unacceptable glycaemic control (defined as HbA1c >8.0%). METHODS: Analysis of data collected in a cross sectional survey of type 2 diabetic patients in eight SingHealth Polyclinics in January 2009. HbA1c value was measured on the day of the survey, while information on patient and diabetic characteristics was obtained through a questionnaire. Odds ratio of having unacceptable glycaemic control was estimated for selected variables using multiple logistic regression models. RESULTS: A total of 688 patients were included in the analysis. The mean (+/- standard deviation) and median (range) HbA1c levels were 7.6% (+/- 1.35) and 7.3% (5.0% to 14.0%), respectively. 25.4% of the patients had an unacceptable HbA1c level of >8.0% and the odds of this were higher (p < 0.05) in patients with the following characteristics: younger age, longer diabetes duration, presence of insulin treatment, and poorer compliance to medication. CONCLUSION: Younger adult patients were found to have poorer glycaemic control, and hence targeted educational and behaviour modification programmes would be required to effectively manage this group of patients. PMID- 23725199 TI - Host-guest interaction of adamantine with a beta-cyclodextrin-functionalized AuPd bimetallic nanoprobe for ultrasensitive electrochemical immunoassay of small molecules. AB - A modular labeling strategy was presented for electrochemical immunoassay via supramolecular host-guest interaction between beta-cyclodextrin (beta-CD) and adamantine (ADA). An ADA-labeled antibody (ADA-Ab) was synthesized via amidation, and the number of ADA moieties loaded on a single antibody was calculated to be ~7. The beta-CD-functionalized gold-palladium bimetallic nanoparticles (AuPd-CD) were synthesized in aqueous solution via metal-S chemistry and characterized with transmission electron microscopy and X-ray photoelectron spectra. After the ADA Ab was bound to the antigen-modified electrode surface with a competitive immunoreaction, AuPd-CD as a signal tag was immobilized onto the immunosensor by a host-guest interaction, leading to a large loading of AuPd nanoparticles. The highly efficient electrocatalysis by AuPd nanoparticles for NaBH4 oxidation produced an ultrasensitive response to chloramphenicol as a model of a small molecule antigen. The immunoassay method showed a wide linear range from 50 pg/mL to 50 MUg/mL and a detection limit of 4.6 pg/mL. The specific recognition of antigen by antibody resulted in good selectivity for the proposed method. The host-guest interaction strategy provided a universal labeling approach for the ultrasensitive detection of small molecule targets. PMID- 23725200 TI - Eyes on new product development. PMID- 23725201 TI - Co-assembled white-light-emitting hydrogel of melamine. AB - A coassembled light-harvesting hydrogel of melamine (M), 6,7-dimethoxy-2,4[1H, 3H]-quinazolinedione (Q) with riboflavin (R), is used to produce a white-light emitting hydrogel (W-gel) by mixing with the dye rhodamine B (RhB) in a requisite proportion. Addition of R to the Q solution causes both static and dynamic quenching to the emission of Q as evident from the Stern-Volmer plot and the emission of R shows a gradual increase in intensity. On addition of RhB to an aqueous solution of R, fluorescence resonance energy transfer (FRET) occurs, showing an emission peak at 581 nm. In a solution of constant molar ratio of Q and R, addition of RhB causes a quenching of emission of R with no effect on the emission of Q, indicating that the energy transfer takes place only between R and RhB. In the MQR coassembled hydrogel containing RhB, the gel melting temperature is lower than those of MQ and MQR gel, but the storage modulus remains almost unaffected. The oscillatory stress experiment indicates a gradual decrease of critical stress values for breaking of MQ, MQR, and W-gels attributed to the coassembly. In contrast to the solution of Q and R, energy transfer occurs on addition of RhB to the MQ gel. By varying the RhB and R concentration in the 1:1 MQ gel white light emission is observed for the W-gel composition having molar ratio of M:Q:R:RhB = 100:100:0.5:0.02 with the Commission Internationale de L'eclairage (CIE) coordinates of 0.31 and 0.36 for the excitation at 360 nm. However, in the sol state, the CIE coordinates of the hybrid differ significantly from those of the white light. PMID- 23725202 TI - The 'peptidome' of tumour-derived chaperone-rich cell lysate anti-cancer vaccines reveals potential tumour antigens that stimulate tumour immunity. AB - Tumour-derived chaperone-rich cell lysate (CRCL) when isolated from tumour tissue or when embedded with peptide antigens is a potent anti-cancer vaccine consisting of numerous chaperone/heat shock proteins, including the highly immunogenic Hsp70, Hsp90, glucose regulated protein 94, and calreticulin. We have previously documented that CRCL provides both a source of tumour antigens and danger signals triggering antigen presenting cell activation. In this report we describe the 'peptidome' of potential antigens extracted from CRCL prepared from a murine tumour. Using mass spectrometry techniques we identify almost 60 different proteins of origin for the CRCL peptides; we determine that the parental proteins come from essentially all parts of the cell, and are involved in a broad range of functions. Further in silico analysis demonstrates that the parental proteins are components of major signalling networks of vital importance for cancer cell survival, proliferation, and migration. In many instances the peptides identified possess amino acid sequences that would allow their putative binding and display by murine major histocompatibility complex class I and II molecules, and there are also predicted binding motifs for Hsp70-type chaperones. By mixing fractionated pools of peptides with antigen-free (normal liver) CRCL, we were able to reconstitute effective anti-tumour activity of the vaccine, showing that the peptides are indeed the major purveyors of CRCL vaccines' efficacy. PMID- 23725203 TI - Effect of sleeve gastrectomy on postprandial lipoprotein metabolism in morbidly obese patients. AB - BACKGROUND: Obesity is associated with abnormal fasting and postprandial lipids, which may link obesity with atherosclerosis. We explored fasting and postprandial lipids in morbidly obese patients treated with sleeve gastrectomy and in control subjects. METHODS: After fasting for 12 h 15 morbidly obese patients (BMI 51.4+/ 6.5 kg/m2, 43.7+/-12.6 years) received a standardized oral fat load before and 3 months after bariatric surgery (sleeve gastrectomy). Controls (n=9, BMI 23.1+/ 1.4 kg/m2) were studied once. Plasma was obtained fasting and then postprandially every 2 h for 8 h. Triglycerides (TG), chylomicron-TG (CM-TG), VLDL/chylomicron remnant (VLDL/CR)-TG, cholesterol, LDL-cholesterol, VLDL/CR-cholesterol and HDL cholesterol were isolated by ultracentrifugation at each time point. Postprandial values were expressed as area under the curve (AUC) and incremental area under the curve (iAUC). In addition, fasting glucose and insulin values and HOMA-IR Index was measured (n=14). RESULTS: Compared to controls morbidly obese patients had elevated TG and slightly altered postprandial lipids. Following surgery (weight loss 23.4 kg+/-6.2 kg; p<0.001) fasting TG (-19.1%; p=0.04), VLDL/CR-TG ( 20.0%; p=0.05) decreased significantly, while fasting cholesterol, VLDL-, HDL- and LDL-cholesterol did not change. AUC and iAUC decreased significantly for VLDL/CR-TG (-20.4%, p=0.04 and -38.5%, p=0.04, respectively). Neither fasting nor postprandial changes correlated with the change in weight. In patients with preoperatively elevated TG (>150 mg/dl) a similar pattern was observed. Fasting insulin and HOMA were reduced significantly (-51.9%; p=0.004 and -47.9%; p=0.011). CONCLUSIONS: Three months after sleeve gastrectomy fasting and postprandial lipoprotein metabolism and glucose metabolism is improved in morbidly obese patients. The potential mechanisms may relate to decreased caloric intake but also to hormonal changes. PMID- 23725204 TI - Health-related quality of life in genotype 1 treatment-naive chronic hepatitis C patients receiving telaprevir combination treatment in the ADVANCE study. AB - BACKGROUND: Chronic hepatitis C virus (HCV) infection and its treatment impact patients' health-related quality of life (HRQL). AIM: To report on treatment impact and predictors of HRQL among treatment-naive patients with genotype 1 chronic HCV infection who received 12-week telaprevir (T) with 24 (T12PR24) or 48 weeks (T12PR48) peginterferon alpha-2a/ribavirin (PR), or 48 weeks of PR in the ADVANCE study. METHODS: The EQ-5D-3L (EQ-5D) questionnaire (index range: 0-1) was completed at baseline and weeks 4, 12, 24, 36, 48 and 72. Patients indicated their health state on five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Descriptive statistics for the EQ-5D index and descriptive system and area under the curve from baseline to week 12 were calculated. Predictors of EQ-5D index were identified using multivariate analyses. RESULTS: Data from 722 patients were included. The mean EQ-5D index decreased during the first 12 weeks and returned to baseline by week 72 (T12PR24 by week 36) across treatments. In multivariate analysis, sustained virological response (SVR) at week 72 was associated (P < 0.0001) with improved EQ-5D index [mean; SVR+ (0.90), SVR- (0.86)], a 4% difference, within the published range of minimal clinically important difference. CONCLUSIONS: Post hoc analyses of data from ADVANCE suggested that HRQL worsened during the first 12 weeks of therapy and returned to baseline by week 72 across treatments. Improvements were observed early following completion of a 24-week treatment (T12PR24). Telaprevir combination therapy was associated with slightly higher reductions in HRQL during the first 12 weeks (vs. PR). SVR was a statistically significant and meaningful predictor of HRQL at week 72. PMID- 23725205 TI - The protective role of the -735C/T and the -1306C/T polymorphisms of the MMP-2 gene in the development of primary open-angle glaucoma. AB - BACKGROUND: It has been suggested that the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) are involved in the degradation of extracellular matrix components, resulting in ocular tissue damage. The -735C/T and -1306C/T polymorphisms recognized in the promoter region of the MMP-2 gene resulting in its expression level were investigated in association with the development of primary open-angle glaucoma (POAG) in a Polish population. METHODS: DNA samples collected from 271 patients with POAG and 281 healthy controls were used in this study. Polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Clinical parameters of the rim area (RA) and retinal neuron fiber layer (RNFL) were also analyzed. RESULTS: We found that the -735C/T and -1306C/T polymorphisms of MMP-2 were not associated with a risk of POAG. However, both the -735T/T (OR = 0.18 (0.04-0.92) p = 0.03) and the 1306T/T (OR = 0.14 (0.03-0.67) p = 0.007) genotypes of MMP-2 were significantly associated with the rim area factor in early stage of POAG suggesting its protective role in the disease progression. CONCLUSION: Finally, our data suggest that gene polymorphisms of MMP-2 may have a protective role in the progression of primary open-angle glaucoma in a Polish population. PMID- 23725206 TI - Exploitation and community engagement: can community advisory boards successfully assume a role minimising exploitation in international research? AB - It has been suggested that community advisory boards (CABs) can play a role in minimising exploitation in international research. To get a better idea of what this requires and whether it might be achievable, the paper first describes core elements that we suggest must be in place for a CAB to reduce the potential for exploitation. The paper then examines a CAB established by the Shoklo Malaria Research Unit under conditions common in resource-poor settings - namely, where individuals join with a very limited understanding of disease and medical research and where an existing organisational structure is not relied upon to serve as the CAB. Using the Tak Province Border Community Ethics Advisory Board (T-CAB) as a case study, we assess the extent to which it might be able to take on a role minimising exploitation were it to decide to do so. We investigate whether, after two years in operation, T-CAB is capable of assessing clinical trials for exploitative features and addressing those found to have them. The findings show that, although T-CAB members have gained knowledge and developed capacities that are foundational for one-day taking on a role to reduce exploitation, their ability to critically evaluate studies for the presence of exploitative elements has not yet been strongly demonstrated. In light of this example, we argue that CABs may not be able to perform such a role for a number of years after initial formation, making it an unsuitable responsibility for many short-term CABs. PMID- 23725207 TI - Outcome of malaria-associated acute kidney injury: a prospective study from a single center. AB - OBJECTIVE: The aim of this prospective study was to determine the outcome of patients suffering from malaria with acute renal dysfunction. METHODS: All adult patients of laboratory-proven malaria with acute kidney injury (AKI) admitted during the period of May 2010 to June 2011 were included. Patient characteristics, physical examination findings, and laboratory parameters were recorded. Patient outcome was assessed in terms of peak serum creatinine level, duration of hospital stay, need for dialysis, and in-hospital mortality rate. Surviving patients were followed up for 3 months to determine progression to chronic kidney disease. RESULTS: This study enrolled 101 patients of malarial AKI. Mean age was 33.70 +/- 15.39 years. Oliguric AKI was observed in 44.6% cases. Mean duration of hospital stay was 8.75 +/- 7.60 days. Renal replacement therapy was required in 36.6% patients. Ten (9.9%) patients succumbed to illness during hospital stay. Majority of deaths occurred shortly after admission. Mortality risk was significantly associated with raised LDH (p = 0.019), lower hemoglobin level (p = 0.015), raised aspartate transaminases (p < 0.001), and elevated alanine transaminases (p = 0.016). Cerebral malaria was an important determinant of mortality (p = 0.002). Renal parameters, including severity of renal dysfunction and need for dialysis, were not associated with mortality risk. Among 91 survivors, 79 patients completed a 3-month follow-up and all of them had normalization of renal function. CONCLUSION: We observed 9.9% in-hospital mortality rate in the study cohort. Cerebral malaria was an important risk factor for mortality in malarial AKI patients. Severity of renal dysfunction did not correlate with the mortality risk in our study. PMID- 23725208 TI - Effects of emotion recognition training on mood among individuals with high levels of depressive symptoms: study protocol for a randomised controlled trial. AB - BACKGROUND: We have developed a new paradigm that targets the recognition of facial expression of emotions. Here we report the protocol of a randomised controlled trial of the effects of emotion recognition training on mood in a sample of individuals with depressive symptoms over a 6-week follow-up period. METHODS/DESIGN: We will recruit 190 adults from the general population who report high levels of depressive symptoms (defined as a score >= 14 on the Beck Depression Inventory-II). Participants will attend a screening session and will be randomised to intervention or control procedures, repeated five times over consecutive days (Monday to Friday). A follow-up session will take place at end of -treatment, 2-weeks and 6-weeks after training. Our primary study outcome will be depressive symptoms, Beck Depression Inventory- II (rated over the past two weeks). Our secondary outcomes are: depressive symptoms, Hamilton Rating Scale for Depression; anxiety symptoms, Beck Anxiety Inventory (rated over the past month); positive affect, Positive and Negative Affect Schedule (rated as 'how you feel right now'); negative affect, Positive and Negative Affect Schedule (rated as 'how you feel right now'); emotion sensitivity, Emotion Recognition Task (test phase); approach motivation and persistence, the Fishing Game; and depressive interpretation bias, Scrambled Sentences Test. DISCUSSION: This study is of a novel cognitive bias modification technique that targets biases in emotional processing characteristic of depression, and can be delivered automatically via computer, Internet or Smartphone. It therefore has potential to be a valuable cost-effective adjunctive treatment for depression which may be used together with more traditional psychotherapy, cognitive-behavioural therapy and pharmacotherapy. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN17767674. PMID- 23725209 TI - Hormonal regulation of Cyp4a isoforms in mouse liver and kidney. AB - Mouse Cyp4a subfamily, including Cyp4a10, Cyp4a12a, Cyp4a12b and Cyp4a14, demonstrate a gender- and strain-specific expression in liver and kidney. In C57BL/6 mouse liver and kidney, Cyp4a12a and 4a12b are male-predominant, whereas Cyp4a14 is female-predominant. Cyp4a10 is female-predominant in liver, but shows no gender difference in kidney. The present study was aimed to determine whether sex hormones and/or growth hormone (GH) secretion patterns are responsible for the gender-specific Cyp4a expression in C57BL/6 mice. Gonadectomized mice, GH releasing hormone receptor-deficient little (lit/lit) mice and hypophysectomized mice were used with replacement of sex hormones or GH in male or female secretion patterns. Both androgens and male-pattern GH regulated the gender-divergent Cyp4a10, 4a12a and 4a12b in liver, whereas androgens played an exclusive role in regulating Cyp4a10 and 4a12a in kidney. In contrast, Cyp4a12b was increased by male-pattern GH but not androgens in kidney. The female-predominant Cyp4a14 in liver and kidney was due to a combined effect of male-pattern GH and androgens. In addition, estrogens played a minor role in regulation of Cyp4a isoforms through an indirect pathway. In conclusion, gender-divergent Cyp4a mRNA expression in liver is caused by male-pattern GH secretion pattern and androgens, whereas in kidney, Cyp4a mRNA expression is primarily regulated by androgens. PMID- 23725210 TI - Pressure-induced protein adsorption at aqueous-solid interfaces. AB - There seems to be a general relation between the standard Gibbs energy change of unfolding, DeltaG degrees unf, of a protein and its affinity to aqueous-solid interfaces. So-called "hard" proteins (DeltaG degrees unf is large) are found to adsorb less strongly to such interfaces than "soft" proteins (DeltaG degrees unf is small). Here, we provide direct support for this rule by using high pressure to modulate the folding stability of a protein. We have performed high-pressure total internal reflection fluorescence (HP-TIRF) spectroscopy and high-pressure neutron reflectometry (HP-NR) to measure the degree of adsorption and the structure of lysozyme on planar solid surfaces as a function of pressure for the first time. By carrying out these experiments at hydrophilic and hydrophobic surfaces with varying concentrations of glycerol, we have found strong evidence that DeltaG degrees unf has indeed a direct influence. At high pressures, there is a larger degree of lysozyme adsorption, probably because lysozyme becomes a "soft" protein under these conditions. The results of this study demonstrate that high pressure is a very useful tool to explore thermodynamics of protein interface interactions. PMID- 23725211 TI - Human umbilical cord-derived mesenchymal stem cells can secrete insulin in vitro and in vivo. AB - Diabetes mellitus is characterized by autoimmune destruction of pancreatic beta cells, leading to decreased insulin production. Differentiation of mesenchymal stem cells (MSCs) into insulin-producing cells offers novel ways of diabetes treatment. MSCs can be isolated from the human umbilical cord tissue and differentiate into insulin-secreting cells. Human umbilical cord-derived stem cells (hUDSCs) were obtained after birth, selected by plastic adhesion, and characterized by flow cytometric analysis. hUDSCs were transduced with nonintegrated lentivirus harboring PDX1 (nonintegrated LV-PDX1) and was cultured in differentiation medium in 21 days. Pancreatic duodenum homeobox protein-1 (PDX1) is a transcription factor in pancreatic development. Significant expressions of PDX1, neurogenin3 (Ngn3), glucagon, glucose transporter2 (Glut2), and somatostatin were detected by quantitative RT-PCR (P < 0.05). PDX1 and insulin proteins were shown by immunocytochemistry analysis. Insulin secretion of hUDSCs(PDX1+) in the high-glucose medium was 1.8 MUU/mL. They were used for treatment of diabetic rats and could decrease the blood glucose level from 400 mg/dL to a normal level in 4 days. In conclusion, our results demonstrated that hUDSCs are able to differentiate into insulin-producing cells by transduction with nonintegrated LV-PDX1. These hUDSCs(PDX1+) have the potential to be used as a viable resource in cell-based gene therapy of type 1 diabetes. PMID- 23725213 TI - Oxygen contribution to wine aroma evolution during bottle aging. AB - Wine aroma undergoes major changes during bottle aging, which are deeply influenced by the degree of oxygen exposure in the bottle. This review discusses the involvement of oxygen in the main chemical transformations occurring in wine aroma composition during bottle aging, with particular emphasis on the formation of oxidative aroma compounds and formation/degradation of sulfur-containing volatile compounds. The implications for wine sensory properties are discussed, as well as some practical aspects of oxygen management during bottle aging, including the role of closure oxygen permeability. PMID- 23725212 TI - Predictors of relational continuity in primary care: patient, provider and practice factors. AB - BACKGROUND: Continuity is a fundamental tenet of primary care, and highly valued by patients; it may also improve patient outcomes and lower cost of health care. It is thus important to investigate factors that predict higher continuity. However, to date, little is known about the factors that contribute to continuity. The purpose of this study was to analyse practice, provider and patient predictors of continuity of care in a large sample of primary care practices in Ontario, Canada. Another goal was to assess whether there was a difference in the continuity of care provided by different models of primary care. METHODS: This study is part of the larger a cross-sectional study of 137 primary care practices, their providers and patients. Several performance measures were evaluated; this paper focuses on relational continuity. Four items from the Primary Care Assessment Tool were used to assess relational continuity from the patient's perspective. RESULTS: Multilevel modeling revealed several patient factors that predicted continuity. Older patients and those with chronic disease reported higher continuity, while those who lived in rural areas, had higher education, poorer mental health status, no regular provider, and who were employed reported lower continuity. Providers with more years since graduation had higher patient-reported continuity. Several practice factors predicted lower continuity: number of MDs, nurses, opening on weekends, and having 24 hours a week or less on-call. Analyses that compared continuity across models showed that, in general, Health Service Organizations had better continuity than other models, even when adjusting for patient demographics. CONCLUSIONS: Some patients with greater health needs experience greater continuity of care. However, the lower continuity reported by those with mental health issues and those who live in rural areas is concerning. Furthermore, our finding that smaller practices have higher continuity suggests that physicians and policy makers need to consider the fact that 'bigger is not always necessarily better'. PMID- 23725214 TI - Effect of ultraviolet aging on translucency of resin-cemented ceramic veneers: an in vitro study. AB - PURPOSE: The aim of this in vitro study was to evaluate the translucency of ceramic veneers cemented with light- or dual-cured resin cements after accelerated aging. MATERIALS AND METHODS: A total of 392 specimens were made of shade A1 with 0.5- and 1.0-mm thickness. Light-cured RelyX Veneer and dual-cured Maxcem Elite and Variolink II resin cements were applied on the porcelain discs with a thickness of 0.1 mm. Translucency parameter (TP) values of the ceramic veneers after cementation and UV aging test were evaluated. Statistical analyses were done with ANOVA and Tukey's tests and paired sample t-test (p < 0.05). RESULTS: All the resin cements affected the TP values of 0.5-mm-thick ceramic, while RelyX Veneer Tr (TP = 11.15; p = 0.608), Variolink II Tr (TP = 10.98; p = 0.55), and Maxcem Clear (TP = 11.81; p = 0.702) did not affect the translucency of 1-mm-thick ceramics (TP = 11.38). The aging process affected TP values of both ceramics and cemented ceramics, as the TP values decreased after aging. Among the TP values of opaque shade resin cements, there were significant differences between the "ceramic," "ceramic + RelyX Veneer WO," "ceramic + Variolink II WO," and "ceramic + Maxcem WO" variables for both 0.5 and 1 mm thicknesses (p < 0.05). There were no significant differences between "ceramic," "ceramic + RelyX Veneer Tr," "ceramic + Variolink II Tr," and "ceramic + Maxcem Clear" variables at 0.5 mm thickness, and there were no significant differences between "ceramic," "ceramic + RelyX Veneer Tr," and "ceramic + Variolink II Tr" variables after aging (p > 0.05). CONCLUSIONS: The TP of the same color of resin cements varied related to the type or brand. Aging caused both the ceramics and cemented ceramics to become more opaque. PMID- 23725215 TI - Long-acting beta-agonists reduce mortality of patients with severe and very severe chronic obstructive pulmonary disease: a propensity score matching study. AB - BACKGROUND: Long-acting beta-agonists were one of the first-choice bronchodilator agents for stable chronic obstructive pulmonary disease. But the impact of long acting beta-agonists on mortality was not well investigated. METHODS: National Emphysema Treatment Trial provided the data. Severe and very severe stable chronic obstructive pulmonary disease patients who were eligible for volume reduction surgery were recruited at 17 clinical centers in United States during 1988-2002. We used the 6-10 year follow-up data of patients randomized to non surgery treatment. Hazard ratios for death by long-acting beta-agonists were estimated by three models using Cox proportional hazard analysis and propensity score matching were measured. RESULTS: The pre-matching cohort was comprised of 591 patients (50.6% were administered long-acting beta-agonists. Age: 66.6 +/- 5.3 year old. Female: 35.4%. Forced expiratory volume in one second (%predicted): 26.7 +/- 7.1%. Mortality during follow-up: 70.2%). Hazard ratio using a multivariate Cox model in the pre-matching cohort was 0.77 (P = 0.010). Propensity score matching was conducted (C-statics: 0.62. No parameter differed between cohorts). The propensity-matched cohort was comprised of 492 patients (50.0% were administered long-acting beta-agonists. Age: 66.8 +/- 5.1 year old. Female: 34.8%. Forced expiratory volume in one second (%predicted) 26.5 +/- 6.8%. Mortality during follow-up: 69.1%). Hazard ratio using a univariate Cox model in the propensity-matched cohort was 0.77 (P = 0.017). Hazard ratio using a multivariate Cox model in the propensity-matched cohort was 0.76 (P = 0.011). CONCLUSIONS: Long-acting beta-agonists reduce mortality of severe and very severe chronic obstructive pulmonary disease patients. PMID- 23725216 TI - The effect of a systemic angiotensin receptor blocker on vascular endothelial growth factor in the vitreous of patients with proliferative diabetic retinopathy. AB - PURPOSE: Renin-angiotensin system (RAS) is reportedly associated with the vitreous level of vascular endothelial growth factor (VEGF) in proliferative diabetic retinopathy (PDR). This study was conducted to investigate the effect of systemic angiotensin receptor blocker (ARB) on vitreous VEGF in PDR. METHOD: Patients who underwent a vitrectomy due to PDR were divided into two groups: patients who were taking ARB to control hypertension (Group A) and normotensive patients (Group B). Patients having epiretinal membrane or macular hole without diabetes or hypertension were included in the control group (Group C). We assessed the best-corrected visual acuity (BCVA) and VEGF levels of the vitreous fluid and the serum using enzyme-linked immunosorbent assay. RESULTS: Nineteen eyes were in Group A, 27 eyes in Group B, and 30 eyes in Group C. The mean levels of vitreous VEGF were 487.5 pg/ml in Group A and 553.0 pg/ml in Group B. In Group C, the vitreous VEGF was below the detection limit in 29 of the 30 eyes. The mean serum VEGF levels were 384.8 pg/ml, 384.6 pg/ml, and 388.1 pg/ml, respectively. The ratio of vitreous VEGF to serum was 4.0 in Group A and 2.97 in Group B. There were no differences in vitreous and serum VEGF levels between two groups. The median BCVA of Groups A and B significantly improved from 1.55 and 1.10 at baseline to 0.55 and 0.30 respectively at 6 months (logarithm of minimal angle resolution, p < 0.005). No differences were found in visual acuity. CONCLUSION: Systemic ARB did not show beneficial effects with respect to the vitreous level of VEGF or functional outcomes after vitrectomy in patients with PDR. PMID- 23725217 TI - Transition in subicular burst firing neurons from epileptiform activity to suppressed state by feedforward inhibition. AB - The subiculum, a para-hippocampal structure positioned between the cornu ammonis 1 subfield and the entorhinal cortex, has been implicated in temporal lobe epilepsy in human patients and in animal models of epilepsy. The structure is characterized by the presence of a significant population of burst firing neurons that has been shown previously to lead epileptiform activity locally. Phase transitions in epileptiform activity in neurons following a prolonged challenge with an epileptogenic stimulus has been shown in other brain structures, but not in the subiculum. Considering the importance of the subicular burst firing neurons in the propagation of epileptiform activity to the entorhinal cortex, we have explored the phenomenon of phase transitions in the burst firing neurons of the subiculum in an in vitro rat brain slice model of epileptogenesis. Whole-cell patch-clamp and extracellular field recordings revealed a distinct phenomenon in the subiculum wherein an early hyperexcitable state was followed by a late suppressed state upon continuous perfusion with epileptogenic 4-aminopyridine and magnesium-free medium. The suppressed state was characterized by inhibitory post synaptic potentials in pyramidal excitatory neurons and bursting activity in local fast-spiking interneurons at a frequency of 0.1-0.8 Hz. The inhibitory post synaptic potentials were mediated by GABAA receptors that coincided with excitatory synaptic inputs to attenuate action potential discharge. These inhibitory post-synaptic potentials ceased following a cut between the cornu ammonis 1 and subiculum. The suppression of epileptiform activity in the subiculum thus represents a homeostatic response towards the induced hyperexcitability. Our results suggest the importance of feedforward inhibition in exerting this homeostatic control. PMID- 23725218 TI - The clinical application of array CGH for the detection of chromosomal defects in 20,126 unselected newborns. AB - BACKGROUND: Array comparative genomic hybridization (CGH) is a powerful tool for detecting unbalanced chromosomal alterations. To validate the usefulness of array CGH in newborn screening, we examined 20,126 unselected infants. In addition, the number of newborns analyzed with array CGH is the largest one ever reported. FINDINGS: A total of 20,126 unselected newborns were investigated with array CGH and cytogenetic analyses. The analyses revealed 87 cases with chromosome abnormalities. Of these, 53 cases had significant chromosome aneuploidies, including trisomy 13, trisomy 21, 47,XXY or 45,X, and the other 34 cases presented partial chromosomal deletions or duplications. CONCLUSIONS: In this study, we show that array CGH is an appropriate tool for the screening of chromosomal abnormalities in newborns, especially for the infants without distinct clinical features. PMID- 23725220 TI - Cross-talk between cognate and noncognate RpoE sigma factors and Zn(2+)-binding anti-sigma factors regulates photooxidative stress response in Azospirillum brasilense. AB - AIMS: Azospirillum brasilense harbors two redox-sensitive Zinc-binding anti-sigma (ZAS) factors (ChrR1 and ChrR2), which negatively regulate the activity of their cognate extra-cytoplasmic function (ECF) sigma factors (RpoE1 and RpoE2) by occluding their binding to the core enzyme. Both pairs of RpoE-ChrR control responses to photooxidative stress. The aim of this study was to investigate whether the two RpoE-ChrR pairs cross-talk while responding to the stress. RESULTS: In silico analysis showed a high sequence similarity between ChrR1 and ChrR2 proteins, but differences in redox sensitivity. Using in silico and in vitro methods of protein-protein interaction, we have shown that both ChrR1 and ChrR2 proteins physically bind to their noncognate RpoE proteins. Restoration of the phenotypes of chrR1::Tn5 and chrR2::Km mutants related to carotenoid biosynthesis and photooxidative stress tolerance by expressing chrR1 or chrR2 provided in vivo evidence for the cross-talk. In addition, up- or down-regulation of several identical proteins by expressing chrR1 or chrR2 in the chrR1::Tn5 mutant provided another in vivo evidence for the cross-talk. INNOVATION: Although multiple redox-sensitive ZAS anti-sigma factors occur in some Gram-positive bacteria, no cross-talk is reported among them. We report here, for the first time, that the two ZAS anti-sigma factors of A. brasilense also interact with their noncognate sigma factors and affect gene expression. CONCLUSION: The two redox-sensitive ZAS anti-sigma factors in A. brasilense may interact with their cognate as well as noncognate ECF sigma factors to play an important role in redox homeostasis by facilitating recovery from the oxidative stress. PMID- 23725219 TI - MicroRNA signatures and treatment response in patients with advanced classical Hodgkin lymphoma. AB - Although specific microRNA (miRNA) signatures in classical Hodgkin lymphoma (cHL) have been proposed, their relationship with clinical outcome remains unclear. Despite treatment advances, a substantial subset of patients with advanced cHL are refractory to standard therapies based on adriamycin and its variants. Global miRNA expression data of 29 advanced cHL patients and five cHL-derived cell lines were used to identify profiles from Hodgkin-Reed-Sternberg (HRS) cells and their non-tumoural microenvironment. A cHL-miRNA signature was identified with 234 miRNAs differentially expressed. A subset of these miRNAs was associated with outcome and selected for study in an independent set of 168 cHL samples using quantitative reverse transcription polymerase chain reaction. Multivariate Cox regression analyses including cross-validation with failure-free survival (FFS) as clinical endpoint revealed a miRNA signature with MIR21, MIR30E, MIR30D and MIR92B* that identified two risk-groups with significant differences in 5-year FFS (81% vs. 35.7%; P < 0.001). Additionally, functional silencing of MIR21 and MIR30D in L428 cells showed increased sensitivity to doxorubicin-induced apoptosis, pointing towards abnormalities of mitochondrial intrinsic and TP53 CDKN1A pathways as related to miRNA deregulation in cHL. These results suggest that clinical outcome in cHL is associated with a specific miRNA signature. Moreover, functional analyses suggest a role for MIR21 and MIR30D in cHL pathogenesis and therapeutic resistance. PMID- 23725221 TI - A cross sectional study examining social desirability bias in caregiver reporting of children's oral health behaviors. AB - BACKGROUND: Our previous research (Pediatrics 2010:126) found a strong association between caregiver oral health literacy (OHL) and children's oral health status; however, we found a weak association with oral health behaviors (OHBs). We hypothesize that this may be due to social desirability bias (SDB). Our objectives were to compare caregivers' responses to traditional OHB items and newer SDB-modulating items, and to examine the association of caregiver literacy with OHBs. METHODS: We performed a cross-sectional study of 102 caregiver-child dyads, collecting data for OHBs using both traditional and new SDB-modulating items. We measured OHL using REALD-30, a validated word recognition test. We relied upon percent agreement and Cohen's kappa (k) to quantify the concordance in caregivers' responses and multivariate log-binomial regression to estimate the impact of OHL on OHBs. RESULTS: Caregivers' mean REALD-30 score was 20.7 (SD = 6.0), range 1-30. We found an association between OHL and 4 of 8 OHBs examined. A subset of behavior questions compared traditional versus SDB-modulating items: history of bottle-feeding: agreement = 95%, k = 0.83 (95% CL:0.68,0.99); daily tooth brushing: agreement = 78%, k = 0.25 (95% CL:0.04,0.46); fluoridated toothpaste use: agreement = 88%, k = 0.67 (95% CL:0.49,0.85). After controlling for caregivers' race, marital status and study site, higher literacy scores remained associated with a decreased prevalence of parental report of "decided not brush the child's teeth because it would be frustrating". CONCLUSIONS: Agreement between responses was high for 2 of 3 behavior items. Item 3 (tooth brushing frequency) revealed discordance, likely due to SDB. Use of the SDB modulating items appears to yield a better estimate of OHB. PMID- 23725222 TI - Surface plasmon resonance-based real-time bioaerosol detection. AB - AIMS: Rapid and precise bioaerosol detection in different environments has become an important research and technological issue over last decades. Previously, we employed a real-time PCR protocol in conjunction with personal bioaerosol sampler for rapid detection of airborne viruses. The approach has been proved to be specific and sensitive. However, a period of time required for entire procedure was in manner of hours. Some new developments are required to decrease the detection time down to real-time protocols. METHODS AND RESULTS: Presently, a surface plasmon resonance (SPR)-based immunosensor that coupled with a specific antigen-antibody reaction could offer sensitive, specific, rapid and label-free detection. This study describes the possibility of combining the personal sampler with SPR technology for qualitative and extremely rapid detection of airborne micro-organisms. Common viral surrogate MS2 bacteriophage, frequently used in bioaerosol studies, was employed as a model organism. The results of the sensor functionalizing procedure with monoclonal anti-MS2 antibody and optimization of the chip performance are presented. The SPR-based detection of the airborne virus was found to be very fast; the viral presence was detected in less than 2 min, and the entire procedure (sampling and analysis) was undertaken in 6 min, which could be considered as real-time detection for this type of measurements. CONCLUSIONS: The combination of SPR with the personal sampler targeted towards bioaerosol detection was proven to be feasible. The SPR sensor was found to be highly stable and suitable for multiple utilizations without significant decrease in response. The suggested approach opens new possibilities for the development of portable and rapid (almost real time) bioaerosol monitors. SIGNIFICANCE AND IMPACT OF THE STUDY: This technology is the first in the world real-time bioaerosol monitor. This outcome would be of strong interest to individuals representing public health, biosecurity, defence forces, environmental sciences and many others. PMID- 23725224 TI - Formation of regular stripes of chemically converted graphene on hydrophilic substrates. AB - Chemically converted graphene (CCG), from a chemistry point of view, is a giant molecule with a unique two-dimensional (2D) configuration. The availability of CCG dispersion provides a range of scalable methods to assemble graphene-based materials but brings the challenge of understanding and control of the CCG morphology in solution processing. In this study, we found that, similar to conventional colloidal systems (e.g., spherical particles or polymers), a 2D sheet of CCG can be transferred from its aqueous dispersion to solid substrates in the form of highly regular stripe patterns by evaporation-driven deposition. The width and spacing can be defined by the concentration of the CCG dispersion and the properties of the substrate (e.g., roughness and surface charge). Furthermore, the high resolution AFM images illustrate that both 2D flattened and highly wrinkled CCG can be formed in each individual stripe, depending on the location across the stripe. The in situ optical observation of the stripe formation indicates that the morphological change of CCG may occur in the crowded meniscus of the drying front. PMID- 23725223 TI - Concerted hydrogen atom and electron transfer mechanism for catalysis by lysine specific demethylase. AB - We calculate the free energy profile for the postulated hydride transfer reaction mechanism for the catalysis of lysine demethylation by lysine-specific demethylase LSD1. The potential energy surface is obtained by using combined electrostatically embedded multiconfiguration molecular mechanics (EE-MCMM) and single-configuration molecular mechanics (MM). We employ a constant valence bond coupling term to obtain analytical energies and gradients of the EE-MCMM subsystem, which contains 45 quantum mechanics (QM) atoms and which is parametrized with density functional calculations employing specific reaction parameters obtained by matching high-level wave function calculations. In the MM region, we employ the Amber ff03 and TIP3P force fields. The free energy of activation at 300 K is calculated by molecular dynamics (MD) umbrella sampling on a system with 102,090 atoms as the maximum of the free energy profile along the reaction coordinate as obtained by the weighted histogram analysis method with 17 umbrella sampling windows. This yields a free energy of activation of only 10 kcal/mol, showing that the previously postulated direct hydride transfer reaction mechanism is plausible, although we find that it is better interpreted as a concerted transfer of a hydrogen atom and an electron. PMID- 23725225 TI - Loss of fatty acid synthase inhibits the "HER2-PI3K/Akt axis" activity and malignant phenotype of Caco-2 cells. AB - BACKGROUND: Fatty acid synthase (FASN) is frequently activated and overexpressed in human cancers, and plays a crucial role in the carcinogenesis of various cancers. In this study, our aims were to explore the role of FASN in regulating the "HER2-PI3K/Akt axis" activity and malignant phenotype of colorectal cancer. METHODS: Caco-2 cells with a high expression of both HER2 and FASN were selected for functional characterization. Caco-2 cells were transfected with either the FASN specific RNAi plasmid or the negative control RNAi plasmid, followed by the RT-qPCR and western blot to examine the expression of FASN, HER2, PI3K and Akt. The MTT and colony formation assays were used to assess the proliferation potential. The migration was investigated by the transwell, and the apoptosis and cell cycle were assayed by the flow cytometry. RESULTS: Notably, the expression of FASN, HER2, PI3K and Akt were downregulated upon a silence of FASN. The proliferation was decreased after a downregulation of FASN, which was consistent with an increased apoptosis rate. The migration was also impaired in FASN silenced cells. CONCLUSION: A downregulation of FASN effectively inhibits the activity of "HER2-PI3K/Akt axis" and alters the malignant phenotype in colorectal cancer cells. PMID- 23725226 TI - The SYSCILIA gold standard (SCGSv1) of known ciliary components and its applications within a systems biology consortium. AB - The multinational SYSCILIA consortium aims to gain a mechanistic understanding of the cilium. We utilize multiple parallel high-throughput (HTP) initiatives to develop predictive models of relationships between complex genotypes and variable phenotypes of ciliopathies. The models generated are only as good as the wet laboratory data fed into them. It is therefore essential to orchestrate a well annotated and high-confidence dataset to be able to assess the quality of any HTP dataset. Here, we present the inaugural SYSCILIA gold standard of known ciliary components as a public resource. PMID- 23725227 TI - Ethical considerations in determining standard of prevention packages for HIV prevention trials: examining PrEP. AB - The successful demonstration that antiretroviral (ARV) drugs can be used in diverse ways to reduce HIV acquisition or transmission risks--either taken as pre exposure prophylaxis (PrEP) by those who are uninfected or as early treatment for prevention (T4P) by those living with HIV--expands the armamentarium of existing HIV prevention tools. These findings have implications for the design of future HIV prevention research trials. With the advent of multiple effective HIV prevention tools, discussions about the ethics and the feasibility of future HIV prevention trial designs have intensified. This article outlines arguments concerning the inclusion of newly established ARV-based HIV prevention interventions as standard of prevention in HIV prevention trials from multiple perspectives. Ultimately, there is a clear need to incorporate stakeholders in a robust discussion to determine the appropriate trial design for each study population. PMID- 23725228 TI - Clinical drug trials in general practice: a 10-year overview of protocols. AB - BACKGROUND: Drugs predominantly prescribed in general practice should ideally be tested in that setting; however, little is known about drug trials in general practice. Our aim was to describe drug trials in Norwegian general practice over the period of a decade. METHODS: The present work concerns a 10-year retrospective study of protocols submitted to the Norwegian national medicines agency (1998 to 2007) identifying all studies involving general practitioners (GPs) as clinical investigator(s). We analyzed the number of trials, drug company involvement, patients, participating doctors, payment, medications tested and main diagnostic criteria for inclusion. We also analyzed one trial in greater detail. RESULTS: Out of 2,054 clinical drug trials, 196 (9.5%) were undertaken in general practice; 93% were multinational, 96% were industry funded and 77% included patients both from general practice and specialist care. The trials were planned to be completed in the period 1998 to 2012. A total of 23,000 patients in Norway and 340,000 patients internationally were planned to be included in the 196 trials. A median of 5 GPs participated in each trial (range 1 to 402). Only 0.7% of 831 GP investigators had general practice university affiliations. Median payment for participating investigators was ?1,900 (range ?0 to 13,500) per patient completing the trial. A total of 30 pharmaceutical companies were involved. The drugs most commonly studied were antidiabetics (21%), obstructive airway disease medications (12%), agents acting on the renin-angiotensin system (10%), and lipid modifying agents (10%). One trial, presented in more detail, had several characteristics of a seeding or marketing trial. CONCLUSIONS: Only one in four drug trials involving general practice were solely general practice trials and almost all were industry initiated without input from academic general practice. There was a large variation in the number of patients, participating doctors, and economic compensation for trial investigators, with some investigators receiving substantial payments. PMID- 23725229 TI - Antibiotic-induced neurotoxicity in dialysis patients: a retrospective study. AB - OBJECTIVE: The study was to evaluate neurotoxicity caused by antibiotics in dialysis patients, including incidence, clinical features, treatments and prognosis. METHODS: In this retrospective study, we reviewed the medical records of 1066 dialysis patients (254 peritoneal dialysis [PD] cases and 812 hemodialysis [HD] cases) who also received intravenous antibiotics in our hospital during July 2006 - April 2012. Naranjo scale was used for estimating the probability of an adverse drug reaction. RESULTS: The incidence of antibiotic induced neurotoxicity was 5.66% in patients receiving HD, and 7.87% in patients receiving PD. There was no significant difference between the two dialysis modalities about the incidence of antibiotic-induced neurotoxicity (p > 0.05). The risk factors included extremely old age, history of central nervous system disorder, low residual renal function, hypoalbuminemia, and the use of multiple antibiotics that share one mechanism. The neurotoxic antibiotics included cephalosporins, penicillins, carbapenems and quinolones in our study. Most patients could be properly diagnosed early according to their medical history, symptoms, signs, electroencephalography (EEG), other related auxiliary examination, and with the help of experienced neurologists. Most neurotoxic patients showed clinical improvement after the discontinuation of antibiotics and active treatment. CONCLUSIONS: The adverse neurotoxic effects of antibiotics were common in dialysis patients due to wide and incorrect usage. Neurotoxicity could be prevented in high-risk cases with dosage adjustments. Better prognosis can be achieved with early and proper diagnosis, decisive withdrawal, and aggressive treatment including enhanced HD. PMID- 23725230 TI - Functional dyspepsia: the economic impact to patients. AB - BACKGROUND: Although highly prevalent, little is known about the economic impact of functional dyspepsia (FD). AIMS: To quantify FD patients' health care utilisation patterns and to estimate direct and indirect costs of FD to patients. METHODS: ICD-9 codes identified adult patients with dyspepsia. A validated questionnaire was mailed to patients who met Rome III criteria for FD. RESULTS: Three hundred and fifty-five patients met all inclusion criteria. The response rate was 63%. The respondents' mean age was 50 (14) years; 75% were women; 52% of respondents rated their FD as moderate. Patients reported 3 visits (mean) to their PCP over 12 months; 75% reported having blood work, 92% an EGD, 59% an ultrasound and 40% a CT scan. The direct cost of testing using Medicare reimbursement rates per patient was $582. To treat FD symptoms, 89% tried dietary changes, 89% over-the-counter medications, 87% prescription medications and 25% alternative therapies. Mean patient expenditure over the last year was $246 for OTC medications (range $0-12,000), $290 for co-payments (range $0-9,000) and $110 for alternative treatments (range $0-3,741). Total mean direct cost yearly to patients was $699. In the 7 days prior to completing the questionnaire, respondents reported a mean of 1.4 h absence from work. Extrapolating the results to the US population, we conservatively calculate the costs of FD were $18.4 billion in 2009. CONCLUSIONS: Functional dyspepsia patients incur significant direct and indirect costs and work productivity is impaired by dyspeptic symptoms. PMID- 23725232 TI - Bereaved caregivers as educators in pediatric palliative care: their experiences and impact. AB - BACKGROUND: With the continuing growth of pediatric palliative care, there is an increasing need to develop effective training for health care professionals. Bereaved parents have participated in the training of health care professionals utilizing curriculum from the Initiative for Pediatric Palliative Care (IPPC), but the experience of bereaved parents as educators has not been studied. OBJECTIVES: This qualitative research examined the experience of bereaved parents involved in pediatric palliative care education of health care professionals and the challenges and possible benefits for the health care professionals. METHODS: Nine bereaved parents and eleven health care professionals were interviewed about their experiences in a pediatric palliative care education program utilizing the IPPC curriculum. The interviews were recorded, transcribed, coded and analyzed for themes and subthemes. RESULTS: Major themes found were a sense of purpose for the parents and benefits and challenges for both parents and professionals. The experience for parents contributed to their meaning-making for both their children's lives and deaths. Parents and professionals identified mutual learning and increased mutual understanding. Some professionals noted that the presence of parents may have limited the openness of discussion of the professionals and parents acknowledged challenges of emotional management in their participation in the educational program. Both parents and professionals recognized and described challenges involved in working sensitively with patients and families without being overwhelmed by the intensity of situations where children die. CONCLUSION: More benefits than burdens were experienced by both parents and health care professionals from the participation of bereaved parents in the palliative care trainings. PMID- 23725234 TI - Anatomopathological causes of death in patients with advanced cancer: association with the use of anticoagulation and antibiotics at the end of life. AB - BACKGROUND: Anatomopathological studies that described the immediate causes of death of patients with advanced cancer were first published approximately 20 years ago. OBJECTIVE: Our objective was to analyze if causes of death changed with a wider use of broad spectrum antibiotics and prophylactic anticoagulation. METHODS: We conducted a retrospective study of all patients with an advanced cancer hospitalized in the Division of Palliative Medicine at the University Hospital Geneva from 2004 to 2010 who had an autopsy. RESULTS: Two hundred forty patients were included (130 men, mean age: 74+/-13). Main causes of death discovered at the autopsy were pulmonary infection (n=131; 55%), advanced cancer (n=39; 16%), pulmonary infection together with pulmonary embolism (PE) (n=27; 12%), PE alone (n=22; 9%), cardiac complications (n=19; 5%) and others (n=2; 1%). In a logistic regression model, with adjusting for age, gender, main diagnosis, comorbidities, blood count, corticosteroids, and antibiotics, there were no independent factors associated with pulmonary infection at autopsy. In a similar model, with adjusting for age, gender, main diagnosis, comorbidities, and anticoagulation, the only independent factor associated with PE at autopsy was the history of thrombo-embolic disease and therapeutic anticoagulation. CONCLUSION: The results of this retrospective study demonstrate that causes of death did not change with the modification of our practice. The high rate of pulmonary infection and embolism in this population, including in patients who received broad spectrum and prophylactic anticoagulation should encourage us to pursue other prospective studies to actually demonstrate the benefit of these treatments in this population. PMID- 23725233 TI - A randomized controlled trial of a cardiopulmonary resuscitation video in advance care planning for progressive pancreas and hepatobiliary cancer patients. AB - BACKGROUND: Cardiopulmonary resuscitation (CPR) is an important advance directive (AD) topic in patients with progressive cancer; however such discussions are challenging. OBJECTIVE: This study investigates whether video educational information about CPR engenders broader advance care planning (ACP) discourse. METHODS: Patients with progressive pancreas or hepatobiliary cancer were randomized to an educational CPR video or a similar CPR narrative. The primary end-point was the difference in ACP documentation one month posttest between arms. Secondary end-points included study impressions; pre- and post-intervention knowledge of and preferences for CPR and mechanical ventilation; and longitudinal patient outcomes. RESULTS: Fifty-six subjects were consented and analyzed. Rates of ACP documentation (either formal ADs or documented discussions) were 40% in the video arm (12/30) compared to 15% in the narrative arm (4/26), OR=3.6 [95% CI: 0.9-18.0], p=0.07. Post-intervention knowledge was higher in both arms. Posttest, preferences for CPR had changed in the video arm but not in the narrative arm. Preferences regarding mechanical ventilation did not change in either arm. The majority of subjects in both arms reported the information as helpful and comfortable to discuss, and they recommended it to others. More deaths occurred in the video arm compared to the narrative arm, and more subjects died in hospice settings in the video arm. CONCLUSIONS: This pilot randomized trial addressing downstream ACP effects of video versus narrative decision tools demonstrated a trend towards more ACP documentation in video subjects. This trend, as well as other video effects, is the subject of ongoing study. PMID- 23725235 TI - Punishing hypocrisy: the roles of hypocrisy and moral emotions in deciding culpability and punishment of criminal and civil moral transgressors. AB - Three experiments explored how hypocrisy affects attributions of criminal guilt and the desire to punish hypocritical criminals. Study 1 established that via perceived hypocrisy, a hypocritical criminal was seen as more culpable and was punished more than a non-hypocritical criminal who committed an identical crime. Study 2 expanded on this, showing that negative moral emotions (anger and disgust) mediated the relationships between perceived hypocrisy, criminal guilt, and punishment. Study 3 replicated the emotion finding from Study 2 using new scenarios where group agents were clearly aware of the hypocrisy of their actions, yet acted anyway. Again, perceived hypocrisy worked through moral emotions to affect criminal guilt and punishment. The current studies provide empirical support for theories relating hypocrisy and moral transgressions to moral emotions, also informing the literature on the role of moral emotions in moral reasoning and legal decision making. PMID- 23725236 TI - Diabetes and the patient-centered medical home. AB - Should you choose to adopt the PCMH, you need to recognize that there will be early adopters and there will be skeptics and it will most likely require a culture change for your organization. Starting small with a targeted population, such as diabetes, is helpful in allowing everyone an opportunity to test this change before implementing it with all patients. You will likely struggle with IT and you can expect confusion as to how the PCMH and care coordination fit with the day-to-day work flow. And, everyone will struggle with staff turnover at some point. This will make it especially necessary to maintain organizational memory of the process. In summary, the core concepts of the PCMH have demonstrated results. However, to get there, leadership support for not only the concept but also for the work is essential. Although the application and certification are important, the real results come from embedding the principles in your standard operating procedures. The PCMH becomes the way you do your work. PMID- 23725238 TI - Managing benefits for diabetes: changing payer strategies for changing times. AB - Just as there are many ways to treat a condition such as diabetes, there are also many ways for payers to manage the diabetes benefit. Although none of these methods is specifically right or wrong, they are grounded in a payer's philosophy and created in response to the needs of the time. Yet, just as in any other business, new ideas and, for diabetes, new scientific discoveries will surely mandate new strategies to achieve goals. As payers find themselves adapting to new political realities and new partnerships, one cannot be sure if their new strategies will succeed or not. But, in actuality, this becomes moot as the 1 point we can be sure of is that benefit management will continue to evolve. PMID- 23725237 TI - Measuring the value of better diabetes management. PMID- 23725239 TI - Examining models of care and reimbursement, including patient management fees, ACOs, and PCMHs: a panel discussion. PMID- 23725240 TI - Is there a business case for diabetes disease management? PMID- 23725241 TI - Real-world examples of patient-centered healthcare. PMID- 23725242 TI - Targeting insulin resistance: the ongoing paradigm shift in diabetes prevention. PMID- 23725243 TI - Can financial incentives improve self-management behaviors? PMID- 23725244 TI - New approaches to defining and measuring the quality of healthcare. PMID- 23725245 TI - Reexamining the roles of diabetes educators. PMID- 23725246 TI - The controversial question of metabolic syndrome. PMID- 23725247 TI - New developments in the treatment of type 2 diabetes mellitus. PMID- 23725248 TI - The power of one. PMID- 23725249 TI - Breathe deeply and say "ninety-nine". PMID- 23725250 TI - Evidence-based medical workforce planning and education: the MSOD project. PMID- 23725251 TI - Prevention of peripheral intravenous catheter-related bloodstream infections: the need for a new focus. PMID- 23725252 TI - From the consumers health forum of Australia. PMID- 23725254 TI - Immigration screening for latent tuberculosis infection. PMID- 23725255 TI - Should we screen for prostate cancer? A re-examination of the evidence. PMID- 23725256 TI - The dilemmas of prostate cancer screening. PMID- 23725257 TI - Burns from motorcycle exhausts among children in New South Wales: a continuing problem. PMID- 23725258 TI - Clinical software on personal mobile devices needs regulation. PMID- 23725259 TI - In reply. PMID- 23725260 TI - Stent insertion for palliation of advanced oesophageal carcinoma symptoms by level of socioeconomic disadvantage in urban New South Wales. PMID- 23725261 TI - Attitudes of a private hospital community to medical student teaching. PMID- 23725262 TI - It's time to examine the status of our undergraduate mental health curricula. PMID- 23725263 TI - Where is the next generation of medical educators? PMID- 23725264 TI - Where is the next generation of medical educators? PMID- 23725265 TI - In reply. PMID- 23725266 TI - Take a deep breath . . . and talk. PMID- 23725267 TI - Expanding the evidence on cancer screening: the value of scientific, social and ethical perspectives. AB - We propose an expanded approach to evidence for cancer screening policy and practice. First, we need to better understand why and how screening happens the way it does, sometimes at odds with evidence of benefits and harms. Second, we need to systematically investigate the ethics of cancer screening to illuminate moral concerns and expand the scope of screening research to address ethical dilemmas. An expanded approach will offer essential information to better support well reasoned judgements, and develop more accountable and less contested cancer screening policies. PMID- 23725268 TI - Patterns of care for men diagnosed with prostate cancer in Victoria from 2008 to 2011. AB - OBJECTIVE: To describe patterns of care for men diagnosed with prostate cancer in Victoria, Australia, between 2008 and 2011. DESIGN, SETTING AND PATIENTS: Men who were diagnosed with prostate cancer at 11 public and six private hospitals in Victoria from August 2008 to February 2011, and for whom prostate cancer notifications were received by the Prostate Cancer Registry. MAIN OUTCOME MEASURES: Characteristics of men diagnosed with prostate cancer; details of treatment provided within 12 months of diagnosis, according to National Comprehensive Cancer Network risk categories; and characteristics of men who did not receive active treatment within 12 months of diagnosis. RESULTS: Treatment details were collected for 98.1% of men who were assessed as eligible to participate in the study (2724/2776) and were confirmed by telephone 12 months after diagnosis for 74.4% of them (2027/2724). Most patients (2531/2724 [92.9%]) were diagnosed with clinically localised disease, of whom 1201 (47.5%) were at intermediate risk of disease progression. Within 12 months of diagnosis, 299 of the 736 patients (40.6%) who had been diagnosed as having disease that was at low risk of progression had received no active treatment, and 72 of 594 patients (12.1%) who had been diagnosed as having disease that was at high risk of progression had received no active treatment. Of those diagnosed as having intermediate risk of disease progression, 54.5% (655/1201) had undergone radical prostatectomy. Those who received no active treatment were more likely than those who received active treatment to be older (odds ratio [95% CI], 2.96 [2.01-4.38], 10.94 [6.96-17.21] and 32.76 [15.84-67.89], respectively, for age 65-74 2013s, 75 84 2013s and >= 85 2013s, compared with < 55 2013s), to have less advanced disease (odds ratio [95% CI], 0.20 [0.16-0.26], 0.09 [0.06-0.12] and 0.05 [0.02 0.90], respectively, for intermediate, high and very high-risk [locally advanced] or metastatic disease, compared with low-risk disease) and to have had their prostate cancer notified by a private hospital (odds ratio [95% CI], 1.35 [1.10 1.66], compared with public hospital). CONCLUSION: Our data reveal a considerable "stage migration" towards earlier diagnosis of prostate cancer in Victoria and a large increase in the use of radical prostatectomy among men with clinically localised disease. PMID- 23725269 TI - Risk assessment to guide prostate cancer screening decisions: a cost effectiveness analysis. AB - OBJECTIVES: To apply the most recent evidence from randomised trials of prostate specific antigen (PSA) screening and explore the potential value of risk assessments to guide the use of PSA screening in practice. DESIGN: A decision model that incorporated a Markov process was developed in 2012 to estimate the net benefit and cost of PSA screening versus no screening as a function of baseline risk. MAIN OUTCOME MEASURES: Quality-adjusted life-2013s (QALYs) and costs. RESULTS: The harms of screening outweighed the benefits under a number of plausible scenarios. Conclusions were sensitive to the estimated quality-of-life impacts of prostate cancer treatment as well as the incidence of cancers not detected by screening tests (poorer prognosis) and those that were detected by screening tests (better prognosis). The base-case incremental cost-effectiveness ratio of PSA screening was $168,611 per QALY for men with average risk, $73,452 per QALY for men with two times the average risk, and $22,938 [corrected] per QALY for men with five times the average risk. CONCLUSIONS: PSA screening was not found to be cost-effective for men at an average-to-high risk of prostate cancer, but may be cost-effective for men at very high risk. Inexpensive approaches for identifying men at very high risk are needed, as is further research on the size of clinical benefit of early detection in this population. The potential for the costs of risk assessment to be offset by reduced costs of PSA screening also warrants investigation. PMID- 23725270 TI - Peripheral intravenous catheter-associated Staphylococcus aureus bacteraemia: more than 5 years of prospective data from two tertiary health services. AB - OBJECTIVES: To determine the incidence, risk factors for and outcomes of Staphylococcus aureus bacteraemia (SAB) associated with peripheral intravenous catheters (PIVCs). DESIGN, SETTING AND PATIENTS: A review of prospectively collected data from two tertiary health services on all health care-associated SAB episodes occurring in adults aged > 17 2013s from January 2007 to July 2012. MAIN OUTCOME MEASURES: Numbers of health care-associated SAB episodes; device type, location of insertion, device dwell time and outcome at 7 and 30 days for all SAB episodes associated with use of a PIVC; rates of SAB per 10 000 occupied bed-days (OBDs). RESULTS: Overall, 137 of 583 health care-associated-SAB episodes (23.5%) were deemed to be PIVC associated, with an incidence of 0.26/10 000 OBD. The mean dwell time for PIVCs was 3.5 days (range, 0.25-9 days) and 45.2% of SABs occurred in PIVCs with a dwell time >= 4 days. Of the PIVC-associated SAB episodes, 39.6% involved PIVCs inserted in the ED, 39.6% involved PIVCs inserted on wards and 20.8% involved PIVCs inserted by the ambulance service. Of the PIVC associated SABs occurring within 4 days of insertion, 61% were inserted by ED staff or the ambulance service. PIVC-associated SAB were associated with a 30-day all-cause mortality rate of 26.5%. CONCLUSION: PIVC-associated SAB is an under recognised complication. The high incidences of SAB associated with PIVCs inserted in emergency locations and with prolonged dwell times support recommendations in clinical guidelines for routine removal of PIVCs. PMID- 23725271 TI - Human papillomavirus vaccine in boys: background rates of potential adverse events. AB - OBJECTIVES: To determine background rates of potential adverse events following immunisation (AEFI) before expansion of the quadrivalent human papillomavirus (4vHPV) vaccination program to adolescent boys. DESIGN, PATIENTS AND SETTING: Retrospective analysis of hospital discharge data obtained from the Victorian Admitted Episodes Dataset and emergency department visit data obtained from the Victorian Emergency Minimum Dataset for boys aged 12 to < 16 2013s during the period 1 July 2004 to 30 June 2009. MAIN OUTCOME MEASURES: Numbers of and incidence rates for Guillain-Barre syndrome, anaphylaxis, seizures, syncope and other potential AEFI from 1 July 2004 to 30 June 2009, and estimated numbers of events after 4vHPV vaccination assuming no association (other than temporal) with the vaccine. RESULTS: We estimated background rates of neurological and allergic events in adolescent boys to be 252.9 and 175.2 per 100 000 person-2013s, respectively. Assuming an 80% vaccination rate with three doses per person - which equates to 1 440 000 doses administered nationally per 2013 in the first 2 2013s of the program - about 2.4 episodes of Guillain-Barre syndrome would be expected to occur in the 6 weeks following vaccination. Within 1 day of vaccination, about 3.9 seizures, 0.3 episodes of anaphylaxis and 6.5 acute allergy presentations would be expected. CONCLUSIONS: Routinely collected health outcome administration data can inform postlicensure safety surveillance of target conditions that might be perceived as AEFI. PMID- 23725272 TI - Resistant hypercalcaemia in metastatic parathyroid carcinoma. PMID- 23725273 TI - Iron deficiency anaemia in a young woman: a plea for early investigation. PMID- 23725274 TI - Investigating iron deficiency anaemia. PMID- 23725275 TI - Cytotoxic T lymphocytes: the future of cancer stem cell eradication? PMID- 23725276 TI - Diagnostic approaches for identifying acute graft-versus-host disease: what comes next? PMID- 23725277 TI - Counteracting immunosuppressive cofactor B7-H1 may enhance the effects of chemotherapy in cancer patients. PMID- 23725279 TI - Requirement of tumor-associated antigen-specific CD4+ T cells for an efficient dendritic cell vaccine in antitumor immunotherapy. AB - Evaluation of: Aarntzen EH, De Vries IJ, Lesterhuis WJ et al. Targeting CD4(+) T helper cells improves the induction of antitumor responses in dendritic cell based vaccination. Cancer Res. 73(1), 19-29 (2012). The induction of antitumor immune responses in patients is one of the most sought-after goals in cancer treatment. The proposed clinical approach is to use autologous mature dendritic cells (DCs) loaded with class I peptides from tumor-associated antigens (TAAs), as DCs are the most efficient immune cells to generate strong and specific cytotoxic CD8(+) T-lymphocyte (CTL) responses. To optimize DC-based cancer vaccines, Aarntzen et al. evaluated the necessity to stimulate TAA-specific CD4(+) T-helper cells to reinforce antitumor CTL responses. They demonstrated that intranodal injection of DCs pulsed with class I- and II-restricted TAA epitopes increases TAA-specific CTL responses and induces better clinical responses in stage III/IV melanoma patients than the use of DCs pulsed with class I-restricted TAA epitopes alone. This study highlights the interest of concomitant stimulation of TAA-specific CD4(+) and CD8(+) T cells for DC-based antitumor immunotherapy. PMID- 23725280 TI - Tolerogenic dendritic cells for Type 1 diabetes. AB - Evaluation of: Pujol-Autonell I, Ampudia RM, Monge P et al. Immunotherapy with tolerogenic dendritic cells alone or in combination with rapamycin does not reverse diabetes in NOD mice. ISRN Endocrinol. doi:10.1155/2013/346987 (2013) (Epub ahead of print). Many reports confirm that dendritic cells (DCs) can prevent autoimmune diseases in mice and rats including Type 1 diabetes mellitus. Reversal of new-onset Type 1 diabetes mellitus using DCs has not yet been reported in the literature. The findings of Pujol-Autonell and colleagues suggest that reversal using DCs may not be possible, at least in the NOD/LtJ mouse strain. At first sight, these data suggest that DC-based therapies may not be effective in treating new-onset disease in humans. This evaluation provides a potential explanation for why the approach of Pujol-Autonell was not successful and offer alternatives that may result in a successful outcome. Based on this analysis, the importance of quality control testing DCs to ensure that their tolerogenic character is stable in vitro and in vivo is highlighted. PMID- 23725281 TI - Mature peripheral T cells are important to preserve thymus function and selection of thymocytes during Mycobacterium tuberculosis infection. AB - Evaluation of: Nobrega C, Nunes-Alves C, Cerqueira-Rodrigues B et al. T cells home to the thymus and control infection. J. Immunol. 190, 1646-1658 (2013). It is well documented that the thymus is a target organ for a large variety of pathogens (virus, bacteria, fungi and protozoa). Moreover, the presence of pathogen-derived antigens in the thymus of infected mice seems to interfere with the capacity of mature T cells to respond to the invading organism. In this way, Nobrega and colleagues demonstrated in 2010 that Mycobacterium avium infection in the thymus leads to the appearance of differentiated T cells tolerogenic for bacterial antigens. In the present and elegant study, the same group demonstrates that T-cell recirculation from the periphery to the thymus is a mechanism that allows the immune system to respond to thymic infection. A Mycobacterium-infected thymus increases the production of Th1-effector chemokines, such as CXCL9 and CXCL10, which in turn recruit CXCR3(+) peripheral T cells involved in intrathymic bacterial control. Taken together, these findings may represent an important issue of the host response, in terms of different pathogens able to infect the thymus. PMID- 23725282 TI - Chimeric antigen receptor-redirected T cells display multifunctional capacity and enhanced tumor-specific cytokine secretion upon secondary ligation of chimeric receptor. AB - AIM: The aim of the current study was to fully elucidate the functions of T cells genetically modified with an erbB2-specific chimeric antigen receptor (CAR). MATERIAL & METHODS: In this study, key functional parameters of CAR T cells were examined following antigen-specific stimulation of the chimeric anti-erbB2 receptor. RESULTS: Gene-modified T cells produced the cytokines IFN-gamma, IL-2, IL-4, IL-10, TNF-alpha and IL-17, and the chemokine RANTES upon CAR ligation. A multifunctional capacity of these CAR T cells was also demonstrated, where 13.7% of cells were found to simultaneously express IFN-gamma and CD107a, indicative of cytolytic granule release. In addition, the CAR T cells were able to respond to a greater degree on the second ligation of CAR, which has not been previously shown. IFN-gamma secretion levels were significantly higher on second ligation than those secreted following initial ligation. CAR-expressing T cells were also demonstrated to lyze erbB2-expressing tumor cells in the absence of activity against bystander cells not expressing the erbB2 antigen, thereby demonstrating exquisite specificity. CONCLUSION: This study demonstrates the specificity of CAR gene-engineered T cells and their capacity to deliver a wide range of functions against tumor cells with an enhanced response capability after initial receptor engagement. PMID- 23725283 TI - The potential role of dendritic cells in the therapy of Type 1 diabetes. AB - Type 1 diabetes (T1D) is the result of T-cell mediated autoimmune destruction of pancreatic islet beta-cells. The two current treatments for T1D are based on insulin or islet-cell replacement rather than the pathogenesis of T1D and remain problematic. Islet/pancreas transplantation does not cater for the majority of sufferers due to the lack of supply of organs and the need for continuous immunosuppression regimens. The mainstay treatment is insulin replacement, but this is disruptive to lifestyle and does not protect against severe long-term complications. An early vaccination and long-term restoration of immune tolerance to self-antigens in T1D patients (reversing the immunopathogenesis of the disease) would be preferable. Dendritic cells (DCs) are potent APCs and play an important role in inducing and maintaining immune tolerance. Targeting DCs through different DC surface molecules shows effective modulation of immune responses. Their feasibility for immunotherapy to prolong transplant survival and cancer immunotherapy has been demonstrated. Therefore, DCs could potentially be used in the treatment of autoimmune diseases. This review summarizes new insights into DCs as a potential therapeutic target for the treatment of T1D. PMID- 23725284 TI - Progress and potential of immune checkpoint blockade for treating advanced renal cell carcinoma. AB - Adaptive immune responses appear to influence the natural history of cancer progression, as well as therapeutic outcomes, in cancer patients. However, accumulating evidence suggests resistance mechanisms exploited by tumors may play a dominant role in limiting the effectiveness of T cell-mediated cancer therapies. Inhibitory coreceptors expressed by T lymphocytes, or so-called immune checkpoints, are now recognized to play critical roles in regulating the termination of adaptive immune responses. An overview of early-phase trial results distinguish blocking antibodies targeting inhibitory coreceptors as a highly promising approach to cancer immunotherapy for patients with advanced clear cell renal cell carcinoma. Prospects for advanced-phase clinical testing and novel therapy combinations with immune checkpoint blocking agents are discussed. PMID- 23725285 TI - Dendritic cells in myelodysplastic syndromes: from pathogenesis to immunotherapy. AB - Myelodysplastic syndromes (MDS) are clonal disorders of the hematopoietic stem cell characterized by ineffective hematopoiesis leading to peripheral cytopenias. Different processes are involved in its pathogenesis, such as (epi)genetic alterations and immunological dysfunctions. The nature of immune dysregulation is markedly different between various MDS risk groups. In low-risk MDS, the immune system is in a proinflammatory state, whereas in high-risk disease, immunosuppressive features facilitate expansion of the dysplastic clone and can eventually lead to disease progression to acute myeloid leukemia. Various cell types contribute to dysregulation of immune responses in MDS. Dendritic cells (DCs) are important regulators of immunity. However, the role of DCs in MDS has yet to be elucidated. It has been suggested that impaired DC function can hamper adequate immune responses. This review focuses on the involvement of DCs in immune dysregulation in low- and high-risk MDS and the implications for DC targeted therapies. PMID- 23725286 TI - The future of B cell-targeted therapies in Sjogren's syndrome. AB - Primary Sjogren's syndrome is a systemic autoimmune disease characterized by progressive exocrine gland destruction, resulting clinically in eyes and mouth dryness. To date, no treatment has been proven effective to modify the course of this slow-evolving disease. B cells are now considered to play a central role in the pathogenesis of primary Sjogren's syndrome because their functions are not restrained to antibody production. Thus, several B-cell targeting therapies are under clinical investigation. Rituximab, a monoclonal antibody directed to CD20 and leading to transient blood B-cell depletion, has shown partial improvements in subjective and objective sicca symptoms in small studies. However, the results of two large controlled trials are awaited before considering its use in large populations of patients. Several other therapeutic strategies are being studied, targeting other B-cell surface proteins (epratuzumab and anti-CD22) or major cytokines of B-cell homeostasis (e.g., BAFF, IL-6 and lymphotoxin-beta). Although great hope is generated by the trials of these specific therapies, another challenge for clinical researchers is the development of reliable tools to assess the activity of Sjogren's syndrome and its response to treatment. PMID- 23725287 TI - Radioimmunotherapy for high-grade glioma. AB - Patients with high-grade glioma (HGG) still have a very poor prognosis. The infiltrative nature of the tumor and the inter- and intra-tumoral cellular and genetic heterogeneity, leading to the acquisition of new mutations over time, represent the main causes of treatment failure. Radioimmunotherapy represents an emerging approach for the treatment of HGG. Radioimmunotherapy utilizes a molecular vehicle (monoclonal antibodies) to deliver a radionuclide (the drug) to a selected cell population target. This review will provide an overview of preclinical and clinical studies to date and assess the effectiveness of radioimmunotherapy, focusing on possible future therapies for the treatment of HGG. PMID- 23725289 TI - Hydrogen-producing Escherichia coli strains overexpressing lactose permease: FT IR analysis of the lactose-induced stress. AB - The lactose permease gene (lacY) was overexpressed in the septuple knockout mutant of Escherichia coli, previously engineered for hydrogen production from glucose. It was expected that raising the lactose transporter activity would elevate the intracellular lactose concentration, inactivate the lactose repressor, induce the lactose operon, and as a result stimulate overall lactose consumption and conversion. However, overexpression of the lactose transporter caused a considerable growth delay in the recombinant strain on lactose, resembling to some extent the "lactose killing" phenomenon. Therefore, the recombinant strain was subjected to selection on lactose-containing media. Selection on plates with 3% lactose yielded a strain with a decreased content of the recombinant plasmid but with an improved ability to grow and produce hydrogen on lactose. Macromolecular analysis of its biomass by means of Fourier transform infrared spectroscopy demonstrated that increase of the cellular polysaccharide content might contribute to the adaptation of E. coli to lactose stress. PMID- 23725290 TI - Adsorption and aqueous lubricating properties of charged and neutral amphiphilic diblock copolymers at a compliant, hydrophobic interface. AB - We have investigated the adsorption and lubricating properties of neutral and charged amphiphilic diblock copolymers at a hydrophobic polydimethylsiloxane (PDMS) interface in an aqueous environment. The diblock copolymers consist of a hydrophilic block of either neutral poly(ethylene glycol) (PEG) or negatively charged poly(acrylic acid) (PAA) and of a hydrophobic block of polystyrene (PS) or poly(2-methoxyethyl acrylate) (PMEA), thus generating PEG-b-X or PAA-b-X, where X block is either PS or PMEA. The molecular weight ratios were roughly 1:1 with each block ca. 5 kDa. Comparing the neutral PEG and charged PAA buoyant blocks with all other conditions identical, the former showed superior adsorption onto nonpolar, hydrophobic PDMS surfaces from a neutral aqueous solution. PEG based copolymers showed substantial adsorption for both PS and PMEA as the anchoring block, whereas PAA-based copolymers showed effective adsorption only when PMEA was employed as the anchoring block. For PAA-b-PS, the poor adsorption properties are chiefly attributed to micellization due to the high interfacial tension between the PS core and water. The poor lubricating properties of PAA-b PS diblock copolymer for a PDMS-PDMS sliding contact was well correlated with the poor adsorption properties. PAA-b-PMEA copolymers, despite their sizable amount of adsorbed mass, showed insignificant lubricating effects. When the charges of the PAA-b-PMEA diblock copolymers were screened by either adding NaCl to the aqueous solution or by lowering the pH, both the adsorption and lubricity improved. We ascribe the poor adsorption and inferior aqueous lubricating properties of the PAA-based diblock copolymers compared to their PEG-based counterparts mainly to the electrostatic repulsion between charged PAA blocks, hindering the facile formation of the lubricating layer under cyclic tribological stress at the sliding PDMS-PDMS interface. PMID- 23725291 TI - Water network perturbation in ligand binding: adenosine A(2A) antagonists as a case study. AB - Recent efforts in the computational evaluation of the thermodynamic properties of water molecules have resulted in the development of promising new in silico methods to evaluate the role of water in ligand binding. These methods include WaterMap, SZMAP, GRID/CRY probe, and Grand Canonical Monte Carlo simulations. They allow the prediction of the position and relative free energy of the water molecule in the protein active site and the analysis of the perturbation of an explicit water network (WNP) as a consequence of ligand binding. We have for the first time extended these approaches toward the prediction of kinetics for small molecules and of relative free energy of binding with a focus on the perturbation of the water network and application to large diverse data sets. Our results support a qualitative correlation between the residence time of 12 related triazine adenosine A(2A) receptor antagonists and the number and position of high energy trapped solvent molecules. From a quantitative viewpoint, we successfully applied these computational techniques as an implicit solvent alternative, in linear combination with a molecular mechanics force field, to predict the relative ligand free energy of binding (WNP-MMSA). The applicability of this linear method, based on the thermodynamics additivity principle, did not extend to 375 diverse A(2A) receptor antagonists. However, a fast but effective method could be enabled by replacing the linear approach with a machine learning technique using probabilistic classification trees, which classified the binding affinity correctly for 90% of the ligands in the training set and 67% in the test set. PMID- 23725292 TI - The effects of dementia care mapping on nursing home residents' quality of life and staff attitudes: design of the quasi-experimental study Leben-QD II. AB - BACKGROUND: The main objective of care for people with dementia is the maintenance and promotion of quality of life (Qol). Most of the residents in nursing homes have challenging behaviors that strongly affect their Qol. Person centered care (PCC) is an approach that aims to achieve the best possible Qol and to reduce challenging behaviors. Dementia Care Mapping (DCM) is a method of implementing PCC that has been used in Germany for several years. However, there are no data on the effectiveness of DCM or the challenges of implementation of DCM in German nursing homes. METHODS/DESIGN: In this quasi-experimental non randomized cluster-controlled study, the effects of DCM will be compared to 2 comparison groups. 9 nursing homes will take part: 3 will implement DCM, 3 will implement a comparison intervention using an alternative Qol assessment, and 3 have already implemented DCM. The main effect outcomes are Qol, challenging behaviors, staff attitudes toward dementia, job satisfaction and burnout of caregivers. These outcomes will be measured on 3 data points. Different quantitative and qualitative data sources will be collected through the course of the study to investigate the degree of implementation as well as facilitators of and barriers to the implementation process. DISCUSSION: This study will provide new information about the effectiveness of DCM and the implementation process of DCM in German nursing homes. The study results will provide important information to guide the national discussion about the improvement of dementia-specific Qol, quality of care in nursing homes and allocation of resources. In addition, the study results will provide information for decision-making and implementation of complex psychosocial interventions such as DCM. The findings will also be important for the design of a subsequent randomized controlled trial (e.g. appropriateness of outcomes and measurements, inclusion criteria for participating nursing homes) and the development of a successful implementation strategy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43916381. PMID- 23725293 TI - Surface characteristics and cell adhesion: a comparative study of four commercial dental implants. AB - PURPOSE: The aims of this study were to compare surface properties of four commercial dental implants and to compare those implant systems' cell adhesion, which may be affected by the surface properties, and to provide scientific information on the selection of implants for clinicians. MATERIALS AND METHODS: The surface properties of four commonly used dental implants (3i NanotiteTM, Astra OsseoSpeedTM, Nobel Biocare TiUnite(r), and Straumann SLActive(r)) were studied using MicroSpy profiler, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy, and Raman microspectroscopy. Primary mouse alveolar bone cells were cultured on the surface of implants from the four companies. After 48-hour culture, SEM in combination with a quantitative analysis of SEM images was used to examine the cell adhesion. Cell adhesion rates (ratios of cell surface to implant surface) among different systems were compared. RESULTS: Distinct differences were found among these implants. Comparisons of roughness among three locations: flank, top, and valley within the same implant system, or in the same location among different implants were made. Generally Astra and Straumann systems showed the roughest surface, whereas 3i showed the smoothest surface. Multiple cracks were found on the surface of the Nobel Biocare system, which also had a dramatically lower level of titanium. In addition, rutile phase of titanium oxide was found in 3i, Astra, and Straumann systems, and anatase phase of titanium oxide was only detected in the Nobel Biocare system. After 48-hour culture, Astra and Straumann systems displayed the highest cell adhesion at the areas of flank, top, and valley of the implant surface. Primary cells also reached confluence on the valley, but significantly less in the 3i system. Nobel Biocare showed the least cell adhesion on the flank and valley. CONCLUSION: Implant systems have distinct differences in surface properties, leading to different cell adhesion results. Further in vivo study is needed to study the impact of the surface characteristics and different cell adhesion on the osseointegration between implant and bone. PMID- 23725294 TI - Regulation of mitochondrial dynamics and distribution by synapse position and neuronal activity in the axon. AB - Proper distribution of axonal mitochondria is critical for multiple neuronal functions. To understand the underlying mechanisms for population behavior, quantitative characterisation of elemental dynamics on multiple time scales is required. Here we investigated the stability and transport of axonal mitochondria using live-cell imaging of cultured mouse hippocampal neurons. We first characterised the long-term stability of stationary mitochondria. At a given moment, about 10% of the mitochondria were in a state of transport and the remaining 90% were stationary. Among these stationary mitochondria, 40% of them remained in the same position over several days. The rest of the mitochondria transited to mobile state stochastically and this process could be detected and quantitatively analysed by time-lapse imaging with intervals of 30 min. The stability of axonal mitochondria increased from 2 to 3 weeks in culture, was decreased by tetrodotoxin treatment, and was higher near synapses. Stationary mitochondria should be generated by pause of moving mitochondria and subsequent stabilisation. Therefore, we next analysed pause events of moving mitochondria by repetitive imaging at 0.3 Hz. We found that the probability of transient pause increased with field stimulation, decreased with tetrodotoxin treatment, and was higher near synapses. Finally, by combining parameters obtained from time-lapse imaging with different time scales, we could estimate transition rates between different mitochondrial states. The analyses suggested specific developmental regulation in the probability of paused mitochondria to transit into stationary state. These findings indicate that multiple mitochondrial behaviors, especially those regulated by neuronal activity and synapse location, determine their distribution in the axon. PMID- 23725296 TI - Effects of Lactobacillus rhamnosus on asthma with an adoptive transfer of dendritic cells in mice. AB - AIM: This study was designed to investigate whether the protective effects of Lactobacillus rhamnosus (Lcr35) on allergic asthma are associated with the adoptive transfer of dendritic cells (DCs) and regulatory T cells (Tregs), using a mouse experimental model of asthma. METHODS AND RESULTS: BALB/c mice were orally administered Lcr35 or intravenously treated with in vivo Lcr35-treated DCs daily and were then sensitized and challenged with ovalbumin (OVA) in accordance with a model of asthma protocol. Both the oral application of Lcr35 and intravenous administration of Lcr35-treated DCs suppressed all aspects of the asthmatic response, including bronchial hyperresponsiveness (BHR), total cell counts in the bronchoalveolar lavage (BAL) fluid, the production of OVA specificimmunoglobulin E (IgE), and pulmonary eosinophilic inflammation. The mechanism of action of Lcr35 is related to Tregs, which suppress the Th2 response in the respiratory organs, and this is mediated by DCs in the mouse model of asthma. CONCLUSIONS: These results confirm that the mechanism underlying the effects of Lcr35 on asthma involves the adoptive transfer of DCs. SIGNIFICANCE AND IMPACT OF THE STUDY: This finding broadens the possibility that Lcr35 has potential as an alternative therapeutic approach to the treatment of human asthma. PMID- 23725297 TI - MicroRNA-mediated regulation of target genes in several brain regions is correlated to both microRNA-targeting-specific promoter methylation and differential microRNA expression. AB - BACKGROUND: Public domain databases nowadays provide multiple layers of genome wide data e.g., promoter methylation, mRNA expression, and miRNA expression and should enable integrative modeling of the mechanisms of regulation of gene expression. However, researches along this line were not frequently executed. RESULTS: Here, the public domain dataset of mRNA expression, microRNA (miRNA) expression and promoter methylation patterns in four regions, the frontal cortex, temporal cortex, pons and cerebellum, of human brain were sourced from the National Center for Biotechnology Informations gene expression omnibus, and reanalyzed computationally. A large number of miRNA-mediated regulation of target genes and miRNA-targeting-specific promoter methylation were identified in the six pairwise comparisons among the four brain regions. The miRNA-mediated regulation of target genes was found to be highly correlated with one or both of miRNA-targeting-specific promoter methylation and differential miRNA expression. Genes enriched for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that were related to brain function and/or development were found among the target genes of miRNAs whose differential expression patterns were highly correlated with the miRNA-mediated regulation of their target genes. CONCLUSIONS: The combinatorial analysis of miRNA-mediated regulation of target genes, miRNA targeting-specific promoter methylation and differential miRNA expression can help reveal the brain region-specific contributions of miRNAs to brain function and development. PMID- 23725295 TI - An overview of autophagy: morphology, mechanism, and regulation. AB - SIGNIFICANCE: Autophagy is a highly conserved eukaryotic cellular recycling process. Through the degradation of cytoplasmic organelles, proteins, and macromolecules, and the recycling of the breakdown products, autophagy plays important roles in cell survival and maintenance. Accordingly, dysfunction of this process contributes to the pathologies of many human diseases. RECENT ADVANCES: Extensive research is currently being done to better understand the process of autophagy. In this review, we describe current knowledge of the morphology, molecular mechanism, and regulation of mammalian autophagy. CRITICAL ISSUES: At the mechanistic and regulatory levels, there are still many unanswered questions and points of confusion that have yet to be resolved. FUTURE DIRECTIONS: Through further research, a more complete and accurate picture of the molecular mechanism and regulation of autophagy will not only strengthen our understanding of this significant cellular process, but will aid in the development of new treatments for human diseases in which autophagy is not functioning properly. PMID- 23725298 TI - Optimization of bacteriocin production by Lactobacillus sp. MSU3IR against shrimp bacterial pathogens. AB - BACKGROUND: Aquaculture is one amongst the growing and major food producing sectors. Shrimp culture is one of the subsectors of aquaculture that attracts more attention because of the economic interest. However, the shrimp culture systems have been facing severe consequences and economical losses due to disease outbreaks. Risk of disease outbreak can be combated with the application of probiotics. For economically viable production of such probiotic products, the present study provides information on the optimization and partial purification of bacteriocin produced by a goat milk isolate Lactobacillus sp. MSU3IR against the shrimp bacterial pathogens. RESULTS: Bacteriocin production was estimated as a measure of bactericidal activity (arbitrary Unit/ml) over the test strains. The optimum culture conditions and media components for maximum bacteriocin production by Lactobacillus sp. MSU3IR were: pH: 5.0, temperature: 30 degrees C, carbon source: lactose; nitrogen source: ammonium acetate; NaCl: 3.0% and surfactant: Tween 80. MRS medium was found to extend better bacteriocin production than other tested media. Upon partial purification of bacteriocin, the SDS-PAGE analysis had manifested the presence of two peptide bands with the molecular weight of 39.26 and 6.38 kDa, respectively. CONCLUSION: The present results provide baseline trend for the statistical optimization, scale up process and efficient production of bacteriocin by the candidate bacterial strain Lactobacillus sp. MSU3IR which could be used to replace the usage of conventional chemotherapeutics in shrimp culture systems. PMID- 23725300 TI - The mark of a generation: understanding how cosmetic practices shape the world. PMID- 23725299 TI - Rationale and design of the HepZero study: a prospective, multicenter, international, open, randomized, controlled clinical study with parallel groups comparing heparin-free dialysis with heparin-coated dialysis membrane (Evodial) versus standard care: study protocol for a randomized controlled trial. AB - BACKGROUND: Anticoagulation for chronic dialysis patients with contraindications to heparin administration is challenging. Current guidelines state that in patients with increased bleeding risks, strategies that can induce systemic anticoagulation should be avoided. Heparin-free dialysis using intermittent saline flushes is widely adopted as the method of choice for patients at risk of bleeding, although on-line blood predilution may also be used. A new dialyzer, Evodial (Gambro, Lund, Sweden), is grafted with unfractionated heparin during the manufacturing process and may allow safe and efficient heparin-free hemodialysis sessions. In the present trial, Evodial was compared to standard care with either saline flushes or blood predilution. METHODS: The HepZero study is the first international (seven countries), multicenter (10 centers), randomized, controlled, open-label, non-inferiority (and if applicable subsequently, superiority) trial with two parallel groups, comprising 252 end-stage renal disease patients treated by maintenance hemodialysis for at least 3 months and requiring heparin-free dialysis treatments. Patients will be treated during a maximum of three heparin-free dialysis treatments with either saline flushes or blood predilution (control group), or Evodial. The first heparin-free dialysis treatment will be considered successful when there is: no complete occlusion of air traps or dialyzer rendering dialysis impossible; no additional saline flushes to prevent clotting; no change of dialyzer or blood lines because of clotting; and no premature termination (early rinse-back) because of clotting.The primary objectives of the study are to determine the effectiveness of the Evodial dialyzer, compared with standard care in terms of successful treatments during the first heparin-free dialysis. If the non-inferiority of Evodial is demonstrated then the superiority of Evodial over standard care will be tested. The HepZero study results may have major clinical implications for patient care. TRIAL REGISTRATION: ClinicalTrials.gov NCT01318486. PMID- 23725301 TI - Topically delivered dissolved oxygen reduces inflammation and positively influences structural proteins in healthy intact human skin. AB - BACKGROUND: As oxygen is essential for wound healing and there is limited diffusion across the stratum corneum into the epidermis, we wanted to evaluate whether the topical delivery of a total dissolved oxygen in dressing form on intact human subject skin would improve clinical and histologic skin functioning. AIMS: Fifty normal, healthy subjects completed a pilot clinical evaluation to assess the efficacy and tolerability of a dissolved oxygen dressing (OxygeneSysTM Continuous) to improve the health and appearance of intact skin. METHODS: Clinical analysis was performed on 50 subjects; histological and gene expression analysis was performed on 12 of the 50 subjects to assess the effect of the dissolved oxygen dressing. RESULTS: Clinical data demonstrate that the dressing is well tolerated, and several measures of skin health and integrity showed improvements compared with a control dressing site. Skin hydration measurements showed a statistically significant increase in skin hydration at 0-4, 4-8, and 0 8 weeks (P < 0.05 at each time point). The blinded clinical investigator's grading of desquamation, roughness, and skin texture show significant decreases from baseline to the 8-week time point (P < 0.05). The dressings were removed prior to the blinded clinical investigator's grading. These data were supported by the histological and gene expression studies, which showed a general reduction in inflammatory response markers and transcription products (IL-6, IL-8, TNF alpha, MMP-1, and MMP-12), while facilitating a general increase in structural skin proteins (collagen I, elastin, and filaggrin). Additionally, p53 signals from biopsy samples support the clinical investigator's observations of no safety concerns. CONCLUSION: The data from this study demonstrate that the dressing has no deleterious effects and stimulates beneficial effects on intact, nonwounded skin. PMID- 23725302 TI - Preparation, characterization, and moisturizing effect of liposomes containing glucosamine and N-acetyl glucosamine. AB - BACKGROUND: N-acetyl glucosamine (NAG) is a precursor for hyaluronic acid (HA) biosynthesis in the body. The main role of HA is to preserve the hydration and elasticity of the skin. AIMS: To prepare and characterize liposomes containing N acetyl glucosamine and glucosamine (GA) and to assess their effects on the skin moisture content. METHODS: Liposomal formulations containing NAG and GA were prepared using fusion and dehydration-rehydration (DRV) methods. The amount of the moisture contents of the skin before application and 0.5, 1, 3, and 5 h postapplication of the formulations were measured in human volunteers using corneometer. The occlusive factor was also estimated by in vitro method. RESULTS: Mean size of prepared liposomes was <2 MUm, and all formulations showed negative surface charge. The highest effect on skin moisture content was achieved by NAG liposomal prepared using fusion method after 3 h. The difference between moisture content of the skin treated by preparations containing GA (solution and liposomes) and empty liposomes was negligible in all tests and duration times of the experiment. The results of the moisturizing effect according to the in vivo method indicated that there was a significant difference (P < 0.05) between the skin moisture contents after application of liposomal formulation containing NAG 7 mm and empty liposomes during the 5-h postapplication period. CONCLUSIONS: Our study demonstrated the potential of liposomes for improved NAG localization in the skin, and so it could be suggested as a new topical moisturizing formulation in skin care products. PMID- 23725303 TI - Efficacy and safety of adapalene gel 0.1% and 0.3% and tretinoin gel 0.05% for acne vulgaris: results of a single-center, randomized, double-blinded, placebo controlled clinical trial on Mexican patients (skin type III-IV). AB - BACKGROUND: The efficacy of topical retinoids is well known according to several clinical studies conducted predominantly among Caucasian patients. This study aimed to evaluate the efficacy and safety profile of adapalene and tretinoin among Mexican patients. AIMS: To compare adapalene 0.1 and 0.3% and tretinoin 0.05% in Mexican subjects with acne vulgaris. METHODS: We enrolled 171 patients in this single-center, randomized, double-blinded, placebo-controlled clinical trial. The patients applied on the face either adapalene 0.1%, adapalene 0.3%, tretinoin 0.05%, or placebo for 90 days and were evaluated for the reduction in total lesion counts and for the level of irritation. RESULTS: Tretinoin 0.05% and adapalene 0.3% were more effective than adapalene 0.1% and placebo in the reduction of both inflammatory and noninflammatory lesions. Most of adverse events to adapalene and many on tretinoin group were related to skin irritation, dry skin, scaling, pruritus, burning, and postinflammatory hyperpigmentation. CONCLUSION: Adapalene 0.3% and tretinoin 0.05% are comparable in efficacy, and adapalene 0.1% offers a better safety profile in Mexican patients. PMID- 23725304 TI - Hypo-collagenesis in photoaged skin predicts response to anti-aging cosmeceuticals. AB - BACKGROUND: Chronic sun exposure causes photoaging, the appearance of prematurely aged skin. This phenomenon is characterized by progressive alteration of the dermal extracellular matrix, including elastin and collagen fibers. While many cosmeceuticals claim to improve the appearance of photoaged skin, data are lacking regarding their ability to induce molecular responses associated with wrinkle effacement, particularly increased collagen production. AIMS: To conduct a meta-analysis to determine whether there was a factor(s) that could predict response to various cosmeceuticals. PATIENTS/METHODS: Hundred subjects enrolled in five separate studies of cosmeceuticals containing: L-ascorbic acid, pentapeptide, alpha-lipoic acid, yeast extract, or 1% idebenone. Five groups consisting of 16-20 volunteers applied one cosmeceutical to their photodamaged forearms for several weeks. Punch biopsies were obtained pretreatment and post treatment and analyzed for type I procollagen by ELISA. RESULTS: Analysis of basal collagenesis reinforced the notion that hypo-collagenesis is associated with photoaging severity, independent of age or gender. Treatment outcome varied greatly among subjects, ranging from no improvement to a 7-fold increase in collagenesis. Retrospective statistical meta-analysis was conducted to determine whether age, gender, type of cosmeceutical, or evidence of hypo-collagenesis in untreated skin could predict responsiveness to cosmeceuticals. Our analysis revealed that subjects with hypo-collagenesis responded 6.4 times more often than subjects with normo-collagenesis. DISCUSSION: Hypo-collagenesis was the only factor that influenced treatment outcome. This study therefore identifies hypo collagenesis as the unique parameter predicting anti-aging cosmeceutical treatment outcome. These findings provide a basis for future cosmetic testing and the potential development of custom formula skin care. PMID- 23725305 TI - Combination of herbal extracts and platelet-rich plasma induced dermal papilla cell proliferation: involvement of ERK and Akt pathways. AB - BACKGROUND AND AIMS: Recently, platelet-rich plasma (PRP) has attracted attention in various medical fields, including plastic surgery, treatment for problematic wounds, and dermatology. Specifically, PRP has been tested during hair transplantation to reduce swelling and pain and to increase hair density. We examined the effects of PRP and herbal extracts combination in order to identify potential stimulants of hair growth. METHODS: PRP was prepared using the double spin method and applied to dermal papilla cells (DPCs). MTT viability test and BrdU cell proliferation assay were used to study the effect of herbal extracts and PRP on proliferation of DPCs. To understand the mechanisms of herbal extracts and PRP involved in the regulation of hair growth, we evaluated signaling pathways and measured the expressions of ERK and Akt, by Western blot. RESULTS: Combination of herbal extracts and PRP was found to induce significant proliferation of human DPCs at concentrations ranging from 1.5% to 4.5%. The present study shows that herbal extracts and PRP affect the expressions of extracellular signal-regulated kinase (ERK) and Akt in DPCs. CONCLUSION: In this study, we have shown that combination of herbal extracts and PRP plays an active role in promoting the proliferation of human dermal papilla (DP) cells via the regulation of ERK and Akt proteins, and this may be applicable to the future development of herbal extracts and PRP combination therapeutics to enhance hair growth. PMID- 23725306 TI - Global 3-dimensional approach to natural rejuvenation: recommendations for perioral, nose, and ear rejuvenation. AB - BACKGROUND: There is a move toward a global, 3-dimensional approach to facial rejuvenation that has been prompted by advances in techniques and available products. However, little published literature exists on the procedures involved in this global approach, and currently, no validated recommendations exist. OBJECTIVES: To provide a detailed, practical guide to rejuvenation of the perioral area, nose, and ears based on expert consensus recommendations. METHODS: The aim of this approach was to take into account both volumetric and dynamic aspects of treatment, as well as the benefits of treatment combinations, for example, combining botulinum toxins with hyaluronic acid (HA) fillers and volumizers. Each set of recommendations was documented, comprising a clinical definition of the aging severity scale, together with recommendations of appropriate products, doses, site, depth, and injection techniques, as well as indication-specific rules to be respected. RESULTS: HA fillers are ideal for replenishing volume loss in the lips, while rhytides around the lips can be treated with small doses of botulinum toxin. Botulinum toxin can also be used to raise the tip of the nose, to reshape nostrils, and to narrow nasal flare, with HA fillers also be used to correct small defects. HA fillers can also be used to rejuvenate sagging, atrophic or irregular ear lobes, repair torn earlobes, or erase vertical rhytides. CONCLUSIONS: By providing practical guidance on rejuvenation of the perioral area, nose, and ears, esthetic facial physicians can achieve optimum patient outcomes. PMID- 23725307 TI - Tannase-converted green tea catechins and their anti-wrinkle activity in humans. AB - BACKGROUND: This study was performed to investigate the anti-wrinkle effects of topical applications of green tea extract with high antioxidant activity by tannase treatment. Increases in gallic acid (GA), (-)-epigallocatechin (EGC), and (-)-epicatechin (EC) were observed in the green tea extract after tannase treatment. OBJECTIVES: This study was performed to investigate the anti-wrinkle effects of topical applications of green tea extract exhibiting high antioxidant activity after tannase treatment. METHODS: Subjects, randomly divided into two groups, received the application of either tannase-converted green tea extract (TGE) or normal green tea extract (NGE) on their crow's feet for 8 weeks. The anti-wrinkle effects were evaluated with two methods: (i) self-assessment; and (ii) average roughness of skin surface (R(a), R(z), and R(t) value) using skin replica and Skin-Visiometer SV 600. RESULTS: The scavenging abilities of TGE against radicals were significantly higher compared to NGE. The evaluation of skin wrinkle index values after 8 weeks of treatment showed that reductions of R(a), R(z), and R(t) values in the TGE group were significantly greater than in the NGE group, which indicated that tannase treatment improved the anti-wrinkle effects of green tea extract. According to the overall ratings for wrinkle treatment by applying the formulations, most of the TGE group (63.60%) reported marked or moderate improvement in wrinkles compared with only 36.30% of the NGE group. CONCLUSION: Tannase treatment can improve the antioxidant activity of green tea extract, conferring anti-wrinkle activities. These results suggest that TGE may have beneficial properties as an anti-wrinkle agent. PMID- 23725308 TI - Brazilian keratin hair treatment: a review. AB - Brazilian keratin treatments are widely available products that are used by women all over the world to straighten hair. Marketers of these products claim that the keratin treatments render naturally curly hair more manageable and frizz-free while enhancing color and shine, giving the hair a healthier appearance. Although widely used, there have been virtually no reports of adverse side effects. Unfortunately, many of the products that are applied by salon professionals contain formaldehyde or its derivatives and are being marketed as safe. PMID- 23725309 TI - Longitudinal evaluation of cryolipolysis efficacy: two case studies. AB - Cryolipolysis treatment, or cold-induced destruction of adipocytes, provides a noninvasive option for localized subcutaneous fat reduction without damaging the overlying skin or adjacent structures. This case study examines the long-term visibility of fat layer reduction subsequent to cryolipolysis treatment, through longitudinal evaluation. Two male subjects were unilaterally treated on one flank. Baseline and postprocedure photographs (at 2 or 5 years) of the treated and contralateral untreated flanks display durable results despite natural fluctuations in body weight. PMID- 23725310 TI - From flint razors to lasers: a timeline of hair removal methods. AB - Today, most do not go a day without practicing or hearing about new hair removal methods. However, little is discussed about the history of hair removal and the development of most hair removal methods since the period of cavemen. Avoiding decapitation and fitting in with society are two of many reasons for the development of this now normative practice. Knowledge of the hair growth cycle is vital in understanding the efficacy of various hair removal methods as well as the difference between epilation and depilation. While laser hair removal (LHR) is one of the most common cosmetic procedures practiced in the world, according to the FDA, the only current permanent form of hair removal is electrolysis. These two methods as well as various other ones are discussed in this article. Further developments are being made every day to better treat the removal of blonde and white hair as well as to diminish the pain of hair removal. With these developments, dermatologists will better understand the advancement of hair removal methods and the reasons why patients may seek treatment. PMID- 23725311 TI - Lateral oblique forehead lines: redefining sleeping lines and treatment with botulinum toxin A. AB - BACKGROUND: Lateral oblique forehead lines had previously been defined as "sleeping lines." We present arguments to support the premise that these lines are not caused by sleeping position, but arise instead from the repeated contraction of powerful frontalis and orbicularis oculi muscles and can therefore be successful treated with onabotulinum toxin A. OBJECTIVES: To understand the causes behind the development of lateral oblique forehead lines and to look at treatment outcomes using onabotulinum toxin A. METHODS: An examination of facial anatomy and physical laws that could influence the formation of lateral oblique forehead lines was performed. Case studies of two male subjects presenting with these lines and treated with onabotulinum toxin A are discussed. RESULTS: Lateral oblique forehead lines were shown to be the result of muscular contraction rather than sleeping position. There were positive esthetic results in the appearance of these forehead lines in the two patients treated with onabotulinum toxin A. CONCLUSION: This new definition of lateral oblique forehead lines is important because it allows for the possibility of treating overactive muscular activity with onabotulinum toxin A thereby diminishing the appearance of the lines. PMID- 23725312 TI - Right atrial to left atrial area ratio on early echocardiography predicts long term survival after acute pulmonary embolism. AB - BACKGROUND: Current guidelines recommend that transthoracic echocardiography (TTE) should be performed for acute risk stratification following acute pulmonary embolism (PE), but it is unclear whether the initial TTE can predict long-term outcome beyond six months. We sought to assess the potential of the initial right atrial (RA) to left atrial (LA) area ratio (RA/LA ratio) on TTE to predict long term mortality in survivors of submassive PE. METHODS: A derivation cohort comprised a previously reported group of 35 consecutive patients with acute PE who were intensively studied by serial TTE at 1, 2, 5 days, 2, 6, 12 and 26 weeks and RA/LA ratio related to long-term outcome. The Day 1 RA/LA ratio findings were then further related to long-term outcome in 158 patients followed for 3.6 +/- 2.3 years. RESULTS: In the derivation cohort, total mortality was 28.6% (n = 10) following a mean (+/-standard deviation) follow-up of 4.3 +/- 1.9 years. The RA/LA ratio was highly dynamic, being increased at day 1, but normalised rapidly within 2-5 days of presentation and this was most marked amongst long-term non survivors. A RA/LA ratio > 1.0 on day 1 was independently associated with a three fold increase in long-term mortality on Kaplan-Meier analysis. Pooled analysis of 158 patient indicated that age, Charlson Comorbidity Index (CCI), simplified Pulmonary Embolism Severity Score (PESI), troponin T, day 1 RA/LA Ratio and pulmonary arterial systolic pressure (PASP) were univariate predictors of long term mortality. Multivariate analysis identified Day 1 RA/LA Ratio (HR 1.7 per 10% increase, p = 0.002), CCI (HR 2.2 per 1 unit increase, p = 0.004) and age (HR 1.1, p = 0.03) as the only independent predictors of long-term mortality. CONCLUSION: A RA/LA Ratio >1.0 at presentation with acute PE was associated with a three-fold increased risk of long-term mortality. The RA/LA ratio on presentation with an acute PE is a simple, novel predictor of long-term survival. PMID- 23725314 TI - Effects of transient forebrain ischemia on the hippocampus of the Mongolian gerbil (Meriones unguiculatus): an immunohistochemical study. AB - In the Mongolian gerbil, bilateral common carotid artery occlusion (BCCAO) for several minutes induces ischemia and delayed neuronal cell death in the CA1 region of the hippocampus due to their incomplete Circle of Willis. In the present study, the expression of fibroblast growth factor 2 (FGF2), its receptors (FGFR1 and FGFR2), glial fibrillary acidic protein (GFAP), and isolectin B4 (ISLB4) was investigated by immunohistochemical and lectin-binding methods after BCCAO was performed for 5 min in gerbils. One day after BCCAO, the pyramidal cells of the CA1 region of the hippocampus showed degenerative changes and lowered expression of FGF2, FGFR1, and FGFR2. Three days after BCCAO, there was an increase in GFAP-positive astrocytes and ISLB4-positive microglial cells. From five to 10 days after BCCAO, intense neuronal cell death in the stria pyramidale of the hippocampal CA1 region was observed, as well as an increase in GFAP positive astrocytes and decrease in ISLB4-positive microglial cells. These results indicate that transient forebrain ischemia induces neuronal cell death with lowered expression of FGF2 and its receptors, and that the activation of glial cells may not directly lead to neuronal cell death. PMID- 23725315 TI - Central European Acer- and Salicaceae-feeding aphids of the genus Stomaphis (Insecta: Aphidoidea: Lachnidae) -separate species or populations? AB - In Europe, there are three aphid species of the genus Stomaphis Walker that feed on trees in the genus Acer and one that feeds on trees in the family Salicaceae. Although these species are considered morphologically distinct, their uncertain host specificity and variation in morphological features has led to misidentifications or questionable attribution of subspecies status. The aim of the present study was to clarify the identity of the Central European representatives on the basis of morphological and molecular analyses. Our study is based on 42 samples from Central Europe and Northern Italy. Mitochondrial markers COXI and COXII were used to determine the molecular identity of the specimens studied. Our molecular analyses revealed the existence of three clades (two on Acer, one on Salicaceae) as defined by both molecular markers. Morphological analysis showed a broad range of variability of the key morphological features in all three clades. Despite significant differences in the mean values of morphometric traits, their range of variability strongly overlapped. Samples from COXI clades on Acer showed two different patterns of geographical distribution. Host specificity is recognized only at the level of host plant genera (Acer) and family (Salicaceae), excluding the possibility of the existence of separate subspecies on single host plant species. PMID- 23725313 TI - Oral cancer prognosis based on clinicopathologic and genomic markers using a hybrid of feature selection and machine learning methods. AB - BACKGROUND: Machine learning techniques are becoming useful as an alternative approach to conventional medical diagnosis or prognosis as they are good for handling noisy and incomplete data, and significant results can be attained despite a small sample size. Traditionally, clinicians make prognostic decisions based on clinicopathologic markers. However, it is not easy for the most skilful clinician to come out with an accurate prognosis by using these markers alone. Thus, there is a need to use genomic markers to improve the accuracy of prognosis. The main aim of this research is to apply a hybrid of feature selection and machine learning methods in oral cancer prognosis based on the parameters of the correlation of clinicopathologic and genomic markers. RESULTS: In the first stage of this research, five feature selection methods have been proposed and experimented on the oral cancer prognosis dataset. In the second stage, the model with the features selected from each feature selection methods are tested on the proposed classifiers. Four types of classifiers are chosen; these are namely, ANFIS, artificial neural network, support vector machine and logistic regression. A k-fold cross-validation is implemented on all types of classifiers due to the small sample size. The hybrid model of ReliefF-GA-ANFIS with 3-input features of drink, invasion and p63 achieved the best accuracy (accuracy = 93.81%; AUC = 0.90) for the oral cancer prognosis. CONCLUSIONS: The results revealed that the prognosis is superior with the presence of both clinicopathologic and genomic markers. The selected features can be investigated further to validate the potential of becoming as significant prognostic signature in the oral cancer studies. PMID- 23725318 TI - Silicon nanowire-based surface-enhanced raman spectroscopy endoscope for intracellular pH detection. AB - Very recently, one-dimensional nanowire (NW) sensors have attracted great attention as smart optical endoscopes to probe and manipulate intracellular biological processes. However, NWs often have limited optical response to the intracellular environment changes. In this work, a near-infrared nanowire optical endoscope for high-resolution intracellular pH detection was developed by integrating the advantages of silicon nanowires and surface-enhanced Raman spectroscopy (SERS). This optical endoscope has a high-resolution, sensitive response to local pH changes over the wide range of pH 4.0-9.0, an important range for most biological processes in cells, with high reproducibility, good reversibility, and at least one-week stability in an aqueous environment. The results indicate the great potential of a single SiNW SERS endoscope for intracellular pH monitoring. PMID- 23725317 TI - Depressive symptomatology, quality of life and disease control among individuals with well-characterized severe asthma. AB - OBJECTIVES: A thorough examination of the relationship of asthma severity and control with symptoms of depression is needed to identify groups of asthmatics at high risk for poor disease control outcomes. This study examines the relationship of symptoms of depression with severity and control in a well-characterized cohort of asthmatics and healthy controls. METHODS: Depressive symptoms and quality of life were assessed using the Beck Depression Inventory. Disease control was measured by a composite index incorporating symptoms, activity limitation and rescue medication use. RESULTS: Individuals with asthma (n = 91) reported more symptoms of depression than controls (n = 36; p < 0.001). Those with severe asthma (n = 49) reported more symptoms of depression (p = 0.002) and poorer asthma control (p < 0.0001) than those with not severe asthma. Worse asthma control was associated with more depressive symptoms in severe (r = 0.46, p = 0.002) but not in not severe (r = 0.13, p = 0.40) asthmatics. The relationship of symptoms of depression among severe asthmatics was attenuated by disease control. Exploratory analyses identified specific disease symptom characteristics, as opposed to exacerbations, as associated with symptoms of depression. CONCLUSIONS: Among individuals with severe asthma, increased symptom burden is positively associated with risk for co-morbid depression. These findings point to a need for regular mood disorder screenings and treatment referrals among this group. Further research is warranted to examine whether treatment of comorbid depression improves treatment adherence and asthma-related quality of life. PMID- 23725316 TI - The FiCTION dental trial protocol - filling children's teeth: indicated or not? AB - BACKGROUND: There is a lack of evidence for effective management of dental caries (decay) in children's primary (baby) teeth and an apparent failure of conventional dental restorations (fillings) to prevent dental pain and infection for UK children in Primary Care. UK dental schools' teaching has been based on British Society of Paediatric Dentistry guidance which recommends that caries in primary teeth should be removed and a restoration placed. However, the evidence base for this is limited in volume and quality, and comes from studies conducted in either secondary care or specialist practices. Restorations provided in specialist environments can be effective but the generalisability of this evidence to Primary Care has been questioned. The FiCTION trial addresses the Health Technology Assessment (HTA) Programme's commissioning brief and research question "What is the clinical and cost effectiveness of restoration caries in primary teeth, compared to no treatment?" It compares conventional restorations with an intermediate treatment strategy based on the biological (sealing-in) management of caries and with no restorations. METHODS/DESIGN: This is a Primary Care-based multi-centre, three-arm, parallel group, patient-randomised controlled trial. Practitioners are recruiting 1461 children, (3-7 years) with at least one primary molar tooth where caries extends into dentine. Children are randomized and treated according to one of three treatment approaches; conventional caries management with best practice prevention, biological management of caries with best practice prevention or best practice prevention alone. Baseline measures and outcome data (at review/treatment during three year follow-up) are assessed through direct reporting, clinical examination including blinded radiograph assessment, and child/parent questionnaires. The primary outcome measure is the incidence of either pain or infection related to dental caries. Secondary outcomes are; incidence of caries in primary and permanent teeth, patient quality of life, cost-effectiveness, acceptability of treatment strategies to patients and parents and their experiences, and dentists' preferences. DISCUSSION: FiCTION will provide evidence for the most clinically-effective and cost-effective approach to managing caries in children's primary teeth in Primary Care. This will support general dental practitioners in treatment decision making for child patients to minimize pain and infection in primary teeth. The trial is currently recruiting patients. TRIAL REGISTRATION: Protocol ID: NCTU: ISRCTN77044005. PMID- 23725319 TI - Pharmacological characterization of FE 201874, the first selective high affinity rat V1A vasopressin receptor agonist. AB - BACKGROUND AND PURPOSE: Distinct vasopressin receptors are involved in different physiological and behavioural functions. Presently, no selective agonist is available to specifically elucidate the functional roles of the V1A receptor in the rat, one of the most widely used animal models. FE 201874 is a new derivative of the human selective V1A receptor agonist F180. In this study, we performed a multi-approach pharmacological and functional characterization of FE 201874 to determine whether it is selective for V1A receptors. EXPERIMENTAL APPROACH: We modified an available human selective V1A receptor agonist (F180) and determined its pharmacological properties in cell lines expressing vasopressin/oxytocin receptors (affinity and coupling to second messenger cascades), in an ex vivo model (aorta ring contraction) and in vivo in rats (proliferation of adrenal cortex glomerulosa cells and lactation). KEY RESULTS: FE 201874 exhibited nanomolar affinity for the rat V1A receptor; it was highly selective towards the rat V1B and V2 vasopressin receptors and behaved as a full V1A agonist in all the pharmacological tests performed. FE 201874 bound to the oxytocin receptor, but with moderate affinity, and behaved as an oxytocin antagonist in vitro, but not in vivo. CONCLUSIONS AND IMPLICATIONS: On functional grounds, all the data demonstrate that FE 201874 is the first selective agonist of the rat V1A receptor isoform available. Hence, FE 201874 may have potential as a treatment for the vasodilator-induced hypotension occurring in conditions such as septic shock and could be the most suitable compound for discriminating between the behavioural effects of arginine vasopressin and oxytocin. PMID- 23725320 TI - Colonisation by Faecalibacterium prausnitzii and maintenance of clinical remission in patients with ulcerative colitis. AB - BACKGROUND: Although incrimination of the intestinal microbiota in the pathogenesis of IBD is widely accepted, few data are available about the role of specific bacteria. Potentially, Faecalibacterium prausnitzii, bacteria with anti inflammatory properties, might be deficient in ulcerative colitis (UC). AIM: To quantify F. prausnitzii in the faecal microbiota of UC patients in remission and determine its relationship with relapse. METHODS: A cross-sectional study included 116 UC patients in remission, 29 first-degree relatives and 31 healthy controls. A subset of eighteen patients, recruited during the first month of remission, underwent a 1-year follow-up. Total bacteria and F. prausnitzii were measured by quantitative Real Time PCR (qPCR, copies/g). Calprotectin was determined as inflammatory index (MUg/g). RESULTS: We found that F. prausnitzii was reduced in patients (median, IQR: 1.4 * 108 , 5.1 * 107-4.5 * 108) and relatives (1.7 * 108, 9.3 * 107-5.1 * 108) vs. controls (6.5 * 108, 3.7 * 108-1.6 * 109, P < 0.0001). Moreover, low counts of F. prausnitzii were associated with less than 12 months of remission (8.0 * 107, 2.0 * 107-3.5 * 108 vs. 2.1 * 108, 1.0 * 108-7.9 * 108, P < 0.001) and more than 1 relapse/year (8.0 * 107, 3.2 * 107-3.8 * 108 vs. 1.9 * 108, 6.8 * 107-6.0 * 108, P < 0.01). When patients were followed up, F. prausnitzii increased steadily until reaching similar levels to those of controls if remission persisted (2.9 * 108, 9.3 * 106-1.2 * 109; calprotectin: 76, 19-212), whereas it remained low if patients relapsed (2.2 * 108, 1.4 * 106-3.3 * 108; calprotectin: 1760, 844-3662 P < 0.05 vs. controls). CONCLUSIONS: Defective gut colonisation by F. prausnitzii occurred in UC patients during remission and in their unaffected relatives. The recovery of the F. prausnitzii population after relapse is associated with maintenance of clinical remission. PMID- 23725321 TI - Searching for clinical and economic value in pancreatic cancer. PMID- 23725322 TI - Chemoprevention in prostate cancer: identifying patients at greatest risk may provide greatest value. PMID- 23725323 TI - Five trends emerge in payer management of oncology. PMID- 23725324 TI - Measuring quality cancer care. PMID- 23725325 TI - Bundled payment: practice savior or killer? PMID- 23725326 TI - The future of melanoma treatment. PMID- 23725327 TI - Value-based contracting for pharmaceuticals: getting ready for prime time? PMID- 23725328 TI - Performance metrics in oncology. PMID- 23725329 TI - Applying accountable care to oncology: developing an oncology ACO. PMID- 23725330 TI - The nature of the relationship of psychomotor slowing with negative symptomatology in schizophrenia. AB - INTRODUCTION: Psychomotor slowing is an important feature of schizophrenia and the relation with negative symptoms is not fully understood. This study aims, first, to investigate the association between negative symptoms and psychomotor slowing. Second, we want to investigate whether fine motor slowing reflects clinically observable gross motor slowing. METHODS: In 53 stabilised adult patients with schizophrenia, negative symptoms were assessed using the Positive and Negative Syndrome Scale negative subscale (PANSS-N) with two calculated factors entering the analysis: an expressivity factor and a volitional factor. Psychomotor slowing was assessed by using a modified version of the Salpetriere Retardation Rating Scale, the Finger Tapping Test, and a writing task measuring fine psychomotor slowing. RESULTS: Negative symptomatology is associated with difficulties in the initiation of fine motor movements, r=.334, p<.05, whilst planning and execution are not. The volitional factor, r=-.407, p=.005, but not the expressivity factor, r=.060, p=.689, is significantly associated with psychomotor slowing. No associations between fine and clinically observable gross psychomotor functioning were found. CONCLUSIONS: These findings indicate that higher values of negative symptomatology-more specifically the volitional deficit cluster-affect motor initiation, indicating a heterogeneity in the PANSS-N factorial structure, and that gross and fine psychomotor functioning are affected independently. PMID- 23725331 TI - Pharmacological characteristics of Kv1.1- and Kv1.2-containing channels are influenced by the stoichiometry and positioning of their alpha subunits. AB - Voltage-sensitive neuronal Kv1 channels composed of four alpha subunits and four associated auxiliary beta subunits control neuronal excitability and neurotransmission. Limited information exists on the combinations of alpha subunit isoforms (i.e. Kv1.1-1.6) or their positions in the oligomers, and how these affect sensitivity to blockers. It is known that TEA (tetraethylammonium) inhibits Kv1.1 channels largely due to binding a critical tyrosine (Tyr379) in the pore, whereas Val381 at the equivalent location in Kv1.2 makes it insensitive. With the eventual aim of developing blockers for therapeutic purposes, Kv1.1 and 1.2 alpha subunit genes were concatenated to form combinations representing those in central neurons, followed by surface expression in HEK (human embryonic kidney)-293 cells as single-chain functional proteins. Patch-clamp recordings demonstrated the influences of the ratios and positioning of these alpha subunits on the biophysical and pharmacological properties of oligomeric K+ channels. Raising the ratio of Kv1.1 to Kv1.2 in Kv1.2-1.2-1.1-1.2 led to the resultant channels being more sensitive to TEA and also affected their biophysical parameters. Moreover, mutagenesis of one or more residues in the first Kv1.2 to resemble those in Kv1.1 increased TEA sensitivity only when it is adjacent to a Kv1.1 subunit, whereas placing a non-interactive subunit between these two diminished susceptibility. The findings of the present study support the possibility of alpha subunits being precisely arranged in Kv1 channels, rather than being randomly assembled. This is important in designing drugs with abilities to inhibit particular oligomeric Kv1 subtypes, with the goal of elevating neuronal excitability and improving neurotransmission in certain diseases. PMID- 23725332 TI - Regarding the universality of some consequences of the van der Waals equation in the supercritical domain. AB - We show that some of the thermodynamic regularities, following from the van der Waals (VDW) equation, are valid for the real substances and models described by completely different equations of state. These regularities relate to lines of ideal enthalpy, enthalpy minima, and isothermal compressibility maxima. The first one appears to be the straight line on the density-temperature plane, while for the two others there are universal relations, which are the same for various substances and models (argon and Lennard-Jones system as examples). The model systems were studied by Monte Carlo simulations (NVT MC), while experimental data were analyzed for the real substances. Our numerical calculations and the analysis of experimental data have shown that for the considered systems these curves are similar to the VDW ones. PMID- 23725333 TI - High-density liquid-crystalline azobenzene polymer brush attained by surface initiated ring-opening metathesis polymerization. AB - High-density polynorbornene azobenzene liquid-crystalline brushes are synthesized on quartz substrates by surface-initiated ring-opening metathesis polymerization (SI-ROMP) using Grubbs third-generation catalyst. The grafting process is controlled over the thickness of the brush from a solid-supported substrate in a stoichiometric manner. A highly ordered liquid-crystal arrangement was formed for such brushes as revealed by spectroscopic measurements and grazing angle X-ray diffraction analysis. Marked features of this method in the structure and photoalignment behavior are unveiled by comparison with brushes made by surface initiated atom-transfer radical polymerization (SI-ATRP). PMID- 23725334 TI - Inappropriate use of nonsteroidal anti-inflammatory drugs and other drugs in chronic kidney disease patients without renal replacement therapy. AB - OBJECTIVE: The main goal of chronic kidney disease (CKD) treatment is the prevention of progression of the disease and complications. Inappropriate drug use in patients with CKD is an important issue, which may cause adverse effects on patients and progression of chronic renal failure. The aim of this study is to find the rate of inappropriate drug use among CKD patients. METHODS: The subjects of this study were selected from the patients with a CKD history of minimum one year, who did not receive renal replacement therapy. Patients were asked to provide a digital record of the drugs they used over the last one year. Individually, for each patient, the drugs that may be contraindicative and that require dose adjustment were identified based on glomerular filtration rate (GFR). RESULTS: This study includes a total of 185 participants - 97 female (52.4%) and 88 male (47.6%) patients. The average age of patients was 60.50 +/- 14.56. It was shown that 149 patients (80.5%) were using inappropriate drugs. Seventy (47.0%) were using one, 79 (53.0%) two, 30 (20/1%) three, and 9 (6.4%) four inappropriate drugs. Of CKD patients, 44.3% were aged 65 or over; and in this age group, inappropriate drug use was more frequent compared to the population below 65 (86.6% vs. 75.7%). The drugs used inappropriately were, respectively, nonsteroidal anti-inflammatory drugs (65.8%), quinolone antibiotics (39.0%), ACE inhibitors (26.9%). DISCUSSION: Health professionals are required to consider renal functions of all patients, mainly those aged over 65, when administering a treatment. PMID- 23725335 TI - Mutational analysis of conserved regions harboring catalytic triad residues of the levansucrase protein encoded by the lsc-3 gene (lsc3) of Pseudomonas syringae pv. tomato DC3000. AB - Levansucrase encoded by the lsc-3 (lsc3) gene at genomic locus PSPTOA0032 of Pseudomonas syringae pv. tomato DC3000 was mutationally analyzed. Altogether, 18 single-amino-acid mutants of 13 positions of Lsc3 were studied for catalytic properties, including production of fructooligosaccharides (FOS). Asp62, Asp219, and Glu303 were proved as members of the catalytic triad. Respective alanine replacement mutants were practically inactive with their kcat values reduced up to ~130,000 times. Additionally, the requirements of Trp61, Gln301, and Arg304, located in conserved sequence blocks around the catalytic triad positions for the catalysis were shown. The catalytic significance of the position equivalent to Arg304 was shown for levansucrases for the first time. Replacement of Gln301 specifically affected the polymerizing ability of Lsc3. The Gln301Ala mutant was largely hydrolytic and produced 31 times less FOS than the wild type. Despite high conservation grades, Leu66, Pro220, Asp225, and His306 tolerated replacement well. Quantification of produced FOS showed a high biotechnological potential of Lsc3. Using 1 mg of Lsc3 protein, 15.4 g of FOS with a degree of polymerization from 3 to 7 can be synthesized in a 20 H reaction with 1,200 mM sucrose. Our expression system allowed us to produce up to 30 mg of Lsc3 protein from 1 L of induced culture of recombinant Escherichia coli. PMID- 23725336 TI - DOLINA--docking based on a local induced-fit algorithm: application toward small molecule binding to nuclear receptors. AB - Docking algorithms allowing for ligand and - to various extent - also protein flexibility are nowadays replacing techniques based on rigid protocols. The algorithm implemented in the Dolina software relies on pharmacophore matching for generating potential ligand poses and treats associated local induced-fit changes by combinatorial rearrangement of side-chains lining the binding site. In Dolina, ligand flexibility is not treated internally, instead a pool of low-energy conformers identified in a conformational search is screened for extended binding pose candidates. Grouping rearranged residues in sterically independent families and side-chain conformer clustering are employed to achieve efficient use of the computational resources along with a good accuracy of the generated poses. Dolina was applied toward docking of small-molecule ligands to three different nuclear receptor ligand binding domains for which in total 18 high-resolution crystal structures were used as reference. The selected nuclear receptors feature a deeply buried ligand-binding site where local induced-fit is to be expected, particularly for receptor antagonists. For each receptor, a crystal structure with a cocrystallized small steroid ligand (template) was chosen as a target system, to which several synthetic ligands of different sizes were docked. Poses within an RMSD of 2.0 A from the crystal reference pose were generated in 91% of the cases. In 28%, the pose with the lowest RMSD to the reference pose was ranked as the top one, and in 76% it was ranked among the top five poses. Detailed descriptions of the docking algorithm and observed results are included. Dolina is available free of charge for academic institutions. PMID- 23725337 TI - Diagnostic value of immunoglobulin G antibodies against Candida enolase and fructose-bisphosphate aldolase for candidemia. AB - BACKGROUND: The yeast Candida is one of the most frequent pathogens isolated from bloodstream infections and is associated with significant morbidity and mortality. Problems with clinical and microbiological diagnosis of invasive candidiasis (IC) have prompted the development of non-culture-based laboratory methods. Previous reports suggest that serological detection of antibodies might be useful for diagnosing systemic candidiasis. METHODS: Diagnosis of IC using antibodies against recombinant Candida albicans enolase (Eno) and fructose bisphosphate aldolase (Fba1) was evaluated. Using recombinant Eno and Fba1 as coating antigens, enzyme-linked immunosorbent assays (ELISAs) were used to analyze sera from patients with candidemia (n = 101), Candida colonization (n = 50), bacteremia (n = 84), invasive aspergillosis (n = 40); and from healthy controls (n = 200). RESULTS: The results demonstrated that ELISA detection of anti-Eno and anti-Fba1 IgG distinguished IC from other pathogenic infections in patients and healthy individuals. The sensitivity, specificity, and positive and negative predictive values were 72.3%, 94.7%, 78.5% and 93% for anti-Eno, and 87.1%, 92.8%, 76.5% and 96.4% for anti-Fba1 antibodies, respectively. Combining these two tests improved sensitivity up to 90.1% and negative predictive value up to 97.1%, with specificity and positive predictive values of 90.6% and 72.2%. The tests were specific to the Candida genus and antibody titers were higher for candidemia patients than for controls. Positive antibody tests were obtained before blood culture results for 42.2% of patients for anti-Eno and 51.1% for anti-Fba1. CONCLUSION: These data suggest that tests that detect IgG antibodies against Candida enolase and fructose-bisphosphate aldolase, especially when used in combination, could be a powerful tool for diagnosing IC. PMID- 23725338 TI - Availability, consistency and evidence-base of policies and guidelines on the use of mask and respirator to protect hospital health care workers: a global analysis. AB - BACKGROUND: Currently there is an ongoing debate and limited evidence on the use of masks and respirators for the prevention of respiratory infections in health care workers (HCWs). This study aimed to examine available policies and guidelines around the use of masks and respirators in HCWs and to describe areas of consistency between guidelines, as well as gaps in the recommendations, with reference to the WHO and the CDC guidelines. METHODS: Policies and guidelines related to mask and respirator use for the prevention of influenza, SARS and TB were examined. Guidelines from the World Health Organization (WHO), the Center for Disease Control and Prevention (CDC), three high-income countries and six low/middle-income countries were selected. RESULTS: Uniform recommendations are made by the WHO and the CDC in regards to protecting HCWs against seasonal influenza (a mask for low risk situations and a respirator for high risk situations) and TB (use of a respirator). However, for pandemic influenza and SARS, the WHO recommends mask use in low risk and respirators in high risk situations, whereas, the CDC recommends respirators in both low and high risk situations. Amongst the nine countries reviewed, there are variations in the recommendations for all three diseases. While, some countries align with the WHO recommendations, others align with those made by the CDC. The choice of respirator and the level of filtering ability vary amongst the guidelines and the different diseases. Lastly, none of the policies discuss reuse, extended use or the use of cloth masks. CONCLUSION: Currently, there are significant variations in the policies and recommendations around mask and respirator use for protection against influenza, SARS and TB. These differences may reflect the scarcity of level-one evidence available to inform policy development. The lack of any guidelines on the use of cloth masks, despite widespread use in many low and middle-income countries, remains a policy gap. Health organizations and countries should jointly evaluate the available evidence, prioritize research to inform evidence gaps, and develop consistent policy on masks and respirator use in the health care setting. PMID- 23725339 TI - Direction-specific adaptation of motion-onset auditory evoked potentials. AB - Auditory evoked potentials (AEPs) to motion onset in humans are dominated by a fronto-central complex, with a change-negative deflection 1 (cN1) and a change positive deflection 2 (cP2) component. Here the contribution of veridical motion detectors to motion-onset AEPs was investigated with the hypothesis that direction-specific adaptation effects would indicate the contribution of such motion detectors. AEPs were recorded from 33 electroencephalographic channels to the test stimulus, i.e. motion onset of horizontal virtual auditory motion (60 degrees per s) from straight ahead to the left. AEPs were compared in two experiments for three conditions, which differed in their history prior to the motion-onset test stimulus: (i) without motion history (Baseline), (ii) with motion history in the same direction as the test stimulus (Adaptation Same), and (iii) a reference condition with auditory history. For Experiment 1, condition (iii) comprised motion in the opposite direction (Adaptation Opposite). For Experiment 2, a noise in the absence of coherent motion (Matched Noise) was used as the reference condition. In Experiment 1, the amplitude difference cP2 - cN1 obtained for Adaptation Same was significantly smaller than for Baseline and Adaptation Opposite. In Experiment 2, it was significantly smaller than for Matched Noise. Adaptation effects were absent for cN1 and cP2 latencies. These findings demonstrate direction-specific adaptation of the motion-onset AEP. This suggests that veridical auditory motion detectors contribute to the motion-onset AEP. PMID- 23725340 TI - Depression and cardiac symptoms among AL amyloidosis patients: the mediating role of coping strategies. AB - BACKGROUND: Amyloidosis is a rare disease group. AL amyloidosis represents the most common type of systemic amyloidosis and cardiac involvement determines prognosis. Although some studies have revealed that amyloidosis patients present high levels of depression, few data are available about depression-contributing factors. No investigations have been conducted about the coping strategies that AL amyloidosis patients use to face the disease and there is little research on patients with cardiac symptoms that are strongly related to the prognosis. OBJECTIVES: to examine coping strategies (avoidance, social support seeking and problem-solving) as potential mediator in the relationship between cardiac symptom severity (independent variable) and depressive symptoms (dependent variable) in AL cardiologic patients. METHOD: Thirty-four AL patients with cardiac-related symptoms were administered the Coping Strategy Indicator and the Centre for Epidemiological Study-Depression Scale. Clinical variables such as months since cardiac symptom onset and cardiac symptom severity were collected. RESULTS: According to questionnaire normative values, all patients presented clinical depression. Moreover, out of the coping strategies, avoidance and social support seeking mediated the link between cardiac symptom severity and depressive symptoms. No mediational effect was found for problem-solving. DISCUSSION: As cardiac symptoms have low severity, AL patients can avoid the disease. However, as cardiac symptoms proceed and interfere with daily activities, they can no longer ignore their signs thus perceiving the severity of their medical condition. This status makes individuals prone to seek less social support and thus to prefer social isolation. Results suggest the need for early psychological support on coping strategies for AL cardiologic patients. PMID- 23725341 TI - Rh-catalyzed (5+2) cycloadditions of 3-acyloxy-1,4-enynes and alkynes: computational study of mechanism, reactivity, and regioselectivity. AB - The mechanism of Rh-catalyzed (5+2) cycloadditions of 3-acyloxy-1,4-enyne (ACE) and alkynes is investigated using density functional theory calculations. The catalytic cycle involves 1,2-acyloxy migration, alkyne insertion, and reductive elimination to form the cycloheptatriene product. In contrast to the (5+2) cycloadditions with vinylcyclopropanes (VCPs), in which alkyne inserts into a rhodium-allyl bond, alkyne insertion into a Rh-C(sp(2)) bond is preferred. The 1,2-acyloxy migration is found to be the rate-determining step of the catalytic cycle. The electron-rich p-dimethylaminobenzoate substrate promotes 1,2-acyloxy migration and significantly increases the reactivity. In the regioselectivity determining alkyne insertion step, the alkyne substituent prefers to be distal to the forming C-C bond and thus distal to the OAc group in the product. PMID- 23725342 TI - Synthesis of redox-active molecules and their signaling functions during the expression of plant disease resistance. AB - SIGNIFICANCE: Activation of immune responses in plants is associated with a parallel burst of both reactive oxygen intermediates (ROIs) and nitric oxide (NO). The mechanisms by which these small redox-active molecules are synthesized and their signaling functions are critical for plants to defend themselves against pathogen infection. RECENT ADVANCES: The synthesis of apoplastic ROIs by plants after pathogen recognition has long been attributed to membrane-bound NAPDH oxidases. However, the emerging data suggest a role for other enzymes in various subcellular locations in ROI production after defense activation. It is becoming widely appreciated that NO exerts its biochemical function through the S nitrosylation of reactive cysteine thiols on target proteins, constituting a key post-translational modification. Recent evidence suggests that S-nitrosylation of specific defense-related proteins regulates their activity. CRITICAL ISSUES: The source(s) of NO production after pathogen recognition remain(s) poorly understood. Some NO synthesis can be attributed to the activity of nitrate reductase but to date, no nitric oxide synthase (NOS) has been identified in higher plants. However, the signaling functions of S-nitrosylation are becoming more apparent and thus dissecting the molecular machinery underpinning this redox based modification is vital to further our understanding of plant disease resistance. FUTURE DIRECTIONS: In addition to identifying new contributors to the oxidative burst, the discovery of an NOS in higher plants would significantly move the field forward. Since S-nitrosylation has now been confirmed to play various roles in immune signaling, this redox-based modification is a potential target to exploit for improving disease resistance in crop species. PMID- 23725343 TI - Bond strength of the porcelain repair system to all-ceramic copings and porcelain. AB - PURPOSE: The purpose of this study was to investigate the shear bond strength of the porcelain repair system on alumina and zirconia core ceramics, comparing this strength with that of veneering porcelain. MATERIALS AND METHODS: Veneering ceramic (n = 12), alumina core (n = 24), and zirconia core (n = 24) blocks measuring 10 * 5 * 5 mm(3) were fabricated. Veneering ceramic blocks were used as the control. Alumina and zirconia core blocks were divided into 2 groups (n = 12 each), and a slot (2 * 2 * 4 mm(3)) filled with veneering ceramics was prepared into one of the alumina and zirconia core groups (n = 12). Followed by surface treatments of micro-abrasion with 30 MUm alumina particles, etching with 35% phosphoric acid and silane primer and bond, composite resin blocks (2 * 2 * 2 mm(3)) were built up and light polymerized onto the treated surfaces by 3 configurations: (a) composite blocks bonded onto veneering ceramic surface alone, (b) composite blocks bonded onto alumina core or zirconia core surfaces, (c) a 50% surface area of the composite blocks bonded to veneering ceramics and the other 50% surface area of the composite blocks to alumina core or zirconia core surfaces. The shear bond strength of the composite to each specimen was tested by a universal testing machine at a 0.5 mm/min crosshead speed. The shear bond strength was analyzed by unpaired t-tests for within the configuration groups and ANOVA for among the different configuration groups. RESULTS: When the mean shear bond strength was compared within groups of the same configuration, there were no statistically significant differences. Comparison of the shear bond strength among groups of different configurations revealed statistically significant differences. The mean shear bond strength of composite onto 100% veneering ceramic surface and composite onto 50% veneering 50% all-ceramic cores was statistically higher than that of composite onto 100% all-ceramic cores; however, the differences of the shear bond strength of composite bonded only onto the veneering ceramic surface were not statistically significant from those of 50% surface area of composite bonded onto all-ceramic cores. CONCLUSION: No statistically significant differences in the bond strength of a porcelain repair system to alumina and zirconia copings were observed. Increasing the surface of veneering ceramics to a porcelain repair system improved the repair material's bond strength. PMID- 23725344 TI - On the mixing and evaporation of secondary organic aerosol components. AB - The physical state and chemical composition of an organic aerosol affect its degree of mixing and its interactions with condensing species. We present here a laboratory chamber procedure for studying the effect of the mixing of organic aerosol components on particle evaporation. The procedure is applied to the formation of secondary organic aerosol (SOA) from alpha-pinene and toluene photooxidation. SOA evaporation is induced by heating the chamber aerosol from room temperature (25 degrees C) to 42 degrees C over 7 h and detected by a shift in the peak diameter of the SOA size distribution. With this protocol, alpha-pinene SOA is found to be more volatile than toluene SOA. When SOA is formed from the two precursors sequentially, the evaporation behavior of the SOA most closely resembles that of SOA from the second parent hydrocarbon, suggesting that the structure of the mixed SOA resembles a core of SOA from the initial precursor coated by a layer of SOA from the second precursor. Such a core-and shell configuration of the organic aerosol phases implies limited mixing of the SOA from the two precursors on the time scale of the experiments, consistent with a high viscosity of at least one of the phases. PMID- 23725346 TI - Value of serum and induced sputum surfactant protein-D in chronic obstructive pulmonary disease. AB - BACKGROUND: Surfactant Protein D (SP-D) is an important marker in chronic obstructive pulmonary disease (COPD). Serum SP-D levels increase while lung production of SP-D decreases in COPD. SP-D is a specific biomarker for monitoring COPD, assessment of exacerbation frequency and arrangement of treatment modalities. In the present study, we aimed to investigate the correlation between serum and induced sputum SP-D levels with severity and acute exacerbations of COPD. METHOD: 20 healthy subjects, older than 40 years, with at least 10 pack/years smoking history (group 1), 20 stage I-II COPD patients (group 2) , and 20 stage III-IV COPD patients (group 3) were enrolled in the study. All subjects performed pulmonary function tests. Venous blood samples were taken to determine complete blood count, C-reactive protein(CRP) and serum SP-D levels. Induced sputum samples were obtained to determine SP-D level. COPD patients were followed up for acute exacerbations for 6 months. RESULTS: Serum SP-D levels of group 3 were the highest and induced sputum SP-D levels of group 2 were the lowest among the three groups. SP-D levels of induced sputum decreased in patients with increasing number of cigarette pack/years (p = 0.03, r = -0.115), whereas serum SP-D levels increased in these patients (p = 0.0001, r = 0.6 ). Induced sputum SP D levels in COPD patients receiving inhaled corticosteroid treatment were significantly higher than in patients who were not receiving inhaler corticosteroid treatment (p = 0.005). An inverse correlation between serum SP-D levels and FEV1 (%) was found and there was a positive correlation between the serum SP-D levels and exacerbations frequency in 6-month follow up period (p = 0.049 ,r = -0.252; p = 0.0001, r = 0.598 respectively). CONCLUSION: Our study demonstrates the adverse effects of smoking on local SP-D levels since low levels of induced sputum SP-D were found in the group of current smokers, who were not receiving inhaled corticosteroid treatment. Relationship between serum SP-D and COPD exacerbations frequency suggests that serum SP-D level may be used as a lung specific biomarker during the follow up and progression of COPD. PMID- 23725345 TI - Aging aggravates ischemic stroke-induced brain damage in mice with chronic peripheral infection. AB - Ischemic stroke is confounded by conditions such as atherosclerosis, diabetes, and infection, all of which alter peripheral inflammatory processes with concomitant impact on stroke outcome. The majority of the stroke patients are elderly, but the impact of interactions between aging and inflammation on stroke remains unknown. We thus investigated the influence of age on the outcome of stroke in animals predisposed to systemic chronic infection. Th1-polarized chronic systemic infection was induced in 18-22 month and 4-month-old C57BL/6j mice by administration of Trichuris muris (gut parasite). One month after infection, mice underwent permanent middle cerebral artery occlusion and infarct size, brain gliosis, and brain and plasma cytokine profiles were analyzed. Chronic infection increased the infarct size in aged but not in young mice at 24 h. Aged, ischemic mice showed altered plasma and brain cytokine responses, while the lesion size correlated with plasma prestroke levels of RANTES. Moreover, the old, infected mice exhibited significantly increased neutrophil recruitment and upregulation of both plasma interleukin-17alpha and tumor necrosis factor-alpha levels. Neither age nor infection status alone or in combination altered the ischemia-induced brain microgliosis. Our results show that chronic peripheral infection in aged animals renders the brain more vulnerable to ischemic insults, possibly by increasing the invasion of neutrophils and altering the inflammation status in the blood and brain. Understanding the interactions between age and infections is crucial for developing a better therapeutic regimen for ischemic stroke and when modeling it as a disease of the elderly. PMID- 23725347 TI - GeneRIF indexing: sentence selection based on machine learning. AB - BACKGROUND: A Gene Reference Into Function (GeneRIF) describes novel functionality of genes. GeneRIFs are available from the National Center for Biotechnology Information (NCBI) Gene database. GeneRIF indexing is performed manually, and the intention of our work is to provide methods to support creating the GeneRIF entries. The creation of GeneRIF entries involves the identification of the genes mentioned in MEDLINE(r); citations and the sentences describing a novel function. RESULTS: We have compared several learning algorithms and several features extracted or derived from MEDLINE sentences to determine if a sentence should be selected for GeneRIF indexing. Features are derived from the sentences or using mechanisms to augment the information provided by them: assigning a discourse label using a previously trained model, for example. We show that machine learning approaches with specific feature combinations achieve results close to one of the annotators. We have evaluated different feature sets and learning algorithms. In particular, Naive Bayes achieves better performance with a selection of features similar to one used in related work, which considers the location of the sentence, the discourse of the sentence and the functional terminology in it. CONCLUSIONS: The current performance is at a level similar to human annotation and it shows that machine learning can be used to automate the task of sentence selection for GeneRIF annotation. The current experiments are limited to the human species. We would like to see how the methodology can be extended to other species, specifically the normalization of gene mentions in other species. PMID- 23725348 TI - A phase 3 trial assessing the efficacy and safety of grass allergy immunotherapy tablet in subjects with grass pollen-induced allergic rhinitis with or without conjunctivitis, with or without asthma. AB - BACKGROUND: Design and execution of immunotherapy trials for seasonal allergies may be complicated by numerous factors including variable allergy testing methods, pollen levels, and timing and intensity of other seasonal allergens. We evaluated grass allergy immunotherapy tablet (AIT) treatment in North American adults with grass pollen-induced allergic rhinitis with or without conjunctivitis (AR/C), with/without asthma. METHODS: Subjects age 18-65 with clinical history of grass pollen-induced AR/C, with/without asthma were randomized 1:1 to once-daily 2800 BAU Timothy grass AIT (oral lyophilisate, Phleum pratense, 75,000 SQ-T, containing approximately 15 MUg of Phl p 5) or placebo. The AR/C symptom and medication scores were recorded daily. The primary end point was the average AR/C daily symptom score (DSS) during the entire grass pollen season (GPS). Ranked key secondary end points were Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, daily medication score (DMS), and percentage of well days, all over entire GPS. Safety was monitored through adverse event reporting. RESULTS: Efficacy analysis included 289 subjects. Over the entire GPS, mean DSS was 6% lower with AIT versus placebo (5.69 vs. 6.06), but this difference was not statistically significant (p = 0.3475) despite significantly higher immunological response in the grass AIT group. No significant between-group differences were seen for key secondary end points. In general, DSS was high before GPS began and no clear relationship between DSS and grass pollen counts was seen during GPS. In post hoc analysis of subjects with pre-seasonal DSS <=3, mean DSS and DMS were both significantly lower with grass AIT versus placebo (27%; p = 0.0327 and 68%; p = 0.0060, respectively). In this subgroup a relationship between DSS and grass pollen counts was observed. Grass AIT was generally well tolerated, with no events of anaphylactic shock or respiratory compromise. CONCLUSIONS: In this trial, 2800 BAU grass AIT did not demonstrate significant symptom improvement versus placebo. Lack of relationship between pollen count and symptom score in the study population, and post hoc findings among subjects with low pre-seasonal symptoms, suggest that the symptoms reported in this study were not primarily reflective of the effects of grass pollen exposure. TRIAL REGISTRATION: NCT00421655. PMID- 23725350 TI - Impact of Schizophyllum sensitization on decline of lung function in asthma. AB - OBJECTIVE: There is increasing interest in the association between the severity of asthma and fungal sensitization, and lung function decline in relation to mold and dampness in the home has recently been reported. This study was performed to determine the correlation between sensitization to Schizophyllum commune and decline of lung function, and to elucidate the outcomes and risk factors, especially from Schizophyllum allergy. METHODS: The medical records of 50 patients with asthma who satisfied the following inclusion criteria were collected and reviewed retrospectively: (1) at least 5 years of follow-up with five evaluations; (2) intradermal skin tests including S. commune performed at the initial assessment; and (3) severity ranging from mild-to-moderate. Lung function decline (evaluated as adjusted delta FEV1/year) was compared in a cross sectional manner with regard to gender, age, BMI, smoking habit, allergological characteristics and exacerbation frequency. RESULTS AND CONCLUSIONS: There were significant differences in lung function decline between females and males (p < 0.05), positive and negative results of late-phase skin reaction to S. commune (p < 0.001), and positive and negative late-phase skin reaction to Aspergillus (p < 0.05). Lung function decline was correlated with exacerbation frequency (r = 0.428, p = 0.002). On multiple regression analysis, the probability of lung function decline in asthma was found to be significantly associated with female gender and positive late-phase skin reaction against S. commune. Our results suggested that sensitization to S. commune may be one of the risk factors involved in lung function decline in asthmatic patients. PMID- 23725351 TI - APC promoter 1B deletion in familial polyposis--implications for mutation negative families. AB - Over 1500 adenomatous polyposis coli (APC) gene mutations have already been identified as causative of familial adenomatous polyposis (FAP). However, routine genetic testing fails to detect mutations in about 10% of classic FAP cases. Recently, it has been shown that a proportion of mutation-negative FAP cases bear molecular changes in deep intronic and regulatory sequences. In this study, we used direct sequencing, followed by multiplex ligation-dependent probe amplification (MLPA) of genomic DNA from family members, affected by classic FAP. We first reported the family as mutation negative. With the launch of a new version of MLPA kit, we retested the family and a novel full deletion of promoter 1B was detected. The exact breakpoints of the deletion were determined by array comparative genomic hybridization (CGH) and long range polymerase chain reaction (PCR), followed by direct sequencing. The total APC expression levels were investigated by quantitative polymerase chain reaction (qPCR) assay and allele specific expression (ASE) analysis. The APC gene expression was highly reduced, which indicates causative relationship. We suggest that there is a significant possibility that APC promoter 1B mutations could be found in mutation-negative FAP patients. In the light of our findings it seems reasonable to consider targeted genetic re-analysis of APC promoter 1B region in a larger cohort of unsolved cases. PMID- 23725349 TI - Urine metabolic profile changes of CCl4-liver fibrosis in rats and intervention effects of Yi Guan Jian Decoction using metabonomic approach. AB - BACKGROUND: Yi Guan Jian Decoction (YGJD), a famous Chinese prescription, has long been employed clinically to treat liver fibrosis. However, as of date, there is no report on the effects of YGJD from a metabonomic approach. In this study, a urine metabonomic method based on gas chromatography coupled with mass spectrometry (GC/MS) was employed to study the protective efficacy and metabolic profile changes caused by YGJD in carbon tetrachloride (CCl4)-induced liver fibrosis. METHODS: Urine samples from Wistar rats of three randomly divided groups (control, model, and YGJD treated) were collected at various time-points, and the metabolic profile changes were analyzed by GC/MS with principal component analysis (PCA) and partial least squares-discriminate analysis (PLS-DA). Furthermore, histopathology and biochemical examination were also carried out to ensure the success of CCl4-induced liver fibrosis model. RESULTS: Urine metabolic profile studies suggested distinct clustering of the three groups, and YGJD group was much closer to the control group by showing a tendency of recovering towards the control group. Fourteen significantly changed metabolites were found, and YGJD treatment could reverse the levels of these metabolites to normal levels or close to normal levels. CONCLUSIONS: The current study indicates that the YGJD has significant anti-fibrotic effects on CCl4-induced liver fibrosis in rats, which might be by regulating the dysfunction of energy metabolism, amino acid metabolism, tryptophan metabolism, cytochrome P450 metabolism, and gut microflora metabolism. The metabonomic approach can be recommended to study the pharmacological effect and mechanism of complex Chinese medicines. PMID- 23725352 TI - Influence of traditional markets on plant management in the Tehuacan Valley. AB - BACKGROUND: The Tehuacan Valley, Mexico is a region with exceptionally high biocultural richness. Traditional knowledge in this region comprises information on nearly 1,600 plant species used by local peoples to satisfy their subsistence needs. Plant resources with higher cultural value are interchanged in traditional markets. We inventoried the edible plant species interchanged in regional markets documenting economic, cultural and ecological data and about their extraction and management in order to: (1) assess how commercialization and ecological aspects influence plant management, (2) identify which species are more vulnerable, and (3) analyze how local management contributes to decrease their risk. We hypothesized that scarcer plant species with higher economic value would be under higher pressure motivating more management actions than on more abundant plants with lower economic value. However, construction of management techniques is also influenced by the time-span the management responses have taken as well as biological and ecological aspects of the plant species that limit the implementation of management practices. Plant management mitigates risk, but its absence on plant species under high risk may favor local extinction. METHODS: Six traditional markets were studied through 332 semi-structured interviews to local vendors about barter, commercialization, and management types of local edible plant species. We retrieved ethnobotanical information on plant management from ten communities in a workshop and sampled regional vegetation in a total of 98 sites to estimate distribution and abundance of plant species commercialized. Through Canonical Correspondence Analysis (CCA) we analyzed the amount of variation of management types that can be explained from socioeconomic and ecological information. A risk index was calculated relating distribution, abundance, economic value and management of plant resources to identify the most vulnerable species. RESULTS: We recorded 122 edible plant species interchanged in the main regional markets. CCA explained significantly 24% of management variation, spatial distribution and plant parts used being particularly important in management decisions. The indeterminate 76% of variation suggests that management decisions depend on particular variables that are not explained by the ecological and socioeconomic factors studied and/or their high variation in the context at the regional scale. The risk index indicated that management was the factor that mostly influences decreasing of risk of interchanged plant species. We identified Clinopodium mexicanum, Pachycereus weberi, Dasylirion serratifolium, Disocorea sp., Ceiba aesculifolia, Neobuxbamia tetetzo, Lippia graveolens, Litsea glaucescens, L. neesiana, Jatropha neopauciflora, Agave potatorum and other agave species used for producing mescal among the more endangered plant species due to human pressure, their relative scarcity and limited or inexistent management. CONCLUSION: Spatial distribution and plant parts used are particularly meaningful factors determining risk and influencing management actions on edible plant species interchanged in the region. Limited or inexistent management may favor extinction of local populations under risk. Local management techniques synthesize knowledge and experiences crucial for designing sustainable management programs. Traditional management techniques supported by ecological information and environmental management approaches could make valuable contributions for sustainable use of plant species, particularly those becoming economically important more recently. PMID- 23725353 TI - Effect of chain length on the sensing of volatile organic compounds by means of silicon nanowires. AB - Molecularly modified silicon nanowire field effect transistors (SiNW FETs) are starting to appear as promising devices for sensing various volatile organic compounds (VOCs). Understanding the connection between the molecular layer structure attached to the SiNWs and VOCs is essential for the design of high performance sensors. Here, we explore the chain length influence of molecular layers on the sensing performance to polar and nonpolar VOCs. SiNW FETs were functionalized with molecular layers that have similar end (methyl) group and amide bridge bond, but differ in their alkyl chain lengths. The resulting devices were then exposed to polar and nonpolar VOCs in various concentrations. Our results showed that the sensing response to changing the threshold voltage (DeltaVth) and changing the relative hole mobility (DeltaMUh/MUh-a) have a proportional relationship to the VOC concentration. On exposure to a specific VOC concentration, DeltaVth response increased with the chain length of the molecular modification. In contrast, DeltaMUh/MUh-a did not exhibit any obvious reliance on the chain length of the molecular layer. Analysis of the responses with an electrostatic-based model suggests that the sensor response in DeltaVth is dependent on the VOC concentration, VOC vapor pressure, VOC-molecular layer binding energy, and VOC adsorption-induced dipole moment changes of molecular layer. PMID- 23725354 TI - Clinical features of familial juvenile cases of moyamoya disease: analysis of patients treated in a single institute over a 28-year period. AB - OBJECT: The authors compared the clinical features between familial and sporadic cases of moyamoya disease (MMD) by retrospectively analyzing data on patients with MMD registered in the database of Tokyo Medical and Dental University over a period of 28 years. METHODS: In total, 383 patients with hospital records at Tokyo Medical and Dental University from 1980 to 2007 were registered into the database. The data on all of these patients were retrospectively reviewed to clarify the occurrence of familial cases. Clinical features of child or adolescent patients (< 20 years of age) with MMD were compared between familial and sporadic cases in a subgroup of patients who were registered after 1995, initially diagnosed using MR angiography, and assessed using an intelligence scale. RESULTS: Familial occurrence was observed in 59 patients (15.4%) in 40 pedigrees. The clinical features of juvenile patients were analyzed in 124 patients, 22 (17.7%) of whom had familial histories. In comparison with the sporadic cases, patients with familial histories were significantly younger at onset (4.7 vs 6.6 years old), had significantly more cortical infarction (59.1% vs 25.5%), and had significantly more stenoocclusive lesions in the posterior cerebral artery (45.4% vs 24.5%). The rate of patients with intellectual disturbance (intelligence quotient < 75) was significantly larger in the familial cases (47.4%) than in the sporadic cases (17.8%). CONCLUSIONS: This survey of the clinical features of familial MMD suggests that patients with familial MMD had a more serious clinical course in childhood than the sporadic MMD cases. PMID- 23725355 TI - In vivo gastric cancer targeting and imaging using novel symmetric cyanine dye conjugated GX1 peptide probes. AB - To facilitate the translation of cancer fluorescence imaging into clinical practice, the development of stable and highly specific and sensitive targeted fluorescence probes with low toxicity is desirable. GX1, a gastric tumor angiogenesis marker candidate, holds promise in the target-specific delivery of molecular imaging probes for early gastric cancer detection in vivo. In this study, we describe the design and synthesis of a series of novel penta-methine cyanine dyes using the symmetric synthesis method and further conjugated the dyes with GX1, allowing specific binding to the vasculature of gastric cancer. This efficient synthetic route can decrease the undesired byproducts, while increasing yield. Furthermore, in vivo fluorescence imaging revealed that this novel targeted probe accumulates selectively in the tumor site of SGC-7901 subcutaneous xenograft models. The combination of such novel vasculature-targeted molecular probes with fluorescence imaging technology may improve early detection, metastasis detection, and antitumor angiogenesis therapy for gastric cancer. PMID- 23725356 TI - Eph receptor B4 is a regulator of estrogen receptor alpha in breast cancer cells. AB - BACKGROUND: Estrogen receptor alpha (ER-alpha) plays an important role in breast cancer initiation and progression and represents a major target in cancer therapy. The expression and activity of ER-alpha is regulated by multiple mechanisms at the transcriptional and post-translational level. Interaction of tyrosine kinase receptor-activated signaling pathways with ER-alpha function has been reported. We previously performed a kinome-wide small interfering RNA high throughput screen to identify novel protein kinases involved in the regulation of ER-alpha transcriptional activity in human breast cancer cells. Our screening analysis identified the Eph receptor tyrosine kinases (Eph) as potential positive regulators of ER-alpha. RESULTS: In this study, we demonstrate Eph receptor B4 (EphB4), a member of Eph kinase family, a positive regulator of ER-alpha in human breast cancer cell lines (MCF-7, T-47D and BT-474). Down-regulation of EphB4 by RNA interference technology impairs estrogen-dependent ER-alpha transcriptional activity in breast cancer cells. Decreased activity of ER-alpha after EphB4 knockdown is the consequence of diminished ER-alpha messenger RNA and protein expression. Furthermore, phosphorylation of Akt, a downstream mediator of EphB4, is reduced following EphB4 silencing. CONCLUSIONS: Our data suggests EphB4 as an upstream regulator of ER-alpha in human breast cancer cells by modulating ER alpha transcription. The results also suggest Akt as a relevant downstream signaling molecule in this novel EphB4-ER-alpha pathway. PMID- 23725358 TI - Health plan innovations in delivery system reforms. PMID- 23725357 TI - A novel role of proteasomal beta1 subunit in tumorigenesis. AB - p27Kip1 is a key cell-cycle regulator whose level is primarily regulated by the ubiquitin-proteasome degradation pathway. Its beta1 subunit is one of seven beta subunits that form the beta-ring of the 20S proteasome, which is responsible for degradation of ubiquitinated proteins. We report here that the beta1 subunit is up-regulated in oesophageal cancer tissues and some ovarian cancer cell lines. It promotes cell growth and migration, as well as colony formation. beta1 binds and degrades p27Kip1directly. Interestingly, the lack of phosphorylation at Ser158 of the beta1 subunit promotes degradation of p27Kip1. We therefore propose that the beta1 subunit plays a novel role in tumorigenesis by degrading p27Kip1. PMID- 23725359 TI - More comprehensive discussion of CRC screening associated with higher screening. AB - OBJECTIVES: Examine association of comprehensiveness of colorectal cancer (CRC) screening discussion by primary care physicians (PCPs) with completion of CRC screening. STUDY DESIGN: Observational study in Kaiser Permanente Northwest, a group-model health maintenance organization. METHODS: A total of 883 participants overdue for CRC screening received an automated telephone call (ATC) between April and June 2009 encouraging CRC screening. Between January and March 2010, participants completed a survey on PCPs' discussion of CRC screening and patient beliefs regarding screening. PRIMARY OUTCOME MEASURE: receipt of CRC screening (assessed by electronic medical record [EMR], 9 months after ATC). Primary independent variable: comprehensiveness of CRC screening discussion by PCPs (7 item scale). Secondary independent variables: perceived benefits of screening (4 item scale assessing respondents' agreement with benefits of timely screening) and primary care utilization (EMR; 9 months after ATC). The independent association of variables with CRC screening was assessed with logistic regression. RESULTS: Average scores for comprehensiveness of CRC discussion and perceived benefits were 0.4 (range 0-1) and 4.0 (range 1-5), respectively. A total of 28.2% (n = 249) completed screening, 84% of whom had survey assessments after their screening date. Of screeners, 95.2% completed the fecal immunochemical test. More comprehensive discussion of CRC screening was associated with increased screening (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.03-2.21). Higher perceived benefits (OR = 1.46, 95% CI = 1.13 1.90) and 1 or more PCP visits (OR = 5.82, 95% CI = 3.87-8.74) were also associated with increased screening. CONCLUSIONS: More comprehensive discussion of CRC screening was independently associated with increased CRC screening. Primary care utilization was even more strongly associated with CRC screening, irrespective of discussion of CRC screening. PMID- 23725360 TI - Comparative effectiveness of early natalizumab treatment in JC virus-negative relapsing-remitting multiple sclerosis. AB - OBJECTIVES: To estimate the long-term comparative effectiveness of first-line treatment in patients negative for anti-JC virus (JCV) antibodies with glatiramer acetate (GA), fingolimod, or natalizumab for relapsing-remitting multiple sclerosis (RRMS). STUDY DESIGN: We developed a simulation model to estimate the average 20-year clinical risks and benefits of GA, fingolimod, and natalizumab for RRMS patients initially negative for anti-JCV antibodies. METHODS: Model inputs included published natural history progressions of the Expanded Disability Status Scale (EDSS), treatment effects from randomized controlled trials on slowing disease progression and reducing relapse rates, risk of progressive multifocal leukoencephalopathy (PML), and utility preference scores. Outputs were long-term risks (PML risk and other non-PML risks), benefits (average relapse rate and time to disability [EDSS >7]), and quality-adjusted life years (QALYs). RESULTS: Compared with GA, natalizumab resulted in 4.6 fewer relapses, 0.6 more years of disability free time, 0.0165 more cases of PML per treated patient, and an incremental 1.2 QALYs gained. Compared with fingolimod, natalizumab resulted in 1.7 fewer relapses, 0.1 more years of disability free time, 0.0165 more cases of PML per treated patient, and an incremental 0.4 QALYs gained. The probability that incremental QALYs favored natalizumab over GA was 0.963 and natalizumab over fingolimod was 0.720. CONCLUSIONS: Average QALYs, a measure that aggregates across risks and benefits, favored natalizumab, suggesting more aggressive early intervention with natalizumab in the negative anti-JCV population. For certain decision makers, more evidence may be needed to further reduce the uncertainty in these comparative projections prior to making population-based adoption decisions. PMID- 23725361 TI - Prescription opioid abuse: challenges and opportunities for payers. AB - OBJECTIVES: Prescription opioid abuse and addiction are serious problems with growing societal and medical costs, resulting in billions of dollars of excess costs to private and governmental health insurers annually. Although difficult to accurately assess, prescription opioid abuse also leads to increased insurance costs in the form of property and liability claims, and costs to state and local governments for judicial, emergency, and social services. This manuscript's objective is to provide payers with strategies to control these costs, while supporting safe use of prescription opioid medications for patients with chronic pain. METHOD: A Tufts Health Care Institute Program on Opioid Risk Management meeting was convened in June 2010 with private and public payer representatives, public health and law enforcement officials, pain specialists, and other stakeholders to present research and develop recommendations on solutions that payers might implement to combat this problem. RESULTS: While protecting access to prescription opioids for patients with pain, private and public payers can implement strategies to mitigate financial risks associated with opioid abuse, using internal strategies such as formulary controls, claims data surveillance, and claims matching; and external policies and procedures that support and educate physicians on reducing opioid risks among patients with chronic pain. CONCLUSIONS: Reimbursement policies, incentives, and health technology systems that encourage physicians to use universal precautions, to consult prescription monitoring program (PMP) data, and to implement Screening, Brief Intervention, and Referral to Treatment protocols have a high potential to reduce insurer risks while addressing a serious public health problem. PMID- 23725362 TI - Effects of coverage gap reform on adherence to diabetes medications. AB - OBJECTIVES: To investigate the impact of Part D coverage gap reform on diabetes medication adherence. STUDY DESIGN: Retrospective data analysis based on pharmacy claims data from a national pharmacy benefit manager. METHODS: We used a difference-in-difference-indifference method to evaluate the impact of coverage gap reform on adherence to diabetes medications. Two cohorts (2010 and 2011) were constructed to represent the last year before Affordable Care Act (ACA) reform and the first year after reform, respectively. Each patient had 2 observations: 1 before and 1 after entering the coverage gap. Patients in each cohort were divided into groups based on type of gap coverage: no coverage, partial coverage (generics only), and full coverage. RESULTS: Following ACA reform, patients with no gap coverage and patients with partial gap coverage experienced substantial drops in copayments in the coverage gap in 2011. Their adherence to diabetes medications in the gap, measured by percentage of days covered, improved correspondingly (2.99 percentage points, 95% confidence interval [CI] 0.49-5.48, P = .019 for patients with no coverage; 6.46 percentage points, 95% CI 3.34-9.58, P <.0001 for patients with partial coverage). Patients with full coverage also had lower copayments in the gap in 2011. However, their adherence did not increase (-0.13 percentage point, P = .8011). CONCLUSIONS: In the first year of ACA coverage gap reform, copayments in the gap decreased substantially for all patients. Patients with no coverage and patients with partial coverage in the gap had better adherence in the gap in 2011. PMID- 23725363 TI - Predicting complicated Crohn's disease and surgery: phenotypes, genetics, serology and psychological characteristics of a population-based cohort. AB - BACKGROUND: Predictors of complicated Crohn's disease (CD), defined as stricturing or penetrating behaviour, and surgery have largely been derived from referral centre populations. AIM: To investigate whether serological markers, susceptibility genes or psychological characteristics are associated with complicated CD or surgery in a population-based cohort. METHODS: One hundred and eighty-two members of the Manitoba IBD Cohort with CD phenotyped using the Montreal classification underwent genetic and serological analysis at enrolment and after 5 years. One hundred and twenty-seven had paired sera at baseline and 5 years later and their data were used to predict outcomes at a median of 9.3 years. Serological analysis consisted of a seven antibody panel, and DNA was tested for CD-associated NOD2 variants (rs2066845,rs2076756,rs2066847), ATG16L1 (rs3828309, rs2241880) and IL23R (rs11465804). Psychological characteristics were assessed using semi-structured interviews and validated survey measures. RESULTS: Sixty-five per cent had complicated CD and 42% underwent surgery. Multivariate analysis indicated that only ASCA IgG-positive serology was predictive of stricturing/penetrating behaviour (OR = 3.01; 95% CI: 1.28-7.09; P = 0.01) and ileal CD (OR = 2.2; 95% CI: 1.07-4.54, P = 0.03). Complicated CD behaviour was strongly associated with surgery (OR = 5.6; 95% CI: 2.43-12.91; P < 0.0001), whereas in multivariate analysis, only ASCA IgG was associated (OR = 2.66; 95% CI, 1.40-5.06, P = 0.003). ASCA titre results were similar at baseline and follow up. Psychological characteristics were not significantly associated with disease behaviour, serological profile or genotype. CONCLUSIONS: ASCA IgG at baseline was significantly associated with stricturing/penetrating disease at 9-10 years from diagnosis. Stricturing/penetrating disease was significantly associated with surgery. In a model including serology, the genotypes assessed did not significantly associate with complicated disease or surgery. PMID- 23725364 TI - Strain- and temperature-dependent changes of fatty acid composition in Wickerhamomyces anomalus and Blastobotrys adeninivorans. AB - The fatty acid (FA) profiles of two strains of the yeasts Wickerhamomyces anomalus and Blastobotrys (Arxula) adeninivorans at cultivation temperatures from 15 to 30 degrees C were characterized. Besides the common even-numbered C16 and C18 FAs, substantial proportions of the uneven-numbered C17:1 were found in both species. C18:3(n-3) (alpha linolenic acid) made up to 3% of the total FAs in all strains. Considerable strain differences occurred, with regard to both the presence of single FAs and parameters like the double binding index (DBI) and C16:C18 ratio. W. anomalus J121 formed C18:1(n-5) (up to 10.9% of the total FAs) but no C18:1(n-7), whereas in W. anomalus VKM160, no C18:1(n-5) was found but up to 14.6% C18:1(n-7). Similarly, B. adeninivorans CBS 8244 formed exclusively C18:1(n-7) (maximum 9%) and CBS 7377 C18:1(n-5) (maximum 12.6%). W. anomalus J121 had the lowest DBI (0.72) at 15 degrees C and the highest (0.92) at 20 degrees C, at which point the values decreased with increasing temperatures. In W. anomalus VKM160 and both B. adeninivorans strains, DBI was highest at 15 degrees C and decreased with increasing temperature. In J121, the C16:C18 ratio was highest at 15 degrees C, decreasing at higher temperatures, whereas in the other strains, the opposite trend was observed. PMID- 23725365 TI - Prevalence and incidence of dengue virus and antibody placental transfer during late pregnancy in central Brazil. AB - BACKGROUND: Maternal dengue antibodies are considered to play a significant role in dengue pathogenesis among infants. Determining the transplacental specific antibody transfer is invaluable for establishing the optimal vaccination age among infants in endemic regions. METHODS: We conducted a cross-sectional study among pairs of maternal and corresponding umbilical cord blood samples in public hospitals. The prevalence and incidence of dengue infection were determined in 505 pairs of pregnant women and neonates during a large outbreak (2009-2010) in central Brazil. The women were interviewed at late pregnancy to assess current or past symptoms of dengue. All parturients and their neonates were screened using Dengue IgG Indirect ELISA (Panbio) to assess previous dengue exposure. A semi quantitative measurement of the IgG antibody expressed by the index ratio was calculated using optical density (OD) values according to the manufacturer's instructions. The studied population of parturients and their offspring was also screened for recent dengue infection by the Dengue IgM-capture ELISA (Panbio). Those participants with history of fever and two or more symptoms of dengue at least 10 days before the delivery were also tested for the dengue NS1 antigen using the Dengue Early ELISA (Panbio) and RT-PCR. RESULTS: The mean maternal age was 25.8 (SD = 6.4), and 83.6% of deliveries were between 37 and 41 weeks. Approximately half of the 505 women and neonates were IgG-seropositive, yielding 99.3% co-positive mother-child frequency of antibody transfer (Kappa = 0.96). The incidence of dengue infection was 2.8% (95% CI 1.4-4.4%) among the women considering 14 IgM-positive results and one DENV2 detected by RT-PCR. The dengue NS1 antigen was undetectable in the matched pairs. CONCLUSION: This study provides critical data on the prevalence of transplacental transferred maternal infant anti-dengue antibodies and incidence of infection. The design of future vaccine trials should consider diverse regional epidemiological scenarios. PMID- 23725366 TI - Rapid detection of haemotropic mycoplasma infection of feline erythrocytes using a novel flow cytometric approach. AB - BACKGROUND: The haemotropic mycoplasmas Mycoplasma haemofelis and Candidatus Mycoplasma haemominutum cause feline infectious anaemia with infection rates in feline populations reflecting widespread subclinical infection. Clinically significant infections are much rarer but can be life-threatening. Current diagnosis is dependent upon visualising organisms in stained blood smears, PCR or quantitative PCR (qPCR). These procedures are labour-intensive and time consuming. Furthermore, PCR-based approaches offer limited insight into the disease burden of the infected animal. METHODS: We have developed a novel and rapid flow cytometric system that permits diagnosis of haemotropic mycoplasma infections and quantitation of the percentage of erythrocytes that are parasitized. The method exploits the fact that mature mammalian erythrocytes, the host cell for haemoplasmas, are enucleated and thus lack nucleic acid. DRAQ5 is a synthetic anthrocycline dye which rapidly crosses cell membranes and binds to nucleic acids. The presence of exogenous bacterial DNA in mammalian erythrocytes can, therefore, be detected by DRAQ5 uptake and flow cytometric detection of DRAQ5 fluorescence. RESULTS: Here, we show that this system can detect epi erythrocytic infection of companion felines by haemotropic mycoplasma. Due to their differences in size, and hence the quantity of DNA, the two major feline hemoplasmas M. haemofelis and Candidatus M. haemominutum can be distinguished according to DRAQ5 fluorescence. We have also shown the usefulness of DRAQ5 uptake in monitoring a cat infected with M. haemofelis sequentially during treatment with doxycycline. CONCLUSIONS: The technique described is the first report of a flow cytometric method for detecting haemotropic mycoplasmas in any species and could be applied to widespread screening of animal populations to assess infection by these epi-erythrocytic parasites. PMID- 23725367 TI - Differential responses of circadian Per2 rhythms in cultured slices of discrete brain areas from rats showing internal desynchronisation by methamphetamine. AB - Chronic methamphetamine (MAP) treatment desynchronises the behavior rhythms of rats from light-dark cycles. Our previous study (Masubuchi et al., 2000) demonstrated the phase reversal of circadian rhythms in clock gene expression in several brain areas of rats treated with MAP. However, for technical reasons, it was not clear whether the phase shifts were the consequence of phase-shifted behavior rhythms or reflected phase shifts of extra-suprachiasmatic nucleus (SCN) oscillators in these areas. In the present study, circadian gene expression rhythms in discrete brain areas were continuously monitored in slice cultures of MAP-treated rats. Methamphetamine was given to rats carrying a Period2 dLuciferase reporter system via the drinking water for more than 2 weeks. When behavior rhythms were completely phase reversed, the brain was sampled for slice cultures and circadian bioluminescence rhythms were measured for 5 days in the SCN and four areas of the dopaminergic system, the olfactory bulb, caudate putamen, parietal cortex and substantia nigra. The circadian rhythms in the SCN and caudate putamen were not significantly phase shifted, whereas those in the parietal cortex and substantia nigra showed significant phase-delay shifts of 6-8 h and that in the olfactory bulb showed phase-advance shifts of ca. 8 h. Neither the period nor the amplitude of the circadian rhythm was changed by MAP treatment. These findings indicate that the extra-SCN oscillators in several brain areas are desynchronised from the SCN circadian pacemaker by MAP treatment in parallel with the desynchronisation of behavior rhythms in rats. As the direction and extent of phase shifts of circadian rhythms were different among the areas examined, the brain extra-SCN oscillators responded differentially to MAP. PMID- 23725368 TI - Dispersion forces and counterintuitive steric effects in main group molecules: heavier group 14 (Si-Pb) dichalcogenolate carbene analogues with sub-90 degrees interligand bond angles. AB - The synthesis and spectroscopic and structural characterization of an extensive series of acyclic, monomeric tetrylene dichalcogenolates of formula M(ChAr)2 (M = Si, Ge, Sn, Pb; Ch = O, S, or Se; Ar = bulky m-terphenyl ligand, including two new acyclic silylenes) are described. They were found to possess several unusual features-the most notable of which is their strong tendency to display acute interligand, Ch-M-Ch, bond angles that are often well below 90 degrees . Furthermore, and contrary to normal steric expectations, the interligand angles were found to become narrower as the size of the ligand was increased. Experimental and structural data in conjunction with high-level DFT calculations, including corrections for dispersion effects, led to the conclusion that dispersion forces play an important role in stabilizing their acute interligand angles. PMID- 23725369 TI - Influence of abutment type and esthetic veneering on preload maintenance of abutment screw of implant-supported crowns. AB - PURPOSE: The effect of veneering materials on screw joint stability remains inconclusive. Thus, this study evaluated the preload maintenance of abutment screws of single crowns fabricated with different abutments and veneering materials. MATERIALS AND METHODS: Sixty crowns were divided into five groups (n = 12): UCLA abutment in gold alloy with ceramic (group GC) and resin (group GR) veneering, UCLA abutment in titanium with ceramic (group TiC) and resin (group TiR) veneering, and zirconia abutment with ceramic veneering (group ZiC). Abutment screws made of gold were used with a 35 Ncm insertion torque. Detorque measurements were obtained initially and after mechanical cycling. Data were analyzed by ANOVA and Fisher's exact test at a significance level of 5%. RESULTS: For the initial detorque means (in Ncm), group TiC (21.4 +/- 1.78) exhibited statistically lower torque maintenance than groups GC (23.9 +/- 0.91), GR (24.1 +/- 1.34), and TiR (23.2 +/- 1.33) (p < 0.05, Fisher's exact test). Group ZiC (21.9 +/- 2.68) exhibited significantly lower torque maintenance than groups GC, GR, and TiR (p < 0.05, Fisher's exact test). After mechanical cycling, there was a statistically significant difference between groups TiC (22.1 +/- 1.86) and GR (23.8 +/- 1.56); between groups ZiC (21.7 +/- 2.02) and GR; and also between groups ZiC and TiR (23.6 +/- 1.30) (p < 0.05, Fisher's exact test). CONCLUSIONS: Detorque reduction occurred regardless of abutment type and veneering material. More irregular surfaces in the hexagon area of the castable abutments were observed. The superiority of any veneering material concerning preload maintenance was not established. PMID- 23725370 TI - Influence of antiviral therapy in the long-term outcome of recurrent hepatitis C virus infection following liver transplantation. AB - INTRODUCTION: Severity of recurrent hepatitis C virus (HCV) infection in liver transplant recipients (LTR) is variable and the influence of different factors, including the administration of antiviral therapy in the long-term outcome is controversial. METHODS: We analyzed the outcome of a cohort of HCV-infected LTR who were transplanted in our institution. Patients were divided into 2 groups (severe and non-severe HCV disease) depending on the presence of a fibrosis score of F >= 2 in the Scheuer index and/or fibrosing cholestasic hepatitis (FCH) in a graft biopsy. Risk factors were studied using logistic regression analysis. Survival of patients was estimated using Kaplan-Meier plots. A total of 146 patients were followed for a mean of 58 months. RESULTS: Fifty-six (34%) patients developed severe HCV disease and showed shorter survival (P < 0.024). Donor age (odds ratio [OR]: 1.04; 95% confidence interval [CI]: 1.02-1.06) and pre transplant viral load (VL) >10(6) UI/mL (OR: 3.5; 95% CI: 1.42-10.61) were the only factors associated with severe HCV infection. Over-immunosuppression (OR: 2.3; 95% CI: 1.2-4.41) was specifically associated with the development of FCH. Overall, patient survival in recipients who received a full course of anti-HCV therapy was higher than in patients who did not complete antiviral therapy (P = 0.004) or received no treatment (P = 0.007). Patients with non-severe HCV infection have a higher probability of receiving a full course of antiviral therapy (P = 0.033). CONCLUSION: In conclusion, donor age, pre-transplant VL, and over-immunosuppression were associated with the long-term development of severe HCV recurrence in liver grafts. Administration of a full course of antiviral therapy was associated with better survival. PMID- 23725371 TI - Testing the rebound peer review concept. AB - This invited editorial addresses the rescue of the article by Skrzypek et al. "Interplay between heme oxygenase-1 and miR-378 affects non-small cell lung carcinoma growth, vascularization, and metastasis." The work was rejected by the standard peer review system and subsequently rescued by the Rebound Peer Review (RPR) mechanism offered by Antioxidants and Redox Signaling (Antioxid Redox Signal 16: 293-296, 2012). The reviewers who openly rescued the article were James F. George, Justin C. Mason, Mahin D. Maines, and Yasufumi Sato. The initial article was a de novo resubmission of a previously rejected article, which was then reviewed by six reviewers. The reviewers raised substantial scientific concerns, including questions pertaining to the specificity of the findings, quality of the presentation, and other technical concerns; the editor returned a decision of reject. The authors voluntarily chose to exercise the option to rescue the article utilizing the RPR system, where the authors found qualified reviewers who were willing to advocate for acceptance with scientific reasoning. The open reviewers felt that the scientific and technical concerns raised by the reviewers were outweighed by the strengths and novelty of the findings to justify acceptance. The RPR, in this case, was a "success" in that it rescued a rejected article. Despite this assessment, we question the necessity of open peer review as a means to overturn a peer review decision, with concerns for the larger-than usual peer review process, and the voluntary relinquishing of editorial privilege and disclosure of reviewer identity. PMID- 23725372 TI - Complex regional pain syndrome of the knee - a case report. AB - BACKGROUND: Persistent unexplained pain around the knee can be a perplexing problem. Reports of complex regional pain syndrome involving primarily knee have been published, yet complex regional pain syndrome of the knee is infrequently included in differential diagnosis of pain out of proportion. CASE PRESENTATION: A 54 year old female presented to the physiotherapy outpatient department with complains of severe anterior knee pain and stiffness, persisting for more than 2 months post arthroscopic medial plical excision. The patient met the criteria for establishing a probable diagnosis of complex regional pain syndrome (CRPS) knee. Pressure algometre, goniometric measurements and knee outcome survey activities of daily living scale were used to document any changes. This patient was managed for a period of four sessions using graded desensitization therapy, TENS and mobilisation with feedback. Patient showed marked improvement in range of movement (ROM), hypersensitivity, pain and function. CONCLUSION: Meticulous examination, early diagnosis and prompt treatment resulted in a quick improvement in the patient's condition. PMID- 23725373 TI - Historical records of mercury, lead, and polycyclic aromatic hydrocarbons depositions in a dated sediment core from the Eastern Mediterranean. AB - Depth profiles of mercury, lead and its stable isotopes, and polycyclic aromatic hydrocarbons were determined in a dated sediment core from the Levantine basin. Sedimentary records show that preindustrial fluxes and levels of Hg, Pb, and PAHs remained generally constant in the region before 1850. An almost concurrent uniform increase of both metals and PAHs deposition occurring at the beginning of the Industrial Revolution suggests coal combustion as a main source of these contaminants in the Levantine basin after the 1850s. However, none of the contaminant profiles indicates a decline after 1950-60, the characteristic period of coal use reduction. The modern fluxes of Hg and Pb reveal a 3- to 5-fold increase over preindustrial loads, while the contemporaneous flux of PAHs rises by 4-7 times. On the whole, records in the Eastern Mediterranean suggest atmospheric inputs from relatively distant sources, likely from Central and Eastern Europe. PMID- 23725374 TI - A semi-automated genome annotation comparison and integration scheme. AB - BACKGROUND: Different genome annotation services have been developed in recent years and widely used. However, the functional annotation results from different services are often not the same and a scheme to obtain consensus functional annotations by integrating different results is in demand. RESULTS: This article presents a semi-automated scheme that is capable of comparing functional annotations from different sources and consequently obtaining a consensus genome functional annotation result. In this study, we used four automated annotation services to annotate a newly sequenced genome--Arcobacter butzleri ED-1. Our scheme is divided into annotation comparison and annotation determination sections. In the functional annotation comparison section, we employed gene synonym lists to tackle term difference problems. Multiple techniques from information retrieval were used to preprocess the functional annotations. Based on the functional annotation comparison results, we designed a decision tree to obtain a consensus functional annotation result. Experimental results show that our approach can greatly reduce the workload of manual comparison by automatically comparing 87% of the functional annotations. In addition, it automatically determined 87% of the functional annotations, leaving only 13% of the genes for manual curation. We applied this approach across six phylogenetically different genomes in order to assess the performance consistency. The results showed that our scheme is able to automatically perform, on average, 73% and 86% of the annotation comparison and determination tasks, respectively. CONCLUSIONS: We propose a semi-automatic and effective scheme to compare and determine genome functional annotations. It greatly reduces the manual work required in genome functional annotation. As this scheme does not require any specific biological knowledge, it is readily applicable for genome annotation comparison and genome re-annotation projects. PMID- 23725376 TI - Primary adenocarcinoma of the thymus: an immunohistochemical and molecular study with review of the literature. AB - BACKGROUND: Primary adenocarcinoma of thymus is extremely rare. CASE PRESENTATION: This is a case of primary adenocarcinoma with intestinal differentiation and focal mucin production in the thymus. Thymic cyst was associated with this tumor. Intestinal differentiation was confirmed by immunohistochemical stain with positivity for CDX-2, CK20, villin, MOC31 and focal positivity of CK7. Array comperative genomic hybridization (CGH) analysis showed a complex pattern of chromosomal imbalances including homozygous deletion at the HLA locus in chromosomal region 6p21.32. CONCLUSION: This rare tumor shows a similar genetic aberration with other studied thymic epithelial tumors. PMID- 23725375 TI - Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan. AB - Studies of aging and longevity are revealing how diseases that shorten life can be controlled to improve the quality of life and lifespan itself. Two strategies under intense study to accomplish these goals are rapamycin treatment and calorie restriction. New strategies are being discovered including one that uses low-dose myriocin treatment. Myriocin inhibits the first enzyme in sphingolipid synthesis in all eukaryotes, and we showed recently that low-dose myriocin treatment increases yeast lifespan at least in part by down-regulating the sphingolipid controlled Pkh1/2-Sch9 (ortholog of mammalian S6 kinase) signaling pathway. Here we show that myriocin treatment induces global effects and changes expression of approximately forty percent of the yeast genome with 1252 genes up-regulated and 1497 down-regulated (P < 0.05) compared with untreated cells. These changes are due to modulation of evolutionarily conserved signaling pathways including activation of the Snf1/AMPK pathway and down-regulation of the protein kinase A (PKA) and target of rapamycin complex 1 (TORC1) pathways. Many processes that enhance lifespan are regulated by these pathways in response to myriocin treatment including respiration, carbon metabolism, stress resistance, protein synthesis, and autophagy. These extensive effects of myriocin match those of rapamycin and calorie restriction. Our studies in yeast together with other studies in mammals reveal the potential of myriocin or related compounds to lower the incidence of age-related diseases in humans and improve health span. PMID- 23725377 TI - Insight into the role of physicochemical parameters in a novel series of amphipathic peptides for efficient DNA delivery. AB - Amphipathic peptides constitute a class of molecules with the potential to develop as efficient and safer alternatives to viral and other nonviral vectors for intracellular delivery of therapeutics. These peptides can be useful for nucleic acid delivery and hence promise to have pharmaceutical application, particularly in gene therapy. In order to design novel amphipathic peptides and improve their efficiency of therapeutic cargo delivery, one needs to understand the role of the physicochemical properties of the peptide. There are very few reports in the literature where the physicochemical properties of the peptide have been correlated with efficiency of plasmid DNA delivery. In the present work we hunted out a naturally occurring amphipathic peptide termed Mgpe-1 (derived from HUMAN Protein phosphatase 1E) as a possible novel DNA delivery agent. We systematically altered the physicochemical parameters of this peptide to further enhance its DNA delivery efficiency. We changed its amphipathicity (from secondary to primary), the total charge (from +6 to +9), hydrophobicity, and the amino acid composition (lysine and serines to arginine; substitution of tryptophan) and studied which of these alterations affect DNA delivery efficiency. Our results showed that although Mgpe-1 exhibited very strong cellular uptake, its plasmid DNA delivery efficiency was poor. The presence of nine arginines improved the DNA delivery efficiency, and the effect was observed in both the primary and the secondary amphipathic variants. We further observed that the presence of tryptophan was important but not essential and the effect of its removal was stronger in the case of the secondary amphipathic peptide. However, increase in total hydrophobicity of the peptide led to a fall in transfection efficiency in the primary amphipathic peptide whereas the secondary amphipathic peptide having the same chemical composition was almost unaffected by this change. The primary amphipathic peptides with high positive charge and low hydrophobicity formed colloidally stable polyplexes with DNA and avoided a major impediment in DNA delivery, namely, the aggregation of polyplexes and cytotoxicity. The secondary amphipathic variants by virtue of the positional arrangement of the amino acids led to formation of polyplexes with partly hydrophilic surfaces which prevented aggregation and controlled particle size irrespective of the hydrophobicity. Two variants in the series Mgpe-3 and Mgpe-4 having nine positive charges with less hydrophobicity showed high transfection efficiency in multiple cell lines along with serum stability and much less cytotoxicity and promise to be novel and efficient DNA delivery vectors. PMID- 23725378 TI - Linking distant relatives with BRCA gene mutations: potential for cost savings. AB - Thousands of individuals have undergone mutational analysis of BRCA1 and BRCA2. The Ohio State University Clinical Cancer Genetics program has identified 466 individuals from 289 families with a mutation in BRCA1 or BRCA2. Excluding Ashkenazi Jewish founder mutations, we observed 9 deleterious BRCA mutations five or more times in ostensibly unrelated families and another 13 mutations in 3-4 families. We hypothesized that some of the rarer recurrent mutations observed in our population were due to different branches of the same family being tested independently without knowledge of previous testing of relatives. We examined 90 pedigrees for individuals with the same mutations that were seen three or more times for shared reported family medical history or surnames. Familial links were made in four instances out of a total of 22 shared mutations despite the fact that individuals were not aware that another family member had been tested. As more individuals undergo BRCA testing, we propose that this phenomenon will become more common. Being unaware of previous testing in a family not only affects the risk assessment but also likely increases the costs associated with the genetic testing and subsequent cancer screening in many cases. PMID- 23725379 TI - Ecological and socio-cultural factors influencing plant management in Nahuatl communities of the Tehuacan Valley, Mexico. AB - BACKGROUND: Management types and their intensity may vary according to indicators such as: (1) practices complexity, (2) degree of techniques specialization, (3) occurrence and types of social regulations, (4) artificial selection intensity, (5) energy invested, (6) tools types, and (7) amounts of resources obtained. Management types of edible plants were characterized and analyzed in Nahuatl communities of the Tehuacan Valley. We expected that both natural and human pressures generate risk on plant resources availability, influencing human responses of management directed to decrease risk. We particularly hypothesized that magnitude of risk would be a direct function of human pressures favored by cultural and economic value and ecological factors such as scarcity (restricted distribution and abundance). Management practices may decrease risk of plant resources, more effectively when they are more intense; however, absence or insufficiency of management practices on endangered plants may favor loss of their populations. Understanding current management motives and their consequences on the purpose of ensuring availability of plant resources might allow us to understand similar processes occurring in the past. This issue is particularly important to be studied in the Tehuacan Valley, where archaeologists documented possible scenarios motivating origins of plant management by agriculture during prehistory. METHODS: Through ethnobotanical collecting, 55 semi-structured and free listing interviews we inventoried edible plant species used in five villages of Coyomeapan, Mexico. We identified: (1) native plant species whose products are obtained exclusively through simple gathering, (2) native species involving simple gathering and other management types, and (3) non native species managed by agricultural management. We conducted in depth studies on the 33 native species managed through gathering and other types of practices. We carried out a total of 660 sessions of detailed interviews to 20 households randomly selected. We showed to people voucher specimens and photos of the sample of species chosen and documented their cultural and economic values. Spatial availability of these plant species was evaluated through vegetation sampling. Values for each cultural, economic, and ecological indicator were codified and averaged or summed and weighed according to frequency of interviewees' responses or ecological conditions per plant species. With the standardized values of these indicators we performed a PCA and scores of the first principal component were considered as a risk index, which summarizes information of thirteen indicators of human use, demand and scarcity of each plant species. Similarly, eleven indicators of energy invested, complexity, tools and management strategies were used for performing PCA and scores of the first principal component were considered as management intensity index for each plant species. A linear regression analysis was performed to analyze the relation between risk and management intensity indexes. Amounts of variation of management data explained by ecological, cultural and economic information, as well as their risk level were analyzed through canonical correspondence analyses (CCA). RESULTS: A total of 122 edible plant species were recorded, nearly 30% of them were introduced domesticated plants, 51 were wild species obtained exclusively by simple gathering and 33 were native species obtained by simple gathering and other management practices, these latter were the ones more deeply studied. People recognized variants in 21 of these latter 33 species, the variants receiving differential use, management, artificial selection and incipient domestication. The lowest values of management intensity corresponded to species under simple gathering and tolerance, mostly annual abundant plants, occasionally consumed by few people. The highest management intensity values were recorded in species with economic importance, mostly perennial with recognized variants whose management requires using tools, and which are protected by collective regulations. The regression analysis indicated significant value R2 = 0.433 (P < 0.001) between risk and management indexes. CCA explained 65.5% of variation of management intensity, mainly by socio-cultural factors (32.6%), whereas ecological data explained 21.3% and the intersection of all factors 11.6%. Variation of management intensity is 67.6% explained by risk variables. Length-span of life cycle, reproductive system type, distribution, number of parts used, number of management and use forms and type of regulations were statistically significant. CONCLUSION: People manage plant resources according to the role these play in households' subsistence, the quantity available and the quality of their useful products; particularly important is the balance between resources availability and demand. Management responses to risk are also influenced by the ease to propagate or manipulate individual plants and time requiring the construction of manipulation strategies and techniques. PMID- 23725380 TI - A simplified severity score for acute asthma exacerbation. AB - BACKGROUND: To evaluate a simplified severity score designed to facilitate decision making in the Emergency Department (ED) regarding hospital admission of young adult patients with acute asthma exacerbation (AAE). METHODS: All AAE related ED encounters during two calendar years of patients aged 17-35 years were retrospectively classified as "mild", "moderate" or "severe", according to vital and readily available signs and symptoms, including pulse rate, presence of respiratory wheezes, rales or prolonged expirium, oxygen saturation, and the use of accessory muscles, measured upon arrival to the ED. All medical records of ED and hospital admissions were reviewed for treatment and outcomes. RESULTS: During the study period, 723 AAE-related ED encounters were recorded among 551 asthma patients. Of them, 35.0% were classified as "mild", 37.9% "moderate" and 27.1% "severe". For increasing levels of AAE severity, hospital admission rate increased (11.5%, 42.0%, 61.2%, respectively, p < 0.001). Adjusting for age and sex, odds ratios for hospitalization were 12.2 (95% CI: 7.5-19.9) and 5.6 (95% CI: 3.5-8.9) for the "severe" and "moderate" categories, respectively, compared to the "mild" category. "Mild" asthma patients also had shorter length of hospital stay and none required mechanical ventilation or died during hospitalization. CONCLUSION: The simplified asthma severity score requires no additional tests or costs in the ED, and could facilitate the decision of whether to hospitalize or discharge adult AAE patients. Prospective validation of this tool is needed. PMID- 23725381 TI - Co-morbid depression and chronic illness related to coping and physical and mental health status. AB - A partial latent structural regression analysis was used to evaluate the role of coping resources, depression, diet and exercise on mental and physical health status. The sample consisted of 113 participants (59 females and 54 males) with a mean age of 59.38 years (SD = 10.52). Coping resources, depression and exercise explained 52 and 26% of the variance in mental and physical health status, respectively. Fewer coping resources predicted higher levels of depression and both predicted worse mental health. Only higher levels of depression predicted worse physical health status. There were also significant indirect effects of coping on mental and physical health status through depression. The development of cognitive, social and emotional coping strategies is important for managing depression and supporting positive mental health. These results highlight the important role of health psychologists in the care of individuals with chronic illness. Additionally, the management of depression is important in maintaining positive physical health. PMID- 23725382 TI - Mediastinal mature teratoma with complex rupture into the lung, bronchus and skin: a case report. AB - Mature teratoma is the most common primary germ cell tumor in the mediastinum. On rare occasions, cystic teratomas rupture in adjacent structures, such as pleural space, pericardium, lung or tracheobronchial tree. We present a case of a mediastinal mature cystic teratoma in 16-year-old female with complex rupture into the lung, bronchus and skin. Mature mediastinal teratoma fistulized to the skin has not been previously described. PMID- 23725383 TI - Synthesis of Au-decorated tripod-shaped Te hybrids for applications in the ultrasensitive detection of arsenic. AB - Novel Au-decorated Te hybrids with a tripod-shaped planar microstructure were prepared through a two-step hydrothermal process: the synthesis of Te single crystals and the subsequent self-sacrificial reaction of Te template with HAuCl4. Based on the influences of reaction temperature and solvent compositions on the as-obtained microstructures, a plausible mechanism was proposed to account for the formation of the tripod-shaped Te and Au/Te crystals. The as-prepared Au/Te hybrids have the sensitivity of 6.35 MUA/ppb in the electrochemical detection of As(III), which represents the highest sensitivity reported in literature. The Au/Te sensor also has a low detection limit of 0.0026 ppb and could work in complex mixtures containing As(III), Cu(II) and other heavy metal ions, exhibiting excellent selectivity on As(III) and Cu(II) ions. The enhanced electrocatalytic property may be attributed to the synergetic interactions between the noble metal and semiconductor and the presence of a large number of active sites on the hybrids surface. PMID- 23725384 TI - T-cell immunoglobulin mucin-3 is underexpressed on myeloblasts in untreated myelodysplastic syndrome. PMID- 23725385 TI - Cytotoxic T cell-mediated gastritis after rituximab treatment for gastric malt lymphoma. PMID- 23725386 TI - MLL-SEPT5 fusion transcript in infant acute myeloid leukemia with t(11;22)(q23;q11). AB - Chromosomal rearrangements involving the MLL gene at band 11q23 are the most common genetic alteration encountered in infant acute myeloid leukemia. Reciprocal translocation represents the most frequent form of MLL rearrangement. Currently, more than 60 partner genes have been identified. We report here a case of de novo acute myeloid leukemia with a t(11;22)(q23;q11) in a 23-month-old child. Fluorescence in situ hybridization study revealed that the 3'MLL segment was translocated onto the derivative chromosome 22 and the breakpoint on chromosome 22 was located in or near the SEPT5 gene at 22q11.21. Long distance inverse-polymerase chain reaction was used to identify precisely the MLL partner gene and confirmed the MLL-SEPT5 fusion transcript. Involvement of the SEPT5 gene in MLL rearrangement occurs very rarely. Clinical, cytogenetic and molecular features of acute myeloid leukemia with a MLL-SEPT5 fusion gene are reviewed. PMID- 23725387 TI - Prognostic significance of isolated t(8:14) in chronic lymphocytic leukemia. PMID- 23725388 TI - Cryptic chromosome abnormalities in a patient with mixed phenotype acute leukemia. PMID- 23725389 TI - Polymorphism of CYP1A1 gene and susceptibility to childhood acute lymphoblastic leukemia in Egypt. AB - The origin of acute lymphoblastic leukemia (ALL) may be explained by a combination of genetic susceptibility and environmental exposure. We aimed to study the frequency of CYP1A1 allelic variants in Egyptian patients with ALL, to evaluate their role in the development of ALL and to correlate these allelic variants with clinical and biological characteristics of the patients. Polymorphism of CYP1A1*2A, *2B and *4 alleles was examined in 186 Egyptian children with ALL and 200 normal individuals using polymerase chain reaction single stranded conformation polymorphism (PCR-SSCP). A higher prevalence of the CYP1A1*4 allele was found in patients with ALL than in the normal population (19.4%vs. 10.0%, odds ratio [OR] = 2.160, 95% confidence interval [CI] = 1.200 3.89, p = 0.01), especially in the homozygous variant (OR = 6.6, 95% CI = 2.23 19.58, p = 0.001) and in male patients (p = 0.005), particularly those aged 2-10 years (OR = 5.214, 95% CI = 1.535-17.706, p = 0.008). CYP1A1*2A showed a significant difference between age groups (p = 0.046), with a higher incidence in the 10-17-year-old group (21.1%). Multivariate analysis showed that only the CYP1A1*4 allele remained as a probable independent risk factor for ALL development (OR = 2.250, 95% CI = 1.244-4.069; p = 0.007). Our results suggest that polymorphic variants in the CYP1A1*4 gene may increase the risk of childhood ALL, particularly in male patients aged 2-10 years. PMID- 23725390 TI - Clinical significance of down-regulated cylindromatosis gene in chronic lymphocytic leukemia. AB - Loss of cylindromatosis gene (CYLD) expression has been observed in various cancers, including chronic lymphocytic leukemia (CLL). As a deubiquitination enzyme, CYLD regulates the proliferation, development and activation of lymphoid cells. Here we determined the CYLD mRNA expression by quantitative polymerase chain reaction (PCR) in 125 patients with CLL. CYLD was considerably down regulated in CLL cells compared to normal B cells. Low CYLD expression was associated with unmutated status of the immunoglobulin heavy-chain variable region (IGHV) gene (p = 0.0018) and CD38 positivity (p = 0.0499). Patients with high CYLD expression showed a trend toward improved overall survival (OS) (10 year OS: CYLD high: 94.74%, CYLD low: 52.71%; p = 0.0534). For patients with mutated IGHV gene, high CYLD was also associated with better OS (10-year OS: CYLD high: 100%, CYLD low: 66.67%; p = 0.0547). In conclusion, low CYLD expression identifies a subgroup of patients with CLL with inferior outcome, indicating the role of CYLD as a tumor suppressor in the pathogenesis of CLL. PMID- 23725391 TI - There is life in the old dog yet: thymidine kinase as predictive marker in diffuse large B-cell lymphoma. PMID- 23725392 TI - Are we close to a prognostic index for cutaneous T cell lymphoma? PMID- 23725393 TI - Highly reactive trans-cyclooctene tags with improved stability for Diels-Alder chemistry in living systems. AB - One of the challenges of pretargeted radioimmunotherapy, which centers on the capture of a radiolabeled probe by a preinjected tumor-bound antibody, is the potential immunogenicity of biological capturing systems. A bioorthogonal chemical approach may circumvent this drawback, but effective in vivo chemistry in mice, larger animals, and eventually humans, requires very high reagent reactivity, sufficient stability, and retained selectivity. We report here that the reactivity of the fastest bioorthogonal reaction, the inverse-electron-demand Diels-Alder cycloaddition between a tetrazine probe and a trans-cyclooctene tagged antibody, can be increased 10-fold (k2 = 2.7 * 10(5) M(-1) s(-1)) via the trans-cyclooctene, approaching the speed of biological interactions, while also increasing its stability. This was enabled by the finding that the trans cyclooctene tag is probably deactivated through isomerization to the unreactive cis-cyclooctene isomer by interactions with copper-containing proteins, and that increasing the steric hindrance on the tag can impede this process. Next, we found that the higher reactivity of axial vs equatorial linked TCO can be augmented by the choice of linker. The new, stabilized, and more reactive tag allowed for improved tumor-to-nontumor ratios in pretargeted tumor-bearing mice. PMID- 23725394 TI - Can low-grade spondylolisthesis be effectively treated by either coflex interlaminar stabilization or laminectomy and posterior spinal fusion? Two-year clinical and radiographic results from the randomized, prospective, multicenter US investigational device exemption trial: clinical article. AB - OBJECT: Posterolateral spinal fusion (PSF) has long been the standard of care for degenerative spondylolisthesis, but less invasive, motion-preserving alternatives have been proposed to reduce the complications associated with fusion while still providing neural decompression and stabilization. The object of the current study is to evaluate the safety and efficacy of coflex Interlaminar Stabilization compared with PSF to treat low-grade spondylolisthesis with spinal stenosis. METHODS: This is a prospective, randomized, multicenter FDA investigational device exemption (IDE) trial comparing coflex Interlaminar Stabilization with laminectomy and PSF. A total of 322 patients from 21 sites in the US were enrolled between 2006 and 2008 for the IDE trial. The current study evaluated only the subset of patients from this overall cohort with Grade 1 spondylolisthesis (99 in the coflex group and 51 in the fusion group). Subjects were randomized 2:1 to receive decompression and coflex interlaminar stabilization or decompression and posterolateral spinal fusion with spinal instrumentation. Data collected included perioperative outcomes, Oswestry Disability Index (ODI), back and worse leg visual analog scale (VAS) scores, 12 Item Short Form Health Survey, Zurich Claudication Questionnaire (ZCQ), and radiographic outcomes at a minimum of 2 years. The FDA criteria for overall device success required the following to be met: 15-point reduction in ODI, no reoperations, no major device-related complications, and no postoperative epidural injections. RESULTS: At a minimum of 2 years, patient follow-up was 94.9% and 94.1% in the coflex and fusion control groups, respectively. There were no group differences at baseline for any demographic, clinical, or radiographic parameter. The average age was 63 years in the coflex cohort and 65 years in the fusion cohort. Coflex subjects experienced significantly shorter operative times (p < 0.0001), less estimated blood loss (p < 0.0001), and shorter length of stay (p < 0.0001) than fusion controls. Both groups experienced significant improvements from baseline at 2 years in ODI, VAS back, VAS leg, and ZCQ, with no significant group differences, with the exception of significantly greater ZCQ satisfaction with coflex at 2 years. FDA overall success was achieved in 62.8% of coflex subjects (59 of 94) and 62.5% of fusion controls (30 of 48) (p = 1.000). The reoperation rate was higher in the coflex cohort (14 [14.1%] of 99) compared with fusion (3 [5.9%] of 51, p = 0.18), although this difference was not statistically significant. Fusion was associated with significantly greater angulation and translation at the superior and inferior adjacent levels compared with baseline, while coflex showed no significant radiographic changes at the operative or index levels. CONCLUSIONS: Low-grade spondylolisthesis was effectively stabilized by coflex and led to similar clinical outcomes, with improved perioperative outcomes, compared with PSF at 2 years. Reoperation rates, however, were higher in the coflex cohort. Patients in the fusion cohort experienced significantly increased superior and inferior level angulation and translation, while those in the coflex cohort experienced no significant adjacent or index level radiographic changes from baseline. Coflex Interlaminar Stabilization is a less invasive, safe, and equally efficacious clinical solution to PSF to treat low-grade spondylolisthesis, and it appears to reduce stresses at the adjacent levels. Clinical trial registration no.: NCT00534235 (ClinicalTrials.gov). PMID- 23725395 TI - Reliability in the location of hindlimb motor representations in Fischer-344 rats: laboratory investigation. AB - OBJECT: The purpose of the present study was to determine the feasibility of using a common laboratory rat strain for reliably locating cortical motor representations of the hindlimb. METHODS: Intracortical microstimulation techniques were used to derive detailed maps of the hindlimb motor representations in 6 adult Fischer-344 rats. RESULTS: The organization of the hindlimb movement representation, while variable across individual rats in topographic detail, displayed several commonalities. The hindlimb representation was positioned posterior to the forelimb motor representation and posterolateral to the motor trunk representation. The areal extent of the hindlimb representation across the cortical surface averaged 2.00 +/- 0.50 mm(2). Superimposing individual maps revealed an overlapping area measuring 0.35 mm(2), indicating that the location of the hindlimb representation can be predicted reliably based on stereotactic coordinates. Across the sample of rats, the hindlimb representation was found 1.25-3.75 mm posterior to the bregma, with an average center location approximately 2.6 mm posterior to the bregma. Likewise, the hindlimb representation was found 1-3.25 mm lateral to the midline, with an average center location approximately 2 mm lateral to the midline. CONCLUSIONS: The location of the cortical hindlimb motor representation in Fischer-344 rats can be reliably located based on its stereotactic position posterior to the bregma and lateral to the longitudinal skull suture at midline. The ability to accurately predict the cortical localization of functional hindlimb territories in a rodent model is important, as such animal models are being increasingly used in the development of brain-computer interfaces for restoration of function after spinal cord injury. PMID- 23725396 TI - Analysis of association between IL-1beta, CASP-9, and GDF5 variants and low-back pain in Chinese male soldier: clinical article. AB - OBJECT: Recent studies have suggested that genetic risk factors play an important role in the occurrence of low-back pain (LBP) and lumbar disc disease. The authors' study aimed to assess the association between 3 single-nucleotide polymorphisms (SNPs) and susceptibility to LBP related to military training. METHODS: In this case-control study, data from 892 Chinese male soldiers were retrospectively reviewed. The case group was made up of 305 soldiers with LBP related to military training and a control group of 587 soldiers without constant LBP for more than 2 weeks. Genomic DNA was extracted from peripheral blood leukocytes of all subjects and polymerase chain reaction products were genotyped. RESULTS: No association was found between the SNP of interleukin-1beta (IL-1beta; +3954C/T) and LBP at both the genotypic (p = 0.104) and the allelic (p = 0.098) level. However, the G allele of caspase-9 (CASP-9) and the T allele of growth differentiation factor 5 (GDF5) were more common in patients with LBP than in patients without LBP (p < 0.001). CONCLUSIONS: The findings in a Chinese military cohort indicated that CASP-9 (-1263A/G) and GDF5 (+104T/C) polymorphisms are associated with a susceptibility to LBP related to military training. PMID- 23725397 TI - Traumatic spinal perimedullary arteriovenous fistula due to knife stabbing and subsequent kyphosis: case report. AB - Perimedullary arteriovenous fistula (AVF) is a relatively rare spinal vascular malformation. Although it has traditionally been considered to be a congenital lesion, some cases identified in adults have suggested that the lesion may be acquired. The etiology and exact mechanism of these lesions are unknown. The authors present a case of a perimedullary AVF caused by a direct stabbing injury of the spinal cord and induced by subsequent kyphosis, and they discuss the pathogenesis and treatment strategy. PMID- 23725398 TI - Operating room radiation exposure in cone beam computed tomography-based, image guided spinal surgery: clinical article. AB - OBJECT: Surgeon and operating room (OR) staff radiation exposure during spinal surgery is a concern, especially with the increasing use of multiplanar fluoroscopy in minimally invasive spinal surgery procedures. Cone beam computed tomography (cbCT)-based, 3D image guidance does not involve the use of active fluoroscopy during instrumentation placement and therefore decreases radiation exposure for the surgeon and OR staff during spinal fusion procedures. However, the radiation scatter of a cbCT device can be similar to that of a standard 64 slice CT scanner and thus could expose the surgeon and OR staff to radiation during image acquisition. The purpose of the present study was to measure radiation exposure at several unshielded locations in the OR when using cbCT in conjunction with 3D image-guided spinal surgery in 25 spinal surgery cases. METHODS: Five unshielded badge dosimeters were placed at set locations in the OR during 25 spinal surgery cases in which cbCT-based, 3D image guidance was used. The cbCT device (O-ARM) was used in conjunction with the Stealth S7 image-guided platform. The radiology department analyzed the badge dosimeters after completion of the last case. RESULTS: Fifty high-definition O-ARM spins were performed in 25 patients for spinal registration and to check instrumentation placement. Image guided placement of 124 screws from C-2 to the ileum was accomplished without complication. Badge dosimetry analysis revealed minimal radiation exposure for the badges 6 feet from the gantry in the area of the anesthesiology equipment, as well as for the badges located 10-13 feet from the gantry on each side of the room (mean 0.7-3.6 mrem/spin). The greatest radiation exposure occurred on the badge attached to the OR table within the gantry (mean 176.9 mrem/spin), as well as on the control panel adjacent to the gantry (mean 128.0 mrem/spin). CONCLUSIONS: Radiation scatter from the O-ARM was minimal at various distances outside of and not adjacent to the gantry. Although the average radiation exposure at these locations was low, an earlier study, undertaken in a similar fashion, revealed no radiation exposure when the surgeon stood behind a lead shield. This simple precaution can eliminate the small amount of radiation exposure to OR staff in cases in which the O-ARM is used. PMID- 23725399 TI - The effect of explicit solvent on photodegradation of decabromodiphenyl ether in toluene: insights from theoretical study. AB - Polybrominated diphenyl ethers (PBDEs) have received special environmental concern because of their potential toxicity to humans and wildlife worldwide. However, their photochemical degradation mechanisms remain largely unknown. Herein, a PCM/TD-DFT scheme (time-dependent density functional theory combined with the polarizable continuum model) augmented with explicit solute-solvent interactions is used to explore the promotive effects of the toluene solvent on the photochemical degradation debromination of deca-BDE (BDE209). The face-to face pi-pi interactions between penta-bromine-substituted phenyl and toluene are investigated. The calculations indicate that the face-to-face pi-pi interaction plays an important role in the low-lying pi->sigma* transitions of BDE209-toluene pi-stacking complex at around 300 nm in the sunlight region, which leads to notable changes for the pisigma* excited states and which promotes the breaking of the C-Br bonds. The photodegradation reaction via an intermolecular charge transfer excited state formed by the electronic transition from a pi orbital of toluene to a sigma* orbital of BDE209 is found to be a dominant mechanism. Our calculation results reveal the mechanism of how the participation of an explicit toluene solvent molecule catalyzes the photodegradation of BDE209 and explain the experimental results successfully. The present study may provide helpful information for the removal of PBDE contamination. PMID- 23725400 TI - Role of total artificial heart in the management of heart transplant rejection and retransplantation: case report and review. AB - Cardiac allograft rejection and failure may require mechanical circulatory support as bridge-to-retransplantation. Prognosis in this patient group is poor and implantable ventricular assist devices have had limited success due to organ failure associated with the high dose immunosuppression required to treat ongoing rejection. We present a case from our institution and the world-wide experience utilizing the SynCardia CardioWest Total Artificial Heart (TAH-t; SynCardia Systems, Inc., Tucson, AZ, USA) for replacement of the failing graft, recovery of patient and end-organ failure with ultimate bridge to retransplantation. We present our experience and review of world-wide experience for use of TAH-t in this type patient. PMID- 23725401 TI - Longitudinal characterization of a model of chronic allergic lung inflammation in mice using imaging, functional and immunological methods. AB - The present study investigated the role that imaging could have for assessing lung inflammation in a mouse model of HDM (house dust mite)-provoked allergic inflammation. Inflammation is usually assessed using terminal procedures such as BAL (bronchoalveolar lavage) and histopathology; however, MRI (magnetic resonance imaging) and CT (computed tomography) methods have the potential to allow longitudinal, repeated study of individual animals. Female BALB/c mice were administered daily either saline, or a solution of mixed HDM proteins sufficient to deliver a dose of 12 or 25 MUg total HDM protein+/-budesonide (1 mg/kg of body weight, during weeks 5-7) for 7 weeks. AHR (airway hyper-responsiveness) and IgE measurements were taken on weeks 3, 5 and 7. Following imaging sessions at weeks 3, 5 and 7 lungs were prepared for histology. BAL samples were taken at week 7 and lungs prepared for histology. MRI showed a gradual weekly increase in LTI (lung tissue intensity) in animals treated with HDM compared with control. The 25 MUg HDM group showed a continual significant increase in LTI between weeks 3 and 7, the 12 MUg HDM-treated group showed a similar rate of increase, and plateaued by week 5. A corresponding increase in AHR, cell counts and IgE were observed. CT showed significant increases in lung tissue density from week 1 of HDM exposure and this was maintained throughout the 7 weeks. Budesonide treatment reversed the increase in tissue density. MRI and CT therefore provide non-invasive sensitive methods for longitudinally assessing lung inflammation. Lung tissue changes could be compared directly with the classical functional and inflammatory readouts, allowing more accurate assessments to be made within each animal and providing a clinically translatable approach. PMID- 23725402 TI - Establishment and application of real-time quantitative PCR for diagnosing invasive aspergillosis via the blood in hematological patients: targeting a specific sequence of Aspergillus 28S-ITS2. AB - BACKGROUND: Invasive aspergillosis (IA) is an important cause of morbidity and mortality in immunocompromised individuals. This study was conducted to identify a desirable target DNA sequence for the diagnosis of aspergillosis using real time quantitative polymerase chain reaction (qPCR). METHODS: Genomic DNA was extracted from Aspergillus, Candida, and bacteria species, and qPCR was applied to validate a partial ribosomal DNA 28S-ITS2 sequence. Ethylenediaminetetraacetic acid-anticoagulated blood samples were collected from 72 febrile hematological patients, while total DNA was isolated from plasma and whole blood for the Aspergillus qPCR. The results were analyzed using a receiver operating characteristic curve. All cases were evaluated using the revised European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) diagnostic criteria. RESULTS: Use of qPCR yielded positive results for 15 Aspergillus species but negative results for Candida species, bacterial strains, and human DNA. The limit of detection was one copy per microliter of DNA. Analytical sensitivity and specificity were six copies of DNA and 100%, respectively. The standard curve showed that qPCR was reliable for Aspergillus detection and that significantly more DNA copies were obtained from whole blood than from plasma (P < 0.001). At a cut-off value >= 25 copies/MUL, the diagnostic sensitivity and specificity for IA using 28S-ITS2 qPCR were 90.9% and 73.4%, respectively. CONCLUSIONS: The use of qPCR with whole blood to detect and verify the 28S-ITS2 sequence is a specific and useful way to diagnose IA. PMID- 23725403 TI - Regional density of private dentists: empirical evidence from Austria. AB - OBJECTIVES: We investigated the determinants of disparities in the regional density of private dentists in Austria. Specifically, we focused on the relationship between the density of private dentists and their public counterparts, thereby controlling for other possible covariates of dentist density. METHODS: Dentist density was measured at the district level. We used panel data of dentist density from 121 Austrian districts over the years 2001 2008. We applied a Hausman-Taylor framework to cope with possible endogeneity and to control for cross-district effects in the dentist density. RESULTS: A significant negative relationship was found between the density of private and public dentists, indicating a substitution effect between the two dentist groups. A significant positive spatial relationship also existed for private and public dentists in the neighboring regions. Dental capacities in public and private hospitals and dental laboratories run by the public health insurance system did not have a significant effect on private dentist density. CONCLUSIONS: Although a strong negative relationship existed between private and public dentists within the districts, one should not draw the conclusion that private dentists in Austria are close substitutes for public dentists. Such a conclusion would require further empirical analysis on the utilization patterns of dental services and their relationships with financing mechanisms. PMID- 23725404 TI - Paradoxical tolerance to cocaine after initial supersensitivity in drug-use-prone animals. AB - There is great interest in outlining biological factors and behavioral characteristics that either predispose or predict vulnerability to substance use disorders. Response to an inescapable novel environment has been shown to predict a "drug-use-prone" phenotype that is defined by rapid acquisition of cocaine self administration. Here, we showed that response to novelty can also predict the neurochemical and behavioral effects of acute and repeated cocaine in rats. We used cocaine self-administration under a fixed-ratio 1 schedule followed by fast scan cyclic voltammetry in brain slices to measure subsecond dopamine (DA) release and uptake parameters in drug-use-prone and -resistant phenotypes. Despite no significant differences in stimulated release and uptake, animals with high responses to a novel environment had DA transporters that were more sensitive to cocaine-induced uptake inhibition, which corresponded to greater locomotor activating effects of cocaine. These animals also acquired cocaine self administration more rapidly and, after 5 days of extended access cocaine self administration, high-responding animals showed robust tolerance to DA uptake inhibition by cocaine. The effects of cocaine remained unchanged in animals with low novelty responses. Similarly, the rate of acquisition was negatively correlated with DA uptake inhibition by cocaine after self-administration. Thus, we showed that tolerance to the cocaine-induced inhibition of DA uptake coexists with a behavioral phenotype that is defined by increased preoccupation with cocaine as measured by rapid acquisition and early high intake. PMID- 23725406 TI - Effectiveness of alcohol prevention interventions based on the principles of social marketing: a systematic review. AB - BACKGROUND: Alcohol education aims to increase knowledge on the harm related to alcohol, and to change attitudes and drinking behaviour. However, little (lasting) evidence has been found for alcohol education, in changing alcohol related attitudes and behaviour. Social marketing uses marketing techniques to achieve a social or healthy goal, and can be used in alcohol education. Social marketing consists of eight principles: customer orientation, insight, segmentation, behavioural goals, exchange, competition, methods mix, and is theory based. This review investigates the application of social marketing in alcohol prevention interventions, and whether application of social marketing influences alcohol-related attitudes or behaviour. METHOD: A literature search was conducted in PubMed, PsychInfo, Cochrane and Scopus. Inclusion criteria were that original papers had to describe the effects of an alcohol prevention intervention developed according to one or more principles of social marketing. No limits were set on the age of the participants or on the kind of alcohol prevention intervention. The abstracts of the 274 retrieved studies were reviewed and the full texts of potentially relevant studies were screened. RESULTS: Six studies met the inclusion criteria and were included in this review. These six studies showed associations for the application of social marketing techniques on alcohol-related attitudes or behaviour; one study relates to participation in a drinking event, four to alcohol drinking behaviour, two to driving a car while under the influence of alcohol, two to recognition of campaign messages or campaign logo, and one to awareness of the campaign. However, no associations were also found. In addition, the studies had several limitations related to a control group, response rate and study methodology. CONCLUSION: Based on this review, the effect of applying the principles of social marketing in alcohol prevention in changing alcohol-related attitudes or behaviour could not be assessed. More research, with a good quality methodology, like using a randomized control trial and measuring short, medium, and long-term effects, is required on this topic. Policy implications are discussed. PMID- 23725405 TI - Long non-coding RNA: a new player in cancer. AB - Emerging evidence showed that long non-coding RNAs (lncRNAs) play important roles in a wide range of biological processes and dysregulated lncRNAs are involved in many complex human diseases, including cancer. Although a few lncRNAs' functions in cancer have been characterized, the detailed regulatory mechanisms of majority of lncRNAs in cancer initiation and progression remain largely unknown. In this review, we summarized recent progress on the mechanisms and functions of lncRNAs in cancer, especially focusing on the oncogenic and tumor suppressive roles of the newly identified lncRNAs, and the pathways these novel molecules might be involved in. Their potentials as biomarkers for diagnosis and prognosis in cancer are also discussed in this paper. PMID- 23725407 TI - Crystalline arrays of pairs of molecular rotors: correlated motion, rotational barriers, and space-inversion symmetry breaking due to conformational mutations. AB - The rod-like molecule bis((4-(4-pyridyl)ethynyl)bicyclo[2.2.2]oct-1-yl)buta-1,3 diyne, 1, contains two 1,4-bis(ethynyl)bicyclo[2.2.2]octane (BCO) chiral rotators linked by a diyne fragment and self-assembles in a one-dimensional, monoclinic C2/c centrosymmetric structure where two equilibrium positions with large occupancy imbalance (88% versus 12%) are identified on a single rotor site. Combining variable-temperature (70-300 K) proton spin-lattice relaxation, (1)H T1(-1), at two different (1)H Larmor frequencies (55 and 210 MHz) and DFT calculations of rotational barriers, we were able to assign two types of Brownian rotators with different activation energies, 1.85 and 6.1 kcal mol(-1), to the two (1)H spin-lattice relaxation processes on the single rotor site. On the basis of DFT calculations, the low-energy process has been assigned to adjacent rotors in a well-correlated synchronous motion, whereas the high-energy process is the manifestation of an abrupt change in their kinematics once two blades of adjacent rotors are seen to rub together. Although crystals of 1 should be second harmonic inactive, a large second-order optical response is recorded when the electric field oscillates in a direction parallel to the unique rotor axle director. We conclude that conformational mutations by torsional interconversion of the three blades of the BCO units break space-inversion symmetry in sequences of mutamers in dynamic equilibrium in the crystal in domains at a mesoscopic scale comparable with the wavelength of light used. A control experiment was performed with a crystalline film of a similar tetrayne molecule, 1,4-bis(3 ((trimethylsilyl)ethynyl)bicyclo[1.1.1]pent-1-yl)buta-1,3-diyne, whose bicyclopentane units can rotate but are achiral and produce no second-order optical response. PMID- 23725408 TI - David S. McKay, 1936-2013. PMID- 23725409 TI - Maxillary rehabilitation using fixed and removable partial dentures with attachments: a clinical report. AB - Despite requiring dental crown preparation and possible root canal treatment, besides the difficulty of clinical and laboratory repairs, and financial burden, the association between fixed (FPD) and removable partial dentures (RPD) by means of attachments is an important alternative for oral rehabilitation, particularly when the use of dental implants and FPDs is limited or not indicated. Among the advantages of attachment-retained RPDs are the improvements in esthetics and biomechanics, as well as correction of the buccal arrangement of anterior teeth in Kennedy Class III partially edentulous arches. This article describes the treatment sequence and technique for the use of attachments in therapy combining FPD/RPD. PMID- 23725410 TI - Pericarditis mediated by respiratory syncytial virus in a hematopoietic stem cell transplant patient. AB - We describe a case of pericarditis and large pericardial effusion in a 63-year old African-American man undergoing autologous hematopoietic stem cell transplant for multiple myeloma. Pericardial tissue biopsy demonstrated fibrinous pericarditis, and immunohistochemistry stains were positive for respiratory syncytial virus. The patient improved with oral ribavirin and intravenous immune globulin infusions. PMID- 23725411 TI - Plasma in the PICU: why and when should we transfuse? AB - Whereas red blood cell transfusions have been used since the 19th century, plasma has only been available since 1941. It was originally mainly used as volume replacement, mostly during World War II and the Korean War. Over the years, its indication has shifted to correct coagulation factors deficiencies or to prevent bleeding. Currently, it remains a frequent treatment in the intensive care unit, both for critically ill adults and children. However, observational studies have shown that plasma transfusion fail to correct mildly abnormal coagulation tests. Furthermore, recent epidemiological studies have shown that plasma transfusions are associated with an increased morbidity and mortality in critically ill patients. Therefore, plasma, as any other treatment, has to be used when the benefits outweigh the risks. Based on observational data, most experts suggest limiting its use either to massively bleeding patients or bleeding patients who have documented abnormal coagulation tests, and refraining for transfusing plasma to nonbleeding patients whatever their coagulation tests. In this paper, we will review current evidence on plasma transfusions and discuss its indications. PMID- 23725412 TI - Region-based progressive localization of cell nuclei in microscopic images with data adaptive modeling. AB - BACKGROUND: Segmenting cell nuclei in microscopic images has become one of the most important routines in modern biological applications. With the vast amount of data, automatic localization, i.e. detection and segmentation, of cell nuclei is highly desirable compared to time-consuming manual processes. However, automated segmentation is challenging due to large intensity inhomogeneities in the cell nuclei and the background. RESULTS: We present a new method for automated progressive localization of cell nuclei using data-adaptive models that can better handle the inhomogeneity problem. We perform localization in a three stage approach: first identify all interest regions with contrast-enhanced salient region detection, then process the clusters to identify true cell nuclei with probability estimation via feature-distance profiles of reference regions, and finally refine the contours of detected regions with regional contrast-based graphical model. The proposed region-based progressive localization (RPL) method is evaluated on three different datasets, with the first two containing grayscale images, and the third one comprising of color images with cytoplasm in addition to cell nuclei. We demonstrate performance improvement over the state-of-the-art. For example, compared to the second best approach, on the first dataset, our method achieves 2.8 and 3.7 reduction in Hausdorff distance and false negatives; on the second dataset that has larger intensity inhomogeneity, our method achieves 5% increase in Dice coefficient and Rand index; on the third dataset, our method achieves 4% increase in object-level accuracy. CONCLUSIONS: To tackle the intensity inhomogeneities in cell nuclei and background, a region-based progressive localization method is proposed for cell nuclei localization in fluorescence microscopy images. The RPL method is demonstrated highly effective on three different public datasets, with on average 3.5% and 7% improvement of region- and contour-based segmentation performance over the state-of-the-art. PMID- 23725413 TI - Deconvolution of mixture spectra and increased throughput of peptide identification by utilization of intensified complementary ions formed in tandem mass spectrometry. AB - A cornerstone of mass spectrometry based proteomics is to relate with high statistical significance experimentally obtained tandem mass spectrometry (MS/MS) data to peptide sequences from a protein database. Most sequence specific fragment ions in MS/MS spectra are represented by a subset of complementary ion pairs. Here, we investigated the reliabilities of complementary ion pairs formed in CAD and CAD/ETD MS/MS and developed a reliability-based approach of intensification of ion signals of complementary pairs prior to database searching. In a large-scale proteomics experiment using high-resolution orbitrap mass spectrometry, an increase in the number of peptide identifications was obtained relative to the original CAD MS/MS spectra when intensified golden complementary (+18.6%) and CAD complementary pairs (+17.2%) were submitted to the Mascot search engine. This also exceeded the results obtained by deisotoping/deconvolution of CAD MS/MS spectra. A novel approach for extracting sequence-specific fragment ions of co-isolated peptides was developed based on the complementarity rules. This technique demonstrated an impressive gain of 42.4% more peptide identifications as compared with the use of the initial data set. PMID- 23725414 TI - A field-validated model for in situ transport of polymer-stabilized nZVI and implications for subsurface injection. AB - Nanoscale zerovalent iron (nZVI) particles have significant potential to remediate contaminated source zones. However, the transport of these particles through porous media is not well understood, especially at the field scale. This paper describes the simulation of a field injection of carboxylmethyl cellulose (CMC) stabilized nZVI using a 3D compositional simulator, modified to include colloidal filtration theory (CFT). The model includes composition dependent viscosity and spatially and temporally variable velocity, appropriate for the simulation of push-pull tests (PPTs) with CMC stabilized nZVI. Using only attachment efficiency as a fitting parameter, model results were in good agreement with field observations when spatially variable viscosity effects on collision efficiency were included in the transport modeling. This implies that CFT-modified transport equations can be used to simulate stabilized nZVI field transport. Model results show that an increase in solution viscosity, resulting from injection of CMC stabilized nZVI suspension, affects nZVI mobility by decreasing attachment as well as changing the hydraulics of the system. This effect is especially noticeable with intermittent pumping during PPTs. Results from this study suggest that careful consideration of nZVI suspension formulation is important for optimal delivery of nZVI which can be facilitated with the use of a compositional simulator. PMID- 23725415 TI - Sleep disorders in children with Down syndrome: Stores and Stores reply. PMID- 23725416 TI - Trait emotional intelligence and inflammatory diseases. AB - Researchers have become increasingly interested in the psychological aspects of inflammatory disorders. Within this line of research, the present study compares the trait emotional intelligence (trait EI) profiles of 827 individuals with various inflammatory conditions (rheumatoid arthritis [RA], ankylosing spondylitis, multiple sclerosis, and RA plus one comorbidity) against 496 healthy controls. Global trait EI scores did not show significant differences between these groups, although some differences were observed when comparisons were carried out against alternative control groups. Significant differences were found on the trait EI factors of Well-being (where the healthy group scored higher than the RA group) and Sociability (where the healthy group scored higher than both the RA group and the RA plus one comorbidity group). The discussion centers on the multifarious links and interplay between emotions and inflammatory conditions. PMID- 23725417 TI - Senior medical student perceived ability and experience in giving peer feedback in formative long case examinations. AB - BACKGROUND: Learning to provide feedback on a peer's performance in formative clinical assessments can be a valuable way of enriching the students' own learning experience. Students are often reluctant to provide honest, critical feedback to their peers. Nevertheless, it is an area of practice that is important to develop as students report feeling ill prepared in feedback techniques when entering the medical workforce. We sought to investigate students' perceptions of their ability to provide feedback to their peers using the positive critique method, and their perceived benefits and challenges during the experience. METHODS: Over a two year period (2011 to 2012), senior medical students assessed and gave feedback to their peers alongside academic examiners during formative long case clinical examinations. Rating scales, open ended questions and focus group discussions were used to evaluate student perceptions. RESULTS: Of the 94 participants, 89/94 (95%) completed the questionnaire, and 39/94 (41%) participated in focus groups. Students found the positive critique method provided a useful framework. Some students raised concerns about the accuracy of their feedback, and felt that further training was required. A substantial number of respondents (42%) did not report feeling confident providing negative feedback to their peers, and qualitative analysis indicated concerns around potential impacts on social relationships. Despite these concerns, the majority (90%) of respondents found the exercise useful, identifying several benefits, including development in the understanding of knowledge content; development of professionalism skills, and increased responsibility. CONCLUSION: Students identified several challenging aspects to providing feedback to their peers. While the experience of giving feedback to peers was perceived by students to provide a valuable learning experience, further training in this area may help to improve the learning experience for students and better prepare them for their future careers. PMID- 23725419 TI - With pet owners already using the drug as medicine, veterinarians need to join the debate. PMID- 23725420 TI - Unemployment and underemployment. PMID- 23725421 TI - Prospects for collaboration between the veterinary professions in the United States and China. PMID- 23725422 TI - What is your diagnosis? Pulmonary adenocarcinoma. PMID- 23725423 TI - What is your neurologic diagnosis? Porencephaly. PMID- 23725424 TI - Diagnostic imaging in veterinary dental practice. External replacement resorption. PMID- 23725425 TI - ECG of the month. Atrial flutter in dog. PMID- 23725427 TI - Pathology in practice. Johne's disease. PMID- 23725428 TI - Pathology in practice. Spinal cord (ectopic) nephroblastoma in a dog. PMID- 23725430 TI - Doxycycline concentration over time after storage in a compounded veterinary preparation. AB - OBJECTIVE: To determine the concentration of doxycycline compounded from doxycycline hyclate tablets into liquid formulations for oral administration in veterinary species and stored for 28 days. DESIGN: Evaluation study. SAMPLE: Doxycycline hyclate tablets (100 mg) crushed and mixed with a 50:50 mixture of syrup and suspension vehicles for oral administration to produce 3 batches each of 2 doxycycline formulations: 33.3 and 166.7 mg/mL. PROCEDURES: Formulations were stored, protected from light, at room temperature (22 degrees to 26 degrees C [71.6 degrees to 78.8 degrees F]) and at a controlled cold temperature (refrigerated 2 degrees to 8 degrees C [35.6 degrees to 46.4 degrees F]). Doxycycline was extracted from the formulations, and concentration was measured by high-pressure liquid chromatography on days 0 (date of preparation), 1, 4, 7, 14, 21, and 28. Concentrations were compared with those of a US Pharmacopeial Convention reference standard. Formulation quality at each point was also assessed through color change, formulation consistency, and suspension uniformity. RESULTS: On days 0, 1, 4, and 7, the concentration of each formulation was within 90% to 110% of the reference standard (range, 93% to 109%), which was deemed acceptable. However, doxycycline concentrations had decreased dramatically by day 14 and remained low for the duration of the study period. Doxycycline concentrations on days 14, 21, and 28 were all < 20% (range, 14% to 18%) of the reference standard, and the quality of the formulations decreased as well. No effect of storage temperatures on doxycycline concentration was identified. CONCLUSIONS AND CLINICAL RELEVANCE: The concentration of doxycycline, compounded from commercial tablets in the vehicles evaluated to yield doses of 33.3 and 166.7 mg/mL, cannot be assured beyond 7 days. PMID- 23725431 TI - Development of a survey instrument to assess health-related quality of life in small animal cancer patients treated with chemotherapy. AB - OBJECTIVE: To develop a quality of life (QOL) survey for use in a canine cancer chemotherapy setting, validate the instrument's utility, identify key questions that facilitate client and clinician communication regarding decisions in patient care, and use human and veterinary QOL literature to develop a comprehensive yet simple proxy survey instrument. DESIGN: Survey. ANIMALS: 29 canine chemotherapy patients. PROCEDURES: Patients were evaluated by both owners and veterinarians at the time of initial visit to the clinic and at 3 and 6 weeks after the initiation of chemotherapy. This survey consisted of a longitudinal evaluation of QOL with 6 components addressing the animal's QOL retrospectively, before onset of cancer; changes in the animal's QOL since manifestation of disease; changes in the animal's QOL with regard to treatment response; owner's QOL and its impact on priorities in decision making; clinician's impression of the owner's priorities and QOL; and clinician's impression of the dog's QOL. RESULTS: Multiple regression analysis indicated 3 significant predictors of canine cancer patient QOL to be play behaviors, signs of illness, and canine happiness as perceived by owners. CONCLUSIONS AND CLINICAL RELEVANCE: The QOL instrument was easy to use and enhanced client perception of patient care and clinician concern. Owners enjoyed the opportunity to complete the survey. Since questions regarding play behaviors, clinical signs of disease, and canine happiness were significant indicators of changes in QOL, these should be included in future studies. Quality of life assessment may facilitate treatment decisions and assessment of canine patients undergoing chemotherapy. PMID- 23725432 TI - Interobserver agreement and diagnostic accuracy of brain magnetic resonance imaging in dogs. AB - OBJECTIVE: To evaluate interobserver agreement and diagnostic accuracy of brain MRI in dogs. DESIGN: Evaluation study. ANIMALS: 44 dogs. PROCEDURES: 5 board certified veterinary radiologists with variable MRI experience interpreted transverse T2-weighted (T2w), T2w fluid-attenuated inversion recovery (FLAIR), and T1-weighted-FLAIR; transverse, sagittal, and dorsal T2w; and T1-weighted FLAIR postcontrast brain sequences (1.5 T). Several imaging parameters were scored, including the following: lesion (present or absent), lesion characteristics (axial localization, mass effect, edema, hemorrhage, and cavitation), contrast enhancement characteristics, and most likely diagnosis (normal, neoplastic, inflammatory, vascular, metabolic or toxic, or other). Magnetic resonance imaging diagnoses were determined initially without patient information and then repeated, providing history and signalment. For all cases and readers, MRI diagnoses were compared with final diagnoses established with results from histologic examination (when available) or with other pertinent clinical data (CSF analysis, clinical response to treatment, or MRI follow-up). Magnetic resonance scores were compared between examiners with kappa statistics. RESULTS: Reading agreement was substantial to almost perfect (0.64 < kappa < 0.86) when identifying a brain lesion on MRI; fair to moderate (0.14 < kappa < 0.60) when interpreting hemorrhage, edema, and pattern of contrast enhancement; fair to substantial (0.22 < kappa < 0.74) for dural tail sign and categorization of margins of enhancement; and moderate to substantial (0.40 < kappa < 0.78) for axial localization, presence of mass effect, cavitation, intensity, and distribution of enhancement. Interobserver agreement was moderate to substantial for categories of diagnosis (0.56 < kappa < 0.69), and agreement with the final diagnosis was substantial regardless of whether patient information was (0.65 < kappa < 0.76) or was not (0.65 < kappa < 0.68) provided. CONCLUSIONS AND CLINICAL RELEVANCE: The present study found that whereas some MRI features such as edema and hemorrhage were interpreted less consistently, radiologists were reasonably constant and accurate when providing diagnoses. PMID- 23725433 TI - Prevalence of and risk factors associated with atherosclerosis in psittacine birds. AB - OBJECTIVE: To estimate the prevalence of clinically relevant atherosclerotic lesions in birds and identify epidemiological variables and illness types associated with development of atherosclerosis. DESIGN: Retrospective case control study. SAMPLE: Records of 7683 psittacine birds, including 525 with advanced atherosclerosis. PROCEDURES: 5 pathology centers provided databases and access to histopathology slides. Age and sex were collected for all birds of the Amazona, Ara, Cacatua, Nymphicus, and Psittacus genera. Databases were searched for atherosclerosis cases, and slides were reviewed for the presence of type IV through VI atherosclerotic lesions. Results were used to build several multiple logistic models to define the association between advanced atherosclerosis and age, sex, genus, illness type, and specific lesions. Prevalence was reported as a function of age, sex, and genus. RESULTS: In the first model including 7683 birds, age, female sex, and the genera Psittacus, Amazona, and Nymphicus were significantly associated with clinically relevant atherosclerosis detected via necropsy. Subsequent models of 1,050 cases revealed further associations with reproductive disease, hepatic disease, and myocardial fibrosis, controlling for age, sex, and genus. CONCLUSIONS AND CLINICAL RELEVANCE: Age, female sex, and 3 genera appeared to be positively associated with the presence of advanced atherosclerotic lesions in psittacine birds. This information may be useful in clinical assessment of the cardiovascular system and patient management. Reproductive diseases were the only potentially modifiable risk factor identified and could be a target for prevention in captive psittacine birds. PMID- 23725434 TI - Comparison of a chlorambucil-prednisolone combination with an azathioprine prednisolone combination for treatment of chronic enteropathy with concurrent protein-losing enteropathy in dogs: 27 cases (2007-2010). AB - OBJECTIVE: To compare treatment protocols for chronic enteropathy and concurrent protein-losing enteropathy that used prednisolone in conjunction with either azathioprine or chlorambucil in dogs. DESIGN: Retrospective case series. ANIMALS: 27 dogs. PROCEDURES: All dogs had hypoalbuminemia (serum albumin concentration, < 18.0 g/L) and chronic enteropathy as diagnosed via complete gastrointestinal tract investigations including intestinal biopsy. Dogs received either an azathioprine-prednisolone combination (group A; n = 13) or a chlorambucil prednisolone combination (group C; 14). Response to treatment was assessed by evaluation of body weight gain, serum albumin concentration, and duration of primary treatment. RESULTS: No significant pretreatment differences were detected between groups for any baseline variable (signalment and weight), clinicopathologic variable (albumin, cobalamin, and folate concentrations), or histopathologic findings. After treatment, serum albumin concentration and weight gain were significantly greater in group C. Median survival time for group A dogs was 30 days (95% confidence interval, 15 to 45 days) and was not reached for group C dogs. Duration of primary treatment was positively associated with the histopathologic presence of mild lacteal dilatation and use of a chlorambucil prednisolone combination. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that a chlorambucil-prednisolone protocol is more efficacious for treatment of chronic enteropathy and concurrent protein-losing enteropathy, compared with an azathioprine-prednisolone combination. Given these findings, a prospective randomized clinical trial is warranted. PMID- 23725435 TI - Evaluation of risk factors for outcome associated with adrenal gland tumors with or without invasion of the caudal vena cava and treated via adrenalectomy in dogs: 86 cases (1993-2009). AB - OBJECTIVE: To evaluate risk factors for outcome for dogs with adrenal gland tumors with or without invasion of the caudal vena cava treated via adrenalectomy. DESIGN: Retrospective study. ANIMALS: 86 dogs that underwent adrenalectomy for treatment of adrenal gland tumors. PROCEDURES: Medical records of dogs that underwent adrenalectomy for treatment of an adrenal gland tumor from 1993 to 2009 were reviewed; data collected including signalment, clinical signs, diagnostic test findings, treatments prior to surgery, findings at surgery including additional procedures performed and extent of caudal vena caval invasion (local invasion [caudal to the hepatic portion of the vena cava] or extensive invasion [cranial to the hepatic portion of the vena cava]), procedures performed during surgery, histopathologic diagnosis, perioperative complications, follow-up data, and necropsy findings. RESULTS: Of the 86 dogs, 14 had adenomas, 45 had adrenocortical carcinomas, and 27 had pheochromocytomas. Fourteen dogs had invasion of the caudal vena cava; of these tumors, 7 were locally invasive and 7 were extensively invasive. Risk factors for poor short-term survival (death within 14 days following surgery) were vena caval invasion, extent of invasion, pheochromocytoma, intraoperative transfusion, and postoperative factors including disseminated intravascular coagulation, pancreatitis, hypotension, hypoxemia, and renal failure. Multivariate analysis of risk factors for poor short-term survival revealed that extensive invasion was the most important factor. Regardless of extent of invasion or tumor type, long-term survival was possible. CONCLUSIONS AND CLINICAL RELEVANCE: Invasion of the caudal vena cava, particularly tumor thrombus extension beyond the hepatic hilus, was associated with a higher postoperative mortality rate, but did not affect long-term prognosis in dogs undergoing adrenalectomy because of an adrenal gland tumor. PMID- 23725436 TI - Structural and functional cardiovascular changes and their consequences following interventional patent ductus arteriosus occlusion in dogs: 24 cases (2000-2006). AB - OBJECTIVE: To investigate cardiovascular changes and survival times following complete interventional device occlusion of uncomplicated left-to-right shunting patent ductus arteriosus in dogs. DESIGN: Retrospective cohort study. ANIMALS: 24 dogs with uncomplicated patent ductus arteriosus that was fully occluded and reevaluated within 24 hours, approximately 3 months, and 1 year after the procedure. PROCEDURES: Information on medical history, diagnostic imaging findings, treatment received, and survival times were obtained from medical records. Patients were allocated into 2 groups on the basis of age (< 1 year [n = 14] and >= 1 year [10]) at the time of the procedure. Additional follow-up information was obtained through interviews of owners and referral veterinarians. RESULTS: Following ductal occlusion, decreases were detected in vertebral heart scale size, left ventricular chamber diameter in diastole and in systole, left atrial dimension, fractional shortening, aortic velocity, and ventricular wall thickness. There were no differences between age groups for postocclusion changes except vertebral heart scale size. Systolic dysfunction was detected in 14 (58%) patients on the final visit. Median survival time for all dogs after ductal occlusion was > 11.5 years. CONCLUSIONS AND CLINICAL RELEVANCE: Complete ductal occlusion resulted in immediate removal of the volume overload state and eventual return of cardiac chamber dimensions to reference range, suggesting regression of eccentric hypertrophy. Systolic dysfunction persisted in some dogs but appeared to be clinically unimportant. Most cardiovascular changes were independent of patient age at the time of the procedure. PMID- 23725437 TI - Unilateral laryngeal paralysis subsequent to surgical ligation of a patent ductus arteriosus in an 8-week-old domestic shorthair cat. AB - CASE DESCRIPTION: An 8-week-old female domestic shorthair cat was treated for patent ductus arteriosus (PDA) with surgical ligation. Seven weeks postoperatively, the cat was evaluated because of increased upper respiratory noise, inspiratory stridor, wheezing, and episodes of intermittent open-mouth breathing that had developed 1 week following the surgical ligation. CLINICAL FINDINGS: The cat was sedated, and examination of the larynx revealed left-sided laryngeal paralysis. TREATMENT AND OUTCOME: At the time left-sided laryngeal paralysis was diagnosed, the clinical signs of laryngeal dysfunction were not considered severe enough to warrant surgical intervention. No treatment was administered, and the owner monitored the cat for respiratory distress and worsening of clinical signs for an additional 5 months. During those 5 months, the clinical signs improved but persisted. Seven months after PDA ligation, the cat was again sedated and the larynx examined. The examination revealed persistent left arytenoid dysfunction, which was believed to be the result of permanent damage to the recurrent laryngeal nerve that was sustained during the surgical ligation of the PDA. The owner was counseled about surgical and medical treatment options for laryngeal paralysis but elected to forego treatment at that time. CLINICAL RELEVANCE: Unilateral laryngeal paralysis caused by iatrogenic damage to the recurrent laryngeal nerve is a potential complication subsequent to surgical ligation of a PDA. The frequency of iatrogenically induced laryngeal paralysis is likely underestimated in small animal patients. Laryngoscopy should be performed in any small animal with a history of PDA attenuation and clinical signs of respiratory tract disease. PMID- 23725438 TI - Management factors associated with veterinary usage by organic and conventional dairy farms. AB - OBJECTIVE: To identify management factors associated with veterinary usage by organic and conventional dairy farms. DESIGN: Prospective case-control study. SAMPLE: 292 farms. PROCEDURES: Organic farms in New York, Oregon, and Wisconsin were matched to conventional farms on the basis of location and herd size. During a single herd visit, a questionnaire was administered, information about animal disease incidence and number of veterinarian visits in the preceding 60 days was collected, and forms to record similar information during the 60 days after the visit were left for the herd manager to complete. For analysis, conventional herds were classified as either grazing or nongrazing. Multiple correspondence analysis was used to assess relationships among management factors and selected outcomes for frequency of veterinary usage. RESULTS: Intensive management practices were closely associated with frequent veterinary usage. Generally, organic management practices were associated with less frequent veterinary usage than were conventional management practices. Conventional grazing practices were associated with intermediate veterinary usage (more than organic practices but less than intensive practices), whereas conventional nongrazing practices were associated with frequent veterinary usage. Cost of routinely scheduled veterinarian visits/45 kg (100 lb) of milk produced/y was greater for small farms than that for large farms. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that management intensiveness was more closely associated with frequency of veterinary usage than was organic status; therefore, veterinarians should characterize farms by factors other than organic status when investigating which farms are most likely to use their services. Economic factors substantially affected routine veterinary usage on small farms. PMID- 23725439 TI - Cystoscopic sex identification of posthatchling chelonians. AB - OBJECTIVE: To describe a noninvasive technique for sex identification of posthatchling chelonians and to assess its safety in Hermann's tortoises (Testudo hermanni). DESIGN: Validation study and clinical trial. ANIMALS: 15 recently dead posthachling chelonians and 25 healthy posthatchling Hermann's tortoises. PROCEDURES: Cystoscopy was performed on both dead and anesthetized live chelonians. Dead chelonians ranged in body weight from 32.4 to 75.1 g (0.07 to 0.17 lb; median, 45.7 g [0.10 lb]). Dead chelonians were dissected immediately after cystoscopy, and gonads were collected for histologic examination. Urinary bladder was macroscopically evaluated in situ to assess its integrity after retrograde injection of saline (0.9% NaCl) solution. Hermann's tortoises ranged in body weight from 27.3 to 57.8 g (0.06 to 0.13 lb; median, 37.0 g [0.08 lb]). Cystoscopic examination of live tortoises was performed following induction of general anesthesia with a mixture of morphine, dexmedetomidine, and ketamine administered IM. The Pearson coefficient was used to assess the consistency between procedure time and body weight; kappa statistic was used to evaluate agreement between sex identified by cystoscopy and histologic examination beyond that expected by mere chance. RESULTS: Visualization of gonads was feasible through the thin, transparent urinary bladder wall in all the animals evaluated in this study. Blinded histologic examination confirmed the results of cystoscopic gonad identification in all dead chelonians (kappa = 1.0). The urinary bladder did not have evidence of macroscopic leakage or microscopic alterations of normal tissue architecture within the representative sections chosen for histologic examination. In live tortoises, median procedure time (range) was 90 (39 to 345) seconds. No significant correlations were found between procedure time and body weight. CONCLUSIONS AND CLINICAL RELEVANCE: Cystoscopy performed by means of rigid endoscopy with fluid instillation was found to be an effective method for sex identification of immature chelonians. Furthermore, no complications were observed when this procedure was performed in vivo. PMID- 23725440 TI - Laparoscopic upper vaginectomy for post-hysterectomy high risk vaginal intraepithelial neoplasia and superficially invasive vaginal carcinoma. AB - BACKGROUND: The aim of this study is to describe the feasibility and efficacy of the laparoscopic upper vaginectomy (LUV) in vaginal intraepithelial neoplasia(VAIN) and superficially invasive vaginal carcinoma. METHODS: We studied patients with vaginal intraepithelial neoplasia (VAIN) 2, VAIN 3, and superficially invasive vaginal carcinoma after hysterectomy who have been under laparoscopic upper vaginectomy between March 2010 and March 2012. RESULTS: Four patients underwent LUV after hysterectomy for high risk VAIN and early vaginal cancer. The mean age was 50.8 (range 40-56) years; the mean operation time was 162.5 (range 145-205) minutes; and the mean estimated blood loss was 55 (range 20 100) ml. All the patients restituted bladder function after the removal of the foley catheter. Mean hospital stay was 2 days. Two patients had postoperative complications. One patient with warfarin administration had vaginal stump bleeding and another developed vesico-vaginal fistula. Three of the patients had no residual lesion, but 1 patient had VAIN 1 in the resection margin. Colposcopy was followed on all patients and cytology proved no recurrence. CONCLUSIONS: LUV after hysterectomy is a feasible procedure and attentively applicable to high risk VAIN or superficially invasive vaginal carcinoma. PMID- 23725441 TI - Benefits of a worksite or home-based bench stepping intervention for sedentary middle-aged adults - a pilot study. AB - The aim of this study was to investigate the benefits of a low-volume, vigorous intensity bench stepping programme in sedentary middle-aged adults. Thirty-one healthy but sedentary adults (12 men; 55-64 years) took part in the study. Participants accumulated up to 9 min per day of stepping exercise on three days per week over the 4-week experimental period. Parameters of cardiorespiratory fitness, body composition and lower limb muscle strength were measured on three occasions: TS1 (baseline test), TS2 (following a 4-week control period) and TS3 (following the 4-week intervention). Data were analysed using a repeated-measures ANOVA. Adherence to the programme was excellent (96%). Relative to the insignificant changes following the control period, parameters of cardiorespiratory fitness were significantly improved following training. No alterations in body composition or lower limb muscle strength were detected. These results show that less than 30 min per week of bench step exercise, accumulated in short bouts throughout the day, can improve parameters of cardiorespiratory fitness after only 4 weeks in previously sedentary middle-aged adults. Due to its low-cost, time-efficient and discrete aspects, stepping exercise may have important implications for public health initiatives that promote physical activity in a population who commonly report 'lack of time' as a barrier to physical activity. PMID- 23725442 TI - Emerging technology in evaluation of nanomedicine. PMID- 23725443 TI - Ab initio path integral simulations for the fluoride ion-water clusters: competitive nuclear quantum effect between F(-)-water and water-water hydrogen bonds. AB - Small hydrated fluoride ion complexes, F(-)(H2O)n (n = 1-3), have been studied by ab initio hybrid Monte Carlo (HMC) and ab initio path integral hybrid Monte Carlo (PIHMC) simulations. Because of the quantum effect, our simulation shows that the average hydrogen-bonded F(-)...HO distance in the quantum F(-)(H2O) is shorter than that in the classical one, while the relation inverts at the three water molecular F(-)(H2O)3 cluster. In the case of F(-)(H2O)3, we have found that the nuclear quantum effect enhances the formation of hydrogen bonds between two water molecules. In F(-)(H2O)2 and F(-)(H2O)3, the nuclear quantum effect on two different kinds of hydrogen bonds, F(-)-water and water-water hydrogen bonds, competes against each other. In F(-)(H2O)3, thus, the nuclear quantum effect on the water-water hydrogen bond leads to the elongation of hydrogen-bonded F( )...HO distance, which we suggest this as the possible origin of the structural inversion from F(-)(H2O) to F(-)(H2O)3. PMID- 23725444 TI - The multicomponent medication lymphomyosot improves the outcome of experimental lymphedema. AB - BACKGROUND: Secondary lymphedema is a life-long disease of painful tissue swelling that often follows axillary lymph node dissection to treat breast cancer. It is hypothesized that poor lymphatic regeneration across the obstructive scar tissue during the wound healing process may predispose the tissue to swell at a later date. Treatment for lymphedema remains suboptimal and is in most cases palliative. The purpose of this study was to evaluate the ability of Lymphomyosot to treat tissue swelling and promote lymphangiogenesis in experimental models of murine lymphedema. METHODS: Experimental models of mouse lymphedema were injected with varied amounts of Lymphomyosot and saline as control. Measurements of tail swelling and wound closure were taken and compared amongst the groups. Three separate groups of mice were analyzed for lymphatic capillary migration, lymphatic vessel regeneration, and macrophage recruitment. RESULTS: Lymphomyosot significantly reduced swelling and increased the rate of surgical wound closure. Lymphomyosot did not increase the migration of lymph capillaries in a mouse tail skin regeneration model or regeneration of lymph vessels following murine axillary lymph node dissection. CONCLUSIONS: Lymphomyosot may act through inflammatory and wound repair pathways to reduce experimental lymphedema. Its ability to regulate inflammation as well as assist in tissue repair and extracellular formation may allow for the production of a scar-free matrix bridge through which migrating cells and accumulated interstitial fluid can freely spread. PMID- 23725445 TI - B-type natriuretic peptide versus amino terminal pro-B type natriuretic peptide: selecting the optimal heart failure marker in patients with impaired kidney function. AB - BACKGROUND: The effect of impaired kidney function on B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) is vague. This study was performed to examine the effect of kidney dysfunction on the afore-mentioned markers and determine appropriate cutoffs for systolic heart failure (SHF). METHODS: In this cross sectional study adults with estimated glomerular filtration rate (eGFR) <60 ml/min for >=3 months were identified in consulting clinics from June 2009 to March 2010. SHF was defined as documented by a cardiologist with ejection fraction of < 40% and assessed by New York Heart Association classification (NYHA). Plasma was assayed for creatinine (Cr), BNP and NT-proBNP. RESULTS: A total of 190 subjects were enrolled in the study, 95 with and 95 without SHF. The mean age of patients was 58 (+/-15) years, 67.4% being males. Mean BNP levels showed a 2.5 fold and 1.5 fold increase from chronic kidney disease (CKD) stage 3 to stage 5 in patients with and without SHF respectively. NT-proBNP levels in non heart failure group were 3 fold higher in CKD stage 5 compared to stage 3. Mean NT-proBNP levels were 4 fold higher in CKD stage 5 compared to stage 3 in patients with SHF. Optimal BNP and NT-proBNP cutoffs of SHF diagnosis for the entire CKD group were 300 pg/ml and 4502 pg/ml respectively. CONCLUSION: BNP and NT-proBNP were elevated in kidney dysfunction even in the absence of SHF; however the magnitude of increase in NT-proBNP was greater than that of BNP. BNP and NT proBNP can be useful in diagnosing SHF, nonetheless, by using higher cutoffs stratified according to kidney dysfunction. NT-proBNP appears to predict heart failure better than BNP. PMID- 23725446 TI - Expression of Lewis y antigen and integrin alphav, beta3 in ovarian cancer and their relationship with chemotherapeutic drug resistance. AB - OBJECTIVE: This study investigates the expression of Lewis y antigen, integrin alphav, beta3 in epithelial ovarian cancer tissues. We further evaluate the relationship between their expression and chemotherapy resistance of ovarian cancer and its possible clinical significance. METHODS: Tissues of 92 patients with ovarian cancer meeting the inclusion criteria with complete follow-up data were enrolled and divided into chemotherapy resistant group and sensitive group. The expression and relationship of Lewis y antigen and integrin alphav, beta3 are assessed in paraffin sections using immunohistochemistry and double-labeling immunofluorescence method. Multivariate logistic regression analysis was used to investigate the relationship between age, clinical stage, differentiation, histologic subtype, Lewis y antigen and integrin alphav, beta3 expression in ovarian cancer patients. RESULTS: The expression rates of Lewis y antigen and integrin alphav in the resistant group, significantly higher than the rates found in the sensitive group (p <0.05). Multivariate analysis showed that the expression of Lewis y antigen, integrin alphav and ovarian cancer's clinical stage were independent, drug resistance-related risk factors. The expression levels of Lewis y antigen and integrin alphav, beta3 were positively correlated with each other. CONCLUSIONS: A close correlation between Lewis y antigen, integrin alphav, beta3 and ovarian cancer was observed. Lewis y antigen can influence the biological behavior of a tumor cell as an important composition of integrin alphav, beta3 by some signal pathway. And the expression of Lewis y antigen, integrin alphav and ovarian cancer's clinical stage are both independent, drug resistance-related risk factors. PMID- 23725447 TI - Effects of sprint interval and continuous endurance training on serum levels of inflammatory biomarkers. AB - Chronic and inflammatory diseases are major causes of mortality. Although the anti-inflammatory effects of exercise have been confirmed, but the effect of different types of exercise on inflammatory markers is different. The aim of this study is comparing the effects of two types of sprint interval (SIT) and continuous endurance (CET) training on inflammatory markers. Sixteen students who had recreational activities participated in this study and were randomly assigned to one of the two protocols. The SIT protocol consisted of four to six 30-s "all out" Wingate tests separated by 4 minutes of recovery and The CET protocol included 90-120 minutes of cycling at 65% Vo2max. The two protocols were performed 3 days per week and for two weeks. In each group, two blood samples were collected before and 2 days (24 and 48 hrs) after the training. Results showed that there was no significant difference between the two training protocols on all measured parameters (p>0.05). The results of present study showed that the SIT and CET have identical effects on inflammatory markers. PMID- 23725448 TI - Switchable binding affinity of mannose tethered to collagen peptide by temperature-dependent triple-helix formation. AB - Novel glycopeptides were created with a view to regulate the bindings of carbohydrates to lectins as a means of controlling biological function. We synthesized glycopeptides containing mannose (Man) tethered to a collagen peptide moiety (MPOG10: -(Pro-Hyp-Gly)10- or MGPP10: -(Gly-Pro-Pro)10-). Circular dichroism spectra showed formation of a triple helical structure for MPOG10, and the melting temperature indicates that MPOG10 forms a more stable triple helical structure than MGPP10 in phosphate buffered saline (PBS). At 25 degrees C, fluorescence polarization (FP) values of MPOG10 and MGPP10 increased following the addition of concanavalin A (ConA), and the addition of alpha-methyl-mannose (MeMan) to a mixed solution of each glycopeptide with ConA resulted in a decrease in FP values. These results confirm that the previous increase in FP values observed was caused by ConA binding to Man on MPOG10 or MGPP10. The binding affinity of MPOG10 was higher than that of MGPP10, and the dissociation constant of MPOG10 to ConA was 1.9 * 10(-5) (mol/L). The observed binding of MPOG10 to ConA at 25 degrees C was reduced at higher temperature (50 degrees C). Therefore, the enhanced binding affinity of MPOG10 to ConA could be accounted for by formation of a clustered Man moiety triggered by the formation of a more stable triple helical structure of MPOG10 compared with MGPP10. PMID- 23725449 TI - Use of web-based shared medical records among patients with HIV. AB - OBJECTIVES: To compare use of 7 shared electronic medical record (SMR) features by adult HIV patients. STUDY DESIGN: Observational cohort study of adult HIV positive patients in the first 36 months following implementation of the SMR at Group Health and Kaiser Permanente Northern California. METHODS: Automated data from the 36 months following SMR implementation were assessed in 2 integrated delivery systems. Cox proportional hazards analysis identified factors associated with any SMR use. RESULTS: Most (3888/7398) patients used the SMR at least once. Users were most likely to view medical test results (49%), use secure messaging (43%), or request appointments (31%) or medication refills (30%). Initial use was associated with new prescription for antiretroviral therapy (rate ratio [RR] 1.65, P <.001), recent change to a CD4+ count of fewer than 200 cells per microliter (RR = 1.34, P <.02), new HIV RNA of 75 or more copies per milliliter (RR = 1.63, P <.001), or recent increase in non-HIV comorbidity score (RR = 1.49, P = .0001). Users were less likely to be women (RR = 0.49, P = .0001), injection drug users (RR = 0.59, P = .0001), or from lower-socioeconomic status neighborhoods (RR = 0.68, P = .0001), and were less likely to be black (RR = 0.38, P = .0001), Hispanic (RR = 0.52, P = .0001) or Asian/Pacific Islander (RR = 0.59, P = .001). CONCLUSIONS: SMR use was higher among HIV patients who had indicators of recent increases in healthcare needs and lower among several vulnerable populations. PMID- 23725450 TI - Trends in hospital-based childbirth care: the role of health insurance. AB - OBJECTIVES: Childbirth is the leading reason for hospitalization in the United States, and maternity related expenditures are substantial for many health insurance programs, including Medicaid. We studied the relationship between primary payer and trends in hospital-based childbirth care. STUDY DESIGNS: Retrospective analysis of hospital discharge data from the Nationwide Inpatient Sample (NIS) of the Healthcare Cost and Utilization Project, a 20% stratified sample of US hospitals. METHODS: Data on 6,717,486 hospital-based births for the years 2002 through 2009 came from the NIS. We used generalized estimating equations to measure associations over time between primary payer (Medicaid, private insurance, or self) and cesarean delivery, vaginal birth after cesarean (VBAC), labor induction, and episiotomy. RESULTS: Controlling for clinical, demographic, and hospital factors, births covered by Medicaid had lower odds of cesarean delivery (adjusted odds ratio [AOR], 0.91), labor induction (AOR, 0.73), and episiotomy (AOR, 0.62) and higher odds of VBAC (AOR, 1.20; P <.001 for all AORs) compared with privately insured births. Cesarean rates increased 6% annually among births paid by private insurance (AOR, 1.06; P <.001) and less rapidly (5% annually) among those covered by Medicaid. CONCLUSIONS: US hospital based births covered by private insurance were associated with higher rates of obstetric intervention than births paid for by Medicaid. After controlling for clinical, demographic, and hospital factors, cesarean delivery rates increased more rapidly among births covered by private insurance, compared with Medicaid. Changes in insurance coverage associated with healthcare reform may impact costs and quality of care for women giving birth in US hospitals. PMID- 23725451 TI - Primary nonadherence to statin therapy: patients' perceptions. AB - OBJECTIVES: To identify self-reported reasons for not filling a new prescription for statin therapy. STUDY DESIGN: A cross-sectional telephone survey. METHODS: Potential participants were identified from a randomized, controlled trial among Kaiser Permanente Southern California (KPSC) members aged >24 years with no record of redeeming a new statin medication, defined as primary nonadherence. Among 1158 eligible patients, 98 were randomly selected and participated in a semi-structured telephone interview that included questions on whether the respondent redeemed their statin prescription, why the patient may have chosen not to use a KPSC pharmacy, reasons for not filling the prescription, use of non prescription products for elevated cholesterol levels, and questions to assess health literacy. RESULTS: At 12 weeks post-index prescription date, 75% of 98 respondents reported not filling their new statin prescription, 20% reported picking it up from a non-KPSC pharmacy, 4% had already picked up the prescription at a KPSC pharmacy, and 1% did not know if it had been filled. The 3 most commonly cited reasons for primary nonadherence were general concerns about taking the medication (63%), a decision to try lifestyle modifications (63%), and fear of side effects (53%). A substantial proportion (33%) of respondents reported inadequate health literacy. CONCLUSIONS: These data suggest the need for interventions that address patients' negative perceptions of statins while emphasizing the benefits of statin therapy for reducing cardiovascular morbidity and mortality in formats accessible to those with limited health literacy. PMID- 23725452 TI - Disease management programs: barriers and benefits. AB - OBJECTIVES: The healthcare system in Israel faces difficulties similar to those of most industrialized countries, including limited resources, a growing chronically ill population, and demand for high quality care. Disease management programs (DMPs) for patients with a chronic illness aim to alleviate some of these problems, primarily by improving patient self-management skills and quality of care. This study surveyed the opinions of senior healthcare administrators regarding barriers, benefits, and support for implementing DMPs. STUDY DESIGN: Cross-sectional survey. METHODS: A 21-item questionnaire was self-completed by 87 of 105 (83%) healthcare administrators included in the study. Participants were 65.5% male and 47% physicians, 25.3% nurses, 17.3% administrators, and 10.3% other healthcare professionals. RESULTS: The main perceived benefit of DMPs among all respondents was improving quality of care. Other benefits noted were better contact with patients (81.6%) and better compliance with treatment (75.9%). Efficient long-term utilization of system resources was perceived as a benefit by only 58.6%. The main perceived barriers to implementing DMPs were lack of budgetary resources (69%) and increased time required versus financial compensation received (63.2%). CONCLUSIONS: The benefits of DMPs were patient oriented; barriers were perceived as financial and limiting professional autonomy. Information regarding long-term benefits (better patient outcomes) that ultimately provide better value for the system versus short-term barriers (increased costs and expenditures of time without compensation) might encourage the implementation of DMPs in countries faced with a growing population of patients with at least 1 chronic illness. PMID- 23725453 TI - Retail clinic utilization associated with lower total cost of care. AB - OBJECTIVES: To better understand the impact of retail clinic use on a patient's annual total cost of care. STUDY DESIGN: A propensity score matched-pair, cohort design was used to analyze healthcare spending patterns among CVS Caremark employees in the year following a visit to a MinuteClinic, the retail clinics inside CVS pharmacies. METHODS: De-identified medical and pharmacy claims for CVS Caremark employees and their dependents who received care at a retail clinic between June 1, 2009, and May 31, 2010, were matched to those of subjects who received care elsewhere. High-dimensional propensity score and greedy matching techniques were used to create a 1-to-1 matched cohort that was analyzed using generalized linear regression models. RESULTS: Individuals using a retail clinic had a lower total cost of care (-$262; 95% confidence interval, -$510 to -$31; P = .025) in the year following their clinic visit than individuals who received care in other settings. This savings was primarily due to lower medical expenses at physicians' offices ($77 savings, P = .008) and hospital inpatient care ($121 savings, P = .049). The 6022 retail clinic users also had 142 (12%) fewer emergency department visits (P = .01), though this was not related to significant cost savings. CONCLUSIONS: This study found that retail clinic use was associated with lower overall total cost of care compared with that at alternative sites. Savings may extend beyond the retail clinic visit itself to other types of medical utilization. PMID- 23725454 TI - Development of a highly visual, simple, and rapid test for the discovery of novel insulin mimetics in living vertebrates. AB - Diabetes mellitus is a global epidemic with major impacts on human health and society. Drug discovery for diabetes can be facilitated by the development of a rapid, vertebrate-based screen for identifying new insulin mimetic compounds. Our study describes the first development of a zebrafish-based system based on direct monitoring of glucose flux and validated for identifying novel anti-diabetic drugs. Our system utilizes a fluorescent-tagged glucose probe in an experimentally convenient 96-well plate format. To validate our new system, we identified compounds that can induce glucose uptake via activity-guided fractionation of the inner shell from the Japanese Chestnut (Castanea crenata). The best performing compound, UP3.2, was identified as fraxidin and validated as a novel insulin mimetic using a mammalian adipocyte system. Additional screening using sets of saponin- and triazine-based compounds was undertaken to further validate this assay, which led to the discovery of triazine PP-II-A03 as a novel insulin mimetic. Moreover, we demonstrate that our zebrafish-based system allows concomitant toxicological analysis of anti-diabetic drug candidates. Thus, we have developed a rapid and inexpensive vertebrate model that can enhance diabetes drug discovery by preselecting hits from chemical library screens, before testing in relatively expensive rodent assays. PMID- 23725455 TI - Electron-withdrawing trifluoromethyl groups in combination with hydrogen bonds in polyols: Bronsted acids, hydrogen-bond catalysts, and anion receptors. AB - Electron-withdrawing trifluoromethyl groups were characterized in combination with hydrogen-bond interactions in three polyols (i.e., CF3CH(OH)CH2CH(OH)CF3, 1; (CF3)2C(OH)C(OH)(CF3)2, 2; ((CF3)2C(OH)CH2)2CHOH, 3) by pKa measurements in DMSO and H2O, negative ion photoelectron spectroscopy and binding constant determinations with Cl(-). Their catalytic behavior in several reactions were also examined and compared to a Bronsted acid (HOAc) and a commonly employed thiourea ((3,5-(CF3)2C6H3NH)2CS). The combination of inductive stabilization and hydrogen bonds was found to afford potent acids which are effective catalysts. It also appears that hydrogen bonds can transmit the inductive effect over distance even in an aqueous environment, and this has far reaching implications. PMID- 23725456 TI - Inositol pyrophosphates: between signalling and metabolism. AB - The present review will explore the insights gained into inositol pyrophosphates in the 20 years since their discovery in 1993. These molecules are defined by the presence of the characteristic 'high energy' pyrophosphate moiety and can be found ubiquitously in eukaryotic cells. The enzymes that synthesize them are similarly well distributed and can be found encoded in any eukaryote genome. Rapid progress has been made in characterizing inositol pyrophosphate metabolism and they have been linked to a surprisingly diverse range of cellular functions. Two decades of work is now beginning to present a view of inositol pyrophosphates as fundamental, conserved and highly important agents in the regulation of cellular homoeostasis. In particular it is emerging that energy metabolism, and thus ATP production, is closely regulated by these molecules. Much of the early work on these molecules was performed in the yeast Saccharomyces cerevisiae and the social amoeba Dictyostelium discoideum, but the development of mouse knockouts for IP6K1 and IP6K2 [IP6K is IP6 (inositol hexakisphosphate) kinase] in the last 5 years has provided very welcome tools to better understand the physiological roles of inositol pyrophosphates. Another recent innovation has been the use of gel electrophoresis to detect and purify inositol pyrophosphates. Despite the advances that have been made, many aspects of inositol pyrophosphate biology remain far from clear. By evaluating the literature, the present review hopes to promote further research in this absorbing area of biology. PMID- 23725457 TI - Aggrephagy: lessons from C. elegans. AB - Autophagy is a lysosome-mediated degradation process that involves the formation of an enclosed double-membrane autophagosome. Yeast genetic screens have laid the groundwork for a molecular understanding of autophagy. The process, however, exhibits fundamental differences between yeast and higher eukaryotes. Very little is known about essential autophagy components specific to higher eukaryotes. Recent studies have shown that a variety of protein aggregates are selectively removed by autophagy (a process termed aggrephagy) during Caenorhabditis elegans embryogenesis, establishing C. elegans as a multicellular genetic model to delineate the autophagic machinery. The genetic screens were carried out in C. elegans to identify essential autophagy genes. In addition to conserved and divergent homologues of yeast Atg proteins, several autophagy genes conserved in higher eukaryotes, but absent from yeast, were isolated. The genetic hierarchy of autophagy genes in the degradation of protein aggregates in C. elegans provides a framework for understanding the concerted action of autophagy genes in the aggrephagy pathway. PMID- 23725458 TI - AKT-ing out: SGK kinases come to the fore. AB - The success of targeted therapies in treating cancer over the last decade has been tempered by acquired drug resistance that follows long-term treatment. There is also emerging evidence for innate mechanisms of cancer cell resistance to targeted therapy that pre-exist as parallel signalling pathways. This aspect is explored by the Alessi group and collaborators from AstraZeneca in this issue of the Biochemical Journal, who identify a subset of breast cancer cell lines that are intrinsically resistant to Akt inhibition through constitutive up-regulation of the related AGC serine/threonine kinase SGK1 (serum- and glucocorticoid regulated kinase 1). The study could help to profile tumours for sensitivity to Akt inhibitors and once more highlights the therapeutic complexity of cancer and the importance of exploring combination therapies in the clinic. PMID- 23725459 TI - Adapting glycolysis to cancer cell proliferation: the MAPK pathway focuses on PFKFB3. AB - Besides the necessary changes in the expression of cell cycle-related proteins, cancer cells undergo a profound series of metabolic adaptations focused to satisfy their excessive demand for biomass. An essential metabolic transformation of these cells is increased glycolysis, which is currently the focus of anticancer therapies. Several key players have been identified, so far, that adapt glycolysis to allow an increased proliferation in cancer. In this issue of the Biochemical Journal, Novellasdemunt and colleagues elegantly identify a novel mechanism by which MK2 [MAPK (mitogen-activated protein kinase)-activated protein kinase 2], a key component of the MAPK pathway, up-regulates glycolysis in response to stress in cancer cells. The authors found that, by phosphorylating specific substrate residues, MK2 promotes both increased the gene transcription and allosteric activation of PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6 bisphosphatase 3), a key glycolysis-promoting enzyme. These results reveal a novel pathway through which MK2 co-ordinates metabolic adaptation to cell proliferation in cancer and highlight PFKFB3 as a potential therapeutic target in this devastating disease. PMID- 23725460 TI - An abnormal bone lesion of the scapula in a collegiate basketball player: a case report. AB - OBJECTIVE: To present the case of a bone lesion of the scapula in a collegiate basketball player. BACKGROUND: A 19-year-old National Collegiate Athletic Association Division I male basketball player presented with pain in the posterior region of the right shoulder. During practice, he was performing a layup when his arm was forced into hyperflexion by a defender. Evaluation revealed a bone lesion involving the scapular spine and base of the acromion. DIFFERENTIAL DIAGNOSIS: Acromioclavicular joint sprain, subacromial bursitis, subscapular bursitis, humeral head contusion, acromial fracture. TREATMENT: The patient was treated for 2 months with therapeutic modalities and rehabilitation exercises. Because of persistent pain and the risk of a pathologic fracture, open surgical biopsy and bone grafting were then undertaken. UNIQUENESS: Most simple bone cysts affect the proximal humerus and femur, whereas our patient's lesion was in the acromial complex. CONCLUSIONS: Athletic trainers should be alert to the unusual possibility of bone cysts, which are usually identified incidentally when radiographs are obtained for other reasons. Most simple bone cysts are asymptomatic, but a pathologic fracture can occur with trauma. PMID- 23725461 TI - Female athletic training students' perceptions of motherhood and retention in athletic training. AB - CONTEXT: Motherhood appears to be a catalyst in job turnover for female athletic trainers, especially those employed at the National Collegiate Athletic Association Division I level. However, most researchers examining this topic have investigated the perspectives of those who are currently employed rather than those who are preparing to enter the profession. OBJECTIVE: To evaluate female athletic training students' perceptions of motherhood and retention. DESIGN: Qualitative study. SETTING: Athletic training education program. PATIENTS OR OTHER PARTICIPANTS: A total of 18 female athletic training students volunteered to participate. They were enrolled in 1 Commission on Accrediting Athletic Training Education-accredited athletic training program and represented 3 levels of academic STUDY. DATA COLLECTION AND ANALYSIS: The participants responded to a series of questions related to work-life balance and retention in athletic training. Analysis of the data followed a general inductive process. Credibility was established by interpretive member checks and peer review. RESULTS: The first theme, clinical setting, speaks to the belief that work-life balance and retention in athletic training require an employment setting that fosters a family-friendly atmosphere and a work schedule (including travel) that allows for time at home. The second theme, mentorship, reflects the acknowledgment that a female mentor who is successful in balancing the roles of mother and athletic trainer can serve as a role model. The final theme, work-life balance strategies, illustrates the need to have a plan in place to meet the demands of both home and work life. CONCLUSIONS: A female athletic trainer who is successfully balancing her career and family responsibilities may be the most helpful factor in retention, especially for female athletic training students. Young professionals need to be educated on the importance of developing successful work-life balance strategies, which can be helpful in reducing attrition from the profession. PMID- 23725462 TI - Muscle heating with Megapulse II shortwave diathermy and ReBound diathermy. AB - CONTEXT: A new continuous diathermy called ReBound recently has been introduced. Its effectiveness as a heating modality is unknown. OBJECTIVE: To compare the effects of the ReBound diathermy with an established deep-heating diathermy, the Megapulse II pulsed shortwave diathermy, on tissue temperature in the human triceps surae muscle. DESIGN: Crossover study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: Participants included 12 healthy, college-aged volunteers (4 men, 8 women; age = 22.2 +/- 2.25 years, calf subcutaneous fat thickness = 7.2 +/- 1.9 mm). INTERVENTION(S): Each modality treatment was applied to the triceps surae muscle group of each participant for 30 minutes. After 30 minutes, we removed the modality and recorded temperature decay for 20 minutes. MAIN OUTCOME MEASURE(S): We horizontally inserted an implantable thermocouple into the medial triceps surae muscle to measure intramuscular tissue temperature at 3 cm deep. We measured temperature every 5 minutes during the 30-minute treatment and each minute during the 20-minute temperature decay. RESULTS: Tissue temperature at a depth of 3 cm increased more with Megapulse II than with ReBound diathermy over the course of the treatment (F6,66 = 10.78, P < .001). ReBound diathermy did not produce as much intramuscular heating, leading to a slower heat dissipation rate than the Megapulse II (F20,220 = 28.84, P < .001). CONCLUSIONS: During a 30-minute treatment, the Megapulse II was more effective than ReBound diathermy at increasing deep, intramuscular tissue temperature of the triceps surae muscle group. PMID- 23725463 TI - Have androgen receptor gene CAG and GGC repeat polymorphisms an effect on sperm motility in infertile men? AB - Androgens and a normal androgen receptor (AR) are required for normal spermatogenesis. We investigated polyglutamine (CAG) and a polyglycine (GGC) tract in Italian men with defective spermatogenesis. We studied a group of 40 infertile men with spermatogenesis failure without Y-chromosome microdeletions compared with 60 normozoospermic ones. The distributions of both polymorphisms, within the normal range of Caucasian populations, were similar among infertile men and controls. Nonetheless, we observed that the frequency comparison of each CAG allele showed a statistical difference in the allele CAG 22; GGC 17 was the more predominant allele in infertile men than in controls. Moreover, to investigate the hypothesis that semen characteristics are perturbed by androgen receptor allele variants, we tried to detect a link between triplets and sperm motility in all subjects (cases plus controls). Subjects were subdivided into three groups, based on calculated allele frequencies. A significantly decreased motility, related to a longer CAG and GGC tracts, and marked differences between the groups exist for both polymorphisms. Our data highlight a probable relationship between the allele CAG 22/GGC 17 and a defective spermatogenesis in infertile men, suggesting that these polymorphisms might have an important effect on AR function. PMID- 23725464 TI - Roseomonas bacteremia in a recipient of an allogeneic hematopoietic stem cell transplantation. AB - Roseomonas are pink-pigmented, oxidative, slowly growing, nonfermentative, gram negative coccobacilli whose identification may require extensive biochemical testing and molecular profiling. Roseomonas infections vary in severity and clinical presentation, and they predominantly occur in immunocompromised and chronically ill patients. The organism is generally susceptible to carbapenems and aminoglycosides, but resistant to most of the cephalosporins and broad spectrum penicillins. Reported here is a patient with lymphoblastic lymphoma who developed Roseomonas mucosa bacteremia after receiving her hematopoietic stem cell allograft. The bacteremic episode was successfully treated with imipenem and amikacin in addition to removal of the central venous catheter. To our knowledge, this is the first report of Roseomonas bacteremia in a stem cell transplantation recipient. PMID- 23725465 TI - Participation in children with disabilities--a public health perspective. PMID- 23725466 TI - PMTED: a plant microRNA target expression database. AB - BACKGROUND: MicroRNAs (miRNAs) are identified in nearly all plants where they play important roles in development and stress responses by target mRNA cleavage or translation repression. MiRNAs exert their functions by sequence complementation with target genes and hence their targets can be predicted using bioinformatics algorithms. In the past two decades, microarray technology has been employed to study genes involved in important biological processes such as biotic response, abiotic response, and specific tissues and developmental stages, many of which are miRNA targets. Despite their value in assisting research work for plant biologists, miRNA target genes are difficult to access without pre processing and assistance of necessary analytical and visualization tools because they are embedded in a large body of microarray data that are scattered around in public databases. DESCRIPTION: Plant MiRNA Target Expression Database (PMTED) is designed to retrieve and analyze expression profiles of miRNA targets represented in the plethora of existing microarray data that are manually curated. It provides a Basic Information query function for miRNAs and their target sequences, gene ontology, and differential expression profiles. It also provides searching and browsing functions for a global Meta-network among species, bioprocesses, conditions, and miRNAs, meta-terms curated from well annotated microarray experiments. Networks are displayed through a Cytoscape Web-based graphical interface. In addition to conserved miRNAs, PMTED provides a target prediction portal for user-defined novel miRNAs and corresponding target expression profile retrieval. Hypotheses that are suggested by miRNA-target networks should provide starting points for further experimental validation. CONCLUSIONS: PMTED exploits value-added microarray data to study the contextual significance of miRNA target genes and should assist functional investigation for both miRNAs and their targets. PMTED will be updated over time and is freely available for non-commercial use at http://pmted.agrinome.org. PMID- 23725467 TI - Pseudomonas syringae pv. tomato DC3000: a model pathogen for probing disease susceptibility and hormone signaling in plants. AB - Since the early 1980s, various strains of the gram-negative bacterial pathogen Pseudomonas syringae have been used as models for understanding plant-bacterial interactions. In 1991, a P. syringae pathovar tomato (Pst) strain, DC3000, was reported to infect not only its natural host tomato but also Arabidopsis in the laboratory, a finding that spurred intensive efforts in the subsequent two decades to characterize the molecular mechanisms by which this strain causes disease in plants. Genomic analysis shows that Pst DC3000 carries a large repertoire of potential virulence factors, including proteinaceous effectors that are secreted through the type III secretion system and a polyketide phytotoxin called coronatine, which structurally mimics the plant hormone jasmonate (JA). Study of Pst DC3000 pathogenesis has not only provided several conceptual advances in understanding how a bacterial pathogen employs type III effectors to suppress plant immune responses and promote disease susceptibility but has also facilitated the discovery of the immune function of stomata and key components of JA signaling in plants. The concepts derived from the study of Pst DC3000 pathogenesis may prove useful in understanding pathogenesis mechanisms of other plant pathogens. PMID- 23725468 TI - Manipulation of host proteasomes as a virulence mechanism of plant pathogens. AB - The ubiquitin-26S proteasome degradation system (UPS) in plants is involved in the signal transduction of many cellular processes, including host immune responses triggered by pathogen attack. Attacking pathogens produce effectors that are translocated into host cells, where they interfere with the host's defense signaling in very specific ways. Perhaps not surprising in view of the broad involvement of the host proteasome in plant immunity, certain bacterial effectors exploit or require the host UPS for their action, as currently best studied in Pseudomonas syringae. Intriguingly, some P. syringae strains also secrete the virulence factor syringolin A, which irreversibly inhibits the proteasome by a novel mechanism. Here, the role of the UPS in plant defense and its exploitation by effectors are summarized, and the biology, taxonomic distribution, and emerging implications for virulence strategies of syringolin A and similar compounds are discussed. PMID- 23725469 TI - Considerations of scale in the analysis of spatial pattern of plant disease epidemics. AB - Scale is an important but somewhat neglected subject in plant pathology. Scale serves as an abstract concept, providing a framework for organizing observations and theoretical models, and plays a functional role in the organization of ecological communities and physical processes. Rich methodological resources are available to plant pathologists interested in considering either or both aspects of scale in their research. We summarize important concepts in both areas of the literature, particularly as they apply to the spatial pattern of plant disease, and highlight some new results that emphasize the importance of scaling on the emergence of different types of probability distribution in empirical observation. We also highlight the important links between heterogeneity and scale, which are of central importance in plant disease epidemiology and the analysis of spatial pattern. We consider statistical approaches that are available, where actual physical scale is known, and for more conceptual research on hierarchies, where scale plays a more abstract role, particularly for field based research. For the latter, we highlight methods that plant pathologists could consider to account for the effect of scale in the design of field studies. PMID- 23725470 TI - Diseases in intercropping systems. AB - Intercropping, the simultaneous cultivation of multiple crop species, has been used throughout history and remains common among farmers of small landholdings in the tropics. One benefit of this practice may be disease control. In phenomenological research comparing disease in monocrops and intercrops, primarily due to foliar fungi, intercropping reduced disease in 73% of more than 200 studies. Nematodes are the primary pathogen for which disease increases are reported, but variability in disease impacts among studies can be high for all types of diseases. The mechanisms by which intercrops affect disease dynamics include alteration of wind, rain, and vector dispersal; modification of microclimate, especially temperature and moisture; changes in host morphology and physiology; and direct pathogen inhibition. The effect of intercropping on host density is a factor underlying many of these mechanisms. By synthesizing our growing understanding of mechanisms and their interactions with phenomenological studies, we may develop a theoretical grounding that allows us to improve the application of intercropping for tropical smallholders and industrial farmers alike. PMID- 23725471 TI - The role of prophage in plant-pathogenic bacteria. AB - A diverse set of phage lineages is associated with the bacterial plant-pathogen genomes sequenced to date. Analysis of 37 genomes revealed 5,169 potential genes (approximately 4.3 Mbp) of phage origin, and at least 50% had no function assigned or are nonessential to phage biology. Some phytopathogens have transcriptionally active prophage genes under conditions that mimic plant infection, suggesting an association between plant disease and prophage transcriptional modulation. The role of prophages within genomes for cell biology varies. For pathogens such as Pectobacterium, Pseudomonas, Ralstonia, and Streptomyces, involvement of prophage in disease symptoms has been demonstrated. In Xylella and Xanthomonas, prophage activity is associated with genome rearrangements and strain differentiation. For other pathogens, prophage roles are yet to be established. This review integrates available information in a unique interface ( http://propnav.esalq.usp.br ) that may be assessed to improve research in prophage biology and its association with genome evolution and pathogenicity. PMID- 23725472 TI - Engineering plant disease resistance based on TAL effectors. AB - Transcription activator-like (TAL) effectors are encoded by plant-pathogenic bacteria and induce expression of plant host genes. TAL effectors bind DNA on the basis of a unique code that specifies binding of amino acid residues in repeat units to particular DNA bases in a one-to-one correspondence. This code can be used to predict binding sites of natural TAL effectors and to design novel synthetic DNA-binding domains for targeted genome manipulation. Natural mechanisms of resistance in plants against TAL effector-containing pathogens have given insights into new strategies for disease control. PMID- 23725473 TI - Nonhost resistance against bacterial pathogens: retrospectives and prospects. AB - Nonhost resistance is a broad-spectrum plant defense that provides immunity to all members of a plant species against all isolates of a microorganism that is pathogenic to other plant species. Upon landing on the surface of a nonhost plant species, a potential bacterial pathogen initially encounters preformed and, later, induced plant defenses. One of the initial defense responses from the plant is pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI). Nonhost plants also have mechanisms to detect nonhost-pathogen effectors and can trigger a defense response referred to as effector-triggered immunity (ETI). This nonhost resistance response often results in a hypersensitive response (HR) at the infection site. This review provides an overview of these plant defense strategies. We enumerate plant genes that impart nonhost resistance and the bacterial counter-defense strategies. In addition, prospects for application of nonhost resistance to achieve broad-spectrum and durable resistance in crop plants are also discussed. PMID- 23725474 TI - Performance comparison of the medtronic sof-sensor and enlite glucose sensors in inpatient studies of individuals with type 1 diabetes. AB - OBJECTIVE: Knowledge of the accuracy of continuous glucose monitoring (CGM) devices is important for its use as a management tool for individuals with diabetes and for its use to assess outcomes in clinical studies. Using data from several inpatient studies, we compared the accuracy of two sensors, the Medtronic EnliteTM using MiniMed Paradigm((r)) VeoTM calibration and the Sof-Sensor((r)) glucose sensor using Guardian((r)) REAL-Time CGM calibration (all from Medtronic Diabetes, Northridge, CA). SUBJECTS AND METHODS: Nocturnal data were analyzed from eight inpatient studies in which both CGM and reference glucose measurements were available. The analyses included 1,666 CGM-reference paired glucose values for the Enlite in 54 participants over 69 nights and 3,627 paired values for the Sof-Sensor in 66 participants over 91 nights. RESULTS: The Enlite sensor tended to report glucose levels lower than the reference over the entire range of glucose values, whereas the Sof-Sensor values tended to be higher than reference values in the hypoglycemic range and lower than reference values in the hyperglycemic range. The overall median sensor-reference difference was -15 mg/dL for the Enlite and -1 mg/dL for the Sof-Sensor (P<0.001). The median relative absolute difference was 15% for the Enlite versus 12% for the Sof-Sensor (P=0.06); 66% of Enlite values and 73% of Sof-Sensor values met International Organization for Standardization criteria. CONCLUSIONS: We found that the Enlite tended to be biased low over the entire glucose range, whereas the Sof-Sensor showed the more typical sensor pattern of being biased high in the hypoglycemic range and biased low in the hyperglycemic range. PMID- 23725475 TI - A common polymorphic allele of the LH beta-subunit gene is associated with higher exogenous FSH consumption during controlled ovarian stimulation for assisted reproductive technology. AB - BACKGROUND: V-betaLH is a common genetic variant of LH caused by two polymorphic base changes in the beta subunit gene, altering the amino acid sequence (Trp8Arg and Ile15Thr). In a previous-preliminary trial performed in women undergoing IVF, it was demonstrated that carriers of v-betaLH show sub-optimal ovarian response to a standard long GnRH-agonist down -regulation protocol when stimulated with pure recombinant FSH (r-hFSH). The aim of this study was to confirm the hypothesis that women with v-betaLH display hypo-sensitivity to exogenous FSH in a larger IVF population and to explore the frequency of this variant in a Danish female population. METHODS: In the present study, the effect of v-betaLH was retrospectively investigated in a larger series of women undergoing controlled ovarian stimulation (COS) and, for the first time, in a Danish IVF population. A total of 220 normogonadotrophic women following a long GnRH-agonist down regulation protocol received an individualized dose of r-hFSH (100 IU and 375 IU s.c. daily) according to antral follicle count, baseline FSH, body mass index and age. The LH genotype was assessed in all patients by immunofluorometric assay. RESULTS: V-betaLH was present in 11% of patients, whereas the allelic frequency was 12%. The study population was divided into two groups according to their LH genotype. Group A consisted of 196 wt/wt women. Group B included 24 individuals with v-betaLH (21 heterozygous and 3 homozygous). No statistically significant differences in the mean number of oocytes retrieved, fertilization rate and pregnancy rate per cycle were observed between groups. However, Group B received a significantly higher cumulative-dose of r-hFSH than Group A (2435.86 +/- 932.8 IU versus 1959.8 +/- 736.45 p = 0.048). When one-way ANOVA in a within design was applied, the LH genotype had a statistically significant effect (p < 0.01) on the cumulative dose of r-hFSH, showing a progressive increase from wt/wt (1959.8 +/- 736.45 IU) to v-betaLH hetero- (2267.5 +/- 824.3) and homozygotic women (3558.3 +/- 970.9). CONCLUSIONS: These results confirm that carriers exhibit hypo sensitivity to exogenous FSH during COS, documenting that the frequency of v betaLH in Denmark is similar to a number of European countries. PMID- 23725476 TI - MicroRNA-491 is involved in metastasis of hepatocellular carcinoma by inhibitions of matrix metalloproteinase and epithelial to mesenchymal transition. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide; the prognosis of HCC patient remains poor owing to intrahepatic and extrahepatic metastasis and postsurgical recurrence. The aim of the present study is to determine the molecular mechanisms underlying the metastasis of HCC. METHODS: HCC patients and treated HCC cells were molecularly characterized by miRNA microarray analysis, qRT-PCR, Western blots, transwell assay, and immunohistochemistry. RESULTS: Here, by employing a miRNAs microarray analysis, we found that miR-491 level was the most significant down regulation in poorly differentiated HCC tissue compared with well-differentiated HCC tissue. We then selected HepG2 (very low migratory capacity), MHCC97L (low migratory capacity) and MHCC97H (high migratory capacity), as well as HCC tissues with different status to further investigate the effects of miR-491 on the metastasis of HCC. Our data showed that miR-491 levels were inversely correlated with different status of differentiation in HCC tissues and with migratory potential in HCC cell lines. In HepG2 cells, inhibition of miR-491 increased the expression of matrix metalloproteinase 2/9 (MMP-2/9) and the migratory potential; however, in MHCC97H cells, overexpression of miR-491 level decreased the expression of MMP-2/9 and the migratory capacity. Moreover, miR-491 had a positive relationship with E-cadherin level; however, it had a negative relationship with vimentin level both in cell lines and tissue samples of HCC. MiR-491 levels of non-metastasis HCC tissue are higher than that of metastasis HCC tissue. CONCLUSION: Our results suggest that miR-491 is involved in metastasis of HCC by blocking EMT and decreasing MMP-9 levels, which may provide a new clue for preventing tumour metastasis of HCC. PMID- 23725477 TI - Development process and initial validation of the Ethical Conflict in Nursing Questionnaire-Critical Care Version. AB - BACKGROUND: Ethical conflicts are arising as a result of the growing complexity of clinical care, coupled with technological advances. Most studies that have developed instruments for measuring ethical conflict base their measures on the variables 'frequency' and 'degree of conflict'. In our view, however, these variables are insufficient for explaining the root of ethical conflicts. Consequently, the present study formulates a conceptual model that also includes the variable 'exposure to conflict', as well as considering six 'types of ethical conflict'. An instrument was then designed to measure the ethical conflicts experienced by nurses who work with critical care patients. The paper describes the development process and validation of this instrument, the Ethical Conflict in Nursing Questionnaire Critical Care Version (ECNQ-CCV). METHODS: The sample comprised 205 nursing professionals from the critical care units of two hospitals in Barcelona (Spain). The ECNQ-CCV presents 19 nursing scenarios with the potential to produce ethical conflict in the critical care setting. Exposure to ethical conflict was assessed by means of the Index of Exposure to Ethical Conflict (IEEC), a specific index developed to provide a reference value for each respondent by combining the intensity and frequency of occurrence of each scenario featured in the ECNQ-CCV. Following content validity, construct validity was assessed by means of Exploratory Factor Analysis (EFA), while Cronbach's alpha was used to evaluate the instrument's reliability. All analyses were performed using the statistical software PASW v19. RESULTS: Cronbach's alpha for the ECNQ-CCV as a whole was 0.882, which is higher than the values reported for certain other related instruments. The EFA suggested a unidimensional structure, with one component accounting for 33.41% of the explained variance. CONCLUSIONS: The ECNQ-CCV is shown to a valid and reliable instrument for use in critical care units. Its structure is such that the four variables on which our model of ethical conflict is based may be studied separately or in combination. The critical care nurses in this sample present moderate levels of exposure to ethical conflict. This study represents the first evaluation of the ECNQ-CCV. PMID- 23725478 TI - Experimental assessment of CO2-mineral-toxic ion interactions in a simplified freshwater aquifer: implications for CO2 leakage from deep geological storage. AB - The possible intrusion of CO2 into a given freshwater aquifer due to leakage from deep geological storage involves a decrease in pH, which has been directly associated with the remobilization of hazardous trace elements via mineral dissolution and/or via desorption processes. In an effort to evaluate the potential risks to potable water quality, the present study is devoted to experimental investigation of the effects of CO2 intrusion on the mobility of toxic ions in simplified equilibrated aquifers. We demonstrate that remobilization of trace elements by CO2 intrusion is not a universal physicochemical effect. In fact goethite and calcite, two minerals frequently found in aquifers, could successfully prevent the remobilization of adsorbed Cu(II), Cd(II), Se(IV), and As(V) if CO2 is intruded into a drinking water aquifer. Furthermore, a decrease in pH resulting from CO2 intrusion could reactivate the adsorption of Se(IV) and As(V) if goethite and calcite are sufficiently available in underground layers. Our results also suggest that adsorption of cadmium and copper could be promoted by calcite dissolution. These adsorbed ions on calcite are not remobilized when CO2 is intruded into the system, but it intensifies calcite dissolution. On the other hand, arsenite As(III) is significantly adsorbed on goethite, but is partially remobilized by CO2 intrusion. PMID- 23725479 TI - The impact of flattening-filter-free beam technology on 3D conformal RT. AB - BACKGROUND: The removal of the flattening filter (FF) leads to non-uniform fluence distribution with a considerable increase in dose rate. It is possible to adapt FFF beams (flattening-filter-free) in 3D conformal radiation therapy (3D CRT) by using field in field techniques (FiF). The aim of this retrospective study is to clarify whether the quality of 3D CRT plans is influenced by the use of FFF beams. METHOD: This study includes a total of 52 CT studies of RT locations that occur frequently in clinical practice. Dose volume targets were provided for the PTV of breast (n=13), neurocranium (n=11), lung (n=7), bone metastasis (n=10) and prostate (n=11) in line with ICRU report 50/62. 3D CRT planning was carried out using FiF methods. Two clinically utilized photon energies are used for a Siemens ARTISTE linear accelerator in FFF mode at 7MVFFF and 11MVFFF as well as in FF mode at 6MVFF and 10MVFF. The plan quality in relation to the PTV coverage, OAR (organs at risk) and low dose burden as well as the 2D dosimetric verification is compared with FF plans. RESULTS: No significant differences were found between FFF and FF plans in the mean dose for the PTV of breast, lung, spine metastasis and prostate. The low dose parameters V5Gy and V10Gy display significant differences for FFF and FF plans in some subgroups. The DVH analysis of the OAR revealed some significant differences. Significantly more fields (1.9-4.5) were necessary in the use of FFF beams for each location (p<0.0001) in order to achieve PTV coverage. All the tested groups displayed significant increases (1.3-2.2 times) in the average number of necessary MU with the use of FFF beams (p<0.001). CONCLUSIONS: This study has shown that the exclusive use of a linear accelerator in FFF mode is feasible in 3D CRT. It was possible to realize RT plans in comparable quality in typical cases of clinical radiotherapy. The 2D dosimetric validation of the modulated fields verified the dose calculation and thus the correct reproduction of the characteristic FFF parameters in the planning system that was used. PMID- 23725480 TI - Multicentre, randomized, phase III study of a single dose of incobotulinumtoxinA, free from complexing proteins, in the treatment of glabellar frown lines. PMID- 23725481 TI - Threshold photoionization of fluorenyl, benzhydryl, diphenylmethylene, and their dimers. AB - Two pi-conjugated radicals, fluorenyl (C13H9) and benzhydryl (C13H11), as well as the carbene diphenylmethylene (C13H10) were studied by imaging photoelectron photoion coincidence spectroscopy using VUV synchrotron radiation. The reactive intermediates were generated by flash pyrolysis from 9-bromofluorene and alpha aminodiphenylmethane (adpm), respectively. Adiabatic ionization energies (IEad) for all three species were extracted. Values of 7.01 +/- 0.02 eV for fluorenyl and 6.7 +/- 0.1 eV for benzhydryl are reported. For the triplet diphenylmethylene, an IEad of 6.8 +/- 0.1 eV is found. The dissociative photoionization of 9-bromofluorene, the precursor for fluorenyl, was also studied and modeled with an SSACM approach, yielding an appearance energy AE0K(C13H9(+)/C13H9Br) of 9.4 eV. All experimental values are in very good agreement with computations. For fluorenyl, the IEad agrees well with earlier values, while for the benzhydryl radical, we report a value that is more than 0.6 eV lower than the one previously reported. The geometry change upon ionization is small for all three species. Although individual vibrational bands cannot be resolved, some vibrational transitions in the threshold photoelectron spectrum of fluorenyl are tentatively assigned based on a Franck-Condon simulation. In addition, the dimerization products of fluorenyl and the benzhydryl radical were detected. Ionization energies of (7.69 +/- 0.04) and (8.11 +/- 0.04) eV were determined for C26H18 and C26H22, respectively. On the basis of the ionization energies, we identified both molecules to be the direct dimerization products, formed in the pyrolysis without further rearrangement. Both dimers might be expected to play a role in soot formation because the radical monomers do appear in flames. PMID- 23725482 TI - Complete mitochondrial genome of the common cuttlefish Sepia pharaonis (Sepioidea, Sepiidae). AB - In this study, the complete mitochondrial genome of the common cuttlefish Sepia pharaonis was determined first. The genome was 16,208 bp in length and contained 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and 2 main non-coding regions [both are control regions (CR)], the gene composition and order of which were similar to most other invertebrates. The overall base composition of S. pharaonis is T: 36.3%, C: 14.7%, A: 40.9% and G: 8.1%, with a hightly A + T bias of 77.2%. Two control regions all contain termination associated sequences and conserved sequence blocks. This mitogenome sequence data would play an important role in the investigations of the phylogenetic relationships, taxonomic resolution and phylogeography of the Sepiidae. PMID- 23725483 TI - The complete mitochondrial genome sequence of Sarcocheilichthys sinensis sinensis (Cypriniformes: Cyprinidae). AB - In this study, the total mitochondrial genome of Sarcocheilichthys sinensis sinensis (Cypriniformes: Cyprinidae) was firstly determined. The genome is 16,683 bases in length. It consists of 13 protein-coding genes, 22 tRNA genes, 2 rRNA genes and 2 non-coding regions. The overall nucleotide composition of the H strand of S. sinensis sinensis mitochondrial genome is A: 30.48%, G: 16.65%, T: 26.30% and C: 26.58%, respectively, with an A + T rich feature (56.78%). These results provide useful data to further study of the molecular systematics, species identification and conservation genetics. PMID- 23725484 TI - Medical risk factors of diabetes mellitus among professional drivers. AB - BACKGROUND: Road transport drivers are one of the professional groups whose activities have a strong impact of public safety. In view of the natural professional activity, the drivers are at a higher risk of obesity, hypertension and hyperlipidemia, and carbohydrate metabolism disorders such as diabetes mellitus. MATERIALS AND METHODS: Medical documentation was the source of data for the reported study. It derived from medical examinations of 1903 drivers applying for driving license. RESULTS: Hyperglycemia was found in 52.1% of the drivers, 9.1% of them were in diabetic stage, and with HbA1C criteria 77.6% of these drivers were in this stage. Excessive body weight was recorded in 65.6% of the study population, 44.8% were diagnosed with overweight and 20.8% with obesity. High blood pressure was recorded in 16.4% of drivers. CONCLUSION: High prevalence of excessive body weight and high blood pressure and hyperlipidemia are risk factors for diabetes mellitus in professional drivers that indicates a need to undertake multidimensional actions target on this particular profession and involving various health care sectors. Prophylactic and detailed pre-placement examinations should be considered, depending on the rate and the intensity of disorders. These should be coupled with an introduction of primary and secondary prophylactic activities and monitoring of relevant treatment. PMID- 23725485 TI - Proximal metatarsal osteotomy for hallux valgus: an audit of radiologic outcome after single screw fixation and full postoperative weightbearing. AB - BACKGROUND: Proximal metatarsal osteotomy combined with a distal soft-tissue procedure is a common treatment for moderate to severe hallux valgus. Secure stabilisation of the metatarsal osteotomy is necessary to avoid complications such as delayed union, nonunion or malunion as well as loss of correction. The aim of this study was to report our results using a single screw for stabilisation of the osteotomy. METHODS: We retrospectively reviewed 151 patients with severe hallux valgus who were treated by the above mentioned way with full postoperative weightbearing in a stiff soled shoe. Mean age of patients at time of surgery was 54 years, 19 patients were male and 132 female. Assessment of clinical and radiographic results was performed after 2 days and 6 weeks. Results were also correlated to the experience of the performing surgeon. RESULTS: Mean preoperative HVA (hallux valgus angle) was 36.4 degrees, and then 3.5 degrees 2 days and 13.4 degrees 6 weeks after the procedure (p < 0.001). Mean preoperative IMA (intermetarsal angle) was 16.8 degrees, and then 6.4 degrees after 2 days and 9.8 degrees after 6 weeks (p < 0.001). Mean preoperative first metatarsal length of 56.4 mm decreased to 53.6 mm after 6 weeks. Possible non-union of the osteotomy was observed in 4 patients (2.6%) after 6 weeks. Performing residents (n = 40) operated in 65 minutes and attending surgeons (n = 111) in 45 minutes, with no significant differences in radiographic measurements between both groups. CONCLUSIONS: Single screw stabilisation of proximal chevron osteotomy is a reliable method for treating severe hallux valgus deformities with satisfactory results. PMID- 23725486 TI - Mapping peptide thiol accessibility in membranes using a quaternary ammonium isotope-coded mass tag (ICMT). AB - The plasma membrane contains a diverse array of proteins, including receptors, channels, and signaling complexes, that serve as decision-making centers. Investigation of membrane protein topology is important for understanding the function of these types of protein. Here, we report a method to determine protein topology in the membrane that utilizes labeling of cysteine with isotope-coded mass tags. The mass tags contain a thiol reactive moiety, linker, and a quaternary ammonium group to aid ionization in the mass spectrometer and were synthesized in both light and heavy (deuterated) forms. The probes were found to be membrane impermeable when applied to lipid vesicles. To assess the utility of the probes for mapping peptide thiol topology, we employed a two-step labeling procedure. Vesicles containing alpha-helical transmembrane peptides were labeled with heavy (or light) probe, solubilized by detergent, and then labeled by an excess of the complementary probe. Peptide for which the cysteine was oriented in the center of the lipid bilayer was not labeled until the lipid vesicles were lysed with detergent, consistent with the membrane impermeability of the probes and reduced ionization of the thiol in the hydrophobic membrane. Peptide for which the cysteine was positioned in the headgroup zone of the lipid bilayer was labeled rapidly. Peptide for which the cysteine was positioned below the headgroup abutting the hydrocarbon region was labeled at a reduced rate compared to the fully accessible cysteine. Moreover, the effect of lipid bilayer structure on the kinetics of peptide and lipid flipping in the bilayer was readily measured with our two-step labeling method. The small sample size required, the ease and rapidity of sample preparation, and the amenability of MALDI-TOF mass spectral analysis to the presence of lipids will enable future facile investigation of membrane proteins in a cellular context. PMID- 23725487 TI - Epstein-Barr virus encoded RNA detected by in situ hybridization using cytological preparations. AB - OBJECTIVE: Detection of Epstein-Barr virus (EBV) status might help in the diagnosis of EBV-related neoplasms. The rate of successful assays for the detection of EBV-infected cells in cytological preparations has not been fully explored. Our aims were to examine the rate of successful in situ hybridization (ISH) assays for EBV-encoded RNA (EBER) in cytological specimens and to explore reasons for failure. METHODS: An electronic search selected cases with ISH-EBER assays performed on cytological preparations during a 10-year period. Data regarding patient age, gender and immune status, sample type and site, type of preparation, ISH-EBER results, immunophenotyping and immunohistochemistry results, final diagnosis and correspondent histopathological samples were retrieved. RESULTS: Sixty specimens from 58 patients with diagnoses of lymphoproliferative disorder (n = 35), carcinoma (n = 24) and sarcoma (n = 1) were identified. ISH-EBER assays were performed on 50 cell block sections and on 10 cytospin preparations, with 22 positive and 32 negative results. Six tests (four cytospins and two cell block sections) failed owing to loss of material during the assay and background staining, with an overall failure rate of 10% and 4% if cytospins were excluded. Assays were performed on 13 cytology and surgical specimens from the same site, with only one discrepant result. CONCLUSIONS: Cell block sections had more successful ISH-EBER assays when compared with cytospins. Reasons for failure were loss of material on the slide and background staining. A high concordance rate with surgical specimens emphasizes the usefulness of cytological samples for determining EBV status in patients with exhausted or no histological material available. PMID- 23725488 TI - Myofascial release as a treatment for orthopaedic conditions: a systematic review. AB - OBJECTIVE: To critically analyze published literature to determine the effectiveness of myofascial release therapy as a treatment for orthopaedic conditions. DATA SOURCES: We searched the following electronic databases: MEDLINE, CINAHL, Academic Search Premier, Cochrane Library, and Physiotherapy Evidence Database (PEDro), with key words myofascial release, myofascial release therapy, myofascial release treatment, musculoskeletal, and orthopedic. No date limitations were applied to the searches. STUDY SELECTION: Articles were selected based upon the use of the term myofascial release in the abstract or key words. Final selection was made by applying the inclusion and exclusion criteria to the full text. Studies were included if they were English-language, peer-reviewed studies on myofascial release for an orthopaedic condition in adult patients. Ten studies were eligible. DATA EXTRACTION: Data collected were number of participants, condition being treated, treatment used, control group, outcome measures and results. Studies were analyzed using the PEDro scale and the Center for Evidence-Based Medicine's Levels of Evidence Scale. DATA SYNTHESIS: Study scores on the PEDro scale ranged from 6 of 10 to 8 of 10. Based on the Levels of Evidence Scale, the case studies (n = 6) were of lower quality, with a rank of 4. Three of the 4 remaining studies were rated at 2b, and the final study was rated at 1b. CONCLUSIONS: The quality of studies was mixed, ranging from higher-quality experimental to lower-quality case studies. Overall, the studies had positive outcomes with myofascial release, but because of the low quality, few conclusions could be drawn. The studies in this review may serve as a good foundation for future randomized controlled trials. PMID- 23725490 TI - The impact of methylphenidate on seizure frequency and severity in children with attention-deficit-hyperactivity disorder and difficult-to-treat epilepsies. PMID- 23725489 TI - Does an individual's fitness level affect baseline concussion symptoms? AB - CONTEXT: Variables that may influence baseline concussion symptoms should be investigated. OBJECTIVE: To evaluate the effect of physical fitness on self report of baseline concussion symptoms in collegiate athletes and students. DESIGN: Controlled laboratory study. PATIENTS OR OTHER PARTICIPANTS: A total of 125 undergraduates, including 95 collegiate athletes and 30 recreational athletes (83 males, 42 females). INTERVENTION(S): Participants completed the Standardized Concussion Assessment Tool 2 (SCAT2; symptom report) at baseline, within 10 minutes of completing the Leger test, and within 24 hours of the initial baseline test. The Leger (beep) test is a shuttle-run field test used to predict maximal aerobic power. MAIN OUTCOME MEASURE(S): The total symptom score on the SCAT2 was calculated and analyzed with a repeated-measures analysis of variance. A linear regression analysis was used to determine if 3 variables (sport type, sex, or fitness level) accounted for a significant amount of the variance in the baseline symptom report. RESULTS: Participants reported more symptoms postactivity but fewer symptoms at 24 hours compared with baseline, representing a time effect in our model (F2,234 = 47.738, P < .001). No interactions were seen among the independent variables. We also found an effect for fitness level, with fitter individuals reporting fewer symptoms at all 3 time intervals. The regression analysis revealed that fitness level accounted for a significant amount of the variance in SCAT2 symptoms at baseline (R (2) = 0.22, F3,121 = 11.44, P < .01). CONCLUSIONS: Fitness level affected the baseline concussion symptom report. Exercise seems to induce concussion symptom reporting, and symptom severity may be a function of an athlete's level of conditioning. Sports medicine professionals should consider an athlete's level of fitness when conducting baseline concussion symptom assessments. PMID- 23725491 TI - Histological evaluation of different abutments in the posterior maxilla and mandible: an experimental study in humans. AB - OBJECTIVES: To histologically evaluate and compare the performance of healing abutments with either hydrophobic or hydrophilic surface properties in humans. MATERIALS AND METHODS: According to a parallel-group design, titanium implants placed in the posterior mandible and maxilla of 30 patients were randomly assigned to either (1) hydrophobic machined (M), (2) chemically modified hydrophilic (mod) acid etched (MA) titanium (Ti) (modMA1) or (3) modMA Ti- Zirconium alloy (modMA2) healing abutments and left to heal in a transmucosal position. At 8 weeks, the abutments and a limited soft tissue biopsy were harvested according to a standardized procedure and processed for histological analysis (primary outcomes: percentage epithelial- (EC) and subepithelial connective tissue contact (CTC) to the abutment surface). RESULTS: The surgical procedure was associated with an incomplete mucosal coverage of the study abutments in nine patients, and an unintentional submerged healing procedure in three patients. Per protocol analysis (18 patients) has pointed to an improved quantitative EC [modMA2 (53.45 +/- 28.25) > modMA1 (32.25 +/- 24.3) > M (23.15 +/ 16.09)] and CTC [modMA2 (75.12 +/- 43.22) > modMA1 (69.41 +/- 46.74) > M (47.63 +/- 19.28)] (%) to modMA surfaced abutments. CONCLUSIONS: It was concluded that modMA surfaces may have the potential to enhance soft tissue adhesion at the transmucosal aspect of titanium dental implants. PMID- 23725493 TI - Think before you measure. PMID- 23725492 TI - Phylogenetic analysis of symbionts in feather-feeding lice of the genus Columbicola: evidence for repeated symbiont replacements. AB - BACKGROUND: Many groups of insects have obligate bacterial symbionts that are vertically transmitted. Such associations are typically characterized by the presence of a monophyletic group of bacteria living in a well-defined host clade. In addition the phylogeny of the symbiotic bacteria is typically congruent with that of the host, signifying co-speciation. Here we show that bacteria living in a single genus of feather lice, Columbicola (Insecta: Phthiraptera), present an exception to this typical pattern. RESULTS: The phylogeny of Columbicola spp. symbionts revealed the presence of three candidate clades, with the most species rich clade having a comb-like topology with very short internodes and long terminal branches. Evolutionary simulations indicate that this topology is characteristic of a process of repeated symbiont replacement over a brief time period. The two remaining candidate clades in our study exhibit high levels of nucleotide substitution, suggesting accelerated molecular evolution due to relaxed purifying selection or smaller effective population size, which is typical of many vertically transmitted insect symbionts. Representatives of the fast-evolving and slow-evolving symbiont lineages exhibit the same localization, migration, and transmission patterns in their hosts, implying direct replacement. CONCLUSIONS: Our findings suggest that repeated, independent symbiont replacements have taken place over the course of the relatively recent radiation of Columbicola spp. These results are compatible with the notion that lice and other insects have the capability to acquire novel symbionts through the domestication of progenitor strains residing in their local environment. PMID- 23725494 TI - Counting disability: global and national estimation. AB - PURPOSE: How many people with disabilities are in the world? How is disability defined? How can we measure disability in an accurate and comparable way? These are some of the key questions which the recently published World Bank/WHO World Report on Disability (WRD) addresses. METHOD: Multiple data sources and methods were used by WHO and the World Bank to estimate a global figure, with the ICF as the underlying data standard. Key international data sources were the World Health Survey of 2002-2004 and the 2004 updates from the Global Burden of Disease study. The World Report on Disability also includes a compilation of country reported prevalence from census and surveys. This paper presents and discusses key findings of the Irish National Disability Survey (2006) to illustrate the value of the ICF framework for disability statistics and most especially the environmental factors component. RESULTS: The World Report estimates that globally one billion people or 15% of the world's population experience disabilities. Between 110-190 million people (2% of the world's population) experience severe or extreme difficulties in functioning. Definitions and measures of disability vary widely across countries. The Irish Disability Survey shows the substantial impact of environmental factors on people's functioning. For example, attitudes, and the presence or absence of facilitating equipment, support services, flexible working arrangements and transport significantly affect participation of people with disabilities in Irish society. CONCLUSIONS: To improve the quality of disability information, the World Report recommends the use of a common definition and concepts of disability based on WHO's International Classification of Functioning Disability and Health (ICF). Furthermore, disability measurement needs to apply a multidimensional approach, in particular, measuring disability in terms of the level of difficulty a person is experiencing in multiple areas of life, rather than head counting severe impairment types in a dichotomous way. Environmental factors have significant effects on individual functioning and should be considered as an integral part in disability measurement. PMID- 23725495 TI - Developing applications of the ICF in education systems: addressing issues of knowledge creation, management and transfer. AB - PURPOSE: Since its endorsement, the International Classification of Functioning, Disability and Health (ICF) has been applied in many policy contexts, including education. While so far the focus has been on showing ways in which it can be used to describe functioning and disability, this article seeks to focus on its value to represent knowledge. METHODS: Two applications of the ICF and ICF-CY in the context of the Swiss education system highlight ways in which the classification can be used to assist multidisciplinary teams in acquiring and mapping existing knowledge, in creating new knowledge and in applying it for specific purposes. RESULTS: The conceptual analysis illustrates that "disability in education" is a hybrid conceptual world that needs to bridge disability related information with information relevant for learning and education. The ICF can be used to adequately map such knowledge in complex social settings. CONCLUSION: More attention needs to be paid to the ICF as an information system to help negotiate between different views on reality and different areas of expertise. The selection of content and ways of representing it need to be considered in the light of the specific purposes during collaborative knowledge creation processes. PMID- 23725496 TI - Metabolic syndrome, C-reactive protein and microalbuminuria in a rural Chinese population: a cross-sectional study. AB - BACKGROUND: Microalbuminuria is an early marker of chronic kidney disease (CKD). Previous studies have shown that either metabolic syndrome (MetS) or chronic inflammation is related to renal impairment. The aim of this study was to investigate the association between MetS, C-reactive protein (CRP) and microalbuminuria in a rural Chinese population. METHODS: This was a cross sectional study using data from the Handan Eye Study. MetS was defined according to the Chinese Diabetes Society (CDS) criteria. CRP levels >= 3 mg/L were classified as high CRP. Microalbuminuria was defined as a urinary albumin/creatinine ratio (ACR) of 30-300 mg/g. RESULTS: We included 4191 subjects aged >= 30 years in this analysis. The prevalence of MetS and microalbuminuria in the group was 25.7% and 15.6%, respectively. The odds ratio (OR) of microalbuminuria in subjects with MetS was 1.25 (95% confidence interval (CI): 1.03 - 1.51) compared with those without microalbuminuria. In multivariate logistic regression analysis, high blood pressure (OR 1.36, 95% CI: 1.10 - 1.67) and high fasting blood glucose (OR 1.44, 95% CI: 1.17 - 1.76) were independently associated with microalbuminuria. Subjects with high CRP and MetS had a 1.46-fold greater risk of having microalbuminuria compared with those with low CRP without MetS (95% CI: 1.06 - 2.01). CONCLUSIONS: In this rural Chinese population aged >=30 years, MetS and microalbuminuria were independently related and the combination of high CRP and MetS was associated with an increased risk of microalbuminuria. PMID- 23725497 TI - Influence of e-waste dismantling and its regulations: temporal trend, spatial distribution of heavy metals in rice grains, and its potential health risk. AB - Enhanced regulations, centralized dismantling processes, and sophisticated recycling technologies have been implemented in some e-waste dismantling areas in China with regard to environmental and economic aspects since 2005. In this study, rice grain samples were collected from 2006 to 2010 in an e-waste dismantling area to investigate the temporal trends and spatial distribution of As, Cd, Cu, and Pb. Geometric means of As, Cd, Cu, and Pb in rice samples from the e-waste dismantling area were 111, 217, 4676, and 237 ng g(-1), respectively. Levels of Pb showed a significant decreasing trend during the sampling period, whereas the other three elements remained relatively constant or even increased. Concentrations of Cd, Cu, and Pb in the e-waste dismantling area were significantly higher than those in the non-e-waste dismantling area (p < 0.05), which showed a close connection between e-waste dismantling activities and elevated Pb, Cu, and Cd contents. Risk assessment for human via rice consumption indicated that over 60% of the hazard quotient of Cd exceeded 1 in the e-waste dismantling area. Our study implied that stricter implementation of regulatory measures might lead to positive effects in controlling the release of some heavy metals to the environment. However, environmental behaviors differed with geochemical characteristics of individual elements. Further remediation actions to reduce heavy metal pollution to the surrounding environment might still be needed. PMID- 23725498 TI - Overview of age-related ocular conditions. AB - The United States is an aging society. The number of Americans 65 years or older is expected to more than double over the next 40 years, from 40.2 million in 2010 to 88.5 million in 2050, with aging baby boomers accounting for most of the increase. As the society ages, the prevalence of age-related diseases, including diseases of the eye, will continue to increase. By 2020, age-related macular degeneration, one of the leading causes of vision loss, is expected to affect 2.95 million individuals in the United States. Likewise, the prevalence of open angle glaucoma, estimated at 2.2 million in 2000, is projected to increase by 50%, to 3.36 million by 2020. As the eye ages, it undergoes a number of physiologic changes that may increase susceptibility to disease. Environmental and genetic factors are also major contributors to the development of age-related ocular diseases. This article reviews the physiology of the aging eye and the epidemiology and pathophysiology of 4 major age-related ocular diseases: age related macular degeneration, glaucoma, diabetic retinopathy, and dry eye. PMID- 23725499 TI - Current treatment strategies for age-related ocular conditions. AB - Treatment for several major age-related ocular diseases has undergone a paradigm shift in recent years. Advances in basic science and clinical research have led to a more thorough understanding of the complex pathophysiology underlying common ocular diseases of aging, and to the development of highly effective new therapies for these conditions. The use of intraocular anti-angiogenic drugs, for example, has transformed the management of neovascular age-related macular degeneration and diabetic retinopathy. Many patients achieve impressive and durable gains in vision with these agents that were unattainable with older treatments. For glaucoma and dry eye disease, clinicians have a variety of pharmacologic and surgical options to choose from. However, significant challenges remain: not all patients respond to treatment, many older patients have difficulty complying with complex drug regimens, frequent office visits put a substantial strain on patients and caregivers, and therapies may cause unpleasant side effects. This article reviews the current treatment landscape for 4 major age-related ocular diseases: age-related macular degeneration, glaucoma, diabetic retinopathy, and dry eye. PMID- 23725500 TI - Managed care implications of age-related ocular conditions. AB - The economic costs of age-related ocular diseases and vision loss are increasing rapidly as our society ages. In addition to the direct costs of treating age related eye diseases, elderly persons with vision loss are at significantly increased risk for falls and fractures, experiencing social isolation, and suffering from an array of comorbid medical conditions compared with individuals with normal vision. Recent studies estimate the total economic burden (direct and indirect costs) of adult vision impairment in the United States at $51.4 billion. This figure is expected to increase as the baby boomer generation continues to age. While a number of highly effective new therapies have caused a paradigm shift in the management of several major age-related ocular diseases in recent years, these treatments come at a substantial cost. This article reviews the economic burdens and treatment-related costs of 4 major ocular diseases of aging glaucoma, age-related macular degeneration, diabetic retinopathy, and dry eye disease-and the implications for managed care. PMID- 23725501 TI - Immunohistochemical expression and significance of NM23 suppressor protein in primary gastric adenocarcinoma. AB - NM 23 protein was originally identified as a metastasis suppressor protein. The expression of NM23 has been correlated with tumour metastatic potential in various human carcinoma, mostly in ductal breast and colorectal carcinomas. Evidence for their expression in gastric cancer is rather contradictory, both for protein expression status and prognostic value. This study was done to analyze the immunohistochemical expression of NM23 in gastric carcinoma, and correlation of the degree of staining with clinicopathological parameters was investigated. In a retrospective immunohistochemical study specimens obtained from 56 gastric cancer patients who had undergone gastrectomy with perigastric lymphadenectomy were analysed, in correlation with classical clinical-pathological parameters of tumours, WHO-, Lauren-, Goseki-, and Ming- classification. NM 23 gene expression was compared in gastric adenocarcinoma and tumour-adjacent non-neoplastic gastric mucosa. A semiquantitative immunostaining evaluation (score 0-3) was used, counting the percentage of stained cells. Statistical analysis was performed using Kolmogorov-Smirnov test, and Spearman rank correlation test. The investigated group consisted of 40 males and 16 females (2.5:1) with a mean age of 63 years (range: 48-81 years). The percentage of positive expression of NM23 (score 3) were in 30 (53.5%) specimens in non-neoplastic mucosa in adjacent gastric carcinoma, and negative (score 0-2) in all 56 (100%) specimens of gastric adenocarcinoma. NM23 expression was higher in non-neoplastic mucosa than in adjacent gastric adenocarcinoma tissue (p<0.0001). NM23 protein expression did not correlate with gender (p=0.115), tumour size (p=0.844), tumour grade (p=0.172), lymphovascular invasion (p=0.606), lymph node metastases (p=0.311), Lauren classification (p=0.426), Goseki classification (p=0.458) and Ming classification (p=0.212). Our series did not show a significant correlation between NM23 expression and analysed clinico-pathological variables, but these results suggest that protein NM23 may have a role in gastric carcinoma pathogenesis. PMID- 23725502 TI - Effects of urotensin II and its specific receptor antagonist urantide on rat vascular smooth muscle cells. AB - We investigated the effects of urantide, a receptor antagonist of urotensin II (U II), on the expression of U-II and its receptor GPR14 in rat vascular smooth muscle cells. Vascular smooth muscle cells from rat thoracic aorta were cultured by explant method. Subjects in this experiment were divided into eight groups: normal control group (group C), U-II group (group M), positive control group (Flu group) and urantide-treated groups (10-10, 10-9, 10-8, 10-7 and 10-6 mol/L). Cultured vascular smooth muscle cells in vitro were studied by immunocytochemistry, biochemistry, and flow cytometry. U-II (10-8 mol/L) promoted the proliferation of vascular smooth muscle cells at each time point, influenced cell cycle, increased proliferation index and S-phase cell fraction, and dramatically promoted the expression of U-II and GPR14. In the concentration range from 10-10 to 10-6 mol/L, urantide dramatically inhibited the proliferation of vascular smooth muscle cells and the protein expression of U-II and GPR14, especially at a concentration of 10-6 mol/L. U-II, binding with its receptor GPR14, promotes vascular smooth muscle cells proliferation and migration, which can be inhibited by urantide. This study provides an evidence for understanding the effects of U-II and its receptor GPR14 on vascular smooth muscle cells. PMID- 23725503 TI - Impact of sustained virus elimination on natural anticoagulant activity in patients with chronic viral hepatitis C. AB - Previous studies have reported reduced synthesis of various hemostatic factors in patients with chronic liver disease. Whether changes in plasma levels of these proteins reflect recovered liver synthetic function following virological eradication therapy has not been approved yet. The aim of the study was to determine the impact of sustained viral suppression achieved with pegylated interferon alpha and ribavirin on hemostatic parameters including natural anticoagulants in patients with chronic hepatitis C. The following coagulation screening tests were obtained in thirty patients with chronic viral hepatitis C before and after completion of antiviral treatment: activated partial thromboplastin time, prothrombin time, plasma fibrinogen and natural anticoagulant proteins antithrombin III, protein C (PC) and total protein S (PS) activity. Only patients who achieved durable virus suppression were included. The mean PC and PS levels were significantly lower in patients with chronic viral hepatitis C before antiviral therapy than in healthy controls (79.04 +/- 16.19 % vs. 109.92 +/- 21.33% and 54.04 +/- 16.11% vs. 87.60 +/- 8.15%, respectively; (p<0.001). Mean levels of PC exhibited a significant increase by 14.69 % after the completion of antiviral treatment (93.73 +/- 14.18%, p<0.001) as well as PS levels, which significantly increased by 21.46% (75.50 +/- 15.43, p<0.001) when compared with pre-treatment values. No remarkable fluctuations in other hemostatic parameters were noted. Protein C and protein S are sensitive markers of hepatocyte synthetic impairment and are valuable markers in monitoring the efficacy of antiviral treatment in chronic hepatitis C patients. Larger studies are needed to confirm our results. PMID- 23725504 TI - Hormonal risk factors for ovarian cancer in the Albanian case-control study. AB - The role of reproductive factors in the aetiology of ovarian cancer had been evaluated in hospital-based case-control study conducted in Albania, providing a total dataset of 283 cases and 1019 controls. Logistic regression models were used to obtain relative risk (OR) estimates. The present results showed that parity had protective effects which increased until the forth birth and the trend in risk was significant (p < 0.01). In each stratum and overall, nulliparous women appeared to be at highly increased risk compared to those who had different number of births (OR=12.5, 95%, CI: 2.4-63.8). Evaluation of early age at menarche and late age at menopause, showed statistically significant increased risk. Furthermore, increased risk was observed between pre-menopausal women and never-married nulliparity women, respectively (OR=1.44 95%, CI: 0.88-2.36; OR=8.98, 95%, CI: 1.44 - 56.14), but ovarian cancer risk was reduced for hysterectomized women. These findings suggest that Albanian women have risk factors similar to women in western countries. PMID- 23725505 TI - The influence of chronic intake of saccharin on rat hepatic and pancreatic function and morphology: gender differences. AB - There are opposite hypotheses on the effect of saccharin. Our aim was reviewing the influence of chronically ingested saccharin on the function and histological structure of liver and pancreas and all this in light of gender differences. The rats were divided into control group - (Group C) and saccharin-treated group - (Group S) which was given a normal diet and 0.0005% saccharin in drinking water for 6 weeks. Liver and pancreas were histologically processed and quantitative histological analysis was performed. Glucose blood levels and plasma activities of aspartate transaminase (AST) and alanine transaminase (ALT), body weight, and food intake were analyzed. Quantitative histological analysis determined that the values of diameter and volume density of both Langerhans islets and exocrine acini were significantly higher in S group, especially in males. AST levels were significantly higher in treated group. Glucose levels were higher in treated group, mainly due to the values of the female subgroup. Food intake was significantly higher in control group, while weight gain was higher in treated group. Treated males had significantly higher food intake and weight gain in comparison with treated females. The data presented here suggests that chronic saccharin intake affects the examined parameters. Reported facts reflect various metabolic, hormonal and neural responses in males and females. PMID- 23725506 TI - Hypolipidemic and antioxidant effects of buckwheat leaf and flower mixture in hyperlipidemic rats. AB - As a source of biologically active compounds, buckwheat has beneficial effects in nutrition due to its high content of flavonoids, particularly rutin. Aim of our study was to examine effects of buckwheat on plasma lipid status and phospholipids fatty acids composition, histological and parameters of oxidative stress in Wistar rats fed a high-fat diet. This study showed that buckwheat leaf and flower (BLF) mixture supplementation significantly reduce weight gain, plasma lipid concentrations and atherogenic index in rats fed a high-fat diet. Treatment of the high-fat group of animals with buckwheat significantly increased percentage of n-6 fatty acids as well as eicosapentaenoic acid (EPA) and decreased percentage of saturated fatty acids (SFA) and oleic acid. Buckwheat antioxidant effects diminished negative influence of high-fat diet in hyperlipidemic rats, while pathohistological analysis of liver confirmed changes after high-fat consumption. Our results showed hypolipidemic, antiatherogenic and antioxidative features of buckwheat leaf and flower mixture, and these parts of the plant with the highest rutin content could be beneficial in prevention and curing of hyperlipidemia. PMID- 23725507 TI - Analysis of manganese superoxide dismutase (MnSOD: Ala-9Val) and glutathione peroxidase (GSH-Px: Pro 197 Leu) gene polymorphisms in mood disorders. AB - We investigated the etiopathogenetic role of manganese superoxide dismutase (MnSOD) (Ala-9Val) and glutathione peroxidase (GSH-Px) (Pro 197 Leu) gene polymorphisms in patients diagnosed with major depressive disorder (MDD) and bipolar I disorder (BD). Eighty patients with MDD, 82 patients with BD (total 162 patients) and 96 healthy controls were enrolled in this study and genotyped using a Real Time-Quantitative Polymer Chain Reaction (RT-qPCR)-based method. The patients with BD and MDD and the controls had a similar distribution of the genotypes and alleles in the Ala-9Val MnSOD gene polymorphism. Comparison of the MDD group and control group regarding the Pro 197 Leu GSH-Px gene polymorphism revealed similar genotype distribution but different allele distribution. The BD group and control group were similar both for genotypes and for alleles when compared regarding the Pro 197 Leu GSH-Px gene polymorphism. The combined analysis (MDD plus BD) also failed to find any association between the Ala-9Val MnSOD and Pro 197 Leu GSH-Px gene polymorphism. Although small statistical power of the current study the significant difference between patients with depression and the control group for the Pro 197 Leu GSH-Px polymorphism indicates that the distribution of these alleles may have a contribution in the physiopathogenesis of depression. One of the limitation of the current study is that the sample size is too small. Understanding of the exact role of Pro 197 Leu GSH-Px polymorphism in the development of depression needs to further studies with more sample size and high statistical power. PMID- 23725508 TI - Effect of interferon-gamma on NF-kappaB and cytokine IL-18 and IL-27 in acute pancreatitis. AB - The objective of our work was to evaluate the effect of interferon-gamma (IFN gamma) on cytokine expression in rat acute pancreatitis (AP). AP was introduced to rats which were divided into Control, AP and IFN-gamma group. Rats in the AP and IFN-gamma group were sacrificed as 6, 12 and 24 h after IFN-gamma treatment. The serum amylase (AMA), endotoxin and cytokines were detected. The pathological examination and immunofluorescence staining of pancreas for TNF-alpha, NF-kappaB and IL-18 were performed. The serum AMA increased significantly at 6 h and reduced at 48 h after AP. The increase in IFN-gamma was higher than that in AMA. IL-18 increased in the AP and IFN group, and IFN increased markedly at 48 h after AP. IL-27 reduced at 24 h after AP compared with AP group. In the AP group, the immunostaining of cytokines increased. In the IFN group, the edema in the pancreas was more severe, and NF-kappaB and IL-18 expression was higher than that in the other two groups. IFN-gamma can increase serum IL-18 and reduce IL-27 in AP. IFN-gamma can increase serum IL-18 and reduce serum IL-27 in AP. The increase in NF-kappaB and IL-18 may exert influence on pro-inflammatory cytokines to deteriorate inflammation in the pancreas. Thus, to control the IFN-gamma might has promise to attenuate pancreatitis. PMID- 23725509 TI - Role of D1/D2 dopamin receptors antagonist perphenazine in morphine analgesia and tolerance in rats. AB - While opioid receptors have been implicated in the development of tolerance, the subsequent mechanisms involved in these phenomena have not been completely understood. The purpose of this study was to investigate effects of D1/D2 dopamine receptors antagonist perphenazine on morphine analgesia and tolerance in rats. Male Wistar albino rats weighing 190-205 g were used in these experiments. To constitute of morphine tolerance, animals received morphine (50 mg/kg) once daily for 3 days. After last dose of morphine was injected on day 4, morphine tolerance was evaluated by the analgesia tests. The analgesic effects of perphenazine (1, 5, and 10 mg/kg ), D1-dopamine receptor antagonist SCH 23390 (1 mg/kg), D2-dopamine receptor antagonist eticlopride (1 mg/kg), and morphine were considered at 30-min intervals (0, 30, 60, 90, and 120 min) by tail-flick and hot plate analgesia tests. Obtained data suggested that D1/D2 dopamine receptors antagonist perphenazine was capable of suppressing opioid tolerance, possibly by the mechanism of inhibiting D2-dopamine receptor. Because the data indicated that D2-dopamine receptor antagonist eticloride, but not D1-dopamine receptor antagonist SCH 23390, significantly decreased morphine tolerance in analgesia tests. In addition, administration of perphenazine with morphine increased morphine analgesia. Results from the present study suggested that dopamine receptors play a significant role in the morphine analgesic tolerance. In particular, D2-dopamine receptor has an important role rather than D1-dopamine receptor in development tolerance to morphine. PMID- 23725510 TI - Spleen-preserving surgery in treatment of large mesothelial splenic cyst in children--a case report and review of the literature. AB - The nonparasitic primary splenic cysts are very rare clinical entity. In the past, splenectomy was the treatment of choice but with the recognition of the spleen's important immunological function, spleen-preserving surgery is the preferred treatment modality. We hereby present a case of a large splenic mesothelial cyst and its treatment with preservation of the remaining splenic parenchyma. Our case shows that spleen-preserving surgery in treatment of the large splenic cysts is possible and safe procedure with maintenance of the splenic function. PMID- 23725511 TI - Solitary intracranial tuberculoma mimicking a malignant tumor in a patient without tubercular lesions or a history of disease: a case report. AB - Cerebral tuberculoma is a rare cause of intracranial mass. In Latin America and Colombia where tuberculosis is endemic, it represents between 5 and 30% of brain tumours. A 53-year-old Colombian woman was admitted to a third-level hospital in Cali, Colombia, after reporting loss of consciousness, headache, paresthesia, and flight of ideas for a two-week period. Imaging studies showed a left frontal mass of malignant appearance whose first possible diagnosis was metastatic neoplasia or glioma. With the initial results, absence of history of chronic infectious diseases and a history of thyroidectomy, a surgical procedure was carried out and a histopathological and molecular evaluation was conducted. The pathology report noted necrotizing granulomatous inflammation and tissue staining and molecular tests for detection of M. tuberculosis were positive and the patient was managed with anti-tubercular treatment. Intracranial masses are frequently targeted as a malignant neoplastic disease for surgical treatment. Considering an infectious etiology must be a diagnostic option. PMID- 23725512 TI - Human comparative experimental study of surgical treatment of atrial fibrillation by epicardial techniques. AB - BACKGROUND: To set up an experimental model of cadaveric heart in order to evaluate and compare histologic transmurality of lesions immediately caused by different energy sources of anti-arrhythmic epicardial devices. METHODS: Procedures were performed on a cadaveric human heart in orthotopic position with an ischemic time of 48 h at 37 degrees and supported through the use of cardiopulmonary bypass. Three anti-arrhythmic epicardial devices were studied: the bipolar forceps Cardioblate BP (Medtronic) for the radiofrequency, the Epicor Ultracinch LP Ablation device (St. Jude) for ultrasound and the Cardioblate CryoFlex (Medtronic) device for cryoablation. Histological features of lesions made at the pulmonary venous confluence assessed the effectiveness of different energy sources. RESULTS: Over 45 experimentations performed, only 28 were considered correct and retained for histological analysis. Three distinct groups were studied according to the type of procedure performed: group 1 (Radiofrequency, n = 12), group 2 (ultrasound, n = 4), group 3 (cryoablation, n = 10) and controls (n = 2). All analysed samples showed histological changes with a success rates of transmurality of 33% for radiofrequency, 25% for ultrasound and 90% for cryotherapy (p <0.001). The average length of transmurality, when it was reached and the proportion of transmurality over the total length of the lesion were respectively 12 +/- 6 mm and 37 +/- 18% for group 1, 10 mm and 33% for group 2 and 11.1 +/- 1.1 mm and 35 +/- 5% for group 3. CONCLUSION: Immediate detectable histological transmural lesions after epicardial procedure are discontinuous whatever the kind of energy source tested in this work and it strongly encourages the repetition of radiofrequency procedures. Nevertheless, our experimental model seems inadequate to assess ultrasound energy efficacy. PMID- 23725513 TI - Characterization of Enterobacteriaceae isolates obtained from a tertiary care hospital in Mexico, which produces extended-spectrum beta-lactamase. AB - The prevalence and genetic characteristics of Escherichia coli and Klebsiella pneumoniae clinical isolates producing extended-spectrum beta-lactamase (ESBL) were examined. Between October 2010 and March 2011, E. coli (n=460) and K. pneumoniae (n=78) isolates were collected at a tertiary care hospital in Guadalajara, Mexico. The minimum inhibitory concentration (MIC) for each isolate was determined using a broth microdilution method, and ESBL production was assayed. The presence of beta-lactamase genes, blaSHV, blaCTX-M, and blaTLA-1, was detected by PCR and confirmed with sequencing. Only ESBL-producing isolates were further subjected to pulsed-field gel electrophoresis (PFGE) and plasmid profiling. All of the ESBL isolates were multidrug resistant and 75/460 (16.3%) E. coli isolates and 21/78 (26.9%) K. pneumoniae isolates were found to produce ESBL. For the E. coli isolates, >95% susceptibility to amikacin, meropenem, fosfomycin, imipenem, and nitrofurantoin was observed. For K. pneumoniae, similar results were obtained, with discrepancies observed for gentamicin and nitrofurantoin. PFGE further identified eleven pulsotypes for E. coli and three clusters of K. pneumoniae. CTX-M-15 was detected in 85% of ESBL-producing E. coli and in 76% of ESBL-producing K. pneumoniae. In contrast, SHV-5 ESBL was identified in 17% of E. coli isolates and in 86% of K. pneumoniae isolates. The bla-TLA-1 gene was not detected in any of the 96 isolates analyzed. Overall, CTX M-15 and SHV-5 were found to have a high rate of spread throughout the hospital and were associated with strong multidrug resistance. PMID- 23725515 TI - Photochemical properties of some Cl-containing halogenated alkanes. AB - Rate constants for the gas-phase reactions of OH radicals with three partially halogenated alkanes, CH3Cl (kMC), CHFClCFCl2 (k122a), and CH2FCFCl2 (k132c), were measured using a discharge flow-electron paramagnetic resonance technique over the temperature range from 298 to 460 K. The temperature dependences of the rate constants can be represented by the expressions kMC(298-460 K) = (3.09 +/- 0.94) * 10(-12) exp[-(1411 +/- 85)/T] cm(3) molecule(-1) s(-1), k122a(298-460 K) = (1.26 +/- 0.24) * 10(-12) exp[-(1298 +/- 66)/T] cm(3) molecule(-1) s(-1), and k132c(298-370 K) = (8.1 +/- 2.2) * 10(-13) exp[-(1247 +/- 89)/T] cm(3) molecule( 1) s(-1). The atmospheric lifetimes of CH3Cl, CHFClCFCl2, and CH2FCFCl2 due to their reaction with OH were estimated to be 1.6, 3.5, and 4.5 years, respectively. The UV absorption cross sections of halogenated ethanes, CHFClCFCl2, and CH2FCFCl2, were measured at T = 295 K between 190 and 240 nm, as were those for CHCl2CF2Cl (HCFC-122), CHCl2CF3 (HCFC-123), CHFClCF2Cl (HCFC 123a), and CH3CFCl2 (HCFC-141b). The atmospheric lifetimes due to stratospheric photolysis were also estimated. PMID- 23725516 TI - Fulfillment of Work-Life Balance From the Organizational Perspective: A Case Study. AB - CONTEXT: Researchers studying work-life balance have examined policy development and implementation to create a family-friendly work environment from an individualistic perspective rather than from a cohort of employees working under the same supervisor. OBJECTIVE: To investigate what factors influence work-life balance within the National Collegiate Athletic Association (NCAA) Division I clinical setting from the perspective of an athletic training staff. DESIGN: Qualitative study. SETTING: Web-based management system. PATIENTS OR OTHER PARTICIPANTS: Eight athletic trainers (5 men, 3 women; age = 38 +/- 7 years) in the NCAA Division I setting. DATA COLLECTION AND ANALYSIS: Participants responded to a series of questions by journaling their thoughts and experiences. We included data-source triangulation, multiple analyst triangulation, and peer review to establish data credibility. We analyzed the data via a grounded theory approach. RESULTS: Three themes emerged from the data. Family-oriented and supportive work environment was described as a workplace that fosters and encourages work-life balance through professionally and personally shared goals. Nonwork outlets included activities, such as exercise and personal hobbies, that provide time away from the role of the athletic trainer. Individualistic strategies reflected that although the athletic training staff must work together and support one another, each staff member must have his or her own personal strategies to manage personal and professional responsibilities. CONCLUSIONS: The foundation for a successful work environment in the NCAA Division I clinical setting potentially can center on the management style of the supervisor, especially one who promotes teamwork among his or her staff members. Although a family-friendly work environment is necessary for work life balance, each member of the athletic training staff must have personal strategies in place to fully achieve a balance. PMID- 23725514 TI - Discovery of small-molecule modulators of the Sonic Hedgehog pathway. AB - The Hedgehog signaling pathway is involved in the development of multicellular organisms and, when deregulated, can contribute to certain cancers, among other diseases. The molecular characterization of the pathway, which has been enabled by small-molecule probes targeting its components, remains incomplete. Here, we report the discovery of two potent, small-molecule inhibitors of the Sonic Hedgehog (Shh) pathway, BRD50837 and BRD9526. Both compounds exhibit stereochemistry-based structure-activity relationships, a feature suggestive of a specific and selective interaction of the compounds with as-yet-unknown cellular target(s) and made possible by the strategy used to synthesize them as members of a stereochemically and skeletally diverse screening collection. The mechanism-of action of these compounds in some ways shares similarities to that of cyclopamine, a commonly used pathway inhibitor. Yet, in other ways their mechanism-of-action is strikingly distinct. We hope that these novel compounds will be useful probes of this complex signaling pathway. PMID- 23725517 TI - Lower Extremity Muscle Strength After Anterior Cruciate Ligament Injury and Reconstruction. AB - CONTEXT: Quadriceps and hamstrings weakness occurs frequently after anterior cruciate ligament (ACL) injury and reconstruction. Evidence suggests that knee injury may precipitate hip and ankle muscle weakness, but few data support this contention after ACL injury and reconstruction. OBJECTIVE: To determine if hip, knee, and ankle muscle weakness present after ACL injury and after rehabilitation for ACL reconstruction. DESIGN: Case-control study. SETTING: University research laboratory. PATIENTS OR OTHER PARTICIPANTS: Fifteen individuals with ACL injury (8 males, 7 females; age = 20.27 +/- 5.38 years, height = 1.75 +/- 0.10 m, mass = 74.39 +/- 13.26 kg) and 15 control individuals (7 men, 8 women; age = 24.73 +/- 3.37 years, height = 1.75 +/- 0.09 m, mass = 73.25 +/- 13.48 kg). INTERVENTION(S): Bilateral concentric strength was assessed at 60 degrees /s on an isokinetic dynamometer. The participants with ACL injury were tested preoperatively and 6 months postoperatively. Control participants were tested on 1 occasion. MAIN OUTCOME MEASURES: Hip-flexor, -extensor, -abductor, and adductor; knee-extensor and -flexor; and ankle-plantar-flexor and -dorsiflexor strength (Nm/kg). RESULTS: The ACL-injured participants demonstrated greater hip extensor (percentage difference = 19.7, F1,14 = 7.28, P = .02) and -adductor (percentage difference = 16.3, F1,14 = 6.15, P = .03) weakness preoperatively than postoperatively, regardless of limb, and greater postoperative hip-adductor strength (percentage difference = 29.0, F1,28 = 10.66, P = .003) than control participants. Knee-extensor and -flexor strength were lower in the injured than in the uninjured limb preoperatively and postoperatively (extensor percentage difference = 34.6 preoperatively and 32.6 postoperatively, t14 range = -4.59 to 4.23, P <= .001; flexor percentage difference = 30.6 preoperatively and 10.6 postoperatively, t14 range = -6.05 to -3.24, P < .05) with greater knee-flexor (percentage difference = 25.3, t14 = -4.65, P < .001) weakness preoperatively in the injured limb of ACL-injured participants. The ACL-injured participants had less injured limb knee-extensor (percentage difference = 32.0, t28 = -2.84, P = .008) and -flexor (percentage difference = 24.0, t28 = -2.44, P = .02) strength preoperatively but not postoperatively (extensor: t28 = -1.79, P = .08; flexor: t28 = 0.57, P = .58) than control participants. Ankle-plantar-flexor weakness was greater preoperatively than postoperatively in the ACL-injured limb (percentage difference = 31.9, t14 = -3.20, P = .006). CONCLUSIONS: The ACL-injured participants presented with hip-extensor, -adductor, and ankle-plantar-flexor weakness that appeared to be countered during postoperative rehabilitation. Our results confirmed previous findings suggesting greater knee-extensor and -flexor weakness postoperatively in the injured limb than the uninjured limb. The knee extensors and flexors are important dynamic stabilizers; weakness in these muscles could impair knee joint stability. Improving rehabilitation strategies to better target this lingering weakness seems imperative. PMID- 23725518 TI - Treatment of diabetic nephropathy with Tripterygium wilfordii Hook F extract: a prospective, randomized, controlled clinical trial. AB - BACKGROUND: Diabetic nephropathy (DN) is the most common cause of end-stage renal failure. Although angiotensin II receptor blockers (ARBs) can be used to attenuate proteinuria in DN patients, their efficacy remains limited. This clinical trial aimed to evaluate the efficacy of Tripterygium wilfordii Hook F (TwHF) extract in the treatment of type 2 diabetes mellitus (DM)-induced nephropathy. METHODS: A total of 65 DN patients with proteinuria levels >= 2.5 g/24 h and serum creatinine levels<3 mg/dl were enrolled in this six-month, prospective, randomized, controlled study. The patients were randomized into treatment groups that received either 120 mg of TwHF extract per day for three months, followed by 60 mg per day for three more months, or 160 mg of valsartan daily for six months. The urinary protein and estimated glomerular filtration (eGFR) level were measured at one, three, and six months after the commencement of treatment. The primary measure of treatment efficacy was a reduction in the 24 h urine protein level between baseline and the end of the study, and the secondary measure of treatment efficacy was a reduction in the eGFR value. RESULTS: At the end of the treatment period, the mean urine protein level in the TwHF group was dramatically decreased (4.99 +/- 2.25 g/24 h vs 2.99 +/- 1.81 g/24 h, p< 0.01), with decreases at one, three, and six months of 32.9%, 38.8%, and 34.3%, respectively. In contrast, the proteinuria in the valsartan group was not significantly attenuated, and the decreases in urine protein levels at treatment months one, three, and six were 1.05%, 10.1%, and -11.7%, respectively. The mean decrease in eGFR in the valsartan group was greater than that in the TwHF group (26.4% vs. 13.7%, respectively; p =0.067). CONCLUSIONS: TwHF extract can reduce the urine protein level of DN patients and represents a novel, potentially effective, and safe drug for the treatment of DN patients with proteinuria. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00518362. PMID- 23725519 TI - Measurement of the friction between single polystyrene nanospheres and silicon surface using atomic force microscopy. AB - In the present work, the individual nanoparticles have been manipulated on a silicon surface, using atomic force microscope (AFM) techniques. As a model system, near-spherical polystyrene nanoparticles with radii from 28.85 nm to 228.2 nm were deposited on a nanosmooth silicon wafer. Experiments demonstrated that when the normal force is above a threshold load, nanoparticles could steadily be pushed by the tip of the AFM along the defined pathway. The tests allow us to quantitatively study the interfacial friction between the nanoparticle and the surface. It was found that the friction could be affected by various factors such as the load, the particle size, and the surface treatment. The results showed that the friction between particles and substrate is proportional to the two-third power of the radius, which is in agreement with the Hertzian theory. It can also be seen that the ratio between the kinetic and the static friction was slightly changed from 0.3 to 0.6, depending on the size of the particles. However, the value of the ratio was little affected by other factors such as the particles' location, the tip normal force and the surface modification. The results provided new insights into the intriguing friction phenomenon on the nanoscale. PMID- 23725520 TI - Emergency cricothyrotomy--a systematic review. AB - BACKGROUND: An emergency cricothyrotomy is the last-resort in most airway management protocols and is performed when it is not possible to intubate or ventilate a patient. This situation can rapidly prove fatal, making it important to identify the best method to establish a secure airway. We conducted a systematic review to identify whether there exists superiority between available commercial kits versus traditional surgical and needle techniques. METHODS: Medline, EMBASE and other databases were searched for pertinent studies. The inclusion criteria included manikin, animal and human studies and there were no restrictions regarding the professional background of the person performing the procedure. RESULTS: In total, 1,405 unique references were identified; 108 full text articles were retrieved; and 24 studies were included in the review. Studies comparing kits with one another or with various surgical and needle techniques were identified. The outcome measures included in this systematic review were success rate and time consumption. The investigators performing the studies had chosen unique combinations of starting and stopping points for time measurements, making comparisons between studies difficult and leading to many conflicting results. No single method was shown to be better than the others, but the size of the studies makes it impossible to draw firm conclusions. CONCLUSIONS: The large majority of the studies were too small to demonstrate statistically significant differences, and the limited available evidence was of low or very low quality. That none of the techniques in these studies demonstrated better results than the others does not necessarily indicate that each is equally good, and these conclusions will likely change as new evidence becomes available. PMID- 23725522 TI - The nature of outsourced preclinical research--the example of chemical synthesis. AB - The possibility to buy standardized external services or even new and innovative methods within drug discovery has increased dramatically during the last decades. Service providers are able to provide timely and efficient solutions to any given problem within preclinical research. The outsourcing behavior depends on the specific company type. Generally, the outsourcing level of emerging pharmaceutical and biotechnology companies is much higher than established companies due to low or missing internal resources. Whereas the "make-or-buy" decisions of large and fully integrated pharmaceutical companies are mainly competency driven, those of mid-size and small pharmaceutical, as well as biotech companies show a specific combination of cost/capacity and competency. The three different cooperation models "price competition", "project selection," and "strategic partnership" were identified. For all types of companies, the cooperation model of "strategic partnership" offers access to high-level expertise while reducing fixed costs and complexity. This was shown using chemical synthesis as an example but is also true for other areas of preclinical research. PMID- 23725521 TI - Factors influencing participation in a vascular disease prevention lifestyle program among participants in a cluster randomized trial. AB - BACKGROUND: Previous research suggests that lifestyle intervention for the prevention of diabetes and cardiovascular disease (CVD) are effective, however little is known about factors affecting participation in such programs. This study aims to explore factors influencing levels of participation in a lifestyle modification program conducted as part of a cluster randomized controlled trial of CVD prevention in primary care. METHODS: This concurrent mixed methods study used data from the intervention arm of a cluster RCT which recruited 30 practices through two rural and three urban primary care organizations. Practices were randomly allocated to intervention (n = 16) and control (n = 14) groups. In each practice up to 160 eligible patients aged between 40 and 64 years old, were invited to participate. Intervention practice staff were trained in lifestyle assessment and counseling and referred high risk patients to a lifestyle modification program (LMP) consisting of two individual and six group sessions over a nine month period. Data included a patient survey, clinical audit, practice survey on capacity for preventive care, referral and attendance records at the LMP and qualitative interviews with Intervention Officers facilitating the LMP. Multi-level logistic regression modelling was used to examine independent predictors of attendance at the LMP, supplemented with qualitative data from interviews with Intervention Officers facilitating the program. RESULTS: A total of 197 individuals were referred to the LMP (63% of those eligible). Over a third of patients (36.5%) referred to the LMP did not attend any sessions, with 59.4% attending at least half of the planned sessions. The only independent predictors of attendance at the program were employment status - not working (OR: 2.39 95% CI 1.15-4.94) and having high psychological distress (OR: 2.17 95% CI: 1.10 4.30). Qualitative data revealed that physical access to the program was a barrier, while GP/practice endorsement of the program and flexibility in program delivery facilitated attendance. CONCLUSION: Barriers to attendance at a LMP for CVD prevention related mainly to external factors including work commitments and poor physical access to the programs rather than an individuals' health risk profile or readiness to change. Improving physical access and offering flexibility in program delivery may enhance future attendance. Finally, associations between psychological distress and attendance rates warrant further investigation. TRIAL REGISTRATION: ACTRN12607000423415. PMID- 23725523 TI - A short-term evaluation of the relationship between plasma ascorbic acid levels and periodontal disease in systemically healthy and type 2 diabetes mellitus subjects. AB - BACKGROUND: Deficient ascorbic acid levels (AALs) and Type 2 diabetes mellitus (T2DM) are associated with periodontal disease. This study evaluated the relationship between plasma AAL and periodontitis in systemically healthy and T2DM subjects, which to the best of our knowledge is being reported for the first time. METHODS: One hundred twenty subjects were categorized into four groups of 30 each as group 1: without periodontal disease; group 2: chronic gingivitis; group 3: chronic periodontitis, and group 4: chronic periodontitis and freshly diagnosed T2DM. Plaque index (PlI), sulcus bleeding index (SBI), and probing pocket depths (PPDs) were evaluated. Venous blood was evaluated for plasma AAL spectrophotometrically. Randomized subjects were subgrouped within groups 2-4, to receive either scaling and root planing (SRP) with dietary supplementation (450 mg) of ascorbic acid (AA) for two weeks or only SRP. After two weeks, the clinical parameters were reassessed. Tukey's multiple post hoc procedures and paired t test were used with the level of statistical significance adjusted to p <= .05. RESULTS: AAL plasma levels were significantly greater in group 1 than in group 2 (p = .0007) and in group 4 (p = .0003). A significant reduction in the SBI was seen in the subgroups that received dietary supplementation of vitamin C within group 2 (p = .0012) and group 4 (p = .036). CONCLUSIONS: Plasma AAL is below the normal range in systemically healthy subjects with gingivitis and diabetics with periodontitis. Dietary AA supplementation with SRP improves the SBI in subjects with gingivitis and diabetics with periodontitis. PMID- 23725524 TI - The effect of green tea and sour tea on blood pressure of patients with type 2 diabetes: a randomized clinical trial. AB - INTRODUCTION: The use of herbal medicines including different types of tea is among the different strategies for preventing and controlling the side-effects of diabetes. The aim of the present study was to compare the effect of sour tea and green tea on mildly hypertensive patients with diabetes. METHODS: The present study was a randomized clinical trial in which 100 mildly hypertensive patients with diabetes were randomly assigned into sour tea group (ST) and green tea group (GT). They were instructed to drink sour tea and green tea infusion, respectively, three times a day 2 hr after each meal for 4 weeks. The participants' blood pressure was measured at days 1, 15, and at the end of study. RESULTS: The systolic pressure of both groups statistically decreased at the end of the study; it decreased from 123.1 +/- 15.5 to 116.8 +/- 16.3 mmHg in the ST and from 119.4 +/- 15.1 to 114.8 +/- 15.9 mmHg in the GT. The diastolic pressure of both groups statistically decreased by the end of the study; it decreased from 79.4 +/- 11.1 to 74.5 +/- 9.3 mmHg in the ST and from 78.9 +/- 8.3 to 75.3 +/- 7.7 mmHg in the GT. The therapeutic effectiveness of tea drinking by the end of intervention was 43.5% in the ST and 39.6% in the GT compared to the beginning. CONCLUSIONS: The present study revealed that mildly hypertensive type 2 diabetic individuals who drink three glasses of green or sour tea daily for 4 weeks show significant decreased systolic and diastolic blood pressures. PMID- 23725526 TI - Improvement of fasting plasma glucose level after ingesting moderate amount of dietary fiber in Japanese men with mild hyperglycemia and visceral fat obesity. AB - A double-blind, randomized, controlled study was conducted to evaluate the effects of a moderate amount of dietary fiber intake on fasting plasma glucose level and physical characteristics in Japanese men with mild hyperglycemia and visceral fat obesity. Thirty men with mild hyperglycemia (>5.6 mmol/L) and visceral fat accumulation (>100 cm2) ingested 7.5 g/day of dietary fiber for 12 weeks. An abdominal computed tomography scan was performed at baseline and at week 12. Blood was drawn every 4 weeks. In the test food group, fasting plasma glucose level was reduced with time, and the difference between the test food group and placebo group was statistically significant at week 12. Body weight and body mass index were also reduced with time, but visceral and subcutaneous fat areas did not change significantly during the study period. The results suggest that even a moderate amount of dietary fiber intake may be beneficial for managing the fasting plasma glucose level concomitant with insulin resistance, body weight, and body mass index in Japanese men with mild hyperglycemia and visceral fat obesity. PMID- 23725525 TI - Antihypercholesterolemic effect of Macrotyloma uniflorum (Lam.) Verdc (Fabaceae) extract on high-fat diet-induced hypercholesterolemia in Sprague-Dawley rats. AB - OBJECTIVE: The present study evaluated the antihypercholesterolemic effect of Macrotyloma uniflorum (Lam.) Verdc extract by examining its effects on food consumption, weight gain, serum lipid profile, serum glutamate oxaloacetate transamianse (SGOT), serum glutamate pyruvate transaminase (SGPT), and body fat in rats. METHODS: Animals were fed with experimental high-fat diets (HFD) that contain 10% lard plus, 5% corn oil. Food intake and body weight were measured. Serum samples were analyzed for the estimation of lipid profiles and other biochemical parameters by using kits. RESULTS: The consumption of ethanol and water extract of experimental plant for 5 weeks caused the decrease in total cholesterol (TC), triglycerides, low-density lipoprotein (LDL), very low density lipoprotein (VLDL) SGOT and SGPT significantly (p < .01), and increase in high density lipoprotein (HDL) significantly (p < .01). The rat group fed with HFD has shown higher serum TC, TG, LDL, VLDL, SGOT, SGPT, and lower HDL than in the normal control group (p < .01). Fecal excretion of cholesterol in the ethanol extract-treated groups was significantly higher than those treated with water extract. Body weight in the water extract-treated groups was significantly lower than that in the ethanol extract-treated groups. CONCLUSION: This study demonstrated that M. uniflorum (Lam.) Verdc extracts have strong activities against hypercholesterolemia and obesity suggesting a potential usefulness of M. uniflorum (Lam.) Verdc extracts as functional ingredients. PMID- 23725527 TI - Differences in dietary supplement use and secular and seasonal trends assessed using three different instruments in the EPIC-Norfolk population study. AB - OBJECTIVE: Supplement use has increased over time and measurements of supplement use are dependent on instruments chosen. Therefore, we investigated three different questionnaires to measure supplement use and whether these results were associated with age, year of recruitment (secular trend, 1993-1998), and seasonal trends. DESIGN: The questionnaires were self-administered within a median time interval of 54 days and included a Health and Lifestyle Questionnaire (1-year recall), a Food Frequency Questionnaire (1-year recall), and a 7-day diet diary. SETTING: Men and women, aged 40-79 years from the general population living in Norfolk (East Anglia, UK), recruited between 1993 and 1998 in the European Prospective Investigation into Cancer Study (EPIC-Norfolk). RESULTS: The prevalence of supplement use estimated with different instruments ranged from 31.7% to 39.0% for men and 45.0% to 54.3% for women. Agreement was substantial with kappa-statistics between 0.72 and 0.81. Participants' age (men only) and recruitment year were independently associated with supplement use; season showed inconsistent results. CONCLUSIONS: The diary provides a good agreement as measured by the kappa-statistic, compared to more long-term measures of supplement use classification. The secular and seasonal trends in supplement use and type of assessment instrument need to be taken into account in studies on health and supplement use. PMID- 23725528 TI - An evidence-based systematic review of kratom (Mitragyna speciosa) by the Natural Standard Research Collaboration. AB - An evidence-based systematic review of kratom (Mitragyna speciosa) by the Natural Standard Research Collaboration consolidates the safety and efficacy data available in the scientific literature using a validated, reproducible grading rationale. This article includes written and statistical analysis of clinical trials, plus a compilation of expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. PMID- 23725529 TI - JPOG in the future: building on credibility, visibility and readability. PMID- 23725530 TI - Secondary prophylaxis of variceal bleeding for cirrhotic patients: a multiple treatments meta-analysis. AB - OBJECTIVE: To evaluate comprehensively the effects of 12 prophylaxis interventions for secondary prophylaxis of variceal bleeding using multiple treatments meta-analysis. METHODS: PubMed, EMBASE and the Cochrane Library were searched prior to November 2011. Randomized controlled trials (RCTs) comparing the interventions for secondary prophylaxis of variceal bleeding. The primary study outcomes were variceal rebleeding, mortality due to rebleeding and mortality due to all causes. RESULTS: We systematically reviewed 51 RCTs. Transjugular intrahepatic portosystemic shunt (TIPS), beta-blockers combined with endoscopic injection sclerotherapy (EIS) and endoscopic banding ligation (EBL) combined with EIS were superior to beta-blockers [odds ratios (OR) 0.13, 0.23 and 0.13, respectively] and EIS (0.19, 0.34 and 0.18, respectively) in reducing the rate of rebleeding. To reduce the mortality rate due to rebleeding, TIPS was more efficacious than beta-blockers (0.11), EBL (0.13), EIS (0.19), beta-blockers combined with isosorbide-5-mononitrate (5-ISMN) (0.16) and beta-blockers combined with EIS (0.14). In addition, beta-blockers combined with 5-ISMN were significantly more efficacious than beta-blockers (0.56) and EBL (0.64) to reduce the mortality rate due to all causes. EBL combined with argon plasma coagulation showed the best profile of reduction in rebleeding rate and mortality rate due to all causes. To reduce the mortality rate due to rebleeding, TIPS had the highest probability. EBL combined with EIS was the best choice according to the cumulative probabilities of being among the three most efficacious interventions for the three outcomes. CONCLUSIONS: Endoscopic banding ligation combined with EIS might be the first choice in the secondary prophylaxis of varices bleeding. PMID- 23725531 TI - A citation analysis of nurse education journals using various bibliometric indicators. PMID- 23725533 TI - More than a drop in the bucket: decentralized membrane-based drinking water refill stations in southeast Asia. AB - Decentralized membrane-based water treatment and refill stations represent a viable and growing business model in Southeast Asia, which rely upon the purchase of water from refill stations by consumers. This feature article discusses these water treatment and refill stations, including the appropriateness of the technology, the suitability of the business models employed, and the long-term environmental and operational sustainability of these systems. We also provide an outlook for the sector, highlighting key technical challenges that need to be addressed in order to improve the capacity of these systems, such that they can become an effective and financially viable solution. PMID- 23725534 TI - Progressive striatal necrosis associated with anti-NMDA receptor antibodies. AB - BACKGROUND: We report a case of childhood onset, generalized dystonia due to slowly progressive bilateral striatal necrosis associated with anti-N-methyl-D aspartate receptor (NMDAR) antibodies. This clinical phenotype has not been previously associated with NMDA receptor autoimmunity. CASE PRESENTATION: An eighteen year old man presented with a history of childhood-onset, progressive generalized dystonia. Clinical examination revealed a pure generalized dystonia with no cognitive or other neurological findings. Magnetic resonance imaging showed bilateral high T2 signal striatal lesions, which were slowly progressive over a period of nine years. New parts of the lesion showed restricted water diffusion suggesting cytotoxic oedema. Positron emission tomography of the brain showed frontal hypermetabolism and cerebellar hypometabolism. Antibodies against the NR1 subunit of the NMDA receptor were detected in the patient's serum and cerebrospinal fluid. There was no neoplasia or preceding infection or vaccination. CONCLUSION: This is the first report of chronic progressive bilateral striatal necrosis associated with anti-NMDAR antibodies. Our findings expand the clinical spectrum of disease associated with anti-NMDAR antibodies and suggest that these should be included in the work-up of dystonia with striatal necrosis. PMID- 23725535 TI - Dual-functional abeo-taxane derivatives destabilizing microtubule equilibrium and inhibiting NF-kappaB activation. AB - Taxchinin A, with a 11(15->1)-abeo-taxane skeleton, is a major, but inactive taxoid contained in leaves of Taxus chinensis . In our design of dual-functional antitumor abeo-taxane derivatives, two fragments from antitumor agents with different molecular targets (the N-acyl-3'-phenylisoserine side chain from the antimitotic agent paclitaxel and an alpha,beta-unsaturated carbonyl system from NF-kappaB inhibitors) were incorporated into the scaffold of taxchinin A. The resulting compounds displayed broad inhibitory effects against proliferation of tumor cell lines, with notable selectivity toward colon cancer, melanoma, and renal cancer, when evaluated in the NCI-60 human tumor cell line screening panel. On the basis of the NCI-60 assay data, structure-activity relationship (SAR) correlations were elucidated. Mechanistic studies indicated that this new compound type can both destabilize microtubules and inhibit NF-kappaB activation, thereby inducing tumor cell apoptosis. This first report of the dual-functional taxoid-core compounds thus provides new opportunities for future drug development based on natural axoid scaffolds. PMID- 23725536 TI - Solution structures of the linear leaderless bacteriocins enterocin 7A and 7B resemble carnocyclin A, a circular antimicrobial peptide. AB - Leaderless bacteriocins are a class of ribosomally synthesized antimicrobial peptides that are produced by certain Gram-positive bacteria without an N terminal leader section. These bacteriocins are of great interest due to their potent inhibition of many Gram-positive organisms, including food-borne pathogens such as Listeria and Clostridium spp. We now report the NMR solution structures of enterocins 7A and 7B, leaderless bacteriocins recently isolated from Enterococcus faecalis 710C. These are the first three-dimensional structures to be reported for bacteriocins of this class. Unlike most other linear Gram positive bacteriocins, enterocins 7A and 7B are highly structured in aqueous conditions. Both peptides are primarily alpha-helical, adopting a similar overall fold. The structures can be divided into three separate alpha-helical regions: the N- and C-termini are both alpha-helical, separated by a central kinked alpha helix. The overall structures bear an unexpected resemblance to carnocyclin A, a 60-residue peptide that is cyclized via an amide bond between the C- and N termini and has a saposin fold. Because of synergism observed for other two peptide leaderless bacteriocins, it was of interest to probe possible binding interactions between enterocins 7A and 7B. However, despite synergistic activity observed between these peptides, no significant binding interaction was observed based on NMR and isothermal calorimetry. PMID- 23725537 TI - The economic impact of Medicare Part D on congestive heart failure. AB - Medicare Part D has had important implications for patient outcomes and treatment costs among beneficiaries with congestive heart failure (CHF). This study finds that improved medication adherence associated with expansion of drug coverage under Part D led to nearly $2.6 billion in reductions in medical expenditures annually among beneficiaries diagnosed with CHF and without prior comprehensive drug coverage, of which over $2.3 billion was savings to Medicare. Further improvements in adherence could potentially save Medicare another $1.9 billion annually, generating upwards of $22.4 billion in federal savings over 10 years. PMID- 23725539 TI - Significant differences in nonmelanoma skin cancers of the upper and lower lip. AB - BACKGROUND: Squamous cell carcinomas (SCCs) generally have been reported to be more prevalent on the lips than basal cell carcinomas (BCCs), but in our experience, BCCs of the lips are common, particularly in women. OBJECTIVES: To determine the tumor characteristics of lip SCCs and BCCs, including tumor type, anatomic location, and size; and to identify the relationship between patient characteristics, including age and sex, and lip tumor characteristics. METHODS AND MATERIALS: Retrospective review of all BCCs and SCCs located on the lip treated between January 1995 and October 2010. RESULTS: Of 470 lip nonmelanoma skin cancers (NMSCs) identified, 71.4% were BCCs, and 28.6% were SCCs. Lower lip tumors were predominantly SCCs (79.8%, p < .01), whereas upper lip tumors were predominantly BCCs (85.7%, p < .01). Patients with lower lip tumors were significantly older (68.8 vs. 64.7, p = .02) and were largely male (70.8%, p < .01). Patients with SCCs were mostly male (62.2%, p = .02), whereas those with BCCs were predominantly female (68.8%, p < .01). Subgroup analysis showed that upper lip tumors were 98.1% cutaneous or more than 50% cutaneous, whereas 56.3% of lower lip tumors were mucosal or more than 50% mucosal; 87.1% of mucosal tumors were SCCs, whereas 83.6% of cutaneous tumors were BCCs (p < .01). Seventy one percent of patients with mucosal tumors were men, whereas 67% of patients with cutaneous only tumors were women (p < .01). CONCLUSION: These data provide evidence of significant differences in patient and tumor characteristics between NMSCs of the upper and lower lips. PMID- 23725538 TI - Surgical treatment of innominate artery and aortic aneurysm: a case report and review of the literature. AB - Innominate artery (IA) aneurysms represent 3% of all arterial aneurysms. Due to the risk of thromboembolic complications and spontaneous rupture, surgical repair is usually recommended on an early elective basis. We present the case of 81-year old Caucasian male presenting with atypical anterior chest pain secondary to a large innominate artery aneurysm who underwent successful open surgical repair at our institution. In our experience, open correction via median sternotomy with extension into the right neck provides excellent exposure and facilitates rapid reconstruction with good short and long-term outcomes. Minimally invasive and endovascular approaches provide emerging alternatives to open IA aneurysm repair, however further research is required to better define optimal patient selection criteria and determine the long-term outcomes of these novel therapies. PMID- 23725541 TI - Different FCER1A polymorphisms influence IgE levels in asthmatics and non asthmatics. AB - BACKGROUND: Recently, three genome-wide association studies (GWAS) demonstrated FCER1A, the gene encoding a ligand-binding subunit of the high-affinity IgE receptor, to be a major susceptibility locus for serum IgE levels. The top association signal differed between the two studies from the general population and the one based on an asthma case-control design. In this study, we investigated whether different FCER1A polymorphisms are associated with total serum IgE in the general population and asthmatics specifically. METHODS: Nineteen polymorphisms were studied in FCER1A based on a detailed literature search and a tagging approach. Polymorphisms were genotyped by the Illumina HumanHap300Chip (6 polymorphisms) or MALDI-TOF MS (13 polymorphisms) in at least 1303 children (651 asthmatics) derived from the German International Study of Asthma and Allergies in Childhood II and Multicentre Asthma Genetics in Childhood Study. RESULTS: Similar to two population-based GWAS, the peak association with total serum IgE was observed for SNPs rs2511211, rs2427837, and rs2251746 (mean r(2) > 0.8), with the lowest p-value of 4.37 * 10(-6). The same 3 polymorphisms showed the strongest association in non-asthmatics (lowest p = 0.0003). While these polymorphisms were also associated with total serum IgE in asthmatics (lowest p = 0.003), additional polymorphisms (rs3845625, rs7522607, and rs2427829) demonstrated associations with total serum IgE in asthmatics only (lowest p = 0.01). CONCLUSIONS: These data suggest that FCER1A polymorphisms not only drive IgE levels in the general population but that specific polymorphisms may also influence IgE in association with asthma, suggesting that disease specific mechanisms in IgE regulation exist. PMID- 23725540 TI - Hypervariable antigen genes in malaria have ancient roots. AB - BACKGROUND: The var genes of the human malaria parasite Plasmodium falciparum are highly polymorphic loci coding for the erythrocyte membrane proteins 1 (PfEMP1), which are responsible for the cytoaherence of P. falciparum infected red blood cells to the human vasculature. Cytoadhesion, coupled with differential expression of var genes, contributes to virulence and allows the parasite to establish chronic infections by evading detection from the host's immune system. Although studying genetic diversity is a major focus of recent work on the var genes, little is known about the gene family's origin and evolutionary history. RESULTS: Using a novel hidden Markov model-based approach and var sequences assembled from additional isolates and species, we are able to reveal elements of both the early evolution of the var genes as well as recent diversifying events. We compare sequences of the var gene DBLalpha domains from divergent isolates of P. falciparum (3D7 and HB3), and a closely-related species, Plasmodium reichenowi. We find that the gene family is equally large in P. reichenowi and P. falciparum -- with a minimum of 51 var genes in the P. reichenowi genome (compared to 61 in 3D7 and a minimum of 48 in HB3). In addition, we are able to define large, continuous blocks of homologous sequence among P. falciparum and P. reichenowi var gene DBLalpha domains. These results reveal that the contemporary structure of the var gene family was present before the divergence of P. falciparum and P. reichenowi, estimated to be between 2.5 to 6 million years ago. We also reveal that recombination has played an important and traceable role in both the establishment, and the maintenance, of diversity in the sequences. CONCLUSIONS: Despite the remarkable diversity and rapid evolution found in these loci within and among P. falciparum populations, the basic structure of these domains and the gene family is surprisingly old and stable. Revealing a common structure as well as conserved sequence among two species also has implications for developing new primate-parasite models for studying the pathology and immunology of falciparum malaria, and for studying the population genetics of var genes and associated virulence phenotypes. PMID- 23725543 TI - Argon-induced pressure broadening, shifting, and narrowing in the CN A2Pi X2Sigma+ (1-0) band. AB - Selected isolated rotational transitions in the 1-0 band of the red A(2)Pi-X (2)Sigma(+) system in CN have been recorded with transient frequency modulation spectroscopy as a function of argon pressure up to 0.2 atm at room temperature. Line shapes were fit using Fourier transforms of a parametrized time correlation function, including Doppler and velocity-dependent collisional broadening, and collisional shifts. Deviations from Voigt line shapes can be equally well fit by modeling the narrowing with a speed-dependent collision model or with a velocity changing collisional narrowing model. Pressure broadening coefficients were observed with little rotational state dependence, in the range of 0.070-0.075 cm( 1) atm(-1). In contrast, stronger and qualitatively different rotational state dependences are observed for both pressure-dependent blue shift coefficients and the narrowing parameters. No asymmetry in the pressure broadened lines was observed. PMID- 23725542 TI - Using a periclinal chimera to unravel layer-specific gene expression in plants. AB - Plant organs are made from multiple cell types, and defining the expression level of a gene in any one cell or group of cells from a complex mixture is difficult. Dicotyledonous plants normally have three distinct layers of cells, L1, L2 and L3. Layer L1 is the single layer of cells making up the epidermis, layer L2 the single cell sub-epidermal layer and layer L3 constitutes the rest of the internal cells. Here we show how it is possible to harvest an organ and characterise the level of layer-specific expression by using a periclinal chimera that has its L1 layer from Solanum pennellii and its L2 and L3 layers from Solanum lycopersicum. This is possible by measuring the level of the frequency of species-specific transcripts. RNA-seq analysis enabled the genome-wide assessment of whether a gene is expressed in the L1 or L2/L3 layers. From 13 277 genes that are expressed in both the chimera and the parental lines and with at least one polymorphism between the parental alleles, we identified 382 genes that are preferentially expressed in L1 in contrast to 1159 genes in L2/L3. Gene ontology analysis shows that many genes preferentially expressed in L1 are involved in cutin and wax biosynthesis, whereas numerous genes that are preferentially expressed in L2/L3 tissue are associated with chloroplastic processes. These data indicate the use of such chimeras and provide detailed information on the level of layer-specific expression of genes. PMID- 23725544 TI - Efficacy of a group-based parenting program on stress and self-efficacy among Japanese mothers: a quasi-experimental study. AB - Early child development and the impact of parenting on later life are of global concern. The rise in child abuse and maltreatment in Japan suggests that measures to increase self-efficacy and reduce stress would benefit Japanese parents. In this study, we explored if Japanese parents attending a 123Magic parenting program reported reduced stress and enhanced self-efficacy. Questionnaire data were collected from 49 mothers attending a parenting program conducted in public nursery schools in one prefecture in Japan. There were significant changes in parenting self-efficacy scores (P < 0.001) and parenting stress scores (P < 0.01). Focus groups with 16 parents also found that there were benefits to parents in terms of increased confidence and less stress. The findings provide support for the role of public health nurses in delivering group-based parenting support in Japan. PMID- 23725545 TI - Bifunctional unnatural sialic acids for dual metabolic labeling of cell-surface sialylated glycans. AB - Sialic acid analogues containing a unique chemical functionality or chemical reporter have been metabolically incorporated into sialylated glycans. This process, termed metabolic glycan labeling, has emerged as a powerful tool for studying sialylation as well as other types of glycosylation. Currently, this technique can install only a single functionality. Here we describe a strategy for dual labeling of sialylated glycans using a new class of bifunctional sialic acid analogues containing two distinct chemical reporters at the N-acyl and C9 positions. These bifunctional unnatural sialic acids were metabolically incorporated into cellular glycans, where the two chemical reporters exerted their distinct functions. This approach expands the capability of metabolic glycan labeling to probe sialylation and glycan-protein interactions. PMID- 23725546 TI - Sorting inactivated cells using cell-imprinted polymer thin films. AB - Previous work showed that cell imprinting in a poly(dimethylsiloxane) film produced artificial receptors to cells by template-assisted rearrangement of functional groups on the surface of the polymer thin film which facilitated cell capture in the polymer surface indentations by size, shape, and, most importantly, chemical recognition. We report here that inactivation of cells by treatment with formaldehyde (4%), glutaraldehyde (2%), or a combination of the two leads to markedly improved capture selectivity (a factor of 3) when cells to be analyzed are inactivated in the same manner. The enhanced capture efficiency compared to living cells results from two factors: (1) rigidification of the cell surface through cross-linking of amine groups by the aldehyde; and (2) elimination of chemicals excreted from living cells which interfere with the fidelity of the cell-imprinting process. Moreover, cell inactivation has the advantage of removing biohazard risks associated with working with virulent bacteria. These results are demonstrated using different strains of Mycobacterium tuberculosis. PMID- 23725547 TI - A comparison of three-dimensional culture systems to evaluate in vitro chondrogenesis of equine bone marrow-derived mesenchymal stem cells. AB - OBJECTIVE: To compare in vitro three-dimensional (3D) culture systems that model chondrogenesis of bone marrow-derived mesenchymal stem cells (MSCs). METHODS: MSCs from five horses 2-3 years of age were consolidated in fibrin 0.3% alginate, 1.2% alginate, 2.5*10(5) cell pellets, 5*10(5) cell pellets, and 2% agarose, and maintained in chondrogenic medium with supplemental TGF-beta1 for 4 weeks. Pellets and media were tested at days 1, 14, and 28 for gene expression of markers of chondrogenic maturation and hypertrophy (ACAN, COL2B, COL10, SOX9, 18S), and evaluated by histology (hematoxylin and eosin, Toluidine Blue) and immunohistochemistry (collagen type II and X). RESULTS: alginate, fibrin alginate (FA), and both pellet culture systems resulted in chondrogenic transformation. Adequate RNA was not obtained from agarose cultures at any time point. There was increased COL2B, ACAN, and SOX9 expression on day 14 from both pellet culture systems. On day 28, increased expression of COL2B was maintained in 5*10(5) cell pellets and there was no difference in ACAN and SOX9 between FA and both pellet cultures. COL10 expression was significantly lower in FA cultures on day 28. Collagen type II was abundantly formed in all culture systems except alginate and collagen type X was least in FA hydrogels. CONCLUSION: equine MSCs respond to 3D culture in FA blended hydrogel and both pellet culture systems with chondrogenic induction. For prevention of terminal differentiation and hypertrophy, FA culture may be superior to pellet culture systems. PMID- 23725548 TI - Neural stem cells as tools for drug discovery: novel platforms and approaches. AB - INTRODUCTION: Neural stem cells catalyze strong interests for the development of systems to screen for effective drugs to treat neurodegenerative conditions and/or improve neurogenesis, fields where the classical approaches have so far failed in discovering successful drugs. AREAS COVERED: The authors review the known biology of NSCs, their normal function in development, the adult brain, and in vitro culture systems. The authors also discuss the scientific and technological progress which will aid wider applications of NSCs for drug screening/development purposes. The authors base this article on literature searches performed through PubMed and Google Scholar. EXPERT OPINION: NSC systems present unique opportunities that are starting to be successfully explored for genetic and chemical screening. These systems provide the possibility of identifying and optimizing molecules/drugs that could lead to the tighter control in self-renewal and lineage specification of NSCs as well as their functional maturation. This could be crucial in moving forward NSC-based therapies. It is expected that recent advances in the method of producing NSCs from patient specific human induced pluripotent stem (iPS) cells and in the technologies to grow them in vitro, while preserving their full developmental potential, will allow a full exploitation of NSCs both in drug discovery programs and in predictive toxicology studies. PMID- 23725549 TI - Expanding the environment: gene * school-level SES interaction on reading comprehension. AB - BACKGROUND: Influential work has explored the role of family socioeconomic status (SES) as an environmental moderator of genetic and environmental influences on cognitive outcomes. This work has provided evidence that socioeconomic circumstances differentially impact the heritability of cognitive abilities, generally supporting the bioecological model in that genetic influences are greater at higher levels of family SES. The present work expanded consideration of the environment, using school-level SES as a moderator of reading comprehension. METHODS: The sample included 577 pairs of twins from the Florida Twin Project on Reading, Behavior and Environment. Reading comprehension was measured by the Florida Comprehensive Achievement Test (FCAT) Reading in third or fourth grade. School-level SES was measured by the mean Free and Reduced Lunch Status (FRLS) of the schoolmates of the twins. RESULTS: The best-fitting univariate G * E moderation model indicated greater genetic influences on reading comprehension when fewer schoolmates qualified for FRLS (i.e., 'higher' school level SES). There was also an indication of moderation of the shared environment; there were greater shared environmental influences on reading comprehension at higher school-level SES. CONCLUSIONS: The results supported the bioecological model; greater genetic variance was found in school environments in which student populations experienced less poverty. In general, 'higher' school-level SES allowed genetic and probably shared environmental variance to contribute as sources of individual differences in reading comprehension outcomes. Poverty suppresses these influences. PMID- 23725551 TI - Role of black carbon electrical conductivity in mediating hexahydro-1,3,5 trinitro-1,3,5-triazine (RDX) transformation on carbon surfaces by sulfides. AB - Recent research has demonstrated that black carbons catalyze the transformation of a range of nitrated explosives sorbed to the carbon surfaces in the presence of sulfides. Although surface oxygenated functional groups, particularly quinones, and electrical conductivity have both been hypothesized to promote these reactions, the importance of these properties has not been tested. In this work, the importance of electrical conductivity was addressed by producing chars of increasing electrical conductivity via pyrolysis of wood shavings at increasing temperature. The reactivity of chars with respect to transformation of the explosive RDX in the presence of sulfides correlated with electrical conductivity. Oxygenated functional groups were apparently not involved, as demonstrated by the elimination of reactivity of an activated carbon after ozone treatment or sorption of model quinones to the activated carbon surface. Although RDX transformation correlated with char electrical conductivity, no RDX transformation was observed when RDX was physically separated from sulfides but electrically connected through an electrochemical cell. RDX transformation occurred in the presence of a surface-associated sulfur species. The correlation with char electrical conductivity suggests that sulfides are oxidized on carbon surfaces to products that serve as potent nucleophiles promoting RDX transformation. PMID- 23725550 TI - Low-dose temozolomide before dendritic-cell vaccination reduces (specifically) CD4+CD25++Foxp3+ regulatory T-cells in advanced melanoma patients. AB - BACKGROUND: In cancer immunotherapy, dendritic cells (DCs) play a fundamental role in the dialog between innate and adaptive immune response, but several immunosuppressive mechanisms remain to be overcome. For example, a high number of CD4+CD25++Foxp3+ regulatory T-cells (Foxp3+Tregs) have been observed in the peripheral blood and tumor microenvironment of cancer patients. On the basis of this, we conducted a study on DC-based vaccination in advanced melanoma, adding low-dose temozolomide to obtain lymphodepletion. METHODS: Twenty-one patients were entered onto our vaccination protocol using autologous DCs pulsed with autologous tumor lysate and keyhole limpet hemocyanin. Patients received low-dose temozolomide before vaccination and 5 days of low-dose interleukin-2 (IL-2) after vaccination. Circulating Foxp3+Tregs were evaluated before and after temozolomide, and after IL-2. RESULTS: Among the 17 evaluable patients we observed 1 partial response (PR), 6 stable disease (SD) and 10 progressive disease (PD). The disease control rate (PR+SD = DCR) was 41% and median overall survival was 10 months. Temozolomide reduced circulating Foxp3+Treg cells in all patients. A statistically significant reduction of 60% was observed in Foxp3+Tregs after the first cycle, whereas the absolute lymphocyte count decreased by only 14%. Conversely, IL-2 increased Foxp3+Treg cell count by 75.4%. Of note the effect of this cytokine, albeit not statistically significant, on the DCR subgroup led to a further 33.8% reduction in Foxp3+Treg cells. CONCLUSIONS: Our results suggest that the combined immunological therapy, at least as far as the DCR subgroup is concerned, effectively reduced the number of Foxp3+Treg cells, which exerted a blunting effect on the growth-stimulating effect of IL-2. However, this regimen, with its current modality, would not seem to be capable of improving clinical outcome. PMID- 23725552 TI - Effectiveness of nurse case management compared with usual care in cancer patients at a single medical center in Taiwan: a quasi-experimental study. AB - BACKGROUND: In order to improve treatment and care quality for cancer patients, nurse case management model has applied generally in the clinical practice. However there were only few evidence-based studies on the relative benefits in Taiwan. Further analysis and feedback application are needed. The aim of this study is to evaluate the effectiveness of care quality in cancer patients with nurse case management. METHODS: This study was conducted with a quasi experimental design in a national medical center in Northern Taiwan. Patients diagnosed as lung, liver, breast, colon, buccal or cervical cancers were eligible for inclusion. A total number of 600 subjects randomly selected from the cancer case management system enrolled in the case managed group, and 600 patients who received usual care were randomly selected from cancer registry and enrolled in the control group. The study instrument was developed to measure care effectiveness, including the rates of patient continuing treatment, non-adherence to treatment, prolonged hospitalization, unplanned readmission, and planned admission for active treatment. The content validity of expert was assessed as 0.9. RESULTS: The nurse case management significantly decreased the unplanned readmission rate caused by infection (1.5% vs. 4.7% in the control group, p = 0.002). The rate of patient continuing treatment in the institution significantly increased in the case managed group (93.8% vs. 84.8% in the control group, p < 0.001). The planned admission rates in 14 days and in 15-30 days for active treatment also significantly increased in the case managed group (18.4.% vs. 3.9% in the control group and 34.5% vs. 10.4% in the control group, respectively, p < 0.001). The results indicated that nurse case management provided better control in timeliness and continuity of patient treatment. CONCLUSIONS: This study demonstrated that cancer case management could improve the effectiveness of cancer care services and concretely illustrated a comprehensive model for oncology patients in Taiwan. In addition, the model could be optimized for further application and improvement of cancer care. Future investigations are needed to develop precise and rigorous evaluation to optimize the utilization of cancer case management. PMID- 23725553 TI - The impact of fatigue and psychosocial variables on quality of life for patients with motor neuron disease. AB - Our objective was to evaluate the direct and indirect relationships between psychosocial variables, fatigue and quality of life for patients with motor neuron disease (MND). A cross-sectional sample of 147 MND patients was recruited from five neurological care centres in England. Variables included anxiety, coping, depression, fatigue, functional status, social withdrawal and quality of life. Direct and indirect relationships between study variables were assessed using structural equation modelling (SEM), using linear values derived from Rasch analyses of study questionnaires. Following some modification, Rasch analysis confirmed the suitability of all measures for use in this population. The final SEM model consisting of anxiety, coping, depression, fatigue, social withdrawal and quality of life showed excellent fit to the data. The model accounted for 59% of the variance in quality of life and 50% of the variance in depression. In conclusion, our data support a model that explains a large degree of the variance in quality of life for MND patients. Coping was most strongly related to quality of life, with the largest proportion of its influence mediated by anxiety and depression. Significant direct effects upon quality of life were exhibited by depression, fatigue and social withdrawal. PMID- 23725554 TI - Longitudinal associations between violence and suicidality from adolescence into adulthood. AB - The link between violence and suicide is well documented. Previous studies, however, largely rely on cross-sectional designs or only consider violence as an antecedent of suicide. The purpose of the current study was to investigate the longitudinal relationship between violence and suicide from adolescence into young adulthood. Data were derived from Wave II (1995-1996), Wave III (2001 2002), and Wave IV (2007-2008) of the National Longitudinal Study of Adolescent Health (N = 8,966). We tested (2011-2013) a series of path analysis models in Mplus to determine the longitudinal associations between violence and suicidality. Results from the path analyses indicated that violence and suicidality mutually affect each other from adolescence into young adulthood. We found some evidence that the association between suicidality and violence was stronger for males compared to females, particularly in early and young adulthood. The current study confirms previous findings by demonstrating that violence is a risk factor for future suicide. We also extended the previous literature by demonstrating that a history of suicidality is associated with future risk for violence. Our findings highlight the importance of further integrating prevention efforts to reduce violence and suicidality during adolescence and early/young adulthood. PMID- 23725555 TI - The effects of chronic AMPK activation on hepatic triglyceride accumulation and glycerol 3-phosphate acyltransferase activity with high fat feeding. AB - BACKGROUND: High fat feeding increases hepatic fat accumulation and is associated with hepatic insulin resistance. AMP Activated Protein Kinase (AMPK) is thought to inhibit lipid synthesis by the acute inhibition of glycerol-3-phosphate acyltransferase (GPAT) activity and transcriptional regulation via sterol regulatory element binding protein-1c (SREBP-1c). METHODS: The purpose of this study was to determine if chronic activation of AMPK prevented an increase in GPAT1 activity in rats fed a high fat diet. Rats were fed a control (C), or a high fat (HF) diet (60% fat) for 6 weeks and injected with saline or a daily aminoimidazole carboxamide ribnucleotide (AICAR) dose of 0.5 mg/g body weight. RESULTS: Chronic AMPK activation by AICAR injections resulted in a significant reduction in hepatic triglyceride accumulation in both the C and HF fed animals (C, 5.5+/-0.7; C+AICAR, 2.7 +/-0.3; HF, 21.8+/-3.3; and HF+AICAR, 8.0+/-1.8 mg/g liver). HF feeding caused an increase in total GPAT and GPAT1 activity, which was not affected by chronic AMPK activation (GPAT1 activity vs. C, C+AICAR, 92+/-19%; HF, 186+/-43%; HF+AICAR, 234+/-62%). Markers of oxidative capacity, including citrate synthase activity and cytochrome c abundance, were not affected by chronic AICAR treatment. Interestingly, HF feeding caused a significant increase in long chain acyl-CoA dehydrogenase or LCAD (up 66% from C), a marker of fatty acid oxidation capacity. CONCLUSIONS: These results suggest that chronic AMPK activation limits hepatic triglyceride accumulation independent of a reduction in total GPAT1 activity. PMID- 23725556 TI - Healing of the goat anterior cruciate ligament after a new suture repair technique and bioscaffold treatment. AB - Primary suture repair of the anterior cruciate ligament (ACL) has been used clinically in an attempt to heal the ruptured ACL. The results, however, were not satisfactory, which in retrospect can be attributed to the used suturing technique and the suboptimal healing conditions. These constraining conditions can be improved by introducing a new suturing technique and by using small intestinal submucosa (SIS) as a bioscaffold. It is hypothesized that the suturing technique keep the torn ends together and that SIS enhance and promote the healing of the ACL. The goat was used as the study model. In the Suture group, the left ACL was transected and suture repaired with a new locking suture repair technique (n=5) allowing approximation and fixation under tension. The Suture-SIS group underwent the same procedure with the addition of SIS (n=5). The right ACL served as control. After 12 weeks of healing, anterior-posterior translation and in situ force of the healing ACL were measured, followed by the measurement of the cross-sectional area and structural stiffness. Routine histology was performed on tissue samples. Gross morphology showed that the healing ACL was continuous with collagenous tissue in both groups. The cross-sectional area of the Suture and the Suture-SIS group was 35% and 50% of the intact control, respectively. The anterior-posterior translations at different flexion angles were statistically not different between the Suture group and the Suture-SIS group. Only the in situ force at 30 degrees in the Suture-SIS group was higher than in the Suture group. Tensile tests showed that the stiffness for the Suture group was not different from the Suture-SIS group (31.1+/-8.1 N/mm vs. 41.9+/ 18.0 N/mm [p>0.05]). Histology showed longitudinally aligned collagen fibers from origo to insertion. More fibroblasts were present in the healing tissue than in the control intact tissue. The study demonstrated the proof of concept of ACL repair in a goat model with a new suture technique and SIS. The mechanical outcome is not worse than previously reported for ACL reconstruction. In conclusion, the approach of using a new suture technique, with or without a bioscaffold to heal the ACL is promising. PMID- 23725557 TI - Experiences of Thai individuals awaiting coronary artery bypass grafting: a qualitative study. AB - This qualitative descriptive study, underpinned by the naturalistic inquiry, explored the lived experiences of individuals awaiting coronary artery bypass grafting in Thailand. Eleven northern Thai individuals volunteered to participate. Data were gathered through in-depth interviews and analyzed using content analysis. Two major themes arose: uncertainty of life and striving to balance well-being. The first of these themes is presented in this paper. Uncertainty of life was recognized as a dynamic emotional state of being unsure or insecure in life, but its occurrence depended on the individual situation; it was described through two subthemes that had a profound effect on the participants: fear of death and fear of disability. Participants' uncertainty of life encompassed being unsure about the risks of dying from illness, both prior to and following the surgery, and surviving the surgery with a disability. These findings provide insight into the experiences of individuals awaiting coronary artery bypass grafting and will assist nurses and other healthcare providers in creating timely programs and appropriate interventions to reduce uncertainty of life while awaiting surgery. PMID- 23725558 TI - Prediction of maternal quality of life on preterm birth and low birthweight: a longitudinal study. AB - BACKGROUND: Preterm birth is a significant cause of newborn morbidity and mortality and strains society's healthcare resources due to its long-term effects on the health of the newborn. Prenatal maternal quality of life (QoL) may be related to the occurrence of preterm birth and low birthweight infants. Few studies, however, have investigated maternal QoL, especially throughout the continuum of pregnancy and the immediate postpartum period. Therefore, the purposes of this longitudinal study were to measure the levels of QoL during and immediately after pregnancy in women with uncomplicated pregnancies, investigate the relationships between the dimensions of QoL, and determine whether prenatal QoL can predict preterm birth and low birthweight. METHODS: Using convenience sampling in one hospital in Taiwan, we recruited 198 pregnant women without pregnancy complications after 24 gestational weeks and followed up monthly until one-month postpartum. The Duke Health Profile was used to measure QoL. Data were analyzed using descriptive statistics, the Mann-Whitney U test, the Kruskal Wallis test, generalized estimation equations, Pearson correlations, and hierarchical logistic regression. RESULTS: Pregnant women did not perceive that they had a high level of QoL. Women at late pregnancy experienced a significant decrease in their level of physical and general health. After childbirth, although the mothers had better physical health, they had poorer social health. Poor QoL at late pregnancy predicted preterm birth. Employment, parity, educational level, and happiness about pregnancy were related to prenatal maternal QoL; employment was a factor related to postpartum maternal QoL. CONCLUSIONS: Early assessment of QoL, including its dimensions, of pregnant women may help us to understand women's health status. Based on this understanding, healthcare professionals can develop interventions to promote pregnant women's QoL and to lessen the occurrence of preterm birth and low birthweight infants. Further, an emphasis on the positive aspects of pregnancy may increase maternal QoL. PMID- 23725559 TI - The influence of sun exposure in childhood and adolescence on atopic disease at adolescence. AB - BACKGROUND: It has been postulated that ultraviolet ray exposure in childhood might influence the development of allergic disease. We examined whether reported sun exposure during childhood or in adolescence is related to the occurrence of atopy or allergic disease. METHODS: Population-based longitudinal cohort study with sixteen-year follow-up (N = 415). Subjects were recruited at birth as part of an infant health study. The reported daily duration of sun exposure in the summer months was recorded at 8 and 16 yrs of age. Allergen sensitization and the presence of eczema, asthma, and rye grass positive rhinitis were recorded at age 16. RESULTS: Reported sun exposures of more than 4 h per day during summer holidays in adolescence were associated with reduced eczema and rhinitis but not inhalant allergen sensitization or asthma risk. Thus, higher sun exposure during summer holidays and summer weekends in adolescence was associated with significantly reduced eczema (test of trend p-value = 0.001 summer holidays; test of trend p-value = 0.003 summer weekends) and rye grass positive rhinitis (test of trend p-value = 0.03 summer holidays; test of trend p-value = 0.02 summer weekends). Sun exposure at adolescence or age 8 was not related to inhalant allergen sensitization. There was no association between serum 25(OH)D levels at adolescence with either inhalant allergen sensitization or allergic disease and adjustment for serum 25(OH)D levels did not alter these findings. CONCLUSIONS: Increased sun exposure during summer holidays in adolescence was associated with reduced eczema and rhinitis risk, independently of measured vitamin D levels but no difference in inhalant allergen sensitization or asthma. The beneficial effects of sun exposure on allergic disease may operate independently from vitamin D or an effect on allergen sensitization. PMID- 23725560 TI - Quantitative analysis of histone demethylase probes using fluorescence polarization. AB - We previously reported methylstat as a selective inhibitor of jumonji C domain containing histone demethylases (JHDMs). Herein, we describe the synthesis of a fluorescent analogue of methylstat and its application as a tracer in fluorescence polarization assays. Using this format, we have evaluated the binding affinities of several known JHDM probes, as well as the native cofactor and substrate of JHDM1A. This fluorophore allowed a highly robust and miniaturized competition assay sufficient for high-throughput screening. PMID- 23725561 TI - "PTCH"-ing it together: a basal cell nevus syndrome review. AB - BACKGROUND: Basal cell nevus syndrome (BCNS) has existed at least since Dynastic Egyptian times. In 1960, Gorlin and Goltz first described the classic clinical triad: multiple basal cell carcinomas (BCCs), jaw keratocysts, and bifid ribs. As an autosomal-dominant disorder, it is characterized by tumorigenesis and developmental defects. OBJECTIVE: To review the current literature on BCNS, including reports on epidemiology, pathogenesis, clinical presentation, diagnostic criteria, management, treatment, and prognosis. METHODS: A literature review of currently available articles related to BCNS. RESULTS: Individuals with a mutation in the tumor suppressor gene PTCH1 are predisposed to tumorigenesis and developmental defects. Clinical features include BCCs, often with onset in adolescence, jaw keratocysts, bifid ribs, craniofacial defects, palmar-plantar pits, and ectopic intracranial calcification. Despite high cure rates for individual lesions and various treatment modalities including excision, Mohs micrographic surgery, photodynamic therapy, and topical imiquimod, management of BCCs is challenging. The development of an oral hedgehog pathway inhibitor, vismodegib, has added a new dimension to current treatment algorithms. CONCLUSIONS: Adolescents and young adults with BCC should be evaluated for BCNS. Early diagnosis of BCNS is critical for possible prevention of the devastating effects of BCCs and establishment of multidisciplinary care. PMID- 23725562 TI - Fine mapping of fatness QTL on porcine chromosome X and analyses of three positional candidate genes. AB - BACKGROUND: Porcine chromosome X harbors four QTL strongly affecting backfat thickness (BFT), ham weight (HW), intramuscular fat content (IMF) and loin eye area (LEA). The confidence intervals (CI) of these QTL overlap and span more than 30 cM, or approximately 80 Mb. This study therefore attempts to fine map these QTL by joint analysis of two large-scale F2 populations (Large White * Meishan and White Duroc * Erhualian constructed by INRA and JXAU respectively) and furthermore, to determine whether these QTL are caused by mutations in three positional candidate genes (ACSL4, SERPINA7 and IRS4) involved in lipid biosynthesis. RESULTS: A female-specific linkage map with an average distance of 2 cM between markers in the initial QTL interval (SW2456-SW1943) was created and used here. The CI of QTL for BFT, HW and LEA were narrowed down to 6-7 cM, resulting from the joint analysis. For IMF, two linked QTL were revealed in the INRA population but not in the JXAU population, causing a wider CI (13 cM) for IMF QTL. Linkage analyses using two subsets of INRA F1 dam families demonstrate that the BFT and HW QTL were segregating in the Meishan pigs. Moreover, haplotype comparisons between these dams suggest that within the refined QTL region, the recombination coldspot (~34 Mb) flanked by markers MCSE3F14 and UMNP1218 is unlikely to contain QTL genes. Two SNPs in the ACSL4 gene were identified and showed significant association with BFT and HW, but they and the known polymorphisms in the other two genes are unlikely to be causal mutations. CONCLUSION: The candidate QTL regions have been greatly reduced and the QTL are most likely located downstream of the recombination coldspot. The segregation of SSCX QTL for BFT and HW within Meishan breed provides an opportunity for us to make effective use of Meishan chromosome X in crossbreeding. Further studies should attempt to identify the impact of additional DNA sequence (e.g. CNV) and expression variation in the three genes or their surrounding genes on these traits. PMID- 23725563 TI - Identification of a cyanobacterial CRR6 protein, Slr1097, required for efficient assembly of NDH-1 complexes in Synechocystis sp. PCC 6803. AB - Despite significant progress in clarifying the subunit compositions and functions of the multiple NADPH dehydrogenase (NDH-1) complexes in cyanobacteria, the subunit maturation and assembly of their NDH-1 complexes are poorly understood. By transformation of wild-type cells with a transposon-tagged library, we isolated three mutants of Synechocystis sp. PCC 6803 defective in NDH-1-mediated cyclic electron transfer and unable to grow under high light conditions. All the mutants were tagged in the same slr1097 gene, encoding an unknown protein that shares significant homology with the Arabidopsis protein chlororespiratory reduction 6 (CRR6). The slr1097 product was localized in the cytoplasm and was required for efficient assembly of NDH-1 complexes. Analysis of the interaction of Slr1097 with 18 subunits of NDH-1 complexes using a yeast two-hybrid system indicated a strong interaction with NdhI but not with other Ndh subunits. Absence of Slr1097 resulted in a significant decrease of NdhI in the cytoplasm, but not of other Ndh subunits including NdhH, NdhK and NdhM; the decrease was more evident in the cytoplasm than in the thylakoid membranes. In the ?slr1097 mutant, NdhH, NdhI, NdhK and NdhM were hardly detectable in the NDH-1M complex, whereas almost half the wild-type levels of these subunits were present in NDH-1L complex; similar results were observed in the NdhI-less mutant. These results suggest that Slr1097 is involved in the maturation of NdhI, and that assembly of the NDH-1M complex is strongly dependent on this factor. Maturation of NdhI appears not to be crucial to assembly of the NDH-1L complex. PMID- 23725564 TI - Children choose their own stories: the impact of choice on children's learning of new narrative skills. AB - Despite evidence that early narrative abilities are predictive of literacy skills and academic achievement, only limited progress has been made in understanding how the development of these narrative skills can be facilitated. The current study measured the effectiveness of a new narrative intervention conducted with 26 preschoolers. Children were assigned to one of two intervention conditions: an active-choice condition (able to choose story components) or a no-choice condition (story components were preselected). Both groups otherwise received the same explicit and engaging teaching of story grammar. As predicted, greater narrative skill gains were evident for the active-choice intervention; including larger gains on both central story grammar components and story information overall. Future implications for how stories might be presented to young children in order to more richly facilitate narrative skill acquisition are discussed. PMID- 23725565 TI - Overlapping photodegradable and biodegradable organic nitrogen in wastewater effluents. AB - Photochemical degradation of dissolved organic nitrogen (DON) in final effluent of trickling filter and activated sludge wastewater treatment plants (WWTPs) was studied. Inorganic N, mostly nitrite, was produced from the photodegradation of DON for samples from both WWTPs. Photodegradable DON (PDON), biodegradable DON (BDON), and overlapping photodegradable-biodegradable DON (OPBDON) were determined. BDON was associated with PDON as well as non-PDON. BDON and PDON concentrations in the final effluent samples were 4.71 and 4.62 mg N/L for the trickling filter plant and 3.95 and 3.73 mg N/L for the activated sludge plant, indicating that photodegradation is as important as biodegradation in the mineralization of effluent DON in receiving waters. OPBDON, which is more problematic in the water environment because it can be mineralized by light or bacteria or both, was 3.68 and 2.64 mg N/L (57% and 43% of total DON) in the final effluent samples from the trickling filter and activated sludge plants, respectively. The DON fraction that is resistant to biodegradation and photodegradation was 10% to 20% of total DON. PMID- 23725566 TI - N-N bond cleavage of mid-valent Ta(IV) hydrazido and hydrazidium complexes relevant to the Schrock cycle for dinitrogen fixation. AB - Chemical reduction of the Ta(V) hydrazido chloride 1 generates the open-shell, mononuclear Ta(IV) hydrazido complex 2, which upon N-methylation yields the corresponding structurally characterized Ta(IV) hydrazidium 6. Chemical reduction of 6 results in N-N bond cleavage to generate a cis/trans mixture of the [Ta(V),Ta(V)] bis(MU-nitrido) product 7 in tetrahydrofuran and the mononuclear Ta(V) parent imide 8 in toluene. These results serve to establish an important foundation for the pursuit of a group-5 metal variant of the Schrock cycle for dinitrogen fixation. PMID- 23725567 TI - Emerging tyrosine kinase inhibitors for esophageal cancer. AB - INTRODUCTION: Because of the poor prognosis for patients with esophagogastric cancers (EGCs), increasing attention has focused on targeted agents. AREAS COVERED: Targets include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), Her2, mammalian target of rapamycin (mTOR), and MET. We briefly discuss preclinical data and the rationale for targeting these pathways and summarize the results of clinical trials of tyrosine kinase inhibitors (TKIs) against these targets. EXPERT OPINION: While anti-EGFR therapy has been extensively investigated, completed Phase III trials suggest that this is not a promising target. A Phase III trial of an anti-VEGF antibody failed to show improvement in the primary endpoint of overall survival but response rates and progression-free survival were improved; a Phase III trial of an anti-VEGF receptor 2 antibody in second-line therapy did show improved survival. As such, Phase II and III evaluations of anti-VEGF TKIs are ongoing. The only Food and Drug Administration-approved targeted therapy in EGC is trastuzumab, an anti-Her2 antibody, and the results of a Phase III evaluation of lapatinib, an anti-Her2 TKI, are awaited. Phase III evaluation of an mTOR inhibitor has been negative. Finally, MET inhibition appears to have significant clinical potential and early testing of MET TKIs is underway. PMID- 23725568 TI - Emerging therapies for rheumatoid arthritis. AB - INTRODUCTION: With the introduction of biologic therapies, tremendous progress has been made in the treatment of rheumatoid arthritis (RA). However, up to 40% of patients do not respond to these treatments. AREAS COVERED: Several new treatment strategies are discussed, with brief overview of currently performed clinical trials. The development of molecules targeting cytokines other than TNF is discussed, as well as chemokine-directed drugs. Finally, the area of small molecular inhibitors is explored. EXPERT OPINION: Since RA is a life-long disease often evolving into disability, development of new treatment strategies remains crucial. Especially small molecules targeting JAK, Syk and PDE4 may provide novel therapeutic options. PMID- 23725569 TI - Emerging gliptins for type 2 diabetes. AB - INTRODUCTION: The dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are novel oral hypoglycemic drugs which have been in clinical use for the past 7 years. The drugs are safe, weight neutral and widely prescribed. There are currently eight gliptins registered worldwide with several more in advanced stages of development. AREAS COVERED: The place of the gliptins in the treatment algorithm of type 2 diabetes is discussed as well as unique features of the individual drugs. The gliptins may possess cardiovascular protective effects and their administration may promote beta-cell survival; claims currently being evaluated in clinical and preclinical studies. The global market revenues and future prospects of the gliptins are discussed and the gliptins in Phases II and III of development are reviewed. EXPERT OPINION: The gliptins are an optional second line therapy after metformin; they are generally well tolerated with low risk of hypoglycemia. The various compounds differ with respect to their pharmacokinetic and pharmacodynamic properties; however, their clinical efficacy appears to be similar. The clinical differences between the various compounds stem from effects other than hypoglycemic effects, their safety and side effects profile. The currently registered compounds appear to have maximized the clinical potential of DPP-4 inhibition, and the new compounds in the companies' pipelines seem to be as effective as the ones presently in use. There are two gliptins in advanced stages of development which will be registered for once-weekly dosing, possibly increasing patient adherence to therapy. Several individual gliptins are being evaluated for treatment in diabetes subpopulations such as type 1 patients or adolescents. PMID- 23725571 TI - Deep ultraviolet plasmon resonance in aluminum nanoparticle arrays. AB - Small aluminum nanoparticles have the potential to exhibit localized surface plasmon resonances in the deep ultraviolet region of the electromagnetic spectrum, however technical and scientific challenges make it difficult to attain this limit. We report the fabrication of arrays of Al/Al2O3 core/shell nanoparticles with a metallic-core diameter between 12 and 25 nm that display sharp plasmonic resonances at very high energies, up to 5.8 eV (down to lambda = 215 nm). The arrays were fabricated by means of a straightforward self organization approach. The experimental spectra were compared with theoretical calculations that allow the correlation of each feature to the corresponding plasmon modes. PMID- 23725572 TI - Validation of the Pelvic Floor Distress Inventory-20 and the Pelvic Floor Impact Questionnaire-7 in Danish women with pelvic organ prolapse. AB - OBJECTIVE: To translate the Pelvic Floor Distress Inventory-20 (PFDI-20) and the Pelvic Floor Impact Questionnaire-7 (PFIQ-7) and to evaluate their psychometric properties in Danish women with symptomatic pelvic organ prolapse. DESIGN AND SETTING: Cross-sectional, university hospital setting. SAMPLE: Women with symptomatic pelvic organ prolapse (n = 132). METHODS: A panel of gynecologists performed three independent translations, which were combined and psychometrically evaluated through interviews and pretesting. MAIN OUTCOME MEASURES: Construct, content and convergent validity. Internal consistency and reliability. Sensitivity to change, responsiveness and minimal clinical important difference. RESULTS: After two revisions PFDI-20 demonstrated good construct and content validity but PFIQ-7 showed major ceiling effect and lacked items describing affection of health-related quality of life. Convergent validity was moderate with only single items of PFDI-20 correlating with the pelvic organ prolapse quantification system (POP-Q) and only weak to moderate correlations between PFDI-20 and PFIQ-7 scores. Cronbach's alpha and inter-item-total correlation analysis were satisfactory overall. Intra-class correlation coefficient demonstrated good reliability for all but one subscale (r = 0.701 0.894 p < 0.001). Wilcoxon signed rank test showed significant sensitivity to change. Effect size and standardized response mean was good in pelvic organ prolapse subscales and correlated with the Patient Global Index of Improvement scale (PGI-I). Minimal clinical important difference could not be clearly demonstrated. CONCLUSION: The Danish version of PFDI-20 is valid while the PFIQ-7 has a major ceiling effect and lacks items about health-related quality of life. The subscales of PFDI-20 and PFIQ-7 demonstrate good internal consistency and reliability. Pelvic organ prolapse subscales show good responsiveness. PMID- 23725573 TI - Autologous fat transfer with in-situ mediation (AIM): a novel and compliant method of adult mesenchymal stem cell therapy. AB - BACKGROUND: In an attempt to engineer a regulatory compliant form of cell assisted lipotransfer in the U.S., the authors developed Autologous Fat Transfer with In-situ Mediation (AIM) for reconstruction of a refractory surgical scar. METHODS: This method incorporates use of accepted standard procedures like autologous fat grafting and intradermal injection of NB6 collagenase to release adipose stem cells from a naturally occurring high concentration stromal vascular fraction (SVF) fat graft. To prevent off-target effects of collagenase, a hyaluronic acid and serum deactivation barrier is placed circumferentially around the operative site. FINDINGS: This novel protocol was well tolerated by the patient and improved scar appearance, mobility and texture. Deepest scar contour defect correction was 80% and 77% at 4 and 12 weeks respectively. CONCLUSION: AIM appears to be a practical and viable option for scar reconstruction requiring small to moderate volume correction. PMID- 23725574 TI - BAD overexpression inhibits cell growth and induces apoptosis via mitochondrial dependent pathway in non-small cell lung cancer. AB - BACKGROUND: The pro-apoptotic Bcl-2 protein BAD initiated apoptosis in human cells and has been identified as a prognostic marker in non-small cell lung cancer (NSCLC). In this study, we aimed to explore the functions of BAD in NSCLC. METHODS: Overexpression of BAD was performed by transfecting different NSCLC cell lines with wild-type BAD. Cell proliferation, cell cycle, apoptosis, and invasion were characterized in vitro. Tumorigenicity was analyzed in vivo. Western blot was performed to determine the effects of BAD overexpression on the Bcl-2 family proteins and apoptosis-related proteins. RESULTS: Overexpression of BAD significantly inhibited cell proliferation in H1299, H292, and SPC-A1 but not in SK-MES-1 and H460 cell lines in vitro. BAD overexpression also reduced the tumorigenicity of H1299/SPC-A1 cell in vivo. However, no appreciable effects on cell cycle distribution and invasion were observed in all these cell lines. BAD overexpression also induced apoptosis in all cell types, in which process expression of mitochondrial cytochrom c (cyto-c) and caspase 3 were increased, whereas Bcl-xl, Bcl-2, Bax and caspase 8 expressions did not changed. These findings indicated that a mitochondrial pathway, in which process cyto-c was released from mitochondrial to activate caspase 3, was involved in BAD overexpression-mediated apoptosis. CONCLUSIONS: Our data suggested that increased expression of BAD enhance apoptosis and has negative influence on cell proliferation and tumor growth in NSCLC. Bad is a new potential target for tumor interventions. PMID- 23725575 TI - Effective peer education in HIV: defining factors that maximise success. AB - Background Peer education is considered an effective health promotion and education strategy, particularly to populations traditionally resistant to conventional forms of health information dissemination. This has made it very applicable to HIV education and prevention, where those who are affected or at risk are often amongst the most vulnerable in society. However, there still remains uncertainty as to the reasons for its effectiveness, what constitutes an effective methodology and why a consistent methodology can often result in widely variable outcomes. METHOD: Between 2008 and 2010, three separate reviews of peer education were undertaken across more than 30 countries in three distinct geographical regions across the globe. The reviews sought to identify determinants of the strengths and weaknesses inherent in approaches to peer education, particularly targeting young people and the most at-risk populations. RESULTS: By assessing the implementation of peer education programs across a variety of social environments, it was possible to develop a contextual understanding for peer education's effectiveness and provide a picture of the social, cultural, political, legal and geographic enablers and disablers to effective peer education. Several factors were significant contributors to program success, not as strategies of methodology, but as elements of the social, cultural, political and organisational context in which peer education was situated. CONCLUSION: Contextual elements create environments supportive of peer education. Consequently, adherence to a methodology or strategy without proper regard to its situational context rarely contributes to effective peer education. PMID- 23725576 TI - Assessing motivations for suicide attempts: development and psychometric properties of the inventory of motivations for suicide attempts. AB - This study describes the psychometric properties of the Inventory of Motivations for Suicide Attempts (IMSA). The IMSA was designed to comprehensively assess motivations for suicide emphasized by major theories of suicidality. The IMSA was administered to two samples of recent suicide attempters, undergraduates (n = 66) and outpatients (n = 53). The IMSA exhibited a reliable two-factor structure in which one factor represented Intrapersonal motivations related to ending emotional pain, and the second represented Interpersonal motivations related to communication or help-seeking. Convergent validity and divergent validity of IMSA scales were supported by expected patterns of correlations with another measure of suicide motivations. In addition, the IMSA scales displayed clinical utility, in which greater endorsement of intrapersonal motivations was associated with greater intent to die, whereas greater endorsement of interpersonal motivations was associated with less lethal intent and greater likelihood of rescue. Findings suggest the IMSA can be of use for both research and clinical purposes when a comprehensive assessment of suicide motivations is desired. PMID- 23725577 TI - Diagnosis of dementia as a turning point among Finnish families: a qualitative study. AB - The experiences of receiving a diagnosis of dementia from the viewpoint of people with dementia and their family members were explored in this study. Purposive sampling was used to recruit people with newly-diagnosed dementia (n = 8) and their family members (n = 8) from a university hospital's memory clinic in northern Finland. Data were collected using low-structured interviews, and analyzed using the stages of grounded theory. The diagnosis of dementia was a mutual turning point in the family, and it was experienced and responded to in shared processes within the family. In a changing life situation, close ones became a significant resource, and focus on the present day was emphasized. Individuals with dementia and their family members aimed to live meaningful lives by being active agents. Understanding the individual and shared experiences of both those with dementia and their family members can help health professionals design and carry out tailored early psychosocial interventions for families to assist them to create a shared understanding of living with dementia. PMID- 23725578 TI - [Pelvic floor rehabilitation in female urinary incontinence: how does it work?]. PMID- 23725579 TI - [Pelvic floor rehabilitation for female urinary incontinence: mechanisms of action]. AB - OBJECTIVE: To analyze the proven mechanisms of action of pelvic rehabilitation in women presenting with urinary incontinence. METHODS: Review of literature (PubMed, Embase, Cochrane Database) using following keywords: female; urinary incontinence; overactive bladder syndrome; stress urinary incontinence; bladder training; bladder diary; pelvic floor muscle training; pelvic floor rehabilitation; physiotherapy; cognitive therapies. Among 2906 articles (animal and anatomical studies have been excluded); 66 have been selected because they focused on the evaluation of the pathophysiological mechanisms of pelvic floor rehabilitation concerning female urinary incontinence. RESULTS: Studies on pelvic floor muscles training exercises showed a significant increase in the force of contraction of these muscles and it was correlated with improved scores of urinary incontinence and pad test (coefficient of correlation r ranged from 0.23 to 0.34) for women presenting with stress urinary incontinence. These studies have not observed an increase in the maximum urethral closure pressure (MUCP) or correction of urethral hypermobility related with the improvement of incontinence after rehabilitation sessions. Studies concerning pelvic floor stimulation observed an increase in the force of contraction of pelvic floor muscles after rehabilitation and a decrease in the intensity of detrusor contractions without changing the MUCP. There is very little data on the precise mechanisms of action of biofeedback and cognitive behavioral therapy. CONCLUSION: In studies that objectively evaluated the mechanisms of action of pelvic rehabilitation, it was observed that pelvic floor muscles voluntary exercises and electrostimulation resulted an increase in force of contraction of these muscles without changing the MUCP. PMID- 23725580 TI - [Role of estrogens in lower urinary tract physiology and physiopathology]. AB - GOAL: The aim was to review the literature on estrogens and lower urinary tract. MATERIAL: A review of literature through the PubMed library until December 31, 2012 was carried out using the following keywords: lower urinary tract, bladder, urethra, nervous central system, innervation, female, women, estrogen, estradiol, urogenital atrophy, urinary incontinence, overactive bladder, urinary tract infection. RESULTS: On the bladder, estrogens are involved in the trophicity, vascularisation, alpha-adrenergic, cholinergic and muscarinic receptor density, detrusor contractility and inflammation. On the urethra, they impact vascularisation, contractility, urethral pulse and tone, anatomical and functional length. On the neurological control, they act on capsaicin-sensitive afferent fibres, neurological regeneration, nerve growth factor expression and viscerovisceral sensitisation. CONCLUSION: Estrogens play a major role on the lower urinary tract physiology and physiopathology both on the urethra and the bladder. PMID- 23725581 TI - [Levator ani trauma after childbirth, from stretch injury to avulsion: review of the literature]. AB - OBJECTIVE: Pelvic floor injuries as avulsion (disruption of the muscle) or overdistension were identified in 15 to 35% of deliveries. Our objective is to clarify the consequences of these muscles trauma on pelvic floor symptoms, pelvic organ prolapse and the management of postnatal assessment of pelvic floor function. METHOD: The literature search was conducted over a period from 2000 to January 2013 using the PubMed database and the following keywords: levator ani, ultrasound, magnetic resonance imaging, pelvic floor, obstetric trauma, pelvic organ prolapse, incontinence, delivery, avulsion. Seventy-four articles were identified, 43 were selected. The level of evidence was determined using the Oxford table. RESULTS: The instrumental extraction was found as the main risk factor with a prevalence of avulsions from 35% (NP3) to 72% (NP3) and an odd ratio of 3.4 (NP3). Whatever the mode of assessment, the strength of the pelvic floor was reduced in 100% of cases of avulsion. Avulsions were diagnosed clinically and could be confirmed by ultrasound or MRI (correlation palpation imaging/k=0.497 (NP2) to 86% (NP3). An association was found with the risk of genital prolapse (odd-ratio from 2 [NP4] to 7 for prolapse grade 1 [NP4]) and fecal incontinence (16% [NP3] to 72% [NP4] with an odd-ratio of 14 [NP4]). CONCLUSION: This review has shown that obstetric muscle avulsions had an impact on pelvic organ prolapse and anal continence. The mode of the pelvic floor muscle postnatal assessment remains to be defined. PMID- 23725582 TI - [Bladder-sphincter disorders associated with Wolfram syndrome]. AB - OBJECTIVES: To identify and describe functional urinary symptoms, uro nephrological complications and their impact on quality of life in a cohort of patients diagnosed with the Wolfram syndrome (SW). PATIENTS AND METHODS: A transversal descriptive patient's cohort study was performed. The Urinary Symptom Profile (USP) and the International Consultation Incontinence Questionnaire - Female Lower Urinary Tracts Symptoms (ICIQ-FLUTS) were used to evaluate urinary symptoms and their impact on quality of life through direct interviews conducted by telephone. A less than 6-month old renal ultrasound and serum creatinine results were asked to the patient or physician. RESULTS: Thirty-three patients have been contacted and 22 (73%) agreed to participate in this study. Eighteen patients over 22 had spontaneous micturition when four of them had an urinary diversion (two definitive, two temporaries) before being included in this study. Seventy-three percent of patients with spontaneous micturition had urinary symptoms. A severe or moderate symptoms score was noted in 67% (12/18 patients) and 11% (2/18 patients) respectively. CONCLUSION: Functional urinary dysfunctions were frequent and impacted quality of life in more than one half of patients diagnosed with SW in this study. Early diagnostic and regular urological follow up can improve the quality of life and prevent severe urinary complications. PMID- 23725583 TI - [Comparison between autonomic nervous system cardiovascular tests (ANSCVT) and lacrymal and or salivary secretion tests (LSST) in overactive bladder syndrome and voiding dysfunction]. AB - PURPOSE: To compare autonomic nervous system cardiovascular tests (ANSCVT) and lacrymal and or salivary secretion tests (LSST). METHOD: One hundred and twenty four patients (57 females, 67 males, mean age 45) with lower urinary tract symptoms (overactive bladder syndrome or voiding dysfunction) without neurogenic or urological causes, were included. Urodynamic was performed in all the patients with LSST (saliva flowmetry-sialometry [SFS], candy weight-loss test [CWT], Schirmer test [SchT]) and ANSCVT (ratio 30:15, orthostatic hypotension analysis, deep breath test [DBT], Valsalva maneuver [VM], cold pressor test [CPT] and hand grip test [HGT]). RESULTS: In eight cases, ANSCVT were altered (four in OAB syndrome, four in voiding dysfunction). No correlation was found between positive ANSCVT and LSST (P=0.72 for CWT, P=1 for SFS, P=0.1 for SchT). In contrary, there is a significant correlation between SchT and CWT (P=0.049), but not between SchT and SFS (P=0.69) or SFS vs CWT (P=0.06). CONCLUSION: In this series LSST were not sufficient to track down autonomic nervous system alterations and ANSCVT always necessary. Autonomic dysfunctions were infrequent in OAB syndrome and "idiopathic" voiding dysfunctions (6.5%). PMID- 23725584 TI - Prospective ultrasonographic follow-up of synthetic mesh in cohort of patients after vaginal repair of cystocele. AB - OBJECTIVE: We sought to validate a sequence of ultrasonographic mesh measurements to determine the relevant time points in the postoperative monitoring of mesh size. METHODS: Mesh was measured preoperatively ex vivo, prior to insertion, in 25 patients scheduled to undergo vaginal repair of cystocele involving insertion of a UgytexTM transobturating polypropylene mesh. A 2D/3D perineal ultrasound scan was performed at the end of the surgical procedure (D0), then on third day after surgery (D3) and 6 weeks (W6) after the operation. Medio-sagittal view was used to measure mesh total length and the sagittal arc (length between the most distant points of the mesh). RESULTS: Time-course changes in sagittal arc were marked by a 8% increase on D3 (with respect to D0) and a 20% decrease at W6 (with respect to D3). Mesh total length at W6 on average corresponded to 74% (+/-20) of mesh total length measured on D3. CONCLUSION: This study showed the changes in the mesh ultrasonographic measurements following vaginal placement by vaginal route. The D3 ultrasound scan should appear to be suitable as a reference for subsequent ultrasonographic monitoring. PMID- 23725585 TI - [Purple urine bag syndrome...]. PMID- 23725586 TI - Fractional carbon dioxide laser improves nodular basal cell carcinoma treatment with photodynamic therapy with methyl 5-aminolevulinate. AB - BACKGROUND: The major limitation of photodynamic therapy with 5-aminolevulinic acid (ALA-PDT) is proper photosensitizer penetration. The nodular form of BCC (nBCC) is perceived as a contraindication to ALA-PDT because the tumor layer is thicker than 2 mm. We have improved on the results of previous studies that used an ablative laser to limit tumor thickness. A fractional laser produces skin microtubules that can improve the penetration of ALA into tumors. OBJECTIVE: To evaluate the use of a fractional laser as pretreatment before ALA-PDT for nBCC treatment in an 18-month single-blind clinical trial. METHODS: Fifty-six verified nBCCs were ablated using a diode laser under ultrasound control. Half of the tumors were treated 3 weeks later using a fractional carbon dioxide laser, and the other half were treated using curettage (control). We then immediately treated with ALA-PDT. Fluorescence and photography were evaluated and compared each month, and a final histopathologic examination was performed. RESULTS: Fifty two of 56 nBCCs in the fractional laser treatment group responded to ALA-PDT, compared with only 45 of 56 in the control group. Fluorescence was higher in 53 cases in the treatment group; 3 cases demonstrated the same fluorescence level in both groups. Healing took longer in the treatment group, and there were more side effects. CONCLUSION: Fractional laser pretreatment increases the fluorescence and clinical effectiveness of ALA-PDT for the treatment of nBCC. PMID- 23725587 TI - Accuracy of superlocalization imaging using Gaussian and dipole emission point spread functions for modeling gold nanorod luminescence. AB - We present a study comparing the accuracy of superlocalization imaging of plasmon mediated emission from gold nanorods (AuNRs) using both Gaussian and dipole emission point-spread function (PSF) models. By fitting the emission PSF of single AuNR luminescence, we have shown that a 3-axis dipole PSF gives improved localization accuracy over the Gaussian PSF, especially for nonplanar AuNRs, while also allowing the AuNR three-dimensional orientation and emission wavelength to be determined. On the other hand, when a single-axis dipole PSF model is applied to the AuNR emission, the fit estimates converge to values that are inconsistent with their experimentally measured values, affecting both the localization accuracy and precision of the fitted centroid position. These results indicate that when applying superlocalization techniques to plasmonic nanostructures, care must be taken to understand the nature of the emission before a correct dipole PSF can be applied. PMID- 23725588 TI - The electronic nature of terminal oxo ligands in transition-metal complexes: ambiphilic reactivity of oxorhenium species. AB - The synthesis of the Lewis acid-base adducts of B(C6F5)3 and BF3 with [DAAmRe(O)(X)] DAAm = N,N-bis(2-arylaminoethyl)methylamine; aryl = C6F5 (X = Me, 1, COCH3, 2, Cl, 3) as well as their diamidopyridine (DAP) (DAP=(2,6 bis((mesitylamino)methyl)pyridine) analogues, [DAPRe(O)(X)] (X = Me, 4, Cl, 5, I, 6, and COCH3,7), are described. In these complexes the terminal oxo ligands act as nucleophiles. In addition we also show that stoichiometric reactions between 3 and triarylphosphine (PAr3) result in the formation of triarylphosphine oxide (OPAr3). The electronic dependence of this reaction was studied by comparing the rates of oxygen atom transfer for various para-substituted triaryl phosphines in the presence of CO. From these experiments a reaction constant rho = -0.29 was obtained from the Hammett plot. This suggests that the oxygen atom transfer reaction is consistent with nucleophilic attack of phosphorus on an electrophilic metal oxo. To the best of our knowledge, these are the first examples of mono-oxo d(2) metal complexes in which the oxo ligand exhibits ambiphilic reactivity. PMID- 23725589 TI - Actinobacillus pleuropneumoniae genes expression in biofilms cultured under static conditions and in a drip-flow apparatus. AB - BACKGROUND: Actinobacillus pleuropneumoniae is the Gram-negative bacterium responsible for porcine pleuropneumonia. This respiratory infection is highly contagious and characterized by high morbidity and mortality. The objectives of our study were to study the transcriptome of A. pleuropneumoniae biofilms at different stages and to develop a protocol to grow an A. pleuropneumoniae biofilm in a drip-flow apparatus. This biofilm reactor is a system with an air-liquid interface modeling lung-like environment. Bacteria attached to a surface (biofilm) and free floating bacteria (plankton) were harvested for RNA isolation. Labelled cDNA was hybridized to a microarray to compare the expression profiles of planktonic cells and biofilm cells. RESULTS: It was observed that 47 genes were differentially expressed (22 up, 25 down) in a 4 h-static growing/maturing biofilm and 117 genes were differentially expressed (49 up, 68 down) in a 6h static dispersing biofilm. The transcriptomes of a 4 h biofilm and a 6 h biofilm were also compared and 456 genes (235 up, 221 down) were identified as differently expressed. Among the genes identified in the 4 h vs 6h biofilm experiment, several regulators of stress response were down-regulated and energy metabolism associated genes were up-regulated. Biofilm bacteria cultured using the drip-flow apparatus differentially expressed 161 genes (68 up, 93 down) compared to the effluent bacteria. Cross-referencing of differentially transcribed genes in the different assays revealed that drip-flow biofilms shared few differentially expressed genes with static biofilms (4 h or 6 h) but shared several differentially expressed genes with natural or experimental infections in pigs. CONCLUSION: The formation of a static biofilm by A. pleuropneumoniae strain S4074 is a rapid process and transcriptional analysis indicated that dispersal observed at 6 h is driven by nutritional stresses. Furthermore, A. pleuropneumoniae can form a biofilm under low-shear force in a drip-flow apparatus and analyses indicated that the formation of a biofilm under low-shear force requires a different sub-set of genes than a biofilm grown under static conditions. The drip-flow apparatus may represent the better in vitro model to investigate biofilm formation of A. pleuropneumoniae. PMID- 23725590 TI - Constructions of sex and intimacy after cancer: Q methodology study of people with cancer, their partners, and health professionals. AB - BACKGROUND: The increasing number of individuals living with cancer has led to a focus on the quality of life of survivors, and their families. Sexual wellbeing is a central component of quality of life, with a growing body of research demonstrating the association between cancer and changes to sexuality and intimacy. However, little is known about patient and professional understanding of cancer and sexuality post-cancer. This study was designed to explore the complex perspectives that people with personal and professional experience with cancer hold about sexuality in the context of cancer. METHODS: An interview study using Q methodology was conducted with 44 people with cancer, 35 partners of a person with cancer and 37 health professionals working in oncology. Participants were asked to rank-order 56 statements about sexuality and intimacy after cancer and asked to comment on their rankings in a subsequent semi-structured interview. A by-person factor analysis was performed with factors extracted according to the centroid method with a varimax rotation. RESULTS: A three-factor solution provided the best conceptual fit for the perspectives regarding intimacy and sexuality post-cancer. Factor 1, entitled "communication - dispelling myths about sex and intimacy" positions communication as central to the acceptance of a range of satisfying sexual and intimate practices post-cancer. Factor 2, "valuing sexuality across the cancer journey," centres on the theme of normalizing the experience of sex after cancer through the renegotiation of sex and intimacy: the development of alternative sexual practices. Factor 3, "intimacy beyond sex," presents the view that even though sex may not be wanted, desired, or even possible following cancer, quality of life and relationship satisfaction are achieved through communication and non-genital intimacy. CONCLUSIONS: This study has demonstrated the complexity of perspectives about sexuality and intimacy post cancer, which has practical implications for those working in cancer care and survivorship. Therapists and other health professionals can play an important role in ameliorating concerns surrounding sexual wellbeing after cancer, by opening and facilitating discussion of sexuality and intimacy amongst couples affected by cancer, as well as providing information that normalizes a range of sexual and intimate practices. PMID- 23725592 TI - The use of null models and partial least squares approach path modelling (PLS-PM) for investigating risk factors influencing post-weaning mortality in indoor pig farms. AB - Although post-weaning mortality (PWM) in pig farming is mainly due to the effect of pathogens, farm type or swine management are also directly or indirectly involved. In this work, we used null models and the partial least squares approach (PLS) to structural equation modelling, also known as PLS path modelling (PLS-PM), to explore whether farm type, swine management and pathogens, including porcine circovirus type 2, swine influenza virus, porcine reproductive and respiratory syndrome virus and Aujeszky's disease virus, directly or indirectly influenced PWM in 42 Spanish indoor pig farms. The null model analysis revealed that contact with multiple combinations of viruses could occur by chance. On the other hand, PLS-PM showed that farm characteristics do not influence virus infections, and thus neither farm type nor associated management practices shaped PWM due to pathogens. Accordingly, preventive programmes aimed at controlling PWM in intensive farming should prioritize the control of major pig pathogens. PMID- 23725591 TI - Characterization of maleimide-based glycogen synthase kinase-3 (GSK-3) inhibitors as stimulators of steroidogenesis. AB - Inhibition of GSK-3beta has been well documented to account for the behavioral actions of the mood stabilizer lithium in various animal models of mood disorders. Recent studies have showed that genetic or pharmacological inhibition of GSK-3beta resulted in anxiolytic-like and pro-social behavior. In our ongoing efforts to develop GSK-3beta inhibitors for the treatment of mood disorders, SAR studies on maleimide-based compounds were undertaken. We present herein for the first time that some of these GSK-3beta inhibitors, in particular analogues 1 and 9, were able to stimulate progesterone production in the MA-10 mouse tumor Leydig cell model of steroidogenesis without any significant toxicity. These two compounds were tested in the SmartCube behavioral assay and showed anxiolytic like signatures following daily dose administration (50 mg/kg, ip) for 13 days. Taken together, these results support the hypothesis that GSK-3beta inhibition could influence neuroactive steroid production thereby mediating the modulation of anxiety-like behavior in vivo. PMID- 23725593 TI - High-temperature, high-pressure hydrothermal synthesis and characterization of a salt-inclusion mixed-valence uranium(V,VI) silicate: [Na9F2][(U(V)O2)(U(VI)O2)2(Si2O7)2]. AB - A salt-inclusion mixed-valence uranium(V,VI) silicate, [Na9F2][(U(V)O2)(U(VI)O2)2(Si2O7)2], was synthesized under hydrothermal conditions at 585 degrees C and 160 MPa and structurally characterized by powder and single-crystal X-ray diffraction (XRD). The valence states of uranium were established by U 4f X-ray photoelectron spectroscopy (XPS). The structure contains two-dimensional (2D) sheets of uranyl disilicate with the composition [UO2Si2O7], which are connected by U(1)(V)O6 tetragonal bipyramids to form thick layers. The Na(+) cations are located at sites in the intralayer and interlayer regions. In addition to Na(+) cations, the interlayer region also contains F(-) anions such that infinite chains with the formula FNa1/1Na4/2 are formed. The same type of chain was observed in K2SnO3. The title compound is not only the first example of salt-inclusion metal silicate synthesized under high temperature, high-pressure hydrothermal conditions, as well as the first salt inclusion mixed-valence uranium silicate, but it is also the first mixed-valence uranium(V,VI) silicate in the literature. Crystal data: [Na9F2][(U(V)O2)(U(VI)O2)2(Si2O7)2], triclinic, P1 (No. 2), a = 5.789(1) A, b = 7.423(2) A, c = 12.092(2) A, alpha = 90.75(3) degrees , beta = 96.09(3) degrees , gamma = 90.90(3) degrees , V = 516.5(2) A(3), Z = 1, R1 = 0.0241, and wR2 = 0.0612. PMID- 23725594 TI - Future horizons. PMID- 23725595 TI - In reply to "ibuprofen for prevention of acute mountain sickness-is bigger really better?". PMID- 23725596 TI - Vestibular stimulation attenuates unrealistic optimism. AB - INTRODUCTION: Unrealistic optimism refers to the pervasive tendency of healthy individuals to underestimate their likelihood of future misfortune, including illness. The phenomenon shares a qualitative resemblance with anosognosia, a neurological disorder characterized by a deficient appreciation of manifest current illness or impairment. Unrealistic optimism and anosognosia have been independently associated with a region of right inferior frontal gyrus, the pars opercularis. Moreover, anosognosia is temporarily abolished by vestibular stimulation, particularly by irrigation of the left (but not right) ear with cold water, a procedure known to activate the right inferior frontal region. We therefore hypothesized that left caloric stimulation would attenuate unrealistic optimism in healthy participants. METHODS: Thirty-one healthy right-handed adults underwent cold-water caloric vestibular stimulation of both ears in succession. During each stimulation episode, and at baseline, participants estimated their own relative risk of contracting a series of illnesses in the future. RESULTS: Compared to baseline, average risk estimates were significantly higher during left-ear stimulation, whereas they remained unchanged during right-ear stimulation. Unrealistic optimism was thus reduced selectively during cold caloric stimulation of the left ear. CONCLUSIONS: Our results point to a unitary mechanism underlying both anosognosia and unrealistic optimism, and suggest that unrealistic optimism is a form of subclinical anosognosia for prospective symptoms. PMID- 23725597 TI - A planar Bezier profiled horn for reducing penetration force in ultrasonic cutting. AB - An ultrasonic planar horn with a Bezier profile is developed. The first longitudinal displacement mode of the horn is exploited for high displacement amplification in order to reduce the penetration force required to enter and cut materials. The displacement amplification and stress distribution characteristics of the Bezier horn and the commonly used catenary horn are examined. The penetration force by the Bezier horn is nearly 75% of that by the catenary horn with a penetration speed of 0.25 mm/s during cutting a tissue stimulant. At a penetration speed of 0.5 mm/s, the penetration force by the Bezier horn is nearly 85% of that by the catenary horn for cutting a polymethylmethacrylate (PMMA) material. The decrease in the penetration force by the Bezier horn is attributed to the fact that the displacement amplification of the Bezier horn is 30% higher than that of the traditional catenary horn with the same length and end surface widths. PMID- 23725599 TI - Controlling acoustic streaming in an ultrasonic heptagonal tweezers with application to cell manipulation. AB - Acoustic radiation force has been demonstrated as a method for manipulating micron-scale particles, but is frequently affected by unwanted streaming. In this paper the streaming in a multi-transducer quasi-standing wave acoustic particle manipulation device is assessed, and found to be dominated by a form of Eckart streaming. The experimentally observed streaming takes the form of two main vortices that have their highest velocity in the region where the standing wave is established. A finite element model is developed that agrees well with experimental results, and shows that the Reynolds stresses that give rise to the fluid motion are strongest in the high velocity region. A technical solution to reduce the streaming is explored that entails the introduction of a biocompatible agar gel layer at the bottom of the chamber so as to reduce the fluid depth and volume. By this means, we reduce the region of fluid that experiences the Reynolds stresses; the viscous drag per unit volume of fluid is also increased. Particle Image Velocimetry data is used to observe the streaming as a function of agar-modified cavity depth. It was found that, in an optimised structure, Eckart streaming could be reduced to negligible levels so that we could make a sonotweezers device with a large working area of up to 13 mm * 13 mm. PMID- 23725600 TI - Tolerance induction in hemophilia A animal models: battling inhibitors with antigen-specific immunotherapies. AB - Hemophilia A is an X-linked recessive bleeding disorder due to either a lack of or greatly reduced activity in the blood coagulation protein factor VIII (FVIII), due to mutations in the F8 gene. This poses significant challenges for FVIII replacement therapy since hemophilic patients are not immunologically tolerant to the protein. Thus, a proportion of patients who receive plasma-derived or recombinant FVIII replacement therapy develop anti FVIII neutralizing antibodies, known as "inhibitors." These patients require long-term regimens of high dose FVIII administration, which has varying success rates and prohibitive costs. Therefore, therapeutics for tolerance induction in such patients with inhibitors are desired. In this review, we address the current progress of immunotherapies for inducing FVIII specific tolerance in animal models of hemophilia A. Specifically we discuss the beneficial effects of B-cell depletion on immune tolerance induction (ITI), B-cell mediated gene therapy, antigen-coupled lymphocyte therapy, and regulatory T-cell epitopes (Tregitopes). PMID- 23725601 TI - The human genome: its modifications and interactions with those of the microbiome, and the practice of genomic medicine. AB - In genomic medicine, the nuclear genome is usually the focus of discussion. However, recent developments in genomics show that our interaction with the biological world at large alters our susceptibility to disease and our response to drugs. For example, in addition to causing infection, the trillions of microbial cells that inhabit our bodies (our microbiome), are now known to shape our immune system and our metabolic health. Moreover, mitochondria, the long assimilated symbionts, are the focus of considerable current genomic research that is making possible, interventions that were at one time in the realms of science fiction. Furthermore, genomics research of the cancer cell is sufficiently refined to enable us to define its genome as a distinct entity suitable for selective drug-targeting. In this contribution we discuss, within their historical contexts, some of these seemingly disparate scientific strands to highlight the importance of embracing a broader multiple-genomic vista when dealing with disease causation, prevention, and management. PMID- 23725602 TI - Novel therapeutic approaches for corneal disease. AB - Congenital and acquired corneal opacities, and diseases of the ocular surface, are blinding conditions that impose physical, psychological, and financial constraints upon the sufferer. In the past, corneal and corneal epithelial stem cell transplantation have been the major treatment for severe corneal and ocular surface disease, respectively, but the sequelae of neovascularization and inflammatory eye disease cause many grafts to undergo irreversible immunological rejection. Furthermore, in the case of corneal dystrophies, the original disease may recur in the graft. New therapeutic options for diseases of the cornea and ocular surface are now being actively explored in experimental animals and in clinical trials. Antibody-based biologics are being tested for their ability to reduce blood and lymphatic vessel ingrowth into the cornea, and to reduce inflammation. Many new biomaterials are being examined for their capacity to transfer drugs and corneal epithelial cell progenitor cells to the ocular surface and anterior segment of the eye. New component-cell corneal transplantation procedures that may reduce the risk of immunological rejection have been developed and are already in clinical practice. Finally, gene therapy is being tested in experimental animals to improve the outcomes of corneal transplantation, and to halt or reverse the pathophysiology of some corneal dystrophies. PMID- 23725604 TI - Innovative approaches for enhancing cancer gene therapy. AB - Gene therapy provides a novel platform for therapeutic intervention of several genetic and non-genetic disorders. With the recent developments in the field, a wide variety of viral and non-viral vectors have emerged that can deliver genetic payloads to target cells. However, non-targeted delivery of transgenes often results in undesirable effects, low tumor transduction, and reduced therapeutic index. In this review, we focus on some of the novel approaches that can be used to meet the present challenges in the field and translate the potential of cancer gene therapy from 'bench to bedside' in the near future. PMID- 23725603 TI - Colorectal cancer immunotherapy. AB - Antitumor immunotherapy for colorectal cancer has been studied at the bench and bedside for decades. Some clinical trials of cancer immunotherapy have demonstrated a potential benefit for patients with colorectal cancer, yet immunotherapy remains only an experimental option for this disease. Here, we review the major immunotherapeutic approaches currently under investigation for colorectal cancer, including cancer vaccines and adoptive cell therapy. Weakness and advantages of each strategy and progress in clinical trials will be described. Examination of previous and ongoing research in colorectal cancer therapy should define a path towards identification, approval, and mainstream adoption of colorectal cancer immunotherapeutics. PMID- 23725606 TI - Effect of beta-hydroxy-beta-methylbutyrate (HMB) on lean body mass during 10 days of bed rest in older adults. PMID- 23725605 TI - Advances in the development of vaccines for Alzheimer's disease. AB - One of the challenges of our society is to find a treatment or cure for Alzheimer's disease (AD). AD is the leading form of age-related dementia and with the increase of life expectancy worldwide, the social and economic burden from this disease will increase dramatically. It is a progressive and, in regard to clinical scores, a highly variable disease. AD pathogenesis has been associated with the accumulation, aggregation, and deposition of amyloid beta (Abeta) peptides in the brain. Hallmarks of AD are the amyloid plaques consisting of fibrillar Abeta and neurofibrillary tangles which are intracellular fibrils of hyperphosphorylated tau protein that develop later in this disease. The amyloid cascade hypothesis postulates that Abeta deposition is an initial event in the multifactorial pathogenesis and Abeta deposition may precede AD symptoms in some patients by at least 20 years. Amyloid beta therapy with active and passive immunizations against Abeta has a high possibility to be effective in removing Abeta from brain and might thus prevent the downstream pathology. Since 2000 a number of clinical trials for AD immunotherapy have started, have failed, and are continuing to be pursued. This article will review these clinical trials and ongoing research in this regard. PMID- 23725607 TI - Sex modulates approach systems and impulsivity in substance dependence. AB - BACKGROUND: Personality traits such as pathological engagement in approach behaviors, high levels of impulsivity and heightened negative affect are consistently observed in substance dependent individuals (SDI). The clinical course of addiction has been shown to differ between sexes. For example, women increase their rates of consumption of some drugs of abuse more quickly than men. Despite the potential influence of personality and sex on features of addiction, few studies have investigated the interaction of these factors in substance dependence. METHODS: Fifty-one SDI (26 males, 25 females) and 66 controls (41 males, 25 females) completed the Behavioral Inhibition/Behavioral Activation System (BIS/BAS) Scales, the Barratt Impulsiveness Scale, and the Positive and Negative Affect Schedule (PANAS-X). Data were analyzed with 2*2 ANCOVAs testing for main effects of group, sex and group by sex interactions, adjusting for education level. RESULTS: Significant group by sex interactions were observed for BAS scores [F(1,116)=7.03, p<.01] and Barratt Motor Impulsiveness [F(1,116)=6.11, p<.02] with female SDI showing the highest approach tendencies and impulsivity followed by male SDI, male controls, and finally female controls. SDI scored higher on negative affect [F(1,116)=25.23, p<.001] than controls. Behavioral Inhibition System scores were higher in women than men [F(1,116)=14.03, p<.001]. CONCLUSION: Higher BAS and motor impulsivity in SDI women relative to SDI men and control women suggest that personality traits that have been previously associated with drug use may be modulated by sex. These factors may contribute to differences in the disease course observed in male compared to female drug users. PMID- 23725608 TI - Sociodemographic determinants of prevalence and incidence of Helicobacter pylori infection in Portuguese adults. AB - BACKGROUND: Understanding the determinants of Helicobacter pylori infection in adults is essential to predict the burden of H. pylori-related diseases. We aimed to estimate the prevalence and incidence of H. pylori infection and to identify its major sociodemographic correlates in an urban population from the North of Portugal. MATERIAL AND METHODS: A representative sample of noninstitutionalized adult inhabitants of Porto (n = 2067) was evaluated by ELISA (IgG) and a subsample (n = 412) was tested by Western Blot to assess infection with CagA positive strains. Modified Poisson and Poisson regression models were used to estimate crude and sex-, age-, and education-adjusted prevalence ratios (PR) and incidence rate ratios (RR), respectively. RESULTS: The prevalence of H. pylori infection was 84.2% [95% confidence interval (95%CI): 82.4-86.1]. It increased across age-groups in the more educated subjects, (18-30 years: 72.6%; >=71 years: 88.1%; p for trend <0.001) and decreased with education in the younger (<=4 schooling years: 100.0%; >=10 schooling years: 72.6%; p for trend <0.001). Living in a more deprived neighborhood was associated with a higher prevalence of infection, only in the younger (PR = 1.20, 95%CI: 1.03-1.38) and more educated participants (PR = 1.15, 95%CI: 1.03-1.29). Among the infected, the proportion with CagA-positive strains was 61.7% (95%CI: 56.6-66.9). The incidence rate was 3.6/100 person-years (median follow-up: 3 years; 95%CI: 2.1-6.2), lower among the more educated (>=10 vs <=9: RR = 0.25, 95%CI: 0.06-0.96). The seroreversion rate was 1.0/100 person-years (95%CI: 0.6-1.7). CONCLUSIONS: The prevalence of infection among adults is still very high in Portugal, suggesting that stomach cancer rates will remain high over the next few decades. PMID- 23725609 TI - "Big data" in the intensive care unit. Closing the data loop. PMID- 23725610 TI - Maternal distress and childhood wheeze: mechanisms and context. PMID- 23725611 TI - B cells produce CXCL13 in lymphoid neogenesis during chronic obstructive pulmonary disease. The new kid on the block? PMID- 23725612 TI - Intensive care unit research and informed consent: still a conundrum. PMID- 23725613 TI - Study design and "evidence" in patient-oriented research. AB - Individual studies in patient-oriented research, whether described as "comparative effectiveness" or using other terms, are based on underlying methodological designs. A simple taxonomy of study designs includes randomized controlled trials on the one hand, and observational studies (such as case series, cohort studies, and case-control studies) on the other. A rigid hierarchy of these design types is a fairly recent phenomenon, promoted as a tenet of "evidence-based medicine," with randomized controlled trials receiving gold standard status in terms of producing valid results. Although randomized trials have many strengths, and contribute substantially to the evidence base in clinical care, making presumptions about the quality of a study based solely on category of research design is unscientific. Both the limitations of randomized trials as well as the strengths of observational studies tend to be overlooked when a priori assumptions are made. This essay presents an argument in support of a more balanced approach to evaluating evidence, and discusses representative examples from the general medical as well as pulmonary and critical care literature. The simultaneous consideration of validity (whether results are correct "internally") and generalizability (how well results apply to "external" populations) is warranted in assessing whether a study's results are accurate for patients likely to receive the intervention-examining the intersection of clinical and methodological issues in what can be called a medicine-based evidence approach. Examination of cause-effect associations in patient-oriented research should recognize both the strengths and limitations of randomized trials as well as observational studies. PMID- 23725614 TI - "Lies, damned lies ..." and observational studies in comparative effectiveness research. AB - A new federal initiative has allocated $1.1 billion to comparative effectiveness research, and many have emphasized the importance of including observational studies in this effort. The rationale for using observational studies to assess comparative effectiveness is based on concerns that randomized controlled trials (RCTs) are not "real world" because they enroll homogeneous patient populations, measure study outcomes that are not important to patients, use protocols that are overly complex, are conducted in specialized centers, and use study treatments that are not consistent with usual care, and that RCTs are not always feasible because of a lack of equipoise, the need to assess delayed endpoints, and concerns that they take years to complete and are expensive. This essay questions the validity of each of these proposed limitations, summarizes concerns raised about the accuracy of results generated by observational studies, provides some examples of discrepancies between results of observational studies and RCTs that pertain to pulmonary and critical care, and suggests that using observational studies for comparative effectiveness research may increase rather than decrease the cost of health care and may harm patients. PMID- 23725616 TI - Bronchial varices in congenital unilateral pulmonary vein atresia. PMID- 23725617 TI - Idiopathic pulmonary fibrosis: clinically meaningful primary endpoints in phase 3 clinical trials. PMID- 23725615 TI - An official American Thoracic Society Clinical Practice Guideline: sleep apnea, sleepiness, and driving risk in noncommercial drivers. An update of a 1994 Statement. AB - BACKGROUND: Sleepiness may account for up to 20% of crashes on monotonous roads, especially highways. Obstructive sleep apnea (OSA) is the most common medical disorder that causes excessive daytime sleepiness, increasing the risk for drowsy driving two to three times. The purpose of these guidelines is to update the 1994 American Thoracic Society Statement that described the relationships among sleepiness, sleep apnea, and driving risk. METHODS: A multidisciplinary panel was convened to develop evidence-based clinical practice guidelines for the management of sleepy driving due to OSA. Pragmatic systematic reviews were performed, and the Grading of Recommendations, Assessment, Development, and Evaluation approach was used to formulate and grade the recommendations. Critical outcomes included crash-related mortality and real crashes, whereas important outcomes included near-miss crashes and driving performance. RESULTS: A strong recommendation was made for treatment of confirmed OSA with continuous positive airway pressure to reduce driving risk, rather than no treatment, which was supported by moderate-quality evidence. Weak recommendations were made for expeditious diagnostic evaluation and initiation of treatment and against the use of stimulant medications or empiric continuous positive airway pressure to reduce driving risk. The weak recommendations were supported by very low-quality evidence. Additional suggestions included routinely determining the driving risk, inquiring about additional causes of sleepiness, educating patients about the risks of excessive sleepiness, and encouraging clinicians to become familiar with relevant laws. DISCUSSION: The recommendations presented in this guideline are based on the current evidence, and will require an update as new evidence and/or technologies becomes available. PMID- 23725618 TI - Selection of clinically meaningful primary endpoints in phase 3 clinical trials in idiopathic pulmonary fibrosis. PMID- 23725619 TI - Mortality, a bar too high for idiopathic pulmonary fibrosis clinical trials! PMID- 23725620 TI - Importance of idiopathic pulmonary fibrosis staging for clinical trial endpoints. PMID- 23725621 TI - Primary endpoints in phase 3 clinical trials in idiopathic pulmonary fibrosis: one step at a time. PMID- 23725622 TI - External cooling applied to febrile patients with septic shock: control for cointerventions? PMID- 23725623 TI - Reply: idiopathic pulmonary fibrosis: perspectives on clinically meaningful primary endpoints in phase 3 clinical trials. PMID- 23725624 TI - Fever control in septic shock: import of microorganisms and antimicrobial therapy. PMID- 23725625 TI - Fever control using external cooling in septic shock. PMID- 23725626 TI - Does cooling really improve outcomes in patients with septic shock? PMID- 23725627 TI - Reply: Does cooling really improve outcomes in patients with septic shock? PMID- 23725628 TI - Residual effect of THN hypoglossal stimulation in obstructive sleep apnea: a disease-modifying therapy. PMID- 23725629 TI - Lessons learned from a tuberculosis contact investigation associated with a disaster volunteer after the 2011 Great East Japan Earthquake. PMID- 23725630 TI - A woman with progressive dyspnea with multiple lung cavitations. PMID- 23725631 TI - Determination of Methylenetetrahydrofolate Reductase (MTHFR) gene polymorphism in Turkish patients with nonsyndromic cleft lip and palate. AB - OBJECTIVE: To investigate the association between MTHFR C677T polymorphism and Turkish patients with nonsyndromic cleft lip and/or palate (nsCL/P) and to determine the prevalence of the Turkish population. PATIENTS AND METHODS: Molecular analysis of gene polymorphisms were carried out using polymerase chain reactions and restriction enzyme digestions. In our study, 80 patients with nsCL/P and 125 unrelated individuals from Turkey were studied. RESULTS: We found that MTHFR C677T polymorphism is a significant risk factor for nsCL/P in Turkey (p=0.0004). These results support the impact of MTHFR C677T polymorphism and importance of folic acid intake in the etiology of nsCL/P. CONCLUSIONS: MTHFR gene which is localized in the relevant region of chromosome 1p36.3 not been studied Turkish patients with nsCL/P and the prevalence of our country not to be determined. We revealed statistically association between the MTHFR C677T gene polymorphism and nonsyndromic cleft lip and/or palate in the Turkish population. PMID- 23725632 TI - Using the suicide index score to predict treatment outcomes among psychiatric inpatients. AB - For many suicidal people, the desire to die is moderated by a competing desire to live. This study aimed to demonstrate the ability of a wish-to-live versus wish to-die index score to measure ambivalence and trichotomize suicidal inpatients into distinct stratified risk groups. Analyses revealed that index scores calculated for patients at treatment start significantly discriminated among the groups at index and uniquely predicted suicidal ideation, hopelessness, and depression scores across treatment. On average, patients with wish-to-live and wish-to-die orientations resolved suicidal ideation by discharge. Changes in suicidal ideation among ambivalently oriented patients were more variable. Clinical and research implications are discussed. PMID- 23725634 TI - The use of porcine small intestine submucosa implants might be associated with a high recurrence rate following laparoscopic herniorrhaphy. AB - BACKGROUND/PURPOSE: The efficacy of porcine small intestine submucosa (SIS) implants in hernia repair has rarely been reported and remained elusive. We herein report our experience to further elucidate the efficacy of SIS mesh in herniorrhaphy. METHODS: Between June 2008 and October 2009, a total of 82 patients with 125 inguinal hernias undergoing endoscopic total extraperitoneal (TEP) herniorrhaphy were included. Seventy patients (with 108 hernias) had traditional polypropylene and 12 patients (with 17 hernias) had SIS mesh repair. Postoperative complications and recurrence rates were compared between the two meshes. RESULTS: The demographics between two groups were similar. All operations were performed smoothly with laparoscopy, and the postoperative courses were uneventful. After a median follow-up of 18 months, five (7%) in the polypropylene group and three (25%) in the SIS group had chronic pain (p = 0.09). Five of 17 (29.4%) hernia repairs in the SIS group had an ipsilateral recurrence, compared to no recurrence in the polypropylene group. In the five cases, the second laparoscopy revealed the SIS mesh had been totally degraded and there was no obvious fibrotic tissue in the previous mesh sites. CONCLUSION: Our data suggest that the use of SIS mesh in endoscopic TEP herniorrhaphy might be associated with a high recurrence rate. The second look laparoscopy in these recurrent cases revealed slow and inadequate integration of host tissue. More evidence is still required to further evaluate the efficacy of SIS mesh in endoscopic TEP herniorrhaphy. PMID- 23725633 TI - Comparative genomics of Salmonella enterica serovars Derby and Mbandaka, two prevalent serovars associated with different livestock species in the UK. AB - BACKGROUND: Despite the frequent isolation of Salmonella enterica sub. enterica serovars Derby and Mbandaka from livestock in the UK and USA little is known about the biological processes maintaining their prevalence. Statistics for Salmonella isolations from livestock production in the UK show that S. Derby is most commonly associated with pigs and turkeys and S. Mbandaka with cattle and chickens. Here we compare the first sequenced genomes of S. Derby and S. Mbandaka as a basis for further analysis of the potential host adaptations that contribute to their distinct host species distributions. RESULTS: Comparative functional genomics using the RAST annotation system showed that predominantly mechanisms that relate to metabolite utilisation, in vivo and ex vivo persistence and pathogenesis distinguish S. Derby from S. Mbandaka. Alignment of the genome nucleotide sequences of S. Derby D1 and D2 and S. Mbandaka M1 and M2 with Salmonella pathogenicity islands (SPI) identified unique complements of genes associated with host adaptation. We also describe a new genomic island with a putative role in pathogenesis, SPI-23. SPI-23 is present in several S. enterica serovars, including S. Agona, S. Dublin and S. Gallinarum, it is absent in its entirety from S. Mbandaka. CONCLUSIONS: We discovered a new 37 Kb genomic island, SPI-23, in the chromosome sequence of S. Derby, encoding 42 ORFS, ten of which are putative TTSS effector proteins. We infer from full-genome synonymous SNP analysis that these two serovars diverged, between 182kya and 625kya coinciding with the divergence of domestic pigs. The differences between the genomes of these serovars suggest they have been exposed to different stresses including, phage, transposons and prolonged externalisation. The two serovars possess distinct complements of metabolic genes; many of which cluster into pathways for catabolism of carbon sources. PMID- 23725635 TI - The role of complement in CD4+ T cell homeostasis and effector functions. AB - The complement system is among the evolutionary oldest 'players' of the immune system. It was discovered in 1896 by Jules Bordet as a heat-labile fraction of the serum responsible for the opsonisation and subsequent killing of bacteria. The decades between the 1920s and 1990s then marked the discovery and biochemical characterization of the proteins comprising the complement system. Today, complement is defined as a complex system consisting of more than 30 membrane bound and soluble plasma proteins, which are activated in a cascade-like manner, very similarly to the caspase proteases and blood coagulation systems. Complement is engrained in the immunologist's mind as a serum-effective, quintessential part of innate immunity, vitally required for the detection and removal of pathogens or other dangerous entities. Three decades ago, this rather confined definition was challenged and then refined when it was shown that complement participates vitally in the induction and regulation of B cell responses, thus adaptive immunity. Similarly, research work published in more recent years supports an equally important role for the complement system in shaping T cell responses. Today, we are again facing paradigm shifts in the field: complement is actively involved in the negative control of T cell effector immune responses, and thus, by definition in immune homeostasis. Further, while serum complement activity is without doubt fundamental in the defence against invading pathogens, local immune cell-derived production of complement emerges as key mediator of complement's impact on adaptive immune responses. And finally, the impact of complement on metabolic pathways and the crosstalk between complement and other immune effector systems is likely more extensive than previously anticipated and is fertile ground for future discoveries. In this review, we will discuss these emerging new roles of complement, with a focus on Th1 cell biology. PMID- 23725637 TI - Magnesium impacts myosin V motor activity by altering key conformational changes in the mechanochemical cycle. AB - We investigated how magnesium (Mg) impacts key conformational changes during the ADP binding/release steps in myosin V and how these alterations impact the actomyosin mechanochemical cycle. The conformation of the nucleotide binding pocket was examined with our established FRET system in which myosin V labeled with FlAsH in the upper 50 kDa domain participates in energy transfer with mant labeled nucleotides. We examined the maximum actin-activated ATPase activity of MV FlAsH at a range of free Mg concentrations (0.1-9 mM) and found that the highest activity occurs at low Mg (0.1-0.3 mM), while there is a 50-60% reduction in activity at high Mg (3-9 mM). The motor activity examined with the in vitro motility assay followed a similar Mg-dependence, and the trend was similar with dimeric myosin V. Transient kinetic FRET studies of mantdADP binding/release from actomyosin V FlAsH demonstrate that the transition between the weak and strong actomyosin.ADP states is coupled to movement of the upper 50 kDa domain and is dependent on Mg with the strong state stabilized by Mg. We find that the kinetics of the upper 50 kDa conformational change monitored by FRET correlates well with the ATPase and motility results over a wide range of Mg concentrations. Our results suggest the conformation of the upper 50 kDa domain is highly dynamic in the Mg free actomyosin.ADP state, which is in agreement with ADP binding being entropy driven in the absence of Mg. Overall, our results demonstrate that Mg is a key factor in coupling the nucleotide- and actin-binding regions. In addition, Mg concentrations in the physiological range can alter the structural transition that limits ADP dissociation from actomyosin V, which explains the impact of Mg on actin-activated ATPase activity and in vitro motility. PMID- 23725638 TI - Cell segmentation in phase contrast microscopy images via semi-supervised classification over optics-related features. AB - Phase-contrast microscopy is one of the most common and convenient imaging modalities to observe long-term multi-cellular processes, which generates images by the interference of lights passing through transparent specimens and background medium with different retarded phases. Despite many years of study, computer-aided phase contrast microscopy analysis on cell behavior is challenged by image qualities and artifacts caused by phase contrast optics. Addressing the unsolved challenges, the authors propose (1) a phase contrast microscopy image restoration method that produces phase retardation features, which are intrinsic features of phase contrast microscopy, and (2) a semi-supervised learning based algorithm for cell segmentation, which is a fundamental task for various cell behavior analysis. Specifically, the image formation process of phase contrast microscopy images is first computationally modeled with a dictionary of diffraction patterns; as a result, each pixel of a phase contrast microscopy image is represented by a linear combination of the bases, which we call phase retardation features. Images are then partitioned into phase-homogeneous atoms by clustering neighboring pixels with similar phase retardation features. Consequently, cell segmentation is performed via a semi-supervised classification technique over the phase-homogeneous atoms. Experiments demonstrate that the proposed approach produces quality segmentation of individual cells and outperforms previous approaches. PMID- 23725639 TI - Neighbourhood approximation using randomized forests. AB - Leveraging available annotated data is an essential component of many modern methods for medical image analysis. In particular, approaches making use of the "neighbourhood" structure between images for this purpose have shown significant potential. Such techniques achieve high accuracy in analysing an image by propagating information from its immediate "neighbours" within an annotated database. Despite their success in certain applications, wide use of these methods is limited due to the challenging task of determining the neighbours for an out-of-sample image. This task is either computationally expensive due to large database sizes and costly distance evaluations, or infeasible due to distance definitions over semantic information, such as ground truth annotations, which is not available for out-of-sample images. This article introduces Neighbourhood Approximation Forests (NAFs), a supervised learning algorithm providing a general and efficient approach for the task of approximate nearest neighbour retrieval for arbitrary distances. Starting from an image training database and a user-defined distance between images, the algorithm learns to use appearance-based features to cluster images approximating the neighbourhood structured induced by the distance. NAF is able to efficiently infer nearest neighbours of an out-of-sample image, even when the original distance is based on semantic information. We perform experimental evaluation in two different scenarios: (i) age prediction from brain MRI and (ii) patch-based segmentation of unregistered, arbitrary field of view CT images. The results demonstrate the performance, computational benefits, and potential of NAF for different image analysis applications. PMID- 23725641 TI - The risk of cancer development in systemic sclerosis: a meta-analysis. AB - OBJECTIVES: Systemic sclerosis is a multi-system disorder of connective tissue characterized by Raynaud's phenomenon and fibrosis of various organs. The risk of development of cancer in systemic sclerosis (SSc) has been extensively investigated with inconclusive results. To shed some light on the controversy, we conducted a meta-analysis of all published articles linking SSc to the risk of cancer development. METHODS: Relevant electronic databases were searched for English-language studies characterizing the association of cancers in patients with SSc. Standardized incidence rate (SIR) with its 95% confidence interval (CI) of each study was combined using a fixed/random effect model. RESULTS: A total of seven papers including 7183 SSc patients were identified, of which 7 reported the SIR for lung cancer, 4 for non-Hodgkin's lymphoma (NHL) and 4 for hematopoietic cancer and 7 for breast cancer. Compared with the general population, the combined SIR was 3.14 (95% CI: 2.02-4.89), 2.68 (95% CI: 1.58-4.56), 2.57 (95% CI: 1.79-3.68) and 1.09 (95% CI: 0.86-1.38), respectively. Significant heterogeneity was observed in lung cancer group (Q=26.13, P<0.001, I(2)=77%). Potential publication bias was absent. CONCLUSIONS: This present meta-analysis demonstrated an increased risk of lung, non-Hodgkin's lymphoma and hematopoietic cancers among patients with SSc, but not for breast cancer. However, some of the available data were several decades old, and future studies taking new treatment strategies into account are required. PMID- 23725640 TI - Longitudinal effects of weight loss and regain on cytokine concentration of obese adults. AB - OBJECTIVE: To describe patterns of weight loss and regain and their effect on the pro-inflammatory cytokines IL-6 and TNF-alpha, and anti-inflammatory cytokines adiponectin and IL-10 during a 24-month weight loss trial. MATERIALS/METHODS: Participants were obese adults (N=66) who lost and regained >= 10lb during a 24 month clinical trial of behavioral weight loss treatment. Measurements of cytokines and weight were conducted at baseline, 6, 12, 18, and 24 months. Linear mixed modeling was used to determine percent change in weight and cytokines from baseline. RESULTS: The sample was predominantly female (80.3%) and White (86.4%), with a mean age of 48.4 +/- 7.3 years and mean BMI of 34.5 +/- 4.4 kg/m(2). At baseline, men had higher waist circumference, body weight, and energy intake, and lower percent body fat and adiponectin. The largest decrease in weight was observed at 6 months with a mean 11% decrease (p<.0001).A significant gender-by weight change interaction on percent change in adiponectin was observed [b(se)=0.9 (0.2), p=.0003], with men having a larger increase in adiponectin with weight loss compared to women. There was a significant effect of weight gain over time with increases in IL-6 [b(se)=0.9 (0.3), p=.001]. CONCLUSIONS: Overall, weight loss was significantly associated with improvements in adiponectin and IL 6. Those improvements remained at 24 months, following weight regain. The association between weight change and adiponectin was different between genders. Implementing strategies that support sustained weight loss can help prevent a state of chronic systemic inflammation and its associated adverse effects. PMID- 23725642 TI - Association of multiple drug resistance-1 gene polymorphism with multiple drug resistance in breast cancer patients from an ethnic Saudi Arabian population. AB - Chemotherapy has been used widely to treat cancer, both as a systemic therapy and as a local treatment. Unfortunately, many types of cancer are still refractory to chemotherapy. The mechanisms of anticancer drug resistance have been extensively explored but have not been fully characterized. This study analyzed the occurrences of polymorphism (SNP) in the MDR1 gene in breast cancer patients and determined a possible association with chemotherapy. The study group included one hundred breast carcinoma patients who subsequently received chemotherapy (the regimen generally consisted of commonly used drugs such as cyclophosphamide, adriamycin, 5-fluorouracil, docetaxel and their combinations). Blood samples from 100 healthy individuals are used, as controls were also genotyped for the MDR1 gene. This investigation revealed a significant correlation with response to various regimens of chemotherapy showing a low response to therapy with the CT/TT genotype at (exon 12) 1236 codon (p<0.001). These findings demonstrate, for the first time, that the polymorphisms in (exon 12) 1236 codon of the MDR1 gene greatly influence the drug response in patients from the Arab population of Saudi Arabia. PMID- 23725643 TI - Shift work, circadian gene variants and risk of breast cancer. AB - Circadian (clock) genes have been linked with several functions relevant to cancer, and epidemiologic research has suggested relationships with breast cancer risk for variants in NPAS2, CLOCK, CRY2 and TIMELESS. Increased breast cancer risk has also been observed among shift workers, suggesting potential interactions in relationships of circadian genes with breast cancer. Relationships with breast cancer of 100 SNPs in 14 clock-related genes, as well as potential interactions with shift work history, were investigated in a case control study (1042 cases, 1051 controls). Odds ratios in an additive genetic model for European-ancestry participants (645 cases, 806 controls) were calculated, using a two-step correction for multiple testing: within each gene through permutation testing (10,000 permutations), and correcting for the false discovery rate across genes. Interactions of genotypes with ethnicity and shift work (<2 years vs >=2 years) were evaluated individually. Following permutation analysis, two SNPs (rs3816360 in ARNTL and rs11113179 in CRY1) displayed significant associations with breast cancer and one SNP (rs3027188 in PER1) was marginally significant; however, none were significant following adjustment for the false discovery rate. No significant interaction with shift work history was detected. If shift work causes circadian disruption, this was not reflected in associations between clock gene variants and breast cancer risk in this study. Larger studies are needed to assess interactions with longer durations (>30 years) of shift work that have been associated with breast cancer. PMID- 23725644 TI - Sensitivity of cognitive tests in four cognitive domains in discriminating MDD patients from healthy controls: a meta-analysis. AB - BACKGROUND: We performed a meta-analysis in order to determine which neuropsychological domains and tasks would be most sensitive for discriminating between patients with major depressive disorder (MDD) and healthy controls. METHODS: Relevant articles were identified through a literature search of the PubMed and Cochrane Library databases for the period between January 1997 and May 2011. A meta-analysis was conducted using the standardized means of individual cognitive tests in each domain. The heterogeneity was assessed, and subgroup analyses according to age and medication status were performed to explore the sources of heterogeneity. RESULTS: A total of 22 trials involving 955 MDD patients and 7,664 healthy participants were selected for our meta-analysis. MDD patients showed significantly impaired results compared with healthy participants on the Digit Span and Continuous Performance Test in the attention domain; the Trail Making Test A (TMT-A) and the Digit Symbol Test in the processing speed domain; the Stroop Test, the Wisconsin Card Sorting Test, and Verbal Fluency in the executive function domain; and immediate verbal memory in the memory domain. The Finger Tapping Task, TMT-B, delayed verbal memory, and immediate and delayed visual memory failed to separate MDD patients from healthy controls. The results of subgroup analysis showed that performance of Verbal Fluency was significantly impaired in younger depressed patients (<60 years), and immediate visual memory was significantly reduced in depressed patients using antidepressants. CONCLUSIONS: Our findings have inevitable limitations arising from methodological issues inherent in the meta-analysis and we could not explain high heterogeneity between studies. Despite such limitations, current study has the strength of being the first meta-analysis which tried to specify cognitive function of depressed patients compared with healthy participants. And our findings may provide clinicians with further evidences that some cognitive tests in specific cognitive domains have sensitivity to discriminate MDD patients from healthy controls. PMID- 23725645 TI - Hypervalent compounds as ligands: I3-anion adducts with transition metal pentacarbonyls. AB - Just a couple of transition metal complexes of the familiar triiodide anion are known. To investigate the bonding in these, as well as isomeric possibilities, we examined theoretically adducts of I3(-) with model organometallic fragments, [Cr(CO)5] and [Mn(CO)5](+). Bonding energy computations were augmented by a Natural Bond Orbital (NBO) perturbation theory analysis and Energy Decomposition Analysis (EDA). The bonding between I3(-) and the organometallic fragment is substantial, especially for the electrostatically driven anion-cation case. "End on" coordination is favored by 5-13 kcal/mol over "side-on" (to the central I of I3(-)), with a ~10 kcal/mol barrier for isomerization. A developing asymmetry in the I-I bonding of "end-on" coordinated I3(-) led us to consider in some detail the obvious fragmentation to a coordinated I(-) and free I2. While the signs of incipient fragmentation in that direction are there, these is a definite advantage to maintaining some I(-) to I2 bonding in triiodide complexes. PMID- 23725646 TI - Effects of carbon phase deposition in silica gel pores on NO2 reactive adsorption at ambient conditions on carbon/silica composites. AB - Silica-carbon composite samples containing various carbon contents deposited within a silica gel matrix were synthesized. The composites were evaluated as nitrogen dioxide adsorbents at ambient conditions in either wet (70% RH) or dry air streams. The surface chemistry and textural features of the initial and exposed samples were characterized using nitrogen adsorption, potentiometric titration, thermal analysis, and FT-IR. The deposition of the carbon phase significantly increased the amount of NO2 adsorbed in comparison with that adsorbed on the silica gel. With an increase in the amount of carbon an increase in the performance was found. The positive effect was especially noticed when water was present in the system. An oxidation of the surface and release of NO was observed. The acidification/oxidation of the surface is more pronounced in moist conditions, and it is linked to the formation of nitric acid adsorbed in the pore system. The carbon phase besides providing some level of hydrophobicity also brings phenolic groups to the system, on which immobilization of NO2 takes place via nitrification reactions. PMID- 23725647 TI - Different phenotypes of HNF1beta deletion mutants in familial multicystic dysplastic kidneys. AB - Multicystic dysplastic kidney (MCDK) is one of the most common congenital abnormalities of the kidney and urinary tract (CAKUT), although its pathophysiology remains unknown. Familial occurrence of MCDK suggests that mutations in genes associated with nephrogenesis are involved in the pathogenesis in at least some cases. Hepatocyte nuclear factor 1beta (HNF1beta) is a member of the homeodomain-containing super family of transcription factors, and is known to regulate tissue-specific gene expression in a number of organs including the kidneys, pancreas and liver. It has been recently postulated to be associated with CAKUT, including MCDK. We recently encountered a family with a deletion mutant of HNF1beta, of which the 2nd son, the proband, developed bilateral MCDK resulting in renal loss of function in infancy while the 1st son developed unilateral MCDK. Their father has two normal kidneys. This family confirmed that mutations in the HNF1beta gene are strongly associated with the development of MCDK. Furthermore, the fact that no clear phenotype-genotype correlation exists suggests that gene(s) other than HNF1beta are also involved in nephrogenesis and the development of MCDK. PMID- 23725648 TI - Membranous glomerulonephritis associated with splenic marginal zone lymphoma mimicking multiple myeloma. AB - Glomerulonephritis may complicate the course of a wide variety of malignant diseases. However, there are relatively few reports of membranous glomerulonephritis (MGN) in patients with non-Hodgkin lymphoma (NHL). We describe for the first time a case of MGN associated with splenic marginal zone lymphoma with extreme plasmacytic differentiation and bone marrow infiltration mimicking multiple myeloma. We also reviewed the literature and summarize the clinical pathological findings and the mechanisms involved in NHL-induced MGN. Our current case highlights the importance of a quick and correct diagnosis of the underlying disease and the value of a thorough physical examination. Clinicians should be aware of the possibility of an underlying hematologic malignancy in such cases, particularly in elderly patients with renal biopsy that shows the presence of atypical histology. PMID- 23725649 TI - Proliferative glomerulonephritis with monoclonal IgG deposits in a patient with autoimmune hemolytic anemia. AB - A 25-year-old woman was admitted because of proteinuria. A renal biopsy showed mesangial/endocapillary proliferative glomerulonephritis with IgG2-kappa deposits. Electron microscopy showed immune complex-type deposits. She also had Coombs-positive hemolytic anemia, anticardiolipin antibodies, and antinuclear antibodies. Middle-dose steroid therapy led to improvement of proteinuria and hemolytic anemia. Six years later, she developed crescentic glomerulonephritis with IgG2-kappa deposits during pregnancy. Middle-dose steroid therapy improved renal dysfunction. This is an exceptional case of proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID), a recently described rare dysproteinemia-related glomerulonephritis, associated with autoimmune disease. This case also suggests that crescentic glomerulonephritis can be superimposed on PGNMID. PMID- 23725650 TI - A patient with hemodialysis-related hyperammonemic encephalopathy: a delayed presentation of congenital arterioportal fistulas. AB - We present a 32-year-old woman who developed hyperammonemic encephalopathy during hemodialysis. She was rather well before 2009 when receiving peritoneal dialysis due to chronic interstitial nephritis. Due to a refractory peritonitis, the treatment was shifted to hemodialysis in January 2009. About 1 year later, she was found with consciousness disturbance during hemodialysis then admitted to the hospital because of hyperammonemia (165 MUg/dl). During hospitalization, the patient's abdominal Doppler sonography showed a hepatofugal flow in the portal trunk while the hepatic artery angiography demonstrated multiple intrahepatic arterioportal fistulas. Her general condition was improved after the treatment of lactulose and hepatic artery embolization. With the occurrence of arterioportal fistulas induced portal hypertension, we speculated that the portal-systemic shunt was enhanced during hemodialysis because of venous hypotension which then resulted in the transient hyperammonemia. To the best of our knowledge, this is the first patient who developed hemodialysis- related hyperammonemic encephalopathy due to multiple arterioportal fistulas. PMID- 23725651 TI - Complications following cranioplasty using autologous bone or polymethylmethacrylate--retrospective experience from a single center. AB - OBJECTIVE: A decompressive hemicraniectomy is a potentially life-saving intervention following head trauma. Once performed patients are obliged to undergo a second procedure with cranioplasty. Two of the most commonly used materials are autologous bone and polymethylmethacrylate (PMMA). We have now evaluated complications following a cranioplasty using these materials. MATERIALS AND METHODS: During a 7-year period (2002-2008) 49 patients were operated with a decompressive craniectomy following head trauma. Patients received a cranioplasty consisting of autologous bone (30 patients, 61.2%) or PMMA (19 patients, 38.8%) and were followed at least 24 months. Patient data were collected retrospectively. RESULTS: Twenty patients (20/49, 40.8%) experienced a complication that prompted a re-operation. There was a significantly higher rate of complications leading to a re-operation (53.3% vs. 21.1%, p=0.03) and a shorter survival time of the cranioplasty (mean 48.1 +/- 7.8 vs. 79.5 +/- 9.0 months, p=0.035) in patients with autologous bone compared to PMMA. Bone resorption and the presence of postoperative hematomas were significantly more common in patients with autologous bone. The material used for cranioplasty was the only variable that significantly correlated to the rate of complications. CONCLUSIONS: In our series we had a high percentage of patients needing re operation due to complications following a cranioplasty. Though generally considered a straightforward procedure, complications and associated morbidity in patients undergoing cranioplasty should not be underestimated. PMID- 23725652 TI - [Anterior staphyloma following keratomycosis]. PMID- 23725653 TI - En face optical coherence tomography visualization of post-traumatic photoreceptor disruption. PMID- 23725654 TI - Acute ethanol administration affects zebrafish preference for a biologically inspired robot. AB - Preclinical animal models constitute a cornerstone against which the reward processes involved in drug addiction are often studied and dissected. While rodents have traditionally represented the species of choice, a growing body of literature indicates that zebrafish are emerging as a valuable model organism. Specifically, several studies demonstrate that the effects of ethanol at the level of emotional- and cognitive-related domains can be reliably investigated using zebrafish. The rapidly evolving nature of these efforts allows substantial room for the development of novel experimental paradigms suited to this freshwater species. The field of ethorobotics may prove particularly beneficial, due to its ability to convey fully controllable and easily reproducible experimental tools. In this study, we addressed the possibility of using a biologically inspired robot to investigate the emotionally related properties of ethanol in a preference task in zebrafish. To this aim, we evaluated wild-type zebrafish preference toward a robotic stimulus and addressed whether ethanol administration (0.25% and 1.00% ethanol/water concentration) may alter such preferences. In accordance with our previous studies, we observed that zebrafish exhibit a natural attraction toward the robot. Additionally, in agreement with our predictions, we showed that ethanol administration abolishes such preferences. This work is the first to demonstrate that robotic stimuli can be used in zebrafish to investigate the reward-related properties of alcohol. PMID- 23725655 TI - New effector functions and regulatory mechanisms of BCL6 in normal and malignant lymphocytes. AB - The BCL6 oncogenic repressor is a master regulator of humoral immunity and B-cell lymphoma survival. Whereas much research has focused on its regulation and function in germinal center B-cells, its role in other mature lymphoid cell compartments is less clear. A novel role for BCL6 in follicular T helper cell development was recently uncovered. The latest discoveries reveal that BCL6 is also an important regulator of other specialized helper T-cell subsets within germinal centers, pre-germinal center events, and peripheral T-cell effector functions. Here, we review newly discovered roles for BCL6 in lymphocyte subsets residing within and outside of germinal centers, and discuss their implications with respect to the molecular mechanisms of BCL6 regulation and potential links to B and T-cell lymphomas. PMID- 23725657 TI - Are there sensitive time periods for dementia caregivers? The occurrence of behavioral and psychological symptoms in the early stages of dementia. AB - BACKGROUND: The behavioral and psychological symptoms associated with dementia (BPSD) can be burdensome to informal/family caregivers, negatively affecting mental health and expediting the institutionalization of patients. Because the dementia patient-caregiver relationship extends over long periods of time, it is useful to examine how BPSD impact caregiver depressive symptoms at varied stages of illness. The goal of this study was to assess the association of BPSD that occur during early stage dementia with subsequent caregiver depressive symptoms. METHODS: Patients were followed from the early stages of dementia every six months for up to 12 years or until death (n = 160). Caregiver symptoms were assessed on average 4.5 years following patient's early dementia behaviors. A generalized estimating equation (GEE) extension of the logistic regression model was used to determine the association between informal caregiver depressive symptoms and BPSD symptoms that occurred at the earliest stages dementia, including those persistent during the first year of dementia diagnosis. RESULTS: BPSD were common in early dementia. None of the individual symptoms observed during the first year of early stage dementia significantly impacted subsequent caregiver depressive symptoms. Only patient agitation/aggression was associated with subsequent caregiver depressive symptoms (OR = 1.76; 95% CI = 1.04-2.97) after controlling for concurrent BPSD, although not in fully adjusted models. CONCLUSIONS: Persistent agitation/aggression early in dementia diagnosis may be associated with subsequent depressive symptoms in caregivers. Future longitudinal analyses of the dementia caregiving relationship should continue to examine the negative impact of persistent agitation/aggression in the diagnosis of early stage dementia on caregivers. PMID- 23725656 TI - Human dendritic cell subsets in vaccination. AB - Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural targets for antigen delivery. DCs provide an essential link between the innate and the adaptive immune responses. DCs are at the center of the immune system owing to their ability to control both tolerance and immunity. DCs are thus key targets for both preventive and therapeutic vaccination. Herein, we will discuss recent progresses in our understanding of DC subsets physiology as it applies to vaccination. PMID- 23725658 TI - Psychological interventions helping pediatric oncology patients cope with medical procedures: a nurse-centered approach. AB - PURPOSE OF THE RESEARCH: This study explored whether psychological interventions are currently used by pediatric oncology nurses to help children cope with their treatment and, if so, which interventions were considered by oncology nurses to be the most effective. METHODS AND SAMPLE: A web-based survey was developed to assess pediatric oncology nurses' impressions of psychological care for pediatric patients during their medical treatment. A sample of 88 pediatric oncologic nurses from twelve leading pediatric oncology departments in the US participated in the survey. The closed questions were analyzed through quantitative methods with statistics. The open questions were examined through qualitative methods with report narratives and discourse analysis. KEY RESULTS: Pediatric oncology nurses identified three psychological interventions to reduce suffering: educating children by explaining the procedure; providing emotional support to children by listening, answering children's worries, or holding their hands; and distracting children through passive and active forms. The survey further showed that nurses spent on average 3 h per day providing emotional support, would be willing to be trained in additional interventions (93%), and could devote at least 10 min per treatment to provide support (77%). CONCLUSIONS: This work demonstrates the central role nurses play as emotional support caregivers. Since nurses would be willing to provide emotional support during treatments, training may be an approach to incorporate the use of psychological interventions. PMID- 23725659 TI - It's time for updating primary nursing in pediatric oncology care: qualitative study highlighting the perceptions of nurses, physicians and parents. AB - PURPOSE: The aim of the study was to describe nurses', physicians' and parents' perceptions of primary nursing as a working model in a paediatric oncology care setting. METHOD: The qualitative descriptive approach was selected in order to obtain rich content by exploring of individual perceptions related to the experiences of primary nursing. Focus group interviews were used with staff and individual interviews with the parents. Data from different participants were analysed together by using inductive content analysis. RESULTS: Primary nursing was revealed as a confused and unstructured tradition which allowed variation in the role of the primary nurse and in the process. Within the role of a primary nurse, the orientation to primary nursing varied consisting of coordinating of care, task orientated and relation orientated primary nursing. The starting of the process was sudden and accidental by nature involving the aspects of commencement and allocation of the process. At the end of the process different emphasis existed in terms of the length of the process as highlighting early phase, comprehensive process and never getting to the end. Staff notions varied more than those of the parents. CONCLUSION: Perceptions related to primary nursing as a working model were revealed to be confusing by nature from the point of view of all involved. Thus, clarification is needed in the role of primary nurses and the process of primary nursing in order to gain expected family and organisational outcomes. PMID- 23725660 TI - Introduction: new horizons in research imaging. Papers from the eighth Omaha Imaging Symposium, April 2012. PMID- 23725662 TI - Vestibular schwannoma and cell-phones. Results, limits and perspectives of clinical studies. AB - The widespread development of cell-phones entails novel user exposure to electromagnetic fields. Health impact is a public health issue and a source of anxiety in the population. Some clinical studies reported an association between cell and cordless phone use and vestibular schwannoma; others found none. A systematic review was performed of all published clinical studies (cohort, registry, case-control and validation studies), with analysis of results, to determine the nature of the association and the level of evidence. Cohort studies were inconclusive due to short exposure durations and poor representativeness. Registry studies showed no correlation between evolution of cell-phone use and incidence of vestibular schwannoma. Case-control studies reported contradictory results, with methodological flaws. Only a small number of subjects were included in long-term studies (>10 years), and these failed to demonstrate any indisputable causal relationship. Exposure assessment methods were debatable, and long-term assessment was lacking. An on-going prospective study should determine any major effect of electromagnetic fields; schwannoma being a rare pathology, absence of association will be difficult to prove. No clinical association has been demonstrated between cell and cordless phone use and vestibular schwannoma. Existing studies are limited by their retrospective assessment of exposure. PMID- 23725663 TI - Success and failure factors for hearing-aid prescription: results of a French national survey. AB - OBJECTIVES: To identify epidemiological, socioeconomic, audiometric and environmental factors of success and failure of hearing-aid prescription, and to assess hearing-aid efficacy at 6-9 months after prescription. PATIENTS AND METHODS: A prospective nationwide survey was conducted in France on 184 patients with age-related hearing loss. Inclusion data were collected by a questionnaire filled out by the ENT specialist and patient, and with a second questionnaire filled out by telephone contact with the patient 6-9 months later. RESULTS: One third of patients failed to fulfill the prescription, either for financial reasons or for lack of interest in correcting their disability. For the other two thirds, the factors favoring consultation with a hearing-aid fitting specialist seemed to be: leisure activity requiring good hearing, living in a couple or family, spontaneous initial ENT consultation, strong motivation, monthly income greater than ?1200, longstanding hearing impairment, and difficulty in listening to television and following a conversation in noise. Eighty percent of hearing aid trials were successful; 60% of prescriptions were thus followed by hearing aid purchase. The main three criteria determining purchase were the advice of the hearing-aid fitting specialist, and the price and the effectiveness of the apparatus on trial. In the four daily life situations presented in the questionnaire, the hearing-aid was worn for 8 hours or more in 90% of cases, found useful in 70% and proved satisfactory in 70%. Age-related hearing loss, whether metabolic or sensorineural, benefited from hearing-aid correction in 86% of cases. CONCLUSIONS: Indications for hearing-aid prescription should take account of the patient's degree of motivation, awareness of disability, and income. The advice of the ENT and hearing-aid fitting specialists plays a key role in the patient's acceptance of the hearing-aid. Hearing-aids seem to enhance quality of life significantly in age-related hearing loss subjects. PMID- 23725664 TI - Spontaneous osteo-dural fistulae of petrous bone posterior wall. AB - OBJECTIVE: To raise awareness of the possibility of spontaneous temporal bone cerebrospinal fistula in case of clear retrotympanic effusion. CASE REPORT: A 63 year-old man with no particular history presented with unilateral spontaneous right retrotympanic clear effusion. CT found defects in the posterior part of the right temporal bone, in contact with arachnoid granulations, with no other visible abnormalities. DISCUSSION/CONCLUSION: Unilateral clear retrotympanic effusion in an adult subject should, apart from serous otitis media, suggest possible cerebrospinal fistula. In the absence of otologic or traumatic history, arachnoid granulation is one possible etiology, inducing spontaneous cerebrospinal fluid leakage when facing the temporal bone. Diagnosis is suggested by bone defects in the tegmen tympani or posterior wall of the temporal bone on CT, with the adjacent mastoid cavities filled with fluid. Pneumococcal vaccination and early surgical repair of the fistula should be performed to avoid neuromeningeal infection. PMID- 23725665 TI - Robotic endoscopic sinus and skull base surgery: review of the literature and future prospects. AB - OBJECTIVE: There has been a considerable growth in the indications of endonasal surgery that now include malignant tumours of the nasal fossae and anterior and middle cranial fossa. However, new limitations have also been identified, such as bleeding and cerebrospinal fluid leak, as well as the need to use several instruments simultaneously. Can robotics provide solutions to these problems? METHOD: Review of the literature based on the three main databases: Medline, Pubmed and Cochrane. RESULTS: Ten publications were identified. Some authors have developed surgical approaches to the skull base using the da Vinci((r)) robot, while others have designed specific robots. CONCLUSION: None of the currently available solutions appears to be completely suitable. The da Vinci((r)) robot is very cumbersome and can only be used in the middle cranial fossa via complex and relatively invasive routes. The other robots are laboratory prototypes. We are currently developing an innovative, compact, ergonomic and safe dedicated endoscope holder. PMID- 23725666 TI - "Air cyst" of the neck. PMID- 23725661 TI - The organization and physiology of the auditory thalamus and its role in processing acoustic features important for speech perception. AB - The auditory thalamus, or medial geniculate body (MGB), is the primary sensory input to auditory cortex. Therefore, it plays a critical role in the complex auditory processing necessary for robust speech perception. This review will describe the functional organization of the thalamus as it relates to processing acoustic features important for speech perception, focusing on thalamic nuclei that relate to auditory representations of language sounds. The MGB can be divided into three main subdivisions, the ventral, dorsal, and medial subdivisions, each with different connectivity, auditory response properties, neuronal properties, and synaptic properties. Together, the MGB subdivisions actively and dynamically shape complex auditory processing and form ongoing communication loops with auditory cortex and subcortical structures. PMID- 23725667 TI - Role of the "rising tide sign" in the diagnosis and assessment of the results of surgery for Zenker's diverticulum. AB - OBJECTIVE: To evaluate the role of the videoendoscopic "rising tide sign" (RTS) in the diagnosis and assessment of surgical repair of Zenker's diverticulum. STUDY DESIGN: Retrospective. SUBJECTS AND METHODS: A total of 148 patients with Zenker's diverticulum underwent surgery in our department. A videoendoscopic swallowing study (VESS) was performed pre- and postoperatively, and the two examinations compared for the presence of the RTS. VESS characteristics based on the time to RTS onset and the size of diverticulum, as seen on a barium swallow, were also compared in a subset of 38 patients. RESULTS: All patients presented with the RTS on preoperative VESS. No correlation was observed between the time to onset of the sign and size of the diverticulum. Follow-up data were available for 121 patients (mean follow-up: 8 months): 111 patients were significantly improved during follow-up, with complete disappearance of the RTS. Recurrence of symptoms was observed at this time in 10 patients. Seven of these 10 patients had concomitant recurrence of the RTS and required repeat surgery after a mean follow up of 37 months. CONCLUSION: The RTS observed by videoendoscopy is a supplementary tool for the diagnosis of Zenker's diverticulum and for evaluation of the efficacy of surgery during the postoperative follow-up. PMID- 23725668 TI - Bacteriophage-host interaction: from splendid isolation into a messy reality. AB - In the reductionist era T-type coliphage research became one of the foundations for molecular biology. The technological progress in systems biology makes it now possible to study T-type phage-Escherichia coli interaction in the natural ecological niche, the gut of warm blooded animals. This development gives a second chance to phages as anti-microbial agents ('phage therapy'). Bacteria growing in biofilms are difficult to treat with antibiotics while many phages express naturally depolymerases which attack the polysaccharide matrix that enmesh bacteria in biofilms. Phages were already used successfully to reduce contamination levels with medical catheters and might likewise be of use against infections frequently forming bacterial biofilms. PMID- 23725669 TI - Recent insights into apicomplexan parasite egress provide new views to a kill. AB - A hallmark of apicomplexan pathogens such as Plasmodium, Toxoplasma and Cryptosporidium is that they invade, replicate within, and then egress from their host cells. Egress usually results in lysis of the host cell, with deleterious consequences for the host. In the case of malaria, for example, much of the disease pathology is associated with cyclical waves of host erythrocyte destruction. This review highlights recent advances in mapping the signaling pathways that lead to egress and the parasite molecules involved in responding to and transmitting those signals. The review also discusses new findings for effector molecules that mediate disruption of the bounding membranes that enclose the intracellular parasite and the manner in which membrane rupture occurs to finally release invasive forms of the parasite. PMID- 23725670 TI - An evolutionary perspective on the broad antiviral specificity of MxA. AB - Germ line encoded antiviral defenses in vertebrate cells tend to be either broadly acting factors that exploit general features of viral replication or effectors with strong pathogen preference by virtue of specific recognition of viral proteins. The Mx GTPases, however, are atypical since they have broad antiviral activity against a wide range of RNA and DNA viruses despite specifically targeting different proteins across virus families. This review presents recent advances in understanding the biochemical properties and evolution of the primate ortholog MxA, and discusses how this information begins to provide molecular insights into the mechanisms behind the intriguing conundrum of how MxA is able to engage a diversity of viral proteins yet elicit antiviral breadth. PMID- 23725671 TI - Protein export in malaria parasites: many membranes to cross. AB - The continuous multiplication of Plasmodium parasites in red blood cells leads to a rapid increase in parasite numbers and is responsible for the disease symptoms of malaria. Survival and virulence of the parasite are linked to parasite-induced changes of the host red blood cells. These alterations require export of a large number of parasite proteins that are trafficked across multiple membranes to reach the host cell. Two classes of exported proteins are known, those with a conserved Plasmodium export element (PEXEL/HT) or those without this motif (PNEPs). Recent work has revealed new aspects of the determinants required for export of these 2 protein classes, shedding new light on the mode of trafficking during the different transport steps en route to the host cell. PMID- 23725673 TI - Antibiotic prescription and knowledge about antibiotic costs of physicians in primary health care centers in Greece. AB - The aim of this questionnaire-based study is to investigate antibiotic prescription practices among primary health care physicians in Greece using the 2007 Hellenic Center for Diseases Control and Prevention guidelines as the gold standard. Seven case scenarios were used. A total of 527 physicians participated. The mean compliance rate with the first recommended antibiotic by the guidelines was 51%, ranging from 22.9% to 71.5% by scenario. Younger physicians and female physicians had higher scores of compliance. PMID- 23725672 TI - Viral pathogen discovery. AB - Viral pathogen discovery is of critical importance to clinical microbiology, infectious diseases, and public health. Genomic approaches for pathogen discovery, including consensus polymerase chain reaction (PCR), microarrays, and unbiased next-generation sequencing (NGS), have the capacity to comprehensively identify novel microbes present in clinical samples. Although numerous challenges remain to be addressed, including the bioinformatics analysis and interpretation of large datasets, these technologies have been successful in rapidly identifying emerging outbreak threats, screening vaccines and other biological products for microbial contamination, and discovering novel viruses associated with both acute and chronic illnesses. Downstream studies such as genome assembly, epidemiologic screening, and a culture system or animal model of infection are necessary to establish an association of a candidate pathogen with disease. PMID- 23725675 TI - Characterization of Cu-tolerant bacteria and definition of their role in promotion of growth, Cu accumulation and reduction of Cu toxicity in Triticum aestivum L. AB - The effects of Cu-tolerant bacteria strain USTB-O on Cu accumulation, plant growth and reduction of Cu toxicity in wheat seedlings Triticum aestivum L. were investigated. The strain was identified as belonging to Bacillus species and showed a specific tolerance to Cu through binding the Cu ions to the cell walls to reduce their entry into the cells. The bacteria not only increased Cu accumulation in wheat seedlings, but also secreted indole-3-acetic acid (IAA) and therefore promoted plant growth. Moreover, the bacteria effectively improved the antioxidant defence system to alleviate the oxidative damage induced by Cu. The bacteria promoted superoxide dismutase (SOD) in both shoots and roots to reduce superoxide radicals. The bacteria stimulated all enzymes activities under Cu exposure conditions, peroxidase (POD) and catalase (CAT) in shoots and ascorbate peroxidase (APX) and dehydroascorbate reductase (DHAR) in roots were major enzymes to eliminate H2O2 in wheat seedlings. PMID- 23725674 TI - Targeting protein-protein interactions as an anticancer strategy. AB - The emergence and convergence of cancer genomics, targeted therapies, and network oncology have significantly expanded the landscape of protein-protein interaction (PPI) networks in cancer for therapeutic discovery. Extensive biological and clinical investigations have led to the identification of protein interaction hubs and nodes that are critical for the acquisition and maintenance of characteristics of cancer essential for cell transformation. Such cancer-enabling PPIs have become promising therapeutic targets. With technological advances in PPI modulator discovery and validation of PPI-targeting agents in clinical settings, targeting of PPI interfaces as an anticancer strategy has become a reality. Future research directed at genomics-based PPI target discovery, PPI interface characterization, PPI-focused chemical library design, and patient genomic subpopulation-driven clinical studies is expected to accelerate the development of the next generation of PPI-based anticancer agents for personalized precision medicine. Here we briefly review prominent PPIs that mediate cancer-acquired properties, highlight recognized challenges and promising clinical results in targeting PPIs, and outline emerging opportunities. PMID- 23725676 TI - Toxicity and endocrine disruption in zebrafish (Danio rerio) and two freshwater invertebrates (Daphnia magna and Moina macrocopa) after chronic exposure to mefenamic acid. AB - Pharmaceuticals have been frequently detected in the aquatic environment. Their potential effects on the endocrine system in wildlife are of special concern because these alterations could lead to impaired reproduction. We evaluated ecotoxicities associated with long-term exposure to mefenamic acid (MFA) and potential endocrine disruption. For this purpose, acute and chronic toxicities of MFA on several aquatic organisms, including two cladocerans, Daphnia magna and Moina macrocopa, and a teleost, Danio rerio were evaluated. The 48 h acute median effective concentration (EC50) of D. magna and M. macrocopa was 17.16 mg/L and 2.93 mg/L, respectively. In chronic toxicity test, D. magna and M. macrocopa showed significant changes in reproduction (number of young per adult) after the exposure to 1.0 mg/L and 0.25 mg/L MFA, respectively. In early life stage exposure using D. rerio, significant decrease of larval survival was observed at 1 mg/L. Changes in vitellogenin (VTG) protein concentrations in 32 day post fertilization fish and vtgI mRNA expression in adult male fish suggest endocrine disruption potentials of MFA. Among the genes of hypothalamus-pituitary-gonad axis, transcriptions of gnrh, gnrhr, cyp19a, and cyp19b increased, supporting estrogenic potential of MFA. Along with histological changes in ovaries, the results of this study provide evidences of endocrine disruption capacity of MFA. However, the effective concentrations are orders of magnitude greater than those occurring in the ambient aquatic environment. PMID- 23725677 TI - Analgesic effect of a single preoperative dose of the antibiotic ceftriaxone in humans. AB - Repeated injections of the antibiotic ceftriaxone cause analgesia in rodents by upregulating the glutamate transporter, GLT-1. No evidence is available in humans. We studied the effect of a single intravenous administration of ceftriaxone in patients undergoing decompressive surgery of the median or ulnar nerves. Forty-five patients were randomized to receive saline, ceftriaxone (2 g), or cefazolin (2 g), 1 hour before surgery. Cefazolin, which is structurally related to ceftriaxone, was used as a negative control. Pain thresholds were measured 10 minutes before drug injections and then 4 to 6 hours after surgery. Ceftriaxone caused analgesia in all patients, whereas cefazolin was inactive. We also performed animal studies to examine whether a single dose of ceftriaxone was sufficient to induce analgesia. A single intraperitoneal injection of ceftriaxone (200 mg/kg), but not cefazoline (200 mg/kg), caused analgesia in mouse models of inflammatory or postsurgical pain, and upregulated GLT-1 in the spinal cord. Ceftriaxone-induced analgesia was additive to that produced by blockade of mGlu5 receptors, which are activated by extrasynaptic glutamate. These data indicate that a single dose of ceftriaxone causes analgesia in humans and mice and suggest that ceftriaxone should be used for preoperative antimicrobial prophylaxis when a fast relief of pain is desired. PERSPECTIVE: The study reports for the first time that a single preoperative dose of ceftriaxone causes analgesia in humans. A single dose of ceftriaxone could also relieve inflammatory and postsurgical pain and upregulate GLT-1 expression in mice. Ceftriaxone should be preferred to other antibiotics for antimicrobial prophylaxis to reduce postoperative pain. PMID- 23725678 TI - Biomechanical comparison of long head of biceps tenodesis with interference screw and biceps sling soft tissue techniques. AB - PURPOSE: The purpose of our study was to compare biomechanically a long head biceps tenodesis using an all soft tissue biceps sling technique versus an interference screw technique. METHODS: Six paired fresh frozen shoulder specimens were separated into 2 groups. One group used an all soft tissue biceps sling technique for tenodesis. The other group used the interference screw technique for subpectoral tenodesis of the long head biceps tendon. Specimens in both groups were sequentially loaded for 200 cycles, and the difference between the initial and final displacements were recorded. Specimens were then loaded to failure. Load and mode of failure were recorded. RESULTS: The mean displacement of all specimens undergoing the sling technique was significantly less than that of the interference technique at 3.0 mm (+/-0.80) versus 5.0 mm (+/-1.08) (P < .05). The biceps sling technique had a higher mean ultimate failure load (UFL) than did the interference screw tenodesis (216.9 N +/- 91.6 v 171.7 N +/- 101.4), although this was not statistically significant (P = .63). In the interference screw technique, 4 specimens failed at the tenodesis site by either tearing or complete pullout, whereas 2 failed at the biceps myotendinous junction. In the sling technique, 4 specimens failed at the biceps myotendinous junction, whereas one specimen tore at the tenodesis site and one detached the pectoralis tendon insertion from the humerus. One specimen in the biceps sling technique and 2 specimens in the interference screw technique failed before completing all 200 cycles. CONCLUSIONS: The results of this biomechanical study show that the biceps sling technique has construct stability similar to that of the interference screw technique. CLINICAL RELEVANCE: The biceps sling may be a reasonable alternative for treating symptomatic pathologic conditions of the long head biceps tendon. PMID- 23725679 TI - Is Millennium Development Goal 4 achievable in Tanzania? PMID- 23725680 TI - Health inequality and governance in Scotland since 2007. AB - BACKGROUND: Since Scottish devolution in 1999, successive governments have accorded priority to reducing health inequality and increasing economic growth. The Scottish Nationalist Party Government elected in 2007 and re-elected in 2011 has accorded considerable attention and allocated substantial resources to addressing these priorities. This article describes why, how and with what results to date the participants in the governance of Scotland, broadly defined to include persons outside as well as within central government, have addressed the determinants of health in order to reduce inequality and, as a result, improve the health status of the population. STUDY DESIGN: Interpretive analysis. METHODS: Research for this article applied the methods of interpretive social science to obtain and analyse published and unpublished public documents; secondary sources in relevant disciplines; and interviews with ministers, officials, staff of National Health Service Scotland and its regions, and other persons active in health governance in Scotland. RESULTS: Participants in the governance of health affairs in Scotland are making important contributions to the reduction of health inequality and the improvement of population health by: (1) linking policy to address health inequality with policy to make health care, public health, social and housing services, and education more effective and efficient; (2) linking policy to address the determinants of health with policy to stimulate economic growth and, as a result, increase employment and income; and (3) embracing and applying a unique synthesis of research findings about the causes of deficiencies in population health status that contribute to health inequality. CONCLUSIONS: These findings could contribute to revising the assumptions and recommendations of some of the researchers and policy advisers who study the determinants of population health, and thus of health inequality, in order to recommend policy. Many contributors to the literature on population health argue that the determinants of health are universal, and that effective interventions to address them are also likely to be universal. Research for this article suggests, however, that participants in the governance of one country, and perhaps of each country, take account of its culture, history and current politics when they describe the determinants of health in order to propose policy to reduce health inequality. The Scottish experience described in this article could, therefore, contribute to conversations about health policy that involve leaders in governance from numerous jurisdictions; conversations that have been occurring regularly for two decades. PMID- 23725681 TI - Does dexmedetomidine provide cardioprotection in coronary artery bypass grafting with cardiopulmonary bypass? A pilot study. AB - OBJECTIVE: The purpose of this pilot study was to evaluate whether dexmedetomidine has a cardioprotective effect during coronary artery bypass graft surgery with cardiopulmonary bypass (CPB). DESIGN: A prospective, double-blind, randomized controlled trial. SETTING: A university hospital. PARTICIPANTS: Thirty eight patients undergoing coronary artery bypass graft surgery. INTERVENTIONS: Patients were randomized into 2 groups: dexmedetomidine and placebo groups. In the dexmedetomidine group, dexmedetomidine infusion was started by a loading dose of 0.5 MUg/kg/10 min, followed by a continuous infusion of 0.5 MUg/kg/h. The placebo group received the same volume of saline. Measurements of central venous pressure, mean pulmonary artery pressure (MPAP) and cardiac index were performed before and after dexmedetomidine loading dose and 2, 24 and 48 hours after CPB. Simultaneously, arterial blood was sampled for CK-MB, cardiac troponin T, and N terminal probrain natriuretic peptide. MEASUREMENTS AND MAIN RESULTS: CK-MB, cardiac troponin T and N-terminal probrain natriuretic peptide values were elevated in the periods after CPB in both groups (p<0.05) and there were no statistically significant differences between groups. MPAP was decreased in the dexmedetomidine group at the 2nd, 24th and 48th hour after CPB (p<0.001, p<0.001, p = 0.002, respectively). Higher cardiac index values were seen earlier in the dexmedetomidine group than in the placebo group (p< 0.05). CONCLUSIONS: Myocardial damage was not reduced by administration of 0.5 MUg/kg loading dose and 0.5 MUg/kg/h infusion of dexmedetomidine. However MPAP tended to be lower in the dexmedetomidine group. Large-scale clinical outcome studies are indicated to confirm the effect of dexmedetomidine. PMID- 23725682 TI - Tricuspid annular geometry: a three-dimensional transesophageal echocardiographic study. AB - OBJECTIVE: To demonstrate the clinical feasibility of accurately measuring tricuspid annular area by 3-dimensional (3D) transesophageal echocardiography (TEE) and to assess the geometric differences based on the presence of tricuspid regurgitation (TR). Also, the shape of the tricuspid annulus was compared with previous descriptions in the literature. DESIGN: Prospective. SETTING: Tertiary care university hospital. INTERVENTIONS: Three-dimensional TEE. PARTICIPANTS: Patients undergoing cardiac surgery. MEASUREMENTS AND MAIN RESULTS: Volumetric data sets from 20 patients were acquired by 3D TEE and prospectively analyzed. Comparisons in annular geometry were made between groups based on the presence of TR. The QLab (Philips Medical Systems, Andover, MA) software package was used to calculate tricuspid annular area by both linear elliptical dimensions and planimetry. Further analyses were performed in the 4D Cardio-View (TomTec Corporation GmBH, Munich, Germany) and MATLAB (Natick, MA) software environments to accurately assess annular shape. It was found that patients with greater TR had an eccentrically dilated annulus with a larger annular area. Also, the area as measured by the linear ellipse method was overestimated as compared to the planimetry method. Furthermore, the irregular saddle-shaped geometry of the tricuspid annulus was confirmed through the mathematic model developed by the authors. CONCLUSIONS: Three-dimensional TEE can be used to measure the tricuspid annular area in a clinically feasible fashion, with an eccentric dilation seen in patients with TR. The tricuspid annulus shape is complex, with annular high and low points, and annular area calculation based on linear measurements significantly overestimates 3D planimetered area. PMID- 23725683 TI - Preoperative angiotensin system inhibitor use attenuates heparin-induced hypotension in patients undergoing cardiac surgery. AB - OBJECTIVE: Both angiotensin system inhibitor (ASI) use and heparin are associated with hypotension. This study attempted to determine whether preoperative ASI therapy affected the hemodynamic response to heparin administered to patients undergoing cardiac surgery. DESIGN: Sixty-two patients undergoing elective cardiac surgery requiring full (300 units/kg) systemic heparinization were studied prospectively. Thirty-three patients were receiving preoperative ASI therapy, whereas 29 patients were not. Anesthetic technique and mechanical ventilation parameters were standardized. Hemodynamics were recorded at 3 time points: baseline (just before the administration of heparin), 1-minute post heparin administration, and 4-minute post-heparin administration. SETTING: Single university hospital. PARTICIPANTS: Patients undergoing elective cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The 2 groups were similar regarding preoperative demographics and baseline hemodynamics. Baseline mean arterial pressure (MAP) in non-ASI patients was 82.0 mmHg, and it decreased significantly to 76.3 mmHg (1 min; p<0.05) and 70.7 mmHg (4 min; p<0.05) following heparin administration. MAP values in ASI patients were 81.9 mmHg, 81.8 mmHg, and 76.8 mmHg at baseline, 1-minute post-heparin, and 4-minute post-heparin administration, respectively (changes not significant).Within-group analysis revealed that non-ASI patients experienced significant decrease in MAP at 1 minute (-6.6%, p = 0.01) and 4-minute (-13.0%, p = 0.0011) post-heparin administration, whereas ASI patients did not (+1.9%, p = 0.52; -3.8%, p = 0.16, respectively). Between-group analysis revealed that differences in MAP values at 1 minute were significant (p = 0.03), whereas differences at 4 minutes were not significant (p = 0.05). CONCLUSIONS: This prospective clinical study indicated that preoperative ASI therapy until the day before surgery may attenuate heparin induced hypotension. Definitive mechanistic insight requires further clinical study. PMID- 23725684 TI - Cognitive function and oxidative stress after carotid endarterectomy: comparison of propofol to sevoflurane anesthesia. AB - OBJECTIVE: To examine the antioxidant role of propofol in ischemia-reperfusion during carotid endarterectomy (CEA) and its influence on cognitive dysfunction after CEA. DESIGN: A randomized prospective study. SETTING: Single-center study in a university hospital. PARTICIPANTS: Forty-four patients. INTERVENTIONS: Patients underwent elective CEA under general anesthesia with either sevoflurane (group S, n = 21) or propofol (group P, n = 23). MEASUREMENTS AND MAIN RESULTS: Cognitive function was assessed with the Mini-Mental State Examination (MMSE) before CEA, 1 hour after CEA, and 24 hours after CEA. Blood samples from the radial artery and the internal jugular vein were drawn before carotid clamping and 5 minutes following unclamping, and peripheral blood was obtained 24 hours postoperatively. Samples were analyzed for lactate, S100B, and P-selectin concentrations and for the antioxidative markers malondialdehyde/low-density lipoprotein ratio and nitrate + nitrite concentrations. Compared with group S, patients in group P exhibited a greater increase in their MMSE values 24 hours postoperatively. Patients who had their MMSE performance reduced at 24 hours also were significantly fewer in group P (13% v 43% in group S, p<0.05). Significantly lower levels of lactate and S100B were observed in arterial and jugular vein samples in group P. In addition, the jugular vein-arterial differences of malondialdehyde-to-low-density lipoprotein ratio and nitrates + nitrites concentrations were lower during propofol anesthesia. CONCLUSIONS: Propofol seemed to improve cognitive performance after CEA. This improvement was associated with decreased indices of ischemic cerebral damage and seemed to be due to antioxidative effect in the ischemic cerebral circulation. PMID- 23725685 TI - Late diagnosis of congenital methemoglobinemia in an elderly patient during cardiac surgery. PMID- 23725686 TI - Computerized tomographic anatomic relationships of the thoracic paravertebral space. AB - OBJECTIVES: A wide range of insertion points lateral to the midline are recommended for paravertebral blockade. The authors hypothesized that in a given subject, using an insertion point at the tip of the transverse process has a superficial but consistent depth to the pleura. The authors also hypothesized that for a given insertion point, depths to the pleura are related directly to the patient's anthropomorphic indices. DESIGN: Retrospective observational study. SETTING: Adult tertiary teaching hospital. PARTICIPANTS: Forty-two adult patients. INTERVENTIONS N/A MEASUREMENTS AND MAIN RESULTS: The authors reviewed the computerized tomography scans of 42 adult patients and correlated patients' body mass index, weight, height, and body surface area with skin and transverse process-to-pleura depths at the level of T4, 25 mm from the midline and from the tip of the transverse process. The authors found that the depth to the pleura from the transverse process was significantly deeper at 25 mm lateral to the midline than at the tip of the transverse process (21 mm [4.2mm] v 12 mm [2.7 mm], p<0.0001), and its variability was significantly larger (p = 0.005). The authors found significant correlation between anthropomorphic indices and depths to pleura and transverse process (r>0.8, p<0.0001); however, the prediction bands around their regression lines proved too broad to be clinically useful. CONCLUSIONS: The authors concluded that an insertion point at the tip of the transverse process may provide effective and safer paravertebral blockade and that depth to the pleura cannot be predicted reliably by patients' morphometric profiles. PMID- 23725687 TI - Anesthetic management for a patient with transcatheter mitral valve implantation. PMID- 23725688 TI - Randomized trial on the effect of sevoflurane on polypropylene membrane oxygenator performance. AB - OBJECTIVES: Volatile anesthetics have cardioprotective properties that improve clinically relevant outcomes in cardiac surgery, and can be used during cardiopulmonary bypass (CPB) through adapted calibrated vaporizers together with air and oxygen (O2). The effect of volatile agents on the membrane oxygenator is unknown. The aim of this study was to evaluate, for the first time, the performance of semiporous polypropylene membrane oxygenators after the use of sevoflurane vaporized during CPB in cardiac surgery. DESIGN: A prospective, randomized, controlled trial. SETTING: Teaching hospital. PARTICIPANTS: Thirty two consecutive patients scheduled to undergo coronary artery bypass graft with CPB. INTERVENTIONS: Patients were allocated randomly to receive either a volatile anesthetic (sevoflurane 1%-3%, 16 patients) or an intravenous hypnotic (midazolam, 16 patients) during CPB. After surgery, the membrane oxygenators used during CPB were tested with regard to O2 transfer, carbon dioxide transfer, and pressure drop. MEASUREMENTS AND MAIN RESULTS: The authors observed no protocol deviation or crossover. The performance of the membrane oxygenator was similar between the 2 groups, as documented by O2 transfer (55+/-6.4 mL/min/L in the sevoflurane group versus 57+/-4.7 mL/min/L in the midazolam group, p = 0.4), carbon dioxide transfer, and pressure drop. CONCLUSIONS: The use of sevoflurane during CPB in cardiac surgery does not affect membrane oxygenator performance. PMID- 23725689 TI - A non-enzymatic method for isolating human adipose tissue-derived stromal stem cells. AB - BACKGROUND AIMS: The isolation of human adipose stromal/stem cells (ASCs) currently relies on the use of the enzyme collagenase, which digests the triple helix region of peptide bonds in the collagen of adipose tissue. Collagenase is an expensive reagent derived from a bacterial source, and its use in isolating ASCs is a time-consuming procedure. This experiment evaluated the extraction of ASCs without an enzymatic digest. METHODS: We used a simple method of washing adipose tissue to isolate and characterize the cells and compared this method with the enzymatic procedure in terms of processing time, stem cell yield, differentiation potential and immunophenotype. RESULTS: Based on fluorescence activated cell sorting analysis, the stromal vascular fractions isolated with the washing method displayed a distinct and potentially favorable immunophenotype relative to the collagenase digestion. This difference may reflect the absence of chemical alteration of the cells by collagenase digestion. Independent of the isolation procedure, the resulting passaged ASCs were comparable based on immunophenotype and adipogenic and osteogenic differentiation potential. CONCLUSIONS: Although using collagenase substantially increases cell yield, the two methods yield a similar cell product. PMID- 23725690 TI - Nocardiosis: a 15-year experience in a tertiary medical center in Israel. AB - OBJECTIVES: The objective of this study is to characterize the common risk factors, clinical presentation, imaging findings, treatment and outcome of nocardial infection. DESIGN AND SETTINGS: A retrospective cohort study. We reviewed the charts of all patients with nocardiosis in the Chaim Sheba Medical Center, a tertiary medical center in Israel, between the years 1996 and 2011. RESULTS: A total of 39 patients who had positive culture of Nocardia were analyzed. The majority of our patients were immunocompromised (74.5%), mostly due to corticosteroid therapy. None had HIV/AIDS. The clinical presentation was either acute or a chronic smoldering illness. The three major clinical syndromes were pleuropulmonary, neurological and skin/soft tissue infection about 20.5% each. Pathology in the lungs was seen in most of the patients by CT scan; discrete nodules and wedge shaped pleural based consolidations were the most frequent findings. Brain lesions consistent with abscesses were detected in 10 patients by brain imaging. Some cases had relapsing disease in spite of antimicrobial treatment. 25% of examined isolates were resistant to trimethoprim/sulfamethoxazole. The duration of intravenous antimicrobial treatment ranged from one month to over a year in the severe cases. One year mortality rate was 32%. CONCLUSION: Nocardiosis requires a high clinical index of suspicion in order to diagnose and treat promptly. Disease extent and bacterial susceptibility have important implications for prognosis and treatment. PMID- 23725691 TI - Deletion of virulence associated genes from attenuated African swine fever virus isolate OUR T88/3 decreases its ability to protect against challenge with virulent virus. AB - African swine fever virus (ASFV) causes an acute haemorrhagic disease of domestic pigs against which there is no effective vaccine. The attenuated ASFV strain OUR T88/3 has been shown previously to protect vaccinated pigs against challenge with some virulent strains including OUR T88/1. Two genes, DP71L and DP96R were deleted from the OUR T88/3 genome to create recombinant virus OUR T88/3DeltaDP2. Deletion of these genes from virulent viruses has previously been shown to reduce ASFV virulence in domestic pigs. Groups of 6 pigs were immunised with deletion virus OUR T88/3DeltaDP2 or parental virus OUR T88/3 and challenged with virulent OUR T88/1 virus. Four pigs (66%) were protected by inoculation with the deletion virus OUR T88/3DeltaDP2 compared to 100% protection with the parental virus OUR T88/3. Thus the deletion of the two genes DP71L and DP96R from OUR T88/3 strain reduced its ability to protect pigs against challenge with virulent virus. PMID- 23725692 TI - Regulatory elements in the viral genome. AB - The small DNA genomes of papillomaviruses contain a surprisingly large number of regulatory or cis-responsive elements, which regulate replication and transcription of the virus, and control details like specificity for certain epithelial cells, specificity for layers in squamous epithelia, feedback mechanisms and coupling between host cell physiology and virus biology. Most of these elements occur in the long control region, while others are located elsewhere in the genome. Many papillomaviruses show a similar composition of cis responsive elements, although these are scattered and do not occur as long segments of sequence similarity. This review summarizes our knowledge of the regulatory elements in several well-studied Alphapapillomavirus types, and indicates some similarities to other papillomavirus genera, whose properties are yet poorly understood. PMID- 23725693 TI - Regulation of the human papillomavirus type 16 late promoter by E7 and the cell cycle. AB - Human papillomaviruses (HPVs) are the causative agents of cervical and other cancers. The oncoprotein E7 activates the cell cycle and makes possible replication of the viral genome in differentiating epithelia. The HPV16 late promoter is activated upon cellular differentiation and regulates late gene expression. We investigated the effect of E7 on the late promoter and found that E7 was able to activate the promoter. In contrast, the other known viral transcriptional regulator, E2, had no effect on the late promoter. Promoter activation by E7 occurred despite inhibition of promoter activity by factors involved in the cell cycle, such as cyclin dependent kinases and E2F transcription factors, and by the ability of E7 to disrupt several aspects of cellular differentiation. These results suggest a new role for E7 in the context of the viral life cycle and shed light on the complex regulation of viral gene expression in infected, differentiating epithelia. PMID- 23725695 TI - Characterization of the transport signals that mediate the nucleocytoplasmic traffic of low risk HPV11 E7. AB - We previously discovered that nuclear import of low risk HPV11 E7 is mediated by its zinc-binding domain via a pathway that is independent of karyopherins/importins (Piccioli et al., 2010. Virology 407, 100-109). In this study we mapped and characterized a leucine-rich nuclear export signal (NES), 76IRQLQDLLL84, within the zinc-binding domain that mediates the nuclear export of HPV11 E7 in a CRM1-dependent manner. We also identified a mostly hydrophobic patch 65VRLVV69 within the zinc-binding domain that mediates nuclear import of HPV11 E7 via hydrophobic interactions with the FG-repeats domain of Nup62. Substitutions of hydrophobic residues to alanine within the 65VRLVV69 sequence disrupt the nuclear localization of 11E7, whereas the R66A mutation has no effect. Overall the data support a model of nuclear entry of HPV11 E7 protein via hydrophobic interactions with FG nucleoporins at the nuclear pore complex. PMID- 23725697 TI - UK Government panders to tobacco industry and lacks social conscience. PMID- 23725696 TI - Ribonuclease L is not critical for innate restriction and adaptive immunity against Friend retrovirus infection. AB - Ribonuclease L (RNase L) is a type I interferon regulated factor that can significantly inhibit retroviruses in vitro and may activate cytoplasmic sensing pathways to augment adaptive immunity. However, the antiretroviral activity of RNase L remains to be validated in vivo. We investigated the role of RNaseL in counteracting Friend retrovirus (FV) infection relative to a well-described restriction factor, Apobec3. C57BL/6 wild-type (WT) and RNaseL knock-out (KO) mice exhibited similar acute FV infection levels despite significant transcriptional induction of oligoadenylate synthetase 1, which produces activators of RNase L. Apobec3 KO mice showed higher FV infection levels relative to WT mice, but deletion of RNaseL in Apobec3 KO mice did not augment FV infection. Moreover, RNaseL did not influence FV-specific IgG responses and recovery from viremia by 28 days post-infection. The results suggest that RNase L is not an evolutionarily-conserved host defense mechanism to counteract retroviruses in vivo. PMID- 23725698 TI - Integration of general oncology and palliative care. PMID- 23725699 TI - Asbestos is not just asbestos: an unrecognised health hazard. PMID- 23725694 TI - Frequency and patterns of reassortment in natural influenza A virus infection in a reservoir host. AB - Influenza A viruses (IAV) can dramatically alter both genotype and phenotype at a rapid rate as a product of co-infection and reassortment. Avian IAV exhibit high levels of phylogenetic incongruence, suggesting high levels of reassortment in the virus reservoir. Using a natural-experimental system, we reconstructed relationships amongst 92 viruses across 15 subtypes from 10 Mallards in an autumn season. Phylogenetic analyses estimated that 56% of the isolated viruses were reassorted. Network analysis demonstrated different patterns of reassortment and limited exchange of segments between primary and secondary infections. No clear patterns of linkage between segments were found, and patterns within a season were likely the consequence of continued introduction of new constellations, high viral load and diversity in the wild bird reservoir, and co-infections. This is the first IAV study to implement multiple tools available for elucidating factors governing reassortment patterns in naturally infected Mallards. PMID- 23725700 TI - Cancer stem cells--therapeutic targeting or therapy? PMID- 23725701 TI - Cancer apps. PMID- 23725702 TI - Speculation overinflates long-term efficacy of vaccine for anal dysplasia. PMID- 23725703 TI - Axillary versus sentinel-lymph-node dissection for micrometastatic breast cancer. PMID- 23725704 TI - Axillary versus sentinel-lymph-node dissection for micrometastatic breast cancer. PMID- 23725705 TI - Axillary versus sentinel-lymph-node dissection for micrometastatic breast cancer- authors' reply. PMID- 23725706 TI - Extending the case for oestradiol in androgen-sensitive prostate cancer. PMID- 23725707 TI - Extending the case for oestradiol in androgen-sensitive prostate cancer - Authors' reply. PMID- 23725708 TI - Contralateral risk-reducing mastectomy in sporadic breast cancer. AB - Recent studies have shown that the number of women undergoing risk-reducing mastectomy has increased rapidly in the USA in the past 15 years. Although a small rise in the number of bilateral risk-reducing procedures has been noted in high-risk gene mutation carriers who have never had breast cancer, this number does not account for the overall increase in procedures undertaken. In patients who have been treated for a primary cancer and are judged to be at high risk of a contralateral breast cancer, contralateral risk-reducing mastectomy is often, but not universally, indicated. However, many patients undergoing contralateral risk reducing mastectomy might not be categorised as high risk and therefore any potential benefit from this procedure is unproven. At a time when breast conserving surgery has become more widely used, this sharp increase in contralateral risk-reducing mastectomy is surprising. We have reviewed the literature in an attempt to establish what is driving the increase in this procedure in moderate-to-low-risk populations and to assess its justification in terms of risk-benefit analysis. PMID- 23725709 TI - Treatment of early-stage lung cancer detected by screening: surgery or stereotactic ablative radiotherapy? AB - A randomised trial of screening for lung cancer using CT showed a survival benefit with screening, but issues surrounding risks arising from screening remain. The appropriate treatment of early-stage lung cancer detected in this way is receiving increasing attention. This Review discusses treatment-related issues for such tumours and explores the merits of surgery versus stereotactic ablative radiotherapy (SABR), both of which are effective treatments but have different risks for acute toxicity. Although surgery is widely deemed to be the preferred treatment for patients who are fit, growing evidence suggests that SABR achieves similar local control rates, but without the risks associated with surgery. Choice of local treatment should also be made with consideration of the high rates of disease recurrence and second primary lung tumours in patients after curative therapy for early-stage lung cancer. Careful collaborative evaluation by pulmonologists, interventional radiologists, thoracic surgeons, and radiation oncologists should guide decision making for each patient with a screen-detected early-stage lung cancer. PMID- 23725710 TI - Reproductive organ involvement in non-Hodgkin lymphoma during pregnancy: a systematic review. AB - Data for pregnancy-associated non-Hodgkin lymphoma are limited to case reports, making it difficult to define this disorder. We did a systematic search for articles published between 1967 and 2011 with the aim to determine the characteristics, management, and outcome of pregnancy-associated non-Hodgkin lymphoma. We identified 121 patients from 74 papers. Most patients with stage information available presented with stage IV disease (75%, 82 of 108 patients). Patients were classified into three clinical groups; those with indolent lymphomas accounted for 5% (five of 108), aggressive lymphomas (diffuse large B cell lymphoma and T-cell lymphomas) made up 48% of patients (52 of 108), and highly aggressive lymphomas (Burkitt's lymphoma, immunoblastic lymphoma, and unspecified highly aggressive lymphomas) accounted for 47% of patients (51 of 108). Reproductive organ involvement (breast, ovary, uterus, placenta) was reported in 49% of 110 patients with information available on extranodal involvement, and prevailed in endemic Burkitt's lymphoma (100%, 19 of 19), followed by non-endemic Burkitt lymphoma (70%, 14 of 20), immunoblastic lymphoma (67%, two of three), peripheral T-cell lymphoma (46%, six of 13), and indolent (40%, two of five) and diffuse large cell lymphoma (23%, nine of 40). Most patients received antepartum (45%, 55 of 121) or postpartum therapy (45%, 54 of 121), resulting in 6-month survival of 53% for mothers and a livebirth rate of 83%. Pregnancy-associated non-Hodgkin lymphoma has unique clinical characteristics with frequent reproductive organ involvement. Collaborative prospective studies are needed to further characterise pathophysiological and clinical aspects of this complication. PMID- 23725711 TI - The antiangiogenic ceiling in hepatocellular carcinoma: does it exist and has it been reached? AB - The recommendation of sorafenib as standard of care in advanced hepatocellular carcinoma has lent support to the increased use of antiangiogenic therapies. However, in three phase 3 randomised trials that compared other antiangiogenics with sorafenib, results did not show superiority or non-inferiority of the new therapies. The 10-month median overall survival shown in these studies for patients given sorafenib might be a ceiling for single-agent antiangiogenic therapy. Strategies to increase survival time include combination therapies that pair antiangiogenic treatment with biological therapy or chemotherapy. The combination of sorafenib and erlotinib was not superior to sorafenib alone, which suggests no positive interaction between antiangiogenics and tyrosine kinase inhibitors in the treatment of advanced hepatocellular carcinoma. A combination of sorafenib and doxorubicin is being assessed in a randomised phase 3 trial. Differences in patient outcome with sorafenib because of disease cause and the ethnic origin of patients suggest that sorafenib's multitarget capacity, including RAF kinase inhibition, might be important. MET inhibitors cabozantinib and tivantinib are drugs that might also bypass the so-called antiangiogenic ceiling and have led to selective treatment of patients that overexpress MET with these drugs. Although this intense period of research activity has not yet resulted in significant improvements in survival for patients with advanced hepatocellular carcinoma, we are certainly closer to a customised treatment, which should increase the antiangiogenic survival ceiling. PMID- 23725712 TI - Novel pathogenic pathways in diabetic neuropathy. AB - Diabetic peripheral neuropathy (DPN) is a common complication affecting more than one third of diabetes mellitus (DM) patients. Although all cellular components participating in peripheral nerve function are exposed to and affected by the metabolic consequences of DM, nodal regions, areas of intense interactions between Schwann cells and axons, may be particularly sensitive to DM-induced alterations. Nodes are enriched in insulin receptors, glucose transporters, Na(+) and K(+) channels, and mitochondria, all implicated in the development and progression of DPN. Latest results particularly reinforce the idea that changes in ion-channel function and energy metabolism, both of which depend on axon-glia crosstalk, are among the important contributors to DPN. These insights provide a basis for new therapeutic approaches aimed at delaying or reversing DPN. PMID- 23725713 TI - Children with disabilities--invisible no more. PMID- 23725714 TI - Improving the health response to humanitarian crises. PMID- 23725715 TI - A revolution in psychiatry. PMID- 23725716 TI - Nicotine regulation and tobacco harm reduction in the UK. PMID- 23725717 TI - A narrative future for health care. PMID- 23725719 TI - Alex Coutinho: transforming HIV care in Africa. PMID- 23725720 TI - SYNTAX score II - Authors' reply. PMID- 23725721 TI - SYNTAX score II. PMID- 23725722 TI - Neuroprosthetic control and tetraplegia. PMID- 23725723 TI - Neuroprosthetic control and tetraplegia--authors' reply. PMID- 23725724 TI - Regulation and the food industry. PMID- 23725725 TI - Regulation and the food industry. PMID- 23725726 TI - Promotion of improvement as a science. PMID- 23725727 TI - Regulation and the food industry. PMID- 23725728 TI - Medical advice and patient's religion. PMID- 23725729 TI - Pharmacogenetic testing in the UK clinical setting. PMID- 23725730 TI - Surviving in a crevasse. PMID- 23725731 TI - Interests conflicted? PMID- 23725732 TI - Is type 2 diabetes a category error? PMID- 23725733 TI - Infantile eczema caused by formula milk. PMID- 23725734 TI - [The participation of patients with dementia in individualised intervention plan meetings: the impact on their well-being and the quality of life]. AB - INTRODUCTION: An individualised intervention plan (IIP) offers a new paradigm in the care of the elderly with dementia, with the aim of increasing their quality of life through personalisation, respect for their freedom, and their participation in the decisions that affect their lives. OBJECTIVE: To evaluate the impact of the residential home patient with dementia and their quality of care when they take part in the interdisciplinary meeting in which their care plan is decided. MATERIAL AND METHODS: A total of 52 elderly patients with dementia took part in the study. They were distributed into two groups, one experimental (37 residents) and another control (15 residents). The Dementia Care Mapping (DCM) tool was used to assess the well-being and quality of care of the residents. This tool was used twice, before and after the intervention. RESULTS: The well-being of the resident, evaluated using the DCM, was similar before and after the intervention in the experimental group. No differences were observed either on comparing the control and experimental groups. However, some indicators of carer behaviour were different before and after the intervention, and when the control and experimental group were compared. CONCLUSION: The inclusion of elderly persons with dementia in their IIP meeting had a positive effect in the interaction of the staff with the residents, but not on the well-being of the resident. PMID- 23725735 TI - Two-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema: interim analysis of the RESTORE extension study. AB - OBJECTIVE: To evaluate the 2-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema (DME). DESIGN: Twenty-four-month, open-label, multicenter, Phase IIIb extension study. PARTICIPANTS: Two hundred forty of 303 patients with visual impairment due to DME who completed the RESTORE core study and entered the extension. METHODS: All patients were eligible to receive ranibizumab 0.5 mg pro re nata (PRN) from month 12 (end of core study) to month 36 based on best corrected visual acuity (BCVA) stability and disease progression retreatment criteria. Patients were also eligible to receive laser PRN according to Early Treatment Diabetic Retinopathy Study guidelines. A preplanned interim analysis was performed at month 24, stratifying by treatment groups as in the RESTORE core study and referred to as prior ranibizumab, ranibizumab plus laser, or laser groups in the extension. MAIN OUTCOME MEASURES: Incidence of ocular and nonocular adverse events (AEs) and mean change in BCVA. RESULTS: Two hundred twenty patients (92%) completed the month 24 visit. Over 2 years, the most frequent ocular serious AE (SAE) and AE were cataract (2.1%) and eye pain (14.6%), respectively. The main nonocular AEs were nasopharyngitis (18.8%) and hypertension (10.4%). There were no cases of endophthalmitis, and the incidences of nonocular SAEs were low. Of the patients entering the extension, 4 deaths were reported in the second year, none of which were related to study drug or procedure. Mean BCVA gain, central retinal thickness (CRT) decrease, and National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) composite score observed at month 12 were maintained at month 24 (prior ranibizumab: +7.9 letters, -140.6 MUm, and 5.6, respectively; prior ranibizumab plus laser: +6.7 letters, -133.0 MUm, and 5.8, respectively), with an average of 3.9 (prior ranibizumab) and 3.5 ranibizumab injections (prior ranibizumab plus laser). In patients treated with laser alone in the core study, the mean BCVA, CRT, and NEI VFQ-25 composite score improved from month 12 to month 24 (+5.4 letters, -126.6 MUm, and 4.3, respectively), with an average of 4.1 ranibizumab injections. CONCLUSIONS: Ranibizumab 0.5 mg administered according to prespecified visual stability and disease progression criteria was well tolerated, with no new safety concerns identified over 2 years. Overall, an average of 3.8 ranibizumab injections was sufficient to maintain (prior ranibizumab) or improve (prior laser) BCVA, CRT, and NEI VFQ-25 outcomes through the second year. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23725736 TI - Adenoid cystic carcinoma of the lacrimal gland: MYB gene activation, genomic imbalances, and clinical characteristics. AB - PURPOSE: To investigate genetic alterations in lacrimal gland adenoid cystic carcinomas (ACCs) with emphasis on the MYB-NFIB fusion oncogene and its downstream targets, MYB rearrangements, and copy number alterations in relation to clinical data and survival. DESIGN: Experimental study. PARTICIPANTS AND CONTROLS: Fourteen patients with primary lacrimal gland ACC were included. As a control, we also studied the expression of MYB-NFIB in 19 non-ACC lacrimal gland tumors. METHODS: The expression and identity of MYB-NFIB fusion transcripts were studied using reverse transcriptase polymerase chain reaction (RT-PCR) and nucleotide sequence analyses. Quantitative polymerase chain reaction (PCR) and immunohistochemistry were used to evaluate the expression of MYB/MYB-NFIB target genes. High-resolution array-based comparative genomic hybridization (arrayCGH) and fluorescence in situ hybridization were used to study copy number alterations and MYB rearrangements. MAIN OUTCOME MEASURES: mRNA or protein expression of MYB NFIB, MYB, and its down stream targets; copy number alterations; and genomic rearrangements. RESULTS: The median age of the patients was 43 years (equal gender distribution), and the median time of survival was 8.6 years. The MYB-NFIB fusion was expressed in 7 of 14 ACCs. In contrast, all non-ACC tumors were fusion negative. All 13 ACCs tested stained positive for the MYB protein, and for the MYB targets KIT and BCL2, 12 were positive for MYC and CCNE1, and 9 were positive for CCNB1. Rearrangements of MYB were detected in 8 of 13 cases, including 2 cases with gain of an apparently intact MYB gene. The arrayCGH analysis revealed recurrent copy number alterations with losses involving 6q23-q27, 12q12-q14.1, and 17p13.3-p12, and gains involving 19q12, 19q13.31-qter, 8q24.13-q24.21, 11q12.3-q14.1, and 6q23.3. Neither MYB-NFIB fusion nor any copy number alteration correlated with survival. CONCLUSIONS: Lacrimal gland ACCs are frequently positive for the MYB-NFIB fusion, overexpress MYB and its downstream targets, and have genomic profiles characterized by losses involving 6q, 12q, and 17p, and gains involving 19q, 8q, and 11q. Our findings show that lacrimal gland ACCs are genetically and clinically similar to their salivary gland counterparts and that MYB-NFIB is a clinically useful diagnostic biomarker for ACC. Our data also suggest that MYB and its downstream targets are potential therapeutic targets for these tumors. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23725737 TI - Diagnostic potential of iris cross-sectional imaging in albinism using optical coherence tomography. AB - PURPOSE: To characterize in vivo anatomic abnormalities of the iris in albinism compared with healthy controls using anterior segment optical coherence tomography (AS-OCT) and to explore the diagnostic potential of this technique for albinism. We also investigated the relationship between iris abnormalities and other phenotypical features of albinism. DESIGN: Prospective cross-sectional study. PARTICIPANTS: A total of 55 individuals with albinism and 45 healthy controls. METHODS: We acquired 4.37*4.37-mm volumetric scans (743 A-scans, 50 B scans) of the nasal and temporal iris in both eyes using AS-OCT (3-MUm axial resolution). Iris layers were segmented and thicknesses were measured using ImageJ software. Iris transillumination grading was graded using Summers and colleagues' classification. Retinal OCT, eye movement recordings, best-corrected visual acuity (BCVA), visual evoked potential (VEP), and grading of skin and hair pigmentation were used to quantify other phenotypical features associated with albinism. MAIN OUTCOME MEASURES: Iris AS-OCT measurements included (1) total iris thickness, (2) stroma/anterior border (SAB) layer thickness, and (3) posterior epithelial layer (PEL) thickness. Correlation with other phenotypical measurements, including (1) iris transillumination grading, (2) retinal layer measurements at the fovea, (3) nystagmus intensity, (4) BCVA, (5) VEP asymmetry, (6) skin pigmentation, and (7) hair pigmentation (of head hair, lashes, and brows). RESULTS: The mean iris thickness was 10.7% thicker in controls (379.3 +/- 44.0 MUm) compared with the albinism group (342.5 +/- 52.6 MUm; P>0.001), SAB layers were 5.8% thicker in controls (315.1 +/- 43.8 MUm) compared with the albinism group (297.7 +/- 50.0 MUm; P=0.044), and PEL was 44.0% thicker in controls (64.1 +/- 11.7 MUm) compared with the albinism group (44.5 +/- 13.9 MUm; P<0.0001). The most ciliary quartile of the PEL yielded a sensitivity of 85% and specificity of 78% for detecting albinism. Phenotypic features of albinism, such as skin and hair pigmentation, BCVA, and nystagmus intensity, were significantly correlated to AS-OCT iris thickness measurements. CONCLUSIONS: We have characterized in vivo abnormalities of the iris associated with albinism for the first time and show that PEL thickness is particularly affected. We demonstrate that PEL thickness has diagnostic potential for detecting iris abnormalities in albinism. Anterior segment OCT iris measurements are significantly correlated to BCVA and nystagmus intensity in contrast to iris transillumination grading measurements that were not. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23725738 TI - Cone dystrophy with supernormal rod response: novel KCNV2 mutations in an underdiagnosed phenotype. AB - OBJECTIVE: To study the clinical variability and KCNV2 mutation spectrum in cone dystrophy with supernormal rod response (CDSRR) in the Israeli population. DESIGN: Case series. PARTICIPANTS: Patients with cone-dominated diseases and unaffected relatives were included. The protocol was approved by the institutional review board and informed consent was obtained from all participants. METHODS: Genomic DNA was extracted and Sanger sequencing was performed on polymerase chain reaction products. Whole genome single nucleotide polymorphism analysis was performed using Affymetrix (Santa Clara, CA) platforms. MAIN OUTCOME MEASURES: Single nucleotide polymorphism microarray and homozygosity analysis, DNA sequence analysis, visual function testing, and electroretinography. RESULTS: Aiming to study the genetics of inherited retinal degenerations in the Israeli and Palestinian populations, we recruited 220 index cases with cone-dominated diseases, of which 2 carried the clinical diagnosis of CDSRR. Mutation screening of KCNV2 revealed 2 compound heterozygous mutations in 2 affected sisters in 1 family and a homozygous mutation in the other family. Inquiring whether KCNV2 is the cause of disease in the remaining patients with cone-dominated diseases, we performed whole genome homozygosity mapping in 52 consanguineous families (of the initial 220), 2 of which had homozygous regions encompassing KCNV2. Mutation analysis revealed a different homozygous mutation in each family. In addition, KCNV2 was screened in 4 families in which review of the clinical data suggested CDSRR misdiagnosis. The analysis revealed 2 compound heterozygous mutations in 1 family. After the genetic analysis and the review of the clinical findings, the diagnosis was revised to CDSRR in all patients with KCNV2 mutations. Clinical data of 13 KCNV2 patients suggested that, although in some cases the classic phenotype of CDSRR was present, others may have dark adapted electroretinographic responses that are within normal range. The delay in dark-adapted responses may be a more reliable indicator. CONCLUSIONS: This is the first report of genetic and clinical analysis of CDSRR in the Israeli population leading to the identification of 4 novel KCNV2 mutations. Our results support recent studies showing that CDSRR can be misdiagnosed, and therefore screening of KCNV2 for mutations should be considered in patients with cone-dominated diseases, particularly when dark-adapted responses are delayed. PMID- 23725739 TI - Use of a titanium cutting guide to assist with raising and inset of a DCIA free flap. AB - Reconstructing maxillary defects can be challenging. In particular, Class 3 and 4 defects require careful planning. Bone for reconstruction must be placed in the correct three dimensional (3D) position in order to achieve a good cosmetic and functional result. Correct size and positioning of the harvested bone also enables placement of dental implants and allows rehabilitation. We describe the use of a Deep Circumflex Iliac Artery Flap (DCIA) cutting guide to aid safe harvest and positioning of the correct quality and quantity of bone. We illustrate the benefits of using a guide based upon stereolithographic planning models of the pelvis by presenting 4 cases where planning to this level has been used. Our experiences clearly demonstrate the potential benefits that preformed cutting guides may have on outcomes when reconstructing complex maxillary defects. In particular, we note a reduction in operative time and improved functional and aesthetic results. The use of such a guide has not previously been described. PMID- 23725740 TI - Acute neonatal encephalopathy and seizures recurrence: a combined aEEG/EEG study. AB - PURPOSE: To evaluate amplitude-integrated EEG (aEEG) in comparison with conventional (cEEG) for the identification of electrographic seizures in neonates with acute neonatal encephalopathies. METHODS: Thirty-one conventional cEEG/aEEG long-term recordings from twenty-eight newborns were reviewed in order to assess the electrographic seizure detection rate and recurrence in newborns. Two paediatric neurologists and one neonatologist, blinded to the raw full array cEEG, were asked to mark any events suspected to be an electrographic seizures on aEEG. They were asked to decide if the displayed aEEG trace showed the pattern of a single seizure (SS), repetitive seizures (RS) or status epilepticus (SE). Their ability to recognize electrographic seizures on aEEG was compared to seizures identified on full array cEEG. RESULTS: 25 of the 31 long-term cEEGs recordings showed electrographic seizures. The two paediatric neurologists and the neonatologist identified SE in 100% of the reviewed traces using aEEG alone while they identified 49.4% and 37.5% of electrographic seizures using aEEG alone. Overall, the correct identification ranged from 23.5% to 30.7% for SS and 66% for RS. The inter-observer agreement (k) for the identification of SE for the two paediatric neurologists and the neonatologist was 1.0. Overall the inter-observer agreement (k) for the detection of SS, RS and SE of the two paediatric neurologists was 0.91. CONCLUSIONS: In our study the observers identified SE in 100% of the reviewed traces using raw aEEG alone, thus aEEG might represent a useful tool to detect SE in the setting of NICU. SS may not be reliably identified using aEEG alone. Simultaneous recording of the raw cEEG/aEEG provides a good level of sensitivity for the detection of neonatal electrographic seizures. PMID- 23725741 TI - Predictors of seizure occurrence in children undergoing pre-surgical monitoring. AB - PURPOSE: Long-Term-Monitoring (LTM) is a valuable tool for seizure localization/lateralization among children with refractory-epilepsy undergoing pre-surgical-monitoring. The aim of this study was to examine the factors predicting occurrence of single/multiple seizures in children undergoing pre surgical monitoring in the LTM unit. METHODS: Chart review was done on 95 consecutive admissions on 92 children (40 females) admitted to the LTM-unit for pre-surgical workup. Relationship between occurrence of multiple (>= 3) seizures and factors such as home seizure-frequency, demographics, MRI-lesions/seizure type and localization/AED usage/neurological-exam/epilepsy-duration was evaluated by logistic-regression and survival-analysis. Home seizure-frequency was further categorized into low (up-to 1/month), medium (up-to 1/week) and high (>1/week) and relationship of these categories to the occurrence of multiple seizures was evaluated. Mean length of stay was 5.24 days in all 3 groups. RESULTS: Home seizure frequency was the only factor predicting the occurrence of single/multiple seizures in children undergoing presurgical workup. Other factors (age/sex/MRI-lesions/seizure-type and localization/AED-usage/neurological exam/epilepsy-duration) did not affect occurrence of single/multiple seizures or time-to-occurrence of first/second seizure. Analysis of the home-seizure frequency categories revealed that 98% admissions in high-frequency, 94% in the medium, and 77% in low-frequency group had at-least 1 seizure recorded during the monitoring. Odds of first-seizure increased in high vs. low-frequency group (p=0.01). Eighty-nine percent admissions in high-frequency, 78% in medium frequency, versus 50% in low-frequency group had >= 3 seizures. The odds of having >= 3 seizures increased in high-frequency (p=0.0005) and in medium frequency (p=0.007), compared to low-frequency group. Mean time-to-first-seizure was 2.7 days in low-frequency, 2.1 days in medium, and 2 days in high-frequency group. Time-to-first-seizure in high and medium-frequency was less than in low frequency group (p<0.0014 and p=0.038). CONCLUSION: Majority of the admissions (92%) admitted to the LTM-unit for pre-surgical workup had at-least one seizure during a mean length of stay of 5.24 days. Home seizure-frequency was the only predictor influencing occurrence of single/multiple seizures in the LTM unit. Patients with low seizure-frequency are at risk for completing the monitoring with less than the optimum number (<3) of seizures captured. PMID- 23725742 TI - PIP silicone breast implants: rupture rates based on the explantation of 676 implants in a single surgeon series. AB - INTRODUCTION: To determine the true rupture rates of PIP implants from a large single surgeon cohort and to assess whether rupture rates varied depending on time of implant insertion. In addition, the efficacy of ultra sound scanning (USS) in determining rupture is examined. DESIGN: Predominantly prospectively based analysis of patient records, investigations and surgical findings. PARTICIPANTS: 338 patients (676 implants) were included in the study and they all had removal of their implants. The senior author operated on all patients at some stage of their treatment. 160 patients were imaged pre-operatively with USS. Patients had implants inserted between 1999 and 2007 for cosmetic breast augmentation. RESULTS: A total of 144 ruptured implants were removed from 119 patients, giving a rupture rate of 35.2% per patient and 21.3% per implant over a mean implantation period of 7.8 years. A statistical difference (P < 0.001) in rupture rates between implants inserted prior to 2003 and those inserted from 2003 was demonstrated, with higher failure rates in the latter group. There was a significant difference in rupture rates depending on pocket placement of the implants. The sensitivity and specificity of USS at detecting rupture was 90.6% and 98.3% respectively. A proportion of patients (29.4%) demonstrated loco regional spread of silicone to the axilla on scanning. CONCLUSIONS: Our paper has confirmed high rates of PIP implant failure in the largest published series to date. The significant difference in rupture rates between implants inserted prior to 2003 and those after this time supports the view that industrial silicone was used in the devices after 2003. Implants are more likely to rupture if inserted in the sub muscular plane compared to the sub glandular plane. USS is highly effective at detecting rupture in PIP implants and loco-regional spread is high compared to other devices. We believe this paper provides hard data enabling more informed decision making for patients, clinicians and providers in what remains an active issue affecting thousands of women. PMID- 23725743 TI - [Endobronchial stent for the treatment of a traumatic rupture of the left bronchial due to a bull horn. Anesthetic implications]. PMID- 23725744 TI - [Airway management of patients with severe obstruction of the glottic opening. Experience with the Bonfils optical stylet]. PMID- 23725745 TI - Perforated peptic ulcer in a child with a vagus nerve stimulator for seizure control. PMID- 23725746 TI - Genetic analysis of the VP2-encoding gene of canine parvovirus strains from Africa. AB - Since the emergence of canine parvovirus type-2 (CPV-2) in the early 1970s, it has been evolving into novel genetic and antigenic variants (CPV-2a, 2b and 2c) that are unevenly distributed throughout the world. Genetic characterization of CPV-2 has not been documented in Africa since 1998 apart from the study carried out in Tunisia 2009. A total of 139 field samples were collected from South Africa and Nigeria, detected using PCR and the full length VP2-encoding gene of 27 positive samples were sequenced and genetically analyzed. Nigerian samples (n=6), South Africa (n=19) and vaccine strains (n=2) were compared with existing sequences obtained from GenBank. The results showed the presence of both CPV-2a and 2b in South Africa and only CPV-2a in Nigeria. No CPV-2c strain was detected during this study. Phylogenetic analysis showed a clustering not strictly associated with the geographical origin of the analyzed strains, although most of the South African strains tended to cluster together and the viral strains analyzed in this study were not completely distinct from CPV-2 strains from other parts of the world. Amino acid analysis showed predicted amino acid changes. PMID- 23725748 TI - Next generation sequencing in psychiatric research: what study participants need to know about research findings. AB - The use of next generation sequencing (NGS) technologies in psychiatric genetics research and its potential to generate individual research results will likely have far reaching implications for predictive and diagnostic practices. The extent of this impact may not be easily understood by psychiatric research participants during the consent process. The traditional consent process for studies involving human subjects does not address critical issues specific to NGS research, such as the return of results. We examined which type of research findings should be communicated, how this information should be conveyed during the consent process and what guidance is required by researchers and IRBs to help psychiatric research participants understand the peculiarities, the limits and the impact of NGS. Strong standards are needed to ensure appropriate use of data generated by NGS, to meet participants' expectations and needs, and to clarify researchers' duties regarding the disclosure of data and their subsequent management. In the short term, researchers and IRBs need to be proactive in revising current consent processes that deal with the disclosure of research findings. PMID- 23725747 TI - Genetic analysis of Streptococcus suis isolates from wild rabbits. AB - This work aims to investigate the presence of Streptococcus suis in wild rabbits. A total of 65 S. suis isolates were recovered from 33.3% of the wild rabbits examined. Most isolates (86.2%) belong to genotype cps9. These isolates were further characterized by pulsed field gel electrophoresis (PFGE), multilocus sequence typing (MLST) and virulence genotyping. Overall, S. suis exhibited a low genetic diversity. Only 5 genetic profiles were obtained by PFGE and most isolates (71.4%) were included in two pulsotypes that were also widely distributed among the wild rabbit population. MLST analysis assigned all cps9 isolates into three new singlestones (ST216, ST217 and ST284), which were not genetically related to the European ST87 and Spanish ST61 widespread swine clones, indicating a different genetic background for the S. suis isolates from wild rabbits and pigs. Wild rabbit isolates exhibited the genotype mrp-/epf-/sly , different from those showed by most of the swine S. suis isolates of the ST87 and ST61 clones. None of the S. suis isolated from wild rabbits exhibited the genotype cps2/mrp+/epf+/sly+ associated with human infections. These results indicate that S. suis isolates from wild rabbits are not genetically related with prevalent clones usually associated with infections in pigs or humans in Europe and do not exhibit either their virulence genotypes. Therefore, although wild rabbits could represent an unknown reservoir of this pathogen, they could not represent a potential risk for pigs or humans. PMID- 23725749 TI - Hypoxia influences stem cell-like properties in multidrug resistant K562 leukemic cells. AB - OBJECTIVES: The present study investigates the potential role of hypoxia in maintaining stem cell-like properties and therapeutic resistance in K562 leukemic cell. METHODS: Western blot, flow cytometry and cell viability assays were used to investigate the effects of hypoxia (1% O2) on cell proliferation, drug resistance and expression of the hypoxia inducible factor-2alpha (HIF-2alpha), the octamer-binding transcription factor 4 (Oct4), CD133, CD34 and the ATP binding cassette sub-family G member 2 (ABCG2) as well as Smad2 phosphorylation in the drug resistant cell line K562/DOX and its parental cell line. RESULTS: Hypoxia induced growth inhibition and significantly upregulated HIF-2alpha, CD133, Oct4, CD34 and ABCG2 expression in the wild type K562 cells (p<0.05). The IC50 of doxorubicin was also enhanced about 2.5-fold in hypoxia. In contrast, the K562/DOX cells, which showed significantly higher ABCG2 expression and IC50 for various drugs, no significant difference in cell proliferation was observed between hypoxia and normoxia. The hypoxia-induced upregulation of HIF-2alpha, CD133, Oct4, CD34 and ABCG2 expression was significantly lower than in the wild type cells (p<0.05). Moreover, hypoxia induced the phosphorylation of Smad2 and additional treatment with SD-208, an inhibitor of the TGF-beta receptor I kinase, resulted in a dose-dependent downregulation of CD133 and Oct4 in the K562/DOX cells. CONCLUSIONS: Hypoxia plays an important role in enhancing the stem cell like properties and to induce multidrug resistance of leukemia cells. The activation of the TGF-beta/Smad2 signaling pathway may be involved in the regulation of this pathophysiological process. PMID- 23725750 TI - Accumulation of hydroxylated polychlorinated biphenyls (OH-PCBs) and implications for PCBs metabolic capacities in three porpoise species. AB - The present study investigated polychlorinated biphenyls (PCBs) and hydroxylated metabolites of PCBs (OH-PCBs) in blood from three porpoise species: finless porpoises (Neophocaena phocaenoides), harbor porpoises (Phocoena phocoena), and Dall's porpoises (Phocoenoides dalli). The porpoises were found stranded or were bycaught along the Japanese coast. Concentrations of OH-PCB were the highest in Dall's porpoises (58pgg(-1) wet wt), second highest in finless porpoises (20pgg( 1) wet wt), and lowest in harbor porpoises (8.3pgg(-1) wet wt). The concentrations in Dall's porpoises were significantly higher than the concentrations in finless porpoises and harbor porpoises (p<0.05 and p<0.01, respectively). There was a positive correlation between PCB and OH-PCB concentrations (r=0.67, p<0.001), suggesting the possible concentration-dependent induction of CYP enzymes. The three porpoise species may have exceptionally low metabolic capacities compared with other marine and terrestrial mammals, because low OH-PCB/PCB concentration ratios were found, which were 0.0016 for Dall's porpoises, 0.0013 for harbor porpoises, and 0.00058 for finless porpoises. Distinct differences in the OH-PCB congener patterns were observed for the three species, even though they are taxonomically closely related. PMID- 23725751 TI - Response to comment on "In situ air-water and particle-water partitioning of perfluorocarboxylic acids, perfluorosulfonic acids and perfluorooctyl sulfonamide at a wastewater treatment plant". PMID- 23725752 TI - Detection of transfluthrin and metofluthrin genotoxicity in the ST cross of the Drosophila Wing Spot Test. AB - In this study, different concentrations of transfluthrin and metofluthrin have been assayed for genotoxicity by using the Wing Spot Test on Drosophila melanogaster. Standard cross was used in the experiment. Third-instar larvae that were trans-heterozygous for the two genetic markers mwh and flr(3) were treated at different concentrations (0.0103mgmL(-1), 0.103mgmL(-1) for transfluthrin and 6MUgmL(-1), 60MUgmL(-1) for metofluthrin) of the test compounds. Feeding ended with pupation of the surviving larvae and the genetic changes induced in somatic cells of the wing's imaginal discs lead to the formation of mutant clones on the wing blade. Results indicated that two experimental concentrations of transfluthrin and 60MUgmL(-1) metofluthrin showed mutagenic and recombinogenic effects in both the marker-heterozygous (MH) flies and the balancer-heterozygous (BH) flies. PMID- 23725753 TI - Kinetics of CH3S(-) reaction with in situ ferrate(VI) in aqueous alkaline solution. AB - This study introduced a new treatment process named "in situ ferrate(VI) oxidation (IFO)" in which odorous compounds such as CH3S(-) can be quickly degraded by in situ freshly generated ferrate(VI) through electrolysis in aqueous alkaline solution. Two kinetic models to describe the in situ ferrate(VI) generation and its reaction with CH3S(-) were established mathematically by considering three main reaction mechanisms of ferrate(VI) electrochemical generation, ferrate(VI) self-decomposition and CH3S(-) degradation in aqueous strong alkaline solution. The effects of three key factors: (i) NaOH concentration, (ii) applied current density, and (iii) initial CH3S(-) concentration on the performance of the IFO process were investigated by conducting three sets of experiments and the kinetic models were validated by fitting the experimental data. The goodness of the fittings demonstrated that the new models could well describe both the kinetics of ferrate(VI) generation reaction and CH3S(-) degradation reaction. The experimental results confirmed that the higher NaOH concentration and current density applied would be beneficial to the electrochemical generation of ferrate(VI) and also elimination of its self-decomposition, but the experiments also demonstrated an optimum NaOH concentration at 10M to achieve the best performance of CH3S(-) degradation reaction in such an IFO system. PMID- 23725754 TI - Final year students' experiences of the Bachelor of Midwifery course. AB - AIM: : the aim of the study was to explore the experiences of final year Bachelor of Midwifery students. BACKGROUND: earlier research indicates that midwifery students experience a number of difficulties and concerns during their studentship. These difficulties can lead to a lack of confidence and poorer integration and socialisation into the profession. Ultimately, poorer integration may lead to dissatisfaction and attrition from the profession. METHODS: a qualitative approach, informed by interpretative phenomenological analysis (IPA), was used in this study. Ten completing Bachelor of Midwifery students participated in in-depth interviews and reflected on their experiences over their three year course. Data were subjected to IPA analytic steps as proposed by Smith and Osborn (2008). KEY FINDINGS: demographics revealed that participants were generally aged more than 35 years and worked 16 hours or less per week. Most had two or more children and lived with a spouse/partner. Four main themes emerged from the analysis: (1) a challenging start; (2) coming to terms with course requirements; (3) developing strategies; and (4) overall satisfaction with the course. Participants generally considered that their individual strengths and determination helped them to negotiate the many challenges they encountered during the course. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: this study indicates that students undergo a process of adjustment as they travel through the Bachelor of Midwifery course. The most critical transition phase appears to occur in the first year and students may require additional supports to assist their socialisation into both the university and their course. Particular needs identified include return to study skills for mature-aged students and counselling and support group needs generally. The provision of such supports may assist with the retention of students within the course and may contribute to overall student satisfaction. PMID- 23725755 TI - STAT pathway in the regulation of zoledronic acid-induced apoptosis in chronic myeloid leukemia cells. AB - In this study, we aimed to evaluate the cytotoxic and apoptotic effects of zoledronic acid on K562 chronic myeloid leukemia (CML) cells and to examine the roles of STAT genes on zoledronic acid-induced apoptosis. The results showed that zoledronic acid decreased proliferation, and induced apoptosis in K562 cells in a dose- and time-dependent manner. mRNA and protein levels of STAT3, -5A and -5B genes were significantly reduced in zoledronic acid-treated K562 cells. These data indicated that STAT inhibition by zoledronic acid may be therapeutic in CML patients following the confirmation with clinical studies. PMID- 23725756 TI - NDRG3 and NDRG4, two novel tumor-related genes. AB - The N-myc downstream-regulated genes, NDRG3 and NDRG4, are suggested to play important roles in biological processes and pathogenesis. Expression of NDRG3 and NDRG4 has been shown to be reduced or absent in numerous cancer cell lines and tumor types, suggesting that they may exert function as a tumor suppressor gene. In this review, we will summarize the current research on NDRG3 and NDRG4, including the molecular structure, cellular and tissue distribution, biological function, and function in cancer. We tried to show their significance in studying disease and their therapeutic potential. PMID- 23725757 TI - Upregulation of the TPX2 gene is associated with enhanced tumor malignance of esophageal squamous cell carcinoma. AB - PURPOSE: To explore the expression of TPX2 and its significance in esophageal squamous cell carcinoma (ESCC) tissue and approach relationship between the TPX2 and clinicopathological characteristic of esophageal squamous cell carcinoma. METHOD: RT-PCR and immunohistochemical staining were used to compare the expression of TPX2 in 62 esophageal squamous cell carcinoma, 31 atypical hyperplasia and 62 normal esophageal mucosa. RESULTS: In ESCC, atypical hyperplasia and in normal mucous membrane tissues, the positive rate of TPX2 protein expression was 85.5% (53/62), 51.6% (16/31) and 4.8% (3/62); the positive rate of TPX2 mRNA expression was 65.5% (40/62), 35.5 (11/31) and 4.83% (3/62). The expression of TPX2 protein and mRNA were correlated with invasive depth and lymphatic metastasis of ESCC (P<0.01). CONCLUSIONS: Overexpression of TPX2 may be risk factor of lymph node in esophageal carcinoma, and maybe a potential biomarker for early diagnosis and prognosis of esophageal squamous cell carcinoma. PMID- 23725758 TI - Proteolytic remodeling of the ECM and the geometric control of stem cell fate. AB - The mechanism by which mechanosignal transduction regulates stem cell fate is not well understood. In this issue of Developmental Cell, Tang et al. (2013) demonstrate that catalytic function of the metalloproteinase MT1-MMP controls ECM structure, cell shape, and an integrin/Rho/YAP-TAZ signaling axis to control osteogenic stem cell fate. PMID- 23725759 TI - Turtle origins: picking up speed. AB - Genomes for three species of turtles were recently reported in Nature Genetics and Genome Biology. The findings of Wang et al. (2013) and Abramyan et al. (2013) place the turtles as a sister group to birds and crocodiles and offer clues to the origins of this group's remarkable physiological traits. PMID- 23725760 TI - Filopodia: the cellular quills of hedgehog signaling? AB - Reporting in Nature, Sanders et al. (2013) implicate filopodial projections in Sonic hedgehog (Shh) patterning of the limb. Actin-based filopodia transport Shh from producing cells, while filopodia of responding cells bear Cdon and Boc: coreceptors in the Shh pathway. These findings suggest a new mechanism of ligand movement and transmission. PMID- 23725761 TI - A close look at wiggly chromosomes. AB - In a recent issue of Cell, Fisher et al. (2013) use high-resolution time-lapse imaging to peer into bacterial genome (nucleoid) structure. The nucleoid, an elastic filament confined via an internal network, undergoes periodic fluctuations critical in relieving tension. Programmed tethers and their release highlight a primordial mechanical cycle for chromosome segregation. PMID- 23725762 TI - Deficiency of lipid phosphatase SHIP enables long-term reconstitution of hematopoietic inductive bone marrow microenvironment. AB - A dysfunctional bone marrow (BM) microenvironment is thought to contribute to the development of hematologic diseases. However, functional replacement of pathologic BM microenvironment through BM transplantation has not been possible. Furthermore, the study of hematopoietic inductive BM microenvironment is hampered by the lack of a functional nonhematopoietic reconstitution system. Here, we show that a deficiency of SH2-containing inositol-5'-phosphatase-1 (SHIP) in a nonhematopoietic host microenvironment enables its functional reconstitution by wild-type donor cells. This microenvironment reconstitution normalizes hematopoiesis in peripheral blood and BM and alleviates pathology of spleen and lung in the SHIP-deficient recipients. SHIP-deficient BM contains a significantly smaller population of multipotent stromal cells with distinct properties, which may contribute to the reconstitution by wild-type cells. We further demonstrate that it is the nonhematopoietic donor cells that are responsible for the reconstitution. Thus, we have established a nonhematopoietic BM microenvironment reconstitution system to functionally study specific cell types in hematopoietic niches. PMID- 23725763 TI - The BH3-only SNARE BNip1 mediates photoreceptor apoptosis in response to vesicular fusion defects. AB - Intracellular vesicular transport is important for photoreceptor function and maintenance. However, the mechanism underlying photoreceptor degeneration in response to vesicular transport defects is unknown. Here, we report that photoreceptors undergo apoptosis in a zebrafish beta-soluble N-ethylmaleimide sensitive factor attachment protein (beta-SNAP) mutant. beta-SNAP cooperates with N-ethylmaleimide-sensitive factor to recycle the SNAP receptor (SNARE), a key component of the membrane fusion machinery, by disassembling the cis-SNARE complex generated in the vesicular fusion process. We found that photoreceptor apoptosis in the beta-SNAP mutant was dependent on the BH3-only protein BNip1. BNip1 functions as a component of the syntaxin-18 SNARE complex and regulates retrograde transport from the Golgi to the endoplasmic reticulum. Failure to disassemble the syntaxin-18 cis-SNARE complex caused BNip1-dependent apoptosis. These data suggest that the syntaxin-18 cis-SNARE complex functions as an alarm factor that monitors vesicular fusion competence and that BNip1 transforms vesicular fusion defects into photoreceptor apoptosis. PMID- 23725764 TI - The Hippo effector Yorkie controls normal tissue growth by antagonizing scalloped mediated default repression. AB - The Hippo tumor suppressor pathway restricts tissue growth by inactivating the transcriptional coactivator Yki. Although Sd has been implicated as a DNA-binding transcription factor partner for Yki and can genetically account for gain-of function Yki phenotypes, how Yki regulates normal tissue growth remains a long standing puzzle because Sd, unlike Yki, is dispensable for normal growth in most Drosophila tissues. Here we show that the yki mutant phenotypes in multiple developmental contexts are rescued by inactivation of Sd, suggesting that Sd functions as a default repressor and that Yki promotes normal tissue growth by relieving Sd-mediated default repression. We further identify Tgi as a cofactor involved in Sd's default repressor function and demonstrate that the mammalian ortholog of Tgi potently suppresses the YAP oncoprotein in transgenic mice. These findings fill a major gap in Hippo-mediated transcriptional regulation and open up possibilities for modulating the YAP oncoprotein in cancer and regenerative medicine. PMID- 23725766 TI - Early weight-bearing in operatively fixed ankle fractures: a systematic review. AB - BACKGROUND: Ankle fractures are among the most common lower limb fractures and they can cause significant detrimental effects on quality of life and work. OBJECTIVE: The objective of the review was to evaluate if there is any advantage of early weight-bearing after open reduction and internal fixation of the ankle. METHODS: Electronic databases, reference lists of included studies and relevant systematic reviews were searched for randomized and non-randomized controlled trials in adults comparing early and late weight-bearing after open reduction and internal fixation of the ankle. The search was inclusive up to February 2012. RESULTS: Nine studies comprising 555 subjects were included for review. There were significantly better outcomes for improved early dorsiflexion, time to full weight-bearing, early return to previous work and shorter hospital stay (patient<60 years of age) in the early weight-bearing group. CONCLUSION: The evidence base contained many methodological limitations and was generally poor, and so any conclusion drawn from the research must be done so with caution. The literature suggests that early weight-bearing may allow for quicker rehabilitation and earlier return to work. Future studies should focus on randomized controlled trials with narrow range of clinically useful outcome measures and consistent immobilization strategy between experimental groups. PMID- 23725765 TI - Atrial identity is determined by a COUP-TFII regulatory network. AB - Atria and ventricles exhibit distinct molecular profiles that produce structural and functional differences between the two cardiac compartments. However, the factors that determine these differences remain largely undefined. Cardiomyocyte specific COUP-TFII ablation produces ventricularized atria that exhibit ventricle like action potentials, increased cardiomyocyte size, and development of extensive T tubules. Changes in atrial characteristics are accompanied by alterations of 2,584 genes, of which 81% were differentially expressed between atria and ventricles, suggesting that a major function of myocardial COUP-TFII is to determine atrial identity. Chromatin immunoprecipitation assays using E13.5 atria identified classic atrial-ventricular identity genes Tbx5, Hey2, Irx4, MLC2v, MLC2a, and MLC1a, among many other cardiac genes, as potential COUP-TFII direct targets. Collectively, our results reveal that COUP-TFII confers atrial identity through direct binding and by modulating expression of a broad spectrum of genes that have an impact on atrial development and function. PMID- 23725767 TI - Second- and higher-order structural changes of DNA induced by antitumor-active tetrazolato-bridged dinuclear platinum(II) complexes with different types of 5 substituent. AB - Here, we used circular dichroism (CD) and fluorescence microscopy (FM) to examine the interactions of a series of antitumor-active tetrazolato-bridged dinuclear platinum(II) complexes, [{cis-Pt(NH3)2}2(MU-OH)(MU-5-R-tetrazolato-N2,N3)](n+) (R=CH3 (1), C6H5 (2), CH2COOCH2CH3 (3), CH2COO(-) (4), n=2 (1-3) or 1 (4)), which are derivatives of [{cis-Pt(NH3)2}2(MU-OH)(MU-tetrazolato-N2,N3)](2+) (5-H-Y), with DNA to elucidate the influence of these interactions on the secondary or higher-order structure of DNA and reveal the mechanism of action. The CD study showed that three derivatives, 1-3, with a double-positive charge altered the secondary structures of calf thymus DNA but that 4, the only complex with a single positive charge, induced almost no change, implying that the B- to C-form conformational change is influenced by ionic attraction. Unexpectedly, single molecule observations with FM revealed that 4 changed the higher-order structure of T4 DNA into the compact-globule state most efficiently, at the lowest concentration, which was nearly equal to that of 5-H-Y. These contradictory results suggest that secondary structural changes are not necessarily linked to higher-order ones, and that the non-coordinative interaction could be divided into two distinct interactions: (1) ionic attraction and (2) hydrogen bonding and/or van der Waals contact. The relationship between diffusion-controlled non coordinative DNA interactions and cytotoxicities is also discussed. PMID- 23725768 TI - No proof of synergy at environmentally realistic concentrations of prochloraz and esfenvalerate--a reaction on "synergy in microcosms with environmentally realistic concentrations of prochloraz and esfenvalerate" by Bjergager et al. (Aquat. Toxicol. 101 (2011), 412-422). AB - The aquatic microcosm study by Bjergager et al. (2011) on a mixture of the fungicide prochloraz and the insecticide esfenvalerate concluded that synergistic effects were found at environmentally realistic concentrations for these compounds and thus that current risk assessment procedures might underestimate the effects of synergistically interacting azoles and pyrethroids. Both prochloraz and esfenvalerate are registered in Europe and thus the relevance of the employed concentrations can be assessed against European surface water measurements and risk assessments procedures. A detailed comparison of the employed concentration of prochloraz in the microcosm study with the concentration deemed acceptable in the European Union and those actually measured in the aquatic environment demonstrate that the employed prochloraz concentration was about two orders of magnitude too high. Therefore, on basis of the data presented by Bjergager et al. (2011) it cannot be concluded that current European single substance risk assessment procedures are insufficiently protective and that synergism actually occurs at environmentally relevant concentrations. PMID- 23725769 TI - Improvement of ultrasound speckle image velocimetry using image enhancement techniques. AB - Ultrasound-based techniques have been developed and widely used in noninvasive measurement of blood velocity. Speckle image velocimetry (SIV), which applies a cross-correlation algorithm to consecutive B-mode images of blood flow has often been employed owing to its better spatial resolution compared with conventional Doppler-based measurement techniques. The SIV technique utilizes speckles backscattered from red blood cell (RBC) aggregates as flow tracers. Hence, the intensity and size of such speckles are highly dependent on hemodynamic conditions. The grayscale intensity of speckle images varies along the radial direction of blood vessels because of the shear rate dependence of RBC aggregation. This inhomogeneous distribution of echo speckles decreases the signal-to-noise ratio (SNR) of a cross-correlation analysis and produces spurious results. In the present study, image-enhancement techniques such as contrast limited adaptive histogram equalization (CLAHE), min/max technique, and subtraction of background image (SB) method were applied to speckle images to achieve a more accurate SIV measurement. A mechanical sector ultrasound scanner was used to obtain ultrasound speckle images from rat blood under steady and pulsatile flows. The effects of the image-enhancement techniques on SIV analysis were evaluated by comparing image intensities, velocities, and cross-correlation maps. The velocity profiles and wall shear rate (WSR) obtained from RBC suspension images were compared with the analytical solution for validation. In addition, the image-enhancement techniques were applied to in vivo measurement of blood flow in human vein. The experimental results of both in vitro and in vivo SIV measurements show that the intensity gradient in heterogeneous speckles has substantial influence on the cross-correlation analysis. The image-enhancement techniques used in this study can minimize errors encountered in ultrasound SIV measurement in which RBCs are used as flow tracers instead of exogenous contrast agents. PMID- 23725770 TI - The limited clinical value of a specific diabetic cardiomyopathy. AB - AIMS: Diabetic patients show a higher likelihood of developing heart failure (HF), independently of the atherosclerotic process, than their nondiabetic counterparts. This suggests the presence of an intrinsic vulnerability of the heart in patients with diabetes mellitus. DATA SYNTHESIS: A cardiomyopathy specific to the diabetic patient was first hypothesized by Rubler and co-workers, in 1972 and recognized as a nosologic entity by the World Health Organization (WHO) in 1995. All patients falling under Rubler's definition had ascertained diabetic glomerusclerosis, but were unaffected by major coronary artery disease (CAD). Notably, the mean plasma glucose in those patients was 417 +/- 209 mg/dl. Since then, several studies conducted in both animals and in humans have focused on pathogenetic mechanisms, clinical manifestations, diagnostic as well as therapeutic approaches utilized for the treatment of diabetic cardiomyopathy (DCM). Despite the large body of literature available, the clinical entity and significance of this diabetic complication continue to be elusive. CONCLUSIONS: In the present report, recent pathophysiological findings and diagnostic strategies to treat DCM are reviewed. Particular attention is dedicated to the clinical manifestation of DCM, that is to heart failure (HF), and to the implications of co-morbidities and metabolic control on its evolution. PMID- 23725771 TI - Adherence to recommendations for fruit and vegetable intake, ethnicity and ischemic heart disease mortality. AB - BACKGROUND AND AIMS: Ischemic heart disease (IHD) accounts for one-third of annual deaths in the U.S. and mortality rates vary by ethnicity. The association between adherence to dietary guidelines for fruit and vegetable intake with IHD mortality among different ethnic groups has not previously been examined. METHODS AND RESULTS: A prospective cohort design was used to examine the incidence of fatal IHD among participants in the Multiethnic Cohort Study. Participants included 164,617 men and women from five ethnic groups: African American, Native Hawaiian, Japanese American, Latino, and Caucasian. Cox proportional hazards models, stratified by ethnicity and sex, were used to examine associations between adherence with recommended dietary guidelines for fruit and vegetable intake and risk for fatal IHD. The results did not provide evidence that the association between adherence with dietary recommendations for fruit or vegetable intake and IHD mortality varies by ethnicity. Pooled data did provide evidence that adhering to the recommendations for vegetables lowered risk among men (RR = 0.84, 95% CI: 0.74-0.96) and women (RR = 0.80, 95% CI: 0.69-0.94). No significant effects were observed for fruit intake. CONCLUSIONS: The effect of dietary intake of fruit and vegetables did not vary by ethnicity, providing evidence that recommendations do not need to be individualized for these special populations. The protective effect observed for vegetable intake among both sexes confirms previous findings and supports the evidence base for promoting diet modification in this direction. PMID- 23725772 TI - Changes in serum uric acid levels and cardiovascular events: a meta-analysis. AB - BACKGROUND AND AIMS: The association between serum uric acid (SUA) levels and cardiovascular (CV) risk or all-cause death has been repeatedly reported. However, it has not been assessed whether reduction of SUA levels is associated with reduced CV risk. The aim of the current study was to evaluate the relationship between changes of SUA levels and CV events as well as all-cause death. METHODS AND RESULTS: Randomised trials reporting SUA at baseline and at the end of follow-up and clinical end-points (all-cause death, myocardial infarction (MI), stroke, heart failure (HF) and CV death) were included in the study. Meta-regression analysis was performed to test the relationship between SUA changes and clinical end-points. Eleven trials enrolling 21,373 participants followed up for 2.02 +/- 1.76 years and reporting 4533 events were included. In meta-regression analysis, no relationship between SUA changes from baseline to end of follow-up and the composite outcome including CV death, stroke, MI and HF was found (change in Tau(2) (t) = -0.64; p Tau (p) = 0.541). Similarly, no relationship was found between SUA changes and single components of the composite outcome (MI: t = -0.83; p = 0.493; stroke: t = 0.46; p = 0.667; HF: t = 2.44; p = 0.162; CV death: t = -0.54; p = 0.614) and all-cause death (t = -0.72; p = 0.496). Results were confirmed by sensitivity analysis. No heterogeneity among studies or publication bias was detected. CONCLUSIONS: Changes in SUA levels observed during pharmacologic treatments do not predict the risk of all-cause death or CV events. As SUA levels are associated with increased CV risk, additional studies with direct xanthine-oxidase inhibitors are requested. PMID- 23725773 TI - Re-emergence of animal rabies in northern Greece and subsequent human exposure, October 2012 - March 2013. AB - Greece has been rabies-free since 1987 with no human cases since 1970. During 2012 to 2013, rabies has re-emerged in wild and domestic animals in northern Greece. By end March 2013, rabies was diagnosed in 17 animals including 14 red foxes, two shepherd dogs and one cat; 104 subsequent human exposures required post-exposure prophylaxis according to the World Health Organization criteria. Human exposures occurred within 50 km radius of a confirmed rabies case in a wild or domestic animal, and most frequently stray dogs were involved. PMID- 23725774 TI - Outbreak of listerosis due to imported cooked ham, Switzerland 2011. AB - From 24 April to 31 July 2011, nine cases of listeriosis were registered in the cantons of Aargau, Basel-Land and Zurich, Switzerland. In six of the cases, infection with Listeria monocytogenes was laboratory confirmed, while three remained suspected cases. The suspected cases were family members of confirmed cases with identical or similar symptoms. All confirmed cases were infected with a L. monocytogenes strain belonging to serovar 1/2a: all had an indistinguishable pulsotype by pulsed-field gel electrophoresis (PFGE). The same strain was detected in samples of cooked ham that were on sale from a particular retailer. Two samples of ham tested contained 470 and 4,800 colony-forming units (CFU) L. monocytogenes per gram respectively. Data of shopper cards from two confirmed cases could be evaluated: both cases had purchased the contaminated ham. The outbreak initiated a product recall and alert actions at national and European level, through the Rapid Alert System for Food and Feed (RASFF). Following the RASFF alert, the company producing the contaminated ham was inspected by the responsible authorities. Their investigations showed that the ham was not contaminated in the production plant, but in the premises of a company to which slicing and packing was outsourced. PMID- 23725775 TI - Outbreak of leptospirosis among canyoning participants, Martinique, 2011. AB - Two gendarmes who participated in canyoning activities on 27 June 2011 on the Caribbean island of Martinique were diagnosed with leptospirosis using quantitative real-time polymerase chain reaction (qPCR), 9 and 12 days after the event. Among the 45 participants who were contacted, 41 returned a completed questionnaire, of whom eight met the outbreak case definition. The eight cases sought medical attention and were given antibiotics within the first week after fever onset. No severe manifestations of leptospirosis were reported. In seven of the eight cases, the infection was confirmed by qPCR. Three pathogenic Leptospira species, including L. kmetyi, were identified in four of the cases. None of the evaluated risk factors were statistically associated with having developed leptospirosis. Rapid diagnostic assays, such as qPCR, are particularly appropriate in this setting - sporting events with prolonged fresh-water exposure - for early diagnosis and to help formulate public health recommendations. Participants in such events should be made specifically aware of the risk of leptospirosis, particularly during periods of heavy rainfall and flooding. PMID- 23725776 TI - Deja vu: Ralstonia mannitolilytica infection associated with a humidifying respiratory therapy device, Israel, June to July 2011. AB - Following a bloodstream infection in June 2011 with Ralstonia mannitolilytica in a premature infant treated with a humidifying respiratory therapy device, an investigation was initiated at the Hadassah Medical Centres in Jerusalem. The device delivers a warmed and humidified mixture of air and oxygen to patients by nasal cannula. The investigation revealed colonisation with R. mannitolilytica of two of 15 patients and contamination of components of five of six devices deployed in the premature units of the Hadassah hospitals. Ten isolates from the investigation were highly related and indistinguishable from isolates described in an outbreak in 2005 in the United States (US). Measures successful in containing the US outbreak were not included in user instructions provided to our hospitals by the distributor of the device. PMID- 23725779 TI - The effect of the sex of a model on nocebo hyperalgesia induced by social observational learning. AB - Research shows that placebo analgesia can be induced through social observational learning. Our aim was to replicate and extend this result by studying the effect of the sex of both the model and the subject on the magnitude of placebo analgesia induced by social observational learning. Four experimental (1 through 4) and 2 control (5 and 6) groups were observed: groups 1, 3, and 5 were female; groups 2, 4, and 6 were male. All subjects received pain stimuli of the same intensity preceded by green and red lights. Before receiving pain stimuli, groups 1 and 4 observed a female model and groups 2 and 3 a male model; both models simulated responses to pain stimuli preceded by green lights as less painful than those preceded by red lights. Groups 1 through 4 also rated pain stimuli preceded by green lights as less painful. Further investigation revealed that in fact subjects in experimental groups rated red-associated stimuli as more painful than subjects from control groups who did not observe a model before receiving the same pain stimuli, indicating that nocebo hyperalgesia rather than placebo analgesia was induced. Empathy traits predicted the magnitude of nocebo hyperalgesia. Regardless of the sex of the subject, nocebo hyperalgesia was greater after the male model was observed. The results show that social observational learning is a mechanism that produces placebo effects. They also indicate that the sex of the model plays an important role in this process. PMID- 23725780 TI - Intraoral somatosensory abnormalities in patients with atypical odontalgia--a controlled multicenter quantitative sensory testing study. AB - Intraoral somatosensory sensitivity in patients with atypical odontalgia (AO) has not been investigated systematically according to the most recent guidelines. The aims of this study were to examine intraoral somatosensory disturbances in AO patients using healthy subjects as reference, and to evaluate the percent agreement between intraoral quantitative sensory testing (QST) and qualitative sensory testing (QualST). Forty-seven AO patients and 69 healthy control subjects were included at Universities of Washington, Malmo, and Aarhus. In AO patients, intraoral somatosensory testing was performed on the painful site, the corresponding contralateral site, and at thenar. In healthy subjects, intraoral somatosensory testing was performed bilaterally on the upper premolar gingiva and at thenar. Thirteen QST and 3 QualST parameters were evaluated at each site, z scores were computed for AO patients based on the healthy reference material, and LossGain scores were created. Compared with control subjects, 87.3% of AO patients had QST abnormalities. The most frequent somatosensory abnormalities in AO patients were somatosensory gain with regard to painful mechanical and cold stimuli and somatosensory loss with regard to cold detection and mechanical detection. The most frequent LossGain code was L0G2 (no somatosensory loss with gain of mechanical somatosensory function) (31.9% of AO patients). Percent agreement between corresponding QST and QualST measures of thermal and mechanical sensitivity ranged between 55.6% and 70.4% in AO patients and between 71.1% and 92.1% in control subjects. In conclusion, intraoral somatosensory abnormalities were commonly detected in AO patients, and agreement between quantitative and qualitative sensory testing was good to excellent. PMID- 23725781 TI - Inability to self-report pain after a stroke: a population-based study. AB - The frequency of not being able to self-report pain after a stroke has not been previously assessed in a population-based sample. We studied the epidemiology of this problem using a cohort of patients hospitalized after a stroke in Olmsted County, Minnesota, from June 1, 2008, to June 1, 2012. Overall, 52 of 388 (13.4%) individuals were unable to provide a meaningful response to either a Faces Pain Scale or Numerical Rating Scale on admission. Inability to self-report pain was associated with measures of stroke severity (P<.0001), aphasia severity (P<.0001), and level of consciousness (P<.0001). Inability to self-report pain on admission was further associated with either subsequent death during the hospitalization (P<.0001) or an inability to provide self-report on dismissal (P<.0001). Our study further defines the epidemiology of the inability to self report pain after a stroke as being less common than previously thought. Attempts to validate observational pain scales for poststroke patients should focus on those individuals with aphasia and/or depressed levels of consciousness. PMID- 23725783 TI - Quantification of the visceral and subcutaneous fat by computed tomography: interobserver correlation of a single slice technique. AB - PURPOSE: To assess the interobserver reproducibility of the quantification of the visceral and subcutaneous fat by computed tomography from an umbilical slice and study the effect of the level of the slice (slice going through the navel versus a slice going through disc L3-L4). MATERIALS AND METHODS: Forty-four breast cancer patients who had a CT-scan were included in this study. This is a double blind (junior versus senior) retrospective study to determine the interobserver reproducibility. A junior observer studied the variation between two levels of slice by selecting an image going through L3-L4 and the navel. RESULTS: The measurement of the fat obtained from an umbilical slice seemed to be well correlated and consistent with that obtained from a slice with a disc reference (L3-L4). The interobserver reproducibility is good for the quantification of the umbilical fat (Spearman and Lin at 0.9921 and 0.985 [P<0.001] for the visceral fat). CONCLUSION: The interobserver reproducibility of the single slice CT-scan measurement going through the navel (easily detected) is excellent and may therefore be used in oncology as a predictive tool to measure a characteristic of the host and not the tumor. PMID- 23725784 TI - Ultrasonography and MRI features of the Mayer-Rokitansky-Kuster-Hauser syndrome. AB - Although Mayer-Rokitansky-Kuster-Hauser syndrome is a rare condition with a reported incidence of 1/4500 female live births, it represents the second most common cause of primary amenorrhea and has psychologically devastating consequences. The radiologist plays a pivotal role in both making the accurate initial diagnosis of this condition and assessing findings that may contribute to treatment planning. The purpose of this article is to provide an overview of the capabilities of ultrasound and magnetic resonance imaging (MRI) for the diagnosis and management of this syndrome with emphasis on the relevant clinical and surgical findings and to describe potential associated abnormalities and differential diagnosis. PMID- 23725785 TI - [Myocarditis following smallpox vaccination]. PMID- 23725786 TI - [Pertussis in fully vaccinated infants and children. Are new vaccination strategies required?]. AB - OBJECTIVE: To analyse the vaccination status of children diagnosed with pertussis and to compare the clinical manifestations of fully vaccinated with unvaccinated, or incompletely-vaccinated, children. METHODS: The clinical histories and vaccination cards of patients under 16years of age seen in the Emergency Room of the University Hospital Vall d'Hebron, Barcelona (Spain), for pertussis confirmed by a microbiological study were reviewed. The study period lasted from January 1, 2009 to December 31, 2011. RESULTS: Two hundred and twelve cases were studied: 35 in 2009, 28 in 2010 and 149 in 2011. RT-PCR was positive in 210 patients, and 73 had a positive culture. Infants under 6months of age account for 36.8% of all cases. Forty-four patients (21.5%) were not vaccinated. Forty-four (21.5%) children were between 2 and 5months of age and had received 1-2vaccine doses. One hundred and seventeen (57%) children were fully vaccinated; 76.9% (90cases) had received the last dose less than 4years ago. When clinical manifestations of the fully vaccinated patients were compared with those of the non-vaccinated or incompletely-vaccinated children, only cyanosis was found with a higher frequency in the latter group (P<.001). The age-adjusted probability of hospitalisation was significantly associated with non-vaccination (P=.001). The case mortality rate among inpatients was 1.3%. CONCLUSIONS: The number of pertussis cases seen in our centre has risen significantly in the last year. More than half (57%) of the patients were fully vaccinated, and 76.9% had received the last dose in the previous 4years. Other vaccination strategies, such as vaccination of adolescents, adults, and pregnant women, as well as a cocoon strategy are required to protect infants under 6months of age. More effective vaccines need to be developed. PMID- 23725787 TI - [Myelomatous tubulopathy: the hope of a new drug]. PMID- 23725788 TI - Arousal from sleep pathways are affected by the prone sleeping position and preterm birth: preterm birth, prone sleeping and arousal from sleep. AB - OBJECTIVES: Preterm infants exhibit depressed arousability from sleep when compared with term infants. As the final cortical element of the arousal process may be the most critical for survival, we hypothesized that the increased vulnerability of preterm infants to the Sudden Infant Death Syndrome (SIDS) could be explained by depressed cortical arousal (CA) responses. We evaluated the effects of preterm birth on stimulus-induced arousal processes in both the prone and supine sleeping positions. STUDY DESIGN: 10 healthy preterm infants were studied with daytime polysomnography, in both supine and prone sleeping positions, at 36 weeks gestational age, 2-4 weeks, 2-3 months and 5-6 months post term corrected age. Sub-cortical activations and cortical arousals (CA) were expressed as proportions of total arousal responses. Preterm data were compared with data from 13 healthy term infants studied at the same corrected ages. RESULTS: In preterm infants increased CAs were observed in the prone position at all ages studied. Compared to term infants, preterm infants had significantly fewer CAs in QS when prone at 2-3 months of age and more CAs when prone at 2-4 weeks in AS. There were no differences in either sleep state when infants slept supine. CONCLUSIONS: Prone sleeping promoted CA responses in healthy preterm infants throughout the first six months of post-term age. We have previously suggested that in term infants enhanced CA represents a critical protection against a potentially harmful situation; we speculate that for preterm-born infants the need for this protection is greater than in term infants. PMID- 23725789 TI - Developmental effects of micronutrient supplementation and malaria in Zanzibari children. AB - BACKGROUND: Children's development is affected by the interplay of internal and external factors and changes in one factor can precipitate changes in multiple developmental domains. AIMS: The aim of this study was to test a theoretical model of children's development using structural equation modeling. STUDY DESIGN: This was designed as a substudy of a randomized, placebo-controlled, 2 * 2 factorial trial of the effects of daily supplementation with iron (12.5 mg) + folic acid (50 MUg) (FeFA) with or without zinc (10 mg) (Zn) on child mortality. SUBJECTS: Zanzibari children aged 5-9 mo (n = 106) and 10-14 mo (n = 141) at baseline were included in this sub study. OUTCOME MEASURES: Longitudinal data on children's hemoglobin, growth, malaria infection, motor development, motor activity, and language development and caregiver behavior were used to test the fit of the theoretical model for two age groups and to examine the direct and indirect relationships among the variables in the model. RESULTS: The theoretical models were a good fit to the data for both age groups and revealed that FeFA with or without Zn had positive effects on motor development. FeFA alone had negative effects on language development in both age groups and Zn alone had negative effects on language development in children aged 10-14 mo. The incidence of malaria had negative effects on the majority of health and development outcomes in children aged 5-9 mo, and on motor development and hemoglobin in children aged 10-14 mo. CONCLUSIONS: These findings illustrate how nutrition and health factors can affect different domains of development and how these changes can precipitate changes in other domains. More work is needed to better understand the multiple impacts of internal and external factors on children's development and how changes in developmental domains interact with each other over time to determine children's overall developmental trajectory. The randomized, placebo-controlled study was registered as an International Standard Randomized Controlled Trial, number ISRCTN59549825. PMID- 23725790 TI - GWAS of DNA methylation variation within imprinting control regions suggests parent-of-origin association. AB - Imprinting control regions (ICRs) play a fundamental role in establishing and maintaining the non-random monoallelic expression of certain genes, via common regulatory elements such as non-coding RNAs and differentially methylated regions (DMRs) of DNA. We recently surveyed DNA methylation levels within four ICRs (H19 ICR, IGF2-DMR, KvDMR, and NESPAS-ICR) in whole-blood genomic DNA from 128 monozygotic (MZ) and 128 dizygotic (DZ) human twin pairs. Our analyses revealed high individual variation and intra-domain covariation in methylation levels across CpGs and emphasized the interaction between epigenetic variation and the underlying genetic sequence in a parent-of-origin fashion. Here, we extend our analysis to conduct two genome-wide screenings of single nucleotide polymorphisms (SNPs) underlying either intra-domain covariation or parent-of-origin-dependent association with methylation status at individual CpG sites located within ICRs. Although genome-wide significance was not surpassed due to sample size limitations, the most significantly associated SNPs found through multiple-trait genome-wide association (MQFAM) included the previously described rs10732516, which is located in the vicinity of the H19-ICR. Similarly, we identified an association between rs965808 and methylation status within the NESPAS-ICR. This SNP is positioned within an intronic region of the overlapping genes GNAS and GNAS-AS1, which are imprinted genes regulated by the NESPAS-ICR. Sixteen other SNPs located in regions apart from the analyzed regions displayed suggestive association with intra-domain methylation. Additionally, we identified 13 SNPs displaying parent-of-origin association with individual methylation sites through family-based association testing. In this exploratory study, we show the value and feasibility of using alternative GWAS approaches in the study of the interaction between epigenetic state and genetic sequence within imprinting regulatory domains. Despite the relatively small sample size, we identified a number of SNPs displaying suggestive association either in a domain-wide or in a parent-of-origin fashion. Nevertheless, these associations will require future experimental validation or replication in larger and independent samples. PMID- 23725791 TI - Amino-functionalized mesostructured cellular foams as carriers of glucose oxidase. AB - The mesostructured cellular foams (MCFs) were synthesized in aqueous hydrochloric acid by using dilute Pluronic P123 solutions in the presence of 1,3,5 trimethylbenzene (TMB) as organic cosolvent. And the amino-functionalized MCFs (NH2-MCFs) were prepared from primary MCFs by post-synthesis method using 3 aminopropyl-trimethoxysilane (APTMS) as the chemical modifier. The SEM and TEM observations showed the similar morphologies and pore structures of both MCFs and NH2-MCFs, indicating that the surface modification had little effect on the morphologies and pore structures. Glucose oxidase (GOD) was physically adsorbed on MCFs and NH2-MCFs at different pH. The maximum immobilized amount of GOD on NH2-MCFs (487 mg g-1) was much higher than that of MCFs (216 mg g-1) at pH 5.0. The larger loading capacity of NH2-MCFs suggested that the electrostatic interaction was the dominant force for GOD adsorption. Furthermore, the immobilized GOD exhibited improved thermal and storable stabilities. The GOD immobilized on NH2-MCFs (NH2-MCFs-GOD) still maintained 80% of initial activity after incubation at 60 degrees C for 1 h, whereas the free GOD and the GOD immobilized on MCFs (MCFs-GOD) remained only 40% and 60%, respectively. Moreover, after stored at 4 degrees C for 30 days, the free GOD, the MCFs-GOD and the NH2 MCFs-GOD retained 37%, 52% and 73% of initial activities, respectively. Based on these results, possible mechanisms were also discussed. PMID- 23725792 TI - Influence of static alignment of the knee, range of tibial rotation and tibial plateau geometry on the dynamic alignment of "knee-in" and tibial rotation during single limb drop landing. AB - BACKGROUND: Dynamic alignment of "knee-in & toe-out" is a risk factor for anterior cruciate ligament injury and is possibly influenced by static knee alignment, range of tibial rotation and tibial plateau geometry. METHODS: Twenty eight healthy women were classified into valgus, neutral and varus groups based on static alignment of their knees. A 3-dimensional motion analysis was carried out for a single limb drop landing. The range of tibial rotation and posterior tibial slope angle was measured by MRI. Comparison among the 3 groups and correlation between the angles was analyzed during motion. FINDINGS: The differences between the medial and lateral posterior tibial slope angles were greater (P=0.019), also range of internal tibial rotation for the valgus group (P=0.017) and, for the varus group, the "knee-in" angle (P=0.048). The "knee-in" angle correlated significantly with the tibial rotation angle (R=-0.39, P=0.038), and the range of tibial rotation correlated with the variations between the medial and lateral posterior tibial slope angles (R=0.90, P=0.003). INTERPRETATION: The range of tibial rotation, posterior tibial slope and "knee in" angle varied according to whether the knee was in valgus or varus with the range of tibial rotation dependent on the posterior tibial slope angle. The greater the "knee-in" angle became, the smaller the internal tibial rotation was, acting in a kinetic chain. The results suggest that static alignment of the knee may be utilized as a predictor for potential problems that occur during motion. PMID- 23725793 TI - Metaanalysis of survival, complications, and imaging response following chemotherapy-based transarterial therapy in patients with unresectable intrahepatic cholangiocarcinoma. AB - PURPOSE: Unresectable intrahepatic cholangiocarcinoma represents a devastating illness with poor outcomes when treated with standard systemic therapies. Several smaller nonrandomized outcomes studies have been reported for such patients undergoing transarterial therapies. A metaanalysis was performed to assess primary clinical and imaging outcomes, as well as complication rates, following transarterial interventions in this patient population. MATERIALS AND METHODS: By using standard search techniques and metaanalysis methodology, published reports (published in 2012 and before) evaluating survival, complications, and imaging response following transarterial treatments for patients with unresectable intrahepatic cholangiocarcinoma were identified and evaluated. RESULTS: A total of 16 articles (N = 542 subjects) met the inclusion criteria and are included. Overall survival times were 15.7 months +/- 5.8 and 13.4 months +/- 6.7 from the time of diagnosis and time of first treatment, respectively. The overall weighted 1-year survival rate was 58.0% +/- 14.5. More than three fourths of all subjects (76.8%) exhibited a response or stable disease on postprocedure imaging; 18.9% of all subjects experienced severe toxicities (National Cancer Institute/World Health Organization grade >= 3), and most experienced some form of postembolization syndrome. Overall 30-day mortality rate was 0.7%. CONCLUSIONS: As demonstrated by this metaanalysis, transarterial chemotherapy-based treatments for cholangiocarcinoma appears to confer a survival benefit of 2-7 months compared with systemic therapies, demonstrate a favorable response by imaging criteria, and have an acceptable postprocedural complication profile. Such therapies should be strongly considered in the treatment of patients with this devastating illness. PMID- 23725794 TI - The relationship between plantar pressure and footprint shape. AB - Fossil footprints preserve the only direct evidence of the external foot morphologies and gaits of extinct hominin taxa. However, their interpretation requires an understanding of the complex interaction among foot anatomy, foot function, and soft sediment mechanics. We applied an experimental approach aimed at understanding how one measure of foot function, the distribution of plantar pressure, influences footprint topography. Thirty-eight habitually unshod and minimally shod Daasanach individuals (19 male, 19 female) walked across a pressure pad and produced footprints in sediment directly excavated from the geological layer that preserves 1.5 Ma fossil footprints at Ileret, Kenya. Calibrated pressure data were collected and three-dimensional models of all footprints were produced using photogrammetry. We found significant correlations (Spearman's rank, p < 0.0001) between measurements of plantar pressure distribution and relative footprint depths at ten anatomical regions across the foot. Furthermore, plantar pressure distributions followed a pattern similar to footprint topography, with areas of higher pressure tending to leave deeper impressions. This differs from the results of experimental studies performed in different types of sediment, supporting the hypothesis that sediment type influences the relationship between plantar pressure and footprint topography. Our results also lend support to previous interpretations that the shapes of the Ileret footprints preserve evidence of a medial transfer of plantar pressure during late stance phase, as seen in modern humans. However, the weakness of the correlations indicates that much of the variation in relative depths within footprints is not explained by pressure distributions under the foot when walking on firm ground, using the methods applied here. This warrants caution when interpreting the unique foot anatomies and foot functions of extinct hominins evidenced by their footprint structures. Further research is necessary to clarify how anatomical, functional, and sedimentary variables influence footprint formation and how each can be inferred from footprint morphology. PMID- 23725795 TI - Reducing the risk of hyperammonemia from transfusion of stored red blood cells. AB - Ammonia concentration increases in red cell units (RBCs) during storage. We measured absolute amounts of ammonia (AA) per unit serially in stored RBCs and before and after removal of the supernatant by volume reduction (VR) or washing. Ammonia increased 6.4-fold in untreated units over 31 days. VR decreased AA 3.7 fold, whereas washing decreased it 38-fold (p<0.0001). At least for certain patients, e.g., infants receiving large volume transfusions and patients in liver failure, it may be advisable to use RBCs as fresh as possible and to limit infusion (by VR or washing) of ammonia in the supernatant. PMID- 23725796 TI - [Reactive arthritis]. PMID- 23725798 TI - Foundational concepts of cell fate conversion to the hematopoietic lineage. AB - Direct conversion of cellular fate provides a potential approach to generate cells of the hematopoietic lineage without the requisite reversion to a pluripotent state via somatic cell reprogramming. The utilization of this technology has enabled transcription factor-mediated conversion of somatic cell types to primitive and mature hematopoietic cells. Recent studies demonstrate that the direct conversion of somatic cells to the hematopoietic lineage likely requires the use of pioneer transcription factors to establish an accessible chromatin state that is responsive to enforced expression of hematopoietic specific transcription factors, in combination with appropriate culture conditions that facilitate reprogramming. Developing adaptable, experimental strategies that incorporate these parameters should enable the efficient generation of human hematopoietic cells with translational potential. PMID- 23725799 TI - Morphogen interpretation: the transcriptional logic of neural tube patterning. AB - The spatial organization of cell fates in developing tissues often involves the control of transcriptional networks by morphogen gradients. A well-studied example of this is the Sonic-hedgehog (Shh) controlled pattern of neuronal subtype differentiation in the vertebrate neural tube. Here we discuss recent studies involving genome wide analyses, functional experiments and theoretical models that have begun to characterise the molecular logic by which neural cells interpret Shh signalling. The view that emerges from this work is that cell identity results from the combined input of Shh signalling, uniformly expressed neural factors and the cross-regulatory network of downstream Shh target genes. A similar logic is also likely to underpin the patterning of many developing tissues. PMID- 23725800 TI - The balancing act of DNA repeat expansions. AB - Expansions of microsatellite DNA repeats contribute to the inheritance of nearly 30 developmental and neurological disorders. Significant progress has been made in elucidating the molecular mechanisms of repeat expansions using various model organisms and mammalian cell culture, and models implicating nearly all DNA transactions such as replication, repair, recombination, and transcription have been proposed. It is likely that different models of repeat expansions are not mutually exclusive and may explain repeat instability for different developmental stages and tissues. This review focuses on the contributions from studies in budding yeast toward unraveling the mechanisms and genetic control of repeat expansions, highlighting similarities and differences of replication models and describing a balancing act hypothesis to account for apparent discrepancies. PMID- 23725801 TI - Hedgehog signaling from the primary cilium to the nucleus: an emerging picture of ciliary localization, trafficking and transduction. AB - The unexpected connection between cilia and signaling is one of the most exciting developments in cell biology in the past decade. In particular, the Hedgehog (Hh) signaling pathway relies on the primary cilium to regulate tissue patterning and homeostasis in vertebrates. A central question is how ciliary localization and trafficking of Hh pathway components lead to pathway activation and regulation. In this review, we discuss recent studies that reveal the roles of ciliary regulators, components and structures in controlling the movement and signaling of Hh players. These findings significantly increase our mechanistic understanding of how the primary cilium facilitates Hh signal transduction and form the basis for further investigations to define the function of cilia in other signaling processes. PMID- 23725802 TI - Discovery of biomarkers of endometrial receptivity through a minimally invasive approach: a validation study with implications for assisted reproduction. AB - OBJECTIVE: To determine whether a minimally invasive approach to sampling endometrial cells that can be applied during an active conception cycle can generate robust biomarker candidates for endometrial receptivity by genomewide gene expression profiling. DESIGN: Longitudinal study comparing gene expression profiles of cells isolated from uterine aspirates collected during the prereceptive and receptive phases of a natural cycle. SETTING: University affiliated hospital. PATIENT(S): Healthy volunteers, <=40 years of age, with regular menstrual cycles and no history of infertility. INTERVENTION(S): One menstrual cycle monitored with urinary kits to identify the luteinizing hormone (LH) surge; uterine aspirations collected at LH + 2 days (LH + 2) and at LH + 7; endometrial biopsy obtained on LH + 7; RNA extraction from the cellular material for gene expression profiling, and differential gene expression validated by NanoString assay and cross-validated against a publically available data set. MAIN OUTCOME MEASURE(S): Differentially expressed genes between LH + 2 and LH + 7 samples. RESULT(S): NanoString assay validated 96% of the 245 genes found differentially expressed at LH + 7. Unsupervised hierarchical clustering of aspiration and biopsy samples demonstrated the concordance of the sampling methods. A predictor gene cassette derived by a shrunken centroid class prediction technique correctly classified the receptive phase within an external data set. CONCLUSION(S): Uterine aspiration, which can be performed during an active conception cycle, identified robust candidate biomarkers of endometrial receptivity, and will enable their validation by direct correlation with clinical outcomes. PMID- 23725803 TI - Is neonatal uterine bleeding involved in the pathogenesis of endometriosis as a source of stem cells? PMID- 23725804 TI - Comprehensive chromosome screening alters traditional morphology-based embryo selection: a prospective study of 100 consecutive cycles of planned fresh euploid blastocyst transfer. AB - OBJECTIVE: To determine how often trophectoderm biopsy and rapid, real-time quantitative polymerase chain reaction (PCR)-based comprehensive chromosome screening (CCS) alters clinical management by resulting in the transfer of a different embryo than would have been chosen by traditional day 5 morphology based criteria. DESIGN: Prospective. SETTING: Academic center for reproductive medicine. PATIENT(S): Infertile couples (n = 100; mean age 35 +/- 4 years) with at least two blastocysts suitable for biopsy on day 5. INTERVENTION(S): Prior to trophectoderm biopsy for CCS the embryologist identified which embryo would have been selected for traditional day 5 elective single ET. MAIN OUTCOME MEASURE(S): The risk of aneuploidy in the embryos that would have been selected on day 5 was calculated and compared with the aneuploidy rate of the cohort of all embryos that underwent CCS testing. The aneuploidy risk was compared between age groups. RESULT(S): After quantitative PCR-based CCS, 22% (95% confidence interval 15% 31%) of the embryos selected by day 5 morphology were aneuploid, which was lower than the 32% aneuploidy rate of the cohort. Patients >=35 years had a higher risk of an aneuploid blastocyst being selected by morphology than those <35 years old (31% vs. 14%). Among patients who had selection altered by CCS, 74% (14/19) delivered, including 77% (10/13) after elective single ET. Most patients (77%) had an additional euploid blastocyst vitrified for future use. CONCLUSION(S): The CCS results alter embryo selection due to the presence of aneuploidy in embryos with optimal day 5 morphology. Excellent outcomes were obtained when CCS-based selection was different than morphology-based selection. PMID- 23725805 TI - Costa Rica's absolute ban on in vitro fertilization deemed a human rights violation: implications for U.S. assisted reproductive technology policy and "personhood" initiatives. PMID- 23725806 TI - Affordable in vitro fertilization. PMID- 23725807 TI - Preliminary inferences on the age-specific seriousness of human disease caused by avian influenza A(H7N9) infections in China, March to April 2013. AB - Between 31 March and 21 April 2013, 102 laboratory-confirmed influenza A(H7N9) infections have been reported in six provinces of China. Using survey data on age specific rates of exposure to live poultry in China, we estimated that risk of serious illness after infection is 5.1 times higher in persons 65 years and older versus younger ages. Our results suggest that many unidentified mild influenza A(H7N9) infections may have occurred, with a lower bound of 210-550 infections to date. PMID- 23725808 TI - A major outbreak of gastroenteritis in Reunion Island in 2012: first identification of G12 rotavirus on the Island. AB - Between August and November 2012 a severe outbreak of gastroenteritis occurred on Reunion Island, affecting more than 50,000 cases, particularly young children. Virological analyses showed that the virus responsible for this epidemic was rotavirus. Genotyping of stool samples indicated circulation of rotavirus type G3P[8] but also G12P[8], highlighting the risk of global emergence of this genotype in the coming years. PMID- 23725809 TI - Unusual increase of psittacosis in southern Sweden linked to wild bird exposure, January to April 2013. AB - Free-living wild birds worldwide act as reservoir for Chlamydia psittaci, but the risk of transmission to humans through contact with wild birds has not been widely documented. From 12 January to April 9 2013, a total of 25 cases of psittacosis were detected in southern Sweden, about a threefold increase compared with the mean of the previous 10 years. A matched case-control study investigating both domestic and wild bird exposure showed that cases were more likely than controls to have cleaned wild bird feeders or been exposed to wild bird droppings in other ways (OR: 10.1; 95% CI: 2.1-47.9). We recommend precautionary measures such as wetting bird feeders before cleaning them, to reduce the risk of transmission of C. psittaci when in contact with bird droppings. Furthermore, C. psittaci should be considered for inclusion in laboratory diagnostic routines when analysing samples from patients with atypical pneumonia, since our findings suggest that psittacosis is underdiagnosed. PMID- 23725811 TI - Treatment of a left anterior descending artery chronic total occlusion using a bio-absorbable scaffold, utilising optical coherence tomography. PMID- 23725812 TI - Let's talk about change, cardiac troponin deltas: a step in the right direction. PMID- 23725813 TI - Baicalin pretreatment protects against myocardial ischemia/reperfusion injury by inhibiting mitochondrial damage-mediated apoptosis. PMID- 23725814 TI - Prognostic implication of atrial pressures in patients with nonvalvular atrial fibrillation and preserved systolic function who undergo radiofrequency catheter ablation: a pilot study. PMID- 23725815 TI - Usefulness of neutrophil/lymphocyte ratio in predicting early recurrence after radiofrequency catheter ablation in patients with atrial fibrillation. PMID- 23725816 TI - Response to the letter regarding the article, "late gadolinium enhancement on cardiac magnetic resonance images predicts reverse remodeling in patients with nonischemic cardiomyopathy treated with carvedilol". PMID- 23725817 TI - An elevated cibenzoline level interacted with cyclosporine caused ventricular tachyarrhythmia and high defibrillation threshold in hypertrophic cardiomyopathy. PMID- 23725818 TI - Barley stripe mosaic virus: structure and relationship to the tobamoviruses. AB - Barley stripe mosaic virus (BSMV) is the type member of the genus Hordeivirus, rigid, rod-shaped viruses in the family Virgaviridae. We have used fiber diffraction and cryo-electron microscopy to determine the helical symmetry of BSMV to be 23.2 subunits per turn of the viral helix, and to obtain a low resolution model of the virus by helical reconstruction methods. Features in the model support a structural relationship between the coat proteins of the hordeiviruses and the tobamoviruses. PMID- 23725819 TI - A novel endogenous betaretrovirus group characterized from polar bears (Ursus maritimus) and giant pandas (Ailuropoda melanoleuca). AB - Transcriptome analysis of polar bears (Ursus maritimus) yielded sequences with highest similarity to the human endogenous retrovirus group HERV-K(HML-2). Further analysis of the polar bear draft genome identified an endogenous betaretrovirus group comprising 26 proviral copies and 231 solo LTRs. Molecular dating indicates the group originated before the divergence of bears from a common ancestor but is not present in all carnivores. Closely related sequences were identified in the giant panda (Ailuropoda melanoleuca) and characterized from its genome. We have designated the polar bear and giant panda sequences U. maritimus endogenous retrovirus (UmaERV) and A. melanoleuca endogenous retrovirus (AmeERV), respectively. Phylogenetic analysis demonstrated that the bear virus group is nested within the HERV-K supergroup among bovine and bat endogenous retroviruses suggesting a complex evolutionary history within the HERV-K group. All individual remnants of proviral sequences contain numerous frameshifts and stop codons and thus, the virus is likely non-infectious. PMID- 23725820 TI - Integrating psychology and medicine in CPAP adherence--new concepts? AB - To date, continuous positive airway pressure (CPAP) is the most effective intervention in the treatment of obstructive sleep apnoea, but adherence to this treatment is often less than optimal. A variety of factors and interventions that influence and improve CPAP use have been examined. There is increasing recognition of the multifaceted nature of CPAP adherence: the patient's psychological profile and social environment have been recognised, in addition to the more extensively researched patient's treatment and physiological profile. Understanding how these multiple factors impact on CPAP use in an integrative fashion might provide us with a useful holistic model of CPAP adherence. This concept of integration--a biopsychosocial (BPS) approach to health and illness- has previously been described to understand care provision for various chronic health disorders. This paper proposes an adherence framework, whereby variables integrally affect CPAP use. The BPS model has been considered for nearly 35 years; the presence of poor CPAP adherence was acknowledged in the early 1990s- it is timely to incorporate this approach into our care pathway of CPAP users. PMID- 23725821 TI - Cycads and their association with certain neurodegenerative diseases. AB - INTRODUCTION: Cycads are ornamental plants that in some parts of the world are used as fresh food or raw material for producing flour with a high nutritional value. However, they also contain active compounds, including methylazoxymethanol, beta-methylamino-L-alanine, beta-alanine-L-oxalylamino and cycasin, which may produce neurotoxic effects. Some studies have associated consuming cycads and their derivatives with neurodegenerative diseases such as amyotrophic lateral sclerosis/Parkinsonism dementia complex, and other diseases characterised by motor impairment. Therefore, we must not forget that any product, no matter how natural, may present health risks or benefits depending on the chemical compounds it contains and the susceptibility of those who consume it. DEVELOPMENT: We completed a literature analysis to evaluate the neurotoxic properties of cycads and their association with neurological diseases in order to provide structured scientific information that may contribute to preventing health problems in people who use these plants. CONCLUSION: Cycads contain neurotoxic compounds that may contribute to the development of neurological diseases when ingested improperly. We must be mindful of the fact that while some plants have a high nutritional value and may fill the food gap for vulnerable populations, they can also be toxic and have a negative impact on health. PMID- 23725822 TI - Nutrias and muskrats as bioindicators for the presence of Echinococcus multilocularis in new endemic areas. AB - Nutrias (Myocastor coypus) and muskrats (Ondatra zibethicus) are large invasive semi-aquatic or aquatic rodents, naturalized throughout Europe. They are regarded as pests, and can be infected with several pathogens and parasites transmissible to wildlife, livestock, pets and humans. As a rule, in Europe the life cycle of the cestode Echinococcus multilocularis involves red foxes (Vulpes vulpes) as main definitive hosts and common voles as intermediate hosts. The suitability of nutrias and muskrats as intermediate hosts has already been described. Here, we investigate the occurrence of E. multilocularis in the context of a wide-scale health study on nutrias and muskrats in 12 "departements" in the western part of France. During the sampling period, a total of 817 aquatic rodents were trapped in five rivers or ponds in each "departements". During post-mortem examinations, lesions were observed on the livers of 21 nutrias and 104 muskrats, and analyzed by PCR and sequencing of the mitochondrial cox1 gene for specific identification. Several non-zoonotic parasites were identified: Taenia taeniaformis, Taenia mustelae, Taenia polyacantha and Taenia martis. Four livers from 2 nutrias and 2 muskrats exhibited E. multilocularis infection. One of the muskrats was infected with fertile E. multilocularis lesions. The 4 animals came from 3 French "departements" where foxes have recently been found to be infected by E. multilocularis. These results lead us to consider nutrias and muskrats as relevant bioindicators for the presence of E. multilocularis in this environment. Our results also suggest that, when listed as pests and targeted by large trapping campaigns, nutrias and muskrats could be used to detect the presence of E. multilocularis in areas considered free of this parasite. PMID- 23725823 TI - Multidetector CT investigation of the mummy of Rosalia Lombardo (1918-1920). AB - Whole-body multidetector computed tomography (CT) was performed on the mummified corpse of two-year-old Rosalia Lombardo, an anthropogenic mummy displayed in the Capuchin Catacombs of Palermo, Sicily, Italy. Rosalia Lombardo reportedly died of bronchopneumonia in 1920 and was preserved by the embalmer and taxidermist Alfredo Salafia with a formaldehyde-based fluid. Rosalia Lombardo's body is still exhibited in the Capuchin Catacombs inside the original glass-topped coffin in which she was placed. Only her head is visible: the rest of her body is covered by a sheet. CT images of Rosalia's body within her coffin were of reduced quality because of distinct metal artifacts caused by the coffin itself. Nevertheless, a detailed radiological analysis was possible for most of the body. Analysis of the data from the CT examination revealed indicators for the historically-reported endovasal and intracavity treatment. Rosalia's entire body was preserved in a remarkable state. The exceptional preservation of her internal organs made it possible to consider a radiological diagnosis of pneumonia. For this study, CT was determined to be the ultimate method for investigation, since Rosalia's body had to be kept untouched in her sealed coffin for conservation purposes. The CT examination offered new insights into the current preservation status of the body, and the superior contrast of CT allowed detailed assessment of different tissues. Post-processing methods provided reconstructions on any desired plane, as well as three-dimensional reconstruction, for the best possible visualization and interpretation of the body. PMID- 23725824 TI - Antiseptic phobia in a patient experiencing anesthesia awareness during cleft palate repair surgery: a case report. AB - Specific phobia is an excessive and irrational fear often triggered by a stressor. Among different types of phobias arising in medical settings, we could not find any case reported for exclusively antiseptic fluids without any medical surgical intervention. The term "anesthesia awareness" (AA) signifies the specific surgical period of time when an individual, in spite of being under intended general anesthesia, remains aware of the sensory stimuli and the memories of which also remain available for his subsequent explicit recall in the future. According to the "American Society of Anesthesiologists Practice Advisory", it is explicit recall during general anesthesia. Its hallmark is the presence of awareness of the events going on during the surgical procedure while being under a general anesthesia. AA is a distressing condition with immediate and long-term consequences. In spite of an estimated prevalence of 0.1%-0.2% of all the surgeries, our knowledge about this condition is limited. The most commonly reported consequences of AA are acute painful flashbacks of surgical events along with the emotional turmoil and a sense of helplessness followed later by posttraumatic stress disorder. Here, we report a unique case of occurrence of "antiseptic-phobia" in a patient following the experience of anesthesia awareness during cleft palate repair surgery. PMID- 23725825 TI - Population level effectiveness of implementing collaborative care management for depression. AB - OBJECTIVE: Care management is feasible to deploy in routine care, and the depression outcomes of patients reached by this evidence-based practice are similar to those observed in randomized controlled trials. However, no studies have estimated the population level effectiveness of care management when deployed in routine care. Population level effectiveness depends on both reach into the target population and the clinical effectiveness for those reached. METHOD: This multisite hybrid Type 3 effectiveness-implementation study employed a pre-post, quasi-experimental design. The study was conducted at 22 Veterans Affairs community-based outpatient clinics. Evidence-based quality improvement was used as the facilitation strategy to promote adoption. Medication possession ratios (MPRs) were calculated for 1558 patients with an active antidepressant prescription. Differences in treatment response rates at implementation and control sites were estimated from observed differences in MPR. RESULTS: Reach into the target population at implementation sites was 10.3%. Patients at implementation sites had a significantly higher probability of having MPR>=0.9 than patients at control sites [odds ratio=1.38, confidence interval95=(1.07, 1.78), P=.01]. This increase in MPR was estimated to yield a 1% point increase in response rates. CONCLUSIONS: While depression care management improves outcomes for patients receiving services, low levels of reach can reduce overall population level effectiveness. PMID- 23725826 TI - Cutaneous metastases of laryngeal chondrosarcoma. PMID- 23725827 TI - Contribution of the six major gait determinants on the vertical center of mass trajectory and the vertical ground reaction force. AB - Saunders et al. (1953) stated that the introduction of six gait determinants (pelvic rotation, pelvic obliquity, stance knee flexion, foot and ankle mechanisms, and tibiofemoral angle) to a compass gait model (two rigid legs hinged at the hips) provides an accurate simulation of the actual trajectory of the whole body center of mass (CoM). Their respective actions could also explain the shape of the vertical ground reaction force (GRF) pattern. Saunders' approach is considered as a kinematic description of some features of gait and is subject to debate. The purpose of this study is to realize a rigorous mechanical evaluation of the gait determinants theory using an appropriated mathematical model in which specific experimental data of gait trials are introduced. We first simulate a compass-like CoM trajectory using the proposed 3D mathematical model. Then, factorizing the model to introduce successively the kinematic data related to each gait determinant, we assess their respective contribution to both the CoM trajectory and the pattern of vertical GRF at different gait speeds. The results show that the stance knee flexion significatively decreases the estimated position of the CoM during midstance. Stance knee extension and pelvic obliquity contribute to the appearance of the pattern of vertical GRF during stance. The stance ankle dorsiflexion significatively contributes to CoM vertical excursion and the ankle plantarflexion contributes to the vertical GRF during terminal stance. The largest contribution towards the minimization of the CoM vertical amplitude during the complete gait step appears when considering the foot mechanisms and the pelvic obliquity in the proposed model. PMID- 23725828 TI - Velocity-dependent changes of rotational axes during the control of unconstrained 3D arm motions depend on initial instruction on limb position. AB - The velocity-dependent change in rotational axes observed during the control of unconstrained 3D arm rotations may obey the principle of minimum inertia resistance (MIR). Rotating the arm around the minimum inertia tensor axis (e3) reduces the contribution of muscle torque to net torque by employing interaction torque. The present experiment tested whether the MIR principle still governs rotational movements when subjects were instructed to maintain the humeral long axis (SH-EL) as closely as possible to horizontal. With this view, the variability of 3D trajectories of the minimum inertia axis (e3), shoulder-center of mass axis (SH-CM) and shoulder-elbow axis (SH-EL) was quantified using a VICON V8i motion capture system. The axis for which the 3D variability displacement is minimal is considered as the one constraining the control of arm rotation. Subjects (n=15) rotated their arm in two elbow angular configurations (Elb90 degrees vs. Elb140 degrees ), two angular velocity conditions (slow S vs. fast F), and two sensory conditions (kinaesthetic K vs. visuo-kinaesthetic VK). The minimum inertia axis e3 is angled 5.4 degrees away from SH-CM axis, and varied from 27 degrees to 15 degrees away from de SH-EL axis, for Elb90 degrees and Elb140 degrees , respectively. We tested whether the participants would be able to maintain the instructed SH-EL rotation axis or if increasing the frequency of the arm rotations would override the initial rotation instructions and cause the limb to rotate around an axis closely aligned with e3. We expected that VK inputs would minimize the variability of the SH-EL axis and that K should facilitate the detection and rotation around e3 at the faster velocity. Taken together the results showed that the initial instruction, favoring rotation around the SH-EL axis, prevented the velocity-dependent change towards the minimum inertia (e3) and/or the mass axis (SH-CM), i.e., use of the MIR principle. However, the variability of the SH-EL axis was significantly increased in the F condition, confirming that arm rotations around the SH-EL axis produces larger mechanical instabilities in comparison to when the arm is rotated around a mass/inertial axis (Isableu et al., 2009). PMID- 23725829 TI - Determination of the absolute configuration of natural products. AB - Structural elucidation of natural products is always one of the most important tasks for natural product researchers in related fields. Particularly, the absolute configuration (AC), being a great challenge for natural product chemists, has attracted much attention. During the past few decades, many techniques and approaches have been developed to determine the AC of natural products, including direct (or absolute) methods, e.g. X-ray diffraction (XRD), electronic and vibrational circular dichroism (ECD and VCD), and Raman optical activity (ROA), as well as indirect (or relative) methods using a reference or a derivatizing agent with known AC, e.g. CD with empirical rules and nuclear magnetic resonance (NMR) utilizing anisotropic effects of chiral derivatizing agents. However, none of the currently applied techniques is capable of dominating AC determination, since they each have their respective limitations corresponding to the different structural features. This mini review summarizes most of the techniques and methods which are commonly used in AC assignment of natural products, or have potential application prospects, and briefly describes their principles, advantages and limitations. PMID- 23725830 TI - Hybanthus enneaspermus (L.) F. Muell: a concise report on its phytopharmacological aspects. AB - Hybanthus enneaspermus (L.) F. Muell belonging to the family Violaceae, popularly known as Ratanpurus (Hindi) is a herb or a shrub distributed in the tropical and subtropical regions of the world. In the Ayurvedic literature, the plant is reported to cure conditions of "Kapha" and "Pitta", urinary calculi, strangury, painful dysentery, vomiting, burning sensation, wandering of the mind, urethral discharge, blood trouble, asthma, epilepsy, cough, and to give tone to the breasts. Phytochemically, the plant contains a considerable amount of dipeptide alkaloids, aurantiamide acetate, isoarborinol, and beta-sitosterol, sugars, flavonoids, steroids, triterpenes, phenols, flavones, catachins, tannins, anthraquinones and amino acids. Pharmacologically, the plant is reported to possess antidiabetic, antiplasmodial, antimicrobial, anticonvulsant, nephroprotective, aphrodisiac, hepatoprotective, antiinflammatory, aldose reductase inhibitory and free radical scavenging activities. The information provided in this review will be worthwhile to know the applicability of H. enneaspermus for the treatment of various acute or chronic diseases with a diverse nature of phytoconstituents. The overall data in this review article were collected from various scientific sources on the research of H. enneaspermus. PMID- 23725831 TI - Pinocembrin protects rats against cerebral ischemic damage through soluble epoxide hydrolase and epoxyeicosatrienoic acids. AB - AIM: To investigate the relationship between cerebroprotection of pinocembrin and epoxyeicosatrienoic acids (EETs) and their regulating enzyme soluble epoxide hydrolase (sEH). METHODS: Rats underwent middle cerebral artery occlusion (MCAO) to mimic permanent focal ischemia, and pinocembrin was administrated via tail vein injection at 10 min, 4 h, 8 h and 23 h after MCAO. After 24 MCAO, rats were re-anesthetized, and the blood and brain were harvested and analyzed. RESULTS: Pinocembrin displayed significant protective effects on MCAO rats indicated by reduced neurological deficits and infarct volume. Importantly, co-administration of 0.2 mg.kg(-1) 14, 15-EEZE, a putative selective EET antagonist, weakened the beneficial effects of pinocembrin. 14, 15-EET levels in the blood and brain of rats after 24 h MCAO were elevated in the presence of pinocembrin. In an assay for hydrolase activity, pinocembrin significantly lowered brain sEH activity of MCAO rats and inhibited recombinant human sEH activity in a concentration dependent manner (IC50, 2.58 MUmol.L(-1)). In addition, Western blot and immunohistochemistry analysis showed that pinocembrin at doses of 10 mg.kg(-1) and 30 mg.kg(-1) significantly down-regulated sEH protein in rat brain, especially the hippocampus CA1 region of MCAO rats. CONCLUSION: Inhibiting sEH and then increasing the potency of EETs may be one of the mechanisms through which pinocembrin provides cerebral protection. PMID- 23725832 TI - Wuling san ameliorates urate under-excretion and renal dysfunction in hyperuricemic mice. AB - AIM: The present study was undertaken to characterize the effects of Wuling San on urate excretion and renal function, and explore its possible mechanisms of action in hyperuricemic mice. METHODS: Mice were administered with 250 mg.kg(-1) potassium oxonate by gavage once daily (10 animals/group) for seven consecutive days to develop a hyperuricemia model. Different doses of Wuling powder were orally initiated on the day 1 h after oxonate was given, separately. Allopurinol was used as a positive control. Serum and urine levels of uric acid and creatinine, and fractional excretion of uric acid (FEUA) were measured in hyperuricemic mice treated with Wuling San and allopurinol. Simultaneously, renal mRNA and protein levels of urate transporter 1 (mURAT1), glucose transporter 9 (mGLUT9), organic anion transporter 1 (mOAT1), as well as organic cation/carnitine transporters mOCT1, mOCT2 and mOCTN2, were assayed by semi quantitative RT-PCR and Western blot methods, respectively. RESULTS AND CONCLUSION: Compared to the hyperuricemia control group, Wuling San significantly reduced serum uric acid and creatinine levels, increased 24 h urate and creatinine excretion, and FEUA in hyperuricemic mice, exhibiting its ability to enhance urate excretion and improve kidney function. Wuling San was found to down regulate mRNA and protein levels of mURAT1 and mGLUT9, as well as up-regulate mOAT1 in the kidney of hyperuricemic mice. Moreover, Wuling San up-regulated renal mRNA and protein levels of mOCT1, mOCT2 and mOCTN2, leading to kidney protection in this model. PMID- 23725833 TI - Protective effects of shengmai san and its three fractions on cerebral ischemia reperfusion injury. AB - AIM: To investigate the antioxidant and anti-inflammatory effects of Shengmai San (SMS) and its ethyl acetate extract (SEa), n-butanol extract (SBu), and aqueous extract (SWe), and clarify the material base of SMS and the roles played by its fractions. METHODS: A mouse model of transient forebrain ischemia/reperfusion (I/R) by means of common carotid artery occlusion (CCAO) was used to investigate the effects of SMS and its three fractions. Histopathological damage, blood-brain barrier disruption, and antioxidant and inflammation-related parameters, including malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GPx), myeloperoxidase (MPO), nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha) were measured. The chemical constituents of each fraction were identified by LC-MS. RESULTS: Eighteen lignans in SEa, and thirteen steroidal glycosides and ginsenosides in SBu were determined. SMS significantly inhibited I/R induced formation of histological injury and cerebral MPO activity. SMS showed the strongest antioxidant and anti-inflammatory effects against the I/R caused injuries. SEa showed higher antioxidant activity than the other two fractions and SBu has a slightly stronger inhibition on the productions of NO and TNF-alpha. CONCLUSION: SMS as a whole had the most effective protection against cerebral I/R-caused injuries compared with its fractions, which inferred that it contains different groups of compounds that contribute together to its protective effect. PMID- 23725834 TI - Euphorbia kansui roots induced-diarrhea in mice correlates with inflammatory response. AB - AIM: Euphorbia kansui (E. KS) is a traditional medicine used in China for thousands of years with the effect of propulsion in the gastrointestines. However, there is no reported study of E. KS on gastrointestinal motility until now. The aim of this work is to study the effect of E. KS on the propulsion of gastrointestines, and to elucidate the possible mechanism of action. METHODS: E.KS was prepared as a 30% ethanol extract and used for the experiment of small and large intestines of mice by oral administration with three different dosages (1.2, 0.6 and 0.3 g.kg(-1)). The feces were observed in vivo. The morphology was carried out to detect if there are any changes in the intestines after the extract of E. KS administration. The assays of mRNA and protein expression were employed to observe IL-1beta, TNFalpha and caspase 3. RESULTS: It was shown that the extract of E.KS promoted diarrhea in mouse feces after administration, inhibited the contraction of smooth muscle of mouse small intestine and caused the inflammatory exudation on the mucosa of the intestines, enhanced the expression of both mRNA and the protein levels of IL-1beta and TNFalpha in the small or large intestines. CONCLUSION: The results showed that the extract of E. KS acted on the intestinal smooth muscle with propulsion of feces involving the irritation of the intestines with acute inflammatory reactions. PMID- 23725835 TI - Anti-anxiety activity of Stachys tibetica Vatke. AB - AIM: S. tibetica Vatke is a herb distributed in the tropical and subtropical regions of the world, including Tibet, China, and India. In India it is found in the cold desert regions of Kargil, Ladakh Valley, and in the mountains of Himachal Pradesh. The traditional practitioners in the Kargil and Ladakh use the natural medicine Stachys tibetica for the treatment of various mental disorders and phobias. The present study is aimed at evaluating the anxiolytic effects of the methanolic extract of the root, stem, leaf, and whole plant material of Stachys tibetica Vatke in rats. METHODS: Powdered materials (1 kg) of each plant part were subjected to extraction in a Soxhlet apparatus with methanol (95%); to yield 12.8%, 8.3%, 17.2%, and 19.6% W/W extractives, respectively. Extracts were evaluated for their anxiolytic effects using the elevated plus maze (EPM) test in rats. RESULTS: In the present study, it was found that the methanolic extracts (200 and 400 mg.kg(-1)) of the root, stem, leaf and whole plant of Stachys tibetica Vatke and diazepam (DZ) increased the time spent and the number of entries in the open arm significantly (**P < 0.01), while they decreased the time spent and the number of entries in the closed arm. At the same time, all of the extracts and DZ decreased the time spent at the center of the maze (latency), along with closed arm returns. The head dip counts increased significantly in the rats treated with DZ, SMR400, SML400 and SMW400 in the open arm of EPM, which was a sign of reduction anxiety. The DZ and SMW did not show the fecal bolus, while other groups had reduced fecal bolus (**P < 0.01) as compared to control. These allied parameters helped to assess the anxiolytic potential of Stachys tibetica Vatke. Whole plant and leaf materials have shown the maximum activity, the root intermediate while the stem had the least anxiolytic activity (*P < 0.05, **P < 0.01) in EPM. CONCLUSION: The results strongly justify the use of this plant for the treatment of anxiety. Further studies are in progress in this laboratory to isolate and identify the components responsible for the anxiolytic activity and the mechanism of action involved. PMID- 23725836 TI - Treatment with EGCG in NSCLC leads to decreasing interstitial fluid pressure and hypoxia to improve chemotherapy efficacy through rebalance of Ang-1 and Ang-2. AB - AIM: Microvasculature and microenvironment play important roles in proliferation, invasion, metastasis and prognosis in non-small cell lung cancer (NSCLC), which might be altered by many anti-angiogenic drugs. Epigallocatechin-3-gallate (EGCG), a natural anti-angiogenesis agent refined from green tea, was defined to have multiple effects on angiogenesis factors, such as endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and angiopoietins (ANGs). Hypothesizing that EGCG might regulate microvasculature and microenvironment in NSCLC, the effects of EGCG on microvessel density (MVD), expression of Ang-1 and Ang-2, interstitial fluid pressure (IFP), tumor hypoxia, and chemotherapy sensitivity were examined. METHODS AND RESULTS: EGCG treatment of A549 cells in mice bearing xenografts in vivo led to a significant decrease of MVD detected by CD31, and of Ang-2 expression detected by quantum dots double-label immunofluorescence assessment, while Ang-1 decreased with no significance. Decreased IFP was measured by the Wink-in-needle method, while hypoxia was assessed by polarographic electrode and pimonidazole (PIMO) immunohistochemistry. Assuming that these changes would increase response to chemotherapy, tumor growth studies were p[erformed in nude mice with xenografts, which were then treated with EGCG and the chemotherapeutic agent cisplatin. EGCG therapy combined with cisplatin led to synergistic inhibition of tumor growth, compared with administration of each treatment separately (P < 0.001). According to linear regression analysis, IFP was positively correlated with PIMO staining (R(2) = 0.618, P = 0.002), Ang-2 was correlated with MVD (R(2) = 0.423, P = 0.022), IFP (R(2) = 0.663, P = 0.01) and PIMO staining (R(2) = 0.694, P = 0.01). CONCLUSION: IFP and delivery of oxygen might be improved by rebalance of Ang-1/Ang-2 under the treatment of EGCG in NSCLC, which also acts as a sensitizer of chemotherapy. These studies established a new mechanism for using EGCG as an adjuvant chemotherapy agent through modifying microvasculature and microenvironment. PMID- 23725837 TI - Effects of salvianolic acid and notoginseng triterpenes on angiogenesis in EA hy926 cells in vitro. AB - AIM: To investigate the different effects of salvianolic acid and notoginseng triterpenes on proliferation, angiogenesis and expression of vascular endothelial growth factor in EA-hy926 cells in vitro. METHODS: EA-hy926 cells were cultured in vitro. Salvianolic acid and notoginseng triterpenes at concentrations of 0.4, 0.8 and 1.2 mg.L(-1) were used to culture EA-hy926 cells. EA-hy926 cells in a blank control group were grown in culture solution only. Viability of cells was assessed by CCK-8, and after treated for 12 h, capillary-like structures were examined. After 24 h culture, the expression of VEGF was detected by real-time PCR. RESULTS: Salvianolic acid at 0.4, 0.8 mg.L(-1), the same as notoginseng triterpenes, increased VEGF content in EA-hy926 cells. Expression of VEGF protein in the salvianolic acid at 1.2 mg.L(-1) group, was up-regulated as compared with notoginseng triterpenes group (P < 0.05). CONCLUSION: Salvianolic acid and notoginseng triterpenes can promote EA-hy926 cell proliferation, angiogenesis and expression of VEGF protein. This analysis also provided evidence that salvianolic acid had the better effects as compared with notoginseng triterpenes. PMID- 23725838 TI - Rho kinase inhibition activity of pinocembrin in rat aortic rings contracted by angiotensin II. AB - AIM: To investigate the effects of pinocembrin on angiotensin II (Ang II)-induced vascular contraction, and to explore its molecular mechanism of actions. METHODS: The isometric vascular tone was measured in rat thoracic aortic rings with denuded endothelium. Phosphorylation level of myosin phosphatase target unit 1 (MYPT1), and protein levels of Rho kinase 1 (ROCK1, ROKbeta or p160ROCK) and angiotensin II type-1 receptor (AT1R) were determined by Western blot analysis. RESULTS: Pinocembrin produced a relaxant effect on endothelium-denuded aortic rings contracted by Ang II (100 nmol.L(-1)) in a dose-dependent manner. In endothelium-denuded aortic rings stimulated by Ang II, pretreatment with pinocembrin (25 and 100 MUmol.L(-1)) for 20 min significantly attenuated MYPT1 phosphorylation and ROCK1 protein levels. Meanwhile, the protein level of AT1R in response to Ang II was not affected by pinocembrin in rat aortic rings. CONCLUSION: These findings indicate that pinocembrin inhibits vasoconstriction induced by Ang II in rat endothelium-denuded aortic rings, and the mechanism at least in part, is due to the blockade of the RhoA/ROCK pathway. PMID- 23725839 TI - Chemical constituents of Cinnamomum cebuense. AB - AIM: To investigate the chemical constituents of Cinnamomum cebuense, an endemic and critically endangered tree found only in Cebu, Philippines. METHODS: The compounds were isolated by silica gel chromatography. The structures of the isolates were elucidated by NMR spectroscopy. RESULTS: The dichloromethane (DCM) extract of the bark of C. cebuense afforded a new monoterpene natural product 1 and a new sesquiterpene 2, along with the known compounds, 4-hydroxy-3 methoxycinnamaldehyde (3), 4-allyl-2-methoxyphenol (4), alpha-terpineol (5) and humulene (6). The DCM extract of the leaves of C. cebuense yielded 6, beta caryophyllene (7), squalene (8), and a mixture of alpha-amyrin (9), beta-amyrin (10) and bauerenol (11). The structures of 1-7 were elucidated by extensive 1D and 2D NMR spectroscopy, while the structures of 8-11 were identified by comparison of their (13)C NMR data with those reported in the literature. CONCLUSION: The bark of C. cebuense afforded monoterpenes, sesquiterpenes and phenolics, while the leaves yielded sesquiterpenes and triterpenes. PMID- 23725840 TI - Cytotoxic constituents from the leaves of Broussonetia papyrifera. AB - AIM: To investigate the chemical constituents from the leaves of Broussonetia papyrifera. METHODS: The chemical constituents were isolated and purified by macroporous adsorptive resin D101, silica gel, and ODS column chromatography and preparative HPLC. Their structures were elucidated on the basis of 1D and 2D NMR analyses. In addition, their cytotoxic activity against human hepatoma carcinoma cells (HepG-2) were evaluated by the MTT method. Furthermore, RP-HPLC and colorimetric methods were used for the analysis of cosmosiin and total flavonoids. RESULTS: A new lignan, together with five known compounds were obtained, and their structures were characterized as (+)-pinoresinol-4'-O-beta-D glucopyranosyl-4"-O-beta-D-apiofuranoside (1), cosmosiin (2), luteolin-7-O-beta-D glucopyranoside (3), liriodendrin (4), 3, 5, 4'-trihydroxy-bibenzyl-3-O-beta-D glucoside (5), and apigenin-6-C-beta-D-glucopyranside (6). Furthermore, RP-HPLC and colorimetric methods were established for the analysis of cosmosiin and total flavonoids. CONCLUSION: Compound 1 was a new lignan, and compounds 5 and 6 were isolated for the first time from the title plant. Compounds 1, 4 and 6 showed definite activities against HepG-2, while the other compounds didn't show inhibitory effects. The optimal harvest time of B. papyrifera (L.) Vent. is September. PMID- 23725841 TI - A new isoflavonoid glycoside from the aerial parts of Trachelospermum jasminoides. AB - AIM: To study the chemical constituents from the aerial parts of Trachelospermum jasminoides. METHODS: Compounds were isolated by various chromatographic methods and their structures were elucidated on the basis of spectral techniques. In addition, the inhibitory activity against HepG2 and HL-60 of compound 1 was evaluated. RESULTS: Five compounds were isolated and identified as 3', 7 dimethoxyisoflavanone-4', 5-di-O-beta-D-glucopyranoside (1), tracheloside (2), nortrachelogenin 5'-C-beta-glucopyranoside (3), luteolin-4'-O-beta-D-rutinoside (4), and luteolin-7-O-beta-D-glucopyranoside (5). CONCLUSION: Compound 1 is a new isoflavonoid glycoside. It showed weak inhibitory activity against HepG2 and HL 60 cancer cells with IC50 values of 131.5 and 58.2 MUmol.L(-1), respectively. PMID- 23725842 TI - Synthesis of A B C-ring subunit of C-nor-D-homo-steroidal alkaloids: towards the total synthesis of cyclopamine. AB - A practical approach to the synthesis of the A, B and C-ring subunit of cyclopamine has been developed. This synthetic tactic highlights the utility of mandelate acetal-mediated resolution of the fused ring ketone (+/-)-4 and IBX mediated oxidation cascades from 12 to 9. The availability of advanced intermediates from enantiomerically pure (+)-4 and 2 could provide efficient access to biologically active and structurally diverse C-nor-D-homo-steroidal alkaloids such as cyclopamine. PMID- 23725843 TI - Synthesis and in vitro cytotoxicity evaluation of baicalein amino acid derivatives. AB - AIM: To synthesize the baicalein amino acid derivatives and evaluate their cytotoxicity activities in vitro. METHODS: Amino acids were subjected to methylation and aminoacylation reaction, then reacted with formaldehyde and baicalein to synthesize baicalein-8 benzyl amino acid derivatives. Through carboxyl group protection and aminoacylation of amino acid and benzyl protection of baicalein, derivatives of baicalein-6-O-amino acid esters were obtained. All of the target compounds were identified by IR, MS and (1)H NMR. RESULTS: Thirteen novel derivatives were synthesized and characterized. Their cytotoxic activities were assessed by the MTT method on the inhibition of HepG2 cells in vitro. CONCLUSION: Compounds 4c, 4d, 7a and 7b showed a significant increase in cytotoxicity compared with baicalein. PMID- 23725844 TI - Glycosylation of ent-kaurene derivatives and an evaluation of their cytotoxic activities. AB - AIM: To discover more active and water-soluble derivatives of tetracyclic diterpenoids containing an exo-methylene cyclopentanone or an alpha methylenelactone moiety. METHODS: All of the key intermediates were synthesized from stevioside, and the target compounds were obtained through glycosylation of the 4-carboxyl group. The cytotoxicity of the target compounds against six human cancer cell lines, HepG2, Bel-7402, A549, U251, MCF-7 and MDA-MB-231, were evaluated by the MTT assay. RESULTS: Compound 1b was more effective than the positive control adriamycin against the HepG2, Bel-7402, A549, MCF-7, and MDA-MB 231 cell lines with IC50 values of 0.12, 0.91, 0.35, 0.08, and 0.07 MUmol.L(-1), respectively. Moreover, compound 3c exhibited the most potent and selective cytotoxic activity against the HepG2 cell line (IC50, 0.01 MUmol.L(-1)). CONCLUSION: Compounds 1b and 3c could be considered as potential anticancer candidates for further study. PMID- 23725845 TI - Synthesis and hypoglycemic activity of esterified-derivatives of mangiferin. AB - AIM: To synthesize three novel esterified-derivatives of mangiferin and evaluate their hypoglycemic activities. METHODS: Acetic, propionic, and butyric anhydride were reacted with mangiferin, respectively. The hypoglycemic activity of the derivatives was evaluated using a hyperglycemic mouse model induced by streptozotocin (STZ), and the islet cells were checked by biopsy inspection. RESULTS: 7, 2', 3', 4', 6'-penta-acetyl-mangiferin (PAM), 3, 6, 7, 2', 3', 4', 6' hepta-propionyl-mangiferin (HPM) and 3, 6, 7, 2', 3', 4'-hexa-butyryl-mangiferin (HBM) were synthesized and their structures were identified by MS,(1)H, (13)C NMR, and 2D NMR. These three compounds were reported for the first time. PAM group (0.5, 0.25 mmol.kg(-1)), HPM group (0.5, 0.25 mmol.kg(-1)), and HBM group (0.5, 0.25, 0.125 mmol.kg(-1)) mice showed strong hypoglycemic activity (P < 0.01); mangiferin group (1, 0.5 mmol.kg(-1)), PAM group (0.125 mmol.kg(-1)) and HPM group (0.125 mmol.kg(-1)) showed marginal hypoglycemic activity (P < 0.05); mangiferin group (0.25 mmol.kg(-1)) had the potential for a hypoglycemic effect, although it did not demonstrate that statistically. In histological examination, the islet cells of the PAM, HPM, and HBM groups could recover from the STZ damage; islet cells of the mangiferin group could recover also, but less than the esterified-derivative groups. CONCLUSION: Derivatives could repair the damaged islet cells, and had higher lipid-solubility and stronger hypoglycemic activity than mangiferin itself. There existed a structure activity effect, and a solubility effect relationship: the larger esterification moieties, or the higher lipid-solubility, the stronger the hypoglycemic activity (no ester -> acetyl -> propionyl -> butyryl). Esterified derivatives of mangiferin are potential compounds for new anti-diabetes drugs. PMID- 23725846 TI - Assessment of the effects of Radix bupleuri and vinegar-baked Radix bupleuri on cytochrome 450 activity by a six-drug cocktail approach. AB - AIM: To assess the effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on cytochrome 450 activity of rats. METHODS: Six probe drugs (caffeine, midazolam, dextromethorphan, tolbutamide, omeprazole, chlorzoxazone) were simultaneously given to rats after different dosing of Radix Bupleuri or vinegar-baked Radix Bupleuri for seven days. The plasma concentrations of the six probes were measured by high performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-MS/MS) and their corresponding pharmacokinetic parameters were calculated. RESULTS: The AUC and T1/2 of midazolam, dextromethorphan and chlorzoxazone decreased significantly (P < 0.05) in rats after different dosing of Radix Bupleuri or vinegar-baked Radix Bupleuri for seven days. Treatment of Radix Bupleuri decreased T1/2 and AUC of omeprazole, but treatment of vinegar baked Radix Bupleuri with normal dose did not change the pharmacokinetics of omeprazole. The pharmacokinetics of tolbutamide in all vinegar-baked Radix Bupleuri-treated rats showed no statistically significant difference (P > 0.05) from that of controlled rats, however, treatment of Radix Bupleuri decreased tolbutamide T1/2. The pharmacokinetics of caffeine in all Radix Bupleuri or vinegar-baked Radix Bupleuri-treated rats showed no statistically significant difference (P > 0.05) from that of controlled rats. CONCLUSION: The Radix Bupleuri and vinegar-baked Radix Bupleuri have different effects on the CYP2C9 and CYP2C19. Radix Bupleuri and vinegar-baked Radix Bupleuri have strong induction effects on the CYP2E1, CYP2D6 and CYP3A4, however, have no impact on CYP1A2. The reason of different therapeutic effects of Radix Bupleuri and vinegar baked Radix Bupleuri extract may be the different effects of Radix Bupleuri and vinegar-baked Radix Bupleuri on the CYP2C9 and CYP2C19. PMID- 23725847 TI - Effect of diammonium glycyrrhizinate on entecavir pharmacokinetics in rats. AB - AIM: This study was designed to explore the effects of short-term and long-term pretreatment of diammonium glycyrrhizinate (GLN) on the pharmacokinetics of entecavir (ETV) in rats. METHODS: Male SD rats were randomized into short-term and long-term experimental groups, respectively. In the short-term experiment, the control group received saline, the low dose group received GLN 13.5 mg.kg(-1) and the high dose group received GLN 40.5 mg.kg(-1). ETV (0.09 mg.kg(-1)) was given i.g. 0.5 h after saline/GLN administration. For the long-term experiment, rats were allocated into two experimental designs. The control group received saline/ETV (0.09 mg.kg(-1)), the low dose group received GLN 13.5 mg.kg(-1)/ETV 0.09 mg.kg(-1) + GLN 13.5 mg.kg(-1), while the high dose group received GLN 40.5 mg.kg(-1)/ETV 0.09 mg.kg(-1) + GLN 40.5 mg.kg(-1); all administration was continued for 15 days. On the 16(th) day, 0.09 mg.kg(-1) ETV was administrated to all groups. Blood samples were obtained at different time points after ETV administration to determine plasma ETV concentrations. RESULTS: Pretreatment with glycyrrhizin resulted in no significant alterations in the main pharmacokinetic parameters of ETV in the short-term and long-term administration experiments. CONCLUSION: Diammonium glycyrrhizinate has no effect on ETV pharmacokinetics in rats. PMID- 23725848 TI - Statistical and graphical approaches for disproportionality analysis of spontaneously-reported adverse events in pharmacovigilance. AB - AIM: Combine disproportionality analysis with dynamically interactive graphics to understand spontaneously-reported adverse events in pharmacovigilance. METHODS: Four statistical methods, including Reporting Odds Ratio, Proportional Reporting Ratio, Multi-Item Gamma Poisson Shrinker and Bayesian Confidence Propagation Neural Network that are used for computing disproportionality are described. Tree maps and other graphical techniques are used to display the disproportionality results. RESULTS: Spontaneously-reported adverse events in pharmacovigilance are collected from physicians, patients, or the medical literature by regulatory agencies, pharmaceutical companies and device manufacturers to monitor the safety of a product once it reaches the market. In order to identify potential safety signals, disproportionality analysis methods compare the rate at which a particular event of interest co-occurs with a given drug with the rate this event occurs without the drug in the event database. Tree maps are employed to interactively display the adverse events for particular drugs and compare the adverse events among the drugs. CONCLUSION: Interactive graphical displays of disproportionality allow the analyst to quickly identify safety signals and perform additional follow-up analyses. Combining statistical methods with dynamically interactive graphics affords insights into the data inaccessible by traditional analysis methods. PMID- 23725849 TI - Medical record validation of maternal recall of pregnancy and birth events from a twin cohort. AB - This study aims to assess the validity of maternal recall for several perinatal variables 8-10 years after pregnancy in a twin sample. Retrospective information was collected 8-10 years after the delivery event in a cohort of mothers from the University of Southern California Twin Study (N = 611) and compared with medical records for validity analysis. Recall of most variables showed substantial to perfect agreement (kappa = 0.60-1.00), with notable exceptions for specific medical problems during pregnancy (kappa <= 0.40) and substance use when mothers provided continuous data (e.g., number of cigarettes per day; r <= 0.24). With the exception of delivery method, neonatal intensive care unit admission, birth weight, neonatal information, and post-delivery complications were also recalled with low accuracy. For mothers of twins, maternal recall is generally a valid measure for perinatal variables 10 years after pregnancy. However, caution should be taken regarding variables such as substance use, medical problems, birth length, and post-delivery complications. PMID- 23725850 TI - Trends in pulmonary embolism morbidity and mortality in Australia. AB - INTRODUCTION: Pulmonary embolism (PE) is a common cause of morbidity and mortality. In this study, we investigated patterns of morbidity and mortality from PE in Australia. MATERIALS & METHODS: Australian government databases were used to extract data on age and sex specific rates of mortality between 1997 and 2007, and hospital separations between 1998/9 and 2009/10 to examine changes over time and between age and sex groups. RESULTS: In 2007, 320 deaths were ascribed to PE in Australia, corresponding to a mortality rate of 1.73 per 100,000 population per year. Between 1997 and 2007, the Australian mortality rate decreased in both sexes, but this was significant only in females. By comparison, in 2009/10 there were 9,847 hospital separations for PE, corresponding to a rate of 53.1 per 100,000 population per year. In contrast to the fall in mortality rates, hospital separation rates significantly increased over the study period. Females had higher rates of morbidity and mortality from PE than males. While the mortality rates among the elderly population decreased significantly (from 48.4 to 34.3 per 100,000 population per year in those aged over 85 years), there were significant increases in PE mortality in the younger female age groups. CONCLUSIONS: Although mortality rates are decreasing, PE remains a significant cause of morbidity and mortality in Australia, especially in females and the elderly. The burden of morbidity and mortality from PE in Australia is comparable to that found in America and a number of European countries. PMID- 23725852 TI - Will PICCOLO affect metastatic colorectal cancer therapy? PMID- 23725853 TI - Ultrasound bladder wall thickness measurement in diagnosis of recurrent urinary tract infections and cystitis cystica in prepubertal girls. AB - OBJECTIVE: To evaluate urinary bladder wall thickness (BWT) assessed by ultrasound as a diagnostic tool for cystitis cystica. PATIENTS AND METHODS: This was a 9-year prospective study comprising 120 prepubertal girls. Sixty subjects of whom half underwent cystoscopy represented cases while the other 60 (those with a single urinary tract infection and healthy subjects) represented controls. RESULTS: Based on receiver operating characteristics (ROC) analysis, BWT discriminated very well between cases and controls with area under the ROC curve close to 1.0. At the optimum cut-off defined at 3.9 mm, negative predictive value (NPV) was 100% leaving no probability of cystic cystitis with BWT <3.9 mm. Positive predictive value (PPV) was also very high (95.2%), indicating only around 4.82% probability of no cystic cystitis in patients with BWT values >=3.9 mm. BWT could also distinguish between healthy subjects and those with a cured single urinary tract infection, although discriminatory properties were moderate (area under ROC 86.7%, PPV 78.8%, NPV 85.2%). CONCLUSION: Ultrasound mucosal bladder wall measurement is a non-invasive, simple and quite reliable method in diagnosis of cystitis cystica in prepubertal girls with recurrent urinary tract infections. PMID- 23725851 TI - Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial. AB - BACKGROUND: Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer. METHODS: In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m(2) intravenous irinotecan every 3 weeks (300 mg/m(2) if aged >=70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146, BRAF, NRAS, and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876. RESULTS: Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12-13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1.01, 95% CI 0.83-1.23; p=0.91), but individuals in the IrPan group had longer progression-free survival (0.78, 0.64-0.95; p=0.015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p<0.0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 [29%] of 219 patients vs 39 [18%] of 218 patients), skin toxicity (41 [19%] vs none), lethargy (45 [21]% vs 24 [11%]), infection (42 [19%] vs 22 [10%]) and haematological toxicity (48 [22%] vs 27 [12%]) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group. INTERPRETATION: Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents. FUNDING: Cancer Research UK, Amgen Inc. PMID- 23725854 TI - Which type of urethroplasty in failed hypospadias repair? An 8-year follow up. AB - OBJECTIVE: To report our 8-year follow up for redo hypospadias repair. METHODS: A total of 56 patients with previous failed hypospadias repair were included in our study. Patients' data were analyzed regarding age, number of previous repairs, meatal location, procedure performed, operative time and complications. Patients were followed up for 3 to 102 (mean 52) months. RESULTS: Patient age ranged from 15 to 204 (mean 90.7) months. Forty-two patients had a single previous hypospadias repair, eleven had two previous repairs and three had four previous repairs. Of the 56 patients, 16 underwent oral mucosal graft urethroplasty, 15 onlay island flap, 14 parameatal flap, 10 tubularized incised plate urethroplasty, and 1 tubularized preputial flap. Complications were encountered in 16 (28.5%) patients in the form of graft contracture in 3, meatal stenosis in 2, urethral stricture in 2 including the patient with tubularized flap, urethra cutaneous fistula in 7, bleeding in 1 and skin disruption in 1. The final complication rate was 25%. CONCLUSIONS: Decision making in redo hypospadias surgery depends mainly on local tissue availability and the degree of tissue scarring. The characteristics of oral mucosal graft make it suitable for urethroplasty in the absence of local donor tissues. A long-term follow up for redo hypospadias repair is required to assess the late neourethral stricture and residual penile curvature. PMID- 23725855 TI - Use of older donors for lung transplantation-you can't get there from here. PMID- 23725856 TI - What is required for the validation of in vitro assays for predicting contaminant relative bioavailability? Considerations and criteria. AB - A number of studies have shown the potential of in vitro assays to predict contaminant in vivo relative bioavailability in order to refine human health exposure assessment. Although the term 'validated' has been used to describe the goodness of fit between in vivo and in vitro observations, its misuse has arisen from semantic considerations in addition to the lack of defined criteria for establishing performance validation. While several internal validation methods may be utilised, performance validation should preferably focus on assessing the agreement of model predictions with a set of data which are independent of those used to construct the model. In order to achieve robust validated predictive models, a number of parameters (e.g. size of data set, source of independent soils, contaminant concentration range, animal model, relative bioavailability endpoint) need to be considered in addition to defined criteria for establishing performance validation which are currently lacking. PMID- 23725857 TI - Review on the effects of toxicants on freshwater ecosystem functions. AB - We reviewed 122 peer-reviewed studies on the effects of organic toxicants and heavy metals on three fundamental ecosystem functions in freshwater ecosystems, i.e. leaf litter breakdown, primary production and community respiration. From each study meeting the inclusion criteria, the concentration resulting in a reduction of at least 20% in an ecosystem function was standardized based on median effect concentrations of standard test organisms (i.e. algae and daphnids). For pesticides, more than one third of observations indicated reductions in ecosystem functions at concentrations that are assumed being protective in regulation. Moreover, the reduction in leaf litter breakdown was more pronounced in the presence of invertebrate decomposers compared to studies where only microorganisms were involved in this function. High variability within and between studies hampered the derivation of a concentration-effect relationship. Hence, if ecosystem functions are to be included as protection goal in chemical risk assessment standardized methods are required. PMID- 23725859 TI - Volumetric modulated arc therapy with flattening filter free (FFF) beams for stereotactic body radiation therapy (SBRT) in patients with medically inoperable early stage non small cell lung cancer (NSCLC). AB - PURPOSE: To assess the impact of volumetric modulated arc therapy (VMAT) with flattening filter free (FFF) beams for stereotactic body radiotherapy (SBRT) in inoperable stage I NSCLC. Current data were compared against a cohort of patients previously treated with advanced conformal techniques (3DCRT) based on conformal arcs. METHODS AND MATERIALS: From July 2006 to December 2011 132 patients underwent SBRT, 86 by 3DCRT with flattened beams (FF), while the last 46 with VMAT RapidArc and unflattened beams (FFF). All patients were treated with 48 Gy in four fractions of 12 Gy each. Patients underwent follow-up. Clinical outcome was evaluated with thoracic and abdominal CT scan and 18FDG-CTPET before and after treatment. RESULTS: Both techniques achieved adequate dose conformity to the target but with a statistically significant reduction of ipsilateral lung doses in RapidArc plans and also of Beam-on-Time (BOT) with FFF mode. The median follow up was 16 months (range 2-24 months). At 1 year, local control rate was 100% with FFF beams compared with 92.5% with FF beams (p=0.03). CONCLUSIONS: SBRT with FFF beams permitted us a safe delivery of high dose per fraction in a short treatment time and resulted in an earlier radiological response compared with FF beams. PMID- 23725858 TI - The autoimmune basis of narcolepsy. AB - Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns. Narcolepsy is caused by the loss of hypocretin (orexin) producing neurons in the lateral hypothalamus. Evidence, such as a strong association with HLA DQB1*06:02, strongly suggests an autoimmune basis targeting hypocretin neurons. Genome-wide association studies have strengthened the association between narcolepsy and immune system gene polymorphisms, including the identification of polymorphisms in the T cell receptor alpha locus, TNFSF4 (also called OX40L), Cathepsin H (CTSH) the purinergic receptor P2RY11, and the DNA methyltransferase DNMT1. Recently, attention has been raised regarding a spike in cases of childhood narcolepsy in 2010 following the 2009 H1N1 pandemic (pH1N1) in China and vaccination with Pandemrix, an adjuvanted H1N1 vaccine that was used in Europe. How the immune system may be involved in disease initiation and/or progression remains a challenge to researchers. Potential immunological pathways that could lead to the specific elimination of hypocretin producing neurons include molecular mimicry or bystander activation, and are likely a combination of genetic and environmental factors, such as upper airway infections. PMID- 23725862 TI - New directives in cardiac imaging: imaging the adult with congenital heart disease. AB - Advances in pediatric surgical and interventional techniques and medical care over the past 50 years have revolutionized the care of children with congenital heart disease. Survival to adulthood is now expected and, as such, there is a growing population of adults which is exceeding the pediatric population with congenital heart disease. Noninvasive cardiac imaging with modalities such as echocardiography, computed tomography, and cardiac magnetic resonance imaging are integral to the care of adults with congenital heart disease. These modalities are used for diagnosis, surveillance for complications late after surgery and catheter-based interventions, and in decision-making for medical, interventional, and surgical therapies. In this review we will discuss noninvasive imaging modalities used to assess congenital cardiac lesions, imaging strategies for select congenital lesions, and comment on the future of cardiac imaging in congenital heart disease. PMID- 23725861 TI - Adaptation of the Palliative Prognostic Index in patients with advanced medical conditions. AB - OBJECTIVE: To analyze the accuracy of the Palliative Prognostic Index (PPI) in patients with advanced medical diseases and to recalibrate it in order to adapt it to the profile of these patients. METHODS: Multicenter, prospective, observational study that included patients with one or more advanced medical diseases. Calibration (Hosmer-Lemeshow goodness of fit) and discriminative power (ROC and area under the curve [AUC]) of PPI were analyzed in the prediction of mortality at 180 days. Recalibration was carried out by analyzing the scores on the PPI of each quartile upward of dying probability. Accuracy of PPI was compared with that obtained for the Charlson index. RESULTS: Overall mortality of the 1.788 patients was 37.5%. Calibration in the prediction of mortality was good (goodness of fit with P=.21), the prognostic probabilities ranging from 0-0,25 in the first quartile of risk and from 0,48-0,8 in the last quartile. Discriminative power was acceptable (AUC=69; P=.0001). In recalibrated groups, mortality of patients with 0/1-2/2.5-9.5/>=10 points was 13, 23, 39 and 68%, respectively. Sensitivity (S) and negative predicative value (NPF) of the cutoff point above 0 points were 96 and 87%, respectively; while specificity (sp) and positive predictive value (PPV) of the cutoff point above 9.5 points were 95 and 68%. Calibration of the Charlson index was good (P=.2), and its discriminative power (AUC=.52; P=.06) was suboptimal. CONCLUSIONS: PPI can be a useful tool in predicting 6-month survival of patients with advanced medical conditions. PMID- 23725863 TI - Effectiveness of prenatal screening for congenital heart disease: assessment in a jurisdiction with universal access to health care. AB - BACKGROUND: Neonates with certain forms of severe congenital heart disease (CHD) diagnosed prenatally might have better outcomes in comparison with those diagnosed after birth. The proportion of prenatally detected neonates with severe CHD and the effect of prenatal diagnosis on clinical outcomes have not been previously investigated in Canada. METHODS: We retrospectively studied infants in Alberta, Canada, who required surgical or catheter intervention for CHD at younger than 1 year of age, between January 2007 and December 2010, and pregnancy terminations affected by CHD. RESULTS: Of the 374 subjects identified (327 infants, 47 pregnancies with termination), 188 (50%) were detected prenatally. Failure of prenatal diagnosis was associated with anomalies not involving the 4 chamber view on ultrasound (odds ratio, 1.86; 95% confidence interval, 1.48-2.35; P < 0.001) and region of residence (P = 0.04). Prenatal detection was associated with fewer days to hospital admission (P < 0.001), fewer days to surgery (P = 0.003), and greater use of prostaglandins (P = 0.001). Infants diagnosed prenatally who underwent surgery within 15 days of age had higher preductal O2 saturations (P = 0.04), fewer days to admission (P = 0.03), and less frequently required preoperative intubation (P = 0.004), and inotropes (P = 0.001). Pregnancy termination occurred among 49% of fetuses detected before 24 weeks' gestation. CONCLUSIONS: Only 50% of fetuses and/or neonates with severe CHD managed in Alberta have a prenatal diagnosis. The likelihood of prenatal detection is influenced by the status of the 4-chamber view on ultrasound and the region of maternal residence indicating heterogeneous access to fetal echocardiography within Alberta. Prenatal detection might improve clinical outcomes for neonates with severe CHD. PMID- 23725864 TI - Reply to letter from Kopjar et al.-the IMPACT-CABG Pilot Trial. PMID- 23725865 TI - Surveillance of avian influenza A(H7N9) virus infection in humans and detection of the first imported human case in Taiwan, 3 April to 10 May 2013. AB - On 3 April 2013, suspected and confirmed cases of influenza A(H7N9) virus infection became notifiable in the primary care sector in Taiwan, and detection of the virus became part of the surveillance of severe community-acquired pneumonia. On 24 April, the first imported case, reported through both surveillance systems, was confirmed in a man returning from China by sequencing from endotracheal aspirates after two negative throat swabs. Three of 139 contacts were ill and tested influenza A(H7N9)-negative. PMID- 23725866 TI - Epidemiological link between exposure to poultry and all influenza A(H7N9) confirmed cases in Huzhou city, China, March to May 2013. AB - We analysed the association between influenza A(H7N9) confirmed cases and exposure to poultry in Huzhou city, China. All cases (n=12) had a history of direct exposure to poultry or live poultry markets. We detected A(H7N9)-positive poultry samples from each site that was epidemiologically associated with cases. None of the cases' close contacts tested positive. After closure of the markets, no new cases were identified, suggesting an epidemiological link between poultry exposure and A(H7N9) virus infection. PMID- 23725867 TI - Outbreak with a novel avian influenza A(H7N9) virus in China--scenarios and triggers for assessing risks and planning responses in the European Union, May 2013. AB - As part of the risk assessment and strategic planning related to the emergence of avian influenza A(H7N9) in China the European Centre for Disease Prevention and Control (ECDC) has considered two major scenarios. The current situation is the one of a zoonotic epidemic (Scenario A) in which the virus might be transmitted sporadically to humans in close contact with an animal reservoir. The second scenario is the movement towards efficient human to human transmission (a pandemic Scenario B). We identified epidemiological events within the different scenarios that would trigger a new risk assessment and a review of the response activities to implement in the European Union (EU). Further, we identified the surveillance activities needed to detect these events. The EU should prepare for importation of isolated human cases infected in the affected area, though this event would not change the level of public health risk. Awareness among clinicians and local public health authorities, combined with nationally available testing, will be crucial. A 'one health' surveillance strategy is needed to detect extension of the infection towards Europe. The emergence of a novel reassortant influenza A(H7N9) underlines that pandemic preparedness remains important for Europe. PMID- 23725868 TI - Analysis of national measles surveillance data in Italy from October 2010 to December 2011 and priorities for reaching the 2015 measles elimination goal. AB - From 1 October 2010 to 31 December 2011, Italy experienced high measles burden with 5,568 measles cases (37.4% laboratory-confirmed) reported to the enhanced measles surveillance system (cumulative incidence in the 15-month reference period: 9.2/100,000 population). Adolescents and young adults were especially affected, and the median age of cases was 18 years. Most cases (95.8%) were either unvaccinated or incompletely vaccinated. Complications were reported for 20.3% of cases, including 135 cases of pneumonia, seven of encephalitis and one case of Guillain-Barre syndrome. One death occurred in an immunocompromised adult. Over 1,300 cases were hospitalised. Identified priorities for reaching the measles elimination goal include evidence-based interventions such as reminder/recall for both doses of measles vaccine, supplementary immunisation activities aimed at susceptible age cohorts, and vaccinating healthcare workers. PMID- 23725869 TI - Comment on Ran et al.: floating knee: a modified Fraser's classification and the results in a series of 28 cases. PMID- 23725870 TI - Simultaneous bilateral tibial tuberosity avulsion fractures in adolescence: case report and review of 60 years of literature. AB - Simultaneous bilateral avulsion fracture of the tibial tuberosity is a rare injury. Since the first reported case in the 1950s only 21 such cases have been reported in literature. When they do occur, it is usually in an adolescent athletic male, generally in the absence of any underlying pathology although rarely it may be associated with an underlying connective tissue disorder. The age range of the injury corresponds to the time of growth plate closure and maturation of the fibro-cartillagenous attachment of the tuberosity. Most of the fractures require open reduction and internal fixation and usually heal well without any significant complications. PMID- 23725871 TI - Patient distribution in a mass casualty event of an airplane crash. AB - INTRODUCTION: Difficulties have been reported in the patient distribution during Mass Casualty Incidents. In this study we analysed the regional patient distribution protocol (PDP) and the actual patient distribution after the 2009 Turkish Airlines crash near Amsterdam. METHODS: Analysis of the patient distribution of 126 surviving casualties of the crash by collecting data on medical treatment capacity, number of patients received per hospital, triage classification, Injury Severity Score (ISS), secondary transfers, distance from the crash site, and the critical mortality rate. RESULTS: The PDP holds ambiguous definitions of medical treatment capacity and was not followed. There were 14 receiving hospitals (distance from crash: 5.8-53.5 km); four hospitals received 133-213% of their treatment capacity, and 5 hospitals received 1 patient. Three hospitals within 20 km of the crash did not receive any casualties. Level I trauma centres received 89% of the 'critical' casualties and 92% of the casualties with ISS >= 16. Only 3 casualties were secondarily transferred, and no casualties died in, or on the way to hospital (critical mortality rate=0%). CONCLUSION: Patient distribution worked out well after the crash as secondary transfers were low and critical mortality rate was zero. However, the regional PDP was not followed in this MCI and casualties were unevenly distributed among hospitals. The PDP is indistinctive, and should be updated in cooperation between Emergency Services, surrounding hospitals, and Schiphol International Airport as a high risk area. PMID- 23725872 TI - The implications of the patterns of error associated with acute trauma care in rural hospitals in South Africa for quality improvement programs and trauma education. AB - INTRODUCTION: This audit uses error theory to analyze inappropriate trauma referrals from rural district hospitals in South Africa. The objective of the study is to inform the design of quality improvement programs and trauma educational programs. METHODS: At a weekly metropolitan morbidity and mortality meeting all trauma admissions to the Pietermaritzburg Metropolitan Trauma Service are reviewed. At the meeting problematic and inappropriate referrals and cases of error are identified. We used the (JCAHO) taxonomy to analyze these errors. RESULTS: During the period July 2009-2011 we received 1512 trauma referrals from our rural hospitals. Of these referrals we judged 116 (13%) to be problematic. This group sustained a total of 142 errors. This equates to 1.2 errors per patient. There were 87 males and 29 females in this group. The mechanism of injury was as follows, blunt trauma (66), stabs (32), gunshot wounds (GSW) (13) and miscellaneous five. The types of error consisted of assessment errors (85), resuscitation errors (26), logistics errors (14) and combination errors (17). The cause of the errors was planning failure in 68% of cases and execution failure in the remaining 32% of cases. The assessment errors involved the abdomen (50), chest (9), vascular system (8) and miscellaneous (18). The resuscitation errors involved airway (4), chest (11), vascular access (8) and cervical spine immobilization (3). CONCLUSIONS: Rural areas are error prone environments. Errors of execution revolve around the resuscitation process and current trauma courses specifically address these resuscitation deficits. However planning or assessment failure is the most common cause of error with blunt trauma being more prone to error of assessment than penetrating trauma. PMID- 23725873 TI - Monitoring the immune response in sepsis: a rational approach to administration of immunoadjuvant therapies. AB - Preliminary studies suggest that a subgroup of septic patients with severe immune alterations is at high risk of death or nosocomial infection and therefore could benefit from adjunctive immune stimulating therapies. There is thus an urgent need for robust biomarkers usable in routine conditions evaluating rapidly evolving immune status in patients. Although functional testing remains a gold standard, its standardization remains challenging. Therefore, surrogate markers such as monocyte HLA-DR expression, are being developed. Such biomarkers of immune functionality will enable a novel approach in the design of clinical trials evaluating immunostimulating therapies in sepsis at the right time and in the right patient. PMID- 23725874 TI - Multiple players in mouse B cell memory. AB - B cell memory has long been considered the attribute of the sole IgG-positive B cell subset. Since a few years, and due to new B-cell subset identification procedures, increasing heterogeneity has been identified among the memory B cell pool. IgM-positive cells and germinal center-independent subsets are recent additions to the field. This review describes the diversity of memory B cells, as well as controversial issues on their relative contribution to the recall response. The impact of a protracted germinal center response to the specific mobilization of IgM memory B cells is proposed. PMID- 23725875 TI - Inflammation in tuberculosis: interactions, imbalances and interventions. AB - Inflammation is critical for tuberculosis (TB) pathogenesis. The nonresolving aspect of inflammation in TB is caused by sophisticated intracellular survival strategies of tubercle bacilli. TB is a continuum comprising a spectrum of lesions as a consequence of complex regulation of inflammation. Proinflammatory cytokines, including interferons, tumor necrosis factor and interleukin 1 along with microRNAs and eicosanoids form an interactive network during TB. Cross regulation between proinflammatory mediators strongly impacts on infected cell death patterns. These processes, in concert with local concentrations of proteases, such as cathepsins, serpins and matrix-metalloproteinases, affect tissue integrity, shape the architecture of granulomas and modulate tissue repair. With inflammation networks being uncovered in TB, the relevance of several pathways for novel interventions becomes clearer. PMID- 23725876 TI - Novel oral anticoagulants in gastroenterology practice. PMID- 23725877 TI - The aromatase inhibitors (plus ovarian function suppression) in premenopausal breast cancer patients: ready for prime time? AB - Tamoxifen alone or the combination of ovarian function suppression (OFS) and tamoxifen are the mainstay of hormonal therapy in premenopausal women with endocrine-responsive breast cancer. The results of large trials conducted with the third generation of aromatase inhibitors (AIs) in the metastatic, neoadjuvant and adjuvant setting, indicated better outcomes among postmenopausal breast cancer patients with endocrine responsive disease given AIs than among those given tamoxifen. These results supported the investigation of AIs in combination with OFS in premenopausal women with hormone receptor positive breast cancer. In this article we reviewed the efficacy and toxicity data on the use of AIs combined with OFS in premenopausal breast cancer patients in metastatic, neoadjuvant and adjuvant setting. Given the available evidence at the time in metastatic setting for premenopausal patients suitable of endocrine therapy the AI is a viable option, if tamoxifen resistance is proven, although mandates the use of OFS. In neoadjuvant setting the AIs in combination of OFS should not be used outside of a clinical trial. In the adjuvant setting, tamoxifen alone or OFS plus tamoxifen are reasonable options. Despite the lack of conclusive data favoring the combination of tamoxifen plus OFS, this treatment might be a reasonable option for subgroups of patients such as very young patients, OFS alone should nort be considered unless tamoxifen was contraindicated. Similarly, in cases where tamoxifen is contraindicated, AIs as an adjunct to OFS is a treatment option in premenopausal patients. New large randomized studies are required to confirm the role of OFS plus an AI in premenopausal women. PMID- 23725878 TI - Immunotherapy for advanced melanoma: fulfilling the promise. AB - The incidence of melanoma is increasing worldwide and despite early detection and intervention, the number of patients dying from metastatic disease continues to rise. The prognosis of advanced melanoma remains poor, with median survival between 6 and 9 months. Over the past thirty years and despite extensive clinical research, the treatment options for metastatic disease were limited and melanoma is still considered as one of the most therapy-resistant malignancies. Single agent and combination chemotherapy, hormonal therapy, biochemotherapy, immunotherapy, targeted agent therapy and combination regimes failed to show significant improvement in overall survival. Recent advances and in-depth understanding of the biology of melanoma, have contributed in the development of new agents. Based on the molecular and immunological background of the disease, the new drugs have shown benefit in overall and progression free survival. As the picture of the disease begins to change, oncologists need to alter their approach to melanoma treatment and consider disease biology together with targeted individualized treatment. In this review the authors attempt to offer an insight in present and past melanoma treatment options, with a focus on the recently approved immunotherapeutic agents and the clinical perspectives of these new weapons against metastatic melanoma. PMID- 23725879 TI - Norms of vagal nerve activity, indexed by Heart Rate Variability, in cancer patients. AB - Recent research has begun to show the role of the activity of the vagus nerve in cancer prognosis. However, it remains unknown whether cancer severity can impair vagal nerve activity. This study combined data (N=657) of five different cancers (colorectal, pancreas, prostate, lung and ovarian) concerning patients' Heart Rate Variability (HRV), a vagal nerve activity index. These data were compared to HRV levels of a healthy sample in another study. In addition, we examined the moderating effects of age, gender and cancer stage on HRV. The mean HRV of the cancer patients sample was significantly lower (HRV=22 ms) compared to the healthy sample (HRV=50 ms) (p<0.000001). While age and gender did not significantly affect HRV, cancer patients with advanced stages had significantly lower HRV than those with early stages (p=0.011). A possible bi-directional relation between cancer and vagal nerve activity is discussed. These findings are of importance for prognostication since they provide researchers and clinicians with expected values of vagal nerve activity in cancer patients. PMID- 23725880 TI - Acquiring wisdom in the information age. PMID- 23725881 TI - Cytoplasmic receptors recognizing nucleic acids and mediating immune functions in neutrophils. AB - Cells belonging to the innate immune system, including neutrophils, rapidly respond to invading microorganisms by recognizing a wide range of microbial derived products referred to as pathogen-associated molecular patterns (PAMPs). Generally speaking, PAMPs include molecular structures associated with microbial envelopes (such as bacterial lipopolysaccharide, lipoproteins, and flagellin) and microbial nucleic acids. PAMPs bind to and activate various families of germline encoded receptors carried by cells of the innate immune system, known as pattern recognition receptors (PRRs). This group of receptors, located in various subcellular compartments, in turn generates a series of intracellular signaling pathways that coordinately modulate the transcription of hundreds of inflammatory genes, the products of which directly control infection and/or contribute to promote the development of the innate and adaptive immune responses. Herein, we summarize current knowledge on neutrophil recognition and response to foreign cytoplasmic nucleic acids. PMID- 23725882 TI - Single-cell transcriptomics for drug target discovery. AB - Single cell sequencing is currently in its relative infancy although an unprecedented amount of information is already being generated. These techniques are providing new insight into intercellular variability as well as identification of previously unrecognized drug targets. As more groups are gaining an interest in this fruitful technique, new sample preparation techniques, sequencing platforms, and bioinformatics tools are being developed which only improve the quantity and quality of data generated in these studies. Great advancements in harvest (in vivo pipette), sample preparation, and sequencing (Illumina HiSeq 2500/MiSeq, Ion Torrent PGM, Pacific Biosciences RS) are allowing for previously untestable questions to be answered and for expanded accessibility of these technologies. PMID- 23725883 TI - Spatio-temporal clusters of incident human brucellosis cases in Ecuador. AB - This study aimed to determine whether variations in the incidence of reported cases of human brucellosis in Ecuador were clustered in space and time. In addition, the effects of cattle and small ruminant population density and other socio-economic factors on the incidence were investigated. Significant space-time clusters were found in the northern and southern highlands and parts of Ecuadorian Amazonia. Customs of people, cattle, goat and sheep population density appeared to influence the incidence of brucellosis. In this study, the incidence of reported cases of human brucellosis was found to be higher in the highlands (sierra) and in municipalities near Peru and Colombia. The results of this study highlight the need for prevention and control measures aimed at abating the incidence of brucellosis among livestock and humans. PMID- 23725885 TI - Efficient mapping and geographic disparities in breast cancer mortality at the county-level by race and age in the U.S. AB - This study identified geographic disparities in breast cancer mortality across the U.S. using kriging to overcome unavailability of data because of confidentiality and reliability concerns. A structured additive regression model was used to detect where breast cancer mortality rates were elevated across nine divisions with 3109 U.S. counties during 1982-2004. Our analysis identified at least 25.8% of counties where breast cancer mortality rates were elevated. High risk counties compared to lower-risk counties had higher relative risks for African American women than for White women. Greater geographic disparities more likely present in African American women and younger women. To sum up, our statistical approach reduced the impact of unavailable data, and identified the number and location of counties with high breast cancer mortality risk by race and age across the U.S. PMID- 23725884 TI - The built environment and depressive symptoms among urban youth: A spatial regression study. AB - This study evaluated spatial relationships between features of the built environment and youth depressive symptoms. Data used in this study came from the 2008 Boston Youth Survey Geospatial Dataset, which includes Boston high school students with complete residential information (n=1170). Features of the built environment (such as access to walking destinations and community design features) were created for 400- and 800-m street network buffers of the youths' residences. We computed standard Ordinary Least Squares (OLS) regression and spatial simultaneous autoregressive models. We found significant positive spatial autocorrelation in all of the built environment features at both spatial scales (all p=0.001), depressive symptoms (p=0.034) as well as in the OLS regression residuals (all p<0.001), and, therefore, fit spatial regression models. Findings from the spatial regression models indicate that the built environment can have depressogenic effects, which can vary by spatial scale, gender and race/ethnicity (though sometimes in unexpected directions, i.e. associations opposite to our expectations). While our results overall suggest that the built environment minimally influences youth depressive symptoms, additional research is needed, including to understand our results in the unexpected direction. PMID- 23725886 TI - Spatial clusters in a global-dependence model. AB - Spatial data often possess multiple components, such as local clusters and global clustering, and these effects are not easy to be separated. In this study, we propose an approach to deal with the cases where both global clustering and local clusters exist simultaneously. The proposed method is a two-stage approach, estimating the autocorrelation by an EM algorithm and detecting the clusters by a generalized least square method. It reduces the influence of global dependence on detecting local clusters and has lower false alarms. Simulations and the sudden infant disease syndrome data of North Carolina are used to illustrate the difference between the proposed method and the spatial scan statistic. PMID- 23725887 TI - Jointly optimal bandwidth selection for the planar kernel-smoothed density-ratio. AB - The kernel-smoothed density-ratio or 'relative risk' function for planar point data is a useful tool for examining disease rates over a certain geographical region. Instrumental to the quality of the resulting risk surface estimate is the choice of bandwidth for computation of the required numerator and denominator densities. The challenge associated with finding some 'optimal' smoothing parameter for standalone implementation of the kernel estimator given observed data is compounded when we deal with the density-ratio per se. To date, only one method specifically designed for calculation of density-ratio optimal bandwidths has received any notable attention in the applied literature. However, this method exhibits significant variability in the estimated smoothing parameters. In this work, the first practical comparison of this selector with a little-known alternative technique is provided. The possibility of exploiting an asymptotic MISE formulation in an effort to control excess variability is also examined, and numerical results seem promising. PMID- 23725888 TI - Studies on the synthesis and biological evaluation of the metabolite of clausenamide CM2 and its stereoisomers. AB - The synthesis and biological evaluation of 5-hydroxy clausenamide (CM2), one of the major metabolites of clausenamide, and its stereoisomers have been carried out. The absolute configurations of (-)- and (+)-CM2 were assigned as 3S,4S,5S,6S and 3R,4R,5R,6R respectively based on (1)H NMR spectroscopic investigation and their chemical correlation to (-)- and (+)-clausenamidone (3). Electrophysiological assay showed that compound (+)-CM2 and its C6 epimer (+)-8a had significant effects on synaptic transmission and thus induced the long-term potentiation of the dentate gyrus. PMID- 23725889 TI - Inherited colorectal cancer: a plea for a national registry. PMID- 23725890 TI - An honour and a privilege. PMID- 23725891 TI - Pre-operative diagnosis of thyroid cancer: clinical, radiological and pathological correlation. AB - AIM: Ultrasonography and fine-needle aspiration biopsy (FNAB) are the mainstays of diagnosing thyroid cancer accurately and reducing the number of diagnostic lobectomies. No benchmark for diagnostic accuracy has been published in the South African context. This single-institution study addresses this deficit. METHODS: The oncology, pathology and surgical records of all patients diagnosed with thyroid carcinoma from 2004 to 2010 at Groote Schuur Hospital, Cape Town, South Africa, were reviewed and data were recorded on a standardised confidential proforma. The findings on pre-operative clinical assessment, ultrasound and FNAB were correlated with the histopathology results. Diagnostic accuracy for thyroid cancer was determined by correlating pre-operative investigations with the final diagnosis. Sensitivity of ultrasound and FNAB were calculated. RESULTS: A total of 109 patients, 79 female and 30 male, were identified. The majority (99, 90.8%) had well-differentiated thyroid cancers (56 papillary, 30 follicular, 10 mixed and 3 Hurtle cell carcinomas). There were 6 anaplastic and 4 medullary carcinomas. Of the 109 patients 38 had a definite pre-operative diagnosis, in 61 a malignant tumour was suspected, and 10 had surgery for benign disease. FNAB was inadequate in 11 cases and the findings indicated a benign lesion in 47, a suspicious lesion in 13 and a malignant lesion in 38 patients diagnosed with thyroid carcinoma. FNAB diagnosed all patients with medullary and anaplastic carcinoma but less than half of those with well-differentiated thyroid carcinoma. Ultrasound scans detected at least one suspicious feature in 44 patients. Microcalcification was the most common sign. CONCLUSION: The rate of pre operative diagnosis of well-differentiated thyroid carcinomas in this unit is under 50%, well below international norms. Our standard practice needs to change to include ultrasound-guided FNAB and standardised reporting of high-resolution ultrasound and cytology, before reassessment of our diagnostic accuracy. PMID- 23725892 TI - Pseudomonas aeruginosa burn wound infection in a dedicated paediatric burns unit. AB - BACKGROUND: Pseudomonas aeruginosa infection is a major cause of morbidity in burns patients. There is a paucity of publications dealing with this infection in the paediatric population. We describe the incidence, microbiology and impact of P. aeruginosa infection in a dedicated paediatric burns unit. METHODS: A retrospective review of patients with clinically significant P. aeruginosa infection between April 2007 and January 2010 in the burns unit at Red Cross War Memorial Children's Hospital in Cape Town, South Africa, was performed. RESULTS: During the 36-month study period, 2 632 patients were admitted. Of 2 791 bacteriology samples sent for microscopy, culture and sensitivity, 406 (14.5%) were positive for P. aeruginosa. Thirty-four patients had clinically significant P. aeruginosa wound infection, giving an incidence of 1.3%. Three patients had loss of Biobrane or allografts, and 23 cases of skin graft loss occurred in 18 patients. An average of 12 dressing days was needed to obtain negative swabs. All isolates were sensitive to chlorhexidine, whereas 92.5% were resistant to povidone-iodine. Piperacillin-tazobactam was the systemic antimicrobial to which there was most resistance (36.1%), and tobramycin had least resistance (3.3%). CONCLUSIONS: The incidence of clinically significant burn wound infection is low in our unit, yet the morbidity due to debridement and re-grafting is significant. We observed very high resistance to topical povidone-iodine. Resistance to systemic antimicrobials is lower than that reported from other burns units. PMID- 23725893 TI - Laparoscopic splenectomy for immune thrombocytopenic purpura. AB - BACKGROUND: Laparoscopic splenectomy has become the preferred method of splenectomy for refractory immune thrombocytopenic purpura (ITP). We present our experience with the introduction of laparoscopic splenectomy for ITP. METHODS: Over a 2-year period, retrospective and prospective data were collected on all patients undergoing laparoscopic splenectomy for ITP at our institution. We analysed demographic data, peri-operative courses, platelet count responses and complications. RESULTS: Twenty laparoscopic splenectomies were performed. There were 2 conversions to an open procedure. The average operating time was 100 minutes (range 30 - 170 minutes), and mean blood loss was 106 ml (range 50 - 200 ml). There were no deaths or major complications. The mean follow-up period was 7 months. Ninety-five per cent of patients had a complete or partial response to splenectomy. CONCLUSION: Laparoscopic splenectomy can be introduced safely with an acceptable conversion rate, and is an effective treatment for ITP on short term follow-up. PMID- 23725894 TI - Palpable discrete breast masses in young women: two of the components of the modified triple test may be adequate. AB - BACKGROUND: Palpable breast masses in young women, though usually benign, are a common source of anxiety. Current practice is assessment using the modified triple test (MTT). This entails clinical breast examination (CBE), ultrasound scans and cytological examination of a fine-needle aspiration biopsy specimen (FNAC). It is unclear whether it is necessary to utilise all three components in most patients. OBJECTIVES: We aimed to determine the diagnostic value of the MTT for the evaluation of palpable discrete breast masses in women under 35 years of age, and to assess the performance of its components when used individually or in combinations of two. DESIGN AND SETTING: This was a cross-sectional study carried out between August 2010 and October 2010 in the breast and general surgical outpatient clinics at Kenyatta National Hospital, Nairobi, Kenya. PATIENTS AND METHODS: Fifty-eight patients presenting during the study period with palpable discrete breast masses satisfying the inclusion criteria were recruited. All patients had a CBE, ultrasound scans and FNAC. A core biopsy was performed as a reference standard. Main outcome measures. The test results of the MTT and its elements (CBE, ultrasonography and FNAC) were compared with the histological findings (the reference standard). RESULTS: The age range of the 58 patients was 18 - 34 years (mean 25.5 years, standard deviation 5.1 years). Forty-five patients (77.6%) had concordant MTT results (agreement in all the three components). Concordant MTTs had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100%. Sensitivity, specificity, PPV and NPV were 100%, 92.3%, 60% and 100%, respectively, for CBE; 100%, 94.2%, 66.7% and 100%, respectively, for ultrasonography; and 100%, 98.1%, 83.3% and 100%, respectively, for FNAC. The combinations CBE plus ultrasound and CBE plus FNAC had sensitivities, specificities, PPVs and NPVs of 100%. CONCLUSION: Use of the MTT for diagnosis of palpable breast masses in young women ( PMID- 23725895 TI - Ten-year survival of patients with oesophageal squamous cell carcinoma. AB - OBJECTIVES: The standard predictive factors of actuarial survival such as T and N stage become less important as patients live for more than 10 years after treatment of cancer. Reports of actual 10-year survivors of oesophageal squamous cell carcinoma (SCC) are rare, and demographic and clinicopathological factors associated with 10-year survival have not been well documented. In this research we evaluated factors predictive of actual, as opposed to actuarial, 10-year survival. METHODS: We retrospectively analysed 1 046 patients who had undergone oesophagectomy for oesophageal SCC. The demographic and clinicopathological characteristics of patients who were alive more than 10 years after oesophagectomy and those of patients who had died were compared. RESULTS: Univariate analysis showed that 18 factors differed significantly between the two groups. Based on logistic regression analysis, factors associated with 10-year survival were younger age, female gender, absence of dysphagia, a left transthoracic surgical approach, lower pathological T stage, and fewer metastatic lymph nodes. CONCLUSION: The independent positive predictors of actual as opposed to actuarial 10-year survival are younger age, female gender, absence of dysphagia, lower pathological T stage, and fewer metastatic lymph nodes. PMID- 23725896 TI - Outcome of colorectal cancer resection in octogenarians. AB - INTRODUCTION: Octogenarians constitute a rapidly growing segment of patients undergoing colorectal cancer resection, but their outcomes remain understudied and under-reported. Our aims were to analyse outcomes of octogenarian patients undergoing curative colorectal resections compared with a similar cohort 2 decades younger. METHODS: Data from a prospectively collected database of consecutive patients undergoing colorectal resection between 2004 and 2006 were analysed. Primary endpoints were 30-day mortality and morbidity. The secondary endpoint was long-term survival. RESULTS: Eighty-one consecutive patients aged >80 years and 61 patients aged 60 - 70 years undergoing elective and emergency resections were identified. In the octogenarian group, 75.3% of resections were elective compared with 78.0% in the younger cohort (p=0.9), with pelvic procedures accounting for 34.6% and 44.3%, respectively (p=0.34). The elderly had a significantly higher median CR-Possum (performance status) score than the younger cohort (18.0 v. 14.0; p=0.001). Permanent stoma rates were similar (22% for octogenarians v. 27% for younger patients; p=0.8), as was pathological stage (p=0.24). There was 1 death within 30 days after resection in each group. Median survival in the octogenarian cohort was 73 months compared with 74 months in the younger cohort, and 5-year survival rates were 53.1% and 66.0%, respectively (p=0.2, Mantel-Cox). CR-Possum score did not affect overall survival (p=0.711, Mantel-Cox), but a higher score correlated with more postoperative complications in both groups. CONCLUSIONS: Octogenarians have poor performance status, but can undergo resection with acceptable mortality and morbidity. Overall survival in the two age groups studied was similar, with poor performance status being associated with higher postoperative complications but no long-term difference in survival. PMID- 23725897 TI - Posterolateral diaphragmatic hernia with small-bowel incarceration in an adult. AB - Bochdalek hernia (BH), a closing defect of the peripheral posterior aspect of the diaphragm, is the commonest of the congenital diaphragmatic hernias and is usually diagnosed in neonates. Symptomatic presentation of a right-sided diaphragmatic hernia in an adult is unusual. Owing to their rarity and varied presentation, they can pose a diagnostic challenge. A right-sided BH in a 40-year old woman who presented with respiratory distress associated with abdominal pain and symptoms of small-bowel obstruction is reported. Midline laparotomy revealed necrotic small bowel and faecothorax of the pleural cavity. Diaphragmatic hernias should be included in the differential diagnosis of patients with acute or chronic gastrointestinal, or less frequently respiratory, symptoms. PMID- 23725898 TI - Post-traumatic diaphragmatic hernias - importance of basic radiographic investigations. AB - This case presentation highlights important principles in the management of post traumatic diaphragmatic hernia. A suggestive history should prompt early diagnosis even if the patient appears well. The chest radiograph, although not pathognomonic, is extremely useful in the detection of diaphragmatic hernia if accurately interpreted. Herniated bowel is at high risk of strangulation, especially in the presence of a 'ribbon sign'. Delayed operative intervention can prove fatal. PMID- 23725899 TI - Bilateral blunt carotid artery injury: a case report and review of the literature. AB - A 22-year-old man sustained a strangulation-type injury to the neck, with bilateral blunt carotid artery injuries detected on computed tomography (CT) angiography. His Glasgow Coma Score was 15/15, and he was managed conservatively with therapeutic low-molecular-weight heparin and antiplatelet therapy. A repeat CT angiogram 6 weeks later showed complete resolution of an intimal flap, and he demonstrated no neurological deterioration. There are no definitive management guidelines regarding this type of injury, and our report emphasises the role of conservative anticoagulation therapy in the management of this rare condition. PMID- 23725900 TI - Errors in prenatal diagnosis. AB - Prenatal screening and diagnosis are integral to antenatal care worldwide. Prospective parents are offered screening for common fetal chromosomal and structural congenital malformations. In most developed countries, prenatal screening is routinely offered in a package that includes ultrasound scan of the fetus and the assay in maternal blood of biochemical markers of aneuploidy. Mistakes can arise at any point of the care pathway for fetal screening and diagnosis, and may involve individual or corporate systemic or latent errors. Special clinical circumstances, such as maternal size, fetal position, and multiple pregnancy, contribute to the complexities of prenatal diagnosis and to the chance of error. Clinical interventions may lead to adverse outcomes not caused by operator error. In this review I discuss the scope of the errors in prenatal diagnosis, and highlight strategies for their prevention and diagnosis, as well as identify areas for further research and study to enhance patient safety. PMID- 23725901 TI - The bionomic approach to patient safety and its application in gynaecological surgery. AB - In the past 2 decades, a gradual shift has taken place from the 'person approach' to patient safety (in which the individual clinician at the sharp end is blamed for any accident) to a 'systems approach' (in which causation of accidents is attributed to loopholes in the organisational defences). Increasingly, however, concern has been expressed that the systems approach risks absolving individuals from responsibility for patient safety, and a balance between the systems and person approaches has been sought. In this paper, resolution of the tension between the person and the systems approaches is advocated through the use of a paradigm that places more emphasis on the relationships between the individual at the sharp end and other components of the system. This paradigm, which is adapted from ecosystems, has been labelled the 'bionomic approach'. A bionomic approach to patient safety incorporates principles and concepts of human ecology and applies them to the healthcare system, situating the individual as an intrinsic component of the system rather than an adjunct. It builds on the notion that 'people create safety' and on the recognition that, in some clinical areas, particularly surgery, the individual is the primary defence against patient safety incidents. Skills required for 'error wisdom' are described, and the principles of the bionomic approach are applied to gynaecological surgery, using an illustrative case study. PMID- 23725902 TI - Protective effects of melatonin against spinal cord injury induced oxidative damage in rat kidney: A morphological and biochemical study. AB - Spinal cord injury (SCI) induced oxidative stress affects multiple organ systems including the kidney. We studied the possible protective effects of melatonin on SCI-induced oxidative damage in renal tissues of rats. Wistar albino rats (n = 24) were exposed to SCI and divided into vehicle- or melatonin-treated SCI groups. Melatonin was administred intraperitoneally at a dose of 10 mg/kg for seven days. Renal tissues were investigated by light and electron microscopy. Furthermore, tissue malondialdehyde (MDA) and glutathione (GSH) levels and myeloperoxidase (MPO) and superoxide dismutase (SOD) activities were also determined. In the vehicle-treated SCI group, the renal histology was disturbed compared to controls, whereas the melatonin-treated SCI group showed significantly reduced degeneration of renal tissue as seen by both light and electron microscopy. MDA levels, MPO and SOD activities were increased and GSH levels were decreased in the vehicle-treated SCI group compared to controls. On the other hand, decreased MDA levels and MPO activities and increased GSH levels were observed in the melatonin-treated SCI group compared to vehicle-treated SCI group. These results showed that experimentally induced SCI caused oxidative stress in the rat kidney, whereas melatonin treatment reduced oxidative stress, suggesting that it may be used as a complementary therapy of renal problems occurring following SCI. PMID- 23725903 TI - [Disseminated fusariosis during autologous stem cells transplant]. AB - Fusarium is a filamentous brown fungus found in soil, on plants and outdoors responsible for localized or disseminated infections. Diagnosis is based on blood cultures and skin biopsy. Disseminated fusariosis is a rare and serious fungal infection, that occurs especially in neutropenic immunosuppressed patients. Treatment is difficult and mortality is estimated between 50 and 70% in adult patients. This infection is rare in Morocco. We report a case of systemic fusariosis in patient with multiple myeloma during a second autologous stem cell transplant. At day 4 of the autologous stem cells transplant the patient had febrile neutropenia and diarrhea; he received ceftazidime, metronidazole and amikacin for 2 days. The patient still febrile was treated by imipenem and vancomycin without bacteriological proof. At day 10 the patient presented difficulty of breathing and wheezing on auscultation of the lungs, and received nebulization with salbutamol every 6 hours. The CT scan shows interstitial infiltrate of the right lung with micronodules. At day 11 he was treated by voriconazole with clinical improvement. At day 19, Fusarium sp. was identified on the Sabouraud blood culture. The patient left the transplant unit at day 25, he received 6 weeks of voriconazole with clinical and radiological improvement. PMID- 23725904 TI - [Fusariosis diagnosed in the laboratory of an UH in Tunisia: epidemiological, clinical and mycological study]. AB - The genus Fusarium, initially known for its important agro-economic impact, is more and more often implicated in human pathology. In fact, multiples allergic, toxic and infectious manifestations are more reported in immunocompetent and immunocompromised hosts. The objective of our study was to analyse the epidemiological, mycological and clinical features of fusariosis reported in our CHU. Eighty-seven cases of Fusarium infections were collected: 34 cases of onychomycosis (39%), 26 cases of intertrigos (30%), 25 cases of keratomycosis (29%), one case of atypical invasive fusariosis due to Fusarium oxysporum species complex (FOSC) and one case of localized gingivolabial fusariosis due to Fusarium solani species complex (FSSC) in a patient with leukemia in phase of deep bone marrow aplasia, whose outcome was favorable after exiting of aplasia period and a treatment by amphotericine B. The case of pseudotumoral cutaneous fusariosis to F. oxysporum complicated with osteolysis and septic arthritis occurred in a pregnant woman without any immune deficit. The evolution was fatal in spite of prescription of multiple systemic antifungals. Concerning keratomycosis, Fusarium was the first agent responsible for these infections (43%). The corneal traumatism was found in 37.5% of cases and FSSC was the most isolated (72%). For superficial dermatomycosis, Fusarium was the third agent of onychomycosis in molds (25%). The most isolated species were FSSC (68%) and FOSC (20%). The intertrigo frequency was 0.07% and they were mostly caused by FSSC (84%) and FOSC (16%). Fusarium is an important cause of mold infections in our region. So, the species identification is useful because some species are resistant to the most common systemic antifungal agents. PMID- 23725905 TI - Autism, will vitamin D treat core symptoms? AB - No medication exists to treat the core symptoms of autism. However, some children spontaneously improve and have optimal outcomes. Parents of autistic children who have access to swimming pool have reported summertime improvement in symptoms to me. A Japanese case report found the same summer times improvements. If the cause of that summertime improvement could be identified, it may lead to effective treatment. Vitamin D is highly seasonal with a summertime surfeit and a wintertime deficit. The hypotheses that the increased prevalence in the diagnosis of autism is due to better detection imply that parents, teachers and physicians of the 1950s, 60s, and 70s missed this non subtle diagnosis, an unlikely scenario. Recent research indicates that autism often first present itself during the second and third year of life. This is a time when most toddlers have no known sources of vitamin D. Vitamin D has remarkable antioxidant, anti inflammatory, and anti-autoimmune properties. In vitro, in vivo, and animal experiments provide compelling data for vitamin D's role brain proliferation, differentiation, neurotrophism, neuroprotection, neurotransmission, and neuroplasticity. It also upregulates glutathione, upregulates a suit of genes involved in DNA repair and raises the seizure threshold. Adequate, perhaps pharmacological, doses of vitamin D may have a treatment effect in the core symptoms of autism. PMID- 23725907 TI - Progress towards the responsible application of nanotechnology for water treatment. PMID- 23725908 TI - Oral epithelial changes in HIV-positive individuals. AB - HIV infections frequently affect the oral cavity, and local changes may be utilized as indicators of immunosuppression in HIV-positive patients. Morphometric and morphological features of the lining, masticatory, and specialized epithelium of the oral mucosa were studied in 12 HIV-positive and 12 HIV-negative patients autopsied from 2007 to 2010. Mucosal samples from the cheek, gingival, and tongue of 24 individuals were fixed in Carnoy solution and stained with hematoxylin-eosin. Various morphometric characteristics (epithelial thickness, number of cell layers, mean cell diameter) and morphological parameters (basal layer hyperplasia, exocytosis of inflammatory cells, glycogenic acanthosis, cell ballooning degeneration) were then measured. The HIV-positive group had a greater epithelial thickness (mean: 304.4MUm) and a higher mean cell diameter (11.84MUm), whereas the HIV-negative group had more epithelial layers (26.7). Basal layer hyperplasia did not differ significantly between the two groups, but exocytosis of inflammatory cells, glycogenic acanthosis, cell ballooning, and spongiosis were more prevalent in the HIV-positive group. Our findings demonstrate that HIV infection causes diverse epithelial changes in the oral cavity, including thickening, increased cell diameter, increased migration of inflammatory cells, and inter- and intra-cellular edema. PMID- 23725909 TI - Prevention of healthcare associated infections: medical and nursing students' knowledge in Italy. AB - BACKGROUND: The training of health workers is a key issue for the prevention of healthcare associated infections. OBJECTIVES: To evaluate knowledge of nursing and medical students concerning the prevention of healthcare associated infections. DESIGN: A cross-sectional study. SETTING: University hospitals in nine Italian cities. PARTICIPANTS: One thousand four hundred sixty one healthcare students (607 medical students and 854 nursing students). METHODS: The study was performed using a questionnaire investigating 3 areas, each having different possible points: standard precautions=12; hand hygiene=8; healthcare associated infections=5, for an overall perfect score of 25. Scores that met a cutoff >=17.5 were considered to be indicative of an acceptable level of knowledge. Factors associated with an acceptable level of knowledge were analyzed using a logistic regression model. RESULTS: Mean overall score (+/-SD) was 18.1 +/- 3.2. Nursing students (18.6 +/- 2.9) obtained a higher overall score than medical students (17.4 +/- 3.5) (p<0.001). Weighed scores (+/-SD) by area were: 10.3 (+/-2.0) for standard precautions, 5.0 (+/-1.3) for hand hygiene and 2.8 (+/-1.1) for healthcare associated infections. Knowledge level concerning the three areas was different between medical and nursing students (p<0.001). The probability of finding acceptable knowledge was smaller for medical students (OR: 0.54 p<0.0001) and for students aged >=24 years (OR: 0.39 p<0.0001). CONCLUSION: The overall score showed an acceptable level of knowledge for the whole sample; but, considering separately the two curricula, only nursing students reached the minimum acceptable score. It seems important to investigate what is working better in nursing than in medical education in order to implement and validate new teaching approaches. PMID- 23725910 TI - 21st century challenges faced by nursing faculty in educating for compassionate practice: embodied interpretation of phenomenological data. AB - Nursing faculty are facing challenges in facilitating student learning of complex concepts such as compassionate practice. Compassion is a stated expectation of Registered Nurse (RN) and student nurse practice, and yet how it is enabled and learned within the challenging environments of university and health service provider organisations are not yet understood. There is currently an international concern that student nurses are not being adequately prepared for compassion to flourish and for compassionate practice to be sustained upon professional qualification. In order to investigate the experiences of nursing faculty in their preparation of student nurses for compassionate practice, an exploratory aesthetic phenomenological research study was undertaken using in depth interviews with five nurse teachers in the North of England. Findings from this study were analysed and presented using embodied interpretation, and indicate that nurse teachers recognise the importance of the professional ideal of compassionate practice alongside specific challenges this expectation presents. They have concerns about how the economically constrained and target driven practice reality faced by RNs promotes compassionate practice, and that students are left feeling vulnerable to dissonance between learned professional ideals and the RNs' practice reality they witness. Nurse teachers also experience dissonance within the university setting, between the pressures of managing large student groups and the time and opportunity required for small group discussion with students that enables compassion to develop in a meaningful and emotionally sustainable way. Teachers also express discomfort due to a perceived promotion of an 'unachievable utopia' within practice, identifying how the constraints within practice could be better managed to support professional ideals. The nurse teachers within this exploratory study identify the need for strong nurse leadership in practice to challenge constraints and realign the reality of practice with professional ideals, and the need to foster student resilience for maintaining the professional ideals of compassionate practice. This exploratory study promotes the use of embodied interpretation for shared understanding of phenomenological research findings. PMID- 23725911 TI - Breastfeeding behavior among adolescents: initiation, duration, and exclusivity. AB - PURPOSE: Despite a substantial amount of evidence on breastfeeding among non adolescent mothers, research and strategies uniquely designed to target adolescent mothers are critical because their rates of breastfeeding are disproportionately low and their transition to parenthood is often unlike that of older mothers. Literature to date, however, offers limited evidence for designing effective interventions. Therefore, we aimed to fill this gap in the literature by examining breastfeeding behaviors among a cohort of female adolescents as they transition to parenthood. METHODS: Data were derived from a longitudinal cohort of pregnant adolescent females (ages 14-21 years) and their male partners, observed from pregnancy through 6 months postpartum. Means and frequencies were used to describe breastfeeding experiences, breastfeeding behaviors, and sociodemographic characteristics. We used multivariate logistic regression and Cox proportional hazards models to identify factors independently associated with breastfeeding initiation, exclusive breastfeeding, and breastfeeding duration. RESULTS: Approximately 71% initiated breastfeeding. Intending to breastfeed, having had complications in labor and delivery, and lower social support were associated with greater odds of breastfeeding initiation. Of the adolescent mothers who initiated breastfeeding, 84% had stopped by 6 months postpartum; among those, average breastfeeding duration was 5 weeks. Participants who exclusively breastfed had longer breastfeeding duration, and participants who had experienced intimate partner violence had shorter breastfeeding duration. Obese women and women who had more difficulty breastfeeding had lower odds of exclusive breastfeeding. CONCLUSIONS: Enhanced clinical support and the promotion of exclusive breastfeeding should be considered when designing interventions to improve breastfeeding rates among adolescent mothers. PMID- 23725912 TI - Prevalence and predictors of worsened left ventricular diastolic dysfunction after catheter ablation of atrial fibrillation. AB - BACKGROUND: The interactions between atrial fibrillation (AF) and left ventricular diastolic dysfunction (LVDD) are complex and not well defined. Despite the high prevalence of LVDD in the AF population, therapies for LVDD remain limited. Previous studies have suggested that restoration of sinus rhythm with catheter ablation has a positive effect on LVDD, but the prevalence and predictors for worsened LVDD are unknown. METHODS: 70 consecutive patients included in prospective AF catheter ablation registry (61+/-10 years, 66% male) with paroxysmal (n=40) or persistent AF (n=30) were examined by transthoracic echocardiography, before and 12 months after ablation. LVDD was classified according to current guidelines. Rhythm outcome of the ablation was verified by serial 7-day Holter ECG. RESULTS: LVDD was present in 27 patients (38%) at baseline and in 33 patients (47%) at 12 months follow-up (p=.327). An improvement of LVDD was observed in 13 patients (19%), an aggravation was found in 19 (27%), while it was unchanged in the remaining 38 patients (54%). In uni- and multivariable regression analysis, total ablation time (OR 1.611 per 10 min ablation time, 95% CI 1.088-2.386, p=.017) was associated with LVDD progression, while neither baseline characteristics nor rhythm during follow-up influenced LVDD alterations. There was no association between echocardiographic deterioration and symptoms. CONCLUSIONS: Catheter ablation of AF can worsen LVDD in a substantial proportion of patients with more aggressive ablation leading to aggravation of LVDD. While there are no apparent negative short-term effects, long-term consequences need to be determined. PMID- 23725913 TI - Indexed maximal left atrial volume predicts response to cardiac resynchronization therapy. AB - AIMS: Cardiac resynchronization therapy (CRT) has shown morbidity and mortality benefits in patients with advanced congestive heart failure (HF). Since about one third of the patients did not appear to respond to CRT, it would seem reasonable to try to identify patients more accurately before implantation. Left atrial (LA) dimension has been proposed as a powerful outcome predictor in patients with heart disease. Accordingly, the aim of this study is to prospectively assess the predictive value of LA for selecting CRT responders. METHODS: Fifty two consecutive patients with refractory HF, sinus rhythm and left bundle branch block were enrolled in the study and planned for CRT implantation. Clinical and echocardiographic evaluations were performed before CRT implantation and after 6 months. Three LA volumes indexed to body surface area (iLAV) were computed to evaluate the LA complexity: maximal LAV (iLAVmax), LAV just before atrial systole (iLAVpre), and minimal LAV (iLAVpost). CRT responders were defined as those who presented a reduction of >10% in LVESVi at 6-month follow-up. RESULTS: Responders (63%) and nonresponders (37%) had similar baseline clinical characteristics and pre-implantation LV volumes. However, baseline LA volumes were significantly associated with the extent of LV reverse remodeling: in particular, baseline iLAVmax was remarkably lower in responders than in nonresponders (50.2+/-14.1 ml/m(2) vs 65.8+/-15.7 ml/m(2), p=0.001) resulting predictive for CRT response. CONCLUSION: Patients with small iLAV result as better responders to CRT than larger one. iLAVmax is an independent predictor of LV reverse remodeling and allows to indentify the best candidates for CRT. PMID- 23725914 TI - Aortic and brachial blood pressures and blood pressure amplification in relation to novel and conventional cardiovascular risk factors: the SU.VI.MAX study. PMID- 23725917 TI - A randomized trial of coenzyme Q10 in patients with statin myopathy: rationale and study design. AB - BACKGROUND: Statins are the most commonly prescribed and effective medications for reducing low-density lipoprotein levels. Some patients experience myopathic symptoms during statin treatment. The etiology is not known, but depletion of mevalonate pathway metabolites, including coenzyme Q10 (CoQ10), has been suggested. Despite a lack of conclusive evidence supporting its utility, CoQ10 supplementation has been recommended to patients who experience myalgic symptoms. OBJECTIVE: The Co-Enzyme Q10 in Statin Myopathy study is designed to examine the effect of CoQ10 supplementation on the extent and intensity of muscle pain during treatment with simvastatin. METHODS: We will recruit patients with a documented history of myalgia during statin treatment. The presence of statin-related myalgia will be confirmed in a crossover run-in trial during which the presence and absence of symptoms will be documented during statin and placebo treatment, respectively. Individuals experience myalgic symptoms while taking statins but not placebo will be randomized to receive simvastatin 20 mg daily plus either 600 mg daily of CoQ10 or placebo. Muscle pain intensity will be documented during weekly phone calls via use of the Brief Pain Inventory, Short Form. Treatment will continue for 8 weeks or until muscle symptoms are reported continuously for 1 week or become intolerable, and then subjects will crossover to the alternative treatment (CoQ10 or placebo). RESULTS: This study is an ongoing clinical trial. CONCLUSIONS: This study will determine the utility of CoQ10 for reducing pain intensity in myalgic patients and will provide guidance for clinicians treating patients with hypercholesterolemia who are intolerant to statins. PMID- 23725918 TI - Low prevalence of type 2 diabetes mellitus among patients with high levels of high-density lipoprotein cholesterol. AB - BACKGROUND: Diabetes mellitus and low levels of high-density lipoprotein cholesterol (HDL-C) are among several known risk factors for coronary artery disease. Recent research has shown potential mechanistic links between these two diseases. OBJECTIVES: The aim of our study was to characterize, by examining particular coronary artery disease risk factors, patients with extremely high and low levels of HDL-C who were referred to a prevention clinic. METHODS: We compared the phenotypes of 113 patients with HDL-C levels greater than the 90th percentile with 212 patients with levels less than the 10th percentile by using a retrospective chart review. RESULTS: The cohort with high HDL-C had a remarkable difference in the incidence of type 2 diabetes (1.8% vs 21.7%). The high HDL-C cohort also had a greater age (52.1 years vs 46.7 years), more light or moderate alcohol consumption (70.8% vs 49.4%), more healthy diet (30.1% vs 22.4%), more light or moderate exercise (90.8% vs 52.2%), and a lower body mass index (25.2 kg/m2 vs 28.1 kg/m2). CONCLUSIONS: Compared with the low HDL-C group--and also the general population--the high HDL-C cohort had a remarkably low prevalence of diabetes mellitus. PMID- 23725919 TI - Efficacy and safety of TAK-085 compared with eicosapentaenoic acid in Japanese subjects with hypertriglyceridemia undergoing lifestyle modification: the omega-3 fatty acids randomized double-blind (ORD) study. AB - BACKGROUND: Hypertriglyceridemia is a risk factor for cardiovascular disease, and clinical practice guidelines advocate treatment to reduce triglyceride (TG) levels. In Japan, an EPA-E (eicosapentaenoic acid-ethyl ester) product has been used clinically for treating dyslipidemia. OBJECTIVE: We investigated the TG lowering effects of TAK-085 (EPA-E + docosahexaenoic acid-ethyl ester) in comparison with EPA-E in Japanese patients with hypertriglyceridemia (TG >=150 mg/dL and <750 mg/dL). METHODS: In this multicenter, 12-week, double-blind study, subjects were stratified for coadministration of a 3-hydroxy-3-methyl-glutaryl CoA reductase inhibitor then randomized to TAK-085 2 g once daily (n = 205), TAK 085 2 g twice daily (n = 210), or EPA-E 0.6 g three times daily (n = 195). Each one gram of fatty acid in TAK-085 contains approximately 465 mg of EPA plus 375 mg of docosahexaenoic acid-ethyl as ethyl esters. Guidance on lifestyle modifications was provided throughout. RESULTS: The primary end point was the percent change in TG levels (baseline from end of treatment), which was -10.8 +/- 22.6, -22.9 +/- 23.1, and -11.2 +/- 25.7 in the TAK-085 2 g/day, TAK-085 4 g/day, and EPA-E 1.8 g/day groups, respectively. TAK-085 4 g/day produced a significantly greater reduction in TG than EPA-E 1.8 g/day (P < .0001), whereas TAK-085 2 g/day was not inferior to EPA-E 1.8 g/day. Changes in other lipid parameters were relatively modest. There were no notable safety or tolerability differences between the groups. CONCLUSIONS: In Japanese patients with modest hypertriglyceridemia who also underwent lifestyle intervention, TAK-085 4 g/day reduced TG more than EPA-E 1.8 g/day. TAK-085 2 g/day had similar effects on TG as EPA-E 1.8 g/day. TAK-085 was well-tolerated. PMID- 23725920 TI - Relationship among low cholesterol levels, depressive symptoms, aggression, hostility, and cynicism. AB - BACKGROUND: Treatment guidelines for lipids have become increasingly more aggressive. However, naturally low or therapeutically reduced cholesterol levels may be associated with adverse psychological health symptoms, including depression, aggression, and hostility. OBJECTIVE: To examine relationships between low total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol levels and measures of psychosocial status among middle-aged adults. METHODS: A total of 1995 subjects enrolled in the Heart Strategies Concentrating on Risk Evaluation study with data on TC, LDL cholesterol, and self-reported ratings of psychological health were evaluated. To quantify ratings of depression, aggression, cynicism, and hostility, psychological measures included the Center for Epidemiologic Studies Depression Scale (CES-D) and Cook-Medley Hostility Inventory. RESULTS: Of 1995 participants, 25.1% were taking a lipid-lowering agent at baseline. Mean CES-D scores were similar between participants with low (<150 mg/dL) versus greater (>=150 mg/dL) TC and low (<100 mg/dL) versus higher (>=100 mg/dL) LDL cholesterol. However, among 22 participants with LDL cholesterol <70 mg/dL, the prevalence of clinically significant depressive symptomatology (CES-D score >=16) was 31.8% compared with 12.1% in the remaining cohort (P = .005). In multivariable analysis, low LDL cholesterol (<100 mg/dL) was associated with cynicism (partial r = -0.14, P = .02) and hostility (partial r = -0.18, P = .004), but only in the subgroup of white subjects currently taking lipid-lowering medications. Low LDL cholesterol (versus non-low) was associated with greater aggression scores but only among participants currently taking psychiatric medications (3.4 +/- 1.7 vs 2.8 +/- 1.5, P = .02). CONCLUSIONS: Our data indicate mixed evidence for independent relationships between low total and LDL cholesterol levels and impaired psychological health. PMID- 23725921 TI - Management of familial heterozygous hypercholesterolemia: Position Paper of the Polish Lipid Expert Forum. AB - Heterozygous familial hypercholesterolemia (HFH) affects on average 1 in 500 individuals in European countries, and it is estimated that HeFH in Poland may affect more than 80,000 people. Cardiovascular mortality in individuals with FH between 20 and 39 years of age is 100 times higher than in the general population. HFH is a relatively common lipid disorder, but usually still remaining undiagnosed and untreated. A very high risk of cardiovascular diseases and a shortened lifespan in patients with this condition require early diagnosis and intensive treatment. The aim of the position paper was to present the importance and scale of this problem in Poland, which has not been raised enough so far, as well as the recommendations of diagnosis, treatment and prevention methods. PMID- 23725922 TI - Point: why statins have failed to reduce mortality in just about anybody. PMID- 23725923 TI - Counterpoint: statins do reduce fatal events. PMID- 23725925 TI - New-onset hypercholesterolemia as an unusual presenting manifestation of eosinophilic gastroenteritis. AB - We describe an unusual case of new-onset hypercholesterolemia in a 28-year-old man. The presence of low serum albumin and hypercholesterolemia established the suspicion of gastrointestinal disease. Technetium-99m diethylenetriaminepentaacetic acid scintigraphy was performed to identify possible protein-losing enteropathy. The results were consistent with eosinophilic gastroenteritis, a rare disease characterized by eosinophilic infiltration that may involve several digestive tract layers. To our knowledge, this is the first time that hypercholesterolemia has been recognizing as the presenting manifestation of eosinophilic gastroenteritis. The patient has been successfully treated with prednisone and budesonide. Hypercholesterolemia may be an early manifestation of a serious underlying disease, among which eosinophilic gastroenteritis should also be considered. PMID- 23725926 TI - Mid-term study of bone remodeling after femoral cemented stem implantation: comparison between DXA and finite element simulation. AB - This five-year prospective study was designed to investigate periprosthetic bone remodeling associated with two cemented stem models, ABG-II (Stryker) and VerSys (Zimmer), randomly implanted in patients older than 75 years. The sample consisted of 64 cases (32, ABG-II; 32, VerSys). Inclusion criterion was diagnosis of osteoarthritis recommended for cemented total hip arthroplasty. Besides clinical study, Finite Element (FE) simulation was used to analyze biomechanical changes caused by hip arthroplasty. Bone Mineral Density (BMD) measurements showed a progressive increase in bone mass throughout the entire follow-up period for both stems, well correlated with FE results except in Gruen zones 4, 5, 6 for ABG-II and in zones 4, 5 for VerSys, denoting that remodeling in those zones does not depend on mechanical factors but rather on biological or physiological ones. PMID- 23725927 TI - The effect of knee flexion contracture following total knee arthroplasty on the energy cost of walking. AB - This study evaluated the energy cost of walking (Cw) with knee flexion contractures (FC) simulated with a knee brace, in total knee arthroplasty (TKA) recipients (n=16) and normal controls (n=15), and compared it to baseline (no brace). There was no significant difference in Cw between the groups at baseline but TKA recipients walked slower (P=0.048) and with greater knee flexion in this condition (P=0.003). Simulated FC significantly increased Cw in both groups (TKA P=0.020, control P=0.002) and this occurred when FC exceeded 20 degrees in the TKA group and 15 degrees in the controls. Reported perceived exertion was only significantly increased by FC in the control group (control P<0.001, TKA P=0.058). Simulated knee FCs less than 20 degrees do not increase Cw or perceived exertion in TKA recipients. PMID- 23725928 TI - Osteonecrosis of the knee - which joint preservation procedures work? AB - There is no consensus with respect to the best procedures to preserve the knee joint in patients with osteonecrosis of the knee. We performed a systematic review of the literature between 1999 and 2012. Only 10 of 1057 studies met our inclusion criteria. Core decompression prevented additional surgical treatment in pre-collapse knees with a failure rate of 10.4% (7 of 67 knees). Autogenous and osteochondral grafts decreased the need for additional surgery in both pre collapse (0%, 20 of 20) and post-collapse knees (10.5%, 8 of 76 knees). Although these results are quite promising multi-center randomized trials are needed to identify the optimal procedures to treat this disease. PMID- 23725929 TI - Smartphones or tablets for a better communication and education between residents and consultant in a teaching hospital. PMID- 23725930 TI - Academic differences among male and female candidates applying for obstetrics and gynecology residency: the experience of one program. AB - OBJECTIVE: The purpose of this study was to identify academic differences between male and female candidates applying to our obstetrics and gynecology (OBGYN) residency. METHODS: We reviewed the Electronic Residency Application Service applications of candidates applying to our residency program from 2005 to 2009. Academic qualifications of male and female candidates were compared using the Fisher exact and Student t tests. RESULTS: Of 2263 applicants, 1710 (75.6%) were women. Compared with male candidates, female candidates in the United States were more likely to have earned honors in OBGYN (51.3% vs 41.2%, p = 0.02) and internal medicine clerkships (27.6% vs 19.1%, p = 0.03). There was a nonsignificant trend toward more female membership in the Alpha Omega Alpha. There were no differences in United States Medical Licensing Exam scores based on gender. CONCLUSIONS: Although no difference in United States Medical Licensing Exam scores were observed, female applicants performed better in select clerkships during medical school than their male counterparts. This difference in clerkship grades may contribute to the low proportion of male residents in OBGYN, although the overall low proportion of male applicants is likely an important factor as well. PMID- 23725932 TI - Development and validation of a musculoskeletal physical examination decision making test for medical students. AB - OBJECTIVE: Despite a renewed emphasis among educators, musculoskeletal education is still lacking in medical school and residency training programs. We created a musculoskeletal multiple-choice physical examination decision-making test to assess competency and physical examination knowledge of our trainees. DESIGN: We developed a 20-question test in musculoskeletal physical examination decision making test with content that most medical students and orthopedic residents should know. All questions were reviewed by ratings of US orthopedic chairmen. It was administered to postgraduate year 2 to 5 orthopedic residents and 2 groups of medical students: 1 group immediately after their 3-week musculoskeletal course and the other 1 year after the musculoskeletal course completion. We hypothesized that residents would score highest, medical students 1 year post-musculoskeletal training lowest, and students immediately post-musculoskeletal training midrange. We administered an established cognitive knowledge test to compare student knowledge base as we expected the scores to correlate. SETTING: Academic medical center in the Midwestern United States. PARTICIPANTS: Orthopedic residents, chairmen, and medical students. RESULTS: Fifty-four orthopedic chairmen (54 of 110 or 49%) responded to our survey, rating a mean overall question importance of 7.12 (0 = Not Important; 5 = Important; 10 = Very Important). Mean physical examination decision-making scores were 89% for residents, 77% for immediate post musculoskeletal trained medical students, and 59% 1 year post-musculoskeletal trained medical students (F = 42.07, p<0.001). The physical examination decision making test was found to be internally consistent (Kuder-Richardson Formula 20 = 0.69). The musculoskeletal cognitive knowledge test was 78% for immediate post musculoskeletal trained students and 71% for the 1 year post-musculoskeletal trained students. The student physical examination and cognitive knowledge scores were correlated (r = 0.54, p<0.001), but were not significantly different for either class. CONCLUSIONS: The physical examination decision-making test was found to be internally consistent in exposing the deficiencies of musculoskeletal education skills of our medical students and differentiated between ability levels in musculoskeletal physical examination decision-making (residents vs recently instructed musculoskeletal students vs 1 year post-musculoskeletal instruction). PMID- 23725931 TI - Construction and validation of a low-cost laparoscopic simulator for surgical education. AB - INTRODUCTION: To construct a trainer that would achieve the equivalent goals of the Fundamentals of Laparoscopic Surgery (FLS) trainer at an economical cost. A validation study comparing our homemade (HM) trainer vs the FLS trainer was performed. A literature search as well as a price comparison with other commercially available laparoscopic trainers is presented. METHODS: The HM laparoscopic trainer was constructed using a prefabricated hard plastic frame with a vinyl plastic sheet affixed as the roof. A row of light-emitting diode lights and a charge-coupled device camera were mounted on the inside roof of the frame. Electrical wires were spliced to supply power to both the light-emitting diode lights and the camera. The charge-coupled device camera was connected to a liquid crystal display screen which was affixed directly across from the user. Subjects were prospectively randomized to perform the 5 tasks put forth by the McGill Inanimate System for Training and Evaluation of Laparoscopic Skills on both the HM trainer and the FLS trainer (pegboard transfer, pattern cut, placement of ligating loop, extracorporeal knot suture, and intracorporeal knot suture). Simple paired t test was performed to compare times between the trainers. SETTING: The construction of the trainer and the validation study were performed at the Central Michigan University College of Medicine Department of Simulation. PARTICIPANTS: Subjects consisted of third- and fourth-year medical students (n = 30). RESULTS: A laparoscopic trainer box was constructed and assembled in 2 hours. The HM trainer cost $309 representing a cost savings of $1371. Results of the validation study demonstrated no statistical difference in times to complete 3 out of the 5 tasks as well as no difference in total time to complete all 5 tasks (p value< 0.05). CONCLUSION: Valid laparoscopic simulators can be constructed at an economical cost. PMID- 23725933 TI - Home-field advantage: the role of selection bias in the general surgery national residency matching program. AB - BACKGROUND: For academic general surgery residency programs, graduation from the affiliated allopathic medical school is one criterion used in resident selection. The magnitude of this criterion is unknown. The aim of this study is to describe the nature of this phenomenon, with the hypothesis that states with fewer medical schools would accept more home program graduates than states with more medical schools. METHODS: In this cross-sectional study from 2012, each allopathic medical school that participates in the American Medical College Application Service was geographically matched to its academic general surgery program that participates in the Electronic Residency Application Service. Program websites were evaluated for categorical resident rosters with medical school matriculation data. The percentage of categorical home program residents was described for each program. A 1-tailed 2-sample t-test was performed between programs in states with fewer (n<=2) medical schools and programs in states with more (n>2) medical schools, using an alpha = 0.05. RESULTS: Of the 127 residency programs that met inclusion criteria, there were 64/127 (50.4%) programs with online categorical resident rosters and medical school graduation data. There was a mean of 26.4+/ 12.3 included residents per residency training program. The mean program percentage of home program categorical general surgery residents was 24.6%+/ 15.2%. The median number of medical schools per state was 2 (Interquartile Range [1-4]). A 1-tailed 2-sample t-test showed that the home program percentage rate in states with<=2 medical schools [n = 17] (30.1%+/-18.4%) was greater than the home program percentage rate in states with>2 medical schools [n = 47] (22.6%+/ 13.5%) (p = 0.04). CONCLUSIONS: Approximately, one-quarter of categorical general surgery slots are filled with home program graduates. States with fewer medical schools are more likely to fill general surgery slots with home program graduates than states with more medical schools. These selection criteria are important to general surgery programs and future applicants. PMID- 23725934 TI - Incorporation of fresh tissue surgical simulation into plastic surgery education: maximizing extraclinical surgical experience. AB - BACKGROUND: As interest in surgical simulation grows, plastic surgical educators are pressed to provide realistic surgical experience outside of the operating suite. Simulation models of plastic surgery procedures have been developed, but they are incomparable to the dissection of fresh tissue. We evolved a fresh tissue dissection (FTD) and simulation program with emphasis on surgical technique and simulation of clinical surgery. We hypothesized that resident confidence could be improved by adding FTD to our resident curriculum. METHODS: Over a 5-year period, FTD was incorporated into the curriculum. Participants included clinical medical students, postgraduate year 1 to 7 residents, and attending surgeons. Participants performed dissections and procedures with structured emphasis on anatomical detail, surgical technique, and rehearsal of operative sequence. Resident confidence was evaluated using retrospective pretest and posttest analysis with a 5-point scale, ranging from 1 (least confident) to 5 (most confident). Confidence was evaluated according to postgraduate year level, anatomical region, and procedure. RESULTS: A total of 103 dissection days occurred, and a total of 192 dissections were reported, representing 73 different procedures. Overall, resident predissection confidence was 1.90+/-1.02 and postdissection confidence was 4.20+/-0.94 (p<0.001). The average increase in confidence correlated with training year, such that senior residents had greater gains. When compared by anatomical region, confidence was lowest for the head and neck region. When compared by procedure, confidence was lowest for rhinoplasty and face-lift, and highest for radial forearm and latissimus flaps. CONCLUSIONS: A high-volume FTD experience was successfully incorporated into the residency program over 5 years. Training with FTD improves resident confidence, and this effect increases with seniority of training. Although initial data demonstrate that resident confidence is improved with FTD, additional evaluation is needed to establish objective evidence that patient outcomes and surgical quality can be improved with FTD. PMID- 23725935 TI - Multisource feedback to assess surgical practice: a systematic review. AB - BACKGROUND: The assessment, maintenance of competence, and recertification for surgeons have recently received increased attention from many health organizations. Assessment of physicians' competencies with multisource feedback (MSF) has become widespread in recent years. The aim of the present study was to investigate further the use of MSF for assessing surgical practice by conducting a systematic review of the published research. METHODS: A systematic literature review was conducted to identify the use of MSF in surgical settings. The search was conducted using the electronic databases EMBASE, PsycINFO, MEDLINE, PubMed, and CINAHL for articles in English up to August 2012. Studies were included if they reported information about at least 1 out of feasibility, reliability, generalizability, and validity of the MSF. RESULTS: A total of 780 articles were identified with the initial search and 772 articles were excluded based on the exclusion criteria. Eight studies met the inclusion criteria for this systematic review. Reliability (Cronbach alpha >= 0.90) was reported in 4 studies and generalizability (Ep2 >= 0.70) was reported in 4 studies. Evidence for content, criterion-related, and construct validity was reported in all 8 studies. CONCLUSION: MSF is a feasible, reliable, and valid method to assess surgical practice, particularly for nontechnical competencies such as communication skills, interpersonal skills, collegiality, humanism, and professionalism. Meanwhile, procedural competence needs to be assessed by different assessment methods. Further implementation for the use of MSF is desirable. PMID- 23725936 TI - Planting the 'SEAD': early comprehensive exposure to surgery for medical students. AB - INTRODUCTION: The popularity of surgical specialties is declining amongst Canadian medical students. Limited early exposure of students to surgery and minor involvement of surgeons in preclerkship education are barriers to creating interest in the field. Although many informal observerships and interest groups exist, there are no structured programs in Canada that offer preclerkship medical students a comprehensive exposure to surgery. METHODS: Twenty first-year medical students participated in the Surgical Exploration and Discovery (SEAD) Program. SEAD is a pilot project at the University of Toronto providing a unique combination of (1) observerships, (2) informal discussions on surgical careers, and (3) hands-on simulation workshops across all 7 direct-entry specialties within the Department of Surgery. All participants underwent pretraining and posttraining evaluation of learning through a paper-based knowledge test and all completed a structured survey on the benefit of the course. RESULTS: Comparison of test scores revealed an overall significant improvement in learning (p<0.0001). The improvement in test scores was seen in the knowledge of all 3 components of the course (p<0.0001). Qualitative evaluation revealed a positive student experience, with 100% of students indicating that SEAD helped them identify new interests in surgical subspecialties. Finally, 100% of students stated that they would recommend the program to incoming medical students. CONCLUSION: The SEAD Program successfully improves preclerkship students' knowledge of surgical principles, understanding of a career in surgery, and basic surgical skills. Participation in the program also positively influenced their interest in pursuing a career in surgery. Programs such as SEAD may be offered to preclerkship medical students to improve their exposure to surgery at this level of training and to enhance perspectives toward surgical careers. PMID- 23725937 TI - Quantifying factors influencing operating theater teaching, participation, and learning opportunities for medical students in surgery. AB - AIMS: Operating room experience offers a unique learning resource, potentially exposing medical students to surgical disease and treatments, use of anesthesia, basic science, team working, and communication skills. However, the alien nature of this environment to newcomers poses particular difficulties in harnessing this resource. This study aimed to assess the operating theater-based teaching and learning experiences of new medical graduates during their medical school course. METHODS: A 41-item, self-administered questionnaire survey was distributed to newly qualified medical school graduates from 1 university consisting of 5 separate teaching hospitals. Results were analyzed using GraphPad Prism 5.0. RESULTS: Questionnaires were returned by 209 of 312 graduates (67%). Overall, 121 (59%) respondents attended <=50% of opportunities available to attend operating theater; 47% felt they knew what was expected of them when attending and only 13% had specific learning objectives set. An interest in pursuing a surgical career was stated by 24 (12%) respondents; this group was more likely to have attended >=50% of operating theater opportunities (p = 0.0064). Those not intending to pursue a surgical career were more likely to have been discouraged by their experiences (p = 0.0001). Active participation while scrubbed, knowing what was expected, being made to feel welcome, and being set learning objectives were all significantly positively correlated with attendance. Although female respondents felt equally welcome, in comparison with their male colleagues, they were more likely to receive negative comments (p = 0.0106). The majority of respondents (80%) stated that attendance at operating theater sessions should be a mandatory component of the curriculum. CONCLUSIONS: Although operating theater attendance is recognized as an important component of the medical school curriculum, overall attendance at sessions was low. Attendance could be increased by ensuring students knowing what is expected of them, making them feel welcome, setting learning objectives, and allowed them to actively participate. These results highlight the need to ensure that the time spent by medical students in the operating room is positive and maximized to its full potential through structured learning involving all members of the theater team. PMID- 23725938 TI - Social networking profiles and professionalism issues in residency applicants: an original study-cohort study. AB - OBJECTIVE: To determine the frequency of social networking, the degree of information publicly disclosed, and whether unprofessional content was identified in applicants from the 2010 Residency Match. BACKGROUND: Medical professionalism is an essential competency for physicians to learn, and information found on social networking sites may be hazardous to the doctor-patient relationship and an institution's public perception. No study has analyzed the social network content of applicants applying for residency. METHODS: Online review of social networking Facebook profiles of graduating medical students applying for a residency in orthopedic surgery. Evidence of unprofessional content was based upon Accreditation Council for Graduate Medical Education guidelines. Additional recorded applicant data included as follows: age, United States Medical Licensing Examination part I score, and residency composite score. Relationship between professionalism score and recorded data points was evaluated using an analysis of variance. RESULTS: Nearly half of all applicants, 46% (200/431), had a Facebook profile. The majority of profiles (85%) did not restrict online access to their profile. Unprofessional content was identified in 16% of resident applicant profiles. Variables associated with lower professionalism scores included unmarried relationship status and lower residency composite scores. CONCLUSION: It is critical for healthcare professionals to recognize both the benefits and risks present with electronic communication and to vigorously protect the content of material allowed to be publically accessed through the Internet. PMID- 23725939 TI - Standardized laparoscopic simulation positively affects a student's surgical experience. AB - OBJECTIVE: The aim of the study was to determine whether a standardized orientation to basic laparoscopy makes a positive effect on the experience of third-year medical students. STUDY DESIGN: Fifty-three third-year medical students at the University of Missouri, Columbia were randomly divided into 2 groups during their clerkship orientation. Both groups received a 40-minute laparoscopic hands-on training simulation guided by instructors. However, only 1 group was given a 20-minute multimedia presentation on introduction to laparoscopy that covered equipment, set up, troubleshooting, and different methods of access into the abdomen. Both groups were given a preclerkship and postclerkship survey where students were asked to rate their experience, comfort, and interest in surgery on a 10-point Likert scale. RESULTS: Hundred percent of the students receiving the combined hands-on training simulation and the 20 minute presentation felt that the experience helped during their clerkship (p = 0.002) and 92% felt it had a positive effect (p = 0.501). In contrast, only 72% of the group that received the hands-on training simulation alone found it helpful (p = 0.029) and 86% thought it had a positive effect (p = 0.508). There was no statistical difference between either group with regard to their perceived comfort with assistance in the operating room and with laparoscopy. Neither experience had a statistical effect on a students' interest in surgery as a career. CONCLUSIONS: Our results demonstrate how a standardized orientation to basic laparoscopy can make a positive effect on a student's experience; however, it fails to transition into a student's interest in surgery as a profession or in their perceived comfort level in the operating room. Our study suggests that a student's surgical interest is highly variable and composed of multiple experiences that occur during their clerkship that ultimately affects their perception of surgery as a field and profession. PMID- 23725940 TI - The assessment of emotional intelligence among candidates interviewing for general surgery residency. AB - BACKGROUND: There is an increasing demand for physicians to possess strong personal and social qualities embodied in the concept of emotional intelligence (EI). However, the residency selection process emphasizes mainly academic accomplishments. In this system, the faculty interview is the primary means of evaluating the nontangible, nonacademic attributes of a candidate. OBJECTIVE: To determine whether the impressions derived from faculty interviews correlate with an applicant's actual EI as measured by a validated objective instrument. STUDY DESIGN: Participating applicants interviewing for a surgical residency position at Stanford completed an EI inventory Trait Emotional Intelligence Questionnaire (TEIQue). Faculty estimated the EI of the applicants they interviewed using a corresponding 360 degrees evaluation form. Multivariate linear regression was performed to identify demographic and academic factors predictive of EI. Applicant TEIQue scores and faculty 360 degrees impressions were correlated using Pearson coefficients. RESULTS: Mean EI of the cohort was higher than that of the average population (5.43 vs 4.89, p<0.001). Age was the only demographic variable that significantly informed EI (B = 0.07, p = 0.005). Among the academic factors considered, United States Medical Licensing Examination Step 1 score was a slight negative predictor of EI (B =-0.007, p = 0.04). Applicant global EI scores did not correlate with faculty impressions of overall EI (r = 0.27, p = 0.06). Of the 4 domains that comprise global EI, sociability and emotionality demonstrated a moderate correlation between applicant and faculty scores (r = 0.31, p = 0.03 and r = 0.27, p = 0.05, respectively). None of the fifteen individual facets of EI demonstrated any correlation between applicant and faculty ratings (r =-0.12 to 0.26, p = 0.06-0.91). No association was found between applicant TEIQue and traditional faculty interview evaluations (r = 0.18, p = 0.19). CONCLUSIONS: Applicant EI correlated poorly with academic parameters and was not accurately assessed by faculty interviews. Methods that better capture this dimension should be incorporated into the residency selection process. PMID- 23725941 TI - The effect of model fidelity on colonoscopic skills acquisition. A randomized controlled study. AB - INTRODUCTION: Colonoscopic simulators offer the opportunity for skill acquisition in the preclinical setting. Currently available simulators vary widely with respect to level of fidelity and technological sophistication. Despite the belief that more realistic is better, there is a paucity of evidence regarding the relative effectiveness of simulator fidelity (high vs low) on the acquisition of basic colonoscopic skills. We hypothesized that novice learners can acquire basic colonoscopic skills using simulators, however fidelity of the simulator does not make a difference. METHODS: We randomly assigned novice third-year and fourth year medical students to practice on either a low-fidelity or high-fidelity colonoscopy model. The low-fidelity model used is described in the module 16 of the American College of Surgeons/Association of Program Directors in Surgery surgical skills curriculum for residents, Phase 1: basic or core skills and tasks < http://elearning.facs.org/mod/resource/view.php?1d=450 >. The high-fidelity model was the AccuTouch colonoscopy simulator, Immersion Medical (AccuTouch CS) that has 6 different simulated scenarios for diagnostic colonoscopy (level 1-6). Both groups had 16 students and were given standard instruction by an expert with respect to the procedure and instrument handling on both models. Both groups were pretested and posttested on level 1 of the AccuTouch CS. The high-fidelity group practiced on level 2 and 4 of the AccuTouch CS, whereas the low-fidelity group practiced on the low-fidelity model for 2 sessions of 1 hour each. The computer based evaluation parameters available on the AccuTouch CS were used to compare performances. RESULTS: Both groups had similar demographics. There were no significant differences in the baseline performances of either group. Each group demonstrated significant improvement for insertion time and percentage of mucosa visualized. However, there were no significant differences between the groups on posttesting on any of the measured parameters. CONCLUSIONS: Colonoscopic skill training on a low-fidelity model appears to be as effective as high-fidelity model training for basic endoscopic skill acquisition for novice learners. PMID- 23725942 TI - The orthopaedic in-training examination: perspectives of program directors and residents from the United States and Canada. AB - OBJECTIVE: Objective assessment of resident performance continues to task program directors (PDs) with a formidable challenge. This study evaluated attitudes toward the Orthopaedic In-Training Examination (OITE), compared its value between countries, assessed its value against other metrics of resident performance, and examined program and resident factors predictive of high achievement. DESIGN: Survey. SETTING: Orthopedic surgery residency programs across the United States and Canada. PARTICIPANTS: One hundred sixty-six PDs and 945 residents. RESULTS: Eighty-eight PDs and 331 residents completed the surveys (response rates, 54% and 35%, respectively). PDs and residents in the United States assigned greater importance to the OITE than did those in Canada and reported OITE scores from the United States were significantly higher. PDs in the United States reported greater consequences for residents with poor scores than did PDs from Canada, including remediation and reprimand. Observed structured clinical examinations, internal examinations, and in-training evaluation reports were assigned greater importance by PDs and residents in Canada, but low or no importance by those in the United States. In preparation for the OITE, residents strongly favored prior OITE and American Academy of Orthopaedic Surgeons self-assessment questions, the 'AAOS Comprehensive Orthopaedic Review' textbook, the Journal of the American Academy of Orthopaedic Surgeons, and an OITE-based multiple-choice question website. Regression analysis identified resident and program emphasis on OITE studying and higher level of training as positive predictors for higher OITE scores. CONCLUSIONS: The OITE is more important to PDs and residents in the United States than it is in Canada, and the reported OITE scores reflect these attitudes. PDs in Canada also employ a greater diversity of evaluative tools, a practice in keeping with recent advances toward competency-based medical education. The findings of this report may help PDs be aware of alternative methods of formative resident evaluation and ultimately improve the training of future independent surgeons. PMID- 23725943 TI - Trends in matching to urology residency in Canada: are we becoming noncompetitive? AB - BACKGROUND: Urology is perceived as a competitive specialty choice. Declining undergraduate exposure and the preference for "lifestyle specialties" may jeopardize urology's popularity. Our objective was to assess trends in application and matching rates to urology compared with other surgical specialties. METHODS: We reviewed data collected by Canadian Residency Matching Service (CaRMS) and the Canadian Post-MD Education Registry since expansion in Canadian medical school enrollment began (2002-2011). The following were examined: applicant preference, number of positions, gender patterns, and match results. "Surgery" included general surgery, orthopedics, plastics, ENT, and urology. RESULTS: From 2002 to 2011 CaRMS applicants increased from 1117 to 2528 (126%). The number of applicants selecting surgery first increased from 178 to 338(90%). The number of surgery positions increased from 138 to 275 (100%). Urology positions increased from 15 to 31 (113%). Applicants to urology increased only 40% (30-42). The proportion of all CARMs applicants selecting urology as their first choice decreased from 2.7% (30) to 1.7% (42). The ratio of first choice urology applicants to positions decreased from 2 to 1.35. The probability of matching urology as first choice increased from 50% to 76%. Female medical graduates increased from 51% to 58%. The female applicants selecting surgery first increased from 21% (49) to 41% (173). In contrast, females selecting urology first rose from 13% (4) to 17% (7). CONCLUSION: Urology in Canada is becoming less competitive. Residency positions have doubled since 2002 whereas the number of applicants remains static. This trend was not reflected in other surgical specialities. Factors accounting for this may include poor undergraduate exposure, demand for specialties with controllable lifestyles, gender shifts in undergraduate medicine, and lack of role models. The need for undergraduate exposure to urology and vetting numbers of residency positions remains a matter of paramount importance. PMID- 23725944 TI - Using the mind as a simulator: a randomized controlled trial of mental training. AB - OBJECTIVES: Laparoscopic simulators have been introduced as safe and effective methods of developing basic skills. Mental training is a novel training method likened to using the mind as a simulator to mentally rehearse the movements of a task or operation. It is widely used by professional athletes and musicians and has been suggested as a technique that could be used by surgical trainees. The purpose of this study was to assess the use of mental training in developing basic laparoscopic skills in novices. METHODS: Sixty-four medical students without laparoscopic experience were randomized into 4 groups. The first 3 groups were trained to cut a circle on a box trainer. Group 1 received no additional training (BT), Group 2 received additional virtual reality training (BT + VRS), and Group 3 received additional mental training (BT + MT). The fourth group was trained on a virtual reality simulator with additional mental training (box free). The following 4 assessment criterias: time, accuracy, precision and overall performance were measured on both the box-trainer and virtual simulator. RESULTS: The mental training group (BT + MT) demonstrated improved laparoscopic skills over both assessments. The improvement in skills in the VRS group (BT + VRS) was limited to VRS assessment and not observed in the box assessment. The fourth group (box-free) had the worst performance on both methods of assessment. CONCLUSION: The addition of mental training led to improved laparoscopic skills development. It is a flexible technique and has the potential to challenge VRS as a more cost-effective training method associated with lower capital investment. Given the benefits of mental training with further research, it could be considered for inclusion in training curricula. PMID- 23725945 TI - Better never stops: What can surgeons learn from Olympians? PMID- 23725946 TI - Excuse me, there is an 'elephant in the room'. PMID- 23725947 TI - A new algorithm for the diagnosis of all forms of tuberculosis is required for South Africa. PMID- 23725948 TI - Chesed Children's Clinic: a non-profit, paediatric primary care outreach clinic in the Eastern Cape created by junior doctors and volunteers. PMID- 23725949 TI - 'Boston' skin cloning an exception - burns surgeons. PMID- 23725950 TI - Is your prescribing serving a hidden addiction? PMID- 23725951 TI - RWOPS clampdown - a crisis in the offing. PMID- 23725952 TI - Starch safety in resuscitation - when will we ever learn? AB - Recent trials have failed to demonstrate a survival benefit from the use of hydroxyethyl starches (HES) as a colloid in fluid resuscitation and have raised concerns of renal harm. In severe sepsis, there is a concerning signal of increased mortality. New high-quality systematic reviews consistently demonstrate a statistically non-significant relative risk of death of 1.08 - 1.10 and a significant 25% increased chance of requiring renal replacement therapy. The HES literature contains many industry-affiliated reviews of indifferent quality. Traditional efficacy confidence limits may warrant re-evaluation when considering these harms. Newer formulations of HES and more focused indications for use show benefit on surrogate endpoints, but these trials are currently underpowered to ensure safety. PMID- 23725953 TI - Latex allergy: 'plight, rights and fights'. PMID- 23725954 TI - Microbiological surveillance and antimicrobial stewardship minimise the need for ultrabroad-spectrum combination therapy for treatment of nosocomial infections in a trauma intensive care unit: an audit of an evidence-based empiric antimicrobial policy. AB - BACKGROUND: Nosocomial infections are a major cause of morbidity in the critically injured, and the incidence of resistant strains of bacteria is increasing. Management requires a strategy that achieves accurate empiric cover without antibiotic overuse - a goal that may be achieved by surveillance and antibiotic stewardship. OBJECTIVES: With the aim of minimising the use of empirical ultrabroad-spectrum combination antimicrobial prescriptions and reducing bacterial resistance, the level I Trauma Intensive Care Unit (TICU) at Inkosi Albert Luthuli Central Hospital (IALCH) in Durban employs stewardship and an antimicrobial policy based on surveillance. This study was undertaken with three aims: (i) to describe the spectrum and sensitivities of nosocomial pathogens in a level I TICU; (ii) to ascertain, based on surveillance data, how frequently initial empiric choice of antimicrobials was correct; and (iii) to determine how frequently ultrabroad-spectrum antimicrobials were prescribed and were actually necessary. METHODS: Over a 12-month period, all critically injured patients who underwent mechanical ventilation in the TICU were identified from a prospectively gathered database. Information regarding every specimen submitted to the National Health Laboratory Services (NHLS) situated at IALCH was extracted from the laboratory computer database. For each patient, bacterial isolates and antimicrobial susceptibility were identified using standard laboratory techniques. Empiric prescriptions for presumed nosocomial sepsis were identified from the hospital's computerised patient record system and compared with culture results. Acinetobacter species were regarded as colonisers and treatment not offered unless this was the sole isolate in the presence of signs of severe sepsis. Results. Of 227 patients, 106 (46.6%) had 136 culture-positive isolates with a total of 323 pathogens (201 Gram-negative, 119 Gram-positive, 3 Candida albicans). There were 19 species of Gram-negative pathogens, of which 56% comprised Enterobacteriaceae. Extended spectrum beta-lactamase (ESBL) production was found in 6/31 (19%) Escherichia coli coli and 6/24 (25%) Klebsiella isolates. Staphyloccocal species accounted for 60% of the Gram-positive isolates, of which 18 were methicillin-resistant Staphylococcus aureus (MRSA). All Candida isolates were sensitive to fluconazole. One hundred and one empiric and 14 directed prescriptions were issued. Despite positive cultures, antimicrobials were not prescribed for 21 patients who had no evidence of sepsis. Excluding multidrug resistant Acinetobacter isolates, there were 87 (93.5%) appropriate and 6 (6.5%) incorrect prescriptions. Ultrabroad-spectrum combination therapy (U-bSCT) was employed for 11 patients but was necessary in only 2. CONCLUSIONS: When combined with regular bacterial surveillance, antimicrobial stewardship allows accurate empiric antimicrobial prescription with minimal need for ultrabroad-spectrum combination therapy. This policy can potentially reduce the emergence of multidrug-resistant pathogens, precluding the need for broad-spectrum antimicrobials and the attendant problems of overuse. PMID- 23725955 TI - Antimicrobial susceptibility of organisms causing community-acquired urinary tract infections in Gauteng Province, South Africa. AB - BACKGROUND: Patients with community-acquired urinary tract infections (UTIs) frequently present to healthcare facilities in South Africa (SA). AIM: To provide information on UTI aetiology and antimicrobial susceptibility of pathogens. METHODS: We recruited women with UTI-related symptoms, who tested positive for >=2 urine dipstick criteria (proteinuria, blood, leucocytes or nitrites) at 1 public and 5 private primary healthcare facilities in 2011. Demographic and clinical data were recorded and mid-stream urine (MSU) specimens were cultured. UTI pathogens were Gram-stained and identified to species level. Etest-based antimicrobial susceptibility testing was performed for amoxicillin/clavulanic acid, cefixime, cefuroxime, ciprofloxacin, fosfomycin, levofloxacin, nitrofurantoin, norfloxacin and trimethoprim/sulphamethoxazole. RESULTS: Of the 460 women recruited, 425 MSU samples were processed and 204 UTI pathogens were identified in 201 samples. Most pathogens were Gram-negative bacilli (GNB) (182; 89.2%) and 22 (10.8%) were Gram-positive cocci (GPC). Escherichia coli was the most frequent GNB (160; 79.6%), while Enterococcus faecalis was the predominant GPC (8; 4.0%). The UTI pathogens had similar susceptibility profiles for fosfomycin (95.5%; 95% confidence interval (CI) 92.6 - 98.4), the 3 fluoroquinolones (94.1%; 95% CI 90.8 - 97.4), nitrofurantoin (91.7%; 95% CI 87.8 95.6), cefuroxime (90.1%; 95% CI 86.0 - 94.3) and cefixime (88.2%; 95% CI 83.7 - 92.6). UTI pathogens were less susceptible to amoxicillin/clavulanic acid (82.8%; 95% CI 77.5 - 88.0) when compared with fluoroquinolones and fosfomycin. Trimethoprim/ sulphamethoxazole was the least efficacious antimicrobial agent (44.3% susceptible; 95% CI 37.4 - 51.2). CONCLUSION: This study provides relevant data for the empirical treatment of community-acquired UTIs in SA. PMID- 23725956 TI - Extremely high prevalence of multi-resistance among uropathogens from hospitalised children in Beira, Mozambique. AB - OBJECTIVES: A prospective surveillance study was conducted to investigate the epidemiology and patterns of antibiotic resistance among uropathogens from hospitalised children in Beira, Mozambique. Additionally, information regarding determinants of a urinary tract infection (UTI) was obtained. METHODS: Bacterial species identification, antimicrobial susceptibility testing and extended spectrum beta-lactamase testing were performed for relevant bacterial isolates. RESULTS: Analysis of 170 urine samples from 148 children yielded 34 bacterial isolates, predominantly Escherichia coli and Klebsiella spp., causative of a urinary tract infection in 29 children; 30/34 isolates (88.2%) from 26/29 children (89.7%) were considered highly resistant micro-organisms (HRMOs). No significant determinants of urinary tract infection with HRMOs were detected when analysing gender, antibiotic use during hospital admission and HIV status. CONCLUSION: This study shows, for the first time in Mozambique, an extremely high prevalence of HRMOs among uropathogens from hospitalised children with a urinary tract infection. PMID- 23725957 TI - Bacterial contamination of re-usable laryngoscope blades during the course of daily anaesthetic practice. AB - BACKGROUND AND OBJECTIVES: Hospital-acquired infections (HAIs) are largely preventable through risk analysis and modification of practice. Anaesthetic practice plays a limited role in the prevention of HAIs, although laryngoscope use and decontamination is an area of concern. We aimed to assess the level of microbial contamination of re-usable laryngoscope blades at a public hospital in South Africa. SETTING: The theatre complex of a secondary-level public hospital in Johannesburg. METHODS: Blades from two different theatres were sampled twice daily, using a standardised technique, over a 2-week period. Samples were quantitatively assessed for microbial contamination, and stratified by area on blade, theatre and time using Fisher's exact test. RESULTS: A contamination rate of 57.3% (63/110) was found, with high-level contamination accounting for 22.2% of these. Common commensals were the most frequently isolated micro-organisms (79.1%), but important hospital pathogens such as Enterobacter species and Acinetobacter baumannii were isolated from blades with high-level contamination. No significant difference in the level of microbial contamination by area on blade, theatre or time was found (p<0.05). CONCLUSIONS: A combination of sub optimal decontamination and improper handling of laryngoscopes after decontamination results in significant microbial contamination of re-usable laryngoscope blades. There is an urgent need to review protocols and policies surrounding the use of these blades. PMID- 23725958 TI - Latex allergy and its clinical features among healthcare workers at Mankweng Hospital, Limpopo Province, South Africa. AB - BACKGROUND AND OBJECTIVES: Latex allergy, caused by sensitisation in atopic individuals, is a common occupational disease among healthcare workers who use latex gloves. It may be present in non-atopic individuals as well. The main objective of this study was to document the prevalence and disease spectrum of latex allergy at Mankweng Hospital, Limpopo Province, South Africa. The secondary objective was to determine clinical presentation of the disease. METHODS: A cross sectional descriptive study, with an analytical component, was conducted among healthcare workers who worked in high-risk areas for latex sensitisation. ImmunoCAP testing was performed and followed by a skin-prick test (SPT) in those who tested negative to the blood test. RESULTS: Two hundred screening questionnaires were distributed to healthcare workers at the hospital. Of these 158 (79.0%) were returned, with 59 participants meeting the inclusion criteria (experiencing symptoms due to wearing latex gloves). The mean age of the participants was 39.6 years (standard deviation 9.8 years, range 20 - 60 years). There were more females (98.1%) than males (1.9%). Glove-related symptoms were present in 59 subjects (37.1%), in 7 (11.9%) of whom the ImmunoCAP was positive to latex (95% confidence interval 4.2 - 22.9%). Fourteen participants were lost to follow-up before the SPT was performed. Thirty-eight of the participants with negative ImmunoCAP tests underwent SPT. Positive SPTs were reported in 5 of these 38 workers (13.2%), indicating that the ImmunoCAP test missed 11.1% (5/45) of latex-allergic individuals. The prevalence of latex allergy in this study was 8.3% (12/144). A denominator of 144 was used, as there is a possibility that some of the 14 individuals lost to follow-up could have tested positive to latex sensitisation by SPT. The symptoms experienced by latex-sensitised workers were rhinitis (100.0%), asthma (50.0%), dermatitis (25.0%), severe anaphylaxis (8.3%), abdominal pain (8.3%) and angio-oedema (8.3%). CONCLUSION: Our findings reveal that latex allergy is a problem at our hospital. The prevalence of 8.3% is comparable to findings in other South African centres. We recommend a latex-free protocol for high-risk areas and healthcare workers. PMID- 23725959 TI - The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care. AB - BACKGROUND: There is a paucity of data on the pharmacokinetics of fixed-dose combination enteral antituberculosis treatment in critically ill patients. OBJECTIVES: To establish the pharmacokinetic profile of a fixed-dose combination of rifampicin, isoniazid, pyrazinamide and ethambutol given according to weight via a nasogastric tube to patients admitted to an intensive care unit (ICU). METHODS: We conducted a prospective, observational study on 10 patients (mean age 32 years, 6 male) admitted to an ICU and treated for tuberculosis (TB). Serum concentrations of the drugs were determined at eight predetermined intervals over 24 hours by means of high-performance liquid chromatography. RESULTS: The therapeutic maximum plasma concentration (Cmax) for rifampicin at time to peak concentration was achieved in only 4 patients, whereas 2 did not achieve therapeutic Cmax for isoniazid. No patient reached sub-therapeutic Cmax for pyrazinamide (6 were within and 4 above therapeutic range). Three patients reached sub-therapeutic Cmax for ethambutol, and 6 patients were within and 1 above the therapeutic range. Patients with a sub-therapeutic rifampicin level had a higher mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score (p=0.03) and a lower estimated glomerular filtration rate (GFR) (p=0.03). CONCLUSIONS: A fixed-dose combination tablet, crushed and mixed with water, given according to weight via a nasogastric tube to patients with TB admitted to an ICU resulted in sub-therapeutic rifampicin plasma concentrations in the majority of patients, whereas the other drugs had a more favourable pharmacokinetic profile. Patients with a sub-therapeutic rifampicin concentration had a higher APACHE II score and a lower estimated GFR, which may contribute to suboptimal outcomes in critically ill patients. Studies in other settings have reported similar proportions of patients with 'sub-therapeutic' rifampicin concentrations. PMID- 23725960 TI - AIDS-related progressive multifocal leukoencephalopathy (PML): a retrospective study from Pretoria, South Africa. AB - INTRODUCTION AND OBJECTIVES: Progressive multifocal leukoencephalopathy (PML), caused by the John Cunningham (JC) virus, results from lytic infection of predominantly oligodendrocytes. Following the HIV pandemic, the incidence of PML has risen sharply, but has rarely been reported in Africa. An increasing number of PML cases were seen recently in a tertiary South African hospital, and this study describes their clinical and radiological features. METHODS: Patients with positive cerebrospinal fluid (CSF) JC virus confirmed by real-time polymerase chain reaction (PCR) were retrospectively identified from January 2008 to June 2012. Adults seen at Neurology with PML were identified, and clinical features, laboratory findings and imaging studies were analysed. RESULTS: Of 121 specimens, 19 were positive; records of 17 patients were available (ages 27 - 64; CD4 counts 11 - 328 x106/MUl); clinical manifestations included focal weakness (47%), impaired co-ordination (41%), and speech disturbances (12%), and CSF analysis showed high protein in 76%, and pleocytosis in 35%. Fifteen patients had CT brain scans, showing white matter involvement in 12; MRI studies in 13 patients showed typical PML lesions. CONCLUSION: This report is the first case series of patients with PML from a South African neurology unit, emphasising the fact that PML occurs commonly in South African patients with HIV infection. PMID- 23725961 TI - Burden of fetal alcohol syndrome in a rural West Coast area of South Africa. AB - BACKGROUND: Fetal alcohol syndrome (FAS) is common in parts of South Africa; rural residence is a frequently cited risk factor. We conducted a FAS school prevalence survey of an isolated rural community in a West Coast village of Western Cape Province, so obtaining the first directly measured rate, focusing specifically on a South African rural area, of FAS and partial FAS (PFAS). METHODS: The study area (Aurora village), a community of about 2 500 people in a grain-producing region, has one primary school. All learners were eligible for study inclusion. Initial anthropometry screening was followed by a diagnostic stage entailing examination by a dysmorphologist for features of FAS, neurodevelopmental assessment, and an interview assessing maternal alcohol consumption. RESULTS: Of 160 learners screened, 78 (49%) were screen-positive, of whom 63 (81%) were clinically assessed for FAS. The overall FAS/PFAS rate among the screened learners was 17.5% (95% confidence interval 12.0 - 24.2%), with 16 (10.0%) children having FAS and 12 (7.5%) PFAS. High rates of stunting, underweight and microcephaly were noted in all learners, especially those with FAS or PFAS. Five (18%) mothers of affected children were deceased by the time of assessment. CONCLUSION: We describe very high rates of FAS/PFAS in an isolated rural part of the Western Cape that is not located in a viticultural region. Our study suggests that the prevalence of FAS may be very high in isolated communities, or in particular hot-spots. It adds to the growing evidence that FAS/PFAS is a significant, and underestimated, health problem in South Africa. Expanded screening and surveillance programmes, and preventive interventions, are urgently needed. PMID- 23725962 TI - Factors associated with contraceptive use in a rural area in Western Cape Province. AB - BACKGROUND: Safe and effective contraceptive use can substantially improve women's reproductive health. Although the contraceptive prevalence rate (CPR) in South Africa is comparable to rates globally, inequalities in CPR affect poor and rural women. This study aimed to determine the CPR and factors associated with contraceptive use in a rural district of Western Cape Province. METHOD: Cross sectional survey data based on 412 face-to-face interviews with female participants between 18 and 44 years of age were collected in 2006 for a primary fetal alcohol syndrome prevention study in a rural district in Western Cape Province. The study used effective contraception (ECC) as the outcome variable. ECC included use of oral contraceptives, condoms, injectables or sterilisation. Independent variables included socio-demographic factors, substance use, psychosocial factors, community factors, childbearing characteristics and partner characteristics. RESULTS: Women were more likely to use ECC if they reported high self-esteem (compared with low or moderate self-esteem (prevalence risk ratio (PRR)=1.23; 95% confidence interval (CI) 0.99 - 1.53); if they strongly or moderately agreed that their culture entitled men to make decisions regarding child-bearing compared with those who disagreed (PRR=1.28; 95% CI 0.96 - 1.71); and if they had one child or more compared with no children (PRR=1.62; 95% CI 1.24 - 2.11). CONCLUSION: The CPR for sexually active women in this study was low at 39.3%. To promote contraceptive use in similar rural populations, family planning programmes should focus on increasing men's approval of contraception, improving partner communication around family planning and bolstering women's confidence in their reproductive decision-making, and particularly their self esteem. There should be greater focus on nulliparous women. PMID- 23725963 TI - Acute kidney injury risk factor recognition in three teaching hospitals in Ethiopia. AB - BACKGROUND: A key objective of the Nephrology Sister Centre Programme between the renal units in Cardiff and Addis Ababa, sponsored by the International Society of Nephrology, is to facilitate development of the local clinical service in Ethiopia specifically focused on the management of acute kidney injury (AKI). OBJECTIVES: To examine the relationship between AKI risk factor recognition and monitoring of renal function in three hospitals in Ethiopia. METHODS: Cross sectional data were gathered regarding renal function monitoring, recording the presence of AKI risk-associated comorbidities and prescription of nephrotoxic medications across the disciplines of medicine, surgery, obstetrics and gynaecology. Results. Patients were more likely to have their renal function checked at the hospital with specialist services. Across all centres, the highest proportion of patients who had renal function measurements were those admitted to a medical ward. There was a positive relationship between documented comorbidities and the measurement of renal function but not between the prescription of nephrotoxic drugs and measurement of renal function. CONCLUSION: There was great variability in the extent to which doctors recognised the presence of risk factors for the development of AKI. Failure to identify these risk factors represents a lost opportunity to identify patients at high risk of developing renal injury who would benefit from renal function monitoring. PMID- 23725964 TI - Chronic rhinitis in South Africa: update 2013. AB - The term rhinitis implies inflammation of the lining of the nose. Characteristic symptoms are a blocked nose, anterior and posterior rhinorrhea, sneezing and itching. Not all cases of chronic rhinitis have an allergic basis. Chronic non allergic rhinitis is defined as a condition where ongoing rhinitic symptoms are present for many months (as for persistent allergic rhinitis) but there is no IgE basis. Many common conditions may present as chronic rhinitis, which will need to be investigated and managed on their own merits. Not all cases of chronic rhinitis respond to allergic rhinitis therapy: continued attempts to manage chronic rhinitis as allergic rhinitis may be hampered by pathophysiological conditions where other specific therapy may be required. Chronic rhinitis impacts on patient quality of life, and therefore therapy is important. Managing patients with chronic rhinitis requires attention to patient education in order to achieve the maximal therapeutic benefit of medication. This update is intended to provide clinicians with a sound basis for management of a common condition. PMID- 23725965 TI - Spinal cord stimulation for the management of pain: Recommendations for best clinical practice. AB - Spinal cord stimulation (SCS) is an accepted method of pain control. SCS has been used for many years and is supported by a substantial evidence base. A multidisciplinary consensus group has been convened to create a guideline for the implementation and execution of an SCS programme for South Africa (SA). This article discusses the evidence and appropriate context of SCS delivery, and makes recommendations for patient selection and appropriate use. The consensus group has also described the possible complications following SCS. This guideline includes a literature review and a summary of controlled clinical trials of SCS. The group notes that, in SA, SCS is performed mainly for painful neuropathies, failed back surgery, and chronic regional pain syndrome. It was noted that SCS is used to treat other conditions such as angina pectoris and ischaemic conditions, which have therefore been included in this guideline. These recommendations give guidance to practitioners delivering this treatment, to those who may wish to refer patients for SCS, and to those who care for patients with stimulators in situ. The recommendations also provide a resource for organisations that fund SCS. This guideline has drawn on the guidelines recently published by the British Pain Society, and parts of which have been reproduced with the society's permission. These recommendations have been produced by a consensus group of relevant healthcare professionals. Opinion from outside the consensus group has been incorporated through consultation with representatives of all groups for whom these recommendations have relevance. The recommendations refer to the current body of evidence relating to SCS. The consensus group wishes to acknowledge and thank the task team of the British Pain Society for their help and input into this document. PMID- 23725966 TI - Feline companions and demography. PMID- 23725967 TI - Continuing danger of glucose point-of-care test devices in the neonatal setting. PMID- 23725968 TI - Big pharma under the spotlight. PMID- 23725969 TI - Thieves of the state and the South African Medical Association. PMID- 23725970 TI - Surveillance alone plays a key role in curbing the overuse of antimicrobials: the major role of antibiotic stewardship. PMID- 23725971 TI - Rape in South Africa. PMID- 23725972 TI - Comparison of life participation activities among adults treated by hemodialysis, peritoneal dialysis, and kidney transplantation: a systematic review. AB - BACKGROUND: A comprehensive assessment of the association of patients' renal replacement therapy (RRT) modality with their participation in life activities (physical function, travel, recreation, freedom, and work) is needed. STUDY DESIGN: Systematic review of peer-reviewed published studies. SETTING & POPULATION: Adults undergoing RRT (hemodialysis, peritoneal dialysis, or transplantation). SELECTION CRITERIA FOR STUDIES: We searched PubMed, Cochrane Library, and EMBASE from January 1980 through April 2012 for English-language articles that compared participation in life activities among patients receiving: (1) hemodialysis compared with peritoneal dialysis, (2) hemodialysis compared with kidney transplantation, or (3) peritoneal dialysis compared with kidney transplantation. PREDICTOR: RRT modality. OUTCOMES: Reported rates of physical function, travel, recreation, freedom, and work-related activities by RRT modality. RESULTS: 46 studies (6 prospective cohort, 38 cross-sectional, and 2 pre-post transplantation) provided relevant comparisons of life participation activities among patients treated with hemodialysis, peritoneal dialysis, and kidney transplantation. Studies were conducted in 1985-2011 among diverse patient populations in 16 distinct locations. A majority of studies reported greater life participation rates for patients with kidney transplants compared with patients receiving either hemodialysis or peritoneal dialysis. In contrast, a majority of studies reported no differences in outcomes between patients receiving hemodialysis and patients receiving peritoneal dialysis. These results were consistent throughout the study period, across diverse populations, and among the subset of studies that performed appropriate adjustments for potential confounding factors. LIMITATIONS: Many studies included in the review had significant design weaknesses. CONCLUSIONS: Evidence suggests that patients with kidney transplants may experience better rates of life participation compared with patients receiving dialysis, whereas patients receiving hemodialysis and patients receiving peritoneal dialysis may experience similar rates of life participation. Rigorously performed studies are needed to better inform patients about the association of RRT with these important patient-reported outcomes. PMID- 23725973 TI - Effect of an L-carnitine-containing peritoneal dialysate on insulin sensitivity in patients treated with CAPD: a 4-month, prospective, multicenter randomized trial. AB - BACKGROUND: In peritoneal dialysis, the high glucose load absorbed from dialysis fluid contributes to several metabolic abnormalities, including insulin resistance. We evaluate the efficacy of a peritoneal dialysis solution containing l-carnitine as an additive to improve insulin sensitivity. STUDY DESIGN: Multicenter parallel randomized controlled trial. SETTING & PARTICIPANTS: Nondiabetic uremic patients on continuous ambulatory peritoneal dialysis enrolled in 8 peritoneal dialysis centers. INTERVENTION: Patients were randomly assigned to receive peritoneal dialysis diurnal exchanges with either a standard glucose based solution (1.5% or 2.5% according to the patient's need) or a glucose-based solution (identical glucose amount) enriched with l-carnitine (0.1%, weight/volume; 2 g/bag) for 4 months, the nocturnal exchange with icodextrin being unmodified. OUTCOMES & MEASUREMENTS: The primary outcome was insulin sensitivity, measured by the magnitude of change from baseline in glucose infusion rate (in milligrams per kilogram of body weight per minute) during a euglycemic hyperinsulinemic clamp. Secondary outcomes were safety and tolerability, body fluid management, peritoneal dialysis efficiency parameters, and biochemistry tests. RESULTS: 35 patients were randomly assigned, whereas 27 patients (standard solution, n=12; experimental solution, n = 15) were analyzed. Adverse events were not attributable to treatment. Glucose infusion rates in the l-carnitine-treated group increased from 3.8 +/- 2.0 (SD) mg/kg/min at baseline to 5.0 +/- 2.2 mg/kg/min at day 120 (P = 0.03) compared with 4.8 +/- 2.4 mg/kg/min at baseline and 4.7 +/- 2.4 mg/kg/min at day 120 observed in the control group (P = 0.8). The difference in glucose infusion rates between groups was 1.3 (95% CI, 0.0-2.6) mg/kg/min. In patients treated with l-carnitine containing solution, urine volume did not change significantly (P = 0.1) compared to a significant diuresis reduction found in the other group (P = 0.02). For peritoneal function, no differences were observed during the observation period. LIMITATIONS: Small sample size. CONCLUSIONS: The use of l-carnitine in dialysis solutions may represent a new approach to improving insulin sensitivity in nondiabetic peritoneal dialysis patients. PMID- 23725974 TI - Role of vaptans in the management of hyponatremia. AB - Hyponatremia, the most commonly encountered electrolyte abnormality, affects as many as 30% of hospitalized patients. It is a powerful predictor of poor outcomes, especially in patients with congestive heart failure or cirrhosis. The failure to excrete electrolyte-free water that results from persistent secretion of antidiuretic hormone despite low serum osmolality usually underlies the development of hyponatremia. Treatment depends on several factors, including the cause, overall volume status of the patient, severity of hyponatremic symptoms, and duration of hyponatremia at presentation. This review focuses on the role of the vasopressin receptor antagonists, or vaptans, in the treatment of hyponatremia. These recently introduced agents have the unique ability to induce an aquaresis, the excretion of electrolyte-free water without accompanying solutes. After a brief historical perspective and discussion of pharmacologic characteristics of vaptans, we review the accumulated experience with vaptans for the treatment of hyponatremia. Vaptans have been shown to increase serum sodium concentrations in patients with euvolemic or hypervolemic hyponatremia in a reproducible manner, but their safe use requires full understanding of their indications and contraindications. PMID- 23725975 TI - Non-sterilized fermentative co-production of poly(gamma-glutamic acid) and fibrinolytic enzyme by a thermophilic Bacillus subtilis GXA-28. AB - Poly(gamma-glutamic acid), as a naturally occurring homopolymer, is widely used in industry, agriculture, food and medicine. Fibrinolytic enzyme has a great potential for the prevention and/or treatment of vascular diseases caused by fibrin clots. Co-production of gamma-PGA and fibrinolytic enzyme by Bacillus subtilis GXA-28 (CCTCC M 2012347) from soybean residue using cane molasses and monosodium glutamate waste liquor under sterilized and non-sterilized condition were investigated. It was observed that total sugar from cane molasses of 3% (w/w) and glutamate from monosodium glutamate waste liquor of 2% (w/w) were favorable for gamma-PGA and fibrinolytic enzyme co-production at pH 7.0 and 45 degrees C. Based on the optimal medium, the gamma-PGA and fibrinolytic activity reached 103.5 g/kg-substrates at 22 h and 986 U/g-substrates at 24h under non sterilized condition, respectively. To our knowledge, the yield of gamma-PGA was highest in all reported literatures. PMID- 23725976 TI - Ongoing outbreak of rubella among young male adults in Poland: increased risk of congenital rubella infections. PMID- 23725977 TI - Detection on four continents of dengue fever cases related to an ongoing outbreak in Luanda, Angola, March to May 2013. PMID- 23725978 TI - Hepatitis A outbreak in Bijeljina, Bosnia and Herzegovina, August 2012 - April 2013. PMID- 23725979 TI - Evidence of false-positive results in a commercially available rotavirus assay in the vaccine era, Australia, 2011 to 2012. PMID- 23725980 TI - A comparison of rapid point-of-care tests for the detection of avian influenza A(H7N9) virus, 2013. PMID- 23725981 TI - Temporal trends of extended-spectrum cephalosporin-resistant Escherichia coli and Klebsiella pneumoniae isolates in in- and outpatients in Switzerland, 2004 to 2011. AB - Increasing trends for invasive infections with extended-spectrum cephalosporin resistant (ESC-R) Enterobacteriaceae have been described in many countries worldwide. However, data on the rates of ESC-R isolates in non-invasive infections and in the outpatient setting are scarce. We used a laboratory-based nationwide surveillance system to compare temporal trends of ESC-R rates in Escherichia coli and Klebsiella pneumoniae for in- and outpatients in Switzerland. Our data showed a significant increase in ESC-R rates from 1% to 5.8% in E. coli (p<0.001) and from 1.1% to 4.4% in K. pneumoniae (p=0.002) during an eight-year period (2004-2011). For E. coli, the increase was significantly higher in inpatients (from 1.2% to 6.6%), in patients residing in eastern Switzerland (from 1.0% to 6.2%), in patients older than 45 years (from 1.2% to 6.7%), and in male patients (from 1.2% to 8.1%). While the increase in inpatients was linear (p<0.001) for E. coli, the increase of ESC R K. pneumoniae isolates was the result of multiple outbreaks in several institutions. Notably, an increasing proportion of ESC-R E. coli was co-resistant to both trimethoprim sulfamethoxazole and quinolones (42% in 2004 to 49.1% in 2011, p=0.009), further limiting the available oral therapeutic options. PMID- 23725982 TI - "Even a donation one time in your live will help...": the effect of the legitimizing paltry contribution technique on blood donation. AB - Previous research has found that the statement "Even a penny will help" incorporated in charity donation requests increases compliance. The present study analyzed the effectiveness of this technique using a novel solicitation and an intermediate delay between the statement and the actual execution of the requested act. University students were solicited to give blood during a special one-day drive. Solicitations were made through face-to-face interactions. Solicitors wore a tee-shirt on which the statement "Even a donation one time in your live will help..." was either present or not. Results show that more participants gave their blood when this statement appeared on the tee-shirt. PMID- 23725983 TI - Registered nurses' personal responses to postoperative pain: a descriptive qualitative study. AB - This paper explores if nurses' personal responses to postoperative pain contribute to its continuing poor management. A descriptive qualitative design used a purposive sample of 16 registered nurses (RNs), from inpatient surgical areas in the United Kingdom, to participate in one semistructured interview. These were recorded and transcribed verbatim. Analysis used Morse and Field's four stages. A complex picture of collective and individual responses emerged; uncritical adoption of the medical model, with pain as normal and focus on technical aspects of management conforming to a "reference typology." However, individual RNs were also influenced by other personal factors, and findings indicate that scrutinizing individual competency is essential to improve individual and collective practice. PMID- 23725984 TI - Hepatitis B virus reactivation associated with atorvastatin. AB - It is well known that statins may cause elevation of liver enzymes, but the association of statins with hepatitis B reactivation has never been reported before. A case of hepatitis B reactivation induced by atorvastatin is reported herein. Atorvastatin not only caused significant increases in aminotransferases, but also caused ongoing viral replication by evidence of a several-log increase in hepatitis B virus. The reactivation recovered spontaneously by discontinuation of atorvastatin. The evolving concept of a double-edged sword with regard to statins in patients with hepatitis B is discussed. PMID- 23725985 TI - A study on the discrimination of human skeletons using X-ray fluorescence and chemometric tools in chemical anthropology. AB - Forensic anthropological investigations are often restricted in their outcomes by the resources allocated to them, especially in terms of positively identifying the victims exhumed from commingled mass graves. Commingled mass graves can be defined as those graves that contain a number of disarticulated human remains from different individuals that have been mixed by either natural processes or human interventions. The research developed aimed to apply the technique of non destructive XRF analysis to test whether there is substantial differentiation within the trace elemental composition and their ratios of individuals to separate them using chemometric analysis. The results of the different atomic spectroscopic analyses combined with the use of multivariate analysis on a set of 5 skeletons produced a series of plots using Principal Component Analysis that helped to separate them with a high percentage of accuracy when two, three or four skeletons needed to be separated. Also, two new elemental ratios, Zn/Fe related to metabolic activities and K/Fe related to blood flow into the bone, have been defined for their use in forensic anthropology for the first time to aid in the separation. PMID- 23725986 TI - rHDL administration increases reverse cholesterol transport in mice, but is not additive on top of ezetimibe or cholestyramine treatment. AB - OBJECTIVE: Promoting reverse cholesterol transport (RCT) is a major atheroprotective property of HDL. The present study explored the effect of stimulating the first step of RCT (cholesterol efflux from macrophages) alone or in combination with stimulating the last step of RCT (fecal sterol excretion). METHODS AND RESULTS: Reconstituted HDL (rHDL) was injected into wild-type mice either with or without administration of the cholesterol absorption inhibitor ezetimibe or the bile acid sequestrant cholestyramine. Single dose administration of rHDL (100 mg apoA-I/kg) resulted in an early (4 h) increase in plasma free cholesterol levels (p < 0.001), without affecting hepatic cholesterol levels or fecal mass sterol excretion. rHDL injection also increased [(3)H]cholesterol appearance in plasma at an early time-point (4 h) after intraperitoneal administration of [(3)H]cholesterol-labeled mouse macrophage foam cells and fecal radioactivity excretion indicating completed RCT was increased by 26% (p < 0.05). Ezetimibe treatment inhibited intestinal cholesterol absorption by 74% (p < 0.01), but also the bile acid sequestrant cholestyramine decreased cholesterol absorption significantly (24%, p < 0.01). Consequently, ezetimibe increased RCT 2.1-fold (p < 0.001) primarily within fecal neutral sterols, while cholestyramine increased RCT by 3.6-fold (p < 0.001), primarily within bile acids (p < 0.001), but also within neutral sterols (p < 0.001). However, no additive effects of both intestinal sterol uptake inhibitors were observed on top of rHDL administration. CONCLUSION: These data demonstrate that increasing the first step of RCT by rHDL administration results in transient cholesterol mobilization from macrophages to plasma. This effect is not further enhanced by stimulating the last step of RCT, fecal sterol excretion. PMID- 23725987 TI - Letter from the editors. PMID- 23725988 TI - Radionuclide breast cancer imaging 2013: state of the art. PMID- 23725989 TI - Radionuclide methods and instrumentation for breast cancer detection and diagnosis. AB - Breast cancer mammography is a well-acknowledged technique for patient screening due to its high sensitivity. However, in addition to its low specificity the sensitivity of mammography is limited when imaging patients with dense breasts. Radionuclide imaging techniques, such as coincidence photon-based positron emission tomography and single photon emission computed tomography or scintimammography, can play a role in assisting screening of such patients. Radionuclide techniques can also be useful in assessing treatment response of patients with breast cancer to therapy, and staging of patients to diagnose the disease extent. However, the performance of these imaging modalities is generally limited because of the poor spatial resolution and sensitivity of the commercially available multipurpose imaging systems. Here, we describe some of the dedicated imaging systems (positron emission mammography [PEM] and breast specific gamma imaging [BSGI]) that have been developed both commercially and in research laboratories for radionuclide imaging of breast cancer. Clinical studies with dedicated PEM scanners show improved sensitivity to detecting cancer in patients when using PEM in conjunction with additional imaging modalities, such as magnetic resonance imaging or mammography or both, as well as improved disease staging that can have an effect on surgical planning. High-resolution BSGI systems are more widely available commercially and several clinical studies have shown very high sensitivity and specificity in detecting cancer in high-risk patients. Further development of dedicated PEM and BSGI systems is ongoing, promising further expansion of radionuclide imaging techniques in the realm of breast cancer detection and treatment. PMID- 23725990 TI - Status of sentinel lymph node for breast cancer. AB - Long-awaited results from randomized clinical trials designed to test the validity of sentinel lymph node biopsy (SLNB) as replacement of axillary lymph node dissection (ALND) in management of early breast cancer have recently been published. All the trials conclude SLNB has survival rates comparable to those of ALND (up to 10 years in one study) and conclude SLNB has less morbidity than ALND. All the trials support replacing ALND with SLNB for staging in early breast cancer; all support SLNB as the standard of care for such cancer. The SLNB protocols used in the trials varied, and no consensus that would suggest a standard protocol exists. The results of the trials and of other peer-reviewed research do, however, suggest a framework for including some specific methodologies in accepted practice. This article highlights the overall survival and disease-free survival data as reported from the clinical trials. This article also reviews the status of SLN procedures and the following: male breast cancer, the roles of various imaging modalities (single-photon emission computed tomography/computed tomography, positron emission tomography/computed tomography, and ultrasound), ductal carcinoma in situ, extra-axillary SLNs, SLNB after neoadjuvant chemotherapy, radiation exposure to patients and medical personnel, and a new radiotracer that is the first to label SLNs not by particle trapping but by specific macrophage receptor binding. The proper Current Procedural Terminology (CPT) code for lymphoscintigraphy and SLN localization prior to surgery is 78195. PMID- 23725991 TI - Radionuclide methods for breast cancer staging. AB - Staging at initial presentation is one of the important prognostic factors for patients with breast cancer. Depending on the extent of disease spread, staging is divided into locoregional and distant or systemic. Locoregional staging includes axillary and internal mammary lymph node evaluation and distant or systemic staging includes evaluation of sites beyond the lymph node. Fluorodeoxyglucose-positron emission tomography (FDG-PET) is not sensitive to detect small metastasis in axillary lymph node. The current standard of axillary lymph node staging in early-stage breast cancer is therefore sentinel lymph node biopsy. Internal mammary lymph nodes are not commonly included in routine staging. In advanced-stage breast cancer, FDG-PET and PET/computed tomography (CT) are the modalities of choice to evaluate locoregional and distant metastasis. FDG-PET and PET/CT often detect occult metastasis, which is not visible on any other modalities including diagnostic CT scan. Detection of occult metastasis may potentially change in treatment options. This is particularly important in locally advanced breast cancer, which tends to develop early distant metastasis. PMID- 23725992 TI - Radionuclide response assessment of breast cancer. AB - Preoperative systemic therapy with cytotoxic or biologic anticancer regimens has gained significant popularity in the management of breast cancer. Moreover, there is a worldwide paradigm shift toward an individualized approach to identify predictive surrogate markers for stratifying patients into distinct subgroups to improve outcome after neoadjuvant or adjuvant therapy. Although achievement of pathologic complete response constitutes the gold standard for assessing therapeutic efficacy only a minority of patients achieve a pathologic complete response. Imaging has evolved to play a crucial role in monitoring treatment effectiveness, particularly, early during therapy. There is mounting evidence that (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a more superior metabolic imaging modality than anatomic modalities for assessment of the response during or at completion of treatment. Ultimately, the prediction of therapeutic effectiveness or survival or both by FDG-PET imaging could successfully tailor treatment and avoid unnecessary toxicities. This paper provides an overview of current use and the main indications of FDG-PET and integrated PET/computed tomography in response assessment of breast cancer as well as the future directions for the management using non-FDG-based tracers developed against specific targets. PMID- 23725993 TI - Imaging breast cancer bone metastases: current status and future directions. AB - The skeleton is commonly affected in the context of metastatic breast cancer and is a cause of significant morbidity in these individuals. Therapeutic options include systemic therapy, radiotherapy, and surgery given with the intent of preserving function and quality of life. As the spectrum of available therapies increases, key challenges comprise reliable diagnosis of bony metastatic disease and accurate evaluation of response that permits rapid therapeutic transition in those responding inadequately prior to development of significant skeletal morbidity. The (99m)Tc-diphosphonate bone scan remains one of the most commonly requested investigations for skeletal evaluation in patients with breast cancer. However a time lag of 3-6 months for accurate response evaluation from the start of treatment limits its utility for response evaluation in routine clinical practice or as a progression end point in the research setting. Functional imaging strategies using more tumor-specific radiopharmaceuticals show promise as an effective means of imaging response at a clinically relevant time point and are the subject of this review. PMID- 23725994 TI - Novel methods and tracers for breast cancer imaging. AB - Although positron emission tomography (PET) using [(18)F]fluorodeoxyglucose (FDG) has an established role in breast cancer staging and monitoring response to therapy, more specifically novel targeted tracers are under investigation and hold promise toward identification of critical molecular targets of therapy. We review herein novel tracers in breast cancer including steroidal endocrine tracers, 16alpha-[(18)F]fluoro-17beta-estradiol (FES) to measure tumor estrogen receptor density and function and 21-(18)F-fluoro-16alpha,17alpha-[(R)-(1'-alpha furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione (FFNP) to assay tumor progesterone receptor (PgR) expression, and to asses nuclear proliferation using 3'-deoxy-3'-fluorothymidine (FLT), membrane lipids using (11)C- or (18)F-labeled choline and amino acid transport using (11)C-methionine. These investigational tracers are moving closer to clinical use, and are likely to affect clinical care by aiding in characterization of breast cancer biology, which can have an important effect in the selection of targeted therapy and monitoring responsiveness to such therapy. PMID- 23725995 TI - Effect on cardiac function of cardiac resynchronization therapy in patients with right bundle branch block (from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT] trial). AB - Cardiac resynchronization therapy (CRT) is effective for the treatment of patients with heart failure and a wide QRS duration, particularly left bundle branch block. However, subjects with right bundle branch block (RBBB) do not appear to benefit from CRT. The aim of this study was to determine whether patients with specific RBBB conduction patterns responded to CRT in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) trial. In the present post hoc analysis, patients with RBBB who received CRT with an implantable cardioverter defibrillator (n = 132) were divided into 2 groups according to the baseline QRS morphology in the inferior and high lateral leads: group 1: left anterior fascicular block (LAFB) pattern (n = 80; 60.6%); and group 2: non-LAFB pattern (n = 52; 39.4%). Subjects with RBBB who received an implantable cardioverter defibrillator served as the control group (n = 87). The primary end point was echocardiographic response to CRT, defined as percent change in left ventricular (LV) and left atrial volumes from baseline to 1 year. The secondary end point was heart failure or death. The non-LAFB group demonstrated a significantly larger percent reduction in LV end-diastolic volume, LV end-systolic volume, and left atrial volume compared to controls (-11%, p <0.0001; -17%, p <0.0001; -15%, p <0.0001, respectively) and LAFB (-5%, p = 0.028; -7%, p = 0.019; -6%; p = 0.022; respectively) by multivariate analysis. No difference was found in the 3-year crude event rates for death or heart failure among the LAFB (22%), non-LAFB (21%), or ICD-only (20%) groups (p = NS). In conclusion, conduction patterns influence echocardiographic response to CRT in patients with RBBB, with favorable reductions in the LV and left atrial volumes in those without an LAFB conduction pattern. This echocardiographic benefit did not translate into a reduction in heart failure or death during a 3-year follow-up period. PMID- 23725996 TI - Relation between six-minute walk test performance and outcomes after transcatheter aortic valve implantation (from the PARTNER trial). AB - Functional capacity as assessed by 6-minute walk test distance (6MWTD) has been shown to predict outcomes in selected cohorts with cardiovascular disease. To evaluate the association between 6MWTD and outcomes after transcatheter aortic valve implantation (TAVI) among participants in the Placement of AoRTic TraNscathetER valve (PARTNER) trial, TAVI recipients (n = 484) were stratified into 3 groups according to baseline 6MWTD: unable to walk (n = 218), slow walkers (n = 133), in whom 6MWTD was below the median (128.5 meters), and fast walkers (n = 133) with 6MWTD >128.5 meters. After TAVI, among fast walkers, follow-up 6MWTD decreased by 44 +/- 148 meters at 12 months (p <0.02 compared with baseline). In contrast, among slow walkers, 6MWTD improved after TAVI by 58 +/- 126 meters (p <0.001 compared with baseline). Similarly, among those unable to walk, 6MWTD distance increased by 66 +/- 109 meters (p <0.001 compared with baseline). There were no differences in 30-day outcomes among 6MWTD groups. At 2 years, the rate of death from any cause was 42.5% in those unable to walk, 31.2% in slow walkers, and 28.8% in fast walkers (p = 0.02), driven primarily by differences in noncardiac death. In conclusion, among high-risk older adults undergoing TAVI, baseline 6MWTD does not predict procedural outcomes but does predict long-term mortality. Nonetheless, patients with poor baseline functional status exhibit the greatest improvement in 6MWTD. Additional work is required to identify those with poor functional status who stand to benefit the most from TAVI. PMID- 23725997 TI - Concurrent stereotactic radiosurgery and bevacizumab in recurrent malignant gliomas: a prospective trial. AB - PURPOSE: Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG. METHODS AND MATERIALS: Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status. RESULTS: One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months. CONCLUSIONS: Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach. PMID- 23725998 TI - Patterns of local recurrence and dose fractionation of adjuvant radiation therapy in 462 patients with soft tissue sarcoma of extremity and trunk wall. AB - PURPOSE: To study the impact of dose fractionation of adjuvant radiation therapy (RT) on local recurrence (LR) and the relation of LR to radiation fields. METHODS AND MATERIALS: LR rates were analyzed in 462 adult patients with soft tissue sarcoma who underwent surgical excision and adjuvant RT at five Scandinavian sarcoma centers from 1998 to 2009. Medical records were reviewed for dose fractionation parameters and to determine the location of the LR relative to the radiation portals. RESULTS: Fifty-five of 462 patients developed a LR (11.9%). Negative prognostic factors included intralesional surgical margin (hazard ratio [HR]: 7.83, 95% confidence interval [CI]: 3.08-20.0), high malignancy grade (HR: 5.82, 95% CI: 1.31-25.8), age at diagnosis (HR per 10 years: 1.27, 95% CI: 1.03 1.56), and malignant peripheral nerve sheath tumor histological subtype (HR: 6.66, 95% CI: 2.56-17.3). RT dose was tailored to margin status. No correlation between RT dose and LR rate was found in multiple Cox regression analysis. The majority (65%) of LRs occurred within the primary RT volume. CONCLUSIONS: No significant dose-response effect of adjuvant RT was demonstrated. Interestingly, patients given 45-Gy accelerated RT (1.8 Gy twice daily/2.5 weeks) had the best local outcome. A total dose of 50 Gy in 25 fractions seemed adequate following wide margin surgery. The risk of LR was associated with histopathologic subtype, which should be included in the treatment algorithm of adjuvant RT in soft tissue sarcoma. PMID- 23725999 TI - RTOG 0913: a phase 1 study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. AB - PURPOSE: To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. METHODS AND MATERIALS: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m(2) per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m(2) on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established daily dose of 10 mg/d. Dose escalation continued if a dose level produced dose limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. RESULTS: Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. CONCLUSIONS: Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response. PMID- 23726000 TI - Late toxicity and patient self-assessment of breast appearance/satisfaction on RTOG 0319: a phase 2 trial of 3-dimensional conformal radiation therapy accelerated partial breast irradiation following lumpectomy for stages I and II breast cancer. AB - PURPOSE: Late toxicities and cosmetic analyses of patients treated with accelerated partial breast irradiation (APBI) on RTOG 0319 are presented. METHODS AND MATERIALS: Patients with stages I to II breast cancer <=3 cm, negative margins, and <=3 positive nodes were eligible. Patients received three dimensional conformal external beam radiation therapy (3D-CRT; 38.5 Gy in 10 fractions twice daily over 5 days). Toxicity and cosmesis were assessed by the patient (P), the radiation oncologist (RO), and the surgical oncologist (SO) at 3, 6, and 12 months from the completion of treatment and then annually. National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, was used to grade toxicity. RESULTS: Fifty-two patients were evaluable. Median follow up was 5.3 years (range, 1.7-6.4 years). Eighty-two percent of patients rated their cosmesis as good/excellent at 1 year, with rates of 64% at 3 years. At 3 years, 31 patients were satisfied with the treatment, 5 were not satisfied but would choose 3D-CRT again, and none would choose standard radiation therapy. The worst adverse event (AE) per patient reported as definitely, probably, or possibly related to radiation therapy was 36.5% grade 1, 50% grade 2, and 5.8% grade 3 events. Grade 3 AEs were all skin or musculoskeletal-related. Treatment related factors were evaluated to potentially establish an association with observed toxicity. Surgical bed volume, target volume, the number of beams used, and the use of bolus were not associated with late cosmesis. CONCLUSIONS: Most patients enrolled in RTOG 0319 were satisfied with their treatment, and all would choose to have the 3D-CRT APBI again. PMID- 23726001 TI - A fully automated method for CT-on-rails-guided online adaptive planning for prostate cancer intensity modulated radiation therapy. AB - PURPOSE: This study was designed to validate a fully automated adaptive planning (AAP) method which integrates automated recontouring and automated replanning to account for interfractional anatomical changes in prostate cancer patients receiving adaptive intensity modulated radiation therapy (IMRT) based on daily repeated computed tomography (CT)-on-rails images. METHODS AND MATERIALS: Nine prostate cancer patients treated at our institution were randomly selected. For the AAP method, contours on each repeat CT image were automatically generated by mapping the contours from the simulation CT image using deformable image registration. An in-house automated planning tool incorporated into the Pinnacle treatment planning system was used to generate the original and the adapted IMRT plans. The cumulative dose-volume histograms (DVHs) of the target and critical structures were calculated based on the manual contours for all plans and compared with those of plans generated by the conventional method, that is, shifting the isocenters by aligning the images based on the center of the volume (COV) of prostate (prostate COV-aligned). RESULTS: The target coverage from our AAP method for every patient was acceptable, while 1 of the 9 patients showed target underdosing from prostate COV-aligned plans. The normalized volume receiving at least 70 Gy (V70), and the mean dose of the rectum and bladder were reduced by 8.9%, 6.4 Gy and 4.3%, 5.3 Gy, respectively, for the AAP method compared with the values obtained from prostate COV-aligned plans. CONCLUSIONS: The AAP method, which is fully automated, is effective for online replanning to compensate for target dose deficits and critical organ overdosing caused by interfractional anatomical changes in prostate cancer. PMID- 23726002 TI - Low-dose radiation therapy (2 Gy * 2) in the treatment of orbital lymphoma. AB - PURPOSE: Low-dose radiation has become increasingly used in the management of indolent non-Hodgkin lymphoma (NHL), but has not been studied specifically for cases of ocular adnexal involvement. The objective of this study is to investigate the effectiveness of low-dose radiation in the treatment of NHL of the ocular adnexa. METHODS AND MATERIALS: We reviewed the records of 20 NHL patients with 27 sites of ocular adnexal involvement treated with low-dose radiation consisting of 2 successive fractions of 2 Gy at our institution between 2005 and 2011. The primary endpoint of this study is freedom from local relapse (FFLR). RESULTS: At a median follow-up time of 26 months (range 7-92), the overall response rate for the 27 treated sites was 96%, with a complete response (CR) rate of 85% (n=23) and a partial response rate of 11% (n=3). Among all treated sites with CR, the 2-year FFLR was 100%, with no in-treatment field relapses. The 2-year freedom from regional relapse rate was 96% with 1 case of relapse within the ipsilateral orbit (outside of the treatment field). This patient underwent additional treatment with low-dose radiation of 4 Gy to the area of relapse achieving a CR and no evidence of disease at an additional 42 months of follow-up. Orbital radiation was well tolerated with only mild acute side effects (dry eye, conjunctivitis, transient periorbital edema) in 30% of treated sites without any reports of long-term toxicity. CONCLUSIONS: Low-dose radiation with 2 Gy * 2 is effective and well tolerated in the treatment of indolent NHL of the ocular adnexa with high response rates and durable local control with the option of reirradiation in the case of locoregional relapse. PMID- 23726003 TI - Replanning during intensity modulated radiation therapy improved quality of life in patients with nasopharyngeal carcinoma: in regard to Yang et al. PMID- 23726004 TI - Molecular imaging of the ATM kinase activity. AB - PURPOSE: Ataxia telangiectasia mutated (ATM) is a serine/threonine kinase critical to the cellular DNA-damage response, including from DNA double-strand breaks. ATM activation results in the initiation of a complex cascade of events including DNA damage repair, cell cycle checkpoint control, and survival. We sought to create a bioluminescent reporter that dynamically and noninvasively measures ATM kinase activity in living cells and subjects. METHODS AND MATERIALS: Using the split luciferase technology, we constructed a hybrid cDNA, ATM-reporter (ATMR), coding for a protein that quantitatively reports on changes in ATM kinase activity through changes in bioluminescence. RESULTS: Treatment of ATMR expressing cells with ATM inhibitors resulted in a dose-dependent increase in bioluminescence activity. In contrast, induction of ATM kinase activity upon irradiation resulted in a decrease in reporter activity that correlated with ATM and Chk2 activation by immunoblotting in a time-dependent fashion. Nuclear targeting improved ATMR sensitivity to both ATM inhibitors and radiation, whereas a mutant ATMR (lacking the target phosphorylation site) displayed a muted response. Treatment with ATM inhibitors and small interfering (si)RNA-targeted knockdown of ATM confirm the specificity of the reporter. Using reporter expressing xenografted tumors demonstrated the ability of ATMR to report in ATM activity in mouse models that correlated in a time-dependent fashion with changes in Chk2 activity. CONCLUSIONS: We describe the development and validation of a novel, specific, noninvasive bioluminescent reporter that enables monitoring of ATM activity in real time, in vitro and in vivo. Potential applications of this reporter include the identification and development of novel ATM inhibitors or ATM-interacting partners through high-throughput screens and in vivo pharmacokinetic/pharmacodynamic studies of ATM inhibitors in preclinical models. PMID- 23726005 TI - Correlation of clinical and dosimetric factors with adverse pulmonary outcomes in children after lung irradiation. AB - PURPOSE: To identify the incidence and the risk factors for pulmonary toxicity in children treated for cancer with contemporary lung irradiation. METHODS AND MATERIALS: We analyzed clinical features, radiographic findings, pulmonary function tests, and dosimetric parameters of children receiving irradiation to the lung fields over a 10-year period. RESULTS: We identified 109 patients (75 male patients). The median age at irradiation was 13.8 years (range, 0.04-20.9 years). The median follow-up period was 3.4 years. The median prescribed radiation dose was 21 Gy (range, 0.4-64.8 Gy). Pulmonary toxic chemotherapy included bleomycin in 58.7% of patients and cyclophosphamide in 83.5%. The following pulmonary outcomes were identified and the 5-year cumulative incidence after irradiation was determined: pneumonitis, 6%; chronic cough, 10%; pneumonia, 35%; dyspnea, 11%; supplemental oxygen requirement, 2%; radiographic interstitial lung disease, 40%; and chest wall deformity, 12%. One patient died of progressive respiratory failure. Post-irradiation pulmonary function tests available from 44 patients showed evidence of obstructive lung disease (25%), restrictive disease (11%), hyperinflation (32%), and abnormal diffusion capacity (12%). Thoracic surgery, bleomycin, age, mean lung irradiation dose (MLD), maximum lung dose, prescribed dose, and dosimetric parameters between V22 (volume of lung exposed to a radiation dose >=22 Gy) and V30 (volume of lung exposed to a radiation dose >=30 Gy) were significant for the development of adverse pulmonary outcomes on univariate analysis. MLD, maximum lung dose, and Vdose (percentage of volume of lung receiving the threshold dose or greater) were highly correlated. On multivariate analysis, MLD was the sole significant predictor of adverse pulmonary outcome (P=.01). CONCLUSIONS: Significant pulmonary dysfunction occurs in children receiving lung irradiation by contemporary techniques. MLD rather than prescribed dose should be used to perform risk stratification of patients receiving lung irradiation. PMID- 23726006 TI - Biochemical responses in armored catfish (Pterygoplichthys anisitsi) after short term exposure to diesel oil, pure biodiesel and biodiesel blends. AB - Biodiesel fuel is gradually replacing petroleum-based diesel oil use. Despite the biodiesel being considered friendlier to the environment, little is known about its effects in aquatic organisms. In this work we evaluated whether biodiesel exposure can affect oxidative stress parameters and biotransformation enzymes in armored catfish (Pterygoplichthys anisitsi, Loricariidae), a South American endemic species. Thus, fish were exposed for 2 and 7d to 0.01mLL(-1) and 0.1mLL( 1) of pure diesel, pure biodiesel (B100) and blends of diesel with 5% (B5) and 20% (B20) biodiesel. Lipid peroxidation (malondialdehyde) levels and the activities of the enzymes glutathione S-transferase, superoxide dismutase, catalase and glutathione peroxidase were measured in liver and gills. Also, DNA damage (8-oxo-7, 8-dihydro-2'-deoxyguanosine) levels in gills and 7 ethoxyresorufin-O-deethylase activity in liver were assessed. Pure diesel, B5 and B20 blends changed most of the enzymes tested and in some cases, B5 and B20 induced a higher enzyme activity than pure diesel. Antioxidant system activation in P. anisitsi was effective to counteract reactive oxygen species effects, since DNA damage and lipid peroxidation levels were maintained at basal levels after all treatments. However, fish gills exposed to B20 and B100 presented increased lipid peroxidation. Despite biodiesel being more biodegradable fuel that emits less greenhouse gases, the increased lipid peroxidation showed that biofuel and its blends also represent hazards to aquatic biota. PMID- 23726007 TI - Effects of complex organohalogen contaminant mixtures on thyroid homeostasis in hooded seal (Cystophora cristata) mother-pup pairs. AB - Many lipid-soluble and phenolic compounds present in the complex mixture of orgaohalogen contaminants (OHCs) that arctic wildlife is exposed to have the ability to interfere with the thyroid hormone (TH) system. The aim of this study was to identify compounds that might interfere with thyroid homeostasis in 14 nursing hooded seal (Cystophora cristata) mothers and their pups (1-4d old) sampled in the West Ice in March 2008. Multivariate modelling was used to assess the potential effects of measured plasma levels of OHCs on circulating TH levels of the measured free (F) and total (T) levels of triidothyrine (T3) and thyroxine (T4). Biological factors were important in all models (e.g. age and sex). In both mothers and pups, TT3:FT3 ratios were associated with alpha- and beta hexachlorocyclohexane (HCH), ortho-PCBs, chlordanes and DDTs. The similarities between the modelled TT3:FT3 responses to OHC levels in hooded seal mothers and pups most probably reflects similar exposure patterns, but could also indicate interconnected TH responses. There were some differences in the modelled TH responses of mothers and pups. Most importantly, the negative relationships between many OH-PCBs (particularly 3'-OH-CB138) and TT3:FT3 ratio and the positive relationships between TT4:FT4 ratios and polybrominated diphenyl ether [PBDE]-99, -100 and 4-OH-CB107 in pups, which was not found in mothers. Although statistical associations are not evidence per se of biological cause-effect relationships, the results suggest that thyroid homeostasis is affected in hooded seals, and that the inclusion of the fullest possible OHC mixture is important when assessing TH related effects in wildlife. PMID- 23726008 TI - Synergistic increase in cell lethality by dieldrin and H2O2 in rat thymocytes: effect of dieldrin on the cells exposed to oxidative stress. AB - Dieldrin, one of persistent pesticides, is highly resistant to biotic and abiotic degradation. It is accumulated in organisms. Recent studies suggest that dieldrin exerts a potent cytotoxic action on cells exposed to oxidative stress. In this study, the effect of dieldrin on rat thymocytes exposed to hydrogen peroxide (H2O2)-induced oxidative stress was examined. Dieldrin at 5MUM and H2O2 at 300MUM slightly increased cell lethality from a control value of 5.4+/-0.5% (mean+/ standard deviation of four experiments) to 7.8+/-1.3% and 9.0+/-0.3%, respectively. Simultaneous application of dieldrin and H2O2 significantly increased cell lethality to 46.2+/-1.8%. The synergistic increase in cell lethality was dependent on dieldrin concentration (0.3-5MUM) but not on H2O2 concentration (30-300MUM). Dieldrin accelerated H2O2-induced cell death, which was estimated with the help of annexin V-FITC and propidium iodide. Presence of either dieldrin or H2O2 decreased the cellular content of nonprotein thiol and increased intracellular Zn(2+) concentration. The combination of dieldrin and H2O2 further pronounced these effects. TPEN, a chelator of intracellular Zn(2+), significantly attenuated the synergistic increase in cell lethality induced by dieldrin and H2O2. It is, therefore, suggested that dieldrin augments the cytotoxicity of H2O2 in a Zn(2+)-dependent manner. PMID- 23726009 TI - Biomethylation and volatilization of arsenic by the marine microalgae Ostreococcus tauri. AB - Ostreococcus tauri is a marine green microalga, recognized as a model organism of the marine phytoplankton assemblage and widely distributed from coastal to oligotrophic waters. This study showed it could tolerate both arsenite and arsenate concentrations of up to 100MUM, and cellular As concentration increased significantly (P<0.01) with increasing concentration of As(V) in the medium (0 50MUM). It was revealed that As biotransformations were mediated by algal cells. Volatilized As was detected and the ability of As biovolatilization by O. tauri was demonstrated. The reduction of As(V) to As(III) might be the limiting step for As methylation and volatilization from seawater since the treatment with As(III) yielded five times more volatile As as compared to that with As(V). Arsenic biogeochemical cycle in the marine environment might play an important role based on the huge surface area of ocean (71%) and the massive number of marine phytoplankton. PMID- 23726010 TI - Degradation of chlorophenoxy herbicides by coupled Fenton and biological oxidation. AB - A combined treatment for the degradation of the chlorophenoxy herbicides 2,4-D and MCPA in water by means of Fenton and biological oxidation has been studied. The chemical oxidation step was necessary to achieve an efficient removal of these pollutants due to their toxicity and low biodegradability. Aqueous herbicide solutions (180mgL(-1)) were subjected to Fenton oxidation upon different H2O2 doses (from the theoretical stoichiometric amount referred to initial COD to 20% of this value). The toxicity and biodegradability tests of the Fenton effluents suggested that the ones resulting upon treatment with 80% and 60% of stoichiometric H2O2 were the optimal for subsequent biological treatment dealing with 2,4-D and MCPA, respectively. These effluents were treated in a sequencing batch reactor achieving nearly 90% conversion of organic matter measured as COD. PMID- 23726011 TI - Microcystin-LR-induced phytotoxicity in rice crown root is associated with the cross-talk between auxin and nitric oxide. AB - Irrigation with cyanobacterial-blooming water containing microcystin-LR (MC-LR) poses threat to the growth of agricultural plants. Large amounts of rice (Oryza sativa) field in the middle part of China has been irrigating with cyanobacterial blooming water. Nevertheless, the mechanism of MC-LR-induced phytotoxicity in the root of monocot rice remains unclear. In the present study, we demonstrate that MC-LR stress significantly inhibits the growth of rice root by impacting the morphogenesis rice crown root. MC-LR treatment results in the decrease in IAA (indole-3-acetic acid) concentration as well as the expression of CRL1 and WOX11 in rice roots. The application of NAA (1-naphthylacetic acid), an IAA homologue, is able to attenuate the inhibitory effect of MC-LR on rice root development. MC LR treatment significantly inhibits OsNia1-dependent NO generation in rice roots. The application of NO donor SNP (sodium nitroprusside) is able to partially reverse the inhibitory effects of MC-LR on the growth of rice root and the expression of CRL1 and WOX11 by enhancing endogenous NO level in rice roots. The application of NO scavenger cPTIO [2-(4-carboxy-2-phenyl)-4,4,5,5 tetramethylinidazoline-1-oxyl-3-oxide] eliminates the effects of SNP. Treatment with NAA stimulates the generation of endogenous NO in MC-LR-treated rice roots. Treatment with NO scavenger cPTIO abolishes the ameliorated effect of NAA on MC LR-induced growth inhibition of rice root. Treatment with SNP enhanced IAA concentration in MC-LR-treated rice roots. Altogether, our data suggest that NO acts both downstream and upstream of auxin in regulating rice root morphogenesis under MC-LR stress. PMID- 23726012 TI - Effects on activated sludge bacterial community exposed to sulfamethoxazole. AB - The bacterial community shift on a lab scale Sequencing Batch Reactor (SBR) fed with synthetic wastewater and exposed to 50MUgL(-1) of sulfamethoxazole (SFX) for 2months was investigated in this study. The impact on biological nutrient removal performance and SFX removal efficiencies were also studied. Satisfactory biological nutrient removal was observed as regards to COD and Nitrogen. SFX removal efficiencies ranged between 20% and 50% throughout the experimental period, enhanced within the aerobic phases of the SBR cycle, with no evident signs of biomass acclimation. Nevertheless, denaturing gradient gel electrophoresis (DGGE) analysis showed significant variance leading to not only the fading, but also the emergence of new species in the bioreactor bacterial community after SFX dosage. According to the phylogenetic analysis, bacteria belonging to Betaproteobacteria and Gammaproteobacteria classes were the dominant species, among them, the Thiotrix spp. (Gammaproteobacteria) cell number increased due to its tolerance to the antibiotic. On the other hand, the classes Sphingobacteria, Actinobacteria, Chloroflexi and Chlorobi were found to be more vulnerable to the antibiotic load and disappeared. The sulphonamide resistance gene sulI was also quantified and discussed, as there are very few studies on bacterial resistance in lab-scale treatment reactors. PMID- 23726013 TI - Persistent organic pollutants in sea bass (Dicentrarchus labrax L.) in two fish farms in the Mediterranean Sea. AB - We analyzed polychlorobiphenyls (PCBs), perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA) in the edible part of farmed sea bass reared in two fish farms in Liguria (Northern Italy). The aim was to determine the contamination levels and human exposure to these chemicals through fish consumption. Concentrations of "dioxin-like" PCBs (DL-PCBs) ranged from 0.033 to 0.759pg SigmaTEQ-PCBg(-1) whole weight (w.w.) in fish farm 1 and from 0.032 to 1.60pg SigmaTEQ-PCBg(-1) w.w. in fish farm 2, and the six indicators of "non dioxin-like" (NDL-PCBs) from 0.538 to 9.33ng Sigma6PCBg(-1) w.w. and from 1.62 to 27.6ng Sigma6PCBg(-1) w.w. Concentrations were generally lower in farm 1 than in farm 2. One reason for this difference might be the proximity of farm 2 to the seaport of La Spezia, which could be a punctual source of pollutants influencing the contamination of the water in the farm. Principal component analysis (PCA) showed differences also in the congeners profiles for the two sites, with higher chlorinated PCBs more abundant in farm 1, and lower-chlorinated PCBs were more abundant in farm 2. Most of the concentrations of PFOS and PFOA were below the limit of detection (LOD 0.05ngg(-1) w.w.). Only about 10% of the samples analyzed had levels slightly higher than the LOD. Assessments of exposure using these data showed that consumption of farmed fish may contribute significantly to PCBs through the diet, whereas the contribution of PFOS and PFOA seems to be low. PMID- 23726014 TI - A new look at ultrasound-mediated extravasation. PMID- 23726015 TI - Spatial modelling of Bacillus anthracis ecological niche in Zimbabwe. AB - Anthrax continues to cause significant mortalities in livestock, wildlife and humans worldwide. In Zimbabwe, anthrax outbreaks have been reported almost annually over the past four decades. In this study we tested whether anthrax outbreak data and a set of environmental variables can be used to predict the ecological niche for Bacillus anthracis using maximum entropy modelling for species geographical distribution (Maxent). Confirmed geo-referenced anthrax outbreaks data for the period 1995-2010 were used as presence locations and a set of environmental parameters; precipitation, temperature, vegetation biomass, soil type and terrain as predictor variables. Results showed that the environmental variables can adequately predict the ecological niche of B. anthracis (AUC for test data=0.717, p<0.001), with soil type as the most important predictor followed by variance of vegetation biomass and maximum temperature. These results imply that the model we tested may be used by animal health authorities in devising better control strategies for anthrax. PMID- 23726016 TI - Ofatumumab in rituximab-refractory autoimmune hemolytic anemia associated with chronic lymphocytic leukemia: a case report and review of literature. PMID- 23726017 TI - Complete response of relapsed systemic and cutaneous anaplastic large cell lymphoma using brentuximab vedotin: 2 case reports. PMID- 23726018 TI - The use of the pulse oximetric saturation/fraction of inspired oxygen ratio for risk stratification of patients with severe sepsis and septic shock. AB - PURPOSE: Our aims were to determine whether the pulse oximetric saturation/fraction of inspired oxygen (S/F) can be used for the early identification of patients with sepsis who are at increased risk for death and to compare the S/F ratio with the Pao2/fraction of inspired oxygen (P/F) ratio. MATERIALS AND METHODS: This is a retrospective cohort study in 260 patients admitted to 2 tertiary mixed intensive care units (ICUs) with severe sepsis or septic shock. We studied the association between tertiles of S/F ratio and ICU mortality using Cox regression. Subsequently, we compared corresponding measurements of S/F ratio and P/F ratio upon ICU admission using Pearson correlation coefficient (r). RESULTS: We observed an overall case fatality of 72 (28%) of 260. After adjustment for severity of the illness, the lowest tertile (S/F, <164) at ICU admission was associated with increased mortality (hazard ratio, 1.87 [95% confidence interval, 1.02-3.41]) comparing to the highest tertile (S/F, >236). The S/F ratio was correlated with P/F ratio (r=0.48; P<.0001). CONCLUSION: A low S/F at ICU admission is associated with increased risk of death in patients with severe sepsis or septic shock. PMID- 23726019 TI - Topography of the mental foramen in human skulls originating from different time periods. AB - The location of the mental foramen is used in a number of maxillofacial surgical procedures and in anthropological examinations. The position of the mental foramen has been reported to vary in different ethnic groups and in different historical populations. The aim of this work was to analyse the topography of the mental foramen in mandibles from selected historical populations from the Pomeranian region in Poland. The material consisted of three groups: 92 skulls from the beginning of the 20th century from Szczecin (earlier name Stettin), and two Mediaeval groups -31 skulls from Rurka (historic Rorchen), 18th-19th centuries, and 50 skulls from Sypniewo (historic Zyppnow), 11th-13th centuries. Distances of the mental foramen in relation to the midline, and to the second corresponding point were measured. Additionally, non-metric traits of the mental foramen were recorded. No significant differences in average diameters of the mental foramina measured on the right and the left sides were observed between historical populations. On both sides, in all groups, the foramen was mainly located between positions of the lower first and lower second premolars. In all three groups the direction of the opening of the mental foramen was superoposterior. The similar level of epigenetic variation was observed in all groups. The position and the direction of the exit were similar to other previously studied European populations. PMID- 23726020 TI - Tumor suppression by p53: is apoptosis important or not? AB - The mechanisms by which p53 suppresses tumor growth remain ill defined. In this issue of Cell Reports, Timofeev et al. (2013) and Valente et al. (2013) reveal context-dependent contributions of p53-dependent apoptosis to its tumor suppressive function. PMID- 23726021 TI - Redefining the role of retinoic acid in limb development. AB - In recent years, the function of retinoic acid (RA) in limb development has been debated. In this issue of Cell Reports, Cunningham et al. show that RA antagonizes fibroblast growth factors for limb initiation, but not for limb patterning. PMID- 23726023 TI - Mechanical guidance of cell migration: lessons from chemotaxis. AB - For an organism to develop, for a wound to heal, or for a tumor to invade, cells must be able to migrate following directional cues. It is widely accepted that directed cell migration is enabled by cellular sensing of local gradients in the concentration of chemical factors. The main molecular players involved in this mode of cellular guidance--chemotaxis--have been identified and the combination of modeling and experimental approaches is progressively unveiling a clear picture of the underlying mechanisms. Evidence obtained over the past decade has shown that cells can also be guided by mechanical stimuli such as physical forces or gradients in extracellular matrix stiffness. Mechanical guidance, which we refer here globally as mechanotaxis, is also thought to drive processes in development, cancer, and wound healing, but experimental evidence is scattered and mechanisms remain largely unknown. Here we use the better understood process of chemotaxis as a reference to define the building blocks that are required for cell guidance, and then discuss how these building blocks might be organized in mechanotaxis. We show that both chemotaxis and mechanotaxis involve an exquisite interplay between physical and chemical mechanisms to sense gradients, establish polarization, and drive directed migration. PMID- 23726022 TI - Lysosome-related organelles: unusual compartments become mainstream. AB - Lysosome-related organelles (LROs) comprise a group of cell type-specific subcellular compartments with unique composition, morphology and structure that share some features with endosomes and lysosomes and that function in varied processes such as pigmentation, hemostasis, lung plasticity and immunity. In recent years, studies of genetic diseases in which LRO functions are compromised have provided new insights into the mechanisms of LRO biogenesis and the regulated secretion of LRO contents. These insights have revealed previously unappreciated specialized endosomal sorting processes in all cell types, and are expanding our views of the plasticity of the endosomal and secretory systems in adapting to cell type-specific needs. PMID- 23726024 TI - Anti-CD3 clinical trials in type 1 diabetes mellitus. AB - Two humanized, anti-CD3 mAbs with reduced FcR binding, teplizumab and otelixizumab, have been evaluated in over 1500 subjects, ages 7-45, with new and recently diagnosed T1D with a range of intravenous doses (3-48mg) and regimens (6 14 days, single or repeat courses). In general, studies that used adequate dosing demonstrated improvement in stimulated C-peptide responses and reduced need for exogenous insulin for two years and even longer after diagnosis. Drug treatment causes a transient reduction in circulating T cells, but the available data suggest that the mechanism of action may involve induction of regulatory mechanisms. The adverse effects of anti-CD3 treatment are infusion-related and transient. The studies have identified significant differences in efficacy among patient groups suggesting that a key aspect for development of this immune therapy is identification of the demographic, metabolic, and immunologic features that distinguish subjects who are most likely to show beneficial clinical responses. PMID- 23726025 TI - Identification of cellular proteins interacting with octaarginine (R8) cell penetrating peptide by photo-crosslinking. AB - Octaarginine (R8) is a representative cell-penetrating peptide. Lanthionine synthetase component C-like protein 1 (LanCL1) was identified as a potential intracellular target of R8 by using a photo-crosslinking assay that utilized a phenyl-trifluoromethyl diazirine moiety and peptide mass fingerprinting. Increased cellular uptake of R8 by LanCL1-overexpressing cells was observed. PMID- 23726026 TI - Activity-lipophilicity relationship studies on P-gp ligands designed as simplified tariquidar bulky fragments. AB - A series of alkyloxyquinoline derivatives has been developed to evaluate the relationship between P-gp potency and lipophilicity. The results show a satisfactory lipophilicity-activity correlation although a series of derivatives showing higher P-gp potency is needed in order to confirm this hypothesis. PMID- 23726027 TI - Synthesis and biological evaluation of a novel (99m)Tc labeled 2-nitroimidazole derivative as a potential agent for imaging tumor hypoxia. AB - Tumor hypoxia plays a major role in reducing the efficacy of therapeutic modalities like chemotherapy and radiation therapy in combating cancer. In order to target hypoxic tissues, a tripeptide ligand having a 2-nitroimidazole moiety, as a bioreductive species, was synthesized. The latter was radiolabeled with (99m)Tc for imaging hypoxic regions of tumors and was characterized by means of its rhenium analogue. The biodistribution and scintigraphic image of the corresponding (99m)Tc-complex showed accumulation in tumor and these results suggest that it could be a marker for imaging tumor hypoxia. PMID- 23726028 TI - Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors. AB - To reduce the pro-angiogenic effects of sEH inhibition, a structure-activity relationship (SAR) study was performed by incorporating structural features of the anti-angiogenic multi-kinase inhibitor sorafenib into soluble epoxide hydrolase (sEH) inhibitors. The structural modifications of this series of molecules enabled the altering of selectivity towards the pro-angiogenic kinases C-RAF and vascular endothelial growth factor receptor-2 (VEGFR-2), while retaining their sEH inhibition. As a result, sEH inhibitors with greater potency against C-RAF and VEGFR-2 were obtained. Compound 4 (t-CUPM) possesses inhibition potency higher than sorafenib towards sEH but similar against C-RAF and VEGFR-2. Compound 7 (t-CUCB) selectively inhibits sEH, while inhibiting HUVEC cell proliferation, a potential anti-angiogenic property, without liver cancer cell cytotoxicity. The data presented suggest a potential rational approach to control the angiogenic responses stemming from sEH inhibition. PMID- 23726029 TI - The synthesis of isopropylidene mRNA cap analogs modified with phosphorothioate moiety and their evaluation as promoters of mRNA translation. AB - Synthetic mRNA cap analogs are valuable tools in the preparation of modified mRNA transcripts with improved translational activity and increased cellular stability, and have recently attracted more attention because of their great potential in therapeutic applications. We have synthesized and tested isopropylidene dinucleotide cap analogs bearing a phosphorothioate group at the beta position of the 5',5'-triphosphate bridge (two diastereomers of 2',3'-iPr m(7)GppSpG), as synthetically simpler alternatives to previously obtained phosphorothioate cap analogs. To evaluate the utility of the new compounds in biological systems we determined their affinity to translation initiation factor 4E (eIF4E), and tested their translational properties in rabbit reticulocyte lysates (RRL) and in human immature dendritic cells (hiDCs). In order to explain the properties of isopropylidene analogs we performed (1)H NMR conformational analysis and correlated the absolute configuration at the beta-phosphorous atom with previously synthesized m(7)GppSpG. PMID- 23726030 TI - Affinity-based screening of MDM2/MDMX-p53 interaction inhibitors by chemical array: identification of novel peptidic inhibitors. AB - MDM2 and MDMX are oncoproteins that negatively regulate the activity and stability of the tumor suppressor protein p53. The inhibitors of protein-protein interactions (PPIs) of MDM2-p53 and MDMX-p53 represent potential anticancer agents. In this study, a novel approach for identifying MDM2-p53 and MDMX-p53 PPI inhibitor candidates by affinity-based screening using a chemical array has been established. A number of compounds from an in-house compound library, which were immobilized onto a chemical array, were screened for interaction with fluorescence-labeled MDM2 and MDMX proteins. The subsequent fluorescent polarization assay identified several compounds that inhibited MDM2-p53 and MDMX p53 interactions. PMID- 23726031 TI - Rhodanine-based PRL-3 inhibitors blocked the migration and invasion of metastatic cancer cells. AB - PRL-3, phosphatase of regenerating liver-3, plays a role in cancer progression through its involvement in invasion, migration, metastasis, and angiogenesis. We synthesized rhodanine derivatives, CG-707 and BR-1, which inhibited PRL-3 enzymatic activity with IC50 values of 0.8 MUM and 1.1 MUM, respectively. CG-707 and BR-1 strongly inhibited the migration and invasion of PRL-3 overexpressing colon cancer cells without exhibiting cytotoxicity. The specificity of the inhibitors on PRL-3 phosphatase activity was confirmed by the phosphorylation recovery of known PRL-3 substrates such as ezrin and cytokeratin 8. The compounds selectively inhibited PRL-3 in comparison with other phosphatases, and CG-707 regulated epithelial-to-mesenchymal transition (EMT) marker proteins. The results of the present study reveal that rhodanine is a specific PRL-3 inhibitor and a good lead molecule for obtaining a selective PRL-3 inhibitor. PMID- 23726032 TI - Synthesis and neuroprotective effect of E-3,4-dihydroxy styryl aralkyl ketones derivatives against oxidative stress and inflammation. AB - E-3,4-Dihydroxy styryl aralkyl ketones as well as their 3,4-diacetylated derivatives as the analogues of neuroprotective agent CAPE were designed and synthesized for improving stability and lipid solubility. The neuroprotective activities of target compounds 10a-g and 11a-g were tested by three models in vitro, including 1,1-diphenyl-2-picrylhydrazyl radical scavenging capacity, neuronal protecting effect against damage induced by H2O2 in PC12 cells and nitric oxide suppression effect in BV2 microglial cells. The results demonstrated that compounds 10f and 11f exhibited the most potent neuroprotective effect against oxidative stress and inflammation, which is higher than that of the lead compound CAPE. PMID- 23726033 TI - Synthesis and biological evaluation of nonsymmetrical aromatic disulfides as novel inhibitors of acetohydroxyacid synthase. AB - 46 Novel nonsymmetrical aromatic disulfides containing [1,3,4]thiadiazole or [1,3,4]oxadiazole groups were synthesized and their biological activities were evaluated as inhibitors of acetohydroxyacid synthase (AHAS, EC 2.2.1.6). Besides their strong in vitro inhibition against plant AHAS, compounds 3e and 3f also display 80-100% post-emergence herbicidal activities in greenhouse bioassay at 1500g /ha dosage. The assay of exogenous branched-chain amino acids supplementation on rape root growth of 3e suggests that the herbicidal activity has relationship with AHAS inhibition. PMID- 23726034 TI - Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. AB - Phosphatidylinositol-3-kinase alpha (PI3Kalpha) is a therapeutic target of high interest in anticancer drug research. On the basis of a binding model rationalizing the high selectivity and potency of a particular series of 2 aminothiazole compounds in inhibiting PI3Kalpha, a medicinal chemistry program has led to the discovery of the clinical candidate NVP-BYL719. PMID- 23726035 TI - The psychometric properties of the McCarron Assessment of Neuromuscular Development as a longitudinal measure with Australian youth. AB - The importance of considering age and sex differences in the assessment of motor performance has been largely overlooked. This study examines the psychometric properties of the US developed McCarron Assessment of Neuromuscular Development (MAND) using data from a longitudinal sample of 986 Australian youth at 10, 14 and 17 years. A key finding was the sex and age interaction of the Neuromuscular Developmental Index (NDI) (F=121.46, p<.001). Males had a significantly lower mean NDI score at 10 years and the females had a lower score at 17 years. The factor structure differed from the US samples (McCarron, 1997) at each age and between males and females. The sex specific analyses showed that the underlying structure was more complex for younger females. Although the MAND remains a useful test of motor performance for Australian children, further consideration is warranted regarding sex differences, the relevance of the US based normative tables and factor structures. PMID- 23726036 TI - Contextual interference effects on the acquisition of skill and strength of the bench press. AB - The purpose of this study was to investigate contextual interference effects on skill acquisition and strength gains during the learning of the bench press movement. Twenty-four healthy, college-aged males and females were stratified to control, high contextual interference (HCI), and low contextual interference (LCI) groups. Treatment groups were provided with written and visual instruction on proper bench press form and practiced the bench press and dart throwing for four weeks. Within each session, LCI performed all bench press sets before undertaking dart-throws. HCI undertook dart-throws immediately following each set of bench press. Control only did testing. Measurements, including one repetition maximum (1RM), checklist scores based on video recordings of participants' 1RM's, and dart-throw test scores were taken at pre-test, 1 week, 2 week, post-test, and retention test. Results were consistent with the basic premise of the contextual interference effect. LCI had significant improvements in percent 1RM and checklist scores during training, but were mostly absent after training (post test and retention test). HCI had significant improvements in percent 1RM and checklist scores both during and after training. Thus, HCI may augment strength and movement skill on the bench press since proper technique is an important component of resistance exercise movements. PMID- 23726037 TI - The first case of CDK5RAP2-related primary microcephaly in a non-consanguineous patient identified by next generation sequencing. AB - Primary autosomal recessive microcephaly (MCPH) is a genetically heterogeneous condition characterized by congenital microcephaly and intellectual disability. To date, 10 MCPH loci have been identified and due to the genetic heterogeneity of this condition, molecular testing for MCPH can be complicated. Our methods involved employing a next generation sequencing panel of MCPH-related genes allowing for the evaluation of multiple disease loci simultaneously. Next generation sequencing analysis of a 6 year old female with primary microcephaly identified novel compound heterozygous mutations (c.524_528del and c.4005-1G>A) in the CDK5RAP2 gene. A review of the published literature to date reveals that only three mutations have been previously reported in the CDK5RAP2 gene in the homozygous state in three Northern Pakistani and one Somali consanguineous MCPH families. Our patient represents the first non-consanguineous Caucasian individual to have been identified with CDK5RAP2-related MCPH. As only a handful of patients have been reported in the literature with CDK5RAP2-related MCPH, we anticipate the identification of individuals with CDK5RAP2 mutations from all ethnic backgrounds will continue. Our patient contributes to the ethnic and genotypic spectrum of CDK5RAP2-related MCPH and supports the occurrence of this genetic condition beyond that of consanguineous families of certain ethnic populations. Our results also highlight the utility of multi-gene sequencing panels to elucidate the etiology of genetically heterogeneous conditions. PMID- 23726038 TI - Design of the EpiPen Auto-Injector. PMID- 23726039 TI - Defective TH17 development in human neonatal T cells involves reduced RORC2 mRNA content. PMID- 23726040 TI - CD11a polymorphisms regulate TH2 cell homing and TH2-related disease. AB - BACKGROUND: TH2-dependent diseases vary in severity according to genotype, but relevant gene polymorphisms remain largely unknown. The integrin CD11a is a critical determinant of allergic responses, and allelic variants of this gene might influence allergic phenotypes. OBJECTIVE: We sought to determine major CD11a allelic variants in mice and human subjects and their importance to allergic disease expression. METHODS: We sequenced mouse CD11a alleles from C57BL/6 and BALB/c strains to identify major polymorphisms; human CD11a single nucleotide polymorphisms were compared with allergic disease phenotypes as part of the international HapMap project. Mice on a BALB/c or C57BL/6 background and congenic for the other strain's CD11a allele were created to determine the importance of mouse CD11a polymorphisms in vivo and in vitro. RESULTS: Compared with the C57BL/6 allele, the BALB/c CD11a allele contained a nonsynonymous change from asparagine to aspartic acid within the metal ion binding domain. In general, the BALB/c CD11a allele enhanced and the C57BL/6 CD11a allele suppressed TH2 cell dependent disease caused by the parasite Leishmania major and allergic lung disease caused by the fungus Aspergillus niger. Relative to the C57BL/6 CD11a allele, the BALB/c CD11a allele conferred both greater T-cell adhesion to CD54 in vitro and enhanced TH2 cell homing to lungs in vivo. We further identified a human CD11a polymorphism that significantly associated with atopic disease and relevant allergic indices. CONCLUSIONS: Polymorphisms in CD11a critically influence TH2 cell homing and diverse TH2-dependent immunopathologic states in mice and potentially influence the expression of human allergic disease. PMID- 23726041 TI - Dose-ranging study of lebrikizumab in asthmatic patients not receiving inhaled steroids. AB - BACKGROUND: Asthma is a disease with marked heterogeneity in its clinical course and response to treatment. IL-13 is central to type 2 inflammation, which contributes to many key features of asthma. Lebrikizumab is an anti-IL-13 mAb previously reported to significantly improve lung function in patients with inadequately controlled asthma despite inhaled corticosteroid therapy, especially in periostin-high patients. OBJECTIVE: This phase II study investigated the efficacy and safety of IL-13 blockade with different doses of lebrikizumab in asthmatic patients not receiving inhaled corticosteroids. METHODS: Patients were randomized to receive 125, 250, or 500 mg of lebrikizumab or placebo subcutaneously monthly for 12 weeks with an 8-week follow-up period. The primary efficacy end point was the relative change in prebronchodilator FEV1 from baseline to week 12. RESULTS: A total of 212 patients were randomized. The mean relative change in FEV1 was numerically higher in all lebrikizumab dose groups versus the placebo group, although the difference was neither statistically nor clinically significant. There were no meaningful differences in changes in FEV1 between the dose groups and the placebo group by the periostin subgroup. Lebrikizumab treatment was associated with a reduced risk of treatment failure at all doses versus placebo (P < .001), and results were similar by the periostin subgroup, with no apparent differences between doses of lebrikizumab. Lebrikizumab was generally well tolerated. CONCLUSION: Blocking IL-13, a single cytokine, in this population of asthmatic patients is insufficient to improve lung function. There is evidence that IL-13 blockade may improve disease control, as measured by prevention of protocol-defined treatment failure in these patients. PMID- 23726042 TI - Fungal protein MGL_1304 in sweat is an allergen for atopic dermatitis patients. AB - BACKGROUND: Sweat is a major aggravating factor of atopic dermatitis (AD) and approximately 80% of patients with AD show type I hypersensitivity against sweat. OBJECTIVE: To identify and characterize an antigen in sweat that induces histamine release from basophils of patients with AD. METHODS: Basophil histamine releasing activity in sweat was purified by a combination of chromatographies, and proteins were analyzed with mass spectrometry. Recombinant proteins of the sweat antigen were generated, and their biological characteristics were studied by immunoblots, histamine release tests, and neutralization assays. RESULTS: We identified a fungal protein, MGL_1304, derived from Malassezia globosa (M globosa) in the purified sweat antigen. Recombinant MGL_1304 induced histamine release from basophils of most of the patients with AD, in accordance with the semi-purified sweat antigen. Moreover, recombinant MGL_1304 abolished the binding of serum IgE of patients with AD to the semi-purified sweat antigen, or vice versa in immunoblot analysis, and attenuated the sensitization of RBL-48 mast cells expressing human FcERI by serum IgE. Studies of truncated mutants of MGL_1304 indicated that IgE of patients with AD recognized the conformational structure of MGL_1304 rather than short peptide sequences. Western blot analysis of the whole lysate, the culture supernatant of M globosa, and the semi-purified sweat antigen showed that MGL_1304 was produced as a minor immunological antigen of M globosa with posttranslational modification, cleaved, and secreted as a 17 kDa major histamine-releasing sweat antigen. CONCLUSION: MGL_1304 is a major allergen in human sweat and could cause type I allergy in patients with AD. PMID- 23726043 TI - Reply: To PMID 23265692. PMID- 23726044 TI - [Constraints of the dentist are consistent with the results of an optimal irradiation with modulated intensity in N0 oropharyngeal cancer]. AB - PURPOSE: We compared intensity-modulated radiotherapy and 3D-conformal irradiation in oropharyngeal cancers according to the requirement of dentists. MATERIAL AND METHODS: From the files of seven patients with cancer of the oropharynx, two dosimetry plannings for 3D-conformal radiotherapy and intensity modulated radiotherapy with tomotherapy were performed. The dose distributions in the target volumes and organs at risk in relation to the dental sphere were compared. RESULTS: For the planning target volume of the primitive tumour sites, average values of V95%, D2%, D98% and of the conformal index were statistically in favour of tomotherapy. For the planning target volume of node areas, averages values of V95%, D2%, D98% were statistically in favour of tomotherapy. For ipsi- and controlateral parotide glands, average values of V15Gy, V26Gy, V30Gy, V40Gy were significantly lower for tomotherapy. For the submaxillary glands, average values of mean doses and V40Gy were statistically in favour of tomotherapy. For the buccal cavity, the average values of V45Gy were statistically in favour of tomotherapy. For ipsi- and controlateral masseter muscles, the average values of mean doses were statistically in favour of tomotherapy. For the ipsi- and controlateral temporomandibular joints, average values of mean doses and V60Gy were statistically in favour of tomotherapy. For mandibular bone, average values of mean doses and V40Gy, V50Gy, V60Gy and V70Gy were statistically in favour of tomotherapy. For maxillary bone, average values of V40Gy, V50Gy and V60Gy were statistically in favour of tomotherapy. CONCLUSION: The radiation oncologist can constrain the intensity-modulated radiotherapy dosimetry to the needs of dentists to prevent or improve dental care and quality of life. PMID- 23726045 TI - Influence of mu-opioid receptor variant on morphine use and self-rated pain following abdominal hysterectomy. AB - A common variant in the mu-opioid receptor gene (OPRM1) has been associated with response to opioid analgesia. Our previous data revealed significantly higher amounts of morphine self-administered by patients carrying the 118G allele compared to those with the 118A allele after elective cesarean section. In this study, the association of this genetic variation with pressure pain, postoperative pain scores, and amount of morphine used was investigated in 973 patients undergoing scheduled total hysterectomy under general anesthesia. Preoperative pressure pain threshold and tolerance were also measured for most patients. For pressure pain, OPRM1 genotype was not significantly associated with either pain threshold or pain tolerance. Statistically significant associations were found for postoperative pain and the total amount of morphine used, with the GG group reporting higher pain scores and using the most morphine. When analysis was stratified by ethnic group, differences in weight-adjusted morphine for the 3 genotypic groups were also significant for the Chinese and Asian Indians. These results extend our previous finding on the association of higher self-reported pain and morphine use for acute postoperative pain with OPRM1 118G to patients who had total hysterectomy under general anesthesia. PERSPECTIVE: In a large cohort of patients undergoing hysterectomy, we found large variability in the self-rated pain scores and the amount of morphine required for pain relief. Both are associated with OPRM1 genotypes and preoperative experimental pressure pain threshold. Experimental pressure pain tolerance is also associated with postoperative pain. PMID- 23726046 TI - Primary somatosensory cortex function in complex regional pain syndrome: a systematic review and meta-analysis. AB - That complex regional pain syndrome (CRPS) is associated with functional reorganization in the primary somatosensory cortex (S1) is widely accepted and seldom questioned. Despite more than a decade of research, there has been no systematic review of the CRPS literature concerning the changes in S1 function, and therefore the extent of these changes is unclear. Here we conduct a systematic review and meta-analysis to quantify the spatial and temporal aspects of S1 function in CRPS. A comprehensive search strategy identified functional neuroimaging studies of S1 in CRPS. We adhered to a rigorous systematic review protocol when extracting data and appraising risk of bias. Outcomes were grouped into spatial representation; activation levels, including disinhibition; peak latency of activation; and glucose metabolism. Meta-analysis was conducted where possible. Fifteen studies were included, all investigating upper-extremity CRPS. In patients with CRPS, the S1 spatial representation of the affected hand is smaller than that of the unaffected hand and that of non-CRPS controls; however, this evidence comes from only a few studies. There is no difference in activation, disinhibition, or latency of peripherally evoked S1 responses in CRPS. The risk of bias was high across studies, mainly from unclear sampling methods and unblinded analysis of outcomes. PERSPECTIVE: The evidence for a difference in function of the primary somatosensory cortex in CRPS compared with controls is clouded by high risk of bias and conflicting results, but reduced representation size seems consistent. PMID- 23726048 TI - Eradication of invasive species: why the biology matters. AB - Published bi- and tri-trophic physiologically based demographic system models having similar sub components are used to assess prospectively the geographic distributions and relative abundance (a measure of invasiveness) of six invasive herbivorous insect species across the United States and Mexico. The plant hosts and insect species included in the study are: 1) cotton/pink bollworm, 2) a fruit tree host/Mediterranean fruit fly, 3) olive/olive fly, 4) a perennial host/light brown apple moth, 5) grapevine/glassy-winged sharpshooter and its two egg parasitoids, and 6) grapevine/European grapevine moth. All of these species are currently or have been targets for eradication. The goal of the analyses is to predict and explain prospectively the disparate distributions of the six species as a basis for examining eradication or containment efforts against them. The eradication of the new world screwworm is also reviewed in the discussion section because of its pivotal role in the development of the eradication paradigm. The models used are mechanistic descriptions of the weather driven biology of the species. Observed daily weather data (i.e., max-min temperatures, solar radiation) from 1,221 locations across the United States and Mexico for the period 1983-2003 were used to drive the models. Soil moisture and nutrition were assumed nonlimiting. The simulation results were mapped using GRASS GIS. The mathematical underpinnings of the modeling approach are reviewed in the appendix and in the supplemental materials. PMID- 23726049 TI - Simulating the spread of an invasive termite in an urban environment using a stochastic individual-based model. AB - Invasive termites are destructive insect pests that cause billions of dollars in property damage every year. Termite species can be transported overseas by maritime vessels. However, only if the climatic conditions are suitable will the introduced species flourish. Models predicting the areas of infestation following initial introduction of an invasive species could help regulatory agencies develop successful early detection, quarantine, or eradication efforts. At present, no model has been developed to estimate the geographic spread of a termite infestation from a set of surveyed locations. In the current study, we used actual field data as a starting point, and relevant information on termite species to develop a spatially-explicit stochastic individual-based simulation to predict areas potentially infested by an invasive termite, Nasutitermes corniger (Motschulsky), in Dania Beach, FL. The Monte Carlo technique is used to assess outcome uncertainty. A set of model realizations describing potential areas of infestation were considered in a sensitivity analysis, which showed that the model results had greatest sensitivity to number of alates released from nest, alate survival, maximum pheromone attraction distance between heterosexual pairs, and mean flight distance. Results showed that the areas predicted as infested in all simulation runs of a baseline model cover the spatial extent of all locations recently discovered. The model presented in this study could be applied to any invasive termite species after proper calibration of parameters. The simulation herein can be used by regulatory authorities to define most probable quarantine and survey zones. PMID- 23726047 TI - Angiotensin II receptor type 2 activation is required for cutaneous sensory hyperinnervation and hypersensitivity in a rat hind paw model of inflammatory pain. AB - Many pain syndromes are associated with abnormal proliferation of peripheral sensory fibers. We showed previously that angiotensin II, acting through its type 2 receptor (AT2), stimulates axon outgrowth by cultured dorsal root ganglion neurons. In this study, we assessed whether AT2 mediates nociceptor hyperinnervation in the rodent hind paw model of inflammatory pain. Plantar injection of complete Freund's adjuvant (CFA), but not saline, produced marked thermal and mechanical hypersensitivity through 7 days. This was accompanied by proliferation of dermal and epidermal PGP9.5-immunoreactive (ir) and calcitonin gene-related peptide-immunoreactive (CGRP-ir) axons, and dermal axons immunoreactive for GFRalpha2 but not tyrosine hydroxylase or neurofilament H. Continuous infusion of the AT2 antagonist PD123319 beginning with CFA injection completely prevented hyperinnervation as well as hypersensitivity over a 7-day period. A single PD123319 injection 7 days after CFA also reversed thermal hypersensitivity and partially reversed mechanical hypersensitivity 3 hours later, without affecting cutaneous innervation. Angiotensin II-synthesizing proteins renin and angiotensinogen were largely absent after saline but abundant in T cells and macrophages in CFA-injected paws with or without PD123319. Thus, emigrant cells at the site of inflammation apparently establish a renin angiotensin system, and AT2 activation elicits nociceptor sprouting and heightened thermal and mechanical sensitivity. PERSPECTIVE: Short-term AT2 activation is a potent contributor to thermal hypersensitivity, whereas long-term effects (such as hyperinnervation) also contribute to mechanical hypersensitivity. Pharmacologic blockade of AT2 signaling represents a potential therapeutic strategy aimed at biologic mechanisms underlying chronic inflammatory pain. PMID- 23726050 TI - Parasitism of Dasineura oxycoccana (Diptera: Cecidomyiidae) in North Central Florida. AB - Blueberry gall midge, Dasineura oxycoccana (Johnson), is a key pest of blueberries in Florida. As a larva, this insect feeds in developing flower and leaf buds. Management of D. oxycoccana relies principally on chemical insecticides; however, efficacy is limited because D. oxycoccana is sheltered within the plant during most of its life cycle. Natural enemies, particularly parasitoids, may play an important role in regulating D. oxycoccana populations. To determine the seasonal dynamics and parasitism rates of eulophid and platygastrid wasps parasitizing D. oxycoccana larvae, we sampled D. oxycoccana larvae by collecting infested blueberry leaf buds from a minimally-managed farm in north central Florida. Midge larvae were examined under a microscope to determine parasitism status of host instars. Parasitism rates ranged from 25 to 40% over the 3-yr study. Percent parasitization was significantly higher in third instars than first or second instars. Midge larvae in the centers of leaf buds were significantly less likely to be parasitized than larvae in outer layers of leaf buds. Thirty-seven percent of midge larvae had been parasitized multiple times, suggesting these parasitoids do not discriminate between parasitized and unparasitized hosts. Implications for pesticide use in relation to the conservation of natural enemies and management of D. oxycoccana populations are discussed. PMID- 23726051 TI - Community-level patterns of insect herbivory in a fragmented Atlantic forest landscape. AB - Insect herbivores largely affect plant population structure, community organization, and ecosystem functioning, but little is known on how insect herbivory is altered in human-modified landscapes. Here we assessed 3,566 woody seedlings inhabiting 20 Atlantic forest fragments (3-91 ha) in northeast Brazil to examine the extent to which standing levels of herbivory on woody seedlings correlated with forest fragment metrics (fragment area and distance to forest edge) and resource availability (pioneer plants). Overall, 78% of all seedlings and 36% of the 23,003 recorded leaves experienced injuries caused by folivorous insects, the bulk of them promoted by chewing insects (85.9% of damaged leaves). This insect guild removed 9.2 +/- 1.9 cm(2) of foliar tissue per leaf, which represented 10.2 +/- 1.8% of the standing leaf area. Contrary to our expectations, frequency and magnitude of foliar damage by insects were statistically uncorrelated to either basic forest fragment metrics (fragment area, edge proximity) or resource abundance (percentage of pioneer seedlings). Our findings indicate that insect herbivory is a pervasive ecological process in fragmented landscapes. However, rather than being a function of simple fragment metrics or resource availability, its variation seems to be caused by a range of drivers, such as dispersal ability of folivorous insects and vulnerability of their parasitoids and predators to human disturbance. PMID- 23726052 TI - Likelihood of stink bugs colonizing crops: a case study in southeastern farmscapes. AB - Stink bugs, including Nezara viridula (L.), Euschistus servus (Say), and Chinavia hilaris (Say), are economic pests across agricultural farmscapes where they can colonize closely associated crops. This 4-yr on-farm study was conducted to examine the likelihood of these three stink bug species colonizing crops in corn cotton, corn-peanut-cotton, and peanut-cotton farmscapes by using odds ratios. Corn (Zea mays L.), peanut (Arachis hypogaea L.), and cotton (Gossypium hirsutum L.) served as host plants for E. servus and N. viridula. Corn did not serve as a host plant for C. hilaris. Although peanut was a relatively poor host plant, cotton was a relatively good host plant for this stink bug. For N. viridula and E. servus adults, the risk of crop colonization was higher for peanut in peanut cotton farmscapes with corn than without corn and was highest for cotton in corn peanut-cotton, followed by peanut-cotton, and lastly corn-cotton farmscapes. The likelihood of oviposition by E. servus, though, was higher in cotton in corn cotton than peanut-cotton farmscapes. For C. hilaris adults, the risk of crop colonization was highest for cotton in peanut-cotton, followed by corn-peanut cotton, and lastly corn-cotton farmscapes. Corn was more likely than peanut or cotton to harbor adults and immatures, i.e., egg masses and young nymphs, of N. viridula and E. servus. Adults of all three stink bug species colonized cotton more often than peanut in peanut-cotton farmscapes. However, oviposition by N. viridula and E. servus occurred more often in peanut than in cotton. These assessments of the likelihood of stink bug colonization are essential for modeling predictions of stink bug colonization and designing more comprehensive landscape management approaches for control of stink bugs in these farmscapes. PMID- 23726053 TI - Host-symbiont interactions in spider mite Tetranychus truncates doubly infected with Wolbachia and Cardinium. AB - Inherited bacteria Wolbachia, and more recently Cardinium, have received a great deal of attention for their ability to manipulate the reproduction and fitness of their host species. Wolbachia and Cardinium have been found to co-infect the same host species. In this study, both Wolbachia and Cardinium were found to manipulate host reproduction through cytoplasmic incompatibility and to affect the male-biased sex-ratio in the doubly infected spider mite Tetranychus truncates Ehara. We also investigated effects of double infection with Wolbachia and Cardinium on host fecundity and longevity. Results indicated that Wolbachia and Cardinium increased the fecundity of doubly infected females, although no infection effect on host longevity was observed. Our most important finding was that the mating of uninfected mites facilitated the proliferation of Wolbachia and Cardinium in double-infected mites. We discuss the results observed with respect to the spread of bacterial infection in natural populations and the evolution of the endosymbiont-T. truncates symbiosis. PMID- 23726054 TI - Pseudomonas reactans, a bacterial strain isolated from the intestinal flora of Blattella germanica with anti-Beauveria bassiana activity. AB - Anti-Beauveria bassiana activity of aqueous fecal extracts from conventional German cockroaches [Blattella germanica (L.)] was detected, but was not detected in samples from germ-free German cockroaches. Subsequently, bacterial strain BGI 14 was isolated from the gut of conventional German cockroaches and was identified as Pseudomonas reactans based on 16S rDNA sequence. The strain BGI-14 not only inhibited the germination of conidia, but also inhibited the growth of B. bassiana hyphae. Further studies demonstrated that B. bassiana infections in German cockroaches orally treated with the extracts of BGI-14 fermentation were significantly weakened. Compared with the control group, the cumulative mortality rate of treatment group was reduced by 10.3% at 20 d postinoculation. These studies imply that intestinal flora with anti-B. bassiana activity might contribute to resistance of infection by entomopathogenic fungi. PMID- 23726055 TI - Interaction between Linepithema micans (Hymenoptera: Formicidae) and Eurhizococcus brasiliensis (Hemiptera: Margarodidae) in vineyards. AB - Eurhizococcus brasiliensis (Wille) (Hemiptera: Margarodidae) is a soil scale that is considered the main pest of vineyards in Brazil. The ant Linepithema micans (Forel) (Hymenoptera: Formicidae) is frequently found associated with this species of scale in infested areas. The effect of the presence of L. micans on the infestation and dispersal capacity of E. brasiliensis on vine roots was measured in a greenhouse, using Paulsen 1103 rootstock seedlings planted in simple and double "Gallotti Cages." Treatments measured were: infestation of roots with E. brasiliensis or L. micans, and infestation with both species together. In the experiment using simple Gallotti Cages, with E. brasiliensis associated with L. micans, higher mean numbers of cysts and ants per plant were recorded, a result significantly different from that found for infestation with scale only. When double Gallotti Cages were used, first-instar nymphs were transported between the cages. The results showed that L. micans transports and aids in the attachment of E. brasiliensis to vine plants. PMID- 23726056 TI - Overwintering survival of olive fruit fly (Diptera: Tephritidae) and two introduced parasitoids in California. AB - The overwintering survival and development of olive fruit fly, Bactrocera oleae (Rossi), and the endoparasitoids, Psyttalia humilis Silvestri and P. lounsburyi (Silvestri), were investigated at sites in California's interior valley and coastal region. In the interior valley, adult flies survived up to 4-6 mo during the winter when food was provided. Adult female flies could oviposit in late fall and early winter on nonharvested fruit and, although egg survival was low (0.23 8.50%), a portion of the overwintered cohort developed into adults the following spring; percentage of survival was negatively correlated to daily minimum temperature. P. humilis and P. lounsburyi successfully oviposited into host larvae in late fall, and their progeny developed into adults the following spring, although with a low percentage (0-11.9%) survivorship. Overwintering survival of puparia of the olive fruit fly and immature larvae of P. humilis and P. lounsburyi (inside host puparia), buried in the soil, were tested at an interior valley and coastal site. Survival of olive fruit fly ranged from 0 to 60% and was affected by the trial date and soil moisture. Overwintering survival of both the fruit fly and tested parasitoids was lower at the colder interior valley than the coastal site; P. humilis immature stages had the highest mortality levels while B. oleae pupae had the lowest mortality levels. The spring emergence pattern of the tested insects was well predicted by a degree-day model. We discuss factors potentially impeding establishment of introduced olive fruit fly parasitoids in California and elsewhere. PMID- 23726057 TI - Factors influencing aster leafhopper (Hemiptera: Cicadellidae) abundance and aster yellows phytoplasma infectivity in Wisconsin carrot fields. AB - In Wisconsin, vegetable crops are threatened annually by infection of the aster yellows phytoplasma (AYp), the causal agent of aster yellows (AY) disease, vectored by the aster leafhopper, Macrosteles quadrilineatus Forbes. Aster leafhopper abundance and infectivity are influenced by processes operating across different temporal and spatial scales. We applied a multilevel modeling approach to partition variance in multifield, multiyear, pest scouting data sets containing temporal and spatial covariates associated with aster leafhopper abundance and infectivity. Our intent was to evaluate the relative importance of temporal and spatial covariates to infer the relevant scale at which ecological processes are driving AY epidemics and identify periods of elevated risk for AYp spread. The relative amount of aster leafhopper variability among and within years (39%) exceeded estimates of variation among farm locations and fields (7%). Similarly, time covariates explained the largest amount of variation of aster leafhopper infectivity (50%). Leafhopper abundance has been decreasing since 2001 and reached its minimum in 2010. The average seasonal pattern indicated that periods of above average abundance occurred between 11 June and 1 August. Annual infectivity appears to oscillate around an average value of 2% and seasonal periods of above average infectivity occur between 19 May and 15 July. The coincidence of the expected periods of high leafhopper abundance and infectivity increases our knowledge of when the insect moves into susceptible crop fields and when it spreads the pathogen to susceptible crops, representing a seasonal interval during which management of the insect can be focused. PMID- 23726058 TI - Seasonal patterns of aster leafhopper (Hemiptera: Cicadellidae) abundance and aster yellows phytoplasma infectivity in Wisconsin carrot fields. AB - In Wisconsin, vegetable crops are threatened annually by the aster yellows phytoplasma (AYp), which is obligately transmitted by the aster leafhopper. Using a multiyear, multilocation data set, seasonal patterns of leafhopper abundance and infectivity were modeled. A seasonal aster yellows index (AYI) was deduced from the model abundance and infectivity predictions to represent the expected seasonal risk of pathogen transmission by infectious aster leafhoppers. The primary goal of this study was to identify periods of time during the growing season when crop protection practices could be targeted to reduce the risk of AYp spread. Based on abundance and infectivity, the annual exposure of the carrot crop to infectious leafhoppers varied by 16- and 70-fold, respectively. Together, this corresponded to an estimated 1,000-fold difference in exposure to infectious leafhoppers. Within a season, exposure of the crop to infectious aster leafhoppers (Macrosteles quadrilineatus Forbes), varied threefold because of abundance and ninefold because of infectivity. Periods of above average aster leafhopper abundance occurred between 11 June and 2 August and above average infectivity occurred between 27 May and 13 July. A more comprehensive description of the temporal trends of aster leafhopper abundance and infectivity provides new information defining when the aster leafhopper moves into susceptible crop fields and when they transmit the pathogen to susceptible crops. PMID- 23726059 TI - Effects of elevated CO2 leaf diets on gypsy moth (Lepidoptera: Lymantriidae) respiration rates. AB - Elevated levels of CO2 affect plant growth and leaf chemistry, which in turn can alter host plant suitability for insect herbivores. We examined the suitability of foliage from trees grown from seedlings since 1997 at Aspen FACE as diet for the gypsy moth (Lymantria dispar L.) Lepidoptera: Lymantriidae: paper birch (Betula papyrifera Marshall) in 2004-2005, and trembling aspen (Populus tremuloides Michaux) in 2006-2007, and measured consequent effects on larval respiration. Leaves were collected for diet and leaf chemistry (nutritional and secondary compound proxies) from trees grown under ambient (average 380 ppm) and elevated CO2 (average 560 ppm) conditions. Elevated CO2 did not significantly alter birch or aspen leaf chemistry compared with ambient levels with the exception that birch percent carbon in 2004 and aspen moisture content in 2006 were significantly lowered. Respiration rates were significantly higher (15-59%) for larvae reared on birch grown under elevated CO2 compared with ambient conditions, but were not different on two aspen clones, until larvae reached the fifth instar, when those consuming elevated CO2 leaves on clone 271 had lower (26%) respiration rates, and those consuming elevated CO2 leaves on clone 216 had higher (36%) respiration rates. However, elevated CO2 had no apparent effect on the respiration rates of pupae derived from larvae fed either birch or aspen leaves. Higher respiration rates for larvae fed diets grown under ambient or elevated CO2 demonstrates their lower efficiency of converting chemical energy of digested food stuffs extracted from such leaves into their biosynthetic processes. PMID- 23726060 TI - Effectiveness of glues for harmonic radar tag attachment on Halyomorpha halys (Hemiptera: Pentatomidae) and their impact on adult survivorship and mobility. AB - We evaluated the effectiveness of three cyanoacrylate glues (trade names: Krazy [Elmer's Products Inc., Westerville, OH], Loctite [Henkel Corporation, Rocky Hill, CT], and FSA [Barnes Distribution, Cleveland, OH]) to attach harmonic radar tags securely on adult Halyomorpha halys (Stal) (Hemiptera: Pentatomidae) and quantified the effect of the radar tag attachment on insect survivorship and mobility. In the laboratory, the strength of the glue bond between the radar tag and H. halys pronotum was significantly increased when the pronotum was sanded to remove cuticular waxes. The adhesive bond of the radar tag to the sanded pronotum of H. halys had strength of 160-190-g force and there was no significant difference among the three types of glue tested. The three glues had no measurable effect on the survivorship of radar-tagged H. halys over 7 d, compared with untagged insects. Over a 7-d period in the laboratory, horizontal distance traveled, horizontal walking velocity, and vertical climbing distance were all unaffected by the presence of the tags regardless of glue. A field experiment was conducted to compare the free flight behavior of untagged and radar-tagged H. halys. Adults were released on a vertical dowel and their flights were tracked visually up to ?200 m from the release point. There was no significant difference in take-off time or in flight distance, time, or speed between untagged and radar tagged individuals. In addition, prevailing flight direction was not significantly different between untagged and radar-tagged individuals. The absence of measurable impact of the radar tag attachment on H. halys survivorship or mobility validates the use of harmonic radar tags to study the dispersal ecology of this insect in field conditions. PMID- 23726061 TI - Spatial-temporal dynamics of stable fly (Diptera: Muscidae) trap catches in Eastern Nebraska. AB - Spatial and temporal relationships among catches of adult stable flies, Stomoxys calcitrans (L.), on sticky traps in eastern Nebraska were evaluated. Twenty-five alsynite sticky traps were placed in a 5 by 5 grid with ?1.6-km intervals in a mixed agricultural environment from 2003 to 2011. Denser grids of 45-90 traps were implemented for varying lengths of time during the course of the study. More than two million stable flies were collected over 9 yr. Seasonal abundances based upon total collections from the primary grid of 25 traps were bimodal most years with population peaks in June and September or October. Individual trap catches varied greatly, both spatially and temporally. Trap catches were spatially aggregated with autocorrelation extending to ?2 km. Synchrony among trap catches declined linearly with respect to distance between traps and differences in seasonal distribution increased asymptotically relative to distance between traps. Proximity to confined livestock facilities increased catch and proportion of catch collected later in the season. Fifteen to 20 traps were adequate for estimating stable fly populations with the standard error of the mean equal to 30% of the mean for most of the stable fly season. Early and late in the season, when mean trap catches were low, between 100 and 135 traps would be needed to maintain that level of confidence. Seasonal collection distributions from permutations of subsets of the data with fewer than 24 traps differed significantly from those of the complete grid of 25 traps, indicating that 20 or more traps may be needed to evaluate the seasonal dynamics of a stable fly population. PMID- 23726062 TI - Modeling Agrilus planipennis (Coleoptera: Buprestidae) within-tree colonization patterns and development of a subsampling technique. AB - Emerald ash borer, Agrilus planipennis Fairmaire, an insect native to central Asia, was first detected in southeast Michigan in 2002, and has since killed millions of ash trees (Fraxinus spp.) in North America. The objectives of this study were to 1) determine an optimal sampling location on girdled ash trap trees for detection of A. planipennis larvae based on measurements of tree characteristics, and 2) develop a whole-tree estimation method for extrapolating larval densities from subsampled heights. We conducted sampling at 1-m increments, recording larval presence, height on tree bole, bolt diameter, and bark roughness for 58 infested ash trees. Analyzing height and diameter separately, generalized linear mixed models indicated the probability of A. planipennis detection was maximized at 17.2 cm for diameter and increased linearly as vertical height increased. There was also a positive relationship between intermediate bark roughness and A. planipennis presence. Stepwise regression indicated the optimal bolts for extrapolating whole tree larval densities were, in order of importance, at heights of 1-2 m, 4-5 m, 7-8 m, and 0 1 m. Subsampling with just one or two bolts explained 70% and 86%, respectively, of the variance in A. planipennis densities. Our results can be used by resource managers to improve efficiency of detection efforts and estimate infestations of A. planipennis. PMID- 23726063 TI - Interruption of the semiochemical-based attraction of ambrosia beetles to ethanol baited traps and ethanol-injected trap trees by verbenone. AB - We examined the extent to which verbenone, a bark beetle antiaggregation pheromone, interrupted the semiochemical-based attraction of ambrosia beetles. Field trapping studies conducted in Ohio showed that a verbenone dispenser with a release rate of 50 mg/d at 25 degrees C reduced the attraction of Anisandrus sayi Hopkins, Euwallacea validus (Eichhoff), Hypothenemus dissimilis (Zimmermann), Xylosandrus germanus (Blandford), and Xyleborinus saxesenii (Ratzeburg) to ethanol-baited traps. A verbenone dispenser attached to ethanol-injected Magnolia virginiana L. trap trees deployed in Ohio also reduced ambrosia beetle attacks compared to trap trees without a verbenone dispenser. Subsequent field trials demonstrated a direct relationship between distance from a verbenone dispenser and ambrosia beetle attacks on trap trees in Ohio in 2011 and 2012 and Tennessee in 2012, but not in Tennessee and Virginia in 2011. Assessment of the influence of verbenone on the probability of attacks above a density threshold found that although attacks occurred on trap trees regardless of their proximity to a verbenone dispenser, the higher density of attacks per tree occurred on trap trees farthest away from the verbenone source in Ohio and Tennessee. Verbenone alone could be somewhat useful for discouraging ambrosia beetle attacks on individual trees or on a small spatial scale, but deployment of verbenone might be most effective when integrated as part of a "push-pull" strategy. PMID- 23726064 TI - Sensory adaptation of antennae and sex pheromone-mediated flight behavior in male oriental fruit moths (Leptidoptera: Tortricidae) after prolonged exposure to single and tertiary blends of synthetic sex pheromone. AB - Sensory adaptation has been measured in the antennae of male Grapholita molesta (Busck) after 15 min of exposure to its main pheromone compound (Z)-8-dodecen-1 yl acetate (Z8-12:OAc) at the aerial concentration of 1 ng/m(3) measured in orchards treated with pheromone for mating disruption. Exposing males to this aerial concentration of Z8-12:OAc for 15 min, however, had only a small effect on their ability to orientate by flight to virgin calling females in a flight tunnel. Experiments were undertaken to determine if exposure to the main pheromone compound in combination with the two biologically active minor compounds of this species, (E)-8-dodecen-1-yl acetate (E8-12:OAc) and (Z)-8 dodecen-1-ol (Z8-12:OH) would induce greater levels of sensory adaptation and have a greater effect on male sexual behavior. The exposure of male antennae to 0.5 g/m(3) air of one of the three pheromone compounds induced sensory adaptation to this compound and to the other two pheromone compounds demonstrating cross adaptation. Average percentage sensory adaptation to a pheromone compound was similar after 15 min of exposure to 1 ng/m(3) air of Z8-12:OAc, or to 1 ng/m(3) air of a 1:1:1 or 93:6:1 blend of Z8-12:OAc, E8-12:OAc, and Z8-12:OH. The exposure of males to 1 ng/m(3) air of Z8-12:OAc or the two ratios of Z8-12:OAc, E8-12:OAc, and Z8-12:OH for 15 min had no effect on their ability to orientate to a virgin calling female. The implications of these results for the operative mechanisms of sex pheromone-mediated mating disruption of this species are discussed. PMID- 23726065 TI - Blend chemistry and field attraction of commercial sex pheromone lures to grape berry moth (Lepidoptera: Tortricidae), and a nontarget tortricid in vineyards. AB - Anecdotal reports by scientists and growers suggested commercial sex pheromone lures were ineffective with monitoring field populations of grape berry moth, Paralobesia viteana (Clemens), in vineyards. This study addressed the need to evaluate commercial sex pheromone lures for chemical purity and efficacy of attracting grape berry moth and a nontarget tortricid, the sumac moth, Episumus argutanus (Clemens). The percentage of chemical components from a set of eight lures from each manufacturer was found using gas chromatography-mass spectrometry and confirmed by chemical standards. No lures adhered to the 9:1 blend of (Z)-9 dodecenyl acetate (Z9-12:Ac) to (Z)-11-tetradecenyl acetate (Z11-14:Ac), though Suterra (9.1:1), ISCA (5.7:1), and Trece (5.4:1) lures were closest. The Trece lures contained ?98 MUg Z9-12:Ac, which is 3-51 times more than the other lures. The Suterra and ISCA lures were loaded with ?29 and 33 MUg Z9-12:Ac, and the Alpha Scents lures only contained ?2 MUg Z9-12:Ac. An antagonistic impurity, (E) 9-tetradecenyl acetate (E9-12:Ac), was found in all manufacturer lures at concentrations from 3.2 to 4.8%. Field attraction studies were done in summer 2010, and again in 2011, to evaluate commercial lures for their potential to attract P. viteana and E. argutanus in the presence of lures from other manufacturers. Separate experiments were established in two vineyards in Augusta County, VA, one with open and the other with wooded surroundings. In field experiments, Suterra lures detected P. viteana most often, Trece lures detected more E. argutanus, and ISCA lures detected P. viteana in the open vineyard the least, while Alpha Scents lures were least attractive to E. argutanus in both environments. Fewer P. viteana were captured in the wooded versus open vineyard, which may limit the potential for sex pheromone monitoring of P. viteana in wooded vineyards. PMID- 23726066 TI - Life history characteristics of diorhabda carinulata under various temperatures. AB - Tamarisk leaf beetles, Diorhabda spp., have been released in the western United States as a biological control agent for the invasive weed Tamarix spp. There have been a few studies on the life cycle, host preferences, and field observations of Diorhabda; however, their ecophysiological characteristics under various temperature regimes are not clearly understood. In this study, life history characteristics such as growth, fecundity, and mortality of Diorhabda Carinulata (Desbrochers), the species established in the Colorado River basin, were investigated under various temperatures. Beetles were housed at various temperatures (room, constant high, and variable high) and their life cycle from eggs to reproductive adult was observed. Body size at various larval and adult stages, as well as their developmental time decreased with increasing temperature. Between the two temperature treatments, beetles at diurnally fluctuating temperature (variable high treatment) grew slower and produced fewer eggs per clutch when compared with the constant high treatment. Despite smaller in size, beetles grew fastest at the constant high temperature and produced most eggs per clutch compared with the other two treatments. Overall, severely high temperatures seem to have a debilitating effect on Diorhabda at early larval stages with nearly 50% mortality. The study has potential implications for the tamarisk beetle biocontrol program in the southwestern United States. PMID- 23726067 TI - Lowered salinity tolerance in sea skaters Halobates micans, Halobates sericeus, and Halobates sp. (Heteroptera: Gerridae). AB - Adult specimens of three species of oceanic sea skater, Halobates sericeus Eschscholtz, Halobates micans Eschscholtz, and Halobates sp. were placed in one of four solutions of different salinity (sea water [35-360/00], sea water : fresh water = 2:1 [23-240/00], sea water : fresh water = 1:2 [11-130/00], and fresh water [00/00]) after collection from the temperate and subtropical Pacific Ocean, tropical Indian Ocean, and Tomini Gulf in Indonesia, and observed in 2-h intervals until they died. H. micans collected from the tropical Indian Ocean survived twice a long (80-100 h) on average as H. sericeus collected from the temperate and subtropical Pacific Ocean (35-45 h) under salinities of 12-360/00. Paralysis from freshwater treatment occurred within 2-9 h in all specimens of both species of H. sericeus from the Pacific Ocean and H. micans from the Indian Ocean, and all insects died within 2 hr of starting the paralysis. In fresh water, oceanic sea skaters of H. sp. collected from the inner water of Tomini Gulf survived for ?24 h on average, significantly longer than those collected from the open ocean. Significantly longer length of survival was shown by the three species on one-thirds, two-thirds brackish, and 1000/00 sea water than on fresh water. The long length of survival shown by oceanic sea skaters even in brackish water may be an adaptation to the occasional rain fall on the sea water film. PMID- 23726068 TI - The effects of enhanced ultraviolet-B radiation on the biology of green and brown morphs of Sitobion avenae (Hemiptera: Aphididae). AB - The effects of enhanced UV-B radiation on the biology of green and brown morphs of Sitobion avenae (F.) (Hemiptera: Aphididae) were tested under laboratory conditions. The two S. avenae morphs were exposed directly to different doses (0, 216, 432, and 864 kJ/m(2)) of artificial UV-B. Under low doses of UV-B (216 kJ/m(2)), the nymphal development period was significantly shorter, whereas mean relative growth, total fecundity, and gross reproductive rate were significantly higher for both aphid morphs compared with those morphs under control treatments (0 kJ/m(2)). Under high doses of UV-B (432 kJ/m(2) and/or 864 kJ/m(2)), the nymphal development period was significantly longer, whereas the reproductive period, postreproductive period, difference in weight, mean relative growth, and life table parameters were significantly reduced for both aphid morphs. Moreover, the nymphal development period was significantly shorter and the differences in weight, mean relative growth, total fecundity, and life table parameters were significantly higher for the brown morph under high doses of UV-B compared with the green morph. The results showed that enhanced UV-B affects the performance of the green and brown S. avenae morphs from positively to negatively. The brown morph exhibited stronger adaptability than the green morph at high doses of UV-B. PMID- 23726069 TI - Direct and indirect effects of the synthetic-auxin herbicide dicamba on two lepidopteran species. AB - Herbicides are the most commonly applied pesticides in agroecosystems, and therefore pose potentially significant ecotoxicological risks to plants and insects. Glyphosate is the most common herbicide worldwide, and glyphosate resistant weeds are quickly becoming serious challenges in some agroecosystems. Because of this resistance epidemic and the recent development of crops with resistance to dicamba or 2,4-D, herbicide-use patterns are likely to change. Presently, dicamba and 2,4-D cause most herbicide-drift damage to nontarget plants despite limited agricultural usage, but the effects of these synthetic auxin herbicides on insects have been poorly explored. To understand the influence of dicamba on insects, we applied several sublethal, drift-level rates of dicamba to soybean, Glycine max L., and Carduus thistle, and measured growth and survival of Helicoverpa zea (Boddie) and Vanessa cardui (L.) larvae, respectively. For thistle, we measured percent nitrogen content before and after dicamba application. We also performed direct toxicity bioassays on the two caterpillar species with several rates of dicamba. Dicamba was not directly toxic to larvae of either species, and H. zea showed no negative effects when feeding on soybeans dosed with dicamba. We did, however, detect significant negative, indirect effects of higher rates of dicamba on V. cardui larval and pupal mass, total nitrogen of thistles post application, and thistle biomass in the presence of V. cardui larvae. Notably, thistle biomass was not related to dicamba dose in absence of larvae. Our results indicate that dicamba can indirectly influence the performance of some caterpillar species, possibly by altering plant nutritional content. PMID- 23726070 TI - Influence of media type and moisture on adult development and pupal mortality in Rhagoletis indifferens (Diptera: Tephritidae). AB - The influence of media type and moisture on adult development and pupal mortality in western cherry fruit fly, Rhagoletis indifferens Curran (Diptera:Tephritidae), was assessed using the pupal-adult and the larval-pupal stage. Inside containers, a higher percent of flies that emerged from dry loam was deformed (44.2%, 1-cm depth loam; 84.4%, 5-cm-depth loam) than flies from 16% moist loam and dry and 16% moist lab soil (peat moss-sand mix) (0-14.9%). Percent of flies deformed from dry sand (22.1%, 1-cm depth; 49.5%, 5-cm depth) was greater than from 16% moist sand and dry and 16% moist peat moss (0-10.5%). Percents of flies deformed from 8% moist loam, lab soil, sand, and peat moss (0-5.8%) did not differ. Pupae suffered higher mortality at 7 and 14 d after larvae were dropped onto dry loam and dry sand (68.2-94.0%) than dry lab soil and dry peat moss (3.0-53.0%); respective mortalities at 21 and 28 d were similar (81.3-96.0 versus 64.7-97.9%). Pupal mortality in moist media was lower (0.5-40.3%) than in dry media. In outdoor tests, pupal mortality was also higher in dry loam than other dry media. In nature, 60.9% of pupae in dry sandy loams in late summer were dead. Results suggest R. indifferens has not yet evolved to fully cope with dry soils and that pupation in media with traits similar to those of peat moss or a peat moss-sand mix could reduce negative effects of dry environments on fly survival. PMID- 23726072 TI - Electroenhanced solid-phase microextraction of methamphetamine with commercial fibers. AB - Electroenhanced solid-phase microextraction (EE-SPME) method with gas chromatographic mass spectrometric analysis was investigated for the determination of methamphetamine in urine sample with commercial fibers. In this approach, commercial SPME fibers were used in direct immersion mode with an applied potential to extract methamphetamine. EE-SPME was more effective in the extraction compared to conventional SPME (i.e. application of potential). The method was simple to use, and avoided the need for alkalization and derivatization of methamphetamine. Experimental conditions were optimized to achieve better extraction performance. Various conditions including applied potential, sample pH, extraction and desorption time were investigated. Based on the optimized conditions, EE-SPME achieved a higher enrichment factor of 159-fold than conventional SPME. The calibration plot under the best selected parameters was linear in the range of 0.5-15ng/mL (r=0.9948). The feasibility of EE-SPME was demonstrated by applying it to the analysis of human urine samples. The limit of detection of methamphetamine was 0.25ng/mL with a satisfactory relative standard deviation of 6.12% (n=3) in human urine. PMID- 23726071 TI - New options for the treatment of obesity and type 2 diabetes mellitus (narrative review). AB - Moderate weight loss (>5%), which has been associated with improvements in glycemic parameters in patients with dysglycemia, also reduces the presence of other comorbidities, including dyslipidemia and hypertension, culminating in a reduced risk of cardiovascular disease. Lifestyle changes are the recommended preliminary approach to weight loss, with an initial weight-loss goal of 10% of body weight achieved over 6 months at a rate of 1-2 pounds per week selected as an appropriate target to decrease the severity of obesity-related risk factors. Implementing and maintaining the lifestyle changes associated with weight loss can, however, be challenging for many patients. Therefore, additional interventions sometimes may be necessary. Bariatric surgery can also be a highly effective option for weight loss and comorbidity reduction, but surgery carries considerable risks and is still applicable only to selected patients with type 2 diabetes. Thus, attention is turning to the use of weight-loss medications, including 2 recently approved compounds: twice-daily lorcaserin and a once-daily combination of phentermine and topiramate extended-release, both shown to be safe and effective therapies in the management of obesity in patients with type 2 diabetes. PMID- 23726073 TI - Analysis of herb-herb interaction when decocting together by using ultra-high performance liquid chromatography-tandem mass spectrometry and fuzzy chemical identification strategy with poly-proportion design. AB - A novel and generally applicable approach was established for the herb-herb interaction analysis when decocting together by using ultra-high-performance liquid chromatography coupled with a triple quadrupole electrospray tandem mass spectrometer and fuzzy chemical identification with poly-proportion design. A simple programme was originally developed for the rapid identification and classification of herbal constituents on the basis of the establishment of herbal constituent databases, recognition of the reference compound peaks, selection of the diagnostic ions or fragmentation pathways, classification of chemical groups and formation of group networks. In this study, the exact structures of the chemical constituents did not need to be determined, and only the constituents attributed to different groups were further considered for quantitative analysis. Such a novel approach was successfully applied to kansui-licorice interaction analysis when decocting together. A total of 26 constituents from kansui and 45 constituents from licorice were classified into different chemical groups, and they were further quantitatively analyzed on the basis of semi-symmetric proportion design. The results showed that kansui could significantly promote the concentration of most triterpenoid saponins, phenylpropanoids and their glycosides (the constituents from licorice) in solution when co-decocting, and licorice could clearly promote the concentration of most diterpenes and triterpenes (the constituents from kansui) in solution, potentially explaining the incompatibility of kansui and licorice. Overall, the presently developed strategy should be useful for the interaction analysis for complex mixtures containing various complicated constituents, such as herbal, environmental, agricultural and biological samples. PMID- 23726074 TI - Comprehensive impurity profiling and quantification of Sudan III dyes by gas chromatography/mass spectrometry. AB - A novel analysis strategy was created for comprehensive qualitative and quantitative impurity profiling of the coloring agent Sudan III by gas chromatography/mass spectrometry (GC/MS). The identification of impurities in commercial Sudan III was performed by GC/MS combined with trimethylsilylation (TMS). A total of 24 impurities were identified or tentatively characterized in commercial Sudan III dyes by GC/MS and were mainly classified as phenylazo and naphtholazo analogs. Four new impurities with coplanar structures, suspected of being toxic compounds, were observed in commercial Sudan III dyes. For further identification and sensitive detection of polar impurities, an extract was trimethylsilyl-derivatized to improve the GC chromatographic properties and mass spectrometric detection sensitivity. On the basis of the impurities identified by GC/MS, pathways for the formation of the major impurities during the manufacture of Sudan III were suggested. Four impurities regulated by the EU commission and the US Code of Federal Regulations (CFR) in Sudan III were quantified by GC/MS scan mode. Method validation was conducted to determine linearity, precision, accuracy, and limit of quantification (LOQ). The linear dynamic range extended from 0.001 to 4.0%, with a correlation coefficient (R(2)) greater than 0.997 for GC/MS. The LOQs of the impurities ranged from 2.73 to 4.39MUg/g for GC/MS. Based on the established method, the levels of regulated impurities in five commercial Sudan III dyes manufactured by different chemical companies were successfully determined. This study provides very useful information for the quality control of Sudan III and evaluation of its manufacture. PMID- 23726075 TI - Determination of alcohols in essential oils by liquid chromatography with ultraviolet detection after chromogenic derivatization. AB - An HPLC-UV method to determine compounds having a hydroxyl functional group in plant essential oils is developed. The sample is diluted with 1,4-dioxane and the analytes are derivatized with phthalic anhydride. The derivatives (phthalates hemiesters) are separated on a C8 column using an acetonitrile (ACN)/water gradient. Separation conditions were optimized using the DryLab((r)) method development software. For the alcohols and phenols present in mint and rose essential oils, optimization led to a ca. 40min gradient time and a column temperature of 8 degrees C. The alcohol and its derivatives were identified using HPLC with mass spectrometry (MS) detection. A large sensitivity enhancement was obtained by derivatization protocol. The HPLC-UV method was compared to GC with flame ionization detector (FID) and GC-MS. The limits of detection (LODs) obtained by the proposed method were better than those obtained by GC-FID and of the same order as those achieved by GC-MS. The three methods were satisfactorily applied to the determination of alcohols in essential oils. Therefore, the recommended method is of interest as an alternative to GC methods, to investigate the presence of compounds having an alcohol group at low concentrations in essential oils. PMID- 23726076 TI - Amino modified multi-walled carbon nanotubes/polydimethylsiloxane coated stir bar sorptive extraction coupled to high performance liquid chromatography-ultraviolet detection for the determination of phenols in environmental samples. AB - In this work, amino modified multi-walled carbon nanotubes/polydimethylsiloxane (multi-walled carbon nanotubes-4,4'-diaminodiphenylmethane/polydimethylsiloxane, MWCNTs-DDM/PDMS) was synthesized, and utilized as a novel coating for stir bar sorptive extraction (SBSE) of seven phenols (phenol, 2-chlorophenol, 2 nitrophenol, 4-nitrophenol, 2,4-dimethylphenol, p-choro-m-cresol and 2,4,6 trichlorphenol) in environmental water and soil samples, followed by high performance liquid chromatography-ultraviolet detection (HPLC-UV). The prepared MWCNTs-DDM/PDMS coated stir bar was characterized and good preparation reproducibility was obtained with the relative standard deviations (RSDs) ranging from 4.7% to 11.3% (n=9) in one batch, and from 4.8% to 13.9% (n=8) among different batches. Several parameters affecting the extraction of seven target phenols by MWCNTs-DDM/PDMS-SBSE including extraction time, stirring rate, pH, ionic strength, desorption solvent and desorption time were investigated. Under the optimal experimental conditions, the limits of detection (LODs, S/N=3) were found to be in the range of 0.14MUg/L (2-nitrophenol) to 1.76MUg/L (phenol) and the limits of quantification (LOQs, S/N=10) were found to be in the range of 0.46MUg/L (2-nitrophenol) to 5.8MUg/L (phenol). The linear range was 5-1000MUg/L for phenol and 4-nitrophenol, 1-1000MUg/L for 2-nitrophenol and 2-1000MUg/L for other phenols, respectively. The RSDs of the developed method were in the range of 6.2-11.6% (n=8, c=10MUg/L) and the enrichment factors were from 6.5 to 62.8 fold (theoretical enrichment factor was 100-fold). The proposed method was successfully applied to the analysis of phenols in environmental water and soil samples, and good recoveries were obtained for the spiked samples. The proposed method is simple, highly sensitive and suitable for the analysis of trace phenols in environmental samples with complex matrix. PMID- 23726077 TI - Determination and evaluation of gas holdup time with the quadratic equation model and comparison with nonlinear models for isothermal gas chromatography. AB - Gas holdup time (tM) is a basic parameter in isothermal gas chromatography (GC). Determination and evaluation of tM and retention behaviors of n-alkanes under isothermal GC conditions have been extensively studied since the 1950s, but still remains unresolved. The difference equation (DE) model [J. Chromatogr. A 1260: 215-223] reveals retention behaviors of n-alkanes excluding tM, while the quadratic equation (QE) model [J. Chromatogr. A 1260: 224-231] including tM is suitable for applications. In the present study, tM values were calculated with the QE model, which is referred to as tMT, evaluated and compared with other three typical nonlinear models. The QE model gives an accurate estimation of tM in isothermal GC. The tMT values are highly accurate, stable, and easy to calculate and use. There is only one tMT value at each GC condition. The proper classification of tM values can clarify their disagreement and facilitate GC retention data standardization for which tMT values are promising reference tM values. PMID- 23726078 TI - Preparation and evaluation of 1,6-hexanediol ethoxylate diacrylate-based alkyl methacrylate monolithic capillary column for separating small molecules. AB - Due to the high porosity, good thermal stability, and good physical stability at high pressure, polymer monoliths have been successfully utilized as the stationary phases for capillary liquid chromatography (LC) analysis. In this study, we introduced 1,6-hexanediol ethoxylate diacrylate (HEDA) as a cross linker to prepare alkyl methacrylate monoliths for efficient separation of polar small molecules. HEDA provided additional dipole-dipole interactions between the monolithic stationary phases and polar analytes. For comparison, ethylene dimethacrylate and 1,6-hexanediol dimethacrylate were also utilized as cross linkers to prepare alkyl methacrylate monoliths. A series of alkyl methacrylate polymeric monoliths were synthesized in fused-silica capillaries using the three different cross-linkers. The porosity, permeability and column efficiency of the synthesized alkyl methacrylate monoliths were characterized. A mixture of phenol derivatives was employed to evaluate the applicability of the prepared monolithic columns for separating small molecules using capillary LC. The HEDA-based alkyl methacrylate monoliths offered the most efficient chromatographic separation for phenol derivatives. Moreover, the capability of applying the novel HEDA-based alkyl methacrylate monolithic columns for potential environmental analysis was demonstrated by separating eight phenylurea herbicides. PMID- 23726079 TI - Studies of long chain lipids in insects by high temperature gas chromatography and high temperature gas chromatography-mass spectrometry. AB - The organic compounds occurring naturally on the cuticles (surfaces) of insects are important for insect communication, help to act as protective water barriers and are useful in chemical taxonomy. Typically the cuticular lipids are only studied by gas chromatography-mass spectrometry (GC-MS) of hexane or pentane extracts, so the normal limitations of GC-MS makes it perhaps unsurprising that compounds with more than about 35 carbon atoms have only rarely been reported. Here we show by high temperature (HT) GC and HTGC-MS of extracts of eleven species of insects from nine genera, that longer chain compounds are actually common. Wax esters and triacylglycerides are virtually ubiquitous in such extracts, but long chain (>C35) hydrocarbons also sometimes occur. Whilst the latter have occasionally been reported previously from mass spectrometry studies, the use of the HTGC combination with MS allowed even some isobaric isomers to be separated and thus more complete lipid distributions to be monitored. Since the physical properties of cuticular compounds depend on this composition of the mixtures, such differences may influence the water loss rates of the insects, amongst other effects. In addition, the high molecular weight compound profiles may allow species to be more easily differentiated, one from another. It would be interesting to apply these methods to examination of the cuticular lipids of insects on a more routine basis, ideally in combination with MALDI-TOF-MS and imaging methods. PMID- 23726080 TI - The fabrication of monolithic capillary column based on poly (bisphenol A epoxy vinyl ester resin-co-ethylene glycol dimethacrylate) and its applications for the separation of small molecules in high performance liquid chromatography. AB - A new polymeric monolith was synthesized in fused-silica capillary by in situ polymerization technique. In the polymerization, bisphenol A epoxy vinyl ester resin (VER) was used as the functional monomer, ethylene glycol dimethacrylate (EDMA) as the crosslinking monomer, 1,4-butanediol, 1-propanol and water as the co-porogens, and azobisisobutyronitrile (AIBN) as the initiator. The conditions of polymerization have been optimized. Morphology of the prepared poly (VER-co EDMA) monolith was investigated by the scanning electron microscopy (SEM); pore properties were assayed by mercury porosimetry and nitrogen adsorption. The optimized poly (VER-co-EDMA) monolith showed a uniform structure, good permeability and mechanical stability. Then, the column was used as the stationary phase of high performance liquid chromatography (HPLC) to separate the mixture of benzene derivatives. The best column efficiency achieved for phenol was 235790 theoretical plates per meter. Baseline separations of benzene derivatives and halogenated benzene compounds under optimized isocratic mode conditions were achieved with high column efficiency. The column showed good reproducibility: the relative standard deviation (RSD) values based on the retention times (n=3) for run-to-run, column-to-column and batch-to-batch were less than 0.98, 1.68, 5.48%, respectively. Compared with poly (BMA-co-EDMA) monolithic column, the proposed monolith exhibited more efficiency in the separation of small molecules. PMID- 23726081 TI - In situ aqueous derivatization as sample preparation technique for gas chromatographic determinations. AB - The use of derivatization reactions is a common practice in analytical laboratories. Although in many cases it is tedious and time-consuming, it does offer a good alternative for the determination of analytes not compatible to gas chromatography. Many of the reactions reported in the literature occur in organic medium. However, in situ aqueous derivatization reactions, which can be performed directly in aqueous medium, offer important advantages over those mentioned above, such as no need of a previous extraction step and easy automation. Here we review the most recent developments and applications of in situ aqueous derivatization. The discussion focuses on the derivatization reactions used for the determination of alcohols and phenols, carboxylic acids, aldehydes and ketones, nitrogen-containing compounds and thiols in different aqueous matrices, such as environmental, biological and food samples. Several reactions are described for each functional group (acylation, alkylation, esterification, among others) and, in some cases, the same reagents can be used for several functional groups, such that there is an unavoidable overlap between sections. Finally, attention is also focused on the techniques used for the introduction of the derivatives formed in the aqueous medium into the chromatographic system. The implementation of in situ aqueous derivatization coupled to preconcentration techniques has permitted the enhancement of recoveries and improvements in the separation, selectivity and sensitivity of the analytical methods. PMID- 23726082 TI - Combinatorial ligand libraries as a two-dimensional method for proteome analysis. AB - The present report tries to assess the possibility of performing capture of proteomes via combinatorial peptide ligand libraries (CPLL) in a two-dimensional (2D) mode, i.e. via orthogonal complementarity in the capture phase. To that aim, serum proteins are captured at physiological pH either at low ionic strength (25mM NaCl) or at high concentrations of lyotropic salts of the Hofmeister series (1M ammonium sulphate) favouring hydrophobic interaction. Indeed such 2D mechanisms seems to be operative, since 52% of the captured proteins are common to the two capture modes, 20% are specific only of the "ionic" interaction mode and 28% are found only in the "hydrophobically" driven interaction. As an additional bonus, losses of protein species from the initial sample, one of the major drawbacks of CPLLs, are diminished to about 5% and are found only in the ionic capture, whereas the hydrophobically engendered capture is loss-free. PMID- 23726083 TI - Microreactions in separation science: reagents and techniques. Foreword. PMID- 23726084 TI - Tandem sulfur chemiluminescence and flame ionization detection with planar microfluidic devices for the characterization of sulfur compounds in hydrocarbon matrices. AB - The detection of sulfur compounds in different hydrocarbon matrices, from light hydrocarbon feedstocks to medium synthetic crude oil feeds provides meaningful information for optimization of refining processes as well as demonstration of compliance with petroleum product specifications. With the incorporation of planar microfluidic devices in a novel chromatographic configuration, sulfur compounds from hydrogen sulfide to alkyl dibenzothiophenes and heavier distributions of sulfur compounds over a wide range of matrices spanning across a boiling point range of more than 650 degrees C can be characterized, using one single analytical configuration in less than 25min. In tandem with a sulfur chemiluminescence detector for sulfur analysis is a flame ionization detector. The flame ionization detector can be used to establish the boiling point range of the sulfur compounds in various hydrocarbon fractions for elemental specific simulated distillation analysis as well as profiling the hydrocarbon matrices for process optimization. Repeatability of less than 3% RSD (n=20) over a range of 0.5-1000 parts per million (v/v) was obtained with a limit of detection of 50 parts per billion and a linear range of 0.5-1000 parts per million with a correlation co-efficient of 0.998. PMID- 23726085 TI - Intergroup cross-comparison for the evaluation of data-interchangeability from various chromatographic tests. AB - The recently dramatic increase in the available choices of reversed-phase columns could be an advantage of this mode of separation. However, due to the insufficiency of available information in terms of the exact functionality of these phases and the similarities and differences between these newly introduced and conventional reversed-phase columns, it is now somehow problematic to determine which could be the best column for a given analytical problem. There is no single column that will give us a good separation for all applications. As a result, there have been several attempts to develop testing strategies to characterize column chemistries. In this study three of the most widely used and acceptable approaches for the characterization of reversed-phase columns, which are Tanaka, United States Pharmacopeia (USP), and Snyder-Dolan, are systemically applied to investigate the chromatographic properties of calixarene- and resorcinarene-bonded stationary phases, polar-embedded and polar-endcapped stationary phases, phenyl and ether-linked phenyl with the presence of conventional alkyl-bonded phases (octyl- and octadecylsilane). Although all column classification systems aim to evaluate "more or less" the same characteristics, each system uses different test mixtures in different chromatographic conditions. It is therefore very important to evaluate the similarities and differences in the resulted "column parameters" and the possible interchangeability of them. The results of this comparative study show that the used parameters of Tanaka and of Snyder-Dolan have in many cases a good to very good correlation. The USP approach, which is based on single run, is related to Tanaka and Snyder-Dolan only in terms of hydrophobic characters, and no relation could establish in the other parameters. The hydrophobic-subtraction model could be extended to describe the ligand-solute interactions of calixarene- and resorcinarene-bonded stationary phases, which are belonging to reversed phase material. However they show, depending on the analytes, some additional interactions, since their steric, polar and ionic properties are different compared to those of conventional alkyl-bonded phases. PMID- 23726086 TI - Bidentate urea-based chiral selectors for enantioselective high performance liquid chromatography: synthesis and evaluation of "Crab-like" stationary phases. AB - A rational approach for the design and preparation of two new "Crab-like" totally synthetic, brush-type chiral stationary phases is presented. Enantiopure diamines, namely 1,2-diaminocyclohexane and 1,2-diphenyl-1,2-ethylene-diamine were treated with 3-(triethoxysilyl)propyl isocyanate, to yield reactive ureido selectors that were eventually attached to unmodified silica particles through a stable, bidentate tether, through a facile two-step one-pot procedure. A full chemical characterization of the new materials has been obtained through solid state NMR (both (29)Si and (13)C CPMAS) spectroscopy. Columns packed with the two Crab-like chiral stationary phases allow for different mechanisms of separation: normal phase liquid chromatography, reversed phase liquid chromatography and polar organic mode and show a high stability at basic pH values. In particular, the Crab-like column containing the 1,2-diphenyl-1,2-ethylene-diamine selector proved a promising candidate for the resolution of a wide range of racemates (including benzodiazepines, N-derivatized amino acids, and free carboxylic acids) both in normal phase and polar organic mode. An Hmin of 9.57 at a MUsf of 0.80mm/s (corresponding to 0.8mL/min) was obtained through van Deemter analysis, based on toluene, for the Crab-like column with the 1,2-diphenyl-1,2-ethylene diamine selector (250mm*4.6mm I.D.), with a calculated reduced height equivalent to a theoretical plate (h) of only 1.91. Finally, comparative studies were performed with a polymeric commercially available P-CAP-DP column in order to evaluate enantioselectivity and resolution of the Crab-like columns. PMID- 23726087 TI - Determination of drugs in river and wastewaters using solid-phase extraction by packed multi-walled carbon nanotubes and liquid chromatography-quadrupole-linear ion trap-mass spectrometry. AB - The present paper describes a solid-phase extraction by packed multi-walled carbon nanotubes, followed by liquid chromatography-mass spectrometry, method for the determination of some of the most consumed drugs including four beta-blockers and eight non-steroidal anti-inflammatory drugs, in river and wastewater samples. High extraction efficiency was found for most drugs due to the large specific surface area and high adsorption capacity of this nanomaterial compared with other conventional solid-phase extraction sorbents, and matrix effect was present only for two of the twelve studied drugs. Only 20mg of carbon nanotubes was enough to preconcentrate the analytes with recoveries from 68% to 107% for most of them. The pharmaceuticals were analyzed by liquid chromatography coupled to a hybrid triple quadrupole-linear ion trap-mass spectrometer at ultra-trace levels. Data acquisition was carried out in selected reaction monitoring mode, using two transitions for simultaneous identification and quantification of the analytes. Additionally, an information dependent acquisition scan was performed to carry out the identification of those analytes whose second transition was absent or was present at low intensity. The analytical performance of the whole method was evaluated in two environmental water matrices (river and wastewaters). Matrix effect was not found in river water, quantitation being carried out with calibration graphs built with solvent based standard. On the contrary, matrix effect was present in wastewater for some of the target drugs and, therefore, quantitation was carried out using the standard addition method. Limits of detection and quantitation in river waters were in the range of 9-36 and 23 121ngL(-1), respectively and the relative standard deviation of the full method was less than 17%. The proposed methodology was applied to the analysis of three river water and two wastewater (influent and effluent) samples, all of them from Almeria (Spain). Some pharmaceuticals were found in river water at concentration levels near to or lower than their quantitation limits, whereas the most consumed pharmaceuticals were found at high concentration levels in influent wastewater and were not detected or were found at lower levels in the effluent wastewater sample. PMID- 23726088 TI - Determination of glutathione in baker's yeast by capillary electrophoresis using methyl propiolate as derivatizing reagent. AB - In this study we demonstrate - for the first time - the suitability of methyl propiolate - an alkylester of propiolic acid - as a thiol derivatizing reagent for capillary electrophoresis. Glutathione (as analyte in yeast samples) and N acetylcysteine (as internal standard) were selected as model compounds. Several parameters affecting the separation efficiency (buffer pH, concentration, and separation voltage) and the derivatization yield (pH, reaction time and reagent concentration) were thoroughly investigated. Validation was carried out towards the determination of glutathione in commercially available yeast samples. The LOD was 1.5MUmolL(-1) and the linearity was obeyed in the range of 25-200MUmolL(-1). The accuracy in terms of recoveries ranged between 95.9% and 113.6%. The approach proved to be free from matrix effects, while the results were confirmed by a corroborative method based on liquid chromatography coupled to post-column derivatization. PMID- 23726089 TI - The Choosing Wisely((r)) campaign and nurses role in dissemination. PMID- 23726090 TI - Platelet reactivity evaluated with the VASP assay following ticagrelor loading dose in acute coronary syndrome patients undergoing percutaneous coronary intervention. AB - BACKGROUND: The level of platelet reactivity (PR) inhibition obtained after P2Y12 ADP receptor antagonist loading dose (LD) is associated with the ischemic and bleeding risk following percutaneous coronary intervention (PCI) in acute coronary syndromes (ACS). OBJECTIVE: We aimed to evaluate the level of PR inhibition achieved by a 180 mg LD of ticagrelor and the rate of high on treatment platelet reactivity (HTPR) in ACS patients undergoing PCI. METHODS: We performed a multicentre prospective observational study enrolling ACS patients undergoing PCI. Patients were included if they were admitted for ST-elevation myocardial infarction or non ST-elevation ACS. To assess PR, a VASP index was measured at least 6 and within 24 hours following a 180 mg LD of ticagrelor. HTPR was defined as a VASP index >=50%. RESULTS: One hundred and fifteen patients were included: 31.3% of STEMI, 49.6% of NSTEMI and 19.1% of unstable angina. Following ticagrelor LD the mean VASP index was 17+/-14%. However the response to ticagrelor was not uniform with a small inter-individual variability: inter quartile range: 7.6-22.8% and a rate of HTPR of 3.5%. A high number of patients, 65.6%, had a VASP index <16%. None of the baseline characteristics of the study population was associated with PR. In addition, PR was similar in STEMI, NSTEMI and unstable angina (p=0.9). CONCLUSION: In ACS patients the level of PR inhibition achieved by a 180 mg loading dose of ticagrelor is not uniform and the rate of HTPR is 3.5%. A high proportion of patients exhibited a VASP index <16%. PMID- 23726091 TI - Genetic determinants of high on-treatment platelet reactivity in clopidogrel treated Chinese patients. AB - INTRODUCTION: Cytochrome P450 (CYP), ATP-binding cassette transporters (ABCB1), and paraoxonase-1 (PON1) play crucial roles in clopidogel absorption and bioactivation. Genetic polymorphisms in these genes have been associated with the variability of the response to clopidogrel, however their contribution to high on treatment platelet reactivity (HPR) in clopidogrel treated Chinese patients is less known. MATERIALS AND METHODS: Five-hundred Chinese-Han patients treated with clopidogrel for acute coronary syndrome (ACS) were consecutively recruited from the Department of Geriatric Cardiology, General Hospital of Chinese People's Liberation Army, from September 2010 to September 2012. We assessed the relations of CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), CYP2C19*17 (rs12248560), PON1Q129R (rs662) and ABCB1C3435T (rs1045642) to the platelet aggregation after 5 days maintenance dose of clopidogrel administration, and the risk for HPR. The cutoff of HPR was defined as 20 MUmol/L adenosine diphosphate (ADP)-induced platelet aggregation>50%. RESULTS: Both CYP2C19*2 and *3 alleles were significantly associated with higher platelet aggregation after 5 days maintenance dose of clopidogrel administration (P<0.00001 and P=0.042, respectively). The platelet aggregation in carriers of at least one CYP2C19 loss of-function allele (*2 or *3, accounted for 58% of the study population) was obviously higher than that in non-carriers (P<0.00001). Patients with the CYP2C19*2 allele had a higher risk of HPR than those with the CYP2C19 wild-type genotype [adjusted hazard ratio (HR), 1.56; 95% confidence interval(CI), 1.04 2.33, P=0.03]. The carriers of at least one CYP2C19 loss-of-function allele could also predict significantly greater risk of HPR compared with non-carriers (adjusted HR1.79,95% CI: 1.33-2.4,P=0.003). However, the carriage of CYP2C19*3 alone could not predict the risk of HPR significantly (adjusted HR, 1.5; 95% CI: 0.83-3, P=0.16). Significant relation of CYP2C19*17, PON1Q129R and ABCB1C3435T to the platelet aggregation was not found. CONCLUSION: In clopidogrel treated Chinese patients with ACS, carriers of at least one CYP2C19 loss-of-function allele could predict greater risk of HPR, with the impact mainly attributing to CYP2C19*2. Neither ABCB1 nor PON1 genotype could influence the antiplatelet response of clopidogrel in the cohort of Chinese patients. PMID- 23726092 TI - Characteristics of the complement system gene expression deficiency in patients with symptomatic pulmonary embolism. AB - INTRODUCTION: Pulmonary embolism (PE) is a disease with a high mortality and morbidity rate, and the pathogenesis of PE remains still unclear. We aimed to investigate the gene expression differences of the complement system in peripheral blood mononuclear cells (PBMCs) from patients with symptomatic PE and controls. METHODS: Twenty cases of PE patients and twenty sex and age matched controls were recruited into the study. Human cDNA microarray analysis was used to detect the gene expression difference of the complement system between the two groups. RESULTS: 1). Expression of twenty-one genes encoding complement components was detected. In PE patients, expression of the genes encoding C1qalpha, C1qbeta, C4b, C5 and Factor P was significantly greater (P<0.05) than controls, while C6, C7, C9, mannose-binding lectin (MBL) and mannan-binding lectin serine peptidase 1 (MASP1) mRNAs were lower (P<0.05) than controls. 2). Expression of seven genes encoding complement receptors was examined. In PE patients, CR1, integrin alphaM, integrin alphaX and C5aR mRNAs were significantly up-regulated (P<0.01) compared with controls. 3). Seven genes encoding complement regulators were examined. The mRNA expression of CD59 and CD55 was significantly up-regulated (P<0.05), whereas Factor I mRNA was significantly down-regulated (P<0.05) in PE patients than controls. CONCLUSIONS: In PE patients, the mRNA expressions of complement components, receptors and regulators were unbalanced, suggesting dysfunction and/or deficiency of the complement system, which leads to decreased function of MAC-induced cell lysis in PE patients finally. PMID- 23726093 TI - Coagulofibrinolytic changes in patients with disseminated intravascular coagulation associated with post-cardiac arrest syndrome--fibrinolytic shutdown and insufficient activation of fibrinolysis lead to organ dysfunction. AB - INTRODUCTION: Post-cardiac arrest syndrome (PCAS) is often associated with disseminated intravascular coagulation (DIC), thus leading to the development of multiple organ dysfunction syndrome (MODS). The aim of this study was to examine the pathophysiological relationships between coagulation, fibrinolysis and fibrinolytic shutdown by evaluating the levels of coagulofibrinolytic markers, including soluble fibrin, thrombin-activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPAIC), plasmin-alpha2 plasmin inhibitor complex (PPIC), neutrophil elastase and fibrin degradation product by neutrophil elastase (EXDP). MATERIALS AND METHODS: Fifty two resuscitated patients were divided into two groups: 22 DIC and 30 non-DIC patients. RESULTS: The levels of soluble fibrin, PPIC, tPAIC, EXDP and neutrophil elastase in the DIC patients with PCAS were significantly higher than those observed in the non-DIC patients. The values of the tPAIC and JAAM DIC scores were found to be independent predictors of increased SOFA scores in the DIC patients. The MODS patients demonstrated significantly higher levels of soluble fibrin and tPAIC; however, the levels of TAFI and EXDP were identical between the patients with and without MODS. In addition, positive correlations were observed between the levels of tPAIC and EXDP in the patients with non-MODS; however, no correlations were observed between these markers in the MODS patients. CONCLUSIONS: Thrombin activation and fibrinolytic shutdown play important roles in the development of organ dysfunction in PCAS patients. Neutrophil elastase mediated fibrinolysis cannot overcome the fibrinolytic shutdown that occurs in DIC patients with PCAS, thus resulting in the development of MODS. PMID- 23726094 TI - Analytical application of carbon nanotubes, fullerenes and nanodiamonds in nanomaterials-based chromatographic stationary phases: a review. AB - An overview of the most significative results so far attained in the application of carbon nanotubes, fullerenes and nanodiamonds as chromatographic separation media is presented. In particular, the authors focus on their use in capillary and packed-column gas chromatography, in high performance liquid chromatography and capillary electrochromatography, paying also attention to recently developed stationary phases for fast chromatography and nanochromatography. The performance of the nanomaterials is compared to that of planar and amorphous carbon sorbents and critically discussed in regard to retentive capability and selectivity. A wide part of this review is devoted to the most recent improvements achieved in terms of selectivity by use of functionalized nanotubes and by combination of carbon nanotubes with ionic liquids. Practical aspects of synthetic procedures in preparing novel stationary phases in relationship with their chromatographic behaviour are also commented. PMID- 23726095 TI - Sensitive electrochemical monitoring of nucleic acids coupling DNA nanostructures with hybridization chain reaction. AB - Methods based on metal nanotags have been developed for metallobioassay of nucleic acids, but most involve complicated labeling or stripping procedures and are unsuitable for routine use. Herein, we report the proof-of-concept of a novel and label-free metallobioassay for ultrasensitive electronic determination of human immunodeficiency virus (HIV)-related gene fragments at an ultralow concentration based on target-triggered long-range self-assembled DNA nanostructures and DNA-based hybridization chain reaction (HCR). The signal is amplified by silver nanotags on the DNA duplex. The assay mainly consists of capture probe, detection probe, and two different DNA hairpins. In the presence of target DNA, the capture probe immobilized on the sensor sandwiches target DNA with the 3' end of detection probe. Another exposed part of detection probe at the 5' end opens two alternating DNA hairpins in turn, and propagates a chain reaction of hybridization events to form a nicked double-helix. Finally, numerous silver nanotags are immobilized onto the long-range DNA nanostructures, each of which produces a strong electronic signal within the applied potentials. Under optimal conditions, the target-triggered long-range DNA nanostructures present good electrochemical behaviors for the detection of HIV DNA at a concentration as low as 0.5 fM. Importantly, the outstanding sensitivity can make this approach a promising scheme for development of next-generation DNA sensors without the need of enzyme labeling or fluorophore labeling. PMID- 23726096 TI - A simple microextraction and preconcentration approach based on a mixed matrix membrane. AB - A simple adsorption/desorption procedure using a mixed matrix membrane (MMM) as extraction medium is demonstrated as a new miniaturized sample pretreatment and preconcentration technique. Reversed-phase particles namely polymeric bonded octadecyl (C18) was incorporated through dispersion in a cellulose triacetate (CTA) polymer matrix to form a C18-MMM. Non-steroidal anti-inflammatory drugs (NSAIDs) namely diclofenac, mefenamic acid and ibuprofen present in the environmental water samples were selected as targeted model analytes. The extraction setup is simple by dipping a small piece of C18-MMM (7 mm * 7 mm) in a stirred 10 mL sample solution for analyte adsorption process. The entrapped analyte within the membrane was then desorbed into 100 MUL of methanol by ultrasonication prior to high performance liquid chromatography (HPLC) analysis. Each membrane was discarded after single use to avoid any analyte carry-over effect. Several important parameters, such as effect of sample pH, salting-out effect, sample volume, extraction time, desorption solvent and desorption time were comprehensively optimized. The C18-MMM demonstrated high affinity for NSAIDs spiked in tap and river water with relative recoveries ranging from 92 to 100% and good reproducibility with relative standard deviations between 1.1 and 5.5% (n=9). The overall results obtained were found comparable against conventional solid phase extraction (SPE) using cartridge packed with identical C18 adsorbent. PMID- 23726097 TI - Simple fabrication of hydrophobic surface target for increased sensitivity and homogeneity in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis of peptides, phosphopeptides, carbohydrates and proteins. AB - To enhance sample signals and improve homogeneity in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) analysis, a simple, rapid, and efficient sample preparation method was developed in this study. Polydimethylsiloxane (PDMS) was coated on a stainless steel MALDI plate, forming a transparent, hydrophobic surface that enhanced sample signals without producing observable background signals. Compared to the use of an unmodified commercial metal MALDI plate, peptide signals were enhanced by ~7.1-11.0-fold due to the reduced sample spot area of the PDMS-coated plate, and showed improved peptide mass fingerprinting (PMF) and MS/MS peptide sequencing results. In the analysis of phosphopeptides and carbohydrates with a 2,5-dihydroxybenzoic acid (DHB) matrix, the PDMS-coated plate showed improved sample homogeneity and signal enhancements of ~5.2-8.2-fold and ~2.8-3.2-fold, respectively. Improved sensitivity in the observation of more unique fragment ions by MS/MS analysis, to successfully distinguish isomeric carbohydrates, was also illustrated. In protein analysis with a sinapinic acid (SA) matrix, a ~3.4-fold signal enhancement was observed. The PDMS film coating was easily removed and refabricated to avoid sample carryover, and was applicable to diverse commercial MALDI plates. The PDMS coated approach is a simple, practical, and attractive method for enhancing analyte signals and homogeneity. PMID- 23726098 TI - Development of sensitive and rapid analytical methodology for food analysis of 18 mycotoxins included in a total diet study. AB - A rapid and sensitive method for the determination of 18 mycotoxins in 24 different food matrices has been developed and validated. With the exception of beverages and oil samples, a simple extraction with acetonitrile:water 80:20 (0.1% formic acid) was applied. Fruit juice, wine and beer samples were simply diluted with water containing 0.1% formic acid. Oil samples were partitioned with acetonitrile/hexane in order to remove fats. Analyses were made by ultra-high performance liquid chromatography (UHPLC) coupled to tandem mass spectrometry with triple quadrupole. Validation was carried out in all selected matrices using blank samples spiked at two analyte concentrations. Extraction recoveries between 70 and 120% and relative standard deviations lower than 20% were obtained for the wide majority of analyte-matrix combinations. Matrix-matched calibration was used for a correct quantification in order to compensate for matrix effects. Limits of quantification were lower than maximum permitted levels for every regulated mycotoxin-matrix combination. The acquisition of three SRM transitions per compound allowed the unequivocal confirmation of positive samples, supported by the accomplishment of ion intensity ratios and retention time when compared with reference standards. The developed methodology was applied to the analysis of 240 samples within a total diet study performed at Comunidad Valenciana (Spain). The most frequently found mycotoxins were deoxynivalenol, fumonisin B1, ochratoxin A and zearalenone at low MUg kg(-1) levels, mainly in bread, breakfast cereals and beer. PMID- 23726099 TI - An ultrasensitive luminol cathodic electrochemiluminescence immunosensor based on glucose oxidase and nanocomposites: graphene-carbon nanotubes and gold-platinum alloy. AB - In the present study, a novel and ultrasensitive electrochemiluminescence (ECL) immunosensor based on luminol cathodic ECL was fabricated by using Au nanoparticles and Pt nanoparticles (nano-AuPt) electrodeposited on graphene carbon nanotubes nanocomposite as platform for the detection of carcinoembryonic antigen (CEA). For this introduced immunosensor, graphene (GR) and single wall carbon nanotubes (CNTs) dispersed in chitosan (Chi-GR-CNTs) were firstly decorated on the bare gold electrode (GE) surface. Then nano-AuPt were electrodeposited (DpAu-Pt) on the Chi-GR-CNTs modified electrode. Subsequently, glucose oxidase (GOD) was employed to block the non-specific sites of electrode surface. When glucose was present in the working buffer solution, GOD immediately catalyzed the oxidation of glucose to in situ generate hydrogen peroxide (H2O2), which could subsequently promote the oxidation of luminol with an amplified cathodic ECL signal. The proposed immunosensor was performed at low potential ( 0.1 to 0.4V) and low concentration of luminol. The CEA was determined in the range of 0.1 pg mL(-1) to 40 ng mL(-1) with a limit of detection down to 0.03 pg mL(-1) (SN(-1)=3). Moreover, with excellent sensitivity, selectivity, stability and simplicity, the as-proposed luminol-based ECL immunosensor provided great potential in clinical applications. PMID- 23726100 TI - Feasibility of the use of disposable optical tongue based on neural networks for heavy metal identification and determination. AB - This study presents the development and characterization of a disposable optical tongue for the simultaneous identification and determination of the heavy metals Zn(II), Cu(II) and Ni(II). The immobilization of two chromogenic reagents, 1-(2 pyridylazo)-2-naphthol and Zincon, and their arrangement forms an array of membranes that work by complexation through a co-extraction equilibrium, producing distinct changes in color in the presence of heavy metals. The color is measured from the image of the tongue acquired by a scanner working in transmission mode using the H parameter (hue) of the HSV color space, which affords robust and precise measurements. The use of artificial neural networks (ANNs) in a two-stage approach based on color parameters, the H feature of the array, makes it possible to identify and determine the analytes. In the first stage, the metals present above a threshold of 10(-7) M are identified with 96% success, regardless of the number of metals present, using the H feature of the two membranes. The second stage reuses the H features in combination with the results of the classification procedure to estimate the concentration of each analyte in the solution with acceptable error. Statistical tests were applied to validate the model over real data, showing a high correlation between the reference and predicted heavy metal ion concentration. PMID- 23726101 TI - A highly selective turn-on ATP fluorescence sensor based on unmodified cysteamine capped CdS quantum dots. AB - Unmodified cysteamine capped nanocrystalline cadmium sulfide quantum dots (Cys CdS QDs) were demonstrated as a selective turn-on fluorescence sensor for sensing adenosine-5'-triphosphate (ATP) in aqueous solution for the first time. The fluorescence intensity of the Cys-CdS QDs was significantly enhanced in the presence of ATP. In addition, the fluorescence intensity of the Cys-CdS QDs increased when increasing ATP concentrations. On the other hand, other phosphate metabolites and other tested common anions did not significantly alter the fluorescence intensity of the Cys-CdS QDs. In addition, this sensor showed excellent discrimination of pyrophosphate (PPi) from ATP detection. The proposed sensor could efficiently be used for ATP sensing at very low concentration with LOD of 17 MUM with the linear working concentration range of 20-80 MUM. The feasibility of the proposed sensor for determining ATP in urine samples was also studied, and satisfactory results were obtained. PMID- 23726102 TI - A selective electromembrane extraction of uranium (VI) prior to its fluorometric determination in water. AB - A novel method for the selective electromembrane extraction (EME) of U(6+) prior to fluorometric determination has been proposed. The effect of extraction conditions including supported liquid membrane (SLM) composition, extraction time and extraction voltage were investigated. An SLM composition of 1% di-2-ethyl hexyl phosphonic acid in nitrophenyl octyl ether (NPOE) showed good selectivity, recovery and enrichment factor. The best performance was achieved at an extraction potential of 80 volts and an extraction time of 14 minutes Under the optimized conditions, a linear range from 1 to 1000 ng mL(-1) and LOD of 0.1 ng mL(-1) were obtained for the determination of U(6+). The EME method showed good performance in sample cleanup and the reduction of the interfering effects of Mn(2+), Zn(2+), Cd(2+), Ni(2+), Fe(3+), Co(2+), Cu(2+), Cl(-) and PO4(3-) ions during fluorometric determination of uranium in real water samples. The recoveries above 54% and enrichment factors above 64.7 were obtained by the proposed method for real sample analysis. PMID- 23726103 TI - "I found it on the internet:" how reliable and readable is patient information? PMID- 23726104 TI - A biological approach to orthopaedic surgery: are they lost in translation? PMID- 23726105 TI - Authors' reply. PMID- 23726106 TI - Addition of a suture anchor for coracoclavicular fixation to a superior locking plate improves stability of type IIB distal clavicle fractures. AB - PURPOSE: The purpose of this study was to determine the effect of coracoclavicular (CC) fixation on biomechanical stability in type IIB distal clavicle fractures fixed with plate and screws. METHODS: Twelve fresh-frozen matched cadaveric specimens were used to create type IIB distal clavicle fractures. Dual-energy x-ray absorptiometry (DEXA) scans ensured similar bone quality. Group 1 (6 specimens) was stabilized with a superior precontoured distal clavicle locking plate and supplemental suture anchor CC fixation. Group 2 (6 specimens) followed the same construct without CC fixation. Each specimen was cyclically loaded in the coronal plane at 40 to 80 N for 17,500 cycles. Load-to failure testing was performed on the specimens that did not fail cyclic loading. Outcome measures included mode of failure and the number of cycles or load required to create 10 mm of displacement in the construct. RESULTS: All specimens (12 of 12) completed cyclic testing without failure and underwent load-to-failure testing. Group 1 specimens failed at a mean of 808.5 N (range, 635.4 to 952.3 N), whereas group 2 specimens failed at a mean of 401.3 N (range, 283.6 to 656.0 N) (P = .005). Group 1 specimens failed by anchor pullout without coracoid fracture (4 of 6) and distal clavicle fracture fragment fragmentation (1 of 6); one specimen did not fail at the maximal load the materials testing machine was capable of exerting (1,000 N). Group 2 specimens failed by distal clavicle fracture fragment fragmentation (3 of 6) and acromioclavicular (AC) joint displacement (1 of 6); 2 specimens did not fail at the maximal load of the materials testing machine. CONCLUSIONS: During cyclic loading, type IIB distal clavicle fractures with and without CC fixation remain stable. CC fixation adds stability to type IIB distal clavicle fractures fixed with plate and screws when loaded to failure. CLINICAL RELEVANCE: CC fixation for distal clavicle fractures is a useful adjunct to plate-and-screw fixation to augment stability of the fracture. PMID- 23726107 TI - Footprint contact restoration between the biceps-labrum complex and the glenoid rim in SLAP repair: a comparative cadaveric study using pressure-sensitive film. AB - PURPOSE: To compare pressurized footprint contact and interface pressure between the biceps-labrum complex and the superior glenoid rim after SLAP repair using 3 different techniques. METHODS: Twenty-four fresh-frozen human cadaveric shoulders were divided into 3 groups. SLAP lesions were repaired by (1) 2 single-loaded anchors in a simple suture configuration (group T), (2) a double-loaded anchor in a simple suture configuration in a V shape (group V), or (3) a double-loaded anchor by use of a hybrid simple and mattress suture configuration (group H). Pressure-sensitive film quantified pressurized contact areas and interface pressures between the biceps-labrum complex and the glenoid rim after SLAP repair. RESULTS: Groups T and V showed significantly larger contact areas than group H (P < .0001). However, there was no significant difference between groups T and V. Despite a substantial contact area around the biceps-labrum complex in group T, there was a lack of sufficient contact area just below the biceps anchor. Group V showed a uniform contact area around the entire biceps-labrum complex, but in group H the contact area was concentrated only around the posterior superior labrum, where the simple suture was used. CONCLUSIONS: The methods using 2 single-loaded suture anchors and using 1 double-loaded suture anchor with a simple suture configuration showed significantly larger pressurized contact areas than the method using 1 double-loaded suture anchor with both a simple and mattress suture configuration. The interface pressure was not significantly different among groups. CLINICAL RELEVANCE: Although there have been several kinds of repair techniques and biomechanical studies for the type II SLAP lesion, there has been no study about footprint restoration on the superior glenoid rim. This study analyzed and compared the footprint contact restoration after type II SLAP repair among 3 different techniques. PMID- 23726108 TI - Arthroscopic excision of dorsal wrist ganglion: factors related to recurrence and postoperative residual pain. AB - PURPOSE: The purpose of this study was to assess the recurrence rate and postoperative residual pain rate after arthroscopic excision of dorsal wrist ganglia and the risk factors for recurrence and residual pain. METHODS: A total of 115 wrists (111 patients: 57 men, 54 women; average age 34 years; range, 9 to 72 years) treated with arthroscopic excision for wrist dorsal ganglia between April 2005 and December 2009 were enrolled. The follow-up averaged 32 months (range, 12 to 67 months). Demographic data and operative details, including the presence of a ganglion stalk, were retrospectively reviewed and tested against recurrence and residual pain at final follow-up. RESULTS: The recurrence rate of dorsal wrist ganglia after arthroscopic excision was 11% (13 of 115 wrists). Recurrence was on the dominant side in 12 of 13 (91%) patients, which was the most important risk factor for recurrence (odds ratio [OR], 8.0; 95% confidence interval [CI], 0.94 to 68.49), followed by female sex (OR, 4.9; 95% CI, 0.84 to 28.39) and age 24 years or younger (OR, 3.1; 95% CI, 0.75 to 12.74). Twenty-seven wrists (23%) had postoperative residual pain at final follow-up. The results of logistic regression showed that pain before surgery was the most important risk factor for residual pain after surgery (OR, 4.9; 95% CI, 1.36 to 18.3), followed by female sex (OR, 3.2; 95% CI, 1.22 to 8.53). CONCLUSIONS: Dominant side, female sex, and age of 24 years or younger are considered to be the most influential risk factors for recurrence after arthroscopic excision of dorsal wrist ganglia. However, the presence or absence of the cyst stalk was not a significant factor for recurrence. Female patients who have preoperative pain around the dorsal wrist ganglia were most likely to experience residual pain after surgery. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23726109 TI - Synovial membrane-derived mesenchymal stem cells supported by platelet-rich plasma can repair osteochondral defects in a rabbit model. AB - PURPOSE: The aim of this study was to determine the in vivo effectiveness of synovial membrane-derived mesenchymal stem cell (SDSC)-encapsulated injectable platelet-rich plasma (PRP) gel in the repair of damaged articular cartilage in the rabbit. METHODS: An osteochondral defect was created in the trochlear groove of the rabbit femur, and the defects were divided into 3 treatment groups: untreated control group, PRP group, and PRP-SDSC group. After 4, 12, and 24 weeks, the tissue specimens were assessed by macroscopic examination and histologic evaluation and stained immunohistochemically for type II collagen and proliferating cell nuclear antigen. In addition, total glycosaminoglycan content was determined at 24 weeks. RESULTS: Rabbit PRP contained a high concentration of platelets and high concentration of growth factors compared with those in whole blood. Twenty-four weeks after transplantation, there was fibrous tissue in the control group. In both the PRP group and the PRP-SDSC group, the defects were repaired with hyaline cartilage and exhibited significantly higher safranin O staining, type II collagen immunostaining, glycosaminoglycan content, cumulative histologic scores, and number of proliferating cell nuclear antigen-positive cells. However, incomplete bone regeneration and irregular cartilage surface integration were observed in the PRP group. CONCLUSIONS: Our results indicate that SDSC-embedded PRP gel could successfully resurface the defect with cartilage and restore the subchondral bone in the rabbit model. CLINICAL RELEVANCE: This study indicates that in an animal model, the application of PRP and SDSC in combination for the treatment of local cartilage defects appears promising; however, PRP-SDSC products might be more or less appropriate to treat different types of tissues and pathologies. The clinical efficacy of PRP remains under debate. Therefore further research is needed at both the basic science and clinical levels. PMID- 23726110 TI - Biological and biomechanical evaluation of the ligament advanced reinforcement system (LARS AC) in a sheep model of anterior cruciate ligament replacement: a 3 month and 12-month study. AB - PURPOSE: The purposes of this study were to assess tissue ingrowth within the Ligament Advanced Reinforcement System (LARS) artificial ligament (LARS AC; LARS, Arc sur Tille, France) and to study the biomechanical characteristics of the reconstructed knees in a sheep model of anterior cruciate ligament (ACL) replacement. METHODS: Twenty-five female sheep underwent excision of the proximal third of the left ACL and intra-articular joint stabilization with a 44-strand polyethylene terephthalate ligament (mean ultimate tensile failure load, 2,500 N). Animals were killed either 3 or 12 months after surgery. Explanted knees were processed for histology (n = 10) or mechanical tests including tests of laxity and loading to failure in tension (n = 15). RESULTS: Well-vascularized tissue ingrowth within the artificial ligament was only observed in the portions of the ligament in contact with the host's tissues (native ligament and bone tunnels). Ligament wear was observed in 40% of explanted knees. The ultimate tensile failure loads of the operated knees at both time points were inferior to those of the contralateral, intact knees (144 +/- 69 N at 3 months and 260 +/- 126 N at 12 months versus 1,241 +/- 270 N and 1,218 +/- 189 N, respectively) (P < .01). In specimens with intact artificial ligaments, failure occurred by slippage from the bone tunnels in all specimens explanted 3 months postoperatively and in half of the specimens explanted 12 months postoperatively. CONCLUSIONS: This study provides evidence that the LARS AC has a satisfactory biointegration but that it is not suitable for ACL replacement if uniform tissue ingrowth is contemplated. Despite good clinical performance up to 1 year after implantation, none of the reconstructions approached the mechanical performance of the normal ACL in the ovine model. Partial tearing of the artificial ligament, which led to a significant decrease in ultimate tensile strength, was observed in 40% of cases in the ovine model. CLINICAL RELEVANCE: The LARS is not a suitable scaffold for ACL replacement. Further animal studies are needed to evaluate its potential for augmentation of ligament repair. PMID- 23726111 TI - Readability of arthroscopy-related patient education materials from the American Academy of Orthopaedic Surgeons and Arthroscopy Association of North America Web sites. AB - We sought to assess the readability levels of arthroscopy-related patient education materials available on the Web sites of the American Academy of Orthopaedic Surgeons (AAOS) and the Arthroscopy Association of North America (AANA). We identified all articles related to arthroscopy available in 2012 from the online patient education libraries of AAOS and AANA. After performing follow up editing, we assessed each article with the Flesch-Kincaid (FK) readability test. Mean readability levels of the articles from the AAOS Web site and the AANA Web site were compared. We also determined the number of articles with readability levels at or below the eighth-grade level (the average reading ability of the US adult population) and sixth-grade level (the widely recommended level for patient education materials). Intraobserver reliability and interobserver reliability of FK grade assessment were evaluated. A total of 62 articles were reviewed (43 from AAOS and 19 from AANA). The mean overall FK grade level was 10.2 (range, 5.2 to 12). The AAOS articles had a mean FK grade level of 9.6 (range, 5.2 to 12), whereas the AANA articles had a mean FK grade level of 11.4 (range, 8.7 to 12); the difference was significant (P < .0001). Only 3 articles had a readability level at or below the eighth-grade level and only 1 was at or below the sixth-grade level; all were from AAOS. Intraobserver reliability and interobserver reliability were excellent (intraclass correlation coefficient of 1 for both). Online patient education materials related to arthroscopy from AAOS and AANA may be written at a level too difficult for a large portion of the patient population to comprehend. PMID- 23726112 TI - Elbow fracture-dislocation combined with Galeazzi fracture in adult: A case report and literature review. AB - INTRODUCTION: Galeazzi fracture associated with ipsilateral posterior elbow dislocation and radial head fracture is a rare pattern of injury. Few reports exist that describes this injury pattern and its treatment. We describe a case report of simultaneous occurrence of Galeazzi fracture and ipsilateral dislocation of elbow. PRESENTATION OF CASE: A 58 year-old female presented with Galeazzi fracture and posterior elbow dislocation associated with radial head fracture of left upper extremity. This was managed with closed reduction of the elbow, open reduction and internal fixation of the radial shaft fracture and K wire stabilisation of the unstable distal radioulnar joint. Prophylactic fasciotomy was performed. At 10 months follow-up, the outcome was favourable with the American shoulder and elbow surgeon score of 92 and the disabilities of the arm, shoulder and hand score of 18. DISCUSSION: The presumed mechanism of the injury was a forceful axial loading of a hyperpronated forearm and extended elbow. Our literature review shows that this pattern of injury occurs as a result of high energy trauma in young individuals, and successful outcome can be achieved by addressing each component of this complex injury individually. CONCLUSION: Simultaneous occurrence of elbow dislocation and Galeazzi fracture seems to be the result of extreme axial force and unique position of upper extremity at the time of impact. Individualised approach to each component of this injury can result in favourable outcome. PMID- 23726113 TI - [Should the whole population be screened for coeliac disease?]. AB - To address the issue of mass screening in coeliac disease strict criteria shall be defined. Principles and practice of screening for disease have been defined 40 years ago by Wilson and Jungner, there are still accurate and applied, specially in France for neonatal screening. Screening the whole population for gluten intolerance is not recommended at this time. Aress with gap in scientific knowledge are identified and further prospective epidemiologic studies are needed. These include the timing of screening, defining the natural history of screening-identified asymptomatic patients, developing tools to predict disease onset and disease remission and the potential risks of screening. At the present time, only identification and testing of high-risks groups is recommended. PMID- 23726114 TI - Population-based validation of a policy change to use long-term androgen deprivation therapy for cT3-4 prostate cancer: impact of the EORTC22863 and RTOG 85-31 and 92-02 trials. AB - PURPOSE: After publication of EORTC-22863 trial, prolonged androgen deprivation therapy (ADT) combined with radiation therapy (RT) became standard policy for high-risk prostate cancer patients in British Columbia (BC) in 1997. We evaluated whether population-based survival improved after this policy change. PATIENTS AND METHODS: Two cohorts comprising all patients with T3-T4 prostate cancer treated with curative-intent RT in BC were reviewed. The Early cohort (n=730) was all patients treated between 1993 and 1995, and the Late cohort (n=584) was all patients treated between 1999 and 2001. The BC Cancer Registry, which collects data on survival, was linked to RT and pharmacy databases. Duration of ADT, age, stage, grade, presenting PSA, and Charlson comorbidity index (CCI; none=0, minor=1, major=2+), were abstracted from charts. RESULTS: Usage of >=6 months and >=18 months of neoadjuvant and adjuvant ADT increased from 14% and 1% to 97% and 59% (p<0.0001). Baseline characteristics were similar, except for lower Gleason score (G2-6: 45% vs. 20%, G7: 35% vs. 48%, G8-10: 19% vs. 32%; p<0.0001), higher T-stage (T4: 9% vs. 5%, p=0.004) and higher comorbidity (CCI 0: 62% vs. 71%, CCI 1: 26% vs. 20%, CCI 2+: 11% vs. 9%, p=0.002) in the Early cohort. Disease specific survival adjusted for competing risks from other causes mortality was improved (90% vs. 86%, p=0.042). On multivariate analysis, the Late cohort was independently associated with improved 8-year overall survival (76% vs. 64%, p=0.0002). CONCLUSIONS: This population-based study demonstrated improved overall survival following a policy change to use of prolonged ADT with curative RT for patients with T3-T4 prostate cancer. PMID- 23726115 TI - The UK HeartSpare Study: randomised evaluation of voluntary deep-inspiratory breath-hold in women undergoing breast radiotherapy. AB - PURPOSE: To determine whether voluntary deep-inspiratory breath-hold (v_DIBH) and deep-inspiratory breath-hold with the active breathing coordinatorTM (ABC_DIBH) in patients undergoing left breast radiotherapy are comparable in terms of normal tissue sparing, positional reproducibility and feasibility of delivery. METHODS: Following surgery for early breast cancer, patients underwent planning-CT scans in v_DIBH and ABC_DIBH. Patients were randomised to receive one technique for fractions 1-7 and the second technique for fractions 8-15 (40 Gy/15 fractions total). Daily electronic portal imaging (EPI) was performed and matched to digitally-reconstructed radiographs. Cone-beam CT (CBCT) images were acquired for 6/15 fractions and matched to planning-CT data. Population systematic (Sigma) and random errors (sigma) were estimated. Heart, left-anterior-descending coronary artery, and lung doses were calculated. Patient comfort, radiographer satisfaction and scanning/treatment times were recorded. Within-patient comparisons between the two techniques used the paired t-test or Wilcoxon signed rank test. RESULTS: Twenty-three patients were recruited. All completed treatment with both techniques. EPI-derived Sigma were <= 1.8mm (v_DIBH) and <= 2.0mm (ABC_DIBH) and sigma <= 2.5mm (v_DIBH) and <= 2.2mm (ABC_DIBH) (all p non significant). CBCT-derived Sigma were <= 3.9 mm (v_DIBH) and <= 4.9 mm (ABC_DIBH) and sigma <= 4.1mm (v_DIBH) and <= 3.8mm (ABC_DIBH). There was no significant difference between techniques in terms of normal-tissue doses (all p non significant). Patients and radiographers preferred v_DIBH (p=0.007, p=0.03, respectively). Scanning/treatment setup times were shorter for v_DIBH (p=0.02, p=0.04, respectively). CONCLUSIONS: v_DIBH and ABC_DIBH are comparable in terms of positional reproducibility and normal tissue sparing. v_DIBH is preferred by patients and radiographers, takes less time to deliver, and is cheaper than ABC_DIBH. PMID- 23726116 TI - Dosimetric and clinical predictors of toxicity following combined chemotherapy and moderately hypofractionated rotational radiotherapy of locally advanced pancreatic adenocarcinoma. AB - BACKGROUND AND PURPOSE: Hypofractionated radiotherapy (RT) of pancreatic adenocarcinoma is limited by the tolerance of adjacent normal tissues. A better understanding of the influence of dosimetric variables on the rate of toxicity after RT must be considered an important goal. METHODS AND MATERIALS: Sixty-one patients with histologically proven locally advanced disease (LAPD) were analyzed. The therapeutic strategy consisted of induction chemotherapy (ChT) followed by concurrent chemoradiotherapy (CRT). In 39 out of 61 patients the target volume was based on a four-dimensional CT (4D-CT) procedure. Delivered dose was 44.25Gy in 15 fractions to PTV2, which consisted of pancreatic tumor and regional lymph nodes considered radiologically involved; 23 out of 61 patients received a simultaneous integrated boost (SIB) to a tumor sub-volume infiltrating the great abdominal vessels (PTV1) with dose in the range of 48-58Gy. RT was delivered with Helical Tomotherapy. Dose-volume histograms (DVHs) of target volumes and organs at risk (OARs) were collected for analysis. The predictive value of clinical/dosimetric parameters was tested by univariate/multivariate analyses. RESULTS: The crude incidence of acute gastrointestinal (GI) grade 2 toxicity was 33%. The 12-month actuarial rate of "anatomical" (gastro-duodenal mucosa damage) toxicity was 13% (95% CI: 4-22%). On univariate analysis, several stomach and duodenum DVH endpoints are predictive of toxicity after moderately hypofractionated radiotherapy. Multivariate analysis confirmed that baseline performance status and the stomach V20[%] were strong independent predictors of acute GI grade ?2 toxicity. The high-dose region of duodenum DVH (V45[%]; V40[%]) was strongly correlated with grade ?2 "anatomical" toxicity; the best V40[%] and V45[%] cut-off values were 16% and 2.6% respectively. CONCLUSION: Regarding dosimetric indices, stomach V20[%] correlates with a higher rate of acute toxicity; more severe acute and late anatomical toxicities are related to the high dose region of duodenum DVH. PMID- 23726117 TI - Development of radiation pneumopathy and generalised radiological changes after radiotherapy are independent negative prognostic factors for survival in non small cell lung cancer patients. AB - BACKGROUND AND PURPOSE: To investigate the risk factors for radiation pneumopathy (RP) and survival rate of non-small cell lung cancer patients with RP and generalised interstitial lung changes (gen-ILC). MATERIAL AND METHODS: A total of 147 consecutive patients receiving curative radiotherapy were analysed. RP was graded according to Common Terminology Criteria for Adverse Events v. 3. Computed tomography images were assessed for the presence of gen-ILC after radiotherapy. Univariate and multivariate analyses were performed to identify significant factors. RESULTS: Median follow-up was 16.2 months (range 1.4-58.6). Radiological changes after radiotherapy were confined to high dose irradiation volume in 111 patients, while 31 patients developed gen-ILC. Dosimetric parameters and level of C-reactive protein before radiotherapy were significantly associated with severe RP. Development of gen-ILC (p=0.008), as well as severe RP (p=0.03) had significant negative impact on patients' survival. These two factors remained significant in the multivariate analysis. CONCLUSIONS: Severe radiation pneumopathy and generalised radiographic changes were significant independent prognostic factors for survival. More studies on pathophysiology of radiation induced damage are necessary to fully understand the mechanisms behind it. PMID- 23726118 TI - Spirometry. Spanish Society of Pulmonology and Thoracic Surgery (SEPAR). AB - Spirometry is the main pulmonary function test and is essential for the evaluation and monitoring of respiratory diseases. Its utility transcends the field of Respiratory Medicine, is becoming increasingly important in primary care and applications have even been described outside the field of respiratory diseases. This document is therefore intended to serve as support for all health professionals who use spirometry, providing recommendations based on the best scientific evidence available. An update of the indications and contraindications of the test is proposed. The document sets out recommendations on the requirements necessary for conventional spirometers and portable office equipment, as well as on spirometer hygiene and quality control measures. Spirometric parameters that must be considered, performance of manoeuvres, criteria for acceptability and repeatability of measurements and their quality control are defined. A proposal is also established for presentation of the results and an evaluation and interpretation is proposed according to information generated in recent years. Finally, lines of adaptation and integration of spirometry in the field of new technologies are considered. PMID- 23726119 TI - Modeling and comparative assessment of municipal solid waste gasification for energy production. AB - Gasification is the thermochemical conversion of organic feedstocks mainly into combustible syngas (CO and H(2)) along with other constituents. It has been widely used to convert coal into gaseous energy carriers but only has been recently looked at as a process for producing energy from biomass. This study explores the potential of gasification for energy production and treatment of municipal solid waste (MSW). It relies on adapting the theory governing the chemistry and kinetics of the gasification process to the use of MSW as a feedstock to the process. It also relies on an equilibrium kinetics and thermodynamics solver tool (Gasify((r))) in the process of modeling gasification of MSW. The effect of process temperature variation on gasifying MSW was explored and the results were compared to incineration as an alternative to gasification of MSW. Also, the assessment was performed comparatively for gasification of MSW in the United Arab Emirates, USA, and Thailand, presenting a spectrum of socioeconomic settings with varying MSW compositions in order to explore the effect of MSW composition variance on the products of gasification. All in all, this study provides an insight into the potential of gasification for the treatment of MSW and as a waste to energy alternative to incineration. PMID- 23726120 TI - Early hospital readmission in the trauma population: are the risk factors different? AB - INTRODUCTION: Hospital readmission rates will soon impact Medicare reimbursements. While risk factors for readmission have been described for medical and elective surgical patients, little is known about their predictive value specifically in trauma patients. PATIENTS AND METHODS: We retrospectively identified all admissions after trauma resuscitation to our urban level 1 trauma centre from 1/1/2004 to 8/31/2010. All patients discharged alive were included. Data collected included demographics, Injury Severity Score (ISS), and length of stay (LOS). We analyzed these index admissions for the development of complications that have previously been shown to be associated with readmission. Readmissions that occurred within 30 days of index admission were identified. Univariable and multivariable analyses were performed. p<0.05 was considered significant. RESULTS: We identified 10,306 index admissions, with 447 (4.3%) early (within 30 days) readmissions. Mean ISS was 11.1 (SD 10.4). On multivariable analysis, African-American race (OR 1.3, p=0.009), pre-existing chronic obstructive pulmonary disease (COPD) (OR 1.5, p=0.02), and diabetes mellitus (OR 1.8, p<0.001) were associated with readmission, along with higher ISS (OR 1.01, p<0.001), ICU admission (OR 2.1, p<0.001), and increased LOS (OR 1.01, p<0.001). Among many in-hospital complications examined, only the development of surgical site infection (SSI) (OR 1.9, p=0.02) was associated with increased risk of readmission. CONCLUSIONS: Trauma patients have a low risk of readmission. In contrast to elective surgical patients, the only modifiable risk factor for readmission in our trauma population was SSI. Other risk factors may present clinicians with opportunities for targeted interventions, such as proactive follow up or early phone contact. With future changes to health care policy, clinicians may have even greater motivation to prevent readmission. PMID- 23726121 TI - Elastography of the pancreas. AB - Elastography has recently been presented in clinical studies as a new technique applied to US imaging. The challenge of this new technique is to distinguish different tissues on the basis of their specific consistency. Since malignant tumors tend to be harder than benign lesions and parenchyma, this new approach could result clinically relevant. Initial clinical experiences in US elastography have been promising in differentiating breast, thyroid and prostate nodules. Pancreatic applications of US elastography are relatively recent and under validation with several studies so far published in literature. PMID- 23726122 TI - Comparison of two different thermal techniques for the treatment of hepatocellular carcinoma. AB - PURPOSE: To compare the safety and efficacy of radiofrequency ablation (RFA) and microwave ablation (MWA) in treating hepatocellular carcinoma (HCC) while conforming to the Milan criteria. MATERIALS AND METHODS: The study was approved by the Institutional Review Board, and informed consent was waived due to the retrospective study design. One hundred ninety-eight patients met the inclusion criteria and were included in the study. Eighty-five patients with 98 lesions received RFA, and 113 patients with 131 lesions underwent MWA. Complete ablation rates, local recurrence rates, disease-free survival rates, cumulative survival rates, and major complications were compared between the two treatment groups. RESULTS: Complete ablation rates were 99.0% for RFA and 98.5% for MWA (P=1.000). Local recurrence rates were 5.2% for RFA and 10.9% for MWA (P=0.127). Disease free survival rates at 1, 2, 3, and 4 years were 80.3%, 61.8%, 39.5%, and 19.0% in the RFA group and 75.0%, 59.4%, 32.1%, and 16.1% in the MWA group, respectively (P=0.376). Cumulative survival rates at 1, 2, 3, and 4 years were 98.7%, 92.3%, 82.7%, and 77.8% in the RFA group and 98.0%, 90.7%, 77.6%, and 77.6% in the MWA group, respectively (P=0.729). Major complication rates were 2.4% and 2.7% in the RFA group and the MWA group, respectively (P=1.000). There were no patient deaths due to treatment. CONCLUSION: RFA and MWA have the same clinical value in treating HCC conforming to the Milan criteria. RFA and MWA are both safe and effective techniques for HCC as clinical application. PMID- 23726123 TI - CT and MR features of xanthogranulomatous cholecystitis: an analysis of consecutive 49 cases. AB - OBJECTIVE: To study the CT and MR features of xanthogranulomatous cholecystitis (XGC). MATERIALS AND METHODS: 49 patients had pathologically confirmed XGC. All patients underwent contrast enhanced CT, and 10 patients had additional plain MRI. The CT and MRI results were retrospectively analyzed. RESULTS: On CT, all patients had thickening of gallbladder wall, with 87.8% cases showed diffuse thickening. 85.7% cases had intramural hypo-attenuated nodules in the thickened wall. Continuous mucosal line and luminal surface enhancement were noted in 79.6% and 85.7% cases, respectively. Gallbladder stones were seen in 69.4% patients. The coexistence of the above 5 CT features was seen in 40% cases, and 80% cases had the coexistence of >= 4 features. Diffused gallbladder wall thickening in XGC is more likely to have disrupted mucosal line, and XGC with disrupted mucosal line is more likely to be associated with liver infiltration. In 60% patients the inflammatory process extended beyond gallbladder, with the interface between gallbladder and liver and/or the surrounding fat blurred. 40% cases had an early enhancement of liver parenchyma. Infiltration to other surrounding tissues included bowel (n=3), stomach (n=2), and abdominal wall (n=1). On MR images, 7 of 9 intramural nodules in 7 subjects with T1-weighted dual echo MR images showed higher signal intensity on in-phase images than out-of-phase images. CONCLUSION: Coexisting of diffuse gallbladder wall thickening, hypo-attenuated intramural nodules, continuous mucosal line, luminal surface enhancement, and gallbladder stone highly suggest XGC. XGC frequently infiltrate liver and surrounding fat. Chemical-shift MRI helps classifying intramural nodules in the gallbladder wall. PMID- 23726124 TI - Value of whole body MRI and dynamic contrast enhanced MRI in the diagnosis, follow-up and evaluation of disease activity and extent in multiple myeloma. AB - PURPOSE: To evaluate the significance of dynamic contrast enhanced MRI (DCE-MRI) and whole body MRI (WB-MRI) in the diagnosis, prognosis and assessment of therapy for patients with monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). MATERIALS AND METHODS: The retrospective study includes 219 patients providing 463 WB-MRI and DCE-MRI investigations for the subgroups MGUS (n=70), MM active disease (n=126; this includes 70 patients with new diagnosis of MM, according to the International Staging System (ISS): 41.4% ISS stage I, 20.0% ISS stage II, 7.1% ISS stage III, 31.4% insufficient for staging; and 56 patients with '(re-)active disease': 16.07% relapse, 32.14% progressive disease and 51.79% stable disease) and MM remission (n=23; 60.87% complete remission, 17.39% very good partial remission and 21.74% partial remission). Investigations of patients with hereditary multiple exostoses (n=5), neurofibromatosis (n=7) and healthy persons (n=9) were added as control subjects (n=21). WB-MRI evaluation was done by evaluating thirteen skeletal regions, providing a 'skeletal score'. DCE-MRI images of the spine, were analyzed with regions-of-interest and time-intensity-curves (TIC). RESULTS: All TIC parameters can significantly differentiate between the predefined subgroups (p<0.001). One hundred days after autologous stem cell transplantation a 75% decrease of the slope wash-in value (p<0.001) can be seen. A cubic regression trend between 'skeletal score' and slope wash-in (adj.R(2)=0.412) could demonstrate a significant increase bone marrow perfusion if MM affects more than 10 skeletal regions (p<0.001), associated with a poorer prognosis (p<0.001). CONCLUSION: DCE MRI evaluation of the spine is useful for diagnosis of MM, follow-up after stem cell transplantation and evaluation of disease activity. A combined evaluation with WB-MRI and DCE-MRI provides additional micro-vascular information on the morphologic lesions and could help categorize patients with MM in two different groups to offer useful therapeutic and prognostic advise. PMID- 23726125 TI - Response to "the detection of internal cocaine drug packs: a radiological challenge in the future?". PMID- 23726126 TI - Reduction of contrast medium volume in abdominal aorta CTA: multiphasic injection technique versus a test bolus volume. AB - OBJECTIVE: The purpose of this study is to reduce the administered contrast medium volume in abdominal CTA by using a test bolus injection, with the preservation of adequate quantitative and qualitative vessel enhancement. STUDY DESIGN: For this technical efficacy study 30 patients, who were referred for a CTA examination of the abdominal aorta, were included. Randomly 15 patients were assigned to undergo a multiphasic injection protocol and received 89 mL of contrast medium (Optiray 350) (protocol I). Fifteen patients were assigned to the test bolus injection protocol (protocol II), which implies injection of a 10 mL test bolus of Optiray 350 prior to performing CTA with a 40 mL of contrast medium. Quantitative assessment of vascular enhancement was performed by measuring the amount of Hounsfield Units in the aorta at 30 positions from the celiac trunk to the iliac arteries in both groups. Qualitative assessment was performed by three radiologists who scored the images at a 5-point scale. RESULTS: Quantitative assessment showed that there was no significant difference in vascular enhancement for patients between the two protocols, with mean attenuation values of 280.9 +/- 50.84 HU and 258.60 +/- 39.28 HU, respectively. The image quality of protocol I was rated 4.31 (range: 3.67/5.00) and of protocol II 4.11 (range: 2.67/5.00). These differences were not statistically significant. CONCLUSION: This study showed that by using a test bolus injection and the administration of 50 mL of contrast medium overall, CTA of the abdominal aorta can reliably be performed, with regard to quantitative and qualitative adequate vessel enhancement. PMID- 23726127 TI - Physical properties and depth of cure of a new short fiber reinforced composite. AB - OBJECTIVES: To determine the physical properties and curing depth of a new short fiber composite intended for posterior large restorations (everX Posterior) in comparison to different commercial posterior composites (Alert, TetricEvoCeram Bulk Fill, Voco X-tra base, SDR, Venus Bulk Fill, SonicFill, Filtek Bulk Fill, Filtek Superme, and Filtek Z250). In addition, length of fiber fillers of composite XENIUS base compared to the previously introduced composite Alert has been measured. MATERIALS AND METHODS: The following properties were examined according to ISO standard 4049: flexural strength, flexural modulus, fracture toughness, polymerization shrinkage and depth of cure. The mean and standard deviation were determined and all results were statistically analyzed with analysis of variance ANOVA (a=0.05). RESULTS: XENIUS base composite exhibited the highest fracture toughness (4.6MPam(1/2)) and flexural strength (124.3MPa) values and the lower shrinkage strain (0.17%) among the materials tested. Alert composite revealed the highest flexural modulus value (9.9GPa), which was not significantly different from XENIUS base composite (9.5GPa). Depth of cure of XENIUS base (4.6mm) was similar than those of bulk fill composites and higher than other hybrid composites. The length of fiber fillers in XENIUS base was longer (1.3-2mm) than in Alert (20-60MUm). CONCLUSIONS: The new short fiber composite differed significantly in its physical properties compared to other materials tested. This suggests that the latter could be used in high-stress bearing areas. PMID- 23726128 TI - Post-hot isostatic pressing: a healing treatment for process related defects and laboratory grinding damage of dental zirconia? AB - OBJECTIVE: Processing parameters (powder granulation, compaction, debinding, greenbody shaping, sintering) and post-sinter rough, even fine grinding are influencing the final mechanical properties of 3Y-TZP. The hypothesis of this study was that post-sinter hot isostatic pressing (post-HIP) would be beneficial for improving reliability and strength of both sintered and coarse ground sintered zirconia by closing or reducing surface and/or small volume defects. METHODS: 75 sintered bars of an experimental 3Y-TZP (3mm*4mm*45mm) with chamfered edges and 15MUm diamond surface finish were provided by the manufacturer (Ivoclar Vivadent) and randomly distributed in five groups of N=15 each. G1 served as control (as received); G2 was post-HIPed at 1400 degrees C and G3 at 1350 degrees C, both using a pressure of 195MPa in Ar for 1h; G4 was coarse ground with 120MUm diamond disk grain size; G5 was ground 120MUm and post-HIPed at 1350 degrees C at 195MPa, 1h in Ar. The specimens were fractured in air in 4 point-bending. Weibull characteristic strength (sigma0) in MPa, m parameter (reliability) and confidence intervals (CI) at 90% confidence level are reported. Identification of the critical flaw was performed by SEM on the fractured surface of all specimens and XRD performed in all groups. RESULTS: G1: sigma0=973 (932-1016), m=10.6 (7.45 15.1); G2: sigma0=930 (871-995), m=6.9 (4.87-9.9); G3: sigma0=898 (848-952), m=7.94 (5.6-11.4); G4: sigma0=921 (857-991), m=6.35 (4.48-9.11); G5: sigma0=881 (847-918), m=11.4 (8.03-16.3). G5 had a significantly lower sigma0 than G1. No significant differences were seen in the reliability (m) among the groups. Fractography revealed critical intrinsic subsurface flaws of 10-60MUm present in all groups resulting from the processing parameters. No "healing" (i.e. closing of defects by densification) resulted after post-HIP. Grinding sintered zirconia with 120MUm diamond disks induced radial cracks of 10-20MUm and an important pseudo-cubic phase transformation (56wt%) that was not completely removed after post-HIP. Post-HIP increased slightly the relative density by 0.1% but without improving the strength and reliability. SIGNIFICANCE: Post-HIP was not efficient in closing large (10-60MUm) subsurface (volume) processing defects. PMID- 23726129 TI - Intraoperative detection of sentinel lymph nodes in breast cancer patients using ultrasonography-guided direct indocyanine green dye-marking by real-time virtual sonography constructed with three-dimensional computed tomography-lymphography. AB - PURPOSE: This study aims to determine the utility of ultrasonography (US)-guided direct dye-marking of sentinel lymph nodes (SLNs) by real-time virtual sonography (RVS) constructed with three-dimensional (3D) computed tomography (CT) lymphography (LG). PATIENTS AND METHODS: We identified SLNs in 258 clinically node-negative breast cancer patients using an RVS system to display in real time a virtual multiplanar reconstruction CT image obtained from CT volume data corresponding to the same cross-sectional image from US. CT volume data were obtained using our original 3D CT-LG, which accurately detects SLNs in breast cancer. We then perform US-guided dye-marking close to SLNs using indocyanine green (ICG). Subsequently, indigo carmine blue dye was injected into the subareolar and peritumoral areas around each primary tumor. All patients underwent SLN biopsy and SLN metastases were examined pathologically. RESULTS: In all 258 patients, we were able to detect the same SLNs visualized on 3D CT-LG, using the RVS system. We detected ICG close to SLNs in 257 of 258 patients (99.6%) during SLN biopsy. In 25 patients (9%), we failed to follow the blue lymphatic route stained by indigo carmine and SLNs were not stained by indigo carmine, but easily detected SLNs by ICG marking. CONCLUSION: US-guided direct ICG dye-marking of SLNs using this RVS system seems useful for the detection of SLNs, allowing easy detection of SLNs even when the stained lymphatic route is not followed. PMID- 23726131 TI - [Displaced dental material]. PMID- 23726130 TI - Patterns of metastatic spread in early breast cancer. AB - AIMS: The aim of this study was to prospectively investigate metastatic pathways of spread to lymph node versus bone marrow and identify biological characteristics that determine these patterns in early invasive breast cancer. PATIENTS AND METHODS: In all, 177 patients with early invasive breast cancer underwent surgical extirpation of the primary tumour with sentinel lymph node biopsy (SLNB). Bone marrow (BM) aspiration was performed to screen for cytokeratin-positive cells by immunocytochemistry. Lymphatic spread was assessed by histopathological examination of lymph nodes (LN). A representative subset of 87 tumours was analysed by tissue microarray (TMA) to evaluate expression of markers that potentially influence haematogenous vs. lymphatic spread. Patients were followed up for a median of 54.7 months. RESULTS: Of the 177 patients, 114 (64%) were BM-/LN-, 38 (22%) BM-/LN+, 19 (11%) BM+/LN- and 6 (3%) BM+/LN+. Multivariate analysis of histopathological characteristics revealed that increasing tumour size was significantly associated with both LN positivity (p = 0.003) and BM positivity (p = 0.01), the presence of lymphovascular invasion significantly correlated with LN+ (p = 0.01), whereas lower histological grade was significantly associated with BM+ (p = 0.03). LN+ and BM+ were non significantly negatively related to each other. Univariate analysis of the TMA data showed differential expression patterns for several factors; significant differences between effects on the two metastatic pathways (lymphatic vs. haematogenous) were found for expression of CD54 (p = 0.03), osteopontin (p = 0.04), bone sialoprotein (p = 0.04) and CXCR4 (p = 0.009). High expression of CD54, osteopontin and bone sialoprotein (BSP) was positively associated with BM + but was either not associated, or negatively associated, with LN+. High CXCR4 expression was positively associated with LN+ and negatively with BM+. High VEGF C expression was associated with both LN+ and BM+, although this did not attain statistical significance. Due to the small number of clinical events during clinical follow-up, no associations were identified between metastatic spread patterns, recurrence and/or death. CONCLUSION: These findings suggest that distinct lymphatic and haematogenous metastatic pathways exist in early breast cancer and that these pathways are governed by specific biological markers. PMID- 23726132 TI - Window of opportunity for estrogen and progestin intervention in brain aging and Alzheimer's disease. PMID- 23726133 TI - Complications and visual outcomes after glued foldable intraocular lens implantation in eyes with inadequate capsules. AB - PURPOSE: To evaluate the complications and visual outcomes of glued intrascleral fixated foldable intraocular lens (IOL) in eyes with deficient capsules. SETTING: Dr Agarwal's Eye Hospital and Eye Research Centre, Chennai, India. DESIGN: Case series. METHODS: Data were evaluated from the records of patients with a primary glued foldable IOL for intraoperative capsular loss or subluxated lens or secondary glued foldable IOL for aphakia. Exclusion criteria included preoperative glaucoma, aniridia, macular scar, traumatic subluxation, combined surgeries, incomplete operative medical records, and postoperative follow-up less than 6 months. The intraoperative and postoperative complication rates, reoperation rate, and visual outcomes were analyzed. RESULTS: The study comprised 208 eyes (185 patients). The mean follow-up was 16.7 months +/- 10.2 (SD). The intraoperative complications were hyphema (0.4%), haptic breakage (0.4%), and deformed haptics (0.9%). Early complications occurred in 29 eyes (13.9%) and included corneal edema (5.7%), epithelial defect (1.9%), and grade 2 anterior chamber reaction (2.4%). Late complications occurred in 39 eyes (18.7%) and included optic capture (4.3%), IOL decentration (3.3%), haptic extrusion (1.9%), subconjunctival haptic (1.4%), macular edema (1.9%), and pigment dispersion (1.9%). Reoperation was required in 16 eyes (7.7%). Haptic position was altered in eyes with IOL decentration. Corrected distance visual acuity (CDVA) improved or remained unchanged in 84.6% of eyes. The postoperative CDVA was 20/40 or better and 20/60 or better in 38.9% and 48.5% of eyes, respectively. CONCLUSIONS: The foldable glued-IOL procedure showed satisfactory visual outcomes without serious complications. Intraocular lens decentration was due to haptic-related problems. PMID- 23726134 TI - The role of religion in decision-making on antenatal screening of congenital anomalies: a qualitative study amongst Muslim Turkish origin immigrants. AB - OBJECTIVE: to explore what role religious beliefs of pregnant Muslim women play in their decision-making on antenatal screening, particularly regarding congenital abnormalities and termination, and whether their interpretations of the religious doctrines correspond to the main sources of Islam. DESIGN: qualitative pilot study using in-depth interviews with pregnant Muslim women. SETTING: one midwifery practice in a medium-sized city near Amsterdam participated in the study. PARTICIPANTS: 10 pregnant Muslim women of Turkish origin who live in a high density immigrant area and who attended primary midwives for antenatal care were included in the study. DATA COLLECTION AND DATA ANALYSIS: to explore the role of religion in decision-making on antenatal screening tests, a topic list was constructed, including four subjects: being a (practising) Muslim, the view on unborn life, the view on disabled life and the view on termination. To analyse the interviews, open and axial coding based on the Grounded Theory was used and descriptive and analytical themes were identified and interpreted. FINDINGS: all 10 interviewees stated that their faith played a role in their decision-making on antenatal screening, specific to the combined test. They did not consider congenital anomalies as a problem and did not consider termination to be an option in case of a disabled fetus. However, the Islamic jurisprudence considers that termination is allowed if the fetus has serious abnormalities, but only before 19 weeks plus one day of gestation. KEY CONCLUSIONS: religious convictions play a role regarding antenatal screening in pregnant Muslim women of Turkish origin. The interviewees did not consider a termination in case of an affected child. Women were unaware that within Islamic tradition there is the possibility of termination if a fetus has serious anomalies. Incomplete knowledge of religious doctrines may be influencing both decisions of antenatal screening and diagnostic tests uptake and of terminating a pregnancy for fetuses with serious anomalies. IMPLICATIONS FOR PRACTISE: counsellors should be aware of the role of religious beliefs in the decision making process on antenatal screening tests. PMID- 23726135 TI - Differences in the management of adolescents with polycystic ovary syndrome across pediatric specialties. AB - STUDY OBJECTIVE: Evaluate for differences in the management of adolescents with polycystic ovarian syndrome (PCOS) across 3 pediatric specialties. DESIGN: Retrospective review of medical records. SETTING: Academic children's hospital. PARTICIPANTS: 181 adolescents seen between July 2008 and June 2010 by providers in Pediatric Endocrinology (PEndo), Adolescent Medicine (AMed), or Pediatric and Adolescent Gynecology (PGyn) identified via billing data (ICD-9 code for PCOS, 256.4). INTERVENTIONS: None. MAIN OUTCOME MEASURES: (1) Percentage of adolescents with a billing diagnosis of PCOS who met diagnostic criteria; (2) Percentage of individuals screened for comorbidities and differences across specialties; (3) Differences in treatment recommendations across specialties; (4) Factors associated with recommendation for metformin and hormonal contraceptives. RESULTS: Thirteen percent of PEndo patients did not meet diagnostic criteria for PCOS; 20% of AMed and PGyn patients did not meet criteria. There were significant differences in rates of screening for obesity, insulin resistance, and Type 2 diabetes. There were significant differences in treatment recommendations for lifestyle changes, metformin, and anti-androgen therapy across specialties. Specialty and obesity were significant predictors of metformin recommendation; specifically PEndo predicted metformin recommendation. PGyn and AMed specialties predicted hormonal contraceptive recommendation. CONCLUSIONS: The variability observed among specialties may be due to differences in training, accounting for a range of comfort with aspects of PCOS. Formulation of consensus guidelines for diagnosis and management of PCOS are needed, along with broad educational efforts. By correctly diagnosing, screening for comorbidities, and managing PCOS appropriately during adolescence, providers may reduce the risk for long-term consequences. PMID- 23726136 TI - Delaying Pap test screening in the adolescent population: an evidence-based approach. AB - Cervical cancer screening guidelines have evolved significantly over the past ten years in the adolescent population. The objective of this article is to review the cervical screening guidelines in the adolescent population as well as examine the evidence and studies that support delaying screening until 21 years old. Delaying HPV and Papanicolaou testing until 21 years old is safe and will not increase cervical cancer rates in the adolescent population. PMID- 23726137 TI - Acute urinary retention in an adolescent as the presenting symptom of lichen sclerosus et atrophicus. AB - BACKGROUND: A rare case of acute urinary retention caused by labial fusion in an adolescent is described and the possible causes are discussed. CASE: A 17-year old girl, not sexually active, presented to our emergency service for acute urinary retention. Genital examination revealed labia minora fusion from the clitoris to the vaginal fourchette; urethra, and clitoris were not visualized. Sexual abuse and trauma were excluded. The labia minora were manually separated in the operating room revealing a normal vagina and urethral meatus. Skin biopsies taken from the fused labia minora revealed Lichen Sclerosus et Atrophicus. SUMMARY AND CONCLUSION: Urinary retention may be seen in the face of complete adhesion of the labia minora, a rare event in postpubertal individuals. In such cases, a suspicion of underlying pathology such as asymptomatic Lichen Sclerosus should be raised and be confirmed by a biopsy. PMID- 23726139 TI - HPV vaccination in female children with special health care needs. AB - STUDY OBJECTIVE: Potential barriers between parents of children with special health needs (CSHCN) and their health care providers in regards to the patient receiving a full course of the human papillomavirus (HPV) immunization are explored in this study. STUDY DESIGN: Parents of female CSHCN between ages of 9 26 years completed a questionnaire asking about personal receptivity of vaccines and potential barriers to vaccinating their child against HPV. A separate survey was completed by members of the Wisconsin and Illinois chapters of the American Academy of Pediatrics about HPV vaccination practices provided to patients with special health care needs. SETTING: Outpatient urban health clinic and the Children's Hospital of Wisconsin's Adolescent Medicine and Neurology clinics from January 2009-2010. RESULTS: Seventeen parents completed the survey. Forty-seven percent of parents answered that their child's pediatrician had offered the HPV vaccine; 17% reported that their child was vaccinated against HPV. Most parents knew that HPV is a sexually transmitted infection, causes genital warts, and can cause abnormal pap smears. For the provider survey, 77 out of 130 respondents offer HPV vaccine as part of their practice and see CSHCN. Ninety percent have vaccinated CSHCN against HPV. CONCLUSIONS: This study suggests that acceptability of the HPV vaccine is high for health care providers, but acceptability in parents of CSHCN is lower than in the general population. This study raises awareness that health care providers need to be aware of the possibility that parents of CSHCN may not perceive their child as needing or being offered the HPV vaccine. PMID- 23726140 TI - Understanding the requirements of geographical data for blind and partially sighted people to make journeys more independently. AB - Previous research has highlighted that blind and partially sighted people find various factors inhibit their abilities to make journeys. This paper proposes that the lack of accurate, appropriate and usable geographical data is one of the reasons for this and these can be tracked back to core human factors issues such as situational awareness, mental workload and environmental ergonomics. Following a review of applicable literature a hierarchical task analysis was performed to better understand the problems in terms of the complexity of various journey types and to identify the geographical data requirements in order to make successful journeys. The task analysis produced a number of results including highlighting four underlying principles which have an impact on the data requirements during any given journey. Finally the need for accessible and accurate geographical data requirements is introduced as a result of the literature review and the task analysis. These highlight the information required in order to facilitate more accessible travel for blind and partially sighted people by providing geographical information about their surroundings in a relevant, meaningful and usable way. PMID- 23726141 TI - Factors affecting the appreciation generated through applying human factors/ergonomics (HFE) principles to systems of work. AB - This retrospective study examined the levels of appreciation (applause) given by clients to Human Factors/Ergonomic (HFE) specialists after they have modified the systems of work. Thirteen non-academic projects were chosen because the HFE interventions involved changed the way workers work at their workplaces. Companies involved range from multi-national corporations and military organizations with thousands of employees to small trading companies with less than 10 employees. In 5 cases the HFE recommendations were fully adopted and well appreciated. In 4 they were largely ignored and not appreciated, with partial adoption and some appreciation in the other 4 cases. Three factors that predict appreciation were identified: (i) alignment between the benefits HFE can provide and the project's key performance indices; (ii) awareness of HFE among the client's senior management; and (iii) a team organization appropriate for applying HFE recommendations. Having an HFE specialist on the client's side can greatly increase levels of appreciation, but lack of such a specialist will not affect levels of appreciation. A clear contractual requirement for HFE intervention does not promote appreciation significantly, but its absence can greatly reduce levels of appreciation. These relationships are discussed using the Kano's model of quality. Means to generate greater appreciation of the benefits of HFE are discussed. PMID- 23726138 TI - Examining links between sexual risk behaviors and dating violence involvement as a function of sexual orientation. AB - STUDY OBJECTIVE: To examine the association between dating violence perpetration and victimization and sexually risky behaviors among sexual minority and heterosexual adolescent girls. DESIGN: Adolescent girls reported on sexual orientation, sexual behaviors, and risk-taking, and their use of, and experience with, dating violence in the past year. Data were analyzed using multinomial regression adjusted for race, poverty, living in a single parent household, and gender of current partner to examine (1) whether sexual minority status was associated with sexual risk behaviors after sociodemographic correlates of sexual risk were controlled; and (2) whether dating violence context accounted for elevated risk. SETTING: Urban, population-based sample of girls interviewed in the home. PARTICIPANTS: 1,647 adolescent girls (38% European American, 57% African American, and 5% other) aged 17 years. Over one-third of the sample lived in poverty. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Sexual risk-taking. RESULTS: Sexual minority status differentiated girls engaging in high sexual risk taking from those reporting none, after controlling for sociodemographic and relationship characteristics. Dating violence perpetration and victimization made unique additional contributions to this model and did not account for the elevated risk conferred by sexual minority status. CONCLUSIONS: Sexual minority girls (SMGs) were more likely than heterosexual girls to report high sexual risk taking and teen dating violence victimization. As with heterosexual girls, sexual risk-taking among SMGs was compounded by dating violence, which was not explained by partner gender. Adolescent girls' risky sexual behavior may be reduced by interventions for teen dating violence regardless of sexual minority status. PMID- 23726142 TI - Oral mucoceles: a clinical, histopathological and immunohistochemical study. AB - The aim of study was to evaluate the clinicopathological features of oral mucoceles and the immunohistochemical expression of cellular and extracellular matrix components in these lesions. One hundred cases of oral mucoceles were examined for clinicopathological features. The expression of mast cell tryptase, CD68, MMP-1 (matrix metalloproteinase-1), MMP-9 (matrix metalloproteinase-9) and CD34 was investigated immunohistochemically in 32 cases. The lesions arose as nodules or blisters of variable color. The mean age was 23.2 years and a higher male frequency was observed. The most common locations were the lower lip (92%), followed by the floor of the mouth (7%), and palate (1%). The lesion size ranged from 0.4 to 3.0cm. Unusual histopathological findings as superficial mucoceles (n=16, 16%), pseudopapillary projections (n=3, 3%), epithelioid histiocytes (n=4, 4%), multinucleated giant cells (n=1, 1%) and myxoglobulosis (n=9, 9%) were also seen. Mast cells and CD68-positive macrophages, MMP-1, MMP-9 and CD34-positive blood vessels were seen in all cases. A significant association was seen between mast cells and MMP-1 (p=0.03) and between macrophages and MMP-1 (p=0.01). This study provided important insight into the demographic and histopathological occurrence of oral mucoceles. The tissue remodeling seen in these lesions mainly involved the migration and interaction of mast cells, macrophages and MMP-1. PMID- 23726143 TI - Application of negative-pressure wound therapy for the management of battlefield scrotum trauma. PMID- 23726144 TI - Integrative analysis of copy number alteration and gene expression profiling in ovarian clear cell adenocarcinoma. AB - Ovarian clear cell adenocarcinoma (Ov-CCA) is a distinctive subtype of ovarian epithelial carcinoma. In this study, we performed array comparative genomic hybridization (aCGH) and paired gene expression microarray of 19 fresh-frozen samples and conducted integrative analysis. For the copy number alterations, significantly amplified regions (false discovery rate [FDR] q <0.05) were 1q21.3 and 8q24.3, and significantly deleted regions were 3p21.31, 4q12, 5q13.2, 5q23.2, 5q31.1, 7p22.1, 7q11.23, 8p12, 9p22.1, 11p15.1, 12p13.31, 15q11.2, 15q21.2, 18p11.31, and 22q11.21 using the Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. Integrative analysis revealed 94 genes demonstrating frequent copy number alterations (>25% of samples) that correlated with gene expression (FDR <0.05). These genes were mainly located on 8p11.21, 8p21.2-p21.3, 8q22.1, 8q24.3, 17q23.2-q23.3, 19p13.3, and 19p13.11. Among the regions, 8q24.3 was found to contain the most genes (30 of 94 genes) including PTK2. The 8q24.3 region was indicated as the most significant region, as supported by copy number, GISTIC, and integrative analysis. Pathway analysis using differentially expressed genes on 8q24.3 revealed several major nodes, including PTK2. In conclusion, we identified a set of 94 candidate genes with frequent copy number alterations that correlated with gene expression. Specific chromosomal alterations, such as the 8q24.3 gain containing PTK2, could be a therapeutic target in a subset of Ov CCAs. PMID- 23726145 TI - Biogas final digestive byproduct applied to croplands as fertilizer contains high levels of steroid hormones. AB - In this study we evaluate and demonstrate the occurrence of nine natural and one synthetic steroid hormone, including estrogens, androgens and progestagens in biogas final digestate byproduct (digestion liquid) commonly used as an agricultural fertilizer. We investigated two biogas sites that utilize different anaerobic digestion technologies (mesophilic and thermophilic) from swine manure and other organic wastes. Individual hormone concentration levels were observed up to 1478 ng g(-1) dry weight or 22.5 mg kg(-1) N with estrone and progesterone reaching highest concentration levels. Evaluation of the potential environmental burden through the application in agriculture was also assessed on the basis of predicted environmental concentrations. This study indicates that the biogas digestion process does not completely remove steroid hormones from livestock manure and use of final digestate byproduct on croplands contributes to the environmental emission of hormones. PMID- 23726146 TI - Characterization and monitoring of linezolid-resistant clinical isolates of Staphylococcus epidermidis in an intensive care unit 4 years after an outbreak of infection by cfr-mediated linezolid-resistant Staphylococcus aureus. AB - Resistance to linezolid is emerging among Staphylococcus epidermidis isolates. During the 4 years following an outbreak of cfr-mediated linezolid-resistant S. aureus in our intensive care unit in 2008, we analyzed the clinical context and characterized the resistance mechanisms of 100 linezolid-resistant strains of S. epidermidis. The prevalence of the cfr gene in our strains reached 50% alone or in combination with other mechanisms. The mutation G2576T in domain V was found in 22% of strains, and both the cfr gene and G2576T in 44%. We also found an association between the cfr gene and mutations in the ribosomal protein L3. All 3 mechanisms co-occurred in 1 strain. MICs in combinations rose to >256 MUg/mL. 58% of colonized patients, and 90% of infected patients had previously received linezolid for at last 10 days. Vancomycin was the main antibiotic in these infections, most of which were bacteremia. We found a high prevalence of the cfr gene in our clinical S. epidermidis isolates after the 2008 outbreak, despite having implemented isolation and control measures. The potential transmissibility of this agent, even without prior exposure to linezolid, can have serious epidemiological repercussions. PMID- 23726147 TI - In vitro activity of fosfomycin in combination with imipenem, meropenem, colistin and tigecycline against OXA 48-positive Klebsiella pneumoniae strains. AB - Carbapenem resistance due to OXA-48 enzymes in Klebsiella pneumoniae is increasing particularly in the Middle Eastern and European regions. Treatment options are limited. The aim of this study was to evaluate the in vitro synergistic activity of fosfomycin in combination with imipenem, meropenem, colistin and tigecycline against OXA-48 producing K. pneumoniae strains. Twelve carbapenem-resistant OXA-48 producing K. pneumoniae isolates were enrolled in this study. Synergistic activity of fosfomycin combined with imipenem, meropenem, colistin, and tigecycline was assessed by chequerboard method. The combination of fosfomycin was synergistic with imipenem, meropenem and tigecycline with the ratios of 42%, 33%, and 33%, respectively. Whilst the combination of fosfomycin with colistin was fully antagonistic against all of the strains, there was no statistically significant difference between the in vitro synergistic activities of fosfomycin in combination with imipenem, meropenem and tigecycline combinations (P > 0.05). Fosfomycin in combination with other agents can be preferred against multidrug resistant K. pneumoniae strains. PMID- 23726148 TI - Prevalence of Ambler class A beta-lactamases and ampC expression in cephalosporin resistant isolates of Acinetobacter baumannii. AB - We examined the prevalence of various cephalosporins' resistance mechanisms in Acinetobacter baumannii clinical isolates. Phenotypic and molecular detection of Ambler classes A, B and D beta-lactamases was performed on 75 isolates. Clonal relatedness was defined using Repetitive Extragenic Palindromic PCR. PCR mapping was used to examine the linkage of insertion sequences and the ampC gene, and ampC expression was analyzed by TaqMan reverse transcriptase-PCR. Twenty-six (37%) isolates carried at least one of the blaPER-1 or blaTEM-1. Sixty-nine (98.5%) out of 70 cephalosporin-resistant isolates had insertions upstream of the ampC gene, of which 48 (69%) and 6 (8%) were identified as ISAba1and ISAba125, respectively. Higher level of expression was obtained in resistant isolates lacking ISAba1/ampC combination in comparison with that in positive ones. The ability to up-regulate the expression of ampC gene in association with different insertion elements has become an important factor in A. baumannii resistance to cephalosporins. PMID- 23726149 TI - [Total trapeziectomy and suspension ligamentoplasty: is there any interest to interpose a pyrocarbon Pi2(r) implant?]. AB - Total trapeziectomy with suspensioplasty remains one of the most widely used techniques in thumb osteoarthritis. Nevertheless, such a technique does not completely prevent collapse of the trapezial space. We wanted to know whether adding a pyrocarbon spacer allowed better keeping trapezial space and increasing strength. We compared two groups of patients matched on sex, age, manual labor and dominant side. In each group, they were 23 patients suffering from CMC1 osteoarthrosis, mean age was 62 years. Surgical technique consisted in a total trapeziectomy and suspensioplasty with a Gore-Tex((r)) slip without spacer (group A) or associated with spacer Pi2((r)) (group B). The follow-up was 25 months for group A and 15 months for group B. Height of the scaphometacarpal space represented 81.5% of trapezium height in group B versus 61.6% in group A. Better correction of hyperextension of the metacarpophalengeal joint was noted in group B. Between group A and group B, no difference was found according to pain (VAS 1.6 versus 1/10), mobility (opposition 9.44 versus 9.31; commissural opening 35.2 degrees versus 37.2 degrees ) or strength (Jamar 19.1kg/F versus 16.8kg/F, pinch 4.35kg/F versus 4.67kg/F). DASH score was 16.9 and 25.1/100 respectively. We deplore three symapthetic reflex dystrophies in group A and seven radiological subluxations of the implant in group B. The total trapeziectomy with suspensioplasty gave satisfactory results for both series. The implant Pi2((r)) seems to contribute keeping trapezial height, without functional advantages and with a risk of dislocation. PMID- 23726151 TI - Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. AB - Traditional antidepressants require many weeks to reveal their therapeutic effects. However, the widely replicated observation that a single subanesthetic dose of the N-methyl-D-aspartate glutamate receptor antagonist ketamine produced meaningful clinical improvement within hours, suggested that rapid-acting antidepressants might be possible. The ketamine studies stimulated a new generation of basic antidepressant research that identified new neural signaling mechanisms in antidepressant response and provided a conceptual framework linking a group of novel antidepressant mechanisms. This article presents the path that led to the testing of ketamine, considers its promise as an antidepressant, and reviews novel treatment mechanisms that are emerging from this line of research. PMID- 23726152 TI - From pathophysiology to novel antidepressant drugs: glial contributions to the pathology and treatment of mood disorders. AB - Several structural and cellular changes, including marked glial anomalies, have been observed in association with major depressive disorder. Here we review these cellular alterations and highlight the importance of glial cell pathology, especially astroglial dysfunction, in the pathophysiology of neuropsychiatric disorders with a particular interest in major depressive disorder. The functional role of astrocytes in glutamate uptake and glutamate/glutamine cycling is discussed, as is the deleterious effects of chronic stress on glial cell function. Lastly, we discuss the effect of antidepressants on glial cell function and the possibility of targeting glial cells in the quest to develop novel therapeutics. PMID- 23726153 TI - Nano-sized polymers and liposomes designed to deliver combination therapy for cancer. AB - The standard of care for cancer patients comprises more than one therapeutic agent. Treatment is complex since several drugs, administered by different routes, need to be coordinated, taking into consideration their side effects and mechanisms of resistance. Drug delivery systems (DDS), such as polymers and liposomes, are designed to improve the pharmacokinetics and efficacy of bioactive agents (drugs, proteins or oligonucleotides), while reducing systemic toxicity. Using DDS for co-delivery of several agents holds great potential since it targets simultaneously synergistic therapeutic agents increasing their selective accumulation at the tumor site and enhancing their activity allowing administration of lower doses of each agent, thus reducing their side effects. Taken together, implementation of smart DDS will hopefully result in increased patient's compliance and better outcome. This review will focus on the latest developments of combination therapy for cancer using DDS. PMID- 23726155 TI - New approaches to an age-old problem. AB - Progress in the last decades indicated that ageing might be a universal fact of life. However, the molecular mechanisms underlying this process remain a major challenge in biology. Our relatively long life span and huge variations in lifestyle make detailed studies of ageing in humans difficult to interpret. In contrast, the relatively simple yeast Saccharomyces cerevisiae (budding yeast) has been a critical model in the field of ageing research for decades. Systems biology has contributed to the ageing field by mapping complex regulatory networks and resolving the dynamics of signal transduction pathways. In this review we first review the current understanding of ageing in yeast, then highlight the recent high-throughput systems and system biology approaches that could be used to further our understanding of ageing in yeast. PMID- 23726154 TI - Metabolic flux rewiring in mammalian cell cultures. AB - Continuous cell lines (CCLs) engage in 'wasteful' glucose and glutamine metabolism that leads to accumulation of inhibitory byproducts, primarily lactate and ammonium. Advances in techniques for mapping intracellular carbon fluxes and profiling global changes in enzyme expression have led to a deeper understanding of the molecular drivers underlying these metabolic alterations. However, recent studies have revealed that CCLs are not necessarily entrenched in a glycolytic or glutaminolytic phenotype, but instead can shift their metabolism toward increased oxidative metabolism as nutrients become depleted and/or growth rate slows. Progress to understand dynamic flux regulation in CCLs has enabled the development of novel strategies to force cultures into desirable metabolic phenotypes, by combining fed-batch feeding strategies with direct metabolic engineering of host cells. PMID- 23726156 TI - Extracellular matrix signaling in morphogenesis and repair. AB - The extracellular matrix (ECM) is critically important for many cellular processes including growth, differentiation, survival, and morphogenesis. Cells remodel and reshape the ECM by degrading and reassembling it, playing an active role in sculpting their surrounding environment and directing their own phenotypes. Both mechanical and biochemical molecules influence ECM dynamics in multiple ways; by releasing small bioactive signaling molecules, releasing growth factors stored within the ECM, eliciting structural changes to matrix proteins which expose cryptic sites and by degrading matrix proteins directly. The dynamic reciprocal communication between cells and the ECM plays a fundamental roll in tissue development, homeostasis, and wound healing. PMID- 23726157 TI - High-fat diet and age-dependent effects on enteric glial cell populations of mouse small intestine. AB - Diabetes and obesity are increasing in prevalence at an alarming rate throughout the world. Autonomic diabetic neuropathy is evident in individuals that experience a long-standing diabetic disease state, and gastrointestinal (GI) dysmotility is thought to be the outcome of neuropathies within the enteric nervous system (ENS) of these patients. To date, an analysis of enteric glial cell population changes during diabetic symptoms has not been performed, and may bring insight into disease pathology and neuropathy, given glial cell implications in gastrointestinal and neuronal homeostasis. Diabetes and obesity were monitored in C57Bl/6J mice fed a 72% high-fat diet, and duodenal glial expression patterns were evaluated by immunohistochemistry and RT-PCR for S100beta, Sox10 and GFAP proteins and transcripts, as well as transmission electron microscopy (TEM). The high-fat diet caused obesity, hyperglycemia and insulin resistance after 4 weeks. These changes were associated with a significant decline in the area density indices of mucosa-associated glial cell networks, evidenced by S100beta staining at 8 and 20 weeks. All three markers and TEM showed that myenteric glial cells were unaffected by early and late disease periods. However, analysis of Sox10 transcript expression and immunoreactivity showed a diet independent, age-associated decline in glial cell populations. This is the first study showing that mucosal glia cell damage occurs during diabetic symptoms, suggesting that mucosal enteric glia injury may have a pathophysiological significance during this disease. Our results also provide support for age-associated changes in longitudinal studies of enteric glial cells. PMID- 23726158 TI - Our common vision for the positioning and role of health to advance the UN development agenda beyond 2015. PMID- 23726160 TI - An optimum blood pressure target after lacunar stroke? PMID- 23726161 TI - Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo controlled, phase 3 trial. AB - BACKGROUND: A vaccine for enterovirus 71 (EV71) is needed to address the high burden of disease associated with infection. We assessed the efficacy, safety, immunogenicity, antibody persistence, and immunological correlates of an inactivated alum-adjuvant EV71 vaccine. METHODS: We did a randomised, double blind, placebo-controlled, phase 3 trial. Healthy children aged 6-35 months from four centres in China were randomly assigned (1:1) to receive vaccine or alum adjuvant placebo at day 0 and 28, according to a randomisation list (block size 30) generated by an independent statistician. Investigators and participants and their guardians were masked to the assignment. Primary endpoints were EV71 associated hand, foot, and mouth disease (HFMD) and EV71-associated disease during the surveillance period from day 56 to month 14, analysed in the per protocol population. This study is registered with ClinicalTrials.gov, number NCT01508247. FINDINGS: 10,245 participants were enrolled and assigned: 5120 to vaccine versus 5125 to placebo. 4907 (with three cases of EV71-associated HFMD and eight cases of EV71-associated disease) versus 4939 (with 30 cases of EV71 associated HFMD and 41 cases of EV71-associated disease) were included in the primary efficacy analysis. Vaccine efficacy was 90.0% (95% CI 67.1-96.9) against EV71-associated HFMD (p=0.0001) and 80.4% (95% CI 58.2-90.8) against EV71 associated disease (p<0.0001). Serious adverse events were reported by 62 of 5117 (1.2%) participants in the vaccine group versus 75 of 5123 (1.5%) in the placebo group (p=0.27). Adverse events occurred in 3644 (71.2%) versus 3603 (70.3%; p=0.33). INTERPRETATION: EV71 vaccine provides high efficacy, satisfactory safety, and sustained immunogenicity. FUNDING: China's 12-5 National Major Infectious Disease Program, Beijing Vigoo Biological. PMID- 23726162 TI - The Global Drug Facility and its role in the market for tuberculosis drugs. AB - Universal access to high-quality treatment is central to the Global Plan to Stop TB. The Global Drug Facility (GDF) was launched in 2001 to help to achieve this goal, through services including the supply of affordable, quality-assured drugs to countries in need. We assess the scale of GDF drug supplies worldwide and find that the GDF commands a substantial proportion of the market for drugs for first line and second-line treatment regimens, having supplied, for example, first-line drugs for roughly 35% of cases reported worldwide in 2011. Significant potential remains for GDF expansion, especially in the provision of second-line drugs, which would be aided by future increases in case detection. PMID- 23726163 TI - EV71 vaccine: protection from a previously neglected disease. PMID- 23726164 TI - Transperitoneal laparoscopic radical nephrectomy in a patient with severe scoliosis. AB - OBJECTIVE: To report the first case of a left transperitoneal laparoscopic nephrectomy in a patient with a severe left convex lumbar scoliosis and to elaborate on the technical difficulties of this procedure. METHODS: The surgical procedure was performed by an experienced laparoscopic surgeon after rigorous pre operative visualization of the altered visceral and vascular abdominal anatomy. A transperitoneal laparoscopic approach with an open introduction technique according to Hasson and a caudo-cranial dissection of the left renal hilum were performed to prevent major vascular and visceral injury in this challenging surgical procedure. RESULTS: The operation time was 102 minutes and the estimated blood loss was 100 mL. The surgeon was able to complete the transperitoneal laparoscopic radical nephrectomy without complications. CONCLUSION: Transperitoneal laparoscopic radical nephrectomy in patients with severe spinal deformities is feasible, but should only be performed by experienced laparoscopic surgeons to ensure patient safety and cancer control. PMID- 23726166 TI - Primary epithelioid hemangioendothelioma of the kidney: the first case report in a child and literature review. AB - Epithelioid hemangioendothelioma is a distinct vascular tumor with low malignant biologic behavior that is very rare in the kidney. Only 3 adult patients have been reported to date in English-language reports. We report the case of a 9-year old boy who presented with painless gross hematuria. Magnetic resonance imaging and positron emission tomography-computed tomography demonstrated a primary mass in the left kidney. The pathologic diagnosis of the tumor was epithelioid hemangioendothelioma after radical nephrectomy. To the best of our knowledge, this is the first reported case of primary renal epithelioid hemangioendothelioma in the pediatric age group. PMID- 23726165 TI - Safe initiation of a laparoendoscopic single site living donor nephrectomy program in a small-volume transplant center. AB - OBJECTIVE: To describe keys to successful programmatic implementation of laparoendoscopic single-site (LESS)-living donor nephrectomy (LDN) in a small volume center. Laparoscopic LDN has become the standard of care. Technically challenging LESS-LDN has been limited to high-volume centers. However, approximately half of all U.S. transplant centers perform <=15 LDNs/year, including our center. METHODS: A hand-assisted laparoscopy (HAL) device was used as the LESS platform at a periumbilical midline incision. We used an adhesive drape to cover the platform to prevent gas leakage. A 30 degrees telescope and 3 4 instruments were inserted through its gel-cap. After careful dissection, the kidney was bagged into a recovery device with an external handle before its vessels were ligated with staples and was then removed immediately through the LESS wound. RESULTS: LESS-LDN was successful in all of 10 living donors without any multisite laparoscopic or open conversion and without any instruments inserted through extra wounds. No patient had perioperative complications or received transfusions. Median operative time was 271 minutes with a warm ischemia time (WIT) of 3.5 minutes. Hospital stay averaged 2 days with visual analog pain score 4 of 10 at discharge and 2 of 10 at 2 weeks. All recipients recuperated well with immediate graft function. CONCLUSION: Our LESS-LDN technique offers improved cosmesis, favorable perioperative outcomes, and versatile options for conversion, if necessary, making it a viable approach for small-volume centers. PMID- 23726167 TI - Predicting the clinical outcome of antenatally detected unilateral pelviureteric junction stenosis. AB - OBJECTIVE: To determine, in children with antenatally detected pelviureteric junction (PUJ) stenosis, what factors may be predictive for deterioration of differential renal function (DRF) in case of conservative treatment or improvement of DRF in case of pyeloplasty. METHODS: This study analyzed and compared the initial level of hydronephrosis, DRF, quality of renal drainage, and cortical transit with the late DRF outcome. We reviewed the medical charts of 161 consecutive children with antenatally diagnosed PUJ stenosis during a 10-year period (between 1997 and 2007). From this cohort, we retained 81 children with unilateral PUJ and strictly normal contralateral kidney, with a median follow-up of 67 months. Repeated ultrasounds, voiding cystourethrography, and radionuclide renograms were performed in all children. RESULTS: Fifty patients never underwent a surgical intervention (62%), whereas surgical repair (Anderson-Hynes dismembered pyeloplasty) was performed in 31 (38%). During conservative follow up, DRF deterioration was observed in 11% of patients. After pyeloplasty, DRF improvement was observed in 25% of patients. Abnormal cortical transit was the only predictive factor of DRF deterioration in case of conservative approach, whereas the initial degree of hydronephrosis, or renal drainage, and the initial DRF level were not predictive. In children who were operated on, only impaired cortical transit was predictive of DRF improvement postoperatively. CONCLUSION: Conservative management of children with unilateral PUJ stenosis is a safe procedure. Impaired cortical transit although imperfect, seems the best criterion for identifying children for whom pyeloplasty is warranted. PMID- 23726169 TI - Association between socioeconomic status and ectopic pregnancy rate in the Republic of Korea. AB - OBJECTIVE: To estimate the ectopic pregnancy rate in the Republic of Korea and to identify whether socioeconomic factors contribute to the incidence of ectopic pregnancy. METHODS: Korean National Health Insurance data from January to December 2009 were analyzed to calculate the rate of ectopic pregnancy. RESULTS: Among the patient sample (n=599186), 59261 had diagnosis codes for ectopic pregnancies, abortions, or deliveries, and 1102 ectopic pregnancies were identified. The frequency of ectopic pregnancy treated by either surgery or methotrexate was 16.60 per 1000 pregnancies. Low socioeconomic status was a risk factor for ectopic pregnancy (odds ratio [OR], 1.718; 95% confidence interval [CI], 1.065-2.772; P=0.03), as was older age (OR, 1.016; 95% CI, 0.998-1.033, P=0.07), although the association was not significant. Among women aged 25 44years, low socioeconomic status and age were associated with a high incidence of ectopic pregnancy (OR, 1.863; 95% CI, 1.074-3.233, P=0.03; and OR, 1.061; 95% CI, 1.041-1.081, P<0.01, respectively). Surgical and methotrexate treatment rates were 90.7% and 9.3%, respectively. The methotrexate failure rate was 30.7%. The recorded ectopic pregnancy sites were tubal or ovarian (90.2%), cornual (6.0%), cervical (2.8%), and abdominal (1.0%). CONCLUSION: Older age and low socioeconomic status were risk factors for ectopic pregnancy. PMID- 23726170 TI - A rare but classical cause of HIV infection discovery. PMID- 23726171 TI - Solid pseudopapillary neoplasm of the pancreas. PMID- 23726159 TI - Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. AB - BACKGROUND: Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown. We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke. METHODS: In this randomised open-label trial, eligible patients lived in North America, Latin America, and Spain and had recent, MRI-defined symptomatic lacunar infarctions. Patients were recruited between March, 2003, and April, 2011, and randomly assigned, according to a two-by-two multifactorial design, to a systolic-blood-pressure target of 130-149 mm Hg or less than 130 mm Hg. The primary endpoint was reduction in all stroke (including ischaemic strokes and intracranial haemorrhages). Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00059306. FINDINGS: 3020 enrolled patients, 1519 in the higher-target group and 1501 in the lower-target group, were followed up for a mean of 3.7 (SD 2.0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137-139) in the higher-target group and 127 mm Hg (95% CI 126-128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0.81, 95% CI 0.64-1.03, p=0.08), disabling or fatal stroke (0.81, 0.53-1.23, p=0.32), and the composite outcome of myocardial infarction or vascular death (0.84, 0.68-1.04, p=0.32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0.37, 0.15-0.95, p=0.03). Treatment related serious adverse events were infrequent. INTERPRETATION: Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial. FUNDING: National Institutes of Health National Institute of Neurological Disorders and Stroke (NIH-NINDS). PMID- 23726172 TI - CT diagnosis of small bowel perforation by ingestion of a blister pack: two case reports. PMID- 23726168 TI - A cytoprotective perspective on longevity regulation. AB - There are many mechanisms of lifespan extension, including the disruption of insulin/insulin-like growth factor 1 (IGF-1) signaling, metabolism, translation, and feeding. Despite the disparate functions of these pathways, inhibition of each induces responses that buffer stress and damage. Here, emphasizing data from genetic analyses in Caenorhabditis elegans, we explore the effectors and upstream regulatory components of numerous cytoprotective mechanisms activated as major elements of longevity programs, including detoxification, innate immunity, proteostasis, and oxidative stress response. We show that their induction underpins longevity extension across functionally diverse triggers and across species. Intertwined with the evolution of longevity, cytoprotective pathways are coupled to the surveillance of core cellular components, with important implications in normal and aberrant responses to drugs, chemicals, and pathogens. PMID- 23726173 TI - Comparison of incidence and predictors of left bundle branch block after transcatheter aortic valve implantation using the CoreValve versus the Edwards valve. AB - Conduction disorders and permanent pacemaker implantation are common complications in patients who undergo transcatheter aortic valve implantation (TAVI). The aim of this study was to assess the incidence and clinical significance of new bundle branch block in patients who underwent TAVI with the Medtronic CoreValve Revalving System (MCRS) or the Edwards SAPIEN valve (ESV). Data from 238 patients with no previous pacemaker implantation, left bundle branch block (LBBB) or right bundle branch block at baseline electrocardiography who underwent TAVI with either MCRS (n = 87) or ESV (n = 151) bioprostheses from 2007 to 2011 were analyzed. New-onset LBBB occurred in 26.5% patients (n = 63): 13.5% with the ESV (n = 20) and 50.0% with the MCRS (n = 43) (p = 0.001). Permanent pacemaker implantation was required in 12.7% of patients (n = 8) because of complete atrioventricular block (ESV n = 2, MCRS n = 4), LBBB and first degree atrioventricular block (MCRS n = 1) and new-onset LBBB associated with sinus bradycardia (MCRS n = 1). At discharge, LBBB persisted in 8.6% of ESV patients (n = 13) and 32.2% of MCRS patients (n = 28) (p = 0.001). On multivariate analysis, the only predictor of LBBB was MCRS use (odds ratio 7.2, 95% confidence interval 2.9 to 17.4, p <0.001). Persistent new-onset LBBB at discharge was not associated with overall (log-rank p = 0.42) or cardiovascular (log-rank p = 0.46) mortality. New-onset right bundle branch block was documented in 4.6% of patients (n = 11), with no statistically significant differences between the ESV and MCRS. In conclusion, new-onset LBBB is a frequent intraventricular conduction disturbance after TAVI with a higher incidence with the MCRS compared with the ESV. LBBB persists in most patients, but in this cohort, it was not a predictor of overall or cardiovascular mortality or permanent pacemaker implantation. PMID- 23726174 TI - Natural history of unoperated aortic stenosis during a 50-year period of cardiac valve replacement. AB - Although a number of publications have described the natural history of patients with aortic stenosis (AS), the definition of "natural history" varies widely. Those describing a large number of patients with AS without operative therapy with necropsy findings are rare. Two hundred sixty patients >15 years of age with AS were studied at necropsy over a 50-year period by the same investigator. Of the 260 patients, the valve in 37 (14%) was congenitally unicuspid, in 123 (47%), congenitally bicuspid, and in 100 (38%), tricuspid. Aortic valve structure varied with age of death (in years; unicuspid 52 +/- 17, bicuspid 63 +/- 12, and tricuspid 70 +/- 14 years); gender (men/women: unicuspid 95%/5%, bicuspid 78%/22%, and tricuspid 63%/37%), and frequency of calcium in the mitral valve annulus and epicardial coronary arteries. The patients with cardiac-related symptoms compared with those without were more likely to have a congenitally malformed valve (unicuspid 17% vs 12%; bicuspid 51% vs 29%; tricuspid 31% vs 60%; unadjusted p = 0.013), to die from cardiac disease (86% vs 54%; unadjusted p = 0.001), and to have larger hearts (mean cardiac weight 606 +/- 138 g vs 523 +/- 121 g; unadjusted p = 0.009) and a larger quantity of calcium in the aortic valve cusps. In conclusion, the length of survival in adults with AS is related to valve structure, gender, presence of cardiac-related symptoms, cardiac mass, and quantity of calcium in the aortic valve cusps. PMID- 23726175 TI - Effectiveness of moxonidine to reduce atrial fibrillation burden in hypertensive patients. AB - There is substantial evidence that the autonomic system plays an important part in the pathogenesis of atrial fibrillation (AF). It appears that, although some patients have a preponderantly sympathetic or vagal overactivation leading to AF, a combined sympathovagal drive is most commonly responsible for AF triggering. The purpose of this hypothesis-generating study was to test whether moxonidine, a centrally acting sympathoinhibitory agent, on top of optimal antihypertensive treatment, can lead to a decrease in AF burden in hypertensive patients with paroxysmal AF. This was a prospective, double-blind, 1-group, crossover study. Hypertensive patients with paroxysmal AF sequentially received treatment with placebo and moxonidine for two 6-week periods, respectively. The change in AF burden (measured as minutes of AF per day in three 48-hour Holter recordings) between the 2 treatment periods was the primary outcome measure. Fifty-six patients (median age 63.5 years, 35 men) were included. During moxonidine treatment, AF burden was reduced from 28.0 min/day (interquartile range [IQR] 15.0 to 57.8) to 16.5 min/day (IQR 4.0 to 36.3; p <0.01). European Heart Rhythm Association symptom severity class decreased from a median of 2.0 (IQR 1.0 to 2.0) to 1.0 (IQR 1.0 to 2.0; p = 0.01). Systolic blood pressure levels were similar in the 2 treatment periods, whereas diastolic blood pressure was lower (p <0.01) during moxonidine treatment. The most frequent complaint was dry mouth (28.6%). No serious adverse events were recorded. In conclusion, treatment with moxonidine, a centrally acting sympathoinhibitory agent, results in reduction of AF burden and alleviation of AF-related symptoms in hypertensive patients with paroxysmal AF. PMID- 23726176 TI - QRS duration on electrocardiography and cardiovascular mortality (from the National Health and Nutrition Examination Survey-III). AB - The relation of bundle branch block (BBB) with adverse outcome is controversial. We hypothesized that increased QRS duration is an independent predictor of cardiovascular (CV) mortality in a cross-sectional US population. This is a retrospective cohort study on prospectively collected data to assess the relationship between QRS duration on routine ECG and CV mortality. Participants included 8,527 patients with ECG data available from the National Health and Nutrition Examination Survey data set, representing 74,062,796 individuals in the United States. Mean age was 60.5 +/- 13.6 years. Most subjects were white (87%) and women (53%). During the follow-up period of 106,244.6 person-years, 1,433 CV deaths occurred. Multivariate analysis revealed that the highest quartile of QRS duration was associated with higher CV mortality than lowest quartile (hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.01 to 1.7, p = 0.04) after adjustment for established risk factors. Both left BBB (HR 2.4, 95% CI 1.3 to 4.7, p = 0.009) and right BBB (HR 1.90, 95% CI 1.2 to 3.0, p = 0.008) were significantly associated with increased CV mortality. The addition of the QRS duration in 10-millisecond increments to the Framingham Risk Score model resulted in 4.4% overall net reclassification improvement (95% CI 0.02 to 0.04; p = 0.00006). In conclusion, increased QRS duration was found to be an independent predictor of CV mortality in this cross-sectional US population. A model including QRS duration in addition to traditional risk factors was associated with improved CV risk prediction. PMID- 23726177 TI - Trends in the prevalence, awareness, treatment and control of high low density lipoprotein-cholesterol among United States adults from 1999-2000 through 2009 2010. AB - Marked increases in the awareness, treatment, and control of high low-density lipoprotein (LDL) cholesterol occurred among United States (US) adults from 1988 1994 to 1999-2004. An update to the Third Adult Treatment Panel guidelines was published in 2004, and it is unknown if these improvements have continued since the publication of these revised treatment recommendations. The aim of this study was to determine trends in the awareness, treatment, and control of high LDL cholesterol among US adults from 1999-2000 to 2009-2010 using nationally representative samples of US adults aged >=20 years from 6 consecutive National Health and Nutrition Examination Surveys (NHANES) in 1999-2000 (n = 1,659), 2001 2002 (n = 1,897), 2003-2004 (n = 1,698), 2005-2006 (n = 1,692), 2007-2008 (n = 2,044), and 2009-2010 (n = 2,318). LDL cholesterol was measured after an overnight fast, and high LDL cholesterol and controlled LDL cholesterol were defined using the 2004 updated Third Adult Treatment Panel guidelines. Awareness and treatment of high cholesterol were defined using self-report. Among US adults, the prevalence of high LDL cholesterol did not change from 1999-2000 (37.2%) to 2009-2010 (37.8%). Awareness of high LDL cholesterol increased from 48.9% in 1999-2000 to 62.8% in 2003-2004 but did not increase further through 2009-2010 (61.5%). Among those aware of having high LDL cholesterol, treatment increased from 41.3% in 1999-2000 to 72.6% in 2007-2008 and was 70.0% in 2009 2010. Among US adults receiving treatment for high LDL cholesterol, the percentage with controlled LDL cholesterol increased from 45.0% in 1999-2000 to 65.3% in 2005-2006 and had decreased slightly by 2009-2010 (63.6%). In conclusion, high LDL cholesterol remains common among US adults. Additional efforts are needed to prevent high LDL cholesterol and increase the awareness, treatment, and control of high LDL cholesterol among US adults. PMID- 23726178 TI - Efficacy of the CHADS2 scoring system to assess left atrial thrombogenic milieu risk before cardioversion of non-valvular atrial fibrillation. AB - The CHADS2 scoring system was found to be a good predictor for risk stratification of stroke in patients with atrial fibrillation. The effectiveness of this scoring system in assessing thrombogenic milieu before direct-current cardioversion has not yet fully been established on a large scale. In this study, data from 2,369 consecutive patients in whom transesophageal echocardiography was performed for screening before direct-current cardioversion from 1999 to 2008 were analyzed. Left atrial (LA) or LA appendage (LAA) thrombogenic milieu (spontaneous echo contrast, sludge, and thrombus) was investigated. The results were correlated with CHADS2 score findings. The mean age was 66 +/- 13 years, and the ratio of men to women was 2.2:1. CHADS2 scores of 0, 1, 2, 3, 4, 5 and 6 were present in 11%, 25%, 30%, 22%, 8%, 3%, and 1% of the studies, respectively. The prevalence of LA or LAA sludge or thrombus increased with increasing CHADS2 scores (2.3%, 7%, 8.5%, 9.9%, 12.3%, and 14.1% for scores of 0, 1, 2, 3, 4, and 5 or 6, respectively, p = 0.01). In a multivariate model, an ejection fraction <=20% was the best predictor of LA or LAA sludge or thrombus (odds ratio 2.99, p <0.001). In conclusion, transesophageal echocardiographic markers of thrombogenic milieu were highly correlated with increasing CHADS2 scores in patients who underwent transesophageal echocardiography-guided cardioversion. Giving more value to echocardiographic findings, such as the left ventricular ejection fraction, and its different levels (especially an ejection fraction <=20%) might improve the precision of the CHADS2 scoring scheme to predict thrombogenic milieu in the left atrium or LAA as a surrogate to cardioembolic risk in patients with atrial fibrillation. PMID- 23726179 TI - Comparison by meta-analysis of percutaneous coronary intervention versus coronary artery bypass grafting in patients with a mean age of >=70 years. AB - A paucity of published data evaluating the outcomes of older patients (age >=70 years) undergoing revascularization for unprotected left main coronary artery disease is available. We performed aggregate data meta-analyses of the clinical outcomes (all-cause mortality, nonfatal myocardial infarction, stroke, repeat revascularization, and major adverse cardiac and cerebrovascular events at 30 days and 12 and 22 months) in studies comparing percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with a mean age of >=70 years and unprotected left main coronary artery disease. A comprehensive, time-unlimited literature search to January 31, 2013 identified 10 studies with a total of 2,386 patients (PCI, n = 909; CABG, n = 1,477). Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using the random-effects model. The patients in the PCI group were more likely than those in the CABG group to present with acute coronary syndrome (59.6% vs 44.8%, p <0.001). PCI was associated with a shorter hospital stay (4.2 +/- 0.8 vs 8.3 +/- 0.01 days, p <0.001). No significant differences were found between PCI and CABG for all cause-mortality, nonfatal myocardial infarction, and major adverse cardiac and cerebrovascular events at 30 days and 12 and 22 months. However, PCI was associated with lower rates of stroke at 30 days (OR 0.14, 95% CI 0.02 to 0.76) and 12 months (OR 0.14, 95% CI 0.03 to 0.60) and higher rates of repeat revascularization at 22 months (OR 4.34, 95% CI 2.69 to 7.01). These findings were consistent with the findings from a subgroup analysis of patients aged >=75 years. In conclusion, older patients (age >=70 years) with unprotected left main coronary artery disease had comparable rates of all-cause mortality, nonfatal myocardial infarction, and major adverse cardiac and cerebrovascular events after PCI or CABG. The patients undergoing PCI had a shorter hospital stay and lower rates of early stroke; however, they experienced higher repeat revascularization rates at longer term follow-up. PMID- 23726182 TI - Correlation between back shape and spinal loads. AB - The purpose of this study was to determine the correlation between the back shape of the lumbar region and the spinal loads during activities performed in the sagittal plane. Measurements were performed in four subjects who had suffered from a compression fracture of a lumbar vertebral body which was treated with a telemeterized vertebral body replacement that is able to measure six load components in vivo. An Epionics SPINE measurement system was used to determine the lumbar lordosis angle. The relationship between the lordosis angle and the corresponding loads was quantified with the Spearman's rank correlation coefficient method. Measurements were performed during thirteen exercises in lying, standing or sitting. During upper body flexion, the force increased on average by approximately 285N and the lordosis angle decreased by 15 degrees . The change of the force for elevating 30N in one hand was on average approximately 190N and for the lordosis angle 2 degrees . Correlation coefficients greater than 0.6 were found for exercises that involved both large back shape and load changes, such as upper body flexion. A strong increase in spinal load can be associated with an increase or a decrease of the lordosis angle. Only for considerable changes of the lordosis angle in an upright body position was a strong correlation between lordosis angle and implant force found. PMID- 23726180 TI - Trends in the prevalence of hospitalization attributable to hypertensive diseases among United States adults aged 35 and older from 1980 to 2007. AB - We aimed to examine the trend in the prevalence of hospitalization attributable to hypertensive disease and its subtypes among United States adults aged >=35 years from 1980 to 2007. Data (n = 4,598,488,000 hospitalized cases) from the National Hospital Discharge Surveys were used to examine the trends of hospitalized patients with first (the reason for admission) and patients with any second to seventh (a co-morbid condition when admission) diagnosis of hypertensive disease (International Classification of Disease, 9th Revision, Clinical Modification: 401 to 405) by gender and geographic region. Age-adjusted rates of disease were calculated using the United States 2000 standard population. The results show that age-adjusted hospitalization rates due to first diagnosis of hypertensive disease increased from 1.74% to 2.06% in men (p <0.01), and from 2.0% to 2.09% in women (p = 0.06) from 1980 to 1981 to 2006 to 2007. Age adjusted rates due to any second to seventh diagnosis of hypertensive disease significantly increased from 7.06% to 35.09% in men (p <0.001), and from 7.88% to 31.98% (p <0.001) in women from 1980 to 1981 to 2006 to 2007. Patients with second to seventh diagnosis of essential hypertension and hypertensive chronic kidney disease had the highest and the second highest annual percent increases. Subjects living in the Southern region of the United States had the highest prevalence of hospitalization due to any second to seventh diagnosis of hypertensive disease compared with all other regions in 2006 to 2007. In conclusion, the prevalence of hospitalization due to hypertensive disease significantly increased in the United States from 1980 to 2007. PMID- 23726183 TI - Persons with unilateral lower-limb amputation have altered and asymmetric trunk mechanical and neuromuscular behaviors estimated using multidirectional trunk perturbations. AB - Among persons with unilateral lower-limb amputation (LLA), proximal compensations and preferential use of the sound limb during gait and movement may lead to chronic alterations and/or asymmetries in trunk mechanical and neuromuscular behaviors. Trunk stiffness, the magnitude and timing of maximum reflex force, and EMG reflex delays of superficial trunk muscles, were estimated here using multidirectional (anteriorly- and laterally-directed) position-controlled horizontal trunk perturbations (+/-5mm, applied at T8) with the pelvis immobilized. Alterations and asymmetries in these trunk behaviors were quantified and compared among eight males with unilateral LLA, and eight male non-amputation controls. During anteriorly-directed perturbations, trunk stiffness and maximum reflex force were 24% and 23% lower, respectively, among participants with LLA compared to non-amputation controls, and the timing of maximum reflex force was 8% later. During lateral perturbations, trunk stiffness and maximum reflex force were also significantly lower among participants with LLA, by 22% and 27%, respectively. Bilateral asymmetries were present in trunk stiffness and the timing of maximum reflex force among persons with LLA. Specifically, trunk stiffness was 20% lower and timing of maximum reflex force was 9% later during perturbations involving spinal tissues and muscles ipsilateral to the side of amputation. Reduced and asymmetric trunk mechanical and neuromuscular behaviors may suggest a condition of reduced trunk stability among individuals with LLA, which could be due to repeated exposure to altered and asymmetric gait and movement and/or compensatory muscle recruitment in response to lost or altered musculature subsequent to LLA. PMID- 23726185 TI - "Thermal inactivation of campylobacter jejuni in broth," a comment on: J. Food Prot. 75(6):1029-1035 (2012). PMID- 23726184 TI - Ultrasonic characterization of the nonlinear properties of canine livers by measuring shear wave speed and axial strain with increasing portal venous pressure. AB - Elevated hepatic venous pressure is the primary source of complications in advancing liver disease. Ultrasound imaging is ideal for potential noninvasive hepatic pressure measurements as it is widely used for liver imaging. Specifically, ultrasound based stiffness measures may be useful for clinically monitoring pressure, but the mechanism by which liver stiffness increases with hepatic pressure has not been well characterized. This study is designed to elucidate the nonlinear properties of the liver during pressurization by measuring both hepatic shear wave speed (SWS) and strain with increasing pressure. Tissue deformation during hepatic pressurization was tracked in 8 canine livers using successively acquired 3-D B-mode volumes and compared with concurrently measured SWS. When portal venous pressure was increased from clinically normal (0-5mmHg) to pressures representing highly diseased states at 20mmHg, the liver was observed to expand with axial strain measures up to 10%. At the same time, SWS estimates were observed to increase from 1.5-2m/s at 0-5mmHg (baseline) to 3.25-3.5m/s at 20mmHg. PMID- 23726186 TI - Recalls of foods due to microbiological contamination classified by the U.S. Food and Drug Administration, fiscal years 2003 through 2011. AB - Recalls of foods contaminated with pathogens help reduce the transmission of infectious diseases. Here, we summarize the number and nature of foods recalled as a result of microbiological contamination, classified by the U.S. Food and Drug Administration for the period 1 October 2002 through 30 September 2011. Microbiological contamination accounted for 1,395 (42%) of 3,360 recalls of food during this period. Nuts and edible seeds, followed by fishery-seafood products and spices, were the types of products most commonly recalled for microbiological contamination. Salmonella contamination accounted for the greatest number of food products recalled due to microbiological contamination, and was the pathogen most often linked to reported outbreaks involving recalled food products. PMID- 23726187 TI - Multistate outbreak of Escherichia coli O145 infections associated with romaine lettuce consumption, 2010. AB - Non-O157 Shiga toxin-producing Escherichia coli (STEC) can cause severe illness, including hemolytic uremic syndrome (HUS). STEC O145 is the sixth most commonly reported non-O157 STEC in the United States, although outbreaks have been infrequent. In April and May 2010, we investigated a multistate outbreak of STEC O145 infection. Confirmed cases were STEC O145 infections with isolate pulsed field gel electrophoresis patterns indistinguishable from those of the outbreak strain. Probable cases were STEC O145 infections or HUS in persons who were epidemiologically linked. Case-control studies were conducted in Michigan and Ohio; food exposures were analyzed at the restaurant, menu, and ingredient level. Environmental inspections were conducted in implicated food establishments, and food samples were collected and tested. To characterize clinical findings associated with infections, we conducted a chart review for case patients who sought medical care. We identified 27 confirmed and 4 probable cases from five states. Of these, 14 (45%) were hospitalized, 3 (10%) developed HUS, and none died. Among two case-control studies conducted, illness was significantly associated with consumption of shredded romaine lettuce in Michigan (odds ratio [OR] = undefined; 95% confidence interval [CI] = 1.6 to undefined) and Ohio (OR = 10.9; 95% CI = 3.1 to 40.5). Samples from an unopened bag of shredded romaine lettuce yielded the predominant outbreak strain. Of 15 case patients included in the chart review, 14 (93%) had diarrhea and abdominal cramps and 11 (73%) developed bloody diarrhea. This report documents the first foodborne outbreak of STEC O145 infections in the United States. Current surveillance efforts focus primarily on E. coli O157 infections; however, non-O157 STEC can cause similar disease and outbreaks, and efforts should be made to identify both O157 and non O157 STEC infections. Providers should test all patients with bloody diarrhea for both non-O157 and O157 STEC. PMID- 23726188 TI - Modeling uncertainty of estimated illnesses attributed to non-O157:H7 Shiga toxin producing escherichia coli and its impact on illness cost. AB - Because of numerous reported foodborne illness cases due to non-O157:H7 Shiga toxin-producing Escherichia coli (STEC) bacteria in the United States and elsewhere, interest in requiring better control of these pathogens in the food supply has increased. Successfully putting forth regulations depends upon cost benefit analyses. Policy decisions often depend upon an evaluation of the uncertainty of the estimates used in such an analysis. This article presents an approach for estimating the uncertainties of estimated expected cost per illness and total annual costs of non-O157 STEC-related illnesses due to uncertainties associated with (i) recent FoodNet data and (ii) methodology proposed by Scallan et al. in 2011. The FoodNet data categorize illnesses regarding hospitalization and death. We obtained the illness-category costs from the foodborne illness cost calculator of the U.S. Department of Agriculture, Economic Research Service. Our approach for estimating attendant uncertainties differs from that of Scallan et al. because we used a classical bootstrap procedure for estimating uncertainty of an estimated parameter value (e.g., mean value), reflecting the design of the FoodNet database, whereas the other approach results in an uncertainty distribution that includes an extraneous contribution due to the underlying variability of the distribution of illnesses among different sites. For data covering 2005 through 2010, we estimate that the average cost per illness was about $450, with a 98% credible interval of $230 to $1,000. This estimate and range are based on estimations of about one death and 100 hospitalizations per 34,000 illnesses. Our estimate of the total annual cost is about $51 million, with a 98% credible interval of $19 million to $122 million. The uncertainty distribution for total annual cost is approximated well by a lognormal distribution, with mean and standard deviations for the log-transformed costs of 10.765 and 0.390, respectively. PMID- 23726189 TI - Development and validation of a mathematical model for growth of pathogens in cut melons. AB - Many outbreaks of foodborne illness associated with the consumption of fresh-cut melons have been reported. The objective of our research was to develop a mathematical model that predicts the growth rate of Salmonella on fresh-cut cantaloupe over a range of storage temperatures and to validate that model by using Salmonella and Escherichia coli O157:H7 on cantaloupe, honeydew, and watermelon, using both new data and data from the published studies. The growth of Salmonella on honeydew and watermelon and E. coli O157:H7 on cantaloupe, honeydew, and watermelon was monitored at temperatures of 4 to 25 degrees C. The Ratkowsky (or square-root model) was used to describe Salmonella growth on cantaloupe as a function of storage temperature. Our results show that the levels of Salmonella on fresh-cut cantaloupe with an initial load of 3 log CFU/g can reach over 7 log CFU/g at 25 degrees C within 24 h. No growth was observed at 4 degrees C. A linear correlation was observed between the square root of Salmonella growth rate and temperature, such that ?growth rate = 0.026 * (T - 5.613), R(2) = 0.9779. The model was generally suitable for predicting the growth of both Salmonella and E. coli O157:H7 on cantaloupe, honeydew, and watermelon, for both new data and data from the published literature. When compared with existing models for growth of Salmonella, the new model predicts a theoretic minimum growth temperature similar to the ComBase Predictive Models and Pathogen Modeling Program models but lower than other food-specific models. The ComBase Prediction Models results are very similar to the model developed in this study. Our research confirms that Salmonella can grow quickly and reach high concentrations when cut cantaloupe is stored at ambient temperatures, without visual signs of spoilage. Our model provides a fast and cost-effective method to estimate the effects of storage temperature on fresh-cut melon safety and could also be used in subsequent quantitative microbial risk assessments. PMID- 23726190 TI - Absence of direct association between coliforms and Escherichia coli in irrigation water and on produce. AB - Irrigation water is considered a potential source of preharvest pathogen contamination of vegetables. Hence, several organizations have recommended microbiological standards for water used to irrigate edible plants. The purpose of this study was to determine the strength of association between microbial quality indicators (coliforms and Escherichia coli) in irrigation water and on irrigated vegetables. Data analyzed included original results from a cross sectional study conducted in the Midwestern United States during summer 2009 and information presented in two previously published studies performed in France and Portugal to investigate microbial quality of irrigation water and watered produce. In the cross-sectional study, repetitive PCR (rep-PCR) was used to characterize genetic relatedness of E. coli isolates from water and vegetables. No significant correlations were found between fecal indicators on leafy greens (lettuce and parsley, n = 91) or fruit (tomatoes and green peppers, n = 22) and those found in irrigation water used in the cross-sectional study (P > 0.40) or in the previously published data sets (data set 1: lettuce and waste irrigation water, n = 15, P > 0.40; data set 2: lettuce and irrigation water, n = 32, P = 0.06). Rep-PCR banding patterns of E. coli strains were all distinguishable among the pairs of E. coli isolates recovered from produce and irrigation water on the same farm. From the available data, the concentration of indicator organisms based on a single measure of irrigation water quality was not associated with the presence of these indicators on produce. In the absence of additional information, the use of a single microbial water quality parameter as an indicator of produce safety is of limited value for predicting the safety of the produce. PMID- 23726191 TI - Comparing source of agricultural contact water and the presence of fecal indicator organisms on the surface of 'juliet' grape tomatoes. AB - Consumption of fresh tomatoes (Solanum lycopersicum) has been implicated as the cause of several foodborne illness outbreaks in the United States, most notably in cases of salmonellosis. How the levels of fecal indicator organisms (FIOs) in water relate to the counts of these microorganisms on the tomato fruit surface is unknown, although microbial water quality standards exist for agricultural use. This study utilized four types of FIOs currently and historically used in microbial water quality standards (Enterobacteriaceae, total coliforms, fecal coliforms, and Escherichia coli) to monitor the water quality of two surface ponds and a groundwater source. The groundwater tested contained significantly lower counts of all FIOs than the two surface water sources (P < 0.05). Considerable variability in bacterial counts was found in the surface water sources over the course of the season, perhaps explained by environmental variables, such as water temperature, pH, precipitation, and air temperature (R(2) of 0.13 to 0.27). We also monitored the fruit surface of grape tomatoes treated with overhead applications of the different water sources over the 2009 and 2010 growing seasons. The type of water source and time of year significantly affected the populations of FIOs in irrigation water (P < 0.05). Despite up to 5 log differences in fecal coliforms and 3-log differences in E. coli between the water sources, there was little difference in the populations measured in washes taken from tomato fruits. This lack of association between the aforementioned FIOs present in the water samples and on the tomato fruit surface demonstrates the difficulty in developing reliable metrics needed for testing of agricultural water to ensure the effectiveness of food safety programs. PMID- 23726192 TI - Microbiological performance of dairy processing plants is influenced by scale of production and the implemented food safety management system: a case study. AB - The effects of existing food safety management systems and size of the production facility on microbiological quality in the dairy industry in Kenya were studied. A microbial assessment scheme was used to evaluate 14 dairies in Nairobi and its environs, and their performance was compared based on their size and on whether they were implementing hazard analysis critical control point (HACCP) systems and International Organization for Standardization (ISO) 22000 recommendations. Environmental samples from critical sampling locations, i.e., workers' hands and food contact surfaces, and from end products were analyzed for microbial quality, including hygiene indicators and pathogens. Microbial safety level profiles (MSLPs) were constructed from the microbiological data to obtain an overview of contamination. The maximum MSLP score for environmental samples was 18 (six microbiological parameters, each with a maximum MSLP score of 3) and that for end products was 15 (five microbiological parameters). Three dairies (two large scale and one medium scale; 21% of total) achieved the maximum MSLP scores of 18 for environmental samples and 15 for the end product. Escherichia coli was detected on food contact surfaces in three dairies, all of which were small scale dairies, and the microorganism was also present in end product samples from two of these dairies, an indication of cross-contamination. Microbial quality was poorest in small scale dairies. Most operations in these dairies were manual, with minimal system documentation. Noncompliance with hygienic practices such as hand washing and cleaning and disinfection procedures, which is common in small dairies, directly affects the microbial quality of the end products. Dairies implementing HACCP systems or ISO 22000 recommendations achieved maximum MSLP scores and hence produced safer products. PMID- 23726193 TI - Microbiological safety of domestic refrigerators and the dishcloths used to clean them in Guadalajara, Jalisco, Mexico. AB - Household refrigerators are a potential pathogen contamination source for foods. An evaluation of the microbiological safety of 200 refrigerators in Guadalajara, Jalisco, Mexico, was made by visual inspection, ATP-bioluminescence levels, indicator microorganisms including Escherichia coli and Staphylococcus aureus, and the presence of Listeria monocytogenes and Salmonella. Additionally, interviews of the owners of the refrigerators were carried out to determine relationships between food storage practices, demographic aspects, and microbiological status. Dishcloths used to clean refrigerators were also analyzed. Operational conditions (cleanliness, fullness, organization, frequency of cleaning, and temperature) were evaluated by trained observers. Results showed deficient cleanliness in 55% of refrigerators, 22% were completely full, 43% very disorganized, 28% were usually cleaned only once in 3 to 6 months, and 53% had internal temperatures >7.1 degrees C. ATP-bioluminescence levels were >300 relative light units on 67 and 74% of shelves and drawers, respectively, indicating that surfaces were dirty according to the luminometer manufacturer. Psychrotrophic aerobic bacteria counts on shelves, drawers, and dishcloths were 6.3, 5.2, and 6.3 log CFU/cm(2); for coliform bacteria, 5.2, 3.9, and 4.7 CFU/cm(2); for E. coli, 3.7, 3.5, and 4.8 CFU/cm(2); and for Staphylococcus aureus, 2.1, 2.5, and 2.3 CFU/cm(2), respectively. L. monocytogenes and Salmonella were isolated from 59.5, 20.5, and 17% and 32.5, 8.0 and 12.5% of shelves, drawers, and dishcloths, respectively. Four Salmonella serotypes and nine serogroups (partially serotyped isolates) were identified. The most prevalent were Salmonella Anatum (39.5%), Salmonella group E1 (19.7%), and Salmonella group E1 monophasic (12.5%). Operational conditions and microbiological status were clearly deficient in sampled refrigerators, highlighting the consequent risk of foodborne disease among users. Educational programs are needed to improve the domestic food safety in Mexico. PMID- 23726194 TI - Screening of Lactobacillus isolated from pork sausages for potential probiotic use and evaluation of the microbiological safety of fermented products. AB - The aim of this study was to select strains of Lactobacillus isolated from pork sausage for use as probiotics. Lactobacillus isolates were evaluated in tests based on probiotic characteristics and microbiological safety. The UFLA SAU 14, 52, and 91 isolates were differentiated by coaggregation with Listeria monocytogenes, production of lactic acid, and survival at pH 2. UFLA SAU 172 and 187 isolates had high levels of coaggregation with Salmonella Typhi and Escherichia coli, tolerance to pancreatic fluid, and adhesion to chloroform. UFLA SAU 20 and 34 isolates were characterized by exopolysaccharide production, autoaggregation, and resistance to simulated intestinal fluid. UFLA SAU 185, 238, and 258 isolates exhibited resistance to bile and adhesion to xylene. A cocktail of these 10 Lactobacillus isolates with potential probiotic properties was inoculated into pork sausage and inhibited the growth of L. monocytogenes. PMID- 23726195 TI - Method for rapid detection and identification of chaetomium and evaluation of resistance to peracetic acid. AB - In the beverage industry, peracetic acid has been increasingly used as a disinfectant for the filling machinery and environment due to merits of leaving no residue, it is safe for humans, and its antiseptic effect against fungi and endospores of bacteria. Recently, Chaetomium globosum and Chaetomium funicola were reported resistant to peracetic acid; however, little is known concerning the detail of peracetic acid resistance. Therefore, we assessed the peracetic acid resistance of the species of Chaetomium and related genera under identical conditions and made a thorough observation of the microstructure of their ascospores by transmission electron microscopy. The results of analyses revealed that C. globosum and C. funicola showed the high resistance to peracetic acid (a 1-D antiseptic effect after 900 s and 3-D antiseptic effect after 900 s) and had thick cell walls of ascospores that can impede the action mechanism of peracetic acid. We also developed specific primers to detect the C. globosum clade and identify C. funicola by using PCR to amplify the beta-tubulin gene. PCR with the primer sets designed for C. globosum (Chae 4F/4R) and C. funicola (Cfu 2F/2R) amplified PCR products specific for the C. globosum clade and C. funicola, respectively. PCR with these two primer sets did not detect other fungi involved in food spoilage and environmental contamination. This detection and identification method is rapid and simple, with extremely high specificity. PMID- 23726196 TI - Virus inactivation on hard surfaces or in suspension by chemical disinfectants: systematic review and meta-analysis of norovirus surrogates. AB - Norovirus (NoV) infections are the leading cause of foodborne illness in the United States. Effective disinfection is important for controlling outbreaks caused by this highly infectious virus but can be difficult to achieve because NoV is very resistant to many common disinfection protocols. The inability of human NoV to replicate in tissue culture complicates NoV research, generally necessitating genome copy quantification, the use of surrogate viruses, or the use of other substitutes such as virus-like particles. To date, comprehensive comparisons among NoV surrogates and between surrogates and human NoV are missing, and it is not clear how best to extrapolate information from surrogate data. We conducted a systematic review and meta-analysis of comparisons of NoV surrogates with regard to their susceptibility to disinfection on hard surfaces or in suspension. Restricting our analysis to those studies in which two or more virus surrogates were compared allowed us to improve the signal-to-noise ratio in our analysis, similar to the epidemiological concept of matching. Using meta analysis methods, our results indicate that hepatitis A virus, murine norovirus 1, and phage MS2 are significantly more resistant to disinfection than is feline calicivirus, but average differences in viral titer reduction appeared to be modest, 1.5 log PFU or less in all cases. None of the studies that compared surrogates and human NoV met our inclusion criteria, precluding a direct comparison between human NoV and NoV surrogates in this study. For all surrogates with sufficient data available to permit subgroup analyses, we detected strong evidence that the type of disinfectant impacted the relative susceptibility of the surrogates. Therefore, extrapolation of results between surrogates or from surrogates to human NoV must consider the type of disinfectant studied. PMID- 23726197 TI - Accreditation of a screening method for non-dioxin-like polychlorinated biphenyl detection in fishery products according to European legislation. AB - European Commission Regulation 882/2004/EC requires that official control laboratories for foodstuffs in the member states are certified according to UNI EN ISO/IEC 17025:2005 (general requirement for the competence of calibration and testing laboratories). This mandatory requirement has resulted in a continuous adaptation and development of analytical procedures. The aim of this study was to develop a method for semiquantitative screening of polychlorinated biphenyls in fish for human consumption. According to the Commission Decision 657/2002/CE, the detection capability, the precision, the selectivity-specificity, and applicability-ruggedness-stability were determined to validate the method. Moreover, trueness was verified. This procedure resulted in rapid execution, which allowed immediate and effective intervention by the local health authorities to protect the health of consumers. Finally, the procedure has been recognized by the Italian accrediting body, ACCREDIA. PMID- 23726198 TI - Distribution of radioactive cesium ((134)Cs Plus(137)Cs) in a contaminated Japanese soybean cultivar during the preparation of tofu, natto, and nimame (Boiled Soybean). AB - We investigated the fate of radioactive cesium ((134)Cs plus (137)Cs) during the production of tofu, natto, and nimame (boiled soybean) from a contaminated Japanese soybean cultivar harvested in FY2011. Tofu, natto, and nimame were made from soybean grains containing radioactive cesium (240 to 340 Bq/kg [dry weight]), and the radioactive cesium in the processed soybean foods and in by product fractions such as okara, broth, and waste water was measured with a germanium semiconductor detector. The processing factor is the ratio of radioactive cesium concentration of a product before and after processing. For tofu, natto, nimame, and for the by-product okara, processing factors were 0.12, 0.40, 0.20, and 0.18, respectively; this suggested that these three soybean foods and okara, used mainly as an animal feed, can be considered safe for human and animal consumption according to the standard limit for radioactive cesium of soybean grains. Furthermore, the ratio of radioactive cesium concentrations in the cotyledon, hypocotyl, and seed coat portions of the soybean grain was found to be approximately 1:1:0.4. PMID- 23726199 TI - Effect of lime juice on Vibrio parahaemolyticus and Salmonella enterica inactivation during the preparation of the raw fish dish ceviche. AB - Ceviche is a raw fish dish common in Peru and other Latin American counties. The most characteristic feature of ceviche is the use of lime juice for marinating or "cooking" the raw fish. Confirmed cases of cholera in Peru, New Jersey, and Florida have been associated with ceviche. Although the effect of organic acids on pathogenic bacteria has been well characterized, few data exist on the effect of these acids in seafood systems. The objective of the study was to evaluate the effects of lime juice marination on pathogens likely to be present in ceviche. Tilapia (Oreochromis niloticus) fillet pieces were inoculated with Vibrio parahaemolyticus and Salmonella enterica (>7 log CFU/g) and incubated at 25 and 4 degrees C for 30 or 120 min in the presence of fresh lime juice at concentrations typical for the preparation of ceviche. Similar levels of cells were also inoculated into fresh lime juice without tilapia. Surviving cells were enumerated on selective (xylose lysine Tergitol 4 and thiosulfate-bile-citrate-sucrose) and nonselective (tryptic soy agar) media. V. parahaemolyticus levels were reduced to below detection limits (~5-log reduction) under all conditions studied. Salmonella strains on tilapia were much more resistant to inactivation and were only slightly reduced (~1- to 2-log reduction). Salmonella and V. parahaemolyticus inoculated directly into lime juice without tilapia were all reduced to below detection limits (~5-log reduction). A typical ceviche recipe reduces V. parahaemolyticus risk significantly but is less effective for control of S. enterica. PMID- 23726200 TI - Chlorine inactivation of nonresistant and antibiotic-resistant strains of salmonella typhimurium isolated from chicken carcasses. AB - A study was conducted to test the hypothesis that strains of Salmonella Typhimurium that are resistant to antibiotics are more resistant to chlorine in chilled water than strains of Salmonella Typhimurium that are not resistant to antibiotics. To test this hypothesis, strains (n = 16) of Salmonella Typhimurium with four antibiotic resistance profiles were tested for their inactivation kinetics in chlorinated (30 ppm, pH 6) water at 4 degrees C. The four antibiotic resistance profiles were (i) none; (ii) tetracycline-sulfisoxazole (T-Su); (iii) tetracycline-ampicillin-amoxicillin-cefoxitin-ceftiofur-sulfisoxazole (T-A-Am-C Ce-Su); and (iv) tetracycline-ampicillin-amoxicillin-cefoxitin-ceftiofur sulfisoxazole-kanamycin (T-A-Am-C-Ce-Su-K). Inactivation of Salmonella Typhimurium in chlorinated water displayed nonlinear kinetics with a concave downward curve that fit well (R(2) = 0.964) to the power law model, with a shape parameter of 1.37. The time for a single log reduction (D-value) of Salmonella Typhimurium from an initial concentration of 5.36 log/ml did not differ (P > 0.05) among the four antibiotic resistance groups and ranged from 3.8 to 4.3 min for n = 4 strains per group. Thus, the hypothesis was rejected, and it was concluded that expression of an antibiotic resistance phenotype does not confer cross-protection in Salmonella Typhimurium to chlorine inactivation in chilled water. PMID- 23726201 TI - Validation of a predictive model for survival and growth of Salmonella typhimurium DT104 on chicken skin for extrapolation to a previous history of frozen storage. AB - The U.S. Department of Agriculture's tertiary Pathogen Modeling Program (PMP) model for survival and growth of Salmonella enterica ser. Typhimurium definitive type 104 (DT104) on chicken skin stored for 0 to 8 h at 5 to 50 degrees C was evaluated for its ability to predict survival and growth of the same organism on chicken skin after frozen storage for 6 days at -20 degrees C. Experimental design and methods used to collect data for model development (dependent data) were the same as those used to collect data for survival and growth after frozen storage (independent data for extrapolation). This was done to provide a valid comparison of observed and predicted values. The model was classified as providing acceptable predictions of the test data when the proportion of residuals in an acceptable prediction zone (pAPZ) from -1 log (fail-safe) to 0.5 log (fail-dangerous) was >=0.7. The pAPZ for dependent data, independent data for interpolation, and independent data for extrapolation to a new independent variable of previous frozen storage were all acceptable (pAPZ >=0.7), with the exception of the pAPZ for dependent data at 50 degrees C, where an unacceptable pAPZ of 0.625 was obtained. Although a majority of observed log counts were less than predicted log counts, indicating that frozen storage of chicken skin for 6 days at -20 degrees C had injured some Salmonella Typhimurium DT104, the injury was not large enough to cause the tertiary PMP model to provide unacceptable predictions. Thus, it was concluded that the tertiary PMP model provided valid predictions of survival and growth of Salmonella Typhimurium DT104 on chicken skin that had a previous history of frozen storage for 6 days at -20 degrees C. Additional research is needed to determine how broadly the model can be applied to other conditions of previous frozen storage. PMID- 23726202 TI - Inactivation of Alicyclobacillus acidoterrestris using high pressure homogenization and dimethyl dicarbonate. AB - Vegetative cells and spores of five strains of Alicyclobacillus acidoterrestris (N-1100, N-1108, N-1096, SAC, and OS-CAJ) were screened for their sensitivity to high pressure homogenization (HPH, 0 to 300 MPa) in Bacillus acidoterrestris thermophilic broth. The most and least resistant strains, SAC and OS-CAJ, respectively, were further tested for their sensitivity to inactivation or growth inhibition by dimethyl dicarbonate (DMDC, 250 ppm). The combined effects of HPH and DMDC were then evaluated against SAC spores over a 24-h period after treatment. HPH alone significantly inactivated (P < 0.05) vegetative cells of all five strains. SAC vegetative cells were least affected by HPH, with only about a 0.5-log reduction after the 300-MPa treatment. Spores were not significantly reduced by HPH for any of the five strains. DMDC reduced the initial vegetative cell population by 2 log CFU/ml and significantly increased the time to reach stationary phase. For spores, a 0.5-log decrease from the initial spore population was achieved and growth was not significantly delayed. No significant difference was found between the two strains. Treatment with DMDC plus HPH slightly enhanced the inactivation effect over a 24-h period compared with treatment with HPH alone, but these differences were statistically inconsistent. Although HPH and DMDC treatments may help control vegetative cells of A. acidoterrestris, these treatments may not provide adequate overall control. Neither treatment, alone or in combination, is very effective against spores. PMID- 23726203 TI - Pathogenic microbiological baseline survey of pork carcasses in Taiwan. AB - From 2004 to 2010, pork carcass swabs from state-inspected slaughter plants in Taiwan were intermittently analyzed to determine the prevalence of selected pathogenic microorganisms associated with foodborne illness. The prevalences of Staphylococcus aureus each year from 2006 to 2010 were 6.6, 10.8, 5.1, 6.4, and 7.4%, respectively, while those of Listeria monocytogenes were 1.2% in 2004, 1.3% in 2005, and 3.5% in 2008. The prevalences of Clostridium perfringens were 0.9% in 2004, 3.2% in 2005, and 1.1% in 2008. Campylobacter jejuni and Campylobacter coli had a higher recovery rate than the other surveyed microorganisms, with prevalences during 2004, 2005, and 2008 of 21.1, 13.7, and 8.1%, respectively. Salmonella strains were analyzed each year, and their prevalences ranged between 3.0 and 6.9%. Derby, Typhimurium, Anatum, Choleraesuis, and Agona were the five serovars most frequently identified among the Salmonella isolates. Escherichia coli O157:H7 was not detected in 2004, 2005, or 2010. Routine baseline surveying of pork carcasses to determine the prevalence of selected pathogens of concern for food safety can provide valuable information regarding the effectiveness of the slaughtering procedures or the need for interventions. PMID- 23726204 TI - Identification of Aspergillus flavus isolates as potential biocontrol agents of aflatoxin contamination in crops. AB - Aspergillus flavus, a haploid organism found worldwide in a variety of crops, including maize, cottonseed, almond, pistachio, and peanut, causes substantial and recurrent worldwide economic liabilities. This filamentous fungus produces aflatoxins (AFLs) B1 and B2, which are among the most carcinogenic compounds from nature, acutely hepatotoxic and immunosuppressive. Recent efforts to reduce AFL contamination in crops have focused on the use of nonaflatoxigenic A. flavus strains as biological control agents. Such agents are applied to soil to competitively exclude native AFL strains from crops and thereby reduce AFL contamination. Because the possibility of genetic recombination in A. flavus could influence the stability of biocontrol strains with the production of novel AFL phenotypes, this article assesses the diversity of vegetative compatibility reactions in isolates of A. flavus to identify heterokaryon self-incompatible (HSI) strains among nonaflatoxigenic isolates, which would be used as biological controls of AFL contamination in crops. Nitrate nonutilizing (nit) mutants were recovered from 25 A. flavus isolates, and based on vegetative complementation between nit mutants and on the microscopic examination of the number of hyphal fusions, five nonaflatoxigenic (6, 7, 9 to 11) and two nontoxigenic (8 and 12) isolates of A. flavus were phenotypically characterized as HSI. Because the number of hyphal fusions is reduced in HSI strains, impairing both heterokaryon formation and the genetic exchanges with aflatoxigenic strains, the HSI isolates characterized here, especially isolates 8 and 12, are potential agents for reducing AFL contamination in crops. PMID- 23726205 TI - Effects of pH, sodium chloride, and curing salt on the infectivity of Toxoplasma gondii tissue cysts. AB - Toxoplasma gondii is one of the most common zoonotic parasites in the world. The parasite causes no or mild symptoms in immunocompetent humans. However, a high potential hazard exists for seronegative pregnant women and immunocompromised patients. The consumption of meat containing tissue cysts or oocyst-contaminated vegetables and fruits or the handling of cat feces poses a high risk of infection with T. gondii. It is known that raw minced meat, raw fresh sausages, and locally produced raw meat products are possible causes of T. gondii infection. The infectivity of T. gondii tissue cysts in meat products depends, among other factors, on the pH and the salt concentration. Therefore, the impact of these two factors on the tissue cysts was examined. For this purpose, dissected musculature and brain from experimentally infected mice (donor mice) were placed in a cell culture medium (RPMI 1640). The medium was adjusted to different pH values (pH 5, 6, and 7) with lactic acid and to different salt concentrations (2.0, 2.5, and 3.0%) with sodium chloride (NaCl) or nitrite-enriched curing salt (NCS) for the various tests. After storage at 4 degrees C for different time periods, the materials were fed to bioassay mice. Later, the brains were examined for presence of T. gondii to assess the infectivity. The data show that T. gondii tissue cysts have a high pH tolerance. Cysts were infectious in the muscle for up to 26 days (pH 5). In contrast to their tolerance to pH, cysts were very sensitive to salt. Muscle cysts survived at an NaCl concentration of up to 2.0% only, and for no longer than 8 days. At NaCl concentrations of 2.5 and 3.0%, the cysts lost their infectivity after 1 day. When NCS instead of NaCl was used under the same conditions, T. gondii muscle cysts retained infectivity for only 4 days at 2.0%. Consequently, NCS (NaCl plus 0.5% nitrite) has a stronger effect on T. gondii cysts than does common table salt. Sausages produced with low NaCl concentration and short contact times pose a potential risk for susceptible individuals. PMID- 23726206 TI - A framework for developing research protocols for evaluation of microbial hazards and controls during production that pertain to the application of untreated soil amendments of animal origin on land used to grow produce that may be consumed raw. AB - Application of manure or soil amendments of animal origin (untreated soil amendments; UTSAs) to agricultural land has been a long-standing practice to maintain or improve soil quality through addition of organic matter, nitrogen, and phosphorus. Much smaller quantities of these types of UTSAs are applied to land used for food crops than to land used for animal grain and forage. UTSAs can harbor zoonotic enteric pathogens that may survive for extended periods after application. Additional studies are needed to enhance our understanding of preharvest microbial food safety hazards and control measures pertaining to the application of UTSAs especially for land used to grow produce that may be consumed raw. This document is intended to provide an approach to study design and a framework for defining the scope and type of data required. This document also provides a tool for evaluating the strength of existing data and thus can aid the produce industry and regulatory authorities in identifying additional research needs. Ultimately, this framework provides a means by which researchers can increase consistency among and between studies and facilitates direct comparison of hazards and efficacy of controls applied to different regions, conditions, and practices. PMID- 23726207 TI - Utilization of mathematical models to manage risk of holding cold food without temperature control. AB - This document describes the development of a tool to manage the risk of the transportation of cold food without temperature control. The tool uses predictions from ComBase predictor and builds on the 2009 U.S. Food and Drug Administration Model Food Code and supporting scientific data in the Food Code annex. I selected Salmonella spp. and Listeria monocytogenes as the organisms for risk management. Salmonella spp. were selected because they are associated with a wide variety of foods and grow rapidly at temperatures >17 degrees C. L. monocytogenes was selected because it is frequently present in the food processing environment, it was used in the original analysis contained in the Food Code Annex, and it grows relatively rapidly at temperatures <17 degrees C. The suitability of a variety of growth models under changing temperature conditions is largely supported by the published literature. The ComBase predictions under static temperature conditions were validated using 148 ComBase database observations for Salmonella spp. and L. monocytogenes in real foods. The times and temperature changes encompassed by ComBase Predictor models for Salmonella spp. and L. monocytogenes are consistent with published data on consumer food transport to the home from the grocery store and on representative foods from a wholesale cash and carry food service supplier collected as part of this project. The resulting model-based tool will be a useful aid to risk managers and customers of wholesale cash and carry food service suppliers, as well as to anyone interested in assessing and managing the risks posed by holding cold foods out of temperature control in supermarkets, delis, restaurants, cafeterias, and homes. PMID- 23726208 TI - From pig to pork: methicillin-resistant Staphylococcus aureus in the pork production chain. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major global public health concern and could be a food safety issue. Recurrent reports have documented that pig herds are an important reservoir for MRSA, specifically the livestock-associated sequence type 398. The high prevalence of MRSA in pig primary production facilities and the frequent detection of MRSA of the same types in pork and pig meat products raise the question of underlying mechanisms behind the introduction and transmission of MRSA along the pork production chain. A comprehensive review of current literature on the worldwide presence of livestock-associated MRSA in various steps of the pork production chain revealed that the slaughter process plays a decisive role in MRSA transmission from farm to fork. Superficial heat treatments such as scalding and flaming during the slaughter process can significantly reduce the burden of MRSA on the carcasses. However, recontamination with MRSA might occur via surface treating machinery, as a result of fecal contamination at evisceration, or via increased human handling during meat processing. By optimizing processes for carcass decontamination and avoiding recontamination by effective cleaning and personal hygiene management, transmission of MRSA from pig to pork can be minimized. PMID- 23726209 TI - Estimating the causal effect of alcohol consumption on well-being for a cross section of 9 former Soviet Union countries. AB - While the adverse health and economic consequences attributable to alcohol consumption are widely acknowledged, its impact on psychological wellbeing is less well understood. This is to a large extent due to the challenge of establishing causal effects of alcohol consumption when using standard single equation econometric analyses. Using a unique dataset collected in 2010/11 of 18,000 individuals and also community characteristics from nine countries of the former Soviet Union, a region with a major burden of alcohol related ill health, we address this problem by employing an instrumental variable approach to identify any causal effects of alcohol consumption on mental well-being. The availability of 24-h alcohol sales outlets in the neighbourhood of the individuals is used as an instrument, based on theoretical reasoning and statistical testing of its validity. We find that increased alcohol consumption decreases well-being and that ignoring endogeneity leads to underestimation of this effect. This finding adds a further and previously under-appreciated dimension to the expected benefits that could be achieved with more effective alcohol policy in this region. PMID- 23726210 TI - Predictors of health behaviors after the economic downturn: a longitudinal study. AB - Economic declines and their associated stress, shortage of financial resources, and changes in available time can impair health behaviors. This study tested the association between change in working hours, change in employment status, and financial strain and health behaviors measured after the 2008 recession after controlling for pre-recession levels of the health behaviors. The moderating influences of demographic factors and pre-recession levels of the health behaviors on the association between change in working hours and employment status and financial strain and the health behaviors were also tested. Participants (N = 3984) were from a longitudinal study of a U.S. Midwestern community-based sample. Regression analyses tested the unique relations between change in hours worked per week, change in employment status, and financial strain and five health behaviors over and above demographic factors and pre recession levels of the same behavior. Models included predictor by covariate interactions. Participants who reported higher levels of financial strain engaged in lower levels of all but one of the five health behaviors, but there were no significant main effects of a change in the number of hours worked per week or change in employment status. Significant interactions revealed moderation of these relations by demographic characteristics, but findings differed across health behaviors. Financial strain negatively affected engagement in multiple healthy behaviors. Promoting the maintenance of healthy behaviors for disease prevention is an important public health goal during times of economic decline. PMID- 23726211 TI - Race, gender, class, sexuality (RGCS) and hypertension. AB - Informed by intersectionality theory, a tradition that theorizes intersecting power relations of racism, patriarchy, classism and heterosexism, this paper investigates the degree to which race, gender, class and sexuality manifest distinct and interconnected associations with self-reported hypertension in nationally-representative survey data from Canada. Binary logistic regression is used to model the main effects of, and interactions between, race, gender, education, household income and sexual orientation on hypertension, controlling for age, using data from the 2003 Canadian Community Health Survey (n = 90,310). From a main effects ('additive') perspective, Black respondents, respondents with less than high school and poorer respondents were significantly more likely than White respondents, university-educated Canadians and wealthier Canadians, respectively, to report hypertension. However, the interactive models indicate that the additive models were poor predictors of hypertension for wealthy Black men, wealthy South Asian women, women with less than a high school diploma and wealthy bisexual respondents, who were more likely than expected to report hypertension, and for poor Black men, poor South Asian women, poor South Asian men and women with a university degree, who were less likely than expected to report hypertension. It appears that, with regard to blood pressure at least, Canadians experience the health effects of education differently by their genders and the health effects of income differently by their identities defined at the intersection of race and gender. This study provides empirical support for the intersectional approach to cardiovascular health inequalities by demonstrating that race, gender, class and sexuality cannot be disentangled from one another as predictors of hypertension. PMID- 23726212 TI - Horizontal equity and efficiency at primary health care facilities in rural Afghanistan: a seemingly unrelated regression approach. AB - Producing services efficiently and equitably are important goals for health systems. Many countries pursue horizontal equity - providing people with the same illnesses equal access to health services - by locating facilities in remote areas. Staff are often paid incentives to work at such facilities. However, there is little evidence on how many fewer people are treated at remote facilities than facilities in more densely settled areas. This research explores if there is an association between the efficiency of health centers in Afghanistan and the remoteness of their location. Survey teams collected data on facility level inputs and outputs at a stratified random sample of 579 health centers in 2005. Quality of care was measured by observing staff interact with patients and determining if staff completed a set of normative patient care tasks. We used seemingly unrelated regression to determine if facilities in remote areas have fewer outpatient visits than other rural facilities. In this analysis, one equation compares the number of outpatient visits to facility inputs, while another compares quality of care to determinants of quality. The results indicate remote facilities have about 13% fewer outpatient visits than non-remote facilities, holding inputs constant. Our analysis suggests that facilities in remote areas are realizing horizontal equity since their clients are receiving comparable quality of care to those at non-remote facilities. However, we find the average labor cost for a visit at a remote facility is $1.44, but only $0.97 at other rural facilities, indicating that a visit in a remote facility would have to be 'worth' 1.49 times a visit at a rural facility for there to be no equity - efficiency trade-off. In determining where to build or staff health centers, this loss of efficiency may be offset by progress toward a social policy objective of providing services to disadvantaged rural populations. PMID- 23726214 TI - The association between relative deprivation and self-rated health, depressive symptoms, and smoking behavior in Taiwan. AB - Relative deprivation has been hypothesized as one explanation for the association between income inequality and health. However, few studies have examined the effect of relative deprivation on psychosocial and behavioral outcomes. Using a cross-sectional data from the National Survey on Knowledge, Attitude, and Practice of Health Promotion in Taiwan, this study examined the relationship between relative deprivation and physical health (self-rated health), psychosocial health (depressive symptoms), and behavioral health (smoking) among working-age Taiwanese men and women. We found that higher relative deprivation (measured by the Yitzhaki Index) is significantly associated with a higher prevalence of poor self-rated health, depressive symptoms, and current smoking in both genders. After controlling for demographic variables and absolute income, the prevalence ratios (PRs) of reporting poor health for each 10,000 NT-dollars higher in the Yitzhaki Index are between 1.25 and 1.57, depending on the reference groups. The PRs were between 1.33 and 1.77 for depressive symptoms, and between 1.04 and 1.46 for smoking. Additionally, the depressive symptoms attenuated the association between relative deprivation and self-rated health. The results were consistent with various definitions of reference groups. In conclusion, this study suggests that the psychosocial process of relative deprivation is a crucial mechanism linking income inequality to health. Narrowing the income gap between rich and poor may protect the physical and mental well being of the population and reduce the prevalence of smoking. PMID- 23726213 TI - Racial disparities in travel time to radiotherapy facilities in the Atlanta metropolitan area. AB - Low-income women with breast cancer who rely on public transportation may have difficulty in completing recommended radiation therapy due to inadequate access to radiation facilities. Using a geographic information system (GIS) and network analysis we quantified spatial accessibility to radiation treatment facilities in the Atlanta, Georgia metropolitan area. We built a transportation network model that included all bus and rail routes and stops, system transfers and walk and wait times experienced by public transportation system travelers. We also built a private transportation network to model travel times by automobile. We calculated travel times to radiation therapy facilities via public and private transportation from a population-weighted center of each census tract located within the study area. We broadly grouped the tracts by low, medium and high household access to a private vehicle and by race. Facility service areas were created using the network model to map the extent of areal coverage at specified travel times (30, 45 and 60 min) for both public and private modes of transportation. The median public transportation travel time to the nearest radiotherapy facility was 56 min vs. approximately 8 min by private vehicle. We found that majority black census tracts had longer public transportation travel times than white tracts across all categories of vehicle access and that 39% of women in the study area had longer than 1 h of public transportation travel time to the nearest facility. In addition, service area analyses identified locations where the travel time barriers are the greatest. Spatial inaccessibility, especially for women who must use public transportation, is one of the barriers they face in receiving optimal treatment. PMID- 23726215 TI - Dividuality, masculine respectability and reputation: how masculinity affects men's uptake of HIV treatment in rural eastern Uganda. AB - There is increasing evidence in SSA that once infected with HIV men are disadvantaged compared to women in terms of uptake of treatment. In Uganda fewer men are on treatment, they tend to initiate treatment later, are difficult to retain on treatment and have a higher mortality while on treatment. This article discusses how men's response to HIV infection relates to their masculinity. We conducted participant observation and in-depth interviews with 26 men from a rural setting in eastern Uganda, in 2009-2010. They comprised men receiving HIV treatment, who had dropped treatment or did not seek it despite testing HIV positive, who had not tested but suspected infection, and those with other symptoms unrelated to HIV. Thematic analysis identified recurrent themes and variations across the data. Men drew from a range of norms to fulfil the social and individual expectations of being sufficiently masculine. The study argues that there are essentially two forms of masculinity in Mam-Kiror, one based on reputation and the other on respectability, with some ideals shared by both. Respectability was endorsed by 'the wider society', while reputation was endorsed almost entirely by men. Men's treatment seeking behaviours corresponded with different masculine ideologies. Family and societal expectations to be a family provider and respectable role model encouraged treatment, to regain and maintain health. However, reputational concern with strength and the capacity for hard physical work, income generation and sexual achievement discouraged uptake of HIV testing and treatment since it meant acknowledging weakness and an 'HIV patient' identity. Men's 'dividuality' allowed them to express different masculinities in different social contexts. We conclude that characteristics associated with respectable masculinity tend to encourage men's uptake of HIV treatment while those associated with reputational masculinity tend to undermine it. PMID- 23726216 TI - Higher-status occupations and breast cancer: a life-course stress approach. AB - Using the 1957-2011 data from 3682 White non-Hispanic women (297 incident breast cancer cases) in the Wisconsin Longitudinal Study, United States, we explore the effect of occupation in 1975 (at age 36) on breast cancer incidence up to age 72. Our study is motivated by the paradoxical association between higher-status occupations and elevated breast cancer risk, which presents a challenge to the consistent health advantage of higher social class. We found that women in professional occupations had 72122% and women in managerial occupations had 57 89% higher risk of a breast cancer diagnosis than housewives and women in lower status occupations. We explored an estrogen-related pathway (reproductive history, health behaviors, and life-course estrogen cycle) as well as a social stress pathway (occupational experiences) as potential explanations for the effect of higher-status occupations. The elevated risk of breast cancer among professional women was partly explained by estrogen-related variables but remained large and statistically significant. The association between managerial occupations and breast cancer incidence was fully explained by job authority defined as control over others' work. Exercising job authority was related to higher breast cancer risk (HR = 1.57, 95% CI: 1.12, 2.18), especially with longer duration of holding the professional/managerial job. We suggest that the assertion of job authority by women in the 1970s involved stressful interpersonal experiences that may have promoted breast cancer development via prolonged dysregulation of the glucocorticoid system and exposure of the breast tissue to adverse effects of chronically elevated cortisol. Our study emphasizes complex biosocial pathways through which women's gendered occupational experiences become embodied and drive forward physiological repercussions. PMID- 23726217 TI - A level set based algorithm to reconstruct the urinary bladder from multiple views. AB - The urinary bladder can be visualized from different views by imaging facilities such as computerized tomography and magnetic resonance imaging. Multi-view imaging can present more details of this pelvic organ and contribute to a more reliable reconstruction. Based on the information from multi-view planes, a level set based algorithm is proposed to reconstruct the 3D shape of the bladder using the cross-sectional boundaries. The algorithm provides a flexible solution to handle the discrepancies from different view planes and can obtain an accurate bladder surface with more geometric details. PMID- 23726218 TI - Appropriateness and reliability testing of the modified Richmond Agitation Sedation Scale in Spanish patients with advanced cancer. AB - CONTEXT: A tool to quantify agitation severity and sedation level in patients with advanced cancer is needed. OBJECTIVES: To test the appropriateness and reliability of the Richmond Agitation-Sedation Scale (RASS) in Spanish patients with advanced cancer. METHODS: The original RASS was translated into Spanish according to the standard guidelines. Face validity was assessed by members of the palliative care team, and interrater reliability was assessed, using a weighted kappa, from observations of patients admitted to the palliative care unit. The association between scores of the RASS, Ramsay Sedation Scale, and Glasgow Coma Scale was evaluated using Spearman's rho. RESULTS: Three hundred twenty-two observations were performed in 156 patients: 116 observations were performed for delirious patients, 76 observations for sedated patients, and 130 observations for patients admitted for other symptom control. The weighted kappa values were practically equal to or greater than 0.90 between nurses and nurses and physicians. The agreement level between observers for each RASS score was roughly 90%. The correlation between the RASS and the Ramsay and Glasgow Scale values was analyzed for 196 observations recorded in 80 patients. The sedation scale of the RASS had a strong correlation with both the Ramsay (Spearman's rho, 0.89; P < 0.001) and the Glasgow Coma Scales (Spearman's rho, 0.85; P < 0.001). CONCLUSION: These data support the use of the RASS in Spanish patients with advanced cancer. PMID- 23726219 TI - Using design science and artificial intelligence to improve health communication: ChronologyMD case example. AB - OBJECTIVE: This paper describes how design science theory and methods and use of artificial intelligence (AI) components can improve the effectiveness of health communication. METHODS: We identified key weaknesses of traditional health communication and features of more successful eHealth/AI communication. We examined characteristics of the design science paradigm and the value of its user centered methods to develop eHealth/AI communication. We analyzed a case example of the participatory design of AI components in the ChronologyMD project intended to improve management of Crohn's disease. RESULTS: eHealth/AI communication created with user-centered design shows improved relevance to users' needs for personalized, timely and interactive communication and is associated with better health outcomes than traditional approaches. Participatory design was essential to develop ChronologyMD system architecture and software applications that benefitted patients. CONCLUSION: AI components can greatly improve eHealth/AI communication, if designed with the intended audiences. Design science theory and its iterative, participatory methods linked with traditional health communication theory and methods can create effective AI health communication. PRACTICE IMPLICATIONS: eHealth/AI communication researchers, developers and practitioners can benefit from a holistic approach that draws from theory and methods in both design sciences and also human and social sciences to create successful AI health communication. PMID- 23726220 TI - Nucleotide excision repair in chronic neurodegenerative diseases. AB - Impaired DNA repair involving the nucleotide excision repair (NER)/transcription coupled repair (TCR) pathway cause human pathologies associated with severe neurological symptoms. These clinical observations suggest that defective NER/TCR might also play a critical role in chronic neurodegenerative disorders (ND), such as Alzheimer's and Parkinson's disease. Involvement of NER/TCR in these disorders is also substantiated by the evidence that aging constitutes the principal risk factor for chronic ND and that this DNA repair mechanism is very relevant for the aging process itself. Our understanding of the exact role of NER/TCR in chronic ND, however, is extremely rudimentary; while there is no doubt that defective NER/TCR can lead to neuronal death, evidence for its participation in the etiopathogenesis of ND is inconclusive thus far. Here we summarize the experimental observations supporting a role for NER/TCR in chronic ND and suggest questions and lines of investigation that might help in addressing this important issue. We also present a preliminary yet unprecedented meta-analysis on human brain microarray data to understand the expression levels of the various NER factors in the anatomical areas relevant for chronic ND pathogenesis. In summary, this review intends to highlight elements supporting a role of NER/TCR in these devastating disorders and to propose potential strategies of investigation. PMID- 23726221 TI - Brh2 and Rad51 promote telomere maintenance in Ustilago maydis, a new model system of DNA repair proteins at telomeres. AB - Recent studies implicate a number of DNA repair proteins in mammalian telomere maintenance. However, because several key repair proteins in mammals are missing from the well-studied budding and fission yeast, their roles at telomeres cannot be modeled in standard fungi. In this report, we explored the dimorphic fungus Ustilago maydis as an alternative model for telomere research. This fungus, which belongs to the phylum Basidiomycota, has a telomere repeat unit that is identical to the mammalian repeat, as well as a constellation of DNA repair proteins that more closely mimic the mammalian collection. We showed that the two core components of homology-directed repair (HDR) in U. maydis, namely Brh2 and Rad51, both promote telomere maintenance in telomerase positive cells, just like in mammals. In addition, we found that Brh2 is localized to telomeres in vivo, suggesting that it acts directly at chromosome ends. We surveyed a series of mutants with DNA repair defects, and found many of them to have short telomeres. Our results indicate that factors involved in DNA repair are probably also needed for optimal telomere maintenance in U. maydis, and that this fungus is a useful alternative model system for telomere research. PMID- 23726222 TI - Vibrio ordalii antimicrobial susceptibility testing--modified culture conditions required and laboratory-specific epidemiological cut-off values. AB - The present study aimed to determine oxytetracycline (OTC), florfenicol (FLO) and oxolinic acid (OXO) MICs and zone diameters for 24 Chilean Vibrio ordalii isolates using the methods for broth dilution susceptibility testing of bacteria isolated from aquatic animals and the methods for antimicrobial disk susceptibility testing of bacteria isolated from aquatic animals guidelines published by the Clinical Laboratory Standards Institute (CLSI). The results were then used in a normalized resistance interpretation (NRI) analysis to establish tentative laboratory-specific epidemiological cut-off (ECOFF) values. MIC results were similar at the two tested temperatures (22 degrees C and 18 degrees C). At 18 degrees C, the NRI analysis of OTC, FLO and OXO MIC data calculated laboratory-specific ECOFF values and non-wild-type (NWT) rates to be <=4 mg/l (24%), <=16 mg/l (4%) and <=8 mg/l (25%), respectively. Tests performed with all V. ordalii isolates following the officially recommended incubation temperature (22 degrees C) revealed difficulties in measuring inhibition zone diameters. When disk diffusion tests were performed using Mueller-Hinton agar with 1% NaCl (MHA-1) at 18 degrees C the inhibition zone diameter distributions showed the formation of WT populations which could be defined using NRI analysis. For OTC the laboratory-specific ECOFF value was >=38 mm with NWT rate of 16.7%. For FLO and OXO, the laboratory-specific ECOFF values were >=38 and >=40, respectively, generating NWT rates of 25 and 46%, respectively. Although the CLSI suggests testing Vibrio spp. on MHA-1 at 22 degrees C, we found measurements of the 24 isolates were better defined and normally distributed at 18 degrees C. This is the first study determining the MIC and disk diffusion test of V. ordalii isolated from diseased salmonids, where laboratory-specific ECOFF values could be established. Also resistance to OTC, FLO and OXO among some Chilean isolates was demonstrated. PMID- 23726223 TI - Effect of Bovine Viral Diarrhea Virus on the ovarian functionality and in vitro reproductive performance of persistently infected heifers. AB - The aim of this study was to study the effect of Bovine Viral Diarrhea Virus on the reproductive female tract by means of analyzing the ovarian follicular population of persistently infected (PI) heifers, and evaluating the performance of oocytes procured form those heifers in in vitro fertilization procedures. Seven BVDV PI Aberdeen Angus and British crossbred heifers ranging from 18 to 36 months of age were spayed and their ovaries used for viral isolation, microscopic examination, and in vitro fertilization procedures. Bovine Viral Diarrhea Virus was detected from the follicular fluid and sera of all PI heifers. Microscopic examination of the ovaries from PI heifers showed a significant drop in the number of follicles cortical regions, compared with controls. A comparative analysis of the stages of follicular development showed a significant decrease in the number of primordial and tertiary follicles in the cortical regions of ovaries from PI heifers. Viral antigen was detected by immunohistochemistry, and was widely distributed throughout the ovarian tissues. There were differences in the rate of cleavage and embryo development between oocytes obtained from the ovaries of control animals and PI heifers. Furthermore, two developed embryos obtained from oocytes from one of the PI heifers were positive to BVDV, as well as two media from in vitro fertilization (IVF) procedures. The results of this study demonstrate that BVDV PI heifers exhibit alterations in follicular population through of the early interaction between the virus and germ cell line affecting directly the mechanisms involved in the ontogenesis of the ovary. PMID- 23726224 TI - Postoperative recovery from the perspective of day surgery patients: a phenomenographic study. AB - BACKGROUND: Today, many patients undergo surgical procedures in a day surgery setting. The shift from inpatient care to care at the patients' own home following discharge places various demands on patients and their families during the recovery process. There is a need for knowledge of how the postoperative recovery process is perceived, as research indicates a lack of support for patients managing recovery at home. OBJECTIVE: To explore day surgery patients' different perceptions of postoperative recovery. DESIGN: A qualitative design with a phenomenographic approach was used. METHODS AND SETTINGS: Semi-structured interviews with 31 patients undergoing an orthopaedic, general or urologic day surgical procedure were carried out face to face at the patients' homes, 11-37 days post-discharge. Patients were recruited from two day surgery settings: one private unit and one unit associated with a local county hospital. RESULTS: The patients perceived postoperative recovery as comprising internal and external prerequisites and implying changes in ordinary life with varying levels of support. The effective production at the day surgery unit was perceived as having an impact on patients' prerequisites for recovery. The results are elucidated in three descriptive categories: 'Conditions for recovery at home', 'The rollback to ordinary life' and 'Being a cog in a flow of care'. CONCLUSIONS: The postoperative phase seems to be a weak link in day surgery care. From the patients' perspective, postoperative recovery following day surgery implies extensive responsibility at home. Patients need knowledge and understanding concerning what constitutes the normal range in recovery and how to manage self care following their specific surgical procedure. PMID- 23726225 TI - Dopamine D2 receptors and striatopallidal transmission in addiction and obesity. AB - Drug addiction and obesity share the core feature that those afflicted by the disorders express a desire to limit drug or food consumption yet persist despite negative consequences. Emerging evidence suggests that the compulsivity that defines these disorders may arise, to some degree at least, from common underlying neurobiological mechanisms. In particular, both disorders are associated with diminished striatal dopamine D2 receptor (D2R) availability, likely reflecting their decreased maturation and surface expression. In striatum, D2Rs are expressed by approximately half of the principal medium spiny projection neurons (MSNs), the striatopallidal neurons of the so-called 'indirect' pathway. D2Rs are also expressed presynaptically on dopamine terminals and on cholinergic interneurons. This heterogeneity of D2R expression has hindered attempts, largely using traditional pharmacological approaches, to understand their contribution to compulsive drug or food intake. The emergence of genetic technologies to target discrete populations of neurons, coupled to optogenetic and chemicogenetic tools to manipulate their activity, have provided a means to dissect striatopallidal and cholinergic contributions to compulsivity. Here, we review recent evidence supporting an important role for striatal D2R signaling in compulsive drug use and food intake. We pay particular attention to striatopallidal projection neurons and their role in compulsive responding for food and drugs. Finally, we identify opportunities for future obesity research using known mechanisms of addiction as a heuristic, and leveraging new tools to manipulate activity of specific populations of striatal neurons to understand their contributions to addiction and obesity. PMID- 23726226 TI - Targeted drug delivery and cross-linking induced apoptosis with anti-CD37 based dual-ligand immunoliposomes in B chronic lymphocytic leukemia cells. AB - Despite advances in chemo and immunotherapeutic agents for B chronic lymphocytic leukemia (B-CLL), the undesirable adverse side effects due to non-specific cellular uptake remain to be addressed. We identified anti-CD37 monoclonal antibody immunoliposomes (ILs) as vehicles for targeted delivery to B chronic lymphocytic leukemia cells. To achieve maximal benefits for all patients, a new strategy of dual-ligand immunoliposomes (dILs) was developed. A combinatorial antibody microarray technology was adapted to quickly identify optimal antibody combinations for individual patient cells. For proof-of-concept, a B-cell specific antibody, either anti-CD19 or anti-CD20, was combined with anti-CD37 to construct dILs with enhanced selectivity and efficacy. Consistent with data from the antibody microarray, these dILs provided highly specific targeting to both leukemia cell lines and B-CLL patient cells. Compared with the single antibody ILs, the anti-CD19/CD37 dILs clearly demonstrated superior delivery efficiency and apoptosis induction to B-CLL patient cells, whereas the anti-CD20/anti-CD37 dILs were found to be the most efficient for delivery to leukemia cell lines. In addition, it was observed that anti-CD37 ILs without payload drug mediated effective CD37 cross-linking and induced potent apoptosis induction. The anti CD19/CD20 dILs showed the improved cell apoptosis induction compared to either anti-CD19 ILs or anti-CD20 ILs. Our findings suggest that the dual-ligand ILs may provide a preferred strategy of personalized nanomedicine for the treatment of B cell malignancies. PMID- 23726228 TI - Imaging and therapy of liver fibrosis using bioreducible polyethylenimine/siRNA complexes conjugated with N-acetylglucosamine as a targeting moiety. AB - Diagnosis and therapy of early stage liver fibrosis is very important for the treatment of fatal liver diseases. Here, we report on the targeted imaging and therapy of activated hepatic stellate cells (HSCs) and fibrotic liver tissue using N-acetylglucosamine (GlcNAc)- and indocyanine green (ICG)-conjugated PEI/siRNA complexes. The conjugation of a disulfide bond to PEI (PEI-D) was achieved by Michael addition. We modified PEI with N-acetylglucosamine (PEI-D GlcNAc), which can specifically interact with desmin on activated HSCs, using the EDC coupling method. Confocal microscopic analysis showed that the PEI-D GlcNAc/siRNA was internalized by HSCs upon interaction with surface desmin. In vitro western blot analysis confirmed that PEI-D-GlcNAc provided strong protein knock-down after transfection with TGFbeta1siRNA into HSCs. After a tail vein injection of ICG-conjugated complexes, the PEI-D-GlcNAc-ICG/siRNA complex accumulated to a greater extent in the livers of fibrotic mice than in normal mice over an extended duration. Moreover, immunohistofluorescence analysis confirmed that the PEI-D-GlcNAc-ICG/siRNA complex specifically colocalized with HSCs, which are desmin-positive cells, in fibrotic liver tissues. In vivo TGFbeta1siRNA delivery also resulted in superior protein knock-down when using the PEI-D-GlcNAc complex. These results demonstrate that the PEI-D-GlcNAc ICG/TGFbeta1siRNA complex is a useful tool for imaging and treatment of liver fibrosis. PMID- 23726229 TI - A biodegradable hydrogel system containing curcumin encapsulated in micelles for cutaneous wound healing. AB - A biodegradable in situ gel-forming controlled drug delivery system composed of curcumin loaded micelles and thermosensitive hydrogel was prepared and applied for cutaneous wound repair. Curcumin is believed to be a potent antioxidant and anti-inflammatory agent. Due to its high hydrophobicity, curcumin was encapsulated in polymeric micelles (Cur-M) with high drug loading and encapsulation efficiency. Cur-M loaded thermosensitive hydrogel (Cur-M-H) was prepared and applied as wound dressing to enhance the cutaneous wound healing. Cur-M-H was a free-flowing sol at ambient temperature and instantly converted into a non-flowing gel at body temperature. In vitro studies suggested that Cur-M H exhibited well tissue adhesiveness and could release curcumin in an extended period. Furthermore, linear incision and full-thickness excision wound models were employed to evaluate the in vivo wound healing activity of Cur-M-H. In incision model, Cur-M-H-treated group showed higher tensile strength and thicker epidermis. In excision model, Cur-M-H group exhibited enhancement of wound closure. Besides, in both models, Cur-M-H-treated groups showed higher collagen content, better granulation, higher wound maturity, dramatic decrease in superoxide dismutase, and slight increase in catalase. Histopathologic examination also implied that Cur-M-H could enhance cutaneous wound repair. In conclusion, biodegradable Cur-M-H composite might have great application for wound healing. PMID- 23726230 TI - DSA image registration using non-uniform MRF model and pivotal control points. AB - In order to reduce the motion artifacts in DSA, non-rigid image registration is commonly used before subtracting the mask from the contrast image. Since DSA registration requires a set of spatially non-uniform control points, a conventional MRF model is not very efficient. In this paper, we introduce the concept of pivotal and non-pivotal control points to address this, and propose a non-uniform MRF for DSA registration. We use quad-trees in a novel way to generate the non-uniform grid of control points. Our MRF formulation produces a smooth displacement field and therefore results in better artifact reduction than that of registering the control points independently. We achieve improved computational performance using pivotal control points without compromising on the artifact reduction. We have tested our approach using several clinical data sets, and have presented the results of quantitative analysis, clinical assessment and performance improvement on a GPU. PMID- 23726231 TI - Timing is everything-colectomy performed on Monday decreases length of stay. AB - BACKGROUND: Perioperative care of patients undergoing colon resection requires a multidisciplinary approach by the operating surgeon, residents, and nurses. Operations performed on Monday take full advantage of hospital resources throughout the week to meet expected discharge by Friday. In a current health care environment of diminishing means, improving the timing of surgery in relation to expected length of stay may play an important role in preserving health care resources. METHODS: A retrospective review of a prospectively collected colorectal surgical database identified all patients who underwent segmental colon resection at a single tertiary care referral center from 2004 to 2010. Length of stay for patients undergoing elective open and minimally invasive segmental colectomy was compared for Monday versus Tuesday through the weekend. Patient and surgeon demographics were recorded as well as postoperative outcomes and complications. RESULTS: A total of 868 segmental colectomies were performed during the study period. Length of stay was significantly decreased by .73 days (P < .01) for all segmental colectomies performed on Monday compared with those performed Tuesday through Sunday. There was also a significant decrease in length of stay looking independently at right (.96 days, P < .01) and left or sigmoid colectomies (.56 days, P < .01). There was no significant difference in patient or surgeon demographics to account for this difference. CONCLUSIONS: Segmental colectomies have a significantly decreased length in stay when performed on Monday compared with the rest of the week. The decrease is independent of surgeon, comorbidities, and complications. This difference may be the result of patients' taking full advantage of hospital resources and ancillary support. Cost effective measures may be evaluated and directed at adjustment of resources available throughout the week to reduce length of stay. PMID- 23726227 TI - A review of nanotechnological approaches for the prophylaxis of HIV/AIDS. AB - Successful treatment and control of HIV/AIDS is one of the biggest challenges of 21st century. More than 33 million individuals are infected with HIV worldwide and more than 2 million new cases of HIV infection have been reported. The situation demands development of effective prevention strategies to control the pandemic of AIDS. Due to lack of availability of an effective HIV vaccine, antiretroviral drugs and nucleic acid therapeutics like siRNA have been explored for HIV prophylaxis. Clinical trials shave shown that antiretroviral drugs, tenofovir and emtricitabine can offer some degree of HIV prevention. However, complete prevention of HIV infection has not been achieved yet. Nanotechnology has brought a paradigm shift in the diagnosis, treatment and prevention of many diseases. The current review discusses potential of various nanocarriers such as dendrimers, polymeric nanoparticles, liposomes, lipid nanocarriers, drug nanocrystals, inorganic nanocarriers and nanofibers in improving efficacy of various modalities available for HIV prophylaxis. PMID- 23726232 TI - Prediction score for effective bleeding control using recombinant activated factor VII in perioperative nonhemophilic patients. AB - BACKGROUND: Although there has been growing evidence from off-label use of recombinant activated factor VII (rFVIIa) in surgical bleeding, there is limited information on prediction scores. METHODS: A retrospective study was conducted from 2004 to 2009. The primary outcome was efficacy of bleeding control. Multivariate logistic regression was performed to develop a new prediction score for success of rFVIIa. RESULTS: A total of 320 bleeding episodes from 243 nonhemophilic patients who underwent surgery were analyzed. Effective bleeding control was demonstrated in 153 patients. The overall in-hospital mortality rate was 40%. Multivariate analysis identified 4 independent predictors for effective bleeding control: timing of rFVIIa administration, intraoperative blood loss, postoperative international normalization ratio values, and total units of platelets transfused. A rFVIIa success prediction score was developed. CONCLUSIONS: The use of this new prediction score may support decision making by identifying patients with a high probability of obtaining effective bleeding control from rFVIIa therapy. PMID- 23726233 TI - Utility of a microwave surgical instrument in sealing lymphatic vessels. AB - BACKGROUND: This study assessed the ability of a novel microwave coagulation surgical instrument (MWCX) to seal lymphatic vessels when compared with LigaSure (Valleylab, Boulder, CO), the Harmonic Scalpel (HS; Ethicon Endo-Surgery, Cincinnati, OH), and electric cautery. METHODS: The burst pressure of pig inguinal lymphatic vessels was assessed after the sealing of vessels with each surgical instrument. The rate of lymphorrhea from pig mesenteric lymphatic vessels was also investigated using indocyanine green and visualized with the Photodynamic Eye system (Hamamatsu Hotoniks, Hamamatsu, Japan). RESULTS: Burst pressures were higher with MWCX (average, 300 mm Hg), LigaSure (average, 290 mm Hg), and HS (average, 253 mm Hg) when compared with electric cautery (average, 152.3 mm Hg; vs MWCX: P = .002, vs LigaSure: P = .002, vs HS: P = .004). The rate of lymphorrhea was significantly lower with LigaSure (13.3%), HS (18.8%), and MWCX (13.3%) when compared with electric cautery (77.3%; vs LigaSure: P < .001, vs HS: P < .001, vs MWCX: P < .001). CONCLUSIONS: MWCX was equivalent to LigaSure and HS in terms of the ability to seal lymphatic vessels. PMID- 23726234 TI - [Bio-guided isolation of an antifungal from Haliclona enamela collected from Jorf Lasfar port, Morocco]. AB - In the context of our search for new biologically active secondary metabolites from marine invertebrates, we have isolated an antifungal from Haliclona enamela collected from Jorf Lasfar Port, El Jadida, Morocco. This has a strong antifungal activity against three yeasts (two Candida spp. and one Cryptococcus spp.) involved in human mycology and especially against Candida tropicalis resistant to nystatin and amphotericin B. PMID- 23726236 TI - Role of mesenchymal stem cells in partial liver transplantation. PMID- 23726235 TI - Radiofrequency ablation of the pancreas with and without intraluminal duodenal cooling in a porcine model. AB - OBJECTIVE: To determine the short-term outcome of radiofrequency ablation (RFA) of pancreatic tissue near the duodenum and portomesenteric vessels (PMV) in a porcine model with and without intraluminal duodenal cooling. BACKGROUND: RFA has been proposed as a new treatment strategy in patients with unresectable locally advanced pancreatic cancer. RFA may cause thermal damage to the duodenum and vascular structures, but these risks and potential protective measures have never been systematically addressed. Intraluminal duodenal cooling during RFA could prevent thermal damage to the duodenum. METHODS: RFA was performed in 11 pigs during laparotomy with a bipolar probe of 30 mm active length at a power of 30 W until a total energy of 15 kJ was administered. The RFA probe was inserted in the pancreas at 5 or 15 mm from the duodenum, PMV, and in the pancreatic tail. RFA near the duodenum was performed with and without intraluminal duodenal cooling using 100 mL/min saline of 5 degrees C. Histopathologic assessment was performed. RESULTS: The maximum RFA-induced temperature was 92 degrees C. RFA with one single probe induced adequate ablation lesions with a diameter of 20 mm over a length of 30 mm. Without duodenal cooling, RFA induced duodenal thermal damage, whereas with duodenal cooling, no damage was observed. RFA at 15 mm from the PMV resulted in minimal superficial focal vascular damage, without thrombosis or hemorrhage. CONCLUSIONS: RFA provides adequate ablation zones in the pancreas of the porcine. Thermal damage to the duodenum can be prevented by intraluminal duodenal cooling without loss of ablation effectivity. PMID- 23726237 TI - Microglial activation induced by traumatic brain injury is suppressed by postinjury treatment with hyperbaric oxygen therapy. AB - BACKGROUND: The mechanisms underlying the protective effects of hyperbaric oxygen (HBO) therapy on traumatic brain injury (TBI) are unclear. TBI initiates a neuroinflammatory cascade characterized by activation of microglia and increased production of proinflammatory cytokines. In this study, we attempted to ascertain whether the occurrence of neuroinflammation exhibited during TBI can be reduced by HBO. METHODS: TBI was produced by the fluid percussion technique in rats. HBO (100% O2 at 2.0 absolute atmospheres) was then used at 1 h (HBO I) or 8 h (HBO II) after TBI. Neurobehavior was evaluated by the inclined plane test on the 72 h after TBI and then the rats were killed. The infarction area was evaluated by Triphenyltetrazolium chloride. Immunofluorescence staining was used to evaluate neuronal apoptosis (TUNEL + NeuN), microglial cell aggregation count (OX42 + DAPI), and tumor necrosis factor-alpha (TNF-alpha) expression in microglia cell (OX42 + TNF-alpha). RESULTS: The maximum grasp angle in the inclined plane test and cerebral infarction of the rats after TBI were significantly attenuated by HBO therapy regardless of whether the rats were treated with HBO 1 or 8 h after TBI compared with the controls. TBI-induced microglial activation, TNF-alpha expression, and neuronal apoptosis were also significantly reduced by HBO therapy. CONCLUSIONS: Our results demonstrate that treatment of TBI during the acute phase of injury can attenuate microgliosis and proinflammatory cytokine TNF alpha expression resulting in a neuroprotective effect. Even treating TBI with HBO after 8 h had a therapeutic effect. PMID- 23726238 TI - Intentional foreign object ingestions: need for endoscopy and surgery. AB - BACKGROUND: Intentional ingestion of foreign objects (IIFO) is common in the incarcerated population. This study was undertaken in order to better define clinical patterns of IIFO among prisoners. We sought to determine factors associated with the need for endoscopic and surgical therapy for IIFO. METHODS: After obtaining permission to conduct IIFO research in incarcerated populations, study patients were identified by ICD-9 codes. Patient charts were reviewed for demographics; past medical history; IIFO characteristics; and diagnostic, endoscopic, and surgical findings. Univariate and multivariate analyses were performed using statistical software. RESULTS: Thirty patients with 141 episodes of IIFO were identified. The mean number of ingested items per episode was 4.60. Endoscopy was performed in 97 of 141 IIFO instances, with failure to retrieve the ingested object in 21 of 97 cases (22%). Eleven instances (7.8%) required surgical intervention. On multivariate analyses, hospital admission was associated with elevated white blood cell count (odds ratio [OR] 1.4, P < 0.05) and number of items ingested (OR 1.3, P < 0.05). The need for endoscopy was independently associated with ingestion of multiple objects (OR 3.3, P < 0.05) and elevated white blood cell count (OR 1.3, P < 0.05). Surgical therapy was significantly associated with elevated white blood cell count (OR 1.6, P < 0.01) and with increasing number of ingested items (OR 1.07 per item, P < 0.05). Endoscopy is associated with significantly lower odds of surgery (OR 0.13, P < 0.01). CONCLUSIONS: Intentional ingestion of foreign objects continues to pose a significant human and economic burden. The need for admission or therapy is frequently associated with leukocytosis. Further investigation is warranted into resource-appropriate triage of patients who present with IIFO. PMID- 23726239 TI - Hepatic ischemia-reperfusion increases circulating bone marrow-derived progenitor cells and tumor growth in a mouse model of colorectal liver metastases. AB - BACKGROUND: Hepatic pedicle clamping is often required to reduce blood loss and transfusion during liver resection. However, the question remains whether use of hepatic pedicle clamping promotes tumor growth. Endothelial progenitor cells (EPCs) are mobilized from bone marrow in response to tissue ischemia, which allows neovascularization of ischemic tissue. It has been suggested that EPCs are involved in tumor progression. We hypothesized that hepatic ischemia reperfusion (I/R)-induced mobilization of EPCs could enhance growth of microscopic tumor, therefore promoting liver metastasis in a mouse model of colorectal cancer. MATERIALS AND METHODS: We used mouse models of hepatic I/R and hind limb ischemia. For comparison, we studied mice that underwent limb ischemia as positive controls of EPC mobilization. At day 0, we divided 40 mice into four groups: hepatic I/R, hind limb ischemia, combined hepatic I/R and hind limb ischemia, and control (sham midline incision laparotomy). At day 2, we induced liver metastasis in all mice by injecting CT-26 cells into the spleen. Time dependent circulating EPCs were determined by flow cytometry. We evaluated liver metastasis and microvascular density on day 21. RESULTS: The number of circulating progenitor cells increased rapidly in the ischemic groups compared with the control group. Hepatic I/R significantly increased tumor outgrowth compared with the control group. Increased tumor growth was associated with enhanced CD31-positive microvascular density in liver tissue. CONCLUSIONS: Hepatic I/R leads to mobilization of bone marrow-derived EPCs and enhanced intra hepatic angiogenesis, which is associated with increased tumor burden in an animal model of colorectal liver metastasis. PMID- 23726240 TI - Dobutamine-mediated heme oxygenase-1 induction via P13K and p38 MAPK inhibits high mobility group box 1 protein release and attenuates rat myocardial ischemia/reperfusion injury in vivo. PMID- 23726241 TI - Pressure redistribution devices: what works, at what cost and what's next? AB - This article discusses the development and usage of pressure redistribution devices (PRDs) and their impact on the prevention and treatment of pressure ulcers within the NHS. The article outlines the history of the development of these devices and discusses the reasons for a lack of substantial evidence in support of the use of these devices, their impact on the NHS on cost and perceived outcome. The article describes the typical usage profile in a 500 bed NHS hospital and concludes with a view as to how that may change in the future. PMID- 23726242 TI - Preparation and characterization of a new microwave immobilized poly(2 phenylpropyl)methylsiloxane stationary phase for reversed phase high-performance liquid chromatography. AB - A new reversed phase high-performance liquid chromatography (RP-HPLC) stationary phase was prepared and its chromatographic and physical-chemical properties were evaluated. The new stationary phase was prepared with a silica support and poly(2 phenylpropyl)methylsiloxane (PPPMS), a phenyl type polysiloxane copolymer. Since this is a new copolymer and there is little information in the literature, it was submitted to physical-chemical characterization by infrared spectroscopy and thermogravimetry. The chromatographic phase was prepared through sorption and microwave immobilization of the copolymer onto a silica support. The chromatographic performance was evaluated by employing test procedures suggested by Engelhardt and Jungheim, Tanaka and co-workers, Neue, and Szabo and Csato. These test mixtures provide information about the hydrophobic selectivity, silanophilic activity, ion-exchange capacity, shape selectivity and interaction with polar analytes of the new Si-PPPMS reversed phase. Stability tests were developed using accelerated aging tests under both basic and acidic conditions to provide information about the lifetime of the packed columns. PMID- 23726243 TI - Direct quantification of bacterial molybdenum and iron metallophores with ultra high-performance liquid chromatography coupled to time-of-flight mass spectrometry. AB - Metallophores are a unique class of organic ligands released, for example, by nitrogen fixing bacteria in their environment in order to recruit the micronutrients molybdenum (Mo) and iron (Fe). Mo and Fe are essential cofactors of nitrogenase that reduces atmospheric nitrogen into bioavailable ammonium. Upon release, these bacterial metallophores bind to both metal cations and oxo-anions in the extracellular medium increasing the bioavailability of the metals to the nitrogen fixers, which can subsequently recruit the complexes. The efficient quantification of those metal complexes is crucial for the understanding of the homeostasis of the metal cofactors of nitrogenase (e.g., Fe and Mo), the dynamics of nitrogen fixation and the nitrogen cycle. A novel direct ultra-high performance liquid chromatography coupled to a time-of-flight mass spectrometer (UHPLC-ToF-MS) was developed to quantify and monitor the production of Fe and Mo complexes of the catecholate metallophores protochelin (Prot) and azotochelin (Azo) in the growth medium of the nitrogen fixer and model organism Azotobacter vinelandii. Chromatographic separations were carried on a reversed C18-phase with a mobile phase ramped from water to acetonitrile spiked with 1 mmol/L ammonium acetate (pH 6.6) to achieve stability of the metal complexes. Linearity for Mo protochelin and Fe-protochelin was found at the concentration range between 5.0*10(-8) and 9.0*10(-7) mol/L with a limit of detection of 2.0*10(-8) and 3.0*10(-8) mol/L, respectively. The coefficient of variation of the procedure is in the range from 1.5 to 3.4%. The validation has hence demonstrated that the UHPLC-ToF-MS methodology is a fast, precise, specific, robust, and sensitive approach allowing the direct measurement of metallophores in growth medium without any sample preparation. The UHPLC-ToF-MS methodology was applied to the analysis of metallophores in our laboratory. Under lower Mo concentration, the Mo protochelin concentration peaks in the middle lag phase, while the Fe-protochelin concentration rises to two maxima at the beginning of the exponential phase and during the stationary phase. The results indicate that the production of metallophores is highly dynamic throughout the growth and has to be monitored with high sensitivity and temporal resolution. PMID- 23726244 TI - Protein and virus-like particle adsorption on perfusion chromatography media. AB - The structural and protein adsorption characteristics of the perfusion chromatography matrix POROS((r)) HS 50 are determined. Transmission electron microscopy shows a broad distribution of pore sizes with 100-500nm through-pores transecting a network of much smaller pores formed by aggregates of microgranules about 100nm in size. Dextran standards, proteins, and virus-like particles (VLPs) show size-exclusion behavior consistent with such a bimodal distribution of pore sizes. For non-binding conditions, the trends in height equivalent to a theoretical plate (HETP) as a function of mobile phase velocity and molecular size are consistent with perfusion suggesting that a fraction of the mobile phase between 0.0005 and 0.0008 flows through the particles. This small fraction provides little or no enhancement of intraparticle mass transfer for relatively small proteins (lysozyme and IgG) even at 1000cm/h, but can contribute substantially to transport for large proteins (thyroglobulin) and VLPs. Intraparticle concentration profiles during transient adsorption are determined by confocal microscopy in batch and flow systems. The profiles are spherically symmetrical indicating a dominance of diffusion for smaller proteins in both batch and flow systems but become highly asymmetrical and skewed in the direction of flow for thyroglobulin at 1000cm/h. Estimates of the convective enhancement of intraparticle transport for these conditions based on the confocal measurements are consistent with estimates of the intraparticle Peclet number and previously published models. Adsorption of VLPs, however, was found to be confined to a thin layer on the outer surface of the particles indicting that bound VLPs block access to the underlying pore network and suggesting that pores larger than those present on the resin studies are needed to take advantage of the effects of perfusion for the adsorption of large VLPs. PMID- 23726245 TI - Analysis of immobilized artificial membrane retention factors for both neutral and ionic species. AB - Retention data on an immobilised artificial membrane have been taken from the work of Li et al. and from Liu et al., and have been correlated with a set of descriptors that includes descriptors for ionized species, that is anions from deprotonated acids and cations from protonated bases. Log k(IAM) values can be predicted for acids or bases that are partially ionized at the experimental pH and log k(IAM) values for acids and bases can be predicted as a function of the fraction present as the ionized species, equivalent to prediction as a function of pH. It is shown that anions reduce the value of log k(IAM) by about 1.1 log units but that cations have almost no effect by comparison to the neutral species. By comparison to non-polar solvents, carboxylate anions and protonated base cations are considerably stabilized by both water and the IAM phase to about 6-8 log units and so the rather small influence of anions (-1.1 log unit) and cations (-0.1 log unit) on log k(IAM) is due to substantial cancellation of these stabilization effects. Indeed, the effect of change of phase from water to IAM on the neutral species is at least as large as the effect of change of phase on the ionic species. PMID- 23726247 TI - Combining poly(dimethyldiphenylsiloxane) and nitrile phases for improving the separation and quantitation of benzalkonium chloride homologues: In-tube solid phase microextraction-capillary liquid chromatography-diode array detection-mass spectrometry for analyzing industrial samples. AB - The retention and separation of four homologues of benzalkonium chloride (alkyl (C12, C14, C16, C18) dimethylbenzylammonium chloride) have been studied in poly(dimethyldiphenylsiloxane) (TRB) and nitrile capillary phases, respectively. Under the optimized conditions (50% acetonitrile in processed samples, 35% of diphenyl content of the TRB, capillary length 43cm and water:methanol 60:40 as replacing solvent), the extraction efficiency was similar for all the homologues with satisfactory reproducibility and independently of the amount and proportion of homologues. Industrial samples with high viscosity or with complex composition and washes waters have been analyzed without previous treatment. The coupling of IT-SPME-CapLC-DAD to MS detection allowed the determination of the minority homologues (C16 and C18) in the industrial samples and washes waters. No matrix effect was found. PMID- 23726246 TI - Simultaneous quantification of Delta(9)-tetrahydrocannabinol, 11-nor-9-carboxy tetrahydrocannabinol, cannabidiol and cannabinol in oral fluid by microflow liquid chromatography-high resolution mass spectrometry. AB - Delta(9)-Tetrahydrocannabinol (THC) is the primary target in oral fluid (OF) for detecting cannabis intake. However, additional biomarkers are needed to solve interpretation issues, such as the possibility of passive inhalation by identifying 11-nor-9-carboxy-THC (THCCOOH), and determining recent cannabis smoking by identifying cannabidiol (CBD) and/or cannabinol (CBN). We developed and comprehensively validated a microflow liquid chromatography (LC)-high resolution mass spectrometry method for simultaneous quantification of THC, THCCOOH, CBD and CBN in OF collected with the Oral-Eze((r)) and QuantisalTM devices. One milliliter OF-buffer solution (0.25mL OF and 0.5mL of Oral-Eze buffer, 1:3 dilution, or 0.75mL Quantisal buffer, 1:4 dilution) had proteins precipitated, and the supernatant subjected to CEREXTM PolycromTM THC solid-phase extraction (SPE). Microflow LC reverse-phase separation was achieved with a gradient mobile phase of 10mM ammonium acetate pH 6 and acetonitrile over 10min. We employed a Q Exactive high resolution mass spectrometer, with compounds identified and quantified by targeted-MSMS experiments. The assay was linear 0.5 50ng/mL for THC, CBD and CBN, and 15-500pg/mL for THCCOOH. Intra- and inter-day and total imprecision were <10.8%CV and bias 86.5-104.9%. Extraction efficiency was 52.4-109.2%, process efficiency 12.2-88.9% and matrix effect ranged from -86 to -6.9%. All analytes were stable for 24h at 5 degrees C on the autosampler. The method was applied to authentic OF specimens collected with Quantisal and Oral Eze devices. This method provides a rapid simultaneous quantification of THCCOOH and THC, CBD, CBN, with good selectivity and sensitivity, providing the opportunity to improve interpretation of cannabinoid OF results by eliminating the possibility of passive inhalation and providing markers of recent cannabis smoking. PMID- 23726248 TI - Monte Carlo simulation of the basic features of the GE Millennium MG single photon emission computed tomography gamma camera. AB - OBJECTIVE: To describe and validate the simulation of the basic features of GE Millennium MG gamma camera using the GATE Monte Carlo platform. MATERIAL AND METHODS: Crystal size and thickness, parallel-hole collimation and a realistic energy acquisition window were simulated in the GATE platform. GATE results were compared to experimental data in the following imaging conditions: a point source of (99m)Tc at different positions during static imaging and tomographic acquisitions using two different energy windows. The accuracy between the events expected and detected by simulation was obtained with the Mann-Whitney-Wilcoxon test. Comparisons were made regarding the measurement of sensitivity and spatial resolution, static and tomographic. Simulated and experimental spatial resolutions for tomographic data were compared with the Kruskal-Wallis test to assess simulation accuracy for this parameter. RESULTS: There was good agreement between simulated and experimental data. The number of decays expected when compared with the number of decays registered, showed small deviation (<= 0.007%). The sensitivity comparisons between static acquisitions for different distances from source to collimator (1, 5, 10, 20, 30 cm) with energy windows of 126-154 keV and 130-158 keV showed differences of 4.4%, 5.5%, 4.2%, 5.5%, 4.5% and 5.4%, 6.3%, 6.3%, 5.8%, 5.3%, respectively. For the tomographic acquisitions, the mean differences were 7.5% and 9.8% for the energy window 126-154 keV and 130 158 keV. Comparison of simulated and experimental spatial resolutions for tomographic data showed no statistically significant differences with 95% confidence interval. CONCLUSIONS: Adequate simulation of the system basic features using GATE Monte Carlo simulation platform was achieved and validated. PMID- 23726249 TI - Role of FDG PET/CT in investigating the mechanisms underlying atherosclerotic plaque formation and evolution. AB - This review article is focused on the role of FDG-PET/CT in visualizing atherosclerosis and on the relevance of inflammatory cells such as macrophages and T-lymphocytes in the formation of the atherosclerotic plaque. The vulnerability of the inflammatory plaque and the risk derived from the provocation of cardio- and cerebrovascular incidents independently from the presence of stenotic vessels are discussed as well as the evolution toward calcified plaque. The important role of FDG-PET/CT in early diagnosis of inflammatory plaque is discussed in both animal studies and in clinical setting. The possibility of curing inflammatory plaques, type of drugs, and the possibility of monitoring the anti-inflammatory treatment by FDG-PET/CT are also discussed. PMID- 23726250 TI - Ambulatory arterial stiffness index in type 1 diabetes mellitus: any different during pregnancy? AB - OBJECTIVE: To analyze the ambulatory arterial stiffness index (AASI) and pulse pressure (PP) during pregnancy and 3 months after delivery in type 1 diabetes mellitus (T1DM) and compare it to healthy pregnant controls. STUDY DESIGN: Prospective, descriptive study of 59 women with T1DM and 42 non-diabetic women. Blood pressure was measured using a portable oscillometry monitor and AASI was calculated as 1 minus the regression slope of diastolic on systolic blood pressure obtained from 24-h monitoring. Main outcome measures were comparisons of the AASI and PP between T1DM women and controls examined during pregnancy, and of the AASI and PP during and after pregnancy in T1DM women. RESULTS: PP and AASI were higher at all times during pregnancy in T1DM compared to postpartum (p<0.01). AASI and PP were significantly associated with albumin excretion rate when adjusting for retinopathy, preeclampsia, duration of diabetes, HbA1c, age, and BMI. The AASI was positively correlated with night-day ratio in the 1st and 3rd trimesters during pregnancy. No difference was found in AASI compared with non-diabetic controls during pregnancy. CONCLUSIONS: AASI and PP increased during diabetic pregnancy and were associated with the women's albuminuria grade. PMID- 23726251 TI - [Atlas of skin perforator arteries of trunk and limbs - guide in the realization of perforator flaps]. AB - INTRODUCTION: Since Harvey, anatomists and surgeons have developed better knowledge of skin vascularization. Descriptive anatomy evolved from the direct and indirect cutaneous arteries concept to that of skin perforator arteries. These skin perforator arteries have preferential locations or clusters. An atlas of skin perforator arteries allows identifying these clusters in relation to anatomical landmarks. MATERIAL AND METHODS: A literature review was undertaken in order to find the characteristics of perforator arteries originating in the source arteries described by Taylor. This research allowed us to uncover 895 citations. We have selected from this abundant literature source only the articles that specifically treated the perforator arteries localization. All the data concerning the perforator arteries localization, their source artery, the caliber and territory, were analyzed and recorded. We described the perforators that were covered most frequently. RESULTS: The definition of these clusters is based on a work of collecting and synthesizing of anatomical, radiological and clinical data. The preferential territories or clusters of skin perforators were defined using simple anatomical landmarks. A synthesized iconography was imagined to allow easy and fast usage of the atlas. CONCLUSIONS: This atlas is a learning tool that helps realizing locoregional or free perforator flaps. It can form a "winning duo" with the acoustic Doppler in preoperatory design of a perforator flap. This duo is easily available, portable, easy to use, non-invasive and inexpensive. In conclusion, the precise localization of perforator arteries associated to adherence to the big principles and definitions of the perforator flaps will allow users to better understand the surface and orientation of the skin paddle that can be taken on one perforator artery. PMID- 23726252 TI - Professor Sir Robert Edwards, 1925-2013. PMID- 23726253 TI - A psychological perspective on male rejuvenation. AB - Male rejuvenation, defined as a process in men to both limit the impact of aging on body image and experience greater virility, is growing among middle-aged and older men. While rejuvenation was primarily in the domain of the younger male athlete with the use of performance enhancing hormones or in the aging woman through the use of cosmetic surgery, it is now more common among middle-aged and older men. Male rejuvenation can occur both through aesthetic surgical means and hormonal manipulation through anabolic steroid use. In this article, the authors review the psychological issues and perceptions surrounding male aesthetic surgeries and the resulting alteration of perception by peers and family; highlight the motives and desires behind the use of anabolic hormones at often supra-physiologic levels, and the intent to improve body image; and clarify the needs that remain to be examined in future research in this field. PMID- 23726254 TI - Scientific overview of hormone treatment used for rejuvenation. AB - A search for a hormonal fountain of youth has been hotly pursued over the last century, predominately by those who wish to market hormones to a gullible public. There is little or no benefit of hormone replacement in persons who do not have a hormone deficiency. Overall, the present state of the art suggests that the findings have been disappointing. In persons who fail to get adequate sunlight, and therefore have low vitamin D levels, vitamin D replacement appears to have positive effects, including decreasing mortality. Testosterone in hypogonadal males has a number of positive effects such as improving libido and erectile capacity, increasing strength and bone mineral density, and perhaps having a small effect on cognition. These effects need to be balanced against long-term side effects, the evidence for which studies are lacking. There is little evidence to recommend DHEA, pregnenolone, growth hormone, ghrelin, or melatonin to older persons. Overall, exercise, adequate exposure to sunlight, and adequate dietary protein appear to have at least as positive an effect as any of the hormones being used to rejuvenate older persons. PMID- 23726255 TI - Reproducibility of maximal cardiopulmonary exercise testing for young cystic fibrosis patients. AB - BACKGROUND: The reproducibility of cardiopulmonary exercise testing (CPET) has not been established in young cystic fibrosis (CF) patients using a valid protocol. METHODS: Thirteen 7-18 year olds completed three CPETs, separated by 48 h and 4-6 weeks. CPET involved a ramp-incremental cycling test with supramaximal verification. RESULTS: Maximal oxygen uptake was repeatedly determined with no learning effect and typical errors expressed as a coefficient of variation (TE(CV%)) of 9.3% (48 h) and 13.3% (4-6 weeks). The reproducibility of additional parameters of aerobic function [gas exchange threshold (TE(CV%): 11.2%, 16.8%); VO2 mean response time (TE(CV%): 37.8%, 89.4%); VO2 gain (TE(CV%): 17.4%, 24.5%)] and clinical utility [e.g. SaO2% (TE(CV%): 2.2%, 3.1%); ventilatory drive (V(E)/VCO2-slope) (TE(CV%): 7.8%, 17.7%)] was also established over the short- and the medium-term, respectively. CONCLUSION: These results establish limits of variability to determine meaningful changes over the short- and the medium-term for CPET outcomes in young CF patients. PMID- 23726256 TI - Unusual movement disorders in spinocerebellar ataxias. PMID- 23726257 TI - External validation of a simplified BCLC staging system for early hepatocellular carcinoma. AB - BACKGROUND AND AIMS: The aim was to externally validate the capability of a simplified Barcelona Clinic Liver Cancer (s-BCLC) staging system in allocating patients to hepatic resection (HR) and the effect on survival: S-BCLC was defined by only 2 groups: AA included BCLC A1 + A2 classes with alpha-fetoprotein (AFP) <= 20 ng/ml and AB included A1 + A2 with AFP > 20 ng/ml plus A3 + A4 subgroups. METHODS: This study compared a training group (TG) with hepatocellular carcinoma (HCC) submitted to hepatic resection (HR) in Milan with another group of patients, the validation group (VG) in Creteil. All patients underwent ultrasound guided anatomical resection (<3 segments). RESULTS: Overall survival got worse from A1 to A4 (p = 0.0271) in TG (n = 132), as well as in VG (n = 100) (p = 0.0044) with a more important overlapping of each curves. According s-BCLC classification, the survival curves of TG (p = 0.0001) and VG (p = 0.0250) showed a definitive separation in two different staging groups. The s-BCLC provided the best predictive accuracy and it also presented the highest separability index and C-statistics in both TG and VG. On the other hand, in the evaluation of discriminatory ability for death, measured by ROC curve areas, the s-BCLC system gave better results than the others. CONCLUSION: This experience stressed the high value of BCLC system in staging of HCC, but the s-BCLC system seems to be more useful for therapeutic decision making. PMID- 23726258 TI - Perioperative chemotherapy for resectable colorectal liver metastases: where now? AB - Following the publication of the EORTC trial (40983), perioperative chemotherapy has become the standard of care for all patients with resectable colorectal cancer liver metastases (CRLM). However recently presented data suggest that the earlier advantage seen in progression free survival (PFS) may not translate over into a meaningful overall survival (OS) advantage. At the other end of the spectrum, patients with irresectable but liver limited CRLM continue to be offered treatment based on improving PFS, at the expense of regimens with greater response rates (but maybe poorer PFS rates) that could bring them to potentially curative liver resection. We therefore argue that patients with liver limited CRLM should be managed in three separate groups: Group One: those with easily resectable disease who should be offered immediate surgery, followed by adjuvant therapy if considered appropriate. Group Two: those with borderline resectable or high recurrence risk CRLM who could be offered appropriate systemic neoadjuvant therapy prior to planned liver surgery. Group Three: those with inoperable but liver limited CRLM who should be offered the most effective and appropriate systemic therapy with the primary purpose of achieving maximal disease response (and not PFS) with the intention of conversion to surgical resectability with curative intent. PMID- 23726259 TI - Risk assessment strategies as a tool in the application of the Appropriate Level of Protection (ALOP) and Food Safety Objective (FSO) by risk managers. AB - In the course of the last decade, the Appropriate Level of Protection (ALOP), the Food Safety Objective (FSO) and their associated metrics have been proposed by the World Trade Organization and Codex Alimentarius as a means for competent authorities to ultimately translate governmental public health policy regarding food safety into risk-based targets for the food industry. The industry needs to meet these targets through the effective choice of control measures that are part of its operational food safety management system. The aim of this study was to put the practical application of ALOP and FSO to the test in the case of Salmonella in chicken meat in the Netherlands. Two different risk assessment approaches were applied to derive potential ALOP and FSO values, a 'top-down' approach based on epidemiological data and a 'bottom-up' approach based on food supply chain data. To this end, two stochastic models specific to the Dutch situation were built. Comparisons between 23 countries in Europe were also made using the top-down model. The mean estimated current Level Of Protection values were similar for the two approaches applied, with the bottom-up model yielding 87 cases per 100,000 inhabitants per year (95% CI: 0.03, 904) and the top-down model 71 (95% CI: 9.9, 155). The estimated FSO values on the other hand were considerably different with the mean 'top down' FSO being -4.6 log CFU/g (95% CI: -5.4, -4.1) and the mean 'bottom-up' FSO -6.0 log CFU/g (95% CI: -8.1, -2.9) reflecting major differences in the output distributions of this parameter obtained with the two approaches. Significant differences were observed between current LOP values for different EU countries, although it was not clear whether this was due to actual differences in the factors influencing the risk of salmonellosis or due to the quality of the available data. PMID- 23726260 TI - Depressive symptoms in Taiwanese women during the peri- and post-menopause years: associations with demographic, health, and psychosocial characteristics. AB - OBJECTIVE: The purpose of this study was to evaluate the prevalence of depressive symptoms in peri- and post-menopausal Taiwanese women, and to investigate the relation between depressive symptoms and demographic variables, chronic disease status, health habits, stress management, menopausal symptoms, and attitudes toward menopause and aging. STUDY DESIGN: Cross-sectional study, using a purposive sample of 566 women between 45 and 60 years of age from a medical center and residential community in Southern Taiwan. MAIN OUTCOME MEASURES: Demographic and health habits questionnaire, Women's Health Initiative Symptom Scale, Attitudes Toward Menopause and Aging Scale, and Center for Epidemiological Studies-Depression Scale (CES-D). RESULTS: The prevalence of depressive symptoms (CES-D score>=16) was 38.7% in peri- and post-menopausal Taiwanese women. Bivariate correlations and analyses of variance indicated that higher CES-D scores were related to lower family income, younger age, smoking for a greater number of years, consuming more alcohol, having multiple chronic diseases, not exercising regularly, consulting with a specialist for stress management, having more severe menopausal symptoms, and more negative attitudes toward menopause and aging. A stepwise multiple regression analysis indicated that the key predictors, accounting for 33.7% of the variance, were menopausal symptoms, attitudes toward menopause and aging, family income, and chronic disease status. CONCLUSIONS: Results highlight the importance of considering psychosocial factors, life style, and chronic disease management in providing health guidance for peri- and post menopausal women to enhance their quality of life and reduce the risk of depressive symptoms. PMID- 23726261 TI - High incidence of heparin-induced allergic delayed-type hypersensitivity reactions in pregnancy. AB - BACKGROUND: Among the most frequent adverse effects of subcutaneous heparin treatment, heparin-induced skin lesions occur with an incidence of 10.3% in nonpregnant female patients. Clinical observations suggest an even higher risk during pregnancy. OBJECTIVES: We sought to determine the incidence and causes of heparin-induced skin reactions during pregnancy in a prospective cohort study. METHODS: Pregnant women with subcutaneous heparin treatment were prospectively examined for skin reactions. If a skin lesion was observed, further diagnostics were performed (skin biopsy, subcutaneous provocation, clinical/laboratory assessment for thrombosis, bleeding, and heparin-induced thrombocytopenia [HIT]). Safety parameters were also analyzed (cross-allergies, frequency of thromboembolic and bleeding complications, HIT, and pregnancy outcome). RESULTS: Among 111 pregnant patients, 22 (19.8%) had heparin-induced skin reactions (95% CI, 13% to 29%). All lesions were caused by allergic delayed-type hypersensitivity (DTH) reactions and not by HIT or other rare conditions. The median time of onset was 50.5 days (range, 5-184 days). The cross-reactivity rate was 33.3%. While nadroparin treatment exhibited a higher DTH risk than dalteparin (hazard ratio [HR], 26.7; 95% CI, 3.4-211.0; P = .00187), enoxaparin treatment was not significantly different from dalteparin treatment (HR, 5.6; 95% CI, 0.3 96.1; P = .238). Three thromboembolic events and 1 major bleeding event occurred. CONCLUSIONS: Among patients receiving long-term heparin anticoagulation during pregnancy, heparin-induced skin lesions are frequent (incidence, 19.8%) and are all caused by allergic DTH reactions. Nadroparin has the highest frequency of skin lesions (approximately 65% at 100 days), which is significantly higher than that of dalteparin (HR, 26.7). Therefore nadroparin use should be avoided in pregnancy when possible. PMID- 23726262 TI - Novel immunologic classification of aspergillosis in adult cystic fibrosis. AB - BACKGROUND: Patients with cystic fibrosis (CF) demonstrate a wide range of hypersensitivity responses to Aspergillus, beyond allergic bronchopulmonary aspergillosis, which require classification. OBJECTIVE: This study integrated 2 new methods of Aspergillus detection-sputum galactomannan (GM) and real-time PCR alongside established serologic markers, to reclassify aspergillosis in CF. METHODS: A total of 146 adult patients with CF had serologic tests (ImmunoCap total IgE, specific Aspergillus fumigatus IgE, and specific A fumigatus IgG), sputum real-time Aspergillus PCR, and sputum GM. Patients were classified by using latent class analysis. RESULTS: Both RT-PCR and GM were more sensitive than culture in detecting Aspergillus in sputum (culture 37%, RT-PCR 74%, and GM 46%). Intraassay and interassay reproducibility of PCR and GM was excellent. Latent class analysis of triazole-naive patients identified a nondiseased group and 3 disease classes: class 1 (n = 49, 37.7%) represented patients with or without positive RT-PCR but no immunologic response to A fumigatus and negative GM (nondiseased); class 2 (n = 23, 17.7%) represented patients with positive RT-PCR, elevated total and specific A fumigatus IgE/IgG, and positive GM (serologic allergic bronchopulmonary aspergillosis); class 3 (n = 19, 14.6%) represented patients with or without positive RT-PCR, elevated A fumigatus IgE (not IgG), and negative GM (Aspergillus sensitized); and class 4 (n = 39, 30%) represented patients with positive RT-PCR, elevated A fumigatus IgG (not IgE), and positive GM (Aspergillus bronchitis). CONCLUSIONS: Three distinct classes of aspergillosis in CF were identified by latent class analysis by using serologic, RT-PCR, and GM data. This novel classification will facilitate improved phenotyping, pathogenesis studies, and management evaluations. PMID- 23726263 TI - MicroRNAs: Essential players in the regulation of inflammation. AB - Regulation of inflammatory responses is ensured by coordinated control of gene expression in participating immune system and tissue cells. One group of gene expression regulators, the functions of which have recently been started to be uncovered in relation to any type of inflammatory condition, is a class of short single-stranded RNA molecules termed microRNAs (miRNAs). miRNAs function together with partner proteins and mainly cause gene silencing through degradation of target mRNAs or inhibition of translation. A particular miRNA can have hundreds of target genes, and thereby miRNAs together influence the expression of a large proportion of proteins. The role of miRNAs in the immune system has been extensively studied since the discovery of miRNAs in mammalian cells approximately 10 years ago. The purpose of the current review is to provide an overview on the functions of miRNAs in the regulation of inflammation, with a specific focus on the mechanisms of allergic inflammation. Because recent studies clearly demonstrate the presence of extracellular miRNAs in body fluids and propose the involvement of miRNAs in cell-cell communication, we will also highlight findings about functions of extracellular miRNAs. The possible use of miRNAs as biomarkers, as well as miRNA-related novel treatment modalities, might open a new future for the diagnosis and treatment of many inflammatory conditions, including allergic diseases. PMID- 23726264 TI - A galactosidase-responsive doxorubicin-folate conjugate for selective targeting of acute myelogenous leukemia blasts. AB - Cytarabine combined with an anthracycline or an anthracenedione represents the usual intensive induction therapy for the treatment of AML. However, this protocol induces severe side effects and treatment-related mortality due to the lack of selectivity of these cytotoxic agents. In this paper, we present the study of the first galactosidase-responsive molecular "Trojan Horse" programmed for the delivery of doxorubicin exclusively inside AML blasts over-expressing the folate receptor (FR). This targeting system allows the selective killing of AML blasts without affecting normal endothelial, cardiac or hematologic cells from healthy donors suggesting that FDC could reduce adverse events usually recorded with anthracyclines. PMID- 23726265 TI - S100A2 is a predictive biomarker of adjuvant therapy benefit in pancreatic adenocarcinoma. AB - BACKGROUND: Prognosis of patients with pancreatic adenocarcinoma (PAC) remains poor. S100A2 has been recently suggested as a negative prognostic biomarker in PAC. We aimed to investigate its prognostic and/or predictive value in a large independent multicentric cohort of patients with resected PAC. METHODS: Sequential samples of 471 patients were retrospectively collected; 142 patients did not receive adjuvant treatment (30%) and 329 (70%) received an adjuvant treatment. We measured protein levels of S100A2 by semiquantitative immunohistochemistry with tissue microarrays and correlated with patients' overall survival (OS) and disease-free survival (DFS). RESULTS: S100A2 protein status was obtained in 462 (98%) patients. Its expression was low, moderate or high in 59%, 12% and 2% of cases, respectively. It was not correlated with DFS or OS in the whole population, neither in the subgroup of patients who did not receive adjuvant treatment. However among patients who received an adjuvant therapy, moderate/high levels of S100A2 were significantly associated with longer OS and DFS in multivariate analysis (hazard ratios of 0.63, p=0.022 and 0.67, p=0.017, respectively), whereas low S100A2 was not. Interaction tests for adjuvant therapy were statistically significant both for the OS and the DFS (p=0.001 and p=0.023, respectively). On multivariate analysis, S100A2 retained independent predictive values (OS: p<0.001, DFS: p=0.003) with a significant benefit of adjuvant therapy for those patients with moderate/high S100A2. CONCLUSIONS: S100A2 expression predicts longer DFS and OS in patients treated with adjuvant therapy and should be evaluated as a predictive biomarker. PMID- 23726266 TI - Long non-coding RNA metastasis associated in lung adenocarcinoma transcript 1 derived miniRNA as a novel plasma-based biomarker for diagnosing prostate cancer. AB - Examining plasma RNA is an emerging non-invasive diagnosis technique. However, whether tumour-derived long non-coding RNAs (lncRNAs) in plasma can be used as a novel approach to detect human prostate cancer (PCa) has not yet been established. The study was divided into three parts: (1) the characteristics of PCa-related lncRNA fragments were systematically studied in the plasma or serum of 25 patients; (2) the source of the circulating lncRNA fragments was explored in vitro and in vivo; and (3) the diagnostic performance of metastasis associated in lung adenocarcinoma transcript 1 (MALAT-1) derived (MD) miniRNA was validated in an independent cohort of 192 patients. The expression levels of lncRNAs were measured by quantitative real time polymerase chain reaction (qRT-PCR). The MD miniRNA copies were calculated using a standard curve in an area under the ROC curve (AUC)-receiver operating characteristic (ROC) analysis. Genome-wide profiling revealed that MALAT-1 and prostate cancer gene 3 (PCA3) are overexpressed in PCa tissues. Plasma lncRNAs probably exist in the form of fragments in a stable form. MD-miniRNA enters cell culture medium at measurable levels, and MD-miniRNA derived from human PCa xenografts actually enters the circulation in vivo and can be measured to distinguish xenografted mice from controls. In addition, plasma MD-miniRNA levels are significantly elevated in PCa patients compared to non-PCa patients (p<0.001). At a cut-off of 867.8 MD-miniRNA copies per microlitre of plasma, the sensitivity is 58.6%, 58.6% and 43.5% and the specificity is 84.8%, 84.8% and 81.6% for discriminating PCa from non-PCa, positive biopsy from negative biopsy and positive biopsy from negative biopsy, respectively. We conclude that MD-miniRNA can be used as a novel plasma-based biomarker for PCa detection and can improve diagnostic accuracy by predicting prostate biopsy outcomes. Further large-scale studies are needed to confirm our findings. PMID- 23726268 TI - Basic cancer research is essential for the success of personalised medicine. AB - The last decade has witnessed significant progress in cancer understanding and therapy: we can now identify the genetic drivers of individual tumours, and tailor drugs able to specifically intercept the driver mutations. While all agree that personalised cancer medicine is a clear outcome of the resources dedicated to cancer research over the last 50 years, some critics question the necessity for continuous investments in sub-fields other than clinical research and drug development. Herein, scientists from the European Association for Cancer Research (EACR) argue that the new ways to diagnose and treat cancer present important and hitherto unaddressed challenges for fundamental research of cancer. Allocating the resources needed for basic studies will likely fuel the next wave of achievements in the long way to conquer cancer. PMID- 23726267 TI - Phase Ib study of tivozanib (AV-951) in combination with temsirolimus in patients with renal cell carcinoma. AB - BACKGROUND: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2 and -3, with a long half-life. Tivozanib has demonstrated clinical activity and acceptable tolerability in renal cell carcinoma (RCC). This phase Ib study determined the recommended phase II dose (RP2D) and evaluated the safety and clinical activity of tivozanib plus temsirolimus, a mammalian target of rapamycin inhibitor. PATIENTS AND METHODS: Patients with advanced RCC were administered open-label tivozanib 0.5, 1.0 or 1.5mg/d orally (3 weeks on/1 week off) and temsirolimus 15 or 25 mg/week intravenously in a 3+3 dose-escalation design and subsequent expansion cohort. RESULTS: Of 27 patients treated, 20 patients had received >= 1 prior VEGF-targeted therapy. No dose-limiting toxicities occurred; the RP2D was determined to be tivozanib 1.5mg/d plus temsirolimus 25mg/week. Combination of tivozanib plus temsirolimus demonstrated acceptable tolerability and suggested no synergistic toxicity. The most common grade <= 3 adverse events were fatigue and thrombocytopenia (15% each). One patient each required dose reduction of tivozanib or temsirolimus due to an adverse event. Confirmed partial responses and stable disease were achieved at 23% and 68%, respectively. Pharmacokinetic analyses may suggest lack of an interaction between tivozanib and temsirolimus. CONCLUSIONS: In this small phase Ib study, tivozanib and temsirolimus were safely combined at the fully recommended dose and schedule of both agents. The observed clinical activity and manageable toxicity profile of this combination warrant further exploration in patients with RCC. PMID- 23726269 TI - A novel missense mutation of FGFR3 in a Chinese female and her fetus with Hypochondroplasia by next-generation sequencing. AB - BACKGROUND: Hypochondroplasia (HCH) is a mild, autosomal dominant human skeletal dysplasias characterized by short extremities, short stature and lumbar lordosis. There are three other kinds of dwarfism (Pseudoachondroplasia, Achondroplasia and Thanatophoric Syndromes) with similar clinical features, which makes it difficult to give a precise diagnosis. Molecular genetic analysis of related genes should be employed. METHODS: In this study, we reported a Chinese family diagnosed as a type of skeletal dysplasia based on clinical and radiologic findings. To make an accurate diagnosis quickly and economically, we performed microarray-based next generation sequencing (NGS) to detect the variants in the disease-related genes (FGFR3 and COMP). RESULTS: The mother presents short limbed stature, short iliac bones, short femoral necks, short stubby tibia and mildly increased fibular length and genu varum. Her fetus demonstrated abnormally short femur at 23 and 28week's gestation by ultrasound scan, and was highly suspected with dwarfism. Eventually, a novel missense mutation (c.1024G>T) in FGFR3 was identified by next generation sequencing. The substitution is found in both the mother and her fetus. The mutation was further confirmed by Sanger sequencing. CONCLUSIONS: This is the first report of missense mutation identified in the IgIII domain of the FGFR3 gene using NGS. Our results extended the mutational spectrum of FGFR3 and proved that applications of NGS and bioinformatics are effective methods for skeletal dysplasia diagnosis in clinical practices. PMID- 23726270 TI - Idursulfase enzyme replacement therapy in an adult patient with severe Hunter syndrome having a novel mutation of iduronate-2-sulfatase gene. AB - Mucopolysaccharidosis II (Hunter syndrome), a lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase (IDS), has variable clinical phenotypes. Total by nearly 400 different mutations have been identified in IDS gene from patients with Hunter syndrome. Herein, we reported a patient who has a novel mutation in IDS gene with a severe clinical phenotype. Genetic analysis of the IDS gene revealed a novel 1-bp deletion in position c.1053T in exon 8 and resulting in a frameshift with a premature stop codon. Enzyme replacement therapy (ERT) using idursulfase (Elaprase(r)) was conducted to the patient and it improved hepatosplenomegaly, white blood cells and platelets number, and decreased the level of urinary glycosaminoglycan. ERT was proved to be effective at least in part in even an adult patient with severe type of Hunter syndrome. PMID- 23726271 TI - MicroRNA-375 sensitizes tumour necrosis factor-alpha (TNF-alpha)-induced apoptosis in head and neck squamous cell carcinoma in vitro. AB - We investigated the effect of microRNA-375 (miR-375) on tumour necrosis factor alpha (TNF-alpha)-induced cell death in head and neck squamous cell carcinoma, and further explored the potential molecular mechanism underlying this phenomenon. Cal27 cells were transfected with miR-375 mimic and subsequently treated with or without TNF-alpha (10 ng/ml). An additional group of cells were treated with TNF-alpha alone. The resulting morphological changes were observed, and the percentage of sub-G1 cells was measured. The protein expression and cleavage of caspase 3, caspase 8, and poly(ADP ribose) polymerase (PARP) were determined through Western blotting. The results showed a significant increase in cell death in the combination group, but not in the groups treated with miR-375 mimic, TNF-alpha alone, or control. The data obtained from sub-G1 cells supported the notion that miR-375 increases the accumulation of sub-G1. In the combination group, the degradation of caspase 3, caspase 8, and PARP was observed and the cleavage of these enzymes was detected. The pan-caspase inhibitor, Z-VAD, inhibited the apoptosis of Cal27 cells treated with a combination of miR-375 mimic and TNF-alpha. In addition, the apoptosis inhibitory proteins, cFLIP-L and cIAP1, were down-regulated in a time-dependent manner. Taken together, these data suggest that miR-375 sensitizes TNF-alpha-induced apoptosis, and the reduction in the expression of the apoptosis inhibitory proteins cFLIP-L and cIAP2 plays an important role in this sensitization. PMID- 23726272 TI - The use of Gamma Knife stereotactic radiosurgery in the treatment of ameloblastic carcinoma. AB - A case of recurrent maxillary ameloblastic carcinoma treated with Gamma Knife stereotactic radiosurgery is reported. This case demonstrates an alternative treatment modality that has not been described previously for this rare and often difficult to treat odontogenic malignancy. PMID- 23726273 TI - Airway space changes after maxillomandibular counterclockwise rotation and mandibular advancement with TMJ Concepts(r) total joint prostheses: three dimensional assessment. AB - This study focused on three-dimensional (3D) airway space changes and stability following simultaneous maxillomandibular counterclockwise rotation, mandibular advancement, and temporomandibular joint (TMJ) reconstruction with custom-made total joint prostheses (TMJ Concepts((r))). Cone beam computed tomography (CBCT) scans of 30 consecutive female patients with irreversibly compromised TMJs were obtained at the following intervals: T1, presurgery; T2, immediately after surgery; and T3, at least 6 months after surgery. The CBCT volumetric datasets were analysed with Dolphin Imaging((r)) software to evaluate surgical and postsurgical changes to oropharyngeal airway parameters. The average changes in airway surface area (SA), volume (VOL), and minimum axial area (MAA) were, 179.50 mm(2), 6302.60 mm(3), and 92.23 mm(2), respectively, at the longest follow-up (T3 T1) (P<=0.001). Significant correlations between the amount of mandibular advancement and counterclockwise rotation of the occlusal plane and 3D airway changes were also found (P<=0.01). The results of this investigation showed a significant immediate 3D airway space increase after maxillomandibular counterclockwise rotation and mandibular advancement with TMJ Concepts total joint prostheses, which remained stable over the follow-up period. PMID- 23726274 TI - The plunging ranula: diagnostic difficulties and a less invasive approach to treatment. AB - Plunging ranulas arise when a simple ranula extends beyond the floor of the mouth into the neck. Diagnosis is difficult even with modern imaging techniques as they mimic other neck lesions, and traditional treatment involves enucleation of the cyst from the neck. Despite this invasive surgery they tend to recur. We describe a less invasive approach to treatment and review the diagnostic pitfalls. From 2002 to 2011, eight patients presented with a plunging ranula. They were split into two groups: those for whom an incorrect diagnosis was made and those where a less invasive treatment approach was employed. Three patients were misdiagnosed with cervical lymphangioma and had inappropriately invasive surgery. Five patients with established plunging ranulas were treated using an intraoral approach alone, eliminating the need for a cervical incision. Misdiagnosis of a plunging ranula leads to extensive and unnecessary surgery. We propose an algorithm to simplify investigation that employs a low threshold for fine-needle aspiration cytology. The cases presented indicate that these lesions can be managed by a less invasive procedure than currently practised. PMID- 23726275 TI - Deferoxamine enhances neovascularization and accelerates wound healing in diabetic rats via the accumulation of hypoxia-inducible factor-1alpha. AB - AIMS: Hypoxia-inducible factor (HIF)-1alpha plays a pivotal role during the process of wound healing. Previous studies reported that deferoxamine (DFO) could increase HIF-1alpha stability. This study aimed to investigate the effects of DFO on wound healing in diabetic rats and explore the underlying mechanism both in vivo and in vitro. METHODS: An excisional diabetic wound model was established and the wound healing among vehicle control, DFO and vascular endothelial growth factor (VEGF) treatment groups was evaluated by macroscopy, histology and Western blot analysis. Human umbilical vein endothelial cells (HUVECs) were treated with DFO or HIF-1alpha siRNA, and then endothelial tube formation, cell proliferation and migration were examined. RESULTS: DFO-treated wounds exhibited accelerated wound healing with enhanced granulation formation and increased re epithelialization. Compared to the vehicle or VEGF treatment, DFO significantly increased neovascularization through up-regulation of HIF-1alpha and target genes including VEGF and stromal cell-derived factor-1alpha (SDF-1alpha). DFO failed to stimulate the expression of VEGF and SDF-1alpha in HUVECs depleted of HIF-1alpha. In addition, DFO promoted the angiogenic-associated processes of endothelial tube formation, cell proliferation and migration in HIF-1alpha dependent manner. CONCLUSIONS: DFO enhances neovascularization and accelerates diabetic wound healing through the accumulation of HIF-1alpha and the regulation of endothelial cell function. PMID- 23726276 TI - Oxidative stress mediated neuronal damage in the corpus striatum of 6 hydroxydopamine lesioned Parkinson's rats: neuroprotection by serotonin, GABA and bone marrow cells supplementation. AB - Oxidative stress-induced neuronal cell death has been implicated in Parkinson's disease (PD). Oxidative stress initiated by 6-hydroxydopamine (6-OHDA) causes mitochondrial dysfunction leading to apoptosis and Parkinsonian neurodegeneration. We investigated the neuroprotective potential of serotonin (5 HT), gamma amino butyric acid (GABA) and autologous bone marrow cells (BMC) in combination against oxidative stress-induced cell death. PD was induced in adult male Wistar rats by intranigral infusion of 6-OHDA (8 MUg/MUl). The activities of antioxidant enzymes--superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were analysed. The extent of lipid peroxidation was quantified by measuring the formation of thiobarbituric acid reactive substances (TBARs). Real Time PCR gene expression of SOD, CAT and GPx were performed using specific Taqman probes. 6-OHDA induced decreased activity of SOD, CAT and GPx in corpus striatum was significantly reversed to near control (p<0.001) by treatment with 5 HT, GABA and bone marrow cells. Gene expression studies of SOD, CAT and GPx using Real Time PCR confirmed the above observation. TBAR levels were elevated (p<0.001) in 6-OHDA treated rats indicating lipid peroxidation. 5-HT and GABA along with autologous bone marrow cell supplementation significantly ameliorated 6-OHDA-induced lipid peroxidation (p<0.001). Our results suggest a new therapeutic strategy of neuroprotection against damage by oxidative stress in Parkinson's disease. PMID- 23726277 TI - Incidence and 30-day case fatality rate of first-ever stroke in urban Nigeria: the prospective community based Epidemiology of Stroke in Lagos (EPISIL) phase II results. AB - BACKGROUND: Stroke is a leading cause of death worldwide and a major contributor to global disease burden. Although epidemiologic information from a community perspective is important in determining the magnitude of the burden in specific regions, and directing equitable distribution of health resources, data on the incidence of stroke in developing countries in Africa are scarce. AIMS: To determine the current incidence rate and short-term (30-day) case fatality rate (CFR) of stroke in urban Nigeria, and provide age-adjusted and gender-specific incidence rates to enable comparison with global populations. METHODS: The study was a prospective community-based stroke registry enrolling hospitalized and non hospitalized first-ever in a lifetime stroke cases presenting at all health facilities (hospitals, homeopathic caregivers, physiotherapy clinics) located in the designated community. Pre-hospitalization deaths due to stroke were not included in our study. The study was conducted between January 1st and December 31st 2007 in Surulere Local Government Area of Lagos State, south western Nigeria, a mixed-income urban locality with a population of approximately 750,000 based on data from the National Population Commission. Stroke was defined using the World Health Organization (WHO) clinical criteria. Case fatality at 30-days post stroke was determined at follow-up on 160 hospitalized stroke cases. RESULTS: 189 first-ever strokes, comprised of 112 men and 77 women (mean+/-SD age 58.5+/-13.5 years) were documented, giving a crude incidence rate of 25.2 per 100,000 per year (95% confidence interval 21.6- 28.8). The gender-specific rates were 28.3/100,000 and 21.3/100,000 for males and females respectively. The age adjusted incidence rate was 54.08 per 100,000 per year (adjusted to the WHO New World Population). Hospitalization rate was 84.6%, while the CFR (hospitalized) was 16.2%. CONCLUSIONS: The stroke incidence in this urban sub-Saharan African community remains lower than that in emerging and developed economies, although the age- and gender-related trends and CFR are comparable to that in developed countries. PMID- 23726278 TI - Developing inclusive design expertise within a client/consultancy relationship. AB - TheAlloy have been working together with British Telecom (BT), as their product design consultants, for over ten years. During that time BT have undergone a key transformation which has had a profound impact on their design focus. This transformation has seen BT actively embrace inclusive design as a core driver for their business objectives. As part of that journey, TheAlloy have in turn developed core competencies which have not only supported BT's transition, but impacted the consultancy's ability to offer these services to other clients. This paper reflects on the development of that relationship and those competencies through a series of project case studies. PMID- 23726279 TI - Paediatric vocal fold paralysis. AB - INTRODUCTION AND OBJECTIVES: Vocal fold paralysis (VFP) is a relatively common cause of stridor and dysphonia in the paediatric population. This report summarises our experience with VFP in the paediatric age group. METHODS: All patients presenting with vocal fold paralysis over a 12-month period were included. Medical charts were revised retrospectively. The diagnosis was performed by flexible endoscopic examination. The cases were evaluated with respect to aetiology of the paralysis, presenting symptoms, delay in diagnosis, affected side, vocal fold position, need for surgical treatment and outcome. RESULTS: The presenting symptoms were stridor and dysphonia. Iatrogenic causes formed the largest group, followed by idiopathic, neurological and obstetric VFP. Unilateral paralysis was found in most cases. The median value for delay in diagnosis was 1 month and it was significantly higher in the iatrogenic group. Surgical treatment was not necessary in most part of cases. CONCLUSIONS: The diagnosis of VFP may be suspected based on the patient's symptoms and confirmed by flexible endoscopy. Infants who develop stridor or dysphonia following a surgical procedure have to be examined without delay. The surgeon has to keep in mind that there is a possibility of late spontaneous recovery or compensation. PMID- 23726280 TI - Primary hydatid cyst of the neck: case report. PMID- 23726281 TI - [Enchondroma of the mastoid secondary to generalised enchondromatosis]. PMID- 23726283 TI - Solvothermal synthesis of copper (I) chloride microcrystals with different morphologies as copper-based catalysts for dimethyldichlorosilane synthesis. AB - CuCl microcrystals with different morphologies such as tetrahedra, etched tetrahedra, tripod dendrites, and tetrapods were synthesized using CuCl2?2H2O as the copper precursor in the mixed solvent of acetylacetone and ethylene glycol. The samples were characterized with X-ray diffraction, scanning electron microscopy, infrared spectroscopy, and transmission electron microscope. Cu(C5H7O2)2 was identified as the key intermediate, and the morphology and structure of the CuCl microcrystals were highly dependent on the reaction time and temperature, as well as the volume of the solvents. The catalytic properties of these CuCl microcrystals were explored in the dimethyldichlorosilane synthesis via Rochow reaction. Compared to the commercial CuCl microparticles with irregular morphology and dense internal structure, the obtained CuCl microcrystals possessed regular morphology and different exposed crystal planes and showed much higher dimethyldichlorosilane selectivity and Si conversion via the Rochow reaction because of the enhanced formation of active CuxSi phase and gas transportation within the dendritic structure, demonstrating the significance of regular morphology of the copper-based catalysts in catalytic organosilane synthesis. PMID- 23726282 TI - A probable case of acquired toxoplasmosis presenting as pyrexia of unknown origin in an immunocompetent individual. AB - Disseminated toxoplasmosis presenting as a prolonged febrile illness is rare in immunocompetent individuals. We report a probable case of acquired toxoplasmosis in an immunocompetent woman who presented with fever of 6 months duration with lymphadenopathy and splenomegaly. The diagnosis was confirmed by serology and the presence of Toxoplasma gondii tachyzoites on bone marrow aspirate. The patient was successfully treated with pyrimethamine plus clindamycin. PMID- 23726285 TI - Patients with non-specific neck disorders commonly report upper limb disability. AB - Patients with neck disorders can report difficulties with functional use of their upper limb because of their neck pain. Yet, there is little information on the frequency and specifically, the nature of these upper limb activities. This study surveyed patients with neck pain disorders (n = 103) presenting for management at private physiotherapy clinics in a large metropolitan area to investigate the frequency and nature of reduced upper limb function. Participants were asked to complete four questionnaires, the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, the Neck Disability Index (NDI), Pictorial Fear of Activity Scale-Cervical (PFActS-C) and Patient Specific Functional Scale (PSFS). Approximately 80% of patients spontaneously reported that upper limb activities aggravated their neck pain (PSFS). Most frequently, these activities involved loading of the upper limb such as lifting. Eight activity items on the DASH were scored positive by >=50% of participants. Participants had mild to moderately severe neck pain (NDI: range 2-68%). The DASH and NDI were moderately-highly correlated (rho = 0.669; p < 0.001), indicating the higher the neck pain severity the greater the upper limb functional restrictions. There was a low correlation between the NDI and PFActS-C (rho = 0.319; p = 0.001). These findings provide evidence that upper limb function is often impaired in association with neck pain disorders and suggest clinicians should routinely question patients regarding upper limb function. The DASH could be used as a suitable outcome measure in its current or possibly a modified form. PMID- 23726286 TI - Precision of 3D scapular kinematic measurements for analytic arm movements and activities of daily living. AB - Electromagnetic devices allow the non invasive and accurate measurement of 3D scapula kinematics. The acromial method allows continuous dynamic measurement using a skin surface sensor fixed to the acromion. Inter-session intra and inter observer repeatability of 3D scapular kinematics have only been partially assessed for analytical movements and never for functional tasks. Inter-session intra and inter-observer repeatability of 3D scapular kinematics were assessed for arm elevation in the sagittal and frontal planes and for two activities of daily living (ADL), hair combing and back washing, in both shoulders of 15 healthy subjects, using the intraclass correlation coefficient (ICC), the standard error of measurement (SEM), the small real difference (SRD) and the Bland and Altman's graphical method. Intra-observer repeatability was good to excellent for every scapular rotation for both arm elevation in isolated planes and ADL (ICC ranged from 0.64 to 0.95). Inter-observer repeatability of scapular rotations was fair to excellent for arm elevation in isolated planes (ICC ranged from 0.49 to 0.92) and poor to excellent for ADL (ICC ranged from 0.35 to 0.89). Inter-observer repeatability of scapular protraction/retraction had the lowest ICC. For both inter-session intra and inter-observer reliability, the SEM and SRD remained low and Bland and Altman's graphical method showed a good repeatability of the measurement method. Longitudinal monitoring of a subject's scapular kinematics by a trained observer is reliable. The inter-observer repeatability of scapular protraction/retraction must be improved. PMID- 23726288 TI - [Specificities of heart failure in the elderly]. AB - Heart failure (HF) is frequent in the elderly population and is associated with high mortality, prolonged and frequent hospitalisations. In old patients with multiple comorbid diseases, clinical symptoms of HF are less typical and the prognosis is poorer. Comprehensive geriatric assessment, using simple tests to evaluate cognitive function, falls, depression, malnutrition, dependency, comorbidities, context of life and social conditions, is needed in order to screen concomitant diseases and loss of autonomy. Because of lack of specific studies on octogenarians, most recommendations for HF treatment in this population have been extrapolated from data based on younger populations. Epidemiological studies show that recommended HF therapies as angiotensin converting enzyme inhibitors and beta-blockers are underused in elderly patients with HF. Reasons for this under prescription are various and include the absence of well-defined therapeutic strategy especially in case of preserved ejection fraction, the existence of comorbidities and the fear of adverse events. Special precautions for the use of HF drugs must be followed because of the comorbidities and age-related changes in drug pharmacokinetics or pharmacodynamics. Increase of drug dose must be closely monitored for adverse reactions. Overall, the therapeutic strategy must not be based on the subject's age, but rather on the individual analysis taking into account the severity of the heart disease, the geriatric assessment, the life expectancy and the quality of life. Clinical and laboratory monitoring should be intensified, especially in case of acute episode (infection, dehydration, introduction of a new treatment, fall...). Therefore, monitoring of heart failure in the elderly, involves multidisciplinary collaboration between cardiologists, geriatricians, general practitioners, pharmacists and paramedical team. PMID- 23726287 TI - Cyclosporine-assisted adipose-derived mesenchymal stem cell therapy to mitigate acute kidney ischemia-reperfusion injury. AB - INTRODUCTION: This study tested the hypothesis that cyclosporine (CsA)-supported syngeneic adipose-derived mesenchymal stem cell (ADMSC) therapy offered superior attenuation of acute ischemia-reperfusion (IR) kidney injury to either therapy alone. METHODS: Adult Sprague-Dawley rats (n = 40) were equally divided into group 1 (sham controls), group 2 (IR injury), group 3 (IR + CsA (20 mg/kg at 1 and 24 hours after procedure)), group 4 (syngeneic ADMSC (1.2*106) at 1, 6 and 24 hours after procedure), and group 5 (IR + CsA-ADMSC). RESULTS: By 72 hours after the IR procedure, the creatinine level and the ratio of urine protein to creatinine were highest in group 2 and lowest in group 1, and significantly higher in groups 3 and 4 than in group 5 (all P <0.05 for inter-group comparisons), but showed no differences between groups 3 and 4 (P >0.05). The inflammatory biomarkers at mRNA (matrix metalloproteinase-9, RANTES, TNF-alpha), protein (TNF-alpha, NF-kappaB, intercellular adhesion molecule-1, platelet derived growth factor), and cellular (CD68+) levels of IR kidney showed a similar pattern compared with that of creatinine in all groups (all P <0.05 for inter group comparisons). The protein expressions of oxidative stress (oxidized protein), reactive oxygen species (NADPH oxidases NOX-1, NOX-2), apoptosis (Bcl-2 associated X protein, caspase-3 and poly(ADP-ribose) polymerase) and DNA damage (phosphorylated H2A histone family member X-positive, proliferating cell nuclear antigen-positive cells) markers exhibited a pattern similar to that of inflammatory mediators amongst all groups (all P <0.05 for inter-group comparisons). Expressions of antioxidant biomarkers at cellular (glutathione peroxidase, glutathione reductase, heme oxygenase-1 (HO-1)) and protein (NADPH dehydrogenase (quinone)-1, HO-1, endothelial nitric oxide synthase) levels, and endothelial progenitor cell markers (C-X-C chemokine receptor type 4-positive, stromal cell-derived factor-1alpha-positive) were lowest in groups 1 and 2, higher in groups 3 and 4, and highest in group 5 (all P <0.05 for inter-group comparisons). CONCLUSION: Combination therapy using CsA plus ADMSCs offers improved protection against acute IR kidney injury. PMID- 23726289 TI - Shape and function of the diaphysis of the human tibia. AB - There is an agreement about the principle that bones are optimized to resist daily loads. This has never been ascertained for the human tibia. One of the main load components in the tibia in vivo is a cantilever load (with a linearly varying bending moment, with its largest component in the sagittal plane). investigated if the cross-section of the diaphysis and its variation along the tibia make it an optimized structure with respect to such loads. Six cadaveric tibias were CT-scanned. The geometry and material properties were extracted from the CT-scans, and analyzed along the tibias. A linear variation along the tibia was found for the second moments of area and inertia, and the section modulus in the sagittal plane (slightly less linear in the frontal plane). Conversely, the other properties (polar moments and cross-section are) were much less linear. This suggests that the structure is optimized to resist a bending moment that varies linearly along the tibia. The tibias were instrumented with 28 triaxial straingauges each. Strain was measured under cantilever loading in the sagittal and frontal planes, under quasi-constant-bending in the sagittal and frontal planes, under torsional loading, and with an axial force. The strain distribution was remarkably uniform when cantilever loading was applied in the sagittal plane and slightly less uniform when cantilever loading was applied in the frontal plane. Strain variations were one order of magnitude larger for all other loading configurations. This shows that the tibia is a uniform-stress structure (i.e. optimized) for cantilever loading. PMID- 23726290 TI - Epileptogenic networks in seizures arising from motor systems. AB - Classification of seizures arising from the cortical motor system classically distinguishes between primary motor seizures and supplementary motor area (SMA) seizures. With the aim of better characterizing the underlying networks of motor seizures, we quantitatively studied the "epileptogenicity" of brain structures in 28 patients investigated by intracerebral recordings (stereoelectroencephalography, SEEG). Epileptogenicity of various motor regions (rolandic, SMA, pre-SMA, cingulate motor area (CMA), lateral area 6) as well as prefrontal and parietal areas, was calculated according to the "epileptogenicity index" (EI), a technique that allows mathematical quantification of rapid discharges at seizure onset. According to the maximal value of EI five groups of patients were identified: precentral, premotor/precentral, mesial premotor, lateral premotor and mesio-lateral premotor groups. Most patients disclosed a complex pattern of motor/premotor involvement, while pure mesial premotor seizures ("SMA seizures") were rare. A positive correlation between the number of structures exhibiting high EI and epilepsy duration was found, as well as a relationship between high EI values in rolandic cortex and poorer surgical outcome. Seizures arising from the motor system appear to be organized in complex electrophysiological patterns that often involve both lateral and mesial aspects of premotor areas together with precentral cortex. PMID- 23726291 TI - Effect of repeated administration of eslicarbazepine acetate on the pharmacokinetics of simvastatin in healthy subjects. AB - OBJECTIVE: To investigate the effect of eslicarbazepine acetate (ESL) on the pharmacokinetics of simvastatin (SMV), a known CYP3A4 substrate, in healthy subjects. METHODS: Single centre, two-way cross-over, randomized, open-label study in 24 healthy volunteers. The volunteers received an oral single-dose of SMV 80mg on two occasions (once administered alone and once after treatment with an oral once-daily dose of 800mg of ESL for 14 days), separated by a wash-out period of 3 weeks or more. The analysis of variance (ANOVA) was used to test for differences between Test (SMV under co-administration with ESL) and Reference (SMV administered alone) treatments for AUC0-infinity, AUC0-t and Cmax of SMV and SMV-acid. RESULTS: Mean systemic exposure (AUC) measurements for both SMV and SMV beta-hydroxyacid (SMV-acid) were up to 54% lower during ESL use. The Test/Reference geometric mean ratios (GMR) (90% CI) for the AUC0-t of SMV and SMV acid were 46% (38%; 55%) and 49% (44%; 55%), respectively. Mean peak concentrations (Cmax) of both SMV and SMV-acid were reduced by 60% and 41%, respectively, when SMV was administered with ESL. CONCLUSIONS: A significant effect of repeated ESL administration on the pharmacokinetics of SMV and its metabolite SMV-acid was observed. Therefore, dose adjustment of SMV may be required when used concomitantly with ESL, if a clinically significant change in lipids is noted. PMID- 23726292 TI - Electronic waste leachate-mediated DNA fragmentation and cell death by apoptosis in mouse fibroblast (NIH/3T3) cell line. AB - This study investigated the apoptotic effect of electronic waste on fibroblast cell line. Cells were treated with different concentrations of the leachate for 24h. Cell viability was detected by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) test, nuclear morphology of cells was explored by acridine orange (AO)/ethidium bromide (EB) double staining, mitochondrial membrane potential was evaluated using JC-1 probe while cell cycle analysis was conducted using flow cytometry. The oxidative status was detected using DCFH-DA (dichlorofluorescin diacetate) probe and the relationship between cell death and ROS (reactive oxygen species) was investigated using N-acetylcysteine. Results showed an increased cell death as detected by MTT assay and AO/EB staining. Cell cycle analysis indicated an induction of sub/G1 events while JC-1 probe showed significant disruption of mitochondrial membrane potential. There was significant induction of ROS, while N-acetylcysteine protected the cells from DNA damage. These suggest apoptotic pathway as a possible mechanism of e-waste induced cyto genotoxicity. PMID- 23726293 TI - Clinical utility of miRNAs in diagnosis and prognosis. PMID- 23726294 TI - MicroRNAs. PMID- 23726295 TI - Effect of royal jelly in ovo injection on embryonic growth, hatchability, and gonadotropin levels of pullet breeder chicks. AB - The objectives of this study were to compare the following: (1) hatchability, (2) chicks' body and internal organs weights, and (3) plasma gonadotropin levels of hatchlings after in ovo administration of royal jelly (RJ) on Day 7 of incubation. Fertile eggs (n = 270) were injected into the air sac or yolk sac with 0.5 mL normal saline solution consisting of four formulations (normal saline solution with antibiotics, ultrafiltrate RJ, pure RJ, and RJ with antibiotics). The eggs were randomly divided into nine groups of 30 eggs each: (i) C: the control eggs received no injection, (ii) ASA: air sac-injected eggs received normal saline solution with antibiotics, (iii) ARJ: air sac-injected eggs received pure RJ, (iv) ARJA: air sac-injected eggs received RJ with antibiotics, (v) ARJF: air sac-injected eggs received RJ ultrafiltrate solution, (vi) YSA: yolk sac-injected eggs received normal saline solution with antibiotics, and (vii) YRJ: yolk sac-injected eggs received pure RJ, (viii) YRJA: yolk sac injected eggs received RJ with antibiotics, and (ix) YRJF: yolk sac-injected eggs received ultrafiltrate RJ solution. Hatchability rate was lower in ARJ (46.7%), ARJA (43.3%), ARJF (43.3%), and YRJF (46.7%) groups than in the control (80.0%; P < 0.05). Hatchability rate in ASA (70.0%), YSA (66.7%), YRJ (66.7%), and YRJA (63.3%) groups were comparable to the control (P > 0.05). In ovo injection of RJ and or RJ with antibiotics in both sacs increased chicks' body weight (CWT), heart weight (HWT), and liver weight (LWT) and FSH and LH levels compared with control (P < 0.05). CWT in YRJ (37.02 g), YRJA (37.03 g), ARJ (36.82 g), and ARJA (36.89 g) groups were higher than control (34.9 g; P < 0.05). Similarly, HWT significantly increased in YRJ (0.22 g), YRJA (0.21 g), ARJ (0.20 g), and ARJA (0.20 g) in comparison to control (0.18 g; P < 0.05). In addition, LWT were higher in YRJ (0.83 g), YRJA (0.82g), ARJ (0.81g), and ARJA (0.81g) than control (0.72 g; P < 0.05). Six hours post-hatch, the mean plasma FSH and LH levels in ARJ (1.13 and 2.80 mIu/mL), YRJ (1.32 and 3.36 mIu/mL), ARJA (1.23 and 2.95 mIu/mL), and YRJA (1.31 and 3.28 mIu/mL) groups were higher than in the control (0.56 and 1.48 mIu/mL, P < 0.05). We concluded that in ovo administration of RJ or RJ with antibiotics might be an effective method to increase CWT, chicks' internal organs weights, and LH and FSH secretion rate without deleterious effect on hatchability. However, further research should be conducted to determine the putative endocrine disruptive effects of RJ and its byproducts. PMID- 23726296 TI - Sexing domestic chicken before hatch: a new method for in ovo gender identification. AB - Male chicks are an unwanted by-product when producing laying hens. The common practice to kill them directly after they have hatched gives rise to ethical concerns worldwide. The aim of this study was to develop an endocrine method to determine the sex of domestic chicken before hatch. On Days 7 to 10 of incubation, the allantoic fluid from brown layers' eggs (n = 750) was analyzed via enzyme immunoassay for their content of estradiol, estrone sulfate, and testosterone in order to detect gender differences. We successfully established a reliable method for in ovo sex identification on Day 9 of incubation by estrone sulfate measurement in the allantoic fluid. Female embryos displayed significantly higher hormone levels in the allantoic fluid than males (female: median = 0.312 ng/mL; male: median = 0.110 ng/mL; P <= 0.001). Our method allows the sexing of domestic chicken at a very early stage of embryonic development, even before the onset of pain perception. The possibility to eliminate eggs containing male embryos on Day 9 of incubation represents a vast improvement compared with culling day-old chicks. PMID- 23726297 TI - Osteopontin improves sperm capacitation and in vitro fertilization efficiency in buffalo (Bubalus bubalis). AB - The aim of this study was to evaluate the effect of osteopontin (OPN), an ubiquitous acid glycoprotein, on in vitro sperm capacitation and on in vitro embryo production (IVEP) efficiency in buffalo. In experiment 1, after swim-up separation the sperm were incubated in Tyrode albumin lactate pyruvate medium in the absence of capacitating agents (control), with the standard concentration of heparin (0.01 mM) and three different concentrations of OPN (0.1, 1, and 10 mcg/mL), both in the presence and absence of heparin, for 2 and 4 hours. Capacitation was assessed indirectly by estimating the percentage of acrosome reacted sperm after incubation with lysophosphatidylcholine. In order to determine the effect of OPN, in the presence of heparin, on fertilization (Experiment 2) and in vitro embryo development (experiment 3), in vitro-matured buffalo oocytes were fertilized in the presence of 0, 0.1, 1, and 10 mcg/mL of OPN. After IVF, the presumptive zygotes were dezonated, fixed, stained, and then evaluated microscopically. At Days 5 and 7 of culture, the cleavage and blastocyst rates were evaluated, respectively. Two hours of treatment with OPN at the two higher concentrations (1 and 10 mcg/mL) promoted in vitro capacitation of buffalo sperm (experiment 1). A synergic action of OPN with heparin was also done for all OPN concentrations tested. At 4 hours incubation, all treatments, including heparin (20.4%), improved (P < 0.01) capacitation compared with the control (16.2%). Interestingly, the best results were reported in all groups treated with OPN + heparin (40.8%, 38.6%, and 33.8%, respectively; P < 0.01). The addition of OPN to the IVF medium had a positive influence on total penetration, synchronous pronuclei formation (experiment 2), and IVEP efficiency (experiment 3). In particular, the two lower concentrations of OPN (0.1 and 1 mcg/mL), compared with the control, gave higher synchronous pronuclei formation (73.5%, 75.0%, and 46.5%, respectively; P < 0.01) and cleavage rates (70.3%, 71.6%, and 59.3%, respectively; P < 0.01). Interestingly, the treatments also improved blastocyst yields (29.3%, 30.3%, and 19.4%, respectively; P < 0.01). In conclusion, these results indicate that adding OPN to the IVF system improves IVEP efficiency by enhancing in vitro sperm capacitation and blastocyst yields in buffalo. PMID- 23726298 TI - Authors' response to "Health service expenditures and efficiencies in Greece" (III). PMID- 23726299 TI - Authors' response to "Health service expenditures and efficiencies in Greece" (II). PMID- 23726300 TI - Research advances in polymer emulsion based on "core-shell" structure particle design. AB - In recent years, quite many studies on polymer emulsions with unique core-shell structure have emerged at the frontier between material chemistry and many other fields because of their singular morphology, properties and wide range of potential applications. Organic substance as a coating material onto either inorganic or organic internal core materials promises an unparalleled opportunity for enhancement of final functions through rational designs. This contribution provides a brief overview of recent progress in the synthesis, characterization, and applications of both inorganic-organic and organic-organic polymer emulsions with core-shell structure. In addition, future research trends in polymer composites with core-shell structure are also discussed in this review. PMID- 23726301 TI - The influence of topography on dynamic wetting. AB - The paramount importance of wetting applications and the significant economic value of controlling wetting-based industrial processes has stimulated a deep interest in wetting science. In many industrial applications the motion of a complex liquid front over nano-textured surfaces controls the fate of the processes. However our knowledge of the impact of nano-heterogeneities on static and dynamic wetting is very limited. In this article, the fundamentals of wetting are briefly reviewed, with a particular focus on hysteresis and roughness issues. Present knowledge and models of dynamic wetting on smooth and rough surfaces are then examined, with particular attention devoted to the case of nano topographical heterogeneities and solid-fluid-fluid systems. PMID- 23726302 TI - Dilational surface rheology studies of n-dodecyl-beta-D-maltoside, hexaoxyethylene dodecyl ether, and their 1:1 mixture. AB - It is time to review latest activities on the dilational surface rheology of the two nonionic surfactants n-dodecyl-beta-D-maltoside (beta-C12G2) and hexaoxyethylene dodecyl ether (C12E6) and their 1:1 mixture as a lot of different data generated with different techniques have been published in the last years. As the data are scattered throughout different papers and were generated with different techniques, we carried out an extensive study with one technique, which we will use as reference for the discussion of different data sets. We found that the results are in most of the cases in line with already published data as regards the general trends. However, a quantitative comparison reveals differences, which may result in different interpretations of the data. In the review at hand, we summarize, compare and discuss our latest and previously published data. PMID- 23726303 TI - Frequency of blood glucose testing in well educated patients with diabetes mellitus type 1: how often is enough? AB - AIMS: Self-monitored blood glucose (SMBG) and knowledge of insulin requirements are pivotal for good metabolic control in patients with diabetes mellitus type 1. However, the SMBG-frequency needed for optimal glycaemic control especially in well educated patients is unclear. METHODS: In patients with type 1 diabetes treated with flexible intensified insulin therapy, we evaluated HbA1c values and the directly preceding computerised SMBG-frequencies over a 12 months period. To estimate the association between HbA1c and SMBG-frequency, we fitted a piecewise linear spline model with a change in slope at 4 SMBGs per day which is the recommended minimal SMBG-frequency at our institution. RESULTS: A total of 150 patients were available for analysis, with a median baseline HbA1c of 7.1% (interquartile range 6.6, 7.8). In the multivariable analysis (adjusted for gender and psychological problems), each additional SMBG measurement was associated with an estimated difference in HbA1c of -0.19% (95% confidence interval (CI) -0.42, 0.05) for <=4 SMBGs per day and of -0.02% (95% CI -0.10, 0.06) for >4 SMBGs per day. CONCLUSIONS: Good diabetes control can be achieved in routine diabetes care with flexible intensified insulin therapy based on continuing patients' education and with a minimum of 4 SMBGs per day. PMID- 23726304 TI - [Eye pathology, an ophthalmology thematic network service platform of the Carlos III Health Institute (Instituto de Salud Carlos III)]. PMID- 23726305 TI - [Circumferential viscocanalostomy with suture tensioning in Schlemm canal (canaloplasty)-one year experience]. AB - PURPOSE: To study the efficacy and the safety of ultrasound biomicroscopy assisted canaloplasty in the treatment of open-angle glaucoma (OAG) METHODS: A prospective study of uncontrolled open-angle glaucoma patients, or patients with cataracts associated with controlled or uncontrolled OAG under maximal medical therapy who had been subjected to canaloplasty alone or combined with cataract surgery, respectively. Complications, Goldmann intraocular pressure (IOP) and mean number of drugs (ND) were evaluated at 1 day, 1 week, 1 month, and every 3 months. RESULTS: Thirty five surgeries were performed (11 canaloplasties, 24 phaco-canaloplasties). The mean IOP (mmHg) dropped from 24.5+/-5.1, in canaloplasty, and from 19.8+/-6.4, in phacocanaloplasty, preoperatively, to medium-low levels at all follow-up periods (13.5+/-1.0 and 11.0+/-4.2, at 1 year in canaloplasty and phaco-canaloplasty, respectively). The number of grugs used dropped from 3.3+/-0.5 before surgery to less than of 1 in all follow-up periods (0.5+/-0.8 at 1 year). The complications were 2 microruptures of the trabeculodescemetic window, 5 entries in the collector channels, 5 choroidal space/anterior chamber passages, 10 hyphemas, 3 hypotonies, one peripheral Descemet detachment, one intracorneal hematoma, two peripheral anterior synechia, one internal iris prolapse, and two suture extrusions to the anterior chamber. CONCLUSIONS: Ultrasound biomicroscopy assisted Canaloplasty, alone or combined, provided a sustained IOP reduction to medium-low levels, led to a decrease in the number of drugs and had a good safety profile, making this a good alternative to trabeculectomy. PMID- 23726306 TI - [Clinical course of patients with exudative-haemorrhagic age-related macular degeneration treated with ranibizumab. Eye2Eye study]. AB - OBJECTIVE: To assess the mean best-corrected visual acuity (BCVA) change in patients with exudative-haemorrhagic age-related macular degeneration (EH-ARMD) after 12-month period of treatment with ranibizumab. METHODS: A retrospective, multicentre and national study of intravitreal administered ranibizumab was conducted on 2 groups of EH-ARMD patients: only one eye affected (group 1) versus second eye affected (group 2), having the first one affected. Eligible subjects were >= 50 years old with primary or secondary active subfoveal EH-ARMD-related choroidal neovascularisation (CNV). RESULTS: A total of 184 patients (91 group 1 and 93 group 2) were included. Mean age (SD) was 75.3 (7.5) years, and 53.6% were women. The BCVA showed a VA improvement at 12 months of 9.3 (18.0) number of letters in group 1 and 5.1 (16.8) number of letters in group 2 (P<.0001 and P=.0042, respectively). No statistical differences between groups were observed. Lesion characteristics in the total population (baseline vs 12-month) were: drusen (69.1% vs 61.1%), macular haemorrhages (59.0% vs 7.3%), lipid exudates (28.1% vs 8.2%), and retinal pigment epithelium detachment (46.8% vs 19.0%). The optical coherence tomography (OCT) in the total population (baseline vs 12-month) showed a reduction in macular oedema (73.6% vs 20.9%), subretinal fluids (71.3% vs 14.7%), and intraretinal cysts (38.5 vs 19.7%), as well as a reduction of the mean foveal thickness 377.4 +/- 109.8MUm vs 249.1 +/- 67.8MUm in group 1 and 354.1 +/- 123.2MUm vs 254.6 +/- 67.4MUm in group 2, P<.0001, both groups, with no significant differences between groups. CONCLUSIONS: Intravitreal administration of ranibizumab for a minimum of 12-months significantly improved the BCVA, decreased lesion characteristics, and reduced the initial mean foveal thickness in patients with CNV primary or secondary to EH-ARMD, both in patients with only one eye affected and in patients with a second eye affected, having the first one affected. PMID- 23726307 TI - [Functional relationship between retinal sensitivity threshold values assessed by standard automated perimetry in glaucoma]. AB - OBJECTIVE: To study the correlation between the sensitivity threshold values of the different points assessed by the Humphrey visual field analyzer (24-2 Swedish interactive threshold algorithm [SITA] standard strategy) in glaucoma patients. SUBJECTS, MATERIAL AND METHODS: Prospective cross-sectorial study. One-hundred and four eyes of 104 glaucoma patients, defined by the appearance of the optic nerve head, were evaluated. Retinal threshold sensitivity points of standard automated perimetry (SA) with SITA standard 24-2 program were obtained. The upper and the lower hemifields were studied separately. Pearson correlation coefficients were calculated between the mean threshold sensitivity value at each point of the visual hemifield and the rest of the threshold points in the same hemifield. RESULTS: Perimetric correlation maps between retinal threshold sensitivity values in the same hemifield were obtained. Most of the points showed moderate to high correlations (r>=0.65. P<0.001) with neighboring points and distant points in the same hemifield. CONCLUSIONS: There is a functional relationship between neighboring and distant points in Humphrey Visual Field Analyzer (SITA Standard 24-2) in glaucoma patients. This correlation is related to the anatomical arrangement of ganglion cell axons. This fact enables perimetric patterns of glaucoma defects to be obtained. PMID- 23726308 TI - [A protocol for the treatment of retinopathy of prematurity in Spain]. AB - OBJECTIVE: To prepare a protocol for the treatment of retinopathy of prematurity (ROP) agreed by the majority of Spanish ophthalmologists dedicated to this topic. MATERIAL AND METHOD: A draft of the protocol was produced taking into account the experience of the participants and up to date publications. This draft was corrected by all the ophthalmologists participating in the project, and the final document was agreed by all of them. RESULTS: We present general guidelines as an aid for the treatment of ROP, including treatment criteria, treatment methods, a calendar of action, and follow-up. CONCLUSIONS: It is important to have a common working protocol for the treatment of ROP to improve care and to avoid mistakes. Although individual Hospitals may adapt the protocol to their daily activity, it is recommended that there is a minimal working protocol agreed by most of professionals dedicated to pediatric ophthalmology in Spain. PMID- 23726311 TI - [Treatment of Charles Bonnet syndrome]. PMID- 23726309 TI - [Corneal chrysiasis. Gold salt deposits in the cornea in a patient with rheumatoid arthritis. An analysis with confocal microscopy]. AB - CASE REPORT: A 60-year-old woman with rheumatoid arthritis of 20 years onset, on treatment with monthly intramuscular gold salts (GS) for the last 7 years. She complained of suffering from halo vision, and the examination showed a visual acuity of 0.6 in both eyes (BE). The slit lamp showed some deposits in the stroma with scattered golden granulated, without any further inflammatory reaction. DISCUSSION: GS deposits are dose-dependent and reversible, although very slowly. In this article, we introduce, for the first time, evidence of deposits of GS in all layers of the cornea, predominantly in the corneal stroma and in the endothelium. PMID- 23726310 TI - [Antiangiogenic therapy in Sorsby's fundus dystrophy without a mutation in the TIMP-3 gene]. AB - CASE REPORT: The case is presented of a 32-year-old man referring to metamorphopsia and blurred vision in both eyes for 3 days. Best corrected visual acuity of 20/32 in the right eye and 20/25 in the left eye. Fundus examination revealed the presence of drusen-like deposits, suggestive of Sorsby's fundus dystrophy (SFD) and choroidal neovascularization (CNV) bilaterally. The patient received intravitreal ranibizumab. Visual acuity improved to 20/20 in both eyes at 6-months follow-up, and results of fundus examination showed complete regression of neovascularization. No mutations were found in the TIMP-3 gene. DISCUSSION: The known mutations in TIMP-3 may not be extended to all patients with SFD. The use of intravitreal ranibizumab may be considered as a therapeutic option in CNV secondary to SFD. PMID- 23726312 TI - [Eyeglasses in XV century Spanish art (II)]. PMID- 23726313 TI - [Eye diseases in the paintings of Georges de la Tour (V). Saint Jerome reading a letter]. PMID- 23726314 TI - High prevalence of diabetes mellitus and hospital-related hyperglycaemia in French general wards. AB - AIM: The study evaluated the in-hospital prevalence of diabetes and hospital related hyperglycaemia in a variety of French general wards. METHODS: The multicentre cross-sectional study involving nine French hospitals measured venous fasting plasma glucose (FPG) on a single day in patients hospitalized in adult medical and surgical short-term wards. Diabetes status and length of stay were recorded. RESULTS: Of the 2141 inpatients included in the study, 355 (16.5%) had known diabetes, 156 (7.3%) had screened diabetes (FPG >=7 mmol/L with no diabetes history), 515 (24.1%) had impaired fasting glucose (IFG; FPG 5.5-6.9 mmol/L) and 1115 (52.1%) had normal glucose values (FPG < 5.5 mmol/L). Diabetes prevalence varied from 11% in hospitals in the west of France to 21% in hospitals in northern and eastern regions. The highest known diabetes prevalence was observed in units for cardiovascular surgery (33%), infectious diseases (27%) and kidney disorders (26%). In cancer units, one-fifth of patients had screened diabetes and one-sixth had known diabetes. Among the known diabetes patients, 127 (36%) were already being treated with insulin, while an additional 41 (12%) started insulin therapy during their hospital stay. Patients with known and screened diabetes were older (70.8 +/- 12.2 and 71.1 +/- 15.6 years, respectively) than the normal glucose patients (65.6 +/- 18.9 years; P<0.001). Average length of stay was no different between known diabetes and normal-glucose patients after adjusting for age (11.3 +/- 7.7 vs 10.0 +/- 7.4 days; NS). CONCLUSION: Overall, metabolic glucose disorders (known or screened diabetes and IFG) were found in 48% of inpatients in various French hospital general wards. PMID- 23726315 TI - The induction expression of human beta-defensins in gingival epithelial cells and fibroblasts. AB - OBJECTIVE: The gingival epithelial cells and fibroblasts can produce antimicrobial peptides when stimulated by inflammatory cytokines. The purpose of the present study was to test whether gingival keratinocytes and gingival fibroblasts respond differently to inflammatory cytokine activation. This will enable us to understand the chronic inflammatory response in the process of periodontal disease. DESIGN: Gingival keratinocytes and fibroblasts were isolated and treated with different concentrations of IL-1beta and quantitative real-time PCR was performed to evaluate the induced expressions of hBD-1, hBD-2 and hBD-3. The induced response was compared between the gingival epithelial cells and fibroblasts. The inhibitors of p38 protein kinase (MAPK) and nuclear factor-kappa B (NF-kappaB) were applied to explore the molecular mechanism during the induction of hBDs in both cells. RESULTS: The results showed that the hBDs expressions were found to be induced by different concentrations of IL-1beta, but with several differences between gingival epithelial cells and fibroblasts. The hBDs mRNA expression in gingival fibroblasts was more sensitive compared with keratinocytes to different concentrations of IL-1beta. The hBD-1 and hBD-3 expressions in these two cells were down-regulated by IL-1beta and hBD-2 expression was up-regulated. The inflammatory cytokine IL-1beta had dual effect on hBDs expression. CONCLUSIONS: The gingival epithelial cells and fibroblasts respond differently to the inflammatory cytokine IL-1beta which indicated different roles played by the two cells in the host defense. The dual effect of IL-1beta on hBDs expression may contribute to the defensins down-regulation in periodontal disease. PMID- 23726317 TI - Association between childhood trauma and low hair cortisol in depressed patients and healthy control subjects. PMID- 23726318 TI - Prereproductive stress to female rats alters corticotropin releasing factor type 1 expression in ova and behavior and brain corticotropin releasing factor type 1 expression in offspring. AB - BACKGROUND: Human and animal studies indicate that vulnerability to stress may be heritable and that changes in germline may mediate some transgenerational effects. Corticotropin releasing factor type 1 (CRF1) is a key component in the stress response. We investigated changes in CRF1 expression in brain and ova of stressed female rats and in the brain of their neonate and adult offspring. Behavioral changes in adulthood were also assessed. METHODS: Adult female rats underwent chronic unpredictable stress. We extracted mature oocytes and brain regions from a subset of rats and mated the rest 2 weeks following the stress procedure. CRF1 expression was assessed using quantitative reverse-transcription polymerase chain reaction. Tests of anxiety and aversive learning were used to examine behavior of offspring in adulthood. RESULTS: We show that chronic unpredictable stress leads to an increase in CRF1 messenger RNA expression in frontal cortex and mature oocytes. Neonatal offspring of stressed female rats show an increase in brain CRF1 expression. In adulthood, offspring of stressed female rats show sex differences in both CRF1 messenger RNA expression and behavior. Moreover, CRF1 expression patterns in frontal cortex of female offspring depend upon both maternal and individual adverse experience. CONCLUSIONS: Our findings demonstrate that stress affects CRF1 expression in brain but also in ova, pointing to a possible mechanism of transgenerational transmission. In offspring, stress-induced changes are evident at birth and are thus unlikely to result from altered maternal nurturance. Finally, brain CRF1 expression in offspring depends upon gender and upon maternal and individual exposure to adverse environment. PMID- 23726316 TI - Prenatal stress induces increased striatal dopamine transporter binding in adult nonhuman primates. AB - BACKGROUND: To determine the effects in adult offspring of maternal exposure to stress and alcohol during pregnancy, we imaged striatal and midbrain dopamine transporter (DAT) binding by positron emission tomography in rhesus monkeys (Macaca mulatta). We also evaluated the relationship between DAT binding and behavioral responses previously found to relate to dopamine D2 receptor density (responsivity to tactile stimuli, performance on a learning task, and behavior during a learning task). METHODS: Subjects were adult offspring derived from a 2 * 2 experiment in which pregnant monkeys were randomly assigned to control, daily mild stress exposure (acoustic startle), voluntary consumption of moderate-level alcohol, or both daily stress and alcohol. Adult offspring (n = 38) were imaged by positron emission tomography with the DAT ligand [(18)F]2beta-carbomethoxy 3beta-(4-chlorophenyl)-8-(2-fluoroethyl)-nortropane ([(18)F]FECNT). RESULTS: Results showed that prenatal stress yielded an overall increase of 15% in [(18)F]FECNT binding in the striatum (p = .016), 17% greater binding in the putamen (p = .012), and 13% greater binding in the head of the caudate (p = .028) relative to animals not exposed to prenatal stress. Striatal [(18)F]FECNT binding correlated negatively with habituation to repeated tactile stimulation and positively with tactile responsivity. There were no significant effects of prenatal alcohol exposure on [(18)F]FECNT binding. CONCLUSIONS: Maternal exposure to mild daily stress during pregnancy yielded increases in striatal DAT availability that were apparent in adult offspring and were associated with behavioral characteristics reflecting tactile hyperresponsivity, a condition associated with problem behaviors in children. PMID- 23726319 TI - Networks in cognitive science. AB - Networks of interconnected nodes have long played a key role in Cognitive Science, from artificial neural networks to spreading activation models of semantic memory. Recently, however, a new Network Science has been developed, providing insights into the emergence of global, system-scale properties in contexts as diverse as the Internet, metabolic reactions, and collaborations among scientists. Today, the inclusion of network theory into Cognitive Sciences, and the expansion of complex-systems science, promises to significantly change the way in which the organization and dynamics of cognitive and behavioral processes are understood. In this paper, we review recent contributions of network theory at different levels and domains within the Cognitive Sciences. PMID- 23726321 TI - Educate your referring dentists. PMID- 23726320 TI - Innate immune detection of microbial nucleic acids. AB - Detection of pathogen-derived nucleic acids by pattern recognition receptors (PRRs) is essential for the host to mount an appropriate immune response, which for viruses involves the induction of type I interferons (IFNs). By contrast, inappropriate activation of PRRs by self nucleic acids can lead to autoimmunity. Recent developments in PRR research have uncovered important new molecular details as to how Toll-like receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) distinguish pathogen from self RNA, while the discovery of cytosolic DNA sensing pathways for IFN induction has revealed completely new innate signaling mechanisms, and also questions how innate immunity discriminates between self and non-self DNA, if at all. PMID- 23726322 TI - Methods used to evaluate "black spaces". PMID- 23726323 TI - Author's response. PMID- 23726325 TI - Efficacy of 3 toothbrush treatments on plaque removal in orthodontic patients assessed with digital plaque imaging: a randomized controlled trial. AB - INTRODUCTION: Good oral hygiene is a challenge for orthodontic patients because food readily becomes trapped around the brackets and under the archwires, and appliances are an obstruction to mechanical brushing. The purpose of this study was to compare plaque removal efficacy of 3 toothbrush treatments in orthodontic subjects. METHODS: This was a replicate-use, single-brushing, 3-treatment, examiner-blind, randomized, 6-period crossover study with washout periods of approximately 24 hours between visits. Forty-six adolescent and young adult patients with fixed orthodontics from a university clinic in Germany were randomized, based on computer-generated randomization, to 1 of 3 treatments: (1) oscillating-rotating electric toothbrush with a specially designed orthodontic brush head (Oral-B Triumph, OD17; Procter & Gamble, Cincinnati, Ohio); (2) the same electric toothbrush handle with a regular brush head (EB25; Procter & Gamble); and (3) a regular manual toothbrush (American Dental Association, Chicago, Ill). The primary outcome was the plaque score change from baseline, which we determined using digital plaque image analysis. RESULTS: Forty-five subjects completed the study. The differences in mean plaque removal (95% confidence interval) between the electric toothbrush with an orthodontic brush head (6% [4.4%-7.6%]) or a regular brush head (3.8% [2.2%-5.3%]) and the manual toothbrush were significant (P <0.001). Plaque removal with the electric toothbrush with the orthodontic brush head was superior (2.2%; P = 0.007) to the regular brush head. No adverse events were seen. CONCLUSIONS: The electric toothbrush, with either brush head, demonstrated significantly greater plaque removal over the manual brush. The orthodontic brush head was superior to the regular head. PMID- 23726326 TI - Survival of palatal miniscrews used for orthodontic appliance anchorage: a retrospective cohort study. AB - INTRODUCTION: The purpose of this study was to examine the overall success of miniscrews inserted in the paramedian palatal region for support of various appliances during orthodontic treatment. METHODS: The patients received 1 or 2 miniscrews in the paramedian anterior palate of 8.0-mm length and 1.6-mm diameter placed during orthodontic treatment by the same experienced orthodontist. RESULTS: In total, 196 patients (121 girls, 75 boys; median age, 11.7; interquartile range, 3.7) who received 384 miniscrews were evaluated. Two hundred four miniscrews were used with rapid palatal expansion appliances, 136 with appliances for distalization of posterior teeth, and 44 with other appliances, such as transpalatal arches for tooth stabilization. The overall survival of the miniscrews was excellent (97.9%) in the cases examined. Cox regression analysis showed no difference in the overall survival rates of miniscrews loaded with different appliances for sex (hazard ratio, 0.95; 95% confidence interval, 0.71 1.27; P = 0.73) after adjusting for appliance and age. CONCLUSIONS: This study shows that miniscrews placed in the paramedian anterior palate for supporting various orthodontic appliances have excellent survival. PMID- 23726327 TI - Real-time monitoring of the growth of the nasal septal cartilage and the nasofrontal suture. AB - INTRODUCTION: The nasal septum is thought to be a primary growth cartilage for the midface and, as such, has been implicated in syndromes involving midfacial hypoplasia. However, this internal structure is difficult to study directly. The aims of this study were to provide direct, continuous measurements of the growth of the nasal septal cartilage and to compare these with similar measurements of the nasofrontal suture to test whether the growth of the cartilage precedes the growth of the suture and whether the growth of the septal cartilage is constant or episodic. METHODS: Ten Hanford minipigs were used. Linear displacement transducers were implanted surgically in the septal cartilage and across the nasofrontal suture. Length measurements of the cartilage and suture were recorded telemetrically each minute for several days. RESULTS: The growth rate of the nasal septal cartilage (0.07% +/- 0.03% length/h) was significantly higher than that of the suture (0.03% +/- 0.02% length/h) (P = 0.004). The growth of both structures was episodic with alternating periods of growth (5-6 per day) and periods of stasis or shrinkage. No diurnal variation in growth of the cartilage was detected. CONCLUSIONS: These results are consistent with the notion that growth of the septal cartilage might drive growth of the nasofrontal suture. Growth of the midface is episodic rather than constant. PMID- 23726328 TI - Comparison of adult and child radiation equivalent doses from 2 dental cone-beam computed tomography units. AB - INTRODUCTION: With the advent of cone-beam computed tomography (CBCT) scans, there has been a transition toward these scans' replacing traditional radiographs for orthodontic diagnosis and treatment planning. Children represent a significant proportion of orthodontic patients. Similar CBCT exposure settings are predicted to result in higher equivalent doses to the head and neck organs in children than in adults. The purpose of this study was to measure the difference in equivalent organ doses from different scanners under similar settings in children compared with adults. METHODS: Two phantom heads were used, representing a 33-year-old woman and a 5-year-old boy. Optically stimulated dosimeters were placed at 8 key head and neck organs, and equivalent doses to these organs were calculated after scanning. The manufacturers' predefined exposure settings were used. RESULTS: One scanner had a pediatric preset option; the other did not. Scanning the child's phantom head with the adult settings resulted in significantly higher equivalent radiation doses to children compared with adults, ranging from a 117% average ratio of equivalent dose to 341%. Readings at the cervical spine level were decreased significantly, down to 30% of the adult equivalent dose. When the pediatric preset was used for the scans, there was a decrease in the ratio of equivalent dose to the child mandible and thyroid. CONCLUSIONS: CBCT scans with adult settings on both phantom heads resulted in higher radiation doses to the head and neck organs in the child compared with the adult. In practice, this might result in excessive radiation to children scanned with default adult settings. Collimation should be used when possible to reduce the radiation dose to the patient. While CBCT scans offer a valuable tool, use of CBCT scans should be justified on a specific case-by-case basis. PMID- 23726329 TI - Changes in the pattern of patients receiving surgical-orthodontic treatment. AB - INTRODUCTION: The characteristics of patients who seek and accept orthognathic surgery appear to be changing over time but have not been well documented in the 21st century. METHODS: Records for patients who had orthognathic surgery at the University of North Carolina from 1996 to 2000 and from 2006 to 2010 were reviewed to collect data for changes in the prevalence of patients with mandibular deficiency (Class II), maxillary deficiency or mandibular prognathism (Class III), long face, and asymmetry problems. The changes were compared with those in previous time periods and at other locations. RESULTS: Between 1996 and 2000 and between 2006 and 2010, the percentage of Class III patients increased from 35% to 54%, and the percentage of Class II patients decreased from 59% to 41%, while the percentages for long face and asymmetry showed little change. The decrease in Class II patients was accentuation of a long-term trend; the increase in Class III patients occurred only after the turn of the century. CONCLUSIONS: A similar but less-marked change has been noted at some but not all other locations in the United States. It appears to be related primarily to an increase in the numbers of African Americans, Native Americans, Hispanics, and Asians who now are seeking surgical treatment, but it also has been affected by changes in where orthognathic surgery is performed, decisions by third-party payers (insurance and Medicaid) about coverage for treatment, and the availability of nonsurgical orthodontic treatment options for Class II patients. PMID- 23726330 TI - Pharyngeal airway characterization in adolescents related to facial skeletal pattern: a preliminary study. AB - INTRODUCTION: The objective of this study was to characterize the volume and the morphology of the pharyngeal airway in adolescent subjects, relating them to their facial skeletal pattern. METHODS: Fifty-four subjects who had cone-beam computed tomography were divided into 3 groups-skeletal Class I, Class II, and Class III-according to their ANB angles. The volumes of the upper pharyngeal portion and nasopharynx, and the volume and morphology of the lower pharyngeal portion and its subdivisions (velopharynx, oropharynx, and hypopharynx) were assessed with software (version 11.5; Dolphin Imaging & Management Solutions, Chatsworth, Calif). The results were compared with the Kruskal-Wallis and the Dunn multiple comparison tests to identify intergroup differences. Correlations between variables assessed were tested by the Spearman correlation coefficient. Correlations between the logarithms of airway volumes and the ANB angle values were tested as continuous variables with linear regression, considering the sexes as subgroups. RESULTS: The minimum areas in the Class II group (112.9 +/- 42.9, 126.9 +/- 45.9, and 142.1 +/- 83.5 mm(2)) were significantly smaller than in Class III group (186.62 +/- 83.2, 234.5 +/- 104.9, and 231.1 +/- 111.4 mm(2)) for the lower pharyngeal portion, the velopharynx, and the oropharynx, respectively, and significantly smaller than the Class I group for the velopharynx (201.8 +/- 94.7 mm(2)). The Class II group had a statistically significant different morphology than did the Class I and Class III groups in the velopharynx. There was a tendency to decreased airway volume with increased ANB angle in the lower pharyngeal portion, velopharynx, and oropharynx. In the upper pharyngeal portion, nasopharynx, and hypopharynx, there seemed to be no association between the airway volume and the skeletal pattern. CONCLUSIONS: The Class II subjects had smaller minimum and mean areas (lower pharyngeal portion, velopharynx, and oropharynx) than did the Class III group and significantly less uniform velopharynx morphology than did the Class I and Class III groups. A negative correlation was observed between the ANB value and airway volume in the lower pharyngeal portion and the velopharynx (both sexes) and in the oropharynx (just in male subjects). PMID- 23726331 TI - Patterns of vertical facial growth in Korean adolescents analyzed with mixed effects regression analysis. AB - INTRODUCTION: To understand the growth patterns of skeletal open bite and deepbite, we present observations from 9 years of pure longitudinal data based on lateral cephalometric radiographs using mixed-effects regression model analysis. METHODS: In total, 51 children (14 years old) with extreme values for the ratio of lower anterior facial height to total anterior facial height were assigned to 1 of 2 groups: a skeletal open-bite group (11 boys, 14 girls) or a skeletal deepbite group (14 boys, 12 girls). Measurements of total anterior facial height, upper anterior facial height, lower anterior facial height, total posterior facial height, ramus height, and ratio of lower anterior facial height to total anterior facial height were obtained for all subjects. All data were analyzed and interpreted using a mixed-effects regression model analysis with random effects. RESULTS: From these 4 groups at 14 years old, statistically significant differences were observed between the groups when subjects of the same sex were compared; however, statistical significance was not reached between subjects of opposite sexes in each group. Morphologic differences were clearly evident from the start and became more pronounced with age. There were statistical significances in the initial values and increases with age in all 6 variables except for increases with age in the ratio of lower anterior facial height to total anterior facial height. Statistical significance was also reached for morphologic differences between the annual increases in the ratio of lower anterior facial height to total anterior facial height and lower anterior facial height. In general, individual random variability was high in all variables when compared with the annual changes over time. CONCLUSIONS: Divergent patterns were established early and became more pronounced with age, with anterior facial height dimensions primarily contributing to these differences. Individual variations were so pronounced that caution is recommended for all clinical decisions. PMID- 23726332 TI - Esthetic evaluation of dynamic smiles with attention to facial muscle activity. AB - INTRODUCTION: Numerous studies of smile esthetics have used still photos. Photos, however, do not capture the dynamics of a smile, an element that can contribute to overall smile esthetics. In this study, we assessed the esthetics of dynamic smiles. METHODS: Four facially balanced female dental students were trained to produce 8 distinct smiles using the facial action coding system. Videos of the models' whole faces were presented to 2 panels of raters: dental students and nondental undergraduate students. Smile attractiveness was rated using a Web based survey. RESULTS: The smile that used 4 labial muscles was rated significantly better than the smile involving only the risorius muscle (P <0.05). The orbicularis oculi improved smile attractiveness (P <0.04), especially among smiles rated less favorably (P <0.05). Visibility of the models' eyes, however, did not influence the ratings (P >0.05), perhaps because orbicularis oculi activation altered activations in other muscles in such a way that smile attractiveness was increased in the lower face. CONCLUSIONS: Smile esthetics increased with increased recruitment of muscles involved in smile production. The results were robust across the models, suggesting that objective rating methods of smile-dynamic esthetics could become an important clinical tool. PMID- 23726333 TI - Periodontal microstructure change and tooth movement pattern under different force magnitudes in ovariectomized rats: an in-vivo microcomputed tomography study. AB - INTRODUCTION: The purpose of this study was to evaluate the dynamic changes in the periodontal microstructure and the molar displacement pattern during orthodontic tooth movement in ovariectomized rats. METHODS: Twenty ovariectomized rats received either 100 or 30 g of orthodontic force to induce mesial movement of the maxillary left first molars over 14 days. Ten healthy rats underwent sham operations as controls. Periodontal ligament thickness, alveolar bone microstructural properties, and displacement of the molar were measured with 6 in vivo microcomputed tomography scans for each sample. RESULTS: The ovariectomized rats that received 100 g of orthodontic force had obvious changes in periodontal ligament thickness at day 1 and poor periodontal ligament thickness recovery from days 5 through 14. The bone volume fraction increased and the trabecular separation decreased significantly in this group at day 3, and obvious bone loss was observed at day 14. Molar linear and angular movements were also higher in this group than in the other 2 groups. CONCLUSIONS: Relatively heavier force applications in ovariectomized rats resulted in poor periodontal ligament thickness recovery and local alveolar bone overcompression, and consequently induced undermining resorption and obvious alveolar bone loss; these led to high rates of tooth movement and molar inclination. PMID- 23726334 TI - Effectiveness of a sealant compared with no sealant in preventing enamel demineralization in patients with fixed orthodontic appliances: a prospective clinical trial. AB - INTRODUCTION: In this study, we tested the efficacy of a tooth sealant polish (Biscover LV; Bisco, Schaumberg, Ill) to prevent enamel demineralization (white spot lesions) for the full duration of orthodontic treatment with fixed appliances. The trial design was an alternating-tooth split-mouth design. METHODS: Patients starting treatment with bonded appliances in a private practice were enrolled. The 6 maxillary anterior teeth received the test sealant or no sealant. The nonblinded orthodontists visually examined the teeth immediately after debonding and rated the presence and severity of white spot lesions using a 4-point scale. The difference in incidence of white spot lesions on treated and control teeth was tested with multivariate binary logistic regression for repeated measures by using the generalized estimating equations approach. RESULTS: Sixty-five subjects were enrolled, and 3 were lost to follow-up, leaving 62 for analysis. There was a slightly lower incidence of white spot lesions on treated teeth (13.5%; 95% confidence interval, 8.6-18.4) compared with the control teeth (17.7%; 95% confidence interval, 12.4-23.7). This difference was statistically significant in the multivariate model (Wald chi-square, 5.07; df = 1; P = 0.024). The odds ratio was equal to 0.68 (95% confidence interval, 0.47 0.95) that treated teeth would show white spot lesions relative to the control teeth. White spot lesion severity was nearly the same for treated and control teeth (mean +/- SD = 1.17 +/- 0.47 and 1.20 +/- 0.48, respectively; Wald chi square, 3.03; df = 1; P = 0.082). No serious adverse effects were reported. CONCLUSIONS: The sealant did not prevent all white spot lesions for the full duration of treatment. The sealant demonstrated a clinically small but statistically significant ability to prevent white spot lesions. PMID- 23726335 TI - The pattern of facial skeletal growth and its relationship to various common indexes of maturation. AB - INTRODUCTION: Sequential stages in the development of the hand, wrist, and cervical vertebrae commonly are used to assess maturation and predict the timing of the adolescent growth spurt. This approach is predicated on the idea that forecasts based on skeletal age must, of necessity, be superior to those based on chronologic age. This study was undertaken to test this reasonable, albeit largely unproved, assumption in a large, longitudinal sample. METHODS: Serial records of 100 children (50 girls, 50 boys) were chosen from the files of the Bolton-Brush Growth Study Center in Cleveland, Ohio. The 100 series were 6 to 11 years in length, a span that was designed to encompass the onset and the peak of the adolescent facial growth spurt in each subject. Five linear cephalometric measurements (S-Na, Na-Me, PNS-A, S-Go, Go-Pog) were summed to characterize general facial size; a sixth (Co-Gn) was used to assess mandibular length. In all, 864 cephalograms were traced and analyzed. For most years, chronologic age, height, and hand-wrist films were available, thereby permitting various alternative methods of maturational assessment and prediction to be tested. The hand-wrist and the cervical vertebrae films for each time point were staged. Yearly increments of growth for stature, face, and mandible were calculated and plotted against chronologic age. For each subject, the actual age at onset and peak for stature and facial and mandibular size served as the gold standards against which key ages inferred from other methods could be compared. RESULTS: On average, the onset of the pubertal growth spurts in height, facial size, and mandibular length occurred in girls at 9.3, 9.8, and 9.5 years, respectively. The difference in timing between height and facial size growth spurts was statistically significant. In boys, the onset for height, facial size, and mandibular length occurred more or less simultaneously at 11.9, 12.0, and 11.9 years, respectively. In girls, the peak of the growth spurt in height, facial size, and mandibular length occurred at 10.9, 11.5, and 11.5 years. Height peaked significantly earlier than both facial size and mandibular length. In boys, the peak in height occurred slightly (but statistically significantly) earlier than did the peaks in the face and mandible: 14.0, 14.4, and 14.3 years. Based on rankings, the hand-wrist stages provided the best indication (lowest root mean squared error) that maturation had advanced to the peak velocity stage. Chronologic age, however, was nearly as good, whereas the vertebral stages were consistently the worst. Errors from the use of statural onset to predict the peak of the pubertal growth spurt in height, facial size, and mandibular length were uniformly lower than for predictions based on the cervical vertebrae. Chronologic age, especially in boys, was a close second. CONCLUSIONS: The common assumption that onset and peak occur at ages 12 and 14 years in boys and 10 and 12 years in girls seems correct for boys, but it is 6 months to 1 year late for girls. As an index of maturation, hand-wrist skeletal ages appear to offer the best indication that peak growth velocity has been reached. Of the methods tested here for the prediction of the timing of peak velocity, statural onset had the lowest errors. Although mean chronologic ages were nearly as good, stature can be measured repeatedly and thus might lead to improved prediction of the timing of the adolescent growth spurt. PMID- 23726336 TI - Class II surgical-orthodontic treatment of a patient with severe coronary disease: 5 years of follow-up. AB - This case study describes the retreatment and long-term follow-up care of a patient with a medical history of 2 heart surgeries and a Class II malocclusion that included a severe anteroposterior skeletal discrepancy characterized by mandibular deficiency. The patient's initial orthodontic camouflage treatment was poorly performed and failed to correct the maxillofacial disorders. In this article, we report the successful retreatment with a surgical-orthodontic protocol and include the 5-year follow-up records showing stable results. Guidelines for the stratification of cardiac risk are included. PMID- 23726337 TI - Interdisciplinary approach for increasing the vertical dimension of occlusion in an adult patient with several missing teeth. AB - This case report describes the interdisciplinary treatment of a 39-year-old man with several missing teeth (including both maxillary lateral incisors), Class II malocclusion, deep overbite, and significant mandibular midline deviation. The treatment plan included placement of endosseous dental implants early in the orthodontic treatment to increase the vertical dimension of the occlusion for deepbite correction, canine substitution for the missing lateral incisors, and distalization of the mandibular right buccal segment with the aid of a temporary anchorage device. PMID- 23726338 TI - Nonsurgical correction of a Class III malocclusion in an adult by miniscrew assisted mandibular dentition distalization. AB - This article reports the successful use of miniscrews in the mandible to treat a 20-year-old Mongolian woman with a chief complaint of anterior crossbite. The patient had a skeletal Class III malocclusion with a mildly protrusive mandible, an anterior crossbite, and a deviated midline. In light of the advantages for reconstruction of the occlusal plane and distal en-masse movement of the mandibular arch, we used a multiloop edgewise archwire in the initial stage. However, the maxillary incisors were in excessive labioversion accompanied by little retraction of the mandibular incisors; these results were obviously not satisfying after 4 months of multiloop edgewise archwire treatment. Two miniscrews were subsequently implanted vertically in the external oblique ridge areas of the bilateral mandibular ramus as skeletal anchorage for en-masse distalization of the mandibular dentition. During treatment, the mandibular anterior teeth were retracted about 4.0 mm without negative lingual inclinations. The movement of the mandibular first molar was almost bodily translation. The maxillary incisors maintained good inclinations by rotating their brackets 180 degrees along with the outstanding performance of the beta-titanium wire. The patient received a harmonious facial balance, an attractive smile, and ideal occlusal relationships. The outcome was stable after 1 year of retention. Our results suggest that the application of miniscrews in the posterior area of the mandible is an effective approach for Class III camouflage treatment. This technique requires minimal compliance and is particularly useful for correcting Class III patients with mild mandibular protrusion and minor crowding. PMID- 23726339 TI - Skeletal and soft-tissue incidental findings on cone-beam computed tomography images. AB - Cone-beam computed tomography provides orthodontists with 3-dimensional images of the craniofacial region and valuable information for diagnosis and treatment planning of craniofacial or dental anomalies. However, a narrow focus on the skeletal and dental contributions to malocclusion can cause failure to identify skeletal or soft-tissue pathologies of the craniofacial structures unrelated to the orthodontic concerns. Two cases are presented that demonstrate skeletal and soft-tissue anomalies identified as incidental findings on cone-beam computed tomography scans of asymptomatic orthodontics patients. One patient was diagnosed with craniofacial fibrous dysplasia; the other had an intrahemispheric lipoma. Their cone-beam computed tomography images are presented, along with a literature review on their pathologies. PMID- 23726340 TI - Accuracy of miniscrew surgical guides assessed from cone-beam computed tomography and digital models. AB - INTRODUCTION: Several methods are available to enhance the precision of miniscrew placement. The use of surgical guides based on cone-beam computed tomography is indicated especially in patients with risky or difficult anatomic situations. The purpose of this study was to evaluate the accuracy of miniscrew placement by using surgical guides developed with computer-aided design and manufacturing techniques. METHODS: Miniscrews were placed in cadaver maxillae using stereolithographic computer-aided design and manufacturing techniques with assistance from surgical guides (surgical guide group, n = 25) or periapical x rays (control group, n = 20). Insertion sites were selected using a 3-dimensional surgical planning program by fusing maxillary digital model images and cone-beam computed tomography images. Deviations between actual and planned placements were measured as 3-dimensional angular deviations and distance (coronal and apical) deviations. RESULTS: In the surgical guide group, the angular deviation was a median of 3.14 degrees (range, 1.02 degrees -10.9 degrees ), and the mesiodistal deviations in the coronal and apical areas were medians of 0.29 mm (range, 0.03 0.73 mm) and 0.21 mm (range, 0.03-0.97 mm), respectively. The deviations differed significantly between operators in the control group, but not in the surgical guide group. In the surgical guide group, there was no root damage from miniscrew placement, and 84% of the miniscrews were placed without contacting adjacent anatomic structures. In the control group, 50% of the miniscrews were placed between the roots (P <0.05). CONCLUSIONS: Surgical guide accuracy was improved when digital model imaging was used. Miniscrews were placed more accurately when using surgical guides than when using a direct method. PMID- 23726341 TI - Litigation and legislation: either she goes, or I do! PMID- 23726342 TI - Review of randomized controlled trials: issues to consider when designing a trial. PMID- 23726343 TI - Design, synthesis and biological evaluation of novel estrogen-derived steroid metal complexes. AB - A new series of estrogen-derived metal complexes were synthesized and characterized. The functionalized estrogen receptor ligands were prepared by a four-step synthetic strategy, and then three transition metal Pd, Ni, Zn were introduced readily to give the title metal complexes, in which the squaramide was introduced as ion acceptor for the first time in the development of estrogen derived metal complexes for estrogen receptor. Upon binding to estrogen receptors, all of the estrogen conjugates exhibited acceptable binding affinity (up to 4.04% relative to estradiol), and in transcription assays, all the compounds are agonists on ERalpha. Molecular modeling studies suggest a structural basis for the agonist activity of these compounds. PMID- 23726344 TI - Heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 receptor antagonist. AB - A convergent synthesis route for the heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 antagonist 2 was developed and the structure activity relationship of these modifications on NPY1 binding is reported. Two heterocyclic analogs 9 and 10 showed comparable Y1 binding potency to 2, but with improved aqueous solubility. Compound 9 demonstrated reduced spontaneous nocturnal food intake in a rat model when dosed ip. Compound 9 was also shown to be orally bioavailable and brain penetrable. PMID- 23726345 TI - Design, synthesis and biological evaluation of novel aminothiazoles as antiviral compounds acting against human rhinovirus. AB - We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure-activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIbeta). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication. PMID- 23726348 TI - Excellent results and minimal complications of total hip arthroplasty in sickle cell hemoglobinopathy at mid-term follow-up using cementless prosthetic components. AB - The purpose of this study was to compare the outcomes of cementless primary total hip arthroplasty (THA) in sickle cell patients compared to the remaining cohort of osteonecrosis patients who did not have this disease. Thirty-two sickle cell patients (42 hips) who had a mean age of 37 years and mean follow-up of 7.5 years (range, 5-11 years) were compared to 87 non-sickle cell osteonecrosis patients (102 hips) who had mean age of 43 years and mean follow-up of 7 years (range, 3 10.5 years). Outcomes evaluated included implant survivorship, Harris hip scores, complication rates, radiographic outcomes, and Short Form-(SF-36) health questionnaire. There were no significant differences in aseptic implant survivorship (95 vs. 97%), Harris hip scores (87 vs. 88 points), SF-36 score, or radiographic findings between the two patient cohorts. In light of these findings, we believe that the outcomes of THA improved in sickle cell patients with optimized medical management and the use of cementless prosthetic devices. PMID- 23726349 TI - Sweeping as a multistep enrichment process in micellar electrokinetic chromatography: the retention factor gradient effect. AB - The application of a new method developed for the assessment of sweeping efficiency in MEKC under homogeneous and inhomogeneous electric field conditions is extended to the general case, in which the distribution coefficient and the electric conductivity of the analyte in the sample zone and in the separation compartment are varied. As test analytes p-hydroxybenzoates (parabens), benzamide and some aromatic amines are studied under MEKC conditions with SDS as anionic surfactant. We show that in the general case - in contrast to the classical description - the obtainable enrichment factor is not only dependent on the retention factor of the analyte in the sample zone but also dependent on the retention factor in the background electrolyte (BGE). It is shown that in the general case sweeping is inherently a multistep focusing process. We describe an additional focusing/defocusing step (the retention factor gradient effect, RFGE) quantitatively by extending the classical equation employed for the description of the sweeping process with an additional focusing/defocusing factor. The validity of this equation is demonstrated experimentally (and theoretically) under variation of the organic solvent content (in the sample and/or the BGE), the type of organic solvent (in the sample and/or the BGE), the electric conductivity (in the sample), the pH (in the sample), and the concentration of surfactant (in the BGE). It is shown that very high enrichment factors can be obtained, if the pH in the sample zone makes possible to convert the analyte into a charged species that has a high distribution coefficient with respect to an oppositely charged micellar phase, while the pH in the BGE enables separation of the neutral species under moderate retention factor conditions. PMID- 23726350 TI - Comparison between the intra-particle diffusivity in the hydrophilic interaction chromatography and reversed phase liquid chromatography modes. Impact on the column efficiency. AB - The effective diffusion coefficients of five low molecular weigh compounds (naphthalene, uracil, uridine, adenosine, and cytosine) were measured at room temperature in a 4.6mm*100mm column packed with 3.5MUm XBridge HILIC particles. The mobile phase was an acetonitrile-water mixture (92.5/7.5, v/v) containing 10mM ammonium acetate and 0.02% acetic acid. Using a physically reliable model of effective diffusion in binary composite media (Torquato's model), accurate estimates of the intra-particle diffusivities in the HILIC particles were obtained as a function of the retention of these analytes. The HILIC diffusion coefficients were compared to those previously obtained for endcapped RPLC-C18 particles (5.0MUm Gemini-C18). The experimental results confirm that adsorption sites are not localized in RPLC whereas they are so in the HILIC mode. In contrast to RPLC columns, HILIC columns provide longitudinal diffusion B/u terms that increase very little with increasing retention factors. This confirms the absence of surface diffusion in HILIC. The impact of intra-particle diffusivity on the column efficiency was projected in HILIC and RPLC on the basis of the measured intra-particle diffusivities and on the well established theory of band broadening in particulate columns. Accordingly, RPLC columns generate short-range eddy dispersion and solid-liquid mass transfer resistance Cu terms that increase less than do HILIC column with increasing retention factors. The HETP contribution caused by the trans-column structure heterogeneity is smaller in the HILIC than in the RPLC modes because the transverse excursion length is smaller in HILIC. Even though the overall column efficiencies are comparable in HILIC and RPLC, this study shows that the individual mass transfer phenomena are inherently different in the HILIC and the RPLC retention modes. PMID- 23726351 TI - Microfluidic lab-on-a-chip derivatization for gaseous carbonyl analysis. AB - We present a microfluidic lab-on-a-chip derivatization technique for the analysis of gaseous carbonyl compounds using O-(2,3,4,5,6-pentafluorobenzyl) hydroxylamine (PFBHA) as the derivatizing reagent. The novel microfluidic lab-on-a-chip derivatization technique has been developed to measure nmol per mole (ppbv) mixing ratios of gaseous carbonyl compounds, which are of particular importance to atmospheric chemistry. The technique utilised a planar glass microreactor comprising three inlets and one outlet, gas and fluid splitting and combining channels, mixing junctions, and a 2.0m long, 620MUm internal diameter reaction microchannel. The microreactor integrated three functions, providing: (1) a gas and liquid mixer and reactor, (2) reagent heating, and (3) sample pre concentration. The concentration of derivatization solution, the volumetric flow rates of the incoming gas sample and PFBHA solution, and the temperature of the microreactor were optimised to achieve a near real-time measurement. The enhanced phase contact area-to-volume ratio and the high heat transfer rate in the microreactor resulted in a fast and high efficiency derivatization reaction, generating an effluent stream which was ready for direct introduction to GC-MS. Good linearity was observed for eight carbonyl compounds over the measurement ranges of 1-500ppbv when they were derivatized under optimal reaction conditions. The method detection limits (MDLs) were below 0.10nmolmol(-1) for most carbonyls in this study, which is below or close to their typical concentrations in clean ambient air. The performance of the technique was assessed by applying the methodology to the quantification of glyoxal (GLY) and methylglyoxal (MGLY) formed during isoprene photo-oxidation in an outdoor photoreactor chamber (EUPHORE). Good agreements between GLY and MGLY measurements were obtained comparing this new technique with Fourier Transform InfraRed (FTIR), which provides support for the potential effectiveness of the microfluidic technique for gaseous measurements. PMID- 23726352 TI - Comparative analysis of mass spectral matching-based compound identification in gas chromatography-mass spectrometry. AB - Compound identification in gas chromatography-mass spectrometry (GC-MS) is usually achieved by matching query spectra to spectra present in a reference library. Although several spectral similarity measures have been developed and compared using a small reference library, it still remains unknown how the relationship between the spectral similarity measure and the size of reference library affects on the identification accuracy as well as the optimal weight factor. We used three reference libraries to investigate the dependency of the optimal weight factor, spectral similarity measure and the size of reference library. Our study demonstrated that the optimal weight factor depends on not only spectral similarity measure but also the size of reference library. The mixture semi-partial correlation measure outperforms all existing spectral similarity measures in all tested reference libraries, in spite of the computational expense. Furthermore, the accuracy of compound identification using a larger reference library in future is estimated by varying the size of reference library. Simulation study indicates that the mixture semi-partial correlation measure will have the best performance with the increase of reference library in future. PMID- 23726353 TI - Development and validation of a QuEChERS based liquid chromatography tandem mass spectrometry method for the determination of multiple mycotoxins in spices. AB - A reliable and rapid method for the determination of multiple mycotoxins was developed using a QuEChERS (quick, easy, cheap, effective, rugged and safe) based extraction procedure in highly pigmented and complex spice matrices, namely red chilli (Capsicum annum ssp.), black and white pepper (Piper nigrum ssp.). High performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was used for the quantification and confirmation of 17 chemically diversified mycotoxins. Different extraction procedures were studied and optimized in order to obtain better recoveries. Mycotoxins were extracted from the hydrated spices using acidified acetonitrile (1% formic acid), followed by partitioning with NaCl and anhydrous MgSO4; excluding the use of dispersive-solid phase extraction. Significant matrix effect was compensated using the matrix matched calibration curves. Electrospray ionization at positive mode was applied to simultaneously detect all the mycotoxins in a single run time of 20min. Multiple reaction monitoring mode, choosing at least two abundant fragment ions per analyte was applied. Coefficients of determination obtained were in the range of 0.9844 0.9997. Recoveries (ranging from 75% to 117%) were in accordance with the performance criteria required by the European Commission. Intra-day reproducibility ranged from 4% to 22% for most of the mycotoxins. The limit of quantification ranged from 2.3 to 146MUgkg(-1). The validated method was finally applied to screen mycotoxins in ten of each spice matrix. Aflatoxins, ochratoxin, fumonisins, sterigmatocystin and citrinin were among the detected analytes. Positive findings were further confirmed using relative ion intensities. The potentiality of the method to be used for confirmatory purposes according to Commission Decision 2002/657/EC was assessed. PMID- 23726354 TI - Determination of water-soluble vitamins in infant milk and dietary supplement using a liquid chromatography on-line coupled to a corona-charged aerosol detector. AB - A simple and rapid method for the simultaneous determination of seven water soluble vitamins (thiamine, folic acid, nicotinic acid, ascorbic acid, pantothenic acid, pyridoxine and biotin) was developed by high performance liquid chromatographic separation and corona-charged aerosol detection. The water soluble vitamins were separated on a Lichrosorb RP-C18 column under isocratic conditions with a mobile phase consisting of 0.05 M ammonium acetate:methanol 90:10 (v/v) at the flow rate 0.5 mL min(-1). The vitamins were extracted from the infant milk (liquid and powder format) using a precipitation step with 2.5 M acetic acid remaining the analyte in the supernatant. As far as dietary supplements are concerned, only a dilution with distilled water was required. The detection limits ranged from 0.17 to 0.62 mg L(-1) for dietary supplements and 1.7 to 6.5 mg L(-1) for milk samples. The precision of the method was evaluated in terms of relative standard deviation (%, RSD) under repeatability and reproducibility conditions, being the average values for each parameter 2.6 and 2.7 for dietary supplements and 4.3 and 4.6 for milk samples. The optimized method was applied to different infant milk samples and dietary supplements. The results of the analysis were in good agreement with the declared values. PMID- 23726355 TI - Cross-column prediction of gas-chromatographic retention of polybrominated diphenyl ethers. AB - In this paper, we predict the retention of polybrominated diphenyl ethers (PBDEs) in capillary gas-chromatography (GC) within a useful range of separation conditions. In a first stage of this study, quantitative structure-retention relationships (QSRRs) of PBDEs in six stationary phases with different polarity are established. The single-column QSRR models are generated using the retention data of 126 PBDE congeners by multilinear regression (MLR) coupled to genetic algorithm variable selection applied to a large set of theoretical molecular descriptors of different classes. A quite accurate fitting of experimental retentions is obtained for each of the six GC columns adopting five molecular descriptors. In a further step of this work six molecular descriptors were extracted within the set of molecular descriptors (17 variables) involved in the various single-column QSRRs. The selected molecular descriptors are combined with observed retentions of ten representative PBDEs, adopted as descriptors of the GC system. These quantities are considered as the independent variables of a multiple-column retention model able to simultaneously relate GC retention to PBDE molecular structure and kind of column. The quantitative structure/column retention relationship is established using a multi-layer artificial neural network (ANN) as regression tool. To optimise the ANN model, a validation set is generated by selecting two out of the six calibration columns. Splitting of columns between training and validation sets, as well as selection of PBDE congeners to be used as column descriptors, is performed with the help of a principal component analysis on the retention data. Cross-column predictive performance of the final model is tested on a large external set consisting of retention data of 180 PBDEs collected in four separation conditions different from those considered in model calibration (different columns and/or temperature program). PMID- 23726357 TI - Physics' insights into pedestrian motion and crowd dynamics: reply to comments on "The emergence of design in pedestrian dynamic: locomotion, self-organization, walking paths and constructal law". AB - Pedestrians' world is not a static one, but rather one which is constantly in flux. The pedestrian dynamics is subject to a wide range of influences and displays an interesting phenomenology. Along with collective self-organization phenomena (e.g., streams of people, rivers of people, collective synchronization), there are also a multitude of applications in the context of crowd management, design of pedestrian facilities and urban planning. Here, I address comments from the discussants of my review paper from the viewpoint of elementary physics laws paying particular attention to the self-organization phenomena in crowds. PMID- 23726356 TI - Physical activity in people with COPD, using the National Health and Nutrition Evaluation Survey dataset (2003-2006). AB - BACKGROUND: People with chronic obstructive pulmonary disease (COPD) are sedentary but the extent of the problem is not fully understood. PURPOSES: This study examines sedentary time and physical activity (PA) and the relative effects of demographic and clinical characteristics on sedentary time and PA in a population-based sample of people with COPD and a comparison group from the general population. METHODS: Subjects were drawn from the National Health and Nutrition Examination Survey dataset (2003-2006). Physical activity was measured by accelerometry. RESULTS: People with COPD were sedentary and spent less time in most levels of PA. Age, gender, race, level of education, working status, shortness of breath, self-reported health, and body mass index were significantly associated with sedentary time or level of PA. CONCLUSION: Findings emphasize the need to decrease sedentary time and increase PA in people with COPD. PMID- 23726358 TI - Effects of fibroblast-derived factors on the proliferation and differentiation of human melanocytes in culture. AB - BACKGROUND: Although keratinocyte-derived factors are known to promote the proliferation and differentiation of human epidermal melanocytes, it is not fully understood whether fibroblast-derived factors work in a similar way. OBJECTIVE: The aim of this study is to clarify whether fibroblast-derived factors are involved in regulating the proliferation and differentiation of human melanocytes with or without keratinocytes using serum-free culture system. METHODS: Human epidermal melanoblasts and melanocytes were cultured in a serum-free growth medium supplemented with fibroblast-derived factors such as keratinocyte growth factor (KGF) with or without keratinocytes, and the effects of KGF on the proliferation and differentiation of melanocytes were studied. RESULTS: KGF stimulated the proliferation of melanoblasts in the presence of dibutyryl cAMP (DBcAMP), basic fibroblast growth factor (bFGF), transferrin (Tf), and endothelin 1 (ET-1). Although KGF stimulated the differentiation, melanogenesis, and dendritogenesis in the presence of DBcAMP, Tf, and ET-1 without keratinocytes, KGF required the presence of keratinocytes for the stimulation of melanocyte proliferation. CONCLUSION: These results suggest that fibroblast-derived KGF stimulates the proliferation of human melanoblasts in synergy with cAMP, bFGF, Tf, and ET-1, the differentiation of melanocytes in synergy with cAMP, Tf, and ET 1, and the proliferation of melanocytes in synergy with cAMP, Tf, ET-1, and undefined keratinocyte-derived factors. PMID- 23726359 TI - Retrospective lifetime dietary patterns are associated with demographic and cardiovascular health variables in an older community-dwelling Australian population. AB - Dietary patterns derived from factor analytic procedures have been demonstrated to predict demographic and health outcomes across a wide range of populations. To examine the potential utility of long-term dietary recall, in the present study, we examined associations between dietary patterns from across the lifespan and demographic and later-life cardiovascular-related health variables, using the Lifetime Diet Questionnaire (LDQ). The LDQ is a self-administered, non quantitative, retrospective FFQ designed to assess dietary intake from childhood to older age. Participants (n 352) from the Older People, Omega-3 and Cognitive Health trial, aged 65-91 years, completed the LDQ. Exploratory factor analysis was conducted on the LDQ and plausible dietary patterns were derived. As a result, three patterns were extracted from each life period, with five distinct patterns overall; these were 'traditional Australian' and 'non-traditional Australian', 'high-sugar and high-fat', 'vegetable' and 'fruit and vegetable' patterns. In separate adjusted regression models, age, sex, education, income, parental background and childhood physical activity all significantly predicted dietary patterns across the lifespan. A 'traditional Australian' pattern in childhood predicted higher HDL-cholesterol levels and lower odds of cholesterol medication use; lower HDL-cholesterol levels were predicted by the adult 'processed, high-sugar and high-fat' pattern, and higher intake of a 'non traditional Australian' pattern in adulthood also predicted lower odds of using cardiac medications. Lifetime dietary recall, as instantiated by the LDQ, provides a hitherto untapped source of long-term dietary information in older adults that may contribute to greater understanding of the impact exerted by early-life and cumulative dietary choices on later-life health. PMID- 23726360 TI - The contribution of chemical bonding to the short- and long-term enamel bond strengths. AB - OBJECTIVES: MDP (10-methacryloyloxydecyl dihydrogenphosphate) has been proven to possess chemical bonding ability to tooth hard tissues, but its contribution to the enamel bond strength has not been recognized. The aim of this study was to investigate the contribution of chemical bonding to the short- and long-term bovine enamel micro-tensile bond strengths (MUTBS). METHODS: The acid-etched enamel surfaces were treated without any primer (control) or with one of three MDP-containing primers (containing different ratio of MDP/HEMA/Bis-GMA, Kuraray Co.) for 5s, water-sprayed and air-dried. Subsequently, the pretreated enamel surfaces were applied with an etch-and-rinse adhesive Durafill Bond (Heraeus Kulzer) and placed with composite resin Durafill VS (Heraeus Kulzer). The specimens were prepared for MUTBS tests after 24-h or 1-yr water storage. The etched enamel surfaces treated with or without MDP-containing primers were analyzed by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). RESULTS: The acid-etched enamel treated with the MDP-primers for a very short time could produce the greater enamel MUTBS than the control did (p<0.05), and change enamel micromorphology. No significant different MUTBS were found between 24-h and 1-yr water storage (p>0.05). The chemical bonding of MDP on the enamel surfaces was re-confirmed by XPS. SIGNIFICANCE: The additional chemical bonding of MDP around the enamel crystallites of the etched enamel substrate could significantly increase the short- and long-term enamel MUTBS, and their MUTBS surpass those of the etch-and-rinse adhesive alone. PMID- 23726361 TI - Influence of substructure design, veneer application technique, and firing regime on the in vitro performance of molar zirconia crowns. AB - OBJECTIVES: The aim of this in vitro study was to evaluate the influence of substructure design, veneer application technique, and firing regime on the failure and fracture resistance of molar zirconia crowns. METHODS: Six groups (n=8/group) of zirconia crowns were fabricated in simple core (SC) or anatomically reduced (AR) design, veneered with different feldspathic or glass ceramic materials, and defined according to the application technique and firing regime (LT: layering technique; LT_L: LT with long-term cooling; PT: press technique; DV: digital veneering technique). The following groups were investigated: SCLT, ARLT, SCLT_L, SCPT, ARPT, ARDV. Crowns were adhesively bonded to polymethylmethacrylate abutment teeth and subjected to thermal cycling (TC: 2*3000*5 degrees /55 degrees ) and mechanical loading (ML: 1.2*10(6); 50N; 1.6Hz) in a chewing simulator with metal-ceramic molar crowns as antagonists. Failures were monitored and fracture resistance determined after aging. Data were statistically analyzed (one-way analysis of variance, ANOVA; post hoc Bonferroni, alpha=0.05). Crowns were subjected to scanning electron microscopy for fractographic failure analysis. RESULTS: Failures (chipping, cracks) during TCML were observed in groups SCLT (2*), ARDV (2*) and SCLT_L (1*). Defect sizes varied between 3.5mm (SCLT: crack) and 30.0mm(2) (SCLT_L: chipping). Mean (SD) fracture forces ranged between 1529.0 (405.2)N for SCPT and 2372.3 (351.8)N for ARDV. SIGNIFICANCE: The failure frequency of veneered zirconia crowns could be reduced by using anatomically reduced substructures, the press veneering technique, and an adapted cooling protocol. Fracture resistance increased with use of anatomically reduced substructures and the digital veneering technique. PMID- 23726362 TI - Virtual volume resection using multi-resolution triangular representation of B spline surfaces. AB - Computer assisted analysis of organs has an important role in clinical diagnosis and therapy planning. As well as the visualization, the manipulation of 3 dimensional (3D) objects are key features of medical image processing tools. The goal of this work was to develop an efficient and easy to use tool that allows the physician to partition a segmented organ into its segments or lobes. The proposed tool allows the user to define a cutting surface by drawing some traces on 2D sections of a 3D object, cut the object into two pieces with a smooth surface that fits the input traces, and iterate the process until the object is partitioned at the desired level. The tool is based on an algorithm that interpolates the user-defined traces with B-spline surface and computes a binary cutting volume that represents the different sides of the surface. The computation of the cutting volume is based on the multi-resolution triangulation of the B-spline surface. The proposed algorithm was integrated into an open source medical image processing framework. Using the tool, the user can select the object to be partitioned (e.g. segmented liver), define the cutting surface based on the corresponding medical image (medical image visualizing the internal structure of the liver), cut the selected object, and iterate the process. In case of liver segment separation, the cuts can be performed according to a predefined sequence, which makes it possible to label the temporary as well as the final partitions (lobes, segments) automatically. The presented tool was evaluated for anatomical segment separation of the liver involving 14 cases and virtual liver tumor resection involving one case. The segment separation was repeated 3 different times by one physician for all cases, and the average and the standard deviation of segment volumes were computed. According to the test experiences the presented algorithm proved to be efficient and user-friendly enough to perform free form cuts for liver segment separation and virtual liver tumor resection. The volume quantification of segments showed good correlation with the prior art and the vessel-based liver segment separation, which demonstrate the clinical usability of the presented method. PMID- 23726363 TI - Power line interference filtering on surface electromyography based on the stationary wavelet packet transform. AB - Power line interference is one of the main problems in surface electromyogram signals (EMG) analysis. In this work, a new method based on the stationary wavelet packet transform is proposed to estimate and remove this kind of noise from EMG data records. The performance has been quantitatively evaluated with synthetic noisy signals, obtaining good results independently from the signal to noise ratio (SNR). For the analyzed cases, the obtained results show that the correlation coefficient is around 0.99, the energy respecting to the pure EMG signal is 98-104%, the SNR is between 16.64 and 20.40dB and the mean absolute error (MAE) is in the range of -69.02 and -65.31dB. It has been also applied on 18 real EMG signals, evaluating the percentage of energy respecting to the noisy signals. The proposed method adjusts the reduction level to the amplitude of each harmonic present in the analyzed noisy signals (synthetic and real), reducing the harmonics with no alteration of the desired signal. PMID- 23726364 TI - Does hormone therapy modify the position of the gold markers in the prostate during irradiation? A daily evaluation with kV-images. AB - PURPOSE: Gold markers are frequently used for a better daily repositioning of the prostate before irradiation. The purpose of this work was to analyze if the combination of an androgen deprivation with the external irradiation could modify the position of the gold markers in the prostate. PATIENTS AND METHODS: Ten patients have been treated for a prostate cancer, using three implanted gold markers. The variations of the intermarker distances in the prostate were measured and collected on daily OBI((r)) kilovoltage images acquired at 0 degrees and 90 degrees . Five patients had a 6-month androgen deprivation started before the external irradiation (H group) and five did not (NH group). RESULTS: A total number of 1062 distances were calculated. No distance variation greater than 3.7mm was seen between two markers, in any of the two groups. The median standard deviations of the daily intermarker distance differences were 0.7mm (range 0.3 1.2mm) for the H group and 0.6mm (range 0.2-1.2mm) for the NH group. The intermarker distances variations were noted as greater than -2mm, between -2mm and 2mm and greater than 2mm in 16.4, 83.4 and 0.2% for the H group and 1.3, 98.5 and 0.2% for the NH group, respectively. CONCLUSION: The distance variations remained less than 4mm in both groups and for all the measurements. In the NH group, the variation of the distance between two markers remained below 2mm in 98.5%. In the H group, the presence of a reduction of distance above 2mm in 16.4% of measurements could indicate the shrinkage of the prostate volume. PMID- 23726365 TI - Comparison of real time diagnostic chemistries to detect Pseudomonas aeruginosa in respiratory samples from cystic fibrosis patients. AB - BACKGROUND: Early eradication therapy is key to keeping the airways Pseudomonas aeruginosa infection-free and rapid identification is essential. METHODS: We used rapid DNA extraction and qPCR assays to detect bacterial, P. aeruginosa and strain-specific targets in samples using two qPCR chemistries. Using 459 respiratory samples from adult and children CF patients, we compared two qPCR methods to culture-based methods in terms of sensitivity and time to result. RESULTS: For adult samples, there was 100% concordance between methods. There was no clear pattern in fluctuations in P. aeruginosa number during exacerbation. In child samples, qPCR methods identified additional P. aeruginosa positive samples. The time-to-result was reduced by over 24h and copy number and colony forming unit could differ dramatically in some samples. CONCLUSION: If adopted, these methods could significantly improve early P. aeruginosa detection in diagnostic laboratories and therefore play a pivotal role in prolonging infection-free airways in CF patients. PMID- 23726366 TI - Genome-wide characterization of shared and distinct genetic components that influence blood lipid levels in ethnically diverse human populations. AB - Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci influencing lipid concentrations in African American and Hispanic American women in the Women's Health Initiative SNP Health Association Resource. We validated one African-specific high-density lipoprotein cholesterol locus at CD36 as well as 14 known lipid loci that have been previously implicated in studies of European populations. Moreover, we demonstrate striking similarities in genetic architecture (loci influencing the trait, direction and magnitude of genetic effects, and proportions of phenotypic variation explained) of lipid traits across populations. In particular, we found that a disproportionate fraction of lipid variation in African Americans and Hispanic Americans can be attributed to genomic loci exhibiting statistical evidence of association in Europeans, even though the precise genes and variants remain unknown. At the same time, we found substantial allelic heterogeneity within shared loci, characterized both by population-specific rare variants and variants shared among multiple populations that occur at disparate frequencies. The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits such as lipids; furthermore, the overlap in lipid loci across populations of diverse ancestral origin argues that additional knowledge can be gleaned from multiple populations. PMID- 23726367 TI - Enhanced localization of genetic samples through linkage-disequilibrium correction. AB - Characterizing the spatial patterns of genetic diversity in human populations has a wide range of applications, from detecting genetic mutations associated with disease to inferring human history. Current approaches, including the widely used principal-component analysis, are not suited for the analysis of linked markers, and local and long-range linkage disequilibrium (LD) can dramatically reduce the accuracy of spatial localization when unaccounted for. To overcome this, we have introduced an approach that performs spatial localization of individuals on the basis of their genetic data and explicitly models LD among markers by using a multivariate normal distribution. By leveraging external reference panels, we derive closed-form solutions to the optimization procedure to achieve a computationally efficient method that can handle large data sets. We validate the method on empirical data from a large sample of European individuals from the POPRES data set, as well as on a large sample of individuals of Spanish ancestry. First, we show that by modeling LD, we achieve accuracy superior to that of existing methods. Importantly, whereas other methods show decreased performance when dense marker panels are used in the inference, our approach improves in accuracy as more markers become available. Second, we show that accurate localization of genetic data can be achieved with only a part of the genome, and this could potentially enable the spatial localization of admixed samples that have a fraction of their genome originating from a given continent. Finally, we demonstrate that our approach is resistant to distortions resulting from long range LD regions; such distortions can dramatically bias the results when unaccounted for. PMID- 23726368 TI - Age-dependent germline mosaicism of the most common noonan syndrome mutation shows the signature of germline selection. AB - Noonan syndrome (NS) is among the most common Mendelian genetic diseases (~1/2,000 live births). Most cases (50%-84%) are sporadic, and new mutations are virtually always paternally derived. More than 47 different sites of NS de novo missense mutations are known in the PTPN11 gene that codes for the protein tyrosine phosphatase SHP-2. Surprisingly, many of these mutations are recurrent with nucleotide substitution rates substantially greater than the genome average; the most common mutation, c.922A>G, is at least 2,400 times greater. We examined the spatial distribution of the c.922A>G mutation in testes from 15 unaffected men and found that the mutations were not uniformly distributed across each testis as would be expected for a mutation hot spot but were highly clustered and showed an age-dependent germline mosaicism. Computational modeling that used different stem cell division schemes confirmed that the data were inconsistent with hypermutation, but consistent with germline selection: mutated spermatogonial stem cells gained an advantage that allowed them to increase in frequency. SHP-2 interacts with the transcriptional activator STAT3. Given STAT3's function in mouse spermatogonial stem cells, we suggest that this interaction might explain the mutant's selective advantage by means of repression of stem cell differentiation signals. Repression of STAT3 activity by cyclin D1 might also play a previously unrecognized role in providing a germline-selective advantage to spermatogonia for the recurrent mutations in the receptor tyrosine kinases that cause Apert syndrome and MEN2B. Looking at recurrent mutations driven by germline selection in different gene families can help highlight common causal signaling pathways. PMID- 23726369 TI - Spontaneous resolution of spinal epidural lipomatosis. AB - Spinal epidural lipomatosis (SEL) is an abnormal accumulation of unencapsulated, epidural fat. SEL can be divided into idiopathic and secondary. Secondary SEL is often associated with chronic steroid use and endocrinopathies. Idiopathic SEL has been associated with obesity. SEL has been implicated in a variety of neurologic impairments and surgical decompression has been shown to prevent further worsening or result in improvement. We report a 53-year-old man with obesity and a history of chronic back pain who developed idiopathic SEL diagnosed by MRI, which subsequently resolved completely over an 8 month follow-up period. To our knowledge, this is the first reported case of complete radiographic resolution of SEL without any treatment. PMID- 23726370 TI - Naturalistic parental pain management during immunizations during the first year of life: observational norms from the OUCH cohort. AB - No research to date has descriptively catalogued what parents of healthy infants are naturalistically doing to manage their infant's pain over immunization appointments during the first year of life. This knowledge, in conjunction with an understanding of the relationships different parental techniques have with infant pain-related distress, would be useful when attempting to target parental pain management strategies in the infant immunization context. This study presents descriptive information about the pain management techniques parents have chosen and examines the relationships these naturalistic techniques have with infant pain-related distress during the first year of life. A total of 760 parent-infant dyads were recruited from 3 pediatric clinics in Toronto, ON, Canada, and were naturalistically followed and videotaped longitudinally over 4 immunization appointments during the infant's first year of life. Infants were full-term, healthy babies. Videotapes were subsequently coded for infant pain related distress behaviors and parental pain management techniques. After controlling for preceding infant pain-related distress levels, parent pain management techniques accounted for, at most, 13% of the variance in infant pain related distress scores. Across all age groups, physical comfort, rocking, and verbal reassurance were the most commonly used nonpharmacological pain management techniques. Pacifying and distraction appeared to be most promising in reducing needle-related distress in our sample of healthy infants. Parents in this sample seldom used pharmacological pain management techniques. Given the psychological and physical repercussions involved with unmanaged repetitive acute pain and the paucity of work in healthy infants, this paper highlights key areas for improving parental pain management in primary care. PMID- 23726371 TI - Pain in multiple sites and sickness absence trajectories: a prospective study among Finns. PMID- 23726372 TI - Migraine, headache and development of metabolic syndrome: an 11-year follow-up in the Nord-Trondelag Health Study (HUNT). AB - Migraine with aura is associated with an increased incidence of stroke and cardiovascular disease, but the biological mechanisms are poorly understood. This study examined the incidence of metabolic syndrome and its relationship to migraine with and without aura and to nonmigraine headache. In the population based the Nord-Trondelag Health Study (HUNT), 19,895 individuals were followed for the development of metabolic syndrome, with a median follow-up time of 11.3 years. Headache diagnoses were based on a validated headache questionnaire, and metabolic syndrome was based on a modified version of the National Cholesterol Education Program's Adult Treatment Panel (ATP) III criteria, using objective anthropometric measurements and blood biochemistry. Using the Poisson regression model, migraine with aura was associated with an increased risk for developing metabolic syndrome. The effect was modified by smoking, with an adjusted incident risk ratio (IRR) among smokers of 2.10 (95% CI 1.53-2.89) and among nonsmokers of 1.39 (95% CI 1.03-1.86), when compared to headache-free controls. A moderate risk increase was seen for migraine without aura (IRR 1.26, 95% CI 1.12-1.42) and nonmigraine headache (IRR 1.22, 95% CI 1.13-1.32), not modified by smoking. The results suggest that traditional risk factors may be one of the mechanisms through which migraine with aura is linked to an increased risk for cardiovascular disease. A heightened vigilance concerning cardiovascular risk factors in this patient group may be warranted. PMID- 23726373 TI - Ghrelin suppresses nocturnal secretion of luteinizing hormone (LH) and thyroid stimulating hormone (TSH) in patients with major depression. AB - Major depression is associated with various endocrine disturbances. Apart from the well-known hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, also the function of the hypothalamic-pituitary-gonadal (HPG) axis and of the hypothalamic-pituitary-thyroid (HPT) axis may be altered compared to healthy subjects. The orexigenic hormone ghrelin is involved in mood regulation and may have antidepressant effects. In addition, it has been shown to suppress secretion of luteinizing hormone (LH) and thyroid stimulating hormone (TSH) in healthy subjects. Aim of this study was therefore to test the effect of ghrelin on the activity of the HPG and HPT axis in patients with major depression. Therefore, secretion profiles of LH and TSH were determined in 14 unmedicated patients with major depression (7 women) twice, receiving 50 MUg ghrelin or placebo at 2200, 2300, 0000, and 0100 h. LH secretion after ghrelin injection as assessed by the AUC (4.05 +/- 1.18 mlIU min/ml) was significantly (P = 0.049) lower than after placebo injection (4.75 +/- 1.33 mlIU min/ml) during the predefined intervention period (2220-0200 h). In addition, LH pulses occurred significantly (P = 0.045) less frequently after ghrelin injection (3.2 +/- 1.4) than after placebo injection (3.9 +/- 1.7). Mean TSH plasma levels were significantly lower at 0240 h and from 0320 until 0420 h after ghrelin injection than after placebo injection. In conclusion, ghrelin suppressed nocturnal secretion of LH and TSH in patients with major depression. However, these effects were weaker than previously shown in healthy subjects. PMID- 23726374 TI - Support system for decision making in the identification of risk for body dysmorphic disorder: a fuzzy model. AB - PURPOSE: To develop a fuzzy linguistic model to quantify the level of distress of patients seeking cosmetic surgery. Body dysmorphic disorder (BDD) is a mental condition related to body image relatively common among cosmetic surgery patients; it is difficult to diagnose and is a significant cause of morbidity and mortality. Fuzzy cognitive maps are an efficient tool based on human knowledge and experience that can handle uncertainty in identifying or grading BDD symptoms and the degree of body image dissatisfaction. Individuals who seek cosmetic procedures suffer from some degree of dissatisfaction with appearance. METHODS: A fuzzy model was developed to measure distress levels in cosmetic surgery patients based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), diagnostic criterion B for BDD. We studied 288 patients of both sexes seeking abdominoplasty, rhinoplasty, or rhytidoplasty in a university hospital. RESULTS: Patient distress ranged from "none" to "severe" (range=7.5 31.6; cutoff point=18; area under the ROC curve=0.923). There was a significant agreement between the fuzzy model and DSM-IV criterion B (kappa=0.805; p<0.001). CONCLUSION: The fuzzy model measured distress levels with good accuracy, indicating that it can be used as a screening tool in cosmetic surgery and psychiatric practice. PMID- 23726375 TI - Epilepsy associated with autism and attention deficit hyperactivity disorder: is there a genetic link? AB - Autism Spectrum Disorders (ASDs) and Attention Deficit and Hyperactivity Disorder (ADHD) are the most common comorbid conditions associated with childhood epilepsy. The co-occurrence of an epilepsy/autism phenotype or an epilepsy/ADHD phenotype has a complex and heterogeneous pathogenesis, resulting from several altered neurobiological mechanisms involved in early brain development, and influencing synaptic plasticity, neurotransmission and functional connectivity. Rare clinically relevant chromosomal aberrations, in addition to environmental factors, may confer an increased risk for ASDs/ADHD comorbid with epilepsy. The majority of the candidate genes are involved in synaptic formation/remodeling/maintenance (NRX1, CNTN4, DCLK2, CNTNAP2, TRIM32, ASTN2, CTNTN5, SYN1), neurotransmission (SYNGAP1, GABRG1, CHRNA7), or DNA methylation/chromatin remodeling (MBD5). Two genetic disorders, such as Tuberous sclerosis and Fragile X syndrome may serve as models for understanding the common pathogenic pathways leading to ASDs and ADHD comorbidities in children with epilepsy, offering the potential for new biologically focused treatment options. PMID- 23726377 TI - 190 th ENMC international workshop: Spinal muscular atrophy with respiratory distress/distal spinal muscular atrophy type 1: 11-13 May 2012, Naarden, The Netherlands. PMID- 23726384 TI - Three-phase contact force equilibrium of liquid drops at hydrophilic and superhydrophobic surfaces. AB - Hydrophilic and superhydrophobic surfaces were obtained by modifying a dendritic Au surface with carboxyl- or methyl-terminated self-assembled monolayers, respectively. The hydrophilic surface generates capillary forces which induce water flow through the grooves defined by the dendritic structure, resulting in a halo structure; the superhydrophobic surface on the other hand completely repels water drops. The contrasting behaviors exhibited by the two surfaces with nominally identical morphology but different surface chemistry are explained semi quantitatively in terms of the equilibrium of surface forces developing at the three-phase (air-solid-water) contact lines. PMID- 23726385 TI - One-way wicking in open micro-channels controlled by channel topography. AB - One-way wicking (microfluidic diode) behaviors of a range of IPA-water mixtures on internally structured PDMS-based open micro-channels were experimentally demonstrated and quantified. The open microfluidic channels, each internally decorated with an array of angled fin-like-structure pairs, were fabricated using a combined photolithography and soft molding procedure. Propagations of wetting fluids were found to be much more impeded on the fin-tilting direction, or the hard wicking direction, comparing to the opposite direction, or the easy wicking direction. This asymmetric wicking behaviors were attributed to the structure induced direction-dependent Laplace pressure. Two key parameters - the contact angle of the wicking fluid and the tilting angle of the fin-like structures - were studied. The effects of preferential evaporation and wetting instability were also investigated. The findings of this study are expected to provide a better understanding of how fluids interact with micro-scaled structures and to offer a new way of manipulating fluids at the micron and nanometer scales. PMID- 23726376 TI - Motor and cognitive assessment of infants and young boys with Duchenne Muscular Dystrophy: results from the Muscular Dystrophy Association DMD Clinical Research Network. AB - Therapeutic trials in Duchenne Muscular Dystrophy (DMD) exclude young boys because traditional outcome measures rely on cooperation. The Bayley III Scales of Infant and Toddler Development (Bayley III) have been validated in developing children and those with developmental disorders but have not been studied in DMD. Expanded Hammersmith Functional Motor Scale (HFMSE) and North Star Ambulatory Assessment (NSAA) may also be useful in this young DMD population. Clinical evaluators from the MDA-DMD Clinical Research Network were trained in these assessment tools. Infants and boys with DMD (n = 24; 1.9 +/- 0.7 years) were assessed. The mean Bayley III motor composite score was low (82.8 +/- 8; p <= .0001) (normal = 100 +/- 15). Mean gross motor and fine motor function scaled scores were low (both p <= .0001). The mean cognitive comprehensive (p=.0002), receptive language (p <= .0001), and expressive language (p = .0001) were also low compared to normal children. Age was negatively associated with Bayley III gross motor (r = -0.44; p = .02) but not with fine motor, cognitive, or language scores. HFMSE (n=23) showed a mean score of 31 +/- 13. NSAA (n = 18 boys; 2.2 +/- 0.4 years) showed a mean score of 12 +/- 5. Outcome assessments of young boys with DMD are feasible and in this multicenter study were best demonstrated using the Bayley III. PMID- 23726386 TI - Intra-abdominal hypertension in the critically ill: interrater reliability of bladder pressure measurement. AB - PURPOSE: Intra-abdominal hypertension is frequently underdiagnosed and defined by intra-abdominal pressure (IAP) 12 mm Hg or higher. Increasing IAP may compromise organ viability and culminate in abdominal compartment syndrome. Bladder pressure measurement is a surrogate for IAP, but measurement properties are unknown in the intensive care unit. Our primary objective was to assess the agreement of bladder pressure measurements in critically ill patients. METHODS: We conducted an observational study examining the correlation of measurement variability of bladder pressure. Four raters (2 nurses and 2 physicians) measured IAP. Patient's age, Acute Physiology and Chronic Health Evaluation II, body mass index, mechanical ventilation parameters, and demographics were collected. RESULTS: Fifty-one patients had bladder pressures measured in quadruplicate, producing 204 measurements. Among 51 patients, the mean age was 61.9 years, Acute Physiology and Chronic Health Evaluation II was 23.8, and body mass index was 27.8 kg/m2. The average bladder pressure was 12.4 (SD, +/-6.2) mm Hg. The interrater agreement by intraclass correlation coefficient was 0.745 (95% confidence interval [CI], 0.637-0.825), 0.804 (95% CI, 0.684-0.882), and 0.626 (95% CI, 0.428-0.767) among all raters, physicians, and nurses, respectively. CONCLUSIONS: Agreement on bladder pressure was high among 4 clinicians and were not significantly different between physicians and nurses. Given that medical/surgical treatments are considered on bladder pressure values, understanding their reliability is essential to monitor critically ill patients. PMID- 23726387 TI - Continuous multiorgan variability analysis to track severity of organ failure in critically ill patients. AB - PURPOSE: The purpose of this study is to evaluate the utility of using continuous heart rate variability (HRV) and respiratory rate variability (RRV) monitoring for (a) tracking daily organ dysfunction in critically ill patients and (b) identifying patterns of variability changes during onset of shock and resolution of respiratory failure. MATERIALS AND METHODS: Thirty-three critically ill patients experiencing respiratory and/or cardiac failure underwent continuous recording of their electrocardiogram and capnogram (CO2) waveforms from admission or intubation until discharge (maximum 14 days). HRV and RRV were computed in 5 minute overlapping windows, using Continuous Individualized Multi-organ Variability Analysis software. Multiple organ dysfunction scores were recorded daily. HRV and RRV trajectories were characterized during onset of shock and resolution of respiratory failure. RESULTS: Both HRV and RRV decreased with increasing severity of multiple organ dysfunction scores for a variety of variability metrics. A decline in several measures of HRV and no decline in RRV were observed before onset of shock (n=6). In contrast, during resolution of respiratory failure, an increase in RRV was observed in patients who successfully passed extubation (n=12), with no change in RRV in those who subsequently failed extubation (n=2). CONCLUSIONS: There is an association between reduced HRV and RRV and increasing organ dysfunction in critically ill patients. The significance of observing trends of decreasing HRV (with onset of shock) and increasing RRV (with resolution of respiratory failure) merits further investigation. PMID- 23726388 TI - Innovating by developing new uses of already-approved drugs: trends in the marketing approval of supplemental indications. AB - BACKGROUND: Much of the literature on trends and factors affecting biopharmaceutical innovation has focused overwhelmingly on the development and approval of never-before approved drugs and biologics. Little attention has been paid to new uses for already-approved compounds, which can be an important form of innovation. OBJECTIVE: This paper aimed to determine and analyze recent trends in the number and type of new or modified US indication approvals for drugs and biologics. We also examine regulatory approval-phase times for new-use efficacy supplements and compare them to approval-phase times for original-use approvals over the same period. METHODS: We developed a data set of efficacy supplements approved by the US Food and Drug Administration (FDA) from 1998 to 2011 that includes information on the type, approval-phase time (time from submission to the FDA of an application for marketing approval to approval of the application), and FDA therapeutic-significance rating for the approved application, which we obtained from an FDA Web site. This data set was merged with a Tufts Center for the Study of Drug Development (CSDD) data set of US new drug and biologics approvals. We developed descriptive statistics on trends in the number and type of new-use efficacy supplements, on US regulatory approval-phase times for the supplements, and on original new drug and biologics approvals over the study period and for the time from original- to new-use approval. RESULTS: The total number of new-use efficacy-supplement approvals did not exhibit a marked trend, but the number of new pediatric-indication approvals increased substantially. Approval-phase times for new-use supplements varied by therapeutic class and FDA therapeutic-significance rating. Mean approval-phase times were highest for central nervous system compounds (13.8 months) and lowest for antineoplastics (8.9 months). The mean time from original to supplement approval was substantially longer for new pediatric indications than for other new uses. Mean approval-phase time during the study period for applications that received a standard review rating from the FDA was substantially shorter for supplements compared to original uses, but the differences for applications that received a priority review rating from the FDA were negligible. CONCLUSIONS: Development of and regulatory approval for new uses of already-approved drugs and biologics is an important source of innovation by biopharmaceutical firms. Despite rising development costs, the output of new-use approvals has remained stable in recent years, driven largely by the pursuit of new pediatric indications. FDA approval phase times have generally declined substantially for all types of applications since the mid-1990s following legislation that provided a new source of income for the agency. However, while the resources needed to review supplemental applications are likely lower in general than for original-use approvals, the approval-phase times for important new uses are no lower than for important original-use applications. PMID- 23726389 TI - Effect of N-acetyl cysteine on enterocyte apoptosis and intracellular signalling pathways' response to oxidative stress in weaned piglets. AB - N-Acetyl cysteine (NAC) has been widely used for preventing reactive oxygen species-induced damage. However, little is known as to whether dietary NAC supplementation would alleviate intestinal injury in weaned piglets. The present study evaluated the effect of NAC on enterocyte apoptosis and intracellular signalling pathways' response to weaning stress. The control piglets were normally suckling, and piglets in the weaning and NAC groups were fed the basal diet and basal+NAC diet from 14 to 25 d of age, respectively. Compared with the control piglets, weaning increased cortisol concentrations (P< 0.05), decreased superoxide dismutase and glutathione peroxidase activities (P< 0.05), increased malondialdehyde content (P< 0.05) in serum and enhanced enterocyte apoptosis index (AI) and concentrations of caspase-3, caspase-8 and caspase-9 (P< 0.05). Gene expression analyses indicated that weaning induced apoptosis via Fas signalling and mitochondrial pathways in weaned piglets. Dietary NAC supplementation decreased (P< 0.05) cortisol concentrations and the AI, increased (P< 0.05) antioxidant status in serum and alleviated histopathological changes in the intestine. It also inhibited Fas, caspase-3, caspase-8 and integrin alphavbeta6 (alphavbeta6) gene expressions in the NAC-treated piglets. However, no significant decrease (P>0.10) in caspase-3, caspase-8 and caspase-9 concentrations was observed in the NAC group compared with the weaning group. In conclusion, weaning may induce enterocyte apoptosis via the activation of Fas dependent and mitochondria-dependent apoptosis. Although NAC had no effect on caspase concentrations, it was clearly beneficial for preserving morphological integrity in weaned piglets via the regulation of cell apoptosis and the inhibition of Fas-dependent apoptosis and alphavbeta6 expression. PMID- 23726391 TI - High-dose non-steroidal anti-inflammatories: painful choices. PMID- 23726390 TI - Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. AB - BACKGROUND: The vascular and gastrointestinal effects of non-steroidal anti inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. METHODS: We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124,513 participants, 68,342 person-years) and 474 trials of one NSAID versus another NSAID (229,296 participants, 165,456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). FINDINGS: Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1.37, 95% CI 1.14-1.66; p=0.0009) or diclofenac (1.41, 1.12-1.78; p=0.0036), chiefly due to an increase in major coronary events (coxibs 1.76, 1.31-2.37; p=0.0001; diclofenac 1.70, 1.19-2.41; p=0.0032). Ibuprofen also significantly increased major coronary events (2.22, 1.10-4.48; p=0.0253), but not major vascular events (1.44, 0.89 2.33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0.93, 0.69-1.27). Vascular death was increased significantly by coxibs (1.58, 99% CI 1.00-2.49; p=0.0103) and diclofenac (1.65, 0.95-2.85, p=0.0187), non-significantly by ibuprofen (1.90, 0.56-6.41; p=0.17), but not by naproxen (1.08, 0.48-2.47, p=0.80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1.81, 1.17-2.81, p=0.0070; diclofenac 1.89, 1.16-3.09, p=0.0106; ibuprofen 3.97, 2.22-7.10, p<0.0001; and naproxen 4.22, 2.71-6.56, p<0.0001). INTERPRETATION: The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. FUNDING: UK Medical Research Council and British Heart Foundation. PMID- 23726392 TI - Association between adverse clinical outcome in human disease caused by novel influenza A H7N9 virus and sustained viral shedding and emergence of antiviral resistance. AB - BACKGROUND: On March 30, a novel influenza A subtype H7N9 virus (A/H7N9) was detected in patients with severe respiratory disease in eastern China. Virological factors associated with a poor clinical outcome for this virus remain unclear. We quantified the viral load and analysed antiviral resistance mutations in specimens from patients with A/H7N9. METHODS: We studied 14 patients with A/H7N9 disease admitted to the Shanghai Public Health Clinical Centre (SPHCC), China, between April 4, and April 20, 2013, who were given antiviral treatment (oseltamivir or peramivir) for less than 2 days before admission. We investigated the viral load in throat, stool, serum, and urine specimens obtained sequentially from these patients. We also sequenced viral RNA from these specimens to study the mutations associated with resistance to neuraminidase inhibitors and their association with disease outcome. FINDINGS: All patients developed pneumonia, seven of them required mechanical ventilation, and three of them further deteriorated to become dependent on extracorporeal membrane oxygenation (ECMO), two of whom died. Antiviral treatment was associated with a reduction of viral load in throat swab specimens in 11 surviving patients. Three patients with persistently high viral load in the throat in spite of antiviral therapy became ECMO dependent. An Arg292Lys mutation in the virus neuraminidase (NA) gene known to confer resistance to both zanamivir and oseltamivir was identified in two of these patients, both also received corticosteroid treatment. In one of them, wild type sequence Arg292 was noted 2 days after start of antiviral treatment, and the resistant mutant Lys292 dominated 9 days after start of treatment. INTERPRETATION: Reduction of viral load following antiviral treatment correlated with improved outcome. Emergence of NA Arg292Lys mutation in two patients who also received corticosteroid treatment led to treatment failure and a poor clinical outcome. The emergence of antiviral resistance in A/H7N9 viruses, especially in patients receiving corticosteroid therapy, is concerning, needs to be closely monitored, and considered in pandemic preparedness planning. FUNDING: National Megaprojects of China for Infectious Diseases, Shanghai Municipal Health and Family Planning Commission, the National Key Basic Research Program of China, Ministry of Science and Technology, and National Natural Science Foundation of China. PMID- 23726394 TI - Surgery or conservative therapy for cerebral haemorrhage? PMID- 23726393 TI - Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial. AB - BACKGROUND: The balance of risk and benefit from early neurosurgical intervention for conscious patients with superficial lobar intracerebral haemorrhage of 10-100 mL and no intraventricular haemorrhage admitted within 48 h of ictus is unclear. We therefore tested the hypothesis that early surgery compared with initial conservative treatment could improve outcome in these patients. METHODS: In this international, parallel-group trial undertaken in 78 centres in 27 countries, we compared early surgical haematoma evacuation within 12 h of randomisation plus medical treatment with initial medical treatment alone (later evacuation was allowed if judged necessary). An automatic telephone and internet-based randomisation service was used to assign patients to surgery and initial conservative treatment in a 1:1 ratio. The trial was not masked. The primary outcome was a prognosis-based dichotomised (favourable or unfavourable) outcome of the 8 point Extended Glasgow Outcome Scale (GOSE) obtained by questionnaires posted to patients at 6 months. Analysis was by intention to treat. This trial is registered, number ISRCTN22153967. FINDINGS: 307 of 601 patients were randomly assigned to early surgery and 294 to initial conservative treatment; 298 and 291 were followed up at 6 months, respectively; and 297 and 286 were included in the analysis, respectively. 174 (59%) of 297 patients in the early surgery group had an unfavourable outcome versus 178 (62%) of 286 patients in the initial conservative treatment group (absolute difference 3.7% [95% CI -4.3 to 11.6], odds ratio 0.86 [0.62 to 1.20]; p=0.367). INTERPRETATION: The STICH II results confirm that early surgery does not increase the rate of death or disability at 6 months and might have a small but clinically relevant survival advantage for patients with spontaneous superficial intracerebral haemorrhage without intraventricular haemorrhage. FUNDING: UK Medical Research Council. PMID- 23726396 TI - Reversing the Slide in US Health Outcomes and Deteriorating Health Care Economics. PMID- 23726395 TI - Activation of Rac1 GTPase promotes leukemia cell chemotherapy resistance, quiescence and niche interaction. AB - Leukemia stem cells (LSCs) reside in bone marrow niche and receive important signals from the microenvironment that support self-renewal, maintain quiescence and endow LSC with the ability of chemotherapy resistance. Rac1 belongs to the small GTP-binding protein superfamily and is implicated in the interactions of hematopoietic progenitors and bone marrow niche. Our previous studies have shown that Rac1 is over-expressed in leukemia patients and activation of Rac1 GTPase is closely associated with the efficient migration of leukemia cells. However, the potential functions for Rac1 GTPase in LSCs behaviors and in the residence of leukemia cells in niche remain unknown. In this study, by forced expression of a dominant-negative form of Rac1 GTPase in a CD34(+) myeloid leukemia cell line, as well as bone marrow cells from leukemia patients, we show that inactivation of Rac1 GTPase causes impaired migration and enhances chemotherapeutic sensitivity. Inactivation of Rac1 in leukemia cells also lead to a reduction in the frequency of cells in quiescent state and inhibition of homing to bone marrow niche. Gene expression analysis shows that inactivation of Rac1 down-regulates the expression of several cell intrinsic cell cycle inhibitors such as p21, p27, and p57, as well as the extrinsic molecules that mediated the interaction of LSC with osteoblastic niche. Furthermore, we show that Rac1 mediated the localization in niche is further attributed to the maintenance of quiescence. Our results provide evidence for the critical role of Rac1 GTPase in leukemia cell chemotherapy resistance, quiescence maintenance and the interaction with bone marrow microenvironment. PMID- 23726397 TI - The syntax of sin taxes: putting it together to improve physical, social, and fiscal health. PMID- 23726398 TI - Family history of chronic disease and meeting public health guidelines for physical activity: the cooper center longitudinal study. AB - We aimed to assess whether a family history of coronary heart disease, diabetes, or cancer is linked to meeting public health guidelines for health-promoting physical activity. To achieve this objective, we analyzed data on 29,513 adults who came to the Cooper Clinic (Dallas, Texas) between January 1, 1990, and December 31, 2010, for a preventive medicine visit. Patients completed a comprehensive medical survey including information on family medical history, physical activity, and other lifestyle behaviors. Bivariate and multivariate logistic regression were used to examine the relationship between having a family history of chronic disease and meeting physical activity guidelines. The results indicated that individuals with a family history of disease had reduced odds for meeting or exceeding physical activity guidelines. For example, participants with a family history of 3 diseases were 36% less likely to meet or exceed physical activity guidelines than their counterparts without a family history of disease (odds ratio, 0.64; 95% CI, 0.58-0.72), while controlling for covariates. Among this large sample of adults, those with a family history of chronic disease were less inclined to regularly engage in physical activity. Thus, targeted programs encouraging adoption and maintenance of health-promoting physical activity might be warranted, specifically targeting individuals with familial history of disease. PMID- 23726400 TI - Promoting health and wellness in the workplace: a unique opportunity to establish primary and extended secondary cardiovascular risk reduction programs. AB - Given the burden of cardiovascular disease (CVD), increasing the prevalence of healthy lifestyle choices is a global imperative. Currently, cardiac rehabilitation programs are a primary way that modifiable risk factors are addressed in the secondary prevention setting after a cardiovascular (CV) event/diagnosis. Even so, there is wide consensus that primary prevention of CVD is an effective and worthwhile pursuit. Moreover, continual engagement with individuals who have already been diagnosed as having CVD would be beneficial. Implementing health and wellness programs in the workplace allows for the opportunity to continually engage a group of individuals with the intent of effecting a positive and sustainable change in lifestyle choices. Current evidence indicates that health and wellness programs in the workplace provide numerous benefits with respect to altering CV risk factor profiles in apparently healthy individuals and in those at high risk for or already diagnosed as having CVD. This review presents the current body of evidence demonstrating the efficacy of worksite health and wellness programs and discusses key considerations for the development and implementation of such programs, whose primary intent is to reduce the incidence and prevalence of CVD and to prevent subsequent CV events. Supporting evidence for this review was obtained from PubMed, with no date limitations, using the following search terms: worksite health and wellness, employee health and wellness, employee health risk assessments, and return on investment. The choice of references to include in this review was based on study quality and relevance. PMID- 23726401 TI - Female genital cutting: an evidence-based approach to clinical management for the primary care physician. AB - The United States has more than 1.5 million immigrants from countries in Africa and the Middle East where female genital cutting (FGC) is known to occur. Often, FGC occurs in infancy and childhood in the countries where it is practiced, but patients of any age can present with complications. Lack of understanding of this common problem can potentially alienate and lower quality of care for this patient population. We provide an introduction to the practice of FGC and practice guidelines for the primary care physician. We reviewed original research, population-based studies, and legal research from PubMed, Scopus, CINAHL plus, PsycINFO, and Legal Trac. The terms searched included female genital cutting, female genital circumcision, and female genital mutilation alone and with the term complications or health consequences; no limit on date published. Legal databases were searched using the above terms, as well as international law and immigration law. Editorials and review articles were excluded. This review discusses the different types of FGC, important cultural considerations for physicians caring for patients with FGC, the common early and late medical complications and their management, and psychosocial issues associated with FGC. Current laws pertaining to FGC are briefly reviewed, as well as implications for patients seeking asylum status in the United States because of FGC. Finally, the article presents evidence-based, culturally sensitive approaches to discussions of FGC with girls and women for whom this is an issue. PMID- 23726399 TI - Scientific decision making, policy decisions, and the obesity pandemic. AB - Rising and epidemic rates of obesity in many parts of the world are leading to increased suffering and economic stress from diverting health care resources to treating a variety of serious, but preventable, chronic diseases etiologically linked to obesity, particularly type 2 diabetes mellitus and cardiovascular diseases. Despite decades of research into the causes of the obesity pandemic, we seem to be no nearer to a solution now than when the rise in body weights was first chronicled decades ago. The case is made that impediments to a clear understanding of the nature of the problem occur at many levels. These obstacles begin with defining obesity and include lax application of scientific standards of review, tenuous assumption making, flawed measurement and other methods, constrained discourse limiting examination of alternative explanations of cause, and policies that determine funding priorities. These issues constrain creativity and stifle expansive thinking that could otherwise advance the field in preventing and treating obesity and its complications. Suggestions are made to create a climate of open exchange of ideas and redirection of policies that can remove the barriers that prevent us from making material progress in solving a pressing major public health problem of the early 21st century. PMID- 23726402 TI - Common curbsides and conundrums in geriatric medicine. AB - Within the next 15 years, the population of adults 65 years and older in the United States will double to approximately 70 million. Physicians must be well prepared to care for this rapidly growing population. Senior adults comprise a large proportion of most primary care practices in the United States, and the unique needs of this population cannot be overstated. Although traditional preventive screening modalities and disease-specific care models are of great utility, these processes may not be appropriate or consistent with the health goals of many older patients with multiple chronic conditions and reduced functional capacity. This Concise Review highlights commonly encountered clinical scenarios important to the care of these older patients. The topics include diagnosis and management of mild cognitive impairment, assessment of the cognitively impaired driver, cancer screening in the older patient, and sarcopenia. PMID- 23726403 TI - 51-year-old man with tinnitus. PMID- 23726404 TI - Formula for fresh frozen plasma dosing for warfarin reversal. PMID- 23726405 TI - In reply-formula for fresh frozen plasma dosing for warfarin reversal. PMID- 23726406 TI - 62-year-old man with painless jaundice and hyponatremia. PMID- 23726407 TI - Jens Skou--nobel prize in chemistry. PMID- 23726409 TI - Caroli syndrome. PMID- 23726410 TI - Reply to the commentaries on "An evolutionary framework for cultural change: selectionism versus communal exchange". PMID- 23726411 TI - Long-chain triazolyl acids as inhibitors of osteoclastogenesis. AB - Saturated fatty acids (e.g., palmitic acid) are known to moderately inhibit the development of osteoclasts in vitro. In pursuit of more effective inhibitors of osteoclastogenesis we explored two new classes of palmitic acid analogues containing either an ether or triazolyl group at various positions along the chain. The compounds were evaluated for their ability to inhibit the formation of osteoclasts in primary mouse bone marrow cultures. The oxyacids were generally prepared by condensation of the appropriate alkyl halides and diols, followed by Jones oxidation. The triazolyl acids were prepared by copper-catalysed click chemistry between alkyl azides and acetylenic acids, or with the appropriately protected azides and alkynes, followed by deprotection and oxidation. The oxyacids were little more effective than palmitic acid, but the triazolyl analogues were much more effective osteoclastogenesis inhibitors, especially when the triazole was distant from the acid unit. PMID- 23726412 TI - Health service expenditure and efficiencies in Greece. PMID- 23726413 TI - The burden of symptoms in myelofibrosis: from patient-reported outcomes to health economics. PMID- 23726414 TI - Idarubicin appears equivalent to dose-intense daunorubicin for remission induction in patients with acute myeloid leukemia. AB - Daunorubicin has historically been considered the anthracycline of choice at many cancer centers for the treatment of acute myeloid leukemia (AML). Drug shortages have required the substitution of daunorubicin with idarubicin. Randomized studies have shown idarubicin (10-12mg/m(2)) to be comparable or superior to standard dose daunorubicin (45-60mg/m(2)) for achieving complete remission (CR). Whether these results can be extrapolated to dose-intense daunorubicin (90mg/m(2)), recently shown to improve CR rates when compared to standard daunorubicin doses remains uncertain. This observational study was conducted at Northwestern Memorial Hospital (NMH) to compare CR rates. The results suggest idarubicin is equivalent to daunorubicin, and for some subsets of patients, idarubicin may have superior CR rates. PMID- 23726415 TI - Development of a rapid assay to detect the dinoflagellate Amyloodinium ocellatum using loop-mediated isothermal amplification (LAMP). AB - Amyloodinium ocellatum is a highly pathogenic dinoflagellate parasite with global distribution that causes high mortalities in the culture of tropical and sub tropical marine and estuarine fishes. Diagnosis typically occurs through gross examination following the onset of morbidity, at which point treatment is of limited benefit. In the present study, a new molecular diagnostic tool for the rapid detection of A. ocellatum (AO) was developed using the loop-mediated isothermal amplification method (LAMP). The AO-LAMP assay designed is highly specific using a set of four primers - two outer and two inner primers targeting six different regions on the 5' end of the Small Subunit rDNA region (SSU rDNA) of A. ocellatum. The AO-LAMP assay, optimized for 25-30 min at 62 degrees C, amplified the DNA from A. ocellatum extracted from both water and gill tissue samples and did not amplify DNA from four closely related dinoflagellate sp ecies. The detection limit of the AO-LAMP assay was 10 fg, exceptionally higher than the conventional PCR (1 pg). In addition, the standardized AO-LAMP assay was capable of detecting single tomonts and trophonts; the assay was not affected by the presence of possible inhibitory substances present in environmental water samples or gill samples. The AO-LAMP assay developed in the present study provides a novel useful tool for the simple, rapid and sensitive detection of A. ocellatum in water and gill tissue samples, which could assist in the early detection and improved control of A. ocellatum infections in aquaculture systems. PMID- 23726416 TI - From targets to action--implementing the global monitoring framework for diabetes. PMID- 23726417 TI - Prediabetes and impaired lung function in asymptomatic adults. AB - Diabetes and metabolic syndrome are associated with impaired lung function. However, it is unknown whether this is also true in prediabetes. In a cross sectional study of 1237 asymptomatic adults, we found that diabetes and prediabetes were both significantly associated with low vital capacity, even after adjustment for relevant confounding factors. PMID- 23726419 TI - Molecular epidemiology of viral diseases in the era of next generation sequencing. PMID- 23726418 TI - Genetic diversity of cosaviruses in nonpolio acute flaccid paralysis cases of undefined etiology, Northern India, 2010-2011. AB - BACKGROUND: No cases of wild poliovirus have been reported for more than one and a half years from India. Cases of acute flaccid paralysis (AFP) of undefined etiology continue to occur in the region. Despite the recent discovery of the human Cosavirus (HCoSV) in the feces of children from developing countries, there have been no studies of cosavirus infection in India. OBJECTIVES: To detect and characterize HCoSVs in stool specimens of nonpolio AFP cases by RT-PCR followed by sequencing. STUDY DESIGN: A total of 387 fecal samples collected from AFP cases in Uttar Pradesh, India, between May 2010 and April 2011, tested negative on cell culture according to WHO algorithm, were subjected to 5'-UTR region specific RT-PCR followed by sequencing to detect HCoSV. Molecular characterization of HCoSV strains was done by sequencing followed by phylogenetic analysis. RESULT: 123 (32%) samples tested positive for cosaviruses and 87 (70.7%) were identified for genetic variants by sequencing a 316-nucleotide interval in the partial 5'-UTR region. Cosavirus strains were characterized as putative species HCoSV-A (n=70; 82%), HCoSV-B (n=7; 8%), HCoSV-C (n=1; 1.1) and HCoSV-D (n=4; 4.5%) while 5 (5%) strains remain uncharacterized. The cosavirus infection appeared highest (63.5%) in younger children, and showed a distinct seasonality, with a late summer peak and winter low. CONCLUSION: This study demonstrates a diversity of cosavirus strains in circulation, and reports the first investigation of HCoSV infection in children with nonpolio acute flaccid paralysis in India. Currently, this study provides baseline data for further studies of HCoSV infections in children with common enteric infections in India. PMID- 23726420 TI - Evaluation of an alternative dosing regimen of a J-5 mastitis vaccine against intramammary Escherichia coli challenge in nonlactating late-gestation dairy cows. AB - The objective of the study was to evaluate the efficacy of an alternative vaccination regimen of a J-5 bacterin against intramammary Escherichia coli challenge in nonlactating late-gestation dairy cows. The parameters analyzed to assess the effect of vaccination were milk yield, milk conductivity, somatic cell count, J-5-specific serum IgG titers, and clinical signs. Twenty multiparous Holstein cows from the Cornell teaching and research dairy herd were paired by days in milk and were randomly selected to receive either the alternative off label regimen of commercial J-5 bacterin or act as nonvaccinated controls. Cows received a first dose of bacterin 15 d before dry off, a second dose with the same product at the day of dry off, and the third dose 2 wk after dry off. The cows in both groups were challenged 10 d before the expected calving date. Serum IgG (total, IgG1 and IgG2) levels were higher in vaccinates compared with control cows. Eighty-five percent of challenged quarters became infected between both groups of animals. Eight of the 10 vaccinated and 9 of the 10 control cows showed signs of clinical mastitis postfreshening. A non-severe clinical mastitis was observed 24 to 48 h postparturition, characterized by flakes or clots in milk and mild swelling or pain. Off-label vaccination did reduce the clinical severity of clinical mastitis in the vaccinated group of cows as evidenced by reduced California mastitis test score, fewer flakes and lower overall clinical mastitis score. No significant differences between vaccinated and control groups were detected for rectal temperature. In conclusion, the alternative off-label vaccination scheme used in our study and evaluated in a novel E. coli challenge model did not prevent new intramammary infections but reduced clinical severity of experimentally induced E. coli mastitis. PMID- 23726421 TI - Effect of feeding according to energy balance on performance, nutrient excretion, and feeding behavior of early lactation dairy cows. AB - The objectives of this study were to evaluate 2 feeding strategies for early lactation cows on performance and efficiency of nutrient utilization. Fifty-eight Holsteins cows were blocked by parity and production during the pretreatment period and then randomly assigned at 21 d postpartum to a control diet [n=29; 16.2% crude protein, 1.64 Mcal of net energy for lactation (NE(L)), 22% starch, and 19% forage neutral detergent fiber (NDF)] or a diet with caloric density manipulated weekly (precision diet; n=29; 16.2% crude protein; 1.59 to 1.68 NE(L); 18 to 26% starch; and 16 to 22% forage NDF) to promote a calculated positive energy balance of 5 Mcal/day. Diets were fed as total mixed rations and precision cows had their diets adjusted individually once a week, by feeding additional grain supplementation from 0 to 25% of daily dry matter (DM) offered, according to the energy balance of the preceding week. Energy balance was calculated daily and then averaged weekly. The study lasted from wk 3 to 19 postpartum, and nutrient digestibility, rumen fluid composition, urinary output, estimates of microbial protein synthesis, and feeding behavior were evaluated between wk 9 and 13 postpartum. Compared with controls, precision cows had similar DM intake (24.3 kg/d), but NE(L) intake tended to be greater primarily between wk 4 and 8 postpartum. Yields of milk (45.2 vs. 41.9 kg/d), milk components, 3.5% fat-corrected milk (44.0 vs. 40.8 kg/d), and energy-corrected milk (43.4 vs. 40.2) were all greater for precision than control cows, resulting in greater energy-corrected milk production per kilogram of diet DM consumed (1.79 vs. 1.72). Precision cows produced more milk calories per kilogram of metabolic weight (0.227 vs. 0.213 Mcal of NE(L)/kg), although the amount of consumed calories partitioned into milk (82.3%) and measures of energy status did not differ between treatments throughout the study. Glucose concentrations were greater throughout the day in precision cows compared with controls at 6 wk, but not 13 wk postpartum. Apparent digestibility of nutrients, composition of rumen fluid, mean and low rumen pH, and estimated rumen microbial N synthesis remained mostly unaltered by treatments. Although precision cows produced more milk true protein, measures of efficiency of dietary N use were not influenced by treatment. On wk 13 postpartum, precision cows consumed a diet with longer NDF particles, which resulted in a tendency for greater intake of NDF >8mm because of less sorting against the long particles than control cows. Meal pattern differed with treatment, and precision cows consumed feed more sparsely throughout the day, spent more time ruminating lying, and had similar meal duration (mean of 36.3 min/meal) compared with control cows, but smaller meal size (3.33 vs. 3.64 kg/meal). Results from the current study indicate that allocating dietary resources according to the individual needs of cows based on energy balance improves lactation performance compared with feeding a single total mixed ration, despite similar average nutrient intake between treatments. Improvements in performance are likely related to allocation of calories based on the needs of the cow and on shifts of feeding behavior that might favor intake of smaller meals. PMID- 23726422 TI - Genomic selection using indicator traits to reduce the environmental impact of milk production. AB - The aim of this simulation study was to test the hypothesis that phenotype information of specific indicator traits of environmental importance recorded on a small-scale can be implemented in breeding schemes with genomic selection to reduce the environmental impact of milk production. A stochastic simulation was undertaken to test alternative breeding strategies. The breeding goal consisted of milk production, a functional trait, and environmental impact (EI). The indicator traits (IT) for EI were categorized as large-, medium-, or small-scale, depending on how the traits were recorded. The large-scale traits were stayability and stature; the medium-scale traits were live weight and methane in the breath of the cow measured during milking; and the small-scale traits were residual feed intake and methane recorded in a respiration chamber. Simulated scenarios considered information for just one IT in addition to information for milk production and functional traits. The annual monetary genetic gain was highest in the large-scale scenario that included stayability as IT. The annual monetary gain in the scenarios with medium- or small-scale IT varied from ?50.5 to 47.5. The genetic gain improvement in EI was, however, best in the scenarios where the genetic correlation between IT and EI was >=0.30 and the accuracy of direct genomic value was >=0.40. The genetic gain in EI was 26 to 34% higher when indicator traits such as greenhouse gases in the breath of the cow and methane recorded in respiration chamber were used compared with a scenario where no indicator trait was included. It is possible to achieve increased genetic gain in EI by using a highly correlated indicator trait, but it requires that the established reference population for the indicator trait is large enough so that the accuracy of direct genomic values will be reasonably high. PMID- 23726423 TI - A new method for the production of low-fat Cheddar cheese. AB - Our objective was to develop an alternative process to produce low-fat Cheddar cheese (LFCC) by combining reduced-fat Cheddar cheese (RFCC) made by a fat removal process with micellar casein concentrate (MCC) to try to achieve the texture and flavor characteristics of full-fat Cheddar cheese (FFCC). The production of LFCC was replicated 3 times. The MCC was produced by ultrafiltration of skim milk, followed by 3 stages of microfiltration, and the final MCC was spray dried. The LFCC was formulated to achieve 6% fat, 28% protein, and 1.2% salt by a combination of RFCC, MCC powder, salt, and water. The 6% fat target was selected to comply with the FDA standard for a low-fat label claim. The pH of the LFCC mixture was adjusted to 5.3 by lactic acid. Rennet was added to the LFCC mixture, followed by pressing and packaging. Chemical and sensory data were analyzed by ANOVA using the Proc GLM of SAS to determine if any differences in chemical composition and sensory properties were present among different cheeses. Descriptive sensory scores were used to construct a principal component analysis biplot to visualize flavor profile differences among cheeses. The LFCC had 83% less fat, 32% less sodium, and higher protein and moisture content than FFCC. When the cheese texture was evaluated in the context of a filled-gel model consisting of matrix and filler (100% minus percentage of matrix) the LFCC had lower filler volume than FFCC, yet the LFCC had a softer texture than FFCC. The LFCC contained some of the original FFCC cheese matrix that had been disrupted by the fat-removal process, and this original FFCC matrix was embedded in the new LFCC matrix formed by the action of rennet on casein from the continuous phase of hydrated MCC. Thus, the texture of the LFCC was desirable and was softer than the FFCC it was made from, whereas commercial RFCC (50 and 75% fat reduction) were firmer than the FFCC. The sulfur flavor in LFCC was closer to FFCC than commercial RFCC. The LFCC had bitter and grape-tortilla off flavors that came from the dried MCC ingredient. The commercial RFCC and LFCC made in this study were missing the typical aged Cheddar character (catty, nutty, fruity, brothy, milk fat flavors) found in aged FFCC. Future work to improve the flavor of LFCC made by the process described in this study should include the addition of a flavoring ingredient (e.g., enzyme-modified cheese) to enhance the aged Cheddar flavors and mask undesirable flavors. PMID- 23726424 TI - Hazard perception of Dutch farmers and veterinarians related to dairy young stock rearing. AB - A group of 110 dairy farmers and 26 bovine veterinarians participated in a web based questionnaire using the adaptive conjoint analysis technique to rank their perception regarding several hazards during 6 subsequent periods of the process of dairy young stock rearing. The method applied only involved selected respondents with a high consistency in their answering (correlation >30%). For the ranking, answers were first transformed into a utility score (US) for each hazard. The final ranking for each of the 6 periods was based on the US per hazard separately for farmers and veterinarians. Besides the ranking, the absolute values and the US itself were also compared between farmers and veterinarians to determine any statistically significant differences between the levels of the score despite the ranking. The overall conclusion is that, for almost every designated period, the ranking of the hazards differed between farmers and veterinarians. Only 1 period was observed (period IV, Pregnancy period until 4 weeks before calving) where veterinarians and farmers had the same top 3 ranking of the hazards, namely "Mastitis," "Abortion," and "Poor growth rate of the pregnant heifer." Major differences between farmers and veterinarians were seen during period II (feeding milk until weaning) for the hazard "Diarrhea in older calf," which was considered less important by farmers compared to veterinarians, and period number III (weaning until insemination) for "Over condition," which, again, was seen as the most important hazard by veterinarians, but only ranked as number 5 by farmers. Besides the ranking, significant differences in absolute US values between veterinarians and farmers were seen in "Infection with Johne's disease" (14.5 vs. 7.8), "Diarrhea in newborn calf" (18.2 vs. 12.2), and "Insufficient feed intake" (16.2 vs. 8.4) in period I (colostrum until transition to milk replacer). Lameness represented the most important significant difference in absolute values in period III (weaning until insemination; 6.3 vs. 14.3), which was again significant in period V (4 wks before calving until calving; 7.4 vs. 12.1). The outcome of this study shows that hazard perception of veterinarians and farmers differs for most rearing periods (in ranking and absolute values). The outcome of this study can be used for 2 purposes: first, to improve communication between farmers and their consulting veterinarian about hazards and hazard perception in young stock rearing; and second, the US scores can be used to select top priority hazards which should at least be integrated into management advisory programs to improve dairy young stock rearing. PMID- 23726425 TI - Angiopoietin-2 (ANGPT2) as a candidate gene for somatic cell score in German Holstein cattle. AB - This study evaluated the bovine angiopoietin-2 (ANGPT2) gene as a functional and positional candidate gene underlying a previously fine mapped quantitative trait locus (QTL) for somatic cell score on bovine chromosome 27. The gene product angiopoietin-2 is directly involved in the extravasation of neutrophils, making it a promising candidate to control the amount of somatic cells in milk. A total of 11 polymorphisms were identified within the gene by comparatively resequencing the entire open reading frame of the gene as well as adjacent intronic regions. Four selected variants were genotyped in the same granddaughter design used for QTL mapping and an association study was carried out applying 2 complementary approaches. A variable number of tandem repeats in intron 7 of the gene was found to be significantly associated with cell score in all approaches and explains approximately half of the QTL variance. Analysis of ANGPT2 mRNA expression in different localizations of the udder in animals putatively carrying divergent QTL alleles revealed differential expression in the udder lymph node. Together with the physiological role of angiopoietin-2, these results support a role of ANGPT2 in the genetic control of somatic cell score. Further studies are, however, needed to further underpin this hypothesis. PMID- 23726426 TI - Genetic parameters for body condition score, locomotion, angularity, and production traits in Italian Holstein cattle. AB - The objectives of this research were to estimate genetic parameters for body condition score (BCS) and locomotion (LOC), and to assess their relationships with angularity (ANG), milk yield, fat and protein content, and fat to protein content ratio (F:P) in the Italian Holstein Friesian breed. The Italian Holstein Friesian Cattle Breeders Association collects type trait data once on all registered first lactation cows. Body condition score and LOC were introduced in the conformation scoring system in 2007 and 2009, respectively. Variance (and covariance) components among traits were estimated with a Bayesian approach via a Gibbs sampling algorithm and an animal model. Heritability estimates were 0.114 and 0.049 for BCS and LOC, respectively. The genetic correlation between BCS and LOC was weak (-0.084) and not different from zero; therefore, the traits seem to be genetically independent, but further investigation on possible departures from linearity of this relationship is needed. Angularity was strongly negatively correlated with BCS (-0.612), and strongly positively correlated with LOC (0.650). The genetic relationship of milk yield with BCS was moderately negative (-0.386), and was moderately positive (0.238) with LOC. These results indicate that high-producing cows tend to be thinner and tend to have better locomotion than low-producing cows. The genetic correlation of BCS with fat content (0.094) and F:P (-0.014) was very weak and not different from zero, and with protein content (0.173) was weak but different from zero. Locomotion was weakly correlated with fat content (0.071), protein content (0.028), and F:P (0.074), and correlations were not different from zero. Phenotypic correlations were generally weaker than their genetic counterparts, ranging from -0.241 (BCS with ANG) to 0.245 (LOC with ANG). Before including BCS and LOC in the selection index of the Italian Holstein breed, the correlations with other traits currently used to improve type and functionality of animals need to be investigated. PMID- 23726427 TI - Postural control in quiet standing in patients with psychotic disorders. AB - There is evidence that patients with psychotic conditions display greater center of pressure (CoP) displacement during quite standing than healthy subjects, but the underlying impairments in the control mechanisms are uncertain. The aim of this study was to identify the nature of possible impairments in the control of posture by modulation of visual and kinesthetic information during quiet standing. Center of pressure (CoP) data and whole-body kinematics of the center of mass (CoM) were recorded during quite standing on a firm surface with eyes open and with eyes closed, and standing with eyes open on a yielding surface. During all three conditions, patients displayed greater migration of CoM and CoP CoM, a measure related to ankle joint torque, whereas CoP-frequency (MPF) was similar in patients and healthy subjects. Our results suggested that greater postural sway in patients may depend on disproportionally large ankle joint torque without corresponding increase in frequency. Furthermore, interactions between groups and conditions suggested that the patients made less use of visual information for postural control than the healthy subjects. PMID- 23726428 TI - Gait initiation impairments in both Essential Tremor and Parkinson's disease. AB - Gait initiation is a transitional task involving a voluntary shift from a static, stable position to a relatively less-stable state of locomotion. During gait initiation, anticipatory postural adjustments precede stepping in order to generate forward momentum while balance is maintained. While deficits in gait initiation are frequently reported for persons with Parkinson's disease, there is a paucity of information regarding gait initiation performance in persons with Essential Tremor. We investigated anticipatory postural adjustments and spatiotemporal characteristics of gait initiation in persons with Essential Tremor and compared them to persons with Parkinson's disease as well as age matched neurologically healthy adults. Twenty-four persons with Essential Tremor, 31 persons with Parkinson's disease, and 38 age-matched controls participated. We compared anterior-posterior and mediolateral center of pressure movements and spatiotemporal stepping characteristics during gait initiation among the three groups using Mann-Whitney U-tests with Bonferroni corrections for multiple comparisons and one-way ANOVAs. Persons with Parkinson's disease demonstrated significantly reduced displacement and velocity of the center of pressure during early phases of anticipatory postural adjustments relative to controls. Displacement of the center of pressure was also reduced in persons with Essential Tremor, although at a later stage of the gait initiation process. Persons with Parkinson's disease and Essential Tremor demonstrated similar reductions in step length during gait initiation when compared to controls. Persons with Parkinson's disease and Essential Tremor exhibit different deficits in gait initiation when compared to healthy older adults. Therefore, this study provides further evidence differentiating motor control features in these movement disorders. PMID- 23726429 TI - Estimating fall risk with inertial sensors using gait stability measures that do not require step detection. AB - Falls have major consequences both at societal (health-care and economy) and individual (physical and psychological) levels. Questionnaires to assess fall risk are commonly used in the clinic, but their predictive value is limited. Objective methods, suitable for clinical application, are hence needed to obtain a quantitative assessment of individual fall risk. Falls in older adults often occur during walking and trunk position is known to play a critical role in balance control. Therefore, analysis of trunk kinematics during gait could present a viable approach to the development of such methods. In this study, nonlinear measures such as harmonic ratio (HR), index of harmonicity (IH), multiscale entropy (MSE) and recurrence quantification analysis (RQA) of trunk accelerations were calculated. These measures are not dependent on step detection, a potentially critical source of error. The aim of the present study was to investigate the association between the aforementioned measures and fall history in a large sample of subjects (42 fallers and 89 non - fallers) aged 50 or older. Univariate associations with fall history were found for MSE and RQA parameters in the AP direction; the best classification results were obtained for MSE with scale factor tau = 2 and for maximum length of diagonals in RQA (72.5% and 71% correct classifications, respectively). MSE and RQA were found to be positively associated with fall history and could hence represent useful tools in the identification of subjects for fall prevention programs. PMID- 23726430 TI - Seasonal and gender-related differences in morphometric features and cellular and biochemical parameters of Carcinus aestuarii from the Lagoon of Venice. AB - In this study, the seasonal variations in the morphometric features and in the cellular and biochemical parameters of the haemolymph were investigated in both male and female crabs (Carcinus aestuarii). Crabs were seasonally (November 2010 August 2011) collected from the Lagoon of Venice, and the moult stage, weight, width and length of the carapace, and width and length of the bigger chela were evaluated. In addition, the total haemocyte count (THC), haemocyte diameter and volume, haemolymph glucose and total protein levels, and haemolymph phenoloxidase (PO) and N-acetyl-beta-glucosaminidase (NAG) activities were measured. The results demonstrated that the collected crabs were all in the intermoult stage and that the males were bigger than the females. A two-way ANOVA revealed a significant effect of season on the THC and the haemocyte volume and a significant influence of gender on the haemocyte diameter. Season and gender significantly affected the haemolymph glucose concentration, whereas haemolymph protein levels were dependent only on the season. In addition, both season and gender significantly influenced the PO and NAG activities in the haemolymph. Overall, the results demonstrated that crab morphometric features as well as haemolymph cellular and biochemical parameters varied markedly as a function of both season and gender. PMID- 23726432 TI - Searching for the common denominator of systemic inflammation and tumor invasion in the cases of bikunin and the inter-alpha-trypsin inhibitor heavy chains. PMID- 23726431 TI - Hypoxia induces the overexpression of microRNA-21 in pancreatic cancer cells. AB - BACKGROUND: Pancreatic cancer cells exist in a hypoxic microenvironment containing numerous factors that impact tumor survival, proliferation, and metastasis. MicroRNAs (miRs) are differentially expressed in cancer but also altered by hypoxia. We hypothesized that hypoxia could induce expression of miR 21, an oncomir in pancreatic cancer cells. MATERIALS AND METHODS: We examined how hypoxia regulates miR-21 expression in pancreatic cancer cell lines (BxPC-3, AsPC 1) by stem-loop RT-PCR. Chromatin immunoprecipitation assays were used to study how hypoxia alters hypoxia-inducible factor (HIF)-1alpha binding to the hypoxia response element of miR-21. BxPC-3 and AsPC-1 cells were transfected with a constitutively stable HIF-1alpha subunit or vector control (pcDNA3.1) to determine the influence of miR-21 in normoxia. The effect of mature miR-21 sense and antisense oligonucleotides on proliferation and apoptosis in hypoxic and normoxic conditions was assessed via WST-1 assay and flow cytometry. RESULTS: MiR 21 levels increased in all cell lines grown in hypoxic conditions versus normoxia, whereas siRNA targeting HIF-1alpha reduced miR-21 expression. Hypoxic conditions resulted in direct binding of HIF-1alpha to the predicted binding site in miR-21. Transfection with a constitutively stable HIF-1alpha expression plasmid in normoxia resulted in upregulated miR-21, similar to that seen in hypoxia. Cells transfected with antisense constructs targeting miR-21 had reduced proliferation and increased apoptosis in normoxia, whereas miR-21 overexpression abrogated hypoxia-associated reductions in proliferation. CONCLUSIONS: MiR-21 is induced by hypoxia in pancreatic cancer cells via HIF-1alpha upregulation. MiR-21 overexpression allows cells to avoid apoptosis in a hypoxic microenvironment. Inhibition of miR-21 expression may increase cellular susceptibility to hypoxia in pancreatic cancer. PMID- 23726433 TI - Effect of enteral nutrition and ecoimmunonutrition on bacterial translocation and cytokine production in patients with severe acute pancreatitis. AB - BACKGROUND: Severe acute pancreatitis (SAP) with severe complications such as multiple organ failure, necrosis, abscess, and formation of pancreatic pseudocysts often gives rise to a high mortality despite intensive treatment. Parenteral nutrition (PN), elemental enteral nutrition, and ecoimmunonutrition (EIN) hastened the recovery of SAP patients, stimulated gastrointestinal motility, and alleviated the degree of systemic inflammatory response syndrome. This study aimed to examine the effects of enteral nutrition (EN) and EIN on bacterial translocation and cytokine production in patients with SAP. METHODS: One hundred eighty-three SAP patients were randomly divided into three groups receiving PN, EN, or EN + EIN. Acute Physiology and Chronic Health Evaluation II scores, complications (systemic inflammatory response syndrome, multiorgan failure, and infections), intestinal bacterial strains of stool, and plasma concentrations of endotoxin, tumor necrosis factor alpha (TNF-alpha), and interleukin (IL) 6 and IL-10 were evaluated. RESULTS: The percentage of pancreatic sepsis, multiple organ dysfunction syndrome, and mortality was significantly lower in the EN group and was further lower in the EN + EIN group than that in the PN group. The plasma concentrations of TNF-alpha and IL-6 and APACHE II scores were significantly decreased in the EN group and were further lowered in the EN + EIN group than those in the PN group. The plasma concentration of IL-10 was higher in the EN group and was further increased in the EN + EIN group than that in the PN group. CONCLUSIONS: EN plays effective roles in the treatment of SAP by decreasing the expression of endotoxin, TNF alpha, and IL-6 and the bacterial translocation, enhancing the expression of IL 10, and the combination of EIN with EN results in more therapeutic benefits than EN alone. PMID- 23726434 TI - Sorafenib prolongs liver regeneration after hepatic resection in rats. AB - BACKGROUND: The multikinase inhibitor sorafenib inhibits angiogenesis and tumor cell proliferation. Sorafenib targets signaling pathways involved in liver regeneration. Previous works on regenerating mouse liver show differing results. We asked to which degree different lengths of sorafenib treatment would influence liver regeneration after hepatic resection in rats. METHODS: Fischer-344 rats received intragastric injections of sorafenib (5-15 mg/kg/d), underwent a two thirds partial hepatectomy (PH), and were sacrificed at different time points thereafter. Sorafenib treatment was stopped 0, 3, or 14 d after PH. Serum levels of aminotransferases and labeling indices of S-phase nuclei (bromodeoxyuridine and MIB-5) were analyzed, body and liver weights measured, and levels of phospho ERK determined by Western blot. RESULTS: Sorafenib increased aminotransferases and the number of S-phase nuclei at baseline, but decreased liver weights and levels of phospho-ERK 24 h after PH. The number of S-phase nuclei and mitotic indices decreased 48 h after PH and increased 7 d after PH in animals on sorafenib treatment. Relative liver weights were restored 5 d after PH in control rats, at 7 d in animals receiving sorafenib prior to surgery, at 10 d in rats where sorafenib was stopped 3 d after surgery, and after 14 d in rats on continuous treatment. CONCLUSIONS: In this rat model, the regenerating liver adapted to the proliferation-inhibitory effect of sorafenib during continuous treatment. Sorafenib given after hepatic resection did not completely inhibit liver regeneration, but it prolonged the regenerative phase in proportion to the length of treatment. PMID- 23726435 TI - Molecular characterisation of resistance to fluoroquinolones in Haemophilus parasuis isolated from China. AB - There are many studies on fluoroquinolone (FQ) resistance in the literature, but little is known regarding the molecular characterisation of FQ-resistant Haemophilus parasuis. In this study, a total of 138 H. parasuis isolates were examined, among which 83 (60.1%) were resistant to enrofloxacin (EFX) and 8 (5.8%) were resistant to levofloxacin (LFX) as determined by Etest. Ten point mutations in the quinolone resistance-determining regions of gyrA, gyrB, parC and parE were detected by PCR and DNA sequencing. Interestingly, 100% of the resistant isolates contained mutations at 87D of gyrA, but other mutations occurred less frequently. Furthermore, it was found that there was synergy between 73S->R/I in parC and other point mutations with respect to FQ resistance. To examine the effect of different point mutations on FQ resistance, the minimum inhibitory concentrations of EFX and LFX were determined for strains generated by site-directed mutagenesis, and three point mutations (gyrA 87D->N, parC 73S->R and parE 551T->A) were shown to be involved in FQ resistance. PMID- 23726436 TI - Characteristics of antimicrobial studies registered in the USA through ClinicalTrials.Gov. AB - Increasing rates of antimicrobial-resistant infections and the dwindling pipeline of new agents necessitate judicious, evidence-based antimicrobial prescribing. Clinical trials represent a vital resource for establishing evidence of safety and efficacy, which are crucial to guiding antimicrobial treatment decisions. The objective of this study was to comprehensively evaluate the characteristics of antimicrobial research studies registered in ClinicalTrials.gov. Primary outcome measures, funding sources, inclusion criteria and the reporting of study results were evaluated for 16055 antimicrobial studies registered in ClinicalTrials.gov as of mid 2012. Interventional studies accounted for 93% of registered antimicrobial studies. Clinical trials of drugs (82%) and biologics (9%) were most common. Antibacterial, antiviral and antifungal studies accounted for 43%, 41% and 16% of drug trials, respectively. Among interventional drug trials, 73% featured randomised allocation to study arms and 71% included measures of safety and/or efficacy as primary endpoints. Children were eligible for enrolment in 26% of studies. Among the studies, 60% were sponsored primarily by non-profit organisations, 30% by industry and 10% by the federal government. Only 7% of studies reported results; however, 71% of these were sponsored primarily by industry. Antimicrobial studies commonly incorporated elements of high-quality trial design, including randomisation and safety/efficacy endpoints. Publication of study results and updating of ClinicalTrials.gov should be encouraged for all studies, with particular attention paid to research sponsored by non-profit organisations and governmental agencies. Leveraging the application of these data to guide the careful selection of antimicrobial agents will be essential to preserve their utility for years to come. PMID- 23726437 TI - Automatic localization of the optic disc by combining vascular and intensity information. AB - This paper describes a new methodology for automatic location of the optic disc in retinal images, based on the combination of information taken from the blood vessel network with intensity data. The distribution of vessel orientations around an image point is quantified using the new concept of entropy of vascular directions. The robustness of the method for OD localization is improved by constraining the search for maximal values of entropy to image areas with high intensities. The method was able to obtain a valid location for the optic disc in 1357 out of the 1361 images of the four datasets. PMID- 23726439 TI - Standing on the shoulders of giants: teaching the history of urology. PMID- 23726438 TI - Impact of family history of cancer on the incidence of mutation in epidermal growth factor receptor gene in non-small cell lung cancer patients. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) activating mutation is an important predictive biomarker of EGFR tyrosine kinase inhibitors (TKIs) in non small cell lung cancer (NSCLC), while family history of cancer also plays an important role in the neoplasia of lung cancer. This study aimed to investigate the association between family history of cancer and EGFR mutation status in NSCLC population. METHODS: From February 2008 to May 2012, 538 consecutive NSCLC patients with known EGFR mutation status were included into this study. Amplification refractory mutation system (ARMS) method was used to detect EGFR mutation. The associations between EGFR mutation and family history of cancer were evaluated using logistic regression models. RESULTS: EGFR activating mutation was found in 220 patients and 117 patients had family cancer histories among first-degree relatives. EGFR mutation was more frequently detected in adenocarcinoma patients (p < 0.001), never-smoker (p < 0.001) and with family history of cancer (p = 0.031), especially who had family history of lung cancer (p = 0.008). In multivariate analysis, the association of EGFR mutation with family history of cancer also existed (p = 0.027). CONCLUSIONS: NSCLC patients with family history of cancer, especially family history of lung cancer, might have a significantly higher incidence of EGFR activating mutation. PMID- 23726440 TI - Elective versus routine postoperative clinic appointments after circumcisions performed under local anesthesia. AB - OBJECTIVE: To evaluate a model of elective postoperative clinic appointments after a minor urological procedure and to compare it to the traditional practice of routine appointments. METHODS: A total of 104 consecutive patients undergoing adult circumcision under local anesthesia were divided into 2 groups; group A (n = 45) received routine postoperative clinic appointments and group B (n = 59) were given the option to make an appointment on an as-needed basis. Both groups received detailed postoperative instructions on the early signs of symptoms of potential adverse events. The 2 groups were compared regarding demographics, clinical profile, postoperative recovery, and outcome. RESULTS: Group A patients ("routine appointments") were younger (51 vs 60 years, P <.0001) and included fewer African Americans (57.8% vs 78.0%, P <.03) compared to group B patients ("elective appointments"). Postoperative clinic appointments were categorized as unnecessary in 84.4% (38/45) and 71.1% (42/59) of the patients in groups A and B, respectively. Of the remaining 17 patients in group B who elected to make an appointment, only 1 patient (1.7%) had a true procedure-related issue that justified the visit and required management. Overall, there was no statistical difference between the 2 groups with regard to the number of patients with perceived postoperative issues (P = .36). CONCLUSION: The traditional practice of routine clinic appointments after uncomplicated adult circumcision is medically unnecessary and provides little value in the majority of cases. The practice of open access elective postoperative evaluation based on clearly defined clinical criteria is efficacious, safe, convenient, and enhances resource utilization. PMID- 23726441 TI - Editorial comment. PMID- 23726442 TI - Reply: To PMID 23726440. PMID- 23726443 TI - Morbidity after transperineal prostate biopsy in 3000 patients undergoing 12 vs 18 vs more than 24 needle cores. AB - OBJECTIVE: To evaluate clinical complications after transperineal prostate biopsy in patients undergoing 12 vs 18 vs more than 24 cores. METHODS: From February 2002 to December 2012, 3000 patients (median age, 66 years) underwent transperineal prostate biopsy after an abnormal result on a digital rectal examination, prostate-specific antigen (PSA) level >10 ng/mL, PSA values between 4.1 and 10, 2.6 and 4, and <2.5 ng/mL with free/total PSA <=25%, <=20%, and <=15%, respectively. Of these, 915 (30.5%), 1330 (48.5%), and 630 patients (21%) underwent 12, 18, and >24 needle cores under antibiotic prophylaxis. Prostate biopsy-related complications were evaluated within 15 to 20 days after the prostate biopsy. The number of patients who needed hospital admission or an emergency department visit (EDV) was recorded. RESULTS: Prostate cancer was found in 1150 (38.3%) patients. Side effects after the biopsy occurred in 40.2% of the patients, and the complications were directly correlated with the number of needle cores: 31.5% with 12 cores, 41.8% with 18 cores, and 57.4% with >24 cores (P = .001). Overall hospital admission and EDV were 1.2% and 9.1% and occurred, respectively, in 1% and 6% (12 cores) vs 1.3% and 9.6% (18 cores) vs 1.6% and 14.4% (>24 cores) of the patients. The most frequent complication that needed hospital admission vs EDV was urinary tract infection (0.7%) vs acute urinary retention (6.7%), respectively. No patients developed sepsis. CONCLUSION: Clinical complications after transperineal prostate biopsy occurred in 40.2% of the patients, but only 1.2% required hospital admission. The number of needle cores (12 vs 18 vs >24) significantly correlated with increased onset of side effects. PMID- 23726444 TI - Nature of crossing vessels in patients with radiographically normal ureteropelvic junctions: prevalence and anatomic characteristics. AB - OBJECTIVE: To evaluate the prevalence and characteristics of crossing vessels in asymptomatic patients with a radiographically normal ureteropelvic junction. MATERIALS AND METHODS: We retrospectively reviewed the computed tomography angiography images of 601 patients who were evaluated for possible living organ donation at the University of Minnesota from 2005 to 2008. One patient had asymptomatic hydronephrosis and was excluded from the analysis. The prevalence and characteristics of crossing vessels at the ureteropelvic junction were determined, including vessel location, origin, size, distance from the ureteropelvic junction, and vessel type (artery or vein). RESULTS: The prevalence of crossing vessels at the radiographically normal ureteropelvic junction was 22.7%. A total of 163 crossing vessels were present in 136 patients; 60.1% were left-sided and 39.9% were right-sided. Arteries accounted for 81.0% of the crossing vessels and veins for 19.0%. Accessory lower pole renal vessels originating from the great vessels constituted 59.5% of the crossing vessels. The location of the crossing vessel relative to the ureteropelvic junction varied and included anterior (25.8%), anterolateral (36.8%), medial (14.6%), anteromedial (2.5%), lateral (12.9%), and posterior (7.4%). The mean diameter and mean distance of the crossing vessel from the ureteropelvic junction was 3.3 mm and 1.8 mm, respectively. CONCLUSION: The prevalence of crossing vessels in asymptomatic, healthy patients with a radiographically normal ureteropelvic junction was 22.7%, lower than that seen in association with ureteropelvic junction obstruction. The location of the crossing vessels varied about the ureteropelvic junction, and no location was consistently free of traversing vessels. PMID- 23726445 TI - Editorial comment. PMID- 23726446 TI - Reply: To PMID 23726444. PMID- 23726447 TI - Effect of chronic low-dose tadalafil on penile cavernous tissues in diabetic rats. AB - OBJECTIVE: To assess the effect of chronic low-dose administration of tadalafil (Td) on penile cavernous tissue in induced diabetic rats. METHODS: The study investigaged 48 adult male albino rats, comprising a control group, sham controls, streptozotocin-induced diabetic rats, and induced diabetic rats that received Td low-dose daily (0.09 mg/200 g weight) for 2 months. The rats were euthanized 1 day after the last dose. Cavernous tissues were subjected to histologic, immunohistochemical, morphometric studies, and measurement of intracavernosal pressure and mean arterial pressure in anesthetized rats. RESULTS: Diabetic rats demonstrated dilated cavernous spaces, smooth muscles with heterochromatic nuclei, degenerated mitochondria, vacuolated cytoplasm, and negative smooth muscle immunoreactivity. Nerve fibers demonstrated a thick myelin sheath and intra-axonal edema, where blood capillaries exhibited thick basement membrane. Diabetic rats on Td showed improved cavernous organization with significant morphometric increases in the area percentage of smooth muscles and elastic tissue and a significant decrease of fibrous tissue. The Td-treated group showed enhanced erectile function (intracavernosal pressure/mean arterial pressure) at 0.3, 0.5, 1, 3, and 5 Hz compared with diabetic group values at the respective frequencies (P <.05) that approached control values. CONCLUSION: Chronic low-dose administration of Td in diabetic rats is associated with substantial improvement of the structure of penile cavernous tissue, with increased smooth muscles and elastic tissue, decreased fibrous tissue, and functional enhancement of the erectile function. This raises the idea that the change in penile architecture with Td treatment improves erectile function beyond its half-life and its direct pharmacologic action on phosphodiesterase type 5. PMID- 23726448 TI - Reply: To PMID 23726447. PMID- 23726449 TI - Editorial comment. PMID- 23726451 TI - Retraction of external iliac vessels and obturator nerve with the vas deferens during extended pelvic lymph node dissection in robot-assisted radical prostatectomy. AB - OBJECTIVE: To determine if the vas deferens during robot-assisted radical prostatectomy can be used to medially retract the iliac vessels and obturator nerve to achieve a dissection plane in the triangle of Marcille free of these structures while performing an extended pelvic lymph node dissection (PLND). METHODS: In a single patient, an extended PLND was performed before prostatectomy. The external iliac lymph node (LN) group was dissected from the node of Cloquet to the ureteric crossing over the internal iliac artery. The vas deferens was then transected along its course medial to the external iliac artery. The vas deferens was subsequently grasped with bipolar forceps, passed under the external iliac vessels, lifted superiorly, and retracted medially in order to apply medial traction to the obturator nerve and external iliac artery and vein. RESULTS: Retraction using the vas deferens permitted excellent visualization of the LN packets. The iliac vessels and obturator nerve were maintained far from the plane of the dissection and were retracted only using the vas deferens. This technique yielded 25 LNs and our median LN yield for high-risk individuals is 20. Surgical time was comparable to PLNDs performed using instruments for retraction. CONCLUSION: Use of the vas deferens for retraction during an extended PLND can be an excellent method to improve visibility without risk of damage to important structures with surgical tools and still achieve an adequate LN yield. Use of this technique in future surgeries will permit a more detailed understanding of outcomes. PMID- 23726450 TI - Immunologic response and proviral load in human T-lymphotropic virus type 1 infected individuals with erectile dysfunction. AB - OBJECTIVE: To evaluate the immune response and proviral load in individuals with human T-lymphotropic virus type 1 (HTLV-1) and erectile dysfunction (ED) compared with those in the controls. MATERIALS AND METHODS: We performed a cross-sectional study of 102 men aged 18-70 years with positive serology for HTLV-1, who were interviewed from 2004 to 2010. The study sample was divided into 2 groups: group 1, 42 HTLV-1-infected men with ED, as determined by the International Index of Erectile Function-5 score; and group 2, 60 HTLV-1-infected men without ED. The cytokines interferon-gamma and tumor necrosis factor-alpha, and the proviral load were analyzed between the 2 groups. RESULTS: Compared with those without ED, the men with ED had greater levels of tumor necrosis factor-alpha (545.37 +/- 877.06 vs 509.39 +/- 724.70 pg/mL) and interferon-gamma (1154.35 +/- 1282.98 vs 1122.78 +/- 1573.16 pg/mL), but this difference was not significant (P = .69 and P = .57, respectively). The proviral load was 135,695 +/- 190,113 copies/10(5) cells in the ED group and 47,607 +/- 83,129 copies/10(5) cells in the non-ED patients, with a statistically significant difference (P = .02). When ED was stratified as mild, moderate, and severe, no difference was found in the proviral load among the ED groups (P = .09); however, the levels were greater in the severe forms. CONCLUSION: The association of a greater proviral load in men with ED with HTLV-1 gives support to the idea that ED is part of the autonomic syndrome related to viral infection and should be investigated for early identification of the syndrome. PMID- 23726452 TI - Reply by the authors. PMID- 23726453 TI - Re: Erturhan et al.: Efficacy of medical expulsive treatment with doxazosin in pediatric patients (Urology 2013;81:640-643). PMID- 23726454 TI - Re: El-Halwagy et al.: Shock wave lithotripsy of vesical stones in patients with infravesical obstruction: an underused noninvasive approach (Urology 2013;81:508 510). PMID- 23726455 TI - Re: Lambert et al.: Using preoperative albumin levels as a surrogate marker for outcomes after radical cystectomy for bladder cancer (Urology 2013;81:587-592). PMID- 23726456 TI - Re: Diallo et al.: Evaluating single-incision slings in female stress urinary incontinence: the usefulness of the CONSORT statement criteria (Urology 2012;80:535-541). PMID- 23726457 TI - Reply by the authors. PMID- 23726458 TI - Reply by the authors. PMID- 23726459 TI - Re: Kozacioglu et al.: Effect of tunical defect size after peyronie's plaque excision on postoperative erectile function: do centimeters matter? (Urology 2012;80:1051-1055). PMID- 23726460 TI - Reply by the authors. PMID- 23726461 TI - Swallowing and deep brain stimulation in Parkinson's disease: a systematic review. AB - The purpose of this review is to assess the current state of the literature on the topic of deep brain stimulation (DBS) and its effects on swallowing function in Parkinson's disease (PD). Pubmed, Cochrane review, and web of science searches were completed on all articles addressing DBS that contained a swallowing outcome measure. Outcome measures included the penetration/aspiration scale, pharyngeal transit time, oropharyngeal residue, drooling, aspiration pneumonia, death, hyolaryngeal excursion, epiglottic inversion, UPDRS scores, and presence of coughing/throat clearing during meals. The search identified 13 studies specifically addressing the effects of DBS on swallowing. Critical assessment of the 13 identified peer-reviewed publications revealed nine studies employing an experimental design, (e.g. "on" vs. "off", pre- vs. post-DBS) and four case reports. None of the nine experimental studies were found to identify clinically significant improvement or decline in swallowing function with DBS. Despite these findings, several common threads were identified across experimental studies and will be examined in this review. Additionally, available data demonstrate that, although subthalamic nucleus (STN) stimulation has been considered to cause more impairment to swallowing function than globus pallidus internus (GPi) stimulation, there are no experimental studies directly comparing swallowing function in STN vs. GPi. Moreover, there has been no comparison of unilateral vs. bilateral DBS surgery and the coincident effects on swallowing function. This review includes a critical analysis of all experimental studies and discusses methodological issues that should be addressed in future studies. PMID- 23726462 TI - Comprehensive LRRK2 and GBA screening in Portuguese patients with Parkinson's disease: identification of a new family with the LRRK2 p.Arg1441His mutation and novel missense variants. AB - Mutations in the LRRK2 and GBA genes are increasingly recognized as frequent determinants of familial and sporadic Parkinson's disease (PD). However, for several populations, accurate data on the prevalence and types of mutations are not available, because previous studies have not investigated the complete coding regions of these genes in large samples. We studied 312 PD patients ascertained at a single centre in Lisbon, Portugal. In 61 patients, with familial PD, we sequenced the entire open reading frames and exon-intron boundaries of LRRK2 and GBA. In LRRK2, we identified ten heterozygous p.Gly2019Ser (16.4%), and two heterozygous p.Arg1441His carriers (3.3%); furthermore, six patients each carried a novel LRRK2 heterozygous variant (five coding and one 3'-UTR variants) of undetermined pathogenic role. Segregation of the p.Arg1441His mutation with PD was observed in the families of both carriers. None of these variants were identified in 138 healthy controls. Screening of GBA revealed no mutations. In the remaining 251 PD patients (25 familial and 226 sporadic) we found ten additional carriers of the heterozygous p.Gly2019Ser and no carriers of the other mutations. Thus, the p.Gly2019Ser mutation was detected in a total number of 20 carriers out of 312 patients (6.4%), including twelve familial (14%) and eight sporadic patients (3.5%). This comprehensive study confirms that p.Gly2019Ser is the most important genetic cause of PD known so far in Portugal and supports the contention that p.Arg1441His is also a PD-causing mutation. These findings have relevance for the genetic testing and counseling of PD patients in this population. PMID- 23726463 TI - Identification and epidemiological relatedness of clinical Elizabethkingia meningoseptica isolates from central Taiwan. AB - BACKGROUND: Elizabethkingia meningoseptica is an opportunistic pathogen. Identification of E. meningoseptica based on conventional methods is rather labor and time-consuming. The information on epidemiological relatedness and microbiological characteristics of E. meningoseptica isolates from central Taiwan was limited. METHODS: Forty E. meningoseptica isolates identified by conventional methods were collected by the Central Laboratory of Central Region Hospital Alliance between 2007 and 2011. The amplification of 16S ribosomalDNA gene by polymerase chain reaction with species-specific or universal primers following DNA sequencing was used as a standard identification method. The feasibility of Vitek 2 GN card was also evaluated. Some clinical information of the patients and the drug susceptibilities and epidemiological relatedness of the isolates were analyzed. RESULTS: For the 40 isolates, 39 E. meningoseptica and one Chryseobacterium indologenes were identified using 16S rDNA sequencing. Among the 39 isolates, all could be identified using species-specific primers, whereas only 84.6% could be identified by Vitek 2 GN card with excellent discrimination. All E. meningoseptica isolates were susceptible to minocycline but resistant to many drugs examined including ceftazidime, amikacin, colistin, and imipenem. The pulsed field gel electrophoresis (PFGE) patterns demonstrated that most isolates were quite genetic diversity. The patients had average age of 72.2 +/- 14.5 years old (excluded one child patient of 1 year old) and 79.5% of patients were male. Twenty-three patients (59.0%) had underlying diseases. CONCLUSION: The designed species-specific primers could be used to identify E. meningoseptica with 100% of specificity and sensitivity, whereas the Vitek 2 GN card showed considerable ability in E. meningoseptica identification. The PFGE patterns showed that most isolates were genetic diversity enough to exclude the possibility of intrahospital spread. PMID- 23726464 TI - Molecular typing and epidemiology of Clostridium difficile in respiratory care wards of central Taiwan. AB - BACKGROUND/PURPOSE: In industrialized countries, Clostridium difficile is the major cause of nosocomial diarrhea. This study involved a broad overview of baseline epidemiology for C. difficile in Taiwan. MATERIALS AND METHODS: Point prevalence was estimated from a prospective survey conducted in the respiratory care wards of six hospitals in central Taiwan. Polymerase chain reaction (PCR) ribotyping and multiple-locus variable-number tandem-repeat analysis (MLVA) were performed on all toxigenic C. difficile isolates, including asymptomatic and symptomatic strains. RESULTS: A total of 149 patients were screened for C. difficile; the point prevalence for C. difficile infection (CDI) and C. difficile colonization was 4% and 19%, respectively. CDI cases were significantly related to end-stage renal disease, and C. difficile colonization cases were significantly associated with previous admission to an acute-care facility. No hypervirulent PCR ribotype 027 strain was found. MLVA detected two clusters of CDI-related and three clusters of asymptomatic C. difficile strains circulating in wards. CONCLUSION: Our results demonstrate a high prevalence of toxigenic C. difficile colonization in hospitals. Infection control personnel should pay attention to the increasing numbers of CDI cases, and molecular typing for C. difficile should be performed when necessary. PMID- 23726465 TI - Molecular epidemiology, antimicrobial susceptibility and carbapenemase resistance determinants among Acinetobacter baumannii clinical isolates in Taiwan. AB - BACKGROUND: Emerging carbapenem resistance among Acinetobacter baumannii clinical isolates is a worldwide problem. Infections caused by A. baumannii are increasing and demonstrate high mortality rates. This study aimed to establish a nationwide surveillance of antimicrobial susceptibility, carbapenemase genes, and clonal relationships of A. baumannii clinical isolates in Taiwan. METHODS: Clinical isolates of Acinetobacter calcoaceticus-A. baumannii (ACB) complex collected by the Taiwan Surveillance of Antimicrobial Resistance-V program between July 2006 and September 2006 were used in this study. Genospecies identification was verified by 16S-23S rRNA intergenic-spacer sequences. Carbapenemase genes were detected by polymerase chain reaction. Pulsed-field gel electrophoresis and multilocus sequence typing (MLST) was applied for identification of clonal relationships. RESULTS: Among the 151 ACB-complex isolates collected, 134 (88.7%) were A. baumannii, 12 (8.0%) were A. pittii, and five (3.3%) were A. nosocomialis. A. baumannii isolates showed higher resistance rates to ciprofloxacin, amikacin, and ampicillin/sulbactam than A. pittii or A. nosocomialis (all p < 0.001). The most commonly detected carbapenemase genes were bla(OxA-51) (n = 135), followed by bla(OxA-24) (n = 4), bla(OxA-23) (n = 2), and bla(OxA-58) (n = 1). Three major A. baumannii clones were found throughout Taiwan, and showed significantly higher resistance rates to ciprofloxacin, amikacin, and ampicillin/sulbactam than the other A. baumannii isolates (100% vs. 68.7%, p < 0.001; 98.4% vs. 61.5%, p < 0.001; and 66.7% vs. 39.8%, p = 0.004; respectively). MLST showed that these major clones were sequence type 2 and belonged to international clonal complex 2. CONCLUSION: Our results demonstrate clonal spreading of A. baumannii in Taiwan hospitals and that these clones were more resistant to many antimicrobial agents. Efforts to prevent and control A. baumannii colonization/infections and prudent use of antibiotics to reduce antimicrobial selective pressure should be emphasized. PMID- 23726466 TI - The effects of simulated fog and motion on simulator sickness in a driving simulator and the duration of after-effects. AB - In the study, we checked: 1) how the simulator test conditions affect the severity of simulator sickness symptoms; 2) how the severity of simulator sickness symptoms changes over time; and 3) whether the conditions of the simulator test affect the severity of these symptoms in different ways, depending on the time that has elapsed since the performance of the task in the simulator. We studied 12 men aged 24-33 years (M = 28.8, SD = 3.26) using a truck simulator. The SSQ questionnaire was used to assess the severity of the symptoms of simulator sickness. Each of the subjects performed three 30-minute tasks running along the same route in a driving simulator. Each of these tasks was carried out in a different simulator configuration: A) fixed base platform with poor visibility; B) fixed base platform with good visibility; and C) motion base platform with good visibility. The measurement of the severity of the simulator sickness symptoms took place in five consecutive intervals. The results of the analysis showed that the simulator test conditions affect in different ways the severity of the simulator sickness symptoms, depending on the time which has elapsed since performing the task on the simulator. The simulator sickness symptoms persisted at the highest level for the test conditions involving the motion base platform. Also, when performing the tasks on the motion base platform, the severity of the simulator sickness symptoms varied depending on the time that had elapsed since performing the task. Specifically, the addition of motion to the simulation increased the oculomotor and disorientation symptoms reported as well as the duration of the after-effects. PMID- 23726467 TI - [Benefits of exercise in healthy population and impact on disease occurrence]. PMID- 23726468 TI - [Costs of temporary disability in Spain related to diabetes mellitus and its complications]. AB - INTRODUCTION AND OBJECTIVES: To ascertain the socioeconomic impact of diabetes, it is essential to estimate overall costs, including both direct and indirect costs (premature retirements, working hours lost, or sick leaves). This study analyzed indirect costs for temporary disability (TD) due to diabetes and its complications in Spain in 2011 by assessing the related ICD-9 MC codes. MATERIAL AND METHOD: For this purpose, the number of TD processes and their mean duration were recorded. The indirect costs associated to loss of working days were also estimated. RESULTS: In 2011, diabetes and its complications were related to 2.567 TD processes, which resulted in the loss of 154.214 days. In terms of costs, this disease represented for Spanish public health administrations an expense of 3,297.095.3 ?, with an estimated cost per patient and year of 141 ?. CONCLUSIONS: These data suggest an urgent need to devise plans for prevention and early diagnosis of diabetes and its complications, as well as programs to optimize the available health care resources by creating multidisciplinary teams where occupational medical services assume an important role. A decrease in absenteeism would result in benefits for diabetic patients, society overall, and companies or public institutions. PMID- 23726469 TI - CLAVATA3-like genes are differentially expressed in grape vine (Vitis vinifera) tissues. AB - The CLAVATA3 (CLV3)/endosperm surrounding region [(ESR) CLE] peptides function as intercellular signaling molecules that regulate various physiological and developmental processes in diverse plant species. We identified five CLV3-like genes from grape vine (Vitis vinifera var. Pinot Noir): VvCLE 6, VvCLE 25-1, VvCLE 25-2, VvCLE 43 and VvCLE TDIF. These CLV3-like genes encode short proteins containing 43-128 amino acids. Except VvCLE TDIF, grape vine CLV3-like proteins possess a consensus amino acid sequence known as the CLE domain. Phylogenic analysis suggests that the VvCLE 6, VvCLE25-1, VvCLE25-2 and VvCLE43 genes have evolved from a single common ancestor to the Arabidopsis CLV3 gene. Expression analyses showed that the five grape CLV3-like genes are expressed in leaves, stems, roots and axillary buds with significant differences in their levels of expression. For example, while all of them were strongly expressed in axillary buds, VvCLE6 and VvCLE43 expression prevailed in roots, and VvCLE25-1, VvCLE25-2 and VvCLE TDIF expression in stems. The differential expression of the five grape CLV3-like peptides suggests that they play different roles in different organs and developmental stages. PMID- 23726470 TI - Smaller stomata require less severe leaf drying to close: a case study in Rosa hydrida. AB - Stomata formed at high relative air humidity (RH) close less as leaf dries; an effect that varies depending on the genotype. We here quantified the contribution of each stomatal response characteristic to the higher water loss of high RH grown plants, and assessed the relationship between response characteristics and intraspecific variation in stomatal size. Stomatal size (length multiplied by width), density and responsiveness to desiccation, as well as pore dimensions were analyzed in ten rose cultivars grown at moderate (60%) or high (85%) RH. Leaf morphological components and transpiration at growth conditions were also assessed. High growth RH resulted in thinner (11%) leaves with larger area. A strong positive genetic correlation of daytime and nighttime transpiration at either RH was observed. Stomatal size determined pore area (r=0.7) and varied by a factor of two, as a result of proportional changes in length and width. Size and density of stomata were not related. Following desiccation, high RH resulted in a significantly lower (6-19%) decline of transpiration in three cultivars, whereas the relative water content (RWC) of high RH-expanded leaflets was lower (29-297%) in seven cultivars. The lower RWC of these leaflets was caused by (a) higher (33-72%) stable transpiration and/or (b) lower (12-143%) RWC at which this stable transpiration occurred, depending on the cultivar. Stomatal size was significantly correlated with both characteristics (r=0.5 and -0.7, respectively). These results indicate that stomatal size explains much of the intraspecific variation in the regulation of transpiration upon water deprivation on rose. PMID- 23726471 TI - Evaluating focused ion beam induced damage in soft materials. AB - Focused ion beam (FIB) microscopy uses Ga(+) ions to remove material from a sample for a variety of imaging and preparation techniques. While considerable work has examined the effects of FIB exposure on a number of materials, optimized FIB conditions for use with softer polymeric materials are yet to be determined. In this report we use phase contrast AFM to measure local changes in the elastic modulus of polycarbonate surfaces parallel to a sectioning FIB at varying beam energies. We show that polycarbonate surfaces exposed to lower FIB energies appear stiffer than the bulk material whereas surfaces exposed to the higher beam energies of up to 25keV are more representative of the bulk material. Energy dispersive spectroscopy (EDS) indicates that the polymer surfaces become stiffer because of Ga(+) implantation from the FIB. Our experimental observations are supported by computer simulations showing an increase in the residual Ga(+) concentration near-surface at lower FIB energies. A high energy FIB is therefore shown to be less invasive, producing a surface more representative of the bulk material, than using low energy FIB when sectioning polymers. PMID- 23726472 TI - Antennal morphology and sensilla ultrastructure of the web-spinning sawfly Acantholyda posticalis Matsumura (Hymenoptera: Pamphiliidae). AB - Acantholyda posticalis (Hymenoptera: Pamphiliidae) is an important pine pest with a world-wide distribution. To clarify the olfactory receptive mechanism of A. posticalis, scanning electron microscopy and transmission electron microscopy were used to examine the morphology, ultrastructure, and distribution of antennal sensilla of adults from two sites in China. The antennae were filiform, and the flagella comprised 32-35 flagellomeres. Six sensillum types were found. Sensilla chaetica were straight setae with sharply pointed tips and without dendrites in the lumen. Sensilla trichodea were characterized by a parallel-grooved wall and one terminal pore and were innervated by four dendrites at the base. Sensilla basiconica I possessed longitudinally grooved surfaces and multiple terminal pores, with five dendrites in the lumen. Sensilla basiconica II not only had a distinct terminal pore but also had numerous tiny wall pores and many dendritic branches within the sensillum lymph. Sensilla coeloconica had deep longitudinal grooves, one terminal pore and six dendrites, while sensilla campaniformia were thick-walled with a terminal opening and sensory nerve bundles in the lumen. Sensilla chaetica and s. trichodea were most abundant and distributed over the entire antennae, while s. basiconica I and II, s. coeloconica, and s. campaniformia were restricted to the ventral flagellar surfaces. Although the shape and structure of antennae were similar in males and females, females had significantly longer antennae than males, and males had significantly more s. basiconica I than females. We compared the morphology and structure of these sensilla to other Hymenoptera and discussed their possible functions. PMID- 23726473 TI - High-spatial-resolution isotropic three-dimensional fast-recovery fast spin-echo magnetic resonance dacryocystography combined with topical administration of sterile saline solution. AB - OBJECTIVE: This study aims to investigate the clinical performance of three dimensional (3D) fast-recovery fast spin-echo (FRFSE) magnetic resonance dacryocystography (MRD) with topical administration of sterile saline solution for the assessment of the lacrimal drainage system (LDS). METHODS: A total of 13 healthy volunteers underwent both 3D-FRFSE MRD and two-dimensional (2D)-impulse recovery (IR)-single-shot fast spin-echo (SSFSE) MRD after topical administration of sterile saline solution, and 31 patients affected by primary LDS outflow impairment or postsurgical recurrent epiphora underwent 3D-FRFSE MRD and conventional T1- and T2-weighted sequences. All patients underwent lacrimal endoscopy or surgery, which served as a standard of reference for confirming the MRD findings. RESULTS: 3D-FRFSE MRD detected more visualized superior and inferior canaliculi and nasolacrimal duct than 2D-IR-SSFSE MRD. Compared with 2D IR-SSFSE MRD, 3D-FRFSE MRD showed more visualized segments per LDS, although the difference was not statistically significant. Significant improvements in the inferior canaliculus and nasolacrimal duct visibility grades were achieved using 3D-FRFSE MRD. 3D-FRFSE MRD had 100% sensitivity and 63.6% specificity for detecting LDS obstruction. In 51 out of the 62 LDSs that were assessed, a 90% agreement was noted between the findings of 3D-FRFSE MRD and lacrimal endoscopy in detecting the obstruction level. CONCLUSION: 3D-FRFSE MRD combined with topical administration of sterile saline solution is a simple and noninvasive method of obtaining detailed morphological and functional information on the LDS. Overall, 3D-FRFSE MRD could be used as a reliable diagnostic method in many patients with epiphora prior to surgery. PMID- 23726474 TI - Making burns count: the impact of varying case selection criteria on the identification of ICD-10 coded hospitalised burns. AB - Routinely collected hospitalisation data are widely used to monitor injury trends, provide estimates of the burden of injury and healthcare costs, and to inform policy. This study examined the impact of different ICD-10 based case selection criteria commonly used by Australian and international reporting bodies on the number and nature of burn-related hospitalisations identified. METHODS: Burn cases from a state-wide administrative hospitalisation dataset were identified and compared using three different case selection criteria: (1) principal diagnosis code of burn 'T20-T31', (2) first external cause code denoting burn 'X00-X19' and (3) both principal diagnosis code of community acquired injury 'S00-T98' and first external cause code denoting burn 'X00-X19'. RESULTS: Principal diagnosis codes 'T20-T31' and first external cause codes 'X00 X19' identified a similar number of cases, however only 78% of these were captured by both definitions. Principal diagnosis codes identified chemical, electrical and contact burns not identified as burns using external cause codes. First external cause codes identified readmission cases which were not identified by principal diagnosis codes. Using principal diagnosis codes of community acquired injury combined with external cause code of burn under-numerated hospitalisations by forty percent. CONCLUSION: The development, implementation and evaluation of health policy and prevention measures rely on good quality, consistent data. Current methods for identifying burn cases in hospitalisation data provide wide differences in estimation of number and nature of cases. It is important for clinicians to understand the implications of coding on the epidemiology and measurement of the burden of burn. PMID- 23726475 TI - Study of the carbapenem resistance mechanisms in clinical isolates of Acinetobacter baumannii: comparison of burn and non-burn strains. AB - We examined the prevalence of various carbapenem resistance mechanisms in clinical isolates of Acinetobacter baumannii collected from hospitalized burn and non-burn patients. Antimicrobial susceptibility testing was performed for 43 burn and 32 non-burn isolates. Carbapenem resistance genes were identified and repetitive extragenic palindromic PCR (REP-PCR) was used to define clonal relatedness. CarO disruption was investigated by PCR and its expression analyzed by real time reverse transcription-PCR. Of the sixty-four (85%) carbapenem resistant A. baumannii isolates, 42 (66%) and 22 (34%) strains were recovered from burn and non-burn patients, respectively. Isolates were categorized into 6 major REP-PCR patterns; with the highest prevalence of non-burn and burn isolates in pattern A (63%) and B (35%), respectively. Prevalence of blaOXA-23 was 68% and isolates harbored this element belonged to all REP clusters. The blaOXA-40-like was detected in 49% of isolates, with higher prevalence among burn isolates. Three of the four isolates lacked carO gene were cultured from burn patients and level of the carO expression was decreased in carbapenem resistant isolates. These findings show that blaOXA-23 is widely distributed in carbapenem resistant A. baumannii isolates and other resistance mechanisms such as blaOXA-40-like and loss or decreased carO expression could be added in burn strains. PMID- 23726476 TI - [Value of tumour resection in colorectal cancer with unresectable metastases]. PMID- 23726478 TI - Treatment outcomes in implant dentistry. PMID- 23726479 TI - Implant dentistry. PMID- 23726480 TI - Dean's update. PMID- 23726481 TI - Meaningful CPD: time to reflect. PMID- 23726482 TI - Promoting primary care research in 2013. PMID- 23726485 TI - The beginning of the rest of our lives: a day with the FGDP(UK). PMID- 23726489 TI - Upper and lower full arch dental reconstruction with implant supported overdentures: a case study. AB - STATEMENT OF PROBLEM: In clinical situations where implant placement in the maxilla is prohibited due to the lack of available bone, more invasive techniques such as autogenous bone grafting and sinus augmentation are often off-putting to patients due to the added expense, risk and morbidity. Purpose of treatment: The intention of this treatment was to dentally restore a patient with a severely resorbed edentulous maxilla, without the use of any grafting techniques. METHODS: Under local anaesthetic, five implants were placed in the patient's maxilla using the combined techniques of alveolar ridge-splitting and a Summer's lift. The crest of the alveolus was dissected bilaterally with a fine rotary disc. A combination of osteotomes and bone spreaders were then used to create the individual osteotomies. In the most distal site on the right side, the floor of the maxillary sinus was tapped up to facilitate implant placement. All implants were submerged under the gum for six months to allow them to ossteointegrate. Restorative stages were then completed. RESULTS: At six months, all five maxillary implants had successfully integrated. The maxilla also showed marked expansion where the alveolus had been dissected and bone had healed between the separated buccal and palatal plates. The final restoration was a metal-framed overdenture attached to a milled titanium bar supported on five implants. CONCLUSION: In this single case study, a patient's atrophic, edentulous maxilla was successfully restored without grafting techniques. The overdenture has been in trouble-free function for two years. PMID- 23726490 TI - Medicolegal implications of dental implant therapy. AB - Despite the recent economic downturn, the dental implant market continues to grow year on year. Many more dentists are involved in the placement restoration of dental implants and dental implants are being placed in an extended range of clinical scenarios. Dental implant therapy remains a high risk area for the inexperienced interns of civil negligence claims and General Dental Council hearings. Risk can be mitigated by:* Ensuring appropriate indemnity * Complying with the published requirements for training * Maintaining detailed and extensive clinical records * Completing the initial phases of history, examination and investigations robustly * Recording a diagnosis * Providing a bespoke written treatment plan that includes details of the need for treatment, the treatment options (the risks and benefits), the phases of treatment, the costs of treatment,the expected normal sequelae of surgery, the risks and complications of implant therapy and the requirement for future maintenance. The provision of treatment that is different in nature or extent to that agreed can result in a breach of contract as well as a claim for negligence * Engaging sufficiently with the patient to obtain consent * Providing written postoperative instructions detailing emergency arrangements, patients who are anxious or in pain may not retain oral information * Making a frank disclosure of complication or collateral damage * Considering referral at an early stage particularly if reparative surgery is required. The stress of complications or failure may impair a dentist's normally sound judgement; there may be financial pressure, or concerns regarding reputation. In some cases, dentists avoid making a frank disclosure, feel obliged to undertake complicated reparative surgery, fail to make a timely referral, fail to respond appropriately to patient's concerns and in some cases attempt to alter the clinical records.However, in the best of hands and without negligence complications can and do occur. Complications that occur in the presence of good planning and communication and are managed appropriately do not amount to negligence, and are unlikely to lead to a successful claim. PMID- 23726491 TI - Clinical record-keeping for monitoring treatment outcomes in implant dentistry: a case study. AB - Sound clinical practice in implant dentistry depends upon defining the methodology that can successfully be used. This can be achieved by identifying literature relating to a specific technique prior to its use. However, clinical observations of outcomes within one's own practice are also very effective. This is particularly true as it becomes specific, by eliminating numerous confounding factors. Appropriate documentation, both clinical and radiographic, permits the practitioner to review clinical cases and establish the efficacy of the methodology used. This is most effective in terms of evaluating survival as well as determining aesthetic and functional outcomes. Software programs such as ImpDAT (Kea Software, Poecking, Germany) provide a platform that easily allows both accurate record-keeping and, importantly, retrieval of data for purposes of review and publication. This paper presents a case report that uses radiographic and photographic records to monitor the ongoing response of the patient to the specific treatment that was carried out; in this case, autogenous onlay bone grafts for the management of congenital partial anodontia. PMID- 23726492 TI - Making clinical governance a fixture of your dental implant practice. PMID- 23726493 TI - Managing the edentulous mandible using recent technological developments: a case study. AB - Safe clinical practice in implant dentistry requires an accurate investigation of the availability of bone for implant placement and the avoidance of critical anatomical structures. Modern imaging techniques using computed tomography (CT) and cone beam computed tomography (CBCT) provide the clinician with the required information. The imaging thus obtained provides accurate representation of the height, width and length of the available bone. In addition, whenever adequate radiation dose is used, accurate information about the bone density in Hounsfield units can be obtained. Important spatial information regarding the orientation of the ridges and the relationship to the proposed prosthetic reconstruction can be obtained with the aid of radiopaque templates during the acquisition of CT scan data. Modern software also provides the facility to decide interactively upon the positioning of the implants and is able to relate this to a stereolithographic model constructed from the imaging data. A surgical guide for the accurate positioning of the implants can be constructed. The construction of screw retained prostheses is fraught with difficulties regarding the accuracy of the construction. Accurate fit of the prosthesis is difficult to obtain due to the inherent errors in impression taking, component discrepancies, investing and casting inaccuracies. CAD/CAM technology eliminates the inaccuracies involved with the investing and casting of superstructures. PMID- 23726494 TI - Teamwork in implant dentistry: the provision of a maxillary implant retained overdenture. AB - This case demonstrates a pragmatic, yet systematic, team approach to resolving a challenging clinical situation. It is essential to understand and accept the challenges presented and limitations of the treatment options available in the provision of an MIO. The dental surgeon and clinical dental technician collaborated using their combined skills set. Working as a team gives each clinician a greater appreciation of the difficulties faced clinically and technically. We believe that an enhanced standard of care is delivered to patients by using this team approach. PMID- 23726495 TI - Implant dentistry: a technician's perspective. PMID- 23726496 TI - The care and maintenance of dental implants: a team approach. PMID- 23726497 TI - An insight into peri-implantitis: a systematic literature review. AB - AIM: This systematic literature review was performed to establish a definition of peri-implantitis, what makes a patient more susceptible to peri-implantitis, the signs and symptoms of peri-implantitis (including radiographic findings), treatment options for peri-implantitis, and to investigate what constitutes a suitable oral hygiene regime. METHOD: A systematic literature review and analysis of publications included in PubMed (articles published between 1998 and 2003; English language; search terms "peri-implantitis"; "mucositis"; "partially edentulous"; "preventative maintenance"; "peri-implantitis and plaque control"; "tissue augmentation"; "diet maintenance of peri-implantitis"; "oral hygiene instruction for implants") was performed to identify papers providing information about peri-implantitis. Separately sourced publications with peri-implantitis related titles and abstracts were reviewed and analysed. The set criteria for inclusion were peer-reviewed articles. Of 53 papers identified, 23 were included for systematic review. RESULTS: Analysis of the papers revealed that patients with implants are more susceptible to developing peri-implantitis than are patients with natural teeth to developing periodontal disease. This is due to the varied peri-implant tissue that surrounds the implant in comparison with the tissue that surrounds a natural tooth. If active periodontal disease is present, peri-implantitis may also develop; however, other secondary factors may also need to be present for this to occur. CONCLUSION: A comprehensive periodontal examination should be carried out prior to implant surgery. The patient should be informed of the necessity of regular maintenance following implant surgery and the prerequisite of maintaining a comprehensive oral hygiene regime to avoid peri implantitis. PMID- 23726498 TI - Heroes of implant dentistry: osseointegration and titanium. PMID- 23726499 TI - Dental tourism: global dental trends. PMID- 23726500 TI - Community dental services. PMID- 23726502 TI - Increased variability of axonal excitability in amyotrophic lateral sclerosis. AB - OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is characterised by the increased excitability of motoneurons and heterogeneous loss of axons. The heterogeneous nature of the disease process among fibres may show variability of excitability in ALS. METHODS: Multiple nerve excitability tests were performed in 28 ALS patients and 23 control subjects, by tracking at the varying threshold levels (10%, 20%, 40% and 60% of maximum amplitudes). RESULTS: In normal controls, excitability measures at low target levels have the following characteristics compared to those at high target levels: longer strength-duration time constant, greater threshold reduction during depolarising currents and smaller threshold increase to hyperpolarising currents. ALS patients had less clear amplitude dependency of the parameters than the controls, indicating variability of axonal excitability. Three ALS patients demonstrated greater target-amplitude-dependent threshold changes in threshold electrotonus than controls, suggesting selective axonal hyperexcitability. CONCLUSIONS: Some of the ALS patients had variable axonal excitability at different target amplitudes, suggesting preferential hyperexcitability in the axons with low target amplitude levels. SIGNIFICANCE: Variable membrane potentials of motor axons in ALS may be assessed by recording excitability testing at different target amplitude levels. PMID- 23726503 TI - [The last 10 years of the Revista Espanola de Anestesiologia y Reanimacion: Its incorporation into "continuing education", its integration to "digital format" and its aim to be included in an international citation index]. PMID- 23726504 TI - Heat immersion therapy--a new approach for contact dermatitis to propolis? PMID- 23726505 TI - Non-Hodgkin's lymphoma in a patient with leucocyte adhesion deficiency. PMID- 23726506 TI - Comparison of 18 FDG PET-CT and bone scintigraphy for detection of bone metastases in breast cancer patients. A meta-analysis. AB - BACKGROUND: We performed a meta-analysis to compare the accuracy of (18)FDG PET CT and bone scintigraphy for the detection of bone metastases in breast cancer patients. METHODS: Studies about (18)FDG PET-CT and bone scintigraphy for the detection of bone metastases in breast cancer patients were systematically searched in the MEDLINE and EMBASE databases. We calculated sensitivities, specificities, diagnostic odds ratios, and likelihood ratios, and constructed summary receiver operating characteristic curves using bivariate regression models for (18)FDG PET-CT and bone scintigraphy, respectively. RESULTS: Across 7 studies (668 patients), sensitivity and specificity of PET-CT 0.93 (95% confidence interval [CI] = 0.82-0.98) and 0.99 (95% CI = 0.95-1.00), and of bone scintigraphy were 0.81 (95% CI = 0.58-0.93) and 0.96 (95%CI = 0.76-1.00), respectively. Area under curves for PET-CT and bone scintigraphy was 0.98 (95% CI = 0.98-1.00) and 0.94 (95% CI = 0.92-0.96), respectively. CONCLUSIONS: Compared with bone scintigraphy, (18)FDG PET-CT may higher sensitivity and accuracy for detection of bone metastases in breast cancer patients. PMID- 23726507 TI - [Prognosis and treatment of dry mouth. Systematic review]. AB - There are no clearly established protocols for the treatment of dry mouth. The aim of this paper is a systematic review of the literature of the past 10 years using the words " dry mouth ", " prognosis ", " treatment " and " dentistry ". The initial search found 1,450 entries and within the restriction " clinical trials OR randomized controlled trial OR systemic reviews " it has been reduced to 522, which 145 were meta-analysis and systematic reviews. Papers not relevant to the issue were removed reducing the entries to 53. Twenty-four were dismissed (8 irrelevant, 7 reviews without adequate information and 9 personal opinions). Of the 29 items tested, 15 were controlled trials, 2 uncontrolled trials, 4 observational studies, 2 systematic reviews and 5 non systematic reviews. The most studied patients were Sjogren's syndrome and the irradiated patients. Treatments are focused on the etiology, prevention, symptomatic, local salivary stimulation and systemic treatments. It can be concluded that treatment must be individualized, salivary substitutes and mechanical stimulation techniques can be applied. PMID- 23726508 TI - Side effects of antidepressants during long-term use in a naturalistic setting. AB - Side effects of antidepressants are usually underreported in clinical trials and large scale naturalistic studies are restricted to six months of use. We examined the prevalence and nature of patient-perceived side effects and their determinants during long-term antidepressant use in a naturalistic setting. Subjects, aged 19 to 67 years, in the Netherlands Study of Depression and Anxiety were recruited from primary care and specialized mental health care covered 927 cases of single antidepressant use. In 64% of cases, on average, 2.9 side effects were reported. The number of side effects was higher when subjects had higher depression severity (OR=1.28; p=0.002), three or more psychiatric diagnoses (OR=1.97; p=0.02), higher dose (OR=1.44; p=0.006) and was lower when subjects were older (OR=0.83; p=0.02) and had longer duration of use (OR=0.94; p=0.04). Tricyclic antidepressants were associated with more side effects (OR=2.52; p=0.003) and, particularly, more anticholinergic effects, like dry mouth and constipation, as compared to selective serotonin reuptake inhibitors. Venlafaxine showed more profuse sweating (OR=1.79; p=0.007), whereas mirtazapine showed more weight gain and less sexual dysfunction (OR=0.36; p=0.03), as compared to selective serotonin reuptake inhibitors. Weight gain was associated with female gender (OR=1.76; p=0.004) and duration of use (OR=1.06; p=0.03). We show that antidepressant side effect, known from short-term studies, persist during long term use and are associated with depression severity and antidepressant dose. A novel finding was that venlafaxine is associated with more profuse sweating and that weight gain appeared more specific in female users. Clinicians should be aware that, during long-term antidepressant use, side effects are common and persistent. PMID- 23726509 TI - Animal models lead the way to further understanding food addiction as well as providing evidence that drugs used successfully in addictions can be successful in treating overeating. PMID- 23726510 TI - Reply to: Subanesthetic dose ketamine does not induce an affective switch in three independent samples of treatment-resistant major depression. PMID- 23726511 TI - Genome-wide association study identifies new susceptibility loci for posttraumatic stress disorder. AB - BACKGROUND: Genetic factors influence the risk for posttraumatic stress disorder (PTSD), a potentially chronic and disabling psychiatric disorder that can arise after exposure to trauma. Candidate gene association studies have identified few genetic variants that contribute to PTSD risk. METHODS: We conducted genome-wide association analyses in 1578 European Americans (EAs), including 300 PTSD cases, and 2766 African Americans, including 444 PTSD cases, to find novel common risk alleles for PTSD. We used the Illumina Omni1-Quad microarray, which yielded approximately 870,000 single nucleotide polymorphisms (SNPs) suitable for analysis. RESULTS: In EAs, we observed that one SNP on chromosome 7p12, rs406001, exceeded genome-wide significance (p = 3.97 * 10(-8)). A SNP that maps to the first intron of the Tolloid-Like 1 gene (TLL1) showed the second strongest evidence of association, although no SNPs at this locus reached genome-wide significance. We then tested six SNPs in an independent sample of nearly 2000 EAs and successfully replicated the association findings for two SNPs in the first intron of TLL1, rs6812849 and rs7691872, with p values of 6.3 * 10(-6) and 2.3 * 10(-4), respectively. In the combined sample, rs6812849 had a p value of 3.1*10( 9). No significant signals were observed in the African American part of the sample. Genome-wide association study analyses restricted to trauma-exposed individuals yielded very similar results. CONCLUSIONS: This study identified TLL1 as a new susceptibility gene for PTSD. PMID- 23726512 TI - Subanesthetic dose ketamine does not induce an affective switch in three independent samples of treatment-resistant major depression. PMID- 23726513 TI - MAOA genotype, childhood maltreatment, and their interaction in the etiology of adult antisocial behaviors. AB - BACKGROUND: Maltreatment by an adult or caregiver during childhood is a prevalent and important predictor of antisocial behaviors in adulthood. A functional promoter polymorphism in the monoamine oxidase A (MAOA) gene has been implicated as a moderating factor in the relationship between childhood maltreatment and antisocial behaviors. Although there have been numerous attempts at replicating this observation, results remain inconclusive. METHODS: We examined this gene environment interaction hypothesis in a sample of 3356 white and 960 black men (aged 24-34) participating in the National Longitudinal Study of Adolescent Health. RESULTS: Primary analysis indicated that childhood maltreatment was a significant risk factor for later behaviors that violate rules and the rights of others (p < .05), there were no main effects of MAOA genotype, and MAOA genotype was not a significant moderator of the relationship between maltreatment and antisocial behaviors in our white sample. Post hoc analyses identified a similar pattern of results among our black sample in which maltreatment was not a significant predictor of antisocial behavior. Post hoc analyses also revealed a main effect of MAOA genotype on having a disposition toward violence in both samples and for violent convictions among our black sample. None of these post hoc findings, however, survived correction for multiple testing (p > .05). Power analyses indicated that these results were not due to insufficient statistical power. CONCLUSIONS: We could not confirm the hypothesis that MAOA genotype moderates the relationship between childhood maltreatment and adult antisocial behaviors. PMID- 23726514 TI - Trajectories of cerebral cortical development in childhood and adolescence and adult attention-deficit/hyperactivity disorder. AB - BACKGROUND: Childhood attention-deficit/hyperactivity disorder (ADHD) persists into adulthood in around half of those affected, constituting a major public health challenge. No known demographic, clinical, or neuropsychological factors robustly explain the clinical course, directing our focus to the brain. Herein, we link the trajectories of cerebral cortical development during childhood and adolescence with the severity of adult ADHD. METHODS: Using a longitudinal study design, 92 participants with ADHD had childhood (mean 10.7 years, SD 3.3) and adult clinical assessments (mean 23.8 years, SD 4.3) with repeated neuroanatomic magnetic resonance imaging. Contrast was made against 184 matched typically developing volunteers. RESULTS: Attention-deficit/hyperactivity disorder persisted in 37 (40%) subjects and adult symptom severity was linked to cortical trajectories. Specifically, as the number of adult symptoms increased, particularly inattentive symptoms, so did the rate of cortical thinning in the medial and dorsolateral prefrontal cortex. For each increase of one symptom of adult ADHD, the rate of cortical thinning increased by .0018 mm (SE = .0004, t = 4.2, p < .0001), representing a 5.6% change over the mean rate of thinning for the entire group. These differing trajectories resulted in a convergence toward typical dimensions among those who remitted and a fixed, nonprogressive deficit in persistent ADHD. Notably, cortical thickening or minimal thinning (greater than -.007 mm/year) was found exclusively among individuals who remitted. CONCLUSIONS: Adult ADHD status is linked with the developmental trajectories of cortical components of networks supporting attention, cognitive control, and the default mode network. This informs our understanding of the developmental pathways to adult ADHD. PMID- 23726515 TI - Resting functional connectivity reveals residual functional activity in Alzheimer's disease. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) has great potential for measuring mechanisms of functional changes in Alzheimer's disease (AD) and mild cognitive impairment, but task fMRI studies have produced conflicting results, partly due to failure to account for underlying morphological changes and to variations in patients' ability to perform the tasks. Resting fMRI has potential for assessing brain function independently from a task, but greater understanding of how networks of resting functional connectivity relate to the functioning of the brain is needed. We combined resting fMRI and task fMRI to examine the correspondence between these methods in individuals with cognitive impairment. METHODS: Eighty elderly (25 control subjects, 25 mild cognitive impairment, 30 AD) underwent a combined multimodal magnetic resonance imaging protocol including task fMRI and resting fMRI. Task fMRI data were acquired during the execution of a memory paradigm designed to account for differences in task performance. Structural and physiological confounds were modeled for both fMRI modalities. RESULTS: Successful recognition was associated with increased task fMRI activation in lateral prefrontal regions in AD relative to control subjects; this overlapped with increased resting fMRI functional connectivity in the same regions. CONCLUSIONS: Our results show that task fMRI and resting fMRI are sensitive markers of residual ability over the known changes in brain morphology and cognition occurring in AD and suggest that resting fMRI has a potential to measure the effect of new treatments. PMID- 23726516 TI - The effects of fat talk on body dissatisfaction and eating behavior: the moderating role of dietary restraint. AB - Although research suggests that fat talk, the normalized conversations that involve degrading one's body shape/weight and size, can increase body dissatisfaction and disordered eating behavior, the extent to which dietary restraint may moderate these relationships remains uncertain. A pilot study (N=30) comparing online videos with researcher-developed vignettes as prospective manipulations for fat talk exposure suggested use of the vignettes as potent yet subtle stimuli. In the main study, women undergraduates (N=116) were randomized to read a fat talk or neutral vignette and then completed standardized measures of body dissatisfaction and dietary restraint while being concurrently presented with food stimuli. Results suggest significant moderation effects for dietary restraint: whereas fat talk exposure was associated with increased body dissatisfaction among low dietary restrainers, it appeared to reduce food consumption among high dietary restrainers. Findings highlight the importance of individual differences in shaping responses to fat talk. PMID- 23726517 TI - More than just body weight: the role of body image in psychological and physical functioning. AB - The current study examined BMI and body image dissatisfaction as predictors of physical and mental health-related quality of life (HRQL) and psychosocial functioning in a sample of 414 undergraduate students (mean age=21.5, SD=4.9; mean BMI=23.6, SD=5.2). In men and women, higher BMI was correlated with body image dissatisfaction and physical HRQL, but not with any measures of psychosocial functioning, whereas higher body image dissatisfaction was associated with poorer physical HRQL and psychosocial functioning. Furthermore, body image dissatisfaction was observed to mediate the relationship between BMI and physical HRQL in men and women. Interestingly, in this model, higher BMI predicted increased self-esteem. These findings suggest that body image dissatisfaction may be an important target for health interventions. PMID- 23726518 TI - Ultra-low gamma-ray measurement system for neutrinoless double beta decay. AB - An experiment for the detection of 0nubeta(+)/EC and 0nuEC/EC in 92Mo nuclei has been carried out with a scintillating crystal, CaMoO4, in coincidence with the HPGe detector. We study the background events inside the event selection window for 0nu beta(+)/EC decays of CaMoO4 detector. For 51.2 days of data taking period, we didn't observe any event in the neutrinoless EC/EC decay event window. The (92)Mo 0nubeta(+)/EC decay half-life limit was set to 0.61*10(20) years with a 90% confidence by method of Feldman and Cousins. This ultra-low gamma ray measurement utilizing coincidence technique can be used for the resonant EC/EC decay process of some nuclei which is potentially important for neutrinoless double beta decay process. PMID- 23726519 TI - Surface-engineering of glycidyl methacrylated dextran/gelatin microcapsules with thermo-responsive poly(N-isopropylacrylamide) gates for controlled delivery of stromal cell-derived factor-1alpha. AB - In situ tissue engineering has been proposed as a promising method to address the need for the clinical regeneration of a wide variety of damaged tissues. This approach comprises the use of a cell-free instructive scaffold that incorporates and releases topical chemotactic factors to recruit host endogenous stem/progenitor cells for tissue regrowth at the locus of implantation. However, the clinical translation of this concept is hampered when repeated doses of medication must be administrated over an extended period of time. In this study, we designed a delivery platform characterized by microcapsules containing thermo responsive poly(N-isopropylacrylamide) (PNIPAAm) gates on their outer pore surfaces for the controlled release of stromal cell-derived factor (SDF)-1alpha, an important chemokine for stem cell recruitment/homing. Double-phase emulsified condensation polymerization was used to prepare interconnected porous glycidyl methacrylated dextran (Dex-GMA)/gelatin microcapsules, and plasma-graft pore filling polymerization was used to graft PNIPAAm into the surface pores of the microcapsules. The in vitro results showed that the PNIPAAm-grafted microcapsules featured thermo-responsive drug release properties due to the swollen-shrunken property of PNIPAAm gates in response to temperature changes. After subcutaneous implantation, the thermally responsive microcapsules resulted in a more sustained and long-term SDF-1alpha release compared with those without PNIPAAm-grafting. In the future, this delivery system may have great potential for use in cell recruiting biomaterials for various tissue engineering and regenerative medicine applications. PMID- 23726520 TI - A combination of genetic, molecular and haemodynamic risk factors contributes to the formation, enlargement and rupture of brain aneurysms. AB - Many people carry cerebral aneurysms but are generally unaware of their presence until they rupture, resulting in high morbidity or mortality. The pathogenesis and aetiology of aneurysms are largely unknown; however, a greater understanding, by analysing the genetic, molecular and haemodynamic risk factors involved in the initiation, enlargement, and rupture of aneurysms, could lead to effective prevention, early diagnosis and more effective treatment. The risk of aneurysm is increased by a family history of aneurysms, and amongst certain populations, namely in Japan and Finland. Several other risk factors are documented, including hypertension, smoking, alcohol consumption, and female sex. Studies indicate a higher occurrence of cerebral aneurysms in females compared to males. Oestrogen protects several components within the artery wall, and inhibits some of the inflammatory molecules that could cause aneurysms. At menopause, the oestrogen level decreases and the incidence of aneurysm increases. Haemodynamic stresses have been shown to be involved in the formation, growth and rupture of aneurysms. This is often associated with hypertension, which also increases the risk of aneurysm rupture. When an unruptured aneurysm is detected the decision to treat can be complicated, since only 1-2% of aneurysms eventually rupture. Haemodynamic simulation software offers an effective tool for the consideration of treatment options for patients who carry unruptured aneurysms. The assessment must consider the risks of interventional treatments versus non-interventional management options, such as controlling blood pressure. PMID- 23726521 TI - Phylogenetic position and virulence apparatus of the pear flower necrosis pathogen Erwinia piriflorinigrans CFBP 5888T as assessed by comparative genomics. AB - Erwinia piriflorinigrans is a necrotrophic pathogen of pear reported from Spain that destroys flowers but does not progress further into the host. We sequenced the complete genome of the type strain CFBP 5888(T) clarifying its phylogenetic position within the genus Erwinia, and indicating a position between its closest relative, the epiphyte Erwinia tasmaniensis and other plant pathogenic Erwinia spp. (i.e., the fire blight pathogen E. amylovora and the Asian pear pathogen E. pyrifoliae). Common features are the type III and type VI secretion systems, amylovoran biosynthesis and desferrioxamine production. The E. piriflorinigrans genome also provided the first evidence for production of the siderophore chrysobactin within the genus Erwinia sensu stricto, which up to now was mostly associated with phytopathogenic, soft-rot Dickeya and Pectobacterium species. Plasmid pEPIR37, reported in this strain, is closely related to small plasmids found in the fire blight pathogen E. amylovora and E. pyrifoliae. The genome of E. piriflorinigrans also gives detailed insights in evolutionary genomics of pathoadapted Erwinia. PMID- 23726522 TI - The relationship between emergency department use and cost-related medication nonadherence among Medicare beneficiaries. AB - STUDY OBJECTIVE: The objective of this study was to evaluate the relationship between self-reported cost-related nonadherence to prescription medications and emergency department (ED) utilization among Medicare beneficiaries. We hypothesized that persons who report cost-related medication nonadherence would have subsequent higher ED use. METHODS: We conducted a retrospective cohort study of continuously enrolled Medicare beneficiaries in 2006 and 2007. We used multivariate logistic regression to evaluate the relationship between ED use and cost-related medication nonadherence. Our principal dependent variable was any ED visit within a 364-day period after an interview assessing cost-related medication nonadherence. Our principal independent variables both denoted cost related medication nonadherence: mild cost-related medication nonadherence, defined as a reduction in dose or a delay in filling medications because of cost; and severe cost-related medication nonadherence, defined as not filling a medication at all because of cost. RESULTS: Our sample consisted of 7,177 Medicare Current Beneficiary Survey respondents. Approximately 7.5% of respondents reported mild cost-related medication nonadherence only (n=541) and another 8.2% reported severe cost-related medication nonadherence (n=581). Disabled Medicare beneficiaries with severe cost-related medication nonadherence were more likely to have at least 1 ED visit (1.53; 95% confidence interval 1.03 to 2.26) compared with both disabled Medicare beneficiaries without cost-related medication nonadherence and elderly Medicare beneficiaries in all cost-related medication nonadherence categories. CONCLUSION: Our results show an association between severe cost-related medication nonadherence and ED use. Disabled beneficiaries younger than 65 years who report severe cost-related medication nonadherence were more likely to have at least 1 ED visit, even when adjusting for other factors that affect utilization. PMID- 23726523 TI - Leptin antagonist ameliorates chronic colitis in IL-10-/- mice. AB - BACKGROUND: Although the etiology of two major forms of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are unknown and evidence suggests that chronic intestinal inflammation is caused by an excessive immune response to mucosal antigens. Previous studies support the role for TGF beta1 through 3 in the initiation and maintenance of tolerance via the induction of regulatory T cells (Tregs) to control intestinal inflammation. Leptin, a satiety hormone produced primarily by adipose tissue, has been shown to increase during colitis progression and is believed to contribute to disease genesis and/or progression. AIM: We investigated the ability of a pegylated leptin antagonist (PG-MLA) to ameliorate the development of chronic experimental colitis. RESULTS: Compared to vehicle control animals, PG-MLA treatment of mice resulted in an (1) attenuated clinical score; (2) reversed colitis-associated pathogenesis including a decrease in body weight; (3) reduced systemic and mucosal inflammatory cytokine expression; (4) increased insulin levels and (5) enhanced systemic and mucosal Tregs and CD39+ Tregs in mice with chronic colitis. The percentage of systemic and mucosal TGF-beta1, -beta2 and -beta3 expressing CD4+ T cells were augmented after PG-MLA treatment. The activation of STAT1 and STAT3 and the expression of Smad7 were also reduced after PG-MLA treatment in the colitic mice. These findings clearly suggest that PG-MLA treatment reduces intestinal Smad7 expression, restores TGF-beta1-3 signaling and reduces STAT1/STAT3 activation that may increase the number of Tregs to ameliorate chronic colitis. CONCLUSION: This study clearly links inflammation with the metabolic hormone leptin suggesting that nutritional status influences immune tolerance through the induction of functional Tregs. Inhibiting leptin activity through PG-MLA might provide a new and novel therapeutic strategy for the treatment of IBD. PMID- 23726524 TI - Chronic administration of methylmalonate on young rats alters neuroinflammatory markers and spatial memory. AB - The methylmalonic acidemia is an inborn error of metabolism (IEM) characterized by methylmalonic acid (MMA) accumulation in body fluids and tissues, causing neurological dysfunction, mitochondrial failure and oxidative stress. Although neurological evidence demonstrate that infection and/or inflammation mediators facilitate metabolic crises in patients, the involvement of neuroinflammatory processes in the neuropathology of this organic acidemia is not yet established. In this experimental study, we used newborn Wistar rats to induce a model of chronic acidemia via subcutaneous injections of methylmalonate (MMA, from 5th to 28th day of life, twice a day, ranged from 0.72 to 1.67 MUmol/g as a function of animal age). In the following days (29th-31st) animal behavior was assessed in the object exploration test and elevated plus maze. It was performed differential cell and the number of neutrophils counting and interleukin-1 beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) levels in the blood, as well as levels of IL-1beta, TNF-alpha, inducible nitric oxide synthase (iNOS) and 3-nitrotyrosine (3-NT) in the cerebral cortex were measured. Behavioral tests showed that animals injected chronically with MMA have a reduction in the recognition index (R.I.) when the objects were arranged in a new configuration space, but do not exhibit anxiety-like behaviors. The blood of MMA-treated animals showed a decrease in the number of polymorphonuclear and neutrophils, and an increase in mononuclear and other cell types, as well as an increase of IL-1beta and TNF-alpha levels. Concomitantly, MMA increased levels of IL-1beta, TNF-alpha, and expression of iNOS and 3-NT in the cerebral cortex of rats. The overall results indicate that chronic administration of MMA increased pro-inflammatory markers in the cerebral cortex, reduced immune system defenses in blood, and coincide with the behavioral changes found in young rats. This leads to speculate that, through mechanisms not yet elucidated, the neuroinflammatory processes during critical periods of development may contribute to the progression of cognitive impairment in patients with methylmalonic acidemia. PMID- 23726525 TI - [Dysautonomic syndrome of the face with Harlequin sign and syndrome: Three new cases and a review of the literature]. AB - INTRODUCTION: Harlequin phenomenon is characterized by a strictly unilateral erythrosis of the face with flushing and hyperhydrosis, and controlaterally a pale anhydrotic aspect. This syndrome can occur alone or associated to other dysautonomic phenomena such as Horner syndrome, Adie syndrome or Ross syndrome. PATIENTS AND METHODS: We report three cases: two patients presented a Harlequin sign, associated with Horner syndrome for one and Ross syndrome for the second. The etiologic investigation was normal, allowing recognizing the idiopathic nature of the disorder. For the third patient, Harlequin syndrome was observed in a neoplastic context due to breast cancer, metastatic dissemination, and bone metastases involving the right side of the T2 body. DISCUSSION: We reviewed the literature: 108 cases have been described. This syndrome occurred alone in 48 patients and was associated with other dysautonomic syndromes such as Horner syndrome in 38 patients, Holmes Adie syndrome in six, and Ross syndrome in six; both Ross and Holmes Adie syndrome were associated five cases and associations were not reported in five patients. The pathophysiological mechanisms of this autonomic cranial neuropathy, the possible etiologies, and therapeutic management were discussed. CONCLUSION: Harlequin phenomenon with flushing and unilateral hyperhydrosis is rare, occurring alone or in combination with other autonomic syndromes of the face. Idiopathic in two-thirds of cases, Harlequin phenomenon does not require specific treatment; sympathectomy may be discussed in the severe cases with a significant social impact. PMID- 23726526 TI - Outcomes of aggressive concurrent radiochemotherapy in highly selected septuagenarians with stage IIIB non-small cell lung carcinoma: retrospective analysis of 89 patients. AB - We retrospectively evaluated the toxicity and efficacy of concurrent radiochemotherapy (C-RCT) in medically fit septuagenarians with stage IIIB non small cell lung carcinoma (NSCLC). Eighty-nine medically fit, stage IIIB NSCLC septuagenarians were included. Thoracic radiotherapy to a total dose of 66 Gy in 2 Gy fractions was delivered concurrently with 1-2 cycles of cisplatin-based doublet chemotherapy. Treatment was relatively well-tolerated with no grade 4/5 acute toxicity. Acute grade 3 hematologic and non-hematologic toxicity rates were 55.1 and 39.3%, respectively. Late toxicity was reported in 3 (3.4%) patients: esophagitis (N = 2) and peripheral neuropathy (N = 1). At median 21.7 months (4.4 42.1), 26 patients (29.2%) were alive. Median overall, local-regional progression free and progression-free survivals were 17.7, 10.5 and 7.8 months, respectively. On univariate analyses, histology (p < 0.03), nodal status (p = 0.038), number of concomitant chemotherapy (p < 0.001), and weight change during C-RCT (p < 0.001) demonstrated significant association with overall survival; while only number of chemotherapy and weight change (p < 0.001 for each) could retain their significance on multivariate analyses. Current results suggested that C-RCT in highly selected medically fit septuagenarians with LA-NSCLC may improve survival outcomes up to that achieved in younger patients, with a relatively acceptable toxicity profile. PMID- 23726527 TI - Detection and comparison of EGFR mutations in matched tumor tissues, cell blocks, pleural effusions, and sera from patients with NSCLC with malignant pleural effusion, by PNA clamping and direct sequencing. AB - Peptide nucleic acid (PNA)-mediated real-time PCR clamping has higher sensitivity than conventional direct sequencing for detecting mutations. Pleural effusion and serum may provide good samples in which to detect epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients. We studied 37 NSCLC patients with malignant pleural effusion. EGFR mutations were assessed by PNA clamping and direct sequencing using tumor tissues, cell blocks, pleural effusion, and serum. Concordance between PNA clamping and direct sequencing results, and the diagnostic performance of pleural effusion were investigated. The kappa coefficients for the two methods were 0.68 (p = 0.0007), 0.91 (p < 0.0001), 0.75 (p < 0.0001) and -0.01 (p = 0.8639) for tissues, cell blocks, pleural effusion, and serum, respectively. The diagnostic performance of pleural effusion compared with the combination of tumor tissue and cell blocks showed 89% sensitivity, 100% specificity, positive predictive value of 100%, and negative predictive value of 95% by PNA clamping, and 67% sensitivity, 90% specificity, positive predictive value of 75%, and negative predictive value of 86% by directing sequencing. A patient in whom an EGFR mutation was identified in pleural effusion only by PNA clamping showed a significant response to EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment. In contrast to the limited role of serum samples, pleural effusion had a diagnostic performance for the detection of EGFR mutations in NSCLC that was comparable to that of tumor tissues and cell blocks. The diagnostic performance of PNA clamping was good compared with that of direct sequencing. A more sensitive and accurate detection of EGFR mutations would benefit patients by allowing a better prediction of the response to EGFR TKI treatment. PMID- 23726528 TI - Re: Lih-Ming Wong, Neil Fleshner, Antonio Finelli. Impact of 5-alpha reductase inhibitors on men followed by active surveillance for prostate cancer: a Time dependent covariate reanalysis. Eur Urol 2013;64:343. PMID- 23726529 TI - The relationship of blood lead with immunoglobulin E, eosinophils, and asthma among children: NHANES 2005-2006. AB - Early life lead exposure may alter immune function and predispose a child to develop asthma. In an initial exploration of this hypothesis, we examined the association between blood lead, and serum immunoglobulin E (IgE), eosinophils, and asthma prevalence in a cross-sectional study of 1788 children from the National Health and Nutrition Examination Survey 2005-2006. Geometric mean blood lead, serum IgE, and percent eosinophils were 1.13 MUg/dL (95% confidence interval (CI): 1.04, 1.22), 46.3 kU/L (95% CI: 40.3, 53.1), and 2.82 percent (95% CI 2.67, 2.98), respectively. Prevalence of asthma, atopic asthma, and atopy were 11.8% (95% CI: 9.5, 14.2), 8.1% (6.2, 9.9), and 44.4% (40.1, 48.7), respectively. Regression models controlled for season, age, sex, race/ethnicity, education, passive smoke exposure, and body mass index. Based on these models, there was an 11.1% (95% CI: 5.6, 16.9) increase in IgE and a 4.9% (95% CI: 2.3, 7.6) increase in eosinophils per 1 MUg/dL increase in blood lead. In independent stratified analyses, lead was found to increase IgE and eosinophils among non-Hispanic whites, but not other children; and stronger associations were observed among children who lived with a smoker vs. not. Lead was not associated with asthma, atopic asthma, or general atopy. This study provides additional evidence of a cross-sectional association between lead with IgE and new evidence for eosinophils. This may be a mechanism for development of downstream allergic disease. The mechanisms that determine ultimate development of allergic disease are currently unknown, but are the focus of ongoing studies. PMID- 23726531 TI - A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. AB - These parameters were developed by the Joint Task Force on Practice Parameters (JTFPP), representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The AAAAI and the ACAAI have jointly accepted responsibility for establishing "A focused parameter update: Hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin converting enzyme inhibitor-associated angioedema." This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the JTFPP, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma and Immunology. The Joint Task Force on Practice Parameters understands that the cost of diagnostic tests and therapeutic agents is an important concern that might appropriately influence the work-up and treatment chosen for a given patient. The JTFPP recognizes that the emphasis of our primary recommendations regarding a medication might vary, for example, depending on third-party payer issues and product patent expiration dates. However, because the cost of a given test or agent is so widely variable and there is a paucity of pharmacoeconomic data, the JTFPP generally does not consider cost when formulating practice parameter recommendations. In some instances the cost benefit of an intervention is considered relevant, and commentary might be provided. These parameters are not designed for use by pharmaceutical companies in drug promotion. The Joint Task Force is committed to ensuring that the practice parameters are based on the best scientific evidence that is free of commercial bias. To this end, the parameter development process includes multiple layers of rigorous review. These layers include the Workgroup convened to draft the parameter, the Task Force Reviewers, and peer review by members of each sponsoring society. Although the Task Force has the final responsibility for the content of the documents submitted for publication, each reviewer comment will be discussed, and reviewers will receive written responses to comments when appropriate. To preserve the greatest transparency regarding potential conflicts of interest, all members of the Joint Task Force and the Practice Parameters Workgroups will complete a standard potential conflict of interest disclosure form, which will be available for external review by the sponsoring organization and any other interested individual. In addition, before confirming the selection of a Workgroup chairperson, the Joint Task Force will discuss and resolve all relevant potential conflicts of interest associated with this selection. Finally, all members of parameter workgroups will be provided a written statement regarding the importance of ensuring that the parameter development process is free of commercial bias. PMID- 23726530 TI - Effect of barrier microbes on organ-based inflammation. AB - The prevalence and incidence of chronic inflammatory disorders, including allergies and asthma, as well as inflammatory bowel disease, remain on the increase. Microbes are among the environmental factors that play an important role in shaping normal and pathologic immune responses. Several concepts have been put forward to explain the effect of microbes on the development of these conditions, including the hygiene hypothesis and the microbiota hypothesis. Recently, the dynamics of the development of (intestinal) microbial colonization, its effect on innate and adaptive immune responses (homeostasis), and the role of environmental factors, such as nutrition and others, have been extensively investigated. Furthermore, there is now increasing evidence that a qualitative and quantitative disturbance in colonization (dysbiosis) is associated with dysfunction of immune responses and development of various chronic inflammatory disorders. In this article the recent epidemiologic, clinical, and experimental evidence for this interaction is discussed. PMID- 23726533 TI - Expanding the paradigm of eosinophilic esophagitis: mast cells and IL-9. PMID- 23726534 TI - Haploidentical hematopoietic stem cell transplantation can lead to viral clearance in severe combined immunodeficiency. PMID- 23726535 TI - Diagnosis and evaluation of primary panhypogammaglobulinemia: a molecular and genetic challenge. PMID- 23726536 TI - Impact of gonadotropins on oocyte maturation, fertilisation and developmental competence in vitro. AB - The aim of the present study was to evaluate the dose-dependent effects of gonadotropins, either singly (Bravelle (B), Luveris (L), Menupur (M), Repronex (R), Gonal-F (G), Follism (F) and Norvarel (N)) or in combination (Menupur+Bravelle; Repronext+Bravelle; and Bravelle+Norvarel), on rates of oocyte maturation, fertilisation and early embryo development in vitro in an animal model. Bovine cumulus-oocyte complexes (COCs) were purchased commercially and cultured in TCM-199 with 10% fetal bovine serum supplemented with varying concentrations of gonadotropin (0, 5, 10, 20, 40IU or United States Pharmacopoeia (USP) mL-1) for 24 and 48h according to current IVF clinical stimulation protocols. All gonadotropins enhanced oocyte maturation in vitro in a dose dependent manner. Individually, Gonal-F (Merck KGaA, Darmstadt, Germany), Follism (Merck Co, Whitehouse Station, NJ, USA) and Repronext (Ferring, Parsippany, NJ, USA) promoted oocyte maturation; in combination, they effectively enhanced COC expansion and increased the maturation competence of MII oocytes. However, high concentrations of gonadotropins may result in maturation arrest. Specific combinations of gonadotropins may change the rate of early embryonic development (8-16-cells) and morula-blastocyst formation. These data provide support for the responsiveness of bovine oocytes to gonadotropins in vitro and the need to consider variations in the relative concentrations and ratio of combinations (FSH/LH or human chorionic gonadotropin) for optimisation of oocyte developmental competence. The results of the present study could be applied to therapeutic clinical stimulation protocols and help improve IVF success rates. PMID- 23726537 TI - Inter-session reliability of the measurement of the deep and superficial layer of lumbar multifidus in young asymptomatic people and patients with low back pain using ultrasonography. AB - STUDY DESIGN: Reliability study. OBJECTIVE: To investigate the inter-session reliability of measuring the thickness of deep (dMF) and superficial layer of lumbar multifidus (sMF) using ultrasonography for participants with and without low back pain (LBP). BACKGROUND: The lumbar multifidus is an important muscle in maintaining spinal stability. The dMF is considered important in maintaining tonic contraction and joint stability. Motor control impairment is also discovered in patients with LBP. However, no study to date has investigated the method of observing both the sMF and dMF through ultrasound imaging (USI). METHODS: Twenty subjects aged 18-35 years old with LBP (N=10) and without LBP (N=10) were recruited. Every subject extended the upper trunk in prone lying with maximal isometric contraction. Simultaneously, the examiner measured the thickness of the dMF and the sMF using ultrasonography after ensuring the muscle belly was located. The participants performed three trials of isometric trunk extension in each session, with 30 min between each session. The reliability of measuring the change of thickness is represented by the intra-class correlation coefficient (ICC). RESULTS: Through averaging three trials of measurement, the reliability of measuring the thickness of the dMF or the sMF in static or in the contracted condition, and the change of the thickness during contraction, is reliable (ICC=0.84-1.00). CONCLUSIONS: The intra-rater inter-session reliability of measurement of the dMF and the sMF with USI has been established. This method could be applied to the qualification of the activation level of the dMF and the sMF with specific tasks. PMID- 23726538 TI - Effects on growth, antioxidant enzyme activity and levels of extracellular proteins in the green alga Chlorella vulgaris exposed to crude cyanobacterial extracts and pure microcystin and cylindrospermopsin. AB - Toxic cyanobacteria and cyanotoxins have been pointed as important players in the control of phytoplankton diversity and species abundance, causing ecological unbalances and contamination of the environment. In vitro experiments have been undertaken to address the impact of toxic cyanobacteria in green algae. In this regard the aim of this work was to compare the toxicity of two cyanobacteria species, Aphanizomenon ovalisporum and Microcystis aeruginosa, to the green alga Chlorella vulgaris by assessing culture growth when exposed for three and seven days to (I) cyanobacterial cell extracts and (II) pure toxins microcystin-LR (MC LR) and cylindrospermopsin (CYN). The biochemical response of the green alga to pure toxins was also characterized, through the activity of the antioxidant markers glutathione S-transferase (GST) and glutathione peroxidase (GPx) and the expressed extracellular proteins in seven-day exposed cultures. A. ovalisporum crude extracts were toxic to C. vulgaris. Pure toxins up to 179.0 ug/L, on the other hand, stimulated the green alga growth. Growth results suggest that the toxicity of A. ovalisporum extracts is likely due to a synergistic action of CYN and other metabolites produced by the cyanobacterium. Regarding the green alga antioxidant defense mechanism, CYN at 18.4 and 179.0 ug/L increased the activity of GPx and GST while MC-LR inhibited the enzymes' activity at a concentration of 179.0 ug/L demonstrating a contrasting mode of action. Moreover the identification of F-ATPase subunit, adenylate cyclase, sulfate ABC transporter, putative porin, aspartate aminotransferase, methylene-tetrahydrofolate dehydrogenase and chlorophyll a binding proteins in the culture medium of C. vulgaris indicates that biochemical processes involved in the transport of metabolites, photosynthesis and amino acid metabolism are affected by cyanobacterial toxins and may contribute to the regulation of green alga growth. PMID- 23726539 TI - Comparative genotoxicity of airborne particulate matter (PM2.5) using Salmonella, plants and mammalian cells. AB - This study compared genotoxicity in bacteria, plants and cell cultures in areas at risk of exposure to airborne pollution. Genotoxicity of moderately polar organic extracts of PM2.5 from areas with urban airborne pollution (Site 1) and urban-industrial pollution (Site 2) was evaluated using microsuspension assays in Salmonella/microsome, micronucleus test with Tradescantia pallida (Trad-MN) with acute exposure, and in V79 (V79-MN) cells, Comet assay in V79 and human lymphocyte, besides Trad-MN in situ at Site 1. In the Salmonella/microsome assay all samples presented frameshift mutagenic activity (-/+S9), most intense at Site 2 (rev/m(3)). The presence of nitro-PAHs and hydroxylamines in PM2.5 was shown by positive mutagenic responses with YG1021 and YG1024. In tests with Trad-MN, no significant genotoxic responses were found (MN %). In V79-MN a genotoxic response was not found. The Comet assay damages were found in the DNA at Site 1 in both cell systems. Non-detection of genotoxicity with Trad-MN at sites or in environmental samples from polluted areas detected using other biomarkers suggests the need for careful evaluation when biomonitoring genotoxic compounds using plants. The microsuspension assay in Salmonella/microsome was sensitive to detect and identify different classes of airborne mutagenic compounds present in fine particulate matter in Porto Alegre city, showing that monitoring air quality with PM2.5 using this methodology is relevant. PMID- 23726540 TI - Phytotoxicity assessment of a methanolic coal dust extract in Lemna minor. AB - Coal mining generates negative effects on environment, human health, hydrodynamics of mining areas and biodiversity. However, the impacts of this activity are less known in plants. Lemna minor is one of the most commonly used plants in aquatic toxicity tests due to its ubiquitous distribution in ponds and lakes, culture conditions and the free-floating habitat that exposes it to hydrophobic as well as dissolved compounds. The goal of this research was to evaluate the effects of a methanolic coal dust extract on L. minor. Macrophytes were exposed to six different concentrations of coal extract (from 7.81 to 250 mg/L) for 5 days, following the OECD test guideline 221. The coal extract had a half inhibitory concentration (IC50) of 99.66 (184.95-54.59) mg/L for the number of fronds. Several signs of toxicity such as chlorosis, reduction in the size of the fronds, abscission of fronds and roots, and the presence of necrotic tissues were observed at concentrations lower than the IC50. Preliminary Gas Chromatography-Mass Spectrometry analysis of the coal dust extract revealed the presence of several compounds, including, among others, alkanes, carboxylic acids and polycyclic aromatic hydrocarbons (PAHs), these lasts, may be responsible for some of the observed effects. These results demonstrated that coal dust has phytotoxic effects and should not be considered as an inert material. PMID- 23726541 TI - Bioequivalent antiepileptic drug switching and the risk of seizure-related events. AB - BACKGROUND: Older antiepileptic drugs (AEDs) are known to have a narrow therapeutic index. As a consequence, switching between bioequivalent AEDs remains controversial in the management of epilepsy. We investigated the association between A-rated switching of each class of currently available AED and emergent treatment for a seizure-related event. METHODS: We used a case-control method and claims data from the 2010 to 2011 Truven Health MarketScan((r)) Commercial Claims Database to estimate the risk of seizure following a medication switch. Cases and controls with an epilepsy diagnosis were identified by emergency/inpatient or outpatient visit claims, respectively. Cases and controls (N=9110) were matched 1:1 by age, epilepsy diagnosis category and seizure medication. The exposure was defined as a switch between A-rated AEDs during the 90 days prior to index date. Conditional logistic regression was used to estimate the association, adjusting for gender, baseline Deyo-Charlson Comorbidity Index (0, 1, 2, or 3+), region (Northeast, Central, South, and West), and total AED medications. RESULTS: A switch between A-rated AEDs occurred in 1053 (23.2%) cases and 827 (18.1%) matched controls. The unadjusted and adjusted odds ratios of a seizure-related event for switching were 1.38 (95% CI: 1.25-1.52) and 1.27 (95% CI: 1.14-1.41), respectively. The independent risk of an event also increased with each category increase in the Charlson score (CCI=1: 1.17, 95% CI: 1.02-1.33; CCI=2: 1.33, 95% CI: 1.09-1.62; CCI=3+: 1.99, 95% CI: 1.64-2.41). Older AEDs had infrequent switches compared to newer agents and were not associated with events. DISCUSSION: We found a modest association between AED switching and seizure related events. Our analysis suggests that the behavior of switching alone may lead to seizure-related events regardless of the medication or type of switch. Other disease or environmental characteristics may contribute to this association. Based on these and other findings, health care professionals and patients should be cautious about switching bioequivalent AEDs. PMID- 23726542 TI - Therapeutic advances in pediatric multiple sclerosis. PMID- 23726543 TI - Early total parenteral nutrition in very low birthweight infants: is it safe? Is it worth it? PMID- 23726544 TI - Postural orthostatic tachycardia syndrome with increased erythrocytic hydrogen sulfide and response to midodrine hydrochloride. AB - OBJECTIVES: To evaluate the use of erythrocytic hydrogen sulfide (H2S) in predicting the therapeutic efficacy of midodrine hydrochloride for children with postural orthostatic tachycardia syndrome (POTS). STUDY DESIGN: Fifty-five children were included in this study, involving 28 children with POTS (POTS group) and 27 healthy children (control group). Children in the POTS group received midodrine hydrochloride treatment. Erythrocytic H2S production was measured; a receiver operating characteristic curve was used to assess if erythrocytic H2S could predict the therapeutic response to midodrine hydrochloride treatment. RESULTS: H2S production from erythrocytes was significantly higher in the POTS group than in the control group (P < .01). H2S production was also significantly higher in responders to midodrine hydrochloride than in non-responders (P < .05). The change in symptom score and baseline erythrocytic H2S production had a positive linear relationship (P < .01). There was also a positive correlation with the change in heart rate (P < .05). The receiver operating characteristic curve showed an area under curve value of 0.813. Erythrocytic H2S production yielded a sensitivity of 78.9% and a specificity of 77.8% in predicting the efficacy of midodrine hydrochloride therapy for children with POTS. CONCLUSION: Erythrocytic H2S could serve as a useful predictor of therapeutic response to midodrine hydrochloride in children with POTS. PMID- 23726545 TI - Self and parent perspectives on health-related quality of life of adolescents born very preterm. AB - OBJECTIVES: To test whether health-related quality of life (HRQL) based on societal standards differs between very low birth weight/very preterm (VLBW/VP) and full-term (FT) adolescents using self and parent proxy reports. Also, to examine whether self and parent reported HRQL is explained by indicators of objective functioning in childhood. STUDY DESIGN: This prospective cohort study followed 260 VLBW/VP adolescents, 12 VLBW/VP adolescents with disability, and 282 FT adolescents. Objective functioning was assessed at 8.5 years; HRQL was assessed at 13 years with the Health Utilities Index Mark 3 (HUI3). RESULTS: Adolescents reported more functional impairment than their parents especially in the psychological aspects of health. The mean difference in HUI3 multi-attribute utility scores between FT and VLBW/VP adolescents was small (parents: 0.91 [95% CI, 0.90, 0.92] vs 0.88 [95% CI, 0.86, 0.90]; adolescents: 0.87 [95% CI, 0.85, 0.89] vs 0.84 [95% CI, 0.82, 0.86]), but high for VLBW/VP adolescents with disabilities (0.18, 95% CI, -0.04, 0.40). Objective function did not predict HRQL in FT adolescents but contributed to prediction of HRQL in VLBW/VP adolescents without disabilities. Different indicators of objective functioning were important for adolescent vs parent reports. More variation in HUI3 scores was explained by objective function in VLBW/VP parent reports compared with adolescent reports (25% vs 18%). CONCLUSIONS: VLBW/VP adolescents reported poorer HRQL than their FT peers in early adolescence. Improvement in HRQL as VLBW/VP children grow up is, at least partly, explained by exclusion of the most disabled in self reports by VLBW/VP adolescents and the use of different reference points by adolescents compared with parents. PMID- 23726548 TI - Twitter as a source of vaccination information: content drivers and what they are saying. AB - Twitter is a popular source of health information. This study reports a content analysis of posts about vaccinations, documenting sources, tone, and medical accuracy. Results can help explain patient knowledge and directions for educational campaigns. A set of 6,827 tweets indicates professional sources were shared most and treated positively. Two-thirds of shared medical content were substantiated. One-third of messages were positive, counter to other research and suggesting that users apply critical thinking when evaluating content. PMID- 23726549 TI - Journal Club: Twitter as a source of vaccination information: content drivers and what they're saying. AB - This Journal Club reviews a study on the use of Twitter as a source of health related information. PMID- 23726551 TI - Impact of health care worker policy awareness on hand hygiene and urinary catheter care in nursing homes: results of a self-reported survey. AB - Utilizing a self-administered questionnaire in 440 health care workers (81% response rate), we evaluated the impact of health care workers policy awareness on hand hygiene and urinary catheter care in nursing homes. We show that health care workers aware of their nursing home policies are more likely to report wearing gloves and practicing hand hygiene as per evidence-based recommendations during urinary catheter care compared with those who are unaware of their facility policies. PMID- 23726552 TI - Snapin accelerates exocytosis at low intracellular calcium concentration in mouse chromaffin cells. AB - Snapin associates with SNAP-25 and with assembled SNARE complexes, stabilizing the coupling between Synaptotagmin-1 and SNAP-25. Deletion of Snapin reduces releasable pools of vesicles in chromaffin cells and reduces synchronous release of neurotransmitter in cortical neurons. Snapin deletion leads to a deficit in exocytosis at low calcium concentration with no change in the threshold calcium concentration for exocytosis in chromaffin cells. In order to determine whether Snapin deletion alters release rates or calcium dependence, we examined the effect of overexpression of wild type Snapin on readily releasable pool kinetics and pool size in mouse chromaffin cells. Modest increases in intracellular calcium induced by flash-photolysis unmasked a rapidly releasing component of secretion which was enhanced when Snapin was overexpressed. This result indicates that Snapin allows rapid release at lower intracellular calcium levels at which release of the remaining RRP occurs more slowly. PMID- 23726553 TI - A student leadership model for promoting educational programs in organ donation and transplantation. AB - The global organ shortage is the strongest factor for the increase in transplant wait time and deaths on waitlists. Here we describe a model for involving high school students in education research around organ donation and transplantation and capitalize on the strength of a pre-existing educational program offered by the local organ procurement organization (OPO). While training in education research at Cleveland Clinic, a high school student embarked on a collaborative project with the local OPO. The project involved evaluating three educational programs, selecting the most appropriate program for administration at her school, coordinating with the student's school administration and teachers, administering an assessment tool for the effectiveness of the program, and analyzing the results. The local OPO program that was selected for implementation consisted of a video presentation entitled "Share your life, share your decision" prepared by the United States Health Resources and Services Administration (HRSA), lectures by invited speakers and an educational assessment (pre- and post education). The assessment survey included 3 multiple choice and 7 true/false questions. Compared to the over 2500 programs administered in the last 5 years by the local OPO, this program had a higher volume of participation (n = 353 compared to an average of 150 students/day). Students correctly classified transplantation status of more organ and tissues post-education (P < .0001 for both). For 5 out of the 7 true/false questions, students correctly answered questions more frequently post-education (P <= .002 for all). This experience included for the first time a formal assessment of the program which will be utilized to address targeted areas for specific improvements. This student collaborative model of involving students in organ donation and transplantation related education research has the potential to promote and maximize the effectiveness of educational programs targeting their peers. PMID- 23726554 TI - Current status of in-hospital donation coordinators in Japan: nationwide survey. AB - OBJECTIVES: When the Japanese Organ Transplantation Act was issued, the Japanese Organ Transplantation Network (JOT) was established in 1997. JOT lists recipients, assesses and manages organ donors, and educates publics and headquarters for organ donations. JOT procurement transplant coordinators (PTC) play roles in obtaining consent from relatives for organ donation, donor evaluation and management, organ recovery management, organ transport, and care of donor families during and after donation. Every prefecture has at least one PTC who is mainly working in public education and hospital development. They also help the JOT PTC at the time of organ procurement. Most prefectures commission hospital staff in the procurement hospital to be an in-hospital PTC (In-Hp PTC), who make their hospital staff aware of organ donation and support organ procurement. Although the Act was revised in 2010 with brain-dead organ donation increased from 13 to 44 cases yearly, the number was still extremely smaller than other developed countries. In these circumstances, In-Hp PTC may play greater roles to increase donation and smooth procurement procedures Our primary aim was to describe the current status of In-Hp PTC in Japan. MATERIALS AND METHODS: Between December 15, 2011, and January 31, 2012, we invited 1889 In-Hp PTC to complete a letter survey using a self-designed questionnaire. In all, 56 In-Hp PTC (40%) completed and returned it. RESULTS: The occupation of the respondents was nurse (66%), physician (18%), or other (16%). Although 52% of respondents belonged to the hospital, which was designated for brain-death organ donation by the government, only 46% had any experience with a cadaveric donor. Only 2% were full-time In-Hp PTC. They mainly played a role in preparing their own manual for organ procurement (57%), providing in-hospital lectures (44%) or their own simulation exercise (29%), as well as coordinating donation cases. Although 77% had attended seminar about organ donation provided by JOT or the prefecture PTC, 93% wanted more professional education. However, it was difficult for them to attend these activities, to manage a rare and sudden donation case, and to find time to learn about organ donation because they had another post. The topics that they wanted to learn were donor family care (72%), overall organ/tissue donation procedures (65%), the role of In-Hp PTC (67%), simulations of donation (65%), legislation and social system of organ donation (61%), medical indications for donation (61%), current status of donation and transplantation in Japan (57%), donor management (56%), and case studies (49%). There were significant variations in the topics of interest among the occupations. As they had another post, they could find only a short period (1 or 2 days) to take professional education, such as lectures. Therefore, it was difficult for them to attend practical on-the-job training. CONCLUSIONS: To establish an organ procurement system and increase organ donation, In-Hp PTC have important roles in Japan. However, none is a full time In-Hp PTC. Most In-Hp PTC require more professional education. A systematic education program for each occupation must be established soon. PMID- 23726555 TI - Effect of a legal initiative on deceased- and living-donor kidney transplantation in Israel. AB - The severe organ shortage in Israel has prompted many patients to undergo kidney transplantation abroad. In May 2008, the Israeli Knesset approved the Israel Transplant Law prohibiting organ trade and disallowing health insurers to reimburse the cost of illegal transplantation abroad. The aim of this study was to assess the initial effect of the law on kidney transplantations inside and outside the country. The number of kidney transplantations performed inside and outside Israel was compared between the 3-year periods before and after implementation of the transplant law (2006-2008 and 2009-2011). Further analysis compared the number of deceased-donor and live-donor transplantations performed in Israel during the same periods. The results showed that the number of transplants performed abroad dropped significantly, from a median of 143 per year during 2006-2008 to <45 per year during 2009-2011. There was a parallel increase in the number of kidney transplantations from living donors, from a median of 56 transplants per year in 2006-2008 to 78 per year in 2008-2011, with a peak of 117 transplants in 2011. In conclusion, the Israel Transplant Law has dramatically affected kidney transplantation practices in Israel by reducing transplantation tourism and increasing living-donor kidney transplantations. PMID- 23726546 TI - Neurodevelopmental outcome of extremely low birth weight infants with Candida infection. AB - OBJECTIVE: Candida remains an important cause of late-onset infection in preterm infants. Mortality and neurodevelopmental outcome of extremely low birth weight (ELBW) infants enrolled in the Candida study were evaluated based on infection status. STUDY DESIGN: ELBW infants born at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers between March 2004 and July 2007 who were screened for suspected sepsis were eligible for inclusion in the Candida study. Primary outcome data for neurodevelopmental impairment (NDI) or death were available for 1317 of the 1515 infants (87%) enrolled in the Candida study. The Bayley Scales of Infant Development-II or -III was administered at 18 months' adjusted age. A secondary comparison was performed with 864 infants enrolled in the NRN Generic Database during the same cohort who were never screened for sepsis and therefore not eligible for the Candida study. RESULTS: Among ELBW infants enrolled in the Candida study, 31% with Candida and 31% with late-onset non-Candida sepsis had NDI at 18 months. Infants with Candida sepsis and/or meningitis had an increased risk of death and were more likely to have the composite outcome of death and/or NDI compared with uninfected infants in adjusted analysis. Compared with infants in the NRN registry never screened for sepsis, overall risk for death were similar but those with Candida infection were more likely to have NDI (OR 1.83, 95% CI 1.01-3.33, P = .047). CONCLUSIONS: In this cohort of ELBW infants, those with infection and/or meningitis were at increased risk for death and/or NDI. This risk was highest among those with Candida sepsis and/or meningitis. PMID- 23726556 TI - Reluctance to donate organs: a survey among medical students. AB - BACKGROUND: The organ shortage is a major obstacle in the development of the modern surgical life-saving techniques of transplantation. Romanians seem to be more reluctant toward deceased organ donation than most Europeans. A significant percentage of respondents from an European survey (31%) were unable to give a reason for their unwillingness to donate. Aim of our study was to assess medical students' perception of deceased donation for transplantation and to identify sources of unwillingness to donate organs from a deceased next of kin. MATERIALS AND METHODS: I performed a cross-sectional study involving 140 randomly selected medical students of mean age 20 years. The self-administered questionnaire contained 22 items; informed consent was obtained prior to completion. RESULTS: The percentage of unwillingness or hesitancy to donate an organ from a deceased close relative was 38.6%, without significant differences in gender or living area. Desire for body integrity preservation and respect toward the deceased person were the most often indicated reasons to excuse the donation denial. Religious motives were indicated by only tbree subjects; church attendance was irrelevant in relation to willingness to donate. CONCLUSIONS: Emotional and moral factors were most frequently invoked by medical students as justification for indecision or refusal of organ donation for transplantation. PMID- 23726557 TI - Spontaneous decision of organ donation in patients signing informed consent for liver transplantation. AB - The shortage of postmortem donor organs is a well-known problem in Germany. Willingness in the general population is 80%, but less than 14% have an organ donor card. We evaluated the free decision of liver transplant candidates who filled out a donor card before signing the informed consent for the transplant procedure. We analyzed 122 patients of mean age 55.9 years (range, 15.4-74.1) who signed an informed consent for liver transplantation between January 10, 2007, and January 24, 2012. The patients received the original text of the German organ donor card with tick boxes on the informed consent form for liver transplantation. All patients were informed that their decision had no impact on further management. Patients were able to choose between (1) becoming a donor, (2) refusal, (3) transfer of the decision to another person, or (4) no decision. All patients signed the informed consent to be listed for liver transplantation: 73.8% (n = 90) chose to become a donor; 5.7% (n = 7) refused; 5.7% (n = 7) transferred the decision to another person; and 14.8% (n = 18) did not come to a decision. Interestingly, not all candidates for liver transplantation were willing to become an organ donor in the time of expressed consent. However, willingness to sign the donor card was much higher among liver transplant candidates compared with the general population. PMID- 23726558 TI - Community attitudes toward kidney donation in India. AB - BACKGROUND: The poor progress in improving kidney donation rates in India spurred this research. METHODS: We first explored the awareness level and attitude of adults in relation to kidney donation as a function of age, gender, and religion (study A). We then ascertained the attitude of individuals towards cadaver kidney donation (study B). The sample in study A consisted of 84 adults from Mumbai representing both genders, 2 age groups, and 3 major religions. The sample in study B consisted of 155 participants from Mumbai, representing both genders, 4 religions, and a varied age group. A questionnaire was employed in both studies. RESULTS: Participants had an average level of awareness regarding kidney donation (M = 29.25; SD = 5.91) and a neutral attitude toward it (M = 255.71; SD = 93.4). Younger adults (M = 32.05) had a higher level of awareness than older adults (M = 28.63; P = .008). Females (M = 280.31) had a more positive attitude than males (M = 231.10; P = .01). Hindus (M = 32.39) had a higher level of awareness than Muslims (M = 28.42; P = .04). Hindus (M = 279.00) and Christians (M = 283.90; P = .006) had a more positive attitude than Muslims (M = 204.22). After death, 76% were willing to donate their kidneys and 63%, those of their family members. Improving the quality of life of the patient with chronic kidney disease was the primary reason for donating a kidney. Prohibition by religion and anticipated objection by other family members were reasons advanced for not donating kidneys. CONCLUSIONS: These findings can help to develop an education program to enhance kidney donation. PMID- 23726559 TI - Estimated organ donor potential in German maximum care hospitals. AB - BACKGROUND: The decreasing number of organ donors in Germany remains a major issue in transplantation medicine. The aim of this study was to estimate the organ donor potential at German maximum care hospitals. METHODS: To critically review potential in comparison with organ donation rates in 2010. We separated Maximum care hospitals into university institutions (A-level) and centers with a neurosurgical unit (B-level) based upon the size of hospital as indicated by the total number of beds. To estimate the number of possible organ donors, we adopted the American model previously published by Sheehy et al: the potential was 0.015 organ donors/bed/year for hospitals with more than 350 beds. RESULTS: In 2010 overall in Germany there were 1296 organ donations resulting in 4205 transplanted organs. University hospitals realized 397 organ donations namely 0.008 organ donors/bed/year (57% of calculated organ donor potential), whereas B-level hospitals accounted for 555 of organ donors with a rate of 0.007 organ donors/bed/year (48% of calculated organ donor potential). Large variations in realizing organ donations occurred among single hospitals. CONCLUSION: Our results indicated a substantial potential to increase organ donation rates in German maximum care hospitals. These hospitals (n = 145) are responsible for 73% (non-maximum care hospital n = 1195) of the absolute organ donor pool. Further studies are needed to evaluate possibilities to address the organ shortage particularly with regard to donor detection in intensive care units and also the refusal rate by families. PMID- 23726560 TI - A new kidney allocation policy in Chile: computer-based simulations. AB - INTRODUCTION: Kidney allocation should reach a balance between equity and efficiency. In Chile kidneys are allocated based on ABO matching, first to medical priorities and then according to a point scheme considering human leukocyte antigen (HLA) match (60%), waiting list time (20%), and panel-reactive antibodies (PRA; 20%); pediatric recipients receive extra points. A new policy maintains ABO matching and medical priorities as the first step, but incorporates other successive steps: previous living donors donors, 0 mismatch, pediatric recipients, and finally all other recipients according to a point scheme incorporating recipient age, HLA match, PRA, and time on waiting list with similar proportions. We compared the resulting transplantations using the new versus the older allocation policy. METHODS: We analyzed computer-generated simulations using actual patients (N = 1176) on the Chilean waiting list in 2011 with the 300 donors over the previous 3 years. RESULTS: The new policy a significantly decreased recipient age from 43 +/- 0.3 years to 41 +/- 0.3 and increased the number of 0-mismatched transplantations from 3% to 4%. The mean HLA mismatch increased from 2.8 +/- 0.1 to 3.6 +/- 0.1. Waiting time increased from a mean of 38 +/- 1 months to 40 +/- 1 months, but patients remaining on the waiting list had less waiting time with the new rule. CONCLUSIONS: With the proposed changes younger patients are being privileged and the importance of compatibility is diminished (except for 0-mismatched transplantations). The chance of a good match is directly related to the size of the recipient pool, thus an allocation policy that privileges HLA matching in a restricted recipient pool is especially unfavorable for younger patients. Including age of the recipient as a continuum can help to compensate for this lack of equity. Computer-generated simulations can help discern which policies are best suited for each country based on their local characteristics. PMID- 23726561 TI - Presumed consent legislation failed to improve organ donation in Chile. AB - BACKGROUND: Presumed consent legislation has been advocated by some as an effective measure to improve organ donation. In Chile, a new presumed consent legislation was passed, replacing an informed consent legislation. As of January 2010, Chilean citizens older than 18 years were considered to be organ donors unless they had previously declined donation. The aim of this study was to evaluate the impact of this legislation on donation rates at 2 years after its implementation. METHODS: Retrospective review of donor registries from Corporacio del Trasplante and Coordinacion Nacional de Trasplante between January 2000 and December 2011 revealed donation rates (donors per million population [pmp]), family refusal, and number/percentage of nondonors. RESULTS: Organ donation rates decreased after passage of the new law from 6.5 (n = 111) in 2009 to 5.4 in 2010 (n = 92) and 6.5 donors pmp in 2011 (n = 113). Mean donation rate from 2000 to 2009 (before presumed consent) was 8.31 and from 2010 to 2011 (after presumed consent) 5.95 donors pmp; which represents a 29% decrease. Family refusal fluctuated between 32% and 41% between 2000 and 2009, but increased to an all time high of 50.4% in 2011. Finally as of December 2011, 2,520, citizens appeared to be nondonors in the Registry, which roughly represents 37% of those renewing their identification card (IC) or driving license (DI). CONCLUSION: In Chile, presumed consent legislation not only did not increase but seems to have had a deleterious effect on organ donation, reflecting an increase in family refusals and a high percentage of nondonors in the registry. PMID- 23726562 TI - Does national sharing of kidneys donated after cardiac death lead to poorer outcomes? AB - BACKGROUND: Kidneys donated after cardiac death (DCD) represent an increasing proportion of transplant activity. There have been concerns that wider sharing of these kidneys increases the cold ischemic time (CIT) and leads to poorer outcomes. METHODS: DCD kidney transplantation was implemented in Scotland in 2005, with each center transplanting locally donated kidneys. A national sharing scheme of DCD kidneys was introduced in 2007, whereby kidneys are shared between the 2 renal transplant centers in the country. A single national multiorgan retrieval team carries out retrievals and kidneys are shipped directly to the 2 units. Donor and recipient demographic data, cold ischemic time, and outcome data were prospectively collected and compared within each center and between centers pre- and postintroduction of the sharing policy. RESULTS: Since 2005, 152 DCD kidney transplants have been performed. Since 2007, 68 kidneys were shared between the centers. Recipient demographics were comparable before and after the introduction for the sharing scheme. The CIT was significantly higher in Glasgow (14.30 +/- 3.79 hours) compared with Edinburgh (10.72 +/- 2.99 hours; P < .001, one-way analysis of variance [ANOVA] prior to the introduction of the sharing scheme. Following the implementation of kidney sharing, there was no significant difference in CIT between Glasgow and Edinburgh (10.50 +/- 3.34 hours vs 10.53 +/ 2.71 hours). A significant reduction in the CIT in Glasgow was noted after sharing was instituted (from 14.30 +/- 3.79 hours to 10.50 +/- 3.34 hours, P < .001, one-way ANOVA). Patient and graft survivals, acute rejection, and delayed graft function as well as 1-year renal function were comparable in both centers before and after the introduction of the scheme. CONCLUSION: Wider sharing of DCD kidneys should be encouraged, as it does not compromise clinical outcomes. A transparent and well-established sharing agreement, with no delays in the offering of DCD kidneys, may lead to an improvement in CIT. PMID- 23726563 TI - Kidney transplantation from donors after brain or cardiac death in China--a clinical analysis of 94 cases. AB - BACKGROUND: We analyzed outcomes of kidney transplantation (KTx) from donation after brain death (DBD) or cardiac death (DCD) in China under the current level of the health care system. METHODS: Among 94 KTx performed from February 2007 to March 2012 in two organ transplant centers in the south of China, 50 KTx were used DBD and 44 DCD donors. We retrospectively analyzed the clinical outcomes. RESULTS: At a mean follow-up of 25.5 months, the 1-year and 2-year graft survival rates were 96.8% and 95.2% respectively. Delayed graft function (DGF) occurred in 27.7% recipients, three of whom lost graft function. Among six observed acute rejection episodes, five were reversed. When compared to the DCD group in DBD patients were apt to recover from DGF. Serum creatinine decreased more promptly in the DBD than in DCD group. Serum creatinine in the DCD group increased after months 12, when it was significantly higher than that in the DBD group (P < .05). CONCLUSIONS: Kidney transplantation from DBD donors showed good outcomes with few complications. Although KTx from DCD donors showed a higher DGF rate and longer duration of graft recovery, we achieved favorable short-term clinical outcome using this source. PMID- 23726564 TI - Donor evaluation and management system (medical consultant system) in Japan: experience from 200 consecutive brain-dead organ donation. AB - PURPOSE: As the donor shortage is extremely severe in Japan because of a strict Organ Transplantation Act, special strategies must be established to maximize organ transplant opportunities. The purpose of this study was to evaluate our strategies to identify and manage 200 consecutive brain-dead organ donors. METHODS AND MATERIALS: We retrospectively reviewed the 200 donors procured since the Organ Transplantation Act was issued in 1997, including 118 males, a mean overall age of 45.1 years and cause of death being cerebrovascular disease (n = 119), head trauma (n = 37), and asphyxia (n = 44). DONOR EVALUATION AND MANAGEMENT SYSTEM: Since November in 2002, special transplant management doctors ("medical consultants") were sent to donor hospitals to assess organ function and identify transplantable organs. They also provided intensive care to stabilize hemodynamics and improve cardiac and lung functions by administering antidiuretic hormone intravenously and providing bronchofiberscopic pulmonary toilet. RESULTS: We obtained 146 heart, 1 heart-lung, and 154 lung (87 single and 67 bilateral), 175 liver (28 splitted liver), 142 pancreas (114 pancreas-kidney), 253 kidney and 12 small bowel grafts. Organs procured from 1 donor increased from 4.5 to 6.8 after applying these strategies. CONCLUSIONS: Although the number of cases was still small, the availability of organs and outcomes of transplantation have been acceptable. PMID- 23726565 TI - Use of liver grafts from anti-hepatitis B core-positive donors: a multicenter study in Argentina. AB - Liver transplantation success is limited by the availability of donors. To overcome this limitation, anti-core-positive donors are increasingly being accepted, but underutilization of this resource still occurs. We performed the current study to determine the prevalence of anti-core-positive donors in our region and to describe the management of these donors and their recipients. Between January 2005 and July 2011, the national transplant database included 2,262 registered liver donors among whom 106 (4.7%) were anti-core-positive including 59 (56%) discarded and 47 (44%) implanted organs. A median of 14.5 offers (range 4-60) were rejected before harvesting and implanting the accepted grafts. The only difference between the implanted and the discarded grafts was found for the alanine aminotransferase level, which was higher among the discarded ones (50 +/- 59 UI/L vs 25 +/- 16, P < .05). Among 40 recipients included in the study, 5 (12.5%) did not receive any prophylaxis; 18 (45%) a nucleos(t)ide analog 11 (25.5%), heptitis B immunoglobulin and nucleos(t)ide analogs and 6 (15%) pretransplant hepatitis B vaccination. Over a mean follow-up of 871 +/- 585 days, 4 de novo hepatitis B cases were identified at 545, 720, 748, and 1,080 days posttransplantation. None of these patients had received any prophylaxis. In all cases entecavir successfully controlled viral replication. We believe that better utilization of these donors and careful management of their recipients represent safe strategies to expand the liver donor pool in Argentina. PMID- 23726566 TI - Infection risk in kidney transplantation from uncontrolled donation after circulatory death donors. AB - BACKGROUND: Uncontrolled donations after circulatory death (DCD) present 2 well established risk factors for infection after kidney transplantation (KT): greater rates of delayed graft function (DGF) and antithymocyte globulin (ATG)-containing sequential therapies. METHODS: We performed a prospective cohort study of our 291 KT patients between November 2008 and July 2011 to compare the incidences of infection between DCD (n = 87) and donation after brain death (DBD; n = 204) recipients. Most DCD donors were uncontrolled Maastricht categories 1 or 2. Backward stepwise Cox proportional hazards models were used to assess the impact of DCD on the primary study outcome. RESULTS: As compared to the DBD group, DCD recipients were younger, less likely to have undergone previous transplantations, exhibited lower dialysis vintage, and displayed a greater incidence of DGF and graft loss, but lower incidence of acute rejection episodes. There were no differences in the non-death-censored graft survival at 2 years (log-rank P = .835). The DCD group showed lower cumulative incidences of overall, bacterial, cytomegalovirus (CMV), and non-CMV viral infections (P < .05 for all). Multivariate analysis, associated DCD with a lower risk of overall infection (hazard ratio: 0.41; 95% confidence interval: 0.28-0.60; P = .012), an effect that remained when the analysis was restricted to patients receiving ATG induction therapy. Finally, there were no differences in the cumulative incidence of overall infection when DCD recipients were compared with age-matched DBD controls: 43.7% vs 47.1% respectively (P = .648). CONCLUSION: Despite the higher rate of DGF and the use of ATG-containing sequential therapy, uncontrolled DCD policies were safe in terms of the risk of post-transplant infection. PMID- 23726567 TI - A positive anti-nuclear antibody result does not contraindicate living kidney donation. AB - Autoantibodies may precede the clinical onset of disease in up to two-thirds of patients with systemic lupus erythematosus (SLE). There is thus concern that antinuclear antibody (ANA) positivity in living kidney donors may eventuate in development of lupus nephritis post-uninephrectomy. Post-uninephrectomy, we routinely examine living kidney donors at 6 weeks, 6 months, 12 months, and annually thereafter. We performed a retrospective review of living kidney donors who had undergone uninephrectomy between July 1, 1999, and December 1, 2008. Data were collected for pre- and post-uninephrectomy renal function, proteinuria, hematuria, ANA, and anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibodies. Among 68 living donor uninephrectomies performed during the study period, we excluded patients with no pre- uninephrectomy ANA or defaulted postoperative follow-up (n = 2). Twelve (18.2%) living donors were ANA-positive (M:F = 4:8) with a median titer of 1:100 (range, 1:100-1:800); 1 was transiently anti-dsDNA-positive. There were no significant differences between ANA-positive and ANA-negative donors in baseline demographics or pre-uninephrectomy creatinine clearance (median 108.0, range 79-179 mL/min vs. 106, range 58-172 mL/min, P = NS). Only 1 ANA-positive patient displayed transient microscopic hematuria (8 red blood cells); none had proteinuria pre-nephrectomy. Median follow-up was 63.5 (range, 21.2-139.3) months. At last clinic review, none of the ANA-positive donors had developed clinical symptoms or signs of SLE. Comparing ANA-positive and ANA-negative live donors at 5 years post-uninephrectomy, there were no significant differences in creatinine clearance (median 86.5, range 67-112 mL/min vs. 85.0, range 35-154 mL/min, P = NS), total urine protein (median 0, range 0 0.196 g/24 h vs 0, range 0-0.190 g/24 h, P = NS), or presence of hematuria (16.7% vs 33.3%, P = NS). Isolated ANA positivity does not contraindicate living kidney donation. Up to 5 years post- uninephrectomy, the risk of developing clinical lupus among low-titer ANA-positive individuals remains low. PMID- 23726568 TI - Restored kidney graft from urologist referrals for renal transplantation. AB - BACKGROUND: A new transplantation program using kidneys after a small tumor excision was initiated in Western Australia in February 2007. The aim of this study was to report the outcomes over 5 years. METHODS: Local urologists were encouraged to refer the kidney to the transplantation service when considering a radical nephrectomy. Recipients are selected according to strict criteria. Between February 2007 and February 2012 24 of 30 referred kidneys were restored for transplantation. Average donor age was 53.4 (range, 32-75) years while the recipients were 66.3 (range, 57-80) years. Twenty-one kidneys were restored after excision of a small tumor (<3.3 cm) and 3 kidneys were restored after being obtained from patients who had experienced complicated ureteric injuries secondary to laparotomy and colectomy. RESULTS: Nineteen of 24 grafts displayed immediate function, 4 had delayed function, and 1 had nonfunction. The first 3 patients developed urinary leakages, which all resolved by subsequent management. One graft showed a pseudoaneurysm on the day 1 Doppler ultrasound, requiring interventional embolization. All patients but 1 have been off dialysis with satisfactory graft function; creatinine (Cr) levels ranged from 70 MUmol/L to 330 MUmol/L. There was no tumor recurrence on close follow-up from 6 to 55 months (median, 26). Three patients died due to other medical issues. CONCLUSION: Kidneys could be restored from urologic disease for transplantation after excision of a small tumor with satisfactory outcomes at an average follow-up of 26 months. Frozen section is necessary to ensure the clearance of the tumor prior to transplantation. A modification of the surgical technique has minimized urine leakage and pseudoaneurysm formation after tumor resection. PMID- 23726569 TI - Characteristics of potential living kidney donors and recipients: donor disqualification reasons--experience of a Polish center. AB - INTRODUCTION: Kidney transplantation is efficacious as a renal replacement, particularly pre-emptive living donation. In Poland, the rate of transplantation of living donor kidneys is only 3%. The aim of the study was to identify the most common reasons to disqualify a potential living kidney donor. METHODS: We evaluated 124 kidney donor candidates for 111 potential recipients at 1 medical center for genders and ages of donor and recipient; thus relation, donor disqualification reasons, number of potential donors for a particular recipient, prior transplantations, and kidney vasculature. RESULTS: The 111 recipients of ages 2-62 years had, 1, 2, or 3 potential donors were tested in 101, 1, and 7, cases respectively. We had 18.9% recipients referred for pre-emptive transplantation; 59.5% were on haemodialysis and 21.6% on peritoneal dialysis. In all, 89% recipients sought first kidney transplantations. Kidneys were procured from 49/124 (39.5%) of the initially evaluated donors. The full examination was completed by 92 potential donors with 68/124 donors disqualified early. Single and multiple renal arteries were detected in 56 and 36 potential donors, respectively. Donor disqualification was due to medical contraindications (39.7%), earlier transplantation from a deceased donor (25%), immunologic constraints (23.5%), donor consent withdrawn (6%) or psychological and social reasons (4.4%). CONCLUSIONS: A considerable number of donor candidates are disqualified for medical reasons. PMID- 23726570 TI - Impact of early incentive spirometry in an enhanced recovery program after laparoscopic donor nephrectomy. AB - BACKGROUND: This study aimed to assess the impact of early incentive spirometry on the incidence of chest infection in patients undergoing laparoscopic donor nephrectomy. METHODS: A retrospective review on all consecutive laparoscopic donor nephrectomies (LDN) performed at a single institution from January 2008 to August 2012 was performed. We performed 84 LDN. Seventy patients had epidural analgesia continued for 48 hours postoperatively and 14 had a combination of spinal followed by oral analgesia. Incentive spirometry was introduced from July 2010 and 45 of the 84 donors used the spirometer as taught, both pre- and postoperatively. RESULTS: We performed 84 LDN; 39 patients did not receive incentive spirometers and had postoperative chest physiotherapy started on postoperative day 1. Of the 45 patients given incentive spirometers, 44 started using their spirometers as taught, after recovery once they were settled in the ward, 1 patient started the exercises the following day. In the group who received no spirometer, 5 patients had a chest infection. In the group of patients who started using their spirometers in the early perioperative period (44/45), no patient developed a chest infection. One patient in this group was excluded from the analysis because he started spirometer exercises on postoperative day 1. This patient did develop a chest infection. CONCLUSIONS: Our results suggest that early introduction of incentive spirometry after LDN significantly reduces the incidence of chest infection (P < .05); however, this benefit may be lost if the introduction of spirometry is delayed. PMID- 23726571 TI - Factors affecting the regeneration of liver graft after living related liver transplantation: a preliminary study. PMID- 23726572 TI - Predicting quality of deceased donor kidneys: the harvesting surgeon as a prognostic factor? AB - INTRODUCTION: The quality of donor organs is a crucial factor with regard to graft survival and function in kidney transplant recipients. The prognostic importance of surgeon-related factors during organ harvesting on graft quality has been almost unknown. Our aim was to find out whether surgical expertise as reflected by the time required for kidney retrieval influences graft survival. METHODS: In this retrospective study, we analyzed the records of 200 patients who received a cadaveric renal graft at our institution between 2000 and 2005. Graft survival and function were examined at discharge and after 1, 2, 3, and 5 years post-transplantation with the estimated glomerular filtration rate (GFR) using the Cockroft-Gault formula as a surrogate marker. We gathered the pertinent data on harvesting procedures from Eurotransplant donor reports. We correlated the length of time from cold organ perfusion to nephrectomy with graft survival. Statistical evaluation was performed using correlation analysis. RESULTS: There was no statistically significant correlation between the time the surgeon needed for kidney retrieval (starting from cold perfusion) and the outcome of transplantation. CONCLUSION: It would seem to be obvious that the longer a cadaveric donor kidney remains in the donor's body after cold perfusion, the worse the outcome will be. Our findings, however, did not prove this hypothesis even when looking at abdominal and combined abdominal and thoracic harvesting procedures separately. PMID- 23726573 TI - Delayed graft function: risk factors and the effects of early function and graft survival. AB - INTRODUCTION: Delayed graft function (DGF), a well-known immediate postoperative complication is defined as the need for dialysis during the first week after deceased donor kidney transplantation. It affects 25% to 50% of recipients. In this study we identified risk factors for DGF and its impact on patient and graft survivals. METHODS: We retrospectively analyzed medical records from renal transplant recipients aged above 18 years who received a deceased donor kidney graft between November 2008 and December 2011, excluding kidney losses during the first week. RESULTS: Among 137 transplantations, 64 (46.5%) displayed DGF. Multivariate analysis showed secondary renal disease (OR 3.7, CI 1.36-10.30; P = .011), HLA mismatches > 3 (OR 4.4, CI 1.53-12.51; P = .006) and donor urine output <= 3000 ml/24h (OR 25.8, CI 3.60-185.70; P = .001) to be significant risk factors for DGF. The hospitalization time was longer in the DGF group (38,2 +/- 20,75 vs. 25,6 +/- 8,18; P < .001). At 1 month, DGF group showed worse graft function based upon serum creatinine: 207.7 +/- 148.52 vs 118.1 +/- 36.63 MUmol/L (P < .001). At 1 year follow-up, incidence of biopsy-proven acute renal rejection episodes was higher in the DGF (28; 51,9%) vs. the non-DGF group (18; 33,3%; P = .05). The 1-year recipient survival in DGF and no DGF groups were 90% vs 97% respectively (P = .124). With 1-year death censored graft survivals of 92% vs 100% respectively (P = .062). CONCLUSION: Secondary renal disease, HLA mismatches and lower donor urinary output were associated with a greater incidence of DGF, leading to prolonged hospitalizations and an increased risk for an acute rejection episode. PMID- 23726574 TI - Urinary neutrophil gelatinase-associated lipocalin after kidney transplantation: is it a good biomarker to assess delayed graft function? AB - Delayed graft function (DGF) is a common complication after transplantation. Its incidence is increased among patients receiving a graft from an expanded-criteria donor. Urinary neutrophil gelatinase-associated lipocalin (uNGAL), an acute kidney injury marker, could in the first days after transplantation be an early marker of DGF. We collected urine samples from 38 renal transplant recipients on days 1, 3, 6, and 10 post-transplantation, and months 1 and 6 creatinine to determine uNGAL, serum creatinine, Cystatin C, and albumin/creatinine ratio. We divided the patients into 2 groups, based on whether they developed DGF. We observed that mean uNGAL concentrations, Cystatin C, serum creatinine, and albumin/creatinine ratio were significantly lower in the non-DGF cohort on all measured days. uNGAL at day 3 showed a positive correlation with serum creatinine at day 10 (R = 0.58; P < .00) and day 30 (R = 0.57; P = .016) as well as with the length of hospital stay (r = 0.47; P < .00). Receiver operating characteristic analyses performed to assess the potential of uNGAL to predict DGF showed an area under the curve for day 3 of uNGAL of 0.917 (confidence interval [CI], 0.79-1.00; P = .00), with an optimal cutoff level of 124 ng/mL, sensitivity of 80% (CI, 62% 97%), and specificity of 83% (62%-104%; P = .001). In the first days after transplantation, uNGAL could be an early marker of DGF, providing additional information to standard biomarkers and potentially helping clinicians to take early measures to mitigate DGF. PMID- 23726575 TI - Should we do cardiac stress tests in asymptomatic renal transplant candidates? AB - BACKGROUND: There is controversy regarding the best method and benefit of cardiac evaluation of asymptomatic renal transplant candidates. The positive predictive value of ischemia on a noninvasive stress test was ~5%-10% in Kidney Disease Outcomes Quality Initative (KDOQI), American Society of Transplantation (AST), and Lisbon guidelines. We compared prediction of cardiac events with the use of simple transthoracic echocardiography versus a noninvasive stress test in asymptomatic candidates. METHODS: We selected asymptomatic patients with good functional capacity who would be recommended a cardiac stress test by both KDOQI and AST guidelines, we excluding those with a history of cardiovascular disease. Group A (n = 124) underwent only echocardiography, and group B (n = 41) underwent echocardiography and noninvasive stress test. We measured the incidences of cardiac events and cardiac death within 3 years after transplantation. RESULTS: The mean age of group A was 39 +/- 7 and group B 40 +/- 5 years. Diabetic patients among groups A and B were 8.8% (11/124) and 9.7% (4/41), respectively. The mean duration of dialysis was 2.9 +/- 5 years. Only 4 group B patients showed a positive result on the noninvasive stress test, but they had no obstructive disease on coronary angiograms. The incidences of ischemic heart disease after transplantation of groups A and B were 4% (5/124) and 4.8% (2/41), respectively (P = .88). There was no death due to cardiac events in either group. CONCLUSIONS: In this study, simple echocardiography showed an ability similar to stress test to predict ischemic heart disease in asymptomatic renal transplant candidates with good functional capacity, relatively younger age, lower prevalence of diabetes, and shorter duration of dialysis. PMID- 23726576 TI - Comparison of clinical outcomes in hepatitis B virus-positive kidney transplant recipients with or without pretransplantation antiviral therapy. AB - BACKGROUND: Antiviral agents have improved the outcomes of hepatitis B virus (HBV)-positive kidney transplant recipients (KTRs). Preemptive therapy has been the main approach to forestall HBV reactivation. We sought to compare prophylactic and preemptive approaches. METHODS: We divided the 69 HBV-positive KTRs into treatment and historical control groups, according to the time of starting pretransplantation antiviral therapy. The treatment group was further divided into prophylactic and preemptive therapy groups. RESULTS: The treatment group showed a significant improvement in 10-year graft (82% vs 34%) and patient (91% vs 57%) survivals. Among the historical control group, the main causes of graft failure were patient deaths (68%), which were mostly caused by liver diseases. In contrast, there was no liver-related death in the treatment group. In addition, there was no difference in graft or patient survival between the prophylactic and preemptive groups, but the incidence of HBV reactivation was lower in the prophylactic group. Antiviral therapy was an independent factor for the improved patient survival (P = .005). CONCLUSIONS: Pretransplantation antiviral therapy is essential to improve clinical outcomes. Prophylactic may be better than preemptive antiviral therapy to decrease HBV reactivation. PMID- 23726577 TI - The impact of pretransplantation serum albumin levels on long-term renal graft outcomes. AB - BACKGROUND: The association between pretransplantation serum albumin concentrations and renal graft outcomes is unclear. Hypoalbuminemia is a strong predictor of cardiovascular and all-cause mortality in chronic renal disease. Protein-energy wasting in dialysis patients is associated with irreversible damage and an increased risk of adverse outcomes. In this retrospective study, we investigated the association between preoperative albumin levels and short-term as well as long-term renal graft outcomes. MATERIALS AND METHODS: We included 375 renal transplant recipients in our center between 1991 to 2011, who were grouped according to their preoperative serum albumin levels: group I (<3.5 g/dL), group II (3.5-3.9 g/dL), group III (4.0-4.4 g/dL), and group IV (>= 4.5 g/dL). We measured the frequencies of delayed graft function (DGF), acute rejection episodes, and viral infections as well as the long-term graft outcomes. RESULT: DGF affected 12.8%, 6.8%, 7.7%, and 9.3% of patients in groups I-IV, respectively. Acute rejection occurred in 27.7%, 27.2%, 31.6%, and 24.1%, while cytomegalovirus (CMV) and fungal infection occurred in 12.8% (6.4%), 23.3% (5.8%), 16.2% (2.6%), and 11.1% (5.6%) of patients, respectively. Serum creatinine levels at 12 months were not significantly different among the groups. Long-term graft survival was poorest in group I and best in group IV (P = .039). A Cox proportional hazards model showed group IV compared with group displayed the lowest relative risk of graft failure (hazard ratio [HR] = .536; P = .029). CONCLUSIONS: Low pretransplantation serum albumin levels were associated with poor long-term graft outcomes and with more post-transplantation complications. It may be necessary to focus on improving patients' nutritional status prior to transplantation to ensure long-term renal graft survival. PMID- 23726578 TI - Superiority of AbCross enzyme-linked immunosorbent assay cross-match over the B cell complement-dependent lymphocytotoxicity cross-match. AB - BACKGROUND: The AbCross enzyme-linked immunosorbent assay (ELISA) cross-match is a recently introduced solid phase cross-match technique with several technical advantages over the currently available Antibody Monitoring System ELISA cross match. METHODS: In the present study, we investigated the potential superiority of AbCross over the traditional complement-dependent lymphocytotoxicity (CDC) B cell cross-match (BXM). Pretransplant sera of 271 kidney transplant recipients who were transplanted at our center between 1998 and 2010 were tested in ELISA screening for the presence of human leukocyte antigen (HLA) antibodies and in AbCross and CDC for antibody reactivity against solubilized donor HLA class I and II antigens and donor B cells, respectively. RESULTS: Patients positive for HLA class I or II antibodies on ELISA screening had a significantly poorer graft outcome 2 years after transplantation than recipients who were negative for HLA antibodies (21% vs 6% graft loss; P = .002). Corresponding with this finding, 37 recipients positive for HLA antibodies in AbCross against donor HLA class I or II antigens had a 2-year post-transplant graft loss rate of 19%, which is significantly higher than the 8% rate in 186 recipients who were negative for both antibody classes in AbCross (P = .043). The 2-year graft loss rate in 34 AbCross positive but BXM negative patients was 21%, compared with 7% in 172 AbCross and BXM negative patients (P = .012) and 9% in 11 AbCross negative but BXM positive patients (P = .39). CONCLUSIONS: Our data indicate that the AbCross ELISA cross-match is superior to the CDC BXM, most likely because it detects antibodies against donor HLA antigens at a higher sensitivity. PMID- 23726579 TI - Anesthesia and kidney transplantation. AB - INTRODUCTION: Chronic kidney disease (CKD) has diverse causes and the outcomes can change with renal transplantation, which has the potential to increase quality of life and improve survival. Because transplant recipients usually have comorbid conditions, presurgical assessment, optimization of health status, monitoring, and intraoperative anesthetic management are essential. OBJECTIVE: The objective of this study was to evaluate available medical literature concerning presurgical anesthetic assessment and intraoperative and postoperative anesthetic management of patients undergoing renal transplantation. REVIEW CRITERIA: A bibliographic search was made in MEDLINE, OVID, and LILIACS without language or design limits. Available evidence from February 1991 to February 2011 was taken. Articles about anesthesia in renal transplantation were included. Information quality was assessed according to design type with "Critical Appraisal Skills Program" (CASP-UK) tools. Epidemiological data in Colombia were obtained from the Social Protection Ministry and FOSYGA (Solidarity and Guarantee Fund) web pages. RESULTS: Regarding prognosis, CKD mortality increases with dialysis and with its duration, whereas transplantation reduces it and enhances survival. Recipient mortality, functionality, and graft lifespan are influenced by donor type (immediate diuresis with living donors, P < .05), hydration (60-90 mL/kg), early diuresis (13% mortality rate at 1 year if delayed and reduction of graft lifetime 20%-40%). When comparing diuresis, clearance creatinine, kidney perfusion, and function, there were no significant differences between general and regional anesthesia. Nevertheless, postoperative analgesia was better with epidural anesthesia. CONCLUSION: Examination of the patient and optimization of the overall health status contributes to graft optimal function and patient survival. Regional anesthesia has better control over postoperative pain, but it has no effect on the prognosis, The intraoperative maintenance of appropriate hydration enhances flux and renal perfusion, which allows early functionality of the graft. This, together with a living donor are considered good prognosis factors, moreover they reduce recipient mortality and improve graft lifetime. PMID- 23726580 TI - Clinical significance of prophylactic antibiotics in renal transplantation. AB - INTRODUCTION: The use of new selective immunosuppressants as well as the emergence of new antimicrobial resistances raise the use of prophylactic antibiotics as a matter of controversy. The purpose of this study was to retrospectively analyze the clinical significance of prophylactic antibiotics in kidney transplantation. METHODS: This retrospective study included 174 renal allograft recipients who were divided into two groups: group A including patients who received perioperative prophylactic antibiotics and group B, who did not receive them. We analyzed who the incidence of infectious complications as well as the causative micro-organisms and their antimicrobial resistance within 1 month after kidney transplantation. RESULTS: Overall bacterial infections were observed during the first postoperative month in 13 cases (7.4%): 6 (3.4%) surgical site 4 (2.3%) urinary tract, 2 (1.1%) bacteremic, and 1 (0.6%) central catheter infections. There was no respiratory infection. The incidence of bacterial infection was not significantly different between the two groups. The major micro-organisms isolated after kidney transplantation, were Staphylococcus aureus and Escherichia coli; both of which had already shown multidrug resistance at the initial time of infection. CONCLUSION: Not only did use of prophylactic antibiotics have little impact to prevent bacterial infections after kidney transplantation, but also it may induce antimicrobial resistance against the antibiotics used for prophylaxis. Moreover, the increased antibiotic resistance prior to kidney transplantation hampers the effectiveness of prophylactic antimicrobial agents. Guidelines for perioperative antibiotic prophylaxis should be therefore revised. PMID- 23726581 TI - Meticulous use of techniques for reconstruction of multiple renal arteries in live donor kidney transplantation. AB - BACKGROUND: The aims of this study were to provide an overview of techniques for renal artery reconstruction and to introduce a novel technique using the gonadal vein as a "Carrel patch." MATERIALS AND METHODS: From January 2005 to December 2011, we performed 128 live donor kidney transplantations. All donor nephrectomies used laparoscopic surgery, yielding 23 grafts with 2 and 3 with 3 renal arteries. The reconstruction technique was based on the length and caliber of the arteries. For 3 renal arteries, we used the gonadal vein as a "Carrel patch". The gonadal vein was harvested with the ureter as a bundle during nephrectomy. The recipients were 1.5 to 71 years old (average, 43.9). RESULTS: All laparoscopic donor nephrectomies were performed successfully with preservation of the multiple arteries. The reconstructions were satisfactory; all grafts functioned immediately. There was no arterial infarction on postoperative Doppler ultrasound and renal nuclear scan. Renal artery stenosis occurred in 2 cases, in which the interventional balloon dilatation was first used; 1 case required subsequent stent insertion. CONCLUSION: In cases of multiple renal arteries, the live donor kidney can be recovered safely by laparoscopic surgery. Our technique to reconstruct multiple renal arteries uses the gonadal vein as a "Carrel patch." The gonadal vein is readily available during laparoscopic donor nephrectomy. PMID- 23726582 TI - Outcomes of living donor renal transplants with a negative cross-match and pretransplant donor-specific antibody. AB - INTRODUCTION: Management of renal transplant recipients with a negative complement-dependent cytotoxicity-antihuman globulin (CDC-AHG) cross-match and pretransplant donor-specific antibody (DSA) is controversial. We sought to compare outcomes of immunologically high-risk living donor (LD) renal transplant recipients with and without DSA. METHODS: We conducted a single-center, retrospective review of all high immune-risk LD renal transplant recipients with a negative CDC-AHG cross-match performed between January 2008 and December 2010. Pretransplant desensitization for DSA was not utilized. Immunosuppression consisted of thymoglobulin induction, followed by tacrolimus, myeophenolate mofetil, and prednisone. DSA was assessed pretransplant and at 1, 3, 6, 9, and 12 months, and every 6 months thereafter. RESULTS: Between January 2008 and December 2010, 44 LD renal transplants were performed in high immune-risk recipients with a negative CDC-AHG cross-match. Outcomes of 14 recipients with pretransplant DSA were compared with 30 recipients with no DSA. After a median follow-up of 26 months (range, 12-40), overall death-censored graft survival was 100%, with no acute rejection episodes in the DSA group and 1 antibody-mediated rejection in the non-DSA cohort. Mean serum creatinines of the DSA and non-DSA groups at 1 year post-transplant were 1.0 +/- 0.4 and 1.2 +/- 0.6 mg/dL (P = NS), respectively. Among the pretransplant DSA cohort, 5 of the 14 (36%) developed persistent post-transplant DSA at a median of 9 months (range, 3-24) versus 2 of 30 (7%; P = .025) at a median of 12 months post-transplant in the non-DSA cohort. All recipients in the pretransplant DSA group underwent renal biopsy for persistent post-transplant DSA. Three of 5 biopsies showed C4D deposition in peritubular capillaries without glomerulopathy or arteriopathy. CONCLUSIONS: Early post-transplant outcomes for LD recipients with a negative cross-match and pretransplant DSA were excellent. In recipients with good and stable renal function, the significance of persistent post-transplant DSA in combination with C4D deposition on biopsy is unclear at this time. PMID- 23726583 TI - Survival of renal transplantation patients older than 60 years: a single-center experience. AB - BACKGROUND: Elderly patients are the fastest growing population requiring renal replacement therapy. It has been stated that renal transplantation may be the best treatment option for these patients. However, it has been observed that older patients have a higher mortality rate than those who are younger. Yet the factors that determine post-transplantation outcomes in this population remain poorly defined. The aims of this study were to evaluate the graft and patient survival in kidney transplant recipients who are older than 60 years of age to identify relevant predictive factors. METHODS: In this population-based retrospective cohort study of 201 kidney transplantations performed in elderly patients from January 2002 throughout June 2009, we estimated the 1-,3-,and 5 year patients and graft survival rates. We also evaluated the complications and the predictors of poor outcomes. Survival times were analyzed using the Kaplan Meier method and survival differences assessed with Mantel-Cox log rank-test. We performed a Cox proportional hazards regression models to evaluate the impact of baseline and treatment characteristics on patient and graft survival. RESULTS: Graft and patient survival rates at 1, 3, and 5 years were 76.4%, 71.3%, and 54.3%, and 78.2%, 73.8%, and 56.4%, respectively. Graft survival rates censored for patient death with a functioning graft were 93.1, 92.1, and 89%. Patient survival rates differed between diabetic and nondiabetic subjects at 1, 3 and 5 years (69.5% versus 83.6%; 59.8% versus 72.3%; 43.6% versus 65.7%; P = .008). On multivariate analysis, the factors associated with patients survival were diabetes mellitus (hazard ratio [HR] 2.058, 95% confidence interval [CI] 1.173 3.611, P = .012) and the 1-month serum creatinine value was > 1.6 mg/dL (HR 2.108 for each point increase, 95% CI 1.521-2.921, P = .000). Furthermore, there was an insignificant trend forward an association between active or past smoker and lower patient survival (HR 1.689, 95% CI 0.937-3.043, P = .08). The main causes of graft loss were patient death (79.5%). acute rejection (6.8%), and chronic allograft nephropathy (5.5%). CONCLUSION: Renal transplantation can be performed safely and with acceptable outcomes in elderly patients after appropriate clinical evaluation. The grafts show excellent survival albeit that deaths with a functional graft continue to be an important issue. PMID- 23726584 TI - Creation of a solid organ transplant program in an underdeveloped country: Mexico's General Hospital transplantation program. AB - BACKGROUND: With a population of >112 million persons, all Mexicans are entitled to receive medical care by the state and more than half have limited access to healthcare. From January 1985 to March 2009, 40 renal transplants were performed from living donors with a high percentage of complications. In April 2009, a new Solid Organ Transplantation Program was started; herein, we present this enterprise to the international community and briefly present a perspective on the Mexican transplant situation. MATERIALS AND METHODS: We performed a retrospective chart review of kidney and liver transplant recipients from April 2009 to November 2011, including demographic features, immunosuppression, complications as well as initial and 1 month function. RESULTS: We performed 68 kidney (59 living and 9 deceased donors) and 5 liver transplants (cadaveric donors). The kidney transplant recipients were 73.5% males and showed an overall mean age of 29.77 years (range, 18-60). The donor mean age was 34.08 years. Mean recipient creatinine pretransplant was 13.32 mg/dL, while at day 5 it was 2.33 and at month one, 1.32 mg/dL. Five grafts were lost (7.3%): 4 due to death with a functioning graft and 1 due to acute pyelonephritis. Five patients experienced delayed graft function Basiliximab induction was required in all but one who received thymoglobulin owing to a high panel reactive antibody. Maintenance therapy included a calcineurin inhibitor, mycophenolate mofetil (MMF), and prednisone. Liver transplant recipients were 83.6% women. The etiologies were alcoholic cirrhosis (n = 2), primary billiary cirrhosis (n = 1) and hepatitis C virus infection (n = 2). Complications included: reperfusion syndrome (n = 1), convulsive crisis (medication; n = 1), acute respiratory distress syndrome (n = 1), and death (n = 1). Their Model for End-Stage Liver Disease scopes were 10-21. After basiliximab induction, they had maintenance therapy with tacrolimus, MMF, and steroids. The donor mean age was 26.2 years. All survivors show normal liver function tests currently. CONCLUSIONS: From 1985 to 2009, 40 kidney transplants were performed, with multiple complications including donor deaths. Our current results were comparable to international standards, with <15% complication rate. PMID- 23726585 TI - The CERTAIN Registry: a novel, web-based registry and research platform for pediatric renal transplantation in Europe. AB - BACKGROUND: The results of pediatric renal transplantation have improved markedly in the last decade. However, a number of relevant clinical problems remain, such as organ damage caused by chronic rejection, long-term toxicity of immunosuppressive therapy, difficulty in developing tolerance-inducing protocols, secondary cardiovascular comorbidity, post-transplantation lymphoproliferative disease, suboptimal longitudinal growth, quality of life, adherence to immunosuppressive medication, and structured transition programs to adult care. These unmet clinical needs require intense collaborative and interdisciplinary clinical research. We recently founded the Cooperative European Paediatric Renal TransplAnt INitiative (CERTAIN; www.certain-registry.eu) as a research network and platform built on a novel, web-based registry. RESULTS: The registry's dataset provides essential information on generic kidney transplantation-related topics and also captures pediatric-specific topics, such as growth, physical and psychosocial development, and adherence. Due to its flexibility the system can be used as follows: (1) as a registry capturing a minimal or an extended dataset; (2) as a center and/or country-specific transplantation database; or (3) as a patient-specific electronic transplantation chart. The data can be exported directly from the CERTAIN web application into statistical software packages for scientific analyses. The rights regarding data ownership, evaluation, and publications are regulated in the registry's rules of procedure. Data quality is ensured by automatic software validation and a manual data review process. To avoid redundant data entry, CERTAIN has established interfaces for data change with Eurotransplant, the Collaborative Transplant Study (CTS), and the registry of the European Society of Pediatric Nephrology (ESPN) and European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) (ESPN/ERA EDTA registry). CERTAIN fulfils all regulatory and ethical requirements of the European Union and Germany, in particular, regarding patients' data privacy and security. CONCLUSION: Using modern information technology, the recently established multinational CERTAIN Registry fills a gap in Europe for collaborative 5 research and quality assurance in the field of pediatric renal transplantation. PMID- 23726586 TI - Evaluation of nutritional status in renal transplant recipients in accordance with changes in graft function. AB - INTRODUCTION AND AIMS: Renal transplantation (RT) is the ultimate treatment modality for end-stage renal disease (ESRD) patients. Malnutrition is a strong predictor of cardiovascular disease among ESRD patients. Body composition analysis using bioimpedance devices (BIA) is a useful noninvasive tool to detect malnutrition in this population. We investigated the impact of graft function on nutritional status and reliability of BIA to detect malnutrition in RT recipients. METHODS: We evaluated retrospectively 189 RT recipients including 59 females, and of overall mean age of 38.3 +/- 10.6 years who had a minimum posttransplant follow-up of 12 months. Body Composition Analyzer (Tanita BC 420MA) determinations were complemented with monthly assessments of biochemical parameters. Patients were divided into 3 groups according to glomerular filtration rate (GFR) levels: normal graft function/high GFR group (group 1, normal creatinine levels, no proteinuria and GFR >= 90 mL/min; n = 59); low renal function/low GFR group (normal or high creatinine levels with low GFR levels; group 2; GFR 89-60 mL/min; n = 87) and group 3, (GFR < 60 mL/min; n = 43). RESULTS: Group 3 patients displayed significantly lower as well as hemoglobin albumin and calcium concentrations, with higher phosphorus and parathyroid hormone levels (P = .0001). They also showed significantly lower body weight (P = .0001), body mass index (P = .002), fat (P = .002) and muscle (P = .0001) contents as well as fat-free mass (P = .0001). Group 2 patients had significantly lower values compared with group 1 and higher values than group 3. GFR values positively correlated with albumin, fat, muscle, and fat-free mass (r = 0.337, 0.299, 0.281, 0.278, respectively; P = .0001). GFR values positively correlated with visceral fat ratio (r = 0.170; P = 0.02), body mass index (r = 0.253; P = .0001), and waist-hip ratio (r = 0.218; P = .006). CONCLUSION: Loss of muscle and fat mass is an early sign of malnutrition among RT recipients. It is closely associated with loss of GFR. BIA is a noninvasive and reliable diagnostic tool that should be included in the follow-up of these patients for an early diagnosis of malnutrition-related complications. PMID- 23726587 TI - Outcome of desensitization in human leukocyte antigen- and ABO-incompatible living donor kidney transplantation: a single-center experience in more than 100 patients. AB - BACKGROUND: Antibody-mediated rejection (AMR) and inferior graft outcome remain the 2 most important obstacles to successful kidney transplantation in human leukocyte antigen (HLA)- and ABO-incompatible recipients. We report a single center experience in the outcome of desensitized living donor HLA- and ABO incompatible kidney transplantation. METHODS: Since 2007 we included 2 groups in our desensitization program. HLA-incompatible living donor kidney transplant candidates displaying donor-specific antibodies (DSA) with or without a positive T-cell and/or B-cell flow crossmatch (FCXM). Second, those displaying DSA with positive T-cell immunoglobulin (Ig)G AHG CDC CXM with a titer of <=1:8, as well as all ABO-incompatible living donor kidney transplant candidates with an IgM isoagglutinin titer <= 256. They were risk stratified for AMR and underwent individualized desensitization protocol: ABO-incompatible and HLA-incompatible candidates with either positive AHG CDC CXM or positive T and/or B IgG flow CXM with repeat HLA mismatch from a previous transplantation were deemed to be high risk and received a single dose of Rituximab, therapeutic plasma exchange and high-dose intravenous immunoglobulin (IVIG) (2 g/kg). HLA-incompatible candidates with negative CDC but positive T and/or B IgG FCXM were deemed intermediate risk, receiving rituximab and high-dose IVIG. Those with positive DSA but negative flow and CDC CXM were deemed low risk, receiving low-dose IVIG (1 g/kg). All patients received induction with thymoglobulin and were maintained on a tacrolimus-based immunosuppressive regimen. RESULTS: Among 124 incompatible recipients, 85 received HLA-incompatible and 39 ABO-incompatible living donor kidney transplantations after desensitization. Risk stratification for HLA-incompatible transplants revealed 61 high-risk, 42 intermediate-risk, and 21 low-risk cases. Ninety-nine (80%) were primary transplants. At a median follow-up of 23 (range 1 53) months, patient survival was 98% and death censored graft survival 96%. Mean serum creatinine was 84 MUmol/L (range 41-169). Acute cellular rejection was observed in 15 (12%) and AMR in 5 (4%) patients. All rejection episodes responded to treatment except 1 AMR in an ABO-incompatible transplant that led to graft failure. CONCLUSION: Our risk stratification for desensitization strategy achieved a low incidence of AMR among HLA- and ABO-incompatible kidney transplant recipients. Their 2-year data appear to be comparable to HLA- and ABO-compatible transplantations. PMID- 23726588 TI - Long-term outcome of kidney retransplantation in comparison with first kidney transplantation: a report from the Thai Transplantation Registry. AB - INTRODUCTION: Kidney retransplantation is a high-risk procedure that is increasingly performed because of previous graft failure. The aim of this study was to determine the long-term outcomes of kidney retransplantations compared with first kidney transplantations under the current era of immunosuppression. METHODS: Since the first retransplantation in Thailand was performed in 1993, this study included all consecutive cases registered in the Thai Transplantation Registry database from January 1993 to December 2011. A total of 3337 kidney transplantations were available for the analysis. Graft loss was defined as a return to dialysis or graft removal. Death with a functioning graft was censored. RESULTS: Of 3337 kidney transplantations during the study period, 113 were second and 3 were third transplantations. Among these 116 retransplantations, the most common identified causes of end-stage renal disease were chronic glomerulonephritis (38.8%), followed by hypertensive nephropathy (13.0%), diabetic nephropathy (6.0%), and lupus nephritis (1.7%). The retransplantation recipients were older (mean age, 46.2 +/- 12.8 years) than the first transplantation group (mean age, 42.2 +/- 12.8 years). The proportion of living related kidney transplantations and male sex were similar between first and retransplantation recipients. Fourteen percent of retransplantation recipients showed high immunologic risk as defined by current panel reactive antibodies >=30% compared with 3% of those in the first transplantation group (P < .001). The percentages of induction therapy with antithymocyte globulin and anti interleukin-2 antibody in the retransplantation and first transplantation groups were 18.3% versus 4.3% and 60.0% versus 32.6%, respectively. The graft survival rates (95% confidence interval [CI]) at 1, 5, and 10 years were 88.6% (80.7 93.3), 87.3% (79.1-92.5), and 74.4% (53.7-86.9) among retransplantation, versus 95.0% (94.1-95.7), 87.0% (85.5-88.5), and 70.7% (67.4-73.8) among first transplantation groups, respectively (P = .63). Patient survival rates were not different between first and retransplantation groups (P = .42). The leading cause of graft loss in the retransplantation group was chronic allograft nephropathy (22%), whereas infection (57%) was the major cause of death in this group. CONCLUSION: The 10-year patient and graft survival rates of kidney retransplantation were acceptable. The combination of induction therapy with a calcineurin inhibitor and a mycophenolate mofetil/mychophenolic acid-based regimen lead to outcomes comparable to first kidney transplantations among our cohort of 3337 patients. PMID- 23726589 TI - High mortality in the first year after kidney graft failure. AB - BACKGROUND: The aim of our cohort study was to assess survival of the patients after kidney graft failure. METHODS: Patients starting dialysis after graft failure between January 1, 2004 and December 31, 2010 were identified from the Slovenian Renal Replacement Therapy (RRT) Registry and followed to December 31, 2011. The control group consisted of 351 incident dialysis patients, who were kidney transplant candidates. Survival data were not censored for retransplantations. RESULTS: After a median of 7.4 (interquartile range [IQR]) 0.4-13.0) years with a functioning graft and a median of 15.5 (IQR 7.8-20.7) years on RRT 82 patients started dialysis. Their mean (+/- standard deviation [SD]) age was 50.4 +/- 12.7 years vs 49.2 +/- 13.9 years for the incidental transplantation candidates (P = .49). There were sixty-one percent men (vs 64%; P = .67), and all subjects were on hemodialysis treatments. By Dec 31, 2011, 19 (23%) patients had undergone retransplantation and 27 (33%) died after a median of 1.6 (IQR 0.2-5.4) months on dialysis. The causes of death were infection (n = 15), cardio-disease-vascular (n = 6), malignancy (n = 4), or cerebrovascular (n = 2). Deceased patients were significantly older: 60.0 +/- 7.9 vs 45.7 +/- 12.0 years (P < .001) and more often men: (78% vs 53% P = .05). The unadjusted overall 1- and 3-year survivals rates after graft failure of 70% and 68% were significantly lower than those in the control candidate group of (98% and 93%, respectively (log-rank; P < .001). This difference remained significant upon multivariate analysis (hazard ratio [HR], 12.0; P < .001). The subgroup of 53 patients who started dialysis after chronic graft failure showed unadjusted 1- and 3-year survival rates of 82% and 80%, respectively which were still worse than the control group (P = .001), a difference that remained significant upon multivariate analysis (HR, 1.75; P < .001). CONCLUSION: After kidney graft failure patients experienced increased mortality in the first year after restarting dialysis. However, subjects who survived the first year showed good survival thereafter. PMID- 23726590 TI - Assessment of the perceived quality of life of successful kidney transplant recipients and their donors pre- and post-transplantation. AB - BACKGROUND: With advanced medical technology, quality of life (QOL) has assumed immense importance. In India, there has been scant research on the QOL of patients with stage 5 chronic kidney disease and their respective donors who make transplantation possible. METHODS: We assessed and compared the QOL of successful kidney transplant recipients (n = 30) and their living-related donors (n = 30) before and after kidney transplantation. RESULTS: For recipients, on the interview schedule the post-transplant QOL score (M = 1528.23, SD = 48.50) was higher than the pretransplant QOL score (M = 1075.80, SD = 95.34; P < .01). On the KDQOL SF 1.3, the physical and mental composite median QOL scores were significantly higher (P < .01) in the post-transplant (49.68, 61.43) than the pretransplant period (29.51, 34.09). For donors, on the interview schedule, the overall post-donation QOL score (M = 463.63, SD = 1.61) was higher than the predonation QOL score (M = 437.07, SD = 8.14; P < .01). On the KDQOL SF 1.3, the mental composite median post-donation QOL score (60.70) was higher than the predonation score (59.84; P < .01). CONCLUSION: Kidney transplantation/donation improved the QOL of patients and donors. PMID- 23726591 TI - The rate of decline of glomerular filtration rate is a predictor of long-term graft outcome after kidney transplantation. AB - BACKGROUND: To improve the long-term outcome of kidney transplantation (KT), it is important to identify and take active steps to reduce the number or severity of novel risk factors. We investigated whether changes in estimated glomerular filtration rate over the first year after KT (DeltaeGFR12-3) was associated with long-term renal allograft function and survival. METHODS: Four hundred twenty eight allograft recipients transplanted between 1990 and 2001 underwent DeltaeGFR12-3 calculation using the equation: DeltaeGFR12-3 = ([eGFR at 12 months post-KT - eGFR at 3 months post-KT]/[eGFR at 3 months post-KT]) * 100%. Recipients were divided into 3 groups according to their DeltaeGFR12-3: group I (n = 150), DeltaeGFR12-3 >= 10%; group II (n = 151), 10 > DeltaeGFR12-3 >= -10%; and group III (n = 127), DeltaeGFR12-3 < -10%. Multiple linear regression analysis was used to adjust for confounding variables that may affect long-term renal allograft function, and Kaplan-Meier analysis, to compare allograft survival. RESULTS: At a mean follow-up of 120 +/- 58 months, we observed 112 renal allograft losses. The DeltaeGFR over 10 years post-KT (DeltaeGFR120-3) was significantly associated with the serum uric acid levels at 3 months post transplantation and DeltaeGFR12-3. Group III showed poor renal allograft survival; group I, 194 +/- 8 months; group II, 197 +/- 7 month and; group III, 163 +/- 4 months; (log-rank test, P < .05). A Cox proportional hazard model revealed DeltaeGFR12-3 to be independently associated with future renal allograft loss (hazard ratio, 0.981; 95% confidence interval, 0.974-0.992). CONCLUSION: Our results suggested that DeltaeGFR12-3 may be an independent predictor of kidney allograft survival. Routine application of eGFR is strongly recommended to identify patients at risk for chronic allograft dysfunction. PMID- 23726592 TI - Rejection is a strong graft survival predictor in live donor pediatric renal transplantation using cyclosporine, mycophenolate mofetil, and steroids: 5-year outcomes in a single Mexican center. AB - Long-term graft function and survival are of particular importance in children assuming that they have a longer transplantation life span than most adults. Because acute rejection episodes (ARE) continue to have a serious impact on graft loss, we analyzed the effects of ARE on 5-year survival and function in our population. Fifty-seven living donor kidney transplant recipients (34 males) younger than 18 years of age (13.5 +/- 2.6 years; range, 5-17) were follow up for at feast 12 months using cyclosporine, mycophenolate mofetil, and steroid therapy with or without induction treatment between February 2003 and December 2010. ARE incidence during the first 12 months following transplantation was 14%. One-, 3- and 5-year serum creatinine values were 1.24 +/- 0.39, 2.16 +/- 2.39, and 1.76 +/ 0.9 mg/dL, respectively. Mean calculated creatinine clearances (Schwartz) at 1, 3, and 5 years were 82.5 +/- 24.8, 64.7 +/- 24.1, and 67 +/- 27.5 mL/min*1.73 m(2), respectively. Patient/graft survival rates were 96/85%, 90/72%, and 88/65% at 1, 3, and 5 years, respectively. Patients who experienced an ARE within 12 months following transplantation displayed a reduced 5-year graft survival rate (37.5%) versus those who did not (78%; P = .005). Patients who did not have an ARE during 60 months had a higher graft survival rate (76%) than those who had ARE (33%; P = .001). Patient without basiliximab induction showed a lower 5-year graft survival rate (61% vs 100%; P = not significant [NS]). ARE is an important risk factor for graft loss in the pediatric kidney transplant population. PMID- 23726593 TI - Donor factors predictive for poor outcomes of living donor kidney transplantation. AB - INTRODUCTION: The aim of this study was to explore donor risk factors that predict the poor outcomes after living donor kidney transplantation. METHODS: We retrospectively analyzed our 219 living donor kidney transplantations collecting donor age and gender, graft glomeular filtration rate (GFR), human leukocyte antigen (HLA) typing, recipient age and gender, acute rejection episodes chronic rejection, and 1-year serum creatinine level. Patient and graft survivals were calculated using the Kaplan-Meier analysis. Independent donor risk factors affecting graft survival and 1-year serum creatinine level were analyzed using Cox regression and logistic regression. RESULTS: One-, 3-, 5-year patient and graft survivals were 98.6%, 98.1%, and 97.4% and 97.7%, 95.0%, and 92.2%, respectively. Acute rejection rate was 12.8%, and chronic rejection, 4.1%. If donor age was over 50 years, there were significantly increased incidences of acute and chronic rejection (chi(2) were 5.385 and 5.039; P < .05). Univariate analysis showed donor age > 50 years, graft GFR < 35 mL/min, female to male, HLA mismatch > 3 loci to be risk factors for an abnormal 1-year serum creatinine. Logistic multivariate regression revealed donor age > 50 years, female to male, and graft GFR before transplant < 35 mL/min to be independent risk factors for an abnormal 1-year serum creatinine level (odds ratio values 5.928, 2.489, and 6.993, respectively; P < .05). Cox multivariate regression demonstrated that graft GFR before transplant < 35 mL/min was an independent risk factor for long term graft survival (relative risk value = 6.984; P = .004). CONCLUSION: Older donor, female to male, and insufficient graft GFR before transplantation are predictive factors for poor outcomes of living donor kidney transplantations. PMID- 23726594 TI - The impact of de novo donor-specific anti-human leukocyte antigen antibodies on 5 year renal transplant outcome. AB - Numerous studies have shown that circulating donor-specific antibodies targeting human leukocyte antigen (HLA) are associated with accelerated renal transplant failure, but many patients with these antibodies have good graft function. The aim of our study was to investigate the long-term graft function and survival in patients with de novo post-transplant donor-specific anti-HLA antibodies (DSA). Our prospective study included 78 consecutive recipients with a negative crossmatch before transplantation. Recipient serum samples were assayed for DSA in week 2 and 1, 3, 6, 9, 12 months after transplantation using a complement dependent lymphocytotoxic technique with donor lymphocytes. Additionally, patients with DSA and stable renal function in the first year were tested with a more sensitive flow-panel-reactive antibody. DSA were present in 34 (44%) of our patients during the first 12 months after transplantation. Biopsy-proved acute rejection occurred in 11 DSA-positive and 10 DSA-negative patients. Seven DSA positive patients had antibody-mediated rejection and no DSA-negative ones developed humoral rejection. The serum creatinine level in DSA-positive patients was significantly higher (2.48 vs 1.43 mg/dL) in year 5. The 13 (38%) DSA positive patients with good graft function in month 12 were stable during a 5 year follow-up: their serum creatinine was 1.46 +/- 0.4 in year 1 and 1.56 +/- 0.4 mg/dL in year 5 and nobody lost their allograft. One- and 5- year graft survivals were appropriately 85% and 59% in DSA-positive patients compared to 93% and 93% in DSA-negative patients. To sum up, post-transplant DSA had a significant influence on kidney function and graft survival but in 38% of patients the presence of DSA did not decrease a 5-year renal function. A good renal allograft function in the presence of DSA in the first year after transplantation and cessation of their production in the subsequent years may be a good prognostic marker for a long-term allograft function and survival. PMID- 23726595 TI - Increase in proteinuria after acute kidney graft rejection is associated with decreased graft function and survival. AB - BACKGROUND: There are limited data on the relationship between acute kidney graft rejection, proteinuria, and outcome. We hypothesized that an increase in proteinuria after an acute rejection episode is associated with decreased graft function and survival. METHODS: We tested our hypothesis in a national historic cohort study of 506 recipients of deceased donor kidney transplantations between January 2000 and December 2010. The selection criterion was a biopsy-confirmed first acute rejection episode. Proteinuria was measured using urine protein/creatinine ratios (UPCR) at baseline (lowest serum creatinine before biopsy), time of biopsy, and 3 months thereafter. We examined the effects on outcomes of a change in UPCR (DeltaUPCR = UPCR at 3 months after biopsy - baseline UPCR). RESULTS: In the observed period, 86 patients experienced a biopsy confirmed acute rejection episode. Three patients with primary graft nonfunction were excluded. Among the remaining 83 patients the median time to acute rejection was 6 (interquartile range, 2-39) months, and median follow-up was 60 (interquartile range, 35-124) months. Receiver operator characteristic analysis demonstrated that DeltaUPCR cutoff value of 20 mg/mmol showed the best discriminatory ability to predict graft loss or patient death (sensitivity, 84%; specificity, 73%). There were 41 patients with DeltaUPCR >=20 mg/mmol, whereas 42 patients had DeltaUPCR <20 mg/mmol. Patients with DeltaUPCR >=20 mg/mmol had worse graft function at 3 months after the biopsy with mean (+/-SD) estimated glomerular-filtration rate (eGFR) of 35 +/- 19 versus 47 +/- 14 mL/min/1.73 m(2) (P = .002), as well as a higher rate of composite graft loss and patient death (37% vs 10%; P = .004). Cox regression analyses revealed DeltaUPCR >=20 mg/mmol, delayed graft function, and antibody-mediated rejection to be significant factors associated with the composite outcome (hazard ratios, 4.3, 2.5, and 3.4, respectively; P < .05). CONCLUSION: Increased proteinuria after an acute kidney graft rejection episode was associated with decreased graft function and survival, serving as a surrogate marker for poor outcomes. PMID- 23726596 TI - Increased plasma tissue inhibitors of metalloproteinase concentrations as negative predictors associated with deterioration of kidney allograft function upon long-term observation. AB - Chronic allograft injury (CAI) is the most frequent cause of progressive kidney allograft impairment and eventual loss, which is due to interstitial fibrosis and tubular atrophy (IF/TA). Mechanisms of CAI are not fully understood. Chemokines, cytokines, metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) play roles in fibrosis development. The aims of this study were to evaluate plasma and urine TIMPs (TIMP-1 and TIMP-2), MMPs (MMP-2 and MMP-9), proinflammatory interleukin-6 (IL-6), chemokine (C-C motif) ligand 2 (CCL2 chemokines previously known as monocyte chemoattractant protein-1 [MCP-1]) among 150 recipients beyond 1 year post-renal transplantations and to explore the usefulness of these potential biomarkers of ongoing allograft injury. Renal transplant recipients compared with healthy volunteers (control group) showed significantly increased plasma and urine IL-6, MMP-9, TIMP-1, and TIMP-2, as well as lower plasma MMP-2 and urine CCL2 concentrations. Compared with recipients showing good function those with impairments displayed higher plasma TIMP-1 (P < .001) and TIMP-2 (P = .003) concentrations. The recipient estimated glomerular filtration rate (eGFR) values negatively correlated with plasma TIMP-1 and TIMP-2 levels (r = -0.43; P < .0001 and rs = -0.42; P < .0001, respectively) and with urine IL-6 excretion (rs = -0.33; P < .0001). Multivariate and receiver operating characteristic (ROC) analyses showed TIMP-1 plasma level assessments to be useful estimates of allograft injury. PMID- 23726597 TI - Long-term follow-up of non-HLA and anti-HLA antibodies: incidence and importance in renal transplantation. AB - BACKGROUND: Detection of antibody-mediated injury is becoming increasingly important in post-transplant patient care. The role of donor-specific anti-human leukocyte antigen (HLA) antibodies in kidney transplant damage is known, whereas the significance of non-HLA antibodies remains an unresolved concern. The aim of the study was to determine the presence and influence on renal function of non HLA and anti-HLA antibodies in stable patients at 5 years after kidney transplantation. METHODS: We evaluated the antibodies in 35 consecutive patients with stable renal function at 5 years after transplantation. RESULTS: Pretransplant screening for donor-specific antibodies by CDC cross-matches was negative in all patients. Anti-endothelial cell antibodies (AECA), anti angiotensin II type 1 receptor antibodies (anti-AT1R), and anti-endothelin receptor antibodies (anti-ETAR) were assayed as non-HLA antibodies. Non-HLA antibodies were observed in 12 (34%) patients, including AECA (n = 5; 14%), anti- AT1R (n = 6; 17%), anti-ETAR (n = 4; 11%), and both anti-AT1R and anti-ETAR (n = 3). Among 13 (37%) patients with anti-HLA antibodies, 7 also had both non-HLA antibodies: AECA (n = 1), anti-AT1R (n = 3), and anti-ETAR (n = 3). The antibody negative group (n = 13) showed significantly better renal function than the antibody-positive group (non-HLA and/or anti-HLA; n = 22). Biopsy-proven acute rejection had occurred in 2 of 13 (15%) antibody-negative versus 8 of 22 (36%) antibody-positive patients. These preliminary data revealed an high prevalence of autoantibody and alloantibody production among stable patients at 5 years after kidney transplantation. CONCLUSION: Simultaneous production of these antibodies and their association with reduced renal function suggests that active humoral immune responses are poorly controlled by immunosuppression. PMID- 23726598 TI - Decreased total CD19+ B lymphocytes and the occurrence of monoclonal proteins are frequent in ultra-long (30 to 44-year) renal transplant recipients: implications for allograft and patient survival. AB - BACKGROUND: The B-cell signature of tolerance in kidney transplant patients receiving no immunosuppression includes a significant increase in total CD19(+) B cells. METHODS: We evaluated kidney transplant recipients with primary functioning allografts for 30-44 years receiving minimal immunosuppression to determine whether they have the same CD19(+) B-cell changes or unusual serologic findings. We included 44 kidney allograft recipients with a graft functioning for 30-44 years, who were treated primarily with minimal prednisone and azathioprine. Twenty-four other recipients whose allografts functioned >30 years were unable to be studied (unable to travel, lost to follow-up, deceased). RESULTS: The number and percentage of CD19(+) B cells were depressed in 70.5% (31/44) and 81.8% (36/44), respectively, of these 44 ultra-long renal transplant recipients. The other major finding was identification by immunofixation of a monoclonal protein (MP) in 45.5% (20/44) of these same recipients. Among the 26 patients with good or excellent renal function (estimated glomerular filtration rate [eGFR] >= 45 mL/min/1.73 m(2); group 1), 12 had a single MP for >1 year, 13 no MP, and 1 a double MP. Conversely, in the 18 patients with fair/failed function (eGFR <40 mL/min/1.73 m(2) in 8, or end-stage renal disease after 30 years in 10; group 2), 3 had a transient single MP or free light chains only, 11 no MP, and 4 a double MP (P = .0425). CONCLUSIONS: These data reveal that about three quarters of ultra long renal transplant recipients had low CD19(+) B cells, compared with the elevated B-cell signature reported in tolerant kidney recipients, and nearly half (45.5%) had a serum MP that was not associated with low B cells or mortality. Those with a stable single MP had better graft function. PMID- 23726599 TI - Mast cell quantitation in renal transplant biopsy specimens as a potential marker for the cumulative burden of tissue injury. AB - Although mast cells (MC) play an ambiguous role in acute rejection, they have been implicated in chronic fibrotic processes overall and also in the kidney. Their morphological assessment in the context of comprehensive renal allograft pathology has not been sufficiently addressed, however. Using the CD117 immunostain in 461 consecutive kidney allograft biopsy specimens we counted the number of MC in the most inflamed biopsy area. The number of MC was correlated with the presence of the Banff defined features of T-cell-mediated and antibody mediated rejection. No correlation was found between the number of MC and the presence or degree of T-cell-mediated rejection or with most parameters defining acute or chronic antibody-mediated rejection. Significant correlation was found, however, with the degree of interstitial fibrosis (IF; P = .000), and time post- transplantation (P = .000). Peritubular C4d staining correlated negatively with the number of MC (P = .000). Correlation of MC infiltration and peritubular capillary multilamellation (P = .000) indicated an association between general interstitial and microvascular chronic pathology. We conclude that MC represent a somewhat unique cellular component that correlates poorly with parameters of active T-cell or antibody-mediated allograft rejection. In contrast, because MC correlate strongly with IF and time post-transplantation, they could potentially be valuable as a surrogate marker for the cumulative burden of tissue injury. PMID- 23726600 TI - Excellent results of high-dose mizoribine combined with cyclosporine, basiliximab, and corticosteroids in renal transplant recipients--4-year results. AB - BACKGROUND: Mizoribine (MZR) at 3 mg/kg/d shows less potent immunosuppressive effects, but high-dose MZR (6 mg/kg/d) was effective and safe in a 2-year study in conjunction with a regimen of cyclosporine (CsA), basiliximab, and corticosteroids. METHODS: We compared 40 living-related kidney recipients administered MZR (6 mg/kg/d), CsA (7 mg/kg/d), prednisolone (maintenance dose 10 mg/d), and basiliximab (20 mg/body) with control group (n = 38) treated with CsA, mycophenolate mofetil (MMF; 25 mg/kg/d), basiliximab, and corticosteroids. RESULTS: The 4-year graft survival rates for the MZR vs MMF groups were 92.5% vs 94.7%, respectively, with serum creatinine levels of 1.66 +/- 1.0 mg/dL vs 1.41 +/- 0.42 mg/dL at 3 years, and 1.72 +/- 1.16 mg/dL vs 1.56 +/- 1.26 mg/dL at 4 years. There was no significant difference in serum creatinine levels between the 2 groups. The MZR group demonstrated a significantly higher rate of elevated serum uric acid values (29.7%). The numbers of patients treated with allopurinol at 4 years were 11/37 (29.7%) for MZR vs 2/36 (5.6%) for the MMF subjects (P < .05). Mean serum uric acid levels of the MZR vs MMF group at 4 years were 7.1 +/- 1.9 mg/dL vs 7.0 +/- 1.6 mg/dL, respectively (NS). There was no significant difference between the 2 groups regarding bone marrow suppression or liver dysfunction. Severe cytomegalovirus infection was not observed at 3 and 4 years in either group. There were no severe gastrointestinal symptoms among the MZR or the MMF group at 3 or 4 years. CONCLUSIONS: The combination of high-dose MZR with CsA, basiliximab, and corticosteroids displayed excellent results over a 4-year follow-up. PMID- 23726601 TI - A Japanese multicenter study of high-dose mizoribine combined with cyclosporine, basiliximab, and corticosteroid in renal transplantation (the fourth report). AB - We examined the efficacy and safety of 4-drug combination therapy using high-dose mizoribine (MZR) (8 mg/kg/d), cyclosporine (CsA), basiliximab (BXM), and steroid (STR) in 39 renal transplant recipients. Acute rejection episodes (ARE), which occurred in 9 (23.1%) patients, correlated with lower blood levels of MZR (trough levels >= 2 MUg/mL). In addition, lower MZR concentrations tended to be associated with a higher incidence of rejection episodes in children aged <= 10 years than in those aged >= 11 years. The area under the received operating characteristics (ROC) curve of MZR trough level to pred ARE was 0.825 (95% confidence interval, 0.690-0.962; P = .002). Based on the ROC analysis, are MZR cut-off of 1.6 MUg/mL showed a sensitivity of 81.8% and a specificity of 75.0%. Adverse events were observed in 23 patients, including infections in 11 (7 patients positive for cytomegalovirus [CMV] antigen and 4 treated with anti-CMV drugs). The MZR trough levels seemed to be higher among patients with adverse events than in those free of them, but it was no significant. All patients experienced successful engraftment except 1 who died of unknown cause with a functioning graft. In conclusion, our study showed that low MZR trough levels correlated with the incidence of ARE. No serious adverse effects were encountered with this therapy. PMID- 23726602 TI - Mizoribine versus mycophenolate mofetil in combination therapy with tacrolimus for de novo kidney transplantation: evaluation of efficacy and safety. AB - The present study compared the efficacy and safety of mizoribine (MZR) with mycophenolate mofetil (MMF) in kidney transplantation. This multicenter, randomized clinical trial. Employed doses of study drug tailored to the immunosuppressive need. The primary efficacy outcome was the incidence of biopsy proven acute rejection episodes (BPAR). The safety of the study drug was assessed using the incidences of adverse events, drug discontinuations, and abnormal laboratory results. The 7 (6.4%) BPARs above grade II were observed in the MZR group noninferior to the 2 (1.8%) in the MMF group (95% confidence interval, 0.007-0.097 > noninferiority limit [-0.2]). BPAR was significantly decreased in the MZR group after the dose change (17/41 [41.4%] vs 8/69 [11.6%]; P < .0001) and the incidence of BPAR was similar between the MZR and MMF groups after the dose change (P = .592). The uric acid level was significantly elevated in the MZR group (P = .002). In conclusion, the efficacy and safety of MZR were similar and statistically noninferior to MMF in combination therapy with tacrolimus. PMID- 23726603 TI - Long-term outcome of azathioprine versus mycophenolate mofetil in cyclosporine based immunosuppression in kidney transplantation: 10 years of experience at a single center. AB - BACKGROUND: Mycophenolate mofetil (MMF) has been used worldwide as part of maintenance immunosuppression since initial large cyclosporine-based trials reported that compared with azathioprine (AZA), MMF reduced acute rejection episodes after renal transplantation. However, long-term benefits of MMF have not been established; the follow-up period of previous studies was within 5 years. The aim of this study was to compare the acute rejection rates, allograft function, and graft and patient survivals of these 2 drugs in conjunction with cyclosporine and steroids over a period of 10 years. METHODS: We reviewed recipients who had undergone kidney transplantation from January 1998 to January 2002. Eighty-six patients were divided into 2 groups (MMF = 43, AZA = 43). All patients received cyclosporine and steroids concomitantly as maintenance immunosuppressive therapy. RESULTS: Baseline characteristics were similar between the 2 groups except donor type. Multiple logistic regression analysis showed MMF therapy to reduce the acute rejection rate in the first 12 months after transplantation (relative risk [RR], 0.181; 95% confidence interval [CI], 0.035 0.936; P = .042). Cox proportional hazard analysis revealed MMF to was not associated with improved graft and patient survival. Graft function was comparable between the 2 groups over 10 years. No significant differences were observed in the incidence of serious infections or malignancy. CONCLUSIONS: Compared with AZA, MMF offered the clinical benefit of prevention of acute rejection episodes, but displayed similar effects on long-term graft and patient survivals in kidney transplant recipients undergoing cyclosporine-based immunosuppression. PMID- 23726604 TI - Long-term follow-up of stable kidney transplant recipients after conversion from tacrolimus twice daily immediate release to tacrolimus once-daily prolonged release: a large single-center experience. AB - BACKGROUND: Adult kidney transplant recipients maintained on tacrolimus twice daily (Tac BD) were given the opportunity to convert to tacrolimus once daily (Tac QD). Conversion was based upon a 1:1 mg:mg total daily dose ratio. METHODS: Between November 2007 and September 2010, 589 patients were converted at a mean post-transplant period of 4.6 years. We retrospectively reviewed routine clinical records to assess the safety of conversion to Tac QD for up to 12 months post conversion. RESULTS: Tac QD mean dose barely changed from preconversion values. Mean exposure (tacrolimus trough blood level [Cmin]) remained within the target window but was reduced by 12% (P = NS) with a trend toward less interpatient variability. Renal function at 12 months remained stable within 2.5% of the preconversion mean value. There were 14 (2.4%) cases of biopsy-proven acute rejection: 6 (1.0%) borderline and 8 (1.4%) Banff grade >= IA. Actuarial first year post-conversion graft survival was 96.3% and patient survival 99.0%. Twenty eight patients (4.8%) discontinued Tac QD and were switched to sirolimus: 19 for malignancy, 6 for thrombotic microangiopathy, and 3 with severe vascular changes; 3 patients were reconverted to Tac BD. CONCLUSIONS: Conversion from Tac BD to Tac QD in renal recipients was accompanied by stable renal function, a low risk of acute rejection, and less interpatient variability in drug exposure. PMID- 23726605 TI - Early steroid withdrawal compared with steroid avoidance correlates with graft failure among kidney transplant recipients with an history of diabetes. AB - BACKGROUND: Steroid minimization strategies attempt to reduce morbidity in kidney transplantation. Concern still exists regarding long-term outcomes using either steroid withdrawal or steroid avoidance regimens. METHODS: During a 10-year period, 572 primary kidney transplant recipients were treated with basiliximab, calcineurin inhibitors, and mycophenolate mofetil: 417 (72.9%) underwent a steroid-taper regimen over 2-3 months (steroid withdrawal) and 155 (27.1%), complete steroid avoidance (steroid avoidance). RESULTS: Despite no significant difference during the first 3 months (hazard ratio [HR], 1.23; P = .5349), steroid withdrawal recipients showed an increased risk of late acute rejection episodes (HR, 4.06; P = .0585), independent of recipient age >55 years (HR, 1.84; P = .0272). The risk of any adverse event was not different among steroid regimen groups (HR, 0.98; P = .8458), independent of recipient age >55 years (HR, 1.69; P = .0002), delayed graft function (DGF) (HR, 1.54; P = .0001), and positive donor Epstein-Barr virus serology (HR, 0.68; P = .0471). Intention-to-treat analyses revealed a significantly greater risk of graft failure only in diabetic recipients in the steroid withdrawal group (HR, 8.18; P = .0065), independent of confounding risk factors such as recipient age >55 years (HR, 1.99; P = .0244), >4 human leukocyte antigen-A, -B, and -DR incompatibilities (HR, 1.64; P = .0475), and DGF occurrence (HR, 2.63; P < .0001). CONCLUSION: Although both steroid minimization strategies were comparable regarding long-term safety and efficacy, an increased rate of graft failure was observed among diabetics who underwent steroid withdrawal compared with steroid avoidance. PMID- 23726606 TI - Urine of patients with acute kidney transplant rejection show high normetanephrine and decreased 2-hydroxyestrogens concentrations. AB - BACKGROUND: A shift from anti- to proinflammatory steroid hormones has been observed in chronic inflammation. We tested the hypothesis that this shift occurs also in kidney transplant rejection together with a rise of urinary catecholamine degradation product concentrations as a consequence of locally produced cytokines, thus further promoting rejection. METHODS: We examined 8 patients with an early rejection episode in the protocol biopsy ~2 weeks, 9 with biopsy-proven rejection at 2-3 months, and 18 without rejection, both at 2 weeks and 3 months after transplantation. Metanephrine, normetanephrine, and 2- and 16 hydroxyestrogens concentrations were measured by EIA. RESULTS: The median urinary concentrations of normetanephrine, but not metanephrine, were significantly higher in acute kidney transplant rejection in the first 2 weeks after transplantation (P < .05). During acute kidney transplant rejection at 2-3 months, but not in the first 2 weeks, after transplantation, 2-, but not 16 hydroxyestrogens, concentrations were significantly decreased (P < .05). CONCLUSIONS: We demonstrated that the downstream product of noradrenaline conversion normetanephrine was elevated in kidney transplant rejection in the first weeks after transplantation. This change may promote rejection together with an important proinflammatory and mitogenic steroid hormone shift, which becomes increasingly relevant over time. PMID- 23726607 TI - Immune monitoring in kidney transplant recipients could predict acute rejection by a new method: flow cytometric microcarrier assay. AB - BACKGROUND: Peripheral blood lymphocytes (PBL) of kidney transplant recipients stimulated in vitro release tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma into the supernate as detected by a flow cytometric microcarrier assay (FCMA) that we used to predict acute rejection episodes. METHODS: Fifty-two kidney transplant recipients were divided into 2 groups; stable function (STA; n = 30) and acute rejection (ARG; n = 22) for comparison with healthy volunteers (n = 10). PBL were stimulated for 8 hours with phorbol myphnistate acetate and ionomycin, thereafter detecting TNF-alpha and IFN-gamma in culture supernates by FCMA. Receiver operating characteristics (ROC) procedures were used to assess the sensitivity and specificity to predict acute rejection. RESULTS: The fluorescence intensity of TNF-alpha and IFN-gamma in culture supernates was significant higher among healthy controls than STA: 68.38 +/- 28.59 vs 51.08 +/- 34.05, respectively (P < .05). The intensity of TNF-alpha and IFN-gamma in ARG (144.47 +/- 81.21 and 116.61 +/- 53.89, respectively) was significant higher than STA (P < .001). The sensitivity and specificity to predict acute rejection were 86.4% and 86.7%, respectively, when analyzed by ROC curves combining TNF-alpha and IFN-gamma. The intensity in noncultured plasma from ARG or STA was significant lower than that in culture supernates from ARG and STA with sensitivity and specificity to predict acute rejection episodes of 63.6% and 73.3%, respectively, when combining TNF-alpha and IFN-gamma. CONCLUSIONS: Monitoring the expression of TNF-alpha and IFN-gamma in cell culture supernates after stimulation of kidney transplant recipient PBL in vitro using FCMA predicted acute rejection episodes. PMID- 23726608 TI - Using metabolomics to monitor kidney transplantation patients by means of clustering to spot anomalous patient behavior. AB - BACKGROUND: NMR spectroscopy-based metabolomics is a system approach used to investigate the metabolic profile of biological fluids with multivariate data analysis tools. The aim of this study was to examine the kidney graft recovery process noninvasively through the examinations of urine samples using (1)H NMR spectroscopy combined with chemometric tools. METHODS: Urine samples were treated as the source of metabolites reflecting the pathological and clinical conditions of patients with transplanted kidneys. We observed 15 subjects (9 males and 6 females) during the graft recovery process and initial days thereafter. The patients provided at least 9 samples each, applying advanced statistical methods of analysis: Principal Component Analysis (PCA) and Partial Least Square Discriminant Analysis PLS-DA). RESULTS: The PCA model (for all subjects exp. var. PC1 13.96% and PC2 9.88%) allowed us to clearly designate 3 stages of recovery: initially the kidney is not working; in the second stage, it regains functions, and the third stage includes follow-up during hospitalization. PCA analysis of a single patient follows graft recovery based on biochemical (metabolites) information, assigning the appropriate recuperation stage. CONCLUSIONS: NMR spectroscopy together with chemometric analysis allow monitoring of kidney graft recovery to identify patients who are not progressing within the normal range. PMID- 23726609 TI - Uridine diphosphate glucuronosyltransferase 2B7 variant p.His268Tyr as a predictor of kidney allograft early acute rejection. AB - BACKGROUND: Uridine diphosphate glucuronosyltransferase (UGT2B7) is responsible for conversion of mycophenolic acid to mycophenolic acyl-glucuronide (acylMPAG). Conflicting data exist regarding the role of UGT2B7 p.His268Tyr (802C>T, rs7439366) variant in the clinical course following organ transplantation. STUDY AIM: The aim of this study was to reveal an association between UGT2B7 p.His268Tyr (802C>T, rs7439366) polymorphism and kidney transplantation outcome. STUDY DESIGN, PATIENTS, AND METHOD: Genomic DNA of 235 kidney transplant recipients was genotyped for UGT2B7 802C>T using TagMan single nucleotide polymorphism (SNP) genotyping assay. Maintenance immunosuppression used mycophenolate mofetil (MMF) and cyclosporine A (n = 137) or tacrolimus (n = 98). Primary end-point was biopsy-confirmed acute rejection within 3 and 12 post transplantation months. Secondary end-points included gastrointestinal side effects, leukopenia, lymphopenia, neutropenia, and infections. Statistical analysis was performed with the aid of SAS System using kernel-smoothed estimates of acute graft rejection hazard function. The log-rank test and hazard ratio were used to reflect association between UGT2B7 802C>T variant and risk of acute graft rejection. RESULTS: Within 3 postimplantation months 38 (16.2%) patients experienced acute rejection; 33 were allele C carriers in UGT2B7 802C>T SNP and 5 were TT homozygotes (P < .0457). Allele C-associated risk of rejection was 2.50 and remained between 2.19 and 3.02 after adjustment for clinical confounders, ie, HLA mismatch, panel-reactive antibodies, donor age, repeated transplantation, induction therapy, donor type, delayed graft function, applied calcineurin inhibitor, or MMF dosing. We found no association between the polymorphism and gastrointestinal side effects, leukopenia, lymphopenia, neutropenia, and infections. CONCLUSION: UGT2B7 802C>T genotyping may help identify patients with excessive early acute rejection risk. PMID- 23726610 TI - Early expression profile of inflammatory markers and kidney allograft status. AB - Cellular rejection after renal transplantation, in general, occurs as a result of an interaction between immunologic processes that maintain graft tolerance versus allograft rejection. A potential mechanism that triggers such processes might be through the activation of the innate immune response initiated during organ procurement and ischemia/reperfusion injury, contributing to delayed graft function or graft dysfunction. Our goal was to test the impact of molecular markers that have key roles in innate immunity such as cytokines, Toll-like receptors (TLRs), and allograft inflammatory factor-1 (AIF- 1) at early times after transplantation. Blood samples from a total of 90 patients who received kidney transplants were included in this study. Three samples from each patient at different time intervals (pretransplantation, day 3, and day 6 after transplantation) were tested using a quantitative reverse transcriptase polymerase chain reaction. The mRNA transcripts were tested in association with glomerular filtration rates (GFR) as a measure of allograft function. Surgical samples obtained from transplant nephrectomy were used in a tissue array for immunohistochemistry testing. In peripheral blood mononuclear cells, the mean +/- standard error of mean (SEM) for interleukin 18 (IL-18), and IL-10 mRNA expression were increased and interferon-gamma was decreased in association with high GFR post-transplantation as compared with the pretransplantation expression levels. The mean +/- SEM for expression level of AIF-1 was increased 1.5-fold and for TLR-2 and TLR-4 were increased 1.2 to 1.4-fold in samples obtained on day 6 post-transplantation in association with low GFR (P < .05). In neutrophils, the mean +/- SEM levels of TLR-2 mRNA was increased 2-fold on day 6 in association with high GFR (P < .005), but was reduced 2.8-fold in association with low GFR (P < .002). In conclusion, the mRNA profiles of biomarkers presented here appeared to be informative for prediction of allograft status and outcome. PMID- 23726611 TI - Plasma exchange and intravenous immunoglobulin in the treatment of antibody mediated rejection after kidney transplantation: a single-center historic cohort study. AB - BACKGROUND: Antibody-mediated rejection (AMR) of a kidney graft has been increasingly recognized as an important cause of graft failure. Our historic cohort study sought to analyze its treatment and outcomes at our center. METHODS: All patients with AMR between 2005 and 2011 were treated with plasma exchange (PE), intravenous low-dose cytomegalovirus (CMV) hyperimmune globulin, and adjustment of basal immunosuppression. We analyzed data regarding baseline characteristics, rejection treatment with focus on PE, complications, and 1-year outcomes. RESULTS: Twenty-three AMRs occurred in 23 patients (10 male, 13 female) of mean age 41 +/- 16 years, all recipients of deceased-donor kidneys with a median of 3 HLA mismatches. The subjects had a median peak panel-reactive antibodies (PRA) of 7% (interquartile range [IQR] 1%-10%). Basal serum creatinine was 174 +/- 84 MUmol/L estimated glomerular filtration rate (eGFR) (eGFR 42 +/- 22 mL/min/1.73 m(2)), while 3 patients were dialysis- dependent. Median period between transplantation and rejection was 38 months (IQR 1.5-88.5). Concomitant T cell-mediated rejection was treated in 78% of cases. Median number of PE procedures per patient was 10 (range, 5-17). Treatment was estimated to be successful in 83%. Donor-specific antibodies documented in 12 patients (52%) disappeared or showed reduced titers in 7/10 patients with repeated measurements. An infection was present during treatment in 7 (30%) patients. Among 237 PE, there was 1 (0.4%) mild allergic reaction to fresh frozen plasma and significant metabolic alkalosis occurred after 7 (3%) procedures. One year after rejection the mean serum creatinine level was 144 +/- 52 MUmol/L and Kaplan-Meier estimated graft and patient survival rates were 62% and 95%, respectively. CONCLUSIONS: Intensive treatment with PE, intravenous immunoglobulin, and adjustment of basal immunosuppression were safe and effective to reverse AMR with improved graft function in the majority of patients. However, AMR was associated with markedly decreased 1-year graft survival and the optimal treatment remains uncertain. PMID- 23726612 TI - Antithymocyte globulin induction and rapid steroid taper leads to excellent results in kidney transplantation with donation after cardiac death donors: importance of rejection and delayed graft function. AB - Recipients of primary transplants from donation after cardiac death (DCD) donors (n = 40) performed from January 2005 to December 2009 were retrospectively reviewed and compared with recipients of primary transplants from donation after brain death (DBD) donors (n = 142). Patients received rabbit antithymocyte globulin induction and rapid steroid taper (RST; steroids stopped 5 days after surgery). Maintenance immunosuppression included tacrolimus and mycophenolate mofetil. Protocol kidney biopsies, creatinine (Cr), and measured glomerular filtration rate (mGFR; determined by cold iothalamate or 24-h creatinine clearance) were obtained at 1, 4, 12, and 24 months. Kidney biopsies for cause were conducted for unexplained elevated Cr, decline in mGFR, or new proteinuria. Biopsies were graded for rejection according to the Banff criteria. Graft survival at 3 years was 90.0% for DCD recipients and 86.6% for DBD recipients (P = NS). Rejection of any grade diagnosed on any biopsy through the first 2 years occurred in 18 DCD (45%) and 50 DBD (35%) recipients. Rejection of a grade more than Banff borderline occurred in 12.5% DCD and 12.7% DBD recipients. At 2 years, the mean +/- SEM Cr and mGFR for DCD recipients with rejection were 1.8 +/- 0.29 mg/dL and 59.2 +/- 8.5 mL/min versus 1.3 +/- 0.11 mg/dL and 67.0 +/- 7.8 ml/min for those without rejection. For DBD recipients with rejection, Cr and mGFR at 2 years were 1.7 +/- 0.12 mg/dL and 54.0 +/- 4.4 mL/min versus 1.4 +/- 0.11 mg/dL and 66.6 +/- 3.3 ml/min for those without rejection (P = NS). Comparing DCD to DBD, there was no statistical difference in mean Cr or mGFR outcomes. Regardless of group, grafts with delayed graft function had lower 3-year survival. DCD primary kidney transplant recipients treated with rabbit antithymocyte induction and RST have short-term graft survival and function equivalent to DBD recipients. RST appears to be acceptable immunosuppression for DCD recipients. PMID- 23726613 TI - Antithymocyte antibody-induced coagulopathy in renal transplant recipients. AB - BACKGROUND: Antithymocyte antibody (ATA) remains the most commonly used induction immunosuppressive agent in renal transplantation (RT). To date, few case reports of ATA-induced coagulopathy exist. METHODS: We performed a single-center, retrospective analysis of renal transplant recipients (RTRs) who underwent RT followed by ATA therapy between 2007 and 2011. The protocol used for deceased donor and unrelated living donor recipient immunosuppression was Thymoglobulin (TMG), methylprednisolone, Cellcept, Prograf, and Rapamune. In related living donor recipients, Simulect (SIM) was substituted for TMG. The international normalized ratio (INR) was routinely checked on days 0 and 2, and thereafter at the discretion of the surgeon. RTRs were transfused packed red blood cells (PRBCs) or fresh frozen plasma (FFP) at the discretion of the surgeon. RESULTS: During the study period, 257 RTs were performed at our institution. The following 18 RTR were excluded: simultaneous kidney and pancreas transplant recipients (4), RTRs on warfarin at the time of admission (2), RTRs who received OKT3 (2), and RTRs with INR >= 1.2 at the time of admission (10). Of the remaining 239 RTR, 208 (87%) underwent TMG induction therapy; 31 RTR (13%) underwent SIM induction therapy. The mean INR peaked in both groups on day 4 but was higher in TMG recipients (TMG 1.35, SIM 1.20). FFP was transfused in 65 TMG (31%) and 3 SIM (10%) recipients (P = .01); PRBCs were transfused in 88 TMG (44%) and 6 SIM (19%) recipients (P = .02). No patients returned to the operating room for bleeding complications within 7 days of RT. Patient age, gender, ethnicity, and diabetes status were not statistically significant factors in the development of coagulopathy. CONCLUSION: TMG administration is associated with coagulopathy. Using an INR screening protocol and an aggressive transfusion protocol, bleeding complications associated with coagulopathy can be avoided in this higher-risk group. PMID- 23726614 TI - Glucose intolerance is associated with increased intimal-medial thickness of the carotid artery and increased pulse-wave velocity in renal transplant recipients. AB - BACKGROUND: Although new-onset diabetes after transplantation has been demonstrated to have a significant negative impact on allograft and patient survival, the role of glucose intolerance (impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT], as asymptomatic hyperglycemia and borderline diabetes, has not been identified in renal transplant recipients. METHODS: We enrolled 32 renal transplant recipients (at least 1 year after transplantation) without prior evidence of diabetes at our institution in this study. Transplant recipients were divided into 2 groups (normal glucose tolerance group and glucose intolerance group) according to the results of their oral glucose tolerance test with 75 g of glucose. Glucose intolerance included IFG, IGT, and IFG/IGT. Normal glucose tolerance was detected in 19 patients, and glucose intolerance in 13: had 6 IGT, 2 IFG, and 5 IGT/IFG. Bilateral brachial-ankle pulse-wave velocity (baPWV) and intimal-media thickness (IMT) measured as markers of atherosclerosis were compared between the 2 groups. Insulin resistance was estimated with the homeostasis model assessment of insulin resistance (HOMA-R), and pancreatic beta cell function evaluated by the homeostasis model assessment of beta-cell function and insulinogenic index. RESULTS: The patients in the glucose intolerance group showed significantly greater baPWV and IMT than those in the normal glucose tolerance group. HOMA-R in the glucose intolerance patients was significantly higher than in the normal glucose tolerance patients. Linear regression analysis showed the increased IMT in the renal transplant recipients to be significantly correlated with HOMA-R. CONCLUSIONS: Renal transplant recipients with glucose intolerance had increased IMT and baPWV, suggesting that glucose intolerance in renal transplant recipients may induce atherosclerosis and that the rise in insulin resistance may contribute to the increased IMT in renal transplant recipients. PMID- 23726615 TI - Insulin resistance and insulin secretion in renal transplant recipients with hepatitis C. AB - BACKGROUND: Several reports have suggested an association between hepatitis C virus (HCV) infection and new-onset diabetes after transplantation (NODAT). NODAT is a common complication after renal transplantation, and it has been associated with increased long-term morbidity and mortality. HCV-positive recipients may have abnormal glucose metabolism, even though NODAT has never been previously diagnosed. The aim of this study was to analyze the pathogenic factors responsible for glucose metabolism in a series of HCV-positive renal transplant recipients. METHODS: The study population comprised 16 renal transplant patients who received their grafts from deceased or living donors with anti-HCV antibodies. HCV-negative transplant recipients were individually matched with these HCV-positive recipients by year of transplantation, sex, age, serum creatinine levels, and type of calcineurin inhibitors. None of the patients had been diagnosed with diabetes. Insulin secretion and insulin resistance were determined by a 75-g oral glucose tolerance test (OGTT) and compared between the 2 groups. Categories of glucose tolerance were defined according to World Health Organization criteria. RESULTS: Glucose intolerance (impaired fasting glucose, impaired glucose tolerance, diabetes mellitus) as assessed by OGTT was detected in 7 of the HCV-positive recipients (43.8%) and 3 of the HCV-negative recipients. The homeostasis model assessment of insulin resistance was greater in the HCV positive recipients than in the HCV-negative recipients. The homeostasis model assessment of beta-cell function was higher in the HCV-positive recipients than in the HCV-negative recipients. CONCLUSIONS: The frequency of glucose intolerance tended to be higher in HCV-positive recipients. Furthermore, insulin resistance was greater and insulin secretion higher in HCV-positive recipients, which indicated that the increase in insulin secretion compensated for insulin resistance observed in these patients. However, HCV-positive renal transplant recipients may ultimately develop NODAT as this compensation diminishes with time. PMID- 23726616 TI - Body fat percentage as a marker of new-onset diabetes mellitus after kidney transplantation. AB - BACKGROUND: New-onset diabetes after transplantation (NODAT) is a serious metabolic complication that can follow kidney transplantation. Several risk factors, including obesity, have been related to NODAT development. Obesity is defined as an excessive accumulation of body fat, and body fat percentage (BF%) has been commonly measured by different techniques, including bioelectrical impedance analysis. However, the correlation between an increase in BF% and the development of NODAT during outpatient follow-up has not yet been explored. We aimed to elucidate the association between BF% changes and the development of NODAT. METHODS: We performed a retrospective study involving 45 patients without diabetes who underwent kidney transplantation in our hospital between March 2008 and December 2010. We compared the BF% and demographic variables of patients who did and did not develop NODAT during follow-up. RESULTS: Four patients (8.9%) developed NODAT during a mean follow-up period of 30.3 months. The post transplantation increase in BF% was much higher in NODAT+ patients than the NODAT patients. Univariate analysis indicated that the rate of increase in BF% was a risk factor for NODAT (hazard ratio [HR], 1.08 [1.02-1.18]; P < .005). CONCLUSIONS: A large increase in BF% may be a risk factor for NODAT. These findings underline the importance of routine BF% measurements in medical practice. PMID- 23726617 TI - The association between serum uric acid levels at 3 months after renal transplantation and the graft outcome in living donor renal transplantation. AB - BACKGROUND: Hyperuricemia is a common complication in renal transplant recipients in the era of cyclosporine-based immunosuppression. The evidence regarding the impact of hyperuricemia on allograft survival is controversial. The aim of this study was to investigate the association between serum uric acid levels and renal allograft outcomes. MATERIALS AND METHODS: Between April 1991 and May 2011, adult renal transplants recipients were assessed retrospectively comparing serum creatinine levels at 3, 12, and 36 months, acute rejection rates, and long-term allograft survivals among normouricemic versus hyperuricemic (>7 mg/dL) patients at 3 months after renal transplantation. RESULTS: Of 378 patients, 152 (40.21%) showed hyperuricemia and 226 (59.79%) showed normouricemia. Mean serum creatinine levels were 1.48 +/- 0.38, 1.72 +/- 2.68 and 1.64 +/- 1.24 mg/dL at 3, 12, and 36 months after renal transplantation, respectively. Serum uric acid levels correlated negatively with serum creatinine levels at 12 months (P = .028). Graft survival rates at 10 years after renal transplantation were 88.6% among the normouricemic versus 78.8% among the hyperuricemic patients (P = .040). CONCLUSIONS: High serum uric acid levels measured at 3 months after renal transplantation were associated with poorer long-term graft function. PMID- 23726618 TI - The impact of post-transplant hemoglobin level on renal allograft outcome. AB - BACKGROUND: Anemia is a common complication of chronic renal disease and renal transplantation. Early post-transplant anemia is the consequence of blood loss, immunosuppressant therapy, and failure to produce sufficient erythropoietin. Late post-transplant anemia has been attributed to drug therapy, renal dysfunction, and infection. The effect of post-transplant anemia on renal allograft survival and acute rejection rates is not established. The aim of this study was to examine the impact of post-transplant anemia on renal function and allograft outcomes. MATERIALS AND METHODS: We included 411 patients who underwent living or deceased donor renal transplantations in our center from April 1990 to March 2010. The patients were divided into 2 groups according to their postoperative hemoglobin level at 1 month: anemic group (<12.0 g/dL in men, <11.0 g/dL in women) and nonanemic group (>= 12.0 g/dL in men, >= 11.0 g/dL in women). The outcome measures included postoperative serum creatinine levels at 12 and 36 months, acute and chronic rejection rates, as well as long-term graft survival. RESULTS: The acute and chronic rejection rates were significantly higher in the anemic group: 28.1% versus 19.7% (P = .000) and 24.1% versus 19.7% (P = .027), respectively. Postoperative serum creatinine levels at 12 and 36 months were not significantly different in patients with functioning grafts regardless of their anemia status (P = .530 and P = .430, respectively). Graft survival was lower with anemia: 85.4% versus 93.8% at 5 years, and 74.8% versus 83.5% at 10 years (P = .040). CONCLUSIONS: Post-transplant anemia was associated with poorer renal function at 12 months, higher acute rejection rates, and worse long-term renal allograft outcomes compared with subjects displaying normal hemoglobin levels. PMID- 23726619 TI - Functional hyposplenism in long-standing renal transplant recipients. AB - BACKGROUND: A nephrologist with expertise in ultrasonography noticed that patients with longstanding renal grafts had smaller spleens than subjects undergoing initial post-transplantation imaging. This putative finding prompted us to pursue a further investigation into splenic function based on Doppler ultrasound and hematologic parameters. METHODS: We enrolled 47 patients with functioning long-standing kidney grafts, measuring longitudinal diameter of the spleen, hilar and intrasplenic peak systolic velocities (PSV), and hilar and intrasplenic resistivity indices of the splenic artery as well as mean arterial blood pressure (MAP). Giemsa-stained peripheral blood smears were examined for the presence of Howell-Jolly bodies (HJBs) using light microscopy. The patients were then divided into HJB present (HJ(+)) or absent (HJ(-)) groups for further comparison. RESULTS: The overall mean age of 21 females and 26 males was 47.8 +/- 12.0 years, and the mean time after transplantation was 2750 +/- 1818 days (range, 208-6446). HJBs were detected in 23/47 patients (48.9%). The intrasplenic artery PSV was significantly lower and MAP higher in the HJ(+) group (P < .05). There was no difference in spleen size between the groups. DISCUSSION: HJBs in peripheral blood red cells, an indicator of hyposplenism, was associated with reduced intrasplenic artery PSV, suggesting dysfunction, which may play a role in the known vulnerability of renal transplant recipients to infections. PMID- 23726620 TI - Low graft function and ongoing hyperparathyroidism are closely related to post transplantation osteoporosis. AB - INTRODUCTION: Renal transplantation (RT) is the gold standard therapy for chronic renal failure. Immunosuppressive drug choice, malnutrition, adynamic bone disease and hyperparathyroidism are important factors impacting the development of posttransplant osteoporosis. Body composition analysis with bioimpedance devices (BIA) is a useful noninvasive tool to detect malnutrition among the RT population. We investigated the effects of graft function, immunosuppressive drug regimens and biochemical characteristics on bone mineral density of RT patients as well as the reliability of BIA measurements to diagnose osteoporosis. METHODS: One hundred three recipients with a minimum of 12 months post-RT follow-up underwent body composition analysis using the Tanita Analyzer. The last 6 months of monthly biochemical parameters and glomerular filtration rates (GFR) as well as drug regimens were collected retrospectively from patient charts. Patients were divided into 2 groups, according to their femoral neck and lumbal T scores, as osteoporosis (n = 42) and control groups (n = 61). RESULTS: The mean GFR of osteoporotic patients was significantly lower (P = .04) and parathyroid hormone (PTH) levels significantly higher (P = .002). According to BIA, osteoporotic patients showed lower bone mass, fat mass, visceral fat ratio, muscle mass, waist hip ratios, and body mass index values (P < .05). Correlation analysis revealed GFR to negatively correlate with PTH (r = -0.231, P = .010) and positively with femur t scores (r = 0.389, P = .0001) as well as with BIA findings (P = .0001). In contrast, PTH levels in negatively correlated with lumbar and femoral neck t scores (r = -0.22, -0.4 and P = .026, .0001, respectively) but not with BIA findings including bone mass. CONCLUSION: Changes in bone density after RT were affected by graft function. The rapid loss of bone mineral density emphasizes the need for prevention started in the early posttransplant period. BMD measurements provided a guide for treatment and for subsequent evaluation. PMID- 23726621 TI - Neither cyclosporine nor tacrolimus deteriorate endothelial function in renal transplant recipients assessed with reactive hyperernia index. AB - BACKGROUND: Cardiovascular mortality in renal transplant recipients is nearer 10 fold higher than in general population. Immunosuppressive therapy is one possible cause, for these drugs can modify cardiovascular risk factors, which can induce endothelial dysfunction, the first step in the process of atherosclerosis. The aim of this study was to compare vasodilatatory function of endothelium in renal transplant recipients in relation to the immunosuppressive drug-cyclosporine or tacrolimus. MATERIALS AND METHODS: We examined 40 patients at 48.9 +/- 36 months post-renal transplantation: 22 taking tacrolimus (group 1) and 18 taking cyclosporine (group 2). The renal transplant recipients were compared with a control group of 18 healthy people. Endothelial function was assessed by peripheral arterial tonometry (PAT) using the EndoPAT 2000 device to measure RHI (reactive hyperemia index) and AI% (augmentation index%). RESULTS: The overall median values of RHI were higher than the value accepted as a normal (1.67). The RHI median value in group 1 was 2.00 (quartile 1: 1.66; quartile 2: 2.72), not different from that in group 2 [1.90 (quartile 1: 1.56; quartile 2: 2.17)] or the controls [2.11 (quartile 1: 1.77; quartile 2: 2.50)]. Multivariate analysis revealed age to be the independent factor influencing RHI in all examined groups but treatment with calcium channel blockers appeared to be the only independent factor influencing RHI among renal transplant recipients. AI% values were not significantly different between the 2 groups of renal transplant recipients, but it was significantly higher among the controls than among subjects treated with tacrolimus. CONCLUSIONS: Vasodilatatory function of endothelium assessed by PAT in renal transplant recipients was not worse than in healthy people. It was not different between cyclosporine or tacrolimus. Arterial stiffness measured as AI% depend on age but not the calcineurin inhibitor, which showed little effect. PMID- 23726622 TI - Effect of reduced sympathetic hyperactivity on cardiovascular risk factors in kidney transplantation patients. AB - BACKGROUND: Hyperactivity of the sympathetic nervous system caused by chronic kidney disease has detrimental effects on hypertension and cardiovascular morbidity. Kidney transplantation does not ameliorate sympathetic nerve overactivity; however, bilateral nephrectomy eliminates it. The aim of the study was to evaluate the effect of bilateral nephrectomy on risk factors for cardiovascular morbidity and mortality in long-term follow-up. MATERIAL AND METHODS: We studied 24 kidney recipients aged 44 +/- 13 years who had undergone native bilateral nephrectomy. The control group included 17 recipients with preserved native kidneys who were matched for age, gender, cause of end-stage renal disease, immunosuppressive treatment, and time after transplantation. The mean follow-up after transplantation was 103 months. We evaluated arterial blood pressure, pulse pressure, metabolic markers, allograft function, echocardiography, and cardiac morbidity in all patients throughout follow-up. RESULTS: Systolic and diastolic blood pressures, number of antihypertensive drugs, and pulse pressure (a marker of arterial stiffness), were significantly lower among the study versus the control group (P < .05). The left ventricular mass, left ventricular mass index, left ventricular posterior wall thickness, and interventricular septum thickness were also lower in the study than in the control group (P < .05). Cardiac morbidity, including ischemic heart disease, atrial fibrillation, heart failure and stroke, occurred in 4 (16%) study group and 6 (35%) control subjects. Metabolic disorders, namely, new onset diabetes after transplantation, hyperuricemia, and dyslipidemia, occurred with similar frequencies in both groups. Serum levels of creatinine and estimated glomerular filtration rates were comparable in both groups, remaining stable throughout the observation time. CONCLUSIONS: Reduction of sympathetic hyperactivity by nephrectomy improved blood pressure control as well as decreased arterial stiffness and left ventricular hypertrophy over long-term follow-up. These results support native renal denervation to prevent the harmful effects of sympathetic hyperactivity on the cardiovascular system of renal transplant recipients. PMID- 23726623 TI - Left ventricular mass index and its relationship to ambulatory blood pressure and renal resistivity index in renal transplant recipients. AB - INTRODUCTION AND AIMS: Left ventricular hypertrophy (LVH) is frequently observed in patients with end-stage renal disease and renal allograft recipients. It is an independent, strong predictor of morbidity and mortality. Renal resistive index (RRI) is an important determinant of graft function in transplant recipients. In essential hypertension, increased RRI is associated with reduced renal function and tubulointerstitial damage. In this present study, we investigated the association of ambulatory blood pressure monitoring parameters and RRI on left ventricular mass index among renal transplant recipients. METHODS: Charts of 98 renal transplant recipients with echocardiography, ambulatory blood pressure monitoring, and renal Doppler ultrasonography as well as laboratory tests including serum creatinine, glomerular filtration rate, and C-reactive protein (CRP) level at the end of post-transplantation year 1 were analyzed in this study. LVMI was calculated using the Devereux formula with echocardiographic findings. RESULTS: Left ventricular mass index (LVMI) positively correlated with mean systolic blood pressure (SBP) (r = 0.512; P = .0001), mean nighttime SBP (r = 0.312; P = .007), mean nighttime diastolic blood pressure (DBP) (r = 0.427; P = .005), renal resistive index (RRI; r = 0.290; P = .004), and age (r = 0.371; P = .001). Multiple logistic regression analysis revealed that mean and maximum nighttime SBP and RRI were independent risk factors for LVMI (P = .001, .035, and .05, respectively). CONCLUSION: High RRI is one of the main indicators of cardiovascular disease in renal transplant recipients. Additionally, older age, high blood pressure, and nondipper pattern are important risk factors of LVH. PMID- 23726624 TI - Infectious complications in the first year post renal transplantation. AB - BACKGROUND: The aim of this study was a prospective assessment and determination of risk factors for infections among renal transplant recipients (Rtr) during the 1st year after renal transplantation (Rtx). METHODS: From June 2004 to October 2005, we performed 133 Rtx in 88 men and 45 women of overall mean age of 46 +/- 14 years (range; 13-75). RESULTS: During the first year post-Rtx, 88 (58 men and 30 women) infectious episodes were observed in 60 patients (45%). Thirty-nine (65%) required >=1 hospitalization. Most common was urinary tract infections (UTI; 54 episodes; 61%). The causative organism was identified in 61 of the 88 (69%) episodes: In 51 it was bacterial, in 8 cytomegalovirus (CMV), and in 2 fungi. Forty-three episodes (49%) were observed during the first 3 months; 22 (25%) between 3 and 6 months and 23 (26%) between 6 and 12 months post-Rtx. There were no significant differences between patients with versus without hospitalization owing to infections with regard to recipient gender and age, duration of dialysis pre-Rtx, donor kidney source, acute rejection episodes, donor age, or arterial hypertension. Diabetes was a significant risk factor for infections (odds ratio [OR], 1.154; 95% confidence interval [CI], 1.045-1.274; P = .001], as well as an immunosuppressive regimen that included tacrolimus, mammalian target of rapamycin inhibitor, corticosteroids, and anti-interleukin-2 monoclonal antibody as initial treatment (OR, 3.053; 95% CI, 1.007-9.349; P = .043). There was an increased prevalence of CMV infections after the chemoprophylaxis period (OR, 0.456; 95% CI, 0.358-0.580; P = .002). Mean duration of hospitalization was 11.5 days (range, 2-109). In 3 of 133 (5%) Rtr, the outcome was fatal. CONCLUSION: The frequency of infections during the 1 st year post-Rtx is influenced by the primary disease of the Rtr as well by the choice of immunosuppressive regimen. UTI remains the commonest infection, accounting for half of all infections in the first 3 months post-Rtx. There was an increased risk for CMV infection after the chemoprophylaxis period. PMID- 23726625 TI - Risk factors for recurrent urinary tract infection in kidney transplant recipients. AB - BACKGROUND: Urinary tract infections (UTIs) are the most common infectious complication in kidney transplant recipients (KTRs). The aim of this study to investigate the risk factors for and causative organisms of UTI as well as to evaluate the impact these diseases on allograft function in KTRs. METHODS: We analyzed patients who underwent kidney transplantation (KT) between January 2000 and December 2010. Among a total of 344 KTRs, 50 (14.5%) patients experienced 106 UTI episodes during a mean follow-up of 35.9 +/- 26.0 months. Twenty three patients experiencing recurrent UTI were compared with 27 nonrecurrent UTI patients and with 50 non-UTI patients matched for age, gender, and transplantation date. RESULTS: The number of patients with renal calculi, diabetes, or prior dialysis was significantly greater among the UTI group compared with control subjects. In addition, the number of patients with renal calculi was significantly higher among the recurrent compared with the nonrecurrent cohort (43.5 vs 7.4%; P = .003). The most common causative organism was Escherichia coli (64.1%), followed by Enterococcus species (20.5%). Higher rates of antibiotic resistance, especially Extended Spectrum Beta-Lactamasc (ESBL) production, were observed among the recurrent compared with the nonrecurrent group (53.1 vs 0%; P = .013). The rate of decline of estimated glomerular filtration rate was significantly faster in the UTI than the non-UTI group, whereas it did not differ between the recurrent and nonrecurrent group. CONCLUSIONS: Adequate treatment of an initial UTI to prevent as recurrent infection and prolong graft longevity is especially reasonable for KTRs with renal calculi or in cases of antibiotic-resistant microorganisms. PMID- 23726626 TI - Urinary tract infection and kidney transplantation: a review of diagnosis, causes, and current clinical approach. AB - Urinary tract infection (UTI), including bacteriuria, cystitis, and pyelonephritis, is the most common infectious complication after kidney transplantation (KTx). Over the past few years, many medical groups assumed this pathological process to be a "benign" disease in kidney transplant recipients (KTxR). However, increased medical and scientific advances in knowledge and management of KTx complications have raised questions about UTI as a pathological process that decreases and worsens kidney allograft function and survival. This review sought to clarify diagnostic criteria, as well as to describe factors associated with UTI in KTxR that expose its effects on the allograft. We sought to show the uncertainty of important topics within the field of UTI among kidney allograft recipients and to propose a practical clinical approach to KTxRs with UTI. PMID- 23726627 TI - Clinical investigation of human parvovirus B19 infection after renal transplantation in China. AB - OBJECTIVE: We investigated the incidence of human parvovirus B19 (HPV B19) infection after renal transplantation as well as the risk of anemia and renal allograft damage among infected transplant recipients in China. METHODS: We selected 114 patients at 1-18 months after renal transplantation for detection of HPV B19 DNA copies compared with a control population. Renal function and hematopoiesis were compared between infected and noninfected groups. RESULTS: Twenty-seven patients diagnosed with HPV B19 infection during follow-up (18.75%),which was a significantly higher number than among the general population over the same period. Infected versus nonaffected patients exhibited a significantly higher incidence of anemia and urinary abnormalities in addition to significantly lower values of hemoglobin, higher serum creatinine concentrations, and lower glomerular filtration rates. The 2 groups did not differ in the types or doses of calcineurin inhibitor (CNI) immunosuppressants. Two cases of pure red cell aplasia (PRCA) as confirmed using bone marrow biopsy, were observed in the infected group. They displayed HPV B19 DNA copy numbers >10(7)/mL and segmental mesangial cell proliferation on renal biopsy. The PRCA cases were cured with immunomodulatory therapy. CONCLUSIONS: The HPV B19 infection rate was significantly higher among renal transplant recipients than normal controls. Infections correlated with damage to the renal allograft, which may in turn cause PRCA. Immunomodulation therapy was effective to treat this complication of HPV B19 infection. PMID- 23726628 TI - Clinical and virologic courses of hepatitis B surface antigen-negative and hepatitis B core or hepatitis B surface antibody-positive renal transplant recipients. AB - Recent findings suggest that reactivation of hepatitis B (HB) virus (HBV) in renal transplantation recipients with a past HBV infection is an important cause of morbidity and mortality. In the present study, we reviewed the clinical and virologic courses of past HBV infections in recipients following renal transplantation. We retrospectively analyzed pretransplant HB surface antigen (HBsAg), HB core antibody (HBcAb), HB surface antibody (HBsAb), and HBV deoxyribonucleic acid (DNA) levels in 147 patients who underwent renal transplantation at our institution between September 2000 and November 2011. Thirty-four (23.1%) of the patients were diagnosed with a past HBV infection. The mean age of patients with a past HBV infection was significantly older than that of those without (48.4 vs 41.1 years, P = .002), while the duration of hemodialysis (HD) was significantly longer (138 vs 79.5 months, P = .027) and ratio of cadaveric transplantation procedures was higher (41.2% vs 21.2%, P = .035). During the follow-up period after renal transplantation, HBsAg was negative, HBV DNA was undetectable, and serum alanine aminotransferase level was normal in all patients. There were no statistically differences for graft and patient survival, and serum creatinine level between patients with and without a past HBV infection. Our results indicate that a past HBV infection is significantly associated with older age, longer duration of HD, and cadaveric transplantation. However, no HBV reactivation occurred in our previously infected patients, and the presence of HBcAb or HBsAb positivity did not influence graft or patient survival or renal function following renal transplantation. PMID- 23726629 TI - Maribavir use in practice for cytomegalovirus infection in French transplantation centers. AB - Maribavir (MBV), a UL97 inhibitor, shows good oral bioavailability, low host cell toxicity, and theoretical benefits to inhibit cross-resistant viruses. We herein examined clinical and virological outcomes of 12 patients, including 3 bone marrow recipients and 9 organ recipients infected with resistant cytomegalovirus (CMV) and treated with MBV during 2011-2012. All received at least 800-mg daily doses. They had developed clinical (12/12) and/or virological (11/12) resistance to CMV infection. Based on a decrease of viral load in blood >1.5 log copies/mL half of them responded to MBV treatment. The individual changes varied from a rapid decrease in viral load (n = 4) to no response (n = 3) with some late response slowly decreasing viremia (n = 3). In 2 cases MBV was used as secondary prophylaxis. No clear parameter emerged as a clinical surrogate for nonresponse to MBV. These results contrast with the lack of efficacy in phase III trials of MBV prophylaxis among stem cell recipients, which were possibly due to low doses or inadequate timing of drug initiation in the study. Additional clinical and surrogate laboratory markers are needed to determine antiviral responses to guide MBV use. Dosage ranging studies might benefit future MBV use. PMID- 23726630 TI - The risk of polyomavirus-associated graft nephropathy is increased by a combined suppression of CD8 and CD4 cell-dependent immune effects. AB - Polyomavirus-associated graft nephropathy (PAN) has emerged as a significant risk factor for kidney graft loss. We analyzed intracellular cytokine responses for possible protective versus permissive immunologic effects on BK-virus replication. One hundred five renal transplant patients included in a prospective single-center study were randomized to receive cyclosporine mycophenolate mofetil (MMF) (CM: n = 31), tacrolimus (Tac)/MMF (TM: n = 32) or Tac/MMF with conversion to everolimus (TErl; n = 32). Ten patients were not randomized (NR) due to contraindications to MMF. The immunosuppressive therapy was monitored pre- and posttransplantation at 4, 12, and 24 months using triple fluorescence flow cytometry for intracellular interleukin (Il)-2 Il-4 and interferon (IFN)-gamma production in phorbol myristate acetate- and lipopolysaccharide- stimulated lymphocyte cultures. BK viremia screening was performed by reverse-transcriptase polymerase chain reaction testing on days 0, 14, 30, 60, 90, 120, 180, 270, 360, and 720. Seven of 105 (6.7%) patients developed biopsy-proven PAN (CM: n = 1, TM: n = 3, TErl: n = 2, NR: n = 1), among whom 4 lost their grafts (TM: n = 1, TErl: n = 2, NR: n = 1). Twenty-one of 105 (20.0%) patients had documented BK viremia. BK viremia which preceded PAN in all cases, was significantly associated with TM immunosuppression: 4/31 (12.9%) CM: 11/32 (34.4%) TM; 5/32 (15.6%) TErl, and 1/10 (10.0%) NR patients (P = .034). BK-viremic patients showed significantly diminished CD8(+) T-cell Il-2 production at 120 days (P = .011) and 1 year posttransplantation (P = .014) compared with non-BK-viremic patients. Patients with PAN displayed significantly lower CD4(+) T-cell Il-4 responses at 1 and 2 years after transplantation (1 year: P = .007; 2 years: P = .001) with diminished IFN-gamma responses at 1 year after transplantation (P = .011). Our analysis showed the incidence of BK viremia to be increased among patients with defective cytotoxic CD8(+) T-cell -dependent immune reactivity. Recipients who progressed from BK viremia to overt PAN showed an additional immunologic defect in CD4(+) T cell function. Patients on a Tac- plus MMF-based immunosuppression were at higher risk to develop BK viremia. PMID- 23726631 TI - Total and free plasma concentrations of the active metabolite of leflunomide in relation to therapeutic outcome in kidney transplant recipients with BK-virus nephropathy. AB - Plasma concentrations of A771726, the active moiety of leflunomide, have been suggested to be associated with antiviral efficacy and/or an increased risk of toxicity. A771726 is >99% bound to serum albumin, which can be relevant in kidney transplant recipients (KTRs) displaying impaired function, which leads to increased pharmacologically active free drug concentrations. This study investigated the relationship of total (t-) and free (f-) A771726 concentrations with clinical outcomes. The 20 KTRs displayed a median daily dose and time on leflunomide of 20 mg (range, 10-50) and 16.5 months (range, 2-28), respectively. A median of 6 (range, 1-15) trough concentrations were measured in each patient. All patients received steroids and a calcineurin inhibitor (CNI) as well as 4 of them, cidofovir. To evaluate therapeutic efficacy, we monitored viral loads in the urine and blood, serum creatinine, and kidney histology. To detect toxicity, we recorded blood and platelet counts, hematocrit, hemoglobin concentrations, liver enzymes (alanine aminotransferase [ALT], and aspartate aminotransferase [AST]), and skin diseases. The median t-A771726 concentration was 31.5 mg/L (interindividual range, 11.0-56.4); the median f-A771726 concentration and fraction were 55.8 MUg/L and 0.19% (interindividual ranges, 27.9-148.4 MUg/L and 0.12%-0.50%), respectively. A weak but significant inverse correlation was observed between the free drug fraction and both the glomerular filtration rate estimated by the Modification of Diet in Renal Disease formula (MDRD-GFR) (r = 0.202) and serum albumin (r = -0.358). Higher MDRD-GFRs were associated with greater t-A771726 concentrations. There were no significant associations between efficacy parameters and either the t- or f-A771726 concentration or between the t A771726 concentration and toxicity parameters. In contrast, the f-A771726 concentration was significantly associated with leukopenia. These results indicated that f-A771726 concentrations may be more reliable than t-A771726 content to estimate the risk of leukopenia. Intensified elimination due to a higher free drug fraction and compromised absorption associated with a low GFR may have been responsible for the positive correlation between MDRD-GFR and t A771726. PMID- 23726632 TI - Pneumocystis jirovecii pneumonia in renal transplant recipients: a national center experience. AB - BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) represents an important cause of morbidity and mortality in kidney transplant recipients. In recent years an increasing number of PCP outbreaks have been reported worldwide. PATIENTS AND METHODS: We performed a retrospective study including the demographic, clinical, laboratory, and therapeutic parameters of all renal transplant recipients with PCP in Slovenia during the period from January 1, 2006, to December 31, 2011. RESULTS: At the end of the 2011, 13/601 (2.2%) kidney transplant recipients followed in our center experienced PCP. The median time from transplantation to development of disease was 17 months (range, 3-148). Three recipients had PCP during the first year after transplantation because of early trimethoprim and sulfamethoxazole (TMP-SMX) discontinuation; in 3, it was related to acute graft rejection treatment; and in 6, to cytomegalovirus (CMV) infection. Pneumocystis jirovecii was microbiologically confirmed in 10 recipients. In 10 of 13 patients serum concentrations of lactic acid dehydrogenase (LDH) were increased. In addition, serum concentrations of beta-d-glucan was determined in 9 cases was elevated in each one. CONCLUSION: The incidence of PCP was low, most probably owing to prolonged (12 months) TMP-SMX prophylaxis. Premature TMP-SMX discontinuation in the first year after transplantation, treatment of graft rejection and CMV infection seemed to be risk factors for PCP. Elevated serum beta-d-glucan concentration was a better noninvasive indicator of P jirovecii infection than elevated serum LDH concentration. In cases with no microbiological conformation, beta-d-glucan and LDH concentrations were helpful to establish the diagnosis of PCP for early treatment. PMID- 23726633 TI - Routine microbiologic culture of kidney transport fluid: a single-center retrospective study. AB - BACKGROUND: Microbiologic culture of renal transplant fluid (RTF) has been performed since the 1950s and remained routine in some transplant centers. Although not evidence based, this conventional practice is relatively time consuming and costly. This single-center study sought to determine the prevalence and clinical significance of positive microbiologic cultures of RTF. METHODS: Data on RTF were collected retrospectively from renal transplant cases who had samples taken from RTF for microbiology from 2000 to 2006. Review of patient notes and microbiology reports identified positive results, time and type of antibiotic, posttransplantation development of sepsis, and any significant infection. RESULTS: Over the 6-year period we performed 370 renal transplantations from cadaveric or non-heart-beating donors. The living related or unrelated cases (n = 67) were excluded because we did not obtain RTF samples. Among the 303 remaining recipients, 237 (78%) had microscopy, culture, and sensitivity reports available. Positive cultures were identified in 66 patients, of whom 2% (n = 6) developed postoperative complications, including those related to organisms identified in the RTF in 3 patients. CONCLUSIONS: Early identification of microorganisms, particularly in transplant patients, affects patient outcomes and quality of life. Routine screening of RTF for contamination allows for RTF-informed treatment of symptomatic patients after transplantation. PMID- 23726634 TI - Influence of ureteric anastomosis technique on urological complications after kidney transplantation. AB - The best technique for anastomosis of the donor ureter remains unresolved and an individual surgeon's preferred technique is likely to be based on training background. This retrospective analysis compares three ureteroneocystostomy techniques in 204 consecutive transplants with an overall ureteric complication rate of 7.3%. Ureteric complications after kidney transplantation present early, are more common when using deceased donor kidneys, and, require complex reconstructive surgery to resolve. Three significant and related findings have been demonstrated with a common theme related to the length of the transplanted ureter, and not, the debate over extravesical versus intravesical techniques. PMID- 23726635 TI - Nutritional status and intrarenal resistive indices after kidney transplantation. AB - BACKGROUND: Obesity predicts vascular stiffness, which is prevalent among kidney transplant patients. However, the influence of obesity has not been established on parameters of renal vascular resistance variation. The aim of this study was to analyze the influence of nutritional status on intrarenal resistive parameters as measured in the early period after successful kidney transplantation by Doppler ultrasound. METHODS: Both pulsatility index (PI) and resistance index (RI) in the kidney graft were measured by Doppler sonography twice: at 2 to 4 days and before hospital discharge (mean 22 days; 95% confidence interval 21-23) after transplantation. Nutritional status was scored according to World Health Organization criteria. RESULTS: Among 513 patients, 29 were underweight; 280, normal; 166, overweight; and 38, obese. Both PI and RI values were significantly increased consistent with recipient nutritional status (analysis of variance: P < .001). Post hoc analysis showed significant differences in PI and RI measurements for obese versus underweight or normal weight groups. Multivariate analysis revealed an influence of body mass index on PI and RI measurements before hospital discharge to be independent of other variables, including recipient age, prior delayed graft function and cold ischemia time. CONCLUSIONS: Excessive nutritional status was associated with increased renal vascular resistance among kidney transplant patients. Nutritional status should be considered for the proper interpretation of intrarenal Doppler measurements. PMID- 23726636 TI - Ultrasonography parameters and histopathology findings in transplanted kidney. AB - BACKGROUND: Until now studies have shown conflicting results about morphologic and hemodynamic parameters in predicting histopathology results in renal graft malfunction. We sought to analyze whether parenchymal thickness relative to graft length and resistive index (RI) measured by ultrasonography can predict histopathology findings on renal biopsy. PATIENTS AND METHODS: We retrospectively analyzed 72 deceased donor renal allograft biopsies and respective allograft ultrasounds, performed on 68 patients (57% men) with mean age of 50 years (range, 21-73), with kidney graft dysfunction in 2010 and 2011. Parenchymal thickness relative to graft length and RI were compared with different histopathology diagnoses: Acute rejection, chronic rejection, chronic kidney changes, acute tubular necrosis (ATN), and other diagnoses. RESULTS: The mean value of the RI and of the parenchymal thickness/graft length ratio (parenchyma size index [PSI]) was 0.81 +/- 0.10 (SD) and 1.48 +/- 0.27 (SD), respectively. Enlarged PSI was significantly higher in ATN (mean 1.72 +/- 0.26) compared with no ATN (mean 1.39 +/- 0.23; P < .001), and lower when chronic changes were present (mean 1.40 +/- 0.25 for chronic changes vs mean 1.62 +/- 0.28 for no chronic changes; P = .004). In the group without ATN, PSI was enlarged in acute graft rejection compared with no graft rejection (mean 1.50 +/- 0.24 vs 1.24 +/- 0.13, respectively; P < .001), whereas in the whole group, including ATN, PSI showed no differentiating power for acute rejection (P = .526). RI was significantly higher in ATN than without it (mean 0.91 +/- 0.10 vs 0.79 +/- 0.08, respectively; P < .001), whereas the RI was not increased (but was actually lower) in acute graft rejection compared with no graft rejection, neither in the whole group (mean 0.81 +/- 0.09 vs 0.82 +/- 0.12, respectively; P = .611). CONCLUSIONS: Enlarged parenchymal thickness/graft length ratio on ultrasonography was observed in ATN and acute allograft rejection. The RI was increased in ATN, but not in acute allograft rejection. Decreased parenchymal thickness/graft length ratio was observed in chronic kidney changes. PMID- 23726637 TI - Proteinuria/creatininuria index and its correlation with the 24-hour proteinuria in renal transplanted patients. AB - BACKGROUND: Proteinuria (P) is a early sign of inflammation and renal damage. It has an important role in the detection, diagnosis, and monitoring of renal disease in transplanted patients. The aim of this study was to examine the correlation between random urinary proteinuria/creatininuria index (P/CI) and 24 hour total protein excretion among stable renal transplant patients. MATERIALS AND METHODS: We obtained 1511 samples of 24-hour protein excretion (24-hr P) with corresponding P/CI were obtained from 197 adult patients beyond 6 months post transplantation between 2009 and 2011. The population was divided into 2 groups: One to obtain a population of justification (755) and another, of validation (755). A scatter graft yielded was obtained by Pearson's coefficient of correlation. A "receiver operater characteristic curve" analysis was carried out to evaluate the sensitivity and specifity of PCI and 24hr-P, showing a cutoff of 0.15 for PCI. RESULTS: The PCI and 24 hr P Pearson's correlation was significant (r = 0.89; P = .0001). The sensitivities of the P/CI for the justification and the validation samples were 97% and 94%, respectively; the a cutoff was 0.15. Their negative predictive values for P/CI were 92% and 84% respectively (cutoff, 0.15). The specificity was below 50% in both groups. CONCLUSIONS: We observed a significant correlation between P/CI and 24 hr P. The sensitivity was slightly higher than the specificity (50%) but the negative predictive value was >92%. The use of P/CI seemed to be adequate for screening of protein excretion during renal transplant recipient follow-up. PMID- 23726638 TI - Nephron underdosing as a risk factor for impaired early kidney graft function and increased graft loss during the long-term follow-up period. AB - BACKGROUND: It is generally accepted that kidneys procured from female donors may not perform optimally in male recipients, mostly due to their smaller size and nephron underdosing. Nowadays, conflicting results have been published regarding the detrimental effect of H-Y incompatibility on the long-term prognosis of male kidneys transplanted into female recipient. The aim of this study was an analysis of the impact of donor-recipient gender matching on early function and survival of grafts among a relatively homogenous cohort of kidney recipients. METHODS: We analyzed 477 consecutive first kidney transplants from deceased donors with longer than 3-month survival. Highly sensitized recipients and those with graft losses attributed to noncompliance were excluded from the study. Early kidney graft function was defined based on serum creatinine (Scr) concentrations at postoperative day 3 and the need for dialysis: immediate graft factors (IGF; Scr < 3mg/dL), slow graft function (Scr > 3mg/dL and no dialysis) or delayed graft function (DGF; dialysis in the first posttransplant week). RESULTS: The lowest 10.7% incidence of IGF was observed among male recipients of female kidneys (F M). For female donor, the relative risk for IGF in female recipient was 3.13 (1.35-7.26) than in male recipient. The frequencies of DGF were similar. During the 5-year follow-up, 54 grafts were lost. The risk for loss was significantly higher in the F-M group: 19.6% vs 8.8% in the three other combined groups (odds ratio = 2.54; 95 confidence interval (1.41-4.59); P = .002). CONCLUSIONS: Transplantation of the female kidney to a male recipient impairs early kidney graft function increasing the risk of graft loss over a 5-year follow-up. This phenomenon seems to be related to nephron underdosing. PMID- 23726639 TI - Comparison of cyclosporine and sirolimus effects on serum creatinine level over five years after kidney transplantation. AB - INTRODUCTION: Conversion from cyclosporine to sirolimus (SRL) after organ transplantation may improve renal function. The current study considers the effects of conversion during a 5-year period. MATERIALS AND METHODS: Among 98 primary kidney recipients, 88 completed the study on cyclosporine (n = 59) or SRL (n = 29) treatment. Conversion to SRL was performed between 3 and 6 months post transplantation. The serum creatinine level was tested on 1 day as well as 3, 6, 9, 12, 15, 18, 21, 24, 36, 48, and 60 months after transplantation. The data were analyzed using student t test, chi square, repeated measures, and a mixed model for multivariate analysis. RESULTS: The mean serum creatinine levels in the cyclosporine and SRL groups were 1.78 +/- 0.68 and 1.62 +/- 1.01, respectively (P = .04). Using repeated measure analysis, there was an interaction between time and the drug (P = .039). A separate comparison showed that serum creatinine levels were significantly different between the 2 groups at time points 11 and 12. Using multivariate analysis to control the possible effect of demographic or clinical features, we confirmed that conversion was the most significant explanation for the renal function improvement. CONCLUSION: Compared with cyclosporine, we observed a preference for SRL as the maintenance immunosuppressant after renal transplantation. PMID- 23726640 TI - Calcineurin inhibitor conversion to rapamycin can improve graft function in living donor kidney transplantation with older donors. AB - BACKGROUND: Recipients of living donor kidney transplantations from older donors often experience a lower glomerular filtration rate (GFR) than those from young donors. Calcineurin inhibitors (CNI) may cause nephrotoxicity, especially in recipients of older donor organs. The aim of this study was to investigate whether CNI withdrawal and conversion to rapamycin improved graft function among transplantation recipients of living donor kidneys from older donors. METHODS: We collected 83 living donor kidney transplantations using donors aged >50 years from January 2004 to December 2009, including 25 who underwent conversion to rapamycin at the end of 3 months, while 58 cases were maintained on CNI. Baseline characteristics, complications, and graft functions were compared between the groups. RESULTS: Donor age, recipient age, body weight, human leukocyte antigen mismatch, delayed graft function, acute rejection rate, serum creatinine, and estimated GFR were comparable between the 2 groups at the end of 3 months. The 1 year serum creatinine were 111.8 +/- 25.5 MUmol/L in CNI withdrawal versus 132.5 +/- 35.9 MUmol/L in the CNI-maintained group (P = .013) with 1-year estimated GFR of 86.9 +/- 8.2 mL/min versus 77.4 +/- 7.2 mL/min and 3-year estimated GFR of 76.1 +/- 7.8 mL/min versus 67.0 +/- 6.4 mL/min, respectively (both P < .001). The rates of acute rejection were 24% versus 22.4%, and chronic rejection, 4.0% versus 10.3% respectively (P > .05). One CNI withdrawal patient (4.0%) lost the graft function while 4 (6.9%) did so in the CNI-maintained group (P > .05). Logistic multivariate regression showed that maintained CNI usage, acute rejection episodes, and female donors to male recipients were independent risk factors for abnormal 1-year serum creatinine levels (P < .05). CONCLUSION: CNI withdrawal with conversion to rapamycin improved graft function in living donor kidney transplantations from older donors. PMID- 23726641 TI - Potential influence of tubular dysfunction on the difference between estimated and measured glomerular filtration rate after kidney transplantation. AB - PURPOSE: Because no consensus exists regarding the most accurate calculation to estimate glomerular filtration rate (GFR) based on serum creatinine concentrations (sCr) after kidney transplantation, this study sought to assess the potential role of tubular dysfunction on GFR estimates using various equations as well as the effect of pharmacologic blockades on tubular secretion of creatinine on creatinine clearance (ClCr). METHODS: Iohexol GFR (mGFR) was performed in 17 stable kidney transplant recipients(R) at >24 months post transplantation. Their mean age was 48.3 +/- 11.3 years. All R were treated with a calcineurin inhibitor (CNI). At the time of study we measured sCr, 24 hour ClCr, cystatin C, 24-hour proteinuria, microalbuminuria, FE Na, alfa1 microglobulinuria (alfa1-MG), and CNI concentrations. To block tubular secretion of Cr, recipients were prescribed cimetidine (2400 mg) 2 days before the sCr measurement. Additionally, to exclude dietary influences on sCr, R did not eat meat for 2 days before testing. GFR was estimated using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD EPI), Cockroft-Gault (C&G), and Cystatin C (Cyst C) GFR equations. Mean kidney graft function over the previous 6 months was used as the control. Pearson correlation was determined between the differences between mGFR and estimatedGFR: Iohexol minus MDRD, EPI, Cyst C or C&G GFR for paired estimates. The diagnostic accuracy of the eGFRs to detect an mGFR of 60 mL/min/1.73 m(2) was examined by receiver operating characteristic curves. RESULTS: Mean mGFR was 75.2 +/- 35.8 mL/min/1.73 m(2). The sCr increased but the 24-hour ClCr, MDRD, EPI, and C&G decreased after vs before cimetidine. The difference was significant for sCr (F = 12.933; P = .002) and MDRD GFR (F = 15.750; P = .001). mGFR was not significantly higher than all pair values of eGFRs, and not significantly lower than 24-hour ClCr before and after cimetidine. However, in comparison to all eGFRs, ClCr after cimetidine most approached mGFR. A significant positive correlation was observed between alfa1-MG and the difference between mGFR and MDRD (before, r = .543 [P = .045]; after cimetidine, 0.568 [P = .034]), EPI (before, r = 0.516 [P = .050]; after cimetidine, r = 0.562 [P = .036]), and ClCr (r = 0.633; P = .016), C&G (P = .581; P = .029) before cimetidine. Accuracy of eGFRs to detect mGFR of 60 mL/min/1.73 m(2) showed EPI GFR before cimetidine to show diagnostic accuracy for patients with GFR >60 mL/min/1.73 m(2) with a sensitivity of 81.8% and a specificity of 71.4%. CONCLUSIONS: Because mGFR is unavailable in many transplant centers, determination of ClCr after cimetidine may help to achieve a more accurate diagnosis of CKD among transplant patients. PMID- 23726642 TI - Antiphospholipid antibodies in renal allograft recipients. AB - BACKGROUND: Antiphospholipid antibodies (APLAs) are associated with an increased risk of thrombosis. The role of APLAs as a marker of thrombosis in renal recipients has not been established. We sought to determine the prevalence of APLAs in renal recipients and investigate their association with thrombosis. MATERIAL: The study included 37 renal recipients: 17 women and 20 men of ages 22 69 years. The 2 subgroups were one of patients without (n = 27; T-) and a second, with a history of severe thrombosis (n = 10; T+) subgroups, We determined lupus anticoagulant (coagulation methods) and anticardiolipin antibodies (ACL), anti Beta2GlicoproteinI antibodies (anti-B2GPI), antiprothrombin antibodies (anti-PT) in immunoglobulin (Ig)G and IgM isotype using enzyme-linked immunosorbent assay. The determinations were made twice at a 6-months interval. The mean duration of follow-up was 12 months. RESULTS: The most commonly detected antibodies were anti beta2GPI IgM (16.22%) and aCL IgG (13.8%). No differences were identified when the prevalence APLA was compared between T- and T+. A significant correlation was found between anti-beta2GPI IgM and aCL IgM (P = .0328); anti-beta2GPI IgM and aCL IgG (P = .0198) and aCL IgM and aCL IgG (P = .0252). No differences in serum creatinine were observed between the T- and T+ cohorts. During the follow-up, 2 female patients in the T+ produced APLAs and were treated with low-molecular weight heparin. During follow-up one patient developed thrombosis (TMA), which led to graft loss. The other patient with normal renal graft function did not experience a recurrence of thrombosis. CONCLUSIONS: The prevalence of APLAs in renal transplant recipients was higher than in the general population. The study did not demonstrate any predictive value of APLAs as markers of thrombosis in renal recipients. Routine determination of APLAs is not necessary in all transplant recipients. PMID- 23726643 TI - Radical cystectomy and orthotopic urinary reconstruction in patients with bladder cancer after renal transplantation: clinical outcomes and description of technique. AB - OBJECTIVES: Radical cystectomy (RC) with pelvic lymph node dissection and urinary diversion is the standard treatment for muscle-invasive bladder cancer. In the setting of prior renal transplantation, surgical treatment remains the mainstay but is technically challenging. We report our patient outcomes in this unique population with a description of the technique. METHODS: We identified five patients with a history of renal transplantation who underwent RC and orthotopic urinary diversion. Preoperative clinical and demographic features were compiled and disease-specific and functional outcomes were assessed. Intraoperative technical challenges and maneuvers for avoiding complications are highlighted. RESULTS: Four patients were male and one was female, with a median age of 64 years. Gross hematuria was the most common sign at presentation. Clinical staging was T2, T2 with carcinoma in situ (CIS), high-grade (HG) Ta with CIS, T2 with squamous differentiation, and HG T1, and pathologic tumor stage was pTisN1, pT3N0, pTisN0, pT3N0, and pT0N0, respectively. One patient received a Studer-type diversion and four underwent Hautmann diversion. Median follow-up after cystectomy was 12.9 months. Graft ureteral identification was aided by the use of intravenous dye in all patients. Ipsilateral pelvic lymph node dissection was not possible in any patient. All patients are alive at follow-up, with two experiencing recurrence at 7.2 months and 66.8 months. No patient experienced a significant decrease in estimated creatinine clearance postoperatively. Postoperative daytime control was reported by all patients whereas two noted complete nighttime control. CONCLUSIONS: RC with orthotopic diversion is a technically demanding procedure in patients with a history renal transplantation. Meticulous technique and careful attention to the altered anatomy are required for successful outcomes. PMID- 23726644 TI - Laparoscopic fenestration versus percutaneous catheter drainage for lymphocele treatment after kidney transplantation. AB - BACKGROUND: Laparoscopic fenestration (LF) and percutaneous catheter drainage (PCD) are widely accepted treatments for symptomatic lymphoceles. The aim of this study was to review the results and compare the outcomes of LF with those of PCD. PATIENTS AND METHODS: Among 1363 patients who underwent kidney transplantation at our institute between 1999 and 2011, 35 (2.5%) developed symptomatic lymphoceles. Among them, 7 were treated by LF after PCD; 10, LF only, and 18 PCD only. The patients were divided into 2 groups based upon the treatment method: LF (n = 17) and PCD-only groups (n = 18). RESULTS: No intergroup differences in age, gender, diabetes prevalence, retransplant rate, delayed graft function, or serum creatinine was observed at 7 days after the treatment. However, acute rejection episodes and sirolimus use were more frequent among the LF group (P = .028). Furthermore, median drainage on the first day was significantly greater in the LF versus PCD group. After catheter insertion, the PCD group showed a significant decrease in drainage on the following day, but no decrease was observed in the LF group. CONCLUSIONS: LF is a safe treatment for symptomatic lymphocele. LF should be held in reserve for treatment failures after PCD. LF seems to be a more reasonable first-line treatment for symptomatic lymphoceles in patients at high risk for graft dysfunction. PMID- 23726645 TI - Influences of implant condyle geometry on bone and screw strains in a temporomandibular implant. AB - A 3D finite element model of an in vitro implanted mandible was analysed. The load point was placed on the condyle in three positions (inside the mouth, centred and outside) to simulate different contact points between the mandible condyle and the temporal bone. The strain fields in the condyle were assessed and detailed around the surgical screws. The temporomandibular implant studied here was modelled on a commercial device that uses four screws to fix it in vivo in a very similar position. The boundary conditions of the numerical model simulated a load on the incisors with a 15 mm mouth aperture. The same contact loads were applied to the two condyles. Numerical results were successfully obtained for the three different contact points: the inside contact produced lower strains on the condyle. The first screw created a critical strain distribution in the bone, just under the screw. The study shows that centred and inside contact induces lower strain distributions. This suggests that spherical condyle geometry should be applied in order to reduce the strains in fixation. As the top screw was observed to play the most critical role, the third screw is in fact unnecessary, since the lower strain distribution suggests that it will be loosened. PMID- 23726647 TI - What we remember from a stressful episode. AB - A stressful episode is thought to be consolidated better because of a stress induced activation of the hypothalamus-pituitary-adrenal (HPA) axis. However, human experimental studies addressing this hypothesis directly are lacking. Thus, we investigated memories of the stressful episode itself. Furthermore, we aimed to determine the influence of stress on recollection and familiarity processes. Participants (n=63) were subjected to a psychosocial stressor (Trier Social Stress Test, TSST) or a newly developed non-stressful control condition (friendly TSST). During both conditions, they were exposed to a committee and visual stimuli, either bound to the situation (central) or not (peripheral). The next day, participants engaged in unexpected recognition tasks. Negative affect and salivary cortisol concentration increased in stressed but not in control participants. The following day, stressed participants recognized central objects and the committees' faces better than control participants. Furthermore, recollection contributed significantly more to memory performance in stressed than in control participants. Our findings are congruent with the idea of enhanced memory binding under stress combined with enhanced memory consolidation of information acquired during stress. What we remember from a stressful episode appears to be determined by the strength of the association between the stressor and the material to be remembered. PMID- 23726646 TI - Examining the developmental interface of cortisol and depression symptoms in young adolescent girls. AB - Despite the substantial amount of data supporting a link between HPA-axis functioning and depression, the ontogeny of this association is not known. The aim of the present study was to contribute data on the developmental interface of HPA-axis functioning and depression in girls by testing associations between repeated measures of depression symptoms and cortisol levels in childhood and early adolescence. Girls (N=232) and their mothers, who were participating in a longitudinal study, were interviewed about depression symptoms annually from ages 9 to 12 years. Cortisol was assayed from saliva at ages 10 and 12 years upon arrival to the lab and following administration of the cold pressor task (CPT). Time of day of collection of saliva and level of pubertal development were included as covariates in model testing. Although most girls did not show an increase in cortisol in response to the CPT, lower levels of output during the CPT were associated with higher levels of depression symptoms. These findings were observed only for cortisol levels assessed at age 12 years. Girls with low levels of cortisol output at age 12, and decreases in output from ages 10 to 12, had stable or slightly increasing depression symptoms from ages 9 to 12 years. We conclude that associations between HPA-axis functioning and depression emerge as early as age 12. However, individual differences in cortisol levels at age 12 also were associated with depression symptoms at earlier ages. The data suggest two possibilities: (1) that childhood depression is associated with HPA-axis dysregulation, but that age related changes in the sensitivity or plasticity of the HPA-axis may result in a delay in the emergence of such an association, or (2) that dysregulation of the functioning of the HPA-axis develops following repeated experience of depression symptoms. PMID- 23726648 TI - The effect of knee brace and knee sleeve on the proprioception of the knee in young non-professional healthy sportsmen. AB - BACKGROUND: Proprioception has been defined as the capacity to feel the position of a joint in space as sensed by the central nervous system. Prophylactic knee braces are supposed to help in knee injury prevention not just with a mechanical support of the joint but also improving proprioception. The main aim of this study was to determine the effects of a knee brace and a knee sleeve on knee proprioception. The secondary aim was to determine if different starting angles of the knee and different movement directions influence knee proprioception. METHODS: We tested a group of twenty healthy male sport students without knee injuries. They were tested with the brace, with the sleeve and without support. The threshold of detection of passive knee movement with a starting knee angle of 30 degrees and 60 degrees , both in flexion and extension was determined. RESULTS: We did not find any statistically significant change in the threshold of detection of passive knee movement wearing the brace or the sleeve compared to the unsupported condition (p=0.462, alpha=0.05). We found a significantly lower proprioceptive sensitivity starting at the more flexed knee angle (p=0.005, alpha=0.05) and moving in extension than in the other test situations (p=0.001, alpha=0.05). CONCLUSION: Movement direction and starting position appear to influence the threshold of detection of passive knee movement. The results of this study also suggest that knee supports do not influence either positively or negatively knee proprioception of uninjured active subjects. PMID- 23726649 TI - Effect of the preservative and temperature conditions on the stability of Leishmania infantum promastigotes antigens applied in a flow cytometry diagnostic method for canine visceral leishmaniasis. AB - The control of canine visceral leishmaniasis (CVL) is imperative, but euthanasia of seropositive dogs has been highly criticized. Commonly used, immunodiagnostic tests, including Dual-Path Platform(r), enzyme-linked immunosorbent assay, and immunofluorescent antibody test, have failed at detecting asymptomatic dogs in endemic areas. In this context, new serological methods are needed. Flow cytometry serology has demonstrated potential as a test with excellent performance for CVL. In this study, we proposed to establish the best conditions for preserving Leishmania infantum promastigote antigens employed in this serology test. During 12 months of follow-up, promastigotes were maintained in different preservatives (phosphate-buffered saline with 3% fetal bovine serum, phenol 0.35%, thimerosal 0.01%, and formaldehyde 0.5%) and stored at 3 distinct temperatures (25 degrees C, 4 degrees C, and -20 degrees C). During the study period, the morphological characteristics of the promastigotes were assessed by flow cytometry according to the forward and side scatter parameters and also under optical microscopic analysis. Reactivity performance was evaluated as the percentage of positive fluorescent parasites in the sera of naturally infected and noninfected dogs. Microbiological analysis was performed at 2 time points, the first and sixth months, to rule out contamination of stored promastigotes. Taken together, our results indicated that the best conditions to preserve fixed L. infantum antigens were storage in formaldehyde at 4 degrees C. Promastigotes presented the best morphological profile, with appropriate antigenic stability even at 4 degrees C, in an inexpensive preservative for a long period of conservation. PMID- 23726650 TI - Predictive genetic risk markers for strong biofilm-forming Staphylococcus aureus: fnbB gene and SCCmec type III. AB - To find predictive genetic risk markers for strong biofilm producers of Staphylococcus aureus, we studied the relatedness of agr and SCCmec types and fnbB and IS256 genes to biofilm-forming ability in 465 clinical isolates. fnbB and SCCmec type III are candidates as genetic risk predictors for the strong biofilm producers. PMID- 23726651 TI - beta-Lactamases in amoxicillin-clavulanate-resistant Escherichia coli strains isolated from a Chinese tertiary hospital. AB - A total of 52 strains were resistant to amoxicillin-clavulanate by disk diffusion method in a Chinese tertiary hospital from July 2011 to December 2011. Among these isolates, 2 isolates possessed a phenotype consistent with production of inhibitor-resistant temoniera (TEM) (IRT) beta-lactamase, and the TEM-type gene was cloned into strains of Escherichia coli JM109 cells. Both had no blaTEM mutations and were identified as TEM-1 beta-lactamase producers. As a result, no IRT beta-lactamase was detected. Multiplex PCR detected most of these strains produced TEM-1 enzymes, and plasmid-mediated AmpC beta-lactamase and oxacillinase 1 beta-lactamases are important mechanisms of resistance as well. PMID- 23726652 TI - Rapid identification of pathogens directly from blood culture bottles by Bruker matrix-assisted laser desorption laser ionization-time of flight mass spectrometry versus routine methods. AB - The use of matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) for identification of microorganisms directly from blood culture is an exciting dimension to the microbiologists. We evaluated the performance of Bruker SepsiTyper kitTM (STK) for direct identification of bacteria from positive blood culture. This was done in parallel with conventional methods. Nonrepetitive positive blood cultures from 160 consecutive patients were prospectively evaluated by both methods. Of 160 positive blood cultures, the STK identified 114 (75.6%) isolates and routine conventional method 150 (93%). Thirty six isolates were misidentified or not identified by the kit. Of these, 5 had score of >2.000 and 31 had an unreliable low score of <1.7. Four of 8 yeasts were identified correctly. The average turnaround time using the STK was 35 min, including extraction steps and 30:12 to 36:12 h with routine method. The STK holds promise for timely management of bacteremic patients. PMID- 23726653 TI - Comparison of real-time polymerase chain reaction and serological tests for the confirmation of Mycoplasma pneumoniae infection in children with clinical diagnosis of atypical pneumonia. AB - BACKGROUND: Mycoplasma pneumoniae is a common pathogen of respiratory tract infection in children, and its correct and rapid diagnosis is a clinical challenge. Real-time polymerase chain reaction (RT-PCR) has been used frequently for the detection of this pathogen. MATERIALS AND METHODS: Medical records from all children with a clinical diagnosis of mycoplasma pneumonia and whose respiratory samples were tested for M. pneumoniae (using RT-PCR) during 2011 were reviewed retrospectively. We compared the sensitivity and specificity of serological assays versus those of RT-PCR for diagnosis of M. pneumoniae infections. We also reviewed retrospectively clinical characteristics, and laboratory and imaging findings of children with laboratory evidence of M. pneumoniae infection. RESULTS: In 2011, 290 children were diagnosed to have mycoplasma pneumonia clinically and had their respiratory samples tested for M. pneumoniae by RT-PCR. Fifty-four children (19%) had a positive result. Meanwhile, 63% (182/290) of these children also underwent serological tests, out of whom 44 (24%) were found to be positive for immunoglobulin M (IgM). Using PCR as a gold standard, M. pneumoniae IgM assay was found to show a sensitivity of 62.2% and a specificity of 85.5%. Positive and negative predictive values of IgM were 52.3% and 89.9%, respectively. In M. pneumoniae IgM-positive children, a negative PCR result was associated with more coinfection by other pathogens and longer duration of prehospitalization fever. Bacterial loads of M. pneumoniae were not correlated with clinical outcomes. CONCLUSION: The majority of clinically diagnosed mycoplasma pneumonia was unconfirmed. Mycoplasma pneumoniae IgM has poor sensitivity and a positive predictive value. Interpretation of Mycoplasma pneumoniae IgM should be done with caution. PMID- 23726654 TI - Value of dynamic contrast-enhanced MRI for tissue characterization of ovarian teratomas: correlation with histopathology. AB - AIM: To analyse the value of double contrast-enhanced (DCE) magnetic resonance imaging (MRI) in addition to conventional MRI to characterize ovarian teratomas subtypes with histological correlation. MATERIALS AND METHODS: From January 2005 to December 2008, 38 women undergoing MRI and subsequent resection of ovarian teratomas were identified [40 mature cystic teratomas (MCT), two struma ovarii, three immature teratomas]. MRI images were analysed blindly by two radiologists according to morphological and vascular abnormalities. An experienced histopathologist reviewed all slides to determine the presence and histological composition of Rokitansky protuberances. RESULTS: Thirty-one MCT (77%) had at least one small, regular Rokitansky protuberance presenting at an acute angle with the cyst wall. Ten out of 31 MCT did not display any enhancement on contrast enhanced MRI related to sebaceous glands, adipose lobules, keratin, and pilosebaceous adnexa at histology. Three different time-intensity curve (TIC), types 1, 2, and 3, were related to presence of smooth muscular cells and fibrous, neuroglial, or thyroid tissue, respectively, found at histology of MCT. Type 3 TIC was also present in one struma ovarii and two immature teratomas. CONCLUSION: TIC types are related to the specific content of the solid tissue of ovarian teratomas but cannot be used to differentiate benign and malignant ovarian teratomas. PMID- 23726655 TI - B95: a new respirator for health care personnel. AB - BACKGROUND: Respiratory protection relies heavily on user compliance to be effective, but compliance among health care personnel is less than ideal. METHODS: In 2008, the Department of Veterans Affairs formed the Project Better Respiratory Equipment using Advanced Technologies for Healthcare Employees (BREATHE) Working Group, composed of a variety of federal stakeholders, to discuss strategies for improving respirator compliance, including the need for more comfortable respirators. RESULTS: The Working Group developed 28 desirable performance characteristics that can be grouped into 4 key themes: (1) respirators should perform their intended function safely and effectively; (2) respirators should support, not interfere, with occupational activities; (3) respirators should be comfortable and tolerable for the duration of wear; and (4) respiratory protective programs should comply with federal/state standards and guidelines and local policies. As a necessary next step, the Working Group identified the need for a new class of respirators, to be called "B95," which would better address the unique needs of health care personnel. CONCLUSION: This article summarizes the outputs of the Project BREATHE Working Group and provides a national strategy to develop clinically validated respirator test methods, to promulgate B95 respirator standards, and to invent novel design features, which together will lead to commercialized B95 respirators. PMID- 23726656 TI - Nosocomial urinary tract infections caused by Pseudomonas aeruginosa and Acinetobacter species: sensitivity to antibiotics and risk factors. AB - BACKGROUND: Pseudomonas aeruginosa and Acinetobacter species frequently cause intrahospital urinary tract infections (IUTI), contributing to increased hospital morbidity and mortality. Our objective was further exploration of possible risk factors for development of IUTI caused by P aeruginosa and Acinetobacter spp, including their resistance to various antibiotics. METHODS: The prospective case control study was conducted in Clinical Center Kragujevac, Serbia, during the period January 2009 to December 2011 and covered all patients with IUTI according to the Centers for Disease Control and Prevention criteria. The patients classified as "cases" had an IUTI caused by P aeruginosa or Acinetobacter spp. The control patients were matched to the cases and selected randomly from the remaining patients. RESULTS: There were 79 cases (11.9%) and 586 (88.1%) controls in the study. According to the multivariate binary logistic regression, there were 3 significant predictors of P aeruginosa and Acinetobacter spp IUTI: male sex (odds ratio [OR], 0.423; 95% confidence interval [CI]: 0.251-0.711; P = .001), stay in another hospital ward before emergence of IUTI (OR, 1.704; 95% CI: 1.013-2.864; P = .044), and previous use of penicillins and their combinations with inhibitors of beta-lactamases (OR, 2.643; 95% CI: 1.044-6.692; P = .040). CONCLUSION: Knowing that IUTI caused by above-mentioned bacteria are especially frequent among male patients, after previous use of penicillins, and in patients who spent some time previously at other wards, sound strategies for prevention of such infections in clinical practice should be developed. PMID- 23726657 TI - The impacts of adenotonsillar hypertrophy on periodontal health in children: a prospective controlled pilot study. AB - OBJECTIVES: To evaluate the impacts of obstructive adenotonsillar disease on periodontal health and to assess the efficacy of adenotonsillectomy in the prevention of chronic periodontitis in children. METHODS: This prospective and controlled clinical study was conducted between August 2012 and February 2013 with 35 pediatric patients who had permanent anterior dentition. The study group included twenty patients (n = 20) who had complaints of chronic mouth breathing and snoring and were diagnosed with obstructive adenotonsillar disease. These patients underwent adenoidectomy with or without tonsillectomy. We performed periodontal examinations to assess the periodontal health status in these children before and two months after surgery. The periodontal measures included plaque index (PI), pocket depth (PD) and gingival index scores (GI). Subsequently, these periodontal measures were compared with healthy control group who had no adenotonsillar disease (n = 15). RESULTS: Among the study group six patients underwent adenoidectomy and 14 patients underwent adenoidectomy combined with either tonsillectomy or tonsillotomy. The preoperative PI, PD and GI scores of the study group were 1.27 +/- 0.39, 1.34 +/- 0.31 and 0.97 +/- 0.37 respectively. These scores were significantly higher compared to the control group (p < 0.001). These periodontal index scores were significantly improved after surgery (p = 0.008 for PI and p < 0.001 for both PD and GI). In addition, we found no difference in postoperative values of PD and GI between the study group and control group. CONCLUSION: We concluded that obstructive adenotonsillar disease adversely affects periodontal health in children and surgical management of obstruction improves the clinical findings. However, more comprehensive research is required to elucidate the association between adenotonsillar hypertrophy and periodontal disease. PMID- 23726658 TI - Diversity in time and space: wanted dead and alive. AB - Current patterns of biological diversity are influenced by both historical and present-day factors, yet research in ecology and evolution is largely split between paleontological and neontological studies. Responding to recent calls for integration, we provide a conceptual framework that capitalizes on data and methods from both disciplines to investigate fundamental processes. We highlight the opportunities arising from a combined approach with four examples: (i) which mechanisms generate spatial and temporal variation in diversity; (ii) how traits evolve; (iii) what determines the temporal dynamics of geographical ranges and ecological niches; and (iv) how species-environment and biotic interactions shape community structure. Our framework provides conceptual guidelines for combining paleontological and neontological perspectives to unravel the fundamental processes shaping life on Earth. PMID- 23726659 TI - Cognitive function in adulthood and elderly euthymic bipolar patients: a comparison to test models of cognitive evolution. AB - OBJECTIVE: Neurocognitive dysfunction is considered as the main predictor of overall outcome of BD. The issue of whether neurocognitive dysfunction in BD is progressive-or not-has become critical in the effort to define staging models for these disorders. Data about cognitive dysfunction evolution are scarce and contradictory. While some studies showed a progressive pattern others have found a stable form of evolution. METHODS: Twenty four patients with BD aged 60 years or older (E-BD), 24 patients with BD aged 40 years or younger (Y-BD) and 20 healthy controls matched by the E-BD group were evaluated with traditional clinical instruments and an extensive neuropsychological battery was completed. We used ANOVA and Chi-squared for comparisons. Raw score of neurocognitive tasks was transformed to standardized Z-score from the normative data of each test to avoid the effect of age. In order to decrease the risk of type I errors, one-way multivariate analysis of variance was conducted. RESULTS: Despite having an illness duration that was 4 times longer, E-BD did not differ in terms of key cognitive domains compared to Y-BD. These data do not support the hypothesis of a progression of cognitive dysfunction due to illness chronicity. PMID- 23726660 TI - Cognitive vulnerability for depression in HIV. AB - Biased inhibitory processing, frequency and valence of automatic thoughts, and inability to use positive schemas to regulate negative mood are cognitive factors linked to depression. These processes may underlie the established link between adaptive cognitive coping strategies (acceptance and positive reframing) and depression in persons with HIV. How individual differences in HIV-related neurocognitive deficits moderate such effects is unknown. In a secondary analysis, we tested the direct effects of coping on depressed affect as mediated by the frequency and valence of automatic thoughts and how this model was moderated by neurocognitive function in a cohort of HIV+ men and women. METHODS: HIV+ adults (mage=39.8, SD=9.5) provided data for the baseline assessment of a randomized trial that investigated the effects of a cognitive-behavioral stress management intervention. Measures included coping, depressive symptoms, positive (PAT) and negative automatic thoughts (NAT), and HIV-dementia. RESULTS: After controlling for covariates, cognitive coping was related to depressed mood as mediated via NAT (beta=-.92) and PATs (beta=.61), (R(2)=.42, F(7, 325)=33.50, p<.0001). The indirect effect of coping on depressive symptoms via NAT and PAT was moderated by neurocognitive function. LIMITATION: Cross-sectional design does not allow for the inference of causation among the variables. CONCLUSION: Results support a cognitive vulnerability model for depression whereby HIV-related neurocognitive deficits interfere with the ability to use acceptance and positive reframing strategies to increase the frequency of PAT and decrease NAT in adults living with symptoms of depression. PMID- 23726661 TI - Neuropeptides stimulate human osteoblast activity and promote gap junctional intercellular communication. AB - Neuropeptides released from the skeletal nerve fibers have neurotransmitter and immunoregulatory roles; they exert paracrine biological effects on bone cells present close to the nerve endings expressing these signaling molecules. The aims of this study were a systematic investigation of the effects of the neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), Neuropeptide Y (NPY) and tyrosine hydroxylase (TH) on the cell viability and function of the human osteoblasts, and comparing their difference in the role of regulating bone formation. Cultures of normal human osteoblasts were treated with SP, CGRP, VIP, NPY or TH at three concentrations. We found that each of the five neuropeptides induced increases in cell viability of human osteoblasts. The stimulatory action of NPY was the highest, followed by VIP, SP and TH, while CGRP had the lowest stimulatory effect. The viability index of osteoblasts was inversely associated with the concentration of neuropeptides, and positively with the time of exposure. Moreover, the five neuropeptides increased the ALP activity and osteocalcin to different extents in a dose-dependent manner. The GJIC of osteoblasts was significantly promoted by neuropeptides. The results demonstrated that neuropeptides released from skeletal nerve endings after a stimulus appeared to be able to induce the proliferation and activity of osteoblasts via enhancing GJIC between cells, and further influence the bone formation. These findings may contribute toward a better understanding of the neural influence on bone remodeling and improving treatments related to bone diseases. PMID- 23726662 TI - Population pharmacokinetic analysis of blood concentrations of robenacoxib in dogs with osteoarthritis. AB - The purpose of this analysis was to investigate whether the recommended daily dosage of 1-2mg/kg robenacoxib provides consistent exposure when administered to dogs with chronic osteoarthritis (OA), and the need for dose adjustment in special patient populations. Data from three prospective, multi-center field studies in 208 OA dogs were analyzed using non-linear mixed effects modeling. A model based assessment was performed with stepwise inclusion and exclusion of population characteristics to explain between-subject variability, and assess the according necessity for dose adjustment. Only the influence of bodyweight on both apparent clearance and volume were found to be significant (p<0.01). No significant influence of sex, age and breed, or kidney and liver variables was identified in this representative sample of OA dogs. The population pharmacokinetic analysis performed showed that the 1-2mg/kg dosage chosen provided consistent robenacoxib exposure in a wide range of canine patients. No other dose adjustment seems necessary. PMID- 23726663 TI - Hyposialylated alpha1-acid glycoprotein inhibits phagocytosis of feline neutrophils. AB - Feline alpha1-acid glycoprotein (fAGP) modifies both its serum concentration and its glycan moiety during diseases. fAGP is hyposialylated in cats with feline infectious peritonitis (FIP), but not in clinically healthy cats or in cats with other diseases. This study was aimed to determine whether hyposialylated fAGP influences phagocytosis. A flow cytometric method based on ingestion of fluoresceinated bacteria and adapted to feline blood was used to assess phagocytosis of leukocytes incubated with 'non-pathological' fAGP (purified from sera with normal concentrations of AGP) and 'pathological' fAGP (purified from sera with >1.5mg/mL hyposialylated AGP). The flow cytometric method provided repeatable results for neutrophils (coefficients of variations, CVs <15%) but not for monocytes (CVs>20%) which had also a high individual variability. Compared with saline solution and with non-pathological fAGP, pathological fAGP significantly decreased phagocytosis in neutrophils and monocytes. This study demonstrated that hyposialylated fAGP down-regulates the phagocytic activity of feline neutrophils. PMID- 23726664 TI - The effect of road transport in comparison to a novel environment on the physiological, metabolic and behavioural responses of bulls. AB - The objective was to investigate the effect of 18 h road transport with a 12h mid journey rest period in comparison to the exposure of bulls to a novel environment on physiological, metabolic and behavioural responses of beef bulls. Thirty Charolais sired crossbred beef bulls (mean 486.0, s.d. 57.0 kg) were assigned by live weight to one of the two treatments, transport (T) (9h+9h) (n=15) and not transported (NT) (n=15) on day 0. The bulls were transported at a spatial allowance of 1.3m(2)/animal by road for 9h, unloaded and rested for a 12h rest period, re-loaded and transported for a further 9h journey by road followed by a 2h rest period on the transporter, then unloaded and rested in a lairage for 24h with access to hay and water. Plasma albumin and urea concentrations increased (P<0.05) after the first 9h journey with values returning to baseline at the end of the 24h recovery period. There was a transient increase in haematocrit% in T and NT at sampling time points corresponding to the completion of the first 9h journey. Bulls spent longer time lying (P<0.05) during the first 9h journey compared with the percentage time spent lying during the second 9h journey. Differences in live weight, behaviour, and some blood variables show that transport is more stressful for bulls than being subjected to a novel environment and management, and while some biological variables returned to baseline values, others require a longer time (plasma haptoglobin, total protein, glucose and NEFA concentrations). Thus, the effective recovery of bulls exposed to an 18 h transport journey by road would suggest that a rest period of at least 24h with access to feed and water is required before further transport. PMID- 23726665 TI - Transjugular tricuspid valve-in-valve implantation. AB - A 60 year-old female underwent tricuspid valve replacement in 2002. Post operative recovery was complicated by severe post-pericardiotomy-syndrome. Seven years later she underwent transcatheter valve-in-valve implantation through the right jugular vein because of early prosthesis deterioration. Moreover intra operative transoesophageal echocardiography showed an important right-to-left shunt through the patent foramen ovale that immediately disappeared after the deployment of a 29-mm Sapien-XT. The patient had an immediate and dramatic improvement in day-by-day activities. This case shows that tricuspid valve deterioration can be safely and successfully treated through this approach. PMID- 23726666 TI - Long-term changes in visual acuity in an older population over a 15-year period: the Blue Mountains Eye Study. AB - PURPOSE: To describe the change in visual acuity (VA) and incidence of visual impairment (VI) in an older population over a 15-year period. DESIGN: Population based cohort. PARTICIPANTS: Of the 3654 participants of the Blue Mountains Eye Study (BMES) baseline examination from 1992 through 1994, 1149 were re-examined during the 15-year follow-up between 2007 and 2010. METHODS: Best-corrected VA by means of subjective refraction was measured with a logarithm of the minimum angle of resolution chart using Early Treatment Diabetic Retinopathy Study methods at each examination. MAIN OUTCOME MEASURES: Unilateral VI was defined as VA worse than 20/40 and blindness was defined as VA worse than 20/200 in the worse eye. Incident bilateral VI and blindness were determined according to VA in the better eye at the 15-year visit. Doubling of the visual angle was defined as a loss of 15 letters or more from baseline to the 15-year visit. Halving of the visual angle was defined as a VA improvement of 15 letters or more over the same period. Causes of VI were determined at examination, by photographic grading, and from medical records. RESULTS: Cumulative 15-year incidence of unilateral and bilateral VI was 12.3% (95% confidence interval [CI], 11.0-13.6) and 5.2% (95% CI, 4.3-6.1), respectively, and for unilateral and bilateral blindness, the cumulative incidence was 3.7% (95% CI, 3.0-4.4) and 0.9% (95% CI, 0.5-1.3), respectively. These incidence rates increased significantly with increasing age (P<0.01 for trend). Doubling and halving of the visual angle occurred in 6.9% (95% CI, 5.9-7.9) and 1.6% (95% CI, 1.0-2.2) of participants, respectively. Cataract accounted for 48.5% of unilateral and bilateral incident VI, followed by age-related macular degeneration (26.9%). Age-related macular degeneration accounted for 56.9% of unilateral and bilateral incident blindness cases, followed by cataract (20.7%). CONCLUSIONS: These data provide population-based estimates of long-term incidence of visual impairment among older persons. Our estimate for cumulative incidence of blindness, accounting for competing risk of death, was similar to that of the Beaver Dam Eye Study (BDES) after age standardization. However, our estimate for cumulative incidence of VI was lower compared with that observed in the BDES population. This difference may be explained in part by a higher mortality rate among our population. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23726667 TI - Preterm birth and later retinal detachment: a population-based cohort study of more than 3 million children and young adults. AB - OBJECTIVE: Ophthalmologic complications after preterm birth are common. Small studies show an association between retinopathy of prematurity and later retinal detachment. There are no population-based studies of preterm birth and risk of retinal detachment, which was the objective of the current investigation. DESIGN: Nationwide Swedish cohort study based on population registries. PARTICIPANTS: Of 3 423 697 subjects born in Sweden, 1 271 725 were born between 1973 and 1986 (i.e., before the national screening program for retinopathy of prematurity started), and 2 151 972 were born between 1987 and 2008. The participants were followed up from 1 year of age until 2009. METHODS: Unadjusted and adjusted hazard ratios (HRs) for retinal detachment were calculated using Cox proportional hazards regression. MAIN OUTCOME MEASURES: Incident retinal detachment, as defined by a diagnosis in the Swedish Patient Register (both inpatient and hospital-based outpatient data). RESULTS: During follow-up (median follow-up, 17.4 years), 1749 subjects were diagnosed with retinal detachment. Among the 188 852 subjects born prematurely (i.e., at <37 weeks of gestation), there were 124 cases of retinal detachment, of which 42 occurred in the 20 470 subjects born before 32 weeks of gestation. Compared with subjects born at term (37-41 weeks), the adjusted HR for retinal detachment after extremely preterm birth (<28 weeks of gestation) was 19.2 (95% confidence interval [CI], 10.3-35.8) for births between 1973 and 1986 and 8.95 (95% CI, 3.98-20.1) for births between 1987 and 2008. The corresponding HRs in subjects born very prematurely (28-31 weeks) were 4.32 (95% CI, 2.70-6.90) and 2.80 (95% CI, 1.38-5.69), respectively. Moderately preterm birth (32-36 weeks) was not associated with an increased risk of retinal detachment. CONCLUSIONS: Birth before 32 weeks of gestation is associated with a substantially increased relative risk of retinal detachment. These findings may have implications for ophthalmologic follow-up of children and adults born very prematurely. PMID- 23726668 TI - A genome-wide association study of a sustained pattern of antidepressant response. AB - Genome-wide association studies (GWAS) have failed to replicate common genetic variants associated with antidepressant response, as defined using a single endpoint. Genetic influences may be discernible by examining individual variation between sustained versus unsustained patterns of response, which may distinguish medication effects from non-specific, or placebo responses to active medication. We conducted a GWAS among 1116 subjects with Major Depressive Disorder from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who were characterized using Growth Mixture Modeling as showing a sustained versus unsustained pattern of clinical response over 12 weeks of treatment with citalopram. Replication analyses examined 585 subjects from the Genome-based Therapeutic Drugs for Depression (GENDEP) trial. The strongest association with sustained as opposed to unsustained response in STAR*D involved a single nucleotide polymorphism (SNP; rs10492002) within the acyl-CoA synthetase short chain family member 3 gene (ACSS3, p-value=4.5*10(-6), odds ratio=0.61). No SNPs met our threshold for genome-wide significance. SNP data were available in GENDEP for 18 of the top 25 SNPs in STAR*D. The most replicable association was with SNP rs7816924 (p=0.008, OR=1.58); no SNP met the replication p-value threshold of 0.003. Joint analysis of these 18 SNPs resulted in the strongest signal coming from rs7816924 (p=2.11*10(-7)), which resides in chondroitin sulfate N acetylgalactosaminyltransferase 1 gene (CSGALNACT1). An exploratory genetic pathway analysis revealed evidence for an involvement of the KEGG pathway of long term potentiation (FDR=.02). Results suggest novel genetic associations to sustained response. PMID- 23726669 TI - Sex differences in resilience to childhood maltreatment: effects of trauma history on hippocampal volume, general cognition and subclinical psychosis in healthy adults. AB - Recent data suggests that a history of childhood maltreatment is associated with reductions in hippocampal volume in healthy adults. Because this association is also evident in adults with psychiatric illness, it has been suggested that reductions in hippocampal volume associated with childhood maltreatment may be a risk factor for psychiatric illness. Such an interpretation suggests that healthy adults with a history of childhood maltreatment are more resilient to the effects of maltreatment. Current models of resilience suggest, however, that resiliency should be measured across multiple domains of functioning. The present study sought to investigate childhood maltreatment in relationship to hippocampal volumes in healthy adults and to address the question of whether the putative resiliency extends to other domains of functioning. Sixty-seven healthy Caucasian adults were assessed for a history of childhood emotional abuse, emotional neglect and physical abuse and received high resolution structural MR imaging scans. Participants with and without histories of abuse or neglect were compared on measures of total hippocampal volume, general cognitive ability and subclinical psychopathology. Our results suggest that childhood emotional abuse is associated with reduced hippocampus volume in males, but not in females. However, emotional abuse was associated with higher levels of subclinical psychopathology in both males and females. These data suggest that while females may be more resilient to the neurological effects of childhood maltreatment, they are not more resilient to the psychiatric symptoms associated with childhood maltreatment. Further research is needed to elucidate the mechanisms involved in these different levels of resilience. PMID- 23726670 TI - Association of glucocorticoid and type 1 corticotropin-releasing hormone receptors gene variants and risk for depression during pregnancy and post-partum. AB - Women with postnatal depression (PND) appear to have abnormal hypothalamic pituitary adrenal (HPA) axis responses to stress, which might involve a genetic variability component. We investigated association of genetic variants in the glucocorticoid receptor (GR, NR3C1) and corticotropin releasing hormone receptor 1 (CRHR1) genes with increased risk for PND. Two hundred pregnant women were recruited prospectively and PND risk was assessed by the Edinburgh Postnatal Depression Scale (EPDS) during pregnancy and again 2-8 weeks post-natally (CW GAPND study). The BclI and ER22/23EK single nucleotide polymorphisms (SNPs) of the GR and the haplotype-tagged rs1876828, rs242939 and rs242941 SNPs of the CRHR1 associated with genetic risk to depressive disorders were genotyped. A cut off score of 10 was used to detect increased risk of PND. Association analysis was carried out in 140 patients that completed the study protocol. The BclI and rs242939 SNPs were over-represented in women with postnatal EPDS score >=10 with significant allele association (p = 0.011 and <0.001, respectively) and risk ratios of 2.9 (95% CI: 1.2-6.9) for BclI, 4.9 (2-12) for rs242939 and 5.48 (2.13 14.10) for both. The rs242939 SNP was also associated with increased EPDS values during pregnancy. Moreover, the G-G-T haplotype of the CRHR1 was significantly over-represented in patients with high EPDS scores, with risk ratio of 3.22 (95% CI: 1.91-5.42). This is the first evidence that specific SNPs of genes involved in 'stress' responses might contribute in the genetics of high-risk for depression during pregnancy and postpartum. PMID- 23726671 TI - Proximity ligation assay combined with flow cytometry is a powerful tool for the detection of cytokine receptor dimerization. AB - Many cytokine receptors are cell surface proteins that promiscuously combine to form active signalling homo- or heterodimers. Thus, receptor chain dimerization can be viewed as a direct measure of a high probability of intracellular signalling by specific cytokines. Proximity ligation assay (PLA) is an antibody based method for selective and highly sensitive detection of protein interactions by microscopy. As proof of concept, the aim of this study was to combine antibodies towards interleukin 7 receptor alpha (IL-7Ralpha) and the common gamma chain (gammac) with PLA and flow cytometry to enable the detection of IL-7 receptor heterodimers. The presence of IL-7 receptor heterodimers on the surface of the HPB-ALL T cell line was detected by PLA and microscopy with a resolution of one complex per cell. Optimisation of the PLA reaction on cell suspensions identified buffer effects with critical importance for the flow cytometric outcome. In addition, blocking, fixation and incubation conditions were optimised to prevent unspecific antibody binding. PLA combined with flow cytometry very sensitively detected receptor heterodimers on the cell surface. Thus, the method is a powerful tool for the investigation of cytokine receptor dimerization. PMID- 23726672 TI - The role of leptin, soluble leptin receptor, adiponectin and visfatin in insulin sensitivity in preterm born children in prepubertal ages. AB - BACKGROUND: There are still controversies whether insulin resistance (IR) develops in preterm born children during early childhood. OBJECTIVE: To investigate the role of leptin, soluble leptin receptor (sOB-R), adiponectin, visfatin and insulin sensitivity in the pathogenesis of possible IR in preterm born children during early childhood. PATIENTS AND METODS: Twenty-nine preterm small for gestational age (SGA) born children (Group 1) and 25 preterm appropriate for gestational age (AGA) born children (Group 2), matched for gestational age and sex were included in the study. Mean chronological age at investigation was 3.3+/-0.7years and not different between the groups. Blood samples for fasting blood glucose, insulin, proinsulin, adiponectin, leptin, sOB R and visfatin were obtained. RESULTS: Mean height and weight standard deviation scores (SDS) at investigation were significantly lower in Group 1 than in Group 2, but there was no significant difference in body mass index (BMI) SDS between the groups. Catch-up growth (CUG) was higher in Group 1 than in Group 2. There was no difference regarding homeostasis model assessment for IR (HOMA-IR), leptin, sOB-R, adiponectin, proinsulin and visfatin values between the groups. In the whole group, log visfatin showed a negative correlation with Deltaweight SDS. There was a positive correlation between HOMA-IR and BMI SDS. Adiponectin levels showed a positive correlation with log visfatin levels in all groups. CONCLUSION: Preterm born children whether AGA or SGA do not show IR in early childhood if BMI is normal. Significant differences between the preterm SGA and preterm AGA groups regarding the adipocytokine levels were not detected. PMID- 23726673 TI - Reperfusion therapy for acute ischemic stroke: how should we react to the Third Interventional Management of Stroke (IMS III) trial? PMID- 23726675 TI - A phase 2, double-blind, randomized, placebo-controlled, dose-escalation study to evaluate the efficacy, safety, and tolerability of naloxegol in patients with opioid-induced constipation. AB - Naloxegol (previously known as NKTR-118) is a peripherally acting MU-opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once-daily agent for the treatment of opioid-induced constipation (OIC). Eligible patients with OIC (n=207), defined as <3 spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30-1000 mg/day morphine equivalents for >= 2 weeks were randomized to receive 4 weeks of double-blind placebo or naloxegol (5, 25, or 50mg) once daily in sequential cohorts after a 1-week placebo run-in. The primary end point, median change from baseline in SBMs per week after week 1 of drug administration, was statistically significant for the 25- and 50-mg naloxegol cohorts vs placebo (2.9 vs 1.0 [P=0.0020] and 3.3 vs 0.5 [P=0.0001], respectively). The increase in SBMs vs placebo was maintained over 4 weeks for naloxegol 25mg (3.0 vs 0.8 [P=0.0022]) and 50mg (3.5 vs 1.0 [P<0.0001]). Naloxegol was generally well tolerated across all dosages. The most frequent adverse events (AEs) were abdominal pain, diarrhea, and nausea. Most AEs at 5 and 25mg/day were mild and transient. Similar AEs occurred with increased frequency and severity in the 50-mg cohort. There was no evidence of a statistically significant increase from baseline in pain, opioid use for the 25- and 50-mg cohorts, or centrally mediated opioid withdrawal signs and/or symptoms with naloxegol. These data demonstrate that once-daily oral naloxegol improves the frequency of SBMs compared with placebo and is generally well tolerated in this population of patients with OIC. PMID- 23726674 TI - Temporomandibular joint pain: a critical role for Trpv4 in the trigeminal ganglion. AB - Temporomandibular joint disorder (TMJD) is known for its mastication-associated pain. TMJD is medically relevant because of its prevalence, severity, chronicity, the therapy-refractoriness of its pain, and its largely elusive pathogenesis. Against this background, we sought to investigate the pathogenetic contributions of the calcium-permeable TRPV4 ion channel, robustly expressed in the trigeminal ganglion sensory neurons, to TMJ inflammation and pain behavior. We demonstrate here that TRPV4 is critical for TMJ-inflammation-evoked pain behavior in mice and that trigeminal ganglion pronociceptive changes are TRPV4-dependent. As a quantitative metric, bite force was recorded as evidence of masticatory sensitization, in keeping with human translational studies. In Trpv4(-/-) mice with TMJ inflammation, attenuation of bite force was significantly less than in wildtype (WT) mice. Similar effects were seen with systemic application of a specific TRPV4 inhibitor. TMJ inflammation and mandibular bony changes were apparent after injections of complete Freund adjuvant but were remarkably independent of the Trpv4 genotype. It was intriguing that, as a result of TMJ inflammation, WT mice exhibited significant upregulation of TRPV4 and phosphorylated extracellular-signal-regulated kinase (ERK) in TMJ-innervating trigeminal sensory neurons, which were absent in Trpv4(-/-) mice. Mice with genetically-impaired MEK/ERK phosphorylation in neurons showed resistance to reduction of bite force similar to that of Trpv4(-/-) mice. Thus, TRPV4 is necessary for masticatory sensitization in TMJ inflammation and probably functions upstream of MEK/ERK phosphorylation in trigeminal ganglion sensory neurons in vivo. TRPV4 therefore represents a novel pronociceptive target in TMJ inflammation and should be considered a target of interest in human TMJD. PMID- 23726676 TI - Response to the commentary "multiple potential mechanisms for context effects on pain". PMID- 23726677 TI - Successful computed tomography angiogram through tibial intraosseous access: a case report. AB - BACKGROUND: Intraosseous access has been used increasingly with proven efficacy in emergent situations for adults when intravenous access could not be obtained. OBJECTIVE: Our aim was to demonstrate if tibial intraosseous (IO) is an effective route for iodinated contrast administration and pulmonary vasculature visualization. CASE REPORT: We report on an obtunded patient requiring a computed tomography angiogram to help with diagnosis and tibial IO was the only viable access appropriate to withstand the pressure of a computed tomography iodinated contrast load. Tibial IO access was used successfully for administration of iodinated contrast to evaluate for massive pulmonary embolism in an obtunded patient in extremis secondary to cardiovascular instability. CONCLUSIONS: The pulmonary arteries were opacified and demonstrated a high-quality CT angiogram can be done via tibial IO device. PMID- 23726679 TI - [Obese children 10 years later: an observational study]. AB - INTRODUCTION: Although childhood obesity is a major public health problem, the long-term follow-up of children who are overweight and obese has rarely been studied in France. METHODS: We conducted a single-center observational study of 85 subjects who received medical follow-up for weight problems or obesity in 2001, at which time they were aged between 2 and 17 years. The study followed-up these subjects in 2012, after a mean of 10 years. We separated the study into two time periods. Initial follow-up periods - (A) from the first consultation to the end of individual or group care -and latency periods - (B) from the end of medical care to the year 2012 - were distinguished. A declarative survey based on questionnaires on dietary habits, activity levels, and anthropometric data of children and their parents was conducted in 2012. Two indicators of effectiveness monitoring (alpha) and post-follow-up (beta) were created. RESULTS: Although 77% of patients had a favorable alpha indicator, demonstrating the effectiveness of initial management, especially if it was prolonged (>32 months, P=0.007), a re ascent of the BMI curve after ceasing monitoring occurred in half of the cases (47%) with subjects' BMI significantly correlated with their parents' BMI (P=0.004 for the mother and P=0.02 for the father). CONCLUSION: These observations encourage us to improve the medical follow-up on offer by educating and strengthening the role of parents to achieve a significant and lasting improvement in BMI and weight. In case of medical failure in supporting patients to achieve enough weight loss, the option of bariatric surgery can be considered, even if its recent introduction means that a long-term risk/benefit analysis has yet to be conducted. PMID- 23726680 TI - [Mendelian susceptibility to mycobacterial disease: a case report of disseminated infection due to Mycobacterium avium]. AB - Mendelian susceptibility to mycobacterial disease (MSMD) is a rare genetic syndrome that predisposes patients to infections caused by weakly virulent mycobacterial species, such as bacillus Calmette-Guerin (BCG) vaccines and nontuberculous environmental mycobacteria in children free of classical immunodeficiencies. This syndrome consists of impaired antimycobacterial immunity (axis IL12/INF-gamma) constituting a new immune deficiency and outlining its major role in mycobacterial immunity. We report a new case of MSMD through the observation of a young girl with a disseminated infection due to Mycobacterium avium. The molecular defect was 2 autosomal recessive mutations of the IL12Rbeta1 gene (gene encoding for the beta1 chain of the IL12 receptor) leading to the absence of the IL12 receptor on the activated T lymphocytes' surface. IL-12RB1 deficiency is the most common genetic etiology of MSMD. Today, there are 6 MSMD causing genes, leading to 13 distinct genetic disorders. The clinical phenotype differs between patients. The description of the molecular and immunological basis of this syndrome has allowed us to explain the pathophysiology of antimycobacterial immunity and is essential to understanding and managing these diseases. PMID- 23726681 TI - [Benign acute myositis in a 17-year-old boy]. AB - We describe the case of a 17-year-old teenager who consulted in an emergency unit for acute lateral chest pain with tumefaction. The boy was healthy and had no medical problems or allergies. Upon awakening, he felt faintness and a left lateral chest pain. Movement of the left shoulder was difficult. In the emergency department, the clinical examination showed a painful left axillary mass, normal respiratory and heart function, and normal clinical parameters. Biological assessment revealed substantial cytolysis with major elevation of creatine phosphokinase (CPK) (41 times the normal value) and moderately elevated liver enzymes (2.5 times the normal value), with no inflammatory syndrome, hematology signs, or kidney failure. Axillary ultrasound found a low echogenic and well limited mass, 6.2cm long, compatible with lipoma. MRI showed a T2-weighted hypersignal of the left serratus anterior muscle, with intramuscular infiltrate compatible with inflammatory disease of this muscle. Clinical symptoms ended in a few days with no after-effects and CPK gradually decreased. This study reports a case of benign acute myositis of the serratus anterior muscle in a healthy 17 year-old teenager. Although no infectious etiology was found, it seems that this semiological entity is a form of benign acute myositis (BAM), a benign muscular inflammation, arising from viral infection and occurring in school-age children, more frequently in males, between 6 and 12 years of age. On average, the symptoms begin 7 days after infection, more often the flu (Influenza virus B or A, parainfluenza virus). It is important to note that this pathology is acute and benign and there is no need for any invasive investigations. The family should be reassured because BAM is a self-limited disease and in the great majority of cases has no after-effects. PMID- 23726682 TI - [Renal ultrasound in fat necrosis]. AB - Subcutaneous fat necrosis is an uncommon disease that may be complicated with potentially fatal hypercalcemia or with nephrocalcinosis. We report on the case of a patient with a history of significant perinatal asphyxia, hospitalized for a urinary tract infection. Lesions of subcutaneous fat necrosis were noted, with asymptomatic hypercalcemia at 3.9mmol/L. A renal ultrasound was performed and showed echogenic medullary pyramids bilaterally, consistent with nephrocalcinosis and left nephrolithiasis. The treatment of hypercalcemia included hyperhydration, a diuretic and corticosteroids. Progression was characterized by the total regression of skin lesions and normalization of serum calcium. Hypercalcemia is a rare complication of subcutaneous fat necrosis. It develops within days to weeks after the appearance of skin lesions. Nephrocalcinosis appears after several weeks or months. Hypercalcemia must be treated in due time to avoid the impact on the kidney. PMID- 23726683 TI - [Meatal stenosis secondary to lichen sclerosus]. PMID- 23726684 TI - [Pleural catheter rupture: a report of 2 cases]. PMID- 23726685 TI - [Sydenham's hemichorea as a manifestation of rheumatic fever]. PMID- 23726686 TI - [Prevalence of overweight and obesity in 9 and 10 year-old children in the Principality of Asturias: evaluation bias by parents]. AB - INTRODUCTION: Overweight and obesity in children is a very important issue in the field of health. The aim of this study was to determine the prevalence of overweight and obesity in pre-adolescent children aged 9 to 10 years old in the Principality of Asturias, and to assess the reliability of the measurements of weight and height reported by parents. MATERIAL AND METHOD: A sample of 291 subjects, 142 girls and 149 boys were chosen at random from the network of schools in the Principality of Asturias. They were weighed and measured individually at the school. All participants brought the signed consent of their parents, which also contained the anthropometric measurements of they made of their children. RESULTS: The results showed that 28.17% of children aged 9 and 10 years old in the Principality of Asturias were overweight and 15.80% obese. This means that 44% of the sample had some degree of overweight. Data reported by parents underestimated the weight of both the boys and girls by an average of 2.07kg. CONCLUSIONS: The high percentage of excess weight observed is due to the categorisation system used (IOFT) and the age of the sample. The results call into question the research with data indirectly recorded data. PMID- 23726687 TI - [Symptomatic treatment of acute upper respiratory tract infections: are we doing it right?]. PMID- 23726688 TI - [Meningitis and Streptococcus pyogenes: a rare cross-roads]. PMID- 23726689 TI - [Oral rush desensitization for cow milk allergy: Clinical and immunological follow-up]. AB - OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of oral rush desensitization in children with cow milk allergy. MATERIAL AND METHODS: Prospective study. We included IgE-mediated cow milk allergy children over 3 years in 3 Spanish hospitals. Increasing doses of cow milk for 5 days from 1 cc of 1% to 200 cc of pure milk were administered. Clinical follow-up was conducted and we compared specific IgE levels at onset, 6, 12 and 24 months after desensitization. RESULTS: We included 18 children (13 males) between 3 and 14 years (mean 5.96). A total of 271 doses were administered; there were 55 adverse reactions (84% mild). At the end of the protocol, 100% showed some degree of tolerance (39% total). Full tolerance was achieved in 72% of patients after two years. Two children failed to achieve tolerance. There was a significant decrease in the levels of specific IgE to cow milk and alpha-lactalbumin at 24 months, and to casein at 6, 12 and 24 months, compared to baseline. CONCLUSIONS: Oral rush desensitization is a safe and effective therapeutic option for patients with persistent cow milk allergy to medium term. PMID- 23726690 TI - [Blood cell chimerism in dizygotic twins conceived by in vitro fertilization]. AB - We present a case of hematopoietic chimerism in dizygotic twins (male and female) conceived by in vitro fertilization (IVF). At 8 years of age a blood karyotype was performed on the female due to the presence of clitoromegaly. Two different lines: 46,XX (53%) and 46,XY (47%) were found. FISH studies confirmed the presence of the SRY gene in 46,XY cells. Karyotyping of the male showed two different lines: 46,XY (58%) and 46,XX (42%). SRY gene was present in 46,XY cells. Microsatellite analyses of blood DNA revealed tetra-allelic contribution at some autosomal loci with similar proportions of maternal and paternal alleles and X/Y chromosome dose. FISH in buccal mucous showed that all cells from the female were 46,XX and those from the male 46,XY. The gonadal karyotype in the female was 46,XX without SRY. Hence, we report 46,XX/46,XY chimerism in dizygotic twins. Blood chimerism was confirmed by performing FISH on the buccal cells of the patients. PMID- 23726691 TI - Myiasis (fly disease) and insectal disease generally are causing mental illness. AB - Mental illness by which psychosis is meant here is known to be caused mainly by imbalances of certain neurotransmitters in the brain. But, what is causing these imbalances? There has been a recent flurry of interest focusing on the possibility of parasitical disease. The appropriateness of this is based on the fact that organisms of the animal kingdom produce the same neurotransmitters. In fact stinging insects release them in their venoms. The proposal here is that insect larval parasites acting on the human brain and body may release such neurotransmitters and cause imbalances and altered mental states and is supported by the occurrence of previously unexplained physical symptoms such as; diarrhoea, constipation, spasms, anaemia, bloating, insomnia, headache, migraine, weight loss, low blood pressure, low grade fever, amnesia and signs of allergy which may accompany mental illness. Some of these symptoms have been previously attributed to the medications prescribed to alleviate the psychotic symptoms but, many are also parasitical signs. It is proposed that the minute larvae may make sudden movements and may be highly motile and may move from pressure, hence evading the phlebotomist's needle. There is also the testimony of those with delusional parasitosis and related addictions, I propose the regularity with which humans are bitten, stung and have their foods infected with insects at all stages as a demonstration of how insectal disease may have the potential for common infection and disease; mental and physical. PMID- 23726692 TI - Removal of dissolved organic carbon and nitrogen during simulated soil aquifer treatment. AB - Soil aquifer treatment was simulated in 1 m laboratory soil columns containing silica sand under saturated and unsaturated soil conditions to examine the effect of travel length through the unsaturated zone on the removal of wastewater organic matter, the effect of soil type on dissolved organic carbon removal and also the type of microorganisms involved in the removal process. Dissolved organic carbon removal and nitrification did enhance when the wastewater travelled a longer length through the unsaturated zone. A similar consortium of microorganisms was found to exist in both saturated and unsaturated columns. Microbial concentrations however were lowest in the soil column containing silt and clay in addition to silica sand. The presence of silt and clay was detrimental to DOC removal efficiency under saturated soil conditions due to their negative effect on the hydraulic performance of the soil column and microbial growth. PMID- 23726693 TI - Electrocatalytic activity of Pd-loaded Ti/TiO2 nanotubes cathode for TCE reduction in groundwater. AB - A novel cathode, Pd loaded Ti/TiO2 nanotubes (Pd-Ti/TiO2NTs), is synthesized for the electrocatalytic reduction of trichloroethylene (TCE) in groundwater. Pd nanoparticles are successfully loaded on TiO2 nanotubes which grow on Ti plate via anodization. Using Pd-Ti/TiO2NTs as the cathode in an undivided electrolytic cell, TCE is efficiently and quantitatively transformed to ethane. Under conditions of 100 mA and pH 7, the removal efficiency of TCE (21 mg/L) is up to 91% within 120 min, following pseudo-first-order kinetics with the rate constant of 0.019 min(-1). Reduction rates increase from 0.007 to 0.019 min(-1) with increasing the current from 20 to 100 mA, slightly decrease in the presence of 10 mM chloride or bicarbonate, and decline with increasing the concentrations of sulfite or sulfide. O2 generated at the anode slightly influences TCE reduction. At low currents, TCE is mainly reduced by direct electron transfer on the Pd Ti/TiO2NT cathode. However, the contribution of Pd-catalytic hydrodechlorination, an indirect reduction mechanism, becomes significant with increasing the current. Compared with other common cathodes, i.e., Ti-based mixed metal oxides, graphite and Pd/Ti, Pd-Ti/TiO2NTs cathode shows superior performance for TCE reduction. PMID- 23726694 TI - High efficiency removal of phosphate from water by zirconium sulfate-surfactant micelle mesostructure immobilized on polymer matrix. AB - A zirconium sulfate-surfactant micelle mesostructure (ZS) was synthesized to investigate its capacity for phosphate removal from water. Its phosphate adsorption kinetics, the effect of pH and interfering anions, adsorption isotherm, desorption capacity, and reusability were investigated. The adsorption isotherms could be described by the Langmuir model. The ZS was an effective adsorbent for phosphate with a very high adsorption capacity (114 mg P/g ZS). The phosphate adsorption capacity increased with decrease in pH. Although the adsorption of nitrate, chloride and acetate ions was negligible, bicarbonate ions were found to be possible interfering anions. The adsorbed phosphate was desorbed effectively using NaOH solution. Since breakage of ZS particles resulted when using NaOH, ZS was immobilized on a polymer matrix and a 50-cycle adsorption desorption test was carried out to determine the ZS-immobilized polymer (P-ZS) reusability. The P-ZS retained its functionality and adsorption and desorption capacity over 50 cycles without loss of original capacity. A phosphate solution containing about 10 mg P/L was treated in a column packed with P-ZS. The phosphate could be adsorbed completely onto P-ZS up to 1020 bed volumes. These results indicate clearly that ZS is a highly effective adsorbent for phosphate and enables the removal of phosphate from water. PMID- 23726695 TI - Endotoxin contamination and control in surface water sources and a drinking water treatment plant in Beijing, China. AB - In this paper, endotoxin contamination was determined in treated water following each unit of a drinking water treatment plant (WTP) in Beijing, China and its source water (SW) from a long water diversion channel (Shijiazhuang-Beijing) originating from four reservoirs in Hebei province, China. The total-endotoxin activities in SW ranged from 21 to 41 EU/ml at five selected cross sections of the diversion channel. The total-endotoxin in raw water of the WTP ranged from 11 to 16 EU/ml due to dilution and pretreatment during water transportation from Tuancheng Lake to the WTP, and finished water of the WTP ranged from 4 to 10 EU/ml, showing a 49% decrease following the full-scale treatment process at the WTP. Compared with the 31% removal of free-endotoxin, the WTP removed up to 71% of bound-endotoxin in raw water. The traditional treatment processes (coagulation, sedimentation and filtration) in the WTP removed substantial amounts of total-endotoxin (up to 63%), while endotoxin activities increased after granular activated carbon (GAC) adsorption and chlorination. The total endotoxin in the actual water was composed of free-endotoxin and bound-endotoxin (endotoxin aggregates, bacteria-bound endotoxins and particle-attached endotoxins). The endotoxin aggregates, bacteria-bound endotoxins and particle attached endotoxins co-exist as suspended particles in water, and only the bacteria-bound endotoxins were correlated with bacterial cells suspended in water. The particle distribution of endotoxin aggregates in ultrapure water was also tested and the results showed that the majority (64-89%) of endotoxin aggregates had diameters <2 MUm. The endotoxin contamination and control in treated water following each unit of the WTP processes and its SW from reservoirs are discussed and compared with regard to bacterial cell counts and particle characteristics, which were dependent, to a certain extent, on different flow rates and turbulence of the water environments. PMID- 23726696 TI - Addition of polyaluminiumchloride (PACl) to waste activated sludge to mitigate the negative effects of its sticky phase in dewatering-drying operations. AB - This paper presents a new application of polyaluminiumchloride (PACl) as a conditioner for waste activated sludge prior its dewatering and drying. It is demonstrated at lab scale with a shear test-based protocol that a dose ranging from 50 to 150 g PACl/kg MLSS (mixed liquor suspended solids) mitigates the stickiness of partially dried sludge with a dry solids content between 25 and 60 %DS (dry solids). E.g., at a solids dryness of 46% DS the shear stress required to have the pre-consolidated sludge slip over a steel surface is reduced with 35%. The salient feature of PACl is further supported by torque data from a full scale decanter centrifuge used to dewater waste sludge. The maximal torque developed by the screw conveyor inside the decanter centrifuge is substantially reduced with 20% in the case the sludge feed is conditioned with PACl. The beneficial effect of waste sludge conditioning with PACl is proposed to be the result of the bound water associated with the aluminium polymers in PACl solutions which act as a type of lubrication for the intrinsically sticky sludge solids during the course of drying. It can be anticipated that PACl addition to waste sludge will become a technically feasible and very effective method to avoid worldwide fouling problems in direct sludge dryers, and to reduce torque issues in indirect sludge dryers as well as in sludge decanter centrifuges. PMID- 23726697 TI - Stable isotope composition of suspended particulate organic matter in twenty reservoirs from Guangdong, southern China: implications for pelagic carbon and nitrogen cycling. AB - We studied seasonal variations in the carbon and nitrogen stable isotopes (delta(13)C and delta(15)N) of particulate organic matter (POM) in the surface water of 20 man-made reservoirs in southern China during March, August and December 2010. These reservoirs are located from subtropical to tropical region, varied in trophic states and were influenced by several types of human activities. The geomorphometric and biogeochemical gradients in tropical/subtropical regions are complicated and poorly understood because of low variation in temperature and high variation in hydrological processes. The POM samples were collected from all the reservoirs to assess the seasonal variation patterns of delta(13)CPOM and delta(15)NPOM. Variation in delta(13)CPOM followed seasonal thermal and hydrological cycles. By contrast, delta(15)NPOM did not seasonally differ, which may have been complicated by phytoplankton assimilation of N originating in agricultural waste entering the reservoirs and of atmospheric nitrogen during the wet season as well as an increased relative contribution of animal waste in the reservoirs in the dry season. Within each sampling period, nutrient availability is more important than thermal and solar radiation inputs in the summer, and these physical drivers are more important during the dry and cold winter month in controlling delta(13)CPOM and delta(15)NPOM. On an annual basis, trophic states (total P, total N and chlorophyll a) are the primary drivers for the changes in both delta(13)CPOM and delta(15)NPOM across reservoirs. When the seasonal effect is removed using annual averages from each reservoir, we found that latitude, trophic states, pH, rainfall, water temperature, reservoir age, catchment area to reservoir area (CA:RA) ratio and together explained about 80% of the variance in both delta(13)CPOM and delta(15)NPOM. Our findings also suggest that the trend of delta(15)NPOM is less predictable than delta(13)CPOM. The consistent (15)N depletion and enrichment of POM in different reservoirs point to the importance of different anthropogenic sources of nitrogen in the reservoirs. PMID- 23726698 TI - Superparamagnetic magnesium ferrite nanoadsorbent for effective arsenic (III, V) removal and easy magnetic separation. AB - By doping a proper amount of Mg(2+) (~10%) into alpha-Fe2O3 during a solvent thermal process, ultrafine magnesium ferrite (Mg0.27Fe2.50O4) nanocrystallites were successfully synthesized with the assistance of in situ self-formed NaCl "cage" to confine their crystal growth. Their ultrafine size (average size of ~3.7 nm) and relatively low Mg-content conferred on them a superparamagnetic behavior with a high saturation magnetization (32.9 emu/g). The ultrafine Mg0.27Fe2.50O4 nanoadsorbent had a high specific surface area of ~438.2 m(2)/g, and demonstrated a superior arsenic removal performance on both As(III) and As(V) at near neutral pH condition. Its adsorption capacities on As(III) and As(V) were found to be no less than 127.4 mg/g and 83.2 mg/g, respectively. Its arsenic adsorption mechanism was found to follow the inner-sphere complex mechanism, and abundant hydroxyl groups on its surface played the major role in its superior arsenic adsorption performance. It could be easily separated from treated water bodies with magnetic separation, and could be easily regenerated and reused while maintaining a high arsenic removal efficiency. This novel superparamagnetic magnesium ferrite nanoadsorbent may offer a simple single step adsorption treatment option to remove arsenic contamination from water without the pre-/post treatment requirement for current industrial practice. PMID- 23726699 TI - Phosphates (V) recovery from phosphorus mineral fertilizers industry wastewater by continuous struvite reaction crystallization process. AB - Continuous DT MSMPR (Draft Tube Mixed Suspension Mixed Product Removal) crystallizer was provided with typical wastewater from phosphorus mineral fertilizers industry (pH < 4, 0.445 mass % of PO4(3-), inorganic impurities presence), dissolved substrates (magnesium and ammonium chlorides) and solution alkalising the environment of struvite MgNH4PO4.6H2O reaction crystallization process. Research ran in constant temperature 298 K assuming stoichiometric proportions of substrates or 20% excess of magnesium ions. Influence of pH (8.5 10) and mean residence time (900-3600 s) on product size distribution, its chemical composition, crystals shape, size-homogeneity and process kinetics was identified. Crystals of mean size ca. 25-37 MUm and homogeneity CV 70-83% were produced. The largest crystals, of acceptable homogeneity, were produced using 20% excess of magnesium ions, pH 9 and mean residence time 3600 s. Under these conditions nucleation rate did not exceed 9 * 10(7) 1/(s m(3)) according to SIG (Size Independent Growth) MSMPR kinetic model. Linear crystal growth rate was 4.27 * 10(-9) m/s. Excess of magnesium ions influenced struvite reaction crystallization process yield advantageously. Concentration of phosphate(V) ions decreased from 0.445 to 9.2 * 10(-4) mass %. This can be regarded as a very good process result. In product crystals, besides main component - struvite, all impurities from wastewater were detected analytically. PMID- 23726700 TI - Biotic and abiotic processes contribute to successful anaerobic degradation of cyanide by UASB reactor biomass treating brewery waste water. AB - In contrast to the general aerobic detoxification of industrial effluents containing cyanide, anaerobic cyanide degradation is not well understood, including the microbial communities involved. To address this knowledge gap, this study measured anaerobic cyanide degradation and the rearrangements in bacterial and archaeal microbial communities in an upflow anaerobic sludge blanket (UASB) reactor biomass treating brewery waste water using bio-methane potential assays, molecular profiling, sequencing and microarray approaches. Successful biogas formation and cyanide removal without inhibition were observed at cyanide concentrations up to 5 mg l(-1). At 8.5 mg l(-1) cyanide, there was a 22 day lag phase in microbial activity, but subsequent methane production rates were equivalent to when 5 mg l(-1) was used. The higher cumulative methane production in cyanide-amended samples indicated that part of the biogas was derived from cyanide degradation. Anaerobic degradation of cyanide using autoclaved UASB biomass proceeded at a rate more than two times lower than when UASB biomass was not autoclaved, indicating that anaerobic cyanide degradation was in fact a combination of simultaneous abiotic and biotic processes. Phylogenetic analyses of bacterial and archaeal 16S rRNA genes for the first time identified and linked the bacterial phylum Firmicutes and the archaeal genus Methanosarcina sp. as important microbial groups involved in cyanide degradation. Methanogenic activity of unadapted granulated biomass was detected at higher cyanide concentrations than reported previously for the unadapted suspended biomass, making the aggregated structure and predominantly hydrogenotrophic nature of methanogenic community important features in cyanide degradation. The combination of brewery waste water and cyanide substrate was thus shown to be of high interest for industrial level anaerobic cyanide degradation. PMID- 23726701 TI - The effect of environmental and therapeutic concentrations of antibiotics on nitrate reduction rates in river sediment. AB - The use of antibiotics in both human and veterinary medicine has led to increased presence of these compounds and antibiotic resistance in the environment. In this study, the effect of low, environmentally relevant (mg L(-1)) concentrations of vancomycin (VA), flumequine (FLU), and sulfamethoxazole (SMX) on nitrate reduction rates was studied in river sediments. Nitrate reduction rates were determined by supplying intact sediments for several weeks with both nitrate and antibiotics (ng L(-1), MUg L(-1), and mg L(-1) concentrations), including a non-amended control. Furthermore the concentrations of the three investigated antibiotics were measured in the initial (natural) sediments and the sediments supplied with the antibiotics. The antibiotic concentrations in the sediments decreased (on average 62% for FLU and 93% for SMX) during the experiments, indicating loss of antibiotics due to sorption or (bio) degradation. Nitrate reduction rates were not affected by environmental concentrations of VA, FLU and SMX. FLU and SMX only partially inhibited nitrate reduction rates at high, therapeutic concentrations by 41 and 39% respectively. The three tested antibiotics significantly enhanced the production of nitrite, an intermediate in dissimilatory nitrate reduction. Nitrite production increased 1.9 and 1.4 fold for environmental VA concentrations (107 and 187 MUg L(-1) respectively), application of 58 mg L(-1) SMX resulted in a 7.5 fold increase and augmented 16 and 8.5 fold in the presence of respectively 13 MUg L(-1) and 52 mg L(-1) FLU. Even though inhibition of nitrate reduction rates was observed at therapeutic antibiotic concentrations, nitrate reduction proceeded under all experimental conditions, indicating the presence of resistance toward these antibiotics among the nitrate reducing bacteria. The accumulation of nitrite suggests that the nitrite reduction step was more affected than the overall nitrate reduction process. PMID- 23726702 TI - A free nitrous acid (FNA)-based technology for reducing sludge production. AB - Sludge treatment and disposal is one of the major challenges for biological wastewater treatment plants and can represent up to 60% of their total operating costs. This study presents a novel strategy based on free nitrous acid (FNA or HNO2) treatment to achieve sludge reduction. Two sequencing batch reactors treating synthetic domestic wastewater were used, with one serving as an experimental reactor and the other as a control. In the experimental system, 50% of the excess sludge was exposed to FNA at 2.0 mg N/L for 24-42 h in an FNA treatment unit and then returned to the parent reactor. The sludge wastage flow from the experimental reactor was adjusted to obtain a similar mixed liquor suspended solids concentration to that in the control reactor, which was operated at a sludge retention time of 15 days. It was found that sludge production in the experimental system was 28% lower in comparison to the control. The addition of the FNA-treated sludge did not negatively affect the treatment performance and sludge properties of the experimental reactor, namely the organic carbon and nitrogen removal, nitrous oxide (N2O) emission and sludge settleability. Endogenous denitrification batch tests indicate that FNA-treated sludge is available as a carbon source for denitrification. PMID- 23726703 TI - Effect of gamma irradiation on bacteriophages used as viral indicators. AB - This study aimed to examine the susceptibility of indicator bacteriophages towards gamma-radiation to evaluate their appropriateness as viral indicators for water quality control. The effects of gamma-radiation on naturally occurring somatic coliphages, F-specific coliphages and Escherichia coli were examined in raw sewage and sewage sludge. As well, the effects of radiation on bacteriophages PhiX174 and MS2, and E. coli all grown in the laboratory and seeded in distilled water, autoclaved raw sewage and a 1% peptone solution were evaluated. The inactivation of E. coli was fairly similar in all matrices. In contrast, inactivation of bacteriophages was significantly greater in distilled water than in the other matrices. These results showed the great influence of the matrix characteristics on virus inactivation. Somatic coliphages in raw sewage and sewage sludge and PhiX174 in autoclaved sewage were inactivated similarly and were far more resistant than F-specific coliphages, MS2 and E. coli. As well, F specific RNA bacteriophages in raw sewage and sewage sludge and MS2 in autoclaved sewage were inactivated similarly and were more resistant than E. coli. In contrast, MS2 was more susceptible to gamma-radiation than E. coli in distilled water. Our results showed that PhiX174 is a suitable indicator for estimating virus inactivation by gamma-irradiation and corroborate the use of somatic coliphages to survey the viral quality of treated water and sludges. PMID- 23726704 TI - How green are environmental technologies? A new approach for a global evaluation: the case of WWTP effluents ozonation. AB - The research on the impact of chemical pollution is now increasingly attracted by the topic of organic micropollutants: as secondary biological treatment of wastewater does not provide the complete elimination of these substances, an advanced treatment downstream the biological process can be implemented. Notwithstanding, the benefits of improved effluent quality can be weakened by the negative effects on air quality, when energy consumption and related pollutants emissions deriving from the advanced treatment technologies are taken into account. It is the aim of this work to present an innovative methodology to judge the environmental compatibility of wastewater treatment processes on the basis of the damage on human health produced/avoided, expressed as an economic value. In particular, while for air pollution the established external costs were applied, for water pollution the rates of the impacts on human health have been evaluated in terms of Global Burden of Disease and measured in units of DALY (Disability Adjusted Life Years), then converted into costs based on Gross Domestic Product. As a first application, this procedure was used for assessing environmental compatibility of a final ozonation: the results of this study showed that the reduction of water pollution achieved by means of ozonation might be beneficial for human health at an extent which is in the same order of magnitude of damage caused by air pollution, emphasizing that the question if the use of advanced (energy-intensive) treatments is a proper solution to remove organic micropollutants from wastewater remains still open. PMID- 23726705 TI - Quantifying the loss of methane through secondary gas mass transport (or 'slip') from a micro-porous membrane contactor applied to biogas upgrading. AB - Secondary gas transport during the separation of a binary gas with a micro-porous hollow fibre membrane contactor (HMFC) has been studied for biogas upgrading. In this application, the loss or 'slip' of the secondary gas (methane) during separation is a known concern, specifically since methane possesses the intrinsic calorific value. Deionised (DI) water was initially used as the physical solvent. Under these conditions, carbon dioxide (CO2) and methane (CH4) absorption were dependent upon liquid velocity (V(L)). Whilst the highest CO2 flux was recorded at high V(L), selectivity towards CO2 declined due to low residence times and a diminished gas-side partial pressure, and resulted in slip of approximately 5.2% of the inlet methane. Sodium hydroxide was subsequently used as a comparative chemical absorption solvent. Under these conditions, CO2 mass transfer increased by increasing gas velocity (VG) which is attributed to the excess of reactive hydroxide ions present in the solvent, and the fast conversion of dissolved CO2 to carbonate species reinitiating the concentration gradient at the gas-liquid interface. At high gas velocities, CH4 slip was reduced to 0.1% under chemical conditions. Methane slip is therefore dependent upon whether the process is gas phase or liquid phase controlled, since methane mass transport can be adequately described by Henry's law within both physical and chemical solvents. The addition of an electrolyte was found to further retard CH4 absorption via the salting out effect. However, their applicability to physical solvents is limited since electrolytic concentration similarly impinges upon the solvents' capacity for CO2. This study illustrates the significance of secondary gas mass transport, and furthermore demonstrates that gas-phase controlled systems are recommended where greater selectivity is required. PMID- 23726706 TI - Extension of pipe failure models to consider the absence of data from replaced pipes. AB - Predictions of the expected number of failures of water distribution network pipes are important to develop an optimal management strategy. A number of probabilistic pipe failure models have been proposed in the literature for this purpose. They have to be calibrated on failure records. However, common data management practices mean that replaced pipes are often absent from available data sets. This leads to a 'survival selection bias', as pipes with frequent failures are more likely to be absent from the data. To address this problem, we propose a formal statistical approach to extend the likelihood function of a pipe failure model by a replacement model. Frequentist maximum likelihood estimation or Bayesian inference can then be applied for parameter estimation. This approach is general and is not limited to a particular failure or replacement model. We implemented this approach with a Weibull-exponential failure model and a simple constant probability replacement model. Based on this distribution assumptions, we illustrated our concept with two examples. First, we used simulated data to show how replacement causes a 'survival selection bias' and how to successfully correct for it. A second example with real data illustrates how a model can be extended to consider covariables. PMID- 23726707 TI - Catalytic hydrodechlorination of trichloroethylene in water with supported CMC stabilized palladium nanoparticles. AB - In this work, we developed and tested a new class of supported Pd catalysts by immobilizing CMC (carboxymethyl cellulose) stabilized Pd nanoparticles onto alumina support. The alumina supported Pd nanoparticles were able to facilitate rapid and complete hydrodechlorination of TCE (trichloroethylene) without intermediate by-products detected. With a Pd mass loading of 0.33 wt% of the alumina mass, the observed pseudo first order reaction rate constant, k(obs), for the catalyst was increased from 28 to 109 L/min/g when CMC concentration was raised from 0.005 to 0.15 wt%. The activity increase was in accord with an increase of the Pd dispersion (measured via CO chemisorption) from 30.4% to 45.1%. Compared to the commercial alumina supported Pd, which has a lower Pd dispersion of 21%, our CMC-stabilized Pd nanoparticles offered more than 7 times greater activity. Pre-calcination treatment of the supported catalyst resulted in minor drop in activity, yet greatly reduced bleeding (<6%) of the Pd nanoparticles from the support during multiple cycles of applications. The presence of DOM (dissolved organic matter) at up to 10 mg/L as TOC had negligible effect on the catalytic activity. The alumina supported CMC-stabilized Pd nanoparticles may serve as a class of more effective catalysts for water treatment uses. PMID- 23726708 TI - Rotating cylinder technique for assessing the effectiveness of anti-scalants. AB - A novel technique for evaluating the relative inhibition effectiveness of different anti-scalants is presented. The technique is based on the ability of anti-scalants to modify the scale deposition mechanism from mass transfer control to surface control. A rotating cylinder system which is known to provide well controlled mass transfer conditions is used to determine the scaling rate of a supersaturated solution dosed with various feed concentrations of an anti scalant. Mass transfer conditions were characterized by turbulent flow at hydrodynamically smooth surface. In the absence of an anti-scalant, scale deposition is mass transfer controlled and scaling rate increases with rotation speed. With sufficient anti-scalant dosage, precipitation is modified to surface control and rotation speed has no effect on the scale deposition rate. Determination of the critical anti-scalant dosage enabling surface controlled precipitation provides a sensitive technique for comparing the relative effectiveness of different anti-scalants. PMID- 23726709 TI - Selective oxidation of bromide in wastewater brines from hydraulic fracturing. AB - Brines generated from oil and natural gas production, including flowback water and produced water from hydraulic fracturing of shale gas, may contain elevated concentrations of bromide (~1 g/L). Bromide is a broad concern due to the potential for forming brominated disinfection byproducts (DBPs) during drinking water treatment. Conventional treatment processes for bromide removal is costly and not specific. Selective bromide removal is technically challenging due to the presence of other ions in the brine, especially chloride as high as 30-200 g/L. This study evaluates the ability of solid graphite electrodes to selectively oxidize bromide to bromine in flowback water and produced water from a shale gas operation in Southwestern PA. The bromine can then be outgassed from the solution and recovered, as a process well understood in the bromine industry. This study revealed that bromide may be selectively and rapidly removed from oil and gas brines (~10 h(-1) m(-2) for produced water and ~60 h(-1) m(-2) for flowback water). The electrolysis occurs with a current efficiency between 60 and 90%, and the estimated energy cost is ~6 kJ/g Br. These data are similar to those for the chlor-alkali process that is commonly used for chlorine gas and sodium hydroxide production. The results demonstrate that bromide may be selectively removed from oil and gas brines to create an opportunity for environmental protection and resource recovery. PMID- 23726710 TI - High-rate iron-rich activated sludge as stabilizing agent for the anaerobic digestion of kitchen waste. AB - Anaerobic digestion is a key technology in the bio-based economy and can be applied to convert a wide range of organic substrates into CH4 and CO2. Kitchen waste is a valuable substrate for anaerobic digestion, since it is an abundant source of organic matter. Yet, digestion of single kitchen waste often results in process failure. High-rate activated sludge or A-sludge is produced during the highly loaded first stage of the two-phase 'Adsorptions-Belebungsverfahren' or A/B activated sludge system for municipal wastewater treatment. In this specific case, the A-sludge was amended with FeSO4 to enhance phosphorous removal and coagulation during the water treatment step. This study therefore evaluated whether this Fe-rich A-sludge could be used to obtain stable methanation and higher methane production values during co-digestion with kitchen waste. It was revealed that Fe-rich A-sludge can be a suitable co-substrate for kitchen waste; i.e. methane production rate values of 1.15 +/- 0.22 and 1.12 +/- 0.28 L L(-1) d( 1) were obtained during mesophilic and thermophilic co-digestion respectively of a feed-mixture consisting of 15% KW and 85% A-sludge. The thermophilic process led to higher residual VFA concentrations, up to 2070 mg COD L(-1), and can therefore be considered less stable. Addition of micro- and macronutrients provided a more stable digestion of single kitchen waste, i.e. a methane production of 0.45 L L(-1) d(-1) was obtained in the micronutrient treatment compared to 0.30 L L(-1) d(-1) in the control treatment on day 61. Yet, methane production during single kitchen waste digestion still decreased toward the end of the experiment, despite the addition of micronutrients. Methane production rates were clearly influenced by the total numbers of archaea in the different reactors. This study showed that Fe-rich A-sludge and kitchen waste are suitable for co-digestion. PMID- 23726711 TI - Silicate minerals for CO2 scavenging from biogas in Autogenerative High Pressure Digestion. AB - Autogenerative High Pressure Digestion (AHPD) is a novel concept that integrates gas upgrading with anaerobic digestion by selective dissolution of CO2 at elevated biogas pressure. However, accumulation of CO2 and fatty acids after anaerobic digestion of glucose resulted in pH 3-5, which is incompatible with the commonly applied high-rate methanogenic processes. Therefore, we studied the use of wollastonite, olivine and anorthosite, with measured composition of CaSi1.05O3.4, Mg2Fe0.2Ni0.01Si1.2O5.3 and Na0.7Ca1K0.1Mg0.1Fe0.15Al3.1Si4O24, respectively, to scavenge CO2 during batch AHPD of glucose. Depending on the glucose to mineral ratio the pH increased to 6.0-7.5. Experiments with wollastonite showed that Ca(2+)-leaching was caused by volatile fatty acid (VFA) production during glucose digestion. At 1, 3 and 9 bar, the CH4 content reached 74%, 86% and 88%, respectively, indicating CO2 scavenging. Fixation of produced CO2 by CaCO3 precipitation in the sludge was confirmed by Fourier Transferred InfraRed, Combined Field emission Scanning Electron Microscopy-Energy-dispersive X-ray spectroscopy and Thermogravimetric Analysis-Mass Spectroscopy. PMID- 23726712 TI - Using digital flow cytometry to assess the degradation of three cyanobacteria species after oxidation processes. AB - Depending on drinking water treatment conditions, oxidation processes may result in the degradation of cyanobacteria cells causing the release of toxic metabolites (microcystin), odorous metabolites (MIB, geosmin), or disinfection byproduct precursors. In this study, a digital flow cytometer (FlowCAM((r))) in combination with chlorophyll-a analysis was used to evaluate the ability of ozone, chlorine, chlorine dioxide, and chloramine to damage or lyse cyanobacteria cells added to Colorado River water. Microcystis aeruginosa (MA), Oscillatoria sp. (OSC) and Lyngbya sp. (LYN) were selected for the study due to their occurrence in surface water supplies, metabolite production, and morphology. Results showed that cell damage was observed without complete lysis or fragmentation of the cell membrane under many of the conditions tested. During ozone and chlorine experiments, the unicellular MA was more susceptible to oxidation than the filamentous OSC and LYN. Rate constants were developed based on the loss of chlorophyll-a and oxidant exposure, which showed the oxidants degraded MA, OSC, and LYN according to the order of ozone > chlorine ~ chlorine dioxide > chloramine. Digital and binary images taken by the digital flow cytometer provided qualitative insight regarding cell damage. When applying this information, drinking water utilities can better understand the risk of cell damage or lysis during oxidation processes. PMID- 23726713 TI - Hydrodynamic effects of air sparging on hollow fiber membranes in a bubble column reactor. AB - Air sparging is now a standard approach to reduce concentration polarization and fouling of membrane modules in membrane bioreactors (MBRs). The hydrodynamic shear stresses, bubble-induced turbulence and cross flows scour the membrane surfaces and help reduce the deposit of foulants onto the membrane surface. However, the detailed quantitative knowledge on the effect of air sparging remains lacking in the literature due to the complex hydrodynamics generated by the gas-liquid flows. To date, there is no valid model that describes the relationship between the membrane fouling performance and the flow hydrodynamics. The present study aims to examine the impact of hydrodynamics induced by air sparging on the membrane fouling mitigation in a quantitative manner. A modelled hollow fiber module was placed in a cylindrical bubble column reactor at different axial heights with the trans-membrane pressure (TMP) monitored under constant flux conditions. The configuration of bubble column without the membrane module immersed was identical to that studied by Gan et al. (2011) using Phase Doppler Anemometry (PDA), to ensure a good quantitative understanding of turbulent flow conditions along the column height. The experimental results showed that the meandering flow regime which exhibits high flow instability at the 0.3 m is more beneficial to fouling alleviation compared with the steady flow circulation regime at the 0.6 m. The filtration tests also confirmed the existence of an optimal superficial air velocity beyond which a further increase is of no significant benefit on the membrane fouling reduction. In addition, the alternate aeration provided by two air stones mounted at the opposite end of the diameter of the bubble column was also studied to investigate the associated flow dynamics and its influence on the membrane filtration performance. It was found that with a proper switching interval and membrane module orientation, the membrane fouling can be effectively controlled with even smaller superficial air velocity than the optimal value provided by a single air stone. Finally, the testing results with both inorganic and organic feeds showed that the solid particle composition and particle size distribution all contribute to the cake formation in a membrane filtration system. PMID- 23726714 TI - Towards temperature driven forward osmosis desalination using Semi-IPN hydrogels as reversible draw agents. AB - We report a study to explore new materials and a new concept for temperature driven quasi-continuous desalination using hydrogels as draw agents in forward osmosis (FO). This concept is enabled by the design and preparation of thermally responsive hydrogels having a semi-interpenetrating network (semi-IPN) structure. Thermally responsive semi-IPN hydrogels were synthesized by polymerization of N isopropylacrylamide (NIPAm) in the presence of polysodium acrylate (PSA) or polyvinyl alcohol (PVA). Their functions as draw agents in FO were systematically studied and compared with hydrogels prepared from the PNIPAm homopolymer or the NIPAM-SA copolymer. While the semi-IPN hydrogels displayed the desirable balanced thermally responsive swelling and dewatering behavior, the NIPAm-SA copolymer hydrogels were found to have poor dewatering behavior, making them unsuitable for a continuous temperature driven desalination process. At 40 degrees C, the semi IPN hydrogels rapidly release nearly 100% of the water absorbed during the FO drawing process carried out at room temperature. Results clearly indicate the potential of semi-IPN hydrogels as semi-solid draw agents in the FO process, in which quasi-continuous desalination could be achieved by cyclic heating and cooling within a moderate temperature change. PMID- 23726715 TI - Broad spectrum detection and "barcoding" of water pollutants by a genome-wide bacterial sensor array. AB - An approach for the rapid detection and classification of a broad spectrum of water pollutants, based on a genome-wide reporter bacterial live cell array, is proposed and demonstrated. An array of ca. 2000 Escherichia coli fluorescent transcriptional reporters was exposed to 25 toxic compounds as well as to unpolluted water, and its responses were recorded after 3 h. The 25 toxic compounds represented 5 pollutant classes: genotoxicants, metals, detergents, alcohols, and monoaromatic hydrocarbons. Identifying unique gene expression patterns, a nearest neighbour-based model detected pollutant presence and predicted class attribution with an estimated accuracy of 87%. Sensitivity and positive predictive values varied among classes, being higher for pollutant classes that were defined by mode of action than for those defined by structure only. Sensitivity for unpolluted water was 0.90 and the positive predictive value was 0.79. All pollutant classes induced the transcription of a statistically significant proportion of membrane associated genes; in addition, the sets of genes responsive to genotoxicants, detergents and alcohols were enriched with genes involved in DNA repair, iron utilization and the translation machinery, respectively. Following further development, a methodology of the type described herein may be suitable for integration in water monitoring schemes in conjunction with existing analytical and biological detection techniques. PMID- 23726716 TI - Differential chemical profiling to identify ozonation by-products of estrone sulfate and first characterization of estrogenicity in generated drinking water. AB - For a few years, the concern of water treatment companies is not only focused on the removal of target micropollutants but has been extended to the investigation of potential biologically active by-products generated during the treatment processes. Therefore, some methods dedicated to the detection and structural characterization of such by-products have emerged. However, most of these studies are usually carried out under simplified conditions (e.g. high concentration levels of micropollutants, drastic treatment conditions, use of deionized or ultrapure water) and somewhat unrealistic conditions compared to that implemented in water treatment plants. In the present study, a real field water sample was fortified at the part-per-billion level (50 MUg L(-1)) with estrone-3-sulfate (E1 3S) before being ozonated (at 1 mg L(-1)) for 10 min. In a first step, targeted measurements evidenced a degradation of the parent compound (>80%) in 10 min. Secondly, a non-targeted chemical profiling approach derived from metabolomic profiling studies allowed to reveal 11 ozonation by-products, among which 4 were found predominant. The estrogenic activity of these water samples spiked with E1 3S before and after treatment was assessed by the ER-CALUX assay and was found to decrease significantly after 10 min of ozonation. Therefore, this innovative methodological strategy demonstrated its suitability and relevancy for revealing unknown compounds generated from water treatment, and permitted to generate new results regarding specifically the impact of ozonation on estrone-3-sulfate. These results confirm that ozonation is effective at removing E1-3S in drinking water and indicate that the by-products generated have significantly lower estrogenic activity. PMID- 23726717 TI - Association between SYP with attention-deficit/hyperactivity disorder in Chinese Han subjects: differences among subtypes and genders. AB - Dysfunction of neurotransmitters has been suggested to be involved in the etiology of attention-deficit/hyperactivity disorder (ADHD). Hence, genes encoding proteins involved in the vesicular release process of those neurotransmitters are attractive candidates in ADHD genetics. One of these genes is SYP, which encodes synaptophysin, a protein known to participate in regulating neurotransmitter release and synaptic plasticity. Several studies have reported an association between SYP and ADHD, but more work is needed to refine the association. In the present study, we attempt to investigate their association in Chinese Han subjects by family-based and case-control studies. Transmission disequilibrium tests (TDTs) in 1112 trios found significant association between SYP and the predominantly inattentive subtype (ADHD-I), especially for males with ADHD-I, both from single nucleotide polymorphism (SNP) and haplotypic analyses. Chi-square tests in 1682 ADHD probands and 957 comparison subjects indicated possible association of SYP with female ADHD and female ADHD-I. However, the associated alleles and haplotypes between males and females were reversed. In conclusion, our results suggested that SYP may be primarily associated with ADHD I and its genetic mechanism may be gender-specific. Thus, it is necessary to take subtype and gender into account in ADHD genetic studies. PMID- 23726718 TI - VPS35 and EIF4G1 mutations are rare in Parkinson's disease among Indians. AB - Mutations in 2 genes, vacuolar protein sorting homolog 35 (VPS35) and eukaryotic translation initiation factor 4 gamma 1 (EIF4G1), have been recently reported as causal in autosomal dominant Parkinson's disease (PD) among Caucasians. Their contribution to PD in other ethnic groups remains limited with 1% of VPS35 mutations observed in Caucasian and Japanese populations, but none in Chinese, and 11.57% of EIF4G1 mutations in Caucasian families and 0.09% and 0.17% in Caucasian and Chinese sporadic cases, respectively. We investigated the contribution, if any, of these 2 genes to familial and sporadic PD among the ethnically distinct Indian population. Complete exonic regions of these 2 genes were resequenced in 15 well-characterized PD families; the reported p.Asp620Asn in VPS35 and p.Arg1205His in EIF4G1 mutations were screened in an additional 54 familial and 251 sporadic PD cases, and no mutations were observed. These results, together with our previous reports on the absence of mutations in SNCA and LRRK2, warrant a continuing search for novel causative genes for PD among Indians. PMID- 23726719 TI - Safety and efficacy of 5-azacytidine treatment in myelodysplastic syndrome patients with moderate and mild renal impairment. AB - Myelodysplastic syndrome (MDS) patients with renal impairment (RI) were not assessed in the approval trials of 5-azacytidine, thus the optimal use of 5 azacytidine in such patients is currently undefined. We retrospectively analyzed 42 IPSS intermediate-2 and high-risk patients with moderate, mild or no RI undergoing 5-azacytidine therapy in a non-trial setting. We demonstrate that patients in all three groups achieved comparable responses and had similar overall and event-free survival. Likewise, both treatment toxicity and dose adjustments were not significantly influenced by renal function status. A transient but reversible decline in glomerular filtration rate was observed in patients either with or without RI, without affecting the therapeutic schedule. Our results provide the first evidence that 5-azacytidine is effective and well tolerated in patients with mild and moderate RI and, if confirmed by prospective randomized studies, advocate that such patients can be managed in an analogous fashion to patients with normal renal function. PMID- 23726720 TI - Computerized facial analysis for understanding constricted/blunted affect: initial feasibility, reliability, and validity data. AB - Diminished expression is a diagnostic feature of a range of schizophrenia spectrum disorders/conditions and is often unresponsive to treatment, is present across premorbid, first episode and various clinical states, and is considered a poor prognostic indicator. Surprisingly, little is known about diminished expression. The present study sought to address this issue by evaluating a commercially-available computerized facial analysis software for understanding diminished expressivity. We analyzed natural facial expression from a series of laboratory interaction tasks in 28 individuals with psychometric schizotypy - defined as the personality organization reflecting a putative genetic schizophrenia liability, and 26 matched controls. We evaluated (a) feasibility - defined in terms of the number of video frames recognized by the software, (b) reliability - defined in terms of correlations between facial expression variables across the three laboratory interactions, and (c) construct validity - defined in terms of relationships to clinical variables. For most subjects (~80%), approximately three-quarters of the video frames were analyzable by the software; however, a minority of the videos were essentially unreadable. The facial expression variables showed excellent reliability across interaction conditions. In terms of construct validity, facial expression variables were significantly related to a measure of psychoticism, tapping subjective cognitive concerns and "first-rank" schizophrenia symptoms, but were generally not different between groups. Facial expression variables were generally not significantly related to measures of depression, anxiety, paranoia or, surprisingly, self-reported negative schizotypy. While computerized facial analysis appears to be a reliable and promising method of understanding diminished expressivity across the schizophrenia-spectrum, some work remains. Implications are discussed. PMID- 23726721 TI - Drug and alcohol trajectories among adults with schizophrenia: data from the CATIE study. AB - OBJECTIVE: The primary aim is to describe drug and alcohol trajectories in adults with schizophrenia. METHOD: Growth mixture models were used to examine disordered and non-disordered use and abstinence in the Clinical Antipsychotic Trials of Intervention Effectiveness study. RESULTS: Five classes - always abstinent; fluctuating use, abuse, and occasional abstinence; occasional (ab)use; stopped (ab)use; abusing - fit best. Overlap exists between always abstinent drug and alcohol classes; less overlap exists across other classes. CONCLUSION: There is heterogeneity in drug and alcohol use among adults with schizophrenia. The lack of overlap between classes, save always abstinent, suggests modeling drug and alcohol use separately. PMID- 23726722 TI - Reduced neuro-integration from the dorsolateral prefrontal cortex to the whole brain and executive dysfunction in schizophrenia patients and their relatives. AB - Executive dysfunction is one of the core symptoms of schizophrenia. Functional neuro-imaging studies have suggested an association between deficits in activating the dorsolateral prefrontal cortex (DLPFC) and executive dysfunction, but neuro-integration from the DLPFC to the whole brain remains unclear. Studies investigating the neuro-integration from the DLPFC to the whole brain in unaffected but genetically liable family members are scant. In this study, we report DLPFC neuro-integrative deficits correlated with executive dysfunction and family history of schizophrenia using resting-state functional magnetic resonance imaging (fMRI). Using seed regions in DLPFC, we examined resting-state functional connectivity in 25 patients with schizophrenia, 25 unaffected first-degree relatives (UR), and 25 healthy control (HC) persons. Schizophrenia patients and UR have impaired connectivity from DLPFC to its coordinated regions (ANOVA: F=7.316-10.974, p<0.001). These coordinated brain regions are distributed in the bilateral caudate, left middle/inferior frontal gyrus, left precentral gyrus, and right cerebellum. The individual functional connectivity strength between the left DLPFC and its coordinated regions was correlated with individual executive function performance among whole persons. (Pearson's r=0.244-0.366, p=0.035 0.008) Our findings support that distributed neuro-integrative DLPFC deficits reflect a genetic risk for schizophrenia and that these deficits are present, to a lesser degree, in unaffected first-degree relatives. Our findings also support that neuro-integration might correlate with a patient's executive function performance. PMID- 23726723 TI - Increased medication compliance of liver transplant patients switched from a twice-daily to a once-daily tacrolimus-based immunosuppressive regimen. AB - BACKGROUND: Compliance with immunosuppressive therapy plays a major role in the long-term success of liver transplantation. Thus, the development of strategies to promote compliance of liver transplant patients and its evaluation over time are of particular interest. OBJECTIVE: The main objective of this study was to compare medication compliance rates among liver transplant patients over time after transplantation where switched from a twice- to once-daily tacrolimus-based regimen. METHODS: Sixty-five liver transplant patients being administered tacrolimus-based therapy were classified into three subgroups with regard to time posttransplantation. Medication compliance with tacrolimus-based therapy was measured using an electronic medication event monitoring system over a 12-month period: for 6 months tacrolimus was administered twice-daily and for 6 months, once-daily. Dosing, taking, and timing compliance as well as drug holidays were compared intra-individually between twice- and once-daily intake and among the three subgroups. In addition, patient compliance and quality of life were evaluated using questionnaires. RESULTS: A per protocol analysis of electronically obtained data showed 63 patients to be eligible. The resulting dosing, taking, and timing compliance rates of the patients were higher during the once-daily dosing period. No significant differences in compliance rates with tacrolimus therapy were observed among three subgroups independent of the dosing regimen. More patients failed the correct timing of the evening compared to the morning dose. Missing doses occurred particularly during weekends. Compliance variables measured by questionnaires (Morisky score, self-report, Medication Experience Scale for Immunosuppressants (MESI) score) and the Hospital Anxiety and Depression Scale score were similar in the two dosing periods. The short-form health survey (SF-36) score was higher with once-daily intake. CONCLUSION: The high measured compliance rates did not vary significantly dependent upon the time after transplantation. Nevertheless, compliance rates were greater using once daily tacrolimus dosing. PMID- 23726724 TI - Quantifying the effect of settlement and gas on solute flow and transport through treated municipal solid waste. AB - The effect of degradation and settlement on transport properties of mechanically and biologically treated (MBT) waste was examined by applying three different tracers to two waste columns (~0.5 m diameter) in a series of closed-loop experiments. One column was allowed to biodegrade and the other was bio suppressed. Permeability and drainable porosity were reduced by settlement, in line with previous results. A dual-porosity model performed well against the data and suggested that more preferential flow occurred early on in the un-degraded column. Diffusion timescales were found to be between 0.8 and 6 days. Volumetric water contents of the mobile region were found to be small in the bio-suppressed cell (~0.01) and even smaller values were found in the degrading waste, possibly due to displacement by gas. Once either settlement or gas production had disrupted this pattern into a more even flow, subsequent compression made little difference to the diffusion time-scale. This may indicate that transport was thereafter dominated by other aspects of the waste structure such as the distribution of low-permeability objects. The presence of gas in the degrading waste reduced the volumetric water content through displacement. The model indicated that the gas was primarily located in the more mobile porosity fraction. Primary compression of the degrading waste tended to squeeze this gas out of the waste in preference to water. PMID- 23726725 TI - The MSCT and MRI findings of collecting duct carcinoma. AB - AIM: To characterize the multi-section computed tomography (MSCT) and magnetic resonance imaging (MRI) features of collecting duct carcinoma (CDC). MATERIALS AND METHODS: Twenty patients with CDC were studied retrospectively using MSCT (n = 20), and MSCT and MRI (n = 5). MSCT and MRI were undertaken to investigate tumour location, size, radiodensity, cystic or solid appearance, calcification, capsule, signal, enhancement pattern, and metastases. RESULTS: Tumours (mean diameter 3.6 +/- 1.7 cm) were solitary (20/20), solid (18/20), had cystic components (12/20), calcifications (12/20), poorly defined (18/20), were centred in the medulla (20/20), compressed the renal pelvis (12/20), and had lymph node metastases (2/20). On unenhanced computed tomography (CT), the radiodensity of the CDC was greater than that of the normal renal cortex or medulla (43.8 +/- 2.4 versus 37.6 +/- 5.1 or 32.6 +/- 4.1, p = 0.041, n = 20). Five patients with CDC underwent MRI, which revealed cystic components (4/5), poorly defined CDC (5/5), and none of the patients had lymph node metastasis. The CDC was isointense on T1 weighted imaging, and iso- or hypointense on T2-weighted imaging. Enhancement was lower within the CDC than the renal cortex and medulla during all enhanced phases (p = 0.032, 0.001, 0.018, respectively, n = 20). CONCLUSION: CDC should be considered when a renal tumour is centred in the medulla, with increased radiodensity on unenhanced CT and reduced enhancement compared to the adjacent cortex or medulla. PMID- 23726726 TI - [Severe pre-eclampsia. An evidence-based practice proposal]. AB - OBJECTIVES: There are several treatment proposals for the obstetric patient with pre-eclampsia, but there is limited evidence on the adequacy of standard treatment. International healthcare organisations recommend that hospitals or anaesthesia departments have written guidelines, protocols or recommendations for dealing with common or severe situations. We propose evidence-based recommendations for the treatment of pre-eclampsia. MATERIAL AND METHODS: A literature review was performed using several sources, bibliography databases, recommendations made by specialist societies, and reviews. Four anaesthesiologists reviewed the references selected, in order to design clinical questions (these were obtained from recent pre-eclampsia review articles). Consensus of at least 3 out of 4 experts was required. The Oxford criteria for evidence were chosen to classify the scientific articles, and the Jadad score was applied to the final articles selected. RESULTS: A total of 50 clinical questions were designed and answered. These were classified into: general questions, influence of the type of delivery, pre-anaesthesia evaluation, peripartum treatment (including analgesia and anaesthesia), eclampsia, post-delivery period, and intensive care and transport. Most of the responses showed low scientific evidence. CONCLUSIONS: Evidence-based recommendations for severe pre-eclampsia treatment were provided with special emphasis on the anaesthesiologist point of view. PMID- 23726727 TI - Transcriptomics approaches in the early Arabidopsis embryo. AB - Early plant embryogenesis condenses the fundamental processes underlying plant development into a short sequence of predictable steps. The main tissues, as well as stem cells for their post-embryonic maintenance, are specified through genetic control networks. A key question is how cell fates are instructed by unique cellular transcriptomes, and important insights have recently been gained through cell type-specific transcriptomics during post-embryonic development. However, the poor accessibility and small size of Arabidopsis (Arabidopsis thaliana) embryos have obstructed similar progress during embryogenesis. Here, we review the current situation in plant embryo transcriptomics, and discuss how the recent development of novel cell-specific analysis technologies will enable the identification of cellular transcriptomes in the early Arabidopsis embryo. PMID- 23726728 TI - [Objective: impact factor]. PMID- 23726729 TI - [The appropriate use of pharmacological treatment in patients with chronic heart failure. A perspective from Primary Care]. AB - INTRODUCTION AND OBJECTIVE: The appropriate use of pharmacological treatment according to the indications in Clinical Guidelines reduces morbidity and mortality in patients with chronic heart failure (CHF). There are numerous studies regarding this in the hospital environment, but there are few studies done in Primary Care. The objective of this study is to evaluate the degree of compliance by Primary Care doctors to the Clinical Guidelines of the European Society of Cardiology in patients with CHF. METHODS: A descriptive, observational study on the use of indication-prescription drugs was conducted. POPULATION AND SAMPLE: Primary Care teams of the Leon Health Area (9 urban and 19 rural). The study population included patients with a diagnosis of New York Heart Association (NYHA) Grade II-IV chronic heart failure, from a register of 2047 with chronic heart failure patients treated by 97 Primary Care doctors. A proportional representative random sample of 474 patients from the urban and rural areas was studied. MAIN MEASUREMENTS: Adherence to the drugs recommended in the Clinical Guidelines was evaluated using two indicators; one overall, and another for drugs with a higher level of evidence (A1: angiotensin converting enzyme inhibitors angiotensin II receptor antagonists [ACE-I/ARA-II], beta-blockers [BB] and spironolactone). RESULTS: A total of 456 patients were studied, with a mean age of 78.4 years, and 53.1% females. Arterial hypertension (AHT) and ischaemic heart disease were present in 64.7% of patients. The mean comorbidity rate, excluding CHF, was 2.9. Around 40% were diagnosed a NYHA Grade 11-1V. The overall compliance rate (diuretics, ACE-I/ARA-II, beta-blockers, spironolactone, digoxin, and oral anticoagulants) and rate of adherence to evidence-based ones was 55.2% and 44.6%, respectively. There was low compliance by 39.5%, and only 12.9% of patients showed perfect compliance with the drugs with a higher level of evidence, while to be less than 70 years-old, a history of ischaemia, AHT, and a hospital admission, were variables associated with better adherence to treatment. CONCLUSION: There is a low use of the drugs recommended by the Clinical Guidelines for heart failure, particularly of those with better evidence for reducing morbidity and mortality. PMID- 23726730 TI - [Lung cancer projections for Aragon (Spain)]. AB - INTRODUCTION AND OBJECTIVE: Lung cancer has a high incidence in Aragon (Spain). Current measures, such as stopping smoking, may lead to a change in lung cancer trends. The objective of the study is to track the trends during the period of 15 years from 2008 to 2022. PARTICIPANTS AND METHODS: The mortality from all causes and that specific to lung cancer in Aragon between 1998 and 2007 was analysed using the statistical program MIAMOD/PIAMOD to estimate incidence rates, prevalence, and mortality until 2022. RESULTS: Projections between 2008 and 2022 in men: adjusted incidence rates per 100,000 will decline from 64.62 to 58.49. The mortality will decline from 57.41 to 51.95, and the prevalence of 94.13 cases per 100,000 inhabitants to 88.45. In women, the adjusted incidence rate will increase from 8.3 to 10.58, with a mortality of 7.21 to 9.18 and a prevalence from 14.78 to 18.75. CONCLUSIONS: These projections indicate that lung cancer incidence and mortality will remain a serious problem in the Aragon (Spain), and that a more intense primary prevention program is needed. PMID- 23726732 TI - [Update on gluteus medius syndrome]. AB - Back pain and/or gluteal region pain is a frequent complaint in primary care and often is difficult to determine their origin. When a patient consults us for this reason we tend to direct the focus to the study of bone and nerve structures, without considering that in a large number of cases the myofascial system is involved. In a study with 250 patients in order to determine the prevalence of tendinosis and tear of the gluteus medius or minimus muscles, was found by MRI that 14% of patients who went to the doctor for pain in the buttock, hip or groin had this type of injury in any of the muscles mentioned (1). In these cases a diagnosis and early treatment with injections is essential to prevent progression to persistent pain and decreased muscle function. PMID- 23726731 TI - [Urine incontinence referral criteria for primary care]. AB - Despite the high incidence of urinary incontinence (UI), health professional awareness of this disease is low, which in itself is not serious but significantly limits the lives of the patients. The Primary Care associations, Sociedad Espanola de Medicos de Atencion Primaria [SEMERGEN], Sociedad Espanola de Medicos Generales y de Familia [SEMG], Sociedad Espanola de Medicina de Familia y Comunitaria [semFYC]) along with the Asociacion Espanola de Urologia (EAU) have developed this consensus with the proposal of making GPs aware, and to help them in the diagnosis, treatment and referral to Urologists. The first goal in primary care must be the detection of UI, thus an opportunistic screening at least once in the lifetime of asymptomatic women > 40 years old and asymptomatic men > 55 years old. The diagnosis, based on medical history and physical examination, must determine the type and severity of the UI in order to refer severe cases to the Urologist. Except for overactive bladder (OAB), non pharmacological conservative treatment is the first approach to uncomplicated UI in females and males. Antimuscarinics are the only drugs that have demonstrated efficacy and safety in urge urinary incontinence (UUI) and OAB. In men with mixed symptoms, excluding severe obstruction cases, a combination therapy of alpha blockers and antimuscarinics should be chosen. PMID- 23726733 TI - [Hydrochlorothiazide induced bullous pemphigoid]. AB - We report the case of a 55 year-old man who consulted for pruritic bullous lesions of three months onset located on the body, hands and scalp. After ruling out various illnesses to justify the situation described, it was thought that the cause could be pharmacological. The patient had been on treatment with hydrochlorothiazide for several years due to hypertension. The lesions improved with the withdrawal of diuretic therapy, and the introduction of oral corticosteroids. PMID- 23726734 TI - [Dyspnea caused by Coxiella Burnetii]. AB - Dyspnea is a subjective sensation of difficult or uncomfortable breathing caused by increased excitation of brain respiratory centres,(1) and is usually secondary to pulmonary or cardiac disease.(2) Heart failure is a serious public health problem in industrialised countries, with an increasing prevalence and incidence. It is more common in the elderly, and is usually caused by a defect in myocardial contraction, coronary atherosclerosis, or less frequently, valvular disease.(3) Aortic insufficiency (AI) is one of them. It may originate from infective endocarditis, congenital or valvular heart disease, or rheumatic fever. It may lead to a medical emergency due to the inability of the left ventricle to adapt to the rapid increase in the end-diastolic volume caused by regurgitation of blood from aorta to left ventricle. If not corrected, the AI can lead to acute cardiogenic shock.(4.) PMID- 23726735 TI - [A case of diarrhoea by Clostridium difficile]. AB - We present a patient who developed a pseudomembranous colitis due to Clostridium difficile with a prolonged course. The diarrhoea symptoms worsened after two hospitalisations, but there was an improvement with outpatient treatment. The first diagnosis was made in Primary Care. We summarise the preventive measures, and present the severity criteria of this condition, as well as the failure antibiotic treatment with metronidazole and the possible aggravation by the use of other antibiotics in these patients. The patient recovered from the diarrhoea episodes after prolonged treatment. As with this case, the family doctor should note that, sometimes after hospital admissions of frail patients, there may be diarrhoea caused by this microorganism. An early diagnosis, outpatient treatment with appropriate antibiotics, and the implementation of preventive measures can be used in the Primary Care setting. PMID- 23726736 TI - [Pharmacological iatrogenesis in a cardiac-renal patient: presentation of a case]. AB - A case is presented of a 75 year-old patient with chronic kidney failure, atrial fibrillation, diabetes mellitus, and hypertension. She had regularly been admitted to hospital due to episodes of rapid atrial fibrillation that were not well tolerated in relation to the concomitant hypotension and dyspnea. An adverse drug reaction was deduced from the clinical course, and the relative importance of this in daily medical practice is emphasized. PMID- 23726737 TI - [Dyspnoea in a schizophrenic patient: an unexpected diagnosis]. AB - Dyspnoea is mainly of cardio-respiratory origin. A diagnosis of psychogenic origin should not be made without having undertaken the necessary complementary tests to rule out any underlying organic cause, even if the patient has a psychiatric history. We present a clinical case with a clinical picture of dyspnoea, in a 30 year-old male of African origin with a history of schizophrenia. Oedemas can also be associated with dyspnoea. Cardiomegaly and hypertrophy of the left ventricle were established, using additional basic tests. The diagnostic confirmation of dilated cardiomyopathy was obtained from the echocardiogram. He was diagnosed in D phase, with decompensated heart failure, which was refractory to treatment, and after several incidents of malignant arrhythmias, the patient died. According to the ACC/AHA classification, the definitive treatment in this phase is the heart transplant. In the present case, urgent intervention was not considered, due to the worsening of the psychiatric pathology and active drug-taking. PMID- 23726738 TI - [Subphrenic abscess in the context of low back pain and reading analytics in the primary care consultations]. AB - The subphrenic space is defined as the area below the diaphragm and above the transverse colon. Most abscesses are due to direct subphrenic contamination associated with, surgery, local disease, or trauma, but the cause still remain undefined or unknown. It is a disease rarely diagnosed in primary care. About 55% of subphrenic abscesses are located on the right side, with 25% on the left, and 20% are multiple. These can be extended to the thoracic cavity, which sometimes produce empyema, lung abscess, or pneumonia. The mortality of subphrenic abscess is between 11%-31%, and may be due to uncontrolled infection, malnutrition, and complications of prolonged hospitalization, such as nosocomial infections. Ultrasound or computed tomography-guided percutaneous drainage is now the preferred treatment, combined with antibiotics. PMID- 23726739 TI - [Streptococcus anginosus pancreatic abscess after dental extraction]. PMID- 23726740 TI - [A patient with erythroderma desquamativa and eosinophilia]. PMID- 23726741 TI - Dry eye and its correlation to diabetes microvascular complications in people with type 2 diabetes mellitus. AB - AIMS: This study was performed to investigate the correlation between dry eye disease and diabetes microvascular complications. METHODS: In this study 243 people with type 2 diabetes were enrolled. Tear osmolarity was measured using tear lab osmolarity system. All of the participants were evaluated for diabetes microvascular complications. The Michigan neuropathy screening instrument was used for detection of peripheral neuropathy, and the albumin/creatinine ratio in a spot urine sample was considered to diagnose diabetic nephropathy. RESULTS: The prevalence of dry eye disease was 27.7%. The mean value for tear osmolarity was 301.97+/-13.52 mOsm/L. We found a significant correlation between dry eye disease and diabetic retinopathy (P=0.01). However no significant correlation was found between dry eye disease, diabetic neuropathy, and diabetic nephropathy. Dry eye disease was more prevalent in people with proliferative diabetic retinopathy and/or clinically significant macular edema (0.006). In a binary logistic regression analysis model, there was a significant correlation between dry eye disease and retinopathy (OR=2.29, CI=1.16-4.52, P=0.016). In addition, both dry eye and retinopathy had significant correlation with HbA1C. CONCLUSIONS: Dry eye disease is common in people with type 2 diabetes, especially in those with diabetic retinopathy. In addition, it is more prevalent in people who suffer from advanced stages of diabetic retinopathy. PMID- 23726742 TI - Condom use errors among sexually unfaithful and consensually nonmonogamous individuals. AB - This research involved comparisons of the condom use behaviours of people who are in monogamous relationships but who have engaged in extradyadic sex (i.e. committed infidelity) to those who are in consensually nonmonogamous (CNM) relationships. Consensual nonmonogamy is the practice of openly having multiple sexual or romantic partners simultaneously, with the full knowledge and consent of all participating partners. Participants in CNM relationships used condoms more correctly in their last instance of intercourse than those who were committing infidelity. PMID- 23726743 TI - Axis I and Axis II diagnoses in women with PCOS. AB - OBJECTIVE: The objective was to determine the current prevalence of Axis I and Axis II psychiatric diagnoses in patients with polycystic ovary syndrome (PCOS). METHOD: The study sample included 73 patients with PCOS and 73 control subjects. Psychiatric disorders were determined by structured clinical interviews. RESULTS: The rate of any Axis I psychiatric disorder (28.8% vs. 15.1%), social phobia (13.7% vs. 2.7%), generalized anxiety disorder (11.0% vs. 1.4%), any Axis II psychiatric disorder (23.3% vs. 9.6%) and avoidant personality disorder (12.3% vs. 1.4%) was significantly more common in the patient group compared to the control group. Of women with PCOS, 21 (28.8%) had at least one Axis I and 17 (23.3%) had at least one Axis II diagnosis. The most common Axis I disorder was social phobia (13.7%) and the most common Axis II disorder was avoidant personality disorder (12.3%) in women with PCOS. Social phobia, generalized anxiety disorder, and avoidant personality disorder were significantly more common in the patient group compared to the control group. CONCLUSION: Our results suggest that a considerable proportion of women with PCOS also present with anxiety and personality disorders. PMID- 23726744 TI - An evaluation of nursing and midwifery sign off mentors, new mentors and nurse lecturers' understanding of the sign off mentor role. AB - This paper presents the findings of a small scale evaluation examining nursing and midwifery mentors and nursing lecturers perceptions of the Nursing and Midwifery Council 'sign off' mentor role (NMC, 2008). For this evaluation 114 new sign off mentors, 37 preparation for mentorship students and 13 nursing and midwifery lecturers within a Higher Education Institute (HEI) in the United Kingdom participated in the evaluation project. Nursing and midwifery students were not included in this initial evaluation. The initial findings suggested that all participants viewed the introduction of sign off mentors positively; offering a more robust mechanism for ensuring students were competent, helped to protect the public, and offered an increased level of support for students themselves. Concerns were raised about varying levels of support available for sign off mentors and some Stage 2 mentors' abilities to assess competence. Several participants felt the 1 h protected time per week per final placement student would be difficult to implement, whilst anxieties were also expressed about levels of responsibility for ensuring fitness to practice alongside concern that some mentors may leave sign off mentors to manage and identify under-achieving students. PMID- 23726745 TI - Low plasma C-reactive protein level as an early diagnostic tool for heatstroke vs central nervous system-associated infection in the ED. AB - PURPOSES: Heatstroke (HS) is a life-threatening condition, manifested by systemic inflammation and multiorgan failure. Rapid recognition and treatment are life saving. We report a laboratory-oriented characterization of HS by low plasma C reactive protein (CRP) level and propose its usefulness in distinguishing this type of hyperpyrexia from central nervous system-associated high core temperature. METHODS: After institutional review board approval, records of patients admitted to general intensive care unit between August 2008 and September 2011 with core temperature 39.0 degrees C or higher due to HS or meningoencephalitis (ME) were reviewed. Patients' demographics, CRP on admission and 24 to 48 hours later, serum creatinine, creatine phosphokinase, platelets count, international normalized ratio, alanine transaminase, serum pH, and lactate levels were retrieved. RESULTS: Thirty-six patients were admitted to the intensive care unit with high core temperature: 19 patients, aged 21 to 85 years, had HS; 17 individuals, aged 22 to 81 years, had ME. None of the HS individuals had infection. Twelve HS patients were previously healthy; in 13 patients, the event occurred postexercise. Mean admission CRP levels was 2.1 +/- 3.3 mg/L in the HS group compared with 129 +/- 84 mg/L in the ME patients (P < .0001); mean 24- to 48-hour CRP levels were 14.6 +/- 16.8 vs 139 +/- 98 mg/L, respectively (P < .0001). There were no clinically significant differences between the groups regarding laboratory parameters indicative of end-organ damage. Six HS patients underwent computed tomography and/or lumbar puncture before starting intensive cooling, due to misdiagnosis; 5 of them died subsequently. CONCLUSIONS: Low serum CRP levels characterize non-central nervous system-associated HS. This available laboratory test could identify noninfectious hyperthermic patients upon admission, saving precious time until treatment and avoiding unnecessary diagnostic tests. PMID- 23726746 TI - The effect of communication skills training on residents' physiological arousal in a breaking bad news simulated task. AB - OBJECTIVE: Breaking bad news (BBN) is a complex task which involves dealing cognitively with different relevant dimensions and a challenging task which involves dealing with intense emotional contents. No study however has yet assessed in a randomized controlled trial design the effect of a communication skills training on residents' physiological arousal during a BBN task. METHODS: Residents' physiological arousal was measured, in a randomized controlled trial design, by heart rate and salivary cortisol before, during and after a BBN simulated task. RESULTS: Ninety-eight residents were included. MANOVA showed significant group-by-time effects. Trained residents' mean heart rate levels remained elevated after training and cortisol areas under the curve increased after training compared to untrained residents. CONCLUSION: Communication skills training has an effect on residents' physiological arousal. Residents' self efficacy and communication skills improvements in a BBN simulated task are associated with an elevated physiological arousal, which becomes proportional to the complexity of the task and reflects a better engagement and performance. PRACTICE IMPLICATIONS: Residents should be informed that, to perform a task, they need to engage in the task with a physiological arousal proportional to the complexity of this task. Communication skills training should be adapted. PMID- 23726748 TI - [Systemic aneurysms in Behcet's disease]. PMID- 23726747 TI - Adding coping-related strategies to biomedical argumentation in computer generated genetic counseling patient letters. AB - OBJECTIVE: Previously an experimental computer system was developed to automatically produce first drafts of genetic counseling patient letters containing biomedical evidence-based arguments. However, letters written by genetic counselors also employ strategies to help clients cope. The objectives of this research were to discover methods for addition of coping-related strategies to the drafts and to explore their efficacy. METHODS: Using an argumentation based approach, the system design was modified to add coping-related strategies used by actual genetic counselors. An evaluation of computer-produced drafts was performed comparing those containing only biomedical arguments to those with coping strategies added to biomedical arguments. RESULTS: The evaluation mainly found no significant impact of adding coping strategies. CONCLUSION: The main contribution of this work was to show how coping-related strategies can be produced by an artificial intelligence approach within an argumentation-based theoretical framework. A possible future application would be to improve computer drafted genetic counseling patient letters. PRACTICE IMPLICATIONS: Computer assisted drafting of letters has potential to aid in the practice of genetic counseling. Further research is needed to demonstrate the efficacy of adding coping strategies to computer-produced drafts. PMID- 23726749 TI - [Granulomatous myositis and cardiac dysfunction]. PMID- 23726750 TI - [Thallium poisoning in an adolescent girl]. PMID- 23726751 TI - Chelidonium majus L. does not potentiate the hepatic effect of acetaminophen. AB - AIM: The present study assessed the ability of Chelidonium majus to potentiate the hepatic effect of a sub-toxic dose of acetaminophen, in rats. RESULTS: C. majus, when administered alone, did not alter the liver function parameters in male, whereas an increase in fibrinogen level was found in female rats. Moreover, it did not affect the hepatic histomorphology in both male and female rats. The sub-toxic dose of acetaminophen induced: a significant increase in activated partial thromboplastin time in both genders, a focal hepatocellular necrosis with minor lymphocytes infiltrate and a slight but significant increase in total bilirubin, AST, and ALT in male rats, and in prothrombin time in female rats. The co-administration of C. majus did not increase the effects induced by acetaminophen, in both genders. CONCLUSIONS: C. majus does not modify the hepatic effects of acetaminophen in our in vivo experimental model. PMID- 23726752 TI - The improvement of in vivo model (Balb/c mice) for cervical carcinogenesis using diethylstilbestrol (DES). AB - Cervical cancer is the most common gynecological cancer and one of the major causes of female cancer-related death worldwide particularly in developing countries. Thus far, there are a few in vivo models have been developed in investigating this type of cancer. In this study, we induced cervical cancer in Balb/c mice by exploiting the carcinogenic property of diestylstilbestrol (DES). The Balb/c pregnant mice were given subcutaneous (SC) injection of 67MUg/kg body weight of DES on GD 13, and the mice gave birth approximately at gestation day 19 22. Female offspring were reared and the body weight was recorded once weekly. The female offspring were sacrificed at age of 5 months. Upon termination, blood was collected in a plain tube via cardiac puncture and the reproductive tracts were collected and weighed. The reproductive tract sections were stained using H&E for observation of pathological changes. The progression of disease state was monitored by measuring the level of serum interleukin (IL-6) using the Mouse IL-6 ELISA Assay Kit (BD OptEIATM, USA). All parameters were compared with Not-induced group. The outcome of this study demonstrated a significant difference in body weight gain, reproductive organ weight, diameter of cervix and the level of serum IL-6 in the Induced group as compared to the Not-induced group (P<0.05). Histopathological findings revealed the presence of adenosis only in the Induced group. It shows that DES could be employed as an agent to induce cervical carcinogenesis in animal model. In addition to that, new potential anti-cancer agents from various sources could be further evaluated using this technique. PMID- 23726753 TI - [Current status and management of patients with bipolar disorder in France: the MONTRA survey]. AB - OBJECTIVES: The objectives were to assess the characteristics of patients with bipolar disorder (BD) and to evaluate the prescribing practices. METHODS: MONTRA is a quantitative survey conducted between December 2010 and February 2011. Data were extracted by the psychiatrists from the medical files of BD patients seen on four consecutive days of consulting. RESULTS: Four hundred and thirty-nine psychiatrists included 2529 patients (inpatients, n=319; outpatients from mental clinics, n=1090; outpatients consulting in private practice, n=1020). In the total patient population (mean age: 47 years; women, 58%), BD was distributed as follows: BD type I, 56%; BD type II, 40%; other types of BD, 4%; rapid cyclers, 10%. The prevalence of psychiatric comorbidities was high (anxiety disorders, 48%; abuse and dependence on toxic substances, 17 and 10% respectively), 36% of the patients had a history of suicide attempt and the risk of suicide, when assessed, was 6%. In about half the patients (48%), the polarity of the initial bipolar episode was of the depressive type (versus 39% for the manic/hypomanic type). Outpatients were globally independent and did not require assistance in the management of their disease or its treatment whereas the social and professional lives of inpatients were negatively affected by their condition. Based on the psychiatrist's declarations, 39 to 50% of the outpatients were symptom-free, 36 to 40% were in the intercurrent phase with residual symptoms, 11 to 17% presented either a manic or depressive acute BP episode, and 3 to 4% were in a mixed state; among inpatients, 52% presented an acute episode either manic or depressive, 38% were in the intercurrent phase and 9% were in a mixed state. In the symptomatic patients from the total population (61%), the most prevalent symptoms were depressive and corresponded to acute symptoms (patients with a depressive episode, 14%) or residual symptoms (patients in the intercurrent phase, 27%). The predominant depressive polarity was observed in both hospitalized and outpatients. The pharmacological treatment of BD included polytherapy in 73% of the patients. In the manic episodes (n=126), the patients were treated with a Mood Stabilizer (MS, 56%) or an atypical antipsychotic (AAP, 52%) in association. In the depressive episodes (n=342), the patients received an antidepressant drug associated with a MS or an AAP (70%). In symptom-free or symptomatic intercurrent periods (n=1943), the patients were treated with a MS (49-58%) or an AAP (37-49%), in association. CONCLUSION: BD patients evaluated in our survey were in majority diagnosed with BD type I, associated with considerable comorbidity. In the symptomatic patients, the most prevalent symptoms, either acute or residual, were of the depressive type. In the majority of the patients, whatever the clinical status, polytherapy was prescribed for the BD. PMID- 23726754 TI - Improving immunization delivery using an electronic health record: the ImmProve project. AB - OBJECTIVE: Though an essential pediatric preventive service, immunizations are challenging to deliver reliably. Our objective was to measure the impact on pediatric immunization rates of providing clinicians with electronic health record-derived immunization prompting. METHODS: Operating in a large, urban, hospital-based pediatric primary care clinic, we evaluated 2 interventions to improve immunization delivery to children ages 2, 6, and 13 years: point-of-care, patient-specific electronic clinical decision support (CDS) when children overdue for immunizations presented for care, and provider-specific bulletins listing children overdue for immunizations. RESULTS: Overall, the proportion of children up to date for a composite of recommended immunizations at ages 2, 6, and 13 years was not different in the intervention (CDS active) and historical control (CDS not active) periods; historical immunization rates were high. The proportion of children receiving 2 doses of hepatitis A immunization before their second birthday was significantly improved during the intervention period. Human papillomavirus (HPV) immunization delivery was low during both control and intervention periods and was unchanged for 13-year-olds. For 14-year-olds, however, 4 of the 5 highest quarterly rates of complete HPV immunization occurred in the final year of the intervention. Provider-specific bulletins listing children overdue for immunizations increased the likelihood of identified children receiving catch-up hepatitis A immunizations (hazard ratio 1.32; 95% confidence interval 1.12-1.56); results for HPV and the composite of recommended immunizations were of a similar magnitude but not statistically significant. CONCLUSIONS: In our patient population, with high baseline uptake of recommended immunizations, electronic health record-derived immunization prompting had a limited effect on immunization delivery. Benefit was more clearly demonstrated for newer immunizations with lower baseline uptake. PMID- 23726755 TI - Physicochemical and immunochemical assays for monitoring consistent production of tetanus toxoid. AB - The detoxification of tetanus toxin by formaldehyde is a crucial step in the production of tetanus toxoid. The inactivation results in chemically modified proteins and it determines largely the ultimate efficacy and safety of the vaccine. Currently, the quality of tetanus toxoid lots is evaluated in potency and safety tests performed in animals. As a possible alternative, this article describes a panel of in vitro methods, which provides detailed information about the quality of tetanus toxoid. Ten experimental lots of tetanus toxoid were prepared using increasing concentrations of formaldehyde and glycine to obtain tetanus toxoids having differences in antigenicity, immunogenicity, residual toxicity and protein structure. The structural properties of each individual toxoid were determined using immunochemical and physicochemical methods, including biosensor analysis, ELISA, circular dichroism, TNBS assay, differential scanning calorimetry, fluorescence and SDS-PAGE. The quality of a tetanus toxoid lot can be assessed by these set of analytical techniques. Based on antigenicity, immunogenicity and residual toxicity data, criteria are formulated that tetanus toxoids lot have to meet in order to have a high quality. The in vitro methods are a valuable selection of techniques for monitoring consistency of production of tetanus toxoid, especially for the detoxification process of tetanus toxin. PMID- 23726756 TI - Patient safety in nursing education: contexts, tensions and feeling safe to learn. AB - Education is crucial to how nurses practice, talk and write about keeping patients safe. The aim of this multisite study was to explore the formal and informal ways the pre-registration medical, nursing, pharmacy and physiotherapy students learn about patient safety. This paper focuses on findings from nursing. A multi-method design underpinned by the concept of knowledge contexts and illuminative evaluation was employed. Scoping of nursing curricula from four UK university programmes was followed by in-depth case studies of two programmes. Scoping involved analysing curriculum documents and interviews with 8 programme leaders. Case-study data collection included focus groups (24 students, 12 qualified nurses, 6 service users); practice placement observation (4 episodes=19 hrs) and interviews (4 Health Service managers). Within academic contexts patient safety was not visible as a curricular theme: programme leaders struggled to define it and some felt labelling to be problematic. Litigation and the risk of losing authorisation to practise were drivers to update safety in the programmes. Students reported being taught idealised skills in university with an emphasis on 'what not to do'. In organisational contexts patient safety was conceptualised as a complicated problem, addressed via strategies, systems and procedures. A tension emerged between creating a 'no blame' culture and performance management. Few formal mechanisms appeared to exist for students to learn about organisational systems and procedures. In practice, students learnt by observing staff who acted as variable role models; challenging practice was problematic, since they needed to 'fit in' and mentors were viewed as deciding whether they passed or failed their placements. The study highlights tensions both between and across contexts, which link to formal and informal patient safety education and impact negatively on students' feelings of emotional safety in their learning. PMID- 23726757 TI - The role of beta2-integrins and CD44 in intrahepatic leukocyte sequestration. AB - BACKGROUND: Intrahepatic leukocyte sequestration is a component of the systemic inflammatory response, and can be triggered by systemic immune dysfunction during sepsis. METHODS: To examine leukocyte sequestration over time during endotoxemia, its influence on liver function, and the role of specific cell adhesion molecules, endotoxemia was induced in mice by intraperitoneal application of lipopolysaccharides. Leukocyte sequestration was measured at different times after induction using fluorescence microscopy. Liver injury was evaluated by measuring liver enzymes and tissue histology. RESULTS: Endotoxin induces a strong leukocyte sequestration in the liver microvasculature. This was associated with an induction of liver injury, as reflected by an increase in enzyme levels and histomorphologic changes. Intrahepatic leukocyte sequestration was reduced in CD44(-/-), but not in intercellular adhesion molecule-1 (ICAM-1)(-/-), lymphocyte function-associated antigen-1(-/-), and macrophage-1(-/-) antigen mice. Leukocyte sequestration dropped in ICAM-1(-/-), lymphocyte function-associated antigen-1(-/ ), and macrophage-1(-/-) mice in later stages, but remained stable in wild-type and CD44(-/-) animals. Reduced leukocyte sequestration in CD44(-/-) mice was accompanied by a significant decrease in transferase levels. CONCLUSIONS: Endotoxemia induces stable intra-sinusoidal leukocyte sequestration, which contributes to liver injury. At the initial stage of the endotoxemia, leukocyte sequestration depends on CD44 but is independent of ICAM-1 and beta2-integrins. Intercellular adhesion molecule-1 and beta2-integrins, but not CD44, stabilize leukocyte sequestration during the later stage of endotoxemia. The molecular modulation of intrahepatic leukocyte sequestration may have important therapeutic implications in sepsis, reducing liver injury, and improving immune defense capabilities. PMID- 23726758 TI - Gender differences in the incidence of background and chemically induced primary pulmonary neoplasms in B6C3F1 mice: a retrospective analysis of the National Toxicology Program (NTP) carcinogenicity bioassays. AB - The National Toxicology Program (NTP) database of technical reports on carcinogenicity bioassays has been interrogated for the incidence of primary pulmonary neoplasms in B6C3F1 mice. A total of 170 study reports were selected, from studies that completed the in-life phase during 1983-2007, which included neoplasm incidence data for 180 control groups comprising both male and female mice. The incidence (median and inter-quartile range) of males with alveolar/bronchiolar adenoma was 16% (12-20%), and for females it was 5% (2-8%); the incidence of males with alveolar/bronchiolar carcinoma was 8% (4-12%), and for females it was 2% (0-4%); and the incidence of males with combined alveolar/bronchiolar adenoma or carcinoma was 24% (18-30%), and for females it was 8% (6-12%). Comparing the incidence of animals bearing these lesions on a per study basis showed the median incidence in males to be 3.0-fold, 2.0-fold, and 2.8-fold higher than in females. The incidence of other primary pulmonary neoplasms was <10% of the alveolar/bronchiolar neoplasms. Comparison of gender specific response to lung tumorigens showed that the increase in incidence of tumors above control levels was greater in females than in males. PMID- 23726759 TI - Caring for loved ones with frontotemporal degeneration: the lived experiences of spouses. AB - There is an abundant literature about the experience of caregiving for a spouse living with Alzheimer's disease (AD), but there are very few qualitative studies about caregiving for persons living with Frontotemporal Degeneration (FTD). FTD causes a change in personality and affected persons may lose the ability to adhere to social norms. Thus, the emotional loss caregivers experience is often confounded by anger in response to embarrassing and socially inappropriate behaviors. In this paper, we offer a glimpse of this lived experience through the voices of two spouses whom we interviewed, each with experience caring for persons living with FTD. We suggest that FTD caregivers experience a loss of emotional attachment to their spouse because of their partner's behavioral symptoms. This loss gives rise to feelings of isolation and anger as caregivers assume new roles and reimagine their future. The findings from these interviews illuminate the need for more research and greater attention and support for FTD caregivers early in the disease trajectory. PMID- 23726760 TI - Symptoms, aging-stereotyped beliefs, and health-promoting behaviors of older women with and without osteoarthritis. AB - The purposes of this study were to examine differences in symptoms, aging stereotyped beliefs about management of symptoms, and health-promoting behaviors depending on a diagnosis of osteoarthritis and to investigate the associations between symptoms, aging-stereotyped beliefs, and health-promoting behaviors in 171 older Korean women. Compared to older women without osteoarthritis, those with osteoarthritis reported significantly more symptoms, a higher level of aging stereotyped beliefs, and a lower level of health-promoting behaviors. Regardless of osteoarthritis, older women suffered from multiple symptoms, and musculoskeletal symptoms were the most frequently reported symptoms. Aging stereotyped beliefs had a negative influence on health-promoting behaviors, whether or not older women were diagnosed with osteoarthritis. Findings of this study suggest that a broader assessment of multiple symptoms, specifically including musculoskeletal symptoms, is needed in order to enhance their management of symptoms. Health care providers should consider age stereotypes with regard to experience and management of symptoms in order to improve self care behaviors of older people, and development of nursing intervention strategies in order to modify stereotypes and misconceptions about aging and to facilitate positive attitudes about old age is warranted. PMID- 23726761 TI - Modeling gender effects on electrical activity of single ventricular myocytes. AB - In this study we investigate the mechanisms underlying gender differences in the generation of arrhythmias in the long QT and Brugada syndromes. Simulations were conducted at the single myocyte level using a detailed mathematical model of human ventricular myocytes. Given the scarce human data on the gender-related differences in single cardiac cells, we assumed gender-related differences in five ionic-current systems: fast sodium current (INa), slowly inactivating late sodium current (INal), transient outward potassium current (Ito), slow delayed rectifier potassium current (IKs), and calcium current through the L-type channel (ICa(L)), based on experimental results obtained in canine myocytes. Our modeling results suggest that in left ventricular myocytes, enhanced INal under conditions of reduced repolarization reserve results in sex-dependent development of early afterdepolarizations (EADs) in the post-pause action potentials (APs). Moreover, this modeling study demonstrates increased propensity for the development of the loss of the AP dome in male epicardial myocytes of the right ventricle compared with other types of myocytes from the left and right ventricles. Finally, we also found a slight effect of INal on gender-dependent loss of AP dome in epicardial right ventricular myocytes. In conclusion, at the cellular level, gender differences in the development of EADs and the propensity to develop the loss of the AP dome can be attributed to male/female related differences in INa, INal, Ito, IKs, and ICa(L). PMID- 23726762 TI - Volumetric changes after sinus augmentation using blocks of autogenous iliac bone or freeze-dried allogeneic bone. A non-randomized study. AB - OBJECTIVES: To compare volumetric bone changes after sinus augmentation for implant positioning using blocks of autogenous iliac bone or freeze-dried allogeneic bone (FDBA) from the hip. Variables were compared between the two sources and for each surgical procedure at set times (pre- and post-augmentation procedure). PATIENTS AND METHODS: A non-randomized retrospective chart review of 7 patients who had autogenous and 7 allogeneic block grafts was carried out (1 procedure per patient). Analysis of Computer Tomographic (CT) data of maxillary sinuses, acquired with high-speed, double-detector CT scanner, was performed using dentascan software. The change between the preoperative (T0) and postoperative volume was measured at 4-6 months (T2) and 1.5 year after transplantation (T3). Annual- and overall-rates of bone change were calculated for the two sources. RESULTS: All patients were partially edentulous with a residual maxillary floor thickness in the planned implant insertion sites of 2.7 (0.5) mm and 2.8 (0.5) mm for allogeneic and autogenous procedures respectively. From identical intraoperative volume of grafts (2.25 cc at T1), volumetric changes were recorded at T2 and T3. The final volume of the grafts was 1.44 cc for allogeneic group and 1.78 cc for the autogenous group. Significant volumetric changes over time of transplanted grafts for both sources (23% for autograft and 18% for allograft) were found at T2. At 1.5-years post-operatively comparisons of volumes and rates of bone loss between sources were not statistically significant. No failure was recorded for either bone grafts or dental implants. CONCLUSIONS: Short-term sinus grafting procedure for dental implant placement performed with FDBA showed an outcome close to that reported for autogenous bone. Volumetric changes were comparable between the sources. These data suggest that performing maxillary sinus augmentation with dry-preserved bone allogeneic materials in block form could be considered even when the residual floor thickness is less than 3 mm. PMID- 23726763 TI - The influence of non-HLA gene polymorphisms and interactions on disease risk in a Western Australian multiple sclerosis cohort. AB - Non-Human Leukocyte Antigen (HLA) genes have concomitant, although modest, effects on multiple sclerosis (MS) susceptibility; however findings have varied in different populations. Here we present the results of an association study of 16 single nucleotide polymorphisms (SNPs) in 10 non-HLA genes (IL7R, IL2RA, CLEC 16A, TYK2, CD58, IRF5, STAT3, CTLA-4, APOE, ICAM-1) in a Western Australian cohort of 350 MS patients and 498 population control subjects. Our results indicate that in this population, SNPs in IL7R, TYK2, IRF5 and APOE have modifying effects on MS susceptibility. We also found evidence of interactive protective effects between polymorphisms in the IL7R/CD58, CLEC-16A/CTLA-4, and TYK2/IRF5 genes, which in some instances are restricted within HLA- or gender defined groups. PMID- 23726764 TI - IL-22 secreting CD4+ T cells in the patients with neuromyelitis optica and multiple sclerosis. AB - Interleukin (IL)-22 secreting CD4(+) T (Th22) cells and IL-22 are involved in the pathogenesis of autoimmune disease, but their role in neuromyelitis optica (NMO) and multiple sclerosis (MS) is unclear. We measured the proportion of Th22, Th17, CD4(+)IL-22(+)IL-17A(+) T cells and serum IL-22 in NMO and MS patients. The proportion of Th22 cells, Th17 cells and serum IL-22 were increased in patients with NMO and MS. Our findings suggest that increased Th22 cells may play an important role in the pathogenesis of NMO and MS. PMID- 23726765 TI - Involvement of microglial CD40 in murine retrovirus-induced peripheral neuropathy. AB - B6 mice infected with LP-BM5 develop severe immunodeficiency (termed murine acquired immunodeficiency syndrome (MAIDS)) and peripheral neuropathy. To determine whether microglial CD40 is involved in LP-BM5-induced peripheral neuropathy, B6-CD40 knockout (KO) mice and B6-CD40 KO mice adoptively transferred either total leukocytes or B cells were examined for behavioral sensitivity, tissue viral loads, cytokine responses, and the development of MAIDS. All three CD40 KO groups developed MAIDS, the severity of which was correlated with peripheral cytokine responses. CD40 KO mice displayed significantly reduced mechanical hypersensitivity post-infection compared to wild-type mice regardless of cell transfer. These findings support microglial CD40 involvement in LP-BM5 induced peripheral neuropathy. PMID- 23726766 TI - The possible relationship between allergic manifestations and elevated serum levels of brain specific auto-antibodies in autistic children. AB - Etiology of autism has become an area of a significant controversy. Allergy induced autism is an area of research wherein immune responses to some allergens may play a pathogenic role in autism. Allergy may induce the production of brain specific auto-antibodies in a subgroup of autistic children. We are the first to investigate the possible link between allergic manifestations and serum levels of both anti-myelin basic protein (anti-MBP) and anti-myelin associated glycoprotein (anti-MAG) brain-specific auto-antibodies, which were measured by ELISA method, in 42 autistic children in comparison to 42 healthy-matched children. Allergic manifestations (bronchial asthma, atopic dermatitis and/or allergic rhinitis) were found in 47.6% of autistic patients. Increased serum levels of anti-MBP and anti-MAG auto-antibodies were found in 57.1% and 66.7%, respectively of autistic children. In addition, 78.5% of autistic children had increased serum levels of both anti-MBP and/or anti-MAG auto-antibodies. Autistic patients with allergic manifestations had significantly higher serum levels of anti-MBP and anti-MAG auto-antibodies than those without these manifestations (P<0.001 and P=0.001, respectively). In conclusion, allergy may be a contributing factor to the increased serum levels of anti-MBP and anti-MAG auto-antibodies in some autistic children. Indeed, we need to know more about the links between allergy, immune system and brain in autism for finding new therapeutic modalities in autism. PMID- 23726767 TI - A distinguished trio, introduction to the Saxton-Smith-Van Dyck 65th-birthday issue. AB - The careers in the theory and practice of electron microscopy of W.O. Saxton, D. Van Dyck and D.J. Smith are sketched briefly, with a small sample of their publications. PMID- 23726768 TI - Growth mode and oxidation state analysis of individual cerium oxide islands on Ru(0001). AB - The growth of cerium oxide on Ru(0001) by reactive molecular beam epitaxy has been investigated using low-energy electron microscopy (LEEM) and diffraction as well as local valence band photoemission. The oxide islands are found to adopt a carpet-like growth mode, which depending on the local substrate morphology and misorientation leads to deviations from the otherwise almost perfect equilateral shape at a growth temperature of 850 degrees C. Furthermore, although even at this high growth temperature the micron-sized CeO2(111) islands are found to exhibit different lattice registries with respect to the hexagonal substrate, the combination of dark-field LEEM and local intensity-voltage analysis reveals that the oxidation state of the islands is homogeneous down to the 10 nm scale. PMID- 23726769 TI - Near field and exit wave computations for electron microscopy. AB - The partial wave phase shift formalism of atomic scattering is applied to compute exit wave functions for isolated Au and Si atoms under both plane wave and focused probe illumination. Connections between the far field and near field (exit) waves are clarified. This approach treats the Coulomb singularity properly though at 100 keV large numbers of phase shifts are required. In principle any form of incident wave can be handled so it may provide a means for testing traditional scattering theories used in electron microscopy. By applying the analysis to an atom embedded in a constant potential rather than free space, exit spheres of radius half the interatomic spacing can be used. PMID- 23726770 TI - Diagnostic performance of computed tomography angiography in peripheral arterial injury due to trauma: a systematic review and meta-analysis. AB - OBJECTIVES: To evaluate the diagnostic accuracy of computed tomography angiography (CTA) in detecting arterial lesions in patients with suspected arterial injury of the upper or lower extremity due to trauma. METHODS: A systematic review and meta-analysis was carried out. Medline and Embase were searched on August 13, 2012, for studies comparing CTA with surgery, digital subtraction angiography (DSA), or follow-up, which allowed extraction of data into two-by-two tables. The methodological quality of included studies was assessed using the QUADAS tool. Summary estimates of sensitivity and specificity of CTA in identifying or excluding arterial lesions were obtained using a bivariate model. RESULTS: This review included 11 studies making up a total of 891 trauma patients. The included studies were of moderate methodological quality and at risk of misclassification and verification bias. Some 4.2% of all CTA studies were non-diagnostic. The summary estimates of sensitivity and specificity of CTA were 96.2% (95% CI 93.5-97.8%) and 99.2% (95% CI 96.8-99.8%), respectively. CONCLUSION: Despite methodological flaws, the excellent estimates of sensitivity and specificity indicate that CTA is an accurate modality for evaluating arterial lesions in patients with extremity trauma and can replace DSA. PMID- 23726771 TI - Transcription factor MYB46 is an obligate component of the transcriptional regulatory complex for functional expression of secondary wall-associated cellulose synthases in Arabidopsis thaliana. AB - Cellulose, the most abundant biopolymer on Earth, is a central component in plant cell walls and highly abundant (up to 50%) in the secondary walls. In Arabidopsis thaliana, the cellulose biosynthesis in the secondary walls is catalyzed by three cellulose synthases CESA4, CESA7 and CESA8. The transcription factor MYB46 and its close homolog MYB83 directly regulate the expression of the three secondary wall cellulose synthases (CESAs). However, it is not known whether MYB46 is the necessary regulator for functional expression of the secondary wall CESAs or one of the multiple transcriptional factors involved in the transcriptional regulatory program. To address this question, we used a series of genetic complementation experiments of the cesa knock-out mutants with the CESA coding sequence driven by either native- or mutated promoter of the genes. The mutant promoters have two nucleotide point mutations in the MYB46 binding cis element (M46RE) such that MYB46 cannot bind to the promoter, while the binding of other known secondary wall transcription factors is not affected. The mutant complementation results showed that MYB46 is essential to restore normal phenotype from the cesa mutants. We conclude that MYB46 is an obligate component of the transcriptional regulatory complex toward the commitment of secondary wall cellulose synthesis in Arabidopsis. PMID- 23726772 TI - Update on the use of steroids in rheumatoid arthritis. AB - Corticosteroids are a mainstay in the therapy of rheumatoid arthritis (RA). In recent years, a number of high-quality controlled clinical trials have shown their effect as a disease-modifying anti-rheumatic drug (DMARD) and a favourable safety profile in recent-onset RA. Despite this, they are more frequently used as bridge therapy while other DMARDs initiate their action than as true disease modifying agents. Low-dose corticosteroid use during the first two years of disease slows radiologic damage and reduces the need of biologic therapy aimed at reaching a state of clinical remission in recent-onset RA. Thus, their systematic use in this clinical scenario should be considered. PMID- 23726773 TI - Humeral artery thrombosis simulating an elbow monoarthritis in a woman with primary antiphospholipid syndrome (Hughes syndrome). PMID- 23726774 TI - Fever and exanthema in a young patient: drug reaction with eosinophilia and systemic symptoms due to allopurinol. PMID- 23726776 TI - Interpersonal problems and impacts: further evidence for the role of interpersonal functioning in treatment outcome in major depressive disorder. AB - INTRODUCTION: Empirical research has converged to support the concurrent association between social difficulties and psychiatric symptoms; yet, longitudinal associations between interpersonal problems and treatment outcome require clarification. The current investigation evaluated the influence of interpersonal problems assessed prior to treatment on interpersonal impacts assessed during treatment as well as on treatment outcome in outpatients with major depressive disorder (MDD). METHOD: 125 participants with a primary diagnosis of MDD were randomized to receive cognitive behavioural therapy or interpersonal therapy. Participants completed the Beck Depression Inventory-II, Hamilton Depression Rating Scale, and Inventory of Interpersonal Problems Circumplex before and after treatment. Therapists completed the Impact Message Inventory during and after treatment. RESULTS: Interpersonal distress improved over the course of treatment; all other interpersonal changes were non significant when distress was taken into account. Pre-treatment rigidity and agentic problems predicted less reduction in depressive symptoms, whereas agentic and communal impacts upon therapists during treatment predicted greater symptom change. Overall interpersonal distress was only indirectly associated with treatment response later in treatment, through its association with agentic style. Results did not differ across therapy type, and were replicated across self-report and interviewer-rated measures of depression severity. LIMITATIONS: Limitations include the brief duration of treatment, lack of medication arm, and potentially restricted generalizability of patients in a randomized control trial to those in routine practice. CONCLUSIONS: Interpersonal style demonstrated a trait-like stability over treatment, and appears to fluctuate due to co-occurring distress. Yet, specific interpersonal styles were negative prognostic indicators, even within therapy specifically targeting interpersonal functioning. PMID- 23726775 TI - Omega-6 fatty acids and greater likelihood of suicide risk and major depression in early pregnancy. AB - OBJECTIVE: To estimate the prevalence of suicide risk (SR) and major depressive episodes (MDEs) in early pregnancy, as well as the relationship of serum fatty acid status to these outcomes. METHODS: Cross-sectional analyses were performed on data from 234 pregnant women enrolled in a prospective cohort study in Rio de Janeiro, Brazil. SR and MDE were defined according to the Mini International Neuropsychiatric Interview. Fatty acid compositions were determined for serum samples obtained between the 6th and 13th gestational week. Fatty acid data were expressed as the percent of total fatty acids, converted to Z scores and then entered as continuous variables in logistic regression models. RESULTS: The prevalence of SR was 19.6% and that of MDE was 17.0%. In the adjusted logistic regressions, a higher likelihood of SR was observed among women with higher arachidonic acid levels [AA (20:4, n-6): OR=1.45, 95%CI 1.02-2.07] and adrenic acid levels [AdA (22:4, n-6): OR=1.43, 95%CI 1.01-2.04]. A higher likelihood of MDE was also observed among women with higher AA levels [OR=1.47, 95%CI 1.03 2.10] and AdA levels [OR=1.59, 95%CI 1.09-2.32]. CONCLUSION: Higher serum levels of AA and AdA were associated with a greater likelihood of SR and MDE among pregnant Brazilian women. PMID- 23726777 TI - Cooperation and depressive symptoms. AB - BACKGROUND: Deficits in pro-social cooperation are common in many individuals with mental illnesses such as depression. For decades, researchers have used economic game paradigms to compare cross-cultural cooperative behavior. However, research using economic games to assess cooperative behavior in clinical populations is in the early stages. We hypothesized that individuals with greater depressive symptoms would struggle to maintain reciprocity in iterative games, but not in single-iteration games measuring personal values. METHODS: Participants (n=41) played four computer-based economic games (prisoner's dilemma, the public goods game, the ultimatum game, and the trust game) measuring different aspects of cooperation. Participants completed the Depression Anxiety and Stress Scale (DASS) and other measures of personality and demographics. Analyses assessed the relationships between game performance and psychological distress as measured by the DASS. RESULTS: Significant correlations were found between game performance and depressive symptoms, but not symptoms of anxiety or stress. Performance in the prisoner's dilemma and public goods game was significantly related to depression in a linear regression even when known associations with depressive affect such as age, gender, race, education, marital status, and neuroticism were controlled for. CONCLUSIONS: Depressive symptoms were associated with an inability to sustain reciprocal cooperation. Participants showed the predicted deficits in cooperation in these economic games. Economic games show the potential for assessing the social deficits associated with depressive symptoms. PMID- 23726778 TI - Psychometric properties of the List of Threatening Experiences--LTE and its association with psychosocial factors and mental disorders according to different scoring methods. AB - BACKGROUND: The List of Threatening Experiences (LTE) questionnaire is frequently used to assess stressful events; however, studies of its psychometric properties are scarce. We examined the LTE's reliability, factorial structure, construct validity and explored the association between LTE scores and psychosocial variables and mental disorders. METHOD: This study involved interviewing 5442 primary care attendees from Spain. Associations between four different methods of quantifying LTE scores, psychosocial factors, major depression (CIDI), anxiety disorders (PRIME-MD), alcohol misuse and dependence (AUDIT) were measured. RESULTS: The LTE showed high test-retest reliability (Kappa range=0.61-0.87) and low internal consistency (alpha=0.44). Tetrachoric factorial analysis yielded four factors (spousal and relational problems; employment and financial problems; personal problems; illness and bereavement in close persons). Logistic multilevel regression found a strong association between greater social support and a lower occurrence of stressful events (OR range=0.36-0.79). The association between religious-spiritual beliefs and the LTE, was weaker. The association between mental disorders and LTE scores was greater for depression (OR range=1.64-2.57) than anxiety (OR range=1.35-1.97), though the highest ORs were obtained with alcohol dependence (OR range=2.86-4.80). The ordinal score (ordinal regression) was more sensitive to detect the strength of association with mental disorders. LIMITATIONS: We are unable to distinguish the direction of the association between stressful events, psychosocial factors and mental disorders, due to our cross-sectional design of the study. CONCLUSIONS: The LTE is a valid and reliable measure of stress in mental health, and the strength of association with mental disorders depends on the method of quantifying LTE scores. PMID- 23726779 TI - Altered affective processing in bipolar disorder: an fMRI study. AB - BACKGROUND: Previous studies have reported that patients with bipolar disorder (BPD) exhibit altered emotional processing and regulation. However, results remain largely inconsistent across studies. The aim of the current study was to further examine affective processing in patients with bipolar disorder. METHODS: Twenty-three patients diagnosed with BPD (Type I) and 18 healthy matched controls completed a backward-masked affect paradigm while undergoing functional magnetic resonance imaging. Participants also completed a computerized, overt task of facial emotional discrimination after scanning. RESULTS: Results demonstrated altered affective processing of happy and fearful stimuli in bipolar participants in the amygdala, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC) relative to controls. BPD participants also displayed significant deficits in identifying fearful facial affect. LIMITATIONS: This study has a moderate sample size, and the patients with BPD were significantly older than the healthy control participants; this did not appear to impact results, and although statistically significant, it is not likely biologically significant. CONCLUSIONS: These findings may have implications for patients with BPD, as altered affective processing could result in deficits in reading social cues. PMID- 23726781 TI - Impulsive responses to emotion as a transdiagnostic vulnerability to internalizing and externalizing symptoms. AB - INTRODUCTION: This study explored the hypothesis that impulsive reactions to heightened emotion may reflect a transdiagnostic vulnerability to both externalizing and internalizing symptoms. METHODS: A sample of undergraduates completed self-report measures of aggression, borderline personality disorder symptoms, anxiety symptoms, and alcohol problems, and a subset completed interviews that assessed suicidality. All participants also completed self-report measures relating to impulsivity. We predicted that emotion-reactive impulsivity, but not other aspects of impulsivity, would be related to the set of psychopathology symptoms. RESULTS: Multiple regression analyses found that emotion-reactive impulsivity was uniquely related to each of the psychopathology scales, whereas non-emotion-relevant impulsivity was uniquely related only to alcohol problems. CONCLUSION: Discussion focuses on limitations and clinical implications. PMID- 23726780 TI - Prevalence and correlates of depression among HIV-infected and -affected older people in rural South Africa. AB - BACKGROUND: Little is known about depression in older people in sub-Saharan Africa, the associated impact of HIV, and the influence on health perceptions. OBJECTIVES: Examine the prevalence and correlates of depression; explore the relationship between depression and health perceptions in HIV-infected and affected older people. METHODS: In 2010, 422 HIV-infected and -affected participants aged 50+ were recruited into a cross-sectional study. Nurse professionals interviewed participants and a diagnosis of depressive episode was derived from the Composite International Diagnostic Interview (Depression module) using the International Classification of Diseases diagnostic criteria and categorised as major (MDE) or brief (BDE). RESULTS: Overall, 42.4% (n=179) had a depressive episode (MDE: 22.7%, n=96; BDE: 19.7%, n=83). Prevalence of MDE was significantly higher in HIV-affected (30.1%, 95% CI 24.0-36.2%) than HIV-infected (14.8%, 95% CI 9.9-19.7%) participants; BDE was higher in HIV-infected (24.6%, 95% CI 18.7-30.6%) than in HIV-affected (15.1%, 95% CI 10.3-19.8%) participants. Being female (aOR 3.04, 95% CI 1.73-5.36), receiving a government grant (aOR 0.34, 95% CI 0.15-0.75), urban residency (aOR 1.86, 95% CI 1.16-2.96) and adult care-giving (aOR 2.37, 95% CI 1.37-4.12) were significantly associated with any depressive episode. Participants with a depressive episode were 2-3 times more likely to report poor health perceptions. LIMITATIONS: Study limitations include the cross-sectional design, limited sample size and possible selection biases. CONCLUSIONS: Prevalence of depressive episodes was high. Major depressive episodes were higher in HIV-affected than HIV-infected participants. Psycho social support similar to that of HIV treatment programmes around HIV-affected older people may be useful in reducing their vulnerability to depression. PMID- 23726782 TI - Suicidal behaviours in South East London: prevalence, risk factors and the role of socio-economic status. AB - BACKGROUND: Low socio-economic status (SES) is an established risk factor of suicidal behaviours, but it is unknown to what extent its association is direct, indirect or confounded, given its strong association to mental health. We aimed to (I) estimate the prevalence of suicidal behaviours; (II) describe relevant risk factors; and (III) investigate direct and indirect effects of SES on suicidal behaviours. METHODS: We used cross-sectional community survey data of adults from randomly selected South East London households (SELCoH). Suicidal outcome measures replicated the 2007 Adult Psychiatric Morbidity Survey in England (APMS). Lifetime prevalence was described by socio-demographics, SES, mental health indicators, and life events. Structured symptom screens and a drug use questionnaire measured mental health. Structural equation models estimated direct and indirect effects of a latent SES variable on suicidal ideation and suicide attempts, adjusting for covariates. RESULTS: 20.5% (95% CI: 18.4-22.7) reported suicidal ideation and 8.1% (95% CI: 6.8-9.7) reported suicide attempts (higher than APMS estimates: 13.7%, 4.8%, respectively). Unadjusted risk factors included poor mental health, low SES, and non-married/non-cohabitating relationship status. Black African ethnicity was protective, and women reported more suicide attempts. SES was directly associated to suicide attempts, but not suicidal ideation. SES had indirect effects on suicidal outcomes via mental health and life events. LIMITATIONS: The cross-sectional design and application of measures for different time periods did not allow for causal inferences. CONCLUSIONS: Suicidal behaviours were more prevalent than in the general UK population. Interventions targeting low SES individuals may prove effective in preventing suicide attempts. PMID- 23726783 TI - Tardive dyskinesia from atypical antipsychotic agents in patients with mood disorders in a clinical setting. AB - BACKGROUND: There is a paucity of information on the risks and clinical characteristics of tardive dyskinesia with atypical antipsychotic agents in patients with mood and anxiety disorders in clinical practice. METHODS: The authors retrospectively screened the charts of 268 patients with a mood or anxiety disorder treated with atypical antipsychotic agents from a psychiatric practice. Fifteen patients who developed tardive dyskinesia were identified and further data was collected on these patients. RESULTS: Tardive dyskinesia occurred in 5.9% of patients after exposure to an atypical antipsychotic agent for a mean of 28.7 months (range: 1-83). The average dosage of the offending agent in chlorpromazine equivalents was 350 mg/day (range: 67-969). All patients experienced oral-buccal-lingual stereotypy, which was frequently severe in nature, but completely resolved in all but one patient. Most patients (90.9%) who consented to a second trial of an atypical antipsychotic did not experience a relapse of TD. LIMITATIONS: All patients were treated in a clinical practice setting by a single psychiatrist, which may limit the generalizability of the findings. CONCLUSIONS: The observed rate of TD represents a real world estimate of the risk of TD with atypical antipsychotic agents in patients with mood disorders. Fortunately, with early recognition symptoms appear to be reversible and further treatment with another atypical antipsychotic does not necessarily lead to relapse. PMID- 23726784 TI - Mycobacterial growth inhibition in murine splenocytes as a surrogate for protection against Mycobacterium tuberculosis (M. tb). AB - Development of an improved vaccine against tuberculosis (TB) is hindered by the lack of a surrogate of protection. Efficacy of new TB vaccines in humans can only be evaluated by expensive and time consuming efficacy trials within TB endemic areas. It is critical that vaccines with the greatest potential to protect are selected for these trials. Mycobacterial growth inhibition assays (MGIAs) have been developed with the hope that these in-vitro functional assays will correlate with protection, which could aid in the selection of the best vaccine candidates. The present study describes the use of the BACTEC system to perform MGIAs in mice. We demonstrate reproducible mycobacterial growth inhibition in splenocytes from BCG immunised mice compared with unimmunised mice (P < 0.023), which corresponded with in-vivo efficacy against Mycobacterium tuberculosis (M. tb) challenge. Microarray data showed extensive differential gene expression in splenocyte responses to ex-vivo BCG stimulation between unimmunised and BCG immunised mice. TH1 responses, including IFN-gamma, nitric oxide synthase (NOS2) and Interleukin -17 (IL-17) expression were enhanced in BCG immunised mice, indicating a possible mechanism for mycobacterial growth inhibition. Further investigation into whether the BACTEC MGIA can be used as a surrogate of protection in humans and preclinical animal models is now warranted. PMID- 23726785 TI - Recurrent posterior reversible encephalopathy syndrome in a pediatric patient with end-stage renal disease. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a condition manifested by altered mental status, seizures, headaches, and visual loss. Specific abnormalities are seen by computed tomography or magnetic resonance imaging. Awareness of this syndrome is important for Emergency Physicians because visual loss can be reversible with prompt treatment of the underlying cause. OBJECTIVE: We present a case of recurrent PRES in a 14-year-old female who presented to the Emergency Department (ED) for headache and photosensitivity. CASE REPORT: A patient with a history of end-stage renal disease of unknown etiology was brought in by her mother for headache and photosensitivity. The patient developed blurry vision, seized in the ED, and required intubation. She was discharged 2 weeks later with complete return of vision. The same patient presented to the ED many times during the next several months for hypertensive emergencies, with three subsequent episodes that involved either seizures, vision loss, or both. Each of the episodes resolved with aggressive control of blood pressure in the pediatric intensive care unit. CONCLUSIONS: PRES should be considered in all patients presenting to the ED with visual loss, seizures, or headache, and can be recurrent in some individuals. Prompt treatment can help prevent permanent vision loss. PMID- 23726786 TI - Emergency percutaneous tracheostomy in a patient with thrombocytopenia. PMID- 23726787 TI - Febrile illness in a young traveler: dengue fever and its complications. AB - BACKGROUND: Dengue fever, a tropical disease once confined mostly to endemic areas in developing countries, is becoming more prevalent. Globalization has led to an increased incidence of the virus both in foreign travelers returning home and local outbreaks in traditionally nonendemic areas, such as the southern United States and southern Europe. Advances in diagnostic tests, therapies, and vaccines for dengue virus have been limited, but research is ongoing. OBJECTIVES: To review the current literature regarding the diagnosis and management of dengue fever. CASE REPORT: This case report describes a young woman returning from Central America with many of the common signs and symptoms who was misdiagnosed both abroad and at home. We explore the epidemiology, disease course, complications, and treatment of dengue fever. CONCLUSION: Emergency physicians should consider dengue fever in patients with acute febrile illnesses, especially among those with recent travel. PMID- 23726788 TI - Hemodynamically unstable: accidental atenolol toxicity? AB - BACKGROUND: Antihypertensive medications, including beta-blockers, are widely used in patients with chronic kidney disease. Unlike most beta-blockers, atenolol is excreted primarily by the kidney, and its clearance by peritoneal dialysis is poor. These pharmacokinetic factors may predispose patients to gradual accumulation of the drug over time. OBJECTIVES: To review the management of a diagnostic dilemma, the role of glucagon therapy, and the clinical implications of atenolol clearance. CASE REPORT: A young woman with end-stage renal disease requiring peritoneal dialysis presented with sudden onset of abdominal pain and hemodynamic instability with hypotension and relative bradycardia. The patient reported that she took her regular four antihypertensive agents, including atenolol, with no excess ingestion or recent dose changes. After resuscitation and consideration of a broad differential diagnosis, the most likely cause of the patient's illness was determined to be unintentional atenolol toxicity, with secondary mesenteric ischemia due to a low-flow state that caused her abdominal pain. Glucagon therapy led to rapid correction of the patient's hemodynamic instability and pain. CONCLUSION: The unique pharmacokinetics of long-term medications must be considered in patients with impaired clearance, such as this patient with end-stage renal disease treated by peritoneal dialysis. Medications may gradually accumulate to supratherapeutic levels, which over time may lead to symptoms of significant toxicity. PMID- 23726789 TI - Quantitative evaluation of therapeutic effect of Liriope platyphylla on phthalic anhydride-induced atopic dermatitis in IL-4/Luc/CNS-1 Tg mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: A variety of previous pharmacological studies have suggested that Liriope platyphylla may exert beneficial biological effects on inflammation, diabetes, neurodegenerative disorder, obesity, and atopic dermatitis (AD). AIM OF THE STUDY: The therapeutic effect of aqueous extract of Liriope platyphylla (AEtLP) on AD was quantified using the luciferase report system in IL-4/Luc/CNS-1 transgenic (Tg) mice. MATERIALS AND METHODS: Alteration of the luciferase signal was quantified in IL-4/Luc/CNS-1 Tg mice co-treated with phthalic anhydride (PA) and AEtLP for 2 weeks using the IVIS imaging system. Phenotypes of AD were assessed by ear thickness analysis, measurement of immune related organ weights, ELISA, and histological and pathological analysis in Tg mice. RESULTS: A strong luciferase signal was detected in the abdominal region of IL-4/Luc/CNS-1 Tg mice treated with only PA. However, this signal was significantly reduced in IL-4/Luc/CNS-1 Tg mice co-treated with PA+AEtLP in an AEtLP concentration-dependent manner. Especially, three organs, the thymus, pancreas, and submandibular lymph node (SL), showed a high signal response to PA treatment. Furthermore, to verify whether or not alteration of the luciferase signal is associated with AD, these disease response phenotypes were measured in the same group of mice. Common allergenic responses including increases in ear thickness, lymph node weight, IgE concentration, and infiltrated mast cells were detected in IL-4/Luc/CNS-1 Tg mice treated with PA. However, these responses were dramatically decreased by AEtLP treatment for 2 weeks. CONCLUSION: These results indicate that the luciferase signal may successfully reflect the therapeutic effects of AEtLP in IL-4/Luc/CNS-1 Tg mice. Further, we suggest additional evidence that Liriope platyphylla may be considered as an effective therapeutic drug for the treatment of AD. PMID- 23726790 TI - Using next-generation sequencing as a genetic diagnostic tool in rare autosomal recessive neurologic Mendelian disorders. AB - Next-generation sequencing was used to investigate 9 rare Chinese pedigrees with rare autosomal recessive neurologic Mendelian disorders. Five probands with ataxia-telangectasia and 1 proband with chorea-acanthocytosis were analyzed by targeted gene sequencing. Whole-exome sequencing was used to investigate 3 affected individuals with Joubert syndrome, nemaline myopathy, or spastic ataxia Charlevoix-Saguenay type. A list of known and novel candidate variants was identified for each causative gene. All variants were genetically verified by Sanger sequencing or quantitative polymerase chain reaction with the strategy of disease segregation in related pedigrees and healthy controls. The advantages of using next-generation sequencing to diagnose rare autosomal recessive neurologic Mendelian disorders characterized by genetic and phenotypic heterogeneity are demonstrated. A genetic diagnostic strategy combining the use of targeted gene sequencing and whole-exome sequencing with the aid of next-generation sequencing platforms has shown great promise for improving the diagnosis of neurologic Mendelian disorders. PMID- 23726791 TI - Macula-less rat and macula-bearing monkey retinas exhibit common lifelong proteomic changes. AB - The visual consequences of age-related alterations in the neural retina have been well documented, but little is known about their molecular bases. We performed a comparative proteomic analysis of the retinas in marmosets and rats to identify proteins for which the expression profiles are altered with maturation and aging. Protein profiles were compared in the newborn, juvenile, middle-age, and aged retinas using 2-dimensional gel electrophoresis. Matrix-assisted desorption ionization-time-of-flight mass spectrometry revealed common proteins in rats and marmosets that exhibited changes in concentration throughout life. Western blot, quantitative reverse-transcriptase polymerase chain reaction, and immunohistochemistry analyses of selected proteins and their mRNA were used to determine whether the changes identified by proteomics were verifiable at the cellular and molecular levels. We found 4 proteins common to both species (Parkinson disease [autosomal recessive, early onset] 7/DJ-1, stathmin, peroxiredoxin, and beta-synuclein) whose concentrations were regulated with age. These findings were confirmed by Western blot, immunohistochemistry, and quantitative reverse-transcriptase polymerase chain reaction analyses. The proteins were localized in certain layers and subsets of cells within the retinas of both species. The expression of these proteins in the adult human retina was confirmed with immunohistochemistry. The present study is the first to provide evidence that the retina is physiologically characterized by specific lifelong changes in its proteome. These changes are independent of whether the retina bears a macula, occur in key functional pathways during the processing of visual signals, and might be involved in the development of age-related pathologic entities. PMID- 23726792 TI - Relative expression of bacterial and host specific genes associated with probiotic survival and viability in the mice gut fed with Lactobacillus plantarum Lp91. AB - The present investigation was aimed at studying the relative expression of atpD (a key part of F1F0-ATPase operon), bsh (bile salt hydrolase), mub (mucus-binding protein) and MUC2 (mucin) genes in mouse model for establishing the in vivo functional efficacy of Lactobacillus plantarum Lp91 (MTCC5690) by reverse transcription-quantitative PCR (RT-qPCR). The atpD gene was significantly up regulated to 2.0, 2.4 and 3.2 folds in Lp91 after 15, 30 and 60 min transit in the stomach of mice. The maximal significant (P<0.00) level of relative bsh gene expression was recorded in Lp91 with 41.6 fold in comparison to only 5.0 fold in reference strain Lp5276 after seven days of mice feeding. Simultaneously, mub gene expression increased to 12.8 and 22.7 fold in both Lp91 and Lp5276, respectively. The expression level of MUC2 was at the level of 1.6 and 2.1 fold in the host colon on administration with Lp91 and Lp5276 feeding, respectively. Hence, the expression of atpD, bsh, mub, MUC2 could be considered as prospective and potential biomarkers for screening of novel probiotic lactobacillus strains for optimal functionality in the gut. PMID- 23726793 TI - Site-specific mutagenesis and functional analysis of active sites of sulfur oxygenase reductase from Gram-positive moderate thermophile Sulfobacillus acidophilus TPY. AB - Sequence alignments revealed that the conserved motifs of SORSa which formed an independent branch between archaea and Gram-negative bacteria SORs according to the phylogenetic relationship were similar with the archaea and Gram-negative bacteria SORs. In order to investigate the active sites of SORSa, cysteines 31, 101 and 104 (C31, C101, C104), histidines 86 and 90 (H86 and H90) and glutamate 114 (E114) of SORSa were chosen as the target amino acid residues for site specific mutagenesis. The wild type and six mutant SORs were expressed in E. coli BL21, purified and confirmed by SDS-PAGE and Western blotting analysis. Enzyme activity determination revealed that the active sites of SORSa were identical with the archaea and Gram-negative bacteria SORs reported. Replacement of any cysteine residues reduced SOR activity by 53-100%, while the mutants of H86A, H90A and E114A lost their enzyme activities largely, only remaining 20%, 19% and 32% activity of the wild type SOR respectively. This study will enrich our awareness for active sites of SOR in a Gram-positive bacterium. PMID- 23726794 TI - Characterization of an autonomously replicating sequence in Candida guilliermondii. AB - Candida guilliermondii is an ascomycetous yeast widely studied due to its clinical importance, biotechnological interest, and biological control potential. During a series of preliminary experiments aiming at optimizing the electroporation procedure of C. guilliermondii cells, we observed that the efficiency of transformation of an ura5 recipient strain with the corresponding dominant marker URA5 was more than a thousand fold higher as compared with the transformation of an ura3 strain with the URA3 wild type allele. This result allowed the identification of an autonomously replicating sequence (ARS) within an A/T rich region located upstream of the URA5 open reading frame (ORF). Interestingly, linear double strand DNAs (dsDNAs) containing this putative ARS are circularized and then autonomously replicated in C. guilliermondii transformed cells. We demonstrated that the C. guilliermondii Lig4p ligase, involved in the canonical non-homologous end-joining (NHEJ) pathway, was responsible for this phenomenon since a lig4 mutant was unable to circularize and to autonomously maintain transforming dsDNAs containing the putative ARS. Finally, a functional dissection of the C. guilliermondii A/T rich region located upstream of the URA5 ORF revealed the presence of a 60 bp-length sequence essential and sufficient to confer ARS properties to shuttle plasmid and linear dsDNAs. PMID- 23726795 TI - Detection of a novel large deletion causing alpha-thalassemia in South China. AB - alpha-Thalassemia is an inherited autosomal recessive disorder. It is one of the most common monogenic abnormalities known in the world and is prevalent in tropical and subtropical regions. alpha-Thalassemia is more frequently caused by deletional type than non-deletional type. Recently, we identified a novel large deletional type of alpha-thalassemia named --(FZ)/alphaalpha from a family in South China. Multiplex ligation-dependent probe amplification was used for diagnosing the carrier and prenatal diagnosing for a fetus. Real-time PCR was employed for characterizing the deletion breakpoints and the deletional segment was determined as 300 kb in length extending from the telomere to AXIN1 gene on the short arm of chromosome 16. The carriers in the family members were detected by real-time PCR using designed primers. PMID- 23726796 TI - Overexpression of thymidylate synthetase confers an independent prognostic indicator in nasopharyngeal carcinoma. AB - Data mining on public domain identified that thymidylate synthetase (TYMS) and dihydrofolate reductase (DHFR) transcripts were significantly higher expressed in nasopharyngeal carcinoma (NPC). In the folate pathway, TYMS catalyzes the methylation of deoxyuridylate to deoxythymidylate using 5,10 methylenetetrahydrofolate [5,10-CH2=THF, derived from tetrahydrofolate (THF)], as a cofactor. This function maintains the thymidine-5-prime monophosphate pool critical for DNA replication and repair and, THF is generated from dihydrofolate (DHF) through the activity of DHFR. Immunoexpression of TYMS and DHFR were retrospectively assessed in biopsies of 124 consecutive NPC patients without initial distant metastasis and treated with consistent guidelines. The outcome was correlated with clinicopathological features and patient survivals. Results indicated that high TYMS (50%) expressions were correlated with primary tumor (p=0.008) and AJCC stage (p=0.006), and high DHFR (50%) expression were correlated with nodal status (p=0.039) and AJCC stage (p=0.029) (7th American Joint Committee on Cancer), respectively. In multivariate analyses, high TYMS expression emerged as an independent prognosticator for worse disease-specific survival (p<0.001), distal metastasis-free survival (p=0.002) and local recurrence-free survival (p<0.001), along with AJCC stage. Therefore, TYMS expression is common and associated with adverse prognosticators and might confer tumor aggressiveness through dysregulation of the nucleotide biosynthetic process. PMID- 23726797 TI - Detection of cysteine protease in Taenia solium-induced brain granulomas in naturally infected pigs. AB - In order to further characterize the immune response around the viable or degenerating Taenia solium cysts in the pig brain, the involvement of cysteine protease in the immune evasion was assessed. Brain tissues from 30 adult pigs naturally infected with T. solium cysticercosis were subjected to histopathology using hematoxylin and eosin stain, and immunohistochemistry using caspase-3 antibodies. Histopathological evaluation revealed lesions of stage I which was characterized by presence of viable parasite surrounded with minimal to moderate inflammatory cells and stage III characterized by the presence of a disintegrating parasite surrounded with high inflammatory cells. The results of immunohistochemistry indicated caspase-3 positive cells interspaced between inflammatory infiltrate mainly in stage I lesions, indicating the presence of cysteine protease. This result confirms the earlier hypothesis that cysteine protease may play a role in inducing immune evasion through apoptosis around viable T. solium cysts. PMID- 23726798 TI - Frequency and implications of HIV superinfection. AB - HIV superinfection occurs when an individual with HIV is infected with a new distinct HIV viral strain. Superinfection has been reported throughout the world, and studies have recorded incidence rates of 0-7.7% per year. Use of next generation sequencing has improved detection of superinfection, which can be transmitted by injecting drug use and sexual intercourse. Superinfection might have incidence rates comparable to those of initial HIV infection. Clinicians should encourage safe sexual and injecting drug use practices for HIV-infected patients because superinfection has detrimental effects on clinical outcomes and could pose a concern for large-scale antiretroviral treatment plans. The occurrence of superinfection has implications for vaccine research, since it seems initial HIV infection is not fully protective against a subsequent infection. Additional collaborative research could benefit care of patients and inform future vaccine design. PMID- 23726799 TI - Encoding- and retrieval-related brain activity underlying false recognition. AB - We examined the neural activity associated with true and false recognition during both encoding and retrieval using the Remember/Know procedure to separate recollection (i.e., mental reinstatement of experienced events during which unique details of a memory are recalled) and familiarity (i.e., mental awareness that an event has been experienced previously without the unique details of the event) in recognition memory. Neuroimaging data at retrieval revealed that the right parahippocampal gyrus was activated during recollection-based true recognition compared with familiarity-based true recognition, indicating the item specific retrieval of visual details. This effect in the right parahippocampal gyrus was not observed for false recognition. Contrary to our expectation, the reactivation effect in early visual cortex was not observed during true recognition, as opposed to false recognition. Neuroimaging data at encoding revealed that the right visual cortex (the right occipitotemporal sulcus) was activated during the encoding of items that yielded recollection-based true recognition compared with familiarity-based true recognition, indicating item specific visual processing. This effect in the right visual cortex was not observed for false recognition. These results suggest that the subjective feeling of Remember/Know with respect to both veridical and false memories varies with the neural activity during both encoding and retrieval. PMID- 23726800 TI - Protective effect of zinc supplementation against cadmium-induced oxidative stress and the RANK/RANKL/OPG system imbalance in the bone tissue of rats. AB - It was investigated whether protective influence of zinc (Zn) against cadmium (Cd)-induced disorders in bone metabolism may be related to its antioxidative properties and impact on the receptor activator of nuclear factor (NF)-kappaBeta (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. Numerous indices of oxidative/antioxidative status, and Cd and Zn were determined in the distal femur of the rats administered Zn (30 and 60mg/l) or/and Cd (5 and 50mg/l) for 6months. Soluble RANKL (sRANKL) and OPG were measured in the bone and serum. Zn supplementation importantly protected from Cd-induced oxidative stress preventing protein, DNA, and lipid oxidation in the bone. Moreover, Zn protected from the Cd induced increase in sRANKL concentration and the sRANKL/OPG ratio, and decrease in OPG concentration in the bone and serum. Numerous correlations were noted between indices of the oxidative/antioxidative bone status, concentrations of sRANKL and OPG in the bone and serum, as well as the bone concentrations of Zn and Cd, and previously reported by us in these animals (Brzoska et al., 2007) indices of bone turnover and bone mineral density. The results allow us to conclude that the ability of Zn to prevent from oxidative stress and the RANK/RANKL/OPG system imbalance may be implicated in the mechanisms of its protective impact against Cd-induced bone damage. This paper is the first report from an in vivo study providing evidence that beneficial Zn impact on the skeleton under exposure to Cd is related to the improvement of the bone tissue oxidative/antioxidative status and mediating the RANK/RANKL/OPG system. PMID- 23726801 TI - The cytochrome P450 2AA gene cluster in zebrafish (Danio rerio): expression of CYP2AA1 and CYP2AA2 and response to phenobarbital-type inducers. AB - The cytochrome P450 (CYP) 2 gene family is the largest and most diverse CYP gene family in vertebrates. In zebrafish, we have identified 10 genes in a new subfamily, CYP2AA, which does not show orthology to any human or other mammalian CYP genes. Here we report evolutionary and structural relationships of the 10 CYP2AA genes and expression of the first two genes, CYP2AA1 and CYP2AA2. Parsimony reconstruction of the tandem duplication pattern for the CYP2AA cluster suggests that CYP2AA1, CYP2AA2 and CYP2AA3 likely arose in the earlier duplication events and thus are most diverged in function from the other CYP2AAs. On the other hand, CYP2AA8 and CYP2AA9 are genes that arose in the latest duplication event, implying functional similarity between these two CYPs. A molecular model of CYP2AA1 showing the sequence conservation across the CYP2AA cluster reveals that the regions with the highest variability within the cluster map onto CYP2AA1 near the substrate access channels, suggesting differing substrate specificities. Zebrafish CYP2AA1 transcript was expressed predominantly in the intestine, while CYP2AA2 was most highly expressed in the kidney, suggesting differing roles in physiology. In the liver CYP2AA2 expression but not that of CYP2AA1, was increased by 1,4-bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) and, to a lesser extent, by phenobarbital (PB). In contrast, pregnenolone 16alpha-carbonitrile (PCN) increased CYP2AA1 expression, but not CYP2AA2 in the liver. The results identify a CYP2 subfamily in zebrafish that includes genes apparently induced by PB-type chemicals and PXR agonists, the first concrete in vivo evidence for a PB-type response in fish. PMID- 23726802 TI - Cigarette smoking substantially alters plasma microRNA profiles in healthy subjects. AB - Circulating microRNAs (miRNAs) are receiving attention as potential biomarkers of various diseases, including cancers, chronic obstructive pulmonary disease, and cardiovascular disease. However, it is unknown whether the levels of circulating miRNAs in a healthy subject might vary with external factors in daily life. In this study, we investigated whether cigarette smoking, a habit that has spread throughout the world and is a risk factor for various diseases, affects plasma miRNA profiles. We determined the profiles of 11 smokers and 7 non-smokers by TaqMan MicroRNA array analysis. A larger number of miRNAs were detected in smokers than in non-smokers, and the plasma levels of two-thirds of the detected miRNAs (43 miRNAs) were significantly higher in smokers than in non-smokers. A principal component analysis of the plasma miRNA profiles clearly separated smokers and non-smokers. Twenty-four of the miRNAs were previously reported to be potential biomarkers of disease, suggesting the possibility that smoking status might interfere with the diagnosis of disease. Interestingly, we found that quitting smoking altered the plasma miRNA profiles to resemble those of non smokers. These results suggested that the differences in the plasma miRNA profiles between smokers and non-smokers could be attributed to cigarette smoking. In addition, we found that an acute exposure of ex-smokers to cigarette smoke (smoking one cigarette) did not cause a dramatic change in the plasma miRNA profile. In conclusion, we found that repeated cigarette smoking substantially alters the plasma miRNA profile, interfering with the diagnosis of disease or signaling potential smoking-related diseases. PMID- 23726803 TI - Urinary exosome miRNome analysis and its applications to salt sensitivity of blood pressure. AB - OBJECTIVES: To investigate microRNAs (miRNAs) in urinary exosomes and their association with an individual's blood pressure response to dietary salt intake. DESIGN AND METHODS: Human urinary exosomal miRNome was examined by microarray. RESULTS: Of 1898 probes tested, 194 miRNAs were found in all subjects tested. 45 miRNAs had significant associations with salt sensitivity or inverse salt sensitivity. CONCLUSION: The expression of 45 urinary exosomal miRNAs associates with an individual's blood pressure response to sodium. PMID- 23726804 TI - Plasma osteoprotegerin levels increase with the severity of cerebral artery atherosclerosis. AB - OBJECTIVES: Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor superfamily and suggested as a marker of atherosclerosis. We investigated whether plasma OPG levels were associated with the presence and severity of cerebral atherosclerosis. DESIGN AND METHODS: We used an enzyme linked immunosorbent assay to measure the plasma OPG levels of 107 patients with acute cerebral infarction. We compared the plasma OPG levels according to the presence and number of arteries with cerebral atherosclerosis (>= 50% stenosis). RESULTS: Of 107 patients, 73 (68.2%) had cerebral atherosclerosis. OPG levels were increased in patients with cerebral atherosclerosis (374.69 +/- 206.48 vs 261.17 +/- 166.91 pg/mL, p=0.006). OPG levels showed positive correlation with the number of cerebral arteries with atherosclerosis (Spearman's rho=0.342, p<0.001). After adjustment for vascular risk factors, OPG>229.9 pg/mL was independently associated with the presence [OR 4.61, 95% CI 1.57-13.55, p=0.005, binary logistic regression] of cerebral atherosclerosis and number [OR 3.20, 95% CI 1.26-8.12, p=0.014, ordinal logistic regression] of arteries with cerebral atherosclerosis. CONCLUSIONS: Plasma OPG levels were significantly associated with the presence and severity of cerebral atherosclerosis. This finding suggests that plasma OPG might have a role in cerebral atherosclerosis. PMID- 23726805 TI - Validation of a new standardized cystatin C turbidimetric assay: evaluation of the three novel CKD-EPI equations in hypertensive patients. AB - OBJECTIVES: Analytical and clinical performances of the new standardized cystatin C particle-enhanced turbidimetric immunoassay (PETIA) using DiaSys reagents on Olympus AU2700(r) analyzer were evaluated. DESIGN AND METHODS: We have studied imprecision, linearity, limit of detection and limit of quantification of this new immunoassay. Method comparison was assessed in relation to results generated by the standardized Siemens-particle-enhanced nephelometric immunoassay (PENIA). In order to evaluate the clinical relevance of this assay, estimated glomerular filtration rate (GFR) was calculated using MDRD, CKD-EPI creatinine, CKD-EPI cystatin C 2012 and CKD-EPI creatinine-cystatin C 2012 equations and compared to GFR measured using urinary clearance of (99m)Tc-DTPA in 100 hypertensive patients. RESULTS: Cystatin C measurements using DiaSys reagents have reliable analytical performances and are comparable to the standardized Siemens-PENIA method (bias of 0.01 mg/L). The mean measured GFR was 90.0+/-29.7 mL/min/1.73 m2. Bias and accuracy of the three CKD-EPI equations were better than the MDRD. Both CKD-EPI creatinine-based and cystatin C-based formulae had similar bias, precision and accuracy. The combined creatinine-cystatin C equation was significantly more accurate and precise than the CKD-EPI creatinine equation in patients with GFR above 60 mL/min/1.73 m2. CONCLUSIONS: The use of cystatin C in a combined equation with creatinine could improve the accuracy of eGFR in the reference interval. PMID- 23726806 TI - Analysis of urinary metabolites for breast cancer patients receiving chemotherapy by CE-MS coupled with on-line concentration. AB - OBJECTIVE: This study aimed to explore the relationship between urinary metabolites and clinical chemotherapy response in breast cancer by CE-MS coupled with on-line concentration. DESIGN AND METHODS: Urine samples were obtained from patients with advanced or locally advanced breast cancer (n=21) before and after chemotherapy and healthy volunteers (n=21). A rapid and sensitive hexadimethrine bromide-coating CE-MS method coupled with normal stacking is developed for the determination of organic acids in human urine. Another CE-MS method coupled with pH-mediated sample stacking is used for the analysis of amino acids and organic acids. RESULTS: After receiving chemotherapy, chemotherapy-sensitive patients showed 30% change in metabolite levels compared to healthy people, while chemotherapy-insensitive patients showed only 9% change in metabolite levels compared to healthy people showing recurrence. The extent of energy insufficiency for chemotherapy-insensitive patients was greater than that for chemotherapy sensitive patients. CONCLUSIONS: Urinary metabolic products may be new potential predictive markers for therapy efficacy. However, more studies with a larger sample size are required to confirm these conclusions. PMID- 23726807 TI - A systematic review of statistical methods used in constructing pediatric reference intervals. AB - OBJECTIVES: This study aims to investigate current medical literature with focus on statistical methods used to construct pediatric reference intervals and identify potential gaps within the process of reference interval estimation. DESIGN AND METHODS: A systematic review of methods was performed. Extensive search criteria were developed and search was conducted on Embase, Medline, and PubMed databases to identify relevant articles. The articles were further screened using predefined inclusion and exclusion criteria. The selected articles were then included in our final systematic review. RESULTS: Our review reveals that there are gaps within current methodology and reporting of pediatric reference intervals. Not all publications followed the Clinical and Laboratory Standards Institute (CLSI) guidelines, and there is a large variation in the methods used. Discrepancies particularly arose when reference intervals were calculated for partitions with small sample sizes. In addition, the dynamic nature of pediatric data was not mostly captured when certain partitioning techniques were used. CONCLUSIONS: There are areas within the pediatric reference interval development process that need attention. Partitioning methods particularly need to be explored with the goals of reducing subjectivity and enabling researchers to capture the best representative partitions possible. Moreover, the complicated nature of pediatric data often limits the sample size available for each partition and appropriate methods need to be considered in such cases. Researchers are also strongly encouraged to accompany their reference limits with confidence intervals to show sampling variability and demonstrate precision of their limits. These issues exemplify the need for a pediatric specific guideline that outlines a standardized way of establishing reference intervals. PMID- 23726808 TI - Interleukin 1B rs16944 G>A polymorphism was associated with a decreased risk of esophageal cancer in a Chinese population. AB - OBJECTIVE: Esophageal cancer is the sixth leading cause of cancer-associated deaths worldwide and represents a particularly aggressive type of cancer. Genetic polymorphisms may partly explain individual differences in esophageal cancer susceptibility. DESIGNS AND METHODS: We conducted a hospital-based case-control study to evaluate the genetic effects of functional single nucleotide polymorphisms (SNPs) in the interleukin 1 (IL1A and IL1B), IL1f7, IL3 and IL7Ra genes on the development of esophageal cancer. A total of 380 esophageal squamous cell carcinoma (ESCC) cases and 380 controls were recruited for this study. The genotypes were determined using a custom-by-design 48-Plex SNPscanTM Kit. RESULTS: When the IL1B rs16944 GG homozygote genotype was used as the reference group, the GA genotype was associated with a significantly decreased risk of ESCC (GA vs. GG: adjusted OR=0.69, 95% CI=0.49-0.99, p=0.041). However, there were no significant associations between the other five SNPs and ESCC risk. Stratified analyses indicated no significantly different risks of ESCC associated with the IL1B rs16944 G>A polymorphism according to sex, age, smoking status or alcohol consumption. IL3 rs2073506 G>A polymorphism was associated with an increased risk for ESCC higher tumor, nodal, and metastatic (TNM) stages. CONCLUSIONS: These findings indicated that the functional IL1B rs16944 G>A polymorphism might contribute to ESCC susceptibility. IL3 rs2073506 G>A polymorphism was associated with an increased risk for ESCC higher TNM stages. However, the results were based on a limited sample size and larger well-designed studies are warranted to confirm these initial findings. PMID- 23726809 TI - Reference intervals for serum creatinine levels in the healthy geriatric population. AB - BACKGROUND: There are few reliable reference values of enzymatically assayed serum creatinine (Scr) levels categorized within a small age interval in the healthy geriatric population. The aim of this study was to establish the reference intervals (RIs) for Scr in the elderly population. METHODS: Healthy, elderly Chinese Han ethnic individuals aged between 60 and 89 years old were recruited for this study. We stratified the reference individuals by gender and age (60-69, 70-79 and 80-89 years), and the Scr values were measured by an enzymatic method. The central 95 percentile RIs were determined using non parametric statistical methods. RESULTS: The Scr values in the elderly population show a Gaussian distribution and age/sex related differences. The RIs for Scr in the reference population with respect to age (ranges of 60-69, 70-79 and 80-89 years) were 52.9-94.5, 57.3-106.2 and 59.0-110.8 MUmol/L for males, respectively, and 44.3-75.4, 47.1-85.5 and 45.1-90.9 MUmol/L for females, respectively. CONCLUSIONS: We have established the RIs for Scr measured with an enzymatic method in the healthy Chinese Han ethnic elderly population, which can provide a reference for both clinical and laboratory studies. PMID- 23726810 TI - Does morphology of carotid plaque depend on patient's oxidative stress? AB - OBJECTIVES: This study explored the relationship between oxidative stress biomarkers and stability of carotid plaque. We decided to analyze the broad range of parameters describing oxidative stress in patients with carotid stenosis. DESIGN AND METHODS: 124 consecutive patients undergoing carotid endarterectomy were enrolled in the study group. The control group consisted of 49 patients without symptoms of atherosclerosis. The stability of carotid plaques was assessed using GSM (gray-scale median) scoring system and the study group was divided into three subgroups according to echogenicity of the plaque. The following parameters of oxidative stress/DNA damage were analyzed: i) urinary excretion of the products of oxidative DNA damage repair; ii) the background level of 8-oxo-7,8-dihydro-2'-deoxyguanosine in leukocytes' DNA and in atherosclerotic plaques; and iii) the concentrations of antioxidant vitamins, uric acid and C-reactive protein in plasma. RESULTS: Oxidative stress (described by redox status) was higher in the patient group than in the control group. There is a correlation between oxidative stress of the patients and stability of the plaque, echolucent plaques (GSM<25) being associated with the highest antioxidant level and lowest excretion of DNA repair markers. CONCLUSIONS: The plaque formation/morphology may depend on local environment and is independent of oxidative stress/inflammation observed on the level of the whole body. PMID- 23726811 TI - Vitamin D levels and relative insufficiency in Saskatchewan. AB - OBJECTIVE: To determine the extent of vitamin D3 deficiency and levels in pregnant First Nations and non-First Nations women in SK. Also, to determine the distribution of vitamin D3 values in the general population in SK. METHODS: Vitamin D3 levels were measured by LC-MS/MS from 19,181 consecutive patient blood/serum samples received at the Saskatchewan Disease Control Laboratory, and from 743 First Nations, and 301 non-First Nations pregnant women in SK. RESULTS: The ages of the 19,181 patient samples ranged from day 1 (0 years) to 102 years. Of the total, 14,658 were female, and 4523 were males. 30.8% had relative vitamin D3 insufficiency (50-75 nmol/L), and 22.5% were in the deficient range (<50 nmol/L). In summer, a larger percentage of SK patients are in the optimum range, whereas in winter, the number of patients in the vitamin D3 deficiency range increased to 33.0% from 14.1%. Samples from pregnant women were collected during the first trimester of pregnancy. Whereas non-First Nations pregnant women had similar vitamin D3 levels to non-pregnant women in SK, vitamin D3 levels were significantly lower than the optimum of 75 nmol/L in pregnant First Nations women than in non-First Nations women. 29.7% of First Nations pregnant women were in the relative insufficiency range, and 45.6% were vitamin D3 deficient. CONCLUSIONS: First Nations pregnant women have lower vitamin D3 levels than non First Nations pregnant women. This puts them and their unborn babies at high risk of a diverse range of disorders associated with vitamin D3 deficiency or insufficiency. PMID- 23726812 TI - Reliable analysis of phenylalanine and tyrosine in a minimal volume of blood. AB - OBJECTIVES: Phenylketonuria (PKU) is an inborn error of phenylalanine metabolism due to a defect in phenylalanine hydroxylase (PAH). Treatment principle is to reduce phenylalanine concentration sufficiently to prevent neuropathological effects. Dietary management is performed and the effect of treatment is monitored by regular analysis of phenylalanine and tyrosine. The aim of the study was to develop a rapid method to routinely measure both metabolites in minimal bloodspot volume (1.5 mm O, corresponding with a volume of 1.3 MUL blood). METHOD: Whole blood was spiked with phenylalanine and tyrosine at 24 different concentrations. Dried blood spots (DBS) were prepared, after which punches of 1.5 mm O and 6 mm O (corresponding with a volume of 12.4 MUL) were taken. Additionally, punches of both sizes were prepared from DBS of PKU-patients (n=77). All samples were analyzed by tandem mass-spectrometry and results between both punches were compared. RESULTS: A good correlation between concentrations of phenylalanine and tyrosine in 1.5 and 6 mm punches was found (r(2)=0.9917 and r(2)=0.9892, respectively). Analysis of phenylalanine and tyrosine in punches of PKU-patients (n=77) showed similar results and fitted within the procentual range of the between run variation. CONCLUSION: We developed an accurate and rapid method to analyze phenylalanine and tyrosine concentrations in a 1.5 mm O bloodspot punch with an estimated whole blood volume of 1.3 MUL. This technical improvement does not only result in a 10 fold reduction in required patients' material, but also in a 30-60 min time saving in sample preparation. PMID- 23726813 TI - Identification of TLR downstream pathways in stroke patients. AB - OBJECTIVE: Toll-like receptors (TLRs) are important molecules for detecting both pathogen invasion and tissue damage. The expression of TLR4 is upregulated in ischemic stroke, at least in the subacute stage. However, the TLR downstream pathways in the context of stroke have not been well studied in previous research. The purpose of this study is to elucidate the TLR4 downstream pathways following ischemic stroke. DESIGN AND METHODS: In this study, 12 ischemic stroke patients and 12 controls were selected from among 89 ischemic stroke patients and 166 controls. The chosen subjects had the highest levels of TLR4 mRNA in the peripheral blood. The differences in the TLR downstream signaling pathways, which were studied by using an RT2 Profiler TM PCR array system (Qiagen), were analyzed. The differentially expressed genes were analyzed by using GeneSpring GX and visualized based on the TLR pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS: The genes upregulated in stroke patients were found to be involved in the MyD88-independent pathway and in UBE2V1-TRAF6 ubiquitin mediated proteolysis. The genes were more expressed in extracellular space, receptor binding, and cytokine receptor binding by use of gene ontology (GO) terms than in control patients. CONCLUSIONS: We found that the MyD88-independent pathway and the ubiquitin-mediated proteolysis pathway, especially TRAF6, may be the most vital molecules among TLR downstream pathways in incidences of ischemic stroke. PMID- 23726814 TI - Impact of alloantibody strength in crossmatch negative DSA positive kidney transplantation. AB - OBJECTIVES: The clinical relevance of pre-transplant "low-level" donor specific anti-HLA antibodies (DSAs) in crossmatch negative kidney transplant recipients remains unclear. To determine what level of DSA associates with antibody mediated rejection (AMR) could be the way to measure the clinical relevance of pre transplant "low-level" donor specific anti-HLA antibodies (DSAs) in crossmatch negative kidney transplant recipients. DESIGN AND METHODS: A retrospective analysis of 221 patients from October 2008 to December 2009 was included in this study. Sera were obtained pre-transplant and two weeks post-transplant and tested for DSA using LABScreen single antigen beads. RESULTS: Among the 221 patients, 11 experienced AMR within 200days after transplant (5%). Pre-transplant DSA was associated with AMR at multiple mean fluorescence intensity (MFI) cutoffs (500, 1000, 2000, 3000, 5000; p=0.003, 0.001, 0.007, 0.003, and 0.003, respectively). No correlation was seen between acute T-cell mediated rejection (CMR) and pre transplant DSA at any of the same MFI cutoffs. There was an increased risk of AMR with higher levels of pre-transplant DSA. Finally, an increase in DSA MFI from pre- to two weeks post-transplant was indicative of a higher probability of AMR. CONCLUSION: Overall, this data supports using the single antigen bead to detect "low-level" DSA both pre- and post- as having a positive and persistent DSA may be predictive of higher AMR rates and poorer graft survival. PMID- 23726815 TI - The effect of iron and zinc supplementation and discontinuation of this practice on iron and zinc level in tissues in rats fed deficient diets. AB - The effect of iron and iron/zinc supplementation on their levels in tissues of rats fed initially one of the three following regimen: C - control AIN-93 diet, D - iron deficient diet and R - diet with 50% reduction of all vitamins and minerals was investigated. The study was conducted on 6-week male Wistar rats, in 3 stages: (1) 4-week adaptation to the diets (C, D or R); (2) 4-week supplementation with the same regimen enriched with 10-times more iron (CSFe, DSFe, RSFe) or iron/zinc (CSFeZn, DSFeZn, RSFeZn); (3) 2-week post supplementation period (the same diets as the stage I). Iron and zinc content in serum, the initial segment of intestine, liver and kidney were measured using FAAS method. After supplementation period (stage II) the content of iron in the intestine, liver and kidney in groups of rats fed DSFe and DSFeZn-diet were significantly higher (all p-values<=0.05) than in rats fed D-diet (intestine: DSFe=50.1+/-9.0 MUg/g wet weight, DSFeZn=43.0+/-9.9 MUg/g vs. D=16.5+/-2.1 MUg/g; liver: DSFe=149+/-30 MUg/g, DSFeZn=152+/-25 MUg/g vs. D=56+/-13 MUg/g; kidney: DSFe=74.0+/-8.1 MUg/g, DSFeZn=72.7+/-6.6 MUg/g vs. D=59.3+/-9.5 MUg/g). The same significant associations (all p-values<=0.05) were observed in R rats in the intestine and liver (intestine: RSFe=60.8+/-6.6 MUg/g, RSFeZn=54.8+/-6.6 MUg/g vs. R=31.5+/-8.2 MUg/g; liver: RSFe=161+/-10 MUg/g, RSFeZn=166+/-21 MUg/g vs. R=136+/-24MUg/g). After post-supplementation period the statistically significant differences between supplemented and non-supplemented rats fed D- and R-diets were still observed. There was not found the effect of applied treatments on zinc status. In conclusion, iron or iron/zinc supplementation increased similarly iron level in tissues of rats fed D-diet or R-diet with prolonged effect after supplementation discontinuation. PMID- 23726816 TI - Comparative study on the influence of fluoride on lipid peroxidation and antioxidants levels in the different brain regions of well-fed and protein undernourished rats. AB - Effects of fluoride on the levels of Lipid peroxidation (LP) and antioxidant enzymes in the brain regions of protein undernourished (PU) and well-fed rats (WF) rats exposed to 100 ppm fluoride in drinking water were investigated. The results indicate that the mean body weights and the total brain weights of PU rats as well as those given fluoride (both WF and PU) were significantly (P < 0.05) lower than their respective controls. The weights of different brain regions were also significantly reduced (P < 0.05) in PU rats compared to WF rats except in the brain stem. Fluoride ingestion diminished the weights of WF and PU rats affecting the cerebrum only (in the case of PU rats) and the cerebellum of both WF and PU rats without an effect on the brain stem of both WF and PU. Additionally, increased LP was observed in the cerebrum and cerebellum of PU rats but after fluoride ingestion, 30% increase in LP was observed only in the cerebrum. In the brain stem however, protein undernutrition was accompanied with a significant reduction in LP but the region seems insensitive to fluoride. There were significant reductions (P < 0.05) in CAT, SOD and GSH in all the brain regions (except the GSH level in the brain stem only) of PU rats. Fluoride induced reduction in the activity of CAT in the three brain regions and on SOD activity in cerebrum only for WF rats but no effect of fluoride on all the antioxidants studied in the three brain regions for PU rats. It is concluded that WF and PU rats responded differently to fluoride toxicity. However, it seems that at the dosage used, fluoride toxicity may be a direct effect on the antioxidant enzymes. PMID- 23726817 TI - Novel ideas about salt, blood pressure, and pregnancy. AB - The molecular mechanisms leading to preeclampsia are poorly understood. It has been related to certain immune mechanisms, as well as the pathological regulation of the renin-angiotensin system together with perturbed salt and plasma volume regulation. Finally, a non-specific, vascular, inflammatory response is generated, which leads to the clinical syndrome. Here, we present novel findings in salt (NaCl) metabolism implying that salt is not only important in blood pressure control and volume homeostasis, but also in immune regulation. Sodium and chloride can be stored without accumulation of water in the interstitium at hypertonic concentrations through interactions with proteoglycans. Macrophages in the interstitium act as osmosensors for salt, producing increased amounts of vascular endothelial factor C, which increases the density of the lymph-capillary network and the production of nitric oxide in vessels. An increased interstitial salt concentration activates the innate immune system, especially Th17 cells, and may be an important trigger for autoimmune diseases. The novel findings with the idea of sodium storage and local mechanisms of volume and immune regulation are appealing for preeclampsia and may unify the "immune" and "vascular" hypotheses of preeclampsia. PMID- 23726818 TI - Contribution of cyclo-oxygenase-2 to the angiogenic switch in canine inflammatory mammary carcinomas. PMID- 23726819 TI - Assessment of the wind-up phenomenon in the equine nociceptive trigeminal system. AB - Repeated sub-threshold nociceptive electrical stimulation resulting in temporal summation of the limb nociceptive withdrawal reflex is a well-established non invasive model to investigate the wind-up phenomenon in horses. Due to structural similarities of the trigeminal sensory nucleus to the dorsal horn of the spinal cord, temporal summation should be evoked by repeated transcutaneous electrical stimulation of trigeminal afferents. To evaluate this hypothesis repeated transcutaneous electrical stimulation was applied to the supraorbital and infraorbital nerves of 10 horses. Stimulation intensities varied between 0.5 and 1.3 times the trigemino-cervical reflex threshold defined for single stimulation. Evoked electromyographic activity of the orbicularis oculi, splenius and cleidomastoideus muscles was recorded and the signals analysed in the previously established epochs typical to the early and late component of the blink reflex and to the trigemino-cervical reflex. Behavioural reactions were evaluated with the aid of numerical rating scale. The nociceptive late component and the trigemino-cervical reflex were not elicited by sub-threshold intensity repeated transcutaneous electrical stimulation. Furthermore, the median reflex amplitude for the 10 horses showed a tendency to decline over the stimulation train so temporal summation of afferent trigeminal inputs could not be observed. Therefore, the modulation of trigeminal nociceptive processing attributable to repeated Adelta fibre stimulations seems to differ from spinal processing of similar inputs as it seems to have an inhibitory rather than facilitatory effect. Further evaluation is necessary to highlight the underlying mechanism. PMID- 23726820 TI - Cardiovascular health: associations with race-ethnicity, nativity, and education in a diverse, population-based sample of Californians. AB - PURPOSE: This study examined how race-ethnicity, nativity, and education interact to influence disparities in cardiovascular (CV) health, a new concept defined by the American Heart Association. We assessed whether race-ethnicity and nativity disparities in CV health vary by education and whether the foreign-born differ in CV health from their U.S.-born race-ethnic counterparts with comparable education. METHODS: We used data from the 2009 California Health Interview Survey to determine the prevalence of optimal CV health metrics (based on selected American Heart Association guidelines) among adults ages 25 and older (n = 42,014). We examined the interaction between education and ethnicity-nativity, comparing predicted probabilities of each CV health measure between U.S.-born and foreign-born White, Asian, and Latino respondents. RESULTS: All groups were at high risk of suboptimal physical activity levels, fruit and vegetable and fast food consumption, and overweight/obesity. Those with greater education were generally better off except among Asian respondents. Ethnicity-nativity differences were more pronounced among those with less than a college degree. The foreign-born respondents exhibited both advantages and disadvantages in CV health compared with their U.S.-born counterparts that varied by ethnicity-nativity. CONCLUSIONS: Education influences ethnicity-nativity disparities in CV health, with most race-ethnic and nativity differences occurring among the less educated. Studies of nativity differences in CV health should stratify by education in order to adequately address SES differences. PMID- 23726821 TI - Prospective study of alcohol consumption and the risk of colorectal cancer before and after folic acid fortification in the United States. AB - PURPOSE: To evaluate the influence of alcohol consumption on the risk of colorectal cancer according to folic acid fortification period in the United States. METHODS: We evaluated the association between alcohol consumption and colorectal cancer by fortification period (before 1998 vs. after 1998) in 2 prospective cohort studies, the Nurses' Health Study (NHS) of women and the Health Professionals Follow-up Study (HPFS) of men, in which 2793 cases of invasive colorectal cancer were documented. RESULTS: Alcohol consumption was associated with an increased risk of colorectal cancer. Among nonusers of multivitamins and/or folic acid supplements, the pooled multivariate relative risk for >=30 g/d drinkers versus nondrinkers was 1.36 (95% confidence interval [95% CI], 1.09-1.70; P for trend, 0.02). The effect of alcohol consumption was slightly stronger in the prefolic acid fortification period (1980 NHS/1986 HPFS 1998) than in the postfortification period (1998-2008); the pooled multivariate relative risks for >=30 g/d drinkers versus nondrinkers were 1.31 (95% CI, 1.00 1.71; P for trend, 0.10) in the prefortification period and 1.07 (95% CI, 0.69 1.65; P for trend, 0.67) in the postfortification period. CONCLUSIONS: Folic acid fortification may attenuate the adverse effect of high alcohol consumption on the risk of colorectal cancer. PMID- 23726822 TI - Medically induced preterm birth and the associations between prenatal care and infant mortality. AB - PURPOSE: During the last 30 years, the use of prenatal care, both the proportion of women receiving the recommended number of visits and the average number of visits, has increased substantially. Although infant mortality has decreased, the incidence of preterm birth has increased. We hypothesized that prenatal care may lead to lower infant mortality in part by increasing the detection of obstetrical problems for which the clinical response may be to medically induce preterm birth. METHODS: We examined whether medically induced preterm birth mediates the association between prenatal care and infant mortality by using newly developed methods for mediation analysis. Data are the cohort version of the national linked birth certificate and infant death data for 2003 births. Analyses were adjusted for maternal sociodemographic, geographic, and health characteristics. RESULTS: Receiving more prenatal care visits than recommended was associated with medically induced preterm birth (odds ratio [OR], 2.44; 95% confidence interval [95% CI], 2.40-2.49) compared with fewer visits than recommended). Medically induced preterm birth was itself associated with greater infant mortality (OR, 5.08; 95% CI, 4.61-5.60) but that association was weaker among women receiving extra prenatal care visits (OR 3.08; 95% CI, 2.88-3.30) compared with women receiving the recommended number of visits or fewer. CONCLUSIONS: These analyses suggest that some of the benefit of prenatal care in terms of infant mortality may be in part due to medically induced preterm birth. If so, the use of preterm birth rates as a metric for tracking birth policy and outcomes could be misleading. PMID- 23726823 TI - Virus-like particles for enterovirus 71 produced from Saccharomyces cerevisiae potently elicits protective immune responses in mice. AB - Human Enterovirus 71 (EV71) is recognized as the leading causative agent of hand foot-and-mouth disease (HFMD) in the Asia-Pacific region in recent years. There are still no approved antiviral drugs or vaccines against EV71 infection yet. In this study, we have developed an advanced platform for production of the virus like particles (VLPs) for EV71 in Saccharomyces Cerevisiae by co-expressing P1 and 3CD genes of EV71. These VLPs exhibited similar morphology and protein composition as EV71 empty particles produced from EV71-infected cells. Immunization with VLPs in mice elicited robust neutralization antibodies against EV71 and potent cellular immune response. In vivo challenge experiments showed that the immune sera induced by VLP conferred protection in neonate mice against lethal EV71 challenge. Together, our study indicated that VLP from yeast is another potential vaccine candidate against EV71 infection. PMID- 23726824 TI - Submission of articles to Vaccine: a fast and fair peer review process. PMID- 23726825 TI - Oncolytic myxoma virus: the path to clinic. AB - Many common neoplasms are still noncurative with current standards of cancer therapy. More therapeutic modalities need to be developed to significantly prolong the lives of patients and eventually cure a wider spectrum of cancers. Oncolytic virotherapy is one of the promising new additions to clinical cancer therapeutics. Successful oncolytic virotherapy in the clinic will be those strategies that best combine tumor cell oncolysis with enhanced immune responses against tumor antigens. The current candidate oncolytic viruses all share the common property that they are relatively nonpathogenic to humans, yet they have the ability to replicate selectively in human cancer cells and induce cancer regression by direct oncolysis and/or induction of improved anti-tumor immune responses. Many candidate oncolytic viruses are in various stages of clinical and preclinical development. One such preclinical candidate is myxoma virus (MYXV), a member of the Poxviridae family that, in its natural setting, exhibits a very restricted host range and is only pathogenic to European rabbits. Despite its narrow host range in nature, MYXV has been shown to productively infect various classes of human cancer cells. Several preclinical in vivo modeling studies have demonstrated that MYXV is an attractive and safe candidate oncolytic virus, and hence, MYXV is currently being developed as a potential therapeutic for several cancers, such as pancreatic cancer, glioblastoma, ovarian cancer, melanoma, and hematologic malignancies. This review highlights the preclinical cancer models that have shown the most promise for translation of MYXV into human clinical trials. PMID- 23726827 TI - Medial pectoral pedicle is a reliable landmark for axillary lymph node dissection. AB - BACKGROUND: The anatomical orientation of structures in the axilla has not been well studied, although it is essential for a neat and safe dissection. The objective of this study was to determine the relations between neurovascular structures in the axilla as they were encountered during axillary lymph node dissection (ALND) for breast cancer. METHODS: This was a prospective study of 29 consecutive ALNDs accompanying either mastectomy or wide local excision. The dissections were conducted in a stepwise manner and the orientation of the structures was determined as the dissections advanced from superficial to deeper planes. RESULTS: The medial pectoral pedicle was the most superficial neurovascular structure encountered during the dissections and was curled around the lateral border of the pectoralis minor muscle in most cases. The intercostobrachial nerve lay 1-2 cm behind and below, and the axillary vein was located 2-3 cm behind and above the pedicle. The long thoracic nerve was constantly found 2-3 cm behind the intercostobrachial nerve. The thoracodorsal nerve was always accompanied by a posterior tributary of the axillary vein. CONCLUSION: Relations between neurovascular structures in the axilla are predictable. The medial pectoral pedicle, which is consistently found and superficially located, could be used as a landmark for ALND. PMID- 23726826 TI - Gender differences in substance use treatment utilization in the year prior to deployment in Army service members. AB - Although military men have heavier drinking patterns, military women experience equal or higher rates of dependence symptoms and similar rates of alcohol-related problems as men at lower levels of consumption. Thus, gender may be important for understanding substance use treatment (SUT) utilization before deployment. Military health system data were analyzed to examine gender differences in both substance use diagnosis (SUDX) and SUT in 152,447 Army service members returning from deployments in FY2010. Propensity score analysis of probability of SUDX indicated that women had lower odds (AOR: 0.91, 95% CI: 0.86-0.96) of military lifetime SUDX. After adjusting for lifetime SUDX using propensity score analysis, multivariate regression found women had substantially lower odds (AOR: 0.61; 95% CI: 0.54-0.70) of using SUT the year prior to deployment. Findings suggest gender disparities in military-provided SUT and a need to consider whether military substance use assessment protocols are sensitive to gender differences. PMID- 23726828 TI - Intraoperative retrograde ureteroscopy during laparoscopic ureteroureterostomy: Precise localization of the lesion. AB - In a case of upper ureteral stricture refractory to laser ureterotomy, laparoscopic ureteroureterostomy was performed for resection of the stricture and reanastomosis of the ureter. Precise localization of the stricture segment was achieved by retrograde ureteroscopy performed concurrently with laparoscopy, with minimal change in the patient's position. PMID- 23726829 TI - Acute appendicitis: diagnostic accuracy of Alvarado scoring system. AB - OBJECTIVE: To evaluate the usefulness of the Alvarado scoring system in reducing the percentage of negative appendectomy in our unit. MATERIALS AND METHODS: A cross-sectional study was conducted, comprising 110 patients, admitted to Surgical Unit I, Civil Hospital, Karachi, in 2011 with a preliminary diagnosis of acute appendicitis. Patients of both sexes and all age groups except younger than 10 years were included in the study and their Alvarado scores calculated, on the basis of which patients were divided into two groups: Group A (Alvarado score <6) and Group B (Alvarado score >=6). The signs, symptoms, laboratory values, surgical interventions, and pathology reports of each patient were evaluated. Diagnosis was confirmed by histopathological examination. Sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: Out of 110 cases (79 males, 31 females), 31 belonged to Group A (28.2%) and 79 belonged to Group B (71.8%). Surgical procedures were performed in 98.2% of cases, along with conservative treatment. Final diagnosis by histopathology was confirmed in 77 cases (71.3%). The overall negative appendectomy rate was 28.7% (males: 28.2%, females: 30%). Sensitivity and specificity of the Alvarado scoring system were found to be 93.5% and 80.6% respectively. Positive and negative predictive values were 92.3% and 83.3%, respectively, and accuracy was 89.8%. CONCLUSION: Alvarado score can be used effectively in our setup to reduce the incidence of negative appendectomies. However, its role in females was not satisfactory and needs to be supplemented by other means. PMID- 23726830 TI - Comparison of transurethral plasmakinetic and transvesical prostatectomy in treatment of 100-149 mL benign prostatic hyperplasia. AB - OBJECTIVE: To compare the safety and efficacy of transurethral plasmakinetic resection of the prostate (PKRP) versus transvesical prostatectomy (TVP) in the treatment of large-volume benign prostatic hyperplasia (LV-BPH) (100-149 mL). METHODS: Ninety-nine BPH patients who had a prostate volume of 100-149 mL were divided into two groups to undergo PKRP or TVP. Preoperative clinical data were analyzed. Patients had follow-up appointments at 1 month, 3 months, 6 months, and 12 months postoperatively. Outcome measures included the International Prostate Symptom Score, quality of life score, maximum urinary flow rate, and postvoid residual urine volume. Adverse effects were also recorded. RESULTS: A total of 96 patients completed the 12-month follow-up. The operative time was longer, but intraoperative blood loss was lower in the PKRP group. Despite a higher percentage of patients requiring a blood transfusion, there was an obvious advantage in gland removal rate in the TVP group. The duration of postoperative catheterization, bladder irrigation, and hospital stay was significantly shorter in the PKRP group. Outcome measures were significantly improved in both groups 1 month postoperatively. The improvement in lower urinary tract symptoms was maintained throughout the 12 months after surgery. There were no significant differences in International Prostate Symptom Score, quality of life, maximum urinary flow rate, and postvoid residual urine volume between the two groups. CONCLUSION: PKRP has the advantage over TVP of being minimally invasive in the treatment of LV-BPH while achieving the same postoperative outcomes. PMID- 23726831 TI - Evaluation of two hemorrhoidectomy techniques: harmonic scalpel and Ferguson's with electrocautery. AB - AIM: The prevalence of symptomatic hemorrhoidal disease is a common disease that usually needs surgery for treatment. Although conservative treatment is often enough for early stages, late stage disease usually needs surgical treatment. The most common and effective approaches used for conventional surgical treatment are harmonic scalpel (HS) and Ferguson's with electrocautery hemorrhoidectomy (FEH). We aimed to use the HS device for hemorrhoidectomy in Grade III and Grade IV hemorrhoids and compare our results with FEH MATERIALS AND METHODS: Enrolled into the study were 151 patients who were operated for symptomatic Grade III-IV hemorrhoids. Patients were randomized into FEH and HS groups. The present review focused on comparing HS hemorrhoidectomy versus FEH with regards to operating time, postoperative pain, duration of disease, number of issued analgesics, length of hospital stay, time to return to normal activity, and postoperative complications. RESULTS: The mean ages of patients who underwent HS and FEH were 34.1 +/- 9.2 years and 33.7 +/- 8.4 years, respectively. The average postoperative stay in the HS group was 1.0 +/- 0.1 days and in the FEH group was 1.2 +/- 0.4 (p = 0.001). The time of return to normal activity was less for the HS groups than for the FEH groups (10.6 +/- 2.1 days vs. 16.0 +/- 6.3 days; p = 0.001). The mean operating time of the HS and FEH groups was 16.8 +/- 4.1 minutes and 25.5 +/- 7.7 minutes, respectively (p = 0.001). The total analgesic doses for the HS group were 790 +/- 206 mg, 619 +/- 234 mg, and 30 +/- 99 mg, and for the FEH group were 1096 +/- 194 mg, 1000 +/- 259 mg, and 40 +/- 0 mg for postoperative Day 1, Day 7, and Day 28, respectively. There was no significant difference between the HS group and the FEH group in the terms of the number of excised hemorrhoid masses (2.0 +/- 0.6 vs. 1.88 +/- 0.6). CONCLUSION: HS hemorrhoidectomy is safe and effective, causes less blood loss and postoperative pain, and fewer complications compared to FEH. PMID- 23726832 TI - [The referral of infectious diseases is a key activity for infectious diseases departments and units, as well as for the hospital]. AB - Infectious diseases referrals (IDR) is a core activity of infectious diseases departments, and is certainly the one with the greatest potential impact on the hospital due to their cross-sectional nature, and with the emergence of a bacterial resistance and antimicrobial crisis. However, there is no standard model for IDR, no official training, and evaluation is merely descriptive. Paradoxically IDR are at risk in a health system that demands more quality and efficiency. The aim of this review is to assess what is known about IDR, its definition, key features, objectives, method, and the evaluation of results, and to suggest improvements to this key activity for the infectious diseases departments and the hospital. PMID- 23726833 TI - Fetal growth restriction caused by MIMT1 deletion alters brain transcriptome in cattle. AB - We examined levels of gene expression in the brains of bovine fetuses carrying a truncated MIMT1 allele, MIMT1(Del), shown to cause late abortion and stillbirth as a result of fetal growth restriction. MIMT1 is a non-protein coding gene that forms part of the imprinted PEG3 (paternally expressed gene 3) domain. Microarray analysis of brain cortex samples from mid-gestation MIMT1(Del/WT) bovine fetuses and wild-type siblings was performed to study the effect of fetal growth restriction on brain gene expression. Statistical analysis revealed 134 genes with increased mRNA levels and 22 with reduced levels in MIMT1(Del/WT) fetuses. Gene set enrichment analysis identified a relatively small number of significant functional clusters representing three major biological processes: response to oxidative stress, angiogenesis, and epithelial cell proliferation. Gene expression microarray analyses identified increased expression of VIPR2, HTRA1, S100A4 and MYH8 in fetuses carrying the deletion and decreased expression of DRD2, ADAM18, miR345, ZNF585A. ADAM18, DRD2 and S100A4 are known to be involved in prenatal brain development. ZNF585A, miR-345, VIPR2, HTRA1, and MYH8 are known to be involved in cell growth and differentiation, but any role in neural developmental has yet to be elucidated. PMID- 23726834 TI - alpha2,3-Sialyltransferase ST3Gal IV promotes migration and metastasis in pancreatic adenocarcinoma cells and tends to be highly expressed in pancreatic adenocarcinoma tissues. AB - Sialyltransferases have received much attention recently as they are frequently up-regulated in cancer cells. However, the role played by each sialyltransferase in tumour progression is still unknown. alpha2,3-Sialyltransferases ST3Gal III and ST3Gal IV are involved in sialyl-Lewis(x) (SLe(x)) synthesis. Given that the role of ST3Gal III in pancreatic adenocarcinoma cells has been previously reported, in this study we have focused on investigating the role of ST3Gal IV in the acquisition of adhesive, migratory and metastatic capabilities and, secondly, in analyzing the expression of ST3Gal III and ST3Gal IV in pancreatic adenocarcinoma tissues versus control tissues. ST3Gal IV overexpressing pancreatic adenocarcinoma MDAPanc-28 cell lines were generated. They showed a heterogeneous increase in SLe(x), and enhanced E-selectin adhesion and migration. Furthermore, when injected into nude mice, increased metastasis and decreased survival were found in comparison with controls. The behaviour of MDAPanc-28 ST3Gal IV overexpressing cells in these processes was similar to the already reported MDAPanc-28 ST3Gal III overexpressing cells. Furthermore, pancreatic adenocarcinoma tissues tended to express high levels of ST3Gal III and ST3Gal IV together with other fucosyltransferase genes FUT3 and FUT6, all involved in the last steps of sialyl-Lewis(x) biosynthesis. In conclusion, both alpha2,3 sialyltransferases are involved in key steps of pancreatic tumour progression processes and are highly expressed in most pancreatic adenocarcinoma tissues. PMID- 23726835 TI - Slow growth and unstable ribosomal RNA lacking pseudouridine in mouse embryonic fibroblast cells expressing catalytically inactive dyskerin. AB - Pseudouridine is the most abundant modified nucleotide in ribosomal RNA throughout eukaryotes and archaea but its role is not known. Here we produced mouse embryonic fibroblast cells expressing only catalytically inactive dyskerin, the pseudouridine synthase that converts uridine to pseudouridine in ribosomal RNA. The mutant dyskerin protein, D125A, was extremely unstable but cells were able to divide and grow very slowly. Abnormalities in ribosome RNA synthesis were apparent but mature cytoplasmic RNAs lacking pseudouridine were produced and were very unstable. We conclude that pseudouridine is required to stabilize the secondary structure of ribosomal RNA that is essential for its function. PMID- 23726836 TI - Tetramethylpyrazine attenuates TNF-alpha-induced iNOS expression in human endothelial cells: Involvement of Syk-mediated activation of PI3K-IKK-IkappaB signaling pathways. AB - Endothelial cells produce nitric oxide (NO) by activation of constitutive nitric oxide synthase (NOS) and transcription of inducible NO synthase (iNOS). We explored the effect of tetramethylpyrazine (TMP), a compound derived from chuanxiong, on tumor necrosis factor (TNF)-alpha-induced iNOS in human umbilical vein endothelial cells (HUVECs) and explored the signal pathways involved by using RT-PCR and Western blot. TMP suppressed TNF-alpha-induced expression of iNOS by inhibiting IkappaB kinase (IKK) phosphorylation, IkappaB degradation and nuclear factor kappaB (NF-kappaB) nuclear translocation, which were required for NO gene transcription. Exposure to wortmannin abrogated IKK/IkappaB/NF-kappaB mediated iNOS expression, suggesting activation of such a signal pathway might be phosphoinositide-3-kinase (PI3K) dependent. Spleen tyrosine kinase (Syk) inhibitor piceatannol significantly inhibited NO production. Furthermore, piceatannol obviously suppressed TNF-alpha-induced IkappaB phosphorylation and the downstream NF-kappaB activation, suggesting that Syk is an upstream key regulator in the activation of PI3K/IKK/IkappaB-mediated signaling. TMP significantly inhibited TNF-alpha-induced phosphorylation of Syk and PI3K. Our data indicate that TMP might repress iNOS expression, at least in part, through its inhibitory effect of Syk-mediated PI3K phosphorylation in TNF-alpha stimulated HUVECs. PMID- 23726837 TI - Adverse effect of demineralized bone powder on osteogenesis of human mesenchymal stem cells. AB - Demineralized bone powder (DBP) has been used by clinicians for years to treat bone defects. Although DBP treatment often leads to successful bone healing, a number of studies using DBP have demonstrated poor bone formation. It is known that soluble factors released from DBP modulate bone formation. We hypothesized that DBP releases or interacts with soluble factors that modulate osteogenesis of mesenchymal stem cells (MSCs). Our in vitro study demonstrated that the expression of mRNA transcripts of bone-related markers decreased in osteogenic culture of human MSCs (hMSCs) with DBP compared to that without DBP. Using a high throughput protein array, we identified insulin-like growth factor binding protein-1, thrombospondin, and angiostatin that were found abundant in the medium cultured with DBP. Separately, we detected a significant reduction of soluble calcium and phosphate in the DBP-present medium compared to that in the DBP absent medium, and showed that hMSC osteogenesis was regulated by the amounts of soluble calcium and phosphate in the medium. Moreover, DBP was shown to sequester soluble calcium and phosphate in the medium, thereby depleting them from interacting with hMSCs during osteogenesis. This study provides a possible explanation to an important question associated with the use of DBP in clinical treatments. PMID- 23726838 TI - The emerging roles of 3' untranslated regions in cancer. AB - Accumulating evidence suggests that 3' untranlated regions (3' UTRs) are critical for spatial and temporal gene expression in both physiological and pathological conditions. The reprogramming of 3' UTRs by various means is a common phenomenon in cancer; disturbances of 3' UTRs significantly increase the risk of cancer susceptibility by acting both in cis and in trans. In this manuscript, we provide an update and perspective on recent advances made in understanding the emerging roles for 3' UTRs in cancer development and hint at the potential future applications of 3' UTRs in cancer diagnosis and therapy. PMID- 23726839 TI - Profiles of circulating inflammatory cytokines in colorectal cancer (CRC), high cancer risk conditions, and health are distinct. Possible implications for CRC screening and surveillance. AB - Alternate colorectal cancer (CRC) screening and surveillance strategies are needed to pre-select candidates for invasive methods. We compared systemic inflammatory profiles in CRC (n=99), health (n=98), high CRC-risk conditions (n=48) and overt inflammation (n=69) by multiplexed analysis of IL-1beta, IL-6, IL-8, FGF-2, G-CSF, GM-CSF, MCP-1, MIP-1alpha, TNF-alpha, VEGF-A, and PDGF-B and CEA. Cytokines corresponded with CRC advancement. FGF2, GM-CSF, IL-1beta, IL-6, MIP-1alpha, PDGF-BB, TNF-alpha, and VEGF-A were higher than in controls already in stage I CRC with FGF2, IL1-beta, and MIP-1alpha higher than in high CRC-risk individuals as well. Cytokine panels devised to differentiate early CRC from controls, adenomas, or inflammatory bowel disease patients (IBD) had good accuracy but only IBD panel had promising specificity at 95% sensitivity. PMID- 23726840 TI - Enhanced therapeutic effect of cisplatin on the prostate cancer in tumor-bearing mice by transfecting the attenuated Salmonella carrying a plasmid co-expressing p53 gene and mdm2 siRNA. AB - Prostate cancer urgently needs an efficient therapy. Here we demonstrated that cisplatin combined with gene therapy by transfecting the attenuated Salmonella that carry a plasmid containing p53 gene and MDM2 siRNA provided a super synergistic effect on the inhibition of prostate cancer growth in vivo. This synergistic therapy was associated with the induction of apoptotic cell death with a decreased Bcl2 to Bax expression ratio and increased expression of cleaved caspase 3 and caspase 9 in the prostate cancer xenograft. These results indicate that cisplatin-chemotherapy in combination with targeting the MDM2/p53 axis is an attractive strategy to treat prostate cancer. PMID- 23726841 TI - miR-211 promotes the progression of head and neck carcinomas by targeting TGFbetaRII. AB - miR-211 up-regulation and transforming growth factor-beta type II receptor (TGFbetaRII) down-regulation are associated with poor prognosis of head and neck squamous cell carcinoma (HNSCC). miR-211 directly targets TGFbetaRII with the miR 211-TGFbetaRII-c-Myc axis promoting HNSCC progression. An inverse correlation of miR-211 and TGFbetaRII expression was found in metastatic HNSCC samples. After 4 nitroquinoline 1-oxide induction, more severe epithelial tumorigenesis was detected on K14-miR-211 transgenic mouse dorsal tongues. Human metastatic lesions and mouse tongue tumors showed increased nuclear c-Myc expression. A novel role for miR-211 in the regulation of TGFbetaRII and c-Myc during tumorigenesis being revealed should help to develop anti-HNSCC therapies. PMID- 23726842 TI - Oncogenic B-Raf(V600E) abrogates the AKT/B-Raf/Mps1 interaction in melanoma cells. AB - Activating B-Raf mutations that deregulate the mitogen-activated protein kinase (MAPK) pathway commonly occur in cancer. Although B-Raf(V600E) induces increased Mps1 protein contributing to centrosome amplification and chromosome instability, the regulatory mechanisms of Mps1 in melanoma cells is not fully understood. Here, we report that Mps1/AKT and B-Raf(WT)/ERK signaling form an auto-regulatory negative feedback loop in melanoma cells; notably, oncogenic B-Raf(V600E) abrogates the negative feedback loop, contributing the aberrant Mps1 functions and tumorigenesis. Our findings raise the possibility that targeting the oncogenic B-Raf and Mps1, especially when used in combination could potentially provide great therapeutic opportunities for cancer treatment. PMID- 23726843 TI - P97/CDC-48: proteostasis control in tumor cell biology. AB - P97/CDC-48 is a prominent member of a highly evolutionary conserved Walker cassette - containing AAA+ATPases. It has been involved in numerous cellular processes ranging from the control of protein homeostasis to membrane trafficking through the intervention of specific accessory proteins. Expression of p97/CDC-48 in cancers has been correlated with tumor aggressiveness and prognosis, however the precise underlying molecular mechanisms remain to be characterized. Moreover p97/CDC-48 inhibitors were developed and are currently under intense investigation as anticancer drugs. Herein, we discuss the role of p97/CDC-48 in cancer development and its therapeutic potential in tumor cell biology. PMID- 23726844 TI - A long non-coding RNA signature in glioblastoma multiforme predicts survival. AB - Long non-coding RNAs (lncRNAs) represent the leading edge of cancer research, and have been implicated in cancer biogenesis and prognosis. We aimed to identify lncRNA signatures that have prognostic values in glioblastoma multiforme (GBM). Using a lncRNA-mining approach, we performed lncRNA expression profiling in 213 GBM tumors from The Cancer Genome Atlas (TCGA), randomly divided into a training (n=107) and a testing set (n=106). We analyzed the associations between lncRNA signatures and clinical outcome in the training set, and validated the findings in the testing set. We also validated the identified lncRNA signature in another two independent GBM data sets from Gene Expression Omnibus (GEO), which contained specimens from 68 and 101 patients, respectively. We identified a set of six lncRNAs that were significantly associated with the overall survival in the training set (P<=0.01). Based on this six-lncRNA signature, the training-set patients could be classified into high-risk and low-risk subgroups with significantly different survival (HR=2.13, 95% CI=1.38-3.29; P=0.001). The prognostic value of this six-lncRNA signature was confirmed in the testing set and the two independent data sets. Further analysis revealed that the prognostic value of this signature was independent of age and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. The identification of the prognostic lncRNAs indicates the potential roles of lncRNAs in GBM pathogenesis. This six-lncRNA signature may have clinical implications in the subclassification of GBM. PMID- 23726845 TI - CREB phosphorylation regulates striatal transcriptional responses in the self administration model of methamphetamine addiction in the rat. AB - Neuroplastic changes in the dorsal striatum participate in the transition from casual to habitual drug use and might play a critical role in the development of methamphetamine (METH) addiction. We examined the influence of METH self administration on gene and protein expression that may form substrates for METH induced neuronal plasticity in the dorsal striatum. Male Sprague-Dawley rats self administered METH (0.1mg/kg/injection, i.v.) or received yoked saline infusions during eight 15-h sessions and were euthanized 2h, 24h, or 1month after cessation of METH exposure. Changes in gene and protein expression were assessed using microarray analysis, RT-PCR and Western blots. Chromatin immunoprecipitation (ChIP) followed by PCR was used to examine epigenetic regulation of METH-induced transcription. METH self-administration caused increases in mRNA expression of the transcription factors, c-fos and fosb, the neurotrophic factor, Bdnf, and the synaptic protein, synaptophysin (Syp) in the dorsal striatum. METH also caused changes in DeltaFosB, BDNF and TrkB protein levels, with increases after 2 and 24h, but decreases after 1month of drug abstinence. Importantly, ChIP-PCR showed that METH self-administration caused enrichment of phosphorylated CREB (pCREB), but not of histone H3 trimethylated at lysine 4 (H3K4me3), on promoters of c-fos, fosb, Bdnf and Syp at 2h after cessation of drug intake. These findings show that METH-induced changes in gene expression are mediated, in part, by pCREB-dependent epigenetic phenomena. Thus, METH self-administration might trigger epigenetic changes that mediate alterations in expression of genes and proteins serving as substrates for addiction-related synaptic plasticity. PMID- 23726846 TI - Immune modulation by genetic modification of dendritic cells with lentiviral vectors. AB - Our work over the past eight years has focused on the use of HIV-1 lentiviral vectors (lentivectors) for the genetic modification of dendritic cells (DCs) to control their functions in immune modulation. DCs are key professional antigen presenting cells which regulate the activity of most effector immune cells, including T, B and NK cells. Their genetic modification provides the means for the development of targeted therapies towards cancer and autoimmune disease. We have been modulating with lentivectors the activity of intracellular signalling pathways and co-stimulation during antigen presentation to T cells, to fine-tune the type and strength of the immune response. In the course of our research, we have found unexpected results such as the surprising immunosuppressive role of anti-viral signalling pathways, and the close link between negative co stimulation in the immunological synapse and T cell receptor trafficking. Here we review our major findings and put them into context with other published work. PMID- 23726848 TI - Viral protein R upregulates expression of ULBP2 on uninfected bystander cells during HIV-1 infection of primary CD4+ T lymphocytes. AB - HIV-1 Vpr triggers NK cell-mediated lysis of infected cells by upregulating ULBP2, a ligand of the NKG2D receptor, through activation of the ATR-mediated DNA damage response. Herein, we demonstrate that Vpr augments ULBP2 expression on both infected and uninfected bystander cells during HIV-1 infection of primary CD4+ T lymphocytes. Indeed, the frequency of uninfected bystander cells expressing high levels of ULBP2 was elevated in a Vpr-dependent manner. Nevertheless, the same does not hold true for a Vpr mutant that is not packaged into virions, suggesting the involvement of virion-associated Vpr in this process. Additionally, we show that soluble Vpr has the ability to induce a DNA damage response and to augment cell-surface ULBP2 upon transducing target cells, including T cells, conditions known to promote NK cell-mediated killing. Overall, these findings suggest that Vpr could contribute to CD4+ T cell loss by rendering uninfected bystander cells susceptible to NK cell-mediated killing. PMID- 23726849 TI - Treatment of acute ischaemic stroke with thrombolysis or thrombectomy in patients receiving anti-thrombotic treatment. AB - Systemic thrombolysis with alteplase is the only approved medical treatment for patients with acute ischaemic stroke. Thrombectomy is also increasingly used to treat proximal occlusions of the cerebral arteries, but has not shown superiority over systemic thrombolysis with alteplase. Many patients with acute ischaemic stroke are pretreated with antiplatelet or anticoagulant drugs, which can increase the bleeding risk of thrombolysis or thrombectomy. Pretreatment with aspirin monotherapy increases the bleeding risk of alteplase in both observational and randomised trials with no effect on clinical outcome, and the risk of intracerebral haemorrhage is increased with the combination of aspirin and clopidogrel. Antiplatelet drugs should not be given in the first 24 h after alteplase treatment. Data from pooled randomised trials and a large observational study show that thrombolysis can probably be done safely in patients given vitamin-K antagonists if the international normalised ratio is less than 1.7, although bleeding risk is slightly raised. Almost no data are available for the safety of alteplase in patients with atrial fibrillation who have been given novel oral anticoagulants (NOAC) for stroke prevention. Some coagulation parameters could help to identify patients treated with NOAC who might be eligible for thrombolysis. Thrombectomy can be done in patients given antiplatelets and probably in those given anticoagulants; however, conclusions about anticoagulants are based on findings from observational studies with small patient numbers. PMID- 23726847 TI - H5N1 vaccines in humans. AB - The spread of highly pathogenic avian H5N1 influenza viruses since 1997 and their virulence for poultry and humans has raised concerns about their potential to cause an influenza pandemic. Vaccines offer the most viable means to combat a pandemic threat. However, it will be a challenge to produce, distribute and implement a new vaccine if a pandemic spreads rapidly. Therefore, efforts are being undertaken to develop pandemic vaccines that use less antigen and induce cross-protective and long-lasting responses, that can be administered as soon as a pandemic is declared or possibly even before, in order to prime the population and allow for a rapid and protective antibody response. In the last few years, several vaccine manufacturers have developed candidate pandemic and pre-pandemic vaccines, based on reverse genetics and have improved the immunogenicity by formulating these vaccines with different adjuvants. Some of the important and consistent observations from clinical studies with H5N1 vaccines are as follows: two doses of inactivated vaccine are generally necessary to elicit the level of immunity required to meet licensure criteria, less antigen can be used if an oil in-water adjuvant is included, in general antibody titers decline rapidly but can be boosted with additional doses of vaccine and if high titers of antibody are elicited, cross-reactivity against other clades is observed. Prime-boost strategies elicit a more robust immune response. In this review, we discuss data from clinical trials with a variety of H5N1 influenza vaccines. We also describe studies conducted in animal models to explore the possibility of reassortment between pandemic live attenuated vaccine candidates and seasonal influenza viruses, since this is an important consideration for the use of live vaccines in a pandemic setting. PMID- 23726850 TI - Factors influencing haemorrhagic transformation in ischaemic stroke. AB - Haemorrhagic transformation (HT) of ischaemic infarction occurs when an area of brain infarction is stained with blood products, mainly red blood cells. An abnormally permeable blood-brain barrier resulting from ischaemia of the capillary endothelium allows this extravasation of blood products. HT is part of the natural history of some forms of ischaemic infarction, especially cerebral embolism, but it can be precipitated or enhanced by therapeutic interventions used in the acute phase of ischaemic stroke. The old view of HT after cerebral embolism as a generally asymptomatic change in a tissue that is already necrotic has been challenged by observations from therapeutic thrombolysis that suggest that HT can have a negative effect on patients' outcomes. Understanding of the risk factors for and the underlying mechanisms and clinical variability of HT in the context of acute therapeutic interventions in ischaemic stroke could help in the early detection of this complication, in determining the safety of recanalisation approaches, and in setting the stage for future research into the prevention or treatment of HT in patients with acute ischaemic stroke. PMID- 23726851 TI - Pramipexole in patients with early Parkinson's disease (PROUD): a randomised delayed-start trial. AB - BACKGROUND: In models of dopaminergic neuronal loss, the dopamine agonist pramipexole has exhibited neuroprotective properties. The Pramipexole On Underlying Disease (PROUD) study was designed to identify whether early versus delayed pramipexole initiation has clinical and neuroimaging benefits in patients with Parkinson's disease (PD). METHODS: Between May 24, 2006, and April 22, 2009, at 98 centres, we recruited patients with PD diagnosed within 2 years and aged 30 79 years. We randomly assigned eligible patients (ratio 1:1), by a centralised, computerised randomisation schedule, to receive double-blind either placebo or pramipexole (1.5 mg a day) and followed them up for 15 months. At 9 months, or as early as 6 months if considered necessary, placebo recipients were assigned to pramipexole. In a neuroimaging substudy, striatal dopamine-transporter binding was assessed by SPECT. All patients, investigators, and independent raters were masked to study treatment. The primary endpoint was the 15-month change from baseline in total score on the unified Parkinson's disease rating scale (UPDRS). This trial is registered with ClinicalTrials.gov, number NCT00321854. FINDINGS: Of 535 patients, 261 were randomly assigned to receive pramipexole and 274 to receive placebo. At 15 months (n=411), adjusted mean change in UPDRS total score showed no significant difference between early and delayed pramipexole (-0.4 points, 95% CI -2.2 to 1.4, p=0.65). 62 patients in the early pramipexole group and 61 patients in the delayed pramipexole group were included in the neuroimaging substudy, for which the adjusted mean 15-month change in striatal (123)I-FP-CIT binding was -15.1% (SE 2.1) for early and -14.6% (2.0) for delayed pramipexole (difference -0.5 percentage points, 95% CI -5.4 to 4.4, p=0.84). Overall, 180 (81%) of patients given early pramipexole and 179 (84%) patients given delayed pramipexole reported adverse events (most frequently nausea), and 22 (10%) patients in the early pramipexole group and 17 (8%) in the delayed pramipexole group had serious events, two of which (hallucinations and orthostatic hypotension) were deemed related to study drug. INTERPRETATION: By clinical and neuroimaging measures, pramipexole showed little evidence differentiating 15-month usage from usage delayed for 6-9 months. The results do not support the hypothesis that pramipexole has disease-modifying effects. FUNDING: Boehringer Ingelheim GmbH. PMID- 23726852 TI - PROUD stands tall: delayed-start studies in Parkinson's disease. PMID- 23726853 TI - Pinnatoxin G is responsible for atypical toxicity in mussels (Mytilus galloprovincialis) and clams (Venerupis decussata) from Ingril, a French Mediterranean lagoon. AB - Following a review of official control data on shellfish in France, Ingril Lagoon had been identified as a site where positive mouse bioassays for lipophilic toxins had been repeatedly observed. These unexplained mouse bioassays, also called atypical toxicity, coincided with an absence of regulated toxins and rapid death times in mice observed in the assay. The present study describes pinnatoxin G as the main compound responsible for the toxicity observed using the mouse bioassay for lipophilic toxins. Using a well-characterised standard for pinnatoxin G, LC-MS/MS analysis of mussel samples collected from 2009 to 2012 revealed regular occurrences of pinnatoxin G at levels sufficient to account for the toxicity in the mouse bioassays. Baseline levels of pinnatoxin G from May to October usually exceeded 40 MUg kg(-1) in whole flesh, with a maximum in September 2010 of around 1200 MUg kg(-1). These concentrations were much greater than those at the other 10 sites selected for vigilance testing, where concentrations did not exceed 10 MUg kg(-1) in a 3-month survey from April to July 2010, and where rapid mouse deaths were not typically observed. Mussels were always more contaminated than clams, confirming that mussel is a good sentinel species for pinnatoxins. Profiles in mussels and clams were similar, with the concentration of pinnatoxin A less than 2% that of pinnatoxin G, and pteriatoxins were only present in non-quantifiable traces. Esters of pinnatoxin G could not be detected by analysis of extracts before and after alkaline hydrolysis. Analysis with a receptor-binding assay showed that natural pinnatoxin G was similarly active on the nicotinic acetylcholine receptor as chemically synthesized pinnatoxin G. Culture of Vulcanodinium rugosum, previously isolated from Ingril lagoon, confirmed that this alga is a pinnatoxin G producer (4.7 pg cell(-1)). Absence of this organism from the water column during prolonged periods of shellfish contamination and the dominance of non-motile life stages of V. rugosum both suggest that further studies will be required to fully describe the ecology of this organism and the accumulation of pinnatoxins in shellfish. PMID- 23726854 TI - Role of lysine and acidic amino acid residues on the insecticidal activity of Jackbean urease. AB - Canavalia ensiformis has three isoforms of urease: Jackbean urease (JBU), Jackbean urease II and canatoxin. These isoforms present several biological activities, independent from the enzymatic property, such as entomotoxicity and antifungal properties. The entomotoxic activity is a property of the whole protein, as well as of a 10 kDa peptide released by insect digestive enzymes. Here we have used chemical modification to observe the influence of lysines and acidic residues on JBU enzymatic and insecticidal activities. Chemical modification of lysine residues was performed with dimethylamine-borane complex and formaldehyde, and acidic residues were modified by 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide and ethylenediamine. Derivatized ureases, called JBU-Lys (lysine-modified) and JBU-Ac (acidic residues-modified), were assayed for their biochemical and insecticidal properties. Neither modification altered significantly the kinetic parameters analyzed, indicating that no residue critical for the enzyme activity was affected and that the modifications did not incur in any significant structural alteration. On the other hand, both modifications reduced the toxic activity of the native protein fed to Dysdercus peruvianus. The changes observed in the entomotoxic property of the derivatized proteins reflect alterations in different steps of JBU's toxicity towards insects. JBU-Ac is not susceptible to hydrolysis by insect digestive enzymes, hence impairing the release of toxic peptide(s), while JBU-Lys is processed as the native protein. On the other hand, the antidiuretic effect of JBU on Rhodnius prolixus is altered in JBU-Lys, but not in JBU-Ac. Altogether, these data emphasize the role of lysine and acidic residues on the insecticidal properties of ureases. PMID- 23726855 TI - Glycolic acid inhibits enzymatic, hemorrhagic and edema-inducing activities of BaP1, a P-I metalloproteinase from Bothrops asper snake venom: insights from docking and molecular modeling. AB - Glycolic acid (GA) (2-Hydroxyethanoic acid) is widely used as chemical peeling agent in Dermatology and, more recently, as a therapeutic and cosmetic compound in the field of skin care and disease treatment. In this work we tested the inhibitory ability of glycolic acid on the enzymatic, hemorrhagic and edema inducing activities of BaP1, a P-I metalloproteinase from Bothrops asper venom, which induces a variety of toxic actions. Glycolic acid inhibited the proteolytic activity of BaP1 on azocasein, with an IC50 of 1.67 mM. The compound was also effective at inhibiting the hemorrhagic activity of BaP1 in skin and muscle in experiments involving preincubation of enzyme and inhibitor prior to injection. When BaP1 was injected i.m. and then, at the same site, different concentrations of glycolic acid were administered at either 0 or 5 min, 7 mM solutions of the inhibitor partially abrogated hemorrhagic activity when administered at 0 min. Moreover, glycolic acid inhibited, in a concentration-dependent manner, edema forming activity of BaP1 in the footpad. In order to have insights on the mode of action of glycolic acid, UV-vis and intrinsic fluorescence studies were performed. Results of these assays suggest that glycolic acid interacts directly with BaP1 and chelates the Zn2+ ion at the active site. These findings were supported by molecular docking results, which suggested that glycolic acid forms hydrogen bonds with residues Glu143, Arg110 and Ala111 of the enzyme. Additionally, molecular modeling results suggest that the inhibitor chelates Zn2+, with a distance of 3.58 A, and may occupy part of substrate binding cleft of BaP1. Our results suggest that glycolic acid is a candidate for the development of inhibitors to be used in snakebite envenomation. PMID- 23726856 TI - Synthesis and characterization of amino acid deletion analogs of kappa-hefutoxin 1, a scorpion toxin on potassium channels. AB - Nine analogs of scorpion toxin peptide kappa-hefutoxin 1 were synthesized by stepwise deletion of its amino acid residues. Disulfide bond pairings of the synthetic analogs were confirmed by enzymatic digestion followed by MALDI-TOF-MS measurements. Functional characterization shows that analogs in which N-terminal residues were deleted retained biological activity, whereas deletion of middle part residues resulted in loss of activity. Furthermore, kappa-hefutoxin 1 and analogs were subjected to a screening on voltage-gated potassium channels in order to determine their subtype selectivity. It is shown that kappa-hefutoxin 1 is suitable as template for peptidomimetics in order to design small peptide based therapeutic compounds. PMID- 23726857 TI - Synthesis and biological characterization of synthetic analogs of Huwentoxin-IV (Mu-theraphotoxin-Hh2a), a neuronal tetrodotoxin-sensitive sodium channel inhibitor. AB - Huwentoxin-IV (HWTX-IV, also named Mu-theraphotoxin-Hh2a) is a typical inhibitor cystine knot peptide isolated from the venom of Chinese tarantula Ornithoctonus huwena and is found to inhibit tetrodotoxin-sensitive (TTX-S) sodium channels from mammalian sensory neurons. This peptide binds to neurotoxin receptor site 4 located at the extracellular S3-S4 linker of domain II in neuronal sodium channels. However, the molecular surface of HWTX-IV interaction with sodium channels remains unknown. In this study, we synthesized HWTX-IV and three mutants (T28D, R29A and Q34D) and characterized their functions on TTX-S sodium channels from adult rat dorsal root ganglion (DRG) neurons. Analysis of liquid chromatography, mass spectrometry and circular dichroism spectrum indicated that all four synthetic peptides are properly folded. Synthetic HWTX-IV exhibited the same activity as native HWTX-IV, while three mutations reduced toxin binding affinities by 10-200 fold, indicating that the basic or vicinal polar residues Thr28, Arg29, and Gln34 in C-terminus might play critical roles in the interaction of HWTX-IV with TTX-S sodium channels. PMID- 23726859 TI - Copper ion-exchanged channel waveguides optimization for optical trapping. AB - Optical trapping of particles has become a powerful non-mechanical and non destructive technique for precise particle positioning. The manipulation of particles in the evanescent field of a channel waveguide potentially allows for sorting and trapping of several particles and cells simultaneously. Channel waveguide designs can be further optimized to increase evanescent field prior to the fabrication process. This is crucial in order to make sure that the surface intensity is sufficient for optical trapping. Simulation configurations are explained in detail with specific simulation flow. Discussion on parameters optimization; physical geometry, optical polarization and wavelength is included in this paper. The effect of physical, optical parameters and beam spot size on evanescent field has been thoroughly discussed. These studies will continue toward the development of a novel copper ion-exchanged waveguide as a method of particle sorting, with biological cell propulsion studies presently underway. PMID- 23726858 TI - Pulmonary and hepatic lesions caused by the dehydropyrrolizidine alkaloid producing plants Crotalaria juncea and Crotalaria retusa in donkeys. AB - The effects and susceptibility of donkeys to Crotalaria juncea and Crotalaria retusa poisoning were determined at high and low doses. Seeds of C. juncea containing 0.074% of dehydropyrrolizidine alkaloids (DHPAs) (isohemijunceines 0.05%, trichodesmine 0.016%, and junceine 0.008%) were administered to three donkeys at 0.3, 0.6 and 1 g/kg body weight (g/kg) daily for 365 days. No clinical signs were observed and, on liver and lung biopsies, the only lesion was a mild liver megalocytosis in the donkeys ingesting 0.6 and 1 g/kg/day. Two other donkeys that received daily doses of 3 and 5 g seed/kg showed initial respiratory signs 70 and 40 days after the start of the administration, respectively. The donkeys were euthanized following severe respiratory signs and the main lung lesions were proliferation of Clara cells and interstitial fibrosis. Three donkeys ingested seeds of C. retusa containing 5.99% of monocrotaline at daily doses of 0.025, 0.05 and 0.1 g/kg for 365 days. No clinical signs were observed and, on liver and lung biopsies, the only lesion was moderate liver megalocytosis in each of the three donkeys. One donkey that received a single dose of 5 g/kg of C. retusa seeds and another that received 1 g/kg daily for 7 days both showed severe clinical signs and died with diffuse centrilobular liver necrosis. No lung lesions were observed. Another donkey that received a single dose of 2.5 g/kg of C. retusa seeds showed no clinical signs. The hepatic and pneumotoxic effects observed are consistent with an etiology involving DHPAs. Furthermore, the occurrence of lung or liver lesions correlates with the type of DHPAs contained in the seeds. Similarly as has been reported for horses, the data herein suggest that in donkeys some DHPAs are metabolized in the liver causing liver disease, whereas others are metabolized in the lung by Clara cells causing lung disease. PMID- 23726860 TI - Treatment with cholesterol-loaded methyl-beta-cyclodextrin increased the cholesterol in rabbit oocytes, but did not improve developmental competence of cryopreserved oocytes. AB - Membrane cholesterol:phospholipids ratio is an important determinant of cell chilling sensitivity. At low temperatures, major membrane destabilisation occurs when the membrane undergoes a phase transition. To increase membrane fluidity and stability during cooling and thus increase oocyte cryoresistance, cholesterol has been added to the plasma membrane. This study was conducted to determine if cholesterol could be incorporated into rabbit oocytes by incubation with cholesterol-loaded methyl-beta-cyclodextrin (CLC) and if added cholesterol could improve the developmental ability of cryopreserved oocytes after parthenogenetic activation or intracytoplasmic sperm injection. Fresh, frozen and vitrified oocytes incubated with CLC containing 20% NBD-labelled cholesterol (NBD-CLC) were evaluated using confocal microscopy. Fluorescence intensity was higher in fresh oocytes than in cryopreserved ones. Pre-treating rabbit oocytes with 1mg of NBD CLC/mL did not improve cleavage and developmental rates after cryopreservation. Results showed that treatment with CLC increased the cytoplasmic cholesterol content, but did not improve cleavage rate and developmental competence of cryopreserved oocytes. PMID- 23726861 TI - Pulmonary involvement in Fabry disease: overview and perspectives. AB - Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A, which leads to storage of sphingolipids in virtually all human cells and consequently to organ dysfunction. Pulmonary involvement is still debated. But, obstructive lung disease is up to ten times more prevalent in patients with FD compared to general public. Also, an accelerated decline in forced expiratory volume in one second (FEV1) over time was observed in these patients. Lysosomal storage of glycosphingolipids is considered leading to small airway disease via hyperplasia of the bronchiolar smooth muscle cells. Larger airways may become involved with ongoing disease process. There is no evidence for involvement of the lung interstitium in FD. The effect of enzyme replacement therapy on respiratory involvement remains to be determined in large, prospective controlled trials. PMID- 23726862 TI - TiO2, CeO2 and ZnO nanoparticles and modulation of the degranulation process in human neutrophils. AB - Inflammation is frequently associated with nanoparticle (NP) exposures. Given that excessive polymorphonuclear neutrophil cell degranulation is a common feature of inflammatory disorders, and since these cells are key players in inflammation, we decided to test the hypothesis that NPs could act as modulators of degranulation in human neutrophils. TiO2, CeO2 and ZnO NPs slightly down regulated cell surface expression of the granule marker CD35, but increased CD66b and CD63 expression, as assessed by flow cytometry. In addition, expression of myeloperoxidase, MMP-9 and albumin stored in azurophil, specific/gelatinase and secretrory granules, respectively, was significantly increased in the supernatants of NPs-induced neutrophils when compared to untreated cells. Moreover, NPs were more potent than the classical bacterial tripeptide N-formyl methionine-leucine-phenylalanine (fMLP) agonist. Finally, TiO2 and CeO2 markedly increased the enzymatic activity of MMP-9 released into the supernatant, as assessed by gelatin zymography, while ZnO exerted only a modest effect. We conclude that NPs can differentially affect all steps involved during neutrophil degranulation, namely, cell surface expression of granule markers, liberation of proteins in the supernatants and enzymatic activity. These results are expected to be helpful to understand the toxicity of TiO2, CeO2 and ZnO. PMID- 23726863 TI - Brain metabolism in patients with hepatic encephalopathy studied by PET and MR. AB - We review PET- and MR studies on hepatic encephalopathy (HE) metabolism in human subjects from the point of views of methods, methodological assumptions and use in studies of cirrhotic patients with clinically overt HE, cirrhotic patients with minimal HE, cirrhotic patients with no history of HE and healthy subjects. Key results are: (1) Cerebral oxygen uptake and blood flow are reduced to 2/3 in cirrhotic patients with clinically overt HE but not in cirrhotic patients with minimal HE or no HE compared to healthy subjects. (2) Cerebral ammonia metabolism is enhanced due to increased blood ammonia in cirrhotic patients but the kinetics of cerebral ammonia uptake and metabolism is not affected by hyperammonemia. (3) Recent advantages in MR demonstrate low-grade cerebral oedema not only in astrocytes but also in the white matter in cirrhotic patients with HE. PMID- 23726864 TI - Validation of a HTS-amenable assay to detect drug-induced mitochondrial toxicity in the absence and presence of cell death. AB - Drug-induced mitochondrial dysfunction is known to contribute to late stage compound attrition. Recently, assays that identify mitochondrial dysfunction have been developed but many require expensive reagents, specialized equipment, or specialized expertise such as isolation of mitochondria. Here, we validate a new 384-well format cell-based dual parameter assay that uses commonly available detection methods to measure both mitochondrial toxicity and cytotoxicity. In our initial evaluation, antimycin A, CCCP, nefazodone, flutamide, and digitonin were tested in K562 cells in both glucose- and galactose-supplemented media with a 2h incubation. The assay was able to correctly differentiate these compounds into mitochondrial toxicants and non-mitochondrial toxicants, and had excellent reproducibility. We next tested 74 compounds in K562 cells in both types of media and show that the assay was able to correctly identify some of the compounds as mitochondrial toxicants. Moreover, the assay could be simplified, without loss of information, by using K562 cells in galactose-containing medium alone. This simple, robust assay can be positioned as a rapid, early readout of mitochondrial and cellular toxicity. However, since the assay fails to identify some mitochondrial toxicants, further assays may be required to detect mitochondrial toxicity once lead compounds have been selected. PMID- 23726865 TI - Ethanol-induced apoptosis in human liver adenocarcinoma cells (SK-Hep1): Fas- and mitochondria-mediated pathways and interaction with MAPK signaling system. AB - For studying molecular mechanisms regulating the fate of ethanol-treated hepatocytes, involvement of Fas in ethanol-induced apoptosis was examined in human liver adenocarcinoma (SK-Hep1) cells in which the function of Fas associated death domain (FADD) protein was knocked down by transfection. In FADD knocked down cells, while ethanol-induced increase in generation of reactive oxygen species (ROS) was unaffected, apoptosis was significantly suppressed, demonstrating the involvement of Fas in ethanol-induced hepatocyte apoptosis more directly than in the past reports. On the other hand, effects of mitogen activated protein kinase (MAPK), which is well known to determine the fate of various cells, on ethanol-induced apoptosis have not been examined in SK-Hep1 cells. Of three major MAPKs, only p38 MAPK and JNK were found activated by 200 mM ethanol treatment. When cells were incubated with inhibitors of p38 MAPK and JNK, ethanol-induced apoptosis was decreased while ROS generation was unaffected, and examination of pro-apoptotic Bax and anti-apoptotic Bcl-2 levels showed decrease of the former and increase of the latter. We concluded that oxidative stress inflicted by ROS triggered Fas-mediated and mitochondria-mediated apoptotic pathways in ethanol-treated SK-Hep1 cells, and that p38 MAPK and JNK were promoting mitochondrial pathway, suggesting interaction between apoptosis and MAPK signaling systems. PMID- 23726866 TI - Time course study of Abeta formation and neurite outgrowth disruption in differentiated human neuroblastoma cells exposed to H2O2: protective role of autophagy. AB - Here, we tried to elucidate the possible role of autophagy against H2O2 and Amyloid beta (Abeta) induced neurotoxicity using retinoic acid differentiated SH SY5Y cells. We found that H2O2 disrupted neurite outgrowth concomitant with production of Abeta. Furthermore, we showed that H2O2 could increase the apoptotic factors such as Bax/Bcl-2 ratio, caspase-3 level, and PARP activity in a time course manner. These findings were confirmed by acridine orange/ethidium bromide and Hoechst staining. In addition, we observed that H2O2 led to conversion of LC3 protein from LC3I to LC3II and an increase in autophagy flux. Autophagy factors including LC3B, Atg7, and Atg12 increased and reached their highest level after 2h of insulting and then dropped to a lower level. Our results showed that autophagy could internalize and degrade intra- and extracellular Abeta after 3h treatment with H2O2. However, the remaining amount of Abeta accelerated morphological atrophy and, as a result, increased neuronal death (apoptosis). Inhibition of autophagy influx, using 3-methyl-adenine, increased intra- and extracellular levels of Abeta, providing more proof for a protective role of autophagy against oxidative stress. Further studies can shed light on the important role of autophagy by finding new pathways involved in Abeta degeneration. PMID- 23726867 TI - Cylindrospermopsin induced transcriptional responses in human hepatoma HepG2 cells. AB - The newly emerging cyanotoxin cylindrospermopsin (CYN) is showing genotoxic effects in a range of test systems. However, the knowledge on the mechanisms involved is limited. To get insight into the cellular responses to CYN a toxicogenomic analysis of selected genes commonly affected by genotoxic stress was performed on HepG2 cells exposed to a non-cytotoxic but genotoxic concentration of CYN (0.5 MUg/ml for 12 and 24h). CYN increased expression of the immediate-early response genes from the FOS and JUN gene families and there was strong evidence for the involvement of P53 and NF-kappaB signaling. Strong up regulation of the growth arrest and DNA damage inducible genes (GADD45A and GADD45B), cyclin-dependent kinase inhibitors (CDKN1A and CDKN2B), checkpoint kinase 1 (CHEK1), and genes involved in DNA damage repair (XPC, ERCC4 and others) indicated cell-cycle arrest and induction of nucleotide excision and double strand break repair. Up-regulation of metabolic enzyme genes provided evidence for the involvement of phase I (CYP1A1, CYP1B1, ALDH1A2 and CES2) and phase II (UGT1A6, UGT1A1, NAT1 and GSTM3) enzymes in the detoxification response and potential activation of CYN. The obtained transcriptional patterns after exposure of HepG2 cells to CYN provide valuable new information on the cellular response to CYN. PMID- 23726868 TI - Hydrogen sulfide slows down progression of experimental Alzheimer's disease by targeting multiple pathophysiological mechanisms. AB - It has been previously reported that brain hydrogen sulfide (H2S) synthesis is severely decreased in Alzheimer's disease (AD) patients, and plasma H2S levels are negatively correlated with the severity of AD. Here we extensively investigated whether treatment with a H2S donor and spa-waters rich in H2S induces neuroprotection and slows down progression of AD. Studies with sodium hydrosulfide (a H2S donor) and Tabiano's spa-water were carried out in three experimental models of AD. Short-term and long-term treatments with sodium hydrosulfide and/or Tabiano's spa-water significantly protected against impairment in learning and memory in rat models of AD induced by brain injection of beta-amyloid1-40 (Abeta) or streptozotocin, and in an AD mouse model harboring human transgenes APPSwe, PS1M146V and tauP301L (3xTg-AD mice). The improvement in behavioral performance was associated with hippocampus was size of Abeta plaques and preservation of the morphological picture, as found in AD rats. Further, lowered concentration/phosphorylation levels of proteins thought to be the central events in AD pathophysiology, namely amyloid precursor protein, presenilin-1, Abeta1-42 and tau phosphorylated at Thr181, Ser396 and Ser202, were detected in 3xTg-AD mice treated with spa-water. The excitotoxicity-triggered oxidative and nitrosative stress was counteracted in 3xTg-AD mice, as indicated by the decreased levels of malondialdehyde and nitrites in the cerebral cortex. Hippocampus reduced activity of c-jun N-terminal kinases, extracellular signal regulated kinases and p38, which have an established role not only in phosphorylation of tau protein but also in inflammation and apoptosis, was also found. Consistently, decrease in tumor necrosis factor-alpha level, up-regulation of Bcl-2, and down-regulation of BAX and the downstream executioner caspase-3, also occurred in the hippocampus of 3xTg-AD mice after treatment with Tabiano's spa-water, thus suggesting that it is also able to modulate inflammation and apoptosis. Our findings indicate that appropriate treatments with H2S donors and Tabiano's spa-waters, and may be other spa-waters rich in H2S content, might represent an innovative approach to slow down AD progression in humans by targeting multiple pathophysiological mechanisms. PMID- 23726869 TI - Psychiatric comorbidity among adults with schizophrenia: a latent class analysis. AB - Schizophrenia is a severe mental illness that often co-occurs with and can be exacerbated by other psychiatric conditions. There have not been adequate efforts to examine schizophrenia and psychiatric comorbidity beyond pairwise examination using clusters of diagnoses. This study used latent class analysis to characterize patterns of 5-year psychiatric comorbidity among a national sample of adults with schizophrenia. Baseline data from 1446 adults with schizophrenia across 57 sites in the United States were analyzed. Three latent classes were identified labeled Solely Schizophrenia, Comorbid Anxiety and Depressive Disorders with Schizophrenia, and Comorbid Addiction and Schizophrenia. Adults in the Solely Schizophrenia class had significantly better mental health than those in the two comorbid classes, but poorer illness and treatment insight than those with comorbid anxiety and depressive disorders. These results suggest that addiction and schizophrenia may represent a separate latent profile from depression, anxiety, and schizophrenia. More research is needed on how treatment can take advantage of the greater insight possessed by those with schizophrenia and comorbid anxiety and depression. PMID- 23726870 TI - Can sleep disturbance in depression predict repetitive transcranial magnetic stimulation (rTMS) treatment response? AB - Treatment for depression is not effective in all patients and it is therefore important to identify factors that can be used to tailor treatments. One potential factor is insomnia. Several repetitive transcranial magnetic stimulation (rTMS) studies have reported on this symptom, however, they did not take into account the presence of hypersomnia or that insomnia was related to their outcome measure. Our aim was to investigate whether baseline sleep disruption was related to rTMS treatment response. We pooled data from four clinical trials using rTMS to treat depression, including 139 subjects in data analysis. Insomnia was measured using the Hamilton Depression Rating Scale (HamD) sleep questions and hypersomnia from the Beck Depression Inventory (BDI). To reduce the possible impact of insomnia on our treatment response outcome we created an adjusted HamD score which omitted sleep items. Sleep disturbances were common in our study: 66% had insomnia and 38% hypersomnia. Using regression analysis with our adjusted HamD score we found no relation between baseline insomnia or hypersomnia and rTMS treatment response. Our data are consistent with previous studies; however, this is the first rTMS study to our knowledge that has attempted to dissociate baseline insomnia from the HamD outcome measure and to report no relationship between hypersomnia and rTMS outcome. PMID- 23726871 TI - Bilateral ischemic lumbosacral plexopathy from chronic aortoiliac occlusion presenting with progressive paraplegia. AB - Spinal cord ischemia is rare but causes significant morbidity and mortality. Spinal cord ischemia has been reported after open and endovascular interventions of the thoracic and abdominal aorta, and, rarely, acute occlusion of aorta from in situ thrombosis or acute embolic occlusion. Acute interruption of the critical blood supply to the spinal cord or root contributes to this devastating neurologic deficit. However, gradually worsening lumbosacral plexopathy and consequent paraplegia related to chronic aortic occlusion is extremely rare. We present a case of a 58-year-old man with progressive lower limb paralysis from atherosclerotic aortoiliac occlusion without history of aortic surgery or evidence of thromboembolism. PMID- 23726872 TI - [Statement of the Spanish Interdisciplinary Cardiovascular Prevention Committee (CEIPC for its Spanish acronym) on the 2012 European Cardiovascular Prevention Guidelines]. AB - Based on the two main frameworks for evaluating scientific evidence (SEC and GRADE) European cardiovascular prevention guidelines recommend interventions across all life stages using a combination of population-based and high-risk strategies with diet as the cornerstone of prevention. The evaluation of cardiovascular risk (CVR) incorporates HDL levels and psychosocial factors, a very high risk category, and the concept of age-risk. They also recommend cognitive-behavioural methods (e.g., motivational interviewing, psychological interventions) led by health professionals and with the participation of the patient's family, to counterbalance psychosocial stress and reduce CVR through the institution of positive habits such as a healthy diet, physical activity, smoking cessation, and adherence to treatment. Additionally, public health interventions - such as smoking ban in public areas or the elimination of trans fatty acids from the food chain - are also essential. Other innovations include abandoning antiplatelet therapy in primary prevention and the recommendation of maintaining blood pressure within the 130-139/80-85mmHg range in diabetic patients and individuals with high CVR. Finally, due to the significant impact on patient progress and medical costs, special emphasis is given to the low therapeutic adherence levels observed. In sum, improving cardiovascular prevention requires a true partnership among the political class, public administrations, scientific and professional associations, health foundations, consumer associations, patients and their families. Such partnership would promote population-based and individual strategies by taking advantage of the broad spectrum of scientific evidence available, from clinical trials to observational studies and mathematical models to evaluate population-based interventions, including cost-effectiveness analyses. PMID- 23726873 TI - The bootlace thighplasty technique: making use of sutures and staples. PMID- 23726874 TI - Increased bone mineral density in patients with ossification of the ligamentum flavum: a case-control study. AB - The present study investigated the bone mineral density (BMD) and the prevalence of osteoporosis in an ossification of the ligamentum flavum (OLF) patient group and a matched control group. We also investigated the correlation of BMD with the number of spine levels exhibiting OLF. From January 1999 to August 2012, 120 patients with spinal OLF underwent dual-energy X-ray absorptiometry at our institute, and 102 of those were included in our study. Control group members were age, sex, and body mass index (BMI) matched to OLF group members on a 1:1 basis. Age, sex, and BMI were similar in the OLF and control groups. BMDs of the OLF and control groups were significantly different in the lumbar spine (mean T scores: -0.2 +/- 1.5 and -0.7 +/- 1.5, respectively; p = 0.03). The prevalences of osteopenia and osteoporosis tended to be lower in the OLF group (28.3% and 4.0%, respectively) than those in the control group (31.3% and 9.1%, respectively); however, the differences were not statistically significant (p = 0.41). A significant positive correlation was detected between the lumbar spine BMD and the number of spine levels exhibiting OLF (p = 0.03). PMID- 23726875 TI - Selection of resistant-associated variants to the NS5A inhibitor daclatasvir: revenge of the hepatitis C virus. PMID- 23726876 TI - Primary liver carcinomas can originate from different cell types: a new level of complexity in hepatocarcinogenesis. PMID- 23726878 TI - Intratumor heterogeneity: finding the needle in a haystack for cancer treatment. PMID- 23726879 TI - What you see is not always what you get: raising the bar on clinical trial methodology in ulcerative colitis. PMID- 23726880 TI - Involvement of chymase in allergic conjunctivitis of guinea pigs. AB - It has been reported that chymase activity was increased in allergic conjunctivitis patients and this activity was correlated with the severity of the disease. However, the precise roles of chymase in allergic conjunctivitis are unclear, and whether chymase inhibitors are effective for allergic conjunctivitis has not been reported even in experimental animal models. In this study, the roles of chymase in the pathogenesis were evaluated using a selective chymase inhibitor, ONO-WH-236, in a guinea pig model of allergic conjunctivitis induced by cedar pollen. Sensitized guinea pigs were challenged by the pollen, followed by assessing redness and edema in the conjuntiva, and counting the frequency of eye scratching as an itch-associated response. Treatment with the ONO-WH-236 (40 and 80 mg/kg, p.o.) dose-dependently inhibited the induction of redness, edema and scratching behavior. An anti-histaminic drug, ketotifen (3 mg/kg, p.o.), also significantly inhibited conjunctivitis symptoms. Chymase activity was increased in ophthalmic lavage fluid immediately after the pollen challenge. The increase in chymase activity was inhibited by in vivo treatment with ONO-WH-236. Interestingly, increased histamine in the ophthalmic lavage fluid immediately after the challenge was also inhibited by the chymase inhibitor. Administration of human recombinant chymase by eye dropping (0.09 and 0.9 MUg/eye) dose dependently induced scratching behavior, which was inhibited by not only ONO-WH 236 but also ketotifen; however, chymase administration induced only weak redness in the conjunctiva, which was resistant to treatment with anti-histaminic drugs. In conclusion, it was suggested that chymase was released from mast cells after antigen challenge, followed by the induction of conjunctivitis symptoms through histamine release from mast cells. Thus, chymase could be a potential target for pharmacotherapy for allergic conjunctivitis. PMID- 23726881 TI - Transplantation of induced pluripotent stem cells without C-Myc attenuates retinal ischemia and reperfusion injury in rats. AB - Induced pluripotent stem cells (iPSC) are novel stem cell populations, but the role of iPSC in retinal ischemia and reperfusion (I/R) injury remains unknown. Since oncogene c-Myc is substantially contributed to tumor formation, in this study, we investigated the effects, mechanisms and safety of subretinal transplantation of iPSC without c-Myc (non-c-Myc iPSC) in a rat model of retinal I/R injury. Retinal I/R injury was induced by raising the intraocular pressure of Sprague-Dawley rats to 110 mmHg for 60 min. A subretinal injection of non-c-Myc iPSC or murine epidermal fibroblast was given 2 h after I/R injury. Electroretinograms (ERG) were performed to determine the functionality of the retinas. The surviving retinal ganglion cells (RGCs) and retinal apoptosis following I/R injury were determined by counting NeuN-positive cells in whole mounted retinas and TUNEL staining, respectively. The generation of reactive oxygen species (ROS) and the activities of superoxide dismutase (SOD) and catalase (CAT) in the retinal tissues were determined by lucigenin- and luminol enhanced chemiluminescence and enzyme-linked immunosorbent assay (ELISA). The degree of retinal oxidative damage was assessed by nitrotyrosine, acrolein, and 8 hydroxy-2'-deoxyguanosine (8-OHdG) staining. The expression of brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and basic fibroblast growth factor (bFGF) in retinas was measured by immunohistochemistry and ELISA. We found that subretinal transplantation of non-c-Myc iPSC significantly suppressed the I/R-induced reduction in the ERG a- and b-wave ratio, attenuated I/R-induced loss of RGCs and remarkably ameliorated retinal morphological changes. Non-c-Myc iPSC potentially increased the activities of SOD and CAT, decreased the levels of ROS, which may account for preventing retinal cells from apoptotic cell death. In addition, the levels of BDNF and CNTF in retina were significantly elevated in non-c-Myc iPSC-treated eyes. Track the non c-Myc iPSC after transplantation, most transplanted cells are remained in the subretinal space, with spare cells express neurofilament M markers at day 28. Six months after transplantation in I/R injured rats, no tumor formation was seen in non-c-Myc iPSC graft. In conclusion, non-c-Myc iPSC effectively rescued I/R induced retinal damages and diminished tumorigenicity. Non-c-Myc iPSC transplantation attenuated retinal I/R injury, possibly via a mechanism involving the regulation of oxidative parameters and paracrinal secretion of trophic factors. PMID- 23726882 TI - Facilitation of corticospinal tract excitability by transcranial direct current stimulation combined with voluntary grip exercise. AB - Previous studies have established that transcranial direct current stimulation (tDCS) is a powerful technique for the deliberate manipulation of the activity of human cerebral cortex. Moreover, it has also been shown that the non-exhausted voluntary motor exercise increases the excitability of corticospinal tract. We conducted this study to define the facilitation effect following anodal tDCS combined with the voluntary grip exercise as compared with single use of tDCS or voluntary grip exercise. Our result showed that the combination of anodal tDCS with voluntary grip exercise produced a 2-fold increase in the amplitude of MEP as compared with single use of anodal tDCS or voluntary grip exercise. In conclusion, our result could indicate that the treatment outcomes of brain and neurorehabilitation using tDCS would be better when tDCS is combined with the appropriate method of voluntary exercise as compared with single use of tDCS. PMID- 23726883 TI - Investigation on extracellular polymeric substances from mucilaginous cyanobacterial blooms in eutrophic freshwater lakes. AB - Enhanced knowledge on extracellular polymeric substances (EPSs) of mucilaginous cyanobacterial blooms could improve our understanding of its ecological significance. This study for the first time investigated the extraction and fractionation of EPS matrix from cyanobacterial blooms in a eutrophic freshwater lake, and the changes in chemical compositions in EPS matrix during extraction were systematically investigated by two-dimensional correlation spectroscopy (2D COS). The analyses demonstrated that organic matters were unevenly distributed among the EPS matrix, with most of organic matters being tightly bound to cyanobacterial cells. In addition, the soluble and loosely bound EPS fractions mainly consisted of proteins, while polysaccharides became the predominant compounds in the tightly bound EPS fraction. Heating extraction at 60 degrees C for 30min led to a high EPS yield and low cell lysis when compared with other extraction methods. The 2D-COS results revealed a preferential release of OH in polysaccharides versus amide I in proteins in the initial heating; whereas further extension of heating resulted in EPS degradation, with degradation rates arranging in a decreased order from amide I, amide II, polysaccharides-like substances to polysaccharides. These results obtained would help enhance our insights into EPS characterization from cyanobacterial blooms in eutrophic lakes. PMID- 23726884 TI - Effects and mechanisms of the combined pollution of lanthanum and acid rain on the root phenotype of soybean seedlings. AB - Rare earth pollution and acid rain pollution are both important environmental issues worldwide. In regions which simultaneously occur, the combined pollution of rare earth and acid rain becomes a new environmental issue, and the relevant research is rarely reported. Accordingly, we investigated the combined effects and mechanisms of lanthanum ion (La(3+)) and acid rain on the root phenotype of soybean seedlings. The combined pollution of low-concentration La(3+) and acid rain exerted deleterious effects on the phenotype and growth of roots, which were aggravated by the combined pollution of high-concentration La(3+) and acid rain. The deleterious effects of the combined pollution were stronger than those of single La(3+) or acid rain pollution. These stronger deleterious effects on the root phenotype and growth of roots were due to the increased disturbance of absorption and utilization of mineral nutrients in roots. PMID- 23726885 TI - Effects of cadmium on the activities of photosystems of Chlorella pyrenoidosa and the protective role of cyclic electron flow. AB - Cadmium (Cd) shows high toxicity to aquatic microalgae. Many studies showed that Cd inhibited activities of photosystem II (PSII) but the effects of heavy metals on photosystem I (PSI) and cyclic electron flow (CEF) were still controversial and unclear. The effects of CdCl2 on the activities of PSI, PSII and CEF in Chlorella pyrenoidosa was measured simultaneously in the present study. In presence of 200MUM of Cd, ultrastructure of some cells was strongly modified. Cd exposure led to decrease of the activities of photosynthetic oxygen evolution and respiration. PSII was more sensitive to Cd treatment than PSI. Cd treatment showed significant inhibition on the photochemical quantum yield and electron transport rate of PSII. Cd increased the quantum yield of non-light-induced non photochemical fluorescence quenching, indicating the damage of PSII. The activity of PSI showed tolerance to Cd treatment with concentration less than 100MUM in the experiment. Linear electron flow (LEF) made significant contribution to the photochemical quantum yield of PSI of the untreated cells, but decreased with increasing Cd concentration. The contribution of CEF to the yield of PSI increased with increasing Cd concentration. The activation of CEF after exposure to Cd played an essential role for the protection of PSI. PMID- 23726886 TI - Phylogenetic revision of the claudin gene family. AB - Claudins are four-transmembrane proteins acting to collectively regulate paracellular movement of water and ions across cellular tight junctions in vertebrate tissues. Despite the prominence of zebrafish (Danio rerio) as a developmental model and the existence of an annotated genome, the diversity and evolutionary history of these claudins, with respect to other vertebrate groups, is poorly described. In this study, we identify 54 zebrafish claudins, including 24 that were previously unreported, and infer homology of the encoded polypeptide sequences with other vertebrate claudin groups using Bayesian phylogenetic analysis. In this analysis, 197 vertebrate claudin and claudin-like proteins were classified into discrete 'superclades' of related proteins. Based on these groupings, an interim reclassification is proposed, which will resolve ambiguity in the present nomenclature of several vertebrate models. Fifty-two of the 54 identified claudins were detected in cDNA preparations from whole, adult zebrafish, and 43 exhibited distinct tissue expression profiles. Despite prolific expansion of the claudin gene family in teleost genomes, these claudins can still be broadly separated into two functional groups: (1) "classic" claudins that characteristically contain an equal number of opposing, charged residues in the first extracellular loop (ECL1) and (2) "non-classic" claudins that typically have an ECL1 containing a variable number of charged residues. Functional analysis of these groups indicates that 'classic' claudins may act to reduce overall paracellular permeability to water and dissolved ions, whereas 'non classic' claudins may constitute pores that facilitate selective ion permeability. PMID- 23726887 TI - Investigating siRNA delivery to chronic myeloid leukemia K562 cells with lipophilic polymers for therapeutic BCR-ABL down-regulation. AB - RNAi represents a new alternative for treatment of chronic myeloid leukemia (CML) to overcome the difficulties of current drug treatments such as the acquired resistance. However, potent carriers that can overcome delivery barriers to RNAi agents and have therapeutic efficacy especially in difficult-to-transfect CML cells are needed. Here, we explored the use of lipid-modified polyethylenimines (PEI) of low molecular weights (0.6, 1.2 and 2.0kDa) in K562 cells and showed that the delivery efficiency was dependent on the type of lipid used for polymer modification, degree of lipid substitution and polymer molecular weight. Among the lipid-substituted polymers investigated, palmitic acid (PA)-substituted 1.2kDa PEI (~2 lipids/PEI) has proven to be highly efficient in delivering siRNA and silencing of the reporter gene green fluorescent protein (GFP). The silencing efficacy achieved with this polymer was found to be higher than the 25kDa PEI and is similar to commercial reagent LipofectamineTM 2000. Moreover, when BCR-ABL protein was targeted in K562 cells, a reduction in the corresponding mRNA levels was observed, as well as an induction of early and late stage apoptosis. The results of this study demonstrated that PA-substitutions on low MW polymers could be useful for siRNA delivery in CML cells for therapeutic purposes. PMID- 23726888 TI - Current standards of care for chemotherapy of optimally cytoreduced advanced epithelial ovarian cancer. AB - There has been limited change in evidence-based primary chemotherapeutic management of optimal residual advanced ovarian cancer for more than a decade. The backbone of therapy remains a platinum agent (generally carboplatin) and a taxane (generally paclitaxel). Phase 3 randomized trial data provide support for the use of weekly paclitaxel in this setting (compared to the traditional every 3 week schedule) and the addition of bevacizumab as a component of primary management. Recently available data provide increasingly solid support for a role of regional platinum administration in at least a subset of patients with optimal residual advanced ovarian cancer and an important retrospective analysis has suggested a novel biomarker that may predict for the utility (or lack thereof) of this method of drug delivery. PMID- 23726889 TI - Future directions for peptide therapeutics development. AB - The notable expansion of peptide therapeutics development in the late 1990s and the 2000s led to an unprecedented number of marketing approvals in 2012 and has provided a robust pipeline that should deliver numerous approvals during the remainder of the 2010s. To document the current status of the pipeline, we collected data for peptide therapeutics in clinical studies and regulatory review, as well as those recently approved. In this Foundation review, we provide an overview of the pipeline, including therapeutic area and molecular targets, with a focus on glucagon-like peptide 1 receptor agonists. Areas for potential expansion, for example constrained peptides and peptide-drug conjugates, are profiled. PMID- 23726890 TI - Model-based drug discovery: implementation and impact. AB - Model-based drug discovery (MBDDx) aims to build and continuously improve the quantitative understanding of the relation between drug exposure (target engagement) efficacy and safety, to support target validation; to define compound property criteria for lead optimization and safety margins; to set the starting dose; and to predict human dose and scheduling for clinical candidates alone, or in combination with other medicines. AstraZeneca has systematically implemented MBDDx within all drug discovery programs, with a focused investment to build a preclinical modeling and simulation capability and an in vivo information platform and architecture, the implementation, impact and learning of which are discussed here. PMID- 23726891 TI - Six-week Latino family prevention pilot program effectively promotes healthy behaviors and reduces obesogenic behaviors. AB - OBJECTIVE: To test the effectiveness of a 6-week family-based healthy eating pilot program aimed to reduce obesogenic behaviors among Latino parents and children. METHODS: A 6-week healthy eating pilot program focused on dietary changes within Latino families with a 6- to 13-year-old child. A 1-group, pre posttest design with 2-month follow-up examining fruit, vegetable, and sugar sweetened beverage consumption. RESULTS: The program was effective at increasing parent-report of child fruit consumption, (P < .001, effect size = .26), vegetable consumption, (P = .001, effect size = .20), and decreasing sugar sweetened beverage consumption, (P = .002, effect size = .16). CONCLUSIONS AND IMPLICATIONS: This family-based prevention program was effective at improving healthy eating in Latino families, especially for children. The curriculum can be used in future prevention programs for Latino families with a 6- to 13-year-old child. PMID- 23726892 TI - Front-of-package references to fiber on foods in Canadian supermarkets highlight the need for increased nutrition knowledge among consumers. AB - OBJECTIVE: To assess the nature of the guidance on fiber, a nutrient for which many Canadians' intakes are suboptimal, provided by manufacturers' use of front of-package references on food in Canadian supermarkets. DESIGN/SETTING: Survey of all prepackaged food sold in 3 large supermarkets in Toronto. VARIABLES MEASURED: Front-of-package references to fiber and other forms of nutrition-related marketing were recorded from all products. For a subsample of breads, Nutrition Facts table information was also collected. ANALYSIS: Descriptive statistics; t test. RESULTS: Front-of-package references to fiber were found on 6% of all foods, but large proportions of high fiber foods bore no front-of-package references to fiber. Many foods making a reference to fiber (17%) are "foods to limit," according to Canada's Food Guide. Front-of-package references to fiber were declared in at least 30 different ways, and 31% used unregulated language. Among breads, use of regulated language was associated with higher fiber content. CONCLUSIONS AND IMPLICATIONS: Consumers may be faced with challenges in seeking out healthful sources of fiber in the grocery store, given the complexity of existing front-of-package nutrition-related marketing and limited references to fiber in some categories. This work suggests that current nutrition-related marketing cannot function as a substitute for nutrition education. PMID- 23726893 TI - Iodine nutrition status and knowledge, attitude, and behavior in Tehranian women following 2 decades without public education. AB - OBJECTIVE: To evaluate the association of iodine nutrition status and knowledge, attitude, and behavior in Tehranian women after 2 decades without updating public education. DESIGN: Cross-sectional study. SETTING: Eight health care centers from 4 district areas of Tehran. PARTICIPANTS: A total of 383 women aged >= 19 years, randomly selected. MAIN OUTCOME MEASURES: Iodine concentration of 24-hour urine samples, iodine content of household salts, and knowledge, attitude, and practice scores regarding iodine nutrition and iodized salt. ANALYSIS: Multiple logistic regression was used to identify the association of knowledge, attitude, and practice scores with urinary iodine concentration (UIC) < 100 MUg/L. RESULTS: The percentages of Tehranian women with high knowledge, attitude, and practice scores were 26%, 26%, and 14%, respectively. Practice score was significantly different between females with UIC < 100 and > 100 MUg/L (P = .001). Risk of UIC < 100 MUg/L in women of childbearing age (19-45 years) after adjustment of education level, region of residence, and iodine content of salt was significantly associated with intermediate practice score (odds ratio = 2.6; 95% confidence interval, 1.3-13.2). CONCLUSIONS AND IMPLICATIONS: Marginally suboptimal iodine status in women of childbearing age can be attributed to inappropriate practices, but not to knowledge and attitude. PMID- 23726894 TI - Development and reliability testing of a food store observation form. AB - OBJECTIVE: To develop a reliable food store observational data collection instrument to be used for measuring product availability, pricing, and promotion. DESIGN: Observational data collection. SETTING: A total of 120 food stores (26 supermarkets, 34 grocery stores, 54 gas/convenience stores, and 6 mass merchandise stores) in the Chicago metropolitan statistical area. MAIN OUTCOME MEASURES: Inter-rater reliability for product availability, pricing, and promotion measures on a food store observational data collection instrument. ANALYSIS: Cohen's kappa coefficient and proportion of overall agreement for dichotomous variables and intra-class correlation coefficient for continuous variables. RESULTS: Inter-rater reliability, as measured by average kappa coefficient, was 0.84 for food and beverage product availability measures, 0.80 for interior store characteristics, and 0.70 for exterior store characteristics. For continuous measures, average intra-class correlation coefficient was 0.82 for product pricing measures; 0.90 for counts of fresh, frozen, and canned fruit and vegetable options; and 0.85 for counts of advertisements on the store exterior and property. CONCLUSIONS AND IMPLICATIONS: The vast majority of measures demonstrated substantial or almost perfect agreement. Although some items may require revision, results suggest that the instrument may be used to reliably measure the food store environment. PMID- 23726895 TI - Regulation of autophagy by stress-responsive transcription factors. AB - Autophagy is an evolutionarily conserved process that promotes the lysosomal degradation of intracellular components including organelles and portions of the cytoplasm. Besides operating as a quality control mechanism in steady-state conditions, autophagy is upregulated in response to a variety of homeostatic perturbations. In this setting, autophagy mediates prominent cytoprotective effects as it sustains energetic homeostasis and contributes to the removal of cytotoxic stimuli, thus orchestrating a cell-wide, multipronged adaptive response to stress. In line with the critical role of autophagy in health and disease, defects in the autophagic machinery as well as in autophagy-regulatory signaling pathways have been associated with multiple human pathologies, including neurodegenerative disorders, autoimmune conditions and cancer. Accumulating evidence indicates that the autophagic response to stress may proceed in two phases. Thus, a rapid increase in the autophagic flux, which occurs within minutes or hours of exposure to stressful conditions and is entirely mediated by post-translational protein modifications, is generally followed by a delayed and protracted autophagic response that relies on the activation of specific transcriptional programs. Stress-responsive transcription factors including p53, NF-kappaB and STAT3 have recently been shown to play a major role in the regulation of both these phases of the autophagic response. Here, we will discuss the molecular mechanisms whereby autophagy is orchestrated by stress-responsive transcription factors. PMID- 23726896 TI - Autophagy proteins regulate cell engulfment mechanisms that participate in cancer. AB - Recent evidence has uncovered cross-regulation of mechanisms of cell engulfment by proteins of the autophagy pathway, in what is called LC3-Associated Phagocytosis, or LAP. By LAP, lysosome fusion to phagosomes and the degradation of engulfed extracellular cargo are facilitated by autophagy proteins that lipidate LC3 onto phagosome membranes. Here we discuss the contexts where LAP is known to occur by focusing on potential roles in tumorigenesis, including predicted consequences of LAP inhibition. PMID- 23726898 TI - Breaking worse: the emergence of krokodil and excessive injuries among people who inject drugs in Eurasia. AB - BACKGROUND: Krokodil, a homemade injectable opioid, gained its moniker from the excessive harms associated with its use, such as ulcerations, amputations and discolored scale-like skin. While a relatively new phenomenon, krokodil use is prevalent in Russia and the Ukraine, with at least 100,000 and around 20,000 people respectively estimated to have injected the drug in 2011. In this paper we review the existing information on the production and use of krokodil, within the context of the region's recent social history. METHODS: We searched PubMed, Google Advanced Search, Google Scholar, YouTube and the media search engine www.Mool.com for peer reviewed or media reports, grey literature and video reports. Survey data from HIV prevention and treatment NGOs was consulted, as well as regional experts and NGO representatives. FINDINGS: Krokodil production emerged in an atypical homemade drug production and injecting risk environment that predates the fall of communism. Made from codeine, the active ingredient is reportedly desomorphine, but - given the rudimentary 'laboratory' conditions - the solution injected may include various opioid alkaloids as well as high concentrations of processing chemicals, responsible for the localized and systemic injuries reported here. Links between health care and law enforcement, stigma and maltreatment by medical providers are likely to thwart users seeking timely medical help. CONCLUSION: A comprehensive response to the emergence of krokodil and associated harms should focus both on the substance itself and its rudimentary production methods, as well as on its micro and macro risk environments - that of the on-going syndemic of drug injecting, HIV, HCV, TB and STIs in the region and the recent upheaval in local and international heroin supply. The feasibility of harm reduction strategies for people who inject krokodil may depend more on political will than on the practical implementation of interventions. The legal status of opioid substitution treatment in Russia is a point in case. PMID- 23726897 TI - A closer examination of the relationship between children's weight status and the food and physical activity environment. AB - OBJECTIVES: Conflicting findings on associations between food and physical activity (PA) environments and children's weight status demand attention in order to inform effective interventions. We assess relationships between the food and PA environments in inner-city neighborhoods and children's weight status and address sources of conflicting results of prior research. METHODS: Weight status of children ages 3-18 was assessed using parent-measured heights and weights. Data were collected from 702 children living in four low-income cities in New Jersey between 2009 and 2010. Proximity of a child's residence to a variety of food and PA outlets was measured in multiple ways using geo-coded data. Multivariate analyses assessed the association between measures of proximity and weight status. RESULTS: Significant associations were observed between children's weight status and proximity to convenience stores in the 1/4 mile radius (OR = 1.9) and with presence of a large park in the 1/2 mile radius (OR = 0.41). No associations were observed for other types of food and PA outlets. CONCLUSIONS: Specific aspects of the food and PA environments are predictors of overweight and obese status among children, but the relationships and their detection are dependent upon aspects of the geospatial landscape of each community. PMID- 23726900 TI - De jure decriminalisation of cannabis use matters: some recent trends from France. PMID- 23726899 TI - Non-prescribed use of substitution medication among German drug users- prevalence, motives and availability. PMID- 23726901 TI - Mapping the translation initiation landscape of an S. cerevisiae gene using fluorescent proteins. AB - Accurate and efficient gene expression requires that protein translation initiates from mRNA transcripts with high fidelity. At the same time, indiscriminate initiation of translation from multiple ATG start-sites per transcript has been demonstrated, raising fundamental questions regarding the rate and rationale governing alternative translation initiation. We devised a sensitive fluorescent reporter assay for monitoring alternative translation initiation. To demonstrate it, we map the translation initiation landscape of a Saccharomyces cerevisiae gene (RMD1) with a typical ATG sequence context profile. We found that up to 3%-5% of translation initiation events occur from alternative out-of-frame start codons downstream of the main ATG. Initiation from these codons follows the ribosome scanning model: initiation rates from different start sites are determined by ATG order, rather than their context strength. Genomic analysis of S. cerevisiae further supports the scanning model: ATG codons downstream rather than upstream of the main ATG tend to have higher context scores. PMID- 23726903 TI - Use of experimental design methodology for the development of new magnetic siRNA nanovectors (MSN). AB - Short interfering RNAs (siRNAs) can downregulate the synthesis of proteins and thus be used to treat certain diseases where the protein synthesis is upregulated, such as cancer. The challenge is to deliver siRNAs in the target cell as they are rapidly degraded by nucleases and have difficulties to cross the cellular membranes. Superparamagnetic iron oxide nanoparticles (SPIONs) are widely studied as platforms for smart biocompatible nanosystems which can be used for magnetic drug targeting and magnetic resonance imaging. The aim of this work was to combine siRNAs, SPIONs, and chitosan, to develop new magnetic siRNA nanovectors suitable for systemic administration. In a first time, the one factor at a time (OFAT) methodology was used to adjust different formulation parameters and to test the feasibility of such a formulation. In a second time, design of experiment (DOE) methodology was used to analyze the influence of these formulation parameters on the physicochemical characteristics hydrodynamic diameter (DH) and zeta-potential. Finally, four MSNs suitable for systemic administration could be identified using the OFAT method. The DOE method showed a significant effect of CR and [NaNO3] on the DH and a significant effect of MR and [siRNA] on the zeta-potential of the nanocarriers. PMID- 23726902 TI - Prognosis following local recurrence after breast conserving treatment in young women with early breast cancer. AB - BACKGROUND: Few studies have focussed on the prognosis of young women with local recurrence (LR) after breast-conserving therapy and the factors that can be used to predict their prognosis. METHODS: We studied the outcome and related prognostic factors in 124 patients with an isolated local recurrence in the breast following breast-conserving surgery and radiotherapy for early stage breast cancer diagnosed at the age of 40 years or younger. RESULTS: The median follow-up of the patients after diagnosis of LR was 7.0 years. At 10 years from the date of salvage treatment, the overall survival rate was 73% (95% CI, 63-83), the distant recurrence-free survival rate was 61% (95% CI, 53-73), and the local control rate (i.e. survival without subsequent LR or local progression) was 95% (95% CI, 91-99). In the multivariate analysis, the risk of distant metastases also tended to be higher for patients with LR occurring within 5 years after BCT, as compared to patients with LR more than 5 years after BCT (Hazard ratio [HR], 1.89; p = 0.09). A worse distant recurrence-free survival was also observed for patients with a LR measuring more than 2 cm in diameter, compared to those with a LR of 2 cm or smaller (HR, 2.88; p = 0.007), and for patients with a LR causing symptoms or suspicious findings at clinical breast examination, compared to those with a LR detected by breast imaging only (HR 3.70; p = 0.03). CONCLUSIONS: These results suggest that early detection of LR after BCT in young women can improve treatment outcome. PMID- 23726904 TI - Development of oil-in-water microemulsions for the oral delivery of amphotericin B. AB - Amphotericin B (AmB) is a very efficient drug against serious diseases such as leishmaniasis and systemic fungal infections. However, its oral bioavailability is limited due to its poor solubility in water. Nevertheless, it is marketed as high-cost lipid parenteral formulations that may induce serious infusion-related side effects. In this study, oil-in-water (O/W) microemulsions (MEs) were developed and characterized with a view to their use as solubility enhancers and oral delivery systems for AmB. Therefore, different nonionic surfactants from the Tween((r)) and Span((r)) series were tested for their solubilization capacity in combination with several oils. Based on pseudoternary phase diagrams, AmB-loaded MEs with mean droplet sizes about 120 nm were successfully produced. They were able to improve the drug solubility up to 1000-fold. Rheological studies showed the MEs to be low-viscosity formulations with Newtonian behavior. Circular dichroism and absorption spectra revealed that part of the AmB in the MEs was aggregated as an AmB reservoir carrier. Cytotoxicity studies revealed limited toxicity to macrophage-like cells that may allow the formulations to be considered as suitable carriers for AmB. PMID- 23726905 TI - dUev1a modulates TNF-JNK mediated tumor progression and cell death in Drosophila. AB - Loss of cell polarity cooperates with oncogenic Ras to induce JNK-dependent tumor growth and invasion. To identify additional genes that modulate tumor progression, we have performed a genetic screen in Drosophila and found that loss of dUev1a, the ortholog of mammalian Uev1, suppressed lgl(-/-)/Ras(V12) induced JNK-mediated tumor growth and invasion. Furthermore, loss of dUev1a suppressed TNF ortholog Eiger-induced JNK-mediated cell invasion and cell death. Finally, dUev1a cooperated with Bendless to activate JNK signaling through dTRAF2. Together, our data indicate that dUev1a encodes an essential component of the evolutionary conserved TNF-JNK signaling pathway that modulates tumor progression and cell death in metazoan. PMID- 23726906 TI - Intrathecal injection of P/Q type voltage-gated calcium channel antibodies from paraneoplastic cerebellar degeneration cause ataxia in mice. AB - The role of antibodies against the P/Q type voltage-gated calcium channels (VGCC ab) in the pathogenesis of paraneoplastic cerebellar degeneration (PCD) and lung cancer is unclear. We evaluated in mice the effect of intrathecal injection of IgG purified from serum of a patient with both PCD and Lambert-Eaton myasthenic syndrome (LEMS), and from another patient with isolated LEMS. Mice injected with PCD/LEMS IgG developed marked, reversible ataxia compared with those injected with LEMS or control IgG. These findings suggest that P/Q-type VGCC-ab may play a role in the pathogenesis of ataxia in patients with PCD and SCLC. PMID- 23726907 TI - Dexamethasone-FITC staining application for measurement of circadian rhythmicity of glucocorticoid receptor expression in mouse living thymocyte subsets. AB - Glucocorticoids are involved in the regulation of immune homeostasis and thymopoiesis and the integration of the thymus function with the neuroendocrine system. Their regulatory function is closely related to glucocorticoid receptor (GCR) expression. The aim of this study was to develop a method for the measurement of GCR expression in mouse living thymocytes by flow cytometry. Using dexamethasone binding we have shown differences in GCR expression among thymocyte subsets and their dependence on the circadian rhythm. PMID- 23726908 TI - Influence of focal adhesion kinase on the mechanical behavior of cell populations. AB - Mechanical forces play an important role in the organization, growth, maturation, and function of living tissues. At the cellular level, the transmission of forces from outside the cell through cell-matrix and cell-cell contacts are believed to control spreading, motility, maturation as well as intracellular signaling cascades that may change many characteristics in cells. We looked at cell populations of mouse embryonic fibroblasts that are deficient of focal adhesion kinase (FAK) and examined their mechanical profile. We observed that the lack of FAK induces a mesenchymal-epithelial switch including the regulation of adherens junctions via E-cadherin, leading to increased cell-cell-cohesion. Our results show that the absence of FAK influences the macroscopic cell colony spreading in two (2D) and three (3D) dimensions as well as the velocity fields of the tissue, the single cell persistence and correlation length, changing from an independent to a collective mode of migration. Additionally, the single cell size in the sheet decreases significantly. PMID- 23726909 TI - Localization and function of KLF4 in cytoplasm of vascular smooth muscle cell. AB - The Kruppel-like factor 4 is a DNA-binding transcriptional regulator that regulates a diverse array of cellular processes, including development, differentiation, proliferation, and apoptosis. The previous studies about KLF4 functions mainly focused on its role as a transcription factor, its functions in the cytoplasm are still unknown. In this study, we found that PDGF-BB could prompt the translocation of KLF4 to the cytoplasm through CRM1-mediated nuclear export pathway in vascular smooth muscle cells (VSMCs) and increased the interaction of KLF4 with actin in the cytoplasm. Further study showed that both KLF4 phosphorylation and SUMOylation induced by PDGF-BB participates in regulation of cytoskeletal organization by stabilizing the actin cytoskeleton in VSMCs. In conclusion, these results identify that KLF4 participates in the cytoskeletal organization by stabilizing cytoskeleton in the cytoplasm of VSMCs. PMID- 23726910 TI - The parallel reaction monitoring method contributes to a highly sensitive polyubiquitin chain quantification. AB - Ubiquitylation is an essential posttranslational protein modification that is implicated in a diverse array of cellular functions. Although cells contain eight structurally distinct types of polyubiquitin chains, detailed function of several chain types including K29-linked chains has remained largely unclear. Current mass spectrometry (MS)-based quantification methods are highly inefficient for low abundant atypical chains, such as K29- and M1-linked chains, in complex mixtures that typically contain highly abundant proteins. In this study, we applied parallel reaction monitoring (PRM), a quantitative, high-resolution MS method, to quantify ubiquitin chains. The ubiquitin PRM method allows us to quantify 100attomole amounts of all possible ubiquitin chains in cell extracts. Furthermore, we quantified ubiquitylation levels of ubiquitin-proline-beta galactosidase (Ub-P-betagal), a historically known model substrate of the ubiquitin fusion degradation (UFD) pathway. In wild-type cells, Ub-P-betagal is modified with ubiquitin chains consisting of 21% K29- and 78% K48-linked chains. In contrast, K29-linked chains are not detected in UFD4 knockout cells, suggesting that Ufd4 assembles the K29-linked ubiquitin chain(s) on Ub-P-betagal in vivo. Thus, the ubiquitin PRM is a novel, useful, quantitative method for analyzing the highly complicated ubiquitin system. PMID- 23726911 TI - Long noncoding RNAs: new regulators in plant development. AB - Plant long noncoding RNAs (lncRNAs) play important roles in a wide range of biological processes, especially in plant reproductive development and response to stresses. They are transcribed by RNA polymerase II (Pol II), Pol III and Pol V, and exert their functions by a variety of regulation pathways. In this review, we summarized the current knowledge of lncRNAs discoveries in plant, including their identification, functions and regulation pathways as well as production and mediators, with an emphasizing on the novel regulation mechanisms in plant development. PMID- 23726912 TI - Substrate specificity of undecaprenyl diphosphate synthase from the hyperthermophilic archaeon Aeropyrum pernix. AB - Cis-prenyltransferase from a hyperthermophilic archaeon Aeropyrum pernix was expressed in Escherichia coli and purified for characterization. Properties such as substrate specificity, product chain-length, thermal stability and cofactor requirement were investigated using the recombinant enzyme. In particular, the substrate specificity of the enzyme attracts interest because only dimethylallyl diphosphate and geranylfarnesyl diphosphate, both of which are unusual substrates for known cis-prenyltransferases, are likely available as an allylic primer substrate in A. pernix. From the enzymatic study, the archaeal enzyme was shown to be undecaprenyl diphosphate synthase that has anomalous substrate specificity, which results in a preference for geranylfarnesyl diphosphate. This means that the product of the enzyme, which is probably used as the precursor of the glycosyl carrier lipid, would have an undiscovered structure. PMID- 23726913 TI - Sialic acid-dependent attachment of mucins from three mouse strains to Entamoeba histolytica. AB - Mouse strain-specific differences in the carbohydrate composition of intestinal mucins were hypothesized to account for strain-dependent susceptibility to Entamoeba histolytica. To test this hypothesis, intestinal mucins from susceptible and resistant inbred strains of mice were analyzed for their O-glycan content and for their ability to inhibit amoebic adherence to (GalNAc)12-27-HSA neo-glycoproteins. The results showed that the colorectal mucin O-glycan of susceptible CBA mice was lower in sialic acid content than that of resistant C57BL/6 and BALB/c mice. Mucins from CBA mice were more potent inhibitors of E. histolytica adherence to neo-glycoproteins than were mucins from C57BL/6 or BALB/c mice. Consistent with the role of terminal Gal/GalNAc as a receptor for amoebic adherence, sialidase treatment of C57BL/6 and BALB/c colorectal mucins increased their ability to inhibit E. histolytica adherence to the neo glycoproteins. These results provide evidence of mouse strain-specific differences in the sialic acids content of mucin O-glycans. These dissimilarities likely contribute to the differential susceptibility of the three mouse strains to E. histolytica infection. PMID- 23726914 TI - Synergistically killing activity of aspirin and histone deacetylase inhibitor valproic acid (VPA) on hepatocellular cancer cells. AB - Aspirin and valproic acid (VPA) have been extensively studied for inducing various malignancies growth inhibition respectively, despite their severe side effects. Here, we developed a novel combination by aspirin and VPA on hepatocellular cancer cells (HCCs). The viability of HCC lines were analyzed by MTT assay, apoptotic analysis of HepG2 and SMMC-7721 cell was performed. Real time-PCR and Western blotting were performed to determine the expression of apoptosis related genes and proteins such as Survivin, Bcl-2/Bax, Cyclin D1 and p15. Moreover, orthotopic xenograft tumors were challenged in nude mice to establish murine model, and then therapeutic effect was analyzed after drug combination therapy. The viability of HCC lines' significantly decreased after drug combination treatment, and cancer cell apoptosis in combination group increasingly induced compared with single drug use. Therapeutic effect was significantly enhanced by combination therapy in tumor volume and tumor weight decrease. From the data shown here, aspirin and VPA combination have a synergistic killing effect on hepatocellular cancers cells proliferation and apoptosis. PMID- 23726915 TI - Intracellular NAADP increase induced by extracellular NAADP via the P2Y11-like receptor. AB - The aim of the study was to identify a signalling pathway allowing NAADP-induced intracellular NAADP increase and involving the P2Y11-like receptor. P2Y11-like and beta-adrenergic receptors may play important regulatory roles within the cardiovascular system. Both receptors have been shown to be involved in triggering myocardial preconditioning. Using a Langendorff model we report a positive inotropic response induced by extracellular NAADP via P2Y11-like receptor stimulation. In cardiomyocyte cultures, P2Y11-like receptor stimulation by extracellular NAADP ([NAADP]e) increased intracellular cADP-ribose and NAADP concentration as evidenced by direct measurements. NF546, a new selective P2Y11 receptor agonist, increased intracellular cAMP, cADP-ribose and NAADP concentration confirming the involvement of the P2Y11-like receptor in this signalling pathway. NF157, a P2Y11 receptor antagonist, suppressed the increase in intracellular cADPr, NAADP and NAAD induced by either [NAADP]e or NF546. The response profile for intracellular cADP-ribose and NAADP concentration following P2Y11-like stimulation with NF546 was similar to reported data relating beta adrenergic stimulation with isoprenaline. This response represents the signature of the Gs/ADP-ribosyl cyclase activity. Moreover, this study provides a signalling pathway: intracellular NAADP increase induced by extracellular NAADP via metabotropic activity of P2Y11-like receptor. This pathway implying P2Y11 like could take part in the intracellular calcium rise reported for extracellular NAADP. PMID- 23726916 TI - Compound K is able to ameliorate the impaired cognitive function and hippocampal neurogenesis following chemotherapy treatment. AB - Chemotherapy frequently results in neurocognitive deficits that include impaired learning and memory. Thus, it is important to prevent or ameliorate the persistence of cognitive impairment. Compound K was employed to examine the ameliorating effect on chronic treatment with cyclophosphamide. Eight week-old ICR mice were given 80 mg/kg cyclophosphamide, cyclophosphamide combined with compound K (2.5, 5 and 10 mg/kg) or saline injections once per week for 4 weeks. Passive avoidance test and Y maze were used to evaluate memory and learning ability. Immunohistochemical staining for progenitor cell and immature neurons was used to assess changes in neurogenesis. Compound K (10 mg/kg) is able to ameliorate the decrease of neurogenesis in the hippocampus caused by cyclophosphamide. These results suggest that compound K might be a potential strategy to ameliorate or repair the disrupted hippocampal neurogenesis induced by the side effect of chemotherapy agent. PMID- 23726917 TI - Distinct physiological roles for the two L-asparaginase isozymes of Escherichia coli. AB - Escherichia coli expresses two L-asparaginase (EC 3.5.1.1) isozymes: L asparaginse I, which is a low affinity, cytoplasmic enzyme that is expressed constitutively, and L-asparaginase II, a high affinity periplasmic enzyme that is under complex co-transcriptional regulation by both Fnr and Crp. The distinct localisation and regulation of these enzymes suggest different roles. To define these roles, a set of isogenic mutants was constructed that lacked either or both enzymes. Evidence is provided that L-asparaginase II, in contrast to L asparaginase I, can be used in the provision of an anaerobic electron acceptor when using a non-fermentable carbon source in the presence of excess nitrogen. PMID- 23726918 TI - Differential anti-tumor activities of curcumin against Ras- and Src-activated human adenocarcinoma cells. AB - Although curcumin has been studied as a potential anticancer drug targeting multiple signaling molecules, the role of oncogenic Src and Ras in curcumin sensitivity remains unknown. Using HAG-1 human adenocarcinoma cells transfected with either activated Src or Ras, we investigated here the functional role of these oncogenes in curcumin sensitivity. Activation of either Src or Ras did not confer resistance to curcumin, compared to vehicle-transfected cells. Curcumin enhanced Erk1/2 predominantly in Ras-activated cells, but inhibited Akt and its downstream molecules (mTOR and S6K1) regardless of these oncogene activations. The sub-G0/G1 apoptotic populations were substantially increased with demonstrable cleavage of PARP, but this increase was most prominent in Src activated cells. Suppression of Bcl-xL level and enhanced expression of Bax were demonstrated in Src-activated, but not Ras-activated cells. By contrast, drastic increases of G2/M cell populations were seen in Ras-activated cells rather than Src-activated cells, suggesting a potential role of Ras/Erk1/2 activation in curcumin-induced G2/M arrest. These data indicate that curcumin-induced growth inhibition would be mediated mainly by G2/M arrest in Ras-driven cells but by apoptosis induction in Src-driven cells, providing a mechanistic rationale for the potential use of curcumin in the treatment of human cancers with activated Src or Ras. PMID- 23726919 TI - Human UBL5 protein interacts with coilin and meets the Cajal bodies. AB - UBL5 protein, a structural homologue of ubiquitin, was shown to be involved in pre-mRNA splicing and transcription regulation in yeast and Caenorhabditis elegans, respectively. However, role of the UBL5 human orthologue is still elusive. In our study, we observed that endogenous human UBL5 that was localized in the nucleus, partially associates with Cajal bodies (CBs), nuclear domains where spliceosomal components are assembled. Simultaneous expression of exogenous UBL5 and coilin resulted in their nuclear colocalization in HeLa cells. The ability of UBL5 to interact with coilin was proved by GST pull-down assay using coilin that was either in vitro translated or extracted from HEK293T cells. Further, our results showed that the UBL5-coilin interaction was not influenced by coilin phosphorylation. These results suggest that UBL5 could be targeted to CBs via its interaction with coilin. Relation between human UBL5 protein and CBs is in the agreement with current observations about yeast orthologue Hub1 playing important role in alternative splicing. PMID- 23726920 TI - Aegyptin inhibits collagen-induced coagulation activation in vitro and thromboembolism in vivo. AB - Aegyptin is a mosquito salivary gland protein and potent inhibitor of platelet aggregation. Aegyptin binds to the von Willebrand factor-binding site on collagen and prevents its interaction with platelets. Because collagen also induces plasma clotting by activation of factor XII, we evaluated the effects of aegyptin on collagen-induced coagulation activation and how it interferes with thrombosis in three different in vivo models. Our results demonstrate that aegyptin abolishes collagen-induced clot formation and thrombin generation in platelet-free plasma. Aegyptin has no antithrombotic activity in the arteriovenous shunt model (collagen-independent) but it prevents laser-induced collagen-mediated thrombus formation in rats. Furthermore, aegyptin protects mice from collagen and epinephrine-induced thromboembolism. Therefore, aegyptin has a dual antithrombotic mechanism: inhibition of platelet-collagen interaction and collagen's pro-coagulant activity. This is the first description of a collagen binding protein that also inhibits collagen-mediated coagulant activity. PMID- 23726921 TI - Microscale surface friction of articular cartilage in early osteoarthritis. AB - Articular cartilage forms the articulating surface of long bones and facilitates energy dissipation upon loading as well as joint lubrication and wear resistance. In normal cartilage, boundary lubrication between thin films at the cartilage surface reduces friction in the absence of interstitial fluid pressurization and fluid film lubrication by synovial fluid. Inadequate boundary lubrication is associated with degenerative joint conditions such as osteoarthritis (OA), but relations between OA and surface friction, lubrication and wear in boundary lubrication are not well defined. The purpose of the present study was to measure microscale boundary mode friction of the articular cartilage surface in an in vivo experimental model to better understand changes in cartilage surface friction in early OA. Cartilage friction was measured on the articular surface by atomic force microscopy (AFM) under applied loads ranging from 0.5 to 5 MUN. Microscale AFM friction analyses revealed depth dependent changes within the top most few microns of the cartilage surface in this model of early OA. A significant increase of nearly 50% was observed in the mean engineering friction coefficient for OA cartilage at the 0.5 MUN load level; no significant differences in friction coefficients were found under higher applied loads. Changes in cartilage surface morphology observed by scanning electron microscopy included cracking and roughening of the surface indicative of disruption and wear accompanied by an apparent disintegration of the thin surface lamina from the underlying matrix. Immunohistochemical staining of lubricin - an important cartilage surface boundary lubricant - did not reveal differences in spatial distribution near the cartilage surface in OA compared to controls. The increase in friction at the 0.5 MUN force level is interpreted to reflect changes in the interfacial mechanics of the thin surface lamina of articular cartilage: increased friction implies reduced lubrication efficiency and a higher potential for cartilage surface wear in OA. The effects of mechanical or biochemical changes or loss of the thin surface lamina on the remaining tissue with respect to OA progression is unknown and requires further study, but preservation of the surface lamina seems an important early target for the maintenance of cartilage health and prevention of OA. PMID- 23726922 TI - Nanomechanical properties of hybrid coatings for bone tissue engineering. AB - Bone tissue engineering has emerged as a promising alternative approach in the treatment of bone injuries and defects arising from malformation, osteoporosis, and tumours. In this approach, a temporary scaffold possessing mechanical properties resembling those of natural bone is needed to serve as a substrate enhancing cell adhesion and growth, and a physical support to guide the formation of the new bone. In this regard, the scaffold should be biocompatible, biodegradable, malleable and mechanically strong. Herein, we investigate the mechanical properties of three coatings of different chemical compositions onto silanized glass substrates; a hybrid material consisting of methacryloxypropyl trimethoxysilane and zirconium propoxide, a type of a hybrid organic-inorganic material of the above containing also 50 mol% 2-(dimethylamino)ethyl methacrylate (DMAEMA) moieties and a pure organic material, based on PDMAEMA. This study investigates the variations in the measured hardness and reduced modulus values, wear resistance and plastic behaviour before and after samples' submersion in cell culture medium. Through this analysis we aim to explain how hybrid materials behave under applied stresses (pile-up formations), how water uptake changes this behaviour, and estimate how these materials will react while interaction with cells in tissue engineering applications. Finally, we report on the pre osteoblastic cell adhesion and proliferation on three-dimensional structures of the hybrid materials within the first hour and up to 7 days in culture. It was evident that hybrid structure, consisting of 50 mol% organic-inorganic material, reveals good mechanical behaviour, wear resistance and cell adhesion and proliferation, suggesting a possible candidate in bone tissue engineering. PMID- 23726923 TI - Nanocrystalline forsterite for biomedical applications: synthesis, microstructure and mechanical properties. AB - Forsterite (Mg2SiO4) because of its exceptionally high fracture toughness which is close to that of cortical bones has been nominated as a possible successor to calcium phosphate bioceramics. Recent in vitro studies also suggest that forsterite possesses good bioactivity and promotes osteoblast proliferation as well as adhesion. However studies on preparation and sinterability of nanocrystalline forsterite remain scarce. In this work, we use a solid-state reaction with magnesium oxide (MgO) and talc (Mg3Si4(OH)2) as the starting precursors to synthesize forsterite. A systematic investigation was carried out to elucidate the effect of preparatory procedures including heat treatment, mixing methods and sintering temperature on development of microstructures as well as the mechanical properties of the sintered forsterite body. PMID- 23726924 TI - Analysis of the effect of a compliant layer on indentation of an elastic material. AB - Considering the possible effect of the thin protein-rich sheath on the indentation deformation of an enamel rod, we analyzed the indentation response of an elastic cylinder with a compliant layer between the cylinder and rigid surrounding material. For the film thickness much less than the characteristic dimension of the cylinder, closed-form solutions were obtained between the indentation load and the indentation depth, which depends on the film thickness and the ratio of the Young's modulus of the cylinder to the Young's modulus of the film. The finite element results supported the relationships for the ratio of the film thickness to the characteristic dimension of the cylinder less than or equal to 1/3. The indentation load required to produce the same indentation displacement decreases with increasing the ratio of the Young's modulus of the cylinder to the Young's modulus of the film for compressible-elastic films. Incompressible-elastic films have no significant effect on the indentation response of the elastic cylinder. PMID- 23726925 TI - Mechanical and tribological behavior of silicon nitride and silicon carbon nitride coatings for total joint replacements. AB - Total joint replacements currently have relatively high success rates at 10-15 years; however, increasing ageing and an active population places higher demands on the longevity of the implants. A wear resistant configuration with wear particles that resorb in vivo can potentially increase the lifetime of an implant. In this study, silicon nitride (SixNy) and silicon carbon nitride (SixCyNz) coatings were produced for this purpose using reactive high power impulse magnetron sputtering (HiPIMS). The coatings are intended for hard bearing surfaces on implants. Hardness and elastic modulus of the coatings were evaluated by nanoindentation, cohesive, and adhesive properties were assessed by micro scratching and the tribological performance was investigated in a ball-on-disc setup run in a serum solution. The majority of the SixNy coatings showed a hardness close to that of sintered silicon nitride (~18 GPa), and an elastic modulus close to that of cobalt chromium (~200 GPa). Furthermore, all except one of the SixNy coatings offered a wear resistance similar to that of bulk silicon nitride and significantly higher than that of cobalt chromium. In contrast, the SixCyNz coatings did not show as high level of wear resistance. PMID- 23726926 TI - Tissue properties of the human vertebral body sub-structures evaluated by means of microindentation. AB - PURPOSE: The better understanding of vertebral mechanical properties can help to improve the diagnosis of vertebral fractures. As the bone mechanical competence depends not only from bone mineral density (BMD) but also from bone quality, the goal of the present study was to investigate the anisotropic indentation moduli of the different sub-structures of the healthy human vertebral body and spondylophytes by means of microindentation. METHODS: Six human vertebral bodies and five osteophytes (spondylophytes) were collected and prepared for microindentation test. In particular, indentations were performed on bone structural units of the cortical shell (along axial, circumferential and radial directions), of the endplates (along the anterio-posterior and lateral directions), of the trabecular bone (along the axial and transverse directions) and of the spondylophytes (along the axial direction). A total of 3164 indentations down to a maximum depth of 2.5 um were performed and the indentation modulus was computed for each measurement. RESULTS: The cortical shell showed an orthotropic behavior (indentation modulus, Ei, higher if measured along the axial direction, 14.6+/-2.8 GPa, compared to the circumferential one, 12.3+/-3.5 GPa, and radial one, 8.3+/-3.1 GPa). Moreover, the cortical endplates (similar Ei along the antero-posterior, 13.0+/-2.9 GPa, and along the lateral, 12.0+/-3.0 GPa, directions) and the trabecular bone (Ei= 13.7+/-3.4 GPa along the axial direction versus Ei=10.9+/-3.7 GPa along the transverse one) showed transversal isotropy behavior. Furthermore, the spondylophytes showed the lower mechanical properties measured along the axial direction (Ei=10.5+/-3.3 GPa). CONCLUSIONS: The original results presented in this study improve our understanding of vertebral biomechanics and can be helpful to define the material properties of the vertebral substructures in computational models such as FE analysis. PMID- 23726927 TI - Cytokeratin-positive epithelioid gastrointestinal stromal tumor of the stomach - a comment on "gastric undifferentiated carcinoma with diffuse c-kit overexpression and focal neuroendocrine differentiation". PMID- 23726928 TI - Epstein-Barr virus (EBV) positive diffuse large B cell lymphoma of the elderly experience of a single center from Turkey. AB - In the 2008 WHO lymphoma classification, 'EBV-positive diffuse large B cell lymphoma (DLBCL) of the elderly is included as a new provisional entity. We aimed to evaluate the morphological, immunophenotypic, and clinical characteristics of the cases diagnosed as 'EBV-positive DLBCL of the elderly' in our center and compared them with the 'EBV-negative DLBCL' patients older than 50 years of age. EBV status was detected by Epstein-Barr early RNA (EBER) in situ hybridization analysis. By immunohistochemistry, a panel of antibodies for CD10, Bcl-2, Bcl-6, IRF4/MUM1, CD30, and Ki67 was performed. Out of 149 DLBCL patients older than 50 years, without any known history of immunodeficiency or prior lymphoma, eight patients who fulfill the criteria were re-evaluated. Five patients were male and three were female, with a median age of 67.6 years. Four patients presented with nodal involvement; others presented with bone and soft tissue, bone marrow, and spleen infiltrations. Five cases revealed predominantly monomorphic morphology, one also contained focal areas consistent with polymorphous subtype; and three patients revealed a polymorphous infiltrate. When classified according to 'Hans criteria', five were non-GCB, and three were of the GCB cell phenotype. All cases with polymorphous morphology were revealed to be of the non-GCB cell phenotype, and all expressed IRF4/MUM1. Two patients died with disease, four patients are alive and in complete remission following R-CHOP therapy, and two patients have just recently been diagnosed. When compared with the EBV-negative group, there are no reliable morphological and immunohistochemical features indicating EBV positivity. Therefore, EBER in situ hybridization analysis is necessary to identify 'EBV-positive DLBCL of the elderly'. Further studies are needed to fully understand the details of this disease, which can lead to new treatment modalities. PMID- 23726929 TI - Breast cancer characteristics-comparison of preoperative and postoperative values. AB - Breast cancer characteristics obtained at the time of diagnosis are important for setting the basic strategy of the treatment. Reliability of preoperative investigation differs for various features of the disease. The aim of this study was to ascertain the agreements and differences between preoperative and postoperative values. This retrospective study analyzed the results of 617 women with primary surgery of the breast and axilla. Cohen's kappa coefficient has been employed to measure the degree of agreement between preoperative and postoperative values. Substantial or "almost perfect" agreement has been documented for the histological type of the tumors, their histopathological grade, proliferation index Ki67, as well as for estrogen, progesterone, and HER 2/neu receptors. Substantial differences exist between preoperative and postoperative diagnoses of invasiveness of the tumor, determination of the size of the tumors, and the number of tumor foci. Preoperative imaging and clinical examination of lymph nodes exhibited unacceptably high false negative rates. Heterogeneity of breast cancer cell population, methodology of histology examinations, and insufficient imaging of lymph nodes are the major limitations precluding satisfactory accuracy of preoperative diagnosis. Preoperatively diagnosed in situ carcinomas, as well as multifocal lesions, were the most often sources of diagnostic failures. PMID- 23726930 TI - [Antisynthetase syndrome and lung carcinoma: a fortuitous association?]. AB - INTRODUCTION: Dermatomyositis and polymyositis are sometimes associated with neoplasia. Conversely, a link between antisynthetase syndrome and neoplasia has not been clearly demonstrated. CASE REPORT: We report a 54-year-old smoker male patient who presented with an antisynthetase syndrome with anti-Jo1 and anti-Ro 52 antibodies. An adenocarcinoma of the lung was diagnosed at the same time. CONCLUSION: Two recent studies showed that patients with an antisynthetase syndrome associated with anti-Jo1 antibodies have more severe prognosis than antisynthetase syndrome associated with other antibodies (i.e. PL7/PL12). The risk of cancer occurrence seems to be increased when the anti-Jo1 antisynthetase syndrome is associated with anti-Ro-52 antibodies. To date, there is no demonstrated association between antisynthetase syndrome and neoplasia. PMID- 23726931 TI - Population changes across the Neanderthal-to-modern-human transition in western France: a reply to Dogandzic and McPherron (2013). PMID- 23726932 TI - Pedogenic carbonate stable isotopic evidence for wooded habitat preference of early Pleistocene tool makers in the Turkana Basin. AB - The origin and evolution of early Pleistocene hominin lithic technologies in Africa occurred within the context of savanna grassland ecosystems. The Nachukui Formation of the Turkana Basin in northern Kenya, containing Oldowan and Acheulean tool assemblages and fossil evidence for early members of Homo and Paranthropus, provides an extensive spatial and temporal paleosol record of early Pleistocene savanna flora. Here we present new carbon isotopic (delta(13)CVPDB) values of pedogenic carbonates (68 nodules, 193 analyses) from the Nachukui Formation in order to characterize past vegetation structure and change through time. We compared three members (Kalochoro, Kaitio, and Natoo) at five locations spanning 2.4-1.4Ma and sampled in proximity to hominin archaeological and paleontological sites. Our results indicate diverse habitats showing a mosaic pattern of vegetation cover at each location yet demonstrate grassland expansion through time influenced by paleogeography. Kalochoro floodplains occurred adjacent to large river systems, and paleosols show evidence of C3 woodlands averaging 46-50% woody cover. Kaitio habitats were located along smaller rivers and lake margins. Paleosols yielded evidence for reduced portions of woody vegetation averaging 34-37% woody cover. Natoo environments had the highest percentage of grasslands averaging 21% woody cover near a diminishing Lake Turkana precursor. We also compared paleosol delta(13)CVPDB values of lithic archaeological sites with paleosol delta(13)CVPDB values of all environments available to hominins at 2.4-1.4Ma in the Nachukui and Koobi Fora Formations. Grassy environments became more widespread during this interval; woody canopy cover mean percentages steadily decreased by 12%. However, significantly more wooded savanna habitats were present in the vicinity of lithic archaeological sites and did not mirror the basin-wide trend of grassland spread. Hominin lithic archaeological sites consistently demonstrated woody cover circa 40% throughout our study interval and were 4-12% more woody than coeval basin environs. We propose that Turkana Basin early tool makers may have preferred a more wooded portion of the savanna ecosystem to reduce heat stress and to gain differential access to potable water, raw materials, animal carcasses, and edible plants. PMID- 23726933 TI - Management of acute whiplash: a randomized controlled trial of multidisciplinary stratified treatments. AB - Acute whiplash is a heterogeneous disorder that becomes persistent in 40% to 60% of cases. Estimates of recovery have not changed in recent decades. This randomized, single-blind, controlled trial tested whether multidisciplinary individualized treatments for patients with acute whiplash (<4 weeks postinjury) could reduce the incidence of chronicity at 6 mo by 50% compared to usual care. Participants (n=101) were recruited from accident and emergency centres and the community. It was hypothesized that better recovery rates were achievable if the heterogeneity was recognised and patients received individualised interventions. Patients randomized to pragmatic intervention (n=49) could receive pharmaceutical management (ranging from simple medications to opioid analgesia), multimodal physiotherapy and psychology for post-traumatic stress according to their presentations. The treatment period was 10 wks with follow-up at 11 weeks and 6 and 12-months. The primary outcome was neck pain and disability (Neck Disability Index (NDI)). Analysis revealed no significant differences in frequency of recovery (NDI <= 8%) between pragmatic and usual care groups at 6 months (OR 95%, CI=0.55, 0.23-1.29), P=0.163) or 12 mo (OR 95%, CI=0.65, 0.28-1.47, P=0.297). There was no improvement in current nonrecovery rates at 6 mo (63.6%, pragmatic care; 48.8%, usual care), indicating no advantage of the early multiprofessional intervention. Baseline levels of pain and disability had a significant bearing on recovery both at 6 and 12 mo in both groups, suggesting that future research focus on finding early effective pain management, particularly for the subgroup of patients with initial high levels of pain and disability, towards improving recovery rates. PMID- 23726934 TI - Perceptual bias in pain: a switch looks closer when it will relieve pain than when it won't. AB - Pain is fundamental to survival, as are our perceptions of the environment. It is often assumed that we see our world as a read-out of the sensory information that we receive; yet despite the same physical makeup of our surroundings, individuals perceive differently. What if we "see" our world differently when we experience pain? Until now, the causal effect of experimental pain on the perception of an external stimulus has not been investigated. Eighteen (11 female) healthy volunteers participated in this randomised repeated-measures experiment, in which participants estimated the distance to a switch placed on the table in front of them. We varied whether or not the switch would instantly stop a stimulus, set to the participant's pain threshold, being delivered to their hand, and whether or not they were required to reach for the switch. The critical result was a strong interaction between reaching and pain [F(1,181)=4.8, P=0.03], such that when participants experienced pain and were required to reach for a switch that would turn off the experimental stimulus, they judged the distance to that switch to be closer, as compared to the other 3 conditions (mean of the true distance 92.6%, 95% confidence interval 89.7%-95.6%). The judged distance was smaller than estimates in the other 3 conditions (mean+/-SD difference >5.7%+/-2.1%, t(181) >3.5, P<0.01 for all 3 comparisons). We conclude that the perception of distance to an object is modulated by the behavioural relevance of the object to ongoing pain. PMID- 23726935 TI - Conceptual overlap of psychological constructs in low back pain. AB - The biopsychosocial model is increasingly accepted in low back pain (LBP) research and clinical practice. In order to assess the role of psychological factors in the development and persistence of pain, a wide array of measures has been developed. Yet there is likely to be considerable conceptual overlap between such measures, and consequently, a lack of clarity about the importance of psychological factors. The aims of this study were to investigate the extent of any such overlap. An observational cohort study of 1591 LBP patients consulting in primary care completed data on a range of psychological instruments. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were carried out at the subscale level (n=20) to investigate factor structure. The influences of the derived factors on clinical outcomes (pain intensity and self reported disability) were then tested using linear regression. EFA yielded 4 factors, termed "Pain-related distress," "Cognitive coping," "Causal beliefs," and "Perceptions of the future," which accounted for 65.5% of the variance. CFA confirmed the validity of these factors models. The pain-related distress factor was found to have the strongest association to LBP patients' outcomes, accounting for 34.6% of the variance in pain intensity, and 51.1% of the variance in disability. Results confirmed that considerable overlap exists in psychological measures commonly used in LBP research. Most measures tap into patients' emotional distress. These findings help us to understand how psychological constructs relate together; implications for future research and clinical practice are discussed. PMID- 23726936 TI - Pain treatment for older adults during prehospital emergency care: variations by patient gender and pain severity. AB - Older adults are less likely than younger adults to receive analgesic treatment during emergency department visits. Whether older adults are less likely to receive analgesics during protocolized prehospital care is unknown. We analyzed all ambulance transports in 2011 in the state of North Carolina and compared the administration of any analgesic or an opioid among older adults (aged 65 and older) versus adults aged 18 to 64. Complete data were available for 407,763 transports. Older men were less likely than younger men to receive an analgesic or an opioid regardless of pain severity. Among women with mild or moderate pain, older women were less likely than younger women to receive either form of pain treatment, but among women with more severe pain (pain score 8 or more), older women were more likely than younger women to receive pain treatment. Further, among women with mild or moderate pain, the oldest patients (aged 85 and older) were the least likely to receive any analgesic or an opioid, but among women with severe pain the oldest patients were the most likely to receive treatment. Further research is needed to assess the generalizability of this interaction between age, gender, and pain severity on pain treatment. PERSPECTIVE: During prehospital care in North Carolina in 2011, older adults were generally less likely to receive pain treatment. However, older women with severe pain were more likely to receive treatment than younger women with severe pain. These results suggest an interaction between age, gender, and pain severity on pain treatment. PMID- 23726938 TI - Haemoglobin genotypes in cod (Gadus morhua L): their geographic distribution and physiological significance. AB - Haemoglobin polymorphism in cod (Gadus morhua L) has been investigated throughout the last 50years. Field studies have shed light on the geographic distribution of the two common alleles (HbI(1) and HbI(2)), and laboratory studies have shown effects of genotype on physiological traits such as growth, reproduction and hypoxia tolerance. The geographic distribution of alleles shows a correlation with temperature, with increasing frequency of HbI(1) in warmer areas. This is likely due to temperature-related differences in oxygen affinity of the three genotypes. We provide a general ecological introduction to cod haemoglobin polymorphism and a detailed discussion of physiological studies, particularly laboratory growth studies. Although differences in oxygen uptake are almost certainly a contributory mechanism to observed differences in traits such as growth rate, many other environmental, behavioural and social factors may also contribute, making it difficult to quantify the effect of HbI either experimentally or in the field. PMID- 23726937 TI - Induction of monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 in primary sensory neurons contributes to paclitaxel-induced peripheral neuropathy. AB - The use of paclitaxel (Taxol), a microtubule stabilizer, for cancer treatment is often limited by its associated peripheral neuropathy (chemotherapy-induced peripheral neuropathy [CIPN]), which predominantly results in sensory dysfunction, including chronic pain. Here we show that paclitaxel CIPN was associated with induction of chemokine monocyte chemoattractant protein-1 (MCP-1) and its cognate receptor CCR2 in primary sensory neurons of dorsal root ganglia. Immunostaining revealed that MCP-1 was mainly expressed in small nociceptive neurons whereas CCR2 was expressed in large and medium-sized myelinated neurons. Direct application of MCP-1 consistently induced intracellular calcium increases in dorsal root ganglia large and medium-sized neurons but not in small neurons mainly dissociated from paclitaxel-treated but not vehicle-treated animals. Paclitaxel also induced increased expression of MCP-1 in spinal astrocytes, but no CCR2 signal was detected in the spinal cord. Local blockade of MCP-1/CCR2 signaling by anti-MCP-1 antibody or CCR2 antisense oligodeoxynucleotides significantly attenuated paclitaxel CIPN phenotypes including mechanical hypersensitivity and loss of intraepidermal nerve fibers in hindpaw glabrous skin. These results suggest that activation of paracrine MCP-1/CCR2 signaling between dorsal root ganglion neurons plays a critical role in the development of paclitaxel CIPN, and targeting MCP-1/CCR2 signaling could be a novel therapeutic approach. PERSPECTIVE: CIPN is a severe side effect accompanying paclitaxel chemotherapy and lacks effective treatments. The current study suggests that blocking MCP-1/CCR2 signaling could be a new therapeutic strategy to prevent or reverse paclitaxel CIPN. This preclinical evidence encourages future clinical evaluation of this strategy. PMID- 23726939 TI - Linking sex differences in corticosterone with individual reproductive behaviour and hatch success in two species of uniparental shorebirds. AB - In birds, corticosterone (CORT) appears to facilitate reproductive activity because baseline and stress-induced CORT levels are elevated in breeding individuals compared with other times of the year. In particular, CORT is lower in the sex providing most of the parental care (i.e., incubation), which could be an important adaptation to tolerate stressors that result in abandoning reproduction. Therefore, one explanation for sex differences in CORT is that lower levels are favoured during the incubation/parental phase of reproduction. Using two species of uniparental shorebird - polyandrous red phalaropes (Phalaropus fulicarius) and polygynous white-rumped sandpipers (Calidris fuscicollis) - we predicted that the incubating sex would have lower baseline and stress-induced CORT, and incubating individuals with lower CORT would more effectively defend nests against a simulated intrusion, would return more quickly afterwards, and would ultimately have higher hatch success. We found that phalaropes followed the predicted pattern: incubating individuals (males) had lower baseline and stress-induced CORT than females but for baseline CORT these differences existed prior to males commencing incubation. Incubating male phalaropes with lower baseline and stress-induced CORT returned to incubate more quickly after a disturbance and there was non-significant tendency for baseline CORT to be lower in successful nests. In sandpipers, we observed no sex differences and no significant relationships between individual CORT levels and nest defence behaviours or hatch success. Our results demonstrate that in phalaropes at least, selection favours lower baseline and stress-induced CORT during the nesting period. These results can explain sex differences in stress induced levels of CORT, however sex differences in baseline CORT were present prior to incubation. PMID- 23726940 TI - How ubiquitous is endothelial NOS? AB - The ability to regulate vascular tone is an essential cardiovascular control mechanism, with nitric oxide (NO) assumed to be a ubiquitous smooth muscle relaxant. However, the literature contains reports of vasoconstrictor, vasodilator and no response to nitroergic stimulation in non-mammalian vertebrates. We examined functional (branchial artery myography), structural (immunohistochemistry of skeletal muscle), proteomic (Western analysis) and genomic (RT-PCR, sequence orthologues, syntenic analysis) evidence for endothelial NO synthase (NOS3) in model and non-model fish species. A variety of nitrodilators failed to elicit any changes in vascular tone, although a dilatation to exogenous cyclic GMP was noted. NOS3 antibody staining does not localise to endothelial markers in cryosections, and gives rise to non-specific staining of Western blots. Abundant NOS2 mRNA was found in all species but NOS3 was not found in any fish, while putative orthologues are not flanked by similar genes to NOS3 in humans. We conclude that NOS3 does not exist in fish, and that previous reports of its presence may reflect use of antibodies raised against mammalian epitopes. PMID- 23726942 TI - Global parameter estimation for thermodynamic models of transcriptional regulation. AB - Deciphering the mechanisms involved in gene regulation holds the key to understanding the control of central biological processes, including human disease, population variation, and the evolution of morphological innovations. New experimental techniques including whole genome sequencing and transcriptome analysis have enabled comprehensive modeling approaches to study gene regulation. In many cases, it is useful to be able to assign biological significance to the inferred model parameters, but such interpretation should take into account features that affect these parameters, including model construction and sensitivity, the type of fitness calculation, and the effectiveness of parameter estimation. This last point is often neglected, as estimation methods are often selected for historical reasons or for computational ease. Here, we compare the performance of two parameter estimation techniques broadly representative of local and global approaches, namely, a quasi-Newton/Nelder-Mead simplex (QN/NMS) method and a covariance matrix adaptation-evolutionary strategy (CMA-ES) method. The estimation methods were applied to a set of thermodynamic models of gene transcription applied to regulatory elements active in the Drosophila embryo. Measuring overall fit, the global CMA-ES method performed significantly better than the local QN/NMS method on high quality data sets, but this difference was negligible on lower quality data sets with increased noise or on data sets simplified by stringent thresholding. Our results suggest that the choice of parameter estimation technique for evaluation of gene expression models depends both on quality of data, the nature of the models [again, remains to be established] and the aims of the modeling effort. PMID- 23726941 TI - Using evolutionary computations to understand the design and evolution of gene and cell regulatory networks. AB - This paper surveys modeling approaches for studying the evolution of gene regulatory networks (GRNs). Modeling of the design or 'wiring' of GRNs has become increasingly common in developmental and medical biology, as a means of quantifying gene-gene interactions, the response to perturbations, and the overall dynamic motifs of networks. Drawing from developments in GRN 'design' modeling, a number of groups are now using simulations to study how GRNs evolve, both for comparative genomics and to uncover general principles of evolutionary processes. Such work can generally be termed evolution in silico. Complementary to these biologically-focused approaches, a now well-established field of computer science is Evolutionary Computations (ECs), in which highly efficient optimization techniques are inspired from evolutionary principles. In surveying biological simulation approaches, we discuss the considerations that must be taken with respect to: (a) the precision and completeness of the data (e.g. are the simulations for very close matches to anatomical data, or are they for more general exploration of evolutionary principles); (b) the level of detail to model (we proceed from 'coarse-grained' evolution of simple gene-gene interactions to 'fine-grained' evolution at the DNA sequence level); (c) to what degree is it important to include the genome's cellular context; and (d) the efficiency of computation. With respect to the latter, we argue that developments in computer science EC offer the means to perform more complete simulation searches, and will lead to more comprehensive biological predictions. PMID- 23726943 TI - Design, fabrication and characterization of drug delivery systems based on lab-on a-chip technology. AB - Lab-on-a-chip technology is an emerging field evolving from the recent advances of micro- and nanotechnologies. The technology allows the integration of various components into a single microdevice. Microfluidics, the science and engineering of fluid flow in microscale, is the enabling underlying concept for lab-on-a-chip technology. The present paper reviews the design, fabrication and characterization of drug delivery systems based on this amazing technology. The systems are categorized and discussed according to the scales at which the drug is administered. Starting with the fundamentals on scaling laws of mass transfer and basic fabrication techniques, the paper reviews and discusses drug delivery devices for cellular, tissue and organism levels. At the cellular level, a concentration gradient generator integrated with a cell culture platform is the main drug delivery scheme of interest. At the tissue level, the synthesis of smart particles as drug carriers using lab-on-a-chip technology is the main focus of recent developments. At the organism level, microneedles and implantable devices with fluid-handling components are the main drug delivery systems. For drug delivery to a small organism that can fit into a microchip, devices similar to those of cellular level can be used. PMID- 23726944 TI - Lab-on-a-chip synthesis of inorganic nanomaterials and quantum dots for biomedical applications. AB - The past two decades have seen a dramatic raise in the number of investigations leading to the development of Lab-on-a-Chip (LOC) devices for synthesis of nanomaterials. A majority of these investigations were focused on inorganic nanomaterials comprising of metals, metal oxides, nanocomposites and quantum dots. Herein, we provide an analysis of these findings, especially, considering the more recent developments in this new decade. We made an attempt to bring out the differences between chip-based as well as tubular continuous flow systems. We also cover, for the first time, various opportunities the tools from the field of computational fluid dynamics provide in designing LOC systems for synthesis inorganic nanomaterials. Particularly, we provide unique examples to demonstrate that there is a need for concerted effort to utilize LOC devices not only for synthesis of inorganic nanomaterials but also for carrying out superior in vitro studies thereby, paving the way for faster clinical translation. Even though LOC devices with the possibility to carry out multi-step syntheses have been designed, surprisingly, such systems have not been utilized for carrying out simultaneous synthesis and bio-functionalization of nanomaterials. While traditionally, LOC devices are primarily based on microfluidic systems, in this review article, we make a case for utilizing millifluidic systems for more efficient synthesis, bio-functionalization and in vitro studies of inorganic nanomaterials tailor-made for biomedical applications. Finally, recent advances in the field clearly point out the possibility for pushing the boundaries of current medical practices towards personalized health care with a vision to develop automated LOC-based instrumentation for carrying out simultaneous synthesis, bio-functionalization and in vitro evaluation of inorganic nanomaterials for biomedical applications. PMID- 23726946 TI - Comparative analyses of influenza virus receptor distribution in the human and mouse brains. AB - Accumulating evidence suggests a potential link between influenza A virus infection and the occurrence of influenza-associated neurological disorders. As influenza infection is mediated by specific receptors on the host cell surface, it is important to understand the distribution patterns of influenza receptors in target organs. We carried out comprehensive experiments to localize influenza receptors in the brains of two different mouse strains and the human brain for comparison using lectin histochemistry. We further compared the brain regions in which influenza receptors were expressed and the regions in which experimental influenza infection was observed. Our results show that the expression patterns for influenza receptors in mouse and human brains are different. In the mouse brain, human influenza virus receptors (HuIV-R) were expressed in part of brainstem and cerebellar white matter while avian influenza virus receptors (AIV R) were expressed in the cerebellar Purkinje neurons. In contrast, in the human brain, many neurons and glia in widespread regions, including the cerebral cortex, hippocampus, brainstem, and cerebellum, express both AIV-R and HuIV-R. Importantly, vascular endothelial cells, choroid plexus epithelial cells and ependymal cells in both mouse and human brains express high levels of HuIV-R and AIV-R. The regional reciprocity was not observed when comparing regions with influenza receptor expression and the regions of influenza infection within the mouse brain. Our results demonstrate a differential influenza receptor expression pattern in mouse and human brains, and a disparity between influenza receptor distribution and regions with actual influenza infection. PMID- 23726945 TI - Molecular modeling in structural nano-toxicology: interactions of nano-particles with nano-machinery of cells. AB - Over the past two decades, nanotechnology has emerged as a key player in various disciplines of science and technology. Some of the most exciting applications are in the field of biomedicine - for theranostics (for combined diagnostic and therapeutic purposes) as well as for exploration of biological systems. A detailed understanding of the molecular interactions between nanoparticles and biological nano-machinery - macromolecules, membranes, and intracellular organelles - is crucial for obtaining adequate information on mechanisms of action of nanomaterials as well as a perspective on the long term effects of these materials and their possible toxicological outcomes. This review focuses on the use of structure-based computational molecular modeling as a tool to understand and to predict the interactions between nanomaterials and nano biosystems. We review major approaches and provide examples of computational analysis of the structural principles behind such interactions. A rationale on how nanoparticles of different sizes, shape, structure and chemical properties can affect the organization and functions of nano-machinery of cells is also presented. PMID- 23726947 TI - Stbd1 is highly elevated in skeletal muscle of Pompe disease mice but suppression of its expression does not affect lysosomal glycogen accumulation. AB - Previous studies strongly suggest that starch binding domain containing protein 1 (Stbd1) plays an important role in intracellular glycogen trafficking into lysosomes. We report here that Stbd1 expression is markedly increased in skeletal muscles but not in heart and liver of GAA-KO mice. An AAV2/9 vector expressing a Stbd1-specific shRNA effectively suppressed Stbd1 expression but did not alter lysosomal glycogen accumulation in the affected tissues of GAA-KO mice. Our results indicate that inhibition of Stbd1 does not appear to be an effective therapeutic approach for Pompe disease. PMID- 23726948 TI - Three phase partitioning leads to subtle structural changes in proteins. AB - Three phase partitioning consists of precipitation of proteins due to simultaneous presence of ammonium sulphate and t-butanol. The technique has been successfully used for purification and refolding of proteins. There are however indications that the structures of proteins subjected to three phase partitioning are different from native structure of proteins. Taking several proteins, the present work examines the structural changes in proteins by comparing their thermal stabilities, secondary structure contents, surface hydrophobicities, hydrodynamic radii and solubilities in the presence of ammonium sulphate. The results show that while the nature or extent of structural changes may vary, in all the cases the changes are rather subtle and not drastic in nature. Hence, the technique can be safely used for protein purification and refolding. PMID- 23726949 TI - SIRT1 inhibition by melatonin exerts antitumor activity in human osteosarcoma cells. AB - Melatonin, the main secretory product of the pineal gland, has potent antitumor activity against various types of cancer. However, the molecular mechanisms underlying the effects of melatonin remain largely unknown. SIRT1, a conserved nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase, has been implicated in modulating transcriptional silencing and cell survival and plays a key role in carcinogenesis through the deacetylation of important regulatory proteins. In this study, we assessed the antitumor activity of melatonin against human osteosarcoma cells (9607 cell line) and explored the role of SIRT1 in the activity of melatonin. Melatonin treatment resulted in strong antitumor activity, as evidenced not only by reductions in tumor cell vitality, adhesion ability, migration ability and glutathione (GSH) levels but also by increase in the apoptotic index and reactive oxygen species. Additionally, melatonin treatment down-regulated SIRT1 and up-regulated acetylated-p53. Sirtinol (a known SIRT1 inhibitor) and SIRT1 siRNA further enhanced the antitumor activity of melatonin, while SRT1720 (a known SIRT1 activator) attenuated the antitumor activity of melatonin. In summary, melatonin is a potent inhibitor of osteosarcoma cell growth that targets SIRT1 signaling, and the inhibition of SIRT1 signaling is a novel mechanism of action for melatonin during therapeutic intervention in osteosarcoma. PMID- 23726950 TI - Macrophage-stimulating protein attenuates hydrogen peroxide-induced apoptosis in human renal HK-2 cells. AB - Macrophage-stimulating protein (MSP) and its receptor, recepteur d'origine nantais (RON), play an important role in cell proliferation and migration. We have investigated the role of MSP in hydrogen peroxide (H2O2)-induced renal tubular apoptosis. Human renal proximal tubular (HK-2) cells were incubated with H2O2 for 24h in the presence of different concentrations of MSP, and cell viability was measured by MTT assay. The protein expression of Bax, Bcl-2, caspase-3, mitogen-activated protein kinases (MAPKs), phosphatidylinositol-3 kinase (PI3K)/Akt, and nuclear factor-kappa B (NF-kappaB) was determined by semiquantitative immunoblotting. Apoptosis was assessed by flow cytometry analysis after HK-2 cells were stained with fluorescein isothiocyanate-conjugated annexin V protein and propidium iodide. H2O2 treatment decreased cell viability in HK-2 cells; this was counteracted by MSP pretreatment. H2O2 treatment induced an increased ratio of Bax/Bcl-2, cleaved caspase-3, and the number of condensed nuclei, which was also counteracted by MSP. Flow cytometry analysis showed H2O2 induced apoptosis, and its prevention by MSP treatment. Increased protein expression of phospho-p38 MAPK was attenuated by MSP, while phospho-extracellular signal-regulated kinase and c-Jun-N-terminal kinase were not affected. H2O2 induced NF-kappaB activation and IkappaB-alpha degradation, but the increased nuclear NF-kappaB activation was counteracted by MSP or by a p38 MAPK inhibitor. H2O2 treatment decreased expression of phospho-PI3K and phospho-Akt, which was reversed by MSP pretreatment. These findings suggest that MSP attenuates H2O2 induced apoptosis in HK-2 cells by modulating the p38 and NF-kappaB, as well as PI3K/Akt, signaling pathways. PMID- 23726951 TI - Biochemical and molecular characterization of Pseudomonas aeruginosa CTM50182 organic solvent-stable elastase. AB - An extracellular alkaline elastase was produced from Pseudomonas aeruginosa CTM50182. It was chromatographically purified using HPLC and Mono Q Sepharose column. Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/MS) analysis revealed that the purified enzyme (called AMPP) was a monomer with a molecular mass of 33,015.18 Da. The N-terminal 29 amino acid sequence of AMPP showed high homology with those of Pseudomonas elastases. It showed optimal activity at pH 12 and 80 degrees C and was stable at a pH range of 9-12 after 120 h of incubation. Its thermoactivity and thermostability were upgraded in the presence of 5 mM Co(2+). Its half-life times at 70 and 80 degrees C were 16 and 10 h, respectively. It was completely inhibited by ethylene glycol-bis (beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), and 1,10-phenanthroline, suggesting that it belongs to the metalloprotease family. AMPP also exhibited high catalytic efficiency, organic solvent-tolerance, and hydrolysis. The lasB gene encoding AMPP was cloned, sequenced, and expressed in Escherichia coli. The biochemical properties of the extracellular purified recombinant enzyme (rAMPP) were similar to those of native AMPP. This organic solvent-stable protease could be considered a potential candidate for application as a biocatalyst in the synthesis of enzymatic peptides. PMID- 23726952 TI - Tracheostomy in mucopolysaccharidosis type II (Hunter's Syndrome). AB - OBJECTIVE: Patients with mucopolysaccharidosis type II (MPS II) may develop progressive multi-level upper airway obstruction. Despite the unique challenges presented by these complex patients, tracheostomy remains an important intervention to safeguard the airway when other interventions have failed or when the airway obstruction involves multiple sites. Airway involvement is largely responsible for the significant anaesthetic risk seen in MPS II. We reviewed our tertiary unit's experience of tracheostomies in patients with MPS II. STUDY DESIGN: Retrospective study. METHODS: Case note review of MPS II patients requiring tracheostomy at our tertiary institution. The primary outcome measure used for this study was complications following tracheostomy. RESULTS: We identified 10 MPS II patients requiring tracheostomy to manage upper airway obstruction. Mean age at which tracheostomy was 11 years 2 months (range 4 years 6 months to 28 years 10 months). Tracheostomy insertion was indicated in 3 scenarios: (1) to safeguard an anticipated difficult airway prior to a planned non-ENT surgical procedure, (2) to treat refractory progressive upper airway obstruction and (3) emergency airway management. Complications recorded included infratip and suprastomal granulations, local wound infection and skin ulceration from mechanical trauma. There were no immediate postoperative complications. CONCLUSIONS: Progressive upper airway obstruction is common in children with MPS II. Tracheostomy is an effective way of managing airway obstruction when less invasive interventions are no longer adequate. Tracheostomy in these patients can be technically difficult and although the complications of tracheostomy in MPS II do not significantly differ from other patient groups, the implications and management complexity vary considerably. The impact of ERT on airway obstruction is not yet fully understood, with tracheostomies likely to remain an important airway adjunct in some patients who fail to respond to ERT, or in those patients surviving into adulthood. It is vital that a multidisciplinary team, comprising clinicians with experience in managing such patients, are involved in airway management of patients with MPS II to enable the best standard of care to be given. The significant additional implications of a tracheostomy in a patient with MPS II, in terms of safety, aftercare and potentially life-threatening complications must be discussed in detail with the patient's family and/or carers. LEVEL OF EVIDENCE: 2c. PMID- 23726953 TI - Otological aspects and surgical outcome in a consanguineous family with a novel ANKH gene mutation. AB - OBJECTIVES: To report the hearing impairment in a new autosomal recessive metabolic disorder due to a mutation in the ANKH gene and to report the outcomes of exploratory tympanotomy. STUDY DESIGN: Retrospective chart study. SETTING: Tertiary referral center. PATIENTS: One large consanguineous family was examined. Three patients underwent exploratory tympanotomy. INTERVENTION: Exploratory tympanotomies in three patients. MAIN OUTCOME MEASURES: Medical and otological histories; postoperative hearing outcomes. RESULTS: In the patients who received tympanotomies, a postoperative hearing gain of between 5 and 20 dB was noted, with a residual air-bone gap of between 6 and 35 dB (follow-up between 4 and 67 months). The sensorineural component of the hearing impairment varies greatly, between 4 and 23 dB, and this factor might also affect the final hearing outcome. CONCLUSIONS: Exploratory tympanotomy might improve the hearing outcome in patients with this syndrome and therefore surgery has a limited audiometric benefit in general. Based on anatomical findings, a congenital origin for the ossicular chain anomaly seems likely. It remains unclear whether the sensorineural component of the hearing impairment is progressive and this should be investigated further. PMID- 23726954 TI - Habitual use of push and pull plastic bottle caps is more prevalent among children with recurrent acute otitis media. AB - OBJECTIVE: The use of a pacifier has been reported to be a causative factor of recurrent acute otitis media (RAOM) because the negative pressure which is generated during sucking may cause a negative intra-tympanic pressure and favour the reflux of nasopharyngeal secretions into the Eustachian tube. Push and pull (P&P) plastic bottle caps, recently marketed in Italy, might also induce negative nasopharyngeal pressure. This study was aimed to investigate if there is a difference in the prevalence of habitual use of P&P plastic bottle caps among children with a positive history of RAOM and healthy controls. METHODS: A telephonic interview was performed in order to retrospectively evaluate the prevalence of habitual use of P&P plastic bottle cap among children with a history of RAOM and healthy controls, comparable to the former for environmental risk factors for RAOM. RESULTS: Data were obtained from 57 Caucasian patients (males=36/57; 63.2%) with a median age of 59 (range=21-90) months, including 28 children with a history of RAOM and 29 healthy controls. Habitual use of P&P plastic bottle cap was significantly (p=0.047) more frequent in children with a history of RAOM (14/28; 50.0%) than in control group (7/29; 24.2%). Multivariate logistic regression analysis adjusted for age confirmed a significant association (p<0.01; Pseudo R(2)=0.2) between the use of P&P plastic bottle cap and a positive history of RAOM (adjusted OR=4.0; range=1.1-15.0). CONCLUSIONS: Our preliminary data show a significantly increased prevalence of P&P plastic cap bottle habitual users among children with a history or RAOM and support the need for larger studies to confirm the role of using P&P bottles as risk factor of RAOM and to identify the age groups at higher risk. PMID- 23726955 TI - Feasibility of 1000 Hz tympanometry in infants: tympanometric trace classification and choice of probe tone in relation to age. AB - OBJECTIVES: Universal newborn hearing screening (UNHS) has significantly reduced the age of children undergoing audiological examinations. Middle ear function is usually evaluated with tympanometry using a probe tone of 226 Hz, although higher frequencies are recommended in infants. The aim of this study was to compare the feasibility of 226 and 1000 Hz tympanometry for different trace classification systems in relation to age, risk factors for hearing loss and ear canal volume. METHODS: Data from 577 infants (915 ears) <1 year were analyzed. Tympanograms were classified according to the classification systems of Jerger, Marchant et al. and Kei et al. and correlated with ear microscopy as the gold standard. Test quality parameters of tympanometry with probe tones of 226 and 1000 Hz were compared in four different age groups. RESULTS: The trace classification following Kei et al. presented the best correlation to ear microscopy and reduced the number of unclassified tympanograms. The use of probe tones of 226 Hz in infants below the age of nine months showed a poor level of sensitivity. CONCLUSIONS: We recommend the use of a 1000 Hz probe tone in infants at least up to the age of nine months. In this age group, 226 Hz tympanometry is inappropriate. In children with craniofacial abnormalities and smaller ear canal volumes, 1000 Hz tympanometry could be taken into consideration, even for older children. High-frequency tympanograms should be evaluated according to the classification system of Kei et al., which differentiates between peaked (normal) and flat (abnormal) curves. PMID- 23726956 TI - Nonorganic hearing loss in children: audiometry, clinical characteristics, biographical history and recovery of hearing thresholds. AB - OBJECTIVES: The term "nonorganic hearing loss" (NOHL) (pseudohypacusis, functional or psychogenic hearing loss) describes a hearing loss without a detectable corresponding pathology in the auditory system. It is characterized by a discrepancy between elevated pure tone audiometry thresholds and normal speech discrimination. The recommended audiological management of NOHL in children comprises history taking, diagnosis, and counseling. According to the literature, prognosis depends on the severity of the patient's school and/or personal problems. Routine referral to a child psychiatrist is discussed as being controversial. METHODS: The clinical history of 34 children with NOHL was retrospectively evaluated. In 15 children, follow up audiometry was performed. Results of biographical history, subjective and objective audiometry, additional speech and language assessment, psychological investigations and follow up audiometry are presented and discussed. RESULTS: The prevalence of NOHL was 1.8% in children with suspected hearing loss. Mean age at diagnosis was 10.8 years. Girls were twice as often affected as boys. Patient history showed a high prevalence of emotional and school problems. Pre-existing organic hearing loss can be worsened by nonorganic causes. Children with a fast recovery of hearing thresholds (n=6) showed a high rate (4/6) of family, social and emotional problems. In children with continuous threshold elevation (n=9), biographical history showed no recognizable or obvious family, social or emotional problems; learning disability (4/9) was the most frequently presented characteristic. CONCLUSIONS: Due to advances in objective audiometry, the diagnosis of NOHL is less challenging than management and counseling. Considering the high frequency of personal and school problems, a multidisciplinary setting is helpful. On the basis of our results, drawing conclusions from hearing threshold recovery on the severity of underlying psychic problems seems inappropriate. As a consequence, a referral to a child psychiatrist can be generally recommended. PMID- 23726957 TI - Clinical utility of fine needle aspiration cytology in pediatric parotid tumors. AB - OBJECTIVE: The purpose of this study was to evaluate the usefulness and accuracy of fine needle aspiration cytology (FNAC) in the diagnosis of pediatric parotid tumors. METHODS: From June 2002 to June 2012, 22 patients <=18-years-of-age with parotid mass were treated at Chonnam National University Hospital. Included in the study were 21 cases with preoperative FNAC. A retrospective chart review analyzed the results of FNAC and compared them with the corresponding histopathological diagnosis. RESULTS: Twenty-one of the 22 patients had undergone preoperative FNAC, which diagnosed pleomorphic adenoma in 13 patients. The remaining eight patients were diagnosed with benign tumor (n = 6), malignant tumor (n = 1) or Kimura disease (n = 1). All 21 patients underwent parotid tumor removal. FNAC had a diagnostic sensitivity of 92.3%, positive-predictive value of 92.3% and accuracy of 90.5% for diagnosing pleomorphic adenoma of pediatric parotid tumor. FNAC had a diagnostic sensitivity of 100%, a positive-predictive value of 85% and accuracy of 85.7% for diagnosing benign parotid tumor. CONCLUSIONS: Preoperative FNAC is a useful and accurate adjunct for preoperative evaluation of pediatric parotid tumors. We recommend that preoperative FNAC should be part of the initial evaluation of pediatric patients with parotid masses. PMID- 23726959 TI - Lack of type VI adenylyl cyclase (AC6) leads to abnormal sympathetic tone in neonatal mice. AB - Visceral functions are regulated by a basal sympathetic nerve discharge (SND), also known as 'sympathetic tone'. We demonstrate herein that AC6 existed in tyrosine hydroxylase-positive rostral ventrolateral medulla neurons in the brainstem. Adenylyl cyclase (AC) assays showed lower basal and pituitary adenylate cyclase-activating peptide-evoked AC activities in the brainstem of AC6 null mice, indicating that AC6 is a prominent AC isozyme in the brainstem. Furthermore, two independent lines of AC6-null mice exhibited a much higher SND, recorded from splanchnic sympathetic nerves of neonatal brainstem-spinal cord preparations, than wildtype mice. An assay of urine noradrenaline confirmed this observation. Collectively, AC6 plays a critical role in the regulation of sympathetic tone. PMID- 23726960 TI - Intermittent hypoxia training after C2 hemisection modifies the expression of PTEN and mTOR. AB - In this study, we examined modulations in phosphatase and tensin homolog (PTEN) and mammalian target of rapamycin (mTOR) protein expression after a lateral C2 hemisection and subsequent intermittent hypoxia (IH) exposure and training, which initiates respiratory motor plasticity and recovery. PTEN and mTOR are significant molecules within a signaling pathway that directly influences dendritic sprouting, axonal plasticity, and regeneration. Expression levels of PTEN, mTOR and downstream effectors within this pathway were investigated, and it was found that following injury and IH exposure the expression of these molecules was significantly altered. This study directly demonstrates the implementation and feasibility of a non-invasive strategy to modulate the expression levels of intrinsic signaling molecules known to influence plasticity and regeneration in the CNS. PMID- 23726958 TI - A survey from 2012 of evidence for the role of neuroinflammation in neurotoxin animal models of Parkinson's disease and potential molecular targets. AB - Parkinson's disease (PD) is a neurodegenerative movement disorder that results from the progressive loss of dopaminergic neurons in the midbrain substantia nigra pars compacta (SNpc). The specific molecular events that cause PD are currently not known; however, progress to better understand PD pathogenesis has been made using various animal models of the disease. In this review, we have highlighted reports from 2012 in which neurochemical/neurotoxins have been used in rodents to specifically address the role of neuroinflammation in the development and/or progression of PD-like pathology and in particular nigral degeneration. A number of studies have been summarized in which plausible pro inflammatory, anti-inflammatory, or therapeutic agents targeting inflammatory pathways were introduced and/or investigated by various groups for neuroprotective effects. From these studies, it is clear that neuroinflammation acts to exacerbate the toxic outcomes that are set in motion within neurons following exposure to neurotoxins. Additionally, it is noted that future work is still needed to better understand the underlying mechanisms mediating the neuroinflammatory and neurotoxic phenotypes reported in rodent models of PD-like pathology to maximize the translation potential of these interventions to the clinic to prevent and/or delay PD onset and/or progression in humans. PMID- 23726961 TI - New DNA probes to detect aneugenicity in rat bone marrow micronucleated cells by a pan-centromeric FISH analysis. AB - When characterizing the genotoxicity of chemicals that induce micronuclei, it is practical to be able to classify the chemicals as aneugens or clastogens. This classification gives information on the mechanistic properties of chemicals and is indispensable for setting the threshold safety margins for genotoxicity in pharmaceutical development. A widely used method for detecting aneugens is fluorescence in situ hybridization (FISH) but, even though the rat is an experimental animal generally used in preclinical studies in drug development, DNA probes that hybridize to all the centromeres of rat chromosomes have not yet been established. In the present study, in addition to the previously known satellite I sequence, we identified two novel satellite sequences, satellite II and satellite III, from the rat genome database. DNA probes with a mixture of these satellite DNA sequences were used to establish a FISH method for pan centromeric staining of rat chromosomes. To confirm the feasibility of the method, vinblastine (VBS) and mitomycin C (MMC) were administered to rats as a typical aneugen and clastogen, respectively. Micronucleated polychromatic erythrocytes (MNPCE) from bone marrow were enriched by sorting in flow cytometry and subjected to the FISH method. As a result, the ratio of centromere-positive MNPCE increased in VBS-treated rats but not in MMC-treated ones. Since the FISH method using the novel DNA probes clearly discriminates the aneugens from the clastogens, we suggest this method as a useful tool for providing mechanistic information for micronucleus induction in vivo. PMID- 23726962 TI - Bone histomorphometric analysis in a patient with anorexia nervosa. AB - A 34-year-old Japanese woman with anorexia nervosa (AN) of a body mass index (BMI) of 11.0 kg/cm(2) was admitted to our hospital for assessment of renal dysfunction with a serum creatinine of 1.8 mg/dL and hypokalemia (3.0 mEq/L). Renal biopsy showed chronic interstitial fibrosis with hypertrophy of the juxtaglomerular apparatus. Iliac crest biopsy was performed because of a severe decrease in bone mineral density. It showed active resorption at the periosteal and endosteal surfaces of cortical bone by numerous osteoclasts, as well as bone island formation in cancellous bone due to marked decrease of trabecular connections. A dynamic study using double labeling showed that mineralization of cancellous bone adjacent to cortical bone occurred between the first and second labelings, but did not occur between the second labeling and osteoid formation during the 28-day period before biopsy, which implied that the mineralization was related to promotion of food intake after hospitalization, while the lack of mineralization was due to poor food intake outside hospital. Empty lacunae that indicated the death of osteocytes were seen. Because her bone mass and kidney injury improved after weight gain and normokalemia were achieved by a highly nutritious diet, malnutrition with hypokalemia may have a negative influence on bone formation due to impaired mineralization and may activate bone resorption by osteoclasts secondary to the formation of empty lacunae. This is the first report about the histological features of premenopausal osteoporosis in a patient with AN and kidney injury. PMID- 23726963 TI - Quality of life assessment in children commencing home INR self-testing. AB - INTRODUCTION: Management of oral anticoagulant therapy (OAT) in children is complex and frequent testing of the International Normalised Ratio (INR) is a significant burden. This study evaluates the impact of a home INR self-testing (home ST) program on the quality of life (QoL) of children and their families. The aim of the study was to determine if participation in a home ST program improves QoL for children requiring long-term OAT and their families. MATERIALS AND METHODS: Children aged eight to 18 years requiring long-term OAT and parents of children participated. Quantitative methods comprised three validated QoL questionnaires; the anticoagulation specific PAC QL(c), the PedsQLTM and the PedsQL FIMTM. Questionnaires were completed before commencing home ST and 6-12 months later. Qualitative methods consisted of open-ended questions which participants answered when completing the questionnaires for the second time. Results of INRs tested at home were collected. RESULTS: Fifty-five parents and 35 children participated. The percentage of time the children's INRs were in their target therapeutic range was 71.3. Parents reported statistically significant improvements in QoL for themselves (mean increase 6.9), their family (mean increase 8.6) and their child (mean increase 11.1) following the commencement of home ST (difference p<=0.003 on all questionnaires). The children did not report a statically significant improvement in QoL. CONCLUSION: Parents reported significant improvement for their child's QoL, their QoL and the families' function following commencement of home ST. Children did not report a significant improvement in their QoL, but clearly identified satisfaction with home ST. PMID- 23726964 TI - Long-term mortality and incidence of cancer after pregnancy-related venous thrombosis: results of a population-based cohort study. AB - The long-term mortality and incidence of cancer after pregnancy-related venous thrombosis (VT) is not known. In this population-based cohort study we identified women with a first-ever pregnancy-related VT (cases, n = 557)) from 18 Norwegian hospitals during 1990-2003. Hospital controls (n = 1214) were selected among women who gave birth at the same time as a case. All participants were linked to the Norwegian Cause of Death Registry and to the Cancer Registry of Norway in 2012. The general age-adjusted Norwegian female population was used as a second control group to calculate the standardized mortality ratio (SMR) and the standardized incidence ratio (SIR) for cancer. Ten cases (1.8%) and seven hospital controls (0.6%) died during follow-up. Mortality was 3.2 times higher among cases as compared with hospital controls when adjusted for age (HR 3.2, 95% confidence interval 1.2-8.5, p = 0.018). The SMR for the first year of follow-up was 18.8 (7.8-45.3) and for the rest of the study period 0.9 (0.4-2.0). Fifteen cases (2.7%) and 13 hospital controls (1.1%) were diagnosed with cancer after index pregnancy. The incidence of cancer was 2.6 times higher among cases compared with hospital controls when adjusted for age (HR 2.6, 1.3-5.6, p = 0.011), but compared with the age-adjusted female population in Norway there was no excess risk of cancer (SIR 1.0, 95% CI 0.6-1.7). Mortality and incidence of cancer after pregnancy-related VT was low. Both were increased among cases compared with hospital controls, but not when compared with the general population, except for mortality during the first year after VT. PMID- 23726965 TI - Major bleeding risk in anticoagulated patients receiving concomitant antiplatelet therapy: a prospective study. AB - INTRODUCTION: Current literature suggesting a higher bleeding risk during combination therapy compared to oral anticoagulation alone is primarily based on retrospective studies or specific populations. We aimed to prospectively evaluate whether unselected medical patients on oral anticoagulation have an increased risk of bleeding when on concomitant antiplatelet therapy. MATERIAL AND METHODS: We prospectively studied consecutive adult medical patients who were discharged on oral anticoagulants between 01/2008 and 03/2009 from a Swiss university hospital. The primary outcome was the time to a first major bleed on oral anticoagulation within 12 months, adjusted for age, international normalized ratio target, number of medications, and history of myocardial infarction and major bleeding. RESULTS: Among the 515 included anticoagulated patients, the incidence rate of a first major bleed was 8.2 per 100 patient-years. Overall, 161 patients (31.3%) were on both anticoagulant and antiplatelet therapy, and these patients had a similar incidence rate of major bleeding compared to patients on oral anticoagulation alone (7.6 vs. 8.4 per 100 patient-years, P=0.81). In a multivariate analysis, the association of concomitant antiplatelet therapy with the risk of major bleeding was not statistically significant (hazard ratio 0.89, 95% confidence interval, 0.37-2.10). CONCLUSIONS: The risk of bleeding in patients receiving oral anticoagulants combined with antiplatelet therapy was similar to patients receiving oral anticoagulants alone, suggesting that the incremental bleeding risk of combination therapy might not be clinically significant. PMID- 23726966 TI - Down-regulation of endothelial protein C receptor shedding by persicarin and isorhamnetin-3-O-galactoside. AB - Increasing evidence has shown that beyond its role in coagulation, endothelial protein C receptor (EPCR) plays an important role in the cytoprotective pathway. Previous reports have shown that EPCR can be shed from the cell surface, and that this is mediated by tumor necrosis factor-alpha converting enzyme (TACE) and that sEPCR levels are increased in patients with systemic inflammatory diseases. Persicarin and isorhamnetin-3-O-galactoside (I3G) are active compounds from Oenanthe javanica, which has been widely studied for its neuroprotective, antioxidant, and barrier protective activities. However, little is known of the effects of persicarin on EPCR shedding. Here, we investigated this issue by monitoring the effects of persicarin and I3G on phorbol-12-myristate 13-acetate (PMA) and on cecal ligation and puncture (CLP)-mediated EPCR shedding and underlying mechanisms. According to the results, persicarin and I3G induced potent inhibition of PMA and CLP-induced EPCR shedding by suppressing expression of TACE. In addition, persicarin and I3G reduced PMA-stimulated phosphorylation of p38MAPK, extracellular regulated kinases (ERK) 1/2, and c-Jun N-terminal kinase (JNK). Given these results, persicarin and I3G could be used as a candidate therapeutic for treatment of severe vascular inflammatory diseases. PMID- 23726968 TI - Difference in the D-dimer rise between women with singleton and multifetal pregnancies. AB - INTRODUCTION: The differences in the d-dimer rise between women with singleton and multifetal pregnancies have not been studied extensively. MATERIALS AND METHODS: d-Dimer levels were determined in 1089 blood specimens from 1089 women in various stages of pregnancy, including 977 and 112 women with singleton and multifetal pregnancies, respectively. None of the 1089 women developed hypertension or clinical venous thromboembolism during pregnancy or in the postpartum period. RESULTS: The D-dimer levels were significantly and positively correlated with gestational week at examination in women with singleton or multifetal pregnancies. The d-dimer levels (MUg/ml, mean +/- SD [number of specimens]) determined at the 1st trimester did not differ significantly (0.81 +/ 0.82 [102] for singleton vs. 1.20 +/- 0.77 [7] for multifetal), but those at the 2nd (1.61 +/- 1.45 [216] vs. 2.62 +/- 2.26 [59]) and 3rd (2.37 +/- 2.22 [659] vs. 4.02 +/- 2.14 [46]) trimesters were significantly higher in women with multifetal than singleton pregnancies. The 90th percentile value was 4.31 MUg/ml for 1089 specimens. A significantly greater number of women exceeded 4.31 MUg/ml during the 2nd (16.9% vs. 5.6%, P=0.0043) and 3rd (34.8% vs. 10.6%, P < 0.0001) trimesters among those with multifetal than with singleton pregnancies. CONCLUSIONS: The degree of D-dimer rise in pregnancy was greater in women with multifetal than with singleton pregnancies. PMID- 23726967 TI - Resequencing of VKORC1, CYP2C9 and CYP4F2 genes in Italian patients requiring extreme low and high warfarin doses. AB - PURPOSE: The aim of the present study was to investigate the genetic variability of VKORC1, CYP2C9 and CYP4F2 genes in patients who required a very low and high warfarin dose, in order to identify novel variants that could help to explain the particular extreme dose requirements. METHODS: Among patients followed and treated with warfarin at the Center of Haemostasis and Thrombosis of the PTV, we selected twelve patients showing a high divergence from warfarin standard doses required to achieve the therapeutic effect. All VKORC1, CYP2C9 and CYP4F2 coding regions, 3' and 5' UTR and exon/intron boundaries were analyzed by direct sequencing. RESULTS: The 1173T and -1639A allele variants in VKORC1 gene, associated with warfarin sensitivity, were present, as expected, mostly in low dose patients while 3730A allele, linked to warfarin resistance, has been found only in high dose patients. Interestingly, we found that three out of six low dose subjects presented CYP2C9*3/*3 homozygous genotype, very rare in Caucasians. Besides these common polymorphisms, we identified 5 SNPs in CYP2C9 gene and 19 SNPs in CYP4F2 gene. Among these, all polymorphisms identified in CYP2C9 gene were present only in low dose patients and three of them resulted in linkage with CYP2C9*2 and CYP2C9*3. Regarding CYP4F2 SNPs, we did not observe differences between the high and low dose patients. At the end, the whole sequencing did not reveal any novel polymorphism/mutation. CONCLUSION: Further studies are required to identify other genetic factors contributing to extreme warfarin requirement. PMID- 23726969 TI - Vascular endothelial growth factor as a biomarker for endostatin gene therapy. AB - Renal cell carcinoma (RCC) is characterized by high vascular endothelial growth factor (VEGF) production and, consequently, excessive angiogenesis. Several strategies have been developed to target angiogenesis as a method for treating metastatic RCC (mRCC). Endostatin (ES) is a C-terminal fragment of collagen XVIII that has antiangiogenic activity. The aim of this study was to investigate the predictive value of circulating VEGF-A in a murine model of mRCC after ES gene therapy. ES therapy did not affect the levels of collagen XVIII/ES or ES in the tissue. The circulating level of ES was increased in the control and ES-treated groups (normal vs. control, P<0.05 and ES-treated vs. control, P<0.001), and the intratumoral vessels were significantly decreased (ES-treated vs. control, P<0.05). ES therapy decreased the VEGF mRNA levels. The tissue and circulating levels of VEGF in the control group were significantly higher than normal (P<0.01 and P<0.05, respectively). Treatment with ES significantly reduced the VEGF concentrations in both compartments (P<0.001 for tissue and P<0.05 for plasma). Our findings indicate that in addition to the directly targeted tumor vessels, ES exerts its antitumor effect by down-regulating VEGF gene expression in renal tumor cells. Additionally, our findings point to the predictive value of VEGF for ES therapy. PMID- 23726971 TI - Phase II study of pemetrexed in combination with cisplatin and cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck. AB - PURPOSE: Platinum/5-fluorouracil plus cetuximab is a standard systemic treatment for recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Pemetrexed has shown activity in SCCHN. This phase II study evaluated pemetrexed with cisplatin and cetuximab in recurrent/metastatic SCCHN. METHODS: Patients received cetuximab 250 mg/m(2) (loading dose: 400mg/m(2))days 1, 8 and 15; pemetrexed 500 mg/m(2)+cisplatin 75 mg/m(2) on day 1, q3w up to six cycles and folic acid, vitamin B12 and prophylactic medications. After a minimum of four cycles, responding patients were eligible for maintenance with pemetrexed and cetuximab, or either as monotherapy, until progression or toxicity. Efficacy (primary end-point: progression-free survival [PFS]) and toxicity were evaluated. RESULTS: Sixty-six patients received >=1 cycle of the triplet. Most patients were male (80.3%), with a median age of 62 years and Eastern Cooperative Oncology Group (ECOG) performance status of 1 (71.2%). Diagnoses included oropharynx (45.5%) and larynx (24.2%) cancers, with locoregional disease (51.5%) alone, or combined with distant metastases (48.5%). Median (m) PFS was 4.4 months (95% confidence interval [CI]: 3.6, 5.4); median overall survival was 9.7 months (95% CI: 6.5, 13.1). Objective response rate was 29.3%; 23 patients had stable disease (39.7%). Drug-related grade 3/4 toxicities included neutropaenia (33.3%), fatigue (24.2%), anorexia (12.1%) and infection (10.6%). Five treatment-related deaths (7.6%) occurred. CONCLUSIONS: Efficacy results were consistent with current standard treatment for this patient population, but the pre-specified mPFS of 5.5 months was not achieved. Grade 3/4 toxicities were also consistent with standard treatment, although treatment-related deaths were higher than expected. PMID- 23726970 TI - Conserved mechanisms of vocalization coding in mammalian and songbird auditory midbrain. AB - The ubiquity of social vocalizations among animals provides the opportunity to identify conserved mechanisms of auditory processing that subserve communication. Identifying auditory coding properties that are shared across vocal communicators will provide insight into how human auditory processing leads to speech perception. Here, we compare auditory response properties and neural coding of social vocalizations in auditory midbrain neurons of mammalian and avian vocal communicators. The auditory midbrain is a nexus of auditory processing because it receives and integrates information from multiple parallel pathways and provides the ascending auditory input to the thalamus. The auditory midbrain is also the first region in the ascending auditory system where neurons show complex tuning properties that are correlated with the acoustics of social vocalizations. Single unit studies in mice, bats and zebra finches reveal shared principles of auditory coding including tonotopy, excitatory and inhibitory interactions that shape responses to vocal signals, nonlinear response properties that are important for auditory coding of social vocalizations and modulation tuning. Additionally, single neuron responses in the mouse and songbird midbrain are reliable, selective for specific syllables, and rely on spike timing for neural discrimination of distinct vocalizations. We propose that future research on auditory coding of vocalizations in mouse and songbird midbrain neurons adopt similar experimental and analytical approaches so that conserved principles of vocalization coding may be distinguished from those that are specialized for each species. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives". PMID- 23726972 TI - Apolipoprotein(a) acts as a chemorepellent to human vascular smooth muscle cells via integrin alphaVbeta3 and RhoA/ROCK-mediated mechanisms. AB - Lipoprotein(a) (Lp(a)) is an independent risk factor for the development of cardiovascular disease. Vascular smooth muscle cell (SMC) motility and plasticity, functions that are influenced by environmental cues, are vital to adaptation and remodelling in vascular physiology and pathophysiology. Lp(a) is reportedly damaging to SMC function via unknown molecular mechanisms. Apolipoprotein(a) (apo(a)), a unique glycoprotein moiety of Lp(a), has been demonstrated as its active component. The aims of this study were to determine functional effects of recombinant apo(a) on human vascular SMC motility and explore the underlying mechanism(s). Exposure of SMC to apo(a) in migration assays induced a potent, concentration-dependent chemorepulsion that was RhoA and integrin alphaVbeta3-dependent, but transforming growth factor beta-independent. SMC manipulation through RhoA gene silencing, Rho kinase inhibition, statin pre treatment, alphaVbeta3 neutralising antibody and tyrosine kinase inhibition all markedly inhibited apo(a)-mediated SMC migration. Our data reveal unique and potent activities of apo(a) that may negatively influence SMC remodelling in cardiovascular disease. Circulating levels of Lp(a) are resistant to lipid lowering strategies and hence a greater understanding of the mechanisms underlying its functional effects on SMC may provide alternative therapeutic targets. PMID- 23726973 TI - TIGAR is required for efficient intestinal regeneration and tumorigenesis. AB - Regulation of metabolic pathways plays an important role in controlling cell growth, proliferation, and survival. TIGAR acts as a fructose-2,6-bisphosphatase, potentially promoting the pentose phosphate pathway to produce NADPH for antioxidant function and ribose-5-phosphate for nucleotide synthesis. The functions of TIGAR were dispensable for normal growth and development in mice but played a key role in allowing intestinal regeneration in vivo and in ex vivo cultures, where growth defects due to lack of TIGAR were rescued by ROS scavengers and nucleosides. In a mouse intestinal adenoma model, TIGAR deficiency decreased tumor burden and increased survival, while elevated expression of TIGAR in human colon tumors suggested that deregulated TIGAR supports cancer progression. Our study demonstrates the importance of TIGAR in regulating metabolism for regeneration and cancer development and identifies TIGAR as a potential therapeutic target in diseases such as ulcerative colitis and intestinal cancer. PMID- 23726975 TI - Drug use disorders and post-traumatic stress disorder over 25 adult years: role of psychopathology in relational networks. AB - BACKGROUND: In traumatized populations, drug use disorders and post-traumatic stress disorder (PTSD) persist for many years. Relational factors that mediate this persistence have rarely been systematically examined. Our aim is to examine the relative effects of psychopathology in familial and non-familial networks on the persistence of both disorders over adulthood. METHODS: We utilized longitudinal data from an epidemiologically ascertained sample of male Vietnam veterans (n=642). Measures included DSM-IV drug use disorders, other psychiatric disorders, network problem history and time-varying marital and employment characteristics. Longitudinal measures of veterans' psychopathology and social functioning were retrospectively obtained for each year over a 25 year period. We used generalized estimating equations (GEE) to estimate the relative effects of network problems on veteran's drug use disorders and PTSD after adjusting for covariates. RESULTS: Veterans' mean age was 47 years in 1996. Prevalence of illicit drug disorders declined from 29.8% in 1972 to 8.3% in 1996, but PTSD remained at 11.7% from 13.2% in 1972. While 17.0% of veterans reported a familial drug use problem, 24.9% reported a non-familial drug use problem. In full GEE models, a non-familial drug problem was a significant predictor of illicit drug use disorders over 25 years (OR=2.21, CI=1.59-3.09), while both familial depression (OR=1.69, CI=1.07-2.68) and non-familial drinking problem (OR=1.66, CI=1.08-2.54) were significant predictors of PTSD over 25 years. CONCLUSIONS: Familial and non-familial problems in networks differentially affect the persistence of drug use disorders and PTSD in traumatized male adults. PMID- 23726974 TI - The yeast Alix homolog Bro1 functions as a ubiquitin receptor for protein sorting into multivesicular endosomes. AB - Sorting of ubiquitinated membrane proteins into lumenal vesicles of multivesicular bodies is mediated by the Endosomal Sorting Complex Required for Transport (ESCRT) apparatus and accessory proteins such as Bro1, which recruits the deubiquitinating enzyme Doa4 to remove ubiquitin from cargo. Here we propose that Bro1 works as a receptor for the selective sorting of ubiquitinated cargoes. We found synthetic genetic interactions between BRO1 and ESCRT-0, suggesting that Bro1 functions similarly to ESCRT-0. Multiple structural approaches demonstrated that Bro1 binds ubiquitin via the N-terminal trihelical arm of its middle V domain. Mutants of Bro1 that lack the ability to bind Ub were dramatically impaired in their ability to sort Ub-cargo membrane proteins, but only when combined with hypomorphic alleles of ESCRT-0. These data suggest that Bro1 and other Bro1 family members function in parallel with ESCRT-0 to recognize and sort Ub-cargoes. PMID- 23726976 TI - Testing different thresholds for risky episodic drinking--what's so special about five drinks? AB - BACKGROUND: Studies of episodic drinking typically use a measure based on the frequency of drinking five or more standard drinks (a definition which itself varies based on the standard units being used). While this threshold clearly defines drinking behaviour with a range of risks and negative consequences, there has been limited research outside of US college-based studies to determine the appropriateness of this definition. This study examines fifteen different risky drinking thresholds to assess which definitions of risky drinking best predict negative outcomes. METHODS: This paper presents an analysis of a national survey sample of 19,757 drinkers. The appropriateness of each threshold is assessed using basic risk-curves, specificity and sensitivity analyses and the performance of each threshold definition in multivariate logistic regression models. Risky drinking was defined in fifteen ways (based on frequency and volume) and tested against a series of self-reported negative outcomes and risky behaviours. RESULTS: The study finds that the most appropriate risky drinking threshold for these data varies based on the mode of analysis and on the type of outcome being considered. Across all approaches used, risky drinking thresholds of seven or fewer drinks performed better than higher thresholds. CONCLUSIONS: While individual level risks peak at higher levels of consumption, these findings support the continuing use of relatively low thresholds for defining risky drinking, as risk across the total population is highest at these levels. PMID- 23726977 TI - Effects of bupropion on cognitive performance during initial tobacco abstinence. AB - BACKGROUND: Bupropion may aid tobacco abstinence by quickly relieving symptoms of nicotine withdrawal, perhaps including impaired cognitive performance. We examined whether bupropion would attenuate abstinence-induced cognitive deficits on the first day of a brief quit attempt, when smokers are most likely to relapse. METHODS: Smokers (N=24) with high quit interest were recruited for within-subjects cross-over test of bupropion vs placebo on ability to abstain during separate short-term practice quit smoking attempts. After introduction to working memory (N-back) and sustained attention (continuous performance task; CPT) tasks during the pre-quit smoking baseline, performance on these tasks was assessed after abstaining overnight (CO<10 ppm) on the first day of each quit attempt, while on bupropion and on placebo. RESULTS: Compared to placebo, bupropion after abstinence improved correct response times for working memory (p=.01 for medication by memory load interaction) and for one measure of sustained attention (numbers, but not letters; p<.05). DISCUSSION: Bupropion may attenuate some features of impaired cognitive performance due to withdrawal on the first day of a quit attempt. Future studies could examine whether this effect of bupropion contributes to its efficacy for longer-term smoking cessation. PMID- 23726978 TI - Neighborhood socioeconomic status and substance use by U.S. adults. AB - BACKGROUND: This study examined relationships of extremes in neighborhood socioeconomic status with use of tobacco, alcohol, marijuana and other drugs. Hypotheses were (1) residence in disadvantaged neighborhoods would be positively associated with stress-related and higher-risk substance use patterns (e.g., drug use), and (2) residence in affluent neighborhoods would be positively associated with "healthy" substance use (e.g., drinking within recommended guidelines) and negatively associated with substance use patterns incompatible with a culture of health. Age was examined as a potential moderator. METHODS: Data were from nationally-representative samples of U.S. adults (N=14,531) from the 2000 and 2005 National Alcohol Surveys linked with indicators of neighborhood SES from the 2000 U.S. Decennial Census. Analyses included gender-stratified multivariate logistic regression using weights to adjust for sampling and non-response. RESULTS: As hypothesized, compared to middle-class neighborhoods, residence in disadvantaged neighborhoods was associated with higher odds of both men's and women's tobacco use and with women's other drug use. Residence in affluent neighborhoods was associated with lower odds of men's tobacco use and women's marijuana use. The association of neighborhood SES with men's tobacco use was modified by age, with the highest odds of daily tobacco use evident for all men in disadvantaged neighborhoods, as well as for younger men in middle-class neighborhoods. There were no significant associations of either alcohol outcome with neighborhood SES. CONCLUSIONS: Increased risk of substance use for younger residents in both disadvantaged and middle-class neighborhoods and for older residents in disadvantaged neighborhoods suggest a need for targeted prevention interventions. PMID- 23726979 TI - Effects of 14-day treatment with the schedule III anorectic phendimetrazine on choice between cocaine and food in rhesus monkeys. AB - BACKGROUND: The clinical utility of monoamine releasers such as phenmetrazine or d-amphetamine as candidate agonist medications for cocaine dependence is hindered by their high abuse liability. Phendimetrazine is a clinically available schedule III anorectic that functions as a prodrug for phenmetrazine and thus may have lower abuse liability. This study determined the effects of continuous 14-day treatment with phendimetrazine on cocaine vs. food choice in rhesus monkeys (N=4). METHODS: Responding was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and cocaine injections (0 0.1mg/kg/injection, fixed-ratio 10 schedule). Cocaine choice dose-effect curves were determined daily before and during 14-day periods of continuous intravenous treatment with saline or (+)-phendimetrazine (0.32-1.0mg/kg/h). Effects of 14-day treatment with (+)-phenmetrazine (0.1-0.32 mg/kg/h; N=5) and d-amphetamine (0.032 0.1mg/kg/h; N=6) were also examined for comparison. RESULTS: During saline treatment, food was primarily chosen during availability of low cocaine doses (0, 0.0032, and 0.01 mg/kg/injection), and cocaine was primarily chosen during availability of higher cocaine doses (0.032 and 0.1mg/kg/injection). Phendimetrazine initially decreased overall responding without significantly altering cocaine choice. Over the course of 14 days, tolerance developed to rate decreasing effects, and phendimetrazine dose-dependently decreased cocaine choice (significant at 0.032 mg/kg/injection cocaine). Phenmetrazine and d-amphetamine produced qualitatively similar effects. CONCLUSIONS: These results demonstrate that phendimetrazine can produce significant, though modest, reductions in cocaine choice in rhesus monkeys. Phendimetrazine may be especially suitable as a candidate medication for human studies because of its schedule III clinical availability. PMID- 23726980 TI - Changing patterns of first injection across key periods of the French Harm Reduction Policy: PrimInject, a cross sectional analysis. AB - BACKGROUND: Monitoring of emerging modes of drug consumption in France has identified new patterns of injection among youths with diverse social backgrounds, which may explain the persistence of high rates of hepatitis C virus infection. The circumstances surrounding the first injection have been poorly documented in the group of heavy drug users and in the context of the French opioid substitution treatment (OST) policy that provides expanded access to high dosage buprenorphine (BHD) METHODS: An Internet survey (Priminject) was conducted from October 2010 to March 2011 with French drug users. Four time periods were compared based on critical dates throughout the implementation of the Harm Reduction Policy in France. RESULTS: Compared with drug users who injected for the first time prior to 1995, the aspects of drug use for users who recently injected for the first time were as follows: (1) experimentation with miscellaneous drugs before the first injection; (2) an older age at the time of first injection; (3) heroin as the drug of choice for an individual's first injection, notwithstanding the increased usage of stimulant drugs; (4) BHD did not appear to be a pathway to injection; and (5) an increased number of users who injected their first time alone, without the help or presence of another individual. CONCLUSION: The PrimInject study showed that there is a group of injection drug users that is larger than the group of injection drug users observed in previous studies; therefore, it is necessary to diversify programs to reach the entire spectrum of high-risk users. PMID- 23726981 TI - Reduced striatal brain volumes in non-medicated adult ADHD patients with comorbid cocaine dependence. AB - BACKGROUND: Adult attention deficit/hyperactivity disorder (ADHD) is highly comorbid with other psychiatric disorders, including substance use disorders (SUD). Patients with ADHD and SUD comorbidity respond less well to pharmacological treatment (e.g., methylphenidate), have more severe ADHD symptoms, and are generally more impulsive than ADHD patients without SUD. However, little is known about structural brain abnormalities that may differentiate ADHD patients with and without comorbid SUD. METHODS: We compared regional grey matter volumes of 10 non-medicated male ADHD patients with comorbid cocaine dependence, 14 non-medicated male ADHD patients without cocaine dependence and 15 healthy control participants matched for age and premorbid intellectual functioning, using voxel-based morphometry (VBM) using both a whole brain analysis and a priori ROI analysis based on the existing ADHD VBM literature. RESULTS: In a whole brain analysis, ADHD patients with and without cocaine dependence showed smaller volumes in the right putamen and cerebellum compared to healthy controls. In addition, ADHD patients without cocaine dependence showed larger volumes in the midbrain and in the precentral gyrus compared to healthy control participants and larger volumes in the occipital cortex compared to ADHD patients with comorbid cocaine dependence. A direct comparison using the a priori defined ROI approach showed that ADHD patients with cocaine dependence had smaller putamen volumes than ADHD patients without cocaine dependence. CONCLUSIONS: ADHD patients with cocaine dependence show more profound grey matter volume reductions in the striatum compared to ADHD patients without cocaine dependence. Possible implications for treatment are discussed. PMID- 23726982 TI - Perioperative nutritional support in the ERAS approach. PMID- 23726983 TI - Crystal structure of the periplasmic disulfide-bond isomerase DsbC from Salmonella enterica serovar Typhimurium and the mechanistic implications. AB - The disulfide-bond isomerase DsbC plays a crucial role in the folding of bacterial proteins in the periplasmic space. DsbC has a V-shaped dimeric structure with two domains, and Cys98 in the C-terminal domain attacks inappropriate disulfide bonds in substrate proteins due to its high nucleophilic activity. In this article, we present the crystal structure of DsbC from Salmonella enterica serovar Typhimurium. We evaluated the conserved residues Asp95 and Arg125, which are located close to Cys98. The mutation of Asp95 or Arg125 abolished the disulfide isomerase activity of DsbC in an in vitro assay using a protein substrate, and the R125A mutation significantly reduced the chaperone activity for the substrate RNase I in vivo. Furthermore, a comparative analysis suggested that the conformation of Arg125 varies depending on the packing or protein-protein interactions. Based on these findings, we suggest that Asp95 and Arg125 modulate the pKa of Cys98 during catalysis. PMID- 23726985 TI - Emergency department image interpretation accuracy: The influence of immediate reporting by radiology. AB - INTRODUCTION: The misinterpretation of radiographs is recognised as a key source of emergency department (ED) errors, regardless of clinician profession. This article compares ENP and medical staff accuracy in the interpretation of musculoskeletal trauma X-rays between immediate and delayed radiology reporting pathways. METHOD: The data for this study was drawn from a larger pragmatic randomized controlled trial of immediate reporting. Patients were recruited and randomly assigned to immediate or delayed reporting arms and treated according to group assignment. Image interpretive accuracy between ED staff groups and arms was undertaken together with an assessment of the influence of immediate reporting on patient pathways and journey times. RESULTS: Six hundred and seventy four radiographic examinations were performed (598 patients). There was a significant reduction in the interpretive errors in the immediate reporting arm for all ED clinicians (proportional difference=4.2%; 95% CI [0.017,0.068]; p=0.001), but no significant difference in proportion of interpretive errors was evident between ENPs and medical staff. Patient journey times, discharge and referral rates were not significantly different between study arms, although admission rates varied for medical staff collectively. CONCLUSION: ENP X-ray interpretation accuracy is comparable with that of medical staff, but immediate reporting was seen to reduce errors without increasing patient journey times. PMID- 23726986 TI - Food neophobia, nanotechnology and satisfaction with life. AB - This study investigates the relationship between food neophobia, satisfaction with life and food-related life, and acceptance of the use of nanotechnology in food production. Questionnaire data was collected from a sample of 400 supermarket shoppers in southern Chile. The questionnaire measured knowledge of nanotechnology and willingness to purchase food products involving nanotechnology, and included the SWLS (Satisfaction with Life Scale), SWFL (Satisfaction with Food-related Life) and FNS (Food Neophobia Scale) scales. Using cluster analysis, four consumer types were distinguished with significant differences in their scores on the SWLS, SWFL and FNS. The types differed in their knowledge of nanotechnology, willingness to purchase foods involving nanotechnology, age, socioeconomic level and lifestyle. The least food-neophobic type had the highest levels of satisfaction with life and with food-related life and also had the highest acceptance of packaging and foods produced with nanotechnology. The results suggest that the degree of food neophobia is associated with satisfaction with life and with food-related life, as well as with the acceptance of products with nanotechnological applications. PMID- 23726984 TI - Structural studies on full-length talin1 reveal a compact auto-inhibited dimer: implications for talin activation. AB - Talin is a large adaptor protein that activates integrins and couples them to cytoskeletal actin. Talin contains an N-terminal FERM (band 4.1, ezrin, radixin, moesin) domain (the head) linked to a flexible rod comprised of 13 amphipathic helical bundles (R1-R13) that terminate in a C-terminal helix (DD) that forms an anti-parallel dimer. We derived a three-dimensional structural model of full length talin at a resolution of approximately 2.5nm using EM reconstruction of full-length talin and the known shapes of the individual domains and inter-domain angles as derived from small angle X-ray scattering. Talin adopts a compact conformation consistent with a dimer in which the two talin rods form a donut shaped structure, with the two talin heads packed side by side occupying the hole at the center of this donut. In this configuration, the integrin binding site in the head domain and the actin-binding site at the carboxy-terminus of the rod are masked, implying that talin must unravel before it can support integrin activation and engage the actin cytoskeleton. PMID- 23726987 TI - Genetically encoded fluorescent redox sensors. AB - BACKGROUND: Life is a constant flow of electrons via redox couples. Redox reactions determine many if not all major cellular functions. Until recently, redox processes remained hidden from direct observation in living systems due to the lack of adequate methodology. Over the last years, imaging tools including small molecule probes and genetically encoded sensors appeared, which provided, for the first time, an opportunity to visualize and, in some cases, quantify redox reactions in live cells. Genetically encoded fluorescent redox probes, such as HyPer, rxYFP and roGFPs, have been used in several models, ranging from cultured cells to transgenic animals, and now enough information has been collected to highlight advantages and pitfalls of these probes. SCOPE OF REVIEW: In this review, we describe the main types of genetically encoded redox probes, their essential properties, advantages and disadvantages. We also provide an overview of the most important, in our opinion, results obtained using these probes. Finally, we discuss redox-dependent photoconversions of GFP and other prospective directions in redox probe development. MAJOR CONCLUSIONS: Fluorescent protein-based redox probes have important advantages such as high specificity, possibility of transgenesis and fine subcellular targeting. For proper selection of a redox sensor for a particular model, it is important to understand that HyPer and roGFP2-Orp1 are the probes for H2O2, whereas roGFP1/2, rxYFP and roGFP2 Grx1 are the probes for GSH/GSSG redox state. Possible pH changes should be carefully controlled in experiments with HyPer and rxYFP. GENERAL SIGNIFICANCE: Genetically encoded redox probes are the only instruments allowing real-time monitoring of reactive oxygen species and thiol redox state in living cells and tissues. We believe that in the near future the palette of FP-based redox probes will be expanded to red and far-red parts of the spectrum and to other important reactive species such as NO, O2 and superoxide. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. PMID- 23726988 TI - Iron release from ferritin by flavin nucleotides. AB - BACKGROUND: Extensive in-vitro studies have focused on elucidating the mechanism of iron uptake and mineral core formation in ferritin. However, despite a plethora of studies attempting to characterize iron release under different experimental conditions, the in-vivo mobilization of iron from ferritin remains poorly understood. Several iron-reductive mobilization pathways have been proposed including, among others, flavin mononucleotides, ascorbate, glutathione, dithionite, and polyphenols. Here, we investigate the kinetics of iron release from ferritin by reduced flavin nucleotide, FMNH2, and discuss the physiological significance of this process in-vivo. METHODS: Iron release from horse spleen ferritin and recombinant human heteropolymer ferritin was followed by the change in optical density of the Fe(II)-bipyridine complex using a Cary 50 Bio UV-Vis spectrophotometer. Oxygen consumption curves were followed on a MI 730 Clark oxygen microelectrode. RESULTS: The reductive mobilization of iron from ferritin by the nonenzymatic FMN/NAD(P)H system is extremely slow in the presence of oxygen and might involve superoxide radicals, but not FMNH2. Under anaerobic conditions, a very rapid phase of iron mobilization by FMNH2 was observed. CONCLUSIONS: Under normoxic conditions, FMNH2 alone might not be a physiologically significant contributor to iron release from ferritin. GENERAL SIGNIFICANCE: There is no consensus on which iron release pathway is predominantly responsible for iron mobilization from ferritin under cellular conditions. While reduced flavin mononucleotide (FMNH2) is one likely candidate for in-vivo ferritin iron removal, its significance is confounded by the rapid oxidation of the latter by molecular oxygen. PMID- 23726989 TI - Astaxanthin inhibits NF-kappaB and Wnt/beta-catenin signaling pathways via inactivation of Erk/MAPK and PI3K/Akt to induce intrinsic apoptosis in a hamster model of oral cancer. AB - BACKGROUND: The oncogenic transcription factors NF-kappaB and beta-catenin, constitutively activated by upstream serine/threonine kinases control several cellular processes implicated in malignant transformation including apoptosis evasion. The aim of this study was to investigate the chemopreventive effects of astaxanthin, an antioxidant carotenoid, in the hamster buccal pouch (HBP) carcinogenesis model based on its ability to modulate NF-kappaB and Wnt signaling pathways and induce apoptosis. METHODS: We determined the effect of dietary supplementation of astaxanthin on the oncogenic signaling pathways - NF-kappaB and Wnt/beta-catenin, their upstream activator kinases - Erk/MAPK and PI-3K/Akt, and the downstream event - apoptosis evasion by real-time quantitative RT-PCR, western blot, and immunohistochemical analyses. RESULTS: We found that astaxanthin inhibits NF-kappaB and Wnt signaling by downregulating the key regulatory enzymes IKKbeta and GSK-3beta. Analysis of gene expression and docking interactions revealed that inhibition of these pathways may be mediated via inactivation of the upstream signaling kinases Erk/Akt by astaxanthin. Astaxanthin also induced caspase-mediated mitochondrial apoptosis by downregulating the expression of antiapoptotic Bcl-2, p-Bad, and survivin and upregulating proapoptotic Bax and Bad, accompanied by efflux of Smac/Diablo and cytochrome-c into the cytosol, and induced cleavage of poly (ADP-ribose) polymerase (PARP). CONCLUSIONS: The results provide compelling evidence that astaxanthin exerts chemopreventive effects by concurrently inhibiting phosphorylation of transcription factors and signaling kinases and inducing intrinsic apoptosis. GENERAL SIGNIFICANCE: Astaxanthin targets key molecules in oncogenic signaling pathways and induces apoptosis and is a promising candidate agent for cancer prevention and therapy. PMID- 23726990 TI - Using exomarkers to assess mitochondrial reactive species in vivo. AB - BACKGROUND: The ability to measure the concentrations of small damaging and signalling molecules such as reactive oxygen species (ROS) in vivo is essential to understanding their biological roles. While a range of methods can be applied to in vitro systems, measuring the levels and relative changes in reactive species in vivo is challenging. SCOPE OF REVIEW: One approach towards achieving this goal is the use of exomarkers. In this, exogenous probe compounds are administered to the intact organism and are then transformed by the reactive molecules in vivo to produce a diagnostic exomarker. The exomarker and the precursor probe can be analysed ex vivo to infer the identity and amounts of the reactive species present in vivo. This is akin to the measurement of biomarkers produced by the interaction of reactive species with endogenous biomolecules. MAJOR CONCLUSIONS AND GENERAL SIGNIFICANCE: Our laboratories have developed mitochondria-targeted probes that generate exomarkers that can be analysed ex vivo by mass spectrometry to assess levels of reactive species within mitochondria in vivo. We have used one of these compounds, MitoB, to infer the levels of mitochondrial hydrogen peroxide within flies and mice. Here we describe the development of MitoB and expand on this example to discuss how better probes and exomarkers can be developed. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. PMID- 23726991 TI - The expression and proangiogenic effect of nucleolin during the recovery of heat denatured HUVECs. AB - BACKGROUND: The present study aims to examine the expression patterns and roles of nucleolin during the recovery of heat-denatured human umbilical vein endothelial cells (HUVECs). METHODS: Deep partial thickness burn model in Sprague Dawley rats and the heat denatured cell model (52 degrees C, 35s) were used. The expression of nucleolin was measured using Western blot analysis and real-time PCR. Angiogenesis was assessed using in vitro parameters including endothelial cell proliferation, transwell migration assay, and scratched wound healing. Gene transfection and RNA interference approaches were employed to investigate the roles of nucleolin. RESULTS: Nucleolin mRNA and protein expression showed a time dependent increase during the recovery of heat-denatured dermis and HUVECs. Heat denaturation time-dependently promoted cell growth, adhesion, migration, scratched wound healing and formation of tube-like structures in HUVECs. These effects of heat denaturation on endothelial wound healing and formation of tube like structures were prevented by knockdown of nucleolin, whereas over-expression of nucleolin increased cell growth, migration, and formation of tube-like structures in cultured HUVEC endothelial cells. In addition, we found that the expression of vascular endothelial growth factor (VEGF) increased during the recovery of heat-denatured dermis and HUVECs, and nucleolin up-regulated VEGF in HUVECs. CONCLUSIONS: The present study reveals that the expression of nucleolin is up-regulated, and plays a pro-angiogenic role during the recovery of heat denatured dermis and its mechanism is probably dependent on production of VEGF. GENERAL SIGNIFICANCE: We find a novel and important pro-angiogenic role of nucleolin during the recovery of heat-denatured dermis. PMID- 23726992 TI - Structural basis of the 14-3-3 protein-dependent activation of yeast neutral trehalase Nth1. AB - BACKGROUND: Trehalases are highly conserved enzymes catalyzing the hydrolysis of trehalose in a wide range of organisms. The activity of yeast neutral trehalase Nth1 is regulated in a 14-3-3- and a calcium-dependent manner. The Bmh proteins (the yeast 14-3-3 isoforms) recognize phosphorylated Nth1 and enhance its enzymatic activity through an unknown mechanism. METHODS: To investigate the structural basis of interaction between Nth1 and Bmh1, we used hydrogen/deuterium exchange coupled to mass spectrometry, circular dichroism spectroscopy and homology modeling to identify structural changes occurring upon the complex formation. RESULTS: Our results show that the Bmh1 protein binding affects structural properties of several regions of phosphorylated Nth1: the N-terminal segment containing phosphorylation sites responsible for Nth1 binding to Bmh, the region containing the calcium binding domain, and segments surrounding the active site of the catalytic trehalase domain. The complex formation between Bmh1 and phosphorylated Nth1, however, is not accompanied by the change in the secondary structure composition but rather the change in the tertiary structure. CONCLUSIONS: The 14-3-3 protein-dependent activation of Nth1 is based on the structural change of both the calcium binding domain and the catalytic trehalase domain. These changes likely increase the accessibility of the active site, thus resulting in Nth1 activation. GENERAL SIGNIFICANCE: The results presented here provide a structural view of the 14-3-3 protein-dependent activation of yeast neutral trehalase Nth1, which might be relevant to understand the process of Nth1 activity regulation as well as the role of the 14-3-3 proteins in the regulation of other enzymes. PMID- 23726994 TI - Altered resting-state brain activity at functional MRI during automatic memory consolidation of fear conditioning. AB - Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms of fear acquisition and extinction. However, the neural mechanism of automatic memory consolidation of fear conditioning is still unclear. To address this question, we measured brain activity following fear acquisition using resting-state functional magnetic resonance imaging (rs-fMRI). In the current study, we used a marker of fMRI, amplitude of low-frequency (0.01 0.08Hz) fluctuation (ALFF) to quantify the spontaneous brain activity. Brain activity correlated to fear memory consolidation was observed in parahippocampus, insula, and thalamus in resting-state. Furthermore, after acquired fear conditioning, compared with control group some brain areas showed ALFF increased in ventromedial prefrontal cortex (vmPFC) and anterior cingulate cortex (ACC) in the experimental group, whereas some brain areas showed decreased ALFF in striatal regions (caudate, putamen). Moreover, the change of ALFF in vmPFC was positively correlated with the subjective fear ratings. These findings suggest that the parahippocampus, insula, and thalamus are the neural substrates of fear memory consolidation. The difference in activity could be attributed to a homeostatic process in which the vmPFC and ACC were involved in the fear recovery process, and change of ALFF in vmPFC predicts subjective fear ratings. PMID- 23726993 TI - Allosteric modulation of zinc speciation by fatty acids. AB - BACKGROUND: Serum albumin is the major protein component of blood plasma and is responsible for the circulatory transport of a range of small molecules that include fatty acids, hormones, metal ions and drugs. Studies examining the ligand binding properties of albumin make up a large proportion of the literature. However, many of these studies do not address the fact that albumin carries multiple ligands (including metal ions) simultaneously in vivo. Thus the binding of a particular ligand may influence both the affinity and dynamics of albumin interactions with another. SCOPE OF REVIEW: Here we review the Zn(2+) and fatty acid transport properties of albumin and highlight an important interplay that exists between them. Also the impact of this dynamic interaction upon the distribution of plasma Zn(2+), its effect upon cellular Zn(2+) uptake and its importance in the diagnosis of myocardial ischemia are considered. MAJOR CONCLUSIONS: We previously identified the major binding site for Zn(2+) on albumin. Furthermore, we revealed that Zn(2+)-binding at this site and fatty acid binding at the FA2 site are interdependent. This suggests that the binding of fatty acids to albumin may serve as an allosteric switch to modulate Zn(2+) binding to albumin in blood plasma. GENERAL SIGNIFICANCE: Fatty acid levels in the blood are dynamic and chronic elevation of plasma fatty acid levels is associated with some metabolic disorders such as cardiovascular disease and diabetes. Since the binding of Zn(2+) to albumin is important for the control of circulatory/cellular Zn(2+) dynamics, this relationship is likely to have important physiological and pathological implications. This article is part of a Special Issue entitled Serum Albumin. PMID- 23726995 TI - Expression and functional role of metallothioneins I and II in the spinal cord in inflammatory and neuropathic pain models. AB - In this study, the expression and functional role of metallothioneins I and II (MT-I/II) were evaluated in the spinal cord in rat models of inflammatory and neuropathic pain. Complete Freund's adjuvant (CFA) injection into the hindpaw induced an increase in MT-I/II protein expression in bilateral dorsal and ventral horns throughout the spinal cord, while chronic constriction injury (CCI) of the sciatic nerve induced an increase in MT-I/II expression in the ipsilateral dorsal and ventral horns of the lower lumbar spinal cord. Increased MT-I/II immunoreactivity was predominantly localized to vascular endothelial cells. CFA injection- and CCI-induced MT-I/II expression was inhibited by intrathecal administration of MT-I siRNA. Treatment with MT-I siRNA before CFA injection or at early time points after CCI resulted in a significant attenuation of mechanical allodynia and thermal hyperalgesia, while treatment at later time points had no effect on established pain behaviors. Our results suggest that endogenous MT-I/II might play an important role in the pathogenesis of pain behaviors, participating in the initiation of inflammatory and neuropathic pain rather than in their maintenance. PMID- 23726996 TI - Genotype-phenotype analysis of S326C OGG1 polymorphism: a risk factor for oxidative pathologies. AB - 8-Oxoguanine DNA glycosylase (OGG) activity was measured by an in vitro assay in lymphocytes of healthy volunteers genotyped for various OGG1 polymorphisms. Only homozygous carriers of the polymorphic C326 allele showed a significantly lower OGG activity compared to the homozygous S326 genotype. The purified S326C OGG1 showed a decreased ability to complete the repair synthesis step in a base excision repair reaction reconstituted in vitro. The propensity of this variant to dimerize as well as its catalytic impairment were shown to be enhanced under oxidizing conditions. Mass spectrometry revealed that the extra cysteine of the variant protein is involved in disulfide bonds compatible with significant conformational changes and/or dimerization. We propose that the S326C OGG1 catalytic impairment and its susceptibility to dimerization and disulfide bond formation in an oxidizing environment all concur to decrease repair capacity. Consequently, the C326 homozygous carriers may be at increased risk of oxidative pathologies. PMID- 23726998 TI - Evolutionary origin and divergence of the growth hormone receptor family: insight from studies on sea lamprey. AB - Sea lamprey, one of the oldest extant lineages of vertebrates, Agnatha, was used to clarify the evolutionary origin and divergence of the growth hormone receptor (GHR) family. A single full-length cDNA encoding a protein that shares amino acid identity with GHRs and prolactin receptors (PRLRs) previously characterized from teleost fish was identified. Expression of the GHR/PRLR-like transcript was widespread among tissues, including brain, pituitary, heart, liver, and skeletal muscle, which is consistent with the broad physiological roles of GH-family peptides. Phylogenetic analysis suggests that the lamprey possess an ancestral gene encoding a common GHR/PRLR that diverged to give rise to distinct GHRs and PRLRs later in the course of vertebrate evolution. After the divergence of the Actinopterygian and Sarcopterygian lineages, the GHR gene was duplicated in the Actinopterygian lineage during the fish-specific genome duplication event giving rise to two GHRs in teleosts, type 1 GHR and type 2 GHR. A single GHR gene orthologous to the teleost type 1 GHR persisted in the Sarcopterygian lineage, including the common ancestor of tetrapods. Within the teleosts, several subsequent independent duplication events occurred that led to several GHR subtypes. A revised nomenclature for vertebrate GHRs is proposed that represents the evolutionary history of the receptor family. Structural features of the receptor influence ligand binding, receptor dimerization, linkage to signal effector pathways, and, ultimately, hormone function. PMID- 23726997 TI - High-fat diet induces changes in adipose tissue trans-4-oxo-2-nonenal and trans-4 hydroxy-2-nonenal levels in a depot-specific manner. AB - Protein carbonylation is the covalent modification of proteins by alpha,beta unsaturated aldehydes produced by nonenzymatic lipid peroxidation of polyunsaturated fatty acids. The most widely studied aldehyde product of lipid peroxidation, trans-4-hydroxy-2-nonenal (4-HNE), is associated with obesity induced metabolic dysfunction and has demonstrated reactivity toward key proteins involved in cellular function. However, 4-HNE is only one of many lipid peroxidation products and the lipid aldehyde profile in adipose tissue has not been characterized. To further understand the role of oxidative stress in obesity induced metabolic dysfunction, a novel LC-MS/MS method was developed to evaluate aldehyde products of lipid peroxidation and applied to the analysis of adipose tissue. 4-HNE and trans-4-oxo-2-nonenal (4-ONE) were the most abundant aldehydes present in adipose tissue. In high fat-fed C57Bl/6J and ob/ob mice the levels of lipid peroxidation products were increased 5- to 11-fold in epididymal adipose, unchanged in brown adipose, but decreased in subcutaneous adipose tissue. Epididymal adipose tissue of high fat-fed mice also exhibited increased levels of proteins modified by 4-HNE and 4-ONE, whereas subcutaneous adipose tissue levels of these modifications were decreased. High fat feeding of C57Bl/6J mice resulted in decreased expression of a number of genes linked to antioxidant biology selectively in epididymal adipose tissue. Moreover, TNFalpha treatment of 3T3-L1 adipocytes resulted in decreased expression of GSTA4, GPx4, and Prdx3 while upregulating the expression of SOD2. These results suggest that inflammatory cytokines selectively downregulate antioxidant gene expression in visceral adipose tissue, resulting in elevated lipid aldehydes and increased protein carbonylation. PMID- 23726999 TI - Hydroxylation of quinocetone and carbadox is mediated by CYP1As in the chicken (Gallus gallus). AB - Quinoxaline derivatives (quinoxalines) comprise a class of drugs that have been widely used as animal antimicrobial agents and feed additives. Although the metabolism of quinoxaline drugs has been mostly studied using chicken liver microsomes, the biochemical mechanism of biotransformation of these chemicals in the chicken has yet to be characterized. In this study, using bacteria produced enzymes, we demonstrated that both CYP1A4 and CYP1A5 participate in the oxidative metabolism of quinoxalines. For CYP1A5, three hydroxylated metabolites of quinocetone were generated. In addition, CYP1A5 is able to hydroxylate carbadox. For CYP1A4, only one hydroxylated product of quinocetone on the phenyl ring was identified. Neither CYP1A5 nor CYP1A4 showed hydroxylation activity towards mequindox and cyadox. Our results suggest that CYP1A4 and CYP1A5 have different and somewhat overlapping substrate specificity in quinoxaline metabolism, and CYP1A5 represents a crucial enzyme in hydroxylation of both quinocetone and carbadox. PMID- 23727001 TI - Is there an authentic increased risk of pneumococcal pneumonia among young mothers whose children were fully vaccinated with PCV7? The role of methodological shortcomings. PMID- 23727000 TI - Protection against avian necrotic enteritis after immunisation with NetB genetic or formaldehyde toxoids. AB - NetB (necrotic enteritis toxin B) is a recently identified beta-pore-forming toxin produced by Clostridium perfringens. This toxin has been shown to play a major role in avian necrotic enteritis. In recent years, a dramatic increase in necrotic enteritis has been observed, especially in countries where the use of antimicrobial growth promoters in animal feedstuffs has been banned. The aim of this work was to determine whether immunisation with a NetB toxoid would provide protection against necrotic enteritis. The immunisation of poultry with a formaldehyde NetB toxoid or with a NetB genetic toxoid (W262A) resulted in the induction of antibody responses against NetB and provided partial protection against disease. PMID- 23727002 TI - Immunogenicity and safety of an investigational hepatitis B vaccine with a Toll like receptor 9 agonist adjuvant (HBsAg-1018) compared to a licensed hepatitis B vaccine in healthy adults 40-70 years of age. AB - BACKGROUND: The currently licensed hepatitis B vaccines have limitations including hyporesponsiveness in older adults, poor compliance, and the extended time for most persons to develop seroprotection (e.g. >6months). A vaccine containing HBsAg combined with a Toll-like receptor 9 agonist adjuvant (HBsAg 1018) has been developed to overcome these limitations. METHODS: A Phase 3, multicenter, randomized, subject- and observer-blinded, active-controlled trial was conducted among healthy subjects 40-70years of age comparing the immunogenicity and safety of two doses of HBsAg-1018 at 0 and 4weeks to three doses of licensed hepatitis B vaccine, HBsAg-Eng, at 0, 4, and 24weeks. The primary immunogenicity endpoint was noninferiority of the seroprotection rate (SPR; % with anti-HBs>=10mIU/mL) of HBsAg-1018 compared to the SPR of HBsAg-Eng at 8 weeks following the last dose of vaccine. Conditional upon meeting noninferiority, superiority of HBsAg-1018 over HBsAg-Eng was assessed. Safety was compared between the two vaccines. RESULTS: At the primary endpoint, the SPR for the HBsAg-1018 group (90.0%) was superior to the SPR for the HBsAg-Eng group (70.5%) with an SPR difference of 19.5% (95% CI, 14.7%, 24.7%). At week 28 when the SPR peaked in the HBsAg-Eng group (72.8%), the SPR in the HBsAg-1018 group (94.8%) was significantly higher than in the HBsAg-Eng group. The SPR in the HBsAg-1018 group was significantly higher than in the HBsAg-Eng group at each study visit from week 4 through week 52. The safety profiles for the two vaccines were similar. CONCLUSION: When compared to the HBsAg-Eng three-dose regimen given at 0, 1, and 6months, HBsAg-1018 demonstrated superior seroprotection with only two doses at 0 and 1month. The safety profile of HBsAg-1018 was comparable to that of the licensed vaccine, HBsAg-Eng. HBsAg-1018 would provide a significant public health contribution toward the prevention of hepatitis B infection. PMID- 23727003 TI - Deciphering the protective role of adaptive immunity to CHIKV/IRES a novel candidate vaccine against Chikungunya in the A129 mouse model. AB - Chikungunya virus (CHIKV), a mosquito-borne alphavirus, recently re-emerged in Africa and spread to islands in the Indian Ocean, the Indian subcontinent, and to South East Asia. Viremic travelers have also imported CHIKV to the Western hemisphere highlighting the importance of CHIKV in public health. In addition to the great burden of arthralgic disease, which can persist for months or years, epidemiologic studies have estimated case-fatality rates of ~0.1%, principally from neurologic disease in older patients. There are no licensed vaccines or effective therapies to prevent or treat human CHIKV infections. We have developed a live CHIKV vaccine (CHIKV/IRES) that is highly attenuated yet immunogenic in mouse models, and is incapable of replicating in mosquito cells. In this study we sought to decipher the role of adaptive immunity elicited by CHIKV/IRES in protection against wild-type CHIKV infection. A single dose of vaccine effectively activated T cells with an expansion peak on day 10 post immunization and elicited memory CD4(+) and CD8(+) T cells that produced IFN-gamma, TNF-alpha and IL-2 upon restimulation with CHIKV/IRES. Adoptive transfer of CHIKV/IRES immune CD4(+) or CD8(+) T cells did not confer protection against wtCHIKV-LR challenge. By contrast, passive immunization with anti-CHIKV/IRES immune serum provided protection, and a correlate of a minimum protective neutralizing antibody titer was established. Overall, our findings demonstrate the immunogenic potential of the CHIKV/IRES vaccine and highlight the important role that neutralizing antibodies play in protection against an acute CHIKV infection. PMID- 23727004 TI - Protection against pneumococcal infection elicited by immunization with multiple pneumococcal heat shock proteins. AB - Heat shock proteins (HSPs) play important roles in the pathogenesis of pneumococcal infection, and they are considered as potential protein vaccine antigens. In this study, we investigated the efficacy of immunization with pneumococcal HSPs, including ClpP (hsp100/Clp peptidase subunit), DnaJ (hsp40) and GroEL (hsp60), to protect against pneumococcal carriage, lung colonization and sepsis in mouse models using different serotypes of Streptococcus pneumoniae. In a nasopharyngeal colonization model by serotype 6B or 14 and in a lung colonization model by serotype 19F, immunization with pneumococcal HSPs could elicit effective protection. Likewise, vaccination with ClpP, DnaJ or GroEL allowed significantly longer mouse survival times after lethal intranasal challenge with serotype pneumococcal 2, 3 or 4. Interestingly, combinations of these HSPs could consistently enhance the protection against nasopharynx carriage, lung colonization as well as invasive infection caused by different pneumococcal serotypes. In an in vitro killing assay, anti-sera against ClpP, DnaJ or GroEL could kill S. pneumoniae by polymorphonuclear leukocytes in a complement-dependent way, and combinations of multiple anti-sera against these HSPs could increase the killing ability compared with single anti-sera. Finally, passive immunization studies with anti-sera against pneumococcal HSPs also demonstrated that an additive effect could be achieved by using multiple anti sera when compared with single anti-sera. Thus, inclusion of multiple pneumococcal HSPs is important for the development of protein-based pneumococcal vaccines. PMID- 23727005 TI - Synthesis of mixed-chain phosphatidylcholines including coumarin fluorophores for FRET-based kinetic studies of phospholipase A(2) enzymes. AB - Phospholipase A2 (PLA2) enzymes catalyze the hydrolysis of the sn-2 ester linkage of glycerophospholipids to produce fatty acids and lysophospholipids. A significant number of mammalian phospholipases comprise a family of secreted PLA2 enzymes, found in specific tissues and cellular locations, exhibiting unique enzymatic properties and distinct biological functions. Development of new real time spectrofluorimetric PLA2 assays should facilitate the kinetic characterization and mechanistic elucidation of the isozymes in vitro, with the potential applicability to detect and measure catalytic PLA2 activity in tissues and cellular locations. Here we report a new synthesis of double-labeled phosphatidylcholine analogs with chain-terminal reporter groups including coumarin fluorophores for fluorescence resonance energy transfer (FRET)-based kinetic studies of PLA2 enzymes. The use of coumarin derivatives as fluorescent labels provides reporter groups with substantially decreased size compared to the first generation of donor-acceptor pairs of fluorescent phospholipids. The key advantage of the design is to interfere less with the physicochemical properties of the acyl chains, thereby improving the substrate quality of the synthetic probes. In order to assess the impact of the fluorophore substituents on the catalytic hydrolysis and on the phospholipid packing in the lipid-water interface of the assay, we used the experimentally determined specific activity of bee venom phospholipase A2 as a model for the secretory PLA2 enzymes. Specifically, the rate of PLA2 hydrolysis of the coumarin labeled phosphatidylcholine analogs was less than three times slower than the natural substrate dipalmitoyl phosphatidylcholine (DPPC) under the same experimental conditions. Furthermore, variation of the mole fraction of the synthetic phosphatidylcholine vs. that of the natural DPPC substrate showed nearly ideal mixing behavior in the phospholipid-surfactant aggregates of the assay. The synthesis provides a rapid and efficient method for preparation of new synthetic phosphatidylcholines with the desired target structures for enzymatic and physicochemical studies. PMID- 23727007 TI - Proteomics reveals energy and glutathione metabolic dysregulation in the prefrontal cortex of a rat model of depression. AB - Major depressive disorder (MDD) is a prevalent debilitating psychiatric mood that contributes to increased rates of disability and suicide. However, the pathophysiology underlying MDD remains poorly understood. A growing number of studies have associated dysfunction of the prefrontal cortex (PFC) with depression, but no proteomic study has been conducted to assess PFC protein expression in a preclinical model of depression. Using the chronic unpredictable mild stress (CUMS) rat model of depression, differential protein expression between the PFC proteomes of CUMS and control rats was assessed through two dimensional electrophoresis followed by matrix-assisted laser desorption ionization-time of flight-tandem mass spectrometry. Differential protein expression was analyzed for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway over-representation. Four differential proteins were selected for Western blotting validation. Twenty-nine differential proteins were identified in the PFC of CUMS rats relative to control rats. Through KEGG analysis, energy and glutathione metabolic pathways were determined to be the most significantly altered biological pathways. Two of the four differential proteins selected for Western blotting validation - glyoxalase 1 and dihydropyrimidinase-related protein 2 - were found to be significantly downregulated in CUMS relative to control rats. In conclusion, proteomic analysis reveals that energy and glutathione metabolism are the most significantly altered biological pathways in the CUMS rat model of depression. Further investigation on these processes and proteins in the PFC is key to a better understanding of the underlying pathophysiology of MDD. PMID- 23727008 TI - Transcriptome characterization by RNA-Seq reveals the involvement of the complement components in noise-traumatized rat cochleae. AB - Acoustic trauma, a leading cause of sensorineural hearing loss in adults, induces a complex degenerative process in the cochlea. Although previous investigations have identified multiple stress pathways, a comprehensive analysis of cochlear responses to acoustic injury is still lacking. In the current study, we used the next-generation RNA-sequencing (RNA-Seq) technique to sequence the whole transcriptome of the normal and noise-traumatized cochlear sensory epithelia (CSE). CSE tissues were collected from rat inner ears 1d after the rats were exposed to a 120-dB (sound pressure level) noise for 2 h. The RNA-Seq generated over 176 million sequence reads for the normal CSE and over 164 million reads for the noise-traumatized CSE. Alignment of these sequences with the rat Rn4 genome revealed the expression of over 17,000 gene transcripts in the CSE, over 2000 of which were exclusively expressed in either the normal or noise-traumatized CSE. Seventy-eight gene transcripts were differentially expressed (70 upregulated and 8 downregulated) after acoustic trauma. Many of the differentially expressed genes are related to the innate immune system. Further expression analyses using quantitative real time PCR confirmed the constitutive expression of multiple complement genes in the normal organ of Corti and the changes in the expression levels of the complement factor I (Cfi) and complement component 1, s subcomponent (C1s) after acoustic trauma. Moreover, protein expression analysis revealed strong expression of Cfi and C1s proteins in the organ of Corti. Importantly, these proteins exhibited expression changes following acoustic trauma. Collectively, the results of the current investigation suggest the involvement of the complement components in cochlear responses to acoustic trauma. PMID- 23727009 TI - Olfactory bulb monoamine concentrations vary with time of day. AB - The olfactory bulb (OB) has been recently identified as a circadian oscillator capable of operating independently of the master circadian pacemaker, the suprachiasmatic nuclei of the hypothalamus. OB oscillations manifest as rhythms in clock genes, electrical activity, and odor sensitivity. Dopamine, norepinephrine, and serotonin have been shown to modulate olfactory information processing by the OB and may be part of the mechanism that underlies diurnal changes in olfactory sensitivity. Rhythmic release of these neurotransmitters could generate OB rhythms in electrical activity and olfactory sensitivity. We hypothesized that these monoamines were rhythmically released in the OB. To test our hypotheses, we examined monoamine levels in the OB, over the course of a day, by high-performance liquid chromatography coupled to electrochemical detection. We observed that dopamine and its metabolite, 3-4-dihydroxyphenylacetic acid, rhythmically fluctuate over the day. In contrast, norepinephrine is arrhythmic. Serotonin and its metabolite hydroxyindoleacetic acid appear to rhythmically fluctuate. Each of these monoamines has been shown to alter OB circuit behavior and influence odor processing. Rhythmic release of serotonin may be a mechanism by which the suprachiasmatic nuclei communicate, indirectly, with the OB. PMID- 23727006 TI - Post-transcriptional regulatory elements and spatiotemporal specification of neocortical stem cells and projection neurons. AB - The mature neocortex is a unique six-layered mammalian brain region. It is composed of morphologically and functionally distinct subpopulations of primary projection neurons that form complex circuits across the central nervous system. The precisely-timed generation of projection neurons from neural stem cells governs their differentiation, postmitotic specification, and signaling, and is critical for cognitive and sensorimotor ability. Developmental perturbations to the birthdate, location, and connectivity of neocortical neurons are observed in neurological and psychiatric disorders. These facts are highlighting the importance of the precise spatiotemporal development of the neocortex regulated by intricate transcriptional, but also complex post-transcriptional events. Indeed, mRNA transcripts undergo many post-transcriptional regulatory steps before the production of functional proteins, which specify neocortical neural stem cells and subpopulations of neocortical neurons. Therefore, particular attention is paid to the differential post-transcriptional regulation of key transcripts by RNA-binding proteins, including splicing, localization, stability, and translation. We also present a transcriptome screen of candidate molecules associated with post-transcriptional mRNA processing that are differentially expressed at key developmental time points across neocortical prenatal neurogenesis. PMID- 23727010 TI - The circadian system: plasticity at many levels. AB - Over the years it has become crystal clear that a variety of processes encode time-of-day information, ranging from gene expression, protein stability, or subcellular localization of key proteins, to the fine tuning of network properties and modulation of input signals, ultimately ensuring that physiology and behavior are properly synchronized to a changing environment. The purpose of this review is to put forward examples (as opposed to generate a comprehensive revision of all the available literature) in which the circadian system displays a remarkable degree of plasticity, from cell autonomous to circuit-based levels. In the literature, the term circadian plasticity has been used to refer to different concepts. The obvious one, more literally, refers to any change that follows a circadian (circa=around, diem=day) pattern, i.e. a daily change of a given parameter. The discovery of daily remodeling of neuronal structures will be referred herein as structural circadian plasticity, and represents an additional and novel phenomenon modified daily. Finally, any plasticity that has to do with a circadian parameter would represent a type of circadian plasticity; as an example, adjustments that allow organisms to adapt their daily behavior to the annual changes in photoperiod is a form of circadian plasticity at a higher organizational level, which is an emergent property of the whole circadian system. Throughout this work we will revisit these types of changes by reviewing recent literature delving around circadian control of clock outputs, from the most immediate ones within pacemaker neurons to the circadian modulation of rest activity cycles. PMID- 23727011 TI - [Oesophageal localization: a rare complication of anisakidosis due to Pseudoterranova]. PMID- 23727013 TI - [Heart, vessels and age, main theme of the XXIIIrd European days of the French Society of Cardiology]. PMID- 23727012 TI - [Cocaine addiction: current data for the clinician]. AB - Cocaine remains the second most commonly used illicit drug worldwide after cannabis. Observed levels of cocaine use among countries considerably vary. An increased cocaine use is recorded in the general European population. Cocaine addiction is a worldwide public health problem, which has somatic, psychiatric, socio-economic and judicial complications. It is a multifactorial disorder variable in its clinical manifestations and heritable. Compared to the general population, there is a high prevalence of somatic and psychiatric disorders among cocaine-dependent patients. There are predictable dose-related effects of pharmacological action of cocaine and effects which are uncommon, unrelated to dose and occur randomly in this population. The number of patients entering drug treatment for primary cocaine use has been increasing in Europe for several years. However, there is no specific pharmacotherapy with established efficacy for the treatment of cocaine addiction, nor is any medication approved by regulatory authorities for such treatment. Recent controlled clinical studies and laboratory studies have highlighted some very promising medications. The perfect therapeutic platform for abstinence initiation and relapse prevention of cocaine addiction is a combination of pharmacological treatments and behavioral treatments. Targeting somatic and psychiatric comorbidity is another way to use pharmacological treatments in addictions. PMID- 23727014 TI - Bioregeneration of hyper-cross-linked polymeric resin preloaded with phenol. AB - In this study, the preliminary feasibility of bio-regeneration of a hyper-cross linked polymeric resin NDA-802 preloaded with phenol was investigated. As compared to the abiotic experiments, phenol preloaded with NDA-802 could be effectively desorbed and biodegraded, and the bioregenerated NDA-802 could be employed for multiple use. The concentration gradient hypothesis could interpret such bioregeneration process reasonably. A slight drop in adsorption capacity of NDA-802 after bioregeneration possibly resulted from the mesopore blockage by microbial metabolic by-products. In general, bioregeneration could serve as a potential choice for the exhausted hyper-cross-linked polymeric resin in wastewater treatment. PMID- 23727015 TI - Comparative study on methyl- and ethylmercury-induced toxicity in C6 glioma cells and the potential role of LAT-1 in mediating mercurial-thiol complexes uptake. AB - Various forms of mercury possess different rates of absorption, metabolism and excretion, and consequently, toxicity. Methylmercury (MeHg) is a highly neurotoxic organic mercurial. Human exposure is mostly due to ingestion of contaminated fish. Ethylmercury (EtHg), another organic mercury compound, has received significant toxicological attention due to its presence in thimerosal containing vaccines. This study was designed to compare the toxicities induced by MeHg and EtHg, as well as by their complexes with cysteine (MeHg-S-Cys and EtHg-S Cys) in the C6 rat glioma cell line. MeHg and EtHg caused significant (p<0.0001) decreases in cellular viability when cells were treated during 30min with each mercurial following by a washing period of 24h (EC50 values of 4.83 and 5.05MUM, respectively). Significant cytotoxicity (p<0.0001) was also observed when cells were treated under the same conditions with MeHg-S-Cys and EtHg-S-Cys, but the respective EC50 values were significantly increased (11.2 and 9.37MUM). l Methionine, a substrate for the l-type neutral amino acid carrier transport (LAT) system, significantly protected against the toxicities induced by both complexes (MeHg-S-Cys and EtHg-S-Cys). However, no protective effects of l-methionine were observed against MeHg and EtHg toxicities. Corroborating these findings, l methionine significantly decreased mercurial uptake when cells were exposed to MeHg-S-Cys (p=0.028) and EtHg-S-Cys (p=0.023), but not to MeHg and EtHg. These results indicate that the uptake of MeHg-S-Cys and EtHg-S-Cys into C6 cells is mediated, at least in part, through the LAT system, but MeHg and EtHg enter C6 cells by mechanisms other than LAT system. PMID- 23727016 TI - eIF5A promotes translation of polyproline motifs. AB - Translation factor eIF5A, containing the unique amino acid hypusine, was originally shown to stimulate Met-puromycin synthesis, a model assay for peptide bond formation. More recently, eIF5A was shown to promote translation elongation; however, its precise requirement in protein synthesis remains elusive. We use in vivo assays in yeast and in vitro reconstituted translation assays to reveal a specific requirement for eIF5A to promote peptide bond formation between consecutive Pro residues. Addition of eIF5A relieves ribosomal stalling during translation of three consecutive Pro residues in vitro, and loss of eIF5A function impairs translation of polyproline-containing proteins in vivo. Hydroxyl radical probing experiments localized eIF5A near the E site of the ribosome with its hypusine residue adjacent to the acceptor stem of the P site tRNA. Thus, eIF5A, like its bacterial ortholog EFP, is proposed to stimulate the peptidyl transferase activity of the ribosome and facilitate the reactivity of poor substrates like Pro. PMID- 23727017 TI - MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2. AB - The mitochondrial ubiquitin ligase MITOL regulates mitochondrial dynamics. We report here that MITOL regulates mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) domain formation through mitofusin2 (Mfn2). MITOL interacts with and ubiquitinates mitochondrial Mfn2, but not ER-associated Mfn2. Mutation analysis identified a specific interaction between MITOL C-terminal domain and Mfn2 HR1 domain. MITOL mediated lysine-63-linked polyubiquitin chain addition to Mfn2, but not its proteasomal degradation. MITOL knockdown inhibited Mfn2 complex formation and caused Mfn2 mislocalization and MAM dysfunction. Sucrose-density gradient centrifugation and blue native PAGE retardation assay demonstrated that MITOL is required for GTP-dependent Mfn2 oligomerization. MITOL knockdown reduced Mfn2 GTP binding, resulting in reduced GTP hydrolysis. We identified K192 in the GTPase domain of Mfn2 as a major ubiquitination site for MITOL. A K192R mutation blocked oligomerization even in the presence of GTP. Taken together, these results suggested that MITOL regulates ER tethering to mitochondria by activating Mfn2 via K192 ubiquitination. PMID- 23727019 TI - Genome-wide kinase-chromatin interactions reveal the regulatory network of ERK signaling in human embryonic stem cells. AB - The extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase signal-transduction cascade is one of the key pathways regulating proliferation and differentiation in development and disease. ERK signaling is required for human embryonic stem cells' (hESCs') self-renewing property. Here, we studied the convergence of the ERK signaling cascade at the DNA by mapping genome-wide kinase chromatin interactions for ERK2 in hESCs. We observed that ERK2 binding occurs near noncoding genes and histone, cell-cycle, metabolism, and pluripotency associated genes. We find that the transcription factor ELK1 is essential in hESCs and that ERK2 co-occupies promoters bound by ELK1. Strikingly, promoters bound by ELK1 without ERK2 are occupied by Polycomb group proteins that repress genes involved in lineage commitment. In summary, we propose a model wherein extracellular-signaling-stimulated proliferation and intrinsic repression of differentiation are integrated to maintain the identity of hESCs. PMID- 23727018 TI - USP15 negatively regulates Nrf2 through deubiquitination of Keap1. AB - Nrf2 is a master regulator of the antioxidant response. Under basal conditions, Nrf2 is polyubiquitinated by the Keap1-Cul3 E3 ligase and degraded by the 26S proteasome. In response to Nrf2 inducers there is a switch in polyubiquitination from Nrf2 to Keap1. Currently, regulation of the Nrf2-Keap1 pathway by ubiquitination is largely understood. However, the mechanism responsible for removal of ubiquitin conjugated to Nrf2 or Keap1 remains unknown. Here we report that the deubiquitinating enzyme, USP15, specifically deubiquitinates Keap1, which suppresses the Nrf2 pathway. We demonstrated that deubiquitinated Keap1 incorporates into the Keap1-Cul3-E3 ligase complex more efficiently, enhancing the complex stability and enzymatic activity. Consequently, there is an increase in Nrf2 protein degradation and a reduction in Nrf2 target gene expression. Furthermore, USP15-siRNA enhances chemoresistance of cells through upregulation of Nrf2. These findings further our understanding of how the Nrf2-Keap1 pathway is regulated, which is imperative in targeting this pathway for chemoprevention or chemotherapy. PMID- 23727020 TI - Peaceful coexistence amongst Borrelia plasmids: getting by with a little help from their friends? AB - Borrelia species comprise a unique genus of bacterial pathogens. These organisms contain a segmented genome with up to two dozen plasmids ranging in size from 5 kb up to about 200 kb. The plasmids have also been referred to as mini chromosomes or essential genetic elements, as some of them carry information important for infection of vertebrates or for survival in the tick vector. Most of the plasmids are linear with covalently closed hairpin telomeres and these linear plasmids are in a constant state of genetic rearrangement. The mechanisms of plasmid replication, maintenance and partitioning remain largely obscure and are complicated by a long doubling time, the requirement for expensive media and inefficient genetic manipulation. A set of five parologous protein families (PFs) are believed to confer the ability for autonomous replication and plasmid maintenance. The number of plasmids also complicates analyses because of the possibility that PFs from one plasmid may sometimes function in trans on other plasmids. Two papers in the last year have moved the field forward and their combined data suggest that trans complementation amongst Borrelia plasmids may sometimes occur. PMID- 23727021 TI - Physiological changes in Labeo rohita during nitrite exposure: detoxification through dietary vitamin E. AB - This study investigated the effect of sub-lethal nitrite-nitrogen exposure on Labeo rohita. Fishes fed with different levels of vitamin E (VE) for 60days were exposed to nitrite for another 45days with same feeding regime. There were four treatment groups, viz., VE100-N, VE100+N, VE150+N and VE300+N. After 45days of exposure, lowest specific growth rate was observed in VE100+N and highest in VE100-N. Reno-somatic index and methaemoglobin reductase activity were significantly increased by nitrite exposure. Highest Hb and Hct were observed in VE100-N and significantly decreased upon nitrite exposure. Significant differences were observed in the activities of catalase and SOD as well as serum potassium and chloride levels among different treatments. However, serum calcium and osmolality was not significantly varied. Nitrite exposure caused marked increase in nitrite concentration in gill, liver and muscle. In liver and muscle dietary supplementation of higher amounts of VE found to reduce nitrite accumulation. It was noticed that nitrite exposure has adversely affected growth, haematological variables, ionic balance and dietary supplementation with additional amounts of VE found to overcome the adverse effects of nitrite nitrogen. Detoxification of nitrite by methaemoglobin reductase system was enhanced by dietary supplementation of additional amounts of VE. PMID- 23727023 TI - Reoxygenation using a novel CO2 therapy decreases the metastatic potential of osteosarcoma cells. AB - Osteosarcoma is the most common primary solid malignant bone tumor. Despite substantial improvements in surgery and chemotherapy, metastasis remains a major cause of fatal outcomes, and the molecular mechanisms of metastasis are still poorly understood. Hypoxia, which is common in malignant tumors including osteosarcoma, increases expressions of hypoxia inducible factor (HIF)-1alpha, matrix metalloproteinase (MMP)-2 and MMP-9, and can induce invasiveness. As we previously showed a novel transcutaneous CO2 application to decrease HIF-1alpha expression and induce apoptosis in malignant fibrous histiocytoma, we hypothesize that transcutaneous CO2 application could suppress metastatic potential of osteosarcoma by improving hypoxic conditions. Here, we examined the effects of transcutaneous CO2 application on apoptosis, and development of pulmonary metastasis using a highly metastatic osteosarcoma cell line, LM8. Transcutaneous CO2 application significantly decreased tumor growth and pulmonary metastasis in LM8 cells. Apoptotic activity increased, and intratumoral hypoxia was improved with decreased expressions of HIF-1alpha, MMP-2 and MMP-9, significantly, in the CO2-treated tumors. In conclusion, we found that transcutaneous CO2 application can induce tumor cell apoptosis and might suppress pulmonary metastasis by improvement of hypoxic conditions with decreased expressions of HIF-1alpha and MMPs in highly metastatic osteosarcoma cell. These findings strongly indicate that this novel transcutaneous CO2 therapy could be a therapeutic breakthrough for osteosarcoma patients. PMID- 23727022 TI - A critical role for notch signaling in the formation of cholangiocellular carcinomas. AB - The incidence of cholangiocellular carcinoma (CCC) is increasing worldwide. Using a transgenic mouse model, we found that expression of the intracellular domain of Notch 1 (NICD) in mouse livers results in the formation of intrahepatic CCCs. These tumors display features of bipotential hepatic progenitor cells, indicating that intrahepatic CCC can originate from this cell type. We show that human and mouse CCCs are characterized by high expression of the cyclin E protein and identified the cyclin E gene as a direct transcriptional target of the Notch signaling pathway. Intriguingly, blocking gamma-secretase activity in human CCC xenotransplants results in downregulation of cyclin E expression, induction of apoptosis, and tumor remission in vivo. PMID- 23727024 TI - Towards structured sharing of raw and derived neuroimaging data across existing resources. AB - Data sharing efforts increasingly contribute to the acceleration of scientific discovery. Neuroimaging data is accumulating in distributed domain-specific databases and there is currently no integrated access mechanism nor an accepted format for the critically important meta-data that is necessary for making use of the combined, available neuroimaging data. In this manuscript, we present work from the Derived Data Working Group, an open-access group sponsored by the Biomedical Informatics Research Network (BIRN) and the International Neuroimaging Coordinating Facility (INCF) focused on practical tools for distributed access to neuroimaging data. The working group develops models and tools facilitating the structured interchange of neuroimaging meta-data and is making progress towards a unified set of tools for such data and meta-data exchange. We report on the key components required for integrated access to raw and derived neuroimaging data as well as associated meta-data and provenance across neuroimaging resources. The components include (1) a structured terminology that provides semantic context to data, (2) a formal data model for neuroimaging with robust tracking of data provenance, (3) a web service-based application programming interface (API) that provides a consistent mechanism to access and query the data model, and (4) a provenance library that can be used for the extraction of provenance data by image analysts and imaging software developers. We believe that the framework and set of tools outlined in this manuscript have great potential for solving many of the issues the neuroimaging community faces when sharing raw and derived neuroimaging data across the various existing database systems for the purpose of accelerating scientific discovery. PMID- 23727025 TI - tDCS-enhanced motor and cognitive function in neurological diseases. AB - Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation tool that is now being widely used in neuroscientific and clinical research in humans. While initial studies focused on modulation of cortical excitability, the technique quickly progressed to studies on motor and cognitive functions in healthy humans and in patients with neurological diseases. In the present review we will first provide the reader with a brief background on the basic principles of tDCS. In the main part, we will outline recent studies with tDCS that aimed at enhancing behavioral outcome or disease-specific symptoms in patients suffering from mild cognitive impairment, Alzheimer's disease, movement disorders, and epilepsy, or persistent deficits after stroke. The review will close with a summary statement on the present use of tDCS in the treatment of neurological disorders, and an outlook to further developments in this realm. tDCS may be an ideal tool to be administered in parallel to intensive cognitive or motor training in neurological disease, but efficacy for the areas of activities and participation still needs to be established in controlled randomized trials. Its use in reducing disease-specific symptoms like dystonia or epileptic seizures is still unclear. PMID- 23727026 TI - Transforming growth factor beta induces expression of connective tissue growth factor in hepatic progenitor cells through Smad independent signaling. AB - Hepatic progenitor cells (HPCs) are activated in the chronic liver injury and are found to participate in the progression of liver fibrosis, while the precise role of HPCs in liver fibrosis remains largely elusive. In this study, by immunostaining of human liver sections, we confirmed that HPCs were activated in the cirrhotic liver and secreted transforming growth factor beta (TGF-beta) and connective tissue growth factor (CTGF), both of which were important inducers of liver fibrosis. Besides, we used HPC cell lines LE/6 and WB-F344 as in vitro models and found that TGF-beta induced secretion of CTGF in HPCs. Moreover, TGF beta signaling was intracrine activated and contributed to autonomous secretion of CTGF in HPCs. Furthermore, we found that TGF-beta induced expression of CTGF was not mediated by TGF-beta activated Smad signaling but mediated by TGF-beta activated Erk, JNK and p38 MAPK signaling. Taken together, our results provide evidence for the role of HPCs in liver fibrosis and suggest that the production of CTGF by TGF-beta activated MAPK signaling in HPCs may be a therapeutic target of liver fibrosis. PMID- 23727027 TI - Disambiguation of PharmGKB drug-disease relations with NDF-RT and SPL. AB - PharmGKB is a leading resource of high quality pharmacogenomics data that provides information about how genetic variations modulate an individual's response to drugs. PharmGKB contains information about genetic variations, pharmacokinetic and pharmacodynamic pathways, and the effect of variations on drug-related phenotypes. These relationships are represented using very general terms, however, and the precise semantic relationships among drugs, and diseases are not often captured. In this paper we develop a protocol to detect and disambiguate general clinical associations between drugs and diseases using more precise annotation terms from other data sources. PharmGKB provides very detailed clinical associations between genetic variants and drug response, including genotype-specific drug dosing guidelines, and this procedure will armGKB. The availability of more detailed data will help investigators to conduct more precise queries, such as finding particular diseases caused or treated by a specific drug. We first mapped drugs extracted from PharmGKB drug-disease relationships to those in the National Drug File Reference Terminology (NDF-RT) and to Structured Product Labels (SPLs). Specifically, we retrieved drug and disease role relationships describing and defining concepts according to their relationships with other concepts from NDF-RT. We also used the NCBO (National Center for Biomedical Ontology) annotator to annotate disease terms from the free text extracted from five SPL sections (indication, contraindication, ADE, precaution, and warning). Finally, we used the detailed drug and disease relationship information from NDF-RT and the SPLs to annotate and disambiguate the more general PharmGKB drug and disease associations. PMID- 23727028 TI - Circulating cell free DNA: Preanalytical considerations. AB - Despite the growing interest in circulating cell-free DNA (ccfDNA) analysis in various clinical fields, especially oncology and prenatal diagnosis, few studies on sample handling have been reported and no analytical consensus is available. The lack of consistency between the various protocols for sample handling and the techniques used for ccfDNA analysis is one of the major obstacles in translating ccfDNA analysis to clinical practice. Although this point is highlighted regularly in the published reviews on ccfDNA analysis, no standard operating procedure currently exists despite several ongoing clinical studies on ccfDNA analysis. This review examines the preanalytical parameters potentially affecting ccfDNA concentration and fragmentation at each preanalytical step from blood drawing to the storage of ccfDNA extracts. Analysis of data in the literature and our own observations revealed the influence of preanalytical factors on ccfDNA analysis. Based on these data, we determined the optimal preanalytical protocols for ccfDNA analysis and ultimately, a guideline for the translation of ccfDNA analysis in routine clinical practice. PMID- 23727029 TI - Clinical performance evaluation of a novel rapid response chemiluminescent immunoassay for the detection of autoantibodies to extractable nuclear antigens. AB - BACKGROUND: We analyzed the performance of a novel ENA screening chemiluminescent immunoassay (CIA) and the confirmation QUANTA Flash tests. METHODS: Sera (n=1079) from patients referred to a rheumatology clinic were screened by QUANTA Flash ENA7 (INOVA Diagnostics). All positive (n=89) and a matched control group (n=90) were reflexed for autoantibodies to the individual antigens. Moreover, sera from patients with systemic lupus erythematosus (SLE, n=252), systemic sclerosis (SSc, n=64), polymyositis/dermatomyositis (PM/DM, n=72), Sjogren's syndrome (SjS, n=39) as well as disease controls (n=605) were tested by ENA7 CIA and by Quanta Lite ENA6 ELISA (INOVA). RESULTS: 89/1079 (8.3%) samples were ENA7 CIA positive with the following reactivity profile: RNP (36.0%), Sm (13.5%), Scl-70 (9.0%), Jo-1 (0.0%), Ro60 (44.9%), Ro52 (39.3%) and SS-B (24.7%). In the negative group, the reactivity profile was: RNP (1.1%), Sm (1.1%), Scl-70 (2.2%) and 0.0% for Jo-1, Ro60, Ro52 and SS-B. The positive/negative/total agreements (ENA7 CIA vs. confirmation assays) were 95.3%/91.5%/93.3%. The sensitivity of the ENA7 CIA was 62.3% in SLE, 54.7% in SSc, 92.3% in SjS, 50.0% in PM/DM, and 61.8% in the total systemic autoimmune rheumatic disease (SARD) population (specificity 95.0%). CONCLUSION: The QUANTA Flash ENA7 CIA is a reliable screening test. PMID- 23727030 TI - Associations between circulating microRNAs (miR-21, miR-34a, miR-122 and miR-451) and non-alcoholic fatty liver. AB - BACKGROUND: In many industrialized countries, non-alcoholic fatty liver disease (NAFLD) is recognized as an important disease that increases the risk of cardiovascular disease, type-2 diabetes, and metabolic syndrome. Most people with NAFLD are asymptomatic, and the disease is discovered incidentally during clinical laboratory tests. Present screening methods for NAFLD use ultrasound, and CT scans that are time-consuming, and a simple screening method for NAFLD is needed. In this study, we investigated whether serum miRNAs are associated with NAFLD and assessed the potential of serum miRNAs as a biomarker for NAFLD. METHODS: We assessed intrahepatic fat by ultrasound scan, and the serum levels of five miRNAs (miR-21, miR-34a, miR-122, miR-145, and miR-451), which help regulate cholesterol and fatty acid homeostasis in liver tissue, by real-time PCR in a cross-sectional sample of 403 participants who attended health examinations. RESULTS: Serum levels of miRNAs, miR-21, miR-34a, miR-122, and miR-451 were higher in participants with NAFLD. The serum level of miR-122 was correlated with the severity of liver steatosis. CONCLUSION: Serum levels of miRNAs, particularly miR-122, may be a useful biomarker for NAFLD. PMID- 23727031 TI - Gonadotropin releasing hormone (GnRH) and gonadotropin inhibitory hormone (GnIH) in the songbird hippocampus: regional and sex differences in adult zebra finches. AB - Hypothalamic gonadotropin releasing hormone (GnRH) and gonadotropin inhibitory hormone (GnIH) are vital to reproduction in all vertebrates. These neuropeptides are also present outside of the hypothalamus, but the roles of extra-hypothalamic GnRH and GnIH remain enigmatic and widely underappreciated. We used immunohistochemistry and PCR to examine whether multiple forms of GnRH (chicken GnRH-I (GnRH1), chicken GnRH-II (GnRH2) and lamprey GnRH-III (GnRH4)) and GnIH are present in the hippocampus (Hp) of adult zebra finches (Taeniopygia guttata). Using immunohistochemistry, we provide evidence that GnRH1, GnRH2 and GnRH4 are present in hippocampal cell bodies and/or fibers and that GnIH is present in hippocampal fibers only. There are regional differences in hippocampal GnRH immunoreactivity, and these vary across the different forms of GnRH. There are also sex differences in hippocampal GnRH immunoreactivity, with generally more GnRH1 and GnRH2 in the female Hp. In addition, we used PCR to examine the presence of GnRH1 mRNA and GnIH mRNA in micropunches of Hp. PCR and subsequent product sequencing demonstrated the presence of GnRH1 mRNA and the absence of GnIH mRNA in the Hp, consistent with the pattern of immunohistochemical results. To our knowledge, this is the first study in any species to systematically examine multiple forms of GnRH in the Hp or to quantify sex or regional differences in hippocampal GnRH. Moreover, this is the first demonstration of GnIH in the avian Hp. These data shed light on an important issue: the sites of action and possible functions of GnRH and GnIH outside of the HPG axis. PMID- 23727032 TI - Post-infarct treatment with [Pyr1]-apelin-13 reduces myocardial damage through reduction of oxidative injury and nitric oxide enhancement in the rat model of myocardial infarction. AB - Apelin is a newly discovered peptide that has been recently shown to have cardioprotective effects in the animal model of myocardial infarction (MI) and ischemia/reperfusion (I/R) injuries. The aim of the present study was to investigate the long term cardioprotective effect of [Pyr1]-apelin-13 in the rat model of MI. Male Wistar rats (n=22) were randomly divided into three groups: (1) sham operated group (2) control MI group and (3) MI treated with apelin (MI-AP group). MI animals were subjected to 30 min of left anterior descending coronary artery (LAD) ligation and 14 days of reperfusion. 24h after LAD ligation, apelin (10 mol/kg/day) was administered i.p. for 5 days. Blood sampling was performed at days 1, 3, 5 and 7 after MI for determination of serum changes of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), malondialdehyde (MDA) and nitric oxide (NO). Myocardial infarct size (IS) and hemodynamic function were also measured at the end of the study at day 14. We found out that post infarct treatment with apelin decreases infarct size, serum levels of LDH, CK-MB and MDA and increases heart rate and serum level of NO in the consecutive days, but there were no significant differences in blood pressure in the MI-AP group in comparison with MI. In conclusion, apelin has long term cardioprotective effects against myocardial infarction through attenuation of cardiac tissue injury and lipid peroxidation and enhancement of NO production. PMID- 23727033 TI - Stearylated antimicrobial peptide [D]-K6L9 with cell penetrating property for efficient gene transfer. AB - Stearyl-cell penetrating peptides (CPPs) have been proved to be efficient nonviral gene vectors. Due to the similarities between antimicrobial peptides and CPPs, we constructed a novel type of gene vectors by introducing stearyl moiety to the N-terminus of antimicrobial peptide [D]-K6L9. In this study, stearyl-[D] K6L9 delivered plasmids into cells by clathrin- and caveolin-mediated endocytosis. Gratifyingly, stearyl-[D]-K6L9 exhibited high transfection efficiency and almost reached the level of Lipofectamine 2000. Taken together, the combination of the stearyl moiety with [D]-K6L9 provides a novel framework for the development of excellent nonviral gene vectors. PMID- 23727034 TI - Dogs show left facial lateralization upon reunion with their owners. AB - Domestic dogs demonstrate behavioral laterality in response to emotional stimuli; those responses include tail wagging and head turning. The dog is the species with the closest relationship to humans; dogs can express strong social emotions (e.g., attachment and separation anxiety) to specific persons, such as their owners. In this study, we examined whether dogs demonstrate more facial laterality when reunited with their owners than when they encounter an unfamiliar person in an unfamiliar situation. We also examined whether the observed laterality was specific to positive social stimuli (i.e., the owner) or a general response to nonsocial positive stimuli (i.e., toys). The dogs' facial expressions were recorded by a high-speed video camera during the presentation of emotional stimuli and the acceleration rates of parts of their faces were analyzed. The results showed that the left eyebrow moved more when the owner was present than at baseline. No bias in terms of eyebrow movement was observed when the dogs saw attractive toys. These results suggest that dogs show facial laterality in response to emotional stimuli. This laterality was specific to social stimuli, probably reflecting the dog's attachment to the owner. PMID- 23727035 TI - Differential reinforcement of an approach response in zebrafish (Danio rerio). AB - Five zebrafish were trained to approach a target using a fully automated training procedure. During a training session, if the distance between the fish and the target was closer than an arbitrarily set distance, the approach response was reinforced by food. The fish continued to respond under this reinforcement contingency and the distance criterion could be shortened up to eighty times within a 1h session. The initial distance limit was then shortened for the next test training session. Once the initial distance criterion was reduced to a final minimum distance, the distance criterion was fixed at this value for the next nine successive sessions. In a second experiment using different fish, we manipulated approach distances in three conditions. The first condition was identical to the changing criterion training as in Experiment 1. In the second condition, only response distances under a distance criterion were reinforced. And in the last condition, only response distances over the distance criterion were reinforced. Results show that zebrafish can control the distance between themselves and a target. In other words, zebrafish are sensitive to the spatial consequences of their behavior. The present results show that a differential reinforcement paradigm can be successfully applied to zebrafish which therefore enhances their value as a vertebrate model for studies of complex behavior including visuomotor learning. PMID- 23727036 TI - A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency. AB - BACKGROUND: Combined immunodeficiency (CID) is characterized by severe recurrent infections with normal numbers of T and B lymphocytes but with deficient cellular and humoral immunity. Most cases are sporadic, but autosomal recessive inheritance has been described. In most cases, the cause of CID remains unknown. OBJECTIVE: We wanted to identify the genetic cause of CID in 2 siblings, the products of a first-cousin marriage, who experienced recurrent bacterial and candidal infections with bronchiectasis, growth delay, and early death. METHODS: We performed immunologic, genetic, and biochemical studies in the 2 siblings, their family members, and healthy controls. Reconstitution studies were performed with T cells from mucosa-associated lymphoid tissue lymphoma-translocation gene 1 deficient (Malt1(-/-)) mice. RESULTS: The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients. Whole genome sequencing of 1 patient and her parents, followed by DNA sequencing of family members and healthy controls, showed the presence in both patients of a homozygous missense mutation in MALT1 that resulted in loss of protein expression. Analysis of T cells that were available on one of the patients showed severely impaired IkappaBalpha degradation and IL-2 production after activation, 2 events that depend on MALT1. In contrast to wild-type human MALT1, the patients' MALT1 mutant failed to correct defective nuclear factor-kappaB activation and IL-2 production in MALT1-deficient mouse T cells. CONCLUSIONS: An autosomal recessive form of CID is associated with homozygous mutations in MALT1. If future patients are found to be similarly affected, they should be considered as candidates for allogeneic hematopoietic cell transplantation. PMID- 23727038 TI - Rhinovirus colocalizes with CD68- and CD11b-positive macrophages following experimental infection in humans. PMID- 23727037 TI - Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T cell microRNA-150 to effector T cells to inhibit contact sensitivity. AB - BACKGROUND: T-cell tolerance of allergic cutaneous contact sensitivity (CS) induced in mice by high doses of reactive hapten is mediated by suppressor cells that release antigen-specific suppressive nanovesicles. OBJECTIVE: We sought to determine the mechanism or mechanisms of immune suppression mediated by the nanovesicles. METHODS: T-cell tolerance was induced by means of intravenous injection of hapten conjugated to self-antigens of syngeneic erythrocytes and subsequent contact immunization with the same hapten. Lymph node and spleen cells from tolerized or control donors were harvested and cultured to produce a supernatant containing suppressive nanovesicles that were isolated from the tolerized mice for testing in active and adoptive cell-transfer models of CS. RESULTS: Tolerance was shown due to exosome-like nanovesicles in the supernatants of CD8(+) suppressor T cells that were not regulatory T cells. Antigen specificity of the suppressive nanovesicles was conferred by a surface coat of antibody light chains or possibly whole antibody, allowing targeted delivery of selected inhibitory microRNA (miRNA)-150 to CS effector T cells. Nanovesicles also inhibited CS in actively sensitized mice after systemic injection at the peak of the responses. The role of antibody and miRNA-150 was established by tolerizing either panimmunoglobulin-deficient JH(-/-) or miRNA-150(-/-) mice that produced nonsuppressive nanovesicles. These nanovesicles could be made suppressive by adding antigen-specific antibody light chains or miRNA-150, respectively. CONCLUSIONS: This is the first example of T-cell regulation through systemic transit of exosome-like nanovesicles delivering a chosen inhibitory miRNA to target effector T cells in an antigen-specific manner by a surface coating of antibody light chains. PMID- 23727039 TI - What is an "eosinophilic phenotype" of asthma? PMID- 23727040 TI - The obstetrical and neonatal impact of maternal opioid detoxification in pregnancy. AB - OBJECTIVE: The purpose of this study was to analyze the obstetric and neonatal impact of an opioid detoxification program during pregnancy, as well as to examine variables associated with successful opioid detoxification. STUDY DESIGN: This is a retrospective cohort study of women electing inpatient detoxification and subsequently delivering at our hospital from Jan. 1, 2006, through Dec. 31, 2011. Detoxification was considered successful if women had no illicit drug supplementation at the time of delivery. Maternal characteristics were ascertained by chart review and analyzed for variables associated with success. Obstetric and neonatal outcomes were also assessed based on maternal success at delivery. RESULTS: Of the 95 women during the study period with complete data, 53 (56%) were successful. There were no demographic or social risk factors identified associated with success. Women with successful detoxification at delivery had longer inpatient detoxification admissions (median 25 vs 15 days, P < .001) and were less likely to leave prior to completion of the program than women who had relapsed at delivery (9% vs 33%, respectively, P < .001). Infants of mothers who were successfully detoxified had shorter hospitalizations (median 3 vs 22 days, P < .001), lower maximum neonatal abstinence syndrome scores (0 vs 8.3, P < .001), and were less likely to be treated for withdrawal (10% vs 80%, P < .001). CONCLUSION: Opiate detoxification in pregnancy requires a significant time commitment and extended treatment, however, can be successfully achieved in compliant parturients. Importantly, maternal demographics and drug histories do not portend success, supporting continued opiate detoxification being offered to all women expressing intent. PMID- 23727041 TI - Genetic associations of relaxin: preterm birth and premature rupture of fetal membranes. AB - OBJECTIVE: Relaxin H2 (RLN2) is a systemic hormone (sRLN) that is produced by the corpus luteum, whereas decidual RLN (dRLN) acts only locally. Elevated sRLN is associated with spontaneous preterm birth (sPTB) and elevated dRLN with preterm premature rupture of membranes (PPROM). Associations were sought between single nucleotide polymorphisms (SNPs) in the RLN2 promoter with levels of dRLN and sRLN in Filipino patients with sPTB, PPROM, or normal term delivery. STUDY DESIGN: Stringent selection of women with sPTB (n = 20) or PPROM (n = 20) and term control subjects (n = 20) was made from >8000 samples from Filipino patients who delivered at 34-36 weeks' gestation. Twelve SNPs were genotyped on maternal blood, with 9 excluded based on the high linkage disequilibrium or being the same as in the control population. Quantitative immunocytochemistry on parietal decidual tissue was performed (n = 60); sRLN was measured by enzyme-linked immunosorbent assay in a subset of patients (n = 21). RESULTS: SNP rs4742076 was associated significantly with PPROM (P < .001) and increased expression of dRLN (P < .001). The genotype TT had increased dRLN in PPROM (P < .05). SNP rs3758239 was associated significantly with both PPROM and sPTB (P < .01), and genotype AA had increased dRLN expression (P < .05). The sRLN showed a trend of higher levels in PPROM and sPTB, but was not significant. CONCLUSION: SNP rs4742076 in the RLN2 promoter was associated with increased dRLN expression and PPROM; SNP rs3758239 was associated with both PPROM and sPTB in these Filipino patients. Specific homozygous genotypes were identified for both SNPs and were shown to be associated with increased dRLN tissue expression. PMID- 23727042 TI - Neurodevelopmental outcomes of children with periventricular leukomalacia. AB - OBJECTIVES: To examine the neurodevelopmental outcomes of children with periventricular leukomalacia (PVL). MATERIALS AND METHODS: Twenty-five children diagnosed with grade 1, 2 or 3 PVL on the basis of magnetic resonance imaging (MRI) findings between January 2002 and December 2011 were enrolled and followed from 15 months to 10 years of age. RESULTS: Of the 25 children, one was a term and 24 were preterm-births. Nine (36%) had spastic diplegia and 12 (48%) had quadriplegia. Ten of the 25 (40%) were able to walk independently at 36 months utilizing short leg braces, whereas 13 children (52%) were unable to walk independently. MRI findings revealed grade 1 PVL in nine (36%), grade 2 in 12 (48%), and grade 3 in four (16%) of the 25 children. Eleven of the 16 children (69%) with grade 2 or 3 PVL had Papile III or IV intraventricular hemorrhage (IVH), and many of these children had severe neurologic motor abnormalities, severe psychomotor delay, and seizures. Five of the nine children (56%) with grade 1 PVL had normal psychomotor development. There were statistically significant differences in the motor impairment and walking ability between the children with grade 1 and those with grade 2 PVL (p = 0.008 and 0.005, respectively). CONCLUSION: Most children with grade 2 or 3 PVL had severe neurodevelopmental delays, but attention should also be paid to the 56% of children with grade 1 PVL who presented with normal psychomotor development. Further studies of larger populations, including long-term follow-up, are necessary to evaluate the outcomes of children with PVL. PMID- 23727043 TI - Postoperative complications after major head and neck surgery with free flap repair--prevalence, patterns, and determinants: a prospective cohort study. AB - This study aims to give a better understanding of the prevalence, patterns, and determinants of postoperative complications, to evaluate the Clavien-Dindo classification of surgical complications, and to set out a protocol to improve postoperative recovery. Over a period of 27 months we studied 192 patients who had had major head and neck operations with free flaps. Data on complications were gathered prospectively along with patients' details, comorbidities, factors indicative of the magnitude of the surgical insult, and variations in perioperative care. Complications were classified according to the Clavien-Dindo system. Outcomes analysed comprised any complication, major complications (Clavien-Dindo III and above), wound complications, and pulmonary complications. A total of 64% of patients had complications, and in around one third they were serious; wound and pulmonary complications were the most common. Factors significantly associated with complications reflected an interaction between coexisting conditions of the patient at operation and the magnitude of the surgery. Perioperative interventions to ensure preoperative optimisation of patients, and to lessen the systemic inflammatory response that results from operation offer the best prospect of reducing the burden of surgical complications. A protocol to improve recovery after operation would be appropriate. The Clavien-Dindo classification of surgical complications is useful in this group. PMID- 23727044 TI - Discovery of non-LBD inhibitor for androgen receptor by structure-guide design. AB - In this study, we synthesized the BF-3 binding small molecules, a series of pyridazinone-based compounds, as a novel class of non-LBP antiandrogens for treating prostate cancer by inhibiting androgen receptor. The new class compound was discovered to inhibitor the viability of AR-dependent human prostate LNCap cells and AR activity combining with the computational method. It showed a good physicochemical and PK property. PMID- 23727046 TI - N-Acyl-N'-arylpiperazines as negative allosteric modulators of mGlu1: identification of VU0469650, a potent and selective tool compound with CNS exposure in rats. AB - Development of SAR in an N-acyl-N'-arylpiperazine series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. Characterization of selected compounds in protein binding assays was used to aid in selecting VU0469650 for further profiling in ancillary pharmacology assays and pharmacokinetic studies. VU0469650 demonstrated an excellent selectivity profile and good exposure in both plasma and brain samples following intraperitoneal dosing in rats. PMID- 23727047 TI - Local landmark alignment for high-resolution fMRI group studies: toward a fine cortical investigation of hand movements in human. AB - Converging evidence conclusively demonstrates the robust relationship between anatomical landmarks and underlying functional organization in primary cortical regions. In consequence, a precise alignment across subjects of such specific individual landmarks should improve the overlap of the corresponding functional areas and thus the detection of active clusters at the group level. In an effort to define a dedicated processing pipeline for a fine non-invasive exploration of the motor cortex in human, we evaluated four recent non-linear registration methods based on anatomical and functional indexes. We used high-resolution functional MRI data to finely reveal the impact of the registration on the cortical assignment of the detected clusters. Our results first demonstrate that the quality of registration strongly affects the statistical significance and the assignment of activated clusters to specific anatomical regions, here in the primary motor area. Our results also illustrate the bias induced by the chosen reference template on the detected clusters. The analysis of the Jacobian of the deformation field informs us about how each method deforms the anatomical structures and functional maps. The methodology we propose, combining high resolution fMRI and non-linear registration method, allows a robust non-invasive exploration of the motor cortex. PMID- 23727045 TI - Macrocyclic inhibitors of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus. AB - The design, synthesis, and in vitro evaluation of the first macrocyclic inhibitor of 3C and 3C-like proteases of picornavirus, norovirus, and coronavirus are reported. The in vitro inhibitory activity (50% effective concentration) of the macrocyclic inhibitor toward enterovirus 3C protease (CVB3 Nancy strain), and coronavirus (SARS-CoV) and norovirus 3C-like proteases, was determined to be 1.8, 15.5 and 5.1 MUM, respectively. PMID- 23727048 TI - Intercultural health and ethnobotany: how to improve healthcare for underserved and minority communities? AB - ETHNOPHARMACOLOGICAL RELEVANCE: The present conceptual review explores intercultural healthcare--defined as the integration of traditional medicine and biomedicine as complementary healthcare systems--in minority and underserved communities. This integration can take place at different levels: individuals (patients, healers, biomedical healthcare providers), institutions (health centers, hospitals) or society (government policy). BACKGROUND: Contemporary ethnobotany research of traditional medicine has primarily dealt with the botanical identification of plants commonly used by local communities, and the identification of health conditions treated with these plants, whereas ethnopharmacology has focused on the bioactivity of traditional remedies. On the other hand, medical anthropology seems to be the scholarship more involved with research into patients' healthcare-seeking itineraries and their interaction with traditional versus biomedical healthcare systems. The direct impact of these studies on public health of local communities can be contested. AIM OF THE REVIEW: To compare and discuss the body of scholarly work that deals with different aspects of traditional medicine in underserved and minority communities, and to reflect on how gaps identified in research can be bridged to help improve healthcare in these communities. KEY FINDINGS: The literature covers a broad range of information of relevance to intercultural healthcare. This information is fragmented across different scientific and clinical disciplines. A conceptual review of these studies identifies a clear need to devote more attention to ways in which research on traditional medicine can be more effectively applied to improve local public health in biomedical resource-poor settings, or in geographic areas that have disparities in access to healthcare. CONCLUSIONS: Scholars studying traditional medicine should prioritize a more interdisciplinary and applied perspective to their work in order to forge a more direct social impact on public health in local communities most in need of healthcare. PMID- 23727049 TI - Design and characterization of a recombinant colorimetric SAG1-alkaline phosphatase conjugate to detect specific antibody responses against Toxoplasma gondii. AB - The purpose of this study was to design a novel in vitro tool by using recombinant protein technology to detect specific antibody responses against Toxoplasma gondii in a simple, rapid and highly sensitive reagent. The surface T. gondii SAG1 protein is an important immunodominant target, which provides a great interest as a diagnostic antigen. To further exploit its immunodetection capacity, in the present study, the full length sag1 gene was inserted into the pLIP6 prokaryotic expression vector so as to produce a SAG1 antigen genetically fused to the bacterial alkaline phosphatase (AP). After expression optimization, the recombinant fusion protein folded correctly in soluble form in the periplasmic space and preserved both the AP enzymatic activity and the SAG1 immunoreactivity. Subsequently, direct-ELISA and dot-blot immunoassays were designed, using crude preparation SAG1-AP conjugate, to explore its value in serodiagnosis of human toxoplasmosis. We demonstrate that the recombinant SAG1-AP can detect specific T. gondii antibodies in one-step procedure and can successfully discriminate between T. gondii immune and non-immune patients, in agreement with the standard gold test. In conclusion, the present study shows that the genetic fusion protein provides a new tool for one-step T. gondii immunodetection, which was easily, quickly and reproducibly produced as homogeneous bi-functional reagent. Thus, this recombinant immunoconjugate is a promising marker for Toxoplasma serodiagnosis, requiring further evaluation on a larger series and could provide the basis for direct antibody capture enzyme immunoassay for specific immunoglobulin M and G detection. PMID- 23727050 TI - Association between asymptomatic carotid stenosis and cognitive function: a systematic review. AB - BACKGROUND: Asymptomatic carotid stenosis (CS), traditionally considered clinically silent, may be an independent risk factor for a cognitive impairment. METHODS: To determine whether an association exists between asymptomatic CS and cognitive function, we systematically reviewed the literature in the Cochrane Library, MEDLINE, EMBASE and the China National Knowledge Infrastructure databases. RESULTS: A total of 8 cross-sectional studies and 2 community-based cohort studies were included, comprising 763 participants in the CS group and 6308 participants in the non-CS group. All but one study supported the association between asymptomatic CS and cognitive impairment. Pooled analysis identified older age (2 studies) and cerebral hypoperfusion (2 studies) as additional factors in patients with asymptomatic CS that may linked to cognitive decline. CONCLUSIONS: These results suggest that rather than being clinically silent, asymptomatic CS may be associated with cognitive impairment, and this should be further investigated in high-quality studies. PMID- 23727051 TI - A new field in monkey's frontal cortex: premotor ear-eye field (PEEF). AB - In macaque monkey, area 8B is cytoarchitectonically considered a transitional area between the granular Brodmann area 9, rostrally, and the rostral part of the dorsal agranular Brodmann area 6, caudally. As for electrophysiological data, microstimulation of area 8B evokes ear and/or eye movements; unit activity recording shows neurons encoding different auditory environmental stimuli and ear and/or eye movements. Moreover, visual attentive fixation modulates the discharge of auditory environmental neurons and auditory-motor neurons. As for anatomical data, area 8B is connected with auditory cortical areas, superior colliculus and cerebellum. Current functional and anatomical evidences support that area 8B is a specific Premotor Ear-Eye Field (PEEF) involved in auditory stimuli recognition and in orienting processes. In conclusion, we suggest that PEEF could play an important role in engaging the auditory spatial attention for the purpose of orienting eye and ear towards the sound source. PMID- 23727052 TI - Substratum stiffness and latrunculin B modulate the gene expression of the mechanotransducers YAP and TAZ in human trabecular meshwork cells. AB - The compliance of the human trabecular meshwork (HTM) has been shown to dramatically stiffen in glaucomatous patients. The purpose of this study was to determine the impact of substratum stiffness and latrunculin-B (Lat-B) on the expression and activity of the mechanotransducers, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ), in primary HTM cells as the cells start to recover from Lat-B treatment. Primary human trabecular meshwork (HTM) cells were cultured on hydrogels possessing stiffness values mimicking those found in normal (5 kPa) and glaucomatous meshworks (75 kPa), or tissue culture polystyrene (TCP; >1 GPa). Cells were treated with 2.0 MUM Lat-B in DMSO or DMSO alone. RT-PCR was used to determine the impact of substratum stiffness and/or Lat-B treatment on the expression of YAP, TAZ, 14-3 3sigma, plasminogen activator inhibitor-1 (PAI-1), and connective tissue growth factor (CTGF). Immunoblotting was used to determine the expression of YAP and TAZ as well as the phosphorylation status of YAP. Immunofluorescence was used to determine YAP protein localization. YAP and TAZ mRNA expression were upregulated on the 75 kPa hydrogels in comparison to the 5 kPa hydrogels and TCP. Treatment with Lat-B resulted in a rapid and dramatic downregulation of YAP and TAZ on the 75 kPa hydrogels. On hydrogels, Lat-B treatment increased the phosphorylation of YAP at S127, while decreasing it on TCP. Similarly, Lat-B treatment resulted in markedly decreased nuclear localization of YAP on the hydrogels but elevated nuclear localization on TCP. Lat-B treatment of HTM cells on the 75 kPa hydrogels also increased 14-3-3sigma mRNA, a protein important in YAP/TAZ degradation. In addition, Lat-B treatment decreased CTGF and PAI-1 mRNA on the 75 kPa hydrogels. In conclusion, substratum stiffness alters YAP/TAZ expression and YAP localization in primary HTM cells which then may modulate the expression of extracellular matrix proteins important in glaucoma. During the recovery period after Lat-B treatment, gene expression changes are more dramatic on substrates with stiffness similar to glaucomatous meshwork. Use of these hydrogels may more accurately reflect the alterations occurring in HTM cells in glaucoma after treatment with this drug. PMID- 23727053 TI - SYFSA: a framework for systematic yet flexible systems analysis. AB - Although technological or organizational systems that enforce systematic procedures and best practices can lead to improvements in quality, these systems must also be designed to allow users to adapt to the inherent uncertainty, complexity, and variations in healthcare. We present a framework, called Systematic Yet Flexible Systems Analysis (SYFSA) that supports the design and analysis of Systematic Yet Flexible (SYF) systems (whether organizational or technical) by formally considering the tradeoffs between systematicity and flexibility. SYFSA is based on analyzing a task using three related problem spaces: the idealized space, the natural space, and the system space. The idealized space represents the best practice-how the task is to be accomplished under ideal conditions. The natural space captures the task actions and constraints on how the task is currently done. The system space specifies how the task is done in a redesigned system, including how it may deviate from the idealized space, and how the system supports or enforces task constraints. The goal of the framework is to support the design of systems that allow graceful degradation from the idealized space to the natural space. We demonstrate the application of SYFSA for the analysis of a simplified central line insertion task. We also describe several information-theoretic measures of flexibility that can be used to compare alternative designs, and to measure how efficiently a system supports a given task, the relative cognitive workload, and learnability. PMID- 23727054 TI - A new multi-locus timescale reveals the evolutionary basis of diversity patterns in triggerfishes and filefishes (Balistidae, Monacanthidae; Tetraodontiformes). AB - Balistoid fishes (triggerfishes, filefishes, leatherjackets) represent one of the most successful radiations of tetraodontiform fishes across the world's oceans. Balistids (triggerfishes) are largely circumtropical in coral reef environments while most monacanthids (filefishes, leatherjackets) are distributed across reef and non-reef habitats in the Indo-western Pacific. Although members of these clades share a distinctive mode of locomotion that relies upon coordinated oscillation or undulation of enlarged dorsal and anal fins, species richness as well as morphologial and ecological diversity are generally considered to be higher in monacanthids than in triggerfishes. Explicit evolutionary comparisons of diversity patterns between these sister clades have been hampered by the paucity of systematic studies of filefishes relative to triggerfishes. Furthermore, a well-sampled molecular timescale for balistoids is lacking, hindering our understanding of the evolutionary history of these fishes. Here, we produce the largest balistoid molecular dataset to date, based on two mitochondrial and three nuclear loci, for a total of 86 species, and we time calibrate it using three tetraodontiform fossils. We show that several of the traditional monacanthid genera are not monophyletic and that the balistid Xenobalistes tumidipectoris is nested within the genus Xanthichthys, and suggest that the generic name Xenobalistes be dissolved. Our timetree reveals a Late Miocene origin of balistids, in accordance with previous studies, but a Late Eocene age for the crown monacanthids, which experienced significant diversification during the Late Oligocene and Early Miocene. Comparative analyses reveal no significant family-level differences in rates of speciation or body size evolution, suggesting that the greater diversity of filefishes can be attributed to their more ancient crown age compared to triggerfishes. PMID- 23727055 TI - Molecular phylogeny of broken-back shrimps (genus Lysmata and allies): a test of the 'Tomlinson-Ghiselin' hypothesis explaining the evolution of hermaphroditism. AB - The 'Tomlinson-Ghiselin' hypothesis (TGh) predicts that outcrossing simultaneous hermaphroditism (SH) is advantageous when population density is low because the probability of finding sexual partners is negligible. In shrimps from the family Lysmatidae, Bauer's historical contingency hypothesis (HCh) suggests that SH evolved in an ancestral tropical species that adopted a symbiotic lifestyle with, e.g., sea anemones and became a specialized fish-cleaner. Restricted mobility of shrimps due to their association with a host, and hence, reduced probability of encountering mating partners, would have favored SH. The HCh is a special case of the TGh. Herein, I examined within a phylogenetic framework whether the TGh/HCh explains the origin of SH in shrimps. A phylogeny of caridean broken-back shrimps in the families Lysmatidae, Barbouriidae, Merguiidae was first developed using nuclear and mitochondrial makers. Complete evidence phylogenetic analyses using maximum likelihood (ML) and Bayesian inference (BI) demonstrated that Lysmatidae+Barbouriidae are monophyletic. In turn, Merguiidae is sister to the Lysmatidae+Barbouriidae. ML and BI ancestral character-state reconstruction in the resulting phylogenetic trees indicated that the ancestral Lysmatidae was either gregarious or lived in small groups and was not symbiotic. Four different evolutionary transitions from a free-living to a symbiotic lifestyle occurred in shrimps. Therefore, the evolution of SH in shrimps cannot be explained by the TGh/HCh; reduced probability of encountering mating partners in an ancestral species due to its association with a sessile host did not favor SH in the Lysmatidae. It is proposed that two conditions acting together in the past; low male mating opportunities and brooding constraints, might have favored SH in the ancestral Lysmatidae+Barbouridae. Additional studies on the life history and phylogenetics of broken-back shrimps are needed to understand the evolution of SH in the ecologically diverse Caridea. PMID- 23727056 TI - Computational studies of TGF-betaRI (ALK-5) inhibitors: analysis of the binding interactions between ligand-receptor using 2D and 3D techniques. AB - ALK-5 (Activin-Like Kinase 5) is a biological receptor involved in a variety of pathological processes such as cancer and fibrosis. ALK-5 receptor propagates an intracellular signaling that forms a protein complex capable of reaching the nucleus and modulating the gene transcription. In the present study, comparative molecular field analysis (CoMFA) and hologram quantitative structure-activity relationship (HQSAR) studies were conducted on a series of potent ALK-5 inhibitors. Significant correlation coefficients (CoMFA, r(2)=0.99 and q(2)=0.85; HQSAR, r(2)=0.92 and q(2)=0.72) were obtained, indicating the predictive potential of the 2D and 3D models for untested compounds. The models were then used to predict the potency of a test set, and the predicted values from the HQSAR and CoMFA models were in good agreement with the experimental results. The final QSAR models, along with the information obtained from 3D (steric and electrostatic) contour maps and 2D contribution maps, can be useful for the design of novel bioactive ligands. PMID- 23727057 TI - Microdose pharmacogenetic study of 14C-tolbutamide in healthy subjects with accelerator mass spectrometry to examine the effects of CYP2C9*3 on its pharmacokinetics and metabolism. AB - Microdose study enables us to understand the pharmacokinetic profiles of drugs in humans prior to the conventional clinical trials. The advantage of microdose study is that the unexpected pharmacological/toxicological effects of drugs caused by drug interactions or genetic polymorphisms of metabolic enzymes/transporters can be avoided due to the limited dose. With a combination use of accelerator mass spectrometry (AMS) and (14)C-labaled compounds, the pharmacokinetics of both parent drug and its metabolites can be sensitively monitored. Thus, to demonstrate the usability of microdose study with AMS for the prediction of the impact of genetic polymorphisms of CYP enzyme on the pharmacokinetics of unchanged drugs and metabolites, we performed microdose pharmacogenetic study using tolbutamide as a CYP2C9 probe drug. A microdose of (14)C-tolbutamide (100 MUg) was administered orally to healthy volunteers with the CYP2C9(*)1/(*)1 or CYP2C9(*)1/(*)3 diplotype. Area under the plasma concentration-time curve for the (14)C-radioactivity, determined by AMS, or that for the parent drug, determined by liquid chromatography/mass spectrometry, was about 1.6 times or 1.7 times greater in the CYP2C9(*)1/(*)3 than in the CYP2C9(*)1/(*)1 group, which was comparable to the previous reports at therapeutic dose. In the plasma and urine, tolbutamide, carboxytolbutamide, and 4 hydroxytolbutamide were detected and practically no other metabolites could be found in both diplotype groups. The fraction of metabolites in plasma radioactivity was slightly lower in the CYP2C9(*)1/(*)3 group. Microdose study can be used for the prediction of the effects of genetic polymorphisms of enzymes on the pharmacokinetics and metabolic profiles of drugs with minimal care of their pharmacological/toxicological effects. PMID- 23727058 TI - Mono-PEGylated radix ophiopogonis polysaccharide for the treatment of myocardial ischemia. AB - This work aimed to improve the clinical application of Radix Ophiopogonis polysaccharide (ROP), a natural anti-myocardial ischemic fructan with Mw of 4.80 kDa, by mono-PEGylation. Three mono-PEGylated ROPs were prepared by a moderate coupling reaction between amino-terminated methoxy-PEG (20-, 30-, or 40-kDa) and excessive hydroxyl-activated ROP. After being fully characterized by proton nuclear magnetic resonance as well as high-performance gel permeation chromatography and anthrone-sulfuric acid colorimetry coupled assay, they were evaluated for pharmacokinetics and anti-myocardial ischemic activities in rats with coronary artery ligation. The results showed that mono-PEGylated ROPs were successfully and effectively prepared. Compared with ROP, the three mono PEGylated ROPs showed approximately 32-, 85-, and 100-fold prolonged retention in systemic circulation with plasma half-lives reaching 16.1, 42.4, and 49.8 h, respectively. Studies on anti-myocardial ischemic effects of the conjugates showed that administrated at the same molar dose of 4 MU mol/kg per injection as ROP, they could achieve comparable or even better therapeutic effects although their administration intervals were 2- to 6-fold longer than that of ROP. These findings confirm that PEGylation would be a promising approach to markedly reducing the injection-administered frequency of ROP and hence patient compliance without sacrifice of the therapeutic efficacy by significantly improving its pharmacokinetics. PMID- 23727059 TI - Failure of a defibrillator lead: how durable is Durata? PMID- 23727060 TI - Peer support and interpersonal psychotherapy groups experienced decreased prenatal depression, anxiety and cortisol. AB - Forty-four prenatally depressed women were randomly assigned to peer support or interpersonal psychotherapy groups at 22 weeks gestation. The peer support group participated in a 20-minute group session once per week for 12 weeks, and the interpersonal psychotherapy group met for one hour per week for 12 weeks. Assessments were conducted before and after the sessions at 22 and 34 weeks gestation. Despite the peer support group having lower socioeconomic status and higher depression scores at the beginning of the treatment period and having shorter group sessions, both groups had lower summary depression (CES-D) scores and lower anxiety (STAI) scores by the end of the treatment period. In addition, cortisol levels decreased for both groups after the last day session, although the decrease was greater for the peer support group. The groups did not differ on neonatal outcomes including gestational age and birthweight. These data suggest that peer support group sessions may be a cost-effective form of treatment for prenatal depression. PMID- 23727061 TI - Activation of cultured astrocytes by amphotericin B: stimulation of NO and cytokines production and changes in neurotrophic factors production. AB - Amphotericin B (AmB) is a polyene antibiotic and reported to be one of a few reagents having therapeutic effects on prion diseases, such as the delay in the appearing of the clinical signs and the prolongation of the survival time. In prion diseases, glial cells have been suggested to play important roles by proliferating and producing various factors such as nitric oxide, proinflammatory cytokines, and neurotrophic factors. However, the therapeutic mechanism of AmB on prion diseases remains elusive. We have previously reported that AmB changed the expression of neurotoxic and neurotrophic factors in microglia (Motoyoshi et al., 2008, Neurochem. Int. 52, 1290-1296). In the present study, we examined the effects of AmB on cellular functions of rat cultured astrocytes. We found that AmB could activate astrocytes to produce nitric oxide via inducible nitric oxide synthase induction. AmB also induced mRNA expression of interleukin-1beta and tumor necrosis factor-alpha, and productions of their proteins in astrocytes. Moreover, AmB changed levels of neurotrophic factor mRNAs and proteins. Among three neurotrophic factors examined here, neurotrophin-3 mRNA expression and its protein production in the cells were down-regulated by AmB stimulation. On the other hand, AmB significantly enhanced the amounts of glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor proteins in the cells and the medium. These results suggest that AmB might show therapeutic effects on prion diseases by controlling the expression and production of such mediators in astrocytes. PMID- 23727062 TI - Cdh1 inhibits reactive astrocyte proliferation after oxygen-glucose deprivation and reperfusion. AB - Anaphase-promoting complex (APC) and its co-activator Cdh1 are required for cell cycle regulation in proliferating cells. Recent studies have defined diverse functions of APC-Cdh1 in nervous system development and injury. Our previous studies have demonstrated the activity of APC-Cdh1 is down-regulated in hippocampus after global cerebral ischemia. But the detailed mechanisms of APC Cdh1 in ischemic nervous injury are unclear. It is known that astrocyte proliferation is an important pathophysiological process following cerebral ischemia. However, the role of APC-Cdh1 in reactive astrocyte proliferation is not determined yet. In the present study, we cultured primary cerebral astrocytes and set up in vitro oxygen-glucose deprivation and reperfusion model. Our results showed that the expression of Cdh1 was decreased while Skp2 (the downstream substrate of APC-Cdh1) was increased in astrocytes after 1h oxygen-glucose deprivation and reperfusion. The down-regulation of APC-Cdh1 was coupled with reactive astrocyte proliferation. By constructing Cdh1 expressing lentivirus system, we also found exogenous Cdh1 can down-regulate Skp2 and inhibit reactive astrocyte proliferation induced by oxygen-glucose deprivation and reperfusion. Moreover, Western blot showed that other downstream proteins of APC-Cdh1, PFK-1 and SnoN, were decreased in the inhibition of reactive astrocyte proliferation with Cdh1 expressing lentivirus treatment. These results suggest that Cdh1 plays an important role in the regulation of reactive astrocyte proliferation induced by oxygen-glucose deprivation and reperfusion. PMID- 23727063 TI - NF-kappaB-dependent and -independent pathways in the protective effects of activated protein C in hippocampal and cortical neurons at excitotoxicity. AB - The transcription factor NF-kappaB regulates the expression of multiple genes involved in inflammation, apoptotic cell death and cell survival. We previously demonstrated that activated protein C (APC), a serine protease of hemostasis with anticoagulant activity, protected cultured rat cortical and hippocampal neurons against glutamate-induced excitotoxicity, a model of ischemic stroke. We reported that APC suppressed the translocation of NF-kappaBp65/RelA into the nucleus of neurons. However, it is not known whether APC-induced protection of neurons against cell death occurs via regulation of NF-kappaB activation or NF-kappaB independent p53 expression. It is also unclear whether cleaved caspase-3 and caspase-independent AIF and Bax/Bcl-2 expression are involved at excitotoxicity. To elucidate the NF-kappaB dependent and -independent mechanisms in the APC mediated cell survival, we analyzed in cortical and hippocampal neurons the effects of helenalin, a specific inhibitor of NF-kappaB activity, and APC on neuronal cell death and on the level of nuclear AIF, p53, caspase-3 and the apoptotic index (Bax/Bcl-2 ratio). We could demonstrate that helenalin (5 MUM), like APC (1 nM), protects cultured neurons from glutamate-induced excitotoxicity. Both APC and helenalin inhibit AIF release from mitochondria and its translocation into the nucleus. They decrease the apoptotic index in neurons at excitotoxicity. However, APC, but not helenalin, reduced the glutamate-induced activation of caspase-3. Incubation of neurons with APC blocked the glutamate induced increase in the nuclear level of p53 via NF-kappaB-independent pathway. Our findings demonstrate that, in the protective effect of APC in neurons at excitotoxicity, the NF-kappaB pathway is an important, but not the only pathway, and is significantly connected with neuronal survival at excitotoxicity. PMID- 23727064 TI - Association of POL1, MALT1, MC4R, PHLPP and DSEL single nucleotide polymorphisms in chromosome 18q region with type 2 diabetes in Tunisians. AB - Previous studies and replication analyses have linked chromosome 18q21.1-23 with type 2 diabetes (T2DM) and its complications, including diabetic nephropathy (DN). Here we investigated the association of POL1-nearby variant rs488846, MALT1 nearby variant rs2874116, MC4R-nearby variant rs1942872, PHLPP rs9958800 and DSEL nearby variant rs9966483 single nucleotide polymorphisms (SNPs) in the 18q region, previously linked with DN in African-Americans, with T2DM in (North African) Tunisian subjects, followed by their association with DN, which was performed subsequent to the analysis of the association with T2DM. Study subjects comprised 900 T2DM cases and 748 normoglycemic control, and genotyping was carried out by PCR-RFLP analysis. Of the 5 SNPs analyzed, POL1-nearby variant rs488846 [P=0.044], and MC4R-nearby variant rs1942872 [P=0.012] were associated with moderate risk of T2DM. However, there was a lack of consistency in the association of the 5 tested SNPs with DN. As such, it appears that the three chromosome 18q region variants appear to play a role in T2DM pathogenesis, but not with DN in North African Tunisian Arabs. PMID- 23727065 TI - Evaluation of the protection exerted by Pisum sativum Ferredoxin-NADP(H) Reductase against injury induced by hypothermia on Cos-7 cells. AB - Hypothermia is employed as a method to diminish metabolism rates and preserve tissues and cells. However, low temperatures constitute a stress that produces biochemical changes whose extension depends on the duration and degree of cold exposure and is manifested when physiological temperature is restored. For many cellular types, cold induces an oxidative stress that is dependent on the elevation of intracellular iron, damages macromolecules, and is prevented by the addition of iron chelators. Pisum sativum Ferredoxin-NADP(H) Reductase (FNR) has been implicated in protection from injury mediated by intracellular iron increase and successfully used to reduce oxidative damage on bacterial, plant and mammalian systems. In this work, FNR was expressed in Cos-7 cells; then, they were submitted to cold incubation and iron overload to ascertain whether this enzyme was capable of diminishing the harm produced by these challenges. Contrary to expected, FNR was not protective and even exacerbated the damage under certain circumstances. It was also found that the injury induced by hypothermia in Cos-7 cells presented both iron-dependent and iron-independent components of damage when cells were actively dividing but only iron-independent component when cells were in an arrested state. This is in agreement with previous findings which showed that iron-dependent damage is also an energy-dependent process. PMID- 23727066 TI - An evaluation of soybean lecithin as an alternative to avian egg yolk in the cryopreservation of fish sperm. AB - Plant-derived lecithin has been used as a more sanitary alternative to avian egg yolk in livestock sperm cryopreservation protocols but its efficacy for cryopreserving fish sperm has not previously been tested comparatively. Here various concentrations of soybean lecithin were evaluated for the cryopreservation of carp (Cyprinus carpio) sperm. Sexually mature fish were induced to spermiation and ovulation with ovopel. The extenders were prepared by using 300 mM glucose, 10% DMSO, supplemented with different ratios of lecithin (5%, 10%, 15%, and 20%) and 10% egg yolk (control I). Negative control was made without egg yolk and soybean lecithin (control II). The pooled semen was diluted separately at ratio of 1:3 (v/v) by using egg yolk and soybean-based extenders. Diluted semen placed into 0.25 ml straws were equilibrated at 4 degrees C for 15 min and frozen in liquid nitrogen vapor. Fertilization was conducted using a ratio of 1 * 10(5)spermatozoa/egg. Supplementation of 10% lecithin to extender showed the best cryoprotective effect for sperm motility and duration of motility against freezing damage compared to 15%, 20% and control II groups (p<0.05). Cryopreserved sperm with extender containing 10% lecithin provided a greater result in terms of fertilization success when compared to extenders containing 20% lecithin or control II (p<0.05). It is concluded that the animal protein-free extender containing 10% soybean lecithin has a similar cryoprotective actions with conventional egg yolk-based extender against freezing damages and fertilization. Therefore, soybean lecithin is a suitable alternative to avian egg yolk for the cryopreservation of fish sperm. PMID- 23727067 TI - Effect of cryopreservation on human sperm messenger RNAs crucial for fertilization and early embryo development. AB - During recent years, several studies have pointed out the importance of key paternal transcripts in early embryo development. Sperm cryopreservation is commonly applied in assisted reproductive technologies (ARTs) and it is important to know if it produces any relevant effect at this level. In this study, using normozoospermic donors, we present a candidate transcript approach in which we quantify the presence of sperm mRNAs considered as markers for male fertility and pregnancy success. Analyses were done using quantitative PCR. Our results demonstrated that the used cryopreservation protocol, which is routinely employed in clinical practice, alter transcripts considered as spermatozoa quality markers and markers for pregnancy success. Most of the studied transcripts considered as male quality markers (PRM1, PRM2, and PEG1/MEST) and one of studied mRNAs reported as markers of pregnancy success (ADD1) were reduced after cryopreservation. In order to check if vitrification protocols could reduce this alteration, another assay was carried out analyzing those transcripts with higher differences in the first study (PRM1 and PRM2). The results showed the same tendency. Although maternal mRNAs can compensate these deficiencies, these results could make advisable the optimization of freezing/thawing procedures. PMID- 23727069 TI - Suppression of CD3/CD28 antibody stimulated responses by human granulocytic myeloid-derived suppressor cells: fact or artefact? AB - T cell responses to CD3/CD28 antibodies are widely used to demonstrate the immunosuppressive activity of added human granulocytic myeloid-derived suppressor cells (G-MDSC). Granulocytic populations have the well established capability to chemically modify antibody structure and/or, phagocytose stimulatory CD3/CD28 antibody coated beads. However the possibility that the suppression observed in CD3/CD28 antibody based assays may result from the effects of the G-MDSC on the stimulatory antibodies rather than the T cells is not routinely controlled for experimentally. In the absence of controls to evaluate potential antibody associated artefacts considerable caution should be applied to the use and interpretation of this assay system as a means of defining suppressive G-MDSC populations. PMID- 23727068 TI - The effects of cooling rates and type of freezing extenders on cryosurvival of rat sperm. AB - Cryopreservation of rat sperm is very challenging due to its sensitivity to various stress factors. The objective of this study was to determine the optimal cooling rate and extender for epididymal sperm of outbred Sprague Dawley (SD) and inbred Fischer 344 (F344) rat strains. The epididymal sperm from 10 to 12 weeks old sexually mature SD and F344 strains were suspended in five different freezing extenders, namely HEPES buffered Tyrode's lactate (TL-HEPES), modified Kreb's Ringer bicarbonate (mKRB), 3% dehydrated skim milk (SM), Salamon's Tris-citrate (TRIS), and tes/tris (TES). All extenders contained 20% egg yolk, 0.75% Equex Paste and 0.1 M raffinose or 0.1 M sucrose. The sperm samples in each extender were cooled to 4 degrees C and held for 45 min for equilibration before freezing. The equilibrated sperm samples in each extender were placed onto a shallow quartz dish inserted into Linkam Cryostage (BCS 196). The samples were then cooled to a final temperature of -150 degrees C by using various cooling rates (10, 40, 70, and 100 degrees C/min). For thawing, the quartz dish containing the sperm samples were rapidly removed from the Linkam cryo-stage and placed on a 37 degrees C slide warmer and held for 1 min before motility analysis. Sperm membrane and acrosomal integrity and mitochondrial membrane potential (MMP) were assessed by SYBR-14/Propidium iodide, Alexa Fluor-488-PNA conjugate and JC-1, respectively. The total motility, acrosomal integrity, membrane integrity and MMP values were compared among cooling rates and extenders. Both cooling rate and type of extender had significant effect on cryosurvival (P < 0.05). Sperm motility increased as cooling rate was increased for both strains (P < 0.05). Highest cryosurvival was achieved when 100 degrees C/min cooling rate was used in combination with TES extender containing 20% egg yolk, 0.75% Equex paste and either 0.1M sucrose or raffinose (P < 0.05). This study showed that TES extender containing 0.1 M raffinose or sucrose with 70 degrees C/min and 100 degrees C/min cooling rate improved post-thaw motility of rat sperm. PMID- 23727070 TI - Cell mediated innate responses of cattle and swine are diverse during foot-and mouth disease virus (FMDV) infection: a unique landscape of innate immunity. AB - Pathogens in general and pathogenic viruses in particular have evolved a myriad of mechanisms to escape the immune response of mammalian species. Viruses that cause acute disease tend to bear characteristics that make them very contagious, as survival does not derive from chronicity of infection, but spread of disease throughout the herd. Foot-and-mouth disease virus (FMDV) is one of the most contagious viruses known. Upon infection of susceptible species, cloven-hoofed animals, the virus proliferates rapidly and causes a vesicular disease within 2-4 days. Disease symptoms resolve by 10 days to 2 weeks and in most cases, virus can no longer be detected. Periods of fever and viremia are usually brief, 1-3 days. In vivo control of virus infection and clearance of the virus during and following acute infection is of particular interest. The interaction of this virus with cells mediating the early, innate immune response has been analyzed in a number of recent studies. In most reports, the virus has a distinct inhibitory effect on the response of cells early in infection. Here we review these new data and discuss the dynamics of the interaction of virus with different cell types mediating the immune response to infection. PMID- 23727074 TI - The role of physical and rehabilitation medicine specialist in lymphoedema. PMID- 23727075 TI - Disturbance of aerobic metabolism accompanies neurobehavioral changes induced by nickel in mice. AB - The oral ingestion of soluble nickel compounds leads to neurological symptoms in humans. Deficiencies in aerobic metabolism induced by neurotoxic stimulus can cause an energy crisis in the brain that results in a variety of neurotoxic effects. In the present study, we focused on the aerobic metabolic states to investigate whether disturbance of aerobic metabolism was involved in nickel induced neurological effects in mice. Mice were orally administered nickel chloride, and neurobehavioral performance was evaluated using the Morris water maze and open field tests at different time points. Aerobic metabolic states in the cerebral cortex were analyzed at the same time points at which neurobehavioral changes were evident. We found that nickel exposure caused deficits in both spatial memory and exploring activity in mice and that nickel was deposited in their cerebral cortex. Deficient aerobic metabolism manifested as decreased O2 consumption and ATP concentrations, lactate and NADH accumulation, and oxidative stress. Meanwhile, the activity of prototypical iron sulfur clusters (ISCs) containing enzymes that are known to control aerobic metabolism, including complex I and aconitase, and the expression of ISC assembly scaffold protein (ISCU) were inhibited following nickel deposition. Overall, these data suggest that aerobic metabolic disturbances, which accompanied the neurobehavioral changes, may participate in nickel-induced neurologic effects. The inactivation of ISC containing metabolic enzymes may result in the disturbance of aerobic metabolism. A better understanding of how nickel impacts the energy metabolic processes may provide insight into the prevention of nickel neurotoxicity. PMID- 23727076 TI - Response to Breckenridge et al. (2013). PMID- 23727077 TI - Editorial comment. PMID- 23727079 TI - Extracellular matrix transcriptome dynamics in hepatocellular carcinoma. AB - The extracellular matrix undergoes extensive remodeling during hepatocellular carcinoma and functions as a critical component of the tumor microenvironment by providing a substratum for cell adhesion and serving as a reservoir for a variety of cytokines and growth factors. Despite the clinical correlation between ECM deposition and hepatocellular carcinoma progression, it remains unclear how global extracellular matrix gene expression is altered in hepatocellular carcinoma and the molecular pathways that govern this change. Herein, a comprehensive analysis of the extracellular matrix transcriptome using an RNA sequencing dataset provided by The Cancer Genome Atlas consortium was conducted and indicates substantial differential gene expression of key extracellular matrix collagens, glycoproteins, and proteoglycans in hepatocellular carcinoma. This analysis also reveals alternative expression of extracellular matrix gene transcript variants that could impact biological activity and serves as a framework for exploring the dynamic nature of the extracellular matrix transcriptome in cancer and identifying candidate genes for future exploration. PMID- 23727078 TI - Calcineurin-mediated dephosphorylation of eNOS at serine 116 affects eNOS enzymatic activity indirectly by facilitating c-Src binding and tyrosine 83 phosphorylation. AB - It has been shown previously that phosphorylation of the endothelial nitric oxide synthase (eNOS) at serine 116 (S116) under basal conditions suppresses eNOS enzymatic activity in endothelial cells. It has also been shown that vascular endothelial growth factor (VEGF) treatment of endothelial cells produces a rapid S116 dephosphorylation, which is blocked by the calcineurin inhibitor, cyclosporin A (CsA). In this study, we show that activation of eNOS in response to a variety of other eNOS-activating agonists and the cytosolic calcium elevating agent, thapsigargin also involves CsA-inhibitable S116 dephosphorylation. Studies with the purified eNOS enzyme also demonstrate that neither mimicking phosphorylation at S116 nor phosphorylation of the purified enzyme at S116 in vitro has any effect on enzymatic activity. Phospho-mimicking, however, does interfere with the interaction of eNOS with c-Src, an interaction which is known to activate eNOS by phosphorylation at tyrosine 83 (Y83). Agonist stimulated eNOS-Src complex formation, as well as agonist-stimulated Y83 phosphorylation, are blocked by calcineurin inhibition by CsA and by a cell permeable calcineurin inhibitory peptide. Taken together, these data suggest a mechanism of eNOS regulation whereby calcineurin-mediated dephosphorylation of eNOS at S116 affects eNOS enzymatic activity indirectly, rather than directly, by facilitating c-Src binding and Y83 phosphorylation. PMID- 23727080 TI - Diagnosing Alzheimer's disease: a systematic review of economic evaluations. AB - BACKGROUND: The objective of this study is to systematically review the literature on economic evaluations of interventions for the early diagnosis of Alzheimer's disease (AD) and related disorders and to describe their general and methodological characteristics. We focused on the diagnostic aspects of the decision models to assess the applicability of existing decision models for the evaluation of the recently revised diagnostic research criteria for AD. METHODS: PubMed and the National Institute for Health Research Economic Evaluation database were searched for English-language publications related to economic evaluations on diagnostic technologies. Trial-based economic evaluations were assessed using the Consensus on Health Economic Criteria list. Modeling studies were assessed using the framework for quality assessment of decision-analytic models. RESULTS: The search retrieved 2109 items, from which eight decision analytic modeling studies and one trial-based economic evaluation met all eligibility criteria. CONCLUSIONS: Diversity among the study objective and characteristics was considerable and, despite considerable methodological quality, several flaws were indicated. Recommendations were focused on diagnostic aspects and the applicability of existing models for the evaluation of recently revised diagnostic research criteria for AD. PMID- 23727081 TI - Variants in PPP3R1 and MAPT are associated with more rapid functional decline in Alzheimer's disease: the Cache County Dementia Progression Study. AB - BACKGROUND: Single-nucleotide polymorphisms (SNPs) located in the gene encoding the regulatory subunit of the protein phosphatase 2B (PPP3R1, rs1868402) and the microtubule-associated protein tau (MAPT, rs3785883) gene were recently associated with higher cerebrospinal fluid (CSF) tau levels in samples from the Knight Alzheimer's Disease Research Center at Washington University (WU) and Alzheimer's Disease Neuroimaging Initiative (ADNI). In these same samples, these SNPs were also associated with faster functional decline, or progression of Alzheimer's disease (AD) as measured by the Clinical Dementia Rating sum of boxes scores (CDR-sb). We attempted to validate the latter association in an independent, population-based sample of incident AD cases from the Cache County Dementia Progression Study (DPS). METHODS: All 92 AD cases from the DPS with a global CDR-sb <=1 (mild) at initial clinical assessment who were later assessed on CDR-sb data on at least two other time points were genotyped at the two SNPs of interest (rs1868402 and rs3785883). We used linear mixed models to estimate associations between these SNPs and CDR-sb trajectory. All analyses were performed using Proc Mixed in SAS. RESULTS: Although we observed no association between rs3785883 or rs1868402 alone and change in CDR-sb (P > .10), there was a significant association between a combined genotype model and change in CDR-sb: carriers of the high-risk genotypes at both loci progressed >2.9 times faster than noncarriers (P = .015). When data from DPS were combined with previously published data from WU and ADNI, change in CDR-sb was 30% faster for each copy of the high-risk allele at rs3785883 (P = .0082) and carriers of both high-risk genotypes at both loci progressed 6 times faster (P < .0001) than all others combined. CONCLUSIONS: We replicate a previous report by Cruchaga et al that specific variations in rs3785883 and rs1868402 are associated with accelerated progression of AD. Further characterization of this association will provide a better understanding of how genetic factors influence the rate of progression of AD and could provide novel insights into preventative and therapeutic strategies. PMID- 23727082 TI - Parkinsonism and distinct dementia patterns in a family with the MAPT R406W mutation. AB - BACKGROUND: The Arg406Trp (R406W) missense mutation in the microtubule-associated protein-tau gene (MAPT) is a known cause of early-onset dementia. Various dementia phenotypes have been described, including frontotemporal dementia (FTD), FTD with parkinsonism, and early-onset Alzheimer disease (EOAD)-like presentations. METHODS: Using whole-exome capture with subsequent sequencing, we identified the R406W mutation in a family with multiple individuals with clinically diagnosed EOAD, in a pattern suggesting autosomal dominant inheritance. We reevaluated all available family members clinically. RESULTS: Each of the affected individuals had a course meeting clinical criteria for EOAD. Two distinct disease trajectories were apparent: one rapidly progressive, and the other long and gradual. Four of five affected individuals also manifested parkinsonian symptoms. FTD features were not prominent and, when present, appeared only late in the course of dementia. CONCLUSIONS: The MAPT R406W mutation is associated with EOAD-like symptoms and parkinsonism without FTD, as well as distinct cognitive courses. PMID- 23727083 TI - Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study. AB - OBJECTIVES: The study sought to test whether high-dose statin treatment would result in greater reductions in plaque inflammation than low-dose statins, using fluorodeoxyglucose-positron emission tomography/computed tomographic imaging (FDG PET/CT). BACKGROUND: Intensification of statin therapy reduces major cardiovascular events. METHODS: Adults with risk factors or with established atherosclerosis, who were not taking high-dose statins (n = 83), were randomized to atorvastatin 10 versus 80 mg in a double-blind, multicenter trial. FDG-PET/CT imaging of the ascending thoracic aorta and carotid arteries was performed at baseline, 4, and 12 weeks after randomization and target-to-background ratio (TBR) of FDG uptake within the artery wall was assessed while blinded to time points and treatment. RESULTS: Sixty-seven subjects completed the study, providing imaging data for analysis. At 12 weeks, inflammation (TBR) in the index vessel was significantly reduced from baseline with atorvastatin 80 mg (% reduction [95% confidence interval]: 14.42% [8.7% to 19.8%]; p < 0.001), but not atorvastatin 10 mg (% reduction: 4.2% [-2.3% to 10.4%]; p > 0.1). Atorvastatin 80 mg resulted in significant additional relative reductions in TBR versus atorvastatin 10 mg (10.6% [2.2% to 18.3%]; p = 0.01) at week 12. Reductions from baseline in TBR were seen as early as 4 weeks after randomization with atorvastatin 10 mg (6.4% reduction, p < 0.05) and 80 mg (12.5% reduction, p < 0.001). Changes in TBR did not correlate with lipid profile changes. CONCLUSIONS: Statin therapy produced significant rapid dose-dependent reductions in FDG uptake that may represent changes in atherosclerotic plaque inflammation. FDG-PET imaging may be useful in detecting early treatment effects in patients at risk or with established atherosclerosis. PMID- 23727084 TI - Inverse relationship between fractionated electrograms and atrial fibrosis in persistent atrial fibrillation: combined magnetic resonance imaging and high density mapping. AB - OBJECTIVES: This study sought to evaluate the relationship between fibrosis imaged by delayed-enhancement (DE) magnetic resonance imaging (MRI) and atrial electrograms (Egms) in persistent atrial fibrillation (AF). BACKGROUND: Atrial fractionated Egms are strongly related to slow anisotropic conduction. Their relationship to atrial fibrosis has not yet been investigated. METHODS: Atrial high-resolution MRI of 18 patients with persistent AF (11 long-lasting persistent AF) was registered with mapping geometry (NavX electro-anatomical system (version 8.0, St. Jude Medical, St. Paul, Minnesota)). DE areas were categorized as dense or patchy, depending on their DE content. Left atrial Egms during AF were acquired using a high-density, 20-pole catheter (514 +/- 77 sites/map). Fractionation, organization/regularity, local mean cycle length (CL), and voltage were analyzed with regard to DE. RESULTS: Patients with long-lasting persistent versus persistent AF had larger left atrial (LA) surface area (134 +/- 38 cm(2) vs. 98 +/- 9 cm(2), p = 0.02), a higher amount of atrial DE (70 +/- 16 cm(2) vs. 49 +/- 10 cm(2), p = 0.01), more complex fractionated atrial Egm (CFAE) extent (54 +/- 16 cm(2) vs. 28 +/- 15 cm(2), p = 0.02), and a shorter baseline AF CL (147 +/- 10 ms vs. 182 +/- 14 ms, p = 0.01). Continuous CFAE (CFEmean [NavX algorithm that quantifies Egm fractionation] <80 ms) occupied 38 +/- 19% of total LA surface area. Dense DE was detected at the left posterior left atrium. In contrast, the right posterior left atrium contained predominantly patchy DE. Most CFAE (48 +/- 14%) occurred at non-DE LA sites, followed by 41 +/- 12% CFAE at patchy DE and 11 +/- 6% at dense DE regions (p = 0.005 and p = 0.008, respectively); 19 +/- 6% CFAE sites occurred at border zones of dense DE. Egms were less fractionated, with longer CL and lower voltage at dense DE versus non DE regions: CFEmean: 97 ms versus 76 ms, p < 0.0001; local CL: 153 ms versus 143 ms, p < 0.0001; mean voltage: 0.63 mV versus 0.86 mV, p < 0.0001. CONCLUSIONS: Atrial fibrosis as defined by DE MRI is associated with slower and more organized electrical activity but with lower voltage than healthy atrial areas. Ninety percent of continuous CFAE sites occur at non-DE and patchy DE LA sites. These findings are important when choosing the ablation strategy in persistent AF. PMID- 23727085 TI - High-sensitivity C-reactive protein and cardiovascular disease: a resolute belief or an elusive link? AB - The role of inflammation in the propagation of atherosclerosis and susceptibility to cardiovascular (CV) events is well established. Of the wide array of inflammatory biomarkers that have been studied, high-sensitivity C-reactive protein (hsCRP) has received the most attention for its use in screening and risk reclassification and as a predictor of clinical response to statin therapy. Although CRP is involved in the immunologic process that triggers vascular remodeling and plaque deposition and is associated with increased CV disease (CVD) risk, definitive randomized evidence for its role as a causative factor in atherothrombosis is lacking. Whether measurement of hsCRP levels provides consistent, clinically meaningful incremental predictive value in risk prediction and reclassification beyond conventional factors remains debated. Despite publication of guidelines on the use of hsCRP in CVD risk prediction by several leading professional organizations, there is a lack of clear consensus regarding the optimal clinical use of hsCRP. This article reviews 4 distinct points from the literature to better understand the current state and application of hsCRP in clinical practice: 1) the biology of hsCRP and its role in atherosclerosis; 2) the epidemiological association of hsCRP with CVD; 3) the quality of hsCRP as a biomarker of risk; and 4) the use of hsCRP as a tool to initiate or tailor statin therapy. Furthermore, we highlight recommendations from societies and important considerations when using hsCRP to guide treatment decisions in the primary prevention setting. PMID- 23727087 TI - In vivo evaluation of atherosclerotic plaque inflammation and of anti inflammatory effects of statins by 18F-fluorodeoxyglucose positron emission tomography. PMID- 23727088 TI - Delayed enhancement abnormalities as a substrate for persistent atrial fibrillation: bright horizons or white noise? PMID- 23727086 TI - Candidate gene association study of coronary artery calcification in chronic kidney disease: findings from the CRIC study (Chronic Renal Insufficiency Cohort). AB - OBJECTIVES: This study sought to identify loci for coronary artery calcification (CAC) in patients with chronic kidney disease (CKD). BACKGROUND: CKD is associated with increased CAC and subsequent coronary heart disease (CHD), but the mechanisms remain poorly defined. Genetic studies of CAC in CKD may provide a useful strategy for identifying novel pathways in CHD. METHODS: We performed a candidate gene study (~2,100 genes; ~50,000 single nucleotide polymorphisms [SNPs]) of CAC within the CRIC (Chronic Renal Insufficiency Cohort) study (N = 1,509; 57% European, 43% African ancestry). SNPs with preliminary evidence of association with CAC in CRIC were examined for association with CAC in the PennCAC (Penn Coronary Artery Calcification) (N = 2,560) and AFCS (Amish Family Calcification Study) (N = 784) samples. SNPs with suggestive replication were further analyzed for association with myocardial infarction (MI) in the PROMIS (Pakistan Risk of Myocardial Infarction Study) (N = 14,885). RESULTS: Of 268 SNPs reaching p < 5 * 10(-4) for CAC in CRIC, 28 SNPs in 23 loci had nominal support (p < 0.05 and in same direction) for CAC in PennCAC or AFCS. Besides chr9p21 and COL4A1, known loci for CHD, these included SNPs having reported genome-wide association study association with hypertension (e.g., ATP2B1). In PROMIS, 4 of the 23 suggestive CAC loci (chr9p21, COL4A1, ATP2B1, and ABCA4) had significant associations with MI, consistent with their direction of effect on CAC. CONCLUSIONS: We identified several loci associated with CAC in CKD that also relate to MI in a general population sample. CKD imparts a high risk of CHD and may provide a useful setting for discovery of novel CHD genes and pathways. PMID- 23727089 TI - Mapping of complex atrial tachycardia circuits by 3-dimensional body surface mapping: the first step in the dawn of a new era. PMID- 23727090 TI - Validation of novel 3-dimensional electrocardiographic mapping of atrial tachycardias by invasive mapping and ablation: a multicenter study. AB - OBJECTIVES: This study prospectively evaluated the role of a novel 3-dimensional, noninvasive, beat-by-beat mapping system, Electrocardiographic Mapping (ECM), in facilitating the diagnosis of atrial tachycardias (AT). BACKGROUND: Conventional 12-lead electrocardiogram, a widely used noninvasive tool in clinical arrhythmia practice, has diagnostic limitations. METHODS: Various AT (de novo and post atrial fibrillation ablation) were mapped using ECM followed by standard-of-care electrophysiological mapping and ablation in 52 patients. The ECM consisted of recording body surface electrograms from a 252-electrode-vest placed on the torso combined with computed tomography-scan-based biatrial anatomy (CardioInsight Inc., Cleveland, Ohio). We evaluated the feasibility of this system in defining the mechanism of AT-macro-re-entrant (perimitral, cavotricuspid isthmus dependent, and roof-dependent circuits) versus centrifugal (focal-source) activation-and the location of arrhythmia in centrifugal AT. The accuracy of the noninvasive diagnosis and detection of ablation targets was evaluated vis-a-vis subsequent invasive mapping and successful ablation. RESULTS: Comparison between ECM and electrophysiological diagnosis could be accomplished in 48 patients (48 AT) but was not possible in 4 patients where the AT mechanism changed to another AT (n = 1), atrial fibrillation (n = 1), or sinus rhythm (n = 2) during the electrophysiological procedure. ECM correctly diagnosed AT mechanisms in 44 of 48 (92%) AT: macro-re-entry in 23 of 27; and focal-onset with centrifugal activation in 21 of 21. The region of interest for focal AT perfectly matched in 21 of 21 (100%) AT. The 2:1 ventricular conduction and low-amplitude P waves challenged the diagnosis of 4 of 27 macro-re-entrant (perimitral) AT that can be overcome by injecting atrioventricular node blockers and signal averaging, respectively. CONCLUSIONS: This prospective multicenter series shows a high success rate of ECM in accurately diagnosing the mechanism of AT and the location of focal arrhythmia. Intraprocedural use of the system and its application to atrial fibrillation mapping is under way. PMID- 23727091 TI - Demonstrating efficacy in preclinical studies of cellular therapies for spinal cord injury - how much is enough? AB - Cellular therapies represent a novel treatment approach for spinal cord injury (SCI), with many different cellular substrates showing promise in preclinical animal models of SCI. Considerable interest therefore exists to translate such cellular interventions into human clinical trials. Balanced against the urgency for clinical translation is the desire to establish the robustness of a cellular therapy's efficacy in preclinical studies, thereby optimizing its chances of succeeding in human trials. Uncertainty exists, however, on the extent to which a therapy needs to demonstrate efficacy in the preclinical setting in order to justify the initiation of a lengthy, expensive, and potentially risky clinical trial. The purpose of this initiative was to seek perspectives on the level of evidence required in experimental studies of cellular therapies before proceeding with clinical trials of SCI. We conducted a survey of 27 SCI researchers actively involved in either preclinical and/or clinical research of cellular interventions for SCI, and then held a focus group meeting to facilitate more in-depth discussion around a number of translational issues. These included: the use of animal models, the use of injury models and mechanisms, the window for demonstrating efficacy, independent replication, defining "relevant, meaningful efficacy" in preclinical studies, and the expectation of therapeutic benefits for cellular interventions. Here we present the key findings from both the survey and focus group meeting in order to summarize and underscore the areas of consensus and disagreement amongst the sampled researchers. It is anticipated that the knowledge generated from this initiative will help to incite future scientific discussions and expert guidelines towards translation of a cell therapy for persons with SCI. PMID- 23727092 TI - Context-dependent decay of motor memories during skill acquisition. AB - Current models of motor learning posit that skill acquisition involves both the formation and decay of multiple motor memories that can be engaged in different contexts. Memory formation is assumed to be context dependent, so that errors most strongly update motor memories associated with the current context. In contrast, memory decay is assumed to be context independent, so that movement in any context leads to uniform decay across all contexts. We demonstrate that for both object manipulation and force-field adaptation, contrary to previous models, memory decay is highly context dependent. We show that the decay of memory associated with a given context is greatest for movements made in that context, with more distant contexts showing markedly reduced decay. Thus, both memory formation and decay are strongest for the current context. We propose that this apparently paradoxical organization provides a mechanism for optimizing performance. While memory decay tends to reduce force output, memory formation can correct for any errors that arise, allowing the motor system to regulate force output so as to both minimize errors and avoid unnecessary energy expenditure. The motor commands for any given context thus result from a balance between memory formation and decay, while memories for other contexts are preserved. PMID- 23727093 TI - Event-based prospective memory in the rat. AB - People plan to act in the future when an appropriate event occurs, a capacity known as event-based prospective memory. Prospective memory involves forming a representation of a planned future action, subsequently inactivating the representation, and ultimately reactivating it at an appropriate point in the future. Recent studies suggest that monkeys, chimpanzees, and rats display elements of prospective memory, but it is uncertain if the full sequence (activation-inactivation-reactivation) that occurs in humans also occurs in nonhumans. Here, we asked if rats exhibit event-based prospective memory. Rats completed an ongoing temporal-discrimination task while waiting for a large meal. To promote the use of event-based prospective memory, we created an event (tone pulses) that provided information that the meal could be obtained soon. Event based prospective memory was suggested by the dramatic decline in ongoing-task performance after the event, with excellent performance at other times. To document that the event initiated memory activation, we arranged for the event to occur at novel times. Finally, multiple, repeated presentations of the event on the same day demonstrate that rats inactivate and reactivate the memory representation in an on-demand, event-based fashion. Development of an animal model of prospective memory may be valuable to probe the biological underpinnings of memory disorders. PMID- 23727094 TI - GMF severs actin-Arp2/3 complex branch junctions by a cofilin-like mechanism. AB - BACKGROUND: Branched actin filament networks driving cell motility, endocytosis, and intracellular transport are assembled in seconds by the Arp2/3 complex and must be equally rapidly debranched and turned over. One of the only factors known to promote debranching of actin networks is the yeast homolog of glia maturation factor (GMF), which is structurally related to the actin filament-severing protein cofilin. However, the identity of the molecular mechanism underlying debranching and whether this activity extends to mammalian GMF have remained open questions. RESULTS: Using scanning mutagenesis and total internal reflection fluorescence microscopy, we show that GMF depends on two separate surfaces for debranching. One is analogous to the G-actin and F-actin binding site on cofilin, but we show using fluorescence anisotropy and chemical crosslinking that it instead interacts with actin-related proteins in the Arp2/3 complex. The other is analogous to a second F-actin binding site on cofilin, which in GMF appears to contact the first actin subunit in the daughter filament. We further show that GMF binds to the Arp2/3 complex with low nanomolar affinity and promotes the open conformation. Finally, we show that this debranching activity and mechanism are conserved for mammalian GMF. CONCLUSIONS: GMF debranches filaments by a mechanism related to cofilin-mediated severing, but in which GMF has evolved to target molecular junctions between actin-related proteins in the Arp2/3 complex and actin subunits in the daughter filament of the branch. This activity and mechanism are conserved in GMF homologs from evolutionarily distant species. PMID- 23727095 TI - Evolutionary origin of the turtle shell. AB - The origin of the turtle shell has perplexed biologists for more than two centuries. It was not until Odontochelys semitestacea was discovered, however, that the fossil and developmental data could be synthesized into a model of shell assembly that makes predictions for the as-yet unestablished history of the turtle stem group. We build on this model by integrating novel data for Eunotosaurus africanus-a Late Guadalupian (~260 mya) Permian reptile inferred to be an early stem turtle. Eunotosaurus expresses a number of relevant characters, including a reduced number of elongate trunk vertebrae (nine), nine pairs of T shaped ribs, inferred loss of intercostal muscles, reorganization of respiratory muscles to the ventral side of the ribs, (sub)dermal outgrowth of bone from the developing perichondral collar of the ribs, and paired gastralia that lack both lateral and median elements. These features conform to the predicted sequence of character acquisition and provide further support that E. africanus, O. semitestacea, and Proganochelys quenstedti represent successive divergences from the turtle stem lineage. The initial transformations of the model thus occurred by the Middle Permian, which is congruent with molecular-based divergence estimates for the lineage, and remain viable whether turtles originated inside or outside crown Diapsida. PMID- 23727096 TI - Actin filament severing by cofilin dismantles actin patches and produces mother filaments for new patches. AB - BACKGROUND: Yeast cells depend on Arp2/3 complex to assemble actin filaments at sites of endocytosis, but the source of the initial filaments required to activate Arp2/3 complex is not known. RESULTS: We tested the proposal that cofilin severs actin filaments during endocytosis in fission yeast cells using a mutant cofilin defective in severing. We used quantitative fluorescence microscopy to track mGFP-tagged proteins, including early endocytic adaptor proteins, activators of Arp2/3 complex, and actin filaments. Consistent with the hypothesis, actin patches disassembled far more slowly in cells depending on severing-deficient cofilin than in wild-type cells. Even more interesting, actin patches assembled slowly in these cofilin mutant cells. Adaptor proteins End4p and Pan1p accumulated and persisted at endocytic sites more than ten times longer than in wild-type cells, followed by slow but persistent recruitment of activators of Arp2/3 complex, including WASP and myosin-I. Mutations revealed that actin filament binding sites on adaptor proteins Pan1p and End4p contribute to initiating actin polymerization in actin patches. CONCLUSIONS: We propose a "sever, diffuse, and trigger" model for the nucleation of actin filaments at sites of endocytosis, whereby cofilin generates actin filament fragments that diffuse through the cytoplasm, bind adaptor proteins at nascent sites of endocytosis, and serve as mother filaments to initiate the autocatalytic assembly of the branched actin filament network of each new patch. This hypothesis explains the source of the "mother filaments" that are absolutely required for Arp2/3 complex to nucleate actin polymerization. PMID- 23727097 TI - Intracellular Na+ and cardiac metabolism. AB - In heart failure, alterations of excitation-contraction underlie contractile dysfunction. One important defect is an elevation of the intracellular Na(+) concentration in cardiac myocytes ([Na(+)]i), which has an important impact on cytosolic and mitochondrial Ca(2+) homeostasis. While elevated [Na(+)]i is thought to compensate for decreased Ca(2+) load of the sarcoplasmic reticulum (SR), it yet negatively affects energy supply-and-demand matching and can even induce mitochondrial oxidative stress. Here, we review the mechanisms underlying these pathophysiological changes. The chain of events may constitute a vicious cycle of ion dysregulation, oxidative stress and energetic deficit, resembling characteristic cellular deficits that are considered key hallmarks of the failing heart. This article is part of a Special Issue entitled "Na(+) Regulation in Cardiac Myocytes". PMID- 23727098 TI - Polyethyleneimine and DNA nanoparticles-based gene therapy for acute lung injury. AB - Acute lung injury (ALI) is a devastating clinical syndrome causing a substantial mortality, but to date without any effective pharmacological management in clinic. Here, we tested whether nanoparticles based on polyethylenimine (PEI) and DNA could be a potential treatment. In mouse model of ALI induced by lipopolysaccharide (LPS) (10mg/kg), intravenous injection of PEI/DNA mediated a rapid (in 6h) and short-lived transgene expression in lung, with alveolar epithelial cells as major targets. When beta2-Adrenergic Receptor (beta2AR) was applied as therapeutic gene, PEI/beta2AR treatment significantly attenuated the severity of ALI, including alveolar fluid clearance, lung water content, histopathology, bronchioalveolar lavage cellularity, protein concentration, and inflammatory cytokines in mice with pre-existing ALI. In high-dose LPS (40 mg/kg) induced ALI, post-injury treatment of PEI/beta2AR significantly improved the 5 day survival of mice from 28% to 64%. These data suggest that PEI/DNA nanoparticles could be an effective agent in future clinical application for ALI treatment. FROM THE CLINICAL EDITOR: In this novel study, PEI/DNA nanoparticles are presented as an effective agent for the treatment of the devastating and currently untreatable syndrome of acute lung injury, using a rodent model system. PMID- 23727099 TI - In-vitro cyto-toxicity, geno-toxicity, and bio-imaging evaluation of one-pot synthesized luminescent functionalized mesoporous SiO2@Eu(OH)3 core-shell microspheres. AB - Luminescent functionalized mesoporous SiO2@Eu(OH)3 core-shell microspheres (LFMCSMs) were prepared by coating of europium hydroxide (Eu(OH)3) shell on mesoporous silica (SiO2) nanospheres via a facile one-pot process at low temperature. The FETEM images revealed that a well-defined luminescent europium hydroxide shell was successfully grafted on the surface of mesoporous silica nanospheres. These experimental results showed that the LFMCSM has a typical diameter of ca. 392 nm consisting of the silica core with about 230 nm in diameter and europium hydroxide shell with an average thickness of about 162 nm. LFMCSMs exhibited strong red emission peak upon irradiation with ultraviolet light, which originated from the electric-dipole transition (5)D0 -> (7)F2 (614 nm) of Eu(3+) ion. The biocompatibility of the synthesized LFMCSMs was evaluated in vitro by assessing their cytotoxic and genotoxic effect on human hepatoblastoma (HepG2) cells using MTT, TUNEL, fluorescent staining, DNA ladder and Gene expression assays respectively. FROM THE CLINICAL EDITOR: This paper describes the development of a one-pot synthesis of luminescent mesoporous SiO2@Eu(OH)3 core-shell microspheres and evaluates their favorable in vitro cyto toxicity and geno-toxicity, and their applications in bio-imaging of these particles that emit bright red signal under UV exposure. PMID- 23727100 TI - Nanocapsules generated out of a polymeric dexamethasone shell suppress the inflammatory response of liver macrophages. AB - Dexamethasone (DXM) is a synthetic glucocorticoid with anti-inflammatory properties. Targeted delivery of dexamethasone to inflammatory cells, e.g. macrophages and Kupffer cells represents a promising approach to minimize side effects. The aim of the present study was to induce a targeted transport of novel DXM-based biodegradable nanocapsules to phagocytic cells. Nanocapsules (NCs) consisting of a hydroxyethylated glucose polymer (hydroxyethyl starch, HES) shell with encapsulated DXM and NCs synthesized exclusively in inverse miniemulsion out of DXM were investigated. Non-parenchymal murine liver cells served as target cells. HES-DXM NCs were predominantly incorporated by Kupffer cells (KCs). In contrast, DXM NCs were phagocytized by KCs and endothelial cells. The release of the NC-content was confirmed by incorporation of CellTrackerTM into the NCs. Uptake of DXM NCs by Kupffer cells reduced significantly the release of inflammatory cytokines in response to LPS stimulation. Importantly, the DXM NCs consisting exclusively out of a dexamethasone shell offer the potential to serve as carriers for additional therapeutics. FROM THE CLINICAL EDITOR: In this paper, nanocapsule-based targeted delivery of dexamethasone to inflammatory cells is presented as a promising approach to minimize side effects and increase efficacy of this anti-inflammatory clinically used corticosteroid. PMID- 23727101 TI - Intravenous moderate-dose bumetanide continuous infusion and severe musculoskeletal pain. PMID- 23727102 TI - Effect of manual thrombus aspiration during primary percutaneous coronary intervention on infarct size: evaluation with cardiac computed tomography. PMID- 23727103 TI - Anxiolytics in patients suffering a suspected acute coronary syndrome: multi centre randomised controlled trial in Emergency Medical Service. AB - BACKGROUND: The prehospital treatment of pain and discomfort among patients who suffer from acute coronary syndrome (ACS) needs a treatment strategy which combines relief of pain with relief of anxiety. AIM: The aim of the present study was to evaluate the impact on pain and anxiety of the combination of an anxiolytic and an analgesic as compared with an analgesic alone in the prehospital setting of suspected ACS. METHODS: A multi-centre randomised controlled trial compared the combination of Midazolam (Mi)+Morphine (Mo) and Mo alone. All measures took part: Prior to randomisation, 15 min thereafter and on admission to a hospital. Inclusion criteria were: 1) pain raising suspicion of ACS and 2) pain score >=4. PRIMARY ENDPOINT: Pain score after 15 min. RESULTS: In all, 890 patients were randomised to Mi+Mo and 873 to Mo alone. Pain was reduced from a median of 6 to 4 and finally to 3 in both groups. The mean dose of Mo was 5.3 mg in Mi+Mo and 6.0 mg in Mo alone (p<0.0001). Anxiety was reported in 66% in Mi+Mo and in 64% in Mo alone at randomisation (NS); 15 min thereafter in 31% and 39% (p=0.002) and finally in 12% and 26% respectively (p<0.0001). On admission to a hospital nausea or vomiting was reported in 9% in Mi+Mo and in 13% in Mo alone (p=0.003). Drowsiness differed; 15% and 14% were drowsy in Mi+Mo versus 2% and 3% in Mo alone respectively (p<0.001). CONCLUSION: Despite the fact that the combination of anxiolytics and analgesics as compared with analgesics alone reduced anxiety and the requirement of Morphine in the prehospital setting of acute coronary syndrome, this strategy did not reduce patients' estimation of pain (primary endpoint). More effective pain relief among these patients is warranted. PMID- 23727104 TI - Imaging patterns of heart failure in rheumatoid arthritis evaluated by cardiovascular magnetic resonance. PMID- 23727105 TI - Prehospital ECG signs of acute coronary occlusion are associated with reduced one year mortality. AB - BACKGROUND: We wanted to evaluate predictors of direct admittance to a coronary care unit (CCU) and predictors of death in patients with suspected acute coronary syndromes (ACS). METHODS: During 2004-2007, all consecutive prehospitally triaged patients with suspected ACS were prospectively included. Prehospital and emergency data were collected at point of care. Data from medical records, ECG-, echocardiography- and laboratory databases was collected retrospectively. RESULTS: In all, 2757 patients were included. Out of these 858 were directly admitted to the CCU or cath/lab. Predictors for direct admittance to the CCU were ST-segment elevation on the initial ECG; odds ratio (OR) 46.11, left bundle branch block; OR 3.30, ongoing symptoms; OR 2.90, current smoking; OR 2.18 and ST segment depression; OR 2.05. Independent predictors for 1-year mortality were cardiogenic shock; OR 14.40, increasing age OR (per year) 1.08, diabetes; OR 2.09 and chronic heart failure; OR 1.67. ST-segment elevation was associated with a lower 1-year mortality rate; OR 0.52. CONCLUSIONS: Among patients with a suspected ACS, prehospital ECG-signs indicating an acute coronary occlusion were not only a predictor for direct admission to acute coronary care but also a predictor for increased survival. To improve future outcome in acute ischemic heart diseases we must find and treat not only the STEMI's but also the high-risk NSTEMIs that otherwise would have a poor prognosis. PMID- 23727106 TI - Need for new non-invasive imaging strategies to identify high-risk asymptomatic patients with carotid stenosis. PMID- 23727107 TI - Atrial Fibrillation reduces the Functional REServe of the Heart by a fifth: a pilot FRESH-AF study. PMID- 23727108 TI - Effect of pregnancy on the myocardial non-compaction cardiomyopathy. PMID- 23727109 TI - Poor engraftment potential of epicardial progenitors upon intramyocardial transplantation into the neonatal mouse heart. PMID- 23727110 TI - Significant changes in platelet count, volume and size in acute aortic dissection. PMID- 23727111 TI - Refuting the ticagrelor-aspirin black box warning: and proposing a ticagrelor early-PCI black box warning. AB - CONTEXT: Ticagrelor, a novel reversible antiplatelet agent, has a black box warning to avoid maintenance doses of aspirin>100mg. However, a significant ticagrelor-early percutaneous coronary intervention (PCI) interaction exists. OBJECTIVE: To discuss the inappropriateness of the black box warning for aspirin doses>100mg with ticagrelor and the appropriateness (and need) for a black box warning for ticagrelor patients needing early (within 24 hours of randomization) PCI. RESULTS: The FDA Complete Response Review for ticagrelor indicates that aspirin doses >= 300 mg/daily was not a significant interaction. In the ticagrelor-aspirin >= 300 mg cohort, all-cause mortality (through study end) and cardiovascular (CV) mortality (through study end) were not significantly increased (HR=1.27; 95% CI, 0.84-1.93, p=0.262 and HR=1.39; 95% CI:0.87-2.2, p=0.170), respectively. However, in patients treated with early (within 24 hours) PCI, ticagrelor significantly increased all-cause mortality (30 day: HR=1.89; 95% CI: 1.26-2.81, p=0.002, and through study end, HR=1.41; 95% CI,1.08-1.84, p=0.012) and increased CV mortality (30 day: HR=1.31; 95% CI: 0.97-1.77, p=0.075, and through study end, HR=1.35; 95% CI, 0.995-1.82, p=0.054) compared to clopidogrel. CONCLUSIONS: Early-PCI was more prevalent in the US versus outside US regions (61% versus 49%). The black box warning for the use of maintenance aspirin doses over 100mg/daily with ticagrelor is inappropriate and ignores the more important, credible, and highly significant ticagrelor-early PCI adverse interaction in PLATO. PMID- 23727112 TI - 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions. AB - The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination (HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions of 53BP1 are mediated in part by RIF1, the only known factor that requires 53BP1 phosphorylation for its recruitment to double-strand breaks (DSBs). Here, we show that a 53BP1 phosphomutant, 53BP18A, comprising alanine substitutions of the eight most N terminal S/TQ phosphorylation sites, mimics 53BP1 deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP18A recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP18A. We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP. PMID- 23727113 TI - Identification and characterization of toxin-antitoxin systems in strains of Lactobacillus rhamnosus isolated from humans. AB - The toxin-antitoxin gene systems (TASs) are present in the genomes of the overwhelming majority of bacteria and archaea. These systems are involved in various cellular regulatory processes (including stress response), and have not been previously investigated in Lactobacilli. We identified 6 putative TASs with toxins belonging to the MazE and RelE superfamilies (PemK1-A1Lrh, PemK2-A2Lrh, PemK3-RelB2Lrh, RelE1Lrh, RelB3-RelE3Lrh, and YefM-YoeBLrh) in the genomes of annotated strains of Lactobacillus rhamnosus. PCR analyses revealed that all systems were found in the genomes of 15 strains of L. rhamnosus isolated from humans in central Russia. These strains were highly heterogeneous with respect to the presence of TASs, as well as their nucleotide and amino acid sequences. In three cases, the relE1 genes contained IS3 elements. TAS heterogeneity may be used to reveal inter-genus differences between strains. Cloning of the toxin genes of 3 TASs inhibited Escherichia coli growth, thus confirming their functionality. Cell growth arrest caused by expression of the toxin genes could be reverted by the expression of a cognate antitoxins. Transcription of toxin antitoxin loci in L. rhamnosus was shown by RT-PCR. PMID- 23727114 TI - In patients with post-infarction left ventricular dysfunction, how does impaired basal rotation affect chronic ischemic mitral regurgitation? AB - BACKGROUND: The aim of this study was to explore the contribution of left ventricular (LV) basal rotation to the mechanism of chronic ischemic mitral regurgitation (MR). METHODS: Fifty-seven patients (52 men; mean age, 68.3 +/- 11.8 years) with postinfarction LV dysfunction (defined as an ejection fraction <= 45%) were prospectively enrolled. Each invariably had functional MR. To assess MR degree, the effective regurgitant orifice area (EROA) was quantified by echocardiography using the proximal isovelocity surface area method. Furthermore, mitral valve deformation (valve tenting and annular function) and LV global (systolic and diastolic volumes, function, and sphericity) and local remodeling (displacement of papillary muscles, regional strain, and rotation by speckle tracking) were assessed. The patients were subsequently subdivided into two groups according to the absence (group A) or presence (group B) on transthoracic echocardiography of infarct area in the inferior and/or posterior basal segments. RESULTS: A larger EROA was found in group B than in group A (P = .034) and in subjects with asymmetric rather than symmetric tethering in either group (P = .036 and P = .040 for groups A and B, respectively). Basal radial (P = .009), circumferential (P = .042), and longitudinal (P = .005) strain and rotation (P = .021) were lower in group B than in group A. There was also a significant inverse correlation between EROA and basal rotation in group B (r = -0.75, P < .001). Furthermore, using multivariate linear regression analysis, we found that the independent determinants of EROA were end-diastolic volume (P < .001) and tenting area (P = .004) in group A and asymmetric tethering (P = .029) and basal rotation (P < .001) in group B. CONCLUSIONS: Impaired basal rotational mechanics occurring after an inferior-posterior myocardial infarction is associated with increased MR. PMID- 23727115 TI - New three-dimensional speckle-tracking echocardiography identifies global impairment of left ventricular mechanics with a high sensitivity in childhood cancer survivors. AB - BACKGROUND: The aim of this case-control study was to assess the usefulness of three-dimensional (3D) speckle-tracking echocardiography in the evaluation of global left ventricular (LV) myocardial performance in adolescent and adult survivors of childhood cancers. METHODS: Fifty-three anthracycline-treated survivors of childhood cancers (mean age, 18.6 +/- 5.1 years) and 38 controls were studied. Three-dimensional speckle-tracking echocardiography was performed to assess LV 3D global and segmental strain, time to peak segmental 3D strain, LV torsion, and ejection fraction. LV systolic dyssynchrony index (SDI) was calculated as the percentage of the standard deviation of times to peak strain of the 16 segments divided by the RR interval. A global performance index (GPI) was calculated as (global 3D strain * torsion)/SDI. The area under the receiver operating characteristic curve was calculated to determine the capability of various echocardiographic indices to discriminate between patients and controls. RESULTS: Compared with controls, patients had significantly reduced LV global 3D strain (P < .001), torsion (P < .001), and GPI (P < .001) and greater SDI (P < .001). All except the basal anteroseptal segment in patients had reduced regional 3D strain compared with controls (P < .05 for all). Global 3D strain (P = .018), SDI (P = .003), and GPI (P = .02) were correlated with cumulative anthracycline dose. The areas under the curves for GPI, global 3D strain, 1/SDI, torsion, and ejection fraction were 0.92, 0.79, 0.79, 0.79, and 0.78, respectively. A GPI cutoff of 10.6 degrees /cm had sensitivity of 84.9% and specificity of 81.6% of differentiating patients from controls. CONCLUSIONS: Three-dimensional speckle tracking echocardiography enables the derivation of an index of LV global performance that incorporates LV 3D strain, dyssynchrony, and torsion for the sensitive detection of altered LV mechanics in childhood cancer survivors. PMID- 23727116 TI - [A KEL*02mod allele responsible for an apparent maternity exclusion]. AB - The patient's rare KEL:1,-2 phenotype was highlighted in course of a routine preoperative erythrocyte typing. Unexpectedly, her two daughters presented a KEL: 1,2 phenotype what appeared first as an apparent maternity exclusion. Flow cytometry, genotyping and adsorption-elution analyses were then performed for those three patients. KEL genotyping showed that the patient's genotype was KEL*01/KEL*02 whereas that of her daughters was KEL*02/KEL*02. By using polyclonal anti-KEL2 reagent, weak amount of KEL2 was identified on the patient's erythrocytes, a result which was confirmed by both flow cytometry and adsorption elution assays, suggesting that patient's phenotype was in fact KEL:1,2w. These results are in favour of a weak expressed KEL*02 allele (KEL*2mod) transmission coding for a KEL2 antigen detected in some technical conditions only. Those results allowed to explain the apparent maternity exclusion based on initial KEL phenotype. This study also seems to confirm the presence of a compensatory mechanism of the KELmod allele deficient expression in heterozygote patients. A KEL phenotype retrospective study of 80,000 subjects showed a local KEL:1,-2 frequency four times lower than that described in literature. Moreover, a significant number of those individuals would in reality be KEL:1,2w, what still would decrease the real frequency of the KEL:1,2 subjects. PMID- 23727117 TI - Comparison of the sensitivities of three commercial assays for detection of the high risk HPV types 16, 18 and 45. AB - The relative and analytical sensitivity of the APTIMA HPV test (AHPV, broad spectrum, target amplification) and the PreTect HPV-Proofer (type-specific, target amplification) for the detection of HPV mRNA in various cell lines was compared. Equivalent relative sensitivity for the HPV 16-containing cell lines (2.5 cells/ml with both CaSki and SiHa) was observed for the mRNA assays--and similar sensitivities were observed for the detection of HPV 18 (HeLa) and 45 (MS751); ranging from 2.5 cells/ml (Proofer) to 25 cells/ml (APTIMA). In relation to analytical sensitivity, again, the mRNA assays showed similar sensitivities to each other, ranging from 0.1 to 1 cell per reaction for APTIMA and 0.1 to 10 cells per reaction for PreTect HPV-Proofer (depending on cell line). Both mRNA assays consistently achieved a higher analytical sensitivity than a DNA based comparator--the Hybrid Capture 2 High-Risk HPV DNA test (hc2). This study indicates that mRNA tests had high analytical sensitivity, higher than a well established DNA-test based when using cell lines as target. Implications for clinical application are discussed. PMID- 23727118 TI - Evaluation of methods using celite to concentrate norovirus, adenovirus and enterovirus from wastewater. AB - Enteroviruses, noroviruses and adenoviruses are among the most common viruses infecting humans worldwide. These viruses are shed in the feces of infected individuals and can accumulate in wastewater, making wastewater a source of a potentially diverse group of enteric viruses. In this study, two procedures were evaluated to concentrate noroviruses, adenoviruses and enteroviruses from primary effluent of wastewater. In the first procedure, indigenous enteroviruses, noroviruses and adenoviruses were concentrated using celite (diatomaceous earth) followed by centrifugation through a 30K MWCO filter and nucleic acid extraction. The second procedure used celite concentration followed by nucleic acid extraction only. Virus quantities were measured using qPCR. A second set of primary effluent samples were seeded with Coxsackievirus A7, Coxsackievirus B1, poliovirus 1 or enterovirus 70 before concentration and processed through both procedures for recovery evaluation of enterovirus species representatives. The pairing of the single step extraction procedure with the celite concentration process resulted in 47-98% recovery of examined viruses, while the celite concentration process plus additional centrifugal concentration before nucleic acid extraction showed reduced recovery (14-47%). The celite concentration process followed by a large volume nucleic acid extraction technique proved to be an effective procedure for recovering these important human pathogens from wastewater. PMID- 23727119 TI - Endogenous positive allosteric modulation of GABA(A) receptors by diazepam binding inhibitor. AB - Benzodiazepines (BZs) allosterically modulate gamma-aminobutyric acid type-A receptors (GABAARs) to increase inhibitory synaptic strength. Diazepam binding inhibitor (DBI) protein is a BZ site ligand expressed endogenously in the brain, but functional evidence for BZ-mimicking positive modulatory actions has been elusive. We demonstrate an endogenous potentiation of GABAergic synaptic transmission and responses to GABA uncaging in the thalamic reticular nucleus (nRT) that is absent in both nm1054 mice, in which the Dbi gene is deleted, and mice in which BZ binding to alpha3 subunit-containing GABAARs is disrupted. Viral transduction of DBI into nRT is sufficient to rescue the endogenous potentiation of GABAergic transmission in nm1054 mice. Both mutations enhance thalamocortical spike-and-wave discharges characteristic of absence epilepsy. Together, these results indicate that DBI mediates endogenous nucleus-specific BZ-mimicking ("endozepine") roles to modulate nRT function and suppress thalamocortical oscillations. Enhanced DBI signaling might serve as a therapy for epilepsy and other neurological disorders. PMID- 23727120 TI - The balance between capture and dissociation of presynaptic proteins controls the spatial distribution of synapses. AB - The location, size, and number of synapses critically influence the specificity and strength of neural connections. In axons, synaptic vesicle (SV) and active zone (AZ) proteins are transported by molecular motors and accumulate at discrete presynaptic loci. Little is known about the mechanisms coordinating presynaptic protein transport and deposition to achieve proper distribution of synaptic material. Here we show that SV and AZ proteins exhibit extensive cotransport and undergo frequent pauses. At the axonal and synaptic pause sites, the balance between the capture and dissociation of mobile transport packets determines the extent of presynaptic assembly. The small G protein ARL-8 inhibits assembly by promoting dissociation, while a JNK kinase pathway and AZ assembly proteins inhibit dissociation. Furthermore, ARL-8 directly binds to the UNC-104/KIF1A motor to limit the capture efficiency. Together, molecular regulation of the dichotomy between axonal trafficking and local assembly controls vital aspects of synapse formation and maintenance. PMID- 23727121 TI - Effect of different doses of equine chorionic gonadotropin on follicular and luteal dynamics and P/AI of high-producing Holstein cows. AB - The hypotheses of this study were (1) that the administration of 400IU eCG in a TAI protocol would increase ovarian follicular growth and diameter of the largest follicle (LF), volume of the CL, and produce an earlier rise on serum concentration of progesterone (P4) to ultimately improve P/AI compared to non treated high-producing Holstein cows; and (2) that 600IU of eCG could enhance any potential effects of a greater gonadotropin treatment upon follicular and luteal size and function, improving P/AI. Cows were subjected to a protocol of synchronization of ovulation for timed artificial insemination (TAI): D0-P4 device insert and estradiol benzoate, D8-P4 device removal and PGF2alpha; Experiment 1, D10PM - GnRH plus TAI; and Experiment 2, D10AM - GnRH, D10PM - TAI. In Experiment 1, at P4 device removal, cows were assigned to one of the two treatments to receive none (n=232) or 400IU (n=232) of eCG. In Experiment 2, again at P4 device removal, cows were assigned to one of the three treatments to receive no eCG, (n=166) 400 (n=145) or 600IU (n=145) of eCG. Pregnancy was diagnosed 35 days after TAI. Ultrasonographic examination of both ovaries was done in a subset of cows in Experiments 1 [no eCG (n=27) and 400IU eCG (n=14)], and 2 [no eCG (n=15), 400IU eCG (n=14) and 600IU eCG (n=11)]. Exams were conducted at device removal (D8) and TAI (D10) to measure the diameter of the LF; then twice daily from D10 to 13, to determine time to ovulation and the maximum diameter of the LF; and then 3 (D14), 6 (D17), 9 (D20) and 12 (D23) days after presumed ovulation, concurrent with blood sampling, to measure the volume of the CL and serum concentration of P4. In both studies, eCG (400 or 600IU)-treated cows had similar diameter of the LF on D8 and D10, growth rate of the LF from Days 8 to 10, ovulation rate, time to ovulation, volume of the CL, serum concentration of P4 and P/AI as compared to control animals. Thus, adding either 400 or 600IU eCG to TAI protocols was inefficient to alter follicular and luteal dynamics and increase P/AI in high-producing dairy cows under the conditions of these experiments. The lack of positive effects of eCG in the present study might be explained by the small percentage of cows with poor body condition score and lesser incidence of anestrus. PMID- 23727122 TI - Clinical significance of serum transforming growth factor-beta1 in lung cancer. AB - BACKGROUND: Transforming growth factor-beta1 (TGF-beta1) plays a critical role in human cancer development. Present study aimed to explore the clinical significance of serum TGF-beta1 levels in patients with lung cancer and analyze the relationship between TGF-beta1 and existing tumor markers for lung cancer. METHODS: Serum was collected from 118 patients with lung cancer and 40 healthy volunteers. Serum TGF-beta1 levels were measured by enzyme-linked immunosorbent assay (ELISA), and the association with various clinical characteristics was analyzed. The diagnostic value of TGF-beta1 was assessed alone and in combination with existing tumor markers for lung cancer. RESULTS: Serum TGF-beta1 levels were significantly higher in patients with lung cancer compared to healthy volunteers [0.6 * 10(5) (0.4 * 10(5), 0.9 * 10(5))pg/ml vs 0.5 * 10(5) (0.3 * 10(5), 0.7 * 10(5))pg/ml, P=0.040]. Although there was a positive correlation between serum TGF-beta1 levels and advanced stages, the significant difference was not found between early stages and advanced stages (P=0.116). The ability of serum TGF beta1 to discriminate lung cancer at a cutoff value of 79,168 pg/ml exhibited sensitivity of 30.6% and specificity of 97.5%. Serum TGF-beta1 levels were correlated to cytokeratin fragment 21-1 (CYFRA21-1; R=0.308, P=0.020) and neuron specific enolase (NSE; R=0.558, P=0.003). The diagnostic accuracy rates for the existing lung-tumor markers, as SCC, CYFRA21-1, and NSE, were increased from 20.0%, 34.6%, and 45.9% to 48.9%, 51.7%, and 54.5%, respectively by the inclusion of serum TGF-beta1 levels. CONCLUSION: Quantification of serum TGF-beta1 levels by ELISA may provide a novel complementary tool for the clinical diagnosis of lung cancer. PMID- 23727123 TI - Caenorhabditis elegans as a model for the screening of anthelminthic compounds: ultrastructural study of the effects of albendazole. AB - This study investigated the effects of albendazole on the viability, morphology and ultrastructure of different life stages of Caenorhabditis elegans. The albendazole EC50 value after seven days of treatment was 18.43 MUM. This concentration was very efficient against all the stages. Light and electron microscopy analysis showed damage to the body wall of the adults and larvae. An intense desquamation of the cuticle of larvae and of the surface of the eggs was observed, preventing their hatching and development. The main ultrastructural damage detected was the degeneration of the mitochondria in the noncontractile muscle of the body wall, which appeared as large vacuoles. This study reaffirmed the use of C. elegans as a screening system for compounds with potential anthelmintic activity and showed the effects of albendazole on the different life stages of these worms. PMID- 23727124 TI - A comparison of automated anatomical-behavioural mapping methods in a rodent model of stroke. AB - Neurological damage, due to conditions such as stroke, results in a complex pattern of structural changes and significant behavioural dysfunctions; the automated analysis of magnetic resonance imaging (MRI) and discovery of structural-behavioural correlates associated with these disorders remains challenging. Voxel lesion symptom mapping (VLSM) has been used to associate behaviour with lesion location in MRI, but this analysis requires the definition of lesion masks on each subject and does not exploit the rich structural information in the images. Tensor-based morphometry (TBM) has been used to perform voxel-wise structural analyses over the entire brain; however, a combination of lesion hyper-intensities and subtle structural remodelling away from the lesion might confound the interpretation of TBM. In this study, we compared and contrasted these techniques in a rodent model of stroke (n=58) to assess the efficacy of these techniques in a challenging pre-clinical application. The results from the automated techniques were compared using manually derived region-of-interest measures of the lesion, cortex, striatum, ventricle and hippocampus, and considered against model power calculations. The automated TBM techniques successfully detect both lesion and non-lesion effects, consistent with manual measurements. These techniques do not require manual segmentation to the same extent as VLSM and should be considered part of the toolkit for the unbiased analysis of pre-clinical imaging-based studies. PMID- 23727125 TI - Angelica sinensis polysaccharide nanoparticles as novel non-viral carriers for gene delivery to mesenchymal stem cells. AB - This study centers on the use of a nanoparticle based on the polysaccharide from Angelica sinensis (ASP) as an efficient and safe non-viral gene vector. After modification with branched low molecular weight polyethylenimine (1200 Da), the cationized ASP (cASP) was combined with the plasmid encoding transforming growth factor-beta 1 (TGF-beta1) to form a spherical nano-scaled particle (i.e., cASP pTGF-beta1 nanoparticle). This nanoparticle was applied to transfect rat bone marrow mesenchymal stem cells and human umbilical cord mesenchymal stem cells. As a result, nanoparticles (cASP/pDNA weight ratio 10:1) had the greatest transfection efficiency in both cells, which was significantly higher than those of Lipofectamine2000 and PEI (25 kDa). This was in agreement with the findings of the semi-quantitative RT-PCR and live cell imaging. These nanoparticles were also less toxic than Lipofectamine2000 and PEI (25 kDa). Therefore, cASP could be a potential candidate for a novel non-viral gene vector. FROM THE CLINICAL EDITOR: These authors demonstrate the use of a nanoparticle-based efficient and safe non viral gene vector delivery system via a spherical nanoparticle based on a polysaccharide from Angelica sinensis, with parameters superior to Lipofectamine2000. PMID- 23727126 TI - Cationic lipid nanoparticles for therapeutic delivery of siRNA and miRNA to murine liver tumor. AB - miR-122, a liver-specific tumor suppressor microRNA, is frequently down-regulated in hepatocellular carcinoma (HCC). LNP-DP1, a cationic lipid nanoparticle formulation, was developed as a vehicle to restore deregulated gene expression in HCC cells by miR-122 delivery. LNP-DP1 consists of 2-dioleyloxy-N,N-dimethyl-3 aminopropane (DODMA), egg phosphatidylcholine, cholesterol and cholesterol polyethylene glycol. In vitro, LNP-DP1-mediated transfection of a miR-122 mimic to HCC cells down-regulated miR-122 target genes by >95%. In vivo, siRNAs/miRNAs encapsulated in LNP-DP1 were preferentially taken up by hepatocytes and tumor cells in a mouse HCC model. The miR-122 mimic in LNP-DP1 was functional in HCC cells without causing systemic toxicity. To demonstrate its therapeutic potential, LNP-DP1 encapsulating miR-122 mimic was intratumorally injected and resulted in ~50% growth suppression of HCC xenografts within 30 days, which correlated well with suppression of target genes and impairment of angiogenesis. These data demonstrate the potential of LNP-DP1-mediated microRNA delivery as a novel strategy for HCC therapy. FROM THE CLINICAL EDITOR: In this study, LNP-DP1 a cationic lipid nanoparticle formulation -is reported as a vehicle to restore deregulated gene expression in hepatic carcinoma cells by siRNA and miRNA delivery using a mouse model. Further expansions to this study may enable transition to clinical trials of this system. PMID- 23727127 TI - Multidomain sumoylation of the ecdysone receptor (EcR) from Drosophila melanogaster. AB - The 20-hydroxyecdysone receptor (EcR) is a transcription factor belonging to the nuclear receptor superfamily. Together with the ultraspiracle nuclear receptor (Usp) it coordinates critical biological processes in insects such as development and reproduction. EcR and its ligands are used in commercially available ecdysone inducible expression systems and are considered to be artificial gene switches with potential therapeutic applications. However, the regulation of EcR action is still unclear, especially in mammals and as far as posttranslational modifications are concerned. Up until now, there has been no study on EcR sumoylation. Using bioinformatic predictors, a Ubc9 fusion-directed sumoylation system and mutagenesis experiments, we present EcR as a new target of SUMO1 and SUMO3 modification. Our research revealed that EcR undergoes isoform-specific multisumoylation. The pattern of modification remains unchanged in the presence of the ligand and the dimerization partner. The SUMO acceptor sites are located in the DNA-binding domain and the ligand-binding domain that both exhibit structural plasticity. We also demonstrated the existence of a sumoylation site in the F region and EcRA-A/B region, both revealing characteristics of intrinsically disordered regions. The consequences of modification and the resulting impact on conformation and function may be especially crucial for the disordered sequences in these two areas. The isoform-specificity of sumoylation may explain the differences in the transcriptional activity of EcR isoforms. PMID- 23727129 TI - Androgen treatment of postmenopausal women. AB - Testosterone is physiologically important for women. Serum testosterone levels decline with age, with the most precipitous fall being prior to menopause. There is no level of testosterone which defines a woman as being testosterone deficient. However, there is substantial high quality evidence to support the use of testosterone for the treatment of hypoactive sexual desire disorder in postmenopausal women. Although preliminary data suggests testosterone has favorable effects on bone and muscle mass, cognitive function and the cardiovascular system, further research regarding its therapeutic effects in these domains is warranted. As no testosterone product has been approved for women there is extensive off-label prescribing of testosterone products for women as well as the prescription of compounded therapy. This raises serious safety concerns and together with the evidence for the negative impact of FSD on quality of life, highlights the need for an approved testosterone formulation for women. This article is part of a Special Issue entitled 'Menopause'. PMID- 23727128 TI - Alzheimer's disease: review of hormone therapy trials and implications for treatment and prevention after menopause. AB - Hormonal changes associated with the menopausal transition and postmenopause have the potential to influence processes linked to Alzheimer's disease symptoms and pathogenesis, but effects of menopause on Alzheimer risk can be addressed only indirectly. Nine randomized clinical trials of estrogen-containing hormone therapy in Alzheimer's disease patients were identified by a systematic literature search. Findings suggest that hormone therapy does not improve cognitive symptoms of women with Alzheimer's disease. No clinical trials of hormone therapy address Alzheimer prevention, but one clinical trial provides moderate evidence that continuous, combined estrogen plus progestogen initiated at age 65 years or older increases the risk of dementia. The timing, or critical window, hypothesis suggests that hormone therapy initiated at a younger age in closer temporal proximity to menopause may reduce the risk of Alzheimer's disease. This hypothesis is supported by observational research but is not addressed by clinical trial data. Unrecognized confounding is of concern in interpreting observational results, and research that helps resolve this issue will have important public health implications. Well-designed cohort studies, convergent evidence from appropriate laboratory models, and long-term clinical trials using surrogate biomarkers of brain function and neural pathology could provide relevant answers. Other estrogenic compounds are of theoretical interest with respect to Alzheimer treatment and risk. Effects of selective estrogen receptor modulators such as raloxifene may differ from those of estrogens; potential effects of phytoestrogens are not well studied. This article is part of a Special Issue entitled 'Menopause'. PMID- 23727130 TI - Nongenomic bronchodilating action elicited by dehydroepiandrosterone (DHEA) in a guinea pig asthma model. AB - Primates secrete large amounts of the precursor steroid dehydroepiandrosterone (DHEA); in humans, its levels are low during childhood and start declining after the fourth decade. It has been postulated that the progressive decline in DHEA levels may be related with the severity of asthma associated with age. To determine whether DHEA may regulate the airway smooth muscle (ASM) activity, isolated tracheal rings with and without epithelium from male guinea pigs were isometrically recorded to characterize the response of ASM to DHEA at different concentrations on KCl- and carbachol (CCh)-induced contraction as well as on ovalbumin (OVA)-induced contraction in sensitized guinea pigs. Additionally, we used barometric plethysmography in sensitized guinea pigs in order to compare changes of the lung resistance increased by the antigen challenge to OVA in the absence and presence of different doses of DHEA. DHEA concentration-dependently abolished the contraction to KCl, CCh and OVA, and no differences were found in preparations with and without epithelium. DHEA-induced relaxation was not modified by the suppression of protein synthesis or transcription, pharmacological inhibition of nitric oxide (NO) synthase, nor by antagonist of beta2-adrenergic receptors or an inhibitor of the 3beta-HSD enzyme. Likewise, Ca(2+)-induced contraction in Ca(2+)-free depolarized tissues was antagonized by DHEA, and the contraction to the L-type voltage-dependent calcium channel activator (Bay K 8644) was inhibited by DHEA. Furthermore, DHEA prevented OVA induced increases in lung resistance. These results indicate that DHEA-induced relaxation in ASM is a nongenomic (membrane) action and is not produced after its bioconversion. The data suggest that DHEA-induced relaxation is an epithelium- and NO-independent mechanism that involves a blockade of voltage-dependent calcium channels and possible non-selective cation channels. PMID- 23727131 TI - Sorafenib enhances proteasome inhibitor-mediated cytotoxicity via inhibition of unfolded protein response and keratin phosphorylation. AB - Hepatocellular carcinoma (HCC) is highly resistant to conventional systemic therapies and prognosis for advanced HCC patients remains poor. Recent studies of the molecular mechanisms responsible for tumor initiation and progression have identified several potential molecular targets in HCC. Sorafenib is a multi kinase inhibitor shown to have survival benefits in advanced HCC. It acts by inhibiting the serine/threonine kinases and the receptor type tyrosine kinases. In preclinical experiments sorafenib had anti-proliferative activity in hepatoma cells and it reduced tumor angiogenesis and increased apoptosis. Here, we demonstrate for the first time that the cytotoxic mechanisms of sorafenib include its inhibitory effects on protein ubiquitination, unfolded protein response (UPR) and keratin phosphorylation in response to endoplasmic reticulum (ER) stress. Moreover, we show that combined treatment with sorafenib and proteasome inhibitors (PIs) synergistically induced a marked increase in cell death in hepatoma- and hepatocyte-derived cells. These observations may open the way to potentially interesting treatment combinations that may augment the effect of sorafenib, possibly including drugs that promote ER stress. Because sorafenib blocked the cellular defense mechanisms against hepatotoxic injury not only in hepatoma cells but also in hepatocyte-derived cells, we must be careful to avoid severe liver injury. PMID- 23727132 TI - Classifying healthy women and preeclamptic patients from cardiovascular data using recurrence and complex network methods. AB - It is urgently aimed in prenatal medicine to identify pregnancies, which develop life-threatening preeclampsia prior to the manifestation of the disease. Here, we use recurrence-based methods to distinguish such pregnancies already in the second trimester, using the following cardiovascular time series: the variability of heart rate and systolic and diastolic blood pressures. We perform recurrence quantification analysis (RQA), in addition to a novel approach, epsilon recurrence networks, applied to a phase space constructed by means of these time series. We examine all possible coupling structures in a phase space constructed with the above-mentioned biosignals. Several measures including recurrence rate, determinism, laminarity, trapping time, and longest diagonal and vertical lines for the recurrence quantification analysis and average path length, mean coreness, global clustering coefficient, assortativity, and scale local transitivity dimension for the network measures are considered as parameters for our analysis. With these quantities, we perform a quadratic discriminant analysis that allows us to classify healthy pregnancies and upcoming preeclamptic patients with a sensitivity of 91.7% and a specificity of 45.8% in the case of RQA and 91.7% and 68% when using epsilon-recurrence networks, respectively. PMID- 23727133 TI - Prenatal stress alters the behavior and dendritic morphology of the medial orbitofrontal cortex in mouse offspring during lactation. AB - Several preclinical and clinical studies have shown that prenatal stress alters neuronal dendritic development in the prefrontal cortex, together with behavioral disturbances (anxiety). Nevertheless, neither whether these alterations are present during the lactation period, nor whether such findings may reflect the onset of anxiety disorders observed in childhood and adulthood has been studied. The central aim of the present study was to determine the effects of prenatal stress on the neuronal development and behavior of mice offspring during lactation (postnatal days 14 and 21). We studied 24 CF-1 male mice, grouped as follows: (i) control P14 (n=6), (ii) stressed P14 (n=6), (iii) control P21 (n=6) and (iv) stressed P21 (n=6). On the corresponding days, animals were evaluated with the open field test and sacrificed. Their brains were then stained in Golgi Cox solution for 30 days. The morphological analysis dealt with the study of 96 pyramidal neurons. The results showed, first, that prenatal stress resulted in a significant (i) decrease in the apical dendritic length of pyramidal neurons in the orbitofrontal cortex at postnatal day 14, (ii) increase in the apical dendritic length of pyramidal neurons in the orbitofrontal cortex at postnatal day 21, and (iii) reduction in exploratory behavior at postnatal day 14 and 21. PMID- 23727134 TI - The dynamics of polycomb group proteins in early embryonic nervous system in mouse and human. AB - Polycomb group (PcG) proteins are transcription regulatory proteins that control the expression of a variety of genes and the antero-posterior neural patterning from early embryogenesis. Although expression of PcG genes in the nervous system has been noticed, but the expression pattern of PcG proteins in early embryonic nervous system is still unclear. In this study, we analyzed the expression pattern of PRC1 complex members (BMI-1 and RING1B) and PRC2 complex members (EED, SUZ12 and EZH2) in early embryonic nervous system in mouse and human by Western blot and Immunohistochemistry. The results of Western blot showed that EED protein was significantly up-regulated with the increase of the day of pregnancy during the early embryogenesis in mouse. BMI-1 protein level was significantly increased from the day 10 of pregnancy, when compared with the day 9 of pregnancy. But the SUZ12, EZH2 and RING1B protein level did not change significantly. From the results of Immunohistochemistry, we found that the four PcG proteins were all expressed in the fetal brain and fetal spinal cord in mouse. In human, the expression of EED, SUZ12, and EZH2 was not significantly different in cerebral cortex and sacral spinal cord, but BMI-1 and RING1B expression was enhanced with the development of embryos in early pregnancy. Collectively, our findings showed that PRC1 and PRC2 were spatiotemporally expressed in brain and spinal cord of early embryos. PMID- 23727135 TI - Hyperprolactinemia and estimated dopamine D2 receptor occupancy in patients with schizophrenia: analysis of the CATIE data. AB - BACKGROUND: Large-scale data are still lacking on the relationship between serum prolactin concentration and dopamine D2 receptor occupancy in patients with schizophrenia treated with antipsychotics. METHODS: The dataset from 481 subjects (risperidone, N = 172, olanzapine, N = 211, and ziprasidone, N = 98) who participated in Phase 1 of the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) was used in the present analysis. Dopamine D2 receptor occupancy levels on the day of the measurement of serum prolactin level were estimated from plasma antipsychotic concentrations. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on serum prolactin concentrations. Individual subjects were divided into two groups, stratified by the presence of hyperprolactinemia. To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cut-off points in the D2 occupancy were calculated. RESULTS: The multivariate general linear model revealed that estimated D2 occupancy levels had significant effects on serum prolactin concentrations while any other variables failed to show significant effects. The cut-off point associated with 0.5 or greater, in both sensitivity and specificity with the greatest accuracy, was 73% (sensitivity, 0.58; specificity, 0.68; accuracy = 0.64) (68-70% for risperidone, 77% for olanzapine, and 55% for ziprasidone.). CONCLUSION: The threshold for hyperprolactinemia in D2 occupancy may lie somewhat on a lower side of the established therapeutic window with antipsychotics (i.e. 65-80%). This finding highlights the need for the use of the lowest possible dose to avoid this hormonal side effect in the treatment of schizophrenia. PMID- 23727136 TI - Intermittent subglottic secretion drainage may cause tracheal damage in patients with few oropharyngeal secretions. AB - OBJECTIVE: Injurious prolapse of tracheal mucosa into the suction port has been reported in up to 50% of intubated patients receiving continuous aspiration of subglottic secretions. We investigated whether similar injury could be inflicted by automated intermittent aspiration. METHODS: Six consecutive patients, intubated with the Mallinckrodt TaperGuard EvacTM endotracheal tube, were studied. A flow sensor was placed between the vacuum regulating system and the mucus collector. Intermittent suctioning was performed at a pressure of -125 mmHg with a 25s interval and duration of 15s. After 24h, a CT scan of the tracheal region was performed. RESULTS: Excessive negative suction pressure, a fast drop in aspiration flow to zero, and important "swinging" movements of secretions in the evacuation line were observed in all patients. Oral instillation of antiseptic mouthwash restored normal aspiration flow and secretion mobility. CT imaging showed marked entrapment of tracheal mucosa into the suction port in all patients. CONCLUSION: In patients with few oropharyngeal secretions, automated intermittent subglottic aspiration may result in significant and potential harmful invagination of tracheal mucosa into the suction lumen. A critical amount of fluid must be present in the oropharynx to assure adequate and safe aspiration. PMID- 23727137 TI - A phenomenological study of experiences of being cared for in a critical care setting: the meanings of the patient room as a place of care. AB - Previous research highlights the impact of care and treatment in ICUs on the patient recovery process and wellbeing. However, little is known about how the interior design in the ICU settings may affect patients' wellbeing. OBJECTIVE: The aim of this study is, by using a lifeworld perspective, to reveal the meanings of the ICU settings as a place of care. DESIGN: Nine patients from three ICUs in Sweden participated. Data were collected using photo-voice methodology and were analysed using a reflective lifeworld phenomenological approach. RESULTS: The ICU setting as a place of care for critically ill patients is a complex and multidimensional phenomenon. The place is constituted of patients, staff and technical equipment. The struggle for life and occurrences taking place there determine how the room is perceived. The tone and touch of caring together with interior design are fundamental for the room as lived. The room is experienced in various moods; a place of vulnerability, a place inbetween, a place of trust and security, a life-affirming place, a place of tenderness and care and an embodied place. CONCLUSION: Promoting patients' well-being and satisfaction of care involves integrating a good design and a caring attitude and paying attention to patients' needs. PMID- 23727138 TI - Patients' transition in the intensive care units: concept analysis. AB - BACKGROUND: Adequate preparation of critically ill patients throughout their transition experience within and following discharge from the Intensive Care Unit is an important element of the nursing care process during critical illness. However, little is known about nurses' perspectives of, and engagement in, caring for critically ill patients during their transition experiences. AIM: This paper aims to review the literature about the concept of transition within the context of critically ill patients in the Intensive Care Unit, focusing on Intensive Care Unit nurses. REVIEW METHOD: CINAHL, MEDLINE, OVID, Science Direct, SAGE eReference and SAGE Journal Online data bases were searched for relevant literature published since 1970. RESULTS: The critically ill patients' transitions in Intensive Care Units are generally described as a period of transfer or change of situation, or the experience of inner change or role during and after the illness. The critically ill patients' transition experience per se is not directly described, nor is nurses' understanding of it. CONCLUSION: Nurses' understanding of critically ill patients' transition may significantly impact the patients' care in the Intensive Care Unit. Thus, research is needed that focuses more on evaluating nurses' understanding of patients' transition and its consequences. PMID- 23727139 TI - Enhanced in vitro transdermal delivery of caffeine using a temperature- and pH sensitive nanogel, poly(NIPAM-co-AAc). AB - Temperature- and pH-responsive poly(N-isopropylacrylamide) (polyNIPAM) copolymerised with 5% (w/v) of acrylic acid (AAc), termed as poly(NIPAM-co-AAc) nanogel was investigated as a novel multi-responsive topical drug delivery carrier, using caffeine as a model permeant. The role of a pH modulator (citric acid) on the nanogel system was also studied. The loading was carried out in deionised water at two different temperatures, which were 2-4 degrees C and 25 degrees C (room temperature, RT) over 3 days. The loading of caffeine into the poly(NIPAM-co-AAc) nanogel was found to be significantly higher at 2-4 degrees C than at RT (p=0.0072). As for the control nanogel (polyNIPAM), a similar pattern of loading level can be observed (p=0.0005). This enhanced loading at low temperatures could be attributed to the hydrophilic behaviour of the polyNIPAM network in response to temperatures lower than its lower critical solution temperature (LCST). In vitro diffusion studies across epidermis porcine skin were carried out at 32 degrees C for the saturated solution of caffeine as well as caffeine-loaded poly(NIPAM-co-AAc) and polyNIPAM nanogels. The in vitro permeation data of caffeine-loaded poly(NIPAM-co-AAc) at 2-4 degrees C were shown to enhance the delivery of the loaded caffeine across the epidermis in comparison to the saturated solution of caffeine, by 3.5 orders of magnitude. Additionally, the study demonstrated that the effect of pH modulator on the release of loaded permeant was insignificant. PMID- 23727140 TI - In vivo study of an instantly formed lipid-water cubic phase formulation for efficient topical delivery of aminolevulinic acid and methyl-aminolevulinate. AB - We demonstrate a rapidly formed cubic liquid crystalline phase, i.e. typically 1g cubic phase in less than 1 min confirmed by X-ray diffraction, consisting of an ether lipid, 1-glyceryl monooleyl ether (GME), an aprotic solvent (propylene glycol or pentane-1,5-diol) and water. The efficacy of the cubic formulation was tested in vivo by administrating formulations containing 3% (w/w) of the HCl salts of delta-aminolevulinic acid (ALA) or methylaminolevulinate (MAL) to hairless mice. The endogenous formation of protoporphyrin IX (PpIX) was monitored spectrophotometrically as a marker for cellular uptake of active compound. As reference, a commercial product containing 16% (w/w) MAL in an oil-in-water emulsion (Metvix((r))), and a cubic phase based on an ester lipid (glyceryl monooleate, GMO), previously shown to facilitate topical delivery of both ALA and MAL, were applied. It was found that in general the cubic phases gave rise to higher fluorescence levels than the mice exposed to the commercial product. The instantly formed cubic formulations based on GME demonstrated the same efficiency as the GMO based formulations. The results imply that instantly formed cubic formulations opens up new opportunities, particularly for transdermal drug delivery of substances subject to stability problems in, e.g. aqueous environments. PMID- 23727141 TI - Application of different analytical methods for the characterization of non spherical micro- and nanoparticles. AB - Non-spherical micro- and nanoparticles have recently gained considerable attention due to their surprisingly different interaction with biological systems compared to their spherical counterparts, opening new opportunities for drug delivery and vaccination. Up till now, electron microscopy is the only method to quantitatively identify the critical quality attributes (CQAs) of non-spherical particles produced by film-stretching; namely size, morphology and the quality of non-spherical particles (degree of contamination with spherical ones). However, electron microscopy requires expensive instrumentation, demanding sample preparation and non-trivial image analysis. To circumvent these drawbacks, the ability of different particle analysis methods to quantitatively identify the CQA of spherical and non-spherical poly(1-phenylethene-1,2-diyl (polystyrene) particles over a wide size range (40 nm, 2 MUm and 10 MUm) was investigated. To this end, light obscuration, image-based analysis methods (Microflow imaging, MFI, and Vi-Cell XR Coulter Counter) and flow cytometry were used to study particles in the micron range, while asymmetric flow field fractionation (AF4) coupled to multi-angle laser scattering (MALS) and quasi elastic light scattering (QELS) was used for particles in the nanometer range, and all measurements were benchmarked against electron microscopy. Results show that MFI can reliably identify particle size and aspect ratios of the 10 MUm particles, but not the 2 MUm ones. Meanwhile, flow cytometry was able to differentiate between spherical and non-spherical 10 or 2 MUm particles, and determine the amount of impurities in the sample. As for the nanoparticles, AF4 coupled to MALS and QELS allowed the measurement of the geometric (rg) and hydrodynamic (rh) radii of the particles, as well as their shape factors (rg/rh), confirming their morphology. While this study shows the utility of MFI, flow cytometry and AF4 for quantitative evaluation of the CQA of non-spherical particles over a wide size range, the limitations of the methods are discussed. The use of orthogonal characterization methods can provide a complete picture about the CQA of non-spherical particles over a wide size range. PMID- 23727142 TI - Film coatings for oral colon delivery. AB - Oral colon delivery is pursued through a number of formulation strategies with the aim of enabling effective and well-tolerated treatments for large bowel pathologies or enhancing the intestinal absorption of peptide and protein drugs. According to such strategies, coated dosage forms for colonic release may be provided with microbiota, pH, pressure or time-dependent polymeric films. Microbiota-activated coatings are mostly obtained from polysaccharides of natural origin mixed with insoluble structuring excipients. Alternatively, synthetic azo compounds have been employed, generally requiring organic solvents for use as spray-coating agents. On the other hand, pH-sensitive films show responsiveness to pH changes in the lower gut, such as the rise generally observed in the terminal ileum and distal colon or the slight acidification of caecal contents by bacterial fermentation products. Pressure-sensitive coatings are intended for rupturing because of the relatively elevated pressure that may affect solid dosage forms in the large bowel. Finally, time-dependent films are expected to undergo timed erosion, break-up or permeabilization processes irrespective of the aforementioned physiological variables. In this review, the differing films applied for colon delivery purposes are surveyed, and details on their composition, manufacturing and performance are reported. PMID- 23727143 TI - Pharmaceutical characterisation and evaluation of cocrystals: Importance of in vitro dissolution conditions and type of coformer. AB - The objectives of this study were to demonstrate the importance of experimental set-up and type of coformer for the enhanced dissolution properties of cocrystals. Carbamazepine-saccharin and carbamazepine-nicotinamide cocrystals were prepared by the sonic slurry method and characterised with SEM, DSC, XRPD and particle size analysis. Solubility and dissolution testing (closed and open system) were performed in compendial media and media with a physiologically relevant amount of surfactant. Carbamazepine cocrystals (1:1 molar ratio) did not show a difference in the equilibrium solubility compared to the carbamazepine in compendial media but a substantial difference was observed in modified media. In compendial media, a faster dissolution rate was obtained only from the carbamazepine-saccharin cocrystal, whereas in modified media both cocrystals had a substantial higher dissolution compared to carbamazepine. With the selected method a clear difference in the dissolution profiles of each cocrystal is shown, driven by the characteristics of the coformer used. This study demonstrated that improved dissolution of carbamazepine from the cocrystal forms can be revealed only by appropriate selection of in vitro conditions. The characteristics of the coformer define a critical variable for dissolution of pharmaceutical cocrystals with important implications for their in vivo performance. PMID- 23727145 TI - The glycophorin A transmembrane sequence within integrin alphavbeta3 creates a non-signaling integrin with low basal affinity that is strongly adhesive under force. AB - Integrin heterodimeric cell adhesion and signaling receptors bind ligands of the extracellular matrix and relay signals bidirectionally across cell membranes. Thereby, integrins adopt multiple conformational and functional states that control ligand binding affinity and linkage to cytosolic/cytoskeletal proteins. Here, we designed an integrin chimera encompassing the strongly dimerizing transmembrane domain (TMD) of glycophorin A (GpA) in the context of the otherwise unaltered integrin alphavbeta3. We hypothesized that this chimera should have a low basal affinity to soluble ligand but should be force-activatable. By cellular expression of this chimera, we found a decreased integrin affinity to a soluble peptide ligand and inhibited intracellular signaling. However, under external forces applied by an atomic force microscope or by a spinning disc device causing shear forces, the mutant caused stronger cell adhesion than the wild-type integrin. Our results demonstrate that the signaling- and migration-incapable integrin alphavbeta3-TMD mutant TMD-GpA shows the characteristics of a primed integrin state, which is of low basal affinity in the absence of forces, but may form strong bonds in the presence of forces. Thus, TMD-GpA may mimic a force activatable signaling intermediate. PMID- 23727146 TI - Inflammatory response to acute hypoxia in humans. AB - BACKGROUND: In animal studies hypoxia is known to cause an inflammatory response, inducing multiple transcription factors and activating molecular processes at the cellular level. However, it is not known whether acute hypoxia causes similar inflammatory effects in humans, although such an assumption is commonly made. METHODS: The effects of acute hypoxic exposure were studied in 12 healthy adults: Each subject was studied on 2 different days. Group 1 (mean age 33 +/- 5.5 years; 2 females, 4 males) was exposed either to a hypoxic gas mixture or room air for 30 min and Group 2 (mean age 26.5 +/- 7.5 years; 3 females, 3 males) for 60 min. Measurements of circulating adhesion molecules (AMs), Clara cell secretory protein (CC16), hypoxia inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), tumor necrosis factor (TNF-alpha), and C reactive protein (hsCRP) were made at baseline and at intervals following exposure for 240 min. RESULTS: No significant changes were seen in circulating AMs, CC16, TNF-alpha, IL-6 or hsCRP, although both HIF-1alpha and VEGF levels increased significantly (p < 0.05) after hypoxic exposure. CONCLUSIONS: Acute hypoxic exposure in normal man does not induce a measurable change in inflammatory or epithelial biomarkers, in contrast to studies at the cellular level in animals. However, acute hypoxic exposure does induce the expression of HIF-1alpha and VEGF. These results indicate that in humans acute hypoxic exposure for up to 60 min does not induce a generalized inflammatory response, indicating that the human response to hypoxia is more complex than inferred from animal/cellular studies. PMID- 23727144 TI - Structural and mechanistic basis for enhanced translational efficiency by 2 thiouridine at the tRNA anticodon wobble position. AB - The 2-thiouridine (s(2)U) at the wobble position of certain bacterial and eukaryotic tRNAs enhances aminoacylation kinetics, assists proper codon-anticodon base pairing at the ribosome A-site, and prevents frameshifting during translation. By mass spectrometry of affinity-purified native Escherichia coli tRNA1(Gln)UUG, we show that the complete modification at the wobble position 34 is 5-carboxyaminomethyl-2-thiouridine (cmnm(5)s(2)U). The crystal structure of E. coli glutaminyl-tRNA synthetase (GlnRS) bound to native tRNA1(Gln) and ATP demonstrates that cmnm(5)s(2)U34 improves the order of a previously unobserved 11 amino-acid surface loop in the distal beta-barrel domain of the enzyme and imparts other local rearrangements of nearby amino acids that create a binding pocket for the 2-thio moiety. Together with previously solved structures, these observations explain the degenerate recognition of C34 and modified U34 by GlnRS. Comparative pre-steady-state aminoacylation kinetics of native tRNA1(Gln), synthetic tRNA1(Gln) containing s(2)U34 as sole modification, and unmodified wild type and mutant tRNA1(Gln) and tRNA2(Gln) transcripts demonstrates that the exocyclic sulfur moiety improves tRNA binding affinity to GlnRS 10-fold compared with the unmodified transcript and that an additional fourfold improvement arises from the presence of the cmnm(5) moiety. Measurements of Gln-tRNA(Gln) interactions at the ribosome A-site show that the s(2)U modification enhances binding affinity to the glutamine codons CAA and CAG and increases the rate of GTP hydrolysis by E. coli EF-Tu by fivefold. PMID- 23727147 TI - Cardiology for gynecologists--a minireview. AB - Despite cardiovascular disease (CVD) being by far the most common cause of death in women worldwide, awareness is low. Myocardial infarction occurs 10 years later in women than in men. Symptoms may be atypical: dyspnea rather than chest pain. Also more women than men have myocardial infarction with normal coronary angiography, probably due to microvascular disease or coronary spasm. The prognosis of non-obstructive disease is now recognized to be the same than for obstructive disease. The conventional risk factors for CVD are the same for both genders but have a different impact for women. One example is psychosocial stress and angina pectoris can more often be induced by mental stress in women than in men. Also there are risk factors specific to women such as a history of pre eclampsia, gestational hypertension or diabetes and polycystic ovary syndrome (PCOS). Furthermore atrial fibrillation increases the risk of stroke more in women than in men. However, 6 out of 10 deaths from CVD can be prevented by a healthy life style and dealing with preexisting risk factors. Hence it is important that gynecologists who start seeing women at an earlier age than cardiologists should be aware of cardiovascular disease. PMID- 23727148 TI - GABAA-receptor activation in the subthalamic nucleus compensates behavioral asymmetries in the hemiparkinsonian rat. AB - The subthalamic nucleus (STN) has a pivotal role in the pathophysiology of Parkinson's disease (PD). Modulation of STN activity (by lesions, pharmacological or electrical stimulation) has been shown to improve motor parameters in PD patients and in animal models of PD. In an attempt to characterize the neurochemical bases for such antiparkinsonian action, we address specific neurotransmitter systems via local pharmacological manipulation of the STN in hemiparkinsonian rats. Here, we have focused on the GABAergic and glutamatergic receptors in the STN. In animals with unilateral 6-hydroxydopamine lesions of the nigro-striatal tract, we administered either the selective GABAA-agonist muscimol (0.5 MUg and 1.0 MUg), the non-competitive N-methyl-d-aspartate (NMDA)-antagonist MK-801 (dizocilpine; 2.5 MUg), or vehicle (0.25 MUl) into the STN. The effects of GABAergic and glutamatergic modulation of the STN on motor parameters were assessed by gauging rotational behavior and locomotion. Application of muscimol ipsilateral to the side of dopamine-depletion influenced turning behavior in a dose-dependent fashion, with the low dose re-adjusting turning behavior to a non biased distribution, and the high dose evoking contraversive turning. The administration of MK-801 did not have such effects. These findings give evidence for the involvement of GABAergic activation in the STN in the compensation of motor asymmetries in the hemiparkinsonian rat, whereas N-methyl-d-aspartate (NMDA)-antagonism was ineffective in this model of PD. PMID- 23727149 TI - Differential behavioral reinforcement effects of dopamine receptor agonists in the rat with bilateral lesion of the posterior ventral tegmental area. AB - Dopamine dysregulation syndrome in Parkinson's disease has been attributed to dopamine replacement therapies and/or a lesion of the dopaminergic system. The dopaminergic neuronal loss targets the substantia nigra and the ventral tegmental area (VTA). We hypothesize that dopamine replacement therapy is responsible for the potential reinforcement effect in Parkinson's disease by acting on the neuronal reward circuitry. Therefore this study was designed to explore the potential motivational effect of dopamine replacement therapy in bilateral VTA lesioned animals. The posterior (p)VTA, which project to the nucleus accumbens (NAc) constitutes the major dopamine neuronal circuitry implicated in addictive disorders. Using the conditioned place preference (CPP) behavioral paradigm, we investigated the motivational effects of dopamine receptor agonists, and cocaine in rat with a 6-OHDA bilateral lesion of the pVTA. Amongst the dopamine receptor agonists used in this study only the D2R and D3R agonists (bromocriptine, PD128907 and pramipexole), induced a significant CPP in pVTA-lesioned animals. Dopamine receptor agonists did not induce behavioral sensitization in sham animals. Moreover, confocal D2R immunostaining analysis showed a significant increase in the number of D2R per cell body in the NAc shell of pVTA lesioned rats compared to sham. This result correlated, for the first time, the dopamine receptor agonists effect with DR2 overexpression in the NAc shell of pVTA lesioned rats. In addition, cocaine, which is known to increase dopamine release, induced behavioral sensitization in sham group but not in dopamine deprived group. Thus, the later result highlighted the importance of pVTA-NAc dopaminergic pathway in positive reinforcements. Altogether these data suggested that the implication of the dopamine replacement therapy in the appearance of dopamine dysregulation syndrome in Parkinson's disease is probably due to both neuronal degeneration in the posterior VTA and dopamine receptor sensitization in the dopamine depleted NAc. PMID- 23727151 TI - Experimental evidence against transmission of Hepatozoon canis by Ixodes ricinus. AB - Hepatozoon canis is among the most widespread tick-borne protozoa infecting domestic and wild carnivores. Its distribution is related to the occurrence of its major vector, the brown dog tick Rhipicephalus sanguineus. However, the role of Ixodes ricinus as a vector of H. canis has been hypothesized. In the present study, the development of H. canis was investigated in I. ricinus and R. sanguineus nymphs collected from a naturally infested dog. All I. ricinus ticks examined (n=133) were negative by cytological examination at days 20, 30, and 90 post collection, although H. canis DNA was detected in one nymph at day 20 and in 2 nymphs at day 30 post collection. On the other hand, H. canis sporogony was documented by cytology, and H. canis DNA was detected by PCR in R. sanguineus at day 30 post collection. These results indicate that H. canis sporogony does not occur in I. ricinus, but in R. sanguineus, suggesting that I. ricinus does not act as a vector of H. canis. PMID- 23727150 TI - Neurohistological and behavioral changes following the four-vessel occlusion/internal carotid artery model of chronic cerebral hypoperfusion: comparison between normotensive and spontaneously hypertensive rats. AB - Chronic cerebral hypoperfusion (CCH) may be a prodromal feature of aging-related dementias, and chronic hypertension is a major risk factor. We used a permanent, four-vessel occlusion/internal carotid artery (4-VO/ICA) model to evaluate the cognitive and neurohistological outcomes of CCH in both young and middle-aged rats. Young rats are asymptomatic after permanent 4-VO/ICA, and we tested the hypothesis that chronic hypertension aggravates the outcomes of CCH. Young normotensive rats (NTRs) and young spontaneously hypertensive rats (SHRs) were first subjected to 4-VO/ICA and then examined for hippocampal and cortical neurodegeneration 7, 15, and 30 days later. In a second experiment, both NTRs and SHRs were then trained in a modified, non-food-rewarded aversive radial maze (AvRM) task until acquiring asymptotic performance and then subjected to 4 VO/ICA. Thirty days later, they were assessed for memory retention of the previously acquired cognition. In a third, post hoc experiment, middle-aged NTRs were trained in the AvRM, subjected to 4-VO/ICA, and tested for memory retention 30 days later. Compared with NTRs, both SHRs and middle-aged NRTs had severe hippocampal and cortical damage, but they did not differ from each other, regardless of the chronicity of 4-VO/ICA. In contrast, NTRs were behaviorally asymptomatic, and retrograde memory performance was persistently impaired in SHRs. This amnesic effect in the SHR group was very similar to the middle-aged NTR group. These findings suggest that chronic hypertension deteriorates the capacity of the brain to adaptively respond to CCH. This influence of hypertension may parallel the effect of aging. PMID- 23727152 TI - Initial experience using Excimer laser for the extraction of chronically implanted pacemaker and implantable cardioverter defibrillator leads in Japanese patients. AB - BACKGROUND: Given the exponential growth in cardiac device implantations, the need for less invasive lead extraction is increasing. The Excimer laser was approved for lead removal in Japan in 2010. The present study reports the initial experience using this novel technique to extract chronically implanted pacemaker and implantable cardioverter defibrillator (ICD) leads from Japanese patients. METHODS AND RESULTS: We performed a retrospective study of consecutive patients undergoing lead extraction using the laser sheath at a single Japanese center. Patient and lead characteristics, indications, and outcomes were analyzed. From August 2010 to September 2012, a total of 70 leads, including 14 ICD leads, were removed using the laser sheath from 40 patients (26 male, 14 female; age 65.5+/ 18.3 [mean+/-SD] years; body mass index 21.8+/-3.5 kg/m2). The median implant duration was 87 months (range 13-328 months). Indications were infection (n=35), venous occlusion (n=4), and pain (n=1). The femoral approach was used in combination with the laser technique in five cases. Complete procedural success was achieved with 68 leads (97.1%). Although the electrode tip was left behind in the remaining two leads, the desired clinical outcomes could be achieved; which were defined as clinical success. No cases resulted in failure. There were no major complications, including death and bleeding requiring open-chest surgery. CONCLUSIONS: Laser sheaths appear to provide a feasible and effective means of extracting chronically implanted pacemaker and ICD leads in Japanese patients. PMID- 23727153 TI - Observation of autophagosome maturation in the interferon-gamma-primed and lipopolysaccharide-activated macrophages using a tandem fluorescent tagged LC3. AB - Macrophages are engaged in many essential host functions, and their activation is a dynamic process that results in diverse functional outcomes such as the potentiation of bactericidal activity and production of chemokines, cytokines, and mediators that coordinate the inflammatory response. This pro-inflammatory response is bimodal, comprising a "prime" event, classically through interferon gamma (IFN-gamma), and a "trigger," such as lipopolysaccharide (LPS). Recently, autophagy, which is one of the major degradative pathways in eukaryotic cells, has been shown to play an important role in both IFN-gamma-primed and LPS activated macrophages. In this study, we sought to characterize the mechanisms of autophagy activation in primed and activated macrophages. To this end, we established a macrophage RAW 264.7 cell line that expressed high levels of a tandem fluorescently tagged LC3 (tfLC3) autophagy marker. By using this macrophage cell line, autophagosome formation was observed in both IFN-gamma- and LPS-stimulated cells. Moreover, our data demonstrated that IFN-gamma, but not LPS, facilitated autophagosome maturation to autophagolysosomes, suggesting that 2 distinct mechanisms regulating autophagy exist in IFN-gamma-primed and LPS activated macrophages. PMID- 23727154 TI - Estimation of grip force using the Grip-ball dynamometer. AB - The Grip-ball is an innovative device that has been designed to measure grip strength. The Grip-ball consists of an airtight ball that contains a pressure sensor and Bluetooth communication system. The Grip-ball can be inflated to different initial pressures, with data available continuously in real time. The aim of this study was to build a model to predict the force applied to the Grip ball dynamometer based only on the pressure measured by the Grip-ball and its initial pressure. Forces ranging from 2 to 70 kg were applied to a hybrid version of the device for 10 different initial pressures, ranging from atmospheric pressure of 100 kPa through to 190 kPa. A model was constructed to predict applied force, with force as a function of the initial pressure and the pressure measured. The error of the model was calculated as 1.29 kg across all initial pressures and forces applied. The results of the study are comparable with the errors observed for the gold standard in grip force measurement, the Jamar dynamometer. The best results for force prediction were obtained over the range in which frailty is typically detected. The Grip-ball will now be tested using a large population in order to establish clinical norms. PMID- 23727155 TI - Study of the effect of cannula rotation on tissue cutting for needle biopsy. AB - Needle biopsy is a medical procedure to extract tissue for diagnosis of cancer and other diseases. The quality of tissue samples acquired by needle biopsy greatly depends on the cutting forces of the cannula. The reduction of cutting forces is crucial for obtaining good tissue samples. There exist many factors that influence the cutting forces, some of which include the cannula tip geometry, translation speed, and rotation speed. In the present paper, the effects of rotating the cannula on tissue cutting for needle biopsy are studied. A fracture-mechanics-based approach is used to analyze the cutting forces. Analysis has shown that the cutting forces decrease with the increases in the slice/push ratio defined as the ratio of speed component parallel to the cutting edge/speed perpendicular to the cutting edge. Experiments are performed to demonstrate this phenomenon. Mathematical models of the slice/push ratio for bevel tip cannulas are formulated. The results are used to determine the optimal cannula rotation/translation speed and the desired tip geometry for needle biopsy. It is shown that a minimal slice/push ratio of 2 is recommended. A cannula with a large bevel angle is more suitable for rotational needle biopsy. PMID- 23727157 TI - Autophagosome formation--the role of ULK1 and Beclin1-PI3KC3 complexes in setting the stage. AB - Autophagy is a conserved and highly regulated degradative membrane trafficking pathway, maintaining energy homeostasis and protein synthesis during nutrient stress. Our understanding of how the autophagy machinery is regulated has expanded greatly over recent years. The ULK and Beclin1-PI3KC3 complexes are key signaling complexes required for autophagosome formation. The nutrient and energy sensors mTORC1 and AMPK signal directly to the ULK complex and affect its activity. Formation and activation of distinct Beclin1-PI3KC3 complexes produces PI3P, a signaling lipid required for the recruitment of autophagy effectors. In this review we discuss how the mammalian ULK1 and Beclin1 complexes are controlled by post-translational modifications and protein-protein interactions and we highlight data linking these complexes together. PMID- 23727156 TI - Modulation of the autophagy pathway by human tumor viruses. AB - Autophagy is a highly conserved and regulated process in eukaryotic cells by which components of the cytoplasm, such as damaged organelles and foreign pathogens, become enveloped into double-membrane autophagosome vesicles that fuse with the lysosome for degradation. Viruses are adept at subverting host cellular pathways for their replication and survival. The human tumor viruses, Epstein Barr virus (EBV), Kaposi's Sarcoma-Associated Herpesvirus (KSHV), Hepatitis B virus (HBV), and Hepatitis C virus (HCV), have evolved novel ways of modulating autophagy during productive and latent stages of the virus life cycle. This review will discuss how the autophagy pathway becomes activated upon viral infection and the role of viral proteins in regulating the autophagy pathway. Specifically, we will examine how virus-encoded homologs of autophagy proteins evade autophagy-mediated degradation by blocking the induction, elongation, or maturation steps in the autophagy pathway. We will also discuss how certain viruses enhance autophagy induction or usurp autophagic machinery for their own replication. A comprehensive understanding of the autophagic response to tumor viruses may enable the discovery of novel antiviral and/or anticancer drug therapies. PMID- 23727158 TI - Greater diaphragm fatigability in individuals with recurrent low back pain. AB - The diaphragm plays an important role in spinal control. Increased respiratory demand compromises spinal control, especially in individuals with low back pain (LBP). The objective was to determine whether individuals with LBP exhibit greater diaphragm fatigability compared to healthy controls. Transdiaphragmatic twitch pressures (TwPdi) were recorded in 10 LBP patients and 10 controls, before and 20 and 45 min after inspiratory muscle loading (IML). Individuals with LBP showed a significantly decreased potentiated TwPdi, 20 min (-20%) (p=0.002) and 45 min (-17%) (p=0.006) after IML. No significant decline was observed in healthy individuals, 20 min (-9%) (p=0.662) and 45 min (-5%) (p=0.972) after IML. Diaphragm fatigue (TwPdi fall >= 10%) was present in 80% (20 min after IML) and 70% (45 min after IML) of the LBP patients compared to 40% (p=0.010) and 30% (p=0.005) of the controls, respectively. Individuals with LBP exhibit propensity for diaphragm fatigue, which was not observed in controls. An association with reduced spinal control warrants further study. PMID- 23727160 TI - Simvastatin induces caspase-dependent apoptosis and activates P53 in OCM-1 cells. AB - Simvastatin is a cholesterol-lowering drug which exhibits numerous pleiotropic effects including anti-cancer activity. Yet, the anti-cancer effects in choroidal melanoma remain poorly characterized. Therefore, in this study, we investigated the effects of simvastatin on OCM-1 cells growth, apoptosis and cycle. Simvastatin showed an inhibitory effects on OCM-1 cells viability in dose dependent (2-10 MUM) and time-dependent (24-72 h) manner. Further study suggested that simvastatin-induced inhibition OCM-1 cells proliferation was associated with G1 phase arrest, decreased protein and mRNA expression of proliferation marker cyclin D1, cyclin E, cyclin dependent kinase (CDK)2 and increased expression of CDK inhibitory protein P21. In addition, simvastatin resulted in an increase in levels of reactive oxygen species (ROS) in OCM-1 cells and simvastatin significantly triggered apoptosis in OCM-1 cells, which was characterized by increased chromatin condensation, activation of caspase-9 and cleaved-caspase-3, increased expression mitochondrion-related apoptosis protein of P53, Bax and decreased expression of Bcl2 and iASPP. Collectively, our study demonstrated that simvastatin can efficiently inhibit proliferation and induce apoptosis in OCM-1 cells. PMID- 23727159 TI - Bicarbonate-sensitive soluble and transmembrane adenylyl cyclases in peripheral chemoreceptors. AB - Stimulation of the carotid body (CB) chemoreceptors by hypercapnia triggers a reflex ventilatory response via a cascade of cellular events, which includes generation of cAMP. However, it is not known if molecular CO2/HCO3(-) and/or H(+) mediate this effect and how these molecules contribute to cAMP production. We previously reported that the CB highly expresses HCO3(-)-sensitive soluble adenylyl cyclase (sAC). In the present study we systematically characterize the role of sAC in the CB, comparing the effect of isohydric hypercapnia (IH) in cAMP generation through activation of sAC or transmembrane-adenylyl cyclase (tmAC). Pharmacological deactivation of sAC and tmAC decreased the CB cAMP content in normocapnia and IH with no differences between these two conditions. Changes from normocapnia to IH did not effect the degree of PKA activation and the carotid sinus nerve discharge frequency. sAC and tmAC are functional in CB but intracellular elevations in CO2/HCO3(-) in IH conditions on their own are insufficient to further activate these enzymes, suggesting that the hypercapnic response is dependent on secondary acidosis. PMID- 23727161 TI - Interventions targeting pain or behaviour in dementia: a systematic review. AB - BACKGROUND: Both pain and challenging behaviour are highly prevalent in dementia, and multiple studies show that some of these behaviours may be correlated. Pain, especially in non-communicative patients, can cause challenging behaviour, and treatment of pain therefore may have an effect on behaviour. This review aims to provide a comprehensive overview of the current state of evidence regarding the effectiveness of interventions targeting pain on the outcome behaviour, and interventions targeting behaviour on pain, in dementia. METHOD: PubMed (MEDLINE), EMBASE, COCHRANE, CINAHL, PsychINFO and Web of Science were searched systematically. Studies were included if they focused on an intervention targeting a reduction in the person's distress, pain, and/or behaviour, and included adults with a main diagnosis of dementia. RESULTS: Of a total of 893 potentially relevant publications that were identified, 16 publications met the inclusion criteria and were eligible for further analysis; 6 studies focused on a pain intervention targeting behaviour, 1 study focused on a behavioural intervention targeting pain, and 9 studies focused on an intervention targeting both pain and behaviour. CONCLUSION: Available evidence suggests that (pain) interventions targeting behaviour, and (behavioural) interventions targeting pain are effective in reducing pain and behavioural symptoms in dementia. PMID- 23727162 TI - The Plesiomonas shigelloides wb(O1) gene cluster and the role of O1-antigen LPS in pathogenicity. AB - The Plesiomonas shigelloides 302-73 strain (serotype O1) wb gene cluster encodes 15 proteins which are consistent with the chemical structure of the O1-antigen lypopolysaccharide (LPS) previously described for this strain. The P. shigelloides O1-antigen LPS export uses the Wzy-dependent pathway as correspond to heteropolysaccharides structures. By the isolation of two mutants lacking this O1-antigen LPS, we could establish that the presence of the O1-antigen LPS is crucial for to survive in serum mainly to become resistant to complement. Also, it is an important factor in the bacterial adhesion and invasion to some eukaryotic cells, and in the ability to form biofilms. This is the first report on the genetics from a P. shigelloides O-antigen LPS cluster (wb) not shared by Shigella like P. shigelloides O17, the only one reported until now. PMID- 23727164 TI - Kidney failure: aims for the next 10 years and barriers to success. AB - Although in some parts of the world acute and chronic kidney diseases are preventable or treatable disorders, in many other regions these diseases are left without any care. The nephrology community needs to commit itself to reduction of this divide between high-income and low-income regions. Moreover, new and exciting developments in fields such as pharmacology, genetic, or bioengineering, can give a boost, in the next decade, to a new era of diagnosis and treatment of kidney diseases, which should be made available to more patients. PMID- 23727165 TI - Evolving importance of kidney disease: from subspecialty to global health burden. AB - In the past decade, kidney disease diagnosed with objective measures of kidney damage and function has been recognised as a major public health burden. The population prevalence of chronic kidney disease exceeds 10%, and is more than 50% in high-risk subpopulations. Independent of age, sex, ethnic group, and comorbidity, strong, graded, and consistent associations exist between clinical prognosis and two hallmarks of chronic kidney disease: reduced glomerular filtration rate and increased urinary albumin excretion. Furthermore, an acute reduction in glomerular filtration rate is a risk factor for adverse clinical outcomes and the development and progression of chronic kidney disease. An increasing amount of evidence suggests that the kidneys are not only target organs of many diseases but also can strikingly aggravate or start systemic pathophysiological processes through their complex functions and effects on body homoeostasis. Risk of kidney disease has a notable genetic component, and identified genes have provided new insights into relevant abnormalities in renal structure and function and essential homoeostatic processes. Collaboration across general and specialised health-care professionals is needed to fully address the challenge of prevention of acute and chronic kidney disease and improve outcomes. PMID- 23727166 TI - Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease. AB - Developmental programming of non-communicable diseases is now an established paradigm. With respect to hypertension and chronic kidney disease, adverse events experienced in utero can affect development of the fetal kidney and reduce final nephron number. Low birthweight and prematurity are the most consistent clinical surrogates for a low nephron number and are associated with increased risk of hypertension, proteinuria, and kidney disease in later life. Rapid weight gain in childhood or adolescence further compounds these risks. Low birthweight, prematurity, and rapid childhood weight gain should alert clinicians to an individual's lifelong risk of hypertension and kidney disease, prompting education to minimise additional risk factors and ensuring follow-up. Birthweight and prematurity are affected substantially by maternal nutrition and health during pregnancy. Optimisation of maternal health and early childhood nutrition could, therefore, attenuate this programming cycle and reduce the global burden of hypertension and kidney disease in the future. PMID- 23727167 TI - Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission. AB - BACKGROUND: Human infection with a novel coronavirus named Middle East Respiratory Syndrome coronavirus (MERS-CoV) was first identified in Saudi Arabia and the Middle East in September, 2012, with 44 laboratory-confirmed cases as of May 23, 2013. We report detailed clinical and virological data for two related cases of MERS-CoV disease, after nosocomial transmission of the virus from one patient to another in a French hospital. METHODS: Patient 1 visited Dubai in April, 2013; patient 2 lives in France and did not travel abroad. Both patients had underlying immunosuppressive disorders. We tested specimens from the upper (nasopharyngeal swabs) or the lower (bronchoalveolar lavage, sputum) respiratory tract and whole blood, plasma, and serum specimens for MERS-CoV by real-time RT PCR targeting the upE and Orf1A genes of MERS-CoV. FINDINGS: Initial clinical presentation included fever, chills, and myalgia in both patients, and for patient 1, diarrhoea. Respiratory symptoms rapidly became predominant with acute respiratory failure leading to mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Both patients developed acute renal failure. MERS-CoV was detected in lower respiratory tract specimens with high viral load (eg, cycle threshold [Ct] values of 22.9 for upE and 24 for Orf1a for a bronchoalveolar lavage sample from patient 1; Ct values of 22.5 for upE and 23.9 for Orf1a for an induced sputum sample from patient 2), whereas nasopharyngeal specimens were weakly positive or inconclusive. The two patients shared the same room for 3 days. The incubation period was estimated at 9-12 days for the second case. No secondary transmission was documented in hospital staff despite the absence of specific protective measures before the diagnosis of MERS-CoV was suspected. Patient 1 died on May 28, due to refractory multiple organ failure. INTERPRETATION: Patients with respiratory symptoms returning from the Middle East or exposed to a confirmed case should be isolated and investigated for MERS-CoV with lower respiratory tract sample analysis and an assumed incubation period of 12 days. Immunosuppression should also be taken into account as a risk factor. FUNDING: French Institute for Public Health Surveillance, ANR grant Labex Integrative Biology of Emerging Infectious Diseases, and the European Community's Seventh Framework Programme projects EMPERIE and PREDEMICS. PMID- 23727168 TI - Pre-eclampsia and the risk of kidney disease. PMID- 23727169 TI - Chronic kidney disease: global dimension and perspectives. AB - Chronic kidney disease is defined as a reduced glomerular filtration rate, increased urinary albumin excretion, or both, and is an increasing public health issue. Prevalence is estimated to be 8-16% worldwide. Complications include increased all-cause and cardiovascular mortality, kidney-disease progression, acute kidney injury, cognitive decline, anaemia, mineral and bone disorders, and fractures. Worldwide, diabetes mellitus is the most common cause of chronic kidney disease, but in some regions other causes, such as herbal and environmental toxins, are more common. The poorest populations are at the highest risk. Screening and intervention can prevent chronic kidney disease, and where management strategies have been implemented the incidence of end-stage kidney disease has been reduced. Awareness of the disorder, however, remains low in many communities and among many physicians. Strategies to reduce burden and costs related to chronic kidney disease need to be included in national programmes for non-communicable diseases. PMID- 23727170 TI - Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. AB - Since the first description of the association between chronic kidney disease and heart disease, many epidemiological studies have confirmed and extended this finding. As chronic kidney disease progresses, kidney-specific risk factors for cardiovascular events and disease come into play. As a result, the risk for cardiovascular disease is notably increased in individuals with chronic kidney disease. When adjusted for traditional cardiovascular risk factors, impaired kidney function and raised concentrations of albumin in urine increase the risk of cardiovascular disease by two to four times. Yet, cardiovascular disease is frequently underdiagnosed and undertreated in patients with chronic kidney disease. This group of patients should, therefore, be acknowledged as having high cardiovascular risk that needs particular medical attention at an individual level. This view should be incorporated in the development of guidelines and when defining research priorities. Here, we discuss the epidemiology and pathophysiological mechanisms of cardiovascular risk in patients with chronic kidney disease, and discuss methods of prevention. PMID- 23727171 TI - Acute kidney injury: an increasing global concern. AB - Despite an increasing incidence of acute kidney injury in both high-income and low-income countries and growing insight into the causes and mechanisms of disease, few preventive and therapeutic options exist. Even small acute changes in kidney function can result in short-term and long-term complications, including chronic kidney disease, end-stage renal disease, and death. Presence of more than one comorbidity results in high severity of illness scores in all medical settings. Development or progression of chronic kidney disease after one or more episode of acute kidney injury could have striking socioeconomic and public health outcomes for all countries. Concerted international action encompassing many medical disciplines is needed to aid early recognition and management of acute kidney injury. PMID- 23727172 TI - Equity and economics of kidney disease in sub-Saharan Africa. PMID- 23727173 TI - Specific frequency band of amplitude low-frequency fluctuation predicts Parkinson's disease. AB - Resting-state functional magnetic resonance imaging (RS-fMRI) has been considered for development as a biomarker and analytical tool for evaluation of Parkinson's disease (PD). Here we utilized analysis of the amplitude low-frequency fluctuations (ALFF) to determine changes in intrinsic neural oscillations in 72 patients with PD. Two different frequency bands (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz) were analyzed. In the slow-5 band, PD patients compared with controls had increased ALFF values mainly in the caudate and several temporal regions, as well as decreased ALFF values in the cerebellum and the parieto temporo-occipital cortex. Additionally, in the slow-4 band, PD patients relative to controls exhibited reduced ALFF value in the thalamus, cerebellum, and several occipital regions. Together, our data demonstrate that PD patients have widespread abnormal intrinsic neural oscillations in the corticostriatal network in line with the pathophysiology of PD, and further suggest that the abnormalities are dependent on specific frequency bands. Thus, frequency domain analyses of resting state BOLD signals may provide a useful means to study the pathophysiology of PD and the physiology of the brain's dopaminergic pathways. PMID- 23727174 TI - Environmental enrichment effects on the neurobehavioral profile of selective outbred trait anxiety rats. AB - Environmental enrichment attenuates the response to psychostimulants and has been shown to reduce both anxiety and stress-related behaviors. Since stress is a major vulnerability factor for addiction, we investigated whether enrichment could reverse stress profiles in high anxious rats as well as reduce their amphetamine sensitivity. Using selectively-bred high and low anxiety males (filial 3) from enriched, social or isolated environments, we tested elevated plus maze exploration, novelty place preference and amphetamine (AMPH; 0.5mg/kg, IP)-induced hyperactivity. We measured plasma corticosterone (CORT) response after forced novel object exposure, phosphorylation of the tropomyosin-related kinase B receptor (pTrkB) in the hippocampus and striatum, and dopamine (D2) receptor mRNA levels in the striatum and nucleus accumbens. Results indicate that high anxiety animals reared in social or enriched environments spent more time on open arms of the EPM while low anxiety animals raised in enriched environments spent more time on open arms when compared to either isolated or social groups. There were no group differences or interactions found for novelty place preference. Enriched environments decreased the response to AMPH and stress induced CORT regardless of trait but selectively decreased pTrkB and increased D2 mRNA levels in high anxiety animals. The results suggest that selectively-bred trait anxiety rats show state anxiety that is influenced by rearing environments, and D2 protein levels and BDNF/TrkB signaling may differentially contribute to integrating these effects. PMID- 23727175 TI - Pair housing differentially affects motivation to self-administer cocaine in male and female rats. AB - Female rats exhibit greater intake and motivation to self-administer cocaine. In females but not males, isolation by itself is a stressor, which could lead to increased drug intake. Therefore, we hypothesized that social housing would buffer against stress and reduce the motivation to self-administer cocaine primarily in females. Male and female Sprague-Dawley rats were housed individually or in same-sex pairs. The individually housed rats and one of each pair were allowed to self-administer (SA) a low dose of cocaine (0.2 mg/kg/inf) on a fixed ratio (FR1) schedule for one week. Motivation for cocaine SA was measured for an additional 2 weeks on a progressive ratio schedule. Isolated females had greater cocaine-intake on the FR1 schedule and greater motivation to take cocaine than males. Pair-housing in females, but not males, attenuated the motivation to take cocaine. Isolated females, but not males, showed escalation of their motivation to take cocaine, which was attenuated by pair housing of females. Concluding, the motivation to take cocaine escalates in females but not males, and pair-housing of females attenuates this escalation. PMID- 23727176 TI - Possible contribution of chemokine receptor CCR2 and CCR5 polymorphisms in the pathogenesis of chronic spontaneous autoreactive urticaria. AB - BACKGROUND: Autoimmune mechanisms play a role in the pathophysiology of chronic urticaria. As the genetic background of autoimmunity is well proven, the role of genetics in chronic urticaria is hypothesised. METHODS: 153 unrelated chronic spontaneous urticaria patients with a positive result of autologous serum skin test were included into the study, as were 115 healthy volunteers as control group. In all subjects we analysed CCR2 G190A and CCR5 d32 polymorphisms. RESULTS: We noticed higher prevalence of CCR2 A allele as well as lower frequency of CCR5 d32 in chronic urticaria group in comparison to control group, with borderline statistical significance. Additionally, we assumed haplotype Gd statistically significant negative chronic urticaria association with tendency to higher frequency of Aw haplotype in this group. CONCLUSIONS: The results of our study imply the role of autoimmune components in chronic urticaria pathogenesis and present chronic urticaria as possibly genetically related disorder. PMID- 23727177 TI - Bisabolangelone inhibits dendritic cell functions by blocking MAPK and NF-kappaB signaling. AB - Bisabolangelone (BISA), isolated from the roots of Angelica koreana, has many pharmacological activities, such as anti-tumor, anti-microbial, antioxidant, and anti-inflammatory activities. In this study, we investigated the anti inflammatory mechanisms of BISA in dendritic cells (DCs), which play an essential role in innate and adaptive immune responses. BISA attenuated the production of pro-inflammatory cytokines including interleukin (IL)-12, IL-1beta, and tumor necrosis factor-alpha (TNF-alpha), migration to macrophage inflammatory protein-3 beta, and allo-T cell activating ability of DCs. In addition, BISA affected endocytosis of DCs. Molecular studies showed that BISA suppressed MAPK phosphorylation and nuclear translocation of NF-kappaB p50/p65. Taken together, our data suggest that BISA inhibited DC functions by blocking MAPK and NF-kappaB signaling. PMID- 23727178 TI - Effects of zearalenone on oxidative stress and inflammation in weanling piglets. AB - Zearalenone (ZEN) is a non-steroidal estrogenic mycotoxin produced by the fungi of Fusarium genera. Piglets were fed for 18 days with a control or a ZEN (316 ppb) contaminated diet. At the end of the experiment tissue samples were taken for assessment of: lymphocyte proliferation, monocytes and granulocytes respiratory burst, inflammatory cytokine synthesis in blood and liver, expression of genes involved in oxidative stress or in inflammation, plasma biochemical parameters, total antioxidant status and nitric oxide synthesis. In blood, ZEN increases the respiratory burst of monocytes and the inflammatory cytokine (TNF alpha, IL-1 beta, IFN gamma) synthesis, while in liver, ZEN decreases the synthesis of all inflammatory cytokines investigated. In liver and spleen, different effect on the expression of genes involved in oxidative stress and inflammation was observed. While in liver, ZEN decrease the expression of cyclooxigenase gene, but increase the expression of glutathione peroxydase and catalase genes; in spleen, ZEN induces a decrease of the superoxide dismutase gene expression together with an increase of the cyclooxigenase. In conclusion, our results showed that liver, spleen and blood may also be target tissues in weanling piglets fed ZEN contaminated diet, with different effects on oxidative stress and inflammation. PMID- 23727179 TI - Suppression of iNOS and COX-2 expression by flavokawain A via blockade of NF kappaB and AP-1 activation in RAW 264.7 macrophages. AB - Flavokawain A, a major constituent of chalcones derived from kava extracts, exerts various biological activities such as anti-tumor activities. In this study, we examined the suppressive effect of flavokawain A on LPS-induced expression of pro-inflammatory mediators and the molecular mechanisms responsible for these activities in the murine macrophages. Flavokawain A significantly suppressed expression of iNOS and COX-2, as well as the subsequent production of NO and PGE2 in the LPS-stimulated RAW 264.7 cells. Flavokawain A significantly inhibited LPS-induced activation of NF-kappaB and AP-1 signaling pathways. In addition, flavokawain A inhibited activation of JNK and p38 MAPK which was responsible for expression of iNOS and COX-2 in the LPS-stimulated RAW 264.7 cells. Furthermore, flavokawain A suppressed LPS-induced expression of pro inflammatory cytokines, such as TNF-alpha, IL-1beta and IL-6. These results suggest that flavokawain A may exert anti-inflammatory responses by suppressing LPS-induced expression of pro-inflammatory mediators via blockage of NF-kappaB-AP 1-JNK/p38 MAPK signaling pathways in the murine macrophages. PMID- 23727163 TI - Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial. AB - BACKGROUND: Venous thromboembolism is a common, potentially avoidable cause of death and morbidity in patients in hospital, including those with stroke. In surgical patients, intermittent pneumatic compression (IPC) reduces the risk of deep vein thrombosis (DVT), but no reliable evidence exists about its effectiveness in patients who have had a stroke. We assessed the effectiveness of IPC to reduce the risk of DVT in patients who have had a stroke. METHODS: The CLOTS 3 trial is a multicentre parallel group randomised trial assessing IPC in immobile patients (ie, who cannot walk to the toilet without the help of another person) with acute stroke. We enrolled patients from day 0 to day 3 of admission and allocated them via a central randomisation system (ratio 1:1) to receive either IPC or no IPC. A technician who was masked to treatment allocation did a compression duplex ultrasound (CDU) of both legs at 7-10 days and, wherever practical, at 25-30 days after enrolment. Caregivers and patients were not masked to treatment assignment. Patients were followed up for 6 months to determine survival and later symptomatic venous thromboembolism. The primary outcome was a DVT in the proximal veins detected on a screening CDU or any symptomatic DVT in the proximal veins, confirmed on imaging, within 30 days of randomisation. Patients were analysed according to their treatment allocation. TRIAL REGISTRATION: ISRCTN93529999. FINDINGS: Between Dec 8, 2008, and Sept 6, 2012, 2876 patients were enrolled in 94 centres in the UK. The included patients were broadly representative of immobile stroke patients admitted to hospital and had a median age of 76 years (IQR 67-84). The primary outcome occurred in 122 (8.5%) of 1438 patients allocated IPC and 174 (12.1%) of 1438 patients allocated no IPC; an absolute reduction in risk of 3.6% (95% CI 1.4-5.8). Excluding the 323 patients who died before any primary outcome and 41 without any screening CDU, the adjusted OR for the comparison of 122 of 1267 patients vs 174 of 1245 patients was 0.65 (95% CI 0.51-0.84; p=0.001). Deaths in the treatment period occurred in 156 (11%) patients allocated IPC and 189 (13%) patients allocated no IPC died within the 30 days of treatment period (p=0.057); skin breaks on the legs were reported in 44 (3%) patients allocated IPC and in 20 (1%) patients allocated no IPC (p=0.002); falls with injury were reported in 33 (2%) patients in the IPC group and in 24 (2%) patients in the no-IPC group (p=0.221). INTERPRETATION: IPC is an effective method of reducing the risk of DVT and possibly improving survival in a wide variety of patients who are immobile after stroke. FUNDING: National Institute of Health Research (NIHR) Health Technology Assessment (HTA) programme, UK; Chief Scientist Office of Scottish Government; Covidien (MA, USA). PMID- 23727180 TI - Immunostimulatory and antiangiogenic activities of low molecular weight hyaluronic acid. AB - The immunostimulatory activities of two low molecular weight hyaluronic acids (LMWHA-1 and LMWHA-2 with MW of 1.45*10(5) and 4.52*10(4) Da, respectively) and HA (MW, 1.05*10(6) Da) were evaluated by using in vitro cell models and in vivo animal models, and their effects on angiogenesis were measured in vivo by using the chick embryo chorioallantoic membrane (CAM) assay. The results demonstrated that LMWHA-1, LMWHA-2 and HA could promote the splenocyte proliferation, increase the activity of acid phosphatase in peritoneal macrophages and strengthen peritoneal macrophages to devour neutral red in vitro in a dose-dependent manner. Furthermore, LMWHA-1 and LMWHA-2 exhibited much stronger immunostimulatory activity than HA. For assay in vivo, LMWHA-1 and LMWHA-2 significantly increased the indices of spleen and thymus, the activity of lysozyme in serum and the swelling rate of earlap in delayed-type hypersensitivity in a dose-dependent manner. In the CAM model, the results showed that LMWHA-1, LMWHA-2 and HA suppressed angiogenesis in chicken embryos. Moreover, LMWHA-1 exhibited higher antiangiogenesis activity than LMWHA-2 and HA. All these results suggested that LMWHA might be a potential natural immunomodulator and a potential candidate compound for antiangiogenic. PMID- 23727181 TI - Effects of taraxasterol on ovalbumin-induced allergic asthma in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Taraxasterol was isolated from the Chinese medicinal herb Taraxacum officinale which has been frequently used as a remedy for inflammatory diseases. In the present study, we determined the in vivo protective effect of taraxasterol on allergic asthma induced by ovalbumin (OVA) in mice. MATERIALS AND METHODS: Mice were sensitized and challenged with OVA, and were orally treated daily with taraxasterol at 2.5, 5 and 10mg/kg from day 23 to 27 after sensitization. The number of inflammatory cells in bronchoalveolar lavage fluid (BALF) was determined. Th2 cytokine interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13) production in BALF and OVA-specific immunoglobulin E (IgE) production in sera were measured using ELISA. Histological changes in lung tissues were examined using hematoxylin and eosin (H&E) and periodic acid-Schiff staining (PAS). Airway hyperresponsiveness (AHR) to inhaled methacholine was assessed. RESULTS: Taraxasterol dramatically decreased the total inflammatory cell and main inflammatory cell counts, reduced the production of Th2 cytokine IL-4, IL-5, IL-13 in BALF and OVA-specific IgE in sera, and suppressed AHR in a dose-dependent manner. Histological studies demonstrated that taraxasterol substantially suppressed OVA-induced inflammatory cells infiltration into lung tissues and goblet cell hyperplasia in airways. CONCLUSIONS: This finding suggests that taraxasterol protects against OVA-induced allergic asthma in mice. PMID- 23727183 TI - The ethyl acetate fraction of Polytrichum commune L.ex Hedw induced cell apoptosis via reactive oxygen species in L1210 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Polytrichum commune L.ex Hedw is a traditional Chinese herb for treatment of fever, hemostatic, uterine prolapse and especially for leukemia. Previous studies indicated its anti-leukemia effect but the potential mechanisms have not been fully explained. AIMS OF THE STUDY: The present study was further to investigate the underlying mechanism of ethyl acetate extract of Polytrichum commune L.ex Hedw (EEF)-induced toxicity and apoptosis in L1210 cells. MATERIALS AND METHODS: Viability, DNA damage and apoptotic protein expressions of L1210 cells were analyzed by ViaCount, comet assay and western blot, respectively. At different times after EEF treatment, Bax redistribution in L1210 cells was examined using confocal microscopy; loss of mitochondrial membrane potential (MMP) was monitored by fluorescence microscope using rhodamine 123 staining; Intracellular reactive oxygen species (ROS) generation and DNA fragmentation were measured by flow cytometry using fluorescent dye, DCFH-DA and PI, respectively. RESULTS: EEF significantly inhibited L1210 cell survival, promoted Bax translocation onto mitochondria, stimulated caspase-9 activation and subsequent DNA damage in L1210 cells. Abundant ROS was detected in L1210 cells after EEF treatment, and the ROS scavenger NAC significantly relieved EEF-induced cell viability decline, MMP loss, and DNA fragmentation. CONCLUSION: EEF could induce mitochondria-dependent cell apoptosis in L1210 cells, and ROS may play an important role in this action. PMID- 23727184 TI - Ethnobotanical study of medicinal plants commonly used by local Bedouins in the Badia region of Jordan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The harsh dry environment of the Badia region in Jordan harbors many valuable plant species that are well known to be used by the local Bedouins (Bedu) for medicinal purposes. An ethnobotanical study was conducted as a part of the local knowledge study which was carried out in 2010. The target participants were livestock owners in the arid Jordanian Badia region. AIM OF THE STUDY: The objective of the study was to document traditional knowledge in using wild plants to treat health problems in order to conserve this valuable knowledge from loss; to identify the key plant species used; and to calculate the Informant Consensus Factor (ICF) for each category of health disorder, the Fidelity Level (FL%) and the Use Value (UV) of the plant species used by the Bedouin. MATERIALS AND METHODS: The data was collected by interviewing 80 participants whom were interviewed face to face of whom 21% were women. The team designed a questionnaire that helped in the data gathering, and also recorded the procedures used by the local communities on video. RESULTS: A total of 47 plant species are used by local Bedouins for medicinal purposes. The majority of these species are native to the study area, for example: Artemisia judaica, Citrullus colocynthis, Ecballium elaterium and Rheum palaestinum. The study showed that the plant species with the highest UV is Artemisia herba-alba and that Ducrosia flabellifolia is a remarkable native plant species with a high FL% in curing dental pain. Moreover, the highest value of ICF was scored for dental disorders, followed by gastrointestinal disorders, and jaundice which may indicate the high incidental occurrences of these diseases and/or the lack of dental care services in the rural areas. CONCLUSION: The study showed an agreement of the local Bedouins on using certain plant species, particularly natives in their dry surroundings, in treating certain health disorders. Some plants showed high use values and fidelity levels to treat certain health problem. Further investigation should be carried out in Jordan on the pharmaceutical value and production practices of these native medicinal plants that have very low water requirements in a country with extreme water shortages. PMID- 23727182 TI - Protective effects of aqueous extract from Acanthopanax senticosus against corticosterone-induced neurotoxicity in PC12 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acanthopanax senticosus, classified into the family of Araliaceae, has been known for thousands of years as a remedy and is used to treat various diseases in traditional Chinese medicine system including hypertension, ischemic heart disease and hepatitis. AIM OF THE STUDY: This study aimed to examine the protective effects of aqueous extract from Acanthopanax senticosus (ASE) on corticosterone-induced neurotoxicity and its possible mechanisms, using PC12 cells as a suitable in vitro model of depression. MATERIALS AND METHODS: In this paper, PC12 cells were treated with 200 MUM of corticosterone in the absence or presence of ASE in varying concentrations for 24 h. Then, cell viability was measured by MTT assay. The release amount of lactate dehydrogenase (LDH) was quantified using LDH assay kit. Apoptosis of PC12 cells was measured by Annexin V-FITC and PI labeling. The intracellular Ca(2+) content was tested by fluorescent labeling. The mRNA level of brain-derived neurotrophic factor (BDNF) was examined by real-time RT-PCR, and the expression of cAMP response element binding protein (CREB) was determined by western blotting. RESULTS: The results showed that treatment with 200 MUM of corticosterone could induce cytotoxicity in PC12 cells. However, different concentrations of ASE (50, 100, 200, and 400 MUg/mL) significantly increased the cell viability, decreased the LDH release, suppressed the apoptosis of PC12 cells, attenuated the intracellular Ca(2+) overloading, up-regulated the BDNF mRNA level and CREB protein expression compared with the corresponding corticosterone-treated group. CONCLUSION: The present results suggest that ASE exerts a neuroprotective effect on corticosterone-induced neurotoxicity in PC12 cells, which may be one of the acting mechanisms that accounts for the in vivo antidepressant activity of ASE. PMID- 23727185 TI - Antifungal activity and cytotoxicity of isolated compounds from leaves of Breonadia salicina. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Breonadia salicina is used traditionally to treat wounds, ulcers, fevers, headaches, and fungal infections. The aim of this study was to investigate the antifungal activity of the plant extract and compounds isolated there from. MATERIALS AND METHODS: Leaf extracts of Breonadia salicina were screened for antifungal activity against seven plant pathogens: Aspergillus niger, Aspergillus parasiticus, Colletotrichum gloeosporioides, Trichoderma harzianum, Penicillium expansum, Penicillium janthinellum and Fusarium oxysporum. Bioautography assay was used to determine the presence and number of antifungal compounds of the plant extracts. Bioassay-guided fractionation using column chromatography of the chloroform extract led to the isolation of four antifungal compounds. Nuclear Magnetic Resonance (NMR) spectroscopy, Mass Spectrometry (MS) and Electron Impact Mass Spectrometry (EIMS) were used for the identification of antifungal compounds. Cytotoxicity of the chloroform crude extract and isolated compounds was determined using the MTT (3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium bromide) assay against Vero monkey kidney cells. RESULTS: Compound 1 was identified as ursolic acid, while compounds 2, 3 and 4 were not identified conclusively owing to the presence of mixtures of long chain fatty acids. Compounds 3 and 4 had good antifungal activity against Aspergillus parasiticus and Penicillium janthinellum with MIC values of 10 and 16 ug/ml respectively. Compound 2 and ursolic acid had some activity with MIC values ranging between 20 and 250 ug/ml. The crude extract was less toxic to the Vero cells (LC50=82 ug/ml) than ursolic acid (LC50=25 ug/ml). Compounds 2 and 3 were not toxic at the highest concentration tested (LC50=200 ug/ml). Compound 4 was the most toxic to the cells with an LC50 of 35 ug/ml. CONCLUSIONS: The results support the traditional use of Breonadia salicina for antifungal applications, and demonstrate the potential value of developing antifungal compounds from plant natural products. Indications of toxicity should be evaluated at an early stage as the selectivity of the product in affecting fungi preferentially to plant or mammalian cells should be identified when assessing the potential usefulness of the product. PMID- 23727186 TI - Increased mRNA expression of genes involved in pronociceptive inflammatory reactions in bladder tissue of interstitial cystitis. AB - PURPOSE: We assayed mRNA expression of the TRP family of channels and ASIC1 in bladder tissue from patients with interstitial cystitis. MATERIALS AND METHODS: Bladder biopsies of 1) nonclassic interstitial cystitis, 2) nonulcerative portions of classic interstitial cystitis, 3) ulcerative portions of classic interstitial cystitis and 4) noncancerous portions of bladder cancer as the control were placed immediately in ice-cold RNAlater(r) and subjected to real time reverse transcriptase-polymerase chain reaction. We compared the mRNA expression of TRP channels, ASIC1, NGF, CXCL9 and UPK3A with that of controls, and correlated expression with symptom severity. RESULTS: We analyzed specimens from 17 patients with nonclassic interstitial cystitis, 22 with classic interstitial cystitis and 11 controls. In nonclassic interstitial cystitis samples TRPV2 and NGF showed significantly increased expression. In classic interstitial cystitis samples nonulcerative portions demonstrated a significant increase in the expression of TRPA1, TRPM2 and 8, TRPV1 and 2, ASIC1, NGF and CXCL9, and a significant decrease in UPK3A and TRPV4. Ulcerative portions showed similar changes for TRPM2, TRPV1, 2 and 4, CXCL9 and UPK3A. Increased expression of TRPM2, first noted in interstitial cystitis tissue, was the most pronounced one of the TRP family. All symptom measures correlated with TRPM2 and TRPV2 expression, and partially with that of the other genes. CONCLUSIONS: This study showed increased expression of the genes involved in pronociceptive inflammatory reactions in interstitial cystitis, including TRPV1, 2 and 4, ASIC1, NGF and CXCL9, and to our knowledge TRPM2 for the first time. The different expression patterns suggest distinct pathophysiologies for classic and nonclassic interstitial cystitis. The genes and their products are potential candidates for use as biomarkers or novel therapy targets. PMID- 23727187 TI - Interactions between lower urinary tract symptoms and cardiovascular risk factors determine distinct patterns of erectile dysfunction: a latent class analysis. AB - PURPOSE: An epidemiological association between lower urinary tract symptoms and erectile dysfunction is well established. However, interactions among multiple risk factors and the role of each in pathological mechanisms are not fully elucidated MATERIALS AND METHODS: We enrolled 898 men undergoing prostate cancer screening for evaluation with the International Prostate Symptom Score (I-PSS) and simplified International Index of Erectile Function-5 (IIEF-5) questionnaires. Age, race, hypertension, diabetes, dyslipidemia, metabolic syndrome, cardiovascular disease, serum hormones and anthropometric parameters were also evaluated. Risk factors for erectile dysfunction were identified by logistic regression. The 333 men with at least mild to moderate erectile dysfunction (IIEF 16 or less) were included in a latent class model to identify relationships across erectile dysfunction risk factors. RESULTS: Age, hypertension, diabetes, lower urinary tract symptoms and cardiovascular event were independent predictors of erectile dysfunction (p<0.05). We identified 3 latent classes of patients with erectile dysfunction (R2 entropy=0.82). Latent class 1 had younger men at low cardiovascular risk and a moderate/high prevalence of lower urinary tract symptoms. Latent class 2 had the oldest patients at moderate cardiovascular risk with an increased prevalence of lower urinary tract symptoms. Latent class 3 had men of intermediate age with the highest prevalence of cardiovascular risk factors and lower urinary tract symptoms. Erectile dysfunction severity and lower urinary tract symptoms increased from latent class 1 to 3. CONCLUSIONS: Risk factor interactions determined different severities of lower urinary tract symptoms and erectile dysfunction. The effect of lower urinary tract symptoms and cardiovascular risk outweighed that of age. While in the youngest patients lower urinary tract symptoms acted as a single risk factor for erectile dysfunction, the contribution of vascular disease resulted in significantly more severe dysfunction. Applying a risk factor interaction model to prospective trials could reveal distinct classes of drug responses and help define optimal treatment strategies for specific groups. PMID- 23727188 TI - Tumor lesion diameter on diffusion weighted magnetic resonance imaging could help predict insignificant prostate cancer in patients eligible for active surveillance: preliminary analysis. AB - PURPOSE: We analyzed the pathological outcomes of candidates for active surveillance according to tumor lesion diameter on diffusion weighted magnetic resonance imaging. MATERIALS AND METHODS: We retrospectively analyzed 188 candidates for active surveillance who had undergone diffusion weighted magnetic resonance imaging before radical prostatectomy between 2006 and 2012. We measured the diameter of the suspicious tumor lesion on diffusion weighted magnetic resonance imaging and stratified the cohort into 2 groups. Group 1 included patients with normal magnetic resonance imaging or a suspicious tumor lesion smaller than 1 cm and group 2 included patients with a suspicious tumor lesion larger than 1 cm. We compared pathological outcomes including insignificant prostate cancer in each group and analyzed whether different tumor diameters resulted in a change in insignificant prostate cancer rates. RESULTS: Group 1 consisted of 115 (61.2%) patients and group 2 included 73 (38.8%) patients. In group 1 magnetic resonance imaging was normal in 72 patients. Mean +/- SD diameter of suspicious tumor lesions was 12.0 +/- 5.58 mm. Tumor volume was significantly different between the groups (0.73 +/- 0.86 vs 1.09 +/- 1.07 cm(3), p = 0.018), as was the rate of insignificant prostate cancer (48.7% vs 24.7%, p = 0.001). The rate of insignificant prostate cancer decreased as tumor diameter increased over 1 cm. On multivariate logistic regression analysis the diameter of suspicious tumor lesions was an important predictor of insignificant prostate cancer (OR 0.319, p = 0.014). CONCLUSIONS: Our analysis demonstrates that the simple measurement of the diameter of suspicious tumor lesions on diffusion weighted magnetic resonance imaging could improve the prediction of insignificant prostate cancer in candidates for active surveillance. PMID- 23727189 TI - Development of the penis during the human fetal period (13 to 36 weeks after conception). AB - PURPOSE: We analyzed the development of the area of the penis and erectile structures (corpora cavernosa and corpus spongiosum) and the thickness of the tunica albuginea during the fetal period (13 to 36 weeks after conception) in humans to establish normative patterns of growth. MATERIALS AND METHODS: We studied 56 male human fetuses at 13 to 36 weeks after conception. We used histochemical and morphometric techniques to analyze the parameters of total penile area, area of corpora cavernosa, area of corpus spongiosum, and thickness of tunica albuginea in the dorsal and ventral regions using ImageJ software (National Institutes of Health, Bethesda, Maryland). RESULTS: Between 13 and 36 weeks after conception the area of the penis varies from 0.95 to 24.25 mm2. The area of the corpora cavernosa varies from 0.28 to 9.12 mm2, and the area of the corpus spongiosum varies from 0.14 to 3.99 mm2. The thickness of the tunica albuginea varies from 0.029 to 0.296 mm in the dorsal region and from 0.014 to 0.113 mm in the ventral region of the corpora cavernosa. CONCLUSIONS: We found a strong correlation between the total penile area, corpora cavernosa and corpus spongiosum with fetal age (weeks following conception). The growth rate was more intense during the second trimester (13 to 24 weeks of gestation) compared to the third trimester (25 to 36 weeks). Tunica albuginea thickness also was strongly correlated with fetal age and this structure was thicker in the dorsal vs ventral region. PMID- 23727190 TI - Designing a new proof-of-principle trial for treatment of partial seizures to demonstrate efficacy with minimal sample size and duration-a case study. AB - The ideal proof-of-principle study design provides a strong efficacy signal over the shortest duration, while exposing the fewest patients possible. Data from a large database (Pfizer Inc) which studied add-on pregabalin for the treatment of partial seizures was used to model how duration of baseline, post-randomization treatment period, and number of subjects impact the likelihood of an interpretable efficacy signal. Data from four double-blind, randomized, placebo controlled, phase III studies that had at least one 600 mg/day treatment arm were combined. The common 6-week baseline period was divided into weekly intervals, as was the 12-week post-randomization period. Two methods of analysis were used: logistic regression performed on 50% responder rate and the Hodges-Lehmann estimate on percentage reduction from baseline seizure rate. A simulation-based re-sampling approach was used to determine sufficient sample size. Four weeks of baseline with 3 weeks of treatment were determined to be clinically and statistically sufficient. A reasonable sample size was estimated to be 40-50 patients per group, if a highly efficacious drug was used. These modeling results indicate that the efficacy of an antiepileptic drug can be demonstrated in a relatively short period of time with a reasonable sample size. PMID- 23727191 TI - Metabolic engineering of Escherichia coli for limonene and perillyl alcohol production. AB - Limonene is a valuable monoterpene used in the production of several commodity chemicals and medicinal compounds. Among them, perillyl alcohol (POH) is a promising anti-cancer agent that can be produced by hydroxylation of limonene. We engineered E. coli with a heterologous mevalonate pathway and limonene synthase for production of limonene followed by coupling with a cytochrome P450, which specifically hydroxylates limonene to produce POH. A strain containing all mevalonate pathway genes in a single plasmid produced limonene at titers over 400mg/L from glucose, substantially higher than has been achieved in the past. Incorporation of a cytochrome P450 to hydroxylate limonene yielded approximately 100mg/L of POH. Further metabolic engineering of the pathway and in situ product recovery using anion exchange resins would make this engineered E. coli a potential production platform for any valuable limonene derivative. PMID- 23727192 TI - Targeting enzymes to the right compartment: metabolic engineering for itaconic acid production by Aspergillus niger. AB - Itaconic acid is an unsaturated dicarboxylic acid which has a high potential as a biochemical building block. It can be microbially produced from some Aspergillus species, such as Aspergillus itaconicus and Aspergillus terreus. However, the achieved titers are significantly lower as compared to the citric acid production by A. niger. Heterologous expression of cis-aconitate decarboxylase in A. niger leads to the accumulation of small amounts of itaconic acid. Additional expression of aconitase, the second enzyme metabolically linking citric acid and itaconic acid improves productivity. However, proper organelle targeting of the enzymes appears to be an important point to consider. Here we compare the mitochondrial expression with the cytosolic expression of cis-aconitate decarboxylase or aconitase in A. niger. Heterologous expression of both enzymes in the mitochondria doubles the productivity compared to strains which express the enzymes in the cytosol. It is essential to target enzymes to the correct compartment in order to establish a proper flux through a compartmentalized pathway. PMID- 23727193 TI - The path to an RSV vaccine. AB - Respiratory syncytial virus (RSV) is the greatest remaining unmet infant vaccine need in developed countries and an important unmet infant vaccine need worldwide. More than 40 years of effort have yet to result in a licensed RSV vaccine for humans. Key challenges to RSV vaccine development include a peak of severe disease at 2-3 months of age, problematic biochemical behavior of key vaccine antigens, a history of vaccine-mediated disease enhancement, and reliance on animal models that may not accurately reflect human disease processes. Potential paths to overcome these challenges include maternal immunization, structure-based engineering of vaccine antigens, the design of a novel platform for safe infant immunization, and the development of improved animal models for vaccine-enhanced disease. PMID- 23727194 TI - 1-substituted apomorphines as potent dopamine agonists. AB - A novel set of 1-substituted apomorphines as dopaminergic agonists were synthesized according to our new strategy employing the acid-catalyzed rearrangement of diversely functionalized 5beta-substituted-6-demethoxythebaines. The activities of new compounds for dopamine receptors subtypes were evaluated using HEK293 based stable cell lines expressing D1, D2L or D3 receptor subtypes. All studied compounds had affinities in nanomolar range for D2L and D3 receptors and the change of the nature of substituent in position 1 had only moderate effect. D1 receptors were sensitive to the introduction of the 4-OH-benzyl function resulting in an increased affinity. The small hydrophilic group (hydroxymethyl) highly reduced the agonist affinity and potency thereby increasing subtype selectivity. This strategy for selective modulation of affinities and potencies of 1-substituted apomorphines gives essential hints for future design of subtype selective dopaminergic ligands. PMID- 23727195 TI - 6'-Methyl-5'-homoaristeromycin: a structural variation of the anti-orthopox virus candidate 5'-homoaristeromycin. AB - The synthesis of 6'-methyl-5'-homoaristeromycin is described from a known 6' ethyl ester. Antiviral analysis showed the (S)-6' stereoisomer retained the vaccinia activity of the parent 5'-homoaristeromycin (1) while the (R)-6' isomer was less active. Both were weaker than 1 towards cowpox. The diastereomers were equally active versus Epstein Barr virus while (S)-6' was three times more active toward vesicular stomatitis virus than (R)-6'. The diastereomers were inactive towards numerous other viruses. The CC50 for both diastereomers was >300MUM. PMID- 23727196 TI - Catechol-functionalized adhesive polymer nanoparticles for controlled local release of bone morphogenetic protein-2 from titanium surface. AB - We report on a novel surface functionalization approach to equip the titanium (Ti) surfaces with osteogenic properties. A key feature of the approach is the treatment of the Ti surfaces with Ti-adhesive nanoparticles that can stably load and controllably release bone morphogenetic protein-2 (BMP-2). Ti-adhesive nanoparticles were prepared by self-assembly of a catechol-functionalized poly(amino acid) diblock copolymer, catechol-poly(L-aspartic acid)-b-poly(L phenylalanine) (Cat-PAsp-PPhe). The nanoparticles consist of Ti-adhesive peripheral catechol groups, anionic PAsp shells, and PPhe inner cores. Field emission scanning electron microscopy (Fe-SEM) images showed that the Ti-adhesive nanoparticles could be uniformly immobilized on Ti surfaces. X-ray photoelectron spectroscopy (XPS) confirmed the successful anchoring of nanoparticles onto Ti surfaces. After surface immobilization of the nanoparticles, the static water contact angle of the Ti substrate decreased from 75.3 degrees to 50.0 degrees or 36.4 degrees , depending on the surface nanoparticle. Fluorescence microscopic analysis showed that BMP-2 could be effectively incorporated onto the Ti surface with adhesive nanoparticles. BMP-2 was controllably released for up to 40 days. The Ti substrate functionalized with BMP-2-incorporated nanoparticles significantly promoted attachment, proliferation, spreading, and alkaline phosphatase (ALP) activity of human adipose-derived stem cell (hADSC). The catechol-functionalized adhesive nanoparticles may be applied to various medical devices to create surfaces for improved performance. PMID- 23727197 TI - Maturation of the immune system of the male house cricket, Acheta domesticus. AB - The immune system functions to counteract the wide range of pathogens an insect may encounter during its lifespan, ultimately maintaining fitness and increasing the likelihood of survival to reproductive maturity. In this study, we describe the maturation of the innate immune system of the male house cricket Acheta domesticus during the last two nymphal stages, and during early and late adulthood. Total hemolymph phenoloxidase enzyme activity, lysozyme-like enzyme activity, the number of circulating hemocytes, and encapsulation ability were all determined for each developmental stage or age examined. The number of circulating hemocytes and lysozyme-like enzyme activity were similar for all developmental stages examined. Nymphs and newly molted adult males, however, had significantly lower total phenoloxidase activity than later adult stages, yet nymphs were able to encapsulate a nylon thread just as well as adults. Encapsulation ability would thus appear to be independent of total phenoloxidase activity. PMID- 23727198 TI - Caffeine inhibits adipogenic differentiation of primary adipose-derived stem cells and bone marrow stromal cells. AB - Caffeine consumption has been related to loss of body weight and modulates lipid metabolism. However, impacts of caffeine on adipogenic differentiation have not been well determined yet. The present study evaluated the effects of caffeine on adipogenesis using primary rat adipose-derived stem cells (ADSCs) and a mouse bone marrow stromal cell line (M2-10B4) in vitro. ADSCs and M2-10B4 were continuously exposed to caffeine (0.1-1mM) during adipogenic differentiation for 7 and 12 days, respectively. Oil red O and Nile red staining showed that caffeine reduced lipid droplet and adipocyte levels in both cell types. In addition, Nile red staining and FACScan flow cytometry showed that caffeine dose-dependently decreased adipocyte differentiation from 20% to 50% of the control ADSCs and M2 10B4 cells. Caffeine decreased the expression of adipogenesis-related genes including peroxisome proliferator-activated receptor-gamma, CCAAT/enhancer binding protein-alpha, adipocyte lipid binding protein, lipoprotein lipase, leptin, and TNFalpha in a dose-dependent manner. Rather, low concentration of caffeine (0.1mM) significantly increased IL-6 expression, but unexpectedly inhibited that at a concentration more than 0.3mM. Taken together, caffeine was able to effectively inhibit adipogenic differentiation of ADSCs and M2-10B4 cells partly through its inhibition of adipogenesis-related factors. PMID- 23727199 TI - Post-embryonic root organogenesis in cereals: branching out from model plants. AB - The root architecture of higher plants is amazingly diverse. In this review, we compare the lateral root developmental programme in cereals and Arabidopsis thaliana. In cereals, cells in the endodermis are recruited to form the new root cap and overlying cortical cells divide to facilitate the emergence of the lateral root primordium. The TIR1/ABF2 auxin receptors and the AUX/IAA, ARF, and LBD transcriptional regulatory proteins are conserved in cereals and Arabidopsis. Several elements of this regulatory network are common to lateral and crown roots in cereals. Also, the ground meristem from which crown roots differentiate shows similarities with the root pericycle. Studies in cereals promise to give complementary insights into the mechanisms regulating the development of post embryonic roots in plants. PMID- 23727200 TI - Advances in modeling trait-based plant community assembly. AB - In this review, we examine two new trait-based models of community assembly that predict the relative abundance of species from a regional species pool. The models use fundamentally different mathematical approaches and the predictions can differ considerably. Maxent obtains the most even probability distribution subject to community-weighted mean trait constraints. Traitspace predicts low probabilities for any species whose trait distribution does not pass through the environmental filter. Neither model maximizes functional diversity because of the emphasis on environmental filtering over limiting similarity. Traitspace can test for the effects of limiting similarity by explicitly incorporating intraspecific trait variation. The range of solutions in both models could be used to define the range of natural variability of community composition in restoration projects. PMID- 23727201 TI - The eukaryotic genome, its reads, and the unfinished assembly. AB - In recent years, readily affordable short read sequences provided by next generation sequencing (NGS) have become longer and more accurate. This has led to a jump in interest in the utility of NGS-only approaches for exploring eukaryotic genomes. The concept of a static, 'finished' genome assembly, which still appears to be a faraway goal for many eukaryotes, is yielding to new paradigms. We here motivate an object-view concept where the raw reads are the main, fixed object, and assemblies with their annotations take a role of dynamically changing and modifiable views of that object. PMID- 23727202 TI - Cytochrome bd oxidase from Escherichia coli displays high catalase activity: an additional defense against oxidative stress. AB - Cytochrome bd oxygen reductase from Escherichia coli has three hemes, b558, b595 and d. We found that the enzyme, as-prepared or in turnover with O2, rapidly decomposes H2O2 with formation of approximately half a mole of O2 per mole of H2O2. Such catalase activity vanishes upon cytochrome bd reduction, does not compete with the oxygen-reductase activity, is insensitive to NO, CO, antimycin-A and N-ethylmaleimide (NEM), but is inhibited by cyanide (Ki ~2.5MUM) and azide. The activity, possibly associated with heme-b595, was also observed in catalase deficient E. coli cells following cytochrome bd over-expression suggesting a protective role against oxidative stress in vivo. PMID- 23727203 TI - Nek5, a novel substrate for caspase-3, promotes skeletal muscle differentiation by up-regulating caspase activity. AB - Accumulating evidence suggests that caspase-3-mediated cleavage of protein kinase could be a key event to regulate cell differentiation. In this study, we investigated the role of Nek5 kinase, identified as a novel substrate for caspase 3, in skeletal muscle differentiation. Up-regulation of Nek5 mRNA expression was accompanied by cell differentiation. Myotube formation was promoted in Nek5 expressing cells, and was conversely inhibited in Nek5 knockdown cells. Furthermore, we found that caspase-3 activity, an important factor for myogenic differentiation, was enhanced by Nek5 cleavage. Although caspase-3-cleaved Nek5 partially exerted a promyogenic effect, it tended to induce apoptotic cell death. In summary, our findings suggest that Nek5 promotes myogenic differentiation through up-regulation of caspase activity. PMID- 23727204 TI - Stable complex formation of thylakoidal processing peptidase and PGRL1. AB - The thylakoid-transfer signal is required for energy-dependent translocation of preproteins into the thylakoid lumen and is removed by the thylakoidal processing peptidase (TPP). PGRL1 is an essential component of antimycin A-sensitive photosynthetic cyclic electron flow in chloroplasts. Here we report that one of the TPP isoforms, Plsp1, forms a stable complex with PGRL1. Genetic data demonstrate that PGRL1 is not essential for Plsp1 activity in vivo, leading to a possibility that PGRL1 may act as a regulator of TPP. PMID- 23727205 TI - Environmental concentrations of irgarol, diuron and S-metolachlor induce deleterious effects on gametes and embryos of the Pacific oyster, Crassostrea gigas. AB - Irgarol and diuron are the most representative "organic booster biocides" that replace organotin compounds in antifouling paints, and metolachlor is one of the most extensively used chloroacetamide herbicides in agriculture. The toxicity of S-metolachlor, irgarol and diuron was evaluated in Pacific oyster (Crassostrea gigas) gametes or embryos exposed to concentrations of pesticides ranging from 0.1* to 1000*, with 1* corresponding to environmental concentrations of the three studied pesticides in Arcachon Bay (France). Exposures were performed on (1) spermatozoa alone (2) oocytes alone and (3) both spermatozoa and oocytes, and adverse effects on fertilization success and offspring development were recorded. The results showed that the fertilizing capacity of spermatozoa was significantly affected after gamete exposure to pesticide concentrations as low as 1* of irgarol and diuron and 10* of metolachlor. The offspring obtained from pesticide exposed spermatozoa displayed a dose-dependent increase in developmental abnormalities. In contrast, treating oocytes with pesticide concentrations up to 10* did not alter fertilization rate and offspring quality. However, a significant decline in fertilization success and increase in abnormal D-larvae prevalence were observed at higher concentrations 10* (0.1 MUg L(-1)) for S metolachlor and 100* for irgarol (1.0 MUg L(-1)) and diuron (4.0 MUg L(-1)). Irgarol, diuron and S-metolachlor also induced a dose-dependent increase in abnormal D-larvae prevalence when freshly fertilized embryos were treated with pesticide concentrations as low as concentration of 1* (0.01 MUg L(-1) for irgarol or S-metolachlor, and 0.04 MUg L(-1) for diuron). The two bioassays on C. gigas spermatozoa and embryos displayed similar sensitivities to the studied pesticides while oocytes were less sensitive. Diuron, irgarol and S-metolachlor induced spermiotoxicity and embryotoxicity at environmentally relevant concentrations and therefore might be a threat to oyster recruitment in coastal areas facing chronic inputs of pesticides. PMID- 23727206 TI - Aggregate plaque volume by coronary computed tomography angiography is superior and incremental to luminal narrowing for diagnosis of ischemic lesions of intermediate stenosis severity. AB - OBJECTIVES: This study examined the performance of percent aggregate plaque volume (%APV), which represents cumulative plaque volume as a function of total vessel volume, by coronary computed tomography angiography (CTA) for identification of ischemic lesions of intermediate stenosis severity. BACKGROUND: Coronary lesions of intermediate stenosis demonstrate significant rates of ischemia. Coronary CTA enables quantification of luminal narrowing and %APV. METHODS: We identified 58 patients with intermediate lesions (30% to 69% diameter stenosis) who underwent invasive angiography and fractional flow reserve. Coronary CTA measures included diameter stenosis, area stenosis, minimal lumen diameter (MLD), minimal lumen area (MLA) and %APV. %APV was defined as the sum of plaque volume divided by the sum of vessel volume from the ostium to the distal portion of the lesion. Fractional flow reserve <= 0.80 was considered diagnostic of lesion-specific ischemia. Area under the receiver operating characteristic curve and net reclassification improvement (NRI) were also evaluated. RESULTS: Twenty-two of 58 lesions (38%) caused ischemia. Compared with nonischemic lesions, ischemic lesions had smaller MLD (1.3 vs. 1.7 mm, p = 0.01), smaller MLA (2.5 vs. 3.8 mm(2), p = 0.01), and greater %APV (48.9% vs. 39.3%, p < 0.0001). Area under the receiver operating characteristic curve was highest for %APV (0.85) compared with diameter stenosis (0.68), area stenosis (0.66), MLD (0.75), or MLA (0.78). Addition of %APV to other measures showed significant reclassification over diameter stenosis (NRI 0.77, p < 0.001), area stenosis (NRI 0.63, p = 0.002), MLD (NRI 0.62, p = 0.001), and MLA (NRI 0.43, p = 0.01). CONCLUSIONS: Compared with diameter stenosis, area stenosis, MLD, and MLA, %APV by coronary CTA improves identification, discrimination, and reclassification of ischemic lesions of intermediate stenosis severity. PMID- 23727207 TI - Use of stress testing and diagnostic catheterization after coronary stenting: association of site-level patterns with patient characteristics and outcomes in 247,052 Medicare beneficiaries. AB - OBJECTIVES: The aim of this study was to determine diagnostic testing patterns after percutaneous coronary intervention (PCI). BACKGROUND: Little is known about patterns of diagnostic testing after PCI in the United States or the relationship of these patterns to clinical outcomes. METHODS: Centers for Medicare and Medicaid Services inpatient and outpatient claims were linked to National Cardiovascular Data Registry CathPCI Registry data from 2005 to 2007. Hospital quartiles of the cumulative incidence of diagnostic testing use within 12 and 24 months after PCI were compared for patient characteristics, repeat revascularization, acute myocardial infarction, and death. RESULTS: A total of 247,052 patients underwent PCI at 656 institutions. Patient and site characteristics were similar across quartiles of testing use. There was a 9% and 20% higher adjusted risk for repeat revascularization in quartiles 3 and 4 (highest testing rate), respectively, compared with quartile 1 (lowest testing rate) (p = 0.020 and p < 0.0001, respectively). The adjusted risk for death or acute myocardial infarction did not differ among quartiles. CONCLUSIONS: Although patient characteristics were largely independent of rates of post-PCI testing, higher testing rates were not associated with lower risk for myocardial infarction or death, but repeat revascularization was significantly higher at these sites. Additional studies should examine whether increased testing is a marker for improved quality of post-PCI care or simply increased health care utilization. PMID- 23727208 TI - Does practice variation matter? PMID- 23727210 TI - Stress cardiac magnetic resonance imaging: it is time to trust the magnetic crystal ball. PMID- 23727209 TI - Prognostic value of stress cardiac magnetic resonance imaging in patients with known or suspected coronary artery disease: a systematic review and meta analysis. AB - OBJECTIVES: This study sought to perform a systematic review and meta-analysis to understand the role of stress cardiac magnetic resonance imaging (CMR) in assessing cardiovascular prognosis in patients with known or suspected coronary artery disease (CAD). BACKGROUND: Although stress CMR is excellent for the diagnosis of obstructive CAD, the prognostic value of stress CMR has been less well described. METHODS: PubMed, Cochrane CENTRAL, and metaRegister of Controlled Trials were searched for stress CMR studies with >6 months of prognostic data. Primary endpoints were cardiovascular death, myocardial infarction (MI), and a composite outcome of cardiovascular death or MI during follow-up. Summary effect estimates were generated with random-effects modeling, and annualized event rates were assessed. RESULTS: Nineteen studies (14 vasodilator, 4 dobutamine, and 1 that used both) involved a total of 11,636 patients with a mean follow-up of 32 months. Patients had a mean age of 63 +/- 12 years, 63% were male, and 26% had previous MI; mean left ventricular ejection fraction was 61 +/- 12%; and late gadolinium enhancement was present in 29% and ischemia in 32%. Patients with ischemia had a higher incidence of MI (odds ratio [OR]: 7.7; p < 0.0001), cardiovascular death (OR: 7.0; p < 0.0001), and the combined endpoint (OR: 6.5; p < 0.0001) compared with those with a negative study. The combined outcome annualized events rates were 4.9% for a positive versus 0.8% for a negative stress CMR (p < 0.0001), 2.8% versus 0.3% for cardiovascular death (p < 0.0001), and 2.6% versus 0.4% for MI (p < 0.0005). The presence of late gadolinium enhancement was also significantly associated with a worse prognosis. CONCLUSIONS: A negative stress CMR study is associated with very low risk of cardiovascular death and MI. Stress CMR has excellent prognostic characteristics and may help guide risk stratification of patients with known or suspected CAD. PMID- 23727211 TI - More is more. PMID- 23727212 TI - Chronic kidney disease: the "perfect storm" of cardiometabolic risk illuminates genetic diathesis in cardiovascular disease. PMID- 23727213 TI - Transcatheter aortic valve implantation: a treatment we are going to need! PMID- 23727214 TI - Aortic stenosis in the elderly: disease prevalence and number of candidates for transcatheter aortic valve replacement: a meta-analysis and modeling study. AB - OBJECTIVES: The purpose of this study was to evaluate the prevalence of aortic stenosis (AS) in the elderly and to estimate the current and future number of candidates for transcatheter aortic valve replacement (TAVR). BACKGROUND: Severe AS is a major cause of morbidity and mortality in the elderly. A proportion of these patients is at high or prohibitive risk for surgical aortic valve replacement, and is now considered for TAVR. METHODS: A systematic search was conducted in multiple databases, and prevalence rates of patients (>75 years) were pooled. A model was based on a second systematic literature search of studies on decision making in AS. Monte Carlo simulations were performed to estimate the number of TAVR candidates in 19 European countries and North America. RESULTS: Data from 7 studies (n = 9,723 subjects) were used. The pooled prevalence of all AS in the elderly was 12.4% (95% confidence interval [CI]: 6.6% to 18.2%), and the prevalence of severe AS was 3.4% (95% CI: 1.1% to 5.7%). Among elderly patients with severe AS, 75.6% (95% CI: 65.8% to 85.4%) were symptomatic, and 40.5% (95% CI: 35.8% to 45.1%) of these patients were not treated surgically. Of those, 40.3% (95% CI: 33.8% to 46.7%) received TAVR. Of the high-risk patients, 5.2% were TAVR candidates. Projections showed that there are approximately 189,836 (95% CI: 80,281 to 347,372) TAVR candidates in the European countries and 102,558 (95% CI: 43,612 to 187,002) in North America. Annually, there are 17,712 (95% CI: 7,590 to 32,691) new TAVR candidates in the European countries and 9,189 (95% CI: 3,898 to 16,682) in North America. CONCLUSIONS: With a pooled prevalence of 3.4%, the burden of disease among the elderly due to severe AS is substantial. Under the current indications, approximately 290,000 elderly patients with severe AS are TAVR candidates. Nearly 27,000 patients become eligible for TAVR annually. PMID- 23727215 TI - Optimized prognostic score for coronary computed tomographic angiography: results from the CONFIRM registry (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter Registry). AB - OBJECTIVES: The aim of this study was to analyze the predictive value of coronary computed tomography angiography (CCTA) and to model and validate an optimized score for prognosis of 2-year survival on the basis of a patient population with suspected coronary artery disease (CAD). BACKGROUND: Coronary computed tomography angiography carries important prognostic information in addition to the detection of obstructive CAD. But it is still unclear how the results of CCTA should be interpreted in the context of clinical risk predictors. METHODS: The analysis is based on a test sample of 17,793 patients and a validation sample of 2,506 patients, all with suspected CAD, from the international CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry. On the basis of CCTA data and clinical risk scores, an optimized score was modeled. The endpoint was all-cause mortality. RESULTS: During a median follow-up of 2.3 years, 347 patients died. The best CCTA parameter for prediction of mortality was the number of proximal segments with mixed or calcified plaques (C-index 0.64, p < 0.0001) and the number of proximal segments with a stenosis >50% (C-index 0.56, p = 0.002). In an optimized score including both parameters, CCTA significantly improved overall risk prediction beyond National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) score as best clinical score. According to this score, a proximal segment with either a mixed or calcified plaque or a stenosis >50% is equivalent to a 5-year increase in age or the risk of smoking. CONCLUSIONS: In CCTA, both plaque burden and stenosis, particularly in proximal segments, carry incremental prognostic value. A prognostic score on the basis of this data can improve risk prediction beyond clinical risk scores. PMID- 23727216 TI - Risk of neutropenia in a clozapine-treated elderly population. PMID- 23727217 TI - Links among resting-state default-mode network, salience network, and symptomatology in schizophrenia. AB - Neuroimaging data support the idea that schizophrenia is a brain disorder with altered brain structure and function. New resting-state functional connectivity techniques allow us to highlight synchronization of large-scale networks, such as the default-mode network (DMN) and salience network (SN). A large body of work suggests that disruption of these networks could give rise to specific schizophrenia symptoms. We examined the intra-network connectivity strength and gray matter content (GMC) of DMN and SN in 26 schizophrenia patients using resting-state functional magnetic resonance imaging and voxel-based morphometry. Resting-state data were analyzed with independent component analysis and dual regression techniques. We reported reduced functional connectivity within both DMN and SN in patients with schizophrenia. Concerning the DMN, patients showed weaker connectivity in a cluster located in the right paracingulate cortex. Moreover, patients showed decreased GMC in this cluster. With regard to the SN, patients showed reduced connectivity in the left and right striatum. Decreased connectivity in the paracingulate cortex was correlated with difficulties in abstract thinking. The connectivity decrease in the left striatum was correlated with delusion and depression scores. Correlation between the connectivity of DMN frontal regions and difficulties in abstract thinking emphasizes the link between negative symptoms and the likely alteration of the frontal medial cortex in schizophrenia. Correlation between the connectivity of SN striatal regions and delusions supports the aberrant salience hypothesis. This work provides new insights into dysfunctional brain organization in schizophrenia and its contribution to specific schizophrenia symptoms. PMID- 23727218 TI - A user-friendly chromatographic method to purify small regulatory RNAs. AB - The discovery of the small regulatory RNAs has changed our vision of cellular regulations. Indeed, when loaded on Argonaute proteins they form ribonucleoprotein complexes (RNPs) that target complementary sequences to achieve widespread silencing mechanisms conserved in most eukaryotes. The recent development of deep sequencing approaches highly contributed to their detection. Small RNA isolation from cells and/or tissues remains a crucial stage to generate robust and relevant sequencing data. In 2006, a novel strategy based on anion exchange chromatography has been proposed as an alternative to the standard size isolation purification procedure. Using bioinformatic comparative analysis, we here demonstrate that anion-exchange chromatographic RNP purification prior to small RNA extraction unbiasedly enriches datasets in bona fide reads (small regulatory RNA sequences) and depletes endogenous contaminants (ribosomal RNAs and degradation RNA products). The resulting increase in sequencing depth provides a major benefit to study rare populations. We then developed a fast and basic manual procedure to purify such small non-coding RNAs using anion-exchange chromatography at the bench. We validated the efficiency of this new method and used this strategy to purify small RNAs from various tissues and organisms. We moreover determined that our manual purification increases the output of the previously described anion-exchange chromatography procedure. PMID- 23727219 TI - Memantine block depends on agonist presentation at the NMDA receptor in substantia nigra pars compacta dopamine neurones. AB - NMDA glutamate receptors (NMDARs) have critical functional roles in the nervous system but NMDAR over-activity can contribute to neuronal damage. The open channel NMDAR blocker, memantine is used to treat certain neurodegenerative diseases, including Parkinson's disease (PD) and is well tolerated clinically. We have investigated memantine block of NMDARs in substantia nigra pars compacta (SNc) dopamine neurones, which show severe pathology in PD. Memantine (10 MUM) caused robust inhibition of whole-cell (synaptic and extrasynaptic) NMDARs activated by NMDA at a high concentration or a long duration, low concentration. Less memantine block of NMDAR-EPSCs was seen in response to low frequency synaptic stimulation, while responses to high frequency synaptic stimulation were robustly inhibited by memantine; thus memantine inhibition of NMDAR-EPSCs showed frequency-dependence. By contrast, MK-801 (10 MUM) inhibition of NMDAR-EPSCs was not significantly different at low versus high frequencies of synaptic stimulation. Using immunohistochemistry, confocal imaging and stereological analysis, NMDA was found to reduce the density of cells expressing tyrosine hydroxylase, a marker of viable dopamine neurones; memantine prevented the NMDA evoked decrease. In conclusion, memantine blocked NMDAR populations in different subcellular locations in SNc dopamine neurones but the degree of block depended on the intensity of agonist presentation at the NMDAR. This profile may contribute to the beneficial effects of memantine in PD, as glutamatergic activity is reported to increase, and memantine could preferentially reduce over activity while leaving some physiological signalling intact. PMID- 23727221 TI - Novel and functional sequence variants within the TBX2 gene promoter in ventricular septal defects. AB - Congenital heart disease (CHD) is the most common birth defects in humans. To date, genetic causes for CHD remain largely unknown. T-box transcription factor 2 (TBX2) gene is expressed in the myocardium of atrioventricular canal, outflow tract and inflow tract and plays a critical role in heart chamber formation. Genomic deletion and duplication of TBX2 gene have been associated with cardiac defects. As TBX2 acts in a dose-dependent manner, we hypothesized that DNA sequence variants (DSVs) within TBX2 gene promoter may mediate CHD development by changing TBX2 levels. In this study, TBX2 gene promoter was genetically analyzed in large cohorts of patients with ventricular septal defect (VSD) (n = 324) and ethnic-matched healthy controls (n = 328). Four novel and heterozygous DSVs, g.59477201C > T, g.59477347G > A, g.59477353delG and g.59477371G > A were identified in VSD patients, but in none of controls. Functional analyses revealed that all of the four DSVs significantly decreased transcriptional activities of TBX2 gene promoter. Therefore, our data suggested that the DSVs within TBX2 gene promoter identified in VSD patients may contribute to VSD etiology. PMID- 23727220 TI - P2X7 receptors at adult neural progenitor cells of the mouse subventricular zone. AB - Neurogenesis requires the balance between the proliferation of newly formed progenitor cells and subsequent death of surplus cells. RT-PCR and immunocytochemistry demonstrated the presence of P2X7 receptor mRNA and immunoreactivity in cultured neural progenitor cells (NPCs) prepared from the adult mouse subventricular zone (SVZ). Whole-cell patch-clamp recordings showed a marked potentiation of the inward current responses both to ATP and the prototypic P2X7 receptor agonist dibenzoyl-ATP (Bz-ATP) at low Ca(2+) and zero Mg(2+) concentrations in the bath medium. The Bz-ATP-induced currents reversed their polarity near 0 mV; in NPCs prepared from P2X7(-/-) mice, Bz-ATP failed to elicit membrane currents. The general P2X/P2Y receptor antagonist PPADS and the P2X7 selective antagonists Brilliant Blue G and A-438079 strongly depressed the effect of Bz-ATP. Long-lasting application of Bz-ATP induced an initial current, which slowly increased to a steady-state response. In combination with the determination of YO-PRO uptake, these experiments suggest the dilation of a receptor-channel and/or the recruitment of a dye-uptake pathway. Ca(2+)-imaging by means of Fura-2 revealed that in a Mg(2+)-deficient bath medium Bz-ATP causes [Ca(2+)](i) transients fully depending on the presence of external Ca(2+). The MTT test indicated a concentration-dependent decrease in cell viability by Bz-ATP treatment. Correspondingly, Bz-ATP led to an increase in active caspase 3 immunoreactivity, indicating a P2X7-controlled apoptosis. In acute SVZ brain slices of transgenic Tg(nestin/EGFP) mice, patch-clamp recordings identified P2X7 receptors at NPCs with pharmacological properties identical to those of their cultured counterparts. We suggest that the apoptotic/necrotic P2X7 receptors at NPCs may be of particular relevance during pathological conditions which lead to increased ATP release and thus could counterbalance the ensuing excessive cell proliferation. PMID- 23727222 TI - Caesarean section at term: the relationship between neonatal respiratory morbidity and microviscosity in amniotic fluid. AB - OBJECTIVES: The incidence of neonatal respiratory morbidity following an elective caesarean section is 2-3 times higher than after a vaginal delivery. The microviscosity of surfactant phospholipids, as measured with fluorescence polarisation, is linked with the functional characteristics of fetal surfactant and thus fetal lung maturity, but so far this point has received little attention in newborns at term. The aim of the study is to evaluate the correlation between neonatal respiratory morbidity and amniotic microviscosity (Fluorescence Polarisation Index) in women undergoing caesarean section after 37 weeks' gestation. STUDY DESIGN: The files of 136 women who had undergone amniotic microviscosity studies during elective caesarean deliveries at term were anonymised. Amniotic fluid immaturity (AFI) was defined as a Fluorescence Polarisation Index higher than 0.335. RESULTS: Respiratory morbidity was observed in 10 babies (7.3%) and was independently associated with AFI (OR: 6.11 [95% CI, 1.20-31.1] with p=0.029) and maternal body mass index (OR: 1.12 [95% CI, 1.02 1.22] with p=0.019). Gestational age at the time of caesarean delivery was inversely associated with AFI (odds ratio, 0.46 [95% confidence interval, 0.29 0.71], p<0.001), especially before 39 weeks, and female gender was associated with an increased risk (odds ratio, 3.29 [95% confidence interval, 1.48-7.31], p=0.004). CONCLUSIONS: AFI assessed by amniotic microviscosity was significantly associated with respiratory morbidity and independently correlated with shorter gestational age especially before 39 weeks. This finding provides a physiological rationale for recommending delaying elective caesarean section delivery until 39 weeks of gestation to decrease the risk for respiratory morbidity. PMID- 23727223 TI - Matched-pair analyses of resting and dynamic morphology between Monarc and TVT-O procedures by ultrasound. AB - OBJECTIVE: To determine morphologic differences between Monarc and TVT-O procedures in axial and coronal planes by three- and four-dimensional (3D and 4D) ultrasound. STUDY DESIGN: Retrospective chart audits and ultrasound analyses were conducted on 128 women who had undergone either Monarc or TVT-O procedures for urodynamic stress incontinence. Thirty matched pairs of the two successful procedures were randomly selected and compared. Matched variables were age, parity, body mass index, cesarean status, menopausal status, and primary surgeries. Six-month postoperative 3D and 4D ultrasound results obtained at rest, on straining, and during coughing in these 60 women were analyzed. Assessed ultrasound parameters included the axial tape urethral distance (aTUD), axial central urethral echolucent area (aUCEA), axial tape angle (aTA), and coronal tape angle (cTA), all of which were measured at three equidistant points along the tapes. Paired t-tests were used to compare differences in ultrasound parameters between women after the two procedures and a P value <0.004 was considered significant after Bonferroni correction. RESULTS: At rest, women subjected to Monarc procedures had a significantly wider aTA at one-fourth of the tape and a wider cTA at one-, two-, and three-fourths of the tape than did those subjected to TVT-O procedures. There were no significant differences in other resting ultrasound parameters between these two procedures. Additionally, after both procedures women had comparable straining and coughing ultrasound manifestations as well as respective dynamic changes. CONCLUSION: Despite flatter resting tape angulations in women following Monarc procedures, both Monarc and TVT-O tapes had equivalent dynamic patterns and changes assessed by 4D ultrasound. PMID- 23727224 TI - Treatment of uterine arteriovenous malformation by myometrial lesion resection combined with artery occlusion under laparoscopy: a case report and literature review. AB - Uterine arteriovenous malformation (AVM) is an uncommon, potentially life threatening condition, and the primary therapeutic method is embolization. We describe a case of a 36-year-old woman with acquired uterine AVM accompanied by abnormal vaginal bleeding. The diagnosis was established by Doppler flow ultrasonography combined with magnetic resonance arteriography. Because this uterine AVM was extensive and multiple, uterine arterial embolization could not be considered. We therefore employed a combined method under laparoscopy, in which the uterine arteries were first occluded, then uterine myometrial lesions were resected and abnormal pelvic blood vessels were ablated. Finally, the uterus was reconstructed with an intact uterine cavity. Abnormal vaginal bleeding was successfully stopped after operation, but amenorrhea due to uterine adhesions occurred. This method is suitable for the treatment of uterine AVM with extensive and multiple lesions, but it should be chosen cautiously for women of reproductive age with AVM and fertility requirement. PMID- 23727225 TI - Membrane targeting of the small myristoylated protein 2 (SMP-2) in Leishmania major. AB - Leishmania parasites express three highly conserved small myristoylated proteins (SMPs) that are targeted to distinct membranes. SMP-1 is exclusively found in the flagellum, depending on myristoylation and palmitoylation. In contrast, monoacylated SMP-2 and SMP-4 are localized to the flagellar pocket and plasma membrane, respectively. Here, we demonstrate that unlike SMP-4, SMP-2 resides in detergent resistant membranes, but can be readily solubilized in the presence of high concentrations of salt. We provide evidence that in detergent resistant membranes, SMP-2 forms high molecular weight complexes in vivo. Association with detergent resistant membranes was abrogated in the presence of a C-terminal tag suggesting acylation independent targeting signals. In addition, the N-terminal region of SMP-2 contains sufficient information for membrane targeting, as a GFP chimera localizes to the flagellar pocket. Thus while the core sequences of the SMPs are highly conserved, individual members have evolved different mechanisms for their diverse membrane localization. PMID- 23727227 TI - Frictional resistance sheds light on the multicomponent nature of nasal obstruction: a combined in vivo and computational fluid dynamics study. AB - Exploring nasal flow contributes to better understanding of pathophysiological functions of nasal cavities. We combined the rhinomanometry measurements of 11 patients and computational fluid dynamics (CFD) simulations in 3 nasal airway models to dissect the complex mechanisms that determine nasal flow obstruction: spatial complexity and pressure-dependent deformability of nasal airways. We quantified spatial complexity by calculating longitudinal variations of hydraulic diameter, perimeter and area of nasal cavities, and their impact on flow characteristics by examining the longitudinal variations of the kinetic energy coefficient and the kinetic to potential energy ratio. Airway distensibility variably affected in vivo pressure-flow relationships through the appearance of flow-limitation patterns characterized by maximum flow and/or flow plateau. We quantified deformability and spatial complexity effects on nasal airway resistance by normalizing all data with averaged reference parameters. The results show that discrepancies in nasal flow resistances reflect airway deformability and geometrical complexity, and thereby constitute a framework to better characterize nasal obstruction. PMID- 23727228 TI - Apnea of prematurity--perfect storm. AB - With increased survival of preterm infants as young as 23 weeks gestation, maintaining adequate respiration and corresponding oxygenation represents a clinical challenge in this unique patient cohort. Respiratory instability characterized by apnea and periodic breathing occurs in premature infants because of immature development of the respiratory network. While short respiratory pauses and apnea may be of minimal consequence if oxygenation is maintained, they can be problematic if accompanied by chronic intermittent hypoxemia. Underdevelopment of the lung and the resultant lung injury that occurs in this population concurrent with respiratory instability creates the perfect storm leading to frequent episodes of profound and recurrent hypoxemia. Chronic intermittent hypoxemia contributes to the immediate and long term co-morbidities that occur in this population. In this review we discuss the pathophysiology leading to the perfect storm, diagnostic assessment of breathing instability in this unique population and therapeutic interventions that aim to stabilize breathing without contributing to tissue injury. PMID- 23727226 TI - Common mechanisms of compensatory respiratory plasticity in spinal neurological disorders. AB - In many neurological disorders that disrupt spinal function and compromise breathing (e.g. ALS, cervical spinal injury, MS), patients often maintain ventilatory capacity well after the onset of severe CNS pathology. In progressive neurodegenerative diseases, patients ultimately reach a point where compensation is no longer possible, leading to catastrophic ventilatory failure. In this brief review, we consider evidence that common mechanisms of compensatory respiratory plasticity preserve breathing capacity in diverse clinical disorders, despite the onset of severe pathology (e.g. respiratory motor neuron denervation and/or death). We propose that a suite of mechanisms, operating at distinct sites in the respiratory control system, underlies compensatory respiratory plasticity, including: (1) increased (descending) central respiratory drive, (2) motor neuron plasticity, (3) plasticity at the neuromuscular junction or spared respiratory motor neurons, and (4) shifts in the balance from more to less severely compromised respiratory muscles. To establish this framework, we contrast three rodent models of neural dysfunction, each posing unique problems for the generation of adequate inspiratory motor output: (1) respiratory motor neuron death, (2) de- or dysmyelination of cervical spinal pathways, and (3) cervical spinal cord injury, a neuropathology with components of demyelination and motor neuron death. Through this contrast, we hope to understand the multilayered strategies used to "fight" for adequate breathing in the face of mounting pathology. PMID- 23727229 TI - Posterior fossa tumors and their impact on sleep and ventilatory control: a clinical perspective. AB - The cerebellum, classically viewed as a motor structure of the brain, may play a role in respiration. Brainstem dysfunction has been implicated in sleep disordered breathing (SDB), but apnea after surgery of brain tumors in the posterior fossa, not involving the brainstem has been reported. We report four cases with posterior fossa tumors without brainstem invasion who suffered SDB after surgery diagnosed by polysomnography (PSG). Advanced MRI techniques with DTI were used to find correlations with SDB. Abnormal signals in the superior, middle and inferior cerebellar peduncles were seen in these patients with the most severe changes in the inferior peduncle. SDB may be under diagnosed in the setting of posterior fossa tumors without brainstem involvement. Damage to the cerebellar peduncles, especially the inferior cerebellar peduncle, without brainstem involvement, can cause significant disruption of respiration. PMID- 23727230 TI - Structural basis of Brr2-Prp8 interactions and implications for U5 snRNP biogenesis and the spliceosome active site. AB - The U5 small nuclear ribonucleoprotein particle (snRNP) helicase Brr2 disrupts the U4/U6 small nuclear RNA (snRNA) duplex and allows U6 snRNA to engage in an intricate RNA network at the active center of the spliceosome. Here, we present the structure of yeast Brr2 in complex with the Jab1/MPN domain of Prp8, which stimulates Brr2 activity. Contrary to previous reports, our crystal structure and mutagenesis data show that the Jab1/MPN domain binds exclusively to the N terminal helicase cassette. The residues in the Jab1/MPN domain, whose mutations in human Prp8 cause the degenerative eye disease retinitis pigmentosa, are found at or near the interface with Brr2, clarifying its molecular pathology. In the cytoplasm, Prp8 forms a precursor complex with U5 snRNA, seven Smproteins, Snu114, and Aar2, but after nuclear import, Brr2 replaces Aar2 to form mature U5 snRNP. Our structure explains why Aar2 and Brr2 are mutually exclusive and provides important insights into the assembly of U5 snRNP. PMID- 23727231 TI - A cryptic TOG domain with a distinct architecture underlies CLASP-dependent bipolar spindle formation. AB - CLASP is a key regulator of microtubule (MT) dynamics and bipolar mitotic spindle structure with CLASP mutants displaying a distinctive monopolar spindle phenotype. It has been postulated that cryptic TOG domains underlie CLASP's ability to regulate MT dynamics. Here, we report the crystal structure of a cryptic TOG domain (TOG2) from human CLASP1, demonstrating the presence of a TOG array in the CLASP family. Strikingly, CLASP1 TOG2 exhibits a convex architecture across the tubulin-binding surface that contrasts with the flat tubulin-binding surface of XMAP215 family TOG domains. Mutations in key conserved TOG2 determinants abrogate the ability of CLASP mutants to rescue bipolar spindle formation in Drosophila cells depleted of endogenous CLASP. These findings highlight the common mechanistic use of TOG domains in XMAP215 and CLASP families to regulate MT dynamics and suggest that differential TOG domain architecture may confer distinct functions to these critical cytoskeletal regulators. PMID- 23727232 TI - BCL::MP-fold: folding membrane proteins through assembly of transmembrane helices. AB - Membrane protein structure determination remains a challenging endeavor. Computational methods that predict membrane protein structure from sequence can potentially aid structure determination for such difficult target proteins. The de novo protein structure prediction method BCL::Fold rapidly assembles secondary structure elements into three-dimensional models. Here, we describe modifications to the algorithm, named BCL::MP-Fold, in order to simulate membrane protein folding. Models are built into a static membrane object and are evaluated using a knowledge-based energy potential, which has been modified to account for the membrane environment. Additionally, a symmetry folding mode allows for the prediction of obligate homomultimers, a common property among membrane proteins. In a benchmark test of 40 proteins of known structure, the method sampled the correct topology in 34 cases. This demonstrates that the algorithm can accurately predict protein topology without the need for large multiple sequence alignments, homologous template structures, or experimental restraints. PMID- 23727233 TI - Diversity and similarity of motor function and cross-bridge kinetics in papillary muscles of transgenic mice carrying myosin regulatory light chain mutations D166V and R58Q. AB - Mechanical properties of skinned papillary muscle fibers from transgenic mice expressing familial hypertrophic cardiomyopathy associated mutations D166V and R58Q in myosin regulatory light chain were investigated. Elementary steps and the apparent rate constants of the cross-bridge cycle were characterized from the tension transients induced by sinusoidal length changes during maximal Ca(2+) activation, together with ATP, ADP, and Pi studies. The tension-pCa relation was also tested in two sets of solutions with differing Pi and ionic strength. Our results showed that in both mutants the fast apparent rate constant 2pic and the rate constants of the cross-bridge detachment step (k2) were smaller than those of wild type (WT), demonstrating the slower cross-bridge kinetics. D166V showed significantly smaller ATP (K1) and ADP (K0) association constants than WT, displaying weaker ATP binding and easier ADP release, whereas those of R58Q were not significantly different from WT. In tension-pCa study, both D166V and R58Q mutations exhibited increased Ca(2+) sensitivity and less cooperativity. We conclude that, while the two FHC mutations have similar clinical manifestations and prognosis, some of the mechanical parameters of cross-bridges (K0, K1) are differently modified, whereas some others (Ca(2+)-sensitivity, cooperativity, k2) are similarly modified by these two FHC associated mutations. PMID- 23727235 TI - Reply to: ""wait and see" policy for early hepatocellular carcinoma". PMID- 23727236 TI - Acute kidney injury (AKI) in cirrhosis: should we change current definition and diagnostic criteria of renal failure in cirrhosis? PMID- 23727234 TI - Epico Project. Development of educational recommendations using the DELPHI technique on invasive candidiasis in non-neutropenic critically ill adult patients. AB - BACKGROUND: Although there has been an improved management of invasive candidiasis in the last decade, controversial issues still remain, especially in the diagnostic and therapeutic approaches. AIMS: We sought to identify the core clinical knowledge and to achieve high level agreement recommendations required to care for critically ill adult patients with invasive candidiasis. METHODS: A prospective Spanish survey reaching consensus by the DELPHI technique was made. It was anonymously conducted by electronic mail in a first term to 25 national multidisciplinary experts in invasive fungal infections from five national scientific societies, including intensivists, anesthesiologists, microbiologists, pharmacologists and infectious diseases specialists, who answered to 47 questions prepared by a coordination group after a strict review of the literature in the last five years. The educational objectives spanned five categories, including epidemiology, diagnostic tools, prediction rules, and treatment and de-escalation approaches. The level of agreement achieved among the panel experts in each item should exceed 75% to be selected. In a second term, after extracting recommendations from the selected items, a face to face meeting was performed where more than 80 specialists in a second round were invited to validate the preselected recommendations. RESULTS: In the first term, 20 recommendations were preselected (Epidemiology 4, Scores 3, Diagnostic tools 4, Treatment 6 and De escalation approaches 3). After the second round, the following 12 were validated: (1) Epidemiology (2 recommendations): think about candidiasis in your Intensive Care Unit (ICU) and do not forget that non-Candida albicans-Candida species also exist. (2) Diagnostic tools (4 recommendations): blood cultures should be performed under suspicion every 2-3 days and, if positive, every 3 days until obtaining the first negative result. Obtain sterile fluid and tissue, if possible (direct examination of the sample is important). Use non-culture based methods as microbiological tools, whenever possible. Determination of antifungal susceptibility is mandatory. (3) Scores (1 recommendation): as screening tool, use the Candida Score and determine multicolonization in high risk patients. (4) Treatment (4 recommendations): start early. Choose echinocandins. Withdraw any central venous catheter. Fundoscopy is needed. (5) De-escalation (1 recommendation): only applied when knowing susceptibility determinations and after 3 days of clinical stability. The higher rate of agreement was achieved in the optimization of microbiological tools and the withdrawal of the catheter, whereas the lower rate corresponded to de-escalation therapy and the use of scores. CONCLUSIONS: The management of invasive candidiasis in ICU patients requires the application of a broad range of knowledge and skills that we summarize in our recommendations. These recommendations may help to identify the potential patients, standardize their global management and improve their outcomes, based on the DELPHI methodology. PMID- 23727237 TI - "Wait and see" policy for early hepatocellular carcinoma. PMID- 23727238 TI - Commensal microbiota are required for systemic inflammation triggered by necrotic dendritic cells. AB - The relationship between dendritic cells (DCs) and commensal microflora in shaping systemic immune responses is not well understood. Here, we report that mice deficient for the Fas-associated death domain in DCs developed systemic inflammation associated with elevated proinflammatory cytokines and increased myeloid and B cells. These mice exhibited reduced DCs in gut-associated lymphoid tissues due to RIP3-dependent necroptosis, whereas DC functions remained intact. Induction of systemic inflammation required DC necroptosis and commensal microbiota signals that activated MyD88-dependent pathways in other cell types. Systemic inflammation was abrogated with the administration of broad-spectrum antibiotics or complete, but not DC-specific, deletion of MyD88. Thus, we have identified a previously unappreciated role for commensal microbiota in priming immune cells for inflammatory responses against necrotic cells. These studies demonstrate the impact intestinal microflora have on the immune system and their role in eliciting proper immune responses to harmful stimuli. PMID- 23727239 TI - Transcriptional differences between normal and glioma-derived glial progenitor cells identify a core set of dysregulated genes. AB - Glial progenitor cells (GPCs) are a potential source of malignant gliomas. We used A2B5-based sorting to extract tumorigenic GPCs from human gliomas spanning World Health Organization grades II-IV. Messenger RNA profiling identified a cohort of genes that distinguished A2B5+ glioma tumor progenitor cells (TPCs) from A2B5+ GPCs isolated from normal white matter. A core set of genes and pathways was substantially dysregulated in A2B5+ TPCs, which included the transcription factor SIX1 and its principal cofactors, EYA1 and DACH2. Small hairpin RNAi silencing of SIX1 inhibited the expansion of glioma TPCs in vitro and in vivo, suggesting a critical and unrecognized role of the SIX1-EYA1-DACH2 system in glioma genesis or progression. By comparing the expression patterns of glioma TPCs with those of normal GPCs, we have identified a discrete set of pathways by which glial tumorigenesis may be better understood and more specifically targeted. PMID- 23727240 TI - The touch dome defines an epidermal niche specialized for mechanosensory signaling. AB - In mammalian skin, Merkel cells are mechanoreceptor cells that are required for the perception of gentle touch. Recent evidence indicates that mature Merkel cells descend from the proliferative layer of skin epidermis; however, the stem cell niche for Merkel cell homeostasis has not been reported. Here, we provide genetic evidence for maintenance of mature Merkel cells during homeostasis by Krt17+ stem cells located in epidermal touch domes of hairy skin and in the tips of the rete ridges of glabrous skin. Lineage tracing analysis indicated that the entire pool of mature Merkel cells is turned over every 7-8 weeks in the adult epidermis and that Krt17+ stem cells also maintain squamous differentiation in the touch dome and in glabrous skin. Finally, selective genetic ablation of Krt17+ touch-dome keratinocytes indicates that these cells, and not mature Merkel cells, are primarily responsible for maintaining innervation of the Merkel cell neurite complex. PMID- 23727241 TI - Bivalent chromatin marks developmental regulatory genes in the mouse embryonic germline in vivo. AB - Developmental regulatory genes have both activating (H3K4me3) and repressive (H3K27me3) histone modifications in embryonic stem cells (ESCs). This bivalent configuration is thought to maintain lineage commitment programs in a poised state. However, establishing physiological relevance has been complicated by the high number of cells required for chromatin immunoprecipitation (ChIP). We developed a low-cell-number chromatin immunoprecipitation (low-cell ChIP) protocol to investigate the chromatin of mouse primordial germ cells (PGCs). Genome-wide analysis of embryonic day 11.5 (E11.5) PGCs revealed H3K4me3/H3K27me3 bivalent domains highly enriched at developmental regulatory genes in a manner remarkably similar to ESCs. Developmental regulators remain bivalent and transcriptionally silent through the initiation of sexual differentiation at E13.5. We also identified >2,500 "orphan" bivalent domains that are distal to known genes and expressed in a tissue-specific manner but silent in PGCs. Our results demonstrate the existence of bivalent domains in the germline and raise the possibility that the somatic program is continuously maintained as bivalent, potentially imparting transgenerational epigenetic inheritance. PMID- 23727242 TI - FLT3-ITDs instruct a myeloid differentiation and transformation bias in lymphomyeloid multipotent progenitors. AB - Whether signals mediated via growth factor receptors (GFRs) might influence lineage fate in multipotent progenitors (MPPs) is unclear. We explored this issue in a mouse knockin model of gain-of-function Flt3-ITD mutation because FLT3-ITDs are paradoxically restricted to acute myeloid leukemia even though Flt3 primarily promotes lymphoid development during normal hematopoiesis. When expressed in MPPs, Flt3-ITD collaborated with Runx1 mutation to induce high-penetrance aggressive leukemias that were exclusively of the myeloid phenotype. Flt3-ITDs preferentially expanded MPPs with reduced lymphoid and increased myeloid transcriptional priming while compromising early B and T lymphopoiesis. Flt3-ITD induced myeloid lineage bias involved upregulation of the transcription factor Pu.1, which is a direct target gene of Stat3, an aberrantly activated target of Flt3-ITDs, further establishing how lineage bias can be inflicted on MPPs through aberrant GFR signaling. Collectively, these findings provide new insights into how oncogenic mutations might subvert the normal process of lineage commitment and dictate the phenotype of resulting malignancies. PMID- 23727243 TI - Chlamydia trachomatis inclusion membrane protein CT228 recruits elements of the myosin phosphatase pathway to regulate release mechanisms. AB - Chlamydia trachomatis replicates within a membrane-bound compartment termed an inclusion. The inclusion membrane is modified by the insertion of multiple proteins known as Incs. In a yeast two-hybrid screen, an interaction was found between the inclusion membrane protein CT228 and MYPT1, a subunit of myosin phosphatase. MYPT1 was recruited peripherally around the inclusion, whereas the phosphorylated, inactive form was localized to active Src-family kinase-rich microdomains. Phosphorylated myosin light chain 2 (MLC2), myosin light chain kinase (MLCK), myosin IIA, and myosin IIB also colocalized with inactive MYPT1. The role of these proteins was examined in the context of host-cell exit mechanisms (i.e., cell lysis and extrusion of intact inclusions). Inhibition of myosin II or small interfering RNA depletion of myosin IIA, myosin IIB, MLC2, or MLCK reduced chlamydial extrusion, thus favoring lytic events as the primary means of release. These studies provide insights into the regulation of egress mechanisms by C. trachomatis. PMID- 23727244 TI - Structural basis of actin filament nucleation by tandem W domains. AB - Spontaneous nucleation of actin is very inefficient in cells. To overcome this barrier, cells have evolved a set of actin filament nucleators to promote rapid nucleation and polymerization in response to specific stimuli. However, the molecular mechanism of actin nucleation remains poorly understood. This is hindered largely by the fact that actin nucleus, once formed, rapidly polymerizes into filament, thus making it impossible to capture stable multisubunit actin nucleus. Here, we report an effective double-mutant strategy to stabilize actin nucleus by preventing further polymerization. Employing this strategy, we solved the crystal structure of AMPPNP-actin in complex with the first two tandem W domains of Cordon-bleu (Cobl), a potent actin filament nucleator. Further sequence comparison and functional studies suggest that the nucleation mechanism of Cobl is probably shared by the p53 cofactor JMY, but not Spire. Moreover, the double-mutant strategy opens the way for atomic mechanistic study of actin nucleation and polymerization. PMID- 23727246 TI - In vitro biostability of poly(dimethyl siloxane/hexamethylene oxide)-based polyurethane/layered silicate nanocomposites. AB - We have prepared a number of silicone-based thermoplastic polyurethane (TPU) nanocomposites and demonstrated an enhancement of in vitro biostability against metal-ion-induced oxidation for potential use in long-term implantable medical devices. Organoclays based on both low-aspect-ratio hectorites and high-aspect ratio fluoromicas were evaluated after being dual-modified with two quaternary alkyl ammonium salts with differing degrees of polarity. The resultant nanocomposites were tested for in vitro biostability using physiologically relevant oxidizing conditions. Subsequently, the effects of oxidative treatment on the surface degradation and bulk mechanical integrity of the nanocomposites were investigated and compared with the parent TPUs to identify nanocomposites with the most desirable features for long-term implantation. Here, we demonstrate that the low-aspect-ratio organohectorite was delaminated and well dispersed in the nanocomposites. Importantly, these factors gave rise to the enhanced oxidative stability. In addition, the mechanical properties of all nanocomposites were less adversely affected by the oxidative treatment compared to their parent TPUs. These results suggest the potential for improved mechanical integrity and biostability when suitable dual modified organoclays are incorporated in a silicone-based TPU. PMID- 23727247 TI - Endocytotic uptake of iron oxide nanoparticles by cultured brain microglial cells. AB - Microglia are the phagocytotic cells of the brain that respond rapidly to alterations in brain homeostasis. Since iron oxide nanoparticles (IONPs) are used for diagnostic and therapeutic applications in the brain, the consequences of an exposure of microglial cells to IONPs are of particular interest. To address this topic we have synthesized and characterized fluorescent BODIPY(r)-labelled IONPs (BP-IONPs). The average hydrodynamic diameter and the zeta-potential of BP-IONPs in water were ~65 nm and -49 mV, respectively. Both values increased after dispersion of the particles in serum containing incubation medium to ~130 nm and 8 mV. Exposure of cultured rat microglial cells with BP-IONPs caused a time-, concentration- and temperature-dependent uptake of the particles, as demonstrated by strong increases in cellular iron contents and cellular fluorescence. Incubation for 3h with 150 and 450 MUM iron as BP-IONPs increased the cellular iron content from a low basal level of ~50 nmol iron mg(-1) to 219+/-52 and 481+/ 28 nmol iron (mg protein)(-1), respectively. These conditions did not affect cell viability, but exposure to higher concentrations of BP-IONPs or for longer incubation periods severely compromised cell viability. The BP-IONP fluorescence in viable microglial cells was co-localized with lysosomes. In addition, BP-IONP accumulation was lowered by 60% in the presence of the endocytosis inhibitors 5 (N-ethyl-N-isopropyl)amiloride, tyrphostin23 and chlorpromazin. These results suggest that the rapid accumulation of BP-IONPs by microglial cells is predominantly mediated by macropinocytosis and clathrin-mediated endocytosis, which direct the accumulated particles into the lysosomal compartment. PMID- 23727245 TI - Multisystem resiliency moderates the major depression-telomere length association: findings from the Heart and Soul Study. AB - Major depressive disorder (MDD) has been associated with reduced leukocyte telomere length (LTL). It is not known, however, whether psychosocial and behavioral protective factors moderate this association. In the current study, we examine whether multisystem resiliency--defined by healthy emotion regulation, strong social connections, and health behaviors (sleep and exercise)--predicts LTL and mitigates previously demonstrated associations between depression diagnosis and LTL. LTL was measured, using a quantitative PCR assay, in 954 patients with stable cardiovascular disease in the Heart and Soul Study. In a fully adjusted model, high multisystem resiliency predicted longer LTL (b=80.00, SE=27.17, p=.003), whereas each individual factor did not. Multisystem resiliency significantly moderated the MDD-LTL association (p=.02). Specifically, MDD was significantly related to LTL at 1 SD below the mean of multisystem resiliency (b= 142.86, SE=56.46, p=.01), but not at 1 SD above the mean (b=49.07, SE=74.51, p=.51). This study suggests that MDD associations with biological outcomes should be examined within a psychosocial-behavioral context, because this context shapes the nature of the direct relationship. Further research should explore the cognitive, neural, and other physiological pathways through which multisystem resiliency may confer biological benefit. PMID- 23727249 TI - Unannounced, compared with announced inspections: a systematic review and exploratory study in nursing homes. AB - Politicians and regulators have high expectations of unannounced inspections. Unannounced inspections, unlike announced ones, would, they believe, lead to a clearer insight into the risks and a reduction of the regulatory burden. In order to verify these assumptions, a systematic review of the scientific literature and an exploratory study were conducted. In the systematic review only three relevant articles were found concerned with research into the difference between unannounced and announced inspections. In the exploratory study, Dutch nursing homes were inspected, unannounced, and later announced, in order to compare the risks detected during the inspections. It is concluded that unannounced inspections did not reveal more or different risks, but provided a better insight into the quality of care delivered. Announced inspections are the best option for the assessment both of the organization and of its preconditions for good care. Evidence was found that an unannounced inspection leads to a reduction of the regulatory burden. PMID- 23727248 TI - New biotextiles for tissue engineering: development, characterization and in vitro cellular viability. AB - This work proposes biodegradable textile-based structures for tissue engineering applications. We describe the use of two polymers, polybutylene succinate (PBS) proposed as a viable multifilamentand silk fibroin (SF), to produce fibre-based finely tuned porous architectures by weft knitting. PBS is here proposed as a viable extruded multifilament fibre to be processed by a textile-based technology. A comparative study was undertaken using a SF fibre with a similar linear density. The knitted constructs obtained are described in terms of their morphology, mechanical properties, swelling capability, degradation behaviour and cytotoxicity. The weft knitting technology used offers superior control over the scaffold design (e.g. size, shape, porosity and fibre alignment), manufacturing and reproducibility. The presented fibres allow the processing of a very reproducible intra-architectural scaffold geometry which is fully interconnected, thus providing a high surface area for cell attachment and tissue in-growth. The two types of polymer fibre allow the generation of constructs with distinct characteristics in terms of the surface physico-chemistry, mechanical performance and degradation capability, which has an impact on the resulting cell behaviour at the surface of the respective biotextiles. Preliminary cytotoxicity screening showed that both materials can support cell adhesion and proliferation. These results constitute a first validation of the two biotextiles as viable matrices for tissue engineering prior to the development of more complex systems. Given the processing efficacy and versatility of the knitting technology and the interesting structural and surface properties of the proposed polymer fibres it is foreseen that the developed systems could be attractive for the functional engineering of tissues such as skin, ligament, bone or cartilage. PMID- 23727250 TI - Health professionals' adherence to stroke clinical guidelines: a review of the literature. AB - BACKGROUND: The process of implementation of clinical guidelines i.e. getting guidelines into practice has been extensively reviewed and meta-reviewed from a generic perspective. However, in relation to stroke care, there has been no review of these studies to date, although implementing stroke clinical guidelines is a topic of great interest within the stroke literature. This review aims to identify stroke studies that have addressed adherence to generic and specific stroke care clinical guidelines. METHOD: A computer search was conducted using PubMed, CINAHL, PsychINFO, Web of Science and the Cochrane Systematic Reviews databases. Search terms included those relevant to the implementation of stroke clinical guidelines. We assessed all studies retrieved against specific inclusion criteria and collated only those studies that emphasized adherence to stroke clinical guidelines. RESULTS: Eighty-eight articles were selected for further review from 153 articles retrieved. Of those, 27 were studies on adherence to stroke clinical guidelines and were included in this review - 16 were categorized as generic stroke guidelines and 11 were on specific aspects of stroke care. Each category was further divided into studies that assessed adherence to stroke guidelines only and those that intervened to improve adherence. Adherence was generally greater for studies that included an intervention. Specific stroke care guidelines were poorly adhered to compared to generic stroke guidelines but these studies were better at identifying organizational and team barriers to implementation. Most studies conducted audits of patient medical records and a limited number assessed health professionals' views or used a behavioural framework to assess adherence. DISCUSSION: Adherence to stroke guidelines varied in the studies reviewed. Given the evidence that implementation of clinical guidelines in stroke care leads to better quality of care and improved health outcomes for patients, there is a need to increase adherence behaviours of health professionals towards recommended guidelines, in particular for long term stroke care. PMID- 23727251 TI - Development of micellar reactive oxygen species assay for photosafety evaluation of poorly water-soluble chemicals. AB - A reactive oxygen species (ROS) assay was previously developed for photosafety assessment; however, the phototoxic potential of some chemicals cannot be evaluated because of their limited aqueous solubility. The present study was undertaken to develop a new micellar ROS (mROS) assay system for poorly water soluble chemicals using a micellar solution of 0.5% (v/v) Tween 20 for solubility enhancement. In repeated mROS assay, intra- and inter-day precisions (coefficient of variation) were found to be below 11%, and the Z'-factors for singlet oxygen and superoxide suggested a large separation band between positive and negative standards. The ROS and mROS assays were applied to 65 phototoxins and 18 non phototoxic compounds for comparative purposes. Of all 83 chemicals, 25 were unevaluable in the ROS assay due to poor solubility, but only 2 were in the mROS assay. Upon mROS assay on these model chemicals, the individual specificity was 76.5%, and the positive and negative predictivities were found to be 93.9% and 86.7%, respectively. The mROS assay provided 2 false negative predictions, although negative predictivity for the ROS assay was found to be 100%. Considering the pros and cons of these assays, strategic combined use of the ROS and mROS assays might be efficacious for reliable photosafety assessment with high applicability and predictivity. PMID- 23727252 TI - Assessment of in vitro cellular responses of monocytes and keratinocytes to tannic acid modified silver nanoparticles. AB - Hydrolyzable tannins are known to exhibit diverse biological effects, which can be used in combination with silver nanoparticles (AgNPs). In this study, we tested toxic and inflammatory properties of tannic-acid modified 13, 33, 46 nm and unmodified 10-65 nm AgNPs using murine 291.03C keratinocyte and RAW 264.7 monocyte cell lines. Both cell lines exposed for 24h to 1-10 MUg/ml of 13 nm, 33 nm, 46 nm and unmodified AgNPs showed dose-dependent toxicity and decreased cell proliferation. Only small-sized AgNPs induced production of ROS by monocytes, but not keratinocytes. Monocytes internalized large aggregates of 33, 46 nm and 10-65 nm AgNPs in cytoplasmic vacuoles, whereas keratinocytes accumulated less particles. AgNPs of 13 nm were localized ubiquitously within both cell types. The tested AgNPs strongly down-regulated production of tumor necrosis factor-alpha (TNF-alpha) by monocytes, whereas keratinocytes exposed to AgNPs showed an opposite effect. Unmodified but not tannic acid-modified AgNPs increased production of the pro-inflammatory MCP-1 by monocytes and keratinocytes. In summary, low inflammatory potential and lack of ROS production by tannic-acid modified AgNPs sized above 30 nm suggests that tannic acid modification of large silver nanoparticles may help to increase AgNPs biosafety. PMID- 23727253 TI - Postnatal testosterone levels and disorder relevant behavior in the second year of life. AB - The objective of the current study was to investigate the relationship between testosterone collected at 3-4 months of age and sex-linked disorder-relevant behaviors in the second year of life. Eighty-four children participated at 3-4 (when salivary testosterone levels were obtained and second to fourth digit ratios were measured) and 18-24 months of age (when behavioral ratings of aggression and verbal ability were coded from two 8-min play sessions). Parents also completed the Brief Infant-Toddler Social and Emotional Assessment, and the four subscales (Internalizing, Externalizing, Dysregulation, and Autism Spectrum Disorder) were used to indicate child specific problems. Greater postnatal testosterone levels in early infancy were predictive of more male-typical behaviors in the second year of life (i.e., more autism spectrum behaviors, less time vocalizing, and more Internalizing Problems). These results support the hypothesis that early infancy may be another critical period for the development of gender-linked behavior. PMID- 23727254 TI - Enhanced production of recombinant thermo-stable lipase in Escherichia coli at high induction temperature. AB - Thermostable microbial lipases are potential candidates for industrial applications such as specialty organic syntheses as well as hydrolysis of fats and oils. In this work, basic biochemical engineering tools were applied to enhance the production of BTL2 lipase cloned in Escherichia coli BL321 under control of the strong temperature-inducible lambdaP(L) promoter. Initially, surface response analysis was used to assess the influence of growth and induction temperatures on enzyme production, in flask experiments. The results showed that temperatures of 30 and 45 degrees C were the most suitable for growth and induction, respectively, and led to an enzyme specific activity of 706,000 U/gDCW. The most promising induction conditions previously identified were validated in fed-batch cultivation, carried out in a 2L bioreactor. Specific enzyme activity reached 770,000 U/gDCW, corresponding to 13,000 U/L of culture medium and a lipase protein concentration of 10.8 g/L. This superior performance on enzyme production was a consequence of the improved response of lambdaP(L) promoter triggered by the high induction temperature applied (45 degrees C). These results point out to the importance of taking into account protein structure and stability to adequately design the recombinant protein production strategy for thermally induced promoters. PMID- 23727255 TI - The effects of multivitamin supplementation on mood and general well-being in healthy young adults. A laboratory and at-home mobile phone assessment. AB - Previous research has suggested that multivitamin (MV) supplementation may be associated with beneficial effects for mood and general well-being, although treatment durations have typically been less than 90 days, samples have often been restricted to males only and acute effects have not been adequately differentiated from chronic effects. In the current study a MV supplement containing high levels of B-vitamins was administered daily to 138 healthy young adult participants between the ages of 20 and 50 years over a 16-week period. Chronic mood measures (GHQ-28, POMS, Chalder fatigue, PILL, Bond-Lader and custom visual analogue scales) were administered pre-dose at baseline, 8- and 16-weeks. Changes in Bond-Lader and VAS in response to a multi-tasking framework (MTF) were also assessed at 8- and 16-weeks. For a subset of participants, at-home mobile phone assessments of mood were assessed on a weekly basis using Bond-Lader and VAS. No significant treatment effects were found for any chronic laboratory mood measures. In response to the MTF, a significant treatment x time interaction was found for STAI-S, with a trend towards a greater increase in stress ratings for male participants in the MV group at 16 weeks. However, this finding may have been attributable to a larger proportion of students in the male MV group. In contrast, at-home mobile-phone assessments, where assessments were conducted post dose, revealed significantly reduced stress, physical fatigue and anxiety in the MV group in comparison to placebo across a number of time points. Further research using both acute and chronic dosing regimens are required in order to properly differentiate these effects. PMID- 23727256 TI - Using a smaller dining plate does not suppress food intake from a buffet lunch meal in overweight, unrestrained women. AB - The aim of the study was to determine whether plate size affects ad libitum energy intake (EI) at a buffet-style lunch in overweight, yet unrestrained women. Twenty overweight/obese (BMI=25-40 kg/m(2)) women attended two study visits, and were randomly assigned to small (19.5 cm) or large (26.5 cm) diameter plate size at a free choice lunch meal. At 9 am participants were given a small (0.5 MJ) breakfast, followed at 12 noon by the lunch meal from which they ate ad lib until comfortably full. Mean (SEM) EI at lunch was 3975 (239)kJ and 3901 (249) kJ respectively for small and large plate size. There was no detectable difference in EI between the two plate sizes (P>0.05). When in a raised state of hunger and offered a palatable buffet meal, altering the diameter of the dining plate onto which food was self-served did not significantly alter ad lib EI. We conclude there was no evidence that a smaller plate suppressed EI in a group of unrestrained, overweight women encouraged to eat to appetite from a wide choice of items. Whether plate size is a useful cue for portion size, and hence control of EI, in individuals actively restricting intake however remains possible, and requires investigation. PMID- 23727257 TI - A randomized phase II study of docetaxel with or without vandetanib in recurrent or metastatic squamous cell carcinoma of head and neck (SCCHN). AB - OBJECTIVES: There are limited chemotherapeutic options for advanced recurrent or metastatic SCCHN. The efficacy and toxicity of docetaxel with or without vandetanib was investigated in these patients. MATERIALS AND METHODS: Patients with pathologically confirmed, recurrent or metastatic SCCHN who had progressed on platinum based therapy given as definitive or palliative treatment, were randomized in this open label, multicenter phase II study of docetaxel (75 mg/m2 IV Q3 weeks) with or without vandetanib (100 mg PO daily). The primary objective was response rate (RR) and secondary objectives were progression free survival (PFS), overall survival (OS), disease control rate (DCR) and duration of response (DOR). RESULTS: 29 analyzable patients were enrolled, 14 in docetaxel arm and 15 in combined arm. PR was achieved in 1 patient in the docetaxel arm and 2 patients in the combined arm. The objective RR was 7% (1/14) (95% CI 0.2-33.8%) in the single and 13% (2/15) (95% CI 1.6-40.4%) combined arm. The median PFS was 3.21 (95% CI 3.0-22.0) and 9 (95% CI (5.86-18.1) weeks; median OS was 26.8(95% CI 17.7 100.7+) and 24.1 (95% CI, 16.4-171.1+) weeks. Most common adverse events were fatigue, dysphagia, diarrhea or constipation, cytopenias and alopecia. CONCLUSIONS: Although an initial benefit in response was noted and statistical criteria met there was only a minor trend towards improved PFS for the combined arm. The study was designed with low threshold for activity in each arm and results were deemed not to be of enough clinical significance in this group of patients to continue accrual. PMID- 23727258 TI - Vitellogenins increase stress resistance of Caenorhabditis elegans after Photorhabdus luminescens infection depending on the steroid-signaling pathway. AB - Resistance against environmental stress is a crucial factor in determining the lifespan of organisms. A central role herein has been recently attributed to the transport and storage of lipids with the vitellogenin family emerging as a potential key factor. Here we show that the knockdown of one out of five functional vitellogenin genes, encoding apolipoprotein B homologues, results in a reduced survival of the nematode Caenorhabditis elegans at 37 degrees C subsequent to infection with the bacterial pathogen Photorhabdus luminescens. An active steroid-signaling pathway, including supply of cholesterol by vitellogenins, steroid ligand formation by the cytochrome P450 dependent DAF-9, and activation of the nuclear hormone receptor DAF-12, in the presence of pathogenic bacteria was associated with reduced nuclear translocation of the forkhead transcription factor DAF-16 and increased antioxidative capacity. Taken together, the study provides functional evidence for a crucial role of vitellogenins and the steroid-signaling pathway in determination of resistance against bacteria. PMID- 23727259 TI - Human stem cell-based three-dimensional microtissues for advanced cardiac cell therapies. AB - Cardiac stem cell therapy has been proposed as a therapy option to treat the diseased myocardium. However, the low retention rate of transplanted single-cell suspensions remains a major issue of current therapy strategies. Therefore, the concept of scaffold-free cellular self-assembly into three-dimensional microtissues (3D-MTs) prior to transplantation may be beneficial to enhance retention and survival. We compared clinically relevant, human stem cell sources for their ability to generate 3D-MTs with particular regards to formation characteristics, proliferation-activity, viability and extracellular-matrix production. Single-cell suspensions of human bone marrow- and adipose tissue derived mesenchymal stem cells (hBMMSCs and hATMSCs), Isl1(+) cardiac progenitors derived from human embryonic stem cells (hESC-Isl1(+) cells), and undifferentiated human induced pluripotent cells (hiPSCs) were characterized before to generate 3D-MTs using a hanging-drop culture. Besides the principal feasibility of cell-specific 3D-MT formation, a detailed head-to-head comparison between cell sources was performed using histology, immunocyto- and histo chemistry as well as flow cytometry. Round-oval shaped and uniform 3D-MTs could be successfully generated from all cell types starting with a loose formation within the first 24 h that fully stabilized after 3 days and resulting in a mean 3D-MT diameter of 194.56 +/- 18.01 MUm (hBMMSCs), 194.56 +/- 16.30 MUm (hATMSCs), 159.73 +/- 19.20 MUm (hESC-Isl1(+) cells) and 120.95 +/- 7.97 MUm (hiPSCs). While all 3D-MTs showed a homogenous cell distribution, hiPSC-derived 3D-MTs displayed a compact cell formation primarily located at the outer margin. hESC-Isl1(+) and hiPSC-derived 3D-MTs maintained their proliferation-activity which was rather limited in the MSC-based 3D-MTs. All four 3D-MT types revealed a comparable viability in excess of 70% and showed a cell-specific expression profile being comparable to their single-cell counterparts. Extracellular matrix (ECM) production during 3D-MT formation was observed for all cell-specific 3D-MTs, with hiPSC-derived 3D-MTs being the fastest one. Interestingly, ECM distribution was homogenous for hATMSC- and hiPSC-based 3D-MTs, while it appeared to be primarily concentrated within in the center of hESC-Isl1(+) and hBMMSC-based 3D-MTs. The results of this head-to-head comparative study indicated that 3D-MTs can be successfully generated from hESC-derived Isl1(+) cells, hiPSCs and MSC lines upon hanging drop culture. Cell-specific 3D-MTs displayed sufficient viability and instant ECM formation. The concept of 3D-MT in vitro generation prior to cell transplantation may represent a promising delivery format for future strategies to enhance cellular engraftment and survival. PMID- 23727260 TI - Expression of the alpha5 integrin gene in corneal epithelial cells cultured on tissue-engineered human extracellular matrices. AB - The integrin alpha5beta1 plays a major role in corneal wound healing by promoting epithelial cell adhesion and migration over the fibronectin matrix secreted as a cellular response to corneal damage. Expression of alpha5 is induced when rabbit corneal epithelial cells (RCECs) are grown in the presence of fibronectin. Here, we examined whether alpha5 expression is similarly altered when RCECs or human corneal epithelial cells (HCECs) are grown on a reconstructed stromal matrix used as an underlying biomaterial. Mass spectrometry and immunofluorescence analyses revealed that the biomaterial matrix produced by culturing human corneal fibroblasts with ascorbic acid (ECM/35d) contains several types of collagens, fibronectin, tenascin and proteoglycans. Results from transfection of CAT/alpha5 promoter plasmids, Western blot and EMSA analyses indicated that ECM/35d significantly increase expression of alpha5 in HCECs as a result of alteration in the expression and DNA binding of the transcription factors NFI, Sp1, AP-1 and PAX6. The biological significance of this biomaterial substitute on the expression of the alpha5 gene may therefore contribute to better understand the function played by the alpha5beta1 integrin during corneal wound healing. PMID- 23727261 TI - Gene transfection efficacy and biocompatibility of polycation/DNA complexes coated with enzyme degradable PEGylated hyaluronic acid. AB - Coating the polycation/DNA binary complexes with PEGylated polyanions can improve long-circulation and biocompatibility in vivo. However, it has been certificated PEG dilemma can reduces gene transfection efficiency because of inhibition in cellular uptake and endosomal escape. Herein, two PEGylated anionic polymers, PEGylated hyaluronic acid (HgP) and PEGylated polyglutamic acid (PGgP) were synthesized to coat the binary complexes of core-shell cationic polycaprolactone graft-poly (N, N-dimethylaminoethyl methacrylate) nanoparticles/DNA (NP-D). The effects of polyanion structure were evaluated in terms of particle size, zeta potential, cytotoxicity, cellular uptake and transfect efficiency in vitro and in vivo. In vitro study illustrated that HgP coated complexes showed better efficiencies in both cell uptake and transfection than PGgP coated complexes. The coating of HgP on NP-D improved the biocompatibility without reduction in cell uptake and transfection efficacy, and resulted in higher accumulation and gene expression in tumor after IV injection. The success of HgP coating in overcoming PEG dilemma is attributed to the hyaluronic acid (HA)-receptor-mediated endocytosis and outer shell-detachment through the hyaluronidases catalyzed degradation of HA. These results demonstrated that HgP was a promising anionic polymer for coating the polycation/DNA complexes and ternary complexes (HgP coated NP-D) hold promising potential for cancer therapy. PMID- 23727262 TI - A review of the current status of siRNA nanomedicines in the treatment of cancer. AB - RNA interference currently offers new opportunities for gene therapy by the specific extinction of targeted gene(s) in cancer diseases. However, the main challenge for nucleic acid delivery still remains its efficacy through intravenous administration. Over the last decade, many delivery systems have been developed and optimized to encapsulate siRNA and to specifically promote their delivery into tumor cells and improve their pharmacokinetics for anti-cancer purposes. This review aims to sum up the potential targets in numerous pathways and the properties of recently optimized siRNA synthetic nanomedicines with their preclinical applications and efficacy. Future perspectives in cancer treatment are discussed including promising concomitant treatment with chemotherapies or other siRNA. The outcomes in human clinical trials are also presented. PMID- 23727263 TI - Preservation of micro-architecture and angiogenic potential in a pulmonary acellular matrix obtained using intermittent intra-tracheal flow of detergent enzymatic treatment. AB - Tissue engineering of autologous lung tissue aims to become a therapeutic alternative to transplantation. Efforts published so far in creating scaffolds have used harsh decellularization techniques that damage the extracellular matrix (ECM), deplete its components and take up to 5 weeks to perform. The aim of this study was to create a lung natural acellular scaffold using a method that will reduce the time of production and better preserve scaffold architecture and ECM components. Decellularization of rat lungs via the intratracheal route removed most of the nuclear material when compared to the other entry points. An intermittent inflation approach that mimics lung respiration yielded an acellular scaffold in a shorter time with an improved preservation of pulmonary micro architecture. Electron microscopy demonstrated the maintenance of an intact alveolar network, with no evidence of collapse or tearing. Pulsatile dye injection via the vasculature indicated an intact capillary network in the scaffold. Morphometry analysis demonstrated a significant increase in alveolar fractional volume, with alveolar size analysis confirming that alveolar dimensions were maintained. Biomechanical testing of the scaffolds indicated an increase in resistance and elastance when compared to fresh lungs. Staining and quantification for ECM components showed a presence of collagen, elastin, GAG and laminin. The intratracheal intermittent decellularization methodology could be translated to sheep lungs, demonstrating a preservation of ECM components, alveolar and vascular architecture. Decellularization treatment and methodology preserves lung architecture and ECM whilst reducing the production time to 3 h. Cell seeding and in vivo experiments are necessary to proceed towards clinical translation. PMID- 23727264 TI - Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. AB - BACKGROUND & AIMS: Obeticholic acid (OCA; INT-747, 6alpha-ethyl-chenodeoxycholic acid) is a semisynthetic derivative of the primary human bile acid chenodeoxycholic acid, the natural agonist of the farnesoid X receptor, which is a nuclear hormone receptor that regulates glucose and lipid metabolism. In animal models, OCA decreases insulin resistance and hepatic steatosis. METHODS: We performed a double-blind, placebo-controlled, proof-of-concept study to evaluate the effects of OCA on insulin sensitivity in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. Patients were randomly assigned to groups given placebo (n = 23), 25 mg OCA (n = 20), or 50 mg OCA (n = 21) once daily for 6 weeks. A 2-stage hyperinsulinemic-euglycemic insulin clamp was used to measure insulin sensitivity before and after the 6-week treatment period. We also measured levels of liver enzymes, lipid analytes, fibroblast growth factor 19, 7alpha-hydroxy-4-cholesten-3-one (a BA precursor), endogenous bile acids, and markers of liver fibrosis. RESULTS: When patients were given a low-dose insulin infusion, insulin sensitivity increased by 28.0% from baseline in the group treated with 25 mg OCA (P = .019) and 20.1% from baseline in the group treated with 50 mg OCA (P = .060). Insulin sensitivity increased by 24.5% (P = .011) in combined OCA groups, whereas it decreased by 5.5% in the placebo group. A similar pattern was observed in patients given a high-dose insulin infusion. The OCA groups had significant reductions in levels of gamma-glutamyltransferase and alanine aminotransferase and dose-related weight loss. They also had increased serum levels of low-density lipoprotein cholesterol and fibroblast growth factor 19, associated with decreased levels of 7alpha-hydroxy-4-cholesten-3-one and endogenous bile acids, indicating activation of farnesoid X receptor. Markers of liver fibrosis decreased significantly in the group treated with 25 mg OCA. Adverse experiences were similar among groups. CONCLUSIONS: In this phase 2 trial, administration of 25 or 50 mg OCA for 6 weeks was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Longer and larger studies are warranted. ClinicalTrials.gov, Number: NCT00501592. PMID- 23727266 TI - Chaperone-interacting TPR proteins in Caenorhabditis elegans. AB - The ATP-hydrolyzing molecular chaperones Hsc70/Hsp70 and Hsp90 bind a diverse set of tetratricopeptide repeat (TPR)-containing cofactors via their C-terminal peptide motifs IEEVD and MEEVD. These cochaperones contribute to substrate turnover and confer specific activities to the chaperones. Higher eukaryotic genomes encode a large number of TPR-domain-containing proteins. The human proteome contains more than 200 TPR proteins, and that of Caenorhabditis elegans, about 80. It is unknown how many of them interact with Hsc70 or Hsp90. We systematically screened the C. elegans proteome for TPR-domain-containing proteins that likely interact with Hsc70 and Hsp90 and ranked them due to their similarity with known chaperone-interacting TPRs. We find C. elegans to encode many TPR proteins, which are not present in yeast. All of these have homologs in fruit fly or humans. Highly ranking uncharacterized open reading frames C33H5.8, C34B2.5 and ZK370.8 may encode weakly conserved homologs of the human proteins RPAP3, TTC1 and TOM70. C34B2.5 and ZK370.8 bind both Hsc70 and Hsp90 with low micromolar affinities. Mutation of amino acids involved in EEVD binding disrupts the interaction. In vivo, ZK370.8 is localized to mitochondria in tissues with known chaperone requirements, while C34B2.5 colocalizes with Hsc70 in intestinal cells. The highest-ranking open reading frame with non-conserved EEVD-interacting residues, F52H3.5, did not show any binding to Hsc70 or Hsp90, suggesting that only about 15 of the TPR-domain-containing proteins in C. elegans interact with chaperones, while the many others may have evolved to bind other ligands. PMID- 23727267 TI - Adaptation to facial trustworthiness is different in female and male observers. AB - Face adaptation paradigms have been used extensively to investigate the mechanisms underlying the processing of several different facial characteristics including face shape, identity, view and emotional expression. Judgements of facial trustworthiness can also be influenced by visual adaptation; to date these (un)trustworthy face aftereffects have only been shown following adaptation to emotional expression and facial masculinity/femininity. In this study we assessed how exposure to trustworthy and untrustworthy faces influenced the perception of the trustworthiness of subsequent test faces. In a mixed factorial design experiment, we tested the influence of adaptation to female and male faces on the perception of subsequent female and male faces in both female and male observers. In female observers, we found that following adaptation to trustworthy and untrustworthy faces subsequent test faces appeared less like the adapting stimuli. Sex of the adapting and test faces did not have significant influence on these (un)trustworthy face aftereffects. In male observers, however, we found no significant influence of the effect of adaptation on the subsequent perception of face trustworthiness. The clear difference in the visual aftereffects induced in female and male observers indicates the operation of different mechanisms underlying the perception of facial trustworthiness, and future studies should investigate these mechanisms separately in female and male observers. PMID- 23727265 TI - Mediator complex dependent regulation of cardiac development and disease. AB - Cardiovascular disease (CVD) is a leading cause of morbidity and mortality. The risk factors for CVD include environmental and genetic components. Human mutations in genes involved in most aspects of cardiovascular function have been identified, many of which are involved in transcriptional regulation. The Mediator complex serves as a pivotal transcriptional regulator that functions to integrate diverse cellular signals by multiple mechanisms including recruiting RNA polymerase II, chromatin modifying proteins and non-coding RNAs to promoters in a context dependent manner. This review discusses components of the Mediator complex and the contribution of the Mediator complex to normal and pathological cardiac development and function. Enhanced understanding of the role of this core transcriptional regulatory complex in the heart will help us gain further insights into CVD. PMID- 23727268 TI - Simulation and measurement of characteristics of MICROMEGAS gaseous detectors. AB - MICROMEGAS detectors have been developed for the detection and tracking of charged and neutral particles. The control parameters of MICROMEGAS include materials, the type of gases, the mixing ratio of gases and the geometry. Simulations of MICROMEGAS are conducted to optimize the characteristics and performance with respect to the nature of the gas mixture, applied voltages of drift and amplification regions. Quantities such as the equi-potential lines, electron drift lines, and avalanche process of electrons and ions are calculated. Two MICROMEGAS detectors are built and characterized by using standard X-ray sources. The voltage gains are measured against the applied voltage range for different gas pressures and are compared with our simulation results. PMID- 23727270 TI - Ectopic bone formation in severely combat-injured orthopedic patients -- a hematopoietic niche. AB - Combat-related heterotopic ossification (HO) has emerged as a common and problematic complication of modern wartime extremity injuries, contributing to substantial patient morbidity and loss of function. We have previously reported that HO-forming patients exhibit a more pronounced systemic and local inflammatory response very early in the wound healing process. Moreover, traumatized muscle-derived mesenchymal progenitor cells from these patients have a skewed differentiation potential toward bone. Here, we demonstrate that HO lesions excised from this patient population contain highly vascularized, mature, cancellous bone containing adipogenic marrow. Histologic analysis showed immature hematopoietic cells located within distinct foci in perivascular regions. The adipogenic marrow often contained low numbers of functional erythroid (BFU-E), myeloid (CFU-GM, CFU-M) and multilineage (CFU-GEMM) colony-forming hematopoietic progenitor cells (HPCs). Conversely, tissue from control muscle and non-HO traumatic wound granulation tissue showed no evidence of hematopoietic progenitor cell activity. In summary, our findings suggest that ectopic bone can provide an appropriate hematopoietic microenvironment for supporting the proliferation and differentiation of HPCs. This reactive and vibrant cell population may help maintain normal hematopoietic function, particularly in those with major extremity amputations who have sustained both massive blood loss, prompting systemic marrow stimulation, as well as loss of available native active marrow space. These findings begin to characterize the functional biology of ectopic bone and elucidate the interactions between HPC and non-hematopoietic cell types within the ectopic intramedullary hematopoietic microenvironmental niche identified. PMID- 23727271 TI - Early treatment with inhaled antibiotics postpones next occurrence of Achromobacter in cystic fibrosis. AB - OBJECTIVES: In this nationwide retrospective study, we analysed species distribution, antimicrobial susceptibility and time to next occurrence of Achromobacter in Danish cystic fibrosis (CF) patients from 2000 to 2011. METHODS: Thirty-four primary isolates were identified to species level and subjected to antimicrobial susceptibility testing. Effectiveness of early antimicrobial treatment was assessed by a Kaplan-Meier estimation of time to recurrence. RESULTS: Achromobacter xylosoxidans accounted for 13 (38%) of the isolates, and an unnamed species accounted for 11 (32%) of the isolates. Meropenem, piperacillin-tazobactam and trimethoprim-sulfamethoxazole were highly active against chemotherapy-naive Achromobacter, while ceftazidime, colistin and tobramycin were judged adequate for inhalation therapy. Fifty-five percent of 25 patients treated with inhaled ceftazidime, colistin, or tobramycin remained free of Achromobacter three years after acquisition, in contrast to 17% of 22 patients who did not receive inhaled antibiotics (P<0.01). CONCLUSIONS: Early treatment with inhaled antibiotics may prevent or postpone chronic infection with Achromobacter in CF patients. PMID- 23727272 TI - On the definition and measurement of pleiotropy. PMID- 23727269 TI - Mechanosensitive microRNAs-role in endothelial responses to shear stress and redox state. AB - Endothelial functions are highly regulated by imposed shear stress in vivo. The characteristics of shear stress determine mechanotransduction events that regulate phenotypic outcomes including redox and inflammatory states. Recent data indicate that microRNAs (miRs) in vascular endothelial cells play an essential role in shear stress-regulated endothelial responses. More specifically, atheroprotective pulsatile flow (PS) induces miRs that inhibit mediators of oxidative stress and inflammation while promoting those involved in maintaining vascular homeostasis. Conversely, oscillatory flow (OS) elicits the opposing networks. This is exemplified by the PS-responsive transcription factor Kruppel like factor 2 (KLF2), which regulates miR expression but is also regulated by OS sensitive miRs to ultimately regulate the oxidative and inflammatory state of the endothelium. In this review, we outline important findings demonstrating the multifaceted roles of shear stress-regulated miRs in endothelial redox and inflammatory balance. Furthermore, we discuss the use of algorithms in deciphering signaling networks differentially regulated by PS and OS. PMID- 23727273 TI - Common onion (Allium cepa) extract reverses cadmium-induced organ toxicity and dyslipidaemia via redox alteration in rats. AB - BACKGROUND: Cadmium (Cd) remains an important environmental pollutant of public health concern as it causes organ toxicity, and cardiovascular diseases (CVD), but the roles of common foods such as onion (Allium cepa) need further clarification. The aims of this study were to clarify whether or not Cd-induced organ dysfunction was associated with blood protein, lipid and lipid peroxidation and the effects of onion extract AcE in a rat model. METHODS: Control and Cd treated rats were maintained on control diet, while AcE+Cd-treated rats were also orally administered AcE (1ml/100g body weight). Cd-treated and AcE+Cd-treated rats also received cadmium as CdSO4 (1.5ml/kg body weight of 0.3mg/L of CdSO4) via drinking water. RESULTS: It was found that Cd significantly increased total cholesterol, triglycerides, LDL-cholesterol, serum albumin, and reduced HDL cholesterol, total plasma protein, and plasma testosterone. Administration of AcE restored the liver and kidney toxicities and blood protein and lipid profiles. Moreover, AcE improved Cd-induced decrease in urinary volume and renal clearance, and also protected against Cd-induced oxidative stress by normalizing redox status. However, AcE did not affect Cd-induced altered plasma testosterone. CONCLUSION: Our study suggests that Cd-induced CVD was associated with altered blood dysproteinemia, dyslipidaemia, and oxidative stress. It also provided the first evidence of the therapeutic efficacy of AcE against atherosclerotic conditions and organ toxicity in Cd-intoxicated rats via a mechanism independent of the circulating testosterone level. PMID- 23727274 TI - Influence of repeated maximal exercise testing on biomarkers and fatigue in sarcoidosis. AB - Fatigue in the immune mediated inflammatory disease sarcoidosis is thought to be associated with impaired exercise tolerance. This prospective study assessed fatigue and recuperative capacity after repeated exercise, and examined whether changing concentrations in biomarkers upon exercise are associated with fatigue. Twenty sarcoidosis patients and 10 healthy volunteers performed maximal cardiopulmonary exercise tests on two successive days. Concentrations of cytokines, stress hormones, ACE and CK were assessed before and after the two exercise tests, and 3 days thereafter. All participants completed a sleep diary. Severely fatigued patients showed significant lower VO2 max (p=0.038, p=0.022) and maximal workload (p=0.034, p=0.028) on both exercise tests compared to healthy controls. No impairment of maximal exercise testing was demonstrated during the second cycling test in any group. Fatigue was not correlated with changes in concentrations of biomarkers upon exercise. Severely fatigued patients rated both tests as significantly more fatiguing, and reported significant lower mean subjective night sleeping time during the testing period. Fatigue in sarcoidosis patients cannot be objectified by reduction of exercise capacity after repeated maximal exercise testing, and is not correlated with significant changes in biomarkers. Severe fatigue is only and consistently featured by patient reported outcomes. PMID- 23727275 TI - Liver and lymph node metastases of prostate cancer visualized on post-therapy imaging after treatment with 188Re-HEDP. PMID- 23727276 TI - Non-invasive monitoring of glucocorticoid physiology within highland and lowland populations of native Australian Great Barred Frog (Mixophyes fasciolatus). AB - This study used non-invasive endocrinology to examine baseline corticosterone at different altitudes in a free-living Australian amphibian: the Great Barred Frog (Mixophyes fasciolatus). An enzyme immunoassay (EIA) was performed on urine samples and validated biologically using an adrenocorticotropic hormone (ACTH) challenge. Frogs were injected with ACTH on day 0 and recaptures occurred 1 10days post injection. Urine samples and body condition measurements were collected from lowland (60m) and highland (660m and 790m) sub-populations of M. fasciolatus in South East Queensland (SEQ), close to their post-breeding period during autumn 2011. We simultaneously sampled these sub-populations for Batrachochytrium dendrobatidis (Bd), a pathogenic fungus responsible for mass mortalities of amphibians worldwide. The ACTH challenge successfully validated the urinary corticosterone EIA in M. fasciolatus, with a peak urinary corticosterone response to ACTH injection on day 2 and a return to baseline levels by day 6. Polymerase chain reaction (PCR) analysis of 50 individuals returned only 1 positive result for Bd. Simple linear regression showed a strong positive relationship between baseline urinary corticosterone concentrations and altitude and no relationship with body condition. We hypothesize that higher baseline corticosterone concentrations within highland sub-populations of male M. fasciolatus could be associated with increased environmental challenge at high altitudes and geographic range limits. Whether this pattern is an indication of chronic stress in highland populations or life-time fitness and survival, warrants future investigation. PMID- 23727277 TI - Brief endocardial surge of Ca2+ transient but monotonic suppression of action potential occurs during acute ischemia in canine ventricular tissue. AB - BACKGROUND: Ischemia suppresses action potentials (APs) by elevating interstitial K(+) and activating KATP channels and alters cytosolic Ca(2+) transients (CaTs) via metabolic inhibition. OBJECTIVE: To test the hypothesis that AP and CaT respond to ischemia with different spatiotemporal courses and patterns. METHODS: Thirty-four transmural wedges were isolated from canine left ventricular free walls, perfused arterially, and stained with voltage- and Ca(2+)-sensitive dyes. Twenty-eight wedges underwent 15 minutes of arterial occlusion during pacing at a cycle length (PCL) of 300 ms (n = 19) or 600 ms (n = 9). Six other wedges had a sequential reduction of perfusion flow from full to 50%, 25%, and 10% at 300 ms PCL. AP and CaT were recorded on the cut-exposed transmural surfaces with an optical mapping system. RESULTS: Although ischemia suppressed APs, it enhanced CaT to 150% +/- 10% (more in the endocardium than in the epicardium) and induced CaT alternans during the first 2 minutes of arterial occlusion and then suppressed CaT (PCL = 300 ms). Enhancement of CaT (to 159% +/- 23%) also occurred during low flow (25%) perfusion (PCL = 300 ms). Faster suppression of AP occurred with subepicardial preference as compared to that of CaT. After 15 minutes of arterial occlusion, AP and CaT remained in only small regions during 300 ms PCL but were preserved in most regions during 600 ms PCL. CONCLUSIONS: Early ischemia induced a surge and alternans in CaT and caused its dissociation from AP both in time course of suppression and in spatial distribution. These results suggested that there were different cellular regulatory mechanisms of AP and of CaT in responding to ischemia from arterial occlusion. PMID- 23727278 TI - Extra precision docking, free energy calculation and molecular dynamics simulation studies of CDK2 inhibitors. AB - Molecular docking, free energy calculation and molecular dynamics (MD) simulation studies have been performed, to explore the putative binding modes of 3,5 diaminoindazoles, imidazo(1,2-b)pyridazines and triazolo(1,5-a) pyridazines series of Cyclin-dependent kinase (CDK2) inhibitors. To evaluate the effectiveness of docking protocol in flexible docking, we have selected crystallographic bound compound to validate our docking procedure as evident from root mean square deviations (RMSDs). We found different binding sites namely catalytic, inhibitory phosphorylation, cyclin binding and CKS-binding site of the CDK2 contributing towards the binding of these compounds. Moreover, correlation between free energy of binding and biological activity yielded a statistically significant correlation coefficient. Finally, three representative protein-ligand complexes were subjected to molecular dynamics simulation to determine the stability of the predicted conformations. The low value of the RMSDs between the initial complex structure and the energy minimized final average complex structure suggests that the derived docked complexes are close to equilibrium. We suggest that the phenylacetyl type of substituents and cyclohexyl moiety make the favorable interactions with a number of residues in the active site, and show better inhibitory activity to improve the pharmacokinetic profile of compounds against CDK2. The structure-based drug design strategy described in this study will be highly useful for the development of new inhibitors with high potency and selectivity. PMID- 23727279 TI - A model for the impact of contaminants on fish population dynamics. AB - Mathematical models have been widely applied to perform chemical risk assessments on biological populations for a variety of ecotoxicological processes. In this paper, by introducing a dose-dependent mortality rate function, we formulate a toxin-dependent aquatic population model that integrates mortality as toxin effect in addition to considering the effects of toxin on growth and recruitment. The model describes the direct effect of toxin on population by treating the concentration of toxin in the environment as a parameter. The model is more convenient to connect with data than traditional differential equation models that describe the interaction between toxin and population. We analyze the positive invariant region and the stability of boundary and interior steady states. The model is connected to experimental data via model parametrization. In particular, we consider the toxic effects of mercury on rainbow trout (Oncorhynchus mykiss) and obtain an appropriate range for each model parameter. The parameter estimates are then used to illustrate the long-time behavior of the population under investigation. The numerical results provide threshold values of toxin concentration in the environment to keep the population from extirpation. The findings are consistent with surface water quality guidelines. It may be appropriate to apply our model to other species and other chemicals of interest to consider guideline development. PMID- 23727280 TI - The origin of the genetic code in the ocean abysses: new comparisons confirm old observations. AB - I have analysed the amino acid substitution pattern between two pairs of nonbarophilic-barophilic organisms in order to confirm previous results. Indeed, the pattern deriving from a different pair of such organisms led to establish that the origin of the genetic code might have occurred in the ocean abysses. The hydrostatic pressure asymmetry indices computable from these matrices of amino acid substitutions confirm the correlation previously observed, even when differences in GC content are accounted for. As the three substitution matrices are independent between them, the old conclusion that the genetic code originated in the ocean abysses is considerably strengthened. PMID- 23727281 TI - Density shift, morphological damage, lysosomal fragility and apoptosis of hemocytes of Indian molluscs exposed to pyrethroid pesticides. AB - Bellamya bengalensis (Gastropoda: Prosobranchia) and Lamellidens marginalis (Bivalvia: Eulamellibranchiata) are the molluscs of Indian freshwater ecosystem and important biological resources. These edible species bear economical, ecological, nutritional and medicinal importance. Natural habitat of these organisms is under the ecological threat of contamination by cypermethrin and fenvalerate, the common pyrethroid pesticides of India. Hemocytes are chief immunoeffector cells of molluscs which exhibit responsiveness against environmental toxins and perform diverse immunological functions including phagocytosis, encapsulation and cytotoxicity. Experimental exposure of cypermethrin and fenvalerate resulted in significant shift in density and morphological damage in hemocytes of B. bengalensis and L. marginalis respectively. Pyrethroid induced fragility and destabilization of hemocyte lysosomal membrane was recorded and proposed as an indication of toxin induced stress in molluscs. Apoptosis is an immunologically important cellular response which is modulated by environmental toxins. Pyrethroid exposure suppressed the physiological level of apoptosis and necrosis in hemocytes of B. bengalensis and L. marginalis indicating possible impairment of apoptosis mediated immunoprotection. Differential responses of B. bengalensis and L. marginalis hemocytes may be due to species specificity, toxin specificity, nonidentical immune strategies of Gastropoda and Bivalvia, specific habitat preference and related ecological niches. PMID- 23727282 TI - Differential regulation of cathelicidin in salmon and cod. AB - Antimicrobial peptides (AMPs) are an important component of innate immunity in vertebrates. The cathelicidin family of AMPs is well characterized in mammals and has also been reported in several fish species. In this study we investigated the regulation of cathelicidin expression in a gadoid and a salmonid cell-line in order to dissect the signalling pathways involved. For this, fish cells were treated with microbial lysates, purified microbial components and commercial signalling inhibitors and expression of cathelicidin was assessed with quantitative real-time PCR (qPCR). We found that cathelicidin expression was induced in both cell lines in response to microbial stimuli, but the response patterns differed in these evolutionary distant fish species. Our data suggest that in salmonids, pattern recognition receptors such as TLR5 may be involved in the stimulation of cathelicidin expression and that the signalling cascade can include PI3-kinase and cellular trafficking compartments. A detailed knowledge of the regulating factors involved in AMP-related defence responses, including cathelicidin, could help in developing strategies to enhance the immune defence of fish. PMID- 23727283 TI - Molecular cloning, characterization and expression analysis of coagulation factor VII gene in grass carp (Ctenopharyngodon idella). AB - Coagulation factor VII has been studied in several species but, to date, not in grass carp (Ctenopharyngodon idella), a commercially important freshwater fish found in China. In this study, the full-length cDNA of grass carp coagulation factor VII (GcCFVII) was cloned using a RACE-Ready cDNA Kit, grass carp were challenged with a hemorrhagic virus, and temporal expression profiles of GcCFVII in the thymus, gills, liver, spleen, and head kidney were examined at 0 h, 24 h, 48 h, 72 h, 96 h, and 138 h using fluorescence quantitative PCR. The results showed the 1480 bp GcCFVII to contain three conservative motifs: Gla, EGF-CA, and Tryp-SPc, similar to other species. Phylogenetic analysis showed the evolution of GcCFVII gene to be consistent with the evolution of the species. After viral challenge, GcCFVII expression in five tissues of grass carp showed different patterns of fluctuation. These results provide a solid basis for further investigation of GcCFVII and its relationship with grass carp hemorrhage. PMID- 23727284 TI - Cloning and identification of four Mu-type glutathione S-transferases from the giant freshwater prawn Macrobrachium rosenbergii. AB - Glutathione S-transferases (GSTs) are essential components of the cellular detoxification system because of their capability to protect organisms against the toxicity of reactive oxygen species (ROSs). Four different GSTs (MrMuGST1 MrMuGST4) showing similarities with Mu-type GSTs were cloned from the hepatopancreas of Macrobrachium rosenbergii. These four GSTs have 219, 216, 218 and 219 amino acids in length, respectively. MrMuGST1-MrMuGST4 proteins all have a G-site in the N-terminus and an H-site in the C-terminus. Phylogenetic analysis reveals that four Mu-type GSTs are classified into two different clades (MrMuGST2 one clade; MrMuGST1, MrMuGST3 and MrMuGST4 other clades). Nonetheless, no site under positive selection was detected but rapid evolution was found in the few of MuGST genes. Reverse transcription-polymerase chain reaction (RT-PCR) results showed that MrMuGST1 and MrMuGST2 transcripts were expressed in all detected tissues, however, MrMuGST3 and MrMuGST4 were just mainly expressed in hepatopancreas and intestines. Quantitative RT-PCR analysis showed that MrMuGST1 and MrMuGST2 were down-regulated upon Vibrio anguillarum challenge, whereas MrMuGST3 and MrMuGST4 were quickly up-regulated 2 h after the Vibrio challenge. Our results imply that different Mu-type GSTs may respond to Vibrio challenge with different manners. PMID- 23727285 TI - Molecular characterization of the aryl hydrocarbon receptor (AhR) pathway in goldfish (Carassius auratus) exposure to TCDD: the mRNA and protein levels. AB - In bony fish or other aquatic vertebrates, the aryl hydrocarbon receptor (AhR) signaling pathway is initiated by exposure to polycyclic (or/and halogenated) aromatic hydrocarbons (PAHs, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD), which subsequently induces the up-regulated expression of a series of related genes (such as cytochrome P4501A (CYP1A)). However, a lack of applicable protein reagents hinders our further understanding of the AhR signaling pathway, which focuses only on gene-based investigations. The goldfish (Carassius auratus) is an ideal model for a study of environmental pollution in whole-Asian fresh water. Here, three sensitive and specific polyclonal antisera against goldfish AhR1, AhR2, and CYP1A proteins were developed. These antisera not only bound the in vitro synthesized target proteins, but recognized the real proteins expressed in goldfish tissues, with minimal cross-reactivity to non-specific proteins. Together with the analysis of semi-quantitative RT-PCR and polyclonal-antibody based sandwich ELISA, we confirmed that goldfish AhRs differed in the expression (mRNA and protein levels) patterns among test tissues. Importantly, the relative abundance of each AhR mRNA levels from the different tissues showed no obvious consistency with their protein levels. After exposure to TCDD, goldfish AhR2 showed a more sensitivity than AhR1, and stimulated CYP1A expression directly, similar with the other reported fish models. Overall, development of these antibodies in this study will allow valuable and versatile investigations to further understand the AhR signaling pathway, and different expression (mRNA and protein) patterns represent the first step in determining the regulatory mechanisms underlying the TCDD-exposed aquatic environment. PMID- 23727286 TI - Invasion factors of apicomplexan parasites: essential or redundant? AB - Apicomplexa are obligate intracellular parasites that cause several human and veterinary diseases worldwide. In contrast to most intracellular pathogens these protozoans are believed to invade a rather passive host cell in a process, that is, tightly linked to the ability of the parasites to move by gliding motility. Indeed specific inhibitors against components of the gliding machinery and the analysis of knockdown mutants demonstrate a linkage of gliding motility and invasion. Intriguingly, new data show that it is possible to block gliding motility, while host cell invasion still occurs. This suggests that either the current models established for host cell invasion need to be critically revised or that alternative, motor independent mechanisms are in place including a more active role of the host cell that can complement a missing actin-myosin-system. Here we discuss some of the discrepancies that need to be addressed for a better understanding of invasion. PMID- 23727287 TI - Phytochemical analysis of mature tree root exudates in situ and their role in shaping soil microbial communities in relation to tree N-acquisition strategy. AB - Eperua falcata (Aublet), a late-successional species in tropical rainforest and one of the most abundant tree in French Guiana, has developed an original strategy concerning N-acquisition by largely preferring nitrate, rather than ammonium (H. Schimann, S. Ponton, S. Hattenschwiler, B. Ferry, R. Lensi, A.M. Domenach, J.C. Roggy, Differing nitrogen use strategies of two tropical rainforest tree species in French Guiana: evidence from (15)N natural abundance and microbial activities, Soil Biol. Biochem. 40 (2008) 487-494). Given the preference of this species for nitrate, we hypothesized that root exudates would promote nitrate availability by (a) enhancing nitrate production by stimulating ammonium oxidation or (b) minimizing nitrate losses by inhibiting denitrification. Root exudates were collected in situ in monospecific planted plots. The phytochemical analysis of these exudates and of several of their corresponding root extracts was achieved using UHPLC/DAD/ESI-QTOF and allowed the identification of diverse secondary metabolites belonging to the flavonoid family. Our results show that (i) the distinct exudation patterns observed are related to distinct root morphologies, and this was associated with a shift in the root flavonoid content, (ii) a root extract representative of the diverse compounds detected in roots showed a significant and selective metabolic inhibition of isolated denitrifiers in vitro, and (iii) in soil plots the abundance of nirK-type denitrifiers was negatively affected in rhizosphere soil compared to bulk. Altogether this led us to formulate hypothesis concerning the ecological role of the identified compounds in relation to N-acquisition strategy of this species. PMID- 23727288 TI - Systemic delivery of sticky siRNAs targeting the cell cycle for lung tumor metastasis inhibition. AB - RNA interference allows the design of new inhibitors that target deregulated pathways in cancer. However systemic delivery of siRNA for the treatment of solid tumors still remains an issue. In our study, in order to suppress the progression of lung cancer metastasis in mice, we developed sticky siRNA (ssiRNA) to inhibit survivin and cyclin B1, two candidates involved in cell survival and proliferation. We exploited the linear polyethylenimine (PEI) as potent non-viral carrier to efficiently deliver our inhibitors. As a proof of concept, we have chosen a very aggressive mammary adenocarcinoma model (TSA-Luc cells), which forms lung metastases upon systemic cell injection. We confirmed in vitro, that the ssiRNAs delivered with PEI are not only able to inhibit our target genes at the mRNA and protein levels, but are also able to block the cell cycle and cell proliferation through a mechanism of RNA interference. More importantly, we showed in vivo by luciferase dosage, bioimaging and tissue section, an inhibition of lung tumor metastases after systemic delivery of cyclin B1 and survivin ssiRNA complexed with PEI. Alternating treatment with cisplatin and ssiRNA/PEI showed an additive effect between the two anticancer drugs on lung tumor inhibition leading to a significant increase in animal survival. Moreover a promising window between activity (IC50) and toxicity (LD50), essential for therapeutic application, was observed. Our data show that systemic delivery of ssiRNA/PEI complexes targeting the cell cycle is a valuable strategy for the treatment of lung tumor metastasis and that it can be combined with chemotherapy. PMID- 23727289 TI - Towards elucidation of the drug release mechanism from compressed hydrophilic matrices made of cellulose ethers. III. Critical use of thermodynamic parameters of activation for modeling the water penetration and drug release processes. AB - The two main purposes of this work were: (i) to critically consider the use of thermodynamic parameters of activation for elucidating the drug release mechanism from hydroxypropyl methylcellulose (HPMC) matrices, and (ii) to examine the effect of neutral (pH 6) and acidic (pH 2) media on the release mechanism. For this, caffeine was chosen as model drug and various processes were investigated for the effect of temperature and pH: caffeine diffusion in solution and HPMC gels, and drug release from and water penetration into the HPMC tablets. Generally, the kinetics of the processes was not significantly affected by pH. As for the temperature dependence, the activation energy (E(a)) values calculated from caffeine diffusivities were in the range of Fickian transport (20-40 kJ mol 1). Regarding caffeine release from HPMC matrices, fitting the profiles using the Korsmeyer-Peppas model would indicate anomalous transport. However, the low apparent E(a) values obtained were not compatible with a swelling-controlled mechanism and can be assigned to the dimensional change of the system during drug release. Unexpectedly, negative apparent E(a) values were calculated for the water uptake process, which can be ascribed to the exothermic dissolution of water into the initially dry HPMC, the expansion of the matrix and the polymer dissolution. Taking these contributions into account, the true E(a) would fall into the range valid for Fickian diffusion. Consequently, a relaxation-controlled release mechanism can be dismissed. The apparent anomalous drug release from HPMC matrices results from a coupled Fickian diffusion-erosion mechanism, both at pH 6 and 2. PMID- 23727290 TI - Pulsatile diastolic increase and systolic decrease in arterial blood pressure: their mechanism of production and physiological role. AB - The diastolic pulsatile increase in arterial blood pressure is shown to occur earlier in the aorta than in other arteries. It is thus not a reflection of the systolic pressure wave, as has been generally assumed, but an independent pressure wave produced by the sequential contraction of the arterial tree. Conversely, a systolic pulsatile decrease in the rate of blood pressure rise is also produced by an active relaxation of the arterial tree. Simultaneously with the pulsatile changes in arterial blood pressure, there are corresponding changes in arterial blood flow. All these cyclic changes are reflex responses to decreasing diastolic and increasing systolic baroreceptor firing rates, respectively. The two reflexes contribute, together with the known compliance of the large arteries and the great arteriolar blood flow resistance, to the steadiness of capillary blood flow throughout the systolic and the much longer lasting diastolic phases of the cardiac cycle. PMID- 23727291 TI - Mechanisms of the anti-inflammatory actions of the angiotensin type 1 receptor antagonist losartan in experimental models of arthritis. AB - Angiotensin (Ang) II and its AT1 receptors have been implicated in the pathogenesis of rheumatoid arthritis. Activation of the counter-regulatory Ang-(1 7)-Mas receptor axis may contribute to some of the effects of AT1 receptor blockers (ARBs). In this study, we have used losartan, an ARB, to investigate the role of and the mechanisms by which AT1 receptors participated in two experimental models of arthritis: antigen-induced arthritis (AIA) in mice and adjuvant-induced arthritis (AdIA) in rats. Treatment with losartan decreased neutrophil recruitment, hypernociception and the production of TNF-alpha, IL 1beta and chemokine (C-X-C motif) ligand 1 in mice subjected to AIA. Histopathological analysis showed significant reduction of tissue injury and inflammation and decreased proteoglycan loss. In addition to decreasing cytokine production, losartan directly reduced leukocyte rolling and adhesion. Anti inflammatory effects of losartan were not associated to Mas receptor activation and/or Ang-(1-7) production. Anti-inflammatory effects were reproduced in rats subjected to AdIA. This study shows that ARBs have potent anti-inflammatory effects in animal models of arthritis. Mechanistically, reduction of leukocyte accumulation and of joint damage was associated with local inhibition of cytokine production and direct inhibition of leukocyte-endothelium interactions. The anti inflammatory actions of losartan were accompanied by functional improvement of the joint, as seen by reduced joint hypernociception. These findings support the use of ARBs for the treatment of human arthritis and provide potential mechanisms for the anti-inflammatory actions of these compounds. PMID- 23727292 TI - Chemical synthesis of the tetrasaccharide repeating unit of the O-antigenic polysaccharide from Plesiomonas shigelloides strain AM36565. AB - Chemical synthesis of the tetrasaccharide repeating unit of the O-antigenic polysaccharide from Plesiomonas shigelloides strain AM36565 is reported. Glycosylations between suitably protected monosaccharide synthons were achieved by the activation of thioglycosides in the presence of H2SO4-silica in conjunction with N-iodosuccinimide. The glycosylations accomplished were highly stereoselective and afforded the desired products in good to excellent yields. PMID- 23727293 TI - Tungsten disulfide nanotubes reinforced biodegradable polymers for bone tissue engineering. AB - In this study, we have investigated the efficacy of inorganic nanotubes as reinforcing agents to improve the mechanical properties of poly(propylene fumarate) (PPF) composites as a function of nanomaterial loading concentration (0.01-0.2 wt.%). Tungsten disulfide nanotubes (WSNTs) were used as reinforcing agents in the experimental group. Single- and multi-walled carbon nanotubes (SWCNTs and MWCNTs) were used as positive controls, and crosslinked PPF composites were used as the baseline control. Mechanical testing (compression and three-point bending) shows a significant enhancement (up to 28-190%) in the mechanical properties (compressive modulus, compressive yield strength, flexural modulus and flexural yield strength) of WSNT-reinforced PPF nanocomposites compared to the baseline control. In comparison to the positive controls, significant improvements in the mechanical properties of WSNT nanocomposites were also observed at various concentrations. In general, the inorganic nanotubes (WSNTs) showed mechanical reinforcement better than (up to 127%) or equivalent to that of carbon nanotubes (SWCNTs and MWCNTs). Sol fraction analysis showed significant increases in the crosslinking density of PPF in the presence of WSNTs (0.01-0.2 wt.%). Transmission electron microscopy (TEM) analysis on thin sections of crosslinked nanocomposites showed the presence of WSNTs as individual nanotubes in the PPF matrix, whereas SWCNTs and MWCNTs existed as micron-sized aggregates. The trend in the surface area of nanostructures obtained by Brunauer Emmett-Teller (BET) surface area analysis was SWCNTs>MWCNTs>WSNTs. The BET surface area analysis, TEM analysis and sol fraction analysis results taken together suggest that chemical composition (inorganic vs. carbon nanomaterials), the presence of functional groups (such as sulfide and oxysulfide) and individual dispersion of the nanomaterials in the polymer matrix (absence of aggregation of the reinforcing agent) are the key parameters affecting the mechanical properties of nanostructure-reinforced PPF composites and the reason for the observed increases in the mechanical properties compared to the baseline and positive controls. PMID- 23727294 TI - Shikonin promotes intestinal wound healing in vitro via induction of TGF-beta release in IEC-18 cells. AB - The intestinal barrier is a complex system with a dynamic structure that is designed for the maintenance of homeostasis in healthy individuals. Ulcerative colitis, one of the main manifestations of inflammatory bowel disease, is characterized by an inadequate and delayed wound healing. Shikonin, the active principle in the root of Lithospermum erythrorhizon, has demonstrated its ability to attenuate dextran sulfate sodium-induced ulcerative colitis in mice. Moreover, the root of L. erythrorhizon has been used in traditional Chinese medicine for treatment of burns, anal ulcers, hemorrhoids and skin wounds. However, the effect of shikonin on intestinal wound healing is unknown. Using an in vitro model for wound healing, we observed that shikonin enhances cell migration of intestinal epithelial cells through a mechanism that involves TGF-beta1 induction. The combination of shikonin's anti-inflammatory activity together with its wound healing properties makes it a great potential therapeutic agent for the treatment of injury associated with intestinal inflammation. PMID- 23727295 TI - The intravascular ultrasound elasticity-palpography technique revisited: a reliable tool for the in vivo detection of vulnerable coronary atherosclerotic plaques. AB - Critical to the detection of vulnerable plaques (VPs) is quantification of their mechanical properties. On the basis of intravascular ultrasound (IVUS) echograms and strain images, E. I. Cespedes, C. L. de Korte CL and A. F. van der Steen (Ultrasound Med Biol 2000;26:385-396) proposed an elasticity-palpography technique (E-PT) to estimate the apparent stress-strain modulus palpogram of the thick endoluminal layer of the arterial wall. However, this approach suffers from major limitations because it was developed for homogeneous, circular and concentric VPs. The present study was therefore designed to improve the E-PT by considering the anatomic shape of the VP. This improved E-PT was successfully applied to six coronary lesions of patients imaged in vivo with IVUS. Our results indicate that the mean relative error of the stress-strain modulus decreased from 61.02 +/- 9.01% to 15.12 +/- 12.57% when the IE-PT was used instead of the E-PT. The accuracy of the stress-strain modulus palpograms computed using the improved theoretical framework was also investigated with respect to noise, which may affect prediction of plaque vulnerability. PMID- 23727296 TI - Chronic obstructive pulmonary disease and cardiovascular disease. AB - Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the lung associated with progressive airflow limitation and punctuated by episodes of acute exacerbation. There is growing recognition that the inflammatory state associated with COPD is not confined to the lungs but also involves the systemic circulation and can impact nonpulmonary organs. Epidemiologic and mechanistic studies indicate that COPD is associated with a high frequency of coronary artery disease, congestive heart failure and cardiac arrhythmias, independent of shared risk factors. Possible pathways include complex interrelationships between chronic low-grade systemic inflammation and oxidative stress as well as shared risk factors such as age, cigarette smoking, and environmental pollutants. In this review, we provide an overview of the epidemiologic data linking COPD with cardiovascular disease, comment on the interrelationships among COPD, inflammation, and cardiovascular disease, and highlight diagnostic and therapeutic challenges. PMID- 23727297 TI - Expression pattern of the homeotic gene Bapx1 during early chick gastrointestinal tract development. AB - Regulation of the Bone Morphogenetic Protein (BMP) signaling pathway is essential for the normal development of vertebrate gastrointestinal (GI) tract, but also for the differentiation of the digestive mesenchymal layer into smooth muscles and submucosal layer. Different studies demonstrated that Bapx1 (for bagpipe homeobox homolog 1) negatively regulates the BMP pathway, but its precise expression pattern during the development and the differentiation of the GI tract mesenchyme actually remains to be examined. Here, we present the spatio-temporal expression profile of Bapx1 in the chick GI tract. We show that Bapx1 is first expressed in the undifferentiated mesenchyme of the gizzard and the colon. After the differentiation of the digestive mesenchyme, we found Bapx1 strongly expressed in the gizzard smooth muscle and in the submucosa layer of the colon. This expression pattern provides new insights into the roles of Bapx1 during the regionalization of the GI tract and the differentiation of the digestive mesenchyme of the colon and the stomach. PMID- 23727299 TI - GelClust: a software tool for gel electrophoresis images analysis and dendrogram generation. AB - This paper presents GelClust, a new software that is designed for processing gel electrophoresis images and generating the corresponding phylogenetic trees. Unlike the most of commercial and non-commercial related softwares, we found that GelClust is very user-friendly and guides the user from image toward dendrogram through seven simple steps. Furthermore, the software, which is implemented in C# programming language under Windows operating system, is more accurate than similar software regarding image processing and is the only software able to detect and correct gel 'smile' effects completely automatically. These claims are supported with experiments. PMID- 23727298 TI - Expression of CXCL12 and CXCL14 during eye development in chick and mouse. AB - Vertebrate eye development is a complex multistep process coordinated by signals from the lens, optic cup and periocular mesenchyme. Although chemokines are increasingly being recognized as key players in cell migration, proliferation, and differentiation during embryonic development, their potential role during eye development has not been examined. In this study, we demonstrate by section in situ hybridization that CXCL12 and CXCL14 are expressed during ocular development. CXCL12 is expressed in the periocular mesenchyme, ocular blood vessels, retina, and eyelid mesenchyme, and its expression pattern is conserved between chick and mouse in most tissues. Expression of CXCL14 is localized in the ocular ectoderm, limbal epithelium, scleral papillae, eyelid mesenchyme, corneal keratocytes, hair follicles, and retina, and it was only conserved in the upper eyelid ectoderm of chick and mouse. The unique and non-overlapping patterns of CXCL12 and CXCL14 expression in ocular tissues suggest that these two chemokines may interact and have important functions in cell proliferation, differentiation and migration during eye development. PMID- 23727300 TI - Comparative evaluation of support vector machines for computer aided diagnosis of lung cancer in CT based on a multi-dimensional data set. AB - Lung cancer is one of the most common forms of cancer resulting in over a million deaths per year worldwide. In this paper, the usage of support vector machine (SVM) classification for lung cancer is investigated, presenting a systematic quantitative evaluation against Boosting, Decision trees, k-nearest neighbor, LASSO regressions, neural networks and random forests. A large database of 5984 regions of interest (ROIs) and 488 input features (including textural features, patient characteristics, and morphological features) were used to train the classifiers and evaluate for their performance. The evaluation for classifiers' performance was based on a tenfold cross validation framework, receiver operating characteristic curve (ROC), and Matthews correlation coefficient. Area under curve (AUC) of SVM, Boosting, Decision trees, k-nearest neighbor, LASSO, neural networks, random forests were 0.94, 0.86, 0.73, 0.72, 0.91, 0.92, and 0.85, respectively. It was proved that SVM classification offered significantly increased classification performance compared to the reference methods. This scheme may be used as an auxiliary tool to differentiate between benign and malignant SPNs of CT images in future. PMID- 23727301 TI - Invasion of cooperators in lattice populations: linear and non-linear public good games. AB - A generalized version of the N-person volunteer's dilemma (NVD) Game has been suggested recently for illustrating the problem of N-person social dilemmas. Using standard replicator dynamics it can be shown that coexistence of cooperators and defectors is typical in this model. However, the question of how a rare mutant cooperator could invade a population of defectors is still open. Here we examined the dynamics of individual based stochastic models of the NVD. We analyze the dynamics in well-mixed and viscous populations. We show in both cases that coexistence between cooperators and defectors is possible; moreover, spatial aggregation of types in viscous populations can easily lead to pure cooperation. Furthermore we analyze the invasion of cooperators in populations consisting predominantly of defectors. In accordance with analytical results, in deterministic systems, we found the invasion of cooperators successful in the well-mixed case only if their initial concentration was higher than a critical threshold, defined by the replicator dynamics of the NVD. In the viscous case, however, not the initial concentration but the initial number determines the success of invasion. We show that even a single mutant cooperator can invade with a high probability, because the local density of aggregated cooperators exceeds the threshold defined by the game. Comparing the results to models using different benefit functions (linear or sigmoid), we show that the role of the benefit function is much more important in the well-mixed than in the viscous case. PMID- 23727302 TI - Male control of mating duration following exposure to rivals in fruitflies. AB - Males of many species assess the likely level of sperm competition and respond adaptively, for example by increasing the level of courtship they deliver, by transferring more sperm or seminal fluids or by extending matings. In mechanistic terms, it may be easier for males to adjust the level of their investment to the likely level of sperm competition for male-limited traits such as sperm and seminal fluid production over which they have control. However, for shared traits, such as mating duration, that are expressed at a level determined by direct interactions between males and females, adaptive responses by males to competition could be constrained. This need not be the case, however, if males have significant influence over the expression of such traits. Understanding which sex can most influence the expression of shared traits in response to sexual competition is important in order to document the range of strategic, plastic responses that are available to each sex. However, direct tests of these ideas require, as in this study, measurements of the effect on a shared trait of manipulating the ability of one, but not the other, sex to influence it. We studied the responses of male Drosophila melanogaster to sexual competition, in which mating duration is increased following exposure to rivals, resulting in significantly increased paternity share. Males were allowed to respond normally to the presence of rivals prior to mating, but female responses to males were reduced via decapitation and immobilisation. We found that matings with both intact and decapitated, immobilised females were significantly longer with males that had been exposed to rivals prior to mating. Hence males could maintain their responses to rivals with intact and decapitated females, suggesting significant male influence over the ability to extend mating duration in this context. However, overall, mating duration was significantly longer with intact in comparison to decapitated females. Whether this is due to a female influence over mating duration in general, or whether males respond differently to immobilised females, is not yet known. Gaining a fuller understanding of sex-specific control of plastic traits will be important in the future for understanding how reproductive traits evolve and function. PMID- 23727303 TI - The consequences of alternating diet on performance and food preferences of a specialist leaf beetle. AB - The food quality of a given host plant tissue will influence the performance and may also affect the preference behavior of herbivorous animals. As nutrient contents and defense metabolite concentrations can vary significantly between different parts of a plant and change over time, herbivores are potentially confronted with diet differing in quality even when feeding on a single plant individual. Here we investigated to what extent feeding exclusively either on young or old, mature leaves of Brassica rapa or on a mixed diet of young and old leaves offered in alternating order affects the larval performance, food consumption, and the host preference behavior of adult mustard leaf beetles, Phaedon cochleariae. Analyzing different leaf quality traits, we found lower water contents, no changes in C:N ratio but more than threefold higher glucosinolate concentrations in young compared to old leaves. Individuals reared on mixed diet performed as well as animals reared on young leaves. Thus, compared to animals feeding exclusively on highly nutritious young leaves, diet-mixing individuals may balance the lower nutrient intake by a dilution of adverse secondary metabolites. Alternatively, they may integrate over the variation in their food, using a previously assimilated resource for growth at times of scarcity. Animals reared on old leaves grew less and had a prolonged larval developmental time, although they showed increased consumption indicating compensatory feeding. Additionally, we found that experience with a certain diet affected the preference behavior. Whereas individuals reared exclusively on young leaves preferred young over old leaves for feeding and oviposition, we did not find any preferences by animals reared exclusively on old leaves or by females reared on alternating diet. Thus, in contrast to positive feedbacks for animals reared on young leaves, an integrative growth of diet-mixing individuals potentially leads to a lack of feedback during development. Taken together, our results suggest that different diet regimes can lead to comparable performance of mustard leaf beetles but experienced feedbacks may differ and thus convey distinct diet preferences. PMID- 23727304 TI - Cytomegalovirus viraemia in HIV exposed and infected infants: prevalence and clinical utility for diagnosing CMV pneumonia. AB - BACKGROUND: Human cytomegalovirus (HCMV) is an important pathogen in HIV exposed infants with pneumonia. However, the diagnosis of HCMV pneumonia in this setting is challenging due to limited access to bronchoscopy, lung biopsy and direct sampling of the lower respiratory tract. HCMV viraemia is more accessible, but their diagnostic performance in this context has not been studied. OBJECTIVE: To describe the prevalence of HCMV viraemia and evaluate its clinical utility in HIV exposed infants. STUDY DESIGN: In this cross-sectional study, we performed qualitative and quantitative PCR to detect HCMV viraemia in HIV exposed asymptomatic infants and in infants with severe pneumonia in the Western Cape province of South Africa. RESULTS: 283 asymptomatic HIV exposed infants and 142 HIV exposed infants with severe pneumonia were studied. Infants with pneumonia had a higher prevalence of HCMV viraemia compared to asymptomatic infants (68% vs 24% OR 6.7, 95% CI 4.2-10.8). This increased prevalence remained significant (OR 4.3 95% CI 2.6-7.0) after adjusting for HIV infection. Of the infants with pneumonia, the level of HCMV viraemia was significantly higher in a subset of infants diagnosed with HCMV pneumonia (median HCMV viral load 4.6 vs 2.5 log copies/ml p<0.001). Receiver operator characteristic (ROC) analysis showed the area under the curve was 0.78 (95% CI 0.71-0.86) and a threshold of 4.1 log copies/ml was able to correctly identify 70% of HCMV pneumonia cases. CONCLUSION: Prevalence and level of HCMV viraemia in sub-Saharan HIV-exposed and infected infants peaks at 3-4 months of age. Quantitative HCMV PCR may be useful in diagnosing HCMV pneumonia. PMID- 23727305 TI - Regulatory T-cell directed therapies in liver diseases. PMID- 23727306 TI - Dendritic cells in liver injury and fibrosis: shortcomings and promises. AB - The phenotype and function of liver dendritic cells (LDCs) are poorly understood. This Snapshot summarizes our current knowledge on LDCs in the healthy and injured liver, and their role in fibrosis progression and reversal. It also draws attention to various pitfalls in the current experimental design and conclusions based on available data. PMID- 23727307 TI - Adenocarcinoma of the prostate with Gleason score 9-10 on core biopsy: correlation with findings at radical prostatectomy and prognosis. AB - PURPOSE: There is a paucity of data on the prognosis after radical prostatectomy for Gleason score 9-10 disease on needle biopsy. To our knowledge we report the largest study to date to specifically analyze the correlation of Gleason score 9 10 on needle core biopsy with radical prostatectomy outcomes. MATERIALS AND METHODS: We identified 259 men with Gleason score 9-10 on biopsy who underwent radical prostatectomy from 1987 to 2012 at our institution. Preoperative variables analyzed were age, race, preoperative prostate specific antigen, adenocarcinoma site, perineural invasion, number of total biopsy cores, number of total positive cores, number of positive cores with Gleason score 9-10, maximum percent of core length with Gleason score 9-10 and maximum percent of adenocarcinoma overall. We determined pathological outcomes on univariate and multivariate analysis, including organ confinement, seminal vesicle invasion, margin status, lymph node metastasis, and biochemical-free and cancer specific survival. RESULTS: Statistically significant predictors of radical prostatectomy outcome were organ confinement (total cores with Gleason score 9-10, maximum percent overall and perineural invasion), margin status (preoperative prostate specific antigen and clinical stage), seminal vesicle invasion (maximum percent overall, perineural invasion and clinical stage), lymph node metastasis (total number of cores with Gleason score 9-10 and clinical stage) and biochemical-free survival (maximum percent of Gleason score 9-10, maximum percent overall and clinical stage) (each p<0.05). CONCLUSIONS: In the highly select subset of patients who are good surgical candidates and have the appropriate combination of preoperative variables postoperative findings are sufficiently favorable to justify radical prostatectomy. PMID- 23727309 TI - Population based study of use and determinants of active surveillance and watchful waiting for low and intermediate risk prostate cancer. AB - PURPOSE: Prior studies have reported the underuse of deferred treatment (ie active surveillance or watchful waiting) for low risk prostate cancer in the United States. We examined contemporary trends in active surveillance and watchful waiting in the nationwide Swedish prostate cancer registry. We also examined factors associated with selection of deferred management, which might provide insight into the rational diffusion of this important management strategy. MATERIALS AND METHODS: We identified 57,713 men with very low risk (T1c, Gleason 6 or less, prostate specific antigen less than 10 ng/ml, prostate specific antigen density less than 0.20 ng/ml/cc, 2 or fewer positive biopsy cores or less than 25% of cores positive), low risk (T1-T2, Gleason 6 or less, and prostate specific antigen less than 10 ng/ml) and intermediate risk prostate cancer (T1-T2, Gleason 7 and/or prostate specific antigen 10 to 20 ng/ml) in the PCBaSe (Prostate Cancer database Sweden) from 1998 to 2011. Subclassification of very low risk disease, and active surveillance vs watchful waiting was possible beginning in 2007. We examined primary treatment selection by risk group and used logistic regression to evaluate factors associated with deferred treatment. RESULTS: Overall 13,272 (46%) men with low risk and 8,695 (30%) with intermediate risk prostate cancer chose deferred treatment. Since 2007, 59%, 41% and 16% of very low, low and intermediate risk prostate cancer, respectively, chose active surveillance. Age was by far the strongest determinant of deferred treatment. Education, marital status and comorbidity were significantly but weakly associated with deferring treatment. CONCLUSIONS: Deferred treatment for low and intermediate risk prostate cancer was frequently used in Sweden. Dissociating diagnosis from treatment in men with a low risk of progression can decrease the rate of overtreatment. PMID- 23727308 TI - Survival impact of followup care after radical cystectomy for bladder cancer. AB - PURPOSE: Due to substantial variation in patient followup after radical cystectomy for bladder cancer, we sought to understand the effect of urine and laboratory tests, physician visits and imaging on overall survival. MATERIALS AND METHODS: We analyzed a cohort of patients treated in the fee for service Medicare population from 1992 through 2007 using Surveillance Epidemiology and End Results (SEER)-Medicare data. Using propensity score analysis, we assessed the relationship between time and geography standardized expenditures on followup care and overall survival during 3 postoperative periods, including perioperative (0 to 3 months), early followup (4 to 6 months) and later followup (7 to 24 months). Using instrumental variable analysis, we assessed the overall survival impact of the quantity of followup care by category, including physician visits, imaging, and laboratory and urine tests. RESULTS: We found no improvement in survival due to followup care in the perioperative and early followup periods. Receiving followup care during later followup was associated with improved survival in the low, middle and high expenditure tertiles (HR 0.23, 95% CI 0.15 0.35, HR 0.27, 95% CI 0.18-0.40 and HR 0.47, 95% CI 0.31-0.71, respectively). Instrumental variable analysis suggested that only physician visits and urine testing improved survival (HR 0.96, 0.93-0.99 and 0.95, 0.91-0.99, respectively). CONCLUSIONS: Followup care after radical cystectomy in the later followup period was associated with improved survival. Physician visits and urine tests were associated with this improved survival. Our results suggest that aspects of followup care significantly improve patient outcomes but imaging could be done more judiciously after cystectomy. PMID- 23727310 TI - Utility of multiparametric magnetic resonance imaging suspicion levels for detecting prostate cancer. AB - PURPOSE: We determine the usefulness of multiparametric magnetic resonance imaging in detecting prostate cancer, with a specific focus on detecting higher grade prostate cancer. MATERIALS AND METHODS: Prospectively 583 patients who underwent multiparametric magnetic resonance imaging and subsequent prostate biopsy at a single institution were evaluated. On multiparametric magnetic resonance imaging, lesions were identified and scored as low, moderate or high suspicion for prostate cancer based on a validated scoring system. Magnetic resonance/ultrasound fusion guided biopsies of magnetic resonance imaging lesions in addition to systematic 12-core biopsies were performed. Correlations between the highest assigned multiparametric magnetic resonance imaging suspicion score and presence of cancer and biopsy Gleason score on the first fusion biopsy session were assessed using univariate and multivariate logistic regression models. Sensitivity, specificity, negative predictive value and positive predictive value were calculated and ROC curves were developed to assess the discriminative ability of multiparametric magnetic resonance imaging as a diagnostic tool for various biopsy Gleason score cohorts. RESULTS: Significant correlations were found between age, prostate specific antigen, prostate volume, and multiparametric magnetic resonance imaging suspicion score and the presence of prostate cancer (p<0.0001). On multivariate analyses controlling for age, prostate specific antigen and prostate volume, increasing multiparametric magnetic resonance imaging suspicion was an independent prognosticator of prostate cancer detection (OR 2.2, p<0.0001). Also, incremental increases in multiparametric magnetic resonance imaging suspicion score demonstrated stronger associations with cancer detection in patients with Gleason 7 or greater (OR 3.3, p<0.001) and Gleason 8 or greater (OR 4.2, p<0.0001) prostate cancer. Assessing multiparametric magnetic resonance imaging as a diagnostic tool for all prostate cancer, biopsy Gleason score 7 or greater, and biopsy Gleason score 8 or greater separately via ROC analyses demonstrated increasing accuracy of multiparametric magnetic resonance imaging for higher grade disease (AUC 0.64, 0.69, and 0.72, respectively). CONCLUSIONS: Multiparametric magnetic resonance imaging is a clinically useful modality to detect and characterize prostate cancer, particularly in men with higher grade disease. PMID- 23727311 TI - Pad count is a poor measure of the severity of urinary incontinence. AB - PURPOSE: We analyzed the correlation between pad use, as determined by objective pad count, and the severity of urinary incontinence, as measured by pad weight. MATERIALS AND METHODS: We performed a retrospective study of consecutive incontinent patients who wore pads on a daily basis and were instructed to complete a 24-hour pad test. They were told to use the usual pads, change them as usual and place each in a separate plastic bag the day before the scheduled appointment. All pads were weighed and total urine loss was calculated by subtracting dry pad weight from wet pad weight, assuming that a 1 gm weight increase was equivalent to 1 ml of urine loss. The number of pads was correlated to pad weight using the Spearman rank correlation coefficient due to the nonparametric nature of the data. RESULTS: The 116 patients included 51 men 39 to 89 years old (mean age 66) and 65 women 27 to 95 years old (mean age 72). When comparing the number of pads used to the gm of urine lost, the Spearman rho was 0.26 (p=0.005) in the total cohort, and 0.40 and 0.26 (each p<0.05) in males and females, respectively. CONCLUSIONS: There was little correlation between the number of pads used and the severity of urinary incontinence (r=0.26). These data suggest that pad count should not be used as an objective measure of incontinence severity. Instead, pad weight on a 24-hour pad test should be used. PMID- 23727312 TI - Risk stratification of patients with extraprostatic extension and negative lymph nodes at radical prostatectomy: identifying optimal candidates for adjuvant therapy. AB - PURPOSE: Randomized trials demonstrate a benefit to adjuvant radiation therapy after radical prostatectomy in patients with pathologically locally advanced tumors. However, limited data exist on natural history, specifically in men with extraprostatic extension, and wide variability in outcomes has been reported. We evaluated long-term outcomes in patients with pT3aN0 disease and determined predictors of recurrence in these men. MATERIALS AND METHODS: We evaluated 20,744 patients who underwent radical prostatectomy at our clinic between 1987 and 2011. Of these men 1,073 with pT3aN0 disease were identified who did not receive neoadjuvant or adjuvant therapy. Biochemical recurrence-free survival was estimated using the Kaplan-Meier method. Multivariate stepwise selection was used to develop a prognostic model for biochemical recurrence. RESULTS: Median followup after radical prostatectomy was 10.9 years, during which 449 patients experienced biochemical recurrence. On stepwise selection preoperative prostate specific antigen (HR 1.3, p=0.0003), clinical tumor stage (HR 1.2, p=0.001), pathological Gleason score (HR 1.9, p<0.0001), surgical margin status (HR 1.6, p<0.0001) and detectable first postoperative prostate specific antigen (HR 2.2, p<0.0001) were significantly associated with biochemical recurrence. Cumulative weighted scores of these variables were used to stratify patients into quintiles according to biochemical recurrence risk. The 15-year biochemical recurrence-free survival rate in the lowest to the highest risk group was 70%, 56%, 44%, 34% and 25%, respectively (p<0.0001). The c-index for this model was 0.69. CONCLUSIONS: We present a model to individualize the estimation of biochemical recurrence in men with pT3aN0 disease at radical prostatectomy. These data may be used for patient counseling, specifically in regard to risk stratification when discussing secondary therapy. PMID- 23727313 TI - Vertical transmission of Neisseria gonorrhoeae to a female premature neonate with congenital pneumonia. PMID- 23727314 TI - Rostrocaudal gradients of dopamine D2/3 receptor binding in striatal subregions measured with [(11)C]raclopride and high-resolution positron emission tomography. AB - The human striatum has structural and functional subdivisions, both dorsoventrally and rostrocaudally. To date, the gradients of dopamine D2/3 receptor binding in the human striatum have not been measured with positron emission tomography (PET). Seven healthy male subjects aged 24.5 +/- 3.5 years were scanned with brain-dedicated high-resolution research tomography (HRRT, Siemens Medical Solutions, Knoxville, TN, USA) and [(11)C]raclopride. Coronally defined regions of interest (ROIs) of the caudate nucleus, putamen and ventral striatum (VST) were sampled plane-by-plane, 1.5mm apart, on spatially normalized binding potential (BPND) images. Regional [(11)C]raclopride BPND values were calculated using the simplified reference tissue model (SRTM) from a total of 25 coronal planes. An increasing rostrocaudal gradient of the D2/3 receptor binding was detected in the putamen, which is consistent with the known distribution of D2/3 dopamine receptors. In the caudate nucleus, there was an initial increase in the BPND values in the most anterior planes, suggesting that the highest D2/3 receptor binding occurred in the head; however, there was an overall descending gradient. A declining trend was also observed in the VST. The novelty of this study lies in the presentation, for the first time, of the D2/3 receptor binding gradients in each striatal subregion in the brains of living healthy humans. The high spatial resolution provided by HRRT enables frequent sampling of BPND along the longitudinal extent of striatum; this method is superior to the sectioning used in previous post mortem studies. Regarding the functional organization of the striatum, our findings can inform future investigations of normal neurophysiology as well as efforts to differentiate neuropsychiatric disorders affecting the brain dopamine (DA) system. Furthermore, the average distribution of D2/3 receptor binding revealed in this study could serve as a basis for a database that includes distributions of various DA markers as a function of healthy aging. PMID- 23727315 TI - Groupwise spatial normalization of fMRI data based on multi-range functional connectivity patterns. AB - Spatial alignment of functional magnetic resonance images (fMRI) of different subjects is a necessary precursor to improve functional consistency across subjects for group analysis in fMRI studies. Traditional structural MRI (sMRI) based registration methods cannot achieve accurate inter-subject functional consistency in that functional units are not necessarily located relative to anatomical structures consistently due to functional variability across subjects. Although spatial smoothing commonly used in fMRI data preprocessing can reduce the inter-subject functional variability, it may blur the functional signals and thus lose the fine-grained information. To overcome the limitations of exiting techniques, in this paper, we propose a novel method for spatial normalization of fMRI data by matching their multi-range functional connectivity patterns progressively. In particular, the image registration of different subjects is achieved by maximizing inter-subject similarity of their functional images' local functional connectivity patterns that characterize functional connectivity information for each voxel of the images to its spatial neighbors. The neighborhood size for computing the local functional connectivity patterns is gradually increased with the progression of image registration to capture the functional connectivity information in larger ranges. We also adopt the congealing groupwise image registration strategy to simultaneously warp a group of subjects to an unbiased template. Experimental comparisons between the proposed method and other fMRI image registration methods have demonstrated that the proposed method could achieve superior registration performance for resting state fMRI data. Experiment results based on real resting-state fMRI data have further demonstrated that the proposed fMRI registration method can achieve a statistically significant improvement in functional consistency across subjects. PMID- 23727317 TI - Intrinsic connectivity network mapping in young children during natural sleep. AB - Structural and functional neuroimaging have substantively informed the pathophysiology of numerous adult neurological and psychiatric disorders. While structural neuroimaging is readily acquired in sedated young children, pediatric application of functional neuroimaging has been limited by the behavioral demands of in-scanner task performance. Here, we investigated whether functional magnetic resonance imaging (fMRI) acquired during natural sleep and without experimental stimulation offers a viable strategy for studying young children. We targeted the lengthy epoch of non-rapid eye movement, stage 3 (NREM3) sleep typically observed at sleep onset in sleep-deprived children. Seven healthy, preschool-aged children (24-58 months) were studied, acquiring fMRI measurements of cerebral blood flow (CBF) and of intrinsic connectivity networks (ICNs), with concurrent sleep-stage monitoring. ICN data (T2* fMRI) were reliably obtained during NREM3 sleep; CBF data (arterial spin labeled fMRI) were not reliably obtained, as scanner noises disrupted sleep. Applying independent component analysis (ICA) to T2* data, distinct ICNs were observed which corresponded closely with those reported in the adult literature. Notably, a network associated with orthography in adults was not observed, suggesting that ICNs exhibit a developmental trajectory. We conclude that resting-state fMRI obtained in sleep is a promising paradigm for neurophysiological investigations of young children. PMID- 23727316 TI - Guided exploration of genomic risk for gray matter abnormalities in schizophrenia using parallel independent component analysis with reference. AB - One application of imaging genomics is to explore genetic variants associated with brain structure and function, presenting a new means of mapping genetic influences on mental disorders. While there is growing interest in performing genome-wide searches for determinants, it remains challenging to identify genetic factors of small effect size, especially in limited sample sizes. In an attempt to address this issue, we propose to take advantage of a priori knowledge, specifically to extend parallel independent component analysis (pICA) to incorporate a reference (pICA-R), aiming to better reveal relationships between hidden factors of a particular attribute. The new approach was first evaluated on simulated data for its performance under different configurations of effect size and dimensionality. Then pICA-R was applied to a 300-participant (140 schizophrenia (SZ) patients versus 160 healthy controls) dataset consisting of structural magnetic resonance imaging (sMRI) and single nucleotide polymorphism (SNP) data. Guided by a reference SNP set derived from ANK3, a gene implicated by the Psychiatric Genomic Consortium SZ study, pICA-R identified one pair of SNP and sMRI components with a significant loading correlation of 0.27 (p=1.64*10( 6)). The sMRI component showed a significant group difference in loading parameters between patients and controls (p=1.33*10(-15)), indicating SZ-related reduction in gray matter concentration in prefrontal and temporal regions. The linked SNP component also showed a group difference (p=0.04) and was predominantly contributed to by 1030 SNPs. The effect of these top contributing SNPs was verified using association test results of the Psychiatric Genomic Consortium SZ study, where the 1030 SNPs exhibited significant SZ enrichment compared to the whole genome. In addition, pathway analyses indicated the genetic component majorly relating to neurotransmitter and nervous system signaling pathways. Given the simulation and experiment results, pICA-R may prove a promising multivariate approach for use in imaging genomics to discover reliable genetic risk factors under a scenario of relatively high dimensionality and small effect size. PMID- 23727318 TI - The CONNECT project: Combining macro- and micro-structure. AB - In recent years, diffusion MRI has become an extremely important tool for studying the morphology of living brain tissue, as it provides unique insights into both its macrostructure and microstructure. Recent applications of diffusion MRI aimed to characterize the structural connectome using tractography to infer connectivity between brain regions. In parallel to the development of tractography, additional diffusion MRI based frameworks (CHARMED, AxCaliber, ActiveAx) were developed enabling the extraction of a multitude of micro structural parameters (axon diameter distribution, mean axonal diameter and axonal density). This unique insight into both tissue microstructure and connectivity has enormous potential value in understanding the structure and organization of the brain as well as providing unique insights to abnormalities that underpin disease states. The CONNECT (Consortium Of Neuroimagers for the Non invasive Exploration of brain Connectivity and Tracts) project aimed to combine tractography and micro-structural measures of the living human brain in order to obtain a better estimate of the connectome, while also striving to extend validation of these measurements. This paper summarizes the project and describes the perspective of using micro-structural measures to study the connectome. PMID- 23727320 TI - Print-specific multimodal brain activation in kindergarten improves prediction of reading skills in second grade. AB - Children who are poor readers usually experience troublesome school careers and consequently often suffer from secondary emotional and behavioural problems. Early identification and prediction of later reading problems thus are critical in order to start targeted interventions for those children with an elevated risk for emerging reading problems. In this study, behavioural precursors of reading were assessed in nineteen (aged 6.4 +/- 0.3 years) non-reading kindergarteners before training letter-speech sound associations with a computerized game (Graphogame) for eight weeks. The training aimed to introduce the basic principles of letter-speech sound correspondences and to initialize the sensitization of specific brain areas to print. Event-related potentials (ERP) and functional magnetic resonance imaging (fMRI) data were recorded during an explicit word/symbol processing task after the training. Reading skills were assessed two years later in second grade. The focus of this study was on clarifying whether electrophysiological and fMRI data of kindergarten children significantly improve prediction of future reading skills in 2nd grade over behavioural data alone. Based on evidence from previous studies demonstrating the importance of initial print sensitivity in the left occipito-temporal visual word form system (VWFS) for learning to read, the first pronounced difference in processing words compared to symbols in the ERP, an occipito-temporal negativity (N1: 188-281 ms) along with the corresponding functional activation in the left occipito-temporal VWFS were defined as potential predictors. ERP and fMRI data in kindergarteners significantly improved the prediction of reading skills in 2nd grade over behavioural data alone. Together with the behavioural measures they explained up to 88% of the variance. An additional discriminant analysis revealed a remarkably high accuracy in classifying normal (n=11) and poor readers (n=6). Due to the key limitation of the study, i.e. the small group sizes, the results of our prediction analyses should be interpreted with caution and regarded as preliminary despite cross-validation. Nevertheless our results indicate the potential of combining neuroimaging and behavioural measures to improve prediction at an early stage, when literacy skills are acquired and interventions are most beneficial. PMID- 23727319 TI - Digital reconstruction and morphometric analysis of human brain arterial vasculature from magnetic resonance angiography. AB - Characterization of the complex branching architecture of cerebral arteries across a representative sample of the human population is important for diagnosing, analyzing, and predicting pathological states. Brain arterial vasculature can be visualized by magnetic resonance angiography (MRA). However, most MRA studies are limited to qualitative assessments, partial morphometric analyses, individual (or small numbers of) subjects, proprietary datasets, or combinations of the above limitations. Neuroinformatics tools, developed for neuronal arbor analysis, were used to quantify vascular morphology from 3T time of-flight MRA high-resolution (620 MUm isotropic) images collected in 61 healthy volunteers (36/25 F/M, average age=31.2 +/- 10.7, range=19-64 years). We present in-depth morphometric analyses of the global and local anatomical features of these arbors. The overall structure and size of the vasculature did not significantly differ across genders, ages, or hemispheres. The total length of the three major arterial trees stemming from the circle of Willis (from smallest to largest: the posterior, anterior, and middle cerebral arteries; or PCAs, ACAs, and MCAs, respectively) followed an approximate 1:2:4 proportion. Arterial size co-varied across individuals: subjects with one artery longer than average tended to have all other arteries also longer than average. There was no net right-left difference across the population in any of the individual arteries, but ACAs were more lateralized than MCAs. MCAs, ACAs, and PCAs had similar branch-level properties such as bifurcation angles. Throughout the arterial vasculature, there were considerable differences between branch types: bifurcating branches were significantly shorter and straighter than terminating branches. Furthermore, the length and meandering of bifurcating branches increased with age and with path distance from the circle of Willis. All reconstructions are freely distributed through a public database to enable additional analyses and modeling (cng.gmu.edu/brava). PMID- 23727321 TI - Partial least squares correlation of multivariate cognitive abilities and local brain structure in children and adolescents. AB - Intelligent behavior is not a one-dimensional phenomenon. Individual differences in human cognitive abilities might be therefore described by a 'cognitive manifold' of intercorrelated tests from partially independent domains of general intelligence and executive functions. However, the relationship between these individual differences and brain morphology is not yet fully understood. Here we take a multivariate approach to analyzing covariations across individuals in two feature spaces: the low-dimensional space of cognitive ability subtests and the high-dimensional space of local gray matter volume obtained from voxel-based morphometry. By exploiting a partial least squares correlation framework in a large sample of 286 healthy children and adolescents, we identify directions of maximum covariance between both spaces in terms of latent variable modeling. We obtain an orthogonal set of latent variables representing commonalities in the brain-behavior system, which emphasize specific neuronal networks involved in cognitive ability differences. We further explore the early lifespan maturation of the covariance between cognitive abilities and local gray matter volume. The dominant latent variable revealed positive weights across widespread gray matter regions (in the brain domain) and the strongest weights for parents' ratings of children's executive function (in the cognitive domain). The obtained latent variables for brain and cognitive abilities exhibited moderate correlations of 0.46-0.6. Moreover, the multivariate modeling revealed indications for a heterochronic formation of the association as a process of brain maturation across different age groups. PMID- 23727322 TI - Human connectomics - what will the future demand? AB - Significant resources are now being devoted to large-scale international studies attempting to map the connectome - the brain's wiring diagram. This review will focus on the use of human neuroimaging approaches to map the connectome at a macroscopic level. This emerging field of human connectomics brings both opportunities and challenges. Opportunities arise from the ability to apply a powerful toolkit of mathematical and computational approaches to interrogate these rich datasets, many of which are being freely shared with the scientific community. Challenges arise in methodology, interpretability and biological or clinical validity. This review discusses these challenges and opportunities and highlights potential future directions. PMID- 23727324 TI - Anti-inflammatory effect of ubiquinol-10 on young and senescent endothelial cells via miR-146a modulation. AB - Clinical evidence demonstrates that ubiquinol-10, the reduced active form of coenzyme Q10 (CoQ10H2), improves endothelial function through its antioxidant and probably its anti-inflammatory properties. We previously reported that a biomarker combination including miR-146a, its target protein IL-1 receptor associated kinase (IRAK-1), and released interleukin (IL)-6, here collectively designated as MIRAKIL, indicates senescence-associated secretory phenotype (SASP) acquisition by primary human umbilical vein endothelial cells (HUVECs). We explore the ability of short- and long-term CoQ10H2 supplementation to affect MIRAKIL in HUVECs, used as a model of vascular aging, during replicative senescence in the absence/presence of lipopolysaccharide (LPS), a proinflammatory stimulus. Senescent HUVECs had the same ability as young cells to internalize CoQ10 and exhibit an improved oxidative status. LPS-induced NF-kappaB activation diminished after CoQ10H2 pretreatment in both young and senescent cells. However, short-term CoQ10H2 supplementation attenuated LPS-induced MIRAKIL changes in young cells; in senescent cells CoQ10H2 supplementation significantly attenuated LPS-induced miR-146a and IRAK-1 modulation but failed to curb IL-6 release. Similar results were obtained with long-term CoQ10H2 incubation. These findings provide new insights into the molecular mechanisms by which CoQ10H2 stems endothelial cell inflammatory responses and delays SASP acquisition. These phenomena may play a role in preventing the endothelial dysfunction associated with major age-related diseases. PMID- 23727323 TI - SOD2 in mitochondrial dysfunction and neurodegeneration. AB - The brain is a highly metabolically active tissue that critically relies on oxidative phosphorylation as a means for maintaining energy. One result of this process is the production of potentially damaging radicals such as the superoxide anion (O2(-)). Superoxide has the capacity to damage components of the electron transport chain and other cellular constituents. Eukaryotic systems have evolved defenses against such damaging moieties, the chief member of which is superoxide dismutase (SOD2), an enzyme that efficiently converts superoxide to the less reactive hydrogen peroxide (H2O2), which can freely diffuse across the mitochondrial membrane. Loss of SOD2 activity can result in numerous pathological phenotypes in metabolically active tissues, particularly within the central nervous system. We review SOD2's potential involvement in the progression of neurodegenerative diseases such as stroke and Alzheimer and Parkinson diseases, as well as its potential role in "normal" age-related cognitive decline. We also examine in vivo models of endogenous oxidative damage based upon the loss of SOD2 and associated neurological phenotypes in relation to human neurodegenerative disorders. PMID- 23727325 TI - Differential expression of IL-8 and IL-8 receptors in benign, borderline and malignant ovarian epithelial tumours. AB - INTRODUCTION: Ovarian Cancer is the leading cause of death from gynecological malignancy. The poor prognosis is mainly due to presentation at a late stage and poor response to therapy. Much research is needed to identify diagnostic and prognostic biomarkers as well as therapeutic targets for ovarian cancer. Interleukin-8 is expressed by many tumour types and is known to have mitogenic, motogenic and angiogenic effects on tumour cells. AIMS: The aim of this study was to investigate the expression of IL-8 and IL-8 receptors (IL-8RA and IL-8RB) in different histological subtypes of ovarian tumours, as potential prognostic biomarkers in ovarian tumours. MATERIALS AND METHODS: Immunohitochemistry was used to study the expression of IL-8 and IL-8 receptors in 115 ovarian tumours including 21 benign tumours, 25 borderline tumours and 69 carcinomas of serous, clear cell, endometrioid and mucinous types. The correlation of expression profile, tumour type, stage, and progression free survival and overall survival was statistically analysed. RESULTS: IL-8 and IL-8 receptors were expressed in all types of tumours with variable intensity and subcellular distribution. There was a statistically significant correlation between levels of expression and tumour stage and tumour type, being mostly significant in serous tumours. No correlation with patient progression free survival or overall survival was found. CONCLUSION: This is the first study investigating the expression of IL-8 and IL-8 receptors using immunohistochemistry in different types of ovarian tumours, including benign and borderline tumours. IL-8 and IL-8RA are potential prognostic biomarkers and therapeutic targets in ovarian cancer, particularly in ovarian serous carcinoma. PMID- 23727326 TI - Towards a role of interleukin-32 in atherosclerosis. AB - BACKGROUND: IL-32 has been previously shown to promote inflammation in rheumatoid arthritis patients and to contribute to IL-1beta-induced ICAM-1 as well as other proinflammatory cytokines synthesis in human umbilical endothelial cells (HUVECs). Given the high rate of atherosclerosis in RA, these observations suggest that IL-32 may be involved in the inflammatory pathways of atherosclerosis. METHODS: mRNA and protein levels of IL-32 were determined in human atherosclerotic arterial vessel wall tissue by quantitative real-time PCR and immunohistochemistry. HUVEC and M1/M2 macrophages were stimulated with proinflammatory cytokines and TLR ligands to assess IL-32 mRNA induction. Human THP1 macrophages were transduced with AdIL-32gamma, to investigate induction of several proatherosclerotic mediators. Finally, aortas from IL-32gamma transgenic mice were studied and compared with aortas from age-matched wild-type mice. RESULTS: IL-32 expression was detectable in human atherosclerotic arterial vessel wall, with the expression of IL-32beta and IL-32gamma mRNA significantly enhanced. TLR3-ligand Poly I:C in combination with IFNgamma were the most potent inducers of IL-32 mRNA expression in both HUVEC and M1/M2 macrophages. Adenoviral overexpression of IL-32gamma in human THP1 macrophages resulted in increased production of CCL2, sVCAM-1, MMP1, MMP9, and MMP13. The IL-32gamma transgenic mice chow a normal fat diet exhibited vascular abnormalities resembling atherosclerosis. CONCLUSIONS: IL-32 acts as a proinflammatory factor and may be implicated in the inflammatory cascade contributing to atherosclerosis. By promoting the synthesis of matrix metalloproteinases, it may further contribute to plaque instability. Further studies are warranted to investigate whether IL-32 may serve as a potential therapeutic target in fighting atherosclerosis. PMID- 23727328 TI - Voice disorder in patients with Fibromyalgia. AB - OBJECTIVE: To investigate several perceptual, acoustic and aerodynamic voice evaluation parameters in Fibromyalgia patients. METHODS: A total number of 30 Fibromyalgia patients had voice evaluations by means of laryngostroboscopy, acoustic analysis (jitter, shimmer, and harmonic to noise ratio), aerodynamic measurements (maximum phonation time, s/z ratio), and perceptual analysis (GRBAS and Voice Handicap Index-10 scales). Data obtained from the patients was compared to control subjects. RESULTS: Mean intensity was found to be significantly higher in control subjects (73.70+/-4.73dB) than Fibromyalgia patients (64.50+/-6.92dB), (p<0.001). There was no statistically significant difference in fundamental frequency, perturbation parameters (jitter and shimmer) and harmonic to noise ratio between groups. Maximum phonation time in control subjects (22.53+/-4.95s) was found to be significantly longer than Fibromyalgia patients (16.07+/-4.87s), (p<0.001), and s/z ratio was found to be nearly equal between patients (1.00+/ 0.24) and control subjects (0.96+/-0.16). On the basis of perceptual evaluation by using a GRBAS scale, the patients showed a mean score of 2.50+/-1.97 and the control group showed a mean score of 0.56+/-1.04 (p<0.001). "Grade" and "asthenia" parameters of GRBAS scale in Fibromyalgia patients were significantly different from the parameters of control group (p<0.001). The Voice Handicap Index-10 scales revealed a mean score of 7.90+/-7.58 in Fibromyalgia patients and 1.83+/-2.82 in control subjects (p<0.001). CONCLUSION: Fibromyalgia impairs perceived voice quality either in patient self evaluated or in clinician evaluated rating scales. Furthermore, the results confirm that Fibromyalgia caused short maximum phonation time and low voice intensity. This study is the first report with regards to voice evaluation in Fibromyalgia and in order to make a generalization further researches are needed. PMID- 23727327 TI - Anti-HE4 antibodies in infertile women and women with ovarian cancer. AB - OBJECTIVES: To develop an assay for anti-HE4 antibodies and assess such antibodies in sera from women with increased epidemiologic risk for ovarian cancer (infertility) and patients with ovarian cancer in comparison to controls. METHODS: An ELISA was developed to measure antibodies to recombinant full length HE4 and cut-off values were determined for different levels of specificity (up to 99%). RESULTS: Infertile women more frequently had anti-HE4 antibodies than controls (23% at 98% specificity, p < 0.001) with antibodies most frequent in women with POF (31%) and ovulatory dysfunction (47%). There was also an increased frequency of anti-HE4 antibodies in patients with ovarian cancer (14% at 97% specificity, p < 0.01), but more women with certain types of infertility have anti-HE4 antibodies than women with ovarian cancer. Most patients with ovarian cancer have circulating HE4 antigen, which may interfere with detection of antibodies, while the level of HE4 antigen in sera from infertile women was not higher than in normal controls. There was a statistically significant correlation between antibodies to HE4 and antibodies to mesothelin in the same patients. CONCLUSIONS: Women with certain types of infertility, which have increased risk to develop ovarian cancer, and women with ovarian cancer more frequently than controls have antibodies to HE4, a biomarker for ovarian cancer. The antibodies may reflect a tumor-promoting Th2 type of inflammation. PMID- 23727329 TI - Successful management of hypoparathyroidism following total thyroidectomy with vitamin D(3) alone. AB - OBJECTIVE: To assess the efficacy and safety of a single administration of vitamin D3 for postoperative hypoparathyroidism. PATIENTS AND METHODS: Twelve patients with postoperative hypoparathyroidism were enrolled for this study. They had taken calcium and vitamin D3 orally after the surgery and had shown no symptoms of hypoparathyroidism. Then, all patients had changed their regimen to a single administration of vitamin D3 (1alpha(OH)D3) with monitoring of serum calcium, urine calcium (u-Ca) and creatinine (u-Cre). The dose of vitamin D3 was started at 2.0MUg/day and appropriately adjusted to maintain the ratio of u-Ca and u-Cre (u-Ca/u-Cre) at less than 0.3. The physical findings were carefully checked and the serum intact-parathyroid was also estimated. Those data and physical findings were monitored for at least two years. RESULT: The maintenance dose of vitamin D3 varied from 0.5 to 3.5MUg/day, and the mean dose was 2.04MUg/day. All patients tolerated changes of regimen without any symptoms of hyper-/hypocalcemia. CONCLUSION: A single administration of vitamin D3 is not only safe but also an easy and cost-effective regimen. This also makes drug control easy and worthwhile both for patients and clinicians. LEVEL OF EVIDENCE: 2c. PMID- 23727330 TI - Commentary on "An evolutionary framework for cultural change: selectionism versus communal exchange" by Liane Gabora. PMID- 23727331 TI - Blind-variation and selective-retention theory of creativity. PMID- 23727332 TI - Copper(II) mixed chelate compounds induce apoptosis through reactive oxygen species in neuroblastoma cell line CHP-212. AB - In the present work we report the antiproliferative activity of Cu(II) coordination compounds, CasIIgly ([Cu(4,7-dimethyl-1,10-phenanthroline) (glycinato) (H2O)]NO3), CasIIIia ([Cu(4,4'-dimethyl-2,2'-bipyridine) (glycinato) (H2O)]NO3), and CasIIIEa ([Cu(4,7-dimethyl-1,10-phenanthroline) (acetylacetonato) (H2O)]NO3), against human tumoral cell line CHP-212 (estromal neuroblastoma). Additionally, the molecular structure of CasIIIEa was reported. The IC50 values obtained for the evaluated compounds are in the range 18 to 47 MUM, representing an inhibition potency increase of 5 to 12 times compared with cisplatin (IC50=226.7 MUM). After 2h of incubation with the evaluated compounds, cells showed high levels of reactive oxygen species and a considerable GSH depletion, besides an important disruption of the mitochondrial membrane with release of cytochrome C and besides the presence of caspase-3, an effector caspase that is activated in the last step of apoptosis cascade. The results confirm that cell death in neuroblastoma CHP-212 treated with Casiopeinas occurs via apoptosis. Due to the lack of expression of caspase-8, cell death is principally by the mitochondrial pathway. Thus, one of the most interesting findings of this work is the identification of a very important damage in neuroblastoma cells induced by Cu(II) coordination compounds in a very short exposition times. PMID- 23727333 TI - Antioxidant and anti-fatigue effects of anthocyanins of mulberry juice purification (MJP) and mulberry marc purification (MMP) from different varieties mulberry fruit in China. AB - Anthocyanins, copiously distributed in a variety of colored fruits and vegetables, are probably the most important group of visible plant pigments besides chlorophyll. And the mulberry fruit is one of the anthocyanins-rich fruits. Total flavonols, total phenolic acids and anthocyanins contents of ten varieties mulberry juice purification (MJP) and mulberry marc purification (MMP) were determined. The highest content was 965.63+/-4.90 mg RE/g, 690.83+/-7.38 mg GAE/g and 272.00+/-1.20 mg cyanidin-3-glucoside/g FW, respectively. Moreover, MJP and MMP exhibited high antioxidant activity, including total force reduction (TRP), Fe3+ reducing power (FRAP) and DPPH * radical scavenging capacity. In addition, the anti-fatigue activity of MJP and MMP was determined through mice burden swimming experiments. Interestingly, the antioxidant and anti-fatigue capacities of MMP were much higher than those of MJP. The experimental results suggested that the generally discarded mulberry marc had greater value of development and utilization as food processing waste. PMID- 23727334 TI - Dual role of resveratrol in modulation of genotoxicity induced by sodium arsenite via oxidative stress and apoptosis. AB - The potential benefits of resveratrol as an anticancer (proapoptosis) and antioxidant (pro-survival) compound have been studied extensively. However, the role of resveratrol in modulation of the toxicity induced by sodium arsenite (NaAsO2) is still unclear. In the present study, we examined the effects of resveratrol on NaAsO2-induced cytotoxicity, DNA and chromosomal damage, cell cycle progression, apoptosis and oxidative stress in human lung adenocarcinoma epithelial (A549) cell line at concentrations from 1 to 20 MUM after 24h exposure. Our results revealed that at 1 and 5 MUM, resveratrol was found to exert benefit effects, promoting cell viability and proliferation over 24h NaAsO2 exposure, whereas, resveratrol was showed to inhibit cell survival under the same condition at 20 MUM. Corresponding to the opposing effect of resveratrol at low vs. high concentrations, DNA and chromosomal damage, cell apoptotic rate and level of oxidative stress were also alleviated by lower concentrations (1, 5 MUM) of resveratrol, but exacerbated by higher concentration (20 MUM) resveratrol. Our study implicates that resveratrol is the most beneficial to cells at 1 and 5 MUM and caution should be taken in applying resveratrol as an anticancer therapeutic agent or nutraceutical supplement due to its concentration dependent effect. PMID- 23727335 TI - Polycyclic aromatic hydrocarbons in commercial squids from different geographical origins: levels and risks for human consumption. AB - The concentrations of 18 polycyclic aromatic hydrocarbons (PAHs) were determined in five commercially valuable squid species from different geographical origins (Atlantic, Indic and Pacific Oceans). Out of the 18 quantified PAHs (the 16 PAHs considered by US EPA as priority pollutants, dibenzo(a,l)pyrene and benzo(j)fluoranthene) only dibenz(a,h)anthracene was not detected. The total concentrations of PAHs varied by a factor of more than 100-fold, from 0.22 (Loligo gahi) to 60.9 MUg/kg ww (Loligo reynaudii). Intra- and inter-specific variability of PAH levels was statistically assessed. Nine carcinogenic (probable/possible) PAHs accounted for 1% (L. reynaudii) to 26% (Loligo opalescens) of the total PAHs content being the main contributors naphthalene (in Loligo duvaucelii, L. reynaudii and Loligo vulgaris species), chrysene (in L. opalescens) and indeno(1,2,3-cd)pyrene (in L. gahi). PAHs source analysis indicated that four of the five zones of capture of the different squid species are significantly affected by both petrogenic and pyrolytic sources. Assessment of the target carcinogenic risks, established by the US EPA, suggested that L. gahi (Atlantic Ocean) and L. opalescens (from Pacific Ocean) may pose additional risks for consumers, if not eaten in moderation, derived from benzo(a)pyrene ingestion. PMID- 23727336 TI - CYP19 expression is induced by 2,3,7,8-tetrachloro-dibenzo-para-dioxin in human glioma cells. AB - Dioxins are the most concerned environmental pollutants. Recent studies have shown that these compounds could disrupt the proper functioning of our endocrine system. Estrogen is synthesized in glial cells of the brain. The hormone has been linked to the maintenance of normal brain operation, ranging from neurotransmission to synapse formation. Aromatase or CYP19 is the enzyme responsible for estrogen synthesis. In the present study, we demonstrated that 2,3,7,8-tetrachloro-dibenzo-para-dioxin (TCDD) stimulated the enzyme activity in human brain cells as low as 1pM. Increased brain-specific CYP19 mRNA species was also observed in these cells. Since the brain-specific promoter I.f of CYP19 contains two binding motifs for CCAAT/enhancer binding protein, electrophoretic mobility shift assay was performed to validate the activation. We further traced the triggering signal and found that the mitogen-activated protein kinases ERK 1/2 were activated. In summary, TCDD could induce CYP19 transcription in brain cells. Exposure to the pollutant might perturb the hormonal balance in the brain. PMID- 23727337 TI - Identification and expression of PBAN/diapause hormone and GPCRs from Aedes aegypti. AB - Neuropeptides control various physiological functions and constitute more than 90% of insect hormones. The pheromone biosynthesis activating neuropeptide (PBAN)/pyrokinin family is a major group of insect neuropeptides and is well conserved in Insecta. This family of peptides has at least two closely related G protein-coupled receptors (GPCRs) activated by PBAN and a diapause hormone (DH). They have been shown to control several biological activities including pheromone production and diapause induction in moths. However, beyond some moth species, the biological function(s) of PBAN/pyrokinin peptides are largely unknown although these peptides are found in all insects. In this study we identified and characterized PBAN/pyrokinin peptides and corresponding GPCRs from the mosquito, Aedes aegypti. Ae. aegypti PBAN mRNA encodes four putative peptides including PBAN and DH, and is expressed in females and males during all life stages. The PBAN receptor (PBAN-R) and the DH receptor (DH-R) were functionally expressed and confirmed through binding assays with PBAN and DH peptides. These receptors are differentially expressed from eggs to adults with the relative gene expression of the PBAN-R significantly lower during the 4th instar larval (L4) and pupal (P1 P2) stages compared to the 2nd and 3rd instar larval stages (L2 and L3). However, DH-R expression level is consistently 4-10 times higher than the PBAN-R in the same period, suggesting that PBAN-R is downregulated in the late larval and pupal stages, whereas DH-R stays upregulated throughout all developmental stages. PBAN/pyrokinin mRNA expression remains high in all stages since it produces PBAN and DH peptides. This study provides the foundation for determining the function(s) of the PBAN/pyrokinin peptides in mosquitoes and establishes data critical to the development of methods for disruption of these hormone actions as a novel strategy for mosquito control. PMID- 23727338 TI - Coding and decoding with dendrites. AB - Since the discovery of complex, voltage dependent mechanisms in the dendrites of multiple neuron types, great effort has been devoted in search of a direct link between dendritic properties and specific neuronal functions. Over the last few years, new experimental techniques have allowed the visualization and probing of dendritic anatomy, plasticity and integrative schemes with unprecedented detail. This vast amount of information has caused a paradigm shift in the study of memory, one of the most important pursuits in Neuroscience, and calls for the development of novel theories and models that will unify the available data according to some basic principles. Traditional models of memory considered neural cells as the fundamental processing units in the brain. Recent studies however are proposing new theories in which memory is not only formed by modifying the synaptic connections between neurons, but also by modifications of intrinsic and anatomical dendritic properties as well as fine tuning of the wiring diagram. In this review paper we present previous studies along with recent findings from our group that support a key role of dendrites in information processing, including the encoding and decoding of new memories, both at the single cell and the network level. PMID- 23727339 TI - Bioremediation of Southern Mediterranean oil polluted sites comes of age. AB - Mediterranean Sea is facing a very high risk of oil pollution due to the high number of oil extractive and refining sites along the basin coasts, and the intense maritime traffic of oil tankers. All the Mediterranean countries have adopted severe regulations for minimizing pollution events and bioremediation feasibility studies for the most urgent polluted sites are undergoing. However, the analysis of the scientific studies applying modern 'meta-omics' technologies that have been performed on marine oil pollution worldwide showed that the Southern Mediterranean side has been neglected by the international research. Most of the studies in the Mediterranean Sea have been done in polluted sites of the Northern side of the basin. Those of the Southern side are poorly studied, despite many of the Southern countries being major oil producers and exporters. The recently EU-funded research project ULIXES has as a major objective to increase the knowledge of the bioremediation potential of sites from the Southern Mediterranean countries. ULIXES is targeting four major polluted sites on the coastlines of Egypt, Jordan, Morocco and Tunisia, including seashore sands, lagoons, and oil refinery polluted sediments. The research is designed to unravel, categorize, catalogue, exploit and manage the diversity and ecology of microorganisms thriving in these polluted sites. Isolation of novel hydrocarbon degrading microbes and a series of state of the art 'meta-omics' technologies are the baseline tools for improving our knowledge on biodegradation capacities mediated by microbes under different environmental settings and for designing novel site-tailored bioremediation approaches. A network of twelve European and Southern Mediterranean partners is cooperating for plugging the existing gap of knowledge for the development of novel bioremediation processes targeting such poorly investigated polluted sites. PMID- 23727340 TI - Microbial symbionts of honeybees: a promising tool to improve honeybee health. AB - Among pollinators, honeybees are the most important ones and exert the essential key ecosystem service of pollination for many crops, fruit and wild plants. Indeed, several crops are strictly dependent on honeybee pollination. Since few decades, honeybees are facing large-scale losses worldwide, the causes of which are found in the interaction of several biotic and abiotic factors, such as the use of pesticides, the habitat loss, the spread of pathogens and parasites and the occurrence of climate changes. Insect symbionts are emerging as a potential tool to protect beneficial insects, ameliorating the innate immune homeostasis and contributing to the general insect wellbeing. A review about the microbial symbionts associated to honeybees is here presented. The importance of the honeybee microbial commensals for the maintenance and improvement of honeybee health is discussed. Several stressors like infestations of Varroa mites and the use of pesticides can contribute to the occurrence of dysbiosis phenomena, resulting in a perturbation of the microbiocenosis established in the honeybee body. PMID- 23727341 TI - Targeting C-type lectin receptors with multivalent carbohydrate ligands. AB - C-type lectin receptors (CLRs) represent a large receptor family including collectins, selectins, lymphocyte lectins, and proteoglycans. CLRs share a structurally homologous carbohydrate-recognition domain (CRD) and often bind carbohydrates in a Ca2+-dependent manner. In innate immunity, CLRs serve as pattern recognition receptors (PRRs) and bind to the glycan structures of pathogens and also to self-antigens. In nature, the low affinity of CLR/carbohydrate interactions is overcome by multivalent ligand presentation at the surface of cells or pathogens. Thus, multivalency is a promising strategy for targeting CLR-expressing cells and, indeed, carbohydrate-based targeting approaches have been employed for a number of CLRs, including asialoglycoprotein receptor (ASGPR) in the liver, or DC-SIGN expressed by dendritic cells. Since CLR engagement not only mediates endocytosis but also influences intracellular signaling pathways, CLR targeting may allow for cell-specific drug delivery and also the modulation of cellular functions. Glyconanoparticles, glycodendrimers, and glycoliposomes were successfully used as tools for CLR-specific targeting. This review will discuss different approaches for multivalent CLR ligand presentation and aims to highlight how CLR targeting has been employed for cell specific drug delivery. Major emphasis is directed towards targeting of CLRs expressed by antigen-presenting cells to modulate immune responses. PMID- 23727342 TI - Differential sequence diversity at merozoite surface protein-1 locus of Plasmodium knowlesi from humans and macaques in Thailand. AB - To determine the genetic diversity and potential transmission routes of Plasmodium knowlesi, we analyzed the complete nucleotide sequence of the gene encoding the merozoite surface protein-1 of this simian malaria (Pkmsp-1), an asexual blood-stage vaccine candidate, from naturally infected humans and macaques in Thailand. Analysis of Pkmsp-1 sequences from humans (n=12) and monkeys (n=12) reveals five conserved and four variable domains. Most nucleotide substitutions in conserved domains were dimorphic whereas three of four variable domains contained complex repeats with extensive sequence and size variation. Besides purifying selection in conserved domains, evidence of intragenic recombination scattering across Pkmsp-1 was detected. The number of haplotypes, haplotype diversity, nucleotide diversity and recombination sites of human derived sequences exceeded that of monkey-derived sequences. Phylogenetic networks based on concatenated conserved sequences of Pkmsp-1 displayed a character pattern that could have arisen from sampling process or the presence of two independent routes of P. knowlesi transmission, i.e. from macaques to human and from human to humans in Thailand. PMID- 23727343 TI - Genomic mosaicism in two strains of Dengue virus type 3. AB - Recombination is a significant factor driving genomic evolution, but it is not well understood in Dengue virus. We used phylogenetic methods to search for recombination in 636 Dengue virus type 3 (DENV-3) genomes and unveiled complex recombination patterns in two strains, which appear to be the outcome of recombination between genotype II and genotype I parental DENV-3 lineages. Our findings of genomic mosaic structures suggest that strand switching during RNA synthesis may be involved in the generation of genetic diversity in dengue viruses. PMID- 23727344 TI - Cognitive reserve and symptom experience in multiple sclerosis: a buffer to disability progression over time? AB - OBJECTIVE: To investigate the possible buffering effect of cognitive reserve on symptom experience for multiple sclerosis (MS) disease course. DESIGN: Secondary analysis of longitudinal data from the North American Research Committee on MS Registry. SETTING: Registry study and web-based supplemental survey. PARTICIPANTS: People with MS (N=859). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Two health outcome measures, the Symptom Inventory and the Performance Scales, were collected biannually over 1 and 6 years, respectively. Active and passive cognitive reserve was measured using the Stern Leisure Activities and the Sole-Padulles Childhood Enrichment tools, respectively. Linear regression, chi square, multilevel random-effects modeling, and classification and regression tree modeling were used to compare cross-sectional means, disease course by cognitive reserve, longitudinal trajectories, and active cognitive reserve item endorsement by disability groups, respectively. RESULTS: Patients with high active reserve had a lesser symptom burden than those with low-active reserve independent of passive reserve (P<.01). Cognitive reserve was associated with course of disease, such that high-active patients were overrepresented among relapsing-remitting patients, and underrepresented among patients with progressive disease (chi(2)=14.7, P<.03). Longitudinal modeling revealed a significant interaction of active reserve and time in mobility, fatigue, and overall disability in the whole sample (P<.05 in all comparisons). Among patients whose disability trajectories changed over time, active cognitive reserve was associated with less deterioration (P<.001). Passive cognitive reserve evidenced no effect in the longitudinal analyses. Active cognitive reserve scores across disability groups had a similar range but comprised different items, indicating that patients maintain active cognitive reserve with different activities as the disease progresses. CONCLUSIONS: Our findings suggest that active cognitive reserve is a buffer for functional limitation across disability groupings. Cognitive reserve may provide an alternative lens for thinking about the disease course of MS, providing a longer "runway" until disability accrual through cortical remodeling. Loss of cognitive reserve may explain the onset of progressive disease in MS. PMID- 23727345 TI - Comparison of proximal and distal cross-sectional areas of the median nerve, carpal tunnel, and nerve/tunnel index in subjects with carpal tunnel syndrome. AB - OBJECTIVES: To provide a quantitative analysis of ultrasonographic measurements and possible pathophysiology of carpal tunnel syndrome by comparing cross sectional areas of the median nerve, carpal tunnel, and nerve/tunnel index and the difference in ultrasonographic findings between affected and nonaffected hands and between sexes. DESIGN: Blinded comparison study. SETTING: Secondary referral and training hospital of institutional practice. PARTICIPANTS: Patients (N=51; 42 women, 9 men) with suspected carpal tunnel syndrome who underwent sonography within 1 week after the electrodiagnostic study. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Electrodiagnostic and ultrasonographic studies were conducted on both upper extremities. Cross-sectional areas of the median nerve and carpal tunnel were measured at 2 separate levels; proximal and distal cross-sectional areas of the carpal tunnel were each measured at the scaphoid pisiform and trapezium-hamate levels, respectively. RESULTS: Comparison between normative (n=24) and abnormal hands (n=78) revealed the following: the mean proximal cross-sectional areas of the median nerve, carpal tunnel, and nerve/tunnel index of electrodiagnostically normative hands were 10.941mm(2), 192.43mm(2), and 5.635%, respectively, whereas those of abnormal hands were 13.74mm(2), 208.87mm(2), and 6.693%, respectively, showing statistically significant differences for all (P<.05). Distal measurements of the cross sectional area of the median nerve, carpal tunnel, and nerve/tunnel index were 10.088mm(2), 150.4mm(2), and 6.762%, respectively, in normative hands, and 11.178mm(2), 149.6mm(2), and 7.493%, respectively, in abnormal hands, showing no statistically significant differences (P>.05). In women, proximal cross-sectional areas of the median nerve and nerve/tunnel index of abnormal hands showed statistically significant differences, but no ultrasonographic measurement with a statistically significant difference was observed in men. CONCLUSIONS: Compared with nonaffected hands, the proximal cross-sectional areas of the median nerve and carpal tunnel were greater, but the distal ultrasonographic measurements were not in affected hands. Ultrasonographic findings of carpal tunnel syndrome were different according to sex. PMID- 23727346 TI - Ultrastructure and molecular characterization of the microsporidium, Nosema chrysoperlae sp. nov., from the green lacewing, Chrysoperla carnea (Stephens) (Neuroptera: Chrysopidae) used for biological pest control. AB - Lacewing larvae are generalist predators that are commercially available for aphid control on a variety of crops in both Europe and North America. Although lacewings are known for their symbiotic association with yeasts and bacteria, there are few reports of microsporidia in these natural enemies. An undescribed microsporidium was found in Chrysoperla carnea (Stephens) during the routine examination of specimens that were obtained from a commercial insectary for biological pest control. The objective of this study was to describe the pathogen by means of ultrastructure, molecular characterization and tissue pathology. All stages of the microsporidium were diplokaryotic and developed in direct contact with the host cell cytoplasm. Merogony and sporogony were not observed. Mature spores measured 3.49+/-0.10*1.52+/-0.05MUm and had an isofilar polar filament with 8-10 coils that were frequently arranged in a single row, although double rows were also observed. Spores contained a lamellar polaroplast and a relatively small and inconspicuous polar vacuole was observed in the posterior region of about half of the spores that were examined. Tubular structures, similar in appearance to those in Nosema granulosis were observed in both sporonts and in spores. A cluster of small tubules was also observed in the posterior region of some spores. Microsporidian spores were observed in cells of the proventriculus, diverticulum and in epithelial cells of the posterior midgut. The Malpighian tubules, ileum, and rectum were heavily infected. Spores were also observed in the fat body, peripheral region of the ganglia, within and between the flight muscles, and beneath the cuticle. Although the tissues adjacent to the ovaries were heavily infected, microsporidian spores were not observed within the developing eggs. Pathogen transmission was not studied directly because it was difficult to maintain microsporidia-infected C. carnea in the laboratory. The presence of microsporidian spores in the alimentary canal suggests that the pathogen is transmitted per os and horizontal transmission may occur when infected larvae or adults are cannibalized by uninfected larvae. Molecular analysis of the microsporidian genome showed that the pathogen described in this study was 99% similar to Nosema bombycis, N. furnacalis, N. granulosis and N. spodopterae. Based on information gained during this study, we propose that the microsporidium in C. carnea be given the name Nosema chrysoperlae sp. nov. PMID- 23727347 TI - Podocyte regeneration: who can become a podocyte? AB - This Commentary highlights the article by Pippin et al that showed that renin lineage cells may enhance glomerular regeneration by serving as progenitors for glomerular epithelial cells in glomerular disease characterized by podocyte depletion. PMID- 23727348 TI - Detection of truncated HER2 forms in formalin-fixed, paraffin-embedded breast cancer tissue captures heterogeneity and is not affected by HER2-targeted therapy. AB - Truncated forms of HER2, previously identified in subsets of HER2-positive breast cancer, originate from proteolytic extracellular domain (ECD) cleavage or alternative translation initiation. They lack ECD but may retain intracellular domain functionality, potentially associated with unfavorable prognosis, metastasis, and decreased sensitivity to antibody-based HER2-targeted therapy. To study the distribution of truncated HER2 in breast cancer, we detected loss of membrane-bound ECD independently of its molecular origin in paraffin sections, combining multispectral unmixing of chromogenic duplex IHC for HER2 ECD and intracellular domain with advanced image analysis. HER2 C-terminal fragment 611 transfected MCF7 and 4-aminophenylmercuric acetate-treated SKBR3 cell lines were used as controls. Applying a prototype work flow to whole sections, paired surgical resection/core needle biopsy samples, and paired samples from 69 patients of a phase 2 neoadjuvant clinical trial, we observed unexpected heterogeneity of ECD loss at the single-cell level, and in different areas of individual tumors, indicating that extent and localization of HER2 ECD loss add relevant information to averaging truncated HER2 across whole sections. We show acceptable run-to-run variation (coefficient of variation, <0.15), image analysis results in moderate agreement with conventional slide assessment (Cohen's kappa = 0.59), and no obvious interference with previous HER2-ECD-targeted therapy. We conclude that duplex IHC and digital image processing extend current approaches of truncated HER2 detection. PMID- 23727349 TI - Rapid enzyme production and mycelial growth in solid-state fermentation using the non-airflow box. AB - Solid-state fermentation (SSF) has become an attractive alternative to submerged fermentation (SMF) for the production of enzymes, organic acids, and secondary metabolites, while there are many problems during the culture of SSF. We recently created a SSF system using a non-airflow box (NAB) in order to resolve the problems, which enabled the uniform culture in the whole substrate and high yield of many enzymes. In this paper, further characterization of SSF using the NAB was carried out to obtain other advantages. The NAB culture under the fixed environmental condition exhibited a rapid increase in enzyme production at earlier phase during the culture compared with conventional SSF. Total mycelial growth also exhibited the same trend as enzyme production. Thus, the increase in the rate of the enzyme production was thought to mainly be attributed to that of the growth. To support it, it was suggested that the NAB culture resulted in most optimal water activity for the growth just at the log phase. In addition, the NAB culture was able to achieve high reproducibility of enzyme production, derived from uniform condition of the substrate during the culture. The results indicate that the NAB culture has many benefits for SSF. PMID- 23727350 TI - Phenazine antibiotic production and antifungal activity are regulated by multiple quorum-sensing systems in Pseudomonas chlororaphis subsp. aurantiaca StFRB508. AB - A number of gram-negative bacteria have a quorum-sensing system and produce the N acylhomoserine lactone (AHL) as a signal molecule. Pseudomonas chlororaphis subsp. aurantiaca StFRB508 produces one of the phenazine derivatives, phenazine-1 carboxylic acid (PCA). Whole-genome sequencing of StFRB508 revealed the presence of two sets of AHL-synthase and AHL-receptor gene, phzIR and aurIR. The mutation of phzI drastically decreased PCA production, but the mutation of aurI did not affect PCA production. The phzI and aurI double mutant did not show any PCA production. StFRB508 produces three major AHLs, N-butyryl-L-homoserine lactone (C4-HSL), N-hexanoyl-L-homoserine lactone (C6-HSL), and N-(3-hydroxyhexanoyl)-L homoserine lactone (3-hydroxy-C6-HSL). As the results of TLC analysis, PhzI mainly catalyzes the biosynthesis of 3-hydroxy-C6-HSL, and AurI catalyzes the biosynthesis of C4-HSL and C6-HSL. PCA production in the phzI and aurI double mutant was restored by exogenous AHLs and the most active AHL was 3-hydroxy-C6 HSL. StFRB508 showed high inhibitory activity of the development of mycelia of plant pathogenic fungi, Fusarium oxysporum f. sp. conglutinans. However, the phzI and aurI double mutant could not inhibit the development of mycelia. These results demonstrated that the multiple quorum-sensing system play an important role in PCA production and antifungal activity in StFRB508. PMID- 23727351 TI - DNA fragmentation caused by an overdose of Zeocin. AB - DNA-damaging agent Zeocin is frequently used for vector selection in multiple cell types. We found that vector extracted from the Escherichia coli cells overgrown in the presence of Zeocin was generally contaminated with genomic DNA fragments. High dosage or prolonged cultivation should thus be avoided to minimize the contamination. PMID- 23727352 TI - p38 MAP kinase activation does not stimulate serotonin transport in rat brain: Implications for sickness behaviour mechanisms. AB - AIMS: Several studies suggested an association between dysregulation of immune mediators and behavioural, neuroendocrine and neurochemical features of depression. Available data showed that cytokines affect the serotonin transporter (SERT) activity through p38 MAP kinase (MAPK)-dependent mechanisms in some cell lines and mice neurons (Zhu et al., Neuropsychopharmacology, 2006; 31:2121-31). The aim of this study was to investigate the interaction of Interleukin-1beta (IL 1beta) or p38 MAPK with SERT activity in rat brain and cell lines. MAIN METHODS: Synaptosomes or cells were treated with IL-1beta or the p38 MAPK activator anisomycin at different concentrations and end-points and the modulation of SERT activity as Km and Vmax was evaluated. KEY FINDINGS: Treatments with IL-1beta or anisomycin did not affect serotonin uptake and p38 MAPK activation in rat synaptosomes, in contrast to reports in mice (Zhu et al., Neuropsychopharmacology, 2010; 35:2510-20). The same treatments activated p38 MAPK phosphorylation in HeLa cells used as positive controls. Similarly, no changes after anisomycin treatment could be detected in [(3)H]serotonin uptake rate in LLC-PK cells expressing human SERT, although phosphorylated p38 MAPK levels augmented significantly. Direct cytokine release in brain was induced by intracerebroventricular administration of bacterial lipopolysaccaride. Although pro-inflammatory cytokines, such as IL-1beta, IL6, and Tumor Necrosis Factor alpha, showed significant increases in brain cortex, modulation of SERT activity in term of Km and Vmax was not detected. SIGNIFICANCE: These results imply that the stimulation of serotonin uptake by cytokines may not be a unique and fundamental mechanism in the pathology of depression induced by altered immune response. PMID- 23727353 TI - Role of caveolin-1 and caveolae signaling in endotoxemia and sepsis. AB - Caveolae, plasma membrane invaginations of 60-80nm in diameter, are a subset of lipid rafts enriched in cholesterol and sphingolipids. Caveolae are expressed in various tissues and cell types, such as endothelial cells, macrophages, neutrophils and adipocytes. The functions of caveolae are diverse and include endocytosis, transcytosis, potocytosis, calcium signaling, and regulation of various signaling events. Although growing evidence has increased our understanding of caveolae function, the role of caveolae in sepsis is still a controversial issue. In this review, we present a number of studies addressing caveolae and sepsis and describe the signaling pathways involved, including the LPS-eNOS-TLR4-NFkappaB, MKK3/p38 MAPK, cPLA2/p38 MAPK, STAT3/NFkappaB and IL 1beta-IL-1R1 pathways. Different studies using endotoxemia and bacteremia animal models have provided distinct conclusions about the function of caveolae, and we discuss these inconsistencies. Taken together, the current data suggest that the function of caveolae in sepsis, which involves a number of signaling pathways, is complex and warrants further studies. PMID- 23727354 TI - Effects of sodium hydrosulfide on intestinal mucosal injury in a rat model of cardiac arrest and cardiopulmonary resuscitation. AB - AIMS: Cardiac arrest and cardiopulmonary resuscitation (CPR) can lead to intestinal ischemia/reperfusion (I/R) injury. Increasing studies have indicated that hydrogen sulfide (H2S) is in favor of a variety of tissue I/R injury. The purpose of this study was to explore whether sodium hydrosulfide (NaHS), a H2S donor, can protect intestinal mucosa after CPR and its potential mechanisms. MAIN METHODS: Male Sprague-Dawley rats were subjected to 6min cardiac arrest induced by transcutaneous electrical epicardium stimulation and then resuscitated successfully. A bolus of either NaHS (0.5mg/kg) or placebo (NaCl 0.9%) was blindly injected 1min before the start of CPR intravenously, followed by a continuous injection of NaHS (2mg/kg/h) or placebo for 3h. Intestinal and plasma samples were collected for assessments 24h after CPR. KEY FINDINGS: We found that NaHS can markedly alleviate cardiac arrest induced intestinal mucosal injury. Rats treated with NaHS showed a lower malondialdehyde content, higher superoxide dismutase activity and glutathione content in intestine after CPR. Increased intestinal myeloperoxidase activity was significantly decreased by NaHS after CPR. Moreover, a reduced intestinal apoptotic cells after CPR were evident when pretreated with NaHS. Further studies indicated that NaHS enhances the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) in intestine after CPR. SIGNIFICANCE: Our data demonstrated that NaHS treatment before CPR induces intestinal mucosal protection 24h post-resuscitation. The protective effects may be through oxidative stress reduction, inflammation alleviation, apoptosis inhibition and HIF-1alpha activation. PMID- 23727355 TI - Co-regulation of LPS and tensile strain downregulating osteogenicity via c-fos expression. AB - AIMS: Orthodontic forces are known to aggravate inflammation-induced destruction of the periodontium, but the underlying mechanism has not been elucidated. The present study investigates how inflammation and forces co-regulate periodontium damage. MAIN METHODS: Cultures of MC3T3-E1 osteoblasts were pre-treated with conditioned medium from RAW264.7 macrophages exposed to 100ng/ml Porphyromonas gingivalis (Pg)-LPS. Conditioned medium was analyzed by ELISA for interleukin-1 beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha). Osteoblasts were then subjected to tensile strain (0.5Hz; 1000MU or 3000MU) for 0min, 5min, 15min, 30min, 1h, 3h, and 6h. The cultures were analyzed for mRNA and protein levels of c-fos. Cells were also analyzed for alkaline phosphatase (ALP) activity. KEY FINDINGS: (Pg)-LPS stimulated the secretion of all three cytokines from RAW264.7 cells in a dose- and time-dependent manner. Medium from (Pg)-LPS stimulated cells induced a 10-fold increase in c-fos expression, which decreased to a 4-fold plateau after 3h. In contrast, ALP activity of control osteoblasts decreased during the first 60min, then recovered over the next 4h. Pretreatment with conditioned medium generated the same initial decrease during tensile strain but prevented the recovery. SIGNIFICANCE: Our study showed, for the first time, that the inhibitory effect of inflammation and tensile strain on osteogenicity is associated with the upregulation in c-fos expression. In addition, inflammation may reduce the ability of osteoblasts to restore their osteogenic capacity during sustained tensile stress and contribute to periodontium damage. PMID- 23727356 TI - Comparison of subcellular distribution and functions between exogenous and endogenous M1 muscarinic acetylcholine receptors. AB - AIMS: Recombinant systems have been used for evaluating the properties of G protein-coupled receptors (GPCRs) on the assumption of cell surface expression. However, many GPCRs, including muscarinic acetylcholine receptors (mAChRs), have also been reported to be distributed in intracellular organelles in native tissues and cell lines. In this study, we compared the pharmacological profiles of exogenously and endogenously expressed M1-mAChRs, and evaluated the functional properties of these receptors. MAIN METHODS: Recombinant M1-mAChRs were expressed exogenously in Chinese hamster ovary cells (CHO-M1 cells) and compared with endogenously expressed M1-mAChRs in N1E-115 neuroblastoma cells. The pharmacological and functional profiles were evaluated using cell-permeable antagonists (1-quinuclidinyl-benzilate (QNB), pirenzepine and atropine) and cell impermeable antagonists (N-methylscopolamine (NMS) or MT-7). KEY FINDINGS: M1 mAChRs were seen at the cell surface and intracellular sites in both cell lines. Under whole cell conditions, intracellular M1-mAChRs were mainly recognized by cell-permeable ligands, but scarcely by cell-impermeable ligands (at less than 100nM). In CHO-M1 cells, M1-mAChR activation by carbachol resulted in Ca(2+) mobilization, ERK1/2 phosphorylation and a reduction in thymidine incorporation, all of which were completely inhibited by MT-7, indicating the involvement of surface M1-mAChRs. In N1E-115 cells, Ca(2+) mobilization occurred through surface M1-mAChRs, whereas ERK1/2 phosphorylation and acceleration of thymidine incorporation were mediated through intracellular M1-mAChRs. SIGNIFICANCE: Exogenous and endogenous M1-mAChRs are present at both the cell surface and the intracellular organelles, and the pharmacological properties of geographically distinct M1-mAChRs are different, and may depend on cell background and/or exogenous or endogenous origin. PMID- 23727357 TI - Annexin A1 is regulated by domains cross-talk through post-translational phosphorylation and SUMOYlation. AB - Mouse prostate membrane-associated proteins of the annexin family showed changes in SUMOylation during androgen treatment. Among these the calcium-binding annexin A1 protein (ANXA1) was chosen for further characterization given its role in protein secretion and cancer. SUMOylation of ANXA1 was confirmed by overexpressing SUMO-1 in LNCaP cells. Site-directed mutagenesis indicated that K257 located in a SUMOylation consensus motif in the C-terminal calcium-binding DA3 repeat domain is SUMOylated. Mutation of the N-terminal Y21 decreased markedly the SUMOylation signal while EGF stimulation increased ANXA1 SUMOylation. A structural analysis of ANXA1 revealed that K257 is located in a hot spot where Ca(2+) and SUMO-1 bind and where a nuclear export signal and a polyubiquitination site are also present. Also, Y21 is buried inside an alpha helix structure in the Ca(2+)-free conformation implying that Ca(2+) binding, and the subsequent expelling of the N-terminal alpha-helix in a disordered conformation, is permissive for its phosphorylation. These results show for the first time that SUMOylation can be regulated by an external signal (EGF) and indicate the presence of a cross-talk between the N-terminal and C-terminal domains of ANXA1 through post-translational modifications. PMID- 23727358 TI - Pattern and predictability in memory formation: from molecular mechanisms to clinical relevance. AB - Most long-term memories are formed as a consequence of multiple experiences. The temporal spacing of these experiences is of considerable importance: experiences distributed over time (spaced training) are more easily encoded and remembered than either closely spaced experiences, or a single prolonged experience (massed training). In this article, we first review findings from studies in animal model systems that examine the cellular and molecular properties of the neurons and circuits in the brain that underlie training pattern sensitivity during long-term memory (LTM) formation. We next focus on recent findings which have begun to elucidate the mechanisms that support inter-trial interactions during the induction of LTM. Finally, we consider the implications of these findings for developing therapeutic strategies to address questions of direct clinical relevance. PMID- 23727359 TI - WNT-5A triggers Cdc42 activation leading to an ERK1/2 dependent decrease in MMP9 activity and invasive migration of breast cancer cells. AB - An important role for WNT-5A is implicated in a variety of tumors, including breast carcinoma. We previously showed that WNT-5A signaling inhibits migration and metastasis of breast cancer cells, and that patients with primary breast cancer in which WNT-5A was expressed have a better prognosis. Despite the fact that RhoGTPase Cdc42 is commonly associated with increased cell migration, we here show that recombinant WNT-5A activates the Cdc42 in breast cancer cells (lines MDA-MB468 and MDA-MB231) in a time-dependent manner. Activation of Cdc42 was also observed in MDA-MB468 cells that were stably transfected with a WNT-5A plasmid (MDA-MB468-5A). In all situations, increased Cdc42 activity was accompanied by decreased migration and invasion of the breast cancer cells. To explore these findings further we also investigated the effect of WNT-5A signaling on ERK1/2 activity. Apart from an initial Ca(2+)-dependent rWNT-5A induced activation of ERK1/2, Cdc42 activity was inversely correlated with ERK1/2 activity in both rWNT-5A-stimulated parental MDA-MB468 and MDA-MB468-5A cells. We also demonstrated increased ERK1/2 activity in MDA-MB468-5A cells following siRNA knockdown of Cdc42. Consistent with these results, breast cancer cells transfected with constitutively active Cdc42 exhibited reduced ERK1/2 activity, migration and invasion, whereas cells transfected with dominant negative Cdc42 had increased ERK1/2 activity in response to rWNT-5A. To gain information on how ERK1/2 can mediate its effect on breast cancer cell migration and invasion, we next investigated and demonstrated that WNT-5A signaling and constitutively active Cdc42 both decreased matrix metalloproteinase 9 (MMP9) activity. These data indicate an essential role of Cdc42 and ERK1/2 signaling and MMP9 activity in WNT-5A-impaired breast cancer cells. PMID- 23727360 TI - The metastasis-associated molecule C4.4A promotes tissue invasion and anchorage independence by associating with the alpha6beta4 integrin. AB - C4.4A is a metastasis-associated molecule that functions appear to rely on associated alph6beta4 integrin. To corroborate the impact of the C4.4A alpha6beta4 integrin association on metastasis formation, C4.4A was knocked-down in a highly metastatic rat pancreatic adenocarcinoma (ASML, ASML-C4.4Akd). Metastasis formation by ASML-C4.4Akd cells after intrafootpad application was strongly retarded in draining nodes and lung colonization was rare. Furthermore, cisplatin treatment significantly prolonged the survival time only of ASML C4.4Akd-bearing rats. ASML-C4.4Akd cells display reduced migratory activity and impaired matrix protein degradation due to inefficient MMP14 activation; loss of drug-resistance is due to mitigated PI3K/Akt pathway activation. These losses of function rely on the laminin receptor C4.4A recruiting activated alpha6beta4 integrin into rafts, where C4.4A cooperates with alpha6beta4 and via alpha6beta4 with MMP14. Within this raft-located complex, MMP14 provokes focalized matrix degradation and mostly alpha6beta4 integrin promotes BAD phosphorylation and upregulated Bcl2 and BclXl expression. Thus, metastasis-promoting activities of C4.4A are not genuine characteristics of C4.4A. Instead, the raft-located laminin receptor C4.4A recruits alpha6beta4 integrin and supports via the alpha6beta4 integrin MMP14 activation. Thereby C4.4A acts as a linker to facilitate several steps in the metastatic cascade. Taking the restricted C4.4A expression in non transformed tissue, this knowledge should pave the way toward the use of C4.4A as a therapeutic target. PMID- 23727361 TI - Effect of moderate hyperventilation and induced hypertension on cerebral tissue oxygenation after cardiac arrest and therapeutic hypothermia. AB - AIM: Improving cerebral perfusion is an essential component of post-resuscitation care after cardiac arrest (CA), however precise recommendations in this setting are limited. We aimed to examine the effect of moderate hyperventilation (HV) and induced hypertension (IH) on non-invasive cerebral tissue oxygenation (SctO2) in patients with coma after CA monitored with near-infrared spectroscopy (NIRS) during therapeutic hypothermia (TH). METHODS: Prospective pilot study including comatose patients successfully resuscitated from out-of-hospital CA treated with TH, monitored with NIRS. Dynamic changes of SctO2 upon HV and IH were analyzed during the stable TH maintenance phase. HV was induced by decreasing PaCO2 from ~40 to ~30 mmHg, at stable mean arterial blood pressure (MAP~70 mmHg). IH was obtained by increasing MAP from ~70 to ~90 mmHg with noradrenaline. RESULTS: Ten patients (mean age 69 years; mean time to ROSC 19 min) were studied. Following HV, a significant reduction of SctO2 was observed (baseline 74.7+/-4.3% vs. 69.0+/-4.2% at the end of HV test, p<0.001, paired t-test). In contrast, IH was not associated with changes in SctO2 (baseline 73.6+/-3.5% vs. 74.1+/-3.8% at the end of IH test, p=0.24). CONCLUSIONS: Moderate hyperventilation was associated with a significant reduction in SctO2, while increasing MAP to supra-normal levels with vasopressors had no effect on cerebral tissue oxygenation. Our study suggests that maintenance of strictly normal PaCO2 levels and MAP targets of 70mmHg may provide optimal cerebral perfusion during TH in comatose CA patients. PMID- 23727362 TI - 50Years of poly(ADP-ribosyl)ation. AB - The seminal paper published in 1963 by Chambon, Weil and Mandel reporting a new NAD-dependent protein modification now known as poly(ADP-ribosyl)ation (PARylation) marked the launch of a new era in both protein research and cell biology. In the coming decades, the identity, biochemical characteristics and regulation of enzymes responsible for the synthesis and degradation of protein bound poly(ADP-ribose) have been discovered and the surprisingly multifarious biological roles of PARylation have not ceased to amaze cell and molecular biologists ever since. The review series on PARylation following this preface is comprised of ten papers written by great experts of the field and aims to provide practicing physicians and basic scientists with the state-of-the-art on the "writers, readers and erasers" of poly(ADP-ribose), some recent paradigm shifts of the field and its translational potential. PMID- 23727363 TI - The profiling and identification of the absorbed constituents and metabolites of Paeoniae Radix Rubra decoction in rat plasma and urine by the HPLC-DAD-ESI-IT-TOF MS(n) technique: a novel strategy for the systematic screening and identification of absorbed constituents and metabolites from traditional Chinese medicines. AB - Paeoniae Radix Rubra (PRR, the dried roots of Paeonia lactiflora) is a commonly used traditional Chinese medicine (TCM). A clear understanding of the absorption and metabolism of TCMs is very important in their rational clinical use and pharmacological research. To find more of the absorbed constituents and metabolites of TCMs, a novel strategy was proposed. This strategy was characterized by the following: the establishment and utilization of the databases of parent compounds, known metabolites and characteristic neutral losses; the comparison of base peak chromatograms and ClogPs; and the use of the HPLC-DAD-ESI-IT-TOF-MS(n) technique. This strategy was first applied to screen and identify the absorbed constituents and metabolites of PRR decoction and paeoniflorin in rats. In total, 13 new absorbed constituents and 90 new metabolites of PRR decoction were detected. Among these metabolites, the structures of 70 metabolites were identified, and the conjugation types and structure skeletons of the other 20 metabolites were preliminarily determined. Moreover, 35 new metabolites of some constituents of PRR, i.e., 22 new metabolites of paeoniflorin, 10 new metabolites of gallic acid-related compounds, 1 new metabolite of (epi)catechin-related compounds, and 2 new metabolites of other compounds, were reported for the first time. The results also indicated that (epi)catechin-related compounds, gallic acid-related compounds and paeoniflorin were the main precursors of these metabolites. Phase I reactions (dehydroxylation, decarboxylation, dehydrogenation) and phase II reactions (sulfation, glucuronidation and methylation) were observed as the main metabolic pathways of PRR. According to the literature, the 11 absorbed constituents and 11 metabolites have various bioactivities. This study is the first to explore the absorption and metabolism of PRR decoction, and the result also is a notable improvement in the discovery of paeoniflorin metabolites in vivo. These findings enhance our understanding of the metabolism and Effective forms (the truly active structures) of PRR decoction and paeoniflorin. PMID- 23727365 TI - Proteogenomic insights into salt tolerance by a halotolerant alpha proteobacterium isolated from an Andean saline spring. AB - Tistlia consotensis is a halotolerant Rhodospirillaceae that was isolated from a saline spring located in the Colombian Andes with a salt concentration close to seawater (4.5%w/vol). We cultivated this microorganism in three NaCl concentrations, i.e. optimal (0.5%), without (0.0%) and high (4.0%) salt concentration, and analyzed its cellular proteome. For assigning tandem mass spectrometry data, we first sequenced its genome and constructed a six reading frame ORF database from the draft sequence. We annotated only the genes whose products (872) were detected. We compared the quantitative proteome data sets recorded for the three different growth conditions. At low salinity general stress proteins (chaperons, proteases and proteins associated with oxidative stress protection), were detected in higher amounts, probably linked to difficulties for proper protein folding and metabolism. Proteogenomics and comparative genomics pointed at the CrgA transcriptional regulator as a key factor for the proteome remodeling upon low osmolarity. In hyper-osmotic condition, T. consotensis produced in larger amounts proteins involved in the sensing of changes in salt concentration, as well as a wide panel of transport systems for the transport of organic compatible solutes such as glutamate. We have described here a straightforward procedure in making a new environmental isolate quickly amenable to proteomics. BIOLOGICAL SIGNIFICANCE: The bacterium Tistlia consotensis was isolated from a saline spring in the Colombian Andes and represents an interesting environmental model to be compared with extremophiles or other moderate organisms. To explore the halotolerance molecular mechanisms of the bacterium T. consotensis, we developed an innovative proteogenomic strategy consisting of i) genome sequencing, ii) quick annotation of the genes whose products were detected by mass spectrometry, and iii) comparative proteomics of cells grown in three salt conditions. We highlighted in this manuscript how efficient such an approach can be compared to time-consuming genome annotation when pointing at the key proteins of a given biological question. We documented a large number of proteins found produced in greater amounts when cells are cultivated in either hypo-osmotic or hyper-osmotic conditions. This article is part of a Special Issue entitled: Trends in Microbial Proteomics. PMID- 23727364 TI - Novel sample preparation method for surfactant containing suppositories: effect of micelle formation on drug recovery. AB - Rectal drug delivery is currently at the focus of attention. Surfactants promote drug release from the suppository bases and enhance the formulation properties. The aim of our work was to develop a sample preparation method for HPLC analysis for a suppository base containing 95% hard fat, 2.5% Tween 20 and 2.5% Tween 60. A conventional sample preparation method did not provide successful results as the recovery of the drug failed to fulfil the validation criterion 95-105%. This was caused by the non-ionic surfactants in the suppository base incorporating some of the drug, preventing its release. As guidance for the formulation from an analytical aspect, we suggest a well defined surfactant content based on the turbidimetric determination of the CMC (critical micelle formation concentration) in the applied methanol-water solvent. Our CMC data correlate well with the results of previous studies. As regards the sample preparation procedure, a study was performed of the effects of ionic strength and pH on the drug recovery with the avoidance of degradation of the drug during the procedure. Aminophenazone and paracetamol were used as model drugs. The optimum conditions for drug release from the molten suppository base were found to be 100 mM NaCl, 20-40 mM NaOH and a 30 min ultrasonic treatment of the final sample solution. As these conditions could cause the degradation of the drugs in the solution, this was followed by NMR spectroscopy, and the results indicated that degradation did not take place. The determined CMCs were 0.08 mM for Tween 20, 0.06 mM for Tween 60 and 0.04 mM for a combined Tween 20, Tween 60 system. PMID- 23727366 TI - Brainstem epidermoid cyst in an individual with two previous intracranial epidermoid cysts: a rare diagnosis in a rare individual. PMID- 23727367 TI - Prevalence and incidence of Multiple Sclerosis in Campobasso (Molise region chieftown, southern Italy). AB - OBJECTIVE: Multiple Sclerosis in southern Italy was not epidemiologically studied until 2006 in Salerno (Campania region), with data based on the registry of district MS centers established since 1996 by Italian Ministry of Health. This paper reports data about Molise region by the same metodology as Campanian study. PATIENTS AND METHODS: The registry of MS center was searched for the city of Campobasso, chief town of Molise region. Population screened: 51,633 units. ISTAT 2005 data were used for comparison and age standardization. Prevalence day: September 30, 2009; incidence was calculated by cumulative rates 1996-2000 and 2001-2005. RESULTS: 47 patients were collected, 17 males, 30 females, age 44.10 (9-74, SD 14.38); female/male ratio=1.76/1; age onset 34.61 (4-61, SD 12.40); mean disease duration 9.48 years (0-24; SD 4.28). Males prevalence: 68.62/100,000; females: 111.68/100,000. Total prevalence: 91.02/100,000; standardized: 90.91/100,000. Incidence rates: 1996-2000: 10.84/100,000; 2001 2005: 4.26/100,000. CONCLUSIONS: Prevalence is coherent with previous Campanian data, and with last epidemiologic papers on middle Italy, confirming also the validity of MS district centers registries. A possible underestimation of data, for some patients could still migrate to northern centers, could contribute to the differences in incidence. Nevertheless, prevalence data confirm southern Italy as high risk area for MS, and stands against a latitude gradient in this country. PMID- 23727368 TI - Characterization of fasted human gastric fluid for relevant rheological parameters and gastric lipase activities. AB - PURPOSE: To characterize human gastric fluid with regard to rheological properties and gastric lipase activity. In addition, traditional physicochemical properties were determined. METHODS: Fasted HGA were collected from 19 healthy volunteers during a gastroscopic examination. Rheological characterization of the aspirates was conducted on a TA AR-G2 rheometer, using cone and plate geometry. Lipase activity was measured by continuous titration of released free fatty acid from tributyrate. Further, pH, osmolality, buffer capacity, and surface tension were measured and the total protein content and bile salt level were determined using assay kits. RESULTS: Rheological examination of HGA showed non-Newtonian shear-thinning behavior with predominant elastic behavior in the linear range. The apparent viscosity was measured to be in the range of 1.7-9.3 mPas at a shear rate of 50s(-1). The FaSSGF and HCl pH 1.2 have no shear-thinning properties and showed lower viscosity (1.1 mPas at 50 s(-1)). The observed viscosity of the HGA will decrease the intrinsic dissolution rate of drugs. The activity of the gastric lipase was 7.4 +/- 4.0 U/mL (N = 6, n = 3) and 99.0 +/- 45.3 U/mL (N = 19, n = 3) at pH 2.8 and 5.4, respectively. pH, surface tension, buffer capacity, bile salt concentration, and osmolality were measured and compared with literature data. CONCLUSION: The rheological behavior and the mean apparent viscosity of HGA are significantly different from that of water and should therefore be considered important during development of gastric simulated media. Further, the activity of the HGL is active even under fasted gastric conditions and might contribute to the digestion and emulsification of lipid-based drug delivery systems in the entire gastrointestinal tract. HGL should therefore be considered in gastric evaluation of lipid-based drug delivery systems. PMID- 23727369 TI - Systematic investigation of the effect of lyophilizate collapse on pharmaceutically relevant proteins III: collapse during storage at elevated temperatures. AB - This study investigates the effect of lyophilizate collapse on the stability of pharmaceutical proteins. Recently, it was shown that collapse during freeze drying has no major negative impact on protein stability during storage at elevated temperatures when compared to non-collapsed cakes [1,2]. In this part of the study, lyophilizates that collapsed during the freeze-drying process were compared to cakes that were initially non-collapsed but collapsed during subsequent storage under accelerated stress conditions. Collapsed and non collapsed lyophilizates of identical formulation and comparable residual moisture levels, containing a monoclonal IgG antibody, were stored at 40 degrees C and 50 degrees C for up to 3 months. Protein stability was monitored using a comprehensive set of analytical techniques assessing the formation of soluble and insoluble aggregates as well as protein conformation. The properties of the freeze-dried cake, namely the glass transition temperature, excipient crystallinity, sucrose degradation, reconstitution behavior, and the residual moisture content, were analyzed as well. The incorporated protein was significantly better stabilized in cakes that collapsed during the freeze-drying process when compared to lyophilizates that collapsed during subsequent storage. This effect can be related to the onset of crystallization and hydrolysis of the stabilizer and non-enzymatic browning. PMID- 23727370 TI - Unique SERM-like properties of the novel fluorescent tamoxifen derivative FLTX1. AB - Tamoxifen is a selective estrogen receptor modulator extensively used on estrogen receptor-positive breast cancer treatment. However, clinical evidences demonstrate the increased incidence of undesirable side effects during chronic therapies, the most life threatening being uterine cancers. Some of these effects are related to tissue-dependent estrogenic actions of tamoxifen, but the exact mechanisms remain poorly understood. We have designed and synthesized a novel fluorescent tamoxifen derivative, FLTX1, and characterized its biological and pharmacological activities. Using confocal microscopy, we demonstrate that FLTX1 colocalizes with estrogen receptor alpha (ERalpha). Competition studies showed that FLTX1 binding was totally displaced by unlabeled tamoxifen and partially by estradiol, indicating the existence of non-ER-related triphenylethylene-binding sites. Ligand binding assays showed that FLTX1 exhibits similar affinity for ER than tamoxifen. FLTX1 exhibited antiestrogenic activity comparable to tamoxifen in MCF7 and T47D cells transfected with 3xERE-luciferase reporter. Interestingly, FLTX1 lacked the strong agonistic effect of tamoxifen on ERalpha-dependent transcriptional activity. Additionally, in vivo assays in mice revealed that unlike tamoxifen, FLTX1 was devoid of estrogenic uterotrophic effects, lacked of hyperplasic and hypertrophic effects, and failed to alter basal proliferating cell nuclear antigen immunoreactivity. In the rat uterine model of estrogenicity/antiestrogenicity, FLTX1 displayed antagonistic activity comparable to tamoxifen at lower doses, and only estrogenic uterotrophy at the highest dose. We conclude that the fluorescent derivative FLTX1 is not only a suitable probe for studies on the molecular pharmacology of tamoxifen, but also a potential therapeutic substitute to tamoxifen, endowed with potent antiestrogenic properties but devoid of uterine estrogenicity. PMID- 23727371 TI - D-penicillamine and other low molecular weight thiols: review of anticancer effects and related mechanisms. AB - Low molecular weight thiols (LMWTs) like N-acetyl cysteine, D-penicillamine, captopril, Disulfiram and Amifostine, etc. have been used as chemo-preventive agents. Recent studies have reported cell growth inhibition and cytotoxicity in several different types of cancer cells following treatment with several LMWTs. Cytotoxic and cytostatic effects of LMWTs may involve interaction of the thiol group with cellular lipids, proteins, intermediates or enzymes. Some of the mechanisms that have been proposed include a p53 mediated apoptosis, thiyl radical induced DNA damage, membrane damage through lipid peroxidation, anti angiogenic effects induced by inhibition of matrix metalloproteinase enzymes and angiostatin generation. LMWTs are strong chelators of transition metals like copper, nickel, zinc, iron and cobalt and may cause metal co-factor depletion resulting in cytotoxicity. Oxidation of thiol group can also generate cytotoxic reactive oxygen species (ROS). PMID- 23727372 TI - [Megalencephaly with dystonia revealing Canavan disease]. AB - Canavan disease, or N-acetyl aspartic aciduria, is an autosomal recessive leukodystrophy characterized by spongy degeneration of the brain. The disease results from the accumulation of N-acetyl aspartic acid in the brain, due to aspartoacylase deficiency. We report the case of a 6-month-old girl who presented with megalencephaly, peripheral hypertonia, and a developmental delay noticeable after 4 months of age. Magnetic resonance imaging of the brain with spectroscopy was suggestive of Canavan disease, which was confirmed by chromatography of urinary organic acids. PMID- 23727373 TI - [Meno-metrorrhagia, dysmenorrhea in adolescents]. AB - Menometrorrhagia is a common symptom in adolescents. It is idiopathic in most cases. In case of menometrorrhagia, it is necessary to exclude a pregnancy, a disorder of hemostasis, particularly the von Willebrand disease, as it represents the most common inherited disorder, and more rarely a chronic disease or an endocrinopathy. History of the bleedings, menstrual blood loss quantification by the Higham score and tolerance of the bleedings (blood pressure) should be evaluated. Laboratory testing includes hCG, ferritin level, a complete blood count, a prothrombin time, an activated partial thromboplastin. Management of menometrorrhagia is related to the severity of the blood loss. It associates antifibrinolytics or non-steroidal anti-inflammatory agents (NSAIDS) with hormonal treatments, such as estrogen-progestin oral contraceptive pill or cyclic oral progestins. Primary or functional dysmenorrhea concerns 40 to 90% of the teenagers and represents a frequent cause of school absenteeism. Management of primary dysmenorrhea is primarily based on a treatment by NSAIDS. In case of its inefficacy or if contraception is needed hormonal treatments, such as estrogen progestin combined pill should be prescribed. It is very important when pelvic pain is chronic and not soothed by simple medications to look for a secondary dysmenorrhea, mainly endometriosis. In such cases, pelvic magnetic resonance imaging should be performed. PMID- 23727374 TI - [Diagnosis and management of amenorrhea in adolescent girls]. AB - Amenorrhea in adolescents can be primary, with or without breast development, or secondary. Whether amenorrhea is primary or secondary, height, body mass index, food intake, the level of physical activity per week, the presence of hirsutism or galactorrhea, pelvic pain and past history of intercourse need to be investigated. Initially, blood tests should include hCG, FSH, estradiol, testosterone and prolactin serum levels. This screening will discriminate between hypogonadotropic hypogonadism and amenorrhea from primary ovarian insufficiency (POI). In case of primary amenorrhea, hypogonadism may be due to congenital hypogonadotropic hypogonadism (HH) or more rarely acquired HH. If FSH is elevated, amenorrhea is due to primary ovarian failure, mainly related to Turner syndrome. If pubertal development is normal, a pelvic ultrasound should be performed. It may visualize a hindering of menses output or less frequently an absence of uterus, as in Rokitansky syndrome or androgen insentivity syndrome. The most frequent etiologies of secondary amenorrhea are polycystic ovarian syndrome (PCOS), functional hypothalamic amenorrhea and less frequently POI and hyperprolactinemia. The differential diagnoses of PCOS are late-onset 21 hydroxylase deficiency and very rare ovarian or adrenal tumors. When contraception is not necessary, hormonal replacement therapy, including estrogen and progestins should be administered in order to avoid hypoestrogenism. In case of PCOS, sequential progestins can be prescribed. A contraceptive pill can be considered when contraception is needed and/or when hyperandrogenism needs to be treated. PMID- 23727375 TI - Application of contrast-enhanced ultrasound in the diagnosis of solid pancreatic lesions--a comparison of conventional ultrasound and contrast-enhanced CT. AB - OBJECTIVE: To explore the diagnostic value of contrast-enhanced ultrasound (CEUS) by comparison with conventional ultrasound (US) and contrast-enhanced CT (CECT) in solid pancreatic lesions. METHOD: Ninety patients with solid pancreatic focal lesions were enrolled, including 36 cases of pancreatic carcinoma, 28 cases of pancreatitis, 6 cases of pancreatic neuroendocrine tumor, 12 cases of solid pseudopapillary tumor of the pancreas, 6 cases of pancreatic metastases, 1 case of cavernous hemolymphangioma and 1 case of lymphoma. US and CEUS were applied respectively for the diagnosis of a total of 90 cases of solid pancreatic lesions. The diagnostic results were scored on a 5-point scale. Results of CEUS were compared with CECT. RESULTS: (1) 3-score cases (undetermined) diagnosed by CEUS were obviously fewer than that of US, while the number of 1-score (definitely benign) and 5-score (definitely malignant) cases diagnosed by CEUS was significantly more than that of US. There was a significant difference in the distribution of final scores using the two methods (p<0.001). The overall diagnostic accuracies of the 90 cases for CEUS and US were 83.33% and 44.44%, respectively, which indicated an obvious advantage for CEUS (p<0.001). (2) The diagnostic consistency among three ultrasound doctors: the kappa values calculated for US were 0.537, 0.444 and 0.525, compared with 0.748, 0.645 and 0.795 for CEUS. The interobserver agreement for CEUS was higher than that for US. (3) The sensitivity, specificity and accuracy of the diagnosis of pancreatic carcinoma with CEUS and CECT were 91.7% and 97.2%, 87.0% and 88.9%, and 88.9% and 92.2%, respectively, while for the diagnosis of pancreatitis, the corresponding indices were 82.1% and 67.9%, 91.9% and 100%, and 88.9% and 90%, respectively, showing no significant differences (p>0.05). CONCLUSION: CEUS has obvious superiority over conventional US in the general diagnostic accuracy of solid pancreatic lesions and in the diagnostic consistency among doctors. The performances of CEUS are similar to that of CECT in the diagnosis of pancreatic carcinoma and focal pancreatitis. PMID- 23727376 TI - CT volumetry of artificial pulmonary nodules using an ex vivo lung phantom: influence of exposure parameters and iterative reconstruction on reproducibility. AB - OBJECTIVES: To evaluate the influence of exposure parameters and raw-data based iterative reconstruction (IR) on the measurement variability of computer-aided nodule volumetry on chest multidetector computed tomography (MDCT). MATERIALS AND METHODS: N=7 porcine lung explants were inflated in a dedicated ex vivo phantom and prepared with n=162 artificial nodules. MDCT was performed eight consecutive times (combinations of 120 and 80 kV with 120, 60, 30 and 12 mAs), and reconstructed with filtered back projection (FBP) and IR. Nodule volume and diameter were measured semi-automatically with dedicated software. The absolute percentage measurement error (APE) was computed in relation to the 120 kV 120 mAs acquisition. Noise was recorded for each nodule in every dataset. RESULTS: Mean nodule volume and diameter were 0.32 +/- 0.15 ml and 12.0 +/- 2.6mm, respectively. Although IR reduced noise by 24.9% on average compared to FBP (p<0.007), APE with IR was equal to or slightly higher than with FBP. Mean APE for volume increased significantly below a volume computed tomography dose index (CTDI) of 1.0 mGy: for 120 kV 12 mAs APE was 3.8 +/- 6.2% (FBP) vs. 4.0 +/- 5.2% (IR) (p<0.007); for 80 kV 12 mAs APE was 8.0 +/- 13.0% vs. 9.3 +/- 15.8% (n.s.), respectively. Correlating APE with image noise revealed that at identical noise APE was higher with IR than with FBP (p<0.05). CONCLUSIONS: Computer-aided volumetry is robust in a wide range of exposure settings, and reproducibility is reduced at a CTDI below 1.0 mGy only, but the error rate remains clinically irrelevant. Noise reduction by IR is not detrimental for measurement error in the setting of semi-automatic nodule volumetry on chest MDCT. PMID- 23727377 TI - Discrepancies in determination of abdominal aortic aneurysms maximum diameter and growth rate, using axial and orhtogonal computed tomography measurements. AB - PURPOSE: Maximum diameter and growth rate of abdominal aortic aneurysms (AAAs) which are currently used as the only variables to set the indication for elective repair are recorded through computed tomography (CT) measurements on an axial plane or on an orthogonal plane that is perpendicular to vessel centerline, interchangeably. We will attempt to record possible discrepancies between the two methods, identify whether such differences could influence therapeutic decisions and determine in which cases this should be expected. MATERIALS AND METHODS: We retrospectively reviewed sixty CT-scans performed in thirty-nine patients. Three dimensional reconstruction of AAAs has been performed and differences in maximum diameter measured on axial and orthogonal planes were recorded. A measure for asymmetry was introduced termed ShapeIndex defined as the value of section minor over major axis and was related with differences in maximum diameter recordings. Growth rates were also determined using both axial and orthogonal measurements. RESULTS: Axial measurements overestimate maximum diameter by 2 +/- 2.7 mm (P<0.001) with a range of 0-12.3mm. Overall, 20% of the CTs had an axial maximum diameter >5.5 cm indicating the need for intervention whereas, orthogonal diameter was below that threshold. Asymmetry of the axial sections with ShapeIndex<=0.8 was found to be related to an overestimation of maximum diameter by >5mm. There were no significant differences in growth rates when determined using orthogonal or axial measurements in both examinations (median growth rate: 2.3mm and 3.3mm respectively P=0.2). However there were significant differences when orthogonal measurements were used at initial and axial measurements used at follow-up examination or vice versa (median growth rate: 4.9 mm and 0.9 mm respectively P<0.001). CONCLUSIONS: Although the mean difference between measurements is low there is a wide range among cases, mainly observed in asymmetrical AAAs. ShapeIndex may identify those which are more likely to be misestimated. CT measurements performed to establish AAA growth rates should consistently use either the axial or orthogonal technique to avoid inaccuracies from occurring. PMID- 23727378 TI - Crohn's disease recurrence in patients with ileocolic anastomosis: value of computed tomography enterography with water enema. AB - OBJECTIVES: The main objective of the present work was to determine the diagnostic value of CT-enterography with water enema (CTe-WE) in the assessment of the ileocolic anastomosis in patients with Crohn's disease (CD). The prevalence of synchronous inflammatory lesions (SILs) involving gastrointestinal segments distinct from the anastomosis was also determined. Further, the association between the type of ileocolic anastomosis and the behavior (i.e. inflammatory, stricturing, penetrating) of CD recurrence was evaluated. METHODS: 51 patients were retrospectively included (26 [51%] male and 25 [49%] female; mean age: 52.88 years +/- 13.35). Ileocolic anastomoses were: 18 (35.3%) stapled side-to-side, 17 (33.3%) end-to-side, and 16 (31.4%) end-to-end. CTe-WEs were reviewed in consensus by two gastrointestinal radiologists. Endoscopy and medical records were used as reference standards. RESULTS: CTe-WE yielded 95.35% sensitivity (CI 95%: 84.19-99.43%), 75.00% specificity (CI 95%: 34.91-96.81%), and 92.15% diagnostic accuracy (CI 95%: 81.31-98.02%). Anastomotic recurrence was found in 41/51 (80.4%) patients, including 30/41 (73.2%) cases of isolated anastomotic recurrence, and 11/41 (26.8%) cases of anastomotic recurrence with a SIL. A significant lower prevalence of stricturing recurrence was observed in patients with stapled side-to-side anastomoses (p=0.033). CONCLUSIONS: CTe-WE provides a good distension of both sides of ileocolic anastomoses allowing the detection of SILs. PMID- 23727379 TI - Variability of breast density assessment in short-term reimaging with digital mammography. AB - OBJECTIVE: To evaluate the variability of breast density assessments in short term reimaging with digital mammography. MATERIALS AND METHODS: In 186 women, short term (mean interval, 27.6 days) serial digital mammograms including CC and MLO views were obtained without any treatment. Mammographic density assessments were performed by three blinded radiologists for Breast Imaging Report and Data System (BI-RADS, grades 1-4) and visual percentage density (PD) estimation, and by one radiologist for computer-aided PD estimation. The variability of assessments was analyzed according to the age, breast density, and mammography types by multivariate logistic regression. RESULTS: In BI-RADS assessments, 29% (161 of 558) of breast density categories were assessed differently after short term reimaging and the mean absolute difference in PD for CC and MLO view was 7.6% and 8.1% for visual assessments, and 7.4% and 6.4% for computer-aided assessments, respectively. Among all computer-aided assessments, 29% (54 of 186) of CC view and 22% (41 of 186) of MLO view assessments had discrepancy over 10% in PD. Younger age (<50), greater breast density (grades 3 and 4), and different mammography types were significantly associated with the variability. CONCLUSION: Considerable variability in breast density assessments occurred in short-term reimaging with digital mammography, particularly in women with younger age and greater breast density and when examined using different types of mammography. PMID- 23727380 TI - Value of fusion of PET and MRI for staging of endometrial cancer: comparison with 18F-FDG contrast-enhanced PET/CT and dynamic contrast-enhanced pelvic MRI. AB - PURPOSE: To investigate the diagnostic value of retrospective fusion of pelvic MRI and (18)F-fluorodeoxyglucose ((18)F-FDG) PET images for assessment of locoregional extension and nodal staging of endometrial cancer. MATERIALS AND METHODS: Thirty patients with biopsy-proven endometrial cancer underwent preoperative contrast-enhanced PET/CT (PET/ceCT) and pelvic dynamic contrast enhanced MRI for initial staging. Diagnostic performance of PET/ceCT, contrast enhanced MRI, and retrospective image fusion from PET and MRI (fused PET/MRI) for assessing the extent of the primary tumor (T stage) and metastasis to regional LNs (N stage) was evaluated by two experienced readers. Histopathological and follow-up imaging results were used as the gold standard. The McNemar test was employed for statistical analysis. RESULTS: Fused PET/MRI and MRI detected 96.7% of the primary tumors, whereas PET/ceCT detected 93.3%. Accuracy for T status was 80.0% for fused PET/MRI, and MRI proved significantly more accurate than PET/ceCT, which had an accuracy of 60.0% (p=0.041). Patient-based sensitivity, specificity and accuracy for detecting pelvic nodal metastasis were 100%, 96.3% and 96.7% for both fused PET/MRI and PET/ceCT, and 66.7%, 100% and 96.7% for MRI, respectively. These three parameters were not statistically significant (p=1). CONCLUSION: Fused PET/MRI, which complements the individual advantages of MRI and PET, is a valuable technique for assessment of the primary tumor and nodal staging in patients with endometrial cancer. PMID- 23727381 TI - Diagnostic accuracy of dual-source CT coronary angiography in patients with atrial fibrillation: meta analysis. AB - RATIONALE AND OBJECTIVE: To synthesize the available data to underscore the diagnostic accuracy of dual-source CT (DSCT) coronary angiography in patients with atrial fibrillation (AF). MATERIALS AND METHODS: We searched in the electronic databases of PubMed for all published studies that examined patients with AF using DSCT. We used an exact binomial rendition of the bivariate mixed effects regression model to synthesize the diagnostic data. RESULTS: The positive and negative likelihood ratios (LRs) at the patient level were 6.0 (CI, 3.6-10.1) and 0.03(CI, 0.004-0.2), respectively. The negative predictive values higher than 90% were available for a CAD prevalence <78%. The pooled vessel- and segment level estimates showed higher positive and negative LRs than the patient-level estimates (15.3 [CI, 9.8-23.9] and 0.1 [CI, 0.07-0.3]; 25.1 [CI, 10.8-58.5] and 0.2 [CI, 0.2-0.3], respectively). No statistically significant heterogeneity between studies and publication bias were found at the patient level estimate. A sensitivity analysis showed that no study influenced the pooled results larger than 0.02. CONCLUSIONS: Cardiac angiography with DSCT can be applied as an imaging test for ruling out CAD in patient with AF. However, DSCT angiography may be not an effective tool for risk stratification for the high negative LR at the artery and segment levels. PMID- 23727382 TI - A novel photoinduced electron transfer (PET) primer technique for rapid real-time PCR detection of Cryptosporidium spp. AB - We report the development of a fluorescently labeled oligonucleotide primer that can be used to monitor real-time PCR. The primer has two parts, the 3'-end of the primer is complimentary to the target and a universal 17-mer stem loop at the 5' end forms a hairpin structure. A fluorescent dye is attached to 5'-end of either the forward or reverse primer. The presence of guanosine residues at the first and second position of the 3' dangling end effectively quenches the fluorescence due to the photo electron transfer (PET) mechanism. During the synthesis of nucleic acid, the hairpin structure is linearized and the fluorescence of the incorporated primer increases several-fold due to release of the fluorescently labeled tail and the absence of guanosine quenching. As amplicons are synthesized during nucleic acid amplification, the fluorescence increase in the reaction mixture can be measured with commercially available real-time PCR instruments. In addition, a melting procedure can be performed to denature the double-stranded amplicons, thereby generating fluorescence peaks that can differentiate primer dimers and other non-specific amplicons if formed during the reaction. We demonstrated the application of PET-PCR for the rapid detection and quantification of Cryptosporidium parvum DNA. Comparison with a previously published TaqMan(r) assay demonstrated that the two real-time PCR assays exhibited similar sensitivity for a dynamic range of detection of 6000-0.6 oocysts per reaction. PET PCR primers are simple to design and less-expensive than dual-labeled probe PCR methods, and should be of interest for use by laboratories operating in resource-limited environments. PMID- 23727383 TI - Radicicol, a heat shock protein 90 inhibitor, inhibits differentiation and adipogenesis in 3T3-L1 preadipocytes. AB - Heat shock protein 90 (Hsp90) is involved in various cellular processes, such as cell proliferation, differentiation and apoptosis. As adipocyte differentiation plays a critical role in obesity development, the present study investigated the effect of an Hsp90 inhibitor radicicol on the differentiation of 3T3-L1 preadipocytes and potential mechanisms. The cells were treated with different concentrations of radicicol during the first 8days of cell differentiation. Adipogenesis, the expression of adipogenic transcriptional factors, differentiation makers and cell cycle were determined. It was found that radicicol dose-dependently decreased intracellular fat accumulation through down regulating the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT element binding protein alpha (C/EBPalpha), fatty acid synthase (FAS) and fatty acid-binding protein 4 (FABP4). Flow cytometry analysis revealed that radicicol blocked cell cycle at G1-S phase. Radicicol redcued the phosphorylation of Akt while showing no effect on beta-catenin expression. Radicicol decreased the phosphorylation of phosphoinositide-dependent kinase 1 (PDK1). The results suggest that radicicol inhibited 3T3-L1 preadipocyte differentiation through affecting the PDK1/Akt pathway and subsequent inhibition of mitotic clonal expansion and the expression/activity of adipogenic transcriptional factors and their downstream adipogenic proteins. PMID- 23727384 TI - Multiple red blood cell flows through microvascular bifurcations: cell free layer, cell trajectory, and hematocrit separation. AB - Multiple red blood cell (RBC) flows through a symmetric microvascular bifurcation model have been simulated with the two-dimensional immersed-boundary lattice Boltzmann method. The cell free layer (CFL), the RBC separation process and trajectories, and the resulting hematocrit distributions in the daughter branches have been examined, and the effects of cell deformability, aggregation, and feeding hematocrit on the RBC separation have also been investigated. Our results show that the overall phase separation behavior is mainly related to the RBC distribution in the feeding flow (i.e., the CFL thickness). On the other hand, for individual RBCs, the hydrodynamic interaction plays a non-negligible role in determining their trajectories and destinations. A detailed examination of the flow and pressure fields in the bifurcation region indicates that the difference in flow pressure across the front and rear ends of a flowing RBC is the major driving force for the cell motion; while the shear stress on the back of a cell that has been pressed against the corner wall is responsible for the cell's slow sliding into a vessel branch. The results have also been compared with experimental studies, and reasonable agreement has been observed. The results and information from this study could be helpful for understanding the complex RBC separation process and its effects in microcirculation and relevant biomedical applications. PMID- 23727385 TI - Skin blood flow response to locally applied mechanical and thermal stresses in the diabetic foot. AB - Diabetic foot ulcers are one of the most common complications in diabetics, causing significant disabilities and decreasing the quality of life. Impaired microvascular reactivity contributes to the development of diabetic foot ulcers. However, underlying physiological mechanisms responsible for the impaired microvascular reactivity in response to extrinsic causative factors of foot ulcers such as mechanical and thermal stresses have not been well investigated. A total of 26 participants were recruited into this study, including 18 type 2 diabetics with peripheral neuropathy and 8 healthy controls. Laser Doppler flowmetry was used to measure skin blood flow at the first metatarsal head in response to a mechanical stress at 300mmHg and a fast thermal stress at 42 degrees C. Wavelet analysis of skin blood flow oscillations was used to assess metabolic, neurogenic and myogenic controls. Our results indicated that diabetics have significantly decreased metabolic, neurogenic and myogenic responses to thermal stress, especially in the neurogenic and myogenic controls during the first vasodilatory response and in the metabolic control during the second vasodilatory response. Diabetics have a significantly decreased myogenic response to mechanical stress during reactive hyperemia. Our findings demonstrate that locally applied mechanical and thermal stresses can be used to assess microvascular reactivity and risk of diabetic foot ulcers. PMID- 23727386 TI - Mitochondria in biology and medicine--2012. AB - As the understanding of mitochondria and their importance for the cell and organism is developing, increasing evidence is demonstrating the organelle to be intricately involved in an extensive range of pathologies. This range of pathologies include general signs of premature aging, neuro-muscular dysfunctions, cancer, diabetes, various heart diseases, inflammation and other conditions not previously known to be related to mitochondrial function. A better understanding of mitochondria therefore allows a better understanding of related pathologies. It enables the usage of mitochondrial function as biomarkers for the diseases and most important, it opens the possibility of a treatment or a cure for a disease. "Mitochondria in Biology and Medicine" was the title of the second annual conference of Society of Mitochondrial Research and Medicine-India. The conference was organized by Rana P. Singh, Keshav Singh and Kumarasamy Thangaraj, and was held at the newly opened School of Life Sciences, Central University of Gujarat (CUG), Gandhinagar, India, during 2-3 November 2012. The conference featured talks from internationally renowned scientists within the field of mitochondrial research and offered both students and fellow researchers a comprehensive update to the newest research within the field. This paper summarizes key outcomes of the presentations. PMID- 23727387 TI - The dopamine agonist apomorphine enhances conditioned pain modulation in healthy humans. AB - Although cumulative evidence suggests that dopamine plays a role in pain processing, the mechanisms by which dopaminergic transmission affects pain remain elusive. Conditioned pain modulation (CPM) is a psychophysical paradigm based on endogenous descending inhibitory pain modulation. The current study was aimed to test the effects of apomorphine, a non-specific dopamine agonist, on the magnitude of CPM in healthy subjects. One hundred and five healthy subjects participated in this randomized, double-blind study. CPM was assessed by subtracting the response to a phasic painful heat stimulus administered simultaneously with a conditioning cold pain stimulus from the response to the same heat stimulus administered alone. CPM was tested prior to and 25 min following a subcutaneous injection of either apomorphine (1.5 mg) or a placebo. CPM following apomorphine administration increased by 27.3% and by only 4% following placebo administration. RM-ANOVA revealed a significant interaction between 'session' and 'time' factors (F=5.316, p=0.023, eta=0.054), and significant effect for the 'session' (F=5.719, p=0.019, eta=0.006), but not for the 'time' (F=0.586, p=0.446, eta=0.057). These results suggest that dopaminergic pathways both participate in and enhance pain modulation, represented by CPM. The role of dopamine in pain processing should be further studied. PMID- 23727389 TI - Correlation between gray matter volume in the temporal lobe and depressive symptoms in patients with Alzheimer's disease. AB - Recent studies have suggested that depression might be an aggravating factor in Alzheimer's disease (AD). The aim of the study was to compare depressive symptoms and gray matter volume between AD patients with comorbid depression and patients with dementia only. Forty-nine patients with AD, 57 with mild cognitive impairment (MCI), and 50 healthy control subjects were assessed using the Consortium to Establish a Registry for Alzheimer's disease (CERAD) and the Geriatric Depression Scale (GDS). All magnetic resonance imaging (MRI)s were analyzed using voxel-based morphometry (VBM). Seventeen AD patients with depression versus 32 patients with dementia only showed decreased immediate recall for a word list (8.7+/-1.1 vs. 10.1+/-1.5, z=3.6, p<0.01) and constructional praxis scores (3.7+/-0.9 vs. 5.3+/-2.1, z=2.5, p=0.01). Compared to 32 patients with dementia, seventeen AD patients with depression showed decreased gray matter volume in the left inferior temporal gyrus (-56, -19, -31; KE=578, t=3.80, Puncorr<0.001). The MCI group showed decreased gray matter volume in the right hippocampal gyrus compared to healthy control group. Our results suggest that depressive symptoms may be associated with the volume changes of frontal and temporal lobe in patients with AD. PMID- 23727390 TI - Different modifications of phosphorylated Smad3C and Smad3L through TGF-beta after spinal cord injury in mice. AB - Transforming growth factor-beta (TGF-beta) is an anti-inflammatory cytokine and is expressed in the injured spinal cord. TGF-beta signals through receptors to activate Smad proteins, which translocate into the nucleus. In the present study, we investigated the chronological alterations and cellular locations of the TGF beta/Smad signaling pathway following spinal cord injury (SCI) in mice. ELISA analysis showed that the concentration of interleukin-6 (IL-6) in injured spinal cords significantly increases immediately after SCI, while the concentration of TGF-beta gradually increased after SCI, peaked at 2 days, and then gradually decreased. Immunohistochemical studies revealed that Smad3 was mainly expressed in neurons of the spinal cord. Phosphorylated Smad3 at the C-terminus (p-Smad3C) was stained within the motor neurons in the anterior horn, while phosphorylated Smad3 at the linker regions (p-Smad3L) was expressed in astrocytes within gray matter. These findings suggest that SCI induces gradual increases in TGF-beta and induces different activation of p-Smad3C and p-Smad3L. Phosphorylated Smad3C might be involved in neuronal degeneration after SCI, and p-Smad3L may play a role in glial scar formation by astrocytes. PMID- 23727388 TI - Suppression of cytochrome P450 reductase expression promotes astrocytosis in subventricular zone of adult mice. AB - The aim of this study was to determine the role of NADPH-cytochrome P450 reductase (CPR) and CPR-dependent enzymes in neural stem cell (NSC) genesis in the brain. A mouse model with globally suppressed Cpr gene expression (Cpr-low mouse) was studied for this purpose. Cpr-low and wild-type (WT) mice were compared immunohistochemically for the expression of markers of cell proliferation (Ki67), immature neurons (doublecortin, DCX), oligodendrocytes (oligodendrocyte transcription factor 2, OLIG2), and astrocytes (glial fibrillary acidic protein, GFAP) in the SVZ, and for the in vitro capability of their SVZ cells to form neurospheres and differentiate into astrocytes. We found that the abundance of SVZ cells that are positive for Ki67 or GFAP expression, but not the abundance of SVZ cells that are positive for DCX and OLIG2 expression, was significantly increased in Cpr-low mice, at various ages, compared with WT mice. Furthermore, extents of astrocyte differentiation and growth, but not neurosphere formation, from SVZ cells of the Cpr-low mice were significantly increased, compared with WT mice. These results suggest that CPR and CPR-dependent enzymes play a role in suppressing astrocytosis in the SVZ of adult mice. PMID- 23727391 TI - A clinical and epidemiological review of non-toxigenic Clostridium difficile. AB - Clostridium difficile is a significant nosocomial threat to human health and is the most commonly identified cause of antibiotic-associated diarrhea. The development of C. difficile colitis requires production of toxins A and/or B, but some strains do not express these proteins. These non-toxigenic C. difficile (NTCD) have garnered attention for their capacity to colonize humans and potentially reduce the risk for symptomatic colitis caused by toxigenic strains. Isolates of NTCD have been obtained from the environment as well as from animal and human sources. Studies in a hamster CDI model have demonstrated a protective effect of NTCD against toxigenic infection. The extent to which this protective effect of NTCD occurs in humans remains to be defined. Evidence for a therapeutic or preventive role for NTCD is limited but clinical prophylaxis studies are ongoing. NTCD potentially represents an exciting new tool in preventing CDI and its recurrences. PMID- 23727392 TI - Redox-dependent regulation of the Na+-K+ pump: new twists to an old target for treatment of heart failure. AB - By the time it was appreciated that the positive inotropic effect of cardiac glycosides is due to inhibition of the membrane Na(+)-K(+) pump, glycosides had been used for treatment of heart failure on an empiric basis for ~200 years. The subsequent documentation of their lack of clinical efficacy and possible harmful effect largely coincided with the discovery that a raised Na(+) concentration in cardiac myocytes plays an important role in the electromechanical phenotype of heart failure syndromes. Consistent with this, efficacious pharmacological treatments for heart failure have been found to stimulate the Na(+)-K(+) pump, effectively the only export route for intracellular Na(+) in the heart failure. A paradigm has emerged that implicates pump inhibition in the raised Na(+) levels in heart failure. It invokes protein kinase-dependent activation of nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) and glutathionylation, a reversible oxidative modification, of the Na(+)-K(+) pump molecular complex that inhibits its activity. Since treatments of proven efficacy reverse the oxidative Na(+)-K(+) pump inhibition, the pump retains its status as a key pharmacological target in heart failure. Its role as a target is well integrated with the paradigms of neurohormonal abnormalities, raised myocardial oxidative stress and energy deficiency implicated in the pathophysiology of the failing heart. We propose that targeting oxidative inhibition of the pump is useful for the exploration of future treatment strategies. This article is part of a Special Issue entitled "Na(+)Regulation in Cardiac Myocytes". PMID- 23727394 TI - Risk of tuberculosis infection in anti-TNF-alpha biological therapy: from bench to bedside. AB - Anti-tumor necrosis factor-alpha (TNF-alpha) biological agents, including soluble TNF-alpha receptors and anti-TNF-alpha monoclonal antibodies, bring new hope for treating rheumatic diseases such as rheumatoid arthritis, but also increase the risk of infection, especially tuberculosis (TB) infection. Recent findings have shown that the physiological TNF-mediated signaling was somehow impaired by TNF antagonists, leading to the exacerbation of chronic infection associated with aberrant granuloma formation and maintenance. Although both receptor and antibody agents appear to pose an equally high risk in causing development of new TB infections, monoclonal anti-TNF-alpha antibody seems more inclined to reactivate latent TB infection. This review is focused on the underlying mechanisms that cause the TB risk in the anti-TNF-alpha therapy and also the strategies to deal with it, with the aim of reducing the TB incidence during anti-TNF-alpha biological therapies. PMID- 23727393 TI - Extracorporeal membrane oxygenation promotes long chain fatty acid oxidation in the immature swine heart in vivo. AB - Extracorporeal membrane oxygenation (ECMO) supports infants and children with severe cardiopulmonary compromise. Nutritional support for these children includes provision of medium- and long-chain fatty acids (FAs). However, ECMO induces a stress response, which could limit the capacity for FA oxidation. Metabolic impairment could induce new or exacerbate existing myocardial dysfunction. Using a clinically relevant piglet model, we tested the hypothesis that ECMO maintains the myocardial capacity for FA oxidation and preserves myocardial energy state. Provision of 13-Carbon labeled medium-chain FA (octanoate), long-chain free FAs (LCFAs), and lactate into systemic circulation showed that ECMO promoted relative increases in myocardial LCFA oxidation while inhibiting lactate oxidation. Loading of these labeled substrates at high dose into the left coronary artery demonstrated metabolic flexibility as the heart preferentially oxidized octanoate. ECMO preserved this octanoate metabolic response, but also promoted LCFA oxidation and inhibited lactate utilization. Rapid upregulation of pyruvate dehydrogenase kinase-4 (PDK4) protein appeared to participate in this metabolic shift during ECMO. ECMO also increased relative flux from lactate to alanine further supporting the role for pyruvate dehydrogenase inhibition by PDK4. High dose substrate loading during ECMO also elevated the myocardial energy state indexed by phosphocreatine to ATP ratio. ECMO promotes LCFA oxidation in immature hearts, while maintaining myocardial energy state. These data support the appropriateness of FA provision during ECMO support for the immature heart. PMID- 23727395 TI - Molecular characterization of Mycobacterium tuberculosis isolated from pulmonary tuberculosis patients in Felege Hiwot Referral Hospital, northwest Ethiopia. AB - BACKGROUND: Tuberculosis (TB), caused by the Mycobacterium tuberculosis complex (MTBC), is a serious infection in humans and animals. Ethiopia is one of the countries in Sub-Saharan Africa with the highest burden of TB. However, limited information is available on the genotypic characteristics of M. tuberculosis strains infecting humans. The objective of the present study was to characterize the mycobacterial species isolated from pulmonary TB patients using molecular typing. MATERIALS AND METHODS: A cross-sectional study was conducted on 123 patients with smear-positive pulmonary TB, using Ziehl Neelsen staining and bacteriological culturing. Molecular characterizations of the mycobacterial isolates were performed using region of difference 9 (RD9) deletion typing and spoligotyping methods. RESULTS: The proportion of culture positivity was 95.9% (118/123). All the 118 isolates were confirmed to be M. tuberculosis by polymerase chain reaction-based RD9 deletion typing. Further characterization of all isolates using spoligotyping resulted in the identification of 36 different spoligotype patterns. Out of these, 32 (88.9%) patterns have already been reported in the SpolDB database, whereas the remaining four (11.1%) patterns were new and not registered in the database. The isolates were further grouped into 17 clustered (99 isolates) and 19 nonclustered patterns. The most predominant spoligotypes were SIT25 and SIT53, consisting of 22 isolates and 14 isolates, respectively. Classification of the spoligotype patterns using TB-insight RUN SPOTCLUST showed that the dominant lineages identified in the present study were Euro-American and Central Asian genotypes consisting of 64 isolates and 37 isolates, respectively. CONCLUSION: This study confirmed the presence of known M. tuberculosis strains and revealed new strains circulating in northwest Ethiopia and the distribution of the major phylogenetic families. It thus contributes to a better understanding of the genotypic profile of M. tuberculosis strains circulating in Ethiopia. PMID- 23727396 TI - Antibiotic consumption and resistance: data from Europe and Germany. AB - The use of antibiotics - including the over- and misuse - in human and veterinary practices selected for resistant pathogens and led to their emergence and dissemination along with the transmission of resistant bacteria. The aim of this article is to prescribe the prerequisites for the surveillance of antibiotic use and bacterial resistance, to explain advantage and disadvantage of surveillance parameters used, to present new data from a surveillance network of intensive care units focusing on antibiotic use and resistance and to discuss the impact of antibiotic use on resistance. The Surveillance System of Antibiotic Use and Bacterial Resistance in Intensive Care Units (SARI) is an on-going project that collects data from its network of intensive care units (ICU) in Germany. Antimicrobial use was expressed as daily defined doses (DDD) and normalized per 1000 patient-days (pd). ICU decided either to provide monthly data on antibiotic and resistant pathogens or they decided to provide only yearly data on antibiotic use without resistance data. 85% of all antibiotics used in Germany are administered in animals; 85% of the antibiotics used in humans are prescribed in the outpatient setting and 85% of the antibiotics used in hospitals are prescribed on non-ICUs wards. The mostly widely used parameter for the surveillance of resistance is the percentage of resistant pathogens which is important to guide empirical therapy but does not measure the burden of resistance which is of interest to the public health perspective. The burden of MRSA did not increase over the last 11 years in ICUs and was 4.2MRSA/1000pd in 2011. The burden of 3rd generation resistant E. coli and K. pneumoniae more than quintupled (up to 2.6 and 1.2 respectively) and was followed by a three times increased use of carbapenems and correlated with quinolone and 3rd generation cephalosporin use. The burden VRE faecium also increased dramatically from 0.1 to 0.8 within 11 years; VRE faecium showed no significant correlation to vancomycin use (p=0.190) although glycopeptide use increased lately. Antibiotic use in animals and humans correlates with the risk of resistant microorganisms in a multifactor and complex way; it is of upmost importance that surveillance and interventions focus on all sectors: animal use and in- and outpatient setting in humans. PMID- 23727397 TI - Dimensions of vegetable parenting practices among preschoolers. AB - The objective of this study was to determine the factor structure of 31 effective and ineffective vegetable parenting practices used by parents of preschool children based on three theoretically proposed factors: responsiveness, control and structure. The methods employed included both corrected item-total correlations and confirmatory factor analysis. Acceptable fit was obtained only when effective and ineffective parenting practices were analyzed separately. Among effective items the model included one second order factor (effectiveness) and the three proposed first order factors. The same structure was revealed among ineffective items, but required correlated paths be specified among items. A theoretically specified three factor structure was obtained among 31 vegetable parenting practice items, but likely to be effective and ineffective items had to be analyzed separately. Research is needed on how these parenting practices factors predict child vegetable intake. PMID- 23727398 TI - Effect of blood storage conditions on DNA repair capacity measurements in peripheral blood mononuclear cells. AB - Due to the great number of genes involved in DNA repair and the interactions among the pathways responsible for the repair of different types of DNA damage, there is an increasing need for simple and reliable approaches to phenotypically assess DNA repair capacity (DRC). The use of peripheral blood mononuclear cells (PBMCs) in DRC assays is particularly useful for human monitoring studies. However, in such studies it is not always possible to collect and process samples on the same day as the blood is taken. We performed a genotype-phenotype correlation study on DRC on 225 healthy subjects. Due to the large number of blood samples to be processed, PBMCs were either isolated and cryopreserved on the same day of blood collection (day 1) or on the following day after 24h blood storage at room temperature (day 2-RT). Samples processed in different days showed a significant difference in the DRC evaluated as 8-oxoguanine glycosylase activity (OGG assay) in cell extracts (p<0.0001) and as benzo[a]pyrene diol epoxide (BPDE)-induced damage repair by the comet assay (p=0.05). No apparent effect of the blood storage conditions on the outcome of gamma-ray induced H2AX phosphorylation assay was reported. These results prompted us to further analyze the effects of blood storage conditions by performing a validation study. Three blood samples were simultaneously taken from ten healthy donors, PBMCs were isolated and cryopreserved as follows: immediately after blood collection (day 1); on the following day, after blood storage at RT (day 2-RT); or after blood storage at 4 degrees C (day 2-4 degrees C). DRC was then evaluated using phenotypic assays. The gamma-ray induced H2AX phosphorylation assay has been confirmed as the only assay that showed good reproducibility independently of the blood storage conditions. The measurement of OGG assay was most affected by the blood storage conditions. PMID- 23727399 TI - Health-enhancing physical activity and associated factors in a Spanish population. AB - OBJECTIVES: This study describes the prevalence of health-enhancing physical activity and leisure-time physical activity in a Spanish sample and identifies the characteristics of the physically active and inactive populations. DESIGN: A cross-sectional study. METHODS: A random sample of 1595 adults (18-70 years old) living in Catalonia, Spain were assessed using the International Physical Activity Questionnaire (short version) and categorised according to their physical activity levels. The independent associations between physical activity levels and socio-demographic and health-related variables were investigated. RESULTS: Seventy-seven percent of the population engaged in health-enhancing physical activity. Being a young adult (odds ratio=2.0; 95% confidence interval=1.25-3.21) and having a normal weight (odds ratio=1.46; 95% confidence interval=1.04-2.03) were positively associated with a high health-enhancing physical activity level. Living in a medium-sized town (odds ratio=1.60; 95% confidence interval=1.09-2.35) was positively associated with a moderate health enhancing physical activity level, whereas being male (odds ratio=0.72; 95% confidence interval=0.53-0.96) odds ratio a middle-aged adult (odds ratio=0.67; 95% confidence interval=0.46-0.97) was negatively associated with a moderate health-enhancing physical activity level. Regarding leisure-time physical activity, 16.1% of the participants were active, 28.3% were lightly active and 55.6% were sedentary. Being male, being a non-smoker, having a normal weight and living with a partner increased the odds of engaging in leisure-time physical activity. CONCLUSIONS: Engaging in health-enhancing physical activity is common but not during leisure time, as concluded based on a representative sample of adults from Catalonia, Spain. Being a young adult, having a normal weight odds ratio living in a medium-sized town was positively associated with a high health enhancing physical activity level, whereas being male odds ratio a middle-aged adult was negatively associated with a moderate health-enhancing physical activity level. PMID- 23727400 TI - Transcranial magnetic stimulation as a tool for understanding neurophysiology in Huntington's disease: a review. AB - Structural and functional magnetic resonance imaging modalities have been critical in advancing our understanding of the neuroanatomical and pathophysiological changes that emerge during the premanifest and symptomatic stages of Huntington's disease (HD). However, the relationship between underlying neuropathology and the motor, cognitive and behavioural changes associated with the disorder still remain poorly understood. Less conventional technologies, such as transcranial magnetic stimulation (TMS) and electroencephalography (EEG), provide a unique opportunity to further investigate the causal relationships between targeted neural circuits and objective neurophysiological responses together with overt behaviours. In this review, we discuss previous successful applications of TMS in other neurological disorders and its prospective use in HD. We also address the added value of multimodal TMS techniques, such as TMS EEG, in investigating the integrity of neural networks in non-motor regions in HD. We conclude that neurophysiological outcome measures are likely to contribute towards characterising further the trajectory of decline across functional domains in HD, enhance understanding of underlying neural mechanisms, and offer new avenues for elucidating sensitive endophenotypic biomarkers of disease progression. PMID- 23727401 TI - Altered hippocampal myelinated fiber integrity in a lithium-pilocarpine model of temporal lobe epilepsy: a histopathological and stereological investigation. AB - The damage of white matter, primarily myelinated fibers, in the central nervous system (CNS) of temporal lobe epilepsy (TLE) patients has been recently reported. However, limited data exist addressing the types of changes that occur to myelinated fibers inside the hippocampus as a result of TLE. The current study was designed to examine this issue in a lithium-pilocarpine rat model. Investigated by electroencephalography (EEG), Gallyas silver staining, immunohistochemistry, western blotting, transmission electron microscopy, and stereological methods, the results showed that hippocampal myelinated fibers of the epilepsy group were degenerated with significantly less myelin basic protein (MBP) expression relative to those of control group rats. Stereological analysis revealed that the total volumes of hippocampal formation, myelinated fibers, and myelin sheaths in the hippocampus of epilepsy group rats were decreased by 20.43%, 49.16%, and 52.60%, respectively. In addition, epilepsy group rats showed significantly greater mean diameters of myelinated fibers and axons, whereas the mean thickness of myelin sheaths was less, especially for small axons with diameters from 0.1 to 0.8um, compared to control group rats. Finally, the total length of the myelinated fibers in the hippocampus of epilepsy group rats was significantly decreased by 56.92%, compared to that of the control group, with the decreased length most prominent for myelinated fibers with diameters from 0.4 to 0.8um. This study is the first to provide experimental evidence that the integrity of hippocampal myelinated fibers is negatively affected by inducing epileptic seizures with pilocarpine, which may contribute to the abnormal propagation of epileptic discharge. PMID- 23727402 TI - Glucocorticoid-induced enhancement of contextual fear memory consolidation in rats: Involvement of D1 receptor activity of hippocampal area CA1. AB - This study investigated the role of dopamine (DA) receptors in area CA1 of the hippocampus in modulating the effects of glucocorticoids on the contextual fear memory consolidation. Adult male rats were given systemic injections of corticosterone (CORT; 3mg/kg) immediately after training in a contextual fear conditioning (CFC) task and the percentage of time spent freezing in the CFC context was recorded 24h after training. Intra-CA1 infusion of the DA type 1 (D1) receptor antagonist SCH 23390 (SCH; 30ng/0.5ul per side) immediately after CORT injection attenuated CORT-induced enhancement of memory consolidation. However, intra-CA1 infusion of the DA type 2 (D2) receptor antagonist sulpiride (SUL; 60ng/0.5ul per side) was ineffective. Neither antagonist alone altered freezing behavior in the 24h CFC retention test. Furthermore, the memory enhancing dose of CORT used in these experiments reduced D1, but not D2, receptor mRNA expression in area CA1. Neither D1 nor D2 antagonism in area CA1 affected total locomotor activity. These findings provide evidence for the involvement of hippocampal D1 receptor activity in area CA1 in CORT-induced enhancement of contextual fear memory consolidation. PMID- 23727403 TI - Prolonged protein deprivation, but not food restriction, affects parvalbumin containing interneurons in the dentate gyrus of adult rats. AB - Several studies have demonstrated the vulnerability of the hippocampal formation to malnutrition. In this study, we compared the effects of food restriction and protein malnutrition in the total number of neurons of the dentate gyrus and in the number of parvalbumin-immunoreactive (PV-IR) interneurons, which are related to the control of calcium homeostasis and fine tuning of the hippocampal circuits. Two month-old rats were randomly assigned to control, food-restricted and low-protein diet groups. After 6 months, 10 rats from the low-protein diet group were selected at random and fed with a normal protein diet for 2 months. The total number of granule and hilar cells was reduced in protein-deprived rats and the nutritional reestablishment with a normal protein diet did not recover neuron numbers. Protein deprivation increased the number of PV-IR interneurons in the granule cell layer and hilus, but their number returned to values similar to controls after nutritional rehabilitation. Food restriction did not affect the total number of neurons or the density of PV-IR interneurons in the dentate gyrus. These results support the view that protein deprivation may disturb calcium homeostasis, leading to neuronal death. The up-regulation of PV-IR cells may reflect a protective mechanism to counteract the calcium overload and protect the remaining neurons of the dentate gyrus. This imbalance in cell-ratio favoring GABAergic interneurons may justify some learning and memory impairments described in protein-deprived animals. This contrast between the results of food restriction and protein deprivation should be further analyzed in future studies. PMID- 23727404 TI - The selective MU opioid receptor antagonist beta-funaltrexamine attenuates methamphetamine-induced stereotypical biting in mice. AB - We investigated whether pretreatment with opioid receptor antagonists affected methamphetamine (METH)-induced stereotypy in mice. Pretreatment of male ICR mice with naloxone, a relatively non-selective opioid receptor antagonist, significantly attenuated the total incidence of METH-induced stereotypical behavior compared with saline vehicle-pretreated subjects. Furthermore, the distribution of METH-induced stereotypical behavior was affected by naloxone administration. Thus, METH-induced stereotypical sniffing and persistent locomotion were significantly increased by naloxone treatment while stereotypical biting was reduced. One way to interpret this pattern of effects is that pretreatment with naloxone appeared to produce a shift in the dose-response curve for METH. Thus, while the more intense forms of oral-facial stereotypies were reduced, increased persistent locomotion was observed in mice given naloxone followed by METH. The selective MU opioid receptor antagonist beta funaltrexamine, but not nor-binaltorphimine (a kappa-selective antagonist) nor naltrindole (a delta-selective antagonist), mimicked the effect of naloxone. These observations suggest that opioid receptor antagonists may attenuate METH induced stereotypical biting in mice via MU opioid receptors, and suggest that antagonism of this system may be a potential therapeutic approach to reducing some deleterious effects of METH use and perhaps in the treatment of some forms of self-injurious behavior. PMID- 23727406 TI - Mitochondrial fusion and fission after spinal sacord injury in rats. AB - Responsible for orchestrating cellular energy production, mitochondria are central to the maintenance of life and the gatekeepers of cell death. Its morphology is dynamic and controlled by continual and balanced fission and fusion events. In this study, we analyzed the mitochondrial dynamics and functions after spinal cord injury in rats and further to discuss the mechanisms of the mitochondria regulated cell injury during SCI. Using adult rat spinal cord injury model, it was found that the absolute number of mitochondria per area was significantly less and the individual mitochondrial cross-sectional area was significantly greater in the neurons of rats in SCI group than in the sham operated group at 3h and 6h after SCI, and the reverse pattern at 12h and 24h after SCI. The results from Western blot and RT-PCR assays showed that the protein and mRNA levels of mitochondrial fusion-related genes (Mfn1 and Mfn2) decreased and fission-related genes (Drp1 and Fis1) increased at 3h and 6h after SCI. At 12h and 24h after SCI the reverse pattern of Mfn1, Mfn2, Drp1 and Fis1 expression was found. Taken together the results of the present study showed the mitochondrial tendency of elongation and fusion in the injured spinal cord at 3h and 6h after SCI, and the tendency of mitochondrial fission at 12h and 24h after SCI in our SCI models of rat. These findings have important implications for our understanding of the mechanisms of mitochondrial dynamics and functions after SCI injury. And mitochondrial fusion may potentially be used as a target for improving spinal cord function in the first 6h after SCI. Mitochondrial fusion may be inhibited at 12-24h after SCI for improving functional outcomes following SCI. PMID- 23727405 TI - Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors. AB - The location of glucocorticoid receptors (GR) implicated in depression symptoms and antidepressant action remains unclear. Forebrain glucocorticoid receptor deletion on a C57B/6*129*CBA background (FBGRKO-T50) reportedly produces increased depression-like behavior and elevated glucocorticoids. We further hypothesized that forebrain GR deletion would reduce behavioral sensitivity to glucocorticoids and to antidepressants. We have tested this hypothesis in mice with calcium calmodulin kinase IIalpha-Cre-mediated forebrain GR deletion derived from a new founder on a pure C57BL/6 background (FBGRKO-T29-1). We measured immobility in forced swim or tail suspension tests after manipulating glucocorticoids or after dose response experiments with tricyclic or monoamine oxidase inhibitor antidepressants. Despite forebrain GR deletion that was at least as rapid and more extensive than reported in the mixed-strain FBGRKO-T50 mice (Boyle et al. 2005), and possibly because of their different founder, our FBGRKO-T29-1 mice did not exhibit increases in depression-like behavior or adrenocortical axis hormones. Nevertheless, FBGRKO-T29-1 mice were at least as sensitive as floxed GR controls to the depressive effects of glucocorticoids and the effects of two different classes of antidepressants. FBGRKO-T29-1 mice also unexpectedly exhibited increased mineralocorticoid receptor (MR) gene expression. Our results reinforce prior evidence that antidepressant action does not require forebrain GR, and suggest a correlation between the absence of depression-like phenotype and combined MR up-regulation and central amygdala GR deficiency. Our findings demonstrate that GR outside the areas targeted in FBGRKO-T29-1 mice are involved in the depressive effects of glucocorticoids, and leave open the possibility that these GR populations also contribute to antidepressant action. PMID- 23727407 TI - Serine and cysteine protease-like genes in the genome of a gall midge and their interactions with host plant genotypes. AB - Proteases play important roles in a wide range of physiological processes in organisms. For plant-feeding insects, digestive proteases are targets for engineering protease inhibitors for pest control. In this study, we identified 105 putative serine- and cysteine-protease genes from the genome of the gall midge Mayetiola destructor (commonly known as Hessian fly), a destructive pest of wheat. Among the genes, 31 encode putative trypsins, 18 encode putative chymotrypsins, seven encode putative cysteine proteases, and the remaining may encode either other proteases or protease homologues. Developmental stage- and tissue-specific expression profiles of the genes encoding putative trypsins, chymotrypsins, and cysteine proteases were determined by quantitative reverse transcription PCR. Comparative analyses of stage- and tissue-specific expression patterns suggested that several genes are likely to encode digestive proteases in the M. destructor larval gut, including genes encoding putative trypsins MDP3, MDP5, MDP9, MDP24, MDP48, MDP51, MDP57, MDP61, MDP71, and MDP90; genes encoding putative chymotrypsins MDP1, MDP7, MDP8, MDP18, MDP19, and MDP20; and genes encoding putative cysteine proteases MDP95 and MDP104. The expression of some protease genes was affected by plant genotypes. Genes encoding trypsins MDP3, MDP9, and MPD23, chymotrypsins MDP20 and MDP21, and cysteine proteases MDP99 and MDP104 were upregulated in M. destructor larvae feeding in resistant plants, whereas genes encoding trypsins MDP12, MDP24, and MDP33, and chymotrypsins mdp8, mdp15, and mdp16 were downregulated in M. destructor larvae feeding in resistant plants. This study provides a foundation for further comparative studies on proteases in different insects, and further characterization of M. destructor digestive proteases and their interactions with host plants, as well as potential targets for transgenic wheat plants. PMID- 23727408 TI - The association between vitamin D and cognition: a systematic review. AB - Vitamin D insufficiency and deficiency are a major health care problem. The association between vitamin D levels and cognitive function is still under debate. We conducted a systematic review to assess the association between levels of vitamin D and cognition. Therefore, the databases of Embase and Pubmed were searched through June 2012 for observational studies relating vitamin D levels to cognition. Our initial search yielded 2182 articles. After applying exclusion criteria, there were 28 studies eligible for inclusion: 25 cross-sectional and 6 prospective studies (3 studies show cross-sectional as well as prospective data). The main finding of the 25 cross-sectional studies was a statistically significant worse outcome on one or more cognitive function tests or a higher frequency of dementia with lower vitamin D levels or intake in 18 out of 25 (72%) studies, whereas 7 (28%) studies failed to show an association. Four out of 6 (66.7%) prospective studies showed a higher risk of cognitive decline after a follow-up period of 4-7 years in participants with lower vitamin D levels at baseline. In conclusion, this review supports the hypothesis that hypovitaminosis D is associated with worse outcome on one or more cognitive function tests or a higher frequency of dementia in cross-sectional as well as prospective studies. Further studies should focus on the role of vitamin D supplementation in the prevention of cognitive decline in participants with low vitamin D levels. PMID- 23727410 TI - Special issue: molecular basis of the NCLs. PMID- 23727409 TI - ERK-mediated suppression of cilia in cisplatin-induced tubular cell apoptosis and acute kidney injury. AB - In kidneys, each tubular epithelial cell contains a primary cilium that protrudes from the apical surface. Ciliary dysfunction was recently linked to acute kidney injury (AKI) following renal ischemia-reperfusion. Whether ciliary regulation is a general pathogenic mechanism in AKI remains unclear. Moreover, the ciliary change during AKI and its underlying mechanism are largely unknown. Here we examined the change of primary cilium and its role in tubular cell apoptosis and AKI induced by cisplatin, a chemotherapy agent with notable nephrotoxicity. In cultured human proximal tubular HK-2 epithelial cells, cilia became shorter during cisplatin treatment, followed by apoptosis. Knockdown of Kif3a or Polaris (cilia maintenance proteins) reduced cilia and increased apoptosis during cisplatin treatment. We further subcloned HK-2 cells and found that the clones with shorter cilia were more sensitive to cisplatin-induced apoptosis. Mechanistically, cilia-suppressed cells showed hyperphosphorylation or activation of ERK. Inhibition of ERK by U0126 preserved cilia during cisplatin treatment and protected against apoptosis in HK-2 cells. In C57BL/6 mice, U0126 prevented the loss of cilia from proximal tubules during cisplatin treatment and protected against AKI. U0126 up-regulated Polaris, but not Kif3a, in kidney tissues. It is suggested that ciliary regulation by ERK plays a role in cisplatin-induced tubular apoptosis and AKI. PMID- 23727411 TI - Image based feasibility of renal sparing surgery for very low risk unilateral Wilms tumors: a report from the Children's Oncology Group. AB - PURPOSE: Nephrectomy with lymph node sampling is the recommended treatment for children with unilateral Wilms tumor under the Children's Oncology Group protocols. Using radiological assessment, we determined the feasibility of performing partial nephrectomy in a select group of patients with very low risk unilateral Wilms tumor. MATERIALS AND METHODS: We reviewed imaging studies of 60 patients with a mean age of less than 2 years with very low risk unilateral Wilms tumor (mean weight less than 550 gm) to assess the feasibility of partial nephrectomy. We evaluated percentage of salvageable parenchyma, tumor location and anatomical features preventing a nephron sparing approach. RESULTS: A linear relationship exists between tumor weight and computerized tomography estimated tumor volume. Mean tumor weight in the study population was 315 gm. Partial nephrectomy was deemed feasible in only 5 of 60 patients (8%). CONCLUSIONS: When considering a select population with very low risk unilateral Wilms tumor (lower volume tumor), only a small percentage of nonpretreated patients are candidates for nephron sparing surgery. PMID- 23727412 TI - The efficacy and safety of combined therapy with alpha-blockers and anticholinergics for men with benign prostatic hyperplasia: a meta-analysis. AB - PURPOSE: We performed a meta-analysis to compare treatment with alpha-blockers and anticholinergics (ie combination therapy) to alpha-blocker monotherapy to clarify the efficacy and safety of this treatment approach among men with storage urinary symptoms related to benign prostatic hyperplasia. MATERIALS AND METHODS: We searched for trials of men with benign prostatic hyperplasia/lower urinary tract symptoms that were randomized to combination treatment or alpha-blockers alone. We pooled data from 7 placebo controlled trials meeting inclusion criteria. Primary outcomes of interest included changes in International Prostate Symptom Score (storage subscores) and urinary frequency. We also assessed post void residual volume, maximal flow rate and the incidence of urinary retention. Data were pooled using random effects models for continuous outcomes and the Peto method to generate odds ratios for acute urinary retention. RESULTS: Combination therapy had a significantly greater reduction in International Prostate Symptom Score storage subscores (Delta -0.73, 95% CI -1.09 - -0.37) and voiding frequency (Delta -0.69 voids, 95% CI -0.97 - -0.41). There was also a greater reduction in maximal urinary flow rate (Delta -0.59 ml per second, 95% CI -1.04 - -0.14) and increase in post-void residual urine volume (Delta 11.60 ml, 95% CI 8.50-14.70) with combination therapy. The number needed to treat with combination therapy to cause 1 acute urinary retention episode was 101 (95% CI 60-267). CONCLUSIONS: Combination treatment with alpha-blockers and anticholinergics significantly improved storage voiding parameters compared to men treated with alpha-blocker therapy alone. This treatment approach is safe with a minimal risk of increased post-void residual urine volume, decreased maximal urinary flow rate or acute urinary retention. PMID- 23727413 TI - Hypospadias and genes related to genital tubercle and early urethral development. AB - PURPOSE: We determined whether variants in genes associated with genital tubercle (the anlage for the penis) and early urethral development were associated with hypospadias in humans. MATERIALS AND METHODS: We examined 293 relatively common tag single nucleotide polymorphisms in BMP4, BMP7, FGF8, FGF10, FGFR2, HOXA13, HOXD13, HOXA4, HOXB6, SRY, WT1, WTAP, SHH, GLI1, GLI2 and GLI3. The analysis included 624 cases (81 mild, 319 moderate, 209 severe, 15 undetermined severity) and 844 population based nonmalformed male controls born in California from 1990 to 2003. RESULTS: There were 28 single nucleotide polymorphisms for which any of the comparisons (ie overall or for a specific severity) had a p value of less than 0.01. The homozygous variant genotypes for 4 single nucleotide polymorphisms in BMP7 were associated with at least a twofold increased risk of hypospadias regardless of severity. Five single nucleotide polymorphisms for FGF10 were associated with threefold to fourfold increased risks, regardless of severity. For 4 of them the results were restricted to whites. For GLI1, GLI2 and GLI3 there were 12 associated single nucleotide polymorphisms but results were inconsistent by severity and race/ethnicity. For SHH 1 single nucleotide polymorphism was associated with a 2.4-fold increased risk of moderate hypospadias. For WT1 6 single nucleotide polymorphisms were associated with approximately a twofold increased risk, primarily for severe hypospadias. CONCLUSIONS: This study provides evidence that single nucleotide polymorphisms in several genes that contribute to genital tubercle and early urethral development are associated with hypospadias risk. PMID- 23727414 TI - Simultaneous kidney transplantation and bilateral native nephrectomy for polycystic kidney disease. AB - PURPOSE: Bilateral native nephrectomy with simultaneous kidney transplantation is becoming more common for patients with polycystic kidney disease in the living donor nephrectomy era. Single center reports evaluating the short-term and long term outcomes of simultaneous kidney transplantation have been published but are generally limited by small sample sizes. We examined population level data to broadly define the complications of simultaneous kidney transplantation. MATERIALS AND METHODS: The Nationwide Inpatient Sample (NIS) was used to acquire data on 2,368 patients with polycystic kidney disease treated with bilateral native nephrectomy between 1998 and 2010. We performed unadjusted, multivariable and propensity score adjusted analyses of postoperative outcomes. RESULTS: A total of 2,368 patients were included in this study. The 271 patients (11.4%) who underwent simultaneous kidney transplantation had higher rates of intraoperative hemorrhage, blood transfusion and urological complications (propensity score adjusted OR 3.3, p=0.01, OR 4.2, p<0.0001 and OR 5.5, p<0.0001, respectively) but a lower in-hospital mortality rate (15.8% vs 1.1%, propensity score adjusted OR 0.10, p<0.0001). Median hospitalization was also significantly higher in patients who underwent simultaneous kidney transplantation (6 vs 9 days, p<0.0001). For the top quartile of high volume hospitals the rates of intraoperative hemorrhage, blood transfusion and urological complications remained statistically higher in patients treated with simultaneous kidney transplantation but in-hospital mortality was similar on multivariable logistic regression (OR 0.2, p=0.17). CONCLUSIONS: Except for increased rates of intraoperative hemorrhage, blood transfusion and urological complications there were no significant differences in postoperative adverse outcomes in this large, population based study of patients who underwent simultaneous kidney transplantation compared to bilateral native nephrectomy alone. PMID- 23727415 TI - Urodynamics and safety of the beta3-adrenoceptor agonist mirabegron in males with lower urinary tract symptoms and bladder outlet obstruction. AB - PURPOSE: Bladder outlet obstruction often presents as storage and voiding symptoms. We investigated urodynamic parameters in men with lower urinary tract symptoms and bladder outlet obstruction treated with the beta3 agonist mirabegron, a new therapy for overactive bladder symptoms. MATERIALS AND METHODS: A total of 200 men 45 years old or older with lower urinary tract symptoms and bladder outlet obstruction were randomized to receive once daily mirabegron 50 mg (70) or 100 mg (65), or placebo (65) for 12 weeks. The primary urodynamic parameters assessed were change from baseline to end of treatment in maximum urinary flow and detrusor pressure at maximum urinary flow (noninferiority margins -3 ml per second and 15 cm H2O, respectively). We evaluated adverse events and vital signs. RESULTS: Treatment with mirabegron 50 and 100 mg was noninferior to placebo based on the lower and upper limits of the 95% CI, respectively, for maximum urinary flow and detrusor pressure at maximum urinary flow. The adjusted mean difference vs placebo was 0.40 (95% CI -0.63, 1.42) and 0.62 ml per second (95% CI -0.43, 1.68) for maximum urinary flow, and -5.94 (95% CI -13.98, 2.09) and -1.39 cm H2O (95% CI -9.73, 6.96), respectively, for detrusor pressure at maximum urinary flow. The incidence of adverse events was similar for mirabegron and placebo. CONCLUSIONS: Mirabegron did not adversely affect voiding urodynamics (maximum urinary flow and detrusor pressure at maximum urinary flow) compared with placebo after 12 weeks of treatment. PMID- 23727416 TI - Characterization of ciprofloxacin resistant Escherichia coli isolates among men undergoing evaluation for transrectal ultrasound guided prostate biopsy. AB - PURPOSE: We determine the prevalence of ciprofloxacin resistant gram-negative bacilli in patients scheduled for transrectal ultrasound guided prostate biopsy, characterize the Escherichia coli strains recovered from this patient population, and characterize the mechanisms responsible for beta-lactam and ciprofloxacin resistance. MATERIALS AND METHODS: Rectal swabs from 991 patients were cultured for ciprofloxacin resistant gram-negative bacilli with a selective medium. Recovered E. coli isolates were further analyzed with susceptibility testing, pulsed field gel electrophoresis, plasmid isolation and sequencing. RESULTS: A total of 193 ciprofloxacin resistant gram-negative bacilli were recovered and of these isolates 167 (87%) were E. coli. The prevalence of ciprofloxacin resistant E. coli in the study population was 17%. Only 38 (26%) of the 149 E. coli isolates that received susceptibility testing were susceptible to ampicillin and ampicillin-sulbactam. In select isolates transferrable plasmids carrying beta lactamase were responsible for the resistance to the beta-lactam agents and other nonbeta-lactam antimicrobials. Diverse combinations of gyrA and parC mutations associated with fluoroquinolone resistance were identified. Strain typing and plasmid typing indicated that the E. coli isolates did not share a common origin. CONCLUSIONS: Of the patients in our study 17% carried ciprofloxacin resistant E. coli. Analysis of resistance mechanisms and plasmid analysis along with strain typing demonstrated that this patient population harbored organisms with heterogeneous phenotypic susceptibility, indicating that universal prophylaxis would not provide optimal coverage for patients undergoing transrectal ultrasound guided prostate biopsy. PMID- 23727417 TI - WEE1 inhibition and genomic instability in cancer. AB - One of the hallmarks of cancer is genomic instability controlled by cell cycle checkpoints. The G1 and G2 checkpoints allow DNA damage responses, whereas the mitotic checkpoint enables correct seggregation of the sister chromosomes to prevent aneuploidy. Cancer cells often lack a functional G1 arrest and rely on G2 arrest for DNA damage responses. WEE1 kinase is an important regulator of the G2 checkpoint and is overexpressed in various cancer types. Inhibition of WEE1 is a promising strategy in cancer therapy in combination with DNA-damaging agents, especially when cancer cells harbor p53 mutations, as it causes mitotic catastrophy when DNA is not repaired during G2 arrest. Cancer cell response to WEE1 inhibition monotherapy has also been demonstrated in various types of cancer, including p53 wild-type cancers. We postulate that chromosomal instability can explain tumor response to WEE1 monotherapy. Therefore, chromosomal instability may need to be taken into account when determining the most effective strategy for the use of WEE1 inhibitors in cancer therapy. PMID- 23727418 TI - Prediction of the protein components of a putative Calanus finmarchicus (Crustacea, Copepoda) circadian signaling system using a de novo assembled transcriptome. AB - Diel vertical migration and seasonal diapause are critical life history events for the copepod Calanus finmarchicus. While much is known about these behaviors phenomenologically, little is known about their molecular underpinnings. Recent studies in insects suggest that some circadian genes/proteins also contribute to the establishment of seasonal diapause. Thus, it is possible that in Calanus these distinct timing regimes share some genetic components. To begin to address this possibility, we used the well-established Drosophila melanogaster circadian system as a reference for mining clock transcripts from a 200,000+ sequence Calanus transcriptome; the proteins encoded by the identified transcripts were also deduced and characterized. Sequences encoding homologs of the Drosophila core clock proteins CLOCK, CYCLE, PERIOD and TIMELESS were identified, as was one encoding CRYPTOCHROME 2, a core clock protein in ancestral insect systems, but absent in Drosophila. Calanus transcripts encoding proteins known to modulate the Drosophila core clock were also identified and characterized, e.g. CLOCKWORK ORANGE, DOUBLETIME, SHAGGY and VRILLE. Alignment and structural analyses of the deduced Calanus proteins with their Drosophila counterparts revealed extensive sequence conservation, particularly in functional domains. Interestingly, reverse BLAST analyses of these sequences against all arthropod proteins typically revealed non-Drosophila isoforms to be most similar to the Calanus queries. This, in combination with the presence of both CRYPTOCHROME 1 (a clock input pathway protein) and CRYPTOCHROME 2 in Calanus, suggests that the organization of the copepod circadian system is an ancestral one, more similar to that of insects like Danaus plexippus than to that of Drosophila. PMID- 23727419 TI - Clinical evaluation of transcatheter arterial chemoembolization with 2-day soluble gelatin sponge particles for hepatocellular carcinoma-comparison with insoluble gelatin sponge particles. AB - PURPOSE: To compare therapeutic effect, adverse events, and embolized hepatic artery impairment in transcatheter arterial chemoembolization between Lipiodol plus insoluble gelatin sponge particles (Gelpart) and Lipiodol plus 2-day-soluble gelatin sponge particles (2DS-GSPs). MATERIALS AND METHODS: In a single-center, prospective, randomized controlled trial, patients with hepatocellular carcinoma were assigned to the 2DS-GSP group or the Gelpart group. Radiographic response at 3 months per modified Response Evaluation Criteria In Solid Tumors was evaluated as the primary endpoint; secondary endpoints were safety (per Common Terminology Criteria for Adverse Events, version 4.0) within 3 months and hepatic branch artery impairment at the time of repeat chemoembolization (grade 0, no damage; grade I, mild vessel wall irregularity; grade II, overt stenosis; grade III, occlusion of more peripheral branch artery than subsegmental artery; grade IV, occlusion of subsegmental artery). Grade II, III, or IV indicated significant hepatic artery impairment. RESULTS: Thirty-seven patients with 143 nodules were randomized to the 2DS-GSP group and 36 patients with 137 nodules were randomized to the Gelpart group. No significant differences in patient background existed between groups. Target lesion response and overall tumor response in the 2DS-GSP and Gelpart groups were 77.7% versus 76.9% and 78.3% versus 77.8%, respectively, with no significant differences. No significant difference in adverse events existed between groups. Hepatic artery impairment was observed in 5% of patients in the 2DS-GSP group (n = 32) and in 16% in the Gelpart group (n = 33; P< .001). CONCLUSIONS: Transcatheter arterial chemoembolization with 2DS-GSPs resulted in the same therapeutic and adverse effects as chemoembolization with Gelpart while causing significantly less hepatic artery impairment. PMID- 23727420 TI - Stent-graft repairs of visceral and renal artery aneurysms are effective and result in long-term patency. AB - PURPOSE: To report on the long-term outcomes of endovascular exclusion of visceral and renal artery aneurysms with the use of stent-grafts. MATERIALS AND METHODS: Nineteen consecutive patients (mean age, 59 y +/- 16 [standard deviation]) with a total of 19 visceral artery aneurysms (VAAs; hepatic, n = 6; celiac, n = 4; renal, n = 4; splenic, n = 3; and superior mesenteric, n = 2) were electively (n = 9) or emergently (n = 10) treated with a variety of stent-grafts. The etiology of aneurysms was variable: postoperative (n = 9), infectious (n = 3), idiopathic (n = 4), Ehlers-Danlos syndrome (n = 2), and alpha1-antitrypsin deficiency (n = 1). The patients were followed up with clinical examinations and computed tomographic (CT) angiography. RESULTS: No patient was lost to follow-up. The in-hospital mortality rate was 11% (n = 2). Three patients died of cancer after successful VAA treatment. At the last follow-up, the remaining 14 patients were alive and well. Three patients refused follow-up CT angiography. CT angiography demonstrated stent-graft patency at a mean follow-up of 28 months (range, 2-100 mo) in nine of 11 remaining patients (82%) and thrombosis in two patients (one with a splenic and one with a renal artery stent-graft). These events were asymptomatic. All aneurysms decreased in size. Late repeat intervention was performed to treat a celiac restenosis in a patient with a hepatic stent-graft. CONCLUSIONS: Irrespective of their etiology and acuteness, VAAs can be treated with stent-grafts, with an excellent clinical long-term outcome and a high patency rate. PMID- 23727421 TI - System factors to explain H1N1 state vaccination rates for adults in US emergency response to pandemic. AB - INTRODUCTION: During the 2009-2010 H1N1 pandemic, vaccine in short supply was allocated to states pro rata by population, yet the vaccination rates of adults differed by state. States also differed in their campaign processes and decisions. Analyzing the campaign provides an opportunity to identify specific approaches that may result in higher vaccine uptake in a future event of this nature. OBJECTIVE: To determine supply chain and system factors associated with higher state H1N1 vaccination coverage for adults in a system where vaccine was in short supply. METHODS: Regression analysis of factors predicting state specific H1N1 vaccination coverage in adults. Independent variables included state campaign information, demographics, preventive or health-seeking behavior, preparedness funding, providers, state characteristics, and H1N1-specific state data. RESULTS: The best model explained the variation in state-specific adult vaccination coverage with an adjusted R-squared of 0.76. We found that higher H1N1 coverage of adults is associated with program aspects including shorter lead times (i.e., the number of days between when doses were allocated to a state and were shipped, including the time for states to order the doses) and less vaccine directed to specialist locations. Higher vaccination coverage is also positively associated with the maximum number of ship-to locations, past seasonal influenza vaccination coverage, the percentage of women with a Pap smear, the percentage of the population that is Hispanic, and negatively associated with a long duration of the epidemic peak. CONCLUSION: Long lead-times may be a function of system structure or of efficiency and may suggest monitoring or redesign of distribution processes. Sending vaccine to sites with broad access could be useful when covering a general population. Existing infrastructure may be reflected in the maximum number of ship-to locations, so strengthening routine influenza vaccination programs may help during emergency vaccinations also. Future research could continue to inform program decisions. PMID- 23727422 TI - Immunogenicity and safety of an investigational hepatitis B vaccine with a toll like receptor 9 agonist adjuvant (HBsAg-1018) compared with a licensed hepatitis B vaccine in patients with chronic kidney disease. AB - BACKGROUND: Hemodialysis patients are at increased risk of hepatitis B virus (HBV) infection and patients with chronic kidney disease (CKD) are commonly hyporesponsive to HBV vaccines. Current recommendations for CKD patients are to utilize 4 double-doses (2*20 mcg HBsAg) of a licensed hepatitis B vaccine (HBsAg Eng). METHODS: An observer-blind, randomized, active-controlled, parallel group, multicenter trial was conducted among 521 patients 18-75 years of age with CKD, comparing 3 single doses of an investigational hepatitis B vaccine (20 mcg rHBsAg+3000 mcg 1018, a toll-like receptor 9 agonist) given at 0, 4, and 24 weeks to 4 double-doses of HBsAg-Eng (2*20 mcg rHBsAg+500 mcg alum) given at 0, 4, 8, and 24 weeks (total of 8 injections). Participants were followed for 1 year. RESULTS: Among 467 participants in the modified intent-to-treat population, at the primary endpoint at week 28, the seroprotection rate (SPR: % with anti HBs>=10mIU/mL) in the HBsAg-1018 group (89.9%) met criteria for noninferiority and superiority to the SPR in the HBsAg-Eng group (81.8%). At week 28, the percentage of participants with anti-HBs>=100mIU/mL in the HBsAg-1018 group (73.6%) was significantly higher than in the HBsAg-Eng group (63.2%). In addition, the geometric mean concentration of anti-HBs in the HBsAg-1018 group (587.1mIU/mL) was significantly higher than in the HBsAg-Eng group (156.5mIU/mL). At weeks 8 and 12 after the first study injection, SPRs in the HBsAg-1018 group were significantly higher than in the HBsAg-Eng group. At 52 weeks, the immune response to HBsAg-1018 remained higher than to HBsAg-Eng. HBsAg-1018 was generally well tolerated and had a similar safety profile to HBsAg-Eng. CONCLUSION: In CKD patients, 3 doses of HBsAg-1018 induced significantly higher seroprotection, earlier seroprotection, and more durable seroprotection than 4 double doses of HBsAg-Eng. PMID- 23727423 TI - Nanoparticle-based vaccine for mucosal protection against Shigella flexneri in mice. AB - Shigellosis is one of the leading causes of diarrhea worldwide with more than 130 million cases annually. Hence, the research of an effective vaccine is still a priority. Unfortunately, a safe and efficacious vaccine is not available yet. We have previously demonstrated the capacity of outer membrane vesicles (OMVs) to protect mice against an experimental infection with Shigella flexneri. Now, we present results on the capacity of this antigenic complex to confer a longer-term protection by oral or nasal routes when encapsulated into nanoparticles. OMVs were encapsulated in poly(anhydride) nanoparticles (NP) prepared by a solvent displacement method with the copolymer poly methyl vinyl ether/maleic anhydride. OMVs loaded into nanoparticles (NP-OMVs) were homogeneous and spherical in shape, with a size of 148nm (PdI=0.2). BALB/c mice were immunized with OMVs either free or encapsulated in nanoparticles by nasal (20MUg or 10MUg of OMVs) or oral route (100MUg or 50MUg of OMVs). All immunized animals remained in good health after administration. Challenge infection was performed intranasally on week 8th with a lethal dose of 5*10(7)CFU/mouse of S. flexneri 2a. The number of dead mice after challenge was recorded daily. Results confirmed the value of OMVs as a vaccine. By oral route, the OMV-vaccine was able to protect independently either the dose or the formulation. When vaccine was delivered by nasal route, encapsulation into NPs resulted beneficial in increasing protection from 40% up to 100% when low dose was administered. These results are extraordinary promising and put in relevance the positive effect of nanoencapsulation of the OMV subcellular vaccine. PMID- 23727424 TI - Antioxidant effect of zinc chloride against ethanol-induced gastrointestinal lesions in rats. AB - The aim of the present study was to evaluate the possible effects of zinc chloride against the gastrointestinal lesions caused by oral administration of ethanol in rats. Rats were divided into five groups, namely, saline, ethanol, zn, zn+ethanol and ethanol+zn. Ethanol 70% (2 mL/kg) was administered by gavage in 36 h fasted rats. Zinc chloride (27 mg/kg, ~13 mg/kg of zinc) was given by gavage 1h before or 1h after the administration of ethanol. Oral administration of ethanol consistently induced damage in the rat glandular stomach and intestine. Zinc did not demonstrate effect per se and significantly reduced gastrointestinal lesions when administered either before or after lesion induction. Ethanol induced enhancement of thiobarbituric acid reactive substance and reactive species levels, diminished the ascorbic acid and total protein SH content as well as superoxide dismutase and catalase activity in stomach and intestine of rats. Zinc treatment prevented and reversed these alterations induced by ethanol. Stomach and intestine of rats treated with zinc presented higher zinc content than the tissues of rats treated only with ethanol. Non-protein SH content was not altered by any treatment. Results suggested that the gastrointestinal protective effect of zinc in this experimental model could be due to its antioxidant effect. PMID- 23727425 TI - Antioxidant effect of butylated hydroxytoluene on ferric nitrilotriacetate induced renal hyper proliferation and injury in rats. AB - This study was designed to investigate the effect of butylated hydroxy toluene (BHT), a phenolic antioxidant used in foods, cosmetics and pharmaceutical products, on Fe-NTA-induced nephrotoxicity in rats. Fe-NTA (alone) treatment enhances ornithine decarboxylase activity to 5.3-fold, and [(3)H] thymidine incorporation in DNA to 3.5-fold compared with the corresponding saline treated control. The enhanced ornithine decarboxylase activity and DNA synthesis showed a reduction to 2.12-2.15-fold respectively at a higher dose of 2 mg BHT/day/animal, compared with the Fe-NTA treated group. Fe-NTA treatment also enhanced the renal microsomal lipid peroxidation to 2.0-fold and decreased the activities of glutathione and antioxidant enzymes to a range of 2.2-2.5-fold in kidney. These changes were reversed significantly in animals receiving a pretreatment of BHT. Present data suggests that BHT can prevent the toxic effects of Fe-NTA and can serve as a potent chemopreventive agent to suppress oxidant-induced tissue injury and nephrotoxicity in rats. PMID- 23727426 TI - [Update on L-asparaginase treatment in paediatrics]. AB - L-asparaginase (L-ASP) is one of the cornerstones of the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphoma. It is an enzyme of bacterial origin capable of transforming L-asparagine to aspartic acid. The extracellular depletion of L-asparagine inhibits protein synthesis in lymphoblasts, inducing their apoptosis. Numerous studies have demonstrated that treatment with L-ASP improves survival of patients, but there are clear differences in the characteristics of the three currently available formulations. This article reviews the dosage, activity and side effects of the two L-ASP derived from Escherichia coli (native and pegylated), and the one derived from Erwinia chrysanthemi (Erwinia ASP). Despite its indisputable indication over the past50 years, there are still many points of contention, and its use is still marked by the side effects of the inhibition of protein synthesis. The short half-life of native forms, and the most frequently used parenteral administration by intramuscular injections, affects the quality of life of the patients. Therefore, recent studies claim to evaluate alternatives, such as the formulation of longer half-life pegylated L-ASP, and the use of intravenous formulations. There are encouraging results to date with both preparations. Still, further studies are needed to establish which should be the formulation and frontline indicated route of administration, optimal dosing, and management of adverse effects. PMID- 23727427 TI - Ontogeny of mRNA expression of somatostatin and its receptors in chicken embryos in association with methylation status of their promoters. AB - The present study was designed to investigate the ontogeny and tissue distribution of somatostatin and its five receptor subtypes (SSTR1-5) mRNA expression in embryonic chicken (Gallus gallus). Brain, gonads (male), intestine, kidney, liver, muscle, stomach and yolk sac membrane (YSM) of chicken embryos on the embryonic (E) ages of 10, 16 and 21days (right before hatch) were investigated. Bisulfite sequencing PCR (BSP) was performed to determine the methylation status of the promoter region of all the six genes in the liver. Somatostatin (SST) was predominately expressed in intestine, brain and gonads (male) with different ontogenic patterns. The highest expression in intestine was detected at E10. There was ontogenic shift from intestine to brain as development progressed. Expression pattern of SSTRs in brain, intestine and kidney was similar to human embryonic expression. In liver, the ontogenic expression pattern of SST and its receptors was associated to methylation status of the respective promoters. Methylation of site Sp1 determines expression level of SST, SSTR1, SSTR2 and SSTR3 while site a is important in governing the expression of SSTR4 and SSTR5. The results show that ontogenic expression profile of chicken SST and SSTRs is time and tissue specific. PMID- 23727428 TI - Short hairpin RNA induces methylation of hepatitis B virus covalently closed circular DNA in human hepatoma cells. AB - Small interfering RNAs not only modulate gene expression at a post transcriptional level, but also induce transcriptional gene silencing by RNA interference-mediated heterochromatin formation and RNA-directed DNA methylation (RdDM). However, although established in plants, there have been controversies whether RdDM operates in mammals. Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) serves as a template for viral RNA transcription, and transcriptional activity of HBV cccDNA is regulated by methylation in patients with chronic HBV infection. In this study, we stably expressed short hairpin RNA (shRNA) against HBV in human hepatoma cells to determine whether shRNA induces methylation of HBV cccDNA. HepAD38 cells which permit replication of HBV under control of tetracycline-responsive promoter were transduced with lentiviral vectors which encode sh-1580, a shRNA against the hepatitis B viral protein HBx. Bisulfite sequencing PCR analysis revealed that sh-1580 induced CpG methylations at a higher rate compared to control (31.3% vs. 12.8%, p<0.05). The sh-1580 induced CpG methylation was localized near the target sequence of sh-1580 in more than a half of the clones. Methylation-induced transcriptional suppression was confirmed by in vitro transcription assay. These results confirm the feasibility of RdDM of HBV cccDNA in human cells. Lentiviral vector-mediated transfer of shRNA may be used as a tool for novel transcriptional modulation by epigenetic modification of HBV cccDNA. PMID- 23727429 TI - Neuroglobin: neuroprotection and neurogenesis. AB - Globins, such as hemoglobin, serve as oxygen sensors. Neuroglobin is the globin in brain. It is induced by ischemia and is protective in modeled stroke. Here, Haines et al. describe an additional property of neuroglobin, its expression in progenitor cell populations in brain during development. A physiologic role is offered but other data show progenitor cells response to injury and their neurotropic properties in ischemic brain. PMID- 23727430 TI - Pseudomonas asturiensis sp. nov., isolated from soybean and weeds. AB - Five strains of gram negative bacteria, isolated from soybean (LPPA 221(T), 222 and 223) and weeds (LPPA 816 and 1442), were analyzed by a polyphasic approach. The isolates showed variation in their phenotypic traits and were placed in the Pseudomonas fluorescens lineage, based on 16S rRNA gene sequence phylogeny, as a single but well separated cluster. MLSA analysis based on gyrB and rpoD sequences clustered the strains in a single branch in the Pseudomonas syringae group, and revealed P. viridiflava as closest relative. DNA-DNA hybridizations showed medium levels of DNA-DNA relatedness with the type strain of P. viridiflava (50%) and lower levels (<32%) with other type strains of the P. syringae group, supporting classification within a novel species of the genus Pseudomonas. The strains can be distinguished from species of the P. syringae group by the fatty acid C17:0 cyclo that is present in a low amount (2.5%) and from P. viridiflava by their inability to assimilate d-tartrate and d-sorbitol, and by the formation of red colonies on TTC medium. For this new species, the name Pseudomonas asturiensis sp. nov. is proposed. The type strain is LPPA 221(T) (=LMG 26898(T)=CECT 8095(T)). PMID- 23727431 TI - Brachytherapy: current status and future strategies -- can high dose rate replace low dose rate and external beam radiotherapy? AB - Brachytherapy delivers the most conformal high dose radiotherapy possible to the prostate, using either a low dose rate (LDR) or high dose rate (HDR) technique. It may be used either alone as monotherapy or in combination with external beam radiotherapy (EBRT) as a local boost. Comparative efficacy studies, including one randomised controlled trial, consistently show higher cancer control rates when brachytherapy is used compared with EBRT alone, with even some evidence of improvement in survival. There are now extensive mature data supporting the use of LDR as monotherapy for patients with low-risk and selected intermediate-risk disease, with most series reporting long-term disease control rates of over 90% after high-quality implants. HDR is most commonly combined with EBRT to treat intermediate- and high-risk disease, with disease control rates of over 90% reported. The low alpha/beta ratio of prostate cancer combined and the ability to optimally sculpt dose distribution provides the biological and dosimetric rationale for HDR. HDR enables more consistent implant quality than LDR, with evidence of lower acute and late toxicity. Many dose and fractionation schedules of HDR in combination with EBRT have been investigated, but a single fraction of 10-15 Gy is commonly combined with EBRT to a dose of 40-50 Gy to treat intermediate- and high-risk disease. High disease control rates are also reported with HDR as monotherapy, particularly in patients with low- and intermediate-risk disease. Although older series have delivered four to six fractions of HDR, there is growing evidence to support the delivery of HDR in three or even two fractions. Single-fraction HDR monotherapy is now being investigated and if early data are confirmed with longer follow-up, may well become the treatment of choice for many men with localised prostate cancer. PMID- 23727432 TI - A national standard for early mortality after external beam radiotherapy? PMID- 23727433 TI - Chemotherapeutic and antiresorptive combination therapy suppressed lymphangiogenesis and induced osteonecrosis of the jaw-like lesions in mice. AB - Osteonecrosis of the jaw (ONJ) is a serious adverse event that occurs predominantly in patients on both antiresorptive and antineoplastic therapies. However, how these combination therapies are connected to the high frequency of ONJ in this particular patient population is unclear. This study's aim was to determine a mechanism of ONJ associated with the combination therapy of antiresorptives and chemotherapeutics. Mice received zoledronic acid (ZA) in conjunction with melphalan or dexamethasone. The maxillary first molars were extracted 3 weeks after the initiation of treatment and wound healing assessed at 4 weeks post-extractions using microcomputed tomography and immunohistochemistry. Mice receiving the combination treatment of ZA and melphalan developed ONJ-like lesions, while ONJ-like lesions were not found in mice on ZA or melphalan monotherapy, or the combination treatment of ZA and dexamethasone. ONJ lesions were characterized by a lack of epithelium, exposed necrotic bone, severe inflammatory cell infiltration, and minimal bone formation. Fluorescent immunohistochemistry showed that lymphatic vessel formation was significantly suppressed in ONJ-like lesions with a concomitant decrease in F4/80(+) macrophages expressing vascular endothelial growth factor C (VEGFC). Interestingly, significantly suppressed lymphatics were also found in the draining lymph nodes of mice on the combination treatment of ZA and melphalan. Thus, suppressed lymphangiogenesis was strongly associated with the development of ONJ-like lesions in the current study. Since lymphangiogenesis is critical in the resolution of inflammation during wound healing, inflammation control may serve as a potential strategy to prevent ONJ. PMID- 23727434 TI - 3D image registration is critical to ensure accurate detection of longitudinal changes in trabecular bone density, microstructure, and stiffness measurements in rat tibiae by in vivo microcomputed tomography (MUCT). AB - In the recent decade, in vivo MUCT scanners have become available to monitor temporal changes in rodent bone in response to diseases and treatments. We investigated short-term and long-term precision of in vivo MUCT measurements of trabecular bone density, microstructure and stiffness of rat tibiae and tested whether they can be improved by 3D image registration. Rats in the short-term precision group underwent baseline and follow-up scans within the same day (n = 15) and those in the long-term precision group were scanned at day 0 and day 14 (n = 16) at 10.5 MUm voxel size. A 3D image-registration scheme was applied to register the trabecular bone compartments of baseline and follow-up scans. Prior to image registration, short-term precision ranged between 0.85% and 2.65% in bone volume fraction (BV/TV), trabecular number, thickness, and spacing (Tb.N*, Tb.Th*, Tb.Sp*), trabecular bone mineral density and tissue mineral density (Tb.BMD, and Tb.TMD), and was particularly high in structure model index (SMI), connectivity density (Conn.D), and stiffness (4.29%-8.83%). Image registration tended to improve the short-term precision, but the only statistically significant improvement was in Tb.N*, Tb.TMD, and stiffness. On the other hand, unregistered comparisons between day-0 and day-14 scans suggested significant increases in BV/TV, Tb.N*, Tb.Th*, Conn.D, and Tb.BMD and decrease in Tb.Sp* and SMI. However, the percent change in each parameter from registered comparisons was significantly different from unregistered comparisons. Registered results suggested a significant increase in BV/TV, Tb.BMD, and stiffness over 14 days, primarily caused by increased Tb.Th* and Tb.TMD. Due to the continuous growth of rodents, the direct comparisons between the unregistered baseline and follow-up scans were driven by changes due to global bone modeling instead of local remodeling. Our results suggested that 3D image registration is critical for detecting changes due to bone remodeling activities in rodent trabecular bone by in vivo MUCT imaging. PMID- 23727435 TI - Excess mortality after hip fracture among the elderly in Taiwan: a nationwide population-based cohort study. AB - Osteoporotic hip fractures cause high mortality in the elderly population. However, few population studies reported the long-term mortality of hip fracture among the elderly in Asian population. This study assessed the incidence, excess mortality, and risk factors after osteoporotic hip fractures through inpatients aged 60 years or older. A total of 143,595 patients with hip fracture were selected from Taiwan National Health Insurance database in the years 1999 to 2009 and followed up until the end of 2010. Annual incidence, mortality and SMR, and mortality and SMR at different periods after fracture were measured. From 1999 to 2005, hip fracture incidence gradually increased and then fluctuated after 2006. From 1999 to 2009, the male-to-female ratio of annual incidence increased from 0.60 to 0.66, annual mortality for hip fracture decreased from 18.10% to 13.98%, male-to-female ratio of annual mortality increased from 1.38 to 1.64, and annual SMR decreased from 13.80 to 2.98. Follow-up SMR at one, two, five, and ten years post-fracture was 9.67, 5.28, 3.31, and 2.89, respectively. Females had higher follow-up SMR in the younger age groups (60-69 yr of age) but lower follow-up SMR in the older age groups (over 80 yr of age) compared with males. Among the studied patients, incidence is gradually decreasing along with annual mortality and SMR. Hip fracture affects short-term but not long-term mortality. PMID- 23727436 TI - BDNF in fragile X syndrome. AB - Fragile X syndrome (FXS) is a monogenic disorder that is caused by the absence of FMR1 protein (FMRP). FXS serves as an excellent model disorder for studies investigating disturbed molecular mechanisms and synapse function underlying cognitive impairment, autism, and behavioral disturbance. Abnormalities in dendritic spines and synaptic transmission in the brain of FXS individuals and mouse models for FXS indicate perturbations in the development, maintenance, and plasticity of neuronal network connectivity. However, numerous alterations are found during the early development in FXS, including abnormal differentiation of neural progenitors and impaired migration of newly born neurons. Several aspects of FMRP function are modulated by brain-derived neurotrophic factor (BDNF) signaling. Here, we review the evidence of the role for BDNF in the developing and adult FXS brain. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. PMID- 23727437 TI - Adaptations in AMPA receptor transmission in the nucleus accumbens contributing to incubation of cocaine craving. AB - Cue-induced cocaine craving in rodents intensifies or "incubates" during the first months of withdrawal from long access cocaine self-administration. This incubation phenomenon is relevant to human users who achieve abstinence but exhibit persistent vulnerability to cue-induced relapse. It is well established that incubation of cocaine craving involves complex neuronal circuits. Here we will focus on neuroadaptations in the nucleus accumbens (NAc), a region of convergence for pathways that control cocaine seeking. A key adaptation is a delayed (~3-4 weeks) accumulation of Ca(2+)-permeable AMPAR receptors (CP-AMPARs) in synapses on medium spiny neurons (MSN) of the NAc. These CP-AMPARs mediate the expression of incubation after prolonged withdrawal, although different mechanisms must be responsible during the first weeks of withdrawal, prior to CP AMPAR accumulation. The cascade of events leading to CP-AMPAR accumulation is still unclear. However, several candidate mechanisms have been identified. First, mGluR1 has been shown to negatively regulate CP-AMPAR levels in NAc synapses, and it is possible that a withdrawal-dependent decrease in this effect may help explain CP-AMPAR accumulation during incubation. Second, an increase in phosphorylation of GluA1 subunits (at the protein kinase A site) within extrasynaptic homomeric GluA1 receptors (CP-AMPARs) may promote their synaptic insertion and oppose their removal. Finally, elevation of brain-derived neurotrophic factor (BDNF) levels in the NAc may contribute to maintenance of incubation after months of withdrawal, although incubation-related increases in BDNF accumulation do not account for CP-AMPAR accumulation. Receptors and pathways that negatively regulate incubation, such as mGluR1, are promising targets for the development of therapeutic strategies to help recovering addicts maintain abstinence. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23727438 TI - Tropisetron as a neuroprotective agent against glutamate-induced excitotoxicity and mechanisms of action. AB - The objective of this study was to determine the neuroprotective role of tropisetron on retinal ganglion cells (RGCs) as well as to explore the possible mechanisms associated with alpha7 nAChR-induced neuroprotection. Adult pig RGCs were isolated from all other retinal tissue using a two-step panning technique. Once isolated, RGCs were cultured for 3 days under control untreated conditions, in the presence of 500 MUM glutamate to induce excitotoxicity, and when tropisetron was applied before glutamate to induce neuroprotection. 500 MUM glutamate decreased RGC survival by an average of 62% compared to control conditions. However, RGCs pretreated with 100 nM tropisetron before glutamate increased cell survival to an average of 105% compared to controls. Inhibition studies using the alpha7 nAChR antagonist, MLA (10 nM), support the hypothesis that tropisetron is an effective neuroprotective agent against glutamate-induced excitotoxicity; mediated by alpha7 nAChR activation. ELISA studies were performed to determine if signaling cascades normally associated with excitotoxicity and neuroprotection were up- or down-regulated after tropisetron treatment. Tropisetron had no discernible effects on pAkt levels but significantly decreased p38 MAPK levels associated with excitotoxicity from an average of 15 ng/ml to 6 ng/ml. Another mechanism shown to be associated with neuroprotection involves internalization of NMDA receptors. Double-labeled immunocytochemistry and electrophysiology studies provided further evidence that tropisetron caused internalization of NMDA receptor subunits. The findings of this study suggest that tropisetron could be an effective therapeutic agent for the treatment of degenerative disorders of the central nervous system that involves excitotoxicity. PMID- 23727440 TI - Stochastic sampled-data control for state estimation of time-varying delayed neural networks. AB - This study examines the state estimation problem for neural networks with a time varying delay. Unlike other studies, the sampled-data with stochastic sampling is used to design the state estimator using a novel approach that divides the bounding of the activation function into two subintervals. To fully use the sawtooth structure characteristics of the sampling input delay, a discontinuous Lyapunov functional is proposed based on the extended Wirtinger inequality. The desired estimator gain can be characterized in terms of the solution to linear matrix inequalities (LMIs). Finally, the proposed method is applied to two numerical examples to show the effectiveness of our result. PMID- 23727439 TI - Homeostatic synaptic plasticity in developing spinal networks driven by excitatory GABAergic currents. AB - Homeostatic plasticity refers to mechanisms that the cell or network engage in order to homeostatically maintain a preset level of activity. These mechanisms include compensatory changes in cellular excitability, excitatory and inhibitory synaptic strength and are typically studied at a developmental stage when GABA or glycine is inhibitory. Here we focus on the expression of homeostatic plasticity in the chick embryo spinal cord at a stage when GABA is excitatory. When spinal activity is perturbed in the living embryo there are compensatory changes in postsynaptic AMPA receptors and in the driving force for GABAergic currents. These changes are triggered by reduced GABAA receptor signaling, which appears to be part of the sensing machinery for triggering homeostatic plasticity. We compare and contrast these findings to homeostatic plasticity expressed in spinal systems at different stages of development, and to the developing retina at a stage when GABA is depolarizing. This article is part of the Special Issue entitled 'Homeostatic Synaptic Plasticity'. PMID- 23727441 TI - Characterization of seizure-like events recorded in vivo in a mouse model of Rett syndrome. AB - Rett syndrome is a neurodevelopmental disorder caused by mutations in the X linked gene encoding methyl-CpG-binding protein 2 (MECP2). Spontaneous recurrent discharge episodes are displayed in Rett-related seizures as in other types of epilepsies. The aim of this paper is to investigate the seizure-like event (SLE) and inter-SLE states in a female MeCP2-deficient mouse model of Rett syndrome and compare them to those found in other spontaneous recurrent epilepsy models. The study was performed on a small population of female MeCP2-deficient mice using telemetric local field potential (LFP) recordings over a 24 h period. Durations of SLEs and inter-SLEs were extracted using a rule-based automated SLE detection system for both daytime and nighttime, as well as high and low power levels of the delta frequency range (0.5-4 Hz) of the recorded LFPs. The results suggest SLE occurrences are not influenced by circadian rhythms, but had a significantly greater association with delta power. Investigating inter-SLE and SLE states by fitting duration histograms to the gamma distribution showed that SLE initiation and termination were associated with random and deterministic mechanisms, respectively. These findings when compared to reported studies on epilepsy suggest that Rett-related seizures share many similarities with absence epilepsy. PMID- 23727442 TI - The learning problem of multi-layer neural networks. AB - This manuscript considers the learning problem of multi-layer neural networks (MNNs) with an activation function which comes from cellular neural networks. A systematic investigation of the partition of the parameter space is provided. Furthermore, the recursive formula of the transition matrix of an MNN is obtained. By implementing the well-developed tools in the symbolic dynamical systems, the topological entropy of an MNN can be computed explicitly. A novel phenomenon, the asymmetry of a topological diagram that was seen in Ban, Chang, Lin, and Lin (2009) [J. Differential Equations 246, pp. 552-580, 2009], is revealed. PMID- 23727444 TI - Extracting cortical current dipoles from MEG recordings. AB - A novel way of using synthetic aperture magnetometry to extract local current dipoles is proposed. This method is used to extract the current-dipoles at multiple points in the cortex. It is shown that in this way the correlation between cortical points is lower and falls faster with distance when compared to the original MEG and other methods. Evoked auditory responses are well localized. They show higher signal to noise ratio and are more reproducible then the MEG evoked fields. PMID- 23727443 TI - Recent developments in the antiprotozoal and anticancer activities of the 2 alkynoic fatty acids. AB - The 2-alkynoic fatty acids are an interesting group of synthetic compounds that display antimycobacterial, antifungal, anticancer, and pesticidal activities but their antiprotozoal activity has received little attention until recently. In this review we have summarized our present knowledge of the biomedical potential of the 2-hexadecynoic acid (2-HDA) and 2-octadecynoic acid (2-ODA) together with several mechanistic pieces of work attesting to the fact that these compounds, and their metabolites, are good fatty acid biosynthesis inhibitors. The antiprotozoal activity of 2-HDA and 2-ODA against Leishmania donovani and Plasmodium falciparum, parasites responsible for visceral leishmaniasis and malaria, respectively, is also reviewed. The evidence obtained so far supports the fact that these fatty acids are good inhibitors of the L. donovani DNA topoisomerase IB enzyme (LdTopIB) and the potency of LdTopIB inhibition is chain length dependent. We also demonstrate the generality of the antiprotozoal activity of 2-HDA and 2-ODA against P. falciparum, and review our present knowledge of their inhibition of key P. falciparum enzymes such as PfFabZ, PfFabG, and PfFabI together with some possible modes of inhibition. Recent research by our group has also demonstrated that 2-ODA displays antineoplastic activity, specifically against the neuroblastoma SH-SY5Y cell line via lactate dehydrogenase (LDH) release, which is a cell death mechanism principally associated to necrosis. This is the first comprehensive review of the medicinal chemistry of this interesting group of acetylenic fatty acids. PMID- 23727445 TI - Endothelium-targeted Delta-like 1 promotes hematopoietic stem cell expansion ex vivo and engraftment in hematopoietic tissues in vivo. AB - BACKGROUND: Notch ligands enhance ex vivo expansion of hematopoietic stem cells (HSCs). But to use Notch ligands in HSC therapies of human diseases, efforts are required to improve ex vivo expansion efficiency and in vivo transplant engraftment. DESIGN AND METHODS: We designed and produced an endothelium-targeted soluble Notch ligand, the DSL domain of Delta-like 1 fused with a RGD motif (D1R), and examined the effects of this protein on HSCs ex vivo and in vivo. RESULTS: D1R efficiently promoted ex vivo expansion of both mouse bone marrow (BM) and human umbilical cord blood HSCs. HSCs expanded with D1R up-regulated many of the stemness-related genes, and showed high BM engraftment efficacy with long-term repopulation capacity after transplantation. Moreover, in vivo administration of D1R increased the number of BM HSCs in mice, and facilitated BM recovery of mice after irradiation. Injection of D1R significantly improved HSC engraftment and myeloid recovery after BM transplantation in irradiated mice. D1R enhanced HSC engraftment not only in BM, but also in the liver and spleen after BM transplantation in mice. D1R induced the formation of compact cell clusters containing the transplanted HSCs in close contact with endothelial cells, reminiscent of HSC niches, in the liver and spleen. CONCLUSIONS: D1R might be applied in improving both HSC expansion ex vivo and HSC engraftment in vivo in transplantation. PMID- 23727446 TI - A novel application for a 3-dimensional timelapse assay that distinguishes chemotactic from chemokinetic responses of hematopoietic CD133(+) stem/progenitor cells. AB - Efficient homing/mobilization of human hematopoietic stem/progenitor cells to/from bone marrow niches enhances their therapeutic efficacy. Additionally, homing is dependent on cell source and may be modulated by prior ex vivo cell expansion. Here, we describe a novel application of a 3-dimensional time-lapse method for assessing trafficking of individual human cord blood CD133(+) hematopoietic stem/progenitor cells in vitro, using the key chemokine CXCL12 as a paradigm. This new methodology allows distinction between chemotactic responses (displacement of center of mass and the forward migration index of the cells), and chemokinetic responses such as total cell path traveled in any direction (accumulated distance) and cell velocity in a 3-dimensional matrix. Other key advantages of this novel assay over existing assays include the ability to assess individual cell migration over times comparable to in vivo homing and rapid mobilization assays (18-24h) and to directly compare the strength or response of individual hematopoietic progenitor cells to different or competing stimuli and small molecule inhibitors in a single assay prior to analyses in vivo. Importantly, using this method, our results demonstrate definitively that CXCL12 regulates the chemotactic responses of human cord blood CD133(+) cells, but not their random migration or chemokinesis. PMID- 23727448 TI - Anxiety, depression and quality of life in Chinese women with breast cancer during and after treatment: a comparative evaluation. AB - PURPOSE OF THE RESEARCH: To compare the psychological health and quality of life (QoL) of women with breast cancer, and to determine the relationship between anxiety, depression and QoL during treatment and one year afterwards. METHODS AND SAMPLE: For this secondary analysis, 269 women undergoing adjuvant therapy for breast cancer, and 148 women with breast cancer who had completed all treatment within the last year completed a self-report questionnaire covering the Hospital Anxiety and Depression Scale-Cantonese/Chinese version, Functional Assessment of Cancer Therapy-General, and demographic and clinical characteristics. KEY RESULTS: The ongoing-therapy group showed higher levels of anxiety and depression and lower levels of all QoL dimensions than the post-therapy group. Linear regression results showed that both anxiety and depression were significantly related to physical and functional well-being, while depression was associated with social/family well-being in both groups. In the case of emotional well being, anxiety had a strong significant association in both groups and depression a significant relationship only in the ongoing-therapy group. CONCLUSIONS: The psychological health of women with breast cancer is affected during and after treatment. Psychological distress in these patients, including anxiety and depression, has independent associations with impaired emotional, functional, physical and social well-being. The results highlight the importance of timely detection of anxiety and depression, and their proper management, during the treatment and survivorship phases of the breast cancer trajectory. PMID- 23727447 TI - What basal ganglia changes underlie the parkinsonian state? The significance of neuronal oscillatory activity. AB - One well accepted functional feature of the parkinsonian state is the recording of enhanced beta oscillatory activity in the basal ganglia. This has been demonstrated in patients with Parkinson's disease (PD) and in animal models such as the rat with 6-hydroxydopamine (6-OHDA)-induced lesion and 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, all of which are associated with severe striatal dopamine depletion. Neuronal hyper-synchronization in the beta (or any other) band is not present despite the presence of bradykinetic features in the rat and monkey models, suggesting that increased beta band power may arise when nigro-striatal lesion is advanced and that it is not an essential feature of the early parkinsonian state. Similar observations and conclusions have been previously made for increased neuronal firing rate in the subthalamic and globus pallidus pars interna nuclei. Accordingly, it is suggested that early parkinsonism may be associated with dynamic changes in basal ganglia output activity leading to reduced movement facilitation that may be an earlier feature of the parkinsonian state. PMID- 23727449 TI - Suffering indicators in terminally ill children from the parental perspective. AB - PURPOSE: Suffering is a complex multifaceted phenomenon, which has received limited attention in relation to children with terminal illness. As part of a wider study we interviewed parents of children with terminal illness to elicit their perspectives on suffering, in order to provide initial understanding from which to develop observational indicators and further research. METHODS: Qualitative descriptive study with semi-structured interviews made "ad hoc". Selection through deliberate sampling of mothers and fathers of hospitalised children (0-16 years old) with a terminal illness in Granada (Spain). KEY RESULTS: 13 parents were interviewed. They described children's suffering as manifested through sadness, apathy, and anger towards their parents and the professionals. The isolation from their natural environment, the uncertainty towards the future, and the anticipation of pain caused suffering in children. The pain is experienced as an assault that their parents allow to occur. CONCLUSIONS: The analysis of the interview with the parents about their perception of their ill children's suffering at the end of their lives is a valuable source of information to consider supportive interventions for children and parents in health care settings. An outline summary of the assessed aspects of suffering, the indicators and aspects for health professional consideration is proposed. PMID- 23727450 TI - Genotype-phenotype analysis of 18q12.1-q12.2 copy number variation in autism. AB - Autism Spectrum Disorders (ASD) are complex neurodevelopmental conditions characterized by delays in social interactions and communication as well as displays of restrictive/repetitive interests. DNA copy number variants have been identified as a genomic susceptibility factor in ASDs and imply significant genetic heterogeneity. We report a 7-year-old female with ADOS-G and ADI-R confirmed autistic disorder harbouring a de novo 4 Mb duplication (18q12.1). Our subject displays severely deficient expressive language, stereotypic and repetitive behaviours, mild intellectual disability (ID), focal epilepsy, short stature and absence of significant dysmorphic features. Search of the PubMed literature and DECIPHER database identified 4 additional cases involving 18q12.1 associated with autism and/or ID that overlap our case: one duplication, two deletions and one balanced translocation. Notably, autism and ID are seen with genomic gain or loss at 18q12.1, plus epilepsy and short stature in duplication cases, and hypotonia and tall stature in deletion cases. No consistent dysmorphic features were noted amongst the reviewed cases. We review prospective ASD/ID candidate genes integral to 18q12.1, including those coding for the desmocollin/desmoglein cluster, ring finger proteins 125 and 138, trafficking protein particle complex 8 and dystrobrevin-alpha. The collective clinical and molecular features common to microduplication 18q12.1 suggest that dosage sensitive, position or contiguous gene effects may be associated in the etiopathogenesis of this autism-ID-epilepsy syndrome. PMID- 23727451 TI - A spontaneous state of weakly correlated synaptic excitation and inhibition in visual cortex. AB - Cortical spontaneous activity reflects an animal's behavioral state and affects neural responses to sensory stimuli. The correlation between excitatory and inhibitory synaptic input to single neurons is a key parameter in models of cortical circuitry. Recent measurements demonstrated highly correlated synaptic excitation and inhibition during spontaneous "up-and-down" states, during which excitation accounted for approximately 80% of inhibitory variance (Shu et al., 2003; Haider et al., 2006). Here we report in vivo whole-cell estimates of the correlation between excitation and inhibition in the rat visual cortex under pentobarbital anesthesia, during which up-and-down states are absent. Excitation and inhibition are weakly correlated, relative to the up-and-down state: excitation accounts for less than 40% of inhibitory variance. Although these correlations are lower than when the circuit cycles between up-and-down states, both behaviors may arise from the same circuitry. Our observations provide evidence that different correlational patterns of excitation and inhibition underlie different cortical states. PMID- 23727453 TI - Three distinct motifs within the C-terminus of acid-sensing ion channel 1a regulate its surface trafficking. AB - Various protein motifs play a key role in regulating protein biogenesis and trafficking. Here, we discovered that three distinct motifs regulate the trafficking of acid-sensing ion channel 1a (ASIC1a), the primary neuronal proton receptor which plays critical roles in neurological diseases including stroke, multiple sclerosis and seizures. Mutating the PDZ binding motif of ASIC1a increased its surface expression and current density. In contrast, mutating either a RRGK motif or a KEAKR motif reduced ASIC1a surface expression and acid activated current density. Mutating or deleting the RRGK motif also reduced pH sensitivity and the rate of desensitization of ASIC1a. These changes were likely due to a change in ASIC1a biogenesis; mutating either the RRGK or KEAKR motif reduced N-glycosylation of ASIC1a while mutating the PDZ binding motif had the opposite effect. Our results demonstrate that these C-terminal motifs are important for ASIC1a trafficking and channel function. In addition, in contrast to multiple previous studies, which all show that K/R containing motifs lead to endoplasmic reticulum (ER) retention, our findings indicate that these motifs can also be required for efficient trafficking. PMID- 23727452 TI - Transcript expression of vesicular glutamate transporters in lumbar dorsal root ganglia and the spinal cord of mice - effects of peripheral axotomy or hindpaw inflammation. AB - Using specific riboprobes, we characterized the expression of vesicular glutamate transporter (VGLUT)1-VGLUT3 transcripts in lumbar 4-5 (L4-5) dorsal root ganglions (DRGs) and the thoracolumbar to lumbosacral spinal cord in male BALB/c mice after a 1- or 3-day hindpaw inflammation, or a 7-day sciatic nerve axotomy. Sham animals were also included. In sham and contralateral L4-5 DRGs of injured mice, VGLUT1-, VGLUT2- and VGLUT3 mRNAs were expressed in ~45%, ~69% or ~17% of neuron profiles (NPs), respectively. VGLUT1 was expressed in large and medium sized NPs, VGLUT2 in NPs of all sizes, and VGLUT3 in small and medium-sized NPs. In the spinal cord, VGLUT1 was restricted to a number of NPs at thoracolumbar and lumbar segments, in what appears to be the dorsal nucleus of Clarke, and in mid laminae III-IV. In contrast, VGLUT2 was present in numerous NPs at all analyzed spinal segments, except the lateral aspects of the ventral horns, especially at the lumbar enlargement, where it was virtually absent. VGLUT3 was detected in a discrete number of NPs in laminae III-IV of the dorsal horn. Axotomy resulted in a moderate decrease in the number of DRG NPs expressing VGLUT3, whereas VGLUT1 and VGLUT2 were unaffected. Likewise, the percentage of NPs expressing VGLUT transcripts remained unaltered after hindpaw inflammation, both in DRGs and the spinal cord. Altogether, these results confirm previous descriptions on VGLUTs expression in adult mice DRGs, with the exception of VGLUT1, whose protein expression was detected in a lower percentage of mouse DRG NPs. A detailed account on the location of neurons expressing VGLUTs transcripts in the adult mouse spinal cord is also presented. Finally, the lack of change in the number of neurons expressing VGLUT1 and VGLUT2 transcripts after axotomy, as compared to data on protein expression, suggests translational rather than transcriptional regulation of VGLUTs after injury. PMID- 23727455 TI - Intellectual functioning and multi-dimensional attentional processes in long-term survivors of a central nervous system related pediatric malignancy. AB - AIMS: Central nervous system (CNS) malignancies and/or their treatment in pediatric cancer survivors are known to be associated with deficits in neuropsychological functions. We report findings from a nation-wide study of childhood cancer survivors to investigate intelligence and attention/concentration from a multi-dimensional perspective in a diverse sample from this population. MAIN METHODS: Four hundred forty-four pediatric cancer survivors between 6 and 17 years of age, who had suffered CNS involvement associated with their malignancy, were evaluated. All patients completed a measure of general intelligence. Attention was measured by a continuous performance test (CPT) and by parental report using a standardized psychological inventory. KEY FINDINGS: Social economic status (SES) was a significant predictor of intellectual functioning and scores on independent measures of attention. After controlling for SES, cranial radiation therapy (CRT) was strongly predictive of impairments in intellectual functioning. Patients who had completed a transplant procedure did not have significant impairments in intellectual functioning when compared to other participants. CPT performance was most clearly influenced by a younger age at diagnosis and the presence of a supratentorial brain tumor. Reaction time was lower in patients who had received CRT. Gender did not correlate with CPT performance, but caregiver reports of deficits in attentional functioning were more prevalent in girls compared to boys. SIGNIFICANCE: These findings are important given the large, representative sample and multi-dimensional assessment of attentional functioning. The presence of a very strong SES effect on all dependent variables must be addressed in studies of this nature. PMID- 23727454 TI - Bcl11b transcription factor plays a role in the maintenance of the ameloblast progenitors in mouse adult maxillary incisors. AB - Rodent incisors maintain the ability to grow continuously and their labial dentin is covered with enamel. Bcl11b zinc-finger transcription factor is expressed in ameloblast progenitors in mouse incisors and its absence in Bcl11b(KO/KO) mice results in a defect in embryonic tooth development. However, the role of Bcl11b in incisor maintenance in adult tissue was not studied because of death at birth in Bcl11b(KO/KO) mice. Here, we examined compound heterozygous Bcl11b(S826G/KO) mice, one allele of which has an amino acid substitution of serine at position 826 for glycine, that exhibited hypoplastic maxillary incisors with lower concentrations of minerals at the enamel and the dentin, accompanying the maxillary bone hypoplasia. Histological examinations revealed hypoplasia of the labial cervical loop in incisors, shortening of the ameloblast progenitor region, and impairment in differentiation and proliferation of ameloblast-lineage cells. Interestingly, however, juvenile mice at 5days after birth did not show marked change in these phenotypes. These results suggest that attenuated Bcl11b activity impairs ameloblast progenitors and incisor maintenance. The number of BrdU label retaining cells, putative stem cells, was lower in Bcl11b(S826G/KO) incisors, which suggests the incisor hypoplasia may be in part a result of the decreased number of stem cells. Interestingly, the level of Shh and FGF3 expressions, which are assumed to play key roles in the development and maintenance of ameloblasts and odontoblasts, was not decreased, though the expressed areas were more restricted in ameloblast progenitor and mesenchyme regions of Bcl11b(S826G/KO) incisors, respectively. Those data suggest that the incisor maintenance by Bcl11b is not directly related to the FGF epithelial-mesenchymal signaling loop including Shh but is intrinsic to ameloblast progenitors and possibly stem cells. PMID- 23727456 TI - Guidelines for the intravenous application of recombinant tissue-type plasminogen activator (alteplase), the second edition, October 2012: a guideline from the Japan Stroke Society. AB - In Japan, intravenous alteplase, a recombinant tissue-type plasminogen activator (rt-PA), was approved for an indication of ischemic stroke in 2005 on the basis of the results of a clinical trial with a unique dose of the drug (0.6 mg/kg). The Japan Stroke Society published the guidelines for intravenous application of rt-PA and organized training sessions for proper use all over Japan in an effort to promote the safe, widespread use of intravenous alteplase. Seven years following its approval, clinical experience with intravenous alteplase has accumulated, additional evidence of intravenous alteplase has been found in Japan and overseas, and the medical environment has substantially changed, including approvals for new drugs and medical devices. Notably, the use of alteplase in the extended therapeutic time window (within 4.5 hours of symptom onset) became covered by insurance in Japan in August 2012. To address these changing situations, we have decided to prepare the revised guidelines. In preparing the second edition, we took care to make its contents more practical by emphasizing information needed in clinical practice. While the first edition was developed with emphasis on safety in light of limited clinical experience with intravenous alteplase in Japan in 2005, this second edition is a substantial revision of the first edition mainly in terms of eligibility criteria, on the basis of accumulated evidence and the clinical experience. PMID- 23727457 TI - The growing role of eicosanoids in tissue regeneration, repair, and wound healing. AB - Tissue repair and regeneration are essential processes in maintaining tissue homeostasis, especially in response to injury or stress. Eicosanoids are ubiquitous mediators of cell proliferation, differentiation, and angiogenesis, all of which are important for tissue growth. Eicosanoids regulate the induction and resolution of inflammation that accompany the tissue response to injury. In this review, we describe how this diverse group of molecules is a key regulator of tissue repair and regeneration in multiple organ systems and biologic contexts. PMID- 23727458 TI - Suppression by Delta(9)-tetrahydrocannabinol of the primary immunoglobulin M response by human peripheral blood B cells is associated with impaired STAT3 activation. AB - This study was undertaken to gain insights into the mechanism for Delta(9) tetrahydrocannabinol (Delta(9)-THC)-mediated suppression of primary immunoglobulin M (IgM) responses in humans. An in vitro activation model, which employs cell surface-expressed CD40 ligand (CD40L) and recombinant cytokines (interleukin (IL)-2, -6, and -10), was used to differentiate human peripheral blood (HPB) naive B cells into IgM secreting cells. Pretreatment with Delta(9) THC significantly decreased the number of IgM secreting cells as determined by ELISPOT. The attenuation of IgM secretion by Delta(9)-THC involved, at least in part, the impairment of plasma cell differentiation as evidenced by suppression of immunoglobulin joining chain (IgJ) mRNA expression. The analysis at each of two different stages critically involved in plasma cell differentiation indicates that Delta(9)-THC impaired both the primary activation stage and proliferation of B cells. Interestingly, Delta(9)-THC selectively suppressed the surface expression of CD80, but not other measured B-cell activation markers (CD69, CD86, and ICAM1). Furthermore, pretreatment with Delta(9)-THC was accompanied by a robust decrease of STAT3 phosphorylation, whereas the phosphorylation of the p65 NFkappaB subunit was not affected. Collectively, these data provide new insights into the mechanisms for impaired B cell function by Delta(9)-THC. PMID- 23727459 TI - Osteoimmunology: the study of the relationship between the immune system and bone tissue. AB - Bone tissue is a highly regulated structure, which plays an essential role in various physiological functions. Through autocrine and paracrine mechanisms, bone tissue is involved in hematopoiesis, influencing the fate of hematopoietic stem cells. There are a number of molecules shared by bone cells and immune system cells indicating that there are multiple connections between the immune system and bone tissue. In order to pool all the knowledge concerning both systems, a new discipline known under the term "osteoimmunology" has been developed. Their progress in recent years has been exponential and allowed us to connect and increase our knowledge in areas not seemingly related such as rheumatoid erosion, postmenopausal osteoporosis, bone metastases or periodontal disease. In this review, we have tried to summarize the most important advances that have occurred in the last decade, especially in those areas of interest related to rheumatology. PMID- 23727460 TI - Chronic respiratory disfunction due to diffuse alveolar hemorrhage in patients with systemic lupus erythematosus and primary vasculitis. AB - BACKGROUND: Pulmonary hemorrhage (PH) occurs in 2-5% of SLE patients, and is associated with a high mortality rate (79-90%). Diagnostic criteria for this complication include: 1) Pulmonary infiltrates, with at least 3/4 of lung tissue involved in a chest x ray, 2) Acute respiratory failure, 3) A decrease of 3g/dL or more in hemoglobin levels. PH might lead to organized pneumonia, collagen deposition, and pulmonary fibrosis which in time might cause changes in pulmonary function tests with either restrictive or obstructive patterns. AIM: To evaluate the existence of abnormalities in pulmonary function tests after a PH episode. METHODS: We included patients with SLE and primary vasculitis that developed PH. During the acute episode, we measured SLEDAI in SLE patients, five factor score in microscopic polyangiitis (MPA) and Birmingham Vasculitis Activity Store (BVAS) in granulomatosis with polyangiitis (GPA) (Wegener). We determined the number of PH events, treatment, and ventilator assistance requirements and correlated its association with abnormal pulmonary function tests. RESULTS: We included 10 patients, 7 with SLE, 2 with MPA and 1 with GPA (Wegener). The mean activity measures were: SLEDAI 20.4 +/- 7.5, FFS 2, and BVAS 36. Treatment consisted in methylprednisolone (MPD) in 3 patients, MPD plus cyclophosphamide (CY) in 6 patients, and MPD, CY, IV immunoglobulin, and plasmapheresis in one patient. Five patients required ventilatory support. We found abnormalities in pulmonary function tests in 8 patients, three had an obstructive pattern and five a restrictive pattern; 2 patients did not show any change. We did not find a significant association with any of the studied variables. CONCLUSION: PH might cause abnormalities in pulmonary function tests and prolonged immunosuppressive treatment could be required. PMID- 23727461 TI - Molecular evidence of 'Siisa form', a new genotype related to Onchocerca ochengi in cattle from North Cameroon. AB - Onchocerca ochengi, a filarial nematode parasite from African Zebu cattle is considered to be the closest relative of Onchocerca volvulus, the causative agent of river blindness. Both Onchocerca species share the vector, black flies of the Simulium damnosum complex. Correct identification of their infective third-stage larvae in man-biting vectors is crucial to distinguish the transmission of human or animal parasites. In order to identify different closely related Onchocerca species we surveyed the sequences from the three mitochondrial loci 12S rRNA, 16S rRNA and coxI in both adult worms isolated from Onchocerca-induced nodules in cattle and infective third stage larvae isolated from vector flies from North Cameroon. Two distinct groups of mitochondrial haplotypes were found in cattle as well as in flies. One of them has been formerly mentioned in the literature as Onchocerca sp. 'Siisa', a filaria isolated from the vector S. damnosum sensu lato in Uganda with hitherto unknown host. Both variants are found sympatric, also in the same nodule of the animal host and in the vector. In the flies we also found the mitochondrial haplotype that had been described for O. volvulus which is about equally different from the two previously mentioned ones as they are from each other. These results suggest a higher genetic diversification of Onchocerca ochengi than previously reported. PMID- 23727462 TI - Two-photon imaging of neural population activity in zebrafish. AB - Rapidly developing imaging technologies including two-photon microscopy and genetically encoded calcium indicators have opened up new possibilities for recording neural population activity in awake, behaving animals. In the small, transparent zebrafish, it is even becoming possible to image the entire brain of a behaving animal with single-cell resolution, creating brain-wide functional maps. In this chapter, we comprehensively review past functional imaging studies in zebrafish, and the insights that they provide into the functional organization of neural circuits. We further offer a basic primer on state-of-the-art methods for in vivo calcium imaging in the zebrafish, including building a low-cost two photon microscope and highlight possible challenges and technical considerations. PMID- 23727463 TI - Patterns of multisite pain and associations with risk factors. AB - To explore definitions for multisite pain, and compare associations with risk factors for different patterns of musculoskeletal pain, we analysed cross sectional data from the Cultural and Psychosocial Influences on Disability (CUPID) study. The study sample comprised 12,410 adults aged 20-59 years from 47 occupational groups in 18 countries. A standardised questionnaire was used to collect information about pain in the past month at each of 10 anatomical sites, and about potential risk factors. Associations with pain outcomes were assessed by Poisson regression, and characterised by prevalence rate ratios (PRRs). Extensive pain, affecting 6-10 anatomical sites, was reported much more frequently than would be expected if the occurrence of pain at each site were independent (674 participants vs 41.9 expected). In comparison with pain involving only 1-3 sites, it showed much stronger associations (relative to no pain) with risk factors such as female sex (PRR 1.6 vs 1.1), older age (PRR 2.6 vs 1.1), somatising tendency (PRR 4.6 vs 1.3), and exposure to multiple physically stressing occupational activities (PRR 5.0 vs 1.4). After adjustment for number of sites with pain, these risk factors showed no additional association with a distribution of pain that was widespread according to the frequently used American College of Rheumatology criteria. Our analysis supports the classification of pain at multiple anatomical sites simply by the number of sites affected, and suggests that extensive pain differs importantly in its associations with risk factors from pain that is limited to only a small number of anatomical sites. PMID- 23727465 TI - Determination of cucumarioside A2-2 in mouse spleen by radiospectroscopy, MALDI MS and MALDI-IMS. AB - The distribution of triterpene glycoside cucumarioside A2-2, the main compound of medical lead Cumaside in immunodeficiency diseases, in mouse spleen was determined. For this purpose the stability and dynamics of glycoside content changes over time in Balb/c mouse spleen tissue homogenate as well as the study of the cucumarioside A2-2 spatial distribution in tissue sections were investigated using radiospectroscopy, MALDI-MS and MALDI Imaging Mass Spectrometry (IMS), correspondingly. Cucumarioside A2-2 is reliably detected by MALDI-MS in the mouse spleen tissue after single intraperitoneal (i.p.) injection at a dosage of 5 mg/kg. The glycoside is stable in the spleen and does not undergo metabolic transformation in either tissue homogenates or in the intact organ within 24 h after i.p. injection. The cucumarioside A2-2 was absorbed fairly rapidly: the glycoside maximum concentration (Cmax) in tissue homogenate was observed in the first 30 min after injection; the minimum values were registered in 3 h. These results are in agreement with those obtained in the pharmacokinetic study of (3)H-cucumarioside A2-2. It was established by MALDI-IMS that glycoside was mainly located in the tunica serosa part of the spleen and only a small amount was detected within the red and white pulp of the organ. MALDI MS images obtained 15-30 min post dosage clearly reflect high drug concentrations in the regions surrounding the organ followed by its decline in the surface part and a very slight redistribution to the internal part of the spleen. PMID- 23727464 TI - In silico predictions of gastrointestinal drug absorption in pharmaceutical product development: application of the mechanistic absorption model GI-Sim. AB - Oral drug delivery is the predominant administration route for a major part of the pharmaceutical products used worldwide. Further understanding and improvement of gastrointestinal drug absorption predictions is currently a highly prioritized area of research within the pharmaceutical industry. The fraction absorbed (fabs) of an oral dose after administration of a solid dosage form is a key parameter in the estimation of the in vivo performance of an orally administrated drug formulation. This study discloses an evaluation of the predictive performance of the mechanistic physiologically based absorption model GI-Sim. GI-Sim deploys a compartmental gastrointestinal absorption and transit model as well as algorithms describing permeability, dissolution rate, salt effects, partitioning into micelles, particle and micelle drifting in the aqueous boundary layer, particle growth and amorphous or crystalline precipitation. Twelve APIs with reported or expected absorption limitations in humans, due to permeability, dissolution and/or solubility, were investigated. Predictions of the intestinal absorption for different doses and formulations were performed based on physicochemical and biopharmaceutical properties, such as solubility in buffer and simulated intestinal fluid, molecular weight, pK(a), diffusivity and molecule density, measured or estimated human effective permeability and particle size distribution. The performance of GI-Sim was evaluated by comparing predicted plasma concentration-time profiles along with oral pharmacokinetic parameters originating from clinical studies in healthy individuals. The capability of GI Sim to correctly predict impact of dose and particle size as well as the in vivo performance of nanoformulations was also investigated. The overall predictive performance of GI-Sim was good as >95% of the predicted pharmacokinetic parameters (C(max) and AUC) were within a 2-fold deviation from the clinical observations and the predicted plasma AUC was within one standard deviation of the observed mean plasma AUC in 74% of the simulations. GI-Sim was also able to correctly capture the trends in dose- and particle size dependent absorption for the study drugs with solubility and dissolution limited absorption, respectively. In addition, GI-Sim was also shown to be able to predict the increase in absorption and plasma exposure achieved with nanoformulations. Based on the results, the performance of GI-Sim was shown to be suitable for early risk assessment as well as to guide decision making in pharmaceutical formulation development. PMID- 23727466 TI - Chronic pressure-overload hypertrophy attenuates vortex formation time in patients with severe aortic stenosis and preserved left ventricular systolic function undergoing aortic valve replacement. AB - OBJECTIVE: Transmitral blood flow produces a vortex ring that enhances the hydraulic efficiency of early left ventricular (LV) filling. The effect of pressure-overload hypertrophy on the duration of LV vortex ring formation (vortex formation time [VFT]) is unknown. The current investigation tested the hypothesis that chronic LV pressure-overload hypertrophy produced by severe aortic stenosis (AS) reduces VFT in patients with preserved LV systolic function undergoing aortic valve replacement. DESIGN: Observational study. SETTING: Veterans Affairs Medical Center. PARTICIPANTS: After the Institutional Review Board's approval, 8 patients (7 men and 1 woman; age, 62+/-5 y; and ejection fraction, 59%+/-5%) with AS (peak pressure gradient, 81+/-22 mmHg; aortic valve area, 0.78+/-0.25 cm(2)) scheduled for aortic valve replacement were compared with 8 patients (all men; age, 63+/-3 y; and ejection fraction, 60%+/-7%) without AS undergoing coronary artery bypass graft surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Under general anesthesia, peak early LV filling (E) and atrial systole (A) blood flow velocities and their corresponding velocity-time integrals were obtained using pulse-wave Doppler echocardiography to determine E/A and atrial filling fraction (beta). Mitral valve diameter (D) was calculated as the average of minor and major axis lengths obtained in the midesophageal bicommissural and long-axis transesophageal echocardiography imaging planes, respectively. Posterior wall thickness (PWT) was measured at end-diastole using M-mode echocardiography. VFT was calculated as 4*(1-beta)*SV/piD(3), where SV = stroke volume measured using thermodilution. Systemic and pulmonary hemodynamics, LV diastolic function, PWT, and VFT were determined during steady-state conditions 30 minutes before cardiopulmonary bypass. Early LV filling was attenuated in patients with AS (eg, E/A, 0.77+/-0.11 compared with 1.23+/-0.13; beta, 0.43+/-0.09 compared with 0.35+/-0.02; p<0.05 for each). LV hypertrophy was observed (PWT, 1.4+/-0.1 cm compared with 1.1+/-0.2 cm; p<0.05) and VFT was lower (3.0+/-0.9 v 4.3+/-0.5; p<0.05) in patients with versus without AS. Linear regression analysis showed a significant correlation between VFT and PWT (VFT = -2.57 *PWT + 6.81; r(2) = 0.345; p = 0.017). CONCLUSION: The results indicated that pressure-overload hypertrophy produced by AS reduced VFT in patients with normal LV systolic function undergoing aortic valve replacement. PMID- 23727468 TI - Effects of sodium citrate on melamine-cyanuric acid mixture-induced urolithiasis in rats. AB - BACKGROUND: When melamine is used as an additive in infant formula, it may cause acute nephrotoxicity in humans as well as in other animals. This study was designed to examine the effects of a melamine-cyanuric acid mixture on cytotoxicity in vitro and rat-acute nephrotoxicity. METHODS: In the in vitro study, crystal formations created by the melamine-cyanuric acid mixture were evaluated in media with differing pH conditions over a 24-h period and co treatment with sodium citrate to observe the crystal formation. In the animal study, rats were exposed to a melamine-cyanuric acid mixture (400 mg/kg, 1:1) via oral gavage 14 days and co-treated with sodium citrate to observe the crystal formation in rats. RESULTS: Melamine-cyanuric acid mixture-induced crystal was pH dependent in a conditioned medium, and sodium citrate could decrease the crystal formation. Melamine-cyanuric acid-treated rats showed marked kidney swelling, vacuolization and necrosis in the proximal tubules, and numerous polarizable crystals were located in the distal segments, causing increases in kidney weight, serum BUN and creatinine. After co-treatment with sodium citrate, these increases can all be reversed. Moreover, the degrees of nephrotoxicity, proliferating of cell nuclear antigen protein and urolithiasis-related osteopontin were also decreased in the kidneys. CONCLUSION: Sodium citrate could decrease melamine cyanuric acid mixture-induced crystal formation that leads to urolithiasis and nephrotoxicity in rats. These results may provide a strategy for melamine cyanuric acid-intoxication therapy in animal. PMID- 23727467 TI - fMRI assessment of thalamocortical connectivity during attentional performance. AB - Functional magnetic resonance imaging (fMRI) studies have shown dysfunction in key areas associated with the thalamocortical circuit in patients with schizophrenia. This study examined the functional connectivity involving the frontal-thalamic circuitry during a spatial focusing-of-attention task in 18 unmedicated patients with schizophrenia and 38 healthy controls. Functional connectivity was analyzed by assigning seed regions (in the thalamic nuclei (mediodorsal nucleus (MDN), pulvinar, anterior nucleus (AN)), the dorsolateral prefrontal cortex (Brodmann areas 9 and 46), and the caudate), and correlating their respective activity with that in the non-seed regions voxel-wise. Functional connectivity analysis demonstrated that functional connectivity was significantly impaired in patients, e.g., between the right pulvinar and regions such as the prefrontal and temporal cortices and the cerebellum. On the other hand, enhanced functional connectivity was found in patients, e.g., between the AN and regions such as the prefrontal and temporal cortices. In addition, the patients had significantly lower task performance and less (but non-significant) brain activation than those of controls. These results revealed disturbed functional integration in schizophrenia, and suggested that the functional connectivity abnormalities in the thalamocortical circuitry, especially the frontal-thalamic circuitry, may underlie the attention deficits in schizophrenia patients. Further, this study suggested that functional connectivity analysis might be more sensitive than brain activation analysis in detecting the functional abnormalities in schizophrenia. PMID- 23727469 TI - Incidence and factors of post-adrenalectomy hyperkalemia in patients with aldosterone producing adenoma. AB - BACKGROUND: Hyperkalemia is a potentially serious complication following adrenalectomy of aldosterone-producing adenomas (APA). We analyzed the incidence and risk factors for hyperkalemia after adrenalectomy in patients with APA. METHODS: We retrospectively analyzed the records of 55 patients who underwent adrenalectomy for APA between 2002 and 2011. Demographic features, biochemical and hormonal profiles, imaging, and relevant medications were reviewed. RESULTS: Sixteen of 55 APA patients (29.1%) developed hyperkalemia (mean serum K(+) 5.6+/ 0.3 mmol/l) after adrenalectomy and 3 had persistent hyperkalemia requiring mineralocorticoid supplementation for more than nine months. Compared with normokalemic patients, hyperkalemic patients were characterized by male predominance, older age, longer duration of hypertension (12.8+/-9.3 vs. 6.7+/ 5.0 y, p<0.05), lower nadir serum K(+) (p<0.05), higher preoperative serum creatinine (p<0.01), and higher likelihood of residual hypertension. Using multivariate regression analysis, longer duration of hypertension and impaired renal function were the most important factors of post-adrenalectomy hyperkalemia. CONCLUSIONS: Post-adrenalectomy hyperkalemia in patients with APA is not rare and associated with impaired renal function and longer duration of hypertension. Serum K(+) must be cautiously monitored in patients with long-term hypertension and kidney disease. PMID- 23727470 TI - 2-methyl-L-erythritol glycosides from Gardenia jasminoides. AB - Two new glycosides, 2-methyl-L-erythritol-4-O-(6-O-trans-sinapoyl)-beta-D glucopyranoside (1) and 2-methyl-L-erythritol-1-O-(6-O-trans-sinapoyl)-beta-D glucopyranoside (2), along with two known triterpenoids (3-4), four quinic acid derivatives (5-8) and one flavonoid (9) were isolated from the fruit of Gardenia jasminoides. Their structures were elucidated through MS and 2D NMR experiments (HMQC and HMBC). Inhibitory effects of the isolated compounds on nitric oxide production in lipopolysaccharide-activated macrophages were evaluated. Though 2 methyl-D-erythritol and its glycosides have been reported in a few references, this is the first report about 2-methyl-L-erythritol glycosides. Based on this finding, we propose that 2-methyl-L-erythritol might be a new intermediate in the non-mevalonate biosynthesis of terpenoids. PMID- 23727471 TI - Are acronyms really irregular? Preserved acronym reading in a case of semantic dementia. AB - This paper describes the progressive performance of JD, a patient with semantic dementia, on acronym categorisation, recognition and reading aloud over a period of 18 months. Most acronyms have orthographic and phonological configurations that are different from English words (BBC, DVD, HIV). While some acronyms, the majority, are regularly pronounced letter by letter, others are pronounced in a more holistic, and irregular, way (NASA, AWOL). Semantic dementia at its moderate stage shows deficits in irregular word reading while reading accuracy for regular words and novel words is preserved. Nothing is known about acronym comprehension and reading ability in semantic dementia. Thus, in this study we explore for the first time the impact that semantic decline has on acronym recognition and reading processes. The decline in JD's semantic system led to increasingly impaired semantic categorisation and lexical decision for acronyms relative to healthy controls. However, her accuracy for reading aloud regular acronyms (i.e. those pronounced letter by letter such as BBC) remained near ceiling while reading irregular acronyms (i.e. those pronounced as mainstream words such as NASA) demonstrated impairment. It is therefore argued that consequences of semantic impairment vary across acronym types, a finding that informs our understanding of any reading account of this growing class of words. PMID- 23727472 TI - Phaeohyphomycosis caused by Cladophialophora bantiana. AB - BACKGROUND: Cladophialophora bantiana is the most frequent cause of central nervous system phaeohyphomycosis. AIMS: We report a case of phaeohyphomycosis by C. bantiana in a patient with underlying lung disease on steroid therapy. METHODS: An 81-year-old male was admitted in August 2011 with a history of difficulty speaking and deflection of the oral commeasure to the left side with a brain abscess. Brain tissue was cultured on Sabouraud media and sequence analysis of the internal transcribed spacer region of the ribosomal DNA was done for identification purposes. Susceptibility testing to various antifungal agents was performed using the microdilution test. RESULTS: Histopathological examination of the brain tissue ruled out malignancy and the presence of dematiaceous hyphae was observed. Culture showed the presence of a single black fungus, identified as C. bantiana. It was susceptible to all antifungals, except to caspofungin. The patient was treated with voriconazole plus liposomal amphotericin B. Cerebral cranial computed tomography [CCT] scans demonstrated persistence of the intraparenchymal abscess collection. Despite surgical and medical treatment with antifungal drugs, the patient died 5 months after the first diagnosis of the cerebral occupying lesion was made. CONCLUSIONS: Phaeohyphomycosis is an uncommon infection with severe limitations on the clinical clues that can help in early diagnosis. Fungal species identification is mandatory for epidemiological and therapeutic reasons. The MICs could be useful in selecting the appropriate antifungal agent. Avoiding the unnecessary exposure to soil or other media potentially contaminated with fungal spores should be recommended to any immunosuppressed patient. PMID- 23727473 TI - Biological control of infective larvae of Ancylostoma spp. in beach sand. AB - BACKGROUND: Geohelminths are parasites that stand out for their prevalence and wide distribution, depending on the soil for their transmission. AIMS: The aim of this work was to evaluate the predatory capacity of the fungal isolate of the genus Duddingtonia (CG768) on third stage larvae (L3) of Ancylostoma spp. in beach sand under laboratory conditions. METHODS: In the assay A five treatment groups and 1 control group were formed. The treatment groups contained 5000, 10,000, 15,000, 20,000 or 25,000 chlamydospores of the fungal isolate and 1000 Ancylostoma spp. L3 in pots containing 30g of sand. The control group (without fungus) contained only 1000 Ancylostoma spp. L3 and distilled water in pots with 30g of sand. RESULTS: Evidence of predatory activity was observed at the end of 15 days, where we observed the following percentages of reduction of L3: Group 1 (4.5%); Group 2 (24.5%); Group 3 (59.2%); Group 4 (58.8%); Group 5 (63%). However, difference was noted (p<0.01) only at concentrations 15,000, 20,000 and 25,000 in relation to control group. In the assay B two groups were formed in Petri dishes of 9cm in diameter containing agar water 2% medium. In the treated group, each Petri dish contained 500 Ancylostoma spp. L3 and 5g of sand containing the isolate CG 768 at a concentration of 25,000 chlamydospores/g of sand, and the control group (without fungus) contained only 500 L3. At the end of 7 days the non-predation L3 of Petri dishes using the method of Baermann were recovered. Difference (p<0.01) between groups on reducing the average number of Ancylostoma spp. L3 (percent reduction of 84%) was observed. CONCLUSIONS: The results of this study confirm earlier work on the efficiency of the Duddingtonia genus in the control of Ancylostoma spp. infective larvae. PMID- 23727474 TI - [Adaptability of Brazilian strains of Agaricus subrufescens Peck to fruiting on various casing materials in commercial crops]. AB - BACKGROUND: Agaricus subrufescens Peck is a mushroom whose cultivation has aroused great interest worldwide in recent years, and is becoming increasingly popular. A rapid expansion of culture throughout the world is foreseen because of its medicinal and culinary properties. AIMS: This work assesses the effect of 5 different casing layers on the production of 3 strains of Agaricus subrufescens. METHODS: A growth cycle of Agaricus subrufescens under controlled conditions has been carried out. The main production parameters were evaluated. RESULTS: The best results were provided by the ABL 99/30 strain. Peat-based casings have a better yield than those based on mineral soil. The highest yield (6.75kg/m(2), biological efficiency 27.57kg/dt) was provided by the combination ABL 99/30 Euroveen. CONCLUSIONS: Our results suggest that the combination of the strain ABL 99/30 using a peat-based casing layer (Euroveen) offers a high potential for use on a commercial scale by the edible mushroom production sector. The availability of alternatives to the usually cultivated species can make better use of resources, and increase the profitability of this activity. PMID- 23727475 TI - Regulatory volume decrease of rat kidney principal cells after successive hypo osmotic shocks. AB - Outer Medullary Collecting Duct (OMCD) principal cells are exposed to significant changes of the extracellular osmolarity and thus the analysis of their regulatory volume decrease (RVD) function is of great importance in order to avoid cell membrane rupture and subsequent death. In this paper we provide a sub-second temporal analysis of RVD events occurring after two successive hypo-osmotic challenges in rat kidney OMCD principal cells. We performed experimental cell volume measurements and created a mathematical model based on our experimental results. As a consequence of RVD the cell expels part of intracellular osmolytes and reduces the permeability of the plasma membrane to water. The next osmotic challenge does not cause significant RVD if it occurs within a minute after the primary shock. In such a case the cell reacts as an ideal osmometer. Through our model we provide the basis for further detailed studies on RVD dynamical modeling. PMID- 23727476 TI - Magnetic resonance imaging monitoring dual-labeled stem cells for treatment of mouse nerve injury. AB - BACKGROUND AIMS: Adipose-derived stem cells (ADSCs) have shown great promise in the regenerative repair of injured peripheral nerves. Magnetic resonance imaging (MRI) has provided attractive advantages in tracking superparamagnetic iron oxide nanoparticle (SPION)-labeled cells and evaluating their fate after cell transplantation. This study investigated the feasibility of the use of MRI to noninvasively track ADSCs repair of peripheral nerve injury in vivo. METHODS: Green fluorescent protein (GFP)-expressing ADSCs were isolated, expanded, differentiated into an SC-like phenotype (GFP-dADSCs) at early passages and subsequently labeled with SPIONs. The morphological and functional properties of the GFP-dADSCs were assessed through the use of immunohistochemistry. The intracellular stability, proliferation and viability of the labeled cells were evaluated in vitro. Through the use of a microsurgical procedure, the labeled cells were then seeded into sciatic nerve conduits in C57/BL6 mice to repair a 1 cm sciatic nerve gap. A clinical 3-T MRI was performed to investigate the GFP dADSCs in vitro and the transplanted GFP-dADSCs inside the sciatic nerve conduits in vivo. RESULTS: The GFP-dADSCs were efficiently labeled with SPIONs, without affecting their viability and proliferation. The labeled cells implanted into the mice sciatic nerve conduit exhibited a significant increase in axonal regeneration compared with the empty conduit and could be detected by MRI. Fluorescent microscopic examination, histological analysis and immunohistochemistry confirmed the axon regeneration and MRI results. CONCLUSIONS: These data will elucidate the neuroplasticity of ADSCs and provide a new protocol for in vivo tracking of stem cells that are seeded to repair injured peripheral nerves. PMID- 23727477 TI - IL-27 suppresses the production of IL-22 in human CD4(+) T cells by inducing the expression of SOCS1. AB - IL-27, a member of IL-6/IL-12 cytokine family, plays pro- and anti-inflammatory functions in immune responses. It can promote inflammation by inducing Th1 differentiation and exert the inhibitory effects on Th2 and Th17 mediated immune responses. Moreover, IL-27 suppresses CD28-mediated IL-2 production from mouse naive CD4(+) T cells. In the present study, we demonstrate that IL-27 inhibits the production of IL-22 and induces the expression of IFN-gamma in CD4(+) T cells from human umbilical cord blood mononuclear cells (CBMCs) stimulated with anti CD3 and anti-CD28 in dose-dependent manner. In addition, the suppression of IL-22 is not dependent on the production of IFN-gamma and IL-10. Importantly, IL-27 promotes the expression of SOCS1, which could be inhibited by a Jak2/STAT inhibitor, AG490. Importantly, the expression of IL-22 could not be inhibited under the circumstances with the lower expression of SOCS1. Moreover, IL-27 inhibits the production of IL-22 in CD4(+)CD45RA(+) and CD4(+)CD45RO(+) T cells from PBMCs. These data identify that IL-27 may suppress the production of IL-22 by inducing the expression of SOCS1 in human CD4(+) T cells. Furthermore, it demonstrates that IL-27 may be a therapeutic approach in the treatment of IL-22 mediated diseases. PMID- 23727478 TI - Interactions between indole-3-acetic acid (IAA) with a lectin from Canavalia maritima seeds reveal a new function for lectins in plant physiology. AB - Indole-3-acetic acid (IAA) bound is considered a storage molecule and is inactive. However, some studies have proposed an additional possible regulatory mechanism based on the ability of lectins to form complexes with IAA. We report the first crystal structure of ConM in complex with IAA at 2.15 A resolution. Based on a tetrameric model of the complex, we hypothesize how the lectin controls the availability of IAA during the early seedling stages, indicating a possible new physiological role for these proteins. A free indole group is also bound to the protein. The ConM interaction with different forms of IAA is a strategy to render the phytohormone unavailable to the cell. Thus, this new physiological role proposed for legume lectins might be a novel mechanism by which IAA levels are decreased in addition to the destruction and formation of new complexes in the later stages of seed germination. PMID- 23727479 TI - Second opinion. PMID- 23727480 TI - Reply: To PMID 21130088. PMID- 23727481 TI - A heart of stone. PMID- 23727482 TI - A 44-year-old patient with fever, night sweats, and arthralgia. PMID- 23727483 TI - A rare cause of colitis. PMID- 23727484 TI - Penile nodules: whose problem? PMID- 23727485 TI - Cut loose and cast adrift. PMID- 23727486 TI - A rare cause of caustic gastric injury in a young man. PMID- 23727487 TI - Reply: To PMID 22922013. PMID- 23727488 TI - Low hepatocyte repopulation from stem cells: a matter of hepatobiliary linkage not massive production. PMID- 23727489 TI - The proteomic profile of Stichodactyla duerdeni secretion reveals the presence of a novel O-linked glycopeptide. AB - Sea anemones represent one of the emerging groups of interest concerning venomous animals in toxinology and the goal of the present work was the prospection, and the structural and functional characterization of the compounds present in the secretion of the sea anemone Stichodactyla duerdeni from Brazilian coast. We used a combination of offline RPC-MALDI-TOF and online nano-RPC-ESI-LTQ-Orbitrap proteomic techniques as well as functional bioassays. The mucus was milked by electric stimulation and fractionated by gel filtration on Sephadex G-50 yielding 5 main fractions. The low molecular weight fractions were further submitted to RP HPLC resulting in 35 new subfractions that were subsequently analyzed by offline MALDI-TOF mass spectrometry. MALDI peptide mass fingerprinting yielded up to 134 different molecular masses, ranging from m/z 901 to 10,833. Among these subfractions, a new peptide of 3431Da, named U-SHTX-Sdd1, was purified and completely sequenced by automated Edman's degradation and tandem mass spectrometry. An analysis of U-SHTX-Sdd1 revealed a modified O-HexNAc-Threonine at position 1, which, at the best of our knowledge, constitutes the first sea anemone toxin reported with such post-translational modification. Because of its sequence similarity with other sea anemone toxins, the pharmacological activity of U-SHTX-Sdd1 was assessed by electrophysiological measurements using the two electrode voltage-clamp technique on cloned voltage-gated potassium channel subtypes, expressed in Xenopus laevis oocytes. However, U-SHTX-Sdd1 did not show activity on these channels. A large-scale proteomic approach was also employed to shed lights on the sea anemone compounds, and a total 67 proteins and peptides were identified. BIOLOGICAL SIGNIFICANCE: In this manuscript, we report an extensive characterization of S. duerdeni secretion by means of peptide mass fingerprinting and high-throughput proteome analyses. Also, we report the structure of a new glycopeptide by a combination of biochemical techniques. Despite the previous studies that described proteinaceous compounds present in sea anemone secretions, the number of reported primary sequences is still low. Thus, to access the scenery of protein components from S. duerdeni mucus, including their biological functions, a robust proteomic approach was used together with bioinformatic tools. The demonstrated strategy of analysis is perfectly suitable to other sea anemone secretions and animal venoms. Moreover, new peptide structures can arise contributing to the knowledge of the diversity of these animal peptides. PMID- 23727490 TI - Intraspecies variation in the venom of the rattlesnake Crotalus simus from Mexico: different expression of crotoxin results in highly variable toxicity in the venoms of three subspecies. AB - The composition and toxicological profile of the venom of the rattlesnake Crotalus simus in Mexico was analyzed at the subspecies and individual levels. Venoms of the subspecies C. s. simus, C. s. culminatus and C. s. tzabcan greatly differ in the expression of the heterodimeric neurotoxin complex 'crotoxin', with highest concentrations in C. s. simus, followed by C. s. tzabcan, whereas the venom of C. s. culminatus is almost devoid of this neurotoxic PLA2. This explains the large variation in lethality (highest in C. s. simus, which also exerts higher myotoxicity). Coagulant activity on plasma and fibrinogen occurs with the venoms of C. s. simus and C. s. tzabcan, being absent in C. s. culminatus which, in turn, presents higher crotamine-like activity. Proteomic analysis closely correlates with toxicological profiles, since the venom of C. s. simus has high amounts of crotoxin and of serine proteinases, whereas the venom of C. s. culminatus presents higher amounts of metalloproteinases and crotamine. This complex pattern of intraspecies venom variation provides valuable information for the diagnosis and clinical management of envenoming by this species in Mexico, as well as for the preparation of venom pools for the production and quality control of antivenoms. BIOLOGICAL SIGNIFICANCE: This study describes the variation in venom composition and activities of the three subspecies of Crotalus simus from Mexico. Results demonstrate that there is a notorious difference in these venoms, particularly regarding the content of the potent neurotoxic phospholipase A2 complex 'crotoxin'. In addition, other differences were observed regarding myotoxic and coagulant activities, and expression of the myotoxin 'crotamine'. These findings have implications in, at least, three levels: (a) the adaptive role of variations in venom composition; (b) the possible differences in the clinical manifestations of envenomings by these subspecies in Mexico; and (c) the design of venom mixtures for the preparation of antivenoms effective in the neutralization of the venoms of the three subspecies. PMID- 23727491 TI - The keratoconus corneal proteome: loss of epithelial integrity and stromal degeneration. AB - Keratoconus is a thinning corneal dystrophy that begins in the early teenage years and ultimately requires cornea transplantation to restore vision. Here we conducted a highly sensitive mass spectrometric analysis of the epithelium and the stroma from keratoconus and normal donor corneas. We identified a total of 932 and 1157 proteins in the consolidated data of the epithelium and stroma, respectively. Technical replicates showed strong correlations (>=0.88) in levels of all common proteins, indicating very low technical variations in the data. Analysis of the most increased (>=1.5 fold) and decreased (<=0.8 fold) proteins in the keratoconus corneal epithelial protein extracts identified proteins related to dermal diseases, inflammation, epithelial stratification and mesenchymal changes. Increased proteins included keratins 6A, 16 and vimentin, while the iron transporter lactotransferrin was decreased. The keratoconus stromal proteome suggests endoplasmic reticular stress, oxidative stress and widespread decreases in many extracellular matrix proteoglycan core proteins, lumican and keratocan, collagen types I, III, V and XII. Marked increase in apoptosis and endocytosis-related proteins suggest degenerative changes in keratocytes, the resident cells of the stroma. This is the most comprehensive proteome analysis of the cornea that highlights similarities of keratoconus with other neurodegenerative diseases. BIOLOGICAL SIGNIFICANCE: This study provides, to our knowledge, the most comprehensive proteomic analysis of the vision threatening disease keratoconus, which affects a significant portion of the US and global populations. Using iTRAQ and LC/MS/MS, we have identified significant changes in the human corneal epithelium and stromal proteome that correlate to in vivo clinical findings. The protein changes identified will lead to molecular insights into disease pathogenesis and provide candidate genes for genetic studies of keratoconus. PMID- 23727492 TI - Looking forward to understanding and reducing colorectal cancer risk in inflammatory bowel disease. PMID- 23727493 TI - Novel oral anticoagulants: is the convenience worth the risk? PMID- 23727494 TI - Utility of osteopontin in lineage tracing experiments. PMID- 23727495 TI - Mesenchymal stem cells in models of acute pancreatitis. PMID- 23727496 TI - A rare cause of gastrointestinal bleeding. PMID- 23727497 TI - Molecular diagnostic algorithms in hepatocellular carcinoma: dead-end street or light at the end of the tunnel? PMID- 23727498 TI - Can You Stop Surveillance After Radiofrequency Ablation of Barrett's Esophagus? A Glass Half Full. PMID- 23727500 TI - A self-defense program reduces the incidence of sexual assault in Kenyan adolescent girls. AB - PURPOSE: To determine the effect of a standardized 6-week self-defense program on the incidence of sexual assault in adolescent high school girls in an urban slum in Nairobi, Kenya. METHODS: Population-based survey of 522 high school girls in the Korogocho-Kariobangi locations in Nairobi, Kenya, at baseline and 10 months later. Subjects were assigned by school attended to either a "No Means No Worldwide" self-defense course (eight schools; N = 402) or to a life-skills class (two schools; N = 120). Both the intervention and the life-skills classes were taught in the schools by trained instructors. Participants were administered the same survey at baseline and follow-up. RESULTS: A total of 522 girls (mean age, 16.7 +/- 1.5 years; range, 14-21 years) completed surveys at baseline, and 489 at 10-month follow-up. At baseline, 24.5% reported sexual assault in the prior year, with the majority (90%) reporting assault by someone known to them (boyfriend, 52%; relative, 17%; neighbor, 15%; teacher or pastor, 6%). In the self-defense intervention group, the incidence of sexual assault decreased from 24.6% at baseline to 9.2% at follow-up (p < .001), in contrast to the control group, in which the incidence remained unchanged (24.2% at baseline and 23.1% at follow-up; p = .10). Over half the girls in the intervention group reported having used the self-defense skills to avert sexual assault in the year after the training. Rates of disclosure increased in the intervention group, but not in controls. CONCLUSIONS: A standardized 6-week self-defense program is effective in reducing the incidence of sexual assault in slum-dwelling high school girls in Nairobi, Kenya. PMID- 23727499 TI - Characterization of human beta,beta-carotene-15,15'-monooxygenase (BCMO1) as a soluble monomeric enzyme. AB - The formal first step in in vitamin A metabolism is the conversion of its natural precursor beta,beta-carotene (C40) to retinaldehyde (C20). This reaction is catalyzed by the enzyme beta,beta-carotene-15,15'-monooxygenase (BCMO1). BCMO1 has been cloned from several vertebrate species, including humans. However, knowledge about this protein's enzymatic and structural properties is scant. Here we expressed human BCMO1 in Spodoptera frugiperda 9 insect cells. Recombinant BCMO1 is a soluble protein that displayed Michaelis-Menten kinetics with a KM of 14 MUM for beta,beta-carotene. Though addition of detergents failed to increase BCMO1 enzymatic activity, short chain aliphatic detergents such as C8E4 and C8E6 decreased enzymatic activity probably by interacting with the substrate binding site. Thus we purified BCMO1 in the absence of detergent. Purified BCMO1 was a monomeric enzymatically active soluble protein that did not require cofactors and displayed a turnover rate of about 8 molecules of beta,beta-carotene per second. The aqueous solubility of BCMO1 was confirmed in mouse liver and mammalian cells. Establishment of a protocol that yields highly active homogenous BCMO1 is an important step towards clarifying the lipophilic substrate interaction, reaction mechanism and structure of this vitamin A forming enzyme. PMID- 23727501 TI - Achieving long-term weight maintenance in Mexican-American adolescents with a school-based intervention. AB - PURPOSE: This study evaluated 24-month outcomes of a school-based intensive lifestyle weight management program targeting overweight Mexican-American adolescents. METHODS: We recruited a total of 71 adolescents (32 males; 45.1%) between the ages of 10 and 14 years, at or above the 85th percentile for body mass index (BMI). Participants were randomized to a 6-month instructor-led intervention (ILI) or a self-help (SH) program. Both interventions were aimed at modifying eating and physical activity behaviors using behavior modification strategies. We assessed changes in participants' standardized BMI and BMI percentile at baseline, 1, and 2 years. RESULTS: Repeated-measures analyses showed that ILI participants showed significantly greater decreases in standardized BMI at 1 and 2 years (F = 8.58, p < .01; and F = 9.27, p < .01, respectively) compared with SH controls. Similar results were found for changes in BMI and BMI percentile. At 2 years, the ILI condition decreased their average BMI percentile by 3.9 percentile points, compared to an increase of 1.6 percentile points in the SH condition. CONCLUSIONS: A school-based intervention resulted in improved weight outcomes in overweight Mexican-American adolescents and results were maintained over 2 years. PMID- 23727502 TI - Comorbid alcohol and cannabis use disorders among high-risk youth at intake into residential care. AB - PURPOSE: Alcohol use disorder (AUD) and cannabis use disorder (CUD) are prevalent among high-risk adolescents, such as those referred for residential care. These disorders are often comorbid, and comorbidity is associated with heightened adverse consequences compared with each disorder alone. Little is known about factors that are associated with the development of comorbid AUD and CUD. This study tested individual, family, peer, school, and community variables as common versus specific correlates of singular and comorbid AUDs and CUDs among high-risk youth. METHODS: Participants were 1,662 youth at entry into a large residential group home program. The average age of participants was 15.2 years, and 63% were male. Routine intake assessments, including standardized questionnaires (e.g., Diagnostic Interview Schedule for Children) and structured checklists, provided archival data for the analyses, conducted using multinomial logistic regression (with neither disorder as the reference group). RESULTS: Male gender was a specific positive correlate of CUD-only. Several common positive correlates of the disorder groups were identified, including individual (e.g., anxiety/depression), family (e.g., family history of substance use), peer (e.g., hanging around troubled peers), and school (e.g., truancy) variables. Age at intake and troubled peers had stronger positive associations with comorbid AUD and CUD than with either disorder alone. CONCLUSIONS: Many more common than specific correlates were identified; these variables may be associated with generalized risk for substance use disorders. Two variables were particularly strong positive correlates of comorbid AUD and CUD, and potentially could be targeted in interventions designed to prevent comorbid substance use disorders. PMID- 23727503 TI - Characterization of a novel piscidin-like antimicrobial peptide from Pseudosciaena crocea and its immune response to Cryptocaryon irritans. AB - Piscidins, important components of the innate (nonspecific) immunity system in fish, have potent, broad-spectrum antimicrobial and antiparasitic activities. In this study, we reported a novel antimicrobial cationic peptide from Pseudosciaena crocea. Although this peptide exhibited a genomic (3 exons and 2 introns) and propeptide (signal peptide, mature peptide and prodomain) organization, conserved signal peptide (22 amino acids) and consensus motif I-X5-H-X4-I-H identical to the reported fish piscidins, Pc-pis showed a relatively low overall conservation with other known piscidins, which was obviously embodied in the amino acid composition of the peptide. Pc-pis is strikingly rich in glycine residues (27.3%), which disrupted the amphipathic structure of the peptide. Relative quantitative real-time PCR revealed that Pc-pis is a typically gill-expressed peptide. The sequence analysis, structural features and tissue distribution suggested that Pc-pis was genetically related to the piscidins family and might be a novel piscidin-like antimicrobial peptide. Quantitative PCR analysis revealed that the expression of Pc-pis in the spleen, head-kidney, liver, intestine, skin and gill could be regulated during Cryptocaryon irritans infection and post C. irritans falling off, implicating a role for Pc-pis in immune defense against C. irritans and secondary bacterial infections. Synthetic Pc-pis exhibited broad-spectrum activity against bacteria, fungi and C. irritans in parasitic stages. These results provided the first evidence of piscidins antiparasitic activity against marine fish ectoparasites C. irritants trophonts and further indicated that Pc-pis might be an important component of the P. crocea innate immune system against C. irritans and secondary bacterial infections. Thus, these data provided new insights into P. crocea innate immunity against external protozoan parasite and microbial infections and facilitate the evaluation of Pc-pis as a therapeutic agent against pathogen invasion. PMID- 23727505 TI - Dysregulation of cannabinoid CB1 receptor and associated signaling networks in brains of cocaine addicts and cocaine-treated rodents. AB - The endocannabinoid system is implicated in the neurobiology of cocaine addiction. This study evaluated the status of cannabinoid (CB) CB1 and CB2 receptors, the endocytic cycle of CB1 receptors, G protein-coupled receptor regulatory kinases (GRK), and associated signaling (mammalian target of rapamicin (mTOR) and 70kDa ribosomal protein S6 kinase (p70S6K)) in brain cortices of drug abusers and cocaine- and cannabinoid-treated rodents. The main results indicate that in cocaine adddicts, but not in mixed cocaine/opiate or opiate abusers, CB1 receptor protein in the prefrontal cortex (PFC) was reduced (-44%, total homogenate) with a concomitant receptor redistribution and/or internalization (decreases in membranes and increases in cytosol). In cocaine addicts, the reductions of CB1 receptors and GRK2/3/5 (-26% to -30%) indicated receptor desensitization. CB2 receptor protein was not significantly altered in the PFC of cocacine addicts. Chronic cocaine in mice and rats also reduced CB1 receptor protein (-41% and -80%) in the cerebral cortex inducing receptor redistribution and/or internalization. The CB1 receptor agonist WIN55212-2 caused receptor downregulation (decreases in membranes and cytosol) and the antagonists rimonabant and AM281 induced opposite effects (receptor upregulation in membranes and cytosol). Rimonabant and AM281 also behaved as inverse agonists on the activation of mTOR and its target p70S6K. Chronic cocaine in mice was associated with tolerance to the acute activation of mTOR and p70S6K. In long-term cocaine addicts, mTOR and p70S6K activations were not altered when compared with controls, indicating that CB1 receptor signaling was dampened. The dysregulation of CB1 receptor, GRK2/3/5, and mTOR/p70S6K signaling by cocaine may contribute to alterations of neuroplasticity and/or neurotoxicity in brains of cocaine addicts. PMID- 23727506 TI - Stress and excitatory synapses: from health to disease. AB - Individuals are exposed to stressful events in their daily life. The effects of stress on brain function ranges from highly adaptive to increasing the risk to develop psychopathology. For example, stressful experiences are remembered well which can be seen as a highly appropriate behavioral adaptation. On the other hand, stress is an important risk factor, in susceptible individuals, for depression and anxiety. An important question that remains to be addressed is how stress regulates brain function and what determines the threshold between adaptive and maladaptive responses. Excitatory synapses play a crucial role in synaptic transmission, synaptic plasticity and behavioral adaptation. In this review we discuss how brief and prolonged exposure to stress, in adulthood and early life, regulate the function of these synapses, and how these effects may contribute to behavioral adaptation and psychopathology. PMID- 23727504 TI - Sexually dimorphic and developmentally regulated expression of tubulin-specific chaperone protein A in the LMAN of zebra finches. AB - Sex differences in brain and behavior exist across vertebrates, but the molecular factors regulating their development are largely unknown. Songbirds exhibit substantial sexual dimorphisms. In zebra finches, only males sing, and the brain areas regulating song learning and production are much larger in males. Recent data suggest that sex chromosome genes (males ZZ; females ZW) may play roles in sexual differentiation. The present studies tested the hypothesis that a Z-gene, tubulin-specific chaperone protein A (TBCA), contributes to sexual differentiation of the song system. This taxonomically conserved gene is integral to microtubule synthesis, and within the song system, its mRNA is specifically increased in males compared to females in the lateral magnocellular nucleus of the anterior nidopallium (LMAN), a region critical for song learning and plasticity. Using in situ hybridization, Western blot analysis, and immunohistochemistry, we observed effects of both age and sex on TBCA mRNA and protein expression. The transcript is increased in males compared to females at three juvenile ages, but not in adults. TBCA protein, both the number of immunoreactive cells and relative concentration in LMAN, is diminished in adults compared to juveniles. The latter was also increased in males compared to females at post-hatching day 25. With double-label immunofluorescence and retrograde tract tracing, we also document that the majority of TBCA+ cells in LMAN are neurons, and that they include robust nucleus of the arcopallium-projecting cells. These results indicate that TBCA is both temporally and spatially primed to facilitate the development of a sexually dimorphic neural pathway critical for song. PMID- 23727507 TI - Age and sex-dependent differences in activity, plasticity and response to stress in the dentate gyrus. AB - In the last decade, early-onset of affective illness has been recognized as a major public health problem. However, clinical studies indicate that although children experience the symptoms of anxiety and depression in much the same way as adults, they display and react to those symptoms differently (Bostic et al., 2005). Recently, we have demonstrated that similar differences in symptoms are found also between adult and juvenile rats (Jacobson-Pick and Richter-Levin, 2010). Especially the hippocampus is believed to be vulnerable to stress-related illness, as this brain region has a high density of corticoid receptors. The hippocampus is known to finalize its development, and particularly that of GABA related functions, into adolescence (Bergmann et al., 1991; Harris et al., 1992; Nurse and Lacaille, 1999; Lopez-Tellez et al., 2004; Jacobson-Pick et al., 2008) and may thus be differentially sensitive to environmental challenges in childhood and in adulthood. In this study we explored the differences in activity and plasticity of the dentate gyrus between pre-pubertal and adult rats in vivo. Furthermore, we have examined the impact of exposure to stress either during pre puberty or in adulthood on dentate gyrus electrophysiology. In both male and female rats, marked differences were found for intrinsic excitability and local circuit activity between pre-pubertal and adult animals. Exposure to forced swim stress resulted in significant alterations of dentate gyrus activity and plasticity in male rats with differences between adult and pre-pubertal animals. Stress had far less impact on females' dentate electrophysiology. The results are in agreement with the differences in behavioral response to stress between pre pubertal and adult rats, and with reported differences for the sensitivity of male and female rats in performing hippocampus-dependent tasks under stress, such as the active avoidance task. PMID- 23727508 TI - Activation of D2-like dopamine receptors inhibits GABA and glycinergic neurotransmission to pre-motor cardiac vagal neurons in the nucleus ambiguus. AB - The parasympathetic control of heart rate arises from premotor cardiac vagal neurons (CVNs) located in the nucleus ambiguus (NA). Previous microinjection studies in NA show that dopamine evokes a decrease in heart rate, but the underlying mechanisms responsible for these responses were not identified. This study tested whether dopamine modulates inhibitory GABAergic and glycinergic and/or excitatory glutamatergic neurotransmission to CVNs. Retrogradely labeled CVNs were identified in an in vitro rat brainstem slice preparation and synaptic events were recorded using whole cell voltage clamp techniques. Bath application of dopamine (100 MUM) had no effect on excitatory synaptic events, but reversibly inhibited the frequency (but not amplitude) of GABAergic inhibitory postsynaptic currents (IPSCs) in CVNs. Similarly, dopamine (10 MUM and 100 MUM) inhibited glycinergic IPSC frequency by ~50% and 70% respectively. The reduction in inhibitory neurotransmission to CVNs by dopamine was prevented by the sodium channel blocker TTX (1MUM) indicating that the dopamine mediated effects were action potential dependent. Dopamine evoked responses were mimicked by the D2 like receptor agonist, Quinpirole but not D1-like receptor agonist, SKF 38393. In addition, the dopamine mediated depression of inhibitory synaptic responses were prevented by the D2-like receptor antagonist sulpiride, but not by D1-like or adrenergic or serotonergic receptor antagonists, suggesting that these responses were D2-like receptor mediated and not D1-like or adrenergic or 5-HT receptor mediated. These data suggest that dopamine acts via dis-inhibition, and diminishes inhibitory GABAergic and glycinergic neurotransmission to CVNs, which would be predicted to increase parasympathetic activity to the heart and evoke a bradycardia. PMID- 23727509 TI - Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model. AB - Therapeutic strategies for the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) are actually minimally effective on patients' survival and quality of life. Although stem cell therapy has raised great expectations, information on the involved molecular mechanisms is still limited. Here we assessed the efficacy of the systemic administration of adipose-derived mesenchymal stem cells (ASC), a previously untested stem cell population, in superoxide-dismutase 1 (SOD1)-mutant transgenic mice, the animal model of familial ALS. The administration of ASC to SOD1-mutant mice at the clinical onset significantly delayed motor deterioration for 4-6 weeks, as shown by clinical and neurophysiological tests. Neuropathological examination of ASC-treated SOD1 mutant mice at day 100 (i.e. the time of their best motor performance) revealed a higher number of lumbar motorneurons than in phosphate-buffered saline-treated SOD1-mutant mice and a restricted number of undifferentiated green fluorescent protein-labeled ASC in the spinal cord. By examining the spinal cord tissue factors that may prolong neuronal survival, we found a significant up-regulation in levels of glial-derived neurotrophic factor (GDNF) and basic fibroblast growth factor (bFGF) after ASC treatment. Considering that ASC produce bFGF but not GDNF, these findings indicate that ASC may promote neuroprotection either directly and/or by modulating the secretome of local glial cells toward a neuroprotective phenotype. Such neuroprotection resulted in a strong and long lasting effect on motor performance and encourages the use of ASC in human pathologies, in which current therapies are not able to maintain a satisfying neurological functional status. PMID- 23727510 TI - Human endogenous retrovirus W family envelope gene activates the small conductance Ca2+-activated K+ channel in human neuroblastoma cells through CREB. AB - Numerous studies have shown that human endogenous retrovirus W family (HERV-W) envelope gene (env) is related to various diseases but the underlying mechanism has remained poorly understood. Our previous study showed that there was abnormal expression of HERV-W env in sera of patients with schizophrenia. In this paper, we reported that overexpression of the HERV-W env elevated the levels of small conductance Ca(2+)-activated K(+) channel protein 3 (SK3) in human neuroblastoma cells. Using a luciferase reporter system and RNA interference method, we found that functional cAMP response element site was required for the expression of SK3 triggered by HERV-W env. In addition, it was also found that the SK3 channel was activated by HERV-W env. Further study indicated that cAMP response element binding protein (CREB) was required for the activation of the SK3 channel. Thus, a novel signaling mechanism of how HERV-W env influences neuronal activity and contributes to mental illnesses such as schizophrenia was proposed. PMID- 23727511 TI - Production of dissolvable microneedles using an atomised spray process: effect of microneedle composition on skin penetration. AB - Dissolvable microneedles offer an attractive delivery system for transdermal drug and vaccine delivery. They are most commonly formed by filling a microneedle mold with liquid formulation using vacuum or centrifugation to overcome the constraints of surface tension and solution viscosity. Here, we demonstrate a novel microneedle fabrication method employing an atomised spray technique that minimises the effects of the liquid surface tension and viscosity when filling molds. This spray method was successfully used to fabricate dissolvable microneedles (DMN) from a wide range of sugars (trehalose, fructose and raffinose) and polymeric materials (polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, hydroxypropylmethylcellulose and sodium alginate). Fabrication by spraying produced microneedles with amorphous content using single sugar compositions. These microneedles displayed sharp tips and had complete fidelity to the master silicon template. Using a method to quantify the consistency of DMN penetration into different skin layers, we demonstrate that the material of construction significantly influenced the extent of skin penetration. We demonstrate that this spraying method can be adapted to produce novel laminate-layered as well as horizontally-layered DMN arrays. To our knowledge, this is the first report documenting the use of an atomising spray, at ambient, mild processing conditions, to create dissolvable microneedle arrays that can possess novel, laminate layering. PMID- 23727512 TI - Differences in distribution and antimicrobial susceptibility of anaerobes isolated from complicated intra-abdominal infections versus diabetic foot infections. AB - Few labs isolate and perform susceptibility tests on anaerobes; therefore, we studied the differences between 1185 anaerobes isolated from complicated intra abdominal infections and 470 isolated from moderate to severe diabetic foot infections. They differed markedly in the distribution of species, including Bacteroides fragilis and anaerobic Gram-positive cocci, as well as in resistance patterns, especially to fluoroquinolones. PMID- 23727513 TI - Metameric pattern of intervertebral disc/vertebral body is generated independently of Mesp2/Ripply-mediated rostro-caudal patterning of somites in the mouse embryo. AB - The vertebrae are derived from the sclerotome of somites. Formation of the vertebral body involves a process called resegmentation, by which the caudal half of a sclerotome is combined with the rostral half of the next sclerotome. To elucidate the relationship between resegmentation and rostro-caudal patterning of somite, we used the Uncx4.1-LacZ transgene to characterize the resegmentation process. Our observations suggested that in the thoracic and lumbar vertebrae, the Uncx4.1-expressing caudal sclerotome gave rise to the intervertebral disc (IVD) and rostral portion of the vertebral body (VB). In the cervical vertebrae, the Uncx4.1-expressing caudal sclerotome appeared to contribute to the IVD and both caudal and rostral ends of the VB. This finding suggests that the rostro caudal gene expression boundary does not necessarily coincide with the resegmentation boundary. This conclusion was supported by analyses of Mesp2 KO and Ripply1/2 double KO embryos lacking rostral and caudal properties, respectively. Resegmentation was not observed in Mesp2 KO embryos, but both the IVD and whole VB were formed from the caudalized sclerotome. Expression analysis of IVD marker genes including Pax1 in the wild-type, Mesp2 KO, and Ripply1/2 DKO embryos also supported the idea that a metameric pattern of IVD/VB is generated independently of Mesp2/Ripply-mediated rostro-caudal patterning of somite. However, in the lumbar region, IVD differentiation appeared to be stimulated by the caudal property and suppressed by the rostral property. Therefore, we propose that rostro-caudal patterning of somites is not a prerequisite for metameric patterning of the IVD and VB, but instead required to stimulate IVD differentiation in the caudal half of the sclerotome. PMID- 23727514 TI - Basigin null mutant male mice are sterile and exhibit impaired interactions between germ cells and Sertoli cells. AB - Basigin (BSG) is a multifunctional glycoprotein that plays an important role in male reproduction since male knockout (KO) mice are sterile. The Bsg KO testis lacks elongated spermatids and mature spermatozoa, a phenotype similar to that of alpha-mannosidase IIx (MX) KO mice. MX regulates formation of N-acetylglucosamine (GlcNAc) terminated N-glycans that participate in germ cell-Sertoli cell adhesion. Results showed that Bsg KO spermatocytes displayed normal homologous chromosome synapsis and progression through meiosis. However, only punctate expression of the round spermatid marker SP-10 in the acrosomal granule of germ cells of Bsg KO mice was detected indicating that spermatogenesis in Bsg KO mice was arrested at the early round spermatid stages. We observed a large increase in the number of germ cells undergoing apoptosis in Bsg KO testes. Using lectin blotting, we determined that GlcNAc terminated N-glycans are linked to BSG. GlcNAc terminated N-glycans were significantly reduced in Bsg KO testes. These observations indicate that BSG may act as a germ cell-Sertoli cell attachment molecule. Loss of BSG significantly reduced adhesion between GC-2 and SF7 cells. Moreover, wild type testes showed strong expression of N-cadherin (CDH2) while expression was greatly reduced in the testes of Bsg KO mice. In addition, the integrity of the blood-testis barrier (BTB) was compromised in Bsg KO testes. In conclusion, although some Bsg KO spermatogonia can undergo normal progression to the spermatocyte stage, BSG-mediated germ cell-Sertoli cell interactions appear to be necessary for integrity of the BTB and spermatocyte progression to mature spermatozoa. PMID- 23727515 TI - Sensitive quantification of vascular endothelial growth factor (VEGF) using porosity induced hydrogel microspheres. AB - Vascular endothelial growth factor (VEGF) plays a crucial role in vasculogenesis (blood vessel formation) and angiogenesis (capillary formation from a pre existing blood vessel). Dysregulation of VEGF has been associated with several diseases including cancer, rheumatoid arthritis, and psoriasis. As a result, serum level of VEGF has important implications as biomarker for different clinical disorders as well as for subsequent therapy monitoring. A simple detection method capable of rapid and sensitive analysis of VEGF in serum of patients with different clinical disorders is of paramount importance. Here, we report the fabrication and utilization of capture-antibody immobilized macro porous poly(ethylene) glycol diacrylate (PEGDA) hydrogel microspheres for quantitative and reproducible measurement of VEGF. We demonstrate that induction of porosity using PEG porogen improves the sensitivity of this simple hydrogel microsphere based system with a detection limit of 2.5 pg/ml; indicating that the sensitivity of the assay exceeds that of the conventional technologies. PMID- 23727516 TI - Clinical morbidities, trends, and demographics of eclampsia: a population-based study. AB - OBJECTIVE: We sought to identify trends, demographics, and prepregnancy and peripartum morbidities of eclampsia in California. STUDY DESIGN: We identified cases of eclampsia by International Classification of Diseases, Ninth Revision code using California health discharge data from 2001 through 2007. Cases with missing race/ethnicity as well as age <15 years or >55 years were excluded. Among the remaining cases, patients with eclampsia (n = 1888) were compared against those without (n = 2,768,983). Adjustments were performed for potential confounding variables using logistic regression. Significance was set at P < .05. RESULTS: The incidence of eclampsia decreased over time, from 8.0 cases per 10,000 deliveries in 2001, to 5.6 cases per 10,000 deliveries in 2007 (P < .001). There was a bimodal distribution in age-related risk, with the highest risks at the extremes of age. Non-Hispanic blacks were associated with the highest risk of eclampsia while Asians had the lowest risk. Several antepartum morbidities had increased associations with eclampsia, including preexisting cardiac disease (adjusted odds ratio [OR], 6.84; 95% confidence interval [CI], 5.40-8.66), lupus erythematosus (adjusted OR, 3.68; 95% CI, 1.53-8.86), and twin gestations (adjusted OR, 3.28; 95% CI, 2.70-3.99). Peripartum complications increased in eclampsia included cerebrovascular hemorrhage/disorders (adjusted OR, 112.15; 95% CI, 77.47-162.35), peripartum cardiomyopathy (adjusted OR, 12.88; 95% CI, 6.08 27.25), amniotic fluid embolism (adjusted OR, 11.94; 95% CI, 3.63-39.21), and venous thromboembolism (adjusted OR, 10.71; 95% CI, 5.14-22.32). CONCLUSION: This large population database confirms that there is a decline in eclampsia over time. However, there are extremely morbid complications associated with eclampsia, emphasizing the need for its close monitoring and prevention. PMID- 23727518 TI - Extraperitoneal versus transperitoneal cesarean section: a prospective randomized comparison of surgical morbidity. AB - OBJECTIVE: We sought to test the hypothesis that an extraperitoneal cesarean section (ECS) technique reduces postoperative pain without increasing intraoperative and postoperative complications. STUDY DESIGN: In a single-center, single-blinded prospective trial we randomized 54 patients with an indication for primary or first repeat cesarean section at term pregnancy to an ECS (n = 27) or transperitoneal cesarean section (TCS) (n = 27) procedure. Patients with suspected abnormal placentation, a history of >1 cesarean section, or major abdominal surgery were excluded. The primary endpoint of the study was maximum abdominal pain measured by numeric rating scale ranging from 0-10. RESULTS: Patients after ECS had significantly less maximum surgical site pain than patients after TCS. Median peak pain scores on postoperative day 1 were 4.00 (interquartile range, 3.00-5.00) for ECS and 5.00 (interquartile range, 4.00 7.00) for TCS, respectively (P = .031). Analgesic requirements, intraoperative nausea, and postoperative shoulder pain were significantly less after ECS. Overall operative time was significantly shorter in ECS, with no difference in delivery time. No bladder injury occurred in either group. There were no differences in estimated blood loss and neonatal outcome. Urogenital distress, urinary tract infection, and bowel dysfunction did not differ at discharge from hospital and 6 weeks after. CONCLUSION: An extraperitoneal approach to cesarean section appears to reduce postoperative pain, usage of analgesics, and intraoperative nausea without an increase in significant complications. PMID- 23727517 TI - Elevated glucocorticoids during ovine pregnancy increase appetite and produce glucose dysregulation and adiposity in their granddaughters in response to ad libitum feeding at 1 year of age. AB - OBJECTIVE: Synthetic glucocorticoids (sGCs) are administered to women threatening preterm labor. We have shown multigenerational endocrine and metabolic effects of fetal sGC exposure. We hypothesized that sGC exposure would alter the second filial generation (F2) offspring neonatal leptin peak that controls development of appetitive behavior with metabolic consequences. STUDY DESIGN: F0 nulliparous ewes were bred to a single ram. Beginning at day 103 of gestation (term 150 days), dexamethasone (DEX) ewes received 4 injections of 2 mg DEX intramuscularly, 12 hours apart. Control ewes received saline. Ewes lambed naturally. At 22 months of age, F1 offspring were mated to produce F2 offspring. At 10 months of age, F2 female offspring were placed on an ad libitum feeding challenge for 12 weeks. RESULTS: DEX F2 female offspring did not show a postnatal leptin peak and their plasma cortisol concentration was elevated in the first days of life. During the feeding challenge, DEX F2 offspring consumed 10% more feed and gained 20% more weight compared with control F2 offspring. At the end of the feeding challenge, DEX F2 offspring had greater adiposity compared with control F2 offspring. F2 sGC offspring showed impaired insulin secretion in response to an intravenous glucose tolerance test. CONCLUSION: sGC administration to F0 mothers eliminates the neonatal leptin peak in F2 female offspring potentially by inhibition caused by elevated cortisol in the DEX F2 offspring. F2 offspring showed increased appetite, weight gain, and adiposity during an ad libitum feeding challenge accompanied by decreased insulin response to an intravenous glucose tolerance test. PMID- 23727520 TI - Effect of maternal height and weight on risk for preterm singleton and twin births resulting from IVF in the United States, 2008-2010. AB - OBJECTIVE: To analyze the effects of preconception maternal height and weight on the risk of preterm singleton and twin births resulting from in vitro fertilization (IVF). STUDY DESIGN: We performed a retrospective cohort analysis of the incidence of very early preterm birth (VEPTB), early preterm birth (EPTB), and preterm birth (PTB), before 28, 32, and 37 completed weeks, respectively, in 60,232 singleton and 24,111 twin live births using 2008-2010 live birth outcome data from the Society for Reproductive Technology Clinic Outcome Reporting System. RESULT: Maternal obesity is associated with significantly increased risk of VEPTB, EPTB, and PTB in pregnancies conceived by IVF. For morbidly obese women (body mass index >=35) with singletons, rates of VEPTB, EPTB, and PTB were 1.7%, 3.6%, and 16.4%, with adjusted risk ratios (aRRs) and 95% confidence levels (CIs) of 2.6 (1.8-3.6), 2.2 (1.8-2.6), and 1.5 (1.4-1.7) using corresponding rates for normal body mass index (95% CI, 18.6-24.9) as referent. For morbidly obese women with twins, rate of VEPTB and EPTB were 6.5% and 12.5%, with aRRs and 95% CIs of 2.4 (1.8-3.0) and 1.5 (1.3-1.8). For singletons, the rate of PTB for short stature women (<150 cm) was 14.2%, as compared with 11.8% in those women with height ranging between 160-167 cm (referent), with aRRs and 95% CIs of 1.2 (1.0 1.4). CONCLUSION: Preconception maternal obesity and short stature are associated with significantly increased risk of VEPTB and early preterm singleton and twin births in pregnancies resulting from IVF. PMID- 23727519 TI - Compliance with cervical cancer screening and human papillomavirus testing guidelines among insured young women. AB - OBJECTIVE: In December 2009, the American Congress of Obstetricians and Gynecologists (ACOG) recommended that women under 21 years old should not receive cervical cancer screening (Papanicolaou tests) or human papillomavirus (HPV) tests. This study examined whether clinicians stopped administering Papanicolaou and HPV tests among women younger than 21 years of age after new ACOG guidelines were issued. STUDY DESIGN: This study was a retrospective secondary data analysis of administrative claims data that included insurance enrollees from across the United States that examined the frequency of Papanicolaou tests and HPV tests among 178,898 nonimmunocompromised females 12-20 years old who had a paid claim for a well-woman visit in 2008, 2009, or 2010. Young women with well-woman examinations in each observed year were examined longitudinally to determine whether past diagnoses of cervical cell abnormalities accounted for Papanicolaou testing in 2010. RESULTS: The proportion of women younger than 21 years old that received a Papanicolaou test as part of her well-woman exam dropped from 77% in 2008 and 2009 to 57% by December of 2010, whereas HPV testing remained stable across time. A diagnosis of cervical cell abnormalities in 2009 was associated with Papanicolaou testing in 2010. However, a previous Papanicolaou test was more strongly associated with a Papanicolaou test in 2010. CONCLUSION: These data show that some physicians are adjusting their practices among young women according to ACOG guidelines, but Papanicolaou and HPV testing among insured women younger than 21 years of age still remains unnecessarily high. PMID- 23727521 TI - The prevalence of underlying bleeding disorders in patients with heavy menstrual bleeding with and without gynecologic abnormalities. AB - OBJECTIVE: The purpose of this study was to assess the prevalence of underlying bleeding disorders in women with heavy menstrual bleeding (HMB) with and without gynecologic abnormalities. STUDY DESIGN: We performed a single-center prospective cohort study of 112 consecutive patients who were referred for heavy menstrual bleeding. Control subjects were 28 healthy volunteers who reported no HMB. Patients and control subjects had hemostatic testing in the first week after menstruation. Patients underwent gynecologic evaluation. RESULTS: The median age was 42.5 years (range, 17-55 years) in patients and 40.0 years (range, 25-55 years) in control subjects. Forty-six percent of patients had anemia; the median pictorial bleeding assessment chart score was 271. Seven percent of the control subjects with a subjectively normal menstruation had anemia. Twenty-six percent of patients had gynecologic abnormalities, which was considered to explain HMB. Overall, we found an underlying bleeding disorder in 29% of the patients, which was comparable for unexplained and explained HMB (31% vs 27%; P = .75). We diagnosed 6 cases of Von Willebrand's disease, 4 cases of factor XI deficiency, and 1 case of factor VII deficiency. The only abnormalities that we found in control subjects were platelet aggregation defects (11% in control subjects vs 23% in patients). Patients had a significantly longer activated partial thromboplastin time compared with control subjects (26.5 vs 25.0 seconds; P = .001) that was caused by lower median levels of factor XI (100 vs 124 IU/dL; P < .001). CONCLUSION: Bleeding disorders play an equally important role in the cause of both unexplained and explained heavy menstrual bleeding. A novel finding is the occurrence of low, but not deficient, levels of factor XI. PMID- 23727522 TI - Effect of an oxytocin receptor antagonist (atosiban) on uterine electrical activity. AB - OBJECTIVE: The purpose of this study was to investigate the effect of atosiban (Tractocile; Ferring, Limhamn, Sweden), an oxytocin receptor antagonist, on uterine electrical activity in women with preterm labor and to determine whether this information can assist in the prediction of preterm delivery. STUDY DESIGN: Uterine electrical activity was recorded prospectively in 21 women with preterm labor before and during treatment with Tractocile and, for purpose of comparison, in 4 pregnant women without uterine contractions to set the baseline of uterine electrical activity in a quiescent uterus. Uterine activity was recorded with a noninvasive, 9-channel recorder with an electromyography amplifier and a 3 dimensional position sensor with an automatic data analyzer. Uterine electrical activity was quantified by an electrical uterine monitor (EUM) and measured in microwatts per second (MUW/s). RESULTS: The overall pre-Tractocile EUM index was 3.43 +/- 0.58 MUW/s, which was significantly higher than baseline uterine activity in women without preterm contractions (2.3 +/- 0.11 MUW/s; P = .001). During the administration of Tractocile, the EUM index gradually decreased in a relatively constant rate from 3.43 +/- 0.58 MUW/s to 2.56 +/- 0.88 MUW/s after 330 minutes of continuous therapy (P < .001). The peak effect of Tractocile was observed 4 hours after the initiation of treatment and was followed by a relative plateau. Women with a latency of <7 days from treatment to delivery were characterized by a distinct EUM-pattern in response to Tractocile, compared with women with a latency of >=7 days (P < .001). A similar EUM-pattern after the administration of Tractocile was also observed for women who delivered at <37 weeks of gestation compared with the women who delivered at term. CONCLUSION: Tractocile reduces uterine electrical activity in women with preterm labor. This information can provide more insight into the effects of tocolytic agents and to aid in the risk stratification of preterm delivery in women with preterm contractions. PMID- 23727523 TI - Impact of obesity on incision-to-delivery interval and neonatal outcomes at cesarean delivery. AB - OBJECTIVE: The purpose of this study was to test the hypothesis that increasing body mass index (BMI) is associated with increased time from skin incision to infant delivery and increased neonatal morbidity at cesarean delivery. STUDY DESIGN: We performed a retrospective cohort study of all cesarean deliveries that occurred at 1 institution from 2004-2008. Four comparison groups were defined by BMI of <30 kg/m(2) (n = 668 women), 30-39.9 kg/m(2) (n = 1002 women), 40-49.9 kg/m(2) (n = 403 women), or >=50 kg/m(2) (n = 193 women). The primary outcome was time from skin incision to infant delivery. Secondary outcomes were a composite measure of neonatal morbidity and its individual components: 5-minute Apgar score <7, umbilical cord arterial pH <7.10 and <7.20, umbilical cord arterial base excess <=8 mmol/L, special care nursery admission, and neonatal intensive care unit admission. RESULTS: Increasing BMI was associated with significantly increased time from skin incision to infant delivery, which demonstrated a dose response pattern. Minutes from skin incision to delivery of the infant by BMI strata were 9.4 +/- 5.9 for <30 kg/m(2), 11.0 +/- 6.8 for 30-39.9 kg/m(2), 13.0 +/- 8.0 for 40-49.9 kg/m(2), and 16.0 +/- 11.3 for >=50 kg/m(2) (P < .01). Composite neonatal morbidity was significantly higher with increasing BMI: 23.0% for <30 kg/m(2), 25% for 30-39.9 kg/m(2), 29.8% for 40-49.9 kg/m(2), and 32.1% for >=50 kg/m(2) (P = .02). CONCLUSION: Increasing BMI is associated with a significantly increased time from skin incision to infant delivery and neonatal morbidity. Cesarean delivery technique remains to be optimized for obese women. PMID- 23727524 TI - Uterine electromyography for identification of first-stage labor arrest in term nulliparous women with spontaneous onset of labor. AB - OBJECTIVE: We sought to study whether uterine electromyography (EMG) can identify inefficient contractions leading to first-stage labor arrest followed by cesarean delivery in term nulliparous women with spontaneous onset of labor. STUDY DESIGN: EMG was recorded during spontaneous labor in 119 nulliparous women with singleton term pregnancies in cephalic position. Electrical activity of the myometrium during contractions was characterized by its power density spectrum (PDS). RESULTS: Mean PDS peak frequency in women undergoing cesarean delivery for first stage labor arrest was significantly higher (0.55 Hz), than in women delivering vaginally without (0.49 Hz) or with (0.51 Hz) augmentation of labor (P = .001 and P = .01, respectively). Augmentation of labor increased the mean PDS frequency when comparing contractions before and after start of augmentation. This increase was only significant in women eventually delivering vaginally. CONCLUSION: Contraction characteristics measured by uterine EMG correlate with progression of labor and are influenced by labor augmentation. PMID- 23727525 TI - Uterine packing with chitosan-covered gauze for control of postpartum hemorrhage. AB - OBJECTIVE: To describe the use of gauze covered with chitosan, a potent hemostatic agent derived from chitin, in the treatment of postpartum hemorrhage (PPH). STUDY DESIGN: Patients suffering from postpartum hemorrhage were treated by uterine packing with chitosan-covered gauze, either through the hysterotomy in case of cesarean delivery or transvaginally, for up to 24 hours. RESULTS: Chitosan-covered gauze was used in 19 cases of postpartum hemorrhage due to uterine atony, placenta accreta/increta, or anticoagulation, including 5 severe cases where a hysterectomy seemed inevitable otherwise. In all but one case, the bleeding stopped and further interventions were avoided. Over comparable periods of time (18 months) and births (3822 vs 4077) before and after the introduction of the chitosan gauze in our clinic, the rate of peripartum hysterectomies was reduced by 75% (8 vs 2; odds ratio, 4.27; P = .044). CONCLUSION: Chitosan-covered gauze is a viable option in the treatment of (severe) postpartum hemorrhage. It is easy to use and requires no special training. It can be used after both vaginal and cesarean deliveries, and there are no adverse side effects. Furthermore, it is very inexpensive compared with other treatment options, making it suitable for use also in low resource-countries, where the death toll due to postpartum hemorrhage is especially high. PMID- 23727526 TI - Cerebral ischemic injury is enhanced in a model of oculodentodigital dysplasia. AB - Oculodentodigital dysplasia (ODDD) is a rare autosomal dominant disease that results in visible developmental anomalies of the limbs, face, eyes and teeth. Recently analysis of human connexin43 (Cx43) DNA sequences has revealed a number of different missense, duplication and frame shift mutations resulting in this phenotype. A mouse model of this disorder has been created with a missense point mutation of the glycine amino acid at position 60 to serine (G60S). Heterozygote +/G60S mice exhibit a similar ODDD phenotype as observed in humans. In addition to the malformations listed above, ODDD patients often have neurological findings. In the brain, Cx43 is highly expressed in astrocytes and has been shown to play a role in neuroprotection. We were interested in determining the effect of the +/G60S mutation following stroke. Four days after middle cerebral artery occlusion the volume of infarct was larger in mice with the +/G60S mutation. In astrocyte-neuron co-cultures, exposure to glutamate also resulted in greater cellular death in the +/G60S mutants. Protein levels of Cx43 in the mutant mouse were found to be reduced when compared to the normal tissue. Cx43 protein was observed as a continual line of small punctate aggregates in the plasma membrane with increased intracellular localization, which is distinct from the larger plaques seen in the normal mouse astrocytes. Functionally, primary +/G60S astrocytes exhibited reduced gap junctional coupling and increased hemichannel activity, which may underlie the mechanism of increased damage during stroke. This article is part of the Special Issue Section entitled 'Current Pharmacology of Gap Junction Channels and Hemichannels'. PMID- 23727527 TI - Surface mixing of products and substrate of PLA2 in enzyme-free mixed monolayers reproduces enzyme-driven structural topography. AB - It was proposed that topographic changes in lipid monolayers hydrolyzed by lipolytic enzymes such as Phospholipase A2 (PLA2) are a consequence of enzyme activity at the surface. Lateral packing defects that arise from lipid phase coexistence were suggested as places at which PLA2 activity is preferably localized. Our work employs a method for mixing two lipid monolayers in order to simulate lipid mixing of products and substrate at the surface in the absence of enzyme. In such enzyme-free mixed films, a topographic pattern similar to that actively generated by PLA2 is observed. The main conclusion from our experiments is that mixing-demixing properties of substrate and products generated by PLA2 can determine the evolution of the surface topography. PMID- 23727528 TI - Predicting behavioural response to TDCS in chronic motor stroke. AB - Transcranial direct current stimulation (TDCS) of primary motor cortex (M1) can transiently improve paretic hand function in chronic stroke. However, responses are variable so there is incentive to try to improve efficacy and or to predict response in individual patients. Both excitatory (Anodal) stimulation of ipsilesional M1 and inhibitory (Cathodal) stimulation of contralesional M1 can speed simple reaction time. Here we tested whether combining these two effects simultaneously, by using a bilateral M1-M1 electrode montage, would improve efficacy. We tested the physiological efficacy of Bilateral, Anodal or Cathodal TDCS in changing motor evoked potentials (MEPs) in the healthy brain and their behavioural efficacy in changing reaction times with the paretic hand in chronic stroke. In addition, we aimed to identify clinical or neurochemical predictors of patients' behavioural response to TDCS. There were three main findings: 1) unlike Anodal and Cathodal TDCS, Bilateral M1-M1 TDCS (1 mA, 20 min) had no significant effect on MEPs in the healthy brain or on reaction time with the paretic hand in chronic stroke patients; 2) GABA levels in ipsilesional M1 predicted patients' behavioural gains from Anodal TDCS; and 3) although patients were in the chronic phase, time since stroke (and its combination with Fugl-Meyer score) was a positive predictor of behavioural gain from Cathodal TDCS. These findings indicate the superiority of Anodal or Cathodal over Bilateral TDCS in changing motor cortico-spinal excitability in the healthy brain and in speeding reaction time in chronic stroke. The identified clinical and neurochemical markers of behavioural response should help to inform the optimization of TDCS delivery and to predict patient outcome variability in future TDCS intervention studies in chronic motor stroke. PMID- 23727530 TI - Enhancing dual-task performance with verbal and spatial working memory training: continuous monitoring of cerebral hemodynamics with NIRS. AB - To better understand the mechanisms by which working memory training can augment human performance we continuously monitored trainees with near infrared spectroscopy (NIRS) while they performed a dual verbal-spatial working memory task. Linear mixed effects models were used to model the changes in cerebral hemodynamic response as a result of time spent training working memory. Nonlinear increases in left dorsolateral prefrontal cortex (DLPFC) and right ventrolateral prefrontal cortex (VLPFC) were observed with increased exposure to working memory training. Adaptive and yoked training groups also showed differential effects in rostral prefrontal cortex with increased exposure to working memory training. There was also a significant negative relationship between verbal working memory performance and bilateral VLPFC activation. These results are interpreted in terms of decreased proactive interference, increased neural efficiency, reduced mental workload for stimulus processing, and increased working memory capacity with training. PMID- 23727529 TI - Spatial-temporal atlas of human fetal brain development during the early second trimester. AB - During the second trimester, the human fetal brain undergoes numerous changes that lead to substantial variation in the neonatal in terms of its morphology and tissue types. As fetal MRI is more and more widely used for studying the human brain development during this period, a spatiotemporal atlas becomes necessary for characterizing the dynamic structural changes. In this study, 34 postmortem human fetal brains with gestational ages ranging from 15 to 22 weeks were scanned using 7.0 T MR. We used automated morphometrics, tensor-based morphometry and surface modeling techniques to analyze the data. Spatiotemporal atlases of each week and the overall atlas covering the whole period with high resolution and contrast were created. These atlases were used for the analysis of age-specific shape changes during this period, including development of the cerebral wall, lateral ventricles, Sylvian fissure, and growth direction based on local surface measurements. Our findings indicate that growth of the subplate zone is especially striking and is the main cause for the lamination pattern changes. Changes in the cortex around Sylvian fissure demonstrate that cortical growth may be one of the mechanisms for gyration. Surface deformation mapping, revealed by local shape analysis, indicates that there is global anterior-posterior growth pattern, with frontal and temporal lobes developing relatively quickly during this period. Our results are valuable for understanding the normal brain development trajectories and anatomical characteristics. These week-by-week fetal brain atlases can be used as reference in in vivo studies, and may facilitate the quantification of fetal brain development across space and time. PMID- 23727531 TI - Dissociation of reach-related and visual signals in the human superior colliculus. AB - Electrophysiological and micro-stimulation studies in non-human animal species indicated that the superior colliculus (SC) plays a role in the control of upper limb movements. In our previous work we found reach-related signals in the deep superior colliculus in humans. Here we show that also signals in more dorsal locations are correlated with the execution of arm movements. We instructed healthy participants to reach for visual targets either presented in the left or in the right visual hemifield during an fMRI measurement. Visual stimulation was dissociated from movement execution using a pro- and anti-reaching task. Thereby, we successfully differentiated between signals at these locations induced by the visual input of target presentations on the one hand and by the execution of arm movements on the other hand. Extending our previous report, the results of this study are in good agreement with the observed anatomical distribution of reach related neurons in macaques. Obviously, reach-related signals can be found across a considerable depth range also in humans. PMID- 23727533 TI - Targeted therapies using electrical and magnetic neural stimulation for the treatment of chronic pain in spinal cord injury. AB - BACKGROUND: Chronic neuropathic pain is one of the most common and disabling symptoms in individuals with spinal cord injury (SCI). Over two-thirds of subjects with SCI suffer from chronic pain influencing quality of life, rehabilitation, and recovery. Given the refractoriness of chronic pain to most pharmacological treatments, the majority of individuals with SCI report worsening of this condition over time. Moreover, only 4-6% of patients in this cohort report improvement. Novel treatments targeting mechanisms associated with pain maladaptive plasticity, such as electromagnetic neural stimulation, may be desirable to improve outcomes. To date, few, small clinical trials have assessed the effects of invasive and noninvasive nervous system stimulation on pain after SCI. OBJECTIVE: We aimed to review initial efficacy, safety and potential predictors of response by assessing the effects of neural stimulation techniques to treat SCI pain. SEARCH STRATEGY: A literature search was performed using the PubMed database including studies using the following targeted stimulation strategies: transcranial Direct Current Stimulation (tDCS), High Definition tDCS (HD-tDCS), repetitive Transcranial Magnetical Stimulation (rTMS), Cranial Electrotherapy Stimulation (CES), Transcutaneous Electrical Nerve Stimulation (TENS), Spinal Cord Stimulation (SCS) and Motor Cortex Stimulation (MCS), published prior to June of 2012. We included studies from 1998 to 2012. RESULTS: Eight clinical trials and one naturalistic observational study (nine studies in total) met the inclusion criteria. Among the clinical trials, three studies assessed the effects of tDCS, two of CES, two of rTMS and one of TENS. The naturalistic study investigated the analgesic effects of SCS. No clinical trials for epidural motor cortex stimulation (MCS) or HD-tDCS were found. Parameters of stimulation and also clinical characteristics varied significantly across studies. Three out of eight studies showed larger effects sizes (0.73, 0.88 and 1.86 respectively) for pain reduction. Classical neuropathic pain symptoms such as dysesthesia (defined as an unpleasant burning sensation in response to touch), allodynia (pain due to a non-painful stimulus), pain in paroxysms, location of SCI in thoracic and lumbar segments and pain in the lower limbs seem to be associated with a positive response to neural stimulation. No significant adverse effects were reported in these studies. CONCLUSIONS: Chronic pain in SCI is disabling and resistant to common pharmacologic approaches. Electrical and magnetic neural stimulation techniques have been developed to offer a potential tool in the management of these patients. Although some of these techniques are associated with large standardized mean differences to reduce pain, we found an important variability in these results across studies. There is a clear need for the development of methods to decrease treatment variability and increase response to neural stimulation for pain treatment. We discuss potential methods such as neuroimaging or EEG-guided neural stimulation and the development of better surrogate markers of response such as TMS-indexed cortical plasticity. PMID- 23727534 TI - PHYCAA+: an optimized, adaptive procedure for measuring and controlling physiological noise in BOLD fMRI. AB - The presence of physiological noise in functional MRI can greatly limit the sensitivity and accuracy of BOLD signal measurements, and produce significant false positives. There are two main types of physiological confounds: (1) high variance signal in non-neuronal tissues of the brain including vascular tracts, sinuses and ventricles, and (2) physiological noise components which extend into gray matter tissue. These physiological effects may also be partially coupled with stimuli (and thus the BOLD response). To address these issues, we have developed PHYCAA+, a significantly improved version of the PHYCAA algorithm (Churchill et al., 2011) that (1) down-weights the variance of voxels in probable non-neuronal tissue, and (2) identifies the multivariate physiological noise subspace in gray matter that is linked to non-neuronal tissue. This model estimates physiological noise directly from EPI data, without requiring external measures of heartbeat and respiration, or manual selection of physiological components. The PHYCAA+ model significantly improves the prediction accuracy and reproducibility of single-subject analyses, compared to PHYCAA and a number of commonly-used physiological correction algorithms. Individual subject denoising with PHYCAA+ is independently validated by showing that it consistently increased between-subject activation overlap, and minimized false-positive signal in non gray-matter loci. The results are demonstrated for both block and fast single event task designs, applied to standard univariate and adaptive multivariate analysis models. PMID- 23727532 TI - Relation between variants in the neurotrophin receptor gene, NTRK3, and white matter integrity in healthy young adults. AB - The NTRK3 gene (also known as TRKC) encodes a high affinity receptor for the neurotrophin 3'-nucleotidase (NT3), which is implicated in oligodendrocyte and myelin development. We previously found that white matter integrity in young adults is related to common variants in genes encoding neurotrophins and their receptors. This underscores the importance of neurotrophins for white matter development. NTRK3 variants are putative risk factors for schizophrenia, bipolar disorder, and obsessive-compulsive disorder hoarding, suggesting that some NTRK3 variants may affect the brain. To test this, we scanned 392 healthy adult twins and their siblings (mean age, 23.6 +/- 2.2 years; range: 20-29 years) with 105 gradient 4-Tesla diffusion tensor imaging (DTI). We identified 18 single nucleotide polymorphisms (SNPs) in the NTRK3 gene that have been associated with neuropsychiatric disorders. We used a multi-SNP model, adjusting for family relatedness, age, and sex, to relate these variants to voxelwise fractional anisotropy (FA) - a DTI measure of white matter integrity. FA was optimally predicted (based on the highest false discovery rate critical p), by five SNPs (rs1017412, rs2114252, rs16941261, rs3784406, and rs7176429; overall FDR critical p=0.028). Gene effects were widespread and included the corpus callosum genu and inferior longitudinal fasciculus - regions implicated in several neuropsychiatric disorders and previously associated with other neurotrophin-related genetic variants in an overlapping sample of subjects. NTRK3 genetic variants, and neurotrophins more generally, may influence white matter integrity in brain regions implicated in neuropsychiatric disorders. PMID- 23727535 TI - Prevention of metabolic disorders and reproductive performance deficits by the blockade of Angiotensin II AT1 receptor in female rats fed with cafeteria diet. AB - Besides the well-known detrimental effects of obesity on cardiovascular and metabolic function, studies have shown that obesity is also associated with impaired reproductive function in women. Alterations in Angiotensin II (Ang II) have been associated with obesity and with female reproduction. The aim of the present study was to evaluate the reproductive and metabolic effects of Ang II AT1 receptor blockade with losartan in an animal model of obesity, in which female rats were offered a palatable, high calorie diet from weaning to adulthood. Sexual behavior, ovulation rates and preovulatory levels of the hormones estradiol, progesterone, LH and prolactin were analyzed. Retroperitoneal and perigonadal fat pads, triglycerides and cholesterol (total, HDL and LDL), and insulin resistance were analyzed. Losartan prevented increases in fat pad storage, insulin resistance, as well as triglycerides and LDL levels induced by cafeteria diet intake. Losartan also prevented ovulatory deficits and loss of preovulatory surges of progesterone and LH in cafeteria-fed female rats probably through the prevention of the increase in body weight and body fat. No alterations in sexual behavior were observed. These results suggest, for the first time, that Ang II contributes to the development of the deleterious effects of obesity on preovulatory surges of LH and progesterone and on the reduction of ovulation in obese female rats. PMID- 23727536 TI - The development of a new class of inhibitors for betaine-homocysteine S methyltransferase. AB - Betaine-homocysteine S-methyltransferase (BHMT) is an important zinc-dependent methyltransferase that uses betaine as the methyl donor for the remethylation of homocysteine to form methionine. In the liver, BHMT performs to half of the homocysteine remethylation. In this study, we systematically investigated the tolerance of the enzyme for modifications at the "homocysteine" part of the previously reported potent inhibitor (R,S)-5-(3-amino-3-carboxy-propylsulfanyl) pentanoic acid (1). In the new compounds, which are S-alkylated homocysteine derivatives, we replaced the carboxylic group in the "homocysteine" part of inhibitor 1 with different isosteric moieties (tetrazole and oxadiazolone); we suppressed the carboxylic negative charge by amidations; we enhanced acidity by replacing the carboxylate with phosphonic or phosphinic acids; and we introduced pyrrolidine steric constraints. Some of these compounds display high affinity toward human BHMT and may be useful for further pharmacological studies of this enzyme. Although none of the new compounds were more potent inhibitors than the reference inhibitor 1, this study helped to completely define the structural requirements of the active site of BHMT and revealed the remarkable selectivity of the enzyme for homocysteine. PMID- 23727537 TI - Synthesis of novel 1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-piperazine derivatives and evaluation of their in vivo anticonvulsant activity. AB - A series of novel 1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-piperazine derivatives 8(a-o) were synthesized and characterized by elemental analyses, (1)H NMR, (13)C NMR and mass spectral studies. The newly synthesized compounds were screened for their anticonvulsant activity against maximal electroshock seizure (MES) model in male wistar rats and compared with the standard drug phenytoin. The neurotoxic effects were determined by rotorod test by using mice. Compounds 8d, 8e, 8f and 8h were found to be most potent of this series. The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg). The efforts were also made to establish the structure activity relationships among synthesized compounds. The pharmacophore model was used to validate the anticonvulsant activity of the synthesized molecules. PMID- 23727538 TI - Synthesis of novel guttiferone A derivatives: in-vitro evaluation toward Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani. AB - The catechol pharmacomodulation of the natural product guttiferone A, isolated from the Symphonia globulifera tree, led to the semisynthesis of a collection of twenty derivatives. The ester and ether derivatives of guttiferone A were evaluated for their anti-plasmodial, trypanocidal and anti-leishmanial activities. Some compounds described below have shown potent antiparasitic activity against Plasmodium falciparum, Trypanosoma brucei and Leishmania donovani in a range from 1 to 5 MUM. The evaluation of guttiferone A derivatives against VERO cells highlighted catechol modulations as an interesting tool to decrease the toxicity and keep the activity of this natural compound. The current study revealed new molecules as promising new antiparasitic drug candidates. PMID- 23727539 TI - Synthesis and antimosquito properties of 2,6-substituted benzo[d]thiazole and 2,4 substituted benzo[d]thiazole analogues against Anopheles arabiensis. AB - A novel and efficient one pot synthesis was developed for 2,6-substituted benzo[d]thiazole analogues 4a-k and 2,4-substituted-benzo[d]thiazole analogues 4l pvia three component condensation reaction of substituted arylaldehyde, 2-amino-6 halo/4-methyl-benzo[d]thiazole and 2-naphthol or 6-hydroxyquinoline in presence of 10% w/v NaCl in water by microwave method. This method enabled for short reaction times, easy work-up and significant high yields. The title compound 4b was used for single crystal X-ray studies in order to understand its conformation and packing features. The title compounds 4a-p were screened for antimosquito properties such as repellency, insecticidal and larvicidal activity against Anopheles arabiensis by mosquito feeding-probing assay, cone bio-assay and standard WHO larvicidal assay, respectively. Among these analogous 4b, 4d and 4p exhibit the highest repellent activity comparable to the positive control DEET, and 4a and 4k knockdown most mosquitoes on repellent assays. PMID- 23727540 TI - Indexing molecules for their hERG liability. AB - The human Ether-a-go-go-Related-Gene (hERG) potassium (K(+)) channel is liable to drug-inducing blockage that prolongs the QT interval of the cardiac action potential, triggers arrhythmia and possibly causes sudden cardiac death. Early prediction of drug liability to hERG K(+) channel is therefore highly important and preferably obligatory at earlier stages of any drug discovery process. In vitro assessment of drug binding affinity to hERG K(+) channel involves substantial expenses, time, and labor; and therefore computational models for predicting liabilities of drug candidates for hERG toxicity is of much importance. In the present study, we apply the Iterative Stochastic Elimination (ISE) algorithm to construct a large number of rule-based models (filters) and exploit their combination for developing the concept of hERG Toxicity Index (ETI). ETI estimates the molecular risk to be a blocker of hERG potassium channel. The area under the curve (AUC) of the attained model is 0.94. The averaged ETI of hERG binders, drugs from CMC, clinical-MDDR, endogenous molecules, ACD and ZINC, were found to be 9.17, 2.53, 3.3, -1.98, -2.49 and -3.86 respectively. Applying the proposed hERG Toxicity Index Model on external test set composed of more than 1300 hERG blockers picked from chEMBL shows excellent performance (Matthews Correlation Coefficient of 0.89). The proposed strategy could be implemented for the evaluation of chemicals in the hit/lead optimization stages of the drug discovery process, improve the selection of drug candidates as well as the development of safe pharmaceutical products. PMID- 23727541 TI - The effects of contextual threat and anxiety on affective startle modulation. AB - The startle reflex is attenuated and potentiated when participants are viewing pleasant and unpleasant images, respectively. Research demonstrates that threatening contexts also potentiate startle, but it remains unclear how a threatening context might impact startle modulation to emotional images, especially as a function of trait anxiety. The present study measured startle reactivity while 43 participants viewed pleasant, unpleasant, and neutral images across conditions of threat-of-shock and safety (i.e., no shock). Compared to neutral images, startle was potentiated during unpleasant images and attenuated during pleasant images. Threat-of-shock potentiated startle during all picture types, suggesting that threat-of-shock broadly sensitized the defensive system but did not change affective modulation of startle. Lastly, higher levels of trait anxiety were associated with less startle potentiation during unpleasant images across both conditions-a finding in line with previous research demonstrating deficient threat mobilization in response to unpleasant stimuli among highly anxious individuals. PMID- 23727542 TI - Neural time course of threat-related attentional bias and interference in panic and obsessive-compulsive disorders. AB - Attentional biases to threat are considered central to anxiety disorders, however physiological evidence of their nature and time course is lacking. Event-related potentials (ERPs) characterized sensory and cognitive changes while 20 outpatients with panic disorder (PD), 20 with obsessive-compulsive disorder (OCD), and 20 healthy controls (HCs) responded to the color (emotional Stroop task) or meaning of threatening and neutral stimuli. ERPs indicated larger P1 amplitude and longer N1 latency in OCD, and shorter P1 latency in PD, to threatening (versus neutral) stimuli, across instructions to attend to, or ignore, threat content. Emotional Stroop interference correlated with phobic anxiety and was significant in PD. Participants with emotional Stroop interference had augmented P1 and P3 amplitudes to threat (versus neutral) stimuli when color-naming. The results suggest early attentional biases to threat in both disorders, with disorder-specific characteristics. ERPs supported preferential early attentional capture and cognitive elaboration hypotheses of emotional Stroop interference. PMID- 23727543 TI - Primary cardiac tumors: 32 years of experience from a Spanish tertiary surgical center. AB - INTRODUCTION: Primary cardiac tumors are rare entities with an autopsy frequency ranging between 0.001% and 0.3%. Our objective was to review 32 years of experience from a Spanish tertiary surgical center. METHOD: We collected data on 73 patients with a histopathological diagnosis of a primary cardiac tumor in a retrospective analysis from 1979 to 2012. Tissue samples were obtained either at surgery or from necropsy and subsequently divided into benign and malignant groups. RESULTS: Benign neoplasms accounted for 84.9% of cases. The average age at diagnosis was 61 years, and tumors were twice as frequent among women. It was an incidental finding in one quarter of patients. In symptomatic patients, the typical presentation was of cardioembolic stroke or of congestive symptoms. Myxoma (93.5%) was the most common diagnosis, typically affecting the left atrium (74.2%). Surgical resection was curative for 95% of these patients. Malignant tumors represented 15.1% of cases with an average age at diagnosis of 50 years. Over 90% of these patients were symptomatic at presentation with the cardinal symptom being heart failure. Undifferentiated sarcoma was the most frequent malignant tumor (36.4%). Less than 20% of patients were alive 1 year after diagnosis despite the treatment. CONCLUSIONS: In our study, primary cardiac tumors were insidious. The most common was left atrial myxoma in which surgical resection was considered curative. Undifferentiated sarcoma was the most frequent malignant tumor. Malignant neoplasms carried a worse prognosis with unsuccessful total excision and the presence of metastatic disease being markers of an adverse outcome. PMID- 23727544 TI - Bupropion induced changes in exploratory and anxiety-like behaviour in NMRI male mice depends on the age. AB - The aim of this study was to assess the effects of the antidepressant bupropion on anxiety and novelty-seeking in adolescent mice of different ages and adults. Behavioural differences between early adolescent, late adolescent and adult NMRI mice were measured both in the elevated plus-maze and the hole-board tasks following acute administration of bupropion (5, 10, 15, 20mg/kg) or saline. In the plus maze test, early and late adolescent mice treated with bupropion (10, 15mg/kg, respectively) had lower percentages of entries in the open-arms compared to their vehicle controls. Adult mice treated with bupropion did not differ from their vehicle controls. These results suggest that the effect of this drug on anxiety-like behaviour in mice depends on the age, showing adolescents an anxiogenic-like profile. In the hole-board, adolescents showed more elevated levels of novelty-seeking than adults, exhibiting shorter latency to the first head-dip (HD) and a higher number of HD's. Bupropion increases the latency to the first HD and decreases the number of HD's in all age-groups, indicating a decline in exploratory tendency. Findings reveal that the age can modulate the behaviour displayed by mice in both animal models, and that adolescents are more sensitive to bupropion's anxiogenic effects. PMID- 23727545 TI - Evaluation of a commercial ELISA for H5 low pathogenic avian influenza virus antibody detection in duck sera using Bayesian methods. AB - Following the emergence of highly pathogenic avian influenza (AI), active surveillance of infections due to the H5 and H7 subtypes in poultry has increased and been made compulsory in Europe since 2002, by means of annual serological surveys using the haemagglutination inhibition (HI) test. Domestic anseriforms, particularly ducks and geese, are more frequently infected by H5 low pathogenic AI virus, often subclinically, and represent a threat for other terrestrial poultry. 1783 sera, mainly from ducks, have been used to evaluate and compare a commercial ELISA kit detecting H5 antibodies with the currently recommended HI test. Different approaches to calculating specificity and sensitivity have been used, including the original Bayesian method. Results were similar when data were analyzed at the individual and batch levels, and when using different methods of calculation. However, results showed that H5 ELISA had both a higher sensitivity and a lower specificity than the HI test. Given that sensitivity is the most important factor for a screening test, H5 ELISA could therefore be recommended for AI surveillance, followed in cases of positivity by molecular tests aimed at detecting the virus gene. PMID- 23727546 TI - Long-term potentiation in mammalian autonomic ganglia: an inclusive proposal of a calcium-dependent, trans-synaptic process. AB - Ganglionic synapses have the capability to express long-term potentiation (gLTP) after application of a brief high-frequency stimulus. It has been suggested a possible role of gLTP in some cardiovascular diseases. Although a number of characteristics of gLTP have been described, the precise locations and mechanisms underlying gLTP are not completely known. Current findings support two major conflicting presynaptic and postsynaptic hypotheses. The presynaptic hypothesis posits a presynaptic increase in acetylcholine (ACh) release, whereas the postsynaptic hypothesis proposes a long-lasting enhancement of the nicotinic response on the postsynaptic membrane. An alternative trans-synaptic hypothesis proposes the presynaptic release of a cotransmitter from large dense core vesicles, which postsynaptically enhances synaptic efficacy and accounts for gLTP. Here, we review the studies of LTP, with emphasis on gLTP in mammals, and we examine the findings that support the presynaptic, the postsynaptic and the trans-synaptic hypotheses. We then review our data on the contribution of calcium to gLTP as an approach to elucidate the mechanisms of gLTP. Data on the contribution of calcium to gLTP and on prolonged high-frequency stimulus dependent fading of LTP have led us to support the trans-synaptic process as responsible for gLTP. Finally, we present a formal working model for the mechanisms of gLTP. PMID- 23727547 TI - Serum lipoprotein-A levels in healthy subjects indicate a lurking cerebro- and cardio-vascular risk in the younger population. AB - Lipoprotein-A (LpA) is an emerging independent risk factor for cerebro- and cardio-vascular diseases (CCVD). Recognizing its function and its normal distribution is of fundamental importance for a better understanding of CCVD patho-physiology. The present study evaluated plasma LpA levels of healthy university students using turbidimetric methods. Medians and inter-quartile differences obtained for male and female participants were 11.3mg/dL (3.1-30.7) and 20.9mg/dL (6.5-42.3), respectively, demonstrating a significant difference (P=0.017) between men and women. A third of students showed plasma concentrations above reference values. Our results indicate that 33% of students possess a hidden independent risk factor for CCVD. Multi-disciplinary evaluation and characterization of young individuals should be recommended in an attempt to take early preventive measures and to eliminate possible modifiable risk factors such as sedentary lifestyle, smoking, hypertension, obesity and atherogenic diet. PMID- 23727548 TI - Current status on development of steroids as anticancer agents. AB - Steroids are important biodynamic agents. Their affinities for various nuclear receptors have been an interesting feature to utilize them for drug development particularly for receptor mediated diseases. Steroid biochemistry and its crucial role in human physiology, has attained importance among the researchers. Recent years have seen an extensive focus on modification of steroids. The rational modifications of perhydrocyclopentanophenanthrene nucleus of steroids have yielded several important anticancer lead molecules. Exemestane, SR16157, fulvestrant and 2-methoxyestradiol are some of the successful leads emerged on steroidal pharmacophores. The present review is an update on some of the steroidal leads obtained during past 25 years. Various steroid based enzyme inhibitors, antiestrogens, cytotoxic conjugates and steroidal cytotoxic molecules of natural as well as synthetic origin have been highlighted. This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors". PMID- 23727549 TI - A comparison of the Driving Anger Scale and the Propensity for Angry Driving Scale. AB - The present study investigated the factor structures of the 14-item version of the DAS (Driving Anger Scale) and the Propensity for Angry Driving Scale (PADS) using a sample of New Zealand drivers drawn from the general population. The two scales were also investigated with regards to their relationships with general trait anger, risky driving behaviour, along with crash involvement and a variety of crash-related conditions. Confirmatory Factor Analysis supported both scales as unidimensional, although the PADS was reduced from a 19-item to an 18-item scale. Both the PADS and DAS were significantly related to trait anger, risky driving behaviour and near-misses. However, once the influence of the demographic variables and trait anger had been partialled out, the addition of the PADS and DAS made a significant contribution to predicting violations, but it was only the PADS which was significant. In contrast, after the demographic variables and trait anger had been partialled out, the addition of the DAS and PADS again made a significant contribution to the prediction of near-misses, but this time it was only the DAS which made a significant contribution. The present study clearly shows that both scales are robust measures, measuring similar, but slightly different aspects of driving anger. PMID- 23727550 TI - Multi-level Bayesian analyses for single- and multi-vehicle freeway crashes. AB - This study presents multi-level analyses for single- and multi-vehicle crashes on a mountainous freeway. Data from a 15-mile mountainous freeway section on I-70 were investigated. Both aggregate and disaggregate models for the two crash conditions were developed. Five years of crash data were used in the aggregate investigation, while the disaggregate models utilized one year of crash data along with real-time traffic and weather data. For the aggregate analyses, safety performance functions were developed for the purpose of revealing the contributing factors for each crash type. Two methodologies, a Bayesian bivariate Poisson-lognormal model and a Bayesian hierarchical Poisson model with correlated random effects, were estimated to simultaneously analyze the two crash conditions with consideration of possible correlations. Except for the factors related to geometric characteristics, two exposure parameters (annual average daily traffic and segment length) were included. Two different sets of significant explanatory and exposure variables were identified for the single-vehicle (SV) and multi vehicle (MV) crashes. It was found that the Bayesian bivariate Poisson-lognormal model is superior to the Bayesian hierarchical Poisson model, the former with a substantially lower DIC and more significant variables. In addition to the aggregate analyses, microscopic real-time crash risk evaluation models were developed for the two crash conditions. Multi-level Bayesian logistic regression models were estimated with the random parameters accounting for seasonal variations, crash-unit-level diversity and segment-level random effects capturing unobserved heterogeneity caused by the geometric characteristics. The model results indicate that the effects of the selected variables on crash occurrence vary across seasons and crash units; and that geometric characteristic variables contribute to the segment variations: the more unobserved heterogeneity have been accounted, the better classification ability. Potential applications of the modeling results from both analysis approaches are discussed. PMID- 23727551 TI - The effect of Operation 24 Hours on reducing collision in the City of Edmonton. AB - In the City of Edmonton, in order to reduce the prevalence of collisions, the Operation 24 Hours program (OPS24) was developed by using existing police and transportation services resources. The program uses traditional manned police speed enforcement method, which are supplemented by traffic safety messages displayed on permanent and mobile dynamic messaging signs (DMS). In this paper, collision data analysis was performed by looking at the daily number of collisions from 2008 to 2011 that covers 28 Operation 24 Hours (OPS24) events. The objective of the collision data analysis is to analyze if there is a reduction in collision frequencies after OPS24 was held and examined how long the collision reduction effect last. Weather factors such as temperature, thickness of snow, and wind gust have been considered by many as a great influence on collision occurrences, especially in a city with long and cold winter such as Edmonton. Therefore, collision modeling was performed by considering these external weather factors. To analyze the linear and periodic trend of different collision types (injury, fatal, and property damage only (PDO)) and examine the influence of weather factors on collisions, negative binomial time series model that accounts for seasonality and weather factors was used to model daily collision data. The modeling also considered collision proportion to account for missing traffic volume data; the Gaussian time series model that accounts for seasonality and weather factors was used to model collision proportion. To estimate the collision trend and test for changes in collision levels before/after OPS24, interrupted time series model with segmented regression was used. While for estimating how long the effect of the OPS24 last, change point method was applied. PMID- 23727552 TI - Safety riding program and motorcycle-related injuries in Thailand. AB - A retrospective cohort study was conducted in Thailand from 2007 to 2009 to evaluate the efficacy of a safety riding program in preventing motorcycle-related injuries. A training group of motorcyclists were certified by the Asia-Pacific Honda Safety Riding Program in either 30-h instruction (teaching skills, riding demonstration) or 15-h license (knowledge, skills, and hazard perception) courses. The control group consisted of untrained motorcyclists matched on an approximately 1:1 ratio with the training group by region and date of licensure. In total, there were 3250 subjects in the training group and 2963 in the control group. Demographic data and factors associated with motorcycle-related injuries were collected. Motorcycle-related injuries were identified using the Road Injuries Victims Protection for injuries claims and inpatient diagnosis-related group datasets from the National Health Security Office. The capture-recapture technique was used to estimate the prevalence of injuries. Multivariate analysis was used to identify factors related to motorcycle-related injuries. The prevalence of motorcycle-related injuries was estimated to be 586 out of 6213 riders (9.4%) with a 95% confidence interval (CI): 460-790. The license course and the instruction course were significantly associated with a 30% and 29% reduction of motorcycle-related injuries, respectively (relative risk 0.70, 95% CI: 0.53-0.92 and 0.71, 95% CI: 0.42-1.18, respectively). Other factors associated with the injuries were male gender and young age. Safety riding training was effective in reducing injuries. These training programs differ from those in other developed countries but display comparable effects. Hazard perception skills might be a key for success. This strategy should be expanded to a national scale. PMID- 23727553 TI - Driver perceptions of the safety implications of quiet electric vehicles. AB - Previous research on the safety implications of quiet electric vehicles (EVs) has mostly focused on pedestrians' acoustic perception of EVs, and suggests that EVs are more difficult for pedestrians to hear and, therefore, compromise traffic safety. The two German field studies presented here examine the experiences of 70 drivers with low noise emissions of EVs and the drivers' long-term evaluation of the issue. Participants were surveyed via interviews and questionnaires before driving an EV for the first time, after 3 months of driving, and in the first study, again after 6 months. Based on participants' reports, a catalogue of safety-relevant incidents was composed in Study 1. The catalogue revealed that low noise-related critical incidents only rarely occur, and mostly take place in low-speed environments. The degree of hazard related to these incidents was rated as low to medium. In Study 1, driver concern for vulnerable road users as a result of low noise diminished with increasing driving experience, while perceived comfort due to this feature increased. These results were replicated in Study 2. In the second study, it was additionally examined, if drivers adjust their perceived risk of harming other road users over time. Results show that the affective assessment of risk also decreased with increased driving experience. Based on individual experience, drivers adjust their evaluation of noise-related hazards, suggesting that dangers associated with low noise emissions might be less significant than previously expected. PMID- 23727555 TI - Undergraduate teaching in geriatric medicine using computer-aided learning improves student performance in examinations. AB - BACKGROUND: computer-aided learning (CAL) is increasingly used to deliver teaching, but few studies have evaluated its impact on learning within geriatric medicine. We developed and implemented CAL packages on falls and continence, and evaluated their effect on student performance in two medical schools. METHODS: traditional ward based and didactic teaching was replaced by blended learning (CAL package combined with traditional teaching methods). Examination scores were compared for cohorts of medical students receiving traditional learning and those receiving blended learning. Control questions were included to provide data on cohort differences. RESULTS: in both medical schools, there was a trend towards improved scores following blended learning, with a smaller number of students achieving low scores (P < 0.01). Feedback from students about the CAL packages was positive. DISCUSSION: blended learning was associated with improvement in student examination performance, regardless of the setting or the methods adopted, and without increasing teaching time. Our findings support the use of CAL in teaching geriatric medicine, and this method has been adopted for teaching other topics in the undergraduate curriculum. PMID- 23727554 TI - The effect of male teenage passengers on male teenage drivers: findings from a driving simulator study. AB - Studies have shown that teenage drivers are less attentive, more frequently exhibit risky driving behavior, and have a higher fatal crash risk in the presence of peers. The effects of direct peer pressure and conversation on young drivers have been examined. Little is known about the impact on driving performance of the presence of a non-interacting passenger and subtle modes of peer influence, such as perceived social norms. The goal of this study was to examine if teenagers would engage in more risky driving practices and be less attentive in the presence of a passenger (vs. driving alone) as well as with a risk-accepting (vs. risk-averse) passenger. A confederate portrayed the passenger's characteristics mainly by his non-verbal attitude. The relationship between driver characteristics and driving behavior in the presence of a passenger was also examined. Thirty-six male participants aged 16-17 years old were randomly assigned to drive with a risk-accepting or risk-averse passenger. Main outcomes included speed, headway, gap acceptance, eye glances at hazards, and horizontal eye movement. Driver characteristics such as tolerance of deviance, susceptibility to peer pressure, and self-esteem were measured. Compared to solo driving, the presence of a passenger was associated with significantly fewer eye glances at hazards and a trend for fewer horizontal eye movements. Contrary to the hypothesis, however, Passenger Presence was associated with waiting for a greater number of vehicles to pass before initiating a left turn. Results also showed, contrary to the hypothesis, that participants with the risk-accepting passenger maintained significantly longer headway with the lead vehicle and engaged in more eye glances at hazards than participants with the risk-averse passenger. Finally, when driving with the passenger, earlier initiation of a left turn in a steady stream of oncoming vehicles was significantly associated with higher tolerance of deviance and susceptibility to peer pressure, while fewer eye glances at hazards was linked to lower self esteem. While the results of this study were mixed, they suggest that the presence of a teenage passenger can affect some aspects of teenage driver behavior even in the absence of overt pressure and distraction. Results are discussed in relation to theoretical concepts of social influence and social facilitation models. PMID- 23727556 TI - Characterization of alpha-particle tracks in cellulose nitrate LR-115 detectors at various incident energies and angles. AB - Cellulose nitrate LR-115 detectors were irradiated with alpha particles in the energy range from 1 to 5 MeV at incident angles from 20 degrees to 90 degrees , using an (241)Am source. After etching in a 2.5 N NaOH solution kept at 60 degrees C for various periods, the diameters of the major and minor axes of the track openings, track growing rate, track etch rate, etching ratio, and track length were found as a function of energies and incident angles. The measured track parameters were compared to calculated values, and the etching ratio was formulated as a Durrani-Green's function of the incident energy and angle. PMID- 23727557 TI - An electrochemiluminescence assay for gp340 (DMBT1). AB - Gp340 is a member of the scavenger receptor cysteine-rich family of innate immune molecules and also functions as a tumor suppressor. This study describes a picogram-level assay using electrochemiluminescence technology on the MesoScale Discovery platform. Antibodies were evaluated and the best pair was used to assay whole-mouth stimulated saliva and cervical/vaginal lavage. The assay was tested using specimens obtained from healthy volunteers to determine if gp340 concentration in saliva correlates with levels in vaginal lavage fluid. Interestingly, no correlation was determined between gp340 content in these two fluids. PMID- 23727558 TI - Stable deuterium internal standard for the isotope-dilution LC-MS/MS analysis of elastin degradation. AB - Chemical synthesis of the deuterium isotope desmosine-d4 has been achieved. This isotopic compound possesses all four deuterium atoms at the alkanyl carbons of the alkyl amino acid substitution in the desmosine molecule and is stable toward acid hydrolysis; this is required in the measurement of two crosslinking molecules, desmosine and isodesmosine, as biomarkers of elastic tissue degradation. The degradation of elastin occurs in several widely prevalent diseases. The synthesized desmosine-d4 is used as the internal standard to develop an accurate and sensitive isotope-dilution liquid chromatography-tandem mass spectrometry analysis, which can serve as a generalized method for an accurate analysis of desmosine and isodesmosine as biomarkers in many types of biological tissues involving elastin degradation. PMID- 23727559 TI - Amino acid analysis of spider dragline silk using 1H NMR. AB - The amino acid composition of Nephila clavipes dragline silk fiber was determined by conducting 1H nuclear magnetic resonance (NMR) spectroscopy experiments on acid-hydrolyzed material. N. clavipes dragline silk was found to consist of 43.0+/-0.6% Gly, 29.3+/-0.2% Ala, 9.1+/-0.1% Glx, 4.0+/-0.1% Leu, 3.3+/-0.1% Tyr, 3.4+/-0.2% Ser, 2.7+/-0.1% Pro, 2.1+/-0.1% Arg, 1.07+/-0.05% Asx, 0.96+/-0.05% Val, 0.48+/-0.03% Thr, 0.35+/-0.03% Phe, and 0.28+/-0.03% Ile. Compared with standard chromatography-based amino acid analysis (AAA), the chemical resolution of NMR allows for an amino acid solution to be characterized without separation and is shown to provide considerably higher precision. This allows for more accurate statistics on the variability of amino acids in spider dragline silk. In general, this 1H NMR AAA technique is applicable to a large range of proteins and peptides for precise composition characterization, especially when the precise content of a minor component is critical and relatively large amounts of sample are available (microgram to milligram quantities). PMID- 23727560 TI - Semiquantitative and quantitative analysis of protein-DNA interactions using steady-state measurements in surface plasmon resonance competition experiments. AB - One method commonly used to characterize protein-DNA interactions is surface plasmon resonance (SPR). In a typical SPR experiment, chip-bound DNA is exposed to increasing concentrations of protein; the resulting binding data are used to calculate a dissociation constant for the interaction. However, in cases in which knowledge of the specificity of the interaction is required, a large set of DNA variants has to be tested; this is time consuming and costly, in part because of the requirement for multiple SPR chips. We have developed a new protocol that uses steady-state binding levels in SPR competition experiments to determine protein-binding dissociation constants for a set of DNA variants. This approach is rapid and straightforward and requires the use of only a single SPR chip. Additionally, in contrast to other methods, our approach does not require prior knowledge of parameters such as on or off rates, using an estimate of the wild type interaction as the sole input. Utilizing relative steady-state responses, our protocol also allows for the rapid, reliable, and simultaneous determination of protein-binding dissociation constants of a large series of DNA mutants in a single experiment in a semiquantitative fashion. We compare our approach to existing methods, highlighting specific advantages as well as limitations. PMID- 23727561 TI - Subpicomolar sensing of hydrogen peroxide with ovalbumin-embedded chitosan/polystyrene sulfonate multilayer membrane. AB - The use of ovalbumin (OVA)-immobilized layer-by-layer-assembled chitosan/polystyrene sulfonate membranes for the detection of hydrogen peroxide (H2O2) at subpicomolar levels is reported. The detection of mercuric chloride (HgCl2) and potassium iodide (KI) was also investigated. While the detection limits of HgCl2 and KI remained in the micromolar concentration range, H2O2 could be sensed to a remarkably lower range (subpicomolar). Analysis of fluorescence quenching data of OVA by H2O2 using Stern-Volmer plots revealed a static quenching mechanism with high Stern-Volmer quenching constant (9.10*10(12) L mol( 1)) and k (5.82*10(21) L mol(-1) s(-1)). The possibility of the conformational transition of OVA in the immobilized state is discussed using steady-state and time-resolved spectroscopic techniques. The resulting increased accessibility of tryptophan residues together with the reversibility of the bilayer for the sensing of H2O2 is also illustrated. PMID- 23727562 TI - Trend of dissolved inorganic nitrogen at stations downstream from the Three Gorges Dam of Yangtze River. AB - The TRAMO/SEATS program, combined with the Hodrick-Prescott (HP) filter, was used to detect trends and potential change points in time series of dissolved inorganic nitrogen (DIN) at three stations along the Yangtze River. The trend components were extracted, and two change points were successfully detected. The components revealed that DIN has been increasing at all the stations since the 1990s, although variations exist. Changes visible before 2002 illustrate the differences in agriculture development among regions upstream from the stations. The Three-Gorges Dam (TGD), which began to impound in 2003, led to years of different trends. The DIN concentration, which had been trending upward prior to that date, began a slightly downward trend because of NH4(+) depletion. Readings at the Yichang station revealed this trend most strongly; those at the Hankou station less so. The Datong station was far enough away from the TGD so that no obvious effects were seen. PMID- 23727563 TI - Assessment of PCDD/Fs levels in soil at a contaminated sawmill site in Sweden--a GIS and PCA approach to interpret the contamination pattern and distribution. AB - Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-p-furans (PCDD/Fs) were analysed in soil from a Swedish sawmill site where chlorophenols (CPs) had been used more than 40 years ago. The most contaminated area at the site was the preservation subarea where the PCDD/F WHO2005-TEQ level was 3450 times higher than the current Swedish guideline value of 200 ng TEQ/kg soil for land for industrial use. It was also shown that a fire which destroyed the sawmill might have affected the congener distribution at the concerned areas. To get a broader picture of the contamination both GIS (spatial interpolation analysis) and multivariate data analysis (PCA) were applied to visualize and compare PCDD/F levels as well as congener distributions at different areas at the site. It is shown that GIS and PCA are powerful tools in decisions on future investigations, risk assessments and remediation of contaminated sites. PMID- 23727564 TI - Spatial distribution of polychlorinated naphthalenes in the atmosphere across North China based on gridded field observations. AB - Polychlorinated naphthalenes (PCNs) belong to a group of dioxin-like pollutants; however little information is available on PCNs in North China. In this study, gridded field observations by passive air sampling at 90 sites were undertaken to determine the levels, spatial distributions, and sources of PCNs in the atmosphere of North China. A median concentration of 48 pg m(-3) (range: 10-2460 pg m(-3)) for ?29PCNs indicated heavy PCN pollution. The compositional profile indicated that nearly 90% of PCNs observed were from thermal processes rather than from commercial mixtures. Regarding the source type, a quantitative apportionment suggested that local non-point emissions contributed two-thirds of the total PCNs observed in the study, whereas a point source of electronic-waste recycling site contributed a quarter of total PCNs. The estimated toxic equivalent quantity for dioxin-like PCNs ranged from 0.97 to 687 fg TEQ m(-3), with the electronic-waste recycling site with the highest risk. PMID- 23727565 TI - Evaluating the sub-lethal toxicity of PFOS and PFOA using rotifer Brachionus calyciflorus. AB - The acute and chronic effects of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) on the rotifer Brachionus calyciflorus (B. calyciflorus) were investigated at the organismal and the population level. The acute toxicity of PFOS to rotifers was approximately 2.5-fold greater than that of PFOA. From 0.25 to 2.0 mg L(-1), PFOS exhibited higher toxicity than PFOA on the F0-generation of B. calyciflorus, including effects on body size, juvenile periods, net reproductive rate, and generation time. Both PFOS and PFOA exposure induced a smaller egg size in B. calyciflorus, suggesting that these risks can be transferred from mother to offspring. The 28-day population growth studies showed that PFOS and PFOA reduced the population density and increased the mictic ratio. Our results demonstrated that both PFOS and PFOA had adverse effects on B. calyciflorus, not only at the individual level but also at the population level. PMID- 23727566 TI - New insights into parental effects and toxicity: mate availability and diet in the parental environment affect offspring responses to contaminants. AB - Parental effects manifest as alterations in offspring phenotype resulting from the parental phenotype and/or parental environment. We evaluated the effects of parental diet quality and mating strategy on the toxicant tolerance of offspring in Biomphalaria glabrata snails. We raised snails either individually (self fertilizing) or in groups of three (outcrossing) on a diet of uncooked lettuce, fish food, cooked lettuce, or cooked lettuce plus fish food. We then exposed their offspring to cadmium and malathion challenges. Cadmium tolerance varied with parental diet and was greater in the offspring of outcrossing snails than self-fertilizing snails. Malathion tolerance was not affected by parental diet but was greater in the offspring of outcrossing snails. These results indicate that offspring responses to stressors are heavily influenced by parental experience, but may depend on the specific stressor and the mechanism of action and/or detoxification. PMID- 23727567 TI - Covalent bonding of chloroanilines to humic constituents: pathways, kinetics, and stability. AB - Covalent coupling to natural humic constituents comprises an important transformation pathway for anilinic pollutants in the environment. We systematically investigated the reactions of chlorine substituted anilines with catechol and syringic acid in horseradish peroxidase (HRP) catalyzed systems. It was demonstrated that although nucleophilic addition was the mechanism of covalent bonding to both catechol and syringic acid, chloroanilines coupled to the 2 humic constituents via slightly different pathways. 1,4-addition and 1,2 addition are involved to catechol and syringic acid, respectively. 1,4-addition showed empirical 2nd order kinetics and this pathway seemed to be more permanent than 1,2-addition. Stability experiments demonstrated that cross-coupling products with syringic acid could be easily released in acidic conditions. However, cross-coupling with catechol was relatively stable at similar conditions. Thus, the environmental behavior and bioavailability of the coupling products should be carefully assessed. PMID- 23727568 TI - Responses of ecosystem carbon dioxide exchange to nitrogen addition in a freshwater marshland in Sanjiang Plain, Northeast China. AB - It has widely been documented that nitrogen (N) stimulates plant growth and net primary production. But how N affects net ecosystem CO2 exchange (NEE) is still dispute. We conduct an experimental study to assess the response of NEE to N addition in a freshwater marsh. Experimental treatments involved elevated N and control treatments on triplicate 1 m(2) plots. Gas exchange, air temperature, plant biomass and leaf area as well as N% of leaf were measured from 2004 to 2005. The results indicated that N addition initially decreased the CO2 sequestration but the trend changed in the second year. It was concluded that N addition enhanced the greenhouse effect in marshland as far as global warming potential (GWP) is concerned. This increase was attributed to a substantial increase in CH4 and N2O emissions after N addition. We recommended long-term studies to further clarify the effect of N addition on NEE. PMID- 23727569 TI - Ecotoxicity of non-aged and aged CeO2 nanomaterials towards freshwater microalgae. AB - The ecotoxicity of artificially alterated cerium dioxide nanoparticles (nano CeO2) suspensions was determined using the freshwater microalgae growth inhibition test. The agglomeration or aggregation state of the alterated suspensions was followed because it represents one of the obvious modifications when nanoparticles reached the environment. In addition, its influence on the ecotoxicity of nanoparticles is currently not well-addressed. Our results showed that the suspensions were stable within the first 24 h and then agglomerate up to 10 MUm after 3 and 30 days. The inhibitory effect on the growth of exposed algae was however similar whatever the tested suspension. This supports the fact that the agglomeration state of nano-CeO2, in our conditions, has few influences on the ecotoxicity toward these organisms. The EC50 values were 5.6; 4.1 and 6.2 mg L(-1), after exposure to non aged, 3 and 30 days aged suspensions respectively. The interaction between algal cells and nano-CeO2 was also addressed. PMID- 23727570 TI - The time course of auditory-visual processing of speech and body actions: evidence for the simultaneous activation of an extended neural network for semantic processing. AB - An extensive network of cortical areas is involved in multisensory object and action recognition. This network draws on inferior frontal, posterior temporal, and parietal areas; activity is modulated by familiarity and the semantic congruency of auditory and visual component signals even if semantic incongruences are created by combining visual and auditory signals representing very different signal categories, such as speech and whole body actions. Here we present results from a high-density ERP study designed to examine the time-course and source location of responses to semantically congruent and incongruent audiovisual speech and body actions to explore whether the network involved in action recognition consists of a hierarchy of sequentially activated processing modules or a network of simultaneously active processing sites. We report two main results:1) There are no significant early differences in the processing of congruent and incongruent audiovisual action sequences. The earliest difference between congruent and incongruent audiovisual stimuli occurs between 240 and 280 ms after stimulus onset in the left temporal region. Between 340 and 420 ms, semantic congruence modulates responses in central and right frontal areas. Late differences (after 460 ms) occur bilaterally in frontal areas.2) Source localisation (dipole modelling and LORETA) reveals that an extended network encompassing inferior frontal, temporal, parasaggital, and superior parietal sites are simultaneously active between 180 and 420 ms to process auditory-visual action sequences. Early activation (before 120 ms) can be explained by activity in mainly sensory cortices. . The simultaneous activation of an extended network between 180 and 420 ms is consistent with models that posit parallel processing of complex action sequences in frontal, temporal and parietal areas rather than models that postulate hierarchical processing in a sequence of brain regions. PMID- 23727571 TI - Mental rotation in intellectually gifted boys is affected by the androgen receptor CAG repeat polymorphism. AB - Testosterone was shown to organize brain and modulate cognitive functions. It is currently unknown whether mental rotation is also associated with prenatal testosterone exposure and testosterone-related genetic polymorphisms. The aim of our study was to analyze associations between mental rotation performance, the actual testosterone levels, the prenatal testosterone level (expressed as 2D:4D ratio) and the androgen receptor CAG repeat polymorphism in intellectually gifted boys. One hundred forty-seven boys aged 10-18 years with IQ>130 were enrolled. Saliva samples were collected and used for ELISA of actual levels of salivary testosterone. The 2D:4D finger length ratio as an indicator of prenatal testosterone was measured on both hands and averaged. Amthauer mental rotation test was used for the assessment of this spatial ability. The CAG repeat polymorphism in the androgen receptor gene was analyzed using PCR and capillary electrophoresis. Linear regression revealed that 2D:4D finger length ratio and the number of CAG repeats in the androgen receptor gene were associated with mental rotation. Actual levels of testosterone did not correlate significantly with mental rotation. Multivariate analysis of covariance revealed that after adjustment of age as a confounding variable, only the effect of the genetic polymorphism was significant. The results are in line with our previous genetic analysis of intellectually gifted boys showing the importance of CAG repeat polymorphism in the androgen receptor gene. Details of the interactions between androgen signaling, testosterone levels and its metabolism especially during the prenatal development of brain function remain to be elucidated. PMID- 23727572 TI - Sex hormonal modulation of interhemispheric transfer time. AB - It is still a matter of debate whether functional cerebral asymmetries (FCA) of many cognitive processes are more pronounced in men than in women. Some evidence suggests that the apparent reduction in women's FCA is a result of the fluctuating levels of gonadal steroid hormones over the course of the menstrual cycle, making their FCA less static than for men. The degree of lateralization has been suggested to depend on interhemispheric communication that may be modulated by gonadal steroid hormones. Here, we employed visual-evoked EEG potentials to obtain a direct measure of interhemispheric communication during different phases of the menstrual cycle. The interhemispheric transfer time (IHTT) was estimated from the interhemispheric latency difference of the N170 component of the visual-evoked potential from either left or right visual field presentation. Nineteen right-handed women with regular menstrual cycles were tested twice, once during the menstrual phase, when progesterone and estradiol levels are low, and once during the luteal phase when progesterone and estradiol levels are high. Plasma steroid levels were determined by blood-based immunoassay at each session. It was found that IHTT, in particular from right-to-left, was generally longer during the luteal phase relative to the menstrual phase. This effect occurred as a consequence of a slowed absolute N170 latency of the indirect pathway (i.e. left hemispheric response after LVF stimulation) and, in particular, a shortened latency of the direct pathway (i.e. right hemispheric response after LVF stimulation) during the luteal phase. These results show that cycle-related effects are not restricted to modulation of processes between hemispheres but also apply to cortical interactions, especially within the right hemisphere. The findings support the view that plastic changes in the female brain occur during relatively short-term periods across the menstrual cycle. PMID- 23727573 TI - Loss of Smu1 function de-represses DNA replication and over-activates ATR dependent replication checkpoint. AB - Smu1 is an evolutionarily conserved gene that encodes a member of the WD40-repeat protein family. Disruption of Smu1 function leads to multiple cellular defects including chromosomal instability, aberrant DNA replication and alternative RNA splicing events. In this paper, we show that Smu1 is a chromatin-bound protein that functions as a negative regulator of DNA replication. Knockdown of Smu1 gene expression promotes excessive incorporation of dNTP analogue, implicating the acceleration of DNA synthesis. Smu1-silenced cells show an excessive activation of replication checkpoint in response to ultraviolate (UV) or hydroxyurea treatment, indicating that abnormal stimulation of DNA replication leads to instability of genomic structure. Hence, we propose that Smu1 participates in the protection of genomic integrity by negatively regulating the process of DNA synthesis. PMID- 23727574 TI - MicroRNA-214 provokes cardiac hypertrophy via repression of EZH2. AB - Micro RNAs are small, non-coding RNA molecules that regulate gene expression via either translational inhibition or mRNA degredation. Enhancer of zeste homolog 2 (EZH2)-mediated hypertrophic signaling is a major regulatory response to hypertrophic stimuli. In this study, we constructed AAC rat models and PE-induced hypertrophic cardiomyocytes. We demonstrated that miR-214 relative levels were upregulated, whereas EZH2 was downregulated in both vivo and vitro models. Further, one conserved base-pairing site in the EZH2 3'-untranslated region (UTR) was verified. Mutation of the site in the EZH2 3'-UTR completely blocked the negative effect of miR-214 on EZH2, suggesting that EZH2 is a direct target for miR-214 regulation. Using a gain-of-function approach, incorporating the lentivirus constructed miR-214 and its sponge, we demonstrated that miR-214 significantly regulated endogenous levels of EZH2 gene expression; whereas, changes in the expression of the Sine oculis homeobox homolog gene were induced by an adrenergic receptor agonist in the AAC rat model. Having made this study it is possible to conclude that the negative regulation of EZH2 expression contributed to miR-214-mediated cardiac hypertrophy. PMID- 23727575 TI - NF-kappaB-mediated induction of autophagy in cardiac ischemia/reperfusion injury. AB - Ischemia/reperfusion (I/R) injury severely attenuates the benefit of revascularization after acute myocardial infarction, in which transcription factor NF-kappaB plays an important role. Recently, there is increasing evidence to suggest that autophagy is involved in this process. We sought to define the role of NF-kappaB in the induction of autophagy during cardiac I/R injury. The left circumflex coronary arteries of New Zealand white rabbits were ligated for 1.5h, followed by reperfusion for 1h to induce I/R injury. Production of reactive oxygen species (ROS) was detected in myocardial injury area following I/R injury. Furthermore, the results indicated that the cardiac area at risk (AAR) for ischemia has the most abundant expression of Beclin 1 in parallel to p65 expression after cardiac I/R injury. Inhibition of NF-kappaB significantly attenuated Beclin 1 expression and autophagy in the AAR, which was associated with a marked reduction in the extent of the AAR. Our data thus suggests that I/R injury promotes NF-kappaB activity, in response to ROS, to aggravate myocardial injury through the activation of Beclin 1-mediated autophagy. PMID- 23727576 TI - Activation of PPARalpha by Wy-14643 ameliorates systemic lipopolysaccharide induced acute lung injury. AB - Acute lung injury (ALI) is a major cause of mortality and morbidity worldwide. The activation of peroxisome proliferator-activated receptor-alpha (PPARalpha) by its ligands, which include Wy-14643, has been implicated as a potential anti inflammatory therapy. To address the beneficial efficacy of Wy-14643 for ALI along with systemic inflammation, the in vivo role of PPARalpha activation was investigated in a mouse model of lipopolysaccharide (LPS)-induced ALI. Using age matched Ppara-null and wild-type mice, we demonstrate that the activation of PPARalpha by Wy-14643 attenuated LPS-mediated ALI. This was evidenced histologically by the significant alleviation of inflammatory manifestations and apoptosis observed in the lung tissues of wild-type mice, but not in the corresponding Ppara-null mice. This protective effect probably resulted from the inhibition of LPS-induced increases in pro-inflammatory cytokines and nitroxidative stress levels. These results suggest that the pharmacological activation of PPARalpha might have a therapeutic effect on LPS-induced ALI. PMID- 23727577 TI - A mechanistic overview of TET-mediated 5-methylcytosine oxidation. AB - Methylation of DNA at the carbon-5 position of cytosine plays crucial roles in the epigenetic transcriptional silencing during metazoan development. Recent identification of Ten-Eleven Translocation (TET)-family demethylases have added a new dimension to dynamic regulation of 5-methylcytosine (5mC), and thus, inheritable and somatic gene silencing. The interest in hematology was particularly stimulated by the recent discovery of TET2 mutations in myeloid malignancies which were proven to be leukemogenic in murine knockout models. The TET-family enzymes are Fe(II), 2-oxoglutarate-dependent oxygenases and catalyze demethylation of 5mC by iterative oxidation reactions. In the last decade results from numerous studies have established a key role for these enzymes in epigenetic transcriptional regulation in eukaryotes primarily by hydroxylation reactions. The TET catalyzed hydroxylation and dehydration reactions in the mammalian system exemplify the diversity of oxidation reactions catalyzed by Fe(II), 2 oxoglutarate-dependent oxygenases, and suggest an existence of other types of oxidation reactions catalyzed by these enzymes in the eukaryotes, which are so far only documented in prokaryotes. Here, we review the TET-mediated 5mC oxidation in light of the putative reaction mechanism of Fe(II), 2-oxoglutarate dependent oxygenases. PMID- 23727578 TI - Identification of human guanylate-binding protein 1 gene (hGBP1) as a direct transcriptional target gene of p53. AB - Human guanylate-binding protein 1 (hGBP1) plays an important role in antitumor and antiviral immune responses. Here, we show that tumor suppressor p53 positively regulated hGBP1 transcription via binding to the p53 response element (p53RE) present in the hGBP1 promoter region. p53 activation by 5-fluorouracil significantly increased hGBP1 expression in wild-type p53 cells, but not in p53 null cells. Knockdown of p53 expression remarkably impaired hGBP1 expression induced by 5-fluorouracil, type I interferon treatment, or influenza A virus infection. Among three deductive p53REs present in the hGBP1 promoter region, two p53REs were found to be transactivated by p53. PMID- 23727579 TI - Arsenite retards the cardiac differentiation of rat cardiac myoblast H9c2 cells. AB - It is well known that exposure to inorganic arsenic through groundwater leads not only to cancer and cardiovascular disease, but also to detrimental effects on development. In this study, we investigated the effects of arsenite on the cardiac differentiation of rat myoblast H9c2 cells. The cardiac differentiation of H9c2 cells cultured in media containing 1% fetal bovine serum and all-trans retinoic acid was confirmed by enhanced expression of cardiac troponin T (cTnT), the appearance of multinucleated cells, and cell cycle arrest at G0/G1 phase. Exposure of H9c2 cells to inorganic arsenite (As(III)) during cardiac differentiation suppressed the appearance of the morphological and biological characteristics observed in the cardiac phenotype of H9c2 cells. In addition, As(III) inhibited PKCdelta phosphorylation, which is detected in early-stage differentiation. These results suggest that As(III) retards the cardiac differentiation of H9c2 cells, at least partly, via the inhibition of PKCdelta phosphorylation. PMID- 23727580 TI - Tubulin polymerization promoting protein 1 (TPPP1) increases beta-catenin expression through inhibition of HDAC6 activity in U2OS osteosarcoma cells. AB - The Rho-associated coiled-coil kinase (ROCK) family of proteins, including ROCK1 and ROCK2, are key regulators of actin and intermediate filament morphology. The newly discovered ROCK substrate Tubulin polymerization promoting protein 1 (TPPP1) promotes microtubule polymerization and inhibits the activity of Histone deacetylase 6 (HDAC6). The effect of TPPP1 on HDAC6 activity is inhibited by ROCK signaling. Moreover, it was recently demonstrated that ROCK activity increases the cellular expression of the oncogene beta-catenin, which is a HDAC6 substrate. In this study, we investigated the interplay between ROCK-TPPP1-HDAC6 signaling and beta-catenin expression. We demonstrate that beta-catenin expression is increased with ROCK signaling activation and is reduced with increased TPPP1 expression in U2OS cells. Further investigation revealed that ROCK-mediated TPPP1 phosphorylation, which prevents its binding to HDAC6, negates TPPP1-mediated reduction in beta-catenin expression. We also show that increased HDAC6 activity resulting from ROCK signaling activation reduced beta-catenin acetylation at Lys 49, which was also accompanied by its decreased phosphorylation by Caesin kinase 1 (CK1) and Glycogen synthase kinase 3beta (GSK3beta), thus preventing its proteasomal degradation. Overall, our results suggest that ROCK regulates beta catenin stability in cells via preventing TPPP1-mediated inhibition of HDAC6 activity, to reduce its acetylation and degradation via phosphorylation by CK1 and GSK3beta. PMID- 23727581 TI - Critical contribution of oxidative stress to TNFalpha-induced necroptosis downstream of RIPK1 activation. AB - While apoptosis has been considered to be identical to programmed cell death, necroptosis, which is morphologically related to necrosis, has emerged as a novel type of programmed cell death. Necroptosis depends on two structurally related kinases, receptor-interacting serine-threonine kinase (RIPK)1 and RIPK3. RIPK1 is activated through oligomerization of upstream adaptor molecules such as Fas associated protein with death domain (FADD) and TNF receptor-associated death domain (TRADD) that are triggered by TNFalpha or Fas ligand. Activated RIPK1 subsequently interacts with and activates RIPK3, resulting in necroptosis. However, contribution of oxidative stress to execution of necroptosis is still controversial. We found that a selective inhibitor for RIPK1, necrostatin-1 (Nec 1) significantly blocked TNFalpha-induced cell death and ROS accumulation in NF kappaB activation-deficient cells. This suggests that these cells mostly died by necroptosis upon TNFalpha stimulation. Intriguingly, an antioxidant, butylated hydroxyanisole (BHA) blocked TNFalpha-induced necroptosis and ROS accumulation in NF-kappaB activation-deficient cells. However, Nec-1, but not BHA, inhibited TNFalpha-induced phosphorylation of RIPK1 in these cells, suggesting that ROS play a crucial role in execution of necroptosis downstream of RIPK1 activation. Structural and functional analyses using BHA related compounds revealed that both tert-butyl and hydroxy groups of BHA are crucial for its anti-necroptotic function. Together, these results suggest that TNFalpha-induced necroptosis is tightly associated with oxidative stress, and oxidative stress is induced downstream of RIPK1 activation. PMID- 23727582 TI - Evidence that P12, a specific variant of P16(INK4A), plays a suppressive role in human pancreatic carcinogenesis. AB - The INK4a-ARF locus plays a central role in the development of pancreatic tumors as evidenced by the fact that up to 98% of pancreatic tumor specimens harbored genetic alterations at the INK4a-ARF locus. Interestingly, in addition to the well-known P16(INK4A) (P16) and P14ARF tumor suppressors, the INK4a-ARF locus in pancreas encodes another protein, P12, whose structure, function, and contributions to pancreatic carcinogenesis remain to be elucidated. In the current study, we demonstrated that over-expression of p12 in human pancreatic cancer cells led to cell arrest at the G1 phase and such cell cycle arrest was related to down-regulation of a number of oncogenes, such as c-Jun, Fos, and SEI1. Furthermore, unlike P16, P12 did not retain any cyclin-dependent kinase 4 (CDK4)-inhibitory activity. Instead, P12 exhibited a transactivating activity not found in P16. We also examined the genetic status of p12 in a cohort of 40 pancreatic tumor specimens and found that p12 alteration was prevalent in pancreatic tumors with an incidence of 70% (28/40). These results support that P12 is a tumor suppressive protein distinct from P16, and its genetic inactivation is associated with pancreatic carcinogenesis. PMID- 23727583 TI - Drosophila MagT1 is upregulated by PKC activation. AB - Magnesium transporter subtype 1 (MagT1) is a newly discovered and evolutionarily conservative magnesium membrane transporter with channel like properties. Previous reports have demonstrated that MagT1 is important to cellular magnesium homeostasis. In this study, we investigated whether drosophila MagT1 (dMagT1) was functionally regulated by PKC activation in vitro. With patch clamping, we have observed that whole cell currents of wild type dMagT1 were magnesium selective and non-voltage dependent when expressed in a human neuroblastoma SH-SY5Y cell line. Furthermore, dMagT1 currents were significantly increased in cells treated with a non specific PKC activator PMA, but not in cells treated with the inactive form of PMA, 4alpha-PMA. Lastly, we have demonstrated that upregulation of dMagT1 currents by PKC activation involves specific PKC phorsphorylation sites in dMagT1. Of all three dMagT1 mutants created for testing the putative PKC phorsphorylation sites, dMagT1-S35A displayed a significant increase of whole cell currents while dMagT1-S100A and -S108A were not affected by PKC activation. Thus, we have demonstrated that dMagT1 is a magnesium selective transporter with basic biophysical characters similar to its mammalian homolog and can be functionally upregulated by PKC activation. Both dMagT1 Ser100 and Ser106 are equally important to this PKC-dependent modulation, therefore the most likely molecular sites for PKC phorsphorylation. The data presented here may establish a general regulatory mechanism for MagT1 by PKC activation. PMID- 23727584 TI - Detection of minimal residual disease in patients with multiple myeloma using clonotype-specific PCR primers designed from DNA extracted from archival bone marrow slides. AB - Polymerase chain reaction (PCR)-negative molecular complete remission (mCR) can be induced by stem cell transplantation in some patients with multiple myeloma (MM) and is associated with long-term progression-free survival (PFS). The detection of molecular minimal residual disease (MRD), however, requires fresh or frozen materials for designing clone-specific primers, which are not always readily available. In this study, we used DNA extracted from archival bone marrow (BM) slides for PCR to detect MRD in 50 patients with MM who received various induction therapies and autologous peripheral blood stem cell transplantation (ASCT). Clonotype-specific immunoglobulin (Ig) H PCR primers were prepared for 32 of 50 cases (64%) using BM slides, and for 9 of 14 cases (64%) using fresh BM cells. DNA in peripheral blood stem cell autografts of the 22 patients who achieved at least a partial response after ASCT was subjected to PCR to amplify clonotype-specific rearranged IgH gene sequences. The median PFS of the eight patients with MRD-positive autografts was 18 months, whereas that of 14 patients with MRD-negative autografts was not reached at a median follow-up of 27 months (p = 0.012). Post-ASCT PFS of the four patients who achieved mCR was 100% at a median follow-up of 47 months. These results indicate that archival BM slides can serve as a source of DNA for preparing clonotype-specific primers for MRD monitoring in patients with MM whose cryopreserved myeloma cells are not available for DNA preparation. Our results also suggest that patients with MM who received MRD-negative autografts and achieved mCR have a long PFS. PMID- 23727585 TI - Increased uptake by splenic red pulp macrophages contributes to rapid platelet turnover in WASP(-) mice. AB - Thrombocytopenia caused by rapid platelet consumption contributes to the severe thrombocytopenia of Wiskott-Aldrich syndrome (WAS) and to the milder thrombocytopenia seen in murine WAS. We show that rapid clearance of 111In labeled murine WASP(-) platelets correlates with enhanced splenic uptake. Using platelets labeled with a pH-sensitive fluorescent marker (pHrodo), we quantify normal platelet uptake by red pulp macrophages (RPMs), and demonstrate its enhancement after in vivo opsonization of platelets. The spleens of WASP(-) mice contain an increased number of RPM, and rapid clearance of WASP(-) platelets in WASP(-) mice in turn generates an increased number of pHrodo(+) splenic RPMs. To separately assess the platelet intrinsic and recipient-dependent functions involved in the clearance and splenic phagocyte uptake of WASP(-) platelets, we performed "crossed" pHrodo(+) platelet injection studies (wild type [WT] to WASP( ), WASP(-) to WT). We show that an extrinsic effect of recipient WASP deficiency on the clearance of WASP(-) platelets correlates with increased platelet uptake by RPMs. An intrinsic effect of platelet WASP deficiency on platelet clearance does not, however, correlate with increased total uptake by WT or WASP(-) RPMs. In contrast to other published findings, we find no evidence of a baseline or antibody-induced increase in phosphatidyl serine exposure on WASP(-) platelets. Our findings suggest that an increased number of RPMs in WASP(-) mice contributes significantly to the increased platelet consumption rate in WASP(-) mice. This might explain the consistent efficacy of splenectomy in murine and clinical WAS. PMID- 23727586 TI - Local demixion in plasticized polylactide probed by electron spin resonance. AB - Improving the barrier properties to gas and organic compounds of biosourced polyesters, such as polylactides (PLAs), by increasing their crystallinity has been suggested by several authors. This paper investigates the risk of microphase separation for a technological approach that would involve a plasticization of PLA, to further its crystallization kinetics, with common plasticizers: Acetyl tributyl citrate (ATBC) and Poly(ethylene glycol) (PEG). Overplasticization effects following microphase separation were monitored along the film thickness by exposing dynamically thermo-compressed films to nitroxide spin-probes. The method enabled a scan of the local polymer mobility for different concentration profiles in spin-probes, with in particular a maximum moving continuously in time towards the geometric center. The results were interpreted as excess local temperatures that would give similar ESR spectra motion in the bulk. It was shown that measured excess temperatures could be related to local shifts in the glass transition temperature along the film thickness. PMID- 23727587 TI - MR measurement of alloy magnetic susceptibility: towards developing tissue susceptibility matched metals. AB - Magnetic resonance imaging (MRI) can be used to relate structure to function mapped with high-temporal resolution electrophysiological recordings using metal electrodes. Additionally, MRI may be used to guide the placement of electrodes or conductive cannula in the brain. However, the magnetic susceptibility mismatch between implanted metals and surrounding brain tissue can severely distort MR images and spectra, particularly in high magnetic fields. In this study, we present a modified MR method of characterizing the magnetic susceptibility of materials that can be used to develop biocompatible, metal alloys that match the susceptibility of host tissue in order to eliminate MR distortions proximal to the implant. This method was applied at 4.7T and 11.1T to measure the susceptibility of a model solid-solution alloy of Cu and Sn, which is inexpensive but not biocompatible. MR-derived relative susceptibility values of four different compositions of Cu-Sn alloy deviated by less than 3.1% from SQUID magnetometry absolute susceptibility measurements performed up to 7T. These results demonstrate that the magnetic susceptibility varies linearly with atomic percentage in these solid-solution alloys, but are not simply the weighted average of Cu and Sn magnetic susceptibilities. Therefore susceptibility measurements are necessary when developing susceptibility-matched, solid-solution alloys for the elimination of susceptibility artifacts in MR. This MR method does not require any specialized equipment and is free of geometrical constraints, such as sample shape requirements associated with SQUID magnetometry, so the method can be used at all stages of fabrication to guide the development of a susceptibility matched, biocompatible device. PMID- 23727588 TI - Simple and accurate determination of X-H distances under ultra-fast MAS NMR. AB - We demonstrate that a very simple experiment, Cross-Polarization with Variable Contact-time (CP-VC), is very efficient at ultra-fast MAS (nuR >= 60 kHz) to measure accurately the C-H and N-H distances, and to analyze the dynamics of bio molecules. This experiment can be performed with samples that are either (13)C or (15)N labeled or without any labeling. The method is very robust experimentally with respect to imperfect Hartman-Hahn setting, and presents a large scaling factor allowing a better dipolar determination, especially for long C-H or N-H distances, or for CH3 or NH3 moieties with three-site hopping. At ultra-fast MAS, it can be used quantitatively in a 2D way, because its scaling factor is then little dependent on the offsets. This robustness with respect to offset is related to the ultra-fast spinning speed, and hence to the related small rotor diameter. Indeed, these two specifications lead to efficient n = +/-1 zero quantum Hartman-Hahn CP-transfers with large RF-fields on proton and carbon or nitrogen channels, and large dipolar scaling factor. PMID- 23727589 TI - Purification and characterization of an alpha-galactosidase from Phaseolus coccineus seeds showing degrading capability on raffinose family oligosaccharides. AB - An acidic alpha-galactosidase (EC 3.2.1.22) designated as Phaseolus coccineus seeds galactosidase (PCG) was purified from P. coccineus seeds using ion-exchange chromatography on DEAE- and CM-cellulose, Q- and SP-Sepharose and gel filtration on Superdex 75. The molecular weight of PCG was 43 kDa as judged by SDS-PAGE and gel filtration. Two inner peptides of PCG were sequenced by MALDI-TOF-MS. The optimum pH and temperature was 3.0 and 70 degrees C, respectively but was stable up to 60 degrees C for 30 min. The enzyme activity was inhibited by NBS signifying the pivotal role played by tryptophan in the catalytic activity of the enzyme. The Km for hydrolysis of pNPGal was 0.0025 mM. Besides hydrolyzing pNPGal, alpha-galactosidases also hydrolyzed natural substrates such as melibiose, raffinose and stachyose. Hence it can be exploited commercially for improving the nutritional value of soymilk. Thus the PCG has great potential in the feed industries for removal of non-digestible oligosaccharide from legumes. PMID- 23727590 TI - Phenylpropanoid metabolites and expression of key genes involved in anthocyanin biosynthesis in the shaded peel of apple fruit in response to sun exposure. AB - The shaded peel of 'Fortune' (a red cultivar) and 'Mutsu' (a yellow/green cultivar) apple (Malus domestica Borkh.) was exposed to full sun by turning fruit 180 degrees at about one week before harvest to determine the expression of key genes involved in anthocyanin synthesis in response to sunlight exposure and their relationships with the levels of anthocyanins and other phenolics. For the unturned (control) fruit, the shaded peel had lower expression levels of MdMYB10 (a transcriptional factor in the regulation of anthocyanin biosynthesis) and seven structural genes in anthocyanin synthesis (MdPAL, MdCHS, MdCHI, MdF3H, MdDFR1, MdLDOX, and MdUFGT), and lower levels of anthocyanins and flavonols than the sun-exposed peel in both cultivars. Exposure of the shaded peel to full sun caused marked up-regulation of the expression of MdMYB10 and all seven structural genes, which peaked between 6 h and 30 h after fruit turning, consequently leading to higher levels of anthocyanins, flavonols, and total phenolics than in the shaded peel and even in the sun-exposed peel of control fruit. Interestingly, the levels of flavonols were higher in the shaded peel of turned fruit (the original sun-exposed peel) than in the sun-exposed peel of both control and turned fruit in both cultivars, suggesting that competition for substrates exists in different branches of the phenylpropanoid pathway. These results indicate that sunlight exposure stimulates the expression of MdMYB10 and structural genes in anthocyanin synthesis, thereby elevating the levels of anthocyanins and other phenolic compounds in both red and yellow/green cultivars. PMID- 23727591 TI - In vitro inhibition of vesicular stomatitis virus replication by purified porcine Mx1 protein fused to HIV-1 Tat protein transduction domain (PTD). AB - Vesicular stomatitis virus (VSV) is the causative agent of Vesicular stomatitis (VS), a highly contagious fatal disease of human and pigs. Few effective antiviral drugs are currently available against VSV infection. Mx proteins are interferon (IFN)-induced dynamin-like GTPases present in all vertebrates with a range of antiviral activities. Previous studies have shown that the transfected cell lines expressing either porcine Mx1 or human MxA acquired a high degree of resistance to VSV. To explore the feasibility of taking porcine Mx1 protein expressed in Escherichia coli as an antiviral agent, we applied the pCold system to express this fusion protein (PTD-poMx1), which consisted of an N-terminal HIV 1 Tat protein transduction domain (PTD) and the full-length porcine Mx1, and investigated its effects on the replication of VSV in Vero cells. The results demonstrated that the purified PTD-poMx1 fusion proteins could transduct into cells after incubated for 5h and had no cytotoxic. Furthermore, plaque reduction assay, determination of TCID50, real-time PCR and Western blot analyses were carried out to confirm the antiviral activity of purified fusion proteins in VSV infected Vero cells. Altogether, these data suggested that PTD-poMx1 fusion proteins might be applicable to inhibit VSV replication as a novel antiviral therapeutic agent. PMID- 23727592 TI - A peptide-morpholino oligomer conjugate targeting Staphylococcus aureus gyrA mRNA improves healing in an infected mouse cutaneous wound model. AB - Management of skin wound infections presents a serious problem in the clinic, in the community, and in both civilian and military clinical treatment centers. Staphylococcus aureus is one of the most common microbial pathogens in cutaneous wounds. Peptide-morpholino oligomer (PMO) conjugates targeted to S. aureus gyrase A mRNA have shown the ability to reduce bacterial viability by direct site specific mRNA cleavage via RNase P. As a treatment, these conjugates have the added advantages of not being susceptible to resistance due to genetic mutations and are effective against drug resistant strains. While this strategy has proven effective in liquid culture, it has yet to be evaluated in an animal model of infected surface wounds. In the present study, we combined PMO conjugates with a thermoresponsive gel delivery system to treat full-thickness mouse cutaneous wounds infected with S. aureus. Wounds treated with a single dose of PMO conjugate displayed improved healing that was associated with increased epithelialization, reduced bacterial load, and increased matrix deposition. Taken together, our findings demonstrate the efficacy and flexibility of the PMO conjugate drug delivery system and make it an attractive and novel topical antimicrobial agent. PMID- 23727593 TI - Mucus as a barrier to lipophilic drugs. AB - Mucus is a complex hydrogel, comprising glycoproteins, lipids, salts, DNA, enzymes and cellular debris, covering many epithelial surfaces in the human body. Once secreted, mucin forms a barrier to protect the underlying tissues against the extracellular environment. Mucus can therefore adversely affect the absorption or action of drugs administered by the oral, pulmonary, vaginal, nasal or other routes. Solubility and lipophilicity are key factors determining drug absorption, as a drug has to be soluble in the body fluids at the site of absorption and must also possess enough lipophilicity to permeate the biological membrane. Evidence has accumulated over the past 40 years indicating that poorly soluble drugs will interact with mucus glycoprotein. Studies of the permeability of native or purified mucous gels are important when it comes to understanding the relative importance of hindered diffusion versus drug binding in mucous layers. This review highlights the current understanding of the drug-mucin interaction and also examines briefly the interaction of polymers and particles with the mucus matrix. While the concept of mucoadhesion was thought to provide an intensified and prolonged contact to mucosal absorption sites, mucopenetrating properties are nowadays being discussed for (nano)particulate carriers to overcome the mucus as a barrier and enhance drug delivery through mucus. PMID- 23727594 TI - A highly sustainable and versatile granulation method of nanodrugs via their electrostatic adsorption onto chitosan microparticles as the granulation substrates. AB - Nanodrugs play important roles in enhancing the sustainability of pharmaceutical manufacturing via their ability to enhance the bioavailability of poorly soluble drugs, resulting in less drug wastage and less mass/energy consumed in their manufacturing. Despite their sustainability enhancement capability, solid dosage form manufacturing of nanodrugs remains lacking from the sustainability perspective. One example is the granulation of nanodrugs prior to tablet preparation, where existing methods (e.g. wet granulation, spray granulation, spray drying) require high energy and time expenses, or are highly intricate often leading to product inconsistencies. Herein we present an alternative nanodrug granulation method via electrostatic adsorption of the nanodrugs onto chitosan microparticles acting as granulation substrates. The method is sustainable involving only mixing of aqueous suspensions of the nanodrugs and substrates under ambient conditions, followed by washing and drying. We investigate the effects of substrate's physical characteristics and nanodrug to substrate ratio on the nanodrug loading in the granules, content uniformity, nanodrug recovery, and granule flowability. Ciprofloxacin and curcumin nanoplexes prepared by drug-polyelectrolyte complexation are used as the model nanodrugs with neutrally, positively, and negatively charged chitosan microparticles as the substrates. Granules having 25% (w/w) nanodrug loading at 50% (w/w) recovery with good flowability have been successfully prepared. PMID- 23727595 TI - A new phylogeny of tetraodontiform fishes (Tetraodontiformes, Acanthomorpha) based on 22 loci. AB - Tetraodontiform fishes represent one of the most peculiar radiations of teleost fishes. In spite of this, we do not currently have a consensus on the phylogenetic relationships among the major tetraodontiform lineages, with different morphological and molecular datasets all supporting contrasting relationships. In this paper we present the results of the analysis of tetraodontiform interrelationships based on two mitochondrial and 20 nuclear loci for 40 species of tetraodontiforms (representing all of the 10 currently recognized families), as well as three outgroups. Bayesian and maximum likelihood analyses of the concatenated dataset (18,682 nucleotides) strongly support novel relationships among the major tetraodontiform lineages. Our results recover two large clades already found in mitogenomic analyses (although the position of triacanthids differ), while they strongly conflict with hypotheses of tetraodontiform relationships inferred by previous studies based on morphology, as well as studies of higher-level teleost relationships based on nuclear loci, which included multiple tetraodontiform lineages. A parsimony gene-tree, species tree analysis recovers relationships that are mostly congruent with the analyses of the concatenated dataset, with the significant exception of the position of the pufferfishes+porcupine fishes clade. Our findings suggest that while the phylogenetic placement of some tetraodontiform lineages (triacanthids, molids) remains problematic even after sequencing 22 loci, an overall molecular consensus is beginning to emerge regarding the existence of several major clades. This new hypothesis will require a re-evaluation of the phylogenetic usefulness of several morphological features, such as the fusion of several jaw bones into a parrot like beak, or the reduction and loss of some of the fins, which may have occurred independently more times than previously thought. PMID- 23727596 TI - Integrative analysis of DNA phylogeography and morphology of the European rose chafer (Cetonia aurata) to infer species taxonomy and patterns of postglacial colonisation in Europe. AB - Integrative taxonomy has been proposed as a framework to unify new conceptual and methodological developments in quantitative assessment of trait variation used in species delimitation, but empirical studies in this young branch of systematics are rare. Here we use standard phylogenetic and parsimony network analyses on nuclear and mitochondrial DNA (Cox1, ITS1) of 230 individuals from 65 European sampling sites in order to deduce population structure of Cetonia beetles from geno- and haplotypes. Statistical measures of population differentiation are inferred on genealogical and geographical scales to test hypotheses about species limits and population history. By combining results of phylogenetic structure with features of morphology, including genital shape morphometrics and discrete external body characters, as well as with measures of population genetics, we attempt to integrate the results as a test of the validity of species limits, in particular of currently recognised subspecies. Despite high Cox1 divergence between some haplotype lineages, even some sympatric lineages (9%, e.g. N2 vs. N4), nDNA and morphology, as well as pattern of geographical and genealogical divergence measured by AMOVA analysis did not support the hypothesis of separate species. Highest divergence in nuclear markers was found among Italian populations of C. aurata pisana and C. a. sicula, and moderately high fixation indices along measurable morphological divergence suggest the correctness of their status as 'subspecies'. Divergence time estimates of the lineages suggest a glacial divergence in different refugia between the major haplogroups, while population differentiation in mtDNA among these was primarily attributable to restricted gene flow caused by geographic isolation. PMID- 23727597 TI - Optimal control in the critical phase of movement: a functional approach to motor planning processes. AB - Grasping movements are often planned in a way that they end in a position where joints are in an anatomically medial position. This behaviour is termed the "end state comfort" (ESC) effect (Rosenbaum et al., 1990). We suggest that the anatomically medial position is favoured to control the most difficult part of the movement. In most experiments investigating ESC, objects have to be placed onto a target location, and the highest precision demand occurs at the end of the movement. Thus, ESC is confounded with movement difficulty. In this study, we dissociate movement difficulty and ESC. In our experiments, participants had to execute a task where the critical part of the movement was either at the end or at the beginning of the movement. Participants' grasping behaviour confirmed the hypothesis that movement planning is constrained by a goal for optimal control during the part of the movement that demands the highest precision, rather than by a goal to end in a comfortable state (Rosenbaum, Chapman, Weigelt, Weiss, & van der Wel, 2012). We identified recall and movement plan generating processes of motor planning (Cohen & Rosenbaum, 2004), that ensure the optimal control in the critical part of movement. Our results indicate that recall processes depend on motor experience which is acquired in different time scales. We suggest that motor planning processes are triggered only if the costs for executing movements controlled by recall processes exceed the costs for generating a motor plan. PMID- 23727598 TI - Interactive effects of xenobiotic, abiotic and biotic stressors on Daphnia pulex- results from a multiple stressor experiment with a fractional multifactorial design. AB - Pollutant effects on aquatic key species are confounded by multiple abiotic and biotic stressors. To better discriminate and understand the intrinsic and environmental correlates of changing aquatic ecosystems, we untangle in present study how the effects of a low-dosed fungicide on daphnids (via different exposure routes) becomes modified by increasing temperature and the presence of a predator. Using a fractional multifactorial test design, the individual growth, reproduction and population growth rate of Daphnia pulex were investigated under exposure to the fungicide pyrimethanil at an environmental relevant concentration -either directly (via the water phase), indirectly (via food), dually (via water and food) or for multiple generations (fungicide treated source population)--at three temperatures and in presence/absence of the predator kairomones of Chaoborus flavicans. Our results clearly illustrate that multiple stress factors can modify the response of an aquatic key species to pollutants. The environmentally relevant exposure of the contaminant via food or the medium is of same importance. Nevertheless, temperature and the presence of a predator are the dominant factors controlling the reproduction of D. pulex. We conclude that sublethal pyrimethanil pollution can disturb the zooplankton community at suboptimal temperature conditions, but the effects will become masked by low temperatures or if chaoborid larvae are present. PMID- 23727599 TI - Clinical scaphoid score (CSS) to identify scaphoid fracture with MRI in patients with normal x-ray after a wrist trauma. AB - INTRODUCTION: The aim of this study was to compare a combination of three commonly used tests to identify scaphoid fractures with MRI in patients with normal x-ray after a wrist trauma. PATIENTS AND METHODS: This prospective MRI study included patients between 18 years and 49 years, who attended the Emergency Department, Bergen, Norway after sustaining an acute wrist trauma within the previous week. Initial x-rays of the wrist were normal. MRI was done within a median of 1 day after the trauma. The study period lasted 1 year. The patients were examined with three commonly used clinical scaphoid tests; tenderness in the anatomical snuffbox with the wrist in ulnar deviation (3 points), tenderness over the scaphoid tubercle (2 points) and pain upon longitudinal compression of the thumb (1 point). The clinical scaphoid score (CSS) is a sum of these points, which was compared with MRI verified fracture of the scaphoid. RESULTS: We included 154 patients with wrist sprain and normal x-rays; 13 had occult scaphoid fracture. A CSS of 4 or more was the only statistically significant 'cut-off' value to identify occult scaphoid fractures (p<0.05). Diagnostic sensitivity increased with more experienced Emergency Department doctors. CONCLUSIONS: If a patient with wrist pain after injury and normal x-ray has a CSS>=4 (pain in the anatomical snuffbox in addition to pain at scaphoid tubercle or longitudinal compression or both) we recommend MRI. A CSS <4 has a negative predictive value of 96%, which makes scaphoid fracture unlikely. PMID- 23727600 TI - Spatiotemporal modeling of soil organic carbon stocks across a subtropical region. AB - Given the significance and complex nature of soil organic carbon in the context of the global carbon cycle, the need exists for more accurate and economically feasible means of soil organic carbon analysis and its underlying spatial variation at regional scale. The overarching goal of this study was to assess both the spatial and temporal variability of soil organic carbon within a subtropical region of Florida, USA. Specifically, the objectives were to: i) quantify regional soil organic carbon stocks for historical and current conditions and ii) determine whether the soils have acted as a net sink or a net source for atmospheric carbon-dioxide over an approximate 40 year time period. To achieve these objectives, geostatistical interpolation models were used in conjunction with "historical" and "current" datasets to predict soil organic carbon stocks for the upper 20 cm soil profile of the study area. Soil organic carbon estimates derived from the models ranged from 102 to 108 Tg for historical conditions and 211 to 320 Tg for current conditions, indicating that soils in the study area have acted as a net sink for atmospheric carbon over the last 40 years. A paired resampling of historical sites supported the geostatistical estimates, and resulted in an average increase of 0.8 g carbon m(-2) yr(-1) across all collocated samples. Accurately assessing the spatial and temporal state of soil organic carbon at regional scale is critical to further our understanding of global carbon stocks and provide a baseline so that the effects sustainable land use policy can be evaluated. PMID- 23727601 TI - Systemic solutions for multi-benefit water and environmental management. AB - The environmental and financial costs of inputs to, and unintended consequences arising from narrow consideration of outputs from, water and environmental management technologies highlight the need for low-input solutions that optimise outcomes across multiple ecosystem services. Case studies examining the inputs and outputs associated with several ecosystem-based water and environmental management technologies reveal a range from those that differ little from conventional electro-mechanical engineering techniques through methods, such as integrated constructed wetlands (ICWs), designed explicitly as low-input systems optimising ecosystem service outcomes. All techniques present opportunities for further optimisation of outputs, and hence for greater cumulative public value. We define 'systemic solutions' as "...low-input technologies using natural processes to optimise benefits across the spectrum of ecosystem services and their beneficiaries". They contribute to sustainable development by averting unintended negative impacts and optimising benefits to all ecosystem service beneficiaries, increasing net economic value. Legacy legislation addressing issues in a fragmented way, associated 'ring-fenced' budgets and established management assumptions represent obstacles to implementing 'systemic solutions'. However, flexible implementation of legacy regulations recognising their primary purpose, rather than slavish adherence to detailed sub-clauses, may achieve greater overall public benefit through optimisation of outcomes across ecosystem services. Systemic solutions are not a panacea if applied merely as 'downstream' fixes, but are part of, and a means to accelerate, broader culture change towards more sustainable practice. This necessarily entails connecting a wider network of interests in the formulation and design of mutually-beneficial systemic solutions, including for example spatial planners, engineers, regulators, managers, farming and other businesses, and researchers working on ways to quantify and optimise delivery of ecosystem services. PMID- 23727602 TI - Relationship between polycyclic aromatic hydrocarbons (PAHs) and particle size in dated core sediments in Lake Lianhuan, Northeast China. AB - Atmospheric particle associated with pyrogenic polycyclic aromatic hydrocarbons (PAHs) poses serious threats to human health by inhalation exposure, especially in semiarid areas. Hence, the distributions of PAHs and particle size in two core sediments collected from Lake Lianhuan, Northeast China were studied. The sediments were dated radiometrically, and particle size distribution and PAH concentration were evaluated and potential human health risk was assessed. From 1980 to 2007, the dominant PAHs in the two cores were 2- and 3-ring PAHs, and the concentrations of 3-6 ring PAHs gradually increased from the early 1990s. Diagnostic ratios indicated that pyrogenic PAHs were the main sources of PAHs which changed over time from combustions of wood and coal to liquid fossil fuel sources. Fine particles (<65 MUm) were the predominant particle size (56-97%). Lacustrine source (with the peak towards 200-400 MUm) and eolian sources derived from short (2.0-10 and 30-65 MUm) and long (0.4-1.0 MUm) distance suspension were indentified from frequency distribution pattern of particle size. Significant correlations between 3-6 ring PAHs (especially carcinogenic 5-6 ring PAHs) and 10 35 MUm particulate fractions indicated that eolian particles played an important role in adsorbing pyrogenic PAHs. Petroleum source of PAHs was only identified during the 1980s in one core sediments, in which positive correlations between 2 ring PAHs and particulate fractions of >125 MUm were found. Future research should focus on the seven carcinogenic pyrogenic PAHs due to a rapidly increasing trend since 1995 based on the assessment of toxic equivalency factors. PMID- 23727603 TI - Organochlorine accumulation on a highly consumed bivalve (Scrobicularia plana) and its main implications for human health. AB - Contamination by polychlorinated biphenyls (PCBs) and hexachlorobenzene (HCB) was investigated along a spatial gradient in water, sediments and in commercially important bivalve species Scrobicularia plana, from Ria de Aveiro (Portugal). Organochlorines dissolved in water were below detection limit and concerning suspended particulate matter, only PCBs were quantified, ranging from 3.8 to 5.8 ng?g(-1) DW (Sigma13PCBs). There was a distinct spatial gradient regarding PCB accumulation in sediments. The highest concentrations were found in deeper layers and closest to the pollution source, decreasing gradually along a 3 km area. Contamination in sediments exceeded the Canadian and Norwegian sediment quality guidelines, inducing potential toxic effects in related biota. PCBs tended to bioaccumulate throughout S. plana lifespan but with different annual rates along the spatial gradient. The maximum values were found in older individuals up to 3+ years old, reaching 19.4 ng?g(-1) DW. HCB concentrations were residual and no bioaccumulation pattern was evident. Congeners 138, 153 and 180 were the most accumulated due to their abundance and long-term persistence in the environment. In the inner area of the Laranjo Bay (0.6 km(2)), the species was able to remove up to 0.4 g of PCBs annually from sediments into their own tissues, which is consequently free for trophic transfer (biomagnification). Concerning human health, and despite the high concentrations found in sediments, PCB levels in bivalves do not exceed the limit established by the European Union for fishery products and are largely below tolerable daily intake. Although PCBs in Scrobicularia plana are present at low levels, their impact to human health after consumption over many years might be harmful and should be monitored in future studies. PMID- 23727604 TI - The HMGB1-TLR4 axis contributes to myocardial ischemia/reperfusion injury via regulation of cardiomyocyte apoptosis. AB - Toll-like receptor 4 (TLR4) and its ligand high mobility group box 1 (HMGB1), are known for playing central roles in ischemia-reperfusion injury in myocardium. However, the detailed mechanisms of TLR4 and HMGB1 are not fully understood. The aim of this study was to investigate the effects and possible mechanisms of the HMGB1-TLR4 axis and cardiomyocyte apoptosis on myocardial ischemic damage. Artificial oxygen ventilated anesthetized C3H/HeN mice and C3H/HeJ mice were subjected to 30 min of left anterior descending coronary artery occlusion followed by 6h of reperfusion. The myocardial infarct size, HMGB1 levels, apoptosis index, Bax, Bcl-2 and TNF-alpha mRNA levels were assessed. The results showed that a lowered amount of cardiomyocyte apoptosis and infarct size in the myocardium of TLR4-mutant mice after myocardial I/R and that TLR4 deficiency notably inhibited the expression of HMGB1 and TNF-a, both of which were up regulated by ischemia/reperfusion. These findings suggest that the HMGB1-TLR4 axis plays a pathogenic role in triggering cardiomyocyte apoptosis during myocardial I/R injury and that the possible mechanism for this process is the result of released cytokines and inflammatory response involved in the HMGB1/TLR4 related pathway. PMID- 23727605 TI - A report of two cases of Al-Awadi Raas-Rothschild syndrome (AARRS) supporting that "apparent" Phocomelia differentiates AARRS from Schinzel Phocomelia syndrome (SPS). AB - Although there is a long list of syndromes with phocomelia, there are only two syndromes in which there is concurrent pelvic dysplasia and phocomelia: Al-Awadi Raas-Rothschild syndrome (AARRS) and Schinzel phocomelia syndrome (SPS). Currently, there is a diagnostic confusion between the two syndromes and both have the same MIM entry (MIM 276820). We believe that the two syndromes are different entities and we also believe that the limb defect in SPS is a "true" phocomelia while the limb defect in AARRS is an "apparent" phocomelia. "Apparent" phocomelia describes the most severe form of ulnar ray deficiency in which there is absent ulna with radio-humeral synostosis. "Apparent" phocomelia is diagnosed radiologically by three radiological features: the apparently single bone occupying the arm/forearm appears relatively long, the area of radio-humeral synostosis will have thicker cortex with or without slight angulation, and the lower end of the bone resembles the lower end of a radius and not a humerus. In this paper, we present two new cases of AARRS from two different Saudi Arabian tribes: one case with R292C mutation of WNT7A with bilateral "apparent" phocomelia and a second case with a novel c.814G>T mutation of the WNT7A gene (resulting in wnt7a protein truncation at position 272) with unilateral "apparent" phocomelia. We reviewed previously reported cases of AARRS and SPS to further delineate the differences between these two syndromes. We make the argument that these two syndromes are two different entities and hence require two different MIM entries. PMID- 23727606 TI - Association of ERCC1-C118T and -C8092A polymorphisms with lung cancer risk and survival of advanced-stage non-small cell lung cancer patients receiving platinum based chemotherapy: a pooled analysis based on 39 reports. AB - The published data on the predictive role of ERCC1 polymorphisms in lung cancer risk and survival of patients with advanced non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy remains inconsistent. The aim of this meta analysis was to determine the role of ERCC1 gene polymorphisms (C118T and C8092A) in this clinical situation. Eligible studies were included and assessed for quality using multiple search strategies. Thirty-nine published papers involving 9615 cases (4606 with Stage III/IV disease) and 5542 controls were included in the analysis. Pooled odds ratios (OR) or hazard ratios (HR) with 95% confidence intervals (CI) were used to estimate risk. ERCC1-C118T was associated with lung cancer risk. The OR was 0.90 (95% CI: 0.81-0.99, p=0.043) in an additive genetic model (C allele vs. T allele) and 0.77 (95% CI: 0.63-0.95, p=0.013) in a recessive genetic model (CC/CT vs. TT). The corresponding risk was 0.74 (95% CI: 0.58-0.94, p=0.013) based on a homozygous comparison (CC vs. TT). No significant correlation was found for ERCC1 C8092A and there was no obvious relationship between ERCC1 C118T/C8092A polymorphisms and objective response to platinum-based chemotherapy. Overall survival (OS) of patients with non-small cell lung cancer (NSCLC) receiving platinum-based chemotherapy was significantly related to ERCC1 C118T (HR: 1.29, 95% CI: 1.07-1.56, p=0.007, CT/TT vs. CC). There was no relationship between ERCC1 C8092A and survival (HR: 1.32, 95% CI: 0.84-2.10, p=0.23, CA/AA vs. CC). These findings suggest that ERCC1 C118T polymorphisms may serve as a biomarker for lung cancer risk and have prognostic value in patients with advanced non-small cell lung cancer (NSCLC) undergoing platinum-based treatment. Further studies with larger numbers of subjects from a worldwide arena are needed to validate the associations. PMID- 23727607 TI - MH-DAB gene polymorphism and disease resistance to Flavobacterium columnare in grass carp (Ctenopharyngodon idellus). AB - In this study, the association between MH-DAB gene polymorphism and disease resistance was evaluated by challenging grass carp (Ctenopharyngodon idellus) with Flavobacterium columnare. Eight genotypes and six alleles were found, and named by common nomenclature. The genotypes AA, BB, EE, and DE, and the alleles Ctid-DAB1*0101, Ctid-DAB1*0201 and Ctid-DAB1*0401 were more preponderant in fish. The genotype BB was associated with higher resistance to F. columnare, as well as two alleles Ctid-DAB*0101 and Ctid-DAB*0201. Allele Ctid-DAB*0102 has decreased resistance to F. columnare. The expression of MH-DAB gene was decreased in the liver, kidney, and intestine but not in the spleen, gill, and skin at 2 days post infection (dpi), versus to that in the control group. MH-DAB gene expression was up-regulated in most tissues but remained at normal levels in the intestine at 15 days post infection. Our data suggested that MH-DAB polymorphism can be used as a potential genetic marker for disease resistance breeding of grass carp in the future. PMID- 23727608 TI - Analyzing the suppression of respiratory defects in the yeast model of human mitochondrial tRNA diseases. AB - The respiratory defects associated with mutations in human mitochondrial tRNA genes can be mimicked in yeast, which is the only organism easily amenable to mitochondrial transformation. This approach has shown that overexpression of several nuclear genes coding for factors involved in mitochondrial protein synthesis can alleviate the respiratory defects both in yeast and in human cells. The present paper analyzes in detail the effects of overexpressed yeast and human mitochondrial translation elongation factors EF-Tu. We studied the suppressing activity versus the function in mt translation of mutated versions of this factor and we obtained indications on the mechanism of suppression. Moreover from a more extended search for suppressor genes we isolated factors which might be active in mitochondrial biogenesis. Results indicate that the multiplicity of mitochondrial factors as well as their high variability of expression levels can account for the variable severity of mitochondrial diseases and might suggest possible therapeutic approaches. PMID- 23727609 TI - Replication study of STAT4 rs7574865 G/T polymorphism and risk of rheumatoid arthritis in a Chinese population. AB - AIM: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are common systemic autoimmune diseases with genetic and environmental predisposing factors. Signal transducer and activator of transcription 4 (STAT4) transmits signals induced by interleukin-12, interleukin-23 and interferon-gamma, which are key cytokines and play important roles in the development of autoimmune diseases. Previous studies confirmed the STAT4 rs7574865 G/T locus to be associated with RA. Thus we conducted a replication study to investigate STAT4 rs7574865 G/T polymorphism and RA/AS susceptibility in a Chinese population. METHODS: We studied STAT4 rs7574865 G/T gene polymorphism in 520 patients with RA, 100 AS patients and 520 controls in a Chinese population. Genotyping was done using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). RESULTS: When the STAT4 rs7574865 GG homozygote genotype was used as the reference group, the GT or GT/TT genotypes were associated with the risk for RA. After stratification analyses, a significantly increased risk for RA associated with the STAT4 rs7574865 GT genotype was evident among the rheumatoid factor (RF)-positive patients, patients with higher erythrocyte sedimentation rate (ESR) level and patients with higher RA disease activity score (DAS28) compared with the STAT4 rs7574865 GG genotype. A significantly increased risk for RA associated with the STAT4 rs7574865 TT genotype was evident among older patients and RF-negative patients compared with the STAT4 rs7574865 GG genotype. STAT4 rs7574865 G/T was not associated with susceptibility to AS. CONCLUSION: This replication study confirmed that STAT4 rs7574865 G/T polymorphism was associated with the risk of RA. CONDENSED ABSTRACT: STAT4 polymorphisms are associated with rheumatoid arthritis risk. PMID- 23727610 TI - Single nucleotide polymorphism in hMLH1 promoter and risk of tobacco-related oral carcinoma in high-risk Asian Indians. AB - hMLH1 is a member of mismatch repair genes (MMR) that plays a crucial role in correcting replication errors, cell cycle arrest, apoptosis and oxidative stress. We explored the risk associated with hMLH1 -93 A>G (rs 1800734) single nucleotide polymorphism (SNP) with the oral squamous cell carcinoma (OSCC) in Asian Indians. We genotyped 242 patients with tobacco-related OSCC and 205 healthy controls by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The frequency of AA genotype was found to be significantly (Pc<0.0006) lower in patients as compared to the controls (21.49% vs. 47.8%) while GG genotype showed significantly higher (Pc<0.0006) prevalence in patients as compared to the healthy controls (41.32% vs. 13.66%). In logistic regression analysis AG (adjusted OR=1.95, 95% CI=0.72-5.26) and GG genotype (adjusted OR=4.5, 95% CI=1.54-13.16, P=0.006) appeared susceptible when compared with the wild-type AA genotype. The allelic distribution showed that variant G allele is significantly higher (Pc<0.0004) in patients and associated with increased risk (adjusted OR=2.36, 95% CI=1.33-4.19, P=0.003) as compared to the wild-type A allele. Altogether, our results suggest that the hMLH1 -93 A>G polymorphism is associated with the higher risk of tobacco-related OSCC in Asian Indians and could be useful in screening population at a higher risk. PMID- 23727611 TI - COPI-mediated blood meal digestion in vector mosquitoes is independent of midgut ARF-GEF and ARF-GAP regulatory activities. AB - We have previously shown that defects in COPI coatomer proteins cause 80% mortality in blood fed Aedes aegypti mosquitoes by 96 h post-feeding. In this study we show that similar deficiencies in COPII and clathrin mediated vesicle transport do not disrupt blood meal digestion and are not lethal, even though both COPII and clathrin functions are required for ovarian development. Since COPI vesicle transport is controlled in mammalian cells by upstream G proteins and associated regulatory factors, we investigated the function of the orthologous ADP-ribosylation factor 1 (ARF1) and ARF4 proteins in mosquito tissues. We found that both ARF1 and ARF4 function upstream of COPI vesicle transport in blood fed mosquitoes given that an ARF1/ARF4 double deficiency is required to phenocopy the feeding-induced mortality observed in COPI coatomer deficient mosquitoes. Small molecule inhibitors of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) are often transitory, and therefore, we investigated the role of five Ae. aegypti ARF-GEF and ARF-GAP proteins in blood meal digestion using RNA interference. Surprisingly, we found that ARF-GEF and ARF-GAP functions are not required for blood meal digestion, even though both vitellogenesis and ovarian development in Ae. aegypti are dependent on GBF1 (ARF-GEF) and GAP1/GAP2 (ARF-GAPs) proteins. Moreover, deficiencies in orthologous COPI regulating genes in Anopheles stephensi mosquitoes had similar phenotypes, indicating conserved functions in these two mosquito species. We propose that based on the need for rapid initiation of protein digestion and peritrophic membrane formation, COPI vesicle transport in midgut epithelial cells is not dependent on ARF-GEF and ARF-GAP regulatory proteins to mediate vesicle recycling within the first 48 h post-feeding. PMID- 23727612 TI - The role of desaturases in the biosynthesis of marking pheromones in bumblebee males. AB - Bumblebee males (Hymenoptera) produce species-specific labial gland secretions called marking pheromones (MPs). MPs generally consist of terpenoids and fatty acid-derived aliphatic compounds with various chain lengths predominantly containing one or no double bonds. The unsaturated fatty-acid-derived MP components were hypothesized to be produced by fatty acid desaturases (FADs) that exhibit diverse substrate specificities. To address this hypothesis, we isolated and functionally characterized FADs from three bumblebee species: Bombus lucorum, Bombus terrestris, and Bombus lapidarius. By employing RNA sequencing of the male labial glands and fat bodies of B. lucorum and B. terrestris, we identified five paralogous FAD-like sequences but only two FAD lineages were abundant and differentially expressed in the labial glands. We found that abundant FAD lineages were also expressed in the labial gland and fat body of Bombus lapidarius. Functional characterization of FADs in a yeast expression system confirmed that Delta4-FADs exhibited a unique Delta4-desaturase activity exclusively on 14-carbon fatty acyls and Delta9-FADs displayed Delta9-desaturase activity on 14- to 18-carbon fatty acyls. These results indicate that Delta9-FADs are involved in the biosynthesis of major unsaturated components of MPs in B. lucorum and B. lapidarius despite the diverse MP composition of these bumblebee species. The contribution of lipases, acyltransferases, esterases, and fatty acid reductases to production of the species-specific MP composition is also discussed in light of the transcriptomic data obtained in this study. PMID- 23727613 TI - On the haptic nature of the active electric sense of fish. AB - Electroreception is a sensory modality present in chondrichthyes, actinopterygii, amphibians, and mammalian monotremes. The study of this non-intuitive sensory modality has provided insights for better understanding of sensory systems in general and inspired the development of innovative artificial devices. Here we review evidence obtained from the analysis of electrosensory images, neurophysiological data from the recording of unitary activity in the electrosensory lobe, and psychophysical data from analysis of novelty responses provoked in well-defined stimulus conditions, which all confirm that active electroreception has a short range, and that the influence of exploratory movements on object identification is strong. In active electric images two components can be identified: a "global" image profile depending on the volume, shape and global impedance of an object and a "texture" component depending on its surface attributes. There is a short range of the active electric sense and the progressive "blurring" of object image with distance. Consequently, the lack of precision regarding object location, considered together, challenge the current view of this sense as serving long range electrolocation and the commonly used metaphor of "electric vision". In fact, the active electric sense shares more commonalities with human active touch than with teleceptive senses as vision or audition. Taking into account that other skin exteroceptors and proprioception may be congruently stimulated during fish exploratory movements we propose that electric, mechanoceptive and proprioceptive sensory modalities found in electric fish could be considered together as a single haptic sensory system. This article is part of a Special Issue entitled Neural Coding 2012. PMID- 23727614 TI - Enhancement of FGF-1 release along with cytosolic proteins from rat astrocytes by hydrogen peroxide. AB - We previously observed that the production and release of fibroblast growth factor (FGF-1) are increased in rat astrocytes during in vitro long-term culture, that FGF-1 enhances the generation of apoE-containing high density lipoproteins (apoE/HDL), and that the wound healing of brain cryoinjury delays in apoE deficient mouse. The detail mechanism underlying these phenomena remains unknown. In this study, we examined effects of oxidative stress on release of FGF-1 from cultured rat astrocytes. The treatment of rat astrocytes with 100uM hydrogen peroxide (H2O2) for 10min enhanced FGF-1 release without inducing apoptosis. The conditioned medium prepared from the cells cultured in a fresh medium after the treatment with H2O2 had the FGF-1-like activities, which enhanced cholesterol synthesis, signalings to phosphorylate Akt and ERK, and apoE secretion. The oxidative stress induced by H2O2 enhanced the release of cytosolic proteins such as HSP70 and HSP90 in addition to FGF-1. Antioxidants such as ascorbic acid and ebselen suppressed the release of cytosolic proteins induced by H2O2 treatment. The addition of lipoproteins such as low density lipoproteins (LDL), furthermore, canceled H2O2-induced release of FGF-1 and cytosolic proteins. Proteolysis of cytosolic proteins in the H2O2-treated rat astrocytes was enhanced in the presence of exogenous trypsin, which was attenuated by the pretreatment with LDL, suggesting that H2O2 increases the permeability of the membrane of cells, which was prevented by the addition of lipoproteins. These findings suggest that oxidative stress is one of the candidates which triggers FGF-1 release from astrocytes in the brain, and that the lipid homeostasis in the cell membrane may regulate H2O2-induced release of FGF-1. PMID- 23727615 TI - Fabrication of hierarchical micro-nanotopographies for cell attachment studies. AB - We report on the development of micro/nanofabrication processes to create hierarchical surface topographies that expand from 50 nm to microns in size on different materials. Three different approaches (named FIB1, FIB2, and EBL) that combine a variety of techniques such as photolithography, reactive ion etching, focused ion beam lithography, electron beam lithography, and soft lithography were developed, each one providing different advantages and disadvantages. The EBL approach was employed to fabricate substrates comprising channels with features between 200 nm and 10 MUm in size on polymethylmethacrylate (PMMA), which were then used to investigate the independent or competitive effects of micro- and nanotopographies on cell adhesion and morphology. Rat mesenchymal stem cells (rMSCs) were cultured on four different substrates including 10 MUm wide and 500 nm deep channels separated by 10 MUm distances (MICRO), 200 nm wide and 100 nm deep nanochannels separated by 200 nm distances (NANO), their combination in parallel (PARAL), and in a perpendicular direction (PERP). Rat MSCs behaved differently on all tested substrates with a high degree of alignment (as measured by both number of aligned cells and average angle) on both NANO and MICRO. Furthermore, cells exhibited the highest level of alignment on PARAL, suggesting a synergetic effect of the two scales of topographies. On the other hand, cells on PERP exhibited the lowest alignment and a consistent change in morphology over time that seemed to be the result of interactions with both micro- and nanochannels positioned in the perpendicular direction, also suggesting a competitive effect of the topographies. PMID- 23727616 TI - Spatial arrangement of selected fluorescence labels in lipid bilayer. AB - The method for the determination the orientation factor kappa(2), spatial arrangement and depth position of fluorescence labels located in hydrophilic layers of vesicles bilayer from resonance energy transfer (RET) data is presented. The method is based on the broadened Wolber and Hudson RET model in two dimensions (Biophys J. 1979). The vesicles were labeled with N-(7-nitrobenz-2 oxa-1,3-diazol-4-yl)-1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine (NBD-PE) as the donor and N-(Lissamine rhodamine B sulfonyl) 1,2-dihexadecanoyl-sn-glycero 3-phosphoethanolamine (NRh-PE) as the acceptor. It was found that in basic environment sodium dithionite quenches fluorescence of both labels located in outer leaflet of bilayer. Therefore, RET data prior to and following dithionite treatment were compared and the donor-acceptor cis and trans distances of the closest approach as well as cis and trans Forster radii R0, and orientation factors kappa(2) for cis RET equal to 0.61+/-0.06 and for trans RET equal to 0.17+/-0.01 were assigned. Knowing the kappa(2) data, the spatial arrangement of NBD and NRh labels as dipoles in dipalmitoylphosphatidylcholine bilayer were described. PMID- 23727617 TI - Two novel copper complexes of 2,2'-bipyridine: evaluation of the DNA binding and cytotoxic activity. AB - Two novel copper-2,2'-bipyridine complexes [Cu(SAL)(2,2'-bipy)ClO4]2 (1) and [Cu(MU2-O)(2,2'-bipy)NO3]2 (2) (HSAL=salicylaldehyde) were synthesized and characterized by X-ray single-crystal diffraction, elemental analysis and IR spectra. The interactions of the complexes with salmon sperm DNA were investigated by viscosity analysis, UV, fluorescence and circular dichroism (CD) spectroscopic techniques. Absorption spectral (Kb=3.00*10(5)M(-1) (1), 3.49*10(5)M(-1)(2)), emission spectral ((Ksv) 3.33*10(4)M(-1) (1), 3.40*10(4)M( 1) (2)), and viscosity measurements reveal that 1 and 2 interact with DNA through intercalation. In fluorimetric studies, the enthalpy (DeltaH>0) and entropy (DeltaS>0) changes of the reactions between the Cu (II) complexes with DNA demonstrate hydrophobic interactions. In addition, CD study indicates the Cu (II) complexes cause a more B-like to a more A-like conformational change upon binding DNA. All the experimental results show that the interaction mode of the two complexes was greatly affected by the coordination environments of Cu (II) centers. Their in vitro cytotoxicity towards five selected tumor cell lines HepG 2, HeLa, NCI-H460, MCF-7 and HL-60 has been evaluated by MTT method, and 2 exhibits higher growth inhibition of the selected cell lines at concentration of 50 MUM, this result is identical with their DNA binding ability order. PMID- 23727618 TI - Do local unemployment rates modify the effect of individual labour market status on psychological distress? AB - This study investigates whether the unemployment rate of the area in which an individual lives affects their level of psychological distress, and the extent to which this is dependent on their own labour market status. Data were taken from the British Household Panel Survey (1991-2008) and longitudinal multiple membership multilevel modelling was carried out in order to account for the complex hierarchical structure of the data. The results suggest that living in an area with a high unemployment rate, defined by the claimant count, confers a degree of protection against the negative psychological effects of unemployment. However, psychological distress levels among unemployed people were still significantly and substantially higher than among their securely employed counterparts. PMID- 23727619 TI - An evaluation of an urban renewal program and its effects on neighborhood resident's overall wellbeing using concept mapping. AB - Urban renewal programs aim to improve physical and socioeconomic position of neighborhoods. However, due to the intervention's complexity, there is often little evidence of their impact on health and health inequalities. This study aimed to identify the perception of a group of neighborhood residents towards a large-scale urban renewal program in Barcelona and to explore its effects and importance on their wellbeing using concept mapping methodology. Our results indicate that the majority of urban renewal projects within the initiative, including improved walkability, construction of new public spaces and more community programs, have positive and important effects on the overall wellbeing of participants. This study presents an innovative method that diverts from traditional outcome-based evaluations studies often used within this field. PMID- 23727620 TI - Understanding reasons for participating in a school-based influenza vaccination program and decision-making dynamics among adolescents and parents. AB - Influenza remains a significant cause of morbidity and mortality in the United States. Vaccinating school-aged children has been demonstrated to be beneficial to the child and in reducing viral transmission to vulnerable groups such as the elderly. This qualitative study sought to identify reasons parents and students participated in a school-based influenza vaccination clinic and to characterize the decision-making process for vaccination. Eight focus groups were conducted with parents and students. Parents and students who participated in the influenza vaccination clinic stated the educational brochure mailed to their home influenced participation in the program. Parents of non-participating students mentioned barriers, such as the lengthy and complicated consent process and suspicions about the vaccine clinic, as contributing to their decision not to vaccinate their child. Vaccinated students reported initiating influenza vaccine discussion with their parents. Parental attitudes and the educational material influenced parents' decision to allow their child to receive influenza vaccine. This novel study explored reasons for participating in a school-based vaccination clinic and the decision-making process between parents and child(ren). Persons running future school-based vaccination clinics may consider hosting an 'information session with a question and answer session' to address parental concerns and assist with the consent process. PMID- 23727621 TI - Exome sequencing: how to understand it. PMID- 23727622 TI - Polymorphism of inflammatory genes and arsenic methylation capacity are associated with urothelial carcinoma. AB - Chronic exposure to arsenic can generate reactive oxidative species, which can induce certain proinflammatory cytokines such as tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6) and interleukin-8 (IL-8). TNF-alpha, IL-6 and IL-8 have been shown to be involved in the development and progression of various cancers, including bladder cancer. This study aimed to investigate the joint effect of the polymorphism of TNF-alpha -308 G/A, IL-6 -174 G/C, IL-8 -251 T/A and urinary arsenic profiles on urothelial carcinoma (UC) risk. This study evaluated 300 pathologically-confirmed cases of UC and 594 cancer-free controls. Urinary arsenic species were detected using high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. The polymorphism of TNF-alpha -308 G/A, IL-6 -174 G/C and IL-8 -251 T/A was determined using polymerase chain reaction-restriction fragment length polymorphism. The joint effects on UC risk were estimated by odds ratios and 95% confidence intervals using unconditional logistic regression. We found that the TNF-alpha -308 A/A and IL-8 -251 T/T polymorphisms were significantly associated with UC. Moreover, significant dose-response joint effect of TNF-alpha -308 A/A or IL-8 -251 T/T genotypes and arsenic methylation indices were seen to affect UC risk. The present results also showed a significant increase in UC risk in subjects with the IL-8 -251 T/T genotype for each SD increase in urinary total arsenic and MMA%. In contrast, a significant decrease in UC risk was found in subjects who carried the IL-8 -251 T/T genotype for each SD increase in DMA%. PMID- 23727624 TI - Estrogen receptor-mediated signalling in female mice is locally activated in response to wounding. AB - Estrogen deprivation is associated with delayed healing, while Hormone Replacement Therapy (HRT) accelerates acute wound healing and protects against development of chronic wounds. Estrogen exerts its effects on healing via numerous cell types by signalling through the receptors ERalpha and ERbeta, which bind to the Estrogen Responsive Element (ERE) and initiate gene transcription. The ERE-luciferase transgenic mouse model has been influential in assessing real time in vivo estrogen receptor activation across a range of tissues and pathologies. Using this model we demonstrate novel temporally regulated peri wound activation of estrogen signalling in female mice. Using histological methods we reveal that this signal is specifically localised to keratinocytes of the neoepidermis and wound margin dermal cells. Moreover using pharmacological agonists we reveal that ERbeta induces ERE-mediated signal in both epidermal and dermal cells while ERalpha induces ERE-mediated signal in dermal cells alone. Collectively these novel data demonstrate rapid and regional activation of estrogen signalling in wounded skin. A more complete understanding of local hormonal signalling during repair is essential for the focussed development of new therapies for wound healing. PMID- 23727623 TI - Tissue factor pathway inhibitor prevents airway obstruction, respiratory failure and death due to sulfur mustard analog inhalation. AB - Sulfur mustard (SM) inhalation causes airway injury, with enhanced vascular permeability, coagulation, and airway obstruction. The objective of this study was to determine whether recombinant tissue factor pathway inhibitor (TFPI) could inhibit this pathogenic sequence. METHODS: Rats were exposed to the SM analog 2 chloroethyl ethyl sulfide (CEES) via nose-only aerosol inhalation. One hour later, TFPI (1.5mg/kg) in vehicle, or vehicle alone, was instilled into the trachea. Arterial O2 saturation was monitored using pulse oximetry. Twelve hours after exposure, animals were euthanized and bronchoalveolar lavage fluid (BALF) and plasma were analyzed for prothrombin, thrombin-antithrombin complex (TAT), active plasminogen activator inhibitor-1 (PAI-1) levels, and fluid fibrinolytic capacity. Lung steady-state PAI-1 mRNA was measured by RT-PCR analysis. Airway capillary leak was estimated by BALF protein and IgM, and by pleural fluid measurement. In additional animals, airway cast formation was assessed by microdissection and immunohistochemical detection of airway fibrin. RESULTS: Airway obstruction in the form of fibrin-containing casts was evident in central conducting airways of rats receiving CEES. TFPI decreased cast formation, and limited severe hypoxemia. Findings of reduced prothrombin consumption, and lower TAT complexes in BALF, demonstrated that TFPI acted to limit thrombin activation in airways. TFPI, however, did not appreciably affect CEES-induced airway protein leak, PAI-1 mRNA induction, or inhibition of the fibrinolytic activity present in airway surface liquid. CONCLUSIONS: Intratracheal administration of TFPI limits airway obstruction, improves gas exchange, and prevents mortality in rats with sulfur mustard-analog-induced acute lung injury. PMID- 23727625 TI - Rupture of the anterior cruciate ligament and bucket handle tear of the medial meniscus. PMID- 23727626 TI - Cochlear implant artifact attenuation in late auditory evoked potentials: a single channel approach. AB - Recent evidence suggests that late auditory evoked potentials (LAEP) provide a useful objective metric of performance in cochlear implant (CI) subjects. However, the CI produces a large electrical artifact that contaminates LAEP recordings and confounds their interpretation. Independent component analysis (ICA) has been used in combination with multi-channel recordings to effectively remove the artifact. The applicability of the ICA approach is limited when only single channel data are needed or available, as is often the case in both clinical and research settings. Here we developed a single-channel, high sample rate (125 kHz), and high bandwidth (0-100 kHz) acquisition system to reduce the CI stimulation artifact. We identified two different artifacts in the recording: 1) a high frequency artifact reflecting the stimulation pulse rate, and 2) a direct current (DC, or pedestal) artifact that showed a non-linear time varying relationship to pulse amplitude. This relationship was well described by a bivariate polynomial. The high frequency artifact was completely attenuated by a 35 Hz low-pass filter for all subjects (n = 22). The DC artifact could be caused by an impedance mismatch. For 27% of subjects tested, no DC artifact was observed when electrode impedances were balanced to within 1 kOmega. For the remaining 73% of subjects, the pulse amplitude was used to estimate and then attenuate the DC artifact. Where measurements of pulse amplitude were not available (as with standard low sample rate systems), the DC artifact could be estimated from the stimulus envelope. The present artifact removal approach allows accurate measurement of LAEPs from CI subjects from single channel recordings, increasing their feasibility and utility as an accessible objective measure of CI function. PMID- 23727627 TI - Maintenance of Wakefulness Test scores and driving performance in sleep disorder patients and controls. AB - OBJECTIVE: Sleepiness at the wheel is a risk factor for traffic accidents. Past studies have demonstrated the validity of the Maintenance of Wakefulness Test (MWT) scores as a predictor of driving impairment in untreated patients with obstructive sleep apnea syndrome (OSAS), but there is limited information on the validity of the maintenance of wakefulness test by MWT in predicting driving impairment in patients with hypersomnias of central origin (narcolepsy or idiopathic hypersomnia). The aim of this study was to compare the MWT scores with driving performance in sleep disorder patients and controls. METHODS: 19 patients suffering from hypersomnias of central origin (9 narcoleptics and 10 idiopathic hypersomnia), 17 OSAS patients and 14 healthy controls performed a MWT (4*40 minute trials) and a 40-minute driving session on a real car driving simulator. Participants were divided into 4 groups defined by their MWT sleep latency scores. The groups were pathological (sleep latency 0-19 min), intermediate (20 33 min), alert (34-40 min) and control (>34 min). The main driving performance outcome was the number of inappropriate line crossings (ILCs) during the 40 minute drive test. RESULTS: Patients with pathological MWT sleep latency scores (0-19 min) displayed statistically significantly more ILC than patients from the intermediate, alert and control groups (F (3, 46)=7.47, p<0.001). INTERPRETATION: Pathological sleep latencies on the MWT predicted driving impairment in patients suffering from hypersomnias of central origin as well as in OSAS patients. MWT is an objective measure of daytime sleepiness that appears to be useful in estimating the driving performance in sleepy patients. PMID- 23727628 TI - Anxiety, pCO2 and cerebral blood flow. AB - This study examined the effect of anxiety on cerebral blood flow at different levels of pCO2 in healthy participants (N=29). Three types of breathing were used to manipulate pCO2 in a within-subject threat-of-shock paradigm: spontaneous breathing, CO2-inhalation and hyperventilation resulting in normo-, hyper- and hypocapnia. Transcranial Doppler ultrasonography was used to measure CBF velocity (CBFv) in the right middle cerebral artery, while breathing behavior and end tidal pCO2 were monitored. During normocapnia, elevated anxiety was clearly associated with increased CBFv. Consistent with the cerebral vasoconstrictive and vasodilating effects of, respectively, hypo- and hypercapnia, we observed a positive linear association between CBFv and pCO2. The slope of this association became steeper with increasing anxiety, indicating that anxiety enhances the sensitivity of CBFv to changes in pCO2. The findings may elucidate conflicting findings in the literature and are relevant for brain imaging relying on regional cerebral blood flow. PMID- 23727629 TI - 10 years after baby-friendly designation: breastfeeding rates continue to increase in a US neonatal intensive care unit. AB - BACKGROUND: Mothers of preterm and sick infants admitted to the neonatal intensive care unit (NICU) often encounter more difficulties with breastfeeding than mothers of healthy term newborns. The extent to which Baby-Friendly designation is associated with breastfeeding rates for NICU infants over time is unknown. OBJECTIVE: This study aimed to determine the rate of breastfeeding initiation and continuation in a US, inner-city, level 3 NICU 10 years after Baby Friendly designation. METHODS: We compared the rate of breastfeeding initiation and continuation among breastfeeding-eligible mothers with infants admitted to the Boston Medical Center NICU in 1999 and 2009, using chi-square tests. RESULTS: Breastfeeding initiation increased from 74% in 1999 to 85% in 2009 (P = .04). Any breast milk at 2 weeks of age increased from 66% to 80% (P = .05), and exclusive breastfeeding at 2 weeks remained stable between 1999 and 2009. Breastfeeding initiation increased from 68% to 86% among black mothers from 1999 to 2009 (P = .01). CONCLUSION: Improvement in breastfeeding initiation and any breastfeeding at 2 weeks of age continued 10 years after Baby-Friendly designation among mothers with NICU infants in a US, inner-city, level 3 NICU. PMID- 23727630 TI - Expansion of the baby-friendly hospital initiative ten steps to successful breastfeeding into neonatal intensive care: expert group recommendations. AB - In the World Health Organization/United Nations Children's Fund document Baby Friendly Hospital Initiative: Revised, Updated and Expanded for Integrated Care, neonatal care is mentioned as 1 area that would benefit from expansion of the original Ten Steps to Successful Breastfeeding. The different situations faced by preterm and sick infants and their mothers, compared to healthy infants and their mothers, necessitate a specific breastfeeding policy for neonatal intensive care and require that health care professionals have knowledge and skills in lactation and breastfeeding support, including provision of antenatal information, that are specific to neonatal care. Facilitation of early, continuous, and prolonged skin to-skin contact (kangaroo mother care), early initiation of breastfeeding, and mothers' access to breastfeeding support during the infants' whole hospital stay are important. Mother's own milk or donor milk (when available) is the optimal nutrition. Efforts should be made to minimize parent-infant separation and facilitate parents' unrestricted presence with their infants. The initiation and continuation of breastfeeding should be guided only by infant competence and stability, using a semi-demand feeding regimen during the transition to exclusive breastfeeding. Pacifiers are appropriate during tube-feeding, for pain relief, and for calming infants. Nipple shields can be used for facilitating establishment of breastfeeding, but only after qualified support and attempts at the breast. Alternatives to bottles should be used until breastfeeding is well established. The discharge program should include adequate preparation of parents, information about access to lactation and breastfeeding support, both professional and peer support, and a plan for continued follow-up. PMID- 23727631 TI - Randomized double-blind crossover study of the efficacy of a tart cherry juice blend in treatment of osteoarthritis (OA) of the knee. AB - OBJECTIVE: To assess the efficacy of tart cherry juice in treating pain and other features of knee osteoarthritis (OA). METHODS: 58 non-diabetic patients with Kellgren grade 2-3 OA were randomized to begin treatment with cherry juice or placebo. Two 8 oz bottles of tart cherry juice or placebo were consumed daily for 6 weeks with a 1 week washout period before switching treatments (crossover design). Western Ontario McMaster Osteoarthritis Index (WOMAC) scores and walking times were recorded prior to and after each treatment period. Additionally, plasma urate, creatinine and high sensitivity C-reactive protein (hsCRP) were recorded at baseline, after the first treatment period and after the second treatment period. Acetaminophen was allowed as a rescue drug and self reported after each treatment period. Treatment effect was examined with repeated measures analysis of variance (ANOVA) using an intention-to-treat (ITT) analysis. RESULTS: There were five withdrawals during the cherry juice treatment (four adverse events (AEs)) and seven withdrawals during the placebo treatment (three AEs). WOMAC scores decreased significantly (P < 0.01) after the cherry juice treatment but not after the placebo treatment (P = 0.46); differences between treatments were not significant (P = 0.16). hsCRP declined during the cherry juice treatment vs placebo (P < 0.01). The decline in hsCRP was associated with WOMAC improvement (P < 0.01). Walking time, acetaminophen use, plasma urate and creatinine were unaffected by treatments. CONCLUSIONS: Tart cherry juice provided symptom relief for patients with mild to moderate knee OA, but this effect was not significantly greater than placebo. Tart cherry juice lowered hsCRP levels and this effect was associated with improved WOMAC scores. PMID- 23727632 TI - Classification of vasculitis: EMA classification using CHCC 2012 definitions. PMID- 23727633 TI - Glucocorticoids induce senescence in primary human tenocytes by inhibition of sirtuin 1 and activation of the p53/p21 pathway: in vivo and in vitro evidence. AB - Cellular senescence is an irreversible side effect of some pharmaceuticals which can contribute to tissue degeneration. OBJECTIVE: To determine whether pharmaceutical glucocorticoids induce senescence in tenocytes. METHODS: Features of senescence (beta-galactosidase activity at pH 6 (SA-beta-gal) and active mammalian/mechanistic target of rapamycin (mTOR) in cell cycle arrest) as well as the activity of the two main pathways leading to cell senescence were examined in glucocorticoid-treated primary human tenocytes. Evidence of senescence-inducing pathway induction in vivo was obtained using immunohistochemistry on tendon biopsy specimens taken before and 7 weeks after subacromial Depo-Medrone injection. RESULTS: Dexamethasone treatment of tenocytes resulted in an increased percentage of SA-betagal-positive cells. Levels of phosphorylated p70S6K did not decrease with glucocorticoid treatment indicating mTOR remained active. Increased levels of acetylated p53 as well as increased RNA levels of its pro-senescence effector p21 were evident in dexamethasone-treated tenocytes. Levels of the p53 deacetylase sirtuin 1 were lower in dexamethasone-treated cells compared with controls. Knockdown of p53 or inhibition of p53 activity prevented dexamethasone induced senescence. Activation of sirtuin 1 either by exogenous overexpression or by treatment with resveratrol or low glucose prevented dexamethasone-induced senescence. Immunohistochemical analysis of tendon biopsies taken before and after glucocorticoid injection revealed a significant increase in the percentage of p53-positive cells (p=0.03). The percentage of p21-positive cells also tended to be higher post-injection (p=0.06) suggesting glucocorticoids activate the p53/p21 senescence-inducing pathway in vivo as well as in vitro. CONCLUSION: As cell senescence is irreversible in vivo, glucocorticoid-induced senescence may result in long-term degenerative changes in tendon tissue. PMID- 23727634 TI - MICA, a gene contributing strong susceptibility to ankylosing spondylitis. AB - OBJECTIVE: The human major histocompatibility complex class I chain-related gene A (MICA) controls the immune process by balancing activities of natural killer cells, gammadelta T cells and alphabeta CD8 T cells, and immunosuppressive CD4 T cells. MICA is located near HLA-B on chromosome 6. Recent genomewide association studies indicate that genes most strongly linked to ankylosing spondylitis (AS) susceptibility come from the region containing HLA-B and MICA. While HLA-B27 is a well-known risk genetic marker for AS, the potential effect of linkage disequilibrium (LD) shields any associations of genes around HLA-B with AS. The aim of this study was to investigate a novel independent genetic association of MICA to AS. METHODS: We examined 1543 AS patients and 1539 controls from two ethnic populations by sequencing MICA and genotyping HLA-B alleles. Initially, 1070 AS patients and 1003 controls of European ancestry were used as a discovery cohort, followed by a confirmation cohort of 473 Han Chinese AS patients and 536 controls. We performed a stratified analysis based on HLA-B27 carrier status. We also conducted logistic regression with a formal interaction term. RESULTS: Sequencing of MICA identified that MICA*007:01 is a significant risk allele for AS in both Caucasian and Han Chinese populations, and that MICA*019 is a major risk allele in Chinese AS patients. Conditional analysis of MICA alleles on HLA B27 that unshielded LD effect confirmed associations of the MICA alleles with AS. CONCLUSIONS: Parallel with HLA-B27, MICA confers strong susceptibility to AS in US white and Han Chinese populations. PMID- 23727635 TI - Antibodies from patients with rheumatoid arthritis target citrullinated histone 4 contained in neutrophils extracellular traps. AB - BACKGROUND: Histone deimination regulates gene function and contributes to antimicrobial response, allowing the formation of neutrophil extracellular traps (NETs). Deiminated proteins are target of anti-citrullinated peptides antibodies (ACPA) in rheumatoid arthritis (RA). OBJECTIVE: The objective of this paper is to test the hypothesis that RA sera react with deiminated histones contained in NETs. METHODS: Neutrophils from peripheral blood were stimulated with A23187 and acid treated; NETosis was induced by phorbol myristate acetate, and NET proteins were isolated. Sera were tested by immunoblot on acid extracted proteins from neutrophils and from NETs, and by ELISA on deiminated histone H4 or H4-derived peptides. Bands reactive with RA sera were excised from gels, digested with trypsin and subjected to matrix-assisted laser desorption/ionisation time of flight (MALDI-TOF) analysis, before and after derivatisation to detect citrullinated peptides. RESULTS: RA sera reacted with a deiminated antigen of 11 KDa from activated neutrophils, recognised also by anti-H4 and antideiminated H4 antibodies. A similar reactivity was observed with NET proteins. The antigen from neutrophils or NETs was identified as citrullinated H4 by MALDI-TOF analysis. By ELISA, RA sera bound in vitro citrullinated H4. Citrullinated H4 14-34 and 31-50 peptides detected antibodies in 67% and 63% of RA sera and in less than 5% of controls; antibody titre was correlated with anti-CCP2. CONCLUSIONS: Citrullinated H4 from activated neutrophils and NETs is a target of antibodies in RA, and synthetic citrullinated H4-derived peptides are a new substrate for ACPA detection. As NETosis can generate antigens for ACPA, these data suggest a novel connection between innate and adaptive immunity in RA. PMID- 23727636 TI - Vitamin E depletion enhances liver oxidative damage in rats with water-immersion restraint stress. AB - We examined the effect of vitamin E depletion on liver oxidative damage in rats with water-immersion restraint stress (WIRS). Male Wistar rats were fed a normal diet (N) or vitamin E-depleted diet (VE-D) for 4 wk. N- and VE-D-fed rats were exposed to WIRS for 6 h. The activities of serum transaminases and lactate dehydrogenase and serum ascorbic acid concentration were similar in both diet groups. WIRS exposure increased these serum enzyme activities and the serum ascorbic acid concentration in both diet groups but the ratios of these increases were higher in VE-D-fed rats than in N-fed rats. Serum and liver alpha-tocopherol concentrations in VE-D-rats were approximately 50% and 30% of those in N-fed rats, respectively. WIRS exposure reduced liver alpha-tocopherol concentration in VE-D-fed rats, but not in N-fed rats. Liver ascorbic acid and reduced glutathione concentrations were higher in the VE-D-fed group than in the N-fed group. WIRS exposure reduced liver ascorbic acid and reduced glutathione concentrations in both diet groups. There were no differences in liver concentrations of coenzyme Q9 or coenzyme Q10 in the reduced form between the N- and VE-D-fed groups. WIRS exposure reduced liver concentrations of coenzyme Q9 and coenzyme Q10 in the reduced form in both diet groups. Liver lipid peroxide concentration was higher in the VE-D-fed group than in the N-fed group. WIRS exposure raised liver lipid peroxide concentration more in the VE-D-fed group than in the N-fed group. These results indicate that vitamin E depletion enhances liver oxidative damage in rats with WIRS. PMID- 23727637 TI - The body vitamin B1 levels of rats fed a diet containing the minimum requirement of vitamin B1 is reduced by exercise. AB - It is thought that increasing energy expenditure increases consumption of vitamin B1, leading to an increase in the requirement of vitamin B1. However, evidence supporting this hypothesis is lacking. To examine the hypothesis, initially, we determined the minimum requirement of vitamin B1 for weaning rats. We found that the minimum requirement of vitamin B1 for optimum growth of weaning rats was around 0.786 mg thiamin/kg diet. Next, rats fed a diet containing the minimum requirement of vitamin B1 were forced to swim until exhaustion. Concentrations of vitamin B1 in the blood and liver as well as urinary excretion of swimming rats decreased significantly compared with those of non-swimming rats (p<0.05), while in rats fed the diet containing a sufficient amount of vitamin B1 (4.720 mg thiamin/kg diet), vitamin B1 amounts in the blood, liver and urine were not affected by swimming. We clearly and firstly showed the reduction of body vitamin B1 following increases in energy expenditure. PMID- 23727638 TI - D-pantethine has vitamin activity equivalent to d-pantothenic acids for recovering from a deficiency of D-pantothenic acid in rats. AB - D-Pantethine is a compound in which two molecules of D-pantetheine bind through an S-S linkage. D-Pantethine is available from commercial sources as well as from D-pantothenic acid. We investigated if D-pantethine has the same vitamin activity as D-pantothenic acid by comparing the recovery from a deficiency of D pantothenic acid in rats. D-Pantothenic acid-deficient rats were developed by weaning rats on a diet lacking D-pantothenic acid for 47 d. At that time, the urinary excretion of D-pantothenic acid was almost zero, and the body weight extremely low, compared with the control (p<0.05); the contents of free D pantothenic acid were also significantly reduced in comparison with those of controls (p<0.05). D-Pantothenic acid-deficient rats were administered a diet containing D-pantothenic acid or D-pantethine for 7 d. D-Pantethine and D pantothenic acid contents of the diets were equimolar in forms of D-pantothenic acid. We compared various parameters concerning nutritional status between rats fed D-pantothenic acid- and D-pantethine-containing diets. The recoveries of body weight, tissue weights, and tissue concentrations of free D-pantothenic acid, dephospho-CoA, CoA, and acetyl-CoA were identical between rats fed diets containing D-pantothenic acid and D-pantethine. Thus, the biological efficiency for recovering from a deficiency of D-pantothenic acid in rats was equivalent between D-pantothenic acid and D-pantethine. PMID- 23727639 TI - Is plasma alpha-tocopherol associated with electronegative LDL in obese adolescents? AB - Obesity has increased in children and adolescents. What is reflected in the early occurrence of cardiometabolic alterations, like hypertension and type 2 diabetes, where the oxLDL formation is stimulated. Various studies have shown that plasma alpha-tocopherol (alpha-TP) can protect LDL against oxidation. Nevertheless, the action of plasma alpha-TP in cardiovascular diseases remains controversial. We conducted a cross-sectional study to evaluate plasma alpha-TP and its impact on the concentration of LDL(-). Adolescents (n=150) of both sexes were classified into three groups: healthy weight (HW; 50%), overweight (OV; 22%), and obese (OB; 28%). Lipid profile, LDL(-), anti-oxLDL and anti-LDL(-) antibodies, CRP (ELISA) and plasma alpha-TP (HPLC) were analyzed. Demographic, anthropometric, and food intake data were evaluated. Crude and energy-adjusted intake of vitamin E in the OB group were higher than in the HW group (p<0.001). Crude and energy-adjusted vitamin E intakes were not correlated with plasma alpha-TP (r=-0.07; p=0.412 and r=-0.064; p=0.467, respectively). Subjects in the OB group had higher TC and LDL C and lower HDL-C than in the HW and OV groups. C-reactive protein and anti-oxLDL antibodies changed as a function of BMI. The impact of obesity was reinforced by high values for LDL(-) and low content of plasma alpha-TP in comparison with the HW (p<0.001) and OV groups (p=0.03). This negative profile was maintained for the ratio between alpha-TP and TC or LDL-C. Plasma alpha-TP, alpha-TP/TC and alpha TP/LDL-C were negatively associated with LDL(-) and other cardiometabolic risk factors (BMI, WC, AC and anti-oxLDL). Our results demonstrate that obesity in adolescents is associated with high levels of LDL(-) and low plasma alpha-TP content. PMID- 23727640 TI - Serum gamma-GTP activity is closely associated with serum CRP levels in non overweight and overweight middle-aged Japanese men. AB - The relationship between gamma-glutamyltransferase (gamma-GTP) and C-reactive protein (CRP) has not been established, particularly in the lean or non overweight population. In the present study, we examined the associations between gamma-GTP and CRP in non-overweight and overweight middle-aged Japanese men. We conducted a cross-sectional study of 4,271 apparently healthy men aged 40 to 64 y (mean+/-SD, 50.5+/-6.6 y) who participated in health checkups. Associations between serum CRP levels, other clinical parameters, and lifestyle factors were analyzed using Spearman's rank correlation coefficient analysis and multiple linear regression analysis in the non-overweight (body mass index [BMI]<25 kg/m(2)) and overweight (BMI>=25 kg/m(2)) men. Associations between serum gamma GTP activity and serum CRP levels were analyzed using analysis of covariance by comparisons of serum CRP levels of four subgroups according to gamma-GTP status. In non-overweight men, BMI, high-density lipoprotein cholesterol, triacylglycerols, fasting blood glucose, aspartate aminotransferase, gamma-GTP, and smoking habit were positively associated with serum CRP levels. In overweight men, BMI, diastolic blood pressure, triacylglycerols, and gamma-GTP were positively associated with serum CRP levels. After adjustment for age, BMI, smoking status, and alcohol intake, dose-response relationships were observed between gamma-GTP and CRP levels in both overweight and non-overweight men. The results of this study indicate that an increase in serum gamma-GTP activity is closely associated with elevated CRP levels in both non-overweight and overweight middle-aged Japanese men. PMID- 23727641 TI - Relationship between dietary patterns and depressive symptoms: difference by gender, and unipolar and bipolar depression. AB - Although several studies have reported associations of depressive state with specific nutrients and foods, few have examined the associations with dietary patterns in adults. We investigated the association between major dietary patterns and depressive symptoms in Japanese patients with depression. Subjects were 166 Japanese patients (104 men and 62 women), aged 22-74 y, who were treated at a hospital psychiatry clinic in Tokyo. Depressive symptoms were assessed using the Himorogi Self-rating Depression Scale (H-SDS) and Himorogi Self-rating Anxiety Scale (H-SAS). We categorized depressive symptoms into 3 types: physical, psychiatric, and anxiety symptoms. Dietary patterns were derived using principal component analysis of the consumption of 59 food and beverage items, which was assessed by a validated brief diet history questionnaire. Three dietary patterns were identified: 1) "plant foods and fish products," 2) "fish," and 3) "Western/meat." We calculated the correlation coefficients for the relationship between each dietary pattern score and depressive symptom score in unipolar depression vs. bipolar depression and in men vs. women. In bipolar depression, the plant foods and fish products pattern showed an inverse relationship with physical and psychiatric symptoms, and in men, this pattern showed an inverse relationship with psychiatric symptoms. The fish pattern and Western/meat pattern were not significantly associated with the 3 types of depressive symptoms. In conclusion, we identified 3 dietary patterns and found that associations between these patterns and depressive symptoms were observed only in bipolar depression and only in men. PMID- 23727642 TI - Medium-chain triacylglycerol suppresses the decrease of plasma albumin level through the insulin-Akt-mTOR pathway in the livers of malnourished rats. AB - Recent studies have shown that medium-chain triacylglycerol (MCT) improved serum albumin concentration in elderly people with protein-energy malnutrition (PEM) and in malnourished rats. However, the mechanism for this effect has not been clarified. Dietary MCT promotes insulin secretion from the pancreas, and insulin activates mammalian target of rapamycin (mTOR) complex 1 (mTORC1) via the activation of phosphoinositide 3-kinase (PI3K) and its downstream effecter, Akt. mTORC1 promotes mRNA translation through S6K and 4E-BP1. Therefore, we hypothesized that dietary MCT elevates albumin synthesis through promotion of insulin-Akt-mTOR transduction in the liver. To test this hypothesis, we measured phosphorylated Akt, mTOR and albumin in the livers of malnourished rats. In the present study we examined rats fed low-protein diets containing either MCT or long-chain triacylglycerol (LCT) with energy restriction. The plasma and liver albumin levels were significantly higher in the MCT-fed group than in the LCT-fed group. In addition, plasma insulin concentration, liver phosphorylated Akt/Akt and phosphorylated mTOR/mTOR levels were significantly higher in the MCT-fed group than in the LCT-fed group. These results suggest that one of the mechanisms for the albumin improvement effect of dietary MCT is the promotion of albumin synthesis through the insulin-Akt-mTOR signaling pathway of the liver. PMID- 23727643 TI - Long-term ingestion of monosodium L-glutamate did not induce obesity, dyslipidemia or insulin resistance: a two-generation study in mice. AB - The use of monosodium glutamate (MSG) as a flavor enhancer spans more than 100 y and there are many studies indicating the safety of general use of MSG. Recently, however, Collison et al. (2010) reported a two-generation study with a low dose of MSG that caused abdominal obesity, insulin resistance and dyslipidemia in mice. Due to public health concerns over metabolic syndrome, their report merits careful analysis. The present study attempted to repeat the Collison et al. findings. Groups of male or female C57BL/6J mice were fed a control diet or one supplemented with high-fructose corn syrup (HFCS) at a level of 20%. Drinking water control was provided or treatment groups were given 0.064% MSG solution (w/v). Diets and MSG administration continued throughout mating and during gestation and lactation periods. To further investigate the effects of ingestion of MSG, the offspring were continued on the same dosing conditions until they reached 32 wk of age. MSG administration in mice fed a normal or a HFCS diet throughout gestation and for 32 wk after birth, did not affect growth, girth size, abdominal fat weight or body composition. This study reports that MSG did not trigger insulin resistance, dyslipidemia or hepatic steatosis, regardless of the diet, not reproducing the results of the above-mentioned study (Collison et al., 2010). PMID- 23727644 TI - Effects of dietary sialic acid in n-3 fatty acid-deficient dams during pregnancy and lactation on the learning abilities of their pups after weaning. AB - The effects of dietary sialic acid in dams on the learning abilities of their pups after weaning were investigated using rats deficient in n-3 fatty acids. Nine-week-old female Wistar rats were fed an n-3 fatty acid-deficient diet for 3 wk and were mated at 12 wk of age. During pregnancy and lactation, the female rats were fed the n-3 fatty acid-deficient diet, and were given water or water containing 1% N-acetylneuraminic acid (NANA) ad libitum. After weaning, the learning abilities of the pups were evaluated using a novel object recognition test. The recognition index of pups nursed by dams fed on water containing 1% NANA (NANA-intake dams) was significantly higher than that of pups nursed by dams fed only on water (NANA non-intake dams). There were no significant differences in the total sialic acid or docosahexaenoic acid contents in the cerebral cortex or hippocampus of pups nursed by dams fed on either type of water. The total dimethylacetal (DMA, from plasmalogen) level in the cerebral cortex of pups nursed by NANA-intake dams was significantly higher than that of pups nursed by NANA non-intake dams. These results suggest that dietary sialic acid in dams during pregnancy and lactation might be beneficial for the learning abilities of pups after weaning, which may be related to the plasmalogen level in the brain of pups. PMID- 23727645 TI - Lactobacillus plantarum OLL2712 regulates glucose metabolism in C57BL/6 mice fed a high-fat diet. AB - The aim of the present study was to determine the effect of oral administration of Lactobacillus plantarum OLL2712 (L. plantarum OLL2712) on glucose and lipid metabolism in mice with high-fat diet-induced obesity. Mice that had been administered 10(9) cfu heat-killed L. plantarum OLL2712 for 12 wk showed significant reduction of blood glucose levels in response to insulin. Furthermore, mRNA expression of interleukin-1beta in adipose tissue and serum levels of nonesterified fatty acids in mice administered L. plantarum OLL2712 were significantly lower than those in control mice. These results indicate that L. plantarum OLL2712 regulates glucose metabolism. PMID- 23727646 TI - gamma-Tocotrienol attenuates triglyceride through effect on lipogenic gene expressions in mouse hepatocellular carcinoma Hepa 1-6. AB - Vitamin E is the generic name for tocopherol (Toc) and tocotrienol (T3), which have saturated and unsaturated side chains, respectively. Such differences allow T3 to be different from Toc in terms of their functions. T3 has been known to attenuate cholesterol (Cho) level by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR). Recent reports also showed the efficacy of T3 in improving triglyceride (TG) profiles in both in vivo and in vitro studies. However the mechanism involved in this biological activity is still unclear and needs to be further investigated. In the present study, we elucidated the effect of gamma-T3 on lipid levels and lipogenic gene expressions in mouse hepatocellular carcinoma Hepa 1-6. gamma-T3 showed attenuation of TG through effect on fatty acid synthase, sterol regulatory element-binding transcription factor 1, stearoyl CoA desaturase 1, and carnitine palmitoyl transferase 1A gene expression in Hepa 1-6. In contrast, the Cho level remained unchanged. These results expanded our previous finding of lipid-lowering effects of T3, especially for TG. Therefore, T3 is a potential lipid-lowering compound candidate with realistic prospects for its use as a therapy for lipid-related diseases in humans. PMID- 23727647 TI - GABA affects novel object recognition memory and working memory in rats. AB - gamma-Aminobutyric acid (GABA) is an amino acid found in unpolished rice, chocolate, tea, and other foods. It is an important inhibitory neurotransmitter. However, the influence of GABA on object recognition and working memory is still unknown. In this study, the effects of GABA on novel object recognition (NOR) memory and working memory were examined. The proper retention interval and delay time were also investigated for the NOR test and T-maze test, respectively. Male 3-wk-old Wistar rats were allowed free access to food and water containing 0.5% GABA or 1% GABA for a month. After that, the rats performed the NOR test at a 48 h retention interval and T-maze test at a 900 s delay time to estimate the effects of GABA on learning behavior. The results showed that the object information in the NOR test was stored as long-term memory and the recognition index (RI) was significantly increased after GABA administration. The accuracy rate also significantly increased after GABA administration. These indicate that GABA may be involved in long-term object recognition memory and working memory. PMID- 23727649 TI - A 2D ultrasound evaluation of swallowing in children with unilateral posterior crossbite. AB - BACKGROUND: Swallowing pattern is important in the aetiology of unilateral posterior crossbite (ULCB). The aim of this study was to assess the swallowing pattern and tongue function during swallowing in children with ULCB in deciduous dentition using B-mode and M-mode ultrasonography. MATERIALS AND METHODS: Twenty three children with ULCB, aged 4.1-6.6 years, and 22 children without ULCB, 5.7 6.7 years, were examined with simultaneous B- and M-mode ultrasonography. The swallowing pattern was assessed according to the action of genioglossus muscle in ultrasound images with the scan line of the ultrasound transducer set through the tongue tip. The tongue movements (duration, range, and speed) were compared within each subphase (I, IIa, IIb, IIIa, and IIIb) and in the entire swallowing cycle between the children with ULCB and without ULCB. RESULTS: The visceral swallowing pattern was found in 83 per cent of children with ULCB and in 36 per cent of children without ULCB; the difference was statistically significant. The duration of phase IIb and the entire swallowing act was found to be statistically significantly prolonged in the ULCB group. Furthermore, the range of the tongue movement in phases and in the entire swallowing act was statistically significantly larger in the ULCB group. The speed of the tongue movement was statistically significantly higher in the ULCB group in phase IIa. CONCLUSIONS: The 2D ultrasonography was used to evaluate the prevalent type of swallowing in children with ULCB. Visceral type of swallowing pattern and the changed tongue function during swallowing seem to be important factors in the aetiology of ULCB. PMID- 23727650 TI - Effects of egg shell quality and washing on Salmonella Infantis penetration. AB - The vast majority of eggs in Australia are washed prior to packing to remove dirt and fecal material and to reduce the microbial contamination of the egg shell. The egg contents can be an ideal growth medium for microorganisms which can result in human illness if eggs are stored improperly and eaten raw or undercooked, and it is estimated that egg-related salmonellosis is costing Australia $44 million per year. Egg shell characteristics such as shell thickness, amount of cuticle present, and thickness of individual egg shell layers can affect the ease with which bacteria can penetrate the egg shell and washing could partially or completely remove the cuticle layer. The current study was conducted to investigate the effects of egg washing on cuticle cover and effects of egg shell quality and cuticle cover on Salmonella Infantis penetration of the egg shell. A higher incidence of unfavorable ultrastructural variables of the mammillary layer such as late fusion, type B bodies, type A bodies, poor cap quality, alignment, depression, erosion and cubics were recorded in Salmonella penetrated areas of egg shells. The influence of egg washing on the ability of Salmonella Infantis on the egg shell surface to enter the egg internal contents was also investigated using culture-based agar egg penetration and real-time qPCR based experiments. The results from the current study indicate that washing affected cuticle cover. There were no significant differences in Salmonella Infantis penetration of washed or unwashed eggs. Egg shell translucency may have effects on Salmonella Infantis penetration of the egg shell. The qPCR assay was more sensitive for detection of Salmonella Infantis from egg shell wash and internal contents than traditional microbiological methods. The agar egg and whole egg inoculation experiments indicated that Salmonella Infantis penetrated the egg shells. Egg washing not only can be highly effective at removing Salmonella Infantis from the egg shell surface, but also allows subsequent trans shell and trans-membrane penetration into the egg. Consequently, it is important to prevent recontamination of the egg after washing. PMID- 23727651 TI - Determination of yeast diversity in ogi, mawe, gowe and tchoukoutou by using culture-dependent and -independent methods. AB - The maize based ogi and mawe and the sorghum based gowe and tchoukoutou are traditional, spontaneously fermented products widely consumed by the population of Benin (West Africa). Yeast occurrence in the products, as sold on local markets at different locations, was studied using a combination of culture dependent and independent methods. Number of yeasts is varied from 3.75 log10 colony forming units (cfu)/g for ogi to 5.60 log10 cfu/g for tchoukoutou. Isolated yeasts (236) were identified based on different migration profiles on denaturing gradient gel electrophoresis (DGGE) and 26S rRNA gene sequencing. Candida krusei was the yeast most frequently isolated with strongest predominance in the maize based products. Other predominant yeast present at equal or lower incidence were Clavispora lusitaniae and Saccharomyces cerevisiae in ogi and mawe, Cl. lusitaniae, Candida tropicalis and Kluyveromyces marxianus in gowe and Cl. lusitaniae, S. cerevisiae and Candida rugosa in tchoukoutou. Grouping of C. krusei isolates (164) by rep-PCR analysis indicated that several biotypes were involved in fermentation of the four products. The DGGE analysis on the DNA directly extracted from the food matrices demonstrated the presence of Dekkera bruxellensis and Debaryomyces hansenii, not detected by the culture-based approach. This is the first study combining culture-dependent and independent methods to reveal predominant yeast species and biotypes in traditional foods from Benin. PMID- 23727652 TI - Sample size guidelines for fitting a lognormal probability distribution to censored most probable number data with a Markov chain Monte Carlo method. AB - Levels of pathogenic organisms in food and water have steadily declined in many parts of the world. A consequence of this reduction is that the proportion of samples that test positive for the most contaminated product-pathogen pairings has fallen to less than 0.1. While this is unequivocally beneficial to public health, datasets with very few enumerated samples present an analytical challenge because a large proportion of the observations are censored values. One application of particular interest to risk assessors is the fitting of a statistical distribution function to datasets collected at some point in the farm to-table continuum. The fitted distribution forms an important component of an exposure assessment. A number of studies have compared different fitting methods and proposed lower limits on the proportion of samples where the organisms of interest are identified and enumerated, with the recommended lower limit of enumerated samples being 0.2. This recommendation may not be applicable to food safety risk assessments for a number of reasons, which include the development of new Bayesian fitting methods, the use of highly sensitive screening tests, and the generally larger sample sizes found in surveys of food commodities. This study evaluates the performance of a Markov chain Monte Carlo fitting method when used in conjunction with a screening test and enumeration of positive samples by the Most Probable Number technique. The results suggest that levels of contamination for common product-pathogen pairs, such as Salmonella on poultry carcasses, can be reliably estimated with the proposed fitting method and samples sizes in excess of 500 observations. The results do, however, demonstrate that simple guidelines for this application, such as the proportion of positive samples, cannot be provided. PMID- 23727653 TI - Filament formation by foodborne bacteria under sublethal stress. AB - A number of studies have reported that pathogenic and nonpathogenic foodborne bacteria have the ability to form filaments in microbiological growth media and foods after prolonged exposure to sublethal stress or marginal growth conditions. In many cases, nucleoids are evenly spaced throughout the filamentous cells but septa are not visible, indicating that there is a blockage in the early steps of cell division but the mechanism behind filament formation is not clear. The formation of filamentous cells appears to be a reversible stress response. When filamentous cells are exposed to more favorable growth conditions, filaments divide rapidly into a number of individual cells, which may have major health and regulatory implications for the food industry because the potential numbers of viable bacteria will be underestimated and may exceed tolerated levels in foods when filamentous cells that are subjected to sublethal stress conditions are enumerated. Evidence suggests that filament formation under a number of sublethal stresses may be linked to a reduced energy state of bacterial cells. This review focuses on the conditions and extent of filament formation by foodborne bacteria under conditions that are used to control the growth of microorganisms in foods such as suboptimal pH, high pressure, low water activity, low temperature, elevated CO2 and exposure to antimicrobial substances as well as lack a of nutrients in the food environment and explores the impact of the sublethal stresses on the cell's inability to divide. PMID- 23727654 TI - Sublingual buprenorphine for chronic pain: a survey of clinician prescribing practices. AB - OBJECTIVES: Sublingual buprenorphine, with and without naloxone, is indicated for the treatment of opioid use disorders. Although not approved for pain, some evidence suggests it may be a safe and effective alternative to conventional opioid analgesics, particularly for those with addiction problems. This study surveyed pain specialists to examine the extent to which sublingual buprenorphine was prescribed for chronic pain and explore associated clinician attitudes and characteristics. METHOD: A 36-item survey examining clinician attitudes and characteristics related to sublingual buprenorphine and other opioids was distributed to 1307 members of the American Pain Society, a multidisciplinary professional group. Members were provided a paper copy of the survey and URL to an online version. A follow-up letter was mailed after 2 weeks. RESULTS: Overall, 230 completed surveys were returned (18.5%). Of clinicians who prescribed opioids for chronic pain (92.5%), 19.7% reported prescribing sublingual buprenorphine for chronic pain at least once; of these prescribers, 39.6% did not have a DEA X waiver to prescribe sublingual buprenorphine for opioid dependence. Prescribers were more likely than nonprescribers to find sublingual buprenorphine effective for chronic pain. Prescribers were also significantly more likely to view sublingual buprenorphine as safer than full agonists in terms of addiction, overdose, and drug interaction. No differences emerged between prescribers and nonprescribers regarding perceptions of potential for drug diversion or in terms of overall opioid prescribing behaviors. DISCUSSION: Results suggest that sublingual buprenorphine is indeed being used to treat chronic pain; however, the circumstances when this occurs are not entirely clear. PMID- 23727655 TI - Patient participation in quality pain management during an acute care admission. AB - OBJECTIVES: The objective of the study was to explore patient participation in the context of pain management during a hospital admission for a cardiac surgical intervention of patients with cardiovascular disease. METHODS: This is a single institution study, with a case-study design. The unit of analysis was a cardiothoracic ward of a major metropolitan, tertiary referral hospital in Melbourne, Australia. Multiple methods of data collection were used including preadmission and predischarge patient interviews (n=98), naturalistic observations (n=48), and focus group interviews (n=2). RESULTS: Patients' preference for participation in pain management was not always commensurate with their involvement in pain management. Patients displayed a greater understanding of their role in pain management in terms of reporting pain and the use of multimodal analgesics after surgery. The majority of patients, however, did not understand the importance of reporting pain to avoid complications. Patients had limited opportunity to participate in their pain management. On occasions in which clinicians did involve patients, the involvement appeared to be focused on reporting pain rather than treatment of pain. DISCUSSION: Patient participation in pain management during hospitalization is not optimal. This has implications for the quality of pain management patients receive. Higher engagement of patients in their pain management during hospitalization is required to ensure comfort, reduce potential for complications, and adequately prepare the patients to manage their pain following discharge from hospital. PMID- 23727656 TI - Formulations and processing of nanocrystalline TiO2 films for the different requirements of plastic, metal and glass dye solar cell applications. AB - We carried out a systematic study on the effect of nanocrystalline TiO2 paste formulations and temperature treatment on the performance of dye solar cells (DSCs) over a large temperature range, to provide useful information for the fabrication of both plastic and metal flexible devices. We compared conventional screen-printable and binder-free TiO2 pastes with a new formulation which includes hydroxylethyl cellulose (HEC), enabling the study of the effect of organic materials in the TiO2 layer in the whole 25-600 degrees C temperature range. Differently from the binder-free formulations where the device efficiency rose monotonically with temperature, the use of cellulose binders led to remarkably different trends depending on their pyrolysis and decomposition thresholds and solubility, especially at those temperatures compatible with plastic foils. Above 325 degrees C, where metal foil can be used as substrates, the efficiencies become similar to those of the binder-free paste due to effective binder decomposition and inter-nanoparticle bonding. Finally, we demonstrated, for the first time, that the simultaneous application of both temperature (110-150 degrees C) and pressure (100 MPa) can lead to a large improvement (33%) compared to the same mechanical compression method carried out at room temperature only. PMID- 23727657 TI - Microemulsion-assisted synthesis of hierarchical porous Ni(OH)2/SiO2 composites toward efficient removal of formaldehyde in air. AB - Ni(OH)2/SiO2 composites with hierarchical flake-like nanostructures were synthesized using water-in-oil microemulsion and characterized by X-ray diffraction, thermogravimetry, Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, nitrogen adsorption, and X ray photoelectron spectroscopy. The as-prepared hierarchical porous Ni(OH)2/SiO2 composites show an excellent performance for formaldehyde (HCHO) removal in air at an ambient temperature. It was found that the aging time had a significant impact on the pore structure, surface area and HCHO adsorption. The Ni(OH)2/SiO2 composite aged for 4 h in the presence of tetraethyl orthosilicate (TEOS) exhibited a relatively high HCHO adsorption capacity as well as good recyclability compared with Ni(OH)2, attributed to a relatively large BET surface area, an optimal pore size, a suitable proportion between Ni(OH)2 and SiO2, and a synergistic effect between Ni(OH)2 and SiO2. The results from this work not only demonstrate that hierarchical porous Ni(OH)2/SiO2 composites can act as an efficient adsorbent toward HCHO in air, but suggest a new route for the rational design of cost-effective, high-performance and environmentally benign adsorbents for indoor air cleanup. PMID- 23727658 TI - Symptomatic discoid medial meniscus. PMID- 23727659 TI - Effectiveness, response, and dropout of dialectical behavior therapy for borderline personality disorder in an inpatient setting. AB - To examine the effectiveness of dialectical behavior therapy for inpatients with borderline personality disorder (BPD), small sample sizes and, predominantly, tests of statistical significance have been used so far. We studied 1423 consecutively admitted individuals with BPD, who were seeking a 3-month inpatient treatment. They completed the Borderline Symptom List (BSL) as the main outcome measure, and other self-rating measures at pre- and post-treatment. Therapy outcome was defined in three ways: effect size (ES), response based on the reliable change index, and remission compared to the general population symptom level. Non-parametric conditional inference trees were used to predict dropouts. In the pre-post comparison of the BSL, the ES was 0.54 (95% CI: 0.49-0.59). The response rate was 45%; 31% remained unchanged, and 11% deteriorated. Approximately 15% showed a symptom level equivalent to that of the general population. A further 10% of participants dropped out. A predictive impact on dropout was demonstrated by substance use disorders and a younger age at pre treatment. In future research, follow-up assessments should be conducted to investigate the extent to which response and remission rates at post-treatment remain stable over time. A consistent definition of response appears to be essential for cross-study and cross-methodological comparisons. PMID- 23727660 TI - Urinary liver type fatty acid binding protein in diabetic nephropathy. AB - Deterioration of diabetic nephropathy (DN) is largely determined by the degree of tubulointerstitial changes rather than the extent of histological changes in the glomeruli. Therefore, a tubular marker that accurately reflects tubulointerstitial damage may be an excellent biomarker for early detection or prediction of DN. Liver-type fatty-acid binding protein (L-FABP) is a 14 kDa small molecule that is expressed in the cytoplasm of human proximal tubules. In vivo experimental studies revealed that renal L-FABP gene expression was up regulated by various stresses that cause tubulointerstitial damage, such as massive proteinuria, hyperglycemia, hypertension, ischemia and toxins, and that urinary excretion of L-FABP was increased. Recent clinical studies of patients with type 1 or type 2 diabetes demonstrated that urinary excretion of L-FABP derived from proximal tubules is a suitable biomarker for predicting and monitoring deterioration of renal function in DN. Moreover, therapeutic interventions with renoprotective effects reduced urinary L-FABP concentrations. Therefore, urinary L-FABP measured using the Human L-FABP ELISA Kit developed by CMIC Co., Ltd. (Tokyo, Japan) was confirmed as a newly established tubular biomarker by the Ministry of Health, Labour and Welfare in Japan in 2010. This review article summarizes the clinical significance of urinary L-FABP in DN. PMID- 23727661 TI - Lipid raft-mediated Akt signaling as a therapeutic target in mantle cell lymphoma. AB - Recent evidence shows that lipid raft membrane domains modulate both cell survival and death. Here, we have found that the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway is present in the lipid rafts of mantle cell lymphoma (MCL) cells, and this location seems to be critical for full activation and MCL cell survival. The antitumor lipids (ATLs) edelfosine and perifosine target rafts, and we found that ATLs exerted in vitro and in vivo antitumor activity against MCL cells by displacing Akt as well as key regulatory kinases p PDK1 (phosphatidylinositol-dependent protein kinase 1), PI3K and mTOR (mammalian TOR) from lipid rafts. This raft reorganization led to Akt dephosphorylation, while proapoptotic Fas/CD95 death receptor was recruited into rafts. Raft integrity was critical for Ser473 Akt phosphorylation. ATL-induced apoptosis appeared to correlate with the basal Akt phosphorylation status in MCL cell lines and primary cultures, and could be potentiated by the PI3K inhibitor wortmannin, or inhibited by the Akt activator pervanadate. Classical Akt inhibitors induced apoptosis in MCL cells. Microenvironmental stimuli, such as CD40 ligation or stromal cell contact, did not prevent ATL-induced apoptosis in MCL cell lines and patient-derived cells. These results highlight the role of raft-mediated PI3K/Akt signaling in MCL cell survival and chemotherapy, thus becoming a new target for MCL treatment. PMID- 23727663 TI - Sugar-derived organogels as templates for structured, photoluminescent conjugated polymer-inorganic hybrid materials. AB - Co-assembly of an inorganic-organic hybrid material through the combination of supramolecular organogel self-assembly, phase partitioning of a conjugated polymer (CP) and transcription of an inorganic oxide leads to a hybrid material with structured domains of organogel, CP and silica within tube and rod microstructures. PMID- 23727662 TI - Stimulation of Toll-like receptor-1/2 combined with Velcade increases cytotoxicity to human multiple myeloma cells. AB - An increasing body of evidence supports the important role of adhesion to bone marrow microenvironment components for survival and drug resistance of multiple myeloma (MM) cells. Previous studies suggested that stimulation of Toll-like receptors by endogenous ligands released during inflammation and tissue damage may be pro-tumorigenic, but no studies have been performed in relation to modulation of cell adhesion and drug cytotoxicity. Here, we investigated the effect of TLR1/2 activation on adhesion of human myeloma cells to fibronectin, and their sensitivity to the proteasome inhibitor Velcade. It was found that TLR1/2 activation with Pam3CSK4 increased the cytotoxicity of Velcade in L363, OPM-2 and U266 human myeloma cells. This effect was not related to a decreased adhesion of the cells to fibronectin, but TLR1/2 activation stimulated the caspase-3 activity in Velcade-treated myeloma cells, which may be responsible for the enhanced cell death. Inhibitors of NF-kappaB and MAPK reduced the stimulatory effect. These findings indicate that TLR activation of MM cells could bypass protective effects of cell adhesion and suggest that TLR signaling may also have antitumorigenic potential. PMID- 23727664 TI - Differentiating core and co-opted mechanisms in calculation: the neuroimaging of calculation in aphasia. AB - The role of language in exact calculation is the subject of debate. Some behavioral and functional neuroimaging investigations of healthy participants suggest that calculation requires language resources. However, there are also reports of individuals with severe aphasic language impairment who retain calculation ability. One possibility in resolving these discordant findings is that the neural basis of calculation has undergone significant reorganization in aphasic calculators. Using fMRI, we examined brain activations associated with exact addition and subtraction in two patients with severe agrammatic aphasia and retained calculation ability. Behavior and brain activations during two-digit addition and subtraction were compared to those of a group of 11 healthy, age matched controls. Behavioral results confirmed that both patients retained calculation ability. Imaging findings revealed individual differences in processing, but also a similar activation pattern across patients and controls in bilateral parietal cortices. Patients differed from controls in small areas of increased activation in peri-lesional regions, a shift from left fronto-temporal activation to the contralateral region, and increased activations in bilateral superior parietal regions. Our results suggest that bilateral parietal cortex represents the core of the calculation network and, while healthy controls may recruit language resources to support calculation, these mechanisms are not mandatory in adult cognition. PMID- 23727665 TI - Event-related cerebral hemodynamics reveal target-specific resource allocation for both "go" and "no-go" response-based vigilance tasks. AB - Transcranial Doppler sonography was used to measure cerebral blood flow velocity (CBFV) in the right and left cerebral hemispheres during the performance of a 50 min visual vigilance session. Observers monitored a simulated flight of unmanned aerial vehicles for cases in which one of the vehicles was flying in an inappropriate direction relative to its cohorts. Two types of vigilance tasks were employed: a traditional task in which observers made button press ("go") responses to critical signals, and a modification of the traditional task called the Sustained Attention to Response Task (SART) in which "go" responses acknowledged nonsignal events and response withholding ("no-go") signified signal detection. Signal detections and global CBFV scores declined over time. In addition, fine-grained event-related analyses revealed that the detection of signals was accompanied by an elevation of CBFV that was not present with missed signals. As was the case with the global scores, the magnitude of the transient CBFV increments associated with signal detection also declined over time, and these findings were independent of task type. The results support the view of CBFV as an index of the cognitive evaluation of stimulus significance, and a resource model of vigilance in which the need for continuous attention produces a depletion of information-processing assets that are not replenished as the task progresses. Further, temporal declines in the magnitude of event-related CBFV in response to critical signals only is evidence that the decrement function in vigilance is due to attentional processing and not specific task elements such as the required response format. PMID- 23727666 TI - Facile hydrothermal preparation of graphene oxide nanoribbons from graphene oxide. AB - Graphene oxide nanoribbons (GONR) with regular edges have been prepared by a facile hydrothermal method. The relatively high yield and convenient preparation of GONR eventually make graphene nanoribbons (GNR) accessible in the field of composite materials where bulk quantities of nanoribbons are required. PMID- 23727667 TI - Simple spectrophotometric method for determination of melamine in liquid milks based on green Mannich reaction. AB - A new and simple spectrophotometric method has been developed and validated for measuring the contamination of melamine in different milk products. The method is based upon measuring the absorption of the complex formed from melamine, 4 hydroxyacetophenone (Hap) and 1-pyrene carboxaldehyde (Pcd), which was adapted from the Mannich reaction. Quantitative analysis was done at a wavelength of 236 nm within a few minutes. The reaction was optimized by focusing on both obtaining high performance of the method and to concern the volatility and toxicity of used reagents. This method provided a linear dynamic range, limit of detection and limit of quantification of 0.100-3.78, 0.08 and 0.14 mg L(-1), respectively. The relative standard deviation (RSD) was 3.6% (n=10). The recoveries of melamine spiked liquid milk samples, with melamine concentrations of 0.63, 1.26, 1.89 and 2.52 mg L(-1), were 87.7+/-3.7%, 91.1+/-8.8%, 89.2+/-4.4% and 90.6+/-3.6% (n=3), respectively. PMID- 23727668 TI - A blue emission polymer: synthesis, photophysical and electrochemical properties. AB - A novel pi-conjugated polymer (PCPyrene) containing N-benzylcarbazole and pyrene units has been synthesized and characterized. The polymer possesses high thermal stability with the decomposition temperature of 440 degrees C. It shows higher fluorescence quantum yields of in solution and solid state, respectively. PCPyrene can emit bright blue-lights both in different organic solutions (440-460 nm) and in the solid state (492 nm). Compared the emission spectra of PCPyrene in solutions with in solid state, the solid state emission of PCPyrene is significantly red-shifted. Additionally, it is not obvious changes of the solid emission spectra even after being annealed at 150 degrees C under nitrogen for 24 h. The electrochemical properties and energy levels of PCPyrene were also investigated by cyclic voltammetry. Furthermore, in order to provide a basis forecasting the structure-physical property relationships, the photophysical properties of PCPyrene have been carefully investigated by fluorescence emission and UV-vis absorption spectra. PMID- 23727669 TI - Synthesis, spectral characterization, molecular modeling, thermal study and biological evaluation of transition metal complexes of a bidentate Schiff base ligand. AB - Complexes of copper(II) and nickel(II) of general composition M(L)2X2, have been synthesized [where L=3-Bromoacetophenone thiosemicarbazone and X=CH3COO(-), Cl(-) and NO3(-)]. All the complexes were characterized by elemental analysis, magnetic moments, IR, electronic and EPR spectral studies. The ligand behaved as bidentate and coordinated through sulfur of -C=S group and nitrogen atoms of -C=N group. The copper(II) and nickel(II) complexes were found to have magnetic moments 1.94 2.02 BM, 2.96-3.02 BM respectively which was corresponding to one and two unpaired electrons respectively. The molar conductance of the complexes in solution of DMSO lies in the range of 10-20 Omega(-1) cm(2) mol(-1) indicating their non-electrolytic behavior. On the basis of EPR, electronic and infrared spectral studies, tetragonal geometry has been assigned for copper(II) complexes and an octahedral geometry for nickel(II) complexes. The values of Nephelauxetic parameter beta lie in the range 0.19-0.37 which indicated the covalent character in metal ligand 'sigma' bond. Synthesized ligand and its copper(II) and nickel(II) complexes have also been screened against different bacterial and fungal species which suggested that complexes are more active than the ligands in antimicrobial activities. PMID- 23727670 TI - Conformational stability, vibrational spectra, HOMO-LUMO and NBO analysis of 1,3,4-thiadiazolidine-2,5-dithione with experimental (FT-IR and FT-Raman) techniques and scaled quantum mechanical calculations. AB - The experimental and theoretical study on the structure and vibrations of 1,3,4 thiadiazolidine-2,5-dithione (TDZD) is presented. The FT-IR spectra (4000-400 cm( 1)) and the FT-Raman spectra (4000-50 cm(-1)) of the title molecule have been recorded. The energies of TDZD were obtained for all the possible four conformers from HF and DFT with 6-311G(d,p) and 6-311++G(d,p) basis set calculations. From the computational results, conformer C4 is identified as the most stable conformers of TDZD. The spectroscopic and theoretical results are compared with the corresponding properties for TDZD of C4 conformer. The temperature dependence of thermodynamic properties has been analyzed. Molecular stability and bond strength were investigated by applying the natural bond orbital analysis (NBO). The calculated HOMO and LUMO energies show that charge transfer occurs in the molecules. Information about the size, shape, charge density distribution, and site of chemical reactivity of the molecules has been obtained by mapping electron density isosurface with electrostatic potential (ESP). The dipole moment (lambda) and polarizability (alpha), anisotropy polarizability (Deltaalpha) and first hyperpolarizability (betatotal) of the molecule have been reported. PMID- 23727671 TI - Probing the micellar properties of Quinacrine 2HCl and its binding with surfactants and human serum albumin. AB - This manuscript reports physicochemical behavior of an antimalarial drug Quinacrine 2HCl (QUN) drug as well as its interaction with surfactant and Human Serum Albumin (HSA). Surface tension and specific conductivity were employed to detect the critical micelle concentration (CMC) and thus its surface and thermodynamic parameters were calculated. Solublization of this drug within micelles of anionic surfactant sodium dodecyl sulfate (SDS) has also been studied. UV/Visible spectroscopy was used to calculate partition coefficient (Kx), free energy of partition and number of drug molecules per micelle. The complexation of drug with HSA at physiological conditions (pH 7.4) has been analyzed by using UV/Visible and fluorescence spectroscopy. In this way the values of drug-protein binding constant, number of binding sites and free energy of binding were calculated. PMID- 23727672 TI - FT-IR spectroscopic analyses of 4-hydroxy-1-methyl-3-[2-nitro-2-oxoacetyl 2(1H)quinolinone (HMNOQ). AB - In the present work, a combined experimental and theoretical study on molecular structure and vibrational frequencies of 4-hydroxy-1-methyl-3-[2-nitro-2 oxoacetyl-2(1H)quinolinone (HMNOQ) was reported. The FT-IR spectrum of HMNCQ is recorded in the solid phase. The equilibrium geometries, harmonic vibrational frequencies, thermo-chemical parameters, total dipole moment and HOMO-LUMO energies are calculated by density functional theory DFT/B3LYP utilizing 6 311G(d,p) basis set. Results showed that HMNOQ is highly recommended to be a promising structure for many applications in optoelectronic devices due to its high calculated dipole moment value (9 Debye) which indicates its high reactivity to interact with the surrounding molecules. The HOMO-LUMO energy gap of HMNOQ is 4 eV. PMID- 23727673 TI - Raman spectroscopic characterization of a synthetic, non-stoichiometric Cu-Ba uranyl phosphate. AB - Crystals of phases belonging to the autunite group (general formula X(2+)(UO2)2(X(5+)O4)2.nH2O), specifically the uranyl phosphates (X(5+)=P) metauranocircite (X(2+)=Ba(2+)), metatorbernite (X(2+)=Cu(2+)) and a barian metatorbenite phase (X(2+)=Cu(2+)/Ba(2+)), have been synthesized in a silica gel medium and characterized by Raman spectroscopy. The Raman spectra showed bands in the range 750-1100 cm(-1), which were attributed to the nu1 and nu3 (PO(4))(3-) and (UO(2))(2+) stretching vibrations. By using the wavenumbers of the most intense and well defined nu1 (UO(2))(2+) vibration, the U-O bonds lengths were calculated for the three uranyl phosphate minerals. The results are in good agreement with previous single crystal structure analysis data. Bands in the spectra from 350 to 700 cm(-1) were attributed to the (PO(4))(3-) bending modes. Moreover, in the range 70-350 cm(-1), two groups of bands could be defined. The first group, with vibrations at lower wavenumbers, was attributed to the lattice modes and the second group, from 150 to 350 cm(-1), was assigned to the nu2 (UO(2))(2+) bending mode. Finally, in the case of the barian metatorbernite, bands in the range 1500-3800 cm(-1) were assigned to the OH stretching and the nu2 bending vibrations of water molecules. In this phase, all the vibrations show bandshifts when compared to the vibrations in metatorbernite. These bandshifts can be related to transitional Cu-O and Ba-O bond lengths. PMID- 23727674 TI - Vibrational spectroscopic investigations and computational study of 5-tert-butyl N-(4-trifluoromethylphenyl)pyrazine-2-carboxamide. AB - Pyrazine and its derivatives form an important class of compounds present in several natural flavors and complex organic molecules. Quantum chemical calculations of the equilibrium geometry, harmonic vibrational frequencies, infrared intensities and Raman activities of 5-tert-Butyl-N-(4 trifluoromethylphenyl)pyrazine-2-carboxamide in the ground state were carried out by using density functional methods. Potential energy distribution of normal modes of vibrations was done using GAR2PED program. Nonlinear optical behavior of the examined molecule was investigated by the determination of first hyperpolarizability. The calculated HOMO and LUMO energies show the chemical activity of the molecule. The stability of the molecule arising from hyper conjugative interaction and charge delocalization has been analyzed using NBO analysis. The calculated geometrical parameters are in agreement with that of similar derivatives. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. PMID- 23727675 TI - Comparative study between derivative spectrophotometry and multivariate calibration as analytical tools applied for the simultaneous quantitation of Amlodipine, Valsartan and Hydrochlorothiazide. AB - Four simple, accurate and specific methods were developed and validated for the simultaneous estimation of Amlodipine (AML), Valsartan (VAL) and Hydrochlorothiazide (HCT) in commercial tablets. The derivative spectrophotometric methods include Derivative Ratio Zero Crossing (DRZC) and Double Divisor Ratio Spectra-Derivative Spectrophotometry (DDRS-DS) methods, while the multivariate calibrations used are Principal Component Regression (PCR) and Partial Least Squares (PLSs). The proposed methods were applied successfully in the determination of the drugs in laboratory-prepared mixtures and in commercial pharmaceutical preparations. The validity of the proposed methods was assessed using the standard addition technique. The linearity of the proposed methods is investigated in the range of 2-32, 4-44 and 2-20 MUg/mL for AML, VAL and HCT, respectively. PMID- 23727676 TI - Vibrational spectra, DFT quantum chemical calculations and conformational analysis of P-iodoanisole. AB - The solid phase FT-IR and FT-Raman spectra of P-iodoanisole (P-IA) have been recorded in the regions 400-4000 and 50-4000 cm(-1), respectively. The spectra were interpreted in terms of fundamentals modes, combination and overtone bands. The structure of the molecule was optimized and the structural characteristics were determined by ab initio (HF) and density functional theory (B3LYP) methods with LanL2DZ as basis set. The potential energy surface scan for the selected dihedral angle of P-IA has been performed to identify stable conformer. The optimized structure parameters and vibrational wavenumbers of stable conformer have been predicted by density functional B3LYP method with LanL2DZ (with effective core potential representations of electrons near the nuclei for post third row atoms) basis set. The nucleophilic and electrophilic sites obtained from the molecular electrostatic potential (MEP) surface were calculated. The temperature dependence of thermodynamic properties has been analyzed. Several thermodynamic parameters have been calculated using B3LYP with LanL2DZ basis set. PMID- 23727677 TI - [From the Japanese Journal of Clinical Hematology, vol 54, no.5, May 2013, Picture in Clinical Hematology : Case of tropical malaria]. PMID- 23727678 TI - Innovative cell-modifying technology targeting cancer stem cell. PMID- 23727679 TI - Aberrant cytosine hydroxymethylation in hematologic malignancies. PMID- 23727680 TI - Regulation of hematopoiesis by mesenchymal stem cells. PMID- 23727681 TI - Mesenchymal stem cell-based therapy: Bench to Bedside. PMID- 23727682 TI - Retrospective analysis of eltrombopag for the treatment of refractory primary immune thrombocytopenia in Japan. AB - Eltrombopag, an oral thrombopoietin receptor agonist, is a novel drug that can be used in cases with previously-treated primary immune thrombocytopenia (ITP). In this study, we retrospectively analyzed 22 Japanese ITP patients treated in four hospitals. A responder was defined as a patient achieving a platelet count between 50,000/MUl and 400,000/MUl, at 75% or more of on-treatment assessments. Excluding 2 patients whose treatments were interrupted at their request, 13 of 20 patients (65%) were responders. Ten of the 13 responders had been taking more than 5 mg of a steroid preparation in the form of prednisolone or its equivalent. In 7 of these patients, the steroid dose could be tapered to 5 mg or less. Disappearance or amelioration of hemorrhagic symptoms was observed in 11 of 19 patients who had these symptoms prior to treatment (9 of 10 responders, 2 of 7 non-responders), and the improvement rate was greater in responders (p=0.018). No factors were identified as being related to efficacy. Reported adverse effects were fever (1), malaise (3), headache (2), and muscle pain (1). One severe adverse event, cerebral thromboembolism, was reported in 1 patient. Although eltrombopag is a useful therapeutic agent for refractory ITP, it is necessary to evaluate its position in the overall treatment strategy for ITP after assessing long-term complications as well as therapeutic effects. PMID- 23727683 TI - Safety and effectiveness of low-dose lenalidomide therapy for multiple myeloma complicated with bortezomib-associated interstitial pneumonia. AB - A 78-year-old woman was diagnosed with multiple myeloma (MM: IgG kappa type, stage IIIA, ISS III) at a nearby hospital in August 2010. High-dose dexamethasone therapy was ineffective, and she was treated with 2 courses of bortezomib. She was referred to our hospital with back pain and dyspnea in November. She was diagnosed with interstitial pneumonia (IP) and improved rapidly with steroid pulse therapy. Because the involvement of bortezomib was suspected in IP, lenalidomide therapy was selected for MM. Lenalidomide (15 mg) was administered for 2 courses. The patient achieved a PR and the treatment is still ongoing with a good response. According to the interim report on PMS (post-marketing surveillance), 3 of the 1,177 patients treated with lenalidomide developed IP. The dose level was 25 mg in 2 cases and 10 mg in 1 case. The outcomes of these patients were death in 1 case, not recovered in 1 case, and unknown in 1 case. When lenalidomide is used to treat bortezomib-induced IP, there are no rules or regulations about its dose level. In the present case, the dose of lenalidomide (15 mg) was based on the retreatment dose after bone marrow suppression. Low-dose lenalidomide therapy was effective and safe against MM with a bortezomib associated lung disorder. PMID- 23727684 TI - Very low-dose lenalidomide therapy for elderly multiple myeloma patients. AB - Lenalidomide treatment for refractory or relapsed multiple myeloma in elderly patients may be feasible in an outpatient setting. However, difficulties have been associated with the management of adverse effects. Therefore, a dose reduction in lenalidomide has been recommended in some cases. In this report, we encountered the successful treatment of myeloma in 6 elderly patients (aged above 70 years) with very low-dose lenalidomide (5 mg daily). Four patients exhibited more than a partial response with an 8.6 months median follow-up period, which was comparable with previous findings. The major adverse effect observed was infection, which occurred during the first several cycles. Others were less toxic, especially the absence of grade 3/4 toxicities for hematological adverse effects.Although a dose reduction in lenalidomide therapy for elderly patients is controversial, a very low dose could be safe and effective. Our group is currently conducting a multi-center prospective trial to evaluate the efficacy of low-dose lenalidomide therapy. PMID- 23727685 TI - Primary pleural of mucosa-associated lymphoid tissue lymphoma. AB - A 68-year-old female presented with shortness of breath. Chest radiography showed pleural effusion in the right side only. She was suspected of having ovarian cancer because CA125 levels were increased in the pleural effusion, and she consulted our hospital. A chest CT scan showed right pleural nodular lesions. Thoracoscopic pleural resection was performed. Histologic examination of a biopsy specimen showed the diffuse infiltration of small~medium, mature lymphocytes. These lymphocytes were found to be positive for CD20 and CD79a, but negative for CD3 by immunohistochemistry. These results were interpreted as being consistent with a diagnosis of mucosa-associated lymphoid tissue lymphoma (MALT lymphoma). She commenced chemotherapy with R-CHOP, and the pleural effusion disappeared. MALT lymphoma arising in the pleura is very rare, with only 12 published cases, and most cases have been described in Japan. CA125 levels correlated with the stage, tumor bulk, and presence of effusion. This patient exhibited a high level of CA125 that decreased with therapy. PMID- 23727686 TI - Effective azacitidine treatment for myelodysplastic syndrome transformed from essential thrombocythemia. AB - A 68-year-old woman with essential thrombocythemia had been treated with hydroxycarbamide and aspirin for 13 years. She exhibited the rapid progression of anemia, and a bone marrow examination showed dysplasia of the erythroid cells, myeloid cells, and megakaryocytes. Karyotype analysis indicated complex abnormalities including der (5;21)(p10;q10). She was diagnosed with myelodysplastic syndrome (MDS), refractory anemia with excess blasts-1 (RAEB-1). Lenalidomide was started, but no improvement in anemia was recorded. Lenalidomide was discontinued due to eosinophilia, basophilia, and a skin rash. Azacitidine was administered. The patient became transfusion independent, and a complete cytogenetic response was achieved with three courses of azacitidine. However, disease progression to acute myeloid leukemia (AML) was observed after an additional two courses of azacitidine, which was resistant to induction chemotherapy. The patient died five months later from AML transformation. Azacitidine may be effective in MDS transformed from essential thrombocythemia, and also in lenalidomide-resistant MDS with the deletion of 5q. PMID- 23727687 TI - Development of donor cell leukemia mimicking hematogones after unrelated cord blood transplantation for relapsed acute lymphoblastic leukemia. AB - A 26-year-old woman, who developed ALL when she was eighteen years old, achieved remission after chemotherapy. Her ALL relapsed when she was twenty-two years old. After re-induction therapy, she underwent cord blood transplantation. Her bone marrow examination on the 42nd day revealed a lymphoblast count of 16%. She was observed without any therapy, but her bone marrow blast count continued to be around 6% for three years without any symptoms. The bone marrow blast fraction originated from the cord blood. Surface marker analysis of the blast fraction initially revealed a pattern of hematogones that was CD10 and CD19 positive, but then showed a myeloblast pattern that was CD13 and CD33 positive. AML developed as donor cell leukemia. When blasts appear in the early phase after transplantation and persist, an observation period is necessary with molecular chimerism, morphology, and surface marker analysis of the blast fraction to consider relapse, hematogones, or donor cell leukemia. PMID- 23727689 TI - Tunable spin-orbit coupling and quantum phase transition in a trapped Bose Einstein condensate. AB - Spin-orbit coupling (SOC), the intrinsic interaction between a particle spin and its motion, is responsible for various important phenomena, ranging from atomic fine structure to topological condensed matter physics. The recent experimental breakthrough on the realization of SOC for ultra-cold atoms provides a completely new platform for exploring spin-orbit coupled superfluid physics. However, the SOC strength in the experiment is not tunable. In this report, we propose a scheme for tuning the SOC strength through a fast and coherent modulation of the laser intensities. We show that the many-body interaction between atoms, together with the tunable SOC, can drive a quantum phase transition (QPT) from spin balanced to spin-polarized ground states in a harmonic trapped Bose-Einstein condensate (BEC), which resembles the long-sought Dicke QPT. We characterize the QPT using the periods of collective oscillations of the BEC, which show pronounced peaks and damping around the quantum critical point. PMID- 23727690 TI - A mouse model of adult-onset anaemia due to erythropoietin deficiency. AB - Erythropoietin regulates erythropoiesis in a hypoxia-inducible manner. Here we generate inherited super-anaemic mice (ISAM) as a mouse model of adult-onset anaemia caused by erythropoietin deficiency. ISAM express erythropoietin in the liver but lack erythropoietin production in the kidney. Around weaning age, when the major erythropoietin-producing organ switches from the liver to the kidney, ISAM develop anaemia due to erythropoietin deficiency, which is curable by administration of recombinant erythropoietin. In ISAM severe chronic anaemia enhances transgenic green fluorescent protein and Cre expression driven by the complete erythropoietin-gene regulatory regions, which facilitates efficient labelling of renal erythropoietin-producing cells. We show that the majority of cortical and outer medullary fibroblasts have the innate potential to produce erythropoietin, and also reveal a new set of erythropoietin target genes. ISAM are a useful tool for the evaluation of erythropoiesis-stimulating agents and to trace the dynamics of erythropoietin-producing cells. PMID- 23727691 TI - Biogeochemical processes controlling the mobility of major ions and trace metals in aquitard sediments beneath an oil sand tailing pond: laboratory studies and reactive transport modeling. AB - Increased production and expansion of the oil sand industry in Alberta are of great benefit to the economy, but they carry major environmental challenges. The volume of fluid fine tailings requiring storage is 840*10(6) m(3) and growing, making it imperative that we better understand the fate and transport of oil sand process-affected water (OSPW) seepage from these facilities. Accordingly, the current study seeks to characterize both a) the potential for major ion and trace element release, and b) the principal biogeochemical processes involved, as tailing pond OSPW infiltrates into, and interacts with, underlying glacial till sediments prior to reaching down gradient aquifers or surface waters. Objectives were addressed through a series of aqueous and solid phase experiments, including radial diffusion cells, an isotope analysis, X-ray diffraction, and sequential extractions. The diffusion cells were also simulated in a reactive transport framework to elucidate key reaction processes. The experiments indicate that the ingress and interaction of OSPW with the glacial till sediment-pore water system will result in: a mitigation of ingressing Na (retardation), displacement and then limited precipitation of exchangeable Ca and Mg (as carbonates), sulfate reduction and subsequent precipitation of the produced sulfides, as well as biodegradation of organic carbon. High concentrations of ingressing Cl (~375 mg L(-1)) and Na (~575 mg L(-1)) (even though the latter is delayed, or retarded) are expected to migrate through the till and into the underlying sand channel. Trace element mobility was influenced by ion exchange, oxidation-reduction, and mineral phase reactions including reductive dissolution of metal oxyhydroxides - in accordance with previous observations within sandy aquifer settings. Furthermore, although several trace elements showed the potential for release (Al, B, Ba, Cd, Mn, Pb, Si, Sr), large-scale mobilization is not supported. Thus, the present results suggest that in addition to the commonly cited naphthenic acids, remediation of OSPW-impacted groundwater will need to address high concentrations of major ions contributing to salinization. PMID- 23727692 TI - Fabrication and properties of TiO2 nanofilms on different substrates by a novel and universal method of Ti-ion implantation and subsequent annealing. AB - We report a new, novel and universal method to fabricate high-quality titanium dioxide (TiO2) nanofilms on different substrates by a solid phase growth process of ion implantation and subsequent annealing in oxygen atmosphere. Ti ions were implanted into fused silica, soda lime glass, Z-cut quartz, or (0001) alpha sapphire by a metal vapor vacuum arc (MEVVA) ion source implanter to fluences of 0.75, 1.5 and 3 * 10(17) ions cm(-2) with a nominal accelerating voltage of 20 kV. To understand the influence of the annealing temperature, time, and substrate on the formation and phase transformation of the TiO2 nanofilms, the Ti-ion implanted substrates were annealed in oxygen atmosphere from 500 to 1000 degrees C for 1-6 h. The formation of TiO2 nanofilms resulted from the slow out-diffusion of implanted Ti ions from the substrates which were then oxidized at the surfaces. The thickness and phase of the nanofilms can be tailored by controlling the implantation and annealing parameters. Since the TiO2 nanofilms are formed under high temperature and low growth rate, they show good crystallinity and antibacterial properties, with good film adhesion and stability, suggesting that the TiO2 nanofilms formed by this method have great potential in applications such as antibacterial and self-cleaning transparent glass. PMID- 23727695 TI - Job Perception of Counselors Employed at Integrated Counseling and Testing Centers for HIV in a District of South India. AB - BACKGROUND: The counselors' form the backbone of HIV/AIDS control program, and for voluntary counseling and testing services to be effective counselors' opinions are crucial. PURPOSE: To assess the perceptions of integrated counseling and testing center (ICTC) counselors with respect to the training received, problems faced in providing services, and job satisfaction. METHODS: Qualitative methods such as 1 focus group discussion and 7 in-depth interviews were conducted among 14 counselors employed at 13 ICTCs in a costal district of south India. RESULTS: The counselors identified the need for improving refresher training; job perception and satisfaction among counselors was found to be poor; issues such as shared confidentiality and targets for counseling were perceived to affect the ICTC services. CONCLUSION: The issues identified by counselors such as problems related to refresher training, targets set for counseling and testing, the pay scale and shared confidentiality should be addressed for better service delivery. PMID- 23727696 TI - Exertional rhabdomyolysis in an acutely detrained athlete/exercise physiology professor. AB - The authors report a case of exercise-induced (exertional) rhabdomyolysis in a male athlete/exercise physiology professor who started a high-intensity resistance training program after a period of detraining. The subject performed 1 high-intensity resistance training session that consisted of 48 total sets of push-ups (24) and chin-ups (24) with no rest between the sets. Two days after the exercise session, the subject reported "Cola colored" urine. On arriving at the hospital, test results indicated elevated myoglobin and creatine kinase (CK) levels (59 159 U/L; normal is 20-200 U/L). Treatment included intravenous hydration with sodium bicarbonate to reduce myoglobin, blood work to monitor CK levels, and acupuncture from the shoulder to hand. Three weeks posttreatment, the subject started to exercise again. This case study illustrates that unaccustomed exercise in the form of high-intensity resistance training may be harmful (ie, severe delayed onset muscle soreness or even worse, as reported in this case, rhabdomyolysis) to detrained athletes. PMID- 23727693 TI - Correlative nanoscale imaging of actin filaments and their complexes. AB - Actin remodeling is an area of interest in biology in which correlative microscopy can bring a new way to analyze protein complexes at the nanoscale. Advances in EM, X-ray diffraction, fluorescence, and single molecule techniques have provided a wealth of information about the modulation of the F-actin structure and its regulation by actin binding proteins (ABPs). Yet, there are technological limitations of these approaches to achieving quantitative molecular level information on the structural and biophysical changes resulting from ABPs interaction with F-actin. Fundamental questions about the actin structure and dynamics and how these determine the function of ABPs remain unanswered. Specifically, how local and long-range structural and conformational changes result in ABPs induced remodeling of F-actin needs to be addressed at the single filament level. Advanced, sensitive and accurate experimental tools for detailed understanding of ABP-actin interactions are much needed. This article discusses the current understanding of nanoscale structural and mechanical modulation of F actin by ABPs at the single filament level using several correlative microscopic techniques, focusing mainly on results obtained by Atomic Force Microscopy (AFM) analysis of ABP-actin complexes. PMID- 23727697 TI - The prevalence of undiagnosed concussions in athletes. AB - OBJECTIVE: Previous studies suggest athletes underreport concussions. We sought to determine whether athletes in our clinics have sustained previous concussions that went undiagnosed. DESIGN: Multicentered cross sectional study. SETTING: Two sport concussion clinics. PATIENTS: Patients diagnosed with sport-related concussions or concussions with injury mechanisms and forces similar to those observed in sports were included. MAIN OUTCOME MEASURES: The proportion of patients who answered "yes" to the following question were defined as having a previously undiagnosed concussion: "Have you ever sustained a blow to the head which was NOT diagnosed as a concussion but was followed by one or more of the signs and symptoms listed in the Post Concussion Symptom Scale?" RESULTS: Of the 486 patients included in the final analysis, 148 (30.5%) patients reported a previously undiagnosed concussion. Athletes reporting previously undiagnosed concussions had a higher mean Post Concussion Symptom Scale (PCSS) score (33 vs 25; P < 0.004) and were more likely to have lost consciousness (31% vs 22%; P = 0.038) with their current injury than athletes without previously undiagnosed concussions. CONCLUSIONS: Nearly one-third of athletes have sustained previously undiagnosed concussions, defined as a blow to the head followed by the signs and symptoms included in the PCSS. Furthermore, these previously undiagnosed concussions are associated with higher PCSS scores and higher loss of consciousness rates when future concussions occur. CLINICAL RELEVANCE: Many athletes have sustained previous blows to the head that result in the signs and symptoms of concussion but have not been diagnosed with a concussion. These injuries are associated with increased rates of loss of consciousness and higher symptom scale scores with future concussions. PMID- 23727698 TI - Real-time 3-dimensional dynamics of functional mitral regurgitation: a prospective quantitative and mechanistic study. AB - BACKGROUND: Three-dimensional transthoracic echocardiography (3D-TTE) with dedicated software permits quantification of mitral annulus dynamics and papillary muscle motion throughout the cardiac cycle. METHODS AND RESULTS: Mitral apparatus 3D-TTE was acquired in controls (n=42), patients with left ventricle dysfunction and functional mitral regurgitation (LVD-FMR; n=43) or without FMR (LVD-noMR, n=35). Annulus in both normal and LVD-noMR subjects displayed saddle shape accentuation in early-systole (ratio of height to intercommissural diameter, 10.6 +/- 3.7 to 13.5 +/- 4.0 in normal and 9.1 +/- 4.3 to 12.6 +/- 3.6 in LVD-noMR; P<0.001 for diastole to early-systole motion, P=NS between those groups). In contrast, saddle shape was unchanged from diastole in FMR patients (10.0 +/- 6.4 to 8.0 +/- 5.2; P=NS, P<0.05 compared to both other groups). Papillary tips moved symmetrically towards to the midanterior annulus in control and LVD-noMR subjects, maintaining constant ratio of the distances between both tips to midannulus (PtAR) throughout systole. In LVD-FMR patients midsystolic posterior papillary tip to anterior annulus distance was increased, resulting in higher PtAR (P=0.05 compared to both other groups). Mechanisms of early- and midsystolic FMR differed between different etiologies of LV dysfunction. In patients with anterior MI and global dysfunction annular function and dilatation were the dominant parameters, while papillary muscle motion was the predominant determinant of FMR in patients with inferior MI. CONCLUSIONS: Inadequate early systolic annular contraction and saddle-shape accentuation in patients with impaired LV contribute to early-mitral incompetency. Asymmetric papillary tip movement towards the midanterior annulus is a major determinant of mid- and late systolic functional mitral regurgitation. PMID- 23727699 TI - Impact of prenatal risk factors on congenital heart disease in the current era. AB - BACKGROUND: The healthcare burden related to congenital heart disease (CHD) is increasing with improving survival. We assessed changing trends in prenatal risk factors for CHD in the current era in a Canadian cohort. METHODS AND RESULTS: CHD patients <18 years old (n=2339) and controls without structural heart disease (n=199) were prospectively enrolled in an Ontario province-wide biobank registry from 2008-2011. Family history, frequency of extra-cardiac anomalies (ECAs), and antenatal risk factors were assessed. Temporal trends were analyzed and associations with CHD were measured using linear and logistic regression. Family history of CHD and frequency of major ECAs was higher in cases versus controls (P<0.001). Despite an increase in genetic testing in the recent era, only 9.5% of cases with CHD had a confirmed genetic diagnosis. Yield of genetic testing (ie, frequency of abnormal results) was higher in familial and syndromic cases. There was an increase in parental age at conception, maternal prepregnancy body mass index, maternal urinary tract infections, type 1 diabetes, and exposure to nonfertility medications during pregnancy from 1990-2011. Later year of birth, family history of CHD, presence of major ECAs, maternal smoking during pregnancy, and maternal medication exposure were associated with increased odds of CHD (P<0.05 for all). Advanced parental age was associated with increased odds of CHD caused by genetic abnormalities. CONCLUSIONS: The increase in prenatal risk factors for CHD highlights the need for more rigorous ascertainment of genetic and environmental factors including gene-environment interactions that contribute to CHD. PMID- 23727700 TI - Acute failure of catheter ablation for ventricular tachycardia due to structural heart disease: causes and significance. AB - BACKGROUND: Acute end points of catheter ablation for ventricular tachycardia (VT) remain incompletely defined. The aim of this study is to identify causes for failure in patients with structural heart disease and to assess the relation of this acute outcome to longer-term management and outcomes. METHODS AND RESULTS: From 2002 to 2010, 518 consecutive patients (84% male, 62 +/- 14 years) with structural heart disease underwent a first ablation procedure for sustained VT at our institution. Acute ablation failure was defined as persistent inducibility of a clinical VT. Acute ablation failure was seen in 52 (10%) patients. Causes for failure were: intramural free wall VT in 13 (25%), deep septal VT in 9 (17%), decision not to ablate due to proximity to the bundle of His, left phrenic nerve, or a coronary artery in 3 (6%), and endocardial ablation failure with inability or decision not to attempt to access the epicardium in 27 (52%) patients. In multivariable analysis, ablation failure was an independent predictor of mortality (hazard ratio 2.010, 95% CI 1.147 to 3.239, P=0.004) and VT recurrence (hazard ratio 2.385, 95% CI 1.642 to 3.466, P<0.001). CONCLUSIONS: With endocardial or epicardial ablation, or both, acute ablation failure was seen in 10% of patients, largely due to anatomic factors. Persistence of a clinical VT is associated with recurrence and comparatively higher mortality. PMID- 23727702 TI - Propargylation of arabinogalactan with propargyl halides--a facile route to new functionalized biopolymers. AB - New arabinogalactan propargyl ethers with degree of substitution (DS) up to 2.8 have been obtained by propargylation of arabino-3,6-galactan (AG) with propargyl bromide (PB) in the two-phase system 30-60% KON aqueous solution/toluene in the presence of triethylbenzylammonium chloride (TEBAS) or without catalyst (ambient temperature, 1-24 h) in 20-87% yields. The highest yields have been reached using TEBAS as phase-transfer catalyst, though the non-catalytic version proves to be also efficient (DS 2.8, 70% yield). The propargylation of AG is less effective in the systems MON (M=Na, K)/DMSO. DS of propargyl AG reaches 1.8 (70% yield) when propargyl chloride is used as propargylating agent, while with PB under the same conditions DS value does not exceed 0.4-0.6, the yields being 44-65%. Under the action of t-BuOK/DMSO system, the AG propargyl ethers have been isomerized to the corresponding unstable allenyl ethers. AG propargyl ethers with DS 2.0 have been almost exhaustively metallated with Ag2O/NH3 system to give AG-Ag acetylides derivatives with Ag/C=C ratio equaling 0.95. PMID- 23727701 TI - Selective inactivation of PTEN in smooth muscle cells synergizes with hypoxia to induce severe pulmonary hypertension. AB - BACKGROUND: Pulmonary vascular remodeling in pulmonary hypertension (PH) is characterized by increased vascular smooth muscle cell (SMC) and adventitial fibroblast proliferation, small vessel occlusion, and inflammatory cell accumulation. The underlying molecular mechanisms driving progression remain poorly defined. We have focused on loss of the phosphatase PTEN in SMCs as a major driver of pathological vascular remodeling. Our goal was to define the role of PTEN in human PH and in hypoxia-induced PH using a mouse model with inducible deletion of PTEN in SMCs. METHODS AND RESULTS: Staining of human biopsies demonstrated enhanced inactive PTEN selectively in the media from hypertensive patients compared to controls. Mice with induced deletion of PTEN in SMCs were exposed to normoxia or hypoxia for up to 4 weeks. Under normoxia, SMC PTEN depletion was sufficient to induce features of PH similar to those observed in wild-type mice exposed to chronic hypoxia. Under hypoxia, PTEN depletion promoted an irreversible progression of PH characterized by increased pressure, extensive pulmonary vascular remodeling, formation of complex vascular lesions, and increased macrophage accumulation associated with synergistic increases in proinflammatory cytokines and proliferation of both SMCs and nonSMCs. CONCLUSIONS: Chronic inactivation of PTEN selectively in SMC represents a critical mediator of PH progression, leading to cell autonomous events and increased production of factors correlated to proliferation and recruitment of adventitial and inflammatory cells, resulting in irreversible progression of the disease. PMID- 23727703 TI - Synthesis of 6'-acylamido-6'-deoxy-alpha-D-galactoglycerolipids. AB - Aminoglycoglycerolipid 1a isolated from an algal extract showed activity against the enzyme Myt1 kinase with an IC50 value of 0.12 MUg/mL. Its analogues, 6' acylamido-6'-deoxy-alpha-D-galactoglycerolipids (2a-g) were synthesized in an efficient way with high stereoselectivity. The key step was to employ a 4-OAc protecting group of the galactosyl donor 14 as a remote neighboring participation group to give the glycoside with high alpha-anomeric selectivity (alpha:beta=32:1) in the glycosylation. The preliminary bioactivity screening showed that compound 2g exhibited good inhibition against Myt1 kinase. PMID- 23727704 TI - Anxiety, depression, quality of life and patient satisfaction in acne patients treated with oral isotretinoin. AB - Oral isotretinoin is effective in the clinical control of acne, but the relationship between this treatment and its psychosocial impact on the patient has not been completely clarified. The aim of this study was to determine if the use of oral isotretinoin in total accumulated doses of 120 mg/kg in a sample of 346 patients with moderate acne was useful in controlling symptoms of anxiety and/or depression and improving quality of life. A further objective was to ascertain the level of patient satisfaction with the treatment. After 30 weeks, there was a significant reduction in clinical symptoms (p < 0.001). The negative impact on quality of life, measured with the Dermatology Life Quality Index and the Health Survey Short-Form-36 (p < 0.001), showed a significant reduction, as did the Hospital Anxiety and Depression Scale scores for anxiety (p < 0.001) and depression (p < 0.005). At the end of the study, the mean level of patient satisfaction with improvement of symptoms was 84.4%. PMID- 23727705 TI - Abnormal carbenes derived from the 1,5-cycloaddition product between azides and alkynes: structural characterization of Pd(II) complexes and their catalytic properties. AB - The exclusive formation of the 1,5-cycloaddition product between azides and alkynes is taken advantage of in generating the first examples of abnormal carbenes from these precursors. This new route provides unprecedented post functionalization possibilities for such abnormal carbenes. PMID- 23727706 TI - Is aging recorded in blood Cu and Zn isotope compositions? AB - Recent isotopic observations of animal samples indicate body accumulation of heavy zinc and light copper throughout life. This hypothesis has never been tested for humans, but the existence of a relationship between blood isotopic composition and age could be promising for age assessment methodologies. Dietary habits can also influence the blood zinc isotope composition, being an additional source of isotopic variation. In order to reduce this putative source of variation, we selected a population living in an isolated area (Sakha Republic, Russia) where diverse foods are of limited availability. We sampled blood from 8 male and 31 female Yakut volunteers between the ages of 18 and 74. Zinc, iron and copper were purified by liquid chromatography on ion exchange resin and their stable isotope ratios were measured using multiple-collector inductively coupled plasma mass spectrometry. According to observations of animal samples, the (66)Zn/(64)Zn ratio increases with age. We also observe that the (65)Cu/(63)Cu ratio decreases with age, whereas iron isotopic compositions are unrelated to age. The copper and zinc isotope compositions of the Yakut's blood are significantly lighter and heavier, respectively, than in samples of European and Japanese populations. The Yakut is a circumpolar population in which individuals have an elevated basal metabolic rate in response to cold stress. This elevated basal metabolic rate could enhance copper and zinc isotopic fractionation by accelerating the turnover of the copper and zinc stores. PMID- 23727707 TI - [Adhesins of oral streptococci]. AB - Oral streptococci comprise a numerically prominent group of oral bacteria that occur primarily on the human tooth surface as members of the biofilm community, commonly referred to as dental plaque. These streptococci are not only causative of dental caries and are primers for colonization of periodontopathic bacteria, but also well known for their ability to colonize damaged heart valves, identified most frequently as primary etiological agents of infective endocarditis. A number of streptococcal cell surface components are known to contribute to colonization of the tooth surface including putative adhesins recognizing host sialic acid (sialic acid-binding adhesins). Interactions mediated by these adhesins include the attachment of these bacteria to saliva coated hydroxyapatite and their adhesion to erythrocytes, both of which are abolished or reduced by sialidase pretreatment of the corresponding host sialoglycoconjugate receptors. The sialic acid-binding adhesin on Streptococcus gordonii, an early colonizer on the tooth surface, has been molecularly analyzed. The adhesin, Hsa (203-kDa protein), consists of an N-terminal non repetitive region (NR1) including a signal sequence, a relatively short serine-rich region (SR1), a second non repetitive region (NR2), a long serine-rich region (SR2) containing 113 dodecapeptide repeats accounting for 75% of the whole protein, and a C-terminal cell wall anchoring domain. Therefore, it has been suggested that NR2, the putative sialic acid-binding domain of Hsa, is presented on the bacterial surface at the end of a long molecular stalk formed by SR2. The present review deals with the function and pathogenicity of oral streptococcal adhesins. PMID- 23727708 TI - [Visiting a cultural heritage site in South Korea/ Kudara and attending the 11th International Meeting of the Federation of Korean Microbiological Societies]. PMID- 23727709 TI - Interval data clustering using self-organizing maps based on adaptive Mahalanobis distances. AB - The self-organizing map is a kind of artificial neural network used to map high dimensional data into a low dimensional space. This paper presents a self organizing map for interval-valued data based on adaptive Mahalanobis distances in order to do clustering of interval data with topology preservation. Two methods based on the batch training algorithm for the self-organizing maps are proposed. The first method uses a common Mahalanobis distance for all clusters. In the second method, the algorithm starts with a common Mahalanobis distance per cluster and then switches to use a different distance per cluster. This process allows a more adapted clustering for the given data set. The performances of the proposed methods are compared and discussed using artificial and real interval data sets. PMID- 23727710 TI - Processing of invisible social cues. AB - Successful interactions between people are dependent on rapid recognition of social cues. We investigated whether head direction--a powerful social signal--is processed in the absence of conscious awareness. We used continuous flash interocular suppression to render stimuli invisible and compared the reaction time for face detection when faces were turned towards the viewer and turned slightly away. We found that faces turned towards the viewer break through suppression faster than faces that are turned away, regardless of eye direction. Our results suggest that detection of a face with attention directed at the viewer occurs even in the absence of awareness of that face. While previous work has demonstrated that stimuli that signal threat are processed without awareness, our data suggest that the social relevance of a face, defined more broadly, is evaluated in the absence of awareness. PMID- 23727711 TI - Conscious and unconscious face recognition is improved by high-frequency rTMS on pre-motor cortex. AB - Simulation process and mirroring mechanism appear to be necessary to the recognition of emotional facial expressions. Prefrontal areas were found to support this simulation mechanism. The present research analyzed the role of premotor area in processing emotional faces with different valence (positive vs. negative faces), considering both conscious and unconscious pathways. High frequency rTMS (10 Hz) stimulation was applied to prefrontal area to induce an activation response when overt (conscious) and covert (unconscious) processing was implicated. Twenty-two subjects were asked to detect emotion/no emotion (anger, fear, happiness, neutral). Error rates (ERs) and response times (RTs) were considered in response to the experimental conditions. ERs and RTs decreased in case of premotor brain activation, specifically in response to fear, for both conscious and unconscious condition. The present results highlight the role of the premotor system for facial expression processing, supporting the existence of two analogous mechanisms for conscious and unconscious condition. PMID- 23727712 TI - Putting yourself in the skin of a black avatar reduces implicit racial bias. AB - Although it has been shown that immersive virtual reality (IVR) can be used to induce illusions of ownership over a virtual body (VB), information on whether this changes implicit interpersonal attitudes is meager. Here we demonstrate that embodiment of light-skinned participants in a dark-skinned VB significantly reduced implicit racial bias against dark-skinned people, in contrast to embodiment in light-skinned, purple-skinned or with no VB. 60 females participated in this between-groups experiment, with a VB substituting their own, with full-body visuomotor synchrony, reflected also in a virtual mirror. A racial Implicit Association Test (IAT) was administered at least three days prior to the experiment, and immediately after the IVR exposure. The change from pre- to post experience IAT scores suggests that the dark-skinned embodied condition decreased implicit racial bias more than the other conditions. Thus, embodiment may change negative interpersonal attitudes and thus represent a powerful tool for exploring such fundamental psychological and societal phenomena. PMID- 23727713 TI - Interconnected, ultrafine osmium nanoclusters: preparation and surface enhanced Raman scattering activity. AB - Interconnected Os nanochains consisting of ultrafine particles prepared using a simple procedure yield a coupled surface plasmon peak in the visible region and can be used as substrates for surface enhanced Raman scattering of various analytes. PMID- 23727714 TI - Photocurrent in graphene harnessed by tunable intrinsic plasmons. AB - Graphene's optical properties in the infrared and terahertz can be tailored and enhanced by patterning graphene into periodic metamaterials with sub-wavelength feature sizes. Here we demonstrate polarization-sensitive and gate-tunable photodetection in graphene nanoribbon arrays. The long-lived hybrid plasmon phonon modes utilized are coupled excitations of electron density oscillations and substrate (SiO2) surface polar phonons. Their excitation by s-polarization leads to an in-resonance photocurrent, an order of magnitude larger than the photocurrent observed for p-polarization, which excites electron-hole pairs. The plasmonic detectors exhibit photo-induced temperature increases up to four times as large as comparable two-dimensional graphene detectors. Moreover, the photocurrent sign becomes polarization sensitive in the narrowest nanoribbon arrays owing to differences in decay channels for photoexcited hybrid plasmon phonons and electrons. Our work provides a path to light-sensitive and frequency selective photodetectors based on graphene's plasmonic excitations. PMID- 23727717 TI - College of Nurses of Ontario--discipline decision. PMID- 23727719 TI - 2012 statistics for plastic surgical and nonsurgical procedures. PMID- 23727720 TI - A renewed passion for our profession. PMID- 23727722 TI - Care of patients with deep inferior epigastric perforator reconstruction. AB - Recent trends reflect greater numbers of women opting for mastectomy for invasive breast cancer. Breast reconstruction, either at the time of mastectomy or later, is increasingly an option patients prefer. Although many women opt for implants, reconstruction using autologous tissue offers several advantages including tissue that feels more natural and will age naturally with the patient. The deep inferior epigastric perforator flap has emerged as an alternative to the transverse rectus abdominis myocutaneous flap and allows for preservation of the underlying abdominal muscle. As greater numbers of surgeons are able to offer this microvascular alternative, nurses will care for these postoperative patients in the intensive care unit and medical/surgical settings. This article reviews the evaluation of patients for deep inferior epigastric perforator reconstruction and the unique complexities of postoperative nursing care for these patients. PMID- 23727723 TI - The effect of visible facial difference on personal space during encounters with the general public. AB - Previous research has found that people with visible differences are granted more physical space than people without visible differences during encounters with the general public. This study aimed to examine whether given significant sociocultural changes, this remains the case in contemporary Australia. The personal space afforded to a person with a visible difference (with a temporary difference--a scar and a permanent difference--a strawberry hemangioma) or a person without a visible difference by 408 pedestrians on a busy pedestrian walkway in the central business district of Adelaide, Australia, was measured. This was a replication and extension of a study by N. Rumsey, R. Bull, and D. Gahagan (1982). Pedestrians stood no further away from the model in the visibly different conditions than in the nonvisibly different conditions. Pedestrians stood an average of 128 cm away in the control condition, 120 cm away in the scar condition, and 140 cm away in the birthmark condition. People did not stand to the nonvisibly different (left) side of the model more frequently in the visibly different conditions than in the nonvisibly different conditions. As the original research by N. Rumsey et al. is frequently cited as representing the current situation for people with visible differences, failing to replicate the result is significant. Changes may be due to either recent sociocultural changes promoting inclusion of disability or increasing social taboo against expressing overt prejudice. PMID- 23727724 TI - Optimizing the success of the microvascular free flap. AB - Microvascular free flaps are a valuable plastic surgery option for patients requiring reconstruction surgery. Over the past 10-15 years, the improvement in technology and the multitude of donor sites has increased the number of successful outcomes of reconstructive flaps. PMID- 23727725 TI - Chemical peels and combination therapies. AB - The topical application of acids is one of the most dependable and widely recognized methods of improving the overall health and appearance of the skin. The goal of a chemical peel is to regulate and enhance the cellular turnover process-a complex system that ultimately leads to the shedding of cornified cells. In addition to maintaining healthy cell turnover rates, each of the most commonly used topical acids provides ancillary benefits. Numerous studies have shown that all chemical peel solutions stimulate collagen and glycosaminoglycan production, regardless of depth of penetration (). Other modalities have also gained popularity and many of them may be successfully combined with chemical peels to create dramatic, visible results in the skin. By outlining a variety of chemoexfoliants, as well as some popular modalities, the clinician will gain a deeper understanding of the wide variety of combination therapies available for improving skin health. PMID- 23727726 TI - Facebook fan page: essential applications and promotions. PMID- 23727727 TI - Acute or chronic? What's the difference? AB - Acute and chronic wounds heal and behave differently. An understanding of these differences is imperative to the practitioner in providing and planning appropriate wound care and management. The purpose of this article is to present some of the major differences and enable the practitioner in developing and modifying an appropriate plan of care to enhance healing and manage patient expectations. PMID- 23727728 TI - Alkyl group versus hydrogen atom transfer from metal alkyls to macrocyclic rhodium complexes. AB - Macrocyclic rhodium(II) complexes LRh(H2O)(2+) react with (dmgH)2(H2O)CoR and with (H2O)5CrR(2+) by alkyl transfer for R = CH3 to generate L(H2O)RhCH3(2+). When R = C2H5, C3H7 or C4H9, the reaction takes place by hydrogen atom abstraction from the coordinated alkyl and produces L(H2O)RhH(2+) and an alpha olefin. PMID- 23727729 TI - Metabolic scaling in solid tumours. AB - Tumour metabolism is an outstanding topic of cancer research, as it determines the growth rate and the global activity of tumours. Recently, by combining the diffusion of oxygen, nutrients, and metabolites in the extracellular environment, and the internal motions that mix live and dead cells, we derived a growth law of solid tumours which is linked to parameters at the cellular level. Here we use this growth law to obtain a metabolic scaling law for solid tumours, which is obeyed by tumours of different histotypes both in vitro and in vivo, and we display its relation with the fractal dimension of the distribution of live cells in the tumour mass. The scaling behaviour is related to measurable parameters, with potential applications in the clinical practice. PMID- 23727730 TI - Laser-assisted solid-state synthesis of carbon nanotube/silicon core/shell structures. AB - A single-step solid-state synthetic approach was developed for the synthesis of silicon-coated carbon nanotube (CNT) core/shell structures. This was achieved through laser-induced melting and evaporation of CNT-deposited Si substrates using a continuous wavelength CO2 laser. The synthesis location of the CNT/Si structures was defined by the laser-irradiated spots. The thickness of the coating was controlled by tuning the laser power and synthesis time during the coating process. This laser-based synthetic technique provides a convenient approach for solid-state, controllable, gas-free, simple and cost-effective fabrication of CNT/Si core/shell structures. PMID- 23727731 TI - Simultaneous derivatization and extraction of chlorophenols in water samples with up-and-down shaker-assisted dispersive liquid-liquid microextraction coupled with gas chromatography/mass spectrometric detection. AB - A new up-and-down shaker-assisted dispersive liquid-liquid microextraction (UDSA DLLME) for extraction and derivatization of five chlorophenols (4-chlorophenol, 4 chloro-2-methylphenol, 2,4-dichlorophenol, 2,4,6-trichloro-phenol, and pentachlorophenol) has been developed. The method requires minimal solvent usage. The relatively polar, water-soluble, and low-toxicity solvent 1-heptanol (12 MUL) was selected as the extraction solvent and acetic anhydride (50 MUL) as the derivatization reagent. With the use of an up-and-down shaker, the emulsification of aqueous samples was formed homogeneously and quickly. The derivatization and extraction of chlorophenols were completed simultaneously in 1 min. The common requirement of disperser solvent in DLLME could be avoided. After optimization, the linear range covered over two orders of magnitude, and the coefficient of determination (r (2)) was greater than 0.9981. The detection limit was from 0.05 to 0.2 MUg L(-1), and the relative standard deviation was from 4.6 to 10.8 %. Real samples of river water and lake water had relative recoveries from 90.3 to 117.3 %. Other emulsification methods such as vortex-assisted, ultrasound assisted, and manual shaking-enhanced ultrasound-assisted methods were also compared with the proposed UDSA-DLLME. The results revealed that UDSA-DLLME performed with higher extraction efficiency and precision compared with the other methods. PMID- 23727732 TI - On the use of X-ray absorption spectroscopy to elucidate the structure of lutetium adenosine mono- and triphosphate complexes. AB - Although the physiological impact of the actinide elements as nuclear toxicants has been widely investigated for half a century, a description of their interactions with biological molecules remains limited. It is however of primary importance to better assess the determinants of actinide speciation in cells and more generally in living organisms to unravel the molecular processes underlying actinide transport and deposition in tissues. The biological pathways of this family of elements in case of accidental contamination or chronic natural exposure (in the case of uranium rich soils for instance) are therefore a crucial issue of public health and of societal impact. Because of the high chemical affinity of those actinide elements for phosphate groups and the ubiquity of such chemical functions in biochemistry, phosphate derivatives are considered as probable targets of these cations. Among them, nucleotides and in particular adenosine mono- (AMP) and triphosphate (ATP) nucleotides occur in more chemical reactions than any other compounds on the earth's surface, except water, and are therefore critical target molecules. In the present study, we are interested in trans-plutonium actinide elements, in particular americium and curium that are more rarely considered in environmental and bioaccumulation studies than early actinides like uranium, neptunium and plutonium. A first step in this strategy is to work with chemical analogues like lanthanides that are not radioactive and therefore allow extended physical chemical characterization to be conducted that are difficult to perform with radioactive materials. We describe herein the interaction of lutetium(III) with adenosine AMP and ATP. With AMP and ATP, insoluble amorphous compounds have been obtained with molar ratios of 1:2 and 1:1, respectively. With an excess of ATP, with 1:2 molar ratio, a soluble complex has been obtained. A combination of spectroscopic techniques (IR, NMR, ESI-MS, EXAFS) together with quantum chemical calculations has been implemented in order to assess the lutetium coordination arrangement for the two nucleotides. In all the complexes described in the article, the lutetium cation is coordinated by the phosphate groups of the nucleotide plus additional putative water molecules with various tridimensional arrangements. With AMP 1:2 and ATP 1:1 solid-state compounds, polynuclear complexes are assumed to be obtained. In contrast, with ATP 1:2 soluble compound, the Lu coordination sphere is saturated by two ATP ligands, and this favors the formation of a mononuclear complex. In order to further interpret the EXAFS data obtained at the Lu LIII edge, model structures have been calculated for the 1:1 and 1:2 ATP complexes. They are discussed and compared to the EXAFS best fit metrical parameters. PMID- 23727734 TI - Dental journals in India: a boon or bane ? PMID- 23727733 TI - Matrix-assisted laser desorption/ionization imaging mass spectrometry revealed traces of dental problem associated with dental structure. AB - Periodontal disease is a serious dental problem because it does not heal naturally and leads to tooth loss. In periodontal disease, inflammation at periodontal tissue is thought as predominant, and its effect against tooth itself remains unclear. In this study, we applied matrix-assisted laser desorption/ionization imaging mass spectrometry (IMS) to teeth for the first time. By comparing anatomical structure of tooth affected with periodontal disease with normal ones, we analyzed traces of the disease on tooth. We found signals characteristic of enamel, dentin, and dental pulp, respectively, in mass spectra obtained from normal teeth. Ion images reconstructed using these signals showed anatomical structures of the tooth clearly. Next, we performed IMS upon teeth of periodontal disease. Overall characteristic of the mass spectrum appeared similar to normal ones. However, ion images reconstructed using signals from the tooth of periodontal disease revealed loss of periodontal ligament visualized together with dental pulp in normal teeth. Moreover, ion image clearly depicted an accumulation of signal at m/z 496.3 at root surface. Such an accumulation that cannot be examined only from mass spectrum was revealed by utilization of IMS. Recent studies about inflammation revealed that the signal at m/z 496.3 reflects lyso-phosphatidylcholine (LPC). Infiltration of the signal is statistically significant, and its intensity profile exhibited the influence has reached deeply into the tooth. This suggests that influence of periodontal disease is not only inflammation of periodontal tissue but also infiltration of LPC to root surface, and therefore, anti-inflammatory treatment is required besides conventional treatments. PMID- 23727735 TI - Dental implants in growing children. AB - The replacement of teeth by implants is usually restricted to patients with completed craniofacial growth. The aim of this literature review is to discuss the use of dental implants in normal growing patients and in patients with ectodermal dysplasia and the influence of maxillary and mandibular skeletal and dental growth on the stability of those implants. It is recommended that while deciding the optimal individual time point of implant insertion, the status of skeletal growth, the degree of hypodontia, and extension of related psychological stress should be taken into account, in addition to the status of existing dentition and dental compliance of a pediatric patient. PMID- 23727736 TI - Hemodynamic, ventilator, and ECG changes in pediatric patients undergoing extraction. AB - BACKGROUND: Dental treatment induces pain anxiety and fear. This study was conducted to assess the changes in hemodynamic, ventilator, and electrocardiograph changes during extraction procedure among 12-15-year-old children and compare these changes with anxiety, fear, and pain. MATERIALS AND METHODS: A purposive sample of 60 patients selected based on inclusion and exclusion criteria underwent study procedure in the dental OPD of a medical college and hospital. The anxiety, fear, and pain were recorded by dental anxiety scale, dental fear scale, and visual analogue scale, respectively, before the start of the procedure. The systolic blood pressure, diastolic blood pressure, heart rate, oxygen saturation, and electrocardiogram changes were monitored during the extraction procedure. The recording was taken four times (preinjection phase, injection, extraction, and postextraction) and was analyzed. RESULTS: At the preinjection phase the mean vales were systolic blood pressure (128 +/- 11.2), diastolic blood pressure (85.7 +/- 6.3), heart rate (79.7 +/- 9.3), and oxygen saturation (97.9 +/- 5.8). These values increased in injection phases and decreased in extraction phase and the least values were found after 10 min of procedure and this relation was significant for all parameters except oxygen saturation (P = 0.48, NS). ECG abnormalities were seen among 22 patients and were significant before and after injection of Local anesthetic (P = 0.0001, S). CONCLUSIONS: Anxiety, fear, and pain have an effect on hemodynamic, ventilator, and cardiovascular parameters during the extraction procedure and hence behavioral management has to be emphasized among children in dental clinics. PMID- 23727737 TI - Comparison of the bleaching efficacy of three different agents used for intracoronal bleaching of discolored primary teeth: an in vitro study. AB - Everyone wants whiter teeth to make them feel younger and to provide beautiful smiles with the accompanying increase in self-esteem. Bleaching is an established, simple, cost-effective and conservative method for improving the color of the discolored teeth. AIM: The aim of this in vitro study was to compare the bleaching efficacy of 10% carbamide peroxide, 10% hydrogen peroxide and 2g sodium perborate as bleaching agents on the artificially discolored human primary maxillary central incisors. MATERIALS AND METHODS: Forty extracted human primary central incisors with intact crowns were selected for the study. Pulpectomy was performed and each tooth was artificially stained with 2 ml of fresh human blood and centrifuged. --The teeth were randomly divided into four experimental groups of 10 teeth each and the baseline color evaluation was performed. 0.04 ml of the bleaching agent is syringed into the access cavity of the tooth and, in the control group, 0.04 ml of distilled water was syringed into the access cavity and it was sealed with IRM and placed at 37 degrees C in an incubator throughout the experiment. The color of the bleached teeth was determined at 0, 7 and 14 days. The data obtained were analyzed using ANOVA and Turkey's test. RESULTS: There was statistical significance (P = 0.00) among the carbamide peroxide, sodium perborate, hydrogen peroxide and control groups after 7 and 14 days and a significance of P = 0.013 among the carbamide peroxide, sodium perborate and hydrogen peroxide after two bleaching sessions (day 14) was seen. CONCLUSIONS: The bleaching efficacy of 10% hydrogen peroxide gel was more effective than 10% carbamide peroxide and sodium perborate in bleaching the artificially discolored primary teeth. PMID- 23727738 TI - Dental anxiety prediction using Venham Picture test: a preliminary cross sectional study. AB - Anxiety or fearfulness affects a child's behavior, and to a large extent, determines the success of a dental treatment. It is essential to identify anxious children at the earliest age possible rather than simply deal with them later. It is crucial that every effort be made to ensure a positive experience for each child patient. Appropriate acknowledgment of patient's anxiety can solidify their confidence and allows the pediatric dentist an informed review of potential management options specific to every individual. In the present cross-sectional study, Venham Picture, a psychometric test, was used to estimate the prevalence of dental anxiety among children in the age group 6-10 years, with and without previous dental experience. PMID- 23727739 TI - Oratest: a new concept to test caries activity. AB - Caries activity tests are based on the concept of a specific odontogenic infection, the principle causative organism being streptococci mutans. Their predominance is attributed to its acidogenic and aciduric nature after a selective growth advantages over the other non- acid tolerant organisms. Many studies on caries activity are aimed at finding relevant microorganisms. Till date, the ideal method to evaluate in terms of sensitivity, specialization and reliability has not been found. Many of these caries activity tests require extensive work up time and additional equipment. Rosenberg et al. in 1989 developed Oratest, a simple, economical, non- invasive and less time-consuming test for estimating the oral microbial level. The test is simple and consists of rinsing the mouth with 10 ml of sterile milk, 3 ml of which is mixed with 0.12 ml of 0.1% methylene blue dye and observed for colour change. The present study sample consists of twenty five children with dental caries and twenty five controls, free of caries, gingivitis and other oral ailments. This study is being conducted in the department of Oral Pathology & Microbiology and is in the preliminary phase so further results are awaited. PMID- 23727740 TI - In vitro remineralization of enamel subsurface lesions and assessment of dentine tubule occlusion from NaF dentifrices with and without calcium. AB - Currently, fluoride is the most effective preventive treatment for remineralization of incipient carious lesions and dentinal hypersensitivity due to wasting disorders. The products containing fluoride, calcium and phosphate are also claim to remineralize early, non-cavitated enamel demineralization. The aim of this study was to investigate and compare the efficacy of two such products, Tooth Mousse and Clinpro tooth creme on remineralization and tubule occluding ability with 5000ppm fluoride-containing toothpaste. MATERIALS AND METHODS: Thirty third molar teeth were placed in demineralizing solution for 5 days such that only a window of 1mm x 5mm was exposed to the environment to produce artificial caries-like lesions and randomly assigned to three groups: Group I, 5000ppm sodium fluoride; Group II, GC MI paste plus and Group III, Clinpro tooth creme. Axial longitudinal sections of 140-160 MUm of each tooth which included the artificial carious lesion taken and were photographed under polarized light microscope. The demineralized areas were then quantified with a computerized imaging system. The experimental materials were applied onto the tooth sections as a topical coating and subjected to pH-cycling for 28 days. To evaluate tubule occlusion ability, thirty dentin specimens of 2mm thickness were obtained from cervical third of sound third molars. Specimens were ultrasonicated and etched with 6% citric acid for 2 minutes to simulate the hypersensitive dentin. Specimens were randomly divided into above mentioned three groups (n=10). The test agents were brushed over the specimens with an electric toothbrush, prepared and observed under Scanning Electron Microscope for calculation of the percentage of occluded tubules. RESULTS: Group I showed a significantly greater percentage of remineralization than Group III and Group II. Comparison of the remineralization potential between group II and group III were not significant.In case of dentine hypersensitivity, Group I and group III showed greater percentage of tubule occlusion ability than Group II. Intergroup comparison of the tubule occlusion potential of group I and group III were not significant. INTERPRETATION AND CONCLUSION: Within the limitations of our study, sodium fluoride showed relatively greatest remineralizing and dentinal tubule occlusion property when compared with GC MI paste plus and Clinpro tooth creme. PMID- 23727741 TI - Validation of Tanaka and Johnston's analysis in western UP Indian population. AB - OBJECTIVE: To examine the applicability of the Tanaka and Johnston's method of prediction in a western UP population and to develop a new prediction method for this specific population if necessary. MATERIALS AND METHODS: 150 western UP school children (87 males and 63 females) with a mean age of 15.5 years were randomly selected. The mesio-distal crown diameters of the permanent canine and premolars were measured and comparisons were done between the actual tooth sizes and the values predicted by the Tanaka and Johnston method. RESULTS: Significant sexual dimorphism was found in the tooth sizes. There were significant differences between the actual measurements and the predicted measurements derived by the Tanaka and Johnston prediction method. New linear regression equations were derived for both the genders for tooth size prediction in western UP population. CONCLUSION: There are limitations in the application of the Tanaka and Johnston's prediction method to a western UP population. A gender discrepancy is seen between the males and the females. New regression equations were formulated for both the males and the females separately. PMID- 23727742 TI - Nonfamilial cherubism. AB - Cherubism is a non neoplastic progressive heredity disease affecting the jaw bones. It is a benign disease with a characteristic symmetrical involvement of the maxilla and mandible. It usually affects children before 5 years of age, with painless progressive swelling of the cheeks, frequently associated with dental malformations. Here, we are presenting a case report of a 12-year-old boy suffering from cherubism. PMID- 23727744 TI - Treatment of nursing bottle caries with ribbond. AB - Ribbond is a biocompatible, esthetic material made from high-strength polyethylene fiber. Lenowoven polyethylene ribbon (Ribbond) has been used successfully for tooth splinting, replacement of missing teeth, reinforcement of provisional acrylic resin fixed partial dentures, and orthodontic retention. This article presents the application of this polyethylene ribbon - RIBBOND - for the treatment of nursing bottle caries. To conclude we suggest that this combined technique of polyethylene fibers and composite material could be a very efficient alternative procedure to conventional treatment plans in pedodontic practice, with excellent esthetics and functional results. PMID- 23727745 TI - Tooth fragment embedded in the upper lip after dental trauma: a case report presenting an immediate diagnostic approach and complete rehabilitation. AB - Dental traumas are reasonably common, especially in children and adolescents. They are caused by many factors with fall accounting for the most frequent one. Dental trauma requires a special consideration when dental fractures accompany soft tissue lacerations. Dental fragments occasionally penetrate into soft tissue and may cause severe complications. Early diagnosis and surgical removal of these fragments could prevent undesirable foreign body reaction and scarring. This report presents immediate diagnosis and management of a case in which dental fragment was embedded in the lip soft tissue. PMID- 23727746 TI - Early class III management in deciduous dentition using reverse twin block. AB - Class III malocclusion poses a challenging dilemma for the clinician because these children have of growth patterns that differ from that of children with class I malocclusion. The mandible grows more rapidly than the maxilla, exacerbating the class III malocclusion as the child go through adolescence. Ever since Clark described a version of the twin block, it has steadily gained popularity in the management of early class III malocclusion in children. However, not many cases are reported in the literature on its use in deciduous dentition. This article tries to provide an insight into the reverse twin block appliance and reports two cases of early class III malocclusion treated using reverse twin block. PMID- 23727747 TI - One-step fabrication of intense red fluorescent gold nanoclusters and their application in cancer cell imaging. AB - A one-step method for successfully fabrication of water-soluble and alkanethiol stabilized Au nanoclusters (NCs) was demonstrated. The novel and facile method was based on simply placing histidine (His), HAuCl4 and 11-mercaptoundcanoic acid (MUA) together at room temperature. The resulting Au NCs were exclusively composed of Au17MUA4His22 (AMH), as demonstrated by the photoluminescence, UV-Vis absorption, electrospray ionization mass and X-ray photoelectron spectroscopy. AMH exhibited intense red fluorescence (lambdaem = 600 nm), a long fluorescence lifetime (7.11 MUs), considerable stability, and a large Stoke's shift (320 nm). Based on the excellent properties of the AMH, cell experiments were conducted. Cytotoxicity studies showed that the Au NCs exhibited negligible effects in altering cell proliferation or triggering apoptosis. Cancer cell imaging of HeLa cell lines indicated that the obtained AMH could serve as a promising fluorescent bioprobe for bioimaging. This strategy, based on the one-step method, may offer a novel approach to fabricate other water-soluble and alkanethiol-stabilized metal nanoclusters for application in biolabelling and bioimaging. PMID- 23727748 TI - Hypertension-associated expenditures for medication among US adults. AB - BACKGROUND: We sought to estimate how much the presence of hypertension adds to annual per capita and total expenditures for medication among US adults. METHODS: The sample included 21,782 civilian noninstitutionalized adults aged >= 18 years who participated in the 2007 Medical Expenditure Panel Survey. Hypertension was defined as having a diagnosis of high blood pressure (except during pregnancy) or taking a blood pressure medication. We used a 2-part model to examine all-cause medication expenditure associated with hypertension. RESULTS: The prevalence of hypertension was 32.2%. Overall, 66.7% of adults purchased prescribed medications, with this proportion higher among hypertensive (93.0%) than normotensive (54.4%) adults (P < 0.001). Hypertensive adults were more likely to have medication expenditures than were normotensive adults (odds ratio (OR) = 6.42; P < 0.001). Among hypertensive adults, those aged >= 45 years were more likely to incur medication expenditure than those aged 18-44 years (OR = 3.00, P < 0.001 for those aged 45-64 years; OR = 5.95, P < 0.001 for those aged >= 65 years), whereas women were 2.91 times as likely as men to have medication spending (P < 0.001). Hispanics were less likely than non-Hispanic whites to have such spending (OR = 0.51; P < 0.001). Among those purchasing medications, the average cost was $1,510 higher among hypertensive persons ($2,337) than normotensive persons ($827). Hypertension-associated expenditures for medication were estimated at $68 billion in the US civilian non-institutionalized population in 2007. CONCLUSIONS: The presence of hypertension among US adults is associated with an increase of all-cause expenditures for medication, with this increase varying across groups by age and sex. PMID- 23727749 TI - Importance of factors influencing the decision to proceed with cord blood transplantation in adults: results of a Web-based survey of the Canadian transplant community. PMID- 23727750 TI - Allogeneic SCT for patients with high-risk peripheral T-cell lymphoma in first response. PMID- 23727751 TI - Cadmium diruthenium(II,III) carbonates showing diverse magnetism behavior arising from variety configuration of [Ru2(CO3)4]n(3n-) layer. AB - Two hetero-metallic carbonates, namely KCd(H2O)3Ru2(CO3)4.4H2O (1) and KCd(H2O)3Ru2(CO3)4.3.5H2O (2), have been synthesized in a neutral aqueous solution. Both of the 3D dimensional structured complexes contain mixed-valent diruthenium(II,III) carbonate paddlewheel cores of Ru2(II,III)(CO3)4(3-) that are connected to each other in trans- or cis-modes by carbonate oxygen atoms, forming rectangular square-grid and isomeric parallelogram layers [Ru2(CO3)4]n(3n-) in 1 and 2, respectively. The reaction temperature is found to play an important role in directing the final products with particular topologies and their layered structural diversity is due to the various linking modes between the Ru2(CO3)4(3 ) units. The magnetic studies show that ferromagnetic interactions are propagated between the diruthenium units in both complexes 1 and 2 but their magnetic properties differ at low temperatures, in which the trans linking mode parallelogram layer [Ru2(CO3)4]n(3n-) in complex 2 leads to long-range magnetic ordering below 4.0 K. However, no Curie ordering down to 1.8 K is detected for complex 1 containing the isomeric rectangle square-grid layer linking in the cis mode. PMID- 23727753 TI - An iterative position reconstruction algorithm for radioactive particle techniques. AB - The Computer Automated Radioactive Particle Tracking (CARPT) technique is widely used to monitor the motion of the flow inside a reactor. Usually a single radioactive particle that is neutrally buoyant with respect to the phase is used as a tracker. The particle moves inside the volume of interest and its positions are determined by an array of scintillation detectors counting incoming photons. Well-known reconstruction algorithms have been traditionally used to map measured counts into the particle position coordinates by solving a minimisation problem between measured events and calibration data. However, these algorithms have serious drawbacks. Their accuracy is determined by resolution of a calibration grid, which results in low accuracy measurements in cases where the measurement interval is short. The article presents an original algorithm for reconstruction of the trace position. The reconstruction procedure calculates iteratively the trace position of the specified calibration data. The results of the simulations based on the MCNP5 package showed that compared with results obtained using the classical approach, the accuracy of the reconstruction position is increased by 46% for low noise counts and 38% for high noise counts. The technique can successfully be applied to monitor the motion of a radioactive tracer in a reactor. PMID- 23727752 TI - Radiation-induced upregulation of telomerase activity escapes PI3-kinase inhibition in two malignant glioma cell lines. AB - Tumor relapse after radiotherapy is a great concern in the treatment of high grade gliomas. Inhibition of the PI3-kinase/AKT pathway is known to radiosensitize cancer cells and to delay their DNA repair after irradiation. In this study, we show that the radiosensitization of CB193 and T98G, two high-grade glioma cell lines, by the PI3K inhibitor LY294002, correlates with the induction of G1 and G2/M arrest, but is inconsistently linked to a delayed DNA double strand break (DSBs) repair. The PI3K/AKT pathway has been shown to activate radioprotective factors such as telomerase, whose inhibition may contribute to the radiosensitization of cancer cells. However, we show that radiation upregulates telomerase activity in LY-294002-treated glioma cells as well as untreated controls, demonstrating a PI3K/AKT-independent pathway of telomerase activation. Our study suggests that radiosensitizing strategies based on PI3 kinase inhibition in high-grade gliomas may be optimized by additional treatments targeting either telomerase activity or telomere maintenance. PMID- 23727754 TI - 20 years and no wrinkles--a reason to be proud. PMID- 23727755 TI - [25 years Swiss Medical Society of Phytotherapy - 20 years Research Complementary Medicine: 2 anniversaries together]. PMID- 23727756 TI - [20 years Research Complementary Medicine: the path from avant garde to mainstream]. PMID- 23727757 TI - [Promoting and institutionalizing complementary medicine in Germany]. PMID- 23727758 TI - [Establishing naturopathy and complementary medicine at German universities]. PMID- 23727759 TI - Anti-hyperglycemic effect of Vaccinium arctostaphylos in type 2 diabetic patients: a randomized controlled trial. AB - BACKGROUND: Type 2 diabetes mellitus is a common disease. Preliminary data indicate that Vaccinium arctostaphylos L. (Caucasian whortleberry) has a potential effect in glycemic control. Thus, the efficacy and safety of a standardized whortleberry fruit hydroalcoholic extract in the treatment of type 2 diabetic patients were studied. METHODS: This randomized double-blind placebo controlled clinical trial consisted of 37 patients aged 40-60 years with type 2 diabetes who were resistant to conventional oral anti-hyperglycemic drugs. The patients were treated with the whortleberry fruit hydroalcoholic extract (1 capsule = 350 mg, every 8 h for 2 months) in combination with anti-hyperglycemic drugs, and the effects on the blood levels of fasting glucose, 2-hour postprandial glucose, glycosylated hemoglobin (HbA1c), and liver/kidney function were tested, evaluated, and compared with a placebo group (n = 37). RESULTS: The extract significantly lowered the blood levels of fasting glucose, 2-h postprandial glucose, and HbA1c (p = 0.007, p <0.001, and p = 0.005, respectively) without any significant effects on the liver/kidney function (p >0.05) compared with placebo at the end. No adverse effects were reported. CONCLUSION: Whortleberry may safely improve glycemic control in type 2 diabetic patients. PMID- 23727760 TI - [Cooperation between physicians and non-medically trained practitioners: advantages and obstacles]. AB - BACKGROUND: In Germany, not only physicians are allowed to practice medicine but also non-medically trained practitioners, so-called Heilpraktiker, can obtain a licensure to treat patients. In contrast to cooperation between doctors, a division of tasks and responsibilities between non-medically trained practitioners and physicians seems to be difficult. The aim of the study was to clarify to what extent doctors in private practice are willing to cooperate with non-medically trained practitioners. At the same time, conditions, opportunities, and obstacles of cooperation are described. METHODS: In order to evaluate the willingness to collaborate with non-medically trained practitioners, semi structured interviews were conducted with 15 physicians and 2 dentists in an outpatient setting. The interviews further focused on conditions, advantages, and obstacles to cooperation. The interviews were transcribed literally and analyzed using qualitative content analysis. RESULTS: The interviews showed that physicians partly are willing to cooperate with non-medically trained practitioners, but there were strict conditions and also some serious obstacles to cooperation. Doctors who are open-minded about collaboration consider non medically trained practitioners as additional therapists for minor ailments. Non medically trained practitioners would have to respect their limitations, and health insurances should launch transparent contracts for remuneration and reimbursement. Physicians showed low confidence in training programs for Heilpraktiker. Additionally, it was thought to be harmful when non-medically trained practitioners interfere with the physician-patient relationship and try to interrupt conventional treatment or medication. CONCLUSIONS: Quantitative research is necessary to quantify data and generalize results from the sample to the population of physicians. Further, the willingness of non-medically trained practitioners to collaborate with physicians should be evaluated. Physicians should try to reduce communication obstacles so that patients can speak frankly about consultations of non-medically trained practitioners. PMID- 23727761 TI - [Dance/movement therapy in oncological rehabilitation]. AB - BACKGROUND: Dance/movement therapy may be defined as a psychosocial and body oriented art therapy, which uses dance for the expression of emotional and cognitive issues. Dance/movement therapy is an important intervention for cancer patients to enhance coping strategies. There are only few studies investigating dance therapy with cancer patients. METHODS: The present study investigates effects of dance/movement therapy (n = 115) in the setting of inpatient rehabilitation based on a pre-post design with a control group as well as a follow-up 3 months later. Standardized questionnaires measuring quality of life, anxiety and depression, and self-concept (EORTC QLQ-C30, HADS, FSKN) were used. In addition, at the end of the inpatient rehabilitation program subjective expectations of the dance/movement therapy and the patients' subjective evaluation of the benefits of the intervention were measured by a new developed questionnaire. RESULTS: As process factors of dance/movement therapy, expression of emotions, enhancement of self-esteem, development of the personality, vitality, getting inner balance, and getting in touch with the body have been identified. In terms of quality of life and psychological well-being, the results showed significant improvements with medium to large effect sizes. CONCLUSIONS: Even though those effects may not be attributed to the intervention alone, the analysis of the data and the patients' subjective statements help to reveal therapeutic factors and process characteristics of dance/movement therapy within inpatient rehabilitation. PMID- 23727762 TI - [Complementary medicine and scientific pluralism--from governmental research funding to the dialogue forum of pluralism in medicine]. AB - Medicine is based on a pluralism of different ways of thinking and practical approaches. Given this assumption, the history and experiences of the 2 German governmental research funding programs 'Unconventional Methods of Cancer' (UMK) and 'Unconventional Medicine Directions' (UMR) are described from the perspective of the project supporter of 2 working groups that were based at the University of Witten/Herdecke, Germany, on behalf of the federal government. The results of a nationwide inventory analysis conducted under my direction in the years 1989-1992 showed a distinct lack of human and infrastructural resources for competitive research for complementary medicine at that time. The field of complementary medicine was found to be very heterogeneous and was divided into procedures without any visible research interest, but also contained approaches nourishing mainstream medicine by its different paradigm. The representatives of complementary medicine were and still are recognizably interested in evaluative, empirical research. The following contains our funding recommendations made for the relevant ministries, the advertised funding issues, and the research activities carried out. Although this governmental research funding was limited, a signal function can be awarded, retrospectively. For the subsequent period, there has been a significant improvement in infrastructural, staff, and research conditions. This development led to a significant increase in the level of quality and the acceptability of research results. As a result of an increased willingness for cooperations, the foundations, concerns, and activities of the 'dialogue forum pluralism in medicine' set up in 2000 are presented and compared with the situation at the time of research funding by government. 'Integrative Medicine' is currently being favored and welcomed as a sign of better mutual acceptance. Nevertheless, complementary medicine is still seen as being creative, enriching medical and health care, improving the patient-centeredness, and thus as an educational (unrest) element (of agitation). PMID- 23727763 TI - [Academization of naturopathy and complementary medicine in the German language area]. AB - Nowadays, it seems evident that natural and complementary medicine is represented amongst medical faculties. This was not always the case. Especially in the German speaking countries, more than 100 years of history were necessary. A short history of those academic developments that explicitly led to present day activities in naturopathy and complementary medicine is given by descriptions of persons and institutions. At present, 8 professorships dedicated to either naturopathy or complementary medicine or both could be identified in German speaking countries, thus representing academic medicine at its highest levels. Naturopathy and complementary medicine had received a strong reception in academic medicine. However, the vast majority of present day activities is financed by non-profit organizations and thus depends on their economic development. PMID- 23727764 TI - The evolution of complementary and alternative medicine (CAM) in the USA over the last 20 years. AB - Medical practices that reside outside the mainstream medical structures have existed for centuries, often waxing and waning in prominence and use for various reasons. Recently, there has been a resurgence in interest and use of such practices in the USA generally referred to under the label of 'complementary and alternative medicine' (CAM). In this article we summarize some of the highlight events that punctuated this resurgence over the last 20 years. As in the past, social forces affecting these trends circulate around power, resources, and scope of practice. However, a prominent feature of this dynamic is a discussion about the role of science and 'evidence-based medicine' in addressing pluralistic healthcare-related practices. In the early years of this period, attempts to formulate the place of CAM practices as they relate to epistemology, nonconventional assumptions about health and healing, and the complexity of understanding 'whole systems' were discussed and often examined. Less attention is being paid to those core assumptions in more recent times. The focus now seems to be on how CAM practices can be judiciously and effectively 'integrated' into mainstream medicine. Examples of how this dynamic is evolving are described. PMID- 23727765 TI - [The situation of complementary medicine in Germany]. AB - With the amendment of the German Medicinal Products Act in 1976 and the inclusion of naturopathy and homeopathy into the German Medical Licensure Act from 1988, the German government set up a comparatively favorable framework for Complementary and Alternative Medicine (CAM). But no comprehensive integration into the academic operating systems followed, because the universities as well as the legislative body seemed to have no further interest in CAM. Therefore, research projects in the field and suitable professorships had and still have to be financed by third-party funds. Notwithstanding the success of several CAM projects, no sustainable development could be established: When the third-party funding runs off and the protagonists retire the institutional structures are supposed to vanish as well. Although the public demand for CAM is high in Germany, the administration detached homeopathy as a compulsory subject from the German Medical Licensure Act in 2002 and restricted severely the refunding of naturopathic medicines by the statutory health insurance in 2004. Moreover, the trend for CAM bashing takes root in the media. Unfortunately the CAM scene does not close ranks and is incapable to implement fundamental data collection processes into daily clinical routine: A wide range of data could justify further efforts to the government as well as to the scientific community. To say something positive, it must be mentioned that the scientific standard of CAM research is high for the most part and that third-party funded projects deliver remarkable results ever and on. PMID- 23727766 TI - Study of uranium oxidation states in geological material. AB - A wet chemical method to determine uranium (U) oxidation states in geological material has been developed and tested. The problem faced in oxidation state determinations with wet chemical methods is that U redox state may change when extracted from the sample material, thereby leading to erroneous results. In order to quantify and monitor U redox behavior during the acidic extraction in the procedure, an analysis of added isotopic redox tracers, (236)U(VI) and (232)U(IV), and of variations in natural uranium isotope ratio ((234)U/(238)U) of indigenous U(IV) and U(VI) fractions was performed. Two sample materials with varying redox activity, U bearing rock and U-rich clayey lignite sediment, were used for the tests. The Fe(II)/Fe(III) redox-pair of the mineral phases was postulated as a potentially disturbing redox agent. The impact of Fe(III) on U was studied by reducing Fe(III) with ascorbic acid, which was added to the extraction solution. We observed that ascorbic acid protected most of the U from oxidation. The measured (234)U/(238)U ratio in U(IV) and U(VI) fractions in the sediment samples provided a unique tool to quantify U oxidation caused by Fe(III). Annealing (sample heating) to temperatures above 500 degrees C was supposed to heal ionizing radiation induced defects in the material that can disturb U redox state during extraction. Good agreement between two independent methods was obtained for DL-1a material: an average 38% of U(IV) determined by redox tracer corrected wet chemistry and 45% for XANES. PMID- 23727767 TI - Aptamer degradation inhibition combined with DNAzyme cascade-based signal amplification for colorimetric detection of proteins. AB - Combining the inhibition of aptamer degradation with DNA Enzyme (DNAzyme) cascade based signal amplification, a label-free and sensitive colorimetric protein assay strategy was proposed. PMID- 23727768 TI - Capture and conversion of CO2 at ambient conditions by a conjugated microporous polymer. AB - Conjugated microporous polymers are a new class of porous materials with an extended pi-conjugation in an amorphous organic framework. Owing to the wide ranging flexibility in the choice and design of components and the available control of pore parameters, these polymers can be tailored for use in various applications, such as gas storage, electronics and catalysis. Here we report a class of cobalt/aluminium-coordinated conjugated microporous polymers that exhibit outstanding CO2 capture and conversion performance at atmospheric pressure and room temperature. These polymers can store CO2 with adsorption capacities comparable to metal-organic frameworks. The cobalt-coordinated conjugated microporous polymers can also simultaneously function as heterogeneous catalysts for the reaction of CO2 and propylene oxide at atmospheric pressure and room temperature, wherein the polymers demonstrate better efficiency than a homogeneous salen-cobalt catalyst. By combining the functions of gas storage and catalysts, this strategy provides a direction for cost-effective CO2 reduction processes. PMID- 23727769 TI - Assessment of delivery parameters with the multi-electrode array for development of a DNA vaccine against Bacillus anthracis. AB - Gene electrotransfer (GET) enhances delivery of DNA vaccines by increasing both gene expression and immune responses. Our lab has developed the multi-electrode array (MEA) for DNA delivery to skin. The MEA was used at constant pulse duration (150 ms) and frequency (6.67 Hz). In this study, delivery parameters including applied voltage (5-45 V), amount of plasmid (100-300 MUg), and number of treatments (2-3) were evaluated for delivery of a DNA vaccine. Mice were intradermally injected with plasmid expressing Bacillus anthracis protective antigen with or without GET and alphaPA serum titers measured. Within this experiment no significant differences were noted in antibody levels from varying dose or treatment number. However, significant differences were measured from applied voltages of 25 and 35 V. These voltages generated antibody levels between 20,000 and 25,000. Serum from animals vaccinated with these conditions also resulted in toxin neutralization in 40-60% of animals. Visual damage was noted at MEA conditions of 40 V. No damage was noted either visually or histologically from conditions of 35 V or below. These results reflect the importance of establishing appropriate electrical parameters and the potential for the MEA in non-invasive DNA vaccination against B. anthracis. PMID- 23727772 TI - New President of AMI-2012. PMID- 23727770 TI - Electrochemically driven biocatalysis of the oxygenase domain of neuronal nitric oxide synthase in indium tin oxide nanoparticles/polyvinyl alcohol nanocomposite. AB - Nitric oxide synthase (NOS) plays a critical role in a number of key physiological and pathological processes. Investigation of electron-transfer reactions in NOS would contribute to a better understanding of the nitric oxide (NO) synthesis mechanism. Herein, we describe an electrochemically driven catalytic strategy, using a nanocomposite that consisted of the oxygenase domain of neuronal NOS (D290nNOSoxy), indium tin oxide (ITO) nanoparticles and polyvinyl alcohol (PVA). Fast direct electron transfer between electrodes and D290nNOSoxy was observed with the heterogeneous electron transfer rate constant (ket) of 154.8 +/- 0.1s(-1) at the scan rate of 5 Vs(-1). Moreover, the substrate N(omega) hydroxy-L-arginine (NHA) was used to prove the concept of electrochemically driven biocatalysis of D290nNOSoxy. In the presence of the oxygen cosubstrate and tetrahydrobiopterin (BH4) cofactor, the addition of NHA caused the decreases of both oxidation current at +0.1 V and reduction current at potentials ranging from -0.149 V to -0.549 V vs Ag/AgCl. Thereafter, a series of control experiments such as in the absence of BH4 or D290nNOSoxy were performed. All the results demonstrated that D290nNOSoxy biocatalysis was successfully driven by electrodes in the presence of BH4 and oxygen. This novel bioelectronic system showed potential for further investigation of NOS and biosensor applications. PMID- 23727773 TI - Antitumor activity and DNA-binding investigations of isoeuxanthone and its piperidinyl derivative. AB - The binding mode and affinity of isoeuxanthone (1,6-dihydroxyxanthone) (1) and its piperidinyl derivative (1-hydroxy-6-(2-(1-piperidinyl)ethoxy)xanthone) (2) with calf thymus DNA were studied using absorption spectroscopy, fluorescence spectroscopy, circular dichroism (CD) spectroscopy and viscosity measurements. Results indicate that the two xanthones can intercalate into the DNA base pairs by the plane of xanthone ring and the binding affinity of the piperidinylethoxy substituted xanthone 2 is stronger than 1. In addition, the cytotoxic effects of both compounds were evaluated with the human cervical cancer cell line (HeLa) and human hepatocellular liver carcinoma cell line (HepG2) using acid phosphatase assay. Analyses show that the piperidinylethoxy substituted xanthone exhibits more effective cytotoxic activity than isoeuxanthone against the two cancer cells. The effects on the inhibition of tumor cells in vitro agree with the studies of DNA-binding. PMID- 23727774 TI - The antimicrobial activities of phenylbutyrates against Helicobacter pylori. AB - Three phenyl derivatives of butyrate, 2-phenylbutyrate (2-PB), 3-phenylbutyrate (3-PB) and 4-phenylbutyrate (4-PB), were evaluated in terms of their antibacterial and cytotoxic activities. Our results indicated that PBs demonstrated specific inhibitory activity against Helicobacter pylori and Escherichia coli but did not influence the growth of Bifidobacterium bifidium and Lactobacillus reuteri. PBs also exhibited synergistic effects on H. pylori ATCC 43504 especially at pH 5.5. In the protein expression profiles in H. pylori treated by phenylbutyrates, we also found that three protein spots identified as oxidative stress-related proteins were significantly up-regulated, confirming the response of H. pylori when exposed to PBs. Due to their antibacterial activities and low or slight cytotoxicities, PBs are potential candidates for the treatment of H. pylori infection. This is the first study to discover the antibiotic effects of 2-PB, 3-PB and 4-PB (Buphenyl). PMID- 23727775 TI - Synthesis and antioxidant activity of a variety of sulfonamidomethane linked 1,3,4-oxadiazoles and thiadiazoles. AB - A variety of sulfonamidomethane linked 1,3,4-oxadiazoles and 1,3,4-thiadiazoles were prepared and tested for antioxidant activity. The methyl substituted arylsulfonylaminomethyl-1,3,4-oxadiazole 9b showed excellent antioxidant activity. PMID- 23727776 TI - Sesquiterpene coumarins from Ferula fukanensis and their pro-inflammatory cytokine gene expression inhibitory effects. AB - Six new sesquiterpene coumarin derivatives, fukanefuromarin H-M (1-6), were isolated from an 80% aqueous methanol extract of the roots of Ferula fukanensis. The structures were elucidated on the basis of spectroscopic evidence, particularly heteronuclear multiple-bond connectivity (HMBC) and high-resolution MS. The sesquiterpene coumarin derivatives inhibited nitric oxide (NO) and inducible NO synthase (iNOS), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) gene expression in a murine macrophage-like cell line (RAW264.7), which was activated by lipopolysaccharide (LPS) and recombinant mouse interferon-gamma (IFN-gamma). PMID- 23727777 TI - New rotenoids and coumaronochromonoids from the aerial part of Boerhaavia erecta. AB - From the aerial part of Boerhaavia erecta L., three new rotenoids (3, 8, 10) and two new coumaronochromonoids (6, 11) were isolated, together with ten known compounds. The structure of the new compounds was established by one dimensional (1D)- and 2D-NMR spectroscopy, as well as high resolution-electrospray ionization (HR-ESI)-MS analysis. The absolute configuration of compound 11 was determined by UV circular dichroism spectroscopy. Compounds were evaluated for their cytotoxic activity against HeLa (human epithelial carcinoma), NCI-H460 (human lung cancer) and MCF-7 (human breast cancer) cell lines at the concentration of 100 ug/mL. Rotenoids 3, 4 and 5 showed a strong cytotoxic activity against HeLa cell line and rotenoids 5 and 8 showed good activity against MCF-7 cell line. PMID- 23727778 TI - Concise synthesis of heterocycle-fused naphthoquinones by employing sonogashira coupling and tandem addition-elimination/intramolecular cyclization. AB - A concise method for the synthesis of heterocycle-fused naphthoquinones such as naphtho[2,3-b]-furan-4,9-dione, 1H-benz[f]indole-4,9-dione, and naphtho[2,3 b]thiophene-4,9-dione was developed. This method employed Sonogashira coupling and tandem addition-elimination/intramolecular cyclization, and it enabled the preparation of versatile heterocycle-fused naphthoquinones from one substrate. PMID- 23727779 TI - Medicinal flowers. XXXX . Structures of dihydroisocoumarin glycosides and inhibitory effects on aldose reducatase from the flowers of Hydrangea macrophylla var.thunbergii. AB - Six dihydroisocoumarin glycosides, florahydrosides I and II, thunberginol G 8-O beta-d-glucopyranoside, thunberginol C 8-O-beta-d-glucopyranoside, 4 hydroxythunberginol G 3'-O-beta-d-glucopyranoside, and thunberginol D 3'-O-beta-d glucopyranoside, have been isolated from the flowers of Hydrangea macrophylla Seringe var. thunbergii Makino (Saxifragaceae) together with 20 known compounds. The chemical structures of the new compounds were elucidated on the basis of chemical and physicochemical evidence. Among the constituents, acylated quinic acid analog, neochlorogenic acid, was shown to substantially inhibit aldose reductase [IC50=5.6 um]. In addition, the inhibitory effects on aldose reductase of several caffeoylquinic acid analogs were examined for structure-activity relationship study. As the results, 4,5-O-trans-p-dicaffeoyl-d-quinic acid was found to exhibit a potent inhibitory effect [IC50=0.29 um]. PMID- 23727780 TI - 2",4"-O-diacetylquercitrin, a novel advanced glycation end-product formation and aldose reductase inhibitor from Melastoma sanguineum. AB - A new flavonoid, 2,"4"-O-diacetylquercitrin (1), along with six known flavonoids (2-7) were isolated from the aerial parts of Melastoma sanguineum. The structure of the new flavonoid was established by extensive spectroscopic studies and chemical evidence. The inhibitory effects of isolated compounds (1-7) on advanced glycation end-products (AGEs) formation and rat lens aldose reductase (RLAR) in vitro were examined. Of the tested compounds, compound 1 was the strongest inhibitor of AGEs, with an IC50 of 11.46+/-0.44 um. In the RLAR assay, all tested compounds exhibited greater inhibitory effects on RLAR than that of a positive control, 3,3-tetramethyleneglutaric acid (IC50=28.8+/-1.5 um); compound 1 exhibited the strongest RLAR-inhibitory activity, with an IC50 of 0.077+/-0.003 um. PMID- 23727781 TI - Characterization of carotenoid fatty acid esters from the peels of the persimmon Diospyros kaki. AB - Separation and structural determination of the chloroform-soluble components obtained from the peels of the persimmon (Diospyros kaki Thunb.) were performed. beta-Carotene, lycopene, beta-cryptoxanthin mono-myristic acid ester, zeaxanthin di-myristic acid ester, the latter two of which were accompanied by a small amount of palmitoleic acid in the fatty acid moiety, and oleanolic acid were identified. Among these components, the mono-fatty acid ester of beta cryptoxanthin and the di-fatty acid ester of zeaxanthin were characterized for the first time. PMID- 23727782 TI - Synthesis and cytotoxicity on human leukemia cells of furonaphthoquinones isolated from tabebuia plants. AB - Furonaphthoquinones are promising skeletons for anticancer drug molecules. In particular, methoxylated furonaphthoquinones are characteristic constituents of Tabebuia plants. In this research, we synthesized the furonaphthoquinones by effective one-pot cascade reactions of 3-phenyliodonio-1,2,4-trioxo-1,2,3,4 tetrahydronaphthalenides with 3-butyn-2-ol in the presence of palladium and cuprous catalysts via Sonogashira coupling and intramolecular cyclization. Furthermore, we demonstrated that the synthetic furonaphthoquinones showed moderate cytotoxicity against human leukemia U937 and HL-60 cells. Our work highlights the importance of furonaphthoquinones as antileukemic agents. PMID- 23727783 TI - Triterpenes with cytotoxicity from the leaves of Vernicia fordii. AB - Two new triterpenes, (1alpha,3beta,8alpha,9beta,10alpha,13alpha,14beta)-9,10 dimethyl-25,26-dinorolean-5-en-1,3-diol (1) and (1alpha,3beta,6beta)-olean-12-en 1,3,6-triol (2) were isolated from the leaves of Aleurites fordii, together with five known triterpenes. The structures of isolates were established by one dimensional (1D)- and 2D-NMR spectroscopic data along with MS analysis. Of the isolated compounds, 1, 2 and 4 (daturadiol) displayed moderate cytotoxicities against two or more human cancer cell lines in HepG2 (hepatocellular carcinoma), SK-OV-3 (ovarian carcinoma), A-549 (lung carcinoma) and SNU-1 (gastric carcinoma). PMID- 23727785 TI - Community benefits provided by religious, other nonprofit, and for-profit hospitals: a longitudinal analysis 2000-2009. AB - BACKGROUND: Nonprofit hospitals (NFPs) are expected to provide community benefits to justify the tax benefits they receive, but recent budgetary constraints have called into question the degree to which the tax benefits are justified. The empirical literature comparing community benefits provided by NFPs and their for profit counterparts is mixed. However, NFPs are not a homogenous group and can include religious hospitals, community-owned hospitals, or academic medical centers. PURPOSE: This longitudinal study examines how religious hospitals compare with other NFPs and for-profit hospitals with respect to providing community benefits and how the provision of community benefits by hospitals has changed over time. METHODOLOGY: Using a pooled cross-sectional design, we examine two summated scores based on questions from the American Hospital Association annual survey that focus on community orientation among hospitals. We analyze two regressions with year, facility, and market controls to determine how religious hospitals compare with the other groups over time. FINDINGS: Overall, 11% of U.S. hospitals are religious. Religious hospitals were more likely to engage in each individual community benefit activity examined. In addition, the mean values of community benefits provided by religious hospitals, as measured on two summated scores, were significantly higher than those provided by other hospital types in bivariate and regression analyses. Overall, community benefits provided by all hospitals increased over time and then leveled off during the start of the recent economic downturn. PRACTICE IMPLICATIONS: As the debate continues regarding federal tax exemption status, policymakers should consider religious hospitals separately from NFPs. Managers at religious hospitals should consider how their increased levels of community benefits are related to their missions and set benchmarks that recognize and communicate those achievements. PMID- 23727784 TI - Toll-like receptor agonists induce apoptosis in mouse B-cell lymphoma cells by altering NF-kappaB activation. AB - Toll-like receptor 9 (TLR9) recognizes microbial DNA containing unmethylated cytosyl guanosyl (CpG) sequences, induces innate immune responses, and facilitates antigen-specific adaptive immunity. Recent studies report that in addition to stimulating innate immunity, TLR9 ligands induce apoptosis of TLR9 expressing cancer cells. To understand the mechanism of TLR9-induced apoptosis, we compared the effects of CpG containing oligodeoxynucleotides (CpG ODN) on a mouse B-cell lymphoma line, CH27, with those on mouse splenic B cells. CpG ODN inhibited constitutive proliferation and induced apoptosis in the CH27 B-cell lymphoma line. In contrast, CpG ODN-treated primary B cells were stimulated to proliferate and were rescued from spontaneous apoptosis. The induction of apoptosis required the ODNs to contain the CpG motif and the expression of TLR9 in lymphoma B cells. A decrease in Bcl-xl expression and an increase in Fas and Fas ligand expression accompanied lymphoma B-cell apoptosis. Treatment with the Fas ligand-neutralizing antibody inhibited CpG ODN-induced apoptosis. CpG ODN triggered a transient NF-kappaB activation in the B-cell lymphoma cell line, which constitutively expresses a high level of c-Myc, while CpG ODN induced sustained increases in NF-kappaB activation and c-Myc expression in primary B cells. Furthermore, an NF-kappaB inhibitor inhibited the proliferation of the CH27 B-cell lymphoma line. Our data suggest that the differential responses of lymphoma and primary B cells to CpG ODN are the result of differences in NF kappaB activation. The impaired NF-kappaB activation in the CpG ODN-treated B cell lymphoma cell line alters the balance between NF-kappaB and c-Myc, which induces Fas/Fas ligand-dependent apoptosis. PMID- 23727786 TI - Who chooses, who uses, who rates: the impact of agency on electronic word-of mouth about hospitals stays. AB - BACKGROUND: Patients' agents rather than patients themselves often choose hospitals and rehabilitation centers and evaluate inpatient stays. Thus, online reviews of a hospital may reflect a service experience the patient is not responsible for in two ways. First, a patient may evaluate a hospital that a physician as agent has selected, although he still received the service and is qualified to evaluate it. Second, relatives who may not be directly involved in the inpatient stay may write online reviews, which reflect their own experiences and evaluations. PURPOSE: The study analyzes patient satisfaction data in online hospitals reviews and patients' underlying motives for electronic word-of-mouth according to the type of hospital admission and the perspective of the reviewer. METHODOLOGY: The study uses a sample of 822 reviews from an online platform for hospital reviews and primary data generated by an online survey distributed to the writers of these reviews. FINDINGS: Patients who choose a hospital themselves write more positive online reviews than those with an other-directed choice. Relatives' online reviews more often deal with negative hospital experiences and are more likely to reflect a desire for retaliation. PRACTICE IMPLICATIONS: The study results imply that medical care centers (hospitals and rehabilitation facilities) should pay more attention to agency by focusing on the needs and perceptions of relatives who often act as the critical voice of patients in electronic word-of-mouth behavior. PMID- 23727787 TI - Making the right decisions about new technologies: a perspective on criteria and preferences in hospitals. AB - BACKGROUND: Decision makers in hospitals are regularly faced with choices about the adoption of new technologies. Wrong decisions lead to a waste of resources and can have serious effects on the patients' and hospital's well-being. PURPOSE: The goal of this research was to contribute to the understanding of decision making in hospitals. This study produced insights regarding relevant decision criteria and explored their specific relevance. METHODOLOGY/APPROACH: An initial empirical survey was used to collect the relevant criteria for technological decision making in hospitals. In total, 220 experts in the field of health technology assessment from 34 countries participated in the survey. As a second step, the abovementioned criteria were used to form the basis of an analytic hierarchy process model. A group of 115 physicians, medical technical assistants, and other staff, all of whom worked in the field of radiooncology, prioritized the criteria. An analysis of variance was performed to explore differences among groups in terms of institutional and personal categorization variables. FINDINGS: The first part of the research revealed seven key criteria for technological decision making in hospitals. The analytic hierarchy process model revealed that organizational impact was the most important criterion, followed by budget impact. The analysis of variance indicated that there were differences in the perceptions of the importance of the identified criteria. PRACTICAL IMPLICATIONS: This exploration of the criteria for technological decision making in hospitals will help decision makers consider all of the relevant aspects, leading to more structured and rational decisions. For the optimal resource allocation, all of the relevant stakeholder perspectives and local issues must be considered appropriately. PMID- 23727788 TI - Low-temperature crystallization of anodized TiO2 nanotubes at the solid-gas interface and their photoelectrochemical properties. AB - TiO2 nanotubular arrays formed by electrochemical anodization have attracted significant attention for photoelectrochemical applications that utilize solar energy. However, the as-anodized TiO2 nanotubes are amorphous, and need to be crystallized by high-temperature thermal annealing. Herein, we describe a low temperature hydrothermal solid-gas route to crystallize TiO2 nanotubes. In this process, the as-anodized TiO2 hydroxo nanotubes are dehydrated to yield anatase phase via solid-gas interface reaction in an autoclave at a temperature of less than 180 degrees C. The solid-gas interface reaction alleviates the collapse of as-anodized TiO2 nanotubes during hydrothermal process efficiently. Compared with the common thermal annealing at the same temperature but at atmospheric pressure, the hydrothermal route improves the photocurrent density of TiO2 nanotubes by ~10 times in KOH electrolyte. The duration of the hydrothermal reaction has a substantial effect on the photoelectrochemical properties of TiO2 nanotubes, which is ascribed to the synergetic effect between the crystallization and structural evolution. Electron donors can further suppress the charge recombination in the low-temperature crystallized TiO2 nanotubes and boost the photocurrent density by ~120%. PMID- 23727789 TI - Dextran based sensitive theranostic nanoparticles for near-infrared imaging and photothermal therapy in vitro. AB - Indocyanine green (ICG) nanoparticles were developed via electrostatic interactions of ICG and dextran based block copolymers (PEG-dextran(-SS-NH2)) as near-infrared (NIR) theranostic nanoparticles. The nanoparticles could be activated from "OFF" to "ON" of NIR fluorescence in an intracellular environment and used for NIR imaging and photothermal therapy. PMID- 23727790 TI - Phosphoglycerate kinase 1 as a promoter of metastasis in colon cancer. AB - Oxidative stress due to intratumoral hypoxia in solid cancer has been shown to be associated with increased mortality. Phosphoglycerate kinase 1 (PGK1) is an enzyme of the glycolytic pathway, which is regulated by hypoxia-inducible factor 1alpha (HIF-1alpha) and has been described for its role in tumor progression and metastasis in several malignancies. We investigated whether the expression of PGK1 varies between metastatic and non-metastatic colon cancer. We compared PGK1 expression in colon cancer patients either with or without metastasis via polymerase chain reaction (PCR) and immunohistochemistry. Microarray analysis was performed to test altered gene expression after PGK1 silencing, using isolates from HCT116 cell lines. PCR results showed an increased expression of PGK1 in colon cancer tissue from metastatic patients in comparison to patients with no metastasis (fold change 2.6, p<0.001). Immunohistochemical staining of PGK1 showed stronger staining in metastatic tissue in comparison to non-metastatic cancer tissue according to a semi-quantitative evaluation. Microarray and subsequent pathway analysis provided 4 genes of interest (CYR61, FOS, JUN and EGR1) used for pathway proposal. The results indicate that increased expression of PGK1 in colon cancer tissue is associated with metastasis. Furthermore, we propose several genes induced by PGK1 that could account for cell migration, mainly EGR1 and CYR61 together with the transcription factors FOS and JUN. PMID- 23727791 TI - Improving prenatal health: setting the agenda for increased male involvement. AB - The U.S. infant mortality rate is among the highest in the developed world, with recent vital statistics reports estimating 6.14 infant deaths per 1,000 live births. Traditional health education and promotion to improve maternal, infant, and child health in the United States has focused only on women, leaving men out of important health messages that may affect pregnancy outcomes as well as family well-being. Recently, public health scholars have suggested that men be included in prenatal health education in an effort to improve birth outcomes and reduce infant mortality. Incorporating men in prenatal health promotion and education has been found to improve overall birth preparedness, reduce the risk of maternal infant HIV transmission, and reduce perinatal mortality in less-developed nations. Although these results are positive, research on paternal impact in pregnancy outcomes in the United States to date is lacking. This article proposes a U.S.-specific research agenda to understand the current role of men in pregnancy health, as well as actual involvement, barriers, and the influence men can have in prenatal health. A discussion of culture, individual motivations, health care providers, and social marketing is also considered. PMID- 23727792 TI - Beyond workers' compensation: men's mental health in and out of work. AB - The mental health of men is an important issue with significant direct and indirect costs emerging from work-related depression and suicide. Although the merits of men's community-based and workplace mental health promotion initiatives have been endorsed, few programs are mandated or formally evaluated and reported on. Conspicuously absent also are gender analyses detailing connections between masculinities and men's work-related depression and suicide on which to build men centered mental health promotion programs. This article provides an overview of four interconnected issues, (a) masculinities and men's health, (b) men and work, (c) men's work-related depression and suicide, and (d) men's mental health promotion, in the context of men's diverse relationships to work (including job insecurity and unemployment). Based on the review, recommendations are made for advancing the well-being of men who are in as well as of those out of work. PMID- 23727793 TI - Rapid establishment of CHO cell lines producing the anti-hepatocyte growth factor antibody SFN68. AB - Anti-hepatocyte growth factor (anti-HGF) monoclonal antibodies (mAbs) are potential therapeutics against various cancers. Screening for high-producer clones is a time-consuming and complex process and is a major hurdle in the development of therapeutic mAbs. Here, we describe an efficient approach that allows the selection of high-producer Chinese hamster ovary (CHO) cell lines producing the novel anti-HGF mAb SFN68, which was generated previously by immunizing HGF bound to its receptor c-Met. We selected an SFN68-producing parental cell line via transfection of the dihydrofolate reductase-deficient CHO cell line DG44, which was preadapted to serum-free suspension culture, with an SFN68-expression vector. Subsequent gene amplification via multiple passages of the parental cell line in a methotrexate-containing medium over 4 weeks, followed by clonal isolation, enabled us to isolate two cell lines, 2F7 and 2H4, with 3 fold higher specific productivity. We also screened 72 different media formulated with diverse feed and basal media to develop a suboptimized medium. In the established suboptimized medium, the highest anti-HGF mAb yields of the 2F7 and 2H4 clones were 842 and 861 mg/l, respectively, which were about 10.5-fold higher than that of the parental cell line in a non-optimized basal medium. The selected CHO cell lines secreting high titers of SFN68 would be useful for the production of sufficient amounts of antibodies for efficacy evaluation in preclinical and early clinical studies. PMID- 23727794 TI - Characterization of three antifungal calcite-forming bacteria, Arthrobacter nicotianae KNUC2100, Bacillus thuringiensis KNUC2103, and Stenotrophomonas maltophilia KNUC2106, derived from the Korean islands, Dokdo and their application on mortar. AB - Crack remediation on the surface of cement mortar using microbiological calcium carbonate (CaCO3) precipitation (MICP) has been investigated as a microbial sealing agent on construction materials. However, MICP research has never acknowledged the antifungal properties of calcite-forming bacteria (CFB). Since fungal colonization on concrete surfaces can trigger biodeterioration processes, fungi on concrete buildings have to be prevented. Therefore, to develop a microbial sealing agent that has antifungal properties to remediate cement cracks without deteriorative fungal colonization, we introduced an antifungal CFB isolated from oceanic islands (Dokdo islands, territory of South Korea, located at the edge of the East Sea in Korea.). The isolation of CFB was done using B4 or urea-CaCl2 media. Furthermore, antifungal assays were done using the pairing culture and disk diffusion methods. Five isolated CFB showed CaCO3 precipitation and antifungal activities against deteriorative fungal strains. Subsequently, five candidate bacteria were identified using 16S rDNA sequence analysis. Crack remediation, fungi growth inhibition, and water permeability reduction of antifungal CFB-treated cement surfaces were tested. All antifungal CFB showed crack remediation abilities, but only three strains (KNUC2100, 2103, and 2106) reduced the water permeability. Furthermore, these three strains showed fungi growth inhibition. This paper is the first application research of CFB that have antifungal activity, for an eco-friendly improvement of construction materials. PMID- 23727795 TI - Maximizing biomass productivity and CO2 biofixation of microalga, Scenedesmus sp. by using sodium hydroxide. AB - A series of experiments were carried out with three native strains of microalgae to measure growth rates, biomass, and lipid productivities. Scenedesmus sp. IMMTCC-6 had better biomass growth rate and higher lipid production. The growth, lipid accumulation, and carbon dioxide (CO2) consumption rate of Scenedesmus sp. IMMTCC-6 were tested under different NaOH concentrations in modified BBM. The algal strain showed the maximum specific growth rate (0.474/day), biomass productivity (110.9 mg l(-1) d(-1)), and CO2 consumption rate (208.4 mg l(-1) d( 1)) with an NaOH concentration of 0.005 M on the 8(th) day of cultivation. These values were 2.03-, 6.89-, and 6.88-fold more than the algal cultures grown in control conditions (having no NaOH and CO2). The CO2 fixing efficiency of the microalga with other alternative carbon sources like Na2CO3 and NaHCO3 was also investigated and compared. The optimized experimental parameters at shake-flask scale were implemented for scaling up the process in a self-engineered photobioreactor. A significant increase in lipid accumulation (14.23% to 31.74%) by the algal strain from the logarithmic to stationary phases was obtained. The algal lipids were mainly composed of C16/C18 fatty acids, and are desirable for biodiesel production. The study suggests that microalga Scenedesmus sp. IMMTCC-6 is an efficient strain for biodiesel production and CO2 biofixation using stripping solution of NaOH in a cyclic process. PMID- 23727796 TI - Inhibition of Microcystis aeruginosa by the extracellular substances from an Aeromonas sp. AB - Growth of Microcystis aeruginosa could be inhibited significantly within 24 h by the extracellular substances prepared from Aeromonas sp. strain FM. During the treatment, the concentration of extracellular soluble carbohydrates increased significantly in algal culture. Morphological and ultrastructural changes in M. aeruginosa cells, including breakage of the cell surface, secretion of mucilage, and intracellular disorganization of thylakoids, were observed. HPLC-MS analysis showed that the extracellular substances of Aeromonas sp. strain FM were a mixture of free amino acids, tripeptides, and clavulanate. Among these, the algae lysis effects of lysine and clavulanate were confirmed. PMID- 23727797 TI - Production of acetate from carbon dioxide in bioelectrochemical systems based on autotrophic mixed culture. AB - Bioelectrochemical systems (BESs) have been suggested as a new technology for wastewater treatment while accomplishing energy and chemical generation. This study describes the performance of BESs based on mixed culture that are capable of reducing carbon dioxide to acetate. The cathode potential was a critical factor that affected the performance of the BESs. The rate of acetate production increased as the electrode potential became more negative, from 0.38 mM d(-1) ( 900 mV vs. Ag/AgCl) to 2.35 mM d(-1) (-1,100 mV), while the electron recovery efficiency of carbon dioxide reduction to acetate increased from 53.6% to 89.5%. The microbial population was dominated by relatives of Acetobacterium woodii when a methanogenic inhibitor was added to the BESs initially. PMID- 23727799 TI - Acetone-Butanol-Ethanol (ABE) production in fermentation of enzymatically hydrolyzed cassava flour by Clostridium beijerinckii BA101 and solvent separation. AB - Cassava constitutes an abundant substrate in tropical regions. The production of butanol in ABE fermentation by Clostridium beijerinckii BA101 using cassava flour (CF) was scaled-up to bioreactor level (5 L). Optimized fermentation conditions were applied; that is, 40C, 60 g/l CF, and enzymatic pretreatment of the substrate. The batch fermentation profile presented an acidogenic phase for the first 24 h and a solventogenic phase afterwards. An average of 37.01 g/l ABE was produced after 83 h, with a productivity of 0.446 g/l/h. Butanol production was 25.71 g/l with a productivity of 0.310 g/l/h, high or similar to analogous batch processes described for other substrates. Solvent separation by different combinations of fractioned and azeotropic distillation and liquid-liquid separation were assessed to evaluate energetic and economic costs in downstream processing. Results suggest that the use of cassava as a substrate in ABE fermentation could be a cost-effective way of producing butanol in tropical regions. PMID- 23727798 TI - Biocontrol of Pectobacterium carotovorum subsp. carotovorum using bacteriophage PP1. AB - Pectobacterium carotovorum subsp. carotovorum (formerly Erwinia carotovora subsp. carotovora) is a plant pathogen that causes soft rot and stem rot diseases in several crops, including Chinese cabbage, potato, and tomato. To control this bacterium, we isolated a bacteriophage, PP1, with lytic activity against P. carotovorum subsp. carotovorum. Transmission electron microscopy revealed that the PP1 phage belongs to the Podoviridae family of the order Caudovirales, which exhibit icosahedral heads and short non-contractile tails. PP1 phage showed high specificity for P. carotovorum subsp. carotovorum, and several bacteria belonging to different species and phyla were resistant to PP1. This phage showed rapid and strong lytic activity against its host bacteria in liquid medium and was stable over a broad range of pH values. Disease caused by P. carotovorum subsp. carotovorum was significantly reduced by PP1 treatment. Overall, PP1 bacteriophage effectively controls P. carotovorum subsp. carotovorum. PMID- 23727800 TI - Intermolecular interaction between Cry2Aa and Cyt1Aa and its effect on larvicidal activity against Culex quinquefasciatus. AB - The Cyt1Aa protein of Bacillus thuringiensis susbp. israelensis elaborates demonstrable toxicity to mosquito larvae, but more importantly, it enhances the larvicidal activity of this species Cry proteins (Cry11Aa, Cry4Aa, and Cry4Ba) and delays the phenotypic expression of resistance to these that has evolved in Culex quinquefasciatus. It is also known that Cyt1Aa, which is highly lipophilic, synergizes Cry11Aa by functioning as a surrogate membrane-bound receptor for the latter protein. Little is known, however, about whether Cyt1Aa can interact similarly with other Cry proteins not primarily mosquitocidal; for example, Cry2Aa, which is active against lepidopteran larvae, but essentially inactive or has very low toxicity to mosquito larvae. Here we demonstrate by ligand binding and enzyme-linked immunosorbent assays that Cyt1Aa and Cry2Aa form intermolecular complexes in vitro, and in addition show that Cyt1Aa facilitates binding of Cry2Aa throughout the midgut of C. quinquefasciatus larvae. As Cry2Aa and Cry11Aa share structural similarity in domain II, the interaction between Cyt1Aa and Cry2Aa could be a result of a similar mechanism previously proposed for Cry11Aa and Cyt1Aa. Finally, despite the observed interaction between Cry2Aa and Cyt1Aa, only a 2-fold enhancement in toxicity resulted against C. quinquefasciatus. Regardless, our results suggest that Cry2Aa could be a useful component of mosquitocidal endotoxin complements being developed for recombinant strains of B. thuringiensis subsp. israelensis and B. sphaericus aimed at improving the efficacy of commercial products and avoiding resistance. PMID- 23727801 TI - Analysis of transcriptional profiles to discover biomarker candidates in Mycobacterium avium subsp. paratuberculosis-infected macrophages, RAW 264.7. AB - Paratuberculosis (PTB) or Johne's disease is one of the most serious chronic debilitating diseases of ruminants worldwide that is caused by Mycobacterium avium subsp. paratuberculosis (MAP). MAP is a slow-growing bacterium that has very long latent periods, resulting in difficulties in diagnosing and controlling the disease, especially regarding the diagnosis of fecal shedders of MAP without any clinical signs. Based on this situation, attempts were made to identify biomarkers that show early responses to MAP infection in a macrophage cell line, RAW 264.7. In response to the infection with the bacterium, a lot of genes were turned on and/or off in the cells. Of the altered genes, three different categories were identified based on the time-dependent gene expression patterns. Those genes were considered as possible candidates for biomarkers of MAP infection after confirmation by quantitative RT-PCR analysis. To the best of our knowledge, this is the first attempt at discovering the host transcriptomic biomarkers of PTB, although further investigation will be required to determine whether these biomarker candidates are associated within the natural host. PMID- 23727802 TI - Strain improvement by overexpression of the laeA gene in Monascus pilosus for the production of monascus-fermented rice. AB - Monascus species have been used to produce fermented rice called Monascus fermented rice (MFR). To improve a Monascus strain via activation of secondary metabolite (SM) gene clusters for use in the production of MFR, we overexpressed an ortholog of the laeA gene, which encodes a global positive regulator of secondary metabolism under the control of the strong heterologous Aspergillus nidulans alcA promoter in Monascus pilosus. The OE::laeA transformant produced more SMs, including those not detected under uninduced conditions. MFR produced using the M. pilosus OE::laeA strain contained 4 times more monacolin K, a cholesterol-lowering agent, than MFR produced using the wild-type strain. In addition, pigment production was remarkably increased, and the antioxidant activity was increased as well. The results from this study suggest that Monascus species, which are important industrial fermentative fungi in Asia, can be improved for the production of functional foods by overexpressing the laeA gene. PMID- 23727803 TI - Metabolomic response of Chlamydomonas reinhardtii to the inhibition of target of rapamycin (TOR) by rapamycin. AB - Rapamycin, known as an inhibitor of Target of Rapamycin (TOR), is an immunosuppressant drug used to prevent rejection in organ transplantation. Despite the close association of the TOR signaling cascade with various scopes of metabolism, it has not yet been thoroughly investigated at the metabolome level. In our current study, we applied mass spectrometric analysis for profiling primary metabolism in order to capture the responsive dynamics of the Chlamydomonas metabolome to the inhibition of TOR by rapamycin. Accordingly, we identified the impact of the rapamycin treatment at the level of metabolomic phenotypes that were clearly distinguished by multivariate statistical analysis. Pathway analysis pinpointed that inactivation of the TCA cycle was accompanied by the inhibition of cellular growth. Relative to the constant suppression of the TCA cycle, most amino acids were significantly increased in a time-dependent manner by longer exposure to rapamycin treatment, after an initial down regulation at the early stage of exposure. Finally, we explored the isolation of the responsive metabolic factors into the rapamycin treatment and the culture duration, respectively. PMID- 23727804 TI - In vitro screening for compounds derived from traditional chinese medicines with antiviral activities against porcine reproductive and respiratory syndrome virus. AB - Seventeen compounds derived from traditional Chinese medicines (TCMs) were tested for their antiviral activity against porcine reproductive and respiratory syndrome virus (PRRSV) in vitro. Visualization with the cytopathologic effect (CPE) assay and the 3-(4, 5-dimethyithiazol- 2-yl)-2,5-diphenyltetrazolium bromide test were used to determine the 50% cytotoxic concentration (CC50) and 50% effective concentration (EC50) in cultured Marc-145 cells. Among the tested compounds, chlorogenic acid and scutellarin showed potential anti-PRRSV activity. The EC50 values were 270.8 +/- 14.6 MUg/ml and 28.21 +/- 26.0 MUg/ml and the selectivity indexes were >5.54 and 35.5, respectively. The time-of-addition and virucidal assay indicated that the anti-PRRSV activity of the two compounds could be due to their inhibiting the early stage of virus replication and/or inactivating the virus directly. The inhibition of the virus attachment was not observed in the adsorption inhibition assay. The inhibition ratios of chlorogenic acid and scutellarin were, respectively, 90.8% and 61.1% at the maximum non cytotoxic concentrations. The results have provided a basis for further exploration of their antiviral properties and mechanisms in vivo. We believe that the chlorogenic acid and scutellarin have a great potential to be developed as new anti-PRRSV drugs for clinical application. PMID- 23727805 TI - Orientia tsutsugamushi infection induces CD4+ T cell activation via human dendritic cell activity. AB - Orientia tsutsugamushi, a gram-negative bacterium, causes severe acute febrile illness in humans. Despite this danger, the route of infection, infectivity, and protective mechanisms of the host's immune response to O. tsutsugamushi are unclear. Dendritic cells (DCs) are one of the most important cell types in bridging the innate and adaptive immune responses. In this study, we observed that O. tsutsugamushi infects and replicates in monocyte-derived DCs (MODCs). During infection and replication, the expressions of the cytokines IL-12 and TNF alpha, as well as the co-stimulatory molecules CD80, CD83, CD86, and CD40, were increased in MODCs. When O. tsutsugamushi-treated MODCs were co-cultured with autologous CD4(+) T cells, they enhanced production of IFN-gamma, a major Th1 cytokine. Collectively, our results show that O. tsutsugamushi can replicate in MODCs and can simultaneously induce MODC maturation and increase proinflammatory cytokine levels in MODCs that subsequently activate CD4(+) T cells. PMID- 23727806 TI - Detection of human cytomegalovirus UL97 D605E mutation in Korean stem cell transplantation recipients and donors. AB - Ganciclovir resistance of human cytomegalovirus is associated with mutations in the viral UL97 gene and poses severe problems for immunocompromised patients. In this study, PCRbased restriction fragment length polymorphism and sequencing analyses detected the UL97 D605E mutation in all five clinical isolates from patients with ganciclovir-resistant human cytomegalovirus infection during prolonged ganciclovir therapy, whereas the M460V mutation was only present in 1 of 5 isolates. On the other hand, the detection rates of the D605E mutation in the stored available DNA samples from the donor and allogeneic stem cell transplantation recipients were 66.7% and 93.7%, respectively, suggesting that the presence of D605E mutation was not associated with the ganciclovir exposure. Although the D605E mutation may not be related to ganciclovir resistance, we suggest that this mutation could be an important molecular marker of human cytomegalovirus evolution in East Asian countries. Moreover, the restriction fragment length polymorphism method using the restriction enzyme HaeIII, which is generally used to detect the UL97 A591V mutation, could also detect the D605E mutation and may therefore be a useful tool for future research on the investigation of UL97 gene mutations. PMID- 23727807 TI - Molecular cloning and enzymatic characterization of cyclomaltodextrinase from hyperthermophilic archaeon Thermococcus sp. CL1. AB - Genome organization near cyclomaltodextrinases (CDases) was analyzed and compared for four different hyperthermophilic archaea: Thermococcus, Pyrococcus, Staphylothermus, and Thermofilum. A gene (CL1_0884) encoding a putative CDase from Thermococcus sp. CL1 (tccd) was cloned and expressed in Escherichia coli. TcCD was confirmed to be highly thermostable, with optimal activity at 85C. The melting temperature of TcCD was determined to be 93oC by both differential scanning calorimetry and differential scanning fluorimetry. A size-exclusion chromatography experiment showed that TcCD exists as a monomer. TcCD preferentially hydrolyzed alpha-cyclodextrin (alpha-CD), and at the initial stage catalyzed a ring-opening reaction by cleaving one alpha-1,4-glycosidic linkage of the CD ring to produce the corresponding single maltooligosaccharide. Furthermore, TcCD could hydrolyze branched CDs (G1-alpha-CD, G1-beta- CD, and G2 beta-CD) to yield significant amounts (45%, 40%, and 46%) of isomaltooligosaccharides (panose and 6(2)-alpha-maltosylmaltose) in addition to glucose and maltose. This enzyme is one of the most thermostable maltogenic amylases reported, and might be of potential value in the production of isomaltooligosaccharides in the food industry. PMID- 23727808 TI - Enzymatic hydrolysis of gelatin layers of X-Ray films and release of silver particles using keratinolytic serine proteases from Purpureocillium lilacinum LPS # 876. AB - Enzymatic decomposition of gelatin layers on used X-ray films and repeated utilization of the enzyme for potential application in silver recovery were investigated using keratinolytic serine proteases from Purpureocillium lilacinum LPS # 876. At pH 9.0, the enzymatic reaction was enhanced by the increase of enzyme concentration or by the increase of the temperature up to 60C. Under the conditions of 6.9 U/ml, 60C, and pH 9.0, hydrolysis of the gelatin layers and the resulting release of silver particles were achieved within 6 min. The protective effect of polyols against thermal denaturation was investigated. The presence of glycerol and propylene glycol increased enzyme stability. When the reusability of the enzyme for gelatin hydrolysis was tested, it could be seen that it could be effectively reused for more cycles when glycerol was added, compared with the enzyme without protective agents. The results of these repeated treatments suggested that a continuous process of recycling silver from used X-ray is feasible. Keeping in mind that recycling is (at the present time) needed and imperative, it can be remarked that, in this research, three wastes were successfully used: hair waste in order to produce serine proteases; glycerol in order to enhance enzyme thermal stability; and used Xray films in order to recover silver and PET films. PMID- 23727809 TI - Antibacterial effect of amentoflavone and its synergistic effect with antibiotics. AB - Selaginella tamariscina is a traditional herb used in medicine. Phytochemical amentoflavone, a biflavonoid class of flavonoids, was isolated from the plant of Selaginella tamariscina. In this study, the antibacterial effects and combination effects of amentoflavone and conventional antibiotics such as ampicillin, cefotaxime, and chloramphenicol were investigated. These results showed that amentoflavone had a considerable antibacterial effect and synergistic interaction with antibiotics against various bacterial strains (fractional inhibitory concentration index <= 0.5), except for Streptococcus mutans. To study the mechanism(s) involved in the synergistic activities between amentoflavone and antibiotics, we detected hydroxyl radical formation using 3'-(p-hydroxyphenyl) fluorescein and measured the NAD+/NADH ratio by NAD+ cycling assay. The results indicated that the formation of hydroxyl radical would be a cause of the synergistic effect and that this oxidative stress originated from a transient NADH depletion. This study suggests that amentoflavone synergizes with antibiotics and has potential as a therapeutic agent for antimicrobial chemotherapy. PMID- 23727810 TI - Cr(VI) resistance and removal by indigenous bacteria isolated from chromium contaminated soil. AB - The removal of toxic Cr(VI) by microorganisms is a promising approach for Cr(VI) pollution remediation. In the present study, four indigenous bacteria, named LY1, LY2, LY6, and LY7, were isolated from Cr(VI)-contaminated soil. Among the four Cr(VI)-resistant isolates, strain LY6 displayed the highest Cr(VI)-removing ability, with 100 mg/l Cr(VI) being completely removed within 144 h. It could effectively remove Cr(VI) over a wide pH range from 5.5 to 9.5, with the optimal pH of 8.5. The amount of Cr(VI) removed increased with initial Cr(VI) concentration. Data from the time-course analysis of Cr(VI) removal by strain LY6 followed first-order kinetics. Based on the 16S rRNA gene sequence, strain LY6 was identified as Pseudochrobactrum asaccharolyticum, a species that had never been reported for Cr(VI) removal before. Transmission electron microscopy and energy dispersive X-ray spectroscopy analysis further confirmed that strain LY6 could accumulate chromium within the cell while conducting Cr(VI) removal. The results suggested that the indigenous bacterial strain LY6 would be a new candidate for potential application in Cr(VI) pollution bioremediation. PMID- 23727811 TI - Characterization of a fibrinolytic enzyme secreted by Bacillus amyloliquefaciens CB1 and its gene cloning. AB - Bacillus amyloliquefaciens CB1 was isolated from cheonggukjang, a Korean fermented soy food. B. amyloliquefaciens CB1 secretes proteases with fibrinolytic activities. A gene homologous to aprE of Bacillus subtilis, aprECB1, was cloned from B. amyloliquefaciens CB1, and DNA sequencing showed that aprECB1 can encode a prepro-type serine protease consisting of 382 amino acids. When aprECB1 was introduced into B. subtilis WB600 using an E. coli-Bacillus shuttle vector, pHY300PLK, transformants showed fibrinolytic activity and produced a 28 kDa protein, the size expected for the mature enzyme. The 28 kDa fibrinolytic enzyme was purified from the culture supernatant of B. subtilis WB600 transformant. AprECB1 was completely inhibited by phenylmethylsulfonyl fluoride and almost completely inhibited by EDTA and EGTA, indicating that it is a serine metalloprotease. AprECB1 exhibited the highest specificity for N-succinyl-Ala-Ala Pro-Phe-p-nitroanilide, a known substrate for alpha-chymotrypsin. Aalpha and Bbeta chains of fibrinogen were quickly degraded by AprECB1, but the gamma-chain was resistant. PMID- 23727812 TI - Lipoteichoic acid suppresses effector T cells induced by Staphylococcus aureus pulsed dendritic cells. AB - Lipoteichoic acid (LTA), uniquely expressed on gram-positive bacteria, is recognized by Tolllike receptor 2 (TLR2) on not only antigen-presenting cells but also activated T cells. Therefore, it is reasonable to assume that LTA is acting on T cells. However, little is known about the effect of LTA on T-cell regulation. In the present study, we investigated the immunomodulatory effects of LTA on CD4+ T cells. Effector CD4+ T cells, induced after co-culture with S. aureuspulsed dendritic cells, produced high levels of interferon-gamma, CD25, CD69, and TLRs 2 and 4. When effector CD4+ T cells were treated with LTA, the expressions of the membrane-bound form of transforming growth factor (TGF)-beta and forkhead box P3 increased. Coincidently, the proliferation of effector CD4+ T cells was declined after LTA treatment. When TGF-beta signaling was blocked by the TGF-beta receptor 1 kinase inhibitor, LTA failed to suppress the proliferation of effector CD4+ T cells. Therefore, the present results suggest that LTA suppresses the activity of effector CD4+ T cells by enhancing TGF-beta production. PMID- 23727813 TI - Efficiency and midgut histopathological effect of the newly isolated Bacillus thuringiensis KS delta-endotoxins on the emergent pest Tuta absoluta. AB - Tuta absoluta (Povolny, 1994) is a devastating moth to the Solanaceae plants. It is a challenging pest to control, especially on tomatoes. In this work, we studied the entomopathogenic activity of the Cry-forming delta-endotoxins produced by Bacillus thuringiensis strain KS and B. thuringiensis kurstaki reference strain HD1 against T. absoluta. These strains carried the cry2, cry1Ab, cry1Aa / cry1Ac, and cry1I genes, and KS also carried a cry1C gene. The delta endotoxins of KS were approximately twofold more toxic against the third instar larvae than those of HD1, as they showed lower 50% and 90% lethal concentrations (0.80 and 2.70 MUg/cm2 (delta-endotoxins/tomato leaf)) compared with those of HD1 (1.70 and 4.50 MUg/cm2) (p < 0.05). Additionally, the larvae protease extract showed at least six caseinolytic activities, which activated the KS and HD1 delta endotoxins, yielding the active toxins of about 65 kDa and the protease resistant core of about 58 kDa. Moreover, the histopathological effects of KS and HD1 delta-endotoxins on the larvae midgut consisted of an apical columnar cell vacuolization, microvillus damage, and epithelial cell disruption. These results showed that the KS strain could be a candidate for T. absoluta control. PMID- 23727814 TI - Generation and expression in plants of a single-chain variable fragment antibody against the immunodominant membrane protein of Candidatus phytoplasma aurantifolia. AB - Witches' broom of lime is a disease caused by Candidatus Phytoplasma aurantifolia, which represents the most significant global threat to the production of lime trees (Citrus aurantifolia). Conventional disease management strategies have shown little success, and new approaches based on genetic engineering need to be considered. The expression of recombinant antibodies and fragments thereof in plant cells is a powerful approach that can be used to suppress plant pathogens. We have developed a single-chain variable fragment antibody (scFvIMP6) against the immunodominant membrane protein (IMP) of witches' broom phytoplasma and expressed it in different plant cell compartments. We isolated scFvIMP6 from a naive scFv phage display library and expressed it in bacteria to demonstrate its binding activity against both recombinant IMP and intact phytoplasma cells. The expression of scFvIMP6 in plants was evaluated by transferring the scFvIMP6 cDNA to plant expression vectors featuring constitutive or phloem specific promoters in cassettes with or without secretion signals, therefore causing the protein to accumulate either in the cytosol or apoplast. All constructs were transiently expressed in Nicotiana benthamiana by agroinfiltration, and antibodies of the anticipated size were detected by immunoblotting. Plant-derived scFvIMP6 was purified by affinity chromatography, and specific binding to recombinant IMP was demonstrated by enzyme-linked immunosorbent assay. Our results indicate that scFvIMP6 binds with high activity and can be used for the detection of Ca. Phytoplasma aurantifolia and is also a suitable candidate for stable expression in lime trees to suppress witches' broom of lime. PMID- 23727815 TI - Recent insights in the removal of Klebseilla pathogenicity factors for the industrial production of 2,3-butanediol. AB - 2,3-Butanediol (2,3-BDO) has immense industrial applications. Recently, microbial fermentation has emerged as an alternative way to produce this industrially important chemical. Although 2,3-BDO is produced by several microorganisms, the Klebsiella genera has an excellent production compared with other 2,3-BDO producing microorganisms. In order to produce 2,3- BDO on a large scale, the challenges of removing pathogenic factors from Klebsiella pneumoniae need to be addressed. K. pneumoniae produces a number of virulence factors that contribute to its pathogenesis, including lipopolysaccharides, capsules, fimbrial adhesins, etc. Removal of these pathogenic factors from 2,3-BDO-producing Klebsiella strains will result in avirulent strains for the safe, economic, and efficient production of 2,3-BDO. In this review, we summarize the current trends in 2,3-BDO production using K. pneumoniae and insights into the removal of its virulence factors for industrial applications. PMID- 23727816 TI - Rate-independent dissipation and loading direction effects in compressed carbon nanotube arrays. AB - Arrays of nominally-aligned carbon nanotubes (CNTs) under compression deform locally via buckling, exhibit a foam-like, dissipative response, and can often recover most of their original height. We synthesize millimeter-scale CNT arrays and report the results of compression experiments at different strain rates, from 10(-4) to 10(-1) s(-1), and for multiple compressive cycles to different strains. We observe that the stress-strain response proceeds independently of the strain rate for all tests, but that it is highly dependent on loading history. Additionally, we examine the effect of loading direction on the mechanical response of the system. The mechanical behavior is modeled using a multiscale series of bistable springs. This model captures the rate independence of the constitutive response, the local deformation, and the history-dependent effects. We develop here a macroscopic formulation of the model to represent a continuum limit of the mesoscale elements developed previously. Utilizing the model and our experimental observations we discuss various possible physical mechanisms contributing to the system's dissipative response. PMID- 23727817 TI - Triarylboryl-functionalized dibenzoylmethane and its phosphorescent platinum(II) complexes. AB - An acetylacetonato derivative ligand, dibenzoylmethane (dbm), has been functionalized with a dimesitylboryl group. Phosphorescent N^C-chelate Pt(II) compounds with the new molecule as an ancillary ligand have been achieved and used as effective turn-on phosphorescent sensors for fluoride ions under air. PMID- 23727818 TI - Hexagonal microrods of anatase tetragonal TiO2: self-directed growth and superior photocatalytic performance. AB - Novel TiO2 mesocrystalline microrods with unique hexagonal structure were prepared via a facial thermal method. Their photocatalytic performance under UV irradiation was much higher than that of the Degussa P25 benchmark, one of the best commercial polycrystalline TiO2 photocatalyst. The hexagonal microrods were formed through self-directed self-assembly within intermediate scaffolds. PMID- 23727819 TI - Circuit level defects in the developing neocortex of Fragile X mice. AB - Subtle alterations in how cortical network dynamics are modulated by different behavioral states could disrupt normal brain function and underlie symptoms of neuropsychiatric disorders, including Fragile X syndrome (FXS). Using two-photon calcium imaging and electrophysiology, we recorded spontaneous neuronal ensemble activity in mouse somatosensory cortex. Unanesthetized Fmr1(-/-) mice exhibited abnormally high synchrony of neocortical network activity, especially during the first two postnatal weeks. Neuronal firing rates were threefold higher in Fmr1(-/ ) mice than in wild-type mice during whole-cell recordings manifesting Up/Down states (slow-wave sleep, quiet wakefulness), probably as a result of a higher firing probability during Up states. Combined electroencephalography and calcium imaging experiments confirmed that neurons in mutant mice had abnormally high firing and synchrony during sleep. We conclude that cortical networks in FXS are hyperexcitable in a brain state-dependent manner during a critical period for experience-dependent plasticity. These state-dependent network defects could explain the intellectual, sleep and sensory integration dysfunctions associated with FXS. PMID- 23727822 TI - Reagents and assay strategies for quantifying active enzyme analytes using a personal glucose meter. AB - This communication describes small molecule reagents and a rapid single-step assay for quantifying nanomolar levels of active enzyme analytes using a personal glucose meter. PMID- 23727821 TI - Histone deacetylase inhibitors facilitate partner preference formation in female prairie voles. AB - In the socially monogamous prairie vole (Microtus ochrogaster), mating induces enduring pair-bonds that are initiated by partner preference formation and regulated by a variety of neurotransmitters, including oxytocin, vasopressin and dopamine. We examined potential epigenetic mechanisms mediating pair-bond regulation and found that the histone deacetylase inhibitors sodium butyrate and trichostatin A (TSA) facilitated partner preference formation in female prairie voles in the absence of mating. This was associated with a specific upregulation of oxytocin receptor (OTR, oxtr) and vasopressin V1a receptor (V1aR, avpr1a) in the nucleus accumbens (NAcc), through an increase in histone acetylation at their respective promoters. Furthermore, TSA-facilitated partner preference was prevented by OTR or V1aR blockade in the NAcc. Notably, mating-induced partner preference triggered the same epigenetic regulation of oxtr and avpr1a gene promoters as TSA. These observations indicate that TSA and mating facilitate partner preference through epigenetic events, providing, to the best of our knowledge, the first direct evidence for epigenetic regulation of pair-bonding. PMID- 23727820 TI - Neural coding during active somatosensation revealed using illusory touch. AB - Active sensation requires the convergence of external stimuli with representations of body movements. We used mouse behavior, electrophysiology and optogenetics to dissect the temporal interactions among whisker movement, neural activity and sensation of touch. We photostimulated layer 4 activity in single barrels in a closed loop with whisking. Mimicking touch-related neural activity caused illusory perception of an object at a particular location, but scrambling the timing of the spikes over one whisking cycle (tens of milliseconds) did not abolish the illusion, indicating that knowledge of instantaneous whisker position is unnecessary for discriminating object locations. The illusions were induced only during bouts of directed whisking, when mice expected touch, and in the relevant barrel. Reducing activity biased behavior, consistent with a spike count code for object detection at a particular location. Our results show that mice integrate coding of touch with movement over timescales of a whisking bout to produce perception of active touch. PMID- 23727823 TI - GALR1 methylation in vaginal swabs is highly accurate in identifying women with endometrial cancer. AB - Endometrial cancer has become the most common gynecological cancer in developed countries. Postmenopausal bleeding is indicative of the disease in only 1 of 10 women with this symptom. A noninvasive tool to identify women with cancer would be highly desirable. We analyzed more than 27,000 CpGs in normal endometrial tissue (n = 23) and endometrial cancers (n = 64) and found that DNA methylation of GALR1 is among the most frequent epigenetic alterations in this cancer. We then developed a real-time polymerase chain reaction-based GALR1 methylation test and applied this test to vaginal swabs from 79 women who presented with postmenopausal bleeding. The receiver operating characteristics area under the curve, describing sensitivity and specificity to correctly identify the 41 women with both premalignant and malignant endometrial changes, was 0.93 (95% confidence interval, 0.87-0.97; P < 0.0001).GALR1 DNA methylation is one of the most common molecular alterations in endometrial cancer, and the presence of GALR1 methylation in vaginal swabs from women with postmenopausal bleeding indicates the presence of endometrial malignancy with a sensitivity of 92.7% and a specificity of 78.9%. PMID- 23727824 TI - Expression of DJ-1 in endometrial cancer: close correlation with clinicopathological features and apoptosis. AB - OBJECTIVES: DJ-1 was originally cloned as a putative oncogene capable of transforming NIH3T3 cells in cooperation with H-Ras or c-Myc, which has been implicated in the pathogenesis of some solid tumors. The aim of this study was to investigate the expression and clinical significance of DJ-1 in endometrial cancer and study its effect on cell proliferation and apoptosis in endometrial cancer Ishikawa cells. METHODS: Reverse transcription polymerase chain reaction and Western blotting were performed to determine the DJ-1 expression in 100 surgical specimens of endometrial cancer tissues, paired tumor-adjacent tissues, and 30 surgical specimens of normal endometrium tissues. The proliferation variety of endometrial cancer Ishikawa cells was determined by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium assay after transfecting the interference plasmid pGPU6/GFP/neo-DJ-1-shRNA into Ishikawa cells. Real-time polymerase chain reaction and Western blotting were used to evaluate the effect of interference plasmid on target gene expression. Apoptosis rate was determined by flow cytometry. RESULTS: DJ-1 expression in endometrial cancer tissues was higher than in tumor-adjacent tissues and normal endometrial tissues. At the same time, it was associated with signs of cancer progression, including differentiation, myometrial invasion depth, and presence of lymph node metastasis. Knocking down DJ-1 promoted the apoptosis of Ishikawa cells. CONCLUSIONS: High DJ-1 expression seems to be negatively correlated with apoptosis. Meanwhile, it may be part of the mechanisms for the development, invasion, and metastasis in endometrial cancer. PMID- 23727825 TI - Efficient photocatalytic activity with carbon-doped SiO2 nanoparticles. AB - Photocatalysis provides a 'green' approach to completely eliminate various kinds of contaminants that are fatal for current environmental and energy issues. Semiconductors are one of the most frequently used photocatalysts as they can absorb light over a wide spectral range. However, it is also well known that naked SiO2 is not an efficient photocatalyst due to its relatively large band gap, which could only absorb shortwave ultraviolet light. In this report, nanoscale particles of carbon-doped silicon dioxide (C-doped SiO2) for use in photocatalysis were successfully prepared by a facile one-pot thermal process using tetraethylorthosilicate (TEOS) as the source of both silicon and carbon. These particles were subsequently characterized by thermogravimetric analysis, X ray diffraction, standard and high resolution transmission electron microscopy and X-ray photoelectron spectroscopy. The C-doped SiO2 displayed outstanding photocatalytic properties, as evidenced by its catalysis of Rhodamine B degradation under near-UV irradiation. We propose that carbon doping of the SiO2 lattice creates new energy states between the bottom of the conduction band and the top of the valence band, which narrows the band gap of the material. As a result, the C-doped SiO2 nanoparticles exhibit excellent photocatalytic activities in a neutral environment. The novel synthesis reported herein for this material is both energy efficient and environmentally friendly and as such shows promise as a technique for low-cost, readily scalable industrial production. PMID- 23727826 TI - Cultivating yet-to-be cultivated microbes: the challenge continues. PMID- 23727827 TI - Neural correlates of the essence of conscious conflict: fMRI of sustaining incompatible intentions. AB - The study of intrapsychic conflict has long been central to many key theories about the control of behavior. More recently, by focusing on the nature of conflicting processes in the brain, investigators have revealed great insights about controlled versus automatic processes and the nature of self-control. Despite these advances, many theories of cognitive control or self-control remain agnostic about the function of subjective awareness (i.e., basic consciousness). Why people consciously experience some conflicts in the nervous system but not others remains a mystery. One hypothesis is that people become conscious only of conflicts involving competition for the control of skeletal muscle. To test one aspect of this larger hypothesis, in the present study, 14 participants were trained to introspect the feeling of conflict (the urge to make an error during a Stroop color-word interference task) and then were asked to introspect in the same way while sustaining simple compatible and incompatible intentions during fMRI scanning (to move a finger left or right). As predicted, merely sustaining incompatible skeletomotor intentions prior to their execution produced stronger systematic changes in subjective experience than sustaining compatible intentions, as indicated by self-report ratings obtained in the scanner. Similar ratings held for a modified Stroop-like task when contrasting incompatible versus compatible trials also during fMRI scanning. We use subjective ratings as the basis of parametric analyses of fMRI data, focusing a priori on the brain regions involved in action-related urges (e.g., parietal cortex) and cognitive control (e.g., dorsal anterior cingulate cortex, lateral PFC). The results showed that subjective conflict from sustaining incompatible intentions was consistently related to activity in the left post-central gyrus. PMID- 23727828 TI - Three components of postural control associated with pushing in symmetrical and asymmetrical stance. AB - A number of occupational and leisure activities that involve pushing are performed in symmetrical or asymmetrical stance. The goal of this study was to investigate early postural adjustments (EPAs), anticipatory postural adjustments (APAs), and compensatory postural adjustments (CPAs) during pushing performed while standing. Ten healthy volunteers stood in symmetrical stance (with feet parallel) or in asymmetrical stance (staggered stance with one foot forward) and were instructed to use both hands to push forward the handle of a pendulum attached to the ceiling. Bilateral EMG activity of the trunk and leg muscles and the center of pressure (COP) displacements in the anterior-posterior (AP) and medial-lateral (ML) directions were recorded and analyzed during the EPAs, APAs, and CPAs. The EMG activity and the COP displacement were different between the symmetrical and asymmetrical stance conditions. The COP displacements in the ML direction were significantly larger in staggered stance than in symmetrical stance. In staggered stance, the EPAs and APAs in the thigh muscles of the backward leg were significantly larger, and the CPAs were smaller than in the forward leg. There was no difference in the EMG activity of the trunk muscles between the stance conditions. The study outcome confirmed the existence of the three components of postural control (EPAs, APAs, and CPAs) in pushing. Moreover, standing asymmetrically was associated with asymmetrical patterns of EMG activity in the lower extremities reflecting the stance-related postural control during pushing. The study outcome provides a basis for studying postural control during other daily activities involving pushing. PMID- 23727829 TI - Effects of learning with explicit elaboration on implicit transfer of visuomotor sequence learning. AB - Intervals between stimuli and/or responses have significant influences on sequential learning. In the present study, we investigated whether transfer would occur even when the intervals and the visual configurations in a sequence were drastically changed so that participants did not notice that the required sequences of responses were identical. In the experiment, two (or three) sequential button presses comprised a "set," and nine (or six) consecutive sets comprised a "hyperset." In the first session, participants learned either a 2 * 9 or 3 * 6 hyperset by trial and error until they completed it 20 times without error. In the second block, the 2 * 9 (3 * 6) hyperset was changed into the 3 * 6 (2 * 9) hyperset, resulting in different visual configurations and intervals between stimuli and responses. Participants were assigned into two groups: the Identical and Random groups. In the Identical group, the sequence (i.e., the buttons to be pressed) in the second block was identical to that in the first block. In the Random group, a new hyperset was learned. Even in the Identical group, no participants noticed that the sequences were identical. Nevertheless, a significant transfer of performance occurred. However, in the subsequent experiment that did not require explicit trial-and-error learning in the first session, implicit transfer in the second session did not occur. These results indicate that learning with explicit elaboration strengthens the implicit representation of the sequence order as a whole; this might occur independently of the intervals between elements and enable implicit transfer. PMID- 23727830 TI - Influence of mechanical load on sequential effects. AB - Almost two decades ago, sequential effects of human grasping behaviour were described for the first time: In a sequential task, participants persisted in using the previous grasp type. According to the plan-modification hypothesis, such sequential effects reduce the movement planning costs and occur within a limited range of indifference. In the current study, we asked whether the anticipated mechanical costs of a movement would compete with the movement planning costs and, thus, reduce the magnitude of the sequential effect. To this end, participants were tested in a sequential, perceptual-motor task (opening a column of drawers), which offered a continuous range of posture solutions for each trial. In a pre-/post-test design, the magnitude of the sequential effect was measured before and after a manipulation phase with increased mechanical costs. Participants displayed a sequential effect for the majority of drawers in the pre-test, which was significantly reduced in the post-test. This finding indicates that each executed movement is a weighted function of both its cognitive and mechanical costs. The result also implies that sequential effects do not result solely from dynamical properties of the motor system, but instead reflect computational features of the movement selection process. PMID- 23727831 TI - What is volition? PMID- 23727832 TI - Line bisection by eye and by hand reveal opposite biases. AB - The vision-for-action literature favours the idea that the motor output of an action-whether manual or oculomotor-leads to similar results regarding object handling. Findings on line bisection performance challenge this idea: healthy individuals bisect lines manually to the left of centre and to the right of centre when using eye fixation. In case that these opposite biases for manual and oculomotor action reflect more universal compensatory mechanisms that cancel each other out to enhance overall accuracy, one would like to observe comparable opposite biases for other material. In the present study, we report on three independent experiments in which we tested line bisection (by hand, by eye fixation) not only for solid lines, but also for letter lines; the latter, when bisected manually, is known to result in a rightward bias. Accordingly, we expected a leftward bias for letter lines when bisected via eye fixation. Analysis of bisection biases provided evidence for this idea: manual bisection was more rightward for letter as compared to solid lines, while bisection by eye fixation was more leftward for letter as compared to solid lines. Support for the eye fixation observation was particularly obvious in two of the three studies, for which comparability between eye and hand action was increasingly adjusted (paper-pencil versus touch screen for manual action). These findings question the assumption that ocular motor and manual output are always inter-changeable, but rather suggest that at least for some situations ocular motor and manual output biases are orthogonal to each other, possibly balancing each other out. PMID- 23727833 TI - Drosophila TDP-43 dysfunction in glia and muscle cells cause cytological and behavioural phenotypes that characterize ALS and FTLD. AB - Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are neurodegenerative disorders that are characterized by cytoplasmic aggregates and nuclear clearance of TAR DNA-binding protein 43 (TDP-43). Studies in Drosophila, zebrafish and mouse demonstrate that the neuronal dysfunction of TDP 43 is causally related to disease formation. However, TDP-43 aggregates are also observed in glia and muscle cells, which are equally affected in ALS and FTLD; yet, it is unclear whether glia- or muscle-specific dysfunction of TDP-43 contributes to pathogenesis. Here, we show that similar to its human homologue, Drosophila TDP-43, Tar DNA-binding protein homologue (TBPH), is expressed in glia and muscle cells. Muscle-specific knockdown of TBPH causes age-related motor abnormalities, whereas muscle-specific gain of function leads to sarcoplasmic aggregates and nuclear TBPH depletion, which is accompanied by behavioural deficits and premature lethality. TBPH dysfunction in glia cells causes age related motor deficits and premature lethality. In addition, both loss and gain of Drosophila TDP-43 alter mRNA expression levels of the glutamate transporters Excitatory amino acid transporter 1 (EAAT1) and EAAT2. Taken together, our results demonstrate that both loss and gain of TDP-43 function in muscle and glial cells can lead to cytological and behavioural phenotypes in Drosophila that also characterize ALS and FTLD and identify the glutamate transporters EAAT1/2 as potential direct targets of TDP-43 function. These findings suggest that together with neuronal pathology, glial- and muscle-specific TDP-43 dysfunction may directly contribute to the aetiology and progression of TDP-43-related ALS and FTLD. PMID- 23727834 TI - The Bardet-Biedl syndrome-related protein CCDC28B modulates mTORC2 function and interacts with SIN1 to control cilia length independently of the mTOR complex. AB - CCDC28B encodes a coiled coil domain-containing protein involved in ciliogenesis that was originally identified as a second site modifier of the ciliopathy Bardet Biedl syndrome. We have previously shown that the depletion of CCDC28B leads to shortened cilia; however, the mechanism underlying how this protein controls ciliary length is unknown. Here, we show that CCDC28B interacts with SIN1, a component of the mTOR complex 2 (mTORC2), and that this interaction is important both in the context of mTOR signaling and in a hitherto unknown, mTORC independent role of SIN1 in cilia biology. We show that CCDC28B is a positive regulator of mTORC2, participating in its assembly/stability and modulating its activity, while not affecting mTORC1 function. Further, we show that Ccdc28b regulates cilia length in vivo, at least in part, through its interaction with Sin1. Importantly, depletion of Rictor, another core component of mTORC2, does not result in shortened cilia. Taken together, our findings implicate CCDC28B in the regulation of mTORC2, and uncover a novel function of SIN1 regulating cilia length that is likely independent of mTOR signaling. PMID- 23727835 TI - Deletion of tumor necrosis factor-alpha ameliorates neurodegeneration in Sandhoff disease mice. AB - Sandhoff disease (SD) is a lysosomal storage disorder caused by a lack of a functional beta-subunit of the beta-hexosaminidase A and B enzymes, leading to the accumulation of gangliosides in the central nervous system (CNS). The Hexb-/- mouse model of SD shows a progressive neurodegenerative phenotype similar to the human equivalent. Previous studies have revealed that Hexb-/- mice suffer from chronic neuroinflammation characterized by microglial activation and expansion. Tumor necrosis factor-alpha (TNFalpha), a key modulator of the CNS immune response in models of neurodegeneration, is a hallmark of this activation. In this study, we explore the role of TNFalpha in the development and progression of SD in mice, by creating a Hexb-/- Tnfalpha-/- double-knockout mouse. Our results revealed that the double-knockout mice have an ameliorated disease course, with an extended lifespan, enhanced sensorimotor coordination and improved neurological function. TNFalpha-deficient SD mice also show decreased levels of astrogliosis and reduced neuronal cell death, with no alterations in neuronal storage of gangliosides. Interestingly, temporal microglia activation appears similar between the Hexb-/- Tnfalpha-/- and SD mice. Evidence is provided for the TNFalpha activation of the JAK2/STAT3 pathway as a mechanism for astrocyte activation in the disease. Bone marrow transplantation experiments reveal that both CNS-derived and bone marrow-derived TNFalpha have a pathological effect in SD mouse models, with CNS-derived TNFalpha playing a larger role. This study reveals TNFalpha as a neurodegenerative cytokine mediating astrogliosis and neuronal cell death in SD and points to TNFalpha as a potential therapeutic target to attenuate neuropathogenesis. PMID- 23727836 TI - The DcpS inhibitor RG3039 improves motor function in SMA mice. AB - Spinal muscular atrophy (SMA) is caused by mutations of the survival motor neuron 1 (SMN1) gene, retention of the survival motor neuron 2 (SMN2) gene and insufficient expression of full-length survival motor neuron (SMN) protein. Quinazolines increase SMN2 promoter activity and inhibit the ribonucleic acid scavenger enzyme DcpS. The quinazoline derivative RG3039 has advanced to early phase clinical trials. In preparation for efficacy studies in SMA patients, we investigated the effects of RG3039 in severe SMA mice. Here, we show that RG3039 distributed to central nervous system tissues where it robustly inhibited DcpS enzyme activity, but minimally activated SMN expression or the assembly of small nuclear ribonucleoproteins. Nonetheless, treated SMA mice showed a dose-dependent increase in survival, weight and motor function. This was associated with improved motor neuron somal and neuromuscular junction synaptic innervation and function and increased muscle size. RG3039 also enhanced survival of conditional SMA mice in which SMN had been genetically restored to motor neurons. As this systemically delivered drug may have therapeutic benefits that extend beyond motor neurons, it could act additively with SMN-restoring therapies delivered directly to the central nervous system such as antisense oligonucleotides or gene therapy. PMID- 23727837 TI - Dilysine motifs in exon 2b of SMN protein mediate binding to the COPI vesicle protein alpha-COP and neurite outgrowth in a cell culture model of spinal muscular atrophy. AB - Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder that stems from low levels of survival of motor neuron (SMN) protein. The processes that cause motor neurons and muscle cells to become dysfunctional are incompletely understood. We are interested in neuromuscular homeostasis and the stresses put upon that system by loss of SMN. We recently reported that alpha-COP, a member of the coatomer complex of coat protein I (COPI) vesicles, is an SMN-binding partner, implicating this protein complex in normal SMN function. To investigate the functional significance of the interaction between alpha-COP and SMN, we constructed an inducible NSC-34 cell culture system to model the consequences of SMN depletion and find that depletion of SMN protein results in shortened neurites. Heterologous expression of human SMN, and interestingly over-expression of alpha-COP, restores normal neurite length and morphology. Mutagenesis of the canonical COPI dilysine motifs in exon 2b results in failure to bind to alpha-COP and abrogates the ability of human SMN to restore neurite outgrowth in SMN depleted motor neuron-like NSC-34 cells. We conclude that the interaction between SMN and alpha-COP serves an important function in the growth and maintenance of motor neuron processes and may play a significant role in the pathogenesis of SMA. PMID- 23727838 TI - A mutation in Tubb2b, a human polymicrogyria gene, leads to lethality and abnormal cortical development in the mouse. AB - Human cortical malformations, including lissencephaly, polymicrogyria and other diseases of neurodevelopment, have been associated with mutations in microtubule subunits and microtubule-associated proteins. Here we report our cloning of the brain dimple (brdp) mouse mutation, which we recovered from an ENU screen for recessive perinatal phenotypes affecting neurodevelopment. We identify the causal mutation in the tubulin, beta-2b (Tubb2b) gene as a missense mutation at a highly conserved residue (N247S). Brdp/brdp homozygous mutants have significant thinning of the cortical epithelium, which is markedly more severe in the caudo-lateral portion of the telencephalon, and do not survive past birth. The cortical defects are largely due to a major increase in apoptosis and we note abnormal proliferation of the basal progenitors. Adult brdp/+ mice are viable and fertile but exhibit behavioral phenotypes. This allele of Tubb2b represents the most severely affected mouse tubulin phenotype reported to date and this is the first report of a tubulin mutation affecting neuronal proliferation and survival. PMID- 23727839 TI - Secondary coenzyme Q10 deficiency and oxidative stress in cultured fibroblasts from patients with riboflavin responsive multiple Acyl-CoA dehydrogenation deficiency. AB - Coenzyme Q10 (CoQ10) is essential for the energy production of the cells and as an electron transporter in the mitochondrial respiratory chain. CoQ10 links the mitochondrial fatty acid beta-oxidation to the respiratory chain by accepting electrons from electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO). Recently, it was shown that a group of patients with the riboflavin responsive form of multiple acyl-CoA dehydrogenation deficiency (RR-MADD) carrying inherited amino acid variations in ETF-QO also had secondary CoQ10 deficiency with beneficial effects of CoQ10 treatment, thus adding RR-MADD to an increasing number of diseases involving secondary CoQ10 deficiency. In this study, we show that moderately decreased CoQ10 levels in fibroblasts from six unrelated RR-MADD patients were associated with increased levels of mitochondrial reactive oxygen species (ROS). Treatment with CoQ10, but not with riboflavin, could normalize the CoQ10 level and decrease the level of ROS in the patient cells. Additionally, riboflavin-depleted control fibroblasts showed moderate CoQ10 deficiency, but not increased mitochondrial ROS, indicating that variant ETF-QO proteins and not CoQ10 deficiency are the causes of mitochondrial ROS production in the patient cells. Accordingly, the corresponding variant Rhodobacter sphaeroides ETF-QO proteins, when overexpressed in vitro, bind a CoQ10 pseudosubstrate, Q10Br, less tightly than the wild-type ETF-QO protein, suggesting that molecular oxygen can get access to the electrons in the misfolded ETF-QO protein, thereby generating superoxide and oxidative stress, which can be reversed by CoQ10 treatment. PMID- 23727841 TI - Impact of miscuffing during home blood pressure measurement on the prevalence of masked hypertension. AB - BACKGROUND: Masked hypertension has been associated with obesity. However, because most studies do not mention the specific cuff size used for home measurements, masked hypertension prevalence may have been overestimated in obese patients because of undersized cuffs. In this prospective, observational study, the effect of miscuffing on hypertension status was evaluated in patients with large arms. METHODS: Fifty-three patients with an upper-arm circumference >33cm, undergoing treatment for mild-to-moderate hypertension, took 2 sets of home blood pressure (BP) measurements (standard vs. large cuff) using the validated Microlife BP A100 Plus automated device. RESULTS: Mean BP was 143/85mm Hg at the office using a large cuff, 141/84mm Hg at home using a standard cuff, and 134/80mm Hg at home using a large cuff. Standard vs. large cuff home BP mean differences were 6.9mm Hg (95% confidence interval (CI) = 4.7-9.2; P < 0.0001) for systolic BP and 4.0mm Hg (95% CI = 2.4-5.5; P < 0.0001) for diastolic BP. Hypertension status differed significantly between standard vs. large cuffs: sustained hypertension (56.6% vs. 41.5%, respectively; P = 0.002), controlled hypertension (20.8% vs. 28.3%, respectively; P = 0.04), white coat hypertension (7.5% vs. 22.6%, respectively; P = 0.002), masked hypertension (15.1% vs. 7.5%, respectively; P = 0.04). CONCLUSIONS: In patients with large arms, use of an appropriately sized large cuff for home BP measurements led to a 2-fold reduction in masked hypertension. Regarding clinical and epidemiological implications, future studies investigating masked hypertension should specify cuff size for home BP measurements. The low market availability and increased cost of large cuffs should also be addressed. PMID- 23727840 TI - Factors associated with blood pressure response to the cold pressor test: the GenSalt Study. AB - BACKGROUND: Blood pressure (BP) response to the cold pressor test (CPT) has been associated with increased risk of cardiovascular disease. We studied risk factors associated with BP response to CPT. METHODS: We conducted the CPT among 2,682 individuals in rural north China. BP was measured using a standard mercury sphygmomanometer prior to and at 0, 1, 2, and 4 minutes after the participants immersed their right hand in ice water for 1 minute. RESULTS: Sex, age, and baseline BP levels were significantly associated with BP response to the CPT. For example, maximum systolic BP response (mean +/- SD) was greater in women than in men (15.5+/-10.7 vs. 13.8+/-10.0mm Hg; P < 0.0001), correspondingly higher with age (12.4+/-8.7, 13.8+/-10.0, and 16.4+/-11.2mm Hg for those aged < 35, 35-44, and >= 45 years, respectively; P for trend < 0.0001), and greater with higher BP (13.5+/-10.0, 14.9+/-10.2, and 17.4+/-11.5mm Hg for those with baseline BP < 120/80, 120-139/80-89, and >= 140/90mm Hg, respectively; P for trend < 0.0001). In multivariable analyses, we also observed that higher body mass index, physical inactivity, and alcohol consumption were significantly associated with greater BP response to the CPT. CONCLUSIONS: Our study indicates that females, older age, and elevated baseline BP levels are associated with greater BP response to the CPT. In addition, physical inactivity, higher weight, and alcohol consumption may also be related to BP hyperreactivity to stress. PMID- 23727842 TI - Functional dissection and module swapping of fungal cyclooligomer depsipeptide synthetases. AB - BbBSLS and BbBEAS were dissected and reconstituted in Saccharomyces cerevisiae. The intermodular linker is essential for the reconstitution of the separate modules. Module 1 can be swapped between BbBEAS and BbBSLS, while modules 2 and 3 control the product profiles. BbBSLS is a flexible enzyme that also synthesizes beauvericins. PMID- 23727843 TI - The impact of fruit maturation on bioactive microconstituents, inhibition of serum oxidation and inflammatory markers in stimulated PBMCs and sensory characteristics of Koroneiki virgin olive oils from Messenia, Greece. AB - Olive fruits from the Koroneiki cultivar (Olea europaea L.) grown in Messenia, Greece, were hand-picked from the same trees in progressive maturity stages, covering three months, and processed identically with a commercial olive mill and a three-phase decanter. Data on quality parameters, and antioxidant activity of the obtained oils were collected by employing the conventional analytical methods set by European Union Commission Regulation no. 61/2011. Additionally, the potential of oils' polar extract to inhibit total serum lipid oxidation and inflammatory markers in stimulated human mononuclear cells was assayed. The results showed that ripening caused an increase in monounsaturated and decrease in polyunsaturated fatty acids, as well as an increase in phenolic compounds - mainly hydroxytyrosol - and in squalene. The extracts' ferric reducing power was in line with the increase of phenolic compounds. In later stages of maturation, lipoprotein oxidation was less potent and the decrease of inflammatory markers in stimulated human mononuclear cells was more powerful. Sensory evaluation detected differences in oils' "bitter" attributes, while the analysis of oils' volatiles revealed quantitative differences. PMID- 23727846 TI - Weighing the evidence on patient safety: strategies to implement now. PMID- 23727844 TI - Surveillance of physician-diagnosed skin and soft tissue infections consistent with methicillin-resistant Staphylococcus aureus (MRSA) among Nebraska high school athletes, 2008-2012. AB - Though historically confined to hospital settings, methicillin-resistant Staphylococcus aureus (MRSA) has received increasing attention in the wider community, particularly among athletes. A 2007-2008 investigation in Nebraska concluded that MRSA skin infections were an emerging problem among the state's student athletes. Statewide surveillance was subsequently conducted during 4 school years (2008-2012) to estimate incidence of skin and soft tissue infections (SSTI) consistent with MRSA among student athletes. High school athletic officials completed Internet-based surveys following winter and fall sport seasons. Over 3 school years, incidence estimates per 10,000 athletes decreased substantially from 20.9 (2008-2009) to 11.3 (2010-2011) among football players and from 60.8 (2008-2009) to 28.1 (2010-2011) among wrestlers. Following the 2011 2012 sport seasons, however, incidence estimates increased to 16.6 per 10,000 football players and 43.3 per 10,000 wrestlers. School nurses should support school officials to prioritize prevention and control efforts for SSTI, including MRSA. PMID- 23727847 TI - Family presence in the ICU. PMID- 23727849 TI - Preventing ventilator-associated pneumonia in children: an evidence-based protocol. AB - Ventilator-associated pneumonia, the second most common hospital-acquired infection in pediatric intensive care units, is linked to increased morbidity, mortality, and lengths of stay in the hospital and intensive care unit, adding tremendously to health care costs. Prevention is the most appropriate intervention, but little research has been done in children to identify necessary skills and strategies. Critical care nurses play an important role in identification of risk factors and prevention of ventilator-associated pneumonia. A care bundle based on factors, including evidence regarding the pathophysiology and etiology of pneumonia, mechanical ventilation, duration of ventilation, and age of the child, can offer prompts and consistent prevention strategies for providers caring for children in the pediatric intensive care unit. Following the recommendations of the Centers for Disease Control and Prevention and adapting an adult model also can support this endeavor. Ultimately, the bedside nurse directs care, using best evidence to prevent this important health care problem. PMID- 23727850 TI - The Healthy Skin Project: changing nursing practice to prevent and treat hospital acquired pressure ulcers. AB - BACKGROUND: Hospital-acquired pressure ulcers are serious clinical complications that can lead to increased length of stay, pain, infection, and, potentially, death. The surgical progressive care unit at Sharp Grossmont Hospital, San Diego, California, developed the multidisciplinary Healthy Skin Project to decrease the prevalence of hospital-acquired pressure ulcers. METHODS: The previous treatment plan was reviewed and modified according to current evidence-based practice. The project consisted of 3 components: creation of a position for a unit-based wound liaison nurse, staff education, and involvement of the nursing assistants. The wound liaison nurse developed and conducted bimonthly skin audits, which revealed inconsistencies in clinical practice and documentation. Education for the staff was accomplished via a self-learning module, case presentations, and 1-on-1 training. In addition, a pressure ulcer algorithm tool was developed to demonstrate step-by-step wound management and documentation. RESULTS: From Spring 2003 through Summer 2006, the prevalence of hospital-acquired pressure ulcers ranged from 0.0% to 18.92%, with a mean of 4.85%. After implementation of the project, the prevalence decreased to 0.0% for 17 of 20 quarters, through 2011. CONCLUSION: Prevention and a multidisciplinary approach are effective in reducing the occurrence of hospital-acquired pressure ulcers. PMID- 23727851 TI - Effectiveness of critical care discharge information in supporting early recovery from critical illness. AB - Providing patients with information can alleviate or reduce relocation stress, but how best to provide information to patients being discharged from critical care units is unclear. This narrative critical review describes (1) the current evidence base on the use of discharge information for adult critical care patients and (2) the extent of involvement of service users in the design and evaluation of such information. Seven publications reported data from 121 patients, 252 relatives, and 33 nurses. Overall evidence was of low quality but use of individualized information was associated with beneficial physical effects for patients and increased knowledge and satisfaction for their relatives. Findings highlight the significant gaps in our knowledge and understanding. The consequences of such findings for the future development of information that meets service users' needs are discussed. Results should inform the design of future studies on this topic. PMID- 23727852 TI - Head-of-bed elevation in critically ill patients: a review. AB - Clinicians are confused by conflicting guidelines about the use of head-of-bed elevation to prevent aspiration and pressure ulcers in critically ill patients. Research-based information in support of guidelines for head-of-bed elevation to prevent either condition is limited. However, positioning of the head of the bed has been studied more extensively for the prevention of aspiration than for the prevention of pressure ulcers, especially in critically ill patients. More research on pressure ulcers has been conducted in healthy persons or residents of nursing homes than in critically ill patients. Thus, the optimal elevation for the head of the bed to balance the risks for aspiration and pressure ulcers in critically ill patients who are receiving mechanical ventilation and tube feedings is unknown. Currently available information provides some indications of how to position patients; however, randomized controlled trials where both outcomes are evaluated simultaneously at various head-of-bed positions are needed. PMID- 23727853 TI - Observational pain scales in critically ill adults. AB - Pain is a common and distressing symptom in critically ill patients. Uncontrolled pain places patients at risk for numerous adverse psychological and physiological consequences, some of which may be life-threatening. A systematic assessment of pain is difficult in intensive care units because of the high percentage of patients who are noncommunicative and unable to self-report pain. Several tools have been developed to identify objective measures of pain, but the best tool has yet to be identified. A comprehensive search on the reliability and validity of observational pain scales indicated that although the Critical-Care Pain Observation Tool was superior to other tools in reliably detecting pain, pain assessment in individuals incapable of spontaneous neuromuscular movements or in patients with concurrent conditions, such as chronic pain or delirium, remains an enigma. PMID- 23727854 TI - Priming blood transfusion tubing: a critical review of the blood transfusion process. PMID- 23727855 TI - There is a method to the madness. PMID- 23727856 TI - A foundation for patient safety: phase I implementation of interdisciplinary bedside rounds in the pediatric intensive care unit. PMID- 23727857 TI - I am a critical care nurse. PMID- 23727858 TI - Antibodies to watch in 2013: Mid-year update. AB - The transitions of antibody therapeutics to late-stage clinical development, regulatory review and the market are proceeding at a rapid pace in 2013. Since late 2012, two monoclonal antibody (mAb) therapeutics (itolizumab, trastuzumab emtansine) received their first approvals, first marketing applications for three mAbs (vedolizumab, ramucirumab, obinutuzumab) were submitted to regulatory agencies, and five mAbs (brodalumab, MABp1, moxetumomab pasudotox, tildrakizumab, rilotumumab) entered their first Phase 3 studies. The current total of commercially-sponsored antibody therapeutics undergoing evaluation in late-stage studies is 30. Recently announced study results for farletuzumab, naptumomab estafenatox, and tabalumab indicate that clinical endpoints were not met in some Phase 3 studies of these product candidates. PMID- 23727859 TI - High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. AB - Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds, and recent data indicate a role for autoreactivity in at least a subgroup of patients. FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency. To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis. PMID- 23727860 TI - A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer. AB - Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten loss-driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed with deletion of either Trp53 or Zbtb7a together with Pten, leading to the development of castration-resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1, XIAP and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments. PMID- 23727864 TI - An improved GC-MS method in determining glycerol in different types of biological samples. AB - Glycerol is an important compound participating in the lipid metabolism and energy conversion of body. Its level, especially in the blood circulation, has been considered as an index in assessing the triglycerides level, fat mobilization and potential risk of hyperlipidemia. In this gas chromatography mass spectrometry (GC-MS) method, 1,2,3-butanetriol was selected as an internal standard instead of isotope labeled glycerol. The internal standard and sample were derivatized by trimethylsilyl imidazole. The glycerol and internal standard derivatives in the sample were measured by a selected ion monitor mode of GC-MS. The sensitivity and repeatability of this method were examined by analyzing glycerol in eleven different types of biological tissue and fluid samples. The glycerol level in the measured mouse plasma sample was at 11.71+/-0.48MUg/mL, while it was in a range of 0.15+/-0.01 (brain) to 0.39+/-0.02MUg/mg (liver) in the tissue samples. It was 27.06+/-0.12 and 1.60+/-0.04MUg/mL in the tested human blood and urine samples, respectively. Also, the glycerol recoveries of all samples were higher than 80% and over 90% for the fluid samples, especially. With the satisfactory repeatability and recovery and non-isotope internal standard, the GC-MS method could be a reliable technique in monitoring the glycerol status of biological samples regardless of whether they are from a study in which isotope labeled glycerol or other stable isotope materials were involved. PMID- 23727863 TI - Detection and quantification of quinolone signalling molecule: a third quorum sensing molecule of Pseudomonas aeruginosa by high performance-thin layer chromatography. AB - Sophisticated network of quorum sensing involves the production of chemical signals which regulate the combined expression of virulence genes and biofilm formation in Pseudomonas aeruginosa. Two well-characterized acyl homoserine lactone based las and rhl systems together with alkyl quinolone based Pseudomonas quinolone signalling (PQS) are fundamental components of this network. Third signalling molecule, 2-heptyl-3-hydroxy-4-quinolone (PQS) is of paramount importance because of its interconnecting role in quorum sensing hierarchy in P. aeruginosa. Accurate detection of PQS molecule is very important to understand the involvement of this system in infection process of P. aeruginosa. In this study, high performance-thin layer chromatography (HP-TLC) method was developed for detection as well as quantification of PQS signal molecules in P. aeruginosa, which combines conventional method like TLC with sophisticated instrumentation. This method was validated using parameters like linearity, accuracy, precision, reproducibility and sensitivity. Intra- and inter-day accuracy and precision values were determined which were found to be within acceptable level and hence showed reproducibility. Measurement of PQS in the range of 0.01nmol indicated excellent sensitivity of this approach for quantifying PQS molecule. Automated sampling, rapid and simultaneous analysis of large number of samples and minimal errors make this method more suitable for analysis of PQS signalling molecules. Production of PQS was found to be strain dependent since variation in amount of PQS was observed among different P. aeruginosa isolates. Further, PQS production was also dependent on growth phase of P. aeruginosa with maximum production in late stationary phase. PMID- 23727862 TI - Genome-wide association study identifies two susceptibility loci for osteosarcoma. AB - Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. To better understand the genetic etiology of osteosarcoma, we performed a multistage genome-wide association study consisting of 941 individuals with osteosarcoma (cases) and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: a locus in the GRM4 gene at 6p21.3 (encoding glutamate receptor metabotropic 4; rs1906953; P = 8.1 * 10-9) and a locus in the gene desert at 2p25.2 (rs7591996 and rs10208273; P = 1.0 * 10-8 and 2.9 * 10-7, respectively). These two loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma. PMID- 23727861 TI - Zbtb7a suppresses prostate cancer through repression of a Sox9-dependent pathway for cellular senescence bypass and tumor invasion. AB - Zbtb7a has previously been described as a powerful proto-oncogene. Here we unexpectedly demonstrate that Zbtb7a has a critical oncosuppressive role in the prostate. Prostate-specific inactivation of Zbtb7a leads to a marked acceleration of Pten loss-driven prostate tumorigenesis through bypass of Pten loss-induced cellular senescence (PICS). We show that ZBTB7A physically interacts with SOX9 and functionally antagonizes its transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long noncoding RNA precursor for an RB-targeting microRNA. Inactivation of Zbtb7a in vivo leads to Rb downregulation, PICS bypass and invasive prostate cancer. Notably, we found that ZBTB7A is genetically lost, as well as downregulated at both the mRNA and protein levels, in a subset of human advanced prostate cancers. Thus, we identify ZBTB7A as a context-dependent cancer gene that can act as an oncogene in some contexts but also has oncosuppressive-like activity in PTEN-null tumors. PMID- 23727865 TI - Determination of nitrite and nitrate in cerebrospinal fluid by microchip electrophoresis with microsolid phase extraction pre-treatment. AB - A new method for the determination of nitrite and nitrate, indicators of various neurological diseases (meningitis, multiple sclerosis, Parkinson's disease) in cerebrospinal fluid (CSF) on an electrophoresis chip was developed. An on-line combination of isotachophoresis (ITP) with capillary electrophoresis (CE) on a poly(methylmethacrylate) chip assembled with coupled separation channels (CC) and contact conductivity detectors was employed. ITP separations performed at low pH (3.6) in the first separation channel enabled a highly selective transfer of the analytes to the second CE stage working under micellar conditions implemented by zwitterionic surfactant, 3-(N,N-dimethyldodecylammonio)-propanesulfonate. The proposed method achieved low limits of detection varied from 0.2 to 0.4MUgL(-1) when the sample volume injected onto the chip (9.9MUl) was almost the same as the volume of both separation channels. Preferable working conditions on the CC chip (suppressed hydrodynamic and electroosmotic flow) contributed for reproducible migration velocities (intra-day reproducibility up to 2.1% RSD) and determinations of trace concentrations of nitrite and nitrate (intra-day precision up to 3.0% RSD). Huge amount of chloride present in CSF (approx. 4.5gL( 1)) was removed from analyzed CSF samples by microsolid phase extraction performed on silver-form resin prior to the ITP-CE analysis. Developed method provided fast (approx. 20min total analysis time) and reliable determinations of trace nitrite and nitrate and could be fully integrated into the analysis of CSF samples. PMID- 23727866 TI - On-line screening of matrix metalloproteinase inhibitors by capillary electrophoresis coupled to ESI mass spectrometry. AB - Capillary electrophoresis (CE) with the use of mass spectrometry (MS) has been considered as a unique tool for microscale enzyme assay and inhibitor screening. In this study, matrix metalloproteinase-9 (MMP-9) was selected as target enzyme due to its important role in tumor invasion and metastasis. In order to define the optimal MS parameters, a two level half fraction factorial experimental design was performed. A background electrolyte consisting of 20mM ammonium acetate (pH 6.8) and a sheath liquid of water-methanol (50:50, v/v) containing 0.05% formic acid at a flow rate of 4MUl/min were selected. This system was operated in the positive ion mode with a detection-limit of 10nM for the MMP reaction product and provided 60 folds enhancement of sensitivity by using selected reaction monitoring detection compared with MS full scan mode, which significantly increased the detectability of the system and therefore reduced the enzyme reaction time in both off-line and in-line mode. Both electrophoretically mediated microanalysis and pressure mediated microanalysis combined with MS detection were investigated for MMP inhibitor screening. Good repeatability (RSD of peak area and migration time were lower than 5.0%) and linearity (R(2)>0.996) were obtained for both in-capillary approaches. Several tetracycline antibiotics and natural products were selected to test the system. The results indicated an agreement on the ranking of inhibitory potency for both in-capillary approaches. PMID- 23727867 TI - Semi-preparative isolation of dihydroresveratrol-3-O-beta-d-glucuronide and four resveratrol conjugates from human urine after oral intake of a resveratrol containing dietary supplement. AB - A method for semi-preparative isolation of major resveratrol metabolites from human urine after oral intake of a trans-resveratrol-containing dietary supplement was developed. Pretreatment of the urine (6L) by using solid-phase extraction gave a brown oily residue (9.3g), which was separated using a combination of normal phase column chromatography and reversed-phase flash column chromatography resulting in fractions containing 1.1g crude trans-resveratrol-3-O sulfate (M1), 86mg of a crude mixture of trans-resveratrol-3,5-O-disulfate (M2) and trans-resveratrol-3,4'-O-disulfate (M3), and 568mg of a crude mixture of trans-resveratrol-3-O-beta-d-glucuronide (M4) and dihydroresveratrol-3-O-beta-d glucuronide (M5). Purification of the crude metabolites was performed by semi preparative reversed-phase HPLC using a gradient of aqueous ammonium acetate (2.5mmol/L, pH 6.7)/acetonitrile for purification of M1, M2 and M3 or trifluoroacetic acid in water (pH 2.5)/acetonitrile for purification of M4 and M5. From a part of the crude metabolites (50-75mg), 47mg M1 (purity 98.7%), 14mg M2 (purity 96.1%), 10mg M3 (purity 96.3%), 38mg M4 (purity 98.2%) and 18mg M5 (purity 97.8%) were obtained. The structures of all isolated resveratrol metabolites were elucidated by spectroscopic and spectrometric methods such as 1D and 2D NMR, UV, and LC-MS. This method represents a novel approach to obtain resveratrol metabolites being the first method describing the direct isolation of pure resveratrol metabolites from urine samples in quantities sufficient for full chemical characterization and testing in vitro and in preclinical trials. PMID- 23727868 TI - Simultaneous determination of pregnenolone sulphate, dehydroepiandrosterone and allopregnanolone in rat brain areas by liquid chromatography-electrospray tandem mass spectrometry. AB - Neurosteroids (NSs) are well known modulators of neuronal activity and by binding to different neuronal receptors are responsible for a broad spectrum of biological and pathophysiological conditions. Here, a sensitive liquid chromatographic-electrospray ionization-tandem mass spectrometric method (LC-ESI MS/MS) has been developed and validated for the simultaneous determination in rat brain areas of three NSs, i.e. pregnenolone sulphate (PS), dehydroepiandrosterone (DHEA) and allopregnanolone (AP). NSs were extracted with methanol-formic acid, purified by Hybrid-SPE cartridges and subjected to LC-ESI-MS/MS without any preliminary derivatization or deconjugation procedure. Quantitation was performed by multiple reaction monitoring mode with the internal standard method, using deuterium-labelled analogues of the analyzed NSs. The proposed method provided for the first time a direct quantitative determination of PS without hydrolysis; in particular, PS concentrations were found significantly (p<0.01) higher in hippocampus, the brain area associated primarily with memory, than in cortical tissue of control rats, suggesting the important role of this NS in the process of memory formation. The developed method could be successfully applied to quantify simultaneously PS, DHEA and AP levels in brain tissue in order to study their changes during various neurodegenerative diseases and to investigate the role of PS in the brain. PMID- 23727869 TI - Determination of proline-hydroxyproline dipeptide in rat urine by high performance anion-exchange chromatography coupled with pulsed amperometric detection. AB - A method for determination of proline-hydroxyproline dipeptide (PHP) was developed using high-performance anion-exchange chromatography-pulsed amperometric detection (HPAEC-PAD). This method resulted in good separation of proline (Pro), hydroxyproline (Hyp), and PHP within 20min using a mobile phase of 1.2mM Ba(OH)2+1.5mM Ba(OAc)2. The linear dynamic ranges and their detection limits (S/N=3) were 1-100 (r(2)=0.9990-0.9999) and 0.05-0.3MUM, respectively. Mean recoveries were 91.6-121.3% and 92.2-110.3% for intra- and inter-day assays, respectively. Our HPAEC-PAD method showed clear differences in the corrected PHP levels measured in urine samples from two groups of rats, sham-operated and ovariectomized, without the need for prior acid hydrolysis or sample derivatization. PMID- 23727870 TI - Development of a simple analytical method for the simultaneous determination of paracetamol, paracetamol-glucuronide and p-aminophenol in river water. AB - Paracetamol is among the most worldwide consumed pharmaceuticals. Although its occurrence in the environment is well documented, data about the presence of its metabolites and transformation products is very scarce. The present work describes the development of an analytical method for the simultaneous determination of paracetamol, its principal metabolite (paracetamol-glucuronide) and its main transformation product (p-aminophenol) based on solid phase extraction (SPE) and high performance liquid chromatography coupled to diode array detection (HPLC-DAD). The method was applied to analysis of river waters, showing to be suitable to be used in routine analysis. Different SPE sorbents were compared and the use of two Oasis WAX cartridges in tandem proved to be the most adequate approach for sample clean up and pre-concentration. Under optimized conditions, limits of detection in the range 40-67ng/L were obtained, as well as mean recoveries between 60 and 110% with relative standard deviations (RSD) below 6%. Finally, the developed SPE-HPLC/DAD method was successfully applied to the analysis of the selected compounds in samples from seven rivers located in the north of Portugal. Nevertheless all the compounds were detected, it was the first time that paracetamol-glucuronide was found in river water at concentrations up to 3.57MUg/L. PMID- 23727871 TI - Hydrophilic interaction liquid chromatography with tandem mass spectrometric detection applied for analysis of pteridines in two Graphosoma species (Insecta: Heteroptera). AB - A new separation method involving hydrophilic interaction chromatography with tandem mass spectrometric detection has been developed for the analysis of pteridines, namely biopterin, isoxanthopterin, leucopterin, neopterin, xanthopterin and erythropterin in the cuticle of heteropteran insect species. Two columns, Atlantis HILIC Silica and ZIC((r))-HILIC were tested for the separation of these pteridines. The effect of organic modifier content, buffer type, concentration and pH in mobile phase on retention and separation behavior of the selected pteridines was studied and the separation mechanism was also investigated. The optimized conditions for the separation of pteridines consisted of ZIC((r))-HILIC column, mobile phase composed of acetonitrile/5mM ammonium acetate, pH 6.80, 85/15 (v/v), flow rate 0.5mL/min and column temperature 30 degrees C. Detection was performed by tandem mass spectrometry operating in electrospray ionization with Agilent Jet Stream technology using the selected reaction monitoring mode. The optimized method provided a linearity range from 0.3 to 5000ng/mL (r>0.9975) and repeatability with relative standard deviation<8.09% for all the studied pteridines. The method was applied to the analysis of pteridines in the cuticle of larvae and three adult color forms of Graphosoma lineatum and one form of Graphosoma semipunctatum (Insecta: Hemiptera: Heteroptera: Pentatomidae). The analysis shows that different forms of Graphosoma species can be characterized by different distribution of individual pteridines, which affects the coloration of various forms. Only isoxanthopterin was found in all the five forms tested. PMID- 23727872 TI - Aqueous size-exclusion chromatographic method for the quantification of cyanobacterial native glycogen. AB - Cyanobacterial glycogen has gained interest as a valuable biomass feedstock for biofuel production. However, an ideal method for native glycogen quantification has not been developed. Here, we have proposed a simple methodology that enables the quantitative determination of cyanobacterial glycogen concentration with high repeatability using aqueous size-exclusion chromatography with a differential refractive index detector (SEC/RID). Our SEC/RID system also allows size distributions for native glycogen based on hydrodynamic volumes (Vh), which is proportional to the product of the molecular mass (M) and intrinsic viscosity [eta], obtained by universal calibration using linear homopolymers of known M with Mark-Houwink-Sakurada parameters. The universal calibration curve achieved a broad linear range (Vh parameter [eta]M=2*10(2)-8*10(8)mLg(-1)) with a high correlation coefficient (R(2)=0.9942), because the developed system is equipped with an OHpak SB-806M HQ aqueous column containing four types of polyhydroxy methacrylate-based particles with different particle and pore sizes. Based on the SEC/RID system, response of molecular size distribution of glycogen in microalgae to the cultivation condition was first observed. Our established SEC/RID method has several advantages over conventional techniques, including the simultaneous quantitative and size distribution analyses of glycogen, and represents a potentially useful tool to elucidate the relationship between structural properties and the roles of glycogen in metabolism. PMID- 23727873 TI - Optimized extraction method for LC-MS determination of bisphenol A, melamine and di(2-ethylhexyl) phthalate in selected soft drinks, syringes, and milk powder. AB - Described below is an optimized solid-phase extraction method (SPE) for the simultaneous determination of three hazardous plastic additives. Two high performance liquid chromatographic-electrospray ionization-mass spectrometric (HPLC-ESI-MS) methods were developed and validated to estimate the melamine (MEL), bis(2-ethylhexyl) phthalate (DEHP), and bisphenol A (BPA) contents in drinking water, syringes, soft drinks, and dry milk powder. One extraction procedure optimally recovered all three substances from the different matrices. Two extraction columns were combined and included a silica gel LiChroprep RP-2 column (20:1, g/g, top column) and a Sep-Pak with a C18 column (500mg, bottom column). The analytical column was an Agilent Eclipse XDB-C8 column, 4.6mm*150mm, 5MUm, maintained at 50+/-2 degrees C. MEL and DEHP were monitored by positive triple quad mass spectrometry (TQ-MS) using an acidic mobile phase, while BPA was monitored by negative TQ-MS using a mobile phase containing a 0.05% ammonia solution. The general linear range of the three compounds ranged from 12 to 1000pg/MUL in the injected solution (25MUL). The average extraction recoveries were within the range of 83.0-102.5%. Relatively high concentrations of BPA and DEHP were found in the milk powder and sterile syringes. PMID- 23727874 TI - First liquid chromatography method for the simultaneous determination of levofloxacin, pazufloxacin, gatifloxacin, moxifloxacin and trovafloxacin in human plasma. AB - For the first time a simple, selective and sensitive liquid chromatography method was developed and validated for the simultaneous determination of levofloxacin (LEV), pazufloxacin (PAZ), gatifloxacin (GAT), moxifloxacin (MOX) and trovafloxacin (TRO) in human plasma. Samples were pre-treated with acetonitrile for precipitation of plasma proteins followed by evaporation and reconstitution steps. Chromatographic separation of the analytes and norfloxacin, used as internal standard (IS), was performed under gradient elution on a LiChroCART((r)) Purospher Star C18 column (55mm*4mm, 3MUm). The mobile phase comprised a mixture of 0.1% aqueous formic acid adjusted to pH 3.0 with triethylamine, acetonitrile and methanol pumped at a flow rate of 1.0mL/min. The detector was set at excitation/emission wavelengths of 260/455nm. Calibration curves were linear (r(2)>=0.9923) in the ranges of 0.005-5MUg/mL for GAT, 0.02-5MUg/mL for LEV, PAZ and MOX and 0.04-5MUg/mL for TRO. The intra and interday precision did not exceed 7.32% and the intra and interday accuracy ranged from -11.73 to 8.92%. The limits of quantification were established at 0.005MUg/mL for GAT, 0.02MUg/mL for LEV, PAZ and MOX and 0.04MUg/mL for TRO. No endogenous or tested exogenous compounds were found to interfere at the retention times of the analytes and IS. Since the proposed method proved to be reliable for the quantitative determination of LEV, PAZ, GAT, MOX and TRO it may be a useful tool for routine analysis and to support clinical pharmacokinetic and toxicological studies involving these antibiotics. PMID- 23727875 TI - Multicomponent LC-MS/MS screening method for detection of new psychoactive drugs, legal highs, in urine-experience from the Swedish population. AB - The advent of new not yet legally regulated psychoactive substances sold over the Internet has created a challenge for clinical toxicology and drug testing laboratories. The routine use of immunoassay screening may no longer be the optimal solution in many instances since the number of analytes covered is becoming insufficient. The aim of this work was to design, validate and apply a multi-component LC-MS/MS method suitable for screening of a large number of target analytes belonging to the class of new psychoactive substances - legal highs. The analytical method was using a five-fold dilution of urine with internal standard (pethidine-d5) and injection of 2MUL. The chromatographic system was using a 1.7-MUm 100mm*2.1mm Ethylene Bridged Hybrid (BEH) C18 column and gradient elution with a flow rate of 600MUL/min. Solvent A consisted of 0.1% formic acid and Solvent B was 100% acetonitrile. The gradient elution application was designed to have a wide polarity coverage with total run time of 4.0min. The tandem mass spectrometer was using an electrospray interface and operated in positive mode. Selected reaction monitoring of two ion transitions was used for each of 26 analytes. Method validation demonstrated limited influence from urine matrix, linear response within the measuring range (0.1-10MUg/mL), acceptable imprecision in quantification (CV<15%). Some analytes were found not to be stable in urine upon storage. The method was successfully applied in routine drug testing. A total of 87 positive samples with 100 analytical findings were found to contain O-desmethyl-cis-tramadol (mostly without mitragynine), methylenedioxypyrovalerone, 4-fluoroamphetamine, methoxetamine, desoxypipradol, 4 fluoromethcathinone, 5,6-methylenedioxy-2-aminoindane, 4-methylmethcathinone, 3 fluoromethcathinone, 4-hydroxy-N-methyl-N-ethyltryptamine, alpha-methylamino butyrophenone and 4-methoxymethcathinone. PMID- 23727876 TI - Binding energy determination in a pi-stacked aromatic cluster: the anisole dimer. AB - The binding energies of the neutral and positively charged anisole dimer have been determined in molecular beam-laser spectroscopy experiments. This is the first report on the direct experimental determination of the binding energy for an aromatic cluster in pi stacked configuration. The anisole dimer is formed by two anisole molecules superimposed in a planar arrangement and it has been proposed as a model system in which the pi-stacking interaction, among other intermolecular forces, plays a relevant role. Its binding energy has been determined thanks to both velocity mapping ion/electron imaging experiments and previous spectroscopic information. The binding energy amounts to 3926(250) cm( 1) in the ground state and 4144(250) cm(-1) in the S2 (first spectroscopically accessible) electronic excited state; its value for the positively charged dimer ion increases to 6147(250) cm(-1). These values are quite higher with respect to the results of previous DFT calculations. PMID- 23727877 TI - CA II, a potential biomarker by proteomic analysis, exerts significant inhibitory effect on the growth of colorectal cancer cells. AB - In the Western world, colorectal cancer (CRC) is the third most common cancer with poor prognosis. To identify the proteins and to elucidate the possible mechanisms involved in colorectal carcinogenesis, 2-DE coupled with MS/MS analysis were employed to compare the global protein profile between CRC and individual matched normal tissues from 8 CRC patients. Of 36 proteins identified, carbonic anhydrase II (CA II) was one of most significantly altered and its downregulation in CRC tissues was verified by RT-PCR, western blotting and immunohistochemistry methods, suggesting that CA II may serve as a potential biomarker for CRC diagnosis. To investigate the function and mechanisms of CA II in CRC, a stable SW480 colorectal cancer cell line overexpressing CA II was established. It was shown that overexpression of CA II remarkably suppressed tumor cell growth both in vitro and in vivo, which was in part interpreted by cell cycle arrest at G0/G1 and G2 phase. Further mechanism analysis revealed that the sensitivity of colorectal cancer cells to chemotherapy drugs could be increased by CA II overexpression. Taken together, these data suggest that CA II may be a potential biomarker for early diagnosis of CRC and the results may contribute to a better understanding of the molecular mechanism of CRC and colorectal cancer treatment. PMID- 23727878 TI - Effect of twist and porosity on the electrical conductivity of carbon nanofiber yarns. AB - This study focuses on the effect of twist and porosity on the electrical conductivity of carbon nanofiber (CNF) yarns. The process of fabrication of CNF yarns included the synthesis of aligned ribbons of polyacrylonitrile (PAN) nanofibers via electrospinning. The PAN ribbons were twisted into yarns with twist levels ranging from zero twist to high twists of 1300 turn per meter (tpm). The twist imposed on the ribbons substantially improved the interactions between nanofibers and reduced the porosity. The PAN yarns were subsequently stabilized in air, and then carbonized in nitrogen at 1100 degrees C for 1 h. Compressive stresses developed between the PAN nanofibers as a result of twist promoted interfusion between neighboring nanofibers, which was accelerated by heating the yarns during stabilization to temperatures above the glass transition of PAN. The electrical conductivity of the yarns was measured with a four point probe measurement technique. Although increasing the twist promotes electrical conductivity between nanofibers by forming junctions between them, our results indicate that the electrical conductivity does not continuously increase with increasing twist, but reaches a threshold value after which it starts to decrease. The causes for this behavior were studied through experimental techniques and further explored using a yarn-equivalent electrical circuit model. PMID- 23727879 TI - Subsoil erosion dominates the supply of fine sediment to rivers draining into Princess Charlotte Bay, Australia. AB - The Laura-Normanby River (catchment area: 24,350 km(2)), which drains into Princess Charlotte Bay, has been identified in previous studies as the third largest contributor of sediment to the Great Barrier Reef World Heritage Area. These catchment scale modelling studies also identified surface soil erosion as supplying >80% of the sediment. Here we use activity concentrations of the fallout radionuclides (137)Cs and (210)Pbex to test the hypothesis that surface soil erosion dominates the supply of fine (<10 MUm) sediment in the river systems draining into Princess Charlotte Bay. Our results contradict these previous studies, and are consistent with channel and gully erosion being the dominant source of fine sediment in this catchment. The hypothesis that surface soil erosion dominates the supply of fine sediment to Princess Charlotte Bay is rejected. River sediment samples were collected using both time-integrated samplers and sediment drape deposits. We show that there is no detectable difference in (137)Cs and (210)Pbex activity concentrations between samples collected using these two methods. Two methods were also used to collect samples to characterise (137)Cs and (210)Pbex concentrations in sediment derived from surface soil erosion; sampling of surface-wash deposits and deployment of surface runoff traps that collected samples during rain events. While there was no difference in the (137)Cs activity concentrations for samples collected using these two methods, (210)Pbex activity concentrations were significantly higher in the samples collected using the runoff traps. The higher (210)Pbex concentrations are shown to be correlated with loss-on-ignition (r(2) = 0.79) and therefore are likely to be related to higher organic concentrations in the runoff trap samples. As a result of these differences we use a three end member mixing model (channel/gully, hillslope surface-wash and hillslope runoff traps) to determine the relative contribution from surface soil erosion. Probability distributions for (137)Cs and (210)Pbex concentrations were determined for each of the end members, with these distributions then used to estimate the surface soil contribution to each of the collected river sediment samples. The mean estimate of contribution of surface derived sediment for all river samples (n = 70) is 16 +/- 2%. This study reinforces the importance of testing model predictions before they are used to target investment in remedial action and adds to the body of evidence that the primary source of sediment delivered to tropical river systems is derived from subsoil erosion. PMID- 23727880 TI - Assessment of environmental (226)Ra, (232)Th and (40)K concentrations in the region of elevated radiation background in Segamat District, Johor, Malaysia. AB - Extensive environmental survey and measurements of gamma radioactivity in the soil samples collected from Segamat District were conducted. Two gamma detectors were used for the measurements of background radiation in the area and the results were used in the computation of the mean external radiation dose rate and mean weighted dose rate, which are 276 nGy h(-1) and 1.169 mSv y(-1), respectively. A high purity germanium (HPGe) detector was used in the assessment of activity concentrations of (232)Th, (226)Ra and (40)K. The results of the gamma spectrometry range from 11 +/- 1 to 1210 +/- 41 Bq kg(-1) for (232)Th, 12 +/- 1 to 968 +/- 27 Bq kg(-1) for (226)Ra, and 12 +/- 2 to 2450 +/- 86 Bq kg(-1) for (40)K. Gross alpha and gross beta activity concentrations range from 170 +/- 50 to 4360 +/- 170 Bq kg(-1) and 70 +/- 20 to 4690 +/- 90 Bq kg(-1), respectively. These results were used in the plotting of digital maps (using ARCGIS 9.3) for isodose. The results are compared with values giving in UNSCEAR 2000. PMID- 23727881 TI - Is a neutral expression also a neutral stimulus? A study with functional magnetic resonance. AB - Although neutral faces do not initially convey an explicit emotional message, it has been found that individuals tend to assign them an affective content. Moreover, previous research has shown that affective judgments are mediated by the task they have to perform. Using functional magnetic resonance imaging in 21 healthy participants, we focus this study on the cerebral activity patterns triggered by neutral and emotional faces in two different tasks (social or gender judgments). Results obtained, using conjunction analyses, indicated that viewing both emotional and neutral faces evokes activity in several similar brain areas indicating a common neural substrate. Moreover, neutral faces specifically elicit activation of cerebellum, frontal and temporal areas, while emotional faces involve the cuneus, anterior cingulated gyrus, medial orbitofrontal cortex, posterior superior temporal gyrus, precentral/postcentral gyrus and insula. The task selected was also found to influence brain activity, in that the social task recruited frontal areas while the gender task involved the posterior cingulated, inferior parietal lobule and middle temporal gyrus to a greater extent. Specifically, in the social task viewing neutral faces was associated with longer reaction times and increased activity of left dorsolateral frontal cortex compared with viewing facial expressions of emotions. In contrast, in the same task emotional expressions distinctively activated the left amygdale. The results are discussed taking into consideration the fact that, like other facial expressions, neutral expressions are usually assigned some emotional significance. However, neutral faces evoke a greater activation of circuits probably involved in more elaborate cognitive processing. PMID- 23727882 TI - Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning. AB - Drugs that modulate serotonin (5-HT) synaptic concentrations impact neurogenesis and hippocampal (HPC)-dependent learning. The primary objective is to determine the extent to which psilocybin (PSOP) modulates neurogenesis and thereby affects acquisition and extinction of HPC-dependent trace fear conditioning. PSOP, the 5 HT2A agonist 25I-NBMeO and the 5-HT2A/C antagonist ketanserin were administered via an acute intraperitoneal injection to mice. Trace fear conditioning was measured as the amount of time spent immobile in the presence of the conditioned stimulus (CS, auditory tone), trace (silent interval) and post-trace interval over 10 trials. Extinction was determined by the number of trials required to resume mobility during CS, trace and post-trace when the shock was not delivered. Neurogenesis was determined by unbiased counts of cells in the dentate gyrus of the HPC birth-dated with BrdU co-expressing a neuronal marker. Mice treated with a range of doses of PSOP acquired a robust conditioned fear response. Mice injected with low doses of PSOP extinguished cued fear conditioning significantly more rapidly than high-dose PSOP or saline-treated mice. Injection of PSOP, 25I NBMeO or ketanserin resulted in significant dose-dependent decreases in number of newborn neurons in hippocampus. At the low doses of PSOP that enhanced extinction, neurogenesis was not decreased, but rather tended toward an increase. Extinction of "fear conditioning" may be mediated by actions of the drugs at sites other than hippocampus such as the amygdala, which is known to mediate the perception of fear. Another caveat is that PSOP is not purely selective for 5 HT2A receptors. PSOP facilitates extinction of the classically conditioned fear response, and this, and similar agents, should be explored as potential treatments for post-traumatic stress disorder and related conditions. PMID- 23727883 TI - Vision contingent auditory pitch aftereffects. AB - Visual motion aftereffects can occur contingent on arbitrary sounds. Two circles, placed side by side, were alternately presented, and the onsets were accompanied by tone bursts of high and low frequencies, respectively. After a few minutes of exposure to the visual apparent motion with the tones, a circle blinking at a fixed location was perceived as a lateral motion in the same direction as the previously exposed apparent motion (Teramoto et al. in PLoS One 5:e12255, 2010). In the present study, we attempted to reverse this contingency (pitch aftereffects contingent on visual information). Results showed that after prolonged exposure to the audio-visual stimuli, the apparent visual motion systematically affected the perceived pitch of the auditory stimuli. When the leftward apparent visual motion was paired with the high-low-frequency sequence during the adaptation phase, a test tone sequence was more frequently perceived as a high-low-pitch sequence when the leftward apparent visual motion was presented and vice versa. Furthermore, the effect was specific for the exposed visual field and did not transfer to the other side, thus ruling out an explanation in terms of simple response bias. These results suggest that new audiovisual associations can be established within a short time, and visual information processing and auditory processing can mutually influence each other. PMID- 23727884 TI - The epigenetic regulator PLZF represses L1 retrotransposition in germ and progenitor cells. AB - Germ cells and adult stem cells maintain tissue homeostasis through a finely tuned program of responses to both physiological and stress-related signals. PLZF (Promyelocytic Leukemia Zinc Finger protein), a member of the POK family of transcription factors, acts as an epigenetic regulator of stem cell maintenance in germ cells and haematopoietic stem cells. We identified L1 retrotransposons as the primary targets of PLZF. PLZF-mediated DNA methylation induces silencing of the full-length L1 gene and inhibits L1 retrotransposition. Furthermore, PLZF causes the formation of barrier-type boundaries by acting on inserted truncated L1 sequences in protein coding genes. Cell stress releases PLZF-mediated repression, resulting in L1 activation/retrotransposition and impaired spermatogenesis and myelopoiesis. These results reveal a novel mechanism of action by which, PLZF represses retrotransposons, safeguarding normal progenitor homeostasis. PMID- 23727885 TI - Knocking off their Sox: lineage-specific repression by Polycomb in epidermal stem cells. PMID- 23727886 TI - Structure of the human Parkin ligase domain in an autoinhibited state. AB - Mutations in the protein Parkin are associated with Parkinson's disease (PD), the second most common neurodegenerative disease in men. Parkin is an E3 ubiquitin (Ub) ligase of the structurally uncharacterized RING-in-between-RING(IBR)-RING (RBR) family, which, in an HECT-like fashion, forms a catalytic thioester intermediate with Ub. We here report the crystal structure of human Parkin spanning the Unique Parkin domain (UPD, also annotated as RING0) and RBR domains, revealing a tightly packed structure with unanticipated domain interfaces. The UPD adopts a novel elongated Zn-binding fold, while RING2 resembles an IBR domain. Two key interactions keep Parkin in an autoinhibited conformation. A linker that connects the IBR with the RING2 over a 50-A distance blocks the conserved E2~Ub binding site of RING1. RING2 forms a hydrophobic interface with the UPD, burying the catalytic Cys431, which is part of a conserved catalytic triad. Opening of intra-domain interfaces activates Parkin, and enables Ub-based suicide probes to modify Cys431. The structure further reveals a putative phospho peptide docking site in the UPD, and explains many PD-causing mutations. PMID- 23727887 TI - Supersize me-new insights into cortical expansion and gyration of the mammalian brain. AB - During evolution, the mammalian brain massively expanded its size. However, the exact roles of distinct neural precursors, identified in the developing cortex during embryogenesis, for size expansion and surface folding (i.e., gyration) remain largely unknown. New findings by Nonaka-Kinoshita et al advance our understanding of embryonic neural precursor function by identifying cell type selective functions for size expansion and folding, and challenge previously held concepts of mammalian brain development. PMID- 23727888 TI - The nuclear F-actin interactome of Xenopus oocytes reveals an actin-bundling kinesin that is essential for meiotic cytokinesis. AB - Nuclei of Xenopus laevis oocytes grow 100 000-fold larger in volume than a typical somatic nucleus and require an unusual intranuclear F-actin scaffold for mechanical stability. We now developed a method for mapping F-actin interactomes and identified a comprehensive set of F-actin binders from the oocyte nuclei. Unexpectedly, the most prominent interactor was a novel kinesin termed NabKin (Nuclear and meiotic actin-bundling Kinesin). NabKin not only binds microtubules but also F-actin structures, such as the intranuclear actin bundles in prophase and the contractile actomyosin ring during cytokinesis. The interaction between NabKin and F-actin is negatively regulated by Importin-beta and is responsive to spatial information provided by RanGTP. Disconnecting NabKin from F-actin during meiosis caused cytokinesis failure and egg polyploidy. We also found actin bundling activity in Nabkin's somatic paralogue KIF14, which was previously shown to be essential for somatic cell division. Our data are consistent with the notion that NabKin/KIF14 directly link microtubules with F-actin and that such link is essential for cytokinesis. PMID- 23727889 TI - The pull of the group: conscious conflict and the involuntary tendency towards conformity. AB - Is the reason that majorities exert an undue influence on the actions of individuals revealed through changes in subjective experience? Using an adaptation of the response interference paradigm (Morsella, Wilson, et al., 2009) in which participants are trained to introspect on their own experience of conscious conflict, two studies reported here show that the mere act of recalling counter-majority stances or opinions is associated with stronger subjective effects than recalling stances or opinions that coincide with majorities. Thus, an intention to conform to a majority (even when the majority is known to be wrong, as shown in the second study) seems to interfere with people's recall of their own stance or opinion. These results provide novel evidence for recent yet under-supported suggestions that majorities can influence individuals even when it is improper or illogical because human social cognition is primarily and involuntarily cooperative at the implicit level. PMID- 23727890 TI - Subjective states associated with retrieval failures in Parkinson's disease. AB - Instances in which we cannot retrieve information immediately but know that the information might be retrieved later are subjective states that accompany retrieval failure. These are expressed in feeling-of-knowing (FOK) and Tip-of-the tongue (TOT) experiences. In Experiment 1, participants with Parkinson's disease (PD) and older adult controls were given general questions and asked to report when they experienced a TOT state and to give related information about the missing word. The PD group experienced similar levels of TOTs but provided less correct peripheral information related to the target when in a TOT state. In Experiment 2, participants were given a Semantic (general knowledge questions) and an Episodic (word pairs) FOK task. PD patients failed to accurately predict their future memory performance (FOK) in response to both episodic and semantic cues. Results are interpreted in the context of recent frameworks of memory and metacognition. PMID- 23727891 TI - Polycations-functionalized water-soluble gold nanoclusters: a potential platform for simultaneous enhanced gene delivery and cell imaging. AB - Noble metal nanoclusters have emerged as a fascinating area of widespread interest in nanomaterials. Herein, we report the synthesis of the PEI-templated gold nanoclusters (PEI-AuNCs) as an efficient carrier for gene delivery. The PEI AuNCs integrate the advantages of PEI and AuNCs: the presence of AuNCs can effectively decrease the cytotoxicity of PEI, making it possible to apply them in biological systems, while the cationic polymer layer PEI with positive charges is essential for enhanced gene transfection efficiency. In addition, with excellent photoluminescent properties, the AuNCs also endow our system with the versatility of fluorescent imaging, indicating a great potential as an ideal fluorescent probe to track the transfection behavior. Our studies provide strong evidence that the PEI-AuNCs can be utilized as efficient gene delivery agents. PMID- 23727892 TI - Anti-inflammatory effects of phenolic compounds isolated from the flowers of Nymphaea mexicana Zucc. AB - Nymphaea mexicana Zucc. is an aquatic plant species which belongs to the family Nymphaea and is commonly known as the yellow water lily. The aim of this work was to study the in vitro antiinflammatory effects of phenolic compounds isolated from the flowers of Nymphaea mexicana Zucc. Seven phenolic compounds including vanillic acid, 4-methoxy-3,5-dihydroxybenzoic acid, (2R,3R)-3,7 dihydroxyflavanone, naringenin (4), kaempferol 3-O-(3-O-acetyl-a-L rhamnopyranoside), kaempferol 3-O-(2-O-acetyl-a-L-rhamnopyranoside), and quercetin 3-(30 0-acetylrhamnoside) (7) were isolated from the flowers of Nymphaea mexicana Zucc. These results revealed that compound 4 has the most prominent inhibitory effect on the LPS-stimulated nitric oxide (NO), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-a) production in RAW 264.7 macrophages. In addition, compound 4 also inhibited LPS-mediated induction of protein expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and phospho-ERK in RAW 264.7 macrophages. Thus, compound 4 from the flowers of Nymphaea mexicana Zucc. may provide a potential therapeutic approach for inflammation-associated disorders. PMID- 23727893 TI - A conserved human T cell population targets mycobacterial antigens presented by CD1b. AB - Human T cell antigen receptors (TCRs) pair in millions of combinations to create complex and unique T cell repertoires for each person. Through the use of tetramers to analyze TCRs reactive to the antigen-presenting molecule CD1b, we detected T cells with highly stereotyped TCR alpha-chains present among genetically unrelated patients with tuberculosis. The germline-encoded, mycolyl lipid-reactive (GEM) TCRs had an alpha-chain bearing the variable (V) region TRAV1-2 rearranged to the joining (J) region TRAJ9 with few nontemplated (N) region additions. Analysis of TCRs by high-throughput sequencing, binding and crystallography showed linkage of TCRalpha sequence motifs to high-affinity recognition of antigen. Thus, the CD1-reactive TCR repertoire is composed of at least two compartments: high-affinity GEM TCRs, and more-diverse TCRs with low affinity for CD1b-lipid complexes. We found high interdonor conservation of TCRs that probably resulted from selection by a nonpolymorphic antigen-presenting molecule and an immunodominant antigen. PMID- 23727895 TI - Structure based virtual screening-driven identification of monastrol as a potent urease inhibitor. AB - Virtual screening uses computer based methods to discover new ligands on the basis of biological structures. Among all virtual screening methods structure based docking has received considerable attention. In an attempt to identify new ligands as urease inhibitors, structure-based virtual screening (SBVS) of an in house database of 10,000 organic compounds was carried out. The X-ray crystallographic structure of Bacillus pasteurii (BP) in complex with acetohydroxamic acid (PDB Code 4UBP) was used as a protein structure. As a starting point, ~10,000 compounds of our in-house database were analyzed to check redundancy and the compounds found repeated were removed from the database. Finally 6993 compounds were docked into the active site of BP urease using GOLD and MOE-Dock software. A remarkable feature of this study was the identification of monastrol, a well-known KSP inhibitor already in clinical trials, as a novel urease inhibitor. The hits identified were further evaluated by molecular docking and on examination of the affinity predictions, twenty-seven analogs of monastrol were synthesized by a multicomponent Biginelli reaction followed by their in vitro screening as urease inhibitors. Finally twelve compounds were identified as new urease inhibitors. The excellent in vitro activity suggested that these compounds may serve as viable lead compounds for the treatment of urease related problems. PMID- 23727896 TI - A theoretical study on mechanism of the anticancer drug camptothecin's E-ring opening. AB - A reaction mechanism of the anticancer agent camptothecin (CPT)'s E-ring-opening has been studied by DFT method and IEF-PCM solvation model. Our results indicate that under the physiological PH, CPT's E-ring-opening is a spontaneous process, and it conforms to the addition coupled elimination reaction pathway with a proton translocation. The obtained activation free energies in the explicit water model are in agreement with the available experimental values. More than ten reactions have been studied to provide exhaustive analyses of the relationship between structure and reactivity. On the whole, our results accord with the experimental findings and the mechanism we proposed is reasonable. PMID- 23727894 TI - The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation. AB - Transcription factors of the STAT family are critical in the cytokine-mediated functional differentiation of CD4(+) helper T cells. Signaling inhibitors of the SOCS family negatively regulate the activation of STAT proteins; however, their roles in the differentiation and function of helper T cells are not well understood. Here we found that the SOCS protein CIS, which was substantially induced by interleukin 4 (IL-4), negatively regulated the activation of STAT3, STAT5 and STAT6 in T cells. CIS-deficient mice spontaneously developed airway inflammation, and CIS deficiency in T cells led to greater susceptibility to experimental allergic asthma. CIS-deficient T cells showed enhanced differentiation into the TH2 and TH9 subsets of helper T cells. STAT5 and STAT6 regulated IL-9 expression by directly binding to the Il9 promoter. Our data thus demonstrate a critical role for CIS in controlling the proallergic generation of helper T cells. PMID- 23727897 TI - N-NO2 bond dissociation energies in acetonitrile: an assessment of contemporary computational methods. AB - The assessment of the N-NO2 bond dissociation energies (BDEs) was performed by various calculating methods (B3LYP, B3PW91, B3P86, B1LYP, BMK, MPWB1K, PBE0, CBS 4M and M06-2X) at 6-311+G(2d,p) basis set. Compared with the experimental BDEs, the results show that BMK and B3P86 methods reproduce the experimental values well. The mean absolute deviations from the experimental values obtained by BMK and B3P86 methods were 0.5 and 1.5 kcal/mol, respectively. B3LYP, B3PW91, B1LYP, MPWB1K and PBE0 methods underestimated the homolytic N-NO2 BDEs. B3LYP, B3PW91, B1LYP, M06-2X, CBS-4M methods failed to provide an accurate description of N-NO2 BDEs for N-Nitrosulfonamide compounds and showed larger mean absolute deviations and maximum deviations. Further, substituent effect based on BMK/6-311+G(2d,p) method was analysis. Natural bond orbital analysis shows that there exist good linear correlations between E((2)) of lpN1->BD*(O1-N2) and Hammett constants and a better correlation between the BDEs and the second order stabilization energy E((2)) of lpN1->BD*(O1-N2). PMID- 23727898 TI - Involvement of 5-lipoxygenase in Alzheimer's disease: a role for DNA methylation. AB - Lipoxygenases play a major role in the neuropathology of Alzheimer's disease (AD), even though the underlying mechanisms are as yet poorly understood. Here, we studied the epigenetic regulation of 5-lipoxygenase (5-LOX) in peripheral blood mononuclear cells of subjects with late-onset AD and age-matched controls. We found a significant increase in 5-LOX gene expression in AD subjects compared to healthy controls, paralleled by increased 5-LOX protein and leukotriene B4, the 5-LOX product. In addition, a consistent reduction in DNA methylation at 5 LOX gene promoter was documented in AD versus healthy subjects. Taken together, our findings further support a role for 5-LOX in vulnerability to neurodegeneration. PMID- 23727899 TI - Ferulic acid inhibits the transition of amyloid-beta42 monomers to oligomers but accelerates the transition from oligomers to fibrils. AB - Alzheimer's disease (AD) is neurodegenerative disease that occurs among the aging population and is associated with impaired cognitive function. Amyloid-beta (Abeta) oligomers initiate the pathological cascade and represent a neuropathic hallmark of AD. Therefore, an approach that inhibits Abeta aggregation is an attractive therapeutic strategy for the treatment of AD. Ferulic acid (FA) is a phenolic compound that can inhibit Abeta42 fibril-induced cytotoxicity both in vitro and in vivo. However, few studies have demonstrated that FA interacts with Abeta42 oligomers. Here, we investigated whether FA inhibits Abeta42 oligomer induced cytotoxicity and the effect of FA on Abeta aggregation. Our results showed that FA reduced Abeta42-induced neurotoxicity in SH-SY5Y cells. Moreover, using CD spectroscopy, we found that FA inhibited the formation of the beta sheets that are required for the Abeta42 monomer-to-oligomer transition but accelerated the Abeta42 oligomer-to-fibril transition. These phenomena were confirmed by transmission electron microscopy and thioflavin T fluorescence assay. The docking analysis between FA and Abeta42 monomer showed that FA may inhibit the aggregation of Abeta42 oligomers by blocking the hydrogen bond with the forming beta-sheets. Taken together, we have identified a novel phenomenon in which FA inhibits the formation of Abeta42 oligomers while accelerating the transition of Abeta42 oligomers to fibrils, and we have shown that FA protects against Abeta42-induced toxicity in vitro by preventing Abeta42 from forming oligomers. PMID- 23727900 TI - High-affinity interaction of hnRNP A1 with conserved RNA structural elements is required for translation and replication of enterovirus 71. AB - Human Enterovirus 71 (EV71) is an emerging pathogen of infectious disease and a serious threat to public health. Currently, there are no antivirals or vaccines to slow down or prevent EV71 infections, thus underscoring the urgency to better understand mechanisms of host-enterovirus interactions. EV71 uses a type I internal ribosome entry site (IRES) to recruit the 40S ribosomal subunit via a pathway that requires the cytoplasmic localization of hnRNP A1, which acts as an IRES trans-activating factor. The mechanism of how hnRNP A1 trans activates EV71 RNA translation is unknown, however. Here, we report that the UP1 domain of hnRNP A1 interacts specifically with stem loop II (SLII) of the IRES, via a thermodynamically well-defined biphasic transition that involves conserved bulge 5'-AYAGY-3' and hairpin 5'-RY(U/A)CCA-3' loops. Calorimetric titrations of wild type and mutant SLII constructs reveal these structural elements are essential to form a high-affinity UP1-SLII complex. Mutations that alter the bulge and hairpin primary or secondary structures abrogate the biphasic transition and destabilize the complex. Notably, mutations within the bulge that destabilize the complex correlate with a large reduction in IRES-dependent translational activity and impair EV71 replication. Taken together, this study shows that a conserved SLII structure is necessary to form a functional hnRNP A1-IRES complex, suggesting that small molecules that target this stem loop may have novel antiviral properties. PMID- 23727901 TI - Perinatal outcomes of uninsured immigrant, refugee and migrant mothers and newborns living in Toronto, Canada. AB - Canadian healthcare insurance is not universal for all newcomer populations. New immigrant, refugee claimant, and migrant women face various barriers to healthcare due to the lack of public health insurance coverage. This retrospective study explored the relationships between insurance status and various perinatal outcomes. Researchers examined and compared perinatal outcomes for 453 uninsured and provincially insured women who delivered at two general hospitals in the Greater Toronto Area between 2007 and 2010. Data on key perinatal health indicators were collected via chart review of hospital medical records. Comparisons were made with regional statistics and professional guidelines where available. Four-in-five uninsured pregnant women received less than-adequate prenatal care. More than half of them received clearly inadequate prenatal care, and 6.5% received no prenatal care at all. Insurance status was also related to the type of health care provider, reason for caesarean section, neonatal resuscitation rates, and maternal length of hospital stay. Uninsured mothers experienced a higher percentage of caesarian sections due to abnormal fetal heart rates and required more neonatal resuscitations. No significant difference was found for low birth weight, preterm birth, NCIU admissions, postpartum hemorrhage, breast feeding, or intrapartum care provided. PMID- 23727902 TI - Burnout in relation to specific contributing factors and health outcomes among nurses: a systematic review. AB - Nurses have been found to experience higher levels of stress-related burnout compared to other health care professionals. Despite studies showing that both job satisfaction and burnout are effects of exposure to stressful working environments, leading to poor health among nurses, little is known about the causal nature and direction of these relationships. The aim of this systematic review is to identify published research that has formally investigated relationships between these variables. Six databases (including CINAHL, COCHRANE, EMBASE, MEDLINE, PROQUEST and PsyINFO) were searched for combinations of keywords, a manual search was conducted and an independent reviewer was asked to cross validate all the electronically identified articles. Of the eighty five articles that were identified from these databases, twenty one articles were excluded based on exclusion criteria; hence, a total of seventy articles were included in the study sample. The majority of identified studies exploring two and three way relationships (n = 63) were conducted in developed countries. Existing research includes predominantly cross-sectional studies (n = 68) with only a few longitudinal studies (n = 2); hence, the evidence base for causality is still very limited. Despite minimal availability of research concerning the small number of studies to investigate the relationships between work-related stress, burnout, job satisfaction and the general health of nurses, this review has identified some contradictory evidence for the role of job satisfaction. This emphasizes the need for further research towards understanding causality. PMID- 23727903 TI - Incinerator pollution and child development in the taiwan birth cohort study. AB - This study aimed to investigate the direct and indirect effects of environmental pollutants on child development and parental concerns. It focused on the pathway relationships among the following factors: living within three kilometers of an incinerator, breastfeeding, place of residence, parental concerns about development, and parent-perceived child development. The Taiwan Birth Cohort Study (TBCS) dataset includes randomized community data on 21,248 children at six, 18, and 36 months of age. The Parental Concern Checklist and the Taiwan Birth Cohort Study-Developmental Instrument were used to measure parental concern and parent-perceived child development. Living within three kilometers of an incinerator increased the risk of children showing delayed development in the gross motor domain at six and 36 months. Although breastfeeding is a protective factor against uneven/delayed developmental disability (U/DDD), children living near an incinerator who were breastfed had an increased risk of U/DDD compared with those who did not live near incinerators. The presence of a local incinerator affected parent-perceived child development directly and indirectly through the mediating factor of breastfeeding. Further follow-up of these children to investigate the long-term effects of specific toxins on their development and later diagnostic categorization is necessary. PMID- 23727904 TI - Kinase gene haplotypes and gene-gene interactions in the Ras-Raf-MAPK signaling pathway: association with antidepressant remission. AB - Signal transduction has been reported to be involved in antidepressant treatment outcomes; however, its mechanisms remain unclear. The aims of this study were to explore the associations between antidepressant remission and single nucleotide polymorphisms (SNPs), haplotypes, and gene-gene interactions in the Ras-Raf-MAPK intracellular signaling pathway. A total of 302 inpatients with major depressive disorder (DSM-IV Axis I) were assessed using the 17-item Hamilton Depression Rating Scale before and after 8 weeks of antidepressant treatment to determine the remission rate in the samples. Twenty-four SNPs at five kinase genes (Ras-Raf MEK-ERK-RSK), which are a part of the Ras-Raf-MAPK signaling pathway, were identified to investigate a genetic association with antidepressant drug outcome. Correlations between 24 SNPs at the five kinase genes in the Ras-Raf-MAPK signaling pathway and antidepressant drug outcome were not found. The percentage of the CCAGA haplotype that RSK(2/3/4)-RSKL(1/2) gene loci SNPs constructed was markedly lower in the remitter group when compared with the nonremitter group in female depressed patients (P=0.04), whereas the proportion of AAAGGG haplotype that RSK(2/3/4)-RSKL(1/2) gene loci SNPs constructed in the remitter group was significantly greater than that in the nonremitter group in male patients (P=0.02). In addition, MEK1 (rs28730804) and RSK3 (rs2229712) in the Ras-Raf-MAPK signaling pathway showed a gene-gene interaction that affected antidepressant drug outcome in female depressed patients (P=0.041). Although this study did not find that SNPs at the five kinase genes in the Ras-Raf-MAPK signaling pathway are important markers for antidepressant outcome, certain haplotypes that SNPs at the RSK(2/3/4)-RSKL(1/2) gene constructed may be important markers for antidepressant drug efficacy. We observed a gene-gene interaction in this signaling pathway that influenced antidepressant efficacy in female depressed patients. Therefore, it is likely that in female depressed patients, different haplotypes and gene-gene interaction in the Ras-Raf-MAPK signaling pathway are involved in mediating the pharmacological action of an antidepressant, and eventually influence antidepressant efficacy. PMID- 23727905 TI - Absence of evidence that the pro re nata regimen confers benefit: a review of the studies. AB - Studies were sought that evaluated the prevalence, effectiveness, and safety of pro re nata (p.r.n.) medications in psychiatric practice for which evidence has been scarce despite their wide application. To this end, a systematic literature search was performed using various search engines (last search: October 2012) with cross-referencing. A total of 34 studies were identified: 16 studies on epidemiological usage, 16 retrospective studies on effectiveness/safety as well as reasons, and only two prospective studies on the effectiveness/safety of p.r.n. medications. All the patients studied were inpatients, and the reasons for p.r.n. were acute behavioral dyscontrol in 29 studies. Psychiatric diagnoses and outcome measures to assess effectiveness/safety varied and were described in 27 and 20 studies, respectively. Medications under study included antipsychotics (mainly chlorpromazine, haloperidol, olanzapine, risperidone, or quetiapine), benzodiazepines (mainly diazepam and lorazepam), and antihistamines (mainly diphenhydramine). Altogether, 17 studies reported that p.r.n. medications were effective in psychiatric inpatients. Those two prospective studies targeted solely a child/adolescent population with small sample sizes. Currently available data are limited in number, quality, and scope; there has been only equivocal evidence to guide the choice of p.r.n. medications for psychiatric patients, hence there is a need for more investigations on this important clinical topic. PMID- 23727906 TI - Temperature-responsive enzyme-polymer nanoconjugates with enhanced catalytic activities in organic media. AB - A general approach for preparing enzyme-polymer nanoconjugates that respond to temperature in organic media is presented. These nanoconjugates readily dissolve in organic solvents for homogenous catalysis at 40 degrees C and showed greatly enhanced apparent catalytic activities. The recovery of the soluble enzyme polymer nanoconjugates is accomplished by temperature-induced precipitation. PMID- 23727907 TI - Crack patterns in superlattices made of maghemite nanocrystals. AB - Here, 11 nm gamma-Fe2O3 nanocrystals characterized by a low size distribution of 5% and dispersed in chloroform are deposited onto a substrate as well-defined films. The film thickness is controlled by the initial concentration of the colloidal solution. After drying, the film shows a network of well-defined cracks. It is demonstrated using scanning electron microscopy and small-angle X ray diffraction that the nanocrystals within the film are self-assembled in ordered lattices. It is shown that the nanocrystals self-assemble in superlattices before the cracks appear. In contrast to what was previously observed with a disordered film of maghemite nanocrystals with large size distribution, the top surface of the films is covered with patterns formed before crack formation. The cracks preferentially follow the direction of the hexagonal array observed on the top surface of the film by using a field emission gun scanning electron microscope. The average crack distance as a function of the film height follows the same linear scaling law as in amorphous nanocrystal assemblies. The size of superlattices of nanocrystals evolves with film height, but is usually significantly smaller than the average crack distance except on the border of the films. PMID- 23727908 TI - Polyethyleneglycol: a classical but innovative material. Foreword. PMID- 23727909 TI - Polymeric micelles possessing polyethyleneglycol as outer shell and their unique behaviors in accelerated blood clearance phenomenon. AB - Polymeric micelles are assemblies of synthetic polymers and have been studied and developed as drug carriers for targeting. Polymeric micelles are composed of the inner core and the outer shell, and typically form from AB-type block copolymers in which two polymer blocks are connected in a tandem form. Polyethyleneglycol (PEG) has been most commonly used as one polymer block composing the outer shell. This review describes the reasons that PEG is used for the outer shell of the polymeric micelle carrier systems. On the other hand, accelerated blood clearance (ABC) phenomenon is a well-known immunological response of PEG-coated liposomes. Since the ABC phenomenon greatly influences targeting functions of carrier systems, elaborative studies on polymeric micelles' ABC phenomenon have been done, and revealed different behaviors of the polymeric micelle systems from those of PEG-coated liposomes. These studies indicate that polymeric micelle systems are highly feasible tools for contrast agent targeting as well as theranostics. PMID- 23727910 TI - Current status and prospects of polyethyleneglycol-modified medicines. AB - Polyethyleneglycol (PEG) compounds have a large hydrogen bonding capability and possess various functions that depend on the length of the chain and conformational diversity. Modification of a drug with PEG is a well-known technology for improving the physicochemical properties and biological responses of a drug. There are many reports about the modification of small molecules with PEG, however, there are no modified small molecule products currently on the market. Several protein products for medical use are commercially available. In this review, the effects of modification with PEG on biopharmaceuticals are described through the comparison of two interferon-alpha products modified with PEG, one with 12 kDa linear PEG and the other 40 kDa branched PEG. There is one original drug delivery system product, Doxil((r))/Caelyx((r)), on the market in which liposomes modified with PEG and encapsulating doxorubicin are stabilized sterically and invisible to the reticuloendothelial system. The benefits of modification with PEG are described here with examples of modified products on the market and used in clinical trials. PMID- 23727911 TI - Anti-polyethyleneglycol antibody response to PEGylated substances. AB - In contrast to the general assumption that polyethyleneglycol (PEG)-conjugated substances lack immunogenicity and antigenic, it has been reported that they can elicit antibodies against PEG (mainly anti-PEG immunoglobulin M (IgM)). In patients, the presence of anti-PEG antibodies may limit therapeutic efficacy of PEGylated substances as a consequence of inducing rapid clearance of and neutralizing biological activity of the substances. Here, we introduce specific examples of PEGylated substances including several PEGylated proteins and PEGylated particles (PEGylated nanocarriers) which induce anti-PEG antibody responses. Finally, we emphasize that the immunogenicity of PEGylated substances should be tested in the development stage and that the titer of anti-PEG antibodies in patients should be pre-screened and monitored prior to and throughout a course of treatment with a PEGylated substance. PMID- 23727912 TI - The polyethyleneglycol dilemma: advantage and disadvantage of PEGylation of liposomes for systemic genes and nucleic acids delivery to tumors. AB - Gene and nucleic acid therapy is expected to play a major role in the next generation of agents for cancer treatment. We have recently developed a multifunctional envelope-type nano device (MEND) for use as a novel nonviral gene delivery system. The modification of polyethyleneglycol (PEG), i.e., PEGylation, is a useful method for achieving a longer circulation time for the delivery of MEND to a tumor via the enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits cellular uptake and endosomal escape, which results in significant loss of activity of the delivery system. For successful nucleic acid delivery for cancer treatment, the crucial problem associated with the use of PEG, i.e., the "PEG dilemma" must be resolved. In this review, we describe the development and applications of MEND and discuss various strategies for overcoming the PEG dilemma based on the manipulation of both pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release. To increase cellular uptake, target ligands including proteins, peptides, antibodies and aptamers that recognize molecules specifically expressed on tumors are first introduced. Second, cleavable PEG systems are described. The cleavage of PEG from carriers was achieved in response to the intracellular environment as well as the tumor microenvironment, which improvs cellular uptake and endosomal escape. Then, endosomal fusogenic peptides are discussed. Finally, pH-sensitive liposomes using pH-sensitive lipids are described. PMID- 23727913 TI - Change in the character of liposomes as a drug carrier by modifying various polyethyleneglycol-lipids. AB - When liposomes, as a superior drug carrier, are injected intravenously, active liposomes as medicines require polyethyleneglycol (PEG) as a modification tool around the liposomal membrane. PEG modification of a liposome forms a fixed aqueous layer, and the trapping by cells of the reticuloendothelial system (RES) is avoided. Hence, PEG-modified liposomes have long circulation in the bloodstream, and passive targeting to tumors has been achieved by PEG modification. We have been studying the passive targeting by liposomes with the expectation of more usefulness. It was proved a correlation between the PEG molecular weight of PEG-modified liposomes and blood circulation time and antitumor effect, too. Liposomes modified by PEG2000 were useful for uptake into tumor cells. We thought that the re-uptake in the liposomal membrane also increased accumulation. Moreover, it was proved that mixing two different PEGs to modify the liposome surface gives a bigger fixed aqueous layer thickness (FALT) around the liposome, giving the liposome strong antitumor activity. Then, we designed a novel PEG-lipid, 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine-PEG (different double arms PEG; DDA-PEG), which had two different PEGs (2000 and 500) in one molecule. One of the innovative characteristics of DDA-PEG-modified liposome (DDAL) is that it heightens the contact ability with tumor cells. DDAL may be an effective DDS carrier for solving various PEG dilemmas. It was observed that passive targeting by PEG-modified liposomes had different characteristics by changing PEG length, anchor type or those combination. Thus, it should be applied to liposomes suitable for various diseases. PMID- 23727914 TI - Antinociceptive profiles and mechanisms of orally administered coumarin in mice. AB - In the present study, the antinociceptive profiles of coumarin were examined in ICR mice. Coumarin administered orally (from 1 to 10 mg/kg) showed an antinociceptive effect in a dose-dependent manner as measured in the acetic acid induced writhing test. Duration of antinociceptive action of coumarin maintained at least for 60 min. But, the cumulative response time of nociceptive behaviors induced by a subcutaneous (s.c.) formalin injection, intrathecal (i.t.) substance P (0.7 ug) or glutamate (20 ug) injection was not affected by coumarin. In addition, intracerebroventricular (i.c.v.) or intrathecal (i.t.) administration with coumarin (10-40 ug) attenuated acetic acid-induced writhing response in a dose dependent manner. Intraperitoneal (i.p.) pretreatment with naloxone (an opioid receptor antagonist) attenuated antinociceptive effect induced by coumarin in the writhing test. Furthermore, i.c.v. or i.t. pretreatment with naloxone (5 ug) reversed the decreased acetic acid-induced writhing response. However, methysergide (a 5-HT serotonergic receptor antagonist) or yohimbine (an alpha2 adrenergic receptor antagonist) did not affect antinociception induced by coumarin in the writhing test. Our results suggest that coumarin exerts a selective antinociceptive property in the acetic acid-induced visceral-derived pain model. Furthermore, the antinociceptive effect of coumarin may be mediated by activation of central opioid receptors, but not serotonergic and adrenergic receptors. PMID- 23727915 TI - Quercetin potentiates apoptosis by inhibiting nuclear factor-kappaB signaling in H460 lung cancer cells. AB - The herbal flavonoid quercetin inhibits the growth of various cancer cells, but how it affects human cancer cells, particularly lung cancer cells, is unclear. We investigated the anticancer activity of quercetin and the underlying molecular mechanisms in non-small cell lung cancer (NSCLC) cells. Quercetin strongly inhibited cell proliferation, and increased sub-G1 and apoptotic cell populations regardless of p53 status. Quercetin-induced apoptosis was verified by caspase cleavage, Hoechst staining, trypan blue exclusion, and DNA fragmentation assays. Microarray analysis using H460 cells indicated that quercetin increased the expression of genes associated with death receptor signaling tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAILR), caspase-10, interleukin (IL) 1R DNA fragmentation faotor 45 (DFF45), tumor necrosis factor receptor (TNFR) 1, FAS, inhibitor of kappaBalpha (IkappaBalpha)) and cell cycle inhibition growth arrest and DNA-damage inducible 45 (GADD45), p21(Cip1)), but decreased the expression of genes involved in nuclear factor (NF)-kappaB activation (NF-kappaB, IKKalpha). Further validation assays confirmed that quercetin inhibited growth by suppressing NF-kappaB and by increasing the expression of death receptors and cell cycle inhibitors. Taken together, these findings suggest that quercetin may be useful in the prevention and therapy of NSCLC. PMID- 23727916 TI - Expression and secretion of cholera toxin B subunit in lactobacilli. AB - Lactic acid bacteria (LAB) are used in various fields, including in food and medical supplies. There has been a great deal of research into vaccine development using LAB as carriers due to their "generally recognized as safe" status. Cholera is an infectious disease that causes diarrhea due to cholera toxin (CT) produced by Vibrio cholerae. The pentameric cholera toxin B (CTB) subunit has no toxicity, and is used as an antigen in cholera vaccines and as a delivery molecule in vaccines to various diseases. In this study, we generated recombinant LAB expressing and secreting CTB. Here, we first report that CTB expressed and secreted from LAB bound to GM1 ganglioside. The secreted CTB was purified, and its immunogenicity was determined by intranasal administration into mice. The results of the present study suggested that it may be useful as the basis of a new oral cholera vaccine combining LAB and CTB. PMID- 23727917 TI - Effects of intrathecal dexmedetomidine on low-dose bupivacaine spinal anesthesia in elderly patients undergoing transurethral prostatectomy. AB - Low-dose bupivacaine can limit the spinal block level with minimal hemodynamic effects and yield a rapid recovery, but sometimes it may not provide adequate anesthesia for surgery. Dexmedetomidine, a selective alpha2-adrenoreceptor agonist, was shown to be a potent antinociceptive agent when given intrathecally in animals and humans. The purpose of this study was to evaluate the adjuvant effects of intrathecal dexmedetomidine in elderly patients undergoing transurethral prostate surgery with low-dose bupivacaine spinal anesthesia. Fifty four patients undergoing transurethral prostate surgery were randomized into two groups receiving either dexmedetomidine 3 ug (n=27) or normal saline (n=27) intrathecally with 6 mg of 0.5% hyperbaric bupivacaine. The characteristics of the spinal block and postoperative analgesic effects were evaluated. The peak block level was similar for the two groups. However, the dexmedetomidine group demonstrated a faster onset time to the peak block and longer duration of spinal block than the saline group (p<0.01). The motor block scales at the time of peak sensory block and regression of 2-sensory dermatomes were higher in the dexmedetomidine group than in the saline group (p<0.001). There was less analgesic request and the time to the first analgesic request was longer in the dexmedetomidine group than in the saline group (each 487, 345 min, p<0.05). Dexmedetomidine 3 ug when added to intrathecal bupivacaine 6 mg produced fast onset and a prolonged duration of sensory block and postoperative analgesia in elderly patients for transurethral surgery. However, recovery of motor block could be delayed in dexmedetomidine-added patients. PMID- 23727918 TI - In vitro evaluation of the ciliary beat frequency of the rat nasal epithelium using a high-speed digital imaging system. AB - Mucociliary clearance (MC) is an important factor in determining nasal drug absorption and the ciliary beat of ciliated epithelial cells of the nasal mucosa is the driving force of MC. However, the relationship between MC and ciliary beat frequency (CBF) is still ambiguous. The purpose of this study was to establish an evaluation method of CBF as an index of mucociliary function and examine the relationship between MC and CBF. A sequence of images of ciliary beating of an excised rat nasal septum was captured using a high-speed digital video camera. CBF (beats per second, Hz) was determined from periodic changes in the contrast value of a specific location in a sequence of images. CBF under control conditions was 8.49+/-0.38 Hz, which is similar to values reported for cultured human nasal epithelial cells and rat tracheal cells. beta-Adrenergic and cholinergic antagonists decreased CBF, while beta-adrenergic agonists and acetylcholine increased CBF. These results were similar with those observed for MC in our previous study. It was found that CBFs were significantly and linearly correlated with MC, indicating that MC is directly regulated by CBF and that this evaluation system allows the quantitative determination of nasal mucociliary function. PMID- 23727919 TI - Antiemetic effects of a potent and selective neurokinin-1 receptor antagonist, FK886, on cisplatin- and apomorphine-induced emesis in dogs. AB - The antiemetic properties of a novel neurokinin-1 (NK1) receptor antagonist, FK886 ([3,5-bis(trifluoromethyl)phenyl][(2R)-2-(3-hydroxy-4-methylbenzyl)-4-{2 [(2S)-2-(methoxymethyl)morpholin-4-yl]ethyl}piperazin-1-yl]methanone dihydrochloride), were studied in dog models of cisplatin- and apomorphine induced emesis. Intravenously administered FK886 (0.32-1 mg/kg) significantly inhibited cisplatin-induced acute emesis during the 5-h observation period. Nearly complete inhibition was observed at 1 mg/kg. At an equivalent dose range, orally administered FK886 also significantly inhibited emesis, indicating good oral absorption. Similarly, FK886 inhibited apomorphine-induced emetic responses effectively following both intravenous and oral administration. The effects were long lasting, with 1.6 mg/kg of FK886 completely blocking apomorphine-induced retching and vomiting after a 12-h pretreatment period. Furthermore, FK886 showed rapid onset of antiemetic activity after oral administration. At doses of 0.32 mg/kg or more, a pretreatment time of 0.5 h was sufficient for complete inhibition of apomorphine-induced emetic responses. This fast onset after oral administration was supported by pharmacokinetic data, which demonstrated plasma levels of FK886 after oral administration reached levels similar to those 30 min after intravenous administration. These results suggest that FK886 has excellent antiemetic properties in dogs, and that its rapid-onset and long-lasting properties might make it a promising antiemetic agent. PMID- 23727920 TI - Safe and effective delivery of small interfering RNA with polymer- and liposomes based complexes. AB - We developed binary and ternary complexes based on polymers and liposomes for safe and effective delivery of small interfering RNA (siRNA). Anti-luciferase siRNA was used as a model of nucleic acid medicine. The binary complexes of siRNA were prepared with cationic polymers and cationic liposomes such as polyethylenimine (PEI), polyamidoamine (PAMAM) dendrimer, poly-L-arginine (PLA), trimethyl[2,3-(dioleoxy)-propyl]ammonium chloride (DOTMA), and cholesteryl 3beta N-(dimetylaminnoethyl)carbamate hydrochloride (DC-Chol). The ternary complexes were constructed by the addition of gamma-polyglutamic acid (gamma-PGA) to the binary complexes. The complexes were approximately 54-153 nm in particle size. The binary complexes showed a cationic surface charge although an anionic surface charge was observed in the ternary complexes. The polymer-based complexes did not show a silencing effect in the mouse colon carcinoma cell line expressing luciferase regularly (Colon26/Luc cells). The binary complexes based on liposomes and their ternary complexes coated by gamma-PGA showed a significant silencing effect. The binary complexes showed significant cytotoxicity although the ternary complexes coated by gamma-PGA did not show significant cytotoxicity. The ternary complexes coated by gamma-PGA suppressed luciferase activity in the tumor after their direct injection into the tumors of mice bearing Colon26/Luc cells. Thus, we have newly identified safe and efficient ternary complexes of siRNA for clinical use. PMID- 23727921 TI - A comparative study of the effects of whole red ginseng extract and polysaccharide and saponin fractions on influenza A (H1N1) virus infection. AB - Total extracts of ginseng (the root of Panax ginseng C. A. MEYER) and saponin and polysaccharide fractions have been the main products used to investigate novel effects of ginseng over the last five decades. However, the differences if any between the pharmacological effects of total extract and saponin and polysaccharide fractions are largely unknown. In this study, we compared their effects on influenza A virus infection. Mice received total extract of Korean red ginseng (RG), and polysaccharide and saponin fractions of Korean RG, orally for 14 d prior to influenza A virus infection. Seventy eight percent of mice infected with 2* the 50% lethal dose (LD50) of virus survived when administered the polysaccharide fraction, compared to 67%, 56% and 17% when administered total extract, saponin fraction and phosphate-buffered saline (PBS), respectively. Moreover, body weight loss in mice given the polysaccharide fraction was significantly reduced while there was mild reduction in body weight loss in that receiving saponin fraction or total extract when mice were infected with 0.2* or 0.5*LD50 of virus. We also confirmed that the polysaccharide fraction was most effective in reducing the accumulation of tumor necrosis factor alpha (TNF alpha)/inducible nitric oxide synthase (iNOS)-producing dendritic cells (tipDCs) in the mouse lungs. Our results indicate that the polysaccharides of RG have a pronounced beneficial effect on the symptoms of influenza virus infection. PMID- 23727922 TI - Reduction of enhanced rabbit intraocular pressure by instillation of pyroglutamic acid eye drops. AB - L-Pyroglutamic acid (PGA) is an endogenous molecule derived from l-glutamate. We demonstrate the effects of PGA on intraocular pressure (IOP) in experimentally induced ocular hypertension in rabbits. In the in vitro and in vivo transcorneal penetration studies, the PGA solution (PGA in saline) did not penetrate the rabbit cornea. On the other hand, the penetration of PGA was improved by the addition of zinc chloride and 2-hydroxypropyl-beta-cyclodextrin (HPCD), and PGA penetration was enhanced with increasing HPCD concentration. Therefore, PGA solutions containing 0.5% zinc chloride and 5% or 10% HPCD (PGA/HPCD(5% or 10%) eye drops) were used to investigate the effects for IOP in this study. An elevation in IOP was induced by the rapid infusion of 5% glucose solution (15 mL/kg of body weight) through the marginal ear vein or maintaining under dark phase for 5 h. In the both models, the induced elevation in IOP was prevented by the instillation of PGA/HPCD eye drops, and the IOP-reducing effect enhanced with increasing HPCD concentration in the drops. Nitric oxide (NO) levels elevated in the aqueous humor following the infusion of 5% glucose solution, and this increase was also suppressed by the instillation of PGA/HPCD eye drops. In conclusion, the present study demonstrates that the instillation of PGA/HPCD eye drops has an IOP-reducing effect in rabbits with experimentally induced ocular hypertension, probably as a result of the suppression of NO production. PMID- 23727923 TI - Development of initial loading procedure for teicoplanin in critically ill patients with severe infections. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is now endemic in many hospitals. Infection with MRSA is more frequent in the intensive care unit (ICU) than in general wards. Therefore, appropriate treatments for MRSA infections will lead to good outcomes in the ICU. Teicoplanin is an anti-MRSA agent. Recently, it was recommended at a new target trough concentration of 15-30 ug/mL. However, the initial loading procedure for teicoplanin to allow it to reach the target concentration promptly remains uncertain. Therefore, this study aimed to determine the appropriate initial loading procedure for teicoplanin in critically ill patients with severe infections. We performed a retrospective study in patients given teicoplanin in the ICU in order to determine the initial loading procedure to promptly reach the target trough concentration. We then evaluated the trough concentration on the third day after commencement of teicoplanin therapy. The mean loading dose and trough concentration were 11.5+/-1.0 mg/kg and 18.9+/-5.9 ug/mL, respectively. A correlation (r=0.45, p=0.046) was shown between teicoplanin loading dose and trough concentration. The correlation equation was trough concentration=2.563.loading dose -10.672. In the cases of 11.0 and 15.0 mg/kg for the loading dose, respectively, trough concentrations were 17.5 and 27.8 ug/mL. We suggested that an initial loading dose of 11-15 mg/kg every 12 h for 3 doses should be administered to promptly achieve the target trough concentration of 15-30 ug/mL on the third day after commencement of teicoplanin therapy in the ICU. PMID- 23727924 TI - Acidic sialidase activity is aberrant in obese and diabetic mice. AB - Mammalian sialidases (NEU1, NEU2, NEU3 and NEU4) that remove sialic acids from glycoconjugates have been implicated in diverse cellular functions. Human sialidases are involved in the development of various disease states such as cancer, diabetes and arteriosclerosis. Unregulated acidic sialidase NEU1 activity is associated with the pathogenesis of lysosomal storage disorder (LSD) sialidosis, abnormal immune responses and cancer progression. Obesity is closely related to several chronic diseases such as diabetes, cardiovascular diseases, hyperlipidemia or hypertension that are associated with metabolic syndrome. We examined fluctuations in mRNA levels and sialidase activities of NEU1 in two strains of obese and diabetic mice to assess the involvement of NEU1 in obesity. The activity of NEU1 was preferentially higher in epididymal fat and lower in the livers of two strains of obese and diabetic mice. Fluctuations in NEU1 activity might be associated with the pathological status of these tissues in obesity. PMID- 23727925 TI - Caffeic acid phenethyl ester inhibits endothelial tissue factor expression. AB - Caffeic acid phenethyl ester (CAPE) is a component of honeybee hives with various beneficial properties. Tissue factor (TF), the key trigger of thrombosis, is expressed in human endothelial cells. This study was designed to investigate whether CAPE modulates TF expression in human aortic endothelial cells (HAECs). Western blots and real-time polymerase chain reactions were performed. CAPE (10( 7)-10(-5) M) inhibited tumor necrosis factor (TNF)-alpha induced endothelial TF protein expression by 2.1-fold at 10(-5) M (p<0.0001). Similarly, TF surface activity was reduced (p<0.02). In contrast, TF mRNA expression, TF promoter activity, and mitogen-activated protein (MAP) kinase activation remained unaltered. In conclusion, CAPE inhibits TF protein expression and activity at the posttranscriptional level thereby exhibiting anti-thrombotic potential. PMID- 23727926 TI - Identification of differential expressed proteins and characterization their mRNA expression in thermally stressed Apostichopus japonicus. AB - In this study, we present a comparative proteomic analysis of the global protein expression changes in sea cucumber after 7 days exposure at 25 degrees C. Using two-dimensional electrophoresis followed by MALDI-TOF MS/MS, 27 protein spots with significant differences in abundance were identified and characterized. The identified proteins belonged primarily to the following four functional categories: cytoskeletal, material and energy metabolism, calcium homeostasis and extracellular matrix. The mRNA expression levels of 7 differentially expressed proteins were further assessed by qRT-PCR. The expression levels of 6 genes, including collagen, ATP synthase, major yolk protein, ferritin, nectin and protein disulfide isomerase showed significant differences under thermal stress, and among them, only two genes-ATP synthase and major yolk protein-showed consistent levels of protein and mRNA expression. Our results offer insight into the complex changes in protein turnover during higher temperature exposure in sea cucumber. PMID- 23727928 TI - Microbes and their Role in Sustainable Development. PMID- 23727929 TI - Low-cost and large-scale synthesis of functional porous materials for phosphate removal with high performance. AB - A facile spray drying technique has been developed for large-scale and template free production of nanoporous silica with controlled morphology, large pore size, and high pore volume, using commercially available fumed silica, Aerosil 200, as a sole precursor. This approach can be applied to the preparation of functional nanoporous materials, in this study, lanthanum oxide functionalised silica microspheres by introducing lanthanum nitrate in situ during the spray drying process and followed by a post-calcination process. The resultant lanthanum functionalised Aerosil microspheres manifest high phosphate adsorption capacity (up to 2.317 mmol g(-1)), fast kinetics, and excellent adsorption performance at a low phosphate concentration (1 mg L(-1)). In virtue of the easy and scalable synthesis method, low cost and high performances of the product, the materials we reported here are promising for water treatment. Our approach may be general and extended to the synthesis of other functional nanoporous materials with versatile applications. PMID- 23727927 TI - Monoclonal antibody preparation of Golgi phosphoprotein 2 and preliminary application in the early diagnosis of hepatocellular carcinoma. AB - Golgi phosphoprotein 2 (Golph2) is a type II Golgi-specific membrane protein, which has been found to be overexpressed in hepatocellular carcinoma (HCC) patients. The sensitivity of diagnosis of HCC using Golph2 (76%) was markedly elevated compared with alpha-fetoprotein (AFP) (70%), and Golph2 is expected to be a novel and effective serum biomarker for the diagnosis of HCC. The aim of this study was to prepare monoclonal antibodies against Golph2 and to establish double-antibody sandwich enzyme-linked immunosorbent assay (s-ELISA), which will be used in diagnostics, therapeutics and as a tool in understanding the role of Golph2 in the pathogenesis of liver diseases and cancer. In this study, fusion protein TRX-Golph2 was expressed and purified using an Escherichia coli system. BALB/c mice were immunized with TRX-Golph2 recombinant protein. The hybridoma technique was used for the production of anti-Golph2 monoclonal antibody. Hybridoma clones were screened using indirect ELISA and anti-Golph2 monoclonal antibody was produced in the ascites of BALB/c mice. The specificity of anti Golph2 monoclonal antibody was detected by western blot analysis and immunocytochemistry. s-ELISA was established using horseradish peroxidase (HRP) labeled anti-Golph2 monoclonal antibody and used to detect the antigen in the serum of HCC patients. As a result, five stable hybridoma cell clones (5C6D5, 5B7F5, 7F5F3, 8A7B4, 8C9E8) producing anti-Golph2 monoclonal antibody were established. The highest titer of anti-Golph2 monoclonal antibody (5C6D5) was 1:51,200. Western blot analysis revealed that anti-Golph2 monoclonal antibody had a high specificity for Golph2 protein. Anti-Golph2 monoclonal antibody was HRP labeled and the optimal working concentration was found to be 1:500. The levels of antigen in a proportion of HCC patients were shown to be significantly higher compared to those found in healthy controls. PMID- 23727930 TI - Pharmacokinetics and tissue distribution of a bioactive sesquiterpenoid from Polygonum jucundum following oral and intravenous administrations to rats. AB - Polygonum jucundum is a traditional Chinese medicine used for the treatment of diseases. The major bioactive compound in the ethanol extract of P. jucundum is 2alpha-hydroxyl-3beta-angeloylcinnamolide (HAC), a drimane-type sesquiterpenoid, which possesses anti-inflammatory activities. The purpose of this study was to investigate in vivo pharmacokinetics and tissue distribution of HAC after oral and intravenous administrations to rats by using a reversed-phase high performance liquid chromatography in conjunction with mass spectrometry (LC-MS). Chromatographic separation was achieved on a C18 column within 8 min. Quality control samples for both tissues and plasma demonstrated accuracy and precision within 94.59-107.74% of the nominal values and 1.65-10.77% relative standard derivative (RSD), respectively. The pharmacokinetic profiles, estimated by using non-compartment models, revealed that HAC was rapidly absorbed into the systemic circulation and was widely distributed throughout the body, followed by a rapid elimination phase. The highest amount of HAC was found in kidney, followed in order by lung, heart, spleen and liver. The current paper was the first report on the pharmacokinetic profiles of HAC in rat plasma and tissues after oral and intravenous administrations. It could provide a meaningful insight for the clinical applications of this bioactive compound extracted from the traditional Chinese medicine. PMID- 23727931 TI - A functional CFTR assay using primary cystic fibrosis intestinal organoids. AB - We recently established conditions allowing for long-term expansion of epithelial organoids from intestine, recapitulating essential features of the in vivo tissue architecture. Here we apply this technology to study primary intestinal organoids of people suffering from cystic fibrosis, a disease caused by mutations in CFTR, encoding cystic fibrosis transmembrane conductance regulator. Forskolin induces rapid swelling of organoids derived from healthy controls or wild-type mice, but this effect is strongly reduced in organoids of subjects with cystic fibrosis or in mice carrying the Cftr F508del mutation and is absent in Cftr-deficient organoids. This pattern is phenocopied by CFTR-specific inhibitors. Forskolin induced swelling of in vitro-expanded human control and cystic fibrosis organoids corresponds quantitatively with forskolin-induced anion currents in freshly excised ex vivo rectal biopsies. Function of the CFTR F508del mutant protein is restored by incubation at low temperature, as well as by CFTR-restoring compounds. This relatively simple and robust assay will facilitate diagnosis, functional studies, drug development and personalized medicine approaches in cystic fibrosis. PMID- 23727933 TI - Howyland. PMID- 23727932 TI - Fgf9 from dermal gammadelta T cells induces hair follicle neogenesis after wounding. AB - Understanding molecular mechanisms for regeneration of hair follicles provides new opportunities for developing treatments for hair loss and other skin disorders. Here we show that fibroblast growth factor 9 (Fgf9), initially secreted by gammadelta T cells, modulates hair follicle regeneration after wounding the skin of adult mice. Reducing Fgf9 expression decreases this wound induced hair neogenesis (WIHN). Conversely, overexpression of Fgf9 results in a two- to threefold increase in the number of neogenic hair follicles. We found that Fgf9 from gammadelta T cells triggers Wnt expression and subsequent Wnt activation in wound fibroblasts. Through a unique feedback mechanism, activated fibroblasts then express Fgf9, thus amplifying Wnt activity throughout the wound dermis during a crucial phase of skin regeneration. Notably, humans lack a robust population of resident dermal gammadelta T cells, potentially explaining their inability to regenerate hair after wounding. These findings highlight the essential relationship between the immune system and tissue regeneration. The importance of Fgf9 in hair follicle regeneration suggests that it could be used therapeutically in humans. PMID- 23727934 TI - Epidermal stem cells in orthopaedic regenerative medicine. AB - In the last decade, great advances have been made in epidermal stem cell studies at the cellular and molecular level. These studies reported various subpopulations and differentiations existing in the epidermal stem cell. Although controversies and unknown issues remain, epidermal stem cells possess an immune privileged property in transplantation together with easy accessibility, which is favorable for future clinical application. In this review, we will summarize the biological characteristics of epidermal stem cells, and their potential in orthopedic regenerative medicine. Epidermal stem cells play a critical role via cell replacement, and demonstrate significant translational potential in the treatment of orthopedic injuries and diseases, including treatment for wound healing, peripheral nerve and spinal cord injury, and even muscle and bone remodeling. PMID- 23727936 TI - Wharton's jelly-derived mesenchymal stem cells: phenotypic characterization and optimizing their therapeutic potential for clinical applications. AB - Wharton's jelly (WJ) is a gelatinous tissue within the umbilical cord that contains myofibroblast-like stromal cells. A unique cell population of WJ that has been suggested as displaying the stemness phenotype is the mesenchymal stromal cells (MSCs). Because MSCs' stemness and immune properties appear to be more robustly expressed and functional which are more comparable with fetal than adult-derived MSCs, MSCs harvested from the "young" WJ are considered much more proliferative, immunosuppressive, and even therapeutically active stem cells than those isolated from older, adult tissue sources such as the bone marrow or adipose. The present review discusses the phenotypic characteristics, therapeutic applications, and optimization of experimental protocols for WJ-derived stem cells. MSCs derived from WJ display promising transplantable features, including ease of sourcing, in vitro expandability, differentiation abilities, immune evasion and immune-regulation capacities. Accumulating evidence demonstrates that WJ-derived stem cells possess many potential advantages as transplantable cells for treatment of various diseases (e.g., cancer, chronic liver disease, cardiovascular diseases, nerve, cartilage and tendon injury). Additional studies are warranted to translate the use of WJ-derived stem cells for clinical applications. PMID- 23727935 TI - An overview of biological macromolecule crystallization. AB - The elucidation of the three dimensional structure of biological macromolecules has provided an important contribution to our current understanding of many basic mechanisms involved in life processes. This enormous impact largely results from the ability of X-ray crystallography to provide accurate structural details at atomic resolution that are a prerequisite for a deeper insight on the way in which bio-macromolecules interact with each other to build up supramolecular nano machines capable of performing specialized biological functions. With the advent of high-energy synchrotron sources and the development of sophisticated software to solve X-ray and neutron crystal structures of large molecules, the crystallization step has become even more the bottleneck of a successful structure determination. This review introduces the general aspects of protein crystallization, summarizes conventional and innovative crystallization methods and focuses on the new strategies utilized to improve the success rate of experiments and increase crystal diffraction quality. PMID- 23727937 TI - Towards a molecular understanding of the biosynthesis of amaryllidaceae alkaloids in support of their expanding medical use. AB - The alkaloids characteristically produced by the subfamily Amaryllidoideae of the Amaryllidaceae, bulbous plant species that include well know genera such as Narcissus (daffodils) and Galanthus (snowdrops), are a source of new pharmaceutical compounds. Presently, only the Amaryllidaceae alkaloid galanthamine, an acetylcholinesterase inhibitor used to treat symptoms of Alzheimer's disease, is produced commercially as a drug from cultivated plants. However, several Amaryllidaceae alkaloids have shown great promise as anti-cancer drugs, but their further clinical development is restricted by their limited commercial availability. Amaryllidaceae species have a long history of cultivation and breeding as ornamental bulbs, and phytochemical research has focussed on the diversity in alkaloid content and composition. In contrast to the available pharmacological and phytochemical data, ecological, physiological and molecular aspects of the Amaryllidaceae and their alkaloids are much less explored and the identity of the alkaloid biosynthetic genes is presently unknown. An improved molecular understanding of Amaryllidaceae alkaloid biosynthesis would greatly benefit the rational design of breeding programs to produce cultivars optimised for the production of pharmaceutical compounds and enable biotechnology based approaches. PMID- 23727939 TI - Dietary composition in the treatment of polycystic ovary syndrome: a systematic review to inform evidence-based guidelines. PMID- 23727940 TI - Prevalence of endometriosis diagnosed by laparoscopy in adolescents with dysmenorrhea or chronic pelvic pain: a systematic review. AB - BACKGROUND Endometriosis associated with pain symptoms in adolescents has been extensively reported, but the exact prevalence is unclear because pain symptoms may be atypical and endometriosis can only be diagnosed by laparoscopy. The aim of this paper is to provide a systematic review of the prevalence of endometriosis diagnosed by laparoscopy in adolescents. METHODS A systematic literature search was carried out for relevant articles published between 1980 and 2011 in the databases PUBMED and EMBASE, based on the keywords 'endometriosis', 'laparoscopy', 'adolescents' and 'chronic pelvic pain (CPP)'. In addition, the reference lists of the selected articles were examined. RESULTS Based on 15 selected studies, the overall prevalence of visually confirmed endometriosis was 62% (543/880; range 25-100%) in all adolescent girls undergoing laparoscopic investigation, 75% (237/314) in girls with CPP resistant to treatment, 70% (102/146) in girls with dysmenorrhea and 49% (204/420) in girls with CPP that is not necessarily resistant to treatment. Among the adolescent girls with endometriosis, the overall prevalence of American Society of Reproductive Medicine classified moderate-severe endometriosis was 32% (82/259) in all girls, 16% (17/108) in girls with CPP resistant to treatment, 29% (21/74) in girls with dysmenorrhea and 57% (44/77) in girls with CPP that is not necessarily resistant to treatment. Due to the quality of the included papers an overestimation of the prevalence and/or severity of endometriosis is possible. CONCLUSIONS About two-thirds of adolescent girls with CPP or dysmenorrhea have laparoscopic evidence of endometriosis. About one-third of these adolescents with endometriosis have moderate-severe disease. The value of early detection of endometriosis in symptomatic adolescents and the indications for laparoscopic investigation in adolescents require more research. PMID- 23727941 TI - Cardiac-like flow generator for long-term imaging of endothelial cell responses to circulatory pulsatile flow at microscale. AB - In vitro models of circulatory hemodynamics are required to mimic the microcirculation for study of endothelial cell responses to pulsatile shear stress by live cell imaging. This study reports the design, fabrication and characterisation of a microfluidic device that generates cardiac-like flow in a continuous culture system with a circulatory volume of only 2-3 MUL. The device mimics a single chamber heart, with the following cardiac phases: (1) closure of the ventricle inlet valve, (2) contraction of the ventricle (systole) followed by opening of the outlet valve and (3) relaxation of the ventricle (diastole) with opening of the inlet valve whilst the outlet valve remains closed. Periodic valve states and ventricular contractions were actuated by microprocessor controlled pneumatics. The time-dependent velocity-field was characterised by micro-particle image velocimetry (MU-PIV). MU-PIV observations were used to help tune electronic timing of valve states and ventricular contractions for synthesis of an arterial pulse waveform to study the effect of pulsatile shear stress on bovine artery endothelial cells (BAECs). BAECs elongated and aligned with the direction of shear stress after 48 h of exposure to a pulsatile waveform with a maximum shear stress of 0.42 Pa. The threshold for BAECs alignment and elongation under steady (non-pulsatile) flow reported by Kadohama et al. (2006) is 0.7-1.4 Pa. These cells respond to transient shear stress because the time average shear stress of the pulse waveform to generate this morphological response was only 0.09 Pa, well below the steady flow threshold. The microfluidic pulse generator can simulate circulatory hemodynamics for live cell imaging of shear-induced signalling pathways. PMID- 23727938 TI - Modulation by melatonin of the pathogenesis of inflammatory autoimmune diseases. AB - Melatonin is the major secretory product of the pineal gland during the night and has multiple activities including the regulation of circadian and seasonal rhythms, and antioxidant and anti-inflammatory effects. It also possesses the ability to modulate immune responses by regulation of the T helper 1/2 balance and cytokine production. Autoimmune diseases, which result from the activation of immune cells by autoantigens released from normal tissues, affect around 5% of the population. Activation of autoantigen-specific immune cells leads to subsequent damage of target tissues by these activated cells. Melatonin therapy has been investigated in several animal models of autoimmune disease, where it has a beneficial effect in a number of models excepting rheumatoid arthritis, and has been evaluated in clinical autoimmune diseases including rheumatoid arthritis and ulcerative colitis. This review summarizes and highlights the role and the modulatory effects of melatonin in several inflammatory autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, and inflammatory bowel disease. PMID- 23727943 TI - Assessing dalfampridine efficacy in the physician's office. AB - Dalfampridine (extended release 4-aminopyridine) is shown in three recent randomised controlled trials to improve walking speed in people with multiple sclerosis; however, the trial literature makes it clear that dalfampridine is effective in only a subset of patients. For the neurologist working in an everyday physician's office, a key question arises: How to distinguish the few who experience a meaningful clinical benefit, from the many who do not? This question has not yet been adequately addressed in the available literature. PMID- 23727942 TI - Treatment failure and drug resistance is more frequent in HIV-1 subtype D versus subtype A-infected Ugandans over a 10-year study period. AB - OBJECTIVES: To determine the impact of HIV-1 subtype on treatment outcomes and the emergence of drug resistance in the resource limited setting of Kampala, Uganda. DESIGN: The Joint Clinical Research Centre (JCRC) in Kampala, Uganda has provided over 2000 drug-resistant genotypes (DRGs) over the past 10 years as standard of care for patients failing therapy and 1403 from treatment-naive and experienced patients over the past 10 years have been analyzed for this study. METHOD: Viral loads, CD4 cell count, treatment histories and other relevant clinical data was compared with the infecting HIV-1 subtype and DRGs of Ugandan patients failing treatment. RESULTS: Patients failing HAART with DRGs (n = 937) were more frequently infected with subtype D than expected on the basis of the subtype distribution in the treatment-naive population (n = 655) in Kampala (P < 0.001). Higher proportions of treatment failures among subtype D-infected patients were driven by resistance to nucleoside reverse transcriptase inhibitors (NRTI) (P < 0.0002) more than to non-NRTIs (P > 0.04) or protease inhibitors. CONCLUSION: Higher rates of treatment failure among subtype D as compared with subtype A-infected Ugandans was analogous to the faster disease progression in subtype D-infected patients. The mechanism(s) by which drug resistance may emerge faster in subtype D HIV-1 may relate to higher replicative fitness and increased propensity for a CXCR4 tropism. PMID- 23727944 TI - Emission enhancement and lifetime modification of phosphorescence on silver nanoparticle aggregates. AB - Silver nanoparticle aggregates have been shown to support very large enhancements of fluorescence intensity from organic dye molecules coupled with an extreme reduction in observed fluorescence lifetimes. Here we show that for the same type of aggregates, similar enhancement factors (~75* in intensity and ~3400* in lifetime compared to the native radiative lifetime) are observed for a ruthenium based phosphorescent dye (when taking into account the effect of charge and the excitation/emission wavelengths). Additionally, the inherently long native phosphorescence lifetimes practically enable more detailed analyses of the distribution of lifetimes (compared with the case with fluorescence decays). It was thus possible to unambiguously observe the deviation from mono-exponential decay which we attribute to emission from a distribution of fluorophores with different lifetimes, as we could expect from a random aggregation process. We believe that combining phosphorescent dyes with plasmonic structures, even down to the single dye level, will offer a convenient approach to better characterize plasmonic systems in detail. PMID- 23727945 TI - Coating with mesoporous silica remarkably enhances the stability of the highly active yet fragile flower-like MgO catalyst for dimethyl carbonate synthesis. AB - Flower-like MgO is a highly effective catalyst for the synthesis of dimethyl carbonate through the transesterification method, and coating the catalyst with mesoporous silica significantly enhances the stability of the MgO catalyst. PMID- 23727946 TI - New angiotensin II type 1 receptor blocker, azilsartan, attenuates cardiac remodeling after myocardial infarction. AB - After an acute myocardial infarction (MI), neurohumoral systems including renin angiotensin-aldosterone system (RAAS) are activated which in turn aggravate cardiac remodeling. Angiotensin receptor blockers (ARBs) are useful drugs for suppression of RAAS. The purpose of this study was to evaluate a new ARB, azilsartan, for suppressing cardiac remodeling and progression to heart failure after MI. We created MI by left anterior descending coronary artery ligation in male mice, and these mice were orally administered saline (0.2 mL) in the control group (Group C), 0.1 mg/kg/d of azilsartan in the low dose group (Group L), and 1.0 mg/kg/d in the high dose group (Group H) everyday. Blood pressure was decreased in Group H, but not in Group L, compared to Group C. At 2 weeks after MI creation, infarct size and fibrotic change at the site remote to the myocardial infarcted area were attenuated in Group L and Group H compared to Group C. Echocardiography revealed that cardiac remodeling was suppressed in Group L and Group H compared to Group C. Increases of mRNA expression levels related to fibrotic change were attenuated in Group L and Group H compared to Group C. The new ARB, azilsartan, had a cardiac remodeling suppression effect after MI, and this effect was observed without blood pressure lowering. PMID- 23727947 TI - Fatigue property of a bioabsorbable magnesium alloy with a hydroxyapatite coating formed by a chemical solution deposition. AB - A hydroxyapatite (HAp) coating was directly formed on an extruded AZ31 magnesium alloy by a single-step chemical solution deposition. The HAp coating consists of an outer porous HAp layer, an inner continuous HAp layer, and a thin intermediate MgO layer, and the inner HAp and MgO layers are composed of nanocrystals. Tensile and fatigue tests were performed on the HAp-coated AZ31 in air. The HAp coating microscopically showed neither crack nor detachment at 5% static elongation (1.5% residual strain). With further elongation under tensile stress, cracks were formed perpendicularly to the tensile direction, and fragments of the coating detached with a fracture inside the inner continuous HAp layer. The fatigue strengths at 10(7) cycles (fatigue limit) of HAp-coated and mechanically polished AZ31 were ca. 80 MPa and ca. 90 MPa, respectively. The slight decrease in the fatigue limit with the HAp coating is attributed to small pits with a depth of ca. 10 MUm formed on the substrate during the HAp-coating treatment. The HAp coating remained on the specimen without cracks after 10(7) cycles at the fatigue limit, which provides ca. 3% cyclic elongation. PMID- 23727948 TI - Titanium dxy ferromagnetism at the LaAlO3/SrTiO3 interface. AB - A number of recent transport and magnetization studies have shown signs of ferromagnetism in the LaAlO3/SrTiO3 heterostructure, an unexpected property with no bulk analogue in the constituent materials. However, no experiment thus far has provided direct information on the host of the magnetism. Here we report spectroscopic investigations of the magnetism using element-specific techniques, including X-ray magnetic circular dichroism and X-ray absorption spectroscopy, along with corresponding model calculations. We find direct evidence for in-plane ferromagnetic order at the interface, with Ti(3+) character in the dxy orbital of the anisotropic t2g band. These findings establish a striking example of emergent phenomena at oxide interfaces. PMID- 23727949 TI - Microstructure formation in molecular and polymer semiconductors assisted by nucleation agents. AB - Additives, including nucleating agents, have been used to regulate the solidification process of (semi-)crystalline polymer solids and thus control both their crystallite dimensions and shape. Here, we demonstrate that minute amounts (0.1-1 wt%) of commercially available nucleating agents can be used to efficiently manipulate the solidification kinetics of a wide range of organic semiconductors--including poly(3-alkylthiophene)s, the fullerene derivative [6,6] phenyl-C61-butyric acid methyl ester (PCBM) and 6,13-bis(triisopropyl silylethynyl) (TIPS) pentacene--when processed from the melt, solution or solid state, without adversely affecting the semiconductors' electronic properties. Heterogeneous nucleation increases the temperature of and rate of crystallization of poly(3-alkylthiophene)s, permits patterning of crystallites at pre-defined locations in PCBM, and minimizes dewetting of films of TIPS-pentacene formed by inkjet printing. Nucleating agents thus make possible the fabrication of thin film transistors with uniform electrical characteristics at high yield. PMID- 23727950 TI - Organic semiconductors: Made to order. PMID- 23727951 TI - Solution coating of large-area organic semiconductor thin films with aligned single-crystalline domains. AB - Solution coating of organic semiconductors offers great potential for achieving low-cost manufacturing of large-area and flexible electronics. However, the rapid coating speed needed for industrial-scale production poses challenges to the control of thin-film morphology. Here, we report an approach--termed fluid enhanced crystal engineering (FLUENCE)--that allows for a high degree of morphological control of solution-printed thin films. We designed a micropillar patterned printing blade to induce recirculation in the ink for enhancing crystal growth, and engineered the curvature of the ink meniscus to control crystal nucleation. Using FLUENCE, we demonstrate the fast coating and patterning of millimetre-wide, centimetre-long, highly aligned single-crystalline organic semiconductor thin films. In particular, we fabricated thin films of 6,13 bis(triisopropylsilylethynyl) pentacene having non-equilibrium single-crystalline domains and an unprecedented average and maximum mobilities of 8.1+/-1.2 cm(2) V( 1) s(-1) and 11 cm(2) V(-1) s(-1). FLUENCE of organic semiconductors with non equilibrium single-crystalline domains may find use in the fabrication of high performance, large-area printed electronics. PMID- 23727952 TI - Radiosensitizing effect of oleanolic acid on tumor cells through the inhibition of GSH synthesis in vitro. AB - Oleanolic acid (OA) is a natural pentacyclic triterpenoid that has been used in traditional medicine as an anticancer and anti-inflammatory agent. The aim of our study was to investigate whether or not OA increases the radiosensivity of tumor cells, and the relative mechanism was also investigated. Clonogenic assay was used to observe the radiosensitivity of C6 and A549 cells following different treatments. The alteration of intracellular DNA damage was determined using a micronucleus (MN) assay. In order to identify the mechanism of OA-mediated radiosensitization of tumor cells, the levels of glutathione (GSH) in irradiated cells following various pretreatments were determined using glutathione reductase/5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) recycling assay. Under the same condition, the activities of gamma-glutamylcysteine synthetase (gamma-GCS) and GSH synthase (GSS), both key enzymes for GSH synthesis, were detected using appropriate methods. In order to confirm the radiosensitizing effect of OA on cancer cells by attenuating GSH, N-acetylcysteine (NAC) was added to cells in culture for 12 h before irradiation. The results showed that the combined treatment of radiation with OA significantly decreased the clonogenic growth of tumor cells and enhanced the numbers of intracellular MN compared to irradiation alone. Furthermore, it was found that the synthesis of cellular GSH was inhibited concomitantly with the downregulation of gamma-GCS activity. Therefore, the utilization of OA as a radiosensitizing agent for irradiation-inducing cell death offers a potential therapeutic approach to treat cancer. PMID- 23727953 TI - Distributed fiber optical sensing of oxygen with optical time domain reflectometry. AB - In many biological and environmental applications spatially resolved sensing of molecular oxygen is desirable. A powerful tool for distributed measurements is optical time domain reflectometry (OTDR) which is often used in the field of telecommunications. We combine this technique with a novel optical oxygen sensor dye, triangular-[4] phenylene (TP), immobilized in a polymer matrix. The TP luminescence decay time is 86 ns. The short decay time of the sensor dye is suitable to achieve a spatial resolution of some meters. In this paper we present the development and characterization of a reflectometer in the UV range of the electromagnetic spectrum as well as optical oxygen sensing with different fiber arrangements. PMID- 23727954 TI - Decoupling intensity radiated by the emitter in distance estimation from camera to IR emitter. AB - Various models using radiometric approach have been proposed to solve the problem of estimating the distance between a camera and an infrared emitter diode (IRED). They depend directly on the radiant intensity of the emitter, set by the IRED bias current. As is known, this current presents a drift with temperature, which will be transferred to the distance estimation method. This paper proposes an alternative approach to remove temperature drift in the distance estimation method by eliminating the dependence on radiant intensity. The main aim was to use the relative accumulated energy together with other defined models, such as the zeroth-frequency component of the FFT of the IRED image and the standard deviation of pixel gray level intensities in the region of interest containing the IRED image. By using the abovementioned models, an expression free of IRED radiant intensity was obtained. Furthermore, the final model permitted simultaneous estimation of the distance between the IRED and the camera and the IRED orientation angle. The alternative presented in this paper gave a 3% maximum relative error over a range of distances up to 3 m. PMID- 23727955 TI - Cross-modal sensory integration of visual-tactile motion information: instrument design and human psychophysics. AB - Information obtained from multiple sensory modalities, such as vision and touch, is integrated to yield a holistic percept. As a haptic approach usually involves cross-modal sensory experiences, it is necessary to develop an apparatus that can characterize how a biological system integrates visual-tactile sensory information as well as how a robotic device infers object information emanating from both vision and touch. In the present study, we develop a novel visual tactile cross-modal integration stimulator that consists of an LED panel to present visual stimuli and a tactile stimulator with three degrees of freedom that can present tactile motion stimuli with arbitrary motion direction, speed, and indentation depth in the skin. The apparatus can present cross-modal stimuli in which the spatial locations of visual and tactile stimulations are perfectly aligned. We presented visual-tactile stimuli in which the visual and tactile directions were either congruent or incongruent, and human observers reported the perceived visual direction of motion. Results showed that perceived direction of visual motion can be biased by the direction of tactile motion when visual signals are weakened. The results also showed that the visual-tactile motion integration follows the rule of temporal congruency of multi-modal inputs, a fundamental property known for cross-modal integration. PMID- 23727956 TI - Improvements to and comparison of static terrestrial LiDAR self-calibration methods. AB - Terrestrial laser scanners are sophisticated instruments that operate much like high-speed total stations. It has previously been shown that unmodelled systematic errors can exist in modern terrestrial laser scanners that deteriorate their geometric measurement precision and accuracy. Typically, signalised targets are used in point-based self-calibrations to identify and model the systematic errors. Although this method has proven its effectiveness, a large quantity of signalised targets is required and is therefore labour-intensive and limits its practicality. In recent years, feature-based self-calibration of aerial, mobile terrestrial, and static terrestrial laser scanning systems has been demonstrated. In this paper, the commonalities and differences between point-based and plane based self-calibration (in terms of model identification and parameter correlation) are explored. The results of this research indicate that much of the knowledge from point-based self-calibration can be directly transferred to plane based calibration and that the two calibration approaches are nearly equivalent. New network configurations, such as the inclusion of tilted scans, were also studied and prove to be an effective means for strengthening the self-calibration solution, and improved recoverability of the horizontal collimation axis error for hybrid scanners, which has always posed a challenge in the past. PMID- 23727957 TI - Circular code motifs in transfer RNAs. AB - In 1996, a trinucleotide circular code X is identified in genes of prokaryotes and eukaryotes (Arques and Michel, 1996). In 2012, X motifs are identified in the transfer RNA (tRNA) Phe and 16S ribosomal RNA (Michel, 2012). A statistical analysis of X motifs in all available tRNAs of prokaryotes and eukaryotes in the genomic tRNA database (September 2012, http://lowelab.ucsc.edu/GtRNAdb/, Lowe and Eddy, 1997) is carried out here. For this purpose, a search algorithm of X motifs in a DNA sequence is developed. Two definitions allow to determine the occurrence probabilities of X motifs and the circular codes X, X1=P(X) and X2=P(2)(X) (P being a circular permutation map applied on X) in a population of tRNAs. This approach identifies X motifs in the 5' and/or 3' regions of 16 isoaccepting tRNAs (except for the tRNAs Arg, His, Ser and Trp). The statistical analyses are performed on different and large tRNA populations according to the taxonomy (prokaryotes and eukaryotes), tRNA length and tRNA score. Finally, a circular code property observed in genes of prokaryotes and eukaryotes is identified in the 3' regions of 19 isoaccepting tRNAs of prokaryotes and eukaryotes (except for the tRNA Leu). The identification of X motifs and a gene circular code property in tRNAs strengthens the concept proposed in Michel (2012) of a possible translation (framing) code based on a circular code. PMID- 23727958 TI - Has the Foundation for Physical Therapy advanced the body of knowledge? PMID- 23727959 TI - Clarification on the scoring of the Mini-BESTest. PMID- 23727960 TI - Implementing the obesity care model at a community health center in Hawaii to address childhood obesity. AB - Obesity, the most common chronic disease of childhood, is prevalent among economically disadvantaged children. The Chronic Care and Obesity Care Models are comprehensive health care strategies to improve outcomes by linking primary care best practices and community-based programs. Pediatric providers and community health centers are well positioned to design and implement coordinated and synergistic programs to address childhood health disparities. This article describes a comprehensive project based on the Obesity Care Model initiated at a rural community health center in Hawaii to address childhood obesity including: (1) the health care delivery changes constituting the quality improvement project; (2) capacity and team-building activities; (3) use of the project community level data to strengthen community engagement and investment; and (4) the academic-community partnership providing the project framework. We anticipate that these efforts will contribute to the long-term goal of reducing the prevalence of obesity and obesity associated morbidity in the community. PMID- 23727961 TI - Improving overweight among at-risk minority youth: results of a pilot intervention in after-school programs. AB - Childhood overweight and obesity disproportionately affect low-income communities. Most school-based health promotion efforts occur during the school day and are limited in scope. This study evaluated the effectiveness of an after school program among 3rd-5th graders (n=121; 73% 8 to 9 years old; 57% female; 60% Asian) at eight study sites (four intervention, four comparison). After school staff were trained on implementing the Catch Kids Club Curriculum on nutrition and physical activity. Data were collected on students' nutrition and physical activity knowledge and behavior, and their height and weight measurements. Using Stata 10.1/SE, cross-lagged regression models assessed changes over time. Results showed a reduction in overweight and obesity (defined as body mass index >85th percentile for age and sex) among children in the intervention group, but mixed results regarding diet and physical activity knowledge and behavior. Enhancing after-school physical activity opportunities through evidence-based programs can potentially improve overweight and obesity among low-income children. PMID- 23727962 TI - Evaluation of a childhood obesity awareness campaign targeting head start families: designed by parents for parents. AB - The Communities for Healthy Living program used a community-based participatory research (CBPR) approach to empower Head Start parents in designing and pilot testing a multi-component family-centered obesity prevention program. One program component was a childhood obesity awareness campaign addressing common parental misconceptions about obesity. The campaign was designed by a community advisory board of parents to target specific issues identified within their own community. Results from pre-post intervention surveys (N=108) showed that campaign exposure was high; 92% of responding parents reported noticing the campaign. Parents also demonstrated significant increases in awareness of childhood obesity, along with decreases in obesity-related misconceptions. Findings, supported by growing literature on CBPR, suggest a CBPR approach to campaign development is an effective strategy to promote parent awareness of childhood obesity. PMID- 23727963 TI - Screening and management of obesity and perception of weight status in Medicaid recipients. AB - OBJECTIVE: We sought to identify any correlations among primary care provider weight screening and counseling, patient weight perception, and weight loss attempt. METHODS: We performed a cross-sectional analysis of obesity-related questions from 2009 and 2010 Kentucky Medicaid Adult Patient and Provider survey data. RESULTS: 1,510 patients [46% obese (body mass index (BMI) >=30 kg/m2), 26% overweight (BMI 25 to <30), 26% normal weight (BMI 18 to <25), and 2% underweight (BMI<18)] and 787 providers (41% primary care) met criteria. Patients and providers differed on report of physician weight loss counseling (46% versus 92%). Patient report of physician weight loss counseling and weight loss attempt were positively correlated (77% with versus 38% without counseling, p<.01). One fifth of patients underperceived their weight. Patients reporting physician weight counseling were less likely to underperceive their weight (13% versus 23%, p<.0001). CONCLUSIONS: Weight loss attempt and accurate weight perception were positively correlated with physician weight discussion. PMID- 23727964 TI - Combating Obesity at Community Health Centers (COACH): a quality improvement collaborative for weight management programs. AB - Community health centers (CHCs) seek effective strategies to address obesity. MidWest Clinicians' Network partnered with [an academic medical center] to test feasibility of a weight management quality improvement (QI) collaborative. MidWest Clinicians' Network members expressed interest in an obesity QI program. This pilot study aimed to determine whether the QI model can be feasibly implemented with limited resources at CHCs to improve weight management programs. Five health centers with weight management programs enrolled with CHC staff as primary study participants; this study did not attempt to measure patient outcomes. Participants attended learning sessions and monthly conference calls to build QI skills and share best practices. Tailored coaching addressed local needs. Topics rated most valuable were patient recruitment/retention strategies, QI techniques, evidence-based weight management, motivational interviewing. Challenges included garnering provider support, high staff turnover, and difficulty tracking patient-level data. This paper reports practical lessons about implementing a weight management QI collaborative in CHCs. PMID- 23727965 TI - Action-learning collaboratives as a platform for community-based participatory research to advance obesity prevention. AB - Although process elements that define community-based participatory research (CBPR) are well articulated and provide guidance for bringing together researchers and communities, additional models to implement CBPR are needed. One potential model for implementing and monitoring CBPR is Action Learning Collaboratives (ALCs); short term, team-based learning processes that are grounded in quality improvement. Since 2010, the Prevention Research Center at Dartmouth (PRCD) has used ALCs with three communities as a platform to design, implement and evaluate CBPR. The first ALC provided an opportunity for academia and community leadership to strengthen their relationships and knowledge of respective assets through design and evaluation of community-based QI projects. Building on this work, we jointly designed and are implementing a second ALC, a cross-community research project focused on obesity prevention in vulnerable populations. An enhanced community capacity now exists to support CBPR activities with a high degree of sophistication and decreased reliance on external facilitation. PMID- 23727966 TI - San Diego Healthy Weight Collaborative: a systems approach to address childhood obesity. AB - A collaborative approach to identify opportunities for interactions between multiple systems is an important model for childhood obesity prevention. This paper describes a process aligning multiple partners in primary care, public health, university research, schools, and community organizations. Jointly implemented strategies in a Latino underserved community included: (1) building an effective and sustainable collaborative team; (2) disseminating a healthy weight message across sectors; (3) assessing weight status and healthy weight plans in primary care, school, and early childhood settings; and (4) implementing policy changes to support healthy eating and physical activity. The process and lessons learned were analyzed so other communities can utilize a systems approach to develop culturally appropriate interventions tailored to a specific community. PMID- 23727967 TI - A community-academic partnership to promote student health and education outcomes. AB - Rising childhood obesity rates have spurred the government and school districts to legislate school wellness policies. Policy formulation must be paired with policy implementation. This article describes how a school-wide health education program addressed the needs of students, faculty, and parents while advancing academic achievement. PMID- 23727968 TI - The Healthy Weight Collaborative: using learning collaboratives to enhance community-based prevention initiatives addressing childhood obesity. AB - This report from the field describes the design, implementation, and early evaluation results of the Healthy Weight Collaborative, a federally-supported learning collaborative to develop, test, and disseminate an integrated change package of six promising, evidence-based clinical and community-based strategies to prevent and treat obesity for children and families. PMID- 23727969 TI - Unidas por la Vida (United for Life): implementing a culturally-tailored, community-based, family-oriented lifestyle intervention. AB - Unidas por la Vida, a behavioral weight-loss program, was developed for use among low-income, Mexican-American women with diabetes and their overweight/obese adult daughters. The program leverages community resources in a partnership between primary care and community-based organizations. This paper describes the program's implementation, lessons learned, and implications for sustainability. PMID- 23727970 TI - Family-based risk reduction of obesity and metabolic syndrome: an overview and outcomes of the Idaho Partnership for Hispanic Health. AB - Mexican American women have the highest incidence of metabolic syndrome among all U.S. demographic groups. This paper details an innovative approach to reducing the risks for metabolic syndrome among Hispanic families in rural Idaho. Companeros en Salud (CeS) is a promotora-led wellness program and community-based participatory research project from the Idaho Partnership for Hispanic Health. As behavior change is the first line of prevention and treatment of obesity and metabolic syndrome, the program aimed to improve nutrition and physical activity behaviors as well as increase community support and infrastructure for healthy living. CeS has demonstrated substantial improvement in health outcomes, with statistically significant reductions in weight, BMI, metabolic syndrome risk, A1c, glucose, blood pressure, and cholesterol, from pre-intervention to post intervention and/or pre-intervention to one-year follow-up. These outcomes suggest the CeS model as a promising best practice for effecting individual and family-level physiologic and behavioral outcomes for obesity prevention. PMID- 23727971 TI - Increasing consumption of fruits and vegetables in the school cafeteria: the influence of active choice. AB - This study evaluated a setting-level intervention designed to increase consumption of fruits and vegetables among low-socioeconomic status elementary and middle school students participating in the National School Lunch Program (NSLP). The NSLP provides students with access to fruits and vegetables; however, food served does not necessarily equal food consumed. High rates of waste, especially of fruits and vegetables, are well documented. The current, low-cost intervention altered the choice architecture of the cafeteria by introducing an active, forced choice into the school lunch service. Consumption was measured by observing (n=2,064) and weighing (n=84) student plate waste over two 10-day periods pre-intervention and during implementation. Results show an average daily 15% increase in consumption of both fruits and vegetables during the intervention period. These findings suggest that local schools can actively encourage students to take advantage of fruits and vegetables offered through the NSLP by implementing setting-level changes to the cafeteria environment. PMID- 23727972 TI - Linking pediatric primary care obesity management to community programs. AB - Guidelines for obesity management in primary care call for linking to community services. The Promoting Health Project (PHP) was a multi-component, practice based intervention aimed at improving care of obese children, including referrals to community services. Promoting Health Project staff identified and interviewed representatives of 40 nutrition or physical activity services/programs. Quality improvement (QI) teams at three practices worked to improve overweight/obesity identification and care and implement practice-to-community connections that used the information gathered from the programs/ services. A practice community coordinator (PCC) facilitated interactions between practices, community programs and families. Researchers tracked patients referred, PCC to family interactions, and time spent. They surveyed parents of referred patients and interviewed key clinicians. Forty-six patients participated in programs. Substantial efforts were necessary to create smooth referral systems. Family motivation was perceived as a limiting factor in program attendance. Clinicians were satisfied with systems established. Effectively linking practitioners to community programs requires the use of additional resources. PMID- 23727974 TI - Accelerating progress in reducing childhood obesity disparities: exploring best practices of positive outliers. AB - Childhood obesity rates may have plateaued in some U.S. population subgroups, yet overall rates remain high and racial/ethnic and socioeconomic disparities appear to be widening. Successful strategies and best practices to inform obesity interventions and accelerate progress in reducing disparities in childhood obesity can be found among people who can be categorized as positive outliers, i.e., individuals who have succeeded, where many others have not, in changing their health behaviors, reducing their body mass index, and developing resilience in the context of adverse built and social environments. In this commentary, we discuss the central premise of a positive outlier approach and how successful strategies learned from positive outliers can be generalized and promoted to accelerate progress in childhood obesity. PMID- 23727973 TI - Best practices in policy approaches to obesity prevention. AB - The rapidly rising rate of obesity has prompted a variety of policy responses at national, regional, and local levels. Yet, many have expressed concern that these policy responses have a limited evidence base, are overly paternalistic, and have the potential to increase rather than shrink obesity-related disparities. The purpose of this article is to evaluate obesity policies in terms of the adequacy of evidence for action and along two ethical dimensions: their potential effect on liberty and equity. To evaluate evidence, we engage in a systematic review of reviews and rate policies in terms of the sufficiency of evidence of effectiveness at combating obesity. We then apply a libertarian-paternalist framework to assess policies in terms of their impact on liberty and inverse equity theory to assess impact on disparities. This article provides a framework to assist decision-makers in assessing best practices in obesity using a more multi-faceted set of dimensions. PMID- 23727975 TI - Foreword from Director of the National Institute on Minority Health and Health Disparities (NIMHD), National Institutes of Health (NIH). PMID- 23727976 TI - Advancing obesity prevention: emerging models and best practices. PMID- 23727977 TI - A note from the guest editors. PMID- 23727978 TI - Sequential multi-molecule delivery using vortex-assisted electroporation. AB - We developed an on-chip microscale electroporation system that enables sequential delivery of multiple molecules with precise and independent dosage controllability into pre-selected identical populations of target cells. The ability to trap cells with uniform size distribution contributed to enhanced molecular delivery efficiency and cell viability. Additionally, the system provides real-time monitoring ability of the entire delivery process, allowing timely and independent modification of cell- and molecule-specific electroporation parameters. The precisely controlled amount of inherently membrane-impermeant molecules was transferred into human cancer cells by varying electric field strengths and molecule injection durations. The proposed microfluidic electroporation system's improved viability and comparable gene transfection efficiency to that of commercial systems suggest that the current system has great potential to expand the research fields that on-chip electroporation techniques can be used in. PMID- 23727979 TI - The evolution of complexity in the visual systems of stomatopods: insights from transcriptomics. AB - Stomatopod crustaceans have complex visual systems containing up to 16 different spectral classes of photoreceptors, more than described for any other animal. A previous molecular study of this visual system focusing on the expression of opsin genes found many more transcripts than predicted on the basis of physiology, but was unable to fully document the expressed opsin genes responsible for this diversity. Furthermore, questions remain about how other components of phototransduction cascades are involved. This study continues prior investigations by examining the molecular function of stomatopods' visual systems using new whole eye 454 transcriptome datasets from two species, Hemisquilla californiensis and Pseudosquilla ciliata. These two species represent taxonomic diversity within the order Stomatopoda, as well as variations in the anatomy and physiology of the visual system. Using an evolutionary placement algorithm to annotate the transcriptome, we identified the presence of nine components of the stomatopods' G-protein-coupled receptor (GPCR) phototransduction cascade, including two visual arrestins, subunits of the heterotrimeric G-protein, phospholipase C, transient receptor potential channels, and opsin transcripts. The set of expressed transduction genes suggests that stomatopods utilize a Gq mediated GPCR-signaling cascade. The most notable difference in expression between the phototransduction cascades of the two species was the number of opsin contigs recovered, with 18 contigs found in retinas of H. californiensis, and 49 contigs in those of P. ciliata. Based on phylogenetic placement and fragment overlap, these contigs were estimated to represent 14 and 33 expressed transcripts, respectively. These data expand the known opsin diversity in stomatopods to clades of arthropod opsins that are sensitive to short wavelengths and ultraviolet wavelengths and confirm the results of previous studies recovering more opsin transcripts than spectrally distinct types of photoreceptors. Many of the recovered transcripts were phylogenetically placed in an evolutionary clade of crustacean opsin sequences that is rapidly expanding as the visual systems from more species are investigated. We discuss these results in relation to the emerging pattern, particularly in crustacean visual systems, of the expression of multiple opsin transcripts in photoreceptors of the same spectral class, and even in single photoreceptor cells. PMID- 23727980 TI - 'What is professional ethics?'. AB - The very term 'professional ethics' is puzzling with respect to what both 'professional' and 'ethics' might mean. I argue (1) that professionalism is ambiguous as to whether or not it is implicitly committed to ethical practice; (2) that to be 'professionally' ethical is at best ambiguous, if not in fact bizarre; and (3) that, taken together, these considerations suggest that professional ethics is something to be avoided rather than lauded. PMID- 23727982 TI - Stem cell factor combined with matrix proteins regulates the attachment and migration of melanocyte precursors of human hair follicles in vitro. AB - In conjunction with matrix proteins, stem cell factor (SCF) plays an important role in the migration of melanocyte precursors (MPs) derived from the mouse embryo. However, no studies have demonstrated an effect of SCF on human follicular MPs migration in vitro. In this report, first we demonstrate the immature state of the follicular MPs. Then cell attachment rate was measured by 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Standard 48 well chemotaxis chambers were used for a transfilter migration assay. F-actin was labeled by rhodamine-conjugated phalloidin, and then organization of the actin cytoskeleton was observed by confocal microscope. In the results, we directly show that MPs adhere more strongly to fibronectin (FN), laminin (LN) and type IV collagen (CIV) than to the negative control. SCF decreased the adhesion of MPs to FN and CIV. A chemotaxis analysis showed that FN and CIV have chemotactic effects on MPs. FN showed an obvious increase in chemotactic effects on MPs with SCF treatment comparing with the control group, but there were no significant changes in the levels of chemotaxis with CIV and LN when the cells were treated with SCF. SCF was chemotactic to MPs, and the presence of FN caused a statistically significant increase in MPs migration at various concentrations of SCF. Furthermore, we showed that SCF, in combination with FN, could induce an apparent increase in actin stress fiber formation in MPs. Our results indicate that SCF, in combination with matrix proteins and in particular with FN, regulates the movement of MPs by both altering cell attachment and increasing cell chemotaxis. PMID- 23727983 TI - Janus micro-reactors. AB - Janus hollow spheres, with different compositions compartmentalized onto both interior and exterior surfaces of the same shell and P25 nanoparticles encapsulated in the cavities, are synthesized by the ultrasonic spray method to selectively enrich desired reagents in a confined environment for further reaction. PMID- 23727981 TI - Risk factors for delayed initiation of combination antiretroviral therapy in rural north central Nigeria. AB - BACKGROUND: Timely initiation of combination antiretroviral therapy (ART) in eligible HIV-infected patients is associated with substantial reduction in mortality and morbidity. Nigeria has the second largest number of persons living with HIV/AIDS in the world. We examined patient characteristics, time to ART initiation, retention, and mortality at 5 rural facilities in Kwara and Niger states of Nigeria. METHODS: We analyzed program-level cohort data for HIV infected ART-naive clients (>=15 years) enrolled from June 2009 to February 2011. We modeled the probability of ART initiation among clients meeting national ART eligibility criteria using logistic regression with splines. RESULTS: We enrolled 1948 ART-naive adults/adolescents into care, of whom, 1174 were ART eligible (62% female). Only 74% of the eligible patients (n = 869) initiated ART within 90 days after enrollment. The median CD4 count for eligible clients was 156 cells/MUL (interquartile range: 81-257), with 67% in WHO stage III/IV disease. Adjusting for CD4 count, WHO stage, functional status, hemoglobin, body mass index, sex, age, education, marital status, employment, clinic of attendance, and month of enrollment, we found that immunosuppression [CD4 350 vs. 200, odds ratio (OR) = 2.10, 95% confidence interval (CI): 1.31 to 3.35], functional status [bedridden vs. working, OR = 4.17 (95% CI: 1.63 to 10.67)], clinic of attendance [Kuta Hospital vs. referent: OR = 5.70 (95% CI: 2.99 to 10.89)], and date of enrollment [December 2010 vs. June 2009: OR = 2.13 (95% CI: 1.19 to 3.81)] were associated with delayed ART initiation. CONCLUSIONS: Delayed initiation of ART was associated with higher CD4 counts, lower functional status, clinic of attendance, and later dates of enrollment among ART-eligible clients. Our findings provide targets for quality improvement efforts that may help reduce attrition and improve ART uptake in similar settings. PMID- 23727984 TI - The pathogenic A391E mutation in FGFR3 induces a structural change in the transmembrane domain dimer. AB - Fibroblast growth factor receptor 3 (FGFR3) is a single-pass membrane protein and a member of the receptor tyrosine kinase family of proteins that is involved in the regulation of skeletal growth and development. FGFR3 has three distinct domains: the ligand binding extracellular domain, the cytosolic kinase domain and the transmembrane domain (TMD). Previous work with the isolated FGFR3 TMD has shown that it has the ability to dimerize. Clinical and genetic studies have also correlated mutations in the TMD with a variety of skeletal and cranial dysplasias and cancer. Although the structures of the extracellular and cytosolic domains of FGFR3 have been solved, the structure of the TMD dimer is still unknown. Furthermore, very little is known regarding the effects of pathogenic mutations on the TMD dimer structure. We, therefore, carried out ToxR activity assays to determine the role of the SmXXXSm motif in the dimerization of the FGFR3 TMD. This motif has been shown to drive the association of many transmembrane proteins. Our results indicate that the interaction between wild-type FGFR3 TMDs is not mediated by two adjacent SmXXXSm motifs. In contrast, studies using the TMD carrying the pathogenic A391E mutation suggest that the motifs play a role in the dimerization of the mutant TMD. Based on these observations, here we report a new mechanistic model in which the pathogenic A391E mutation induces a structural change that leads to the formation of a more stable dimer. PMID- 23727985 TI - Sequence-dependent thymine dimer formation and photoreversal rates in double stranded DNA. AB - The kinetics of thymine-thymine cyclobutane pyrimidine dimer (TT-CPD) formation was studied at 23 thymine-thymine base steps in two 247-base pair DNA sequences irradiated at 254 nm. Damage was assayed site-specifically and simultaneously on both the forward and reverse strands by detecting emission from distinguishable fluorescent labels at the 5'-termini of fragments cleaved at CPD sites by T4 pyrimidine dimer glycosylase and separated by gel electrophoresis. The total DNA strand length of nearly 1000 bases made it possible to monitor damage at all 9 tetrads of the type XTTY, where X and Y are non-thymine bases. TT-CPD yields for different tetrads were found to vary by as much as an order of magnitude, but similar yields were observed at all instances of a given tetrad. Kinetic analysis of CPD formation at 23 distinct sites reveals that both the formation and reversal photoreactions depend sensitively on the identity of the nearest neighbour bases on the 5' and the 3' side of a photoreactive TT base step. The lowest formation and reversal rates occur when two purine bases flank a TT step, while the highest formation and reversal rates are observed for tetrads with at least one flanking C. Overall, the results show that the probabilities of CPD formation and photoreversal depend principally on interactions with nearest neighbour bases. PMID- 23727986 TI - Enzymatic production of 'monoclonal stoichiometric' single-stranded DNA oligonucleotides. AB - Single-stranded oligonucleotides are important as research tools, as diagnostic probes, in gene therapy and in DNA nanotechnology. Oligonucleotides are typically produced via solid-phase synthesis, using polymer chemistries that are limited relative to what biological systems produce. The number of errors in synthetic DNA increases with oligonucleotide length, and the resulting diversity of sequences can be a problem. Here we present the 'monoclonal stoichiometric' (MOSIC) method for enzyme-mediated production of DNA oligonucleotides. We amplified oligonucleotides from clonal templates derived from single bacterial colonies and then digested cutter hairpins in the products, which released pools of oligonucleotides with precisely controlled relative stoichiometric ratios. We prepared 14-378-nucleotide MOSIC oligonucleotides either by in vitro rolling circle amplification or by amplification of phagemid DNA in Escherichia coli. Analyses of the formation of a DNA crystal and folding of DNA nanostructures confirmed the scalability, purity and stoichiometry of the produced oligonucleotides. PMID- 23727987 TI - Characterization of 582 natural and synthetic terminators and quantification of their design constraints. AB - Large genetic engineering projects require more cistrons and consequently more strong and reliable transcriptional terminators. We have measured the strengths of a library of terminators, including 227 that are annotated in Escherichia coli -90 of which we also tested in the reverse orientation--and 265 synthetic terminators. Within this library we found 39 strong terminators, yielding >50 fold reduction in downstream expression, that have sufficient sequence diversity to reduce homologous recombination when used together in a design. We used these data to determine how the terminator sequence contributes to its strength. The dominant parameters were incorporated into a biophysical model that considers the role of the hairpin in the displacement of the U-tract from the DNA. The availability of many terminators of varying strength, as well as an understanding of the sequence dependence of their properties, will extend their usability in the forward design of synthetic cistrons. PMID- 23727988 TI - Effects of external electric fields on lysozyme adsorption by molecular dynamics simulations. AB - Lysozyme adsorption on carboxyl-terminated self-assembled monolayers under external electric fields has been studied by all-atom molecular dynamics simulations. Lysozyme adsorption on negatively charged surfaces could generally be enhanced by positive electric fields and retarded by negative ones. Under positive electric fields, electrostatic interactions between protein and surface are strengthened; however, the interaction energy descends with field strength increases probably due to the co-adsorption of counterions onto the surface to neutralize surface charge. Comparison of orientation distributions of lysozyme adsorption on the surface in the presence and in the absence of electric fields reveals that an applied electric field could narrow the distribution and therefore helps to immobilize protein on surface with uniform orientation. Orientation angle analysis shows that lysozyme is adsorbed on the surface with "bottom end-on", "side-on", "back-on" or "top end-on" orientation under different field strengths, suggesting the possibility of controlling the preferred orientation of lysozyme on surface by applying electric fields. Conformation analysis of protein implies that the structure deformation of adsorbed lysozyme does not increase monotonically with the rising field strength. Under some field strengths, there is no additional structure deformation caused by the electric fields compared with that in the absence of electric fields; while under some other field strengths, there are larger conformational change occurrences. We propose that due to the rearrangement of positions of the local atomic charges of protein to couple its dipole with an external electric field, large position alterations of atoms might be avoided and thus conformational changes be restricted. This work may provide guidance for controlling protein adsorption behaviors via external electric fields for applications of protein immobilization and anti-fouling surfaces. PMID- 23727989 TI - IR spectroscopic analyses of amyloid fibril formation of beta2-microglobulin using a simplified procedure for its in vitro generation at neutral pH. AB - beta2-microglobulin (beta2m) is known to be the major component of fibrillar deposits in the joints of patients suffering from dialysis-related amyloidosis. We have developed a simplified procedure to convert monomeric recombinant beta2m into amyloid fibrils at physiological pH by a combination of stirring and heating, enabling us to follow conformational changes associated with the assembly by infrared spectroscopy and electron microscopy. Our studies reveal that fibrillogenesis begins with the formation of relatively large aggregates, with secondary structure not significantly altered by the stirring-induced association. In contrast, the conversion of the amorphous aggregates into amyloid fibrils is associated with a profound re-organization at the level of the secondary and tertiary structures, leading to non-native like parallel arrangements of the beta-strands in the fully formed amyloid structure of beta2m. This study highlights the power of an approach to investigate the formation of beta2m fibrils by a combination of biophysical techniques including IR spectroscopy. PMID- 23727990 TI - Anticancer activity of oncolytic adenoviruses carrying p53 is augmented by 11R in gallbladder cancer cell lines in vitro and in vivo. AB - Gallbladder cancer (GBC) is a rare disease associated with an extremely poor patient prognosis, and occasionally, aberrant expression of p53 is present. Considering that p53 is one of the most widely studied tumor-suppressor genes, we used a cell-penetrating peptide, 11R, to enhance the transferring efficiency of the oncolytic adenovirus carrying the p53 gene by constructing SG7605-11R-p53, a gene-viral therapy system which has higher specificity, enhanced safety, and efficacy. After infection with SG7605-11R-p53 at a multiplicity of infection (MOI) of 1 PFU/cell in vitro, the survival rate of EH-GB1 cells was lower than 50%, and that of EH-GB2 cells was lower than 40%, while the survival rate was higher than 90% for BJ human fibroblast cells, demonstrating that SG7605-11R-p53 has potent specific cytotoxicity against GBC cells. The tumor growth was greatly inhibited in nude mice bearing EH-GB2 xenografts when the total dose of SG7605 11R-p53 was 1x109 PFU, and terminal dUTP nick end-labeling (TUNEL) revealed that the apoptotic rate of cancer cells was 66.75+/-6.702%. Compared with existing gene therapy with long-standing shortcomings, our new system offers an additional option for patients with advanced GBC and other cancers who may not be suitable for chemotherapy, radiotherapy or who are not indicated for surgical treatment. PMID- 23727991 TI - Mechanical ventilation in ICUs in Poland: a multi-center point-prevalence study. AB - BACKGROUND: Mechanical ventilation is the primary method of supporting organ function in patients treated in intensive care units (ICUs). Lung damage from mechanical ventilation can be avoided by using the correct ventilation modes. This study was designed to assess the epidemiology and treatment strategies of patients receiving mechanical ventilation in ICUs in Poland. MATERIAL AND METHODS: This study was done using a point-prevalence methodology. Questionnaires requesting demographic data, indications for ventilation, variables involved in ventilation, airway access, methods of sedation, and mode of weaning were sent to 148 ICUs. RESULTS: Eighty-three ICUs took part in the study. The rate of ventilated patients was 73.6%. The indications for mechanical ventilation were: acute respiratory failure (40%), coma (40%), chronic obstructive pulmonary disease (COPD) exacerbation (14%), and neuromuscular diseases (5%). Patients were ventilated by orotracheal tube (58%), tracheostomy tube (41%), and mask/helmet (1%). The mean tidal volume was 8 ml/kg and positive end-expiratory pressure was commonly used. The mean oxygen concentration was 40%. Synchronized intermittent mandatory ventilation with pressure support was the most frequently used ventilatory mode. Benzodiazepine and opioids were used for sedation in 91% of centers. A systematic testing of the depth of sedation was performed at 48% surveyed ICUs. Ventilation monitoring with biomechanical methods was used at 53% of centers. CONCLUSIONS: Mechanical ventilation is commonly used in ICUs in Poland. Almost half of the ventilated patients had extrapulmonary indications. Patients were ventilated with low concentrations of oxygen, and positive end expiratory pressure (PEEP) was commonly employed. PMID- 23727993 TI - Toxic effects, bioconcentration and depuration of verapamil in the early life stages of common carp (Cyprinus carpio L.). AB - Verapamil is a pharmaceutical that belongs to a group of calcium channel blockers and is mainly used as a treatment of angina pectoris and arterial hypertension. Verapamil has been detected in aquatic environments in concentrations ranging from ng L(-1) to MUg L(-1). In the present study, a series of acute toxicity tests of verapamil on various developmental stages of common carp (Cyprinus carpio) were conducted. As a result, 96hLC50 values of verapamil were estimated at 16.4+/-9.2, 7.3+/-1.5 and 4.8+/-0.2 mg L(-1) for embryos (E5-E9) and common carp larvae L2 and L5, respectively. Lethal concentrations of verapamil decreased with an increase in the age of the fish. Acute exposure to verapamil significantly reduced the heart rate in the embryos and larvae. In an embryo larval toxicity test (sub-chronic exposure), the bioconcentration, depuration, and toxic effects of verapamil were assessed in common carp. The fish were exposed to verapamil in a concentration of 0.463 (environmentally relevant), 4.63, 46.3 and 463 MUg L(-1). Verapamil had no effect on the accumulated mortality, hatching, condition factor, growth or ontogeny of the fish in any of the tested concentrations. In carp exposed to 463 and 46.3 MUg L(-1) of verapamil, significantly higher occurrences of malformations and edemas were observed compared to the control. The bioconcentration factor of verapamil in whole fish homogenates ranged between 6.6 and 16.6 and was therefore below the critical value for hazard substances (BCF>500). The half-life and the 95% depuration time for the tested compound were estimated to be 10.2+/-1.6 days and 44.2+/-8.6 days, respectively. No effects of verapamil on the studied endpoints were observed at environmentally relevant concentrations. PMID- 23727992 TI - SFG analysis of surface bound proteins: a route towards structure determination. AB - The surface of a material is rapidly covered with proteins once that material is placed in a biological environment. The structure and function of these bound proteins play a key role in the interactions and communications of the material with the biological environment. Thus, it is crucial to gain a molecular level understanding of surface bound protein structure. While X-ray diffraction and solution phase NMR methods are well established for determining the structure of proteins in the crystalline or solution phase, there is not a corresponding single technique that can provide the same level of structural detail about proteins at surfaces or interfaces. However, recent advances in sum frequency generation (SFG) vibrational spectroscopy have significantly increased our ability to obtain structural information about surface bound proteins and peptides. A multi-technique approach of combining SFG with (1) protein engineering methods to selectively introduce mutations and isotopic labels, (2) other experimental methods such as time-of-flight secondary ion mass spectrometry (ToF-SIMS) and near edge X-ray absorption fine structure (NEXAFS) to provide complementary information, and (3) molecular dynamic (MD) simulations to extend the molecular level experimental results is a particularly promising route for structural characterization of surface bound proteins and peptides. By using model peptides and small proteins with well-defined structures, methods have been developed to determine the orientation of both backbone and side chains to the surface. PMID- 23727994 TI - A multi-level model of blood lead as a function of air lead. AB - National and local declines in lead (Pb) in blood (PbB) over the past several years coincide with the decline in ambient air Pb (PbA) concentrations. The objective of this work is to evaluate how the relationship between PbB levels and PbA levels has changed following the phase out of leaded gasoline and tightened controls on industrial Pb emissions over the past 30 years among a national population sample. Participant-level data from the National Health and Nutrition Examination Survey (NHANES) were employed for two time periods (1988-1994 and 1999-2008), and the model was corrected for housing, demographic, socioeconomic, and other covariates present in NHANES. NHANES data for PbB and covariates were merged with PbA data from the U.S. Environmental Protection Agency. Linear mixed effects models (LMEs) were run to assess the relationship of PbB with PbA; sample weights were omitted, given biases encountered with the use of sample weights in LMEs. The 1988-1994 age-stratified results found that ln(PbB) was statistically significantly associated with ln(PbA) for all age groups. The consistent influence of PbA on PbB across age groups for the years 1988-1994 suggests a ubiquitous exposure unrelated to age of the sample population. The comparison of effect estimates for ln(PbA) shows a statistically significant effect estimate and ANOVA results for ln(PbB) for the 6- to 11-year and 12- to 19-year age groups during 1999-2008. The more recent finding suggests that PbA has less consistent influence on PbB compared with other factors. PMID- 23727995 TI - Urinary paraben concentrations among pregnant women and their matching newborn infants of Korea, and the association with oxidative stress biomarkers. AB - Parabens have been used in multiple products including personal care products, pharmaceuticals, and foods for more than 50 years but increasing numbers of studies have raised concerns on their safety. The present study was designed to determine urinary paraben levels among pregnant women and their matching newborn infants (<48 h after delivery), and the association between paraben levels and stress markers. Pregnant women (n=46) and their matching newborn infants were recruited from four university hospitals located in Seoul, Ansan and Jeju of Korea, 2011. Parabens including methyl paraben (MP), ethyl paraben (EP), n-propyl paraben (PP), and n-butyl paraben (BP) were measured in the urine using an automatic, high throughput online SPE-LC-MS/MS method. Urinary concentrations were normalized with specific gravity (SG). Free cortisol, malondealdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) were measured in the urine as stress marker. Urinary MP was detected as the highest, and BP was detected as the lowest paraben in the urine samples of both pregnant women and their infants. Significant correlations between paraben concentrations of maternal and their newborn infant's urine were observed. The levels of urinary parabens among Korean pregnant women are comparable to those reported elsewhere, except for EP which were 4-9 folds higher than pregnant women of other countries. The ratios of infant to maternal urinary paraben concentrations varied between 0.5 and 0.6 for MP and PP, but approximately 10 fold lower for EP. Urinary MP or EP levels were associated with several oxidative stress related biomarkers such as urinary 8 OHdG and MDA, even after the adjustment of relevant covariates such as maternal age, mode of delivery, pre-pregnancy BMI, gestational age and parity. This is the first study that reported the levels of major parabens in the first urine of newborn infants. Further studies are warranted to understand the implications of paraben exposure among biologically susceptible human populations. PMID- 23727998 TI - Autophagy and matrix vesicles: new partners in vascular calcification. AB - Vascular calcification is an actively regulated process driven by vascular smooth muscle cell (VSMC) adaptation and ultimately dysfunction, leading to the induction of active osteogenic processes within the vessel wall. Dai et al., for the first time, identify autophagy as a novel adaptive mechanism that protects against phosphate-induced VSMC calcification, by acting to regulate apoptosis and the release of mineralizing matrix vesicles from VSMCs. PMID- 23727999 TI - Capturing the in vivo molecular signature of the podocyte. AB - The podocyte has an essential role in glomerular function. When cultured ex vivo, podocytes do not recapitulate their in vivo phenotype. Several technical barriers have prevented isolation of podocytes from animals with sufficient yield and purity to allow genome-wide assessment of their molecular fingerprint. Boerries et al. overcame some of these barriers and characterized the transcriptome and proteome of freshly isolated podocytes. These data sets and isolation protocol are valuable resources for the podocyte research community. PMID- 23728000 TI - For better or worse: a niche for Notch in parietal epithelial cell activation. AB - Dysfunction and loss of podocytes (glomerular epithelial cells) are the hallmarks of focal segmental glomerulosclerosis (FSGS). In recent years, activation and proliferation of parietal epithelial cells (PECs) have been increasingly appreciated in FSGS. The functional role of PECs in FSGS is still a hotly debated issue. Ueno et al. report that Notch signaling plays a role in orchestrating PEC phenotypic changes in FSGS. PMID- 23728001 TI - Urea channel inhibitors: a new functional class of aquaretics. AB - Using large-scale small-molecule screening techniques, Li et al. have identified a compound that inhibits the UT-B urea channel. They propose that this or similar compounds could be used as aquaretic agents to increase water excretion without changes in electrolyte excretion. Such compounds would potentially be useful in treatment of hyponatremic disorders. Here we review the physiological basis for the action of urea channel inhibitors in the kidney and assess their clinical potential. PMID- 23728002 TI - Fish oil for prevention of sudden death in hemodialysis patients? AB - Friedman et al. report that hemodialysis patients with the highest levels of n-3 fatty acids had impressively low odds of sudden cardiac death. The study is limited by a small sample size, and the analysis relies on only a single baseline measurement of blood levels. Recent randomized evidence indeed fails to support that n-3 fatty acids may prevent sudden death in nonrenal patients. More evidence is needed to advocate fish oil in this setting. PMID- 23728003 TI - How to find a prognostic biomarker for progressive diabetic nephropathy. AB - As a prognostic biomarker for progression of diabetic nephropathy, albuminuria fails in terms of sensitivity and specificity. Better urinary or plasma biomarkers are needed that can predict which diabetic patients are at highest risk for progression. Bhensdadia et al. report proteomic investigations that identified urinary haptoglobin as a potential prognostic biomarker for progressive diabetic nephropathy. Although as a single marker urinary haptoglobin adds little to albuminuria, together the two appear to provide better diagnostic accuracy than albuminuria alone. PMID- 23728004 TI - A new era in the treatment of calcium oxalate stones? AB - Calcium oxalate (CaOx) is the most prevalent type of kidney stone. The amount of oxalate excreted in the urine is a major risk factor for CaOx stone formation. The study by Siener et al. makes a substantial contribution to our understanding of how Oxalobacter formigenes affects oxalate metabolism and excretion in humans and hence influences the risk of developing CaOx kidney stones. PMID- 23728005 TI - The authors reply. PMID- 23728006 TI - Cisplatin nephrotoxicity may be sex related. PMID- 23728007 TI - Is endothelial dysfunction more deleterious than podocyte injury in diabetic nephropathy? PMID- 23728008 TI - Angiotensin II, distal nephron acidification, acid retention, and possibly increased ammonia levels? PMID- 23728009 TI - The authors reply. PMID- 23728010 TI - The author replies. PMID- 23728011 TI - Renal insufficiency should be included in stroke risk scores. PMID- 23728012 TI - Lixivaptan and hyponatremia. PMID- 23728013 TI - Renal biopsy among Indigenous Australians. PMID- 23728014 TI - Retraction: Proteinuria decreases tissue lipoprotein receptor levels resulting in altered lipoprotein structure and increasing lipid levels. PMID- 23728016 TI - Distal renal tubular acidosis in a boy with Proteus syndrome. PMID- 23728017 TI - The Case | A hip fracture in a hemodialysis patient. Pathologic right-hip fracture from beta2-microglobulin amyloidosis. PMID- 23728019 TI - Community health centers' role in family planning. PMID- 23728018 TI - Hydrogel-coated microfluidic channels for cardiomyocyte culture. AB - The research areas of tissue engineering and drug development have displayed increased interest in organ-on-a-chip studies, in which physiologically or pathologically relevant tissues can be engineered to test pharmaceutical candidates. Microfluidic technologies enable the control of the cellular microenvironment for these applications through the topography, size, and elastic properties of the microscale cell culture environment, while delivering nutrients and chemical cues to the cells through continuous media perfusion. Traditional materials used in the fabrication of microfluidic devices, such as poly(dimethylsiloxane) (PDMS), offer high fidelity and high feature resolution, but do not facilitate cell attachment. To overcome this challenge, we have developed a method for coating microfluidic channels inside a closed PDMS device with a cell-compatible hydrogel layer. We have synthesized photocrosslinkable gelatin and tropoelastin-based hydrogel solutions that were used to coat the surfaces under continuous flow inside 50 MUm wide, straight microfluidic channels to generate a hydrogel layer on the channel walls. Our observation of primary cardiomyocytes seeded on these hydrogel layers showed preferred attachment as well as higher spontaneous beating rates on tropoelastin coatings compared to gelatin. In addition, cellular attachment, alignment and beating were stronger on 5% (w/v) than on 10% (w/v) hydrogel-coated channels. Our results demonstrate that cardiomyocytes respond favorably to the elastic, soft tropoelastin culture substrates, indicating that tropoelastin-based hydrogels may be a suitable coating choice for some organ-on-a-chip applications. We anticipate that the proposed hydrogel coating method and tropoelastin as a cell culture substrate may be useful for the generation of elastic tissues, e.g. blood vessels, using microfluidic approaches. PMID- 23728020 TI - Shaping the Jail Inreach Project: program evaluation as a quality improvement measure to inform programmatic decision making and improve outcomes. AB - The Jail Inreach Project was initiated in 2007 as a pilot program by Healthcare for the Homeless-Houston, an FQHC serving homeless individuals in Harris County, Texas, as a collaborative effort with the Harris County Sheriff's Office and the Mental Health Mental Retardation Authority of Harris County. It addresses the disproportionate number of homeless individuals with behavioral health diagnoses cycling through the Harris County Jail without provisions for continuity of care. Throughout the years, several evaluations have been conducted to inform programmatic planning and assess the success of the program on affecting patterns of recidivism of mentally ill homeless clients being served. Findings reinforce the importance of linking releasees to services immediately upon release as a measure for breaking the cycle of repeated incarceration and chronic homelessness. This paper illuminates characteristics of a successful intervention by examining three program evaluations conducted at different times in the program's history. It further illustrates how program evaluation has been utilized to help shape the program design and related policies. PMID- 23728021 TI - Improving the quality of discharge care for the homeless: a patient-centered approach. AB - Homeless patients are at risk for low-quality discharge care, yet there are limited patient-centered data to guide improvement. We explored relationships between assessment of housing status by hospital staff and quality of discharge care using quantitative and qualitative data from interviews and chart reviews with 98 homeless patients: 80% male, mean homelessness 2.8 years, mean age 44. Patient-reported performance of discharge care varied substantially across seven domains from 16-75% and chart review documented lower performance than patient report. Over half (56%) were not asked about their housing status and multivariable logistic regression showed assessment of housing status was independently associated with higher performance in five domains: discussions about cost of medications, physical activity levels, diet, transportation, and mental health follow-up. Qualitative data revealed patient concerns about stigmatization from disclosure of housing status. Our findings suggest that addressing housing status in acute care settings while avoiding stigmatization may improve discharge care for homeless patients. PMID- 23728023 TI - Do official hospitalizations predict medical vulnerability among the homeless?: a postdictive validity study of the vulnerability index. AB - The current study tested the postdictive validity of the Vulnerability Index (VI), an instrument used to assess medical vulnerability among people who are homeless. It also examined the relationship between hospitalization records and self-reported health status. The VI is based on self-reports of hospital utilization and chronic health conditions. Data were collected over a one-year period from individuals receiving homeless services in a southwestern city (N = 97, 53.3% male, 57.7% African American). Vulnerability Index scores and three subcomponents of the measure (chronic health conditions, substance use, and mental health problems) were regressed on official reports of past-year hospitalizations, controlling for gender and race, using four separate regression models. Official hospitalization records significantly predicted overall VI scores, but they did not predict the subcomponents of the measure. Results show that, within the current sample, official hospital records are predictive of overall VI scores and are correlated with self-reported hospitalization. The lack of relationship between hospital records and subcomponents of the VI may indicate an underutilization of health care for those with serious health conditions. PMID- 23728022 TI - Factors associated with geriatric syndromes in older homeless adults. AB - Although older homeless adults have high rates of geriatric syndromes, risk factors for these syndromes are not known. We used multivariable regression models to estimate the association of subject characteristics with the total number of geriatric syndromes in 250 homeless adults aged 50 years and older. Geriatric syndromes included falls, cognitive impairment, frailty, major depression, sensory impairment, and urinary incontinence. A higher total number of geriatric syndromes was associated with having less than a high school education, medical comorbidities (diabetes and arthritis), alcohol and drug use problems, and difficulty performing one or more activities of daily living. Clinicians who care for older homeless patients with these characteristics should consider screening them for geriatric syndromes. Moreover, this study identifies potentially modifiable risk factors associated with the total number of geriatric syndromes in older homeless adults. This knowledge may provide targets for clinical interventions to improve the health of older homeless patients. PMID- 23728024 TI - Perceptions of homelessness in older homeless veterans, VA homeless program staff liaisons, and housing intervention providers. AB - PURPOSE: To understand the needs and challenges encountered by older homeless veterans. METHODS: We conducted six focus groups of older veterans, two focus groups, and one semi-structured interview of VA staff liaisons, and two focus groups and one semi-structured interview of housing intervention providers. RESULTS: Major themes for older veterans: 1) negative homelessness experience; 2) benefits of the structured transitional housing program; 3) importance of peer outreach; and 4) need for age-tailored job placement programs. Major themes for VA staff liaison/housing intervention providers: 1) belief that the transitional housing program has made a positive change; 2) need for individualized criteria to address the unique needs of veterans; 3) distinct differences between older and younger homeless veterans; 4) outreach services; 5) permanent housing issues; and 6) coordination of services. DISCUSSION: Compared with younger veterans, older veterans have less social support, greater employment and health challenges, and, perhaps greater motivation to change. PMID- 23728025 TI - Medical respite programs for homeless patients: a systematic review. AB - Medical respite programs provide care to homeless patients who are too sick to be on the streets or in a traditional shelter, but not sick enough to warrant inpatient hospitalization. They are designed to improve the health of homeless patients while also decreasing costly hospital use. Although there is increasing interest in implementing respite programs, there has been no prior systematic review of their effectiveness. We conducted a comprehensive search for studies of medical respite program outcomes in multiple biomedical and sociological databases, and the grey literature. Thirteen articles met inclusion criteria. The articles were heterogeneous in methods, study quality, inclusion of a comparison group, and outcomes examined. Available evidence showed that medical respite programs reduced future hospital admissions, inpatient days, and hospital readmissions. They also resulted in improved housing outcomes. Results for emergency department use and costs were mixed but promising. Future research utilizing adequate comparison groups is needed. PMID- 23728026 TI - Should I call an interpreter?-How do physicians with second language skills decide? AB - Very little is known about how and when clinicians use their second language skills in patient care and when they rely on interpreters. The purpose of this study was to identify the factors most relevant to physicians' decision-making process when confronting the question of whether their language skills suffice to communicate effectively with patients in particular encounters. We conducted 25 in-depth, semi-structured telephone interviews with physicians in different practice settings who, while not native speakers, routinely interact with LEP patients using second language skills. Physicians consider a variety of factors in deciding whether to use their own language skills in clinical care, including their own and their patient's language proficiency, costs, convenience, and the clinical risk or complexity of the encounter. This study suggests the need for practical guidance and training for clinicians on the appropriate use of second language skills and interpreters in clinical care. PMID- 23728027 TI - Barriers and facilitators of cervical cancer screening among women of Hmong origin. AB - This qualitative study explored the barriers and facilitators of cancer screening among women of Hmong origin. Using a community-based participatory research approach, we conducted focus groups (n=44) with Hmong women who represented four distinct demographic groups among the Hmong community. The participants described sociocultural barriers to screening, which included a lack of accurate knowledge about the causes of cervical cancer, language barriers, stigma, fear, lack of time, and embarrassment. Structural barriers included attitudes and practices of health care providers, lack of insurance, and negative perceptions of services at clinics for the uninsured. Health care providers may require additional training and increased time per visit to provide culturally sensitive care for refugee groups such as the Hmong. Health-related social marketing efforts aimed at improving health literacy may also help to reduce health inequities related to cancer screening among the Hmong. PMID- 23728028 TI - Poverty is the main environmental factor for obesity in a Mexican-border city. AB - INTRODUCTION: Obesity is a pandemic in Mexico. The purpose of this study was to assess the environmental factors that have the strongest association with obesity and abdominal obesity among adults in Tijuana. METHODS: Four neighborhoods differing in socioeconomic status were chosen. A questionnaire for weekly walking, social cohesion, satisfaction with their community, weekly income, and convenience store, education, family income, crime safety, pedestrian safety, street connectivity, walking/cycling facilities, and sociodemographic characteristics was administered. Weight, height, and waist circumference were measured. Univariate and multivariate binomial logistic regressions were conducted. RESULTS: Three hundred and twenty-two (322) individuals, 70% females with a mean age of 39 years, were assessed. The prevalence of obesity and abdominal obesity was 27% and 43.5% respectively. The odds ratio for obesity and abdominal obesity among those living in the lowest-income neighborhood was 2.4 and 7.8 respectively, compared with those living in a middle-class neighborhood. CONCLUSIONS: Residence in a low-income neighborhood was a predictor for obesity. PMID- 23728029 TI - Hepatitis B knowledge, screening, and vaccination among Hmong Americans. AB - We examined Hmong women and men's knowledge of hepatitis B and their screening and vaccination behavior. In-depth interviews were conducted with Hmong in Oregon aged 18 and older (n=83). Independent samples t-test was used to assess mean differences in knowledge by demographic characteristics. Qualitative data were analyzed using content analysis. Most participants had heard of hepatitis B (96.4%). Fifty-three percent of participants had been screened, and half had been vaccinated (50.6%). Transmission knowledge was significantly higher among younger participants, those born in the U.S., and those who reported seeking preventive care. Sequelae knowledge was significantly higher among those who sought preventive care. Transmission and sequelae knowledge were not associated with screening and vaccination. Qualitative data showed that, of those hepatitis B positive participants, most did not have a comprehensive understanding of their illness. Intervention strategies should address knowledge deficits and improve health literacy, especially among Hmong who have hepatitis B. PMID- 23728030 TI - Colorectal cancer screening among Korean American immigrants: unraveling the influence of culture. AB - Screening for colorectal cancer (CRC) is underutilized among ethnic minority groups, particularly among Korean American immigrants. To explore the role of cultural and health beliefs in CRC screening, a structured questionnaire was administered to 281 Korean American immigrants aged between 50 and 88 in the New York metropolitan area. Results showed that 20% of the sample had undergone a fecal occult blood test within the past year, and 35% of the respondents had received a sigmoidoscopy and/or colonoscopy within the previous five years. Binary logistic regression analyses revealed significant predictors including health belief constructs, such as perceived seriousness of cancer and confidence in screening uptake, and gender-specific cultural beliefs and attitudes about CRC screening. Perceived helplessness lowered CRC screening among the women, while fatalism lowered it among the men. The findings reinforce a need for cultural-and gender-specific intervention strategies to increase CRC screening in this particularly vulnerable population. PMID- 23728031 TI - Health behavior changes following breast cancer treatment: a qualitative comparison among Chinese American, Korean American, and Mexican American survivors. AB - This study explored how Chinese American, Korean American, and Mexican American women modify their health behaviors following breast cancer treatment and identified motivators and barriers that influence their changes. An exploratory, descriptive, qualitative study was undertaken using six focus groups. Discussions were transcribed and translated for content analysis. Significant differences among the ethnic groups were noted in the following health behavior practices which were most commonly stated as changed behaviors after a breast cancer diagnosis: 1) eating habits, 2) physical activity, 3) alternative medicine, 4) sleeping, 5) social activity, 6) weight control, and 7) alcohol consumption. Family, financial concerns, environment, and religious faith were commonly mentioned as motivators of and/or barriers to changes in health behaviors. Findings provide insight into different perspectives related to changes in health behaviors by ethnicity, which is critical for developing culturally tailored behavioral interventions to improve underserved breast cancer survivors' quality of life and to reduce health disparities. PMID- 23728032 TI - Effects of race and language on patient-centered cancer nursing care and patient outcomes. AB - Nursing prides itself on the ability to advocate for patients. However, questions are raised in the National Health Care Disparities Reports from the Agency for Healthcare Research and Quality about how well nurses communicate with African Americans, Hispanics, and people who speak languages other than English. Our secondary analysis of patient data collected at an urban safety-net hospital oncology unit examined the relationships among race, language, patient-centered nursing care, and patient outcomes. Using path modeling techniques, findings indicate that patient-centered care and associated outcomes for African American/Black and Others differ from those for Whites. For the African American/Black and Others group, individualization played a more significant role in achieving a sense of well-being, optimism, and authentic self-representation. Patients who spoke a language other than English at home had different perceptions of their nurses' responsiveness; nurses' responsiveness in turn affected patients' trust in nurses. Future testing is recommended for relationships between patient-centered nursing care and patient outcomes in underserved populations. PMID- 23728033 TI - Barriers to care for Cambodian patients with diabetes: results from a qualitative study. AB - Racial and ethnic disparities in diabetes care have been well documented. While root causes have been explored for some minority groups, less is known about smaller immigrant populations such as Cambodians. In this study, we sought to explore the potential barriers to care for Cambodian patients with diabetes. We conducted five focus groups with three study groups: health care providers, bilingual Khmer frontline staff, and Cambodian patients with diabetes. Focus groups findings revealed that certain cultural beliefs, low health literacy, and language barriers strongly affect Cambodian patients' understanding of diabetes and self-management, as well as clinicians' ability to care effectively for Cambodian patients with diabetes. Our study supports previous literature and also adds several new insights not previously described. We recommend education for health care providers on patient-centered, cross-cultural care with an emphasis on the needs of Cambodians as well as culturally appropriate diabetes education for patients. PMID- 23728034 TI - Health care access and utilization among Hispanic manufacturing workers along the Texas-Mexico border. AB - Disparities in health care access, including utilization of preventive health services, are well-documented among ethnic minority populations. This study examines factors associated with health care access and utilization among Hispanic manufacturing employees along the Texas-Mexico border. A cross-sectional survey was administered in 2010 to 228 mostly male (71%) workers. About half of participants (53%) lacked health insurance, which emerged as the most important variable related to health care access and utilization. In multivariate logistic regression analyses, relative to insured workers, uninsured workers were significantly more likely to delay getting medical care (p<.001) and to need medical services that they could not afford (p<.05). They were also less likely to receive a flu vaccine (p<.001). Additionally, uninsured women were less likely to receive screening for cervical cancer compared to insured women (p<.05). Findings support the promotion of employment-based health insurance and education programs stressing the importance of preventive health services. PMID- 23728035 TI - A collaborative mental health research agenda in a community of poor and underserved Latinos. AB - The goal of this project was to engage community members and grassroots organizations in a discussion regarding perceived mental health needs and priorities of the population of underserved Latinos in Montgomery County, Maryland. Community-based participatory research was used to establish structures for participation and to design studies that effectively address local mental health needs. Four focus groups with 30 Latino lay health promoters and 20 key informant interviews were conducted to ascertain communal mental health needs and priorities. The main issues that emerged included mental health stigma, consequences of immigration-related stress, violence and alcoholism, and concerns about psychotropic medications. Ideas to address these issues and foster wellness through research were generated during a community-based workshop that included consumers, primary care and mental health clinicians, researchers, and representatives of local organizations and federal agencies. The product of this process was an implementable mental health research agenda, which is presented and discussed. PMID- 23728036 TI - Identifying patient, community and program specific barriers to free specialty care utilization by uninsured patients in East Baltimore. AB - Uninsured individuals face multiple barriers to accessing specialty care. The Access Partnership (TAP) offers free specialty care and care coordination to qualified uninsured patients at an urban academic medical center for a small program entry fee (waived for financial hardship). In the program's first year, 104 eligible patients (31%) did not enroll. To understand why, we investigated demographic, referral, personal, and program-specific factors. After adjusting for age, gender, and ZIP code, diagnostic and therapeutic referrals were more likely to be completed than ancillary referrals (OR=8.56, p=.001; OR 3.53, p=.03). There was no difference between pain related and ancillary referrals (OR=2.80, p=.139). Eighteen patients were surveyed and reported program and patient-specific barriers. While removing costs is necessary to improve access to specialty care for underserved patients, it is insufficient. Improving communication from program coordinators and enrollment strategies may help to improve utilization of free care programs by the uninsured. PMID- 23728037 TI - Home-based caregiving for people living with HIV/AIDS in South Africa. AB - Caregiving for people living with HIV/AIDS (PLWHAs) reportedly affects the physical, mental, and socioeconomic well-being of family and volunteer caregivers. This study uses the PEN-3 cultural model to examine the positive, existential (unique), or negative roles and expectations that influence HIV and AIDS caregiving among home-based caregivers (HBCs) in Limpopo, South Africa. Data from 41 women who participated in four focus group discussions held in Limpopo provides a deeper understanding of culture in providing care and support to PLWHAs. Using the cultural empowerment domain of PEN-3, our analyses revealed the following themes: perceptions associated with HIV/AIDS caregiving, HBCs assuming the roles of family, and voicelessness of HBCs due to the lack of support. The findings highlight the resilience of HBCs in South Africa in responding to the stigmatized disease of HIV/AIDS in the context of cultural expectation of caring for the sick. PMID- 23728038 TI - Can access to a medical-legal partnership benefit patients with asthma who live in an urban community? AB - Approximately one in 10 children in the U.S. has a diagnosis of asthma. African American and low-income children are more likely to be diagnosed with asthma. They are more likely to suffer the worse outcomes because of low socioeconomic status and environmental exposures. A medical-legal partnership is an interdisciplinary collaboration between a medical entity such as a hospital or clinic and a legal entity such as a lawyer, law school, or legal aid society created to address barriers to health care access and limitations to well-being. Addressing the legal concerns of these patients can improve access to medical services, reduce family stress, and address legal concerns that contribute to poor health. The Health Law Partnership (HeLP) is one such medical-legal partnership that provides a holistic, interdisciplinary approach to health care. During the seven-year study period we found both financial ($501,209) and non financial benefits attributable to interventions by the attorneys at HeLP. PMID- 23728039 TI - Colorectal cancer surgery outcomes for vulnerable patients in safety-net versus non-safety-net hospitals. AB - Extensive research documents disparities in health outcomes for vulnerable populations. Safety-net hospitals-those that serve a greater proportion of vulnerable patients with Medicaid or no insurance-may yield better outcomes for these vulnerable patients because of their expertise with this population. National Inpatient Sample data from 2005-2007 show that predicted rates of complications following colorectal cancer surgery are approximately 20% lower for vulnerable patients in safety-net than in non-safety-net hospitals (0.273 versus 0.340; 95% CI for the difference: -0.11, -0.001). Differences by safety-net status for Medicare and privately-insured patients were smaller and not statistically significant. The lower complication rates are not due to earlier discharge, as vulnerable patients had significantly longer stays at safety-net hospitals (1.79 days; 95% CI 0.13, 3.40). Additional research is needed to determine whether improvement in post-operative outcomes is due to the expertise of safety-net hospitals in caring for patients with Medicaid or no insurance. PMID- 23728040 TI - "The god of death takes half of our children": health of women and children in the Sundarbans Islands. AB - Grassroots level health care workers provided insights into rural women's health concerns at a program development workshop held at Sundarban Islands in West Bengal, India. This report describes these narratives and identifies strategies for potential intervention plans. The narratives suggest layers of disenfranchisement compounded by gender inequality and geographic instability. PMID- 23728041 TI - Organizing uninsured safety-net access to specialist physician services. AB - Arranging referrals for specialist services is often the greatest difficulty that safety-net access programs face in attempting to provide fairly comprehensive services for the uninsured. When office-based community specialists are asked to care for uninsured patients, they cite the following barriers: difficulty determining which patients merit charity care, having to arrange for services patients need from other providers, and concerns about liability for providing inadequate care. Solutions to these barriers to specialist access can be found in the same institutional arrangements that support primary care and hospital services for the uninsured. These safety-net organization structures can be extended to include specialist physician care by funding community health centers to contract for specialist referrals, using free-standing referral programs to subsidize community specialists who accept uninsured patients at discounted rates, and encouraging hospitals through tax exemption or disproportionate share funding to require specialists on their medical staffs to accept an allocation of uninsured office-based referrals. PMID- 23728042 TI - African American women's perspectives on breast cancer: implications for communicating risk of basal-like breast cancer. AB - African American women suffer a disproportionately high burden of basal-like breast cancer, an aggressive subtype that has no targeted therapy. While epidemiologic research has identified key prevention strategies, little is known about how best to communicate risk to this population. This study explored women's knowledge, beliefs, and attitudes about breast cancer to learn about risk perceptions. Six focus groups were conducted in North Carolina with 57 women (ages 18-49). Age, race (especially perceptions of cancer as a "White disease"), and lack of family history of breast cancer were all shown to contribute to women's perceptions of low breast cancer susceptibility. Perceptions of low risk were also attributed to conflicting risk information from family, media, and health providers. Women had little to no knowledge of breast cancer subtypes, and emphasized that health communications should be personally relevant, culturally appropriate, and convenient. These findings will assist in developing health communication tools that encourage prevention. PMID- 23728044 TI - Medical skepticism and complementary therapy use among older rural African Americans and Whites. AB - PURPOSE: This study documents demographic, health, and complementary therapy (CT) correlates of medical skepticism among rural older adults. METHODS: Older (>=65 years) African Americans and Whites in rural North Carolina (N=198) were interviewed. Medical skepticism was assessed using the four items from the Medical Expenditure Survey. Bivariate associations between medical skepticism and demographic and health characteristics and CT use were assessed, and independent effects on CT use. FINDINGS: Positive responses to medical skepticism questions ranged from 19.7% (can overcome illness without help) to 59.6% (believes own behavior determines their health). Medical skepticism indicators were associated with few demographic and health characteristics, and one CT category. CONCLUSIONS: This study shows a high degree of medical skepticism among rural older adults, but limited associations with demographic and health characteristics and CT use. Further research is needed to understand relationships of attitudes towards conventional care and CT use in this population. PMID- 23728045 TI - Factors contributing to poor physical health in incarcerated women. AB - Prisons have become the primary health care provider for some of the poorest and sickest women in the United States. By virtue of both biological sex and gender, incarcerated women have health needs different from those of their male counterparts. The purpose of this qualitative investigation was to understand better women's perceptions of how prison has affected their physical health. We conducted this investigation in a maximum-security women's prison in the United States using focus group methodology (12 focus groups, made up of 65 women). Women described several specific prison-based factors that affected their physical health: limited and complicated access to care; nutritional concerns; limited physical activity; and smoking in prison. We discuss these findings in relation to the gender-based health issues facing incarcerated women. PMID- 23728043 TI - Attitudes surrounding implementation of the HPV vaccine for males among primary care providers serving large minority populations. AB - BACKGROUND: Minority populations are disproportionally affected by human papilloma virus (HPV) infection. We examined the attitudes of primary care providers serving large minority populations towards the implementation of the HPV vaccine for males in their practices. DESIGN: Cross-sectional survey of randomly selected primary care providers in Brooklyn, N.Y. RESULTS: Ninety-three eligible providers were surveyed, of whom 62% were pediatricians. Sixty-two percent of all participants reported that they were very likely or will definitely be offering the vaccine to their male patients. The rate was higher among providers who reported higher numbers of minority patient population and who acknowledged high risk among their patient population. CONCLUSIONS: Primary care providers included in the study were likely to report incorporation of the HPV vaccine for males as part of their regular clinical practice. Their adoption and dissemination of the vaccine will be a significant factor in determining whether its full benefits are achieved. PMID- 23728046 TI - Comparing preventive visits of children in foster care with other children in Medicaid. AB - OBJECTIVE: This study compared preventive medical and dental visits of Georgia children in foster care with other children enrolled in Medicaid to determine if utilization differed. METHODS: Two logistic regressions estimated the likelihood of an annual Health Check screening and the likelihood of at least one dental visit. RESULTS: Compared with children in foster care, children in the adoption assistance ([AOR] .37, 95% confidence interval [CI] = 0.35-0.40), SSI (AOR .37, 95% CI = 0.35-0.38) and low-income (AOR .40, 95% CI = 0.39-0.42) Medicaid categories were less likely to receive an annual Health Check screening. Children in adoption assistance were also less likely to have a dental visit during the study period. CONCLUSION: Policies require a Health Check visit upon placement into foster care and annual check-ups consistent with pediatric guidelines; we found more Early and Periodic Screening, Detection, and Treatment screenings for foster care children in Georgia than for other children receiving Medicaid. PMID- 23728047 TI - Home asthma triggers: barriers to asthma control in Chicago Puerto Rican children. AB - We sought objectively to measure, summarize, and contextualize the asthma triggers found in the homes of urban high-risk Puerto Rican children and adolescents with asthma in Chicago. Data were from the baseline home assessments of Project CURA. Research assistants interviewed caregivers, conducted a home visual inspection, and collected saliva samples for cotinine analysis. A trigger behavior summary score was created. The housing inspected was old with multiple units and obvious structural deficiencies. Many allergic and irritant triggers were observed. Having a controller medicine or private insurance was associated with lower trigger behavior summary scores; caregiver depression, caregiver perceived stress, and child negative life events were associated with high trigger scores. The final multivariate model retained had a controller medicine, private insurance, and caregiver perceived stress. The data from this high-risk cohort identified modifiable areas where environmental interventions could reduce morbidity in Puerto Rican children and adolescents. PMID- 23728048 TI - Providers' perceptions of parental concerns about HPV vaccination. AB - OBJECTIVE: Parental resistance is often posited to explain low rates of human papillomavirus (HPV) vaccine uptake. We sought to describe providers' perceptions of parents' attitudes towards HPV vaccination. METHODS: Thirty-four providers from four federally qualified community health centers participated in semi structured interviews related to their experiences discussing HPV vaccination with low-income and minority parents. RESULTS: Providers found that parents were eager to prevent cancer in their daughters. Safety concerns and feeling that vaccination was unnecessary for virgins were reasons for declining vaccination. Providers found that immigrants from low-resource settings were more receptive to HPV vaccination than White middle-class parents due both to personal experience with vaccine-preventable diseases and cervical cancer and more realistic impressions of their children's sexual activity. CONCLUSIONS: Immigrants from low resource settings may be particularly receptive to HPV vaccination, while White middle-class parents may be more likely to defer vaccination due to concerns about safety or sexual issues. PMID- 23728049 TI - Increasing the relevance of research to underserved communities: lessons learned from a retreat to engage community health workers with researchers. AB - This article presents information on a community retreat developed to seek input from community health workers (CHWs) to increase the relevance of our research to underserved communities in Oregon. Retreats facilitating dialogue between researchers and CHWs could yield important insight to enhance the significance of research for communities. PMID- 23728050 TI - Project ECHO: replicating a novel model to enhance access to hepatitis C care in a community health center. AB - Project Extension for Community Healthcare Outcomes (Project ECHOTM) is an innovative telemedicine program that improves patient care by developing and supporting the competence of primary care providers. The Community Health Center, Inc. replicated this model to address significant access issues and improve hepatitis C management and treatment for its patients. PMID- 23728051 TI - Folic acid awareness vs. supplementation: a new tool to bridge the gap. AB - This Report from the Field describes a folic acid awareness event hosted by a College of Pharmacy in conjunction with a local YWCA in observation of National Birth Defects Prevention Month and includes a discussion of the disparity between folic acid awareness and consumption and proposes a new tool to decrease this gap. PMID- 23728052 TI - The use of financial incentives to increase fresh fruit and vegetable purchases in lower-income households: results of a pilot study. AB - Identifying effective strategies to promote healthier eating in underserved populations is a public health priority. In this pilot study, we examined the use of financial incentives to increase fresh fruit and vegetable purchases in low income households (N=29). Participants received pre-paid coupons to buy fresh produce at the study store during the intervention period. Purchases were compared among the three study phases (baseline, intervention, and follow-up). A financial incentive provided by study coupons increased the average weekly purchase of fresh fruit but was less successful with fresh vegetables. These findings underscore the need for specific targeting of vegetable selection and preparation to exploit this strategy more fully. PMID- 23728053 TI - Implementing Institute of Medicine recommendations on collection of patient race, ethnicity, and language data in a community health center. AB - The Institute for Family Health is one of the first health care organizations to implement the 2009 Institute of Medicine recommendations on collection of patient race, ethnicity, and language data as a means of identifying and addressing health disparities. This paper describes the implementation process and lessons learned from the project. PMID- 23728054 TI - Equal and universal access?: water at mealtimes, inequalities, and the challenge for schools in poor and rural communities. AB - As a result of the rising national obesity rates, public health researchers and advocates have initiated a number of obesity prevention interventions to reduce the rates of overweight and obesity along with their related medical conditions and costs. Policymakers have also initiated a wide range of environmental and policies to support healthy eating and physical activity. Policies such as California's SB1413, which requires that free drinking water be served in school cafeterias during mealtimes, and subsequently the Healthy Hunger-Free Kids Act of 2010, assume an equal access to safe and healthy drinking water. As a result, these policies and their application may unintentionally, exacerbate the inequities already present. Unless we take reasonable steps to address the needs of high-need communities, these one-size-fits-all policy efforts may result in an unequal patchwork of disparities and may have a greater negative impact in high need poor and rural areas. PMID- 23728055 TI - Can midlevel dental providers be a benefit to the American public? AB - The use of midlevel dental providers (MLDPs) is being debated as a means of reducing oral health disparities and increasing access to care among underserved populations. Midlevel dental providers include the advanced dental hygiene practitioner, community dental health coordinator, dental health aide therapist, and dental therapist. While midlevel providers are new to the U.S. dental profession, medicine has utilized these positions for years. Medical literature has shown mixed results as to whether midlevel providers improve access to care and increased practice efficiency, however, it has demonstrated clearly that the quality of care outcomes of these providers have been comparable to those of physicians. Studies of MLDPs suggest potential practice and public health benefits. With appropriate training, licensure, supervision, and deployment to geographical areas of significant need, we believe MLDPs could increase access to care to underserved populations and help in the prevention of deaths attributable to untreated dental disease. PMID- 23728056 TI - Cumulative social risk and racial/ethnic disparities in obesity during the transition to adulthood. AB - Racial/ethnic disparities in adolescent obesity in the U.S. are stark, and the causes of these disparities are largely unknown. We used a cumulative risk index (CRI) to examine the role of social risk in racial/ethnic disparities in obesity. Using the National Longitudinal Study of Adolescent Health and multinomial logistic regression, we examined the role of this CRI in disparities in obesity in the transition from adolescence to adulthood. Controlling for sociodemographic characteristics, compared with White females, Black and Hispanic females had roughly a 50% increase in the odds of newly-developed obesity in adulthood and a 90% increase in the odds of persistent obesity in adolescence and adulthood. After adding our CRI, the Black-White disparities were attenuated to statistical non-significance. Hispanic-White disparities did not change. There were no disparities in obesity for males. Our results suggest that social risk factors accumulate to explain Black-White disparities in obesity for females. PMID- 23728057 TI - Proportional differences in emergency room adult patients with PTSD, mood disorders, and anxiety for a large ethnically diverse geographic sample. AB - Underserved populations often utilize the emergency room in place of primary care, particularly for short term behavioral health services. This study examined emergency department (ED) utilization rates for rurality, insurance, sex, and ethnicity in a large sample of adult patients in Hawai'i hospitals from 2000-2010 with a diagnosis of post-traumatic stress disorder (PTSD), mood disorder, or other anxiety disorder. Findings showed a higher rate of use by rural and suburban residents with a diagnosis of PTSD or other anxiety than by urban residents. Utilization of EDs by African Americans and Other Pacific Islanders with PTSD was proportionally higher than for those with mood disorders or other anxiety disorders. Military ED visits were also proportionally higher for individuals with PTSD than for those with mood or other anxiety disorders. Limited economic resources and increasingly costly mental health disorders such as PTSD highlight the importance of better understanding the needs for behavioral health services for underserved populations. PMID- 23728058 TI - Perspectives on community dental clinics and oral health inequities in British Columbia. AB - BACKGROUND: This study investigates the expansion of community dental clinics to address oral health inequities in the province of British Columbia (BC) from the perspectives of dental professionals and allied service-providers. METHODS: Sixty three people participated in individual and group interviews with dentists (n=4), dental hygienists (n=30), dental clinic staff (n=17), and other health care and social service providers (n=12). RESULTS: We identified two service-models: a volunteer-charitable (VC) model typically operating part-time mostly to relieve pain and a not-for-profit (NFP) model open full-time usually within a community health centre with paid staff providing basic dental services. CONCLUSIONS: Community dental clinics are increasing in number to fill a gap in the oral health care of disadvantaged people in BC. Staff in these clinics raised questions indirectly about distributive justice and health care inequity by suggesting that the unmet dental need of vulnerable people requires political attention and that restricted dentistry for underserved communities is socially unacceptable. PMID- 23728059 TI - When patients govern: federal grant funding and uncompensated care at federally qualified health centers. AB - OBJECTIVE: To determine if the proportion of consumers on federally qualified health center (FQHC) governing boards is associated with their use of federal grant funds to provide uncompensated care. METHODS: Using FQHC data from the Uniform Data System, county-level data from the Area Resource File and governing board data from FQHC grant applications, the uncompensated care an FQHC provides relative to the amount of its federal funding is modeled as a function of board and executive committee composition using fixed-effects regression with FQHC and county-level controls. RESULTS: Consumer governance does not predict how much uncompensated care an FQHC provides relative to the size of its federal grant. Rather, the proportion of an FQHC's patient-mix that is uninsured drives uncompensated care provision. CONCLUSIONS: Aside from a small executive committee effect, consumer governance does not influence FQHCs' provision of uncompensated care. More work is needed to understand the role of consumer governance. PMID- 23728061 TI - Note from the editor. PMID- 23728062 TI - State of microbiology in India. PMID- 23728063 TI - Maternal diet, prenatal exposure to dioxins and other persistent organic pollutants and anogenital distance in children. AB - We investigated the potential endocrine disruptive effect of prenatal exposure to persistent organic pollutants (POPs) through maternal diet, by measuring anogenital distance in newborns and young children. We included 231 mothers and their newborns measured at birth from the Rhea study in Crete, Greece and the Hmar study in Barcelona, Spain and 476 mothers and their children measured between 1 and 2 years from the Rhea study. We used food frequency questionnaires to assess maternal diet and estimated plasma dioxin-like activity by the Dioxin Responsive Chemically Activated LUciferase eXpression (DR-CALUX(r)) and other POPs in maternal samples. We defined a "high-fat diet" score, as a prenatal exposure estimate, that incorporated intakes of red meat, processed meat, fatty fish, seafood, eggs and high-fat dairy products during pregnancy. Increasing maternal "high-fat diet" score was related to increasing dioxin-like activity and serum concentrations of lipophilic persistent organic pollutants in maternal blood. An inverse dose-response association was found between "high-fat diet" score and anoscrotal distance in newborn males. The highest tertile of the maternal score was associated with -4.2 mm (95% CI -6.6 to -1.8) reduction in anoscrotal distance of newborn males, compared to the lowest tertile. A weak positive association was found between the "high-fat diet" score and anofourchetal distance in newborn females. In young children we found no association between maternal "high-fat diet" score and anogenital distances. In conclusion, maternal high-fat diet may be linked to high prenatal exposure to persistent organic pollutants and endocrine disruptive effects, resulting to phenotypic alterations of the reproductive system. PMID- 23728064 TI - Occurrence and potential combined toxicity of dissolved organic contaminants in the Forth estuary and Firth of Forth, Scotland assessed using passive samplers and an algal toxicity test. AB - As an alternative procedure to conventional water quality assessment, the presence and combined toxicity of dissolved organic contaminants in water at five sites in the Forth estuary and the Firth of Forth, Scotland, United Kingdom was investigated using silicone rubber passive sampling devices (SR-PSDs) and an algal growth inhibition bioassay. SR-PSDs were deployed in water at the five sites for ~2 months. Following retrieval, extracts from the deployed SR-PSDs were assessed for both algal growth inhibition and the occurrence of a wide range of organic contaminants, including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), and a variety of plant protection products (PPPs; commonly referred to collectively as 'pesticides'). The 72 h algal growth inhibition test was performed using a native marine phytoplankton (Diacronema lutheri) in 24 well microplates. Freely dissolved (e.g. bioavailable) concentrations of PAHs and PCBs were determined using performance reference compounds (PRCs). The algal toxicity tests exhibited varied effects at the five sites indicating the presence of, and exposure to, phytotoxic compounds and their potential toxicity in the Forth. The individual and total dissolved concentrations of 40 PAHs and 32 PCBs measured in the study were relatively low and showed input of petrogenic, atmospheric and sewage related sources. Several pesticides of diverse polarities were identified in the water suggesting sources from both riverine input and direct discharges. The study thus illustrates the value of combining bioassays and chemical analysis (with effective sampling technique) for a realistic and rapid assessment of organic contaminants in the aquatic environment. PMID- 23728066 TI - Clinical characteristics and natural history of hypertrophic cardiomyopathy with midventricular obstruction. AB - BACKGROUND: The prevalence, clinical characteristics and natural history of patients with hypertrophic cardiomyopathy (HCM) and midventricular obstruction (MVO) have not been adequately studied. METHODS AND RESULTS: A single-center cohort consisting of 423 patients (mean age, 49.3+/-17.2 years; 66.2% male) was thoroughly followed up for a median of 84 months (7 years; range, 6-480 months). MVO, characterized by the echocardiographic appearance of midventricular muscular apposition with a simultaneous mid-cavitary gradient >=30mmHg, was identified in 34 patients (8%). Patients with MVO tended to be more symptomatic during their initial evaluation (>90% presented with NYHA class >=II) compared to the rest of the HCM cohort. Apical aneurysm formation was identified in more than one-fourth of patients with MVO (26.5%), being a characteristic of the group. On multivariate Cox regression hazard analysis, presence of MVO strongly predicted progression to end-stage (burnt out) HCM and related heart failure (HF) deaths (hazard ratio, [HR], 2.62; 95% confidence interval [CI]: 1.2-8.8; P=0.047), as well as sudden death and associated lethal arrhythmic events (HR, 3.3; 95% CI: 1.26-8.85; P=0.016). CONCLUSIONS: MVO is a distinct phenotype of HCM associated with unfavorable prognosis in terms of end-stage HCM, sudden death and lethal arrhythmic events. The high adverse outcome rate necessitates early recognition of MVO and appropriate therapeutic interventions. PMID- 23728065 TI - A double-blind, placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence. AB - OBJECTIVES: To assess the efficacy and safety of varenicline (Chantix) for the treatment of alcohol dependence. Varenicline is a partial alpha4beta2 nicotinic acetylcholine agonist approved by the Food and Drug Administration for smoking cessation. It has reduced drinking in animal studies and in small studies of humans who were both heavy drinkers and smokers. This is the first multisite clinical trial of varenicline in a population of smokers and nonsmokers with alcohol dependence. METHODS: Men and women (n = 200) meeting the criteria for alcohol dependence were recruited across 5 clinical sites. Patients received double-blind varenicline or placebo and a computerized behavioral intervention. Varenicline was titrated during the first week to 2 mg/d, which was maintained during weeks 2 to 13. RESULTS: The varenicline group had significantly lower weekly percent heavy drinking days (primary outcome) (adjusted mean difference = 10.4), drinks per day, drinks per drinking day, and alcohol craving compared with the placebo group (P < 0.05). The average treatment effect on alcohol use was similar for smokers and nonsmokers. Varenicline was well-tolerated; adverse events were expected and mild. CONCLUSIONS: Varenicline significantly reduced alcohol consumption and craving, making it a potentially viable option for the treatment of alcohol dependence. PMID- 23728067 TI - Heart failure with preserved ejection fraction in children: hormonal imbalance between aldosterone and brain natriuretic peptide. AB - BACKGROUND: There is no information on heart failure (HF) with preserved ejection fraction (HFpEF, EF >50%) in children. METHODS AND RESULTS: Through a retrospective review of 3,907 pediatric patients with cardiovascular disease, we examined the characteristics of pediatric HFpEF over a 10-year period. We identified 18 patients with HFpEF (0.5%). They were predominantly young children (1.1+/-0.9 years, no sex preponderance), who had undergone surgery for congenital heart disease. They also had concentric hypertrophy and diastolic dysfunction with elevated blood pressure. Notably, HFpEF patients had more pronounced elevation of serum aldosterone but less pronounced elevation of plasma brain natriuretic peptide (BNP) than 22 systolic HF patients (SHF, EF <=50%) (aldosterone: 1,375+/-1,200 vs. 511+/-563pg/ml, P<0.05, and BNP: 101+/-141 vs. 749+/-818pg/ml, P<0.005). Consequently, the aldosterone/BNP ratio was significantly higher in HFpEF (38+/-63) than in SHF (1.7+/-1.9, P<0.05), and an aldosterone/BNP ratio of 10.3 or higher best predicted HFpEF (area under the curve=0.89). The HF mortality rate was significantly lower in the HFpEF than in the SHF cases, and HF symptoms showed amelioration in 61% of patients during the follow-up period of 4.2+/-2.6 years. CONCLUSIONS: HFpEF does exist in children. A common pathophysiology underlies childhood and adult HFpEF despite considerable epidemiological and etiological differences. Future controlled studies are warranted to assess the cause-effect relationship between unique hormonal profiles and HFpEF. PMID- 23728068 TI - Costal cartilage is a superior implant material than conchal cartilage in the treatment of empty nose syndrome. AB - OBJECTIVE: The objective of this study was to evaluate the outcomes of endonasal microplasty in treating empty nose syndrome by comparing the use of costal and conchal cartilage implants to construct neoturbinates. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: A total of 31 patients who were diagnosed with empty nose syndrome and underwent endonasal microplasty with conchal cartilage (n = 17) or costal cartilage implants (n = 14) were included. Each patient's clinico-demographic profile was reviewed to compare the conchal cartilage group and the costal cartilage groups. Pre- and postoperative Sino-Nasal Outcome Test (SNOT-25) scores were also compared. RESULTS: Both groups showed a significant improvement in SNOT-25 scores following surgery (P < .05). The group who received costal cartilage implants demonstrated more significant improvements than the conchal cartilage group in terms of the mean difference between pre- and postoperative SNOT-25 scores (P = .023). Symptom outcomes related to depression demonstrated significant improvements in the conchal cartilage group (P < .05), while in the costal cartilage group, in addition to these 3 variables, 7 items related to functional problems also demonstrated significant improvements (P < .05). CONCLUSIONS: Costal cartilage is a more useful material than conchal cartilage as implants for the treatment of empty nose syndrome patients. PMID- 23728069 TI - Microstructural changes of the corticospinal tract in idiopathic normal pressure hydrocephalus: a comparison of diffusion tensor and diffusional kurtosis imaging. AB - INTRODUCTION: The goals of this study were to examine the usefulness of diffusional kurtosis imaging (DKI) for assessing microstructural changes in the compressed corticospinal tract (CST) among patients with idiopathic normal pressure hydrocephalus (iNPH). METHODS: Eleven patients with iNPH (mean age: 73.6 years, range: 65-84), who underwent 3-T magnetic resonance imaging, including DKI before surgery, were recruited. Six age-matched, healthy subjects (mean age: 69.8 years, range: 60-75) served as the control group. DKI and diffusion tensor imaging parameters were calculated and compared between the iNPH and the control groups using tract-specific analysis of the CST at the level of the lateral ventricle. RESULTS: Mean diffusional kurtosis (DK) and axial diffusion kurtosis were significantly lower in iNPH patients. However, apparent diffusion coefficient, fractional anisotropy, and axial eigenvalue (lambda1) were significantly higher in the iNPH group than in the control group. CONCLUSIONS: The mechanical pressure caused by ventricular enlargement in iNPH patients might induce formation of well-aligned fiber tracts and increased fiber density in the CST, resulting in decreased DK. DKI is able to depict both the altered microstructure and water molecule movement within neural axons and intra- or extracellular space. In addition, the investigated DKI parameters provide different information about white matter relative to conventional diffusional metrics for iNPH. PMID- 23728070 TI - Dynamic evaluation of stasis filling phenomenon with computed tomography in diagnosis of brain death. AB - INTRODUCTION: Stasis filling, defined as delayed, weak, and persistent opacification of proximal segments of the cerebral arteries, is frequently found in brain dead patients. This phenomenon causes a major problem in the development of reliable computed tomographic angiography (CTA) protocol in the diagnosis of brain death (BD). The aim of our study was to characterize stasis filling in the diagnosis of BD. To achieve this, we performed a dynamic evaluation of contrast enhancement of the cerebral and extracranial arteries in patients with BD and controls. METHODS: Study population included 30 BD patients, who showed stasis filling in computed tomographic perfusion (CTP) series. Thirty patients, after clipping of an intracranial aneurysm, constituted the control group. The study protocol consisted of CTA, CTP, and angiography. Time-density curves (TDCs) of cerebral and extracranial arteries were generated using 40-s series of CTP. RESULTS: Cerebral TDCs in BD patients represented flat curves in contrast to TDCs in controls, which formed steep and narrow Gaussian curves. We found longer time to peak enhancement in BD patients than in controls (32 vs. 21 s; p < 0.0001). In BD patients, peak enhancement in the cerebral arteries occurred with a median delay of 14.5 s to peak in extracranial arteries, while no delay was noted in controls (p < 0.0001). Cerebral arteries in BD patients showed lower peak enhancement than controls (34.5 vs. 81.5 HU; p < 0.0001). In all BD patients, CTP revealed zero values of cerebral blood flow and volume. Angiography showed stasis filling in 14 (46.7 %) and non-filling in 16 (53.3 %) cases. CONCLUSION: A confrontation of stasis filling with CTP results showed that stasis filling is not consistent with preserved cerebral perfusion, thus does not preclude diagnosis of BD. PMID- 23728071 TI - A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features. AB - The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is upregulated in a number of human cancers, including non-small cell lung cancer (NSCLC). Its potential role in NSCLC progression provides an attractive target for anticancer therapy. The expression of phosphorylated mTOR (p-mTOR), phosphorylated AKT (p-AKT), p85alpha and p110gamma subunits of PI3K, phosphorylated p70S6K (p-p70S6K), phosphatase and tensin homolog (PTEN) and phosphorylated 4E-BP1 (p-4E-BP1) was examined by immunohistochemistry in 102 NSCLC specimens. The results were correlated with clinicopathological features. We also examined 61 of our cases for the presence of PIK3CA, AKT1, PTEN and K-RAS mutations. A common PIK3CA mutation was detected at exon 9 in 2 samples (p.E545K), whereas another sample displayed a rare mutation (p.D1018N). Furthermore, 10 out of 54 cases (18.5%) had a K-RAS mutation at codon 12, 5 had a PTEN mutation (exons 7 and 8) and 1 case had an AKT1 mutation (p.E17K). PTEN mutations were associated with nodal metastases. The expression of p-mTOR positively correlated with that of p-AKT and p-p70S6K and was higher in adenocarcinomas along with nuclear p110gammaPI3K expression, whereas p-4E-BP1 expression was higher in squamous cell carcinomas. We also established a positive association between p85alphaPI3K or p110gammaPI3K and cytoplasmic p-AKT and its downstream effectors. An inverse correlation was noted between p-4E-BP1 immunoexpression and tumour status and nuclear p-AKT expression as regards tumour stage. Univariate survival analysis demonstrated that p-4E-BP1 expression, either alone or in combination with cytoplasmic p-AKT expression had an adverse prognostic significance in adenocarcinomas. The combination of p-4E BP1 and cytoplasmic p-AKT expression remained significant in the multivariate analysis as a function of their interaction with histological type. Our data demonstrate the significance of p-4E-BP1 immunoexpression as a molecular marker of prognostic value in adenocarcinomas, particularly when combined with p-AKT. PMID- 23728072 TI - Organocatalytic asymmetric desymmetrization: efficient construction of spirocyclic oxindoles bearing a unique all-carbon quaternary stereogenic center via sulfa-Michael addition. AB - An unprecedented enantioselective desymmetrization of spiro cyclohexadienone oxindoles has been developed successfully via organocatalyzed asymmetric SMA, which provides facile access to spirocyclic oxindoles bearing a unique all-carbon quaternary stereogenic center with excellent levels of stereoselectivity. PMID- 23728073 TI - Nanoparticle synthesis: any way you want it. PMID- 23728074 TI - Exchange bias of the interface spin system at the Fe/MgO interface. AB - The ferromagnet/oxide interface is key to developing emerging multiferroic and spintronic technologies with new functionality. Here we probe the Fe/MgO interface magnetization, and identify a new exchange bias phenomenon manifested only in the interface spin system, and not in the bulk. The interface magnetization exhibits a pronounced exchange bias, and the hysteresis loop is shifted entirely to one side of the zero field axis. However, the bulk magnetization does not, in marked contrast to typical systems where exchange bias is manifested in the net magnetization. This reveals the existence of an antiferromagnetic exchange pinning layer at the interface, identified here as FeO patches that exist even for a nominally 'clean' interface. These results demonstrate that atomic moments at the interface are non-collinear with the bulk magnetization, and therefore may affect the net anisotropy or serve as spin scattering sites. We control the exchange bias magnitude by varying the interface oxygen concentration and Fe-O bonding. PMID- 23728075 TI - Glass-like phonon scattering from a spontaneous nanostructure in AgSbTe2. AB - Materials with very low thermal conductivity are of great interest for both thermoelectric and optical phase-change applications. Synthetic nanostructuring is most promising for suppressing thermal conductivity through phonon scattering, but challenges remain in producing bulk samples. In crystalline AgSbTe2 we show that a spontaneously forming nanostructure leads to a suppression of thermal conductivity to a glass-like level. Our mapping of the phonon mean free paths provides a novel bottom-up microscopic account of thermal conductivity and also reveals intrinsic anisotropies associated with the nanostructure. Ground-state degeneracy in AgSbTe2 leads to the natural formation of nanoscale domains with different orderings on the cation sublattice, and correlated atomic displacements, which efficiently scatter phonons. This mechanism is general and suggests a new avenue for the nanoscale engineering of materials to achieve low thermal conductivities for efficient thermoelectric converters and phase-change memory devices. PMID- 23728076 TI - A general and robust strategy for the synthesis of nearly monodisperse colloidal nanocrystals. AB - Colloidal nanocrystals exhibit a wide range of size- and shape-dependent properties and have found application in myriad fields, incuding optics, electronics, mechanics, drug delivery and catalysis, to name but a few. Synthetic protocols that enable the simple and convenient production of colloidal nanocrystals with controlled size, shape and composition are therefore of key general importance. Current strategies include organic solution-phase synthesis, thermolysis of organometallic precursors, sol-gel processes, hydrothermal reactions and biomimetic and dendrimer templating. Often, however, these procedures require stringent experimental conditions, are difficult to generalize, or necessitate tedious multistep reactions and purification. Recently, linear amphiphilic block co-polymer micelles have been used as templates to synthesize functional nanocrystals, but the thermodynamic instability of these micelles limits the scope of this approach. Here, we report a general strategy for crafting a large variety of functional nanocrystals with precisely controlled dimensions, compositions and architectures by using star like block co-polymers as nanoreactors. This new class of co-polymers forms unimolecular micelles that are structurally stable, therefore overcoming the intrinsic instability of linear block co-polymer micelles. Our approach enables the facile synthesis of organic solvent- and water-soluble nearly monodisperse nanocrystals with desired composition and architecture, including core-shell and hollow nanostructures. We demonstrate the generality of our approach by describing, as examples, the synthesis of various sizes and architectures of metallic, ferroelectric, magnetic, semiconductor and luminescent colloidal nanocrystals. PMID- 23728077 TI - FTIR, FT-Raman and NMR studies on 2,6-dichlorotoluene and 2-chloro-6 fluorotoluene based on density functional theory. AB - In the present work, we reported a combined experimental and theoretical study on molecular structure and vibrational analysis of 2,6-dichlorotoluene (DCT) and 2 chloro-6-fluorotoluene (CFT). FTIR and FT-Raman spectra of the title compounds in the solid phase are recorded in the region 4000-400 cm(-1) and 4000-50 cm(-1) respectively. The structural and spectroscopic data of the molecules in the ground state is calculated using Hartree-Fock (HF) and density functional methods (B3LYP) with 3-21 and 6-31G* basis sets. The DFT (B3LYP/31G*) calculations have been giving energies, optimized structures, harmonic vibrational frequencies, IR intensities and Raman activities. The study is extended to the HOMO-LUMO analysis to calculate the energy gap, ionization potential, electron affinity, global hardness, chemical potential and thermodynamic properties of DCT and CFT. A complete vibrational assignment aided by the theoretical harmonic frequency analysis has been proposed. The calculated HOMO and LUMO energies show the charge transfer occurs in the molecule. The harmonic vibrational frequencies have been compared experimental FTIR and FT-Raman spectra. The observed and calculated frequencies are found to be in good agreement. The complete vibrational assignments are performed on the basis of the Total Energy Distribution (TED) of the vibrational modes calculated with scaled quantum mechanical (SQM) method. (13)C NMR chemical shifts results are compared with the experimental values. The experimental spectra also coincide satisfactorily with those of theoretically constructed spectrograms. PMID- 23728078 TI - Fate of pyribambenz propyl (ZJ0273) in anaerobic soils revealed by position specific 14C labeling. AB - Pyribambenz propyl, or ZJ0273, is a new and widely used pyrimidynyloxybenzoic herbicide; however, its behavior and safety in anaerobic soils remain poorly understood. In this study, ZJ0273 was labeled with (14)C on its benzoate-, pyrimidyl- and benzyl- rings respectively, and applied to anoxic flooding soils to characterize its anaerobic fates. Over the 100 d incubation, the amended (14)C ZJ0273 was slightly mineralized to (14)CO2 (<4%) or redistributed into the overlaying water (<10%), with the majority of the (14)C (82-98%) remaining in the soil. The residues in soil underwent a gradual transformation from extractable residues (ER) to bound residues (BR), with the percentage of (14)C-BR increasing from 1.1 to 2.5% at day 5 to 23.2-47.2% at day 100. The proportion of (14)C-ER, (14)C-BR and (14)CO2 depended both on the soil property and the labeling position. Generally, ZJ0273 has the highest tendency to form BR in fluvio-marine yellow loamy soil, and the mineralization on both the benzoate and benzyl rings tends to be more extensive in red-clayed soil than the other soils. The ring specific labeling (14)C on three aromatic rings respectively provides full molecular information and yield information on sub-molecular level, i.e., the benzoate ring was generally more susceptible to cleavage than the pyrimidyl or benzyl rings (P<0.01). PMID- 23728079 TI - [Discrepancies between primary tumor and metastasis: impact on personalized medicine]. AB - Molecular characterization of tumors is critical for the development and appropriate use of many anti-cancer agents. Potential discrepancies between primary tumor and secondary lesions lead to question on the optimal modalities for evaluation of biomarkers. In light of recent data, the need of iterative biopsies in metastatic setting has been suggested but technical and methodological limits in such analyses should not be ignored and this strategy can not be definitively validated. The evaluation of spatial and temporal variability of biomarkers in solid tumors should take into account tumoral context and therapeutic history of each patient for the development of personalized medicine in oncology. PMID- 23728080 TI - Reduced CXCR4 expression is associated with extramedullary disease in a mouse model of myeloma and predicts poor survival in multiple myeloma patients treated with bortezomib. PMID- 23728082 TI - Identification of synthetic lethal pairs in biological systems through network information centrality. AB - The immense availability of protein interaction data, provided with an abstract network approach is valuable for the improved interpretation of biological processes and protein functions globally. The connectivity of a protein and its structure are related to its functional properties. Highly connected proteins are often functionally cardinal and the knockout of such proteins leads to lethality. In this paper, we propose a new approach based on graph information centrality measures to identify the synthetic lethal pairs in biological systems. To illustrate the efficacy of our approach, we have applied it to a human cancer protein interaction network. It is found that the lethal pairs obtained were analogous to the experimental and computational inferences, implying that our approach can serve as a surrogate for predicting the synthetic lethality. PMID- 23728081 TI - Dissociating frontal regions that co-lateralize with different ventral occipitotemporal regions during word processing. AB - The ventral occipitotemporal sulcus (vOT) sustains strong interactions with the inferior frontal cortex during word processing. Consequently, activation in both regions co-lateralize towards the same hemisphere in healthy subjects. Because the determinants of lateralisation differ across posterior, middle and anterior vOT subregions, we investigated whether lateralisation in different inferior frontal regions would co-vary with lateralisation in the three different vOT subregions. A whole brain analysis found that, during semantic decisions on written words, laterality covaried in (1) posterior vOT and the precentral gyrus; (2) middle vOT and the pars opercularis, pars triangularis, and supramarginal gyrus; and (3) anterior vOT and the pars orbitalis, middle frontal gyrus and thalamus. These findings increase the spatial resolution of our understanding of how vOT interacts with other brain areas during semantic categorisation on words. PMID- 23728083 TI - Biopolymer coated gold nanocrystals prepared using the green chemistry approach and their shape-dependent catalytic and surface-enhanced Raman scattering properties. AB - This study deals with the preparation of multi-shaped nanoscale gold crystals under synthetically simple, green, and efficient conditions using a seed-mediated growth approach in the presence of hyaluronic acid (HA). These highly biocompatible multi-shaped gold nanocrystals were examined to evaluate their catalytic and surface enhanced Raman scattering (SERS) properties. The results show that the size and shape of the nanocrystals are mainly correlated to the amount of seed, seed size, HA concentration, and reaction temperature. Gold seeds accelerate the reduction of the gold precursor to form gold nanocrystals using HA. The HA serves as a reducing agent and a growth template for the reduction of Au(III) and nanocrystal stabilization. The multi-shaped gold nanocrystals showed superior catalytic properties and higher SERS performance. The simple, green approach efficiently controls the nanocrystals and creates many opportunities for future applications. PMID- 23728084 TI - Isolation and genome analysis of single virions using 'single virus genomics'. AB - Whole genome amplification and sequencing of single microbial cells enables genomic characterization without the need of cultivation (1-3). Viruses, which are ubiquitous and the most numerous entities on our planet (4) and important in all environments (5), have yet to be revealed via similar approaches. Here we describe an approach for isolating and characterizing the genomes of single virions called 'Single Virus Genomics' (SVG). SVG utilizes flow cytometry to isolate individual viruses and whole genome amplification to obtain high molecular weight genomic DNA (gDNA) that can be used in subsequent sequencing reactions. PMID- 23728085 TI - Comparison of survival among neoadjuvant chemoradiation responders, non responders and patients receiving primary resection for locally advanced oesophageal squamous cell carcinoma: does neoadjuvant chemoradiation benefit all? AB - OBJECTIVES: While neoadjuvant chemoradiation followed by surgery has been shown to improve the survival of patients with locally advanced oesophageal cancer, it is not known whether neoadjuvant chemoradiation has a beneficial or harmful effect on the non-responders. We aimed to compare the outcomes among neoadjuvant chemoradiation responders, non-responders and patients receiving primary oesophagectomies for resectable locally advanced oesophageal squamous cell carcinoma. METHODS: Eighty-four non-T1-2N0 oesophageal squamous cell carcinoma patients were included. Thirty-eight patients received primary resection and 46 patients received neoadjuvant chemoradiation. The overall survival of chemoradiation responders (<50% residual tumour), non-responders (>50% residual tumour and those who shifted to definitive chemoradiation instead of surgery due to tumour progression) and patients receiving primary resection were compared. Clinical parameters were also compared between responders and non-responders. RESULTS: There was no overall difference in survival between neoadjuvant chemoradiation and primary resection groups (2-year overall survival rates: 45.6 vs 54.3%, P = 0.442). In patients receiving neoadjuvant chemoradiation followed by surgery, pathological responders had significantly higher 2-year overall survival rates than non-responders (64.5 vs 38.9%, P = 0.043). While the pathological responders had the highest survival rate, clinicopathological non responders (pathological non-responders and patients with tumour progression during the neoadjuvant chemoradiation period) demonstrated significantly worse outcomes than those receiving primary resection (32.0 vs 54.3%, P = 0.036). However, none of the clinical parameters, including blood profiles, images and baseline tumour characteristics, predicted the response to chemoradiation before treatment. CONCLUSIONS: Neoadjuvant chemoradiation non-responders demonstrated no benefit and an even worse outcome compared with those receiving primary resection for locally advanced oesophageal squamous cell carcinoma. However, no significant clinical parameters could be implemented in the clinics to predict the response to neoadjuvant chemoradiation before treatment. PMID- 23728086 TI - Bicuspid aortic valve aortopathy: genetics, pathophysiology and medical therapy. AB - The association between ascending aortic aneurysm (AA) and bicuspid aortic valve (BAV) has been well established. Different genetic, haemodynamic and cardiovascular risk factors have been implicated in the development and progression of AA. However, to date, definite conclusions cannot be drawn regarding the exact molecular, cellular and haemodynamic mechanisms causing BAV associated aortopathy. For this study, we performed a thorough electronic systematic review of the literature using MEDLINE (1960-2012) and EMBASE databases. MeSH terms included: 'bicuspid aortic valve and ascending aorta', 'bicommissural aortic valve and aneurysm', 'bicuspid aortopathy', 'bicuspid aortic valve pathophysiology', 'bicuspid aortic valve and genetics' and 'bicuspid aortic valve and treatment'. We aim in this review to discuss the mechanisms, pathophysiology, genetics and modern drug therapy in the context of BAV associated aortopathy. PMID- 23728088 TI - [Pharmacist as a real "gatekeeper" for the prevention of suicide, overdosage and depression: what should we need?]. PMID- 23728087 TI - Is elimination of cardiotomy suction preferable in aortic valve replacement? Assessment of perioperative coagulation, fibrinolysis and inflammation. AB - OBJECTIVES: Guidelines recommend the avoidance of direct return of pericardial blood based on evidence from coronary surgery. A continuous auto-transfusion system (CATS) can be a good alternative to cardiotomy suction by reinfusing aspirated pericardial blood without the necessity of intermittent collection. To clarify the effects of direct return of pericardial blood in aortic valve replacement (AVR), we compared the effects of cardiotomy suction and an alternative CATS on perioperative coagulofibrinolysis and inflammation systems, and clinical outcomes. METHODS: In 40 AVR operations between April 2009 and April 2011, the retransfusion method of pericardial blood during cardiopulmonary bypass (CPB) was allocated to the use of cardiotomy suction (non-Cell-Saver group, n = 20) or CATS (Cell-Saver group, n = 20) under identical protocols of anticoagulation and transfusion. The blood from the left ventricular vent was returned to the venous reservoir. We obtained blood samples at nine points up to the morning after surgery. RESULTS: Perioperative values for coagulofibrinolysis markers, such as thrombin-antithrombin III complex, fibrinogen degeneration products, D-dimer and plasmin-alpha2 plasmin inhibitor complex, were significantly lower in the Cell-Saver group than those in the non-Cell-Saver group from 1 h after the initiation of cardiopulmonary bypass to 3 or 6 h after termination of cardiopulmonary bypass (P < 0.05 for all markers). A fibrinolysis inhibition marker of plasminogen activator inhibitor-1 and the inflammation markers of interleukin-6, 8 and 10 as well as tumour necrosis factor-alpha were not significantly different. The amount of packed red blood cells required after the termination of CPB was significantly less in the Cell-Saver group compared with that in the non-Cell-Saver group (P = 0.004). There were no significant differences in the other clinical outcomes between the two groups. CONCLUSIONS: In AVR, the avoidance of direct return of pericardial blood induced considerable suppressions of coagulofibrinolysis responses. A CATS is a favourable alternative for managing pericardial blood during cardiopulmonary bypass. Our results support the published guidelines and could help to establish ideal strategies for eliminating the use of cardiotomy suction, thus facilitating less-invasive valve surgeries with marked suppression of coagulofibrinolysis responses. PMID- 23728089 TI - [Current situation of suicide in Japan, and what pharmacists contribute to suicide prevention]. AB - In Japan, a national countermeasure has been forwarded since the enactment of the Basic Act on Suicide Countermeasures in 2006 and the Comprehensive Suicide Prevention Initiative in 2007. The distinctive policy of the Japanese countermeasure is expressed as the word, "comprehensive," which means that suicide prevention may not only be carried out only by mental health measures but also by comprehensive measures including chance of administrative practices. This policy is proper, although mental health measures appear to be too simple inclining to psychiatric treatments for the classic type of "depression" by a pharmacotherapy. The authors have insisted that mental health measures including psychiatric treatments are also required to be more comprehensive. This paper describes that benzodiazepine (BZ)-abuse problems including overdosing by suicidal intents have got worse recently as psychiatric clinics have increased and most of BZ abusers obtain the abused drugs form psychiatrists. This current situation indicates that pharmacists need to monitor psychiatrists' prescribing behavior and qualities of psychiatric treatment is required to be refined, suggesting pharmacists may be one of the "Gate Keeper," as supporting resources for suicide prevention. Additionally, this paper explained that basic attitudes and responses acquired by pharmacists as a supporter for suicide prevention. PMID- 23728090 TI - [Pharmacist as gatekeeper: combating medication abuse and dependence]. AB - The nonmedical use of medications, including psychotropic drugs, is a growing health problem in Japan. According to a nationwide survey of mental hospitals, the proportion of patients with sedative (mainly benzodiazepine)-related disorders has more than doubled over the last decade. An association between psychotropic drug overdose and suicide risk has also been reported. Furthermore, over-the-counter drug abuse is still a serious problem in Japan. In recent years, pharmacists have been expected to act as gatekeepers, making timely identifications of suicide risk or substance abuse and directing these individuals to appropriate medical care facilities. In August 2012, the revised Comprehensive Suicide Measures Act identified pharmacists as one professional group that should act as gatekeepers. This article begins by reviewing the fundamental terms involved in understanding the nonmedical use of medications, including abuse, dependence, and intoxication. The current situation of substance abuse and dependence is then introduced through a summary of several epidemiological surveys conducted in Japan. Finally, the role of pharmacists as gatekeepers in preventing substance abuse and dependence on medications is discussed. PMID- 23728091 TI - [Education of pharmacists to enable a connection between physicians and persons unaware of their mental illness]. AB - Pharmacists work in places where they often get in contact with people who may have trouble with their illness, patients and patients' family with prescription, and customers who purchase over-the-counter (OTC) drugs and/or daily goods. Pharmacists can also identify excessive or unsuitable use of OTC drugs resulting from a psychiatric disorder. Moreover, they are in a position in which they can also find the normal-dose addictions and fatigued patient's family resulting from their daily patient's care. Since the consultation to a pharmacist is free of charge, many people often go to the pharmacist to talk about their health concerns. If pharmacists can get in contact with persons who are not aware of their mental illness and send them to the primary care physician, the pharmacists may contribute to prevent suicide and find the unrecognized psychiatric disorder. However, since pharmacists have little knowledge regarding to the psychiatric disorder, they cannot actively contact with this type of people. This article will argue about the methodology and education for pharmacists to connect undiagnosed patients to the appropriate medical care. It is proposed that the pharmacists should encourage the undiagnosed psychiatric patients to contact with the primary care physician. In addition, pharmacists should recommend the change of prescription to the medical doctors who examine the patients expected the addiction to the prescribed drug. PMID- 23728092 TI - [Interluekin-1: from regulation of cell proliferation to chronic inflammatory diseases]. AB - Interleukin 1 (IL-1) was initially defined as a factor which is produced by macrophages and exhibits proliferative activity on thymocytes and fibroblasts, B cell activation and endogenous pyrogen activity. Now IL-1 is known to exhibit pleiotropic activities on various cell types and play important roles in the regulation of immune, nervous and endocrine systems, progression of tumor cells, hematopoietic cell proliferation/differentiation and especially in inflammatory diseases. In 1985 I found that IL-1 exhibits cytocidal activity against human melanoma cells. Since then I have been engaged in the research of various aspects of IL-1. This review summarizes current knowledge of IL-1, including our research and beneficial effect of IL-1 blocking on inflammatory diseases. PMID- 23728093 TI - [Detailed characterization of bile acid and glucocorticoid world by mass spectrometry]. AB - The Nobel Prize in Chemistry for 2002 was shared by John B. Fenn and Koichi Tanaka "for their development of soft desorption methods for mass spectrometric analyses of biological macromolecules". Indeed, electrospray ionization and soft laser desorption ionization have proved to be of great value in "omics", such as metabolomics, transcriptomics and proteomics in providing a systematic and quantitative approach to the study of biological systems and networks. Moreover, these techniques have made great contributions to metabolic studies that are used for development of new drugs, as well as to the diagnosis of diseases including cancer based on the specific and sensitive detection of molecular biomarkers. In this article, we describe our recent results on characterization of bile acid metabolism in hepatobiliary disease as well as measurement of conjugated urinary tetrahydrocorticosteroids for assessment of altered corticoid metabolism in endocrine disease and the metabolic syndrome. PMID- 23728094 TI - [Analysis of the risk factors for severe neutropenia in advanced non-small cell lung cancer after the first course of chemotherapy with third-generation agents]. AB - We retrospectively evaluated clinical data before therapy to determine the risk factors for severe neutropenia in advanced non-small-cell lung cancer (NSCLC) patients treated with third-generation agents. We analyzed 100 patients who received such agents (paclitaxel, docetaxel, gemcitabine, irinotecan, or vinorelbine) for advanced NSCLC. The endpoint of the survey was the occurrence of severe neutropenia (grade 4). Risk factors significantly related to severe neutropenia were identified using logistic regression analysis. Of the 100 patients studied, the median age was 62.0 (32-81 years), and 77 (77.0%) were male. CEA 6.6 (0-2220) ng/dL and cytokeratin 19 fragment 21-1 (CYFRA) 4.8 (0.2 173.8) ng/dL before chemotherapy were higher than normal range. Severe neutropenia occurred in 36.0%, the incidence being highest in the first cycle (61.1%). In the univariate analysis, variables associated with severe neutropenia were sex, chest pain, absolute neutrophil count (ANC), Cr, CRP, and CYFRA. In the multivariate analysis, low CYFRA level was identified as a significant risk factor that contributed independently to chemotherapy-induced severe neutropenia (p<0.05). Our analysis suggests that low CYFRA level is the most important risk factor for severe neutropenia in advanced NSCLC patients after the first course of chemotherapy with third-generation agents. PMID- 23728095 TI - [Effect of storage temperature on gelation of oral methylcellulose formulation]. AB - Heating a methylcellulose solution forms a thermal-reversible hydrogel. After the hydrogel forms, its properties change according to its temperature. However, the effects of heating this solution during storage and then cooling it are unclear. We investigated the effects of this heating and cooling on rheological and drug release characteristics. We prepared samples of methylcellulose solution (2% methylcellulose and 20% D-sorbitol) and examined them under two conditions: 1) storage for 24 hours at 4 to 30C, 2) storage for 24 hours at 4 to 50C, then cooling to 4C and maintained for 4 hours. We performed rheological investigations of viscosity, gelation temperature and gel strength, and examined the drug release characteristics by using a diffusion cell method with acetaminophen as the model drug. It was found that as the storage temperature rose, the methylcellulose solution increased in viscosity and the gelation temperature and gel strength changed. During storage at 30C, the amount of drug released by the solution increased and the diffusion coefficient was high. When cooled to 4C, the solution recovered its viscosity, gelation temperature, gel strength and drug release characteristics, regardless of the previous storage temperature. These results clarify that although the rheological and drug release characteristics of methylcellulose solution change with changes in storage temperature, the original characteristics are recovered after the solution is cooled to 4C and maintained at that temperature for four hours. PMID- 23728096 TI - [Sustained-release progesterone vaginal suppositories 3-development and clinical feasibility testing]. AB - Although progesterone vaginal suppositories (hospital-formulated) are used for the treatment of infertility, their half-life is so short that multiple doses are required. In this study, we aimed to develop sustained-release vaginal suppositories suitable for clinical use which maintain an effective blood concentration by once-a-day treatment, and prepared 7 types of suppository containing the sustained-release progesterone tablets to characterize their sustained-release performance. We selected one candidate suppository among them, taking recovery rate, reproducibility, and hardness, as well as the sustained release performance into consideration. The shell of the selected suppository is composed of VOSCO S-55 and progesterone for rapid release. The molded progesterone tablets for sustained release were embedded inside. The distribution of the weight and content of the suppository was limited, and the release rate of progesterone was significantly slower than that of a conventional progesterone suppository prepared in our hospital. The single-dose administration of the selected suppository to five healthy volunteers led to significant extension of the blood concentration. We also confirmed the rise of the basic value by multiple administration. The simulation comparison suggested that the blood progesterone concentration is controlled by once-a-day administration of the selected suppository better than twice-a-day administration of the conventional suppository. In conclusion, the sustained-release vaginal suppository prepared in this study was considered to be useful for clinical treatment. PMID- 23728097 TI - [Patients' reaction to pharmacists wearing a mask during their consultations]. AB - This study sought to determine the effect of pharmacists wearing a mask on the consultation intention of patients who do not have a trusting relationship with the pharmacists. We conducted a questionnaire survey of customers at a Tokyo drugstore in August 2012. Subjects answered a questionnaire after watching two medical teaching videos, one in which the pharmacist was wearing a mask and the other in which the pharmacist was not wearing a mask. Data analysis was performed using a paired t-test and multiple logistic regression. The paired t-test revealed a significant difference in 'Maintenance Problem' between the two pharmacist situations. After excluding factors not associated with wearing a mask, multiple logistic regression analysis identified three independent variables with a significant effect on participants not wanting to consult with a pharmacist wearing a mask. Positive factors were 'active-inactive' and 'frequency mask use', a negative factor was 'age'. Our study has shown that pharmacists wearing a mask may be a factor that prevents patients from consulting with pharmacist. Those patients whose intention to consult might be affected by the pharmacists wearing a mask tended to be younger, to have no habit of wearing masks preventively themselves, and to form a negative opinion of such pharmacists. Therefore, it was estimated that pharmacists who wear masks need to provide medical education by asking questions more positively than when they do not wear a mask in order to prevent the patient worrying about oneself. PMID- 23728099 TI - Cholinergic regulation of bone. AB - Bone remodeling is regulated by the two branches of the autonomic nervous system: the adrenergic and the cholinergic branches. Adrenergic activity favors bone loss, whereas cholinergic activity has been recently shown to favor bone mass accrual. In vitro studies have reported that cholinergic activity induces proliferation and differentiation of bone cells. In vivo studies have shown that the inhibition of cholinergic activity favors bone loss, whereas its stimulation favors bone mass accrual. Clinical studies have shown that bone density is associated with the function of many cholinergic-regulated tissues such as the hypothalamus, salivary glands, lacrimal glands and langerhans cells, suggesting a common mechanism of control. Altogether, these observations and linked findings are of great significance since they improve our understanding of bone physiology. These discoveries have been successfully used recently to investigate new promising therapies for bone diseases based on cholinergic stimulation. Here, we review the current understanding of the cholinergic activity and its association with bone health. PMID- 23728100 TI - Epigenetic regulation on gene expression induced by physical exercise. AB - It is well established that physical exercise modulates the function of many physiological systems, such as the musculoskeletal, the cardiovascular and the nervous system, by inducing various adaptations to the increased mechanical load and/or metabolic stress of exercise. Many of these changes occur through epigenetic alterations to DNA, such as histone modifications, DNA methylations, expression of microRNAs and changes of the chromatin structure. All these epigenetic alterations may have clinical relevance, thus playing an important role in the prevention and confrontation of neurophysiological disorders, metabolic syndrome, cardiovascular diseases and cancer. Herein we review the known epigenetic modifications induced by physical exercise in various physiological systems and pathologies, and discuss their potential clinical implications. PMID- 23728098 TI - Development and characterization of small bispecific albumin-binding domains with high affinity for ErbB3. AB - Affinity proteins based on small scaffolds are currently emerging as alternatives to antibodies for therapy. Similarly to antibodies, they can be engineered to have high affinity for specific proteins. A potential problem with small proteins and peptides is their short in vivo circulation time, which might limit the therapeutic efficacy. To circumvent this issue, we have engineered bispecificity into an albumin-binding domain (ABD) derived from streptococcal Protein G. The inherent albumin binding was preserved while the opposite side of the molecule was randomized for selection of high-affinity binders. Here we present novel ABD variants with the ability to bind to the epidermal growth factor receptor 3 (ErbB3). Isolated candidates were shown to have an extraordinary thermal stability and affinity for ErbB3 in the nanomolar range. Importantly, they were also shown to retain their affinity to albumin, hence demonstrating that the intended strategy to engineer bispecific single-domain proteins against a tumor associated receptor was successful. Moreover, competition assays revealed that the new binders could block the natural ligand Neuregulin-1 from binding to ErbB3, indicating a potential anti-proliferative effect. These new binders thus represent promising candidates for further development into ErbB3-signaling inhibitors, where the albumin interaction could result in prolonged in vivo half life. PMID- 23728101 TI - Randomized controlled study on resistive vibration exercise (EVE study): protocol, implementation and feasibility. AB - OBJECTIVES: A training intervention comparing resistance exercise with or without whole-body vibration (WBV) was conducted to compare acute and chronic effects on functional and molecular parameters. METHODS: A six-week training intervention was performed including 26 healthy males (26 years, SD=4). Two groups were analyzed in a parallel design performing either resistive exercise (RE, n=13) or resistive vibration exercise (RVE, n=13) training with weekly increasing vibration frequencies (20-40Hz). Resting and exercising blood pressure and heart rate were measured before and after the 6-week intervention. RESULTS: Both training interventions decreased resting systolic blood pressure (P=0.003). Resting diastolic blood pressure was significantly decreased only in the RVE group (P=0.01). Exercising diastolic blood pressure was significantly decreased during the final training (P<0.001) with no additional effect of superimposed vibrations. Resistance exercise with superimposed vibrations evoked back pain to a higher degree than resistance exercise alone when training at frequencies above 30Hz (P<0.01). CONCLUSIONS: These data suggest positive effects of resistance exercise upon cardiovascular health and vascular responsiveness and a further beneficial effect of superimposed vibrations in decreasing resting diastolic blood pressure. Finally, development of back pain may be fostered by superimposed vibrations to high training loads, particularly at higher frequencies. PMID- 23728102 TI - Tactile and Kinesthetic Stimulation (TKS) intervention improves outcomes in weanling rat bone in a neonatal stress model. AB - OBJECTIVES: Preterm infants are born with low bone mineral. Neonatal stress further impedes bone mineralization. Clinical evidence suggests that tactile and kinesthetic stimulation (TKS) improves bone phenotype and decreases stress response. Clinical and translational studies indicate the IGF-1 axis, responsible for postnatal growth and bone mineralization, is a key player. We hypothesized that TKS would attenuate the negative impact of neonatal stress on bone phenotype and the IGF-1 axis in weanling rats. METHODS: Neonatal stress (STRESS) or TKS (STRESS + 10min TKS) was administered from D6 to D10. Control animals received standard care. Tissue was harvested on D21. Dual energy x-ray absorptiometry (DXA) and bone morphometry were performed and serum osteocalcin, type I procollagen N-terminal propeptide (PINP), tartrate-resistant acid phosphatase (TRAP), and bone and liver mRNA levels of IGF-1, IGF-1 receptor (IGF-1R), and growth hormone receptor (GHR) were measured. RESULTS: Neonatal stress increased bone mineral content (BMC), area (BA), growth plate width, liver IGF-1 mRNA, and serum IGF-1. TKS maintained areal bone mineral density (aBMD) and bone specific IGF-1 and IGF-1R mRNA while STRESS decreased compared to controls. CONCLUSIONS: Neonatal stress results in apparent accelerated growth response. TKS differed from STRESS with improved tibia aBMD and increased bone specific IGF-1 mRNA. PMID- 23728103 TI - Bone and muscle structure and quality preserved by active versus passive muscle exercise on a new stepper device in 21 days tail-suspended rats. AB - Human performance in microgravity is characterized by reversed skeletal muscle actions in terms of active vs. passive mode contractions of agonist/antagonist groups that may challenge principal biodynamics (biomechanical forces translated from muscle to bone) of the skeletal muscle-bone unit. We investigated active vs. passive muscle motions of the unloaded hindlimb skeletal muscle-bone unit in the 21 days tail-suspended (TS) rat using a newly designed stepper exercise device. The regimen included both active mode motions (TSA) and passive mode motions (TSP). A TS-only group and a normal cage group (CON) served as positive or negative controls. The muscle and bone decrements observed in TS-only group were not seen in the other groups except TSP. Active mode motions supported femur and tibia bone quality (5% BMD, 10% microtrabecular BV/TV, Tb.Th., Tb.N. parameters), whole soleus muscle/myofiber size and type II distribution, 20% increased sarcolemma NOS1 immunosignals vs. CON, with 25% more hybrid fiber formation (remodeling sign) for all TS groups. We propose a new custom-made stepper device to be used in the TS rat model that allows for detailed investigations of the unique biodynamic properties of the muscle-bone unit during resistive-load exercise countermeasure trials on the ground or in microgravity. PMID- 23728104 TI - Time-dependent effects of sclerostin antibody on a mouse fracture healing model. AB - OBJECTIVES: Treatment with Sclerostin antibody (Scl-Ab) has shown to enhance fracture healing in rodent and non-human primate models. The current study investigated the time-dependent changes during Scl-Ab treatment in a mouse osteotomy model. METHODS: 1 day after osteotomy, C57BL mice received subcutaneous injection with vehicle or Scl-Ab at 25 mg/kg, twice/week for 2, 4, or 6 weeks. 20 mice from each group were necropsied at weeks 2, 4, and 6 for Micro-CT, histomorphmetry and mechanical testing examinations. RESULTS: The bone mineral apposition rate at fracture callus was significantly higher in the Scl-Ab treated groups at all the time points. Micro-CT analysis showed that the volumetric bone mineral density (vBMD) and bone volume over tissue volume (BV/TV) in the Scl-Ab treated groups at 4 and 6 weeks were significantly greater than that of vehicle control groups. Mechanical testing showed that the maximum load of failure at the fracture callus increased significantly by 68% at 6 weeks in the Scl-Ab treated groups. CONCLUSIONS: This study confirmed that mice treated with Scl-Ab increased bone formation from 2 weeks, bone mineral density and bone volume at 4 weeks, followed by significant increase in bone strength at the fracture site at 6 weeks. These results suggest that applying sclerostin antibody at early stage fracture healing promotes fracture healing. PMID- 23728105 TI - Mineralization- and remodeling-unrelated improvement of the post-yield properties of rat cortical bone by high doses of olpadronate. AB - Some pharmacologic effects on bone modeling may not be evident in studies of remodeling skeletons. This study analyzes some effects of olpadronate on cortical bone modeling and post-yield properties in femurs diaphyses (virtually only modeling bones) of young rats by mid-diaphyseal pQCT scans and bending tests. We studied 20/22 male/female animals traetad orally with olpadronate (45-90 mg/kg/d, 3 months) and 8/9 untreated controls. Both OPD doses enhanced diaphyseal cross sectional moments of inertia (CSMI) with no change in cortical vBMD and elastic modulus. Yield stiffness and strength were mildly increased. Post-yield strength, deflection and energy absorption were strikingly enhanced. Ultimate strength was enhanced mainly because of effects on bone mass/geometry and post-yield properties. The large improvement of post-yield properties could be explained by improvements in bone geometry. Improvements in bone mass/geometry over weight bearing needs suggest an enhanced modeling-related response to mechanical stimuli. Effects on tissue microstructural factors (not measured) could not be excluded. Results reveal novel olpadronate effects on bone strength and toughness unrelated to tissue mineralization and stiffness, even at high doses. Further studies could establish whether this could also occur in modeling-remodeling skeletons. If so, they could counteract the negative impact of anti-remodeling effects of bisphosphonates on bone strength. PMID- 23728106 TI - pQCT-assessed relationships between diaphyseal design and cortical bone mass and density in the tibiae of healthy sedentary and trained men and women. AB - In a pQCT study of running-trained and untrained men and women we had shown that bone mass distribution along the tibia was adapted to the usage-derived stress pattern. To study the possible association between the efficiency of diaphyseal design and bone material stiffness, we extend the analysis of the same sample to correlate pQCT indicators of the distribution (CSMIs), mass (BMC), and density (vBMD) of cortical bone tissue as descriptors of "distribution/mass" (d/m) or "distribution/quality" (d/q) relationships. The d/m and d/c curves followed positive (exponential) and negative (hyperbolic-like) equations, respectively. Distribution curves of r coefficients throughout the bone were all bell-shaped, reaching a maximum towards the mid-diaphysis. The CSMIs and BMC were higher, and vBMD was lower in men than women and in runners than non-runners. The d/m relationships were described by unique curves for all groups while d/q relationships were better adjusted to separate curves for men and women. Results support that: 1. diaphyseal design reflects the relative influence of bending/torsion stress along the bones, tending to minimize bone mass; 2. there is a trade-off between cortical bone "quality" and distribution; 3. d/m and d/q relationships are related to bone mechanical environment, and 4. d/q relationships are affected by sex. PMID- 23728107 TI - Geometric indices of hip bone strength in young female football players. AB - OBJECTIVE: The aim of this study was to compare geometric indices of hip bone strength in female football players and controls. METHODS: 18 adult female football players and 18 adult sedentary females participated in this study. The two groups were paired for age, weight and body mass index (BMI). Daily calcium intake (DCI) and daily protein intake (DPI) were evaluated by questionnaires. Total hip bone mineral density (BMD) and femoral neck BMD were measured by DXA. Cross-sectional area (CSA), an index of axial compression strength, section modulus (Z), an index of bending strength and cortical thickness (CT) were evaluated at the femoral neck (FN), the intertrochanteric (IT) and the femoral shaft (FS) regions by the hip structure analysis (HSA) program. RESULTS: Age, weight, height, BMI, DCI and DPI were not different between the two groups. TH BMD, FN BMD, FN CSA, FN Z, FN CT, IT CSA, IT Z, IT CT, FS CSA and FS Z were significantly higher in football players compared to controls (crude percentage differences between the two groups varied between 8 and 19%; P<0.05). After adjusting for body weight using a one-way analysis of covariance (ANCOVA), TH BMD, FN BMD, FN CSA, FN Z, FN CT, IT CSA, IT Z, IT CT, FS CSA and FS Z remained significantly higher in football players compared to controls (adjusted percentage differences between the two groups varied between 7 and 17%; P<0.05). CONCLUSION: This study suggests that, in adult females, football practice is associated with greater geometric indices of hip bone strength. PMID- 23728108 TI - Mechanography in childhood: references for force and power in counter movement jumps and chair rising tests. AB - OBJECTIVE: We sought to procure age- and gender- related reference data and study the characteristics of body weight related peak force (pFrel), body mass related peak power (pPrel) for counter movement jumps (single two-legged jumps, s2LJ) and chair rising tests (CRT) in children. METHODS: We examined 868 healthy participants (436 female) aged 3 to 19 years. Weight-related results of the s2LJ and CRT Mechanography parameters were reported. RESULTS: pPrel during s2LJ (pPrel(s2LJ)) increased linearly with age for males age 5 to 19 and female age 5 to 11 at a rate of 4.6 W/kg per year. pPrel(s2LJ) for females age 12 to 19 increased only by 2.5 W/kg. CRT time per repetition was 1.065 s, independent of age and gender. pPrel per body mass during the rise phase (pPrel(CRT)) showed similar but smaller age and gender relations as peak power during s2LJ. pFrel was 2.5 g (multiples of earth's gravity) for s2LJ and 1.5 g for CRT. CONCLUSION: This data from normal children from a healthy Caucasian population provide reference values for tests that reflect everyday motor function. PMID- 23728109 TI - Mechanography in childhood: references for grip force, multiple one-leg hopping force and whole body stiffness. AB - OBJECTIVE: We sought to study and procure reference values for weight-related maximum isometric grip force (MIGF), maximum voluntary force in relation to body weight (Fmvrel) and peak whole body stiffness (pKwb) in multiple one-legged hopping (m1LH) in childhood. METHODS: We examined 868 children and adolescents (436 female) aged 3 to 19 yrs. Weight related results are reported as multiples of earth's gravity (g). RESULTS: MIFG and Fmv(m1LH) are highly linearly correlated with body weight. After adjustment for weight, mean Fmvrel(m1LH) increases from the age of 3 to 6 yrs, then remains at 3.33 g (SD 0.31 g) between 6 and 19 yrs, independent of age and gender. The difference between legs decreases from 10% at 3 yrs to a constant 5.5% after the age of 7 yrs. Weight adjusted MIGF also increases steeply from 3 to 6 yrs, then shows a further linear, less steep increase - in males through to age 19 yrs while females show a near-standstill after the age of 12 yrs. pKwb(m1LH) increases from the age of 7 yrs. CONCLUSION: This data from normal children from a healthy Caucasian population provide a reference for tests of motor function. PMID- 23728110 TI - Decomposition of the vertical ground reaction forces during gait on a single force plate. AB - Davis and Cavanagh (1993) have proposed a solution to avoid the footstep targeting by using a large force plate but several points of Davis and Cavanagh's method remain unclear and hardly computable. OBJECTIVE: to develop a method that decomposes left and right GRF profiles from the GRF profile recorded on a single platform. This method aims to include a systematic detection of the single to double stand-phase-instants in order to lead to accurate measurement of the vertical GRF component in typically developing children. METHODS: Six children were asked to walk without targeting their footsteps on a set-up composed of independent force platforms. The vertical GRF component, independently measured on the different platforms, was numerically summed to obtain the corresponding global vertical GRF, to which the decomposition method was applied. Then, the validation consisted in comparing the vertical GRF computed from this decomposition to the independently measured vertical GRF. RESULTS: the mean relative error between the computed vertical GRF and the corresponding measured vertical GRF of 36 double stances (6 double stances x 6 children) is equal to 3.8+/-2.6%. CONCLUSION: implemented a new method to assess with known accuracy the vertical GRF component under each foot using a unique large force platform. PMID- 23728111 TI - Kinematic quantification of gait asymmetry in patients with peroneal nerve palsy based on bilateral cyclograms. AB - Nowadays, bipedal walking is undergoing extensive study. Several methods can be used in physiotherapeutic research for identifying defects in bipedal walking as a result of pathology of the musculoskeletal or nervous system. Our work focuses on studying asymmetry of walking based on synchronized bilateral knee-knee cyclograms. Participants presenting with peroneal nerve palsy and foot drop were included in the study. The bilateral cyclograms, also called angle-angle diagrams, were created to quantify gait asymmetry before and immediately after application of a brace. In order to quantify the asymmetry of human walking, we have described and tested the application of the method based on the inclination angle of the synchronized bilateral cyclograms. The symmetry index (SI) was used as a comparative method to evaluate the symmetry of bipedal walking. The method based on the orientation of the cyclograms can be used as an additional method for determining the gait asymmetry. The new technique has never been applied before to study the gait asymmetry in patients with peroneal nerve palsy or patients with leg brace. PMID- 23728112 TI - Pelvic fractures associated with long-term bisphosphonate therapy - case report. AB - Long term bisphosphonate use has been associated with "atypical" subtrochanteric and diaphyseal fractures of the femoral shaft. We are reporting a case of pelvic fractures in addition to atypical long bone fractures, in a patient with osteopenia treated with bisphosphonate for 8 years, and teriparatide for 2 years. After 5 years of bisphosphonate therapy the patient suffered an atraumatic fracture of the femoral shaft. With an additional 3 years of bisphosphonate use she fractured both the upper and lower pubic rami on the left side. Bone histomorphometry performed on a biopsy of right iliac crest was negative for malignancy and calcification defects. It showed normal to low/normal bone turnover which correlated well with a low NTX level. Post-surgical X-rays revealed cortical thickening of the femur and beaking at the femoral shaft fracture, the classic findings associated with alendronate-related fractures. The pelvic fractures also reveal beaking at the fracture sites. Spontaneous fracture of the pelvis with unusual characteristics, in a patient with an atypical fracture of the femur suggests that the pelvic fracture may be related to long term bisphosphonate therapy. PMID- 23728113 TI - Coexistence of paget disease of bone and primary hyperparathyroidism; a diagnostic challenge. PMID- 23728114 TI - Unilateral muscle hypertrophy and focal myositis following S1 radiculopathy. PMID- 23728115 TI - In memoriam of Maria Katsiri. PMID- 23728118 TI - The contribution of prescription chart design and familiarity to prescribing error: a prospective, randomised, cross-over study. AB - PURPOSE OF STUDY: Initiatives to standardise hospital paper-based prescription charts are underway in various countries in an effort to reduce prescribing errors. The aim of this study was to investigate the extent to which prescribing error rates are influenced by prescription chart design and familiarity. STUDY DESIGN: In this prospective, randomised, cross-over study, Foundation Year 1 doctors working in five Scottish National Health Service (NHS) Boards participated in study sessions during which they were asked to prescribe lists of medications for five fictional patients using a different design of paper prescription chart for each patient. Each doctor was timed completing each set of prescriptions, and each chart was subsequently assessed against a predefined list of possible errors. A mixed modelling approach using three levels of variables (design of and familiarity with a chart, prescribing speed and individual prescriber) was employed. RESULTS: A total of 72 Foundation Year 1 doctors participated in 10 data-collection sessions. Differences in prescription chart design were associated with significant variations in the rates of prescribing error. The charts from NHS Highland and NHS Grampian produced significantly higher error rates than the other three charts. Participants who took longer to complete their prescriptions made significantly fewer errors, but familiarity with a chart did not predict error rate. CONCLUSIONS: This study has important implications for prescription chart design and prescribing education. The inverse relationship between the time taken to complete a prescribing task and the rate of error emphasises the importance of attention to detail and workload as factors in error causation. Further work is required to identify the characteristics of prescription charts that are protective against errors. PMID- 23728119 TI - Patient bedside observations: what could be simpler? PMID- 23728120 TI - Patient safety in healthcare preregistration educational curricula: multiple case study-based investigations of eight medicine, nursing, pharmacy and physiotherapy university courses. AB - BACKGROUND: We sought to investigate the formal and informal ways preregistration students from medicine, nursing, pharmacy and the allied healthcare professions learn about patient safety. METHODS: We drew on Eraut's framework on formal and informal acquisition of professional knowledge to undertake a series of phased theoretically informed, in-depth comparative qualitative case studies of eight university courses. We collected policy and course documentation; interviews and focus groups with educators, students, health service staff, patients and policy makers; and course and work placement observations. Data were analysed thematically extracting emerging themes from different phases of data collection within cases, and then comparing these across cases. RESULTS: We conducted 38 focus groups with a total of 162 participants, undertook 82 observations of practice placements/learning activities and 33 semistructured interviews, and analysed 44 key documents. Patient safety tended to be either implicit in curricula or explicitly identified in a limited number of discrete topic areas. Students were predominantly taught about safety-related issues in isolation, with the consequence of only limited opportunities for interprofessional learning and bridging the gaps between educational, practice and policy contexts. Although patient safety role models were key to student learning in helping to develop and maintain a consistent safety ethos, their numbers were limited. CONCLUSIONS: Consideration needs to be given to the appointment of curriculum leads for patient safety who should be encouraged to work strategically across disciplines and topic areas; development of stronger links with organisational systems to promote student engagement with organisation-based patient safety practice; and role models should help students to make connections between theoretical considerations and routine clinical care. PMID- 23728122 TI - Italian cardiological guidelines for sports eligibility: a commentary. PMID- 23728123 TI - The Italian cardiological guidelines for eligibility in competitive sports: food for thought in preventive cardiology. PMID- 23728121 TI - Evaluation of contralateral kidney, liver and lung after extracorporeal shock wave lithotripsy in rabbits. AB - An experimental study was carried out to evaluate the effects of extracorporeal shock wave lithotripsy (ESWL) on contralateral kidney, liver and lung by histopathological and biochemical methods. Twelve New Zealand rabbits were allocated to two groups (n = 6). Tissues of control group (CG, n = 6) were harvested without any intervention. In ESWL group (EG), right kidneys were exposed to 3,000 shock waves at 14 kV energy using electro-hydraulic type ESWL device three times every other day. Both kidneys, liver, and right lobe of lung tissues in EG were harvested on seventh day. Kidneys were examined histopathologically for presence of glomerular and tubular injury, interstitial edema, congestion, inflammation and fibrosis. Livers were examined for hepatocyte vacuolization, congestion, portal inflammation and fibrosis. Lung tissues were examined for loss of normal structure, emphysema, interstitial congestion-edema, prominent alveolar septal vessels, interstitial inflammation, intra-alveolar hemorrhage, intraluminal hemorrhage, peribronchial edema, congestion, inflammation in bronchial wall and epithelial desquamation. Biochemical analysis of tissue samples was performed for oxidative injury markers. Histopathological evaluations revealed that tubular injury was found in both shocked and contralateral kidneys (p < 0.05). EG showed higher grades of portal fibrosis in liver and higher grades of peribronchial congestion in lung when compared to CG (p < 0.05). Biochemical evaluations of both kidneys showed that malondialdehyde levels were higher in EG than in CG (p < 0.05). ESWL causes histopathologic alterations both in shocked and contralateral kidneys. Extrarenal tissues such as liver and lung can be affected by shock waves histopathologically and oxidative injury of contralateral kidney may occur acutely after ESWL. PMID- 23728124 TI - Left ventricular non-compaction in pregnancy. AB - Left-ventricular non-compaction (LVNC) represents an arrest in the normal process of myocardial compaction, resulting in multiple, prominent, persistant trabeculations and deep inter-trabecular recesses communicating with the ventricular cavity. LVNC is a rarely encountered cardiomyopathy and few cases have been reported in pregnancy. In this case report we present a patient who referred to our clinic with symptoms of heart failure during pregnancy and whose echocardiographic examination revealed prominent trabeculations in the left ventricle. PMID- 23728125 TI - Unexpected preserved brain perfusion imaging despite severe and diffuse atherosclerosis of supra-aortic trunks. AB - We report an unusual case of a patient whose whole cerebral circulation was supported by poor vicariate collaterals and a severely atherosclerotic right vertebral artery, with no brain perfusion abnormalities. Our belief is that despite the brain imaging and the absence of symptoms, because of his critical vascular disease and the paucity of data from large randomised clinical trials on vertebra-basilar revascularisation, the case required an extremely cautious approach regarding any kind of revascularisation. An accurate imaging analysis together with clinical features allowed us to decide on a strategy based on optimal medical therapy and careful clinical monitoring. PMID- 23728126 TI - Unusual variant of scimitar syndrome associated with an absent right pulmonary artery, stenosis of the inferior vena cava, hemi-azygous continuation and the VACTERL association. AB - We report on a two-month-old infant with an unusual form of scimitar syndrome, associated with an absent right pulmonary artery, obstructed inferior vena cava, hemi-azygous continuation and the VACTERL association. The infant posed a major management problem and eventually died from a lower respiratory tract infection. PMID- 23728127 TI - Candida parapsilosis endocarditis on a prosthetic aortic valve with unclear echocardiographic features. AB - Fungal endocarditis is rare in comparison with bacterial endocarditis and is associated with a poor prognosis. Despite the proven reliability of echocardiography, false negatives are not uncommon and may influence the therapeutic strategy, as some reports have supported the efficacy of antifungal treatment alone. We report on a case of bioprosthetic aortic valve Candida parapsilosis endocarditis without typical echocardiograhy findings, which we treated with both antifungal and surgical therapy. PMID- 23728128 TI - Robotically assisted ventricular tachycardia substrate modification ablation with the novel Lynx(TM) integrated sheath and RF ablation catheter. AB - Catheter ablation of ventricular tachycardia (VT) is demanding and time consuming. Robotically controlled catheter ablation reduces operator fatigue and exposure to X-rays, and provides greater precision and stability of the catheter. A new flexible, integrated robotic sheath and ablation catheter has recently been introduced (Lynx(TM)) and used in atrial ablation procedures. We describe the first VT substrate modification ablation in the world with the Lynx(TM) robotic radio frequency ablation catheter. PMID- 23728129 TI - Forgotten hardware: how to urinate in a spacesuit. AB - On May 5, 1961, astronaut Alan Shepard became the first American to fly in space. Although National Aeronautics and Space Administration (NASA) had discounted the need for him to urinate, Shepard did, in his spacesuit, short circuiting his electronic biosensors. With the development of the pressure suit needed for high altitude and space flight during the 1950s, technicians had developed the means for urine collection. However, cultural mores, combined with a lack of interagency communication, and the technical difficulties of spaceflight made human waste collection a difficult task. Despite the difficulties, technicians at NASA created a successful urine collection device that John Glenn wore on the first Mercury orbital flight on February 20, 1962. With minor modifications, male astronauts used this system to collect urine until the Space Shuttle program. John Glenn's urine collection device is at the National Air and Space Museum and has been on view to the public since 1976. PMID- 23728130 TI - Using a classic paper by Robin Fahraeus and Torsten Lindqvist to teach basic hemorheology. AB - "The viscosity of the blood in narrow capillary tubes" by Robin Fahraeus and Torsten Lindqvist (Am J Physiol 96: 562-568, 1931) can be a valuable opportunity for teaching basic hemorheological principles in undergraduate cardiovascular physiology. This classic paper demonstrates that a progressive decline in apparent viscosity occurs when blood flows through glass capillary tubes of diminishing radius, which was later designated as the "Fahraeus-Lindqvist effect." Subsequent studies have shown that apparent viscosity continues to decline at diameters that correspond to the arteriolar segments of the systemic vascular tree, where the majority of the total peripheral resistance resides and is actively regulated in vivo. The Fahraeus-Lindqvist effect thus reduces microvascular resistance, thereby maintaining local tissue perfusion at a relatively lower blood pressure. The paper by Fahraeus and Lindqvist can be used as a platform for a plenary discussion of these concepts as well as of the relationships among hematocrit, vessel diameter, red blood cell deformability, and resistance to blood flow and how these factors may affect the work of the heart. PMID- 23728131 TI - Rationale and resources for teaching the mathematical modeling of athletic training and performance. AB - A number of professions rely on exercise prescription to improve health or athletic performance, including coaching, fitness/personal training, rehabilitation, and exercise physiology. It is therefore advisable that the professionals involved learn the various tools available for designing effective training programs. Mathematical modeling of athletic training and performance, which we henceforth call "performance modeling," is one such tool. Two models, the critical power (CP) model and the Banister impulse-response (IR) model, offer complementary information. The CP model describes the relationship between work rates and the durations for which an individual can sustain them during constant work-rate or intermittent exercise. The IR model describes the dynamics by which an individual's performance capacity changes over time as a function of training. Both models elegantly abstract the underlying physiology, and both can accurately fit performance data, such that educating exercise practitioners in the science of performance modeling offers both pedagogical and practical benefits. In addition, performance modeling offers an avenue for introducing mathematical modeling skills to exercise physiology researchers. A principal limitation to the adoption of performance modeling is a lack of education. The goal of this report is therefore to encourage educators of exercise physiology practitioners and researchers to incorporate the science of performance modeling in their curricula and to serve as a resource to support this effort. The resources include a comprehensive review of the concepts associated with the development and use of the models, software to enable hands-on computer exercises, and strategies for teaching the models to different audiences. PMID- 23728132 TI - The effectiveness of separating theory and practicum as a conduit to learning physiology. AB - Many conventional science courses contain subjects embedded with laboratory-based activities. However, research on the benefits of positioning the practicals within the theory subject or developing them distinctly from the theory is largely absent. This report compared results in a physiology theory subject among three different cohorts of students: those taking the theory subject alone, those taking it concurrent with a physiology practicum subject, and those who previously took the subject when it had practicums embedded within the one subject. The path model shows that students taking both physiology theory and physiology practicum attained a significantly higher result in online tests compared with those who took the theory subject alone (P < 0.05) and that this translated to a significantly higher result in the end-of-semester examination. Similarly, students taking both physiology theory and the physiology practicum attained a significantly higher end-examination result compared with those who took the physiology subject in previous years when the practicums were embedded within the theory subject (P < 0.05). In both cases, this increase was largely attained in components that tested critical thinking and deep learning (short theory application questions and extended written questions). We conclude that students undertaking both physiology theory and the physiology practicum likely performed better in the theory subject due to better problem-solving skills and a more developed understanding of theoretical content. We suggest that consideration be given in all science curricula to the separation of theory and practicum by developing two subjects with clearly defined different learning outcomes. PMID- 23728133 TI - Offering an anatomy and physiology course through a high school-university partnership: the Minnesota model. AB - This article describes a one-semester anatomy and physiology course that is currently offered through the concurrent enrollment program at the University of Minnesota. The article explains how high school teachers are prepared to teach the course and describes efforts to promote program quality, student inquiry, and experiential learning. Recommendations are made for anatomy and physiology instructors who are involved in similar endeavors. PMID- 23728134 TI - A teacher-developed inquiry model to teach the molecular basis of hyperbolic kinetics in biological membrane transport. AB - A previously published classroom teaching method for helping students visualize and understand Michaelis-Menten kinetics (19) was used as an anticipatory set with high school and middle school science teachers in an Illinois Math and Science Partnership Program. As part of the activity, the teachers were asked to collect data by replicating the method and to analyze and report the data. All concluded that the rate data they had collected were hyperbolic. As part of a guided inquiry plan, teachers were then prompted to reexamine the method and evaluate its efficacy as a teaching strategy for developing specific kinetic concepts. After further data collection and analysis, the teachers discovered that their data trends were not, in fact, hyperbolic, which led to several teacher-developed revisions aimed at obtaining a true hyperbolic outcome. This article outlines the inquiry process that led to these revisions and illustrates their alignment with several key concepts, such as rapid equilibrium kinetics. Instructional decisions were necessary at several key points, and these are discussed. PMID- 23728135 TI - Development of concept-based physiology lessons for biomedical engineering undergraduate students. AB - Physiology is a core requirement in the undergraduate biomedical engineering curriculum. In one or two introductory physiology courses, engineering students must learn physiology sufficiently to support learning in their subsequent engineering courses and careers. As preparation for future learning, physiology instruction centered on concepts may help engineering students to further develop their physiology and biomedical engineering knowledge. Following the Backward Design instructional model, a series of seven concept-based lessons was developed for undergraduate engineering students. These online lessons were created as prerequisite physiology training to prepare students to engage in a collaborative engineering challenge activity. This work is presented as an example of how to convert standard, organ system-based physiology content into concept-based content lessons. PMID- 23728136 TI - Retrieval practice is an efficient method of enhancing the retention of anatomy and physiology information. AB - Although a great deal of empirical evidence has indicated that retrieval practice is an effective means of promoting learning and memory, very few studies have investigated the strategy in the context of an actual class. The primary purpose of this study was to determine if a series of very brief retrieval quizzes could significantly improve the retention of previously tested information throughout an anatomy and physiology course. A second purpose was to determine if there were any significant differences between expanding and uniform patterns of retrieval that followed a standardized initial retrieval delay. Anatomy and physiology students were assigned to either a control group or groups that were repeatedly prompted to retrieve a subset of previously tested course information via a series of quizzes that were administered on either an expanding or a uniform schedule. Each retrieval group completed a total of 10 retrieval quizzes, and the series of quizzes required (only) a total of 2 h to complete. Final retention of the exam subset material was assessed during the last week of the semester. There were no significant differences between the expanding and uniform retrieval groups, but both retained an average of 41% more of the subset material than did the control group (ANOVA, F = 129.8, P = 0.00, etap(2) = 0.36). In conclusion, retrieval practice is a highly efficient and effective strategy for enhancing the retention of anatomy and physiology material. PMID- 23728137 TI - Online feedback assessments in physiology: effects on students' learning experiences and outcomes. AB - Online formative assessments have become increasingly popular; however, formal evidence supporting their educational benefits is limited. This study investigated the impact of online feedback quizzes on the learning experiences and outcomes of undergraduate students enrolled in an introductory physiology course. Four quiz models were tested, which differed in the amount of credit available, the number of attempts permitted, and whether the quizzes were invigilated or unsupervised, timed or untimed, or open or closed book. All quizzes were composed of multiple-choice questions and provided immediate individualized feedback. Summative end-of-course examination marks were analyzed with respect to performance in quizzes and were also compared with examination performance in the year before the quizzes were introduced. Online surveys were conducted to gather students' perceptions regarding the quizzes. The vast majority of students perceived online quizzes as a valuable learning tool. For all quiz models tested, there was a significant relationship between performance in quizzes and end-of-course examination scores. Importantly, students who performed poorly in quizzes were more likely to fail the examination, suggesting that formative online quizzes may be a useful tool to identify students in need of assistance. Of the four quiz models, only one quiz model was associated with a significant increase in mean examination performance. This model had the strongest formative focus, allowing multiple unsupervised and untimed attempts. This study suggests that the format of online formative assessments is critical in achieving the desired impact on student learning. Specifically, such assessments are most effective when they are low stakes. PMID- 23728138 TI - Effectiveness of integrating case studies in online and face-to-face instruction of pathophysiology: a comparative study. AB - Due to growing demand from students and facilitated by innovations in educational technology, institutions of higher learning are increasingly offering online courses. Subjects in the hard sciences, such as pathophysiology, have traditionally been taught in the face-to-face format, but growing demand for preclinical science courses has compelled educators to incorporate online components into their classes to promote comprehension. Learning tools such as case studies are being integrated into such courses to aid in student interaction, engagement, and critical thinking skills. Careful assessment of pedagogical techniques is essential; hence, this study aimed to evaluate and compare student perceptions of the use of case studies in face-to-face and fully online pathophysiology classes. A series of case studies was incorporated into the curriculum of a pathophysiology class for both class modes (online and face to face). At the end of the semester, students filled out a survey assessing the effectiveness of the case studies. Both groups offered positive responses about the incorporation of case studies in the curriculum of the pathophysiology class. This study supports the argument that with proper use of innovative teaching tools, such as case studies, online pathophysiology classes can foster a sense of community and interaction that is typically only seen with face-to-face classes, based on student responses. Students also indicated that regardless of class teaching modality, use of case studies facilitates student learning and comprehension as well as prepares them for their future careers in health fields. PMID- 23728139 TI - Television format or research project? Team work and the opportunity of choosing classroom-led activities reinforce active learning. PMID- 23728140 TI - Dopamine controls the neural dynamics of memory signals and retrieval accuracy. AB - The human brain is capable of differentiating between new and already stored information rapidly to allow optimal behavior and decision-making. Although the neural mechanisms of novelty discrimination were often described as temporally constant (ie, with specific latencies), recent electrophysiological studies have demonstrated that the onset of neural novelty signals (ie, differences in event related responses to new and old items) can be accelerated by reward motivation. While the precise physiological mechanisms underlying this acceleration remain unclear, the involvement of the neurotransmitter dopamine in both novelty and reward processing suggests that enhanced dopamine levels in the context of reward prospect may have a role. To investigate this hypothesis, we used magnetoencephalography (MEG) in combination with an old/new recognition memory task in which correct discrimination between old and new items was rewarded. Importantly, before the task, human subjects received either 150 mg of the dopamine precursor levodopa or placebo. For the placebo group, old/new signals peaked at ~100 ms after stimulus onset over left temporal/occipital sensors. In contrast, after levodopa administration earliest old/new effects only emerged after ~400 ms and retrieval accuracy was reduced as expressed in lower d' values. As such, our results point towards a previously unreported role of dopamine in controlling the chronometry of neural processes underlying the distinction between old and new information. They also suggest that this relationship follows a nonlinear function whereby slightly enhanced dopamine levels accelerate neural/cognitive processes and excessive dopamine levels impair them. PMID- 23728141 TI - MonoMAC syndrome in a patient with a GATA2 mutation: case report and review of the literature. AB - We report a case of MonoMAC syndrome in a patient with a GATA2 mutation and discuss the manifestations, diagnosis, and treatment of this novel immunodeficiency disorder. PMID- 23728142 TI - Emergence of sequence type 398 as a community- and healthcare-associated methicillin-susceptible staphylococcus aureus in northern Manhattan. AB - The methicillin-susceptible Staphylococcus aureus (MSSA) clone sequence type (ST) 398 has increasingly been identified as a pathogen in diverse geographic settings, yet its epidemiology remains incompletely understood. In this case control study of MSSA infections, we identified ST398 MSSA as both a major community- and hospital-associated MSSA pathogen in the Dominican neighborhood of northern Manhattan. PMID- 23728143 TI - Elimination of hepatitis C virus infection among people who inject drugs through treatment as prevention: feasibility and future requirements. AB - The demonstration that antiretroviral treatment is effective for the prevention of human immunodeficiency virus (HIV) transmission has important implications for HCV prevention. HCV therapeutic development is advancing rapidly, with effective, simplified regimens available in the near future. In contrast to HIV, HCV treatment is both curative and circumscribed in duration-2 features that hold great promise for the potential effectiveness of HCV treatment as prevention, particularly among PWID. Mathematical modeling studies have suggested that modest increases in HCV treatment uptake could lead to substantial reductions in HCV prevalence. This Viewpoint focuses on issues that are important to consider when discussing the feasibility and future requirements of HCV treatment as prevention among PWID. This includes a need to address low rates of HCV screening and treatment, a limited HCV treatment infrastructure, the cost of therapy, and the balance of health priorities at the population and individual levels. PMID- 23728144 TI - Central nervous system herpes simplex and varicella zoster virus infections in natalizumab-treated patients. AB - We report on 20 natalizumab-treated patients with multiple sclerosis who developed laboratory-confirmed central nervous system (CNS) herpesvirus infections. In addition to progressive multifocal leukoencephalopathy, other CNS opportunistic infections have been rarely reported during natalizumab treatment. We encourage heightened awareness due to the risk for serious outcomes. PMID- 23728145 TI - Characterizing vaccine responses using host genomic and transcriptomic analysis. AB - Vaccines have had a profound influence on human health with no other health intervention rivaling their impact on the morbidity and mortality associated with infectious disease. However, the magnitude and persistence of vaccine immunity varies considerably between individuals, a phenomenon that is not well understood. Recent studies have used contemporary technologies to correlate variation in the genome and transcriptome to immunological measures of vaccine responsiveness. These approaches have provided fresh insight into the intrinsic factors determining the potency and duration of vaccine-induced immunity. The fundamental challenge will be to translate these findings into innovative and pragmatic strategies to develop new and more effective vaccines. PMID- 23728146 TI - Polymyxins: wisdom does not always come with age. AB - We currently face a lack of new antimicrobial therapies in an era of increasingly common multidrug-resistant (MDR) bacteria. The polymyxins have become last-line treatments for patients with MDR bacterial infections. An increasing body of published literature has attempted to answer questions about dosing, pharmacology, and susceptibility testing of these drugs, yet each takes for granted purity and potency of the 2 available polymyxin products. In the case of polymyxin B, true potency may vary by as much as 40% from the content reported in prescribing information. This poor accuracy is related to quality assurance assays established in the 1940s and currently in use, which have been shown to be significantly flawed in recent investigations. This review discusses the limitations of pharmacological knowledge about polymyxin antimicrobials, the clinical impact of these limitations, and suggestions for further study of these drugs in order to optimize their use clinically. PMID- 23728148 TI - Medical students' perceptions and knowledge about antimicrobial stewardship: how are we educating our future prescribers? AB - BACKGROUND: Better understanding of medical students' perceptions, attitudes, and knowledge about antimicrobial prescribing practices could facilitate more effective education of these future prescribers. METHODS: A 24-item electronic survey on antimicrobial prescribing and education was administered to fourth-year medical students at the University of Miami, the Johns Hopkins University, and the University of Washington (January-March 2012). RESULTS: Three hundred seventeen of 519 (61%) students completed the survey; 92% of respondents agreed that strong knowledge of antimicrobials is important in their careers, and 90% said that they would like more education on appropriate use of antimicrobials. Mean correct knowledge score (11 items) was 51%, with statistically significant differences between study sites and sources of information used to learn about antimicrobials. Only 15% had completed a clinical infectious diseases rotation during medical school; those who had done so rated the quality of their antimicrobial education significantly higher compared to those who had not (mean, 3.93 vs 3.44, on a 5-point scale; P = .0003). There were no statistically significant associations between knowledge scores and having had an infectious diseases clinical elective. Only one-third of respondents perceived their preparedness to be adequate in some fundamental principles of antimicrobial use. CONCLUSIONS: Differences exist between medical schools in educational resources used, perceived preparedness, and knowledge about antimicrobial use. Variability in formative education could frame behaviors and prescribing practices in future patient care. To help address the growing problem of antimicrobial resistance, efforts should be undertaken to ensure that our future doctors are well educated in the principles and practices of appropriate use of antibiotics and antimicrobial stewardship. PMID- 23728149 TI - Cerebrospinal fluid HIV-1 compartmentalization in a patient with AIDS and acute varicella-zoster virus meningomyeloradiculitis. AB - We report a case of AIDS presenting as varicella-zoster virus (VZV) meningomyeloradiculitis associated with human immunodeficiency virus (HIV) quasispecies compartmentalization within the cerebrospinal fluid (CSF), and a CSF viral load that was 1 log higher than in peripheral blood. Prolonged antiviral therapy for both VZV and HIV type 1 was associated with partial resolution. PMID- 23728151 TI - Luminescence thermochromism of two entangled copper-iodide networks with a large temperature-dependent emission shift. AB - The luminescence thermochromism properties of two entangled copper(I)-iodide coordination polymers formulated [Cu4I4(dmimpr)2]n (1) and [Cu6I6(dimb)3]n (2) (dmimpr = 1,3-di(2-methyl-imidazol-1-yl)propane, dimb = 1,4-di(imidazol-1 yl)butane) are reported. Upon cooling by liquid nitrogen, their solid-state luminescences at room temperature are drastically changed with the large red shifts of 41 and 78 nm for 1 and 2, respectively. The correlation between luminescence thermochromism and temperature-dependent variation of the Cu...Cu distance is also elucidated. PMID- 23728150 TI - Classification of high-resolution manometry data according to videofluoroscopic parameters using pattern recognition. AB - OBJECTIVE: To determine if pattern recognition techniques applied to high resolution manometry (HRM) spatiotemporal plots of the pharyngeal swallow can identify features of disordered swallowing reported on the Modified Barium Swallow Impairment Profile (MBSImP). STUDY DESIGN: Case series evaluating new method of data analysis. SETTING: University hospital. SUBJECTS AND METHODS: Simultaneous HRM and videofluoroscopy was performed on 30 subjects (335 swallows) with dysphagia. Videofluoroscopic studies were scored according to the MBSImP guidelines while HRM plots were analyzed using a novel program. Pattern recognition using a multilayer perceptron artificial neural network (ANN) was performed to determine if 7 pharyngeal components of the MBSImP as well as penetration/aspiration status could be identified from the HRM plot alone. Receiver operating characteristic (ROC) analysis was also performed. RESULTS: MBSImP parameters were identified correctly as normal or disordered at an average rate of approximately 91% (area under the ROC curve ranged from 0.902 to 0.981). Classifications incorporating two MBSImP parameters resulted in classification accuracies over 93% (area under the ROC curve ranged from 0.963 to 0.989). CONCLUSION: Pattern recognition coupled with multiparameter quantitative analysis of HRM spatiotemporal plots can be used to identify swallowing abnormalities, which are currently assessed using videofluoroscopy. The ability to provide quantitative, functional data at the bedside while avoiding radiation exposure makes HRM an appealing tool to supplement and, at times, replace traditional videofluoroscopic studies. PMID- 23728152 TI - Vertebral augmentation in the treatment of pathologic compression fractures in 792 patients with multiple myeloma. PMID- 23728147 TI - Is intrapartum intravenous zidovudine for prevention of mother-to-child HIV-1 transmission still useful in the combination antiretroviral therapy era? AB - BACKGROUND: Intrapartum intravenous zidovudine (ZDV) prophylaxis is a long standing component of prevention of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) in high-resource countries. In some recent guidelines, intravenous ZDV is no longer systematically recommended for mothers receiving combination antiretroviral therapy (cART) with low viral load. We evaluated the impact of intravenous ZDV according to viral load and obstetrical conditions. METHODS: All HIV-1-infected women delivering between 1 January 1997 and 31 December 2010 in the French Perinatal Cohort (ANRS-EPF) were analyzed if they received ART during pregnancy and did not breastfeed. We identified maternal and obstetrical characteristics related to lack of intravenous ZDV and compared its association with MTCT rate and other infant parameters, according to various risk factors. RESULTS: Intravenous ZDV was used in 95.2% of the 11 538 deliveries. Older age, multiparity, and preterm and vaginal delivery were associated with lack of intravenous ZDV (n = 554). In women who delivered with viral load >=1000 copies/mL, the overall MTCT rate was higher without than with intravenous ZDV (7.5% vs 2.9%; P = .01); however, there was no such difference when the neonate received postnatal intensification therapy. Among them, 77% of women who had viral load <400 copies/mL, there was no difference in MTCT rate (0% without intravenous ZDV vs 0.6% with intravenous ZDV; P = .17). Intravenous ZDV was not associated with increased short-term hematological toxicity or lactate level. CONCLUSIONS: Intravenous ZDV remains an effective tool to reduce transmission in cases of virological failure, even in cART-treated women. However, for the vast majority of women with low viral loads at delivery, in the absence of obstetrical risk factors, systematic intravenous ZDV appears to be unnecessary. PMID- 23728153 TI - Psoriasis vulgaris complicated by eosinophilic pneumonia during ustekinumab treatment. PMID- 23728155 TI - Identification of microRNA and bioinformatics target gene analysis in beef cattle intramuscular fat and subcutaneous fat. AB - MicroRNA (miRNA) is endogenous non-coding RNA that has been proposed to play an important role in the formation of body fat. However, the differential expression of miRNA and the role of these miRNAs in bovine intramuscular and subcutaneous fat tissue are still unknown. In this study, the profile of differentially expressed miRNA and the target gene analysis in intramuscular adipose and subcutaneous adipose of adult beef cattle were investigated by microarray and bioinformatics. The data identified 88 differentially expressed miRNAs in 213 miRNAs which were detected on the microarray, and 30 miRNAs among these 88 miRNAs were changed significantly between intramuscular and subcutaneous fat (fold change >1, P < 0.001). miR-143, miR-145, miR-26a, miR-2373-5p and miR-23b-3p were highly expressed in intramuscular fat, whilst miR-26a, miR-2373-5p, miR-2325c, miR-3613 and miR-2361 showed highest abundance in subcutaneous fat. Bioinformatics of KEGG pathway analysis and GO term enrichment suggested that these differentially expressed miRNAs involved in different pathways and target genes may regulate differently the fat deposition. Taken together, our study provides the first evidence for better understanding the differential expression and mechanisms of miRNA in bovine fat deposition, and provides thinking to improve the quality of beef by reducing subcutaneous fat and increasing intramuscular fat of beef cattle. PMID- 23728156 TI - Active learning for noisy oracle via density power divergence. AB - The accuracy of active learning is critically influenced by the existence of noisy labels given by a noisy oracle. In this paper, we propose a novel pool based active learning framework through robust measures based on density power divergence. By minimizing density power divergence, such as beta-divergence and gamma-divergence, one can estimate the model accurately even under the existence of noisy labels within data. Accordingly, we develop query selecting measures for pool-based active learning using these divergences. In addition, we propose an evaluation scheme for these measures based on asymptotic statistical analyses, which enables us to perform active learning by evaluating an estimation error directly. Experiments with benchmark datasets and real-world image datasets show that our active learning scheme performs better than several baseline methods. PMID- 23728157 TI - Is the 1-cm Rule of Distal Bowel Resection Margin in Rectal Cancer Based on Clinical Evidence? A Systematic Review. PMID- 23728158 TI - Three dimensional vestibular ocular reflex testing using a six degrees of freedom motion platform. AB - The vestibular organ is a sensor that measures angular and linear accelerations with six degrees of freedom (6DF). Complete or partial defects in the vestibular organ results in mild to severe equilibrium problems, such as vertigo, dizziness, oscillopsia, gait unsteadiness nausea and/or vomiting. A good and frequently used measure to quantify gaze stabilization is the gain, which is defined as the magnitude of compensatory eye movements with respect to imposed head movements. To test vestibular function more fully one has to realize that 3D VOR ideally generates compensatory ocular rotations not only with a magnitude (gain) equal and opposite to the head rotation but also about an axis that is co-linear with the head rotation axis (alignment). Abnormal vestibular function thus results in changes in gain and changes in alignment of the 3D VOR response. Here we describe a method to measure 3D VOR using whole body rotation on a 6DF motion platform. Although the method also allows testing translation VOR responses (1), we limit ourselves to a discussion of the method to measure 3D angular VOR. In addition, we restrict ourselves here to description of data collected in healthy subjects in response to angular sinusoidal and impulse stimulation. Subjects are sitting upright and receive whole-body small amplitude sinusoidal and constant acceleration impulses. Sinusoidal stimuli (f = 1 Hz, A = 4 degrees ) were delivered about the vertical axis and about axes in the horizontal plane varying between roll and pitch at increments of 22.5 degrees in azimuth. Impulses were delivered in yaw, roll and pitch and in the vertical canal planes. Eye movements were measured using the scleral search coil technique (2). Search coil signals were sampled at a frequency of 1 kHz. The input-output ratio (gain) and misalignment (co-linearity) of the 3D VOR were calculated from the eye coil signals (3). Gain and co-linearity of 3D VOR depended on the orientation of the stimulus axis. Systematic deviations were found in particular during horizontal axis stimulation. In the light the eye rotation axis was properly aligned with the stimulus axis at orientations 0 degrees and 90 degrees azimuth, but gradually deviated more and more towards 45 degrees azimuth. The systematic deviations in misalignment for intermediate axes can be explained by a low gain for torsion (X-axis or roll-axis rotation) and a high gain for vertical eye movements (Y-axis or pitch-axis rotation (see Figure 2). Because intermediate axis stimulation leads a compensatory response based on vector summation of the individual eye rotation components, the net response axis will deviate because the gain for X- and Y-axis are different. In darkness the gain of all eye rotation components had lower values. The result was that the misalignment in darkness and for impulses had different peaks and troughs than in the light: its minimum value was reached for pitch axis stimulation and its maximum for roll axis stimulation. CASE PRESENTATION: Nine subjects participated in the experiment. All subjects gave their informed consent. The experimental procedure was approved by the Medical Ethics Committee of Erasmus University Medical Center and adhered to the Declaration of Helsinki for research involving human subjects. Six subjects served as controls. Three subjects had a unilateral vestibular impairment due to a vestibular schwannoma. The age of control subjects (six males and three females) ranged from 22 to 55 years. None of the controls had visual or vestibular complaints due to neurological, cardio vascular and ophthalmic disorders. The age of the patients with schwannoma varied between 44 and 64 years (two males and one female). All schwannoma subjects were under medical surveillance and/or had received treatment by a multidisciplinary team consisting of an othorhinolaryngologist and a neurosurgeon of the Erasmus University Medical Center. Tested patients all had a right side vestibular schwannoma and underwent a wait and watch policy (Table 1; subjects N1-N3) after being diagnosed with vestibular schwannoma. Their tumors had been stabile for over 8-10 years on magnetic resonance imaging. PMID- 23728154 TI - Modeling catalytic promiscuity in the alkaline phosphatase superfamily. AB - In recent years, it has become increasingly clear that promiscuity plays a key role in the evolution of new enzyme function. This finding has helped to elucidate fundamental aspects of molecular evolution. While there has been extensive experimental work on enzyme promiscuity, computational modeling of the chemical details of such promiscuity has traditionally fallen behind the advances in experimental studies, not least due to the nearly prohibitive computational cost involved in examining multiple substrates with multiple potential mechanisms and binding modes in atomic detail with a reasonable degree of accuracy. However, recent advances in both computational methodologies and power have allowed us to reach a stage in the field where we can start to overcome this problem, and molecular simulations can now provide accurate and efficient descriptions of complex biological systems with substantially less computational cost. This has led to significant advances in our understanding of enzyme function and evolution in a broader sense. Here, we will discuss currently available computational approaches that can allow us to probe the underlying molecular basis for enzyme specificity and selectivity, discussing the inherent strengths and weaknesses of each approach. As a case study, we will discuss recent computational work on different members of the alkaline phosphatase superfamily (AP) using a range of different approaches, showing the complementary insights they have provided. We have selected this particular superfamily, as it poses a number of significant challenges for theory, ranging from the complexity of the actual reaction mechanisms involved to the reliable modeling of the catalytic metal centers, as well as the very large system sizes. We will demonstrate that, through current advances in methodologies, computational tools can provide significant insight into the molecular basis for catalytic promiscuity, and, therefore, in turn, the mechanisms of protein functional evolution. PMID- 23728159 TI - Exploring PLATO-USA paradox and CURRENT-OASIS 7 trials reveals the benefit of higher aspirin dose. PMID- 23728160 TI - Acetylcysteine for Acetaminophen Overdose in Patients Who Weigh >100 kg. PMID- 23728161 TI - Drug therapy of diabetic dyslipidemia: do the statins suffice? PMID- 23728162 TI - Cellulases from insects. AB - Bioethanol is currently produced by the fermentation of sugary and starchy crops, but waste plant biomass is a more abundant source because sugars can be derived directly from cellulose. One of the limiting steps in the biomass-to-ethanol process is the degradation of cellulose to fermentable sugars (saccharification). This currently relies on the use of bacterial and/or fungal cellulases, which tend to have low activity under biorefinery conditions and are easily inhibited. Some insect species feed on plant biomass and can efficiently degrade cellulose to produce glucose as an energy source. Although insects were initially thought to require symbiotic relationships with bacteria and fungi to break down cellulose, several species in the orders Dictyoptera, Orthoptera, and Coleoptera have now been shown to produce their own cellulases in the midgut or salivary glands, and putative cellulase genes have been identified in other orders. Insect cellulases often work in concert with cellulases provided by symbiotic microbiota in the gut to achieve efficient cellulolysis. We discuss the current status of insect cellulases and potential strategies that could be used to find novel enzymes and improve their efficiency. PMID- 23728163 TI - Aphid-proof plants: biotechnology-based approaches for aphid control. AB - Aphids are economically significant agricultural pests that are responsible for large yield losses in many different crops. Because the use of insecticides is restricted in the context of integrated pest management and aphids develop resistance against them rapidly, new biotechnology-based approaches are required for aphid control. These approaches focus on the development of genetically modified aphid-resistant plants that express protease inhibitors, dsRNA, antimicrobial peptides, or repellents, thus addressing different levels of aphid plant interactions. However, a common goal is to disturb host plant acceptance by aphids and to disrupt their ability to take nutrition from plants. The defense agents negatively affect different fitness-associated parameters such as growth, reproduction, and survival, which therefore reduce the impact of infestations. The results from several different studies suggest that biotechnology-based approaches offer a promising strategy for aphid control. PMID- 23728164 TI - Taxonomic profiling and metagenome analysis of a microbial community from a habitat contaminated with industrial discharges. AB - Industrial units, manufacturing dyes, chemicals,solvents, and xenobiotic compounds, produce liquid and solid wastes, which upon conventional treatment are released in the nearby environment and thus are the major cause of pollution. Soil collected from contaminated Kharicut Canalbank (N 22 degrees 57.878'; E 072 degrees 38.478'), Ahmeda bad, Gujarat,India was used for metagenomic DNA preparation to study the capabilities of intrinsic microbial community in dealing with xenobiotics. Sequencing of metagenomic DNA on the Genome Sequencer FLX System using titanium chemistry resulted in 409,782 reads accounting for 133,529,997 bases of sequence information. Taxonomic analyses and gene annotations were carried out using the bioinformatics platform Sequence Analysis and Management System for Metagenomic Datasets. Taxonomic profiling was carried out by three different complementary approaches: (a) 16S rDNA, (b) environmental gene tags, and (c) lowest common ancestor. The most abundant phylum and genus were found to be "Proteobacteria"and "Pseudomonas," respectively. Metagenome reads were mapped on sequenced microbial genomes and the highest numbers of reads were allocated to Pseudomonas stutzeri A1501. Assignment of obtained metagenome reads to Gene Ontology terms, Clusters of Orthologous Groups of protein categories, protein family numbers, and Kyoto Encyclopedia of Genes and Genomes hits revealed genomic potential of indigenous microbial community. In total, 157,024 reads corresponded to 37,028 different KEGG hits, and amongst them, 11,574 reads corresponded to 131 different enzymes potentially involved in xenobiotic biodegradation. These enzymes were mapped on biodegradation pathways of xenobiotics to elucidate their roles in possible catalytic reactions. Consequently, information obtained from the present study will act as a baseline which, subsequently along with other"-omic" studies, will help in designing future bioremediation strategies in effluent treatment plants and environmental cleanup projects. PMID- 23728165 TI - Unraveling how Giardia infections cause disease. AB - A 40-year-old NIH male scientist camped and fished in a remote lake in Alaska. On his return, he developed diarrhea, cramps, and loose stools without blood or mucus in the absence of fever and was diagnosed with giardiasis. A 3-year-old female living in the Florida Keys complained of intermittent stomachaches over a 2-month period. Her stools were variably loose. The patient was diagnosed with giardiasis, which led to examination of her mother, father, and brother, who were mildly symptomatic; all 3 were subsequently diagnosed with giardiasis. The child's only exposure was from swimming in a local community pool. A 40-year-old male from Mexico, who resided in Virginia and worked as a cook in a fast food restaurant, was diagnosed with giardiasis. He denied any symptoms and was not allowed to prepare food. Treatment with metronidazole, nitazoxanide, and albendazole failed to eradicate the infection. He was successfully treated with the combination of paromomycin and metronidazole. PMID- 23728166 TI - A new approach to disease-modifying drug trials in Parkinson's disease. AB - Translating new findings in the laboratory into therapies for patients is a slow and expensive process. The development of therapies for neurodegenerative diseases is further complicated by the difficulty in determining whether the drug truly retards the slow degenerative process or provides only symptomatic benefit. In this issue, Aviles-Olmos et al. describe a first in Parkinson's disease (PD) patient study using a drug previously approved for diabetes treatment. In addition to suggesting that the drug may indeed be disease modifying in PD, their innovative approach suggests there may be more rapid and inexpensive avenues for testing novel therapies in PD. PMID- 23728167 TI - Anger management: bacteria soothe the savage host. AB - A 5-year-old girl has come to you a week after completing a course of antibiotics for a febrile urinary tract infection (UTI). She now seems well and energetic. A urinalysis is now clear without traces of inflammation, including an absence of protein, blood, leukocyte esterase, and nitrites. Her urine is submitted for a test of cure and comes back positive, with over 100,000 colonies per milliliter of E. coli, the same kind of bacteria that was cultured from her urine when she was symptomatic with the UTI. Perplexed, her mother asks how her child can have bacteria once again in her bladder but not be symptomatic and asks if antibiotics are again necessary. PMID- 23728168 TI - RNA-guided diagnostics and therapeutics for next-generation individualized nanomedicine. AB - The absence of reliable quantitative laboratory tests for measurements of microRNAs and other classes of small noncoding RNAs in archived, formalin- fixed, paraffin-embedded human samples with sufficient specificity and sensitivity has significantly limited the development of clinically relevant noncoding RNA-based diagnostic and therapeutic applications. A report by Renwick et al. in this issue of the JCI presents a significant technical and methodological advance toward the development of reliable clinical laboratory- compatible multicolor RNA FISH methodology for molecular diagnostic applications and the near-term prospect of introduction of microRNA- based biomarkers into clinical practice. Further, this work is likely to advance the development of RNA-based therapeutics and next generation individualized nanomedicine. PMID- 23728169 TI - Targeting immunosuppression for cancer therapy. AB - Failing immunity has been acknowledged for its contribution to cancer development and progression. Recent clinical findings have provided payoffs for significant preclinical evaluation and refinement over the last 20 years, but many questions remain to be answered. In this issue of the JCI, Marabelle et al. describe a novel method for targeting the Tregs that infiltrate tumors, demonstrating that dampening the tumor immunosuppressive environment while activating innate antitumor immunity may be an effective approach to cancer treatment. PMID- 23728170 TI - Giardia: both a harmless commensal and a devastating pathogen. AB - The highly prevalent protozoan Giardia lamblia is an enteropathogen that can be asymptomatic in some individuals, while leading to persistent diarrhea and substantial morbidity in others. In this issue of the JCI, Bartelt et al. describe a mouse model of the disease and investigate the contribution of coincident malnutrition with the development of symptomatic infection. This work in part explains how Giardia infection can lead to growth retardation, and may offer insights that guide future therapeutic strategies. PMID- 23728171 TI - Human C3 glomerulopathy provides unique insights into complement factor H-related protein function. AB - The study in this issue of the JCI by Tortajada et al. demonstrates that a duplication within the gene complement factor H-related 1 (CFHR1; encoding FHR1) leads to the production of an aberrant larger form of the protein. Elegant in vitro studies of the mutant and normal variants demonstrate an unexpected mechanism of action of FHR1, wherein homodimeration and hetero- oligomerization with FHR2 and FHR5 generates more avid molecules that very effectively compete with FH binding to surfaces and impair its ability to regulate local complement activation. As variants of FHRs are linked to many human inflammatory and autoimmune diseases, these and other recently published structure/function studies of these proteins provide key insights into their complement regulatory activities and likely roles in disease. PMID- 23728172 TI - Bacterial control of host gene expression through RNA polymerase II. AB - The normal flora furnishes the host with ecological barriers that prevent pathogen attack while maintaining tissue homeostasis. Urinary tract infections (UTIs) constitute a highly relevant model of microbial adaptation in which some patients infected with Escherichia coli develop acute pyelonephritis, while other patients with bacteriuria exhibit an asymptomatic carrier state similar to bacterial commensalism. It remains unclear if the lack of destructive inflammation merely reflects low virulence or if carrier strains actively inhibit disease-associated responses in the host. Here, we identify a new mechanism of bacterial adaptation through broad suppression of RNA polymerase II-dependent (Pol II-dependent) host gene expression. Over 60% of all genes were suppressed 24 hours after human inoculation with the prototype asymptomatic bacteriuria (ABU) strain E. coli 83972, and inhibition was verified by infection of human cells. Specific repressors and activators of Pol II-dependent transcription were modified, Pol II phosphorylation was inhibited, and pathogen-specific signaling was suppressed in cell lines and inoculated patients. An increased frequency of strains inhibiting Pol II was epidemiologically verified in ABU and fecal strains compared with acute pyelonephritis, and a Pol II antagonist suppressed the disease-associated host response. These results suggest that by manipulating host gene expression, ABU strains promote tissue integrity while inhibiting pathology. Such bacterial modulation of host gene expression may be essential to sustain asymptomatic bacterial carriage by ensuring that potentially destructive immune activation will not occur. PMID- 23728173 TI - Persistent G. lamblia impairs growth in a murine malnutrition model. AB - Giardia lamblia infections are nearly universal among children in low-income countries and are syndemic with the triumvirate of malnutrition, diarrhea, and developmental growth delays. Amidst the morass of early childhood enteropathogen exposures in these populations, G. lamblia-specific associations with persistent diarrhea, cognitive deficits, stunting, and nutrient deficiencies have demonstrated conflicting results, placing endemic pediatric giardiasis in a state of equipoise. Many infections in endemic settings appear to be asymptomatic/ subclinical, further contributing to uncertainty regarding a causal link between G. lamblia infection and developmental delay. We used G. lamblia H3 cyst infection in a weaned mouse model of malnutrition to demonstrate that persistent giardiasis leads to epithelial cell apoptosis and crypt hyperplasia. Infection was associated with a Th2-biased inflammatory response and impaired growth. Malnutrition accentuated the severity of these growth decrements. Faltering malnourished mice exhibited impaired compensatory responses following infection and demonstrated an absence of crypt hyperplasia and subsequently blunted villus architecture. Concomitantly, severe malnutrition prevented increases in B220+ cells in the lamina propria as well as mucosal Il4 and Il5 mRNA in response to infection. These findings add insight into the potential role of G. lamblia as a "stunting" pathogen and suggest that, similarly, malnourished children may be at increased risk of G. lamblia- potentiated growth decrements. PMID- 23728174 TI - Exenatide and the treatment of patients with Parkinson's disease. AB - BACKGROUND. There is increasing interest in methods to more rapidly and cost efficiently investigate drugs that are approved for clinical use in the treatment of another condition. Exenatide is a type 2 diabetes treatment that has been shown to have neuroprotective/neurorestorative properties in preclinical models of neurodegeneration. METHODS. As a proof of concept, using a single-blind trial design, we evaluated the progress of 45 patients with moderate Parkinson's disease (PD), randomly assigned to receive subcutaneous exenatide injection for 12 months or to act as controls. Their PD was compared after overnight withdrawal of conventional PD medication using blinded video assessment of the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS), together with several nonmotor tests, at baseline, 6 months, and 12 months and after a further 2-month washout period (14 months). RESULTS. Exenatide was well tolerated, although weight loss was common and l-dopa dose failures occurred in a single patient. Single-blinded rating of the exenatide group suggested clinically relevant improvements in PD across motor and cognitive measures compared with the control group. Exenatide-treated patients had a mean improvement at 12 months on the MDS-UPDRS of 2.7 points, compared with mean decline of 2.2 points in control patients (P = 0.037). CONCLUSION. These results demonstrate a potential cost efficient approach through which preliminary clinical data of possible biological effects are obtainable, prior to undertaking the major investment required for double-blind trials of a potential disease-modifying drug in PD. TRIAL REGISTRATION: Clinicaltrials.gov NCT01174810. FUNDING: Cure Parkinson's Trust. PMID- 23728175 TI - Multicolor microRNA FISH effectively differentiates tumor types. AB - MicroRNAs (miRNAs) are excellent tumor biomarkers because of their cell-type specificity and abundance. However, many miRNA detection methods, such as real time PCR, obliterate valuable visuospatial information in tissue samples. To enable miRNA visualization in formalin-fixed paraffin-embedded (FFPE) tissues, we developed multicolor miRNA FISH. As a proof of concept, we used this method to differentiate two skin tumors, basal cell carcinoma (BCC) and Merkel cell carcinoma (MCC), with overlapping histologic features but distinct cellular origins. Using sequencing-based miRNA profiling and discriminant analysis, we identified the tumor-specific miRNAs miR-205 and miR-375 in BCC and MCC, respectively. We addressed three major shortcomings in miRNA FISH, identifying optimal conditions for miRNA fixation and ribosomal RNA (rRNA) retention using model compounds and high-pressure liquid chromatography (HPLC) analyses, enhancing signal amplification and detection by increasing probe-hapten linker lengths, and improving probe specificity using shortened probes with minimal rRNA sequence complementarity. We validated our method on 4 BCC and 12 MCC tumors. Amplified miR-205 and miR-375 signals were normalized against directly detectable reference rRNA signals. Tumors were classified using predefined cutoff values, and all were correctly identified in blinded analysis. Our study establishes a reliable miRNA FISH technique for parallel visualization of differentially expressed miRNAs in FFPE tumor tissues. PMID- 23728176 TI - MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth. AB - Some solid tumors have reduced posttranscriptional RNA editing by adenosine deaminase acting on RNA (ADAR) enzymes, but the functional significance of this alteration has been unclear. Here, we found the primary RNA-editing enzyme ADAR1 is frequently reduced in metastatic melanomas. In situ analysis of melanoma samples using progression tissue microarrays indicated a substantial downregulation of ADAR1 during the metastatic transition. Further, ADAR1 knockdown altered cell morphology, promoted in vitro proliferation, and markedly enhanced the tumorigenicity in vivo. A comparative whole genome expression microarray analysis revealed that ADAR1 controls the expression of more than 100 microRNAs (miRNAs) that regulate many genes associated with the observed phenotypes. Importantly, we discovered that ADAR1 fundamentally regulates miRNA processing in an RNA binding-dependent, yet RNA editing-independent manner by regulating Dicer expression at the translational level via let-7. In addition, ADAR1 formed a complex with DGCR8 that was mutually exclusive with the DGCR8 Drosha complex that processes pri-miRNAs in the nucleus. We found that cancer cells silence ADAR1 by overexpressing miR-17 and miR-432, which both directly target the ADAR1 transcript. We further demonstrated that the genes encoding miR 17 and miR-432 are frequently amplified in melanoma and that aberrant hypomethylation of the imprinted DLK1-DIO3 region in chromosome 14 can also drive miR-432 overexpression. PMID- 23728177 TI - Osteocalcin regulates murine and human fertility through a pancreas-bone-testis axis. AB - The osteoblast-derived hormone osteocalcin promotes testosterone biosynthesis in the mouse testis by binding to GPRC6A in Leydig cells. Interestingly, Osteocalcin deficient mice exhibit increased levels of luteinizing hormone (LH), a pituitary hormone that regulates sex steroid synthesis in the testes. These observations raise the question of whether LH regulates osteocalcin's reproductive effects. Additionally, there is growing evidence that osteocalcin levels are a reliable marker of insulin secretion and sensitivity and circulating levels of testosterone in humans, but the endocrine function of osteocalcin is unclear. Using mouse models, we found that osteocalcin and LH act in 2 parallel pathways and that osteocalcin-stimulated testosterone synthesis is positively regulated by bone resorption and insulin signaling in osteoblasts. To determine the importance of osteocalcin in humans, we analyzed a cohort of patients with primary testicular failure and identified 2 individuals harboring the same heterozygous missense variant in one of the transmembrane domains of GPRC6A, which prevented the receptor from localizing to the cell membrane. This study uncovers the existence of a second endocrine axis that is necessary for optimal male fertility in the mouse and suggests that osteocalcin modulates reproductive function in humans. PMID- 23728178 TI - C3 glomerulopathy-associated CFHR1 mutation alters FHR oligomerization and complement regulation. AB - C3 glomerulopathies (C3G) are a group of severe renal diseases with distinct patterns of glomerular inflammation and C3 deposition caused by complement dysregulation. Here we report the identification of a familial C3G-associated genomic mutation in the gene complement factor H-related 1 (CFHR1), which encodes FHR1. The mutation resulted in the duplication of the N-terminal short consensus repeats (SCRs) that are conserved in FHR2 and FHR5. We determined that native FHR1, FHR2, and FHR5 circulate in plasma as homo- and hetero-oligomeric complexes, the formation of which is likely mediated by the conserved N-terminal domain. In mutant FHR1, duplication of the N-terminal domain resulted in the formation of unusually large multimeric FHR complexes that exhibited increased avidity for the FHR1 ligands C3b, iC3b, and C3dg and enhanced competition with complement factor H (FH) in surface plasmon resonance (SPR) studies and hemolytic assays. These data revealed that FHR1, FHR2, and FHR5 organize a combinatorial repertoire of oligomeric complexes and demonstrated that changes in FHR oligomerization influence the regulation of complement activation. In summary, our identification and characterization of a unique CFHR1 mutation provides insights into the biology of the FHRs and contributes to our understanding of the pathogenic mechanisms underlying C3G. PMID- 23728181 TI - Discrete, soluble covalent organic boronate ester rectangles. AB - The facile self-assembly of nanoscale boronate ester rectangles from linear bis catechols and 1,4-benzene diboronic acid is described. Spectroscopic and computational analyses reveal the influence of extended pi-conjugation on the rectangles' absorption and fluorescence properties. The rectangles represent a new class of discrete, organic soluble covalent organic polygons. PMID- 23728180 TI - Near-infrared fluorescence goggle system with complementary metal-oxide semiconductor imaging sensor and see-through display. AB - We have developed a near-infrared (NIR) fluorescence goggle system based on the complementary metal-oxide-semiconductor active pixel sensor imaging and see through display technologies. The fluorescence goggle system is a compact wearable intraoperative fluorescence imaging and display system that can guide surgery in real time. The goggle is capable of detecting fluorescence of indocyanine green solution in the picomolar range. Aided by NIR quantum dots, we successfully used the fluorescence goggle to guide sentinel lymph node mapping in a rat model. We further demonstrated the feasibility of using the fluorescence goggle in guiding surgical resection of breast cancer metastases in the liver in conjunction with NIR fluorescent probes. These results illustrate the diverse potential use of the goggle system in surgical procedures. PMID- 23728179 TI - Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. AB - Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti-CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response. PMID- 23728182 TI - Multiple Carrying Capacities from a management-oriented perspective to operationalize sustainable tourism in protected areas. AB - This article describes how the concept of Tourism Carrying Capacity (TCC) has shifted from a uni-dimensional approach to incorporating environmental, social and political aspects. This shift is demonstrated by a study of a large, internationally popular protected area used by trekkers, the Mt. Everest Region, where qualitative data collected from visitors was combined with environmental modeling using a participatory framework. Tourist satisfaction showed positive margins for further tourist industry expansion, but current environmental conditions limit growth and further development. Space and time dimensions were also considered. We observed that the limits on growth and further development can be manipulated, with a certain degree of flexibility, through investments and regulatory measures. We hypothesized that TCC can play an important role in the management of protected areas only if it is viewed as a systematic, strategic policy tool within a planning process rather than as a unique, intrinsic number that is not modifiable. We conclude that to translate the strategy into action using standard measures, further investigation is needed to balance the various TCC components as a part of a decision-making framework that includes the integration of different cultural approaches and policy needs. PMID- 23728183 TI - Investigating site-specific interactions and probing their role in modifying the acid-strength in framework architectures. AB - The ability to adroitly tailor acid-strength using specifically-engineered bimetallic nanoporous materials has been investigated with a view to exploiting their potential in solid-acid catalysed transformations. Further, it has been demonstrated that through site-specific interactions, extra-framework zinc ions can suitably modify the acidity of Bronsted acid sites, to stimulate diverse catalytic responses, when combined with isomorphously-substituted framework metal cations within porous architectures, for the Beckmann rearrangement of cyclohexanone oxime and in the isopropylation of benzene. PMID- 23728184 TI - Osteonecrosis of the jaw and rheumatoid arthritis. Is it the disease or the drugs? PMID- 23728185 TI - Prevention of rheumatoid arthritis: the very first steps. PMID- 23728186 TI - The real world of gout. PMID- 23728187 TI - Jeopardizing validity by mismeasurement of quality of life. PMID- 23728188 TI - Infectious tenosynovitis in a patient with dermatopolymyositis and vasculitis. PMID- 23728190 TI - CCL18 activates fibroblast-like synoviocytes in patients with rheumatoid arthritis. PMID- 23728191 TI - Cyclophosphamide exposure in pediatric systemic lupus erythematosus is associated with reduced serum anti-mullerian hormone levels. PMID- 23728192 TI - Matrix-assisted autologous chondrocyte transplantation for remodeling and repair of chondral defects in a rabbit model. AB - Articular cartilage defects are considered a major health problem because articular cartilage has a limited capacity for self-regeneration (1). Untreated cartilage lesions lead to ongoing pain, negatively affect the quality of life and predispose for osteoarthritis. During the last decades, several surgical techniques have been developed to treat such lesions. However, until now it was not possible to achieve a full repair in terms of covering the defect with hyaline articular cartilage or of providing satisfactory long-term recovery (2 4). Therefore, articular cartilage injuries remain a prime target for regenerative techniques such as Tissue Engineering. In contrast to other surgical techniques, which often lead to the formation of fibrous or fibrocartilaginous tissue, Tissue Engineering aims at fully restoring the complex structure and properties of the original articular cartilage by using the chondrogenic potential of transplanted cells. Recent developments opened up promising possibilities for regenerative cartilage therapies. The first cell based approach for the treatment of full-thickness cartilage or osteochondral lesions was performed in 1994 by Lars Peterson and Mats Brittberg who pioneered clinical autologous chondrocyte implantation (ACI) (5). Today, the technique is clinically well-established for the treatment of large hyaline cartilage defects of the knee, maintaining good clinical results even 10 to 20 years after implantation (6). In recent years, the implantation of autologous chondrocytes underwent a rapid progression. The use of an artificial three-dimensional collagen-matrix on which cells are subsequently replanted became more and more popular (7-9). MACT comprises of two surgical procedures: First, in order to collect chondrocytes, a cartilage biopsy needs to be performed from a non weight-bearing cartilage area of the knee joint. Then, chondrocytes are being extracted, purified and expanded to a sufficient cell number in vitro. Chondrocytes are then seeded onto a three dimensional matrix and can subsequently be re-implanted. When preparing a tissue engineered implant, proliferation rate and differentiation capacity are crucial for a successful tissue regeneration (10). The use of a three-dimensional matrix as a cell carrier is thought to support these cellular characteristics (11). The following protocol will summarize and demonstrate a technique for the isolation of chondrocytes from cartilage biopsies, their proliferation in vitro and their seeding onto a 3D-matrix (Chondro-Gide, Geistlich Biomaterials, Wollhusen, Switzerland). Finally, the implantation of the cell-matrix-constructs into artificially created chondral defects of a rabbit's knee joint will be described. This technique can be used as an experimental setting for further experiments of cartilage repair. PMID- 23728193 TI - Facial, olfactory, and vocal cues to female reproductive value. AB - Facial, olfactory, and vocal cues may advertise women's fertility. However, most of the evidence for this proposal has come from studies of changes in young adult women's attractiveness over the menstrual cycle. By contrast with this emphasis on changes in attractiveness over the menstrual cycle, possible changes in women's attractiveness over their lifespan have received little attention. The present study investigated men's ratings of young girls' (11-15 years old), adult women's (19-30 years old) and circum-menopausal women's (50-65 years old) facial, body odor, and vocal attractiveness and femininity. Faces and voices, but not body odors, of young girls and adult women were perceived to be significantly more attractive and feminine than those of circum-menopausal women. These data suggest that facial and vocal cues may be cues to women's reproductive value, but that body odor cues do not necessarily advertise this information. PMID- 23728194 TI - The impact of prenatal serotonin reuptake inhibitor (SRI) antidepressant exposure and maternal mood on mother-infant interactions at 3 months of age. AB - Exposure to maternal depression increases risks for altered mother-infant interactions. Serotonin reuptake inhibitor (SRI) antidepressants are increasingly prescribed to manage antenatal maternal illness. The impact of SRIs on early mother-infant interactions was unknown. Three-month-old infants of 32 depressed mothers treated with SRI medications during pregnancy and 43 non-medicated mothers were studied. Using an established face-to-face mother-infant interaction paradigm, dyad interactions were studied with and without a toy. Videotaped sessions yielded 4 measures: maternal sensitivity, dyadic organization, infant readiness to interact, and maternal interruptive behaviors. Even with prenatal SRI treatment, depressed mothers interrupted their infants more during toy play. In the absence of prenatal SRI treatment, maternal postnatal depression adversely influenced infant behavior. Higher levels of maternal depression symptoms at 3 months predicted poorer infant readiness to interact during the toy session. Conversely, in the SRI-exposed group, higher prenatal depression scores predicted greater infant readiness to interact at 3 months. Increased infant readiness with SRI exposure suggests a "fetal programming effect" whereby prenatal maternal mood disturbances shaped a future response to a postnatal depressed maternal environment. PMID- 23728195 TI - Infant temperament and maternal parenting self-efficacy predict child weight outcomes. AB - Relationships between infant negative reactivity and self-regulation, parenting self-efficacy, and child weight outcomes were examined. Greater observed negative reactivity predicted more child weight gain when mothers had lower parenting self efficacy. Lower mother-reported self-regulation predicted a greater child weight status. Results highlight potential early risk/protective factors. PMID- 23728196 TI - In situ assembly of porous Au-paper electrode and functionalization of magnetic silica nanoparticles with HRP via click chemistry for Microcystin-LR immunoassay. AB - A simple, low-cost and sensitive origami electrochemical immunoassay-device was developed based on a novel gold nanoparticle modified porous paper working electrode (Au-PWE) for point-of-care testing. Azide-functionalized Au-PWE was prepared by the functionalization of Au-PWE with 1-azidoundecan-11-thiol. Alkyne end-terminated antibody was prepared with 4-pentynoic acid and antibody by the 1 ethyl-3-(3-(dimethylamino) propyl) carbodiimide hydrochloride and N hydroxysuccinimide activation reaction. Alkyne-antibody was coupled to azido-Au PWE by click reaction as a recognition element. Nearly monodispersed sphere-like silica-coated ferroferric oxide (Fe3O4@SiO2) nanoparticles were prepared via the reverse microemulsion method. Azide-functionalized Fe3O4@SiO2 was prepared by the functionalization of silica shell with 3-bromopropyltrichlorosilane followed by substitution with sodium azide. Alkyne-functionalized antibody and horse radish peroxidase were coupled to azide-functionalized Fe3O4@SiO2 by click reaction as signal label. Horse radish peroxidase and ferroferric oxide could catalyze the oxidation of thionine in the presence of hydrogen peroxide. After the sandwich immunoreaction, the current was proportional to the logarithm of the Microcystin LR. The linear regression equation was i(MUA)=119.89+46.27 log cMC-LR (MUg/mL) in the range from 0.01 to 200 MUg/mL. The limit of detection was 0.004 MUg/mL. This immunoassay would provide a universal immunoassay method in environmental monitoring and public health. PMID- 23728197 TI - A multiplexed microfluidic platform for rapid antibiotic susceptibility testing. AB - Effective treatment of clinical infections is critically dependent on the ability to rapidly screen patient samples to identify antibiograms of infecting pathogens. Existing methods for antibiotic susceptibility testing suffer from several disadvantages, including long turnaround times, excess sample and reagent consumption, poor detection sensitivity, and limited combinatorial capabilities. Unfortunately, these factors preclude the timely administration of appropriate antibiotics, complicating management of infections and exacerbating the development of antibiotic resistance. Here, we seek to address these issues by developing a microfluidic platform that relies on fluorescence detection of bacteria that express green fluorescent protein for highly sensitive and rapid antibiotic susceptibility testing. This platform possesses several advantages compared to conventional methods: (1) analysis of antibiotic action in two to four hours, (2) enhanced detection sensitivity (~ 1 cell), (3) minimal consumption of cell samples and antibiotic reagents (<6 uL), and (4) improved portability through the implementation of normally closed valves. We employed this platform to quantify the effects of four antibiotics (ampicillin, cefalexin, chloramphenicol, tetracycline) and their combinations on Escherichia coli. Within four hours, the susceptibility of bacteria to antibiotics can be determined by detecting variations in maxima of local fluorescence intensity over time. As expected, cell density is a major determinant of antibiotic efficacy. Our results also revealed that combinations of three or more antibiotics are not necessarily better for eradicating pathogens compared to pairs of antibiotics. Overall, this microfluidic based biosensor technology has the potential to provide rapid and precise guidance in clinical therapies by identifying the antibiograms of pathogens. PMID- 23728198 TI - Development of a novel bead-based 96-well filtration plate competitive immunoassay for the detection of Gentamycin. AB - We developed a sensitive, simple, inexpensive and rapid bead-based immunoassay platform, composed of liposomal nanovesicle amplification system, Gentamycin sulfate beads and 96-well filtration plates. In the beginning of the assay, Gentamycin sulfate beads, Gentamycin sulfate and Gentamycin specific antibody were incubated in a bottom-sealed 96-well filtration plate. After incubation, washing was done by running washing buffer through the unsealed filtration plate with only gravity and the antibody-Gentamycin bead complexes were retained in the plate. Fluorescent dye-loaded protein G-liposomal nanovesicles were then added to specifically bind to antibodies on the retained beads. After washing unbound nanovesicles, millions of fluorescent dye molecules were released by adding a detergent solution to lyse liposomal nanovesicles. The limit of detection (LOD) of this novel detection platform in TBS and in skim milk were 52.65 ng/mL and 14.16 ng/mL, which are both sufficient for detecting the 200 ng/mL Codex maximum residual level (MRL). The dynamic ranges were both from each of their LODs to 100 MUg/mL. The 50% inhibition concentrations (IC50) in TBS and skim milk were 199.66 ng/mL and 360.81 ng/mL, respectively. We also demonstrated the good specificity of this platform by comparing detection results between pure Gentamycin solution and a mixture solution of 6 different antibiotics including Gentamycin in skim milk. The entire assay with 60 samples was conducted within 2h. In sum, this novel biosensing platform not only fulfilled most benefits of magnetic bead-based assays, but also was inexpensive and convenient by replacing the magnetic separation with filtration plate separation. PMID- 23728199 TI - Label-free detection of low protein concentration in solution using a novel colorimetric assay. AB - Dual pH and temperature sensitive microgel-based etalons were fabricated by sandwiching a "monolithic" microgel layer between two semitransparent, Au layers. The devices exhibit visual color and multipeak reflectance spectra, both of which primarily depend on the distance between the Au surfaces mediated by the microgel diameter. We found that a polycationic polyelectrolyte can penetrate through the Au overlayer to interact with negatively charged microgel confined between Au overlayers. In this submission we report that biotinylated polycationic polymer can penetrate through the Au overlayer of a poly (N-isopropylacrylamide)-co acrylic acid (pNIPAm-co-AAc) microgel-based etalon and cause the microgel layer to collapse. The collapse results in a shift in the spectral peaks of the reflectance spectra. We found that the extent of peak shift depends on the amount of biotinylated polycation added to the etalon, which can subsequently be used to determine the concentration of streptavidin in solution at pM concentrations. PMID- 23728200 TI - Relationship between major histocompatibility complex class I expression and prognosis in canine mammary gland tumors. AB - The aim of this study was to evaluate MHC class I expression and prognosis using tumor tissues surgically removed from 9 dogs with mammary gland carcinomas and from 13 dogs with complex carcinomas. We assessed MHC class I expression and its correlation with tumor size, B2M expression, infiltration of lymphocytes, histological grade and prognosis. Hematoxylin and eosin-stained sections were histologically graded using the Elston and Ellis grading method. MHC class I expression on tumor cells was evaluated using the avidin-biotin peroxidase complex method. Loss of MHC class I expression from canine mammary gland carcinomas was significantly correlated with poor prognosis (P<0.05). Loss of MHC class I expression showed no association with poor prognosis in canine mammary gland complex carcinomas, because the data were not balanced. Only 1 of 13 (7.6%) canine mammary gland complex carcinomas showed loss of MHC class I expression. All 13 of these dogs showed good prognosis. Thus, the low frequency of MHC class I expression loss from canine mammary gland complex carcinomas may be associated with good prognosis. Taken together, these results suggest that loss of MHC class I expression may be associated with poor prognosis in canine mammary gland carcinomas. PMID- 23728201 TI - Genetic structure and different color morphotypes suggest the occurrence and bathymetric segregation of two incipient species of Sebastes off Argentina. AB - Rockfishes of the genus Sebastes are extensively distributed in the Pacific and Atlantic oceans. Although the occurrence of two morphologically similar species in the Southern Hemisphere, Sebastes oculatus and Sebastes capensis, is now clearly established, the taxonomic status and phylogeographic patterns for the genus in the region have not yet been completely resolved. In this study, we provide new insights into the taxonomy and evolutionary relationships of rockfishes inhabiting the Southwestern Atlantic Ocean, off the coast of mainland Argentina, by combining mitochondrial DNA (mtDNA) control region sequences, microsatellite data, and color pattern analyses. Differences in coloration ("dark" and "light" fish) together with bathymetric segregation between color morphotypes were evident from fish collection and literature review. In addition, the mtDNA phylogenetic analysis and Bayesian clustering analysis using microsatellite data separated the fish into two distinct groups (F ST = 0.041), most likely representing incipient species. Our results suggest that speciation by-depth in the absence of physical barriers could be a widespread mechanism of speciation in Sebastes from both the Northern and Southern Hemispheres. Nevertheless, the degree of genetic differentiation found, added to the large number of individuals displaying high levels of admixture, points to the occurrence of incomplete reproductive barriers between color morphotypes. Beyond the taxonomic and phylogeographic implications of our findings, the occurrence of distinct groups of Sebastes off the coast of Argentina being targeted by different fisheries (angling and trawling) has consequences for the design and implementation of appropriate fishery regulations to avoid overharvest of either group. PMID- 23728202 TI - A new ceratopsian dinosaur from the Javelina Formation (Maastrichtian) of West Texas and implications for chasmosaurine phylogeny. AB - Bravoceratops polyphemus gen. et sp. nov. is a large chasmosaurine ceratopsid from the lowermost part of the Javelina Formation (early Maastrichtian) of Big Bend National Park, TX, USA. B. polyphemus has a distinctive narrow snout, a long fenestrate frill, and a fan-shaped median parietal bar with a midline epiparietal on its posterior margin, as well as a symmetrical depression on its dorsal surface at the nexus of the parietal rami. This depression is interpreted to be the attachment point for a second midline epiparietal. This parietal morphology is distinct from that exhibited by Anchiceratops or Pentaceratops. The posterior midline epiparietal in B. polyphemus and its bifurcated quadratojugal-squamosal joint are features shared with the most derived chasmosaurines, Torosaurus and Triceratops. The combination of primitive and derived traits exhibited by B. polyphemus, and its stratigraphic position, is compatible with the gradual transition from basal, to intermediate, to derived chasmosaurines observed throughout the western interior of North America, and with phylogenetic analysis, which suggests that Bravoceratops may be closely related to Coahuilaceratops. PMID- 23728203 TI - Genetic diversity affects colony survivorship in commercial honey bee colonies. AB - Honey bee (Apis mellifera) queens mate with unusually high numbers of males (average of approximately 12 drones), although there is much variation among queens. One main consequence of such extreme polyandry is an increased diversity of worker genotypes within a colony, which has been shown empirically to confer significant adaptive advantages that result in higher colony productivity and survival. Moreover, honey bees are the primary insect pollinators used in modern commercial production agriculture, and their populations have been in decline worldwide. Here, we compare the mating frequencies of queens, and therefore, intracolony genetic diversity, in three commercial beekeeping operations to determine how they correlate with various measures of colony health and productivity, particularly the likelihood of queen supersedure and colony survival in functional, intensively managed beehives. We found the average effective paternity frequency (m e ) of this population of honey bee queens to be 13.6 +/- 6.76, which was not significantly different between colonies that superseded their queen and those that did not. However, colonies that were less genetically diverse (headed by queens with m e <= 7.0) were 2.86 times more likely to die by the end of the study when compared to colonies that were more genetically diverse (headed by queens with m e > 7.0). The stark contrast in colony survival based on increased genetic diversity suggests that there are important tangible benefits of increased queen mating number in managed honey bees, although the exact mechanism(s) that govern these benefits have not been fully elucidated. PMID- 23728204 TI - The development and use of Provider Profiles at the organizational and systems level. AB - While the use of quality of life-related personal outcomes has been broadly reported during the last decade, little attention has been paid to the use of such data as a basis for developing and using Provider Profiles at the organizational and systems level. This article illustrates a way in which these evidence-based outcomes may be used not only to improve clinical decisions, but also managerial and policy strategies. To that end, the quality of life of 11,624 social service recipients was assessed by means of the application of the GENCAT Scale, a questionnaire to assess quality of life according to the eight-domain model (Schalock & Verdugo, 2002). Data were analyzed at organizational and the systems level in order to develop Provider Profiles. Once implemented, these profiles can be used to compare individuals in different diagnostic groups, develop province-level performance standards, encourage continuous program improvement, and guide the development of evidence-based policies. PMID- 23728205 TI - Evaluating a collaborative IT based research and development project. AB - In common with all projects, evaluating an Information Technology (IT) based research and development project is necessary in order to discover whether or not the outcomes of the project are successful. However, evaluating large-scale collaborative projects is especially difficult as: (i) stakeholders from different countries are involved who, almost inevitably, have diverse technological and/or application domain backgrounds and objectives; (ii) multiple and sometimes conflicting application specific and user-defined requirements exist; and (iii) multiple and often conflicting technological research and development objectives are apparent. In this paper, we share our experiences based on the large-scale integrated research project - The HUMBOLDT project - with project duration of 54 months, involving contributions from 27 partner organisations, plus 4 sub-contractors from 14 different European countries. In the HUMBOLDT project, a specific evaluation methodology was defined and utilised for the user evaluation of the project outcomes. The user evaluation performed on the HUMBOLDT Framework and its associated nine application scenarios from various application domains, resulted in not only an evaluation of the integrated project, but also revealed the benefits and disadvantages of the evaluation methodology. This paper presents the evaluation methodology, discusses in detail the process of applying it to the HUMBOLDT project and provides an in-depth analysis of the results, which can be usefully applied to other collaborative research projects in a variety of domains. PMID- 23728206 TI - Neutron diffraction studies of oral stratum corneum model lipid membranes. AB - In this work we have investigated model lipid mixtures simulating a lipid component of oral stratum corneum (OSC). Neutron diffraction experiments on oriented samples have revealed that SM (bovine brain)/dipalmitoylphosphatidylethanolamine/dipalmitoylphosphatidylcholine (DPPE/DPPC) mixtures at molar ratios of 1/2/1 and 1/1/1 are one-phase membranes. The incorporation of low concentrations of ceramide 6 and cholesterol into SM/DPPC/DPPE bilayers does not result in a phase separation, affecting membrane hydration. The model OSC membrane composed of ceramide 6/cholesterol/fatty acids/cholesterol sulfate/SM (bovine brain)/DPPE/DPPC is characterized by coexistence of several lamellar phases, that behave differently during their hydration in water excess. The phase with lamellar repeat distance of about 45 A is likely a ceramide-rich phase and shows a restricted swelling in water, while another phase with repeat distance of 50 A swells very quickly on 15 A and then disappears. Our results indicate that phospholipid-rich and ceramide-rich domains could possibly coexist in the intercellular space of oral epithelium. PMID- 23728207 TI - A new way of tracking motion, shape, and divisions. AB - The process of detecting and tracking biological features such as bacteria and nuclei is complicated by the fact that they constantly change their shape. Shape changes happen both continuously as the biological features grow and discontinuously as they divide or die. In this paper I present a new method of tracking such features for the case that they can be reasonably approximated by a relatively simple mathematical shape such as a cylinder or an ellipse. Using contour plots with multiple levels to detect the features and their shapes, rather than the commonly used single contour detection technique, this method can efficiently detect multiple features even if they have large differences in brightness, as well as reliably track divisions when both brightness and size drop dramatically. PMID- 23728208 TI - Non-cystic fibrosis bronchiectasis. AB - Bronchiectasis is a chronic debilitating condition with considerable phenotypic diversity. A vicious cycle of infection and inflammation exists in damaged airways with patients suffering from persistent cough, purulent sputum production, recurrent chest infections and general malaise. The associated burden of disease in terms of increased morbidity, reduced quality of life and the socioeconomic cost of long-term management is significant. Further research is essential to improve our understanding of the development and progression of this disease. This article reviews what is currently known about bronchiectasis, its pathophysiology, aetiology and management strategies. PMID- 23728209 TI - Consultant volume, as an outcome determinant, in emergency medical admissions. AB - BACKGROUND: Increasing hospital or specialist volumes has been shown to improve outcomes; there are little data on volumes and outcomes in emergency medical admissions. We have examined the hospital length of stay (LOS) and 30-day mortality for patients admitted under a consultant 'of the day' having high- or low-admission volumes. METHODS: An analysis was performed on all emergency medical patients admitted between 1 January 2002 and 31 December 2011, using anonymous patient data. We calculated the numbers of unique patients admitted to each 'on call' consultant and allocated the latter to a high- (70th centile with 8/22 consultants) or low-volume (14/22 consultants) category. We examined outcomes (LOS and in-hospital 30-day mortality), by these cut-offs employing logistic regression to calculate unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The hospital LOS was shorter (P < 0.001) for high [median 4.2, inter-quartile range (IQR) 1.7, 8.7] compared with the lower volume group (median 4.8, IQR 1.9, 9.7). There was a reduced 30-day in hospital mortality for high-volume (8.2%) compared with low-volume consultants (9.6%: P < 0.01). An admission under a high-volume consultant was independently predictive of survival, after adjustment for other outcome predictors including co-morbidity; the relative risk reduction was 25% [OR 0.75 (95% CI 0.68-0.82): P < 0.001]. CONCLUSION: In an era of increasing specialization, these data provide support for the concept that the frequency of being 'on-call' contributes to maintaining competence with an associated improvement in patient outcomes. PMID- 23728210 TI - Predicting coexistence of plants subject to a tolerance-competition trade-off. AB - Ecological trade-offs between species are often invoked to explain species coexistence in ecological communities. However, few mathematical models have been proposed for which coexistence conditions can be characterized explicitly in terms of a trade-off. Here we present a model of a plant community which allows such a characterization. In the model plant species compete for sites where each site has a fixed stress condition. Species differ both in stress tolerance and competitive ability. Stress tolerance is quantified as the fraction of sites with stress conditions low enough to allow establishment. Competitive ability is quantified as the propensity to win the competition for empty sites. We derive the deterministic, discrete-time dynamical system for the species abundances. We prove the conditions under which plant species can coexist in a stable equilibrium. We show that the coexistence conditions can be characterized graphically, clearly illustrating the trade-off between stress tolerance and competitive ability. We compare our model with a recently proposed, continuous time dynamical system for a tolerance-fecundity trade-off in plant communities, and we show that this model is a special case of the continuous-time version of our model. PMID- 23728211 TI - On linear birth-and-death processes in a random environment. AB - We study the probability of extinction for single-type and multi-type continuous time linear birth-and-death processes in a finite Markovian environment. The probability of extinction is equal to 1 almost surely if and only if the basic reproduction number R(0) is <= 1, the key point being to identify a suitable definition of R(0) for such a result to hold. PMID- 23728215 TI - Abstracts of the American Society of Gene & Cell Therapy (ASGGT) 16th Annual Meeting. May 15-18, 2013. Salt Lake City, Utah, USA. PMID- 23728213 TI - Treatment of osteochondral defects in the rabbit's knee joint by implantation of allogeneic mesenchymal stem cells in fibrin clots. AB - The treatment of osteochondral articular defects has been challenging physicians for many years. The better understanding of interactions of articular cartilage and subchondral bone in recent years led to increased attention to restoration of the entire osteochondral unit. In comparison to chondral lesions the regeneration of osteochondral defects is much more complex and a far greater surgical and therapeutic challenge. The damaged tissue does not only include the superficial cartilage layer but also the subchondral bone. For deep, osteochondral damage, as it occurs for example with osteochondrosis dissecans, the full thickness of the defect needs to be replaced to restore the joint surface (1). Eligible therapeutic procedures have to consider these two different tissues with their different intrinsic healing potential (2). In the last decades, several surgical treatment options have emerged and have already been clinically established (3 6). Autologous or allogeneic osteochondral transplants consist of articular cartilage and subchondral bone and allow the replacement of the entire osteochondral unit. The defects are filled with cylindrical osteochondral grafts that aim to provide a congruent hyaline cartilage covered surface (3,7,8). Disadvantages are the limited amount of available grafts, donor site morbidity (for autologous transplants) and the incongruence of the surface; thereby the application of this method is especially limited for large defects. New approaches in the field of tissue engineering opened up promising possibilities for regenerative osteochondral therapy. The implantation of autologous chondrocytes marked the first cell based biological approach for the treatment of full-thickness cartilage lesions and is now worldwide established with good clinical results even 10 to 20 years after implantation (9,10). However, to date, this technique is not suitable for the treatment of all types of lesions such as deep defects involving the subchondral bone (11). The sandwich-technique combines bone grafting with current approaches in Tissue Engineering (5,6). This combination seems to be able to overcome the limitations seen in osteochondral grafts alone. After autologous bone grafting to the subchondral defect area, a membrane seeded with autologous chondrocytes is sutured above and facilitates to match the topology of the graft with the injured site. Of course, the previous bone reconstruction needs additional surgical time and often even an additional surgery. Moreover, to date, long-term data is missing (12). Tissue Engineering without additional bone grafting aims to restore the complex structure and properties of native articular cartilage by chondrogenic and osteogenic potential of the transplanted cells. However, again, it is usually only the cartilage tissue that is more or less regenerated. Additional osteochondral damage needs a specific further treatment. In order to achieve a regeneration of the multilayered structure of osteochondral defects, three-dimensional tissue engineered products seeded with autologous/allogeneic cells might provide a good regeneration capacity (11). Beside autologous chondrocytes, mesenchymal stem cells (MSC) seem to be an attractive alternative for the development of a full thickness cartilage tissue. In numerous preclinical in vitro and in vivo studies, mesenchymal stem cells have displayed excellent tissue regeneration potential (13,14). The important advantage of mesenchymal stem cells especially for the treatment of osteochondral defects is that they have the capacity to differentiate in osteocytes as well as chondrocytes. Therefore, they potentially allow a multilayered regeneration of the defect. In recent years, several scaffolds with osteochondral regenerative potential have therefore been developed and evaluated with promising preliminary results (1,15-18). Furthermore, fibrin glue as a cell carrier became one of the preferred techniques in experimental cartilage repair and has already successfully been used in several animal studies (19-21) and even first human trials (22). The following protocol will demonstrate an experimental technique for isolating mesenchymal stem cells from a rabbit's bone marrow, for subsequent proliferation in cell culture and for preparing a standardized in vitro-model for fibrin-cell-clots. Finally, a technique for the implantation of pre-established fibrin-cell-clots into artificial osteochondral defects of the rabbit's knee joint will be described. PMID- 23728212 TI - Systems virology: host-directed approaches to viral pathogenesis and drug targeting. AB - High-throughput molecular profiling and computational biology are changing the face of virology, providing a new appreciation of the importance of the host in viral pathogenesis and offering unprecedented opportunities for better diagnostics, therapeutics and vaccines. Here, we provide a snapshot of the evolution of systems virology, from global gene expression profiling and signatures of disease outcome, to geometry-based computational methods that promise to yield novel therapeutic targets, personalized medicine and a deeper understanding of how viruses cause disease. To realize these goals, pipettes and Petri dishes need to join forces with the powers of mathematics and computational biology. PMID- 23728219 TI - Trabectedin in patients with metastatic soft tissue sarcoma: a retrospective single center analysis. AB - The aim of this study was to retrospectively evaluate the efficacy and safety of trabectedin treatment in patients with metastatic soft tissue sarcoma (STS) in the routine clinical setting. Further, the type and frequency of systemic treatments before commencing treatment with trabectedin and after its discontinuation, as well as the frequency of pulmonary metastasectomies, were analyzed. The current analysis includes retrospective data from consecutive STS patients treated with trabectedin at the Department of Medicine I, Division of Oncology, Medical University of Vienna, between January 2008 and December 2012. Patients were analyzed for median progression-free survival, overall survival (OS), and therapy-related toxicity. Data of 60 STS patients were included in the present analysis. In total, 198 cycles of trabectedin were administered, whereas the median number of cycles administered per patient was two (range 1-25). The median progression-free survival was 2.2 months and the median OS (mOS) was 11.8 months. mOS calculated from the first time point of detection of metastatic disease was 35.8 months. The 18 patients (30%) who underwent pulmonary metastasectomy had an mOS of 50.2 months. Further, trabectedin had a manageable toxicity profile comparable to data reported in previous phase II trials. Our findings support the use of trabectedin as an active and feasible therapeutic option among advanced, metastatic, and refractory STS patients. The good safety profile and lack of cumulative toxicity allow prolonged administration in highly pretreated patients. As visible from the present data, a considerable percentage of patients with advanced/metastatic STS benefit from sequential lines of drug therapy as well as pulmonary metastasectomy. PMID- 23728220 TI - Cilengitide targets pediatric glioma and neuroblastoma cells through cell detachment and anoikis induction. AB - The prognosis of children with high-grade glioma or high-risk neuroblastoma remains poor. Cilengitide is a selective antagonist of alphavbeta3 and alphavbeta5 integrins, which are involved in tumor growth and development of metastasis. We have evaluated the effects of cilengitide on pediatric glioma and neuroblastoma cell lines for the first time. Expression levels of alphavbeta3 and alphavbeta5 were determined by flow cytometry in three neuroblastoma and five pediatric glioma cell lines compared with adult U87-MG before and after irradiation. Cell detachment, cytotoxicity, and cell growth under nonadhesive conditions were measured using the MTS assay. Cell death and apoptosis were assessed by annexin-V/propidium iodide staining. The varying alphavbeta3 and alphavbeta5 expression levels were unrelated to tumor grade. Irrespective of the alphavbeta5 expression level, the pediatric cells expressing alphavbeta3 were dose dependently sensitive to cilengitide. UW479 cells expressed only alphavbeta5 integrin and were not sensitive to cilengitide, suggesting that cilengitide's action largely depends on alphavbeta3 inhibition. Cell detachment resulted in a higher cytotoxicity in pediatric glioma compared with U87-MG cells, which seem able to grow despite the significant cilengitide-induced cell detachment. Growth kinetics on polyHEMA showed that only pediatric glioma cells were sensitive to anoikis and so died after cilengitide-induced detachment. Furthermore, irradiation of glioma cells increased alphavbeta3 expression slightly but not cilengitide sensitivity. Cilengitide's action on glioma and neuroblastoma cells appears to be dependent on alphavbeta3 expression and sensitivity to anoikis. Cilengitide is able to target pediatric glioma and neuroblastoma cells in vitro directly and efficiently. Tumor context could validate these promising observations. PMID- 23728221 TI - Branched TiO2 nanoarrays sensitized with CdS quantum dots for highly efficient photoelectrochemical water splitting. AB - This paper describes the design, characterization, and utilization of branched TiO2 nanoarrays sensitized with CdS quantum dots as anodes for photoelectrochemical water splitting. The remarkable photocurrent density (~4 mA cm(-2) at a potential of 0 V versus Ag/AgCl) and high solar to hydrogen efficiency of the materials obtained were ascribed to the novel branched nanostructure and efficient electron transfer from CdS to TiO2. PMID- 23728222 TI - ELISA detection of semicarbazide based on a fast sample pretreatment method. AB - A direct ELISA was established for the fast detection of semicarbazide (SEM) using a novel biotin derivative. Without a tedious extraction procedure, as low as 0.07 MUg L(-1) of SEM could be detected reproducibly. This assay has better recovery and accuracy than competitive ELISA. PMID- 23728223 TI - Relationship between aortic valve sclerosis and different vascular damage markers: an observational study. AB - OBJECTIVE: Although aortic valve sclerosis (AVS) and atherosclerosis may share same atherosclerotic process, there is still a controversy whether AVS may be related to atherosclerotic and nonatherosclerotic processes. The purpose of present study was to investigate this relation. METHODS: In this cross-sectional and observational study, we enrolled 60 patients diagnosed with AVS and risk factor matched 76 subjects without AVS. Applanation tonometry was applied to assess the augmentation index and aortic pulse-wave velocity (PWV). Control and AVS group were examined by B-mode ultrasound to measure the intima-media thickness (IMT). Continuous variables were compared using unpaired t-test and Mann-Whitney U test. Logistic regression analysis was performed in order to find independent predictors of AVS. RESULTS: PWV and augmentation index did not differ between control and AVS groups (11.2+/-3.6 vs 12+/-3.2, p=0.18 and 26+/-7.6 vs 27+/-9.8, p=0.2 respectively). But IMT was significantly higher in AVS group than in control one (0.76 mm+/-0.17 vs 0.6 mm+/-0.16; p<0.001). There was a significant positive bivariate correlation between the presence of AVS, IMT (r=0.43, p<0.001), male gender(r=0.31, p<0.001), augmentation index (r=0.17, p:0,04), and age (r=0.36, p<0.001). Logistic regression analysis demonstrated that only IMT (OR: 1.46, 95% CI: 1.1-1.9, p=0.009) and age (OR: 1.1, 95% CI: 1.01 1.16, p=0.013) were independent predictors of AVS. CONCLUSION: Increased IMT but not PWV in subjects with AVS compared to control group may suggest that, AVS is probably a multifactorial disease, related to the both atherosclerotic and nonatherosclerotic processes. PMID- 23728224 TI - Elevated mean pulmonary artery pressure in patients with mild-to-moderate mitral stenosis: a useful predictor of worsening renal functions? AB - OBJECTIVE: Renal dysfunction commonly accompanies the course of cardiac disorders and strongly associates with increased morbidity and mortality. Elevated central venous pressure is related to worsening renal function in patients with heart failure. However, predictors of worsening renal function in mitral stenosis-whose pathophysiologic process is similar to heart failure with regard to right heart dysfunction-are unknown. This study aimed to evaluate whether clinical and echocardiographic parameters might predict worsening renal function in patients with mild-to-moderate mitral stenosis. METHODS: The current study has a prospective cohort design. Sixty consecutive patients (9 male, 51 female, mean age 50+/-13 years) with mild-to-moderate mitral stenosis were followed up for 34+/-13 months (range 1-60) and their renal functions were monitored. Worsening renal function was defined as a decline in glomerular filtration rate of >= 20% on follow-up. In order to presence or absence of worsening renal functions, study patients divided into two groups. Statistical analysis was performed using the Chi-square, Independent samples t / Mann-Whitney U tests, univariate and multivariate Cox proportional hazards analyses, receiver operating characteristic (ROC) and Kaplan-Meier curve analyses. RESULTS: Worsening renal function was observed in 14 patients (23%). In univariate analysis, male gender, mean pulmonary artery pressure (mPAP), peak tricuspid regurgitation velocity, systolic pulmonary artery pressure, digitalis and antiplatelet usage, right atrial size, and TEI index were determined to be predictors of worsening renal function. In a multivariate Cox proportional hazards model, mPAP (HR=1.136, 95% CI: 1.058-1.220, p<0.001) and male gender (HR=4.110, 95% CI: 1.812-9.322, p=0.001) were associated with increased risk of worsening renal function during the follow-up period. In ROC curve analysis, the optimal cut-off value of mPAP to predict worsening renal function was measured as more than 21 mmHg, with 78.6% sensitivity and 58.7% specificity (AUC 0.725, 95% CI 0.595-0.838). According to the Kaplan-Meier curve, a significant difference was found between those who had mPAP of >21 mmHg, and those who did not have, in terms of worsening renal function (p=0.006), and the difference between the groups increased after 30 months of follow-up. CONCLUSION: Elevated mean pulmonary artery pressure at the time of initial evaluation, in patients with mild-to-moderate mitral stenosis, might help to predict worsening renal function. PMID- 23728225 TI - Increased YKL-40 levels in patients with isolated coronary artery ectasia: an observational study. AB - OBJECTIVE: YKL-40, a new biomarker of localized inflammation, is secreted by macrophages within the atherosclerotic plaques. Coronary artery ectasia (CAE) is a clinical entity with unclear etiopathogenesis. Some studies have revealed that CAE may be a form of atherosclerosis that has more localized and intense inflammatory properties than atherosclerosis. The goal of this study was to investigate YKL-40 and C-reactive protein (CRP) levels in patients with isolated CAE compared to patients with normal coronary arteries (NCA) and coronary artery disease (CAD). METHODS: Our study has an observational and cross-sectional design. Forty-nine patients with isolated CAE (mean age: 60+/-10 years), 30 age and gender-matched control participants with NCA (30 patients, mean age: 58+/-12 years) and 30 patients with CAD (mean age: 61+/-10 years), were included in the study. The relationship between YKL-40, CRP levels and the presence of CAE was investigated. Univariate and multiple logistic regression analysis were used for analysis of independent variables to predict CAE. RESULTS: Serum YKL-40 levels were significantly different among study groups (NCA: 110+/-53 MUg/L, CAE: 144+/ 68 and CAD: 180+/-117, p=0.005). CAD group and CAE group had significantly higher YKL-40 levels than NCA group (p=0.004 and p=0.015, respectively). CRP was not significantly different between three groups. In addition, there were no any statistically significant differences, with respect to age, gender, the presence of hypertension or diabetes mellitus, and the smoking status (p>0.05). Logistic regression analysis revealed only YKL-40 level as the determinant of CAE (OR: 1.010, 95% CI: 1.001-1.019, p=0.027). CONCLUSION: YKL-40 levels in patients with isolated CAE compared to patients with NCA were found significantly high and only YKL-40 level was established as the determinant of CAE. We believe that further studies are needed to clarify the possible causative roles of YKL-40 in patients with isolated CAE. PMID- 23728226 TI - Holter ECG assessment of the effects of three different local anesthetic solutions on cardiovascular system in the sedated dental patients with coronary artery disease. AB - OBJECTIVE: The purpose of the study is to compare the effects of lidocaine alone, epinephrine-combined lidocaine and prilocaine with octapressin on the cardiovascular system during minor oral surgery of sedated cardiac dental patients under local anesthesia. METHODS: Connected to a Holter electrocardiogram (ECG) monitor for a total of 5 hours starting 1 hour before the procedure, twenty patients with high risk of coronary artery disease were included in the prospective cohort study. All the patients had three operations at 3 different appointments with at least one-week intervals and each operation was performed under local anesthesia achieved by 3.6 mL of 3% prilocaine with octapressin, 3.6 mL of 2% lidocaine with 1:80.000 epinephrine and 3.6 mL of 2% lidocaine without a vasoconstrictor. Data of the Holter ECG device assessed at the end of every hour and evaluated statistically. Repeated measures ANOVA, Friedman test, and Wilcoxon signed ranks test were used to perform statistical analysis. RESULTS: Heart-rate showed significant differences between lidocaine with epinephrine and pure lidocaine in an hour following the injection (p<0.05 for all). Cardiac rhythm showed significant differences between prilocaine with octapressin and pure lidocaine at the second hour after its administration (p<0.05 for all). There were no significant differences between 3 local anesthetics in terms of ST segment deviation. CONCLUSION: In minor oral operation on the sedated patients with cardiac disease, the use of 3.6 mL or a less amount of local anesthetic injection containing epinephrine appears to be a predictable and safe method. PMID- 23728227 TI - Triple therapy (aspirin, clopidogrel and oral anticoagulant) after percutaneous coronary intervention: another call for personalized medicine. AB - Studies indicate that 5-7% patients undergoing percutaneous coronary intervention (PCI) have an indication for anticoagulation therapy. Most commonly atrial fibrillation (AF) is the indication. These subjects require triple therapy with aspirin, clopidogrel, and an oral anticoagulant (OAC). Several questions, concerns and challenges exist regarding the duration, benefit, risks and alternatives related to triple therapy. These questions constitute a moving target with recently approved antiplatelet and anticoagulant agents. This brief review will summarize the current literature regarding triple therapy, potential solutions that can mitigate the formidable risk of bleeding. Arising from that discussion, a logical consensus can be developed that should be applicable to studies with novel agents that interfere with homeostasis. The ultimate goal is to enhance cardiovascular outcome and decrease thrombotic and bleeding complications. PMID- 23728228 TI - Percutaneous closure of a paravalvular leak after mitral valve replacement and transcatheter aortic-valve implantation. PMID- 23728229 TI - Intrauterine idiopathic severe ductal constriction diagnosed by fetal echocardiography: a cause of hydrops fetalis. PMID- 23728230 TI - Subclavian artery stenosis in a patient undergoing coronary bypass using composite t-grafting technique: is it subclavian artery stenosis or more? PMID- 23728231 TI - Dilated cardiomyopathy due to miliary tuberculosis. PMID- 23728233 TI - Staging Laparoscopy for Hilar Cholangiocarcinoma: Is it Still Worthwhile? PMID- 23728232 TI - Is low individual socioeconomic status (SES) in high-SES areas the same as low individual SES in low-SES areas: a 10-year follow-up schizophrenia study. AB - OBJECTIVE: This study investigates the relationship between individual and neighborhood socioeconomic status (SES) and mortality among patients with schizophrenia. METHODS: A study population was identified from the National Health Insurance Research Database (NHIRD) prior to the end of 1999 that included 60,402 patients with schizophrenia. Each patient was tracked until death or to the end of 2009. Individual SESs were defined by enrollee category. Neighborhood SES was defined by enrollee category (as a proxy for occupation) and education, which were classified according to the conventions of Hollingshead. Neighborhoods were also grouped into advantaged and disadvantaged areas. The Cox proportional hazards model was used to compare the death-free survival rate between the different SES groups after adjusting for possible confounding factors and risk factors. RESULTS: During the 10-year follow-up period, the mortality rates among high, moderate, and low individual SES groups were 12.22, 14.75, and 18.48%, respectively (P < 0.001). Schizophrenia patients with low individual SESs in disadvantaged neighborhoods had a risk of death that was 18-22% higher than that of those with high individual SES in advantaged neighborhoods. The analysis of the combined effect of individual SES and neighborhood SES revealed that the death rates were highest among those with low individual SES and low neighborhood SES (P < 0.001). CONCLUSIONS: Schizophrenia patients with low individual SES in disadvantaged neighborhoods have the highest risk of mortality despite a universal health-care system. Public health strategies and welfare policies must continue to focus on this vulnerable group. PMID- 23728236 TI - The effects of stimulation parameters on clinical outcomes in patients with vagus nerve stimulation implants with major depression. AB - Stimulation techniques, such as vagus nerve stimulation, are a promising new approach for treatment-resistant depression. Most international studies have used fixed stimulation parameters or have varied the stimulation frequencies. Our retrospective examination of 2 parallel groups of 10 patients each compared low strength/high-frequency vagus nerve stimulation parameters (<=1.5 mA, 20 Hz) with high-strength/low-frequency ( >1.5 mA, 15 Hz) parameters. We found a significant decrease in the Hamilton Rating Scale for Depression scores in patients who were treated using the low-strength/high-frequency stimulation parameters. In contrast, the scores of the patients treated with high-strength/low-frequency stimulation did not change. PMID- 23728235 TI - [Molecular pathological diagnosis in cytopathology of non-small-cell lung cancer. Standardization of specimen processing]. AB - BACKGROUND: Personalized medicine is becoming standard for the treatment of non small-cell lung cancer. For example, patients with activating EGFR mutations or EML4-ALK translocations largely benefit from targeted therapies with tyrosine kinase inhibitors with better response rates and progression-free survival compared to standard chemotherapy regimens. However, the application of the respective molecular biomarker analyses requires great expertise in the handling of different cell and tissue specimens. A major challenge for reliable analyses is the usually low amount of tumor material. There are currently relatively few standardized and evidence-based guidelines for the processing and analysis of respective specimens as well as for interpretation of the test results. MATERIALS AND METHODS: To establish a basis for standardized predictive cytopathological analyses, different material processing approaches and molecular pathological tests are discussed, and novel concepts and strategies are lined out in order to improve the quality and reliability of the respective diagnostic procedures. RESULTS AND DISCUSSION: Predictive analyses of cytological specimens can be reliably performed using smears, cytospins or cell blocks; there is no need for histological specimens. The diagnostic work-up of cytological probes should be performed as carefully as possible in order to save further tumor material for subsequent predictive analyses. With standardized and reliable procedures at hand cytopathology is an important contribution to the multidisciplinary, complex care, and treatment of lung cancer patients. PMID- 23728237 TI - Mutation of active site serine residue with cysteine displays change in acyl acceptor preference of beta-peptidyl aminopeptidase from Pseudomonas aeruginosa PAO1. AB - A beta-peptidyl aminopeptidase, a peptidase belonging to the P1 family, catalyzes aminolysis in accordance with its hydrolytic activity. We specifically examined beta-peptidyl aminopeptidase of Pseudomonas aeruginosa PAO1 (BapF) to assess the effects of mutation of catalytic Ser with Cys or Thr on its catalytic ability. Recombinant BapF and its S237C mutant exhibited p-nitroaniline release activity toward beta-homo-Gly-p-nitroanilide (betahGly-pNA), but the products of the enzyme reaction differed completely from one another. Wild-type BapF showed betahGly-betahGly-pNA synthetic activity, but the product vanished in a few minutes and converted to free betahGly. In contrast, the product betahGly betahGly-pNA was synthesized by S237C BapF efficiently without degradation, indicating that because of the mutation, the enzyme came to recognize only the amine group as an acyl acceptor instead of water. Furthermore, a difference in acyl acceptor preference between that of wild type and S237C BapF was observed. When using cysteamine as an acyl acceptor, betahGly-cysteamine was synthesized only in the reaction using S237C BapF. In contrast, S237C BapF was unable to synthesize betahGly-cystamine when using cystamine as an acyl acceptor, although it was synthesized by wild-type BapF. Such a dynamic change in the acyl acceptor by the mutation of catalytic Ser with Cys is regarded as a unique feature of family P1 peptidases. PMID- 23728239 TI - Multinuclear (67Zn, 119Sn and 65Cu) NMR spectroscopy--an ideal technique to probe the cationic ordering in Cu2ZnSnS4 photovoltaic materials. AB - For the very first time, (67)Zn, (119)Sn and (65)Cu NMR investigations have been carried out on Cu2ZnSnS4 derivatives (CZTS) for photovoltaic applications. NMR spectroscopy is shown to be sensitive enough to probe the Cu/Zn disorder within the kesterite structure of the studied compounds. In addition, reference spectra of Cu2ZnSnS4 are provided, and experimental (67)Zn and (65)Cu parameters are compared with ab initio calculations. PMID- 23728238 TI - Effect of different C/N ratios on carotenoid and lipid production by Rhodotorula glutinis. AB - Due to the increasing demand for sustainable biofuels, microbial oils as feedstock for the transesterification into biodiesel have gained scientific and commercial interest. Also, microbial carotenoids have a considerable market potential as natural colorants. The carbon to nitrogen (C/N) ratio of the respective cultivation media is one of the most important parameters that influence the production of microbial lipids and carotenoids. Thus, in the present experiment, the influence of different C/N ratios, initial glucose loadings, and ammonium concentrations of the cultivation medium on microbial cell growth and lipid and carotenoid production by the oleaginous red yeast Rhodotorula glutinis has been assessed. As a general trend, both lipid and carotenoid production increased at high C/N ratios. It was shown that not only the final C/N ratio but also the respectively applied initial carbon and nitrogen contents influenced the observed parameters. The lipid yield was not affected by different ammonium contents, while the carotenoid production significantly decreased both at low and high levels of ammonium supply. A glucose-based increase from C/N 70 to 120 did not lead to an increased lipid production, while carotenoid synthesis was positively affected. Generally, it can be asserted that lipid and carotenoid synthesis are stimulated at higher C/N ratios. PMID- 23728240 TI - Paramuscular perforators in DIEAP flap for breast reconstruction. AB - One of the main steps in perforator flap surgery is to identify the dominant perforator. Using multidetector row computed tomography (MDCT) for the preoperative planning of deep inferior epigastric artery perforator (DIEAP) flap surgery, we identified a perforator with a large caliber, an excellent location in the middle abdominal region, and a totally extramuscular trajectory in a significant number of patients. We describe the frequency of this perforator and determine its characteristics. PATIENTS AND METHODS: We conducted a retrospective study of 482 patients who underwent 526 DIEAP flaps for breast reconstruction from October 2003 to October 2011. Mean age at surgery was 51.3 years old. A preoperative MDCT of abdominal vascularization was performed in all patients. RESULTS: MDCT identified a dominant perforator with a paramuscular course in 12.4% of abdominal walls. In all cases, it was located in the midline and emerged directly from the deep inferior epigastric system. Its mean caliber was 1.9 mm. The flap was harvested based on this perforator in all these patients, and mean harvest time was 51 minutes. The characteristics of this perforator made dissection easier and reduced morbidity at the donor site. There were no flap losses and the only complications were minor. CONCLUSION: We located a paramuscular perforator in 12.4% of patients undergoing breast reconstruction with abdominal perforator flaps. Its morphological features and extramuscular course make it the perforator of choice in DIEAP flap surgery. PMID- 23728241 TI - Alternative surgical treatment of paralytic lagophthalmos using autogenic cartilage grafts and canthopexy. AB - PURPOSE: This study aims to analyze the use of autogenic auricular cartilage grafts as weight for the upper eyelid in conjunction with lateral canthopexy for patients with mild paralytic lagophthalmos. This procedure was also accompanied by elevation of the lower eyelid using the cartilage graft for moderate cases. METHODS: We conducted a retrospective study including case series of 30 patients with paralytic lagophthalmos from 1997 to 2010. For mild cases, cartilage from the auricular scapha was placed in pretarsal space of the upper eyelid and cartilage from the concha was inserted in preaponeurotic space and then sutured to the levator aponeurosis in conjunction with lateral canthopexy. For moderate cases, lower eyelid was also elevated by suturing cartilage graft to tarsum and resting it by the inferior orbital rim. RESULTS: All patients had some degree of keratopathy before the intervention. After treatment, they presented with evident clinical improvement, reduction of eye symptoms, and resolution of keratopathy. During the mean postoperative follow-up of 37.3 months, none of the patients presented with cartilage graft exposition, reabsorption, visibility, infection, or warping. Complete eye closure was achieved in 24 (80%) patients, whereas the remaining 6 (20%) patients had residual asymptomatic lagophthalmos. CONCLUSIONS: The intervention using autogenic auricular cartilage grafts explained in this study was only effective for the treatment of mild and moderate cases of paralytic lagophthalmos. This outpatient surgery is associated with low morbidity and achievement of functional and aesthetic improvement. PMID- 23728242 TI - Distally based adipofascial flaps covering soft-tissue defects of the dorsal foot and ankle in children. AB - Dorsal soft-tissue defects of the foot and ankle are difficult to cover adequately, particularly in children, although multiple options for reconstruction are available. This study reports the long-term clinical outcomes of the use of distally based adipofascial flaps for these injuries in children. Fourteen children, all younger than 9 years, had relatively homogenous local lesions on the dorsum of the foot and ankle or on the distal lower leg. All 14 defects were covered with distally based adipofascial flaps, either lateral supramalleolar flaps (11 cases) or sural flaps (3 cases), after thorough wound debridement. The minimum follow-up interval was 5 years. The appearance of the reconstructed feet aesthetically and functionally satisfied the patients and their parents. Some patients exhibited a growth mismatch between grafted skin and the recipient site, resulting in mild extension contracture of the metatarsophalangeal joints; however, motion of the ankle joints was excellent. PMID- 23728243 TI - Reliability and internal validity of the michigan hand questionnaire. AB - BACKGROUND: The Michigan Hand Outcomes Questionnaire (MHQ) remains one of very few to be based on validated and systematic methods in its creation. However, test-retest reliability and internal validity have not been appropriately investigated in any other English-speaking population outside the original development sample. The objective of this study is to examine the reliability and internal validity of the MHQ in a Canadian population. METHODS: All patients with a clinical hand problem but no hand immobilization who attended our Plastic Surgery Clinic were invited to participate in this study. Patients were asked to complete the MHQ, and then contacted to arrange for completion of the MHQ a second time. Internal validity was estimated using Cronbach alpha. Reliability was estimated using the method of Bland and Altman, and intraclass correlation coefficients. Correlation analysis between score differences and time between tests was performed. RESULTS: Full versions of the MHQ were completed by 116 participants on their initial visit, while only 77 participants completed a second MHQ. Cronbach alpha ranged from 0.84 to 0.95 for the MHQ subscales. Intraclass-correlation coefficients ranged from 0.71 to 0.84 for the subscales. The magnitude of the limits of agreement for the subscales ranged from 13.8 to 26.2. The difference in scores between the first and second tests was not related to the time between tests. CONCLUSION: The high values of Cronbach alpha indicate high internal validity, but that there may be redundancy between items in the MHQ, which could be eliminated without losing information. Reliability of the MHQ is considered moderate. The limits of agreement are considered wide, indicating potential issues with respect to interpretation of a change in score between 2 administrations of the MHQ. PMID- 23728244 TI - Commentary to "current microsurgery training programs in India". PMID- 23728245 TI - Surgical treatment of extensive sacrococcygeal hidradenitis suppurativa with triangular closure technique. AB - BACKGROUND: Recurrence of the sacrococcygeal hidradenitis suppurativa (HS) can significantly be reduced by invasive local excision of all the abscess, sinuses, and scars which often result in large defects on this region. Although a number of surgical procedures have been described, closure of large sacrococcygeal defects resulting from excision of extensive HS still remains a challenge. PURPOSE: Here, we present the use of triangular closure technique as a new alternative in surgical treatment of extensive HS of sacrococcygeal region. MATERIALS AND METHODS: For more than 4 years, triangular closure technique has been used for skin coverage of the large sacrococcygeal defects resulting from excision of the HS in 16 patients (12 men and 4 women) aged between 18 and 52. The size of the defects range from 10 to 25 cm in the greatest dimension. RESULTS: In all patients, a successful tension-free closure of the defect was obtained. Except for 2 patients who had tip necrosis, all patients healed uneventfully. There was no patient with infection and wound dehiscence. A mean follow-up for 36 months (6 months-5 years) revealed no recurrence and an aesthetically acceptable scar formation in all patients. No patient required additional surgery. CONCLUSIONS: Triangular closure technique enables the surgeon to achieve a tension-free defect closure of remarkably large sacrococcygeal defects resulting from surgical excision of extensive HS. Using 2 well vascularized fasciocutaneous flaps, it provides a durable coverage and soft tissue padding over sacrococcygeal and gluteal region with good cosmesis. With these advantages, triangular closure technique seems to be a useful, 1-stage, and safe reconstructive alternative for the closure of these challenging defects. PMID- 23728246 TI - The importance of early flap coverage in deep sternal wounds. AB - BACKGROUND: Chronic or persistent wound infection is one of the key outcome measures after flap reconstruction in deep sternal wound infection (DSWI). This study aimed to assess potentially modifiable factors associated with chronic infection in patients undergoing flap reconstruction. MATERIALS AND METHODS: An analysis of a prospective database of 5239 median sternotomies performed during a 5-year period was carried out. Seventy-seven cases of DSWI were recorded, of which 23 cases proceeded to flap reconstruction. The flap-reconstructed patients were placed into groups according to the primary outcome measure of those who experienced chronic infection and those who remained infection free. RESULTS: Of the flap-reconstructed patients, 22% experienced subsequent chronic infection, whereas 78% remained infection free. The only 2 variables that were associated with chronic infection were the timing of flap reconstruction; median time 29.5 days (vs 12 days in the infection-free group), P=0.011 and time taken from diagnosis of wound infection/dehiscence to referral to the plastic surgical team; median 21 days (vs median 8 days in the infection free group), P=0.02. Each day of delay from the diagnosis of clinical infection to flap cover equated to an increase in risk of chronic infection of 1.2 times per day (OR=1.205, P=0.039). CONCLUSIONS: This study suggests that chronic infection after flap reconstruction in DSWI is associated with late flap cover. We suggest the need for a consensus agreement on the combined care and early management of DSWI. PMID- 23728247 TI - Versatility of tissue expansion in abdominal wall reconstruction after removal of vascular malformations in children. AB - BACKGROUND: Children who have had extensive abdominal wall vascular anomalies (VAs) face 3 common reconstructive options: either tolerating the complications of these lesions, exposure to repeated laser therapy session with its sequelae, or excision followed by a color-matched skin graft. The use of serial tissue expansion and excision of the affected skin offers a potentially better option under the right circumstances. Tissue expanders (TEs) have broad applicability but are not without complications. OBJECTIVE: To study the versatility of use of TEs in the management of children who had extensive VAs in their abdominal wall with special emphasis to the complications and children and parental satisfaction. MATERIALS AND METHODS: Retrospective data collection of 12 patients' charts, operative data of 84 operative procedures, and follow-up visits. Statistical analysis done using Student t test significance and P<0.05 was considered statistically significant. RESULTS: Using 35 different sizes of TEs and 84 operative procedures in 9 boys and 3 girls aged from 2 to 12 years with different types of abdominal wall VAs revealed an overall complications rate of 20%. Child and parental satisfaction was found to be good overall. CONCLUSIONS: Tissue expander is a useful and feasible tool for reconstruction of the abdominal wall with extensive VAs in children; parents and children were satisfied and body image is acceptable. PMID- 23728249 TI - Introducing molecular therapy--methods & clinical development. PMID- 23728248 TI - The social cognition psychometric evaluation study: results of the expert survey and RAND panel. AB - BACKGROUND: In schizophrenia, social cognition is strongly linked to functional outcome and is increasingly seen as a viable treatment target. The goal of the Social Cognition Psychometric Evaluation (SCOPE) study is to identify and improve the best existing measures of social cognition so they can be suitably applied in large-scale treatment studies. Initial phases of this project sought to (1) develop consensus on critical domains of social cognition and (2) identify the best existing measures of social cognition for use in treatment studies. METHODS: Experts in social cognition were invited to nominate key domains of social cognition and the best measures of those domains. Nominations for measures were reduced according to set criteria, and all available psychometric information about these measures was summarized and provided to RAND panelists. Panelists rated the quality of each measure on multiple criteria, and diverging ratings were discussed at the in-person meeting to obtain consensus. RESULTS: Expert surveys identified 4 core domains of social cognition-emotion processing, social perception, theory of mind/mental state attribution, and attributional style/bias. Using RAND panel consensus ratings, the following measures were selected for further evaluation: Ambiguous Intentions Hostility Questionnaire, Bell Lysaker Emotion Recognition Task, Penn Emotion Recognition Test, Relationships Across Domains, Reading the Mind in the Eyes Test, The Awareness of Social Inferences Test, Hinting Task, and Trustworthiness Task. DISCUSSION: While it was possible to establish consensus, only a limited amount of psychometric information is currently available for the candidate measures, which underscores the need for well-validated and standardized measures in this area. PMID- 23728252 TI - FX and host defense evasion tactics by adenovirus. PMID- 23728253 TI - The expanding repertoire of circular RNAs. PMID- 23728254 TI - T lymphocytes are not immune. PMID- 23728255 TI - Further proof for an unpopular concept: a single cell from bone marrow can serve as a stem cell for both hematopoiesis and osteogenesis. PMID- 23728256 TI - Dispersion of Al2O3 nanoparticles stabilized with mussel-inspired amphiphilic copolymers in organic solvents and formation of hierarchical porous films by the breath figure technique. AB - Hierarchical porous inorganic materials have attracted much attention, due to their large surface area and fast substance diffusion. We have prepared hierarchical porous films composed of Al2O3 nanoparticles (NPs) using the breath figure technique. The Al2O3 NPs were stabilized using an amphiphilic copolymer that contained catechol moieties. Porous films of polymer-stabilized Al2O3 NPs were prepared using water droplets as templates. The films were sintered to produce hierarchical porous Al2O3 films that were thermally and chemically stable. PMID- 23728258 TI - The risk of developing AF after cardiac surgery. PMID- 23728257 TI - Evaluation of recombinant forms of the shiga toxin variant Stx2eB subunit and non toxic mutant Stx2e as vaccine candidates against porcine edema disease. AB - Porcine edema disease (ED) is a communicable disease of shoats caused by infection with Shiga toxin (Stx)-producing Escherichia coli. Stx2e is classified as a 1A5B-type toxin and is a decisive virulence determinant of ED. The single A subunit of Stx2e possesses enzymatic activity and is accompanied by a pentamer of B subunits, which binds to the host receptor and delivers the A subunit into the cell. In the present study, we used a mouse model to evaluate the immunogenicity of 3 ED vaccine candidates: a non-toxic mutant holotoxin mStx2e and 2 Stx2eB based fusion proteins, Stx2eA2B-His and Stx2eB-His. Systemic inoculation of mice with mStx2e- and the Stx2eB-derived antigens induced anti-Stx2e IgG responses that were fully and partially capable of neutralizing Stx2e cellular cytotoxicity, respectively. Intranasal immunization with mStx2e protected the mice from subsequent intraperitoneal challenge with a lethal dose of Stx2e, whereas immunization with Stx2eA2B-His and Stx2eB-His afforded partial protection. Analysis of serum cytokines revealed that mStx2e, but not the Stx2eB based antigens, was capable of inducing a Th2-type immune response. These results suggest that although the Stx2eB-based antigens elicited an immune response to Stx2e, they did so through a different mechanism to the Th2-type response induced by mStx2e. PMID- 23728259 TI - Coronary collateral development might be impaired by decreases in glomerular filtration rate. PMID- 23728260 TI - Epidemiological characteristics and in-hospital rhythmic complications of acute coronary syndrome: experience of single-center in Rabat, Morocco. PMID- 23728261 TI - [A case of myopericarditis following butane gas inhalation]. PMID- 23728262 TI - [Changing face of acute rheumatic fever: our clinical observations]. PMID- 23728263 TI - High twin birth rate of offspring in mothers with cardiac disease. PMID- 23728264 TI - On increasing number of percutaneous mitral valve repair with MitraClip in Turkey, and the fate of the high-risk patients. PMID- 23728265 TI - An adult patient with the ruptured aneurysm of mitral valve posterior leaflet. PMID- 23728266 TI - Structural failure of a left atrial appendage occluder device. PMID- 23728267 TI - Fistulous connection of left circumflex coronary artery to coronary sinus presenting with massive pericardial effusion. PMID- 23728268 TI - Giant left atrial myxoma with left and right coronary system blood supply accompanying mitral stenosis; real-time three- dimensional echocardiography imaging. PMID- 23728269 TI - Crossed pulmonary arteries associated with persistent truncus arteriosus and right aortic arch on the three-dimensional computed tomographic imaging. PMID- 23728270 TI - A heart-like cystic image in the heart. Hydatid cyst. PMID- 23728271 TI - Could YKL-40 be used as a new marker for coronary artery ectasia? PMID- 23728272 TI - Almanac 2012, cell therapy in cardiovascular disease: the journals present selected research that has driven recent advances in clinical cardiology. AB - The rapid translation from bench to bedside that has been seen in the application of regenerative medicine to cardiology has led to exciting new advances in our understanding of some of the fundamental mechanisms related to human biology. The first generation of cells used in phase I-II trials (mainly bone marrow mononuclear cells) are now entering phase III clinical trials with the goal of producing a cell based therapeutic that can change the outcome of cardiac disease. First generation cell therapy appears to have addressed safety concerns as well as showing 'activity' in numerous published meta- analyses. With the knowledge gained to date, the field is moving towards the next generation of cells-the 'engineered' cell-that have been developed to display a phenotype that will further enhance the myocardial repair/salvage process. This almanac review covers the latest basic research that may soon have application to humans as well as the results of the latest clinical trials. PMID- 23728273 TI - Telomere length and telomerase activity; a Yin and Yang of cell senescence. AB - Telomeres are repeating DNA sequences at the tip ends of the chromosomes that are diverse in length and in humans can reach a length of 15,000 base pairs. The telomere serves as a bioprotective mechanism of chromosome attrition at each cell division. At a certain length, telomeres become too short to allow replication, a process that may lead to chromosome instability or cell death. Telomere length is regulated by two opposing mechanisms: attrition and elongation. Attrition occurs as each cell divides. In contrast, elongation is partially modulated by the enzyme telomerase, which adds repeating sequences to the ends of the chromosomes. In this way, telomerase could possibly reverse an aging mechanism and rejuvenates cell viability. These are crucial elements in maintaining cell life and are used to assess cellular aging. In this manuscript we will describe an accurate, short, sophisticated and cheap method to assess telomere length in multiple tissues and species. This method takes advantage of two key elements, the tandem repeat of the telomere sequence and the sensitivity of the qRT-PCR to detect differential copy numbers of tested samples. In addition, we will describe a simple assay to assess telomerase activity as a complementary backbone test for telomere length. PMID- 23728274 TI - Periodontal therapy in chronic periodontitis lowers gingival crevicular fluid interleukin-1beta and DAS28 in rheumatoid arthritis patients. AB - To evaluate clinical outcomes and effects of non-surgical periodontal therapy on serum, gingival crevicular fluid (GCF) interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) levels in chronic periodontitis patients with/without rheumatoid arthritis (RA), fifteen RA patients with chronic periodontitis (RA-P) and 15 systemically healthy non-RA chronic periodontitis patients (H-P) were recruited. Clinical periodontal recordings, GCF, and blood samples were obtained at baseline, 1, 3, and 6 months after periodontal treatment. GCF, serum IL-1beta, TNF-alpha levels were analyzed by ELISA. Disease activity score 28 (DAS28) was used to assess RA clinical morbidity. Study groups were compared by Mann-Whitney U test. Wilcoxon test was used to compare the data at baseline, 1, 3, and 6 months after periodontal therapy within the same group. DAS28 decreased significantly after periodontal therapy in RA-P group (p < 0.01). Serum TNF-alpha concentrations of H-P group were significantly higher than those of RA-P group (p < 0.01), whereas IL-1beta levels were similar. No significant change was observed in serum levels of these cytokines after periodontal therapy. GCF IL-1beta amounts decreased significantly in both groups following treatment (p < 0.01). At 6-months, H-P GCF IL-1beta concentrations were significantly lower than baseline. DAS28 and GCF IL-1beta correlated with clinical periodontal indices (p < 0.01). Significant decreases in DAS28 and GCF IL-1beta amounts after periodontal treatment suggest that periodontal therapy synergizes with systemic RA therapy to improve RA status. PMID- 23728275 TI - Do people with benign joint hypermobility syndrome (BJHS) have reduced joint proprioception? A systematic review and meta-analysis. AB - Joint proprioceptive deficit is documented in a variety of musculoskeletal conditions including osteoarthritis, ligament and meniscal injuries, and individuals with increased joint hypermobility, such as those with Ehlers-Danlos. No systematic reviews have assessed joint proprioception in people with benign joint hypermobility syndrome (BJHS). This study addresses this to determine whether people with BJHS exhibit reduced joint proprioception, and, if so, whether this is evident in all age groups. The search strategy was conducted on 31st January 2013. The published literature was assessed using the databases: AMED, CINAHL, MEDLINE, EMBASE, PubMed and the Cochrane Library. Unpublished literature and trial registries were assessed including: OpenGrey, the WHO International Clinical Trials Registry Platform, Current Controlled Trials, the UK National Research Register Archive. All studies comparing the proprioceptive capability of people with and without BJHS were included. Study methodological quality was assessed using the CASP appraisal tool. Meta-analysis techniques were used when study homogeneity permitted. Five studies including 254 people were identified. People with BJHS demonstrated statistically significantly poorer lower limb joint position sense (JPS) (p < 0.001) and threshold detection to movement (p < 0.001) than those without BJHS. The evidence for upper limb proprioceptive difference was less clear, with no statistically significant difference between the cohorts for shoulder JPS (p = 0.10), but a statistically significant difference in finger JPS (p < 0.001). One study which assessed childhood BJHS reported reduced knee proprioceptive capability in those with BJHS (p < 0.001). To conclude, lower limb joint proprioception is reduced in those with BJHS compared to non-BJHS cohorts, whilst unclear in the upper limb. PMID- 23728276 TI - Using the variation of anammox bacteria community structures as a bio-indicator for anthropogenic/terrestrial nitrogen inputs in the Pearl River Delta (PRD). AB - The variation of anammox bacteria community composition was evaluated in sediments collected from the Pearl River Delta area with an anthropogenic/terrestrial input gradient. Results indicated that the community composition of anammox bacteria shifted from estuarine environment to the South China Sea deep ocean along with the anthropogenic/terrestrial input gradient, where Scalindua genus of anammox bacteria predominated in the area with less anthropogenic/terrestrial influences, such as in the open oceanic area, while genera of Kuenenia/Brocadia anammox bacteria have higher proportions in the area with higher anthropogenic/terrestrial impacts. The canonical correspondence analysis demonstrated that salinity, organic matter contents, and ratio of NH4 (+) to (NO2 (-)+NO3 (-)) strongly affected the shifting of anammox bacterial community compositions within the same gradients. The results obtained in this study, together with the similar variation of anammox bacteria community structures in other several estuaries in the world, indicated that anammox bacteria might have a habitat-specific distribution pattern according to their living habits, and their community composition could be served as a bio-indicator to monitor the anthropogenic/terrestrial N inputs in coastal environments. PMID- 23728278 TI - The comprehensive complication index: a novel continuous scale to measure surgical morbidity. AB - OBJECTIVE: To develop and validate a comprehensive complication index (CCI) that integrates all events with their respective severity. BACKGROUND: Reporting of surgical complications is inconsistent and often incomplete. Most studies fail to provide information about the severity of complications, or inform only on the most severe event, ignoring events of lesser severity. METHODS: We used an established classification of complications, adopting methods from operation risk index analysis in marketing research to develop a formula that considers all complications that may occur in a patient. The weights of each grade of complication, defined as median reference values, were obtained from 472 participants, who rated 30 different complications. Validation to assess sensitivity to treatment effects and validity of the CCI was performed by 4 different approaches, based on 1299 patients. RESULTS: The CCI is calculated as the sum of all complications that are weighted for their severity (multiplication of the median reference values from patients and physicians). The final formula yields a continuous scale to rank the severity of any combination of complications from 0 to 100 in a single patient. The CCI was highly sensitive in detecting treatment effect differences in the context of a randomized trial (effect size detected by CCI vs conventional standardized morbidity outcomes). It also showed a negative correlation with postoperative health status (r = -0.24, P = 0.002), and high correlation with the results of patient-rated single and multiple complications on conjoint analysis (r = 0.94, P < 0.001). CONCLUSIONS: The CCI summarizes all postoperative complications and is more sensitive than existing morbidity endpoints. It may serve as a standardized and widely applicable primary endpoint in surgical trials and other interventional fields of medicine. The CCI can be readily computed on the basis of tabulated complications according to the Clavien-Dindo classification (available at www.assessurgery.com). PMID- 23728279 TI - Postoperative complication reporting: more than mortality and morbidity. PMID- 23728280 TI - Postoperative complications and hospital readmissions in surgical patients: an important association. PMID- 23728281 TI - Within-team debriefing versus instructor-led debriefing for simulation-based education: a randomized controlled trial. AB - OBJECTIVE: To compare the effectiveness of an interprofessional within-team debriefing with that of an instructor-led debriefing on team performance during a simulated crisis. BACKGROUND: Although instructor-led simulation debriefing is considered the "gold standard" in team-based simulation education, cost and logistics are limiting factors for its implementation. Within-team debriefing, led by the individuals of the team itself rather than an external instructor, has the potential to address these limitations. METHODS: One hundred twenty subjects were grouped into 40 operating room teams consisting of 1 anesthesia trainee, 1 surgical trainee, and 1 staff circulating operating room nurse. All teams managed a simulated crisis scenario (pretest). Teams were then randomized to either a within-team debriefing group or an instructor-led debriefing group. In the within team debriefing group, the teams reviewed the video of their scenario by themselves. The teams in the instructor-led debriefing group reviewed their scenario guided by a trained instructor. Immediately after debriefing, all teams managed a different intraoperative crisis scenario (posttest). All sessions were videotaped. Blinded expert examiners used the validated Team Emergency Assessment Measure scale to assess crisis resource management performance of all teams in random order. RESULT: Team performance significantly improved from pretest to posttest (P = 0.008) regardless of the type of debriefing. There was no significant difference in the degree of improvement between within-team debriefing and instructor-led debriefing (P = 0.52). CONCLUSIONS: Within-team debriefing results in measurable improvements in team performance in simulated crisis scenarios. This form of debriefing may be as effective as instructor-led team debriefing, which could improve resource utilization and feasibility of team based simulation (NCT01067378). PMID- 23728282 TI - President Eisenhower's bowel obstruction: the story of his surgeons and their decision to operate. PMID- 23728283 TI - Reply to letter: "Limits of neuromonitoring in thyroid surgery": vagus nerve stimulation for diagnosis of a nonrecurrent laryngeal nerve. PMID- 23728284 TI - Preoperative aspirin use in cardiac surgery. PMID- 23728285 TI - Reply to letters: "Preoperative aspirin use and outcomes in cardiac surgery patients: a role of platelet function assessment" and "Preoperative aspirin use in cardiac surgery". PMID- 23728286 TI - Letter Re: Gallbladder cancer involving the extrahepatic bile duct is worthy of resection. PMID- 23728287 TI - Reply to Letter Re: "Gallbladder cancer involving the extrahepatic bile duct is worthy of resection". PMID- 23728288 TI - Letter Re: "Operative outcomes beyond 30-day mortality: colorectal cancer surgery in oldest old" no reply. PMID- 23728289 TI - Removal of mixed pesticides from aqueous solutions using organoclays: evaluation of equilibrium and kinetic model. AB - Removal of mixed pesticides, namely alachlor, metolachlor, chlorpyriphos, fipronil, alpha-endosulfan, beta-endosulfan, p,p'-DDT and two metabolites p,p' DDE and endosulfan sulphate from aqueous solution by batch adsorption onto three commercial organo-modified montmorillonite clays [modified with octadecylamine (ODA-M), modified with dimethyl- dialkylamine (DMDA-M) and modified with octadecylamine and aminopropyltriethoxysilane (ODAAPS-M)] were investigated. Effect of process variables, mainly contact time and initial concentration of mixed pesticides, on adsorption phenomenon were evaluated. To understand the adsorption kinetic pseudo-first-order and pseudo-second-order models were tested. The pseudo-second-order model provided the best fit for explaining adsorption kinetics, on the basis of high correlation coefficient (r) and normalized percent deviation values. The adsorption equilibrium was explained by the Freundlich isotherm (r = 0.951-0.992). High values (0.17-0.52 mg g-1) of Freundlich constant (K(f)) indicated higher affinity of pesticides towards all three organoclays, as a result of hydrophobic interaction between the adsorbent/adsorbate systems. Pesticides with high octanol-water partition coefficient (K(ow)) and low water solubility showed faster adsorption with higher K(f) values as compared to the pesticides with low K(ow) and high water solubility. The order of organoclays for removal efficiency of mixed pesticide was ODAAPS-M > DMDA-M > ODA-M. These findings may find application to decontaminate or treat mixed pesticide contaminated industrial/agricultural waste waters. PMID- 23728290 TI - Integrative genomic analyses reveal clinically relevant long noncoding RNAs in human cancer. AB - Despite growing appreciation of the importance of long noncoding RNAs (lncRNAs) in normal physiology and disease, our knowledge of cancer-related lncRNAs remains limited. By repurposing microarray probes, we constructed expression profiles of 10,207 lncRNA genes in approximately 1,300 tumors over four different cancer types. Through integrative analysis of the lncRNA expression profiles with clinical outcome and somatic copy-number alterations, we identified lncRNAs that are associated with cancer subtypes and clinical prognosis and predicted those that are potential drivers of cancer progression. We validated our predictions by experimentally confirming prostate cancer cell growth dependence on two newly identified lncRNAs. Our analysis provides a resource of clinically relevant lncRNAs for the development of lncRNA biomarkers and the identification of lncRNA therapeutic targets. It also demonstrates the power of integrating publically available genomic data sets and clinical information for discovering disease associated lncRNAs. PMID- 23728291 TI - Nucleosome dynamics regulates DNA processing. AB - The repair of DNA double-strand breaks (DSBs) is critical for the maintenance of genome integrity. The first step in DSB repair by homologous recombination is the processing of the ends by one of two resection pathways, executed by the Saccharomyces cerevisiae Exo1 and Sgs1-Dna2 machineries. Here we report in vitro and in vivo studies that characterize the impact of chromatin on each resection pathway. We find that efficient resection by the Sgs1-Dna2-dependent machinery requires a nucleosome-free gap adjacent to the DSB. Resection by Exo1 is blocked by nucleosomes, and processing activity can be partially restored by removal of the H2A-H2B dimers. Our study also supports a role for the dynamic incorporation of the H2A.Z histone variant in Exo1 processing, and it further suggests that the two resection pathways require distinct chromatin remodeling events to navigate chromatin structure. PMID- 23728292 TI - The glucocorticoid receptor dimer interface allosterically transmits sequence specific DNA signals. AB - Glucocorticoid receptor (GR) binds to genomic response elements and regulates gene transcription with cell and gene specificity. Within a response element, the precise sequence to which the receptor binds has been implicated in directing its structure and activity. Here, we use NMR chemical-shift difference mapping to show that nonspecific interactions with bases at particular positions in the binding sequence, such as those of the 'spacer', affect the conformation of distinct regions of the rat GR DNA-binding domain. These regions include the DNA binding surface, the 'lever arm' and the dimerization interface, suggesting an allosteric pathway that signals between the DNA-binding sequence and the associated dimer partner. Disrupting this pathway by mutating the dimer interface alters sequence-specific conformations, DNA-binding kinetics and transcriptional activity. Our study demonstrates that GR dimer partners collaborate to read DNA shape and to direct sequence-specific gene activity. PMID- 23728293 TI - A ternary AppA-PpsR-DNA complex mediates light regulation of photosynthesis related gene expression. AB - The anoxygenic phototrophic bacterium Rhodobacter sphaeroides uses different energy sources, depending on environmental conditions including aerobic respiration or, in the absence of oxygen, photosynthesis. Photosynthetic genes are repressed at high oxygen tension, but at intermediate levels their partial expression prepares the bacterium for using light energy. Illumination, however, enhances repression under semiaerobic conditions. Here, we describe molecular details of two proteins mediating oxygen and light control of photosynthesis-gene expression: the light-sensing antirepressor AppA and the transcriptional repressor PpsR. Our crystal structures of both proteins and their complex and hydrogen/deuterium-exchange data show that light activation of AppA-PpsR2 affects the PpsR effector region within the complex. DNA binding studies demonstrate the formation of a light-sensitive ternary AppA-PpsR-DNA complex. We discuss implications of these results for regulation by light and oxygen, highlighting new insights into blue light-mediated signal transduction. PMID- 23728294 TI - Positive maternal interaction behavior moderates the relation between maternal anxiety and infant regulatory problems. AB - Regulatory problems in infancy are determined by different risk factors. This study aims to examine how psychosocial risk factors are connected, and how they impact the early regulatory ability of 3-month-old infants. In a sample of 57 mother-infant dyads, maternal anxiety and infant crying, sleeping and feeding habits were assessed. As a possible moderator, the role of positive maternal behavior was analyzed by videotaping face-to-face interactions. During the interaction, interactive stress was provoked with the face-to-face still-face paradigm (FFSF). Thus, this study differentiated between the effects of maternal behavior in both an ordinary play context, as well as a stressful interaction context. Results revealed that the relation between maternal anxiety and infant regulatory problems in crying and sleeping varied as a function of positive maternal engagement in stressful situations. However, a significant moderation effect influencing infant feeding problems could not be demonstrated. These findings stress the importance of positive maternal interaction behavior in at least some parts of regulatory adjustment of at-risk infants. PMID- 23728295 TI - Cerebral hemorrhage and hyponatremia: a demonstrative case presentation. PMID- 23728296 TI - A+KIDS, a web-based antipsychotic registry for North Carolina youths: an alternative to prior authorization. AB - OBJECTIVE: The rise in use of antipsychotics among U.S. children is well documented. Compliance rates with current safety-monitoring guidelines are low. In response, the North Carolina Division of Medical Assistance established the Antipsychotics-Keeping It Documented for Safety (A+KIDS) registry. The initial objectives of the project were to successfully establish a Web-based safety registry and to obtain and evaluate clinical information derived from the registry. METHODS: In April 2011, A+KIDS began asking prescribers of antipsychotics for children age 12 and under to respond to a set of questions regarding dose, indication, and usage history. Antipsychotic registrations were examined by linking North Carolina Medicaid prescription claims to registry entries. Prescribers were classified into different types, and the number of patients and registrations per prescriber were examined. RESULTS: In the initial six months, 730 prescribers registered 5,532 patients, 19% below age seven. By month 6 of the registry, 72% of all fills were registered with the program. Top diagnosis groups for registry patients were unspecified mood disorders, autism spectrum disorders, and disruptive behavior disorders. Top target symptoms were aggression (48%), irritability (19%), and impulsivity (11%). Psychosis accounted for 5% of the target symptoms. Twenty-eight percent of children were receiving no form of psychotherapy. Twenty-five percent of all A+KIDS prescribers were responsible for 81% of the registrations. CONCLUSIONS: The A+KIDS registry initiative has been successful, as measured by rapid uptake, and is providing clinical information not available from claims data alone. Future efforts will allow for detailed examinations of antipsychotic utilization and further safety improvement. PMID- 23728297 TI - Incentives and barriers to research participation and brain donation among African Americans. AB - Successful African American recruitment for aging research requires sensitivity to factors that influence participation. In this work, a structured face-to-face educational interview was used to recruit African Americans for a longitudinal aging study and to collect information about attitudes related to research. The interview was designed to build trust and respect for research and to educate participants about the need for minority participants. Of the 91 African Americans aged 65 and older who completed interviews, 65 (71%) agreed to participate in the longitudinal study and approximately half agreed to brain donation. Those who enrolled and consented to brain donation were more likely to consider benefit to themselves or direct family unit as the main motivator for participation (P < .01). The study also found a significant increase in agreement to brain donation across enrollment periods (P = .0005). PMID- 23728298 TI - Near-IR luminescent neodymium complexes: spectroscopic probes for hydroamination catalysis. AB - Neodymium complexes bearing the sensitising bis(oxazolinylphenyl)amine (BOPA) ligands have been prepared, and analysed spectroscopically under both catalytic and pseudo-catalytic conditions with respect to the intramolecular hydroamination of an aminoalkene, providing a direct means of monitoring binding events and relative space around the metal centre. PMID- 23728299 TI - The bromodomain protein Brd4 insulates chromatin from DNA damage signalling. AB - DNA damage activates a signalling network that blocks cell-cycle progression, recruits DNA repair factors and/or triggers senescence or programmed cell death. Alterations in chromatin structure are implicated in the initiation and propagation of the DNA damage response. Here we further investigate the role of chromatin structure in the DNA damage response by monitoring ionizing-radiation induced signalling and response events with a high-content multiplex RNA-mediated interference screen of chromatin-modifying and -interacting genes. We discover that an isoform of Brd4, a bromodomain and extra-terminal (BET) family member, functions as an endogenous inhibitor of DNA damage response signalling by recruiting the condensin II chromatin remodelling complex to acetylated histones through bromodomain interactions. Loss of this isoform results in relaxed chromatin structure, rapid cell-cycle checkpoint recovery and enhanced survival after irradiation, whereas functional gain of this isoform compacted chromatin, attenuated DNA damage response signalling and enhanced radiation-induced lethality. These data implicate Brd4, previously known for its role in transcriptional control, as an insulator of chromatin that can modulate the signalling response to DNA damage. PMID- 23728300 TI - BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis. AB - Through their functional diversification, distinct lineages of CD4(+) T cells can act to either drive or constrain immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma, Crohn's disease, coeliac disease, vitiligo, multiple sclerosis and type 1 diabetes. Although these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2 in the maintenance of immune homeostasis has not been established. Here, by studying mice in which the Bach2 gene is disrupted, we define BACH2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programs of multiple effector lineages in CD4(+) T cells. BACH2 was required for efficient formation of regulatory (Treg) cells and consequently for suppression of lethal inflammation in a manner that was Treg-cell-dependent. Assessment of the genome wide function of BACH2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during Treg polarization resulted in inappropriate diversion to effector lineages. In addition, BACH2 constrained full effector differentiation within TH1, TH2 and TH17 cell lineages. These findings identify BACH2 as a key regulator of CD4(+) T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity. PMID- 23728301 TI - High-resolution analysis with novel cell-surface markers identifies routes to iPS cells. AB - The generation of induced pluripotent stem (iPS) cells presents a challenge to normal developmental processes. The low efficiency and heterogeneity of most methods have hindered understanding of the precise molecular mechanisms promoting, and roadblocks preventing, efficient reprogramming. Although several intermediate populations have been described, it has proved difficult to characterize the rare, asynchronous transition from these intermediate stages to iPS cells. The rapid expansion of minor reprogrammed cells in the heterogeneous population can also obscure investigation of relevant transition processes. Understanding the biological mechanisms essential for successful iPS cell generation requires both accurate capture of cells undergoing the reprogramming process and identification of the associated global gene expression changes. Here we demonstrate that in mouse embryonic fibroblasts, reprogramming follows an orderly sequence of stage transitions, marked by changes in the cell-surface markers CD44 and ICAM1, and a Nanog-enhanced green fluorescent protein (Nanog eGFP) reporter. RNA-sequencing analysis of these populations demonstrates two waves of pluripotency gene upregulation, and unexpectedly, transient upregulation of several epidermis-related genes, demonstrating that reprogramming is not simply the reversal of the normal developmental processes. This novel high resolution analysis enables the construction of a detailed reprogramming route map, and the improved understanding of the reprogramming process will lead to new reprogramming strategies. PMID- 23728302 TI - Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activation. AB - The functional importance of gene enhancers in regulated gene expression is well established. In addition to widespread transcription of long non-coding RNAs (lncRNAs) in mammalian cells, bidirectional ncRNAs are transcribed on enhancers, and are thus referred to as enhancer RNAs (eRNAs). However, it has remained unclear whether these eRNAs are functional or merely a reflection of enhancer activation. Here we report that in human breast cancer cells 17beta-oestradiol (E2)-bound oestrogen receptor alpha (ER-alpha) causes a global increase in eRNA transcription on enhancers adjacent to E2-upregulated coding genes. These induced eRNAs, as functional transcripts, seem to exert important roles for the observed ligand-dependent induction of target coding genes, increasing the strength of specific enhancer-promoter looping initiated by ER-alpha binding. Cohesin, present on many ER-alpha-regulated enhancers even before ligand treatment, apparently contributes to E2-dependent gene activation, at least in part by stabilizing E2/ER-alpha/eRNA-induced enhancer-promoter looping. Our data indicate that eRNAs are likely to have important functions in many regulated programs of gene transcription. PMID- 23728303 TI - Rev-Erbs repress macrophage gene expression by inhibiting enhancer-directed transcription. AB - Rev-Erb-alpha and Rev-Erb-beta are nuclear receptors that regulate the expression of genes involved in the control of circadian rhythm, metabolism and inflammatory responses. Rev-Erbs function as transcriptional repressors by recruiting nuclear receptor co-repressor (NCoR)-HDAC3 complexes to Rev-Erb response elements in enhancers and promoters of target genes, but the molecular basis for cell specific programs of repression is not known. Here we present evidence that in mouse macrophages Rev-Erbs regulate target gene expression by inhibiting the functions of distal enhancers that are selected by macrophage-lineage-determining factors, thereby establishing a macrophage-specific program of repression. Remarkably, the repressive functions of Rev-Erbs are associated with their ability to inhibit the transcription of enhancer-derived RNAs (eRNAs). Furthermore, targeted degradation of eRNAs at two enhancers subject to negative regulation by Rev-Erbs resulted in reduced expression of nearby messenger RNAs, suggesting a direct role of these eRNAs in enhancer function. By precisely defining eRNA start sites using a modified form of global run-on sequencing that quantifies nascent 5' ends, we show that transfer of full enhancer activity to a target promoter requires both the sequences mediating transcription-factor binding and the specific sequences encoding the eRNA transcript. These studies provide evidence for a direct role of eRNAs in contributing to enhancer functions and suggest that Rev-Erbs act to suppress gene expression at a distance by repressing eRNA transcription. PMID- 23728304 TI - High-intensity focused ultrasound ablation assisted using color Doppler imaging for the treatment of hepatocellular carcinomas. AB - PURPOSE: We evaluated the usefulness of color Doppler flow imaging to compensate for the inadequate resolution of the ultrasound (US) monitoring during high intensity focused ultrasound (HIFU) for the treatment of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: US-guided HIFU ablation assisted using color Doppler flow imaging was performed in 11 patients with small HCC (<3 lesions, <3 cm in diameter). The HIFU system (Chongqing Haifu Tech) was used under US guidance. Color Doppler sonographic studies were performed using an HIFU 6150S US imaging unit system and a 2.7-MHz electronic convex probe. RESULTS: The color Doppler images were used because of the influence of multi-reflections and the emergence of hyperecho. In 1 of the 11 patients, multi-reflections were responsible for the poor visualization of the tumor. In 10 cases, the tumor was poorly visualized because of the emergence of a hyperecho. In these cases, the ability to identify the original tumor location on the monitor by referencing the color Doppler images of the portal vein and the hepatic vein was very useful. HIFU treatments were successfully performed in all 11 patients with the assistance of color Doppler imaging. CONCLUSION: Color Doppler imaging is useful for the treatment of HCC using HIFU, compensating for the occasionally poor visualization provided by B-mode conventional US imaging. PMID- 23728305 TI - Staging accuracy of MR for pancreatic neuroendocrine tumor and imaging findings according to the tumor grade. AB - PURPOSE: To investigate staging accuracy of MR for pancreatic neuroendocrine neoplasms (PNETs) and imaging findings according to the tumor grade. MATERIALS AND METHODS: Our study consisted of 39 patients with PNET G1 (n = 24), PNET G2 (n = 12), and pancreatic neuroendocrine carcinoma (PNEC) (n = 3). All underwent preoperative MRI. Two radiologists retrospectively reviewed MR findings including tumor margin, SI on T2WI, enhancement patterns, degenerative change, duct dilation, and ADC value. They also assessed T-stage, N-stage, and tumor size. Statistical analyses were performed using Chi square tests, ROC analysis, and Fisher's exact test. RESULTS: Specific findings for PNEC or PNET G2 were ill defined borders (P = 0.001) and hypo-SI on venous- and delayed-phase (P = 0.016). ADC value showed significant difference between PNET G1 and G2 (P = 0.007). The Az of ADC value for differentiating PNET G1 from G2 was 0.743. Sensitivity and specificity were 70% and 86%. Accuracy for T-staging was 77% (n = 30) and 85% (n = 33), and for N-staging was 92% (n = 36) and 87% (n = 34) with moderate agreement. T-stage showed significant difference according to tumor grade (P < 0.001), although there was no significant difference in tumor size or N-stage. CONCLUSION: Ill-defined borders and hypo-SI on venous- and delayed-phase imaging are common findings of higher grade PNET, and ADC value is helpful for differentiating PNET G1 from G2. MR is useful for preoperative evaluation of T-, N-stage. Tumor size of PNET and T-stage showed significant difference according to tumor grade. PMID- 23728306 TI - Contrast-enhanced ultrasound of the small bowel in Crohn's disease. AB - Crohn's disease (CD) is a chronic transmural inflammatory disease of the gastrointestinal tract characterized by episodes of inflammation alternating with periods of remission. Unenhanced grey-scale ultrasound may evaluate the localisation and the length of the affected intestinal segments and may detect transmural complications, including fistulas, abscesses and phlegmons, but it is less accurate to assess the CD activity. Contrast-enhanced ultrasound has become an important imaging modality in patients with CD for the grading of disease activity, the differentiation between small bowel stricture due to inflammation or mural fibrosis, and for the assessment of the response to specific therapy. New dedicated software packages allow the accurate quantification of the enhancement within the small bowel wall after microbubble contrast agent injection to obtain different kinetic semi-quantitative parameters-the percentage of the maximal enhancement, the time-to-the peak enhancement, and the area under the time-intensity curve-which are very useful to differentiate the inflammatory oedema from fibrosis and to differentiate responders from non-responders to the specific therapy among patients with CD. PMID- 23728307 TI - Assessment of femtosecond laser induced periodic surface structures on polymer films. AB - In this work we present the formation of laser induced periodic surface structures (LIPSS) on spin-coated thin films of several model aromatic polymers including poly(ethylene terephthalate), poly(trimethylene terephthalate) and poly carbonate bis-phenol A upon irradiation with femtosecond pulses of 795 and 265 nm at fluences well below the ablation threshold. LIPSS are formed with period lengths similar to the laser wavelength and parallel to the direction of the laser polarization vector. Formation of LIPSS upon IR irradiation at 795 nm, a wavelength at which the polymers absorb weakly, contrasts with the absence of LIPSS in this spectral range upon irradiation with nanosecond pulses. Real and reciprocal space characterization of LIPSS obtained by Atomic Force Microscopy (AFM) and Grazing Incidence Small Angle X-ray Scattering (GISAXS), respectively, yields well correlated morphological information. Comparison of experimental and simulated GISAXS patterns suggests that LIPSS can be suitably described considering a quasi-one-dimensional paracrystalline lattice and that irradiation parameters have an influence on the order of such a lattice. Fluorescence measurements, after laser irradiation, provide indirect information about dynamics and structure of the polymer at the molecular level. Our results indicate that the LIPSS are formed by interference of the incident and surface scattered waves. As a result of this process, heating of the polymer surface above its glass transition temperature takes place enabling LIPSS formation. PMID- 23728308 TI - The juvenile face as a suitable age indicator in child pornography cases: a pilot study on the reliability of automated and visual estimation approaches. AB - OBJECTIVE: In cases of suspected child pornography, the age of the victim represents a crucial factor for legal prosecution. The conventional methods for age estimation provide unreliable age estimates, particularly if teenage victims are concerned. In this pilot study, the potential of age estimation for screening purposes is explored for juvenile faces. In addition to a visual approach, an automated procedure is introduced, which has the ability to rapidly scan through large numbers of suspicious image data in order to trace juvenile faces. METHODS: Age estimations were performed by experts, non-experts and the Demonstrator of a developed software on frontal facial images of 50 females aged 10-19 years from Germany, Italy, and Lithuania. To test the accuracy, the mean absolute error (MAE) between the estimates and the real ages was calculated for each examiner and the Demonstrator. RESULTS: The Demonstrator achieved the lowest MAE (1.47 years) for the 50 test images. Decreased image quality had no significant impact on the performance and classification results. The experts delivered slightly less accurate MAE (1.63 years). Throughout the tested age range, both the manual and the automated approach led to reliable age estimates within the limits of natural biological variability. CONCLUSIONS: The visual analysis of the face produces reasonably accurate age estimates up to the age of 18 years, which is the legally relevant age threshold for victims in cases of pedo-pornography. This approach can be applied in conjunction with the conventional methods for a preliminary age estimation of juveniles depicted on images. PMID- 23728309 TI - Measuring intracellular Ca2+ changes in human sperm using four techniques: conventional fluorometry, stopped flow fluorometry, flow cytometry and single cell imaging. AB - Spermatozoa are male reproductive cells especially designed to reach, recognize and fuse with the egg. To perform these tasks, sperm cells must be prepared to face a constantly changing environment and to overcome several physical barriers. Being in essence transcriptionally and translationally silent, these motile cells rely profoundly on diverse signaling mechanisms to orient themselves and swim in a directed fashion, and to contend with challenging environmental conditions during their journey to find the egg. In particular, Ca(2+)-mediated signaling is pivotal for several sperm functions: activation of motility, capacitation (a complex process that prepares sperm for the acrosome reaction) and the acrosome reaction (an exocytotic event that allows sperm-egg fusion). The use of fluorescent dyes to track intracellular fluctuations of this ion is of remarkable importance due to their ease of application, sensitivity, and versatility of detection. Using one single dye-loading protocol we utilize four different fluorometric techniques to monitor sperm Ca(2+) dynamics. Each technique provides distinct information that enables spatial and/or temporal resolution, generating data both at single cell and cell population levels. PMID- 23728311 TI - [Significance of patient adherence in cardiovascular therapy]. AB - The appropriate cooperation of patients is very important during therapy. The term of compliance used earlier for the definition of patient's cooperation refers to a sub- or over-ordination of the relationship betwees physicians and patients. Nowadays the term of adherence is used, which suggests a higher level of patient cooperation because it assumes an active contribution of the patient. The adherence of patients to cardiocascular medical therapy in developed countries is just 50%, and this indicates that half of the patients do not take the prescribed medication. Because of the lack of medication, morbidity and mortality are increasing. There can be many reasons for the lack of patient cooperation, which should be taken account during medical treatment. Improving patient adherence can decrease the risk for complications and progression of the disease, which can improve health condition and reduce health care and social costs. PMID- 23728312 TI - [Antimicrobial therapy of Clostridium difficile infection. Systematic review and meta-analysis of the scientific evidence]. AB - INTRODUCTION: Clostridium difficile is the leading cause of antibiotic associated infectious nosocomial diarrhoea. Limited number of new pharmaceutical products have been developed and registered in the past decades for the treatment of Clostridium difficile infection. The available scientific evidence is limited and hardly comparable. AIM: To analyse the clinical efficacy and safety of metronidazole, vancomycin and fidaxomicin in the therapy of Clostridium difficile infection. METHODS: Systematic review and meta-analysis of the literature data. RESULTS: Meta-analysis of literature data showed no significant difference between these antibiotics in clinical cure endpoint (odss ratios: fidaxomicin vs. vancomycin 1.19; vancomycin vs. metronidazol 1.69 and fidaxomicin vs. metronidazol 2.00). However, fidaxomicin therapy was significantly more effective than vancomicin and metronidazol in endpoints of recurrence and global cure (odds ratios: fidaxomicin vs. vancomycin 0.47; vancomycin vs. metronidazol 0.91 es fidaxomicin vs. metronidazol 0.43). There was no significant difference between fidaxomicin, vancomycin and metronidazole in safety endpoints. CONCLUSIONS: Each antibiotic similarly improved clinical cure. Fidaxomicin was the most effective therapeutic alternative in lowering the rate of recurrent Clostridium difficile infections. PMID- 23728313 TI - [Changing prevalence of Helicobacter pylori infection in the 9th district of Budapest. A retrospective endoscopic study, 1997-2012]. AB - BACKGROUND: The prevalence of Helicobacter pylori infection in developed countries is decreasing. The time-frame of this process is largely unknown. AIM: The aim of the authors was to evaluate the changes in the prevalence of Helicobacter pylori infection in their endoscopic centre. METHODS: This retrospective study included 4647 patients examined between 1997 and 2012. Helicobacter pylori was determined from antral and corpus biopsies by the modified Giemsa stain and rapid urease test. The prevalence of the infection was calculated yearly for the period studied, for age decades from 18 to 85 years, birth cohorts of 10 years from 1920 to 1994 and according to diagnosis. RESULTS: The overall prevalence of Helicobacter pylori infection was 54.7%, which decreased from 71.3% in 1997 to 32.76% in 2011. Functional dyspepsia was found in 37.9%, duodenal ulcer in 25.3%, gastric ulcer in 3.8% and reflux disease in 24.2% of the patients. The mean prevalence of infection was 62.5% in birth cohorts of 10 years between 1920 and 1959, 57.4% in those between 1960 and 1969, and decreased to 39.0% and 26.7% in birth cohorts between 1970 and 1979) and between 1980 and 1989, respectively. According to age cohorts, the prevalence was 21.8% 34.9%, 46.5%, 63.7%, 63.2% and 59.2% in patients aged 18-19 years, 20-29 years, 30-39 years, 40-49 years, 50-59 years and 60-69 years, respectively. The proportion of H. pylori positive duodenal ulcers decreased from 95.9% in 1998 to 59.1% in 2011 (p = 0.001). CONCLUSIONS: The prevalence of Helicobacter pylori infection in the 9th district of Budapest is decreasing, especially in cohorts born in the late 1960s and 1970s, nearly 1.5 decades before the discovery of the bacterium. PMID- 23728314 TI - [Monckeberg's sclerosis -- crystal-induced angiopathy]. AB - INTRODUCTION: Monckeberg's sclerosis is a special form of arteriosclerosis characterized by calcification and ossification of the media of medium size arteries mainly of lower extremities. AIMS: The aim of the authors was to examine medium size arteries with Monckeberg's sclerosis in 22 amputated lower legs of 16 patients in order to demonstrate different crystals in the wall of blood vessels. METHODS: The methodology was based on previous findings of the authors indicating that in different metabolic disorders many crystals remain demonstrable in unstained histological sections unlike in haematoxylin-eosin stained sections. RESULTS: In unstained sections the authors observed rhomboid or prismatic calcium pyrophosphate dihydrate and clusters of elongated narrow hydroxyapatite crystals in the wall of medium size arteries of all examined cases. Both types of crystals showed axis parallel positive birefringence under polarized light. The intensity of birefringence of hydroxyapatite crystals was weaker in comparison with that of calcium pyrophosphate dihydrate crystals. Occasionally, other crystals which were different in shape from both calcium pyrophosphate dihydrate and hydroxyapatite crystals were also observed. CONCLUSIONS: It seems likely that similarly to crystal deposition induced arthropathy, calcium pyrophosphate dihydrate, hydroxyapatite and other crystals cause fibrosis and intimal proliferation, which may contribute to progressive occlusion of blood vessels resulting in ischemic symptoms. Based on this observation Monckeberg's sclerosis may be defined as a crystal-induced angiopathy. PMID- 23728315 TI - [Novel TSC1 mutation associated with variable phenotypes in tuberous sclerosis]. AB - Tuberous sclerosis is an autosomal dominant disorder, caused by mutations of the TSC1 or TSC2 genes resulting in tumor predisposition. Clinical signs include non malignant brain tumors, skin, eye, heart and kidney abnormalities. The authors report a Hungarian family with broad phenotypic variability. First, the 5-year old boy, showing the most symptoms was examined, whose first seizure occurred at 15 months and a cranial magnetic resonance imaging revealed numerous intracerebral calcareous foci. Except of hypopigmented skin spots, no other abnormality was found on physical examination. The mother was completely asymptomatic. Epilepsy of the maternal uncle started at the age of 3 years, of his sister at the age of 17 years and of the maternal grandmother at the age of 39 years. At the age of 52 years the grandmother developed renal cysts. Molecular genetic analysis of the family confirmed a de novo heterozygous point mutation (c.2524 C?>T) [corrected] in exon 20 of the TSC1 gene. The mutation was detected in all examined family members. Despite increasing data on the pathomechanism of tuberous sclerosis, there is still little known about the genetic modifying factors influencing the broad intra- and interfamilial phenotypic variability. PMID- 23728317 TI - Separating the contributions of vascular anatomy and blood viscosity to peripheral resistance and the physiological implications of interspecific resistance variation in amphibians. AB - Amphibian pulmonary and systemic vascular circuits are arranged in parallel, with potentially important consequences for resistance (R) to blood flow. The contribution of the parallel anatomic arrangement to total vascular R (R T), independent of blood viscosity, is unknown. We measured pulmonary (R P) and systemic (R S) vascular R with an in situ Ringer's solution perfusion technique using anesthetized anuran and urodele species to determine: (1) relative contributions of vascular anatomy and blood viscosity to R T; (2) distensibility index (%Delta flow kPa(-1)) of the pulmonary and systemic vascular circuits; and (3) interspecific correlates of variation in these parameters with red blood cell size, cardiac power output, and aerobic capacities. R P was lower than R S in anurans, while R P of the urodeles was greater than R S and significantly greater than anuran R P. Anuran R T was lowest and did not vary interspecifically, whereas urodele R T was significantly greater than anuran, and varied interspecifically. Pulmonary and systemic circuit distensibility differences may explain cardiac shunt patterns in toads with changes in cardiac output from rest to activity. When blood viscosity was taken into account, vascular resistance accounted for about 25 % of R T while blood viscosity accounted for the remaining 75 %. Owing to lower R T, terrestrial anuran species required lower cardiac power outputs when moving fluid through their vasculature compared to aquatic species. These results indicate that physical characteristics of the vasculature can account for interspecific differences in cardiovascular physiology and suggest a co-evolution of cardiac and vascular anatomy among amphibians. PMID- 23728318 TI - Role of serum dehydroepiandrosterone sulfate level on the clearance of chronic hepatitis B virus infection. AB - BACKGROUND: The natural course of chronic hepatitis B virus (HBV) infection and relevant host factors remain unclear. This study aims to investigate the impact of dehydroepiandrosterone sulfate (DHEAS) on the clearance of chronic HBV infection. METHODS: Two hundred and one hepatitis B e antigen (HBeAg)-positive chronic HBV-infected children (101 females) were recruited. Serum DHEAS levels were determined in all subjects at 15 years of age. Serum alanine aminotransferase (ALT) levels, DHEAS levels, HBV seromarkers, genotypes, and viral loads were included for analysis. RESULTS: Subjects with serum DHEAS levels >3.6 MUmol/L at midpuberty had earlier HBeAg seroconversion (median age, 14.7 vs. 18.2 years; HR, 1.9; P = 0.03), and the impact persisted even after adjusting for gender, HBV genotype, peak ALT levels, and viral load. Subjects with DHEAS levels >3.6 MUmol/L at 15 years of age had more HBV viral titers decrement from 15 to 20 years of age (mean +/- SD, 3.5 +/- 2.5 vs. 1.2 +/- 2.2 log10 copies/mL; P = 0.05) and shorter duration for HBeAg seroconversion than others (mean +/- SD, 5.6 +/- 4.4 vs. 9.2 +/- 4.9 years; P = 0.02). Higher serum DHEAS levels at 15 years of age are also associated with greater hepatitis B surface antigen (HBsAg) titer decrement from 15 to 20 years of age (correlation coefficient = 0.45, P = 0.04). CONCLUSIONS: Higher serum DHEAS levels at midpuberty predicts more HBV viral load and HBsAg titer decrement from midpuberty to young adulthood. Higher serum DHEAS levels at midpuberty also correlate with younger age of spontaneous HBeAg seroconversion in chronic genotype B and C HBV-infected patients. PMID- 23728319 TI - Assessment of anatomical and dosimetric changes by a deformable registration method during the course of intensity-modulated radiotherapy for nasopharyngeal carcinoma. AB - The aim of this study was to quantify the anatomic variations and the dosimetric effects accessed by a deformable registration method throughout the entire course of radiotherapy, and to evaluate the necessity of replanning for patients with nasopharyngeal carcinoma (NPC). Plan1(CT1) was based on the original CT, and Plan2(CT2) was generated from the midtreatment CT scan acquired after 25 fractions of IMRT of Plan1. Both sets of CTs, RT structures and RT doses for the two group plans were transferred to a workstation, and then a hybrid IMRT plan, Plan1(CT2), was generated by deforming doses of Plan1 to CT2. Subsequently, the accumulated plan, Plan1 + 2(CT2), was generated to quantify the actual dosimetric effects during the course. The transverse diameter of the neck at the center of the odontoid process was (15.4 +/- 1.0) cm and (14.4 +/- 1.1) cm in CT1 and CT2, respectively (P < 0.05). Compared with CT1, the mean volumes of the right and left parotid glands were significantly decreased by (24.6 +/- 11.9)% and (35.1 +/ 20.1)%, respectively. Comparison of Plan1 (CT1) with Plan1 (CT2) indicated that the doses to targets decreased without replanning. With repeated CT and replanning after 25 fractions, the doses to targets would be improved. The doses to normal tissue were increased without replanning. For eight patients out of 12, the doses to the spinal cord and brainstem exceeded the constraints without replanning, while the corresponding values decreased with replanning. During the entire course of IMRT, the volumes of the targets and the parotid glands would be reduced significantly. Midtreatment CT scanning and replanning are recommended to ensure adaptive doses to the targets and critical normal tissues. PMID- 23728320 TI - Mutational effects of gamma-rays and carbon ion beams on Arabidopsis seedlings. AB - To assess the mutational effects of radiation on vigorously proliferating plant tissue, the mutation spectrum was analyzed with Arabidopsis seedlings using the plasmid-rescue method. Transgenic plants containing the Escherichia coli rpsL gene were irradiated with gamma-rays and carbon ion beams (320-MeV (12)C(6+)), and mutations in the rpsL gene were analyzed. Mutant frequency increased significantly following irradiation by gamma-rays, but not by 320-MeV (12)C(6+). Mutation spectra showed that both radiations increased the frequency of frameshifts and other mutations, including deletions and insertions, but only gamma-rays increased the frequency of total base substitutions. These results suggest that the type of DNA lesions which cause base substitutions were less often induced by 320-MeV (12)C(6+) than by gamma-rays in Arabidopsis seedlings. Furthermore, gamma-rays never increased the frequencies of G:C to T:A or A:T to C:G transversions, which are caused by oxidized guanine; 320-MeV (12)C(6+), however, produced a slight increase in both transversions. Instead, gamma-rays produced a significant increase in the frequency of G:C to A:T transitions. These results suggest that 8-oxoguanine has little effect on mutagenesis in Arabidopsis cells. PMID- 23728321 TI - Effects of shielding on the induction of 53BP1 foci and micronuclei after Fe ion exposures. AB - High atomic number and high-energy (HZE) particles in deep space are of low abundance but substantially contribute to the biological effects of space radiation. Shielding is so far the most effective way to partially protect astronauts from these highly penetrating particles. However, simulated calculations and measurements have predicted that secondary particles resulting from the shielding of cosmic rays produce a significant fraction of the total dose and dose equivalent. In this study, we investigated the biological effects of secondary radiation with two cell types, and with cells exposed in different phases of the cell cycle, by comparing the biological effects of a 200 MeV/u iron beam with a shielded beam in which the energy of the iron ion beam was decreased from 500 MeV/u to 200 MeV/u with PMMA, polyethylene (PE), or aluminum. We found that beam shielding resulted in increased induction of 53BP1 foci and micronuclei in a cell-type-dependent manner compared with the unshielded 200 MeV/u Fe ion beam. These findings provide experimental proof that the biological effects of secondary particles resulting from the interaction between HZE particles and shielding materials should be considered in shielding design. PMID- 23728322 TI - Inverse planning for combination of intracavitary and interstitial brachytherapy for locally advanced cervical cancer. AB - The main purpose of this study was to compare three different treatment plans for locally advanced cervical cancer: (i) the inverse-planning simulated annealing (IPSA) plan for combination brachytherapy (BT) of interstitial and intracavitary brachytherapy, (ii) manual optimization based on the Manchester system for combination-BT, and (iii) the conventional Manchester system using only tandem and ovoids. This was a retrospective study of 25 consecutive implants. The high risk clinical target volume (HR-CTV) and organs at risk were defined according to the GEC-ESTRO Working Group definitions. A dose of 6 Gy was prescribed. The uniform cost function for dose constraints was applied to all IPSA-generated plans. The coverage of the HR-CTV by IPSA for combination-BT was equivalent to that of manual optimization, and was better than that of the Manchester system using only tandem and ovoids. The mean V100 achieved by IPSA for combination-BT, manual optimization and Manchester was 96 +/- 3.7%, 95 +/- 5.5% and 80 +/- 13.4%, respectively. The mean D100 was 483 +/- 80, 487 +/- 97 and 335 +/- 119 cGy, respectively. The mean D90 was 677 +/- 61, 681 +/- 88 and 513 +/- 150 cGy, respectively. IPSA resulted in significant reductions of the doses to the rectum (IPSA D2cm(3): 408 +/- 71 cGy vs manual optimization D2cm(3): 485 +/- 105 cGy; P = 0.03) and the bladder (IPSA D2cm(3): 452 +/- 60 cGy vs manual optimization D2cm(3): 583 +/- 113 cGy; P < 0.0001). In conclusion, combination-BT achieved better tumor coverage, and plans using IPSA provided significant sparing of normal tissues without compromising CTV coverage. PMID- 23728323 TI - Pharmaceutical drugs supporting regeneration of small-intestinal mucosa severely damaged by ionizing radiation in mice. AB - Accidental exposure of the abdomen to high-dose radiation leads to severe consequences initiated by disruption of the mucosa in the small intestine. Therapeutic options are limited, even though various treatments have been investigated, particularly in the field of regenerative therapy. In order to identify readily available treatment methods, we included several current pharmaceutical drugs, for which the clinical trials have already been completed, in tests on mice that had undergone severe mucosal damage by radiation. The drugs were injected into mice 24 h after exposure to 15.7 Gy X-rays. The effects of the drugs on the damaged mucosa of the small intestine were evaluated using early regeneration indices [the expression of c-myb mRNA, and proliferation of epithelial cells in the form of microcolonies (MCs) by Days 4 and 5 post irradiation] and the survival rate of the mice. Enhancement of mucosal regeneration at Day 4 (c-myb: P < 0.01, MC: P < 0.05) and improvement of the survival rate (P < 0.05) were observed when a clinical dose of gonadotropin, a stimulator of androgen, was injected. Similarly, a clinical dose of thiamazole (which prevents secretion of thyroid hormone) stimulated mucosal growth by Day 5 (c-myb: P < 0.01, MC: P < 0.05) and also improved the survival rate (P < 0.05). The nonclinical drugs histamine and high-dose octreotide (a growth hormone antagonist) also gave significant survival-enhancing benefits (P < 0.01 and P < 0.05, respectively). These results can be used to construct therapeutic programs and applied in various experimental studies to control the regeneration of damaged mucosa. PMID- 23728324 TI - Physico-chemical characterisation of the fat from red-skin rambutan (Nephellium lappaceum L.) seed. AB - The seeds (6.9+/-0.2% by weight of fruit) of the red-skin rambutan (Nephelium lappaceum L.) contain a considerable amount of crude fat (38.0+/-4.36%) and thus, the aim of the study was to determine the physico-chemical properties of this fat for potential applications. The iodine and saponification values, and unsaponifiable matter and free fatty acid contents of the seed fat were 50.27 g I2/100g fat, 182.1 mg KOH/g fat, 0.8% and 2.1%, respectively. The fat is pale yellow with a Lovibond color index of 3.1Y+1.1R. The fatty acid profile indicates an almost equal proportion of saturated (49.1%) and unsaturated (50.9%) fatty acids, where oleic (42.0%) and arachidic (34.3%) acids were the most dominant fatty acids. It also contained small amounts of stearic (8.0%), palmitic (4.6%), gadoleic (5.9%), linoleic (2.2%), behenic (2.1%) palmitoleic (0.7%) myristic (0.1%) and erucic (0.1%) acids. HPLC analysis showed that the fat comprised mainly unknown triacylglycerols (TAG) with high retention times indicating they have higher carbon numbers compared with many vegetable oils. The fat has melting and cooling points of 44.2 degrees C and -42.5 degrees C, respectively, making it a semi-solid at room temperature. The solid content at 0 degrees C was 53.5% and the fat melted completely at 40 degrees C. z-Nose analysis showed that the presence of high levels of volatile compounds in red-skin rambutan seed and seed fat. PMID- 23728325 TI - Development of solvent-free offset ink using vegetable oil esters and high molecular-weight resin. AB - In the development of solvent-free offset ink, the roles of resin molecular weight and used solvent on the ink performance were evaluated by examining the relationship between the various properties of resin and solvent and print quality. To find the best performing resin, the soy-oil fatty acid methyl ester (FAME) was applied to the five modified-phenolic resins having different molecular weights. It is found from the experimental results that the ink made of higher molecular weight and better solubility resin gives better printability and print quality. It is because larger molecular weight resin with better solubility gives higher rate of ink transfer. From the ink application of different esters to high molecular weight resin, the best printing performance was yielded from the soy-oil fatty acid butyl ester (FABE). It is due to its high kinematic viscosity resulting in the smallest change of ink transfer weight upon multiple number of printing, which improves the stability of ink quality. PMID- 23728326 TI - Equilibrium surface tension, dynamic surface tension, and micellization properties of lactobionamide-type sugar-based gemini surfactants. AB - A sugar-based gemini surfactant N,N'-dialkyl-N,N'-dilactobionamideethylenediamine (2C(n)Lac, where n represents alkyl chain lengths of 8, 10, 12, and 14) was synthesized by reacting N,N'-dialkylethylenediamine with lactobionic acid. The adsorption properties of 2C(n)Lac were characterized by equilibrium and dynamic surface tension measurements. Their micellization properties were investigated by steady-state fluorescence using pyrene as a probe and dynamic light scattering (DLS) techniques. The dependence of these properties on the alkyl chain length and the number of sugars was determined through a comparison with the corresponding monomeric surfactants C(n)MLA and previously reported sugar-based gemini surfactants containing monosaccharide gluconamide or disaccharide lactobionamide groups with a hexanediamide spacer. The critical micelle concentration (cmc) and surface tension of 2C(n)Lac are both lower than those of C(n)MLA surfactants. These lower values indicate that the synthesized sugar-based gemini surfactants have excellent micelle-forming ability in solution and high adsorption ability at the air-water interface, which result from strong interactions of the hydrogen bonds between the hydroxyls in lactobionamide groups. When the alkyl chain length of 2C(n)Lac increases to 14, premicellar formation occurs in the solution along with adsorption at the air-water interface at concentrations below the cmc. Furthermore, 2C(n)Lac forms micelles measuring 4 to 12 nm in solution, with no dependence on the alkyl chain length, and their size slightly increases with increasing concentration. PMID- 23728327 TI - Effect of water on interfacial chemical properties of nonionic surfactants in hydrophobic ionic liquid bmimPF6. AB - We studied the effect of water addition on interfacial properties and aggregate behavior of nonionic surfactants (polyoxyethylene alkyl ether; CnEm) in an ionic liquid (1-butyl-3-methylimidazolium hexafluorophosphate; bmimPF6). When a small amount of water was added to mixtures of CnEm and bmimPF6, two breaking points (cac1, cac2) were observed in the surface tension/CnEm concentration plots, suggesting the formation of two kinds of aggregates. This two-step aggregate formation was also confirmed by the fluorescence probe method using pyrene. The particle size of the aggregates measured by dynamic light scattering (DLS) was around 200 nm at cac1, and decreased to 4 nm above cac2. These results, together with freeze-fracture TEM observations, showed that the aggregate formed at cac1 was water in bmimPF6 emulsions, which then transformed to micelles solubilizing water in the palisade layer above cac2. This concentration-dependent aggregate formation was supported thermodynamically by studying the dependence of cacs on temperature and alkyl and POE chain lengths of the surfactant. PMID- 23728328 TI - Monolayer behavior of asymmetrical ester-type tartaric gemini amphiphiles. AB - The ester-type asymmetrical tartaric gemini amphiphiles (C(m)-C(n), where m and n are the number of carbon atoms of hydrophobic alkanoyl group, m+n=28) bearing two carboxyl groups and two different alkanoyl groups were prepared from L-tartaric acid, and the pressure-area (pi-A) isotherms for a series of asymmetrical tartaric gemini amphiphiles were studied.The pi-A isotherms of asymmetrical C(m) C(n) monolayers were classified into two groups. Group 1: The asymmetry was small (n/m <1.55), and a phase transition of the monolayer from the liquid-expanded to the liquid condensed state, and a subsequent transition to solid phases were observed. Group 2: The asymmetry was large (n/m >1.8), and only liquid-expanded state of the monolayer film was observed. Based on the subphase temperature (T(sub)) dependence of monolayer static elasticity, es, the melting temperature (T(L)) of asymmetrical C(m)-C(n) monolayer was estimated to be T(L) = 31.7 degrees C and 50.6 degrees C for C13-C15 and C12-C16, respectively. Furthermore, assuming that asymmetrical C13-C15 can be viewed as an equimolar mixture of symmetrical 2C13 and 2C15, the temperature dependence of monolayers of 2C13 and 2C15 mixture at various ratios were also studied. As a result, all TL values of 2C14, C13-C15 and an equimolar mixture of 2C13 and 2C15 were almost the same. However, the variation of T(L) with the molar fraction of 2C15 (X(2C15)) was remarkably different from that of solid melting point T(m) with X(2C15). PMID- 23728329 TI - Production of a novel mannosylerythritol lipid containing a hydroxy fatty acid from castor oil by Pseudozyma tsukubaensis. AB - Mannosylerythritol lipids (MELs) are glycolipid biosurfactants produced by various yeasts belonging to the genus Pseudozyma, which exhibit excellent surface activities as well as versatile biochemical activities. A study on P. tsukubaensis NBRC1940 as a mono-acetylated MEL (MEL-B) producer revealed that the yeast accumulated a novel glycolipid from castor oil at a yield of 22 g/L. Its main chemical structure was identified as 1-O-beta-(2'-O-alka(e)noyl-3'-O hydroxyalka(e)noyl-6'-O-acetyl-D-mannopyranosyl)-D-erythritol designated as "new MEL-B." The new MEL-B, comprising a hydroxy fatty acid had a reduced surface tension of 28.5 mN/m at a critical micelle concentration (CMC) of 2.2*10-5 M in water. The observed CMC was 5-fold higher than that of conventional MEL-B. When conventional MEL-B was dispersed in water, it self-assembled to form the lamellar (L(alpha)) phase at a wide range of concentrations. In contrast, new MEL-B formed spherical oily droplets similar to the sponge (L3) phase, which is observed in aqueous solutions of di-acetylated MEL (MEL-A). The data suggest that the newly identified MEL-B is likely to have a different structure and interfacial properties compared to the conventional MELs, and could facilitate an increase in the application of glycolipid biosurfactants. PMID- 23728330 TI - Structure-activity relationships for bergenin analogues as beta-secretase (BACE1) inhibitors. AB - Here we evaluated the inhibitory effects of bergenin analogues (2-10), prepared from naturally occurring bergenin, (1) on beta-secretase (BACE1) activity. All the bergenin analogues that were analyzed inhibited BACE1 in a dose-dependent manner. 11-O-protocatechuoylbergenin (5) was the most potent inhibitor, with an IC50 value of 0.6 +/- 0.07 MUM. The other bergenin analogues, in particular, 11-O 3',4'-dimethoxybenzoyl)-bergenin (6), 11-O-vanilloylbergenin (7), and 11-O isovanilloylbergenin (8), inhibited BACE1 activity with IC50 values of <10.0 MUM. BACE1 inhibitory activity was influenced by the substituents of the benzoic acid moiety. To the best of our knowledge, this is the first report on the structure activity relationships (SAR) in the BACE1 inhibitory activities of bergenin analogues. These bergenin analogues may be useful in studying the mechanisms of Alzheimer's disease. PMID- 23728331 TI - Effect of magnesium ion supplementation on obesity and diabetes mellitus in Otsuka Long-Evans Tokushima Fatty (OLETF) rats under excessive food intake. AB - Several epidemiologic studies have found that magnesium ion (Mg2+) is related to obesity and type 2 diabetes mellitus. However, there have been almost no reports on the effects of a combination of excessive food intake and Mg2+ supplementation on metabolic syndrome and various blood tests values for diabetes mellitus. In this study, we investigated changes in body weight and blood test values for diabetes mellitus of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model for human type 2 diabetes mellitus via metabolic syndrome, under conditions of combined excessive food intake and Mg2+ supplementation. The rats received Mg2+ supplementation by drinking magnesium water (Mg2+; 200 mg/l). No significant differences were observed in the levels of food or water intake between OLETF rats drinking purified water (PW) or magnesium water (MW). Type 2 diabetes mellitus with metabolic syndrome developed at 30 weeks of age, and the body weights and plasma insulin levels of OLETF rats at 60 weeks of age were lower than those of normal rats. The plasma glucose (PG) levels in 38-week-old OLETF rats drinking MW were significantly lower than in those of rats drinking PW, while the body weights and the levels of triglycerides (TG) and insulin of 38 week-old MW-drinking OLETF rats were significantly higher than those of their PW drinking counterparts. On the other hand, the decreases in body weight and insulin levels in 60-week-old OLETF rats were suppressed by MW supplementation. The present study demonstrates that Mg2+ supplementation delays the development of diabetes mellitus in OLETF rats under conditions of excessive food intake. In addition, obesity and high blood TG levels were observed in OLETF rats receiving Mg2+ supplementation in conjunction with excessive food intake. PMID- 23728332 TI - Preparation of dicarboxylic acid-type gemini surfactant via Diels-Alder reaction & ozone oxidation. AB - We wish to report a novel preparation method for Gemsurf analogs as well as dicarboxylic acid-type Gemini surfactant from Diels-Alder adducts of 2 trimethylsilyloxy-1,3-butadiene, in which ozone oxidation is adopted to convert C=C double bond to dicarboxylic acid without any additional oxidant. PMID- 23728333 TI - Involvement of the salicylic acid signaling pathway in the systemic resistance induced in Arabidopsis by plant growth-promoting fungus Fusarium equiseti GF19-1. AB - Plant growth-promoting fungi (PGPF) are effective biocontrol agents for a number of soil-borne diseases and are known for their ability to trigger induced systemic resistance (ISR). In this study, we investigated the mechanisms triggered by PGPF Fusarium equiseti GF19-1, which is known to increase pathogen resistance in plants, by using GF19-1 spores and the culture filtrate (CF) to treat the roots of Arabidopsis thaliana. Subsequently, the leaves were challenged with Pseudomonas syringae pv tomato DC3000 (Pst) bacteria. Arabidopsis plants treated with GF19-1 spores or the CF elicited ISR against the Pst pathogen, resulting in a restriction of disease severity and suppression of pathogen proliferation. Examination of ISR in various signaling mutants and transgenic plants showed that GF19-1-induced protection was observed in the jasmonate response mutant jar1 and the ethylene response mutant etr1, whereas it was blocked in Arabidopsis plants expressing the NahG transgene or demonstrating a disruption of the NPR1 gene (npr1). Analysis of systemic gene expression revealed that GF19-1 modulates the expression of salicylic acid (SA)-responsive PR-1, PR 2, and PR-5 genes. Moreover, transient accumulation of SA was observed in GF19-1 treated plant, whereas the level was further enhanced after Pst infection of GF19 1-pretreated plants, indicating that accumulation of SA was potentiated when Arabidopsis plants were primed for disease resistance by GF19-1. In conclusion, these findings imply that the induced protective effect conferred by F. equiseti GF19-1 against the leaf pathogen Pst requires responsiveness to an SA-dependent pathway. PMID- 23728334 TI - Synthesis of linoleoyl ethanolamide. AB - Linoleoyl ethanolamide has been showed to serve as a new and additional class of endogenous signaling molecule and exhibited a variety of biological activities in cells and tissues. Herein, we reported an effective method for the synthesis of linoleoyl ethanolamide. Enzymatic and chemical syntheses of linoleoyl ethanolamide were first compared and then reaction conditions were optimized. When the reaction was conducted at 30 degrees C for 1 h by reacting 0.5 mmol methyl linoleate with 5 mmol ethanolamine in the presence of 15 MUL, 5.4 mol/L sodium methoxide in methanol as catalyst, 97.2% linoleoyl ethanolamide was produced in the crude reaction mixture without further purification after the removal of excess ethanolamine. Additionally, the reaction can be conducted on a large scale, which resulted in the formation of 95.9% linoleoyl ethanolamide. Compared to previous studies, the amidation reaction between methyl linoleate and ethanolamine with sodium methoxide as catalyst for the synthesis of linoleoyl ethanolamide is more effective and faster. In addition, the reaction is scalable and reaction conditions are mild. This is the first time to use methyl linoleate to synthesize linoleoyl ethanolamide. Commercial linoleoyl ethanolamide is very expensive. However, the scalability and ease for such synthesis make it possible to study the biological and nutritional functions of the cannabinoid-like linoleoyl ethanolamide in animal or human subjects. PMID- 23728335 TI - Esterification of fatty acid catalyzed by hydrothermally stable propylsulfonic acid-functionalized mesoporous silica SBA-15. AB - Propylsulfonic acid-functionalized mesoporous silica SBA-15 has been synthesized via one-step strategy at 130 degrees C based on the co-condensation of TEOS and MPTMS in the presence of Pluronic 123 polymer and H2O2 in HCl aqueous solution. The synthesized solid exhibited hydrothermal stability in boiling water without significant change in textural properties. The catalytic performance of the synthesized solid was studied in the esterification of oleic acid with methanol. The experimental results revealed that the large mesopore structures of SBA-15 PrSO3H solid synthesized at 130 degrees C could favor a facile access of oleic acid to the acid sites, making the comparable activity to that of phenyl ethyl sulfonic acid functionalized silica and higher than that of dry amberlyst-15. PMID- 23728336 TI - Hypoxia-driven osteopontin contributes to breast tumor growth through modulation of HIF1alpha-mediated VEGF-dependent angiogenesis. AB - Hypoxia is a salient feature of most solid tumors, and hypoxic adaptation of cancer cells has crucial implications in propagation of malignant clonal cell population. Osteopontin (OPN) has been identified as a hypoxia-responsive gene, but the mechanistic and regulatory role of OPN under hypoxia is less characterized. The present study identifies the existence of a positive inter regulatory loop between hypoxia and OPN. We have shown that hypoxia induces OPN expression in breast cancer cells; however, the expression was found to be HIF1alpha independent. OPN enabled transcriptional upregulation of HIF1alpha expression both under normoxia and hypoxia, whereas stability of HIF1alpha protein in breast cancer cells remained unaffected. Moreover, we have shown that OPN induces integrin-linked kinase (ILK)/Akt-mediated nuclear factor (NF)-kappaB p65 activation leading to HIF1alpha-dependent vascular endothelial growth factor (VEGF) expression and angiogenesis in response to hypoxia. These in vitro data are biologically important as OPN expressing cells induce greater tumor growth and angiogenesis through enhanced expressions of proangiogenic molecules as compared with control. Immunohistochemical analysis of human breast cancer specimens revealed significant correlation between OPN and HIF1alpha but not HIF2alpha. Elevated expression of HIF1alpha and OPN was observed in pre neoplastic and early stage infiltrating ductal carcinoma implicating the role of these proteins in neoplastic progression of breast cancer. Together, our results substantiate the prime role of OPN in cellular adaptation through ILK and NF kappaB-mediated HIF1alpha-dependent VEGF expression in response to hypoxia that ultimately controls breast cancer progression and angiogenesis. Our study reinforces the fact that targeting OPN and its regulated signaling network hold important therapeutic implications. PMID- 23728337 TI - EGFRvIII stimulates glioma growth and invasion through PKA-dependent serine phosphorylation of Dock180. AB - Glioblastomas (GBMs), the most common and malignant brain tumors, are highly resistant to current therapies. The failure of targeted therapies against aberrantly activated oncogenic signaling, such as that of the EGFR-PI3K/Akt pathway, underscores the urgent need to understand alternative downstream pathways and to identify new molecular targets for the development of more effective treatments for gliomas. Here, we report that EGFRvIII (DeltaEGFR/de2 7EGFR), a constitutively active EGFR mutant that is frequently co-overexpressed with EGFR in clinical GBM tumors, promotes glioma growth and invasion through protein kinase A (PKA)-dependent phosphorylation of Dock180, a bipartite guanine nucleotide exchange factor (GEF) for Rac1. We demonstrate that EGFRvIII induces serine phosphorylation of Dock180, stimulates Rac1 activation and glioma cell migration. Treatments of glioma cells using the PKA inhibitors H-89 and KT5720, overexpression of a PKA inhibitor (PKI), and in vitro PKA kinase assays show that EGFRvIII induction of serine phosphorylation of Dock180 is PKA-dependent. Significantly, PKA induces phosphorylation of Dock180 at amino acid residue S1250 that resides within its Rac1-activating DHR-2 domain. Expression of the Dock180(S1250L) mutant, but not wild type Dock180(WT), protein in EGFRvIII expressing glioma cells inhibited receptor-stimulated cell proliferation, survival, migration in vitro and glioma tumor growth and invasion in vivo. Together, our findings describe a novel mechanism by which EGFRvIII drives glioma tumorigenesis and invasion through PKA-dependent phosphorylation of Dock180, thereby suggesting that targeting EGFRvIII-PKA-Dock180-Rac1 signaling axis could provide a novel pathway to develop potential therapeutic strategies for malignant gliomas. PMID- 23728338 TI - Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. AB - Inflammation is now acknowledged as an hallmark of cancer. Cancer-associated fibroblasts (CAFs) force a malignant cross talk with cancer cells, culminating in their epithelial-mesenchymal transition and achievement of stemness traits. Herein, we demonstrate that stromal tumor-associated cells cooperate to favor malignancy of prostate carcinoma (PCa). Indeed, prostate CAFs are active factors of monocyte recruitment toward tumor cells, mainly acting through stromal-derived growth factor-1 delivery and promote their trans-differentiation toward the M2 macrophage phenotype. The relationship between M2 macrophages and CAFs is reciprocal, as M2 macrophages are able to affect mesenchymal-mesenchymal transition of fibroblasts, leading to their enhanced reactivity. On the other side, PCa cells themselves participate in this cross talk through secretion of monocyte chemotactic protein-1, facilitating monocyte recruitment and again macrophage differentiation and M2 polarization. Finally, this complex interplay among cancer cells, CAFs and M2 macrophages, cooperates in increasing tumor cell motility, ultimately fostering cancer cells escaping from primary tumor and metastatic spread, as well as in activation of endothelial cells and their bone marrow-derived precursors to drive de novo angiogenesis. In keeping with our data obtained in vitro, the analysis of patients affected by prostate cancers at different clinical stages revealed a clear increase in the M2/M1 ratio in correlation with clinical values. These data, coupled with the role of CAFs in carcinoma malignancy to elicit expression of stem-like traits, should focus great interest for innovative strategies aimed at the co-targeting of inflammatory cells and fibroblasts to improve therapeutic efficacy. PMID- 23728340 TI - Melanoma metastasis: new concepts and evolving paradigms. AB - Melanoma progression is typically depicted as a linear and stepwise process in which metastasis occurs relatively late in disease progression. Significant evidence suggests that in a subset of melanomas, progression is much more complex and less linear in nature. Epidemiologic and experimental observations in melanoma metastasis are reviewed here and are incorporated into a comprehensive model for melanoma metastasis, which takes into account the varied natural history of melanoma formation and progression. PMID- 23728339 TI - miR-30 as a tumor suppressor connects EGF/Src signal to ERG and EMT. AB - Src tyrosine kinase (Src) is implicated in the development of bone metastasis and castration resistance of prostate cancer. Src inhibitors are currently being tested in clinical trials for such diseases. Understanding the molecular and cellular actions of Src inhibitors holds the key to future improvement of this line of therapy. Here we describe the microRNA expression profiles modulated by two Src inhibitors and demonstrate that the miR-30 family members are the most prominently induced species. Consistent with its tumor suppressor role, miR-30 is downmodulated by oncogenic signals such as epidermal growth factor (EGF) and hepatocyte growth factor, and is generally underexpressed in prostate cancer specimens. A number of epithelial-to-mesenchymal transition (EMT)-associated genes are predicted targets of miR-30. Among these genes the Ets-related gene (ERG) is the most frequently overexpressed oncogene in prostate cancer activated by genomic fusion events between promoter upstream sequences of the TMPRSS2 and coding sequences of ERG. We showed by ERG 3' untranslated region reporter and mutagenesis assays that ERG is a direct target of miR-30. Overexpression of miR 30 in prostate cancer cells suppresses EMT phenotypes and inhibits cell migration and invasion. It also inhibits the in vitro and in vivo growth of VCaP cells, which depends on TMPRSS2-ERG for proliferation. TMPRSS2-ERG is generally regulated by androgen at the transcriptional level. Our finding reveals a new post-transcriptional mechanism of TMPRSS2-ERG regulation by Src and growth signals via miR-30 providing a rationale for targeting ERG-positive castration resistant tumors with Src inhibitors. PMID- 23728341 TI - MicroRNA-29c functions as a tumor suppressor by direct targeting oncogenic SIRT1 in hepatocellular carcinoma. AB - Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. This led to hypophosphorylation of pRb, which inactivated E2F/DP1 target gene transcription, and thereby caused significant increase of HCC cells to remain in the G1/S phase. A comprehensive miRNA profiling analysis indentified five putative endogenous miRNAs that are significantly downregulated in HCC. Ectopic expression of miRNA mimics evidenced miR-29c to suppress SIRT1 in HCC cells. Notably, ectopic miR-29c expression repressed cancer cell growth and proliferation, and it recapitulated SIRT1 knockdown effects in HCC cells. In addition, miR-29c expression was downregulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC patients. Taken together, we demonstrated that miR-29c suppresses oncogenic SIRT1 by way of binding to 3'-untranslated region of SIRT1 mRNA causing translational inhibition in liver cancer cells. The loss or suppression of miR 29c may cause aberrant SIRT1 overexpression and promotes liver tumorigenesis. Overall, we suggest that miR-29c functions as a tumor suppressor by regulating abnormal SIRT1 activity in liver. PMID- 23728342 TI - Osteopontin signaling upregulates cyclooxygenase-2 expression in tumor-associated macrophages leading to enhanced angiogenesis and melanoma growth via alpha9beta1 integrin. AB - Tumor-associated macrophages (TAMs) have multifaceted roles in tumor development, particularly linked with tumor angiogenesis and invasion, but the molecular mechanism underlying this association remains unclear. In this study, we report that lack of osteopontin (OPN) suppresses melanoma growth in opn(-/-) mice and macrophages are the crucial component responsible for OPN-regulated melanoma growth. In tumor microenvironment, OPN activates macrophages and influences angiogenesis by enhancing cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production in an autocrine manner. Furthermore, we identify alpha9beta1 integrin as a functional receptor for OPN that mediates its effect and activates ERK and p38 signaling, which ultimately leads to COX-2 expression in macrophages. The major role played by OPN and PGE2 in angiogenesis are further amplified by upregulation of MMP-9. OPN-activated macrophages promote the migration of endothelial and cancer cells via PGE2. These findings provide evidence that TAMs serve as source of key components such as OPN and COX-2-derived PGE2 and MMP-9 in melanoma microenvironment. Clinical specimens analyses revealed that increased infiltration of OPN-positive TAMs correlate with melanoma growth and angiogenesis. These data provide compelling evidence that OPN and COX-2 expressing macrophages are obligatory factors in melanoma growth. We conclude that OPN signaling is involved in macrophage recruitment into tumor, and our results emphasize the potential role of macrophage in modulation of tumor microenvironment via secretion of OPN, PGE2 and MMP-9, which trigger angiogenesis and melanoma growth. Thus, blockade of OPN and its regulated signaling network provides unique strategy to eradicate melanoma by manipulating TAMs. PMID- 23728343 TI - A chemical biology approach identifies AMPK as a modulator of melanoma oncogene MITF. AB - The microphthalmia-associated transcription factor (MITF) is indispensable for the viability of melanocytic cells, is an oncogene in melanoma and has a cell type-specific expression pattern. As the modulation of MITF activity by direct chemical targeting remains a challenge, we assessed a panel of drugs for their ability to downregulate MITF expression or activity by targeting its upstream modulators. We found that the multi-kinase inhibitors midostaurin and sunitinib downregulate MITF protein levels. To identify the target molecules shared by both the drugs in melanocytic cells, a chemical proteomic approach was applied and AMP activated kinase (AMPK) was identified as the relevant target for the observed phenotype. RNA interference and chemical inhibition of AMPK led to a decrease in MITF protein levels. Reduction of MITF protein levels was the result of proteasomal degradation, which was preceded by enhanced phosphorylation of MITF mediated by ERK. As expected, downregulation of MITF protein levels by AMPK inhibition was associated with decreased viability. Together, these results identify AMPK as an important regulator for the maintenance of MITF protein levels in melanocytic cells. PMID- 23728344 TI - Failure to downregulate the BAF53a subunit of the SWI/SNF chromatin remodeling complex contributes to the differentiation block in rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children and young adults, is characterized by a partially differentiated myogenic phenotype. We have previously shown that the blocking of tumor growth and resumption of differentiation can be achieved by re-expression of miR-206, a muscle-enriched microRNA missing in RMS. In this work, we focused on BAF53a, one of the genes downregulated in miR-206-expressing RMS cells, which codes for a subunit of the SWI/SNF chromatin remodeling complex. Here we show that the BAF53a transcript is significantly higher in primary RMS tumors than in normal muscle, and is a direct target of miR-206. Sustained expression of BAF53a interferes with differentiation in myogenic cells, whereas its silencing in RMS cells increases expression of myogenic markers and inhibits proliferation and anchorage-independent growth. Accordingly, BAF53a silencing also impairs embryonal RMS and alveolar RMS tumor growth, inducing their morphological and biochemical differentiation. These results indicate that failure to downregulate the BAF53a subunit may contribute to the pathogenesis of RMS, and suggest that BAF53a may represent a novel therapeutic target for this tumor. PMID- 23728345 TI - Irradiation-induced angiogenesis is associated with an MMP-9-miR-494-syndecan-1 regulatory loop in medulloblastoma cells. AB - Matrix metalloproteinase-9 (MMP-9) represents one of the most prominent proteins associated with tumorigenesis and is a modulator of the tumor microenvironment during angiogenesis. Recently, syndecan-1 (SDC1), a transmembrane heparan sulfate bearing proteoglycan, was also speculated to have a critical role in contributing to angiogenesis when associated with MMP-9. However, the mechanism behind their synergistic regulation is not fully understood. In the current study, we report for the first time that ionizing radiation (IR)-induced MMP-9 enhances SDC1 shedding, corroborating to tube-inducing ability of medulloblastoma (MB) cells. Furthermore, we observed that the tumor angiogenesis is associated with higher MMP-9-SDC1 interactions on both the cell surface and extracellular medium. Our results also revealed the existence of a novel regulatory mechanism where MMP-9 drives the suppression of miR-494, resulting in enhanced SDC1 shedding and angiogenesis. From the in situ hybridization analysis, we found that MMP-9 specific shRNA (shMMP-9) treatment of mouse intracranial tumors resulted in elevated expression of miR-494. This negative correlation between MMP-9 and miR 494 levels was observed to be dependent on the methylation status of a miR-494 promoter-associated CpG island region (-186 to -20), which was confirmed by bisulfite-sequencing and methylation-specific PCR (MSP) analysis. Further, validation of MMP-9 and SDC1 3'-untranslated region (3'-UTR) targets with luciferase reporter assay provided a more favorable result for miR-494-mediated regulation of SDC1 but not of MMP-9, suggesting that the 3'-UTR of SDC1 mRNA is a direct target of miR-494. Overall, our results indicate that angiogenesis induced by radiotherapy is associated with an MMP-9-miR-494-SDC1 regulatory loop and that MMP-9-SDC1 activity creates a negative feedback loop by regulating the expression of miR-494. PMID- 23728346 TI - Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis. AB - Signalling by the toll-like receptor (TLR) family of pathogen recognition receptors has emerged as a key molecular component in the pathogenesis of an increasing number of inflammatory-related cancers, among which gastric cancer rates as the second most lethal cancer world-wide. The myeloid differentiation factor 88 (MyD88) adapter molecule has a critical role in mediating innate immune signalling by members of the TLR and interleukin (IL)-1 families, and has been associated with either pro- or antitumourigenic responses in various cancer models. However, little is known about the in vivo role of MyD88 adapter-like (Mal)/TIR-domain containing adapter protein (TIRAP), which is restricted to facilitating TLR4 and TLR2 signalling. To interrogate the role of these innate immune signalling components in gastric tumourigenesis, here we have employed the spontaneous gastric cancer gp130(F/F) mouse model, in which TLR2 promotes the growth of gastric tumours. Genetic ablation of Myd88 in gp130(F/F) mice suppressed tumourigenesis and was associated with increased apoptosis and reduced proliferation in the gastric tumour epithelium, comparable to that observed previously upon deletion of Tlr2 in gp130(F/F) mice. By contrast, the tumour burden in gp130(F/F):Mal(-/-) mice was equivalent to their gp130(F/F) littermates. At the molecular level, suppressed tumourigenesis in gp130(F/F):Myd88(-/-) mice correlated with reduced expression and activation of TLR2-regulated protumourigenic genes and signalling pathways, respectively. Consistent with the previously defined non-essential role for TLR2 in gastric tumour inflammation, the extent of inflammatory cell infiltrates in gastric tumours from gp130(F/F):Mal(-/-) and gp130(F/F):Myd88(-/-) mice remained unaltered compared with gp130(F/F) mice. Collectively, our data reveal a differential, but inflammation-independent, requirement for Mal and MyD88 during TLR2-promoted gastric tumourigenesis. PMID- 23728347 TI - H-Ras-driven tumoral maintenance is sustained through caveolin-1-dependent alterations in calcium signaling. AB - A growing body of research has highlighted the complex range of tumoral traits acquired during H-Ras-driven transformation and maintenance, which include proliferative signaling, growth suppressor evasion and resistance to cell death. Clear molecular information about these processes is not yet available, but recent evidence has provided solid support for the importance of mitochondria. Here, we show that the induction of oncogenic H-Ras leads to changes in intracellular calcium (Ca(2+)), evaluate the temporal relationship between oncogene expression and mitochondrial physiology, and demonstrate that Ca(2+) homeostasis is altered by caveolin-1, a protein that has a key role in tumor maintenance. Our results indicate that tumor-suppressor caveolin-1 is a core component of the Ca(2+)-dependent apoptotic pathway and participates in the regulation of critical mitochondrial functions during tumor development. The compromised caveolin-1/Ca(2+) axis contributes to failure in both mitochondrial metabolism and apoptosis, thereby sustaining the neoplastic phenotype. These results illustrate a direct link between Ca(2+) regulation and mitochondrial biology in cancer. PMID- 23728348 TI - The ribosomal protein S26 regulates p53 activity in response to DNA damage. AB - Ribosomal proteins have emerged as novel regulators of the Mdm2-p53 feedback loop, especially in the context of ribosomal stress. RPS26 is a recently identified Diamond-Blackfan Anemia-related ribosomal protein and its role in p53 activation has not been previously explored. In this study we found knockdown of RPS26 induced p53 stabilization and activation via a RPL11-dependent mechanism, resulting in p53-dependent cell growth inhibition. Moreover, RPS26 has the ability to interact with Mdm2 and inhibits Mdm2-mediated p53 ubiquitination that leads to p53 stabilization upon overexpression. Importantly, we discovered that RPS26 knockdown impaired p53's ability to transcriptionally activate its target genes in response to DNA damage, without affecting its stability. Accordingly, the cells lost the ability to induce G2/M cell cycle arrest. We further found that upon RPS26 knockdown, the DNA damage induced recruitment of p53 to the promoters of its target genes and p53 acetylation were both greatly reduced. In addition, RPS26 can interact with p53 independent of Mdm2 and coexist in a complex with p53 and p300. These data establish a role of RPS26 in DNA damage response by directly influencing p53 transcriptional activity, and suggest that RPS26 acts distinctively in different scenarios of p53 activation. Our finding also implicates p53 transcriptional activity control as an important mechanism of p53 regulation by ribosomal proteins. PMID- 23728350 TI - COMS eye plaque brachytherapy dosimetric sensitivity to source photon energy and seed design. AB - This study explores the influence of source photon energy on eye plaque brachytherapy dose distributions for a 16 mm COMS plaque filled with (103)Pd, (125)I, or (131)Cs sources or monoenergetic photon emissions ranging from 12 keV to 100 keV. Dose distributions were similarly created for all permutations of three common brachytherapy seed designs. Within this range, sources with average energy <=22 keV may reduce dose to the opposite eye wall by more than a factor of 2 while maintaining tolerable proximal sclera doses when prescribing to depths of 9 mm or less. Current commercially-available brachytherapy sources can exhibit up to 15% relative dosimetric sensitivity to seed design at regions within the eye. PMID- 23728351 TI - Determination of kinetics parameters of the main glow peaks for KMgF3:Lu and LiF:Mg phosphors after long-term high temperature storage. AB - The isothermal decay method is useful for determining the trap activation energy in thermoluminescent material for dosimetry purposes. Recently we proposed new modified expressions for isothermal decay method. As validation of the modified expressions, after long-term (4 h) high temperature storage, the activation energy of experimental TL glow peaks, KMgF3:Lu (0.17 and 0.34 mol%) and LiF:Mg (0.04 mol%), in the framework of the general-order kinetic was calculated. The results of the kinetics parameters were compared with those obtained by the other methods like Initial Rise (IR), Sequential Quadratic Programming Glow Curve Deconvolution (SQPGCD), deconvolution of the TL glow curves by assuming the General Order Kinetic (GOK), and Chen General-Order Kinetics method. It seems that both SQPGCD and GOK deconvolution methods give more accurate kinetics parameters values for the experimental glow curves. PMID- 23728349 TI - Small-molecule inhibition of CBP/catenin interactions eliminates drug-resistant clones in acute lymphoblastic leukemia. AB - Drug resistance in acute lymphoblastic leukemia (ALL) remains a major problem warranting new treatment strategies. Wnt/catenin signaling is critical for the self-renewal of normal hematopoietic progenitor cells. Deregulated Wnt signaling is evident in chronic and acute myeloid leukemia; however, little is known about ALL. Differential interaction of catenin with either the Kat3 coactivator CREBBP (CREB-binding protein (CBP)) or the highly homologous EP300 (p300) is critical to determine divergent cellular responses and provides a rationale for the regulation of both proliferation and differentiation by the Wnt signaling pathway. Usage of the coactivator CBP by catenin leads to transcriptional activation of cassettes of genes that are involved in maintenance of progenitor cell self-renewal. However, the use of the coactivator p300 leads to activation of genes involved in the initiation of differentiation. ICG-001 is a novel small molecule modulator of Wnt/catenin signaling, which specifically binds to the N terminus of CBP and not p300, within amino acids 1-110, thereby disrupting the interaction between CBP and catenin. Here, we report that selective disruption of the CBP/beta- and gamma-catenin interactions using ICG-001 leads to differentiation of pre-B ALL cells and loss of self-renewal capacity. Survivin, an inhibitor-of-apoptosis protein, was also downregulated in primary ALL after treatment with ICG-001. Using chromatin immunoprecipitation assay, we demonstrate occupancy of the survivin promoter by CBP that is decreased by ICG-001 in primary ALL. CBP mutations have been recently identified in a significant percentage of ALL patients, however, almost all of the identified mutations reported occur C terminal to the binding site for ICG-001. Importantly, ICG-001, regardless of CBP mutational status and chromosomal aberration, leads to eradication of drug resistant primary leukemia in combination with conventional therapy in vitro and significantly prolongs the survival of NOD/SCID mice engrafted with primary ALL. Therefore, specifically inhibiting CBP/catenin transcription represents a novel approach to overcome relapse in ALL. PMID- 23728352 TI - Immunogenicity of dendritic cells pulsed with MAGE3, Survivin and B-cell maturation antigen mRNA for vaccination of multiple myeloma patients. AB - The introduction of autologous stem cell transplantation (SCT) and novel drugs has improved overall survival in multiple myeloma (MM) patients. However, minimal residual disease (MRD) remains and most patients eventually relapse. Myeloma plasma cells express tumor-associated antigens (TAA), which are interesting targets for immunotherapy. In this phase 1 study, we investigated the safety and immunological effects of TAA-mRNA-loaded dendritic cell (DC) vaccination for treatment for MRD in MM after SCT. Mature monocyte-derived DCs were pulsed with keyhole limpet hemocyanin (KLH) and electroporated with MAGE3, Survivin or B-cell maturation antigen (BCMA) mRNA. Twelve patients were vaccinated three times with intravenous (5-22 * 10(6) DCs) and intradermal vaccines (4-11 * 10(6) DCs), at biweekly intervals. Immunological responses were monitored in blood and delayed type hypersensitivity (DTH) biopsies. All patients developed strong anti-KLH T cell responses, but not KLH antibodies. In 2 patients, vaccine-specific T cells were detected in DTH biopsies. In one patient, we found MAGE3-specific CD4(+) and CD8(+) T cells, and CD3(+) T cells reactive against BCMA and Survivin. In the other patient, we detected low numbers of MAGE3 and BCMA-reactive CD8(+) T cells. Vaccination was well tolerated with limited toxicity. These findings illustrate that TAA-mRNA-electroporated mature DCs are capable of inducing TAA-T-cell responses in MM patients after SCT. PMID- 23728353 TI - Effect of repeated oral administration of bifenthrin on lipid peroxidation and anti-oxidant parameters in Wistar rats. AB - The oxidative stress-inducing potential of the pyrethroid insecticide, bifenthrin, was evaluated in rats at 5.8 mg/kg body weight once daily for 20 or 30 days. Bifenthrin treated animals showed significantly increased lipid peroxidation, evidenced by increased blood malondialdehyde levels. Blood glutathione levels and activities of catalase and glutathione peroxidase decreased significantly in the bifenthrin treated animals after both 20 and 30 days of treatment, whereas, the activities of superoxide dismutase and glutathione S-transferase decreased significantly only on the 30th day. In conclusion, bifenthrin has a potential to induce severe oxidative stress in rats exposed to sublethal concentrations. PMID- 23728354 TI - Evaluation of the sources of contamination in the suburban area of Koropi Markopoulo, Athens, Greece. AB - Heavy metal concentrations were monitored in agricultural soils and irrigation groundwaters of Koropi-Markopoulo area, a representative agricultural suburb in Athens, Greece, aiming at the identification of the sources of contaminants. Multivariate analyses of geochemical data demonstrated that agricultural practices and industrial activities considerably affected the quality of both environmental compartments. The levels of Ni, Cr, Co, Mn and Fe in agricultural soils were associated with geological parent materials whereas Pb, Zn and Cu mainly originated from anthropic activities. Referring to groundwaters, individual major anions and cations (K+, Na+, Ca2+, Mg2+, NO3-, SO42-, Cl-) were influenced by various natural and anthropogenic factors whereas Ni, Cr, Cu and Zn were controlled by industrial and agronomic activities. The identification of the sources of contaminants in soil and groundwater environments is a valuable basis for encouraging mitigation strategies preventing further quality degradation. PMID- 23728355 TI - Molecular responses to toxicological stressors: profiling microRNAs in wild Atlantic salmon (Salmo salar) exposed to acidic aluminum-rich water. AB - Atlantic salmon (Salmo salar) is among the most sensitive organisms toward acidic, aluminum exposure. Main documented responses to this type of stress are a combination of hypoxia and loss of blood plasma ions. Physiological responses to stress in fish are often grouped into primary, secondary and tertiary responses, where the above mentioned effects are secondary responses, while primary responses include endocrine changes as measurable levels of catecholamines and corticosteroids. In this study we have exposed young (14 months) Atlantic salmon to acid/Al water (pH ~ 5.6, Al(i) ~ 80 MUg L-1) for 3 days, and obtained clear and consistent decrease of Na+ and Cl- ions, and increases of glucose in blood plasma, hematocrit and P(CO2) in blood. We did not measure plasma cortisol (primary response compound), but analyzed effects on microRNA level (miRNA) in muscle tissue, as this may represent initial markers of primary stress responses. miRNAs regulate diverse biological processes, many are evolutionarily conserved, and hundreds have been identified in various animals, although only in a few fish species. We used a novel high-throughput sequencing (RNA-Seq) method to identify miRNAs in Atlantic salmon and specific miRNAs as potential early markers for stress. A total of 18 miRNAs were significantly differentially expressed (FDR<0.1) in exposed compared to control fish, four down-regulated and 14 up regulated. An unsupervised hierarchical clustering of significant miRNAs revealed two clusters representing exposed and non-exposed individuals. Utilizing the genome of the zebrafish and bioinformatic tools, we identified 224 unique miRNAs in the Atlantic salmon samples sequenced. Additional laboratory studies focusing on function, stress dose-responses and temporal expression of the identified miRNAs will facilitate their use as initial markers for stress responses. PMID- 23728356 TI - Predator cues magnify effects of the pesticide endosulfan in water bugs in a multi-species test in outdoor containers. AB - Pesticides have become major stressors in many aquatic communities. Laboratory studies suggest their impact may be further magnified in the presence of cues from predators. Despite their importance for ecological risk assessment, synergisms between pesticides and predator cues have not been confirmed under semi-natural outdoor conditions. We evaluated how the presence of predator cues and the presence of a non-corixid community affect the pesticide sensitivity of five water bug (Corixidae) species in an outdoor, multi-species container experiment. The experiment employed a full factorial design with two pesticide treatments, two predator cue treatments and two (non-corixid) community treatments (absence versus presence of Cloeon dipterum mayfly larvae, Ischnura elegans damselfly larvae and Physa acuta snails). The pesticide treatment negatively affected survival in Cymatia coleoptrata, and to a lesser extent, Sigara lateralis, but not in the other three Corixidae species (Hesperocorixa linnaei, Sigara iactans and Sigara striata). The addition of pesticides did not significantly affect body mass in the latter four species, unless combined with predator cues. To our knowledge this is the first report of this synergism under semi-natural, outdoor conditions. Neither lethal nor sublethal pesticide effects in the Corixidae depended on the community context, yet the presence of the non corixid community when combined with predator cues reduced survival and body mass. Our results suggest that the here documented synergism between pesticides and predator cues may occur in nature. PMID- 23728357 TI - Tissue specific responses of oysters, Crassostrea virginica, to silver nanoparticles. AB - Silver nanoparticle (AgNP) toxicity in eastern oysters, Crassostrea virginica, was investigated in both gill and hepatopancreas tissues, and compared to dissolved Ag exposures. Oysters were exposed to varying concentrations of AgNPs prepared with citrate coatings and dissolved Ag (AgNO3) for 48 h and the effects on a suite of biomarkers of cellular stress were evaluated. Two biomarkers of cellular damage were evaluated-lysosomal destabilization rates of hepatopancreas cells as indicators of lysosomal damage, and lipid peroxidation as an indicator of oxidative damage. Total glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD) assays were used as indicators of impacts on antioxidant capacity. The results indicated that gill tissues were more prone to oxidative damage following dissolved Ag exposures than AgNP exposures, while hepatopancreas tissues were more sensitive to AgNP exposures. Total protein levels increased in hepatopancreas tissues following AgNP exposures, but not dissolved Ag exposures. These tissue specific differences in toxicity and bioreactivity of Ag nanoparticles compared to dissolved metal ions reflect distinct nanoparticle effects. Oysters exposed to dissolved Ag would be more prone to cellular and tissue damage of gills, but oysters exposed to AgNPs could be more prone to hepatopancreas damage contributing to metabolic and reproductive impairment. PMID- 23728358 TI - Effectiveness of criminal justice liaison and diversion services for offenders with mental disorders: a review. AB - OBJECTIVE: The authors reviewed studies of the effectiveness of criminal justice liaison and diversion (CJLD) services in which outcomes of participants in these services were compared with those of offenders with mental illness who received no intervention or a standard intervention. The authors synthesized existing evidence with respect to changes in mental health status or criminal recidivism. METHODS: A comprehensive search (1980-2012) of more than 30 generic and specialist databases identified 6,571 published and unpublished studies. The studies, which varied considerably in methodological approach and overall quality, were systematically appraised according to Campbell-Cochrane guidelines. Ten studies met inclusion criteria. Key outcomes included a reduction in offending and postintervention changes in mental health. RESULTS: Synthesized findings indicated that CJLD services appeared to be effective in identifying offenders with mental disorders and that participation in CJLD services had a positive impact on criminal justice and mental health outcomes. CONCLUSIONS: Although the methodologies of existing studies are only moderately rigorous, the overall findings suggest that CJLD services can be beneficial. Their effectiveness depends on the model of service delivery, the availability of community services, and the engagement of offenders with mental disorders in treatment. The successful implementation of CJLD services requires a clearer recognition of the importance of systems-of-care principles. PMID- 23728359 TI - Syntheses of Cu(I) polymetallic assemblies from reaction of ligands bearing the 2,5-bis(2-pyridyl)phosphole fragment with Cu(II) precursors. AB - Upon reaction with ligands A, 1 and 3 bearing the 2,5-bis(2-pyridyl)phosphole fragment, an unexpected conversion of Cu(II) metal centers to Cu(I) centers is observed affording either bimetallic complexes bearing a bridging phosphane coordination mode or hexametallic metallacycles. PMID- 23728361 TI - Tuneable reactivity with PPh3 and SnX2 of four- and five-coordinate Pd(II) and Pt(II) complexes containing polyphosphines. AB - The reactivity of the unusual d(8) trigonal-bipyramidal systems [MX(PP3)]X (X = Cl: M = Pd(1a), Pt(2a); X = Br: M = Pd(3a), Pt(4a); X = I: M = Pd(5a), Pt(6a); PP3 = tris[2-(diphenylphosphino)ethyl]phosphine) in CHCl3-CH3OH, the square pyramidal compounds [MCl(NP3)]Cl (M = Pd(7a); Pt(8a); NP3 = tris[2 (diphenylphosphino)ethyl]amine) in CD3OD-DMF and the distorted square-planar mononuclear [MX(PNP)]X (M = Pd: X = Cl(10a); M = Pt: X = I(10b); PNP = bis[2 (diphenylphosphino)ethyl]amine) and the heteronuclear [PdAu2X4(PP3)] [X = I(9a), Cl(14a), Br(15a)] and [MAuX2(PP3)]X [M = Pd: X = Cl(16a); M = Pt: X = Cl(17a), Br(18a)] species in CDCl3 with PPh3 + SnX2 has been explored to establish the factors that influence the nature of the products. With the mononuclear precursors the course of the reaction is strongly dependent on the tripodal or linear arrangement of the polydentate ligand and in the former case on the halogen. Thus, while for chlorides (1a-2a, 7a-8a) and bromides (3a-4a) the reaction led to the trigonal-bipyramidal compounds [M(SnCl3)(AP3)][SnCl3] [A = P: M = Pd(1), Pt(2); A = N: M = Pd(7), Pt(8)], [MBr(PP3)][SnBr3] [M = Pd(4), Pt(6)] containing M-Sn and M-Br bonds, respectively, for iodides (5a-6a) resulted in the unknown neutral square-planar compounds [MI2(PP(PO)2)(SnI2)2] [M = Pd(9) and Pt(10)] bearing two dangling P=O-SnI2 units and P2MI2 environments. However, complexes of the type [PtCl(PP2PO)X]X' [X = SnCl2, X' = [SnCl3](-)(11)] and [M(PP(PO)2)2X4]X'2 [X = SnCl2, X' = [SnCl3](-): M = Pd(12), Pt(13)] showing P=O SnCl2 arms were obtained by direct reaction of [PtCl(PP2PO)]Cl (11a) and [M(PP(PO)2)2]Cl2 [M = Pd(12a), Pt(13a)] with SnCl2 in CH3OH. Although complex 9 was also prepared by interaction of the heteronuclear iodide 9a with PPh3 + SnI2 in CDCl3, the use of the neutral and ionic heteronuclear chlorides and bromides (14a-18a) as starting materials afforded the distorted square-planar ionic systems [MAuX'(PP3)(PPh3)][SnX3]2 [M = Pd: X = Cl, X' = SnCl3(-)(14); X = Br, X' = SnBr3(-)(15); M = Pt: X = Cl, X' = SnCl3(-)(17); X = Br, X' = SnBr3(-)(18)] containing M-SnX3 and P-Au-PPh3 functionalities. It was found that these reactions where the heteronuclear species are the precursors proceed via the trigonal-bipyramidal halides not only with X = Cl and Br(1a-4a) but also I(5a). When the precursors were 10a and 10b the reaction occurred with formation of [Pd(PNP)(PPh3)][SnCl3]2 (23) and [Pt(PNP)(PPh3)][SnCl2I]2 (24) showing M-PPh3 units and trihalostannato counter anions. PMID- 23728363 TI - A case report of anesthesia for a child with Hajdu-Cheney syndrome. AB - Hajdu-Cheney syndrome is an extremely rare disorder characterized by progressive skeletal acro-osteolysis, which results in extremity fractures and scoliosis often requiring surgical treatment from childhood. A unique facial structure and deformity of the cervical spine is associated with a difficult airway. We report here a 10-year-old girl with Hajdu-Cheney syndrome who developed progressive basilar impression and medullary compression for which foramen magnum decompression was performed. After slow induction of anesthesia, we were able to perform fiberoptic orotracheal intubation via a VBM bronchoscope airway. This case report contributes to the accumulation of knowledge about anesthesia for this rare syndrome. PMID- 23728362 TI - Broad protection against influenza infection by vectored immunoprophylaxis in mice. AB - Neutralizing antibodies that target epitopes conserved among many strains of influenza virus have been recently isolated from humans. Here we demonstrate that adeno-associated viruses (AAV) encoding two such broadly neutralizing antibodies are protective against diverse influenza strains. Serum from mice that received a single intramuscular AAV injection efficiently neutralized all H1, H2 and H5 influenza strains tested. After infection with diverse strains of H1N1 influenza, treated mice showed minimal weight loss and lung inflammation. Protection lasted for at least 11 months after AAV injection. Notably, even immunodeficient and older mice were protected by this method, suggesting that expression of a monoclonal antibody alone is sufficient to protect mice from illness. If translated to humans, this prophylactic approach may be uniquely capable of protecting immunocompromised or elderly patient populations not reliably protected by existing vaccines. PMID- 23728364 TI - Anesthetic management of the patient with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS), with an incidence of 1.5-2.5 for 100 000 per year, is a rare but rapid progression neuromuscular degeneration disorder that poses unique perioperatively challenges to clinical anesthesiologists. The progressive degeneration of motor neurons causes a constellation of symptoms, including muscular weakness, atrophy, fasciculations, spasticity, and hyperreflexia. Therapeutic and experimental treatments, including riluzole, beta lactams, methylcobalamin, dexpramipexole, antiepileptics, antioxidant agents, neutrophin, antiinflammatory agents, and antiapoptosis drugs, are described. Newer therapies, such as neural stem cells and diaphragmatic pacing, are presented. Because of the inherent muscle weakness and associated respiratory insufficiency, certain precautions must be utilized during anesthetic care of ALS patients. In particular, certain neuromuscular agents are contraindicated and anesthetics that leave the body more rapidly present logical and attractive options in this population. A solid understanding of the disease process, therapeutic interventions, and anesthesia considerations are all paramount for the successful management of a patient with ALS in the perioperative setting. PMID- 23728365 TI - Work and "mass personal" communication as means of navigating nutrition and exercise concerns in an online cancer community. AB - BACKGROUND: Health and psychosocial outcomes for young adults affected by cancer have improved only minimally in decades, partially due to a lack of relevant support and information. Given significant unmet needs involving nutrition and exercise, it is important to understand how this audience handles information about food and fitness in managing their cancer experiences. OBJECTIVE: Using the theory of illness trajectories as a framework, we explored how four lines of work associated with living with a chronic illness such as cancer (illness, everyday life, biographical, and the recently explicated construct of communication work) impacts and is impacted by nutrition and exercise concerns. METHODS: Following a search to extract all nutrition- and exercise-related content from the prior 3 years (January 2008 to February 2011), a sample of more than 1000 posts from an online support community for young adults affected by cancer were qualitatively analyzed employing iterative, constant comparison techniques. Sensitized by illness trajectory research and related concepts, 3 coders worked over 4 months to examine the English-language, de-identified text files of content. RESULTS: An analysis of discussion board threads in an online community for young adults dealing with cancer shows that nutrition and exercise needs affect the young adults' illness trajectories, including their management of illness, everyday life, biographical, and communication work. Furthermore, this paper helps validate development of the "communication work" variable, explores the "mass personal" interplay of mediated and interpersonal communication channels, and expands illness trajectory work to a younger demographic than investigated in prior research. CONCLUSIONS: Applying the valuable concepts of illness, everyday life, biographical, and communication work provides a more nuanced understanding of how young adults affected by cancer handle exercise and nutrition needs. This knowledge can help provide support and interventional guidance for the well documented psychosocial challenges particular to this demographic as they manage the adversities inherent in a young adult cancer diagnosis. The research also helps explain how these young adults meet communication needs in a "mass personal" way that employs multiple communication channels to meet goals and thus might be more effectively reached in a digital world. PMID- 23728366 TI - Non-invasively estimated end-systolic elastance in patients with resistant hypertension and type 2 diabetes mellitus. AB - Ventriculo-arterial coupling (VAC) has been shown to be impaired in patients with type 2 diabetes mellitus (type 2 DM) and hypertension, and to improve with antihypertensive treatment. We examined if VAC in patients with type 2 DM and hypertension improved after a period of intensified antihypertensive treatment. VAC was estimated as the ratio of effective arterial elastance (E A) to end systolic elastance (E ES) using pressure and flow curves obtained non-invasively (applanation tonometry and echocardiography). Left ventricular (LV) systolic and diastolic functions were evaluated using LV volumes, ejection fraction (EF), mitral inflow pattern, and Doppler tissue mitral annulus velocities. In total, 180 patients were included and for 100 patients the data met the quality criteria. Patients were categorized as having controlled (CH, n = 34), uncontrolled (UH, n = 32) or resistant (RH, n = 34) hypertension. In patients with RH, EF at follow-up was reduced from 48 to 42% (p = 0.005) and E ES from 2.18 mmHg/ml to 1.47 mmHg/ml (p = 0.003). EES, however, was also reduced in patients with CH and UH (CH 2.41-2.26, p = 0.05, UH 2.51-2.04, p = 0.05). In the present study, intensified antihypertensive treatment did not improve VAC or LV function in patients with hypertension and type 2 DM despite better control of BP. We speculate whether this is due to a reduction in myocardial perfusion pressure or to a gradual progression of diabetic cardiomyopathy. PMID- 23728367 TI - Mapping the leaf proteome of Miscanthus sinensis and its application to the identification of heat-responsive proteins. AB - Miscanthus sinensis is a promising bioenergy crop; however, its genome is poorly represented in sequence databases. As an initial step in the comprehensive analysis of the M. sinensis proteome, we report a reference 2-DE protein map of the leaf. A total of 316 protein spots were excised from the gels, digested with trypsin and subjected to matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) or MALDI-TOF/TOF MS. Two hundred and thirty-two protein spots were identified, which are involved in a variety of cellular functions through distinct metabolic pathways. Functional annotation of the proteins revealed a nearly complete C3 and C4 cycle, starch and sugar synthesis pathway, glycolysis pathway, a significant portion of the pentose phosphate pathway, and many enzymes involved in secondary metabolism such as flavonoid/isoflavonoid, kaurene, chalcone, sesquiterpene and lignin biosynthesis. Other proteins belong to primary metabolism, transcription, protein synthesis, protein destination/storage, disease/defense, cell growth/division, transportation and signal transduction. To test the applicability of the constructed map, we studied the effect of heat stress on M. sinensis leaf proteome. Twenty-five protein spots were upregulated, five were newly induced and twenty-five spots were downregulated by heat treatment. The differentially accumulated proteins were involved in photosynthesis, energy metabolism, gene transcription, protein kinases and phosphatases, signal transduction, protein synthesis and heat shock responses. C4-specific pyruvate orthophosphate dikinase, Rubisco large subunit, Rubisco activase and some associated proteins were upregulated during heat stress and tend to restore upon recovery. Identification of these proteins provides some important clues regarding the way M. sinensis copes with hot climate. This work represents the first extensive proteomic description of M. sinensis and provides a reference map and heat-responsive candidates for future molecular and physiological studies of this bioenergy crop. PMID- 23728368 TI - Accumulation and distribution of Zn in the shoots and reproductive structures of the halophyte plant species Kosteletzkya virginica as a function of salinity. AB - Kosteletzkya virginica is a wetland halophyte that is a good candidate for rehabilitation of degraded salt marshes and production of oil as biodiesel. Salt marshes are frequently contaminated by heavy metals. The distribution of Zn in vegetative and reproductive organs of adult plants, and the NaCl influence on this distribution remain unknown and were thus explored in the present study. Plants were cultivated in a nutrient film technique system, from seedling stage until seed maturation in a control, Zn (100 MUM), NaCl (50 mM) or Zn + NaCl medium. Photosynthesis, ion nutrition, malondialdehyde and non-protein thiol concentrations were quantified. Zinc distribution in reproductive organs was estimated by a laser ablation-inductively coupled plasma-mass spectrometry procedure (LA-ICP-MS). Adult plants accumulated up to 2 mg g(-1) DW Zn in the shoots. Zinc reduced plant growth, inhibited photosynthesis and reduced seed yield. Zinc accumulation in the seeds was only two times higher in Zn-treated plants than in controls. Exogenous NaCl neutralized the damaging action of Zn and modified the Zn distribution through a preferential accumulation of toxic ions in older leaves. Zinc was present in seed testa, endosperm and, to a lower extent, in embryo. Additional NaCl induced a chalazal retention of Zn during seed maturation and reduced final Zn seed content. It is concluded that NaCl 50 mM had a positive impact on the response of K. virginica to Zn toxicity and acts through a modification in Zn distribution rather than a decrease in Zn absorption. PMID- 23728369 TI - Halobellus inordinatus sp. nov., from a marine solar saltern and an inland salt lake of China. AB - Two halophilic archaeal strains, YC20(T) and XD15, were isolated from a marine solar saltern and an inland salt lake in China. Both had pleomorphic cells that lysed in distilled water, stained Gram-negative and formed red-pigmented colonies. They were neutrophilic, requiring at least 100 g NaCl l(-1) and 0.5-95 g MgCl2 l(-1) for growth at the optimum growth temperature of 37 degrees C. The major polar lipids of the two strains were phosphatidylglycerol (PG), phosphatidylglycerol phosphate methyl ester (PGP-Me), phosphatidylglycerol sulfate (PGS) and two major glycolipids chromatographically identical to sulfated mannosyl glucosyl diether (S-DGD-1) and mannosyl glucosyl diether (DGD-1), respectively. Trace amounts of two unidentified glycolipids were also detected. The 16S rRNA gene sequences of the two strains were 99.5 % identical and showed 94.0-95.9 % similarity to the most closely related members of the genus Halobellus of the family Halobacteriaceae. The rpoB' gene sequence similarity between strains YC20(T) and XD15 was 98.2 % and these sequences showed 89.6-92.8 % similarity to those of the most closely related members of the genus Halobellus. The DNA G+C contents of strains YC20(T) and XD15 were 65.8 mol% and 65.4 mol%, respectively. The DNA-DNA hybridization value between strain YC20(T) and strain XD15 was 92 %, and the two strains showed low DNA-DNA relatedness to members of the genus Halobellus. The phenotypic, chemotaxonomic and phylogenetic properties suggest that strains YC20(T) and XD15 represent a novel species of the genus Halobellus, for which the name Halobellus inordinatus sp. nov. is proposed. The type strain is YC20(T) ( = CGMCC 1.12120(T) = JCM 18361(T)) and the other strain is XD15 ( = CGMCC 1.12236 = JCM 18648). PMID- 23728370 TI - Dactylosporangium siamense sp. nov., isolated from soil. AB - A novel actinomycete strain, designed MW4-36(T), was isolated from tropical forest soil in Nakhon Sawan Province, Thailand. Morphological and chemotaxonomic characteristics of this strain clearly demonstrated that it belongs to the genus Dactylosporangium. The strain formed finger-shaped sporangia on short sporangiophores that emerged directly from substrate hyphae. The cell-wall peptidoglycan contained glutamic acid, glycine, alanine and meso-diaminopimelic acid including 3-hydroxy-meso-diaminopimelic acid; arabinose, glucose, rhamnose, ribose and xylose were found as whole-cell sugars. The diagnostic phospholipids were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol and phosphatidylinositol; no phosphatidylcholine was found. The predominant menaquinones were MK-9(H8) and MK-9(H6). Mycolic acids were not detected. The predominant cellular fatty acids were iso-C15 : 0, iso-C16 : 0, anteiso-C15 : 0 and anteiso-C17 : 0. The G+C content of the genomic DNA was 72.9 mol%. Phylogenetic analysis based on 16S rRNA gene sequences also indicated that the strain should be classified in the genus Dactylosporangium and showed that the closest relative was Dactylosporangium maewongense JCM 15933(T) (99.4 % similarity). These taxonomic data revealed that strain MW4-36(T) could be readily distinguished from its phylogenetically closest relative. On the basis of these phenotypic and genotypic data, strain MW4-36(T) is considered to represent a novel species, for which the name Dactylosporangium siamense sp. nov. is proposed. The type strain is MW4-36(T) ( = BCC 34901(T) = NBRC 106093(T)). PMID- 23728371 TI - Gemmobacter lanyuensis sp. nov., isolated from a freshwater spring. AB - A bacterial strain designated Orc-4(T) was isolated from a freshwater spring in Taiwan and characterized using the polyphasic taxonomic approach. Cells of strain Orc-4(T) were facultatively anaerobic, Gram-reaction-negative, poly-beta hydroxybutyrate-accumulating, non-motile rods surrounded by a thick capsule and forming cream-white colonies. Growth occurred at 15-40 degrees C (optimum, 25-30 degrees C), at pH 6.0-9.0 (optimum, pH 7.0) and with 0-1 % NaCl (optimum, 0-0.5 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain Orc 4(T) belonged to the genus Gemmobacter within the family Rhodobacteraceae of the class Alphaproteobacteria and its most closely related neighbour was Gemmobacter fontiphilus JS43(T) with sequence similarity of 97.8 %. Strain Orc-4(T) contained C18 : 1omega7c as the predominant fatty acid. The major respiratory quinone was Q 10. The DNA G+C content of the genomic DNA was 63.5 mol%. The polar lipid profile consisted of a mixture of phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, one uncharacterized aminolipid and several uncharacterized phospholipids. The DNA-DNA relatedness of strain Orc-4(T) with respect to recognized species of the genus Gemmobacter was less than 48 %. On the basis of the genotypic, chemotaxonomic and phenotypic data, strain Orc-4(T) represents a novel species of the genus Gemmobacter, for which the name Gemmobacter lanyuensis sp. nov. is proposed. The type strain is Orc-4(T) ( = BCRC 80378(T) = LMG 26667(T) = KCTC 23714(T)). PMID- 23728372 TI - Rudaibacter terrae gen. nov., sp. nov., isolated from greenhouse soil. AB - A novel Gram-stain-positive, non-motile, rod-shaped bacterium, designated 5GHs34 4(T), was isolated from greenhouse soil in Yongin, Republic of Korea. Growth occurred in the temperature range of 10-37 degrees C (optimum 28-30 degrees C) and at pH 5.0-9.0 (optimum pH 7.0). It can tolerate up to 3 % (w/v) NaCl. The strain showed 16S rRNA gene sequence similarity levels of 95.1-97.0 % with species of the genus Leifsonia, 95.7-96.7 % with species of the genus Herbiconiux, 95.1-96.4 % with species of the genus Salinibacterium and 96.1 % with Labedella gwakjiensis and Homoserinimonas aerilata. The highest sequence similarities (97.0 %) were with Leifsonia aquatica JCM 1368(T), Leifsonia poae VKM Ac-1401(T) and Leifsonia psychrotolerans LI1(T). The peptidoglycan type determined for strain 5GHs34-4(T) was B2gamma with dl-2,4-diaminobutyric acid at position 3. The murein was of the acetyl type. The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol and two unknown glycolipids. The menaquinones detected were MK-13, MK-12 and MK-14, and the major fatty acids were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c), anteiso-C17 : 0 and anteiso-C15 : 0. The phenotypic and phylogenetic traits of strain 5GHs34-4(T) differed in some respects from those of members of the family Microbacteriaceae. Therefore, strain 5GHs34-4(T) is considered to represent a novel species of a new genus in the family Microbacteriaceae, for which the name Rudaibacter terrae gen. nov., sp. nov. is proposed. The type strain is 5GHs34-4(T) ( = KACC 15523(T) = NBRC 108754(T)). PMID- 23728373 TI - Arsenicicoccus dermatophilus sp. nov., a hypha-forming bacterium isolated from the skin of greater flamingos (Phoenicopterus roseus) with pododermatitis. AB - Dermatophilus-like bacteria were observed in histological examinations of samples of diseased foot skin from greater flamingos (Phoenicopterus roseus) living in zoological gardens in Switzerland. When grown on TSA-SB containing polymyxin B, the bacteria isolated from these skin samples formed hyphae, as is typical for Dermatophilus congolensis, but these bacteria were non-haemolytic. The closest relatives based on 16S rRNA gene sequences were the two members of the genus Arsenicicoccus, Arsenicicoccus bolidensis and Arsenicicoccus piscis. A representative of the isolated strains shared 34.3 % DNA-DNA relatedness with the type strain of A. bolidensis, 32.3 % with the type strain of A. piscis and 34.5 % with the type strain of D. congolensis, demonstrating that these strains do not belong to any of these species. The phenotypic characteristics differed from those of members of the genus Arsenicicoccus as well as from those of D. congolensis. The G+C content of strain KM 894/11(T) was 71.6 mol%. The most abundant fatty acids were iso-C15 : 0, summed feature 3 (including C16 : 1omega7c and/or iso-C15 : 0 2-OH) and C18 : 1omega9c. MK-8(H4) was the predominant menaquinone. Cell-wall structure analysis revealed that the peptidoglycan type was A3gamma ll-Dpm-Gly (type A41.1). Based on genotypic and chemotaxonomic characteristics, the isolated strains represent a novel species within the genus Arsenicicoccus, for which the name Arsenicicoccus dermatophilus sp. nov. is proposed. The type strain is KM 894/11(T) ( = DSM 25571(T) = CCUG 62181(T) = CCOS 690(T)), and strain KM 1/12 ( = DSM 25572 = CCUG 62182 = CCOS 691) is a reference strain. PMID- 23728374 TI - Anoxybacillus vitaminiphilus sp. nov., a strictly aerobic and moderately thermophilic bacterium isolated from a hot spring. AB - A strictly aerobic, Gram-stain-positive, motile and spore-forming bacterium, strain 3nP4(T), was isolated from the Puge hot spring located in the south western geothermal area of China. Strain 3nP4(T) grew at 38-66 degrees C (optimum 57-60 degrees C), at pH 6.0-9.3 (optimum 7.0-7.5) and with 0-4 % (w/v) NaCl (optimum 0-0.5 %). Phylogenetic analysis of 16S rRNA gene sequences, as well as DNA-DNA relatedness values, indicated that the isolate represents a novel species of the genus Anoxybacillus, related most closely to Anoxybacillus voinovskiensis DSM 12111(T). Strain 3nP4(T) had diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and one unidentified phospholipid as major polar lipids and iso-C15 : 0 and iso-C17 : 0 as major fatty acids, which are both typical chemotaxonomic characteristics of the genus Anoxybacillus. The mean DNA G+C content of strain 3nP4(T) was 39.2+/-0.95 mol% (HPLC). A distinctive characteristic of the novel isolate was its extreme reliance on vitamin mixture or yeast extract for growth. Based on data from this taxonomic study using a polyphasic approach, strain 3nP4(T) is considered to represent a novel species of the genus Anoxybacillus, for which the name Anoxybacillus vitaminiphilus sp. nov. is proposed. The type strain is 3nP4(T) ( = CGMCC 1.8979(T) = JCM 16594(T)). PMID- 23728375 TI - Kroppenstedtia guangzhouensis sp. nov., a thermoactinomycete isolated from soil. AB - A Gram-stain-positive, spore-forming, aerobic and filamentous thermoactinomycete, designated GD02(T), was isolated from soil in south China. The isolate could grow in the presence of 0-3.0 % NaCl (w/v), at temperatures of 30-60 degrees C and at pH 5.5-9.5, forming ivory-coloured colonies. When the 16S rRNA gene sequence of the isolate was compared with those of other bacteria, the highest similarity was observed with Kroppenstedtia eburnea DSM 45196(T) (96.1 % 16S rRNA gene sequence similarity). The G+C content of the genomic DNA was 56.3 mol%, the cell-wall peptidoglycan contained ll-diaminopimelic acid, the main polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine and phosphatidylglycerol, and the major menaquinone was MK-7. The major cellular fatty acids (>5 %) were iso-C15 : 0, iso-C16 : 0, iso-C17 : 0 and anteiso-C15 : 0. On the basis of its phenotypic and phylogenetic properties, chemotaxonomic analysis and the results of physiological and biochemical tests, strain GD02(T) ( = CGMCC 1.12404(T) = KCTC 29149(T)) was designated the type strain of a novel species of the genus Kroppenstedtia, for which the name Kroppenstedtia guangzhouensis sp. nov. is proposed. PMID- 23728376 TI - Lactobacillus heilongjiangensis sp. nov., isolated from Chinese pickle. AB - A Gram-stain-positive bacterial strain, S4-3(T), was isolated from traditional pickle in Heilongjiang Province, China. The bacterium was characterized by a polyphasic approach, including 16S rRNA gene sequence analysis, pheS gene sequence analysis, rpoA gene sequence analysis, dnaK gene sequence analysis, fatty acid methyl ester (FAME) analysis, determination of DNA G+C content, DNA DNA hybridization and an analysis of phenotypic features. Strain S4-3(T) showed 97.9-98.7 % 16S rRNA gene sequence similarities, 84.4-94.1 % pheS gene sequence similarities and 94.4-96.9 % rpoA gene sequence similarities to the type strains of Lactobacillus nantensis, Lactobacillus mindensis, Lactobacillus crustorum, Lactobacillus futsaii, Lactobacillus farciminis and Lactobacillus kimchiensis. dnaK gene sequence similarities between S4-3(T) and Lactobacillus nantensis LMG 23510(T), Lactobacillus mindensis LMG 21932(T), Lactobacillus crustorum LMG 23699(T), Lactobacillus futsaii JCM 17355(T) and Lactobacillus farciminis LMG 9200(T) were 95.4, 91.5, 90.4, 91.7 and 93.1 %, respectively. Based upon the data obtained in the present study, a novel species, Lactobacillus heilongjiangensis sp. nov., is proposed and the type strain is S4-3(T) ( = LMG 26166(T) = NCIMB 14701(T)). PMID- 23728377 TI - Hazenella coriacea gen. nov., sp. nov., isolated from clinical specimens. AB - A Gram-staining-positive, endospore-forming rod was isolated independently from clinical specimens in New York State, USA, once in 2009 and twice in 2011. The three isolates had identical 16S rRNA gene sequences and, based on their 16S rRNA gene sequence, are most closely related to the type strains of Laceyella sediminis and L. sacchari (94.6 % similarity). The partial 23S rRNA gene sequences of the three strains were also 100 % identical. Maximum-likelihood phylogenetic analysis suggests that the new isolates belong to the family Thermoactinomycetaceae. Additional biochemical and phenotypic characteristics of the strains support the family designation and suggest that the three isolates represent a single species. In each of the strains, the predominant menaquinone is MK-7, the diagnostic diamino acid is meso-diaminopimelic acid and the major cellular fatty acids are iso-C15 : 0, anteiso-C15 : 0 and iso-C13 : 0. The polar lipids are phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, four unknown phospholipids, four unknown aminophospholipids and an unknown lipid. It is proposed that the novel isolates represent a single novel species within a new genus, for which the name Hazenella coriacea gen. nov., sp. nov. is proposed. The type strain of Hazenella coriacea is strain 23436(T) ( = DSM 45707(T) = LMG 27204(T)). PMID- 23728379 TI - A novel ex vivo culture method for the embryonic mouse heart. AB - Developmental studies in the mouse are hampered by the inaccessibility of the embryo during gestation. Thus, protocols to isolate and culture individual organs of interest are essential to provide a method of both visualizing changes in development and allowing novel treatment strategies. To promote the long-term culture of the embryonic heart at late stages of gestation, we developed a protocol in which the excised heart is cultured in a semi-solid, dilute Matrigel. This substrate provides enough support to maintain the three-dimensional structure but is flexible enough to allow continued contraction. In brief, hearts are excised from the embryo and placed in a mixture of cold Matrigel diluted 1:1 with growth medium. After the diluted Matrigel solidifies, growth medium is added to the culture dish. Hearts excised as late as embryonic day 16.5 were viable for four days post-dissection. Analysis of the coronary plexus shows that this method does not disrupt coronary vascular development. Thus, we present a novel method for long-term culture of embryonic hearts. PMID- 23728378 TI - Mycobacterium sediminis sp. nov. and Mycobacterium arabiense sp. nov., two rapidly growing members of the genus Mycobacterium. AB - Two novel isolates of rapidly growing, Gram-stain-positive, non-chromogenic species of the genus Mycobacterium, strain YIM M13028(T) from a sediment sample collected from the South China Sea (19 degrees 30.261' N 111 degrees 0.247' E) at a depth of 42 m and strain YIM 121001(T) from a coastal zone sand sample collected in Dubai, United Arab Emirates, were obtained in our laboratory. Their taxonomic positions were determined by a polyphasic approach. Good growth of the two strains was observed at 28 degrees C and pH 7.0 with 0-2 % NaCl on tryptic soy agar medium. Both strains formed round orange-red colonies, strain YIM M13028(T) had a rough surface, while YIM 121001(T) was smooth. Cellular fatty acids, whole-cell protein profiles and TLC analysis of their mycolic acids show significant differences from reference stains. Phenotypic characteristics and multilocus sequence analysis (MLSA) of 16S rRNA gene, hsp65, rpoB and 16S-23S internal transcribed spacer (ITS) sequences indicated that both strains YIM M13028(T) and YIM 121001(T) belong to the genus Mycobacterium. DNA-DNA hybridization values revealed a low relatedness (<70 %) of the two isolates with the type strains Mycobacterium neoaurum DSM 44074(T) and Mycobacterium hodleri DSM 44183(T). The low DNA-DNA hybridization values (40.4+/-3.5 %) between strains YIM M13028(T) and YIM 121001(T) and phenotypic distinctiveness indicated that the two strains were representatives of different novel species of the genus Mycobacterium. The names proposed for these novel species are Mycobacterium sediminis sp. nov. and Mycobacterium arabiense sp. nov., and the type strains are YIM M13028(T) ( = DSM 45643(T) = KCTC 19999(T)) and YIM 121001(T) ( = DSM 45768(T) = JCM 18538(T)), respectively. PMID- 23728380 TI - Specific enhancement of vascular endothelial growth factor (VEGF) production in ischemic region by alprostadil--potential therapeutic application in pharmaceutical regenerative medicine. AB - Alprostadil (lipo-PGE1) is a drug delivery system preparation. This preparation is applied to treat refractory skin ulcers and arteriosclerosis obliterans. We investigated the effects of alprostadil by using the earflap ischemic model. The following results were obtained: 1) Treatment with alprostadil significantly increased the VEGF contents in an ischemic ear; 2) Treatment with alprostadil resulted in strongly expressed VEGF levels only in the ischemic region; 3) Image analysis revealed a significant increase in the number of vessel bypasses and paths after flap creation with alprostadil administration compared to the vehicle treated ears. The results suggest that it may be possible to apply alprostadil as one device for regenerative medical technology. PMID- 23728381 TI - Orally administered selective TRPV1 antagonist, JTS-653, attenuates chronic pain refractory to non-steroidal anti-inflammatory drugs in rats and mice including post-herpetic pain. AB - Chronic pain refractory to non-steroidal anti-inflammatory drugs (NSAIDs) is a major problem and drugs for such pain are needed. Many studies suggest that transient receptor potential vanilloid type 1 (TRPV1) is associated with NSAID refractory chronic pain. Therefore, we investigated the involvement of TRPV1 in NSAID-refractory chronic pain using experimental models for NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. The selective TRPV1 antagonist JTS-653 {(3S)-3-(hydroxymethyl)-4-(5-methylpyridin-2-yl)-N-[6 (2,2,2-trifluoroethoxy)pyridin-3-yl]-3,4-dihydro-2H-benzo[b][1,4]oxazine-8 carboxamide} reversed mechanical hyperalgesia on day 7 after injection of complete-Freund-adjuvant into the hindpaw in rats at 0.3 mg/kg, whereas indomethacin showed no effect. JTS-653 reduced chronic pain at 0.3 mg/kg in herpes simplex virus-1-inoculated mice that has been reported as NSAID-refractory pain. JTS-653 partially attenuated mechanical hyperalgesia in the L5 spinal nerve ligation model in rats at 0.3 mg/kg, whereas indomethacin showed no effect. Both JTS-653 and indomethacin reduced formalin-induced pain in the second phase, whereas they showed no effect in the first phase. JTS-653 did not affect the nociception of noxious thermal and mechanical stimuli and motor coordination in normal rats. These findings demonstrate the TRPV1 involvement in NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. TRPV1 antagonists would be useful for the treatment of NSAID-refractory chronic pain. PMID- 23728382 TI - Cerebral oxygenation and brain activity after perinatal asphyxia: does hypothermia change their prognostic value? AB - BACKGROUND: Hypothermia is an established therapy in term neonates to reduce death and disability after perinatal asphyxia. Near-infrared spectroscopy monitored regional cerebral oxygen saturation (rScO2) and amplitude-integrated electroencephalogram (aEEG)-monitored background pattern have been shown to be early predictors of long-term neurodevelopmental outcome. The aim of this study was to investigate the prognostic value of rScO2 and aEEG for neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy (HIE) treated with hypothermia. METHODS: In neonates with HIE who were subjected to hypothermia, the aEEG background pattern and rScO2 were studied prospectively from admission up to 84 h in relation to early magnetic resonance imaging and neurodevelopmental outcome at 18 mo of age. RESULTS: Of 39 infants, 12 neonates died because of neurological deterioration. One had an adverse outcome and 26 had a favorable outcome. The rScO2 was higher in neonates with adverse outcome, although aEEG scores were lower. Positive predictive values at 12, 24, and 36 h of age for adverse outcome ranged from 50 to 67% for rScO2 and aEEG; negative predictive values ranged from 73 to 96% for rScO2 and 90 to 100% for aEEG. Combining rScO2 and aEEG increased positive predictive values (70-91%) and negative predictive values (90-100%). CONCLUSION: During hypothermia, rScO2 and aEEG measurements are early predictors of long-term outcome after HIE. Combining both parameters further improves early prediction. PMID- 23728383 TI - SNAT2 expression and regulation in human growth-restricted placentas. AB - BACKGROUND: Amino acid placental delivery is reduced in human intrauterine growth restricted (IUGR) fetuses, and the activity of placental amino transporters has been consistently shown to be decreased in in vitro studies. We hypothesized lower placental expression and localization of sodium-coupled neutral amino acid transporter 2 (SNAT2 (also known as SLC38A2)), altered levels of intron-1 methylation, and altered distribution of single-nucleotide polymorphisms in human IUGR vs. normal pregnancies. METHODS: We studied 88 IUGR and 84 control placentas from singleton pregnancies at elective caesarean section. SNAT2 expression was investigated by real-time PCR and immunohistochemistry. Intron-1 methylation levels were analyzed by pyrosequencing, and single-nucleotide polymorphism distribution was analyzed by allelic discrimination. RESULTS: mRNA levels were significantly decreased in IUGR placentas with reduced umbilical blood flows. Syncytiotrophoblast immunostaining was lower in IUGR placentas than in control placentas. Methylation levels were steadily low in both IUGR and control placentas. SNP genotype and allele frequencies did not differ between the two groups. CONCLUSION: This is the first study investigating SNAT2 expression and regulation mechanisms in human IUGR placentas. We confirm previous results obtained in rats and cell cultures that support the fundamental role of SNAT2 in fetal growth and well-being, as well as a possible role of oxygen levels in regulating SNAT2 expression, indicating the relevance of hypoxia in IUGR. PMID- 23728385 TI - Erythropoietin prevents lymphoid apoptosis but has no effect on survival in experimental sepsis. AB - BACKGROUND: Lymphoid apoptosis in sepsis is associated with poor outcome, and prevention of apoptosis frequently improves survival in experimental models of sepsis. Recently, erythropoietin (EPO) was shown to protect against lipopolysaccharide (LPS)-induced mortality. As cecal ligation and puncture (CLP) is a clinically more relevant model of sepsis, we evaluated the effect of EPO on CLP-induced lymphoid tissue apoptosis and mortality. METHODS: Young Wistar rats were subjected to polymicrobial sepsis by CLP. EPO (5,000 U/kg intraperitoneal) was administered 30 min before CLP and then 1 and 4 h after CLP. Spleen, thymus, and small intestine were harvested at 24 h and assessed for apoptosis by terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) and caspase-3 staining. A separate group of animals was followed up for mortality. RESULTS: Splenic, thymic, and intestinal apoptosis was increased after CLP; administration of EPO significantly decreased apoptosis as determined by TUNEL and caspase-3 staining. Final survival in the CLP mortality study was 30% in both saline and EPO groups. CONCLUSION: Our results provide the first evidence that EPO attenuates lymphoid apoptosis in the CLP model of sepsis. However, EPO is not associated with a survival benefit in the CLP model of sepsis. PMID- 23728384 TI - Transgenic sickle cell disease mice have high mortality and dysregulated immune responses after vaccination. AB - BACKGROUND: Children with sickle cell disease (SCD) are susceptible to recurrent infections, which are often life threatening and necessitate frequent vaccinations. Given the altered baseline immunity and proinflammatory state associated with SCD, we sought to determine the relative safety and efficacy of vaccination in transgenic SCD mice. METHODS: Eight-week-old SCD mice were vaccinated with ovalbumin and aluminum hydroxide weekly for 3 wk by the intraperitoneal or intramuscular route. One week after the third vaccination, serum cytokines/chemokines, immunoglobulins, and bronchoalveolar lavage fluid cytokines were measured. RESULTS: Only SCD mice were prone to mortality associated with vaccination, as 40% of the animals died after the intraperitoneal vaccinations and 50% died after the intramuscular vaccinations. Serum IgG2b and IgM were significantly lower in SCD mice than in C57BL/6 mice after vaccination, but ovalbumin-specific IgE was significantly higher. Serum interleukin (IL) 1alpha, IL-2, IL-5, macrophage inflammatory protein 1alpha, and granulocyte macrophage-colony stimulating factor were significantly lower in SCD mice than in C57BL/6 mice after vaccination, whereas bronchoalveolar lavage fluid IL-1beta and IL-6 were increased. CONCLUSION: Mice with SCD appear to have a dysregulated immune response to vaccination. Thus, the relative safety and immunogenicity of vaccination should be studied in greater detail in the context of SCD. PMID- 23728386 TI - Solitary intestinal neurofibroma with no associated systemic syndromes causing intussusception: Case report and literature review. AB - INTRODUCTION: The isolated presence of neurofibromatous lesions in the gastrointestinal tract, with no associated systemic syndromes, is a rarely reported clinical entity. PRESENTATION OF CASE: A 48-year-old lady, with no history of neurofibromatosis or other systemic disease, presented with small bowel obstruction secondary to an ileo-ileal intussusception induced by an isolated ileal neurofibromatous mass. The patient underwent a segmental enterectomy and after a smooth recovery, she was put on a long-term follow-up schedule. DISCUSSION: This article presents a review of the literature of this area clinical entity. Very few reports of gastrointestinal isolated neurofibromas could be found. Similarly, extra-digestive isolated lesions have been rarely reported. CONCLUSION: Isolated ileal neurofibroma is a rare pathological entity. The clinical significance of such a diagnosis lies mainly in the need of further follow up of these patients as the bowel involvement could be the first manifestation of neurofibromatosis type 1 or multiple endocrine neoplasia type 2b. PMID- 23728387 TI - An infected urachal cyst presenting as an acute abdomen - A case report. AB - INTRODUCTION: An infected urachal cyst is one of a spectrum of presentations of urachal pathology, all of which are rare in adulthood. PRESENTATION OF CASE: We report the case of a 45-year-old obese Russian lady who presented with a 2-week history of suprapubic pain radiating to the right iliac fossa. Although previously fit and well, she had a history of 17 miscarriages. Both USS and CT suggested a complicated inflammatory mass in the lower abdomen. Ultimately the diagnosis was made by laparotomy, which revealed an abscess of an urachal cyst. The infected cyst and bladder dome were excised. The patient made a good recovery with an uneventful follow up. DISCUSSION: Urachal cysts are the commonest type of urachal anomaly. Infection is the usual mode of presentation amongst adult cases otherwise the condition usually remains asymptomatic. An infected urachal cyst is an important diagnosis to make as complications include sepsis, fistula formation, and rupture leading to peritonitis. Treatment is by complete excision, however, techniques have been debated. CONCLUSION: This is a rare but important diagnosis however we recommend that in patients with atypical histories, it should be included in the differential diagnosis. PMID- 23728388 TI - Staphylococcus aureus abscesses: methicillin-resistance or Panton-Valentine leukocidin presence? AB - INTRODUCTION: Panton-Valentine leukocidin (PVL) is a toxin associated with community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) worldwide and also occurs in community-associated methicillin-susceptible S aureus (CA-MSSA) strains. The aims of the study were to determine the prevalence of PVL in community-onset S aureus skin and soft-tissue infections (SSTIs) and to analyse the influence of methicillin resistance and PVL presence on the clinical characteristics of these infections. PATIENTS AND METHODS: We prospectively enrolled all children with S aureus community-onset SSTIs attending the emergency department of a tertiary hospital between 2007 and 2009. Results A total of 142 S aureus SSTIs were identified, 46 (32%) were PVL positive. The proportion of subjects in each group was: 89 (63%) PVL-MSSA, 33 (23%) PVL+MSSA, 13 (9%) PVL+MRSA and 7 (5%) PVL-MRSA. PVL+infections were more frequently abscesses (63% vs 39%, p<0.01), and more often required incision and drainage (p<0.01) and hospital admission (46% vs 26%, p=0.02). MRSA infections were also more frequently associated with abscesses but in a multivariable analysis only PVL remained independently related (OR 2.33; 95% CI 1.10 to 4.90). CONCLUSIONS: Our study found a high prevalence of PVL presence in community-onset S aureus SSTIs in children in Spain. This toxin is associated with more abscess formation, regardless of methicillin resistance. PMID- 23728389 TI - Co-regulation of exine wall patterning, pollen fertility and anther dehiscence by Arabidopsis apyrases 6 and 7. AB - An NCBI nucleotide blast keyed to apyrase (ATP-diphosphohydrolases, EC 3.6.1.5) conserved regions revealed five apyrases, AtAPYs (3-7), in addition to the previously identified AtAPY1 and 2. Here we report the functional analyses of two of the newly defined apyrases, AtAPY6 and AtAPY7. We analyzed tissue specificity of AtAPY6 and 7 expression by qRT-PCR and promoter:GUS fusion assays. We characterized the phenotypes of single and double knockout mutants for AtAPY6 and 7 in anther and pollen by light microscopy and electron microscopy. The transcripts of both AtAPY6 and 7 are expressed in mature pollen grains. Single knockout mutants of AtAPY6 and 7 displayed a minor change in pollen exine pattern under scanning electron microscopy without obvious change in fertility. Double knockout mutants of AtAPY6 and 7 (apy6apy7) displayed severe defects in pollen exine pattern, deformed pollen shape and reduced male fertility. An analysis of pollen from heterozygous apy6apy7 plants suggests that the defects in pollen exine wall are determined by the diploid genome. Our findings demonstrate that AtAPY6 and AtAPY7 are enzymes that play an important role in exine development of pollen grains, possibly through regulating the production of key polysaccharides needed for proper assembly of the exine layer. PMID- 23728390 TI - NtNAC-R1, a novel NAC transcription factor gene in tobacco roots, responds to mechanical damage of shoot meristem. AB - Topping is the important agronomic measure for flue-cured tobacco, and results in increase of the nicotine content in top leaves. Nicotine content is one of the vitals factors for the quality of tobacco leaves. Nicotine is exclusively synthesized in tobacco roots, and then transported to the leaves through the xylem. To investigate the molecular mechanism of increase in nicotine biosynthesis ability following topping, some responses of tobacco roots to topping were analyzed, and the role of NtNAC-R1 in regulating nicotine synthesis and the development of roots was discussed. The electronic cloning technique combined with RT-PCR was successfully used to clone NtNAC-R1 from tobacco roots. The number of lateral root and nicotine contents in tobacco roots increased following topping. Although spraying MeJA on leaves had no effects on the root phenotype, the nicotine contents and the expression of PMT increased markedly. The miR164 was down-regulated, and NtNAC-R1 was up-regulated in tobacco roots after topping. PMT and ODC were down-regulated in transgenic tobacco with antisense NtNAC-R1, and PMT was up-regulated in transgenic tobacco with over expressed NtNAC-R1. In conclusion, topping can induce the decrease of miR164 and the increase of IAA content in roots, which up-regulate the expression of NtNAC R1, resulting in the increase of lateral roots and nicotine contents. Meanwhile, topping is a mechanical wounding which can induce JA signal, and JA can enhance nicotine biosynthesis in tobacco roots. So the increase of nicotine biosynthesis ability would be related to cross-talking of JA and auxin signaling pathway after topping. PMID- 23728391 TI - Overexpression of TsGOLS2, a galactinol synthase, in Arabidopsis thaliana enhances tolerance to high salinity and osmotic stresses. AB - Galactinol synthase (GOLS, EC 2.4.1.123), a key enzyme in the synthesis of raffinose family oligosaccharides (RFOs), catalyzes the condensation of UDP galactose with myo-inositol to produce galactinol as the sole donor for the synthesis of RFOs. RFOs have been implicated in mitigating effects of environmental stresses on plants. TsGOLS2, was cloned from Thellungiella salsuginea with high homology to AtGOLS2. TsGOLS2 was up-regulated by several abiotic stresses. We overexpressed TsGOLS2 in Arabidopsis thaliana. The contents of galactinol, raffinose, and alpha-ketoglutaric acid were significantly increased in transgenic plants. Compared to wild type plants, salt-stressed transgenic A. thaliana exhibited higher germination rate, photosynthesis ability, and seedling growth. After being treated with osmotic stress by high concentration of sorbitol, transgenic plants retained high germination rates and grew well during early development. These results indicated that overexpression of TsGOLS2 in A. thaliana improved the tolerance of transgenic plants to high salinity and osmotic stress. PMID- 23728392 TI - Expression of rd29A::AtDREB1A/CBF3 in tomato alleviates drought-induced oxidative stress by regulating key enzymatic and non-enzymatic antioxidants. AB - Transgenic tomato lines (cv. Kashi Vishesh) over-expressing AtDREB1A/CBF3 driven by stress-inducible rd29A promoter showed significantly higher activities of key antioxidant enzymes when exposed to water-deficit for 7, 14, and 21 days. Transgenic tomato plants exposed to water-deficit recorded lower levels of hydrogen peroxide and superoxide anion formation compared to the non-transgenic plants, suggesting alleviation of reactive oxygen species (ROS). A significant increase in activities of enzymes superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), glutathione reductase (GR), dehydroascorbate reductase (DHAR), and monodehydroascorbate reductase (MDHAR) was observed in response to the different durations of water-deficit conditions. In contrast, enzyme guaiacol peroxidase (POD) activity was lower in the transgenic lines and showed a negative correlation with ROS, ascorbic acid (AsA), and glutathione levels. The concentrations of AsA, glutathione and their reduced forms were higher in the transgenic plants and increased with ROS levels. These results indicate that AtDREB1A transgenic tomato lines are better adapted to water deficit as they showed lower drought-induced oxidative stress due to activation of the antioxidant response. PMID- 23728393 TI - Metabolites of Ammopiptanthus mongolicus induced by Orgyia ericae attack and mechanical wounding. AB - In plants attacked by insects, metabolic changes can reflect the direct and indirect ability of those plants to resist infestation. However, the metabolic pathways involved in this process remain unclear, especially for plants which belong to ancient Tertiary relict taxon. To analyze the changes in metabolites and identify specific metabolic patterns induced by herbivorous and continuous mechanical wounding, the metabolism of Ammopiptanthus mongolicus seedlings damaged by Orgyia ericae Germar or continuous mechanical wounding were analyzed using nuclear magnetic resonance (NMR) combined with multivariate data analysis (MVDA). Principal component analysis (PCA) and orthogonal signal correction projections to latent structure discriminate analysis (OPLS-DA) showed that O. ericae feeding and mechanical wounding induced different changes in the metabolic profile of A. mongolicus both in local and systemic leaves. O. ericae feeding was associated with higher concentrations of many primary and secondary metabolites in local and systemic leaves than continuous mechanical wounding. In this way, the response of A. mongolicus to wounding was shown to be both specific to the metabolism, systemic, and to involve both primary and secondary metabolic pathways. PMID- 23728394 TI - Early development of PAT-SM6 for the treatment of melanoma. AB - Despite the recent development of novel therapies for patients with metastatic melanoma, this disease remains fatal in the majority of those who develop a relapse. Here, we report the preclinical and early clinical development of a novel IgM antibody PAT-SM6 that specifically binds to a cancer-specific isoform of glucose-regulated protein 78 (GRP78) and low-density lipoprotein. Finding a GRP78 cancer-specific form on the surface of cancer cells, but not normal cells in vivo, presents an opportunity for cancer-specific targeting. PAT-SM6 binding to the cell surface induces apoptosis in a variety of tumors, including melanoma. Recent studies show the specificity of PAT-SM6 binding to the surface of melanoma cells and primary tissue but not to normal tissue. They also confirm, for the first time, cell proliferation inhibition and apoptosis through classical apoptotic pathways as well as induction of lipid accumulation in melanoma cells. These in-vitro data are supported by positive in-vivo data using PAT-SM6 in a xenograft C8161 model. Furthermore, PAT-SM6 was well tolerated in pharmacokinetic/toxicology studies in monkeys. On the basis of these preclinical observations, a clinical study of PAT-SM6 was carried out in patients with 'in transit' melanoma. Even with microdosing, histological analyses of tumor biopsies detected the presence of PAT-SM6 as well as apoptosis. Although there are many small molecules and monoclonal antibodies currently in clinical development for patients with melanoma, PAT-SM6 is the only therapeutic targeting the cancer specific isoform of GRP78. These PAT-SM6 preclinical data and positive findings from the phase 1 safety study provide strong support for the further development of this novel antibody. PMID- 23728395 TI - Intracranial hypotension with a sixth cranial nerve palsy subsequent to massive thoracic CSF hygroma: a rare complication of thoracic disc excision. AB - BACKGROUND: Thoracic cerebrospinal fluid (CSF) hygroma is a rare and potentially devastating complication of the anterior thoracic approach to the spine. We present two cases in which this complication resulted in acute cranial nerve palsy and discuss the pathoanatomy and management options in this scenario. CASE REPORTS: Two male patients presented to our department with neurological deterioration due to a giant herniated thoracic disc. The extruded disc fragment was noted pre-operatively to be calcified in both patients. A durotomy was performed at primary disc prolapse resection in the first patient, whereas an incidental durotomy during the procedure caused complication in the second patient. These were repaired primarily or sealed with Tachosil((r)). Both patients re-presented with acute diplopia. Imaging of both patients confirmed a massive thoracic cerebrospinal fluid hygroma and evidence of intracranial changes in keeping with intracranial hypotension, but no obvious brain stem shift. The hemithorax was re-explored and the dural repair was revised. The first patient made a full recovery within 3 months. The second patient was managed conservatively and took 5 months for improvement in his ophthalmic symptoms. CONCLUSIONS: The risk of CSF leakage post-dural repair into the thoracic cavity is raised due to local factors related to the chest cavity. Dural repairs can fail in the presence of an acute increase in CSF pressure, for example whilst sneezing. Intracranial hypotension can result in subsequent hygroma and possibly haematoma formation. The resultant cranial nerve palsy may be managed expectantly except in the setting of symptomatic subdural haematoma or compressive pneumocephaly. PMID- 23728396 TI - Expert's comment concerning Grand Rounds case entitled ''Intracranial hypotension with a sixth cranial nerve palsy subsequent to massive thoracic CSF hygroma: a rare complication of thoracic disc excision" (by A. Khurana, J. Brousil, A. Russo, A. Evans, N. A. Quraishi, B. M. Boszczyk doi:10.1007/s00586-013-2818-1). PMID- 23728397 TI - Hepatic myelopathy with spastic paraparesis: report of two cases and review of the literature. AB - PURPOSE: The present report illustrates two men aged for 59 and 43 years, respectively, who presented with slowly progressive spastic paraparesis. STUDY DESIGN: Two case reports and review of literature. METHODS: The patent's history, clinical examination, biology, magnetic resonance imaging (MRI) findings and treatment are reported. We also discuss the pathogenesis and various treatment options. RESULTS: Neurologic examination showed spastic paraparesis without other neurological disorders. MRI of the spinal cord and brain were normal. Cytologic examination of cerebrospinal fluid from each patient was normal. Hemogram disclosed a pancytopenia. Partial thromboplastin time was prolonged. Liver function tests revealed raised serum bilirubin, normal alanine aminotransferase and aspartate aminotransferase, reduced total protein and albumin. Plasma ammonia was elevated. Blood vitamin B12 and folate values were in normal ranges. Serum antibodies to human T cell lymphotropic virus, human immunodeficiency virus, syphilis and hepatitis C virus were absent. Hepatitis B virus antibody assay was positive. The electromyographic evaluation for second motor neuron involvement was also normal. Endoscopy revealed esophageal varices and a spleno-renal shunt. CONCLUSIONS: Hepatic myelopathy remains a default diagnosis assigned only after the exclusion of other causes of spastic paraparesis and partial transverse myelopathy. An accurate history, along with appropriate imaging and laboratory findings, is crucial. PMID- 23728398 TI - Triton X-100 for three-plasmon gold nanostars with two photothermally active NIR (near IR) and SWIR (short-wavelength IR) channels. AB - Five-branched gold nanostars are obtained using Triton X-100 in a seed-growth synthesis. They have the uncommon feature of two intense localized surface plasmon resonances (LSPRs) in the 600-900 and 1100-1600 nm ranges. Both LSPRs convert laser radiation into heat, offering two photothermally active channels in the NIR and SWIR ranges. PMID- 23728400 TI - COPD: CardiOPulmonary Disease? PMID- 23728401 TI - Arrhythmias and conduction disturbances in obstructive sleep apnoea: the heart of the problem? PMID- 23728402 TI - Clustering in asthma: why, how and for how long? PMID- 23728403 TI - Lung function, race and ethnicity: a conundrum. PMID- 23728404 TI - Pulmonary arteriole gene expression signature in idiopathic pulmonary fibrosis. AB - A third of patients with idiopathic pulmonary fibrosis (IPF) develop pulmonary hypertension (PH-IPF), which is associated with increased mortality. Whether an altered gene expression profile in the pulmonary vasculature precedes the clinical onset of PH-IPF is unknown. We compared gene expression in the pulmonary vasculature of IPF patients with and without PH with controls. Pulmonary arterioles were isolated using laser capture microdissection from 16 IPF patients: eight with PH (PH-IPF) and eight with no PH (NPH-IPF), and seven controls. Probe was prepared from extracted RNA, and hybridised to Affymetrix Hu133 2.0 Plus genechips. Biometric Research Branch array tools and Ingenuity Pathway Analysis software were used for analysis of the microarray data. Univariate analysis revealed 255 genes that distinguished IPF arterioles from controls (p<0.001). Mediators of vascular smooth muscle and endothelial cell proliferation, Wnt signalling and apoptosis were differentially expressed in IPF arterioles. Unsupervised and supervised clustering analyses revealed similar gene expression in PH-IPF and NPH-IPF arterioles. The pulmonary arteriolar gene expression profile is similar in IPF patients with and without coexistent PH. Pathways involved in vascular proliferation and aberrant apoptosis, which may contribute to pulmonary vascular remodelling, are activated in IPF patients. PMID- 23728405 TI - Sarcoidosis in donor-derived tissues after haematopoietic stem cell transplantation. PMID- 23728406 TI - Disturbance of respiratory muscle control in a patient with early-stage multiple sclerosis. PMID- 23728407 TI - Multidrug-resistant tuberculosis in UK children: presentation, management and outcome. PMID- 23728408 TI - Risk of tuberculosis among contacts in a low-incidence setting. PMID- 23728409 TI - Using the Chartis system to selectively target a lung segment with a persistent air leak. PMID- 23728410 TI - Simvastatin-induced effects on bronchial epithelial cells from COPD donors. PMID- 23728411 TI - Complexities of oestradiol pharmacology in pulmonary arterial hypertension. PMID- 23728412 TI - Complexities of oestradiol pharmacology in pulmonary arterial hypertension. PMID- 23728414 TI - Structural properties of trans hydrido-hydroxo M(H)(OH)(NH2CMe2CMe2NH2)(PPh3)2 (M = Ru, Os) complexes and their proton exchange behaviour with water in solution. AB - We report the synthesis of Ru(II) and Os(II) trans hydrido-hydroxo complexes by reacting the unsaturated amido complexes MH(NHCMe2CMe2NH2)(PPh3)2 (M = Ru, Os) with stoichiometric amounts of water. Proton exchange is rapid at room temperature between the amine/water/hydroxide moieties which leads to signal averaging of the NMR properties which can be slowed at low temperature in order to see resonances of separate complexes. These compounds can also be cleanly converted back to their starting complexes by dehydration in the presence of 3 A molecular sieves. X-ray crystal structures of these Ru(II) and Os(II) trans hydrido-hydroxo complexes reveal that the unit cell contains an additional molecule of water trapped in the crystal lattice which hydrogen bonds with a neighbouring hydroxo ligand, forming a water bridged dimer in the solid state. Although there are many cases of oxidative addition of water to transition metal complexes, relatively few cases are well characterized where water addition occurs via metal-ligand cooperation (bifunctional addition) without altering the oxidation state of the metal center. PMID- 23728415 TI - Symptom reduction identified after offering animal-assisted activity at a cancer infusion center. PMID- 23728416 TI - Patient-provider delays in superior vena caval obstruction of lung cancer and outcomes. AB - This retrospective study investigates the types of delay in the initiation of palliative thoracic radiotherapy for superior vena caval obstruction (SVCO) of lung cancer (LCa) and the effect of treatment delay on patient outcomes. Treatment delays were categorized as patient delay (duration of symptoms), in hospital delay, and professional delay and were determined in 42 people treated by radiation for palliation of the complicated neoplastic condition between 1981 and 2009. The median period of patient delay was 26.2 days, in-hospital delay was 3.5 days, and professional delay was 1.5 days. The majority (80%) of these individuals were uninsured or underinsured, and 69% presented with locally advanced LCa. The overall response rate was 84%, and the 1-year survival rate was 24%. Despite the longest patient-related delay, symptomatic individuals overall derived palliation from conventional treatment. Improved efforts toward early diagnosis and treatment of patients with SVCO-LCa need to be continued. PMID- 23728417 TI - No difference in patellar tracking between symmetrical and asymmetrical femoral component designs in TKA. AB - PURPOSE: Poor knee extension function after total knee arthroplasty (TKA) is associated with factors including articular geometry and alignment. Femoral trochlear geometry has evolved from symmetrical to become more prominent proximal laterally, with the groove aligned proximal-lateral to distal-medial. This study in vitro tested the hypothesis that a modern asymmetrical prosthesis would restore patellar tracking and stability to more natural behaviour than an older symmetrical prosthesis. METHODS: Six knees had their patellar tracking measured optically during active knee extension. Medial-lateral force versus displacement stability was measured at fixed angles of knee flexion. The measurements were repeated after inserting each of the symmetrical and asymmetrical TKAs. RESULTS: Significant differences of patellar lateral displacement stability, compared to normal, were not found at any angle of knee flexion. The patella tracked medial laterally within 2.5 mm of the natural path with both TKAs. However, for both TKAs near knee extension, the patella was tilted laterally by approximately 6 degrees and was also flexed approximately 8 degrees more than in the natural knee. CONCLUSION: The hypothesis was not supported: The more anatomical component design did not provide more anatomical patellar kinematics and stability. PMID- 23728418 TI - Progression of patellar tendinitis following treatment with platelet-rich plasma: case reports. AB - PURPOSE: The use of platelet-rich plasma (PRP) is becoming more attractive given its favourable side effect profile and autologous nature, leading to rapid clinical adoption in the absence of high-level evidence. We are presenting three patients who developed a progression of patellar tendinitis following treatment, which to our knowledge is the first report of worsening of patellar tendinitis following PRP therapy. METHODS: The records of three patients with symptom exacerbation of patellar tendinitis following treatment with PRP were reviewed. IRB exemption was obtained. Clinical and operative records, radiographs, and MR imaging were reviewed for all patients. RESULTS: Three patients reported to our clinic for a second opinion with symptoms of anterior knee pain consistent with patellar tendinitis. Each patient had previously been treated with PRP therapy due to prolonged symptoms. Clinical and radiological findings following treatment included patellar tendon thickening, worsening pain, discontinuation of athletic participation in all three patients, and osteolysis of the distal pole of the patella in one patient identified during surgical intervention. CONCLUSIONS: Growing interest in the use of autologous products for the management of chronic tendinopathies has led to widespread clinical implementation with minimal scientific support. It is tempting to apply a new treatment for management of a difficult clinical entity, especially when the risk/benefit ratio appears favourable. However, caution must be exercised as unexpected results may be encountered. LEVEL OF EVIDENCE: Case reports, level V. PMID- 23728419 TI - Informed consent as an ethical requirement in clinical trials: an old, but still unresolved issue. An observational study to evaluate patient's informed consent comprehension. AB - We explored the comprehension of the informed consent in 77 cancer patients previously enrolled in randomised phase II or phase III clinical trials, between March and July 2011, at the San Raffaele Scientific Institute in Milano. We asked participants to complete an ad hoc questionnaire and analysed their answers. Sixty-two per cent of the patients understood the purpose and nature of the trial they were participating in; 44% understood the study procedures and 40% correctly listed at least one of the major risks or complications related to their participation in the trial. We identified three factors associated with comprehension of the informed consent: age, education and type of tumour/investigator team. We suggest several possible improvements of how to obtain informed consent that will increase patient awareness, as well as the validity and effectiveness of the clinical trials. PMID- 23728421 TI - Evaluations of circumcision should be circumscribed by the evidence. PMID- 23728422 TI - A submicron broadband surface-plasmon-polariton unidirectional coupler. AB - The manipulation of light propagation is a basic subject in optics and has many important applications. With the development of nano-optics, this area has been downscaled to wavelength or even subwavelength scales. One of the most efficient ways to control light propagation is to exploit interference effects. Here, by manipulating the interference between two nanogrooves on a metal surface, we realize a submicron broadband surface-plasmon-polariton (SPP) unidirectional coupler. More importantly, we find an anomalous bandwidth shrinking behavior in the proposed SPP unidirectional coupler as the groove separation is down to a subwavelength scale of one-quarter of the SPP wavelength. This abnormal behavior is well explained by considering the contribution of the near-field quasi cylindrical waves in addition to the interference of propagating SPPs and the dispersion effects of individual grooves. Such near-field effects provide new opportunities for the design of ultracompact optical devices. PMID- 23728423 TI - A spindle-independent cleavage pathway controls germ cell formation in Drosophila. AB - The primordial germ cells (PGCs) are the first cells to form during Drosophila melanogaster embryogenesis. Whereas the process of somatic cell formation has been studied in detail, the mechanics of PGC formation are poorly understood. Here, using four-dimensional multi-photon imaging combined with genetic and pharmacological manipulations, we find that PGC formation requires an anaphase spindle-independent cleavage pathway. In addition to using core regulators of cleavage, including the small GTPase RhoA (Drosophila rho1) and the Rho associated kinase, ROCK (Drosophila drok), we show that this pathway requires Germ cell-less (GCL), a conserved BTB-domain protein not previously implicated in cleavage mechanics. This alternative form of cell formation suggests that organisms have evolved multiple molecular strategies for regulating the cytoskeleton during cleavage. PMID- 23728424 TI - BMI1 represses Ink4a/Arf and Hox genes to regulate stem cells in the rodent incisor. AB - The polycomb group gene Bmi1 is required for maintenance of adult stem cells in many organs. Inactivation of Bmi1 leads to impaired stem cell self-renewal due to deregulated gene expression. One critical target of BMI1 is Ink4a/Arf, which encodes the cell-cycle inhibitors p16(Ink4a) and p19(Arf). However, deletion of Ink4a/Arf only partially rescues Bmi1-null phenotypes, indicating that other important targets of BMI1 exist. Here, using the continuously growing mouse incisor as a model system, we report that Bmi1 is expressed by incisor stem cells and that deletion of Bmi1 resulted in fewer stem cells, perturbed gene expression and defective enamel production. Transcriptional profiling revealed that Hox expression is normally repressed by BMI1 in the adult, and functional assays demonstrated that BMI1-mediated repression of Hox genes preserves the undifferentiated state of stem cells. As Hox gene upregulation has also been reported in other systems when Bmi1 is inactivated, our findings point to a general mechanism whereby BMI1-mediated repression of Hox genes is required for the maintenance of adult stem cells and for prevention of inappropriate differentiation. PMID- 23728426 TI - Micromanipulation of gene expression in the adult zebrafish brain using cerebroventricular microinjection of morpholino oligonucleotides. AB - Manipulation of gene expression in tissues is required to perform functional studies. In this paper, we demonstrate the cerebroventricular microinjection (CVMI) technique as a means to modulate gene expression in the adult zebrafish brain. By using CVMI, substances can be administered into the cerebroventricular fluid and be thoroughly distributed along the rostrocaudal axis of the brain. We particularly focus on the use of antisense morpholino oligonucleotides, which are potent tools for knocking down gene expression in vivo. In our method, when applied, morpholino molecules are taken up by the cells lining the ventricular surface. These cells include the radial glial cells, which act as neurogenic progenitors. Therefore, knocking down gene expression in the radial glial cells is of utmost importance to analyze the widespread neurogenesis response in zebrafish, and also would provide insight into how vertebrates could sustain adult neurogenesis response. Such an understanding would also help the efforts for clinical applications in human neurodegenerative disorders and central nervous system regeneration. Thus, we present the cerebroventricular microinjection method as a quick and efficient way to alter gene expression and neurogenesis response in the adult zebrafish forebrain. We also provide troubleshooting tips and other useful information on how to carry out the CVMI procedure. PMID- 23728425 TI - The perivascular niche regulates breast tumour dormancy. AB - In a significant fraction of breast cancer patients, distant metastases emerge after years or even decades of latency. How disseminated tumour cells (DTCs) are kept dormant, and what wakes them up, are fundamental problems in tumour biology. To address these questions, we used metastasis assays in mice and showed that dormant DTCs reside on microvasculature of lung, bone marrow and brain. We then engineered organotypic microvascular niches to determine whether endothelial cells directly influence breast cancer cell (BCC) growth. These models demonstrated that endothelial-derived thrombospondin-1 induces sustained BCC quiescence. This suppressive cue was lost in sprouting neovasculature; time-lapse analysis showed that sprouting vessels not only permit, but accelerate BCC outgrowth. We confirmed this surprising result in dormancy models and in zebrafish, and identified active TGF-beta1 and periostin as tumour-promoting factors derived from endothelial tip cells. Our work reveals that stable microvasculature constitutes a dormant niche, whereas sprouting neovasculature sparks micrometastatic outgrowth. PMID- 23728428 TI - Genetic structure and natural variation associated with host of origin in Penicillium expansum strains causing blue mould. AB - Blue mould, caused by Penicillium expansum, is one of the most economically damaging postharvest diseases of pome fruits, although it may affect a wider host range, including sweet cherries and table grapes. Several reports on the role of mycotoxins in plant pathogenesis have been published, but few focussed on the influence of mycotoxins on the variation in host preference amongst producing fungi. In the present study the influence of the host on P. expansum pathogenicity/virulence was investigated, focussing mainly on the relationship with patulin production. Three P. expansum strain groups, originating from apples, sweet cherries, and table grapes (7 strains per host) were grown on their hosts of isolation and on artificial media derived from them. Strains within each P. expansum group proved to be more aggressive and produced more patulin than the other two groups under evaluation when grown on the host from which they originated. Table grape strains were the most aggressive (81% disease incidence) and strongest patulin producers (up to 554MUg/g). The difference in aggressiveness amongst strains was appreciable only in the presence of a living host, suggesting that the complex pathogen-host interaction significantly influenced the ability of P. expansum to cause the disease. Incidence/severity of the disease and patulin production proved to be positively correlated, supporting the role of patulin as virulence/pathogenicity factor. The existence of genetic variation amongst isolates was confirmed by the High Resolution Melting method that was set up herein, which permitted discrimination of P. expansum from other species (P. chrysogenum and P. crustosum) and, within the same species, amongst the host of origin. Host effect on toxin production appeared to be exerted at a transcriptional level. PMID- 23728427 TI - Service use and barriers to mental health care among adults with major depression and comorbid substance dependence. AB - OBJECTIVE: The study explored mental health service use patterns and barriers to care among individuals with comorbid mental and substance use disorders. METHODS: Using data from the National Survey on Drug Use and Health (2005-2010) for 18,972 adults with past-year major depressive episodes, the study compared mental health service use and perceived barriers to care among participants with and without co occurring alcohol dependence, nonalcohol drug dependence, and both alcohol and drug dependence. RESULTS: Compared with participants without comorbid substance dependence, participants with alcohol dependence or both alcohol and nonalcohol drug dependence used more mental health services of all types, and participants with only comorbid alcohol dependence used more medication treatments. Participants with comorbid substance dependence were significantly more likely than those without comorbid substance dependence to report unmet mental health treatment need. However, barriers to mental health care were remarkably similar across groups, with financial barriers being the most common in all groups. CONCLUSIONS: Participants with major depression comorbid with substance dependence used more mental health services but also perceived more unmet need for such care than individuals without such comorbidity. However, barriers to mental health care were similar across groups with and without comorbidity. Policies aimed at expanding insurance coverage and mental health parity would likely benefit individuals with major depression and substance dependence comorbidity even more than those without such comorbidity. PMID- 23728429 TI - Application' and validation of autochthonous lactic acid bacteria starter cultures for controlled leek fermentations and their influence on the antioxidant properties of leek. AB - Leek (Allium ampeloprasum var. porrum) is one of Belgium's most important outdoor vegetables, mainly cultivated for its white shaft. Fermentation of leek offers opportunities in view of biomass valorization and product diversification. This study deals with the implementation and validation of starter cultures to perform controlled leek fermentations and to ensure a high quality of the end-products. Therefore, a thorough study of the fermentation microbiology and the influence of three starter culture strains (Lactobacillus plantarum IMDO 788, Lactobacillus sakei IMDO 1358, and Leuconostoc mesenteroides IMDO 1347) on the metabolite kinetics of leek fermentation and antioxidant properties of leek was performed. Overall, the application of lactic acid bacteria starter cultures resulted in a fast prevalence of the species involved, coupled to an accelerated acidification. Of the three starter cultures tested, the mixed starter culture of L. plantarum IMDO 788 and L. mesenteroides IMDO 1347 was most promising, as its application resulted in fermented leek of good microbiological quality and in a more extensive carbohydrate consumption, whereby diverse end-metabolites were produced. However, high residual fructose concentrations allowed yeast outgrowth, resulting in increased ethanol and glycerol concentrations, and indicated the lack of a prevailing strictly heterofermentative LAB species. The antioxidant capacity of fermented leek samples, as measured with the oxygen radical absorbance capacity assay, increased when starter cultures were used, whereas with regard to 2,2-diphenyl-1-picrylhydrazyl free radical scavenging activity, only leek fermented with L. sakei IMDO 1358 scored higher than spontaneously fermented leek. The total phenolic content was not influenced by the use of starter cultures, while the S-alk(en)yl-L-cysteine sulfoxides content decreased strongly. A preliminary sensory analysis revealed that the spontaneously fermented leek and the one obtained with the mixed starter culture were preferred by consumers, emphasizing again the importance of microbial successions in vegetable fermentations. PMID- 23728430 TI - Thermophilic spore-forming bacteria isolated from spoiled canned food and their heat resistance. Results of a French ten-year survey. AB - Thermal processing of Low Acid Canned Foods (LACF), which are safe and shelf stable at ambient temperature for several years, results in heat inactivation of all vegetative microorganisms and the partial or total inactivation of spores. Good Manufacturing Hygienic Practices include stability tests for managing the pathogen risk related to surviving mesophilic bacterial spores. LACF are also often submitted to additional incubation conditions, typically 55 degrees C for 7 days, to monitor spoilage by thermophiles. In this study we identified the bacterial species responsible for non-stability after prolonged at 55 degrees C of incubation of LACF from 455 samples collected from 122 French canneries over 10 years. Bacteria were identified by microsequencing or a recent developed tool for group-specific PCR detection (SporeTraQTM). A single species was identified for 93% of examined samples. Three genera were responsible for more than 80% of all non-stability cases: mostly Moorella (36%) and Geobacillus (35%), and less frequently Thermoanaerobacterium (10%). The other most frequent bacterial genera identified were Bacillus, Thermoanaerobacter, Caldanaerobius, Anoxybacillus, Paenibacillus and Clostridium. Species frequency was dependent on food category, i.e. vegetables, ready-made meals containing meat, seafood or other recipes, products containing fatty duck, and related to the intensity of the thermal treatment applied in these food categories. The spore heat resistance parameters (D or delta and z values) from 36 strains isolated in this study were determined. Taken together, our results single out the species most suitable for use as indicators for thermal process settings. This extensively-documented survey of the species that cause non-stability at 55 degrees C in LACF will help canneries to improve the management of microbial contamination. PMID- 23728431 TI - Influence of lactic acid bacteria on redox status and on proteolytic activity of buckwheat (Fagopyrum esculentum Moench) sourdoughs. AB - Redox potential and proteolysis determine protein networks in doughs and thus dough rheology as well as the structure of baked goods. Namely, gluten-free bakery products needs structural improvements but little is known about these parameters in gluten free dough systems. In this work the influence of lactic acid bacteria (LAB) on redox status and proteolysis of buckwheat sourdoughs was investigated. An increase of free thiol groups was detected as redox potential was decreasing during fermentation. Thiol content at 8 h was higher in doughs fermented with strains with high reductive activity, such as Weissella (W.) cibaria in comparison to Pediococcus (P.) pentosaceus, which exhibited a lower reducing activity. At 24 h each fermentation showed a similar content of free thiol groups. Endogenous buckwheat proteases were characterized using various protease inhibitors in buckwheat doughs. Until pH3.1 a proteolysis increase was monitored in doughs. Employed LAB didn't show any detectable extracellular proteolytic activity. Flour proteases are thus responsible for protein breakdown, and this was demonstrated comparing free amino nitrogen (FAN) values and protein electrophoretic patterns of sourdough fermentations with chemical acidified (CA) doughs. FAN content at 24 h using P. pentosaceus, proteolytic comparative strain of Enterococcus faecalis, W. cibaria, mixed culture (containing P. pentosaceus and W. cibaria), CA and CA doughs containing glutathione (GSH) reached 45.9+/ 1.3, 42.4+/-1.3, 40+/-1, 31+/-2, 29+/-2 and 17.8+/-3.9 mmol kg(-1) flour, respectively. Proteolysis was mainly influenced by pH and incubation time. The addition of GSH showed a decrease of proteolysis and of free amino acids. CA doughs showed a higher total free amino acids content than sourdough fermented with LAB indicating their metabolization. Fermentations with high FAN values exhibited lower band intensity (analyzed under reducing condition) in electrophoretic patterns. These results show that dough proteases are responsible for proteolysis in buckwheat sourdoughs and this activity is influenced from LAB metabolism. Moreover, oxidation-reduction potential (ORP) changes do not show improvements of proteolytic activity in buckwheat sourdoughs. PMID- 23728432 TI - Investigation of the dominance behavior of Saccharomyces cerevisiae strains during wine fermentation. AB - During wine fermentation, different strains of Saccharomyces cerevisiae compete in the same fermenting must and dominance takes place when one strain overcomes all the others. The purpose of this study was to investigate this phenomenon by identifying S. cerevisiae strains endowed with this feature and to test them in laboratory fermentations. First, autochthonous S. cerevisiae from Nebbiolo fermentations were isolated, molecularly identified and characterized. Genetically diverse S. cerevisiae strains were subsequently subjected to physiological characterization and to micro-scale fermentation, the weight loss kinetics was measured and HPLC analysis was performed at the end of the fermentation. Then, the strains that presented good fermentation characteristics were chosen for further analysis and to determine the dominance feature. For this purpose, couples of strains were co-inoculated in Nebbiolo must and the fermentations were monitored by microbiological and chemical analysis. Two different inoculation approaches were used: co-fermentations in flasks with mixed cells and reactor co-fermentations, in which the cells from the two different strains were kept separate by means of a 0.45 MUm filter membrane, which allowed the fermenting must to move freely between the two compartments. During the flask co-fermentations, a minisatellite PCR protocol was applied, in order to differentiate the two strains and determine which one was able to dominate. The protocol included a culture-dependent approach and an independent one. In the first case, DNA extraction was performed on all the colonies scraped off the plates after sampling. In the second case, DNA extraction was performed directly on the fermenting must. The strains that were able to dominate were tested against several S. cerevisiae in order to confirm this dominance behavior. Dominance was observed in the early stages of fermentation, as early as 3days. Combinations of dominant and not-dominant strains were subjected to further tests in a co-fermentation reactor system, in order to perform single-strain analysis so as to obtain a better understanding of the dominance behavior. Surprisingly, the results obtained in the flask co-fermentations were not confirmed. In fact, the two strains, one which was hypothesized to be dominant and the other not dominant, coexisted throughout the fermentation period. The results of this study suggest that the dominant behavior of S. cerevisiae is only expressed when they sense other yeasts in the same environment. PMID- 23728433 TI - Bedside optic nerve sheath diameter ultrasound for the evaluation of suspected pediatric ventriculoperitoneal shunt failure in the emergency department. AB - OBJECTIVE: To determine the feasibility and test characteristics of optic nerve sheath diameter (ONSD) measured by ocular ultrasound as a screening tool for ventriculoperitoneal shunt (VPS) failure. METHODS: Prospective observational study using a convenience sample of children 6 months to 18 years of age, presenting to an academic pediatric emergency department for evaluation of possible VPS failure between September 2008 and March 2009. ONSD was measured by anterior transbulbar and lateral transbulbar techniques. Mean ONSD was compared between subjects with and without shunt failure, as determined by neurosurgical decision to operate. RESULTS: A total of 39 encounters were completed, including 20 VPS failures. The mean ONSD was 4.5 +/- 0.9 and 5.0 +/- 0.6 mm among encounters with and without shunt failure (p = 0.03), respectively. The mean ONSD was not statistically different when obtained by the anterior transbulbar vs. the lateral transbulbar approach (4.8 +/- 1.0 vs. 4.7 +/- 0.8 mm, p = 0.12). ONSD ultrasound had a sensitivity of 61.1 % (95 % CI 35.7-82.7) and specificity of 22.2 % (95 % CI 6.4-47.6 %) for detecting shunt failure in this sample. CONCLUSIONS: ONSD ultrasound does not appear to be a useful primary screening tool in emergency department evaluation of VPS failure. There was no difference between the anterior transbulbar approach and the lateral transbulbar approach. Children with VPS in our sample have larger ONSD measurements than in previously reported studies. PMID- 23728436 TI - Pseudo-micropapillary structures associated with columnar cell lesions of the breast are an artifact due to traumatic epithelial detachment: a potential pitfall which can lead to overtreatment. PMID- 23728438 TI - Occupational homicide of law enforcement officers in the US, 1996-2010. AB - OBJECTIVE: To understand the circumstances surrounding the occupational homicides of law enforcement officers (LEOs) in the USA. METHODS: Narrative text analysis of Federal Bureau of Investigation Law Enforcement Officers Killed and Assaulted reports. RESULTS: A total of 796 officers were killed in the line of duty between 1996 and 2010. The occupational homicide rate during the time peaked in 2001 at 3.76/100 000 (excluding those killed during the September 11 2001 terrorist attacks), and was lowest in 2008 at 1.92/100 000. Most LEOs (67%) were killed by short-barrel firearms; 10% were killed with their own service weapon. The most frequent encounter with a suspect prior to a homicide was responding to a disturbance call. CONCLUSIONS: These results should inform officer training and the policies, as well as procedures used when interacting with suspects, especially when firearms are involved. PMID- 23728437 TI - Renal angiomyolipoma, fat-poor variant--a clinicopathologic mimicker of malignancy. AB - Angiomyolipomas, composed of thick-walled blood vessels, smooth muscle, and adipose tissue, belong to the perivascular epithelioid cell neoplasms (PEComas), a family of tumors believed to be derived from perivascular epithelioid cells which co-express smooth muscle and melanocytic markers. Although most angiomyolipomas are benign, a subset of PEComas has metastatic potential. The pathologic and clinical spectrum of these tumors continues to evolve. We sought to evaluate a subset of renal angiomyolipomas with a minimal amount of fat. We studied 48 renal angiomyolipomas in 41 patients (33 females and 8 males). Based on the amount of adipose tissue, the lesions were categorized as fat-poor, fat average, and fat-rich lesions (<25, 25-75, and >75 % of fat, respectively). Stains for smooth muscle actin, calponin, HMB-45, melanocyte-associated antigen PNL2, estrogen, and progesterone receptor were examined. Four patients (all females) had more than one lesion, four had coexistent uterine leiomyomata, two had coexistent renomedullary interstitial tumor, and males had only single lesions. Except for one woman, all lesions were sporadic. Twenty-nine were fat poor (60 %) lesions; 8, fat-average (17 %) lesions; and 11, fat-rich (23 %) lesions. The fat content did not correlate with tumor size: the largest fat-poor and smallest fat-rich lesions were >6 and <2 cm, respectively. All lesions stained with smooth muscle actin and HMB-45; 41 % of tumors were positive for estrogen receptor (11 females and 1 male). No patient had metastases (follow-up 2 11 years). In our series, fat content in angiomyolipoma was not associated with tumor size. Fat-poor angiomyolipomas affected predominantly women and were morphologically and radiologically distinct as mimickers of malignancy. Whether they are biologically different from conventional tumors requires further studies. PMID- 23728439 TI - Oxidation of C-H bonds to C=O bonds by O2 only or N-oxides and DMSO: synthesis of Delta(1)-bipyrrolinones and pyrrolino[3,2-b]pyrrolinones from 2,6 diazasemibullvalenes. AB - 2,6-Diazasemibullvalenes (NSBVs) readily reacted with oxygen under mild conditions, affording Delta(1)-bipyrrolinones via C-N bond cleavage and C-H bond oxidation. Pyrrolino[3,2-b]pyrrolinone derivatives were efficiently generated when NSBVs were treated with N-oxides in the presence of Lewis acids. Delta(1) Bipyrrolinones thus obtained could be readily transformed into other heterocycles. PMID- 23728440 TI - Monoclinic WO3 nanorods-rutile TiO2 nanoparticles core-shell interface for efficient DSSCs. AB - A core-shell photoanode, composed of a monoclinic WO3 nanorods core encapsulated with a rutile TiO2 nanoparticles shell, reveals ~246% enhancement in power conversion efficiency due to improved current density and open circuit voltage values and longer-lived charge carriers. PMID- 23728441 TI - Internal carotid artery dissection after anterior cervical disc replacement: first case report and literature review of vascular complications of the approach. AB - We report the case of a 41-year-old woman who underwent cervical total disc replacement at C4C5 and C5C6 levels and fusion at C6C7 level through an anterior right-side approach. After anesthesia recovery, the patient presented left hemiparesia and facial palsy due to large right hemispheric stroke. Diffusion weighted magnetic resonance imaging was performed as soon as the patient developed neurologic symptoms of stroke and revealed a right internal carotid artery dissection. Digital substraction angiography, endovascular stenting, angioplasty and thrombectomy were performed. Six months after treatment, clinical examination showed mild left-arm spasticity. To the best of our knowledge, only two cases of internal carotid artery stroke without dissection or thrombosis are reported. In conclusion, although vascular complications are rare after anterior cervical spine procedure, internal carotid artery dissection can occur. Suspected risk factors are prolonged retraction of the carotid artery and neck extension. PMID- 23728442 TI - Treatment for displaced proximal humerus fractures: comparison of interlocking plate fixation versus minimal invasive techniques. AB - BACKGROUND AND PURPOSE: The functional results and the complications following interlocking plate fixation of displaced proximal humerus fractures should be evaluated and compared with those following minimal invasive fixation techniques. PATIENTS AND METHODS: Fifty patients (30 women, 20 men, mean age 62.7 (18-91) years) were treated for a displaced proximal humerus fracture using an interlocking plate fixation (PHILOS(r)) between 2003 and 2004. The mean follow-up time was 12 (9-36) months. Functional and radiographic results (Constant-Murley and Neer scores) were analyzed and compared with an equivalent historical control group of 53 patients operated for the same fracture types using minimal invasive techniques (K-wires and/or cannulated screws) between 1995 and 1997. According to the OTA/AO classification, there were 15 type A, 18 type B, and 17 type C fractures in the plate fixation group, and 23, 25, and 5 of these types in the control group, respectively. RESULTS: The mean Neer score was 85.9, the mean Constant-Murley score 84, whereas 82.4 and 75.4 for the control group, respectively. Good and excellent results were seen in 78%, whereas in 70% in the control group. The results were dependent upon the fracture's type, sex, and patient's age. Complications were seen in 9 patients, whereas in 16 patients in the control group. INTERPRETATION: Using an interlocking plate, the indication of fixation of displaced proximal humerus fractures had been expanded to type C fractures. The implant failure rate can be reduced. The functional results achieved are better compared with those following minimal invasive techniques. PMID- 23728443 TI - The biological and biomechanical comparison of two bulk bone graft techniques used in case of dysplastic acetabulum. AB - BACKGROUND: The incorporation of bulk bone grafts in the replacement of dysplastic acetabulum is determined by the biological environment of the recipient site, the size of the contact surface, and the stability of the osteosynthesis used. Based on these, the present study compares the Harris acetabular plasty used routinely by us with the Radojevic L-shaped graft technique. METHODS: For our measurements, we used 20 hemi-pelvises removed from 10 cadavers. In 10 cases, acetabular plasty according to Harris, in 10 cases Radojevic L-plasty, was performed. The biological environment was analyzed; with geometric calculations, the contact surface was determined, and with a material testing apparatus, the primary stability of the osetosynthesis was measured. For the measurements, a new method was developed. RESULTS: The Radojevic technique provides a better biological environment for graft ingrowth. The contact surface is nearly twice as much as in Harris plasty. No significant difference was found in the primary stability of the osteosynthesis used. The deviation on the value of the stability measurements is explained by the differences in the bone quality of the cadavers used. CONCLUSIONS: Based on the 3 aspects examined, the Radojevic L-shaped graft technique has similar stability when compared to the Harris acetabular plasty, but provides better biological circumstances and larger graft host bone contact. Based on this, we started using the L-shaped technique in our department. PMID- 23728444 TI - Using commercially available tools for multifaceted health assessment: data integration lessons learned. AB - Health monitoring data collected from multiple available intake devices provide a rich resource to support older adult health and wellness. Although large amounts of data can be collected, there is currently a lack of understanding on the integration of these various data sources using commercially available products. This article describes an inexpensive approach to integrating data from multiple sources from a recently completed pilot project that assessed older adult wellness and demonstrates challenges and benefits in pursuing data integration using commercially available products. The data in this project were sourced from electronically captured participant intake surveys and existing commercial software output for vital signs and cognitive function. All the software used for data integration in this project was freeware and was chosen because of its ease of comprehension by novice database users. The methods and results of this approach provide a model for researchers with similar data integration needs to easily replicate this effort at a low cost. PMID- 23728445 TI - Building patient relationships: a smartphone application supporting communication between teenagers with asthma and the RN care coordinator. AB - Smartphone applications used in healthcare are emerging as an adjunct therapy to assist patients in self-management. Often, smartphone technology is not integrated into healthcare delivery and does not build the nurse-patient relationship, an essential mechanism to guide the patient toward health. In a pilot study using smartphones with teenagers with asthma, the application provided a method not only to share health information at the point-of-living, including health assessments, personalized health plans, and disease information, but also to allow text messaging communication between the teenager and his/her RN care coordinator. Twenty-five teenagers piloted the smartphone application and provided feedback about its use. Eighty-five percent of the teenagers responding to the end-of-pilot, semistructured interview indicated a positive change in the nurse-patient relationship. Teenagers perceived that they could ask more questions along with having improved access and quicker response times. The RN care coordinators perceived improved ability to contact teenagers and improved accuracy of assessment data. Although the pilot had several limitations, it demonstrates that smartphone technology and text messaging can further the nurse patient relationship. For this to occur, nurses need to become involved in the development and integration of technology to focus applications on innovative ways to enhance communication in patient care. PMID- 23728446 TI - Technology acceptance and quality of life of the elderly in a telecare program. AB - As information and communication technology applied to telecare has become a trend in elder care services, evaluation of the program is vital for further program design and development. This study evaluated the variables influencing the use of a telecare service program by the elderly. A questionnaire survey was used to explore the relationship between quality of life and technology acceptance of a telecare program in Taiwan. In addition, open-ended questions were used to elicit qualitative information regarding the experience of technology use. The results revealed that elderly persons with better social welfare status and health condition, who used the device frequently, had higher quality of life and accepted technology use. The correlation results also indicated that elderly persons who perceived telecare as useful in solving health problems, had the intention to use the program, and were willing to continue use, also had a better perception toward quality of life regarding their interpersonal relationships and living environment. Nonetheless, cost may be an issue that will impede their willingness to use the technology in care service. PMID- 23728447 TI - Deformable anatomic templates improve analysis of gliomas with minimal mass effect in eloquent areas. AB - BACKGROUND: Despite improvements in advanced magnetic resonance imaging and intraoperative mapping, cases remain in which it is difficult to determine whether viable eloquent structures are involved by a glioma. A novel software program, deformable anatomic templates (DAT), rapidly embeds the normal location of eloquent cortex and functional tracts in the magnetic resonance images of glioma-bearing brain. OBJECTIVE: To investigate the feasibility of the DAT technique in patients with gliomas related to eloquent brain. METHODS: Forty cases of gliomas (grade II-IV) with minimal mass effect were referred for a prospective preoperative and postoperative DAT analysis. The DAT results were compared with the patient's functional magnetic resonance imaging, diffusion tensor imaging, operative stimulation, and new postoperative clinical deficits. RESULTS: Fifteen of the 40 glioma patients had overlap between tumor and eloquent structures. Immediate postoperative neurological deficits were seen in 9 cases in which the DAT showed the eloquent area both within the tumor and within or at the edge of the resection cavity. In 6 cases with no deficits, DAT placed the eloquent area in the tumor but outside the resection cavity. CONCLUSION: This is proof of concept that DAT can improve the analysis of diffuse gliomas of any grade by efficiently alerting the surgeon to the possibility of eloquent area invasion. The technique is especially helpful in diffuse glioma because these tumors tend to infiltrate rather than displace eloquent structures. DAT is limited by tract displacement in gliomas that produces moderate to severe mass effect. PMID- 23728449 TI - Risk factors, incidence, and effect of cardiac failure and myocardial infarction in aneurysmal subarachnoid hemorrhage patients. AB - BACKGROUND: Cardiac dysfunction is a well-known complication of aneurysmal subarachnoid hemorrhage (aSAH). However, the clinical significance of cardiac complications is largely unknown. OBJECTIVE: To determine whether cardiac complications are independently related to outcomes and to identify potential predictors associated with these complications. METHODS: We extracted all hospitalizations for aSAH from the National Inpatient Sample database for years 2002 to 2009. We used generalized estimating equations to determine whether cardiac complications were associated with the patient outcomes and to evaluate potential predictors of cardiac complications. RESULTS: Among 53713 cases of aSAH, there were 3609 (6.72%) and 151 (0.28%) incidences of cardiac failure (CF) and myocardial infarction (MI), respectively. The overall in-hospital mortality rate was 24.8%, whereas the mortality rate for patients with CF was 34.4% and the mortality rate for patients with MI was 29.8%. Patients who experienced CF were significantly more likely than other patients to die in the hospital (odds ratio: 1.6, 95% confidence interval: 1.47-1.68; P < .001). The difference in mortality rates between MI patients and other patients, however, was not statistically significant. The generalized estimating equation model identified 7 factors that were predictive of CF: age, sex, race, primary payer, diabetes, smoker, and cardiac disease. For MI, the model identified age, race, and primary payer as significant predictors of MI. CONCLUSION: Our results suggest that an important association exists between cardiac complications and mortality/morbidity in aSAH patients. aSAH patients with CF appear to have a higher mortality rate, longer hospital length of stay, and higher hospitalization costs compared with those without CF. PMID- 23728448 TI - Inhibition of c-Jun N-terminal kinase activity enhances vestibular schwannoma cell sensitivity to gamma irradiation. AB - BACKGROUND: Radiosurgery is increasingly used to treat vestibular schwannomas (VSs). Increasing the sensitivity of VS cells to irradiation (IR) could allow for lower and/or more effective doses of IR, improving safety and efficacy. Persistent c-Jun N-terminal kinase (JNK) activity in VS cells reduces cell death by suppressing the accumulation of reactive oxygen species (ROS), raising the possibility that JNK activity protects against IR-induced VS cell death, which is mediated by ROS. OBJECTIVE: To determine the extent to which JNK signaling contributes to VS cell radiosensitivity. METHODS: Primary human VS cultures, derived from acutely resected tumors, received single doses (5-40 Gy) of gamma irradiation. Histone 2AX phosphorylation, a marker of IR-induced DNA damage, was assayed by Western blot and immunostaining. ROS levels were quantified by measuring 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) fluorescence. Cell apoptosis was determined by terminal deoxynucleotidyl transferase 2' deoxyuridine, 5'-triphosphate nick end labeling. RESULTS: The JNK inhibitors SP6000125 and I-JIP reduced histone 2AX phosphorylation after IR. They also increased H2DCFDA fluorescence in nonirradiated cultures and significantly increased IR-induced (5-10 Gy) H2DCFDA fluorescence 72 hours, but not 2 hours, after IR. Finally, I-JIP (50 MUmol/L) significantly increased VS cell apoptosis in cultures treated with 20 to 40 Gy. I-JIP (20 MUmol/L), SP600125 (20 MUmol/L), and JNK1/2 short interfering RNA knockdown each increased VS cell apoptosis in cultures treated with 30 to 40 Gy, but not lower doses, of IR. CONCLUSION: Inhibition of JNK signaling decreases histone 2AX phosphorylation and increases ROS and apoptosis in VS cells after gamma irradiation. These results raise the possibility of using JNK inhibitors to increase the effectiveness of radiosurgery for treatment of VSs. PMID- 23728450 TI - Vittorio Marchi, MD (1851-1908): an unsung pioneer of neuroscience. AB - Vittorio Marchi was an Italian neuroscientist who lived during the second half of the 19th century. He is generally remembered for developing a novel staining method to trace the degeneration of nervous fibers in lesions of the central nervous system. This osmium-based method was used worldwide for approximately a century and continues to be cited in modern textbooks. Despite several important original scientific contributions, Marchi was never awarded a university chair. Discouraged, he left to practice neurology in a rural area but continued to write outstanding articles, and in 1897, he became a pioneer of meningioma surgery. Today, he is remembered only in specialized contexts. We hope this article can provide the recognition that Marchi deserves. PMID- 23728451 TI - Deep arteriovenous malformations in the Basal Ganglia, thalamus, and insula: microsurgical management, techniques, and results. AB - BACKGROUND: Arteriovenous malformations (AVMs) in the basal ganglia, thalamus, and insula are considered inoperable given their depth, eloquence, and limited surgical exposure. Although many neurosurgeons opt for radiosurgery or observation, others have challenged the belief that deep AVMs are inoperable. Further discussion of patient selection, technique, and multimodality management is needed. OBJECTIVE: To describe and discuss the technical considerations of microsurgical resection for deep-seated AVMs. METHODS: Patients with deep AVMs who underwent surgery during a 14-year period were reviewed through the use of a prospective AVM registry. RESULTS: Microsurgery was performed in 48 patients with AVMs in the basal ganglia (n=10), thalamus (n=13), or insula (n=25). The most common Spetzler-Martin grade was III- (68%). Surgical approaches included transsylvian (67%), transcallosal (19%), and transcortical (15%). Complete resection was achieved in 34 patients (71%), and patients with incomplete resection were treated with radiosurgery. Forty-five patients (94%) were improved or unchanged (mean follow-up, 1.6 years). CONCLUSION: This experience advances the notion that select deep AVMs may be operable lesions. Patients were highly selected for small size, hemorrhagic presentation, young age, and compactness factors embodied in the Spetzler-Martin and Supplementary grading systems. Overall, 10 different approaches were used, exploiting direct, transcortical corridors created by hemorrhage or maximizing anatomic corridors through subarachnoid spaces and ventricles that minimize brain transgression. The same cautious attitude exercised in selecting patients for surgery was also exercised in deciding extent of resection, opting for incomplete resection and radiosurgery more than with other AVMs to prioritize neurological outcomes. PMID- 23728452 TI - Long-term changes in serum IGF-1 levels after successful surgical treatment of growth hormone-secreting pituitary adenoma. AB - BACKGROUND: Successful treatment of acromegaly is known to normalize serum insulin-like growth factor 1 (IGF-1) levels within days after surgery. However, our clinical observations indicate that many cases of acromegaly show delayed normalization of serum IGF-1 levels after complete tumor resection. OBJECTIVE: To study long-term changes of the serum IGF-1 levels in acromegalic patients for whom surgical treatment was thought to be successful. METHODS: A retrospective observational study was performed with 46 acromegalic patients with no residual tumor on sellar magnetic resonance imaging, and a nadir growth hormone of less than 0.4 MUg/L on a postoperative oral glucose tolerance test. RESULTS: In all patients, serum IGF-1 levels returned to the normal reference values for age and sex during the observational period (12-132 months). The mean duration from the time of surgery until IGF-1 normalization was 10 months (range, 3 days-57 months). Twenty-seven patients (59%) reached normal IGF-1 ranges within 3 months of surgery, whereas 19 patients (41%) experienced delayed (>3 months) IGF-1 normalization. Eleven patients (24%) recovered normal IGF-1 levels 12 to 57 months after surgery. The possibility of delayed IGF-1 cure was increased 8.8 fold with an immediate postoperative IGF-1 level increase of 100 MUg/L. CONCLUSION: Satisfactory remission of acromegaly by IGF-1 criteria was delayed in a large proportion of acromegalic patients, especially those with high postoperative IGF-1 levels. Hence, additional treatment can be delayed in clinically stable acromegalic patients who show no evidence of residual tumors on postoperative magnetic resonance imaging and a normal growth hormone suppressive response to a glucose load. PMID- 23728453 TI - Reconstructive treatment of ruptured blood blister-like aneurysms with stent and coil. AB - BACKGROUND: Controversy remains about the optimal treatment for blood blister- like aneurysms (BBAs). OBJECTIVE: To evaluate clinical and angiographic outcomes after reconstructive treatment for BBA with stent and coil. METHODS: Thirty-four patients (6 men, 28 women; mean age, 47.3 years) with ruptured BBAs underwent reconstructive treatment with stent and coil. Posttreatment courses and outcomes were retrospectively evaluated. RESULTS: Initial treatments were >= 2 overlapping stents with or without coiling (n = 28) and single stent with coiling (n = 6). Three BBAs rebled on days 9, 11, and 15 after treatment, resulting in 1 death. Except for 3 patients who died early, 31 patients were followed up for 7 to 80 months (median, 32 months). One patient recovered completely but died of complications of systemic lupus erythematosus at 25 months. Of the remaining 30 patients, 25 had favorable outcomes (modified Rankin scale, 0-2) and 5 had unfavorable outcomes. Angiographic follow-up was available in the 32 BBAs. Eight (25.0%) recurred, all within 5 weeks. In the multiple stents group (n = 26), 22 BBAs showed improvement or complete healing, but 4 (15.4%, 2 rebleedings) had recurrence. In the single stent with coiling group (n = 6), 2 BBAs were stable but 4 (66.7%, 1 rebleeding) had recurrence. Single stent with coiling and Hunt and Hess grade >= 4 were 2 independent risk factors for recurrence (P < .05). CONCLUSION: Reconstructive treatment with stent and coil appears a viable option for BBAs. Single stent with coiling and Hunt and Hess grade >= 4 were 2 independent risk factors for recurrence. Follow-up angiography should be considered mandatory soon after treatment. ABBREVIATIONS: BBA, blood blister- like aneurysmICA, internal carotid arterymRS, modified Rankin ScaleSAH, subarachnoid hemorrhage. PMID- 23728454 TI - Pituitary centers of excellence. PMID- 23728455 TI - Magnetic resonance evolution of de novo formation of a cavernoma in a thrombosed developmental venous anomaly: a case report. AB - BACKGROUND AND IMPORTANCE: Mechanisms that lead to de novo formations of nonfamilial-type cavernomas are not well understood. One of the interesting hypotheses is the causative relationship between developmental venous anomaly (DVA) and cavernoma formation. We report a unique case in which serial imaging demonstrated the evolution of de novo formation of a cavernoma in association with a thrombosed DVA. A detailed review of the causal hypothesis between a DVA and cavernoma is also provided. CLINICAL PRESENTATION: We report a 37-year-old female patient in whom a cavernoma-like lesion arose 1 year after the progressive thrombosis of a medullary (or caput medusa) vein of a DVA. The presence of an acute angulation in the draining vein may have prompted an intrinsic outflow restriction. Possible worsening of venous disequilibrium led to subsequent thrombus progression, venous congestion, and occlusion of the vein with venous dilation and signs of stasis on follow-up magnetic resonance imaging. Finally, this developed into a lobulated lesion with salt-and-pepper appearance at the converging region of medullary tributaries, which typified the classic features of a cavernoma. CONCLUSION: Compared with other published cases of de novo cavernoma formation in relation to a DVA, our case, for the first time, allows us to witness the temporal evolution from a thrombosed DVA to the birth of a cavernoma around it. This supports the hypothesis that the cavernoma can be an acquired disease that arises from a DVA. PMID- 23728456 TI - Cost-effectiveness analysis of diagnostic tests. PMID- 23728457 TI - Measuring and testing awareness of emotional face expressions. AB - Comparison of behavioural measures of consciousness has attracted much attention recently. In a recent article, Szczepanowski et al. conclude that confidence ratings (CR) predict accuracy better than both the perceptual awareness scale (PAS) and post-decision wagering (PDW) when using stimuli with emotional content (fearful vs. neutral faces). Although we find the study interesting, we disagree with the conclusion that CR is superior to PAS because of two methodological issues. First, the conclusion is not based on a formal test. We performed this test and found no evidence that CR predicted accuracy better than PAS (p=.4). Second, Szczepanowski et al. used the present version of PAS in a manner somewhat different from how it was originally intended, and the participants may not have been adequately instructed. We end our commentary with a set of recommendations for future studies using PAS. PMID- 23728458 TI - Preparation of aqueous colloidal mesostructured and mesoporous silica nanoparticles with controlled particle size in a very wide range from 20 nm to 700 nm. AB - Particle size control of colloidal mesoporous silica nanoparticles (CMPS) in a very wide range is quite significant for the design of CMPS toward various applications, such as catalysis and drug delivery. Various types of CMPS and their precursors (colloidal mesostructured silica nanoparticles (CMSS)) with different particle sizes (ca. 20-700 nm) were newly prepared from tetraalkoxysilanes with different alkoxy groups (Si(OR)4, R = Me, Et, Pr, and Bu) in the presence of alcohols (R'OH, R' = Me, Et, Pr, and Bu) as additives. CMSS with larger particle size were obtained by using tetrabutoxysilane (TBOS) and by increasing the amount of BuOH, which is explained by both the difference in the hydrolysis rates of tetraalkoxysilanes themselves and the effect of added alcohols on the hydrolysis rates of tetraalkoxysilanes. Larger amounts of alcohols with longer alkyl chains decrease the hydrolysis rates of tetraalkoxysilanes and the subsequent formation rates of silica species. Thus, the preferential particle growth of CMSS to nucleation occurs, and larger CMSS are formed. Highly dispersed CMPS were prepared by the removal of surfactants of CMSS by dialysis which can lead to the preparation of CMPS without aggregation. Therefore, the particle size control through the tuning of the hydrolysis rate of tetraalkoxysilanes can be conducted by a one-pot and easy approach. Even larger CMPS (ca. 700 nm in size) show relatively high dispersibility. This dispersibility will surely contribute to the design of materials both retaining nanoscale characteristics and avoiding various nanorisks. PMID- 23728459 TI - Translating experience: thinking outside the box. PMID- 23728460 TI - Control of metastatic progression by microRNA regulatory networks. AB - Aberrant microRNA (miRNA) expression is a defining feature of human malignancy. Specific miRNAs have been identified as promoters or suppressors of metastatic progression. miRNAs control metastasis through divergent or convergent regulation of metastatic gene pathways. Some miRNA regulatory networks govern cell autonomous cancer phenotypes, whereas others modulate the cell-extrinsic composition of the metastatic microenvironment. The use of small RNAs as probes into the molecular and cellular underpinnings of metastasis holds promise for the identification of candidate genes for potential therapeutic intervention. PMID- 23728462 TI - Preventing lysosomal fat indigestion. AB - Autophagy contributes to lipid catabolism through direct mobilization and breakdown of cellular lipid stores. Two recent studies reveal the regulatory mechanisms activated by cells during starvation to ensure that the cellular compartments involved in autophagic lipid catabolism are ready to receive, process and use these lipids. The regulators represent attractive therapeutic targets to help fight lipid-excess-associated diseases. PMID- 23728463 TI - White to brite adipocyte transition and back again. AB - Identification and characterization of a third type of adipocyte known as brite (brown-in-white) adipocytes has drawn considerable attention, as these cells are thought to regulate energy expenditure and may help combat obesity. Remarkably, white adipocytes can adopt the characteristics of brite adipocytes following cold stimulation, and this process is reversible in vivo. PMID- 23728461 TI - Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. AB - Flux through metabolic pathways is inherently sensitive to the levels of specific substrates and products, but cellular metabolism is also managed by integrated control mechanisms that sense the nutrient and energy status of a cell or organism. The mechanistic target of rapamycin complex 1 (mTORC1), a protein kinase complex ubiquitous to eukaryotic cells, has emerged as a critical signalling node that links nutrient sensing to the coordinated regulation of cellular metabolism. Here, we discuss the role of mTORC1 as a conduit between cellular growth conditions and the anabolic processes that promote cell growth. The emerging network of signalling pathways through which mTORC1 integrates systemic signals (secreted growth factors) with local signals (cellular nutrients - amino acids, glucose and oxygen - and energy, ATP) is detailed. Our expanding understanding of the regulatory network upstream of mTORC1 provides molecular insights into the integrated sensing mechanisms by which diverse cellular signals converge to control cell physiology. PMID- 23728464 TI - YAP forces fibroblasts to feel the tension. AB - Cancer-associated fibroblasts (CAFs) may contribute to tissue tension and cancer progression by increasing extracellular matrix (ECM) deposition and remodelling. However, how CAFs become activated and their roles in tumour mechanics have remained unclear. YAP is now identified as a tension-stimulated CAF activator that promotes malignancy through a mechanically reinforced feed-forward loop. PMID- 23728465 TI - Job-splitting among integrins. AB - How different integrin receptors for the same extracellular ligand transduce distinct cellular responses is unclear. The characterization of the class specific adhesomes of beta1 and alphaV integrins now shows that whereas alphaV integrins promote unbranched actin polymerization, beta1 integrins induce myosin II-dependent contractility, and both integrin subtypes synergistically mediate rigidity sensing. PMID- 23728471 TI - Composite reduction labiaplasty. AB - BACKGROUND: The demand for surgery to treat the external female genital area has increased significantly in recent years. Since 2001, the author and his colleagues have performed more than 2,100 surgical procedures to enhance the shape and function of the female genital area. The majority of these procedures were aimed at reduction of the labia minora. Drawing on the technique for labia minora reduction (labiaplasty) that the author first described in 2007 (Gress S, Gynakologisch-Geburtshilfliche Rundschau 47:23-32, 2007), the technique was advanced such that in addition to an even reduction of the labia over their entire length (i.e., not only the part below the clitoris but also the part of the clitoral hood and above), it currently is possible to achieve further tightening of the clitoral hood and correction of a protruding clitoris (clitoral protrusion). This technique creates separate labial segments, the composition of which allows for an optimal shaping and reduction of the labia minora. Since 2006, the author and his colleagues have managed 812 cases using this technique, which has been named "composite reduction labiaplasty." METHODS: After removal of the excessive tissue in an S-shaped line along the internal and external aspects of the labium minus and after cutting of a cranial pedicle flap approximately 2-3 cm long (seen as the caudal extension of the clitoral hood), a crescent-shaped skin segment below the clitoris and a centrally pointed rectangular skin segment above the clitoral hood are removed. By joining the wound margins, a tightening and balanced reduction of the labia minora as well as a correction for the protruding tip of the clitoris (clitoral protrusion) is achieved. RESULTS: All the patients received postoperative care and follow-up assessments during a period of 6 months. Except for a few cases of wound dehiscence requiring surgical correction, wound healing was without complications, and the outcomes were both aesthetically and functionally very satisfactory. CONCLUSION: In contrast to most techniques published to date, the "composite reduction labiaplasty" technique ensures a balanced reduction and a tightening of all parts of the labia minora, especially in the region of the clitoral hood. In addition, this technique results in an optimal correction of clitoris positioning in cases of clitoral protrusion. Concerns regarding impairment of sexual sensation or the ability to be sexually stimulated are unfounded. Approximately 35 % of the patients even reported a postoperative increase in their ability to be sexually stimulated. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23728472 TI - Facile preparation of hierarchically porous carbons from metal-organic gels and their application in energy storage. AB - Porous carbon materials have numerous applications due to their thermal and chemical stability, high surface area and low densities. However, conventional preparing porous carbon through zeolite or silica templates casting has been criticized by the costly and/or toxic procedure. Creating three-dimensional (3D) carbon products is another challenge. Here, we report a facile way to prepare porous carbons from metal-organic gel (MOG) template, an extended metal-organic framework (MOF) structure. We surprisingly found that the carbon products inherit the highly porous nature of MOF and combine with gel's integrated character, which results in hierarchical porous architectures with ultrahigh surface areas and quite large pore volumes. They exhibit considerable hydrogen uptake and excellent electrochemical performance as cathode material for lithium-sulfur battery. This work provides a general method to fast and clean synthesis of porous carbon materials and opens new avenues for the application of metal organic gel in energy storage. PMID- 23728473 TI - Measuring patient safety in the emergency department. AB - As a safety net for the health care system, quality and safety performance in emergency medicine (EM) is important for policy makers, insurers, researchers, health care providers, and patients. Developing performance indicators that are relevant, valid, feasible, and easy to measure has proven difficult. To monitor progress, patient safety should be measured objectively. Although conceptual frameworks and error taxonomies have been proposed, a practical scorecard for measuring patient safety over time in EM has been lacking. This article proposes a framework that measures safety through 4 major domains: (1) how often patients are harmed, (2) how often appropriate interventions are delivered, (3) how well errors in the system are identified and corrected, and (4) emergency department (ED) safety culture. Examples of specific measures for each of these domains are provided, but the EM community should reach consensus on what measures are important for the ED environment and patients. PMID- 23728474 TI - Nontraditional placement of an implantable cardioverter-defibrillator in a heterotaxy patient after the completion of total cavopulmonary connection. AB - A 15-year-old boy with heterotaxy syndrome developed a prolonged QT interval and intractable torsade de pointes after the administration of sodium channel blockers for atrial tachyarrhythmia. Although this situation called for the placement of an implantable cardioverter-defibrillator, a conventional transvenous approach was not available since the patient had previously undergone a nonfenestrated extracardiac total cavopulmonary connection. We were urged to carry out the surgical placement of an epicardial lead for an implantable cardioverter-defibrillator using a single coil transvenous shock lead through re do midline sternotomy. Here we describe the details of this nontraditional surgical procedure for the placement of a lead for an implantable cardioverter defibrillator in a case without venous access into the heart. PMID- 23728475 TI - Medication continuity among Medicaid beneficiaries with schizophrenia and bipolar disorder. AB - OBJECTIVE: This study was conducted to examine whether medication continuity among Medicaid beneficiaries with schizophrenia and bipolar disorder was associated with medication utilization management practices (prior authorization, copayment amounts, and refill and pill quantity limits), managed care enrollment, and other state and beneficiary characteristics. METHODS: With 2007 Medicaid Analytic Extract claims data from 22 states, random-effects logistic regression modeled the odds of high medication continuity, defined as receiving medications for at least 80% of the days enrolled in Medicaid, among beneficiaries ages 18-64 with a diagnosis of schizophrenia (N=91,451) or bipolar disorder (N=33,234). RESULTS: Sixty-four percent of beneficiaries with schizophrenia and 54% of beneficiaries with bipolar disorder had high medication continuity. Medication continuity was worse among beneficiaries with schizophrenia in states that required prior authorization for antipsychotics, $2-$3 copayments for generic medications, or $1 copayments for branded medications (compared with no copayments). For beneficiaries with bipolar disorder, medication continuity was worse among those in states with more prior-authorization requirements for different classes of medications or $1 copayments for branded medications. Medication continuity was worse among beneficiaries who were African American, Hispanic, younger, or enrolled in a health maintenance organization health plan or who had a comorbid substance use disorder or cardiovascular disease. CONCLUSIONS: Prior-authorization requirements and copayments for medications may present barriers to refilling medications for Medicaid beneficiaries with schizophrenia or bipolar disorder. State Medicaid programs should consider the unintended consequences of medication utilization management practices for this population. PMID- 23728476 TI - Comparing the cost-effectiveness of simulation modalities: a case study of peripheral intravenous catheterization training. AB - While the ultimate goal of simulation training is to enhance learning, cost effectiveness is a critical factor. Research that compares simulation training in terms of educational- and cost-effectiveness will lead to better-informed curricular decisions. Using previously published data we conducted a cost effectiveness analysis of three simulation-based programs. Medical students (n = 15 per group) practiced in one of three 2-h intravenous catheterization skills training programs: low-fidelity (virtual reality), high-fidelity (mannequin), or progressive (consisting of virtual reality, task trainer, and mannequin simulator). One week later, all performed a transfer test on a hybrid simulation (standardized patient with a task trainer). We used a net benefit regression model to identify the most cost-effective training program via paired comparisons. We also created a cost-effectiveness acceptability curve to visually represent the probability that one program is more cost-effective when compared to its comparator at various 'willingness-to-pay' values. We conducted separate analyses for implementation and total costs. The results showed that the progressive program had the highest total cost (p < 0.001) whereas the high fidelity program had the highest implementation cost (p < 0.001). While the most cost-effective program depended on the decision makers' willingness-to-pay value, the progressive training program was generally most educationally- and cost effective. Our analyses suggest that a progressive program that strategically combines simulation modalities provides a cost-effective solution. More generally, we have introduced how a cost-effectiveness analysis may be applied to simulation training; a method that medical educators may use to investment decisions (e.g., purchasing cost-effective and educationally sound simulators). PMID- 23728477 TI - Designing and implementing nervous system simulations on LEGO robots. AB - We present a method to use the commercially available LEGO Mindstorms NXT robotics platform to test systems level neuroscience hypotheses. The first step of the method is to develop a nervous system simulation of specific reflexive behaviors of an appropriate model organism; here we use the American Lobster. Exteroceptive reflexes mediated by decussating (crossing) neural connections can explain an animal's taxis towards or away from a stimulus as described by Braitenberg and are particularly well suited for investigation using the NXT platform.(1) The nervous system simulation is programmed using LabVIEW software on the LEGO Mindstorms platform. Once the nervous system is tuned properly, behavioral experiments are run on the robot and on the animal under identical environmental conditions. By controlling the sensory milieu experienced by the specimens, differences in behavioral outputs can be observed. These differences may point to specific deficiencies in the nervous system model and serve to inform the iteration of the model for the particular behavior under study. This method allows for the experimental manipulation of electronic nervous systems and serves as a way to explore neuroscience hypotheses specifically regarding the neurophysiological basis of simple innate reflexive behaviors. The LEGO Mindstorms NXT kit provides an affordable and efficient platform on which to test preliminary biomimetic robot control schemes. The approach is also well suited for the high school classroom to serve as the foundation for a hands-on inquiry based biorobotics curriculum. PMID- 23728478 TI - BUB1 and BUBR1 inhibition decreases proliferation and colony formation, and enhances radiation sensitivity in pediatric glioblastoma cells. AB - PURPOSE: Glioblastoma (GBM) is a very aggressive and lethal brain tumor with poor prognosis. Despite new treatment strategies, patients' median survival is still lower than 1 year in most cases. The expression of the BUB gene family has demonstrated to be altered in a variety of solid tumors, pointing to a role as putative therapeutic target. The purpose of this study was to determine BUB1, BUB3, and BUBR1 gene expression profiles in glioblastoma and to analyze the effects of BUB1 and BUBR1 inhibition combined or not with Temozolomide and radiation in the pediatric SF188 GBM cell line. METHODS: For gene expression analysis, 8 cell lines and 18 tumor samples were used. The effect of BUB1 and BUBR1 inhibition was evaluated using siRNA. Apoptosis, cell proliferation, cell cycle kinetics, micronuclei formation, and clonogenic capacity were analyzed after BUB1 and BUBR1 inhibition. Additionally, combinatorial effects of gene inhibition and radiation or Temozolomide (TMZ) treatment were evaluated through proliferation and clonogenic capacity assays. RESULTS: We report the upregulation of BUB1 and BUBR1 expression and the downregulation of BUB3 in GBM samples and cell lines when compared to white matter samples (p < 0.05). Decreased cell proliferation and colony formation after BUB1 and BUBR1 inhibition were observed, along with increased micronuclei formation. Combinations with TMZ also caused cell cycle arrest and increased apoptosis. Moreover, our results demonstrate that BUB1 and BUBR1 inhibition sensitized SF188 cells to gamma-irradiation as shown by decreased growth and abrogation of colony formation capacity. CONCLUSION: BUB1 and BUBR1 inhibition decreases proliferation and shows radiosensitizing effects on pediatric GBM cells, which could improve treatment strategies for this devastating tumor. Collectively, these findings highlight the potentials of BUB1 and BUBR1 as putative therapeutic targets for glioblastoma treatment. PMID- 23728479 TI - Development of a fluorescent sensor for an illicit date rape drug--GBL. AB - The first fluorescent sensor for an illicit date rape drug, GBL, was developed and named Green Date. It shows high fluorescence enhancement to GBL and allows its detection in different drinks. The mechanism between GBL and Green Date was explored. This discovery may help to prevent the drug-facilitated sexual assault problems. PMID- 23728481 TI - Organization and chemical neuroanatomy of the African elephant (Loxodonta africana) hippocampus. AB - Elephants are thought to possess excellent long-term spatial-temporal and social memory, both memory types being at least in part hippocampus dependent. Although the hippocampus has been extensively studied in common laboratory mammalian species and humans, much less is known about comparative hippocampal neuroanatomy, and specifically that of the elephant. Moreover, the data available regarding hippocampal size of the elephant are inconsistent. The aim of the current study was to re-examine hippocampal size and provide a detailed neuroanatomical description of the hippocampus in the African elephant. In order to examine the hippocampal size the perfusion-fixed brains of three wild-caught adult male African elephants, aged 20-30 years, underwent MRI scanning. For the neuroanatomical description brain sections containing the hippocampus were stained for Nissl, myelin, calbindin, calretinin, parvalbumin and doublecortin. This study demonstrates that the elephant hippocampus is not unduly enlarged, nor specifically unusual in its internal morphology. The elephant hippocampus has a volume of 10.84 +/- 0.33 cm3 and is slightly larger than the human hippocampus (10.23 cm(3)). Histological analysis revealed the typical trilaminated architecture of the dentate gyrus (DG) and the cornu ammonis (CA), although the molecular layer of the dentate gyrus appears to have supernumerary sublaminae compared to other mammals. The three main architectonic fields of the cornu ammonis (CA1, CA2, and CA3) could be clearly distinguished. Doublecortin immunostaining revealed the presence of adult neurogenesis in the elephant hippocampus. Thus, the elephant exhibits, for the most part, what might be considered a typically mammalian hippocampus in terms of both size and architecture. PMID- 23728480 TI - In vivo assembly of the axon initial segment in motor neurons. AB - The axon initial segment (AIS) is responsible for both the modulation of action potentials and the maintenance of neuronal polarity. Yet, the molecular mechanisms controlling its assembly are incompletely understood. Our study in single electroporated motor neurons in mouse embryos revealed that AnkyrinG (AnkG), the AIS master organizer, is undetectable in bipolar migrating motor neurons, but is already expressed at the beginning of axonogenesis at E9.5 and initially distributed homogeneously along the entire growing axon. Then, from E11.5, a stage when AnkG is already apposed to the membrane, as observed by electron microscopy, the protein progressively becomes restricted to the proximal axon. Analysis on the global motor neurons population indicated that Neurofascin follows an identical spatio-temporal distribution, whereas sodium channels and beta4-spectrin only appear along AnkG(+) segments at E11.5. Early patch-clamp recordings of individual motor neurons indicated that at E12.5 these nascent AISs are already able to generate spikes. Using knock-out mice, we demonstrated that neither beta4-spectrin nor Neurofascin control the distal-to-proximal restriction of AnkG. PMID- 23728482 TI - Targeted delivery of photosensitizers: efficacy and selectivity issues revealed by multifunctional ORMOSIL nanovectors in cellular systems. AB - PEGylated and non-PEGylated ORMOSIL nanoparticles prepared by microemulsion condensation of vinyltriethoxy-silane (VTES) were investigated in detail for their micro-structure and ability to deliver photoactive agents. With respect to pure silica nanoparticles, organic modification substantially changes the microstructure and the surface properties. This in turn leads to a modulation of both the photophysical properties of embedded photosensitizers and the interaction of the nanoparticles with biological entities such as serum proteins. The flexibility of the synthetic procedure allows the rapid preparation and screening of multifunctional nanosystems for photodynamic therapy (PDT). Selective targeting of model cancer cells was tested by using folate, an integrin specific RGD peptide and anti-EGFR antibodies. Data suggest the interference of the stealth-conferring layer (PEG) with small targeting agents, but not with bulky antibodies. Moreover, we showed that selective photokilling of tumour cells may be limited even in the case of efficient targeting because of intrinsic transport limitations of active cellular uptake mechanisms or suboptimum localization. PMID- 23728483 TI - Effects of outdoor and indoor air pollution on respiratory health of Chinese children from 50 kindergartens. AB - BACKGROUND: Concentrations of ambient air pollution and pollutants in China have changed considerably during the last decade. However, few studies have evaluated the effects of current ambient air pollution on the health of kindergarten children. METHODS: We studied 6730 Chinese children (age, 3-7 years) from 50 kindergartens in 7 cities of Northeast China in 2009. Parents or guardians completed questionnaires that asked about the children's histories of respiratory symptoms and risk factors. Three-year concentrations of particles with an aerodynamic diameter <=10 um (PM10), sulfur dioxide (SO2), and nitrogen dioxides (NO2) were calculated at monitoring stations in 25 study districts. A 2-stage regression approach was used in data analyses. RESULTS: The prevalence of respiratory symptoms was higher among children living near a busy road, those living near chimneys or a factory, those having a coal-burning device, those living with smokers, and those living in a home that had been recently renovated. Among girls, PM10 was associated with persistent cough (odds ratio [OR]PM10 = 1.44; 95% CI, 1.18-1.77), persistent phlegm (ORPM10 = 1.36; 95% CI, 1.02-1.81), and wheezing (ORPM10 = 1.31; 95% CI, 1.04-1.65). NO2 concentration was associated with increased prevalence of allergic rhinitis (OR = 1.96; 95% CI, 1.27-3.02) among girls. In contrast, associations of respiratory symptoms with concentrations of PM10, SO2, and NO2 were not statistically significant among boys. CONCLUSIONS: Air pollution is particularly important in the development of respiratory morbidity among children. Girls may be more susceptible than boys to air pollution. PMID- 23728484 TI - Linking contact behavior and droplet patterns to dynamically model indoor respiratory infections among schoolchildren. AB - BACKGROUND: We used the results of a contact behavior survey in conjunction with droplet pattern measurement to investigate the indoor population transmission dynamics of respiratory infections. METHODS: A total of 404 questionnaires on all contact behaviors were distributed to junior high school students. Droplet number concentration and size distribution generated by coughing and talking were measured by droplet experimentation. A deterministic susceptible-exposed-infected recovery (SEIR) model was used to simulate the indoor transmission dynamics of influenza infection among schoolchildren. RESULTS: Results indicated that the average contact rates ranged from 9.44 to 11.18 person(-1) day(-1) for grades 7 to 9. We showed that total median droplet number concentrations were 9.01 * 10(7) and 8.23 * 10(7) droplets per cubic meter for coughing and talking, respectively. Population dynamic simulations indicated that the size-dependent median number of droplets per person resulted in a maximum of 8 and 10 infected persons on day 4, respectively, for talking and coughing activities. CONCLUSIONS: Human contact behavior and airborne droplet characteristics may substantially change predicted indoor population transmission dynamics of influenza infection. PMID- 23728485 TI - Effects of health guidance on outpatient and pharmacy expenditures: a disease- and drug-specific 3-year observational study using propensity-score matching. AB - BACKGROUND: Evidence is lacking on whether health guidance for metabolic syndrome reduces health care expenditures. The author used propensity-score matching to evaluate the effects of health guidance on health care expenditure. METHODS: Men who did and did not receive health guidance from a health insurance society (approximately 60 000 covered lives) were matched (n = 397 respectively) using propensity scores. Health insurance claims were compared using cumulative health care expenditures for metabolic syndrome-related outpatient medical care and drug costs for the period from the initial consultation to 3 years later. RESULTS: No difference was observed between intervention and control groups in cumulative outpatient charges or drug costs related to metabolic syndrome. However, regression analysis using the Tobit model showed that health guidance resulted in a small, nonsignificant reduction in health care expenditure. CONCLUSIONS: Health guidance for metabolic syndrome did not reduce outpatient charges or drug costs related to metabolic syndrome during the 3-year period after the intervention. Findings from Tobit regression suggest that health guidance might eventually result in savings, but this hypothesis remains untested. PMID- 23728486 TI - Farm level adaptation to climate change: the case of farmer's in the Ethiopian highlands. AB - In Ethiopia, climate change and associated risks are expected to have serious consequences for agriculture and food security. This in turn will seriously impact on the welfare of the people, particularly the rural farmers whose main livelihood depends on rain-fed agriculture. The level of impacts will mainly depend on the awareness and the level of adaptation in response to the changing climate. It is thus important to understand the role of the different factors that influence farmers' adaptation to ensure the development of appropriate policy measures and the design of successful development projects. This study examines farmers' perception of change in climatic attributes and the factors that influence farmers' choice of adaptation measures to climate change and variability. The estimated results from the climate change adaptation models indicate that level of education, age and wealth of the head of the household; access to credit and agricultural services; information on climate, and temperature all influence farmers' choices of adaptation. Moreover, lack of information on adaptation measures and lack of finance are seen as the main factors inhibiting adaptation to climate change. These conclusions were obtained with a Multinomial logit model, employing the results from a survey of 400 smallholder farmers in three districts in Tigray, northern Ethiopian. PMID- 23728487 TI - Improving technical information use: what can be learnt from a manager's perspective? AB - Conservation practice reportedly suffers from low use of technical information. Understanding of factors that affect the influence of technical information on management decision-making is limited. We sought to identify leverage points for improved technical information dissemination in the New South Wales Parks and Wildlife Service, Australia, given the significant recent investments in monitoring and evaluation that had been made. We did so by exploring the inter relationships between factors affecting the influence of different information types on management decisions. Results indicate that managers have a high inclination toward adaptive behavior, given they operate in an information poor environment. The most influential types of information were those that enabled interaction between information provider and recipient (e.g., staff experience and expertise). An analysis of the concordance in individuals' responses for different information types showed that neither accessibility nor organizational expectation of use was aligned with influence on decision-making. Alignment of responses also varied by work area. Raising expectations of information use or increasing access to particular types of information is therefore unlikely to result in an increase in influence on management decision-making. Rather than focussing on matching accessibility and expected use of particular information types, our results indicate that technical information uptake is best supported through existing peer networks tailored to specific work areas. PMID- 23728488 TI - FRET-based ratiometric fluorescent probes for selective Fe3+ sensing and their applications in mitochondria. AB - Efficient ratiometric fluorescent Fe(3+) probes were designed and synthesized by linking a conjugated naphthalene chromophore to a rhodamine platform and a lipophilic triphenylphosphonium (TPP) cation. The probes could sensitively and selectively detect mitochondrial Fe(3+) in living cells. PMID- 23728489 TI - High-performance flexible electrochromic device based on facile semiconductor-to metal transition realized by WO3.2H2O ultrathin nanosheets. AB - Ultrathin nanosheets are considered as one kind of the most promising candidates for the fabrication of flexible electrochromic devices (ECDs) due to their permeable channels, high specific surface areas, and good contact with the substrate. Herein, we first report the synthesis of large-area nanosheets of tungsten oxide dihydrate (WO3.2H2O) with a thickness of only about 1.4 nm, showing much higher Li(+) diffusion coefficients than those of the bulk counterpart. The WO3.2H2O ultrathin nanosheets are successfully assembled into the electrode of flexible electrochromic device, which exhibits wide optical modulation, fast color-switching speed, high coloration efficiency, good cyclic stability and excellent flexibility. Moreover, the electrochromic mechanism of WO3.2H2O is further investigated by first-principle density functional theory (DFT) calculations, in which the relationship between structural features of ultrathin nanosheets and coloration/bleaching response speed is revealed. PMID- 23728491 TI - Radiofrequency energy in surgery: state of the art. AB - Over a period of more than 100 years, radiofrequency energy has been introduced in many fields and applications in medicine. At present, radiofrequency constitutes the basis of numerous medical devices employed in almost all medical specialties. It is particularly applicable and valuable in various minimally invasive procedures for its locally focused effects. Radiofrequency energy is a technical term established to describe high-frequency alternating electrical currents (with a frequency ranging from 300 kHz to 3 MHz) and their impact on biological tissue. The application of RF energy causes controlled tissue heating with consequent cell protein denaturation and desiccation, which leads to cell death and tissue destruction. The primary principle of radiofrequency is that the generated heat can be used to cut, coagulate or induce metabolic processes in the target tissue. The authors of this paper offer a comprehensive and compact review of the definition, history, physics, biological principles and applications of radiofrequency energy in current surgery. PMID- 23728492 TI - A closer look at osteoarthritis. AB - Osteoarthritis (OA) is the most common form of arthritis affecting 26.9 million Americans. OA is a degenerative disorder of the synovial joint that leads to pain, stiffness, and decreased function of the affected joint. An understanding of both the nonpharmacologic and pharmacologic management of OA is essential for nurse practitioners. PMID- 23728490 TI - Compensating for synaptic loss in Alzheimer's disease. AB - Confirming that synaptic loss is directly related to cognitive deficit in Alzheimer's disease (AD) has been the focus of many studies. Compensation mechanisms counteract synaptic loss and prevent the catastrophic amnesia induced by synaptic loss via maintaining the activity levels of neural circuits. Here we investigate the interplay between various synaptic degeneration and compensation mechanisms, and abnormal cortical oscillations based on a large-scale network model consisting of 100,000 neurons exhibiting several cortical firing patterns, 8.5 million synapses, short-term plasticity, axonal delays and receptor kinetics. The structure of the model is inspired by the anatomy of the cerebral cortex. The results of the modelling study suggest that cortical oscillations respond differently to compensation mechanisms. Local compensation preserves the baseline activity of theta (5-7 Hz) and alpha (8-12 Hz) oscillations whereas delta (1-4 Hz) and beta (13-30 Hz) oscillations are maintained via global compensation. Applying compensation mechanisms independently shows greater effects than combining both compensation mechanisms in one model and applying them in parallel. Consequently, it can be speculated that enhancing local compensation might recover the neural processes and cognitive functions that are associated with theta and alpha oscillations whereas inducing global compensation might contribute to the repair of neural (cognitive) processes which are associated with delta and beta band activity. Compensation mechanisms may vary across cortical regions and the activation of inappropriate compensation mechanism in a particular region may fail to recover network dynamics and/or induce secondary pathological changes in the network. PMID- 23728493 TI - Postoperative pulmonary complications: reducing risks for noncardiac surgery. AB - Postoperative pulmonary complications (PPCs) are a major contributor to the overall risk of noncardiac surgery that may lead to serious postoperative morbidity and long-term mortality. Nurse practitioners should be familiar with risk indices for PPCs, clinical guidelines, and risk reduction strategies to prevent PPCs and improve PPC outcomes. PMID- 23728494 TI - Side pockets provide the basis for a new mechanism of Kv channel-specific inhibition. AB - Most known small-molecule inhibitors of voltage-gated ion channels have poor subtype specificity because they interact with a highly conserved binding site in the central cavity. Using alanine-scanning mutagenesis, electrophysiological recordings and molecular modeling, we have identified a new drug-binding site in Kv1.x channels. We report that Psora-4 can discriminate between related Kv channel subtypes because, in addition to binding the central pore cavity, it binds a second, less conserved site located in side pockets formed by the backsides of S5 and S6, the S4-S5 linker, part of the voltage sensor and the pore helix. Simultaneous drug occupation of both binding sites results in an extremely stable nonconducting state that confers high affinity, cooperativity, use dependence and selectivity to Psora-4 inhibition of Kv1.x channels. This new mechanism of inhibition represents a molecular basis for the development of a new class of allosteric and selective voltage-gated channel inhibitors. PMID- 23728496 TI - Metabolic regulation and chromosomal localization of carbaryl degradation pathway in Pseudomonas sp. strains C4, C5 and C6. AB - Pseudomonas sp. strains C4, C5 and C6 degrade carbaryl (1-naphthyl N methylcarbamate) via 1-naphthol, 1,2-dihydroxynaphthalene, salicylate and gentisate. Carbon source-dependent metabolic studies suggest that enzymes responsible for carbaryl degradation are probably organized into 'upper' (carbaryl to salicylate), 'middle' (salicylate to gentisate) and 'lower' (gentisate to TCA cycle) pathway. Carbaryl and 1-naphthol were found to induce all carbaryl pathway enzymes, while salicylate and gentisate induce middle and lower pathway enzymes. The strains were found to harbor plasmid(s), and carbaryl degradation property was found to be stable. Genes encoding enzymes of the degradative pathway such as 1-naphthol 2-hydroxylase, salicylaldehyde dehydrogenase, salicylate 5-hydroxylase and gentisate 1,2-dioxygenase were amplified from chromosomal DNA of these strains. The gene-specific PCR products were sequenced from strain C6, and phylogenetic tree was constructed. Southern hybridization and PCR analysis using gel eluted DNA as template supported the presence of pathway genes onto the chromosome and not on the plasmid(s). PMID- 23728495 TI - Identification of small molecules for human hepatocyte expansion and iPS differentiation. AB - Cell-based therapies hold the potential to alleviate the growing burden of liver diseases. Such therapies require human hepatocytes, which, within the stromal context of the liver, are capable of many rounds of replication. However, this ability is lost ex vivo, and human hepatocyte sourcing has limited many fields of research for decades. Here we developed a high-throughput screening platform for primary human hepatocytes to identify small molecules in two different classes that can be used to generate renewable sources of functional human hepatocytes. The first class induced functional proliferation of primary human hepatocytes in vitro. The second class enhanced hepatocyte functions and promoted the differentiation of induced pluripotent stem cell-derived hepatocytes toward a more mature phenotype than what was previously obtainable. The identification of these small molecules can help address a major challenge affecting many facets of liver research and may lead to the development of new therapeutics for liver diseases. PMID- 23728497 TI - Distinct eicosanoid profile in exhaled breath condensates from granulomatosis with polyangiitis (Wegener's) patients. PMID- 23728498 TI - Abatacept and its use in the treatment of rheumatoid arthritis (RA) in the Czech Republic-data from the ATTRA registry. AB - The Czech national registry ATTRA collects data from patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and juvenile idiopathic arthritis, treated with the biologic drugs. ATTRA is a prospective centralized computerized registry of patients with a focus on efficacy, safety, and quality of life data. Abatacept is approved as a second-line agent which can be prescribed after a failure of at least one TNF-alfa inhibitor. Data of patients treated with abatacept has been collected since 2008. A statistical analysis of the group of RA patients treated with abatacept was performed recently. ATTRA registered 162 patients with RA treated with abatacept, the mean age 51.0 +/- 12.2 (median 53.1, 19-74 years), the mean duration of the disease was 14 +/- 9.1, median 11.3 years (0-41). One hundred thirty patients (80.2 %) were female. The mean DAS28 was at week 0, 5.9 +/- 1.1, at week 16, 4.1 +/- 1.4, at week 24, 3.8 +/- 1.2, at week 36, 3.6 +/- 1.3, and at week 52, 3.5 +/- 1.2. DAS28 remission was achieved at week 16 in 15.8 %, at week 24 in 10 %, at week 36 in 20.9 %, and at week 2 in 20.8 % of patients. Of those patients with a DAS28 <2.6 (remission) at week 16, 58.3 % remained in remission at the week 52. Of those patients with DAS28 >5.1 (high disease activity) at the week 16, only 41.7 % had DAS >5.1 at week 52. One year on treatment survival was 82 %. Altogether 50 non-serious adverse events (AE) were reported in 36 patients (22 %) and 11 serious AE in 10 patients (6 %) with the most common being infections (31) and skin rashes (5). Just one non-serious allergic reaction was reported. Data from the ATTRA registry confirms a good overall efficacy and safety profile and a very good on drug survival with abatacept. PMID- 23728499 TI - Imaging manifestations of autoimmune disease-associated lymphoproliferative disorders of the lung. AB - Lymphoproliferative disorders (LPDs) may involve intrathoracic organs in patients with autoimmune disease, but little is known about the radiologic manifestations of autoimmune disease-associated LPDs (ALPDs) of the lungs. The purpose of our work was to identify the radiologic characteristics of pulmonary involvement in ALPDs. A comprehensive search for PubMed database was conducted with the combination of MeSH words. All articles which had original images or description on radiologic findings were included in this analysis. Also, CT images of eight patients with biopsy-proven lymphoproliferative disorder observed from our institution were added. Overall, 44 cases of ALPD were identified, and consisted of 24 cases of bronchus-associated lymphoid tissue lymphoma (BALToma), eight cases of non-Hodgkin's lymphoma (NHL), six cases of lymphoid interstitial pneumonia (LIP), two cases of nodular lymphoid hyperplasia, two cases of unclassified lymphoproliferative disorder, and one case each of lymphomatoid granulomatosis and hyperblastic BALT. Multiple nodules (n = 14, 32 %) and single mass (n = 8, 18 %) were the predominant radiologic manifestations. The imaging findings conformed to previously described findings of BALToma, NHL, or LIP. Data suggest that BALToma, NHL, and LIP are the predominant ALPDs of the lung, and ALPD generally shared common radiologic features with sporadic LPDs. Familiarity with ALPDs and their imaging findings may enable radiologists or clinicians to include the disease as a potential differential diagnosis and thus, to prompt early biopsy followed by appropriate treatment. PMID- 23728500 TI - Mitigating effects of external ventricular drain usage in the management of severe head injury. AB - BACKGROUND: Cerebrospinal fluid (CSF) drainage has been variably employed to lower intracranial pressure (ICP) in patients with severe head injury. The efficacy of this manoeuvre remains under-explored (Brain Trauma Foundation Recommendation-optional treatment). This work seeks to report the results of CSF drainage via external ventricular drain (EVD) in severe head injury in comparison to other treatment options. METHODS: Retrospective observational comparative study of all consecutive patients admitted to a major trauma centre with severe traumatic brain injury over a period of 12 months. RESULTS: Out of a total 139 patients, 33 had delayed elevation of ICP despite conventional medical therapy, 16 patients were treated with EVD insertion (4 placed under AxiEM image guidance [Medtronic]) and 17 received either decompressive craniectomy or barbiturate coma. Subsequently, two patients with decompression had further ICP elevation and needed EVD. Two patients with EVD had raised ICP-one underwent decompression and the other was treated with barbiturate coma. One patient with EVD developed infection, which was successfully treated. Patients treated with EVD had a lower risk of needing definitive treatment for ICP control, i.e. decompressive craniectomy or barbiturate coma. CONCLUSIONS: EVD was a safe and less invasive procedure, and achieved sustained control of ICP in this patient group. PMID- 23728501 TI - Early postoperative radiotherapy improves progression free survival in patients with grade 2 meningioma. AB - BACKGROUND: Grade 2 meningiomas are a real problem in therapeutic management because of their tendency to reoccur. The most effective treatment is surgery. The role of adjuvant radiotherapy in this disease is still disputed due to its uncertain effect on progression-free survival. OBJECTIVE: To show that early adjuvant radiotherapy is an effective treatment in patients with grade 2 meningiomas. MATERIALS AND METHODS: A retrospective study was performed on all patients operated on for grade 2 meningioma in our center between 1994 and 2011. For every patient, we recorded the age at diagnosis, sex, background of neurofibromatosis type 2 (NF2) or meningiomatosis, location of meningioma, quality of tumor resection and whether the patient received early postoperative radiotherapy. These prognosis factors were studied using statistical tests. RESULTS: We included 167 patients (94 women, 73 men, sex ratio = 1.28); the mean age at diagnosis was 53.8 years. Twenty-seven patients received early adjuvant radiotherapy after surgery. Patients who received early postoperative radiotherapy had a significantly longer progression-free survival (8.2 years) than patients without radiotherapy (5.7 years, p = 0.04). In multivariate analysis, quality of tumor resection and early postoperative radiotherapy decrease the risk of recurrence of meningioma (p < 0.05). CONCLUSION: Adjuvant radiotherapy is an important therapeutic tool in the treatment of patients with grade 2 meningioma. It delays tumor progression and reduces the need for further surgery. Adjuvant radiotherapy must be considered as a treatment option in oncological multidisciplinary meetings, regardless of the quality of surgical resection. PMID- 23728502 TI - Vascular endothelial growth factor gene polymorphisms and intracranial aneurysms. AB - BACKGROUND: The exact pathophysiology of the development and rupture of saccular aneurysms is still controversial. Several lines of evidence indicate a role for inflammatory processes. Similarly, abnormal angiogenesis might be related to aneurysm growth. Expression of angiogenesis factors is higher in patients harboring aneurysms. The aim of this study was to verify the association of two functionally active polymorphisms (+ 396 C>T and 18 bp microdeletion) in the vascular endothelial growth factor (VEGF) gene with both susceptibility to and clinical features of aneurysmal subarachnoid hemorrhage (SAH) in an Italian population. METHOD: Allelic and genotypic frequencies of the + 396 C>T and the 18 bp microdeletion of the VEGF gene were determined in 200 patients and 200 healthy controls. RESULTS: Both allelic and genotypic frequencies of the examined polymorphisms in the VEGF gene were not significantly different between cases and controls. Furthermore, the different VEGF genotypes did not seem to significantly modify the main clinical features of the disease. CONCLUSIONS: Our data suggest that the VEGF gene is not a major genetic risk factor for aneurysmal subarachnoid hemorrhage. PMID- 23728503 TI - Stimulation sites in the subthalamic nucleus projected onto a mean 3-D atlas of the thalamus and basal ganglia. AB - BACKGROUND: In patients with severe forms of Parkinson's disease (PD), deep brain stimulation (DBS) commonly targets the subthalamic nucleus (STN). Recently, the mean 3-D Morel-Atlas of the basal ganglia and the thalamus was introduced. It combines information contained in histological data from ten post-mortem brains. We were interested whether the Morel-Atlas is applicable for the visualization of stimulation sites. METHODS: In a consecutive PD patient series, we documented preoperative MRI planning, intraoperative target adjustment based on electrophysiological and neurological testing, and perioperative CT target reconstruction. The localization of the DBS electrodes and the optimal stimulation sites were projected onto the Morel-Atlas. RESULTS: We included 20 patients (median age 62 years). The active contact had mean coordinates Xlat = +/ 12.1 mm, Yap = -1.8 mm, Zvert = -3.2 mm. There was a significant difference between the initially planned site and the coordinates of the postoperative active contact site (median 2.2 mm). The stimulation site was, on average, more anterior and more dorsal. The electrode contact used for optimal stimulation was found within the STN of the atlas in 38/40 (95 %) of implantations. CONCLUSIONS: The cluster of stimulation sites in individual patients-as deduced from preoperative MR, intraoperative electrophysiology and neurological testing-showed a high degree of congruence with the atlas. The mean 3D Morel Atlas is thus a useful tool for postoperative target visualization. This represents the first clinical evaluation of the recently created atlas. PMID- 23728504 TI - Nursing students' learning motivation toward technical knowledge and their ethics regarding patients' rights. AB - Nursing students must develop their abilities to provide appropriate nursing services. They need to acquire the level of nursing knowledge to pass the national examination according to Japanese law. Moreover, even if the awareness of the rights of people who receive nursing services increases, students must not have a sense of resistance toward those rights. Therefore, we investigated the factors associated with students' motivation to pass their examination and such a sense of resistance. We produced items related to reasons students wanted to become registered nurses with reference to job satisfaction and their learning environment (e.g., teachers' manners and school events unrelated to the examination). There were 3,417 female nursing students analyzed in 29 vocational schools that allow graduation after a 3-year study period (average age, 21.93 years [standard deviation, 5.44]). Older and third-year students had a stronger motivation to pass the examination and a weaker sense of resistance to people's rights compared with younger and first- to second-year students. Students who answered a "Lack of enthusiasm for becoming a registered nurse" had a weakened motivation and a strengthened sense of resistance. Factors enhancing students' motivation to pass their examination were "Professional commitment," "Desire for companionship," and "School events unrelated to the national examination." Factors strengthening students' sense of resistance to people's rights were "Living stability" and "Social appraisal." Teachers must develop methods to teach ethics so that their students respect the rights of people who receive nursing services and to ensure that they acquire the necessary nursing knowledge. PMID- 23728505 TI - Acquired idiopathic laryngomalacia treated by laser supraglottic laryngoplasty. AB - Laryngomalacia is the most common cause of stridor in neonates and infants, where the soft cartilages and tissues surrounding the upper larynx collapse inward during respiration. On the other hand, acquired idiopathic laryngomalacia in adults is quite rare, but should be borne in mind for differential diagnosis of upper airway distress. Allergic factors may cause airway distress, but have not been highlighted previously as the background of laryngomalacia. In this report, we describe two patients with acquired idiopathic laryngomalacia with reference to allergic rhinitis and high serum levels of immunoglobulin E. The first patient was a 16-year-old female who presented with inspiratory stridor and dyspnea due to attachment between the epiglottis and bilateral arytenoids, and the second patient was an 18-year-old male who also presented with inspiratory stridor due to attachment between the epiglottis and posterior pharyngeal wall. The respiratory function of both patients was within the normal range but the inspiratory stridor interfered with daily life. Laryngomicrosurgery was performed in both patients using a CO2 laser to remove the arytenoid mucosa in the first patient, and to remove the tip of the epiglottis in the second. Both patients were followed up while receiving oral anti-allergic agents. Laser supraglottic laryngoplasty to remove the vibrating excess tissue was effective for resolving the symptoms. However, recurrence occurred three times in the first patient, and inferior turbinotomy to improve nasal respiration was useful for diminishing the symptoms. PMID- 23728506 TI - Dipalmitoyl-phosphatidylcholine biosynthesis is induced by non-injurious mechanical stretch in a model of alveolar type II cells. AB - Dipalmitoylphosphatidylcholine, (DP-PtdCho), the major phospholipid component of lung surfactant is biosynthesized via a de novo pathway, the last step of which is catalyzed by CDP-choline:cholinephosphotransferase (CPT) and two remodeling steps: a deacylation and a reacylation one, catalyzed by an acidic, Ca2+ independent phospholipase A2 (aiPLA2) and a lyso-phosphatidylcholine acyltransferase (LPCAT), respectively. The aim of our study was to investigate whether a low magnitude, non-injurious static mode of mechanical stretch can induce phosphatidylcholine (PtdCho) biosynthesis and its remodeling to DP-PtdCho in the A549 cell-line, a model of alveolar type II cells. The deformation of A549 cells did not cause any release of lactate dehydrogenase, or phospholipids into the cell culture supernatants. An increase in PtdCho levels was observed after 1 h of static stretching, especially among the DP-PtdCho molecular species, as indicated by targeted lipidomics approach and site-directed fatty acyl-chain analysis. Moreover, although sphingomyelin (CerPCho) levels were unaffected, the DP-PtdCho/CerPCho ratio increased. Induction was observed in CPT, LPCAT and aiPLA2 enzymatic activities and gene expression. Finally, incubation of the cells with MJ33 suppressed aiPLA2 activity and DP-PtdCho production. Our data suggest that mild static mechanical stretch can promote the biosynthesis of PtdCho and its remodeling to DP-PtdCho in lung epithelial cells. Thus, low magnitude stretch could contribute to protective mechanisms rather than to injurious ones. PMID- 23728507 TI - Single-incision laparoscopic resection of ovarian masses in children: a preliminary report. AB - PURPOSE: Ovarian masses in the pediatric population are commonly resected with a three or four port laparoscopic approach. Single-incision laparoscopic (SIL) resection is an alternative approach. However, there is limited experience with this modality in ovarian mass resection. METHODS: We reviewed SIL ovarian mass resections performed by our group from 2010 to 2012. We evaluated patient demographics, surgery statistics, and hospital course. RESULTS: Six patients were identified with mean age of 14 years. Imaging studies showed cystic masses ranging 4-6 cm in five patients, and 20 cm in one patient. One patient presented with recurrent teratoma. Pathology revealed four benign teratomas, one benign cyst, and one serous cystadenoma. Average operating time was 75 min. All patients had an ovarian-preserving resection. Three patients had cyst spillage, including the one who presented with recurrence (this was the only patient with a subsequent recurrence). Hospital stay averaged 37 h. Narcotic use averaged 9.9 mg of morphine daily. All patients had excellent cosmetic results, and no postoperative complications. CONCLUSIONS: Ovarian cystic mass excision using the SIL approach carries a higher risk of tumor spillage. Although the incidence of malignancy is low, they cannot be conclusively excluded with our current preoperative evaluations. At this time, we recommend SIL resection only for simple cysts with low malignant potential; however, further experience with this procedure will likely improve the risk of tumor spillage in the future. PMID- 23728508 TI - A novel flexible nanogenerator made of ZnO nanoparticles and multiwall carbon nanotube. AB - In this paper, a novel flexible nanogenerator (FNG) made of zinc-oxide (ZnO) nanoparticles (NPs) and multiwall-carbon nanotubes (MW-CNTs) is presented. In this structure, ZnO NPs and MW-CNTs are mixed with polydimethylsiloxane (PDMS) uniformly to form an entire flexible nanogenerator. Serial tests illustrate that the output voltage and power density are as high as 7.5 V and 18.75 MUW per cycle, respectively. Furthermore, by foot stamp on the FNG, a peak voltage as high as 30 V can be generated. Comparing to the control samples, it is also proved that adding MW-CNTs into the matrix could significantly enhance the output voltage from 0.8 to 7.5 V. In summary, our work indicates that the realization of flexible nanogenerators made of ZnO NPs and MW-CNTs is technologically feasible, which may bring out some important and interesting applications in energy harvesting. PMID- 23728509 TI - CD15s is a potential biomarker of serious bacterial infection in infants admitted to hospital. AB - Early recognition of serious bacterial infection (SBI) in children is essential for better treatment outcome. Flow cytometry analysis of neutrophil surface molecules has been more frequently utilized as a tool for diagnosis of infection. The infants (n = 105) under 6 months of age presenting to the pediatric emergency department with fever without apparent source who were hospitalized with suspicion of having SBI were enrolled in this prospective study. Sixty-nine infants were included into the training pool and were classified into bacterial or viral infection group. Validation pool consisted of 36 infants. The values of white blood cells counts, absolute neutrophil count (ANC), C-reactive protein (CRP), procalcitonin (PCT), neutrophil CD11b, CD15s and CD64 expression, and the percentage (%CD15s+) and absolute count (AC-CD15s+) of CD15s+ neutrophils were determined. In infants with SBI, %CD15s+ was 10.5 times more likely to be higher than the cut-off value. ANC, CRP, PCT, CD64, and AC-CD15s+ were also found as useful biomarkers for differentiation between bacterial and viral infection. The best fit multivariate logistic regression model included CRP, PCT, and %CD15s+ as strong predictors of SBI. The model's sensitivity (87 %) and specificity (83 %) indicated high model's accuracy. After validation on independent dataset, model's accuracy maintained high: 86 % sensitivity and 93 % specificity, confirming its reliability and supporting CRP, PCT, and %CD15s+ as real predictors. The findings of this study support assumption made in the literature on significance of CD15s in inflammation processes. Also, this study demonstrated for the first time that CD15s is potentially valuable biomarker of SBI in infants. PMID- 23728510 TI - Parent-proxy perception of overweight adolescents' health-related quality of life is different according to adolescent gender and age and parent gender. AB - This study assessed health-related quality of life (HRQoL) reported by overweight adolescents and compared to their parent-proxy perception of HRQoL, according to adolescent gender, adolescent age, and parent gender. Patients and a total of 179 adolescents aged 10 to 18 years with excess weight were evaluated for perceived HRQoL prior to beginning a weight-loss intervention, using the Pediatric Quality of Life Inventory (PedsQL 4.0) questionnaire, estimating quality of life in the physical, emotional, social, and school domains, as well as index measures of psychosocial and overall quality of life. Parents completed the same questionnaire estimating his or her child's HRQoL. Compared to their child's self report, parents underestimated all the domains of HRQoL except the school domain. Parents underestimated all the domains of HRQoL among boys; however, they only underestimated the physical domain among girls. Comparisons between parent-proxy perception and self-report of the adolescent according to adolescent's age revealed that parents underestimated their children's HRQoL in the younger adolescents (10 to 13 years) for all except for the school domain and underestimated only the physical domain in older adolescents (14 to 18 years). The same comparison between parent-proxy perception and their child's self-report of HRQoL according to parent gender showed that mothers underestimated HRQoL in all domains except for the school domain, while fathers only underestimated the school domain. CONCLUSION: The differences between self-report of overweight adolescent and perceptions of their parents about the HRQoL of their children are influenced by adolescent gender and age and parent gender. PMID- 23728511 TI - The xanthophyll cycle and NPQ in diverse desert and aquatic green algae. AB - It has long been suspected that photoprotective mechanisms in green algae are similar to those in seed plants. However, exceptions have recently surfaced among aquatic and marine green algae in several taxonomic classes. Green algae are highly diverse genetically, falling into 13 named classes, and they are diverse ecologically, with many lineages including members from freshwater, marine, and terrestrial habitats. Genetically similar species living in dramatically different environments are potentially a rich source of information about variations in photoprotective function. Using aquatic and desert-derived species from three classes of green algae, we examined the induction of photoprotection under high light, exploring the relationship between nonphotochemical quenching and the xanthophyll cycle. In liquid culture, behavior of aquatic Entransia fimbriata (Klebsormidiophyceae) generally matched patterns observed in seed plants. Nonphotochemical quenching was lowest after overnight dark adaptation, increased with light intensity, and the extent of nonphotochemical quenching correlated with the extent of deepoxidation of xanthophyll cycle pigments. In contrast, overnight dark adaptation did not minimize nonphotochemical quenching in the other species studied: desert Klebsormidium sp. (Klebsormidiophyceae), desert and aquatic Cylindrocystis sp. (Zygnematophyceae), and desert Stichococcus sp. (Trebouxiophyceae). Instead, exposure to low light reduced nonphotochemical quenching below dark-adapted levels. De-epoxidation of xanthophyll cycle pigments paralleled light-induced changes in nonphotochemical quenching for species within Klebsormidiophyceae and Trebouxiophyceae, but not Zygnematophyceae. Inhibition of violaxanthin-zeaxanthin conversion by dithiothreitol reduced high-light associated nonphotochemical quenching in all species (Zygnematophyceae the least), indicating that zeaxanthin can contribute to photoprotection as in seed plants but to different extents depending on taxon or lineage. PMID- 23728512 TI - Teaching about photosynthesis with simple equipment: analysis of light-induced changes in fluorescence and reflectance of plant leaves. AB - Solar energy absorbed by plants results in either reflection or absorption. The latter results in photosynthesis, fluorescence, or heat. Measurements of fluorescence changes have been used for monitoring processes associated with photosynthesis. A simple method to follow changes in leaf fluorescence and leaf reflectance associated with nonphotochemical quenching and light acclimation of leaves is described. The main equipment needed consists of a green-light emitting laser pointer, a digital camera, and a personal computer equipped with the camera acquisition software and the programs ImageJ and Excel. Otherwise, only commonly available cheap materials are required. PMID- 23728513 TI - Clinical significance of lung iodine-123 metaiodobenzylguanidine uptake assessment in Parkinson's and heart diseases. AB - OBJECTIVE: Decreased heart iodine-123 metaiodobenzylguanidine ((123)I-MIBG) uptake [heart-to-mediastinum count ratio (H/M)] is reported in heart disease (HD) or Lewy body disease (LBD). When LBD is merged, therefore, information regarding HD severity may be ambiguous. We aimed to examine whether lung (123)I-MIBG uptake [lung-to-mediastinum count ratio (L/M)] assessment might be useful for differentiating two clinical conditions of HD and LBD, and to investigate whether L/M could reflect the grade of left ventricular (LV) dysfunction. METHODS: Three groups were examined: LBD (patient group with Parkinson's disease or dementia with Lewy bodies, n = 33), PS (group with other Parkinsonian syndromes, n = 20) and HD (group with heart disease). HD consisted of 4 subgroups: HD(I) [H/M(<2.30) matched group with LBD, n = 34), HD(II) [H/M(>=2.30)-matched group with PS, n = 33], HD(III) [group for functional analysis, LV ejection fraction, first-third and peak filling rates (1/3FR and PFR) and time to PFR were calculated using gated SPECT, n = 35] and HD(IV) (group for examining cardiac prognosis, follow-up period of 1283 +/- 506 days, n = 54). Using Doppler echocardiography, a diastolic parameter E/e' and pulmonary artery pressure (ePAP) were estimated. RESULTS: H/Ms did not differ between HD(I) and LBD, or between PS and HD(II). However, L/Ms were increased in the order of LBD, PS, HD(II) and HD(I) groups. In combined LBD, PS, HD(I) and HD(II), L/Ms correlated positively with a diastolic parameter E/e'. L/Ms correlated with ePAP, while H/Ms did not. H/Ms correlated with a systolic parameter EF (r = 0.56) and diastolic parameters 1/3FR (r = 0.51) and PFR (r = 0.51), and L/Ms correlated with diastolic parameters 1/3FR (r = -0.36) and PFR (r = -0.36) but not with EF in HD(III). Kaplan-Meier analysis showed earlier cardiac death in patients with decreased H/Ms, but not in patients with increased L/Ms in HD(IV). CONCLUSIONS: Our study suggest that increased lung (123)I-MIBG uptake is useful as a reference marker for differentiating two clinical conditions of HD and LBD, and can reflect the degree of LV diastolic dysfunction. Elevated ePAP caused by LV diastolic dysfunction may be involved in the mechanism(s) of increased lung uptake. PMID- 23728514 TI - Picornavirus uncoating intermediate captured in atomic detail. AB - It remains largely mysterious how the genomes of non-enveloped eukaryotic viruses are transferred across a membrane into the host cell. Picornaviruses are simple models for such viruses, and initiate this uncoating process through particle expansion, which reveals channels through which internal capsid proteins and the viral genome presumably exit the particle, although this has not been clearly seen until now. Here we present the atomic structure of an uncoating intermediate for the major human picornavirus pathogen CAV16, which reveals VP1 partly extruded from the capsid, poised to embed in the host membrane. Together with previous low-resolution results, we are able to propose a detailed hypothesis for the ordered egress of the internal proteins, using two distinct sets of channels through the capsid, and suggest a structural link to the condensed RNA within the particle, which may be involved in triggering RNA release. PMID- 23728515 TI - Isolation of adipose tissue immune cells. AB - The discovery of increased macrophage infiltration in the adipose tissue (AT) of obese rodents and humans has led to an intensification of interest in immune cell contribution to local and systemic insulin resistance. Isolation and quantification of different immune cell populations in lean and obese AT is now a commonly utilized technique in immunometabolism laboratories; yet extreme care must be taken both in stromal vascular cell isolation and in the flow cytometry analysis so that the data obtained is reliable and interpretable. In this video we demonstrate how to mince, digest, and isolate the immune cell-enriched stromal vascular fraction. Subsequently, we show how to antibody label macrophages and T lymphocytes and how to properly gate on them in flow cytometry experiments. Representative flow cytometry plots from low fat-fed lean and high fat-fed obese mice are provided. A critical element of this analysis is the use of antibodies that do not fluoresce in channels where AT macrophages are naturally autofluorescent, as well as the use of proper compensation controls. PMID- 23728516 TI - Uncommon trajectory variations of the mandibular canal and of the mandibular incisive canal: case report. AB - PURPOSE: This paper aims to report and discuss a case in which unusual anatomical variations were observed in the mandibular canal (MC) and the mandibular incisive canal (MIC) in a same patient. MATERIALS AND METHODS: A 49-year-old healthy female was referred for mandibular dental implant placement. Panoramic radiography and cone beam computed tomography (CBCT) were performed. Cross sections, axial, coronal, panoramic reconstructions and volume rendering were obtained. RESULTS: The panoramic radiograph did not show any evidence of abnormality. CBCT showed a bifid MC on the right side. It extended to the buccal cortex, exteriorized for 6 mm and returned to its conventional trajectory to reach the mental foramen. On the left side, the MIC initially followed its normal trajectory for 4 mm but, in the canine region, it also extended to the buccal cortex and exteriorized. CONCLUSION: The advent of CBCT in Dentistry allowed a greater accuracy in the diagnosis of anatomical variations in the jaws, preventing injury to the neurovascular bundle and enabling an adequate surgical planning in the region. PMID- 23728517 TI - Anatomical study of the clavicle: endomedullary morphology. AB - BACKGROUND: The treatment of clavicle fractures remains controversial. The objective of this study was to investigate the possibility of clavicular intramedullary fixation by nailing through an anatomic study combined with CT scan studies. METHODS: For the anatomic study, 20 clavicles of donated bodies to science (10 men, 10 women, 10 right, 10 left) were used. We measured the length of the clavicle, lateral epiphysis diameter, mean diaphysis diameter, medial epiphysis diameter, lateral width, lateral radius of curvature, medial width and medial radius of curvature. Intramedullary cavity diameter (anteroposterior and superoinferior) and calibration were measured by CT scan study on 20 clavicles. RESULTS: Average length was 152 mm for men and 140 mm for women. The anteroposterior curvature was most pronounced. The medullary canal had a gradually decreasing size from the distal portion to the middle segment, but never disappeared. CONCLUSION: Evaluation of morphological data can clarify the specifications of an intramedullary nail: flexibility of the nail to match clavicle curvature and a locking system to ensure primary stability. Intramedullary fixation by nailing in displaced fractures of the middle portion of the clavicle is a minimally invasive surgical technique, with excellent functional and cosmetic results. PMID- 23728518 TI - Ternary copper(II)-polypyridyl enantiomers: aldol-type condensation, characterization, DNA-binding recognition, BSA-binding and anticancer property. AB - Chiral enantiomers [Cu(phen)(L-threo)(H2O)]NO3 1 and [Cu(phen)(D-threo)(H2O)]NO3 2 (threo = threoninate) underwent aldol-type condensation with formaldehyde, with retention of chirality, to yield their respective enantiomeric ternary copper(II) complexes, viz. L- and D-[Cu(phen)(5MeOCA)(H2O)]NO3.xH2O (3 and 4; phen = 1,10 phenanthroline; 5MeOCA = 5-methyloxazolidine-4-carboxylate; x = 0-3) respectively. These chiral complexes were characterized by FTIR, elemental analysis, circular dichroism, UV-Visible spectroscopy, fluorescence spectroscopy (FL), molar conductivity measurement, ESI-MS and X-ray crystallography. Analysis of restriction enzyme inhibition by these four complexes revealed modulation of DNA binding selectivity by the type of ligand, ligand modification and chirality. Their interaction with bovine serum albumin was investigated by FL and electronic spectroscopy. With the aid of the crystal structure of BSA, spectroscopic evidence suggested their binding at the cavity containing Trp134 with numerous Tyr residues in subdomain IA. The products were more antiproliferative than cisplatin against cancer cell lines HK-1, MCF-7, HCT116, HSC-2 and C666-1 except HL-60, and were selective towards nasopharyngeal cancer HK-1 cells over normal NP69 cells of the same organ type. PMID- 23728519 TI - Comparison of Ga-68 DOTA-TATE and Ga-68 DOTA-LAN PET/CT imaging in the same patient group with neuroendocrine tumours: preliminary results. AB - INTRODUCTION: Recent studies have suggested that PET imaging with Ga-68-labelled DOTA-somatostatin analogues such as octreotide and octreotate is useful in diagnosing neuroendocrine tumours (NETs) and has superior value over both computed tomography and planar and SPECT somatostatin receptor scintigraphy. PURPOSE: The aim of the present study was to evaluate the role of Ga-68 DOTA lanreotide (Ga-68-DOTA-LAN) in patients with somatostatin receptor (sst) expressing tumours and to compare the results of Ga-68 DOTA-D-Phe1-Tyr3 octreotate (Ga-68-DOTA-TATE) in the same patient population. MATERIALS AND METHODS: Twelve patients with NETs who were referred to our department for somatostatin receptor scintigraphy were included in the study. There were four patients with well-differentiated neuroendocrine tumour (WDNET) grade 1, two patients with WDNET grade 2, and three patients with poorly differentiated neuroendocrine carcinoma (PDNEC) grade 3. There was also one patient with medullary thyroid cancer, one patient with meningioma and one patient with MEN-1. All patients underwent two consecutive PET imaging studies with Ga-68-DOTA-TATE and Ga-68 DOTA-LAN. All images were evaluated visually, and maximum standardized uptake value was calculated for quantitative evaluation. RESULTS: On visual examination of maximum intensity projection images, GA-68 DOTA-LAN was seen to have high background activity and high bone marrow uptake. Both tracers defined 67 lesions. Ga-68 DOTA-TATE images revealed 63 (94%) clearly defined lesions, missing four lesions. In contrast, Ga-68 DOTA-LAN images defined only 23 (44%) lesions, missing 44 (56%) lesions. Thirty-two bone lesions were detected on Ga-68 DOTA-TATE images. Among them, only 11 (34%) were positive on Ga-68 DOTA-LAN images, whereas 21 (66%) were negative. When we evaluated liver, mediastinum and gastrointestinal tract lesions, Ga-68 DOTA-LAN was seen to be positive for 12 (34%) lesions and negative for 23 (66%) lesions. CONCLUSION: Although the results are preliminary, the image quality obtained by Ga-68-DOTA-TATE seems to be superior to that obtained by Ga-68 DOTA-LAN. With its significantly higher lesion uptake and higher ability to detect lesions, Ga-68-DOTA-TATE seems to be a better radioligand compared with Ga-68-DOTA-LAN for the diagnosis of NETs. PMID- 23728520 TI - 18F-FDG PET/CT findings of radiotherapy-related myocardial changes in patients with thoracic malignancies. AB - OBJECTIVE: The purpose of this study was to investigate myocardial findings of F fluorodeoxyglucose PET/computed tomography (F-FDG PET/CT) after thoracic radiotherapy. METHODS: F-Fluorodeoxyglucose PET/CT examination was performed in 38 patients at least 4 months after radiotherapy. Patients with known cardiac diseases, high cardiovascular risk factors, or diabetes mellitus were excluded. RESULTS: On visual analysis, 28 patients were seen to have regional myocardial F FDG uptake (74%), five patients were seen to have diffuse myocardial F-FDG uptake (13%), and five patients were seen to have no significant myocardial F-FDG uptake (13%). Regions of interest were drawn on irradiated and nonirradiated segments of the myocardium. The standardized uptake value measurements of the 28 patients with regional myocardial F-FDG uptake revealed significantly higher values in the irradiated segments in comparison with nonirradiated segments (P<0.001). CONCLUSION: Annular or focal increased F-FDG uptake in irradiated myocardial segments may be observed after thoracic radiotherapy. These myocardial uptake regions were not consistent with the vascular territory of coronary arteries, and the patients had no prior myocardial infarction or coronary artery disease. The patients with a history of thoracic radiotherapy, who showed increased F-FDG uptake on PET/CT, especially in the basal myocardium, should be followed up cautiously for the early diagnosis of cardiac events. PMID- 23728521 TI - Novel surface modified polymer-lipid hybrid nanoparticles as intranasal carriers for ropinirole hydrochloride: in vitro, ex vivo and in vivo pharmacodynamic evaluation. AB - Here we report fabrication and evaluation of novel surface modified polymer-lipid hybrid nanoparticles (PLN) as robust carriers for intranasal delivery of ropinirole hydrochloride (ROPI HCl). Sustained release, avoidance of hepatic first pass metabolism, and improved therapeutic efficacy are the major objectives of this experiment. PLN were fabricated by emulsification-solvent diffusion technique and evaluated for physicochemical parameters, in vitro mucoadhesion, in vitro diffusion, ex vivo permeation, mucosal toxicity and stability studies. Box Behnken experimental design approach has been employed to assess the influence of two independent variables, viz. surfactant (Pluronic F-68) and charge modifier (stearylamine) concentration on particle size, zeta-potential and entrapment efficiency of prepared PLN. Numerical optimization techniques were used for selecting optimized formulation sample, further confirmed by three dimensional response surface plots and regression equations. Results of ANOVA demonstrated the significance of suggested models. DSC and SEM analysis revealed the encapsulation of amorphous form of drug into PLN system, and spherical shape. PLN formulation had shown good retention with no severe signs of damage on integrity of nasal mucosa. Release pattern of drug-loaded sample was best fitted to zero order kinetic model with non-Fickian super case II diffusion mechanism. In vivo pharmacodynamic studies were executed to compare therapeutic efficacy of prepared nasal PLN formulation against marketed oral formulation of same drug. In summary, the PLN could be potentially used as safe and stable carrier for intranasal delivery of ROPI HCl, especially in treatment of Parkinson's disease. PMID- 23728522 TI - Effects of porous beta-tricalcium phosphate-based ceramics used as an E. coli derived rhBMP-2 carrier for bone regeneration. AB - Recombinant human bone morphogenetic protein-2 (rhBMP-2) requires carriers for clinical effectiveness. In this study, whether porous beta-tricalcium phosphate (beta-TCP)-based ceramics are ideal carriers for rhBMP-2 was investigated. Hydroxyapatite (HA), beta-TCP, TCP/HA (80 %/20 %), HA with rhBMP-2, TCP with rhBMP-2, and TCP/HA (80 %/20 %) with rhBMP-2 were manufactured by a sponge method with a pore size of 300 MUm or more and macro-porosity of 83 %. The alkaline phosphatase (ALP) activity and ALP expression of the cells with 100 % beta-TCP granules were more increased than the those of cells with 100 % HA and TCP/HA (80 %/20 %) at the baseline or when treated with 15 ng/ml of rhBMP-2. In an SD rat calvarial defect model, new bone formation was evidently shown in the TCP 100 % rhBMP-2 and TCP/HA (80 %/20 %)-rhBMP-2 groups, showing that the most affected area was filled with newly-formed bone, that the percent bone volume and trabecular number were larger when compared to the groups without rhBMP-2 treatment at both 4 and 8 weeks after surgery using micro-CT and histology. Porous TCP-based ceramic granules enhanced the osteoblastic differentiation in the hMSC system when treated with 15 ng/ml of rhBMP-2 and accelerated bone healing by trabecular number in a rat calvarial defect model. Thus, in this study it was proposed that TCP-based ceramics might be useful carriers of rhBMP-2. PMID- 23728523 TI - High rates of relationship dissolution among heterosexual HIV-serodiscordant couples in Kenya. AB - HIV-1 serodiscordant couples may experience increased risks of relationship dissolution; however, longitudinal stability of these relationships is poorly understood. We determined rates and correlates of separation among 469 serodiscordant couples in Nairobi and found that 113 (24 %) separated during 2 years of follow-up. Couples with a female HIV-1 infected partner (F+M-) and no income were more likely to separate than M+F- couples without income (HR = 5.0; 95 % CI 1.1-25.0), and F+M- and M+F- couples with income (HR = 2.4; 95 % CI 1.3 4.5 and HR = 2.3; 95 % CI 1.2-4.8, respectively). High separation rates may be important for couple support services and for conducting discordant couple studies. PMID- 23728524 TI - The effect of mirabegron, a potent and selective beta3-adrenoceptor agonist, on the pharmacokinetics of CYP2D6 substrates desipramine and metoprolol. AB - Mirabegron is a potent and selective beta3-adrenoceptor agonist developed for the treatment of overactive bladder. In vitro studies demonstrated that mirabegron partly acts as a (quasi-) irreversible, metabolism-dependent inhibitor of CYP2D6. The effect of steady-state mirabegron on single doses of the sensitive CYP2D6 substrates metoprolol (100 mg) and desipramine (50 mg) was assessed in two open label, one-sequence crossover studies in healthy subjects (CYP2D6 extensive metabolizers). Mirabegron 160 mg/day increased metoprolol maximum plasma concentration (C max) 1.90-fold (90 % confidence interval [CI] 1.54; 2.33) and total exposure (AUC0-infinity) 3.29-fold (90 % CI 2.70; 4.00) in 12 males (study 1). Mean metoprolol half-life increased from 2.96 to 4.11 h. alpha Hydroxymetoprolol C max and AUC to last measurable concentration decreased 2.6 fold and 2.2-fold, respectively. In study 2, mirabegron 100 mg/day increased desipramine C max 1.79-fold (90 % CI 1.69; 1.90) and AUC0-infinity 3.41-fold (90 % CI 3.07; 3.80) in 14 males and 14 females. Mean desipramine half-life increased from 19.5 to 35.8 h. C max of 2-hydroxydesipramine decreased ~twofold, while AUC increased ~1.3-fold. Desipramine was administered again 2 weeks after the last mirabegron dose. Desipramine C max and AUC0-infinity were still ~1.13-fold increased; the 90 % CIs fell within the 0.80-1.25 interval. All treatments were well tolerated. In conclusion, mirabegron is a moderate CYP2D6 inhibitor (ratio and 90 % CI <5.0). PMID- 23728525 TI - Novel benzimidazolium-urea-based macrocyclic fluorescent sensors: synthesis, ratiometric sensing of H2PO4(-) and improvement of the anion binding performance via a synergistic binding strategy. AB - A modular approach to obtain benzimidazolium-urea-based, fluorophore-appended macrocyclic receptors was developed. This class of receptors could be used as selective ratiometric fluorescent sensors for H2PO4(-) due to the synergistic binding effect of benzimidazolium and urea moieties. PMID- 23728527 TI - Hepatic 3D cultures but not 2D cultures preserve specific transporter activity for acetaminophen-induced hepatotoxicity. AB - Primary human hepatocytes (PHH) are the "gold standard" for in vitro toxicity tests. However, 2D PHH cultures have limitations that are due to a time-dependent dedifferentiation process visible by morphological changes closely connected to a decline of albumin production and CYP450 activity. The 3D in vitro culture corresponds to in vivo-like tissue architecture, which preserves functional characteristics of hepatocytes, and therefore can at least partially overcome the restrictions of 2D cultures. Consequently, several drug toxicities observed in vivo cannot be reproduced in 2D in vitro models, for example, the toxic effects of acetaminophen. The objective of this study was to identify molecular differences between 2D and 3D cultivation which explain the observed toxicity response. Our data demonstrated an increase in cell death after treatment with acetaminophen in 3D, but not in 2D cultures. Additionally, an acetaminophen concentration-dependent increase in the CYP2E1 expression level in 3D cultures was detected. However, during the treatment with 10 mM acetaminophen, the expression level of SOD gradually decreased in 3D cultures and was undetectable after 24 h. In line with these findings, we observed higher import/export rates in the membrane transport protein, multidrug resistance-associated protein-1, which is known to be specific for acetaminophen transport. The presented data demonstrate that PHH cultured in 3D preserve certain metabolic functions. Therefore, they have closer resemblance to the in vivo situation than PHH in 2D cultures. In consequence, 3D cultures will allow for a more accurate hepatotoxicity prediction in in vitro models in the future. PMID- 23728528 TI - Picturing recovery: a photovoice exploration of recovery dimensions among people with serious mental illness. AB - OBJECTIVES: Recovery from mental disorders encompasses multiple interrelated dimensions. This study used photovoice to explore how individuals with serious mental illness and a history of substance abuse and homelessness envisioned their recovery. A dimensional recovery model was applied to examine how the interrelationships between recovery dimensions supported consumers' recovery journeys. METHODS: Photovoice is a participatory research method that empowers people by giving them cameras to document their experiences and inform social action. Sixteen consumers recruited from two supported housing agencies participated in six weekly sessions to which they brought photographs that they took of persons and events in their lives that reflected recovery and wellness and discussed the meaning of the photographs in individual interviews and group sessions. The authors used pile-sorting, grounded theory, and a deductive template-analytic technique to analyze narrative and visual data. RESULTS: Spirituality, life achievements, and receiving and providing support were the most salient themes that emerged from the analysis and illustrate beneficial interrelationships between recovery dimensions. Participants discussed how they relied on their spirituality to support their sobriety and cope with addictions aspects of clinical recovery. Educational and vocational achievements represented gains in functioning that contributed to increasing self-esteem and self-agency and reducing self-stigma. Social dimensions of recovery, such as receiving and giving support to loved ones, rippled through consumers' lives reducing isolation and enhancing their self-worth. CONCLUSIONS: The findings illustrate the value of participatory methods to understand what recovery signified to people with serious mental illness and how understanding the interrelationships between recovery dimensions can inform recovery-oriented services. PMID- 23728529 TI - Dying to get out: young drivers, safety and social inequity. AB - OBJECTIVE: Deaths and serious injuries among young drivers are an important public health concern. Road safety researchers and policy makers tend to focus on strategies to restrict the driving activities of young people. Other social research suggests the disadvantages experienced by young people in socially deprived groups are exacerbated by not having a driving licence or owning a car. In this qualitative study, we consider the views of young people from less affluent backgrounds in the south-west of England who took part in a brief intervention to encourage them to delay gaining a driving licence and car ownership. METHODS: Between September 2011 and January 2012, a researcher observed four training sessions involving 173 young people. Postintervention, digitally recorded focus groups were conducted at three venues involving 23 randomly selected young people. Data from the focus group transcripts were sorted into charts in relation to key research questions and scrutinised using constant comparison. RESULTS: These young people believed the ability to drive, and car ownership, could increase their independence, improve access to further education, widen their employment opportunities, and enable them to contribute to family or household responsibilities. CONCLUSIONS: We argue there is a potential conflict between some strategies seeking to promote young driver safety and the impact this may have on equity and social disadvantage. Interdisciplinary work is required between professionals and researchers in transport, road safety, public health and social equity. Government policies should include low-cost, safe, reliable and attractive transport alternatives for young people in more deprived communities. PMID- 23728526 TI - Toxicity of Ag, CuO and ZnO nanoparticles to selected environmentally relevant test organisms and mammalian cells in vitro: a critical review. AB - Nanoparticles (NPs) of copper oxide (CuO), zinc oxide (ZnO) and especially nanosilver are intentionally used to fight the undesirable growth of bacteria, fungi and algae. Release of these NPs from consumer and household products into waste streams and further into the environment may, however, pose threat to the 'non-target' organisms, such as natural microbes and aquatic organisms. This review summarizes the recent research on (eco)toxicity of silver (Ag), CuO and ZnO NPs. Organism-wise it focuses on key test species used for the analysis of ecotoxicological hazard. For comparison, the toxic effects of studied NPs toward mammalian cells in vitro were addressed. Altogether 317 L(E)C50 or minimal inhibitory concentrations (MIC) values were obtained for algae, crustaceans, fish, bacteria, yeast, nematodes, protozoa and mammalian cell lines. As a rule, crustaceans, algae and fish proved most sensitive to the studied NPs. The median L(E)C50 values of Ag NPs, CuO NPs and ZnO NPs (mg/L) were 0.01, 2.1 and 2.3 for crustaceans; 0.36, 2.8 and 0.08 for algae; and 1.36, 100 and 3.0 for fish, respectively. Surprisingly, the NPs were less toxic to bacteria than to aquatic organisms: the median MIC values for bacteria were 7.1, 200 and 500 mg/L for Ag, CuO and ZnO NPs, respectively. In comparison, the respective median L(E)C50 values for mammalian cells were 11.3, 25 and 43 mg/L. Thus, the toxic range of all the three metal-containing NPs to target- and non-target organisms overlaps, indicating that the leaching of biocidal NPs from consumer products should be addressed. PMID- 23728530 TI - Epidemiological profile of hospitalised injuries among electric bicycle riders admitted to a rural hospital in Suzhou: a cross-sectional study. AB - Police reports indicate an increasing burden of electric bike (E-bike) casualties in China; however, hospitalised injury data have not been reported. The aim of the present work was to describe hospitalised injury patterns for E-bikers involved in road crashes and explore injury risk disparities among them. For the period October 2010 to April 2011, this cross-sectional study retrospectively collected information for hospitalised E-bikers involved in road crashes from hospital records, in Suzhou China, using the International Classification of Diseases, 10th revision (ICD-10) injury diagnosis codes. Injury nature and body region were further categorised using ICD-10 codes. Multivariate logistic regression was used to assess the risk of specific injury types. We found that hospitalised E-biker injuries (n=323) accounted for 57.2% of road traffic hospitalisations over the 6-month study period. The average age, length of stay and hospitalisation cost were 43.8 years, 10.0 days and Y8229 (US$1286), respectively. Fractures and head injuries were common. The odds of traumatic brain injuries were significantly elevated for night-time E-bike crashes and incidents other than colliding with motor vehicles. These findings confirm E-bike injuries as an important population health problem and identify elevated injury odds in different E-biker groups. Future injury prevention initiatives should include encouraging helmet use among E-bikers. PMID- 23728531 TI - Social dystonia and psychosis: an alternative perspective. PMID- 23728532 TI - Should the term 'antipsychotic' be changed to 'multidimensional stabiliser' in bipolar disorder? Towards a new denomination for 'atypical antipsychotics'. PMID- 23728533 TI - OCI examination, RANZCP. PMID- 23728534 TI - Repeated embolization of intercostal arteries after blunt chest injury. AB - To deal with an arterial bleeding from the chest wall after a blunt chest injury, embolization of the bleeding arteries can be a valuable therapeutic option, which is less invasive than a thoracotomy. However, its results are variable, being highly operator-dependent. In the present case, we performed successful emergency embolization of the 4th and 5th intercostal arteries for persistent hemorrhage following blunt trauma to the chest. Several days after the first embolization, secondary embolization was required for treating a pseudoaneurysm that was formed in the 5th intercostal artery. Although the mechanisms underlying pseudoaneurysm formation are not clearly understood, its rupture is potentially fatal. Therefore, it is essential to carefully follow-up patients who experience blunt chest injury to avoid this serious complication. PMID- 23728535 TI - Lack of association of platelet-derived growth factor (PDGF) receptor autoantibodies and severity of chronic graft-versus-host disease (GvHD). AB - PURPOSE: The existence of platelet-derived growth factor (PDGF) receptor autoantibodies in systemic sclerosis is conflicting, and such antibodies were also detected in patients with chronic graft-versus-host disease (GvHD) after allogeneic peripheral blood stem cell transplantation (PBSCT). We therefore aimed to screen for PDGF receptor autoantibodies in patients with chronic GvHD. PATIENTS AND METHODS: We evaluated the existence of PDGF receptor autoantibodies in 39 patients, while 17 patients presented with a limited and 8 patients with an extensive chronic GvHD, respectively. Furthermore, 14 out of 39 patients had no chronic GvHD. RESULTS: We detected at least low levels of PDGF receptor autoantibodies in nearly all (35 of 39) patients after allogeneic PBSCT. Interestingly, only one of six patients with high levels of PDGF receptor autoantibodies presented with an extensive chronic GvHD, while the remaining six patients had no clinical signs of chronic GvHD. Thus, there was no correlation between the quantitative detection of antibodies directed against the PDGF receptor and the presence or severity of chronic GvHD. CONCLUSION: Platelet derived growth factor receptor autoantibodies could easily be detected in patient sera. Nevertheless, we did not observe any correlation between the presence of PDGF receptor autoantibodies and the severity of chronic GvHD in patients who underwent allogeneic PBSCT. PMID- 23728536 TI - Enhanced in vitro antitumor activity of a titanocene complex encapsulated into polycaprolactone (PCL) electrospun fibers. AB - PURPOSE: The purpose of this work was to achieve detailed biomaterials characterization of a drug delivery system for local cancer treatment based on electrospun titanocene trichloride-loaded resorbable polycaprolactone (PCL) fibers. METHODS: The PCL fibers were characterized for their structural, morphologic and physical properties. The drug release kinetics of the titanocene complex was investigated at different concentrations, to obtain a set of correlations between structure and tuneable release. After exposing cancer cells directly onto the surface of PCL fibers, the anti-proliferative effects of titanocene-loaded PCL were assessed by: (i) counting viable cells via live/dead staining methods, and (ii) analyzing cell apoptosis. RESULTS AND CONCLUSIONS: Titanocene concentration influenced fiber diameters reduced for PCL filled with titanocene. X-ray analysis suggested that the titanocene, encapsulated into the PCL fibers, is not allowed to crystallize and exists as amorphous aggregates into the fibers. The titanocene release curves presented two stages unrelated to PCL degradation: an initial burst release followed by a release linear with time, extending for a very long time. All of the titanocene-loaded fibers revealed sustained drug release properties suggesting their potential clinical applicability for the treatment of local cancer diseases. PMID- 23728537 TI - Biofilm medium leads to apatite formation on bioactive surfaces. AB - PURPOSE: When investigating apatite formation on biomaterial surfaces, simulated body fluid (SBF) is used as an in vitro solution, however, it does not provide an appropriate environment for the growth of bacterial biofilm. The aim of the present study was to compare the bioactivity in terms of apatite formation on two bioactive glass (BAG) composite surfaces using both SBF and bacterial-biofilm growing medium (BM). METHODS: Polymer composite substrates with different percentages of BAG-particles (50% and 75% by weight) were prepared. Plain resin substrates were used as a negative control. The substrates were immersed in SBF and BM for 3 days. The surface and, subsequently, the cross-sections of the substrates were examined with scanning electron microscopy (SEM) and x-ray energy dispersive spectroscopy (EDS). RESULTS: All the investigated BAG-composite surfaces showed apatite formation after immersion in SBF and BM liquid media. CONCLUSIONS: The use of BM is a promising method for studies involving simultaneous biofilm growth and apatite formation on bioactive surfaces. PMID- 23728538 TI - Comparative in vitro study of four commercial biomaterials used for bone grafting. AB - PURPOSE: This work aimed to study and compare the behavior of macrophages and human osteoclast-like cells cultured in contact with four commercial bone substitute materials used as graft for ridge augmentation techniques. Two materials are of natural origin and two are synthetic bone substitutes. METHODS: Macrophage activation and cytokine release were assessed using SEM analysis and a sandwich ELISA kit while the activity of human osteoclast-like cells was studied quantifying calcium released from the substrata studied together with SEM analysis of cell morphology and pit formation on the bone substitutes. RESULTS: Hydroxyapatite proved to be the greatest macrophage activator, while the bovine derived material turned out to be the only bone substitute that does not induce macrophages to release IFNgamma. No material had direct induction of osteoclast precursor differentiation even if mature osteoclasts showed the highest activity on the human derived material followed by bone ceramic, while the bovine derived material was the substrate with the least osteoclast activity. CONCLUSIONS: The four materials reacted differently with the cells tested and between them, the bovine derived bone, being the lowest macrophage and osteoclast activator may be considered a good bone substitute for clinical situations requiring greater time of permanence of the material at the site of implantation, while human derived bone will be more suitable for clinical applications that require lower time of permanence. PMID- 23728539 TI - The dose response relationship between intervertebral disc flexion-extension neutral zone metrics and injected genipin concentration. AB - PURPOSE: Quantify changes in the flexion--extension neutral zone of the intervertebral disc with injections of increasing genipin concentration. METHODS: Bovine motion segments were treated with varying concentrations of genipin using bilateral injections of constant volume. After overnight static compression loading of the treated segments, anterior-posterior offset loading was used to simulate flexion-extension motion. Range of motion, neutral zone length, neutral zone stiffness, and an instability score were measured. RESULTS: Injection of the disc annulus with increasing concentrations of genipin resulted in corresponding changes in flexion-extension neutral zone. A minimum concentration of 40 mM was needed to observe a significant change. The largest changes were observed with the 400 mM injection. Netural zone stability was the most sensitive of the metrics with a percent change of 48% at 40 mM and over 200% at 400 mM. CONCLUSION: This study establishes the efficacy of using injection delivery to affect disc joint mechanics and quantifies the dose response between injected genipin and the flexion-extension stability of the disc. PMID- 23728540 TI - Structural analysis and ion translocation mechanisms of the muscle-type acetylcholine receptor channel. AB - PURPOSE: The aim of this work is to analyze the conformational changes in the acetylcholine receptor caused by channel opening and to investigate the electrostatic profile during ion translocation through the channel. METHODS: A computational model of the human muscle-type acetylcholine receptor (AChR) was built and used to analyze channel structure and its interactions with different ions. Using the Torpedo AChR crystal structure as a homologous template, the 3D structure of the human muscle-type AChR was reconstructed. RESULTS: This first model is optimized and an open structure of the channel is generated using Normal Mode Analysis in order to assess morphologic and energetic differences between open and closed structures. In addition, the issue of ion translocation is investigated in further detail. Results elucidate different aspects of the channel: channel gate structure, channel interactions with translocating ions, differences between muscle-type AChR and previous neuronal-type AChR models. CONCLUSIONS: The model constructed here is ideal for further computational studies on muscle-type AChR and its pathologic mutations. PMID- 23728541 TI - Gait analysis in anorexia and bulimia nervosa. AB - PURPOSE: Anorexia (AN) and Bulimia Nervosa (BN) are two common eating disorders, which appear to share some reduced motor capacities, such as a reduced balance. The presence and the extent of other motor disorders have not been investigated in a comprehensive way. The aim of this study was to quantify gait pattern in AN and BN individuals in order to ascertain possible differences from the normality range and provide novel data for developing some evidence-based rehabilitation strategies. METHODS: Nineteen AN patients (age 30.16+9.73) and 20 BN patients (age 26.8+8.41) were assessed with quantitative 3D computerized Gait Analysis. Results were compared with a group of healthy controls (CG; 30.7+5.6). RESULTS: AN and BN patients were characterized by different gait strategies compared to CG. Spatio-temporal parameters indicated shorter step length, with AN showing the shortest values. AN walked slower than BN and CG. As for kinematics, AN and BN showed a nonphysiologic pattern at pelvis and hip level on the sagittal and frontal plane, with BN yielding the most abnormal values. Both AN and BN patients were characterized by high ankle plantar flexion capacity at toe-off when compared to CG. As for ankle kinetics, both AN and BN showed physiologic patterns. Stiffness at hip level was close to CG in both pathologic groups; at the ankle level, stiffness was significantly decreased in both groups, with AN displaying lower values. CONCLUSIONS: Both AN and BN were characterized by an altered gait pattern compared to CG. Biomechanical differences were evident mainly at pelvis and hip level. Loss of lean mass may lead to musculoskeletal adaptation, ultimately causing alterations in the gait pattern. PMID- 23728542 TI - Total knee prosthesis polyethylene wear reduction by a new ?metal part finishing method. AB - PURPOSE: The purpose of this study was to assess a new metal component finishing designed to improve total knee prosthesis durability. Wear of ultrahigh molecular weight polyethylene (UHMWPE), with generation of submicrometer- and micrometer sized particles, has been associated with osteolysis and artificial joint failure. Wear extent is influenced by several factors, some of which are related to manufacturing. METHODS: UHMWPE wear was assessed in metal prosthesis components finished with the Microloy(r) technology and in traditionally finished components by wear simulation experiments (pin on disk and knee simulator tests) and analysis of wear debris. RESULTS: Microloy(r)-finished prosthesis showed a 48.5% reduction in UHMWPE total weight loss compared with traditional components (P=0.002). A statistically significant (P<0.05) reduction of UHMWPE debris were detected from the Microloy(r)-finished compared with the traditionally finished components. CONCLUSIONS: These findings suggest the Microloy(r) metal finishing may enhance the long-term performance of knee prostheses. PMID- 23728544 TI - Effect of changes to the manufacturer application techniques ?on the shear bond strength of simplified dental adhesives. AB - PURPOSE: The aim of this work was to assess the shear bond strength (SBS) between a composite resin and dentin, promoted by two dental adhesive systems (one-step self-etching adhesive Easy Bond [3M ESPE], and two-step etch-and-rinse adhesive Scotchbond 1XT [3M ESPE]) with different application protocols (per manufacturer's instruction (control group); with one to four additional adhesive layers; or with an extra hydrophobic adhesive layer). METHODS: Proximal enamel was removed from ninety caries-free human molars to obtain two dentin discs per tooth, which were randomly assigned to twelve experimental groups (n=15). After adhesion protocol, the composite resin (Filtek Z250 [3M ESPE]) was applied. Specimens were mounted in the Watanabe test device and shear bond test was performed in a universal testing machine with a crosshead speed of 5 mm/min. Data were analyzed with ANOVA followed by Student-Newman-Keuls tests (P<0.05). RESULTS: The highest SBS mean value was attained with the Easy Bond three layers group (41.23+/-2.71 MPa) and the lowest with Scotchbond 1XT per manufacturer's instructions (27.15+/-2.99 MPa). Easy Bond yielded higher SBS values than Scotchbond 1XT. There were no statistically significant differences (P>0.05) between the application protocols tested, except for the three and four layers groups, that presented higher SBS results compared to manufacturer's instruction groups (P<0.05). No statistically significant differences were detected between the three and four layers groups (P>=0.05). CONCLUSION: It is recommendable to apply three adhesive layers when using Easy Bond and Scotchbond 1XT adhesives, since it improves SBS values without consuming much time. PMID- 23728545 TI - Assessment of cellular reactions to magnesium as implant ?material in comparison to titanium and to glyconate using ?the mouse tail model. AB - PURPOSE: Nowadays, research in magnesium alloys as a biodegradable implant material has increased. The aim of this study was to examine osteoinductive properties and tissue responses to pure magnesium in comparison to conventional permanent (titanium) and to degradable (glyconate) implant materials. METHODS: Magnesium wires (0.4 mm in diameter, 10 mm length) were implanted into tail veins of mice and examined after 2, 4, 8, 16 and 32 weeks. Titanium and glyconate as controls were assessed after 2, 4, 8 and 24 weeks. u-computed tompgraphy, histology and SEM examinations were performed. RESULTS: Magnesium implants showed increasing structural losses over time with fragmentation after an observation period of 32 weeks. Glyconate was fully degraded and titanium remained almost unaffected after 24 weeks. In contrast to some titanium and glyconate implants, first calcium and phosphate precipitations could be observed around magnesium implants after two weeks. However, ossification could not be observed even after 32 weeks, whereas enchondral ossification was found partially in the sourrounding of glyconate and titanium implants after eight weeks. Nevertheless, magnesium implants showed less inflammatory responses and fibrosing properties than the conventional implant materials. CONCLUSIONS: Although the assumed osteoinductive properties could not be detected, magnesium appears to be a promising degradable implant material because of the low sensitizing and inflammatory potential. PMID- 23728546 TI - Dried blood spot proteomics: surface extraction of endogenous proteins coupled with automated sample preparation and mass spectrometry analysis. AB - Dried blood spots offer many advantages as a sample format including ease and safety of transport and handling. To date, the majority of mass spectrometry analyses of dried blood spots have focused on small molecules or hemoglobin. However, dried blood spots are a potentially rich source of protein biomarkers, an area that has been overlooked. To address this issue, we have applied an untargeted bottom-up proteomics approach to the analysis of dried blood spots. We present an automated and integrated method for extraction of endogenous proteins from the surface of dried blood spots and sample preparation via trypsin digestion by use of the Advion Biosciences Triversa Nanomate robotic platform. Liquid chromatography tandem mass spectrometry of the resulting digests enabled identification of 120 proteins from a single dried blood spot. The proteins identified cross a concentration range of four orders of magnitude. The method is evaluated and the results discussed in terms of the proteins identified and their potential use as biomarkers in screening programs. PMID- 23728547 TI - Electron capture dissociation and collision induced dissociation of S dipalmitoylated peptides. AB - Here we investigate the effect of S-dipalmitoylation on the electron capture dissociation (ECD) behavior of peptides. The ECD and collision induced dissociation (CID) of peptides modified by covalent attachment of [(RS)-2,3 di(palmitoyloxy)-propyl] (PAM2) group to cysteine residues [C(PAM2)LEYDTGFK and RPPGC(PAM2)SPFK] were examined. The results suggest that ECD of S-dipalmitoylated peptides can provide both primary sequence information and structural information regarding the modification. The structural information provided by CID is complementary to that provided by ECD. PMID- 23728548 TI - The preproghrelin 3056 TT genotype is associated with the feeling of hunger and low acylated ghrelin levels in Japanese patients with Helicobacter pylori negative functional dyspepsia. AB - OBJECTIVE: An impairment of gastric motility is strongly associated with the pathophysiology of functional dyspepsia (FD). Plasma ghrelin is one of the key molecules linked to gastric motility. Therefore, this study aimed to evaluate whether ghrelin (GHRL) gene polymorphisms are associated with clinical symptoms, the plasma ghrelin levels and gastric emptying in patients with FD as defined by the Rome III classification. METHODS: We enrolled 74 Helicobacter pylori-negative patients presenting with typical symptoms of FD (epigastric pain syndrome (EPS), n=23; postprandial distress syndrome (PDS), n=51) and 102 healthy volunteers. Gastric motility was evaluated according to the Tmax value and T1/2 using the (13)C-acetate breath test. We used the Rome III criteria to evaluate upper abdominal symptoms and SRQ-D scores to determine the depression status. The Arg51Gln(346G->A), preproghrelin3056T->C, Leu72Met(408C->A) and Gln90Leu(3412T >A) polymorphisms were analyzed in DNA in blood samples obtained from the enrolled subjects. Genotyping was performed using polymerase chain reaction. RESULTS: There was a significant relationship (p=0.048) between the preproghrelin 3056TT genotype and the serum levels of acylated ghrelin in the H. pylori negative FD patients. The preproghrelin 3056TT genotype was significantly (p=0.047) associated with the feeling of hunger in the H. pylori-negative FD patients. CONCLUSION: The preproghrelin 3056TT genotype is significantly associated with the acylated ghrelin levels and the feeling of hunger in H. pylori-negative FD patients. Further studies are needed to clarify the association between the preproghrelin 3056TT genotype and lower plasma acylated ghrelin levels and the impact of this relationship on the feeling of hunger in H. pylori-negative FD patients. PMID- 23728549 TI - Acid reflux in patients with coronary artery disease and refractory chest pain. AB - OBJECTIVE: To investigate the influence of acid reflux on chest pain and ischemic events and the effects of cardiac drugs on acid reflux in patients with coronary artery disease (CAD) and refractory chest pain. METHODS: Simultaneous 24-hour esophageal pH monitoring and 24-hour continuous electrocardiogram (ECG) (Holter) results were obtained for 64 patients. Ischemic events and cardiac drug prescriptions were compared between the patients with and without gastroesophageal reflux disease (GERD). Patients fulfilling the GERD criteria received 14-day therapy with omeprazole at a dose of 20 mg bid. The results of the 24-hour pH monitoring, Holter and the SF-36 questionnaire were compared before treatment and again after two weeks of therapy. RESULTS: GERD was identified in 38 (69%) patients, with 49% of all chest pain occurring in association with acid reflux. A higher incidence (p=0.033) and longer duration (p=0.040) of ischemic events were observed in the GERD (+) patients. More frequent combined use of cardiac drugs was found in the GERD (+) patients. However, fewer ischemic events and greater total SF-36 survey scores were noted after PPI therapy in the GERD (+) patients. CONCLUSION: Acid reflux is common in patients with CAD and refractory chest pain. Refractory chest pain in patients with CAD can be partially noncardiac chest pain (NCCP) secondary to acid reflux. The combined use of common cardiac drugs may predispose or aggravate GERD. Short term proton pump inhibitor (PPI) therapy not only restores a normal esophageal pH, but also significantly improves the general health-related quality of life (HRQL) of patients. PMID- 23728550 TI - Talc pleurodesis for the management of malignant pleural effusions in Japan. AB - OBJECTIVE: Malignant pleural effusions are commonly treated with tube drainage followed by chemical pleurodesis to maintain the patient's quality of life. While talc is now accepted to be a worldwide gold-standard sclerosing agent for treating malignant pleural effusion, it is not yet approved in Japan. Instead, many patients are administered OK-432 for pleurodesis, which carries the risk of complications such as high-grade fever, chest pain, anaphylactic shock, interstitial pneumonia and acute renal failure. To assess the efficacy and safety of talc as a sclerosing agent in the management of malignant pleural effusions in Japanese patients. METHODS: Pleurodesis was performed using 4 g of sterile talc with thoracoscopic talc poudrage or the administration of talc slurry via a chest tube in patients with malignant pleural effusions. RESULTS: A total of 57 patients were included. The success rate of pleurodesis assessed on chest radiography at 30, 90 and 180 days was 90.6%, 80.9% and 76.1%, respectively. Complications occurring after talc pleurodesis included fever in 10.5% of the patients and chest pain in 14.0% of the patients. No major complications were reported. CONCLUSION: Talc pleurodesis is an effective and safe treatment for the management of malignant pleural effusion in Japanese patients. PMID- 23728551 TI - Perforative peritonitis caused by appendicitis in a patient on peritoneal dialysis. AB - A 46-year-old man on peritoneal dialysis (PD) was hospitalized due to suspicious PD-related peritonitis. Because the patient's abdominal pain was unimproved by conventional antibiotics and multiple bacteria were identified in a smear-sample of PD fluid, endogenous peritonitis was suspected. Perforated appendicitis was finally diagnosed under exploratory laparotomy. In this patient, perforated appendicitis was difficult to diagnose due to the attenuated clinical symptoms and inconclusive results of abdominal computed tomography (CT), even though the positive predictive value of CT is >95% in non-PD patients. Quickly deciding to perform exploratory laparotomy in patients suspected of having endogenous peritonitis is thus important, even when the origin has not been clarified. PMID- 23728552 TI - Protein-losing enteropathy associated with collagenous colitis cured by withdrawal of a proton pump inhibitor. AB - A 63-year-old woman was admitted with symptoms of watery diarrhea and generalized edema lasting for five months. She had been administered 15 mg/day of lansoprazole. Laboratory findings revealed severe hypoproteinemia with normal liver, renal, thyroid and adrenal functions and no proteinuria. Colonoscopy revealed edematous mucosa, minor diminished vascular transparency and apparent longitudinal linear lacerations. The histopathological findings were compatible with a diagnosis of collagenous colitis (CC). Protein leakage from the colon was identified on (99m)Tc-human serum albumin scintigraphy. The results indicated CC associated with protein-losing enteropathy. Discontinuing lansoprazole ameliorated the watery diarrhea and generalized edema, increased the serum albumin level and improved the hypoproteinemia. PMID- 23728553 TI - Malfunction of cardiac resynchronization therapy due to subsequent fracture of the ring and tip conductors of a co-radial left ventricular bipolar lead. AB - In two patients treated with cardiac resynchronization therapy (CRT), left ventricular (LV) pacing failure occurred due to ring conductor fractures of the bipolar LV lead (co-radial model). CRT was resumed by pacing between the tip conductor of the LV lead and the coil conductor of the right ventricular lead. However, shortly thereafter, subsequent fracture of the tip conductor developed, and implantation of a new LV lead was required. When one of the bipolar conductors of a co-radial designed LV lead fractures, reimplantation of a new LV lead is a better therapeutic option (than changing the LV pacing mode) in order to reliably continue CRT treatment. PMID- 23728554 TI - Coronary subclavian steal from a left internal thoracic artery coronary bypass graft due to ipsilateral subclavian artery stenosis and an arteriovenous graft in a hemodialysis patient with left vertebral artery occlusion. AB - Coronary subclavian steal syndrome is an unusual cause of myocardial ischemia, secondary to a reversed blood flow in patients with patent internal thoracic artery coronary bypass grafts. The causes of coronary subclavian steal are either ipsilateral subclavian artery stenosis or upper extremity arteriovenous hemodialysis fistula formation or both. This report involves a 68-year-old woman with left vertebral artery occlusion who developed severe coronary steal in the absence of vertebral subclavian steal due to left subclavian artery stenosis and an arteriovenous hemodialysis graft. PMID- 23728555 TI - Male gonadotroph adenoma: report of three cases and a review of the literature. AB - We herein report three cases of gonadotroph adenoma in men (36-72 years of age) presenting with visual impairment and suprasellar masses measuring approximately 20 to 30 mm in diameter. Endocrinological examinations were normal, except for slightly increased follicle stimulating hormone (FSH) levels in two cases. Based on the tentative diagnosis of non-functioning pituitary adenoma, transsphenoidal surgery was performed, which revealed that the tumors consisted of FSH- and LH positive cells. As gonadotroph adenoma is very common among patients with clinically silent pituitary adenoma, it should be diagnosed using pathological examinations. PMID- 23728556 TI - Medical thoracoscopy performed under local anesthesia is useful for diagnosing pleural metastasis of renal cell carcinoma. AB - A patient with a past history of renal cell carcinoma (RCC) presented to us with an exudative pleural effusion. Because pleural effusion cytology was inconclusive, we performed medical thoracoscopy under local anesthesia. Multiple white tumors measuring approximately 2 cm in diameter were observed on the parietal pleura. Metastatic carcinoma from RCC was diagnosed histologically. Although malignant effusions are rare in cases of RCC metastasis, clinicians should be aware of this possibility. When pleural effusion cytology is inconclusive in a patient with a past history of RCC, medical thoracoscopy can be useful for making the diagnosis of pleural metastasis. PMID- 23728557 TI - Endotracheal tuberculous granuloma formation following endobronchial ultrasound transbronchial needle aspiration. AB - Endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) is a useful and safe diagnostic test. We herein report a case of endotracheal granuloma formation that occurred after EBUS-TBNA in a 73-year-old woman. The patient was admitted due to coughing and dyspnea after 70 days of antituberculous therapy for mediastinal lymphadenitis. Computed tomography revealed decreases in the size of the lymph nodes with a new mass protruding into the tracheal lumen. The mass originated from the right paratracheal area, which was a previous puncture site. This case suggests that clinicians should pay attention to complications because tuberculosis can produce new granulomas via the sinus tract after EBUS-TBNA. PMID- 23728558 TI - Bloody pleural effusion--a rare manifestation of sarcoidosis. AB - Sarcoidosis is a multisystemic granulomatous disease of unknown etiology. Pleural effusion is rare in patients with sarcoidosis, occurring in 0.7% to 20% of cumulative series. Bloody pleural effusion is even more rare. We herein report two cases of sarcoidosis with bloody pleural effusion and discuss the clinical manifestations, diagnostic procedures and treatment of these cases. Sarcoidosis should be included in the differential diagnosis when bloody pleural effusions are detected. An increased level of lymphocytes and an increased ratio of CD4+/CD8+ lymphocytes in bronchoalveolar lavage fluid (BALF) are helpful for making a diagnosis of sarcoidosis. Medical thoracoscopy is helpful for determining the definitive diagnosis. Corticosteroids are an effective treatment; however, the dose should be individualized according to the treatment response. PMID- 23728560 TI - Syndrome of inappropriate antidiuretic hormone secretion induced by tacrolimus following allogeneic cord blood transplantation. AB - Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is an important electrolyte abnormality that can occur following allogeneic stem cell transplantation. We herein report the case of a 20-year-old man who developed SIADH three weeks after undergoing cord blood transplantation. Tacrolimus administration was suspected to be a cause of the disorder. In addition to restricting water intake and administering hypertonic sodium, the tacrolimus dosage was reduced, resulting in alleviation of SIADH. Therefore, tacrolimus should be recognized as an important, albeit rare, cause of drug-induced SIADH, even in patients with tacrolimus blood concentrations within the normal range. We believe that dose reduction, not discontinuation, is an effective strategy. PMID- 23728559 TI - The need for continuing chemotherapy for leukemic cell lysis pneumopathy in patients with acute myelomonocytic/monocytic leukemia. AB - Although fatal pulmonary complications frequently occur during the course of acute leukemia, a minor proportion of the complications are due to leukemia itself. Infections, drug reactions and concomitant medical conditions are the major causes of respiratory distress in leukemic patients. We treated four patients with acute myeloid leukemia complicated by leukemic cell lysis pneumopathy (LCLP). All of the patients had leukemia of monocytoid origin and their respiratory function deteriorated soon after chemotherapy initiation. Although two of the patients required mechanical ventilation, all four improved after continued chemotherapy. Our experience indicates that, in cases of LCLP, chemotherapy should be continued with maximal respiratory support. PMID- 23728561 TI - Spontaneous remission in patients with acute myeloid leukemia with t(8;21) or cutaneous myeloid sarcoma: two case reports and a review of the literature. AB - Spontaneous remission (SR) in patients with acute myeloid leukemia (AML) is rare. We herein present two such cases. The first case was of AML-M2 accompanied by a bone marrow cytogenetic analysis revealing 46, XY, t(8;21)(q22,q22). The second case was of isolated cutaneous myeloid sarcoma (MS) that progressed to AML within seven months. Both of the patients had symptoms of infection and anemia and were therefore treated with antibiotics and transfusions. The SR lasted for two months and one month, respectively. Currently, the mechanisms underlying SR remain ambiguous. Possible underlying mechanisms with a review of the related literature are discussed. PMID- 23728562 TI - Stringent complete remission of primary plasma cell leukemia with reduced-dose bortezomib, lenalidomide and dexamethasone: a case report and review of the literature. AB - Plasma cell leukemia (PCL) is an aggressive variant of multiple myeloma characterized by a high level of plasma cells circulating in the peripheral blood. The prognosis of PCL patients treated with conventional chemotherapy remains poor. Some reports have suggested that both bortezomib and lenalidomide are effective in treating PCL. We herein report a case of primary PCL in which the patient achieved stringent complete remission after receiving combination chemotherapy with reduced-dose bortezomib, lenalidomide and dexamethasone (VRd). This regimen was very effective, and no severe adverse events were observed. A reduced-dose VRd regimen can be considered in PCL patients. PMID- 23728563 TI - Successful treatment of severe newly diagnosed immune thrombocytopenia involving an alveolar hemorrhage with combination therapy consisting of romiplostim, rituximab and vincristine. AB - A 51-year-old man was admitted due to a severe bleeding tendency. After he was diagnosed with immune thrombocytopenia (ITP), several therapies, including steroids, steroid pulse, vincristine and rituximab, were administered; however, the patient's bleeding symptoms were not sufficiently controllable with these treatments. Subsequently, a diffuse alveolar hemorrhage was observed. Treatment with a thrombopoietin receptor agonist, romiplostim, was initiated to prevent lethal hemorrhaging, although the efficacy of thrombopoietic receptor agonists in such emergency situations has not been elucidated. The initiation of romiplostim achieved prompt remission in platelets. This case suggests that combination therapy with romiplostim, rituximab and vincristine is effective in cases of newly diagnosed severe therapy-resistant ITP. PMID- 23728564 TI - Oscillating thrombi in bilateral extracranial internal carotid arteries demonstrated on ultrasonography: two autopsy cases of cardioembolic stroke. AB - We herein report two autopsy cases of severe cardioembolic stroke with oscillating thrombi in the bilateral extracranial internal carotid arteries (ICAs) demonstrated on carotid ultrasonography performed on admission. An autopsy study of case 1 conducted on the third hospital day revealed no thrombi, while that of case 2 conducted on the 42nd hospital day revealed red thrombi in the extracranial ICAs. Our postmortem studies confirm that oscillating thrombi may be seen in the region of blood stasis caused by occlusion of the distal portion of the ICA, thus reflecting a pre-state of thrombus formation. PMID- 23728565 TI - Steroid-responsive thalamic lesions accompanying microbleeds in a case of Hashimoto's encephalopathy with autoantibodies against alpha-enolase. AB - A 67-year-old man receiving antithrombotic therapy developed rapidly progressive amnesia. T2-weighted images of brain MRI revealed hyperintense lesions in the bilateral thalami accompanied by microbleeds. Antithyroglobulin antibodies and autoantibodies against the N-terminal of alpha-enolase (NAE) were identified in the patient's serum; therefore, Hashimoto's encephalopathy (HE) was suspected. Although the patient's radiological findings improved following steroid therapy, his symptoms did not improve, possibly due to increased thalamic microbleeds. Because anti-NAE antibodies are possibly associated with vasculitis, HE accompanied by anti-NAE antibodies may be exacerbated by microbleeds in patients receiving antithrombotic therapy. PMID- 23728566 TI - Pigmented purpuric dermatosis associated with primary antiphospholipid syndrome. AB - Pigmented purpuric dermatosis (PPD) is a group of chronic disorders characterized by the extravasation of erythrocytes and marked hemosiderin deposits in the dermis. Schamberg disease is a subtype of pigmented purpuric dermatosis in which nonpalpable purpura is prominent on the lower extremities. No cases of primary antiphospholipid syndrome and pigmented purpuric dermatosis have so far been reported in the literature. We herein report a case of pigmented purpuric dermatosis associated with primary antiphospholipid syndrome. PMID- 23728567 TI - A patient with infective endocarditis caused by community-acquired Pseudomonas aeruginosa infection. AB - An 85-year-old woman complaining of nausea was admitted to our hospital after being found to have complete atrioventricular block. We diagnosed the patient with infective endocarditis after observing vegetation on transesophageal echocardiography (TEE) and detecting Pseudomonas aeruginosa in a blood culture. The patient had no history of intravenous drug use, instrumentation or valvular disease. Although sensitive antibiotics were administered intravenously, the second TEE performed on the 10th day demonstrated increased vegetation. The patient developed septic shock and died on the 14th day. To our knowledge, this is the first report of infective endocarditis caused by community-acquired Pseudomonas aeruginosa in Japan. PMID- 23728568 TI - An unusual case of cavernous hemangioma of the rib in a young man with lung tuberculosis: a brief review and case report. AB - Hemangiomas are benign vascular tumors that usually involve the liver, skin, eyes and central nervous system. Hemangioma of the bone is unusual and is generally observed in the vertebrae or skull while hemangioma of the costae is extremely rare. Hemangioma of the rib and chest wall tuberculosis may be misdiagnosed as chest wall tumors. We herein report a case of hemangioma of the rib with a tuberculosis infection of the pleura. PMID- 23728569 TI - Spontaneous mesenteric hematoma with duodenal stenosis. PMID- 23728570 TI - Obturator hernia. PMID- 23728571 TI - Two adult cases of pulmonary artery sling. PMID- 23728572 TI - Systemic lupus complicated by myocardial vasculitis. PMID- 23728573 TI - Rupture of an infected aortic aneurysm with rapid dilatation. PMID- 23728575 TI - Cryptococcosis: an unusual cause of tracheal obstruction. PMID- 23728574 TI - A pneumopericardium caused by gastric ulcer perforation. PMID- 23728576 TI - Ischemic stroke sparing the motor cortex. PMID- 23728577 TI - Subcortical infarction causes pure motor isolated finger palsy. PMID- 23728578 TI - Midbrain panda sign in a patient with Wilson's disease. PMID- 23728579 TI - Mesothelioma-mimicking multiple myeloma with dumbbell-type progression. PMID- 23728580 TI - The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. AB - Farnesoid X receptor (FXR) has important roles in maintaining bile acid and cholesterol homeostasis. Here we report that the antiparasitic drug ivermectin is a ligand for nuclear FXR. We identify ivermectin using a high-throughput compound library screening and show that it induces the transcriptional activity of the FXR with distinctive properties in modulating coregulator recruitment. The crystal structure of ivermectin complexed with the ligand-binding domain of FXR reveals a unique binding mode of ivermectin in the FXR ligand-binding pocket, including the highly dynamic AF-2 helix and an expanded ligand-binding pocket. Treatment of wild-type mice, but not of FXR-null mice, with ivermectin decreases serum glucose and cholesterol levels, suggesting that ivermectin regulates metabolism through FXR. Our results establish FXR as the first mammalian protein targeted by ivermectin with high selectivity. Considering that ivermectin is a widely used clinical drug, our findings reveal a safe template for the design of novel FXR ligands. PMID- 23728582 TI - A coumarin-based "turn-on" fluorescent sensor for the determination of Al3+: single crystal X-ray structure and cell staining properties. AB - An efficient Al(3+) receptor, 6-(2-hydroxybenzylideneamino)-2H-chromen-2-one (HBC), has been synthesized by condensing salicylaldehyde with 6-aminocoumarin. The molecular structure of HBC has been determined by a single crystal X-ray analysis. It was established that in the presence of Al(3+), HBC shows 25 fold enhancement of fluorescence intensity which might be attributed to the chelation enhanced fluorescence (CHEF) process. HBC binds Al(NO3)3 in a 1 : 1 stoichiometry with a binding constant (K) of 7.9 * 10(4) M(-1). Fe(3+) and Mn(2+) quench the emission intensity of the [HBC + Al(3+)] system to an insignificant extent at a concentration 10 times higher compared to that of Al(3+). HBC is highly efficient in the detection of intracellular Al(3+) under a fluorescence microscope. PMID- 23728581 TI - Individual factors and school-based policies related to adherence to physical activity recommendations in Spanish adolescents. AB - Our objective was to identify individual- and school-level contextual factors related to adherence to the recommendations for physical activity in adolescents. The study used a representative sample of 15,902 students from 328 schools aged 11-18 years participating in the Spanish Health Behaviour in School-aged Children (HBSC) survey 2006. In addition to the student questionnaire, the school management board completed a questionnaire about school-based policies related to physical activity. Adherence to the recommendations was defined as "having carried out moderate and/or vigorous physical activity for at least 60 min a day on five or more days during the last week". Analysis was undertaken using multilevel logistic regression models. Individual factors associated in a statistically significant way with a higher non-compliance were: being female; being older; immigrants; tobacco smoking; being overweight or obese; low consumption of fruit and vegetables; low level of satisfaction with life; not having a high level of academic achievement; and spending a lot of time studying. The family variables were: not undertaking sports activities with the family; low socioeconomic status; and a low level of satisfaction with family relationships. Compared with schools that have a low level of policies to promote physical activities, those with a high level of promotion had an odds ratio of 0.76 (CI 95 %, 0.61-0.94). In summary, irrespective of personal and family factors, students from schools with better policies of promotion of physical activity showed a higher compliance with the recommendations. PMID- 23728583 TI - Aestuariihabitans beolgyonensis gen. nov., sp. nov., a novel alphaproteobacterium isolated from tidal flat sediment. AB - A Gram-negative, non-motile and rod-shaped bacterial strain, designated BB MW15(T), was isolated from a tidal flat of the southern coast of the Korean peninsula, and its taxonomic position was investigated by using a polyphasic taxonomic approach. Strain BB-MW15(T) grew optimally at 30 degrees C, at pH 7.0 8.0 and in the presence of 2-3 % (w/v) NaCl. Strain BB-MW15(T) exhibited the highest 16S rRNA gene sequence similarity values to the type strains of Marivita byunsanensis (96.8 %), Thalassobius maritimus (96.6 %), Sulfitobacter marinus (96.4 %) and Marinovum algicola (96.3 %). Neighbour-joining, maximum-likelihood and maximum-parsimony phylogenetic trees based on 16S rRNA gene sequences revealed that strain BB-MW15(T) forms an independent lineage within the evolutionary radiation encompassed by the Roseobacter clade of the class Alphaproteobacteria. Strain BB-MW15(T) contained Q-10 as the predominant ubiquinone and C18:1 omega7c as the predominant fatty acid. The major polar lipids detected in strain BB-MW15(T) were phosphatidylcholine, phosphatidylglycerol, one unidentified aminolipid and one unidentified lipid. The DNA G+C content of strain BB-MW15(T) is 62.7 mol%. Based on phylogenetic, chemotaxonomic and other phenotypic characteristics, strain BB-MW15(T) represents a new genus and a new species within Alphaproteobacteria, for which the name Aestuariihabitans beolgyonensis gen. nov., sp. nov. is proposed. The type strain of A. beolgyonensis is BB-MW15(T) (= KCTC 32324(T) = CCUG 63829(T)). PMID- 23728584 TI - Shape discrimination and concept formation in the jungle crow (Corvus macrorhynchos). AB - We investigated whether jungle crows can learn concepts by using printouts of shapes in a simultaneous two-alternative task. Jungle crows were first trained with a red triangle and red square until they reached the discrimination criterion (80% of correct choices in two blocks of 10 trials each). Then, we tested crows with successive transfer tests to investigate both the discrimination cues being used and concept formation ability, by using novel triangular and non-triangular stimuli. All of the jungle crows learnt to discriminate between the triangle and square during training. The discrimination performance was generally not affected either by changes in the colour of the stimuli or when both shape and colour cues conflicted, with the previously non rewarded shape but matching colour (red square) versus rewarded shape but non matching colour (green triangle). The use of only outlines of the familiar stimuli also did not affect discrimination behaviour of crows. In addition, crows significantly discriminated novel triangular shapes during the limited trials given, suggesting their ability to form the concept of triangularity. However, failure to discriminate when the novel stimuli size deviated from the original suggests that there is a limit to shape concept formation in a familiar-novel context in the jungle crow. PMID- 23728585 TI - Efficacy and safety of Chinese herbal medicine for benign prostatic hyperplasia: systematic review of randomized controlled trials. AB - Chinese herbal medicine is commonly used as a treatment for benign prostatic hyperplasia (BPH), but its efficacy and safety remain to be examined. To compare the efficacy and adverse events of Chinese herbal medicine alone or used adjuvantly with Western medications for BPH. Two independent reviewers searched the major electronic databases for randomized controlled trials comparing Chinese herbal medicine, either in single or adjuvant use with Western medication, with placebo or Western medication. Relevant journals and grey literature were also hand-searched. The outcome measures included changes in urological symptoms, urodynamic measures, prostate volume and adverse events. The frequency of commonly used herbs was also identified. Out of 13 922 identified citations of publications, 31 studies were included. Eleven studies with a Jadad score >= 3 were selected for meta-analysis. Chinese herbal medicine was superior to Western medication in improving quality of life and reducing prostate volume. The frequency of adverse events in Chinese herbal medicine was similar to that of placebo and less than that of Western medication. The evidence is too weak to support the efficacy of Chinese herbal medicine for BPH due to the poor methodological quality and small number of trials included. The commonly used herbs identified here should provide insights for future clinical practice and research. Larger randomized controlled trials of better quality are needed to truly evaluate the efficacy of Chinese herbal medicine. PMID- 23728586 TI - Further evidence of endogenous hydrogen sulphide as a mediator of relaxation in human and rat bladder. AB - We investigated the expression of hydrogen sulphide (H2S) in human and rat lower urinary tract (including bladder, prostate and urethra) tissues, and we sought to determine whether H2S induces relaxation of human and Sprague-Dawley (SD) rat bladder strips. Human normal lower urinary tract tissue was obtained for the evaluation of endogenous H2S productivity using a sulphide-sensitive electrode and for the analysis of the expression levels of all three synthases of endogenous H2S, cystathionine beta-synthase (CBS), cystathionine gamma lyase (CSE) and 3-mercaptopyruvate sulphur transferase (MPST, as known as 3-MST) by Western blot assay. CBS, CSE and MPST were located in human sample slides by immunohistochemistry. Human and male adult SD rat bladder strips were tested for H2S function with a transducer and recorded. All experiments were repeated six times. The endogenous H2S productivity and the H2S synthases had various distributions in the human and rat lower urinary tract tissues and were located in both epithelial and stromal sections. L-cysteine (L-Cys, a substrate of CBS, CSE and MPST) elicited relaxation in a dose-dependent manner on human bladder strips pre-contracted by acetylcholine chloride. This effect could be diminished by the ATP-sensitive potassium ion (KATP) channel blocker glibenclamide (GLB), the CSE inhibitor DL-propargylglycine (PPG) and the CBS inhibitor hydroxylamine (HA). H2S and its three synthases were present in the human and rat lower urinary tract tissues and relaxed human and rat bladder strips, which implied that endogenous H2S might play a role in physiological function and pathological disorders of the lower urinary tract symptoms (LUTS) or overactive bladder (OAB). PMID- 23728587 TI - Mouse sperm acquire a new structure on the apical hook during epididymal maturation. AB - Spermatozoa emerging from the testis undergo a maturation process in the epididymis during which they change morphologically, biochemically and physiologically to gain motility and the ability to fertilize ova. We examined mouse epididymal sperm with immunostaining and transmission electron microscopy (EM) and identified a previously unknown structure on the apical hook. The structure has a coiled configuration around 11 nm in thickness and is present at the tip of each corner of the triangular-rod shaped perforatorium. Surveying sperm isolated from various regions of the epididymis indicated that mouse sperm acquire the hook rim (HR) structure during its passage through the proximal two thirds of the caput epididymidis. The structure withstands vigorous sonication and harsh chemical treatments and remains intact after the acrosome reaction. Its location and sturdiness suggest a function in protecting the apical hook from mechanical wear during fertilization. Our EM images of epididymal sperm also revealed additional novel structures as well as lateral asymmetry of the sperm head, indicating that mouse sperm head has a structure more complex than previously recognized. PMID- 23728589 TI - Comorbidity and survival of patients selected for radical prostatectomy at an age of 75 years or older. AB - Radical prostatectomy in elderly patients is controversial. To identify very old candidates for radical prostatectomy with the highest probability of long-term survival, we studied 47 consecutive men who underwent radical prostatectomy between 1992 and 2005 at an age of 75 years or older. A heuristic approach was used to search for subgroups with particularly high long-term survival. Several two-sided comorbidity measures and combinations of these measures were investigated to find classifications best identifying healthy, long-living elderly candidates for radical prostatectomy. Four of the 25 two-sided comorbidity classifications or combinations reached the significance level with hazard ratios between 4.00 and 4.80. After 10 years, patients identified as healthy patients according to these comorbidity measurements had exhibited relative survival rates between 129% and 137% and overall survival rates between 86% and 95%, whereas those with comorbidities had exhibited relative survival rates of only 66%-84% and overall survival rates of 44%-58%. In conclusion, classifying comorbidity may identify a meaningful proportion of men selected for radical prostatectomy at an age of 75 years or older with an excellent long-term survival probability superseding that of the general population. PMID- 23728588 TI - Analysis of circulating regulatory T cells (CD4+CD25+CD127-) after cryosurgery in prostate cancer. AB - This study was performed to assess the response of regulatory T cells (Tregs) following cryosurgery in prostate cancer (PCa) patients by measuring their frequency and immune function. Blood was collected prior to and at 4 and 8 weeks after treatment in 30 patients with high-risk PCa who underwent cryosurgery and from 15 healthy volunteers. Circulating CD4(+)CD25(+)CD127(-) Tregs were isolated. Their frequency was detected by flow cytometry, and immune suppressive function was evaluated by measuring the proliferation of CD4(+)CD25(-) T cells cocultured with Tregs. The results showed that the percentage of circulating CD4(+)CD25(+)CD127(-) Tregs was increased in PCa patients compared to healthy volunteers (7.6% +/- 0.73% vs. 5.8% +/- 0.54%, P<0.001). The frequency of circulating CD4(+)CD25(+)CD127(-) Tregs was reduced 4 weeks after cryosurgery compared to before surgery (6.3% +/- 0.58% vs. 7.6% +/- 0.73%, P<0.001), and the decrease persisted for 8 weeks. However, the suppressive function of Tregs was increased in eight of 12 patients, which might contribute to cancer recurrence. Then the response of circulating Tregs is complicated after cryosurgery for PCa, and further studies are warranted. PMID- 23728590 TI - Insulin affects sperm capacity in pig through nitric oxide. AB - Insulin (Ins) has recently been demonstrated to have the ability to induce the capacitation process in pig spermatozoa. In various mammalian species, capacitation has been linked to the nitric oxide (NO) signalling; therefore, this study investigated NO production in Ins-treated pig spermatozoa by fluorescence activated cell sorting. For the same samples, sperm capacitation was evaluated by chlortetracycline staining, protein tyrosine phosphorylation pattern and acrosomal status. A significant increase of the intrasperm NO level and the activation of three capacitation indices were detected in response to Ins treatment. Conversely, sperm preincubation with an NO synthase inhibitor (N-nitro L-arginine methyl ester) or with the anti-Ins receptor beta (IRbeta) antibody reversed all of the Ins-related effects. These results suggest that Ins has the capacity to enhance intracellular NO concentrations in pig spermatozoa and indicate a possible NO implication upon Ins promotion of capacitation. PMID- 23728591 TI - The effect of diet-induced insulin resistance on DNA methylation of the androgen receptor promoter in the penile cavernosal smooth muscle of mice. AB - Population studies have suggested an association between diabetes and the symptoms of testosterone deficiency. Recently, the expression of the androgen receptor (AR) has been shown to be decreased in diabetic patients. Furthermore, diabetes has been shown to induce global methylation. In this study, we used an animal model to investigate whether diabetes results in increased methylation of the AR promoter and whether these changes are associated with the decreased expression of AR in penile cavernosal smooth muscle tissue. Twenty C57BL/6J mice were divided into two groups, receiving either high- (mature diabetic) or low- (mature control) caloric meals for 14 weeks. Another 10 mice were killed at 1 week (young control). Animals in the mature diabetic group showed decreased testosterone levels, although this was not statistically significant. In both control groups, no significant methylation was observed in the AR promoter region CpG island (-85 to +339). In the mature diabetic group, significant methylation was observed at +185 and +200 of the AR promoter. These changes were associated with increased homeostatic model assessment for insulin resistance (HOMA-IR) and decreased corpus cavernosal tissue mass and expression of AR mRNA and protein. We conclude that in these animals, insulin resistance increased the methylation of the GC-rich regions of the AR promoter, leading to decreased AR expression. PMID- 23728593 TI - Extremely fast and highly selective detection of nitroaromatic explosive vapours using fluorescent polymer thin films. AB - A novel sensing material based on pyrene doped polyethersulfone worm-like structured thin film is developed using a facile technique for detection of nitroaromatic explosive vapours. The formation of pi-pi stacking in the thin fluorescent film allows a highly sensitive fluorescence quenching which is detectable by the naked eye in a response time of a few seconds. PMID- 23728592 TI - Protein backbone and sidechain torsion angles predicted from NMR chemical shifts using artificial neural networks. AB - A new program, TALOS-N, is introduced for predicting protein backbone torsion angles from NMR chemical shifts. The program relies far more extensively on the use of trained artificial neural networks than its predecessor, TALOS+. Validation on an independent set of proteins indicates that backbone torsion angles can be predicted for a larger, >=90 % fraction of the residues, with an error rate smaller than ca 3.5 %, using an acceptance criterion that is nearly two-fold tighter than that used previously, and a root mean square difference between predicted and crystallographically observed (phi, psi) torsion angles of ca 12o. TALOS-N also reports sidechain chi(1) rotameric states for about 50 % of the residues, and a consistency with reference structures of 89 %. The program includes a neural network trained to identify secondary structure from residue sequence and chemical shifts. PMID- 23728594 TI - Descriptive profile of PIK3CA-mutated colorectal cancer in postmenopausal women. AB - PURPOSE: Approximately 10-30 % of colorectal cancers exhibit somatic mutations in the phosphoinositide-3-kinase, catalytic, alpha polypeptide gene (PIK3CA). We evaluated the relationship between PIK3CA mutation status and demographic factors, lifestyle factors, and other tumor characteristics and the relationship between PIK3CA mutation status and colorectal cancer survival. METHODS: The population-based study included postmenopausal women with invasive colorectal cancer diagnosed between 1998 and 2002 in Western Washington State. Participants were interviewed, and tumor specimens were tested for PIK3CA mutations in exons 9 and 20 hotspots, KRAS exon 2 mutations, BRAF p.V600E mutation, and microsatellite instability. We used Cox regression to evaluate the association between PIK3CA mutation status and disease-specific and overall survival. Stratified analyses were conducted by KRAS mutation status. RESULTS: PIK3CA mutations were evident in approximately 13 % of cases (N = 35). Women with PIK3CA-mutated colorectal cancer were significantly more likely than those with PIK3CA wild-type disease to be non white, to have proximal colon cancer, and to have KRAS-mutated tumors (p < 0.05). In Cox proportional hazards regression analyses, overall survival was poorer, although not statistically significantly so, for women with PIK3CA-mutated versus wild-type colorectal cancer (hazard ratio = 1.74, 95 % confidence interval 0.86 3.50). This association between PIK3CA mutation status and survival was evident only when analyses were restricted to cases without somatic KRAS mutations (hazard ratio = 2.94, 95 % confidence interval 1.12-7.73). CONCLUSIONS: PIK3CA mutated colorectal cancer appears to have a distinct epidemiologic profile that is of clinical significance. Women with PIK3CA-mutated colorectal cancer experience a poorer prognosis than those with PIK3CA wild-type disease. PMID- 23728595 TI - Challenging diagnosis of intra-diverticular colonic adenocarcinoma with submucosal localization. PMID- 23728597 TI - The promise of large, longitudinal data sets. PMID- 23728596 TI - Comparison between single-incision and conventional three-port laparoscopic appendectomy: a meta-analysis from eight RCTs. AB - PURPOSE: To assess the efficacy and safety of single-incision laparoscopic appendectomy (SILA), we conducted a meta-analysis of randomized controlled trials (RCTs) comparing conventional three-port laparoscopic appendectomy (CTLA). METHODS: RCTs comparing the effects of SILA and CTLA were searched for in PubMed, the Cochrane Central Register of Controlled Trials, and Embase. Operative time, the pain visual analogue scales scores (VAS scores), dose of analgesics, postoperative complications, hospital charges, and duration of postoperative hospitalization in SILA and CTLA were pooled and compared by meta-analysis. Odds ratios and weighted mean differences (WMDs) were calculated with 95% confidence intervals (CIs) to evaluate the effect of SILA. RESULT: Eight original RCTs investigating 760 adults and 684 children, 1,444 patients in total, of whom 721 received SILA only and 723 received CTLA only, met the inclusion criteria. Both in adults and children, the mean operative time was significantly longer in SILA than CTLA (WMD5.45, 95% CI 2.15 to 8.75, p = 0.01). Compared with CTLA, in children, SILA have higher analgesic consumption (WMD 0.69, 95% CI 0.08 to 1.3, p = 0.03) and greater hospital charges (WMD 0.87, 95% CI 1.26 to 1.48, p = 0.005), which was not statistically different in adults (p > 0.05). Pooling the results for SILA and CTLA revealed no significant difference in VAS scores, wound infection rate, overall complications, and postoperative hospital stay. CONCLUSION: SILA failed to show any obvious advantages over CTLA in perioperative and postoperative outcomes. Therefore, it represents a possible alternative to conventional three-port laparoscopic appendectomy. PMID- 23728599 TI - Economic grand rounds: financing first-episode psychosis services in the United States. AB - Adequate financing is essential to implementing services for individuals experiencing a first episode of a psychotic illness. Recovery After an Initial Schizophrenia Episode (RAISE), a project sponsored by the National Institute of Mental Health, is providing a practical test of the implementation and effectiveness of first-episode services in real-world settings. This column describes approaches to financing early intervention services that are being used at five of 18 U.S. sites participating in a clinical trial of a team-based, multielement RAISE intervention. The authors also describe new options for financing that will become available as the Affordable Care Act (ACA) is implemented more fully. The ACA will rationalize coverage of first-episode services, but the all-important Medicaid provisions will also require individual state action to implement services optimally. PMID- 23728600 TI - Research and services partnerships: partnership: a fundamental component of dissemination and implementation research. AB - This column describes the essential role of partnerships in the conduct of dissemination and implementation (D&I) research. This research field, which develops knowledge to support the integration of health information and evidence based practices, has thrived in recent years through research initiatives by federal agencies, states, foundations, and other funders. The authors describe three ongoing studies anchored in research partnerships to improve the implementation of effective practices within various service systems. Inherent in the challenge of introducing evidence-based practices in clinical and community settings is the participation of a wide range of stakeholders who may influence D&I efforts. Opportunities to enhance partnerships in D&I research are described, specifically in light of recent initiatives led by the National Institutes of Health. Partnerships remain a crucial component of successful D&I research. The future of the field depends on the ability to utilize partnerships to conduct more rigorous and robust research. PMID- 23728601 TI - Research to reduce the suicide rate among older adults: methodology roadblocks and promising paradigms. AB - The National Institute of Mental Health and the National Action Alliance for Suicide Prevention have requested input into the development of a national suicide research agenda. In response, a working group of the American Association for Geriatric Psychiatry has prepared recommendations to ensure that the suicide prevention dialogue includes older adults, a large and fast-growing population at high risk of suicide. In this Open Forum, the working group describes three methodology roadblocks to research into suicide prevention among elderly persons and three paradigms that might provide directions for future research into suicide prevention strategies for older adults. PMID- 23728602 TI - Behavioral health and social correlates of reincarceration among Hispanic, Native American, and white rural women. AB - OBJECTIVE: To identify community reentry needs, this study examined mental illness, substance dependence, and other correlates of reincarceration in an ethnically diverse, rural population of women prisoners. METHODS: A purposive, cross-sectional sample of 98 women in a New Mexico state prison completed structured interviews. Analyses examined associations of substance dependence, mental illness, lifetime trauma, and sociodemographic variables with previous incarceration. RESULTS: Eighty-five percent screened positive for substance dependence, 50% for current mental disorders, and 46% for both. Exposure to trauma was pervasive (100%), especially physical or sexual trauma (83%). In adjusted analyses, previous incarceration was associated with precarious housing before imprisonment (odds ratio [OR]=2.19, p=.038) and with having co-occurring mental illness and substance dependence (OR=2.68, p=.019). CONCLUSIONS: Findings support those of similar studies in urban areas and with other ethnic groups. Wraparound programs focusing on harm reduction, housing, and treatment and support services are needed for successful reentry of these underserved women. PMID- 23728603 TI - Health care utilization prior to loss to care among veterans with serious mental illness. AB - OBJECTIVE: This study examined the association between utilization of Veterans Affairs (VA) health services and the probability of treatment dropout among veterans with serious mental illness. METHODS: Utilization of VA health services in the fiscal year (FY) before treatment dropout among veterans with serious mental illness who were lost to care for at least 12 months beginning in FYs 2008 or 2009 (N=6,687) was compared with utilization in FYs 2007 or 2008 among veterans with serious mental illness who remained in care (N=6,687). RESULTS: The veterans (mean age=54) were predominantly male (91%) and Caucasian (76%). After accounting for demographic and clinical variables, the analyses found that more primary care and mental health outpatient visits and fewer general medical and mental health hospitalizations were associated with lower odds of dropout. CONCLUSIONS: Engagement in outpatient health care was associated with lower odds of loss to care among veterans with serious mental illness. PMID- 23728605 TI - IOM committee assesses current and long-term needs of returning service members and veterans. PMID- 23728604 TI - Primary care providers' views on metabolic monitoring of outpatients taking antipsychotic medication. AB - OBJECTIVE: The purpose of this study was to evaluate attitudes of primary care providers toward barriers to metabolic monitoring and to characterize their beliefs about providers' responsibility for monitoring and reducing cardiovascular risk for people with severe mental illness. METHODS: An anonymous survey was administered to 214 primary care providers working in 23 public community health clinics in San Francisco. RESULTS: The response rate was 77% (164 of 214). Nearly 40% of primary care providers were unaware of consensus guidelines for metabolic monitoring of people who take second-generation antipsychotic medications. Responses showed variation in providers' beliefs about who should monitor patients' metabolic risk. The major barriers to metabolic monitoring were severity of psychiatric illness, difficulty collaborating with psychiatrists, and difficulty arranging psychiatric follow-up. CONCLUSIONS: Primary care providers believed that better communication between primary care providers and psychiatrists would facilitate metabolic monitoring and promote better treatment for patients with severe mental illness who are taking antipsychotic medications. PMID- 23728607 TI - Facile synthesis of Pd-based bimetallic nanocrystals and their application as catalysts for methanol oxidation reaction. AB - We employed an efficient and facile route to synthesise monodisperse Pd-based bimetallic nanocrystals (MPd: M = Cu, Co and Ni) via a controlled co-reduction of Pd(ii) chloride and M(ii) nitrate at 200-230 degrees C in the presence of oleylamine (OAm). These monodisperse Pd-based nanocrystals have small dimensions, unique structures and homogeneous morphology, thus exhibit efficient catalytic activities for methanol oxidation in alkaline solution, which is much better than commercial Pd/C with same amount of palladium. The catalytic activities of these nanocrystals followed the order of NiPd/C > CoPd/C > CuPd/C > commercial Pd/C, due to the different synergistic effects. Our results show that these Pd-based bimetallic nanocrystals can be promising as practical catalysts for methanol oxidation reactions and other catalytic reactions in further investigations. PMID- 23728608 TI - Combination of fludarabine, amsacrine, and cytarabine followed by reduced intensity conditioning and allogeneic hematopoietic stem cell transplantation in patients with high-risk acute myeloid leukemia. AB - Sequential use of chemotherapy and reduced-intensity conditioning (RIC) with allogeneic stem cell transplantation (SCT) has been proposed to improve the treatment outcomes in patients with high-risk acute myeloid leukemia (AML). Here, we present our experience with this procedure in a cohort of 60 AML patients with primary induction failure (n = 9); early, refractory, or >= second relapse (n = 41); or unfavorable cytogenetics (n = 10). A combination of fludarabine (30 mg/m2/day), cytarabine (2 g/m2/day), and amsacrine (100 mg/m2/day) for 4 days was used. After 3 days of rest, RIC was carried out, consisting of 4 Gy total body irradiation, antithymocyte globulin (ATG-Fresenius), and cyclophosphamide (fludarabine, amsacrine, and cytarabine (FLAMSA)-RIC protocol). Prophylactic donor lymphocyte infusions (pDLIs) were given in patients with complete remission (CR) and without evidence of graft-versus-host disease >=120 days after SCT. The median time of neutrophil engraftment was 17 days. CR was achieved in 47 of 60 patients (78%). Eleven patients received pDLIs resulting in long-term CR in eight of them. Non-relapse mortality after 1 and 3 years was 25 and 28%, respectively. With a median follow-up of 37 months (range, 10-69), 3-year overall survival and 3-year progression-free survival were 42 and 33%, respectively. In a multivariate analysis, dose of CD34(+) cells >5 * 106/kg (p = 0.005; hazard ratio (HR) = 0.276), remission of AML before SCT (p = 0.044; HR = 0.421), and achievement of complete chimerism after SCT (p = 0.001; HR = 0.205) were significant factors of better overall survival. The use of the FLAMSA-RIC protocol in suitable high-risk AML patients results in a long-term survival rate of over 40%. PMID- 23728609 TI - Persisting fatigue in Hodgkin lymphoma survivors: a systematic review. AB - Hodgkin Lymphoma (HL) survivors are at risk for adverse psychosocial events as a result from cancer diagnosis and treatment. Fatigue is one of the most frequently reported long-term symptoms and is often reported to interfere with daily life. We conducted a systematic review to determine prevalence, severity and predisposing factors of fatigue in HL survivors. A literature search was conducted up to August 2012. Twenty-two articles comparing HL survivors with norm population data met all predefined selection criteria. Prevalence rates, levels of fatigue and clinical relevance of the results were determined. Prevalence of fatigue ranged from 11-76 % in HL survivors compared to 10 % in the general population. Mean fatigue scores were 5-13 % higher compared to the normative population; these findings were clinically relevant in 7 out of 11 studies. Increasing age was associated with higher levels of fatigue in HL survivors. Treatment modality and stage of initial disease were not associated with higher fatigue levels, while comorbidities or other treatment sequelae seemed to impact on the levels of fatigue. HL survivors are at serious risk for developing clinically relevant, long-term fatigue. The impact of patient and treatment characteristics on risk of fatigue is limited. Focus for future research should shift to the role of late-treatment sequelae and psychological distress symptoms. PMID- 23728610 TI - MicroRNAs mark in the MLL-rearranged leukemia. AB - MicroRNAs are short noncoding RNAs, known regulators of several signaling pathways cell differentiation and proliferation, development, and apoptosis, which are deregulated in acute leukemia. Mixed lineage leukemia (MLL) gene encodes a protein with histone methyltransferase activity, which is essential for the fine tuning of hematopoietic stem cell development and differentiation through the regulation of HOXA and MEIS1. MLL gene rearrangements characterize both acute myeloid and acute lymphoblastic leukemia associated with poor outcomes. MicroRNAs and MLL rearrangements are in tight association regulating each other expression, affecting cell cycle regulators, and composing complex networks with factors involved in leukemogenesis such as MYC and FLT3. MLL fusion genes are also capable of recruiting DNA methyltransferases at microRNAs promoters controlling their expression through epigenetic changes. Direct drug targeting of MLL has been difficult to achieve, and in this context, microRNA expression modulation represents an attractive approach. PMID- 23728611 TI - Reactivation of hepatitis B virus in a hepatitis B surface antigen-negative patient with acute promyelocytic leukemia treated with arsenic trioxide. PMID- 23728612 TI - Histamine H1 receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: a positron emission tomography study in healthy volunteers. AB - RATIONALE: Histamine H1 antagonists have hypnotic, appetite-promoting, and sedative effects. The affinities of various antidepressants for histamine receptors have only been partially determined in vitro and animal study. Positron emission tomography (PET) can clarify the in vivo dynamics of antidepressants at histamine receptors. OBJECTIVES: We performed human PET imaging with [11C]doxepin, a selective PET ligand of the histamine H1 receptor (H1R), to study the in vivo affinities of fluvoxamine and mirtazapine for the H1R. METHODS: The subjects were five male healthy Japanese volunteers. We performed cross randomized PET imaging after single oral administration of fluvoxamine (25mg), mirtazapine (15 mg), or placebo. PET data were analyzed by region-of-interest and voxel-by-voxel analysis. We concurrently measured plasma drug concentrations, using liquid chromatography/tandem mass spectrometry and subjective sleepiness. RESULTS: The binding potential ratio of mirtazapine in brain cortex was significantly lower than that of fluvoxamine or placebo. Fluvoxamine did not occupy the H1R, whereas H1R occupancy (H1RO) of mirtazapine reached 80-90 % in the cerebral neocortex. In the voxel-by-voxel analysis, the binding potential of mirtazapine was significantly lower than placebo in the dorsolateral prefrontal cortex, lateral temporal cortex, anterior cingulate gyrus, and posterior cingulate gyrus. The H1RO of mirtazapine depended on the plasma drug concentration (AUC(0-180 min)) and was related to subjective sleepiness. CONCLUSIONS: Our results demonstrate a low affinity of fluvoxamine and a very high affinity of mirtazapine for the human brain H1R in vivo. This study provides a basis for investigating the efficacy of new-generation antidepressants in central histamine systems. PMID- 23728613 TI - Accelerated immunotherapy schedules. AB - Rush and cluster immunotherapy schedules are accelerated immunotherapy build-up schedules. A cluster immunotherapy schedule involves the patient receiving several allergen injections (generally 2-4) sequentially in a single day of treatment on nonconsecutive days. The maintenance dose is generally reached in 4 8 weeks. In rush immunotherapy protocols, higher doses are administered at 15- to 60-min intervals over a 1- to 3-day period until the maintenance dose is achieved. This review will serve as an update for accelerated immunotherapy schedules. The review will include recent investigations demonstrating the safety of cluster schedules in atopic dermatitis, pediatric patients, and inhalant allergen mixtures and an accelerated protocol utilizing an infusion pump for allergen delivery. There has also been further elucidation on the immunological changes which occur during accelerated immunotherapy. Finally, new studies analyzing systemic reaction risk factors are discussed. PMID- 23728614 TI - Current concepts and trends for operative treatment of FAI: hip arthroscopy. AB - There has been an increasing body of literature regarding arthroscopic management of femoroacetabular impingement (FAI). Refinement of arthroscopic techniques has allowed for more complete management of FAI, and meta-analysis and systematic reviews have shown comparable outcomes to surgical hip dislocation with appropriate indications. There are still, however, pathomorphologies that are not accessible or much more challenging to address arthroscopically, and open corrective procedures should be considered in these situations. Extra-articular FAI is receiving increased attention and can be secondary to anterior inferior iliac spine/subspine impingement, trochanteric-pelvic impingement, and ischio femoral impingement. Femoral and acetabular version and their impact on hip stability as well as the concept of impingement induced instability are being increasingly recognized. Acetabular labral and capsular management and repair techniques have also received increased attention. Finally, 3-dimensional imaging and dynamic software analysis are beginning to emerge as potential tools to better evaluate hip pathomorphology. PMID- 23728615 TI - Persistent impairments in hippocampal function following a brief series of photoperiod shifts in rats. AB - The impact of an acute circadian disruption on learning and memory in male and female rats was examined. Circadian disruption was elicited using a brief series of photoperiod shifts. Previous research using male rats showed that acute circadian disruption during acquisition of a spatial navigation task impaired long-term retention and that chronic circadian disruption impaired acquisition of the same task. However, the long-term effects of acute circadian disruption following circadian re-entrainment and whether sex differences in response to circadian disruption exist are still unknown. For the present study, rats were trained on the standard, spatial version of the Morris water task (MWT) and a visual discrimination task developed for the eight-arm radial maze. After reaching asymptotic performance, behavioural training was terminated and the experimental group experienced a series of photoperiod shifts followed by circadian re-entrainment. Following circadian re-entrainment, the subjects were given retention tests on the MWT and visual discrimination task. Following retention testing, an extra-dimensional shift using the eight-arm radial maze was also performed. An acute episode of circadian disruption elicited via photoperiod shifts negatively impacted retention of spatial memory in male and female rats. Retention of the visual discrimination task and the ability to detect extra dimensional shifts were not impaired. The observed impairments on the MWT indicate that hippocampal representations are susceptible to a small number of photoperiod shifts even if the association is acquired prior to rhythm manipulation and retention is assessed following rhythm stabilization. Effects were limited to a hippocampus-dependent task, indicating that impairments are specific, not global. PMID- 23728616 TI - Association between genetic variants in pre-miRNA and colorectal cancer risk in a Chinese population. AB - INTRODUCTION: Single-nucleotide polymorphisms (SNPs) in pre-miRNAs may alter microRNA expression levels or processing and then contribute to the susceptibility of cancer development. We hypothesized that SNPs in pre-miRNAs may be associated with the risk of colorectal cancer (CRC). MATERIALS AND METHODS: We genotyped four common polymorphisms (i.e., rs11614913, rs3746444, rs2910164, and rs2292832) in pre-miRNAs of 353 CRC patients and 540 healthy controls to investigate the association between the SNPs and the risk of CRC using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: The rs11614913 CT, TT genotypes, and T allele were associated with an increased risk of CRC compared with the CC genotype and C allele (CT vs. CC: OR = 7.34, 95% CI 3.76-14.34; TT vs. CC: OR = 13.66, 95% CI 6.76-27.6; T vs. C: OR = 1.99, 95% CI 1.63-2.42, respectively). Interestingly, using the rs2910164 GG genotype as a reference, the rs2910164 GC genotype was associated with an increased risk of CRC (OR = 1.49, 95% CI 1.02-2.18), whereas the rs2910164 CC genotype was associated with a decreased risk of CRC (OR = 0.58, 95% CI 0.37 0.93). When compared with the rs2910164G allele, rs2910164 C allele was associated with a reduced risk of CRC (OR = 0.80, 95% CI 0.66-0.97, p = 0.02). CONCLUSION: These findings suggest that rs11614913 and rs2910164 polymorphisms may be associated with the etiology of CRC. PMID- 23728618 TI - Reply: To PMID 23728734. PMID- 23728619 TI - A homology/ab initio hybrid algorithm for sampling near-native protein conformations. AB - One of the major challenges for protein tertiary structure prediction strategies is the quality of conformational sampling algorithms, which can effectively and readily search the protein fold space to generate near-native conformations. In an effort to advance the field by making the best use of available homology as well as fold recognition approaches along with ab initio folding methods, we have developed Bhageerath-H Strgen, a homology/ab initio hybrid algorithm for protein conformational sampling. The methodology is tested on the benchmark CASP9 dataset of 116 targets. In 93% of the cases, a structure with TM-score >= 0.5 is generated in the pool of decoys. Further, the performance of Bhageerath-H Strgen was seen to be efficient in comparison with different decoy generation methods. The algorithm is web enabled as Bhageerath-H Strgen web tool which is made freely accessible for protein decoy generation (http://www.scfbio iitd.res.in/software/Bhageerath-HStrgen1.jsp). PMID- 23728617 TI - Extracellular HIV-1 viral protein R affects astrocytic glyceraldehyde 3-phosphate dehydrogenase activity and neuronal survival. AB - Extracellular human immunodeficiency virus type 1 (HIV-1) viral protein R (Vpr) is a pleiotropic protein accomplishing several functions within the viral life cycle. While Vpr has been described extensively as an intracellular protein, very little is known about its role as an extracellular protein. In fact, HIV-1 Vpr has been detected in the blood, serum, and cerebrospinal fluid of HIV-1-infected patients, with concentrations increasingly higher in late-stage disease. To determine the role exogenous Vpr plays in HIV-associated central nervous system dysfunction, primary human fetal astrocytes were exposed to recombinant Vpr and a time- and dose-dependent decrease was demonstrated in two fundamental intracellular metabolites (adenosine-5'-triphosphate (ATP) and glutathione (GSH)). Additionally, exposure to exogenous Vpr led to increased caspase activity and secretion of proinflammatory cytokines IL-6 and IL-8 and chemoattractants, monocyte chemotactic protein-1, and migration inhibition factor. Extracellular Vpr also dampened the glycolytic pathway through impairment of glyceraldehyde 3 phosphate dehydrogenase activity, causing a decline in the levels of ATP. The reduction in intracellular ATP increased reactive oxygen species buildup, decreasing GSH concentrations, which affected several genes in the oxidative stress pathway. In addition, exposure of the SK-N-SH neuroblastoma cell line to conditioned medium from exogenous Vpr-treated astrocytes decreased synthesis of GSH, leading to their apoptosis. These observations point to a role that Vpr plays in altering astrocytic metabolism and indirectly affecting neuronal survival. We propose a model that may explain some of the neurological damage and therefore neurocognitive impairment observed during the course of HIV-1 disease. PMID- 23728620 TI - Progressive applications of dissolution, its impact, and implications in the pharmaceutical world. PMID- 23728621 TI - A normal inferior olive in essential tremor--peacemaker or pacemaker? PMID- 23728622 TI - Analysis of the transcriptome of Legionella pneumophila hfq mutant reveals a new mobile genetic element. AB - Hfq is a small RNA-binding protein involved in the post-transcriptional regulation of gene expression by affecting the stability of the mRNA and by mediating efficient pairing between small regulatory RNAs and their target mRNAs. In Legionella pneumophila, the aetiological agent of Legionnaires' disease, mutation of hfq results in increased duration of the lag phase and reduced growth in low-iron medium. In an effort to uncover genes potentially regulated by Hfq, the transcriptome of an hfq mutant strain was compared to that of the wild-type. Unexpectedly, many genes located within a 100 kb genomic island, including a section of the previously identified efflux island, were overexpressed in the hfq mutant strain. Since this island contains a putative conjugative system and an integrase, it was postulated that it could be a new integrated mobile genetic element. PCR analysis revealed that this region exists both as an integrated and as an episomal form in the cell population and that it undergoes differential excision in the hfq mutant background, which was further confirmed by trans complementation of the hfq mutation. This new plasmid-like element was named pLP100. Differential excision did not affect the copy number of pLP100 at the population level. This region contains a copper efflux pump encoded by copA, and increased resistance to copper was observed for the hfq mutant strain that was abrogated in the complemented strain. A strain carrying a mutation of hfq and a deletion of the right side recombination site, attR, showed that overexpression of pLP100 genes and increased copper resistance in the hfq mutant strain were dependent upon excision of pLP100. PMID- 23728624 TI - Large mobile genetic elements carrying resistance genes that do not confer a fitness burden in healthcare-associated meticillin-resistant Staphylococcus aureus. AB - Healthcare-associated (HA) meticillin-resistant Staphylococcus aureus (MRSA) clone CC22 SCCmecIV (EMRSA-15) has recently overtaken CC30/ST36 SCCmecII (EMRSA 16) as the dominant clone in UK hospitals. CC22 SCCmecIV shows greater fitness than CC30 SCCmecII, although both are successful global pathogens. The aim of this study was to test whether mobile genetic elements (MGEs), specifically SCCmec and large plasmids encoding resistance genes, are a burden and contribute to this fitness difference. Thirty-nine clinical isolates of MRSA and meticillin sensitive S. aureus from lineages CC30 and CC22 with a variety of antibiotic resistance genes were grown in the absence of antibiotics. A range of relative fitness measures were used to compare clinical isolates with and without SCCmecII and SCCmecIV. The same fitness measures were used to compare eight isolates with and without naturally occurring large antibiotic resistance plasmids carrying gentamicin resistance (determined by microarray) and an isolate with an introduced plasmid. Growth rate, competitive ability during co-culture and survival after desiccation were then compared. Carriage of SCCmecII contributed to the reduced fitness of CC30 MRSA. However, we found no evidence of a fitness cost due to carriage of SCCmecIV in CC22, or large antibiotic resistance plasmids in CC30 or multiple resistances in both lineages. In conclusion, many large MGEs are not a fitness burden. Surprisingly, lineage background was the most important determinant of fitness. Our results suggest CC22 SCCmecIV will remain a successful healthcare-associated clone, and resistance to meticillin and gentamicin is likely to be maintained even in the absence of antibiotic pressure. PMID- 23728623 TI - Potassium transport of Salmonella is important for type III secretion and pathogenesis. AB - Intracellular cations are essential for the physiology of all living organisms including bacteria. Cations such as potassium ion (K(+)), sodium ion (Na(+)) and proton (H(+)) are involved in nearly all aspects of bacterial growth and survival. K(+) is the most abundant cation and its homeostasis in Escherichia coli and Salmonella is regulated by three major K(+) transporters: high affinity transporter Kdp and low affinity transporters Kup and Trk. Previous studies have demonstrated the roles of cations and cation transport in the physiology of Escherichia coli; their roles in the virulence and physiology of pathogenic bacteria are not well characterized. We have previously reported that the Salmonella K(+) transporter Trk is important for the secretion of effector proteins of the type III secretion system (TTSS) of Salmonella pathogenicity island 1 (SPI-1). Here we further explore the role of Salmonella cation transport in virulence in vitro and pathogenesis in animal models. Impairment of K(+) transport through deletion of K(+) transporters or exposure to the chemical modulators of cation transport, gramicidin and valinomycin, results in a severe defect in the TTSS of SPI-1, and this defect in the TTSS was not due to a failure to regulate intrabacterial pH or ATP. Our results also show that K(+) transporters are critical to the pathogenesis of Salmonella in mice and chicks and are involved in multiple growth and virulence characteristics in vitro, including protein secretion, motility and invasion of epithelial cells. These results suggest that cation transport of the pathogenic bacterium Salmonella, especially K(+) transport, contributes to its virulence in addition to previously characterized roles in maintaining homeostasis of bacteria. PMID- 23728625 TI - Iron restriction-induced adaptations in the wall proteome of Candida albicans. AB - The opportunistic fungal pathogen Candida albicans has developed various ways to overcome iron restriction in a mammalian host. Using different surface proteins, among them membrane- and wall-localized glycosylphosphatidylinositol (GPI) proteins, it can exploit iron from host haemoglobin, ferritin and transferrin. Culturing C. albicans in rich medium supplemented with the ferrous iron chelator bathophenanthroline disulfonic acid or in the minimal medium yeast nitrogen base resulted in a strong decrease of the iron content of the cells. MS analysis of the changes in the wall proteome of C. albicans upon iron restriction showed a strong increase in the levels of the GPI-modified adhesin Als3, which also serves as a ferritin receptor, and of the GPI-modified CFEM (common in fungal extracellular membranes) domain-containing proteins Csa1, Pga7, Pga10, and Rbt5. The wall levels of the GPI-modified proteins Hyr1, the adhesin Als4 and the copper- and zinc-containing superoxide dismutase Sod4 also strongly increased, whereas the levels of Tos1 (a non-GPI protein) and the GPI-modified adhesin Als2 strongly decreased. Strikingly, peptides derived from the CFEM domain of the haem binding proteins Csa1, Pga10 and Rbt5 were capable of forming iron adduct ions during MS analysis, consistent with a key role of this domain in haem binding. PMID- 23728626 TI - The Sinorhizobium meliloti sensor histidine kinase CbrA contributes to free living cell cycle regulation. AB - Sinorhizobium meliloti is alternately capable of colonizing the soil as a free living bacterium or establishing a chronic intracellular infection with its legume host for the purpose of nitrogen fixation. We previously identified the S. meliloti two-component sensor histidine kinase CbrA as playing an important role in regulating exopolysaccharide production, flagellar motility and symbiosis. Phylogenetic analysis of CbrA has highlighted its evolutionary relatedness to the Caulobacter crescentus sensor histidine kinases PleC and DivJ, which are involved in CtrA-dependent cell cycle regulation through the shared response regulator DivK. We therefore became interested in testing whether CbrA plays a role in regulating S. meliloti cell cycle processes. We find the loss of cbrA results in filamentous cell growth accompanied by cells that contain an aberrant genome complement, indicating CbrA plays a role in regulating cell division and possibly DNA segregation. S. meliloti DivK localizes to the old cell pole during distinct phases of the cell cycle in a phosphorylation-dependent manner. Loss of cbrA results in a significantly decreased rate of DivK polar localization when compared with the wild-type, suggesting CbrA helps regulate cell cycle processes by modulating DivK phosphorylation status as a kinase. Consistent with a presumptive decrease in DivK phosphorylation and activity, we also find the steady-state level of CtrA increased in cbrA mutants. Our data therefore demonstrate that CbrA contributes to free-living cell cycle regulation, which in light of its requirement for symbiosis, points to the potential importance of cell cycle regulation for establishing an effective host interaction. PMID- 23728628 TI - yneA mRNA instability is involved in temporary inhibition of cell division during the SOS response of Bacillus megaterium. AB - The SOS response, a mechanism enabling bacteria to cope with DNA damage, is strictly regulated by the two major players, RecA and LexA (Bacillus homologue DinR). Genetic stress provokes formation of ssDNA-RecA nucleoprotein filaments, the coprotease activity of which mediates the autocatalytic cleavage of the transcriptional repressor DinR and ensures the expression of a set of din (damage inducible) genes, which encode proteins that enhance repair capacity, accelerate mutagenesis rate and cause inhibition of cell division (ICD). In Bacillus subtilis, the transcriptional activation of the yneAB-ynzC operon is part of the SOS response, with YneA being responsible for the ICD. Pointing to its cellular function in Bacillus megaterium, overexpression of homologous YneA led to filamentous growth, while ICD was temporary during the SOS response. Genetic knockouts of the individual open reading frames of the yneAB-ynzC operon increased the mutagenic sensitivity, proving - for the first time in a Bacillus species - that each of the three genes is in fact instrumental in coping with genetic stress. Northern- and quantitative real-time PCR analyses revealed - in contrast to other din genes (exemplified for dinR, uvrBA) - transient mRNA presence of the yneAB-ynzC operon irrespective of persisting SOS-inducing conditions. Promoter test assays and Northern analyses suggest that the decline of the ICD is at least partly due to yneAB-ynzC mRNA instability. PMID- 23728627 TI - Three functional beta-carbonic anhydrases in Pseudomonas aeruginosa PAO1: role in survival in ambient air. AB - Bacterial beta-class carbonic anhydrases (CAs) are zinc metalloenzymes catalysing reversible hydration of CO2. They maintain the intracellular balance of CO2/bicarbonate required for biosynthetic reactions and represent a new group of antimicrobial drug targets. Genome sequence analysis of Pseudomonas aeruginosa PAO1, an opportunistic human pathogen causing life threatening infections, identified three genes, PAO102, PA2053 and PA4676, encoding putative beta-CAs that share 28-45 % amino acid sequence identity and belong to clades A and B. The genes are conserved among all sequenced pseudomonads. The CAs were cloned, heterologously expressed and purified. Metal and enzymic analyses confirmed that the proteins contain Zn(2+) and catalyse hydration of CO2 to bicarbonate. PAO102 (psCA1) was 19-26-fold more active, and together with PA2053 (psCA2) showed CA activity at both pH 7.5 and 8.3, whereas PA4676 (psCA3) was active only at pH 8.3. Circular dichroism spectroscopy suggested that psCA2 and psCA3 undergo pH dependent structural changes. Taken together, the data suggest that psCA1 may belong to type I and psCA3 to type II beta-CAs. Immunoblot analysis showed that all three CAs are expressed in PAO1 cells when grown in ambient air and at 5 % CO2; psCA1 appeared more abundant under both conditions. Growth studies of transposon mutants showed that the disruption of psCA1 impaired PAO1 growth in ambient air and caused a minor defect at high CO2. Thus, psCA1 contributes to the adaptation of P. aeruginosa to low CO2 conditions and will be further studied for its role in virulence and as a potential antimicrobial drug target in this organism. PMID- 23728629 TI - Function of formate dehydrogenases in Desulfovibrio vulgaris Hildenborough energy metabolism. AB - The genome of the sulfate-reducing bacterium Desulfovibrio vulgaris Hildenborough encodes three formate dehydrogenases (FDHs), two of which are soluble periplasmic enzymes (FdhAB and FdhABC3) and one that is periplasmic but membrane-associated (FdhM). FdhAB and FdhABC3 were recently shown to be the main enzymes present during growth with lactate, formate or hydrogen. To address the role of these two enzymes, DeltafdhAB and DeltafdhABC3, mutants were generated and studied. Different phenotypes were observed in the presence of either molybdenum or tungsten, since both enzymes were important for growth on formate in the presence of Mo, whereas in the presence of W only FdhAB played a role. Both DeltafdhAB and DeltafdhABC3 mutants displayed defects in growth with lactate and sulfate providing the first direct evidence for the involvement of formate cycling under these conditions. In support of this mechanism, incubation of concentrated cell suspensions of the mutant strains with lactate and limiting sulfate also gave elevated formate concentrations, as compared to the wild-type strain. In contrast, both mutants grew similarly to the wild-type with H2 and sulfate. In the absence of sulfate, the wild-type D. vulgaris cells produced formate when supplied with H2 and CO2, which resulted from CO2 reduction by the periplasmic FDHs. The conversion of H2 and CO2 to formate allows the reversible storage of reducing power in a much more soluble molecule. Furthermore, we propose this may be an expression of the ability of some sulfate-reducing bacteria to grow by hydrogen oxidation, in syntrophy with organisms that consume formate, but are less efficient in H2 utilization. PMID- 23728630 TI - Fetal electrocardiogram (ECG) for fetal monitoring during labour. AB - BACKGROUND: Hypoxaemia during labour can alter the shape of the fetal electrocardiogram (ECG) waveform, notably the relation of the PR to RR intervals, and elevation or depression of the ST segment. Technical systems have therefore been developed to monitor the fetal ECG during labour as an adjunct to continuous electronic fetal heart rate monitoring with the aim of improving fetal outcome and minimising unnecessary obstetric interference. OBJECTIVES: To compare the effects of analysis of fetal ECG waveforms during labour with alternative methods of fetal monitoring. SEARCH METHODS: The Cochrane Pregnancy and Childbirth Group's Trials Register (latest search 12 February 2013). SELECTION CRITERIA: Randomised trials comparing fetal ECG waveform analysis with alternative methods of fetal monitoring during labour. DATA COLLECTION AND ANALYSIS: Trial quality assessment and data extraction were performed by one review author, without blinding. MAIN RESULTS: Six trials (16,295 women) were included: five trials of ST waveform analysis (15,338 women) and one trial of PR interval analysis (957 women). In comparison to continuous electronic fetal heart rate monitoring alone, the use of adjunctive ST waveform analysis made no significant difference to primary outcomes: births by caesarean section (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.91 to 1.08), the number of babies with severe metabolic acidosis at birth (cord arterial pH less than 7.05 and base deficit greater than 12 mmol/L) (RR 0.78, 95% CI 0.44 to 1.37, data from 14,574 babies), or babies with neonatal encephalopathy (RR 0.54, 95% CI 0.24 to 1.25). There were, however, on average fewer fetal scalp samples taken during labour (RR 0.61, 95% CI 0.41 to 0.91) although the findings were heterogeneous; there were fewer operative vaginal deliveries (RR 0.89, 95% CI 0.81 to 0.98) and admissions to special care unit (RR 0.89, 95% CI 0.81 to 0.99); there was no statistically significant difference in the number of babies with low Apgar scores at five minutes or babies requiring neonatal intubation. There was little evidence that monitoring by PR interval analysis conveyed any benefit. AUTHORS' CONCLUSIONS: These findings provide some modest support for the use of fetal ST waveform analysis when a decision has been made to undertake continuous electronic fetal heart rate monitoring during labour. However, the advantages need to be considered along with the disadvantages of needing to use an internal scalp electrode, after membrane rupture, for ECG waveform recordings. PMID- 23728631 TI - Physician advice for smoking cessation. AB - BACKGROUND: Healthcare professionals frequently advise people to improve their health by stopping smoking. Such advice may be brief, or part of more intensive interventions. OBJECTIVES: The aims of this review were to assess the effectiveness of advice from physicians in promoting smoking cessation; to compare minimal interventions by physicians with more intensive interventions; to assess the effectiveness of various aids to advice in promoting smoking cessation, and to determine the effect of anti-smoking advice on disease-specific and all-cause mortality. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group trials register in January 2013 for trials of interventions involving physicians. We also searched Latin American databases through BVS (Virtual Library in Health) in February 2013. SELECTION CRITERIA: Randomised trials of smoking cessation advice from a medical practitioner in which abstinence was assessed at least six months after advice was first provided. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the setting in which advice was given, type of advice given (minimal or intensive), and whether aids to advice were used, the outcome measures, method of randomisation and completeness of follow-up.The main outcome measure was abstinence from smoking after at least six months follow-up. We also considered the effect of advice on mortality where long-term follow-up data were available. We used the most rigorous definition of abstinence in each trial, and biochemically validated rates where available. People lost to follow-up were counted as smokers. Effects were expressed as relative risks. Where possible, we performed meta-analysis using a Mantel-Haenszel fixed-effect model. MAIN RESULTS: We identified 42 trials, conducted between 1972 and 2012, including over 31,000 smokers. In some trials, participants were at risk of specified diseases (chest disease, diabetes, ischaemic heart disease), but most were from unselected populations. The most common setting for delivery of advice was primary care. Other settings included hospital wards and outpatient clinics, and industrial clinics.Pooled data from 17 trials of brief advice versus no advice (or usual care) detected a significant increase in the rate of quitting (relative risk (RR) 1.66, 95% confidence interval (CI) 1.42 to 1.94). Amongst 11 trials where the intervention was judged to be more intensive the estimated effect was higher (RR 1.84, 95% CI 1.60 to 2.13) but there was no statistical difference between the intensive and minimal subgroups. Direct comparison of intensive versus minimal advice showed a small advantage of intensive advice (RR 1.37, 95% CI 1.20 to 1.56). Direct comparison also suggested a small benefit of follow-up visits. Only one study determined the effect of smoking advice on mortality. This study found no statistically significant differences in death rates at 20 years follow-up. AUTHORS' CONCLUSIONS: Simple advice has a small effect on cessation rates. Assuming an unassisted quit rate of 2 to 3%, a brief advice intervention can increase quitting by a further 1 to 3%. Additional components appear to have only a small effect, though there is a small additional benefit of more intensive interventions compared to very brief interventions. PMID- 23728632 TI - Enemas during labour. AB - BACKGROUND: Although the use of enemas during labour usually reflects the preference of the attending healthcare provider, enemas may cause discomfort for women. OBJECTIVES: To assess the effects of enemas applied during the first stage of labour on maternal and neonatal outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (17 May 2012), the Cochrane Central Register of Controlled Trials and Database of Abstracts of Reviews of Effectiveness (The Cochrane Library 2012, Issue 5), PubMed (1966 to 17 May 2012), LILACS (17 May 2012), the Search Portal of the International Clinical Trials Registry Platform (ICTRP) (17 May 2012), Health Technology Assessment Program, UK (17 May 2012), Medical Research Council, UK (17 May 2012), The Wellcome Trust, UK (17 May 2012) and reference lists of retrieved articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) in which an enema was administered during the first stage of labour and which included assessment of possible neonatal or puerperal morbidity or mortality. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion. MAIN RESULTS: Four RCTs (1917 women) met the inclusion criteria. One study was judged as having a low risk of bias. In the meta-analysis we conducted of two trials, we found no significant difference in infection rates for puerperal women (two RCTs; 594 women; risk ratio (RR) 0.66, 95% confidence (CI) 0.42 to 1.04). No significant differences were found in neonatal umbilical infection rates (two RCTs; 592 women; RR 3.16, 95% CI 0.50 to 19.82; I2 0%. In addition, meta-analysis of two studies found that there were no significant differences in the degree of perineal tear between groups. Finally, meta-analysis of two trials found no significant differences in the mean duration of labour. AUTHORS' CONCLUSIONS: The evidence provided by the four included RCTs shows that enemas do not have a significant beneficial effect on infection rates such as perineal wound infection or other neonatal infections and women's satisfaction. These findings speak against the routine use of enemas during labour, therefore, such practice should be discouraged. PMID- 23728633 TI - Thrombolysis (different doses, routes of administration and agents) for acute ischaemic stroke. AB - BACKGROUND: Stroke is a leading cause of death and disability world wide. Thrombolysis with recombinant tissue plasminogen activator (rt-PA) is licensed for treatment of acute ischaemic stroke in the early hours after symptom onset. It has been shown in randomised controlled trials (RCTs) and the 2009 Cochrane review of thrombolysis for acute ischaemic stroke to reduce dependency but at the increased risk of intracranial haemorrhage. Methods to reduce the risk of haemorrhage while retaining or enhancing the benefit could increase the use of thrombolytic treatment. While most available information comes from RCTs of intravenous rt-PA at 0.9 mg/kg, it is possible that other doses, drugs and other routes of administration might increase benefit and reduce the hazard. OBJECTIVES: To assess the risks and benefits of different thrombolytic agents, doses and routes of administration for the treatment of acute ischaemic stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (May 2012), MEDLINE (1966 to May 2012) and EMBASE (1980 to May 2012). We handsearched journals and conference proceedings, searched ongoing trials registers and contacted pharmaceutical companies and researchers. SELECTION CRITERIA: Unconfounded randomised and quasi-randomised trials of different doses of a thrombolytic agent, or different agents, or the same agent given by different routes, in people with confirmed acute ischaemic stroke. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility and quality, and extracted the data using a structured proforma. We cross-checked and resolved discrepancies by discussion to reach consensus. We obtained translations and additional information from study authors where required. MAIN RESULTS: We included 20 trials involving 2527 patients. Concealment of allocation was poorly described. Different doses (of tissue plasminogen activator, urokinase, desmoteplase or tenecteplase) were compared in 13 trials (N = 1433 patients). Different agents (tissue plasminogen activator versus urokinase, tissue-cultured urokinase versus conventional urokinase, tenecteplase versus tissue plasminogen activator) were compared in five trials (N = 875 patients). Five trials (N = 485) compared different routes of administration. As some trials compared different agents and different doses, some patients contributed to two analyses. There was an approximately three-fold increase in fatal intracranial haemorrhages in patients allocated to higher than to lower doses of the same thrombolytic drug (odds ratio (OR) 2.71, 95% confidence interval (CI) 1.22 to 6.04). There was no difference in the number of patients who were dead or dependent at the end of follow-up between those allocated higher or lower doses of thrombolytic drug (OR 0.86, 95% CI 0.62 to 1.19). Higher versus lower doses of desmoteplase were associated with more deaths at the end of follow-up (OR 3.21, 95% CI 1.23 to 8.39). There was no evidence of any benefit for intra-arterial over intravenous treatment. AUTHORS' CONCLUSIONS: These limited data suggest that higher doses of thrombolytic agents may lead to higher rates of bleeding. However, the evidence is inadequate to conclude whether lower doses of thrombolytic agents are more effective than higher doses, or whether one agent is better than another, or which route of administration is the best, for acute ischaemic stroke. At present, intravenous rt-PA at 0.9mg/kg as licensed in many countries appears to represent best practice and other drugs, doses or routes of administration should only be used in randomised controlled trials. PMID- 23728634 TI - Magnesium maintenance therapy for preventing preterm birth after threatened preterm labour. AB - BACKGROUND: Magnesium maintenance therapy is one of the types of tocolytic therapy used after an episode of threatened preterm labour (usually treated with an initial dose of tocolytic therapy) in an attempt to prevent the onset of further preterm contractions. OBJECTIVES: To assess whether magnesium maintenance therapy is effective in preventing preterm birth after the initial threatened preterm labour is arrested. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2013). SELECTION CRITERIA: Randomised controlled trials of magnesium therapy given to women after threatened preterm labour. DATA COLLECTION AND ANALYSIS: The review authors independently assessed the studies for inclusion, assessed risk of bias and carried out data extraction. We checked data entry. MAIN RESULTS: We included four trials involving 422 women. Three trials had high risk of bias and none included any long-term follow-up of infants. No differences in the incidence of preterm birth or perinatal mortality were seen when magnesium maintenance therapy was compared with placebo or no treatment; or alternative therapies (ritodrine or terbutaline). The risk ratio (RR) for preterm birth (less than 37 weeks) for magnesium compared with placebo or no treatment was 1.05, 95% confidence interval (CI) 0.80 to 1.40 (two trials, 99 women); and 0.99, 95% CI 0.57 to 1.72 (two trials, 100 women) for magnesium compared with alternative therapies. The RR for perinatal mortality for magnesium compared with placebo or no treatment was 5.00, 95% CI 0.25 to 99.16 (one trial, 50 infants); and 5.00, 95% CI 0.25 to 99.16 (one trial, 50 infants) for magnesium compared with alternative treatments.Women taking magnesium preparations were less likely to report side effects (RR 0.67, 95% CI 0.47 to 0.96, three trials, 237 women), including palpitations or tachycardia (RR 0.26, 95% CI 0.13 to 0.52, three trials, 237 women) than women receiving alternative therapies. Women receiving magnesium were however, more likely to experience diarrhoea (RR 6.79, 95% CI 1.26 to 36.72, three trials, 237 women). AUTHORS' CONCLUSIONS: There is not enough evidence to show any difference between magnesium maintenance therapy compared with either placebo or no treatment, or alternative therapies (ritodrine or terbutaline) in preventing preterm birth after an episode of threatened preterm labour. PMID- 23728635 TI - Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. AB - BACKGROUND: Methotrexate (MTX) is a disease modifying antirheumatic drug (DMARD) used as a first line agent for treating rheumatoid arthritis (RA). Pharmacologically, it is classified as an antimetabolite due to its antagonistic effect on folic acid metabolism. Many patients treated with MTX experience mucosal, gastrointestinal, hepatic or haematologic side effects. Supplementation with folic or folinic acid during treatment with MTX may ameliorate these side effects. OBJECTIVES: To identify trials of supplementation with folic acid or folinic acid during MTX therapy for rheumatoid arthritis and to assess the benefits and harms of folic acid and folinic acid (a) in reducing the mucosal, gastrointestinal (GI), hepatic and haematologic side effects of MTX, and (b) whether or not folic or folinic acid supplementation has any effect on MTX benefit. SEARCH METHODS: We originally performed MEDLINE searches, from January 1966 to June 1999. During the update of this review, we searched additional databases and used a sensitive search strategy designed to retrieve all trials on folic acid or folinic acid for rheumatoid arthritis from 1999 up to 2 March 2012. SELECTION CRITERIA: We selected all double-blind, randomised, placebo-controlled clinical trials (RCTs) in which adult patients with rheumatoid arthritis were treated with MTX (at a dose equal to or less than 25 mg/week) concurrently with folate supplementation. In this update of the review we only included trials using 'low dose' folic or folinic acid (a starting dose of <= 7 mg weekly). DATA COLLECTION AND ANALYSIS: Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria. MAIN RESULTS: Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as 'moderate' for each outcome as assessed by GRADE, with the exception of haematologic side effects which were rated as 'low'. There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled.For patients supplemented with any form of exogenous folate (either folic or folinic acid) whilst on MTX therapy for rheumatoid arthritis, a 26% relative (9% absolute) risk reduction was seen for the incidence of GI side effects such as nausea, vomiting or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; P = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; P < 0.00001), as well as reducing patient withdrawal from MTX for any reason (60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; P < 0.00001).We analysed the effect of folic or folinic acid on the incidence of stomatitis / mouth sores, and whilst showing a trend towards reduction in risk, the results were not statistically significant (RR 0.72, 95% CI 0.49 to 1.06)It was not possible to draw meaningful conclusions on the effect of folic or folinic acid on haematologic side effects of methotrexate due to small numbers of events and poor reporting of this outcome in included trials.It does not appear that supplementation with either folic or folinic acid has a statistically significant effect on the efficacy of MTX in treating RA (as measured by RA disease activity parameters such as tender and swollen joint counts, or physician's global assessment scores). AUTHORS' CONCLUSIONS: The results support a protective effect of supplementation with either folic or folinic acid for patients with rheumatoid arthritis during treatment with MTX.There was a significant reduction shown in the incidence of GI side effects, hepatic dysfunction (asmeasured by elevated serum transaminase levels) as well as a significant reduction in discontinuation of MTX treatment for any reason. A trend towards a reduction in stomatitis was demonstrated however this did not reach statistical significance.This updated review with its focus on lower doses of folic acid and folinic acid and updated assessment of risk of bias aimed to give a more precise and more clinically relevant estimate of the benefit of folate supplementation for patients with rheumatoid arthritis receiving methotrexate. PMID- 23728636 TI - Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. AB - BACKGROUND: The introduction of enteral feeds for very preterm (< 32 weeks) or very low birth weight (< 1500 g) infants is often delayed for several days or longer after birth due to concern that early introduction may not be tolerated and may increase the risk of necrotising enterocolitis (NEC). However, delaying enteral feeding could diminish the functional adaptation of the gastrointestinal tract and prolong the need for parenteral nutrition with its attendant infectious and metabolic risks. OBJECTIVES: To determine the effect of delayed introduction of progressive enteral feeds on the incidence of necrotising enterocolitis, mortality and other morbidities in very preterm or very low birth weight infants. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2013, Issue 3), MEDLINE (1966 to April 2013), EMBASE (1980 to April 2013), CINAHL (1982 to April 2013), conference proceedings, and previous reviews. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that assessed the effect of delayed (more than four days after birth) versus earlier introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in very preterm or very low birth weight infants. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two review authors. MAIN RESULTS: We identified seven randomised controlled trials in which a total of 964 infants participated. Few participants were extremely preterm (< 28 weeks) or extremely low birth weight (< 1000 g). The trials defined delayed introduction as later than five to seven days after birth and early introduction as less than four days after birth. Meta-analyses did not detect statistically significant effects on the risk of NEC (typical risk ratio (RR) 0.92 (95% confidence interval (CI) 0.64 to 1.34) or all cause mortality (typical RR 1.26 (95% CI 0.78 to 2.01)). Three of the trials restricted participation to growth-restricted infants with Doppler ultrasound evidence of abnormal fetal circulatory distribution or flow. Planned subgroup analyses of these trials did not find any statistically significant effects on the risk of NEC or all-cause mortality. Infants who had delayed introduction of enteral feeds took longer to establish full enteral feeding (reported median difference two to four days). AUTHORS' CONCLUSIONS: The evidence available from randomised controlled trials suggests that delaying the introduction of progressive enteral feeds beyond four days after birth does not affect the risk of developing NEC in very preterm or very low birth weight infants, including growth-restricted infants. Delaying the introduction of progressive enteral feeds results in a few days delay in establishing full enteral feeds but the clinical importance of this effect is unclear. The applicability of these findings to extremely preterm or extremely low birth weight is uncertain. Further randomised controlled trials in this population may be warranted. PMID- 23728637 TI - Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. AB - BACKGROUND: Approximately 25% of adults regularly experience heartburn, a symptom of gastro-oesophageal reflux disease (GORD). Most patients are treated empirically (without specific diagnostic evaluation e.g. endoscopy. Among patients who have an upper endoscopy, findings range from a normal appearance, mild erythema to severe oesophagitis with stricture formation. Patients without visible damage to the oesophagus have endoscopy negative reflux disease (ENRD). The pathogenesis of ENRD, and its response to treatment may differ from GORD with oesophagitis. OBJECTIVES: Summarise, quantify and compare the efficacy of short term use of proton pump inhibitors (PPI), H2-receptor antagonists (H2RA) and prokinetics in adults with GORD, treated empirically and in those with endoscopy negative reflux disease (ENRD). SEARCH METHODS: We searched MEDLINE (January 1966 to November 2011), EMBASE (January 1988 to November 2011), and EBMR in November 2011. SELECTION CRITERIA: Randomised controlled trials reporting symptomatic outcome after short-term treatment for GORD using proton pump inhibitors, H2 receptor antagonists or prokinetic agents. Participants had to be either from an empirical treatment group (no endoscopy used in treatment allocation) or from an endoscopy negative reflux disease group (no signs of erosive oesophagitis). DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: Thirty-four trials (1314 participants) were included: fifteen in the empirical treatment group, fifteen in the ENRD group and four in both. In empirical treatment of GORD the risk ratio (RR) for heartburn remission (the primary efficacy variable) in placebo-controlled trials for PPI was 0.37 (two trials, 95% confidence interval (CI) 0.32 to 0.44), for H2RAs 0.77 (two trials, 95% CI 0.60 to 0.99) and for prokinetics 0.86 (one trial, 95% CI 0.73 to 1.01). In a direct comparison PPIs were more effective than H2RAs (seven trials, RR 0.66, 95% CI 0.60 to 0.73) and prokinetics (two trials, RR 0.53, 95% CI 0.32 to 0.87).In treatment of ENRD, the RR for heartburn remission for PPI versus placebo was 0.71 (ten trials, 95% CI 0.65 to 0.78) and for H2RA versus placebo was 0.84 (two trials, 95% CI 0.74 to 0.95). The RR for PPI versus H2RA was 0.78 (three trials, 95% CI 0.62 to 0.97) and for PPI versus prokinetic 0.72 (one trial, 95% CI 0.56 to 0.92). AUTHORS' CONCLUSIONS: PPIs are more effective than H2RAs in relieving heartburn in patients with GORD who are treated empirically and in those with ENRD, although the magnitude of benefit is greater for those treated empirically. PMID- 23728638 TI - Mitoxantrone for multiple sclerosis. AB - BACKGROUND: This is an updated Cochrane review of the previous published version.Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients. OBJECTIVES: The main objective was to assess the efficacy and safety of MX compared to a control group in relapsing-remitting (RRMS), progressive relapsing (PRMS) and secondary progressive (SPMS) MS participants. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (June 2012) and reference lists of articles. We also undertook handsearching and contacted trialists and pharmaceutical companies. SELECTION CRITERIA: Randomised, double-blinded, controlled trials (RCTs) comparing the administration of MX versus placebo or MX plus steroids treatment versus placebo plus steroids treatment were included. DATA COLLECTION AND ANALYSIS: The review authors independently selected articles for inclusion. They independently extracted clinical, safety and magnetic resonance imaging (MRI) data, resolving disagreements by discussion. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using odds ratios (OR) with 95% confidence intervals (CI) for the binary outcomes and mean differences (MD) with 95% CI for the continuous outcomes. If heterogeneity was absent, a fixed-effect model was used. MAIN RESULTS: Three trials were selected and 221 participants were included in the analyses. MX reduced the progression of disability at two years follow-up (proportion of participants with six months confirmed progression of disability (OR 0.30, 95% CI 0.09 to 0.99 and MD -0.36, 95% CI- 0.70 to -0.02; P = 0.04)). Significant results were found regarding the reduction in annualised relapse rate (MD -0.85, 95% CI 1.47 to -0.23; P = 0.007), the proportion of patients free from relapses at one year (OR 7.13, 95% CI 2.06 to 24.61; P = 0.002) and two years (OR 2.82, 95% CI 1.54 to 5.19; P = 0.0008), and the number of patients with active MRI lesions at six months or one year only (OR 0.24, 95% CI 0.10 to 0.57; P = 0.001). Side effects reported in the trials (amenorrhoea, nausea and vomiting, alopecia and urinary tract infections) were more frequent in treated patients than in controls, while no major adverse events have been reported. These results should be considered with caution because of the heterogeneous characteristics of included trials in term of drug dosage, inclusion criteria and quality of included trials. Moreover, it was not possible to estimate the long-term efficacy and safety of MX. AUTHORS' CONCLUSIONS: MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in patients affected by worsening RRMS, PRMS and SPMS in the short-term follow-up (two years). No major neoplastic events or symptomatic cardiotoxicity related to MX have been reported; however studies with longer follow-up (not included in this review) have raised concerns about the risk of systolic disfunction (~12%) and therapy-related acute leukaemias (0.8%), which are increasingly reported in the literature.MX should be limited to treating patients with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual patients' risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events. PMID- 23728639 TI - Cognitive rehabilitation for attention deficits following stroke. AB - BACKGROUND: Many survivors of stroke complain about attentional impairments, such as diminished concentration and mental slowness. However, the effectiveness of cognitive rehabilitation for improving these impairments is uncertain. OBJECTIVES: To determine whether (1) people receiving attentional treatment show better outcomes in their attentional functions than those given no treatment or treatment as usual, and (2) people receiving attentional treatment techniques have a better functional recovery, in terms of independence in activities of daily living, mood and quality of life, than those given no treatment or treatment as usual. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (October 2012), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library October 2012), MEDLINE (1948 to October 2012), EMBASE (1947 to October 2012), CINAHL (1981 to October 2012), PsycINFO (1806 to October 2012), PsycBITE and REHABDATA (searched October 2012) and ongoing trials registers. We screened reference lists and tracked citations using Scopus. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of cognitive rehabilitation for impairments of attention for people with stroke. The primary outcome was measures of global attentional functions, and secondary outcomes were measures of attention domains, functional abilities, mood and quality of life. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data and assessed trial quality. MAIN RESULTS: We included six RCTs with 223 participants. All six RCTs compared cognitive rehabilitation with a usual care control. Meta-analyses demonstrated no statistically significant effect of cognitive rehabilitation for persisting effects on global measures of attention (two studies, 99 participants; standardised mean difference (SMD) 0.16, 95% confidence interval (CI) -0.23 to 0.56; P value = 0.41), standardised attention assessments (two studies, 99 participants; P value >= 0.08) or functional outcomes (two studies, 99 participants; P value >= 0.15). In contrast, a statistically significant effect was found in favour of cognitive rehabilitation when compared with control for immediate effects on measures of divided attention (four studies, 165 participants; SMD 0.67, 95% CI 0.35 to 0.98; P value < 0.0001) but no significant effects on global attention (two studies, 53 participants; P value = 0.06), other attentional domains (six studies, 223 participants; P value >= 0.16) or functional outcomes (three studies, 109 participants; P value >= 0.21).Thus there was limited evidence that cognitive rehabilitation may improve some aspects of attention in the short term, but there was insufficient evidence to support or refute the persisting effects of cognitive rehabilitation on attention, or on functional outcomes in either the short or long term. AUTHORS' CONCLUSIONS: The effectiveness of cognitive rehabilitation remains unconfirmed. The results suggest there may be a short-term effect on attentional abilities, but future studies need to assess the persisting effects and measure attentional skills in daily life. Trials also need to have higher methodological quality and better reporting. PMID- 23728640 TI - Vaccines for women to prevent neonatal tetanus. AB - BACKGROUND: Tetanus is an acute, often fatal, disease caused by an exotoxin produced by Clostridium tetani. It occurs in newborn infants born to mothers who do not have sufficient circulating antibodies to protect the infant passively, by transplacental transfer. Prevention may be possible by the vaccination of pregnant or non-pregnant women, or both, with tetanus toxoid, and the provision of clean delivery services. Tetanus toxoid consists of a formaldehyde-treated toxin which stimulates the production of antitoxin. OBJECTIVES: To assess the effectiveness of tetanus toxoid, administered to women of childbearing age or pregnant women, to prevent cases of, and deaths from, neonatal tetanus. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2012), The Cochrane Library (2012, Issue 10), PubMed (1966 to 31 October 2012), EMBASE (1974 to 31 October 2012). We also used the results from handsearching and consultations with manufacturers and authors. SELECTION CRITERIA: Randomised or quasi-randomised trials evaluating the effects of tetanus toxoid in pregnant women or women of childbearing age on numbers of neonatal tetanus cases and deaths. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion and trial quality, and extracted data. MAIN RESULTS: Two trials (10,560 infants) were included. It should be noted that these trials are very old,1966 and 1980 respectively, and one trial randomised exclusively non-pregnant women. The main outcomes were measured on infants born to a subset of those randomised women who became pregnant during the course of the studies. One study (1919 infants) assessed the effectiveness of tetanus toxoid in comparison with influenza vaccine in preventing neonatal tetanus deaths. After a single dose, the risk ratio (RR) was 0.57 (95% confidence interval (CI) 0.26 to 1.24), and the vaccine effectiveness was 43%. With a two- or three-dose course, the RR was 0.02 (95% CI 0.00 to 0.30); vaccine effectiveness was 98%. No effect was detected on causes of death other than tetanus. The RR of cases of neonatal tetanus after at least one dose of tetanus toxoid was 0.20 (95% CI 0.10 to 0.40); vaccine effectiveness was 80%. Another study, involving 8641 children, assessed the effectiveness of tetanus-diptheria toxoid in comparison with cholera toxoid in preventing neonatal mortality after one or two doses. The RR was 0.68 (95% CI 0.56 to 0.82); vaccine effectiveness was 32%. In preventing deaths at four to 14 days, the RR was 0.38 (95% CI 0.27 to 0.55), and vaccine effectiveness 62% (95% CI 45% to 73%). AUTHORS' CONCLUSIONS: Available evidence supports the implementation of immunisation practices on women of childbearing age or pregnant women in communities with similar, or higher, levels of risk of neonatal tetanus, to the two study sites. More information is needed on possible interference of vaccination by malaria chemoprophylaxis on the roles of malnutrition and vitamin A deficiency, and on the quality of tetanus toxoid production and storage. PMID- 23728641 TI - Drug therapy for obstructive sleep apnoea in adults. AB - BACKGROUND: The treatment of choice for moderate to severe obstructive sleep apnoea (OSA) is continuous positive airways pressure (CPAP) applied via a mask during sleep. However, this is not tolerated by all individuals and its role in mild OSA is not proven. Drug therapy has been proposed as an alternative to CPAP in some patients with mild to moderate sleep apnoea and could be of value in patients intolerant of CPAP. A number of mechanisms have been proposed by which drugs could reduce the severity of OSA. These include an increase in tone in the upper airway dilator muscles, an increase in ventilatory drive, a reduction in the proportion of rapid eye movement (REM) sleep, an increase in cholinergic tone during sleep, an increase in arousal threshold, a reduction in airway resistance and a reduction in surface tension in the upper airway. OBJECTIVES: To determine the efficacy of drug therapies in the specific treatment of sleep apnoea. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials. Searches were current as of July 2012. SELECTION CRITERIA: Randomised, placebo controlled trials involving adult patients with confirmed OSA. We excluded trials if continuous positive airways pressure, mandibular devices or oxygen therapy were used. We excluded studies investigating treatment of associated conditions such as excessive sleepiness, hypertension, gastro-oesophageal reflux disease and obesity. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures recommended by The Cochrane Collaboration. MAIN RESULTS: Thirty trials of 25 drugs, involving 516 participants, contributed data to the review. Drugs had several different proposed modes of action and the results were grouped accordingly in the review. Each of the studies stated that the participants had OSA but diagnostic criteria were not always explicit and it was possible that some patients with central apnoeas may have been recruited.Acetazolamide, eszopiclone, naltrexone, nasal lubricant (phosphocholinamine) and physiostigmine were administered for one to two nights only. Donepezil in patients with and without Alzheimer's disease, fluticasone in patients with allergic rhinitis, combinations of ondansetrone and fluoxetine and paroxetine were trials of one to three months duration, however most of the studies were small and had methodological limitations. The overall quality of the available evidence was low.The primary outcomes for the systematic review were the apnoea hypopnoea index (AHI) and the level of sleepiness associated with OSA, estimated by the Epworth Sleepiness Scale (ESS). AHI was reported in 25 studies and of these 10 showed statistically significant reductions in AHI.Fluticasone in patients with allergic rhinitis was well tolerated and reduced the severity of sleep apnoea compared with placebo (AHI 23.3 versus 30.3; P < 0.05) and improved subjective daytime alertness. Excessive sleepiness was reported to be altered in four studies, however the only clinically and statistically significant change in ESS of -2.9 (SD 2.9; P = 0.04) along with a small but statistically significant reduction in AHI of -9.4 (SD 17.2; P = 0.03) was seen in patients without Alzheimer's disease receiving donepezil for one month. In 23 patients with mild to moderate Alzheimer's disease donepezil led to a significant reduction in AHI (donepezil 20 (SD 15) to 9.9 (SD 11.5) versus placebo 23.2 (SD 26.4) to 22.9 (SD 28.8); P = 0.035) after three months of treatment but no reduction in sleepiness was reported. High dose combined treatment with ondansetron 24 mg and fluoxetine 10 mg showed a 40.5% decrease in AHI from the baseline at treatment day 28. Paroxetine was shown to reduce AHI compared to placebo (-6.10 events/hour; 95% CI -11.00 to -1.20) but failed to improve daytime symptoms.Promising results from the preliminary mirtazapine study failed to be reproduced in the two more recent multicentre trials and, moreover, the use of mirtazapine was associated with significant weight gain and sleepiness. Few data were presented on the long-term tolerability of any of the compounds used. AUTHORS' CONCLUSIONS: There is insufficient evidence to recommend the use of drug therapy in the treatment of OSA. Small studies have reported positive effects of certain agents on short-term outcomes. Certain agents have been shown to reduce the AHI in largely unselected populations with OSA by between 24% and 45%. For donepezil and fluticasone, studies of longer duration with a larger population and better matching of groups are required to establish whether the change in AHI and impact on daytime symptoms are reproducible. Individual patients had more complete responses to particular drugs. It is possible that better matching of drugs to patients according to the dominant mechanism of their OSA will lead to better results and this also needs further study. PMID- 23728642 TI - Acetylcysteine and carbocysteine for acute upper and lower respiratory tract infections in paediatric patients without chronic broncho-pulmonary disease. AB - BACKGROUND: Acetylcysteine and carbocysteine are the most commonly prescribed mucolytic drugs in Brazil and many European and African countries. To our knowledge, no systematic review has been published on their efficacy and safety for acute upper and lower respiratory tract infections (RTIs) in children without chronic broncho-pulmonary disease. OBJECTIVES: The objective was to assess the efficacy and safety and to establish a benefit-risk ratio of acetylcysteine and carbocysteine as symptomatic treatments for acute upper and lower RTIs in paediatric patients without chronic broncho-pulmonary disease. SEARCH METHODS: We searched CENTRAL (2013, Issue 2), MEDLINE (1966 to February week 3, 2013), EMBASE (1980 to March 2013), Micromedex (2010), Pascal (1987 to 2004) and Science Citation Index (1974 to March 2013). SELECTION CRITERIA: To study efficacy, we used randomised controlled trials (RCTs) comparing the use of acetylcysteine or carbocysteine versus placebo, either alone or as an add-on therapy. To study safety, we used trials comparing acetylcysteine or carbocysteine versus active treatment or no treatment and case reports. DATA COLLECTION AND ANALYSIS: In this review update two review authors (YD, MC), with help from a colleague, extracted data and assessed trial quality. We performed a subgroup analysis of children younger than two years of age. MAIN RESULTS: We included six trials involving 497 participants to study efficacy. They showed some benefit (e.g. reduction of cough at day seven) from mucolytic agents, although differences were of little clinical relevance. No conclusion was drawn about the subgroup of infants younger than two years because data were unavailable. Thirty-four studies, including the previous six trials involving 2064 children, were eligible to study safety. Overall safety was good but very few data were available to evaluate safety in infants younger than two years. However, 59 cases of paradoxically increased bronchorrhoea observed in infants were reported to the French pharmacovigilance system. AUTHORS' CONCLUSIONS: The results have to be interpreted with caution because they are based on a limited number of participants included in studies whose methodological quality is questionable. Acetylcysteine and carbocysteine seem to have a limited efficacy and appear to be safe in children older than two years. These results should take into consideration the fact that acetylcysteine and carbocysteine are prescribed for self limiting diseases (for example, acute cough, bronchitis). Given strong concerns about safety, these drugs should only be used for acute upper and lower RTIs in the context of a RCT with regards to children younger than two years. PMID- 23728643 TI - Strategies for managing sexual dysfunction induced by antidepressant medication. AB - BACKGROUND: Sexual dysfunction (including altered sexual desire, orgasmic and ejaculatory dysfunction, erectile and other problems) is a relatively common side effect of antidepressant medication. These sexual side effects may compromise a person's lifestyle and result in a lack of compliance with the prescribed antidepressant to the detriment of the person's mental health. A wide range of management strategies are possible to address this problem, including behavioural, psychological and pharmacological approaches. OBJECTIVES: 1. To determine the effectiveness of management strategies for sexual dysfunction caused by antidepressants.2. To determine the adverse effects and acceptability of the different management strategies. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Group's Specialized Register (CCDANCTR, to 1 January 2013), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). Additional searches were carried out by the author team on the same biomedical databases (using terms for 'sexual dysfunction' only) together with CINAHL (1982 to Jan 2012). The reference lists of reports of all included studies were screened. SELECTION CRITERIA: We included randomised controlled trials that compared management strategies for antidepressant-induced sexual dysfunction versus placebo or any alternative strategy. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed trial quality. Study authors were contacted for additional information. MAIN RESULTS: We included 23 trials involving 1886 people in this updated review. Twenty-two of these trials investigated the addition of medication to treat the identified dysfunction, with most agents studied in only single studies. One study investigated switching to an alternative antidepressant.In men, data for the phosphodiesterase inhibitors sildenafil (three studies, 255 participants) and tadalafil (one study, 54 participants) indicated they led to a greater improvement in erectile function than placebo. Combined data from three sildenafil studies found benefit over placebo on International Index of Erectile Function ratings of ability to achieve (MD 1.04, 95% CI 0.65 to 1.44), and maintain erections (MD 1.18, 95% CI 0.78 to 1.59). A single point improvement on these ratings is equivalent to an improvement in frequency from 'sometimes' to 'most times'. Men receiving tadalafil were more likely to report improved erectile function (RR 11.50, 95% CI 3.03 to 43.67). For women it remains uncertain whether sildenafil is more effective than placebo. Unpublished data could reduce this uncertainty.Data from three studies in men and women of bupropion 150 mg twice daily indicate a benefit over placebo on rating scale scores (SMD 1.60, 95% CI 1.40 to 1.81), but response rates in two studies of bupropion 150 mg once daily demonstrated no statistically significant difference in effect (RR 0.62, 95% CI 0.09 to 4.41).Other augmentation strategies failed to demonstrate significant improvements in sexual dysfunction compared with placebo.One trial involving 75 people with sexual dysfunction due to sertraline assessed the effect of changing antidepressant. Switching to nefazodone was significantly less likely to result in the re-emergence of sexual dysfunction than restarting sertraline (RR 0.34, 95% CI 0.19 to 0.60), however, nefazodone is no longer available for clinical use.There is an absence of randomised trials assessing the effects of switching to currently-available antidepressant agents with lower rates of adverse sexual effects, the role of psychological or mechanical interventions, or of techniques such as drug holidays.We identified no data for any of the strategies included in the trials assessed that indicated that they led to a worsening of psychiatric symptoms. However, the relatively small numbers assessed for many of the interventions studied means that the possibility of such an effect cannot confidently be excluded in all cases.Given the small numbers of studies assessing most of the strategies assessed, the presence of any unpublished trials could have substantial effects on estimates of effect. In some cases, only results from particular items or subscales within ratings scales are available. It is likely that this could act to bias estimates of effect obtained, increasing apparent effectiveness. AUTHORS' CONCLUSIONS: The evidence currently available is rather limited. For men with antidepressant-induced erectile dysfunction, the addition of sildenafil or tadalafil appears to be an effective strategy. For women with antidepressant-induced sexual dysfunction the addition of bupropion at higher doses appears to be the most promising approach studied so far. PMID- 23728644 TI - Splenectomy versus conservative management for acute sequestration crises in people with sickle cell disease. AB - BACKGROUND: Acute splenic sequestration crises are a complication of sickle cell disease, with high mortality rates and frequent recurrence in survivors of first attacks. Splenectomy and blood transfusion, with their consequences, are the mainstay of long-term management used in different parts of the world. OBJECTIVES: To assess whether splenectomy (total or partial), to prevent acute splenic sequestration crises in people with sickle cell disease, improved survival and decreased morbidity in people with sickle cell disease, as compared with regular blood transfusions. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which comprises of references identified from comprehensive electronic database searches and handsearching relevant journals and abstract books of conference proceedings.Additional trials were sought from the reference lists of the trials and reviews identified by the search strategy.Date of the most recent search: 06 December 2012. SELECTION CRITERIA: All randomized or quasi-randomized controlled trials comparing splenectomy (total or partial) to prevent recurrence of acute splenic sequestration crises with no treatment or blood transfusions in people with sickle cell disease. DATA COLLECTION AND ANALYSIS: No trials of splenectomy for acute splenic sequestration were found. MAIN RESULTS: No trials of splenectomy for acute splenic sequestration were found. AUTHORS' CONCLUSIONS: Splenectomy, if full, will prevent further sequestration and if partial, may reduce the recurrence of acute splenic sequestration crises. However, there is a lack of evidence from trials showing that splenectomy improves survival and decreases morbidity in people with sickle cell disease. There is a need for a well-designed, adequately-powered, randomized controlled trial to assess the benefits and risks of splenectomy compared to transfusion programmes, as a means of improving survival and decreasing mortality from acute splenic sequestration in people with sickle cell disease. PMID- 23728645 TI - Oxcarbazepine versus phenytoin monotherapy for epilepsy. AB - BACKGROUND: This is an updated version of the original Cochrane review published in The Cochrane Library 2006, Issue 2.Worldwide, phenytoin is a commonly used antiepileptic drug. For the newer drugs such as oxcarbazepine, it is important to know how they compare with standard treatments. OBJECTIVES: To review the best evidence comparing oxcarbazepine and phenytoin when used as monotherapy in participants with partial onset seizures or generalised tonic-clonic seizures with or without other generalised seizure types. SEARCH METHODS: We searched the Cochrane Epilepsy Group's Specialised Register (22 January 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 12) and MEDLINE (1946 to 22 January 2013). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators and experts in the field. SELECTION CRITERIA: Randomised controlled trials in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of oxcarbazepine monotherapy with phenytoin monotherapy. DATA COLLECTION AND ANALYSIS: This was an individual participant data review. Outcomes were time to (a) treatment withdrawal (b) 12-month remission (c) six-month remission and (d) first seizure post randomisation. We used Cox proportional hazards models to obtain study-specific estimates of hazard ratios (HR) with 95% confidence intervals (CI) with the generic inverse variance method used to obtain the overall pooled HR and 95% CI. MAIN RESULTS: Individual participant data were available for 480 out of 517 participants (93%) from three included trials. For remission outcomes, a HR > 1 indicates an advantage to phenytoin and for first seizure and withdrawal outcomes a HR > 1 indicates an advantage to oxcarbazepine.The main overall results (pooled HR, 95% CI) were: (i) time to withdrawal of allocated treatment 1.65 (1.08 to 2.52), (ii) time to 12-month remission 0.92 (0.68 to 1.24), (iii) time to six-month remission 0.90 (0.70 to 1.15), (iv) time to first seizure 1.07 (0.83 to 1.39). Results indicate a statistically significant advantage for oxcarbazepine over phenytoin for time to treatment withdrawal, but insufficient evidence to suggest a difference between the drugs for other outcomes. By epilepsy type, there is no significant advantage for either drug for generalised epilepsy, however there is a significant advantage for partial epilepsy with oxcarbazepine for time to treatment withdrawal (HR 1.95; 95% CI 1.15 to 3.33). AUTHORS' CONCLUSIONS: For participants with partial onset seizures oxcarbazepine is significantly less likely to be withdrawn, but current data do not allow a statement as to whether oxcarbazepine is equivalent, superior or inferior to phenytoin in terms of seizure control. However, the design of the studies may have biased seizure outcomes and misclassification of epilepsy type may have biased withdrawal rates. PMID- 23728646 TI - Non-steroidal anti-inflammatory drugs (NSAIDs) for treating lateral elbow pain in adults. AB - BACKGROUND: Lateral elbow pain, or tennis elbow, is a common condition that causes pain in the elbow and forearm. Although self-limiting, it can be associated with significant disability and often results in work absence. It is often treated with topical and oral non-steroidal anti-inflammatory drugs (NSAIDs). This is an update of a review first published in 2002 (search date October 11, 2012). OBJECTIVES: To assess the benefits and harms of topical and oral NSAIDs for treating people with lateral elbow pain. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, CINAHL, EMBASE and SciSearch up to October 11, 2012. No language restriction was applied. SELECTION CRITERIA: Studies were included if they were randomised or quasi randomised controlled trials (RCTs or CCTs) that compared topical or oral NSAIDs with placebo or another intervention, or compared two NSAIDs in adults with lateral elbow pain. Outcomes of interest were pain, function, quality of life, pain-free grip strength, overall treatment success, work loss and adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies for inclusion, extracted the data, and performed a risk of bias assessment. MAIN RESULTS: Fifteen trials, involving 759 participants and reporting 17 comparisons, were included in the review. Four new trials identified from the updated search were included, along with 11 of 14 trials included in the original review (three trials included in the previous review were found not to meet inclusion criteria). Of eight trials that studied topical NSAIDs (301 participants), five compared topical NSAIDs with placebo, one compared manipulative therapy and topical NSAIDs with manipulative therapy alone, one compared leech therapy with topical NSAIDs and one compared two different topical NSAIDs. Of seven trials that investigated oral NSAIDs (437 participants), two compared oral NSAIDs with placebo, one compared oral NSAIDs and bandaging with bandaging alone, three compared oral NSAIDs with glucocorticoid injection, one compared oral NSAIDs with a vasodilator and two compared two different oral NSAIDs. No trials directly compared topical NSAIDs with oral NSAIDs. Few trials used intention-to-treat analysis, and the sample size of most was small. The median follow-up was 2 weeks (range 1 week to 1 year).Low-quality evidence was obtained from three trials (153 participants) suggesting that topical NSAIDs were significantly more effective than placebo with respect to pain in the short term (mean difference -1.64, 95% confidence interval (CI) -2.42 to -0.86) and number needed to treat to benefit (7 (95% CI 3 to 21) on a 0 to 10 scale). Low-quality evidence was obtained from one trial (85 participants) indicating that significantly more participants report fair, good or excellent effectiveness with topical NSAIDs versus placebo at 28 days (14 days of therapy) (risk ratio (RR) 1.49, 95% CI 1.04 to 2.14). No participants withdrew as the result of adverse events, but some studies reported mild adverse effects such as rash in 2.5% of those exposed to topical NSAIDs compared with 1.3% of those exposed to placebo.Low-quality and conflicting evidence regarding the benefits of oral NSAIDs obtained from two trials could not be pooled. One trial found significantly greater improvement in pain compared with placebo, and the other trial found no between-group differences; neither trial found differences in function. One trial reported a withdrawal due to adverse effects for a participant in the NSAIDs group. Use of oral NSAIDs was associated with increased risk of gastrointestinal side effects compared with placebo in one trial in the review. Another trial reported discontinuation of treatment due to gastrointestinal side effects in four participants taking NSAIDs, and another participant developed an allergic reaction in response to oral NSAIDs.Very scant and conflicting evidence regarding the comparative effects of oral NSAIDs and glucocorticoid injection was obtained. One trial reported a significant improvement in pain with glucocorticoid injection, and another found no between group differences; treatment success was similar between groups (RR of fair, good or excellent effectiveness 0.74; 95% CI 0.43 to 1.26). Transient pain may occur following injection. AUTHORS' CONCLUSIONS: There remains limited evidence from which to draw firm conclusions about the benefits or harms of topical or oral NSAIDs in treating lateral elbow pain. Although data from five placebo-controlled trials suggest that topical NSAIDs may be beneficial in improving pain (for up to 4 weeks), non-normal distribution of data and other methodological issues precluded firm conclusions. Some people may expect a mild transient skin rash. Evidence about the benefits of oral NSAIDs has been conflicting, although oral NSAID use may result in gastrointestinal adverse effects in some people. No direct comparisons between oral and topical NSAIDs were available. Some trials demonstrated greater benefit from glucocorticoid injection than from NSAIDs in the short term, but this was not apparent in all studies and was not apparent by 6 months in the only study that included longer-term outcomes. PMID- 23728648 TI - Abdominal surgical incisions for caesarean section. AB - BACKGROUND: Caesarean section is the commonest major operation performed on women worldwide. Operative techniques, including abdominal incisions, vary. Some of these techniques have been evaluated through randomised trials. OBJECTIVES: To determine the benefits and risks of alternative methods of abdominal surgical incisions for caesarean section. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (28 February 2013). SELECTION CRITERIA: Randomised controlled trials of intention to perform caesarean section using different abdominal incisions. DATA COLLECTION AND ANALYSIS: We extracted data from the sources, checked them for accuracy and analysed the data. MAIN RESULTS: Four studies (666 women) were included in this review.Two studies (411 women) compared the Joel-Cohen incision with the Pfannenstiel incision. Overall, there was a 65% reduction in reported postoperative febrile morbidity (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.14 to 0.87) with the Joel-Cohen incision. One of the trials reported reduced postoperative analgesic requirements (RR 0.55, 95% CI 0.40 to 0.76); operating time (mean difference (MD) -11.40, 95% CI -16.55 to -6.25 minutes); delivery time (MD -1.90, 95% CI -2.53 to -1.27 minutes); total dose of analgesia in the first 24 hours (MD -0.89, 95% CI -1.19 to -0.59); estimated blood loss (MD -58.00, 95% CI -108.51 to -7.49 mL); postoperative hospital stay for the mother (MD -1.50, 95% CI -2.16 to -0.84 days); and increased time to the first dose of analgesia (MD 0.80, 95% CI 0.12 to 1.48 hours) compared with the Pfannenstiel group. No other significant differences were found in either trial.Two studies compared muscle cutting incisions with Pfannenstiel incision. One study (68 women) comparing Mouchel incision with Pfannenstiel incision did not contribute data to this review. The other study (97 women) comparing the Maylard muscle-cutting incision with the Pfannenstiel incision, reported no difference in febrile morbidity (RR 1.26, 95% CI 0.08 to 19.50); need for blood transfusion (RR 0.42, 95% CI 0.02 to 9.98); wound infection (RR 1.26, 95% CI 0.27 to 5.91); physical tests on muscle strength at three months postoperative and postoperative hospital stay (MD 0.40 days, 95% CI -0.34 to 1.14). AUTHORS' CONCLUSIONS: The Joel-Cohen incision has advantages compared with the Pfannenstiel incision. These are: less fever, pain and analgesic requirements; less blood loss; shorter duration of surgery and hospital stay. These advantages for the mother could be extrapolated to savings for the health system. However, these trials do not provide information on severe or long term morbidity and mortality. PMID- 23728647 TI - Interventions for intermittent exotropia. AB - BACKGROUND: The clinical management of intermittent exotropia has been discussed extensively in the literature, yet there remains a lack of clarity regarding indications for intervention, the most effective form of treatment and whether or not there is an optimal time in the evolution of the disease at which any treatment should be carried out. OBJECTIVES: The objective of this review was to analyse the effects of various surgical and non-surgical treatments in randomised trials of participants with intermittent exotropia, and to report intervention criteria and determine the significance of factors such as age with respect to outcome. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library, Issue 4, 2012), MEDLINE (January 1966 to May 2012), EMBASE (January 1980 to May 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to May 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 4 May 2012. We are no longer searching the UK Clinical Trials Gateway (UKCTG) for this review. We manually searched the British Orthoptic Journal up to 2002, and the proceedings of the European Strabismological Association (ESA), International Strabismological Association (ISA) and American Academy of Paediatric Ophthalmology and Strabismus meeting (AAPOS) up to 2001. We contacted researchers who are active in the field for information about further published or unpublished studies. SELECTION CRITERIA: We included randomised controlled trials of any surgical or non-surgical treatment for intermittent exotropia. DATA COLLECTION AND ANALYSIS: Each review author independently assessed study abstracts identified from the electronic and manual searches. Author analysis was then compared and full papers for appropriate studies were obtained. MAIN RESULTS: We found one randomised trial that was eligible for inclusion. This trial showed that unilateral surgery was more effective than bilateral surgery for correcting the basic type of intermittent exotropia. AUTHORS' CONCLUSIONS: The available literature consists mainly of retrospective case reviews, which are difficult to reliably interpret and analyse. The one randomised trial included found unilateral surgery more effective than bilateral surgery for basic intermittent exotropia. However, across all identified studies, measures of severity and thus criteria for intervention are poorly validated, and there appear to be no reliable natural history data. There is therefore a pressing need for improved measures of severity, a better understanding of the natural history and carefully planned clinical trials of treatment to improve the evidence base for the management of this condition. PMID- 23728649 TI - Etanercept for the treatment of rheumatoid arthritis. AB - BACKGROUND: Etanercept is a soluble tumour necrosis factor alpha-receptor disease modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). OBJECTIVES: The purpose of this review was to update the previous Cochrane systematic review published in 2003 assessing the benefits and harms of etanercept for the treatment of RA. In addition, we also evaluated the benefits and harms of etanercept plus DMARD compared with DMARD monotherapy in those people with RA who are partial responders to methotrexate (MTX) or any other traditional DMARD. SEARCH METHODS: Five electronic databases were searched from 1966 to February 2003 with no language restriction. The search was updated to January 2012. Attempts were made to identify other studies by contact with experts, searching reference lists and searching trial registers. SELECTION CRITERIA: All controlled trials (minimum 24 weeks' duration) comparing four possible combinations: 1) etanercept (10 mg or 25 mg twice weekly) plus a traditional DMARD (either MTX or sulphasalazine) versus a DMARD, 2) etanercept plus DMARD versus etanercept alone, 3) etanercept alone versus a DMARD or 4) etanercept versus placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias of the trials. MAIN RESULTS: Three trials were included in the original version of the review. An additional six trials, giving a total of 2842 participants, were added to the 2012 update of the review. The trials were generally of moderate to low risk of bias, the majority funded by pharmaceutical companies. Follow-up ranged from six months to 36 months.BenefitAt six to 36 months the American College of Rheumatology (ACR) 50 response rate was statistically significantly improved with etanercept plus DMARD treatment when compared with a DMARD in those people who had an inadequate response to any traditional DMARD (risk ratio (RR) 2.0; 95% confidence interval (CI) 1.3 to 2.9, absolute treatment benefit (ATB) 38%; 95% CI 13% to 59%) and in those people who were partial responders to MTX (RR 11.7; 95% CI 1.7 to 82.5, ATB 36%). Similar results were observed when pooling data from all participants (responders or not) (ACR 50 response rates at 24 months: RR 1.9; 95% CI 1.3 to 2.8, ATB 29%; 36 months: RR 1.6; 95% CI 1.3 to 1.9, ATB 24%). Statistically significant improvement in physical function and a higher proportion of disease remission were observed in combination-treated participants compared with DMARDs alone ((mean difference (MD) -0.36; 95% CI -0.43 to -0.28 in a 0-3 scale) and (RR 1.92; 95% CI 1.60 to 2.31), respectively) in those people who had an inadequate response to any traditional DMARD. All changes in radiographic scores were statistically significantly less with combination treatment (etanercept plus DMARD) compared with MTX alone for all participants (responders or not) (Total Sharp Score (TSS) (scale = 0 to 448): MD -2.2, 95% CI 3.0 to -1.4; Erosion Score (ES) (scale = 0 to 280): MD -1.6; 95% CI -2.4 to -0.9; Joint Space Narrowing Score (JSNS) (scale = 0 to 168): MD -0.7; 95% CI -1.1 to 0.2), and with combination treatment compared with etanercept alone (TSS: MD 1.1; 95% CI -1.8 to -0.5; ES: MD -0.7; 95% CI -1.1 to -0.2; JSNS: MD -0.5, 95% CI -0.7 to -0.2). The estimate of irreversible physical disability over 10 years given the radiographic findings was 0.45 out of 3.0.When etanercept monotherapy was compared with DMARD monotherapy, there was generally no evidence of a difference in ACR50 response rates when etanercept 10 mg or 25 mg was used; at six months etanercept 25 mg was significantly more likely to achieve ACR50 than DMARD monotherapy but this difference was not found at 12, 24 or 36 months. TSS and ES radiographic scores were statistically significantly improved with etanercept 25 mg monotherapy compared with DMARD (TSS: MD -0.7; 95% CI -1.4 to 0.1; ES: MD -0.7; 95% CI -1.0 to -0.3) but there was no evidence of a statistically significant difference between etanercept 10 mg monotherapy and MTX.HarmsThere was no evidence of statistically significant differences in infections or serious infections between etanercept plus DMARD and DMARD alone at any point in time. Infection rates were higher in people receiving etanercept monotherapy compared with DMARD; however, there were no differences regarding serious infections. For those participants who had an inadequate response to DMARDs, the rate of total withdrawals was lower for the etanercept plus DMARD group compared with DMARD alone (RR 0.53; 95% CI 0.36 to 0.77, ATB 18%). No other statistically significant differences were observed in any of the assessed comparisons. AUTHORS' CONCLUSIONS: Etanercept 25 mg administered subcutaneously twice weekly together with MTX was more efficacious than either etanercept or MTX monotherapy for ACR50 and it slowed joint radiographic progression after up to three years of treatment for all participants (responders or not). There was no evidence of a difference in the rates of infections between groups. PMID- 23728650 TI - Hyperbaric oxygen as an adjuvant treatment for malignant otitis externa. AB - BACKGROUND: Malignant, or necrotising, otitis externa is a potentially fatal infection of the external ear canal and surrounding soft tissue and bone. It may be complicated by involvement of cranial nerves, principally the facial nerves and the contents of the jugular foramen. It is an uncommon condition mainly found in the elderly or in diabetics. OBJECTIVES: To assess the effectiveness of adjunctive hyperbaric oxygen treatment for malignant otitis externa. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 4 April 2013. SELECTION CRITERIA: Randomised controlled trials, involving adults, undergoing hyperbaric oxygen therapy in malignant otitis externa. DATA COLLECTION AND ANALYSIS: No identified articles described randomised controlled trials of hyperbaric oxygen therapy in the treatment of malignant otitis externa. MAIN RESULTS: Due to the lack of data we could present no results. AUTHORS' CONCLUSIONS: No clear evidence exists to demonstrate the efficacy of hyperbaric oxygen therapy when compared to treatment with antibiotics and/or surgery. We found no data to compare rates of complication between the different treatment modalities. Further research is required. PMID- 23728651 TI - Rivastigmine for vascular cognitive impairment. AB - BACKGROUND: Vascular dementia represents the second most common type of dementia after Alzheimer's disease. In older patients, in particular, the combination of vascular dementia and Alzheimer's disease is common, and is referred to as mixed dementia. The classification of vascular dementia broadly follows three clinico pathological processes: multi-infarct dementia, single strategic infarct dementia and subcortical dementia. Not all victims fulfil strict criteria for dementia and may be significantly cognitively impaired without memory loss, when the term vascular cognitive impairment (VCI) is more useful. Currently, no established standard treatment for VCI exists. Reductions in acetylcholine and acetyltransferase activity are common to both Alzheimer's disease and VCI, raising the possibility that cholinesterase inhibitors - such as rivastigmine - which are beneficial in Alzheimer's disease, may also be beneficial for VCI. OBJECTIVES: To assess the efficacy of rivastigmine compared with placebo in the treatment of people with vascular cognitive impairment (VCI), vascular dementia or mixed dementia. SEARCH METHODS: We searched ALOIS (the Cochrane Dementia and Cognitive Improvement Group's Specialized Register) on 12 February 2013 using the terms: rivastigmine, exelon, "SDZ ENA 713". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (The Cochrane Library, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS), numerous trial registries and grey literature sources. SELECTION CRITERIA: All unconfounded randomized double-blind trials comparing rivastigmine with placebo in the treatment of people with VCI, vascular dementia or mixed dementia were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two reviewers extracted and assessed data independently, and agreement was reached after discussion. They noted results concerning adverse effects. MAIN RESULTS: Three trials, with a total of 800 participants, were identified for inclusion. The participants in one trial did not have dementia, while the other two studies included participants with dementia of different severities. The dose of rivastigmine was different in each study. No pooling of study results was attempted because of these differences between the studies.One trial included 40 participants with subcortical vascular dementia (age range 40 to 90 years) with a mean mini-mental state examination (MMSE) score of 13.0 and 13.4 in the rivastigmine and placebo arms, respectively. Treatment over 26 weeks was limited to 3 mg rivastigmine twice daily, or placebo. No significant difference was found on any outcome measure relevant to cognition, neuropsychiatric symptoms, function or global rating, or in the number of withdrawals before the end of treatment.Another trial included 710 participants with vascular dementia, including subcortical and cortical forms (age range 50 to 85 years). Over 24 weeks, a mean dose of rivastigmine of 9.4 mg/day was achieved versus placebo. Baseline MMSE was identical for both groups, at 19.1. Statistically significant advantage in cognitive response (but not with global impression of change or non-cognitive measures) was seen with rivastigmine treatment at 24 weeks (MMSE change from baseline MD 0.6, 95% CI 0.11 to 1.09, P value 0.02; Vascular Dementia Assessment Scale (VaDAS) change from baseline MD 1.3, 95% CI-2.62 to 0.02, P value 0.05 ). Significantly higher rates of vomiting, nausea, diarrhoea and anorexia and withdrawals from treatment were noted in the participants randomized to rivastigmine compared with placebo (withdrawals rivastigmine 90/365, placebo 48/345, OR 2.02, 95% CI 1.38 to 2.98) (withdrawals due to an adverse event rivastigmine 49/365, placebo 19/345, OR 2.66, 95% CI 1.53 to 4.62, P value 0.0005).The third study included 50 participants (age range 48 to 84 years) with mean MMSE scores of 23.7 and 23.9 in the rivastigmine and placebo arms, respectively. Over a 24-week period, participants labelled as having cognitive impairment but no dementia (CIND) following ischaemic stroke were given up to 4.5 mg rivastigmine twice daily, or placebo. Primary and secondary outcome measures showed no statistically significant difference when considering neurocognitive abilities, function, neuropsychiatric symptoms and global performance. One participant in the rivastigmine group and two in the placebo group discontinued their medication because of an adverse effect. AUTHORS' CONCLUSIONS: There is some evidence of benefit of rivastigmine in VCI from trial data from three studies. However, this conclusion is based on one large study. Rivastigmine is capable of inducing side effects that lead to withdrawal in a significant proportion of patients. PMID- 23728652 TI - Use of hyperbaric versus isobaric bupivacaine for spinal anaesthesia for caesarean section. AB - BACKGROUND: Bupivacaine is an amide local anaesthetic used in hyperbaric and isobaric forms. These are administered intrathecally into the spine to provide regional anaesthesia for caesarean section. Several trials have compared hyperbaric and isobaric bupivacaine but none have conclusively shown benefit of either. OBJECTIVES: This systematic review aimed to summarize the effectiveness and safety of hyperbaric versus isobaric bupivacaine in providing anaesthesia for caesarean section. We considered the adequacy of anaesthesia for completion of caesarean section and the need for interventions to treat complications. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), MEDLINE (January 1966 to May 2011) and EMBASE (January 1980 to May 2011). We handsearched journals. We imposed no language restriction. We reran our search in the above databases from January 2011 to January 2013; the studies are awaiting assessment and will be dealt with when we update the review. SELECTION CRITERIA: We included all randomized controlled trials involving parturients undergoing spinal anaesthesia for elective caesarean section that compared the use of hyperbaric with isobaric bupivacaine. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data. The data that were extracted included the number of events and the sample sizes in both the intervention and control groups. For continuous outcomes, we extracted mean and standard deviation.We reported odds ratios and risk ratios (RR) for binary outcomes and mean differences (MD) for continuous outcomes. MAIN RESULTS: We included six studies with a total of 394 patients in this review. Anaesthesia performed with hyperbaric bupivacaine appeared to be less likely to need conversion to general anaesthesia (two studies, 158 patients included in meta-analysis; RR 0.17, 95% confidence interval (CI) 0.03 to 0.94). There was no difference in the need for supplemental analgesics. The time till sensory block to the T4 level was also shorter with hyperbaric bupivacaine (two studies, 126 patients; MD -1.06 minutes, 95% CI -1.80 to -0.31). There were no other significant differences between the two anaesthetics. AUTHORS' CONCLUSIONS: The criteria for conversion to general anaesthesia should be clearly defined in future research. This review found that intrathecal hyperbaric bupivacaine had a more rapid onset of sensory blockade at the T4 level than isobaric bupivacaine. It may also result in less need for conversion to general anaesthesia and supplemental analgesia. However, due to the rarity of this outcome, variability in the dose, use of adjuvant drugs and differences in the technique used for regional anaesthesia the evidence is weak. Any apparent advantage of hyperbaric bupivacaine needs to be confirmed in larger randomized trials. There were no differences in the adverse effects studied. PMID- 23728653 TI - Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease. AB - BACKGROUND: Despite the high incidence of muscle weakness in individuals with amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND), the effects of exercise in this population are not well understood. This is an update of a review first published in 2008. OBJECTIVES: To systematically review randomised and quasi-randomised studies of exercise for people with ALS or MND. SEARCH METHODS: We searched The Cochrane Neuromuscular Disease Group Specialized Register (2 July 2012), CENTRAL (2012, Issue 6 in The Cochrane Library), MEDLINE (January 1966 to June 2012), EMBASE (January 1980 to June 2012), AMED (January 1985 to June 2012), CINAHL Plus (January 1938 to June 2012), LILACS (January 1982 to June 2012), Ovid HealthSTAR (January 1975 to December 2012). We also searched ProQuest Dissertations & Theses A&I (2007 to 2012), inspected the reference lists of all papers selected for review and contacted authors with expertise in the field. SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials of people with a diagnosis of definite, probable, probable with laboratory support, or possible ALS, as defined by the El Escorial criteria. We included progressive resistance or strengthening exercise, and endurance or aerobic exercise. The control condition was no exercise or standard rehabilitation management. Our primary outcome measure was improvement in functional ability, decrease in disability or reduction in rate of decline as measured by a validated outcome tool at three months. Our secondary outcome measures were improvement in psychological status or quality of life, decrease in fatigue, increase in, or reduction in rate of decline of muscle strength (strengthening or resistance studies), increase in, or reduction in rate of decline of aerobic endurance (aerobic or endurance studies) at three months and frequency of adverse effects. We did not exclude studies on the basis of measurement of outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted the data. We collected adverse event data from included trials. The review authors contacted the authors of the included studies to obtain information not available in the published articles. MAIN RESULTS: We identified two randomised controlled trials that met our inclusion criteria, and we found no new trials when we updated the searches in 2012. The first, a study with overall unclear risk of bias, examined the effects of a twice-daily exercise program of moderate load endurance exercise versus "usual activities" in 25 people with ALS. The second, a study with overall low risk of bias, examined the effects of thrice weekly moderate load and moderate intensity resistance exercises compared to usual care (stretching exercises) in 27 people with ALS. After three months, when the results of the two trials were combined (43 participants), there was a significant mean improvement in the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) measure of function in favour of the exercise groups (mean difference 3.21, 95% confidence interval 0.46 to 5.96). No statistically significant differences in quality of life, fatigue or muscle strength were found. In both trials adverse effects, investigators reported no adverse effects such as increased muscle cramping, muscle soreness or fatigue AUTHORS' CONCLUSIONS: The included studies were too small to determine to what extent strengthening exercises for people with ALS are beneficial, or whether exercise is harmful. There is a complete lack of randomised or quasi-randomised clinical trials examining aerobic exercise in this population. More research is needed. PMID- 23728654 TI - Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for cardiogenic pulmonary oedema. AB - BACKGROUND: This is an update of a systematic review previously published in 2008 about non-invasive positive pressure ventilation (NPPV). NPPV has been widely used to alleviate signs and symptoms of respiratory distress due to cardiogenic pulmonary oedema. NPPV prevents alveolar collapse and helps redistribute intra alveolar fluid, improving pulmonary compliance and reducing the pressure of breathing. OBJECTIVES: To determine the effectiveness and safety of NPPV in the treatment of adult patients with cardiogenic pulmonary oedema in its acute stage. SEARCH METHODS: We searched the following databases on 20 April 2011: CENTRAL and DARE, (The Cochrane Library, Issue 2 of 4, 2011); MEDLINE (Ovid, 1950 to April 2011); EMBASE (Ovid, 1980 to April 2011); CINAHL (1982 to April 2011); and LILACS (1982 to April 2011). We also reviewed reference lists of included studies and contacted experts and equipment manufacturers. We did not apply language restrictions. SELECTION CRITERIA: We selected blinded or unblinded randomised or quasi-randomised clinical trials, reporting on adult patients with acute or acute on-chronic cardiogenic pulmonary oedema and where NPPV (continuous positive airway pressure (CPAP) or bilevel NPPV) plus standard medical care was compared with standard medical care alone. DATA COLLECTION AND ANALYSIS: Two authors independently selected articles and abstracted data using a standardised data collection form. We evaluated study quality with emphasis on allocation concealment, sequence generation allocation, losses to follow-up, outcome assessors, selective outcome reporting and adherence to the intention-to-treat principle. MAIN RESULTS: We included 32 studies (2916 participants), of generally low or uncertain risk of bias. Compared with standard medical care, NPPV significantly reduced hospital mortality (RR 0.66, 95% CI 0.48 to 0.89) and endotracheal intubation (RR 0.52, 95% CI 0.36 to 0.75). We found no difference in hospital length of stay with NPPV; however, intensive care unit stay was reduced by 1 day (WMD -0.89 days, 95% CI -1.33 to -0.45). Compared with standard medical care, we did not observe significant increases in the incidence of acute myocardial infarction with NPPV during its application (RR 1.24, 95% CI 0.79 to 1.95) or after (RR 0.70, 95% CI 0.11 to 4.26). We identified fewer adverse events with NPPV use (in particular progressive respiratory distress and neurological failure (coma)) when compared with standard medical care. AUTHORS' CONCLUSIONS: NPPV in addition to standard medical care is an effective and safe intervention for the treatment of adult patients with acute cardiogenic pulmonary oedema. The evidence to date on the potential benefit of NPPV in reducing mortality is entirely derived from small-trials and further large-scale trials are needed. PMID- 23728655 TI - Prophylactic antibiotics for transcervical intrauterine procedures. AB - BACKGROUND: The transcervical intrauterine route is commonly used for operative gynaecological procedures in women. The vagina is an area of the body that is abundant with normal bacterial flora. An operative procedure through the vagina may, therefore, be considered to have added potential for post-procedure infection. Prophylactic antibiotics may play a role in the prevention of post procedure transcervical intrauterine infections. OBJECTIVES: To assess the effectiveness and safety of antibiotic prophylaxis compared to placebo or no treatment in women undergoing transcervical intrauterine procedures. SEARCH METHODS: The search strategy was based on the Cochrane Menstrual Disorders and Subfertility Group (MDSG) search strategy. We searched the following databases: the Cochrane MDSG Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (to August 2012); MEDLINE (1946 to August 2012); EMBASE (1980 to August 2012); PsycINFO (to August 2012); CINAHL (to August 2012), Biological Abstracts (1966 to August 2012) and AMED (1966 to August 2012). SELECTION CRITERIA: We planned to include only truly randomised controlled trials that compared antibiotic prophylaxis with placebo or no treatment in order to prevent infectious complications after transcervical intrauterine procedures. Controlled clinical trials without randomisation and pseudo-randomised trials were excluded. DATA COLLECTION AND ANALYSIS: No data collection or analysis was done because no trials were eligible for inclusion in the review. MAIN RESULTS: The search did not identify any randomised controlled trials investigating the effect of antibiotic prophylaxis compared to placebo or no treatment in women undergoing transcervical intrauterine procedures. AUTHORS' CONCLUSIONS: At this time, there are no randomised controlled trials that assess the effects of prophylactic antibiotics on infectious complications following transcervical intrauterine procedures. It is, therefore, not possible to draw any conclusions regarding the use of prophylactic antibiotics for the prevention of post procedure transcervical intrauterine infections. PMID- 23728656 TI - Acupuncture for glaucoma. AB - BACKGROUND: Glaucoma is a multifactorial optic neuropathy characterized by an acquired loss of retinal ganglion cells at levels beyond normal age-related loss and corresponding atrophy of the optic nerve. Although many treatments are available to manage glaucoma, glaucoma is a chronic condition. Some patients may seek complementary or alternative medicine approaches such as acupuncture to supplement their regular treatment. The underlying plausibility of acupuncture is that disorders related to the flow of Chi (the traditional Chinese concept translated as vital force or energy) can be prevented or treated by stimulating relevant points on the body surface. OBJECTIVES: The objective of this review was to assess the effectiveness and safety of acupuncture in people with glaucoma. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 12), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to January 2013), EMBASE (January 1980 to January 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to January 2013), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 1937 to January 2013), ZETOC (January 1993 to January 2013), Allied and Complementary Medicine Database (AMED) (January 1985 to January 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and the National Center for Complementary and Alternative Medicine web site (NCCAM) (http://nccam.nih.gov). We did not use any language or date restrictions in the search for trials. We last searched the electronic databases on 8 January 2013 with the exception of NCCAM which was last searched on 14 July 2010. We also handsearched Chinese medical journals at Peking Union Medical College Library in April 2007.We searched the Chinese Acupuncture Trials Register, the Traditional Chinese Medical Literature Analysis and Retrieval System (TCMLARS), and the Chinese Biological Database (CBM) for the original review; we did not search these databases for the 2013 review update. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which one arm of the study involved acupuncture treatment. DATA COLLECTION AND ANALYSIS: Two authors independently evaluated the search results and then full text articles against the eligibility criteria. We resolved discrepancies by discussion. MAIN RESULTS: We included one completed and one ongoing trial, and recorded seven trials awaiting assessment for eligibility. These seven trials were written in Chinese and were identified from a systematic review on the same topic published in a Chinese journal. The completed trial compared auricular acupressure-a nonstandard acupuncture technique-with the sham procedure for glaucoma. This trial is rated at high risk of bias for masking of outcome assessors, unclear risk of bias for selective outcome reporting, and low risk of bias for other domains. The difference in intraocular pressure (measured in mm Hg) in the acupressure group was significantly less than that in the sham group at four weeks (-3.70, 95% confidence interval [CI] -7.11 to -0.29 for the right eye; -4.90, 95% CI -8.08 to -1.72 for the left eye), but was not statistically different at any other follow-up time points, including the longest follow-up time at eight weeks. No statistically significant difference in visual acuity was noted at any follow-up time points. The ongoing trial was registered with the International Clinical Trials Registry Platform (ICTRP) of the World Health Organization. To date this trial has not recruited any participants. AUTHORS' CONCLUSIONS: At this time, it is impossible to draw reliable conclusions from available data to support the use of acupuncture for the treatment of glaucoma. Because of ethical considerations, RCTs comparing acupuncture alone with standard glaucoma treatment or placebo are unlikely to be justified in countries where the standard of care has already been established. Because most glaucoma patients currently cared for by ophthalmologists do not use nontraditional therapy, clinical practice decisions will have to be based on physician judgments and patient preferences, given this lack of data in the literature. Inclusion of the seven Chinese trials in future updates of this review may change our conclusions. PMID- 23728657 TI - Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour. AB - BACKGROUND: Cardiotocography (known also as electronic fetal monitoring), records changes in the fetal heart rate and their temporal relationship to uterine contractions. The aim is to identify babies who may be short of oxygen (hypoxic), so additional assessments of fetal well-being may be used, or the baby delivered by caesarean section or instrumental vaginal birth. OBJECTIVES: To evaluate the effectiveness of continuous cardiotocography during labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (31 December 2012) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials involving a comparison of continuous cardiotocography (with and without fetal blood sampling) with (a) no fetal monitoring, (b) intermittent auscultation (c) intermittent cardiotocography. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, quality and extracted data from included studies. MAIN RESULTS: Thirteen trials were included with over 37,000 women; only two were judged to be of high quality.Compared with intermittent auscultation, continuous cardiotocography showed no significant improvement in overall perinatal death rate (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.59 to 1.23, n = 33,513, 11 trials), but was associated with a halving of neonatal seizures (RR 0.50, 95% CI 0.31 to 0.80, n = 32,386, nine trials). There was no significant difference in cerebral palsy rates (RR 1.75, 95% CI 0.84 to 3.63, n = 13,252, two trials). There was a significant increase in caesarean sections associated with continuous cardiotocography (RR 1.63, 95% CI 1.29 to 2.07, n = 18,861, 11 trials). Women were also more likely to have an instrumental vaginal birth (RR 1.15, 95% CI 1.01 to 1.33, n = 18,615, 10 trials).Data for subgroups of low-risk, high-risk, preterm pregnancies and high-quality trials were consistent with overall results. Access to fetal blood sampling did not appear to influence the difference in neonatal seizures nor any other prespecified outcome. AUTHORS' CONCLUSIONS: Continuous cardiotocography during labour is associated with a reduction in neonatal seizures, but no significant differences in cerebral palsy, infant mortality or other standard measures of neonatal well-being. However, continuous cardiotocography was associated with an increase in caesarean sections and instrumental vaginal births. The challenge is how best to convey these results to women to enable them to make an informed choice without compromising the normality of labour. PMID- 23728658 TI - Probiotics for the prevention of Clostridium difficile-associated diarrhea in adults and children. AB - BACKGROUND: Antibiotics are widely prescribed; however they can cause disturbances in gastrointestinal flora which may lead to reduced resistance to pathogens such as Clostridium difficile (C. difficile). Probiotics are live organisms thought to balance the gastrointestinal flora. OBJECTIVES: The primary objectives were to assess the efficacy and safety of probiotics for preventing Clostridium difficile-associated diarrhea (CDAD) or C. difficile infection in adults and children. SEARCH METHODS: On February 21, 2013 we searched PubMed (1966-2013), EMBASE (1966-2013), Cochrane Central Register of Controlled Trials (The Cochrane Library 2013, Issue 1), CINAHL (1982-2013), AMED (1985-2013), and ISI Web of Science. Additionally, we conducted an extensive grey literature search including contact with industry representatives. SELECTION CRITERIA: Randomized controlled (placebo, alternative prophylaxis, or no treatment control) trials investigating probiotics (any strain, any dose) for prevention of CDAD, or C. difficile infection were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently and in duplicate extracted data and assessed risk of bias using pre-constructed, and piloted, data extraction forms. Any disagreements were resolved by a third adjudicator. For articles published in abstract form only, further information was sought by contacting principal authors. The primary outcome was the incidence of CDAD. Secondary outcomes included the incidence of C. difficile infection, adverse events, antibiotic associated diarrhea (AAD) and length of hospital stay. Dichotomous outcomes (e.g. incidence of CDAD) were pooled using a random-effects model to calculate the relative risk and corresponding 95% confidence interval (95% CI). Continuous outcomes (e.g. length of hospital) were pooled using a random-effects model to calculate the mean difference and corresponding 95% CI. Sensitivity analyses were conducted to explore the impact of missing data on efficacy and safety outcomes. For the sensitivity analyses, we assumed that the event rate for those participants in the control group who had missing data was the same as the event rate for those participants in the control group who were successfully followed. For the probiotic group we calculated effects using the following assumed ratios of event rates in those with missing data in comparison to those successfully followed: 1.5:1, 2:1, 3:1, and 5:1. To explore possible explanations for heterogeneity, a priori subgroup analysis were conducted on probiotic species, dose, adult versus pediatric population, and risk of bias.The overall quality of the evidence supporting each outcome was assessed using the GRADE criteria. MAIN RESULTS: A total of 1871 studies were identified with 31 (4492 participants) meeting eligibility requirements for our review. Overall 11 studies were rated as a high risk of bias due mostly to missing outcome data. A complete case analysis (i.e. participants who completed the study) of those trials investigating CDAD (23 trials, 4213 participants) suggests that probiotics significantly reduce this risk by 64%. The incidence of CDAD was 2.0% in the probiotic group compared to 5.5% in the placebo or no treatment control group (RR 0.36; 95% CI 0.26 to 0.51). Sixteen of 23 trials had missing CDAD data ranging from 5% to 45%. These results proved robust to sensitivity analyses of plausible and worst-plausible assumptions regarding missing outcome data and were similar whether considering trials in adults versus children, lower versus higher doses, different probiotic species, or higher versus lower risk of bias. Our judgment is that the overall evidence warrants moderate confidence in this large relative risk reduction. We downgraded the overall quality of evidence for CDAD to 'moderate' due to imprecision. There were few events (154) and the calculated optimal information size (n = 8218) was more than the total sample size. With respect to the incidence of C. difficile infection, a secondary outcome, pooled complete case results from 13 trials (961 participants) did not show a statistically significant reduction. The incidence of C. difficile infection was 12.6% in the probiotics group compared to 12.7% in the placebo or no treatment control group (RR 0.89; 95% CI 0.64 to 1.24). Adverse events were assessed in 26 studies (3964 participants) and our pooled complete case analysis indicates probiotics reduce the risk of adverse events by 20% (RR 0.80; 95% CI 0.68 to 0.95). In both treatment and control groups the most common adverse events included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. For the short-term use of probiotics in patients that are not immunocompromised or severely debilitated, we consider the strength of this evidence to be moderate. AUTHORS' CONCLUSIONS: Based on this systematic review and meta-analysis of 23 randomized controlled trials including 4213 patients, moderate quality evidence suggests that probiotics are both safe and effective for preventing Clostridium difficile-associated diarrhea. PMID- 23728659 TI - Driving assessment for maintaining mobility and safety in drivers with dementia. AB - BACKGROUND: Demographic changes are leading to an increase in the number of older drivers: as dementia is an age-related disease, there is also an increase in the numbers of drivers with dementia. Dementia can impact on both the mobility and safety of drivers, and the impact of formal assessment of driving is unknown in terms of either mobility or safety. Those involved in assessment of older drivers need to be aware of the evidence of positive and negative effects of driving assessment. Cognitive tests are felt by some authors to have poor face and construct validity for assessing driving performance; extrapolating from values in one large-scale prospective cohort study, the cognitive test that most strongly predicted future crashes would, if used as a screening tool, potentially prevent six crashes per 1000 people over 65 years of age screened, but at the price of stopping the driving of 121 people who would not have had a crash. OBJECTIVES: PRIMARY OBJECTIVES: 1. to assess whether driving assessment facilitates continued driving in people with dementia; 2. to assess whether driving assessment reduces accidents in people with dementia. SECONDARY OBJECTIVE: 1. to assess the quality of research on assessment of drivers with dementia. SEARCH METHODS: ALOIS, the Cochrane Dementia Group's Specialized Register was searched on 13 September 2012 using the terms: driving or driver* or "motor vehicle*" or "car accident*" or "traffic accident*" or automobile* or traffic. This register contains records from major healthcare databases, ongoing trial databases and grey literature sources and is updated regularly. SELECTION CRITERIA: We sought randomised controlled trials prospectively evaluating drivers with dementia for outcomes such as transport mobility, driving cessation or motor vehicle accidents following driving assessment. DATA COLLECTION AND ANALYSIS: Each review author retrieved studies and assessed for primary and secondary outcomes, study design and study quality. MAIN RESULTS: No studies were found that met the inclusion criteria. A description and discussion of the driving literature relating to assessment of drivers with dementia relating to the primary objectives is presented. AUTHORS' CONCLUSIONS: In an area with considerable public health impact for drivers with dementia and other road users, the available literature fails to demonstrate the benefit of driver assessment for either preserving transport mobility or reducing motor vehicle accidents. Driving legislation and recommendations from medical practitioners requires further research that addresses these outcomes in order to provide the best outcomes for both drivers with dementia and the general public. PMID- 23728660 TI - Autoinflation for hearing loss associated with otitis media with effusion. AB - BACKGROUND: This is an update of a Cochrane review first published in The Cochrane Library in Issue 4, 2006.Otitis media with effusion (OME) or 'glue ear' is an accumulation of fluid in the middle ear, in the absence of acute inflammation or infection. It is the commonest cause of acquired hearing loss in childhood and the usual reason for insertion of 'grommets'. Potential treatments include decongestants, mucolytics, steroids, antihistamines and antibiotics. Autoinflation devices have been proposed as a simple mechanical means of improving 'glue ear'. OBJECTIVES: To assess the effectiveness of autoinflation compared with no treatment in children and adults with otitis media with effusion. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the most recent search was 12 April 2013. SELECTION CRITERIA: We selected randomised controlled trials that compared any form of autoinflation to no autoinflation in individuals with 'glue ear'. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, assessed risk of bias and extracted data from included studies. MAIN RESULTS: Eight studies, with a total of 702 participants, met the inclusion criteria. Overall, the studies were predominantly assessed as being at low or unclear risk of bias; unclear risk was mainly due lack of information. There was no evidence of selective reporting.Pooled estimates favoured the intervention, but did not show a significant effect on tympanometry (type C2 and B) at less than one month, nor at more than one month. Similarly, there were no significant changes for discrete pure-tone audiometry and non-discrete audiometry. Pooled estimates favoured, but not significantly, the intervention for the composite measure of tympanogram or audiometry at less than one month; at more than one month the result became significant (RRI 1.74, 95% CI 1.22 to 2.50). Subgroup analysis based on the type of intervention showed a significant effect using a Politzer device under one month (RRI 7.07, 95% CI 3.70 to 13.51) and over one month (RRI 2.25, 95% CI 1.67 to 3.04).None of the studies demonstrated a significant difference in the incidence of side effects between interventions. AUTHORS' CONCLUSIONS: All of the studies were small, of limited treatment duration and had short follow-up. However, because of the low cost and absence of adverse effects it is reasonable to consider autoinflation whilst awaiting natural resolution of otitis media with effusion. Primary care could prove a beneficial place to evaluate such interventions and there is ongoing research in this area. Further research should also consider the duration of treatment, the long-term impact on developmental outcomes in children and additional quality of life outcome measures for children and families. PMID- 23728661 TI - Flavonoids for treating venous leg ulcers. AB - BACKGROUND: Venous leg ulcers are a major health burden: annually, in the UK alone, they contribute an estimated cost to the NHS of GBP 400 million. Flavonoids are a diverse group of naturally-occurring venotonic compounds that address certain microcirculatory parameters involved in venous leg ulcer pathophysiology. OBJECTIVES: To evaluate the clinical effects of flavonoids on the healing of venous leg ulcers. SEARCH METHODS: In February 2013 we searched the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 1); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. No date or language restrictions were applied. We checked reference lists of included trials, and contacted pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials (RCTs) that investigated the efficacy of any flavonoid-containing compound on venous leg ulcer healing in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for the review and disagreements were referred to a third author. All rejected articles were double-checked by a third author. Assessment of risk of bias and data extraction were performed independently by two authors, discrepancies were resolved by referring to the third author. MAIN RESULTS: Of the nine studies (1075 participants): five investigated Micronised Purified Flavonoid Fraction (MPFF), and four investigated hydroxyethylrutosides (HR).Meta-analysis involving 723 participants from five trials - four of which were characterised by poor reporting - showed more venous leg ulcers were healed in the MPFF groups than in the control groups (RR 1.36; 95% CI 1.07 to 1.74). However, the most rigorously conducted trial, which was at low risk of bias, did not show any additional benefit of MPFF (RR 0.94; 95% CI 0.73 to 1.22). Since this trial was unpublished, the possibility of publication bias in trials involving flavonoids must be acknowledged. Overall, the quality of reporting of trials on HR was also poor. Pooling three trials, all at unclear risk of bias, involving 279 participants showed a statistically significant effect in favour of HR with respect to number of ulcers healed (RR 1.70; 95% CI 1.24 to 2.34). AUTHORS' CONCLUSIONS: Although the overall estimate of the number of healed ulcers appeared to show a significant effect in favour of flavonoids (both MPFF and HR), this result needs to be interpreted cautiously, as most of these trials were poorly reported, and so had an unclear risk of bias for randomisation, allocation concealment, blinding and methods for addressing incomplete outcome data. There was also a possibility of publication bias. PMID- 23728662 TI - Duration of intravenous antibiotic therapy in people with cystic fibrosis. AB - BACKGROUND: Respiratory disease is the major cause of mortality and morbidity in cystic fibrosis (CF). Life expectancy of people with CF has increased dramatically in the last 40 years. One of the major reasons for this increase is the mounting use of antibiotics to treat chest exacerbations caused by bacterial infections. The optimal duration of intravenous antibiotic therapy is not clearly defined. Individuals usually receive intravenous antibiotics for 14 days, but treatment may range from 10 to 21 days. A shorter duration of antibiotic treatment risks inadequate clearance of infection which could lead to further lung damage. Prolonged courses of intravenous antibiotics are expensive and inconvenient and the incidence of allergic reactions to antibiotics also increases with prolonged courses. The use of aminoglycosides requires frequent monitoring to avoid some of their side effects. However, some organisms which infect people with CF are known to be multi-resistant to antibiotics, and may require a longer course of treatment. OBJECTIVES: To assess the optimal duration of intravenous antibiotic therapy for treating chest exacerbations in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings.Most recent search of the Group's Cystic Fibrosis Trials Register: 15 November 2012. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing different durations of intravenous antibiotic courses for acute respiratory exacerbations in people with CF, either with the same drugs at the same dosage, the same drugs at a different dosage or frequency or different antibiotics altogether, including studies with additional therapeutic agents. DATA COLLECTION AND ANALYSIS: No eligible trials were identified. MAIN RESULTS: No eligible trials were identified. AUTHORS' CONCLUSIONS: There are no clear guidelines on the optimum duration of intravenous antibiotic treatment. Duration of treatment is currently based on unit policies and response to treatment. Shorter duration of treatment should improve quality of life and compliance; result in a reduced incidence of drug reactions; and be less costly. However, this may not be sufficient to clear a chest infection and may result in an early recurrence of an exacerbation. This systematic review identifies the need for a multicentre, randomised controlled trial comparing different durations of intravenous antibiotic treatment as it has important clinical and financial implications. PMID- 23728663 TI - Pharmacological treatment of depression in patients with a primary brain tumour. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 3, 2010.Patients with a primary brain tumour often experience depression, for which drug treatment may be prescribed. However, these patients are also at high risk of epileptic seizures, cognitive impairment and fatigue, all of which are potential side effects of antidepressants. The benefit, or harm, of pharmacological treatment of depression in brain tumour patients is unclear. OBJECTIVES: To assess the benefits and harms of pharmacological treatment of depression in patients with a primary brain tumour. SEARCH METHODS: We updated the search to include the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 10), MEDLINE to October 2012, EMBASE to October 2012 and PsycINFO to October 2012. We searched the British Nursing Index, LILACS, PSYNDEX, the NHS National Research Register, the NHS Centre for Reviews and Dissemination's Database of Abstracts of Reviews of Effectiveness (DARE) and Web of Knowledge (covering Science Scisearch, Social Sciences Citation Index and Biological Abstracts) for the original review (to July 2009). In the original review we also handsearched Neuro-oncology, the Journal of Neuro oncology, the Journal of Neurology, Neurosurgery and Psychiatry and the Journal of Clinical Oncology (July 1999 to June 2009) and wrote to all the pharmaceutical companies manufacturing antidepressants for use in the UK. SELECTION CRITERIA: We searched for all randomised controlled trials (RCTs), controlled clinical trials, cohort studies and case-control studies of any pharmacological treatment of depression in patients with a histologically diagnosed primary brain tumour. DATA COLLECTION AND ANALYSIS: No studies met the inclusion criteria. MAIN RESULTS: We found no eligible studies evaluating the benefits of any pharmacological treatment of depression in brain tumour patients. AUTHORS' CONCLUSIONS: No high quality studies have examined the value of pharmacological treatment of depression in patients with a primary brain tumour. RCTs and detailed prospective studies are required to inform the effective pharmacological treatment of this common and important complication of brain tumours. Since the last version of this review none of the new relevant studies have provided additional information to change these conclusions. PMID- 23728664 TI - Hematopoietic stem cell transplantation for people with sickle cell disease. AB - BACKGROUND: Sickle cell disease is a genetic disorder involving a defect in the red blood cells due to its sickled hemoglobin. The main therapeutic interventions include preventive and supportive measures. Hematopoietic stem cell transplantations are carried out with the aim of replacing the defective cells and their progenitors (hematopoietic (i.e. blood forming) stem cells) in order to correct the disorder. OBJECTIVES: To determine whether stem cell transplantation can improve survival and prevent symptoms and complications associated with sickle cell disease. To examine the risks of stem cell transplantation against the potential long-term gain for people with sickle cell disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Group's Haemoglobinopathies Trials Register complied from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library) and quarterly searches of MEDLINE.Unpublished work was identified by searching the abstract books of major conference proceedings and we conducted a search of the website: www.ClinicalTrials.gov.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 16 August 2012. SELECTION CRITERIA: Randomized controlled and quasi-randomized studies that compared any method of stem cell transplantation with either each other or with any of the preventive or supportive interventions (e.g. periodic blood transfusion, use of hydroxyurea, antibiotics, pain relievers, supplemental oxygen) in people with sickle cell disease irrespective of the type of sickle cell disease, gender and setting. DATA COLLECTION AND ANALYSIS: No relevant trials were identified. MAIN RESULTS: Ten trials were identified by the initial search and none for the update. None of these trials were suitable for inclusion in this review. AUTHORS' CONCLUSIONS: Reports on the use of hematopoietic stem cell transplantation improving survival and preventing symptoms and complications associated with sickle cell disease are currently limited to observational and other less robust studies. No randomized controlled trial assessing the benefit or risk of hematopoietic stem cell transplantations was found. Thus, this systematic review identifies the need for a multicentre randomized controlled trial assessing the benefits and possible risks of hematopoietic stem cell transplantations comparing sickle status and severity of disease in people with sickle cell disease. PMID- 23728666 TI - Interventions for clinical and subclinical hypothyroidism pre-pregnancy and during pregnancy. AB - BACKGROUND: Over the last decade there has been enhanced awareness of the appreciable morbidity of thyroid dysfunction, particularly thyroid deficiency. Since treating clinical and subclinical hypothyroidism may reduce adverse obstetric outcomes, it is crucial to identify which interventions are safe and effective. OBJECTIVES: To identify interventions used in the management of hypothyroidism and subclinical hypothyroidism pre-pregnancy or during pregnancy and to ascertain the impact of these interventions on important maternal, fetal, neonatal and childhood outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-randomised controlled trials that compared a pharmacological intervention for hypothyroidism and subclinical hypothyroidism pre-pregnancy or during pregnancy with another intervention or placebo. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and quality and extracted the data. MAIN RESULTS: We included four RCTs of moderate risk of bias involving 362 women. In one trial of 115 women, levothyroxine therapy to treat pregnant euthyroid (normal thyroid function) women with thyroid peroxidase antibodies was not shown to reduce pre eclampsia significantly (risk ratio (RR) 0.61; 95% confidence interval (CI) 0.11 to 3.48) but did significantly reduce preterm birth by 72% (RR 0.28; 95% CI 0.10 to 0.80). Two trials of 30 and 48 hypothyroid women respectively compared levothyroxine doses, but both trials reported only biochemical outcomes. A trial of 169 women compared the trace element selenomethionine (selenium) with placebo and no significant differences were seen for either pre-eclampsia (RR 1.44; 95% CI 0.25 to 8.38) or preterm birth (RR 0.96; 95% CI 0.20 to 4.61). None of the four trials reported on childhood neurodevelopmental delay.There was a non significant trend towards fewer miscarriages with levothyroxine, and selenium showed some favourable impact on postpartum thyroid function and a decreased incidence of moderate to advanced postpartum thyroiditis. AUTHORS' CONCLUSIONS: This review found no difference between levothyroxine therapy and a control for treating pregnant euthyroid women with thyroid peroxidase antibodies for the outcome of pre-eclampsia, however a reduction in preterm birth and a trend towards reduced miscarriage with levothyroxine was shown. This review also showed no difference for pre-eclampsia or preterm birth when selenium was compared with placebo, however a promising reduction in postpartum thyroiditis was shown. Childhood neurodevelopmental delay was not assessed by any trial included in the review.Given that this review is based on four trials of moderate risk of bias, with only two trials contributing data (n = 284), there is insufficient evidence to recommend the use of one intervention for clinical or subclinical hypothyroidism pre-pregnancy or during pregnancy over another, for improving maternal, fetal, neonatal and childhood outcomes. PMID- 23728665 TI - Acupuncture for treating fibromyalgia. AB - BACKGROUND: One in five fibromyalgia sufferers use acupuncture treatment within two years of diagnosis. OBJECTIVES: To examine the benefits and safety of acupuncture treatment for fibromyalgia. SEARCH METHODS: We searched CENTRAL, PubMed, EMBASE, CINAHL, National Research Register, HSR Project and Current Contents, as well as the Chinese databases VIP and Wangfang to January 2012 with no language restrictions. SELECTION CRITERIA: Randomised and quasi-randomised studies evaluating any type of invasive acupuncture for fibromyalgia diagnosed according to the American College of Rheumatology (ACR) criteria, and reporting any main outcome: pain, physical function, fatigue, sleep, total well-being, stiffness and adverse events. DATA COLLECTION AND ANALYSIS: Two author pairs selected trials, extracted data and assessed risk of bias. Treatment effects were reported as standardised mean differences (SMD) and 95% confidence intervals (CI) for continuous outcomes using different measurement tools (pain, physical function, fatigue, sleep, total well-being and stiffness) and risk ratio (RR) and 95% CI for dichotomous outcomes (adverse events). We pooled data using the random effects model. MAIN RESULTS: Nine trials (395 participants) were included. All studies except one were at low risk of selection bias; five were at risk of selective reporting bias (favouring either treatment group); two were subject to attrition bias (favouring acupuncture); three were subject to performance bias (favouring acupuncture) and one to detection bias (favouring acupuncture). Three studies utilised electro-acupuncture (EA) with the remainder using manual acupuncture (MA) without electrical stimulation. All studies used 'formula acupuncture' except for one, which used trigger points.Low quality evidence from one study (13 participants) showed EA improved symptoms with no adverse events at one month following treatment. Mean pain in the non-treatment control group was 70 points on a 100 point scale; EA reduced pain by a mean of 22 points (95% confidence interval (CI) 4 to 41), or 22% absolute improvement. Control group global well-being was 66.5 points on a 100 point scale; EA improved well-being by a mean of 15 points (95% CI 5 to 26 points). Control group stiffness was 4.8 points on a 0 to 10 point; EA reduced stiffness by a mean of 0.9 points (95% CI 0.1 to 2 points; absolute reduction 9%, 95% CI 4% to 16%). Fatigue was 4.5 points (10 point scale) without treatment; EA reduced fatigue by a mean of 1 point (95% CI 0.22 to 2 points), absolute reduction 11% (2% to 20%). There was no difference in sleep quality (MD 0.4 points, 95% CI -1 to 0.21 points, 10 point scale), and physical function was not reported.Moderate quality evidence from six studies (286 participants) indicated that acupuncture (EA or MA) was no better than sham acupuncture, except for less stiffness at one month. Subgroup analysis of two studies (104 participants) indicated benefits of EA. Mean pain was 70 points on 0 to 100 point scale with sham treatment; EA reduced pain by 13% (5% to 22%); (SMD 0.63, 95% CI -1.02 to -0.23). Global well-being was 5.2 points on a 10 point scale with sham treatment; EA improved well-being: SMD 0.65, 95% CI 0.26 to 1.05; absolute improvement 11% (4% to 17%). EA improved sleep, from 3 points on a 0 to 10 point scale in the sham group: SMD 0.40 (95% CI 0.01 to 0.79); absolute improvement 8% (0.2% to 16%). Low-quality evidence from one study suggested that MA group resulted in poorer physical function: mean function in the sham group was 28 points (100 point scale); treatment worsened function by a mean of 6 points (95% CI -10.9 to -0.7). Low-quality evidence from three trials (289 participants) suggested no difference in adverse events between real (9%) and sham acupuncture (35%); RR 0.44 (95% CI 0.12 to 1.63).Moderate quality evidence from one study (58 participants) found that compared with standard therapy alone (antidepressants and exercise), adjunct acupuncture therapy reduced pain at one month after treatment: mean pain was 8 points on a 0 to 10 point scale in the standard therapy group; treatment reduced pain by 3 points (95% CI -3.9 to -2.1), an absolute reduction of 30% (21% to 39%). Two people treated with acupuncture reported adverse events; there were none in the control group (RR 3.57; 95% CI 0.18 to 71.21). Global well-being, sleep, fatigue and stiffness were not reported. Physical function data were not usable.Low quality evidence from one study (38 participants) showed a short-term benefit of acupuncture over antidepressants in pain relief: mean pain was 29 points (0 to 100 point scale) in the antidepressant group; acupuncture reduced pain by 17 points (95% CI -24.1 to 10.5). Other outcomes or adverse events were not reported.Moderate-quality evidence from one study (41 participants) indicated that deep needling with or without deqi did not differ in pain, fatigue, function or adverse events. Other outcomes were not reported.Four studies reported no differences between acupuncture and control or other treatments described at six to seven months follow-up.No serious adverse events were reported, but there were insufficient adverse events to be certain of the risks. AUTHORS' CONCLUSIONS: There is low to moderate-level evidence that compared with no treatment and standard therapy, acupuncture improves pain and stiffness in people with fibromyalgia. There is moderate-level evidence that the effect of acupuncture does not differ from sham acupuncture in reducing pain or fatigue, or improving sleep or global well-being. EA is probably better than MA for pain and stiffness reduction and improvement of global well-being, sleep and fatigue. The effect lasts up to one month, but is not maintained at six months follow-up. MA probably does not improve pain or physical functioning. Acupuncture appears safe. People with fibromyalgia may consider using EA alone or with exercise and medication. The small sample size, scarcity of studies for each comparison, lack of an ideal sham acupuncture weaken the level of evidence and its clinical implications. Larger studies are warranted. PMID- 23728667 TI - Quetiapine versus typical antipsychotic medications for schizophrenia. AB - BACKGROUND: Quetiapine is a widely used atypical antipsychotic drug for schizophrenia that has been on the market for over a decade. However, It is not clear how the effects of quetiapine differ from typical antipsychotics. OBJECTIVES: To review the effects of quetiapine in comparison with typical antipsychotics in the treatment of schizophrenia and schizophrenia-like psychosis. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (March 2010), and inspected references of all identified studies. SELECTION CRITERIA: We included all randomised control trials comparing oral quetiapine with typical antipsychotic drugs in people with schizophrenia or schizophrenia-like psychosis. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data, we calculated risk ratio (RR) and 95% confidence intervals (CI) using a random-effects model. We presented chosen outcomes in a 'Summary of findings' table and comparative risks where appropriate. For continuous data, we calculated mean differences (MD) based on a random-effects model. We assessed risk of bias for included studies. MAIN RESULTS: The review includes 43 randomised controlled trials (RCTs) with 7217 participants. Most studies were from China. The percentages of participants leaving the studies early were similar (36.5% in quetiapine group and 36.9% in typical antipsychotics group) and no significant difference between groups was apparent for leaving early due to any reason (23 RCTs n = 3576 RR 0.91 CI 0.81 to 1.01, moderate quality evidence), however, fewer participants in the quetiapine group left the studies early due to adverse events (15 RCTs, n = 3010, RR 0.48 CI 0.30 to 0.77).Overall global state was similar between groups (no clinically significant response; 16 RCTs, n = 1607, RR 0.96 CI 0.75 to 1.23, moderate quality evidence) and there was no significant difference in positive symptoms (PANSS positive subscore: 22 RCTs, n = 1934, MD 0.02 CI -0.39 to 0.43, moderate quality evidence). General psychopathology was equivocal (PANSS general psychopathology subscore: 18 RCTs, n = 1569, MD -0.20 CI -0.83 to 0.42) between those allocated to quetiapine and typical antipsychotics. However, quetiapine was statistically significantly more efficacious for negative symptoms (PANSS negative subscore: 22 RCTs, n = 1934, MD -0.82 CI -1.59 to -0.04, moderate quality evidence), however, this result was highly heterogeneous and driven by two small outlier studies with high effect sizes. Without these two studies, there was no heterogeneity and no statistically significant difference between quetiapine and typical antipsychotics.Compared with typical antipsychotics, quetiapine might cause fewer adverse effects (9 RCTs, n = 1985, RR 0.76 CI 0.64 to 0.90 number needed to treat to induce harm (NNTH) 10, CI 8 to 17), less abnormal ECG (2 RCTs, n = 165, RR 0.38 CI 0.16 to 0.92, NNTH 8, CI 4 to 55), fewer overall extrapyramidal effects (8 RCTs, n = 1,095, RR 0.17 CI 0.09 to 0.32, NNTH 3, CI 3 to 3, moderate quality evidence) and fewer specific extrapyramidal effects including akathisia, parkinsonism, dystonia and tremor. Moreover, it might cause lower prolactin level (4 RCTs, n = 1034, MD -16.20 CI -23.34 to 9.07, moderate quality evidence) and less weight gain compared with some typical antipsychotics in the short term (9 RCTs, n = 866, RR 0.52 CI 0.34 to 0.80, NNTH 8, CI 6 to 15).However, there was no significant difference between the two groups in suicide attempt, suicide, death, QTc prolongation, low blood pressure, tachycardia, sedation, gynaecomastia, galactorrhoea, menstrual irregularity and white blood cell count. AUTHORS' CONCLUSIONS: Quetiapine may not differ from typical antipsychotics in the treatment of positive symptoms and general psychopathology. There are no clear differences in terms of the treatment of negative symptoms. However, it causes fewer adverse effects in terms of abnormal ECG, extrapyramidal effects, abnormal prolactin levels and weight gain. PMID- 23728668 TI - Cervical pessary for preventing preterm birth. AB - BACKGROUND: Preterm birth is a major health problem and contributes to more than 50% of the overall perinatal mortality. Preterm birth has multiple risk factors including cervical incompetence and multiple pregnancy. Different management strategies have been tried to prevent preterm birth, including cervical cerclage. Cervical cerclage is an invasive technique that needs anaesthesia and may be associated with complications. Moreover, there is still controversy regarding the efficacy and the group of patients that could benefit from this operation. Cervical pessary has been tried as a simple, non-invasive alternative that might replace the above invasive cervical stitch operation to prevent preterm birth. OBJECTIVES: To evaluate the efficacy of cervical pessary for the prevention of preterm birth in women with risk factors for cervical incompetence. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 September 2012), Current Controlled Trials and the Australian New Zealand Clinical Trials Registry (1 September 2012). SELECTION CRITERIA: We selected all published and unpublished randomised clinical trials comparing the use of cervical pessary with cervical cerclage or expectant management for prevention of preterm birth. We did not include quasi-randomised trials. Cluster randomised or cross-over trials were not eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion. MAIN RESULTS: The review included one randomised controlled trial. The study included 385 pregnant women with a short cervix of 25 mm or less who were between 18 to 22 weeks of pregnancy. The use of cervical pessary (192 women) was associated with a statistically significantly decrease in the incidence of spontaneous preterm birth less than 37 weeks' gestation compared with expectant management (22% versus 59 %; respectively, risk ratio (RR) 0.36, 95% confidence interval (CI) 0.27 to 0.49). Spontaneous preterm birth before 34 weeks was statistically significantly reduced in the pessary group (6% and 27% respectively, RR 0.24; 95% CI 0.13 to 0.43). Mean gestational age at delivery was 37.7 + 2 weeks in the pessary group and 34.9 + 4 weeks in the expectant group. Women in the pessary group used less tocolytics (RR 0.63; 95% CI 0.50 to 0.81) and corticosteroids (RR 0.66; 95% CI 0.54 to 0.81) than the expectant group. Vaginal discharge was more common in the pessary group (RR 2.18; 95% CI 1.87 to 2.54). Among the pessary group, 27 women needed pessary repositioning without removal and there was one case of pessary removal. Ninety-five per cent of women in the pessary group would recommend this intervention to other people. Neonatal paediatric care admission was reduced in the pessary group in comparison to the expectant group (RR 0.17; 95% CI 0.07 to 0.42). AUTHORS' CONCLUSIONS: The review included only one well-designed randomised clinical trial that showed beneficial effect of cervical pessary in reducing preterm birth in women with a short cervix. There is a need for more trials in different settings (developed and developing countries), and with different risk factors including multiple pregnancy. PMID- 23728669 TI - Beta-blockers for preventing stroke recurrence. AB - BACKGROUND: Stroke affects 15 million people per year worldwide. Despite recent developments in acute stroke treatment, prevention remains very important. Stroke has a high rate of recurrence; therefore secondary prevention is also important. Many clinical approaches to control risk factors have been proposed. One of these approaches is the prescription of beta-blockers that have effects beyond the reduction of blood pressure, which can reduce the recurrence of stroke. OBJECTIVES: To evaluate the efficacy of beta-blockers for preventing stroke recurrence and for reducing death and major vascular events in people with a previous stroke or transient ischaemic attack (TIA), and to determine their safety, particularly with regard to the development of diabetes mellitus. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews (CDSR) (The Cochrane Library 2011, Issue 12), the Database of Abstracts of Reviews of Effects (DARE) (December 2011), MEDLINE (1966 to December 2011), EMBASE (1980 to December 2011), and Latin American and Caribbean Health Sciences Literature (LILACS) (1982 to December 2011). We also searched ongoing trials registers and reference lists. SELECTION CRITERIA: Randomised controlled trials (RCTs) that included participants with previous stroke or TIA due to arterial thrombosis or embolism.The intervention was any beta-blocker versus control, or beta-blocker plus other treatment versus other treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the trials identified, appraised quality, and extracted data. MAIN RESULTS: We included two RCTs involving 2193 participants in the review. Both studies randomised participants to either beta-blocker (atenolol 5 mg) or placebo. No statistical differences were noted among the groups in risks of fatal and non-fatal stroke (risk ratio (RR) 0.94, 95% confidence interval (CI) 0.75 to 1.17). For all other outcomes analysed (death from all causes, cardiac death, non fatal myocardial infarction, major vascular events), we observed no significant differences between the groups. AUTHORS' CONCLUSIONS: To date, no available evidence supports the routine use of beta-blockers for secondary prevention after stroke or TIA. More studies with larger samples are needed. PMID- 23728670 TI - Combination inhaled steroid and long-acting beta2-agonist versus tiotropium for chronic obstructive pulmonary disease. AB - BACKGROUND: Combination therapy (inhaled corticosteroids and long-acting beta2 agonists) and tiotropium are both used in the treatment of chronic obstructive pulmonary disease (COPD). There is uncertainty about the relative benefits and harms of these treatments. OBJECTIVES: To compare the relative effects of inhaled combination therapy and tiotropium on markers of exacerbations, symptoms, quality of life, lung function, pneumonia and serious adverse events in patients with chronic obstructive pulmonary disease. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (November 2012) and reference lists of articles. We also contacted authors of the studies. SELECTION CRITERIA: We included only parallel, randomised controlled trials comparing inhaled combination corticosteroid and long-acting beta2-agonist against inhaled tiotropium bromide. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion and then extracted data on trial quality and outcome results. We contacted study authors for additional information. We resolved discrepancies through discussion. MAIN RESULTS: One large, two-year trial (INSPIRE) and two smaller, shorter trials on a total of 1528 participants were found. The results from these trials were not pooled. The number of withdrawals from each arm of the INSPIRE trial was large and imbalanced and outcome data were not collected for patients who withdrew, raising concerns about the reliability of data from this study.In INSPIRE, there were more deaths on tiotropium than on fluticasone/salmeterol (Peto odds ratio (OR) 0.55; 95% confidence interval (CI) 0.33 to 0.93). This was a statistically significant difference, however the number of withdrawals from each of the arms was 11 times larger than the observed number of deaths for participants on fluticasone/salmeterol and seven times larger for participants on tiotropium. There were more all-cause hospital admissions in patients on fluticasone/salmeterol than those on tiotropium in INSPIRE (Peto OR 1.32; 95% CI 1.04 to 1.67). There was no statistically significant difference in hospital admissions due to exacerbations, the primary outcome of INSPIRE. There was no significant difference in exacerbations in patients on fluticasone/salmeterol compared to tiotropium when compared as either an odds ratio or a rate ratio (mean number of exacerbations per patient per year). Exacerbations requiring treatment with oral corticosteroids were less frequent in patients on fluticasone/salmeterol (rate ratio 0.81; 95% CI 0.67 to 0.99). Conversely exacerbations requiring treatment with antibiotics were more frequent in patients treated with fluticasone/salmeterol (rate ratio 1.19; 95% CI 1.02 to 1.38). There were more cases of pneumonia in patients on fluticasone/salmeterol than in those on tiotropium (Peto OR 2.13; 95% CI 1.33 to 3.40). Confidence intervals for these outcomes do not reflect the additional uncertainty arising from unknown outcome data for patients who withdrew. AUTHORS' CONCLUSIONS: Since the proportion of missing outcome data compared to the observed outcome data is enough to induce a clinically relevant bias in the intervention effect, the relative efficacy and safety of combined inhalers and tiotropium remains uncertain. Further large, long term randomised controlled trials comparing combination therapy to tiotropium are required, including adequate follow-up of all participants randomised (similar to the procedures undertaken in TORCH and UPLIFT). Additional studies comparing alternative inhaled long-acting beta2-agonist/steroid combination therapies with tiotropium are also required. PMID- 23728671 TI - Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction, and lower esophagus. AB - BACKGROUND: The outcome of patients with locally advanced gastroesophageal adenocarcinoma (adenocarcinoma of the esophagus, gastroesophageal (GE) junction, and stomach) is poor. There is conflicting evidence regarding the effects of perioperative chemotherapy on survival and other outcomes. OBJECTIVES: To assess the effect of perioperative chemotherapy for gastroesophageal adenocarcinoma on survival and other clinically relevant outcomes in the overall population of participants in randomized controlled trials (RCTs) and in prespecified subgroups. SEARCH METHODS: We performed computerized searches in the Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Review of Effectiveness (DARE), the Cochrane Database of Systematic Reviews (CDSR) from The Cochrane Library, MEDLINE (1966 to May 2011), EMBASE (1980 to May 2011), and LILACS (Literatura Latinoamericana y del Caribe en Ciencias de la Salud), combining the Cochrane highly sensitive search strategy with specific search terms. Moreover, we handsearched several online databases, conference proceedings, and reference lists of retrieved papers. SELECTION CRITERIA: We included RCTs which randomized patients with gastroesophageal adenocarcinoma, in the absence of distant metastases, to receive either chemotherapy with or without radiotherapy followed by surgery, or surgery alone. DATA COLLECTION AND ANALYSIS: Two independent review authors identified eligible trials. We solicited individual patient data (IPD) from all selected trials. We performed meta analyses based on intention-to-treat populations using the two-stage method to combine IPD with aggregate data from RCTs for which IPD were unavailable. We combined data from all trials providing IPD in a Cox proportional hazards model to assess the effect of several covariables on overall survival. MAIN RESULTS: We identified 14 RCTs with 2422 eligible patients. For eight RCTs with 1049 patients (43.3%), we were able to obtain IPD. Perioperative chemotherapy was associated with significantly longer overall survival (hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.73 to 0.89). This corresponds to a relative survival increase of 19% or an absolute survival increase of 9% at five years. This survival advantage was consistent across most subgroups. There was a trend towards a more pronounced treatment effect for tumors of the GE junction compared to other sites, and for combined chemoradiotherapy as compared to chemotherapy in tumors of the esophagus and GE junction. Resection with negative margins was a strong predictor of survival. Multivariable analysis showed that tumor site, performance status, and age have an independent significant effect on survival. Moreover, there was a significant interaction of the effect of perioperative chemotherapy with age (larger treatment effect in younger patients). Perioperative chemotherapy also showed a significant effect on several secondary outcomes. It was associated with longer disease-free survival, higher rates of R0 resection, and more favorable tumor stage upon resection, while there was no association with perioperative morbidity and mortality. AUTHORS' CONCLUSIONS: Perioperative chemotherapy for resectable gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should thus be offered to all eligible patients. There is a trend to a larger survival advantage for tumors of the GE junction as compared to other sites and for chemoradiotherapy as compared to chemotherapy in esophageal and GE junction tumors. Likewise, there is an interaction between age and treatment effect, with younger patients having a larger survival advantage, and no survival advantage for elderly patients. PMID- 23728672 TI - Antenatal immunoglobulin for fetal red blood cell alloimmunization. AB - BACKGROUND: Red blood cell alloimmunization in pregnancy can lead to fetal anaemia with potentially disastrous consequences. Traditional management involves the use of intrauterine transfusion, which is associated with significant procedure-related risks. An alternative treatment that has been trialled is the use of immunoglobulin administered intravenously to the mother. OBJECTIVES: The objective of this review was to assess the efficacy and safety of the use of intravenous immunoglobulin antenatally to women with severe fetal red blood cell alloimmunization. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group trials register (19 December 2012), and reference lists of articles. SELECTION CRITERIA: Randomized trials assessing the antenatal use of intravenous immunoglobulin administered at any dose, frequency or duration with a control group (using any other, or no treatment) in the management of fetal red blood cell alloimmunization. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the available evidence. MAIN RESULTS: There are no included studies. AUTHORS' CONCLUSIONS: No information is available from randomized trials to indicate whether the antenatal use of intravenous immunoglobulin is effective in the management of fetal red blood cell alloimmunization. Several case series suggest a beneficial role in delaying the onset of fetal anaemia requiring invasive intrauterine transfusion. PMID- 23728673 TI - Early versus delayed mobilisation for aneurysmal subarachnoid haemorrhage. AB - BACKGROUND: Rebleeding is an important cause of death and disability in patients with aneurysmal subarachnoid haemorrhage (SAH). In order to prevent rebleeding, the preferred strategy is aneurysm ablation (removal) as early as possible. However, in clinical practice some patients are not suitable for surgical treatment, or prefer conservative treatments. In some countries, therefore, total bedrest for four to six weeks has been considered one of the basic interventions to avoid rebleeding. However, the influence of bedrest on outcome in patients with SAH is not well known. OBJECTIVES: To establish whether early mobilisation (less than four weeks after symptom onset) compared with delayed mobilisation (defined as patients staying in bed for at least four weeks after symptom onset) in patients with aneurysmal subarachnoid haemorrhage (SAH), who have not had or could not have any surgical treatment for the aneurysm, will increase the proportion of deaths from rebleeding. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (May 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 6), the Chinese Stroke Trials Register (May 2012), MEDLINE (1950 to June 2012), EMBASE (1980 to June 2012), Web of Science Conference Proceedings (1990 to May 2012), CINAHL (1982 to June 2012), AMED (1985 to June 2012), PEDro (May 2012), REHABDATA (May 2012) and CIRRIE Database of International Rehabilitation Research (May 2012). In addition, we searched five Chinese databases, ongoing trials registers and relevant reference lists. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) comparing early mobilisation (within four weeks after symptom onset) with delayed mobilisation (after four weeks). DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and exclusion. We resolved disagreements by discussion. MAIN RESULTS: In the absence of any suitable RCTs addressing this topic, we were unable to perform a meta analysis. Data from recent observational studies suggested the period of greatest risk for rebleeding occurs more frequently in the early period, especially within 24 hours of the initial SAH. The impact of bedrest on aneurysm care should be clarified. AUTHORS' CONCLUSIONS: There are no RCTs or controlled trials that provide evidence for, or against, staying in bed for at least four weeks after symptom onset in patients with aneurysmal SAH, who have not had, or could not have, surgical treatment for the aneurysm. Treatment strategies to reduce the risk of rebleeding in SAH patients before aneurysm ablation, or in those not suitable for surgical treatment, or who prefer conservative treatments, deserve attention. PMID- 23728674 TI - Airway clearance techniques for bronchiectasis. AB - BACKGROUND: People with non-cystic fibrosis bronchiectasis commonly experience chronic cough and sputum production and these features may be associated with progressive decline in clinical status. Airway clearance techniques (ACTs) are often prescribed to facilitate expectoration of sputum from the lungs, but the efficacy of these techniques in a stable clinical state or during an acute exacerbation of bronchiectasis is unclear. OBJECTIVES: Primary: to determine the effects of ACTs on the rate of acute exacerbations, incidence of hospitalisation and health-related quality of life in individuals with acute and stable bronchiectasis.Secondary: to determine whether a) ACTs are safe for individuals with acute and stable bronchiectasis and b) ACTs have beneficial effects on physiology and symptoms in individuals with acute and stable bronchiectasis. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials from inception to October 2012, PEDro in October 2012 and handsearched relevant journals. SELECTION CRITERIA: Randomised controlled parallel and cross over trials that compared an ACT to no treatment, sham ACT or directed coughing in participants with bronchiectasis. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: Five studies involving 51 participants met the inclusion criteria of the review, all of which were cross-over design. Four studies were on adults with stable bronchiectasis, and the other study was on clinically stable children with bronchiectasis. Three studies were single treatment sessions, two were longer term studies. The interventions varied and some control groups received a sham intervention while others were inactive. The methodological quality of the studies was variable and the studies were not able to blind participants and personal. Heterogeneity between studies precluded these data from meta-analysis and the review was therefore narrative.One study on 20 adults comparing an airway oscillatory device with no treatment found no significant difference in the number of exacerbations at 12 weeks (low-quality evidence). No data were available to assess the impact of ACTs on the time to exacerbation, duration of, incidence of hospitalisation or total number of hospitalised days. The same study reported clinically significant improvements in health-related quality of life in both disease-specific and cough-related measures. While based on a small number of participants and the data were skewed, the median difference in the change in total St George's Respiratory Questionnaire (SGRQ) score over three months in this study was 8.5 units (P value = 0.005 (Wilcoxon), low-quality evidence). Two studies reported mean increases in volume of sputum expectorated with airway oscillatory devices in the short term of 8.4 mL (95% CI 3.4 to 13.4 mL) and in the long term of 3 mL (P value = 0.02), with no significant effect on lung function. One study reported an immediate reduction in pulmonary hyperinflation in adults with non-positive expiratory pressure (PEP) ACTs (difference in functional residual capacity (FRC) of 19%, P value < 0.05) and with airway oscillatory devices (difference in FRC of 30%, P value < 0.05) compared to no ACTs. A similar decrease in pulmonary hyperinflation (difference in FRC of 6%) was found in children using an airway oscillatory device for 3 months compared to sham therapy. No studies reported on the effects of gas exchange, people's symptoms or antibiotic usage. AUTHORS' CONCLUSIONS: ACTs appear to be safe for individuals (adults and children) with stable bronchiectasis, where there may be improvements in sputum expectoration, selected measures of lung function and health-related quality of life. The role of these techniques in people with an acute exacerbation of bronchiectasis is unknown. In view of the chronic nature of bronchiectasis, more data are needed to establish the clinical value of ACTs over the short and long term on patient-important outcomes, including symptoms, on physiological outcomes which may clarify the rationale for each technique and on long-term parameters that impact on disease progression in individuals with stable bronchiectasis. This is necessary in order to provide further guidance of specific ACT prescription for people with bronchiectasis. It may also be important to establish the comparative effect of different types of ACTs in people with bronchiectasis. PMID- 23728675 TI - Continuous versus intermittent physiological monitoring for acute stroke. AB - BACKGROUND: Explanations for the effectiveness of stroke units compared with general wards in reducing mortality, institutionalisation and dependence of people with stroke remain undetermined, and the discussion on the most effective stroke unit model is still up for debate. The intensity of non-invasive mechanical monitoring in many western countries is one of the main issues regarding the different models. This is because of its strong impact on the organisation of the stroke unit in terms of the number of personnel, their expertise, the infrastructure and costs. OBJECTIVES: To assess whether continuous intensive monitoring compared with intermittent monitoring of physiological variables in people with acute stroke can change their prognosis in terms of mortality or disability. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (November 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 8), MEDLINE (1966 to November 2012), EMBASE (1980 to November 2012), CINAHL (1982 to November 2012) and the British Nursing Index (1985 to November 2012). In an effort to identify further published, unpublished and ongoing trials we searched trials registers (November 2012) and reference lists, handsearched conference proceedings and contacted trial authors. SELECTION CRITERIA: We included all randomised, cluster randomised and quasi-randomised controlled trials comparing continuous monitoring with intermittent monitoring in people within three days of stroke onset. We excluded studies confounded by the delivery of care in different settings (that is studies in which the location of the intervention was not in the same ward in the two arms of the trial). DATA COLLECTION AND ANALYSIS: Three review authors independently selected studies for inclusion, assessed methodological quality and extracted data. We sought original data from trialists in two trials and verified the inclusion criteria in another four trials (three presented at conferences and one was from the Chinese Clinical Trial Registry). Where possible, we extracted data on the threshold level of abnormality that triggered intervention for a given physiological variable, the specific intervention given to correct the abnormality and compliance with the allocated therapy. MAIN RESULTS: Three studies, involving a total of 354 participants, met our inclusion criteria for the primary outcome. Compared with intermittent monitoring, continuous monitoring significantly reduced death and disability at three months or discharge (odds ratio (OR) 0.27, 95% confidence interval (CI) 0.13 to 0.56) and was associated with a non-significant reduction in deaths from any cause at discharge (OR 0.72, 95% CI 0.28 to 1.85). These significant results depend on one study that has a high risk of bias.Continuous monitoring was associated with a non-significant reduction of dependency (OR 0.79, 95% CI 0.30 to 2.06), death from vascular causes (OR 0.48, 95% CI 0.10 to 2.39), neurological complications (OR 0.81, 95% CI 0.46 to 1.43), length of stay (mean difference (MD) -5.24, 95% CI -10.51 to 0.03) and institutionalisation (OR 0.83, 95% CI 0.04 to 15.72) (secondary outcomes). For the last two outcomes we detected consistent heterogeneity across trials.Cardiac complications (OR 8.65, 95% CI 2.52 to 29.66), fever (OR 2.17, 95% CI 1.22 to 3.84) and hypotension (OR 4.32, 95% CI 1.68 to 14.38) were detected significantly more often in participants who received continuous monitoring (surrogate outcomes).We detected no significant increase in adverse events due to immobility (pneumonia, other infections or deep vein thrombosis) in participants who were continuously monitored compared with those allocated to intermittent monitoring. AUTHORS' CONCLUSIONS: Continuous monitoring of physiological variables for the first two to three days may improve outcomes and prevent complications. Attention to the changes in physiological variables is a key feature of a stroke unit, and can most likely be aided by continuous monitoring without complications related to immobility or to treatments triggered by the relief of abnormal physiological variables. Well-designed, high-quality studies are needed because many questions remain open and deserve further research. These include when to start continuous monitoring, when to interrupt it, which people should be given priority, and which treatments are most appropriate after the identification of abnormalities in physiological variables. PMID- 23728676 TI - Repetitive transcranial magnetic stimulation for the treatment of amyotrophic lateral sclerosis or motor neuron disease. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a progressive neurodegenerative disease without effective therapies. Several studies have suggested that repetitive transcranial magnetic stimulation (rTMS) may have positive benefit in ALS. However, the efficacy and safety of this therapy remain uncertain. This is the first update of a review published in 2011. OBJECTIVES: To determine the clinical efficacy and safety of rTMS for treating ALS. SEARCH METHODS: On 30 July 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2012, issue 7 in The Cochrane Library), MEDLINE (1966 to July 2012), EMBASE (1980 to July 2012), CINAHL (1937 to July 2012), Science Citation Index Expanded (January 1945 to July 2012), AMED (January 1985 to July 2012). We searched the Chinese Biomedical Database (1979 to August 2012). We also searched for ongoing studies on clinicaltrials.gov (August 2012). SELECTION CRITERIA: Randomised and quasi randomised controlled trials assessing the therapeutic efficacy and safety of rTMS for patients with a clinical diagnosis of ALS.Comparisons eligible for inclusion were:1. rTMS versus no intervention;2. rTMS versus sham rTMS;3. rTMS versus physiotherapy;4. rTMS versus medications;5. rTMS + other therapies or drugs versus sham rTMS + the same therapies or drugs;6. different methods of application of rTMS such as high-frequency (> 1Hz) compared to low-frequency (<= 1Hz) rTMS. DATA COLLECTION AND ANALYSIS: Two authors independently selected papers, assessed risk of bias and extracted data. We resolved disagreements through discussion. We contacted study authors for additional information. MAIN RESULTS: Three randomised, placebo-controlled trials with a total of 50 participants were included in the review. All three trials compared rTMS with sham TMS. All the trials were of poor methodological quality and were insufficiently homogeneous to allow the pooling of results. Moreover, the high rate of attrition further increased the risk of bias. None of the trials provided detailed data on the ALS Functional Rating Scale-Revised (ALSFRS-R) scores at six months follow-up which was pre-assigned as our primary outcome. One trial contained data in a suitable form for quantitative analysis of our secondary outcomes. No difference was seen between rTMS and sham rTMS using the ALSFRS-R scores and manual muscle testing (MMT) scores at 12 months follow-up in this trial. Additionally, none of the trials reported any adverse events associated with the use of rTMS. However, in view of the small sample size, the methodological limitations and incomplete outcome data, treatment with rTMS cannot be judged as completely safe. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to draw conclusions about the efficacy and safety of rTMS in the treatment of ALS. Further studies may be helpful if their potential benefit is weighed against the impact of participation in a randomised controlled trial on people with ALS. PMID- 23728677 TI - Antidepressants for polycystic ovary syndrome. AB - BACKGROUND: The prevalence of depression in women with polycystic ovary syndrome (PCOS) is high; one study has shown it to be four times that of women without PCOS. Therefore, systematic evaluation of the effectiveness and safety of antidepressants for women with PCOS is important. OBJECTIVES: To evaluate the effectiveness and safety of antidepressants in treating depression and other symptoms in women with PCOS. SEARCH METHODS: We searched the following databases from inception to June 2012: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, PsycINFO and Chinese National Knowledge Infrastructure, the metaRegister of Controlled Trials (controlled-trials.com), the National Institute of Health Clinical Trials register (clinicaltrials.gov) and the World Health Organization International Trials Registry Platform search portal (www.who.int/trialsearch/Default.aspx). SELECTION CRITERIA: Only randomised controlled trials (RCTs) studying the effectiveness and safety of antidepressants for women with PCOS were included in this review. DATA COLLECTION AND ANALYSIS: The methodological quality of the trials was assessed independently by two review authors, in parallel with data extraction. The risk of bias in the included study was assessed in six domains: 1. sequence generation; 2. allocation concealment; 3. blinding of participants, personnel and outcome assessors; 4. completeness of outcome data; 5. selective outcome reporting; 6. other potential sources of bias. MAIN RESULTS: We found no studies reporting any of our primary review outcomes (depression and allied mood disorder scores, quality of life and adverse events). Only one study with 16 women was eligible for inclusion. This study compared sibutramine versus fluoxetine in women with PCOS, and reported only endocrine and metabolic outcomes. It was unclear whether the participants had psychological problems at baseline. No significant difference was found between the groups for any of the measured outcomes. AUTHORS' CONCLUSIONS: There is no evidence on the effectiveness and safety of antidepressants in treating depression and other symptoms in women with PCOS. PMID- 23728678 TI - Umbilical cord antiseptics for preventing sepsis and death among newborns. AB - BACKGROUND: The umbilical cord is a structure made of blood vessels and connective tissue that connects the baby and placenta in utero. The umbilical cord is cut after birth, which separates the mother and her baby both physically and symbolically. Omphalitis is defined as infection of the umbilical cord stump. Tracking of bacteria along the umbilical vessels may lead to septicaemia that can result in neonatal morbidity and mortality, especially in developing countries. OBJECTIVES: To determine the effect of application of antimicrobials on newborn's umbilical cord versus routine care for prevention of morbidity and mortality in hospital and community settings. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (1 October 2012). In addition, we also searched LILACS (1982 to 11 October 2012) and HERDIN NeON (October 2012) SELECTION CRITERIA: We included randomized, cluster-randomized and quasi randomized controlled trials of topical cord care compared with no topical care, and comparisons between different forms of care. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, trial quality and subsequently extracted data. Data were checked for accuracy. MAIN RESULTS: The search identified 77 trials. We included 34 trials in the review involving 69,338 babies, five studies are awaiting classification and there are two ongoing community trials. Included studies were conducted in both developed and developing countries. Among the 34 included trials, three were large, cluster randomized trials conducted in community settings in developing countries and 31 studies were conducted in hospital settings mostly in developed countries. Data for community and hospital studies were analyzed separately. The three trials conducted in community settings contributed 78% of the total number of children included in this review. Of the trials conducted in hospital settings, the majority had small sample sizes. There were 22 different interventions studied across the included trials and the most commonly studied antiseptics were 70% alcohol, triple dye and chlorhexidine.Only one antiseptic, chlorhexidine was studied in community settings for umbilical cord care. Three community trials reported data on all-cause mortality that comprised 1325 deaths in 54,624 participants and combined results showed a reduction of 23% (average risk ratio (RR) 0.77, 95% confidence interval (CI) 0.63 to 0.94, random-effects, T2 = 0.02, I2 = 50%) in the chlorhexidine group compared with control. The reduction in omphalitis ranged from 27% to 56% depending on the severity of infection. Cord separation time was increased by 1.7 days in the chlorhexidine group compared with dry cord care (mean difference (MD) 1.75 days, 95% CI 0.44 to 3.05, random effects, T2 = 0.88, I2 = 100%). Washing of umbilical cord with soap and water was not advantageous compared with dry cord care in community settings.Among studies conducted in hospital settings, no study reported data for mortality or tetanus. No antiseptic was advantageous to reduce the incidence of omphalitis compared with dry cord care in hospital settings. Topical triple dye application reduced bacterial colonization with Staphylococcus aureus compared with dry cord care (average RR 0.15, 95% CI 0.10 to 0.22, four studies, n = 1319, random-effects, T2 = 0.04, I2 = 24%) or alcohol application (average RR 0.45, 95% CI 0.25 to 0.80, two studies, n = 487, random-effects, T2 = 0.00, I2 = 0%). There was no advantage of application of alcohol and triple dye for reduction of colonization with streptococcus. Topical alcohol application was advantageous in reduction of colonization with Enterococcus coli compared with dry cord care (average RR 0.73, 95% CI 0.58 to 0.92, two studies, n = 432, random-effects, T2 = 0.00, I2 = 0%) and in a separate analysis, triple dye increased the risk of colonization compared with alcohol (RR 3.44, 95% CI 2.10 to 5.64, one study, n = 373). Cord separation time was significantly increased with topical application of alcohol (MD 1.76 days, 95% CI 0.03 to 3.48, nine studies, n = 2921, random-effects, T2 = 6.54, I2 = 97%) and triple dye (MD 4.10 days, 95% CI 3.07 to 5.13, one study, n = 372) compared with dry cord care in hospital settings. The number of studies was insufficient to make any inference about the efficacy of other antiseptics. AUTHORS' CONCLUSIONS: There is significant evidence to suggest that topical application of chlorhexidine to umbilical cord reduces neonatal mortality and omphalitis in community and primary care settings in developing countries. It may increase cord separation time however, there is no evidence that it increases risk of subsequent morbidity or infection.There is insufficient evidence to support the application of an antiseptic to umbilical cord in hospital settings compared with dry cord care in developed countries. PMID- 23728679 TI - Percutaneous ethanol injection for liver metastases. AB - BACKGROUND: Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. Percutaneous ethanol injection (PEI) causes dehydration and necrosis of tumour cells accompanied by small vessel thrombosis, leading to tumour ischaemia and destruction. OBJECTIVES: To study the beneficial and harmful effects of percutaneous ethanol injection compared with no intervention, other ablation methods, or systemic treatments in patients with liver metastases. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to December 2012. SELECTION CRITERIA: We included all randomised clinical trials assessing the beneficial and harmful effects of percutaneous ethanol injection versus no intervention, other ablation methods, or systemic treatments in patients with liver metastases. DATA COLLECTION AND ANALYSIS: We extracted the relevant information on participant characteristics, interventions, study outcome measures, and data on the outcome measures for our review, as well as information on the design and methodology of the studies. Quality assessment of the trials fulfilling the inclusion criteria and data extraction from the trials retrieved for final evaluation were done by one author and checked by a second author. MAIN RESULTS: One randomised clinical trial was included, comparing transcatheter arterial chemoembolisation (TACE) + percutaneous intratumour ethanol injection (PEI) versus TACE alone. Forty-eight patients with liver metastases were included; 25 received the intervention with PEI and 23 received TACE alone.Mortality data were not reported. The trial reported the survival data after one, two, and three years. In the TACE + PEI group, 92%, 80%, and 64% of the patients survived after 1, 2, and 3 years respectively; in the TACE group, 78.3%, 65.2%, and 47.8% of the patients survived after 1, 2, and 3 years respectively. The hazard ratio was 0.57 (95% CI 0.19 to 1.67). The local recurrence was 16% in the TACE + PEI group and 39.1% in the TACE group, resulting in a relative risk (RR) of 0.41 (95% CI 0.15 to 1.07). Forty-five tumours (66.2%) out of 68 tumours in total shrunk by at least 25% in the TACE + PEI group versus 31 tumours (48.4%) out of 64 tumours in total in the TACE group (RR 2.08; 95% CI 1.03 to 4.2). The authors reported some adverse events, but with very few details. AUTHORS' CONCLUSIONS: On the basis of one small randomised trial, it can be concluded that addition of PEI to TACE, as compared with TACE alone, in patients with liver metastases seems to bring no clear benefit in terms of survival and local recurrence. The size of the tumour necrosis was larger in the combined treatment group. No intervention-related mortality or major complications were reported. More trials are needed. PMID- 23728680 TI - Interventions for preventing falls in people after stroke. AB - BACKGROUND: Falls are one of the most common medical complications after stroke with a reported incidence of 7% in the first week after stroke onset. Studies investigating falls in the later phase after stroke report an incidence of up to 73% in the first year post-stroke. OBJECTIVES: To evaluate the effectiveness of interventions aimed at preventing falls in people after stroke. SEARCH METHODS: We searched the trials registers of the Cochrane Stroke Group (November 2012) and the Cochrane Bone, Joint and Muscle Trauma Group (May 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2012, Issue 5, MEDLINE (1950 to May 2012), EMBASE (1980 to May 2012), CINAHL (1982 to May 2012), PsycINFO (1806 to May 2012), AMED (1985 to May 2012) and PEDro (May 2012). We also searched trials registers, checked reference lists and contacted authors. SELECTION CRITERIA: Randomised controlled trials of interventions where the primary or secondary aim was to prevent falls in people after stroke. DATA COLLECTION AND ANALYSIS: Review authors independently selected studies for inclusion, assessed trial quality, and extracted data. We used a rate ratio and 95% confidence interval (CI) to compare the rate of falls (e.g. falls per person year) between intervention and control groups. For risk of falling we used a risk ratio and 95% CI based on the number of people falling (fallers) in each group. We pooled results where appropriate. MAIN RESULTS: We included 10 studies with a total of 1004 participants. One study evaluated the effect of exercises in the acute and subacute phase after stroke but found no significant difference in rate of falls (rate ratio 0.92, 95% CI 0.45 to 1.90, 95 participants). The pooled result of four studies investigating the effect of exercises on preventing falls in the chronic phase also found no significant difference for rate of falls (rate ratio 0.75, 95% CI 0.41 to 1.38, 412 participants).For number of fallers, one study examined the effect of exercises in the acute and subacute phase after stroke but found no significant difference between the intervention and control group (risk ratio 1.19, 95% CI 0.83 to 1.71, 95 participants). The pooled result of six studies examining the effect of exercises in the chronic phase also found no significant difference in number of fallers between the intervention and control groups (risk ratio 1.02, 95% CI 0.83 to 1.24, 616 participants).The rate of falls and the number of fallers was significantly reduced in two studies evaluating the effect of medication on preventing falls; one study (85 participants) compared vitamin D versus placebo in institutionalised women after stroke with low vitamin D levels, and the other study (79 participants) evaluated alendronate versus alphacalcidol in hospitalised people after stroke.One study provided single lens distance glasses to regular wearers of multifocal glasses. In a subgroup of 46 participants post-stroke there was no significant difference in the rate of falls (rate ratio 1.08, 95% CI 0.52 to 2.25) or the number of fallers between both groups (risk ratio 0.74, 95% CI 0.47 to 1.18). AUTHORS' CONCLUSIONS: There is currently insufficient evidence that exercises or prescription of single lens glasses to multifocal users prevent falls or decrease the number of people falling after being discharged from rehabilitation following their stroke. Two studies testing vitamin D versus placebo and alendronate versus alphacalcidol found a significant reduction in falls and the number of people falling. However, these findings should be replicated before the results are implemented in clinical practice. PMID- 23728681 TI - Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients. AB - BACKGROUND: Lung transplantation is a well-accepted treatment for people with most end-stage lung diseases. Although both tacrolimus and cyclosporin are used as primary immunosuppressive agents in lung transplant recipients, it is unclear which of these drugs is better in reducing rejection and death without causing adverse effects. OBJECTIVES: To assess the benefits and harms of tacrolimus versus cyclosporin for primary immunosuppression in lung transplant recipients. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 10 April 2013 through contact with the Trials Search Co-ordinator using search terms relevant to this review. We also searched Science Citation Index Expanded and the Transplant Library to 20 April 2013. SELECTION CRITERIA: We included all randomised controlled trials (RCT) that compared any dose and duration of administration of tacrolimus versus cyclosporin as primary immunosuppressive treatment in lung transplant recipients. Our selection criteria required that all included patients received the same additional immunosuppressive therapy within each study. DATA COLLECTION AND ANALYSIS: Three authors extracted data. For dichotomous data we used risk ratio (RR) and used mean difference (MD) for continuous data, each with 95% confidence intervals (CI). Methodological components of the included studies were used to assess risk of systematic errors (bias). Trial sequential analysis was used to assess risk of random errors (play of chance). MAIN RESULTS: We included three studies that enrolled a total of 413 adult patients that compared tacrolimus with microemulsion or oral solution cyclosporin. All studies were found to be at high risk of bias. Tacrolimus seemed to be significantly superior to cyclosporin regarding the incidence of bronchiolitis obliterans syndrome (RR 0.46, 95% CI 0.29 to 0.74), lymphocytic bronchitis score (MD -0.60, 95% CI -1.04 to -0.16), treatment withdrawal (RR 0.27, 95% CI 0.16 to 0.46), and arterial hypertension (RR 0.67, 95% CI 0.50 to 0.89). However, the finding for arterial hypertension was not confirmed when analysed using a random-effects model (RR 0.54, 95% CI 0.17 to 1.73). Furthermore, trial sequential analysis found that none of the meta-analyses reached the required information sizes and cumulative Z-curves did not cross trial sequential monitoring boundaries. Diabetes mellitus occurred more frequently among people in the tacrolimus group compared with the cyclosporin group when the fixed-effect model was applied (RR 4.24, 95% CI 1.58 to 11.40), but no difference was found when the random-effects model was used for analysis (RR 4.43, 95% CI 0.75 to 26.05). Again, trial sequential analysis found that the required information threshold was not reached and cumulative Z-curve did not cross the trial sequential monitoring boundary. No significant difference between treatment groups was observed regarding mortality (RR 1.06, 95% CI 0.75 to 1.49), incidence of acute rejection (RR 0.89, 95% CI 0.77 to 1.03), numbers of infections/100 patient-days (MD -0.15, 95% CI -0.30 to 0.00), cancer (RR 0.21, 95% CI 0.04 to 1.16), kidney dysfunction (RR 1.41, 95% CI 0.93 to 2.14), kidney failure (RR 1.57, 95% CI 0.28 to 8.94), neurotoxicity (RR 7.06, 95% CI 0.37 to 135.19), and hyperlipidaemia (RR 0.60, 95% CI 0.30 to 1.20). Trial sequential analysis showed the required information thresholds were not reached for any of these outcome measures. AUTHORS' CONCLUSIONS: Tacrolimus may be superior to cyclosporin regarding bronchiolitis obliterans syndrome, lymphocytic bronchitis, treatment withdrawal, and arterial hypertension, but may be inferior regarding development of diabetes. No difference in mortality and acute rejection was observed between patients treated with tacrolimus and cyclosporin. There were few studies comparing tacrolimus and cyclosporin after lung transplantation, and the numbers of patients and events in the included studies were limited. Furthermore, the included studies were deemed to be at high risk of bias. Hence, more RCTs are needed to assess the results of the present review. Such studies ought to be conducted with low risks of systematic errors (bias) and of random errors (play of chance). PMID- 23728682 TI - Granulocyte colony stimulating factor therapy for acute myocardial infarction. AB - BACKGROUND: Acute myocardial infarction (AMI) is the leading cause of death in developed countries, and current treatment modalities have failed to regenerate the dead myocardium resulting from the ischemic damage. Stem cells have the potential to regenerate the damaged myocardium. These cells can be mobilized from the bone marrow by factors such as granulocyte colony stimulating factor (G-CSF). OBJECTIVES: To assess the effects of stem cell mobilization following granulocyte colony stimulating factor therapy in patients with acute myocardial infarction. SEARCH METHODS: We searched CENTRAL (The Cochrane Library Issue 4, 2010), MEDLINE (1950 to November week 3, 2010), EMBASE (1980 to 2010 week 48), BIOSIS Previews (1969 to 30 November 2010), ISI Science Citation Index Expanded (1970 to 4 December 2010) and ISI Conference Proceedings Citation Index - Science (1990 to 4 December 2010). We also checked reference lists of articles. SELECTION CRITERIA: We included randomized controlled trials including participants with a clinical diagnosis of AMI who were randomly allocated to the subcutaneous administration of G-CSF through a daily dose of 2.5, 5 or 10 microgram/kg for four to six days or placebo. No age or other restrictions were applied for the selection of patients. DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data regarding the clinical efficacy and adverse outcomes. Disagreements were resolved by the third author. MAIN RESULTS: We included seven trials reported in 30 references in the review (354 participants). In all trials, G-CSF was compared with placebo preparations. Dosage of G-CSF varied among studies, ranging from 2.5 to 10 microgram/kg/day. Regarding overall risk of bias, data regarding the generation of randomization sequence and incomplete outcome data were at a low risk of bias; however, data regarding binding of personnel were not conclusive. The rate of mortality was not different between the two groups (RR 0.64, 95% CI 0.15 to 2.80, P = 0.55). Regarding safety, the limited amount of evidence is inadequate to reach any conclusions regarding the safety of G-CSF therapy. Moreover, the results did not show any beneficial effects of G-CSF in patients with AMI regarding left ventricular function parameters, including left ventricular ejection fraction (RR 3.41, 95% CI -0.61 to 7.44, P = 0.1), end systolic volume (RR -1.35, 95% CI -4.68 to 1.99, P = 0.43) and end diastolic volume (RR -4.08, 95% CI -8.28 to 0.12, P = 0.06). It should also be noted that the study was limited since the trials included lacked long enough follow up durations. AUTHORS' CONCLUSIONS: Limited evidence from small trials suggested a lack of benefit of G-CSF therapy in patients with AMI. Since data of the risk of bias regarding blinding of personnel were not conclusive, larger RCTs with appropriate power calculations and longer follow up durations are required in order to address current uncertainties regarding the clinical efficacy and therapy-related adverse events of G-CSF treatment. PMID- 23728683 TI - Repetitive transcranial magnetic stimulation for improving function after stroke. AB - BACKGROUND: It had been assumed that suppressing the undamaged contralesional motor cortex by repetitive low-frequency transcranial magnetic stimulation (rTMS) or increasing the excitability of the damaged hemisphere cortex by high-frequency rTMS will promote function recovery after stroke. OBJECTIVES: To assess the efficacy and safety of rTMS for improving function in people with stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (April 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), the Chinese Stroke Trials Register (April 2012), MEDLINE (1950 to May 2012), EMBASE (1980 to May 2012), Science Citation Index (1981 to April 2012), Conference Proceedings Citation Index-Science (1990 to April 2012), CINAHL (1982 to May 2012), AMED (1985 to May 2012), PEDro (April 2012), REHABDATA (April 2012) and CIRRIE Database of International Rehabilitation Research (April 2012). In addition, we searched five Chinese databases, ongoing trials registers and relevant reference lists. SELECTION CRITERIA: We included randomised controlled trials comparing rTMS therapy with sham therapy or no therapy. We excluded trials that reported only laboratory parameters. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed trial quality and extracted the data. We resolved disagreements by discussion. MAIN RESULTS: We included 19 trials involving a total of 588 participants in this review. Two heterogenous trials with a total of 183 participants showed that rTMS treatment was not associated with a significant increase in the Barthel Index score (mean difference (MD) 15.92, 95% CI -2.11 to 33.95). Four trials with a total of 73 participants were not found to have a statistically significant effect on motor function (standardised mean difference (SMD) 0.51, 95% CI -0.99 to 2.01). Subgroup analyses of different stimulation frequencies or duration of illness also showed no significant difference. Few mild adverse events were observed in the rTMS groups, with the most common events being transient or mild headaches (2.4%, 8/327) and local discomfort at the site of the stimulation. AUTHORS' CONCLUSIONS: Current evidence does not support the routine use of rTMS for the treatment of stroke. Further trials with larger sample sizes are needed to determine a suitable rTMS protocol and the long-term functional outcome. PMID- 23728684 TI - Surgical interventions for treating radial head fractures in adults. AB - BACKGROUND: Radial head fractures are the most common type of elbow fracture and can severely affect the function of the elbow. There is uncertainty and controversy about when surgery is indicated as well as what type of surgical intervention is best. OBJECTIVES: To assess the effects of surgical interventions for treating radial head fractures in adults. We aimed to compare surgical versus non-surgical treatment, and different methods of surgical intervention. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (May 2012), the Cochrane Central Register of Controlled Trials (The Cochrane Library; 2012 Issue 4), MEDLINE (1946 to May 2012), EMBASE (1980 to 2012 Week 19) and trial registers (November 2011). No language restrictions were applied. SELECTION CRITERIA: All randomised and quasi-randomised controlled trials evaluating surgical interventions for treating radial head fractures. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed risk of bias and extracted data. Where appropriate, results were pooled. MAIN RESULTS: We included three randomised controlled trials, involving a total of 251 participants. All three trials were at high risk of performance bias reflecting the fact that surgeons could not be blinded. One trial was at low risk of selection bias but was undermined by a high attrition bias, in part resulting from post-randomisation exclusions. There were incomplete details of methodology for the other two trials, which usually resulted in unclear risk of bias judgements.Two trials compared radial head replacement with open reduction and internal fixation (ORIF) for treating Mason type III radial head fractures. The trial authors reported outcomes at a mean of 2.8 years and 15 months respectively. There were significant differences between the two groups in favour of radial head replacement in the Broberg and Morrey elbow scores (92.1 versus 72.4, mean difference (MD) 19.70; 95% confidence interval (CI) 15.64 to 23.76; one trial, 45 participants), excellent or good Broberg and Morrey elbow scores (33/36 versus 16/31, risk ratio (RR) 1.88; 95% CI 1.27 to 2.77; two trials), and overall adverse events (6/36 versus 15/31, RR 0.33; 95% CI 0.14 to 0.77; two trials). No statistically significant difference was found between the two groups in any of the reported individual adverse events.One trial compared biodegradable pins with standard metal screws in treating radial head fractures of AO classification 21 B2. The two types of fixation devices yielded similar results, with no significant between-group differences in the Broberg and Morrey scores (93.3 versus 90.9, MD 2.40; 95% CI -0.10 to 4.90), excellent or good Broberg and Morrey elbow scores (72/74 versus 56/61, RR 1.06; 95% CI 0.97 to 1.15), and adverse events (13/82 versus 16/82, RR 0.81; 95% CI 0.42 to 1.58) at two-year follow-up. AUTHORS' CONCLUSIONS: Only tentative conclusions can be drawn from the available evidence in this review. Compared with ORIF, there was some evidence that radial head replacement had better elbow function and fewer adverse events for Mason type III radial head fractures in the short term. However, the evidence is of low quality and it is unknown whether these results would apply in the longer term or more generally. Using biodegradable implants may be as good as metallic implants for fixation of some usually more stable fractures but more evidence is needed to confirm this. There is a need for good quality evidence for addressing the areas of uncertainty for the surgical treatment of radial head fractures. PMID- 23728685 TI - Breathing exercises for dysfunctional breathing/hyperventilation syndrome in adults. AB - BACKGROUND: Dysfunctional breathing/hyperventilation syndrome (DB/HVS) is a respiratory disorder, psychologically or physiologically based, involving breathing too deeply and/or too rapidly (hyperventilation) or erratic breathing interspersed with breath-holding or sighing (DB). DB/HVS can result in significant patient morbidity and an array of symptoms including breathlessness, chest tightness, dizziness, tremor and paraesthesia. DB/HVS has an estimated prevalence of 9.5% in the general adult population, however, there is little consensus regarding the most effective management of this patient group. OBJECTIVES: (1) To determine whether breathing exercises in patients with DB/HVS have beneficial effects as measured by quality of life indices (2) To determine whether there are any adverse effects of breathing exercises in patients with DB/HVS SEARCH METHODS: We identified trials for consideration using both electronic and manual search strategies. We searched CENTRAL, MEDLINE, EMBASE, and four other databases. The latest search was in February 2013. SELECTION CRITERIA: We planned to include randomised, quasi-randomised or cluster randomised controlled trials (RCTs) in which breathing exercises, or a combined intervention including breathing exercises as a key component, were compared with either no treatment or another therapy that did not include breathing exercises in patients with DB/HVS. Observational studies, case studies and studies utilising a cross-over design were not eligible for inclusion.We considered any type of breathing exercise for inclusion in this review, such as breathing control, diaphragmatic breathing, yoga breathing, Buteyko breathing, biofeedback guided breathing modification, yawn/sigh suppression. Programs where exercises were either supervised or unsupervised were eligible as were relaxation techniques and acute-episode management, as long as it was clear that breathing exercises were a key component of the intervention.We excluded any intervention without breathing exercises or where breathing exercises were not key to the intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently checked search results for eligible studies, assessed all studies that appeared to meet the selection criteria and extracted data. We used standard procedures recommended by The Cochrane Collaboration. MAIN RESULTS: We included a single RCT assessed at unclear risk of bias, which compared relaxation therapy (n = 15) versus relaxation therapy and breathing exercises (n = 15) and a no therapy control group (n = 15).Quality of life was not an outcome measure in this RCT, and no numerical data or statistical analysis were presented in this paper. A significant reduction in the frequency and severity of hyperventilation attacks in the breathing exercise group compared with the control group was reported. In addition, a significant difference in frequency and severity of hyperventilation attacks between the breathing and relaxation group was reported. However, no information could be extracted from the paper regarding the size of the treatment effects. AUTHORS' CONCLUSIONS: The results of this systematic review are unable to inform clinical practice, based on the inclusion of only one small, poorly reported RCT. There is no credible evidence regarding the effectiveness of breathing exercises for the clinical symptoms of DB/HVS. It is currently unknown whether these interventions offer any added value in this patient group or whether specific types of breathing exercise demonstrate superiority over others. Given that breathing exercises are frequently used to treat DB/HVS, there is an urgent need for further well designed clinical trials in this area. Future trials should conform to the CONSORT statement for standards of reporting and use appropriate, validated outcome measures. Trial reports should also ensure full disclosure of data for all important clinical outcomes. PMID- 23728686 TI - Pedicle screw fixation for traumatic fractures of the thoracic and lumbar spine. AB - BACKGROUND: Spine fractures are common. The treatment of traumatic fractures of the thoracic and lumbar spine remains controversial but surgery involving pedicle screw fixation has become a popular option. OBJECTIVES: To assess the effects (benefits and harms) of pedicle screw fixation for traumatic fractures of the thoracic and lumbar spine. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (March 2011), the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library, 2011 Issue 1), MEDLINE (1948 to March 2011), EMBASE (1980 to 2011 Week 11), the Chinese Biomedical Database (CBM Database) (1978 to March 2011), the WHO International Clinical Trials Registry Platform (March 2011), reference lists of articles and conference proceedings. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-randomised controlled trials comparing pedicle screw fixation and other methods of surgical treatment, or different methods of pedicle screw fixation, for treating traumatic fractures of the thoracic and lumbar spine. DATA COLLECTION AND ANALYSIS: Three review authors independently performed study selection, risk of bias assessment and data extraction. Limited meta-analysis was performed. MAIN RESULTS: Pedicle screw fixation versus other methods of surgery that do not involve pedicle screw fixation was not looked at in any of the identified trials. Studies that were identified investigated different methods of pedicle fixation.Five randomised and three quasi-randomised controlled trials were included. All were at high or unclear risk of various biases, including selection, performance and detection bias. A total of 448 patients with thoracic and lumbar spine fractures were included in the review. Participants were restricted to individuals without neurological impairment in five trials. The mean ages of study populations of the eight trials ranged from 33 to 41 years, and participants had generally experienced traumatic injury. Mean follow-up for trial participants in the eight trials ranged from 28 to 72 months.Five comparisons were tested.Two trials compared short-segment instrumentation versus long-segment instrumentation. These studies found no significant differences between the two groups in self-reported function and quality of life at final follow-up. Aside from one participant, who sustained partial neurological deterioration that was resolved by further surgery (group not known), no neurological deterioration was noted in these trials.One trial comparing short segment instrumentation with transpedicular bone grafting versus short-segment fixation alone found no significant difference between the two groups related to patient-perceived function and pain at final follow-up. All participants had normal findings on neurological examination at final follow-up.Two trials compared posterior instrumentation with fracture level screw incorporation ('including' group) versus posterior instrumentation alone ('bridging' group). Investigators reported no differences between the two groups in patient-reported function, quality of life, or pain at final follow-up. One trial confirmed that all participants had normal findings on neurological examination at final follow up.One trial comparing monosegmental pedicle screw instrumentation versus short segment pedicle instrumentation found no significant differences between the two groups in Oswestry Disability Index results or in pain scores at final follow-up. No neurological deterioration was reported.Three trials compared posterior instrumentation with fusion versus posterior instrumentation without fusion. Researchers found no differences between the two groups in function and quality of life or pain. No participants showed a decline in neurological status in any of the three trials, and no significant difference was reported between groups in the numbers whose status had improved at final follow-up. Two trials stated that patients in the fusion group frequently had donor site pain. Other reported complications included deep vein thrombosis and superficial infection. AUTHORS' CONCLUSIONS: This review included only eight small trials and five different comparisons of methods of pedicle fixation in various participants while looking at a variety of outcomes at different time points. Overall, evidence is insufficient to inform the selection of different methods of pedicle screw fixation or the combined use of fusion. However, in the absence of robust evidence to support fusion, it is important to factor the risk of long-term donor site pain related to bone harvesting into the decision of whether to use this intervention. Further research involving high-quality randomised trials is needed. PMID- 23728687 TI - Telephone delivered interventions for reducing morbidity and mortality in people with HIV infection. AB - BACKGROUND: This is one of three Cochrane reviews examining the role of the telephone in HIV/AIDS services. Telephone interventions, delivered either by landline or mobile phone, may be useful in the management of people living with HIV (PLHIV) in many situations. Telephone delivered interventions have the potential to reduce costs, save time and facilitate more support for PLHIV. OBJECTIVES: To assess the effectiveness of voice landline and mobile telephone delivered interventions for reducing morbidity and mortality in people with HIV infection. SEARCH METHODS: We searched The Cochrane Central Register of Controlled Trials, MEDLINE, PubMed Central, EMBASE, PsycINFO, ISI Web of Science, Cumulative Index to Nursing & Allied Health, World Health Organisation's The Global Health Library and Current Controlled Trials from 1980 to June 2011. We searched the following grey literature sources: Dissertation Abstracts International, Centre for Agriculture Bioscience International Direct Global Health database, The System for Information on Grey Literature Europe, The Healthcare Management Information Consortium database, Google Scholar, Conference on Retroviruses and Opportunistic Infections, International AIDS Society, AIDS Educational Global Information System and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-randomised controlled trials, controlled before and after studies, and interrupted time series studies comparing the effectiveness of telephone delivered interventions for reducing morbidity and mortality in persons with HIV infection versus in-person interventions or usual care, regardless of demographic characteristics and in all settings. Both mobile and landline telephone interventions were included, but mobile phone messaging interventions were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently searched, screened, assessed study quality and extracted data. Primary outcomes were change in behaviour, healthcare uptake or clinical outcomes. Secondary outcomes were appropriateness of the mode of communication, and whether underlying factors for change were altered. Meta analyses, each of three studies, were performed for medication adherence and depressive symptoms. A narrative synthesis is presented for all other outcomes due to study heterogeneity. MAIN RESULTS: Out of 14 717 citations, 11 RCTs met the inclusion criteria (1381 participants).Six studies addressed outcomes relating to medication adherence, and there was some evidence from two studies that telephone interventions can improve adherence. A meta-analysis of three studies for which there was sufficient data showed no significant benefit (SMD 0.49, 95% CI -1.12 to 2.11). There was some evidence from a study of young substance abusing HIV positive persons of the efficacy of telephone interventions for reducing risky sexual behaviour, while a trial of older persons found no benefit. Three RCTs addressed virologic outcomes, and there is very little evidence that telephone interventions improved virologic outcomes. Five RCTs addressed outcomes relating to depressive and psychiatric symptoms, and showed some evidence that telephone interventions can be of benefit. Three of these studies which focussed on depressive symptoms were combined in a meta-analysis, which showed no significant benefit (SMD 0.02, 95% CI -0.18 to 0.21 95% CI). AUTHORS' CONCLUSIONS: Telephone voice interventions may have a role in improving medication adherence, reducing risky sexual behaviour, and reducing depressive and psychiatric symptoms, but current evidence is sparse, and further research is needed. PMID- 23728688 TI - Telephone delivered interventions for preventing HIV infection in HIV-negative persons. AB - BACKGROUND: This is one of the three Cochrane reviews that examine the role of the telephone in HIV/AIDS services. Although HIV infection can be prevented, still a large number of new infections occur. More effective HIV prevention interventions are needed to reduce the number of people newly infected with HIV. Phone calls can be used to potentially more effectively deliver HIV prevention interventions. They have the potential to save time, reduce costs and facilitate easier access. OBJECTIVES: To assess the effectiveness of voice landline and mobile telephone delivered HIV prevention interventions in HIV-negative persons. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed Central, EMBASE, PsycINFO, Web of Science, Cumulative Index to Nursing & Allied Health, the World Health Organization's Global Health Library and Current Controlled Trials from 1980 to June 2011. We searched the following grey literature sources: Dissertation Abstracts International and the Centre for Agricultural Bioscience International Direct Global Health database, the System for Information on Grey Literature Europe, The Healthcare Management Information Consortium, Google Scholar, Conference on Retroviruses and Opportunistic Infections database, International AIDS Society conference database, AIDS Education Global Information System and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-randomised controlled trials, controlled before and after studies, and interrupted time series studies comparing the effectiveness of delivering HIV prevention by phone calls to usual care in HIV-negative people regardless of their demographic characteristics and in all settings. DATA COLLECTION AND ANALYSIS: Two reviewers independently searched databases, screened citations, assessed study quality and extracted data. A third reviewer resolved any disagreement. Primary outcomes were knowledge about the causes and consequences of HIV/AIDS, change in behaviour, healthcare uptake and clinical outcomes. Secondary outcomes were users' and providers' views on the intervention, economic outcomes and adverse outcomes. MAIN RESULTS: Out of 14,717 citations, only one study met the inclusion criteria. The included RCT recruited women and girl children who received post-exposure prophylaxis (PEP) after rape from sexual assault services in South Africa between August 2007 and May 2008.Participants (n (number) =274) were randomised into a telephone support (n=136) and control (n=138) group. Control group participants received usual care (an interactive information session) from the sexual assault service during the 28 days in which they had to take PEP, with no further contact from the study staff. Telephone support group participants received standard care and phone calls from a counsellor throughout the 28 days when they had to take PEP.Overall, adherence to PEP was not significantly (P=0.13) different between the intervention (38.2%) and control (31.9 %) groups. Also, the proportion of participants who read a pamphlet, did not return to collect medication or with a depression were not significantly different between the intervention and control groups (P=0.006, P=0.42, P=0.72 respectively). The proportion of participants who used a diary was significantly (P=0.001) higher in the intervention group (78.8%) versus the control group (69.9%). The study authors reported that there were no recorded adverse events. The RCT did not provide information about participants' and providers' evaluation outcomes, or economic outcomes. The study had a moderate risk of bias. AUTHORS' CONCLUSIONS: We found only one RCT, with a moderate risk of bias, which showed that providing PEP support by phone calls did not result in higher adherence to PEP. However, the RCT was conducted in an upper middle-income country with high HIV prevalence, on a high-risk population and the applicability of its results on other settings and contexts is unclear. There is a need for robust evidence from various settings on the effectiveness of using phone calls for providing PEP support and for other HIV prevention interventions. PMID- 23728689 TI - Rituximab for thyroid-associated ophthalmopathy. AB - BACKGROUND: Thyroid associated ophthalmopathy (TAO) is the most frequent extrathyroidal manifestation of Graves' disease, affecting up to 50% of patients, and has a great impact on quality of life. Rituximab is a human/murine chimeric monoclonal antibody that targets CD20, a transmembrane protein expressed on the surface of pre-B and mature B lymphocytes, but not on stem cells, pro-B lymphocytes or plasma cells. Preliminary work has shown that blocking the CD20 receptor on B-lymphocytes with rituximab affects the clinical course of TAO, by reducing inflammation and the degree of proptosis. OBJECTIVES: The aim of this review was to investigate the effectiveness and safety of rituximab for the treatment of TAO. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to April 2013), EMBASE (January 1980 to April 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to April 2013), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov), the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and the EU Clinical Trials Register (www.clinicaltrialsregister.eu). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 15 April 2013. We manually searched references of review articles and used the Science Citation Index to identify additional studies citing trials. We contacted the lead investigators of relevant trials on ClinicalTrials.gov and the WHO ICTRP for information and data from as yet unpublished clinical trials. We contacted experts in the field for information about any ongoing trials. We contacted the manufacturers of rituximab for details of any sponsored trials. SELECTION CRITERIA: We sought to include randomised controlled trials (RCTs) of rituximab treatment by intravenous infusion for the treatment of patients with TAO, compared with placebo or intravenous glucocorticoid treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently scanned titles and abstracts, as well as independently screened the full reports of the potentially relevant studies. At each stage, the results were compared and disagreements were solved by discussion. MAIN RESULTS: No studies were identified that met the inclusion criteria. There are three ongoing studies which are likely to meet inclusion criteria once published, and thus be included in future updates of this review. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to support the use of rituximab in patients with TAO. There is a need for large RCTs, investigating rituximab versus placebo or corticosteroids in patients with active TAO to make adequate judgement on the efficacy and safety of this novel therapy for this condition. PMID- 23728690 TI - Pharmacological interventions for smoking cessation: an overview and network meta analysis. AB - BACKGROUND: Smoking is the leading preventable cause of illness and premature death worldwide. Some medications have been proven to help people to quit, with three licensed for this purpose in Europe and the USA: nicotine replacement therapy (NRT), bupropion, and varenicline. Cytisine (a treatment pharmacologically similar to varenicline) is also licensed for use in Russia and some of the former socialist economy countries. Other therapies, including nortriptyline, have also been tested for effectiveness. OBJECTIVES: How do NRT, bupropion and varenicline compare with placebo and with each other in achieving long-term abstinence (six months or longer)? How do the remaining treatments compare with placebo in achieving long-term abstinence? How do the risks of adverse and serious adverse events (SAEs) compare between the treatments, and are there instances where the harms may outweigh the benefits? METHODS: The overview is restricted to Cochrane reviews, all of which include randomised trials. Participants are usually adult smokers, but we exclude reviews of smoking cessation for pregnant women and in particular disease groups or specific settings. We cover nicotine replacement therapy (NRT), antidepressants (bupropion and nortriptyline), nicotine receptor partial agonists (varenicline and cytisine), anxiolytics, selective type 1 cannabinoid receptor antagonists (rimonabant), clonidine, lobeline, dianicline, mecamylamine, Nicobrevin, opioid antagonists, nicotine vaccines, and silver acetate. Our outcome for benefit is continuous or prolonged abstinence at least six months from the start of treatment. Our outcome for harms is the incidence of serious adverse events associated with each of the treatments. We searched the Cochrane Database of Systematic Reviews (CDSR) in The Cochrane Library, for any reviews with 'smoking' in the title, abstract or keyword fields. The last search was conducted in November 2012. We assessed methodological quality using a revised version of the AMSTAR scale. For NRT, bupropion and varenicline we conducted network meta analyses, comparing each with the others and with placebo for benefit, and varenicline and bupropion for risks of serious adverse events. MAIN RESULTS: We identified 12 treatment-specific reviews. The analyses covered 267 studies, involving 101,804 participants. Both NRT and bupropion were superior to placebo (odds ratios (OR) 1.84; 95% credible interval (CredI) 1.71 to 1.99, and 1.82; 95% CredI 1.60 to 2.06 respectively). Varenicline increased the odds of quitting compared with placebo (OR 2.88; 95% CredI 2.40 to 3.47). Head-to-head comparisons between bupropion and NRT showed equal efficacy (OR 0.99; 95% CredI 0.86 to 1.13). Varenicline was superior to single forms of NRT (OR 1.57; 95% CredI 1.29 to 1.91), and to bupropion (OR 1.59; 95% CredI 1.29 to 1.96). Varenicline was more effective than nicotine patch (OR 1.51; 95% CredI 1.22 to 1.87), than nicotine gum (OR 1.72; 95% CredI 1.38 to 2.13), and than 'other' NRT (inhaler, spray, tablets, lozenges; OR 1.42; 95% CredI 1.12 to 1.79), but was not more effective than combination NRT (OR 1.06; 95% CredI 0.75 to 1.48). Combination NRT also outperformed single formulations. The four categories of NRT performed similarly against each other, apart from 'other' NRT, which was marginally more effective than NRT gum (OR 1.21; 95% CredI 1.01 to 1.46). Cytisine (a nicotine receptor partial agonist) returned positive findings (risk ratio (RR) 3.98; 95% CI 2.01 to 7.87), without significant adverse events or SAEs. Across the 82 included and excluded bupropion trials, our estimate of six seizures in the bupropion arms versus none in the placebo arms was lower than the expected rate (1:1000), at about 1:1500. SAE meta-analysis of the bupropion studies demonstrated no excess of neuropsychiatric (RR 0.88; 95% CI 0.31 to 2.50) or cardiovascular events (RR 0.77; 95% CI 0.37 to 1.59). SAE meta-analysis of 14 varenicline trials found no difference between the varenicline and placebo arms (RR 1.06; 95% CI 0.72 to 1.55), and subgroup analyses detected no significant excess of neuropsychiatric events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI 0.62 to 2.56). Nortriptyline increased the chances of quitting (RR 2.03; 95% CI 1.48 to 2.78). Neither nortriptyline nor bupropion were shown to enhance the effect of NRT compared with NRT alone. Clonidine increased the chances of quitting (RR 1.63; 95% CI 1.22 to 2.18), but this was offset by a dose-dependent rise in adverse events. Mecamylamine in combination with NRT may increase the chances of quitting, but the current evidence is inconclusive. Other treatments failed to demonstrate a benefit compared with placebo. Nicotine vaccines are not yet licensed for use as an aid to smoking cessation or relapse prevention. Nicobrevin's UK license is now revoked, and the manufacturers of rimonabant, taranabant and dianicline are no longer supporting the development or testing of these treatments. AUTHORS' CONCLUSIONS: NRT, bupropion, varenicline and cytisine have been shown to improve the chances of quitting. Combination NRT and varenicline are equally effective as quitting aids. Nortriptyline also improves the chances of quitting. On current evidence, none of the treatments appear to have an incidence of adverse events that would mitigate their use. Further research is warranted into the safety of varenicline and into cytisine's potential as an effective and affordable treatment, but not into the efficacy and safety of NRT. PMID- 23728691 TI - Primary school-based behavioural interventions for preventing caries. AB - BACKGROUND: Dental caries is one of the most common global childhood diseases and is, for the most part, entirely preventable. Good oral health is dependent on the establishment of the key behaviours of toothbrushing with fluoride toothpaste and controlling sugar snacking. Primary schools provide a potential setting in which these behavioural interventions can support children to develop independent and habitual healthy behaviours. OBJECTIVES: To assess the clinical effects of school based interventions aimed at changing behaviour related to toothbrushing habits and the frequency of consumption of cariogenic food and drink in children (4 to 12 year olds) for caries prevention. SEARCH METHODS: We searched the following electronic databases: the Cochrane Oral Health Group's Trials Register (to 18 October 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 4), MEDLINE via OVID (1948 to 18 October 2012), EMBASE via OVID (1980 to 18 October 2012), CINAHL via EBSCO (1981 to 18 October 2012) and PsycINFO via OVID (1950 to 18 October 2012). Ongoing trials were searched for using Current Controlled Trials (to 18 October 2012) and ClinicalTrials.gov (to 18 October 2012). Conference proceedings were searched for using ZETOC (1993 to 18 October 2012) and Web of Science (1990 to 18 October 2012). We searched for thesis abstracts using the Proquest Dissertations and Theses database (1950 to 18 October 2012). There were no restrictions regarding language or date of publication. Non-English language papers were included and translated in full by native speakers. SELECTION CRITERIA: Randomised controlled trials of behavioural interventions in primary schools (children aged 4 to 12 years at baseline) were selected. Included studies had to include behavioural interventions addressing both toothbrushing and consumption of cariogenic foods or drinks and have a primary school as a focus for delivery of the intervention. DATA COLLECTION AND ANALYSIS: Two pairs of review authors independently extracted data related to methods, participants, intervention design including behaviour change techniques (BCTs) utilised, outcome measures and risk of bias. Relevant statistical information was assessed by a statistician subsequently. All included studies contact authors were emailed for copies of intervention materials. Additionally, three attempts were made to contact study authors to clarify missing information. MAIN RESULTS: We included four studies involving 2302 children. One study was at unclear risk of bias and three were at high risk of bias. Included studies reported heterogeneity in both the intervention design and outcome measures used; this made statistical comparison difficult. Additionally this review is limited by poor reporting of intervention procedure and design. Several BCTs were identified in the trials: these included information around the consequences of twice daily brushing and controlling sugar snacking; information on consequences of adverse behaviour and instruction and demonstration regarding skill development of relevant oral health behaviours.Only one included study reported the primary outcome of development of caries. This small study at unclear risk of bias showed a prevented fraction of 0.65 (95% confidence interval (CI) 0.12 to 1.18) in the intervention group. However, as this is based on a single study, this finding should be interpreted with caution.Although no meta analysis was performed with respect to plaque outcomes (due to differences in plaque reporting between studies), the three studies which reported plaque outcomes all found a statistically significant reduction in plaque in the intervention groups with respect to plaque outcomes. Two of these trials involved an 'active' home component where parents were given tasks relating to the school oral health programme (games and homework) to complete with their children. Secondary outcome measures from one study reported that the intervention had a positive impact upon children's oral health knowledge. AUTHORS' CONCLUSIONS: Currently, there is insufficient evidence for the efficacy of primary school based behavioural interventions for reducing caries. There is limited evidence for the effectiveness of these interventions on plaque outcomes and on children's oral health knowledge acquisition. None of the included interventions were reported as being based on or derived from behavioural theory. There is a need for further high quality research to utilise theory in the design and evaluation of interventions for changing oral health related behaviours in children and their parents. PMID- 23728692 TI - Electro-coagulation for liver metastases. AB - BACKGROUND: Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. Electro-coagulation is the coagulation (clotting) of tissue using a high-frequency electrical current applied locally with a metal instrument or needle with the aim of stopping bleeding. The object of this technique is to destroy the tumour completely, if possible, in a single surgical session. OBJECTIVES: To study the beneficial and harmful effects of electro coagulation compared with no intervention, to other ablation methods, or systemic treatments in patients with liver metastases. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to December 2012. SELECTION CRITERIA: We included one randomised clinical trial that assessed beneficial and harmful effects of electro-coagulation and its comparators in patients with liver metastases, irrespective of the location of the primary tumour. DATA COLLECTION AND ANALYSIS: We extracted relevant information on participant characteristics, interventions, study outcome measures, and data on the outcome measures as well as information on the design and methodology of the trials. Risk of bias of the trials and data extraction was carried out by one author and checked by a second author. MAIN RESULTS: We included one randomised clinical trial that compared four groups: electro-coagulation alone, electro coagulation + dimethyl sulphoxide, electro-coagulation + allopurinol, and control (Salim 1993). The risk of bias in the trial is high. In three groups, patients had their metastases destroyed with diathermy electro-coagulation (current set at No 5) and received: 1) solution of allopurinol by mouth 5 mL 4 x a day or 2) allopurinol by mouth 5 mL (50 mg) 4 x a day or 3) dimethyl sulphoxide by mouth 5 mL (500 mg) 4 x a day. In the control group patients received a solution of allopurinol by mouth 5 mL 4 x a day. The treatment was started in the fifth postoperative day and was continued for five years. Three hundred and six patients who had undergone resection of the sigmoid colon and who had five or more hepatic metastases were included; 75 received electro-coagulation alone (58 were evaluable), 76 received electro-coagulation plus allopurinol (53 were evaluable), 78 received electro-coagulation plus dimethyl sulphoxide (57 were evaluable), and 77 were in the control group (55 evaluable).The authors reported the number of deaths due to disease spread (100% in the control, 98% in electro coagulation, 87% in electro-coagulation + allopurinol, and 86% in the electro coagulation + dimethyl sulphoxide groups). There was a significant benefit in favour of the electro-coagulation + allopurinol (risk ratio (RR) 0.87 (95% confidence interval (CI) 0.78 to 0.96)) and electro-coagulation + dimethyl sulphoxide (RR 0.86 (95% CI 0.77 to 0.95)) groups compared to the control group, but no such benefit in the electro-coagulation alone group (RR 0.98 (95% CI 0.95 to 1.02)) compared to the control group. There were no local recurrences, no positive tests for occult blood, and observed pulmonary metastases were always with ultrasonographic evidence of hepatic secondaries and were not significantly different for the experimental groups compared to the control group (electro coagulation: RR 1.11 (95% CI 0.4 to 3.09)), electro-coagulation + allopurinol (RR 0.86 (95% CI 0.28 to 2.66)), electro-coagulation + dimethyl sulphoxide (RR 0.8 (95% CI 0.26 to 2.48)). None of the adverse events were significantly associated with treatment. AUTHORS' CONCLUSIONS: On the basis of one randomised trial which did not describe its methodology in sufficient detail to assess risk of bias and quality, excluded 27% of patients after randomisation due to various reasons, and is probably not free from selective outcome reporting bias, there is insufficient evidence to conclude that in patients with colonic cancer liver metastases, electro-coagulation alone brings any significant benefit in terms of survival or recurrence compared with the control. In addition, there is insufficient evidence for the effectiveness of adding allopurinol or dimethyl sulphoxide to electro coagulation. The probability for selective outcome reporting bias in the trial is high. More randomised trials are needed in order to sufficiently validate electro coagulation with or without co-interventions. PMID- 23728693 TI - Home- or community-based programmes for treating malaria. AB - BACKGROUND: Malaria is an important cause of morbidity and mortality, in particular among children and pregnant women in sub-Saharan Africa. Prompt access to diagnosis and treatment with effective antimalarial drugs is a central component of the World Health Organization's (WHO) strategy for malaria control. Home- or community-based programmes for managing malaria are one strategy that has been proposed to overcome the geographical barrier to malaria treatment. OBJECTIVES: To evaluate home- and community-based management strategies for treating malaria. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials published in The Cochrane Library; MEDLINE; EMBASE; Science Citation Index; PsycINFO/LIT; CINAHL; WHO clinical trial registry platform; and the metaRegister of Controlled Trials up to September 2012. SELECTION CRITERIA: Randomized controlled trials (RCTs) and non-RCTs that evaluated the effects of a home- or community-based programme for treating malaria in a malaria endemic setting. DATA COLLECTION AND ANALYSIS: Two authors independently screened and selected studies, extracted data, and assessed the risk of bias. Where possible the effects of interventions are compared using risk ratios (RR), and presented with 95% confidence intervals (CI). The quality of the evidence was assessed using the GRADE approach. MAIN RESULTS: We identified 10 trials that met the inclusion criteria. The interventions involved brief training of basic-level health workers or mothers, and most provided the antimalarial for free or at a highly subsidized cost. In eight of the studies, fevers were treated presumptively without parasitological confirmation with microscopy or a rapid diagnostic test (RDT). Two studies trained community health workers to use RDTs as a component of community management of fever.Home- or community-based strategies probably increase the number of people with fever who receive an appropriate antimalarial within 24 hours (RR 2.27, 95% CI 1.79 to 2.88 in one trial; RR 9.79, 95% CI 6.87 to 13.95 in a second trial; 3099 participants, moderate quality evidence). They may also reduce all-cause mortality, but to date this has only been demonstrated in rural Ethiopia (RR 0.58, 95% CI 0.44 to 0.77, one trial, 13,677 participants, moderate quality evidence).Hospital admissions in children were reported in one small trial from urban Uganda, with no effect detected (437 participants, very low quality evidence). No studies reported on severe malaria. For parasitaemia prevalence, the study from urban Uganda demonstrated a reduction in community parasite prevalence (RR 0.22, 95% CI 0.08 to 0.64, 365 participants), but a second study in rural Burkina Faso did not (1006 participants). Home- or community-based programmes may have little or no effect on the prevalence of anaemia (three trials, 3612 participants, low quality evidence). None of the included studies reported on adverse effects of using home or community-based programmes for treating malaria.In two studies which trained community health workers to only prescribe antimalarials after a positive RDT, prescriptions of antimalarials were reduced compared to the control group where community health workers used clinical diagnosis (RR 0.39, 95% CI 0.18 to 0.84, two trials, 5944 participants, moderate quality evidence). In these two studies, mortality and hospitalizations remained very low in both groups despite the lower use of antimalarials (two trials, 5977 participants, low quality evidence). AUTHORS' CONCLUSIONS: Home- or community-based interventions which provide antimalarial drugs free of charge probably improve prompt access to antimalarials, and there is moderate quality evidence from rural Ethiopia that they may impact on childhood mortality when implemented in appropriate settings.Programmes which treat all fevers presumptively with antimalarials lead to overuse antimalarials, and potentially undertreat other causes of fever such as pneumonia. Incorporating RDT diagnosis into home- or community-based programmes for malaria may help to reduce this overuse of antimalarials, and has been shown to be safe under trial conditions. PMID- 23728694 TI - Fibrin glue instillation under skin flaps to prevent seroma-related morbidity following breast and axillary surgery. AB - BACKGROUND: Fibrin glue (FG) combines fibrinogen and thrombin, under the presence of factor XIII and calcium chloride, and produces a 'fibrin clot' as would occur through the natural clotting cascade. FG is thought to close over any small vessels including lymphatics that are too small for conventional surgical closure, thereby reducing seroma formation, seroma incidence and related comorbidities. OBJECTIVES: To assess the evidence on the effectiveness of FG in people undergoing breast and axillary surgery and to establish whether FG is an efficient modality to prevent postoperative seroma and seroma-related outcomes. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's (CBCG) Specialised Register (9 December 2011), the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1 2012), MEDLINE (9 December 2011), EMBASE (9 December 2011), LILACS (22 October 2012), SCI-E (22 October 2012), the World Health Organization's International Clinical Trial Registry (9 December 2011) and ClinicalTrials.gov (22 October 2012). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the effectiveness of FG in terms of reducing the postoperative seroma incidence and related comorbidities in people undergoing breast and axillary surgery. DATA COLLECTION AND ANALYSIS: At least two review authors independently scrutinised search results, selected eligible studies and extracted the data. The pooled analysis of the extracted data was achieved by the statistical analysis on Review Manager software. The quality of studies was assessed using The Cochrane Collaboration's 'Risk of bias' tool. MAIN RESULTS: The search of four standard electronic databases yielded 119 potentially relevant studies but only 18 RCTs involving 1252 people were found suitable for statistical analysis. There was significant heterogeneity among trials and the majority of trials were of poor quality. The use of FG under skin flaps following breast and axillary surgery failed to reduce the incidence of postoperative seroma (risk ratio (RR) 1.02; 95% Confidence Interval (CI) 0.90 to 1.16, P value = 0.73), mean volume of seroma (standardised mean difference (SMD) -0.25; 95% CI 0.92 to 0.42, P value = 0.46), wound infection (RR 1.05; 95% CI 0.63 to 1.77, P value = 0.84), postoperative complications (RR 1.13; 95% CI 0.63 to 2.04, P value = 0.68) and length of hospital stay (SMD -0.2; 95% CI -0.78 to 0.39, P value = 0.51). FG reduced the total volume of drained seroma (SMD -0.75, 95% CI -1.24 to 0.26, P value = 0.003) and duration of persistent seromas requiring frequent aspirations (SMD -0.59; CI 95% -0.95 to -0.23, P value = 0.001). AUTHORS' CONCLUSIONS: FG did not influence the incidence of postoperative seroma, the mean volume of seroma, wound infections, complications and the length of hospital stays in people undergoing breast cancer surgery. Due to significant methodological and clinical diversity among the included studies this conclusion may be considered weak and biased. Therefore, a major multicentre and high quality RCT is required to validate these findings. PMID- 23728695 TI - Xiongshao for restenosis after percutaneous coronary intervention in patients with coronary heart disease. AB - BACKGROUND: Percutaneous coronary intervention (PCI) with stent placement is a standard treatment for coronary heart disease (CHD). In-stent restenosis after PCI remains an important clinical problem. Xiongshao capsule has been reported to be beneficial in preventing restenosis after PCI in CHD patients. However, the strength of evidence to support its use is unclear. OBJECTIVES: To systematically assess the efficacy and safety of Chinese herbal medicine Xiongshao capsule in preventing restenosis after PCI in patients with CHD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 3 of 2012), MEDLINE (OVID) (1948 to week 1 March 2012), EMBASE (OVID) (1980 to week 10 2012), ISI Web of Science with Conference Proceedings (1970 to 14 March 2012), LILACS (1982 to 15 March 2012), Chinese biomedical literature database (1980 to May 2012), China National Knowledge Infrastructure (1994 to May 2012), Chinese Medical Current Contents (1994 to May 2012), VIP Database for Chinese Technical Periodicals (1989 to May 2012), Chinese Master's Theses Full-Text Database (1994 to May 2012), China Doctor Dissertation Full-Text Database (1994 to May 2012), and China Proceedings of Conference Full-Text Database (1994 to May 2012). We also searched ongoing trials and research registries. SELECTION CRITERIA: All randomised controlled trials comparing Xiongshao capsule alone/plus conventional western medicine with the same conventional western medicine alone/plus placebo in participants with CHD who met the recognised diagnostic criteria and had successfully undergone a PCI procedure were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials and extracted data. Two review authors independently assessed the risk of bias of included trials using The Cochrane Collaboration tool, and any disagreements were resolved by discussion with a third review author. Data were pooled for meta-analysis using the fixed-effect model, and the results were expressed as risk ratios (RRs) with 95% confidence intervals (CIs). MAIN RESULTS: Four trials involving 649 participants were included in this review. Two of these trials (459 participants) were designed as randomised, double-blind, placebo controlled trials with an adequate methodological description; the other two trials (190 participants) described an inadequate methodological design. All four trials with 649 participants were included in the meta-analysis. Significant differences were noted in rates of restenosis, recurrence angina pectoris, and serious cardiovascular adverse events between Xiongshao capsule plus conventional western medicine and the same conventional western medicine alone; RR values (95% CIs) were 0.41 (0.22 to 0.75), 0.47 (0.31 to 0.72), and 0.47 (0.25 to 0.90), respectively. Xiongshao capsule plus conventional western medicine showed more significant reductions in restenosis (RR 0.52, 95% CI 0.33 to 0.80), recurrence angina pectoris (RR 0.26, 95% CI 0.18 to 0.38), and serious cardiovascular adverse events (RR 0.45, 95% CI 0.28 to 0.70) than the same conventional western medicine plus placebo. Safety outcomes and adverse events of the Xiongshao capsule were reported in two trials, which reported no adverse events. AUTHORS' CONCLUSIONS: The summary estimates indicate a protective effect of Xiongshao on restenosis and suggest that Xiongshao capsule may be used to prevent restenosis after a PCI procedure in CHD patients. However, this evidence is derived from small randomised trials, all conducted in China, and two of the included trials showed important methodological limitations that undermine the validity of the findings. Additional high-quality research trials with sufficient sample size are required. PMID- 23728696 TI - Flow-regulated versus differential pressure-regulated shunt valves for adult patients with normal pressure hydrocephalus. AB - BACKGROUND: Since 1965 many ventriculo-peritoneal shunt systems have been inserted worldwide to treat hydrocephalus. The most frequent indication in adults is normal pressure hydrocephalus (NPH), a condition that can be difficult to diagnose precisely. Surgical intervention with flow-regulated and differential pressure-regulated ventriculo-peritoneal shunts remains controversial. Knowledge about the benefits and harms of these interventions is limited. OBJECTIVES: The objective of this review is to summarize the evidence on benefits and harms of flow-regulated versus differential pressure-regulated shunt valves for adult patients with NPH, based on reported findings of randomised clinical trials. SEARCH METHODS: The ALOIS (www.medicine.ox.ac.uk/alois), the Cochrane Dementia and Cognitive Improvement Group Specialized Register; MEDLINE (from 1950) (Ovid SP); EMBASE (from 1980) (Ovid SP); CINAHL (from 1980) (EBSCOhost); PsycINFO (from 1806) (Ovid SP); LILACS (from 1982 ) (BIREME); ClinicalTrials.gov; Umin Japan Trial Register; WHO portal;The Cochrane Library's Central Register of Controlled trials (CENTRAL); ISI Web of Knowledge Conference Proceedings; Index to Theses; and Australasian Digital Theses were searched until May 16, 2012.The search terms used were NPH, "normal pressure hydrocephalus," iNPH, idiopathic normal pressure hydrocephalus, sNPH, and "secondary normal pressure hydrocephalus." SELECTION CRITERIA: We planned to include randomised clinical trials comparing flow regulated versus differential pressure-regulated shunt valves. DATA COLLECTION AND ANALYSIS: Two authors with expert knowledge within the field independently reviewed studies for eligibility, assessed risk of bias, and extracted data. MAIN RESULTS: No randomised clinical trials comparing flow-regulated versus differential pressure-regulated shunt valves were found. AUTHORS' CONCLUSIONS: There is no evidence from randomised clinical trials indicates that flow regulated and differential pressure-regulated shunt valves differ with regard to clinical outcome, shunt failure, or intervention risks. Randomised clinical trials are needed that take into account the large number of VP shunts implanted each year in patients with NPH. PMID- 23728697 TI - Foam dressings for venous leg ulcers. AB - BACKGROUND: Venous leg ulcers are a common and recurring type of chronic or complex wound that are associated with considerable cost to patients and to healthcare providers. Primary wound contact dressings are usually applied beneath compression devices with the aim of aiding healing. Foam dressings are used frequently, and a variety of foam products is available on the market. The evidence base to guide dressing choice, however, is sparse. OBJECTIVES: To determine the effects of foam dressings on the healing of venous leg ulcers. SEARCH METHODS: In October 2012 we searched The Cochrane Wounds Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); the Database of Abstracts of Reviews of Effects (DARE) (The Cochrane Library); the Economic Evaluation Database (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; EBSCO CINAHL. There were no restrictions based on language or date of publication. SELECTION CRITERIA: We included published or unpublished randomised controlled trials (RCTs) that evaluated the effects of any type of foam dressing in the treatment of venous ulcers. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction and risk of bias assessment. Meta-analysis was undertaken when deemed feasible and appropriate. MAIN RESULTS: Twelve RCTs (1023 participants) reporting 14 comparisons were included in this review. There was no difference in healing outcomes between hydrocellular foam dressings and polyurethane foam dressings (three RCTs). Pooled data across five RCTs (418 participants) showed no statistically significant difference between foam dressings and hydrocolloid dressings in the proportion of ulcers healed at 12 to 16 weeks (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.81 to 1.22). No statistically significant between-group differences in healing outcomes were detected when foam dressings were compared with: paraffin gauze (two RCTs); hydrocapillary dressing (one RCT); knitted viscose dressing (one RCT); and protease modulating matrix (one RCT). No statistically significant between-group differences in the proportion of participants experiencing adverse events were detected when hydrocellular foam dressings were compared with polyurethane foam dressings, or when foam dressings were compared with hydrocapillary, hydrocolloid, or knitted viscose dressings (one RCT for each comparison). Six RCTs were considered as being at overall high risk of bias, and the remaining six RCTs were considered to be at overall unclear risk of bias. No included RCT had an overall low risk of bias. AUTHORS' CONCLUSIONS: The current evidence base does not suggest that foam dressings are more effective in the healing of venous leg ulcers than other wound dressing treatments. The evidence in this area is of low quality. Further evidence is required from well-designed and rigorously-conducted RCTs, that employ methods to minimise bias and report them clearly, before any definitive conclusions can be made regarding the efficacy of foam dressings in the management of venous leg ulcers. PMID- 23728698 TI - Face to face interventions for informing or educating parents about early childhood vaccination. AB - BACKGROUND: Childhood vaccination (also described as immunisation) is an important and effective way to reduce childhood illness and death. However, there are many children who do not receive the recommended vaccines because their parents do not know why vaccination is important, do not understand how, where or when to get their children vaccinated, disagree with vaccination as a public health measure, or have concerns about vaccine safety.Face to face interventions to inform or educate parents about routine childhood vaccination may improve vaccination rates and parental knowledge or understanding of vaccination. Such interventions may describe or explain the practical and logistical factors associated with vaccination, and enable parents to understand the meaning and relevance of vaccination for their family or community. OBJECTIVES: To assess the effects of face to face interventions for informing or educating parents about early childhood vaccination on immunisation uptake and parental knowledge. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 7); MEDLINE (OvidSP) (1946 to July 2012); EMBASE + Embase Classic (OvidSP) (1947 to July 2012); CINAHL (EbscoHOST) (1981 to July 2012); PsycINFO (OvidSP) (1806 to July 2012); Global Health (CAB) (1910 to July 2012); Global Health Library (WHO) (searched July 2012); Google Scholar (searched September 2012), ISI Web of Science (searched September 2012) and reference lists of relevant articles. We searched for ongoing trials in The International Clinical Trials Registry Platform (ICTRP) (searched August 2012) and for grey literature in The Grey Literature Report and OpenGrey (searched August 2012). We also contacted authors of included studies and experts in the field. There were no language or date restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) and cluster RCTs evaluating the effects of face to face interventions delivered to individual parents or groups of parents to inform or educate about early childhood vaccination, compared with control or with another face to face intervention. Early childhood vaccines are all recommended routine childhood vaccines outlined by the World Health Organization, with the exception of human papillomavirus vaccine (HPV) which is delivered to adolescents. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed database search results for inclusion. Grey literature searches were conducted and reviewed by a single author. Two authors independently extracted data and assessed the risk of bias of included studies. We contacted study authors for additional information. MAIN RESULTS: We included six RCTs and one cluster RCT involving a total of 2978 participants. Three studies were conducted in low- or middle-income countries and four were conducted in high-income countries. The cluster RCT did not contribute usable data to the review. The interventions comprised a mix of single-session and multi-session strategies. The quality of the evidence for each outcome was low to very low and the studies were at moderate risk of bias overall. All these trials compared face to face interventions directed to individual parents with control.The three studies assessing the effect of a single-session intervention on immunisation status could not be pooled due to high heterogeneity. The overall result is uncertain because the individual study results ranged from no evidence of effect to a significant increase in immunisation.Two studies assessed the effect of a multi session intervention on immunisation status. These studies were also not pooled due to heterogeneity and the result was very uncertain, ranging from a non significant decrease in immunisation to no evidence of effect.The two studies assessing the effect of a face to face intervention on knowledge or understanding of vaccination were very uncertain and were not pooled as data from one study were skewed. However, neither study showed evidence of an effect on knowledge scores in the intervention group. Only one study measured the cost of a case management intervention. The estimated additional cost per fully immunised child for the intervention was approximately eight times higher than usual care.The review also considered the following secondary outcomes: intention to vaccinate child, parent experience of intervention, and adverse effects. No adverse effects related to the intervention were measured by any of the included studies, and there were no data on the other outcomes of interest. AUTHORS' CONCLUSIONS: The limited evidence available is low quality and suggests that face to face interventions to inform or educate parents about childhood vaccination have little to no impact on immunisation status, or knowledge or understanding of vaccination. There is insufficient evidence to comment on the cost of implementing the intervention, parent intention to vaccinate, parent experience of the intervention, or adverse effects. Given the apparently limited effect of such interventions, it may be feasible and appropriate to incorporate communication about vaccination into a healthcare encounter, rather than conduct it as a separate activity. PMID- 23728699 TI - Lifestyle interventions for chronic gout. AB - BACKGROUND: Although lifestyle interventions are commonly recommended in the management of patients with chronic gout, the evidence from trial data for their benefits and safety has not been previously examined in a systematic review. OBJECTIVES: The objective of this systematic review was to evaluate the benefits and safety of lifestyle interventions for the treatment of people with chronic gout. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE for studies on 5 April 2013. We also searched the 2010 to 2011 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) abstracts and performed a handsearch of the reference lists of included articles. SELECTION CRITERIA: Studies were included if they were randomised or quasi-randomised controlled trials (RCTs or CCTs) which compared lifestyle interventions to another therapy (active or placebo) in patients with chronic gout. Outcomes of interest were changes in gout attack frequency, joint pain, serum urate levels, tophus size, function, quality of life and adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently applied methods recommended by The Cochrane Collaboration for the selection, appraisal, data collection and synthesis of studies. We assessed the quality of the body of evidence for each outcome using the GRADE approach. MAIN RESULTS: Only one study (120 participants), at moderate risk of bias, was included in the review. Patients were randomised to one of three interventions: either skim milk powder (SMP) enriched with glycomacropeptide (GMP) and G600, non enriched SMP or lactose powder, over a three-month period. The frequency of acute gout attacks, measured as the number of flares per month, decreased in all three groups over the three-month study period. Low quality evidence indicated that there was no difference between the SMP/GMP/G600 group and combined control groups (SMP and lactose powder) at three months (mean difference (MD) -0.21, 95% confidence interval (CI) -0.76 to 0.34). There were no significant between-group differences in terms of withdrawals due to adverse effects (risk ratio (RR) 1.27, 95% CI 0.53 to 3.03), and serious adverse events resulting in hospitalisation (2/40 SMP/GMP/G600 group versus 3/80 controls; RR 1.33, 95% CI 0.23 to 7.66). Gastrointestinal adverse effects were the most commonly reported. Pain from self reported gout flares, measured on a 10-point Likert scale, improved more in the SMP/GMP/G600 group compared to controls (MD -1.03, 95% CI -1.96 to -0.10), an absolute difference of 10% (absolute risk difference -0.10, 95% CI -0.20 to 0.01). This is unlikely to be of clinical significance. Physical function, tophus regression and serum urate normalisation were not reported in this study. AUTHORS' CONCLUSIONS: While there is good evidence from observational studies of an association between various lifestyle risk factors and gout development, there is a paucity of high-quality evidence from randomised controlled trials to either support or refute the use of lifestyle modifications for improving outcomes in people with chronic gout. PMID- 23728700 TI - Laparoscopic versus open liver resection for benign and malignant hepatic lesions in adults. AB - BACKGROUND: Liver (hepatic) resection refers to removal of the whole liver, or one or more of its vascular segments. Elective liver resection is mainly performed for benign and malignant liver tumours. The operation can be performed as an open procedure or with a laparoscopic approach. With the advancement of laparoscopic skills and equipment, liver resection is selectively being carried out with this approach. A laparoscopic procedure is intended to be less severe, allowing for quicker healing, fewer complications, and a shorter hospital stay as the insult to the body is minimised. However, evidence about the efficacy of this approach when compared to an open procedure is still scattered. Current practice at different hepato-pancreato-biliary centres is based on the clinical judgement of experts in their field, which is highly insufficient in terms of evidence. OBJECTIVES: To assess the benefits and harms of laparoscopic versus open liver resection for benign or malignant lesions on the liver in adult patients. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until February 2013. We also conducted searches of reference lists of relevant articles and reviews, conference proceedings, and ongoing trial databases. SELECTION CRITERIA: We searched for randomised clinical trials of participants undergoing liver resection for benign or malignant lesions which reported on benefits and harms. We searched for quasi-randomised or observational studies for reports of harm. DATA COLLECTION AND ANALYSIS: No data from randomised clinical trials could be collected. MAIN RESULTS: Two authors performed study selection independently. We were not able to identify any randomised clinical trials that met the inclusion criteria of our review protocol. We identified two ongoing randomised clinical trials performed in Europe with data yet to be published. We retrieved a few observational studies (prospective and retrospective) with the searches for randomised clinical trials. They included a limited number of participants in whom laparoscopic and open liver resection was compared. Since these studies were non-randomised observational studies, the results for any adverse events are not included in the review as the risk of bias in such studies is high. AUTHORS' CONCLUSIONS: No conclusions can be made at this time as no randomised clinical trials are available. In addition to the two ongoing randomised clinical trials for which results are expected to be published in the near future, well-designed, prospective, randomised clinical trials are needed in order to evaluate the benefits and harms of the laparoscopic procedure versus open liver resection. PMID- 23728702 TI - It's time for alltrials registered and reported. PMID- 23728701 TI - Topical herbal therapies for treating osteoarthritis. AB - BACKGROUND: Before extraction and synthetic chemistry were invented, musculoskeletal complaints were treated with preparations from medicinal plants. They were either administered orally or topically. In contrast to the oral medicinal plant products, topicals act in part as counterirritants or are toxic when given orally. OBJECTIVES: To update the previous Cochrane review of herbal therapy for osteoarthritis from 2000 by evaluating the evidence on effectiveness for topical medicinal plant products. SEARCH METHODS: Databases for mainstream and complementary medicine were searched using terms to include all forms of arthritis combined with medicinal plant products. We searched electronic databases (Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, CINAHL, ISI Web of Science, World Health Organization Clinical Trials Registry Platform) to February 2013, unrestricted by language. We also searched the reference lists from retrieved trials. SELECTION CRITERIA: Randomised controlled trials of herbal interventions used topically, compared with inert (placebo) or active controls, in people with osteoarthritis were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed the risk of bias of included studies and extracted data. MAIN RESULTS: Seven studies (six different medicinal plant interventions; 785 participants) were included. Single studies (five studies) and non-comparable studies (two studies) precluded pooling of results.Moderate evidence from a single study of 174 people with hand osteoarthritis indicated that treatment with Arnica extract gel probably results in similar benefits as treatment with ibuprofen (non-steroidal anti-inflammatory drug) with a similar number of adverse events. Mean pain in the ibuprofen group was 44.2 points on a 100 point scale; treatment with Arnica gel reduced the pain by 4 points after three weeks: mean difference (MD) -3.8 points (95% confidence intervals (CI) -10.1 to 2.5), absolute reduction 4% (10% reduction to 3% increase). Hand function was 7.5 points on a 30 point scale in the ibuprofen-treated group; treatment with Arnica gel reduced function by 0.4 points (MD -0.4, 95% CI -1.75 to 0.95), absolute improvement 1% (6% improvement to 3% decline)). Total adverse events were higher in the Arnica gel group (13% compared to 8% in the ibuprofen group): relative risk (RR) 1.65 (95% CI 0.72 to 3.76).Moderate quality evidence from a single trial of 99 people with knee osteoarthritis indicated that compared with placebo, Capsicum extract gel probably does not improve pain or knee function, and is commonly associated with treatment-related adverse events including skin irritation and a burning sensation. At four weeks follow-up, mean pain in the placebo group was 46 points on a 100 point scale; treatment with Capsicum extract reduced pain by 1 point (MD -1, 95% CI -6.8 to 4.8), absolute reduction of 1% (7% reduction to 5% increase). Mean knee function in the placebo group was 34.8 points on a 96 point scale at four weeks; treatment with Capsicum extract improved function by a mean of 2.6 points (MD -2.6, 95% CI -9.5 to 4.2), an absolute improvement of 3% (10% improvement to 4% decline). Adverse event rates were greater in the Capsicum extract group (80% compared with 20% in the placebo group, rate ratio 4.12, 95% CI 3.30 to 5.17). The number needed to treat to result in adverse events was 2 (95% CI 1 to 2).Moderate evidence from a single trial of 220 people with knee osteoarthritis suggested that comfrey extract gel probably improves pain without increasing adverse events. At three weeks, the mean pain in the placebo group was 83.5 points on a 100 point scale. Treatment with comfrey reduced pain by a mean of 41.5 points (MD -41.5, 95% CI -48 to -34), an absolute reduction of 42% (34% to 48% reduction). Function was not reported. Adverse events were similar: 6% (7/110) reported adverse events in the comfrey group compared with 14% (15/110) in the placebo group (RR 0.47, 95% CI 0.20 to 1.10).Although evidence from a single trial indicated that adhesive patches containing Chinese herbal mixtures FNZG and SJG may improve pain and function, the clinical applicability of these findings are uncertain because participants were only treated and followed up for seven days. We are also uncertain if other topical herbal products (Marhame-Mafasel compress, stinging nettle leaf) improve osteoarthritis symptoms due to the very low quality evidence from single trials.No serious side effects were reported. AUTHORS' CONCLUSIONS: Although the mechanism of action of the topical medicinal plant products provides a rationale basis for their use in the treatment of osteoarthritis, the quality and quantity of current research studies of effectiveness are insufficient. Arnica gel probably improves symptoms as effectively as a gel containing non-steroidal anti inflammatory drug, but with no better (and possibly worse) adverse event profile. Comfrey extract gel probably improves pain, and Capsicum extract gel probably will not improve pain or function at the doses examined in this review. Further high quality, fully powered studies are required to confirm the trends of effectiveness identifed in studies so far. PMID- 23728703 TI - Assessing risk of bias in randomised clinical trials included in Cochrane Reviews: the why is easy, the how is a challenge. PMID- 23728704 TI - Multiple sclerosis documentation system (MSDS): moving from documentation to management of MS patients. AB - The long disease duration of multiple sclerosis and the increasing therapeutic options require a individualized therapeutic approach which should be carefully documented over years of observation. To switch from MS documentation to an innovative MS management, new computer- and internet-based tools could be implemented as we could demonstrate with the novel computer-based patient management system "multiple sclerosis management system 3D" (MSDS 3D). MSDS 3D allows documentation and management of visit schedules and mandatory examinations via defined study modules by integration of data input from various sources (patients, attending physicians and MS nurses). It provides forms for the documentation of patient visits as well as clinical and diagnostic findings. Information can be collected via interactive touch screens. Specific modules allow the management of highly efficacious treatments as natalizumab or fingolimod. MSDS can be used to transfer the documented data to databases as, e.g. the registry of the German MS society or REGIMS. MSDS has already been implemented successfully in clinical practice and is currently being evaluated in a multicenter setting. High-quality management and documentation are crucial for improvements in clinical practice and research work. PMID- 23728705 TI - Clinical potential of the anticancer drug sensitivity test for patients with synchronous stage IV colorectal cancer. AB - PURPOSE: We retrospectively evaluated the clinical efficacy and feasibility of a collagen gel droplet-embedded culture drug sensitivity test (CD-DST) to guide therapy for patients with stage IV colorectal cancer (CRC). METHODS: We investigated 38 patients with stage IV CRC. All patients were younger than 85 years and had untreated evaluable metastatic lesions. The primary tumors were surgically resected, and the tissue samples were investigated by CD-DST. Patients treated with in vitro sensitive drugs were defined as Group A (n = 14), while those treated with in vitro non-sensitive drugs were defined as Group B (n = 24). We evaluated response rate (RR), progression-free survival (PFS), and overall survival (OS). RESULTS: RR was 85.71 % in Group A and 41.67 % in Group B (p = 0.0079). The median PFS was 696.5 days in Group A and 297.5 days in Group B (p = 0.0326). The median OS was 1,023.4 days in Group A and 518.5 days in Group B (p = 0.0061). CONCLUSIONS: The CD-DST can define chemoresistant and chemosensitive tumors. The use of CD-DST might be one of the tools to supplement informed consent prior to initiation of therapy. PMID- 23728706 TI - Multicenter phase II study of capecitabine combined with nedaplatin for recurrent and metastatic nasopharyngeal carcinoma patients after failure of cisplatin-based chemotherapy. AB - PURPOSE: There is no standard second-line regimen for recurrent and metastatic nasopharyngeal carcinoma patients after failure of cisplatin-based chemotherapy. A multicenter phase II study was conducted to evaluate the efficacy and toxicity of capecitabine combined with nedaplatin for these patients. PATIENTS AND METHODS: In the multicenter, open-label, single-arm phase II study, patients with recurrent and metastatic nasopharyngeal carcinoma who failed to previous cisplatin-based chemotherapy were enrolled. Patients received oral capecitabine (1,000 mg/m(2) twice daily from day 1 to 14) and intravenous nedaplatin (80 mg/m(2), day 1) every 3 weeks for two cycles at least. RESULTS: A total of forty eight patients were enrolled and included in the intention-to-treat analysis of efficacy and adverse events. Treatment was well tolerated. Grade 3/4 toxicities included neutropenia (8.4 %), anemia (2.1 %), diarrhea (4.2 %), stomatitis (6.3 %), and hand-foot syndrome (HFS) (4.2 %). There were two complete response (4.2 %), eighteen partial responses (37.5 %), giving an overall response rate of 41.7 % [95 % confidence interval (CI) 27.7-55.8]. With a median follow-up period of 12.1 months, the median time to progression was 5.8 months (95 % CI 3.9-7.8 months) and median overall survival was 12.4 months (95 % CI 9.6-16.8 months). CONCLUSION: Capecitabine combined with nedaplatin offers a satisfactory clinical activity and an acceptable safety profile for recurrent and metastatic nasopharyngeal carcinoma patients after failure of cisplatin-based chemotherapy. PMID- 23728708 TI - Non-invasive speed of sound measurement in cartilage by use of combined magnetic resonance imaging and ultrasound: an initial study. AB - The speed of sound (SOS) is available as an index of elasticity. Using a combination of magnetic resonance imaging (MRI) and ultrasound, one can measure the SOS. In this study, we verified the accuracy of SOS measurements by using a combination of MRI and ultrasound. The accuracy of the thickness measurements was confirmed by comparison of the results obtained with use of MRI with those of a non-contact laser, and the accuracy of the calculated SOS values was confirmed by comparison of the results of the combined method and ultrasound measurements with the transmission method ex vivo. There was no significant difference between thickness measurements by MRI and those with the non-contact laser, and there was a significant linear correlation between SOS measurement results by use of the combined method and those by use of the transmission method. We also showed that the SOS values obtained agreed with those of previously published studies. PMID- 23728707 TI - The number of Japanese radiologic technologists will be increased in 40 years. AB - It is essential to predict the long-term supply and demand for the number of radiologic technologists as medical resources. However, it is difficult to predict the number of Japanese radiologic technologists due to complex and intertwining factors. Our purpose in this study was to predict the future number of radiologic technologists using the concept of system dynamics (SD), and to clarify the effects of relevant factors. In order to estimate the number of Japanese radiologic technologists, we constructed a flow diagram using the concept of SD. We simulated the number of radiologic technologists for the following 4 cases: maintaining the status quo, a change in the pass rate for the national examination, a change in the post-graduate employment rate, and a change in the rate of continuing education. The result for the predicted number of radiologic technologists was 50,509 in 20 years, which is 4,394 (9.5%) more than the present number, and 50,166 in 40 years, which is 4,051 (8.8%) more than the present number. For the factors influencing the number of technologists, the influence of the pass rate on the national examination and that of the rate for post-graduate employment was larger than that of the rate of continuing education in graduate school. The number of Japanese radiologic technologists will increase until 2033 and decrease until 2042, and it does not change after 2042 in case of maintaining the status quo. Implementing the concept of SD allowed us easily to clarify the factors influencing the predicted number of radiologic technologists. PMID- 23728709 TI - A comparison of shimming techniques for optimizing fat suppression in MR mammography. AB - We evaluated the degree of inhomogeneities of fat suppression using the fully automated three-dimensional breast shimming technique (Image Based-Smart: IB Smart) and manual setting of a rectangular parallelepiped shim (volume shimming) in MR mammography. Information on breast shape was collected from 9 patients whose images were insufficiently fat-suppressed. A breast phantom made of a thermoplastic sheet was used. Shimming of the magnetic field was done with IB Smart and various dimensions of volume shims: the anterior to posterior/right to left/head to foot directions were set to 75-150/150-350/50-150 mm. The volumes of inhomogeneously suppressed fat were measured. The calculated volume with inhomogeneous fat suppression with use of IB-Smart was 13.3 * 10(4) mm(3). The smallest volume of inhomogeneous fat suppression with volume shimming was 5.4 * 10(4) mm(3) when the anterior-posterior/right-left/head-foot directions were set to 75/350/50 mm. Our results show that using optimized dimensions of volume shims enables better fat suppression than does IB-Smart. PMID- 23728710 TI - Comment on "nutrient reference values for bioactives: new approaches needed? A conference report" (European Journal of Nutrition, April 2013, Volume 52, Issue 1 Supplement, pp 1-9). PMID- 23728711 TI - Adipose tissue remodeling in rats exhibiting fructose-induced obesity. AB - PURPOSE: To explore the effect of a fructose-rich diet on morphological and functional changes in white adipose tissue (WAT) that could contribute to the development of insulin resistance. METHODS: Adult sedentary rats were fed a fructose-rich diet for 8 weeks. Glucose tolerance test was carried out together with measurement of plasma triglycerides, non-esterified fatty acids and lipid peroxidation. In subcutaneous abdominal and intra-abdominal WAT, number and size of adipocytes together with cellular insulin sensitivity and lipolytic activity were assessed. RESULTS: Rats fed a fructose-rich diet exhibited a significant increase in plasma insulin, triglycerides, non-esterified fatty acids and lipid peroxidation, together with significantly increased body lipids and epididymal and mesenteric WAT, compared to controls. Mean adipocyte volume in subcutaneous abdominal WAT was significantly lower, while mean adipocyte volume in intra abdominal WAT was significantly higher, in rats fed a fructose-rich diet compared to controls. A significant increase in larger adipocytes and a significant decrease in smaller adipocytes were found in intra-abdominal WAT in rats fed a fructose-rich diet compared to controls. Insulin's ability to inhibit lipolysis was blunted in subcutaneous abdominal and intra-abdominal adipocytes from fructose-fed rats. Accordingly, lower p-Akt/Akt ratio was found in WAT in rats fed a fructose-rich diet compared to controls. CONCLUSIONS: Long-term consumption of high levels of fructose elicits remarkable morphological and functional modifications, particularly in intra-abdominal WAT, that are highly predictive of obesity and insulin resistance and that contribute to the worsening of metabolic alterations peculiar in a fructose-rich, hypolipidic diet. PMID- 23728712 TI - Stem-directed growth of highly fluorescent silver nanoclusters for versatile logic devices. AB - This work described for the first time the stem-directed growth of silver nanoclusters (AgNCs) with high brightness using the well-chosen hairpin DNA structure. In comparison with the corresponding double-stranded (ds) DNA capped AgNCs, the fluorescence emission of hairpin DNA structure templated AgNCs were lighted up with 12.5-fold enhancement fluorescent intensity by sequence modification with T-loop. It provided a new prospect for precise placement of nanoscale optical elements onto DNA scaffolds. And these DNA protected AgNCs exhibited the base sequence, strand length and microenvironment-dependent fluorescent properties. Benefiting from these properties, versatile logic gates (or, not, inhibit, XNOR, implication) were constructed using different ions as inputs with AgNCs as signal transducer. PMID- 23728713 TI - Presence, diversity and enumeration of functional genes (bssA and bamA) relating to toluene degradation across a range of redox conditions and inoculum sources. AB - The study investigates two functional genes for toluene degradation across three redox conditions (nitrate and sulfate amended and methanogenic). The genes targeted include benzylsuccinate synthase alpha-subunit (bssA) and a gene recently identified as being a strong indicator of anaerobic aromatic degradation, called 6-oxocylcohex-1-ene-1-carbonyl-CoA hydrolase (bamA). In all, sixteen different anaerobic toluene degrading microcosms were investigated using several primers sets targeting bssA and one primer set targeting bamA. One bssA primer set (7772f/8546r) was the most successful in producing a strong amplicon (eight from sixteen) with the other bssA primers sets producing strong amplicons in six or less samples. In contrast, the bamA primer set (bam-sp9 and bam-asp1) produced a strong amplicon in DNA extracted from all except one microcosm. Partial bssA and bamA sequences were obtained for a number of samples and compared to those available in GenBank. The partial bssA sequences (from nitrate amended and methanogenic microcosms) were most similar to Thauera sp. DNT-1, Thauera aromatica, Aromatoleum aromaticum EbN1 and bssA clones from a study involving sulfate reducing toluene degradation. The bamA sequences obtained could be placed into five previously defined clades (bamA-clade 1, Georgfuchsia/Azoarcus, Magnetospirillum/Thauera Syntrophus and Geobacter clades), with the placement generally depending on redox conditions. Gene numbers were also correlated with toluene degradation and the final gene number for both genes differed considerably between the range of redox conditions. The work is the first in depth investigation of bamA diversity over a range of redox conditions and inoculum sources. PMID- 23728714 TI - Design and synthesis of a ruthenium(II) complex-based luminescent probe for highly selective and sensitive luminescence detection of nitric oxide. AB - Nitric oxide (NO) is one of the most important intercellular signaling molecules, and plays important roles in various biological systems. In this work, a unique Ru(II) complex, tris[(5-(4-methylamino-3-aminobenzylamino)-1,10-phenanthroline)] ruthenium(II) hexafluorophosphate [Ru(MAA-phen)3][PF6]2, has been designed and synthesized as a luminescent probe for the detection of NO in aqueous media. The complex itself is almost non-luminescent, but can specifically react with NO under the aerobic conditions to afford its highly luminescent triazole derivative in aqueous media, [Ru(MTA-phen)3](2+) (MTA-phen: methyl-trazolebenzylamino-1,10 phenanthroline), accompanied by a 302-fold increase in luminescence intensity at 598 nm with a 130 nm Stokes shift. The luminescence response of [Ru(MAA phen)3](2+) to NO is rapid, highly specific without interferences of other reactive oxygen/nitrogen species, and highly stable against the pH changes in the range of pH 4.5-9.5. These features enable [Ru(MAA-phen)3](2+) to be used as a probe for the highly selective and sensitive luminescence detection of NO in weakly acidic, neutral, and weakly basic media. PMID- 23728716 TI - Central pontine and extra-pontine myelinolysis after correction of severe hypoglycemia. PMID- 23728715 TI - Adherence to anti-Parkinson drug therapy in the "REASON" sample of Italian patients with Parkinson's disease: the linguistic validation of the Italian version of the "Morisky Medical Adherence Scale-8 items". AB - Information about patients' adherence to therapy represents a primary issue in Parkinson's disease (PD) management. To perform the linguistic validation of the Italian version of the self-rated 8-Item Morisky Medical Adherence Scale (MMAS-8) and to describe in a sample of Italian patients affected by PD the adherence to anti-Parkinson drug therapy and the association between adherence and some socio demographic and clinical features. MMAS-8 was translated into Italian language by two independent Italian mother-tongue translators. The consensus version was then back-translated by an English mother-tongue translator. This translation process was followed by a consensus meeting between the authors of translation and investigators and then by two comprehension tests. The translated version of the MMAS-8 scale was then administered at the baseline visit of the "REASON" study (Italian Study on the Therapy Management in Parkinson's disease: Motor, Non Motor, Adherence and Quality Of Life Factors) in a large sample of PD patients. The final version of the MMAS-8 was easily understood. Mean +/- SD MMAS-8 score was 6.1 +/- 1.2. There were no differences in adherence to therapy in relationship to disease severity, gender, educational level or decision to change therapy. The Italian version of MMAS-8, the key tool of the REASON study to assess the adherence to therapy, has shown to be understandable to patients with PD. Patients enrolled in the REASON study showed medium therapy adherence. PMID- 23728717 TI - Common functional polymorphisms in SLC6A4 and COMT genes are associated with circadian phenotypes in a South American sample. AB - The molecular study of circadian rhythms in humans could be an excellent approach to understand the relation between genes and behavior. It is possible that variations in genes involved in neurotransmission and/or synaptic plasticity, such as catechol-O-methyltransferase (COMT) and serotonin transporter (SLC6A4) could be of particular interest in understanding human circadian phenotypes. The aim of this study is to analyze the possible and novel associations of the functional polymorphisms in COMT and SLC6A4 genes (Val158Met and 5-HTTLPR) and circadian phenotypes in healthy Colombian subjects. 191 university students were genotyped for two functional polymorphisms in COMT and SLC6A4 genes (rs4680 and rs4795541). We applied two scales to measure phenotypic patterns of human circadian rhythms: Composite Scale of Morningness (CSM) and Epworth Sleepiness Scale (ESS). We found a significant association between 5-HTTLPR polymorphism and morning preference score (CSM) (p = 0.027) using an overdominant genotypic model and association of COMT Val158Met with daytime sleepiness (ESS scores) (p = 0.038) in a genotypic recessive model. These results were supported by differences in genotype frequencies between circadian typologies for SLC6A4 gene (p = 0.007) and categories of diurnal sleepiness for COMT gene (p = 0.032). Our results suggest, for the first time, a significant relationship between functional SLC6A4 and COMT polymorphisms with specific human circadian phenotypes: morning preference and diurnal sleepiness. These results need to be replicated in other populations. Further study of functional polymorphisms in other synaptic genes could be of relevance for the identification of novel candidate genes for circadian phenotypes, and related endophenotypes of neuropsychiatric importance, in healthy humans. PMID- 23728718 TI - Multiple system atrophy with prolonged survival: is late onset of dysautonomia the clue? AB - Multiple system atrophy (MSA) is a neurodegenerative disease characterised by cardiovascular autonomic failure and/or urinary dysfunctions, associated with parkinsonism, cerebellar and/or corticospinal signs, usually leading to death after an average of 7 years. We describe the disease course of five patients diagnosed with probable MSA (4 with predominant parkinsonism and 1 with predominant cerebellar ataxia) who survived for more than 15 years and were followed throughout the disease course at our department. Cardiovascular autonomic dysfunction of any severity occurred late (mean latency from disease onset 9.4 +/- 5 years) in this subgroup of MSA patients. The time of involvement of the urogenital system was more variable (from 0 to 14 years after disease onset) and manifested with symptoms of storage disorders (urinary urgency, frequency and incontinence) and erectile dysfunction in men. Conversely complains suggestive of urinary voiding dysfunction (incomplete bladder emptying and urinary retention) were not recorded and patients required catheterization only late in the disease course. In conclusion, our study showed that late onset of both cardiovascular autonomic failure and urinary voiding disorders may be positive prognostic factors in MSA irrespective of the MSA subtype. PMID- 23728719 TI - Innate and adaptive immune responses in patients with pandemic influenza A(H1N1)pdm09. AB - Innate and adaptive immune responses play critical roles in the body's defense against viruses. We investigated the host immune response against the 2009 pandemic H1N1 influenza virus [A(H1N1)pdm09] in patients before and after anti influenza therapy and found that the numbers of dendritic cells and T cells were significantly reduced compared with those of a healthy control group. In contrast, the frequency of natural killer, gammadeltaT and T regulatory (Treg) cells increased, and the concentrations of plasma interferon (IFN)-alpha/gamma and interleukin (IL-15) were significantly higher than those of the control. Following therapy the frequency of gammadeltaT and Treg cells returned to normal; the counts of myeloid dendritic and plasmacytoid dendritic cells were still lower than the control, while the concentrations of IFN-alpha/gamma and IL-15 remained high. We show that infection with A (H1N1)pdm09 was accompanied by changes in peripheral blood lymphocyte subgroups and cytokine profiles, leading to deleterious imbalances in innate and adaptive immunity. PMID- 23728720 TI - Human immune deficiency virus (HIV) infection and the hypothalamic pituitary adrenal axis. AB - The hypothalamic pituitary adrenal (HPA) axis is the most common of the endocrine lines/axis' to be affected by HIV infection. There are multiple factors that contribute to this HPA axis dysregulation. Direct invasion of the various organs in the axis can be either by opportunistic infections or infiltrative diseases. The soluble factors or cytokines released during viral infection and the chronic inflammatory state that follows, also contribute to these alterations. The actions of these cytokines released by the immune response can both activate the HPA axis and cause a glucocorticoid resistant state. Further, many of the anti retroviral and other medications used to treat HIV infection can contribute to HPA axis dysfunction. While the diagnosis and treatment of endocrine dysfunction is the same as in any other patient, management pathways may be quite different. While some may be adaptive responses, life threatening adrenal insufficiency can also be present. It is important the latter be picked up expeditiously and treated promptly to avoid mortality. PMID- 23728721 TI - Magnetic resonance imaging of the central nervous system in diabetic neuropathy. AB - Diabetic 'peripheral' neuropathy (DPN) is one of the common sequelae to the development of both type-1 and type-2 diabetes mellitus. Neuropathy has a major negative impact on quality of life. Abnormalities in both peripheral vasculature and nerve function are well documented and, in addition, evidence is emerging regarding changes within the central nervous system (CNS) that are concomitant with the presence of DPN. The often-resistant nature of DPN to medical treatment highlights the need to understand the role of the CNS in neuropathic symptomatology and progression, as this may modulate therapeutic approaches. Advanced neuroimaging techniques, especially those that can provide quantitative measures of structure and function, can provide objective markers of CNS status. With that comes great potential for not only furthering our understanding of involvement of the CNS in neuropathic etiology but also most importantly aiding the development of new and more effective, targeted, analgesic interventions. PMID- 23728722 TI - Roles of small molecules in somatic cell reprogramming. AB - The Nobel Prize in Physiology and Medicine 2012 was awarded to Sir John B GURDON and Shinya YAMANAKA for their discovery that mature cells can be reprogrammed to become pluripotent. This event reaffirms the importance of research on cell fate plasticity and the technology progress in the stem cell field and regenerative medicine. Indeed, reprogramming technology has developed at a dazzling speed within the past 6 years, yet we are still at the early stages of understanding the mechanisms of cell fate identity. This is particularly true in the case of human induced pluripotent stem cells (iPSCs), which lack reliable standards in the evaluation of their fidelity and safety prior to their application. Along with the genetic approaches, small molecules nowadays become convenient tools for modulating endogenous protein functions and regulating key cellular processes, including the mesenchymal-to-epithelial transition, metabolism, signal transduction and epigenetics. Moreover, small molecules may affect not only the efficiency of clone formation but also the quality of the resulting cells. With increasing availability of such chemicals, we can better understand the biology of stems cells and further improve the technology of generation of stem cells. PMID- 23728723 TI - Astragalus polysaccharides suppress ICAM-1 and VCAM-1 expression in TNF-alpha treated human vascular endothelial cells by blocking NF-kappaB activation. AB - AIM: To investigate the effects Astragalus polysaccharides (APS) on tumor necrosis factor (TNF)-alpha-induced inflammatory reactions in human umbilical vein endothelial cells (HUVECs) and to elucidate the underlying mechanisms. METHODS: HUVECs were treated with TNF-alpha for 24 h. The amounts of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were determined with Western blotting. HUVEC viability and apoptosis were detected using cell viability assay and Hoechst staining, respectively. Reactive oxygen species (ROS) production was measured by DHE staining. Monocyte and HUVEC adhesion assay was used to detect endothelial cell adhesive function. NF-kappaB activation was detected with immunofluorescence. RESULTS: TNF-alpha (1 80 ng/mL) caused dose- and time-dependent increases of ICAM-1 and VCAM-1 expression in HUVECs, accompanied by significant augmentation of IkappaB phosphorylation and NF-kappaB translocation into the nuclei. Pretreatment with APS (10 and 50 MUg/mL) significantly attenuated TNFalpha-induced upregulation of ICAM-1 VCAM-1 and NF-kappaB translocation. Moreover, APS significantly reduced apoptosis, ROS generation and adhesion function damage in TNF-alpha-treated HUVECs. CONCLUSION: APS suppresses TNFalpha-induced adhesion molecule expression by blocking NF-kappaB signaling and inhibiting ROS generation in HUVECs. The results suggest that APS may be used to treat and prevent endothelial cell injury related diseases. PMID- 23728724 TI - Distribution and quantitation of skin iron in primary haemochromatosis: correlation with total body iron stores in patients undergoing phlebotomy. AB - Measurement of the concentration of iron in the skin, if correlated with total body iron stores, may enable better informed decisions on when to initiate, change or stop therapy in hereditary heamochromatosis. Naive haemochromatosis patients with iron overload and with C282Y and/or H63D HFE mutations were evaluated at the following time-points: disease diagnosis, end of the therapy programme, and 6 months after the end of therapy. The distribution and concentration of iron in the skin were assessed by quantitative nuclear microscopy methods, in parallel with serum and plasma iron concentration. Iron content in the liver was determined by nuclear magnetic resonance. Iron accumulated in the epidermis; its concentration increased from outer to inner layers, being maximal in the basal layer (7.33 +/- 0.98 umol/g). At all 3 time points, most of the iron was associated with the extracellular space. During the phlebotomy programme the iron content of the skin and the liver decreased by a factor of 2. These data suggest that measurements of iron concentration in the epidermis, which is a readily accessible tissue, reflect iron overload in the liver. PMID- 23728726 TI - Neuroscientific information bias in metacomprehension: the effect of brain images on metacomprehension judgment of neuroscience research. AB - In the present study, we investigated how brain images affect metacomprehension judgments of neuroscience research. Participants made a prereading judgment of comprehension of the text topic and then read a text about neuroimaging findings. In Experiment 1, participants read text only or text accompanying brain images. In Experiment 2, participants read text accompanying bar graphs or text accompanying brain images. Then participants were asked to rate their comprehension of the text. Finally, they completed comprehension tests. The results of Experiment 1 showed that the text accompanying brain images was associated with higher metacomprehension judgments than was the text only, whereas the performance of the comprehension test did not differ between each condition. The results of Experiment 2 showed that the text accompanying brain images was associated not only with credibility of the text, but also with higher metacomprehension judgments than was the text accompanying the bar graphs, whereas the performance of the comprehension test did not differ between each condition. The findings suggest that the readers' subjective judgments differ from actual comprehension. PMID- 23728725 TI - Distribution of and factors contributing to chronic kidney disease in a middle aged working population. AB - OBJECTIVES: To clarify the distribution of chronic kidney disease (CKD) and the factors contributing to its development and progression in middle-aged Japanese workers/employees. METHODS: This was a retrospective study involving 3,964 men and 2,698 women aged 35-64 years in 2009 who had been followed-up until 2003. Data on proteinuria determined with a dipstick and glomerular filtration rate estimated from serum creatinine concentration (eGFR) were collected in the annual health check-ups. RESULTS: Proteinuria was detected in 2.9 and 1.1 % of the men and women, respectively, and total CKD was detected in 16.0 and 16.1 % of the men and women respectively. Moderate or severe CKD associated a high risk of cardiovascular diseases and end-stage kidney disease was found mostly in the male subjects [2.0 (men) vs. 0.6 % (women)]. High-risk CKD was found in 3.3 % of the men aged 55-64 years. A body mass index (BMI) of >=30, hypertension, diabetes mellitus (DM), current smoking and some job types were independently related to the development of proteinuria, while age, BMI, hypertriglyceridemia, and job types were related to total CKD. The development of high-risk CKD was related to preceding mild CKD signs of reduced eGFR and proteinuria as well as to hypertension, DM, smoking, and job type. CONCLUSIONS: Chronic kidney disease was found in 16 % of middle-aged workers with an equal prevalence in both sexes, while high-risk CKD was found mostly in men, of whom 3.3 % were aged 55-64 years. Obesity, hypertension, DM, smoking and some job types were related to the development and progression of CKD. PMID- 23728727 TI - Comparison of GC stationary phases for the separation of fatty acid methyl esters in biodiesel fuels. AB - The fatty acid methyl ester (FAME) content of biodiesel fuels has traditionally been determined using gas chromatography with a polar stationary phase. In this study, a direct comparison of the separation of FAMEs present in various biodiesel samples on three polar stationary phases and one moderately polar stationary phase (with comparable column dimensions) was performed. Retention on each column was based on solubility in and polarity of the phase. Quantitative metrics describing the resolution of important FAME pairs indicate high resolution on all polar columns, yet the best resolution, particularly of geometric isomers, is achieved on the cyanopropyl column. In addition, the separation of four C18 monounsaturated isomers was optimized and the elution order determined on each column. FAME composition of various biodiesel fuel types was determined on each column to illustrate (1) chemical differences in biodiesels produced from different feedstocks and (2) chemical similarities in biodiesels of the same feedstock type produced in different locations and harvest seasons. PMID- 23728728 TI - Fluorescent sensing ochratoxin A with single fluorophore-labeled aptamer. AB - We explored a fluorescent strategy for sensing ochratoxin A (OTA) by using a single fluorophore-labeled aptamer for detection of OTA. This method relied on the change of the fluorescence intensity of the labeled dye induced by the specific binding of the fluorescent aptamer to OTA. Different fluorescein labeling sites of aptamers were screened, including the internal thymine bases, 3'-end, and 5'-end of the aptamer, and the effect of the labeling on the aptamer affinity was investigated. Some fluorophore-labeled aptamers showed a signal-on or signal-off response. With the fluorescent aptamer switch, simple, rapid, and selective sensing of OTA at nanomolar concentrations was achieved. OTA spiked in diluted red wine could be detected, showing the feasibility of the fluorescent aptamer for a complex matrix. This method shows potential for designing aptamer sensors for other targets. PMID- 23728729 TI - Imaging mass spectrometry distinguished the cancer and stromal regions of oral squamous cell carcinoma by visualizing phosphatidylcholine (16:0/16:1) and phosphatidylcholine (18:1/20:4). AB - Most oral cancers are oral squamous cell carcinoma (OSCC). The anatomical features of OSCC have been histochemically evaluated with hematoxylin and eosin. However, the border between the cancer and stromal regions is unclear and large portions of the cancer and stromal regions are resected in surgery. To reduce the resected area and maintain oral function, a new method of diagnosis is needed. In this study, we tried to clearly distinguish the border on the basis of biomolecule distributions visualized by imaging mass spectrometry (IMS). In the IMS dataset, eleven signals were significantly different in intensity (p < 0.01) between the cancer and stromal regions. Two signals at m/z 770.5 and m/z 846.6 were distributed in each region, and a clear border was revealed. Tandem mass spectrometric (MS/MS) analysis identified these signals as phosphatidylcholine (PC) (16:0/16:1) at m/z 770.5 in the cancer region and PC (18:1/20:4) at m/z 846.6 in the stromal region. Moreover, the distribution of PC species containing arachidonic acid in the stromal region suggests that lymphocytes accumulated in response to the inflammation caused by cancer invasion. In conclusion, the cancer and stromal regions of OSCCs were clearly distinguished by use of these PC species and IMS analysis, and this molecular identification can provide important information to elucidate the mechanism of cancer invasion. PMID- 23728730 TI - Bucephalidae (Platyhelminthes: Digenea) of Plectropomus (Serranidae: Epinephelinae) in the tropical Pacific. AB - We examined four species of Plectropomus Oken, 1817 (Serranidae: Epinephelinae), Plectropomus areolatus (Ruppell), Plectropomus laevis (Lacepede), Plectropomus leopardus (Lacepede) and Plectropomus maculatus (Bloch) from sites off Heron Island and Lizard Island on the Great Barrier Reef, Australia (GBR), and the Gambier Islands, French Polynesia. Three new species of Neidhartia Nagaty, 1937, five new species of Prosorhynchus Odhner, 1905, and one previously described species, Prosorhynchus freitasi Nagaty, 1937, are characterised. The three species of Neidhartia, Neidhartia haywardi n. sp., Neidhartia plectropomi n. sp. and Neidhartia tyleri n. sp. are readily distinguishable morphologically. Two of the six species of Prosorhynchus (Prosorhynchus lesteri n. sp. and Prosorhynchus wrightae n. sp.) are easily distinguished from their other congeners by morphology but the other four species (P. freitasi, Prosorhynchus heronensis n. sp., Prosorhynchus munozae n. sp. and Prosorhynchus plectropomi n. sp.) are generally similar in morphology and were only distinguished initially by comparing their ITS2 rRNA sequences. Three additional taxa, one from the GBR and two from French Polynesia, were recognised as distinct on the basis that their ITS2 rRNA sequences differed from those of the new taxa described here; these species remain unnamed for the present. Inter-specific divergence observed within these genera in the ITS2 rRNA ranged from 10 to 42 base pairs (4-16 %) for species of Neidhartia and 2-57 base pairs (3-21 %) for species of Prosorhynchus. Inter-generic divergences were 42-55 base pairs (17-21 %). No intraspecific variation in the ITS2 rRNA region was observed for any of the six species for which multiple sequence replicates were obtained. Phylogenetic analysis of 12 operational taxa from Plectropomus together with sequences of three other species from epinepheline serranids demonstrated that Neidhartia and Prosorhynchus were reciprocally monophyletic with the exception that P. wrightae n. sp. fell either within or basal to the Neidhartia species. The richness of bucephalids in species of Plectropomus appears to be exceptional within the Serranidae relative to that observed in other serranid genera in the tropical Indo-West Pacific. PMID- 23728731 TI - Oral toxicity of Photorhabdus luminescens and Xenorhabdus nematophila (Enterobacteriaceae) against Aedes aegypti (Diptera: Culicidae). AB - Dengue fever is an important vector-borne disease, mainly transmitted by Aedes aegypti. To date, there are no vaccines or effective drugs available against this arboviral disease. As mosquito control is practically the only method available to control dengue fever, alternative and cost-effective pest control strategies need to be explored. The gram-negative enteric bacteria Xenorhabdus and Photorhabdus are symbiotically associated with nematode parasites, which themselves are highly pathogenic for insect larvae. Here, we evaluate the oral toxicity of these entomopathogenic bacteria in A. aegypti larvae. The susceptibility of larvae (third late or fourth early instars) was assessed by exposing them to suspensions containing Photorhabdus luminescens or Xenorhabdus nematophila, respectively. Two diet treatments were tested with larvae fed on pet food and unfed larvae. After 24 h, larvae began to die when exposed to the bacteria. Exposure to P. luminescens killed 73% of the fed and 83% of the unfed larvae, respectively. In comparison, X. nematophila was less pathogenic, killing 52% of the larvae in the fed and 42% in the unfed treatment. Remarkably, cannibalism was observed in all bioassays after exposing larvae to either of the bacterial species. To our knowledge, this is the first report demonstrating the efficiency of these entomopathogenic bacteria for oral A. aegypti killing. Our results provide a promising basis for using these bacteria as bioinsecticides for mosquito control in the future. PMID- 23728733 TI - Gap-freezing approach for shortening the lyophilization cycle time of pharmaceutical formulations-demonstration of the concept. AB - During gap freezing, vials are placed on a metal tray, which is separated from the shelf surface with a small air gap that eliminates significant conductive heat transfer from the shelf to the bottom of the vial. The purpose of this freezing approach is to reduce the lyophilization cycle time of various amorphous formulations by nearly isothermal freezing. Such isothermal freezing promotes the formation of large ice crystals, and thus large pores throughout the cake, which subsequently accelerates the primary drying rate. The nucleation temperature using gap freezing, for the experimental conditions tested, was in the range of 1 degrees C to -6 degrees C, much higher than the range of -10 degrees C to -14 degrees C found using conventional shelf freezing. Isothermal freezing becomes effective when the gap is greater than 3 mm. The pore sizes and cake resistance during primary drying for various formulations were determined using the pore diffusion model developed by Kuu et al. (Pharm Dev Technol, 2011, 16(4): 343 357). Reductions in primary drying time were 42% (for 10% sucrose), 45% (for 10% trehalose), and 33% (for 5% sucrose). PMID- 23728732 TI - The global burden of fasciolosis in domestic animals with an outlook on the contribution of new approaches for diagnosis and control. AB - Fasciolosis is an economically important disease for livestock, as well as being zoonotic. Recent figures on the prevalence of this disease have caused alarm concerning its potential for an increased prevalence in the future. The prevalence of fascioliosis has been documented from different regions of the world, helping us identify areas where future research needs to be focused. This manuscript is a review of the current status of the disease, the pathogenic species involved, diagnostic techniques (with new modifications and comparative specificity, sensitivity, and rapidity of these tests), chemotherapy, and vaccination. This also encompasses inaccurate reports on vaccination and drug development as well as the latest technologies to find promising candidates for drugs and vaccines. Drugs with lower efficacy have been used on some farms which lead to exacerbation of the clinical disease, presumably due to the development of drug resistance. Future studies should be focused on (1) the use of the most reliable diagnostic tests for periodic monitoring of the disease, (2) insights of the ecobiology and transmission dynamics of the snail intermediate host and the best possible methods of their control, (3) in vitro and in vivo testing of chemotherapeutic compounds using sensitive methods, and (4) the identification of novel drug and vaccine candidates using modern molecular markers. This approach may help increase the reliability of chemotherapeutic agents and control nuisance, ultimately reducing the economic losses attributable to the livestock industry around the world. PMID- 23728734 TI - Microsatellite polymorphism in the heme oxygenase-1 gene promoter is not associated with alcoholic liver disease severity. PMID- 23728735 TI - Characterization of Dak Nong virus, an insect nidovirus isolated from Culex mosquitoes in Vietnam. AB - In this study, we isolated and characterized an insect nidovirus from the mosquito Culex tritaeniorhynchus Giles (Diptera: Culicidae) in Vietnam, as an additional member of the new family Mesoniviridae in the order Nidovirales. The virus, designated "Dak Nong virus (DKNV)," shared many characteristics with Cavally virus and Nam Dinh virus, which have also been discovered recently in mosquitoes, and these viruses should be considered members of a single virus species, Alphamesonivirus 1. DKNV grew in cultured mosquito cells but could not replicate in the cultured vertebrate cells tested. N-terminal sequencing of the DKNV structural proteins revealed two posttranslational cleavage sites in the spike glycoprotein precursor. DKNV is assumed to be a new member of the species Alphamesonivirus 1, and the current study provides further understanding of viruses belonging to the new family Mesoniviridae. PMID- 23728736 TI - Evaluation of the Oxoid BrillianceTM CRE Agar for the detection of carbapenemase producing Enterobacteriaceae. AB - The adequate detection of carbapenemase-producing Enterobacteriaceae (CPE) is essential for adequate antibiotic therapy and for infection control purposes, especially in an outbreak setting. Selective agars play an important role in the detection of CPE. The Oxoid BrillianceTM CRE Agar (Thermo Fisher Scientific) was evaluated for the detection of CPE using 255 non-repetitive Enterobacteriaceae isolates, including 95 CPE (36 KPC, 4 KPC plus VIM, 4 NDM, 6 GIM, 20 VIM, and 25 OXA-48-producing isolates). The sensitivity of the CRE agar for the detection of CPE was 94 % (89/95), but differed per carbapenemase gene (100 % for KPC, NDM, and GIM, 90 % for VIM, and 84 % for OXA-48-producing isolates). The specificity of the CRE agar was 71 %, due to the growth of AmpC- and/or ESBL-producing isolates. The CRE agar is a sensitive tool for the detection of KPC and metallo carbapenemase-producing Enterobacteriaceae, although the detection of OXA-48 producers is less optimal. The relatively low specificity requires confirmation of carbapenemase production for isolates recovered from the CRE agar. PMID- 23728737 TI - Outpatient parenteral antimicrobial therapy (OPAT) in the Republic of Ireland: results of a national survey. AB - Outpatient parenteral antimicrobial therapy (OPAT) services are not well developed in the Republic of Ireland. A national programme is being instituted to standardise care. This survey aims to assess the current use of outpatient intravenous antibiotics and to quantify the needs that physicians identify in the development of a national programme. General medical consultant physicians and clinical microbiology consultants were contacted through the Royal College of Physicians of Ireland (RCPI) from April to June 2012. Data were analysed using SPSS version 20. A total of 512 physicians were contacted, of which 55 (10.7 %) responded. The majority, 38/55 (69 %), practice general internal medicine in combination with a medical specialty, 2 (4 %) general internal medicine alone, 8 (15 %) clinical microbiology and 7 (13 %) a medical specialty alone. Of those practising a medical specialty, 12 (27 %) practice infectious diseases. Seventy four percent reported having discharged patients with intravenous antibiotics; however, 47 % did not have a designated service available. Of those with no service, 100 % identified a need for these resources. Of those responsible for an OPAT service, 56 % had not audited their service. The most common indications were skin and soft tissue infections, osteomyelitis and respiratory tract infection. Flucloxacillin was the most commonly reported antibiotic. Eleven percent responded that they never monitor laboratory studies for patients discharged with intravenous antibiotics. While OPAT services in Ireland are not well developed, patients are being discharged with intravenous antibiotics. This survey underscores the need to develop the national programme to standardise care and ensure patients receive safe and efficient therapy. PMID- 23728739 TI - Urokinase-coated chitosan nanoparticles for thrombolytic therapy: preparation and pharmacodynamics in vivo. AB - Blood reperfusion of affected limbs is the most effective therapy for peripheral vascular thrombotic disease, restoring nutrition and blood flow to threatened tissues. Because it is more cost-effective than other thrombolytics, urokinase (UK) is widely used to treat venous thrombosis in China. However, its use is limited because of the risk of UK-related hemorrhagic complications. UK-coated nanoparticles (NPs) may decrease adverse effects while simultaneously increasing thrombolytic benefits. The aim of this study was to combine the sustained-release properties of NPs with the clinical benefits of catheter-directed thrombolysis (CDT) to create a promising new therapy. NPs were prepared via self-assembled chitosan and tripolyphosphate, introduced into a thrombosis model in New Zealand white rabbits, and the ratio of the residual thrombus cross-sectional area to the vascular cross-sectional area was calculated. The NPs had a drug-bearing efficiency of 14.5 +/- 1.3%, an encapsulation efficiency of 94.8 +/- 2.1% while the particle size of UK-coated NPs was 236 nm. Transmission electron microscopy results showed that the shape of the NPs were spherical and regular. Whether delivered by intravenation or catheter, UK-coated NPs produced a significant increase in the thrombolytic effect compared with free UK and confirmed the superiority of CDT for improving clot lysis over drug-induced systemic thrombolysis. The intravenous NPs caused an abnormal increase in fibrinogen. In conclusion, a water-soluble UK-WCS-NP suspension with good encapsulation efficiency was easily prepared UK-WCS-NPs were capable of maintaining UK activity, provided sustained-release of UK and exhibited better thrombolytic function than free UK. PMID- 23728738 TI - Culturomics identified 11 new bacterial species from a single anorexia nervosa stool sample. AB - The rebirth of bacterial culture has been highlighted successively by environmental microbiologists, the design of axenic culture for intracellular bacteria in clinical microbiology, and, more recently, by human gut microbiota studies. Indeed, microbial culturomics (large scale of culture conditions with the identification of colonies by MALDI-TOF or 16S rRNA) allowed to culture 32 new bacterial species from only four stool samples studied. We performed culturomics in comparison with pyrosequencing 16S rRNA targeting the V6 region on an anorexia nervosa stool sample because this clinical condition has never been explored before by culture, while its composition has been observed to be atypical by metagenomics. We tested 88 culture conditions generating 12,700 different colonies identifying 133 bacterial species, with 19 bacterial species never isolated from the human gut before, including 11 new bacterial species for which the genome has been sequenced. These 11 new bacterial species isolated from a single stool sample allow to extend more significantly the repertoire in comparison to the bacterial species validated by the rest of the world during the last 2 years. Pyrosequencing indicated a dramatic discrepancy with the culturomics results, with only 23 OTUs assigned to the species level overlapping (17 % of the culturomics results). Most of the sequences assigned to bacteria detected only by pyrosequencing belonged to Ruminococcaceae, Lachnospiraceae, and Erysipelotrichaceae constituted by strictly anaerobic species, indicating the future route for culturomics. This study revealed new bacterial species participating significantly to the extension of the gut microbiota repertoire, which is the first step before being able to connect the bacterial composition with the geographic or clinical status. PMID- 23728740 TI - Cross-facial nerve graft and masseteric nerve cooptation for one-stage facial reanimation: principles, indications, and surgical procedure. AB - BACKGROUND: The use of facial cross-grafting in acquired recent unilateral facial palsy provides spontaneity and emotional activation. Masseteric nerve for facial animation has mainly been described for reinnervation of neuromuscular transplants, babysitter procedures, or direct facial nerve cooptation. The simultaneous use in a single procedure of cross-facial nerve grafting and masseteric cooptation has not been described. METHODS: Eight patients underwent facial animation using single stage cross-facial nerve grafting and masseteric nerve cooptation. The mean duration of facial palsy was 10.2 months (range, 1-23 months). RESULTS: Voluntary contraction in response to masseteric nerve activation was observed after 2 to 4 months. All patients underwent postoperative rehabilitation and spontaneous contraction was achieved in 7 to 13 months postoperatively. Cosmetic outcomes were evaluated as moderate in 1 patient, good in 5 patients, and excellent in the remaining 2 patients. CONCLUSION: This new technique could provide good results with fast, reliable, and powerful reinnervation, spontaneity, and low morbidity. PMID- 23728741 TI - Sir John Meurig Thomas. AB - "My greatest achievement has been to combine being a teacher, a researcher, and a popularizer of science for over 50 years. My worst nightmare is to find myself dumbstruck when I am about to give a lecture ...?" This and more about Sir John Meurig Thomas can be found on page 10938. PMID- 23728743 TI - Ethical and professional challenges of genetic counseling - the case of Austria. AB - Genetic counseling is gaining in importance with the increasing application of genetic testing for diagnosis and clinical treatment. Genetic counseling often raises ethical and professional challenges and prior research has categorized them into 16 domains. The purpose of this study was to analyze the situation in Austria on the basis of these challenges and discuss it in the national and international context. While in some countries there is a special profession for genetic counseling, in Austria it is provided by medical geneticists or other physicians in the context of their specialization. Psychosocial professionals might be consulted or brought in if necessary. Results from 95 survey respondents (including physicians and psychosocial professionals) revealed a greater interest in the topic of genetic counseling by medical specialists other than medical geneticists. The most frequently encountered challenges among physicians were informed consent, organizational constraints, withholding information, and attaining/maintaining proficiency. The psychosocial professionals experienced maintaining proficiency and organizational constraints as the prevalent challenges. Additional findings and practice implications are presented. PMID- 23728742 TI - Charcot-Marie-Tooth causing HSPB1 mutations increase Cdk5-mediated phosphorylation of neurofilaments. AB - Mutations in the small heat shock protein HSPB1 (HSP27) are a cause of axonal Charcot-Marie-Tooth neuropathy (CMT2F) and distal hereditary motor neuropathy. To better understand the effect of mutations in HSPB1 on the neuronal cytoskeleton, we stably transduced neuronal cells with wild-type and mutant HSPB1 and investigated axonal transport of neurofilaments (NFs). We observed that mutant HSPB1 affected the binding of NFs to the anterograde motor protein kinesin, reducing anterograde transport of NFs. These deficits were associated with an increased phosphorylation of NFs and cyclin-dependent kinase Cdk5. As Cdk5 mediates NF phosphorylation, inhibition of Cdk5/p35 restored NF phosphorylation level, as well as NF binding to kinesin in mutant HSPB1 neuronal cells. Altogether, we demonstrate that HSPB1 mutations induce hyperphosphorylation of NFs through Cdk5 and reduce anterograde transport of NFs. PMID- 23728744 TI - Isolation of Chlamydomonas flagella. AB - A simple, scalable, and fast procedure for the isolation of Chlamydomonas flagella is described. Chlamydomonas can be synchronously deflagellated by treatment with chemicals, pH shock, or mechanical shear. The Basic Protocol describes the procedure for flagellar isolation using dibucaine to induce flagellar abscission; we also describe the pH shock method as an Alternate Protocol when flagellar regeneration is desirable. Sub-fractionation of the isolated flagella into axonemes and the membrane + matrix fraction is described in a Support Protocol. PMID- 23728745 TI - Isolation of primary cilia by shear force. AB - The cell's primary cilium is both a mechanical and chemical sensor involved in many signaling pathways. In order to ascertain protein enrichment in the primary cilium or study sub-ciliary localization of various proteins, it is advantageous to remove the primary cilium from the cell body. The protocol described here gives detailed instructions on purifying primary cilia by separating them from the cell body using shear force. This simple technique avoids using harsh purification conditions that may affect signaling proteins in the cilium or cause the ciliary membrane to disintegrate. In addition, as the cell body remains mostly intact, contamination of the isolated cilia by proteins from the cell body is minimized. This protocol is ideally suited for isolating cilia from renal cell lines, as primary cilia in these cells grow to greater lengths than in other cell types (up to 50-um long in Xenopus A6 toad kidney cells as opposed to 1 to 5 um in NIH3T3 fibroblast cells). PMID- 23728746 TI - Two-photon excitation microscopy for the study of living cells and tissues. AB - Two-photon excitation microscopy is an alternative to confocal microscopy that provides advantages for three-dimensional and deep tissue imaging. This unit will describe the basic physical principles behind two-photon excitation and discuss the advantages and limitations of its use in laser-scanning microscopy. The principal advantages of two-photon microscopy are reduced phototoxicity, increased imaging depth, and the ability to initiate highly localized photochemistry in thick samples. Practical considerations for the application of two-photon microscopy will then be discussed, including recent technological advances. This unit will conclude with some recent applications of two-photon microscopy that highlight the key advantages over confocal microscopy and the types of experiments which would benefit most from its application. PMID- 23728747 TI - Image correlation spectroscopy for measurements of particle densities and colocalization. AB - Cells interact with their environment through receptor proteins expressed at their plasma membrane, and protein-protein interactions govern the transduction of signals across the membrane into the cell. Therefore, the ability to measure receptor densities and protein colocalization within the membrane of intact cells is of paramount importance. This unit describes a technique to extract these parameters from fluorescence microscopy images obtained using a commercial confocal laser scanning microscope (CLSM) and other similar types of microscopes. It is based on the analysis of spatial fluorescence intensity fluctuations in the images, which can then be related to particle density and aggregation state via calculation of a spatial autocorrelation function, or used to measure particle colocalization via calculation of a spatial cross-correlation function from dual color images of proteins tagged with two different fluorophores and imaged in two detection channels. These parameters offer key insights on the interaction of the cell with its environment. PMID- 23728749 TI - There are calls for a national screening programme for prostate cancer: what is the evidence to justify such a national screening programme? AB - INTRODUCTION: Prostate cancer is the commonest cancer in men and a major health issue worldwide. Screening for early disease has been available for many years, but there is still no national screening programme established in the United Kingdom. OBJECTIVE: To assess the latest evidence regarding prostate cancer screening and whether it meets the necessary requirements to be established as a national programme for all men. METHODS: Electronic databases and library catalogues were searched electronically and manual retrieval was performed. Only primary research results were used for the analysis. RESULTS: In recent years, several important randomised controlled trials have produced varied outcomes. In Europe the largest study thus far concluded that screening reduced prostate cancer mortality by 20%. On the contrary, a large American trial found no reduction in mortality after 7-10 years follow-up. Most studies comment on the adverse effects of screening - principally those of overdiagnosis and subsequent overtreatment. DISCUSSION: Further information about the natural history of prostate cancer and accuracy of screening is needed before a screening programme can be truly justified. In the interim, doctors and patients should discuss the risks, benefits and sequelae of taking part in voluntary screening for prostate cancer. PMID- 23728748 TI - Molecular Characterization of an Atypical IncX3 Plasmid pKPC-NY79 Carrying bla KPC-2 in a Klebsiella pneumoniae. AB - The IncX family of plasmids has recently been expanded to include at least four subtypes, IncX1-IncX4. The revised classification provides an opportunity for improving our understanding of the sequence diversity of the IncX plasmids and the resistance genes they carried. We described the complete nucleotide sequence of a novel IncX3 plasmid, pKPC-NY79 (42,447 bp) from a sequence-type 258 Klebsiella pneumoniae strain that was isolated from a patient who was hospitalized in New York, United States. In pKPC-NY79, the plasmid scaffold and genetic load region were highly similar to homologous regions in pIncX-SHV (IncX3, JN247852) and the bla KPC carrying pKpQIL (IncFIIk, GU595196), respectively, indicating that it has possibly arisen through recombination of plasmids. The bla KPC-2 gene, as part of a transposon Tn4401a, was found within the genetic load region. The backbone of pKPC-NY79 differs from pIncX-SHV by a deletion involving the gene tandem hns-topB (encoding H-NS protein and topoisomerase III, respectively) and a putative ATPase gene. Unexpectedly, the impact of the hns-topB deletion on host fitness and plasmid stability was found to be small. In conclusion, the findings contribute to a better understanding of the plasmid platforms carrying bla KPC and of variations in the backbone of the IncX3 plasmids. PMID- 23728750 TI - Monitoring and adverse events in relation to ACE inhibitor/angiotensin receptor blocker initiation in people with diabetes in general practice: a population database study. AB - BACKGROUND AND AIM: To determine whether angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) initiation in people with diabetes is monitored as recommended by recent guidelines and the incidence of associated adverse renal events. DESIGN: Retrospective population database analysis of 4056 people in Tayside, Scotland with type 2 diabetes prescribed an ACEI/ARB between 1 January 2005 and 31 December 2009. METHOD: Measurement of urea and electrolytes (U&Es) before and after ACEI/ARB initiation and renal adverse events; defined as a >=30% rise in serum creatinine and post-initiation potassium of >=5.6 mmol/L. Associations of adverse events with patient demographics or co prescription of drugs with known renal effects were examined. RESULTS: Overall, 89% of initiations were with an ACE inhibitor. A total of 18.84% (CI 95% 18.82 18.86) of patients initiating ACE inhibitor or ARB had U&Es measured in the 90 days before initiation and within 5-14 days after initiation. Only 1.7% of patients had an adverse renal event. Patients prescribed with an ARB were less likely to be monitored than those prescribed with an ACE inhibitor, but no less likely to suffer harm. CONCLUSIONS: Current clinical practice of biochemical monitoring of ACE inhibitor/ARB is poor, but adverse events are rare. Further studies with serial U&Es are needed to establish the critical time window for adverse renal events and evaluate whether intensive biochemical monitoring recommended is required in low-risk groups. PMID- 23728751 TI - Multiplex PCR testing requires a robust multi-disciplinary strategy to effectively manage identified cases of chlamydial conjunctivitis. AB - INTRODUCTION: Implementation of an in-house polymerase chain reaction (PCR) multiplex assay by West of Scotland Specialist Virology Centre to improve sample processing means all viral eye swabs are now routinely tested for Adenovirus, Herpes simplex, Varicella and Chlamydia. Concern was raised regarding subsequent management and sexual health attendance for Chlamydia-positive patients identified in eye casualty. METHODS: A retrospective review of virology results identified 76 Chlamydia-positive patients from 1914 eye swabs (4%) from May 2007 to April 2008. Of these results, 12 originated from Glasgow eye casualty and available clinical notes were cross-referenced with the sexual health network (Sandyford). RESULTS: Identified issues included no documentation of implications of testing, poor communication of positive results and poor referral pathways to sexual health for assessment; all leading to inadequate management. A shared care network was created to address these issues. A designated sexual health advisor was identified to improve sexual health referral, specialist assessment, standardised management and contact tracing. Re-audit showed more consistent follow-up. CONCLUSION: New PCR technology has resulted in a shared care approach to address corresponding implications of testing. Effective communication with a structured protocol and a central point of contact has improved follow-up and ensures appropriate best practice management of chlamydial conjunctivitis. PMID- 23728752 TI - Radiofrequency ablation of osteoid osteoma: outcomes from the West of Scotland. AB - BACKGROUND: Osteoid osteoma is a classically described benign bone tumour. Traditionally, the surgical treatment of choice was excision, but this can have significant morbidity. Percutaneous radiofrequency ablation (RFA) has grown in popularity as an alternative treatment. This study reports the outcomes using this technique in our regional bone tumour unit. METHODS: Between May 2003 and October 2007, 14 patients underwent CT-guided RFA. All patients were subsequently offered follow-up in the out-patient clinic. Outcomes were taken from the Scottish Bone Tumour Registry database. RESULTS: Eleven patients (78.6%) had complete resolution of symptoms after one RFA. Three (21.4%) cases were unsuccessful but one of these was due to technical failure. All three of the above patients had complete relief of symptoms after one further RFA. One (7.1%) patient initially had complete relief of symptoms, but suffered recurrence after 9 months. This patient also had a second curative treatment. CONCLUSION: Percutaneous RFA for osteoid osteoma is an attractive treatment due to its efficacy and low morbidity. Our results showed a primary success rate of 78.6%, a secondary success rate of 100% (after one additional procedure). Our results add to the growing literature supporting RFA as the preferred treatment for osteoid osteoma. PMID- 23728753 TI - Is there an increase in the incidence of uterine carcinosarcoma in north-east Scotland? A 19 years population-based cohort study. AB - BACKGROUND AND AIMS: The incidence of uterine carcinosarcoma and factors associated with its survival are little known and this study helps to address this question for women residing in north-east Scotland. METHODS AND RESULTS: Data were collected from women diagnosed with carcinosarcoma of the uterus residing in north-east of Scotland from 1991 to 2009. Kaplan-Meier plots and Cox regression analysis were used for analysis. A total of 43 women were analysed during this period. The median survival was 25 months. The estimated five-year survival for stage I/II disease was 52.5% (95% CI: 30.5-74.5%). The 2-year survival rate for stage III/IV disease was 46% (95% CI: 16-75%). There was an increase in the incidence during this period. Improved survival was seen in early stage disease (FIGO stages I and II) and in the absence of lymphovascular space invasion (LVSI; p = 0.015). A total of 26% of the women had a history of tamoxifen usage with no effect seen on survival. Multivariate analysis showed that when treatment modality and LVSI were adjusted for FIGO staging, there was no statistical significance in the survival outcomes. CONCLUSION: The incidence of uterine carcinosarcomas is increasing parallel with endometrial carcinomas with no significant effect of tamoxifen on survival. PMID- 23728754 TI - Symptoms do not predict colorectal cancer in an FOB screened population. AB - BACKGROUND AND AIMS: The Scottish Bowel Screening Programme aims to detect cancer in asymptomatic individuals. We aimed to measure the prevalence of lower gastrointestinal symptoms in faecal occult blood (FOB) screen-positive patients, to correlate the symptoms with neoplasia and to compare the predictive value of FOB screening with urgent symptomatic referrals in Ayrshire and Arran. METHODS: Data were collected prospectively on FOB screen-positive patients undergoing colonoscopy. Patients completed a symptom questionnaire. Positive predictive values (PPVs) for detecting neoplasia were calculated and a chi-square test was performed to determine any influence of symptoms in diagnosing neoplasia. Symptomatic patients undergoing colonoscopy via a general practice fast-track system were compared. RESULTS: A total of 378 FOB screen-positive patients were included. In all, 198 (52%) had colorectal symptoms. Overall, 32 were diagnosed with colorectal cancer and 93 had polyps . FOB positivity and symptoms gave a PPV of 34% for neoplasia. FOB positivity without symptoms gave a PPV of 32% for neoplasia. Urgent referral of symptomatic patients had a lower PPV of 21% for neoplasia (p < 0.001). CONCLUSION: Half the FOB screen-positive patients had bowel symptoms. Symptoms in these patients had no correlation with an increased rate of neoplasia. The PPV for neoplasia is superior in symptomatic and asymptomatic screen-positive patients when compared to conventional urgent symptom-based referral. PMID- 23728755 TI - Oral fluid testing as an alternative to urine testing for drugs of abuse in inpatient forensic settings: giving patients choice. AB - BACKGROUND AND AIMS: The abuse of illicit substances is very common amongst forensic psychiatry populations and is known to be one of the most potent risk factors for interpersonal violence. Forensic psychiatry units hence strive to keep themselves as free as possible from illicit substances and in Scotland drugs of abuse have traditionally been screened for by means of urine testing. The aim of this study is to examine patients' preferences for drug testing methods and to compare the acceptability of urine testing versus oral fluid testing (OFT) within a secure hospital setting. METHODS: Patients in three continuing care wards at the State Hospital, Carstairs were offered the choice of either urine or oral fluid testing. We developed protocols and recording forms and trained staff in the administration of the OFT. We recorded the sampling time for OFT and urine, and the views of patients and staff on the testing procedures over a six month period. RESULTS: Sixty-two samples were taken, with 53 (85%) opting for OFT and nine (15%) opting for urine sampling. The average time taken for OFT was 13 minutes, while the average time taken for urine sampling was 33 minutes. The majority of patients and staff rated oral fluid and urine testing as comfortable and easy. Patients recorded comments on 46 (87%) of OFT samples, only two of which were negative. In general they preferred the OFT because it was quicker and easier and they commented on it being more dignified and private. Patients recorded comments on five (55%) of urine samples, with one of the primary reasons for opting for urine sampling appearing to be a reluctance to try new things, though a few said they did not want to have anything in their mouths. Staff returned comments on 24 (45%) of OFT samples and one (11%) of urine samples. Comments on the OFT were overwhelmingly positive and pointed out the relative speed and ease of this sampling method. CONCLUSIONS: We concluded that the pilot study was successful. OFT was found to be generally preferred by patients and staff. Although there was an additional financial cost, this was considered to be outweighed by the significant benefits arising from offering patients choice, the preservation of patient dignity and staff time savings. The option of OFT has now been extended to all patients within the State Hospital. Practitioners will wish to consider the value of OFT in forensic psychiatry inpatient settings given the benefits identified within this study. PMID- 23728756 TI - Evaluation of the utility of hospital databases to provide data in assessing the quality of strabismus surgery. AB - AIMS AND BACKGROUND: Rates of re-operation, which may be related to an unsatisfactory surgical outcome, can provide a long-term index of the quality of strabismus surgery. This study aims to evaluate the utility of the Scottish Morbidity Records (SMR1) in determining nature and rates of re-operation for strabismus at the Royal Hospital for Sick Children (RHSC), Glasgow. METHODS: SMR1 data on strabismus surgery performed on children aged between 0 and 17 years at the RHSC, Glasgow, between January 2000 and March 2009 were analysed. RESULTS: In total, 1376 strabismus procedures were carried out on 1274 individuals. The median time between first and subsequent procedures was 19 months; the commonest reasons being under-correction or recurrence. The Kaplan-Meier rate of undergoing re-operation was 7.4% after 9 years with a 95% confidence interval of 5.4-9.9%. CONCLUSIONS: The SMR1 is a useful source of hospital-based and population data. With supplementation from parallel databases, routine administrative databases like the SMR1 can provide better quality data to inform practice. PMID- 23728757 TI - Cracking the code: the accuracy of coding shoulder procedures and the repercussions. AB - BACKGROUND: Coding of patients' diagnosis and surgical procedures is subject to error levels of up to 40% with consequences on distribution of resources and financial recompense. Our aim was to explore and address reasons behind coding errors of shoulder diagnosis and surgical procedures and to evaluate a potential solution. METHODS: A retrospective review of 100 patients who had undergone surgery was carried out. Coding errors were identified and the reasons explored. A coding proforma was designed to address these errors and was prospectively evaluated for 100 patients. The financial implications were also considered. RESULTS: Retrospective analysis revealed the correct primary diagnosis was assigned in 54 patients (54%) had an entirely correct diagnosis, and only 7 (7%) patients had a correct procedure code assigned. Coders identified indistinct clinical notes and poor clarity of procedure codes as reasons for errors. The proforma was significantly more likely to assign the correct diagnosis (odds ratio 18.2, p < 0.0001) and the correct procedure code (odds ratio 310.0, p < 0.0001). Using the proforma resulted in a L28,562 increase in revenue for the 100 patients evaluated relative to the income generated from the coding department. CONCLUSION: High error levels for coding are due to misinterpretation of notes and ambiguity of procedure codes. This can be addressed by allowing surgeons to assign the diagnosis and procedure using a simplified list that is passed directly to coding. PMID- 23728758 TI - Early experience of a CT coronary angiography service in a Scottish regional centre. AB - BACKGROUND: CT coronary angiography (CTCA) is an emerging diagnostic tool in the assessment of patients with suspected coronary artery disease. It has several advantages over conventional coronary angiography (CCA); however, its use is not yet widespread in large teaching centres. AIMS: To determine what proportion of patients who have CTCA, do not require subsequent CCA. METHODS: A prospective analysis of all patients referred for CTCA from the start of the service in January 2008 to April 2010. RESULTS: CTCA provided definitive diagnostic images in 85% of patients. Overall only 12% (n = 33) of patients had subsequent CCA. The proportion of patients who subsequently had CCA reduced with time reflecting increasing confidence with the clinical service. CONCLUSIONS: A CTCA service can be successfully established out with a large teaching centre hospital. Close working between cardiologists and radiologists leads to increased confidence in the service and obviates the need for CCA in a large proportion of patients. PMID- 23728759 TI - Urological complications of inguinal hernia surgery. AB - BACKGROUND AND AIMS: A systematic review of the literature is presented with regard to urological complications resulting from inguinal hernia surgery. Considering the amount of inguinal hernia operations performed, the resulting complications, which may be urological in presentation, have potential late irreversible and medico-legal implications. METHODS AND RESULTS: A Pubmed search of 'urological' 'complications' and 'inguinal hernia surgery' was carried out and clinical practice was also taken into consideration. DISCUSSION: Approximately 75% of hernias occur in the groin; two-third of these are indirect and about one third direct. Most of these repairs are carried out by the general surgeons and any complication, including urological, are often initially managed by the operating general surgeon. Often a urological opinion is sought late for conditions which may be reversible. We present potential urological complications, their presenting features and management. CONCLUSION: Recognition, timely referral and appropriate treatment of urological complications after hernia surgery are necessary to avoid potential consequences and long-term morbidity. PMID- 23728760 TI - Karl Koenig: the Austrian refugee doctor who founded a worldwide movement in Scotland. AB - In this paper, the circumstances which led to the creation of the Camphill Movement in Scotland are described. Attention is drawn to the rejection by Dr Karl Koenig--co-founder of the Movement--of too narrow an approach to the treatment of children and adults with intellectual disabilities and his advocacy of a holistic approach. Koenig was one of the first medical practitioners in Britain to proclaim and demonstrate that all children with an intellectual disability, regardless of the severity of that disability, have a potential that can be unlocked and developed. There are now over 100 Camphill communities in more than 20 countries making it one of the largest independent providers of services for children and adults with intellectual disabilities in the world. PMID- 23728762 TI - Bilateral endogenous Serratia marcescens endophthalmitis secondary to endocarditis following cardiac surgery. AB - INTRODUCTION: Endogenous endophthalmitis is a sight-threatening condition caused by microorganisms crossing the blood-ocular barrier and inducing profound intraocular inflammation. CASE REPORT: A 65-year-old female experienced bilateral loss of vision after developing infective endocarditis as a complication of combined Bentall procedure and coronary artery bypass grafting. She was diagnosed with bilateral endogenous endophthalmitis secondary to Serratia marcescens. Despite aggressive treatment with intravitreal injections of antibiotics and steroids, intensive topical and systemic antibiotic therapy, there was permanent loss of sight in both eyes. CONCLUSION: The case highlights the importance of early recognition of the symptoms and signs of endogenous endophthalmitis in any patient with systemic infection by all clinicians and the necessity of prompt ophthalmological referral if a useful level of vision is to be preserved. PMID- 23728763 TI - Two rare cases of retinal vasculitis following vaccination. AB - We write to report two rare cases of retinal vasculitis following administration of vaccinations. Both patients received recent vaccinations (within 4 weeks and 2 months respectively) and presented with unilateral visual loss due to retinal arteriolar vasculitis. Investigations did not reveal any other causes of vasculitis. The first patient's ocular inflammation settled following periocular steroid injection, whereas the second patient required the additional use of oral corticosteroid. Both patients had improved vision following treatment. Vaccinations can cause an autoimmune reaction. Systemic vasculitis has previously been described, whereas ocular vasculitic involvement is also possible but extremely rare. When seeing a patient with visual loss due to retinal vasculitis of unknown aetiology, a history of any recent vaccinations should be elicited. PMID- 23728764 TI - A young healthy male with syncope and complete heart block. AB - INTRODUCTION: It is rare to see heart block as the first-and-only presentation of Lyme disease, the reported incidence being just 1% in untreated patients. CASE PRESENTATION: We report a patient who presented with syncope secondary to a fluctuating heart block. He had no previous manifestations of Lyme disease. Lyme carditis was suspected after the other usual etiologies of heart block were ruled out. Later, serologies came positive and patient's heart block resolved on ceftriaxone therapy. CONCLUSION: In at-risk individuals, clinicians should rule out this readily-treatable cause of heart block before proceeding with permanent pacemaker implantation due to enormous clinical and cost implications involved. Missing the diagnosis also exposes the patient to the risk of developing the late complications of Lyme disease. Diagnosis of isolated Lyme carditis is a challenge because the clinician does not have the diagnostic-clues that can usually be gleaned from the more common stigmata of Lyme disease. PMID- 23728765 TI - A case of sebaceous carcinoma arising in a benign cystic teratoma of the ovary and review of the literature. AB - OBJECTIVE: To present an extremely rare case of sebaceous carcinoma arising in a mature cystic teratoma of the ovary. CLINICAL PRESENTATION AND INTERVENTION: A 66 year-old woman presented with abdominal discomfort and a pelvic mass. Abdominal and pelvic ultrasound, as well as CT scan, revealed a 27 cm complex right pelvic mass, which was diagnosed histologically as a sebaceous carcinoma arising in a mature cystic teratoma. The patient underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy, peritoneal washings, appendicectomy and infracolic omentectomy. CONCLUSION: This case adds to the rare reports in the literature of sebaceous carcinoma occurring in a mature cystic teratoma. The clinical behaviour and optimal management of this entity are not well established. The patient has been well for 32 months following surgery with no evidence of recurrent disease clinically. PMID- 23728766 TI - An unusual cause of acute internal haemorrhage: cystic artery pseudoaneurysm secondary to acute cholecystitis. AB - Spontaneous cystic artery haemorrhage is a rare complication of acute cholecystitis. Here we describe a case report of this unusual cause of internal haemorrhage, and discuss the pathogenesis and management strategies. PMID- 23728767 TI - Acute distal radial epiphyseal osteomyelitis: a case report. AB - A child developed acute epiphyseal osteomyelitis of the distal radius following a fall. Despite a delay in diagnosis the patient was successfully treated by surgery and antibiotics. Magnetic resonance imaging was the key to the diagnosis and surgical planning. PMID- 23728768 TI - Spontaneous remission in a case of idiopathic retroperitoneal fibrosis. AB - A 54-year-old lady being investigated at the medical clinic for back pain and weight loss, was diagnosed with idiopathic retroperitoneal fibrosis on the basis of CT imaging, biopsy findings and absence of known secondary causes. After lengthy discussions with the patient during several clinic visits she declined the use of corticosteroid treatment due to concerns for the potential side effects. Serial monitoring of inflammatory markers and interval imaging suggested a spontaneous remission in the inflammatory process. We describe the case and discuss the management of retroperitoneal fibrosis. PMID- 23728769 TI - Economic evaluation of 3-drug antiretroviral regimens for the prevention of mother-to-child HIV transmission in Thailand. AB - The current program for prevention of mother-to-child HIV transmission in Thailand recommends a 2-drugs regimen for HIV-infected pregnant women with a CD4 count >200 cells/mm(3). This study assesses the value for money of 3 antiretroviral drugs compared with zidovudine (AZT)+single-dose nevirapine (sd NVP). A decision tree was constructed to predict costs and outcomes using the governmental perspective for assessing cost-effectiveness of 3-drug regimens: (1) AZT, lamivudine, and efavirenz and (2) AZT, 3TC, and lopinavir/ritonavir, in comparison with the current protocol, AZT+sd-NVP. The 3-drug antiretroviral regimens yield lower costs and better health outcomes compared with AZT+sd-NVP. Although these 3-drug regimens offer higher program costs and health care costs for premature birth, they save money significantly in regard to pediatric HIV treatment and treatment costs for drug resistance in mothers. The 3-drug regimens are cost-saving interventions. The findings from this study were used to support a policy change in the national recommendation. PMID- 23728770 TI - Anthropometric characteristics and undernutrition among older persons in a rural area of northern India. AB - This community-based cross-sectional study was conducted to assess anthropometric characteristics and estimate the prevalence of undernutrition among older persons in rural Ballabgarh, Haryana, India. A total of 948 participants aged 60 years and above were examined. Their weight, arm span, mid-upper-arm circumference, triceps skinfold thickness, and calf circumference were measured using standard techniques. The prevalence of undernutrition was estimated to be 53.7% (95% confidence interval [CI] = 50.5-56.9). Logistic regression analysis was done to identify factors independently associated with undernutrition. In the assessment of anthropometric characteristics, the strongest correlation was observed between body mass index and mid-upper-arm circumference (r = 0.88; P < .0001). Receiver operating characteristic analysis showed that mid-upper-arm circumference has a higher ability (area under curve = 0.93; 95% CI = 0.91-0.96) of detecting undernutrition among older persons than triceps skinfold thickness and calf circumference. The high prevalence of undernutrition among older persons in rural India warrants major public health interventions. PMID- 23728771 TI - Enhanced protective efficacy of H5 subtype influenza vaccine with modification of the multibasic cleavage site of hemagglutinin in retroviral pseudotypes. AB - Traditionally, the multibasic cleavage site (MBCS) of surface protein H5 hemagglutinin (HA) is converted to a monobasic one so as to weaken the virulence of recombinant H5N1 influenza viruses and to produce inactivated and live attenuated vaccines. Whether such modification benefits new candidate vaccines has not been adequately investigated. We previously used retroviral vectors to generate wtH5N1 pseudotypes containing the wild-type HA (wtH5) from A/swine/Anhui/ca/2004 (H5N1) virus. Here, we generated mtH5N1 pseudotypes, which contained a mutant-type HA (mtH5) with a modified monobasic cleavage site. Groups of mice were subcutaneously injected with the two types of influenza pseudotypes. Compared to the group immunized with wtH5N1 pseudotypes, the inoculation of mtH5N1 pseudotypes induced significantly higher levels of HA specific IgG and IFN gamma in immunized mice, and enhanced protection against the challenge of mouse adapted avian influenza virus A/Chicken/Henan/12/2004 (H5N1). This study suggests modification of the H5-hemagglutinin MBCS in retroviral pseudotypes enhances protection efficacy in mice and this information may be helpful for development of vaccines from mammalian cells to fight against H5N1 influenza viruses. PMID- 23728772 TI - Analysis of risk factors for late presentation in a cohort of HIV-infected patients in Dresden: positive serology for syphilis in MSM is a determinant for earlier HIV diagnosis. AB - PURPOSE: Late HIV presentation is still a health concern, even in industrialised countries. Data concerning this problem in Eastern Germany are scarce. We investigated associated factors in a cohort of HIV-infected patients in Dresden, Germany, including syphilis serology as a proxy for sexual risk behaviour. METHODS: A retrospective cohort study on 348 patients presenting for the first time in our treatment centre from 1986 to 2010 was undertaken. Risk factors of late (CD4 cells <350/MUl) and very late (CD4 cells <200/MUl) presentation either to care or to diagnosis were identified by means of logistic regression analyses. RESULTS: Of 348 classifiable patients, 54 % were late and 33.9 % were very late presenters to care. In a subgroup of 260 patients with recent HIV diagnosis, 50.4 % were late and 31.2 % were very late presenters to diagnosis. Age >24 years was a significant independent factor associated with late or very late presentation, but not male gender, originating from high-prevalence countries (HPC) or years of presentation. Being MSM alone was not associated with early or late HIV presentation, but MSM with positive TPHA or TPPA showed a lower risk of late presentation, predominantly in those presenting late to diagnosis [odds ratio (OR) 0.42, p = 0.048]. CONCLUSIONS: A positive syphilis screening test seems to be a determinant for lower risk of late presentation to HIV care and diagnosis in MSM. The presence and awareness of sexually transmitted infections (STIs) such as syphilis may lead to earlier utilisation of HIV health care and, thus, promote earlier HIV diagnosis. HIV prevention strategies should focus more on STIs and not only on HIV. PMID- 23728773 TI - Isolated mediastinal necrotizing granulomatous lymphadenopathy due to cat-scratch disease. AB - We report a patient suffering from cat-scratch disease limited to mediastinal lymphadenitis. Although rare, cat-scratch disease should be considered in the differential diagnosis of mediastinal lymphadenitis, especially when patients were exposed to cats. PMID- 23728774 TI - Angiostrongylus cantonensis: tegumental and hypodermic alterations of the fourth stage larvae following administration of tribendimidine in vivo and in vitro. AB - Angiostrongylus cantonensis is a parasitic pathogen whose forth-stage larvae (L4) parasitize in the central nervous system (CNS) of the human cause severe eosinophilic encephalitis or meningoencephalitis. Previous study indicated an impressive anthelmintic efficacy of tribendimidine (TBD) against CNS parasitized L4 of A. cantonensis. Tegument of the larvae is the first physical barrier to protect them from attack by the host immune system. In the present study, tegumental and hypodermic alterations were observed by scanning electron microscopy and transmission electron microscopy after administration of TBD. During treatment of TBD in vivo, L4 presented wizened side sensor, disappearance of mastoids and longitudinal grain, prominent surface coat, heterogeneous tegumental layers, incompact hypodermic cell junctions, blurred myotube, and small scale of vacuole in a basal layer. After incubation with TBD in vitro, L4 exhibited a swollen side sensor and mastoids disappearance in head end. Abundant tegumental blebs and obvious deformation of both cross-grain and longitudinal grain were detected on the surface, and shrinkage of all tegumental layers, chaotic cell junction, turbid muscle cell, disappearance of myotubes, and vacuole like changes were visible under the electron microscope. The results implied the potential mechanism of the anthelmintic effect of tribendimidine against L4 of A. cantonensis by direct damages to tegumental and hypodermic. PMID- 23728775 TI - Expression of murine Unc93b1 is up-regulated by interferon and estrogen signaling: implications for sex bias in the development of autoimmunity. AB - The endoplasmic reticulum transmembrane protein, Unc93b1, is essential for trafficking of endosomal TLRs from the endoplasmic reticulum to endosomes. A genetic defect in the human UNC93B1 gene is associated with immunodeficiency. However, systemic lupus erythematosus (SLE) patients express increased levels of the UNC93B1 protein in B cells. Because SLE in patients and certain mouse models exhibits a sex bias and increased serum levels of type I interferons in patients are associated with the disease activity, we investigated whether the female sex hormone estrogen (E2) or type I interferon signaling could up-regulate the expression of the murine Unc93b1 gene. We found that steady-state levels of Unc93b1 mRNA and protein were measurably higher in immune cells (CD3(+), B220(+), CD11b(+) and CD11c(+)) isolated from C57BL/6 (B6) females than age-matched males. Moreover, treatment of CD11b(+) and B220(+) cells with E2 or interferons (IFN alpha, IFN-beta or IFN-gamma) significantly increased the levels of Unc93b1 mRNA and protein. Accordingly, a deficiency of estrogen receptor-alpha or STAT1 expression in immune cells decreased the expression levels of the Unc93b1 protein. Interestingly, levels of Unc93b1 protein were appreciably higher in B6.Nba2 lupus-prone female mice compared with age-matched B6 females. Furthermore, increased expression of the interferon- and E2-inducible p202 protein in a murine macrophage cell line (RAW264.7) increased the levels of the Unc93b1 protein, whereas knockdown of p202 expression reduced the levels. To our knowledge, our observations demonstrate for the first time that activation of interferon and estrogen signaling in immune cells up-regulates the expression of murine Unc93b1. PMID- 23728776 TI - Mast cell-derived mediators promote murine neutrophil effector functions. AB - Mast cells are able to trigger life-saving immune responses in murine models for acute inflammation. In such settings, several lines of evidence indicate that the rapid and protective recruitment of neutrophils initiated by the release of mast cell-derived pro-inflammatory mediators is a key element of innate immunity. Herein, we investigate the impact of mast cells on critical parameters of neutrophil effector function. In the presence of activated murine bone marrow derived mast cells, neutrophils freshly isolated from bone marrow rapidly lose expression of CD62L and up-regulate CD11b, the latter being partly driven by mast cell-derived TNF and GM-CSF. Mast cells also strongly enhance neutrophil phagocytosis and generation of reactive oxygen species. All these phenomena partly depend on mast cell-derived TNF and to a greater extend on GM-CSF. Furthermore, spontaneous apoptosis of neutrophils is greatly diminished due to the ability of mast cells to deliver antiapoptotic GM-CSF. Finally, we show in a murine model for acute lung inflammation that neutrophil phagocytosis is impaired in mast cell-deficient Kit (W-sh) /Kit (W-sh) mice but can be restored upon mast cell engraftment. Thus, a previously underrated feature of mast cells is their ability to boost neutrophil effector functions in immune responses. PMID- 23728777 TI - Transcriptional and post-transcriptional regulation of IkappaB-zeta upon engagement of the BCR, TLRs and FcgammaR. AB - IkappaB-zeta is a nuclear IkappaB protein robustly induced in macrophages and fibroblasts upon TLR or IL-1R stimulation. IkappaB-zeta associates with NF-kappaB in the cell nucleus and is essential for the induction of a subset of secondary response genes represented by IL-6. Here, we analyzed induction of IkappaB-zeta in mouse B cells and found that IkappaB-zeta is induced by BCR or TLR stimulation. Similar to TLR stimulation, BCR stimulation elicited NF-kappaB mediated transcriptional activation and mRNA stabilization of IkappaB-zeta via a cis-element in IkappaB-zeta mRNA. Proteasome inhibitors inhibited transcriptional activation but not post-transcriptional activation, indicating independency of the two signals. Co-stimulation of the BCR and TLR9 or TLR7, but not TLR2/1, synergistically induced IkappaB-zeta. Co-engagement of inhibitory Fcgamma receptor suppressed BCR-mediated IkappaB-zeta expression but not that induced by TLR stimulation alone or co-stimulation of TLR and the BCR. The PI3K inhibitor LY294002 inhibited BCR-mediated, but not TLR-mediated, induction of IkappaB-zeta, consistent with the role of PI3K in BCR signaling and its suppression by FcgammaR. Analysis of IkappaB-zeta-deficient B cells demonstrated that IkappaB zeta was essential upon stimulation of BCR or TLR for the expression of several genes including IL-10 and CTLA4. IkappaB-zeta-deficient B cells exhibited impaired proliferation and enhanced up-regulation of CD86 following stimulation of TLR9, but not the BCR, indicating critical roles for IkappaB-zeta in TLR signaling in B cells. Strict regulatory mechanisms for the induction of IkappaB zeta via multiple pathways and its essential function upon stimulation indicate that IkappaB-zeta plays an important role in B cells. PMID- 23728778 TI - Differential regulation of marginal zone and follicular B cell responses by CD83. AB - Transgenic over-expression of CD83 on B cells leads to a reduced response to BCR engagement but to an enhanced secretion of IL-10 upon LPS stimulation. In this study, we analyzed the differential influence of CD83 on the stimulation of different B cell subsets via the BCR or TLR4. Neither wild type nor CD83 transgenic (CD83tg) B cells produced any IL-10 in response to BCR stimulation. BCR engagement led to reduced activation of LYN, SYK and ERK1/2 resulting in reduced numbers of proliferating cells in all CD83tg B cell subsets. Moreover, CD83tg follicular (FO) but not marginal zone (MZ) or transitional (TN) B cells showed significantly enhanced cell death. In contrast, LPS stimulation led to normal frequencies of proliferating CD83tg FO, MZ and TN B cells although TLR4 engagement did not rescue FO B cells from apoptosis. Furthermore, LPS stimulation led to high IL-10 production derived from CD83tg MZ B cells that reacted to LPS stimulation with enhanced ERK1/2 activation. Finally, we show that CD83 co localizes with the BCR complex as well as with the LPS receptor complex suggesting that CD83 interacts with components of both signaling complexes. Taken together, the results of this study show that CD83 already inhibits the initiation of BCR signaling leading to insufficient activation signals in all B cells and reduced survival especially of FO B cells. On the other hand, CD83 supports TLR4-mediated IL-10 release exclusively in MZ B cells. Thus, CD83 differentially modulates FO and MZ B cell responses. PMID- 23728779 TI - The impact of polyelectrolyte structure on the shape of nanoassemblies with cationic peptides. AB - We investigated how the structure of nanofibers, resulting from interactions between anionic polyelectrolytes and cationic peptides, relies on the properties of the polyelectrolyte component. By using hyaluronate (H), carboxymethylcellulose (CMC), xanthan (X), and ozarelix (O), a cationic decapeptide, we determined the influence of characteristic polyelectrolyte parameters such as size and charge density on the formation of polyelectrolyte peptide complexes. Transmission electron microscopy of unstained, frozen hydrated, or negatively stained samples revealed that the interaction between different anionic polyelectrolytes and ozarelix led to the formation of distinctly shaped nanofibers. CMC formed rather flexible structures with alternating thin and thick segments within the nanofibers with diameters ranging from 10 to 16 nm and a length of up to 1 MUm. Hyaluronate, a high-molecular-mass molecule, formed extra-long aggregates of more than 5 MUm. Individual fibers with a diameter of 8 nm aggregated to bigger strands. The nonlinear polysaccharide xanthan gum led to highly coiled structures. The diameter of the respective nanofibers varied between 15 and 25 nm. Isothermal titration calorimetry was used to determine the binding constants and the thermodynamic parameters of the different polyelectrolyte-peptide complexes. The binding constant, which was of the order of 10(6) M(-1) , indicated a strong binding affinity, but also showed differences among the polyelectrolytes. These differences might be useful for prospective applications as drug delivery systems. PMID- 23728780 TI - Antisense expression of peach mildew resistance locus O (PpMlo1) gene confers cross-species resistance to powdery mildew in Fragaria x ananassa. AB - Powdery mildew (PM) is one of the major plant pathogens. The conventional method of PM control includes frequent use of sulfur-based fungicides adding to production costs and potential harm to the environment. PM remains a major scourge for Rosaceae crops where breeding approaches mainly resort to gene-for gene resistance. We have tested an alternate source of PM resistance in Rosaceae. Mildew resistance locus O (MLO) has been well studied in barley due to its role in imparting broad spectrum resistance to PM. We identified PpMlo1 (Prunus persica Mlo) in peach and characterized it further to test if a similar mechanism of resistance is conserved in Rosaceae. Due to its recalcitrance in tissue culture, reverse genetic studies involving PpMloI were not feasible in peach. Therefore, Fragaria x ananassa LF9 line, a taxonomic surrogate, was used for functional analysis of PpMlo1. Agrobacterium-mediated transformation yielded transgenic strawberry plants expressing PpMlo1 in sense and antisense orientation. Antisense expression of PpMlo1 in transgenic strawberry plants conferred resistance to Fragaria-specific powdery mildew, Podosphaera macularis. Phylogenetic analysis of 208 putative Mlo gene copies from 35 plant species suggests a large number of duplications of this gene family prior to the divergence of monocots and eudicots, early in eudicot diversification. Our results indicate that the Mlo-based resistance mechanism is functional in Rosaceae, and that Fragaria can be used as a host to test mechanistic function of genes derived from related tree species. To the best of our knowledge, this work is one of the first attempts at testing the potential of using a Mlo-based resistance strategy to combat powdery mildew in Rosaceae. PMID- 23728781 TI - Meningococcal carriage during a clonal meningococcal B outbreak in France. AB - The aim of this study performed in Normandy, France, was to analyze the pharyngeal meningococcal carriage at the peak of a clonal meningococcal B outbreak, which was subsequently controlled using an outer membrane vesicle vaccination. This cross-sectional study included randomly selected subjects aged 1-25 years. Carriers and non carriers were compared using unconditional logistic regression. Among the 3,522 volunteers, there were 196 (standardized rate: 6.46 %) Neisseria meningitidis carriers, of which there were only five with the outbreak strain (B:14:P1.7,16/ST-32; standardized rate: 0.18 %). From the multivariate analysis, older age, smoking, higher degree of socialization, and social deprivation appear to favor the carriage of all the strains included. Prior antibiotic treatment up to 12 months before swabbing, even with beta lactam, was protective against carriage. Our data indicate a low overall meningococcal carriage rate with a surprising protective effect of prior antibiotic exposure. The observed low carriage rate of the epidemic strain (B:14:P1.7,16/ST-32) contrasts with the high incidence of invasive meningococcal diseases (IMD) due to this strain. Hence, our data underline the high virulence of the strain and suggest a low level of natural immunity of the population against this strain. Although highly resource-consuming, carriage studies are helpful in guiding the implementation of control measures of IMD, such as mass vaccination or chemoprophylaxis. PMID- 23728782 TI - Human papillomavirus prevalence and prognostic implication in oropharyngeal squamous cell carcinomas. AB - BACKGROUND: Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC) is associated with favorable survival. The purpose of this study was to evaluate the prevalence and prognostic significance of the HPV infection through both the p16 expression status and the oncogenic HPV DNA viral load. METHODS: A retrospective chart review was conducted on all patients treated for oropharyngeal SCC between January 2007 and June 2009. P16 expression status by immunohistochemistry and HPV DNA viral load by quantitative polymerase chain reaction (qPCR) were evaluated on routine pretreatment tumor samples. RESULTS: One hundred thirty-three patients (94 men and 39 women) were included in the study. Mean age was 59 years. One hundred twenty-two lesions (92%) were localized to lymphoid areas. Sixty-seven patients (50%) were p16+, and 87 patients (65%) harbored HPV DNA. The p16+/HPV DNA+ profile (48%) was associated with the most favorable prognosis. HPV16 was responsible for the majority of the infections (89%). CONCLUSION: HPV is common among oropharyngeal SCC in France, and acts as an independent prognostic factor. PMID- 23728783 TI - Views of genetics health professionals on the return of genomic results. AB - As exome and whole genome sequencing become clinically available, the potential to receive a large number of clinically relevant but incidental results is a significant challenge in the provision of genomic counseling. We conducted three focus groups of a total of 35 individuals who were members of ASHG and/or NSGC, assessing views towards the return of genomic results. Participants stressed that patient autonomy was primary. There was consensus that a mechanism to return results to the healthcare provider, rather than patient, and to streamline integration into the electronic health record would ensure these results had the maximal impact on patient management. All three focus groups agreed that pharmacogenomic results were reasonable to return and that they were not felt to be stigmatizing. With regard to the return of medically relevant results, there was much debate. Participants had difficulty in consistently assigning specific diseases to 'bins' that were considered obligatory versus optional for disclosure. Consensus was reached regarding the importance of informed consent and pretest counseling visits to clarify what the return of results process would entail. Evidence based professional guidelines should continue to be developed and regularly revised to assist in consistently and appropriately providing genomic results to patients. PMID- 23728784 TI - Is there still a role for ultrafiltration in the management of acute heart failure? CARRESS and beyond. AB - The Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial was a prospective, randomized study comparing ultrafiltration versus pharmacological therapy in the treatment of acute decompensated heart failure (ADHF) complicated by cardiorenal syndrome Bart et al. (N Eng J Med 367:2296 2304, 1). The study found that ultrafiltration was inferior to pharmacological therapy, resulting in a significant increase in serum creatinine and serious adverse events while producing no significant difference in weight loss. The CARRESS trial calls into question the viability of ultrafiltration as a preferable treatment strategy in ADHF patients with cardiorenal syndrome. PMID- 23728785 TI - Molecular characterization of chitinase genes from a local isolate of Serratia marcescens and their contribution to the insecticidal activity of Bacillus thuringiensis strains. AB - The chitinase B (chiB) and C (chiC) genes and flanking regions from a local isolate of Serratia marcescens were cloned individually and sequenced. Results showed that these chiB and chiC genes have a 96 % maximum similarity with chiB and chiC from different S. marcescens species (GenBank numbers Z36295.1 and AJ630582.1, respectively). The amplified chiB fragment, including some upstream and downstream regions, is 1,689-bp long with an open reading frame of 1,500 bp. The amplified fragment of chiC is 1,844 bp with an open reading frame of 1,443 bp. These sequences were submitted to the GenBank with accession numbers JX847796 (chiB) and JX847797 (chiC). Putative promoter regions and Shine-Dalgarno sequences were identified in both genes. The genes were cloned into a shuttle vector and the constructs were designated as pHYSB and pHYSC, respectively. Both plasmids were introduced separately into kurstaki and israelensis strains of Bacillus thuringiensis and the insecticidal activities of the engineered B. thuringiensis strains were assayed in larvae of Galleria mellonella and adult of Drosophila melanogaster. Engineered B. thuringiensis strains showed higher insecticidal activity than parental strain and the parental S. marcescens. In addition, pHYSB and pHYSC were stable over 16 daily passages under non-selective conditions in transformed B. t. israelensis 5724 strain. PMID- 23728787 TI - Testing functional and morphological interpretations of enamel thickness along the deciduous tooth row in human children. AB - The significance of a gradient in enamel thickness along the human permanent molar row has been debated in the literature. Some attribute increased enamel thickness from first to third molars to greater bite force during chewing. Others argue that thicker third molar enamel relates to a smaller crown size facilitated by a reduced dentin component. Thus, differences in morphology, not function, explains enamel thickness. This study draws on these different interpretive models to assess enamel thickness along the entire human deciduous tooth row. Average enamel thickness (AET), the area and proportion of crown enamel and dentin, and a crown size proxy are calculated for incisors, canines, and molars. Allometric scaling relationships are assessed within each tooth class, and then comparisons are undertaken along the row. Generally, AET was correlated with crown size and scaled with isometry, except for second molars which scaled with positive allometry. Mean AET increased along the row and was greater on molars, where bite forces are reported to be higher. Second molars combined the largest crown size with the thickest enamel and the smallest proportion of dentin, which is consistent with a reduction in the potential for cusp fracture under high bite forces. Resistance to wear may also account for some enamel thickness variation between tooth classes. Dental reduction did not explain the trend in AET from central to lateral incisors, or from first to second molars. The gradient in AET along the deciduous tooth row is partly consistent with a functional interpretation of enamel thickness. PMID- 23728786 TI - Quantitative analysis of porcine endogenous retroviruses in different organs of transgenic pigs generated for xenotransplantation. AB - The pig appears to be the most promising animal donor of organs for use in human recipients. Among several types of pathogens found in pigs, one of the greatest problems is presented by porcine endogenous retroviruses (PERVs). Screening of the source pig herd for PERVs should include analysis of both PERV DNA and RNA. Therefore, the present study focuses on quantitative analysis of PERVs in different organs such as the skin, heart, muscle, and liver and blood of transgenic pigs generated for xenotransplantation. Transgenic pigs were developed to express the human alpha-galactosidase, the human alpha-1,2-fucosyltransferase gene, or both genetic modifications of the genome (Lipinski et al., Medycyna Wet 66:316-322, 2010; Lipinski et al., Ann Anim Sci 12:349-356, 2012; Wieczorek et al., Medycyna Wet 67:462-466, 2011). The copy numbers of PERV DNA and RNA were evaluated using real-time Q-PCR and QRT-PCR, respectively. Comparative analysis of all PERV subtypes revealed the following relationships: PERV A > PERV B > PERV C. PERV A and B were found in all samples, whereas PERV C was detected in 47 % of the tested animals. The lowest level of PERV DNA was shown in the muscles for PERV A and B and in blood samples for PERV C. The lowest level of PERV A RNA was found in the skin, whereas those of PERV B and C RNA were found in liver specimens. Quantitative analysis revealed differences in the copy number of PERV subtypes between various organs of transgenic pigs generated for xenotransplantation. Our data support the idea that careful pig selection for organ donation with low PERV copy number may limit the risk of retrovirus transmission to the human recipients. PMID- 23728788 TI - Enrichment of putative prostate cancer stem cells after androgen deprivation: upregulation of pluripotency transactivators concurs with resistance to androgen deprivation in LNCaP cell lines. AB - BACKGROUND: Prostate cancer stem cells (PCSC) offer theoretical explanations to many clinical and biological behaviors of the disease in human. In contrast to approaches of using side populations and cell-surface markers to isolate and characterize the putative PCSC, we hypothesize that androgen deprivation leads to functional enrichment of putative PCSC. METHODS AND RESULTS: Human prostate cancer lines LNCaP, LAPC4 and LAPC9 were depleted of androgen in cell cultures and in castrated SCID mice. The resultant androgen deprivation-resistant or castration-resistant populations, in particular in LNCaP and its derivative cell lines, displayed increased expression of pluripotency transactivators and significantly higher tumorigenicity. Individual tumor cell clones were isolated from castration-resistant bulk cultures of LNCaP (CR-LNCaP) and tested for tumorigenicity in male SCID mice under limiting dilution conditions. As few as 200 cells were able to form spheres in vitro, and generate tumors with similar growth kinetics as 10(6) LNCaP or 10(4) CR-LNCaP cells in vivo. These putative PCSC were CD44(+) /CD24(-) and lack the expression of prostate lineage proteins. When transplanted into the prostate of an intact male SCID mouse, these putative PCSC seemed to show limited differentiation into Ck5(+) , Ck8(+) , Ck5(+) /Ck8(+) , and AR(+) cells. On the other hand, stable transduction of LNCaP with retrovirus encoding Sox2 led to androgen-deprivation resistant growth and down regulation of major prostate lineage gene products in vitro. CONCLUSION: Concurrence of overexpression of pluripotency transactivators and resistance to androgen deprivation supported the role of putative PCSC in the emergence of prostate cancer resistant to androgen deprivation. PMID- 23728789 TI - Isolation and characterization of two VpYABBY genes from wild Chinese Vitis pseudoreticulata. AB - The establishment of abaxial-adaxial polarity is an important feature of the development of lateral organs in plants. Members of the YABBY gene family may be specific to seed-plant-specific transcriptional regulators that play critical roles in promoting abaxial cell fate in the model eudicot, Arabidopsis thaliana. However, recent study has shown that the roles of YABBY genes are not conserved in the development of angiosperms. The establishment of abaxial-adaxial polarity has not been studied in perennial fruit crops. Grapes are an important fruit crop in many regions of the world. Investigating YABBY genes in grapevines should help us to discover more about the key genetic and molecular pathways in grapevine development. To understand the characterization of YABBY genes in grapevines, two YABBY genes, VpYABBY1 (GenBank accession No. KC139089) and VpYABBY2 (GenBank accession No. KC139090), were isolated from the wild Chinese species Vitis pseudoreticulata. Both of these encode YABBY proteins. Sequence characterization and phylogenetic analyses show that VpYABBY1 is group classified into the FIL subfamily while VpYABBY2 is a member of the YAB2 subfamily of Arabidopsis thaliana. Subcellular localization analysis indicates that VpYABBY1 and VpYABBY2 proteins are localized in the nucleus. Tissue specific expressional analysis reveals that VpYABBY1 is expressed strongly in young leaves of grape but only weakly in the mature leaves. Meanwhile, VpYABBY2 is expressed in grape stems, flowers, tendrils, and leaves. Transgenic Arabidopsis plants ectopically expressing VpYABBY1 caused the partial abaxialization of the adaxial epidermises of leaves, behaving similarly to those over-expressing FIL or YAB3 with abaxialized lateral organs. By contrast, ectopic expression of VpYABBY2 in Arabidopsis did not cause any alteration in the adaxial-abaxial polarity. Sequence characterization and phylogenetic analysis revealed that VpYABBY1 and VpYABBY2 are group-classified into two different subfamilies. They have diverged functionally in the control of lateral organ development. VpYABBY1 may have a function in leaf development, while VpYABBY2 may play a specific role in carpel development and grape berry morphogenesis. It is further possible that during the evolution of different species, YABBY family members have preserved different expression regulatory systems and functions. PMID- 23728790 TI - mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: evidence from focal cortical dysplasia and tuberous sclerosis. AB - Focal cortical dysplasia (FCD) is a localized malformation of cortical development and is the commonest cause of severe childhood epilepsy in surgical practice. Children with FCD are severely disabled by their epilepsy, presenting with frequent seizures early in life. The commonest form of FCD in children is characterized by the presence of an abnormal population of cells, known as balloon cells. Similar pathological changes are seen in the cortical malformations that characterize patients with tuberous sclerosis complex (TSC). However, the cellular and molecular mechanisms that underlie the malformations of FCD and TSC are not well understood. We provide evidence for a defect in autophagy in FCD and TSC. We have found that balloon cells contain vacuoles that include components of the autophagy pathway. Specifically, we show that balloon cells contain prominent lysosomes by electron microscopy, immunohistochemistry for LAMP1 and LAMP2, LysoTracker labelling and enzyme histochemistry for acid phosphatase. Furthermore, we found that balloon cells contain components of the ATG pathway and that there is cytoplasmic accumulation of the regulator of autophagy, DOR. Most importantly we found that there is abnormal accumulation of the autophagy cargo protein, p62. We show that this defect in autophagy can be, in part, reversed in vitro by inhibition of the mammalian target of rapamycin (mTOR) suggesting that abnormal activation of mTOR may contribute directly to a defect in autophagy in FCD and TSC. PMID- 23728791 TI - Modulation of anti-inflammatory response in lipopolysaccharide stimulated human THP-1 cell line and mouse model at gene expression level with indigenous putative probiotic lactobacilli. AB - The anti-inflammatory potential of eight indigenous probiotic Lactobacillus isolates was evaluated in vitro in terms of modulating the expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in human acute monocytic leukemia (THP-1) cells under inflammatory conditions. Amongst these, Lactobacillus plantarum Lp91 was the most potent anti-inflammatory strain as it evoked a significant (P < 0.001) down-regulation of TNF-alpha by -1.45-fold relative to the control in THP-1 cells. However, in terms of IL-6 expression, all the strains could up-regulate its expression considerably at different levels. Hence, based on in vitro expression of TNF-alpha, Lp91 was selected for in vivo study in lipopolysaccharide (LPS)-induced mouse model to look at the expression of TNF-alpha, IL-6, monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule (ICAM-1) and E selectin in mouse aorta. In LPS challenged (2 h) mice group fed with Lp91 for 10 days, TNF-alpha, IL-6, MCP-1, VCAM-1, ICAM-1 and E-selectin expressions were significantly down-regulated by 3.10-, 10.02-, 4.22-, -3.14-, 2.28- and 5.71-fold relative to control conditions. In conclusion, Lp91 could serve as a candidate probiotic strain to explore it as a possible biotherapeutic anti-inflammatory agent against inflammatory diseases including cardiovascular disease. PMID- 23728792 TI - Relative adrenal insufficiency in decompensated cirrhosis: Relationship to short term risk of severe sepsis, hepatorenal syndrome, and death. AB - The prevalence of relative adrenal insufficiency (RAI) in critically ill cirrhosis patients with severe sepsis is over 60% and associated features include poor liver function, renal failure, refractory shock, and high mortality. RAI may also develop in noncritically ill cirrhosis patients but its relationship to the clinical course has not yet been assessed. The current study was performed in 143 noncritically ill cirrhosis patients admitted for acute decompensation. Within 24 hours after hospitalization adrenal function, plasma renin activity, plasma noradrenaline and vasopressin concentration, and serum levels of nitric oxide, interleukin-6 and tumor necrosis factor alpha were determined. RAI was defined as a serum total cortisol increase <9 MUg/dL after 250 MUg of intravenous corticotropin from basal values <35 MUg/dL. Patients were followed for 3 months. RAI was detected in 26% of patients (n = 37). At baseline, patients with RAI presented with lower mean arterial pressure (76 +/- 12 versus 83 +/- 14 mmHg, P = 0.009) and serum sodium (131 +/- 7 versus 135 +/- 5 mEq/L, P = 0.007) and higher blood urea nitrogen (32 +/- 24 versus 24 +/- 15 mg/dl, P = 0.06), plasma renin activity (7.1 +/- 9.9 versus 3.4 +/- 5.6 ng/mL*h, P = 0.03), and noradrenaline concentration (544 +/- 334 versus 402 +/- 316 pg/mL, P = 0.02). During follow-up, patients with RAI exhibited a higher probability of infection (41% versus 21%, P = 0.008), severe sepsis (27% versus 9%, P = 0.003), type-1 hepatorenal syndrome (HRS) (16% versus 3%, P = 0.002), and death (22% versus 7%, P = 0.01). CONCLUSION: RAI is frequent in noncritically ill patients with acute decompensation of cirrhosis. As compared with those with normal adrenal function, patients with RAI have greater impairment of circulatory and renal function, higher probability of severe sepsis and type-1 HRS, and higher short-term mortality. PMID- 23728793 TI - Timing and consequences of recurrent polyploidy in meadow-rues (thalictrum, ranunculaceae). AB - The discovery of ancient whole-genome duplications in eukaryotic lineages has renewed the interest in polyploidy and its effects on the diversification of organisms. Polyploidy has large-scale effects on both genotype and phenotype and has been linked to the evolution of genome size, dioecy, and changes in ecological interactions, such as pollinator visitation. Here, we take a molecular systematics approach to examine the evolution of polyploidy in the plant genus Thalictrum (Ranunculaceae) and test its correlation to changes in genome size, sexual system, and pollination mode. Thalictrum is an ideal study system due to its extensive ploidy range and floral diversity. Phylogenetic analyses were used for character reconstructions, correlation tests, and dating estimates. Our results suggest that polyploidization occurred frequently and recently in the evolution of Thalictrum, mostly within the last 10.6-5.8 My, coinciding with the diversification of particular clades. In spite of an overall trend of genomic downsizing accompanying polyploidy in angiosperms and proportional increases observed at finer scales, our genome size estimates for Thalictrum show no correlation with chromosome number. Instead, we observe genomic expansion in diploids and genomic contraction in polyploids with increased age. Additionally, polyploidy is not correlated with dioecy in Thalictrum; therefore, other factors must have influenced the evolution of separate sexes in this group. A novel finding from our study is the association of polyploidy with shifts to wind pollination, in particular, during a time period of global cooling and mountain uplift in the Americas. PMID- 23728794 TI - APE-type non-LTR retrotransposons of multicellular organisms encode virus-like 2A oligopeptide sequences, which mediate translational recoding during protein synthesis. AB - 2A oligopeptide sequences ("2As") mediate a cotranslational recoding event termed "ribosome skipping." Previously we demonstrated the activity of 2As (and "2A-like sequences") within a wide range of animal RNA virus genomes and non-long terminal repeat retrotransposons (non-LTRs) in the genomes of the unicellular organisms Trypanosoma brucei (Ingi) and T. cruzi (L1Tc). Here, we report the presence of 2A like sequences in the genomes of a wide range of multicellular organisms and, as in the trypanosome genomes, within non-LTR retrotransposons (non-LTRs)-clustering in the Rex1, Crack, L2, L2A, and CR1 clades, in addition to Ingi. These 2A-like sequences were tested for translational recoding activity, and highly active sequences were found within the Rex1, L2, CR1, and Ingi clades. The presence of 2A-like sequences within non-LTRs may not only represent a method of controlling protein biogenesis but also shows some correlation with such apurinic/apyrimidinic DNA endonuclease-type non-LTRs encoding one, rather than two, open reading frames (ORFs). Interestingly, such non-LTRs cluster with closely related elements lacking 2A-like recoding elements but retaining ORF1. Taken together, these observations suggest that acquisition of 2A-like translational recoding sequences may have played a role in the evolution of these elements. PMID- 23728796 TI - The linkage method: a novel approach for SNP detection and haplotype reconstruction from a single diploid individual using next-generation sequence data. AB - When we sequence a diploid individual, the output actually comprises two genomes: one from the paternal parent and the other from the maternal parent. In this study, we introduce a novel heuristic algorithm for distinguishing single nucleotide polymorphisms (SNPs) from the two parents and phasing them into haplotypes. The algorithm is unique because it simultaneously performs SNP calling and haplotype phasing. This approach can exploit the linkage information of nearby SNPs, which facilitates the efficient removal of haplotypes that originate from incorrectly mapped short reads. Using simulated data we demonstrated that our approach increased the accuracy of SNP calls. The haplotype reconstruction performance depended largely on the density of SNPs. Using current next-generation sequence technology with a relatively short read length, reasonable performance is expected when this approach is applied to species with an average of five heterozygous sites per 1 kb. The algorithm was implemented as the program "linkSNPs." PMID- 23728795 TI - Substrate ambiguous enzymes within the Escherichia coli proteome offer different evolutionary solutions to the same problem. AB - Many enzymes exhibit some catalytic promiscuity or substrate ambiguity. These weak activities do not affect the fitness of the organism under ordinary circumstances, but can serve as potential evolutionary precursors of new catalytic functions. We wondered whether different proteins with the same substrate ambiguous activity evolve differently under identical selection conditions. Patrick et al. (Patrick WM, Quandt EM, Swartzlander DB, Matsumura I. 2007. Multicopy suppression underpins metabolic evolvability. Mol Biol Evol. 24:2716-2722.) previously showed that three multicopy suppressors, gph, hisB, and ytjC, rescue DeltaserB Escherichia coli cells from starvation on minimal media. We directed the evolution of variants of Gph, histidinol phosphatase (HisB), and YtjC that complemented DeltaserB more efficiently, and characterized the effects of the amino acid changes, alone and in combination, upon the evolved phosphoserine phosphatase (PSP) activity. Gph and HisB are members of the HAD superfamily of hydrolases, but they adapted through different, kinetically distinguishable, biochemical mechanisms. All of the selected mutations, except N102T in YtjC, proved to be beneficial in isolation. They exhibited a pattern of antagonistic epistasis, as their effects in combination upon the kinetic parameters of the three proteins in reactions with phosphoserine were nonmultiplicative. The N102T mutation exhibited sign epistasis, as it was deleterious in isolation but beneficial in the context of other mutations. We also showed that the D57N mutation in the chromosomal copy of hisB is sufficient to suppress the DeltaserB deletion. These results in combination show that proteomes can offer multiple mechanistic solutions to a molecular recognition problem. PMID- 23728797 TI - Mammalian predator-prey interaction in a fragmented landscape: weasels and voles. AB - The relationship between predators and prey is thought to change due to habitat loss and fragmentation, but patterns regarding the direction of the effect are lacking. The common prediction is that specialized predators, often more dependent on a certain habitat type, should be more vulnerable to habitat loss compared to generalist predators, but actual fragmentation effects are unknown. If a predator is small and vulnerable to predation by other larger predators through intra-guild predation, habitat fragmentation will similarly affect both the prey and the small predator. In this case, the predator is predicted to behave similarly to the prey and avoid open and risky areas. We studied a specialist predator's, the least weasel, Mustela nivalis nivalis, spacing behavior and hunting efficiency on bank voles, Myodes glareolus, in an experimentally fragmented habitat. The habitat consisted of either one large habitat patch (non-fragmented) or four small habitat patches (fragmented) with the same total area. The study was replicated in summer and autumn during a year with high avian predation risk for both voles and weasels. As predicted, weasels under radio-surveillance killed more voles in the non-fragmented habitat which also provided cover from avian predators during their prey search. However, this was only during autumn, when the killing rate was also generally high due to cold weather. The movement areas were the same for both sexes and both fragmentation treatments, but weasels of both sexes were more prone to take risks in crossing the open matrix in the fragmented treatment. Our results support the hypothesis that habitat fragmentation may increase the persistence of specialist predator and prey populations if predators are limited in the same habitat as their prey and they share the same risk from avian predation. PMID- 23728798 TI - Development of a novel FRET probe for the real-time determination of ceramidase activity. AB - Fretful novelty: We developed two novel doubly labelled fluorescent ceramide analogues that exhibit significant FRET and undergo hydrolysis by ceramidases. We present a fluorescent sphingolipid FRET probe that allows homogeneous ratiometric determination of enzyme activity in real-time. PMID- 23728800 TI - Morphogenetic analysis of peri-implantation development. AB - BACKGROUND: Although successful implantation is required for development in placental mammals, the molecular and morphogenetic events that define peri implantation remain largely unexplored. RESULTS: Here we present detailed morphological and immunohistochemical analysis of mouse embryos between embryonic day 3.75 and 5.25 of gestation, during the implantation process in vivo. We examined expression patterns of key transcription factors (Sox2, Oct4, Nanog, Cdx2, Gata6, Sox17, and Yy1) during pre- and postimplantation development. Additionally, we examined morphogenetic changes through analysis of ZO-1, Laminin, and E-Cadherin localization. The results presented reveal novel changes in gene expression and morphogenetic events during peri-implantation in utero. Here we show: (1) molecular and morphological changes in primitive endoderm cells as they transition from a salt and pepper distribution to a sheet covering the inner cell mass; (2) tissue-specific GATA6 levels; and (3) a striking pattern of SOX17 that is suggestive of a functional role either directing or permitting implantation at specific sites in the uterine epithelium. CONCLUSIONS: A growing number of knockout mice display peri-implantation lethality, and the data presented herein identify key morphogenetic landmarks that can be used to characterize mutant phenotypes, as well as further our basic understanding of peri-implantation development. PMID- 23728799 TI - SPRR2A expression in cholangiocarcinoma increases local tumor invasiveness but prevents metastasis. AB - Cholangiocarcinoma morbidity and mortality is attributable to local invasiveness and regional lymph node and distant organ metastasis. Cholangiocarcinoma progression follows a series of sequential events that resemble wound healing reactions: local invasion resembles the epithelial migration phase involving epithelial-mesenchymal transition (EMT); colonization at distant sites resembles epithelial restitution seen during the reverse process, mesenchymal-epithelial transition (MET). In this study we compare the in vivo local and metastatic growth potential of cholangiocarcinoma cell lines with respect to expression of a novel pSTAT3-dependent, biliary epithelial cell wound healing protein, small proline-rich protein 2A (SPRR2A). SPRR2A has been associated with local aggressiveness, but decreased metastatic capabilities in other cancers. Stable SPRR2A transfection into two cholangiocarcinoma cell lines (SG231 and HuCCT-1), previously shown by us to induce permanent EMT, resulted in local aggressiveness but an inability to form metastases. In contrast, SPRR2A-negative epithelial control cells showed relatively poor local aggressiveness, but readily formed metastatic tumors. Post-intrasplenic injection cell tracking showed that: (a) mesenchymal (SPRR2A+) cells were not trapped in the liver, but were rapidly cleared through mesenteric lymph nodes and did not form metastases; whereas (b) epithelial (SPRR2A-) controls were primarily entrapped within MUC-1-associated liver "micro-infarcts" that later evolved into metastatic colonies. SPRR2A associated tumor behavior was mimicked by MUC1 shRNA, which induced EMT and, like SPRR2A+ cells, showed reduced metastatic capabilities. Cholangiocarcinoma local invasion involves EMT processes, whereas MET and MUC1 expression promote metastasis. A better understanding of disease progression should help target treatment for this deadly neoplasm. PMID- 23728801 TI - Primary sarcomas of the salivary glands: case series and literature review. AB - BACKGROUND: Mesenchymal malignancies of salivary origin are rare and are histologically diverse. We reviewed our experience with these tumors, as well as the published literature, with an emphasis on treatment modalities and prognosis. METHODS: We identified 17 patients treated for malignant mesenchymal cell tumors at The University of Texas MD Anderson Cancer Center between 1990 and 2007. We compared our results to the literature from January 1990 to July 2010. RESULTS: Tumors were located primarily in the parotid gland and were primarily T1 tumors (<5 cm). All patients were treated with surgical resection, and 13 patients were given adjuvant therapy. Seven patients (41%) had recurrence, and 4 developed distant metastases. The overall 5-year and 10-year survival rates were 42% and 20%, respectively. CONCLUSIONS: Our case series and literature review show that sarcomas of the salivary glands have a high rate of recurrence and are associated with a poor prognosis. PMID- 23728802 TI - Recent observations on site reactions in cattle to vaccination against contagious bovine pleuropneumonia (CBPP) using T1/44 vaccine in Zambia. AB - Contagious bovine pleuropneumonia (CBPP), a highly infectious and fatal disease of cattle present in many countries in sub-Saharan Africa, is usually controlled by mass vaccinations. However, vaccination against CBPP is known to cause site reactions in a percentage of cattle especially in primary vaccinations. In Zambia, a record of site reactions was kept for seven consecutive years from 2005 to 2011 to establish the level of the problem. In some areas, after 3 years of consecutive vaccination campaigns, immunization could not be implemented for a period of 2 years because of logistical difficulties or owner resistance. Whereas in the three preceding years when animals were vaccinated annually, site reactions were in the range of 6.2%; on resumption of vaccination in the herds that had not been immunized for 2 years, site reactions averaged 21.3%. This data shows that the T1/44 vaccine may cause severe local reactions in cattle if there is any break in annual vaccinations. It is therefore important for authorities to ensure that the cattle at risk of contracting CBPP are regularly vaccinated to avoid discouraging farmers from presenting their animals. PMID- 23728803 TI - Pain levels associated with ultrasound-guided fine-needle aspiration biopsy for neck masses. AB - BACKGROUND: The purpose of this study was to evaluate the pain levels associated with ultrasound-guided fine-needle aspiration biopsy (FNAB) of neck masses. METHODS: The pain immediately and 5 minutes after the procedure without use of local anesthesia was evaluated via 100-mm visual analog scale (VAS), 11-point numeric rating scale (NRS), and 4-category verbal rating scale (VRS) in 154 patients. RESULTS: The mean scores (SDs) for VAS, NRS, and VRS immediately versus 5 minutes after the procedure were 30.5 (24.4) versus 7.3 (13.7), 3.3 (2.2) versus 0.8 (1.6), and 1.3 (0.6) versus 0.3 (0.6), respectively (all ps < .001). Immediately after ultrasound-guided FNAB, the pain scores associated with lymph node aspiration (VAS, 36.7 [25.5]; NRS, 3.9 [2.1]) were significantly higher (both ps < .05) than those associated with thyroid nodule aspiration (VAS, 25.0 [21.2]; NRS, 2.8 [2.0]). CONCLUSION: Ultrasound-guided FNAB of thyroid nodules was less painful than that of cervical lymphadenopathy. Most patients tolerated mild transient pain after the procedure without use of local anesthesia. Nevertheless, local anesthesia was necessary for the small subgroup of patients who experienced significant pain. PMID- 23728804 TI - Dimensional changes in free gingival grafts: scalpel versus Er:YAG laser--a preliminary study. AB - The aim of this clinical study was to compare dimensional changes of the transplanted grafts when the recipient area was prepared with either erbium:yttrium, aluminum, and garnet (Er:YAG) laser or scalpel in free gingival grafts (FGGs). In the first and second groups of ten patients, the recipient area was prepared with an Er:YAG laser and a scalpel, respectively. All grafts were harvested from the palate at standard dimensions (horizontal, 14 mm; vertical, 8 mm). Probing depth, clinical attachment level, and keratinized tissue width were measured before surgery. FGG dimensions (width, length, and area) were measured using the University of North Carolina-15 manual probe (N15) (Nordent Manufacturing, Inc., IL, USA) during surgery and at 10, 21, and 90 days postoperatively. Differences between the two groups were statistically analyzed. In both groups, there was a statistically significant reduction in vertical and horizontal dimensions (p < 0.05) and graft area (p < 0.05) at all time points compared to the baseline measurements. There were no significant differences between the two groups with respect to vertical and horizontal dimensions and graft area at day 90 (p > 0.05). The Er:YAG laser may be used with similar effectiveness as the scalpel in the preparation of the recipient site for free gingival grafts. PMID- 23728805 TI - Hypnic headache: a review of 2012 publications. AB - Hypnic headache is a rare primary headache disorder affecting middle age and above with a dull pain exclusively at nighttime. This article aims to review and discuss the most recent articles published in the year 2012 regarding hypnic headache. We will also discuss specific cases of pharmacological and nonpharmacologic successes in treating this rare disorder. PMID- 23728806 TI - Increased water activity reduces the thermal resistance of Salmonella enterica in peanut butter. AB - Increased water activity in peanut butter significantly (P < 0.05) reduced the heat resistance of desiccation-stressed Salmonella enterica serotypes treated at 90 degrees C. The difference in thermal resistance was less notable when strains were treated at 126 degrees C. Using scanning electron microscopy, we observed minor morphological changes of S. enterica cells resulting from desiccation and rehydration processes in peanut oil. PMID- 23728807 TI - Extracellular electron transfer to Fe(III) oxides by the hyperthermophilic archaeon Geoglobus ahangari via a direct contact mechanism. AB - The microbial reduction of Fe(III) plays an important role in the geochemistry of hydrothermal systems, yet it is poorly understood at the mechanistic level. Here we show that the obligate Fe(III)-reducing archaeon Geoglobus ahangari uses a direct-contact mechanism for the reduction of Fe(III) oxides to magnetite at 85 degrees C. Alleviating the need to directly contact the mineral with the addition of a chelator or the electron shuttle anthraquinone-2,6-disulfonate (AQDS) stimulated Fe(III) reduction. In contrast, entrapment of the oxides within alginate beads to prevent cell contact with the electron acceptor prevented Fe(III) reduction and cell growth unless AQDS was provided. Furthermore, filtered culture supernatant fluids had no effect on Fe(III) reduction, ruling out the secretion of an endogenous mediator too large to permeate the alginate beads. Consistent with a direct contact mechanism, electron micrographs showed cells in intimate association with the Fe(III) mineral particles, which once dissolved revealed abundant curled appendages. The cells also produced several heme containing proteins. Some of them were detected among proteins sheared from the cell's outer surface and were required for the reduction of insoluble Fe(III) oxides but not for the reduction of the soluble electron acceptor Fe(III) citrate. The results thus support a mechanism in which the cells directly attach and transfer electrons to the Fe(III) oxides using redox-active proteins exposed on the cell surface. This strategy confers on G. ahangari a competitive advantage for accessing and reducing Fe(III) oxides under the extreme physical and chemical conditions of hot ecosystems. PMID- 23728808 TI - Biodegradation of endocrine disruptors in solid-liquid two-phase partitioning systems by enrichment cultures. AB - Naturally occurring and synthetic estrogens and other molecules from industrial sources strongly contribute to the endocrine disruption of urban wastewater. Because of the presence of these molecules in low but effective concentrations in wastewaters, these endocrine disruptors (EDs) are only partially removed after most wastewater treatments, reflecting the presence of these molecules in rivers in urban areas. The development of a two-phase partitioning bioreactor (TPPB) might be an effective strategy for the removal of EDs from wastewater plant effluents. Here, we describe the establishment of three ED-degrading microbial enrichment cultures adapted to a solid-liquid two-phase partitioning system using Hytrel as the immiscible water phase and loaded with estrone, estradiol, estriol, ethynylestradiol, nonylphenol, and bisphenol A. All molecules except ethynylestradiol were degraded in the enrichment cultures. The bacterial composition of the three enrichment cultures was determined using 16S rRNA gene sequencing and showed sequences affiliated with bacteria associated with the degradation of these compounds, such as Sphingomonadales. One Rhodococcus isolate capable of degrading estrone, estradiol, and estriol was isolated from one enrichment culture. These results highlight the great potential for the development of TPPB for the degradation of highly diluted EDs in water effluents. PMID- 23728809 TI - Improved bacterial mutagenesis by high-frequency allele exchange, demonstrated in Clostridium difficile and Streptococcus suis. AB - Here we show that the frequency of mutant isolation by two-step allele exchange can be improved by increasing the length of homologous DNA and the opportunity for recombination, obviating the need for counterselection markers. These principles are demonstrated in Clostridium difficile and Streptococcus suis but are likely to be generally applicable. PMID- 23728810 TI - Evidence for coexistence of distinct Escherichia coli populations in various aquatic environments and their survival in estuary water. AB - Escherichia coli, a commensal bacterium from the intestinal tracts of humans and vertebrate animals, has been used as one of two bacterial indicators of fecal contamination, along with intestinal enterococci, to monitor the microbiological quality of water. However, water environments are now recognized as a secondary habitat where some strains can survive. We investigated the survival of E. coli isolates collected from bodies of water in France exhibiting distinct profiles of contamination, defined according to the following criteria: vicinity of the point sources of contamination, land use, hydrology, and physicochemical characteristics of the receiving water. We selected 88 E. coli strains among a collection of 352 strains to carry out a microcosm experiment in filtered estuarine water for 14 days at 10 degrees C. The relationship between the survival of E. coli strains and genotypic and phenotypic characteristics was analyzed. This work showed that distinct E. coli survival types, able to survive from between 7 and 14 days to less than 2 days, coexisted in the water. E. coli isolates that rapidly lost their culturability were more frequently isolated in water recently contaminated by fecal bacteria of human origin, and most were multiresistant to antibiotics and harbored several virulence factors. In contrast, persistent strains able to survive from 4 to 14 days were more often found in water with low levels of fecal bacteria, belonged mainly to the B1 phylogroup, often harbored only one virulence factor, kspE or ompT, and were able to grow at 7 degrees C. PMID- 23728811 TI - Characterization of the genome of the dairy Lactobacillus helveticus bacteriophage {Phi}AQ113. AB - The complete genomic sequence of the dairy Lactobacillus helveticus bacteriophage PhiAQ113 was determined. Phage PhiAQ113 is a Myoviridae bacteriophage with an isometric capsid and a contractile tail. The final assembled consensus sequence revealed a linear, circularly permuted, double-stranded DNA genome with a size of 36,566 bp and a G+C content of 37%. Fifty-six open reading frames (ORFs) were predicted, and a putative function was assigned to approximately 90% of them. The PhiAQ113 genome shows functionally related genes clustered together in a genome structure composed of modules for DNA replication/regulation, DNA packaging, head and tail morphogenesis, cell lysis, and lysogeny. The identification of genes involved in the establishment of lysogeny indicates that it may have originated as a temperate phage, even if it was isolated from natural cheese whey starters as a virulent phage, because it is able to propagate in a sensitive host strain. Additionally, we discovered that the PhiAQ113 phage genome is closely related to Lactobacillus gasseri phage KC5a and Lactobacillus johnsonii phage Lj771 genomes. The phylogenetic similarities between L. helveticus phage PhiAQ113 and two phages that belong to gut species confirm a possible common ancestral origin and support the increasing consideration of L. helveticus as a health-promoting organism. PMID- 23728812 TI - L-A-lus, a new variant of the L-A totivirus found in wine yeasts with Klus killer toxin-encoding Mlus double-stranded RNA: possible role of killer toxin-encoding satellite RNAs in the evolution of their helper viruses. AB - Yeast killer viruses are widely distributed in nature. Several toxins encoded in double-stranded RNA (dsRNA) satellites of the L-A totivirus have been described, including K1, K2, K28, and Klus. The 4.6-kb L-A genome encodes the Gag major structural protein that forms a 39-nm icosahedral virion and Gag-Pol, a minor fusion protein. Gag-Pol has transcriptase and replicase activities responsible for maintenance of L-A (or its satellite RNAs). Recently we reported a new killer toxin, Klus. The L-A virus in Klus strains showed poor hybridization to known L-A probes, suggesting substantial differences in their sequences. Here we report the characterization of this new L-A variant named L-A-lus. At the nucleotide level, L-A and L-A-lus showed only 73% identity, a value that increases to 86% in the amino acid composition of Gag or Gag-Pol. Two regions in their genomes, however, the frameshifting region between Gag and Pol and the encapsidation signal, are 100% identical, implying the importance of these two cis signals in the virus life cycle. L-A-lus shows higher resistance than L-A to growth at high temperature or to in vivo expression of endo- or exonucleases. L-A-lus also has wider helper activity, being able to maintain not only Mlus but also M1 or a satellite RNA of L-A called X. In a screening of 31 wine strains, we found that none of them had L-A; they carried either L-A-lus or a different L-A variant in K2 strains. Our data show that distinct M killer viruses are specifically associated with L-As with different nucleotide compositions, suggesting coevolution. PMID- 23728813 TI - Biotransformation of Trichoderma spp. and their tolerance to aromatic amines, a major class of pollutants. AB - Trichoderma spp. are cosmopolitan soil fungi that are highly resistant to many toxic compounds. Here, we show that Trichoderma virens and T. reesei are tolerant to aromatic amines (AA), a major class of pollutants including the highly toxic pesticide residue 3,4-dichloroaniline (3,4-DCA). In a previous study, we provided proof-of-concept remediation experiments in which another soil fungus, Podospora anserina, detoxifies 3,4-DCA through its arylamine N-acetyltransferase (NAT), a xenobiotic-metabolizing enzyme that enables acetyl coenzyme A-dependent detoxification of AA. To assess whether the N-acetylation pathway enables AA tolerance in Trichoderma spp., we cloned and characterized NATs from T. virens and T. reesei. We characterized recombinant enzymes by determining their catalytic efficiencies toward several toxic AA. Through a complementary approach, we also demonstrate that both Trichoderma species efficiently metabolize 3,4-DCA. Finally, we provide evidence that NAT-independent transformation is solely (in T. virens) or mainly (in T. reesei) responsible for the observed removal of 3,4-DCA. We conclude that T. virens and, to a lesser extent, T. reesei likely utilize another, unidentified, metabolic pathway for the detoxification of AA aside from acetylation. This is the first molecular and functional characterization of AA biotransformation in Trichoderma spp. Given the potential of Trichoderma for cleanup of contaminated soils, these results reveal new possibilities in the fungal remediation of AA-contaminated soil. PMID- 23728814 TI - Engineering the meso-diaminopimelate dehydrogenase from Symbiobacterium thermophilum by site saturation mutagenesis for D-phenylalanine synthesis. AB - In order to enlarge the substrate binding pocket of the meso-diaminopimelate dehydrogenase from Symbiobacterium thermophilum to accommodate larger 2-keto acids, four amino acid residues (Phe146, Thr171, Arg181, and His227) were targeted for site saturation mutagenesis. Among all mutants, the single mutant H227V had a specific activity of 2.39 +/- 0.06 U . mg(-1), which was 35.1-fold enhancement over the wild-type enzyme. PMID- 23728815 TI - Fusion of a flavin-based fluorescent protein to hydroxynitrile lyase from Arabidopsis thaliana improves enzyme stability. AB - Hydroxynitrile lyase from Arabidopsis thaliana (AtHNL) was fused to different fluorescent reporter proteins. Whereas all fusion constructs retained enzymatic activity and fluorescence in vivo and in vitro, significant differences in activity and pH stability were observed. In particular, flavin-based fluorescent reporter (FbFP) fusions showed almost 2 orders of magnitude-increased half-lives in the weakly acidic pH range compared to findings for the wild-type enzyme. Analysis of the quaternary structure of the respective FbFP-AtHNL fusion proteins suggested that this increased stability is apparently caused by oligomerization mediated via the FbFP tag. Moreover, the increased stability of the fusion proteins enabled the efficient synthesis of (R)-mandelonitrile in an aqueous organic two-phase system at a pH of <5. Remarkably, (R)-mandelonitrile synthesis is not possible using wild-type AtHNL under the same conditions due to the inherent instability of this enzyme below pH 5. The fusion strategy presented here reveals a surprising means for the stabilization of enzymes and stresses the importance of a thorough in vitro characterization of in vivo-employed fluorescent fusion proteins. PMID- 23728816 TI - Development of a new method for detection and identification of Oenococcus oeni bacteriophages based on endolysin gene sequence and randomly amplified polymorphic DNA. AB - Malolactic fermentation (MLF) is a biochemical transformation conducted by lactic acid bacteria (LAB) that occurs in wine at the end of alcoholic fermentation. Oenococcus oeni is the main species responsible for MLF in most wines. As in other fermented foods, where bacteriophages represent a potential risk for the fermentative process, O. oeni bacteriophages have been reported to be a possible cause of unsuccessful MLF in wine. Thus, preparation of commercial starters that take into account the different sensitivities of O. oeni strains to different phages would be advisable. However, currently, no methods have been described to identify phages infecting O. oeni. In this study, two factors are addressed: detection and typing of bacteriophages. First, a simple PCR method was devised targeting a conserved region of the endolysin (lys) gene to detect temperate O. oeni bacteriophages. For this purpose, 37 O. oeni strains isolated from Italian wines during different phases of the vinification process were analyzed by PCR for the presence of the lys gene, and 25 strains gave a band of the expected size (1,160 bp). This is the first method to be developed that allows identification of lysogenic O. oeni strains without the need for time-consuming phage bacterial lysis induction methods. Moreover, a phylogenetic analysis was conducted to type bacteriophages. After the treatment of bacteria with UV light, lysis was obtained for 15 strains, and the 15 phage DNAs isolated were subjected to two randomly amplified polymorphic DNA (RAPD)-PCRs. By combining the RAPD profiles and lys sequences, 12 different O. oeni phages were clearly distinguished. PMID- 23728817 TI - Lytic infection of Lactococcus lactis by bacteriophages Tuc2009 and c2 triggers alternative transcriptional host responses. AB - Here we present an entire temporal transcriptional profile of Lactococcus lactis subsp. cremoris UC509.9 undergoing lytic infection with two distinct bacteriophages, Tuc2009 and c2. Furthermore, corresponding high-resolution whole phage genome tiling arrays of both bacteriophages were performed throughout lytic infection. Whole-genome microarrays performed at various time points postinfection demonstrated a rather modest impact on host transcription. The majority of changes in the host transcriptome occur during late infection stages; few changes in host gene transcription occur during the immediate and early infection stages. Alterations in the L. lactis UC509.9 transcriptome during lytic infection appear to be phage specific, with relatively few differentially transcribed genes shared between cells infected with Tuc2009 and those infected with c2. Despite the apparent lack of a coordinated general phage response, three themes common to both infections were noted: alternative transcription of genes involved in catabolic flux and energy production, differential transcription of genes involved in cell wall modification, and differential transcription of genes involved in the conversion of ribonucleotides to deoxyribonucleotides. The transcriptional profiles of both bacteriophages during lytic infection generally correlated with the findings of previous studies and allowed the confirmation of previously predicted promoter sequences. In addition, the host transcriptional response to lysogenization with Tuc2009 was monitored along with tiling array analysis of Tuc2009 in the lysogenic state. Analysis identified 44 host genes with altered transcription during lysogeny, 36 of which displayed levels of transcription significantly reduced from those for uninfected cells. PMID- 23728818 TI - Mannitol and the mannitol-specific enzyme IIB subunit activate Vibrio cholerae biofilm formation. AB - Vibrio cholerae is a halophilic, Gram-negative rod found in marine environments. Strains that produce cholera toxin cause the diarrheal disease cholera. V. cholerae use a highly conserved, multicomponent signal transduction cascade known as the phosphoenolpyruvate phosphotransferase system (PTS) to regulate carbohydrate uptake and biofilm formation. Regulation of biofilm formation by the PTS is complex, involving many different regulatory pathways that incorporate distinct PTS components. The PTS consists of the general components enzyme I (EI) and histidine protein (HPr) and carbohydrate-specific enzymes II. Mannitol transport by V. cholerae requires the mannitol-specific EII (EII(Mtl)), which is expressed only in the presence of mannitol. Here we show that mannitol activates V. cholerae biofilm formation and transcription of the vps biofilm matrix exopolysaccharide synthesis genes. This regulation is dependent on mannitol transport. However, we show that, in the absence of mannitol, ectopic expression of the B subunit of EII(Mtl) is sufficient to activate biofilm accumulation. Mannitol, a common compatible solute and osmoprotectant of marine organisms, is a main photosynthetic product of many algae and is secreted by algal mats. We propose that the ability of V. cholerae to respond to environmental mannitol by forming a biofilm may play an important role in habitat selection. PMID- 23728819 TI - Transcriptome sequencing (RNA-seq) analysis of the effects of metal nanoparticle exposure on the transcriptome of Chlamydomonas reinhardtii. AB - The widespread use of nanoparticles (NPs) raises concern over their potential toxicological effects in humans and ecosystems. Here we used transcriptome sequencing (RNA-seq) to evaluate the effects of exposure to four different metal based NPs, nano-Ag (nAg), nano-TiO2 (nTiO2), nano-ZnO (nZnO), and CdTe/CdS quantum dots (QDs), in the eukaryotic green alga Chlamydomonas reinhardtii. The transcriptome was characterized before and after exposure to each NP type. Specific toxicological effects were inferred from the functions of genes whose transcripts either increased or decreased. Data analysis resulted in important differences and also similarities among the NPs. Elevated levels of transcripts of several marker genes for stress were observed, suggesting that only nZnO caused nonspecific global stress to the cells under environmentally relevant conditions. Genes with photosynthesis-related functions were decreased drastically during exposure to nTiO2 and slightly during exposures to the other NP types. This pattern suggests either toxicological effects in the chloroplast or effects that mimic a transition from low to high light. nAg exposure dramatically elevated the levels of transcripts encoding known or predicted components of the cell wall and the flagella, suggesting that it damages structures exposed to the external milieu. Exposures to nTiO2, nZnO, and QDs elevated the levels of transcripts encoding subunits of the proteasome, suggesting proteasome inhibition, a phenomenon believed to underlie the development and progression of several major diseases, including Alzheimer's disease, and used in chemotherapy against multiple myeloma. PMID- 23728820 TI - Bacterial tethering analysis reveals a "run-reverse-turn" mechanism for Pseudomonas species motility. AB - We have developed a program that can accurately analyze the dynamic properties of tethered bacterial cells. The program works especially well with cells that tend to give rise to unstable rotations, such as polar-flagellated bacteria. The program has two novel components. The first dynamically adjusts the center of the cell's rotational trajectories. The second applies piecewise linear approximation to the accumulated rotation curve to reduce noise and separate the motion of bacteria into phases. Thus, it can separate counterclockwise (CCW) and clockwise (CW) rotations distinctly and measure rotational speed accurately. Using this program, we analyzed the properties of tethered Pseudomonas aeruginosa and Pseudomonas putida cells for the first time. We found that the Pseudomonas flagellar motor spends equal time in both CCW and CW phases and that it rotates with the same speed in both phases. In addition, we discovered that the cell body can remain stationary for short periods of time, leading to the existence of a third phase of the flagellar motor which we call "pause." In addition, P. aeruginosa cells adopt longer run lengths, fewer pause frequencies, and shorter pause durations as part of their chemotactic response. We propose that one purpose of the pause phase is to allow the cells to turn at a large angle, where we show that pause durations in free-swimming cells positively correlate with turn angle sizes. Taken together, our results suggest a new "run-reverse-turn" paradigm for polar-flagellated Pseudomonas motility that is different from the "run-and-tumble" paradigm established for peritrichous Escherichia coli. PMID- 23728821 TI - Perceptions of under and overutilization of cervical cancer screening services at Latino-serving community health centers. AB - We sought to gather the perceptions of clinic personnel at Latino-serving Federally Qualified Health Centers (FQHCs) about patients' utilization of screening services for cervical cancer. We conducted one-on-one interviews among 17 clinic personnel at four Latino-serving FQHCs in Oregon. The clinic personnel we interviewed observed both under and overutilization of cervical cancer screening services. Clinic personnel estimated that 20-60 % of eligible patients were underscreened for cervical cancer, with 30 % the most commonly cited percentage. Underscreening was thought to occur among low-income, underinsured, and undocumented patients. Overscreening for cervical cancer was estimated to occur in 10-50 % of eligible patients, with 10 % the most frequently cited proportion. Overscreening was thought to occur among women younger than age 21 and women with a recent pregnancy. Our findings may inform future efforts to promote guideline-appropriate cancer screening and coordinated follow-up care. PMID- 23728822 TI - Latent tuberculosis infection: screening and treatment in an urban setting. AB - Despite its benefit for treating active tuberculosis, directly observed therapy (DOT) for latent tuberculosis infection (LTBI) has been largely understudied among challenging inner city populations. Utilizing questionnaire data from a comprehensive mobile healthcare clinic in New Haven, CT from 2003 to July 2011, a total of 2,523 completed tuberculin skin tests (TSTs) resulted in 356 new LTBIs. Multivariate logistic regression correlated covariates of the two outcomes (a) initiation of isoniazid preventative therapy (IPT) and (b) completion of 9 months of IPT. Of the 357 newly positive TSTs, 86.3 % (n = 308) completed screening chest radiographs (CXRs): 90.3 % (n = 278) were normal, and 0.3 % (n = 1) had active tuberculosis. Of those completing CXR screening, 44.0 % (n = 135) agreed to IPT: 69.6 % (n = 94) selected DOT, and 30.4 % (n = 41) selected self administered therapy (SAT). Initiating IPT was correlated with undocumented status (AOR = 3.43; p < 0.001) and being born in a country of highest and third highest tuberculosis prevalence (AOR = 14.09; p = 0.017 and AOR = 2.25; p = 0.005, respectively). Those selecting DOT were more likely to be Hispanic (83.0 vs 53.7 %; p < 0.0001), undocumented (57.4 vs 41.5 %; p = 0.012), employed (p < 0.0001), uninsured (p = 0.014), and have stable housing (p = 0.002), no prior cocaine or crack use (p = 0.013) and no recent incarceration (p = 0.001). Completing 9 months of IPT was correlated with no recent incarceration (AOR 5.95; p = 0.036) and younger age (AOR 1.03; p = 0.031). SAT and DOT participants did not significantly differ for IPT duration (6.54 vs 5.68 months; p = 0.216) nor 9 month completion (59.8 vs 46.3 %; p = 0.155). In an urban mobile healthcare sample, screening completion for LTBI was high with nearly half initiating IPT. Undocumented, Hispanic immigrants from high prevalence tuberculosis countries were more likely to self-select DOT at the mobile outreach clinic, potentially because of more culturally, linguistically, and logistically accessible services and self-selection optimization phenomena. Within a diverse, urban environment, DOT and SAT IPT models for LTBI treatment resulted in similar outcomes, yet outcomes were hampered by differential measurement bias between DOT and SAT participants. PMID- 23728823 TI - HPV vaccination and sexual behavior in a community college sample. AB - Many US parents are concerned that vaccinating daughters against human papillomavirus (HPV) will communicate implicit approval for sexual activity and be associated with early or risky sexual behavior (Scarinci et al. in J Womens Health 16(8):1224-1233, 2007; Schuler et al. in Sex Transm Infect 87:349-353, 2011). The aims of this study were to understand (a) whether the HPV vaccine was associated with risky sexual behavior among a diverse sample of female adolescents and young adults, and (b) to better understand the chronology of HPV vaccination and sexual behavior. An anonymous web-based survey was used to collect data from 114 female community college students. T test and Chi square analyses were used to compare vaccinated and unvaccinated groups on age at first intercourse and proportion who had ever had sexual intercourse. Linear multiple regression was used to predict frequency of condom use and number of sexual partners in the past year, using vaccination status and demographic factors as predictors. About 38% reported receiving at least one dose of the HPV vaccine. Many of those vaccinated (45%) received the vaccine after having initiated sexual activity. The proportion of women who were sexually experienced did not differ by HPV vaccine status, nor did age at first intercourse, number of partners in the past year, or frequency of condom use. Current findings suggest that HPV vaccination is not associated with riskier sexual activity for the young women in this sample. Adolescents and their parents may benefit from education about the need to receive the HPV vaccine before onset of sexual activity. PMID- 23728824 TI - Integrating tristimulus colorimetry into pharmaceutical development for color selection and physical appearance control: a quality-by-design approach. AB - The color of pharmaceutical dosage forms can be an important aspect of product branding and patient compliance with a dosing regimen. During the development of drug products, it is important to understand the stability of not only the active pharmaceutical ingredient but also the color and appearance of the tablet or capsule. Currently, the most common method to ensure color stability is to conduct a visual test throughout a stability study. This visual test is subjective and can be expensive, especially if there is a failure late in development or after marketing approval. This work describes a series of studies using accelerated conditions (i.e., heat, humidity, and light) and logistic regression analyses that have been developed to determine the relative stability ranking of multiple color coatings early in development to provide an increased probability of technical success on long-term stability studies and to avoid coatings whose visual appearance may change over time. Once this relative stability ranking has been established, the stability advantages can be assessed versus any manufacturing/processing liabilities of the selected coating in order to make a data-driven decision around coating selection. This work reviews the basic fundamentals of colorimetry, followed by the description of a consistent experimental approach to correlate a visual rating with an instrumental measurement (e.g., dE(*) from a colorimeter) to remove the subjectivity from the assessment. This approach represents a novel strategy for establishing a probabilized correlation between the quantitative instrumental color measurement and the visual rating of the same color change. PMID- 23728825 TI - Enantioselective organocatalytic domino Michael/aldol reactions: an efficient procedure for the stereocontrolled construction of 2H-thiopyrano[2,3-b]quinoline scaffolds. AB - An efficient procedure for the stereocontrolled construction of 2H-thiopyrano[2,3 b]quinoline scaffolds has been developed, starting from simple compounds. The domino Michael/aldol reactions between 2-mercaptobenzaldehydes and enals, promoted by chiral diphenylprolinol TMS ether, proceed with excellent chemo- and enantioselectivity to give the corresponding synthetically useful and pharmaceutically valuable 2H-thiopyrano[2,3-b]quinolines in high yields with 90 99 % ee. PMID- 23728829 TI - Clinical outcomes, health resource use, and cost in patients with early versus late dual or triple anti-platelet treatment for acute coronary syndrome. AB - BACKGROUND: Acute coronary syndrome (ACS) guidelines recommend early dual anti platelet therapy (thienopyridines + acetylsalicylic acid [aspirin]). However, triple therapy (thienopyridines + aspirin + glycoprotein IIb/IIIa receptor inhibitors [GRIs]) has shown benefit in clinical trials. OBJECTIVE: This study assessed real-world ACS treatment patterns and outcomes in the acute care setting. STUDY DESIGN: A retrospective analysis of patients admitted to hospital with ACS (index event) from January 2007 to December 2009 was conducted (Thomson's MarketScan Hospital Drug Database). PATIENTS: Eligible patients were >=18 years of age, of either sex, and had primary admission and discharge diagnoses of ACS. OUTCOME MEASURES: Cohorts were defined by anti-platelet treatment and then by the timing of treatment initiation (early initiation: within <=2 days of admission; late initiation: >=2 days post-admission). Patient characteristics, clinical outcomes, resource utilization, and costs were assessed using descriptive statistics. RESULTS: A total of 249,907 eligible patients were placed into four treatment cohorts (aspirin assumed for all patients): aspirin only; clopidogrel only (dual therapy); GRI only (dual therapy); and clopidogrel + GRI (triple therapy). Patients in the 'clopidogrel-only' cohort were more likely to be older, female, and have more co-morbidities than those in other cohorts; stroke (6.2 %) and re-hospitalization (15.4 %) rates were higher than in the 'GRI only' and 'triple therapy' cohorts. The GRI-only cohort had higher major bleeding rates (3.3 %), mortality (7.6 %), and costs ($US21,975 [year 2010 values]) than the clopidogrel-only and triple-therapy cohorts. Late initiation cohorts were more likely to be older, female, and have more co-morbidities than early initiation cohorts. Major bleeding was more likely with GRI-only patients (regardless of initiation timing) than with other cohorts. Late-treated clopidogrel-only patients had higher rates of stroke (6.9 %), ACS-related re admissions (6.1 %), and all-cause re-admissions (15.9 %) than other cohorts. Late treatment was associated with longer length of stay and significantly higher costs. CONCLUSIONS: Real-world anti-platelet treatment patterns are consistent with ACS guidelines recommending early initiation and selective GRI use. In contrast to recommendations, some outcomes were improved with triple therapy compared with dual therapy. PMID- 23728826 TI - Electronic monitoring of oral therapies in ethnically diverse and economically disadvantaged patients with rheumatoid arthritis: consequences of low adherence. AB - OBJECTIVE: To quantify adherence to oral therapies in ethnically diverse and economically disadvantaged patients with rheumatoid arthritis (RA), using electronic medication monitoring, and to evaluate the clinical consequences of low adherence. METHODS: A total of 107 patients with RA enrolled in a 2-year prospective cohort study agreed to have their oral RA drug therapy intake electronically monitored using the Medication Event Monitoring System. Adherence to disease-modifying antirheumatic drugs (DMARDs) and prednisone was determined as the percentage of days (or weeks for methotrexate) on which the patient took the correct dose as prescribed by the physician. Patient outcomes were assessed, including function measured by the modified Health Assessment Questionnaire, disease activity measured by the Disease Activity Score in 28 joints (DAS28), health-related quality of life, and radiographic damage measured using the modified Sharp/van der Heijde scoring method. RESULTS: Adherence to the treatment regimen as determined by the percentage of correct doses was 64% for DMARDs and 70% for prednisone. Patients who had better mental health were statistically more likely to be adherent. Only 23 of the patients (21%) had an average adherence to DMARDs >=80%. These patients showed significantly better mean DAS28 values across 2 years of followup than those who were less adherent (3.28 versus 4.09; P = 0.02). Radiographic scores were also worse in nonadherent patients at baseline and at 12 months. CONCLUSION: Only one-fifth of RA patients had an overall adherence to DMARDs of at least 80%. Less than two-thirds of the prescribed DMARD doses were correctly taken. Adherent patients had lower disease activity across the 2 years of followup. PMID- 23728830 TI - Effects of ezetimibe/simvastatin 10/20 mg vs. atorvastatin 20 mg on apolipoprotein B/apolipoprotein A1 in Korean patients with type 2 diabetes mellitus: results of a randomized controlled trial. AB - BACKGROUND: Although the efficacy of ezetimibe/simvastatin and atorvastatin on traditional lipid parameters has been studied extensively, the apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio, which has a better predictive value for cardiovascular events, has not previously been used as a primary endpoint in these two treatment groups. OBJECTIVE: Our objective was to compare the efficacy and safety of ezetimibe/simvastatin 10/20 mg versus atorvastatin 20 mg once daily in Korean patients with type 2 diabetes mellitus. STUDY DESIGN: This study was an open-label, randomized, controlled study. Type 2 diabetes patients with high levels of low-density lipoprotein (LDL) cholesterol (>100 mg/dL) were randomized to receive ezetimibe/simvastatin or atorvastatin. MAIN OUTCOME MEASURE: The primary endpoint was the difference in the percent change of ApoB/ApoA1 at 12 weeks, and secondary endpoints were changes in lipid profiles, glycosylated hemoglobin (HbA1c), homeostatic model assessment (HOMA) index, and C-reactive protein. RESULTS: In total, 132 patients (66 for each group) were enrolled and randomized. After 12 weeks of treatment, the ApoB/ApoA1 ratio was significantly reduced in both groups; however, the difference of changes between the two groups was not statistically significant (ezetimibe/simvastatin -38.6 +/- 18.0 % vs. atorvastatin -34.4 +/- 15.5 %; p = 0.059). There were no significant differences in changes to total cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, triglycerides, ApoB, and ApoB48 between the two groups. However, the increments of ApoA1 were significantly greater in the ezetimibe/simvastatin group than in the atorvastatin group (2.8 +/- 10.0 vs. -1.8 +/- 9.8 %; p = 0.002). In the per-protocol analysis, improvement in ApoB/ApoA1 was significantly greater in the ezetimibe/simvastatin group (-42.8 +/- 11.8 vs. -36.7 +/- 13.2 %; p = 0.019). The changes in HbA1c, HOMA index, and C-reactive protein were comparable between the two groups. The adverse reaction rate was similar between the two groups (24.2 vs. 34.9 %; p = 0.180). CONCLUSION: Ezetimibe/simvastatin 10/20 mg is comparable to atorvastatin 20 mg for the management of dyslipidemia, and may have more favorable effects on apolipoprotein profiles than atorvastatin 20 mg in Korean patients with type 2 diabetes mellitus. PMID- 23728831 TI - Peritransplant absolute lymphocyte count as a predictive factor for advanced recurrence of hepatitis C after liver transplantation. AB - Lymphocytes play an active role in natural immunity against hepatitis C virus (HCV). We hypothesized that a lower absolute lymphocyte count (ALC) may alter HCV outcome after liver transplantation (LT). The aim of this study was to investigate the impact of peritransplant ALC on HCV recurrence following LT. A total of 289 LT patients between 2005 and 2011 were evaluated. Peritransplant ALC (pre-LT, 2-week, and 1-month post-LT) and immunosuppression were analyzed along with recipient and donor factors in order to determine risk factors for HCV recurrence based on METAVIR fibrosis score. When stratifying patients according to pre- and post-LT ALC (<500/MUL versus 500-1,000/MUL versus >1,000/MUL), lymphopenia was significantly associated with higher rates of HCV recurrence with fibrosis (F2-4). Multivariate Cox regression analysis showed posttransplant ALC at 1 month remained an independent predictive factor for recurrence (P = 0.02, hazard ratio [HR] = 2.47 for <500/MUL). When peritransplant ALC was persistently low (<500/MUL pre-LT, 2-week, and 1-month post-LT), patients were at significant risk of developing early advanced fibrosis secondary to HCV recurrence (F3-4 within 2 years) (P = 0.02, HR = 3.16). Furthermore, severe pretransplant lymphopenia (<500/MUL) was an independent prognostic factor for overall survival (P = 0.01, HR = 3.01). The use of rabbit anti-thymocyte globulin induction (RATG) had a remarkable protective effect on HCV recurrence (P = 0.02, HR = 0.6) despite its potential to induce lymphopenia. Subgroup analysis indicated that negative effects of posttransplant lymphopenia at 1 month (<1,000/MUL) were significant regardless of RATG use and the protective effects of RATG were independent of posttransplant lymphopenia. CONCLUSION: Peritransplant ALC is a novel and useful surrogate marker for prediction of HCV recurrence and patient survival. Immunosuppression protocols and peritransplant management should be scrutinized depending on peritransplant ALC. PMID- 23728832 TI - Recommendation for measuring clinical outcome in distal radius fractures: a core set of domains for standardized reporting in clinical practice and research. AB - INTRODUCTION: Lack of standardization of outcome measurement has hampered an evidence-based approach to clinical practice and research. METHODS: We adopted a process of reviewing evidence on current use of measures and appropriate theoretical frameworks for health and disability to inform a consensus process that was focused on deriving the minimal set of core domains in distal radius fracture. RESULTS: We agreed on the following seven core recommendations: (1) pain and function were regarded as the primary domains, (2) very brief measures were needed for routine administration in clinical practice, (3) these brief measures could be augmented by additional measures that provide more detail or address additional domains for clinical research, (4) measurement of pain should include measures of both intensity and frequency as core attributes, (5) a numeric pain scale, e.g. visual analogue scale or visual numeric scale or the pain subscale of the patient-reported wrist evaluation (PRWE) questionnaires were identified as reliable, valid and feasible measures to measure these concepts, (6) for function, either the Quick Disability of the arm, shoulder and hand questionnaire or PRWE-function subscale was identified as reliable, valid and feasible measures, and (7) a measure of participation and treatment complications should be considered core outcomes for both clinical practice and research. CONCLUSION: We used a sound methodological approach to form a comprehensive foundation of content for outcomes in the area of distal radius fractures. We recommend the use of symptom and function as separate domains in the ICF core set in clinical research or practice for patients with wrist fracture. Further research is needed to provide more definitive measurement properties of measures across all domains. PMID- 23728833 TI - Arthroscopic-assisted surgical treatment for developmental dislocation of the hip before the age of 18 months. AB - PURPOSE: The purpose of this study is to evaluate the results of arthroscopy assisted surgical treatment of developmental dislocation of the hip (DDH). METHODS: Arthroscopic assisted surgical treatment was performed on nine hips of nine female children with DDH using our method, published previously, between January 2001 and December 2005. Their ages ranged from 9 to 16 months. Percutaneous adductor tenotomies were performed in seven cases. A spica cast and abduction splint were used for 11-17 weeks postoperatively. Acetabular index and Shenton line were used for preoperative and postoperative radiologic evaluation. Also, the cases were evaluated postoperatively with respect to range of motion restriction, and the leg length discrepancy. RESULTS: The average follow-up was 47.7 months (range 22-79 months). Acetabular index measurements of cases in the preoperative/postoperative periods were as follows: preoperative mean angle 39.9 degrees (range 34 degrees -52 degrees )/postoperative mean angle 26 degrees (range 22 degrees -34 degrees ). Hip joint restriction and leg length discrepancy were not observed postoperatively. However, two patients had acetabular dysplasia. Acetabular dysplasia was completely resolved in one patient in the third year of follow-up, whereas Salter innominate osteotomy, required in another patient, was in the second year of follow-up. The latter patient was the oldest case (16-month-old) in our series. CONCLUSIONS: Based on the results of this study, treatment of developmental hip dysplasia with arthroscopic-assisted surgical treatment technique may be safe and effective method. Further clinical studies will be required to confirm this study. PMID- 23728834 TI - Relationship of red cell distribution width with the presence and severity of preeclampsia. AB - AIM: Although the relationship between red cell distribution width (RDW) and hypertension has been well documented, there is an absence of data on the association between RDW and preeclampsia. In the present study, we have aimed to investigate the correlation of RDW with preeclampsia and its severity. METHODS: The study population consisted of 52 (35 mild and 17 severe) patients with preeclampsia and 50 control pregnancy patients. For the entire study population, baseline RDW was measured using an automatic blood counter. RESULTS: Although there were no significant differences between the preeclampsia group and the control group in terms of hemoglobin and platelet counts, the RDW (14.1 +/- 1.1 vs 16.9 +/- 1.7, P < .001), systolic and diastolic blood pressure, proteinuria, white blood cell, and high-sensitivity C-reactive protein levels were significantly higher in the preeclampsia group. Moreover, subgroup analysis revealed that RDW levels were significantly increased in patients with severe preeclampsia when compared to the patients with mild preeclampsia (18 +/- 1.5 vs 16.4 +/- 1.5, P < .001). CONCLUSION: Our study results revealed that RDW levels were associated with both the presence and the severity of preeclampsia. PMID- 23728835 TI - Platelet Hyperaggregability is Highly Prevalent in Patients With Chronic Kidney Disease: An Underestimated Risk Indicator of Thromboembolic Events. AB - BACKGROUND: Platelet hyperaggregation is known to be associated with arterial and venous thromboembolic events. The prevalence of platelet hyperaggregation in patients with chronic kidney disease (CKD) has not been described to date. METHODS: Platelet hyperaggregation in patients with renal disease was defined by comparison of platelet aggregation patterns to non-CKD patients without thromboembolic disorders and healthy controls. RESULTS: Among the 30 hemodialysis patients and 34 renal transplant recipients, 20 (67%) and 28 (82%) showed significantly decreased median Delta-epinephrine aggregation and increased 0.5 mol/L epinephrine response (65% and 54%) compared to healthy controls and non-CKD patients. In concordance to the laboratory finding of platelet hyperaggregability, renal transplant recipients showed a high rate of thromboembolic events (normal platelet aggregation: 0 events and platelet hyperaggregation: 30 events in 13 of 28 patients). CONCLUSIONS: Patients with CKD exhibit a hitherto unappreciated high prevalence of platelet hyperaggregability indicating sticky platelet syndrome. Laboratory testing of platelet hyperaggregability may supplement the assessment of thromboembolic complications in patients with CKD. PMID- 23728836 TI - Comparing terracotta and earthenware for multiple functionalities in microbial fuel cells. AB - The properties of earthenware and terracotta were investigated in terms of structural integrity and ion conductivity, in two microbial fuel cell (MFC) designs. Parameters such as wall thickness (4, 8, 18 mm), porosity and cathode hydration were analysed. During the early stages of operation (2 weeks), the more porous earthenware lost anolyte quickly and was unstable between feeding compared to terracotta. Three weeks later MFCs of all thicknesses were more stable and could sustain longer periods of power production without maintenance. In all cases, the denser terracotta produced higher open circuit voltage; however, earthenware the more porous and less iron-rich of the two, proved to be the better material for power production, to the extent that the thickest wall (18 mm) MFC produced 15 % higher power than the thinnest wall (4 mm) terracotta. After 6 weeks of operation, the influence of wall thickness was less exaggerated and power output was comparable between the 4 and 8 mm ceramic membranes. Cylindrical earthenware MFCs produced significantly higher current (75 %) and power (33 %) than terracotta MFCs. A continuous dripping mode of cathode hydration produced threefold higher power than when MFCs were submerged in water, perhaps because of a short-circuiting effect through the material. This shows a significant improvement in terms of biosystems engineering, since a previously high-maintenance half-cell, is now shown to be virtually self-sufficient. PMID- 23728837 TI - Calibration and validation of an activated sludge model for greenhouse gases no. 1 (ASMG1): prediction of temperature-dependent N2O emission dynamics. AB - An activated sludge model for greenhouse gases no. 1 was calibrated with data from a wastewater treatment plant (WWTP) without control systems and validated with data from three similar plants equipped with control systems. Special about the calibration/validation approach adopted in this paper is that the data are obtained from simulations with a mathematical model that is widely accepted to describe effluent quality and operating costs of actual WWTPs, the Benchmark Simulation Model No. 2 (BSM2). The calibration also aimed at fitting the model to typical observed nitrous oxide (N2O) emission data, i.e., a yearly average of 0.5% of the influent total nitrogen load emitted as N2O-N. Model validation was performed by challenging the model in configurations with different control strategies. The kinetic term describing the dissolved oxygen effect on the denitrification by ammonia-oxidizing bacteria (AOB) was modified into a Haldane term. Both original and Haldane-modified models passed calibration and validation. Even though their yearly averaged values were similar, the two models presented different dynamic N2O emissions under cold temperature conditions and control. Therefore, data collected in such situations can potentially permit model discrimination. Observed seasonal trends in N2O emissions are simulated well with both original and Haldane-modified models. A mechanistic explanation based on the temperature-dependent interaction between heterotrophic and autotrophic N2O pathways was provided. Finally, while adding the AOB denitrification pathway to a model with only heterotrophic N2O production showed little impact on effluent quality and operating cost criteria, it clearly affected N2O emission productions. PMID- 23728838 TI - In vitro and in vivo protective effects of granulocyte colony-stimulating factor against radiation-induced intestinal injury. AB - Intestinal injury is a major cause of death after high-dose radiation exposure. The use of granulocyte-colony stimulating factor (G-CSF) to treat radiation injury has focused on enhancing recovery from hematopoietic radiation syndrome. We evaluated G-CSF for its ability to protect against radiation-induced intestinal injury in rat intestinal epithelial cells (IEC-6) and BALB/c mouse models. For in vitro tests, pre-radiation addition of G-CSF to IEC-6 prevented cytotoxicity and the loss of cell viability. Pre-radiation G-CSF treatment also reduced radiation-induced cleavage of caspase-3 and p53 in IEC-6. For in vivo tests, examination 12 h after abdominal irradiation showed that G-CSF-treated mice were protected against apoptosis of the jejunal crypts. G-CSF-treated mice also showed attenuated intestinal morphological changes 3.5 days after abdominal radiation (10 Gy). G-CSF also reduced the levels of proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha after radiation. This study showed that G-CSF may protect against radiation-induced intestinal damage through its anti-apoptotic and anti-inflammatory effects. These results suggest that G-CSF is promising candidate for protection against intestinal mucosal injury following irradiation. PMID- 23728839 TI - Incarceration histories of homeless veterans and progression through a national supported housing program. AB - There is increasing concern that adults with a past history of incarceration are at particular disadvantage in exiting homelessness. Supported housing with case management has emerged as the leading service model for assisting homeless adults; however there has been limited examination of the success of adults with past history of incarceration in obtaining housing within this paradigm. Data were examined on 14,557 veterans who entered a national supported housing program for homeless veterans, the Housing and Urban Development-Veterans Affairs Supportive Housing program (HUD-VASH) during 2008 and 2009, to identify characteristics associated with a history of incarceration and to evaluate whether those with a history of incarceration are less likely to obtain housing and/or more likely to experience delays in the housing attainment process. Veterans who reported no past incarceration were compared with veterans with short incarceration histories (<= 1 year) and those with long incarceration histories (>1 year). A majority of participants reported history of incarceration; 43 % reported short incarceration histories and 22 % reported long incarceration histories. After adjusting for baseline characteristics and site, history of incarceration did not appear to impede therapeutic alliance, progression through the housing process or obtaining housing. Within a national supported housing program, veterans with a history of incarceration were just as successful at obtaining housing in similar time frames when compared to veterans without any past incarceration. Supported housing programs, like HUD-VASH, appear to be able to overcome impediments faced by formerly incarcerated homeless veterans and therefore should be considered a a good model for housing assistance programs. PMID- 23728840 TI - Cis-trans isomerization of omega dihedrals in proteins. AB - Peptide bonds in protein structures are mainly found in trans conformation with a torsion angle omega close to 180 degrees . Only a very low proportion is observed in cis conformation with omega angle around 0 degrees . Cis-trans isomerization leads to local conformation changes which play an important role in many biological processes. In this paper, we reviewed the recent discoveries and research achievements in this field. First, we presented some interesting cases of biological processes in which cis-trans isomerization is directly implicated. It is involved in protein folding and various aspect of protein function like dimerization interfaces, autoinhibition control, channel gating, membrane binding. Then we reviewed conservation studies of cis peptide bonds which emphasized evolution constraints in term of sequence and local conformation. Finally we made an overview of the numerous molecular dynamics studies and prediction methodologies already developed to take into account this structural feature in the research area of protein modeling. Many cis peptide bonds have not been recognized as such due to the limited resolution of the data and to the refinement protocol used. Cis-trans proline isomerization reactions represents a vast and promising research area that still needs to be further explored for a better understanding of isomerization mechanism and improvement of cis peptide bond predictions. PMID- 23728841 TI - Novel DICER1 mutation as cause of multinodular goiter in children. AB - BACKGROUND: The aim of this report was to present a rare case of an adolescent with multinodular goiter (MNG) found to have a DICER1 mutation. METHODS AND RESULTS: The methodology includes a presentation and discussion of a chart review including endocrine hormone tests, thyroid ultrasound, and genetic testing for DICER1. A 12-year-old girl presented with a diffusely enlarged thyroid gland. Family history revealed an older sister with a history of bilateral ovarian Sertoli-Leydig cell tumors and MNG. Thyroid function tests were normal. Serial thyroid ultrasounds showed enlarging multiple bilateral nodules. Fine-needle aspiration suggested MNG. Genetic testing revealed a novel heterozygous premature termination mutation (c.1525C>T p.R509X) in the DICER1 gene. CONCLUSIONS: Thyroid nodules are rare in children but carry a higher risk for malignancy. It is essential to inquire about family history and refer for genetic evaluation with a family history of MNG. In patients with DICER1 mutations, tumor surveillance is critical due to the increased risk of multiple tumors, including ovarian tumors and pleuropulmonary blastoma. PMID- 23728842 TI - Adsorption sequence of multifunctional groups: a study on the reaction pathway and the adsorption structure of homocysteine on the Ge(100) surface. AB - We investigated the adsorption mechanism of homocysteine (HS-CH2-CH2-CH(NH2) COOH) on the Ge(100) surface along with its electronic structures and adsorption geometries to determine the sequence of adsorption of this amino acid's functional groups using core-level photoemission spectroscopy (CLPES) in conjunction with density functional theory (DFT) calculations. We found that the "SH-dissociated OH-dissociated N-dative-bonded structure" and the "SH-dissociated OH-dissociation-bonded structure" were preferred at a monolayer (ML) coverage of 0.30 (lower coverage) and 0.60 (higher coverage), respectively. The "SH dissociated OH-dissociated N-dative-bonded structure" was the most stable structure. Moreover, we systematically confirmed the sequence of adsorption of the functional groups of the homocysteine molecule on the Ge(100) surface, which is thiol group (-SH), carboxyl group (-COOH), and amine group (-NH2). PMID- 23728843 TI - Quantifying the effects of pesticide exposure on annual reproductive success of birds. AB - The Markov chain nest productivity model (MCnest) was developed for quantifying the effects of specific pesticide-use scenarios on the annual reproductive success of simulated populations of birds. Each nesting attempt is divided into a series of discrete phases (e.g., egg laying, incubation, nestling rearing), and results from avian toxicity tests are used to represent the types of effects possible in the field during each breeding phase. The expected exposure dose each day throughout the breeding season can be compared to the toxicity thresholds assigned to each breeding phase to determine whether the nest attempt is at risk. The primary output of the model is an estimate of the number of successful nest attempts per female per year, which is multiplied by the number of fledglings per successful nest to estimate the number of fledglings per female per breeding season (i.e., annual reproductive success). In this article, we present a series of MCnest simulations to demonstrate the extent to which the magnitude of change in annual reproductive success can be affected by considering life history attributes and the timing of pesticide applications relative to a species' typical breeding phenology. For a given pesticide-use scenario, MCnest can identify which species are at greatest risk. By allowing multiple species to be run under a single scenario, it can also help to identify the life-history traits that contribute to a species' vulnerability to a given pesticide-use scenario. It also can determine which application dates have the greatest impact and demonstrate the extent to which pesticide characteristics (e.g., residue half life, mode of action) affect productivity. MCnest goes beyond the current qualitative screening-level assessments of risks to avian reproduction to provide an approach for quantifying the reduction in annual reproductive success by integrating species life history and timing of pesticide exposures, despite limitations in existing information on species life history and toxicity responses from existing laboratory tests. PMID- 23728844 TI - Quality of life before and after total laryngectomy: results of a multicenter prospective cohort study. AB - BACKGROUND: The purpose of this study was to determine what quality of life (QOL) areas improve and deteriorate during the first year after total laryngectomy and to identify predictors of these changes. METHODS: One hundred seventy-four patients completed the European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaires before laryngectomy, n = 133 before discharge from hospital, n = 110 at the end of rehabilitation, and n = 86 1 year after laryngectomy. Multivariate regression analysis was performed to estimate the effect of potential predictors on QOL. RESULTS: Areas that did not recover to baseline level were physical functioning, role functioning, social functioning, fatigue, dyspnea, appetite loss, financial difficulties, senses, speech, and social contact, whereas global health status, coughing, and weight improved. There was no evidence for predicting effects of age, sex, education, and tumor site. Tumor stage, recurrent disease, radiotherapy, and mental health did display predicting effects. Smoking status before the treatment had marginally significant effects. CONCLUSION: QOL decreases initially after laryngectomy; some QOL areas recover slowly over the course of the year after surgery, and some remain significantly worse than at baseline. PMID- 23728845 TI - Update on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C). AB - OPINION STATEMENT: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by life-threatening ventricular arrhythmias and slowly progressive ventricular dysfunction. Treatment for families with ARVD/C is directed toward prevention of sudden cardiac death, prevention or delay of disease progression, and adjustment to life with a lifelong chronic genetic disease. As there have been no randomized trials of ARVD/C treatments or screening regimens, treatment decisions are based on clinical expertise, results of retrospective registry-based studies, and understanding of pathologic mechanisms of disease. The first step for treatment is securing an accurate diagnosis through careful application of the diagnostic Task Force criteria. Following diagnosis in an index case, family members are screened. We advise affected individuals and gene carriers to dramatically reduce exercise and strongly recommend that ARVD/C patients discontinue competitive athletics. We generally recommend implantable cardioverter defibrillator (ICD) placement in all probands who meet Task Force criteria, especially if they have a history of sustained ventricular tachycardia (VT), arrhythmogenic syncope, or frequent ventricular ectopy and/or nonsustained VT. We are more circumspect about recommending implantation of an ICD in a family member who has been diagnosed with ARVD/C through family screening, as these individuals are now being identified at a much earlier stage in their disease than was possible previously. Anti-arrhythmic medications and catheter ablation are used to decrease the frequency of ventricular tachycardia and associated implantable cardioverter defibrillator therapies. Epicardial ablation is offered if endocardial ablation fails or as part of an initial combined endocaridal/epicardial ablation strategy, depending on patient preference. We attempt to initiate beta-blocker therapy and therapy with angiotensin-converting enzyme inhibitors to limit structural progression and prevent ventricular arrhythmias. Unaffected family members are screened for disease onset regularly from adolescence through noninvasive cardiac testing. Support to families is provided through ongoing genetic counseling, patient-family web-based support, and in-person seminars for families. PMID- 23728846 TI - Mariculture and natural production of the antitumoural (+)-discodermolide by the Caribbean marine sponge Discodermia dissoluta. AB - Biotechnological research on marine organisms, such as ex situ or in situ aquaculture and in vitro cell culture, is being conducted to produce bioactive metabolites for biomedical and industrial uses. The Caribbean marine sponge Discodermia dissoluta is the source of (+)-discodermolide, a potent antitumoural polyketide that has reached clinical trials. This sponge usually lives at depths greater than 30 m, but at Santa Marta (Colombia) there is a shallower population, which has made it logistically possible to investigate for the first time, on ways to supply discodermolide. We thus performed in situ, 6-month fragment culture trials to assess the performance of this sponge in terms of growth and additional discodermolide production and studied possible factors that influence the variability of discodermolide concentrations in the wild. Sponge fragments cultured in soft mesh bags suspended from horizontal lines showed high survivorship (93 %), moderate growth (28 % increase in volume) and an overall rise (33 %) in the discodermolide concentration, equivalent to average additional production of 8 MUg of compound per millilitre of sponge. The concentration of discodermolide in wild sponges ranged from 8 to 40 MUg mL(-1). Locality was the only factor related to discodermolide variation in the wild, and there were greater concentrations in peripheral vs. basal portions of the sponge, and in clean vs. fouled individuals. As natural growth and regeneration rates can be higher than culture growth rates, there is room for improving techniques to sustainably produce discodermolide. PMID- 23728847 TI - Comparative genome analysis of fish and human isolates of Mycobacterium marinum. AB - Mycobacterium marinum is a major causative agent of mycobacteriosis in fish that has a broad range of hosts, including in human isolates. So far, genomic analyses have focused on the human isolate. Here, we compared the draft genome sequences of two strains of M. marinum isolated from fish (MB2 and Europe) with the M. marinum M isolated from humans. M. marinum MB2 and Europe have single, circular chromosomes of 6,134,389 and 6,029,340 bp, and average G + C contents of 65.7 and 65.5 %, respectively. A total of 5,464 coding DNA sequences were annotated in both M. marinum MB2 and Europe genome. Dot plot analyses showed that M. marinum MB2 and Europe were closer to M. marinum M when compared to three other Mycobacterium species. The insertion/deletion gene analysis showed that M. marinum MB2 and Europe contained 342 and 487 genes that were not found in M. marinum M, and lacked 625 and 776 genes found in M. marinum M, respectively. Most of the inserted and deleted genes were classified in the fatty acid, lipid, and isoprenoid subsystem and the virulence, disease, and defense subsystem. Therefore, these results provide insights into the genomic diversity associated with variable hosts and pathogens. PMID- 23728849 TI - The deployment of ethnographic sciences and psychological warfare during the suppression of the Mau Mau rebellion. AB - This essay provides readers with a critical analysis of the ethnographic sciences and the psychological warfare used by the British and Kenyan colonial regimes during the suppression of the Mau Mau rebellion. In recent years, several survivors of several detention camps set up for Mau Mau suspects during the 1950s have brought cases in British courts, seeking apologies and funds to help those who argue about systematic abuse during the times of "emergency." The author illustrates that the difficulties confronting Ndiku Mutua and other claimants stem from the historical and contemporary resonance of characterizations of the Mau Mau as devilish figures with deranged minds. The author also argues that while many journalists today have commented on the recovery of "lost" colonial archives and the denials of former colonial administrators, what gets forgotten are the polysemic ways that Carothers, Leakey, and other social agents co produced all of these pejorative characterizations. Kenyan settlers, administrators, novelists, filmmakers and journalists have helped circulate the commentaries on the "Mau Mau" mind that continue to influence contemporary debates about past injustices. PMID- 23728848 TI - Proteomic approach to skin regeneration in a marine teleost: modulation by oestradiol-17beta. AB - Skin and scale formation and regeneration in teleosts have mainly been described from a morphological perspective, and few studies of the underlying molecular events exist. The present study evaluates (1) the change in the skin proteome during its regeneration in a marine teleost fish (gilthead sea bream, Sparus aurata) and (2) the impact of oestradiol-17beta (Epsilon2) on regeneration and the involvement of oestrogen receptor (ER) isoforms. Thirty-five candidate proteins were differentially expressed (p < 0.05) between intact and regenerated skin proteome 5 days after scale removal, and 27 proteins were differentially expressed after E2 treatment. Agglomerative hierarchical clustering of the skin proteome revealed that the skin treated with E2 clustered most closely to intact skin, while regenerating untreated skin formed an independent cluster. Gene Ontology classification associated the differentially expressed proteins in E2 treated skin with developmental processes and cellular morphogenesis. The proteins modified during skin regeneration suggest a balance exists between immune response and anatomical repair. Overall, the results indicate that, even after 5 days regeneration, the composition of mature skin is not attained, and endocrine factors, in particular E2, can accelerate wound repair acting possibly via ERbetas expressed in the skin-scales. Several candidate proteins probably involved in scale development, osteoglycin, lipocalin2 and lamin A and the transcription factors PHD and grainyhead were identified. Future studies of fish skin regeneration will be required to provide further insight into this multistage process, and the present study indicates it will be useful to explore immune adaptations of epithelia permanently exposed to an aqueous environment. PMID- 23728850 TI - The effect of 5alpha-reductase inhibitors on prostate growth in men receiving testosterone replacement therapy: a systematic review and meta-analysis. AB - PURPOSE: Androgen replacement therapy is a widely accepted form of treatment worldwide for aging men with late-onset hypogonadism (LOH) syndrome. Urologists have been concerned with the use of androgen supplements due to the possibility of enhancing prostate growth. We performed a systematic review and meta-analysis to assess the effect of 5alpha-reductase inhibitors on prostate growth in men receiving testosterone replacement therapy. METHODS: A literature review was performed to identify all published randomized placebo-controlled trials (RCT) that used exogenous testosterone combined with 5alpha-reductase inhibitor therapy for the treatment of hypogonadism. The search included the following databases: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register. The reference lists of the retrieved studies were also investigated, and a systematic review and meta analysis were conducted. RESULTS: Five publications involving a total of 250 patients were used in the analysis, including 4 RCTs that were short-term (<=6 mo) comparisons of testosterone plus a 5alpha-reductase inhibitor with testosterone plus placebo and 3 RCTs that were long-term (18-36 mo) comparisons of testosterone plus a 5alpha-reductase inhibitor with testosterone plus placebo. In our meta-analysis, we found that testosterone plus a 5alpha-reductase inhibitor may slow the progression of prostate growth. For the comparison of short-term testosterone plus 5alpha-reductase inhibitor treatment with testosterone plus placebo therapy, the prostate-specific antigen (PSA) level (the standardized mean difference (SMD) = -0.24, 95 % confidence interval (CI) = -0.45 to 0.04, p = 0.02)) and the prostate volume (SMD = -1.66, 95 % CI = -4.54 to 1.22, p = 0.26) indicated that, compared with testosterone plus placebo therapy, the testosterone plus 5alpha-reductase inhibitor may decrease the PSA level. For the comparison of long-term testosterone plus 5alpha-reductase inhibitor with testosterone plus placebo, the PSA level (SMD = -0.53, 95 % CI = -0.84 to 0.21, p = 0.001) and the prostate volume (SMD = -8.53, 95 % CI = -15.51 to 1.54, p = 0.02) showed that, compared with testosterone plus placebo therapy, the testosterone plus 5alpha-reductase inhibitor treatment may slow the progression of prostate growth. CONCLUSIONS: Our meta-analysis indicates that the treatment of LOH patients with short-term testosterone plus 5alpha-reductase inhibitor therapy does not lead to prostate growth; however, this treatment could effectively decrease the PSA level. Additionally, long-term testosterone plus 5alpha-reductase inhibitor therapy could slow the progression of prostate growth. PMID- 23728851 TI - Stochastic EM algorithm for doubly interval-censored data. AB - In clinical trials, it is frequently of interest to estimate the time between the onset of two events (e.g. duration of response in oncology). Here, we consider the case where subjects are assessed at fixed visits but the initial event and the terminating event occur in between visits. This type of data, called doubly interval censored, is often analyzed with standard survival techniques, assuming either that the survival time (between initial and terminating event) is known exactly or is single interval censored. We introduce a motivating dataset in which the interest is to evaluate the impact of the treatment on the duration of response endpoint. We review the existing approaches and discuss their limitations with respect to the characteristics of our motivating dataset. Furthermore, we propose a stochastic EM algorithm that overcomes the problems in the existing approaches. We show by simulations the finite sample properties of our approach. PMID- 23728852 TI - Posttranscriptional destabilization of the liver-specific long noncoding RNA HULC by the IGF2 mRNA-binding protein 1 (IGF2BP1). AB - Selected long noncoding RNAs (lncRNAs) have been shown to play important roles in carcinogenesis. Although the cellular functions of these transcripts can be diverse, many lncRNAs regulate gene expression. In contrast, factors that control the expression of lncRNAs remain largely unknown. Here we investigated the impact of RNA binding proteins on the expression of the liver cancer-associated lncRNA HULC (highly up-regulated in liver cancer). First, we validated the strong up regulation of HULC in human hepatocellular carcinoma. To elucidate posttranscriptional regulatory mechanisms governing HULC expression, we applied an RNA affinity purification approach to identify specific protein interaction partners and potential regulators. This method identified the family of IGF2BPs (IGF2 mRNA-binding proteins) as specific binding partners of HULC. Depletion of IGF2BP1, also known as IMP1, but not of IGF2BP2 or IGF2BP3, led to an increased HULC half-life and higher steady-state expression levels, indicating a posttranscriptional regulatory mechanism. Importantly, HULC represents the first IGF2BP substrate that is destabilized. To elucidate the mechanism by which IGF2BP1 destabilizes HULC, the CNOT1 protein was identified as a novel interaction partner of IGF2BP1. CNOT1 is the scaffold of the human CCR4-NOT deadenylase complex, a major component of the cytoplasmic RNA decay machinery. Indeed, depletion of CNOT1 increased HULC half-life and expression. Thus, IGF2BP1 acts as an adaptor protein that recruits the CCR4-NOT complex and thereby initiates the degradation of the lncRNA HULC. CONCLUSION: Our findings provide important insights into the regulation of lncRNA expression and identify a novel function for IGF2BP1 in RNA metabolism. PMID- 23728853 TI - Population pharmacokinetics of carvedilol in patients with congestive heart failure. AB - The aim of this study was to derive population pharmacokinetic (PK) model for clearance (CL) of carvedilol in adult patients with chronic heart failure (CHF). Medication and demographic data were obtained from 52 Caucasian patients with CHF taking carvedilol. Population PK analysis was performed by nonlinear mixed effects modeling (NONMEM) to estimate and identify different factors that could affect carvedilol CL. A total of 55 plasma concentrations were collected from 52 patients with mean age of 63.02 +/- 11.95 years and total body weight (TBW) of 77.96 +/- 13.46 kg. Total daily doses of carvedilol in the target population had wide range of variability (6.25-50 mg), followed by high variability of drug plasma concentrations (1-59.07 ng/mL). The typical mean value for carvedilol CL, estimated by the base model, in the target population was 43.8 L/h. The TBW, concomitant therapy with digoxin, and tobacco using were determinants of a derived population model. The final regression model for the CL of carvedilol is: [Formula: see text] Our results suggest that the TBW, concomitant therapy with digoxin, and tobacco using are the main subjects of carvedilol PK variability. PMID- 23728854 TI - Differentiation of spermatogonial stem cell-like cells from murine testicular tissue into haploid male germ cells in vitro. AB - In vitro differentiation of spermatogonial stem cells (SSCs) promotes the understanding of the mechanism of spermatogenesis. The purpose of this study was to isolate spermatogonial stem cell-like cells from murine testicular tissue, which then were induced into haploid germ cells by retinoic acid (RA). The spermatogonial stem cell-like cells were purified and enriched by a two-step plating method based on different adherence velocities of SSCs and somatic cells. Cell colonies were present after culture in M1-medium for 3 days. Through alkaline phosphatase, RT-PCR and indirect immunofluorescence cell analysis, cell colonies were shown to be SSCs. Subsequently, cell colonies of SSCs were cultured in M2-medium containing RA for 2 days. Then the cell colonies of SSCs were again cultured in M1-medium for 6-8 days, RT-PCR and indirect immunofluorescence cell analysis were chosen to detect haploid male germ cells. It could be demonstrated that 10(-7) mol l(-1) of RA effectively induced the SSCs into haploid male germ cells in vitro. PMID- 23728855 TI - Development of a sandwich ELISA for the quantification of enterovirus 71. AB - Since 2008, enterovirus 71 (EV71) has been responsible for high-mortality seasonal epidemics of hand, foot and mouth disease in China. Currently many groups in the world are in the process of developing EV71 vaccines to combat this deadly disease. We have developed three EV71-specific monoclonal antibodies, and in this study we report the establishment of a fast and cost-effective sandwich ELISA kit for measurement of virus concentration in EV71 vaccines using a pair of mouse anti-EV71 monoclonal antibodies. The system is specific for EV71 virus, with no cross-reactivity to coxsackievirus A16, H1N1, rabies, and hepatitis A. Using a reference EV71 vaccine standard, the sensitivity of the assay kit was determined to be 0.82 U/ml, with a linear range between 3.75 and 120 U/ml. PMID- 23728856 TI - Anatomical coupling among distributed cortical regions in youth varies as a function of individual differences in vocabulary abilities. AB - Patient lesion and functional magnetic resonance imaging (fMRI) studies have provided convincing evidence that a distributed brain network subserves word knowledge. However, little is known about the structural correlates of this network within the context of typical development and whether anatomical coupling in linguistically relevant regions of cortex varies as a function of vocabulary skill. Here we investigate the association between vocabulary and anatomical coupling in 235 typically developing youth (ages 6-19 years) using structural MRI. The study's primary aim was to evaluate whether higher vocabulary performance was associated with greater vertex-level cortical thickness covariation in distributed regions of cortex known to be associated with word knowledge. Results indicate that better vocabulary skills are associated with greater anatomical coupling in several linguistically relevant regions of cortex, including the left inferior parietal (temporal-parietal junction), inferior temporal, middle frontal, and superior frontal gyri and the right inferior frontal and precentral gyri. Furthermore, in high vocabulary scorers, stronger coupling is found among these regions. Thus, complementing patient and fMRI studies, this is the first investigation to highlight the relevance of anatomical covariance within the cortex to vocabulary skills in typically developing youth, further elucidating the distributed nature of neural systems subserving word knowledge. PMID- 23728857 TI - The role of active immunization therapy as preoperative treatment for chronic osteomyelitis. AB - BACKGROUND: This retrospective study was performed to assess the effectiveness of active immunostimulation therapy with bacterial immunotherapy (BIT) in treatment for chronic osteomyelitis (COM). MATERIALS AND METHODS: We analyze 154 patients affected by COM and treated with BIT from 1995 to 2009 at our Institution. Using Cierny and Mader classification, patients were divided according to their clinical status and anatomic nature of septic process. The data were analyzed considering several confounding factors, such as antibiotic therapy and hyperbaric oxygen therapy combined with the administration of BIT. According to clinical and radiographic parameters, patients were considered as unchanged, improved, or healed. RESULTS: After a mean follow-up of 40.4 months (median 38 months), healing was achieved in 41.6 % of cases. Multivariate statistical analysis showed that patient's clinical status is the most important prognostic factor of responding (p < 0.0005) and healing (p = 0.008) after therapy. The best healing rate (62 % of cases) was achieved in patients with a normal clinical condition (Cierny-Mader group A); it was worse (20 % of cases) in those patients with a compromised clinical status (Cierny-Mader group B). There was no healing case in group C. CONCLUSIONS: The results show the effectiveness of BIT in treatment of patients affected by COM with uncompromised clinical status. The use of this therapy must be assessed critically in patients with alterations in clinical conditions. PMID- 23728858 TI - Tongue pressure generation during tongue-hold swallows in young healthy adults measured with different tongue positions. AB - Tongue-hold swallow (THS) has the potential to be a resistance exercise not only for the pharyngeal constrictor but for the tongue muscles. To elucidate the physiological mechanisms of THS, this study investigated intraoral pressure generation during THS in relation to different extents of tongue protrusion. Tongue pressure was measured by a 5-point pressure sensor sheet placed onto the hard palate of 18 healthy young subjects who performed three swallow tasks: normal dry swallow, THS with slight tongue protrusion, and THS with greater tongue protrusion. Subjects randomly repeated each task five times. Maximum range of tongue protrusion was also measured in each subject to estimate lingual flexibility. With an increase in the extent of tongue protrusion, pressure generation patterns became irregular and variable. Duration of pressure generation increased with statistical significance in the posterior circumferential parts of the hard palate (p < 0.05). Maximal magnitude and integrated value of the pressure recorded at these locations increased in eight subjects as the extent of tongue protrusion increased, but it decreased in nine. The former group showed greater lingual flexibility, while the latter group exhibited less flexibility. THS may place different amounts of load on the tongue muscles by adjusting the degree of tongue protrusion. PMID- 23728859 TI - Lack of association between high serum thyroid-stimulating hormone level and risk of papillary thyroid microcarcinomas. AB - BACKGROUND: High serum thyroid-stimulating hormone (TSH) is associated with thyroid carcinoma in patients with thyroid nodules. However, previous studies suggests that TSH is not involved in the pathogenesis of small thyroid carcinomas. We performed this study to evaluate serum TSH as a malignancy predictor in the assessment of small thyroid nodules. METHODS: We retrospectively analyzed 3791 patients who underwent thyroidectomy. We classified all patients into 3 to 5 groups by serum TSH or nodule size and analyzed the association of serum TSH and risk of papillary thyroid carcinoma (PTC). RESULTS: The frequency of PTC increased as serum TSH increased. Serum TSH and older age were associated with the risk of PTC in multivariate analysis (p < .0001). In subgroup analysis, the risk of PTC increased as serum TSH increased with thyroid nodules > 1 cm (p < .05). CONCLUSIONS: Serum TSH may not be useful for clinical risk assessment of small thyroid nodules. PMID- 23728860 TI - Simple suspension culture system of human iPS cells maintaining their pluripotency for cardiac cell sheet engineering. AB - In this study, a simple three-dimensional (3D) suspension culture method for the expansion and cardiac differentiation of human induced pluripotent stem cells (hiPSCs) is reported. The culture methods were easily adapted from two dimensional (2D) to 3D culture without any additional manipulations. When hiPSCs were directly applied to 3D culture from 2D in a single-cell suspension, only a few aggregated cells were observed. However, after 3 days, culture of the small hiPSC aggregates in a spinner flask at the optimal agitation rate created aggregates which were capable of cell passages from the single-cell suspension. Cell numbers increased to approximately 10-fold after 12 days of culture. The undifferentiated state of expanded hiPSCs was confirmed by flow cytometry, immunocytochemistry and quantitative RT-PCR, and the hiPSCs differentiated into three germ layers. When the hiPSCs were subsequently cultured in a flask using cardiac differentiation medium, expression of cardiac cell-specific genes and beating cardiomyocytes were observed. Furthermore, the culture of hiPSCs on Matrigel-coated dishes with serum-free medium containing activin A, BMP4 and FGF 2 enabled it to generate robust spontaneous beating cardiomyocytes and these cells expressed several cardiac cell-related genes, including HCN4, MLC-2a and MLC-2v. This suggests that the expanded hiPSCs might maintain the potential to differentiate into several types of cardiomyocytes, including pacemakers. Moreover, when cardiac cell sheets were fabricated using differentiated cardiomyocytes, they beat spontaneously and synchronously, indicating electrically communicative tissue. This simple culture system might enable the generation of sufficient amounts of beating cardiomyocytes for use in cardiac regenerative medicine and tissue engineering. PMID- 23728861 TI - An interpretation of the "anomalous" changes in the low-wavenumber range of the Raman spectra of L-alanine crystals. AB - "Anomalous changes" in the temperature- and pressure- dependences of the intensities and wavenumbers of the two low-wavenumber modes in Raman spectra of single-crystals of L-alanine have been interpreted in terms of a change in relative contributions of stretching and deformational components into the intermolecular vibrational bands. The relative contributions of the two components into a lattice vibration result from a change of relative orientations of molecules linked by hydrogen bonds in a three-dimensional network on variations of temperature or pressure. PMID- 23728862 TI - Topics in thoracic oncology: from surgical resection to molecular dissection. PMID- 23728863 TI - Idiopathic pulmonary fibrosis: current challenges and future perspectives. PMID- 23728864 TI - Sedation for flexible bronchoscopy: current and emerging evidence. AB - Flexible bronchoscopy is commonly performed by respiratory physicians and is the gold standard for directly visualising the airways, allowing for numerous diagnostic and therapeutic interventions. With the widespread use of flexible bronchoscopy and the evolution of interventional bronchoscopy with more complex and longer procedures, physicians are placing increasing importance on the use of sedation as a necessary adjunct to topical anaesthesia. There is no standardised practice for the use of sedation in bronchoscopy with a good deal of variation among physicians regarding the use of pre-procedure medication and pharmacological sedatives. In addition, there is ongoing debate and controversy about proceduralist-administered versus anaesthetist-administered sedation whilst at the same time there is a growing body of evidence that nonanaesthetist administered sedation is safe and cost-effective. In this review we summarise the evidence for the use of sedation as an adjunct to topical anaesthesia in bronchoscopy and provide the clinician with up-to-date concise guidance for the use of pharmacological sedatives in bronchoscopy and future directions for sedation in the bronchoscopy suite. PMID- 23728865 TI - Desquamative interstitial pneumonia: an analytic review with an emphasis on aetiology. AB - Desquamative interstitial pneumonia (DIP) is characterised by the accumulation of numerous pigmented macrophages within most of the distal airspace of the lung and, sometimes, the presence of giant cells. Diagnosis of DIP is not easy and requires surgical lung biopsy. DIP is usually associated with tobacco smoke. However, the association between smoking and DIP is less robust than that with respiratory bronchiolitis with interstitial lung disease or pulmonary Langerhans' cell histiocytosis; approximately 10-42% of patients with DIP are nonsmokers. DIP can also occur in patients following exposure to certain inhaled toxins (occupational exposure) and drugs, and may occur in the context of certain viral illnesses and autoimmune diseases. In the context of DIP, occupational exposure should be systematically investigated. PMID- 23728866 TI - The airport atmospheric environment: respiratory health at work. AB - Air traffic is increasing, raising concern about local pollution and its adverse health effects on the people living in the vicinity of large airports. However, the highest risk is probably occupational exposure due to proximity. Jet exhaust is one of the main concerns at an airport and may have a health impact, particularly on the respiratory tract. Current studies are neither numerous enough nor strong enough to prove this kind of association. Yet, more and more people work in airports, and occupational exposure to jet exhaust is a fact. The aim of this review was to evaluate the existing knowledge regarding the impact of airport pollution on respiratory health. We conducted systematic literature searches to examine workplace exposures. PMID- 23728867 TI - Small airways diseases, excluding asthma and COPD: an overview. AB - This review is the summary of a workshop on small airways disease, which took place in Porquerolles, France in November 2011. The purpose of this workshop was to review the evidence on small airways (bronchiolar) involvement under various pathophysiological circumstances, excluding asthma and chronic obstructive pulmonary disease. Histopathological patterns associated with small airways disease were reviewed, including cellular and obliterative bronchiolitis. Many pathophysiological conditions have been associated with small airways disease including airway infections, connective tissue diseases and inflammatory bowel diseases, bone marrow and lung transplantation, common variable immunodeficiency disorders, diffuse panbronchiolitis, and diseases related to environmental exposures to pollutants, allergens and drugs. Pathogenesis, clinical presentation, a computed tomography scan and pulmonary function test findings are reviewed, and therapeutic options are described with the objective of providing an integrative approach to these disorders. PMID- 23728868 TI - PROFILEing idiopathic pulmonary fibrosis: rethinking biomarker discovery. AB - Despite major advances in the understanding of the pathogenesis of idiopathic pulmonary fibrosis (IPF), diagnosis and management of the condition continue to pose significant challenges. Clinical management of IPF remains unsatisfactory due to limited availability of effective drug therapies, a lack of accurate indicators of disease progression, and an absence of simple short-term measures of therapeutic response. The identification of more accurate predictors of prognosis and survival in IPF would facilitate counseling of patients and their families, aid communication among clinicians, and would guide optimal timing of referral for transplantation. Improvements in molecular techniques have led to the identification of new disease pathways and a more targeted approach to the development of novel anti-fibrotic agents. However, despite an increased interest in biomarkers of IPF disease progression there are a lack of measures that can be used in early phase clinical trials. Careful longitudinal phenotyping of individuals with IPF together with the application of novel omics-based technology should provide important insights into disease pathogenesis and should address some of the major issues holding back drug development in IPF. The PROFILE (Prospective Observation of Fibrosis in the Lung Clinical Endpoints) study is a currently enrolling, prospective cohort study designed to tackle these issues. PMID- 23728869 TI - The impact of emphysema in pulmonary fibrosis. AB - Several groups have described a syndrome in which idiopathic pulmonary fibrosis (IPF) coexists with pulmonary emphysema. This comes as no surprise since both diseases are associated with a history of exposure to cigarette smoke. The syndrome of combined pulmonary fibrosis and emphysema (CPFE) is characterised by upper lobe emphysema and lower lobe fibrosis. Physiological testing of these patients reveals preserved lung volume indices contrasted by markedly impaired diffusion capacity. The incidence of CPFE remains unknown but several case series suggest that this subgroup may comprise up to 35% of patients with IPF. CPFE is a strong determinant of associated pulmonary hypertension (PH). In addition, CPFE has major effects on measures of physiological function, exercise capacity and prognosis, and may affect the results of pulmonary fibrosis trials. Further studies are needed to ascertain the aetiology, morbidity, mortality and management of the CPFE syndrome, with or without PH, and to evaluate novel therapeutic options in CPFE. PMID- 23728870 TI - Managing diagnostic procedures in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF), the most prevalent of the idiopathic interstitial pneumonias, is associated with a poor prognosis. An accurate diagnosis of IPF is essential for its optimal management. The 2011 American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) recommendations on the diagnosis and management of IPF were developed from a systematic review of the published literature. High-resolution computed tomography (HRCT) scanning has a central role in the IPF diagnostic pathway, with formal designation of criteria for an HRCT pattern of usual interstitial pneumonia. In the correct clinical context, a usual interstitial pneumonia pattern on HRCT is indicative of a definite diagnosis of IPF and negates the need for a surgical lung biopsy. However, although the 2011 ATS/ERS/JRS/ALAT statement is a major advance, the application of the guideline recommendations by clinicians has identified limitations that should be addressed in future statements. Key problems include: 1) HRCT misdiagnosis, particularly by less experienced radiologists; 2) lack of management recommendations for the highly prevalent clinical scenarios of "probable" or "possible" IPF; 3) ongoing confusion concerning the diagnostic role of bronchoalveolar lavage; and 4) the lack of integration of clinical data in the designation of the diagnostic likelihood of IPF, including the treated course of disease. These issues become evident as the recommendations are applied and highlight the need for continued guideline adjustments. PMID- 23728871 TI - Evidence-based treatment strategies in idiopathic pulmonary fibrosis. AB - Recently updated guidelines have provided revised recommendations, based on the GRADE criteria, for the diagnosis and pharmacological and non-pharmacological management of patients with idiopathic pulmonary fibrosis (IPF). Cochrane reviews are also a highly respected and reliable source of evidence-based information that identify and analyse all available data of overall treatment effects from appropriate studies. A recent update of one Cochrane review failed to identify any new evidence supporting the use of corticosteroids in IPF. Another review of data from 15 randomised controlled studies of non-steroid agents for the treatment of IPF identified two trials of interferon-gamma-1b suitable for analysis. However, the pooled analysis revealed no treatment effect in terms of survival. A further meta-analysis of three phase III studies of pirfenidone treatment in IPF patients suggested a significant increase in progression-free survival. The interpretation of recent international and national European guideline updates and treatment recommendations, available clinical data from published and ongoing trials investigating potential pharmacological agents, and the individual patient's preferences, must be considered in the clinical management of this disease. PMID- 23728872 TI - Endobronchial ultrasound in the management of nonsmall cell lung cancer. AB - Flexible bronchoscopy plays a major role in the diagnosis and staging of lung cancer. One of the most important advances in this field is the development of endobronchial ultrasound (EBUS), which has extended the view of the bronchoscopist. These techniques are safe and allow assessment of the depth of tumour invasion in the central airways, detection of peripheral tumours before sampling, localisation of the central tumour in the lung parenchyma close to the central airways for real-time guided sampling, and staging of lymph nodes within the mediastinum. Progress in handling and analyses of the small samples obtained during EBUS procedures also allow modern pathological and molecular studies to be performed. This article reviews the data currently available in the field of convex and radial probe EBUS for the diagnosis and staging of nonsmall cell lung cancer and highlights the strengths but also the weaknesses of these new techniques. PMID- 23728873 TI - Practical recommendations for exercise training in patients with COPD. AB - The aim of this article was to provide practical recommendations to healthcare professionals interested in offering a pulmonary rehabilitation programme for patients with chronic obstructive pulmonary disease (COPD). The latest research findings were brought together and translated into clinical practice. These recommendations focus on the description of useful assessment tests and of the most common exercise modalities for patients with COPD. We provide specific details on the rationale of why and especially how to implement exercise training in patients with COPD, including the prescription of training mode, intensity and duration, as well as suggestions of guidelines for training progression. PMID- 23728874 TI - Pulmonary phaeohyphomycosis: a challenge to the clinician. PMID- 23728875 TI - Diffuse pulmonary ossification in a patient exposed to silica. PMID- 23728876 TI - Differentiating pulmonary cavities. PMID- 23728878 TI - Endoscopic supraomohyoid neck dissection via a retroauricular or modified facelift approach: preliminary results. AB - BACKGROUND: Based on our previous experiences with endoscopic or robotic neck surgery utilizing the retroauricular (RA) or modified facelift (MFL) approach, we realized the value of verifying the feasibility of endoscopic supraomohyoid neck dissection (SOND). Therefore, the purpose of this study was to evaluate the potential role of endoscopic SOND. METHODS: Six patients who underwent elective endoscopic SOND of the ipsilateral neck for biopsy proven head and neck cancer from January 2011 to February 2012 were analyzed. RESULTS: All endoscopic operations via RA or MFL were successfully performed without any significant intraoperative complications or conversion to open surgery. Based on patient reported outcome questionnaires, all patients were satisfied with the cosmetic surgical outcomes. CONCLUSION: Endoscopic selective neck dissection via an RA or an MFL approach is technically feasible and safe with satisfactory cosmetic results for patients with clinically node-negative early-stage head and neck cancer. PMID- 23728879 TI - Experimenting with styles of living: Bernard, Canguilhem and type 2 diabetes education. AB - The paper links a debate in the history of medical science between statistics and the experimental method with contemporary diabetes educational practices. An empirical example of a tension between neglect and concern in diabetes self regulation frames the subsequent theoretical discussion between first, Claude Bernard and statistics and afterwards, Georges Canguilhem as a correlative to Bernard. Through these philosophers of medical science a connection between the experimental method and education is demonstrated. Finally, a case description of an experimental approach to alcohol and experimentation frames and highlights the educational aspect of the methodological discussion. PMID- 23728880 TI - 'Journeys' in the life-writing of adult-child dementia caregivers. AB - This article explores how Alzheimer's disease caregivers struggle under the impact of a parent's memory loss on their own personality. In particular, it analyses how caregivers perceive and, thus, present their experiences of the ever intensifying caregiving activity in terms of a 'journey'. In doing so, this work takes into account both the patient's continuing bodily as well as cognitive decline and its intricately linked influence on the caregiver's physical and emotional stability. Equally, this study investigates how caregivers portray memory loss, and how their portrayal fits into our conceptualisation of illness narratives and the culture of autobiographical writing. PMID- 23728881 TI - Convergent functional genomics of psychiatric disorders. AB - Genetic and gene expression studies, in humans and animal models of psychiatric and other medical disorders, are becoming increasingly integrated. Particularly for genomics, the convergence and integration of data across species, experimental modalities and technical platforms is providing a fit-to-disease way of extracting reproducible and biologically important signal, in contrast to the fit-to-cohort effect and limited reproducibility of human genetic analyses alone. With the advent of whole-genome sequencing and the realization that a major portion of the non-coding genome may contain regulatory variants, Convergent Functional Genomics (CFG) approaches are going to be essential to identify disease-relevant signal from the tremendous polymorphic variation present in the general population. Such work in psychiatry can provide an example of how to address other genetically complex disorders, and in turn will benefit by incorporating concepts from other areas, such as cancer, cardiovascular diseases, and diabetes. PMID- 23728882 TI - Salvage high-dose-rate interstitial brachytherapy for locally recurrent rectal cancer: long-term follow-up results. AB - BACKGROUND: We retrospectively examined outcomes of salvage high-dose-rate interstitial brachytherapy (HDR-ISBT) for locally recurrent rectal cancer (LRRC). METHODS: Nine patients with LRRC were treated with salvage HDR-ISBT. Their median age was 63 years. The median maximum diameter of LRRC was 40 mm (range 20-80 mm). Adenocarcinomas were histologically confirmed in all cases. The prescribed dose was 30 Gy/5 fractions/3 days to 50 Gy/10 fractions/6 days in the combined external-beam radiotherapy group (four patients) and 54 Gy/9 fractions/5 days to 60 Gy/10 fractions/6 days in the monotherapeutic group (five patients). Median follow-up time was 90 months (range 6-221 months). RESULTS: Local control at final follow-up was achieved in five of nine patients. Of these five patients, one experienced a locally re-recurrent tumor in the vaginal wall 33 months after treatment and received re-HDR-ISBT as re-salvage treatment. The 8-year overall survival, local control, and progression-free survival rates were 56, 44, and 33 %, respectively. Based on the Common Terminology Criteria for Adverse Events ver. 4.03, the following Grade 3 adverse events were observed in three patients (>=3 months): Grade 3 skin ulceration in one patient who showed tumor invasion of the skin and whose V100 was 400 cc; Grade 3 vaginal perforation in one patient whose tumor had invaded the vaginal wall; and Grade 3 vagina-to-bladder fistula in one patient whose tumor received re-irradiation. Late adverse events above Grade 3 were not observed. CONCLUSIONS: Long-term follow-up results revealed that salvage HDR-ISBT is a promising treatment for LRRC with tolerable toxicity. PMID- 23728883 TI - Do hormone treatments for prostate cancer cause anxiety and depression? AB - BACKGROUND: To investigate the relationship between hormone therapy (HT) and incidence of anxiety and depression among prostate cancer patients (PCa). METHODS: 526 PCa patients completed a survey about their cancer status, treatment received, anxiety, and depression status. Total scores on anxiety and depression inventories, plus symptom profiles that discriminated between patients with current HT, past HT, and never having received HT, were compiled for analysis. RESULTS: Patients who were currently receiving HT had significantly higher total anxiety and depression scores than patients who had previously received HT or who had never received HT. Analysis of the symptoms of anxiety and depression which distinguished between these groups of patients suggested that patients who had never received HT had significantly lower scores than current or past HT patients. Although several symptoms could be directly allocated to PCa and/or HT, symptom profiles were indicative of clinically significant anxiety and/or depression in patients who were currently receiving, or who had previously received, HT. CONCLUSION: Current HT may lead to symptoms of anxiety and/or depression which require clinical attention. These effects seem to decrease after completion of HT. PMID- 23728884 TI - Bevacizumab combination therapy: a review of its use in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. AB - Bevacizumab (Avastin(r)) is a recombinant, humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody that neutralizes the biological activity of VEGF and inhibits tumor angiogenesis. In the EU, in adult patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer, bevacizumab (in combination with carboplatin and paclitaxel) is approved for the first-line treatment of advanced disease and (in combination with carboplatin and gemcitabine) is approved for the treatment of patients with first recurrence of platinum-sensitive disease who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents. This article summarizes the pharmacology of bevacizumab and reviews the efficacy and tolerability of bevacizumab combination therapy in well-designed clinical studies in these indications. The addition of bevacizumab to first-line carboplatin plus paclitaxel, followed by bevacizumab maintenance therapy significantly prolonged progression-free survival in women with newly-diagnosed advanced disease (GOG 0218 and ICON7 studies). Progression-free survival was also significantly prolonged after second-line treatment with bevacizumab in combination with carboplatin and gemcitabine, followed by maintenance treatment with bevacizumab alone in women with recurrence (>= 6 months after front-line platinum-based therapy) of platinum-sensitive disease (OCEANS study). Bevacizumab combination therapy had a generally acceptable tolerability profile in these studies, with the nature of adverse events generally similar to that observed in previous clinical trials in patients with other solid tumors. Although several unanswered questions remain, such as the optimal dosage and duration of treatment, current evidence suggests that bevacizumab combination therapy extends the treatment options available for patients with ovarian cancer. PMID- 23728885 TI - Therapeutic potential of targeting interleukin 5 in asthma. AB - It is recognised that airway inflammation is key to asthma pathogenesis. Biopharmaceutical approaches have identified new therapies that target key cells and mediators that drive the inflammatory responses in the asthmatic lung. Such an approach resulted in the development of biologics targeted at inhibition of interleukin (IL)-4, IL-5 and IL-13. However, early clinical trials with these biologics in patients with asthma were, for the most part, disappointing even though they were highly effective in animal models of asthma. It is becoming apparent that significant clinical effects with anti-cytokine-based therapies are more likely in carefully selected patient populations that take asthma phenotypes into account. The development of discriminatory biomarkers and genetic profiling may aid identification of such patients with asthma. This review summarises the current evidence, demonstrating the effectiveness or otherwise of the targeting of IL-5 in patients with asthma. PMID- 23728886 TI - Hip resurfacing does not improve proprioception compared with THA. AB - BACKGROUND: Proposed benefits of total hip resurfacing arthroplasty over total hip arthroplasty (THA) include better proprioception, but this has not been rigorously tested or validated. QUESTIONS/PURPOSES: Our purpose was to apply an advanced testing device that objectively quantifies dynamic postural stability to determine if total hip resurfacing is associated with improved proprioception compared with standard or large-head THA. METHODS: Three groups of 25 patients (total hip resurfacing, THA femoral head > 32 mm, THA femoral head <= 32 mm) and a matched control group were recruited. All participants had UCLA scores >= 5 and Harris hip scores >= 90 at the time of testing. Testing was conducted using a commercially available device that uses a multidirectional, powered platform to measure deviations of the center of mass and consisted of trials with both double and single-limb support. RESULTS: Double-limb testing showed no differences between groups. In single-limb testing, the operative side performed better in patients who had undergone total hip resurfacing versus THA, but this difference disappeared when the operative side was normalized to the nonoperative side. When compared with control subjects who had not had arthroplasty, both operative and nonoperative sides showed significantly worse proprioception for all arthroplasty cohorts, suggesting that decreased proprioception is associated with arthritis of the hip in young adults. CONCLUSIONS: Total hip resurfacing arthroplasty did not result in improved proprioception compared with THA. These results tend to refute the concept that improved proprioception is a rationale for selecting total hip resurfacing over THA in young patients. PMID- 23728887 TI - Ankle arthrodesis versus ankle replacement for ankle arthritis. PMID- 23728888 TI - Symposium: Advanced hip arthroscopy: editorial comment. PMID- 23728889 TI - En bloc resection of epiglottic tumors with transoral robotic approach - preliminary results. AB - OBJECTIVE: This study aimed to identify whether it would be possible to excise epiglottic laryngeal tumors en bloc with a transoral robotic approach (TORS), ensuring that basic principles of oncologic surgery are followed. METHODS: TORS was performed on three patients at Umraniye Education and Research Hospital. All patients had T1 epiglottic tumors. Unilateral neck dissections were performed for node-positive patients (n = 2). Postoperative radiotherapy was administered to these two patients. RESULTS: None of the patients had positive surgical margins. The follow-up period on average was 14 months, no recurrences were observed in this follow-up period. Normal food intake was possible in all cases. Tracheostomy was not performed on any patient. No postoperative complications were observed. CONCLUSION: These preliminary results indicate that application of the da Vinci robotic surgical system for en bloc resection of supraglottic partial cancers is technically feasible and safe, with satisfactory oncological outcome and postoperative laryngeal function. PMID- 23728892 TI - A meta-analysis of bisphosphonates for periprosthetic bone loss after total joint arthroplasty. AB - BACKGROUND: Periprosthetic bone loss, which is common after joint arthroplasty, may cause bone loosening and lead to failed prosthetic fixation. Two previous meta-analyses have confirmed the mid-term effect of bisphosphonates (BPs) in preventing bone loss after arthroplasty. To determine long-term efficacy and gender bias of BPs after joint arthroplasty, we conducted a meta-analysis based on 17 RCTs involving 781 patients to evaluate the effect of BPs. METHODS: Meta analysis was conducted after a systematic search of Medline, Embase, the Cochrane Collaboration Central Register of Controlled Clinical Trials, CINAHL, and ISI Web of Science, and manual examination of references in selected articles and conference abstracts of key orthopedic journals. Methodological quality and abstracted relevant data were evaluated. In addition to analysis of bone mineral density (BMD), we also conducted systematic analysis of clinically relevant outcomes and bone biochemical markers. RESULTS: Seventeen trials involving a total of 781 patients were assessed. Significantly less periprosthetic bone loss occurred in the BP-treated group than in the control group at 6 and 12 months (p < 0.0001). This protective effect was not noted at 3 months (p = 0.11) nor from 24-72 months (p = 0.14). The efficacy of BPs in the gender balance, shorter duration, and the non-nitrogenous BPs groups was no different from that for controls. Biochemical bone markers were suppressed in the BPs group. However, clinically relevant outcomes in the BPs group and controls were similar at all times. CONCLUSIONS: The overall moderate-quality evidence from the RCTs confirmed the significant mid-term efficacy of BPs on periprosthetic bone loss after joint arthroplasty. Long-term efficacy of BPs was not observed, and the therapy was of more benefit to women, especially postmenopausal women. To achieve better efficacy, nitrogenous BPs and long duration of treatment may be recommended. PMID- 23728891 TI - Identification of inputs to olivocochlear neurons using transneuronal labeling with pseudorabies virus (PRV). AB - Olivocochlear (OC) neurons respond to sound and provide descending input that controls processing in the cochlea. The identities of neurons in the pathways providing inputs to OC neurons are incompletely understood. To explore these pathways, the retrograde transneuronal tracer pseudorabies virus (Bartha strain, expressing green fluorescent protein) was used to label OC neurons and their inputs in guinea pigs. Labeling of OC neurons began 1 day after injection into the cochlea. On day 2 (and for longer survival times), transneuronal labeling spread to the cochlear nucleus, inferior colliculus, and other brainstem areas. There was a correlation between the numbers of these transneuronally labeled neurons and the number of labeled medial (M) OC neurons, suggesting that the spread of labeling proceeds mainly via synapses on MOC neurons. In the cochlear nucleus, the transneuronally labeled neurons were multipolar cells including the subtype known as planar cells. In the central nucleus of the inferior colliculus, transneuronally labeled neurons were of two principal types: neurons with disc shaped dendritic fields and neurons with dendrites in a stellate pattern. Transneuronal labeling was also observed in pyramidal cells in the auditory cortex and in centers not typically associated with the auditory pathway such as the pontine reticular formation, subcoerulean nucleus, and the pontine dorsal raphe. These data provide information on the identity of neurons providing input to OC neurons, which are located in auditory as well as non-auditory centers. PMID- 23728893 TI - Arthroscopic excision of separated ossicles of the lateral malleolus. AB - BACKGROUND: We have conducted a retrospective review of 19 patients for whom 20 separated ossicles of the lateral malleolus were excised arthroscopically. We examined the operating methods, findings, and overall results. METHODS: The patients' indications for this procedure were as follows. The main complaints were pain alone; ossicle sizes were small and ankle instability was minimal. There were 12 ankles of 12 males and eight ankles of seven females. The patients' average age was 17.6 years. A 2.7-mm, 30 degrees arthroscope was inserted into the ankle joint through the anterolateral portal. Instruments were inserted through the accessory anterolateral portal, and ossicles were removed piece by piece. Talar tilt angles and anterior displacements were examined and compared before and after surgery by use of stress radiographs. Japanese Society for Surgery of the Foot (JSSF) ankle/hindfoot scales were assessed pre and postoperatively. RESULTS: All patients recovered their original levels of activity. The mean talar tilt angle changed from 6.1 degrees +/- 2.4 degrees preoperatively to 6.0 degrees +/- 1.8 degrees postoperatively (p = 0.93), and the mean anterior displacement changed from 5.9 +/- 1.7 mm preoperatively to 6.1 +/- 2.0 mm postoperatively (p = 0.42). Average JSSF ankle/hindfoot scale improved from 77.6 +/- 2.6 points preoperatively to 97.2 +/- 5.2 points postoperatively (p < 0.01). CONCLUSIONS: Arthroscopic excision of separated ossicles of the lateral malleolus achieved good results with minimum incisions, and relatively early resumption of daily and sports activity was possible. However, when the ossicles were embedded within the fibers of the anterior talofibular ligament, it was impossible to avoid cutting of ligament fibers. To reduce the possibility of ligament dysfunction, we believe postoperative treatment should conform to the accepted method for treatment of acute ankle sprains. PMID- 23728894 TI - Identification of unsafe human induced pluripotent stem cell lines using a robust surrogate assay for pluripotency. AB - Human induced pluripotent stem cells (hiPSC) have the potential to generate healthy cells and tissues for the study and medical treatment of a large number of diseases. The utility of putative hiPSC-based therapies is constrained by a lack of robust quality-control assays that address the stability of the cells or their capacity to form teratomas after differentiation. Here we report that virally derived hiPSC, but not human embryonic stem cells (hESC) or hiPSC derived using episomal nonintegrating vectors, exhibit a propensity to revert to a pluripotent phenotype following differentiation. This instability was revealed using our published method to identify pluripotent cells undergoing very early stage differentiation in standard hESC cultures, by fluorescence activated cell sorting (FACS) based on expression of the cell surface markers TG30 (CD9) and GCTM-2. Differentiated cells cultured post-FACS fractionation from virally derived hiPSC lines reacquired immunoreactivity to TG30 (CD9) and GCTM-2, formed stem cell-like colonies, and re-expressed canonical pluripotency markers. Furthermore, differentiated cells from pluripotency-reverting hiPSC lines generated teratomas in immunocompromised mice, raising concerns about their safety in downstream applications. In contrast, differentiated cell populations from hESC and episomally derived hiPSC did not show any of these abnormalities. Our assays may be used to identify "unsafe" hiPSC cell lines and this information should be considered when selecting hiPSC lines for clinical use and indicate that experiments using these "unsafe" hiPSC lines should be interpreted carefully. PMID- 23728895 TI - Transoral videolaryngoscopic surgery for oropharyngeal, hypopharyngeal, and supraglottic cancer. AB - In this retrospective cohort study, we evaluated the oncological and functional outcomes of transoral videolaryngoscopic surgery (TOVS). Using distending laryngoscope and videolaryngoscope, wide operative field and working space could be obtained and tumor could be resected in en bloc. Sixty patients with T1, T2, and selected T3 laryngeal or pharyngeal squamous cell carcinomas (Stage I: n = 17, Stage II: n = 16, Stage III: n = 7, Stage IV: n = 20 cases) were enrolled and followed up for at least 24 months or until the patient's death. Fifty-three patients underwent initial treatment, and seven patients had recurrent cancer after chemoradiation. In principle, node-positive patients underwent a simultaneous neck dissection. Patients with multiple nodal metastases or a positive surgical margin received postoperative radiotherapy. For initial treatment, the 5-year overall survival and disease-specific survival rates were 77 and 95 %, respectively. For supraglottic and hypopharyngeal cancers, the 5 year laryngeal preservation rates were 89 and 96 %, respectively. For salvage surgery, the overall survival, disease-specific survival, and laryngeal preservation rates were 75, 75, and 80 %, respectively. The median times before patients could resume eating and swallowing a soft diet were 6 and 9 days, respectively. The patients' Functional Outcome Swallowing Scale stages were 0-2 in 93.3 % of the cases and 3 or 4 in 6.7 % of the cases. A percutaneous endoscopic gastrostomy was indicated for 1 (1.7 %) patient. Four (6.7 %) patients received transient tracheostomy. TOVS is a satisfactory and minimally invasive treatment option for laryngeal and pharyngeal cancers. PMID- 23728896 TI - Evaluation of hippocampal injury and cognitive function induced by embolization in the rat brain. AB - Embolism is responsible for at least 20% of all stroke and half of cerebral infarctions. A number of animal models have been developed to mimic thromboembolic stroke. However, little aimed directly at hippocampal damage and cognitive function. In the present study, three sizes of emboli (150-178 MUm, 74 124 MUm, and 48-74 MUm) were employed to induce thromboembolic stroke model in rats. Results showed that the diameter of the particle was critical for animal behavioral and histopathological consequences. Hematoxylin-eosin (HE) staining revealed that CA1 and CA2-3, which are two of the main hippocampal subdivisions were injured seriously, especially induced by emboli(48-74 MUm) . At 24 hr, the neurological deficit scores showed that emboli injection could cause significant neurological deficit, and the increase of neurological deficit scores correlated well to the diameter of emboli. At 60 days, emboli(150-178 MUm) and emboli(48-74 MUm) lead to obvious cognitive impairment, which correlated well to the hippocampal CA1 injury. Our research might be helpful to choose suitable size of emboli to induce animal model to research subcortical ischemia and vascular dementia. However, cognitive alterations and cerebral injury following different sizes of emboli injection in rats remains a topic for future investigation. PMID- 23728897 TI - The Salih ataxia mutation impairs Rubicon endosomal localization. AB - We previously described a new form of recessive ataxia, Salih ataxia, in a large consanguineous Saudi Arabian family with three affected children carrying a new identified mutation in the KIAA0226 gene (c.2624delC; p.Ala875ValfsX146) coding for Rubicon. The pathogenicity of such mutation remains to be identified. Hence, we address the cellular impact of Rubicon p.Ala875ValfsX146 on endosomal/lysosomal machinery on cultured cells. We confirm that Rubicon colocalizes with the late endosome marker Rab7 and demonstrate that it also colocalizes with LampI at lysosomes. The Salih ataxia mutation leads to a diffuse cytosolic distribution and mislocalized protein from the late endosomes, indicating that deletion of the diacylglycerol binding-like motif in the mutant protein interferes with normal Rubicon subcellular localization and confirming the pathogenicity of the mutation. PMID- 23728898 TI - Motor cortex excitability in acute cerebellar infarct. AB - Limited evidence to date has demonstrated changes in excitability that develops over the contralateral motor cortex after a cerebellar infarct. As such, the present study investigated changes in excitability over the contra- (contraM1) and ipsilateral motor cortices (ipsiM1), in patients with acute cerebellar infarct, to determine whether the changes may have functional relevance. Paired pulse transcranial magnetic stimulation, combined with detailed clinical assessment, was undertaken in ten patients presenting with acute unilateral cerebellar infarct. Studies were undertaken within 1 week of ictus and followed longitudinally at 3-, 6-, and 12-month periods. Comparisons were made with 15 age matched controls. Immediately following a stroke, short-interval intracortical inhibition (SICI) was significantly reduced over the contraM1 in all patients (P = 0.01), while reduced over the ipsiM1 in those with severe functional impairment (P = 0.01). Moreover, ipsiM1 SICI correlated with impairment (r = 0.69, P = 0.03), such that less SICI was observed in those patients with most impairment. Cortical excitability changes persisted over the follow-up period in the context of clinical improvement. Following an acute cerebellar infarct, excitability abnormalities develop over both motor cortices, more prominently in patients with severe functional impairment. The cortical changes, particularly over the ipsilateral motor cortex, may represent a functionally relevant plastic process that may guide future therapeutic strategies to better facilitate recovery. PMID- 23728899 TI - Dose-dependent effect of landiolol, a new ultra-short-acting beta(1)-blocker, on supraventricular tachyarrhythmias in postoperative patients. AB - BACKGROUND: beta-Adrenoceptor antagonists (beta-blockers) have been reported to be effective for regulation of heart rate (HR) and restoring sinus rhythm in postoperative atrial fibrillation and atrial flutter, as well as in the prevention of those arrhythmias after open-heart surgery. OBJECTIVES: The objectives of this study were to evaluate the dose-dependent effects of landiolol, an ultra-short-acting beta1-blocker, as well as the effectiveness and safety of the drug in suppressing supraventricular tachyarrhythmias (SVT) in postoperative patients. METHODS: Landiolol was administered as a four-dose titration regimen (LL, L, M, and H doses) to postoperative patients who developed SVT. The titration sequence began with a 1-min loading infusion at a rate of 0.015 mg/kg/min, followed by a 10-min continuous infusion at 0.005 mg/kg/min (the LL dose). Infusions at progressively higher doses followed in sequence until 20 % reduction in HR was achieved. The L dose was a 1-min loading infusion at 0.03 mg/kg/min, followed by a 10-min continuous infusion at 0.01 mg/kg/min. The M dose was a 1-min loading infusion at 0.06 mg/kg/min, followed by a 10-min continuous infusion at 0.02 mg/kg/min. The H dose was a 1-min loading infusion at 0.125 mg/kg/min, followed by a 10-min continuous infusion at 0.04 mg/kg/min. The patient was then observed for 30 min to determine the cardiovascular responses to withdrawal of the medication. After completion of this follow-up period, additional maintenance infusion for up to 6 h was permitted if considered necessary by the investigator. RESULTS: A total of 108 patients were enrolled in this study. The cumulative improvement rates (percentage of patients obtaining >=20 % reduction in HR) were 11.4, 32.4, 63.1, and 87.3 % at the LL, L, M, and H doses, respectively, demonstrating the dose-dependent effectiveness of landiolol. Additional infusion for up to 6 h was conducted in 16 patients. HR was maintained between 95.5 and 116.8 beats/min during the maintenance period (mean 259.8 min). Landiolol was generally well tolerated, although one patient with sick sinus syndrome developed an approximately 5-s cardiac arrest. CONCLUSIONS: The overall results, including those pertaining to patient safety, demonstrate that landiolol is effective and useful for the treatment of postoperative SVT. PMID- 23728900 TI - Telomerase-specific oncolytic adenovirus: antitumor effects on radiation resistant head and neck squamous cell carcinoma cells. AB - BACKGROUND: Radioresistance remains a critical issue in the use of radiotherapy for the treatment of head and neck squamous cell carcinoma (HNSCC). This study evaluated the efficacy of combination treatment with OBP-301, a telomerase specific replication-selective adenovirus, and radiotherapy in overcoming radioresistance by examining its effect on radiation-resistant HNSCC cells. METHODS: Radiation-resistant HNSCC cells were treated with OBP-301 and radiation in vitro and in an orthotopic nude mouse model in vivo and synergism was assessed. Apoptosis and expression of MRN complex, which plays a key role in DNA repair machinery, were also analyzed. RESULTS: Infection with OBP-301 was found to enhance the antitumor efficacy of radiation both in vitro and in vivo by inhibiting MRN complex expression and increasing apoptosis induction. CONCLUSION: Combined OBP-301 and radiation therapy seems to overcome radioresistance in HNSCC cells by inhibiting DNA repair machinery, and may thus be a novel therapeutic strategy for treating HNSCC. PMID- 23728901 TI - Carboligation reactions mediated by benzoylformate decarboxylase immobilized on a magnetic solid support. AB - In this study, magnetic nanoparticles (Fe3 O4 , magnetite) with immobilized metal affinity ligands (MSS) were prepared and characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), fourier transform infrared spectroscopy (FTIR), and vibrating-sample magnetometer (VSM) methods for purification and immobilization of the histidine-tagged recombinant benzoylformate decarboxylase (BFD). The MSS support was shown to be eligible for selective binding of HIS-tagged BFD by SDS-page analysis. Loading capacity of the MSS support was determined as 43.6 +/- 1.1 mg/g. The regeneration ability for protein binding was also studied. An immobilized BFD was tested to catalyze benzoin condensation and representative cross acyloin reaction. Conversion and enantiomeric excess values were comparable with that of free enzyme catalyzed reactions. PMID- 23728902 TI - Guidelines for clinical electroretinography in the dog: 2012 update. AB - The full-field, flash electroretinogram (ERG) is now a widely used test of canine retinal function for the clinical diagnosis of hereditary retinal dystrophies and other causes of retinal degeneration, assessment of retinal function in patients with opaque media, ruling out of generalized retinal diseases in patients with sudden loss of vision and in ophthalmological research, as well as in pharmaceutical and toxicological screening for deleterious side effects of drugs and other chemical compounds. In 2002, the first guidelines for clinical ERGs in this species adopted by the European College of Veterinary Ophthalmologists were published. This work provides an update of these guidelines. PMID- 23728903 TI - Report on ocular biometry of microphthalmos, retinal dystrophy, flash electroretinography, ocular coherence tomography, genetic analysis and the surgical challenge of entropion correction in a rare case of Hallermann-Streiff Francois syndrome. AB - PURPOSE: To report new aspects of the phenotype including Retinal dystrophy and surgical challenges in Hallermann-Streiff Francois syndrome (HSFS). METHODS: Detailed phenotype of a female with HSFS was evaluated including skeletal changes, comprehensive eye examination, detailed ocular biometry, electroretinography and macular Ocular coherence tomography. Surgical notes of lid surgery for entropion were reviewed. Genetic screening was also done. RESULTS: Unique Ocular biometry with electroretinography changes, macular folds and fundus changes suggestive of an unreported Retinal dystrophy in a typical patient with HSFS were noted. Surgery was challenging both due to difficulty in endotracheal intubation anaesthesia because of the dento-facial abnormalities and the skin fragility. CONCLUSION: This report provides additional information especially pigmentary retinal dystrophy, macular folds and electroretinography in HSFS. The microphthalmos had overlapping posterior segment findings usually reported with Nanophthalmos and Posterior microphthalmos. The surgical difficulties and outcomes of the rarely encountered adnexal abnormalities emphasize the need for a multi disciplinary approach for appropriate management. PMID- 23728904 TI - Prognostic value of the pretreatment serum level of cytokeratin fraction 21-1 in undifferentiated nasopharyngeal carcinoma: a study of 332 cases. AB - BACKGROUND: Prognostic value of serum cytokeratin fraction 21-1 (CYFRA 21-1) has not been fully validated for nasopharyngeal carcinoma (NPC). METHODS: Serum CYFRA 21-1 levels of 332 patients with NPC were measured before treatment, and their association with overall survival (OS), tumor-free survival (TFS), time to local recurrence (TLR), and time to distant recurrence (TDR) was studied. RESULTS: Pretreatment serum CYFRA 21-1 level of patients with classification of T1+2 , N0 , stage I+II was significantly lower than that of those with T3+4 , N1+2+3 and III+IV, respectively. Multivariate analysis showed that a high pretreatment serum level of CYFRA 21-1 and T classification were independent predictors of poor OS and TDR. A high pretreatment level of CYFRA 21-1 was an independent predictor of shorter TFS and TLR. CONCLUSION: The pretreatment serum level of CYFRA 21-1 would be a reliable biomarker to evaluate the long-term prognosis of patients with undifferentiated NPC. PMID- 23728905 TI - Diffuse Berlin nodules: unusual presentation of ocular sarcoidosis. PMID- 23728907 TI - Dentists as oral physicians: the overlooked primary health care resource. AB - The United States is currently experiencing a primary care shortage. One solution to improving health care is to increase the utilization of existing health care providers, particularly dentists, an opportunity that has been largely ignored. By employing mid-level providers for less complex procedures to deliver more accessible dental care at lower cost, dentists can redistribute tasks to their office workforce. They can then serve as oral physicians who can provide limited preventive primary care, including screening for chronic diseases, while continuing to oversee all dental care, whether provided by dentists or non dentists. Thus, they could improve the health of the US population as well as increase access to dental care at lower cost, while partially alleviating the primary care shortage by filling a need for the screening aspects of primary care. PMID- 23728906 TI - A genome-wide association study of sleep habits and insomnia. AB - Several aspects of sleep behavior such as timing, duration and quality have been demonstrated to be heritable. To identify common variants that influence sleep traits in the population, we conducted a genome-wide association study of six sleep phenotypes assessed by questionnaire in a sample of 2,323 individuals from the Australian Twin Registry. Genotyping was performed on the Illumina 317, 370, and 610K arrays and the SNPs in common between platforms were used to impute non genotyped SNPs. We tested for association with more than 2,000,000 common polymorphisms across the genome. While no SNPs reached the genome-wide significance threshold, we identified a number of associations in plausible candidate genes. Most notably, a group of SNPs in the third intron of the CACNA1C gene ranked as most significant in the analysis of sleep latency (P = 1.3 * 10 6). We attempted to replicate this association in an independent sample from the Chronogen Consortium (n = 2,034), but found no evidence of association (P = 0.73). We have identified several other suggestive associations that await replication in an independent sample. We did not replicate the results from previous genome-wide analyses of self-reported sleep phenotypes after correction for multiple testing. PMID- 23728908 TI - Correlation of 99mTc-DMSA scan with radiological and laboratory examinations in childhood acute pyelonephritis: a time-series study. AB - BACKGROUND: Urinary tract infections are one of the most common diseases in children. They may lead to hypertension and renal failure later in life. Renal scintigraphy with technetium-99m dimercaptosuccinic acid (99mTc-DMSA) is one method used to diagnose acute pyelonephritis (APN) and renal parenchymal scars. The aim of the present study was to determine the ideal time to perform a follow up 99mTc-DMSA scan to detect renal scars and also to evaluate the factors predicting the development of permanent renal damage after APN. METHODS: Sixty four children with a first episode of APN underwent a 99mTc-DMSA scan. If there were abnormal findings on this scan, another scan was performed 6 and 12 months later. RESULTS: The baseline 99mTc-DMSA scan showed cortical changes in 35 patients (54.7 %). One the 6- and 12-month follow-up scans, 25 patients (39.06 %) and 21 patients (32.8 %), respectively, had cortical lesions. In multiple logistic regressions with the final 99mTc-DMSA scan results as the dependent variable, only the age range of the patients (beta = 1.062; 95 % CI 1.014-1.113; p = 0.01) showed an independent and significant association. Gender, therapeutic delay time, ultrasonography, and voiding cystourethrogram results, as well as laboratory test results including the erythrocyte sedimentation rate, C-reactive protein level, white blood cell counts, and type of bacteria in the urine, did not show such an association (p > 0.05). CONCLUSION: There is not a significant difference between the results of 6- and 12-month 99mTc-DMSA follow-up scans. A follow-up 99mTc-DMSA scan should be performed 12 months after the acute scan to yield a more accurate diagnosis of permanent renal damage. If present, long-term follow-up of patients is necessary. PMID- 23728912 TI - Adapalene microemulsion for transfollicular drug delivery. AB - The aim of this study was to develop a microemulsion formulation of adapalene for transfollicular delivery. A pseudoternary phase diagram was developed for microemulsion consisting of oleic acid as oil phase, tween 20 as surfactant, Transcutol(r) as cosurfactant, and deionized water. Differential tape stripping and confocal laser scanning microscopy were performed to determine the penetration of microemulsion through hair follicles. Transmission electron microscopy, dynamic light scattering, polarizing light microscopy, and differential scanning calorimetry were performed to characterize the microstructures of microemulsion. The pH and viscosity of the microemulsions were also determined. Permeation studies were carried out in vitro on porcine ear skin over a period of 24 h using Franz diffusion cells. The drug penetration in the hair follicles increased from 0.109 +/- 0.03 to 0.292 +/- 0.094 MUg, as the microstructure of microemulsion shifted from oil-in-water to bi-continuous, with increase in water content of microemulsion. Confocal laser scanning microscopy images suggested that hair follicles provided the path for transfollicular permeation of adapalene microemulsion. These results suggest that microemulsion penetrated through hair follicles and are promising for transfollicular drug delivery. PMID- 23728913 TI - Loss of caspase-8 in hepatocytes accelerates the onset of liver regeneration in mice through premature nuclear factor kappa B activation. AB - The cytokine tumor necrosis factor alpha (TNF-alpha; TNF) plays a critical role early in liver regeneration following partial hepatectomy (PH). TNF stimulates at least three different pathways leading to nuclear factor kappa B (NF-kappaB) activation, apoptosis signaling by way of caspase-8 (Casp8), and activation of cJun N-terminal kinases (JNK). The present study aimed to better define the role of Casp8 during liver regeneration. We performed PH in mice lacking Casp8 specifically in hepatocytes (Casp8(Deltahepa) ) and determined their liver regeneration capacity by measuring liver mass restoration and kinetics of cell cycle progression. Casp8(Deltahepa) mice showed an accelerated onset of DNA synthesis after PH, delayed hepatocyte mitosis, but overall normal liver mass restoration. Analysis of immediate TNF-dependent signaling pathways revealed that loss of Casp8 prevents proteolytic cleavage of the receptor-interacting protein 1 (RIP1) in hepatocytes and subsequently triggers premature activation of NF-kappaB and JNK/cJun related signals. In order to define the role of NF-kappaB in this setting we blocked NF-kappaB activation in Casp8(Deltahepa) mice by concomitant inactivation of the NF-kappaB essential modulator (NEMO) in hepatocytes. Lack of NEMO largely reverted aberrant DNA synthesis in Casp8(Deltahepa) mice but resulted in incomplete termination of the regeneration process and hepatomegaly. CONCLUSION: Casp8 comprises a nonapoptotic function during liver regeneration by balancing RIP1, NF-kappaB, and JNK activation. While loss of Casp8 triggers NF kappaB activation and thus improves liver regeneration, combined loss of Casp8 and NEMO impairs a controlled regenerative response and drives hepatomegaly. PMID- 23728915 TI - T-cell epitope-dependent immune response in inbred (C57BL/6J, SJL/J, and C3H/HeN) and transgenic P301S and Tg2576 mice. AB - Alzheimer's disease is characterized by two pathological hallmarks, the intracellular deposition of hyperphosphorylated Tau protein and the extracellular deposition of Abeta1-40/42 , both being targets for immunotherapy. This study evaluates the immunogenic properties of three AD-specific B-cell epitopes (Tau229 237 [pT231/pS235], pyroGluAbeta3-8 , and Abeta37/38-42/43 ) linked to five foreign T-cell epitopes (MVFP, TT, TBC Ag85B, PvT19, and PvT53) by immunizing inbred C57BL/6J (H-2(b) ), SJL/J (H-2(s2) ), and C3H/HeN (H-2(k) ) mice. Two promising candidates with respect to MHC II restriction were selected, and two transgenic mouse models of AD, P301S (H-2(b/) (k) ) and Tg2576 (H-2(b/) (s) ) animals, were immunized with one B-cell epitope in combination with two T-cell epitopes. Responders displayed an enhanced immune response compared with wild type animals, which supports the vaccine design and the vaccination strategy. The immune response was also characterized by specific IgG subtype titers, which revealed a strong polarization toward the humoral pathway for immunization of phospho-Tau, whereas for both Abeta vaccines, a mixed cellular/humoral pathway response was observed. Despite the diversity and unpredictability of the immunogenicity of the peptide vaccines, all three peptide vaccine formulations appear to be promising constructs for future evaluation of their therapeutic properties. PMID- 23728914 TI - Infant's engagement and emotion as predictors of autism or intellectual disability in West syndrome. AB - West syndrome (WS) is a rare epileptic encephalopathy with early onset and a high risk of autistic outcome. The PreAut grid assesses this risk following WS onset by taking into account synchrony and emotion in interactions and by evaluating the baby's active desire to engage in pleasant interactions (especially the infant's early active behaviors that encourage being gazed at or kissed by the mother or to share joy with her). We followed a sample of 25 WS patients prospectively from disease onset and assessed whether the PreAut grid before 9 months, and the checklist for autism in toddlers (CHAT) at 18 and 24 months predicted autism or intellectual disability (ID) outcomes at 4 years. We found that the PreAut grid at 9 months (sensitivity = 0.83; specificity = 1) had similar prediction parameters as the CHAT at 18 months (sensitivity = 0.90; specificity = 0.83) and 24 months (sensitivity = 0.92; specificity = 1). WS patients with a positive PreAut screening at 9 months had a risk of having autism or ID at 4 years, which is 38 times that of children with a negative PreAut grid [OR = 38.6 (95 % CI 2.2-2961); p = 0.006]. We conclude that the PreAut grid could be a useful tool for the early detection of autism or ID risk in the context of WS. Further research is needed to assess the PreAut grid in other contexts (e.g. infants at high-risk for non-syndromic autism). PMID- 23728916 TI - Laparoscopic approach for retrorectal tumors. AB - BACKGROUND: Retrorectal tumors are uncommon and may represent a surgical challenge. Laparoscopic excision has been reported in very few papers. We present our experience of nine cases operated by a transabdominal laparoscopic approach, between 2005 and 2011. METHODS: There were two males and seven females with a mean age of 35 years (range 19-48). The tumors were discovered incidentally in four cases or because of nonspecific clinical signs. All patients have had an MRI preoperatively. RESULTS: Only one patient required open conversion due to a huge tumor >7 cm of diameter. Postoperative mortality was nil. One patient developed a hematoma in the pelvic area. The median hospital stay was 4.7 days (range 4-8). Final diagnostic were as follows: four schwannomas, one ganglioneuroma, two tailgut cysts, one anterior meningocele, and one paragangliomas. During the follow-up showed no recurrences, but four of nine patients developed neurologic complications as parenthesis and sciatic pain and one patient developed retrograde ejaculation. CONCLUSIONS: Our case series shows that the laparoscopic approach is a feasible and safe option. It reduces surgical trauma and offers an excellent tool for perfect visualization of the deep structures in the presacral space to minimize the vascular and neurological injuries. PMID- 23728917 TI - Black bears with longer disuse (hibernation) periods have lower femoral osteon population density and greater mineralization and intracortical porosity. AB - Intracortical bone remodeling is persistent throughout life, leading to age related increases in osteon population density (OPD). Intracortical porosity also increases with age in many mammals including humans, contributing to bone fragility and fracture risk. Unbalanced bone resorption and formation during disuse (e.g., physical inactivity) also increases intracortical porosity. In contrast, hibernating bears are a naturally occurring model for the prevention of both age-related and disuse osteoporoses. Intracortical bone remodeling is decreased during hibernation, but resorption and formation remain balanced. Black bears spend 0.25-7 months in hibernation annually depending on climate and food availability. We found longer hibernating bears demonstrate lower OPD and higher cortical bone mineralization than bears with shorter hibernation durations, but we surprisingly found longer hibernating bears had higher intracortical porosity. However, bears from three different latitudes showed age-related decreases in intracortical porosity, indicating that regardless of hibernation duration, black bears do not show the disuse- or age-related increases in intracortical porosity which is typical of other animals. This ability to prevent increases in intracortical porosity likely contributes to their ability to maintain bone strength during prolonged periods of physical inactivity and throughout life. Improving our understanding of the unique bone metabolism in hibernating bears will potentially increase our ability to develop treatments for age- and disuse related osteoporoses in humans. PMID- 23728918 TI - Rhodamine-marked bombesin: a novel means for prostate cancer fluorescence imaging. AB - The gastrin releasing peptide receptor (GRPR) has been found to be strongly expressed in various types of cancers such as prostate and breast carcinomas. The GRPR ligands gastrin releasing peptide and bombesin can play a very significant role in cancer therapy and diagnostics. In this study we synthesized unlabeled bombesin BBN along with two conjugates in which the correct bombesin (BBN-Rhd) and a mutant bombesin (mBBN-Rhd) sequence was coupled to rhodamine, a fluorescent dye. These novel rhodamine fluorescent conjugates were used to study the targeting and uptake of bombesin on a cellular level. Nine different human cell lines including both tumor and healthy cells were examined using flow cytometry and confocal laser scanning microscopy. GRPR mRNA expression analysis was performed and it was found that the receptor is highly expressed in LNCaP and PC3 cells compared to the rest of other cell lines. Competition experiments were performed to verify the receptor dependence of the labeled conjugates using unmarked bombesin. The present study is a first attempt at direct fluorescence imaging of living cells using bombesin and its target, the GRPR. A rhodamine bombesin conjugate can be used as marker to differentiate between healthy cells and malignant cells such as prostate hyperplasia and prostate carcinoma in the early detection of cancer. PMID- 23728919 TI - Vorinostat and bortezomib as third-line therapy in patients with advanced non small cell lung cancer: a Wisconsin Oncology Network Phase II study. AB - INTRODUCTION: The primary objective of this phase II trial was to evaluate the efficacy and tolerability of vorinostat and bortezomib as third-line therapy in advanced non-small cell lung cancer (NSCLC) patients. METHODS: Eligibility criteria included recurrent/metastatic NSCLC, having received 2 prior systemic regimens, and performance status 0-2. Patients took vorinostat 400 mg PO daily days 1-14 and bortezomib 1.3 mg/m2 IV day 1, 4, 8 and 11 in a 21-day cycle. Primary endpoint was 3-month progression free survival (3m-PFS), with a goal of at least 40 % of patients being free of progression at that time point. This study followed a two-stage minimax design. RESULTS: Eighteen patients were enrolled in the first stage. All patients had two prior lines of treatment. Patients received a median of two treatment cycles (range: 1-6) on study. There were no anti-tumor responses; stable disease was observed in 5 patients (27.8 %). Median PFS was 1.5 months, 3m-PFS rate 11.1 %, and median overall survival 4.7 months. The most common grade 3/4 toxicities were thrombocytopenia and fatigue. Two patients who had baseline taxane-related grade 1 peripheral neuropathy developed grade 3 neuropathy. The study was closed at its first interim analysis for lack of efficacy. CONCLUSIONS: Bortezomib and vorinostat displayed minimal anti-tumor activity as third-line therapy in NSCLC. We do not recommend this regimen for further investigation in unselected patients. PMID- 23728920 TI - Liposarcoma of the head and neck: analysis of 318 cases with comparison to non head and neck sites. AB - BACKGROUND: Liposarcomas are rare in the head and neck. We analyzed a large series of head and neck liposarcomas to determine features unique to the head and neck. METHODS: Three hundred eighteen liposarcomas of the head and neck were contrasted with 9485 liposarcomas of other regions using the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: Head and neck liposarcomas were most commonly subcutaneous (81.%), low grade (70.1%; p < .001), and early stage (p < .001). They were more likely to be treated with surgery alone, whereas conventional liposarcomas were more likely to receive adjuvant radiation (p < .001). Treatment that included surgery had better survival than radiation therapy alone (p = .008). Overall, liposarcomas of the head and neck had significantly higher disease-specific survival (DSS) and overall survival (OS) than conventional liposarcomas (p < .001). CONCLUSION: Liposarcomas of the head and neck are usually early stage, low grade, and with fewer nodal metastases than conventional liposarcomas. DSS and OS were significantly greater for liposarcomas of the head and neck. PMID- 23728921 TI - Treatment as prevention: the breaking of taboos is required in the fight against hepatitis C among people who inject drugs. PMID- 23728922 TI - Luteal phase and symptom-onset dosing of SSRIs/SNRIs in the treatment of premenstrual dysphoria: clinical evidence and rationale. AB - Premenstrual dysphoria (PMD) affects 3-8 % of women in their reproductive years worldwide. This paper summarizes the studies establishing the efficacy of continuous, luteal phase, and symptom-onset dosing of selective serotonin reuptake inhibitors (SSRIs) and dual serotonin and norepinephrine reuptake inhibitors (SNRIs) in treating women with PMD. The evidence indicates that for some women, symptom-onset dosing with escitalopram, fluoxetine, and paroxetine controlled release (CR) is as effective as continuous or luteal phase dosing. The wide range of clinical efficacy of SSRIs/SNRIs suggests that they exert their therapeutic effect through multiple pathways. This paper offers a few alternative mechanisms of action to explain the rapid response to SSRIs/SNRIs in women with PMD. PMID- 23728923 TI - Functional hemitongue reconstruction using innervated supraclavicular fasciocutaneous island flaps with the cervical plexus and reinnervated supraclavicular fasciocutaneous island flaps with neurorrhaphy of the cervical plexus and lingual nerve. AB - BACKGROUND: The purpose of this study was to evaluate tongue function in patients with tongue cancer after reconstruction with innervated supraclavicular fasciocutaneous island flaps (iSFIFs) with the cervical plexus (iSFIFs-SPN) or reinnervated SFIFs with neurorrhaphy of the cervical plexus and lingual nerve (rSFIFs-SPN-LN). METHODS: Forty-two tongue defects were reconstructed using iSFIFs-SPN and rSFIFs-SPN-LN. Two-point discrimination tests revealed a significant difference on the dorsal and ventral hemitongue reconstructed using rSFIFs-SPN-LN from control values. RESULTS: No statistical difference in swallowing, speech, or esthetic outcome was found in the iSFIFs-SPN or the rSFIFs SPN-LN. A significant difference was noted in the dorsal aspect and ventral surface of hemitongues reconstructed with rSFIFs-SPN-LN from control values and between 6 and 12 months. CONCLUSION: Sensation after hemitongue reconstruction with the iSFIF-SPN and the neurorrhaphy of the cervical plexus nerve was sutured to the lingual nerve, sensation after hemitongue reconstruction with the rSFIF SPN-LN approached normal 6 to12 months postoperatively. PMID- 23728924 TI - Impact of intravascular ultrasound on the long-term clinical outcomes in the treatment of coronary ostial lesions. AB - OBJECTIVES: To evaluate the long-term outcomes of patients with ostial lesions who underwent percutaneous coronary intervention (PCI) with and without the use of intravascular ultrasound (IVUS). BACKGROUND: A higher rate of adverse cardiac events is associated with PCI of ostial lesions as compared with nonostial disease. METHODS: From 7/2002 to 8/2010, 225 patients with 233 coronary ostial lesions underwent PCI with (n = 82) and without (n = 143) IVUS guidance. Ostial lesions included both native aorto-ostial or major coronary vessel (left anterior descending, left circumflex, and ramus intermedius) lesions. Clinical outcomes [cardiovascular death, myocardial infarction (MI), and target lesion revascularization (TLR)] at a mean follow-up of 4.2 +/- 2.5 years were compared between patients undergoing PCI of an ostial lesion with and without use of IVUS using univariate and propensity score adjusted analyses. RESULTS: Aorto-ostial lesions (n = 109) comprised 47% of lesions, whereas the remaining lesions (53%) involved major coronary vessels. After propensity score adjustment, IVUS use was associated with lower rates of the composite of cardiovascular death, MI, or TLR (HR 0.54, 95% CI 0.29-0.99; P = 0.04), composite MI or TLR (HR 0.39, 95% CI 0.18 0.83; P = 0.01), and MI (HR 0.31, 95% CI 0.11-0.85; P = 0.02) as compared with no IVUS. The use of IVUS was also associated with a trend towards a lower rate of TLR (HR 0.42, 95% CI 0.17-1.02; P = 0.06). CONCLUSIONS: PCI of coronary ostial lesions with the use of IVUS was associated with significantly lower rates of adverse cardiac events. PMID- 23728925 TI - Is the connection between religiosity and psychological functioning due to religion's social value? A failure to replicate. AB - Increasingly, religion and spirituality has been tied to well-being. However, the mediators are likely multifold, contextually dependent, and remain unclear. A recent report suggested that this is due to religion's social value and presented results indicating that religiosity was more strongly related to psychological adjustment within countries with higher mean religiosity. Effect sizes were small, and given previous research suggesting other more proximal mediators, it was my hypothesis that these findings would not be replicated. Analysis of data from the European Social Survey revealed no significant interactions between country-level religiosity and individual religiosity in predicting psychological well-being. These conflicting findings point to the nuanced nature of the religion-health relationship and suggest that this correlation is unlikely to be due to social valuation. Studies using cursory measures are likely to explain only a small proportion of the variance, yield contradictory findings, and fail to significantly enhance theory in this domain. PMID- 23728926 TI - A limited survey of aflatoxin B1 contamination in Indonesian palm kernel cake and copra meal sampled from batches. AB - Samples from large (100-200 tons) batches of palm kernel cake (PKC, n = 20) and copra meal (CM, n = 13) were collected at production facilities of four Indonesian feed mill manufacturers and analysed for aflatoxin B1 (AFB1) by ELISA. Recoveries using spiked samples ranged from 86 to 113%, with relative standard deviations of <9% (PKC) and <6% (CM). All batches were positive for AFB1: in PKC, at levels of 5.8-93.1 MUg/kg (mean 49 MUg/kg), and in CM, at levels of 1.1-147 MUg/kg (mean 38.1 MUg/kg). AFB1 levels were, in most batches, below the maximum level (100 MUg/kg) recommended by the National Standardisation Agency, Republic of Indonesia. However, about half of the batches exceeded both the European Union and USA regulations for AFB1 in animal feed. In conclusion, serious efforts are necessary to control production, storage and shipment of palm kernel cake and copra meal for feed purposes, and clearly not only for products intended for export but also to reduce AFB1 levels in domestic Indonesian feed. PMID- 23728927 TI - Matching-to-sample performance is better analyzed in terms of a four-term contingency than in terms of a three-term contingency. AB - Four pigeons performed a simultaneous matching-to-sample (MTS) task involving two samples and two comparisons that differed in their pixel density and luminance. After a long history of reinforcers for correct responses after both samples, 15 conditions arranged either continuous reinforcement of correct responses after Sample 1 and extinction for all responses after Sample 2, or vice versa. The sample after which correct responses were reinforced alternated across successive conditions. The disparity between the samples and the disparity between the comparisons were varied independently across conditions in a quasifactorial design. Contrary to predictions of extant quantitative models, which assume that MTS tasks involve two 3-term contingencies of reinforcement, matching accuracies were not at chance levels in these conditions, comparison-selection ratios differed after the two samples, and effects on matching accuracies of both sample disparity and comparison disparity were observed. These results were, however, consistent with ordinal and sometimes quantitative predictions of Jones' (2003) theory of stimulus and reinforcement effects in MTS tasks. This theory asserts that MTS tasks involve four-term contingencies of reinforcement and that any tendency to select one comparison more often than the other over a set of trials reflects meaningful differences between comparison-discrimination accuracies after the two samples. PMID- 23728928 TI - Efficient inkjet printing of graphene. AB - An efficient and mature inkjet printing technology is introduced for mass production of coffee-ring-free patterns of high-quality graphene at high resolution (unmarked scale bars are 100 MUm). Typically, several passes of printing and a simple baking allow fabricating a variety of good-performance electronic devices, including transparent conductors, embedded resistors, thin film transistors, and micro-supercapacitors. PMID- 23728929 TI - Parenting an infant with a congenital anomaly: An exploratory study on patterns of adjustment from diagnosis to six months post birth. AB - The present study examined psychological adjustment in parents of infants with congenital anomalies (CAs), focusing on the interval from the disclosure of the diagnosis to six months after the infant's birth and considering the effects of the parent's gender and the timing of diagnosis (pre- vs postnatal). Within-group diversity was also examined by identifying distinct patterns of individual adjustment over time. Parents of 43 infants (43 mothers and 36 fathers) with a pre- or postnatal diagnosis of a CA answered questionnaires assessing psychological distress and quality of life one month after the disclosure of the diagnosis and six months after the infant's birth. Results showed a significant reduction in psychological distress and a significant increase in physical quality of life over time, for both parents, regardless of the timing of diagnosis. In all, 57% of parents presented a pattern of recovery from diagnosis to six months post birth and 26.6% presented a pattern of resilience. However, 15.2% of parents showed chronic adjustment difficulties. Findings suggest that most parents tend to adjust to their infant's CA, although some experienced difficulties and should be targeted for specialised counselling. Both members of the couple should be acknowledged, as both experience similar patterns of adjustment. PMID- 23728930 TI - Predictors of mortality in childhood burns: an 8-year review. AB - This study aims to analyze the epidemiological characteristics and predictors of mortality from burn injuries in childhood patients admitted to our hospital during an eight-year period. The medical records of acute childhood burn patients were reviewed retrospectively. All variables thought to be associated with mortality were entered in a multiple binary logistic regression model (method = stepwise). The magnitude of risk was measured by the odds ratio, and the 95% confidence interval was estimated. A total of 2269 acute childhood burn patients were admitted during the study period. A total of 86 (3.8%) children died due to burn injuries. Deaths were seen 1.849 times more in males than in females. According to the 1%-10% total body surface area (TBSA) burned group, mortality occurred 121.116 times more in the >41% TBSA burned group. Most burn injuries can be avoided by keeping children away from hazardous and dangerous environments. Also, requiring a multidisciplinary management in these patients, quality of care services given by physicians and nurses certainly will create a positive impact on patients' outcomes. PMID- 23728931 TI - Identifying families' reasons for engaging or not engaging with childhood obesity services: A qualitative study. AB - The rise in childhood obesity in recent years has been accompanied by a number of initiatives to treat the condition. However, such interventions have often been characterised by poor levels of adherence to treatment and corresponding high attrition rates. This article presents data drawn from qualitative interviews to examine families' reasons for engaging or not engaging with child obesity services. Interviews took place with 15 families whose children attended a UK based childhood obesity service and 17 families whose children withdrew from treatment. Our data suggested that involvement of children in the decision to attend a clinic was important in building engagement. Specialist diet and exercise advice tailored to individual family circumstance encouraged clinic engagement, but failed to engage some families who felt their personal circumstances had not been considered sufficiently. The clinic environment was viewed as not age appropriate for some children and did not match the expectations of some families. Our findings highlight the value of involving children in the decision to attend an obesity service and practitioners should, as much as possible, tailor advice to the circumstances of each family. Providing clinics for particular age groups in terms of environment and timing may enhance engagement with services. PMID- 23728932 TI - Physical activity in American schools and body mass index percentile. AB - The international physical inactivity epidemic among children has contributed to child obesity. Schools can be an effective source of physical activity opportunity. A cross-sectional sample of 1306 American children was drawn from the Panel Study of Income Dynamics - Child Development Supplement, 2007. The aim of this study was to determine the role of in-school physical activity on body mass index (BMI) percentile among middle and high school-aged children. Multinomial logistic regression was used to assess the associations between the independent variable, physical activity, and the dependent variable, BMI percentile. After adjusting for covariates, children who had no physical activity during physical education (PE) were much more likely to be obese than normal weight in comparison with those who met the US national requirements (odds ratio = 1.58, confidence interval = 1.14, 2.20). This study suggests that meeting US national guidelines for PE-related physical activity may be effective in preventing obesity. PMID- 23728933 TI - Intention of pregnant women to exclusively breastfeed their infants: The role of beliefs in the theory of planned behaviour. AB - This study was aimed at identifying behavioural, normative and control belief influencing intention to practise exclusive breastfeeding among pregnant women in Malaysia. An interviewer-guided questionnaire assessing behavioural, normative and control belief was developed based on the findings elicited from focus group discussions. Intention referred to the respondent's intended duration of exclusive breastfeeding, which was measured in weeks. Bivariate correlational analysis, linear regression analysis and independent t test comparing intenders and non-intenders were conducted to identify the composite belief measures and individual beliefs significantly influencing intention. Composite measures of all the beliefs were significantly correlated with intention, but injunctive normative belief and behavioural belief were the only significant factors identified from linear regression analysis. The respondents agreed to comply with four referents of their mother, husband, nurses and mother-in-law. Non-intenders believed that those referents would oppose them practising exclusive breastfeeding for six months. The behavioural belief concerning difficulty to leave the infant significantly differentiated intenders from non-intenders. Exclusive breastfeeding promotion should include the woman's mother, husband and mother-in-law. Nurses should provide accurate and complete information related to breastfeeding practise. Providing support for women to continue the practise even though separated from their infants may improve their intention and practise of exclusive breastfeeding. PMID- 23728935 TI - Collagen fiber alignment and maximum principal strain in the glenohumeral capsule predict location of failure during uniaxial extension. AB - The glenohumeral joint is frequently dislocated resulting in injury to the glenohumeral capsule. Repair techniques that focus on restoring the capsule after dislocation to re-establish its stabilizing function could benefit from predictions of the location of failure in this continuous sheet of tissue with a random collagen fiber alignment in the unloaded state. Therefore, the objective of this study was to determine the collagen fiber alignment and maximum principal strain in all regions of the capsule during uniaxial extension to failure and to determine whether these parameters could predict the location of tissue failure. Collagen fiber alignment, quantified using a small-angle light-scattering device, and maximum principal strain in the capsule were determined at 5% increments of elongation until tissue failure. A contingency table analyzed with Fischer's exact test demonstrated that peak collagen fiber alignment, represented by the normalized orientation index (p < 0.001) and maximum principal strain (p < 0.001), is significant in predicting location of failure. The direct correlation between the maximum principal strain and collagen fiber alignment measured prior to failure to the location of tissue failure suggests these parameters can be used as a predictive tool to help locate the areas of the glenohumeral capsule that are susceptible to failure. In the future, changes in collagen fiber alignment following injury could be used to develop a constitutive model for injured capsular tissue. PMID- 23728934 TI - Polygenic transmission and complex neuro developmental network for attention deficit hyperactivity disorder: genome-wide association study of both common and rare variants. AB - Attention-deficit hyperactivity disorder (ADHD) is a complex polygenic disorder. This study aimed to discover common and rare DNA variants associated with ADHD in a large homogeneous Han Chinese ADHD case-control sample. The sample comprised 1,040 cases and 963 controls. All cases met DSM-IV ADHD diagnostic criteria. We used the Affymetrix6.0 array to assay both single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Genome-wide association analyses were performed using PLINK. SNP-heritability and SNP-genetic correlations with ADHD in Caucasians were estimated with genome-wide complex trait analysis (GCTA). Pathway analyses were performed using the Interval enRICHment Test (INRICH), the Disease Association Protein-Protein Link Evaluator (DAPPLE), and the Genomic Regions Enrichment of Annotations Tool (GREAT). We did not find genome-wide significance for single SNPs but did find an increased burden of large, rare CNVs in the ADHD sample (P = 0.038). SNP-heritability was estimated to be 0.42 (standard error, 0.13, P = 0.0017) and the SNP-genetic correlation with European Ancestry ADHD samples was 0.39 (SE 0.15, P = 0.0072). The INRICH, DAPPLE, and GREAT analyses implicated several gene ontology cellular components, including neuron projections and synaptic components, which are consistent with a neurodevelopmental pathophysiology for ADHD. This study suggested the genetic architecture of ADHD comprises both common and rare variants. Some common causal variants are likely to be shared between Han Chinese and Caucasians. Complex neurodevelopmental networks may underlie ADHD's etiology. PMID- 23728936 TI - Vitamin D bioavailability and catabolism in pediatric chronic kidney disease. AB - BACKGROUND: Vitamin D-binding protein (DBP) and catabolism have not been examined in the clinical setting of childhood chronic kidney disease (CKD). METHODS: The concentrations of serum vitamin D {25-hydroxyvitamin D [25(OH)D], 1,25 dihydroxyvitamin D [1,25(OH)(2)D], 24,25-dihydroxyvitamin D [24,25(OH)(2)D]}, DBP, intact parathyroid hormone (iPTH), and fibroblast growth factor-23 (FGF23) were measured in 148 participants with CKD stages 2-5D secondary to congenital anomalies of the kidney/urinary tract (CAKUT), glomerulonephritis (GN), or focal segmental glomerulosclerosis (FSGS). Free and bioavailable 25(OH)D concentrations were calculated using total 25(OH)D, albumin, and DBP concentrations. RESULTS: The concentrations of all vitamin D metabolites were lower with more advanced CKD (p < 0.001) and glomerular diagnoses (p <= 0.002). Among non-dialysis participants, DBP was lower in FSGS versus other diagnoses (FSGS-dialysis interaction p = 0.02). Winter season, older age, FSGS and GN, and higher FGF23 concentrations were independently associated with lower concentrations of free and bioavailable 25(OH)D. Black race was associated with lower total 25(OH)D and DBP, but not free or bioavailable 25(OH)D. 24,25(OH)(2)D was the vitamin D metabolite most strongly associated with iPTH. Lower 25(OH)D and higher iPTH concentrations, black race, and greater CKD severity were independently associated with lower levels of 24,25(OH)(2)D, while higher FGF23 concentrations and GN were associated with higher levels of 24,25(OH)(2)D. CONCLUSIONS: Children with CKD exhibit altered catabolism and concentrations of DBP and free and bioavailable 25(OH)D, and there is an important impact of their underlying disease. PMID- 23728937 TI - Differential effects of antipsychotics on the development of rat oligodendrocyte precursor cells exposed to cuprizone. AB - Cuprizone (CPZ) is a copper-chelating agent and has been shown to induce white matter damage in mice and rats. The compromised white matter and oligodendrocytes (OLs) respond to some antipsychotics in vivo. However, little is known about the effects of antipsychotics on cultured OLs in the presence of CPZ. The aim of this study was to examine effects of some antipsychotics on developing OLs in the presence of CPZ. Oligodendrocyte progenitor cells (OPCs) were prepared from rat embryos; OLs at different developing stages were labeled with specific antibodies; levels of CNP and MBP proteins in mature OLs were assessed by Western blot analysis; malondialdehyde (MDA) levels and activity of catalase were evaluated as well for an assessment of oxidative stress and antioxidative status. In immunofluorescent staining, CPZ was shown to inhibit the differentiation of cultured OPCs into O4-positive cells, reduce the maturation of O4-positive cells into CNP- and MBP-positive cells, and decrease levels of CNP and MBP in mature OLs. These inhibitory effects of CPZ were ameliorated by clozapine and quetiapine (QUE), but not by haloperidol and olanzapine. Further experiments were performed to explore the mechanism of the protective effects of QUE. QUE attenuated the decreases in CNP and MBP in CPZ-treated OLs, and blocked the CPZ-induced increase in MDA and decrease in catalase activity in cultured OLs. These results are relevant to the pathophysiology and treatment of schizophrenia considering the aberrant white matter development and evidence suggesting the derangement of the oxidant and antioxidant defense system in some of the patients with schizophrenia. PMID- 23728938 TI - Periostin mediates the increased pro-angiogenic activity of gastric cancer cells under hypoxic conditions. AB - This study was conducted to investigate the biological role of periostin in gastric cancer (GC) under hypoxia. Western blot analysis revealed that along with an upregulation of hypoxia-inducible factor-1alpha, there was a time-dependent induction of periostin in MKN-45 cells under hypoxia (2% O2 ), increasing by eightfold as compared to normoxic cells. Pretreatment with 30 uM PD98059, an inhibitor of ERK1/2, significantly reduced hypoxia-stimulated periostin expression (P < 0.01). Periostin knockdown in MKN-45 cells was achieved by specific small interfering RNA (siRNA). The conditioned medium from periostin siRNA-transfected MKN-45 cells induced significantly less (P < 0.01) endothelial tube formation than control siRNA-transfected cells. Additionally, periostin silencing markedly decreased the mRNA expression and secretion of vascular endothelial growth factor (VEGF) in hypoxic MKN-45 cells. Thus, our data suggest that periostin is a hypoxia-response gene and mediates a cross talk between GC and endothelial cells under hypoxia, partially through regulation of the VEGF expression. PMID- 23728939 TI - Preclinical analysis of resistance and cross-resistance to low-dose metronomic chemotherapy. AB - Low-dose metronomic chemotherapy is an emerging form of chemotherapy with distinct mechanisms of action from conventional chemotherapy (e.g., antiangiogenesis). Although developed to overcome resistance to conventional chemotherapy, metronomic chemotherapy is subject to resistance on its own. However, there is a paucity of information on mechanisms of resistance, on cross resistance between metronomic regimens using different cytotoxic drugs, and on cross-resistance between metronomic versus conventional chemotherapy, or versus targeted antiangiogenic therapy. Herein we show that PC-3 human prostate cancer xenografts were sensitive to both metronomic cyclophosphamide and metronomic docetaxel, but resistant to metronomic topotecan. Conventional docetaxel was only moderately active in parental PC-3 and in metronomic cyclophosphamide resistant PC-3 tumors. However, in metronomic cyclophosphamide resistant PC-3 tumors combining conventional docetaxel or bolus cyclophosphamide therapy with continued metronomic cyclophosphamide was superior to each treatment alone. Furthermore, bevacizumab had single-agent activity against metronomic cyclophosphamide resistant PC-3 tumors. Microarray analyses identified altered regulation of protein translation as a potential mechanism of resistance to metronomic cyclophosphamide. Our results suggest that sensitivity to metronomic chemotherapy regimens using different cytotoxic drugs not only depends on shared mechanisms of action such as antiangiogenesis, but also on as yet unknown additional antitumor effects that appear to be drug-specific. As clinically observed with targeted antiangiogenic agents, the continued use of metronomic chemotherapy beyond progression may amplify the effects of added second-line therapies or vice versa. However, metronomic chemotherapy is no different from other systemic therapies in that predictive biomarkers will be essential to fully exploit this novel use of conventional chemotherapeutics. PMID- 23728940 TI - Bladder preservation therapy for muscle-invading bladder cancers on Radiation Therapy Oncology Group trials 8802, 8903, 9506, and 9706: vascular endothelial growth factor B overexpression predicts for increased distant metastasis and shorter survival. AB - BACKGROUND: From 1988 to 1999, the Radiation Therapy Oncology Group (RTOG) conducted four prospective studies (8802, 8903, 9506, 9706) of patients with clinical stage T2-4a muscle-invasive bladder cancer. Treatment was selective bladder preservation using transurethral surgery (TURBT) plus cisplatin-based induction and consolidation chemoradiation regimens, reserving radical cystectomy for invasive tumor recurrence. We investigated vascular endothelial growth factor (VEGF) pathway biomarkers in this unique clinical dataset (median follow-up of 3.1 years). METHODS: A total of 43 patients with tissue available from the entry TURBT were included in this analysis. Expression of VEGF ligands and receptors were quantified and scored by the AQUA platform (HistoRX, now Genoptix, Carlsbad, CA) and analyzed after median split. RESULTS: VEGF expression levels were not associated with increased rates of complete response to induction chemoradiation. Higher levels of cytoplasmic VEGF-B, VEGF-C, and VEGF-R2 were associated with decreased overall survival rates. The 3-year overall survival estimates for high and low expressers were 43.7% and 75% for VEGF-B cytoplasm (p = .01), 40.2% and 86.7% for VEGF-C cytoplasm (p = .01), and 49.7% and 66.7% for VEGF-R2 cytoplasm (p = .02). Higher expression levels of cytoplasm VEGF-B were associated with higher rates of distant failure (p = .01). CONCLUSIONS: Although VEGF ligands and receptors do not appear to be associated with complete response to induction chemoradiation for muscle-invasive bladder cancer, we report significant associations with overall survival and distant failure for certain VEGF family members. PMID- 23728941 TI - Genomics of squamous cell lung cancer. AB - Approximately 30% of patients with non-small cell lung cancer have the squamous cell carcinoma (SQCC) histological subtype. Although targeted therapies have improved outcomes in patients with adenocarcinoma, no agents are currently approved specifically for use in SQCC. The Cancer Genome Atlas (TCGA) recently published the results of comprehensive genomic analyses of tumor samples from 178 patients with SQCC of the lung. In this review, we briefly discuss key molecular aberrations reported by TCGA and other investigators and their potential therapeutic implications. Carefully designed preclinical and clinical studies based on these large-scale genomic analyses are critical to improve the outcomes of patients with SQCC of lung in the near future. PMID- 23728942 TI - Enhancement of head and neck squamous cell carcinoma proliferation, invasion, and metastasis by tumor-associated fibroblasts in preclinical models. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) has had little improvement in mortality rates in decades. A clearer understanding of the HNSCC tumor microenvironment will aid in finding more effective targeted therapies for this disease. Tumor-associated fibroblasts (TAFs) are the largest stromal cellular components of the tumor microenvironment in HNSCC. METHODS: We isolated TAFs from clinical HNSCC cases and propagated in vitro. The effects of TAF secreted paracrine factors on in vitro HNSCC migration, invasion, and proliferation was assessed. The effect of TAFs on HNSCC growth and metastases was determined in an orthotopic floor-of-the-mouth tumor model. RESULTS: TAF conditioned media increased HNSCC cell migration, invasion, and proliferation. TAFs increased HNSCC tumor growth and metastases in vivo. CONCLUSION: TAFs play a major role in increasing tumor growth and metastasis in HNSCC. Targeting the tumor stroma may be important to reduce the rate of HNSCC metastasis. PMID- 23728943 TI - Identification of driver genes in hepatocellular carcinoma by exome sequencing. AB - Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma (HCC). As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in HCC. We performed whole-exome sequencing on 87 HCCs and matched normal adjacent tissues to an average coverage of 59*. The overall mutation rate was roughly two mutations per Mb, with a median of 45 nonsynonymous mutations that altered the amino acid sequence (range, 2-381). We found recurrent mutations in several genes with high transcript levels: TP53 (18%); CTNNB1 (10%); KEAP1 (8%); C16orf62 (8%); MLL4 (7%); and RAC2 (5%). Significantly affected gene families include the nucleotide-binding domain and leucine-rich repeat-containing family, calcium channel subunits, and histone methyltransferases. In particular, the MLL family of methyltransferases for histone H3 lysine 4 were mutated in 20% of tumors. CONCLUSION: The NFE2L2-KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of HCC. PMID- 23728944 TI - Successful nonsurgical treatment of esophagopericardial fistulas after atrial fibrillation catheter ablation: a case series. AB - BACKGROUND: Esophageal perforations are a rare but devastating complication of atrial fibrillation catheter ablation. Rapid treatment is crucial to avoid permanent disabilities and death. Surgical treatment is considered the treatment of choice. Alternatively, single case reports describe successful esophageal stenting, but others discourage this approach because of fatal consequences. METHODS AND RESULTS: We present 3 patients who developed esophagopericardial fistulas after radiofrequency catheter ablation of atrial fibrillation. Diagnosis and management with pericardial drainage and esophageal stenting, as well as long term follow-up are described. Esophagopericardial fistulas occurred 26, 9, and 18 days after the ablation procedure. Symptoms leading to admission were recurrence of atrial fibrillation (n=1), elective control endoscopy for thermal lesion (n=1), and pain with swallowing (n=1). Computed tomography revealed esophagopericardial fistulas with pericardial effusion in all patients, while contrast leakage and air in the left atrium could be excluded. Broad-spectrum antibiotics were initialized, and minimally invasive pericardial drainage and esophageal stenting were performed. Stent dislocation occurred in 2 patients and was resolved by repositioning and clipping of the proximal stent end. After 45, 22, and 28 days, respectively, fistulas appeared closed and stents were removed. During follow-up, no embolic or septic events occurred. However, 2 patients underwent dilation of symptomatic esophageal stenosis in the formerly stented region. CONCLUSIONS: An early minimally invasive approach consisting of pericardial drainage and esophageal stenting proved effective in treating patients with esophagopericardial fistulas. However, constant interdisciplinary communication and attention is needed to recognize and manage potential evolving complications promptly. PMID- 23728945 TI - Left cardiac sympathetic denervation in long QT syndrome: analysis of therapeutic nonresponders. AB - BACKGROUND: Long QT syndrome (LQTS) is a potentially lethal but highly treatable cardiac channelopathy. Treatment options include pharmacotherapy, device therapy, and left cardiac sympathetic denervation (LCSD). Here, we sought to determine the characteristics of LQTS patients who have had >=1 LQTS-related breakthrough cardiac event (BCE) after LCSD. METHODS AND RESULTS: We performed retrospective chart review for 52 consecutive patients (24 males; mean age at diagnosis, 10.0+/ 10 years; mean QTc, 528+/-74 ms) with LQTS who underwent LCSD between 2005 and 2010 (mean age at LCSD, 14.1+/-10 years) and have been followed up for 3.6+/-1.3 years. A BCE was defined as either (1) an appropriate ventricular fibrillation terminating implantable cardioverter defibrillator shock or (2) arrhythmogenic syncope, seizures, or aborted cardiac arrest after LCSD. Thirty-three patients (61%) had LCSD as primary prevention because of either high-risk assessment or beta-blocker intolerance. So far, 12 of 52 (23%) patients (7 males) have experienced >=1 BCE post LCSD. The clinical phenotype of patients with BCEs was significantly more severe than patients without a BCE. No BCEs were seen in patients undergoing LCSD for beta-blocker intolerance (0/12 versus 17/40; P<0.001). CONCLUSIONS: Although a marked reduction in number of cardiac events is usually seen after LCSD, ~50% of high-risk LQTS patients have experienced >=1 post-LCSD breakthrough. Therefore, LCSD must not be viewed as curative or as an alternative in implantable cardioverter defibrillator for high-risk patients. Prophylactic LCSD may provide another option to counter a suboptimal quality of life resulting from medication-related side effects. PMID- 23728947 TI - Accelerated partial-breast irradiation using intensity-modulated proton radiotherapy: do uncertainties outweigh potential benefits? AB - OBJECTIVE: Passive scattering proton beam (PSPB) radiotherapy for accelerated partial-breast irradiation (APBI) provides superior dosimetry for APBI three dimensional conformal photon radiotherapy (3DCRT). Here we examine the potential incremental benefit of intensity-modulated proton radiotherapy (IMPT) for APBI and compare its dosimetry with PSPB and 3DCRT. METHODS: Two theoretical IMPT plans, TANGENT_PAIR and TANGENT_ENFACE, were created for 11 patients previously treated with 3DCRT APBI and were compared with PSPB and 3DCRT plans for the same CT data sets. The impact of range, motion and set-up uncertainties as well as scanned spot mismatching between fields of IMPT plans was evaluated. RESULTS: IMPT plans for APBI were significantly better regarding breast skin sparing (p<0.005) and other normal tissue sparing than 3DCRT plans (p<0.01) with comparable target coverage (p=ns). IMPT plans were statistically better than PSPB plans regarding breast skin (p<0.002) and non-target breast (p<0.007) in higher dose regions but worse or comparable in lower dose regions. IMPT plans using TANGENT_ENFACE were superior to that using TANGENT_PAIR in terms of target coverage (p<0.003) and normal tissue sparing (p<0.05) in low-dose regions. IMPT uncertainties were demonstrated for multiple causes. Qualitative comparison of dose-volume histogram confidence intervals for IMPT suggests that numeric gains may be offset by IMPT uncertainties. CONCLUSION: Using current clinical dosimetry, PSPB provides excellent dosimetry compared with 3DCRT with fewer uncertainties compared with IMPT. ADVANCES IN KNOWLEDGE: As currently delivered in the clinic, PSPB planning for APBI provides as good or better dosimetry than IMPT with less uncertainty. PMID- 23728948 TI - Bowtie filtration for dedicated cone beam CT of the head and neck: a simulation study. AB - OBJECTIVE: To investigate the influence of bowtie filtration on dedicated cone beam CT (CBCT) of the head and neck. METHODS: A validated hybrid simulation technique was used to model a commercial CBCT system with offset scanning geometry, 90 kV tube potential and 145*75 mm imaging field of view. Three bowtie filters were formulated to produce uniform flux intensity in the projection image of cylindrical objects of diameter 14, 16 and 18 cm. The influence of these simulated filters was compared with the original flat filtration in terms of the output radiation field, the dose delivered to the object, the scatter distribution in projections and the quality of the reconstructed image. RESULTS: Compared against flat filtration, dose reduction for the bowtie case, examined as a function of radial distance within a 16-cm-diameter water cylinder, varied from 8.7% at the centre to 53.8% at the periphery. Scatter reduction, quantified using scatter-to-primary ratio in projection images, was up to 37.6% for a 14-cm diameter cylindrical contrast phantom. Using the supplied routine image reconstruction, bowtie filtration resulted in comparable noise appearance, contrast resolution and artefact pattern for computational anatomical phantoms, with <5% difference in contrast-to-noise ratio. CONCLUSION: Bowtie filtration can effectively reduce the dose and scatter in CBCT of the head and neck. For better image quality, corresponding modification to the image pre-processing and reconstruction is needed. ADVANCES IN KNOWLEDGE: The hybrid simulation approach can usefully explore the impact of proposed system component and design changes. PMID- 23728949 TI - Moderate eugenics and human enhancement. AB - Though the reputation of eugenics has been tarnished by history, eugenics per se is not necessarily a bad thing. Many advocate a liberal new eugenics--where individuals are free to choose whether or not to employ genetic technologies for reproductive purposes. Though genetic interventions aimed at the prevention of severe genetic disorders may be morally and socially acceptable, reproductive liberty in the context of enhancement may conflict with equality. Enhancement could also have adverse effects on utility. The enhancement debate requires a shift in focus. What the equality and/or utility costs of enhancement will be is an empirical question. Rather than philosophical speculation, more social science research is needed to address it. Philosophers, meanwhile, should address head-on the question of how to strike a balance between liberty, equality, and utility in cases of conflict (in the context of genetics). PMID- 23728950 TI - Reports of sexual disorders related to serotonin reuptake inhibitors in the French pharmacovigilance database: an example of underreporting. AB - BACKGROUND: Depressive disorders and use of antidepressants are associated with adverse effects on sexual function. In pharmacoepidemiological studies, sexual disorders are reported by more than 50 % of patients taking serotonin reuptake inhibitors (SRIs). OBJECTIVE: The aim of this study was to determine the reporting rate of sexual disorders in association with SRIs, and to investigate the association between reported cases and the use of SRIs. METHODS: All cases of adverse drug reactions (ADRs) involving sexual disorders, spontaneously reported to the French Pharmacovigilance Database from 1 January 1985 to December 2009, were reviewed. Cases of sexual disorders in SRI users were described. We calculated the rate of reported sexual disorders as a percentage of the total ADRs reported for each drug. The association between reported cases and the use of SRIs was assessed using reporting odds ratios (ROR) with 95 % confidence intervals (CIs). RESULTS: A total of 11,863 ADRs in association with SRIs were collected, of which 98 (0.83 %) were spontaneous reports of sexual disorders. Subjects were, on average, 45.0 +/- 10.6 years of age and mainly male. Sexual disorders were associated with the use of SRI antidepressants (ROR 4.47; 95 % CI 3.61-5.53), milnacipran (ROR 11.72; 95 % CI 5.79-23.72), fluvoxamine (ROR 6.91; 95 % CI 3.79-12.58), paroxetine (ROR 5.54; 95 % CI 3.92-7.83), venlafaxine (ROR 3.50; 95 % CI 1.93-6.36), fluoxetine (ROR 3.46; 95 % CI 2.26-5.29), citalopram (ROR 2.69; 95 % CI 1.28-5.67) and sertraline (ROR 2.49; 95 % CI 1.03-6.01). CONCLUSION: It is likely that there are instances of underreporting, particularly for ADRs that are embarrassing to talk about spontaneously. Despite the likely underreporting of this well-described adverse effect, this case/non-case study performed in a large national pharmacovigilance database confirms the existence of the risk of sexual disorders associated with SRIs, and is an example of the lack of sensitivity of spontaneous notification to measure ADRs. Minimization of antidepressant-induced sexual dysfunction could be an important factor to avoid unsuccessful treatment. Physicians should advise their patients on the possible sexual adverse effects. PMID- 23728951 TI - Conservative management of thyroglobulin-positive, nonlocalizable thyroid carcinoma. AB - BACKGROUND: The purpose of this study was to demonstrate a role for observation of patients with differentiated thyroid cancer (DTC) with persistent, nonlocalizable disease. METHODS: Our study was conducted on outpatients seen at our institution from 1999 to 2009 having total thyroidectomy, radioactive iodine (RAI) ablation, measurable serum thyroglobulin (Tg), and no evidence of disease on whole body or positron emission tomography (PET) scans. RESULTS: Nineteen patients in our study group aged 20 to 73 with an average follow-up of 5.5 years (range, 2-12 years); all were treated with postoperative RAI (99-210 mCi, average 119). Mean Tg ranged from 0.41 to 4.34. Tg levels remained stable or gradually decreased in all patients. CONCLUSION: After total thyroidectomy and RAI therapy, patients may present with mildly elevated Tg values without localizable disease. These patients may have additional RAI treatments based on the Tg elevation. However, our clinical experience has shown that many of these patients will have Tg levels that either achieve stability or decrease over time without further treatment. PMID- 23728952 TI - Dietary selenium influences calcium release and activation of MLCK in uterine smooth muscle of rats. AB - We sought to elucidate the effects of different concentrations of dietary selenium on calcium ion release, MLCK levels, and muscle contraction in the uterine smooth muscle of rats. The selenium (Se) content of blood and of uterine smooth muscle tissues was detected by fluorescence spectrophotometry. Ca(2+) content was measured by atomic absorption spectroscopy. Calmodulin (CaM) and MLCK RNA and protein levels were analyzed by quantitative real-time polymerase chain reaction and Western blot, respectively. Dietary Se intake increased the Se levels in the blood and in uterine smooth muscle tissues and increased the Ca(2+) concentration in uterine smooth muscle tissues. The addition of Se also promoted CaM expression and enhanced MLCK activation in uterine smooth muscle tissues. In conclusion, Ca(2+), CaM, and MLCK were regulated by Se in uterine smooth muscle; Se plays a major role in regulating smooth muscle contraction in the uterus. PMID- 23728953 TI - Traumatic ventricular septal defect and flail tricuspid valve: successful management by an extracorporeal membrane oxygenator-supported hybrid approach. AB - We report the successful management of a critically ill patient with a traumatic ventricular septal defect (VSD) and flail tricuspid valve sustained in a motorcycle accident. Multiple orthopedic injuries prevented emergency cardiac surgery. The patient was stabilized by venous arterial extracorporeal membrane oxygenator support which allowed initial orthopedic repair. Repair of his cardiac injuries was then accomplished using a hybrid approach of percutaneous VSD closure using an Amplatzer post myocardial infarction VSD occluder which was also coil embolized followed by surgical tricuspid valve replacement. PMID- 23728954 TI - Meat and heme iron intake and esophageal adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition study. AB - Although recent studies suggest that high intakes of meat and heme iron are risk factors for several types of cancer, studies in relation to esophageal adenocarcinoma (EAC) are scarce. Previous results in the European Prospective Investigation into Cancer and Nutrition (EPIC) based on a relatively small number of cases suggested a positive association between processed meat and EAC. In this study, we investigate the association between intake of different types of meats and heme iron intake and EAC risk in a larger number of cases from EPIC. The study included 481,419 individuals and 137 incident cases of EAC that occurred during an average of 11 years of follow-up. Dietary intake of meat (unprocessed/processed red and white meat) was assessed by validated center specific questionnaires. Heme iron was calculated as a type-specific percentage of the total iron content in meat. After adjusting for relevant confounders, we observed a statistically significant positive association of EAC risk with heme iron and processed meat intake, with HR: 1.67, 95% CI: 1.05-2.68 and HR: 2.27, 95% CI:1.33-3.89, respectively, for comparison of the highest vs. lowest tertile of intake. Our results suggest a potential association between higher intakes of processed meat and heme iron and risk of EAC. PMID- 23728955 TI - Structure guided inhibitor designing of CDK2 and discovery of potential leads against cancer. AB - On the basis of stereo specific information obtained from crystal structures of CDK2, indole and chromene analogues were designed by suitably substituting the pharmacophores on their moiety and docked with target protein for calculating binding affinities. The binding affinities are represented in glide score. (5E)-5 [(1-methyl-1H-indol-3-yl)methylidene]-2,4,6-trioxotetrahydro-2H-pyrimidin-1-ide (I1), (5E)-5-(1H-indol-3-ylmethylidene)-2,4,6-trioxotetrahydro-2H-pyrimidin-1-ide (I2) and 2-amino-4-(4-methyl phenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3 carbonitrile (C9) were selected for synthesis and biological testing based on vital interactions. (5E)-5-(1H-indol-3-ylmethylidene)-2,4,6-trioxotetrahydro-2H pyrimidin-1-ide(I2) and 2-amino-4-(4-methyl phenyl)-5-oxo-5,6,7,8-tetrahydro-4H chromene-3-carbonitrile (C9) were proved to be active against MCF-7 and HeLa cell lines. PMID- 23728956 TI - Orthopaedic sports medicine 2013. PMID- 23728957 TI - Automobile safety in children: a review of North American evidence and recommendations. AB - In the United States, the rate of vehicle occupant deaths in children aged 1 to 3 years has decreased by over 50% in the past three decades. However, the Centers for Disease Control and Prevention report that motor vehicle crashes remain the leading cause of death in children aged 1 to 17 years. Parental compliance with child safety seats is poor, with up to 99% of children in certain age groups improperly restrained. Epidemiologic data support the proper use of automobile restraint systems to save lives. When appropriate restraint systems (based on age and weight) are used, a significant decrease occurs in the rates of mortality and serious injury. Legislation and public service campaigns can increase awareness regarding appropriate use of automobile restraint systems to decrease pediatric injury and fatality rates. Fluency and awareness, rather than cost, have been found to be the main reasons for improper use of automobile restraint systems; appropriately targeted education programs should continue to be developed. Physicians are optimally poised to educate patients and parents about automobile safety. PMID- 23728958 TI - Shoulder arthroscopy: basic principles of positioning, anesthesia, and portal anatomy. AB - Advances in modern arthroscopy have contributed significantly to greater flexibility and efficacy in addressing shoulder pathology. Advantages of arthroscopy include less invasive approaches, improved visualization, decreased risk of many postoperative complications, and faster recovery. As a result, arthroscopy is often preferred by both orthopaedic surgeons and patients. Common shoulder conditions that can be managed arthroscopically include rotator cuff tears, shoulder instability, and labral pathology. A thorough understanding of anatomic principles in conjunction with proper patient positioning and portal selection and placement are essential for successful arthroscopic shoulder surgery. PMID- 23728959 TI - Nerve injury complicating multiligament knee injury: current concepts and treatment algorithm. AB - Multiligament knee injuries account for <0.02% of all orthopaedic injuries, and 16% to 40% of these patients suffer associated injury to the common peroneal nerve (CPN). The proximity of the CPN to the proximal fibula predisposes the nerve to injury during local trauma and dislocation; the nerve is highly vulnerable to stretch injury during varus stress, particularly in posterolateral corner injuries. CPN injuries have a poor prognosis compared with that of other peripheral nerve injuries. Management is determined based on the severity and location of nerve injury, timing of presentation, associated injuries requiring surgical management, and the results of serial clinical evaluations and electrodiagnostic studies. Nonsurgical treatment options include orthosis wear and physical therapy. Surgical management includes one or more of the following: neurolysis, primary nerve repair, intercalary nerve grafting, tendon transfer, and nerve transfer. Limited evidence supports the use of early one-stage nerve reconstruction combined with tendon transfer; however, optimal management of these rare injuries continues to change, and treatment should be individualized. PMID- 23728960 TI - Lower extremity arthroplasty in patients with inflammatory arthritis: preoperative and perioperative management. AB - Spondylarthritis, which includes conditions such as ankylosing spondylitis and psoriatic arthritis, and rheumatoid arthritis are the most common forms of inflammatory arthritis. Joint inflammation and damage may result in the need for arthroplasty, and the surgeon must be aware of the perioperative challenges associated with these systemic diseases. In patients with inflammatory arthritis who have polyarticular disease and spinal involvement at the time of presentation for lower extremity arthroplasty, preoperative evaluation must include careful evaluation of all joints, including the cervical spine. Preoperative assessment and perioperative management must be appropriate to minimize cardiac and pulmonary complications. Finally, the perioperative management of medications used to manage inflammatory arthritis is critical because these medications may increase the risk of infection and compromise wound healing. PMID- 23728961 TI - Basic principles for conducting human research in orthopaedic medicine. AB - Researchers and clinicians operate in an increasingly complex clinical and regulatory environment in which understanding the principles governing human research is essential. However, most orthopaedic surgeons have not received in depth training in regulatory requirements and scientific research methods. Ensuring that research is conducted in accordance with state and federal laws and ethical principles is essential to guard compromising patient information and avoid severe penalties for noncompliance. The researcher must understand the regulations for compliance and proper data management, including the requirements of the Health Insurance Portability and Accountability Act, proper application of informed consent, use of the Institutional Review Board, and data protection guidelines. Tools such as a regulatory binder can assist investigators in complying with requirements, maintaining regulatory standards, and ensuring a robust study design and conduct. PMID- 23728962 TI - Madelung deformity. AB - Madelung deformity is a rare congenital anomaly of the wrist caused by asymmetric growth at the distal radial physis secondary to a partial ulnar-sided arrest. The deformity is characterized by ulnar and palmar curvature of the distal radius, positive ulnar variance, and proximal subsidence of the lunate. It more commonly occurs in females than males and typically affects both wrists. The deformity can occur in isolation or as part of a genetic syndrome. The pattern of inheritance varies, with some cases following a pseudoautosomal pattern and many others lacking a clear family history. Nonsurgical management is typically advocated in asymptomatic patients. Few studies exist on the natural history of the condition; however, extensor tendon ruptures have been reported in severe and chronic cases. Stiffness, pain, and patient concerns regarding wrist cosmesis have been cited as indications for surgery. Various techniques for surgical management of Madelung deformity have been described, but clear evidence to support the use of any single approach is lacking. PMID- 23728964 TI - Synthesis of nanocomposites from Pd(0) and a hyper-cross-linked functional resin obtained from a conventional gel-type precursor. AB - Hyper-cross-linked resins stemming from a gel-type poly-chloromethylated poly(styrene-co-divinylbenzene) resin (GT) have been investigated by a multi methodological approach based on elemental analysis, scanning electron microscopy, X-ray microanalysis, and solvent absorption. The hyper-cross-linking of the parent resin was accomplished by Friedel-Crafts alkylation of the phenyl rings of the resins with the chloromethyl groups. This produced a permanent pore system comprising both micropores (<2.0 nm in diameter) and mesopores (2.2 nm). The chloromethyl groups that did not react in the hyper-cross-linking step were transformed into methylmercaptan groups and the latter were then converted into sulfonic groups by oxidation with hydrogen peroxide. By this procedure the extensive permanent porosity of the parent unsulfonated hyper-cross-linked polymer (HGT) was retained by the sulfonated polymer (HGTS). The final exchange capacity of HGTS was determined to be 0.36 mmol g(-1). HGTS was easily metalated with Pd(II) and the subsequent reduction of the metal centers with either aqueous sodium borohydride, formaldehyde, or dihydrogen produced three Pd(0)/HGTS nanocomposites. The metal nanoparticles had diameters in the 1-6 nm range for all the nanocomposites, as determined by TEM, but with somewhat different distributions. When formaldehyde was used, more than 90% of the nanoparticles were less than 3 nm and their radial distribution throughout the polymer beads was quite homogeneous. These findings show that with this reducing agent the metal nanoparticles are generated within the pore system of the polymer matrix, hence their size is controlled by the dimensions of the pores of the polymeric support. PMID- 23728965 TI - The importance of ingested soils in supplying fluorine and lead to sheep grazing contaminated pastures in the Peak District mining area of Derbyshire, UK. AB - For sheep grazing pastures in areas of mineralisation and former metalliferous mining activity, an excessive intake of potentially harmful elements (PHEs) such as fluorine (F) and lead (Pb) can result in clinical and subclinical toxicity. The prime aim of our work was to calculate the intakes of both of these PHEs by sheep grazing pastures in the mineralised/mined Peak District area of Derbyshire. The bi-monthly sampling of topsoils (0-15 cm depth) and the faeces of sheep from fields at seven farms was undertaken for a 1-year period. These samples were analysed for titanium that allowed the rates of soil ingestion (and hence also herbage ingestion since we assume that the sheep have an overall diet of 1 kg dry matter (DM)/day) to be determined. Our findings were then combined with previously published soil and soil-free pasture herbage F and Pb concentrations determined from the seven farms to calculate the intakes of both PHEs. The results show seasonal variations of soil ingestion at the seven farms ranging from <0.1 to 20.1 % of the DM intake (median=3 %), with the highest rates of ingestion being associated with the winter-spring (i.e. December-April) period. Our calculations show that at some farms, sheep can be exposed to dietary concentrations in excess of recommended guidelines potentially throughout the whole year, though livestock movement to less-contaminated pastures would lessen any toxic impact. Because the soil concentrations are greater than those associated with soil-free pasture herbage, ingested soils are the main dietary source of Pb and (especially) F to sheep. However, subjecting freshly sampled topsoils to sequential extraction procedures undertaken in the laboratory indicates that the majority of Pb and (especially) F may not be readily soluble in the ovine digestion system, so reducing the quantities of both PHEs available for absorption. PMID- 23728967 TI - Temporal variation of volatile organic compounds and their major emission sources in Seoul, Korea. AB - This study examines the characteristics of volatile organic compounds (VOCs) and their major emission sources at the Bulgwang site in Seoul, Korea. The annual levels of VOCs (96.2-121.1 ppb C) have shown a decreasing trend from 2004 to 2008. The most abundant component in Seoul was toluene, which accounted for over 23.5 % of the total VOCs on the parts per billion on a carbon basis, and the portions of alkanes with two to six carbons constituted the largest major lumped group, ranging from 40.1 to 48.4 % (45.3 +/- 3.7 %) of the total VOCs. Major components of the solvent (toluene, m/p-xylene, o-xylene, and ethylbenzene) showed high in daytime and summer and low in nighttime and winter due mainly to the variation of the ambient temperature. The species mostly emitted from gasoline vapor (i/n-butane, i/n-pentane, n-hexane, and 2-methylpentane) and vehicular exhaust (ethylene, acetylene, and benzene) showed bimodal peaks in the diurnal variation around the commuting hours because of the high traffic volume. For the 14 out of 15 highest concentration species, the weekend effect was only evident on Sundays because of the stepwise implementation of the 5-day work-week system. Principal components analysis (PCA) was applied in order to identify the sources of the 15 highest concentration VOCs and, as a result, three principal components such as gasoline vapor (48.9 %), vehicular exhaust (17.9 %), and evaporation of solvents (9.8 %) were obtained to explain a total of 76.6 % of the data variance. Most influential contributing sources at the sampling site were traffic-related ones although the use of solvent was the dominant emission source based on the official emission inventory. PMID- 23728966 TI - Bioavailability and ecotoxicity of arsenic species in solution culture and soil system: implications to remediation. AB - In this work, bioavailability and ecotoxicity of arsenite (As(III)) and arsenate (As(V)) species were compared between solution culture and soil system. Firstly, the adsorption of As(III) and As(V) was compared using a number of non-allophanic and allophanic soils. Secondly, the bioavailability and ecotoxicity were examined using germination, phytoavailability, earthworm, and soil microbial activity tests. Both As-spiked soils and As-contaminated sheep dip soils were used to test bioavailability and ecotoxicity. The sheep dip soil which contained predominantly As(V) species was subject to flooding to reduce As(V) to As(III) and then used along with the control treatment soil to compare the bioavailability between As species. Adsorption of As(V) was much higher than that of As(III), and the difference in adsorption between these two species was more pronounced in the allophanic than non-allophanic soils. In the solution culture, there was no significant difference in bioavailability and ecotoxicity, as measured by germination and phytoavailability tests, between these two As species. Whereas in the As-spiked soils, the bioavailability and ecotoxicity were higher for As(III) than As(V), and the difference was more pronounced in the allophanic than non allophanic soils. Bioavailability of As increased with the flooding of the sheep dip soils which may be attributed to the reduction of As(V) to As(III) species. The results in this study have demonstrated that while in solution, the bioavailability and ecotoxicity do not vary between As(III) and As(V), in soils, the latter species is less bioavailable than the former species because As(V) is more strongly retained than As(III). Since the bioavailability and ecotoxicity of As depend on the nature of As species present in the environment, risk-based remediation approach should aim at controlling the dynamics of As transformation. PMID- 23728968 TI - Distribution of grape seed flavanols and their metabolites in pregnant rats and their fetuses. AB - SCOPE: Polyphenols have been demonstrated to provide health benefits affecting cellular and physiological processes. This study aims to evaluate the bioavailability and distribution of grape seed flavanol compounds during pregnancy and whether fetuses could be exposed to these compounds. METHODS AND RESULTS: The distribution of flavanols and their metabolites in rat plasma, liver, white adipose tissue, brain, amniotic fluid, placenta, and fetuses after 1 and 2 h of an acute intake of a grape seed proanthocyanidin extract was examined by LC-ESI-TOF/MS. Flavanols and their metabolites were widely distributed in both pregnant and nonpregnant rat plasma and tissues. In liver, the conjugated forms of flavanols were less available in pregnant than nonpregnant rats. Flavanol metabolites were abundant in maternal placenta but detected at low levels in fetuses and amniotic fluid. CONCLUSION: Flavanol metabolization appears to be less active in the liver during pregnancy. Moreover, data indicated that transport across the placenta is not efficient and for flavanols and their metabolites, the placenta seems to act as a barrier. However, these compounds target the fetus and are excreted in the amniotic fluid. PMID- 23728970 TI - Regulation of ion channels by membrane lipids. AB - The major membrane lipid regulators of ion channel function include cholesterol, one of the main lipid components of the plasma membranes, phosphoinositides, a group of regulatory phospholipids that constitute a minor component of the membrane lipids but are known to play key roles in regulation of multiple proteins and sphingolipids, particularly sphingosine-1-phosphate, a signaling biolipid that is generated from ceramide and is known to regulate multiple cellular functions. Furthermore, specific effects of all the lipid modulators are highly heterogeneous varying significantly between different types of ion channels, as well as between different cell types. In terms of the mechanisms, three general mechanisms have been shown to underlie lipid regulation of ion channels: specific lipid-protein interactions, changes in the physical properties of the membrane, and facilitating the association of the channel proteins with other regulatory proteins within multiproteins signaling complexes termed membrane rafts. In this article, we present comprehensive analysis of the roles of several lipid modulators, including cholesterol, bile acids, phosphoinositides, and sphingolipids on ion channel function. PMID- 23728971 TI - Respiratory function during anesthesia: effects on gas exchange. AB - Anaesthesia causes a respiratory impairment, whether the patient is breathing spontaneously or is ventilated mechanically. This impairment impedes the matching of alveolar ventilation and perfusion and thus the oxygenation of arterial blood. A triggering factor is loss of muscle tone that causes a fall in the resting lung volume, functional residual capacity. This fall promotes airway closure and gas adsorption, leading eventually to alveolar collapse, that is, atelectasis. The higher the oxygen concentration, the faster will the gas be adsorbed and the aleveoli collapse. Preoxygenation is a major cause of atelectasis and continuing use of high oxygen concentration maintains or increases the lung collapse, that typically is 10% or more of the lung tissue. It can exceed 25% to 40%. Perfusion of the atelectasis causes shunt and cyclic airway closure causes regions with low ventilation/perfusion ratios, that add to impaired oxygenation. Ventilation with positive end-expiratory pressure reduces the atelectasis but oxygenation need not improve, because of shift of blood flow down the lung to any remaining atelectatic tissue. Inflation of the lung to an airway pressure of 40 cmH2O recruits almost all collapsed lung and the lung remains open if ventilation is with moderate oxygen concentration (< 40%) but recollapses within a few minutes if ventilation is with 100% oxygen. Severe obesity increases the lung collapse and obstructive lung disease and one-lung anesthesia increase the mismatch of ventilation and perfusion. CO2 pneumoperitoneum increases atelectasis formation but not shunt, likely explained by enhanced hypoxic pulmonary vasoconstriction by CO2. Atelectasis may persist in the postoperative period and contribute to pneumonia. PMID- 23728972 TI - Renal medullary circulation. AB - The renal medullary microcirculation is a distinctive arrangement of blood vessels that serve multiple functions in the renal medulla. This article begins with a description of the unique anatomy of this vascular bed and the role it plays in transport and countercurrent exchange in the medulla. A segment of the review is then devoted to the important role mathematical modeling has played in the understanding of this vascular bed's function. Succeeding sections focus upon the hematocrit in the vasa recta capillaries and methods utilized to assess blood flow in the renal medulla. An extensive portion of the article is then devoted to the regulation of the medullary circulation, from ion channel architecture to neurohormonal signaling. Finally, we discuss the importance of the renal medullary circulation in the regulation of fluid and electrolyte homeostasis and arterial blood pressure regulation. PMID- 23728969 TI - Mechanobiology in lung epithelial cells: measurements, perturbations, and responses. AB - Epithelial cells of the lung are located at the interface between the environment and the organism and serve many important functions including barrier protection, fluid balance, clearance of particulate, initiation of immune responses, mucus and surfactant production, and repair following injury. Because of the complex structure of the lung and its cyclic deformation during the respiratory cycle, epithelial cells are exposed to continuously varying levels of mechanical stresses. While normal lung function is maintained under these conditions, changes in mechanical stresses can have profound effects on the function of epithelial cells and therefore the function of the organ. In this review, we will describe the types of stresses and strains in the lungs, how these are transmitted, and how these may vary in human disease or animal models. Many approaches have been developed to better understand how cells sense and respond to mechanical stresses, and we will discuss these approaches and how they have been used to study lung epithelial cells in culture. Understanding how cells sense and respond to changes in mechanical stresses will contribute to our understanding of the role of lung epithelial cells during normal function and development and how their function may change in diseases such as acute lung injury, asthma, emphysema, and fibrosis. PMID- 23728976 TI - Cryo-EM in the study of membrane transport proteins. AB - Electron cryomicroscopy (cryo-EM) has evolved as a widely used approach to understand a range of structure-function questions, particularly of membrane proteins. Studies by both electron crystallography and single particle analysis have provided a wealth of information on membrane transport proteins. Cryo-EM methods with an emphasis on electron crystallography, which has yielded the most membrane transport protein structural information of any of the cryo-EM techniques, are described here. Two-dimensional crystallization approaches are outlined, as well as advances in cryo-EM specimen preparation, data collection, and image processing. Examples of membrane transport protein structure described serve to illustrate some of the advances in both structural understanding and methods. Further examples outline impressive results that were obtained by a combination of electron crystallography and X-ray crystallography as well as additional complementary methods. PMID- 23728977 TI - Peripheral circulation. AB - Blood flow (BF) increases with increasing exercise intensity in skeletal, respiratory, and cardiac muscle. In humans during maximal exercise intensities, 85% to 90% of total cardiac output is distributed to skeletal and cardiac muscle. During exercise BF increases modestly and heterogeneously to brain and decreases in gastrointestinal, reproductive, and renal tissues and shows little to no change in skin. If the duration of exercise is sufficient to increase body/core temperature, skin BF is also increased in humans. Because blood pressure changes little during exercise, changes in distribution of BF with incremental exercise result from changes in vascular conductance. These changes in distribution of BF throughout the body contribute to decreases in mixed venous oxygen content, serve to supply adequate oxygen to the active skeletal muscles, and support metabolism of other tissues while maintaining homeostasis. This review discusses the response of the peripheral circulation of humans to acute and chronic dynamic exercise and mechanisms responsible for these responses. This is accomplished in the context of leading the reader on a tour through the peripheral circulation during dynamic exercise. During this tour, we consider what is known about how each vascular bed controls BF during exercise and how these control mechanisms are modified by chronic physical activity/exercise training. The tour ends by comparing responses of the systemic circulation to those of the pulmonary circulation relative to the effects of exercise on the regional distribution of BF and mechanisms responsible for control of resistance/conductance in the systemic and pulmonary circulations. PMID- 23728978 TI - Cytoskeletal dynamics and lung fluid balance. AB - This article examines the role of the endothelial cytoskeleton in the lung's ability to restrict fluid and protein to vascular space at normal vascular pressures and thereby to protect lung alveoli from lethal flooding. The barrier properties of microvascular endothelium are dependent on endothelial cell contact with other vessel-wall lining cells and with the underlying extracellular matrix (ECM). Focal adhesion complexes are essential for attachment of endothelium to ECM. In quiescent endothelial cells, the thick cortical actin rim helps determine cell shape and stabilize endothelial adherens junctions and focal adhesions through protein bridges to actin cytoskeleton. Permeability-increasing agonists signal activation of "small GTPases" of the Rho family to reorganize the actin cytoskeleton, leading to endothelial cell shape change, disassembly of cortical actin rim, and redistribution of actin into cytoplasmic stress fibers. In association with calcium- and Src-regulated myosin light chain kinase (MLCK), stress fibers become actinomyosin-mediated contractile units. Permeability increasing agonists stimulate calcium entry and induce tyrosine phosphorylation of VE-cadherin (vascular endothelial cadherin) and beta-catenins to weaken or pull apart endothelial adherens junctions. Some permeability agonists cause latent activation of the small GTPases, Cdc42 and Rac1, which facilitate endothelial barrier recovery and eliminate interendothelial gaps. Under the influence of Cdc42 and Rac1, filopodia and lamellipodia are generated by rearrangements of actin cytoskeleton. These motile evaginations extend endothelial cell borders across interendothelial gaps, and may initiate reannealing of endothelial junctions. Endogenous barrier protective substances, such as sphingosine-1-phosphate, play an important role in maintaining a restrictive endothelial barrier and counteracting the effects of permeability increasing agonists. PMID- 23728974 TI - Central chemoreceptors: locations and functions. AB - Central chemoreception traditionally refers to a change in ventilation attributable to changes in CO2/H(+) detected within the brain. Interest in central chemoreception has grown substantially since the previous Handbook of Physiology published in 1986. Initially, central chemoreception was localized to areas on the ventral medullary surface, a hypothesis complemented by the recent identification of neurons with specific phenotypes near one of these areas as putative chemoreceptor cells. However, there is substantial evidence that many sites participate in central chemoreception some located at a distance from the ventral medulla. Functionally, central chemoreception, via the sensing of brain interstitial fluid H(+), serves to detect and integrate information on (i) alveolar ventilation (arterial PCO2), (ii) brain blood flow and metabolism, and (iii) acid-base balance, and, in response, can affect breathing, airway resistance, blood pressure (sympathetic tone), and arousal. In addition, central chemoreception provides a tonic "drive" (source of excitation) at the normal, baseline PCO2 level that maintains a degree of functional connectivity among brainstem respiratory neurons necessary to produce eupneic breathing. Central chemoreception responds to small variations in PCO2 to regulate normal gas exchange and to large changes in PCO2 to minimize acid-base changes. Central chemoreceptor sites vary in function with sex and with development. From an evolutionary perspective, central chemoreception grew out of the demands posed by air versus water breathing, homeothermy, sleep, optimization of the work of breathing with the "ideal" arterial PCO2, and the maintenance of the appropriate pH at 37 degrees C for optimal protein structure and function. PMID- 23728979 TI - Bioenergetics of exercising humans. AB - Human muscles, limbs and supporting ventilatory, cardiovascular, and metabolic systems are well adapted for walking, and there is reasonable transfer of efficiency of movement to bicycling. Our efficiency and economy of movement of bipedal walking (~30%) are far superior to those of apes. This overall body efficiency during walking and bicycling represents the multiplicative interaction of a phosphorylative coupling efficiency of ~60%, and a mechanical coupling efficiency of ~50%. These coupling efficiencies compare well with those of other species adapted for locomotion. We are capable runners, but our speed and power are inferior to carnivorous and omnivorous terrestrial mammalian quadrupeds because of biomechanical and physiological constraints. But, because of our metabolic plasticity (i.e., the ability to switch among carbohydrate (CHO)- and lipid-derived energy sources) our endurance capacity is very good by comparison to most mammals, but inferior to highly adapted species such as wolves and migratory birds. Our ancestral ability for hunting and gathering depends on strategy and capabilities in the areas of thermoregulation, and metabolic plasticity. Clearly, our competitive advantage of survival in the biosphere depends in intelligence and behavior. Today, those abilities that served early hunter-gatherers make for interesting athletic competitions due to wide variations in human phenotypes. In contemporary society, the stresses of regular physical exercise serve to minimize morbidities and mortality associated with physical inactivity, overnutrition, and aging. PMID- 23728980 TI - TRP channels. AB - TRP channels constitute a large superfamily of cation channel forming proteins, all related to the gene product of the transient receptor potential (trp) locus in Drosophila. In mammals, 28 different TRP channel genes have been identified, which exhibit a large variety of functional properties and play diverse cellular and physiological roles. In this article, we provide a brief and systematic summary of expression, function, and (patho)physiological role of the mammalian TRP channels. PMID- 23728981 TI - History of respiratory mechanics prior to World War II. AB - The history of respiratory mechanics is reviewed over a period of some 2,500 years from the ancient Greeks to World War II. A cardinal early figure was Galen (130-199 AD) who made remarkably perceptive statements on the diaphragm and the anatomy of the phrenic nerves. The polymath Leonardo da Vinci (1452-1519) contributed observations on pulmonary mechanics including the pleural space and bronchial airflow that still make good reading. Vesalius (1514-1564) produced magnificent illustrations of the lung, ribcage, and diaphragm. In the 17th century, the Oxford School including Boyle, Hooke, Lower, and Mayow were responsible for many contributions on mechanical functions including the intercostal muscles and the pleura. Hales (1677-1761) calculated the size and surface area of the alveoli, the time spent by the blood in the pulmonary capillaries, and intrathoracic pressures. Poiseuille (1799-1869) carried out classical studies of fluid mechanics including one of the first demonstrations of flow limitation in collapsible vessels. The culmination of the pre-World War II period was the outstanding contributions of Rohrer (1888-1926) and his two Swiss countrymen, Wirz (1896-1978) and von Neergaard (1887-1947). Rohrer developed the first comprehensive, quantitative treatment of respiratory mechanics in the space of 10 years including an analysis of flow in airways, and the pressure-volume behavior of the respiratory system. von Neergaard performed landmark studies on the effects of surface tension on pressure-volume behavior. Progress over the 2,500 years was slow and erratic at times, but by 1940 the stage was set for the spectacular developments of the next 70 years. PMID- 23728982 TI - Micropuncture of the kidney: a primer on techniques. AB - Techniques to evaluate renal function at the single nephron level have been instrumental and indispensible in furthering our understanding of the mammalian kidney. Techniques that were first introduce in the 1920s, and later refined in the 1950s and 1960s, permit sophisticated interrogation of glomerular filtration and hemodynamics, and tubular epithelial transport activity. Much of what we know about the physiology and pathophysiology of the kidney has been produced or, to some degree, confirmed by renal micropuncture. While micropuncture is perhaps not as widely employed as before, it remains an essential tool for comprehensive evaluation of kidney function, particularly in this age of genetically pliable experimental models. This review aims to provide a introduction to common methodologies and approaches used to conduct micropuncture experiments. Topics covered include instrumentation and equipment, pipet fabrication techniques, animal preparation, and experimental procedures for evaluating single nephron hemodynamics and tubular function. PMID- 23728975 TI - Motility, survival, and proliferation. AB - Airway smooth muscle has classically been of interest for its contractile response linked to bronchoconstriction. However, terminally differentiated smooth muscle cells are phenotypically plastic and have multifunctional capacity for proliferation, cellular hypertrophy, migration, and the synthesis of extracellular matrix and inflammatory mediators. These latter properties of airway smooth muscle are important in airway remodeling which is a structural alteration that compounds the impact of contractile responses on limiting airway conductance. In this overview, we describe the important signaling components and the functional evidence supporting a view of smooth muscle cells at the core of fibroproliferative remodeling of hollow organs. Signal transduction components and events are summarized that control the basic cellular processes of proliferation, cell survival, apoptosis, and cellular migration. We delineate known intracellular control mechanisms and suggest future areas of interest to pursue to more fully understand factors that regulate normal myocyte function and airway remodeling in obstructive lung diseases. PMID- 23728983 TI - Phylogenetic analyses: comparing species to infer adaptations and physiological mechanisms. AB - Comparisons among species have been a standard tool in animal physiology to understand how organisms function and adapt to their surrounding environment. During the last two decades, conceptual and methodological advances from different fields, including evolutionary biology and systematics, have revolutionized the way comparative analyses are performed, resulting in the advent of modern phylogenetic statistical methods. This development stems from the realization that conventional analytical methods assume that observations are statistically independent, which is not the case for comparative data because species often resemble each other due to shared ancestry. By taking evolutionary history explicitly into consideration, phylogenetic statistical methods can account for the confounding effects of shared ancestry in interspecific comparisons, improving the reliability of standard approaches such as regressions or correlations in comparative analyses. Importantly, these methods have also enabled researchers to address entirely new evolutionary questions, such as the historical sequence of events that resulted in current patterns of form and function, which can only be studied with a phylogenetic perspective. Here, we provide an overview of phylogenetic approaches and their importance for studying the evolution of physiological processes and mechanisms. We discuss the conceptual framework underlying these methods, and explain when and how phylogenetic information should be employed. We then outline the difficulties and limitations inherent to comparative approaches and discuss potential problems researchers may encounter when designing a comparative study. These issues are illustrated with examples from the literature in which the incorporation of phylogenetic information has been useful, or even crucial, for inferences on how species evolve and adapt to their surrounding environment. PMID- 23728984 TI - Control of breathing during exercise. AB - During exercise by healthy mammals, alveolar ventilation and alveolar-capillary diffusion increase in proportion to the increase in metabolic rate to prevent PaCO2 from increasing and PaO2 from decreasing. There is no known mechanism capable of directly sensing the rate of gas exchange in the muscles or the lungs; thus, for over a century there has been intense interest in elucidating how respiratory neurons adjust their output to variables which can not be directly monitored. Several hypotheses have been tested and supportive data were obtained, but for each hypothesis, there are contradictory data or reasons to question the validity of each hypothesis. Herein, we report a critique of the major hypotheses which has led to the following conclusions. First, a single stimulus or combination of stimuli that convincingly and entirely explains the hyperpnea has not been identified. Second, the coupling of the hyperpnea to metabolic rate is not causal but is due to of these variables each resulting from a common factor which link the circulatory and ventilatory responses to exercise. Third, stimuli postulated to act at pulmonary or cardiac receptors or carotid and intracranial chemoreceptors are not primary mediators of the hyperpnea. Fourth, stimuli originating in exercising limbs and conveyed to the brain by spinal afferents contribute to the exercise hyperpnea. Fifth, the hyperventilation during heavy exercise is not primarily due to lactacidosis stimulation of carotid chemoreceptors. Finally, since volitional exercise requires activation of the CNS, neural feed-forward (central command) mediation of the exercise hyperpnea seems intuitive and is supported by data from several studies. However, there is no compelling evidence to accept this concept as an indisputable fact. PMID- 23728985 TI - The ciliary cytoskeleton. AB - Cilia and flagella are surface-exposed, finger-like organelles whose core consists of a microtubule (MT)-based axoneme that grows from a modified centriole, the basal body. Cilia are found on the surface of many eukaryotic cells and play important roles in cell motility and in coordinating a variety of signaling pathways during growth, development, and tissue homeostasis. Defective cilia have been linked to a number of developmental disorders and diseases, collectively called ciliopathies. Cilia are dynamic organelles that assemble and disassemble in tight coordination with the cell cycle. In most cells, cilia are assembled during growth arrest in a multistep process involving interaction of vesicles with appendages present on the distal end of mature centrioles, and addition of tubulin and other building blocks to the distal tip of the basal body and growing axoneme; these building blocks are sorted through a region at the cilium base known as the ciliary necklace, and then transported via intraflagellar transport (IFT) along the axoneme toward the tip for assembly. After assembly, the cilium frequently continues to turn over and incorporate tubulin at its distal end in an IFT-dependent manner. Prior to cell division, the cilia are usually resorbed to liberate centrosomes for mitotic spindle pole formation. Here, we present an overview of the main cytoskeletal structures associated with cilia and centrioles with emphasis on the MT-associated appendages, fibers, and filaments at the cilium base and tip. The composition and possible functions of these structures are discussed in relation to cilia assembly, disassembly, and length regulation. PMID- 23728986 TI - Neural control of the upper airway: integrative physiological mechanisms and relevance for sleep disordered breathing. AB - The various neural mechanisms affecting the control of the upper airway muscles are discussed in this review, with particular emphasis on structure-function relationships and integrative physiological motor-control processes. Particular foci of attention include the respiratory function of the upper airway muscles, and the various reflex mechanisms underlying their control, specifically the reflex responses to changes in airway pressure, reflexes from pulmonary receptors, chemoreceptor and baroreceptor reflexes, and postural effects on upper airway motor control. This article also addresses the determinants of upper airway collapsibility and the influence of neural drive to the upper airway muscles, and the influence of common drugs such as ethanol, sedative hypnotics, and opioids on upper airway motor control. In addition to an examination of these basic physiological mechanisms, consideration is given throughout this review as to how these mechanisms relate to integrative function in the intact normal upper airway in wakefulness and sleep, and how they may be involved in the pathogenesis of clinical problems such obstructive sleep apnea hypopnea. PMID- 23728987 TI - Mechanics and function of the pulmonary vasculature: implications for pulmonary vascular disease and right ventricular function. AB - he relationship between cardiac function and the afterload against which the heart muscle must work to circulate blood throughout the pulmonary circulation is defined by a complex interaction between many coupled system parameters. These parameters range broadly and incorporate system effects originating primarily from three distinct locations: input power from the heart, hydraulic impedance from the large conduit pulmonary arteries, and hydraulic resistance from the more distal microcirculation. These organ systems are not independent, but rather, form a coupled system in which a change to any individual parameter affects all other system parameters. The result is a highly nonlinear system which requires not only detailed study of each specific component and the effect of disease on their specific function, but also requires study of the interconnected relationship between the microcirculation, the conduit arteries, and the heart in response to age and disease. Here, we investigate systems-level changes associated with pulmonary hypertensive disease progression in an effort to better understand this coupled relationship. PMID- 23728988 TI - Comprehensive phylogenetic analyses of the Ruppia maritima complex focusing on taxa from the Mediterranean. AB - Recent molecular phylogenetic studies reported high diversity of Ruppia species in the Mediterranean. Multiple taxa, including apparent endemics, are known from that region, however, they have thus far not been exposed to phylogenetic analyses aimed at studying their relationships to taxa from other parts of the world. Here we present a comprehensive phylogenetic analyses of the R. maritima complex using data sets composed of DNA sequences of the plastid genome, the multi-copy nuclear ITS region, and the low-copy nuclear phyB gene with a primary focus on the Mediterranean representatives of the complex. As a result, a new lineage, "Drepanensis", was identified as the seventh entity of the complex. This lineage is endemic to the Mediterranean. The accessions included in the former "Tetraploid" entity were reclassified into two entities: an Asia-Australia-Europe disjunct "Tetraploid_alpha" with a paternal "Diploid" origin, and a European "Tetraploid_gamma" originating from a maternal "Drepanensis" lineage. Another entity, "Tetraploid_beta", is likely to have been originated as a result of chloroplast capture through backcrossing hybridization between paternal "Tetraploid_alpha" and maternal "Tetraploid_gamma". Additional discovery of multiple tetraploidizations as well as hybridization and chloroplast capture at the tetraploid level indicated that hybridization has been a significant factor in the diversification of Ruppia. PMID- 23728989 TI - The effect of aspiration pressure over endobronchial ultrasound-guided transbronchial needle aspiration on the diagnosis of intrathoracic lymphadenopathies. AB - BACKGROUND: Data regarding the effect of aspiration pressure over endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) on the diagnosis of intrathoracic lymphadenopathies is limited. The aim of this study was to compare the effect of three levels of aspiration pressure over EBUS-TBNA on the diagnostic yield and numbers of diagnostic cells. METHODS: A prospective study was conducted on 66 patients with enlarged intrathoracic lymph nodes. Three levels of aspiration pressure (0, 20, and 40 mL) were applied after the needle pierced the target and the needle's position was confirmed by EBUS images. The diagnostic yield and the numbers of diagnostic cells attained with each pressure from the same target were compared. The cellularity of the obtained diagnostic cells was classified into four grades (inadequate, minimal, moderate, and numerous) by a cytopathologist in a blinded study. RESULTS: The mean nodal size was 19.1 +/- 6.2 mm. The final diagnoses included 53 malignant and 13 benign lymphadenopathies. Adequate lymph node samples were obtained in 63 patients (95.5%), and EBUS-TBNA revealed definite diagnosis for 58 patients (87.9%). Negative pressure of 40 mL provided a diagnostic yield similar to that of 20 mL (83.3 vs. 75.8%; p = 0.23), but both showed higher diagnostic yields than zero pressure. In terms of cellularity of the specimen, however, high negative pressure (40 mL) gave higher numbers of adequate cells than the comparators (p < 0.001). CONCLUSION: Negative pressure should be applied in an EBUS-TBNA procedure. Although the diagnostic yield was not different, high negative pressure was superior to low negative pressure in obtaining numbers of adequate cells. PMID- 23728990 TI - Mycobacterial infections in patients treated with tumor necrosis factor antagonists in South Korea. AB - BACKGROUND: The aims of this study were to determine the incidence of tuberculosis (TB) and nontuberculous mycobacteria (NTM) lung disease in patients who were treated with tumor necrosis factor (TNF) antagonists in South Korea and to evaluate their clinical characteristics. METHODS: We surveyed all patients (N = 509) who were treated with TNF antagonists at Severance Hospital, South Korea, between January 2002 and December 2011. We reviewed the patients' medical records and collected microbiological, radiographic, and clinical data, including the type of TNF blocker(s) used and the results of tuberculin skin tests and interferon-gamma release assays. RESULTS: Rheumatoid arthritis (43.6 %) and ankylosing spondylitis (27.9 %) were the most common diseases in the patients treated with TNF antagonists. Patients received etanercept (33.4 %), infliximab (23.4 %), or adalimumab (13.2 %). The remaining patients received two or more TNF antagonists (30 %). Nine patients developed TB, and four patients developed NTM lung disease. After adjustment for age and sex, the standardized TB incidence ratio was 6.4 [95 % CI 3.1-11.7] compared with the general population. The estimated NTM incidence rate was 230.7 per 100,000 patients per year. CONCLUSIONS: Our results show that mycobacterial infections increase in patients treated with TNF antagonists. The identification of additional predictors of TB for the treatment of latent tuberculosis infection and the careful monitoring and timely diagnosis of NTM-related lung disease are needed for patients who receive long-term therapy with TNF antagonists. PMID- 23728973 TI - Peripheral chemoreceptors: function and plasticity of the carotid body. AB - The discovery of the sensory nature of the carotid body dates back to the beginning of the 20th century. Following these seminal discoveries, research into carotid body mechanisms moved forward progressively through the 20th century, with many descriptions of the ultrastructure of the organ and stimulus-response measurements at the level of the whole organ. The later part of 20th century witnessed the first descriptions of the cellular responses and electrophysiology of isolated and cultured type I and type II cells, and there now exist a number of testable hypotheses of chemotransduction. The goal of this article is to provide a comprehensive review of current concepts on sensory transduction and transmission of the hypoxic stimulus at the carotid body with an emphasis on integrating cellular mechanisms with the whole organ responses and highlighting the gaps or discrepancies in our knowledge. It is increasingly evident that in addition to hypoxia, the carotid body responds to a wide variety of blood-borne stimuli, including reduced glucose and immune-related cytokines and we therefore also consider the evidence for a polymodal function of the carotid body and its implications. It is clear that the sensory function of the carotid body exhibits considerable plasticity in response to the chronic perturbations in environmental O2 that is associated with many physiological and pathological conditions. The mechanisms and consequences of carotid body plasticity in health and disease are discussed in the final sections of this article. PMID- 23728991 TI - Requests for health education from Chinese cancer patients during their recovery period: a cross-sectional study. AB - To determine the prevalence of posttreatment patient requests for health information from Chinese cancer patients during their recovery period, a cross sectional, descriptive study using a mailed survey was conducted among 374 patients selected randomly. The survey addressed what types of information patients actually wanted but did not receive from their care providers. Questionnaires from 360 patients were received and analyzed. Approximately 76.0% of the patients did not receive health information and expressed the need for the information. The information about how to reduce emotional distress (90.1%), rehabilitation (76.2%), disease symptoms (59.3%), and nutritional support (56.8%) were paramount among patients' concerns. Only 12.8% hoped to acquire information on sexual health. Health information for cancer patients at the recovery stage in China is poor. A tripartite involvement of the hospital-family-community and the combined intervention related to physical sequelae and psychosocial factors are needed at the recovery stage. PMID- 23728992 TI - Sun protection training based on a theater play for preschoolers: an effective method for imparting knowledge on sun protection? AB - Sun protection in childhood is important to reduce the risk of developing skin cancer later in life. The "Periods-of-Life-Program" for primary prevention of skin cancer introduces a combination of individual and environmental interventions for the preschool period. Within this pilot study, an intervention group received cognitive-behavioral and environmental interventions. A control group had solely received the environmental intervention, and a wait-control group received no intervention. Nursery school children (n = 80, 3 to 6 years of age) of four nursery schools were randomly assigned to these groups on school level. The ability of the cognitive-behavioral intervention (a theater play) to enhance sun protection knowledge was examined. The theater play improved knowledge over all age groups (p < .05 eta(2) = .06). Age-specific analyses showed better results for children aged 5 to 6 (p < .05 eta(2) = .20) compared to children aged 3 to 4 years (p = .17 eta(2) = .04). In combining cognitive behavioral and environmental interventions, the "Periods-of-Life-Program" is a promising strategy for primary prevention of skin cancer. PMID- 23728994 TI - AT 100 volumes of JEAB, A brief discussion of change and the road ahead. PMID- 23728993 TI - Mini-review on glycolysis and cancer. AB - Glycolysis is a universal pathway in the living cells. The complete pathway of glycolysis was elucidated in 1940. This pathway is often referred to as Embden Meyerhof pathway in honor of the two biochemists that made a major contribution to the knowledge of glycolysis. The objective of the study was to review the published literature on glycolysis and relation to cancer. The material for this review was taken mostly from up-to-date biochemistry textbooks and electronic journals. To collect publications, PubMed and the Cochrane database of systematic reviews were used. Some other relevant references were collected from personal database of papers on glycolysis and cancer. Several glycolytic inhibitors are currently in preclinical and clinical development. Inhibition of glycolysis in cancer cells is a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. This article is an important topic to be considered by cancer researchers and those who treat cancers. PMID- 23728995 TI - Contrasting responses of heterotrophic and autotrophic respiration to experimental warming in a winter annual-dominated prairie. AB - Understanding how soil respiration (Rs) and its source components respond to climate warming is crucial to improve model prediction of climate-carbon (C) feedback. We conducted a manipulation experiment by warming and clipping in a prairie dominated by invasive winter annual Bromus japonicas in Southern Great Plains, USA. Infrared radiators were used to simulate climate warming by 3 degrees C and clipping was used to mimic yearly hay mowing. Heterotrophic respiration (Rh) was measured inside deep collars (70 cm deep) that excluded root growth, while total soil respiration (Rs) was measured inside surface collars (2 3 cm deep). Autotrophic respiration (Ra) was calculated by subtracting Rh from Rs. During 3 years of experiment from January 2010 to December 2012, warming had no significant effect on Rs. The neutral response of Rs to warming was due to compensatory effects of warming on Rh and Ra. Warming significantly (P < 0.05) stimulated Rh but decreased Ra. Clipping only marginally (P < 0.1) increased Ra in 2010 but had no effect on Rh. There were no significant interactive effects of warming and clipping on Rs or its components. Warming stimulated annual Rh by 22.0%, but decreased annual Ra by 29.0% across the 3 years. The decreased Ra was primarily associated with the warming-induced decline of the winter annual productivity. Across the 3 years, warming increased Rh/Rs by 29.1% but clipping did not affect Rh/Rs. Our study highlights that climate warming may have contrasting effects on Rh and Ra in association with responses of plant productivity to warming. PMID- 23728996 TI - Practical phenotyping of difficult asthma. PMID- 23728997 TI - Interaction effects of lead on bioavailability and pharmacokinetics of arsenic in the rat. AB - Arsenic (As) and lead (Pb) are common contaminants found in mine waste materials. For an evidence-based risk assessment, it is important to better understand the potential interaction of mixed contaminants; and this interaction study was investigated in an in vivo rat model. Following co-administration of a fixed dose of As(V) as in sodium arsenate and different doses of Pb as lead acetate to Sprague-Dawley rats, blood arsenic concentration and bioavailability decreased. A decrease in As blood concentration when lead was co-administered was observed with increasing lead doses. Pharmacokinetic parameters for As in the blood showed faster absorption and elimination of this metalloid in the presence of Pb. The elimination half-life of As decreased from 67 days in As solo group to 27-30 with doses of Pb. Bioavailability of As was also decreased by 30-43 % in the presence of Pb. Decreased urinary excretion of Pb and tissue accumulation were also observed. It indicates lower absorption of As when co-administered with Pb. A probable explanation for these findings is that As co-administration with Pb could have resulted in the formation of less soluble lead arsenate. However, such an interaction between As and Pb could only explain about one-third of the variation when real mine waste materials containing both of these elements were administered to rats. This suggests that other effects from physical and chemical parameters could contribute to the bioavailability of arsenic in complex real environmental samples. PMID- 23728998 TI - Arsenic concentration in rice, fish, meat and vegetables in Cambodia: a preliminary risk assessment. AB - To assess arsenic contaminations and its possible adverse health effects, food samples were collected from Kandal, Kratie and Kampong Cham in Cambodia. The highest and the lowest concentrations were observed in fish (mean 2,832 ng g(-1), ww) collected from Kandal province and cattle stomach (1.86 +/- 1.10 ng g(-1), ww) collected from Kratie, respectively. The daily intake of arsenic via food consumption was 604, 9.70 and 136 MUg day(-1) in Kandal, Kratie and Kampong Cham, respectively. The arsenic dietary intake in Kandal ranked No. 1 among all the 17 compared countries or regions. Fish consumption contributed the greatest proportion of total arsenic daily intake in Kandal (about 63.0 %) and Kampong Cham (about 69.8 %). It is revealed to be a much more important exposure pathway than drinking water for residents in Kampong Cham. The results of risk assessment suggested that the residents in Cambodia, particularly for people in Kandal province, suffer high public health risks due to consuming arsenic-contaminated food. PMID- 23728999 TI - Perturbation of MicroRNA-370/Lin-28 homolog A/nuclear factor kappa B regulatory circuit contributes to the development of hepatocellular carcinoma. AB - MicroRNA 370 (miR-370) is located within the DLK1/DIO3 imprinting region on human chromosome 14, which has been identified as a cancer-associated genomic region. However, the role of miR-370 in malignances remains controversial. Here, we report that miR-370 was repressed in human hepatocellular carcinoma (HCC) tissues and hepatoma cell lines. Using gain-of-function and loss-of-function experiments, we demonstrated that miR-370 inhibited the malignant phenotype of HCC cells in vitro. Overexpression of miR-370 inhibited growth and metastasis of HCC cells in vivo. Moreover, the RNA-binding protein, LIN28A, was identified as a direct functional target of miR-370, which, in turn, blocked the biogenesis of miR-370 by binding to its precursor. LIN28A also mediated the suppressive effects of miR 370 on migration and invasion of HCC cells by post-transcriptionally regulating RelA/p65, which is an important effector of the canonical nuclear factor kappa B (NF-kappaB) pathway. Interleukin-6 (IL-6), a well-known NF-kappaB downstream inflammatory molecule, reduced miR-370 but increased LIN28A levels in HCC. Furthermore, miR-370 levels were inversely correlated with LIN28A and IL-6 messenger RNA (mRNA) levels, whereas LIN28A mRNA expression was positively correlated with IL-6 expression in human HCC samples. Interestingly, reduction of miR-370 expression was associated with the development of HCC in rats, as well as with aggressive tumor behavior and short survival in HCC patients. CONCLUSIONS: These data demonstrate the involvement of a novel regulatory circuit consisting of miR-370, LIN28A, RelA/p65 and IL-6 in HCC progression. Manipulating this feedback loop may have beneficial effect in HCC treatment. PMID- 23729000 TI - Canagliflozin: first global approval. AB - Canagliflozin (InvokanaTM), an oral selective sodium-glucose co-transporter 2 (SGLT2) inhibitor, is under global development with Mitsubishi Tanabe Pharma and Janssen Pharmaceuticals, a subsidiary of Johnson and Johnson, for the treatment of type 2 diabetes mellitus. SGLT2 are mainly located in the proximal tubule of the kidney and are involved in the reabsorption of filtered glucose from the glomeruli into the body. Inhibition of SGLT2 lowers blood glucose in an insulin independent manner as a consequence of blocking reabsorption of filtered glucose in the glomeruli, thereby increasing urinary excretion of glucose and, in turn, potentially reducing bodyweight. Canagliflozin is the first SGLT2 inhibitor to be approved in the USA and is under regulatory review in the EU. This article summarizes the milestones in the development of canagliflozin, leading to its first approval for use in adults with type 2 diabetes. PMID- 23729001 TI - Amphotericin B formulations: a comparative review of efficacy and toxicity. AB - Because of the increasing prevalence and changing microbiological spectrum of invasive fungal infections, some form of amphotericin B still provides the most reliable and broad spectrum therapeutic alternative. However, the use of amphotericin B deoxycholate is accompanied by dose-limited toxicities, most importantly, infusion-related reactions and nephrotoxicity. In an attempt to improve the therapeutic index of amphotericin B, three lipid-associated formulations were developed, including amphotericin B lipid complex (ABLC), liposomal amphotericin B (L-AmB), and amphotericin B colloidal dispersion (ABCD). The lipid composition of all three of these preparations differs considerably and contributes to substantially different pharmacokinetic parameters. ABLC is the largest of the lipid preparations. Because of its size, it is taken up rapidly by macrophages and becomes sequestered in tissues of the mononuclear phagocyte system such as the liver and spleen. Consequently, compared with the conventional formulation, it has lower circulating amphotericin B serum concentrations, reflected in a marked increase in volume of distribution and clearance. Lung levels are considerably higher than those achieved with other lipid-associated preparations. The recommended therapeutic dose of ABLC is 5 mg/kg/day. Because of its small size and negative charge, L-AmB avoids substantial recognition and uptake by the mononuclear phagocyte system. Therefore, a single dose of L-AmB results in a much higher peak plasma level (Cmax) than conventional amphotericin B deoxycholate and a much larger area under the concentration-time curve. Tissue concentrations in patients receiving L-AmB tend to be highest in the liver and spleen and much lower in kidneys and lung. Recommended therapeutic dosages are 3 6 mg/kg/day. After intravenous infusion, ABCD complexes remain largely intact and are rapidly removed from the circulation by cells of the macrophage phagocyte system. On a milligram-to-milligram basis, the Cmax achieved is lower than that attained by conventional amphotericin B, although the larger doses of ABCD that are administered produce an absolute level that is similar to amphotericin B. ABCD exhibits dose-limiting, infusion-related toxicities; consequently, the administered dosages should not exceed 3-4 mg/kg/day. The few comparative clinical trials that have been completed with the lipid-associated formulations have not demonstrated important clinical differences among these agents and amphotericin B for efficacy, although there are significant safety benefits of the lipid products. Furthermore, only one published trial has ever compared one lipid product against another for any indication. The results of these trials are particularly difficult to interpret because of major heterogeneities in study design, disease definitions, drug dosages, differences in clinical and microbiological endpoints as well as specific outcomes examined. Nevertheless, it is possible to derive some general conclusions given the available data. The most commonly studied syndrome has been empiric therapy for febrile neutropenic patients, where the lipid-associated preparations did not appear to provide a survival benefit over conventional amphotericin B deoxycholate, but did offer a significant advantage for the prevention of various breakthrough invasive fungal infections. For treatment of documented invasive fungal infections that usually involved hematological malignancy patients, no individual randomized trial has demonstrated a mortality benefit due to therapy with one of the lipid formulations. Results from meta-analyses have been contradictory, with one demonstrating a mortality benefit from all-cause mortality and one that did not demonstrate a mortality benefit. In the only published study to examine HIV infected patients with disseminated histoplasmosis, clinical success and mortality were significantly better with L-AmB compared with amphotericin B deoxycholate; there were no differences in microbiological outcomes between treatment groups. The lipid-associated preparations were not significantly better than amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis for either clinical or microbiological outcomes that were studied. In all of the trials that specifically examined renal toxicity, the lipid-associated formulations were significantly less nephrotoxic than amphotericin B deoxycholate. Infusion-related reactions occurred less frequently with L-AmB when compared with amphotericin B deoxycholate; however, ABCD had equivalent or more frequent infusion-related reactions than conventional amphotericin B, and this resulted in the cessation of at least one clinical trial. At the present time, this particular lipid formulation is no longer commercially available. For the treatment of most invasive fungal infections, an amphotericin B lipid formulation provides a safer alternative than conventional amphotericin B, with at least equivalent efficacy. As the cost of therapy with these agents continues to decline, these drugs will likely maintain their important role in the antifungal drug armamentarium because of their efficacy and improved safety profile. PMID- 23729002 TI - Teduglutide: a review of its use in the treatment of patients with short bowel syndrome. AB - The recombinant analogue of human glucagon-like peptide-2 (GLP-2) teduglutide (Gattex((r)), Revestive((r))) is a novel therapy for short bowel syndrome (SBS). GLP-2 is a naturally occurring hormone that regulates the growth, proliferation and maintenance of cells lining the gastrointestinal tract. Subcutaneous teduglutide is the first long-term medical therapy approved for the treatment of adult patients with SBS who are dependent on parenteral support (parenteral nutrition and/or intravenous fluids). In a pivotal, double-blind, multicentre, phase III study in adult patients with SBS who were dependent on parenteral support, a significantly higher proportion of teduglutide 0.05 mg/kg/day recipients than placebo recipients achieved at least a 20% reduction from baseline in weekly parenteral support volume at week 20 and maintained at week 24 (primary endpoint). The overall mean reduction in weekly parenteral support volume from baseline was greater in patients who received teduglutide compared with those who received placebo. Additionally, more teduglutide-treated patients achieved at least a one-day reduction in parenteral support than those receiving placebo. Subcutaneous teduglutide had an acceptable tolerability profile; the most frequently reported adverse events were of gastrointestinal origin, consistent with the underlying disease condition and the known mechanism of action of teduglutide. PMID- 23729003 TI - Global DNA methylation status in laryngeal cancer. AB - BACKGROUND: The purpose of our study was to evaluate if DNA methylation level in leukocytes may be used as a surrogate marker of genome methylation status in laryngeal cancer tissues. METHODS: We evaluated global DNA methylation using an ultra performance liquid chromatography (UPLC)-based method to assess the total content of 5-methylcytosine (5 mC). RESULTS: The study was performed on DNA isolated from cancer tissues, adjacent normal tissues, and peripheral blood leukocytes in a group of 72 patients with laryngeal cancer. DNA hypomethylation was found in tumor tissue (56%) and normal tissue (49%). There was a significant correlation between the levels of 5 mC in these 2 types of tissue. There was no significant DNA hypomethylation in blood. A negative correlation between tumor grade and blood levels of 5 mC was found. CONCLUSION: The level of leukocyte DNA methylation measured using total 5 mC content cannot be used as a surrogate marker for genome methylation status in laryngeal cancer tissues. PMID- 23729004 TI - Inactivation of HDAC3 and STAT3 is critically involved in 1-stearoyl-sn-glycero-3 phosphocholine-induced apoptosis in chronic myelogenous leukemia K562 cells. AB - We here investigated the anticancer mechanism of 1-stearoyl-sn-glycero-3 phosphocholine (LPC), one of the lysophosphatidylcholines, in chronic myelogenous leukemia (CML) K562 cells. LPC significantly showed cytotoxicity at 80 MUM and induced apoptosis by sub-G1 accumulation, increase in Annexin V positive and caspase activation. LPC enhanced histone H3 acetylation but decreased histone deacetylase (HDAC) activity and HDAC3 expression. LPC also inhibited phosphorylation of STAT3, its DNA binding activity and nuclear co-localization of HDAC3 and STAT3. In addition, LPC effectively attenuated the expression of survival genes such as Cyclin D1, Cyclin E, Bcl-xL, Bcl-2 and survivin but did not affect COX-2 expression in K562 cells. Furthermore, LPC suppressed phosphorylation of Src and Janus activated kinase 2 while promoted the expression of tyrosine phosphatase Src homology 2 domain-containing phosphatase 1 (SHP-1). Consistently, silencing SHP-1 and pervanadate, an inhibitor of protein tyrosine phosphatase, reversed inactivation of HDAC and STAT3, cleavages of caspase 3 and poly (ADP-ribose) polymerase in LPC-induced apoptosis. Of note, chromatin immunoprecipitation assay revealed that LPC suppressed the binding of HDAC3 and STAT3 to Bcl-xL, Bcl-2 and survivin promoter. Overall, our findings indicate that inactivation of STAT3 and HDAC mediates LPC-induced apoptosis in CML K562 cells. PMID- 23729005 TI - Endonasal endoscopic treatment of recurrent dacryocystitis. AB - This report assessed clinical conditions leading to recurrent dacryocystitis and success rates of its treatment by endonasal endoscopic dacryocystorhinostomy. Forty-eight patients with recurrent dacryocystitis underwent endonasal endoscopic surgery and were followed up for at least 6 months. High bone windows, small bone window openings, small lacrimal sac stomas, scar tissues, and organic diseases of the nasal cavity led to fistula closure. Out of 48 patients, 45 (93.8%) patients were cured by endonasal endoscopic surgery. Endonasal endoscopic dacryocystorhinostomy is beneficial for recurrent dacryocystitis. PMID- 23729006 TI - Deprotonation of C-alkyl groups of cationic triruthenium clusters containing cyclometalated C-alkylpyrazinium ligands: experimental and computational studies. AB - The C-alkyl groups of cationic triruthenium cluster complexes of the type [Ru3(MU H)(MU-kappa(2)N(1),C(2)-L)(CO)10](+) (HL represents a generic C-alkyl-N methylpyrazium species) have been deprotonated to give kinetic products that contain unprecedented C-alkylidene derivatives and maintain the original edge bridged decacarbonyl structure. When the starting complexes contain various C alkyl groups, the selectivity of these deprotonation reactions is related to the atomic charges of the alkyl H atoms, as suggested by DFT/natural-bond orbital (NBO) calculations. Three additional electronic properties of the C-alkyl C-H bonds have also been found to correlate with the experimental regioselectivity because, in all cases, the deprotonated C-H bond has the smallest electron density at the bond critical point, the greatest Laplacian of the electron density at the bond critical point, and the greatest total energy density ratio at the bond critical point (computed by using the quantum theory of atoms in molecules, QTAIM). The kinetic decacarbonyl products evolve, under appropriate reaction conditions that depend upon the position of the C-alkylidene group in the heterocyclic ring, toward face-capped nonacarbonyl derivatives (thermodynamic products). The position of the C-alkylidene group in the heterocyclic ring determines the distribution of single and double bonds within the ligand ring, which strongly affects the stability of the neutral decacarbonyl complexes and the way these ligands coordinate to the metal atoms in the nonacarbonyl products. The mechanisms of these decacarbonylation processes have been investigated by DFT methods, which have rationalized the structures observed for the final products and have shed light on the different kinetic and thermodynamic stabilities of the reaction intermediates, thus explaining the reaction conditions experimentally required by each transformation. PMID- 23729007 TI - Two chromosome 9p21 haplotype blocks distinguish between coronary artery disease and myocardial infarction risk. AB - BACKGROUND: Variants at the 9p21 locus associate with the risk of coronary artery disease (CAD) or myocardial infarction (MI). However, atherosclerotic plaque deposition is distinct from MI (plaque rupture and thrombosis), and recent studies showed no association between these variants and MI in patients with preexisting CAD. We performed haplotype analysis at the 9p21 locus to test whether haplotypes at distinct linkage disequilibrium blocks predict these phenotypes. METHODS AND RESULTS: Using 24 single-nucleotide polymorphisms genotyped in white patients without diabetes mellitus, we reconstructed haplotypes at the 9p21 locus. Patients with angiograhic CAD/MI had >=1 epicardial stenosis >50% (n=2352), whereas controls were asymptomatic and over the age of 60 years (n=2116). For CAD patients, regression models examined the association of haplotypes with initial age of symptomatic CAD, number of diseased vessels, and history of MI. In the case-control study, only haplotypes at 1 block tagged by rs1333049 associated with CAD more so than MI. These haplotypes also associated with early onset of CAD (beta=-0.13; P=1.37*10(-4)) and disease severity (beta=0.1823; P=0.006) but not with prevalent MI among patients with CAD. In contrast, haplotypes at another block tagged by rs518394 associated with prevalent MI (beta=0.239; P=2.05*10(-4)), but remarkably these are inversely associated with disease severity (beta=-0.196; P=0.003). This MI association was replicated in the Cleveland Clinic GeneBank premature CAD cohort (n=1385; beta=0.207; P=0.019). CONCLUSIONS: Variants/haplotypes at 2 blocks are distinguished at 9p21; those at 1 block predispose to atherosclerosis, whereas those at the other predispose to MI among patients with preexisting CAD. PMID- 23729008 TI - PPIcons: identification of protein-protein interaction sites in selected organisms. AB - The physico-chemical properties of interaction interfaces have a crucial role in characterization of protein-protein interactions (PPI). In silico prediction of participating amino acids helps to identify interface residues for further experimental verification using mutational analysis, or inhibition studies by screening library of ligands against given protein. Given the unbound structure of a protein and the fact that it forms a complex with another known protein, the objective of this work is to identify the residues that are involved in the interaction. We attempt to predict interaction sites in protein complexes using local composition of amino acids together with their physico-chemical characteristics. The local sequence segments (LSS) are dissected from the protein sequences using a sliding window of 21 amino acids. The list of LSSs is passed to the support vector machine (SVM) predictor, which identifies interacting residue pairs considering their inter-atom distances. We have analyzed three different model organisms of Escherichia coli, Saccharomyces Cerevisiae and Homo sapiens, where the numbers of considered hetero-complexes are equal to 40, 123 and 33 respectively. Moreover, the unified multi-organism PPI meta-predictor is also developed under the current work by combining the training databases of above organisms. The PPIcons interface residues prediction method is measured by the area under ROC curve (AUC) equal to 0.82, 0.75, 0.72 and 0.76 for the aforementioned organisms and the meta-predictor respectively. PMID- 23729009 TI - Molecular modeling of the piezoelectric effect in the ferroelectric polymer poly(vinylidene fluoride) (PVDF). AB - In this work, computational molecular modeling and exploration was applied to study the nature of the negative piezoelectric effect in the ferroelectric polymer polyvinylidene fluoride (PVDF), and the results confirmed by actual nanoscale measurements. First principle calculations were employed, using various quantum-chemical methods (QM), including semi-empirical (PM3) and various density functional theory (DFT) approaches, and in addition combined with molecular mechanics (MM) methods in complex joint approaches (QM/MM). Both PVDF molecular chains and a unit cell of crystalline beta-phase PVDF were modeled. This computational molecular exploration clearly shows that the nature of the so called negative piezo-electric effect in the ferroelectric PVDF polymer has a self-consistent quantum nature, and is related to the redistribution of the electron molecular orbitals (wave functions), leading to the shifting of atomic nuclei and reorganization of all total charges to the new, energetically optimal positions, under an applied electrical field. Molecular modeling and first principles calculations show that the piezoelectric coefficient d 33 has a negative sign, and its average values lies in the range of d 33 ~ -16.6 to -19.2 pC/N (or pm/V) (for dielectric permittivity epsilon = 5) and in the range of d 33 ~ -33.5 to -38.5 pC/N (or pm/V) (for epsilon = 10), corresponding to known data, and allowing us to explain the reasons for the negative sign of the piezo response. We found that when a field is applied perpendicular to the PVDF chain length, as polarization increases the chain also stretches, increasing its length and reducing its height. For computed value of epsilon ~ 5 we obtained a value of d31 ~ +15.5 pC/N with a positive sign. This computational study is corroborated by measured nanoscale data obtained by atomic force and piezo-response force microscopy (AFM/PFM). This study could be useful as a basis for further insights into other organic and molecular ferroelectrics. PMID- 23729010 TI - Outcomes of incidentally discovered thyroid nodules referred to a high-volume head and neck surgeon. AB - BACKGROUND: Incidental thyroid nodules are commonly found by radiological studies done for other indications. The yearly incidence of thyroid cancer is increasing, in part because of detection of nonpalpable nodules on imaging performed for unrelated issues. METHODS: All new patients referred to a high-volume thyroid surgeon for thyroid nodules were reviewed between February 2009 and January 2011. Data regarding patient demographics, risk factors, referring physician, radiologic findings, fine-needle aspiration (FNA) results, and management were reviewed. RESULTS: One hundred thirty-three of 729 patients (18.2%) had a thyroid nodule or nodules incidentally found on ultrasound, MRI, CT, nuclear imaging, or chest x-ray. Fifty-five patients (41.4%) were managed surgically, with 35 (63.6%) of those having thyroid cancer on final surgical pathology. CONCLUSION: Based on radiologic findings, risk factors, and FNA results, many incidental thyroid nodules can be observed. Incidental thyroid nodules should be evaluated in the same fashion as a palpable thyroid nodule. PMID- 23729011 TI - Birth outcomes among offspring of adult cancer survivors: a population-based study. AB - Do cancer and cancer treatment influence patients' subsequent pregnancies and outcomes for the offspring? In this study, we compared birth outcomes in 3,915 female and male survivors and 144,653 controls from the general population with similar parity, by merging data from the Cancer Registry and the Medical Birth Registry of Norway. The cancer survivors were diagnosed at age 16-45 in the period 1967-2004. Subgroups of nulliparous survivors (childless before cancer) and primiparous (one pregnancy before and one after cancer) were analyzed, using logistic regression to compare birth outcomes with controls, focusing perinatal death, congenital anomalies, preterm birth (<37 gestational weeks) and low birth weight (LBW, <2,500 g). We adjusted for maternal age, birth period and educational level. Nulliparous female survivors' offspring had increased risk of preterm birth (OR = 1.30 [95% CI 1.05-1.61]) but similar risks of LBW and perinatal death as their controls. Primiparous female survivors differed from their controls, with higher frequency of preterm birth (OR = 1.89 [95% CI 1.40 2.56]) and LBW at term (OR = 2.02 [95% CI 1.15-3.55]). A borderline significant increase of perinatal death was seen among offspring of primiparous female survivors, with OR = 1.92 (95% CI 0.98-3.76). Offspring of male survivors did not differ from their controls. For all cancer types combined, no increased risk of congenital anomalies was seen among either female or male survivors' offspring. Pregnant female cancer survivors should be offered close follow-up, as there is an increased risk of adverse birth outcomes, in particular among those with higher parities. PMID- 23729013 TI - Anthocyanin-rich juice does not affect gut-associated immunity in Fischer rats. AB - SCOPE: Most studies on immunomodulatory effects of anthocyanins are concentrated on their anti-inflammatory potential. In vitro studies suggest that anthocyanins possess anti-inflammatory potential, but results from in vivo studies are rare and inconclusive. Sparse information is available about the immune tissues that are affected by anthocyanins. As systemic bioavailability of anthocyanins is rather low, predominantly luminal anthocyanins could influence the gut-associated lymphoid tissue (GALT). Therefore, the present study investigated the immunomodulatory effects of an anthocyanin-rich grape-bilberry juice (ARJ) on the systemic immune system, GALT, and mesenteric adipose tissue (MAT). METHODS AND RESULTS: Fischer rats (n = 24/group) received ARJ or anthocyanin-depleted grape bilberry juice (control) for 10 wk. Lymphocytes were isolated from blood, spleen, Peyer's Patches, and mesenteric lymph nodes. Anthocyanin intake was 15 mg/day and concentrations were determined in plasma and intestinal tract. Number of T and natural killer cells, natural killer cell activity, cytokine secretion from lymphocytes (IL-10, IFN-gamma, and TNF-alpha) and MAT (IL-6, IL-10, and MCP-1), inflammation markers in serum (sICAM, IFN-gamma, and MCP-1), and activation status of NF-kappaB were not influenced by ARJ. CONCLUSION: This in vivo study suggests that anthocyanins at physiological doses affect neither the systemic immune system, nor GALT, or MAT in healthy, unchallenged rats. PMID- 23729014 TI - Idiopathic growth hormone deficiency in adults, Ben Johnson and the somatopause. PMID- 23729015 TI - Means, motive, and opportunity: SDH mutations are suspects in pituitary tumors. PMID- 23729019 TI - Hypoparathyroidism. PMID- 23729020 TI - The effect of young age on outcomes in head and neck cancer. AB - OBJECTIVES/HYPOTHESIS: Many head and neck surgeons believe that young patients with head and neck cancer (HNCA) have poorer outcomes than older patients, whereas the evidence in the literature is mixed. We sought to review our HNCA population to evaluate for survival differences between young and older patients. STUDY DESIGN: Matched pair retrospective cohort study. METHODS: A matched pair retrospective cohort study was completed of mucosal HNCA patients at our academic center (2003-2008). Patients aged 45 or less when diagnosed were identified as cases and matched one-to-one to controls by site of tumor, stage of disease, and gender. Risk factors, disease and treatment variables, and survival outcomes were compared between groups. In addition, a subset survival analysis was completed with oropharyngeal cancer patients and nonoropharyngeal cancer patients. RESULTS: There were 87 cases matched to 87 controls. Despite no difference in T and N stage between groups, cases more frequently underwent neck dissection. On Kaplan Meier and multivariate analysis, overall survival was marginally better for all young patients, whereas disease-free survival was significantly better. Within the subgroup analysis, the statistically significant disease-free survival advantage was lost for young patients with oropharyngeal cancer but maintained for all other sites. CONCLUSIONS: In this cohort, young HNCA patients had mildly improved overall survival but statistically greater disease-free survival. There was no statistically significant survival difference between young and older patients with oropharyngeal cancer, potentially secondary to a human papillomavirus effect. PMID- 23729021 TI - Patient satisfaction about using patient controlled analgesia in managing pain post surgical intervention. AB - Management of postoperative pain using patient controlled analgesia (PCA) has increased for its proven advantages over conventional methods of pain control. The purpose of this study was to investigate patients' satisfaction about using PCA post surgical intervention among patients at Saudi health care settings. A cross-sectional, descriptive correlational design was used to collect data from patients using PCA post surgical interventions. The analysis showed that patients had a moderate to high level of perception about efficacy of PCA, and had a moderate level of knowledge about PCA use and its function. The duration of using a PCA pump, patients' age, gender, marital status, educational level, type of surgery, and their work status were significant predictors (F 7, 76 = 5.13, p < .001; R(2) = 0.59). PCA offers patients with an individualized analgesic therapy that meets the patients' demand of pain control. The implications for nurses and medical staff are discussed. PMID- 23729022 TI - Efficiently assessing patient health literacy: the BHLS instrument. AB - Although health literacy limitations are common among patient populations, no efficient yet comprehensive health literacy assessment tool is available to nurses for use in busy health care settings. This study presents beginning evidence for the validity and reliability of a new health literacy assessment tool, the Brief Health Literacy Screen (BHLS). One hundred patients attending four primary care clinics completed the BHLS and the Test of Functional Health Literacy in Adults (TOFHLA) short form and answered questions about the health literacy tools. Findings indicated significant correlations between BHLS and shortened version of the TOFHLA (S-TOFHLA) scores, with higher correlations between BHLS items addressing written health literacy and the S-TOFHLA. Comparative discrimination findings were significant at BHLS cut point of 18 and S-TOFHLA cut point less than 23. Patients rated the BHLS significantly less difficult to complete than the S-TOFHLA. Results of preliminary testing indicate the BHLS is a potentially efficient, effective, and patient-friendly screening tool for health literacy. PMID- 23729023 TI - Older Hispanic women, health literacy, and cervical cancer screening. AB - Approximately 90 million people in the United States lack basic literacy skills, which affect health behaviors. Cervical cancer is preventable and treatable, yet few older Hispanic women seek screening and continue to be a high-risk group for cervical cancer. A literature review was conducted to address the relationship between cervical cancer screening, health literacy, and older Hispanic women. Eighty studies were reviewed, and nine addressed health literacy and Hispanic women. One study addressed the association between functional health literacy and Pap smear screening among older Hispanic women. Few studies have explored the association between preventive cervical cancer screening and health literacy among older Hispanic women. Nurses must assess health literacy and be prepared to provide care, which is culturally, and linguistically appropriate to improve health outcomes. Further research is needed to be inclusive of all populations including older Hispanic women. PMID- 23729024 TI - Effectiveness of miltefosine treatment in targeting anti-leishmanial HO-1/Nrf-2 mediated oxidative responses in visceral leishmaniasis patients. AB - OBJECTIVES: Miltefosine, an alkylphosphocholine anti-cancer drug, exhibits direct activity against Leishmania donovani and also promotes anti-leishmanial host immunomodulatory functions. Nuclear factor-erythroid 2-related factor 2 (Nrf-2), a redox-sensitive transcription factor, regulates the host stress responses leading to effective microbial clearance by a positive effect on haem oxygenase-1 (HO-1) enzyme expression/activity. We aimed to investigate the role of miltefosine in regulating HO-1/Nrf-2-mediated oxidative responses in visceral leishmaniasis (VL) patients in vivo and in vitro. METHODS: Splenic aspirate and bone marrow aspirate cells of VL patients (n = 23) were used in the study. RT-PCR of HO-1, Nrf-2 translocation analysis and HO-1 ELISA were used to investigate the HO-1/Nrf-2-mediated modulation of oxidative responses by miltefosine in vivo. Fluorometric measurement of reactive oxygen species (ROS) was performed, determination of glutathione peroxidase (GPx) activity was performed, and bilirubin and superoxide dismutase (SOD) levels were determined. The in vitro HO 1/Nrf-2-dependent anti-leishmanial effect of miltefosine was assessed by the use of specific inhibitors/inducers and subsequent microscopic measurement of parasite killing and Th1/Th2 cytokine regulation by ELISA. RESULTS: Increased levels of transcript and serum HO-1, Nrf-2 nuclear translocation, serum bilirubin, GPx and SOD activity in untreated VL patients were reversed after miltefosine chemotherapy. The effectiveness of miltefosine for positive induction of ROS via NADPH correlated with a decrease in HO-1/ERK/Nrf-2-dependent parasite load. Furthermore, HO-1 blockade by miltefosine led to suppression of interleukin 10 and transforming growth factor-beta, but enhanced interleukin-12 and tumour necrosis factor-alpha production, in VL patients. CONCLUSIONS: The antioxidant promoting property of L. donovani is crucial for protection against the mounting redox threat in the host. Therefore, these findings provide direct evidence for targeting HO-1/Nrf-2 as an anti-leishmanial approach for chemotherapy in human VL. PMID- 23729025 TI - Solid-phase synthesis of reduced selenocysteine tetrapeptides and their oxidized analogs containing selenenylsulfide eight-membered rings. AB - A series of protected and reduced forms of model tetrapeptides that mimic the C terminus of human thioredoxin reductases were obtained in good yields, using solid-phase peptide synthesis (SPPS). SPPS was performed on the Knorr Amide MBHA resin for Fmoc chemistry using especially protected cystein and selenocystein derivatives. All amino acids have been coupled according to the HBTU/HOBt/DIPEA method. Furthermore, the corresponding oxidized peptides containing eight membered rings with intramolecular S-S and S-Se bridges were prepared via I[Formula: see text]/MeOH or DMSO/TFA oxidation, respectively. PMID- 23729026 TI - Occurrence, possible sources, and temporal trends of polychlorinated dibenzo-p dioxins and dibenzofurans in water and sediment from the lower Yangtze River basin, Jiangsu and Shanghai areas of Eastern China. AB - The concentrations, compositional profiles, and possible sources of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/PCDF) in water column and surface sediment samples from the lower reaches of the Yangtze River were investigated, and the potential risks posed by these chemicals were evaluated. Concentrations of the 17 2,3,7,8-substituted PCDD/PCDF in the water and sediment samples ranged from 0.45 to 10.0 pg TEQ/L (mean 2.34 pg TEQ/L) and from 0.31 to 51 pg TEQ/g dw (mean 5.25 pg TEQ/g dw), respectively. Water and sediments from the Nanjing-Nantong sections of the Yangtze River were found to have elevated PCDD/PCDF levels, and the PCDD/PCDF TEQ concentrations in 13 sediment samples exceeded the probable effect levels (PEL), above which adverse biological effects are likely. Multivariate statistical analysis indicated that the principal PCDD/PCDF contamination source for the water and sediment was the production and use of pentachlorophenol (PCP) or sodium pentachlorophenate (PCP Na). PCDD/PCDF concentrations were stable over time near the Yangtze River Estuary but had increased sharply in recent decades in the Nanjing-Nantong section, which will have been related to the growth in industrial activities and other anthropogenic PCDD/PCDF sources. Total organic carbon (TOC) and PCDD/PCDF concentrations correlated significantly (R=0.474, P<0.01), suggesting that TOC plays an important role in the transport and re-distribution of PCDD/PCDF in the Yangtze River basin. PMID- 23729028 TI - Air dispersion of heavy metals in the vicinity of the As-Sb-Tl abounded mine and responsiveness of moss as a biomonitoring media in small-scale investigations. AB - A systematic study was carried out to investigate air deposition and to explore the natural distribution and enrichment (contamination) with trace elements in the small area (cca. 13 km(2)) of an antimony-arsenic-thallium mineralization outcrop at an abandoned mine "Allchar." The mine is located on the northwestern part of Kozuf Mount, Republic of Macedonia. The locality of Allchar is unique in its mineral composition; besides a very intriguing mineral, lorandite, there are 45 other minerals, some of which are rare. The distribution of 53 elements (with special attention to As, Sb, and Tl) were detected in 69 moss samples from eight various species collected from this area. Moss samples were analyzed following microwave digestion by inductively coupled plasma-mass spectrometry and inductively coupled plasma-atomic emission spectrometry. It was found that the atmospheric deposition for As in the moss samples on or around the Allchar mine is >6.5 times higher and for Tl is 19 times higher compared to values for the samples from the rest of the Allchar area. By the application of multivariate cluster and R-mode factor analyses (FA), five geochemical associations were determined. Cluster and R-mode FA were used to identify and characterize element associations, and five associations of elements were determined by the method of multivariate statistics. F1 (Co, Cr, Fe, Sc, Li, V, Ga, Y, Ni, Mn, Al, La-Lu, Cu, Ge, Be, Bi, and Hf); F2 (As, Tl, Sb, and Mg); F3 (Rb, Cs, and Mo); F4 (Sr, Ba, Hf, Zr, La-Lu, and Bi), and F5 (Cd, Zn, Ag, and Cu). PMID- 23729027 TI - Levels, compositions, and inventory of polybrominated diphenyl ethers in sewage sludge of Guangdong Province, South China. AB - Polybrominated diphenyl ethers (PBDEs) were measured in sewage sludge samples collected from major wastewater treatment plants in Guangdong Province, South China. Concentrations of ?39PBDE (all 39 compounds including tri- to hepta- PBDE congeners except for BDE-209) ranged from 3.6 to 428 ng/g dw with a mean value of 67.4 ng/g dw and a median value of 25.9 ng/g dw, and those of BDE-209 ranged from 9.9 to 5,010 ng/g dw (mean 1,024 ng/g dw and median 824 ng/g dw). The PBDE mixtures detected were mainly comprised of penta-, octa-, and deca-BDEs, with deca-BDE as the dominant constituent. The most abundant congeners, excluding BDE 209, were BDE-47, BDE-99, and BDE-183. Good correlations were found among the concentrations of BDE-47, BDE-99, BDE-100, BDE-138, and BDE-154 (r>0.8). However, poor correlations were found between the concentrations of BDE-209 and all other congeners (r<0.3). This fact suggests that most tri- to hepta-BDEs detected did not originate from decomposition of deca-BDE. The estimated annual emission of ?allPBDEs, ?39PBDEs, penta-BDE, octa-BDE, and deca-BDE to the Pearl River Delta environment (PRD), based on the sludge samples analyzed, amounts to 232, 20.2, 5.5, 1.7, and 212 kg per year, implicating sewage sludge as a significant source of PBDEs to the PRD environment. PMID- 23729029 TI - Influence of earthworm Eisenia fetida on removal efficiency of N and P in vertical flow constructed wetland. AB - This study investigates biomass, density, photosynthetic activity, and accumulation of nitrogen (N) and phosphorus (P) in three wetland plants (Canna indica, Typha augustifolia, and Phragmites austrail) in response to the introduction of the earthworm Eisenia fetida into a constructed wetland. The removal efficiency of N and P in constructed wetlands were also investigated. Results showed that the photosynthetic rate (P n), transpiration rate (T r), and stomatal conductance (S cond) of C. indica and P. austrail were (p < 0.05) significantly higher when earthworms were present. The addition of E. fetida increased the N uptake value by above-ground of C. indica, T. augustifolia, and P. australis by 185, 216, and 108 %, respectively; and its P uptake value increased by 300, 355, and 211 %, respectively. Earthworms could enhance photosynthetic activity, density, and biomass of wetland plants in constructed wetland, resulting in the higher N and P uptake. The addition of E. fetida into constructed wetland increased the removal efficiency of TN and TP by 10 and 7 %, respectively. The addition of earthworms into vertical flow constructed wetland increased the removal efficiency of TN and TP, which was related to higher photosynthetic activity and N and P uptake. The addition of earthworms into vertical flow constructed wetland and plant harvests could be the significantly sustainable N and P removal strategy. PMID- 23729030 TI - Historical reconstruction of atmospheric lead pollution in central Yunnan province, southwest China: an analysis based on lacustrine sedimentary records. AB - Atmospheric lead (Pb) pollution during the last century in central Yunnan province, one of the largest non-ferrous metal production centers in China, was reconstructed using sediment cores collected from Fuxian and Qingshui Lakes. Lead concentrations and isotopic ratios ((207)Pb/(206)Pb and (208)Pb/(206)Pb) were measured in sediment cores from both lakes. The operationally defined chemical fractions of Pb in sediment core from Fuxian Lake were determined by the optimized BCR procedure. The chronology of the cores was reconstructed using (210)Pb and (137)Cs dating methods. Similar three-phase variations in isotopic ratios and enrichment factors of Pb were observed in the sediment cores from both lakes. Before the 1950s, the sediment data showed low (207)Pb/(206)Pb and (208)Pb/(206)Pb ratios and enrichment factors (EFs=~1), indicating that the sedimentary Pb was predominantly of lithogenic origin. However, these indices were increased gradually between the 1950s and the mid-1980s, implying an atmospheric Pb deposition. The EFs and isotopic ratios of Pb reached their peak during recent years, indicating aggravating atmospheric Pb pollution. The average anthropogenic Pb fluxes since the mid-1980s were estimated to be 0.032 and 0.053 g m(-2) year(-1) recorded in Fuxian and Qingshui cores, respectively. The anthropogenic Pb was primarily concentrated in the reducible fraction. Combining the results of Pb isotopic compositions and chemical speciations in the sediment cores and in potential sources, we deduced that recent aggravating atmospheric Pb pollution in central Yunnan province should primarily be attributed to regional emissions from non-ferrous metal production industries. PMID- 23729031 TI - Transseptal antegrade transcatheter aortic valve replacement for patients with no other access approach - a contemporary experience. AB - OBJECTIVE: To assess the feasibility and outcomes in patients undergoing transvenous transseptal (TS) transcatheter aortic valve replacement (TAVR). BACKGROUND: TS approach for TAVR was abandoned in favor of retrograde transfemoral, transaortic, or transapical approaches. TS TAVR may still be warranted in patients for whom no other approach is feasible. METHODS: Observational consecutive case series at a single center, to evaluate technical outcomes in inoperable patients with aortic stenosis who had contraindications for other approaches and who underwent TAVR via a transvenous TS antegrade approach using the Edwards-Sapien (ES) valve. RESULTS: Over a 4-month period, 9 patients underwent TS TAVR with 26 mm (n = 4) and 23 mm (n = 5) ES valves. Mean age was 84.5 +/- 6.6 years and Society of Thoracic Surgeons predicted risk of mortality was 7.8 +/- 2.8%. Specific contraindications for other access included iliofemoral arterial diameter <7 mm in 9 (100%), porcelain aorta in 6 (66%) patients, multiple (>=2) sternotomies in 2 (22%) patients, severe pulmonary disease in 3 (33%), extreme frailty in 1 (11%), spinal stenosis with impaired ability to rehabilitate postsurgery in 1 (11%) and apical left ventricular thrombus in 1 (11%) patient. Antegrade deployment of the ES prosthetic valve was technically feasible in 8 patients. Major bleeding occurred in 4 patients, two patients suffered acute kidney injury without need for dialysis and one patient required a permanent pacemaker. The median (25th, 75th percentiles) fluoroscopy time was 49 (34, 81) minutes and contrast volume was 150 (120, 225) ml. No patient had hemodynamically significant post-TAVR aortic insufficiency nor damage to the mitral valve. At 6 months follow-up, there were no cerebrovascular events or rehospitalizations and mean NYHA Class improved from 3.4 to 1.7. CONCLUSIONS: The antegrade TS approach to TAVR is a technically feasible option for "no access" patients. Prospective assessment of the safety and efficacy of this approach in the current era warrants further study. PMID- 23729033 TI - Digestive Disorders Federation meeting 17-20 June 2012 Liverpool. Abstracts. PMID- 23729032 TI - Retraction: Cyanobacteria cultivation in industrial wastewaters and biodiesel production from their biomass: a review. PMID- 23729034 TI - Next-generation sequencing: does the next generation still have a right to an open future? PMID- 23729035 TI - [Liver support methods]. PMID- 23729037 TI - Retraction notice to "Prediction of cardiovascular events in statin-treated patients by lipid and non-lipid biomarkers". PMID- 23729036 TI - [Minimal effects of acute liver failure on hemostasis]. PMID- 23729038 TI - Retraction notice to "Plasma PCSK9 levels and clinical outcomes in the TNT (Treating to New Targets) Trial". PMID- 23729039 TI - Retraction: Selective use of hand and forearm muscles during bone screw insertion: a natural torque meter. PMID- 23729040 TI - Hereditary elliptocytosis. PMID- 23729041 TI - Stand up for health. PMID- 23729042 TI - Arthritis answers. PMID- 23729043 TI - So you want to be a scientist. PMID- 23729044 TI - Officers & gentlemen. PMID- 23729046 TI - Snack attack. PMID- 23729045 TI - Nice nibbles. PMID- 23729047 TI - [Objective and subjective findings. There are considerable differences]. PMID- 23729048 TI - Retraction notice to "Non-enzymatic electrochemical glucose sensor based on silver/silver oxide nano-rods reinforced with multiwall carbon nanotubes": [Talanta 104C (2013) 212-218]. PMID- 23729049 TI - Effects of stress on alcohol consumption. PMID- 23729050 TI - Exemplification of the implementation of alternatives to experimental testing in chemical risk assessment - case studies from the CADASTER Project. Preface. PMID- 23729051 TI - We are not a third world country. PMID- 23729052 TI - Support from Joint Committee. PMID- 23729053 TI - Prosthodontics at the crossroads: is this a 'golden age'? PMID- 23729054 TI - North Cork HSE orthodontic treatment waiting list 2009-2010: retrospective audit of patient records. AB - PURPOSE OF THE STUDY: To evaluate the case profile and verify the treatment eligibility (based on the modified IOTN) from written case records, of patients accepted for orthodontic treatment from the North Cork area of HSE South. MATERIALS AND METHODS: A data collection form was designed and applied to the written case records of 200 consecutive patients accepted for orthodontic treatment in 2009/2010. Data relating to the IOTN (DHC and AC, where relevant) were provided by a calibrated examiner. RESULTS: Based on the written case records, most (57%) of the treatment cohort were female and had an average age of 14 years and two months. The predominant malocclusion was Class II division 1 (40%). The prevalence of Class III malocclusion was high at 18%. A total of 61% of patients were in grade 5 and 36% in grade 4. The majority of patients in each of these grades fell into DHC 5a (32%), followed by 5i (24%) and 4d AC > 8 (16%). CONCLUSIONS: Written case records conclude that patients accepted for orthodontic treatment from the North Cork area of HSE South were predominantly female. Class II division 1 malocclusion was the most common accepted for treatment. These records verify that those patients accepted for orthodontic treatment satisfy the eligibility criteria for HSE treatment. PMID- 23729055 TI - Changes in orthodontic treatment modalities in the past 20 years: exploring the link between technology and scientific evidence. AB - STATEMENT OF THE ISSUE: Is there a link between the many perceived advances in orthodontic techniques/therapy and science in the past 20 years? The purpose of this paper is to take five topics and match the perceptions with the scientific evidence. The variety of appliances and the swings in treatment philosophy have been dramatic, including the swing from extraction to non-extraction therapy, the introduction of space-age wires, appliances that grow mandibles, the introduction and extraordinary growth of Invisalign, and reduced friction brackets to reduce treatment time, all with claims by manufacturers of better results than ever before. The focus is on faster treatment, reduced visits/appointments and superior results. Most of these 'advancements' represent what has been the 'juggernaut of technology'. Five questions are posed, and an evidence-based approach is used to critically examine the literature in these selected topics. PMID- 23729056 TI - Social media. AB - There is an argument that with the common use of a variety of media the professional expectations on our everyday life are becoming increasingly important. A moan about a patient on a Monday night 20 years ago may have been harmless. The same comment made using today's communication methods could result in a regulatory challenge. PMID- 23729057 TI - Do not reanimate. PMID- 23729059 TI - Cloud to black hole: eat my dust. PMID- 23729058 TI - Tweaks to the idea factory. PMID- 23729060 TI - What's the buzz? PMID- 23729061 TI - Faux fossils. PMID- 23729062 TI - Soft circuits. PMID- 23729063 TI - Mediterranean mystery. PMID- 23729065 TI - Closer to home. PMID- 23729064 TI - "Nurse, pass the blowtorch". PMID- 23729066 TI - Running on poison. PMID- 23729067 TI - Going to pot. PMID- 23729068 TI - Google's creep factor. PMID- 23729069 TI - Tiny plants that once ruled the seas. PMID- 23729070 TI - Quantum weirdness? It's all in your mind. PMID- 23729071 TI - Breaking the brain barrier. PMID- 23729072 TI - Storm of the century (every two years). PMID- 23729073 TI - Cracks in the periodic table. PMID- 23729074 TI - Ring cycle. PMID- 23729075 TI - Armor against prejudice. PMID- 23729076 TI - Edge of the Internet. Interview by Larry Greenemeier. PMID- 23729077 TI - CSI, science. Where neuroscience meets criminology. PMID- 23729078 TI - These patients wear stripes and chains. PMID- 23729079 TI - Home hemodialysis: a glass half full. PMID- 23729080 TI - Knowledge and perception of home dialysis in ESRD patients: a survey in incident and prevalent patients undergoing in-center HD. PMID- 23729081 TI - Changes and alternatives for dialysis facilities under the bundled payment plan. AB - The new prospective payment system, or bundled payment plan, for dialysis treatments presents dialysis providers with the potential for clinical and economic risk and opportunity, depending on the modality of dialysis therapy used and the frequency and doses of injectable drugs administered. Under the bundle, some financial incentives may encourage starting incident patients on home dialysis, either home hemodialysis or peritoneal dialysis. Administration of injectable medications such as vitamin D and iron, which are no longer separately billable, may require providers to consider oral equivalents or slightly different dosing patterns. Treatment of anemia with erythropoiesis-stimulating agents will also require careful consideration, as will use of oral medications when they are added to the bundle in 2016. These factors are already playing out in the marketplace, and going forward providers will need to balance changes in utilization with patient care. PMID- 23729082 TI - A model for initiating change in the dialysis setting using an implementation plan. AB - Change has become a constant in the workplace. Although the staff may resist change and feel it is happening too quickly, leading change is a critical component for nurse leaders. It is important for the registered nurse to take the lead and guide the staff through the process. PMID- 23729083 TI - Factors influencing excellence in nursing. PMID- 23729084 TI - Highlighting a Pennsylvania nurse Linda Aiken, PhD, FAAN, FRCN, RN. PMID- 23729085 TI - Excellent, ethical and engaging work. PMID- 23729086 TI - Good work feels good: student perceptions of good work. PMID- 23729087 TI - It's all in the numbers. PMID- 23729088 TI - Where are the dental homes? A challenge to dentistry. PMID- 23729089 TI - Insurance connection. PMID- 23729090 TI - Age one exams--the rationale. PMID- 23729091 TI - Medical dental collaboration: quality, cost effective health care. PMID- 23729092 TI - Benefits of the age one exam. PMID- 23729093 TI - CARA Iraq Research Fellowship Programme. PMID- 23729094 TI - CARA Iraq Research Fellowship Programme. Preface. PMID- 23729095 TI - Environmental pollution by depleted uranium in Iraq with special reference to Mosul and possible effects on cancer and birth defect rates. AB - Iraq is suffering from depleted uranium (DU) pollution in many regions and the effects of this may harm public health through poisoning and increased incidence of various cancers and birth defects. DU is a known carcinogenic agent. About 1200 tonnes of ammunition were dropped on Iraq during the Gulf Wars of 1991 and 2003. As a result, contamination occurred in more than 350 sites in Iraq. Currently, Iraqis are facing about 140,000 cases of cancer, with 7000 to 8000 new ones registered each year. In Baghdad cancer incidences per 100,000 population have increased, just as they have also increased in Basra. The overall incidence of breast and lung cancer, Leukaemia and Lymphoma, has doubled even tripled. The situation in Mosul city is similar to other regions. Before the Gulf Wars Mosul had a higher rate of cancer, but the rate of cancer has further increased since the Gulf Wars. PMID- 23729096 TI - Environmental characteristics and prevalence of birth defects among children in post-war Iraq: implications for policies on rebuilding the Iraqi education system. AB - This article explores the relationship between the prevalence of 'birth defects' and environmental characteristics, and considers implications for targeting resources to establish the educational inclusion of children affected. A household survey in four governorates across Iraq in 2010, conducted under the auspices of CARA, achieved interviews with 6032 households and collected data on more than 10,000 children and young people. Analyses suggested an association between reported presence of potential sources of contamination in local environments from human and domestic waste, and to some extent from naturally occurring contaminants and the detritus of warfare, with higher numbers of resident children having 'birth defects'. Children living in Basra were found to be most significantly impacted. This finding adds to a growing literature on associations between potential sources of environmental contaminants and impact on the health of children living in affected localities, PMID- 23729097 TI - Psychosocial paediatric training in Iraq: perspectives of trainers and students. AB - There is an absence of education regarding psychosocial issues in Iraqi paediatric training programmes. The aim of this study is to examine current knowledge and perspectives around these topics and to explore potential development in these programmes. 56 paediatric trainers and students at the Child Central Teaching Hospital, a hospital affiliated to the Al-Mustansyria medical college in Baghdad, responded to a questionnaire to evaluate knowledge and perspectives regarding psychosocial approaches to child and adolescent health as delivered presently via academic training and used in professional practice. The majority of the respondents reported having no training in psychosocial interventions. Using a scale from 0 ('not relevant') to 10 ('very important'), psychosocial issues were rated 7.1 in their relevance to everyday paediatric practice. On a scale of 0 ('very poor') to 10 ('totally adequate'), respondents rated formal current psychosocial training at 2.5. It is concluded that incorporating psychosocial approaches in paediatric training will lead to a broader base of knowledge in children's health and contribute to the promotion of multidisciplinary practice in Iraq. PMID- 23729098 TI - A comparative study of the genetics of Behcet's disease in Iraq: international collaboration to transfer clinical and laboratory skills to Baghdad medical school and hospitals. AB - A collaborative project funded by the Iraqi Research Fellowship Programme of the Council for Assisting Refugee Academics was set up to transfer laboratory and clinical skills in between three clinical research teams in the UK, Jordan and Iraq. The project was set up to study the genetics of the potentially debilitating condition, Behcet's Disease (BD). Blood samples were collected from: 38 BD patients, 28 patients with oral ulcers not related to BD and 32 healthy controls. All samples were analysed using Micro SSP HLA Class I B locus kit (B locus, generic). Logistic regression analysis revealed that samples positive for HLA-B51 were 7.4 times more likely to have BD than the healthy control subjects. The results of this study make a valuable addition to the scientific literature. Additional valuable outcomes include the intellectual exchange and transfer of skills in between the collaborating teams, which led to the establishment of an international research collaboration. PMID- 23729099 TI - Post-conflict health reconstruction: where is the evidence? AB - In the context of the CARA Iraq Research Fellowship Programme, staff from Hawler Medical University in Erbil, Iraq and the London School of Hygiene and Tropical Medicine in the UK collaboratively conducted a multimodal research project analysing challenges and opportunities for reform of the primary care system in Iraq. Through a mix of quantitative and qualitative methods a range of challenges were identified, both in terms of services offered and the utilisation of those services. The collaborative study proved positive in terms of direct research outcomes, in boosting academia with skill development and use of new methodologies, and in reengaging displaced Iraqi academics. PMID- 23729100 TI - The CARA tuberculosis project in Karbala. PMID- 23729101 TI - The antenna team. PMID- 23729102 TI - CARA changed my life. PMID- 23729103 TI - [Eosinophilic and non-eosinophilic nasal polyps]. PMID- 23729104 TI - [Clinical analysis on extramedullary plasmacytoma in the upper airway]. AB - OBJECTIVE: To investigate the clinical manifestation, treatment and prognosis of extramedullary plasmacytoma(EMP) in the upper airway, and to improve the diagnosis and outcome of EMP treatment. METHOD: Clinical data of 26 EMP cases were reviewed retrospectively, and then compared with multiple myeloma(MM) patients presenting with lesions in upper airway. RESULT: Of 26 cases, 9 cases with the tumors occurred in nasal cavities, 7 in nasal sinuses, 6 in pharyngeal, 4 in throat, mainly manifesting with local masses and relevant symptoms. The manifestations of clinical, endoscopy findings and pathologic results in EMP patients were not distinguishable from the lesions of MM patients, while MM patients often accompanied by other findings, such as anemia and bone damage. Involvement of neck lymph nodes was more common in MM patients than in EMP patients. Ten patients were treated with surgery, and 16 patients with surgery and radiotherapy. Of the seven EMP patients with involvement of neck lymph nodes, four patients received additional chemotherapy besides surgery and radiotherapy, and no local relapse and MM happened in them, while of the three patients only received surgery and radiotherapy, one local relapse were found and one progressed to MM. CONCLUSION: The diagnosis of EMPs mainly depends on pathological results. The judgment of pathologists and application of molecular biology technology are vital for the diagnosis of EMP in upper airway, and MM must be excluded very carefully in the diagnosis of EMP. Surgery combined with radiotherapy is the main treatment for EMP in the upper airway, and the prognosis is good but the follow-up should be taken. Besides surgery and radiotherapy, chemotherapy is beneficial for the EMP patients accompanied with lesions in neck lymph nodes. PMID- 23729105 TI - [Clinical characteristics of multiple myeloma involving sphenoid sinus]. AB - OBJECTIVE: To study the clinical characteristics, diagnosis and management of multiple myeloma involving sphenoid sinus. METHOD: The clinical data of 2 patients with multiple myeloma involving sphenoid sinus were reported and the relevant literatures were also reviewed. RESULT: Diplopia and headache were the common symptoms of the patients, and there were also some symptoms related to other organs. Patients often had repeated medical treatments and were finally diagnosed by the biopsy of sphenoid sinus. The disease progressed rapidly in the young patient. CONCLUSION: Characteristics of multiple myeloma are complicated. Biopsy of the sphenoid sinus is meaningful for patients with both sphenoid sinus tumor and systematic symptoms, especially those with rapid progress. PMID- 23729106 TI - [Expression and significance of pulmonary surfactant protein D and IL-16 in allergic rhinitis and nasal polyps]. AB - OBJECTIVE: To detect the expression and distribution of the lung surfactant protein D (surfactant protein D,SP-D ) and IL-16 in nasal mucosa of allergic rhinitis and nasal polyps, and then probe into their significance in the pathology of allergic rhinitis and nasal polyps. METHOD: Fifteen cases of allergic rhinitis, fifteen cases of nasal polyps and fifteen cases of inferior turbinate mucosa were studied to detect the expression of SP-D and IL-16 by immunohistochemistry method. RESULT: The expression of SP-D and IL-16 in allergic rhinitis and nasal polyps were dramatically higher in controls (P < 0.01). There was no remarkable difference in the expression of SP-D and IL-16 between allergic rhinitis and nasal polyps (P > 0.05). CONCLUSION: Both normal tissue and diseased tissue express SP-D and IL-16. SP-D is likely to play key roles in the inflammatory reaction process of allergic rhinitis and nasal polyps. IL-16 is an important eosinophil chemokine in the process of allergic rhinitis and nasal polyps,and it can also enhance the local role of eosinophils,thus it can involve in the process of allergic rhinitis and nasal polyps disease. PMID- 23729107 TI - [Analysis on 6 cases with nasal neuroendocrine carcinoma]. AB - OBJECTIVE: To investigate the clinical features, the CT, MRI features and therapeutic strategy of nasal neuroendocrine carcinoma (NEC). METHOD: A retrospective study was carried out on 6 cases of NEC. 2 were female and 4 were male. Routine preoperative CT and MRI examination were performed. In one case,the tumor had invaded the brain and then was treated in department of oncology. Five cases were undertaken tumor resection under nasal endoscope, and combined with postoperative chemoradiation therapy. RESULT: The postoperative pathological report of 1 cases was large cell type, the remaining 4 cases were small cell type. One case treated in department of oncology had lived for 2 month with tumor in his body. One cases relapsed and died at 4 month after postoperation, 1 case was lost and 3 case did not relapse till now. CONCLUSION: NEC of paranasal sinuses is malignant, but early detection, early diagnosis and treatment can improve the prognosis of this disease. For limited lesion of NEC, nasal endoscopic operation is an effective, safe and minimally injury method. PMID- 23729108 TI - [Primary nasal clear cell carcinoma:a case report and literature review]. AB - OBJECTIVE: To explore the clinical and pathological characteristics of the primary nasal-sinonasal clear cell carcinoma, and then summarize the diagnosis and treatment. METHOD: The clinical, imaging and pathological data were analyzed in one patient with primary nasal-sinonasal clear cell carcinoma. The domestic and foreign related literatures from 1992 were reviewed and summarized. RESULT: In 12 cases of primary nasal-sinonasal clear cell carcinoma, 8 cases (66.7%) mainly presented with nasal bleeding, 4 cases (33.3%) with destroyed bone. CT scan showed the sheet shadow similar to soft tissue density in the nasal cavity and paranasal sinuses. Three cases (25.0%) were only treated by surgical resection, 7 cases (58.3%) were treated by surgical resection combined with radiotherapy and chemotherapy, 2 cases (16.7%) were treated by radiotherapy alone. During the 6 months to 10 years follow up, only one patient died of lung metastasis. CONCLUSION: Primary nasal-sinonasal clear cell carcinoma is rare. Nasal bleeding is commonly one of the early symptoms. It must be differentiated from metastatic clear cell carcinoma and a variety of salivary gland tumors with clear cell in pathology. Surgery combined with radiotherapy and chemotherapy is effective treatment. Short-term prognosis is good. Endoscopic surgery can be used to the tumor with a base limited in the nasal cavity and sinuses in early time. The regular check after surgery should be taken to the patients every half a year. PMID- 23729109 TI - [Early genetic diagnosis in patients with HHT induced severe nosebleed]. AB - OBJECTIVE: To study the early gene diagnosis of hereditary hemorrhagic telangiectasia (HHT) induced severe nosebleed. METHOD: Clinical features of 23 family members in two HHT pedigrees were examined. Genomic DNA was extracted from peripheral blood samples. PCR amplification was conducted to screen ENG and ACVRL 1 genes with their specific primers. Direct sequencing was performed to detect the mutation. Mutation analysis was carried out to evaluate its significance. RESULT: A heterozygous c. 263A > G mutation was identified in exon 3 of ACVRL-1 in 6 out of 11 members in NMG-1 pedigree. In GD-2 pedigree, 5 of 11 members carried c. 199C > G mutation. Mutation detection rate was 100% in subjects with nosebleed history and 25% in family members without epistaxis. CONCLUSION: Gene diagnosis characterized by high sensitivity and specificity is of great practi cal significance and early genetic screening should be a clinical routine test for HHT induced severe nosebleed. PMID- 23729110 TI - [Prevalence of sensitization to aeroallergens in 1 893 patients with allergic rhinitis in Yunnan]. AB - OBJECTIVE: To investigate which aeroallergens were prevalent in patients with allergic rhinitis in Yunnan. METHOD: Retrospective analysis of the medical records of intradermal test performed in 1893 AR patients. The samples were divided into four age groups: 4-17-year-olds, > 17-35-year-olds, > 35-50-year olds and > 50-70-year-olds. According to gender,the samples were decided into two groups: the males and the females. The positive rate of aeroallergens were compared among the groups. RESULT: (1)The total positive rate of intradermal test was 70.1%. The top ten allergens were as follow: dermatophagoides pteronyssinus, dermatophagoides farina, house dust, pollen of the summer and autumn, alnus nepalensis, chenopodiaceae, mugwort, poaceae, brassica and cockroach. (2) In all groups,patients with triple positive allergens were the most common,followed by dual positive allergens and single positive allergen. (3) Among the top ten allergens, the top three positive ones in all groups were dermatophagoides pteronyssinus, dermatophagoides farina and house dust. And there were significant differences between 4-17-year-olds group and the other age groups (P < 0.01). (4) There was no significant difference between male and female patients in distribution of aeroallergens except House dust and mite. CONCLUSION: The most common allergen in patients with allergic rhinitis in Yunnan is mite,the follow are pollen of the summer and autumn, alnus nepalensis, chenopodiaceae, mugwort, poaceae, and brassica. The distribution of aeroallergens are different among the age groups, but has no evident correlation with gender. PMID- 23729111 TI - [CD44 regulates epithelial-mesenchymal transition and metastasis in nasopharyngeal cancer cells]. AB - OBJECTIVE: To study the correlation of CD44 with epithelial-mesenchymal transition(EMT) and metastasis in nasopharyngeal cancer cells, and explore the possible mechanism of CD44 regulates EMT and metastasis in nasopharyngeal cancer cells. METHOD: The CD44 and EMT-associated proteins in 5-8F and 6-10B nasopharyngeal cancer cell lines were assayed by Western blotting. The erasion trace test was performed to observe the migratory ability of 5-8F and 6-10B nasopharyngeal cancer cells. Using lipid-mediated DNA transfection technique, the low metastatic nasopharyngeal cancer cells 6-10B were transfected in vitro with plasmid which contained CD44 gene, and then new nasopharyngeal cancer cells were obtained. The CD44 and EMT-associated proteins in 6-10B, empty vector transfected and CD44-transfected cells were assayed by Western blotting. The erasion trace test was performed to observe the alteration of migratory ability of nasopharyngeal cancer cells before and after CD44 transfection. RESULT: The expression of CD44 and EMT-associated protein MMP-9 in 5-8F was higher than that in 6-10B, but EMT-associated protein E-Cadherin in 5-8F was lower than that in 6 10B. The migratory ability of 5-8F was higher than that of 6-10B. The expression of CD44 and MMP-9 were significantly higher in the CD44-transfected nasopharyngeal cancer cells than in the control groups. Compared with control groups, the migratory ability of CD44-transfected nasopharyngeal cancer cells was significantly increased. CONCLUSION: CD44 positively regulates the metastatic ability of nasopharyngeal cancer cells, which is relevant to the process of EMT. PMID- 23729112 TI - [Changes of extracellular matrix of nasal mucosa in guinea pig model of prolonged allergic-induced rhinitis]. AB - OBJECTIVE: The aim of this study was to explore the changes of the extracellular matrix in nasal mucosa by a guinea pig model of prolonged allergic-induced rhinitis. METHOD: Thirty-two male Hartley guinea pigs were randomly divided into four groups: allergen challenged groups (Group 2 w, Group 6 w and Group 12 w) and a control group. Ovalbumin-sensitized guinea pigs were repeatedly challenged with allergen twice a week from 2 weeks to 12 weeks. Matched control groups were challenged with physiological saline. Nasal mucosa were obtained from the animals killed. Hematoxylin-Eosin, Masson's trichrome, and immunohistochemical staining against transforming growth factor-beta1 (TGF-beta1), Collagen III and Collagen I were performed to nasal mucosa. RESULT: (1) Pathological examination showed obvious infiltration of eosinophils and the enlarged thickness of epithelial layer of nasal mucosa in the experiment groups. (2) The area ratios of blue stained in the extracellular matrix of nasal mucosa were increased. The area ratios of blue stained were statistically different in Group 6 w and Group 12 w compared with the control group. (3) The increasing absorbance of TGF-beta1 were statistically different in the experiment groups with the control group. The absorbance of Collagen III and Collagen I showed a rising trend along prolonged allergen challenged in the experiment groups. CONCLUSION: Prolonged allergen challenge and the inflammation of nasal mucosa, can lead to the increasing of the inflammation relevant factors and the deposit of collagen in the extracellular matrix of nasal mucosa. PMID- 23729113 TI - [Anxiolytics reduce residual dizziness after successful canalith repositioning maneuvers in benign paroxysmal positional vertigo]. PMID- 23729115 TI - [Method of opening blockage in electrical cutting system under endoscopy]. PMID- 23729114 TI - [Expression and significance of survivin and PCNA in sinonasal inverted papilloma]. AB - OBJECTIVE: To explore the expression and significance of survivin and proliferating cell nuclear antigen (PCNA) on the occurrence, proliferation, recurrence and carcinogenesis of the sinonasal inverted papilloma (SNIP). METHOD: Immunohistochemical method was used to detect the expression of survivin and PCNA in 10 cases of nasal cavity mucosal (NM), 45 cases of SNIP and 9 cases of canceration SNIP. RESULT: The positive expression of survivin and PCNA increased gradually in NM,SNIP and canceration PCNA group, and there were significant difference between the three groups. But there was no correlation between survivin and PCNA in the tissue of SNIP (r = 0.135, P > 0.05). CONCLUSION: Survivin and PCNA are involved in the growth and carcinogenesis of SNIP. PMID- 23729116 TI - [Clinical analysis of anterior ethmoidal nerve blocking on 50 cases of allergic rhinitis]. PMID- 23729117 TI - [Comprehensive treatment on refractory rhinosinusitis after surgery]. PMID- 23729118 TI - [Nasal polyps associated with nasopharyngeal carcinoma in child: one case report and review]. PMID- 23729119 TI - [A case report of muscular lipoma in nasal vestibular]. AB - A 53-year-old woman presented with a gradually growing mass on the right nostril. PHYSICAL EXAMINATION: a size of 2.0 cm x 2.0 cm x 1.5 cm, smooth and movable mass was on the right side of lateral ala nasi. In surgery, a taupe neoplasm was found in the nasal vestibular area and some faint yellow adipose tissues were found in the neoplasm. The tumor showed indiscernible boundaries and invaded ipsilateral facial vein and infraorbital nerve. Postoperative pathologic findings were consistent with muscular lipoma. The diagnosis mainly relied on the postoperative pathological findings. PMID- 23729120 TI - [A case of nasal malignant peripheral nerve sheath tumor]. AB - The 52-year-old female patient complained of persistent and progressive obstruction in left nasal cavity for more than 1 years. A grey, hard and smooth tumor with telangiectasia, were seen plugged in left post-nostrils and nasopharynx. CT scanning showed a tumor in the left nasal cavity. Post operational pathologic diagnosis was peripheral nerve sheath tumors of nasal cavity. PMID- 23729121 TI - [Case report and review of a girl with factor VIII deficiency making epistaxis]. AB - The factor VIII gene is located on the X chromosome,making haemophilia A, a sex linked disorder. Thus on pedigree grounds all daughters of such patients are obligate carriers. One female case of haemophilia A was reported and related literatures were reviewed. PMID- 23729122 TI - [A case of diffuse large B-cell lymphoma in ethmoid sinus]. AB - The typical clinical manifestations of diffuse large B-cell lymphoma (DLBCL) included nasal obstruction, rhinorrhea, bleeding in nose, headache,etc. No typical features were seen in CT and MRI. The diagnosis of DLBCL was based on the criteria established by the WHO classification. Morphological and immunohistochemical examination were necessary in the diagnosis of DLBCL. PMID- 23729123 TI - Are health service targets useful? PMID- 23729124 TI - Reducing imaging waiting times: enhanced roles and service-redesign. AB - PURPOSE: The aim of this paper is to explain how University Hospitals of Leicester's Nuclear Medicine service managers needed to reduce waiting times to comply with internal clinical requirements and with external local primary care trust (PCT) and national Department of Health targets. DESIGN/METHODOLOGY/APPROACH: The team undertook a comprehensive service review to identify problem areas and potential improvements, including: process mapping; data gathering (activity and demand, equipment and staff availability/utilisation); external practice reviews, searching evidence bases; and financial implications. This case study describes how an inter-disciplinary team redesigned the service and used new working methods to reduce waiting times. Their aim was to discuss a service's practical elements and show how innovation leading to sustainable change can be implemented effectively. FINDINGS: The review highlighted service delivery bottlenecks for myocardial perfusion imaging, which were linked to medical staff shortages, staff use and equipment between hospital sites, and a silo approach to referrals rather than a coordinated organisation-wide approach. PRACTICAL IMPLICATIONS: Introducing enhanced roles allowed nurses, radiographers and technologists to undertake work previously performed by medical staff thus removing a key service bottleneck. Modifications to service delivery and a cultural change in nuclear medicine resulted in a service that was more efficient, flexible and able to cope with increased demand. ORIGINALITY/VALUE: These changes meant that minimum waiting-time targets were achieved, in particular waiting for myocardial perfusion imaging (reduced from 42 weeks in 2005 to two weeks by 2009). Changes allowed service managers to maintain short waiting times in the current, challenging healthcare climate. PMID- 23729125 TI - Healthcare service quality: towards a broad definition. AB - PURPOSE: The main purpose of this study is to define healthcare quality to encompass healthcare stakeholder needs and expectations because healthcare quality has varying definitions for clients, professionals, managers, policy makers and payers. DESIGN/METHODOLOGY/APPROACH: This study represents an exploratory effort to understand healthcare quality in an Iranian context. In depth individual and focus group interviews were conducted with key healthcare stakeholders. FINDINGS: Quality healthcare is defined as "consistently delighting the patient by providing efficacious, effective and efficient healthcare services according to the latest clinical guidelines and standards, which meet the patient's needs and satisfies providers". Healthcare quality definitions common to all stakeholders involve offering effective care that contributes to the patient well-being and satisfaction. PRACTICAL IMPLICATIONS: This study helps us to understand quality healthcare, highlighting its complex nature, which has direct implications for healthcare providers who are encouraged to regularly monitor healthcare quality using the attributes identified in this study. Accordingly, they can initiate continuous quality improvement programmes to maintain high patient-satisfaction levels. ORIGINALITY/VALUE: This is the first time a comprehensive healthcare quality definition has been developed using various healthcare stakeholder perceptions and expectations. PMID- 23729126 TI - Evaluating Lean in healthcare. AB - PURPOSE: The purpose of this paper is to present findings relating to how Lean is implemented in English hospitals. DESIGN/METHODOLOGY/APPROACH: Lean implementation snapshots in English hospitals were conducted by content analysing all annual reports and web sites over two time periods, giving a thorough analysis of Lean's status in English healthcare. FINDINGS: The article identifies divergent approaches to Lean implementation in English hospitals. These approaches are classified into a typology to facilitate an evaluation of how Lean is implemented. The findings suggest that implementation tends to be isolated rather than system-wide. A second dataset conveys Lean implementation trajectory across the time period. These data signal Lean's increasing use by English hospitals and shows progression towards an increasingly systemic approach. PRACTICAL IMPLICATIONS: Data were collected using content analysis methods, which relies on how "Lean" methods were articulated within the annual report and/or on the organisation's web site, which indicates approaches taken by hospital staff implementing Lean. ORIGINALITY/VALUE: This research is the first to examine more closely "how" Lean is implemented in English hospitals. The emergent typology could prove relevant to other public sector organizations and service organisations more generally. The research also presents a first step to understanding Lean thinking in the English NHS. This article empirically analyses Lean implementation in English hospitals. It identifies divergent approaches that allow inferences about how far Lean is implemented in an organisation. Data represent a baseline for further analysis so that Lean implementation can be tracked. PMID- 23729127 TI - Assessing the influence of switching barriers on patients' expectations and tolerance zone. AB - PURPOSE: The purpose of this paper is to look at the influence of switching barriers on patients' private general practitioner (GP) service expectations and tolerance zone DESIGN/METHODOLOGY/APPROACH: From 750 questionnaires distributed to a convenience sample, 257 were completed and returned, yielding a 34 per cent response rate. FINDINGS: There was a significant association between switching barriers and what patients expected from their GPs. Switching barriers did not have a significant association with the tolerance zone. PRACTICAL IMPLICATIONS: Private GPs can develop strategies to overcome switching barriers. For example, they can develop personal relationships with their patients, re-familiarise themselves with the patient's medical history before the consultation and provide better services to patients who perceive high switching barriers and hence higher adequate expectations. ORIGINALITY/VALUE: This study contributes to the existing literature relating to healthcare service quality. PMID- 23729129 TI - Total hip replacement: patient satisfaction and early outcomes. AB - PURPOSE: The purpose of this paper is to assess patient satisfaction with their healthcare experience, total hip replacement outcome, compliance with post operative rehabilitation and consenting process effectiveness. DESIGN/METHODOLOGY/APPROACH: A consecutive sample of patients between January 2007 and September 2008 was identified. A novel questionnaire was designed to assess outcomes and applied via phone interview by an independent assessor. FINDINGS: All patients recalled the consenting/education process with a high proportion recalling surgical risks/benefits. Overall satisfaction was good or better in 76 per cent of the cohort. Post-operative compliance with the rehabilitation programme in 70 per cent of the cohort was achieved. Walking, as the surrogate functional marker, was deemed good or better in 76 per cent. PRACTICAL IMPLICATIONS: The education process and a purposefully designed booklet helped educate patients. Those dissatisfied with physiotherapy generally underwent surgery late in the week and were assessed/treated by the emergency physiotherapy service. Consequently, full-time weekend physiotherapy for arthroplasty patients was implemented. ORIGINALITY/VALUE: Results revealed a high volume treatment centre with outcomes comparable to international standards. A potential problem with physiotherapy cover was identified and the loop closed. PMID- 23729128 TI - Cost-effectiveness of a quality improvement collaborative for obstetric and newborn care in Niger. AB - PURPOSE: The purpose of this paper is to describe a quality improvement collaborative conducted in 33 Nigerian facilities to improve maternal and newborn care outcomes by increasing compliance with high-impact, evidence-based care standards. Intervention costs and cost-effectiveness were examined and costs to the Niger Health Ministry (MoH) were estimated if they were to scale-up the intervention to additional sites. DESIGN/METHODOLOGY/APPROACH: Facility-based maternal care outcomes and costs from pre-quality improvement collaborative baseline monitoring data in participating facilities from January to May 2006 were compared with outcomes and costs from the same facilities from June 2008 to September 2008. Cost data were collected from project accounting records. The MoH costs were determined from interviews with clinic managers and quality improvement teams. Effectiveness data were obtained from facilities' records. FINDINGS: The average delivery-cost decreased from $35 before to $28 after the collaborative. The USAID/HCI project's incremental cost was $2.43/delivery. The collaborative incremental cost-effectiveness was $147/disability-adjusted life year averted. If the MoH spread the intervention to other facilities, substantive cost-savings and improved health outcomes can be predicted. PRACTICAL IMPLICATIONS: The intervention achieved significant positive health benefits for a low cost. The Niger MoH can expect approximately 50 per cent return on its investment if it implements the collaborative in new facilities. The improvement collaborative approach can improve health and save health care resources. ORIGINALITY/VALUE: This is one of the first studies known to examine collaborative quality improvement and economic efficiency in a developing country. PMID- 23729130 TI - Measuring healthcare quality: the challenges. AB - PURPOSE: Current health care quality performance indicators appear to be inadequate to inform the public to make the right choices. The aim of this paper is to define a framework and an organizational setting in which valid and reliable healthcare information can be produced to inform the general public about healthcare quality. DESIGN/METHODOLOGY/APPROACH: To improve health care quality information, the paper explores the analogy between financial accounting, which aims to produce valid and reliable information to support companies informing their shareholders and stakeholders, and healthcare aiming to inform future patients about healthcare quality. Based on this analogy, the authors suggest a measurement framework and an organizational setting to produce healthcare information. FINDINGS: The authors suggest a five-quality element framework to structure quality reporting. The authors also indicate the best way to report each type of quality, comparing performance indicators with certification/accreditation. Health gain is the most relevant quality indicator to inform the public, but this information is the most difficult to obtain. Finally, the organizational setting, comparable to financial accounting, required to provide valid, reliable and objective information on healthcare quality is described. PRACTICAL IMPLICATIONS: Framework elements should be tested in quantitative studies or case studies, such as a performance indicator's relative value compared to accreditation/certification. There are, however, elements that can be implemented right away such as third party validation of healthcare information produced by healthcare institutions. ORIGINALITY/VALUE: Given the money spent on healthcare worldwide, valid and reliable healthcare quality information's value can never be overestimated. It can justify delivering "expensive healthcare, but also points the way to savings by stopping useless healthcare. Valid and reliable information puts the patient in the driver's seat and enables him or her to make the right decision when choosing their healthcare provider. PMID- 23729131 TI - Maximizing facial potential. PMID- 23729132 TI - Acceptability and attractiveness of intra- and extra-oral orthodontic appliances. AB - OBJECTIVES: To evaluate the acceptability of different intra-oral and extra-oral orthodontic appliances, to rank orthodontic appliances from the most to the least attractive and to investigate the factors that may affect the acceptance of orthodontic treatment. SUBJECTS: A random sample of 800 students (schoolchildren and university students) were invited to participate in this study and a total of 688 students were included (86%). METHODS: A self-administrated structured questionnaire was constructed for the purpose of this study. RESULTS: More than one-half in each age group (53%) claimed that they would accept to have orthodontic treatment. Acceptance of the different orthodontic appliances was affected by gender, age and type of school. Removable appliance was reported as the most acceptable and facemask was reported as the least acceptable orthodontic appliances. Majority of subjects ranked ceramic and facemask appliances as the most and the least attractive orthodontic appliances, respectively. The predictor variables for the acceptance of orthodontic treatment were perceived demand for orthodontic treatment, perceived positive effect of orthodontic treatment and expected benefits from orthodontic treatment. CONCLUSIONS: Removable appliance was the most acceptable orthodontic appliance whereas ceramic appliance was ranked as the most attractive one. Facemask was the least acceptable and the least attractive option. PMID- 23729133 TI - Clinical information in using mini-screws in orthodontics. AB - Mini-screws in orthodontics has become the most commonly used skeletal temporary anchorage device. The basic clinical information regarding its indications, contra-indications, implant sites, angulations, placement, maintenance and complications is presented to enlighten orthodontic practitioners planning to start using them. PMID- 23729134 TI - A simple mini-screw assembly for simultaneous molar uprighting and distalization- a case of adjunctive adult orthodontics. AB - Anchorage is a major concern in adult mutilated dentition. However, with the explosive development of Temporary Anchorage Devices (TADs) newer avenues in orthodontic treatment philosophy have opened up. Mini-screws are found to be stable during such treatments, demonstrating that they could provide absolute anchorage for tooth movement. The present article describes a simple, yet effective technique for simultaneous molar uprighting and distalization, using direct skeletal anchorage using a mini-screw supported assembly in a 38 years old male patient as part of adjunctive adult orthodontics with mutilated dentition. PMID- 23729135 TI - A novel approach in treatment of open bite: a case report. AB - This case illustrates the treatment of a 12-year-old boy with an open bite, a slight Class II jaw relationship, Class I molar relationship, and a steep lower occlusal plane. The patient needed a surgical procedure due to the severity of openbite; however the surgery option was rejected. Therefore, he was treated by a Hyrax, fixed tongue appliance, posterior bite plate, reverse chin cup and fixed orthodontics. His second premolars and lower second molars were extracted during treatment. The active treatment lasted for 34 months after which favorable correction of the malocclusion was observed. The SNA angle increased by 4 degrees and the GoGn-Sn decreased by 6 degrees. This patient was treated nonsurgically and favorable profile and occlusion were obtained. PMID- 23729136 TI - Co-axial computed tomography for optimizing orthodontic miniscrew implant size and site of placement. AB - PURPOSE: Absolute anchorage has been a critical aspect in orthodontics. Quantity and quality is a critical factor MSI placement. The present study was designed using a spiral computed tomography to assess the bone availability and clinically assess the optimized position and site for MSI placement in the posterior region. MATERIAL AND METHODS: Spiral computed tomography images often patients were obtained with requirement of MSI placement. Mesiodistal inter-radicular distance in the posterior region of the maxilla over narrowest inter-radicular space was measured at 2, 4, 6 and 8 mm from cementoenamel junction. RESULTS: In the maxilla, the greatest inter-root distance was observed between the first molar and the second premolar at the 8-mm level from the CEJ. The inter-root distances at 4, 6, and 8 mm were significantly larger than the distance at 2 mm, showing a gradual increment as the level approaches the root apex. CONCLUSION: The optimal site for placement of a frequently used MSI (diameter 1.8 to 2.0 mm) in between 2nd premolar--1st molar could be 4 mm from the CEJ and between 1st molar--2nd molar be 6 mm from the CEJ. PMID- 23729137 TI - Management of Klippel-Feil syndrome combined with Turner syndrome: a case report. AB - A 12-year-old female with Klippel-Feil syndrome (KFS) combined with Turner syndrome (TS) and a submucous cleft palate (CP) was presented. The patient reportedly had TS and had received growth hormone (GH) therapy. Because of her skeletal Class III pattern with a steep mandibular plane angle, facial asymmetry, and fused cervical vertebrae, the effects of the GH on her craniofacial complex needed to be considered at the start of orthopedic/orthodontic treatment. To manage submucous CP with severe maxillary deficiency, a rigid external distraction (RED) device was used. The total active treatment time was 34 months including distraction osteogenesis (DO). Treatment improved both her occlusion and facial appearance. PMID- 23729138 TI - A new method to correct lingual rolling of lower molars (Amini twister). AB - In this report, we present an uncomplicated approach to overcome lingual rolling of mandibular molars during orthodontic treatment, by using rectangular NiTi arch wire in twist fashion through the molar tube. The sequential steps of the twist manoeuvre on a typodont and a case report are exhibited in this article. PMID- 23729139 TI - Effect of the DNA ApplianceTM on migraine headache: case report. AB - The relationship between migraine headaches and craniofacial architecture remains tenuous. Indeed, there is a lack of evidence linking migraines to orthodontic status. However, this case report may be one of the first to document the effect of a biomimetic, orthodontic appliance eliminating symptoms associated with migraine headaches. PMID- 23729140 TI - Camouflage treatment of severe bialveolar protrusion in skeletal Class II using miniscrew anchorage. AB - The aim of this case report was to demonstrate the efficient use of miniscrew as anchorage in a 12-year-old male patient with skeletal and dental Class II and severe biprotrusion and lips procumbency. It was proposed a compensating orthodontic treatment with 4 premolar extraction and maximum anchorage. Since the patient abandoned treatment after one premolar extraction, loss of anchorage occurred and treatment plan was modified to maximize lower retraction with miniscrew anchorage and distalization of the upper arch using two methods: Class II elastics from lower miniscrews to the sliding jig and modified transpalatal arch using palatal miniscrew. The results showed a significant improvement of his facial appearance, lip protrusion and also dental esthetics and function. It was concluded that miniscrews can provide absolute anchorage for maximum anterior retraction in order to correct dentoalveolar biprotrusion in the presence of limited thickness alveolar bone. PMID- 23729141 TI - The origin and development of malocclusions. When, where and how dental malocclusions develop. AB - This article describes the forces of the muscles from the stomatonathic system and how they interact in many children to change the normal forces of growth. Because of this change in muscle forces there is a change from normal teeth and bone growth positions to abnormal positions. These normal and/or abnormal changes in muscle forces are the basis for development into class one, class two and class three occlusions. This is very valuable information for the orthodontic clinician because these muscle forces are the fundamental basis for all orthodontic treatment. By knowing this an orthodontic clinician will be more able to diagnose and treat a malocclusion. This is exceptionally important for the dentist who is just starting to learn diagnosis, treatment planning, functional and fixed orthodontic treatment. PMID- 23729142 TI - Envelope of motion vs. envelope of function. PMID- 23729143 TI - Thinking about complacency. PMID- 23729144 TI - Keeping a firm grasp on proper glove use. PMID- 23729145 TI - Why is skin care important in an industrial environment? PMID- 23729146 TI - Challenges to leather glove quality. PMID- 23729147 TI - Solving a truck loading challenge. PMID- 23729148 TI - 'I fell off the roof today'. PMID- 23729149 TI - Proper foot protection made simple. PMID- 23729150 TI - Testing a better recognition tool. PMID- 23729151 TI - Unmasking the certification mill problem. PMID- 23729152 TI - The cooler solution. PMID- 23729153 TI - Diagnosing IAQ dangers. PMID- 23729154 TI - First aid fundamentals. PMID- 23729155 TI - The wonderful world of gas detection. PMID- 23729156 TI - Building wellness programs with impact. PMID- 23729157 TI - Accountability: a dirty word in safety. PMID- 23729158 TI - Orthostatic intolerance without postural tachycardia: how much dysautonomia? AB - BACKGROUND: Chronic symptoms of orthostatic intolerance occur in postural tachycardia syndrome (POTS) and patients with orthostatic intolerance (OI) without tachycardia. We recently reported that deconditioning is almost universal in both patient groups. In this study, we focussed on the question of how much dysautonomia, besides orthostatic tachycardia, is there in POTS vs. OI, and how the two groups compare in regards to clinical, autonomic, laboratory, and exercise variables. METHODS: We retrospectively studied all patients referred for orthostatic intolerance at Mayo Clinic between January 2006 and June 2011, who underwent standardized autonomic and exercise testing. RESULTS: Eighty-four POTS and 100 OI fulfilled inclusion criteria, 89 % were females. The mean age was 25 and 32 years, respectively. Clinical presentation, autonomic parameters, laboratory findings, and degree of deconditioning were overall similar between the two groups, except for the excessive orthostatic heart rate (HR) rise and mild vasomotor findings observed in POTS but not in OI (slightly larger Valsalva ratio and incomplete blood pressure recovery during Valsalva). Both groups responded poorly to various medications. Severely deconditioned patients were similar to non-deconditioned patients, except for 24 h urine volume (1,555 vs. 2,417 ml), sweat loss on thermoregulatory sweat test (1.5 vs. 0.5 %), and few respiratory parameters during exercise, which are likely clinically insignificant. CONCLUSION: Though similar in clinical presentation, POTS and OI are different entities with greater, albeit still mild, dysautonomia in POTS. The clinical and pathophysiological relevance of minimal dysautonomia in the absence of orthostatic tachycardia as seen in OI remain uncertain. PMID- 23729160 TI - Residual levels, tissue distribution and risk assessment of organochlorine pesticides (OCPs) in edible fishes from Taihu Lake, China. AB - Tissue distribution and bioaccumulation of organochlorine pesticides (OCPs) in edible fishes collected from Taihu Lake, Cyprinus carpio (C. carpio) and Ctenopharyngodon idellus (C. idellus), were studied. OCPs were detected in all samples with hexachlorocyclohexanes (HCHs), aldrins (including aldrin, dieldrin, endrin, endrin aldehyde, and endrin ketone), heptachlors (heptachlor and heptachlor epoxide) and dichlorodiphenyltrichloroethanes (DDTs) being the predominant compounds for both fish species. Gill and gonad were found to be the dominant tissues for OCP bioaccumulation followed by liver, while muscle showed the least affinity of OCPs for both fishes. Tissue distribution indicated the exchange of contaminants between water and gill, as well as the food intake from environment were the dominant pathways for OCP bioaccumulation in gill-breathing fish, and the following tissue distribution was affected by both the physiological properties of target tissues and physicochemical characteristics of pesticides. OCP residues in fish were species-specific (45.63-1575.26 ng/g dry weight (dw) for C. idellus; 8.40-60.23 ng/g dw for C. carpio) mainly due to the growth rate of individuals as well as the metabolic capacity difference among species. HCHs and DDTs observed in fishes from Taihu Lake were comparable and moderate with other reported places in China. Human exposure risk assessment performed with the estimated daily intake values demonstrated the consumption of target fish species in Taihu Lake at present was safe. PMID- 23729161 TI - The use of multiple tracers for tracking wastewater discharges in freshwater systems. AB - The assessment of potential impacts of wastewater effluent discharges in freshwater systems requires an understanding of the likely degrees of dilution and potential zones of influence. In this study, four tracers commonly present in wastewater effluents were monitored to compare their relative effectiveness in determining areas in freshwater systems that are likely to be impacted by effluent discharges. The four tracers selected were the human pharmaceutical carbamazepine, anthropogenic gadolinium, fluorescent-dissolved organic matter (fDOM), and electrical conductivity (EC). The four tracers were monitored longitudinally in two distinct freshwater systems receiving wastewater effluents, where one site had a high level of effluent dilution (effluent <1% of total flow) and the other site had a low level of effluent dilution (effluent ~50% of total flow). At both sites, the selected tracers exhibited a similar pattern of response intensity downstream of discharge points relative to undiluted wastewater effluent, although a number of anomalies were noted between the tracers. Both EC and fDOM are non-specific to human influences, and both had a high background response, relative to the highly sensitive carbamazepine and anthropogenic gadolinium responses, although the ease of measuring EC and fDOM would make them more adaptable in highly variable systems. However, the greater sensitivity and selectivity of carbamazepine and gadolinium would make their combination with EC and fDOM as tracers of wastewater effluent discharges highly desirable to overcome potential limitations of individual tracers. PMID- 23729162 TI - Characterization and pollution potential assessment of Tunceli, Turkey municipal solid waste open dumping site leachates. AB - Environmental monitoring of leachate quality from an open municipal solid waste dumping site in Tunceli, Turkey was studied in this research. The most commonly examined pollution parameters were determined on a seasonal basis. The annual average 5-day biological oxygen demand (BOD5) and chemical oxygen demand (COD) values of station points were measured as 70 and 425 mg/L, respectively, and also the average BOD5/COD ratio (a measure of biodegradability) was calculated as 0.20. The low ratio of biodegradability and slightly alkaline pH values in the leachate samples indicated that the site was characterized by methanogenic conditions. The mean ammonium-nitrogen (NH4 (+)-N) and corresponding phosphate (orthophosphate) values were assayed as 70 and 11 mg/L, respectively. The average solids content in the leachates was measured as 4,681 mg/L (total solids) and 144 mg/L (suspended solids). Very low concentrations of iron, manganese, copper, and zinc in the leachate samples were found and the concentration of cadmium was measured below detection limits. Excessive amount of nutrients and high organic and inorganic pollutant content in the leachates pose serious pollution potential to the environment. Since no drainage system or bio treatment exists in this open dumping site, high permeability of natural soil at the site and in the surrounding area and very fractured and crackled rocks under natural soil are indicators of high groundwater pollution potential in this site. PMID- 23729163 TI - Dissipation pattern and pre-harvest residue limit of abamectin in perilla leaves. AB - The pre-harvest residue limit (PHRL) of abamectin (abamectin B1a and B1b) in Perilla frutescens leaves grown under greenhouse conditions were investigated using high-performance liquid chromatography with a fluorescence detector. Samples were extracted with acetonitrile. The extract was purified through a solid phase extraction procedure. Then the purified extract was derivatized with trifluoroacetic anhydride and N-methylimidazole to form a strong stable fluorescent derivative of abamectin. Finally, derivatized abamectins were conveyed to the detector via an Atlantis C18 column, with water and methanol as a mobile phase. Calibration curves were linear over the calibration ranges with coefficients of determinants r (2) >= 0.999. The limits of detection and quantification were 0.0033 and 0.01 mg kg(-1) for abamectin B1a and B1b, respectively. Recovery was assessed in a control matrix at two different fortification concentrations, with three replicates for each concentration. Good recoveries were obtained for the target analytes and ranged from 82.11 to 93.03%, with relative standard deviations of less than 8%. The rate of disappearance of total abamectin on perilla leaves for recommended and double the recommended doses was described as first-order kinetics with a half-life of 0.7 days. Using the PHRL curve, we could predict the residue level of total abamectin to be 0.92 mg kg(-1) at 7 days before harvest or 0.26 mg kg(-1) at 4 days before harvest, which would be below the provisional MRL designed by the Korea Food and Drug Administration. PMID- 23729164 TI - Pollution and potential mobility of Cd, Ni and Pb in the sediments of a wastewater-receiving river in Hanoi, Vietnam. AB - Large quantities of untreated industrial and domestic wastewater are discharged from the city of Hanoi into urban rivers. Sediment samples from three sites in the To Lich River in Hanoi were assessed with respect to the concentrations and potential mobility of cadmium (Cd), nickel (Ni) and lead (Pb). Due to very high Cd concentrations up to 700 mg kg(-1) at one site, the sediment was considered highly unsuitable for any types of land use if dredged and disposed of on land. Chemical sequential extractions of wet and anoxic sediment samples showed that Cd and Pb were largely associated with the redox-sensitive fractions and could thus be mobilised following measures such as resuspension or dredging. To assess the potential mobilisation of heavy metals from the anoxic sediment due to oxidation, the samples were exposed to different oxidants (i.e. atmospheric air and hydrogen peroxide) and afterwards submitted to a leaching test. These experiments showed that although oxidation may increase the equilibrium pore water concentrations of heavy metals in the sediments, other sediment mineral fractions seem to effectively immobilise heavy metals potentially released from the oxidisable fraction. PMID- 23729165 TI - Soil nitrous oxide emissions following crop residue addition: a meta-analysis. AB - Annual production of crop residues has reached nearly 4 billion metric tons globally. Retention of this large amount of residues on agricultural land can be beneficial to soil C sequestration. Such potential impacts, however, may be offset if residue retention substantially increases soil emissions of N(2)O, a potent greenhouse gas and ozone depletion substance. Residue effects on soil N(2)O emissions have gained considerable attention since early 1990s; yet, it is still a great challenge to predict the magnitude and direction of soil N(2)O emissions following residue amendment. Here, we used a meta-analysis to assess residue impacts on soil N(2)O emissions in relation to soil and residue attributes, i.e., soil pH, soil texture, soil water content, residue C and N input, and residue C : N ratio. Residue effects were negatively associated with C : N ratios, but generally residue amendment could not reduce soil N(2)O emissions, even for C : N ratios well above ca. 30, the threshold for net N immobilization. Residue effects were also comparable to, if not greater than, those of synthetic N fertilizers. In addition, residue effects on soil N(2)O emissions were positively related to the amounts of residue C input as well as residue effects on soil CO(2) respiration. Furthermore, most significant and stimulatory effects occurred at 60-90% soil water-filled pore space and soil pH 7.1-7.8. Stimulatory effects were also present for all soil textures except sand or clay content <=10%. However, inhibitory effects were found for soils with >90% water-filled pore space. Altogether, our meta-analysis suggests that crop residues played roles beyond N supply for N(2)O production. Perhaps, by stimulating microbial respiration, crop residues enhanced oxygen depletion and therefore promoted anaerobic conditions for denitrification and N(2)O production. Our meta-analysis highlights the necessity to connect the quantity and quality of crop residues with soil properties for predicting soil N(2)O emissions. PMID- 23729166 TI - Medicare part D and long-term care: a systematic review of quantitative and qualitative evidence. AB - BACKGROUND: In the largest overhaul to Medicare since its creation in 1965, the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 established Part D in 2006 to improve access to essential medication among disabled and older Americans. Despite previous evidence of a positive impact on the general Medicare population, Part D's overall effects on long-term care (LTC) are unknown. OBJECTIVE: The purpose of this systematic review was to evaluate the literature regarding Part D's impact on the LTC context, specifically costs to LTC residents, providers and payers; prescription drug coverage and utilization; and clinical and administrative outcomes. DATA SOURCES: Four electronic databases [PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Health Business Fulltext Elite and Science Citation Index Expanded], selected US government and non-profit websites, and bibliographies were searched for quantitative and qualitative studies characterizing Part D in the LTC context. Searches were limited to studies that may have been published between 1 January 2006 (date of Part D implementation) and 8 January 2013. STUDY SELECTION: Systematic searches identified 1,624 publications for a three-stage (title, abstract and full-text) review. Included publications were in English language; based in the US; assessed Part D-related outcomes; and included or were directly relevant to LTC residents or settings. News articles, reviews, opinion pieces, letters or commentaries; case reports or case series; simulation or modeling studies; and summaries that did not report original data were excluded. STUDY APPRAISAL AND SYNTHESIS METHODS: A standardized form was used to abstract study type, study design, LTC setting, sources of data, method of data collection, time periods assessed, unit of observation, outcomes and results. Methodological quality was assessed using modified criteria specific to quantitative and qualitative studies. RESULTS: Eleven quantitative and eight qualitative studies met inclusion criteria. In the seven years since its implementation, Part D decreased out-of-pocket costs among enrolled nursing home residents and potentially increased costs borne by LTC facilities. Coverage of prescription drugs frequently used by older adults was adequate, except for certain drugs and alternative formulations of importance to LTC residents. The use of medications that raise safety concerns was decreased, but overall drug utilization may have been unaffected. Although there was uncertain impact on clinical outcomes, quantitative studies demonstrated evidence of unintended health consequences. Qualitative studies consistently revealed increased administrative burden among providers. LIMITATIONS: Empirical evidence of Part D's LTC impact was sparse. Due to limitations in available types of data, quantitative studies were generically lacking in methodological rigor. Qualitative studies suffered from lack of clarity of reporting. As future studies use clinical Medicare data, study quality is expected to improve. CONCLUSION: Although LTC-specific policies continue to evolve, it appears that the prescription drug benefit may require further modifications to more effectively provide for LTC residents' unique medication needs and improve their health outcomes. Adjustments may be needed for Part D to be more compatible with LTC prescription drug delivery processes. PMID- 23729167 TI - Role of T cells in the modulation of PTH action: physiological and clinical significance. AB - Osteoimmunology is new field of research dedicated to the study of the interactions between the immune system and bone. Among the cells of the immune system that regulate bone and hemopoietic cells are T lymphocytes. These cells secrete osteoclastogenic cytokines such as RANKL and TNF, as well as factors that stimulate bone formation and hemopoietic cells, one of which is Wnt10b. This article will review the evidence that T cells are implicated in the mechanism of action of parathyroid hormone (PTH) in bone and on the hemopoietic system. PMID- 23729168 TI - Notch3 is activated by chronic hypoxia and contributes to the progression of human prostate cancer. AB - Prostate cancer (PC) is still the second cause of cancer-related death among men. Although patients with metastatic presentation have an ominous outcome, the vast majority of PCs are diagnosed at an early stage. Nonetheless, even among patients with clinically localized disease the outcome may vary considerably. Other than androgen sensitivity, little is known about which other signaling pathways are deranged in aggressive, localized cancers. The elucidation of such pathways may help to develop innovative therapies aimed at specific molecular targets. We report that in a hormone-sensitive PC cell line, LNCaP, Notch3 was activated by hypoxia and sustained cell proliferation and colony formation in soft agar. Hypoxia also modulated cellular cholesterol content and the number and size of lipid rafts, causing a coalescence of small rafts into bigger clusters; under this experimental condition, Notch3 migrated from the non-raft into the raft compartment where it colocalized with the gamma-secretase complex. We also looked at human PC biopsies and found that expression of Notch3 positively correlated with Gleason score and with expression of carbonic anhydrase IX, a marker of hypoxia. In conclusion, hypoxia triggers the activation of Notch3, which, in turn, sustains proliferation of PC cells. Notch3 pathway represents a promising target for adjuvant therapy in patients with PC. PMID- 23729170 TI - Exploiting nanocarbons in dye-sensitized solar cells. AB - Fullerenes, carbon nanotubes, nanodiamond, and graphene find various applications in the development of solar cells, including dye sensitized solar cells. Nanocarbons can be used as (1) active light-absorbing component, (2) current collector, (3) photoanode additive, or (4) counter electrode. Graphene-based materials have attracted considerable interest for catalytic counter electrodes, particularly in state-of-the-art dye sensitized solar cells with Co-mediators. The understanding of electrochemical charge-transfer at carbon surfaces is key to optimization of these solar cells, but the electrocatalysis on carbon surfaces is still a subject of conflicting debate. Due to the rich palette of problems at the interface of nanocarbons and photovoltaics, this review is selective rather than comprehensive. Its motivation was to highlight selected prospective inputs from nanocarbon science towards the development of novel dye sensitized solar cells with improved efficiency, durability, and cost. PMID- 23729169 TI - Alteration of poly(ADP-ribose) metabolism affects murine sperm nuclear architecture by impairing pericentric heterochromatin condensation. AB - The mammalian sperm nucleus is characterized by unique properties that are important for fertilization. Sperm DNA retains only small numbers of histones in distinct positions, and the majority of the genome is protamine associated, which allows for extreme condensation and protection of the genetic material. Furthermore, sperm nuclei display a highly ordered architecture that is characterized by a centrally located chromocenter comprising the pericentromeric chromosome regions and peripherally positioned telomeres. Establishment of this unique and well-conserved nuclear organization during spermiogenesis is not well understood. Utilizing fluorescence in situ hybridization (FISH), we show that a large fraction of the histone-associated sperm genome is repetitive in nature, while a smaller fraction is associated with unique DNA sequences. Coordinated activity of poly(ADP-ribose) (PAR) polymerase and topoisomerase II beta has been shown to facilitate DNA relaxation and histone to protamine transition during spermatid condensation, and altered PAR metabolism is associated with an increase in sperm histone content. Combining FISH with three-dimensional laser scanning microscopy technology, we further show that altered PAR metabolism by genetic or pharmacological intervention leads to a disturbance of the overall sperm nuclear architecture with a lower degree of organization and condensation of the chromocenters formed by chromosomal pericentromeric heterochromatin. PMID- 23729171 TI - Lipidomics applications in health, disease and nutrition research. AB - The structural and functional diversity of lipids accounts for their involvement into a wide range of homeostatic processes and disease states, including lifestyle-related diseases as well as genetic conditions. Challenges presented by this diversity have been addressed to a great extent by the development of lipidomics, a platform that makes possible the detailed profiling and characterisation of lipid species present in any cell, organelle, tissue or body fluid, and allows for a wider appreciation of the biological role of lipid networks. Progress in the field of lipidomics has been greatly facilitated by recent advances in MS and includes a range of analytical platforms supporting applications spanning from qualitative and quantitative assessment of multiple species to lipid imaging. Here we review these MS techniques currently in routine use in lipidomics, alongside with new ones that have started making an impact in the field. Recent applications in health, disease and nutrition-related questions will also be discussed with a view to convey the importance of lipidomics contributions to biosciences and food technology. PMID- 23729172 TI - The influence of outdoor thermal environment on young Japanese females. AB - The influence of short wave solar radiation appears to be strong outdoors in summer, and the influence of airflow appears to be strong outdoors in winter. The purpose of this paper was to clarify the influence of the outdoor environment on young Japanese females. This research shows the relationship between the physiological and psychological responses of humans and the enhanced conduction corrected modified effective temperature (ETFe). Subjective experiments were conducted in an outdoor environment. Subjects were exposed to the thermal environment in a standing posture. Air temperature, humidity, air velocity, short wave solar radiation, long wave radiation, ground surface temperature, sky factor, and the green solid angle were measured. The temperatures of skin exposed to the atmosphere and in contact with the ground were measured. Thermal sensation and thermal comfort were measured by means of rating the whole-body thermal sensation (cold-hot) and the whole body thermal comfort (comfortable uncomfortable) on a linear scale. Linear rating scales are given for the hot (100) and cold (0), and comfortable (100) and uncomfortable (0) directions only. Arbitrary values of 0 and 100 were assigned to each endpoint, the reported values read in, and the entire length converted into a numerical value with an arbitrary scale of 100 to give a linear rating scale. The ETFe considered to report a neither hot nor cold, thermally neutral sensation of 50 was 35.9 degrees C, with 32.3 degrees C and 42.9 degrees C, respectively, corresponding to the low and high temperature ends of the ETFe considered to report a neither comfortable nor uncomfortable comfort value of 50. The mean skin temperature considered to report a neither hot nor cold, thermally neutral sensation of 50 was 33.3 degrees C, with 31.0 degrees C and 34.3 degrees C, respectively, corresponding to the low and high temperature ends of the mean skin temperature considered to report a neither comfortable nor uncomfortable comfort value of 50. The acceptability raised the mean skin temperature even for thermal environment conditions in which ETFe was high. PMID- 23729173 TI - Aspiration pneumonia after chemo-intensity-modulated radiation therapy of oropharyngeal carcinoma and its clinical and dysphagia-related predictors. AB - BACKGROUND: The purpose of this study was to assess aspiration pneumonia (AsPn) rates and predictors after chemo-irradiation for head and neck cancer. METHODS: The was a prospective study of 72 patients with stage III to IV oropharyngeal cancer treated definitively with intensity-modulated radiotherapy (IMRT) concurrent with weekly carboplatin and paclitaxel. AsPn was recorded prospectively and dysphagia was evaluated longitudinally through 2 years posttherapy by observer-rated (Common Toxicity Criteria version [CTCAE]) scores, patient-reported scores, and videofluoroscopy. RESULTS: Sixteen patients (20%) developed AsPn. Predictive factors included T classification (p = .01), aspiration detected on videofluoroscopy (videofluoroscopy-asp; p = .0007), and patient-reported dysphagia (p = .02-.0003), but not observer-rated dysphagia (p = .4). Combining T classification, patient reported dysphagia, and videofluoroscopy asp, provided the best predictive model. CONCLUSION: AsPn continues to be an under-reported consequence of chemo-irradiation for head and neck cancer. These data support using patient-reported dysphagia to identify high-risk patients requiring videofluoroscopy evaluation for preventive measures. Reducing videofluoroscopy-asp rates, by reducing swallowing structures radiation doses and by trials reducing treatment intensity in patients predicted to do well, are likely to reduce AsPn rates. PMID- 23729174 TI - Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis. AB - We identified, in the transcriptome analysis of patients with alcoholic hepatitis (AH), osteopontin (OPN) as one of the most up-regulated genes. Here, we used a translational approach to investigate its pathogenic role. OPN hepatic gene expression was quantified in patients with AH and other liver diseases. OPN protein expression and processing were assessed by immmunohistochemistry, western blotting and enzyme-linked immunosorbent assay. OPN gene polymorphisms were evaluated in patients with alcoholic liver disease. The role of OPN was evaluated in OPN(-/-) mice with alcohol-induced liver injury. OPN biological actions were studied in human hepatic stellate cells (HSCs) and in precision-cut liver slices. Hepatic expression and serum levels of OPN were markedly increased in AH, compared to normal livers and other types of chronic liver diseases, and correlated with short-term survival. Serum levels of OPN also correlated with hepatic expression and disease severity. OPN was mainly expressed in areas with inflammation and fibrosis. Two proteases that process OPN (thrombin and matrix metalloproteinase 7) and cleaved OPN were increased in livers with AH. Patients with AH had a tendency of a lower frequency of the CC genotype of the +1239C single-nucleotide polymorphism of the OPN gene, compared to patients with alcohol abuse without liver disease. Importantly, OPN(-/-) mice were protected against alcohol-induced liver injury and showed decreased expression of inflammatory cytokines. Finally, OPN was induced by lipopolysaccharide and stimulated inflammatory actions in HSCs. CONCLUSION: Human and experimental data suggest a role for OPN in the pathogenesis of AH. Further studies should evaluate OPN as a potential therapeutic target. PMID- 23729175 TI - Brain activity and perceived exertion during cycling exercise: an fMRI study. AB - BACKGROUND/AIM: Currently, the equipment and techniques available to assess brain function during dynamic exercise are limited, which has restricted our knowledge of how the brain regulates exercise. This study assessed the brain areas activated during cycling by making use of a novel cycle ergometer, constructed to measure functional MRI (fMRI) brain images during dynamic exercise. Furthermore, we compared brain activation at different levels of ratings of perceived exertion (RPE) generated during the exercise. METHODS: Seven healthy adults performed cycling exercise in a novel MRI compatible cycle ergometer while undergoing brain fMRI. Participants completed a cycling block protocol comprising six trials of 2 min cycling with 16-s intervals between trials. Participants reported their RPE every minute through an audio link. The MRI cycling ergometer transferred the torque generated on the ergometer through a cardan system to a cycling ergometer positioned outside the MRI room. For data analysis, the effects of cycling as opposed to rest periods were examined after motion correction. RESULTS: The multiparticipant analysis revealed in particular the activation of the cerebellar vermis and precentral and postcentral gyrus when periods of cycling versus rest were compared. Single participant analysis in four participants revealed that activation of the posterior cingulate gyrus and precuneus occurred in cycling blocks perceived as 'hard' compared with exercise blocks that were less demanding. CONCLUSIONS: The present study offers a new approach to assess brain activation during dynamic cycling exercise, and suggests that specific brain areas could be involved in the sensations generating the rating of perceived exertion. PMID- 23729176 TI - Ionising radiation: three game-changing studies for imaging in sports medicine. PMID- 23729177 TI - Long QT syndrome, implantable cardioverter defibrillator (ICD) and competitive sport participation: when science overcomes ethics. PMID- 23729179 TI - Multiple jobholder mortality patterns in Kentucky: an examination of occupational fatalities. AB - BACKGROUND: The percentage of multiple jobholders was elevated in Kentucky compared to the US from 2002 to 2010. METHODS: Kentucky Fatality Assessment and Control Evaluation (FACE) multiple jobholder fatality data were analyzed to identify contributing injury factors from 2002 to 2010. RESULTS: Kentucky's total occupational fatality rates were higher than US rates for all years (2002-2010). Kentucky multiple jobholder fatalities averaged 8.4 deaths per 100,000 employees compared to the total average occupational fatality rate of 6.5. Almost half of multiple jobholder fatalities (47%) occurred in the agricultural industry and management occupation as the primary industry and occupation; 67% were tractor related. The most prevalent secondary industry and occupation were the construction industry and management occupation. CONCLUSIONS: Increased surveillance of multiple jobholder injuries is needed to improve safety and health on the job. Future investigations should include the relationship between multiple jobholding and agricultural employment as farm owners. PMID- 23729178 TI - Src inhibitors in suppression of papillary thyroid carcinoma growth. AB - BACKGROUND: Papillary thyroid carcinoma is the most common thyroid malignancy. Most papillary thyroid carcinomas contain BRAF mutations or RET/PTC rearrangements, thus providing targets for biologic therapy. Our previous studies had suggested papillary thyroid carcinomas (PTCs) with a BRAF mutation and the RET/PTC1 rearrangement have different sensitivities to MEK1/2 inhibitors, suggesting different signaling transduction pathways were involved. METHODS: Src signaling transduction pathway in PTC cells was examined using Src inhibitors (PP2, SU6656, or dasatinib) and si-Src RNA in vitro by Western blot analysis and proliferation analysis. An orthotopic xenograft mouse model was used for the in vivo studies using dasatinib. RESULTS: In PTC cells, Src inhibitors suppressed p Src and p-FAK and inhibited cell growth. In addition, significant suppression and extension of the p-ERK1/2 dephosphorylation were detected in RET/PTC1-rearranged cells in combination with an MEK inhibitor (CI-1040). The Src family kinase/ABL inhibitor, dasatinib, significantly decreased tumor volume in mice inoculated with PTC cells carrying the RET/PTC1 rearrangement. In BRAF-mutated PTC cells, Src inhibitors effectively suppressed p-Src expression and dasatinib significantly decreased tumor volume with twice daily treatment. CONCLUSION: Src inhibitors effectively inhibited the Src signaling transduction pathway in PTC cells in vitro and dasatinib suppressed tumor growth in vivo. These results suggested that Src signaling transduction pathway plays an important role in regulating growth in PTC cells. Combination of Src and MEK1/2 inhibitors extended the dephosphorylation of extracellular signal-regulated kinase (ERK)1/2 in PTCs carrying the RET/PTC1 rearrangement suggesting that combination therapy with complementary inhibitors of other signaling transduction pathways may be needed to effectively suppress growth and induce apoptosis in these cells. PMID- 23729180 TI - Chemistry and structures of hexakis(halogenomethyl)-, hexakis(azidomethyl)-, and hexakis(nitratomethyl)disiloxanes. AB - An investigation of the structures and chemistry of substituted hexamethyl disiloxanes ((XCH2)3Si)2O; X=F, Cl, Br, I, N3 , and ONO2) is reported. New synthetic routes to the precursor hexakis(chloromethyl)disiloxane are presented. The products with X=Cl, Br, I, and N3 were characterized by NMR, IR, and Raman spectroscopy. In addition, the single-crystal structures of the products with X=Cl, Br, and I are discussed in detail. The compounds with X=F and ONO2 were not obtained in their pure form; instead investigations of the decomposition products revealed their conversion into intermediates. Theoretical calculations of the gas phase structures at the B3LYP/cc-pVDZ, B3LYP/3-21G, MP2/6-31G*, and MP2/3-21G levels of theory are used to explain the chemical and physical behavior of the compounds with X=Cl, Br, I, N3, and ONO2. A new decomposition pathway of hexakis(nitratomethyl)disiloxane is presented and is used to explain their remarkable instability. The energetic properties and values of the nitrate and azide derivatives were calculated at the CBS-4M level of theory by using the improved EXPLO5 computer code version 6.01. PMID- 23729181 TI - Performance evaluation of soft copy display systems according to AAPM TG18 protocol. AB - The purpose of this study was to evaluate the display performance of the liquid crystal display monitors according to the American association of physicists in medicine task group 18 (AAPM TG18) protocol at prior and after new calibration. We measured minimum and maximum luminance, luminance ratio, luminance and contrast response, luminance angular and spatial dependency, resolution, veiling glare and chromaticity quantitatively for 33 medical displays. Display noise was evaluated only visually. The mean maximum luminance and luminance ratio were 386 and 273 cd m(-2), respectively. The mean deviation of measured luminance and contrast response from expected response associated with the digital imaging and communications in medicine (DICOM) grayscale standard display function (GSDF) were 9.76 and 2.35 % at prior calibration and 1.23 and 0.26 % after recalibration, respectively. In luminance uniformity test the mean maximum luminance deviation was 16 %. Luminance method was used in the spatial resolution test and the mean percent luminance difference was 12 % at the center. The mean glare ratio was 1 154. The average color uniformity parameter across the display area of each display device was 0.0093. Majority of the test results were in good agreement with the criteria recommended by AAPM TG18 report. Considerable improvement was observed in display luminance and contrast response with respect to expected response of DICOM GSDF after new calibration for some displays. PMID- 23729183 TI - Comparing gene expression profiles of Kashin-Beck and Keshan diseases occurring within the same endemic areas of China. AB - In this study, differentially expressed genes in peripheral blood from patients with Kashin-Beck disease and Keshan disease were compared to further investigate the etiology and pathogenesis of both diseases, which occur in a common endemic area of China. Twenty Kashin-Beck disease patients and 12 healthy controls, and 16 Keshan disease patients and 16 healthy controls, were grouped into four pairs. Patients and controls were selected from common endemic areas for the two diseases. Total RNA was isolated from peripheral blood mononuclear cells from all patients and controls, and gene expression profiles analyzed by oligonucleotide microarrays. Sixteen genes differentially expressed in both Kashin-Beck disease and Keshan disease (versus controls) were identified, and comprised nine genes showing synchronous and seven asynchronous expression. The Comparative Toxicogenomics Database shows that expression and biological function of these genes can be affected by multiple environmental factors, including mycotoxin and selenium content, potential environmental risk factors for the two diseases. Thus, these shared differentially expressed genes may contribute to the distinct organ lesions, caused by common environmental risk factors of Kashin-Beck disease and Keshan disease. PMID- 23729182 TI - Melanopsin-expressing retinal ganglion cell loss and behavioral analysis in the Thy1-CFP-DBA/2J mouse model of glaucoma. AB - In this study, the role of melanopsin-expressing retinal ganglion cells (mRGCs) in the glaucoma-induced depressive behavioral response pattern was investigated. The CFP-D2 transgenic glaucoma animal model from five age groups was used in this study. Immunohistochemical labeling, quantitative analysis of mRGC morphology, open field test (OFT), and statistical analysis were used. In comparison with C57 BL/6 mice, the age-matched CFP-D2 mice had significantly elevated intraocular pressure (IOP). We observed parallel morphological changes in the retina, including a reduction in the density of cyan fluorescent protein-(CFP) expressing cells (cells mm(-2) at 2 months of age, 1309+/-26; 14 months, 878+/-30, P<0.001), mRGCs (2 months, 48+/-3; 14 months, 19+/-4, P<0.001), Brn3b-expressing RGCs (2 months, 1283+/-80; 14 months, 950+/-31, P <0.001), Brn-3b expressing mRGCs (5 months, 50.17%+/-5.5%; 14 months, 12.61%+/-3.8%, P<0.001), and reduction in the dendritic field size of mRGCs (mm(2) at 2 months, 0.077+/-0.015; 14 months, 0.065+/-0.015, P<0.05). CFP-D2 mice had hyperactive locomotor activity patterns based on OFT findings of the total distance traveled, number of entries into the center, and time spent in the center of the testing apparatus. The glaucoma induced hyperactive response pattern could be associated with dysfunctional mRGCs, most likely Brn-3b-positive mRGCs in CFP-D2 mice. PMID- 23729185 TI - Chiral NMR solvating additives for differentiation of enantiomers. AB - This chapter will describe the general features and main categories of chiral solvating agents (CSAs) for NMR spectroscopy, spanning from low-medium sized CSAs to macrocyclic ones. CSAs based on chiral ionic liquids (CILs) will be introduced in view of their increasing popularity, and, finally, a short paragraph will be dedicated to special applications of CSAs in particular experimental conditions. Several valuable works, which are mainly devoted to investigate enantiodifferentiation mechanisms by NMR, will not be discussed. The main objective is to identify the current trend in the research areas dedicated to the development of new CSAs for NMR spectroscopy. PMID- 23729184 TI - Osteoblastoma of the thyroid cartilage treated with voice preserving laryngeal framework resection. AB - OBJECTIVES/HYPOTHESIS: Osteoblastoma is a slow-growing, locally destructive benign bone neoplasm, rarely occurring in the laryngeal cartilage. We present the case of a professional voice user diagnosed with laryngeal osteoblastoma after microdirect laryngoscopy and endoscopic biopsy. Her treatment required a unique operation, with elements of partial laryngectomy and maintenance of vital endolaryngeal soft tissues, in order to optimize vocal outcome. PMID- 23729186 TI - Effect of postoperative brachytherapy and external beam radiotherapy on functional outcomes of immediate facial nerve repair after radical parotidectomy. AB - BACKGROUND: There is much controversy regarding the effect of radiotherapy on facial nerve regeneration. However, the effect of brachytherapy has not been studied. METHODS: Fifty-three patients underwent total parotidectomy of which 13 were radical with immediate facial nerve repair with sural nerve grafts. Six patients (group 1) did not receive adjuvant treatment whereas 7 patients (group 2) received postoperative brachytherapy plus radiotherapy. Functional outcomes were compared using Facial Clima. RESULTS: Mean percentage of blink recovery was 92.6 +/- 4.2 for group 1 and 90.7 +/- 5.2 for group 2 (p = .37). Mean percentage of commissural excursion restoration was 78.1 +/- 3.5 for group 1 and 74.9 +/- 5.9 for group 2 (p = .17). Mean time from surgery to first movement was 5.7 +/- 0.9 months for group 1 and 6.3 +/- 0.5 months for group 2 (p = .15). CONCLUSION: Brachytherapy plus radiotherapy does not affect the functional outcomes of immediate facial nerve repair with nerve grafts. PMID- 23729187 TI - Leiomyosarcoma: a rare tumor of the thyroid. AB - Primary leiomyosarcoma of the thyroid gland is uncommon. To date, 20 cases have been reported in English in the literature. The tumors usually present in elderly patients with female predilection and are associated with poor clinical outcome. Herein, we report an additional case of primary thyroid leiomyosarcoma in a 64 year-old woman. She underwent total thyroidectomy and later was discovered to have multiple lung and liver metastases. The patient died 3 months after surgery. The major differential diagnoses including undifferentiated (anaplastic) carcinoma of the thyroid, spindle cell variant of medullary thyroid carcinoma, spindle cell tumor with thymus-like differentiation, uncommon primary tumor of the thyroid and metastatic tumors with predominant spindle cells are discussed. PMID- 23729188 TI - The production of phytolith-occluded carbon in China's forests: implications to biogeochemical carbon sequestration. AB - The persistent terrestrial carbon sink regulates long-term climate change, but its size, location, and mechanisms remain uncertain. One of the most promising terrestrial biogeochemical carbon sequestration mechanisms is the occlusion of carbon within phytoliths, the silicified features that deposit within plant tissues. Using phytolith content-biogenic silica content transfer function obtained from our investigation, in combination with published silica content and aboveground net primary productivity (ANPP) data of leaf litter and herb layer in China's forests, we estimated the production of phytolith-occluded carbon (PhytOC) in China's forests. The present annual phytolith carbon sink in China's forests is 1.7 +/- 0.4 Tg CO2 yr(-1) , 30% of which is contributed by bamboo because the production flux of PhytOC through tree leaf litter for bamboo is 3-80 times higher than that of other forest types. As a result of national and international bamboo afforestation and reforestation, the potential of phytolith carbon sink for China's forests and world's bamboo can reach 6.8 +/- 1.5 and 27.0 +/- 6.1 Tg CO2 yr(-1) , respectively. Forest management practices such as bamboo afforestation and reforestation may significantly enhance the long-term terrestrial carbon sink and contribute to mitigation of global climate warming. PMID- 23729189 TI - Prevalence and trends of human papillomavirus in oropharyngeal cancer in a predominantly north Indian population. AB - BACKGROUND: Human papillomavirus (HPV) prevalence in oropharyngeal squamous cell cancer (SCC) remains variable and studies have estimated that up to 60% may be positive. METHODS: One hundred five treatment-naive oropharyngeal SCC patients were included. HPV genotyping was done by consensus polymerase chain reaction (PCR) and reverse line-blot hybridization assay. HPV prevalence was co-related with sex, age, tobacco consumption, alcohol use, and high-risk sexual behavior. RESULTS: HPV prevalence was 22.8%. No significant associations were seen between tobacco or alcohol consumption with HPV status. The mean number of lifetime sexual partners and indulgence in high-risk sexual behavior was significantly more in patients who are HPV positive. There were no significant associations between the 2 groups with respect to the stage of the tumor. CONCLUSION: Results of this study confirms that patients who are HPV positive are younger, and with high-risk sexual behavior. We did not find any impact of smoking and alcohol consumption on HPV status. PMID- 23729190 TI - Development of a whole-cell biocatalyst with NADPH regeneration system for biosulfoxidation. AB - A formate dehydrogenase gene (fdh) originated from Candida boidinii was co expressed in E. coli BL21 (DE3) with the cyclohexanone monooxygenase gene (chmo) cloned from Acinetobacter calcoaceticus NCIMB 9871. The co-expression system was then used as a whole-cell biocatalyst to synthesize chiral phenyl methyl sulfoxide (PMSO) from thioanisole (PMS) and the reaction conditions were investigated. When the initial concentration of PMS was 20 mM, the specific productivity of PMSO in this system was 2.07 MUmol g(-1) cw min(-1) (cw: wet cell weight) and the ee value for the R-sulfoxide was 99 %. In contrast, when chmo was the only gene expressed in E. coli, the specific productivity of PMSO was 0.053 MUmol g(-1) cw min(-1) with no exact enantioselectivity. Further determination of NADPH concentration in the whole-cell catalysts suggested that co-expression of fdh with chmo significantly improved NADPH supply. Thus, this whole-cell biocatalyst system is highly advantageous for the synthesis of optically pure R sulfoxide. PMID- 23729191 TI - Efficient gamma-aminobutyric acid bioconversion by employing synthetic complex between glutamate decarboxylase and glutamate/GABA antiporter in engineered Escherichia coli. AB - Gamma-aminobutyric acid (GABA) is a precursor of one of the most promising heat resistant biopolymers, Nylon-4, and can be produced by the decarboxylation of monosodium glutamate (MSG). In this study, a synthetic protein complex was applied to improve the GABA conversion in engineered Escherichia coli. Complexes were constructed by assembling a single protein-protein interaction domain SH3 to the glutamate decarboxylase (GadA and GadB) and attaching a cognate peptide ligand to the glutamate/GABA antiporter (GadC) at the N-terminus, C-terminus, and the 233rd amino acid residue. When GadA and GadC were co-overexpressed via the C terminus complex, a GABA concentration of 5.65 g/l was obtained from 10 g/l MSG, which corresponds to a GABA yield of 93 %. A significant increase of the GABA productivity was also observed where the GABA productivity increased 2.5-fold in the early culture period due to the introduction of the synthetic protein complex. The GABA pathway efficiency and GABA productivity were enhanced by the introduction of the complex between Gad and glutamate/GABA antiporter. PMID- 23729192 TI - Patient-specific finite element analysis of carotid artery stenting: a focus on vessel modeling. AB - Finite element analysis is nowadays a well-assessed technique to investigate the impact of stenting on vessel wall and, given the rapid progression of both medical imaging techniques and computational methods, the challenge of using the simulation of carotid artery stenting as procedure planning tool to support the clinical practice can be approached. Within this context, the present study investigates the impact of carotid stent apposition on carotid artery anatomy by means of patient-specific finite element analysis. In particular, we focus on the influence of the vessel constitutive model on the prediction of carotid artery wall tensional state of lumen gain and of vessel straightening. For this purpose, we consider, for a given stent design and CA anatomy, two constitutive models for the CA wall, that is, a hyperelastic isotropic versus a fiber-reinforced hyperelastic anisotropic model. Despite both models producing similar patterns with respect to stress distribution, the anisotropic model predicts a higher vessel straightening and a more evident discontinuity of the lumen area near the stent ends as observed in the clinical practice. Although still affected by several simplifications, the present study can be considered as further step toward a realistic simulation of carotid artery stenting. PMID- 23729194 TI - Reply: To PMID 23475565. PMID- 23729193 TI - European hospital adherence to GOLD recommendations for chronic obstructive pulmonary disease (COPD) exacerbation admissions. AB - Understanding how European care of chronic obstructive pulmonary disease (COPD) admissions vary against guideline standards provides an opportunity to target appropriate quality improvement interventions. In 2010-2011 an audit of care against the 2010 'Global initiative for chronic Obstructive Lung Disease' (GOLD) standards was performed in 16 018 patients from 384 hospitals in 13 countries. Clinicians prospectively identified consecutive COPD admissions over a period of 8 weeks, recording clinical care measures on a web-based data tool. Data were analysed comparing adherence to 10 key management recommendations. Adherence varied between hospitals and across countries. The lack of available spirometry results and variable use of oxygen and non-invasive ventilation (NIV) are high impact areas identified for improvement. PMID- 23729195 TI - Solvent-polarity-tuned morphology and inversion of supramolecular chirality in a self-assembled pyridylpyrazole-linked glutamide derivative: nanofibers, nanotwists, nanotubes, and microtubes. AB - The self-assembly of a low-molecular-weight organogelator into various hierarchical structures has been achieved for a pyridylpyrazole linked L glutamide amphiphile in different solvents. Upon gel formation, supramolecular chirality was observed, which exhibited an obvious dependence on the polarity of the solvent. Positive supramolecular chirality was obtained in nonpolar solvents, whereas it was inverted into negative supramolecular chirality in polar solvents. Moreover, the gelator molecules self-assembled into a diverse array of nanostructures over a wide scale range, from nanofibers to nanotubes and microtubes, depending on the solvent polarity. Such morphological changes could even occur for the xerogels in the solvent vapors. We found that the interactions between the pyridylpyrazole headgroups and the solvents could subtly change the stacking of the molecules and, hence, their self-assembled nanostructures. This work exemplifies that organic solvents can significantly involve the gelation, as well as tune the structure and properties, of a gel. PMID- 23729197 TI - Arabinogalactan protein profiles and distribution patterns during microspore embryogenesis and pollen development in Brassica napus. AB - Arabinogalactan proteins (AGPs), present in cell walls, plasma membranes and extracellular secretions, are massively glycosylated hydroxyproline-rich proteins that play a key role in several plant developmental processes. After stress treatment, microspores cultured in vitro can reprogramme and change their gametophytic developmental pathways towards embryogenesis, thereby producing embryos which can further give rise to haploid and double haploid plants, important biotechnological tools in plant breeding. Microspore embryogenesis constitutes a convenient system for studying the mechanisms underlying cell reprogramming and embryo formation. In this work, the dynamics of both AGP presence and distribution were studied during pollen development and microspore embryogenesis in Brassica napus, by employing a multidisciplinary approach using monoclonal antibodies for AGPs (LM2, LM6, JIM13, JIM14, MAC207) and analysing the expression pattern of the BnAGP Sta 39-4 gene. Results showed the developmental regulation and defined localization of the studied AGP epitopes during the two microspore developmental pathways, revealing different distribution patterns for AGPs with different antigenic reactivity. AGPs recognized by JIM13, JIM14 and MAC207 antibodies were related to pollen maturation, whereas AGPs labelled by LM2 and LM6 were associated with embryo development. Interestingly, the AGPs labelled by JIM13 and JIM14 were induced with the change of microspore fate. Increases in the expression of the Sta 39-4 gene, JIM13 and JIM14 epitopes found specifically in 2-4 cell stage embryo cell walls, suggested that AGPs are early molecular markers of microspore embryogenesis. Later, LM2 and LM6 antigens increased progressively with embryo development and localized on cell walls and cytoplasmic spots, suggesting an active production and secretion of AGPs during in vitro embryo formation. These results give new insights into the involvement of AGPs as potential regulating/signalling molecules in microspore reprogramming and embryogenesis. PMID- 23729196 TI - What is the effect of resistance training on the strength, body composition and psychosocial status of overweight and obese children and adolescents? A Systematic review and meta-analysis. AB - BACKGROUND: Overweight and obese children and adolescents face many physical and psychosocial hardships. Resistance training is a modality of exercise which allows this at-risk group to excel and therefore has the potential to positively affect not only their physical but also psychosocial health. OBJECTIVE: To systematically review and meta-analyse the peer-reviewed literature to determine the effect of resistance training on the strength, body composition and psychosocial status of overweight and/or obese children and/or adolescents. DATA SOURCES: Relevant databases (MEDLINE, Embase, Scopus, Web of Science, SPORTDiscus, CINAHL, PsycINFO, Cochrane library, ProQuest) were searched up to and including 30 January 2013. STUDY SELECTION: Included studies (n = 40, from the 2,247 identified) were randomised controlled trials (RCTs), non-randomised controlled trials (NRCTs) and uncontrolled trials (UCTs) which had run an exercise intervention, with a resistance training component, for overweight and/or obese children and/or adolescents, and which had examined the effect of resistance training on either strength, body composition or psychosocial outcomes. STUDY APPRAISAL AND SYNTHESIS METHODS: Studies were initially critically appraised for risk of bias by the lead author, following which both co authors critically appraised five randomly selected studies to assess reliability. RESULTS: Randomised controlled trials and NRCTs were analysed separately from UCTs. To determine the overall intervention effect for each outcome variable for each study design group, standardised mean differences were calculated with each individual study/data set weighted by the inverse of the pooled variance. The overall intervention effect reported for RCTs and NRCTs was relative to the control group whereas the effect reported for UCTs shows an overall post-intervention effect. Subgroup analyses, which determined whether the overall intervention effect was influenced by intervention type, training volume, age, sex, risk of bias or study design (for RCT/NRCT group only), were run using the same summary measure. Typically, resistance training had very small to small effects on body composition and moderate to large effects on strength in favour of the intervention. However, the magnitude and direction of the effect of resistance training on psychological outcomes are still unclear given the limited number of studies which looked at psychosocial outcomes and the inconclusive results shown by this review. Uncontrolled trials typically showed larger intervention effects than RCTs and NRCTs; however, these results may be greatly influenced by maturational changes rather than the intervention itself. LIMITATIONS: The included studies employed a number of different exercise intervention types (e.g. resistance training, resistance plus aerobic training etc.) that ranged from 6 to 52 weeks in duration. Studies also employed a number of different methodologies to assess similar outcome measures (e.g. dual energy X ray absorptiometry versus skinfolds to assess body composition; one-repetition maximum testing versus hand grip strength to assess strength). However, by completing subgroup analyses and using a standardised summary measure these limitations have been accounted for. CONCLUSION: While the effect of resistance training on the body composition and strength of overweight and obese children and adolescents is clear, given the paucity of conclusive data more studies are needed to fully understand the effect of resistance training on the psychosocial status of this population. PMID- 23729198 TI - Different patterns of bundle-branch blocks and the risk of incident heart failure in the Women's Health Initiative (WHI) study. AB - BACKGROUND: We evaluated the risk of incident heart failure (HF) associated with bundle-branch blocks (BBBs) in postmenopausal women. METHODS AND RESULTS: Cox's regression was used to evaluate hazard ratios with 95% confidence intervals for HF among 65975 participants of the Women's Health Initiative (WHI) study during an average follow-up of 14 years. BBBs observed in 1676 women at baseline were categorized into left, right, and indetermined-type BBBs (LBBB, RBBB, and intraventricular conduction defect, respectively). Compared with women with no BBB, LBBB, and intraventricular conduction defect were strong predictors of incident HF in multivariable-adjusted risk models (hazard ratio, 3.79; confidence interval, 2.95-4.87 for LBBB and hazard ratio, 3.53; confidence interval, 2.14 5.81 for intraventricular conduction defect). RBBB was not a significant predictor of incident HF in multivariable-adjusted risk model, but the combination of RBBB and left anterior fascicular block was a strong predictor (hazard ratio, 2.96; confidence interval, 1.77-4.93). QRS duration was an independent predictor of incident HF only in LBBB, with more pronounced risk at QRS >= 140 ms than at <140 ms. QRS nondipolar voltage (RNDPV) was an independent predictor in both RBBB and LBBB and, in addition, in LBBB, QRS/STT angle and ST J point depression in aVL were independent predictors. CONCLUSIONS: LBBB, intraventricular conduction defect, and RBBB combined with left anterior fascicular block are strong predictors of incident HF in multivariable-adjusted risk models, but RBBB is not a significant predictor. QRS duration >= 140 ms may warrant consideration in LBBB as an indication for further diagnostic evaluation for possible therapeutic and preventive action. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611. PMID- 23729199 TI - Plasma vitamin C, but not vitamin E, is associated with reduced risk of heart failure in older men. AB - BACKGROUND: Oxidative stress has been implicated in the pathogenesis of heart failure (HF). However, data on the association between antioxidant intakes and circulating levels and risk of incident HF in the older general population are limited. We have examined prospectively the associations between plasma vitamin C and E, dietary intakes of vitamin C and E, and incident HF. METHODS AND RESULTS: Prospective study of 3919 men aged 60 to 79 years with no prevalent HF followed up for a mean period of 11 years, in whom there were 263 cases with incident HF. Higher plasma vitamin C level was associated with significantly lower risk of incident HF in both men with and without previous myocardial infarction after adjustment for lifestyle characteristics, diabetes mellitus, blood lipids, blood pressure, and heart rate (hazards ratio [95% confidence interval], 0.81 [0.70, 0.93] and 0.75 [0.59, 0.97] for 1 SD increase in log vitamin C, respectively). Plasma vitamin E and dietary vitamin C intake showed no association with HF. High levels of dietary vitamin E intake (which correlated weakly with plasma vitamin E) were associated with increased risk of HF in men with no previous myocardial infarction even after adjustment (adjusted hazards ratio [95% confidence interval], 1.23 [1.06, 1.42] for 1 SD increase). CONCLUSIONS: Higher plasma vitamin C is associated with a reduced risk of HF in older men with and without myocardial infarction. High intake of dietary vitamin E may be associated with increased HF risk. Primary intervention trials assessing the effect of vitamin C supplements on HF risk in the elderly are needed. PMID- 23729200 TI - Circulating nucleosomes and immunogenic cell death markers HMGB1, sRAGE and DNAse in patients with advanced pancreatic cancer undergoing chemotherapy. AB - Serum biomarkers are urgently needed for patient stratification and efficient treatment monitoring in pancreatic cancer (PC). Within a prospective diagnostic observation study, blood samples were obtained from 78 patients with advanced PC before and weekly during the course of palliative chemotherapy. Circulating nucleosomes and immunogenic cell death markers, high-mobility group box 1 (HMGB1), soluble receptors of advanced glycation end products (sRAGE) and DNAse activity, were measured by enzyme-linked immunosorbent assay and correlated with results of radiological staging after 2 months of treatment, with time to progression (TTP) and overall survival (OS). Median TTP and OS of PC patients were 3.9 and 7.7 months, respectively. Pretherapeutic baseline biomarker levels did not correlate with objective response; however, nucleosome levels on day (d) 28 were higher (p = 0.048) and sRAGE levels at time of staging (d56) were lower in progressive patients (p = 0.046). Concerning estimation of prognosis, high nucleosome levels (d7, d14, d21 and d56), low sRAGE levels (d56) and DNAse activity courses (d0-d7) correlated with TTP, whereas high nucleosomes (d7, d14 and d56), high HMGB1 (d21 and d56) and DNAse (d0-d7) were associated with OS. After adjustment to Karnofsky performance score, nucleosomes and HMGB1 (both d56) and DNAse (d0-d7) remained independent prognostic factors. Thus, courses of circulating nucleosomes and immunogenic cell death markers HMGB1 and sRAGE show prognostic relevance in PC patients undergoing chemotherapy. PMID- 23729201 TI - Genetic polymorphism of 17 Y chromosomal STRs in the Rusyn population sample from Vojvodina Province, Serbia. AB - Seventeen short tandem repeats on the Y chromosome were analyzed in the sample of 200 males of Rusyn origin from the Vojvodina Province, Serbia. We observed 180 different haplotypes; 163 of which were unique and 17 occurred between two and four times. The haplotype diversity was 0.9988, and the discrimination capacity was 0.9. Data are available in the Y chromosome haplotype reference database under accession number YA003631. The obtained results were compared to haplotypes from geographically and linguistically close populations. PMID- 23729202 TI - Freshwater catfish jundia (Rhamdia quelen) larvae are prepared to digest inert feed at the exogenous feeding onset: physiological and histological assessments. AB - This study assessed the morphological development of jundia larvae's digestive system and digestive proteolytic activity. Specific serine proteinases activities varied over time, with the highest peak at 12 h after hatching (AH), which corresponded to 296.38 +/- 84.20 mU mg-1 for trypsin and 315.45 +/- 42.16 mU mg-1 for chymotrypsin. Specific aspartic proteinases activities increased up to the start of weaning, oscillated during that phase, but showed a consistent increase after that, resulting in the highest specific activity at 252 h AH (7.88 +/- 0.68 mU mg-1). Gel assays showed different molecular forms, especially of serine proteinases. Histology showed the gastrointestinal tract development onset at 0 h AH and open mouth at 4 h AH. At 16 h AH, the following differentiation of the digestive tract was evident: oropharyngeal cavity, esophagus, liver, pancreas, stomach, and intestine. At 40 h AH, zymogen granules in the pancreas were observed, and at 48 h AH, mucus in the digestive tract and gastric glands in the stomach. Findings indicate that jundia has a functional stomach before the end of vitelline reserves. Therefore, jundia larvae are probably capable to digest inert feed at the exogenous feeding onset. PMID- 23729203 TI - Pre-emptive positioning of a coronary stent in the left anterior descending artery for left main protection: a prerequisite for transcatheter aortic valve-in valve implantation for failing stentless bioprostheses? AB - Transcatheter aortic valve-in-valve (VIV) implantation in high-risk patients with degenerative surgical bioprosthetic aortic valves is a novel application of transcatheter aortic valve replacement technology. Although transcatheter aortic VIV procedure is clinically effective in most patients, it is a more demanding procedure in terms of the technical aspects of procedural planning. VIV carries a higher risk of coronary occlusion which is associated with a higher rate of in hospital mortality. We hereby report a technique of pre-emptive left main (LM) protection, by positioning a coronary stent in the proximal left anterior descending artery prior to VIV implantation. The patient treated was considered to be at an increased risk of LM occlusion as a result of the procedure. The technique was performed in anticipation of emergent bailout stenting of the LM. As predicted, the LM occluded during the procedure and LM protection facilitated the safe and effective treatment of an otherwise life-threatening procedure. PMID- 23729204 TI - Impact of race/ethnicity on laryngeal cancer in patients treated at a Veterans Affairs Medical Center. AB - OBJECTIVES/HYPOTHESIS: Black patients generally present with advanced head and neck cancer resulting in decreased survival. The objective of this study was to determine whether equal access to laryngeal cancer care in a tertiary care Veterans Affairs (VA) Medical Center would result in similar survival for white and black patients. STUDY DESIGN: Retrospective chart review. METHODS: Patient and tumor characteristics, compliance with National Comprehensive Cancer Network (NCCN) guidelines, and survival outcomes were collected for 205 male patients with squamous cell carcinoma of the larynx treated between 2000 and 2012 at the Michael E. DeBakey Veterans Affairs Medical Center. RESULTS: Black patients constituted 33% of the entire cohort, were older (mean age, 65.1 vs. 62.1 years), and consumed less tobacco (46.6 vs. 65.8 mean pack-years) than white patients. Disease stage and compliance with NCCN guidelines were not affected by race. Mean follow up time was 3.6 years. A higher recurrence rate was noted among white patients (24% vs. 15%, P < .05). Neither disease-free survival (DFS) nor overall survival (OS) was significantly different between black and white patients (DFS 69% vs. 68%, P = .7; OS 68% vs. 77%, P = .1). CONCLUSIONS: Utilization of a multidisciplinary approach to laryngeal cancer care at the VA medical center allows for high compliance with NCCN guidelines and excellent oncologic outcomes. Ethnicity did not impact stage at presentation, treatment selection, or treatment intensity in this patient cohort. Our data suggest that cancer care at a VA medical center results in clinical outcomes that do not significantly vary based on patient race. PMID- 23729205 TI - Acute calcific tendinosis of the flexor hallucis brevis: case report. PMID- 23729206 TI - Correlation of AO and Lauge-Hansen classification systems for ankle fractures to the mechanism of injury. AB - BACKGROUND: Our aim was to assess whether the Lauge-Hansen (LH) and the Muller AO classification systems for ankle fractures radiographically correlate with in vivo injuries based on observed mechanism of injury. METHODS: Videos of potential study candidates were reviewed on YouTube.com. Individuals were recruited for participation if the video could be classified by injury mechanism with a high likelihood of sustaining an ankle fracture. Corresponding injury radiographs were obtained. Injury mechanism was classified using the LH system as supination/external rotation (SER), supination/adduction (SAD), pronation/external rotation (PER), or pronation/abduction (PAB). Corresponding radiographs were classified by the LH system and the AO system. RESULTS: Thirty injury videos with their corresponding radiographs were collected. Of the video clips reviewed, 16 had SAD mechanisms and 14 had PER mechanisms. There were 26 ankle fractures, 3 nonfractures, and 1 subtalar dislocation. Twelve fractures with SAD mechanisms had corresponding SAD fracture patterns. Five PER mechanisms had PER fracture patterns. Eight PER mechanisms had SER fracture patterns and 1 had SAD fracture pattern. When the AO classification was used, all 12 SAD type injuries had a 44A type fracture, whereas the 14 PER injuries resulted in nine 44B fractures, two 44C fractures, and three 43A fractures. CONCLUSION: When injury video clips of ankle fractures were matched to their corresponding radiographs, the LH system was 65% (17/26) consistent in predicting fracture patterns from the deforming injury mechanism. When the AO classification system was used, consistency was 81% (21/26). The AO classification, despite its development as a purely radiographic system, correlated with in vivo injuries, as based on observed mechanism of injury, more closely than did the LH system. LEVEL OF EVIDENCE: Level IV, case series. PMID- 23729207 TI - Cystic lung disease. AB - This review addresses the pathology of lung disease in which the predominant finding is diffuse cystic change. Although cysts may be found radiologically in a wide variety of disease states, the entities discussed are those most likely to be encountered in biopsies where the underlying aetiology is unclear. These include Langerhans cell histiocytosis, lymphangioleiomyomatosis and Birt-Hogg Dube syndrome, and recent advances in the molecular pathology of these entities are reviewed. Conditions in which cyst formation may occur but does not represent the predominant pathology are also considered, including alveolar septal amyloidosis, light chain disease, follicular bronchiolitis and lymphocytic interstitial pneumonia. Cystic metastases may present a differential diagnostic dilemma. PMID- 23729208 TI - A powered bone marrow biopsy system versus manual methods: a systematic review and meta-analysis of randomised trials. AB - A significant number of bone marrow biopsies are performed annually. Outcomes of patient pain and sample size of biopsy are important issues as perception of patient pain is underestimated by clinicians and sample size assists in accurate diagnosis. Manual extraction of marrow biopsy is the main method used. Recently a powered system has been introduced. The objectives of this systematic review and meta-analysis were to determine if the powered system reduces patient pain and improves sample capture. A PubMed and Cochrane search for randomised controlled trials was undertaken comparing the powered system with manual methods. Risk of bias assessment and meta-analysis of outcomes using appropriate statistical methods were performed. Five randomised controlled trials were identified. Patient pain (measured via visual analogue scale (VAS)--100 point scale) was significantly reduced using the powered system: mean difference=-6.57; 95% CI 12.93 to -0.22; p=0.04. The relative reduction in pain was 17%-25% with the powered system. Sample biopsy size (length in mm) was also significantly increased with the powered system: mean difference=3.65 mm; 95%; CI 1.61 mm to 5.68 mm; p=0.0005. The relative increase in sample size was 33% with the powered system. Operator ease of use (as measured via VAS) and adverse events were similar. Despite limited operator experience, patients experienced less pain and sample sizes were increased without an increase in adverse events with the powered system. The powered system may offer an option in obtaining samples from patients whose pain is compromised by disease and may reduce redos. PMID- 23729209 TI - HNO/cGMP-dependent antihypertrophic actions of isopropylamine-NONOate in neonatal rat cardiomyocytes: potential therapeutic advantages of HNO over NO. AB - Nitroxyl (HNO) is a redox congener of NO. We now directly compare the antihypertrophic efficacy of HNO and NO donors in neonatal rat cardiomyocytes and compare their contributing mechanisms of actions in this setting. Isopropylamine NONOate (IPA-NO) elicited concentration-dependent inhibition of endothelin-1 (ET1)-induced increases in cardiomyocyte size, with similar suppression of hypertrophic genes. Antihypertrophic IPA-NO actions were significantly attenuated by l-cysteine (HNO scavenger), Rp-8-pCTP-cGMPS (cGMP-dependent protein kinase inhibitor), and 1-H-(1,2,4)-oxodiazolo-quinxaline-1-one [ODQ; to target soluble guanylyl cyclase (sGC)] but were unaffected by carboxy-PTIO (NO scavenger) or CGRP8-37 (calcitonin gene-related peptide antagonist). Furthermore, IPA-NO significantly increased cardiomyocyte cGMP 3.5-fold (an l-cysteine-sensitive effect) and stimulated sGC activity threefold, without detectable NO release. IPA NO also suppressed ET1-induced cardiomyocyte superoxide generation. The pure NO donor diethylamine-NONOate (DEA-NO) reproduced these IPA-NO actions but was sensitive to carboxy-PTIO rather than l-cysteine. Although IPA-NO stimulation of purified sGC was preserved under pyrogallol oxidant stress (in direct contrast to DEA-NO), cardiomyocyte sGC activity after either donor was attenuated by this stress. Excitingly IPA-NO also exhibited acute antihypertrophic actions in response to pressure overload in the intact heart. Together these data strongly suggest that IPA-NO protection against cardiomyocyte hypertrophy is independent of both NO and CGRP but rather utilizes novel HNO activation of cGMP signaling. Thus HNO acutely limits hypertrophy independently of NO, even under conditions of elevated superoxide. Development of longer-acting HNO donors may thus represent an attractive new strategy for the treatment of cardiac hypertrophy, as stand alone and/or add-on therapy to standard care. PMID- 23729210 TI - Distension of central great vein decreases sympathetic outflow in humans. AB - Classic canine studies suggest that central great vein distension evokes an autonomic reflex tachycardia (Bainbridge reflex). It is unclear whether central venous distension in humans is a necessary and sufficient stimulus to evoke a reflex increase in heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA). Prior work from our laboratory suggests that limb venous distension evokes a reflex increase in BP and MSNA in humans. We hypothesized that in humans, compared with the limb venous distension, inferior vena cava (IVC) distension would evoke a less prominent increase in HR and MSNA. IVC distension (monitored with ultrasonography) was induced by two methods: 1) head down tilt (HDT, N = 13); and 2) lower-body positive pressure (LBPP, N = 10). Two minutes of HDT induced IVC distension (Delta2.6 +/- 0.2 mm, P < 0.001, ~27% in cross-sectional area), slightly increased mean BP (Delta2.3 +/- 0.7 mmHg, P = 0.005), decreased MSNA (Delta5.2 +/- 0.8 bursts/min, P < 0.001, N = 10), and did not alter HR (P = 0.37). LBPP induced similar IVC distension, increased BP (Delta2.0 +/- 0.7 mmHg, P < 0.01), and did not alter HR (P = 0.34). Thus central venous distension leads to a rapid increase in BP and a subsequent fall in MSNA. Central venous distension does not evoke either bradycardia or tachycardia in humans. The absence of a baroreflex-mediated bradycardia suggests that the Bainbridge reflex is engaged. Clearly, this reflex differs from the powerful sympathoexcitation peripheral venous distension reflex described in humans. PMID- 23729211 TI - Interleukin 27 inhibits atherosclerosis via immunoregulation of macrophages in mice. AB - Chronic inflammation in arterial wall that is driven by immune cells and cytokines plays pivotal roles in the development of atherosclerosis. Interleukin 27 (IL-27) is a member of the IL-12 family of cytokines that consists of IL-27p28 and Epstein-Barr virus induced gene 3 (EBI3) and has anti-inflammatory properties that regulate T cell polarization and cytokine production. IL-27-deficient (Ldlr /-Ebi3-/-) and IL-27 receptor-deficient (Ldlr-/-WSX-1-/-) Ldlr-/- mice were generated and fed with a high-cholesterol diet to induce atherosclerosis. Roles of bone marrow-derived cells in vivo and macrophages in vitro were studied using bone marrow reconstitution by transplantation and cultured peritoneal macrophages, respectively. We demonstrate that mice lacking IL-27 or IL-27 receptor are more susceptible to atherosclerosis compared with wild type due to enhanced accumulation and activation of macrophages in arterial walls. The number of circulating proinflammatory Ly6C(hi) monocytes showed no significant difference between wild-type mice and mice lacking IL-27 or IL-27 receptor. Administration of IL-27 suppressed the development of atherosclerosis in vivo and macrophage activation in vitro that was indicated by increased uptake of modified low-density lipoprotein and augmented production of proinflammatory cytokines. These findings define a novel inhibitory role for IL-27 in atherosclerosis that regulates macrophage activation in mice. PMID- 23729212 TI - Distinct loading conditions reveal various patterns of right ventricular adaptation. AB - Right ventricular (RV) failure due to chronically abnormal loading is a main determinant of outcome in pulmonary hypertension (PH) and congenital heart disease. However, distinct types of RV loading have been associated with different outcomes. To determine whether the adaptive RV response depends on loading type, we compared hemodynamics, exercise, and hypertrophy in models of pressure overload due to pulmonary artery banding (PAB), pressure overload due to PH, combined pressure and volume overload, and isolated volume load. Ninety-four rats were subjected to either PAB, monocrotaline-induced PH (PH), aortocaval shunt (shunt), or combined monocrotaline and aortocaval shunt (PH + shunt). We performed pressure-volume analysis and voluntary exercise measurements at 4 wk. We compared PAB to PH (part I) and PH + shunt to either isolated PH or shunt (part II). In part I, enhanced contractility (end-systolic elastance and preload recruitable stroke work) was present in PH and PAB, but strongest in PAB. Frank Starling mechanism was active in both PAB and PH. In PAB this was accompanied by diastolic dysfunction (increased end-diastolic elastance, relaxation constant), clinical signs of RV failure, and reduced exercise. These distinct responses were not attributable to differences in hypertrophy. In part II, in PH + shunt the contractility response was blunted compared with PH, which caused pseudonormalization of parameters. Additional volume overload strongly enhanced hypertrophy in PH. We conclude that different types of loading result in distinct patterns of RV adaptation. This is of importance for the approach to patients with chronically increased RV load and for experimental studies in various types of RV failure. PMID- 23729214 TI - Risk of second primary malignancies after nasopharyngeal carcinoma: a population based cohort study in Taiwan. AB - BACKGROUND: The purpose of this study was to examine the risk of second primary malignancy (SPM) after nasopharyngeal carcinoma (NPC). METHODS: We compared the incidence of SPM in patients diagnosed with NPC at the end of 2009 using the data extracted from the Taiwan Longitudinal Health Insurance Database between 2001 and 2008 (n = 10,299), with age-matched controls (1:10; n = 102,990). RESULTS: We found a 55% increased risk of SPM in patients diagnosed with NPC, compared to the risk of first malignancy in the age-matched controls (incidence rate ratio [IRR] = 1.55; p < .0001). Although the diagnosis of SPM was negatively correlated with the survival of patients with NPC (p = .0011), primary NPC did not display any synergic effect on the survival of patients with SPM, compared to age-matched controls with a newly diagnosed malignancy (p = .8986). CONCLUSION: NPC is associated with an increased risk of developing an SPM. PMID- 23729213 TI - Altered ubiquitin-proteasome signaling in right ventricular hypertrophy and failure. AB - Alterations in the ubiquitin-proteasome system (UPS) have been described in left ventricular hypertrophy and failure, although results have been inconsistent. The role of the UPS in right ventricular (RV) hypertrophy (RVH) and RV failure (RVF) is unknown. Given the greater percent increase in RV mass associated with RV afterload stress, as present in many congenital heart lesions, we hypothesized that alterations in the UPS could play an important role in RVH/RVF. UPS expression and activity were measured in the RV from mice with RVH/RVF secondary to pulmonary artery constriction (PAC). Epoxomicin and MG132 were used to inhibit the proteasome, and overexpression of the 11S PA28alpha subunit was used to activate the proteasome. PAC mice developed RVH (109.3% increase in RV weight to body weight), RV dilation with septal shift, RV dysfunction, and clinical RVF. Proteasomal function (26S beta5 chymotrypsin-like activity) was decreased 26% (P < 0.05). Protein expression of 19S subunit Rpt5 (P < 0.05), UCHL1 deubiquitinase (P < 0.0001), and Smurf1 E3 ubiquitin ligase (P < 0.01) were increased, as were polyubiquitinated proteins (P < 0.05) and free-ubiquitins (P = 0.05). Pro apoptotic Bax was increased (P < 0.0001), whereas anti-apoptotic Bcl-2 decreased (P < 0.05), resulting in a sixfold increase in the Bax/Bcl-2 ratio. Proteasomal inhibition did not accelerate RVF. However, proteasome enhancement by cardiac specific proteasome overexpression partially improved survival. Proteasome activity is decreased in RVH/RVF, associated with upregulation of key UPS regulators and pro-apoptotic signaling. Enhancement of proteasome function partially attenuates RVF, suggesting that UPS dysfunction contributes to RVF. PMID- 23729215 TI - Novel neutralising antibodies targeting the N-terminal helical region of the transmembrane envelope protein p15E of the porcine endogenous retrovirus (PERV). AB - Previously, immunising different species with the transmembrane envelope protein p15E of the porcine endogenous retrovirus (PERV), neutralising antibodies were induced which recognised epitopes in the fusion peptide proximal region (FPPR) and in the membrane-proximal external region (MPER). Only the MPER-specific antibodies were shown to neutralise and these antibodies targeted epitopes in the MPER similarly localised as the epitopes recognised by antibodies broadly neutralising HIV-1 such as 2F5 and 4E10. To study whether neutralising antibodies could be induced immunising with subunits of p15E, recombinant proteins corresponding to the N-terminal, the C-terminal helical region (NHR, CHR) and a p15E with a mutation in the Cys-Cys loop were produced. Whereas none of these antigens induced MPER-specific neutralising antibodies, the animals immunised with the FPPR/NHR subunit and the mutated p15E produced neutralising antibodies binding to the NHR. Therefore, for the first time, antibodies specific for the NHR and neutralising PERV were described. PMID- 23729216 TI - Distribution of topical agents to the paranasal sinuses: an evidence-based review with recommendations. AB - BACKGROUND: The objective of this work was to review the literature concerning the distribution of topical therapeutics to the sinuses versus nasal cavity regarding: surgical state, delivery device, head position, and nasal anatomy and to provide evidence-based recommendations. METHODS: A systematic review was conducted using Medline, EMBASE, and Cochrane databases to perform a Medical Subject Heading search of the literature from 1946 until the last week of May 2012. Articles were independently reviewed and graded for level of evidence. All authors came to consensus on recommendations through an iterative process. RESULTS: Recommendations were made for: improved sinus delivery with high-volume devices and after standard sinus surgery. Recommendations were made against low volume delivery devices, such as drops, sprays, or simple nebulizers as they do not reliably reach the sinuses. If large-volume devices are not tolerated, low volume devices are recommended using the lying head back or lateral head low positions to improve nasal cavity distribution to the middle meatus or olfactory cleft. CONCLUSION: Surgery, volume of device, head position, and nasal anatomy were shown to impact distribution to the sinuses. Recommendations are made based upon this evidence as to how to best maximize therapeutic distribution to the sinuses. PMID- 23729218 TI - Spontaneous oesophageal rupture. PMID- 23729219 TI - Hernia surgery is cost effective, finds UK study. PMID- 23729220 TI - New zwitterionic polymethacrylate monolithic columns for one- and two-dimensional microliquid chromatography. AB - We prepared 0.53 and 0.32 mm id monolithic microcolumns by in situ copolymerization of a zwitterionic sulfobetaine functional monomer with bisphenol A glycerolate dimethacrylate (BIGDMA) and dioxyethylene dimetacrylate crosslinkers. The columns show a dual retention mechanism (hydrophilic interaction mode) in acetonitrile-rich mobile phases and RP in highly aqueous mobile phases. The new 0.53 mm id columns provided excellent reproducibility, retention, and separation selectivity for phenolic acids and flavonoids. The new zwitterionic monolithic columns are highly orthogonal, with respect to alkyl silica stationary phases, not only in the hydrophilic-interaction mode but also in the RP mode. The optimized monolithic zwitterionic microcolumn of 0.53 mm id was employed in the first dimension, either in the aqueous normal-phase or in the RP mode, coupled with a short nonpolar core-shell column in the second dimension, for comprehensive 2D LC separations of phenolic and flavonoid compounds. When the 2D setup with the sulfobetaine-BIGDMA column was used for repeated sample analysis, with alternating gradients of decreasing (hydrophilic-interaction mode), and increasing (RP mode) concentration of acetonitrile on the sulfobetaine BIGDMA column in the first dimension, useful complementary information on the sample could be obtained. PMID- 23729221 TI - Intensity-modulated versus conventional radiation therapy for oropharyngeal carcinoma: long-term dysphagia and tumor control outcomes. AB - BACKGROUND: The purpose of this study was to determine the relative clinical benefits of intensity-modulated radiation therapy (IMRT) versus conventional radiotherapy (CRT) in the treatment of patients with oropharyngeal carcinoma. METHODS: We compared tumor control and toxicity outcomes in 132 patients with stage III to IVA/B oropharyngeal carcinoma treated with definitive chemoradiation in the human papillomavirus (HPV) era. RESULTS: Patients treated with IMRT had lower rates of xerostomia (p = .01) and shorter duration of gastrostomy-tube dependence (p < .0001), but increased risk of cervical esophageal stricture (p = .03). The overall rates of late dysphagia were not different between the 2 groups (p = .40). In multivariate analysis, IMRT was a significant predictor of decreased disease-specific mortality (hazard ratio [HR] = 0.24; p = .03) after adjustment for T-category and active smoking. After adjustment for T classification, IMRT use was associated with a trend toward a significant decrease in locoregional failure (HR = 0.17; p = .08). CONCLUSION: The incidence of late dysphagia is similar in IMRT and CRT, but the mechanism of dysphagia is different. PMID- 23729222 TI - Autoimmune hepatitis experimental model based on adenoviral infections. PMID- 23729217 TI - Nonproteinogenic amino acid building blocks for nonribosomal peptide and hybrid polyketide scaffolds. AB - Freestanding nonproteinogenic amino acids have long been recognized for their antimetabolite properties and tendency to be uncovered to reactive functionalities by the catalytic action of target enzymes. By installing them regiospecifically into biogenic peptides and proteins, it may be possible to usher a new era at the interface between small molecule and large molecule medicinal chemistry. Site-selective protein functionalization offers uniquely attractive strategies for posttranslational modification of proteins. Last, but not least, many of the amino acids not selected by nature for protein incorporation offer rich architectural possibilities in the context of ribosomally derived polypeptides. This Review summarizes the biosynthetic routes to and metabolic logic for the major classes of the noncanonical amino acid building blocks that end up in both nonribosomal peptide frameworks and in hybrid nonribosomal peptide-polyketide scaffolds. PMID- 23729223 TI - Variation in hair delta(13)C and delta (15)N values in long-tailed macaques (Macaca fascicularis) from Singapore. AB - Much of the primatology literature on stable isotope ratios of carbon (delta(13)C) and nitrogen (delta(15)N) has focused on African and New World species, with comparatively little research published on Asian primates. Here we present hair delta(13)C and delta(15)N isotope values for a sample of 33 long tailed macaques from Singapore. We evaluate the suggestion by a previous researcher that forest degradation and biodiversity loss in Singapore have led to a decline in macaque trophic level. The results of our analysis indicated significant spatial variability in delta(13)C but not delta(15)N. The range of variation in delta(13)C was consistent with a diet based on C3 resources, with one group exhibiting low values consistent with a closed canopy environment. Relative to other macaque species from Europe and Asia, the macaques from Singapore exhibited a low mean delta(13)C value but mid-range mean delta(15)N value. Previous research suggesting a decline in macaque trophic level is not supported by the results of our study. PMID- 23729224 TI - Circulating extracellular vesicles in cancer diagnosis and monitoring: an appraisal of clinical potential. AB - Mammalian cells, including cancer cells, secrete extracellular vesicles. These vesicles are nanosized, bilayered proteolipids with diameters of 50-1,000 nm. It has been suggested that cancer cell-derived extracellular vesicles play diverse roles in cancer progression, which involve invasion, immune modulation, neovascularization, and metastasis. Moreover, their serum levels are significantly elevated in cancer patients compared with normal controls. Recent high-throughput proteomic and transcriptomic studies of these complex extracellular organelles have accelerated the discovery of cancer-specific biomarkers and the development of novel diagnostic tools based on extracellular vesicles. Although many vesicle-associated biomarker candidates have been reported for various types of cancer, few have been validated for clinical use due to preanalytical, technical, temporal, and financial problems. Here, we discuss the potential of extracellular vesicles as sources of biomarkers for cancer diagnosis and monitoring, as well as the limitations and obstacles to adoption of extracellular vesicle-based diagnosis. PMID- 23729225 TI - Prevalence and predictors of anxiety and depression among family caregivers of cancer patients: a nationwide survey of patient-family caregiver dyads in Korea. AB - PURPOSE: This study aimed to identify the prevalence and predictors of anxiety and depression among family caregivers of patients with cancer in Korea. METHODS: A national, multicenter, cross-sectional survey was conducted with 897 family caregivers. The Hospital Anxiety and Depression Scale was used to assess anxiety and depression in patient-family caregiver dyads. RESULTS: The prevalence of anxiety in family caregivers was 38.1 %:20.3 % reported mild anxiety, 13.3 % reported moderate anxiety, and 4.6 % reported severe anxiety. The prevalence of depression was 82.2 %:40.4 % reported mild depression, 25.5 % reported moderate depression, and 16.3 % reported severe depression. Family caregivers who were younger, were caring for male patients, or had a low quality of life (QOL) in relation to three of the variables measured in the Korean Caregiver Quality of Life Index-Cancer (CQOLC-K): burden, disturbance, and financial concerns reported increased anxiety. Becoming unemployed during caregiving, being the spouse of a patient and having low QOL in relation to three of the variables measured by the CQOLC-K: burden, disturbance, and positive adaptation were associated with depression among family caregivers. The predictive validity of the selected variables were 0.861 (95 % CI: 0.844-0.892) for anxiety and 0.794 (95 % CI: 0.751 0.828) for depression. CONCLUSIONS: Family caregivers of patients with cancer experienced high levels of anxiety and depression. Socio-demographic factors and QOL were predictors of anxiety and depression in family caregivers. PMID- 23729226 TI - Effect of netupitant, a highly selective NK1 receptor antagonist, on the pharmacokinetics of midazolam, erythromycin, and dexamethasone. AB - PURPOSE: Netupitant is a new highly selective neurokinin-1 receptor antagonist being studied for the prevention of nausea and vomiting in patients undergoing chemotherapy. In vitro studies suggest that netupitant inhibits the cytochrome P 450 isoenzyme 3A4 (CYP3A4). Because netupitant may be used with a variety of drugs, which may be substrates of CYP3A4, two studies were designed to establish the potential risk for drug-drug interaction with three different CYP3A4 substrates: midazolam, erythromycin, and dexamethasone. METHODS: Both trials were three-period crossover studies performed in healthy subjects. In the first study, 20 subjects received netupitant and either midazolam or erythromycin. In the second study, 25 subjects received netupitant and dexamethasone. Serial blood samples were collected over the course of the two studies and pharmacokinetic parameters were determined for all analytes. RESULTS: Netupitant, by inhibiting the CYP3A4, increased the C max and AUCinf of midazolam by 40 and 144 %, respectively, and the C max and AUCinf of erythromycin by 30 %. Netupitant was shown to increase the exposure to dexamethasone in a dose-dependent manner with the mean increase in AUC and C max by 72 and 11 %, respectively, on day 1 and by 138 and 75 %, respectively, on day 4 when co-administered with 300 mg of netupitant. CONCLUSIONS: The results of these studies suggest that netupitant is a moderate inhibitor of CYP3A4 and therefore, co-administration with drugs that are substrates of CYP3A4 may require dose adjustments. Treatments were well tolerated in both studies. PMID- 23729227 TI - Dental students' knowledge of characteristics and management of oral complications of cancer therapy. AB - OBJECTIVE: The aim of this study is to investigate the level of Turkish senior dental students' knowledge regarding the orodental complications and their treatment methods of cancer patients. STUDY DESIGN: A 15-item questionnaire which was obtained from National Institute of Dental and Craniofacial Research that contained information about the orodental complications of the cancer therapy and the dentists' role to provide their treatment protocols was used. Seventy-seven senior dental students answered the questionnaire and the replies were analyzed with stratified and logistic data analyses. RESULTS: Overall, correct replies ranged from 5.2 to 98.7 %. The students knew the basic knowledge of the complications of cancer therapy; however, they failed to answer to the questions (ranging between 1.3 and 94.8 %) about the required clinical practices. The respondents preferred not to answer the questions about the prophylactic measures dentist shall take during a precancer treatment oral evaluation (9.1 %), management of pain in cancer treatment (6.5 %), and necessary considerations before a dental procedure in a chemotherapy patient (3.9 %). The multiple logistic regression analysis revealed that gender had no statistically significant effect on the correct or false answers to the questions (p > 0.05). CONCLUSION: Our results disclosed that dental students' knowledge about oral complications of cancer therapy and the modalities to manage these complications vary. Reevaluation of current undergraduate curricula and continuing education for graduates might address the gaps identified and an educational program about oral and dental management of patients who are to receive/receiving/have received cancer therapy can be prepared and augmented into dental curriculum. PMID- 23729228 TI - Printed guide improves knowledge of curative, palliative, and hospice care among women with metastatic breast cancer. PMID- 23729229 TI - FIT false-positives in colorectal cancer screening experience psychological distress up to 6 weeks after colonoscopy. AB - PURPOSE: Screening programs for colorectal cancer aim at reducing cancer mortality. We assessed psychological effects of being invited to an immunochemical fecal test (FIT)-based screening program. METHODS: Asymptomatic persons aged 50-74 years were invited to a Dutch screening pilot. The Psychological Consequences Questionnaire (PCQ) was used to measure the psychological effects of screening. Screen positives had two additional measurements: before undergoing the colonoscopy and 4 weeks after receiving the colonoscopy findings. RESULTS: A number of 3,828 invitees (46 % male, mean age 60 years) completed the first PCQ. FIT positives had a higher mean total PCQ score (8.32, SD 8.84; score range 0-36) than those who declined participation (3.72, SD 6.30); participants still waiting for their FIT result had a mean score of 2.74 (SD 5.11), and those with a negative FIT result had the lowest score (2.06, SD 4.43) (p < 0.001). In the 373 FIT positives who underwent colonoscopy, 195 completed the pre-colonoscopy questionnaire and 253, the post-colonoscopy questionnaire. Mean total, physical, and social PCQ scores had decreased significantly between the first questionnaire and the pre-colonoscopy one, but scores on the emotional subscale did not. In false-positives, mean total, physical, and emotional PCQ scores decreased significantly, while in true positives, a significant decrease in mean emotional PCQ score was observed. CONCLUSION: Psychological consequences for invitees to a Dutch FIT-based colorectal cancer screening pilot differ, depending on timing and FIT result. FIT positives are more distressed than FIT negatives. FIT positives still experience psychological distress 6 weeks after a normal colonoscopy. PMID- 23729231 TI - Photoinduced charge-transfer interactions on a graphene/block copolymer electrostatically bound to tetracationic porphyrin in aqueous media. AB - Stable dispersions of exfoliated graphene in aqueous media with the aid of the amphiphilic block copolymer poly(isoprene-b-acrylic acid) (PI-b-PAA), in the form of its anion, were used to electrostatically bind cationic 5,10,15,20-tetrakis(1 methyl-4-pyridinio)porphine tetra(p-toluenesulfonate) (H2P(4+)). A new graphene/PI-b-PAA(-)-H2P(4+) ensemble was formed and examined by dynamic light scattering, UV/Vis and fluorescence emission spectroscopy. The efficient fluorescence quenching of H2P(4+) in the graphene/PI-b-PAA(-)-H2P(4+) ensemble was probed by using steady-state and time-resolved photoluminescence, suggesting that electron/energy-transfer phenomena occur within the nanoensemble. Blank experiments validated the concept of electrostatic interactions that govern the formation of graphene/PI-b-PAA(-)-H2P(4+) ensemble, which signified the importance of graphene as an electron acceptor toward the preparation of some new donor-acceptor systems. Finally, kinetic analysis of the lifetime profiles of the fluorescence emission gave information regarding the quenching rate constant and quantum yield of the singlet excited state of H2P(4+) in the graphene/PI-b-PAA(-) H2P(4+) ensemble. PMID- 23729230 TI - TACE-dependent TGFalpha shedding drives triple-negative breast cancer cell invasion. AB - The epidermal growth factor receptor (EGFR) is frequently expressed in triple negative breast cancer (TNBC) and is a marker of poor prognosis in this patient population. Because activating mutations in this kinase are very rare events in breast cancer, we screened breast tumor gene expression profiles to examine the distribution of EGFR ligand expression. Of the six known EGFR ligands, transforming growth factor alpha (TGFalpha) was expressed more highly in triple negative breast tumors than in tumors of other subtypes. TGFalpha is synthesized as a transmembrane precursor requiring tumor necrosis factor alpha converting enzyme (TACE)/ADAM17-dependent proteolytic release to activate its receptor. In our study, we show that an inhibitor of this proteolytic release blocks invasion, migration and colony formation by several TNBC cell lines. Each of the effects of the drug was reversed upon expression of a soluble TGFalpha mutant that does not require TACE activity, implicating this growth factor as a key metalloproteinase substrate for these phenotypes. Together, these data demonstrate that TACE dependent TGFalpha shedding is a key process driving EGFR activation and subsequent proliferation and invasion in TNBC cell lines. PMID- 23729232 TI - Trastuzumab plus capecitabine vs. lapatinib plus capecitabine in patients with trastuzumab resistance and taxane-pretreated metastatic breast cancer. AB - The purpose of this prospective, nonrandomized, controlled study was to compare the regimen of continuously administering trastuzumab and capecitabine (HX) with the regimen of lapatinib plus capecitabine (LX) for metastatic breast cancer (MBC) patients who are resistant to trastuzumab and have previously received taxane treatment. The patients in the HX group received trastuzumab (6 mg/kg every 21 days following a loading dose of 8 mg/kg on cycle 1) and capecitabine (2,000 mg/m(2)/day, days 1 to 14 every 21 days). The patients in the LX group received lapatinib (1,250 mg/day) and capecitabine (2,000 mg/m(2)/day, days 1 to 14 every 21 days). The median progression-free survival (PFS) of the patients in the HX and LX groups was 4.5 vs. 6.0 months, respectively (p = 0.006). The proportion of patients having a PFS >= 6 months in the HX and LX groups was 30 vs. 55 %, respectively (p = 0.005). The incidence rate of new brain metastases during treatment was 12 and 3 % in the HX and LX groups, respectively, which was not significantly different (p = 0.16). In conclusion, application of the lapatinib plus capecitabine regimen in MBC patients with a trastuzumab-resistant tumor can more effectively control the disease compared with continuous administration of trastuzumab plus capecitabine. PMID- 23729233 TI - Isolation of Sporothrix schenckii from the claws of domestic cats (indoor and outdoor) and in captivity in Sao Paulo (Brazil). AB - Sporotrichosis is a subcutaneous mycosis and is also a zoonosis (sapro- and anthropozoonosis). The objective of the present study was to determine the occurrence of sporotrichosis in domestic cats and in wild or exotic felines in captivity through the isolation of Sporothrix spp. from claw impressions in a culture medium. The samples included 132 felines, of which 120 (91.0 %) were domestic cats, 11 (8.3 %) were wild felines, and one (0.7 %) was an exotic felid. Twenty-one (17.5 %) were outdoor cats. Of the total, 89 (67.4 %) had contact with other animals of the same species. It was possible to isolate Sporothrix schenckii from the claws of one (0.7 %) of the felids probed; this animal exhibited generalised sporotrichosis and had infected a female veterinarian. The potential pathogenic agents Microsporum canis and Malassezia pachydermatis were isolated in 12.1 and 5.3 % of the animals, respectively. The following anemophilous fungi, which were considered to be contaminants, were also isolated: Penicillium sp. (28 or 21.2 %), Aspergillus sp. (13 or 9.8 %), Rhodotorula sp. (5 or 3.8 %), Candida sp. (5 or 3.8 %), Trichoderma sp. (1 or 0.7 %), and Acremonium sp. (1 or 0.7 %). Due to the low magnitude of occurrence (0.7 %) of Sporothrix in feline claws, the potential of the cats evaluated in this study to be sources of infection in the city of Sao Paulo is considerably low. PMID- 23729234 TI - Tongue suspension: an evidence-based review and comparison to hypopharyngeal surgery for OSA. AB - OBJECTIVES/HYPOTHESIS: Our first objective was to perform a systematic review of suture-based tongue suspension procedures as a stand-alone therapy for hypopharyngeal obstruction in obstructive sleep apnea (OSA). A second objective compared outcomes of tongue suspension as part of a multilevel approach to OSA surgery to genioglossus advancement (GA) with uvulopalatopharyngoplasty (UPPP), and to genioglossus advancement with hyoid suspension (GAHM) with UPPP. STUDY DESIGN: Systematic review. METHODS: The PubMed database was queried for English language studies published after 1997 to create four cohorts: tongue suspension alone, tongue suspension with UPPP, GA + UPPP, and GAHM with UPPP. Chi-squared test was used to compare outcomes between cohorts. RESULTS: Twenty-seven studies were included, broken down into cohorts based on our selection criteria. Six studies qualified for the tongue suspension-alone group with a surgical success rate of 36.6%. Eight studies qualified for our cohort of tongue suspension with UPPP with a surgical success rate of 62.3%. Eighteen studies qualified for our remaining two cohorts: GA + UPPP, and GAHM + UPPP. Their surgical success rates were both 61.1%. A chi-squared test to compare surgical outcomes showed that there was no difference between tongue suspension with UPPP, GA + UPPP, and GAHM + UPPP. CONCLUSION: Tongue suspension is effective and safe as part of a multilevel surgical approach for patients with OSA. As a stand-alone procedure, its success rate is 36.6%, comparable to UPPP procedures for OSA success rates across the board. Tongue suspension should be considered in patients with OSA who demonstrate tongue base obstruction. PMID- 23729235 TI - Optimal spatial filtering for brain oscillatory activity using the Relevance Vector Machine. AB - Over the past decade, various techniques have been proposed for localization of cerebral sources of oscillatory activity on the basis of magnetoencephalography (MEG) or electroencephalography recordings. Beamformers in the frequency domain, in particular, have proved useful in this endeavor. However, the localization accuracy and efficacy of such spatial filters can be markedly limited by bias from correlation between cerebral sources and short duration of source activity, both essential issues in the localization of brain data. Here, we evaluate a method for frequency-domain localization of oscillatory neural activity based on the relevance vector machine (RVM). RVM is a Bayesian algorithm for learning sparse models from possibly overcomplete data sets. The performance of our frequency-domain RVM method (fdRVM) was compared with that of dynamic imaging of coherent sources (DICS), a frequency-domain spatial filter that employs a minimum variance adaptive beamformer (MVAB) approach. The methods were tested both on simulated and real data. Two types of simulated MEG data sets were generated, one with continuous source activity and the other with transiently active sources. The real data sets were from slow finger movements and resting state. Results from simulations show comparable performance for DICS and fdRVM at high signal-to noise ratios and low correlation. At low SNR or in conditions of high correlation between sources, fdRVM performs markedly better. fdRVM was successful on real data as well, indicating salient focal activations in the sensorimotor area. The resulting high spatial resolution of fdRVM and its sensitivity to low-SNR transient signals could be particularly beneficial when mapping event-related changes of oscillatory activity. PMID- 23729236 TI - Psychological distance and reaction time in a Stroop task. AB - Several sources of interference may simultaneously affect the onset of the well known "Stroop effect." Among them is the semantic component, which is reflected in the gradient or semantic effect. This effect consists of an increase in the amount of interference as the semantic distance between the word and the color concept decreases. Shepard (Science 237:1317-1323, 1987) relates psychological space, measured through multidimensional scaling, to mean response times. The present investigation aims to study the function relating the semantic gradient with the psychological distance between the word and the color in a Stroop task. After measuring the gradient, we obtained the subjective rating of the degree of dissimilarity of the gradient words with the concept of "color." In our work, we show that the amount of interference in a Stroop task increases when the semantic distance from the word to the color concept decreases, and it does so exponentially. We replicated the study with different stimuli to test the robustness of the results. PMID- 23729237 TI - Neutralization resistance of hepatitis C virus can be overcome by recombinant human monoclonal antibodies. AB - Immunotherapy and vaccine development for hepatitis C virus (HCV) will depend on broadly reactive neutralizing antibodies (NAbs). However, studies in infectious strain JFH1-based culture systems expressing patient-derived Core-NS2 proteins have suggested neutralization resistance for specific HCV strains, in particular, of genotype 2. To further examine this phenomenon, we developed a panel of HCV genotype 2 recombinants for testing of sensitivity to neutralization by chronic phase patient sera and lead human monoclonal antibodies (HMAbs). The novel Core NS2 recombinants, with patient-derived genotype 2a (strain T9), 2b (strains DH8 and DH10), and 2c (strain S83) consensus sequences, were viable in Huh7.5 hepatoma cells without requirement for adaptive mutations, reaching HCV infectivity titers of 3.9-4.5 log10 focus-forming units per milliliter. In in vitro neutralization assays, we demonstrated that the novel genotype 2 viruses as well as prototype strains J6/JFH1(2a) and J8/JFH1(2b), all with authentic envelope proteins, were resistant to neutralization by genotype 2a, 2b, 2c, 2j, 2i, and 2q patient sera. However, these patient sera had high titers of HCV specific NAbs, because they efficiently reduced the infectivity of J6(2a) and J8(2b) with deleted hypervariable region 1. The genotype 2a, 2b, and 2c viruses, found resistant to polyclonal patient sera neutralization, were efficiently neutralized by two lead HMAbs (AR4A and HC84.26). CONCLUSION: Using novel 2a, 2b, and 2c cell-culture systems, expressing authentic envelope proteins, we demonstrated resistance of HCV to patient-derived polyclonal high-titer NAbs. However, the same genotype 2 culture viruses were all sensitive to HMAbs recognizing conformational epitopes, indicating that neutralization resistance of HCV can be overcome by applying recombinant antibodies. These findings have important implications for HCV immunotherapy and vaccine development. PMID- 23729239 TI - Sentinel node biopsy as an alternative to elective neck dissection for staging of early oral carcinoma. AB - BACKGROUND: We report the outcome of sentinel node biopsy (SNB) for staging the neck in a consecutive cohort of 34 patients with T1/2 clinically N0 oral carcinoma. METHODS: SNB was performed along with resection of primary tumor. Neck dissection was reserved for failure of SNB or pathologically positive sentinel nodes (pN+). RESULTS: Sentinel node identification was successful in 32 of 34 patients (94%); 2 patients with unsuccessful SNB underwent immediate neck dissection. Seven patients (21%) were pN+, 6 by SNB and 1 by elective neck dissection (END). Among 29 patients who were pN0 on SNB, nodal recurrence developed in 2 patients; both were surgically salvaged. Local failure developed in 1 patient. Two-year overall and disease-free survival was 87% and 80%, respectively. CONCLUSION: Successful eradication of lymphatic metastasis noted in this study suggests that SNB may be a safe alternative to END for neck staging in patients with early oral carcinoma. PMID- 23729238 TI - RNA interference-mediated silencing of laminin receptor 1 (LR1) suppresses migration and invasion and down-regulates matrix metalloproteinase (MMP)-2 and MMP-9 in trophoblast cells: implication in the pathogenesis of preeclampsia. AB - Shallow trophoblast invasion is a common pathological feature of preeclampsia. The 67 kDa laminin receptor 1 (LR1) is a laminin-binding protein that has been reported to be down-regulated in preeclamptic placentas. The aim of the present study was to determine the functional role of LR1 in the migration and invasion of the trophoblast cell line, JEG3 cells. RNA interference mediated by plasmid expressing LR1 short hairpin RNA (shRNA) was utilized to knockdown LR1 expression in JEG3 cells. We found that the mRNA and protein expression levels of LR1 were significantly reduced in LR1-specific shRNA transfected cells compared with the untransfected and control shRNA transfected cells. The wound healing and Transwell invasion assays demonstrated that LR1 knockdown remarkably suppressed the migration and invasion potential of JEG3 cells. The gelatin zymography assay showed that LR1 knockdown greatly reduced matrix metalloproteinase (MMP)-2 and MMP-9 activities in the culture supernatants. Western blot analysis showed that LR1 shRNA significantly decreased expression levels of MMP-2, MMP-9 and phospho extracellular signal-regulated kinase, but increased expression levels of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in comparison to the control vector-transfected cells. In conclusion, our data support an important role for LR1 in regulating trophoblast invasion and migration, and suggest a possible pathological mechanism of preeclampsia. PMID- 23729240 TI - Learning curve for intracranial angioplasty and stenting in single center. AB - OBJECTIVE: To identify the specific caseload to overcome learning curve effect based on data from consecutive patients treated with Intracranial Angioplasty and Stenting (IAS) in our center. BACKGROUND: The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke and Intracranial Stenosis trial was prematurely terminated owing to the high rate of periprocedural complications in the endovascular arm. To date, there are no data available for determining the essential caseload sufficient to overcome the learning effect and perform IAS with an acceptable level of complications. METHODS: Between March 2004 and May 2012, 188 consecutive patients with 194 lesions who underwent IAS were analyzed retrospectively. The outcome variables used to assess the learning curve were periprocedural complications (included transient ischemic attack, ischemic stroke, vessel rupture, cerebral hyperperfusion syndrome, and vessel perforation). Multivariable logistic regression analysis was employed to illustrate the existence of learning curve effect on IAS. A risk-adjusted cumulative sum chart was performed to identify the specific caseload to overcome learning curve effect. RESULTS: The overall rate of 30-days periprocedural complications was 12.4% (24/194). After adjusting for case-mix, multivariate logistic regression analysis showed that operator experience was an independent predictor for periprocedural complications. The learning curve of IAS to overcome complications in a risk-adjusted manner was 21 cases. CONCLUSIONS: Operator's level of experience significantly affected the outcome of IAS. Moreover, we observed that the amount of experience sufficient for performing IAS in our center was 21 cases. PMID- 23729241 TI - Association between fatigue and pain in rheumatoid arthritis: does pain precede fatigue or does fatigue precede pain? AB - OBJECTIVE: Fatigue and pain are important symptoms for patients with rheumatoid arthritis (RA), but their temporal association is unknown. Therefore, the objective of this study was to investigate the longitudinal relationship between fatigue and pain in patients with RA using time-lag models. METHODS: Consecutive RA outpatients (n = 228) were enrolled for this 1-year study. Fatigue was assessed monthly with the Checklist Individual Strength (CIS; range 8-56) and pain was assessed monthly with the bodily pain subscale (inverted, range 0-100) of the Short Form 36. The association between monthly changes in fatigue and pain was analyzed using longitudinal regression (mixed models), using the same months and with a 1-month time lag. RESULTS: A total of 198 patients were included in the analyses. At baseline, the mean +/- SD pain score was 35.23 +/- 19.82 and the mean +/- SD CIS fatigue score was 31.0 +/- 12.4. Severe fatigue at baseline (CIS score >=35) was present in 42% of the patients. The mean +/- SD patient-averaged CIS fatigue score over 1 year was 30.9 +/- 6.0 and the mean +/- SD patient averaged pain score over 1 year was 36.4 +/- 18.3. The longitudinal regression analysis showed a significant positive relationship between fatigue and pain during the same month (beta = 2.04; 95% confidence interval 1.82, 2.27). The models using a time lag showed no significant association between changes in pain and changes in fatigue. CONCLUSION: In established RA, pain and fatigue show monthly fluctuations that are synchronous rather than showing a temporal relationship with a time lag; within this timeframe, the results do not indicate that one precedes the other. PMID- 23729244 TI - Sustained water oxidation by a catalyst cage-isolated in a metal-organic framework. PMID- 23729243 TI - Binge/purge thoughts in nonsuicidal self-injurious adolescents: an ecological momentary analysis. AB - OBJECTIVE: Adolescents who self-injure often engage in bingeing/purging (BP). Ecological momentary assessment (EMA) has potential to offer insight into the relationship between self-injury and BP. The aims of this study were to examine the frequency and context of BP using EMA in a sample of nonsuicidal self injurious (NSSI) adolescents. METHOD: Thirty adolescents with a history of NSSI responded to questions regarding self-destructive thoughts/behaviors using a palm pilot device. Descriptive analyses compared thought/behavior contexts during reports of BP and NSSI thoughts/behaviors (occurring together vs. individually). RESULTS: BP thoughts were present in 22 (73%) participants, occurring on 32% of the person-days recorded; 59% of these participants actually engaged in BP behavior. Seventy-nine percent of BP thoughts co-occurred with other self destructive thoughts. Adolescents were more often with friends/peers than alone or with family when having BP thoughts. Worry and pressure precipitated both BP and NSSI thoughts, but perceived criticism and feelings of rejection/hurt were associated more often with BP thoughts than with NSSI thoughts. DISCUSSION: BP thoughts and behaviors were common in this sample, often occurring with other self-destructive thoughts. Future EMA research is needed to address the function of BP symptoms, the contextual variables that increase risk for BP thoughts, and the factors that predict the transition of thoughts into behaviors in adolescents with and without self-injury. PMID- 23729245 TI - Improved visualization of neuronal injury following glial activation by manganese enhanced MRI. AB - Research directed at anatomical, integrative and functional activities of the central nervous system (CNS) can be realized through bioimaging. A wealth of data now demonstrates the utility of magnetic resonance imaging (MRI) towards unraveling complex neural connectivity operative in health and disease. A means to improve MRI sensitivity is through contrast agents and notably manganese (Mn2+). The Mn2+ ions enter neurons through voltage-gated calcium channels and unlike other contrast agents such as gadolinium, iron oxide, iron platinum and imaging proteins, provide unique insights into brain physiology. Nonetheless, a critical question that remains is the brain target cells serving as sources for the signal of Mn2+ enhanced MRI (MEMRI). To this end, we investigated MEMRI's abilities to detect glial (astrocyte and microglia) and neuronal activation signals following treatment with known inflammatory inducing agents. The idea is to distinguish between gliosis (glial activation) and neuronal injury for the MEMRI signal and as such use the agent as a marker for neural activity in inflammatory and degenerative disease. We now demonstrate that glial inflammation facilitates Mn2+ neuronal ion uptake. Glial Mn2+ content was not linked to its activation. MEMRI performed on mice injected intracranially with lipopolysaccharide was associated with increased neuronal activity. These results support the notion that MEMRI reflects neuronal excitotoxicity and impairment that can occur through a range of insults including neuroinflammation. We conclude that the MEMRI signal enhancement is induced by inflammation stimulating neuronal Mn2+ uptake. PMID- 23729246 TI - HPLC with quadrupole TOF-MS and chemometrics analysis for the characterization of Folium Turpiniae from different regions. AB - Folium Turpiniae has been used as a traditional Chinese medicine for the treatment of abscesses, fevers, gastric ulcers, and inflammations. This paper describes a strategy of combining HPLC with photodiode array detection and quadrupole TOF-MS, as well as phytochemical and chemometrics analysis for the characterization, isolation, and simultaneous quantification of the chemical constituents of Folium Turpiniae. 19 constituents were identified, namely, 11 flavonoids, seven gallic acid derivates, and quinic acid. Among them, 15 compounds were identified in this herbal medicine for the first time; compound 10 appears to be novel and was isolated and confirmed as ellagic acid-3-O-alpha-L rhamnopyranoside by NMR spectroscopy and MS. In addition, nine marker compounds, namely gallic acid (2), ellagic acid-3-O-alpha-L-rhamnopyranoside (10), apigenin 7-O-(2''-rhamnosyl)gentiobioside (11), ellagic acid (12), luteolin-7-O-beta-D neohesperidoside (13), ligustroflavone (14), 4'-O-methylellagic acid-3-O-alpha-L rhamnopyranoside (16), rhoifolin (17), and neobudofficide (18), were quantified simultaneously in ten batches of Folium Turpiniae collected from different regions. Moreover, hierarchical clustering analysis and principal component analysis indicated that both samples from Hubei (S1) and Guangxi (S3) provinces showed apparent differences from the others. Samples from Jiangxi province (S2, S4, and S7-10) possessed similar properties and therefore belong to the same group. PMID- 23729247 TI - Protein-ligand interactions: fundamentals. AB - Here are described the basic mechanisms governing the interactions between proteins and their natural or manmade ligands, together with the principles underlying their analysis. The consequences of these principles are detailed for the simplest case of one-to-one binding. The general features of experimental measurements of biomolecular interactions arise from properties of the molecules involved and, thus, are common to many methods of detection. Consequently, an understanding of these principles greatly simplifies adoption and comparison of experimental methods and provides the rationale underlying many common protocols. In seeking to understand and interpret the results of experiments or identify possible sources of error these fundamental ideas are a constant guide. PMID- 23729248 TI - Protein sample characterization. AB - Most biophysical experiments require protein samples of high quality and accurately determined concentration. This chapter attempts to compile basic information on the most common methods to assess the purity, dispersity, and stability of protein samples. It also reminds of methods to measure protein concentration and of their limits. The idea is to make aware and remind of the range of methods available and of commonly overlooked pitfalls. The aim is to enable experimenters to fully characterize their preparations of soluble or membrane proteins and gain reliable and reproducible results from their experimental work. PMID- 23729249 TI - Measurement of protein-ligand complex formation. AB - Experimental approaches to detect, measure, and quantify protein-ligand binding, along with their theoretical bases, are described. A range of methods for detection of protein-ligand interactions is summarized. Specific protocols are provided for a nonequilibrium procedure pull-down assay, for an equilibrium direct binding method and its modification into a competition-based measurement and for steady-state measurements based on the effects of ligands on enzyme catalysis. PMID- 23729250 TI - Isothermal titration calorimetry for studying protein-ligand interactions. AB - Isothermal titration calorimetry (ITC) is a biophysical technique that allows a thermodynamic characterization of an interactive system. It is a free in solution technique that requires no labeling, using heat as signal. ITC allows simultaneous determination of affinity K a, stoichiometry n, enthalpy change DeltaH and calculation of free energy change DeltaG and entropy change DeltaS in one single experiment. It is the only technique that allows direct enthalpy change measurement. By accessing the enthalpy change, we get a step closer in estimating the driving forces that characterize the interaction of a protein with a ligand, information much needed in the drug discovery process. PMID- 23729251 TI - Rapid mixing kinetic techniques. AB - Almost all of the elementary steps in a biochemical reaction scheme are either unimolecular or bimolecular processes that frequently occur on sub-second, often sub-millisecond, time scales. The traditional approach in kinetic studies is to mix two or more reagents and monitor the changes in concentrations with time. Conventional spectrophotometers cannot generally be used to study reactions that are complete within less than about 20 s, as it takes that amount of time to manually mix the reagents and activate the instrument. Rapid mixing techniques, which generally achieve mixing in less than 2 ms, overcome this limitation. This chapter is concerned with the use of these techniques in the study of reactions which reach equilibrium; the application of these methods to the study of enzyme kinetics is described in several excellent texts (Cornish-Bowden, Fundamentals of enzyme kinetics. Portland Press, 1995; Gutfreund, Kinetics for the life sciences. Receptors, transmitters and catalysis. Cambridge University Press, 1995).There are various ways to monitor changes in concentration of reactants, intermediates and products after mixing, but the most common way is to use changes in optical signals (absorbance or fluorescence) which often accompany reactions. Although absorbance can sometimes be used, fluorescence is often preferred because of its greater sensitivity, particularly in monitoring conformational changes. Such methods are continuous with good time resolution but they seldom permit the direct determination of the concentrations of individual species. Alternatively, samples may be taken from the reaction volume, mixed with a chemical quenching agent to stop the reaction, and their contents assessed by techniques such as HPLC. These methods can directly determine the concentrations of different species, but are discontinuous and have a limited time resolution. PMID- 23729252 TI - Protein-Ligand Interactions Using SPR Systems. AB - Surface plasmon resonance (SPR) biosensor technology has become an important tool for drug discovery and basic research. SPR instruments are used for a wide variety of applications including determining the binding kinetics and affinity of an interaction, specificity studies, screening, assay development as well as concentration measurements. The interacting molecules may be proteins, peptides, lipids, viruses, nucleic acids, or small organic molecules such as fragments or drug candidates. The ease with which real time information can be obtained has changed many customer workflows in both antibody and small molecule/fragment interaction analysis, from label based and affinity/IC50 based workflows towards a label free and kinetic based workflow. This chapter focuses on applications for drug discovery, and outlines the experimental design for screening and selection of small molecules from a focused library. Also, determination of kinetics and/or affinity constants of selected ligands, using established SPR methodology is described, together with potential issues during assay development, running of the assay, and results interpretation. PMID- 23729253 TI - Fluorescence techniques in analysis of protein-ligand interactions. AB - Fluorescence spectroscopy may serve as a universal tool for the study of protein ligand interactions. Applications of fluorometry have made use of various aspects of fluorescence such as intensity, emission and excitation spectra, lifetime, quantum yield, polarization state, and anisotropy, as well as energy transfer and other electronic phenomena. An experimentalist has to consider each of these characteristics carefully, frequently in combination with each other, for the analysis of protein-ligand complexes and for the determination of binding constants. Most of the available techniques are of a rather general nature and a wealth of possibilities exists for their utilization. In this chapter we will provide a short survey of selected techniques that can be used for measuring binding constants and probing protein-ligand interactions. Basic principles and phenomena are discussed followed by experimental considerations and examples of binding constant determination. Emphasis is placed on steady-state techniques that employ the use of intrinsic protein fluorescence, labeled ligands, as well as anisotropy and resonance energy transfer. PMID- 23729254 TI - Circular and linear dichroism spectroscopy for the study of protein-ligand interactions. AB - Circular dichroism (CD) is the difference in absorption of left and right circularly polarized light, usually by a solution containing the molecules of interest. A non-zero signal for solutions is only measured for chiral molecules such as proteins whose mirror image is not superposable on the original molecule. A CD spectrum provides information about the bonds and structures responsible for the chirality. When a small molecule (or ligand) binds to a protein, it acquires an induced CD (ICD) spectrum through chiral perturbation to its structure or electron rearrangements (transitions). The wavelengths of this ICD are determined by the ligand's own absorption spectrum, and the intensity of the ICD spectrum is determined by the strength and geometry of its interaction with the protein. Thus, ICD can be used to probe the binding of ligands to proteins. This chapter contains an outline of how to perform protein CD and ICD experiments, together with some of the issues relating to experimental design and implementation. Addition of a quarter wave plate to a CD spectropolarimeter converts it to a linear dichroism (LD) spectrometer. When protein samples are aligned either in flow (as for fibers or membrane proteins in liposomes) or on surfaces the orientations of ligands with respect to the protein backbone or other subunits can be determined. PMID- 23729255 TI - Analyzing protein-ligand interactions by dynamic NMR spectroscopy. AB - Nuclear magnetic resonance (NMR) spectroscopy can provide detailed information on protein-ligand interactions that is inaccessible using other biophysical techniques. This chapter focuses on NMR-based approaches for extracting affinity and rate constants for weakly binding transient protein complexes with lifetimes of less than about a second. Several pulse sequences and analytical techniques are discussed, including line-shape simulations, spin-echo relaxation dispersion methods (CPMG), and magnetization exchange (EXSY) experiments. PMID- 23729256 TI - Studying metal ion-protein interactions: electronic absorption, circular dichroism, and electron paramagnetic resonance. AB - Metal ions play a wide range of important functional roles in biology, and they often serve as cofactors in enzymes. Some of the metal ions that are essential for life are strongly associated with proteins, forming obligate metalloproteins, while others may bind to proteins with relatively low affinity. The spectroscopic tools presented in this chapter are suitable to study metal ion-protein interactions. Metal sites in proteins are usually low symmetry centers that differentially absorb left and right circularly polarized light. The combination of electronic absorption and circular dichroism (CD) in the UV-visible region allows the characterization of electronic transitions associated with the metal protein complex, yielding information on the geometry and nature of the metal ligand interactions. For paramagnetic metal centers in proteins, electron paramagnetic resonance (EPR) is a powerful tool that provides information on the chemical environment around the unpaired electron(s), as it relates to the electronic structure and geometry of the metal-protein complex. EPR can also probe interactions between the electron spin and nuclear spins in the vicinity, yielding valuable information on some metal-ligand interactions. This chapter describes each spectroscopic technique and it provides the necessary information to design and implement the study of metal ion-protein interactions by electronic absorption, CD, and EPR. PMID- 23729257 TI - Monitoring protein-ligand interactions by time-resolved FTIR difference spectroscopy. AB - Time-resolved FTIR difference spectroscopy is a valuable tool to monitor the dynamics and exact molecular details of protein-ligand interactions. FTIR difference spectroscopy selects, out of the background absorbance of the whole sample, the absorbance bands of the protein groups and of the ligands that are involved in the protein reaction. The absorbance changes can be monitored with time-resolutions down to nanoseconds and followed for time periods ranging over nine orders of magnitude even in membrane proteins with a size of 100,000 Da. Here, we discuss the various experimental setups. The rapid scan technique allows a time resolution in the millisecond regime, whereas the step scan technique allows nanosecond time resolution. We show appropriate sample cells and how to trigger a reaction within these cells. The kinetic analysis of the data is discussed. A crucial step in the data analysis is the reliable assignment of bands to chemical groups of the protein and the ligand. This is done either by site directed mutagenesis, where the absorbance bands of the exchanged amino acids disappear or by isotopically labeling, where the band of the labelled group is frequency shifted. PMID- 23729258 TI - Biophysical methods in drug discovery from small molecule to pharmaceutical. AB - Biophysical methods have become established in many areas of drug discovery. Application of these methods was once restricted to a relatively small number of scientists using specialized, low throughput technologies and methods. Now, automated high-throughput instruments are to be found in a growing number of laboratories. Many biophysical methods are capable of measuring the equilibrium binding constants between pairs of molecules crucial for molecular recognition processes, encompassing protein-protein, protein-small molecule, and protein nucleic acid interactions, and several can be used to measure the kinetic or thermodynamic components controlling these biological processes. For a full characterization of a binding process, determinations of stoichiometry, binding mode, and any conformational changes associated with such interactions are also required. The suite of biophysical methods that are now available represents a powerful toolbox of techniques which can effectively deliver this full characterization.The aim of this chapter is to provide the reader with an overview of the drug discovery process and how biophysical methods, such as surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), nuclear magnetic resonance, mass spectrometry (MS), and thermal unfolding methods can answer specific questions in order to influence project progression and outcomes. The selection of these examples is based upon the experiences of the authors at AstraZeneca, and relevant approaches are highlighted where they have utility in a particular drug discovery scenario. PMID- 23729259 TI - Biophysical screening for the discovery of small-molecule ligands. AB - Discovering small-molecule chemical probes of protein function has great potential to elucidate biological pathways and to provide early-stage proof-of concept for target validation. Discovery of such probes therefore underpins many of the chemical biology and drug discovery efforts in both academia and the pharmaceutical industry. The process generally begins with screening small molecules to identify bona fide "hits" that bind non-covalently to a target protein. This chapter is concerned with the application of biophysical and structural techniques to small-molecule ligand screening, and with the validation of hits from both structural (binding mode) and energetic (binding affinity) stand-points. The methods discussed include differential scanning fluorimetry (thermal shift), fluorescence polarization (FP), surface plasmon resonance, ligand-observed NMR spectroscopy, isothermal titration calorimetry, and protein X ray crystallography. The principles of these techniques and the fundamental nature of the observables used to detect macromolecule-ligand binding are briefly outlined. The practicalities, advantages, and disadvantages of each technique are described, particularly in the context of detecting weak affinities, as relevant to fragment screening. Fluorescence-based methods, which offer an attractive combination of high throughput and low cost are discussed in detail. It is argued that applying a combination of different methods provides the most robust and effective way to identify high-quality starting points for follow-up medicinal chemistry and to build structure-activity relationships that better inform effective development of high-quality, cell-active chemical probes by structure based drug design. PMID- 23729260 TI - Screening protein-small molecule interactions by NMR. AB - Nuclear magnetic resonance (NMR) is well suited to probing the interactions between ligands and macromolecular receptors. It is a truly label-free technique, requiring only the presence of atoms (usually (1)H or (19)F) which give rise to observable resonances on either the ligand or the receptor. A number of parameters associated with these resonances can be used to distinguish rapidly tumbling compounds from ligands which bind to a macromolecular receptor. As such, NMR reports directly on the molecular components involved in the binding interaction whilst avoiding artifacts arising from the addition of an observable label. NMR is also unique amongst biophysical techniques in giving information on the chemical nature of almost all of the constituents present in the sample, thus allowing ready identification of sample, contaminants, degraded material and buffers. Solution phase NMR is also free of artifacts introduced by the presence of a solid support or matrix, although some interesting NMR techniques have been developed to identify ligand-receptor interactions in both solid and heterogeneous phase systems.NMR can readily report on molecular interactions across a wide range of affinities and timescales. Although NMR is not an inherently sensitive technique, the development of cryogenic probeheads over the past decade has dramatically increased the range of applicability of the technique and reduced the stringent sample requirements that used to be regarded as an "Achilles' heel" of NMR. The last, but by no means the least, NMR has the ability to determine structural information at atomic resolution; this has proved to be particularly useful when applied to those protein-ligand systems which cannot be readily crystallized. PMID- 23729261 TI - Model membrane systems. AB - The context of the membrane is crucial for the interaction of many membrane proteins with their ligands. However, many detailed studies cannot be carried out in living cells. Therefore, studying these interactions requires model membrane systems that are compatible with the used analytical method. A big variety of these methods is available, each of which has its advantages and disadvantages. This chapter gives an overview over the existing techniques, a basic introduction into work with lipids, and detailed protocols for selected methods. PMID- 23729262 TI - Quantitative fluorescence co-localization to study protein-receptor complexes. AB - Fluorescence microscopy can be used to assess quantitatively the interaction between a ligand and its receptor, between two macromolecules, or between a macromolecule and a particular intracellular compartment by co-localization analysis. In general, this analysis involves tagging potential interacting partners with distinct fluorophores-by direct labeling of a small ligand, by expression of fluorescent cDNA constructs, by immunofluorescence labeling, or by some combination of these methods. Pairwise comparison of the fluorescence intensity of the two fluorophores at each pixel in a two channel digital image of the sample reveals regions where both are present. With appropriate protocols, the image data can be interpreted to indicate where the potential interacting partners are co-localized. Keeping in mind the limited resolution of the light microscope, co-localization is often used to support the claim that two molecules are interacting.All quantitative methods for evaluating co-localization begin with identifying the pixels where the intensities of both color channels are above background. Typically this involves two sequential image segmentation steps: the first to exclude pixels where neither channel is above background, and the second to set overlap thresholds that exclude pixels where only one color channel is present. Following segmentation, various quantitative measures can be computed to describe the remaining subset of pixels where the two color channels overlap. These metrics range from simple calculation of the fraction of pixels where overlap occurs to more sophisticated image correlation metrics. Additional constraints may be employed to distinguish true co-localization from random overlap. Finally, an image map showing only the co-localized pixels may be displayed as an additional image channel in order to visualize the spatial distribution of co-localized pixels. Several commercial and open source software solutions provide this type of co-localization analysis, making image segmentation and calculation of metrics relatively straightforward. As an example, we provide a protocol for the time-dependent co-localization of fluorescently tagged lipoproteins with LDL receptor (LDLR) and with the early endosome marker EEA1. PMID- 23729263 TI - Studying protein-ligand interactions using X-ray crystallography. AB - X-ray crystallography is a powerful technique for studying protein-ligand interactions. Advances in techniques have meant that it is now possible to routinely determine the structures of ligand complexes in the majority of cases where crystallization conditions and protein structures are already known. Ligand soaking or cocrystallization, together with the potential use of molecular replacement, provides data for determining the structures of a protein in complex with ligands. Furthermore, advances in protein structure model building facilitate automatic ligand fitting to residual electron density in the protein ligand complex. PMID- 23729264 TI - Molecular fields in ligand discovery. AB - The discovery of novel biologically active small molecules is now a technologically and economically viable proposition for academic and small biotechnology laboratories wishing to build on their biological research into target proteins. Such small molecules may be useful reagents for further biological research or may form the basis for early-stage drug discovery. The availability of specialized virtual screening software to filter large molecular libraries into manageable numbers of compounds for biological assays is the driving force for finding novel ligands. The main focus of this chapter is the basis and use of molecular field methods to assess the interactions that may be made by small molecules. Molecular field based measures of capability and similarity of interaction may be used to discover novel ligands and expand ligand series for potential use as future therapies. PMID- 23729265 TI - Structure-based virtual screening for novel ligands. AB - Computational searches for novel ligands for a given protein binding site have become ubiquitous in the pharmaceutical industry, and are potentially equally useful in helping identify small-molecule tools for biology. Here we describe the steps needed to carry out a high-throughput docking (HTD) or three-dimensional (3D) pharmacophore virtual screen starting with a model of the target protein's structure. The advice given is, in most cases, software independent but some tips are provided which apply only to certain popular programs. Useful work can be carried out using free programs on a modest workstation. Of course, any resultant "hits" remain in the virtual world until they are experimentally tested. PMID- 23729266 TI - Combination of fractionated irradiation with anti-VEGF expressing vaccinia virus therapy enhances tumor control by simultaneous radiosensitization of tumor associated endothelium. AB - Oncolytic viruses are currently in clinical trials for a variety of tumors, including high grade gliomas. A characteristic feature of high grade gliomas is their high vascularity and treatment approaches targeting tumor endothelium are under investigation, including bevacizumab. The aim of this study was to improve oncolytic viral therapy by combining it with ionizing radiation and to radiosensitize tumor vasculature through a viral encoded anti-angiogenic payload. Here, we show how vaccinia virus-mediated expression of a single-chain antibody targeting VEGF resulted in radiosensitization of the tumor-associated vasculature. Cell culture experiments demonstrated that purified vaccinia virus encoded antibody targeting VEGF reversed VEGF-induced radioresistance specifically in endothelial cells but not tumor cells. In a subcutaneous model of U-87 glioma, systemically administered oncolytic vaccinia virus expressing anti VEGF antibody (GLV-1h164) in combination with fractionated irradiation resulted in enhanced tumor growth inhibition when compared to nonanti-VEGF expressing oncolytic virus (GLV-1h68) and irradiation. Irradiation of tumor xenografts resulted in an increase in VACV replication of both GLV-1h68 and GLV-1h164. However, GLV-1h164 in combination with irradiation resulted in a drastic decrease in intratumoral VEGF levels and tumor vessel numbers in comparison to GLV-1h68 and irradiation. These findings demonstrate the incorporation of an oncolytic virus expressing an anti-VEGF antibody (GLV-1h164) into a fractionated radiation scheme to target tumor cells by enhanced VACV replication in irradiated tumors as well as to radiosensitize tumor endothelium which results in enhanced efficacy of combination therapy of human glioma xenografts. PMID- 23729267 TI - Outcomes of locally advanced breast cancer patients with >= 10 positive axillary lymph nodes. AB - Breast cancers with 10 or more positive lymph nodes at the time of diagnosis are staged as pathological N3a (pN3a) and they have poor prognosis. Recent studies showed five-year disease-free survival (DFS) and overall survival (OS) rates of N3a disease as 43-66 and 58-81 %, respectively. We herein present outcomes of our patients with stage pN3a breast cancer. Among 2,578 patients diagnosed with invasive breast carcinoma at Hacettepe University Hospital between 2002 and 2012, 218 patients (8.4 %) had pN3a disease and were included and analyzed retrospectively in this study. Patients with internal mammary, infraclavicular, and supraclavicular node metastasis or distant metastasis at initial diagnosis were excluded. Demographic features, tumor characteristics, treatment regimens, and patient outcomes in terms of DFS and OS were analyzed. Lymph node ratio was defined as the ratio of positive to total removed lymph nodes. The median age was 49. Most common histological subtype was ductal carcinoma (82.1 %). About 82.6 % of patients had stage T2/T3 cancers and 47.7 % (104) had grade III cancers. Estrogen and progesterone receptors were positive in 133 (61 %) and 121 (55.5 %) patients, respectively. HER2 status was known for 213 patients and was positive in 87 (39.9 %) patients. A total of 27 (12.6 %) patients had triple-negative tumors. Lymphovascular invasion, extracapsular extension, and perineural invasion were present in 106 (48.6 %), 105 (48.2 %), 20 (9.2 %) cases, respectively. A total of 18 patients (8.3 %) received neoadjuvant and 200 patients (91.7 %) received adjuvant chemotherapy, mostly with anthracycline- (95 %) and taxane (60 %)-containing regimens. A total of 210 patients (96.3 %) received radiotherapy. Median follow-up was 39.5 months. A total of 96 patients relapsed on follow-up and 64 patients died. Nineteen of the relapses were locoregional and 77 were distant relapses. The 5-year DFS rate was 46.2 % and the OS rate was 69.8 %. In multivariate Cox regression analysis, grade III disease (HR 1.899, 95 % CI 1.196 3.017, P = 0.007), perineural invasion (HR 2.519, 95 % CI 1.341-4.731, P = 0.004), and lymph node ratio (>= 0.9 vs. <0.9) (HR 2.290, 95 % CI 1.368-3.835, P = 0.002) were significantly associated with DFS, and grade III disease (HR 2.679, 95 % CI 1.500-4.782, P = 0.001) and lymph node ratio (>= 0.9 vs. <0.9) (HR 2.182, 95 % CI 1.211-3.932, P = 0.009) were significantly associated with OS. Patients with pN3a disease in our cohort have comparable survival rates with other reports in the literature. Within this high risk group of patients, those with grade III disease, perineural invasion, and lymph node ratio >= 0.9 seem to confer poorer prognosis. PMID- 23729268 TI - KRAS gene mutations in correlation with clinicopathological features of colorectal carcinomas in Indian patient cohort. AB - KRAS gene mutations have been identified as a predictive molecular marker to predict the sensitivity of tumors to anti-EGFR therapeutics. The variability of clinical response to anti-EGFR agents has highlighted the need to select the appropriate patients who can benefit from the treatment. We examined the prevalence of KRAS mutations in 1,323 colorectal cancer patients from different regions of India and its correlation with geographic distribution and clinicopathological characteristics. DNA was extracted from formalin-fixed, paraffin-embedded tissue samples and was amplified by nested polymerase chain reaction at KRAS exon 2 and subjected to nucleotide sequencing using ABI 3100 Genetic Analyzer. The frequency of KRAS mutations was found to be 20.5 % (271/1,323). There was significant association (p < 0.05) between KRAS mutations, age and the tumor differentiation. Statistical analysis revealed significantly higher prevalence of colorectal cancer with mutated KRAS gene in northern regions of the country. No significant association was observed between KRAS mutations and gender (p > 0.05). Our study indicates that KRAS mutations in Indian colorectal cancer patients occur at lower level compared to that of Western population. PMID- 23729269 TI - Expression of integrin-linked kinase in adenoid cystic carcinoma of salivary glands correlates with epithelial-mesenchymal transition markers and tumor progression. AB - Integrin-linked kinase (ILK) plays a key role in cell-excellular matrix interactions mediated by integrins and several growth factors, regulating cell proliferation, apoptosis, differentiation, and migration. It has also been implicated in the development and progression in several malignancies involving epithelial to mesenchymal transition (EMT). However, the correlations between ILK and EMT markers and the progression of salivary adenoid cystic carcinoma (SACC) have not been well elucidated. Here, by immunohistochemistry, we studied the expression of ILK, Snail, E-cadherin, and N-cadherin in 94 SACC specimens and analyzed their correlations with clinicopathologic characteristics. Positive expression of ILK protein was detected in 76.6 % of the tumors. Increased expression of ILK and Snail and decreased E-cadherin expression correlated strongly with tumor solid type (P = 0.017, P = 0.008, and P = 0.038, respectively), advanced TNM stage (P = 0.021, P = 0.034, and P = 0.009, respectively), and increased risk of recurrence (P = 0.023, P = 0.011, and P = 0.039, respectively) and distant metastasis (P < 0.001, P < 0.001, and P = 0.001, respectively). Moreover, up-regulation of Snail and N-cadherin and down regulation of E-cadherin correlated significantly with ILK over-expression (P < 0.001, P = 0.001, and P < 0.001, respectively) and a neural-invasive phenotype (P = 0.017, P = 0.002, and P < 0.001, respectively). Taken together, our results suggest that ILK may have an important role in progression and metastasis of SACC, possibly through EMT involving up-regulation of Snail and consequent aberrant expression of E-cadherin and N-cadherin. ILK should be considered as a potential therapeutic molecular target for patients with SACC. PMID- 23729270 TI - Late embolization of a vascular plug III device after mitral paravalvular leak closure. AB - We present a case report of an 80-year-old frail woman with hemolytic anemia and cardiac failure secondary to mitral severe paravalvular regurgitation. Her clinical history was significant for mitral valve replacement that was complicated with a paravalvular leak two months after surgery. The leak was closed percutaneously with an Amplatzer Vascular Plug III single device. A year later she is readmitted with heart failure and the transesophageal echocardiogram revealed a severe paravalvular leak beside the Vascular Plug III device that seemed to be dislodged and rocking. During a new attempt of percutaneous leak closure, while trying to lasso the old device, it embolized to the iliac bifurcation. The old device could be removed from the right femoral artery and the leak could be closed with two new Vascular Plug III devices deployed simultaneously. To our knowledge this is the first reported case of a late embolization of a Vascular Plug III device. PMID- 23729271 TI - Ionothermal synthesis of few-layer nanostructures of Bi2Se3 and related materials. PMID- 23729272 TI - Feasibility of super-selective neck dissection for indeterminate lateral neck nodes in papillary thyroid carcinoma. AB - BACKGROUND: Therapeutic lateral compartment neck dissection is recommended for cases of papillary thyroid carcinoma with biopsy-proven lymph node metastasis. The purpose of this study was to evaluate the efficacy and safety of super selective neck dissection for patients with clinically suspicious lymph node metastasis not confirmed by biopsy. METHODS: Among 620 patients treated for papillary thyroid carcinoma between 2008 and 2010, 34 had suspicious lymph node enlargement in the lateral neck and underwent total thyroidectomy with super selective neck dissection. RESULTS: Metastatic disease was confirmed in 38.2% patients (13 of 34) with indeterminate lymph nodes identified by preoperative CT and/or ultrasonography who underwent super-selective neck dissection. Most harvested lymph nodes were located at level IV. There was no recurrence during a mean follow-up period of 31.6 months. CONCLUSION: Patients with clinically suspicious lateral neck nodes that are not confirmed by biopsy may be good candidates for super-selective neck dissection, which had minimal morbidity and did not compromise oncologic outcomes. PMID- 23729273 TI - Frankincense tapping reduces the carbohydrate storage of Boswellia trees. AB - Carbohydrates fixed by photosynthesis are stored in plant organs in the form of starch or sugars. Starch and sugars sum to the total non-structural carbohydrate pool (TNC) and may serve as intermediate pools between assimilation and utilization. We examined the impact of tapping on TNC concentrations in stem wood, bark and root tissues of the frankincense tree (Boswellia papyrifera (Del.) Hochst) in two natural woodlands of Ethiopia. Two tapping treatments, one without tapping (control) and the other with tapping at 12 incisions, are applied on experimental trees. Trees are tapped in the leafless dry period, diminishing their carbon storage pools. If storage pools are not refilled by assimilation during the wet season, when crowns are in full leaf, tapping may deplete the carbon pool and weaken Boswellia trees. The highest soluble sugar concentrations were in the bark and the highest starch concentrations in the stem-wood. The stem wood contains 12 times higher starch than soluble sugar concentrations. Hence, the highest TNC concentrations occurred in the stem-wood. Moreover, wood volume was larger than root or bark volumes and, as a result, more TNC was stored in the stem-wood. As predicted, tapping reduced the TNC concentrations and pool sizes in frankincense trees during the dry season. During the wet season, these carbon pools were gradually filled in tapped trees, but never to the size of non-tapped trees. We conclude that TNC is dynamic on a seasonal time scale and offers resilience against stress, highlighting its importance for tree carbon balance. But current resin tapping practices are intensive and may weaken Boswellia populations, jeopardizing future frankincense production. PMID- 23729274 TI - Development of coffee somatic and zygotic embryos to plants differs in the morphological, histochemical and hydration aspects. AB - In Coffea arabica L., the development of direct sowing of somatic embryos (SE) in planting substrate, with subsequent nursery production of plants, has promoted the industrialization of somatic embryogenesis. However, plant conversion rates are still low and require improvements to enhance the cost-effectiveness of commercial micropropagation. With the aim of improving plant regeneration from SE, we studied the morphological and histological criteria and water characteristics during germination and plant conversion of zygotic embryos (ZE) and SE. At the cotyledonary stage, SE produced in a 1 l RITA((r)) temporary immersion bioreactor (area 55.8 cm(2)) were morphologically similar in size (2-3 mm) but abnormal as compared with mature ZE. Protein and starch reserve levels were extremely low throughout germination and conversion to plantlets, while the water status remained steady [water content (WC) from 76 to 87%, Psi from -0.37 to -0.47 MPa, pressure potential from 0.69 to 0.24 MPa]. In ZE, spectacular hydration occurred during the first 3 weeks (WC from 37 to 75%; Psi from -6.24 to -1.0 MPa). Cotyledons remained undifferentiated for 10 weeks after sowing. Conversely, after only 3 weeks under germination conditions in a RITA((r)) bioreactor, spongy and palisade parenchyma and stomata formed in SE cotyledons. The ZE plant conversion was faster than that of SE (14 vs. 22 weeks) and more efficient (rates 96 vs. 55%), with much more substantial hypocotyl and cotyledon development. The use of a new 5 l MATIS((r)) bioreactor (area 355 cm(2)), designed especially to favor embryo dispersion and light transmittance to SE, markedly improved the embryo-to-plantlet conversion rate (91%). These results highlight the morphological heterogeneity and lack of protein reserves in SE at the beginning of the germination phase and marked differences in water characteristics. However, they also reveal high phenotypic plasticity, leading to a highly efficient plantlet conversion rate due to better embryo dispersion and light transmittance in more horizontal bioreactors. PMID- 23729275 TI - A let-7 binding site polymorphism rs712 in the KRAS 3' UTR is associated with an increased risk of gastric cancer. AB - Recently, single nucleotide polymorphisms in let-7 miRNA binding site in 3' untranslated region (UTR) of KRAS mRNA have been found to be associated with the cancer risk. In this study, we genotyped the frequency of KRAS rs712 to test its effect on gastric cancer (GC) risk in a hospital-based case-control study in a Chinese population, with 181 histologically confirmed GC patients and 674 cancer free controls, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The TT genotype of rs712 was associated with an increased risk of GC when taking GG genotype as a reference (adjusted odds ratio (OR) = 3.05, 95 % confidence interval (CI), 1.53-6.08). Similarly, the T allele of rs712 was associated with a statistically significant increase in susceptibility compared with G allele (adjusted OR = 1.44, 95 % CI, 1.10-1.90). Our data demonstrated that the T allele of the let-7 binding site polymorphism rs712 in KRAS 3' UTR was associated with a significantly increased risk of GC, suggesting that the KRAS rs712 polymorphism may be a genetic marker for the development of GC. PMID- 23729276 TI - Prospective evaluation of health-related quality of life in patients with glioblastoma multiforme treated on a phase II trial of hypofractionated IMRT with temozolomide. AB - To report health-related quality of life (HRQOL) in glioblastoma (GBM) patients treated on a phase II trial of hypofractionated intensity-modulated radiotherapy (hypo-IMRT) with temozolomide (TMZ). GBM patients received postoperative hypo IMRT to 60 Gy in 10 fractions with TMZ. HRQOL was assessed using the EORTC quality of life questionnaire core-30 and the EORTC brain cancer module, performed at baseline, RT completion, 1 mo post-RT, and every 3 mos thereafter. Changes from baseline were calculated for each specific HRQOL scale. A >= 10 point change in any HRQOL scale from the mean baseline score was significant. 24 patients were treated. Compliance with HRQOL assessments at baseline, RT completion, and 1, 3, 6, 9, and 12 mos post-RT was 100, 96, 92, 79, 70, 68 and 53 %, respectively. Up to 12 mos post-RT, no significant changes were seen in global health status, physical functioning, role functioning, emotional functioning, fatigue, nausea, vision, headache or seizure. Significant improvement was seen in insomnia, future uncertainty, motor dysfunction and drowsiness. Significant worsening was observed in cognitive functioning, social functioning, appetite loss and communication deficit. 60 Gy hypo-IMRT in 6-Gy fractions with TMZ does not appear to negatively impact overall HRQOL. PMID- 23729277 TI - Inhibitory control and decision making under risk in bulimia nervosa and binge eating disorder. AB - OBJECTIVE: To investigate neuropsychological mechanisms of impulsivity in patients with bulimia nervosa (BN) and binge-eating disorder (BED). METHOD: Nineteen BN patients and 31 age- and body-mass-index (BMI)-matched healthy controls (c-BN) as well as 54 overweight and obese BED patients and 43 age- and BMI-matched healthy controls (c-BED) were investigated using an inhibitory control task (stop signal task, SST) and a decision-making under risk task (game of dice task, GDT). RESULTS: Compared to c-BN, BN patients demonstrated significant greater stop signal reaction times in the SST, but no differences for the frequency of risky decisions in the GDT. BED patients did not differ from c BED in the SST or the GDT. DISCUSSION: BN but not BED patients differed from their respective control groups concerning the "stopping" component of impulsivity. These differences in motor inhibition may contribute to the behavioral distinctions in binge-eating behavior between BN and BED. PMID- 23729278 TI - Interaction of metabolic syndrome with asthma in postmenopausal women: role of adipokines. AB - The increasing prevalence of both asthma and obesity are major health problems. Recent studies established a possible link between obesity and asthma; however, the underlying mechanism is not clear. The aim of the study was to analyze the prevalence of metabolic syndrome in postmenopausal subjects with asthma and search the interactions between adipokines, metabolic syndrome, and asthma. A total of 45 female patients (57.5 +/- 13.9 years) with asthma and 30 healthy subjects (59.6 +/- 12.8 years) in postmenopausal status were enrolled in this study. For the diagnosis of metabolic syndrome, modified World Health Organization diagnostic criteria were used. Blood levels of glucose, lipid profile, HbA1c, insulin, CRP, leptin, adiponectin, tumor necrosis factor-alpha, interleukin (IL)-6, IL-8 and plasminogen activator inhibitor-1 (PAI-1) were measured. The mean body mass index was 29.6 +/- 5.4 for asthma patients and 28.2 +/- 5.3 for the control group. The incidence of metabolic syndrome was found as 26 % for both groups. Insulin resistance as calculated by homeostasis model assessment (HOMA-IR) and fasting insulin levels were significantly higher in asthma patients (p < 0.001 for both parameters). Leptin levels were significantly higher (p = 0.001) and adiponectin levels were lower (p = 0.029) in asthma patients compared to controls. We concluded that although incidence of obesity and metabolic syndrome was not higher in postmenopausal asthma patients than controls, there was an impairment of glucose metabolism and altered adipokine levels in asthma patients. PMID- 23729280 TI - Developing a system to track meaningful outcome measures in head and neck cancer treatment. AB - BACKGROUND: The health care industry, including consumers, providers, and payers of health care, recognize the importance of developing meaningful, patient centered measures. This article describes our experience using an existing electronic medical record largely based on free text formats without structured documentation, in conjunction with tumor registry abstraction techniques, to obtain and analyze data for use in clinical improvement and public reporting. METHODS: We performed a retrospective analysis of 2467 previously untreated patients treated with curative intent who presented with laryngeal, pharyngeal, or oral cavity cancer in order to develop a system to monitor and report meaningful outcome metrics of head and neck cancer treatment. Patients treated between 1995 and 2006 were analyzed for the primary outcomes of survival at 1 and 2 years, the ability to speak at 1 year posttreatment, and the ability to swallow at 1 year posttreatment. RESULTS: We encountered significant limitations in clinical documentation because of the lack of standardization of meaningful measures, as well limitations with data abstraction using a retrospective approach to reporting measures. Almost 5000 person-hours were required for data abstraction, quality review, and reporting, at a cost of approximately $134,000. Our multidisciplinary teams document extensive patient information; however, data is not stored in easily accessible formats for measurement, comparison, and reporting. CONCLUSION: We recommend identifying measures meaningful to patients, providers, and payers to be documented throughout the patients' entire treatment cycle, and significant investment in the improvements to electronic medical records and tumor registry reporting in order to provide meaningful quality measures for the future. PMID- 23729279 TI - Therapeutic effect of emodin on collagen-induced arthritis in mice. AB - Emodin, an anthraquinone isolated from the Chinese herb Radix et Rhizoma Rhei, has been reported to have anti-inflammatory, antibacterial, and antitumor activities. However, the effect of emodin on collagen-induced arthritis (CIA) has not yet been investigated. The purpose of this study was to investigate whether emodin has a protective effect against collagen-induced arthritis in mice and its possible mechanisms. CIA was induced in mice by immunization with bovine type II collagen. The mice were treated with emodin (5, 10, and 20 mg/kg/day, i.g.) from days 21 to 42 after immunization. The clinical scores and hind paw swelling were evaluated. The expression of prostaglandin E2 (PGE2) and cyclooxygenase-2 (COX-2) in synovial tissues was determined. The levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in the plasma were measured by enzyme-linked immunosorbent assay. The results showed that emodin treatment significantly alleviated the severity of the disease, based on the reduced hind paw swelling and clinical scores, compared with untreated CIA mice. Comparing with untreated CIA mice, emodin treatment inhibited the levels of TNF-alpha and IL-6 in the plasma, PGE2 production, and COX-2 protein expression in synovial tissues in a dose manner. In conclusion, our results suggest that anti-inflammatory effects of emodin against collagen-induced arthritis in mice may be due to its ability to inhibit pro-inflammatory mediators. Emodin may be a promising potential therapeutic reagent for arthritis treatment. PMID- 23729281 TI - The Xenopus TRPV6 homolog encodes a Mg(2+) -permeant channel that is inhibited by interaction with TRPC1. AB - The TRP gene family encodes primarily cation non-selective, Ca2+ permeant channels that are involved in a dizzying array of sensory mechanisms. Two channels in this large family TRPV5 and TRPV6 are highly Ca2+ selective and are expressed in epithelia where they are important in Ca2+ uptake. TRPV5/6 are constitutively active, yet the mechanisms regulating their activation in native tissue remains elusive. Here we functionally characterize the Xenopus TRPV6 homolog. xTRPV6 is expressed in the oocyte and encodes a channel that is permeant to divalents including Ca2+ , and displays a high permeability to Mg2+ . The oocyte does not exhibit functional TRPV6-like current at rest, showing that the endogenous channel is somehow maintained in an inactive state. We show that endogenous as well as overexpressed xTRPV6 interacts with xTRPC1 and that this interaction inhibits xTRPV6 currents. As such TRPC1 is likely to regulate the activity of TRPV6 under physiological conditions. PMID- 23729282 TI - The Glider registry. AB - BACKGROUND: Provisional stenting of the side-branch (SB) is the universally accepted gold standard while there is still controversy on the usefulness of routine dilatation of the SB ostium. Recrossing the struts of a previously deployed stent with a wire and a balloon can prove challenging and is occasionally unsuccessful, mainly because the balloon tip hits a stent strut. This prospective multicenter international registry tested the crossing ability procedural results of a new-dedicated ultrashort balloon specifically designed for side branch dilatation (Glider, TriReme Medical, Pleasanton, CA, USA). METHODS: One hundred and twenty five patients (for a total of 131 bifurcation lesions) were enrolled in the registry between January 2009 and May 2012. The Glider was used as first choice in alternative to conventional balloon (group I, 72%) or as bail-out after unsuccessful previous attempt at crossing with small conventional low-profile balloons (group II, 28%). Postprocedural coronary artery dissections and in-hospital MACE (death, myocardial infarction and repeat revascularization) were assessed. Technical success was defined as the ability of the Glider to recross the struts of a previously deployed stent while procedural success was defined as less of residual 50% diameter stenosis at the origin of the SB with a final TIMI 3 and/or freedom from in-hospital MACE. RESULTS: Technical success was achieved, respectively, in 92% (group I), and 83% (group II). Clinical and angiographic procedural success was achieved in 98% of the lesions. In Group II, no other balloon of the same size could cross in cases where Glider could not. A total of 13 complications were observed, including nine ostial SB dissection four of which needed a second stent on the SB, one stent loss, two severe coronary spasms, and two by thrombus formation. CONCLUSION: The unique possibility offered by this short dedicated balloon to orientate its beveled tip provides an effective strategy for recrossing stent struts when conventional low profile balloons fail achieving greater SB ostial expansion thus reducing the incidence of strut malapposition during provisional treatment of bifurcational lesions. (c) 2016 Wiley Periodicals, Inc. PMID- 23729283 TI - Impact of late preterm and early term infants on Canadian neonatal intensive care units. AB - OBJECTIVE: To examine the short-term morbidities, mortality, and use of neonatal intensive care unit (NICU) resources for late preterm, early term, and term infants. STUDY DESIGN: Infants born between 34 and 40 weeks of gestation and admitted to a Canadian NICU in 2010 were designated late preterm (340/7 to 366/7 weeks), early term (370/7 to 386/7 weeks), or term (390/7 to 406/7 weeks). Mortality, short-term morbidities, and resource utilization were compared between the three groups using chi-square tests and analysis of variance. RESULTS: Among 6,636 included infants, 44.2% (n = 2,935) were late preterm, 26.2% (n = 1,737) early term, and 29.6% (n = 1,964) term. Term infants were more likely to require resuscitation at birth and had lower Apgar scores than late preterm and early term infants (p < 0.001). Length of stay and need for respiratory support decreased with increasing gestational age; however, the proportion of hospital days that intensive care was required increased. CONCLUSION: The greatest impact of late preterm infants is on NICU bed occupancy, whereas for term infants it is on intensity of care. Early term infants experience greater rates of some complications than term, demonstrating that risk persists for these infants. These findings have important implications for NICU resource planning and practice. PMID- 23729284 TI - Intestinal blood flow by Doppler ultrasound: the impact of gestational age and time from first enteral feeding in preterm neonates. AB - OBJECTIVE: To explore whether superior mesenteric artery (SMA) peak systolic velocity (PSV) on Doppler ultrasound varies by gestational age (GA) and time from first enteral feeding and has an impact on feeding intolerance. DESIGN/METHODS: Preterm neonates were assigned to three GA groups at birth, group I: 31 to 356/7 weeks, group II: 27 to 306/7 weeks, and group III: <= 266/7 weeks. SMA PSV and clinical and feeding parameters were assessed before and after enteral feed, with the first enteral feed designated as time 1, time 2 = 1 to 4 days (after first feed), time 3= 5 to 7 days, time 4 = 8 to 14 days, and time 5 = 15 to 28. RESULTS: Forty-one patients completed the study (group I: n = 17, group II: n = 12, group III: n = 12). There was no significant difference in SMA PSV change after feeding between groups at the start of enteral feeding (p = 0.12). There were differences in change in SMA PSV after feeding at times 2, 3 and 5 (p = 0.003, p = 0.004, p = 0.009, respectively). Patients with feeding intolerance exhibited a smaller increase in SMA PSV after feeding. CONCLUSIONS: There were significant differences in PSV by GA group. SMA PSV change after feeding was lower in patients who had feeding intolerance compared with those who did not. PMID- 23729285 TI - Cross-protective effect of antisense oligonucleotide developed against the common 3' NCR of influenza A virus genome. AB - The influenza A virus (IAV) has eight segmented single-stranded RNA genome containing a common and evolutionarily conserved non-coding region (NCRs) at 5' and 3' ends that are important for the virus replication. In this study, we designed an antisense oligonucleotide against the 3' NCR of vital segments of the IAV genome to inhibit its replication. The results demonstrated that the co transfection of Madine Darby Canine Kidney (MDCK) cells with the antisense oligonucleotide and the plasmids encoding the viral genes led to the down regulation of the viral gene expression. The designed antisense molecules reduced the cytopathic effect caused by A/PR/8/34 (H1N1), A/Udorn/307/72 (H3N2), and A/New Caledonia/20/99 (H1N1) strains of IAV for almost 48 h. Furthermore, the intra-venous delivery of this oligonucleotide significantly reduced the viral titers in the lungs of infected mice and protected the mice from lethal effects of all the strains of influenza virus. The study demonstrated that the antisense oligonucleotide designed against the NCR region inhibits the expression of the viral genome. The decrease of the cytopathic effect in the MDCK cells and increase in survival of mice confirmed the reduction of virus multiplication and pathogenesis in the presence of antisense oligonucleotide. Thus, we demonstrate that a single antisense oligonucleotide is capable of providing protection against more than one strains of the IAV. PMID- 23729288 TI - Analysis of extracellular vesicles: new avenues for signaling biology and biomarker discovery. PMID- 23729286 TI - "Immunocytochemical expression of P53, PTEN, FAS (CD95), P16INK4A and HPV L1 major capsid proteins in ThinPrep cervical samples with squamous intraepithelial lesions". AB - The aim of this study was to further investigate the immunocytochemical expression of p53, PTEN, Fas, p16, and HPV L1 capsid proteins in cervical smears with low and high grade squamous intraepithelial lesions (LSIL and HSIL, respectively). A total of 92 ThinPrep cervical samples, comprising 11 cases of HSIL, 61 cases of LSIL, and 20 negative cases were studied by immunocytochemical methods. The results obtained in LSIL cases were correlated with the available follow up data. Abnormal p53, PTEN, or Fas expression was found in a subset of HSIL cases, while positive expression for p16 was significantly associated with the diagnosis of HSIL (P < 0.0001, P = 0.001, P < 0.0001, and P < 0.0001, respectively). Among cases positive for p16 expression, the staining pattern was weak in 88.9% of LSIL cases and strong in 80% of HSIL cases (P < 0.0001). The p16 negative/L1 positive and p16 positive/L1 negative staining patterns were significantly associated with the presence of LSIL and HSIL, respectively (P < 0.0001). None of these markers had a significant prognostic value in LSIL cases (P > 0.05). Our results suggest that loss of PTEN or Fas expression and p53 overexpression may be involved in the process of neoplastic transformation of the cervical epithelium. Furthermore, negative or weak immunocytochemical staining for p16 in a Pap smear may strongly argue against the presence of a high grade lesion, while the combined p16/L1 staining pattern may be useful as a diagnostic adjunct for differentiating between LSIL and HSIL. PMID- 23729292 TI - Peptide-catalyzed stereoselective conjugate addition reactions generating all carbon quaternary stereogenic centers. PMID- 23729293 TI - "Global mental health" is an oxymoron and medical imperialism. PMID- 23729295 TI - Invisible face of boron pollution in fluvial ecosystem: the level in the tissues of sentinel and nectonic organisms. AB - Turkey is the largest producer of borate products in the world. Among four largest boron mines in Turkey two of them are located in basins of Orhaneli and Emet Streams. In this study, boron levels in abiotic (water-sediment) and some biotic elements (sentinel organisms; Asellus aquaticus, Gammarus pulex, Chironomus tentans, Limnodrilus hoffmeisteri and nektonic organism; Squalius cii) of Orhaneli and Emet Streams were investigated and their ranks among the food chain were demonstrated. Since Orhaneli and Emet Streams confluence to form Mustafakemalpasa Brook which feeds Uluabat Lake which is one of the most important Ramsar fields of the world, Boron levels in those two streams have importance in terms of both continuances of aquatic systems. Present study results have shown that boron levels in water of both streams are much higher (vary between 8.64 and 16.73 mg L(-1)) than not only Turkish Standard but also limits determined by WHO, US EPA, and NAS. Boron levels determined in sediments of two streams vary between 18.05 and 36.7 mg kg(-1). The highest boron level in the biotic elements was determined in liver of Squalius cii (34.64 mg kg(-1)), it is followed by Limnodrilus hoffmeisteri (2.84 mg kg(-1)), Chironomus tentans (2.11 mg kg(-1)), and Gammarus pulex (1.98 mg kg(-1)). PMID- 23729294 TI - CD73 (ecto-5'-nucleotidase) hepatocyte levels differ across mouse strains and contribute to mallory-denk body formation. AB - Formation of hepatocyte Mallory-Denk bodies (MDBs), which are aggregates of keratins 8 and 18 (K8/K18), ubiquitin, and the ubiquitin-binding protein, p62, has a genetic predisposition component in humans and mice. We tested the hypothesis that metabolomic profiling of MDB-susceptible C57BL and MDB-resistant C3H mouse strains can illuminate MDB-associated pathways. Using both targeted and unbiased metabolomic analyses, we demonstrated significant differences in intermediates of purine metabolism. Further analysis revealed that C3H and C57BL livers differ significantly in messenger RNA (mRNA) level, protein expression, and enzymatic activity of the adenosine-generating enzyme, ecto-5'-nucleotidase (CD73), which was significantly lower in C57BL livers. CD73 mRNA levels were also dramatically decreased in human liver biopsies from hepatitis C and nonalcoholic fatty liver disease patients. Feeding mice with a diet containing the MDB inducing agent, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), significantly decreased CD73 protein and activity in C57BL livers and resulted in loss of plasma membrane CD73 expression and activity in isolated mouse hepatocytes. To further examine the role of CD73 in MDB formation in vivo, we fed wild-type (WT) and CD73(-/-) mice a DDC-containing diet. Liver enlargement, p62 induction, and disappearance of the K8/K18 cytoskeleton were attenuated in CD73(-/-) , compared to WT livers. MDB formation, as assessed by biochemical and immunofluorescence detection of keratin and ubiquitin complexes, was nearly absent in CD73(-/-) mice. CONCLUSION: Purine metabolism and CD73 expression are linked to susceptibility to MDB formation in livers of different mouse strains. Expression of the adenosine-generating enzyme, CD73, contributes to experimental MDB induction and is highly regulated in MDB-associated liver injury in mice and in chronic human liver disease. PMID- 23729296 TI - Forest die-back modified plankton recovery from acidic stress. AB - We examined long-term data on water chemistry of Lake Rachelsee (Germany) following the changes in acidic depositions in central Europe since 1980s. Despite gradual chemical recovery of Rachelsee, its biological recovery was delayed. In 1999, lake recovery was abruptly reversed by a coincident forest die back, which resulted in elevated terrestrial export of nitrate and ionic aluminum lasting ~5 years. This re-acidification episode provided unique opportunity to study plankton recovery in the rapidly recovering lake water after the abrupt decline in nitrate leaching from the catchment. There were sudden changes both in lake water chemistry and in plankton biomass structure, such as decreased bacterial filaments, increased phytoplankton biomass, and rotifer abundance. The shift from dominance of heterotrophic to autotrophic organisms suggested their substantial release from severe phosphorus stress. Such a rapid change in plankton structure in a lake recovering from acidity has, to the best of our knowledge, not been previously documented. PMID- 23729297 TI - Enantiocontrolled total synthesis of (-)-mersicarpine. AB - A racemic synthesis of mersicarpine (1) was achieved by the Mizoroki-Heck reaction and a DIBALH-mediated reductive ring-expansion reaction. Based on a first-generation synthesis, a second-generation enantiocontrolled total synthesis of (-)-mersicarpine (1) was achieved by an 8-pot/11-step sequence in 21% overall yield from commercially available 2-ethylcyclohexanone. Subjection of a ketoester, which was prepared by an asymmetric Michael addition (according to the protocol by d'Angelo and Desmaele), and phenylhydrazine to modified Fischer indole conditions provided a six-membered tricyclic indole. Benzylic oxidation and subsequent oxime formation provided a ketoxime, which was treated with diisobutylaluminum hydride (DIBALH) to construct the characteristic azepinoindole skeleton in good yield. In the DIBALH-mediated reductive ring-expansion reaction, gradually increasing the reaction temperature and in situ-protection of the nitrogen in an oxygen-sensitive azepinoindole with a benzyloxycarbonyl (Cbz) group were crucial for the high-yielding process. With these methodologies, the short-step and efficient synthesis of (-)-mersicarpine was accomplished. Several synthetic efforts are also described. PMID- 23729299 TI - Characterization of arsenate uptake by cultured primary rat astrocytes. AB - Arsenate is known to be accumulated by cultured astrocytes and to stimulate astrocytic glutathione export, but the arsenate uptake into astrocytes has not been characterized so far. To address this topic, we have exposed primary rat astrocyte cultures to arsenate and determined the cellular arsenic content by atomic absorption spectroscopy. Viable astrocytes accumulated arsenate in a time- and concentration-dependent manner. Their cellular arsenic content increased almost proportional with time for up to 60 min after application of arsenate. Analysis of the concentration-dependent increase in the specific arsenic content of the cells after 30 min of arsenate exposure revealed that cultured astrocytes take up arsenate with saturable kinetics by a transport process that has apparent KM- and Vmax-values of 1.7 +/- 0.2 mM and 28 +/- 4 nmol/(mg protein * 30 min), respectively. Arsenate uptake in viable astrocytes was strongly inhibited by the presence of phosphate or by lowering the incubation temperature to 4 degrees C and was completely abolished in a sodium ion-free medium. These results strongly suggest that the saturable temperature-dependent arsenate uptake into astrocytes is mediated by a sodium-dependent phosphate cotransporter. PMID- 23729298 TI - The neurobiology of LRRK2 and its role in the pathogenesis of Parkinson's disease. AB - Leucine-rich repeat kinase 2 (LRRK2) is a large, widely expressed protein of largely unknown function. Mutations in the gene encoding LRRK2 have been linked to multiple diseases, including a prominent association with familial and sporadic Parkinson's disease (PD), as well as inflammatory bowel disorders such as Crohn's disease. The LRRK2 protein possesses both kinase and GTPase signaling domains, as well as multiple protein interaction domains. Experimental studies in both cellular and in vivo models of mutant LRRK2-induced neurodegeneration have given clues to potential function(s) of LRRK2, yet much remains unknown. For example, while it is known that intact kinase and GTPase activity are required for mutant forms of the protein to trigger cell death, the specific targets of these enzymatic activities that mediate the death of neurons are not known. In this review, we discuss the evidence linking LRRK2 to various cellular/neuronal activities such as extrinsic death and inflammatory signaling, lysosomal protein degradation, the cytoskeletal system and neurite outgrowth, vesicle trafficking, mitochondrial dysfunction, as well as multiple points of interaction with several other genes linked to the pathogenesis of PD. In order for more effective therapeutic strategies to be envisioned and implemented, the mechanisms underlying LRRK2-mediated neurodegeneration need to be better characterized. Furthermore, insights into LRRK2-associated PD pathogenesis can potentially advance our understanding of the more common sporadic forms of PD. PMID- 23729300 TI - Stress during the pre-pubertal period leads to long-term diet-dependent changes in anxiety-like behavior and in oxidative stress parameters in male adult rats. AB - Social isolation during early development is one of the most potent stressors that can cause alterations in the processes of brain maturation, leading to behavioral and neurochemical changes that may persist to adulthood. Exposure to palatable diets during development can also affect neural circuits with long-term consequences. The aims of the present study were to investigate the long-term effects of isolation stress during the pre-pubertal period on the exploratory and anxiety-like behavior, the oxidative stress parameters and the respiratory chain enzymes activities in the hippocampus of adult male rats under chronic palatable diets. The results showed that isolated rats receiving either normal or high-fat diet during the pre-pubertal period presented an anxiolytic-like behavior. The animals exposed to stress and treated with high-carbohydrate diet, rich in disaccharides, on the other hand, presented the opposite pattern of behavior. Stress in the pre-pubertal period also leads to decreased activity of the antioxidant enzymes and the mitochondrial respiratory chain complexes II and IV and decreased total thiol content. These effects were reversed by high-fat diet when it was associated with stress. The effects of a sub-acute pre-pubertal isolation stress on anxiety-like behavior and on hippocampal oxidative imbalance during adulthood appear to be modulated by different types of diets, and probably different mechanisms are involved. PMID- 23729301 TI - Antioxidant, anticonvulsive and neuroprotective effects of dapsone and phenobarbital against kainic acid-induced damage in rats. AB - Excitotoxicity due to glutamate receptors (GluRs) overactivation is a leading mechanism of oxidative damage and neuronal death in various diseases. We have shown that dapsone (DDS) was able to reduce both neurotoxicity and seizures associated to the administration of kainic acid (KA), an agonist acting on AMPA/KA receptors (GluK1-GluK5). Recently, it has been shown that phenobarbital (PB) is also able to reduce epileptic activity evoked by that receptor. In the present study, we tested the antioxidative, anticonvulsive and neuroprotective effects of DDS and PB administered alone or in combination upon KA toxicity to rats. Results showed that KA increased lipid peroxidation and diminished reduced glutathione (GSH), 24 h after KA administration and both drugs in combination or individually inhibited these events. Likewise, KA promotes mortality and this event was antagonized by effect of both treatments. Additionally, the behavioral evaluation showed that DDS and PB administered alone or in combination decreased the number of limbic seizures and reduced the percentage of animals showing tonic clonic seizures versus the control group, which was administered only with KA. Finally, our study demonstrated that all of the treatments prevented the neuronal death of the pyramidal cell layer of hippocampal CA-3. In conclusion, the treatment with DDS and PB administrated alone or in combination exerted antioxidant, anticonvulsive and neuroprotective effects against the neurotoxicity induced by KA in rats, but their effects were not additive. Thus, it may be good options of treatment in diseases such as epilepsy and status epilepicus, administered separately. PMID- 23729304 TI - Transoral laser microsurgery for oral squamous cell carcinoma: oncologic outcomes and prognostic factors. AB - BACKGROUND: Modest survival rates are published for treatment of oral squamous cell carcinoma (OSCC) using conventional approaches. Few cohort studies are available for transoral resection of OSCC. METHODS: Analysis for recurrence, survival, and prognosis of patients with OSCC treated with transoral laser microsurgery (TLM) +/- neck dissection was obtained from a prospective database. RESULTS: Ninety-five patients (71 patients had stages T1-T2 and 24 had stages T3 T4 disease) with minimum follow-up of 24 months met criteria and demonstrated negative margins in 95%. Five-year local control (LC) and disease-specific survival (DSS) were 78% and 76%, respectively. Surgical salvage achieved an absolute final locoregional control of 92%. Immune compromise and final margins were prognostic for LC, whereas T classification, N classification, TNM stage, comorbidity, and perineural invasion were also significant for DSS. CONCLUSION: We document a large series of patients with OSCC treated with TLM, incorporating T1 to T4 primaries. A significant proportion of stage III/IV cases demonstrates feasibility of TLM in higher stages, with final margin positivity of 5%, LC greater than 90%, and comparable survival outcomes. PMID- 23729305 TI - Concordance measures in shared frailty models: application to clustered data in cancer prognosis. AB - Frailty models are gaining interest in prognostic studies, especially because of the spread of multicenter studies. However, little research has been performed to extend prognostic tools to frailty models, including discrimination measures. As previously performed for the Harrell's c-index, we extended two different discrimination measures (the model-based concordance probability estimation of Gonen and Heller and the nonparametric Uno's c-index) to take into account cluster membership. We calculate measures at three levels: between-group, where only patients with different frailties are compared, within-group, where only patients sharing the same frailty are compared, and overall. We performed simulations to study the impact of group size and the number of groups on these measures. Results showed that the two measures can be extended to frailty models while remaining independent from censoring distribution, provided that the group size is sufficient. We apply the extended measures to two real datasets, a meta analysis and a large multicenter trial. PMID- 23729306 TI - Re: Stoehr et al. Lack of evidence for frequent MED12 p.L1224F mutation in prostate tumours from Caucasian patients. J Pathol 2013; 230: 453-456. PMID- 23729307 TI - Regeneration of facial nerve defects with xenogeneic acellular nerve grafts in a rat model. AB - BACKGROUND: Because of ease of harvest and low immunogenicity, xenogeneic acellular nerve graft (XANG) may be an alternative to autologous nerve to repair facial nerve defects. METHODS: Facial nerve defects of Wistar rats were repaired by XANG, and nerve gap regeneration was investigated by electrophysiological test, horseradish peroxidase (HRP) retrograde tracing and histomorphometric analysis, as compared to autograft. RESULTS: Twenty weeks after the grafting, electrophysiology showed that whisker pad muscles responded to the electrical stimuli given at the site proximal to the transplantation in 2 groups. Some HRP labeled facial motorneurons were located on the facial nucleus of the operated side, and an abundance of myelinated axons were found at the middle of the grafts and obvious motor endplates in the target muscles in 2 groups, although they were inferior to the contralateral side in numbers. CONCLUSION: XANG represents an alternative approach for the reconstruction of peripheral facial nerve defects. PMID- 23729308 TI - Utilization of the Impella 2.5 micro-axial pump in children for acute circulatory support. AB - Percutaneous circulatory support is widely available for use in adult patients. Options remain limited in the pediatric population due to limitations of vessel and patient size, resulting in the use of more invasive means of circulatory support. We present a case series of pediatric patients in whom the Impella 2.5 axial flow pump was able to be placed utilizing a hybrid approach that allowed for adequate distal perfusion while providing successful short-term hemodynamic support. PMID- 23729310 TI - Optimal area of retinal photocoagulation necessary for suppressing active iris neovascularisation associated with diabetic retinopathy. AB - To determine the optimal area of retinal photocoagulation required for suppressing active neovascularisation (NVI) associated with diabetic retinopathy. We studied 1 eye each of 4 patients in whom active NVI was ophthalmoscopically shown to have been suppressed by additional photocoagulation. These patients initially underwent pan-retinal photocoagulation for diabetic retinopathy at another hospital, but NVI developed subsequently. We compared the areas of photocoagulation before and after additional photocoagulation and compared the area of retinal photocoagulation. The photocoagulated areas before and after additional photocoagulation in the four eyes were 20.7 and 45.2, 36.6 and 56.3, 30.4 and 67.4, and 11.7 and 53.4 %, respectively. The area of retinal photocoagulation required to suppress active NVI is calculated to be ~50 %. PMID- 23729309 TI - Current and future treatments for Behcet's uveitis: road to remission. AB - Behcet's disease (BD) is a multisystem inflammatory disorder of uncertain origin, although it remains defined within the spectrum of systemic immune-mediated vasculitic disorders and also represents a spectrum of putative autoimmune disease. Major symptoms include oral aphthous ulcers, genital ulcerations, skin lesions, and ocular lesions. Despite afflicting many systems, ocular complications of BD are some of the more devastating for the patient and their quality of life. Eye involvement, which affects 60-80 % of BD patients, is characterized in its more severe form by posterior or panuveitis including occlusive retinal vasculitis. While pathogenesis of BD remains complex, association with Class I MHC (HLA-B*51) predisposing to inflammation with engagement of the innate-immune system (neutrophils, NK cells), and perpetuated by the adaptive T cell responses against infectious- and/or auto-antigens. Despite the choice of conventional immunosuppressive therapies available, only recently with the advent of biologic therapy has visual prognosis and outcomes been substantially and favorably altered. For example, both interferon-alpha (IFN alpha) and tumour necrosis factor (TNF)-alpha antagonists deliver promising results and for the first time improve prognosis. With IFN-alpha therapy, durable remissions of uveitis can be achieved and lead to drug-free remission. Similarly, anti-TNF therapy with infliximab is reported to be rapidly effective in inducing and maintaining remission. Most recently, rising evidence reports on the use of adalimumab, etanercept, and golimumab, while use of anti-interleukin (IL)-1 agents (anakinra, canakinumab, gevokizumab), IL-6 blockers (tocilizumab), and rituximab (depleting anti-CD20 antibody) is also increasing. The aim of this review is to provide evidence for the role of conventional therapies combined with evidence for advantages and disadvantages of biologic therapies in the treatment of ocular BD. Although randomized controlled trials remain sparse, evidence remains strong and enticing that biologic agents are invaluable for the treatment of sight-threatening Behcet's uveitis and makes it an exciting time for Behcet's specialists worldwide. PMID- 23729311 TI - Validation study of an electronic method of condensed outcomes tools reporting in orthopaedics. AB - Patient-reported outcomes (PRO) instruments are a vital source of data for evaluating the efficacy of medical treatments. Historically, outcomes instruments have been designed, validated, and implemented as paper-based questionnaires. The collection of paper-based outcomes information may result in patients becoming fatigued as they respond to redundant questions. This problem is exacerbated when multiple PRO measures are provided to a single patient. In addition, the management and analysis of data collected in paper format involves labor intensive processes to score and render the data analyzable. Computer-based outcomes systems have the potential to mitigate these problems by reformatting multiple outcomes tools into a single, user-friendly tool.The study aimed to determine whether the electronic outcomes system presented produces results comparable with the test-retest correlations reported for the corresponding orthopedic paper-based outcomes instruments.The study is designed as a crossover study based on consecutive orthopaedic patients arriving at one of two designated orthopedic knee clinics.Patients were assigned to complete either a paper or a computer-administered questionnaire based on a similar set of questions (Knee injury and Osteoarthritis Outcome Score, International Knee Documentation Committee form, 36-Item Short Form survey, version 1, Lysholm Knee Scoring Scale). Each patient completed the same surveys using the other instrument, so that all patients had completed both paper and electronic versions. Correlations between the results from the two modes were studied and compared with test-retest data from the original validation studies.The original validation studies established test-retest reliability by computing correlation coefficients for two administrations of the paper instrument. Those correlation coefficients were all in the range of 0.7 to 0.9, which was deemed satisfactory. The present study computed correlation coefficients between the paper and electronic modes of administration. These correlation coefficients demonstrated similar results with an overall value of 0.86.On the basis of the correlation coefficients, the electronic application of commonly used knee outcome scores compare variably to the traditional paper variants with a high rate of test-retest correlation. This equivalence supports the use of the condensed electronic outcomes system and validates comparison of scores between electronic and paper modes. PMID- 23729312 TI - Shear force at failure and stiffness of all-inside meniscal repair devices. AB - The purpose of this study was to determine the failure load and stiffness of various meniscal repair devices. A total of 61 fresh-frozen porcine menisci (medial and lateral) were used for the study. A 30-mm vertical, full-thickness tear was created and repaired using one of three all-inside fixation devices and one inside-out repair in the vertical mattress pattern. We used the MaxBraid (Biomet, Warsaw, IN) inside-out suture as a control. The other devices tested were the Meniscal Cinch (Arthrex, Naples, FL), Ultra FasT-Fix (Smith & Nephew, Andover, MA), and the MaxFire MarXmen (Biomet, Warsaw, IN). In addition, two devices, MaxFire MarXmen and Ultra FasT-Fix, were tested using a horizontal mattress configuration. Using the vertical mattress pattern, the Meniscal Cinch had the highest average load to failure. The Meniscal Cinch was significantly less stiff than the other three devices (p < 0.04). For the MarXmen and Ultra FasT-Fix, no differences were noted for load to failure between horizontal and vertical mattress patterns. The mode of failure was significantly different when comparing the two different surgical techniques for the MaxFire MarXmen (p = 0.005). The MaxFire MarXmen device produced a significantly stiffer (p < 0.001) construct when following the manufacturer's instructions (5.8 N/mm) than with the technique used for the other all-inside devices (2.5 N/mm) The Meniscal Cinch had the highest load-to-failure value but the lowest stiffness of the group in the vertical mattress configuration. There was little difference in biomechanical properties between vertical and horizontal repair. Importantly, there was a significant difference in stiffness and failure mode for the MaxFire MarXmen when the manufacturer guidelines were not specifically followed. PMID- 23729313 TI - Probing the structural properties of DNA/RNA grooves with sterically restricted phosphonium dyes: screening of dye cytotoxicity and uptake. AB - To explore in greater detail the recently reported rare kinetic differentiation between homo-polymeric and alternating AT-DNA sequences by using sterically restricted phosphonium dyes that form dimers within the DNA minor groove, new analogues were prepared in which the quinolone phosphonium moiety was kept constant, while the size and hydrogen bonding properties of the rest of the molecule were varied. Structure-activity relationship studies revealed that a slight increase in length by an additional methylene unit results in loss of kinetic AT selectivity, but yielded an AT-selective fluorescence response. These DNA/RNA-groove-bound dyes combine very low cytotoxicity with efficient cellular uptake and intriguingly specific fluorescent marking of mitochondria. In contrast to longer analogues, a decrease in length (by methylene unit removal) and rearrangement of positive charge resulted in dyes that had switched to the intercalative binding mode to GC DNA/dsRNA but that still form dimers in the minor groove of AT sequences, consequently yielding a significantly different chiro-optical response. The latter dyes also revealed strongly selective antiproliferative activity toward HeLa cancer cells. PMID- 23729314 TI - Predicting unobserved exposures from seasonal epidemic data. AB - We consider a stochastic Susceptible-Exposed-Infected-Recovered (SEIR) epidemiological model with a contact rate that fluctuates seasonally. Through the use of a nonlinear, stochastic projection, we are able to analytically determine the lower dimensional manifold on which the deterministic and stochastic dynamics correctly interact. Our method produces a low dimensional stochastic model that captures the same timing of disease outbreak and the same amplitude and phase of recurrent behavior seen in the high dimensional model. Given seasonal epidemic data consisting of the number of infectious individuals, our method enables a data-based model prediction of the number of unobserved exposed individuals over very long times. PMID- 23729315 TI - Particle manipulation based on optically controlled free surface hydrodynamics. PMID- 23729316 TI - Sublethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma. AB - Radiofrequency ablation (RFA) is a potentially curative therapy for hepatocellular carcinoma (HCC). However, incomplete RFA can induce accelerated invasive growth at the periphery. The mechanisms underlying the RFA-induced tumor promotion remain largely unexplored. Three human HCC cell lines were exposed to 45 degrees C-55 degrees C for 10 minutes, simulating the marginal zone of RFA treatment. At 5-12 days post-treatment cell proliferation, parameters of epithelial-mesenchymal transition (EMT), and activation of mitogen-activated protein kinases were analyzed. Livers from patients with viral hepatitis without and with HCC (n = 114) were examined to confirm the relevance of altered kinase patterns. In vivo tumorigenic potential of heat-treated versus untreated HCC cells was studied in nude mice. Heating to 55 degrees C killed all HCC cells, whereas 65%-85% of cells survived 48 degrees C-50 degrees C, developing spindle like morphology and expressing CD133, cytokeratin (CK)7, CK19, procollagen alpha1(I), and Snail at day 5 after heat exposure, which returned to baseline at day 12. Heat-exposed HCC cells showed enhanced proliferation and prominent activation of p46-Shc (Src homology and collagen) and downstream extracellular signal-related kinase (Erk)1/2. In patients, Shc expression correlated with malignant potential and overall survival. Blocking Erk1/2 reduced proliferation and EMT-like changes of heat-treated HCC cells. Implantation of heat-exposed HEPG2 cells into nude mice induced significantly larger, more aggressive tumors than untreated cells. CONCLUSIONS: Sublethal heat treatment skews HCC cells toward EMT and transforms them to a progenitor-like, highly proliferative cellular phenotype in vitro and in vivo, which is driven significantly by p46Shc Erk1/2. Suboptimal RFA accelerates HCC growth and spread by transiently inducing an EMT-like, more aggressive cellular phenotype. PMID- 23729318 TI - Online drug databases: a new method to assess and compare inclusion of clinically relevant information. AB - BACKGROUND: Evidence-Based Practice requires health care decisions to be based on the best available evidence. The model "Information Mastery" proposes that clinicians should use sources of information that have previously evaluated relevance and validity, provided at the point of care. Drug databases (DB) allow easy and fast access to information and have the benefit of more frequent content updates. Relevant information, in the context of drug therapy, is that which supports safe and effective use of medicines. Accordingly, the European Guideline on the Summary of Product Characteristics (EG-SmPC) was used as a standard to evaluate the inclusion of relevant information contents in DB. OBJECTIVE: To develop and test a method to evaluate relevancy of DB contents, by assessing the inclusion of information items deemed relevant for effective and safe drug use. METHOD: Hierarchical organisation and selection of the principles defined in the EGSmPC; definition of criteria to assess inclusion of selected information items; creation of a categorisation and quantification system that allows score calculation; calculation of relative differences (RD) of scores for comparison with an "ideal" database, defined as the one that achieves the best quantification possible for each of the information items; pilot test on a sample of 9 drug databases, using 10 drugs frequently associated in literature with morbidity-mortality and also being widely consumed in Portugal. Main outcome measure Calculate individual and global scores for clinically relevant information items of drug monographs in databases, using the categorisation and quantification system created. RESULTS: A--Method development: selection of sections, subsections, relevant information items and corresponding requisites; system to categorise and quantify their inclusion; score and RD calculation procedure. B--Pilot test: calculated scores for the 9 databases; globally, all databases evaluated significantly differed from the "ideal" database; some DB performed better but performance was inconsistent at subsections level, within the same DB. CONCLUSION: The method developed allows quantification of the inclusion of relevant information items in DB and comparison with an "ideal database". It is necessary to consult diverse DB in order to find all the relevant information needed to support clinical drug use. PMID- 23729319 TI - Antibiotic prophylaxis and risk of infections in thyroid surgery: results from a national study (UEC-Italian Endocrine Surgery Units Association). AB - Thyroid surgery is considered a clean procedure, and therefore antibiotic prophylaxis is not recommended. However, antibiotic prophylaxis is often used in clinical practice. Aim of the present study is to show the rate of infections in thyroid surgery and whether antibiotic prophylaxis, among other factors, is associated with a lower infection rate in 2,926 patients (constituting the cohort of UEC-Italian Endocrine Surgery Units Association) who had a thyroid surgical operation between the years 2009 and 2011. Antibiotic prophylaxis was used in 1,132 interventions (38.7 %). We recorded 28 cases of infections (rate = 1 %). At univariate analysis the lack of drainage and of antibiotic prophylaxis were factors associated with infection development. However, we noticed a concentration of cases of infections (10 of the 28 total cases) in one single center that showed a very high rate of infection (8.8 %). At logistic regression analysis the only independent predictor of infection development was belonging to that center, while the lack of antibiotic prophylaxis was not. In conclusion, our study shows that infection rate in thyroid surgery was 1 %. The use of an antibiotic prophylaxis was not associated with a protection from these infections. PMID- 23729317 TI - Amyloid beta peptides promote autophagy-dependent differentiation of mouse neural stem cells: Abeta-mediated neural differentiation. AB - Although regarded as neurotoxic, amyloid beta (Abeta) peptides may also mediate a wide range of nonpathogenic processes. Autophagy has been implicated in Abeta mediated effects, although its precise function in neural differentiation remains unknown. Here, we addressed the role of different Abeta fragments in neural stem cell (NSC) proliferation and differentiation, and investigated whether autophagy is involved in Abeta-induced alterations of neural fate. Our results demonstrate that neuronal and glial-specific protein markers are significantly induced by both Abeta1-40 and Abeta1-42. However, Abeta1-40 preferentially enhances neurogenesis of NSCs, as determined by betaIII-tubulin, NeuN, and MAP2 neuronal marker immunoreactivity, while Abeta1-42 appears to favor gliogenesis. In contrast, Abeta25-35 does not influence NSC fate. The effect of Abeta1-40 on neurogenesis is partially dependent on its role in NSC self-renewal as both S phase of the cell cycle and BrdU labeling were markedly increased. Nevertheless, Abeta1-40 resulted also in increased Tuj1 promoter activity. Autophagy, assessed by conversion of endogenous LC3-I/II, fluorescence of pGFP-LC3-transfected cells, and Atg9 protein levels, was evident in both Abeta1-40- and Abeta1-42-treated NSCs, independently of reactive oxygen species production and apoptosis. Finally, inhibition of autophagy by pharmacologic means abrogated Abeta-induced lineage specific protein markers. These results support distinct roles for different Abeta peptides in NSC fate decision and underline the importance of autophagy control of this process. PMID- 23729320 TI - Fine-needle aspiration cytology of renal clear cell carcinoma metastatic to the thyroid gland. PMID- 23729321 TI - Bad medicine: statins. PMID- 23729322 TI - A facile sonochemical route for the fabrication of magnetic protein microcapsules for targeted delivery. PMID- 23729323 TI - Specifications of a continual reassessment method design for phase I trials of combined drugs. AB - In studies of combinations of agents in phase I oncology trials, the dose toxicity relationship may not be monotone for all combinations, in which case the toxicity probabilities follow a partial order. The continual reassessment method for partial orders (PO-CRM) is a design for phase I trials of combinations that leans upon identifying possible complete orders associated with the partial order. This article addresses some practical design considerations not previously undertaken when describing the PO-CRM. We describe an approach in choosing a proper subset of possible orderings, formulated according to the known toxicity relationships within a matrix of combination therapies. Other design issues, such as working model selection and stopping rules, are also discussed. We demonstrate the practical ability of PO-CRM as a phase I design for combinations through its use in a recent trial designed at the University of Virginia Cancer Center. PMID- 23729324 TI - Clinical significance of indeterminate pulmonary nodules in patients with locally advanced head and neck squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to determine whether indeterminate pulmonary nodules (IPNs) at staging are predictive of lung metastasis, primary lung carcinoma, or survival in patients with advanced head and neck squamous cell carcinoma (HNSCC). METHODS: One hundred ten patients with IPN at staging who had follow-up imaging and 100 patients without IPN were identified from an HNSCC database. The primary endpoints were lung progression-free survival (PFS) and overall survival (OS). RESULTS: Two-year lung PFS for the IPN and No-IPN cohorts were 66% versus 61% (p = .92) and the OS for these cohorts were 71% versus 68% (p = .77). Within the IPN cohort, level IV/V lymph node involvement (odds ratio = 4.34; p = .03), hypopharynx primary (odds ratio = 21.5; p = .005), and race (odds ratio = 9.29; p = .001) were independent predictors of developing lung malignancy. CONCLUSION: IPNs at staging in patients with HNSCC do not affect prognosis and should neither influence initial treatment planning nor the frequency of posttreatment surveillance. PMID- 23729325 TI - Reply to 'On the association of cell phone exposure with childhood behaviour' by Sudan et al. PMID- 23729326 TI - The association between binge drinking and birth outcomes: results from the Born in Bradford cohort study. AB - BACKGROUND: Various human and animal studies suggest that peak alcohol exposure during a binge episode, rather than total alcohol exposure, may determine fetal development. Research about the impact of binge drinking on birth outcomes is sparse and inconclusive. Data from the Born in Bradford cohort study were used to explore the impact of binge drinking on birth outcomes. METHODS: Interview administered questionnaire data about the lifestyle and social characteristics of 10 851 pregnancies were linked to maternity and birth data. The impact of self reported binge drinking (5 units: 40 g of pure alcohol) on two birth outcomes (small for gestational age (SGA) and preterm birth (<37 weeks)) was assessed using multivariate logistic regression models, while adjusting for confounders. RESULTS: The percentage of women classified as binge drinkers fell from 24.5% before pregnancy to 9% during the first trimester and 3.1% during the second trimester. There was a significant association between SGA birth and binge drinking (all categories combined; OR 1.68, 95% CI 1.15 to 2.47, p=0.01). No association was observed between moderate drinking and either birth outcome, or between binge drinking and preterm birth. CONCLUSIONS: Binge drinking during the second trimester of pregnancy was associated with an increased risk of SGA birth. No association was found between any level of alcohol consumption and premature birth. This work supports previous research showing no association between SGA and low-alcohol exposure but adds to evidence of a dose-response relationship with significant risks observed at binge drinking levels. PMID- 23729327 TI - Childhood and adulthood socio-economic position and hypertensive disorders in pregnancy: the Uppsala Birth Cohort Multigenerational Study. AB - BACKGROUND: Childhood and adulthood socio-economic position (SEP) is associated with cardiovascular disease in later life, but associations with hypertensive disorders in pregnancy are not well established. OBJECTIVE: The aim of this study was to investigate the association of childhood and adulthood SEP with hypertensive disorders in pregnancy (chronic hypertension, gestational hypertension and pre-eclampsia/eclampsia). METHOD: Study participants were Swedish women (n=9507) from generation 3 of the Uppsala Birth Cohort Multigenerational Study (UBCoS Multigen) who delivered a live singleton offspring between 1982 and 2008. Social and health data were obtained from routine Swedish registers. Associations of own education (adulthood SEP), and parental education and social class (childhood SEP) with hypertensive disorders were studied using logistic regression with adjustments for age, calendar period, parity, smoking and body mass index. RESULTS: Low own education was associated with chronic hypertension, but not with gestational hypertension or pre-eclampsia/eclampsia. Increased risk of chronic hypertension was seen in women whose mothers had medium education compared with women whose mothers had high education (OR 2.18, 95% CI 1.03 to 4.62). Women from a manual social class during childhood had twice the risk of chronic hypertension compared with those from non-manual backgrounds (OR 2.19, 95% CI 1.28 to 3.75). Childhood SEP was not associated with gestational hypertension or pre-eclampsia/eclampsia. CONCLUSIONS: Childhood and adulthood SEP was associated with chronic hypertension in pregnancy. In contrast, no association with childhood or adulthood SEP was seen for gestational hypertension or pre-eclampsia/eclampsia. PMID- 23729328 TI - On the association of cell phone exposure with childhood behaviour. PMID- 23729329 TI - The physiological paradox: reframing the polypill as a vaccine for cardiovascular disease. PMID- 23729331 TI - Ductal variation of the sublingual gland: a predisposing factor for ranula formation. AB - BACKGROUND: The purpose of this study was to evaluate ranula development according to anatomic variation of the sublingual gland (SLG). METHODS: We conducted a prospective, consecutive case series considering other clinical conditions. Twenty-five cases treated by SLG excision were enrolled in this study. The ductal structures of the SLGs of another 11 patients undergoing similar surgeries for other conditions were compared. RESULTS: In 19 of a total of 25 ranulas (76.0%) and 16 of 18 oral nonplunging ranulas (88.9%), the SLG showed an anatomic variation of the main duct called Bartholin's duct structure. Meanwhile, only 3 of 7 plunging ranulas (42.9%) had Bartholin's ducts. Bartholin's duct structure of the SLG was not found in the 11 control cases. CONCLUSION: Anatomic variation of the ductal system of the SLG might be a possible cause of ranulas. Surgical resection of the SLG is a better treatment choice for ranulas than other, more conservative treatments. PMID- 23729330 TI - Loss of caveolin-1 in prostate cancer stroma correlates with reduced relapse-free survival and is functionally relevant to tumour progression. AB - Levels of caveolin-1 (Cav-1) in tumour epithelial cells increase during prostate cancer progression. Conversely, Cav-1 expression in the stroma can decline in advanced and metastatic prostate cancer. In a large cohort of 724 prostate cancers, we observed significantly decreased levels of stromal Cav-1 in concordance with increased Gleason score (p = 0.012). Importantly, reduced expression of Cav-1 in the stroma correlated with reduced relapse-free survival (p = 0.009), suggesting a role for stromal Cav-1 in inhibiting advanced disease. Silencing of Cav-1 by shRNA in WPMY-1 prostate fibroblasts resulted in up regulation of Akt phosphorylation, and significantly altered expression of genes involved in angiogenesis, invasion, and metastasis, including a > 2.5-fold increase in TGF-beta1 and gamma-synuclein (SNCG) gene expression. Moreover, silencing of Cav-1 induced migration of prostate cancer cells when stromal cells were used as attractants. Pharmacological inhibition of Akt caused down regulation of TGF-beta1 and SNCG, suggesting that loss of Cav-1 in the stroma can influence Akt-mediated signalling in the tumour microenvironment. Cav-1-depleted stromal cells exhibited increased levels of intracellular cholesterol, a precursor for androgen biosynthesis, steroidogenic enzymes, and testosterone. These findings suggest that loss of Cav-1 in the tumour microenvironment contributes to the metastatic behaviour of tumour cells by a mechanism that involves up-regulation of TGF-beta1 and SNCG through Akt activation. They also suggest that intracrine production of androgens, a process relevant to castration resistance, may occur in the stroma. PMID- 23729332 TI - Comparative exploration of whole-body MR through locally rigid transforms. AB - PURPOSE: Whole-body MRI is seeing increasing use in the study and diagnosis of disease progression. In this, a central task is the visual assessment of the progressive changes that occur between two whole-body MRI datasets, taken at baseline and follow-up. Current radiological workflow for this consists in manual search of each organ of interest on both scans, usually on multiple data channels, for further visual comparison. Large size of datasets, significant posture differences, and changes in patient anatomy turn manual matching in an extremely labor-intensive task that requires from radiologists high concentration for long period of time. This strongly limits the productivity and increases risk of underdiagnosis. MATERIALS AND METHODS: We present a novel approach to the comparative visual analysis of whole-body MRI follow-up data. Our method is based on interactive derivation of locally rigid transforms from a pre-computed whole body deformable registration. Using this approach, baseline and follow-up slices can be interactively matched with a single mouse click in the anatomical region of interest. In addition to the synchronized side-by-side baseline and matched follow-up slices, we have integrated four techniques to further facilitate the visual comparison of the two datasets: the "deformation sphere", the color fusion view, the magic lens, and a set of uncertainty iso-contours around the current region of interest. RESULTS: We have applied our method to the study of cancerous bone lesions over time in patients with Kahler's disease. During these studies, the radiologist carefully visually examines a large number of anatomical sites for changes. Our interactive locally rigid matching approach was found helpful in localization of cancerous lesions and visual assessment of changes between different scans. Furthermore, each of the features integrated in our software was separately evaluated by the experts. CONCLUSION: We demonstrated how our method significantly facilitates examination of whole-body MR datasets in follow-up studies by enabling the rapid interactive matching of regions of interest and by the explicit visualization of change. PMID- 23729333 TI - Open-source surface mesh-based ultrasound-guided spinal intervention simulator. AB - PURPOSE: Ultrasound is prevalent in image-guided therapy as a safe, inexpensive, and widely available imaging modality. However, extensive training in interpreting ultrasound images is essential for successful procedures. An open source ultrasound image simulator was developed to facilitate the training of ultrasound-guided spinal intervention procedures, thereby eliminating the need for an ultrasound machine from the phantom-based training environment. METHODS: Anatomical structures and surgical tools are converted to surface meshes for data compression. Anatomical data are converted from segmented volumetric images, while the geometry of surgical tools is available as a surface mesh. The pose of the objects are either constants or coming from a pose-tracking device. Intersection points between the surface models and the ultrasound scan lines are determined with a binary space partitioning tree. The scan lines are divided into segments and filled with gray values determined by an intensity calculation accounting for material properties, reflection, and attenuation parameters defined in a configuration file. The scan lines are finally converted to a regular brightness-mode ultrasound image. RESULTS: The simulator was tested in a tracked ultrasound imaging system, with a mock transducer tracked with an Ascension trakSTAR electromagnetic tracker, on a spine phantom. A mesh model of the spine was created from CT data. The simulated ultrasound images were generated at a speed of 50 frames per second, and a resolution of [Formula: see text] pixels, with 256 scan lines per frame, on a PC with a 3.4 GHz processor. A human subject trial was conducted to compare the learning performance of novice trainees, with real and simulated ultrasound, in the localization of facet joints of a spine phantom. With 22 participants split into two equal groups, and each participant localizing 6 facet joints, there was no statistical difference in the performance of the two groups, indicating that simulated ultrasound could indeed replace the real ultrasound in phantom-based ultrasonography training for spinal interventions. CONCLUSIONS: The ultrasound simulator was implemented and integrated into the open-source Public Library for Ultrasound (PLUS) toolkit. PMID- 23729335 TI - [Implementing the "last mile" program in new nurse clinical education]. AB - The shortage of working nurses has made Taiwan's low nursing retention rate a critical issue in domestic healthcare. Main reasons for new nurses leaving their jobs include high pressure, overtime work, heavy workload, interpersonal relationship problems with colleagues, and inadequate support from administrators. In response, nursing educators designed the "last mile" program to improve the hands-on competence of nursing students with the goal of increasing post-graduation retention rates. This article introduces the last mile program in its present form and discusses the challenges faced in transitioning the program from the classroom into the clinical training environment. The authors suggest establishing a challenge test prior to implementing the last mile program, recruiting role-model preceptors, adjusting training program / project budgets, and developing partnerships between nursing educators and clinicians to enhance the clinical competence of new nurses and ultimately increase professional nurse retention rates, competence, and accountability. PMID- 23729334 TI - Review of factor analytic studies examining symptoms of autism spectrum disorders. AB - Factor analytic studies have been conducted to examine the inter-relationships and degree of overlap among symptoms in Autism Spectrum Disorder (ASD). This paper reviewed 36 factor analytic studies that have examined ASD symptoms, using 13 different instruments. Studies were grouped into three categories: Studies with all DSM-IV symptoms, studies with a subset of DSM-IV symptoms, and studies with symptoms that were not specifically based on the DSM-IV. There was consistent support for a common social/communication domain that is distinct from a restricted and repetitive behaviours and interests domain. Implications for symptom conceptualization and diagnosis in ASD are discussed. PMID- 23729336 TI - [The two-year post graduate training program for nurses: implementation status and personal perspectives]. AB - The Taiwan Joint Commission on Hospital Accreditation (TJCHA) authorized the Teaching Quality Improvement Program for Teaching Hospitals as a way for the Department of Health to plan and implement improvements. The program assists medical and paramedical professionals to establish a postgraduate clinical training system. The two-year postgraduate training program for nurses is one of the program's regular activities, divided into three phases that include location based curriculum training (3 months), core curriculum training (9 months), and professional courses training (12 months). This paper describes the origin, current implementation status, and efficacy / key problems of this two-year post graduate training program, Information regarding the opinions of new nurses, preceptors, and nursing managers on the three aspects is drawn from the author's relevant professional experience, interactions with nurses, and a review of the literature. Findings include: (1) nursing departments should operate in accordance with TJCHA guidelines; (2) department training should be adequate to promote the ability and willingness of nurses to train a new generation of clinical preceptors; and (3) participant opinions on project execution progress and difficulties. Findings may be referenced to better achieve Teaching Quality Improvement Program for Teaching Hospital objectives. PMID- 23729337 TI - [Community health nursing: essential education elements]. AB - Community health nursing has undergone significant reform over recent decades in response to ongoing advances in medical technology and increasing national living standards. Taiwan's nursing manpower projections indicate a strong and growing demand for nurses working in primary and tertiary settings. Can our nurses address social trends and face the new challenges of the 21st century? The baccalaureate nursing degree is the minimum preparation for entry-level professionals working in community health nursing in most advanced countries. Significant improvements are necessary in this degree track to improve the quality and quantity of community health nurses. This article introduces the Essentials of Baccalaureate Nursing Education for Entry Level Community / Public Health Nursing proposed by the Association of Community Health Nursing Educators (ACHNE). It is hoped that nursing schools and community health nurses responsible for professional training in Taiwan will reference the ACHNE proposal and develop appropriate domestic curricula that will form an effective professional development consensus and further advance community care. PMID- 23729338 TI - [Midwifery clinical practicum education]. AB - Midwifery is a practical facet of the health sciences that emphasizes professional competence-oriented teaching and learning. Cognitive and practical processes integrate and build midwifery student professional knowledge, attitudes, and skills. Clinical education is a teaching method and strategy used to prepare midwifery students for professional practice. Midwifery clinical teaching plans are designed using literature review, expert opinions, and student comments and determine total required hours and caseloads. Midwifery clinical teaching activities and methods promote self-reflection, childbirth education fundamentals, learning by role model observation, and learning role function through overseas observership programs. This paper discusses midwifery education dilemmas and coping methods in Taiwan. PMID- 23729339 TI - [The transformation of nurses in holding and containing: a reflective group for end-of-life care]. AB - BACKGROUND: Caring for dying patients is an emotional burden for nurses. PURPOSE: This study used reflective groups to explore the process of transition that nurses go through in caring for dying patients. METHODS: We adopted a phenomenological approach. Data were collected from nurses participating in 12 reflective groups. All nurses worked in oncology / hospice units in a general hospital in Taipei. We used thematic analysis to analyze data. RESULTS: Findings identified a transition in how nurses handled and contained their emotions within three main themes: (1) containing unpredictable reality, (2) cautious "holding back" in discussion, and (3) self-cultivation in order to serve others. These findings led us to extrapolate the three issues of wounded healer, facing others, and altruism in caring. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: This study represented the holding and containing of nurses in caring for dying patients and held group dialogues to facilitate reflection. Findings will be used to facilitate nurse self-awareness and improve end-of-life care quality. PMID- 23729340 TI - [Dysmenorrhea: a study of affected factors and approaches to relief among female students at a college in southern Taiwan]. AB - BACKGROUND: Dysmenorrhea is a major problem in the general gynecology clinic. It causes discomfort among healthcare staffs and significant losses in terms of time and finances. PURPOSE: The purpose of this study was to determine the affected factors of dysmenorrhea and evaluate the self-perceived efficacy of relief methods. METHODS: A cross-sectional research design was used to collect data. Participants included 586 female students enrolled at a college in southern Taiwan. Data was analyzed using a t-test, one-way ANOVA, and Scheffe test. RESULTS: Traditional Chinese medicine pattern identifications related significantly to dysmenorrhea frequency perception. Lifestyle characteristics related significantly to dysmenorrhea level perception. Using shenghua decoction, siwu and pig blood decoction, Angelica drink, ginger, ziziphus jujube, brown sugar tea, and analgesics all related significantly to dysmenorrhea relief efficacy. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Strategies found to help relieve dysmenorrhea level perception include increasing the duration and regularity of sleep and avoiding the consumption of pungent foods. Seeking and adhering to physician recommendations can also increase dysmenorrhea self-care efficacy. Dysmenorrhea-relief courses should be improved in hospitals and schools to assist women to self-manage dysmenorrhea more effectively. PMID- 23729341 TI - [The impact of hepatitis B knowledge on screening behavior factors in outpatients]. AB - BACKGROUND: According to Taiwan Department of Health and World Health Organization statistics, hepatic tumors are the second leading cause of death from malignant disease in Taiwan, with 600,000 deaths from HBV (hepatitis B virus ) infected complication annually. Hepatitis B virus infection is thus an important issue in public health policy. PURPOSE: The aims of this study were to investigate hepatitis B knowledge and screening behavior and then identify significant prediction factors of hepatitis B screening behavior. METHODS: A cross-sectional survey and convenience sampling were used to investigate 282 outpatients at the one target hospital. Descriptive statistics, independent t test, one-way ANOVA, Spearman relation, and multiple regression were used to analyze impact factors. RESULTS: Slightly over half (55.7%) of the participants had received HBV screening. The average hepatitis B knowledge score was 9.38, with an average correct rate of 72.2%."Whether friends and relatives suffer from hepatitis B", "knowledge of hepatitis B", "perceived barriers to action", and "cue for action" explained 12.3% of total variance. Of these, "perceived barriers of action" was the most important predictor of hepatitis B screening behavior. CONCLUSION: Although participant knowledge of hepatitis B was relatively good, the screening rate was less than ideal. Results point to "perceived barriers of action" as a key factor affecting screening behavior. We suggest establishing an independent outpatient service to offer screening for hepatitis B in order to reduce waiting time and provide greater convenience. We also suggest the implementation of a policy to unify charges to raise public motivation to undergo screening. PMID- 23729342 TI - [Perceiving gender or profession: the practical experience of male nursing students in the obstetrics and gynecology ward]. AB - BACKGROUND: The impact of general gender stereotypes on nursing is severe and influential, especially with regard to male nursing students working in obstetrics and gynecology wards. PURPOSE: This study examined the experience of male nursing students in obstetrics and gynecology wards. METHODS: We used a phenomenological qualitative research approach and a sample of 10 male nursing students currently studying at a nursing college in central Taiwan. All participants had obstetrics and gynecology ward experience. Individual interviews were transcribed into the procedural record. Colaizzi content analysis analyzed and categorized research data. RESULTS: Based on participants practical experiences in the obstetrics and gynecology ward, the main stages of participants professional development through their internship experience included: (1) Unbalanced self-role recognition; (2) being defined by the gender framework (gender stereotypes); (3) the difference between male doctor and male nurse; (4) learning appropriate communication techniques; (5) mutual and empathetic understanding of the female psychology during childbirth; (6) gaining sources for positive feedback; (7) releasing the shackles of gender and gaining full insight into and comprehension of nursing functions; and (8) given the opportunity to learn. CONCLUSION: Through ongoing examination and learning, participant internships in the obstetrics and gynecology wards were significant and essential learning experiences that validated their necessity. Nursing schools and internship institutions alike must realize the importance of gender equality education to the nursing profession. Medical institutions are encouraged to offer equal learning opportunities to male and female nursing students and provide targeted assistance to males to help them master clinical nursing care practices in the obstetrics and gynecology department. PMID- 23729343 TI - [A project to improve the "do not resuscitation" consent completeness rate for terminal cancer patients]. AB - BACKGROUND: Signed do-not-resuscitate (DNR) consent is the essential first step for terminal cancer patients to choose palliative care and a quality marker of terminal care. DNR consent completeness helps deliver correct information, ensure consent legal validity, reduce medical disputes, and protect patient and family rights. The DNR consent completeness rate during May and June 2005 was only 33.9% in our hospital. Reasons indicated for this low rate included: (1) lack of a standard operating procedure for DNR consent; (2) multiple DNR consent versions; (3) lack of DNR-related education; and (4) lack of monitoring procedures. Our team developed a project to resolve these problems and improve terminal care quality. PURPOSE: The goal of this project was to increase the rate of DNR consent completeness from 33.9% to 80%. RESOLUTION: The plan, implemented between August and December 2009, included the following components: (1) establish standard guidelines for DNR consent; (2) simplify and unify DNR consent procedures; (3) provide DNR education for hospital staff; and (4) establish a DNR consent monitoring system. RESULTS: The DNR consent completeness rate rose from 33.9% to 90%. The goal of this project was thus achieved. CONCLUSION: This project effectively improved the DNR consent completeness rate at our hospital. The project ensured patients a good death and enhanced terminal care quality and patient satisfaction. Our experience may provide a reference to help other hospitals increase DNR their consent completeness rates. PMID- 23729344 TI - [Enhancing the attendance rate of psychiatric day care patients]. AB - BACKGROUND & PROBLEMS: Attending rehabilitation programs at psychiatric daycare wards has been shown to stabilize psychiatric patients' daily routines, reduce patient symptoms, and help them regain social functions. Non-attendance increases risks of patient decompensation and return to the inpatient unit, which reduces quality of care and increases medical costs. The attendance rate for psychiatric daycare patients at our hospital was 73%. To maximize rehabilitation and treatment success, we developed a special project to raise patient program attendance motivation. PURPOSE: This study aimed to enhance the attendance rate of our psychiatric day care patients to improve patient independence and their capacity to return to the community. RESOLUTION: Methods used included rehabilitation game cards, holding medication educational workshops, utilizing reward systems, making attendance passports, and designing activity booklets. RESULTS: The attendance rate of psychiatric day care patients rose from 73% to 89%, a 16% increase. CONCLUSION: This program not only increased the attendance rate of psychiatric day care patients but also improved communications between professional care staff and patient family members. In addition, this program strengthened daycare ward staff teamwork, which further enhanced treatment quality. We suggest considering rehabilitation program attendance as an important ward quality control criterion to assess and improve treatment and nursing care quality. PMID- 23729345 TI - [The nursing shortage and nursing retention strategies in Taiwan]. AB - A chronic shortage of working nurses has led hospitals in Taiwan to close wards and reduce bed numbers. Work overload and job stress are major causes of this shortage. The purpose of this study is to propose a solution to improve the nursing workload situation. We reviewed literature articles and conference presentations to synthesize relevant measures, which included reforming the current care model; using innovation to simplify nursing practice; and creating a culture of workplace respect and inter-team cooperation. Based on this, we proposed our nursing retention strategy after reviewing national Department of Health development policies on nursing manpower. PMID- 23729346 TI - [Being a mother: encounters between mothers of children with Duchenne muscular dystrophy and nurses in Taiwan]. AB - The role of "mother" is understood and represented differently by people from different cultures. In traditional Taiwanese society, mothers demonstrate their existence value by giving birth to and raising sons able to continue her husband's familial line. Sons bear the patriarchal name and care for their parents in old age. However, a son stricken, paralyzed and eventually killed by Duchenne muscular dystrophy (DMD) can destroy a mother's perceived value in this traditional social context. Mothers are thus soundless sufferers. Nurses have a critical role to play in giving encouragement and hope to mothers of children with DMD. Through their own difficult situation, these mothers can also highlight the value and importance of Taiwan's nurses, who work in conditions marked by overloading, high stress, and under-appreciation. Caring for women in critical need of empathy and support help nurses realize their own positive capacity to empower sufferers. PMID- 23729347 TI - [Assay of screening and prevention issues for high risk populations with prodromes of severe mental illness]. AB - Before the appearance of specific psychotic symptoms, most individuals experience a period of prodromal symptoms associated with severe mental illness. Early intervention during this pre-psychotic phase may improve treatment outcomes, alter the natural course of disease, and prevent or delay mental disease onset. This paper aimed to synthesize four screening strategies (genetic high-risk populations selected by family history with mental illness, finding ultra-high risk population, the close-in strategy, and the pre-psychotic phase by assessing basic symptoms); two intervention dimensions (psychosocial interventions and antipsychotic medicine); discussions of ethnic issues; and three Taiwanese nurses' roles (the role of assessment for screening, the role of development for screening tools, and the role of preventive intervention providers) to attain early diagnoses and prevention of mental illness. This article provides more information to advanced Taiwanese mental health nurses responsible to promote /s enhance the health of patients with prodromes of severe mental illness. PMID- 23729348 TI - [Understanding a hospitalized, school-aged child's stress in the PICU: the application of picture books in nursing care]. AB - Hospitalization in the pediatric intensive care unit (PICU) can be a very stressful and sometimes traumatic experience for school-aged children due to illness, painful procedures, unfamiliar environment, and separation from family. We incorporated picture books into PICU nursing care to explore the stress response in a school-aged child with compartment syndrome who was hospitalized in the PICU. Observation, interview and communication with the patient were used to assess her psychological reactions and emotional and behavioral responses to stress related to hospitalization and medical treatment. Autonomy and control were provided and strengthened by giving the patient choices and purposive life plans. Picture books were used to establish rapport and help the patient express her feelings, needs, and desires for parental love and company. This case report highlights the importance of nurses' awareness of children's stresses and needs during hospitalization in the PICU as well as the value of picture books or other age-appropriate tools for this patient population. PMID- 23729349 TI - Compensated cirrhosis, same outcomes no matter which continent. PMID- 23729350 TI - Utility of Ki-67, p53, Bcl-2, and Cox-2 biomarkers for low-grade endometrial cancer and disordered proliferative/benign hyperplastic endometrium by imprint cytology. AB - In this report, the authors examined the characteristic features of morphology and molecular biology of Ki-67, p53, Bcl-2, and cyclooxygenase-2 (Cox-2) immunocytochemistry in low-grade endometrioid endometrial carcinoma (LG-ENEC) and disordered proliferative (DP)/benign hyperplastic (BH) endometrium. We carried out a prospective study by collecting endometrial imprints from freshly resected uteri over a 20-month period and finally 104 patients were evaluated with endometrial cytology. We focused on LG-ENECs, as well as on BH endometrium and its precursor lesion, DP endometrium, firstly because of the overlapping cytomorphology of these pathologic entities and secondly because of the lack of agreement in the differential diagnosis of atypical hyperplasia from complex hyperplasia and well-differentiated endometrial carcinoma, even in curettage specimens. Ki-67 expression of LG-ENEC showed predominance in comparison with DP/BH endometrium. Furthermore, high levels of Bcl-2 (>50%) were expressed only in DP/BH endometrium. DP/BH endometrium was negative for p53 marker, except from two cases of BH endometrium. Cox-2 expression >=50% was found only in LG-ENECs. Using Ki-67, Bcl-2, p53, and Cox-2 markers, we managed to distinguish fully DP/BH endometrium from LG-ENEC. Higher Ki-67%/Bcl-2% rate and also higher Cox-2 expression were found in LG-ENEC cases with FIGO stage >= IC, than in cases with FIGO stage < IC. The immunocytochemical findings from a combination of Ki-67, p53, Bcl-2, and Cox-2, may differentiate LG-ENEC from DP/BH endometrium with overlapping cytomorphology. Immunocytochemistry appeared to be useful also for the correlation between LG-ENEC and FIGO stage. PMID- 23729351 TI - Characterization of the GGPP synthase gene family in Arabidopsis thaliana. AB - Geranylgeranyl diphosphate (GGPP) is a key precursor of various isoprenoids that have diverse functions in plant metabolism and development. The annotation of the Arabidopsis thaliana genome predicts 12 genes to encode geranylgeranyl diphosphate synthases (GGPPS). In this study we analyzed GGPPS activity as well as the subcellular localization and tissue-specific expression of the entire protein family in A. thaliana. GGPPS2 (At2g18620), GGPPS3 (At2g18640), GGPPS6 (At3g14530), GGPPS7 (At3g14550), GGPPS8 (At3g20160), GGPPS9 (At3g29430), GGPPS10 (At3g32040) and GGPPS11 (At4g36810) showed GGPPS activity in Escherichia coli, similar to activities reported earlier for GGPPS1 (At1g49530) and GGPPS4 (At2g23800) (Zhu et al. in Plant Cell Physiol 38(3):357-361, 1997a; Plant Mol Biol 35(3):331-341, b). GGPPS12 (At4g38460) did not produce GGPP in E. coli. Based on DNA sequence analysis we propose that GGPPS5 (At3g14510) is a pseudogene. GGPPS-GFP (green fluorescent protein) fusion proteins of the ten functional GGPP synthases localized to plastids, mitochondria and the endoplasmic reticulum, with the majority of the enzymes located in plastids. Gene expression analysis using quantitative real time-PCR, GGPPS promoter-GUS (beta glucuronidase) assays and publicly available microarray data revealed a differential spatio-temporal expression of GGPPS genes. The results suggest that plastids and mitochondria are key subcellular compartments for the synthesis of ubiquitous GGPP-derived isoprenoid species. GGPPS11 and GGPPS1 are the major isozymes responsible for their biosynthesis. All remaining paralogs, encoding six plastidial isozymes and two cytosolic isozymes, were expressed in specific tissues and/or at specific developmental stages, suggesting their role in developmentally regulated isoprenoid biosynthesis. Our results show that of the 12 predicted GGPPS encoded in the A. thaliana genome 10 are functional proteins that can synthesize GGPP. Their specific subcellular location and differential expression pattern suggest subfunctionalization in providing GGPP to specific tissues, developmental stages, or metabolic pathways. PMID- 23729352 TI - How can plant genetic engineering contribute to cost-effective fish vaccine development for promoting sustainable aquaculture? AB - Aquaculture, the fastest growing food-producing sector, now accounts for nearly 50 % of the world's food fish (FAO in The state of world fisheries and aquaculture. FAO, Rome, 2010). The global aquaculture production of food fish reached 62.7 million tonnes in 2011 and is continuously increasing with an estimated production of food fish of 66.5 million tonnes in 2012 (a 9.4 % increase in 1 year, FAO, www.fao.org/fishery/topic/16140 ). Aquaculture is not only important for sustainable protein-based food fish production but also for the aquaculture industry and economy worldwide. Disease prevention is the key issue to maintain a sustainable development of aquaculture. Widespread use of antibiotics in aquaculture has led to the development of antibiotic-resistant bacteria and the accumulation of antibiotics in the environment, resulting in water and soil pollution. Thus, vaccination is the most effective and environmentally-friendly approach to combat diseases in aquaculture to manage fish health. Furthermore, when compared to >760 vaccines against human diseases, there are only about 30 fish vaccines commercially available, suggesting the urgent need for development and cost-effective production of fish vaccines for managing fish health, especially in the fast growing fish farming in Asia where profit is minimal and therefore given high priority. Plant genetic engineering has made significant contributions to production of biotech crops for food, feed, valuable recombinant proteins etc. in the past three decades. The use of plants for vaccine production offers several advantages such as low cost, safety and easy scaling up. To date a large number of plant-derived vaccines, antibodies and therapeutic proteins have been produced for human health, of which a few have been made commercially available. However, the development of animal vaccines in plants, especially fish vaccines by genetic engineering, has not yet been addressed. Therefore, there is a need to exploit plant biotechnology for cost effective fish vaccine development in plants, in particular, edible crops for oral fish vaccines. This review provides insight into (1) the current status of fish vaccine and vaccination in aquaculture, (2) plant biotechnology and edible crops for fish vaccines for oral administration, (3) regulatory constraints and (4) conclusions and future perspectives. PMID- 23729353 TI - Fistulotomy or seton in anal fistula: a decisional algorithm. AB - Fistula in ano is a common proctological disease. Several authors stated that internal and external anal sphincters preservation is in the interest of continence maintenance. The aim of the present study is to report our experience using a decisional algorithm on sphincter saving procedures that achieved us to obtain good results with low rate of complications. From 2008 to 2011, 206 patients underwent surgical treatment for anal fistula; 28 patients underwent perianal abscess drainage plus seton placement of trans-sphincteric or supra sphincteric fistula (13.6 %), 41 patients underwent fistulotomy for submucosal or low inter-sphincteric or low trans-sphincteric anal fistula (19.9 %) and 137 patients underwent partial fistulectomy or partial fistulotomy (from cutaneous plan to external sphincter muscle plan) and cutting seton placement without internal sphincterotomy for trans-sphincteric anal fistula (66.50 %). Healing rates have been of 100 % and healing times ranged from 1 to 6 months in 97 % of patients treated by setons. Transient fecal soiling was reported by 19 patients affected by trans-sphincteric fistula (11.5 %) for 4-6 months and then disappeared or evolved in a milder form of flatus occasional incontinence. No major incontinence has been reported also after fistulotomy. Fistula recurred in five cases of trans-sphincteric fistula treated by seton placement (one with abscess) (1/28) (3.5 %) and four with trans-sphincteric fistula (4/137) (3 %). Our algorithm permitted us to reduce to 20 % sphincter cutting procedures without reporting postoperative major anal incontinence; it seems to open an interesting way in the treatment of anal fistula. PMID- 23729354 TI - A cyclic silylone ("siladicarbene") with an electron-rich silicon(0) atom. PMID- 23729355 TI - Hispanic ethnicity and acculturation, maternal age and the risk of gastroschisis in the National Birth Defects Prevention Study. AB - Studies indicate that gastroschisis is associated with maternal age, ethnicity, and acculturation. This analysis was conducted to further define the associations between gastroschisis and parental Hispanic ethnicity and acculturation, and to determine whether such associations vary by maternal age. METHODS: This study was based on data from mothers of 753 gastroschisis cases and 6,496 control infants in the National Birth Defects Prevention Study. The relationships between gastroschisis and both parental Hispanic ethnicity and acculturation, within maternal age strata (<20 versus >=20 years at conception), were assessed using logistic regression and principal component analyses. RESULTS: The risk of gastroschisis in offspring of women <20 years old was not significantly associated with parental Hispanic ethnicity or acculturation. Among mothers >=20 years old, US-born non-Hispanic white parents had a lower risk of gastroschisis in offspring as compared to either US-born Hispanic (odds ratios [ORs] ranging from 0.55 to 0.60) or English-speaking Hispanic (ORs ranging from 0.58 to 0.65) parents. Further, compared with US born Hispanic women >=20 years, the risk of gastroschisis was lower for Hispanic women who had lived in the US <5 years (OR=0.35, 95% confidence interval [CI]: 0.17, 0.74) or who migrated to the US at >=20 years (OR=0.47, 95% CI: 0.25, 0.88). CONCLUSION: These results provide further evidence that gastroschisis risk is associated with ethnicity and some aspects of acculturation. Additionally, these associations were limited to the offspring of women who are >=20 at the time of conception. PMID- 23729356 TI - Safety and one year outcomes following vaginally assisted laparoscopic uterine sacropexy (VALUES) for advanced uterine prolapse. AB - AIMS: To assess the safety and outcomes of vaginally assisted laparoscopic uterine sacropexy (VALUES) as a surgical treatment for stage 3 and 4 uterine prolapse. METHODS: Seventy consecutive women with stage 3 and 4 uterine prolapse who underwent VALUES over 2-year period were prospectively evaluated. Women filled the Prolapse Quality of Life Questionnaire (P-QOL), and underwent examination using pelvic organ prolapse quantification system (POP-Q) pre- and post-operatively. In addition, patients filled the patient global impression of improvement questionnaire post-operatively. Mesh related complications were evaluated post-operatively. Patients were followed up at 3 and 12 months following surgery. This study reports the 12 months outcomes. RESULTS: Sixty-four women (91.4%) reported cure of their prolapse symptoms. On examination, 67 women (95.7%) had POP-Q stage 0 or 1 uterine support at 12 months. Six women needed further surgical intervention for prolapse (8.5%); three women developed recurrent uterine prolapse and three other women developed symptomatic recurrent anterior vaginal wall prolapse. The total vaginal length was not different between the pre- and post-operative periods. Two patients developed mesh related complications. Significant improvement was noted in prolapse symptoms and quality of life. CONCLUSIONS: VALUES is a safe and effective treatment for women with stage 3 and 4 uterine prolapse up to 12 months without the risk of vaginal shortening. Long-term results are needed to fully establish the value of this technique. PMID- 23729357 TI - Efficacy of stapler pharyngeal closure after total laryngectomy: A systematic review. AB - BACKGROUND: Some primary studies compare manual and mechanical pharyngeal closures after total laryngectomy. The purpose of this study was to evaluate the advantages of the mechanical suture in pharyngeal closure. METHODS: The literature survey included research in MEDLINE, EMBASE, and LILACS. The intervention analyzed was stapler-assisted pharyngeal closure, whereas the control group was manual suture pharyngeal closure. RESULTS: The survey resulted in 319 studies. However, 4 studies were selected (417 patients). In the group of patients in whom the stapler was used, the incidence of pharyngocutaneous fistula was 8.7%, whereas in the other, it was 22.9%, with an absolute risk reduction of 15% (95% confidence interval [CI], 0.02-0.28; p = .02; I(2) = 66%). Regarding the surgical time, the average difference was 80 minutes in favor of the stapler group (95% CI, 23.16-136.58 minutes; p < .006). CONCLUSION: The difference for starting oral feeding was 8 days in favor of the mechanical suture (95% CI, 4.01 11.73 days; p < .001). Patients who underwent mechanical suture had a shorter hospitalization period. PMID- 23729359 TI - Increased efficacies in magnetofection and gene delivery to hepatocellular carcinoma cells with ternary organic-inorganic hybrid nanocomposites. PMID- 23729358 TI - Cancer-generated lactic acid: a regulatory, immunosuppressive metabolite? AB - The common preference of cancers for lactic acid-generating metabolic energy pathways has led to proposals that their reprogrammed metabolism confers growth advantages such as decreased susceptibility to hypoxic stress. Recent observations, however, suggest that it generates a novel way for cancer survival. There is increasing evidence that cancers can escape immune destruction by suppressing the anti-cancer immune response through maintaining a relatively low pH in their micro-environment. Tumours achieve this by regulating lactic acid secretion via modification of glucose/glutamine metabolisms. We propose that the maintenance by cancers of a relatively low pH in their micro-environment, via regulation of their lactic acid secretion through selective modification of their energy metabolism, is another major mechanism by which cancers can suppress the anti-cancer immune response. Cancer-generated lactic acid could thus be viewed as a critical, immunosuppressive metabolite in the tumour micro-environment rather than a 'waste product'. This paradigm shift can have major impact on therapeutic strategy development. PMID- 23729360 TI - Super-radical surgery for anaplastic thyroid carcinoma: a large cohort study using the Anaplastic Thyroid Carcinoma Research Consortium of Japan database. AB - BACKGROUND: The consequences of super-radical resection in patients with anaplastic thyroid carcinoma (ATC) have not been fully investigated. METHODS: This retrospective study used the multicenter ATC Research Consortium of Japan database. Among 233 stage IVB patients, 23 underwent super-radical resection (group S). Outcomes for group S were compared to those for patients with restricted curative surgery (group R; n = 49), palliative surgery (group P; n = 72) or no surgery (group N; n = 80). RESULTS: One-year cause-specific survival rate for group S was 33%. It was identical to group R (p = .94) and significantly better than groups N and P (p = .0065). Permanent tracheostomy was significantly more frequent in group S than in other groups, but only 5 patients died directly from local disease. CONCLUSIONS: Radical resection offers significantly better outcomes than limited surgery. Super-radical procedures may be indicated in select patients to avoid mortality due to locally uncontrolled disease at the expense of tracheostomy. PMID- 23729362 TI - Inhibition of GSK3B bypass drug resistance of p53-null colon carcinomas by enabling necroptosis in response to chemotherapy. AB - PURPOSE: Evasion from chemotherapy-induced apoptosis due to p53 loss strongly contributes to drug resistance. Identification of specific targets for the treatment of drug-resistant p53-null tumors would therefore increase the effectiveness of cancer therapy. EXPERIMENTAL DESIGN: By using a kinase-directed short hairpin RNA library and HCT116p53KO drug-resistant colon carcinoma cells, glycogen synthase kinase 3 beta (GSK3B) was identified as a target whose silencing bypasses drug resistance due to loss of p53. p53-null colon cancer cell lines with different sets of mutations were used to validate the role of GSK3B in sustaining resistance and to characterize cell death mechanisms triggered by chemotherapy when GSK3B is silenced. In vivo xenograft studies were conducted to confirm resensitization of drug-resistant cells to chemotherapy upon GSK3 inhibition. Colon cancer samples from a cohort of 50 chemotherapy-treated stage II patients were analyzed for active GSK3B expression. RESULTS: Downregulation of GSK3B in various drug-resistant p53-null colon cancer cell lines abolished cell viability and colony growth after drug addition without affecting cell proliferation or cell cycle in untreated cells. Cell death of 5-fluorouracil (5FU)-treated p53-null GSK3B-silenced colon carcinoma cells occurred via PARP1 dependent and AIF-mediated but RIP1-independent necroptosis. In vivo studies showed that drug-resistant xenograft tumor mass was significantly reduced only when 5FU was given after GSK3B inhibition. Tissue microarray analysis of colon carcinoma samples from 5FU-treated patients revealed that GSK3B is significantly more activated in drug-resistant versus responsive patients. CONCLUSIONS: Targeting GSK3B, in combination with chemotherapy, may represent a novel strategy for the treatment of chemotherapy-resistant tumors. PMID- 23729361 TI - ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer. AB - PURPOSE: Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of non-small cell lung cancer (NSCLC). Recently, several case reports and small series have reported that ALK rearrangements can overlap with other oncogenic drivers in NSCLC in crizotinib-naive and crizotinib-resistant cancers. EXPERIMENTAL DESIGN: We reviewed clinical genotyping data from 1,683 patients with NSCLC and investigated the prevalence of concomitant EGFR or KRAS mutations among patients with ALK-positive NSCLC. We also examined biopsy specimens from 34 patients with ALK-positive NSCLC after the development of resistance to crizotinib. RESULTS: Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. Four patients with KRAS mutations were found to have abnormal ALK FISH patterns, most commonly involving isolated 5' green probes. Sufficient tissue was available for confirmatory ALK immunohistochemistry in 3 cases, all of which were negative for ALK expression. Among patients with ALK-positive NSCLC who acquired resistance to crizotinib, repeat biopsy specimens were ALK FISH positive in 29 of 29 (100%) cases. Secondary mutations in the ALK kinase domain and ALK gene amplification were observed in 7 of 34 (20.6%) and 3 of 29 (10.3%) cases, respectively. No EGFR or KRAS mutations were identified among any of the 25 crizotinib-resistant, ALK positive patients with sufficient tissue for testing. CONCLUSIONS: Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK positive cancers with acquired resistance to crizotinib. PMID- 23729363 TI - Spinophilin loss correlates with poor patient prognosis in advanced stages of colon carcinoma. AB - PURPOSE: The genomic region 17q21 is frequently associated with microsatellite instability and LOH in cancer, including gastric and colorectal carcinomas. This region contains several putative tumor suppressor genes, including Brca1, NM23, prohibitin, and spinophilin (Spn, PPP1R9B, neurabin II). The scaffold protein Spn is one of the regulatory subunits of phosphatase-1 (PP1) that targets PP1 to distinct subcellular locations and couples PP1 to its target. Thus, Spn may alter cell-cycle progression via the regulation of the phosphorylation status of the retinoblastoma protein, a direct target of PP1. Therefore, we analyzed whether Spn levels were reduced in colorectal carcinomas and whether Spn levels correlated with prognosis or response to therapy. EXPERIMENTAL DESIGN: By means of immunohistochemistry or quantitative PCR, we studied the levels of Spn in stages II, III, and IV colorectal carcinoma tumors and correlated to other clinicopathologic features as well as prognosis or response to therapy. RESULTS: Spn was lost in a percentage of human gastric, small intestine, and colorectal carcinomas. In patients with colorectal carcinoma, tumoral Spn downregulation correlated with a more aggressive histologic phenotype (poorer tumor differentiation and higher proliferative Ki67 index). Consistent with this observation, lower Spn protein expression levels were associated with faster relapse and poorer survival in patients with stage III colorectal carcinoma, particularly among those receiving adjuvant fluoropyrimidine therapy. We validated this result in an independent cohort of patients with metastatic colorectal carcinoma treated with standard chemotherapy. Although patients that achieved an objective tumor response exhibited Spn levels similar to nontumoral tissue, nonresponding patients showed a significant reduction in Spn mRNA levels. CONCLUSIONS: Our data suggest that Spn downregulation contributes to a more aggressive biologic behavior, induces chemoresistance, and is associated with a poorer survival in patients with advanced stages of colorectal carcinoma. PMID- 23729364 TI - Temporal and spatial evolution of therapy-induced tumor apoptosis detected by caspase-3-selective molecular imaging. AB - PURPOSE: Induction of apoptosis in tumors is considered a desired goal of anticancer therapy. We investigated whether the dynamic temporal and spatial evolution of apoptosis in response to cytotoxic and mechanism-based therapeutics could be detected noninvasively by the caspase-3 radiotracer [(18)F]ICMT-11 and positron emission tomography (PET). EXPERIMENTAL DESIGN: The effects of a single dose of the alkylating agent cyclophosphamide (CPA or 4 hydroperoxycyclophosphamide), or the mechanism-based small molecule SMAC mimetic birinapant on caspase-3 activation was assessed in vitro and by [(18)F]ICMT-11 PET in mice bearing 38C13 B-cell lymphoma, HCT116 colon carcinoma, or MDA-MB-231 breast adenocarcinoma tumors. Ex vivo analysis of caspase-3 was compared to the in vivo PET imaging data. RESULTS: Drug treatment increased the mean [(18)F]ICMT 11 tumor uptake with a peak at 24 hours for CPA (40 mg/kg; AUC40-60: 8.04 +/- 1.33 and 16.05 +/- 3.35 %ID/mL * min at baseline and 24 hours, respectively) and 6 hours for birinapant (15 mg/kg; AUC40-60: 20.29 +/- 0.82 and 31.07 +/- 5.66 %ID/mL * min, at baseline and 6 hours, respectively). Voxel-based spatiotemporal analysis of tumor-intrinsic heterogeneity suggested that discrete pockets of caspase-3 activation could be detected by [(18)F]ICMT-11. Increased tumor [(18)F]ICMT-11 uptake was associated with caspase-3 activation measured ex vivo, and early radiotracer uptake predicted apoptosis, distinct from the glucose metabolism with [(18)F]fluorodeoxyglucose-PET, which depicted continuous loss of cell viability. CONCLUSION: The proapoptotic effects of CPA and birinapant resulted in a time-dependent increase in [(18)F]ICMT-11 uptake detected by PET. [(18)F]ICMT-11-PET holds promise as a noninvasive pharmacodynamic biomarker of caspase-3-associated apoptosis in tumors. PMID- 23729365 TI - Cp*Co(III)-catalyzed C2-selective addition of indoles to imines. PMID- 23729366 TI - CCN2: a mechanosignaling sensor modulating integrin-dependent connective tissue remodeling in fibroblasts? AB - Tensegrity (tensional integrity) is an emerging concept governing the structure of the body. Integrin-mediated mechanical tension is essential for connective tissue function in vivo. For example, in adult skin fibroblasts, the integrin beta1 subunit mediates adhesion to collagen and fibronectin. Moreover, integrin beta1, through its abilities to activate latent TGFbeta1 and promote collagen production through focal adhesion kinase/rac1/nicotinamide adenine dinucleotide phosphate oxidase (NOX)/reactive oxygen species (ROS), is essential for dermal homeostasis, repair and fibrosis. The integrin beta1-interacting protein CCN2, a member of the CCN family of proteins, is induced by TGFbeta1; yet, CCN2 is not a simple downstream mediator of TGFbeta1, but instead synergistically promote TGFbeta1-induced adhesive signaling and fibrosis. Due to its selective ability to sense mechanical forces in the microenvironment, CCN2 may represent an exquisitely precise target for therapeutic intervention. PMID- 23729367 TI - Exacerbation and remission of pulmonary micronodules with lymphangioleiomyomatosis around the time of childbirth. AB - We present a case of multifocal micronodular pneumocyte hyperplasia (MMPH), lymphangiomyomatosis (LAM) and angiomyolipoma (AML) in a 33-year-old woman with tuberous sclerosis complex referred to us during her first pregnancy. Computed tomography of the chest showed diffuse micronodules and cysts in both lungs. Compared to those before pregnancy, the number of micronodules increased evidently. We hypothesized the micronodules in both lungs were either LAM, MMPH, or a combination of the two. Bilateral renal AML also intensified. About one month after childbirth, LAM and renal AML decreased without treatment. Therefore, we observed that LAM and AML were affected by the pregnancy. To the best of our knowledge, this is the first case report regarding the reversible alteration of LAM without treatment. PMID- 23729368 TI - Dendritic and lymphocytic cell infiltration in prostate carcinoma. AB - We examined the distribution of CD1a+ cells and CD8+ and CD4+ T lymphocytes in prostate cancer (PCa) and correlated these with clinicopathological parameters. We also investigated whether the distribution of these cells was related to the expression of the cell membrane protein B7-H3, a putative negative regulator of the immune response expressed on PCa cells. A cohort of 151 PCa patients treated with radical prostatectomy (RP) was followed prospectively from 1985 until 2006 with a median follow-up of 9 years. Whole-mount sections of PCa specimens were immunostained to identify immune cells. A low number of CD1a+ cells was significantly associated with a high Gleason score and high pathological stage of pT3. The number of CD1a+ cells correlated significantly with the number of intratumoral and stromal CD8+ and stromal CD4+ lymphocytes. Kaplan-Meier analysis showed a tendency toward impaired biochemical progression-free survival in patients with few CD1a+ cells within their RP specimens. The expression of B7-H3 correlated inversely with the number of CD1a+ cells and intratumoral CD4+ lymphocytes; there was a trend for a similar inverse relationship between B7-H3 expression and the number of CD8+ lymphocytes. PMID- 23729369 TI - Recognizing breast ductal carcinoma in situ on fine-needle aspiration: a diagnostic dilemma. AB - In this study, we evaluated cytomorphologic features of different subgroups of ductal carcinoma in situ (DCIS); we compared seven cytologic features between DCIS and invasive ductal carcinoma (IDC) aspirates to determine whether diagnosis of stromal invasion can be made based on fine-needle aspiration (FNA) findings. There were 142 cases of DCIS and 1,978 cases of IDC enrolled in our study. FNA analysis revealed 80.3% sensitivity for DCIS and 94.7% sensitivity for IDC. High and intermediate grade DCIS exhibited marked nuclear abnormality (92.1% vs. 35.7%, 30.0%; P1 < 0.001, P2 < 0.001) and necrosis (69.7% vs. 0%, 10.0%; P1 < 0.001, P2 = 0.001) in a higher percentage of cases compared to low grade DCIS and intraductal/intracystic papillary carcinoma. The rates of background macrophages (71.3% for DCIS and 21.9% for IDC, P < 0.001) and extensive necrosis (54.0% for DCIS and 16.7% for IDC, P < 0.001) were significantly higher in DCIS compared to IDC. Lymphocytes were observed in conjunction with tumor cells more frequently in IDC (81.3%) compared to DCIS (36.8%, P < 0.001). Stromal fragments associated with tumor cells were only observed in invasive lesions (11.9% micro-invasive DCIS and 52.1% IDC). Tubular structures were found exclusively in IDC (11.5%). Cytologic criteria for diagnosis of high and low grade DCIS are different. The suspicion of DCIS is raised when background macrophages and extensive necrosis are observed. Stromal invasion is suggested by FNA if lymphocytes are entwined around tumor cells or if stromal fragments associated with tumor cells or tubular structures are observed. PMID- 23729370 TI - Formation of a Pt12 cluster by single-atom control that leads to enhanced reactivity: hydrogenation of unreactive olefins. AB - A platinum subnanocluster catalyst composed of 12 atoms was synthesized using a phenylazomethine dendrimer, which can assemble twelve PtCl4 units by stepwise complexation, followed by reduction to Pt(0). Unreactive olefins that were not activated by conventional 2 nm Pt nanoparticles were successfully hydrogenated by the subnanocluster. EWG = electron-withdrawing group. PMID- 23729371 TI - The anti-melanoma efficiency of the intratumoral injection of cucurbitacin-loaded sustained-release carriers: a PLGA particle system. AB - A dilemma for current cancer therapy is surgical injury in addition to the toxicities and inefficiencies of systemic chemotherapy. Meanwhile, localized therapies have become a noticeable strategy. In this study, Cucurbitacin (Cuc) loaded poly(lactic-co-glycolic acid) particles of different sizes (about 50 MUm, 5 MUm, and 270 nm, respectively) were prepared as the sustained-release system for intratumoral injection, and their physicochemical properties, in vitro cytotoxicity, particles-cells interactions, pharmacokinetics, and pharmacodynamics were systemically investigated for the first time. The results of cytotoxicity experiments and pharmacokinetic/pharmacodynamic studies indicated that the release patterns of the particles would strongly affect the biological efficiency not only at the cell level but also in two types of animal models. Cuc raw material and nanoparticles showed higher initial burst release in vitro, and higher drug concentration in tumor and plasma. Large particles (about 50 MUm) showed lower initial burst and slow drug release, which would not supply enough amount of drug to inhibit the cancer cell growth during the whole treatment period. Particles with mean diameter of about 5 MUm performed the best anti melanoma efficiency both in vitro and in vivo. The release patterns, instead of the particles-cells interactions, would be the key factors to affect the biological effects of the particulate system for intratumoral injection. PMID- 23729372 TI - Children and adults with thrombotic thrombocytopenic purpura associated with severe, acquired Adamts13 deficiency: comparison of incidence, demographic and clinical features. AB - BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) associated with severe, acquired ADAMTS13 deficiency is uncommonly reported in children. The incidence, demographic, and clinical features of these children, compared to adults, have not been described. PROCEDURES: This study focused on children (<18 years old) and adults with TTP associated with severe, acquired ADAMTS13 deficiency, defined as activity <10%. The incidence rates for TTP in children and adults were calculated from patients enrolled in the Oklahoma TTP-HUS (Hemolytic-Uremic syndrome) Registry, 1996-2012. To describe demographic and clinical features, children with TTP were also identified from a systematic review of published reports and from samples sent to a reference laboratory for analysis of ADAMTS13. RESULTS: The standardized annual incidence rate of TTP in children was 0.09 * 10(6) children per year, 3% of the incidence rate among adults (2.88 * 10(6) adults per year). Among the 79 children who were identified (one from the Oklahoma Registry, 55 from published reports, 23 from the reference laboratory), TTP appeared to be more common among females, similar to the relative increased frequency of women among adults with TTP, and more common in older children. Clinical data were available on 52 children; the frequency of severe renal failure, relapse, treatment with rituximab, and systemic lupus erythematosus in these children was similar to adults with TTP. CONCLUSIONS: TTP associated with severe, acquired ADAMTS13 deficiency is uncommon in children. The demographic and clinical features of these children are similar to the features of adults with TTP. PMID- 23729373 TI - A 76-year-old woman with diaphoresis and anxiety. PMID- 23729374 TI - Preoperative 18F-FDG PET/CT and high-risk HPV in patients with oropharyngeal squamous cell carcinoma. AB - BACKGROUND: To evaluate the association of (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG PET/CT) and high-risk human papillomavirus (HPV) status and to establish the histologic correlates in oropharyngeal cancer (OPSCC). METHOD: The medical records of 78 patients who underwent (18)F-FDG PET/CT for OPSCC before surgery were reviewed. RESULTS: The positive rate of high risk HPV in situ hybridization was 36% (28 of 78). The maximum standardized uptake values (SUVmax ) of negativity for the high-risk HPV subtypes (10.29 +/- 4.30) and positivity (6.69 +/- 4.17) were found to be significantly different (p = .001). The SUVmax cutoff value for differentiating negativity for the high-risk HPV subtypes from positivity was 7.10, with the sensitivity of 78% and the specificity of 68%. A median SUVmax (using 7.10 as a cutoff) (p = .041) and high risk HPV status (p = .040) were found to be associated with 5-year disease specific survival (DSS). CONCLUSIONS: Median (18)F-FDG PET/CT SUVmax cutoff values 7.10 or greater are associated with a high-risk HPV negativity in OPSCC patients. PMID- 23729375 TI - What is male LUTS? PMID- 23729376 TI - Interleukin-22 serum levels are a negative prognostic indicator in patients with hepatocellular carcinoma. PMID- 23729377 TI - Primary intraocular ancient schwannoma: a case report and review of the literature. AB - BACKGROUND: Schwannomas comprise 8% to 10% of all primary intracranial tumors. Primary intraorbital schwannomas are rare, accounting for 1% to 2% of all intracranial tumors. Schwannomas arise from Schwann cells in the myelin sheaths of sensory and cranial nerves. METHODS: We present the case of a 56-year-old white man blind since 1970 who presented to an outside hospital for a painful right eye. Physicians identified no clinical or radiologic features of neurofibromatosis. RESULTS: The patient underwent enucleation; the final pathologic diagnosis was ancient schwannoma. CONCLUSION: We describe herein a case of intrascleral schwannoma with ancient changes arising within the globe of the right eye occupying the subretinal space and completely replacing the vitreous body. PMID- 23729379 TI - Conformation-controlled electron transport in single-molecule junctions containing oligo(phenylene ethynylene) derivatives. AB - Understanding the relationships between the molecular structure and electronic transport characteristics of single-molecule junctions is of fundamental and technological importance for future molecular electronics. Herein, we report a combined experimental and theoretical study on the single-molecule conductance of a series of oligo(phenylene ethynylene) (OPE) molecular wires, which consist of two phenyl-ethynyl-phenyl pi units with different dihedral angles. The molecular conductance was studied by scanning tunneling microscopy (STM)-based break junction techniques under different conditions, including variable temperature and bias potential, which suggested that a coherent tunneling mechanism takes place in the OPE molecular wires with a length of 2.5 nm. The conductance of OPE molecular junctions are strongly affected by the coupling strength between the two pi systems, which can be tuned by controlling their intramolecular conformation. A cos(2)theta dependence was revealed between the molecular conductance and dihedral angles between the two conjugated units. Theoretical investigations on the basis of density functional theory and nonequilibrium Green's functions (NEGF) gave consistent results with the experimental observations and provided insights into the conformation-dominated molecular conductance. PMID- 23729378 TI - Quantification of human high-energy phosphate metabolite concentrations at 3 T with partial volume and sensitivity corrections. AB - Practical noninvasive methods for the measurement of absolute metabolite concentrations are key to the assessment of the depletion of myocardial metabolite pools which occurs with several cardiac diseases, including infarction and heart failure. Localized MRS offers unique noninvasive access to many metabolites, but is often confounded by nonuniform sensitivity and partial volume effects in the large, poorly defined voxels commonly used for the detection of low-concentration metabolites with surface coils. These problems are exacerbated at higher magnetic field strengths by greater radiofrequency (RF) field inhomogeneity and differences in RF penetration with heteronuclear concentration referencing. An example is the (31)P measurement of cardiac adenosine triphosphate (ATP) and phosphocreatine (PCr) concentrations, which, although central to cardiac energetics, have not been measured at field strengths above 1.5 T. Here, practical acquisition and analysis protocols are presented for the quantification of [PCr] and [ATP] with one-dimensionally resolved surface coil spectra and concentration referencing at 3 T. The effects of nonuniform sensitivity and partial tissue volumes are addressed at 3 T by the application of MRI-based three-dimensional sensitivity weighting and tissue segmentation. The method is validated in phantoms of different sizes and concentrations, and used to measure [PCr] and [ATP] in healthy subjects. In calf muscle (n = 8), [PCr] = 24.7 +/- 3.4 and [ATP] = 5.7 +/- 1.3 umol/g wet weight, whereas, in heart (n = 18), [PCr] = 10.4 +/- 1.5 and [ATP] = 6.0 +/- 1.1 umol/g wet weight (all mean +/- SD), consistent with previous reports at lower fields. The method enables, for the first time, the efficient, semi-automated quantification of high-energy phosphate metabolites in humans at 3 T with nonuniform excitation and detection. PMID- 23729380 TI - Case report: different metastatic components from anaplastic thyroid carcinoma in mediastinal and neck lymph nodes simultaneously diagnosed by FNA. AB - Anaplastic thyroid carcinoma (ATC) is a rare but aggressive form of undifferentiated thyroid carcinoma which arises from previously well differentiated thyroid carcinomas, such as papillary carcinoma or follicular carcinoma. We report on an interesting case of ATC found in an enlarging neck mass with metastatic papillary carcinoma found in mediastinal lymph nodes sampled by endoscopic bronchial-ultrasound guided- fine-needle aspiration, due to the incidental finding of a lung mass by CT scan. Divergent morphologies on cytology preparations were resolved by immunohistochemistry, which aided in the identification of both sites of malignancy and the common thread between them. The eventual palliative resection demonstrated the various components including undifferentiated thyroid carcinoma, papillary carcinoma, and background lymphocytic thyroiditis. PMID- 23729381 TI - Epidermal biofuel cells: energy harvesting from human perspiration. PMID- 23729382 TI - ADF/cofilin is not essential but is critically important for actin activities during phagocytosis in Tetrahymena thermophila. AB - ADF/cofilin is a highly conserved actin-modulating protein. Reorganization of the actin cytoskeleton in vivo through severing and depolymerizing of F-actin by this protein is essential for various cellular events, such as endocytosis, phagocytosis, cytokinesis, and cell migration. We show that in the ciliate Tetrahymena thermophila, the ADF/cofilin homologue Adf73p associates with actin on nascent food vacuoles. Overexpression of Adf73p disrupted the proper localization of actin and inhibited the formation of food vacuoles. In vitro, recombinant Adf73p promoted the depolymerization of filaments made of T. thermophila actin (Act1p). Knockout cells lacking the ADF73 gene are viable but grow extremely slowly and have a severely decreased rate of food vacuole formation. Knockout cells have abnormal aggregates of actin in the cytoplasm. Surprisingly, unlike the case in animals and yeasts, in Tetrahymena, ADF/cofilin is not required for cytokinesis. Thus, the Tetrahymena model shows promise for future studies of the role of ADF/cofilin in vivo. PMID- 23729383 TI - Fungus-specific sirtuin HstD coordinates secondary metabolism and development through control of LaeA. AB - The sirtuins are members of the NAD(+)-dependent histone deacetylase family that contribute to various cellular functions that affect aging, disease, and cancer development in metazoans. However, the physiological roles of the fungus-specific sirtuin family are still poorly understood. Here, we determined a novel function of the fungus-specific sirtuin HstD/Aspergillus oryzae Hst4 (AoHst4), which is a homolog of Hst4 in A. oryzae yeast. The deletion of all histone deacetylases in A. oryzae demonstrated that the fungus-specific sirtuin HstD/AoHst4 is required for the coordination of fungal development and secondary metabolite production. We also show that the expression of the laeA gene, which is the most studied fungus-specific coordinator for the regulation of secondary metabolism and fungal development, was induced in a DeltahstD strain. Genetic interaction analysis of hstD/Aohst4 and laeA clearly indicated that HstD/AoHst4 works upstream of LaeA to coordinate secondary metabolism and fungal development. The hstD/Aohst4 and laeA genes are fungus specific but conserved in the vast family of filamentous fungi. Thus, we conclude that the fungus-specific sirtuin HstD/AoHst4 coordinates fungal development and secondary metabolism via the regulation of LaeA in filamentous fungi. PMID- 23729384 TI - The plasma membrane proton pump PMA-1 is incorporated into distal parts of the hyphae independently of the Spitzenkorper in Neurospora crassa. AB - Most models for fungal growth have proposed a directional traffic of secretory vesicles to the hyphal apex, where they temporarily aggregate at the Spitzenkorper before they fuse with the plasma membrane (PM). The PM H(+) translocating ATPase (PMA-1) is delivered via the classical secretory pathway (endoplasmic reticulum [ER] to Golgi) to the cell surface, where it pumps H(+) out of the cell, generating a large electrochemical gradient that supplies energy to H(+)-coupled nutrient uptake systems. To characterize the traffic and delivery of PMA-1 during hyphal elongation, we have analyzed by laser scanning confocal microscopy (LSCM) strains of Neurospora crassa expressing green fluorescent protein (GFP)-tagged versions of the protein. In conidia, PMA-1-GFP was evenly distributed at the PM. During germination and germ tube elongation, PMA-1-GFP was found all around the conidial PM and extended to the germ tube PM, but fluorescence was less intense or almost absent at the tip. Together, the data indicate that the electrochemical gradient driving apical nutrient uptake is generated from early developmental stages. In mature hyphae, PMA-1-GFP localized at the PM at distal regions (>120 MUm) and in completely developed septa, but not at the tip, indicative of a distinct secretory route independent of the Spitzenkorper occurring behind the apex. PMID- 23729385 TI - Prognostic impact of atrial fibrillation occurrence in patients with non-ST elevation acute coronary syndromes: is dysrhythmia duration a parameter to focus on? AB - Several studies have evaluated the prognostic impact of atrial fibrillation (AF) in ST-elevation myocardial infarction (STEMI) patients, but scarce data are available on the role of AF in non-ST-elevation acute coronary syndromes (NSTE ACS). The aim of this study was to investigate long-term outcome of NSTE-ACS patients experiencing an episode of AF during in-hospital course. Of 1,147 NSTE ACS patients, 54.4% for non-STEMI (NSTEMI) and 45.6% for unstable angina, 65 (5.7%) had an episode of AF. Long-term survival was compared with that of 1,082 NSTE-ACS patients who did not develop AF. Patients who developed AF, with respect to those who did not, were older and more frequently with NSTEMI at admission (69.2 vs. 53.5%, p = 0.013), diabetes, dyslipidemia and history of heart failure. Moreover, patients who developed AF had a significantly higher New York Heart Association class and lower values of glomerular filtration rate. During a median follow-up of 40.7 months, we observed a significantly higher mortality in NSTE ACS patients who developed AF versus those who did not (42.2 vs. 19.8%, p < 0.001). AF occurrence in NSTE-ACS was a significant predictor of mortality at Cox regression (adjusted HR: 1.85; p = 0.03). After propensity score analysis, only patients with AF duration >6 h showed a significantly higher mortality at Cox regression (p = 0.021). Our results suggest that NSTE-ACS patients who develop AF are characterized by a higher clinical complexity. The occurrence of AF, when longer than 6 h, represents an important negative prognostic factor for long-term survival. PMID- 23729387 TI - Tonsillar cancer: the Peter MacCallum experience with unilateral and bilateral irradiation. AB - BACKGROUND: The primary purpose of this study was to review the efficacy of unilateral treatment of lateralized tonsil primaries, in particular whether laterality of the primary is a more powerful determinant of contralateral neck failure than advanced ipsilateral nodal classification. METHODS: A retrospective study of all patients with tonsillar cancer treated with curative intent between January 1990 and December 2002 was performed. RESULTS: There were 167 patients, 76% men, median age 58 years, 86% current or ex-smokers. The majority of patients (58%) had stage IV disease. Five-year local, nodal, locoregional, and distant failure rates were 14%, 4%, 18%, and 8%, respectively. Of the 58 patients treated unilaterally, 33% had N2a, N2b, or N3 nodal disease. There were no contralateral nodal failures in the unilaterally treated group. CONCLUSION: These results support the potential use of unilateral radiation therapy (RT) for lateralized tonsil primaries even with advanced ipsilateral nodal disease. PMID- 23729388 TI - Constitutional mismatch repair deficiency presenting in childhood as three simultaneous malignancies. AB - A 13-year-old child presented with three simultaneous malignancies: glioblastoma multiforme, Burkitt lymphoma, and colonic adenocarcinoma. She was treated for her diseases without success and died 8 months after presentation. Genetic analysis revealed a homozygous mutation in the PMS2 gene, consistent with constitutional mismatch repair deficiency. Her siblings and parents were screened: three of four siblings and both parents were heterozygous for this mutation; the fourth sibling did not have the mutation. PMID- 23729389 TI - Cynomolgus monkey gallbladder bile contains high concentrations of fibroblast growth factor 19. PMID- 23729390 TI - Autoimmune thyroiditis in benign and malignant thyroid nodules: 16-year results. AB - BACKGROUND: It is controversial whether autoimmune thyroiditis is associated with higher frequency of papillary thyroid carcinoma (PTC). METHODS: This was a cross sectional, retrospective study. PTCs were compared to benign nodules regarding the prevalence of autoimmune thyroiditis over 16 years. RESULTS: A similar proportion of autoimmune thyroiditis was observed in both benign and/or malignant nodules. Mean nodule size in cases with autoimmune thyroiditis was smaller than those without autoimmune thyroiditis. Multivariate analysis showed a negative association between the coexistence of autoimmune thyroiditis and lymph node and/or distant metastases. Lymph nodes involvement and distant metastases were lower in the PTC with autoimmune thyroiditis compared to those without autoimmune thyroiditis. Capsular invasion was a strong predictor for distant metastases attenuated by the presence of autoimmune thyroiditis. CONCLUSION: Thyroid nodules with autoimmune thyroiditis are not more likely to be malignant than those without autoimmune thyroiditis. The coexistent autoimmune thyroiditis may be beneficial as a decreased incidence of lymph nodes involvement and distant metastasis was seen in those patients. PMID- 23729391 TI - Repetitive differential finger motion increases shear strain between the flexor tendon and subsynovial connective tissue. AB - Non-inflammatory fibrosis and thickening of the subsynovial connective tissue (SSCT) are characteristic in carpal tunnel syndrome (CTS) patients. These pathological changes have been linked to repetitive hand tasks that create shear forces between the flexor tendons and SSCT. We measured the relative motion of the flexor digitorum superficialis tendon and SSCT during two repetitive finger tasks using color Doppler ultrasound. Twelve participants performed flexion extension cycles for 30 min with the long finger alone (differential movement) and with all four fingers together (concurrent movement). Shear strain index (SSI, a relative measure of excursion in flexion and extension) and maximum velocity ratio (MVR, the ratio of SSCT versus tendon during flexion and extension) were used to represent shear. A linear effect of exertion time was significant and corresponded with larger tendon shear in differential motion. The flexion SSI increased 20.4% from the first to the 30th minute, while MVR decreased 8.9% in flexion and 8.7% in extension. No significant changes were found during concurrent motion. These results suggest that exposure to repetitive differential finger tasks may increase the risk of shear injury in the carpal tunnel. PMID- 23729392 TI - Cytoplasmic vacuoles: clue in the fine-needle aspiration diagnosis of melanoma. AB - For the fine-needle aspiration (FNA) diagnosis of melanoma recognition of characteristic morphologic features is key. In our practice we noted that cytoplasmic vacuoles in Romanowsky-stained FNA smears of melanoma appeared to be a frequent finding. To investigate this premise, we examined 36 consecutive melanoma FNA cases that had both adequate Papanicolaou-stained and Romanowsky stained smears in an effort to determine the prevalence, and thereby, the potential diagnostic utility of cytoplasmic vacuoles in the diagnosis of melanoma compared to established cytomorphologic parameters of melanoma. We found pigment in 21 cases (58%) and plasmacytoid cells in 28 cases (78%), and in all 36 cases (100%) we found bi/multinucleation, intranuclear cytoplasmic inclusions and prominent nucleoli. Cytoplasmic vacuoles were present in 30 cases (83%) and were found in air-dried Romanowsky-stained smears only. These findings suggest that in FNA smears of melanoma cytoplasmic vacuoles in Romanowsky-stained smears have prevalence and potential diagnostic utility that are comparable to widely recognized cytomorphologic features of melanoma. Numerous articles have focused on the cytomorphologic criteria for the FNA diagnosis of melanoma, but few have noted the presence of cytoplasmic vacuoles in FNA smears of melanoma, and rare reports suggest this finding to be a useful clue to the FNA diagnosis of melanoma. This report appears to be the first to focus on the prevalence and potential diagnostic utility of cytoplasmic vacuoles in FNA samples of melanoma. PMID- 23729393 TI - Serum glycan as a prognostic marker in patients with advanced hepatocellular carcinoma treated with sorafenib. PMID- 23729394 TI - Bioinspired synthesis of ZnS supraparticles toward photoinduced dechlorination of 2,2',4,4',5,5'-hexachlorobiphenyl. PMID- 23729395 TI - Tailoring hydrogel adhesion to polydimethylsiloxane substrates using polysaccharide glue. PMID- 23729396 TI - Dietary supplementation of calcium may counteract obesity in mice mediated by changes in plasma fatty acids. AB - The scope of this study was to assess the impact of calcium and conjugated linoleic acid (CLA) supplementation on plasma fatty acid profiles and to evaluate potential synergistic effects of both compounds against dietary obesity. Mice separated into five experimental groups were followed: control (C), high-fat diet (HF), HF with calcium (Ca), HF plus CLA and HF with both Ca and CLA. Plasma metabolites and fatty acids were determined by commercial kits and gas chromatography, respectively. Both dietary calcium and CLA supplementation contributed to lower body fat gain under a HF diet. Maximum efficacy was seen with calcium; no additional effect was associated with the combined treatment with CLA. Plasma leptin, adiponectin and HOMA index were in accordance with an altered glucose/insulin homeostasis in the HF and HF + CLA groups, whereas control levels were attained under Ca-enriched diets. Plasma fatty acids showed minor changes associated to CLA treatment, but a high impact on PUFA was observed under Ca-enriched diets. Our results show that the mechanism underlying the anti obesity effects of calcium supplementation is mediated mainly by changes in PUFA plasma profile. In addition, the lack of synergy on body weight reduction in combination with associated lipid profiles of calcium and CLA suggests that calcium may interfere with absorption and/or bioactivity of CLA, which can be of relevance when using CLA-fortified dairy products against human obesity. PMID- 23729398 TI - Reliability of pelvic floor measurements on three- and four-dimensional ultrasound during and after first pregnancy: implications for training. AB - OBJECTIVES: To evaluate the reliability of measurements of the levator hiatus and levator-urethra gap (LUG) using three/four-dimensional (3D/4D) transperineal ultrasound in women during their first pregnancy and 6 months postpartum, and to assess the learning process for these measurements. METHODS: An inexperienced observer was taught to perform measurements of the levator hiatus and LUG by an experienced observer. After training, 3D/4D ultrasound volume datasets of 40 women in the first trimester were analyzed by these two observers. Another training session then took place and both observers repeated the analyses of the same volume datasets. Finally, analyses of 40 volume datasets of the women 6 months postpartum were performed by both observers. Intra- and interobserver reliability were determined by intraclass correlation coefficients (ICC) with 95% CIs. RESULTS: For levator hiatal measurements, in the women during their first pregnancy the interobserver reliability was substantial to almost perfect after both the first and second training session (ICC, 0.62-0.83 and 0.71-0.89, respectively, for anteroposterior diameter, transverse diameter and area at rest, on contraction and on Valsalva) and the intraobserver reliability was substantial to almost perfect for both observers. For these measurements performed once the women had delivered, interobserver reliability was moderate to almost perfect. For LUG measurements performed during pregnancy, interobserver reliability was slight to moderate after the first training session (ICC, 0.14-0.54), but improved after the second training session (ICC, 0.38-0.71), and intraobserver reliability was moderate to substantial for the experienced observer and slight to moderate for the inexperienced observer. For these measurements performed when the women had delivered, interobserver reliability was fair to moderate. CONCLUSIONS: The levator hiatus and LUG can be measured reliably using 3D/4D ultrasound in primigravid and primiparous women. The technique to measure dimensions of the levator hiatus requires limited teaching, but LUG measurements are more difficult and require more extensive training. PMID- 23729397 TI - Muscle-specific overexpression of the catalytic subunit of DNA polymerase gamma induces pupal lethality in Drosophila melanogaster. AB - We show the physiological effects and molecular characterization of overexpression of the catalytic core of mitochondrial DNA (mtDNA) polymerase (pol gamma-alpha) in muscle of Drosophila melanogaster. Muscle-specific overexpression of pol gamma-alpha using the UAS/GAL4 (where UAS is upstream activation sequence) system produced more than 90% of lethality at the end of pupal stage at 25 degrees C, and the survivor adult flies showed a significant reduction in life span. The survivor flies displayed a decreased mtDNA level that is accompanied by a corresponding decrease in the levels of the nucleoid-binding protein mitochondrial transcription factor A (mtTFA). Furthermore, an increase in apoptosis is detected in larvae and adults overexpressing pol gamma-alpha. We suggest that the pupal lethality and reduced life span of survivor adult flies are both caused mainly by massive apoptosis of muscle cells induced by mtDNA depletion. PMID- 23729399 TI - Sinonasal mucosal melanomas: the prognostic value of tumor classifications. AB - BACKGROUND: The purpose of this study was to assess the prognostic value of the 3 staging systems found in the literature for sinonasal mucosal melanomas tumors: the Ballantyne staging system modified by Prasad (Ballantyne/Prasad staging system), the American Joint Committee on Cancer (AJCC) TNM classification for mucosal melanomas (mmTNM), and the 2009 AJCC TNM classification for carcinomas of the nasal cavity and sinuses (carTNM). METHODS: A retrospective study of 35 patients treated between 1995 and 2010 was conducted for this study. Each patient was retrospectively staged using the Ballantyne/Prasad staging system, mmTNM, and carTNM. RESULTS: There were 20 women (57.1%) and 15 men (42.9%). Only carTNM was significantly correlated with overall survival (p = .012) and disease-free survival (p = .041). The other 2 classifications were not correlated with survival except for metastatic patients whose overall survival was lower (p = .032). CONCLUSION: On the basis of these findings, we believe that carTNM should be the primary staging system for patients with mucosal melanomas of the sinonasal tract PMID- 23729400 TI - Endoplasmic reticulum stress and the unfolded protein response: targeting the Achilles heel of multiple myeloma. AB - Multiple myeloma is characterized by the malignant proliferating antibody producing plasma cells in the bone marrow. Despite recent advances in therapy that improve the survival of patients, multiple myeloma remains incurable and therapy resistance is the major factor causing lethality. Clearly, more effective treatments are necessary. In recent years it has become apparent that, as highly secretory antibody-producing cells, multiple myeloma cells require an increased capacity to cope with unfolded proteins and are particularly sensitive to compounds targeting proteostasis such as proteasome inhibitors, which represent one of the most prominent new therapeutic strategies. Because of the increased requirement for dealing with secretory proteins within the endoplasmic reticulum, multiple myeloma cells are heavily reliant for survival on a set of signaling pathways, known as the unfolded protein response (UPR). Thus, directly targeting the UPR emerges as a new promising therapeutic strategy. Here, we provide an overview of the current understanding of the UPR signaling in cancer, and outline its important role in myeloma pathogenesis and treatment. We discuss new therapeutic approaches based on targeting the protein quality control machinery and particularly the IRE1alpha/XBP1 axis of the UPR. PMID- 23729401 TI - Cyclooxygenase-2, epidermal growth factor receptor, and aromatase signaling in inflammation and mesothelioma. AB - Malignant mesothelioma or mesothelioma is a rare form of cancer that develops from transformed cells originating in the mesothelium, the protective lining that covers many of the internal organs of the body. It is directly linked to asbestos exposure, which acts as a carcinogen by initiating the carcinogenic process. Because of their shape, asbestos fibers can cross the membrane barriers inside the body and cause inflammatory and fibrotic reactions. Such reactions are believed to be the mechanism by which asbestos fibers may trigger malignant mesothelioma in the pleural membrane around the lungs. Carcinogens are known to modulate the transcription factors, antiapoptotic proteins, proapoptotic proteins, protein kinases, cell-cycle proteins, cell adhesion molecules, COX-2, and growth factor signaling pathways. This article reviews recent studies regarding some malignant mesothelioma molecular targets not only for cancer prevention but also for cancer therapy. PMID- 23729402 TI - Therapeutic potential of the poly(ADP-ribose) polymerase inhibitor rucaparib for the treatment of sporadic human ovarian cancer. AB - Here, we investigate the potential role of the PARP inhibitor rucaparib (CO-338, formerly known as AG014699 and PF-01367338) for the treatment of sporadic ovarian cancer. We studied the growth inhibitory effects of rucaparib in a panel of 39 ovarian cancer cell lines that were each characterized for mutation and methylation status of BRCA1/2, baseline gene expression signatures, copy number variations of selected genes, PTEN status, and sensitivity to platinum-based chemotherapy. To study interactions with chemotherapy, we used multiple drug effect analyses and assessed apoptosis, DNA fragmentation, and gammaH2AX formation. Concentration-dependent antiproliferative effects of rucaparib were seen in 26 of 39 (67%) cell lines and were not restricted to cell lines with BRCA1/2 mutations. Low expression of other genes involved in homologous repair (e.g., BCCIP, BRCC3, ATM, RAD51L1), amplification of AURKA or EMSY, and response to platinum-based chemotherapy was associated with sensitivity to rucaparib. Drug interactions with rucaparib were synergistic for topotecan, synergistic, or additive for carboplatin, doxorubicin or paclitaxel, and additive for gemcitabine. Synergy was most pronounced when rucaparib was combined with topotecan, which resulted in enhanced apoptosis, DNA fragmentation, and gammaH2AX formation. Importantly, rucaparib potentiated chemotherapy independent of its activity as a single agent. PARP inhibition may be a useful therapeutic strategy for a wider range of ovarian cancers bearing deficiencies in the homologous recombination pathway other than just BRCA1/2 mutations. These results support further clinical evaluation of rucaparib either as a single agent or as an adjunct to chemotherapy for the treatment of sporadic ovarian cancer. PMID- 23729403 TI - BIBF 1120 (nintedanib), a triple angiokinase inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and pancreatic cancer. AB - Signaling from other angiokinases may underlie resistance to VEGF-directed therapy. We evaluated the antitumor and biologic effects of BIBF 1120 (nintedanib), a tyrosine kinase inhibitor that targets VEGF receptor, platelet derived growth factor receptor, and fibroblast growth factor receptor in preclinical models of lung and pancreatic cancer, including models resistant to VEGF-targeted treatments. In vitro, BIBF 1120 did not show antiproliferative effects, nor did it sensitize tumor cells to chemotherapy. However, in vivo BIBF 1120 inhibited primary tumor growth in all models as a single agent and in combination with standard chemotherapy. Analysis of tumor tissue posttreatment revealed that BIBF 1120 reduced proliferation (phospho-histone 3) and elevated apoptosis (cleaved caspase-3) to a greater extent than chemotherapy alone. Furthermore, BIBF 1120 showed potent antiangiogenic effects, including decreases in microvessel density (CD31), pericyte coverage (NG2), vessel permeability, and perfusion, while increasing hypoxia. Despite the induction of hypoxia, markers of epithelial-to-mesenchymal transition (EMT) were not elevated in BIBF 1120-treated tumors. In summary, BIBF 1120 showed potent antitumor and antiangiogenic activity in preclinical models of lung and pancreatic cancer where it induced hypoxia but not EMT. The absence of EMT induction, which has been implicated in resistance to antiangiogenic therapies, is noteworthy. Together, these results warrant further clinical studies of BIBF 1120. PMID- 23729404 TI - Adrenergic receptor gene polymorphism and left ventricular reverse remodelling after cardiac resynchronization therapy: preliminary results. AB - AIMS: Several factors can influence the extent of left ventricular (LV) reverse remodelling after cardiac resynchronization therapy (CRT) in patients with heart failure (HF). Polymorphism in genes involved in cardiac remodelling, namely beta adrenergic receptors (ARs), may have a role. We studied the influence of beta-1 Arg389Gly, beta-2 Arg16Gly, and beta-2 Gln27Glu ARs gene polymorphisms on the magnitude of reverse remodelling response to CRT and its possible correlations with the incidence of appropriate implantable cardioverter-defibrillator (ICD) shocks. METHODS AND RESULTS: Beta-ARs were assessed in 101 patients with HF due to idiopathic (50.5%) or ischaemic (49.5%) dilated cardiomyopathy, undergoing CRT for standard indications [left ventricular ejection fraction (LVEF) 23.5 +/- 7.5%, QRS >= 120 ms]. Left ventricular ejection fraction was measured by echocardiography at baseline, 6 months after CRT, and periodically afterwards. The LVEF change from baseline was of 3.1 +/- 11 units among Gln27Gln, 8.3 +/- 10.4 units among Gln27Glu, 11 +/- 6.4 units among Glu27Glu carriers (P = 0.018 for Gln27Gln vs. Glu27Glu carriers), and 8.8 +/- 9.8 units among Gln27Glu + Glu27Glu carriers (P = 0.006 vs. Gln27Gln). Gln27 homozygotes had a higher incidence of appropriate ICD shocks for fast ventricular tachycardia/ventricular fibrillation. CONCLUSION: Beta-2 Gln27Glu ARs gene polymorphism may influence LV reverse remodelling after CRT with Glu27Glu carriers showing the greatest improvement. It may also influence the incidence of malignant ventricular tachyarrhythmias. PMID- 23729405 TI - Cardiac three-dimensional rotational angiography can be performed with low radiation dose while preserving image quality. AB - AIMS: The effective radiation dose (ED) of three-dimensional rotational angiography (3DRA) is 5-8 mSv, leading to reticence on its use. We evaluated the potential of 3DRA with a reduced number of frames (RNF) and a reduced dose per frame. METHODS AND RESULTS: Three-dimensional rotational angiography was performed in 60 patients (52.5 +/- 9.6 years, 16 females) referred for ablation in the right (RA; n = 10) and left atrium (LA; n = 50). In a simulation group (n = 20), the effect of dropping frames from a conventional 248 frames 3DRA LA acquisition was simulated. In a prospective group (n = 40), RNF 3DRA were acquired of LA (n = 30) and RA (n = 10) with 67 frames (0.24 Gy/frame) and 45 frames (0.12 MUGy/frame), respectively. Accuracy was evaluated qualitatively and quantitatively. Effective radiation dose was determined by Monte Carlo simulation on every frame. In the simulation group, surface errors increased minimally and non-significantly when reducing frames from 248 to 124, 83, 62, 50, 42, and 31: 0.49 +/- 0.51, 0.52 +/- 0.46, 0.61 +/- 0.49, 0.62 +/- 0.47, 0.71 +/- 0.48, and 0.81 +/- 0.47 mm, respectively (Pearson coefficient 0.20). All 3D LA images were clinically useful, even with only 31 frames. In the prospective group, good or optimal 3D image quality was achieved in 80% of LA and all of RA reconstructions. These accurate models were obtained with ED of 2.6 +/- 0.4 mSv for LA and 1.2 +/- 0.5 mSv for RA. CONCLUSION: Three-dimensional rotational angiography is possible with a significant reduction in ED (to the level of prospectively gated cardiac computed X-ray tomography) without compromising image quality. Low-dose 3DRA could become the preferred online 3D imaging modality for pulmonary vein isolation and other anatomy-dependent ablations. PMID- 23729406 TI - Jet-fixation: a novel method to improve microscopy of human liver needle biopsies. PMID- 23729407 TI - Remarkable structure effects on chiroptical properties of polyisocyanides carrying proline pendants. AB - Chiral polymers with simple chemical structures and high helical conformation stabilities are important for their applications as chiral supports and asymmetrical catalysts. We report herein the synthesis of a series of aliphatic polyisocyanides carrying proline pendants of different chiralities, and an investigation of the effects of the chemical structures of these pendants on the chiroptical properties of the polymers. The configuration of the chiral center at the 4-position of the proline pendants was changed from S to R to check its effect on the handedness of the helical conformation. To examine the effects of steric hindrance on the stabilities of the helical conformation for these aliphatic representatives, proline pendants with various substituents at both the carboxyl and amine terminals were designed. To further examine the steric effects of the proline pendants, aromatic counterparts were also prepared. In the latter case, the effects of hydrogen bonds between pendant units on the enhancement and stabilities of the helical conformation were investigated by switching from the ester to an amide linkage. The Cotton effects and signal intensities of both aliphatic and aromatic polyisocyanides from circular dichroism spectroscopy were compared based on the bulkiness of the pendant groups, solvent polarities, and solution temperatures. It was found that highly stable helical conformations of polyisocyanides could be imposed by small bulky monoproline pendants. PMID- 23729408 TI - Responsiveness of Lebanon's primary healthcare centers to non-communicable diseases and related healthcare needs. AB - Lebanon currently faces a rise in non-communicable diseases (NCD) that is stressing the population's health and financial well-being. Preventive care is recognized as the optimal health equitable, cost-effective solution. The study aims to assess the responsiveness of primary health care centers (PHCs) to NCD, and identify the needed health arrangements and responsibilities of PHCs, the Ministry Of Public Health and other healthcare system entities, for PHCs to purse a more preventive role against NCD. Single and group interviews were conducted via a semi-structured questionnaire with 10 PHCs from Lebanon's primary health care network that have undergone recent pilot accreditation and are recognized for having quality services and facilities. This manifested administrative aspects and NCD-related services of PHCs and generated information regarding the centers' deficiencies, strengths and areas needing improvement for fulfilling a more preventive role. Administrative features of PHCs varied according to number and type of health personnel employed. Variations and deficiencies within and among PHCs were manifested specifically at the level of cardiovascular and respiratory diseases and cancer. PHCs identified the pilot accreditation as beneficial at the administrative and clinical levels; however, various financial and non-financial resources, in addition to establishing a strong referral system with secondary care settings and further arrangements with MOPH, are necessary for PHCs to pursue a stronger preventive role. The generated results denote needed changes within the healthcare system's governance, financing and delivery. They involve empowering PHCs and increasing their breadth of services, allocating a greater portion of national budget to health and preventive care, and equipping PHCs with personnel skilled in conducting community-wide preventive activities. PMID- 23729410 TI - [3,3]-Sigmatropic rearrangement step in the gold-catalyzed cyclization of allyl (ortho-alkinylphenyl)methyl ethers. AB - The gold-catalyzed conversion of allyl-(ortho-alkynylphenyl)methyl ethers was investigated, and allylated isochromenes were obtained. An optimization of the catalysis conditions with respect to different phosphane and carbene ligands on gold, different counterions, and different solvents was conducted. Subsequently, the scope and limitations of this reaction were investigated with 21 substrates. The mechanistic studies show an allylic inversion, as supported by NMR data and an X-ray crystal structure analysis, as well as an intermolecular reaction, as determined by crossover experiments. There is no competition of protodeauration even in the presence of water. All these observations differ from other related conversions and clearly indicate product formation by a [3,3]sigmatropic rearrangement in the step forming the new C-C bond. PMID- 23729411 TI - Picomolar gradients of progesterone select functional human sperm even in subfertile samples. AB - More than 1 million infertility treatments are practiced around the world per year, but only 30% of the couples succeed in taking a baby home. Reproductive technology depends in part on sperm quality, which influences not only fertilization but also embryo development and implantation. In order to provide a better quality sperm subpopulation, innovative sperm selection techniques based on physiological sperm features are needed. Spermatozoa at an optimum state may be selected by following an increasing concentration gradient of picomolar progesterone, a steroid secreted by the cumulus cells at the time of ovulation. In this study we developed a method to recruit spermatozoa at the best functional state, based on sperm guidance toward progesterone. The sperm selection assay (SSA) consists of a device with two wells connected by a tube. One well was filled with the sperm suspension and the other with picomolar progesterone, which diffused inside the connecting tube as a gradient. The sperm quality after the SSA was analyzed in normal and subfertile semen samples. Several sperm parameters indicative of sperm physiological state were determined before and after the SSA: capacitation, DNA integrity and oxidative stress. After the SSA, the mean level of capacitated spermatozoa increased three times in normal and in subfertile samples. The level of sperm with intact DNA was significantly increased, while sperm oxidative stress was decreased after sperm selection. Interestingly, the exposure to a progesterone gradient stimulated the completion of capacitation in some spermatozoa that could not do it by themselves. Thus, the SSA supplies a sperm population enriched with spermatozoa at an optimum physiological state that may improve the assisted reproductive technology outcome. PMID- 23729412 TI - The use of imaging for electrophysiological and devices procedures: a report from the first European Heart Rhythm Association Policy Conference, jointly organized with the European Association of Cardiovascular Imaging (EACVI), the Council of Cardiovascular Imaging and the European Society of Cardiac Radiology. AB - Implantations of cardiac devices therapies and ablation procedures frequently depend on accurate and reliable imaging modalities for pre-procedural assessments, intra-procedural guidance, detection of complications, and the follow-up of patients. An understanding of echocardiography, cardiovascular magnetic resonance imaging, nuclear cardiology, X-ray computed tomography, positron emission tomography, and vascular ultrasound is indispensable for cardiologists, electrophysiologists as well as radiologists, and it is currently recommended that physicians should be trained in several imaging modalities. There are, however, no current guidelines or recommendations by electrophysiologists, cardiac imaging specialists, and radiologists, on the appropriate use of cardiovascular imaging for selected patient indications, which needs to be addressed. A Policy Conference on the use of imaging in electrophysiology and device management, with representatives from different expert areas of radiology and electrophysiology and commercial developers of imaging and device technologies, was therefore jointly organized by European Heart Rhythm Association (EHRA), the Council of Cardiovascular Imaging and the European Society of Cardiac Radiology (ESCR). The objectives were to assess the state of the level of evidence and a first step towards a consensus document for currently employed imaging techniques to guide future clinical use, to elucidate the issue of reimbursement structures and health economy, and finally to define the need for appropriate educational programmes to ensure clinical competence for electrophysiologists, imaging specialists, and radiologists. PMID- 23729413 TI - Kinetics of patulin degradation in model solution, apple cider and apple juice by ultraviolet radiation. AB - Patulin is a mycotoxin produced by a wide range of molds involved in fruit spoilage, most commonly by Penicillium expansum and is a health concern for both consumers and manufacturers. The current study evaluated feasibility of monochromatic ultraviolet (UV) radiation at 253.7 nm as a possible commercial application for the reduction of patulin in fresh apple cider and juice. The R 52G MINERALIGHT(r) UV bench top lamp was used for patulin destruction. It was shown that 56.5%, 87.5%, 94.8% and 98.6% reduction of patulin can be achieved, respectively, in the model solution, apple cider, apple juice without ascorbic acid addition and apple juice with ascorbic acid addition in 2-mm thickness sample initially spiked by 1 mg.L(-1) of patulin after UV exposure for 40 min at UV irradiance of 3.00 mW.cm(-2). A mathematic model to compare the degradation rate and effective UV dose was developed. The effective UV doses that were directly absorbed by patulin for photochemical reaction were 430, 674, 724 and 763 mJ.cm(-3), respectively. The fluence-based decimal reduction time was estimated to 309.3, 31.3, 28.9 and 5.1 mW.cm(-2).min, respectively, in four media mentioned above. The degradation of patulin followed the first-order reaction model. The time-based and fluence-based reaction rate constants were determined to predict patulin degradation. The time-based reaction rate constant of samples treated in dynamic regime with constant stirring (model solution: 2.95E-4 s(-1), juice: 4.31E-4 s(-1)) were significantly higher than samples treated in static regime (model solution: 2.79E-4 s(-1), juice: 3.49E-4 s(-1), p < 0.05) when applied UV irradiance and sample thickness were consistent. The reaction rate constant of patulin degradation in apple juice was significantly higher than model solution (p < 0.05). Although further investigations are still needed, the results of this study demonstrated that UV radiation may be an effective method for treating patulin-containing apple cider and juice. PMID- 23729414 TI - Simultaneous determination of amino acid nitrogen and total acid in soy sauce using near infrared spectroscopy combined with characteristic variables selection. AB - Amino acid nitrogen and total acid are two most important quality indices to assess the quality of soy sauce in China. This work employed near infrared spectroscopy combined with synergy interval partial least square and genetic algorithm to detect amino acid nitrogen and total acid content in soy sauce. First, synergy interval partial least square was used to select efficient spectral regions from the full spectrum region; and then, genetic algorithm was used to selected variables from the efficient spectral regions, to build partial least square model. The optimal genetic algorithm synergy interval partial least square models were obtained as follows: Rc = 0.9988 and Rp = 0.9988 for amino acid nitrogen content model using 64 variables; Rc = 0.9917 and Rp = 0.9902 for total acid content model using 81 variables. Genetic algorithm synergy interval partial least square models showed superiority over the partial least square and synergy interval partial least square models. The results indicated that amino acid nitrogen and total acid content in soy sauce could be rapidly determined by near infrared spectroscopy technique. Also, the results indicated that genetic algorithm synergy interval partial least square can improve the performance in measurement of amino acid nitrogen and total acid content by near infrared spectroscopy. PMID- 23729415 TI - Effect of concentration temperature on some bioactive compounds and antioxidant proprieties of date syrup. AB - The effect of the concentration temperature on the antioxidant activity, carotenoid and phenolic compounds of date syrup was investigated. Date juice was concentrated at 100 and at "60 in vacuum". After concentration, total phenolic, tannin, non-tannin, flavonoid and carotenoid content were determined spectrophotometrically and high-performance liquid chromatography was used for determination of 5-Hydroxymethyl-2-furfuraldehyde content. The antioxidant activity of date syrup was evaluated by various antioxidant methods including total antioxidant, 2,2-diphenyl-1-picrylhydrazyl free radical scavenging test, ferric reducing antioxidant power and beta-carotene bleaching. All date syrups showed strong antioxidant activity accompanied by high total phenolic contents. Results showed that concentration at 100 significantly enhanced the antioxidant activities and total phenolic contents of date syrups compared to vacuum concentration at 60 . A good correlation between the antioxidant activity and total phenolic content and flavonoid was observed. PMID- 23729416 TI - Combined effect of nisin, carvacrol and a previous thermal treatment on the growth of Salmonella enteritidis and Salmonella senftenberg. AB - The aim of this study was to evaluate the combined effect of a previous mild heat treatment (15 min at 55 ) with the use of antimicrobials, nisin and carvacrol, on the growth of Salmonella enteritidis and Salmonella senftenberg. Natural antimicrobials, alone or combined with a previous mild heat treatment, affected the growth of these two serovars in Tryptone Soy Broth at 37 . Increasing concentrations of carvacrol had a significant effect on both growth rate and lag phase duration of both strains. The time to reach stationary phase was almost doubled in the case of S. enteritidis when a concentration of 0.77 mM in carvacrol was added. For S. senftenberg the effect was smaller. The effect of nisin and of heat, applied individually, was lower for both microorganisms. A combination of 1.2 uM nisin with 0.77 mM carvacrol significantly delayed the growth of heat treated cells, compared to the control without antimicrobials, showing additive effects. PMID- 23729417 TI - Production and characterization of a functional Iranian white brined cheese by replacement of dairy fat with vegetable oils. AB - Full-fat cheese usually contains high amounts of saturated fatty acids and cholesterol, which may have negative health effects. In this study, full-fat white brined cheese, as a control sample, and experimental cheeses with olive and canola oils (T1, white brined cheese containing 50% canola oil, T2, white brined cheese containing 50% olive oil, T3, white brined cheese containing 100% canola oil and T4, white brined cheese containing 100% olive oil) were prepared from bovine milk. Physicochemical properties, lipolysis, proteolysis patterns and sensorial properties in the prepared samples were determined during 80 days of storage at 20-day intervals. Cheese incorporating vegetable oils showed lower amounts of saturated fatty acids and higher amounts of unsaturated fatty acids compared with the full-fat cheese (control) samples. Moisture, pH, lipolysis value, as assessed by the acid-degree value, and proteolysis values (pH 4.6 SN/TN% and NPN/TN%) significantly (p < 0.05) were increased in all samples, whereas total titrable acidity decreased during 40 days of ripening but then increased slightly. Sensory properties of white brined cheese incorporating with vegetable oils were different from those of full-fat cheese samples. White brined cheese containing olive and canola oils (100% fat substitution) received better sensory scores compared to other samples. The results showed that it is possible to replace dairy fat with olive and canola oils, which can lead to produce a new healthy and functional white brined cheese. PMID- 23729418 TI - Light gazpachos contain higher phytochemical levels than conventional gazpachos. AB - Light gazpachos in comparison with conventional alternatives are interesting because of their low percentage of fat and high content of bioactive compounds that are beneficial for human health. An hybrid quadrupole time-of-flight mass spectrometer was used to identify those metabolites that have the greatest impact on the overall metabolic profile in light gazpachos as compared to conventional alternatives. Individual polyphenols were quantified using liquid chromatography electrospray ionization tandem mass spectrometry. Data obtained revealed that light gazpachos displayed a higher significant phytochemical content than conventionally produced alternatives. The compounds found in significantly higher (p < 0.05) amounts in light versus conventional gazpachos were: caffeoylquinic and dicaffeoylquinic acids, caffeic and caffeic acid hexosides, kaempferol-3-O rutinoside, ferulic and ferulic acid hexosides, naringenin-7-O-glucoside, naringenin, rutin and quercetin. Light gazpachos may play a crucial role in terms of health benefits (lower fat and higher bioactive compound intake). Higher consumption levels of phenolic compounds, which are greater in light products, along with caloric restriction and physical activity may be helpful in preventing obesity. PMID- 23729419 TI - Optimization of composite flour biscuits by mixture response surface methodology. AB - Biscuits were produced from blends of pigeon pea, sorghum and cocoyam flours. The study was carried out using mixture response surface methodology as the optimization technique. Using the simplex centroid design, 10 formulations were obtained. Protein and sensory quality of the biscuits were analyzed. The sensory attributes studied were appearance, taste, texture, crispness and general acceptability, while the protein quality indices were biological value and net protein utilization. The results showed that while the addition of pigeon pea improved the protein quality, its addition resulted in reduced sensory ratings for all the sensory attributes with the exception of appearance. Some of the biscuits had sensory ratings, which were not significantly different (p > 0.05) from biscuits made with wheat. Rat feeding experiments indicated that the biological value and net protein utilization values obtained for most of the biscuits were above minimum recommended values. Optimization suggested biscuits containing 75.30% sorghum, 0% pigeon pea and 24.70% cocoyam flours as the best proportion of these components. This sample received good scores for the sensory attributes. PMID- 23729420 TI - Antioxidant activity and inhibitory effects of lead (Leucaena leucocephala) seed extracts against lipid oxidation in model systems. AB - Antioxidant activity of brown lead (Leucaena leucocephala) seed extracts with and without prior chlorophyll removal was studied in comparison with mimosine. Both extracts showed similar hydroxyl radical (HO(*)) scavenging activity, hydrogen peroxide (H2O2) scavenging activity, singlet oxygen inhibition and hypochlorous acid (HOCl) scavenging capacity (p > 0.05). Nevertheless, the extract without prior chlorophyll removal had higher oxygen radical absorbance capacity than that with prior chlorophyll removal (p < 0.05). Generally, lead seed extracts with and without prior chlorophyll removal possessed a lower antioxidant activity, compared with mimosine. When lead seed extract without prior chlorophyll removal (100 and 200 ppm) was used in different lipid oxidation model systems, including beta-carotene-linoleic acid and lecithin liposome systems, the preventive effect toward lipid oxidation was dose-dependent. At the same level of use, mimosine exhibited a higher efficacy in prevention of lipid oxidation in both systems as indicated by the lower increases in thiobarbituric acid reactive substances. A similar result was obtained in minced mackerel. Therefore, lead seed extract containing mimosine could act as a natural antioxidant to prevent lipid oxidation in foods. PMID- 23729421 TI - Survival of acid adapted and non-acid adapted Salmonella Typhimurium in pasteurized orange juice and yogurt under different storage temperatures. AB - The survival capacity of Salmonella enterica serovar Typhimurium acid adapted and non-acid adapted cells was monitored in pasteurized yogurt (pH 4.1) and orange juice (pH 3.6) during storage at different temperatures (4, 10, 25 and 37 ). Acid adapted and non-acid adapted cells were obtained by means of their growth for 36 h in Brain Heart Infusion broth acidified at pH 4.8 with citric acid and buffered (pH 7.0) Brain Heart Infusion broth, respectively. S. typhimurium showed a great ability to survive in both foodstuffs and, especially, in yogurt, where both acid adapted and non-acid adapted populations suffered only a reduction of about 1.3 1.9 log10 cycles after 43 days of storage in the range of temperatures 4-25 . At 37 a higher bacterial inactivation was observed (4.0-4.4 log10 cycles). In orange juice, a different behaviour was observed for acid-adapted and non-acid adapted cells. Whereas non-acid adapted cells survived better than acid adapted cells at 4 and 10 , acid adapted cells showed enhanced survival abilities at higher temperatures (25 and 37 ). Thus, the times required to achieve a 5 log10 cycles reduction for non-acid adapted and acid adapted cells were 10.2 and 6.0 (4 ), 6.3 and 4.2 (10 ), 0.6 and 1.0 (25 ) and 0.10 and 0.15 (37 ) days, respectively. Evidence found in this study demonstrates that refrigeration temperatures protect S. typhimurium from inactivation in acid foods and indicates that S. typhimurium acid tolerance response (ATR) is determined by storage temperature and food composition. PMID- 23729422 TI - Effects of soybean protein, potato starch and pig lard on the properties of frankfurters formulated from mechanically separated chicken meat surimi-like material. AB - Mechanically separated chicken meat has become a common ingredient of comminuted sausage products, as 'frankfurters', mainly due to its low price. The present work aimed to develop a frankfurter from mechanically separated chicken meat surimi-like material, and evaluated the chemical, rheological, microbiological and sensorial properties of this product. The response surface methodology was utilized to investigate the effects of the soybean protein, potato starch and pig lard on the texture of the obtained frankfurters. For this purpose, five levels of each factor were evaluated: soybean protein varied from 0% to 6%, potato starch from 0% to 10% and pig lard from 2% to 12%. The regression analysis of the model showed that the soybean protein exerted a linear positive effect and a quadratic negative effect in the compression force of the product (p < 0.05), and that the variable which more influenced the shear force was the potato starch, presenting linear and quadratic effects (p < 0.05). The highest composite design averages obtained were 202.2 g for breaking force, 7.9 cm for deformation, 10.1 N for shear force, and 90.9 N.s for work of shearing. The obtained models presented high determination coefficients, explaining 97.31%, 97.83%, 97.49%, and 95.39% of the breaking force, deformation, shear force and work of shearing variabilities, respectively. The microbiological analysis demonstrated that the achieved results were below the limits fixed by the FDA. The mechanically separated chicken meat surimi-like material frankfurter presented 72.2% of acceptability and 59.3% of the examiners found the color of the product slightly lighter than the ideal. Finally, the frankfurter-type sausages, without pork fat, produced and characterized here have presented promising characteristics for commercial applications. PMID- 23729423 TI - High-pressure processing of a raw milk cheese improved its food safety maintaining the sensory quality. AB - The effect of high-pressure treatment (400 or 600 MPa for 7 min) on microbiology, proteolysis, texture and sensory parameters was investigated in a mature raw goat milk cheese. At day 60 of analysis, Mesophilic aerobic, Enterobacteriaceae, lactic acid bacteria and Listeria spp. were inactivated after high-pressure treatment at 400 or 600 MPa. At day 90, mesophilic aerobic, lactic acid bacteria and Micrococacceae counts were significantly lower in high-pressure-treated cheeses than in control ones. In general, nitrogen fractions were significantly modified after high-pressure treatment on day 60 at 600 MPa compared with control cheeses, but this effect was not found in cheeses after 30 days of storage (day 90). On the other hand, high-pressure treatment caused a significant increase of some texture parameters. However, sensory analysis showed that neither trained panellists nor consumers found significant differences between control and high pressure-treated cheeses. PMID- 23729424 TI - Natural extracts versus sodium ascorbate to extend the shelf life of meat-based ready-to-eat meals. AB - The effect of grape seed and green tea extracts was compared with effect of sodium ascorbate on bacterial spoilage, lipid stability and sensory quality in cooked pork meatballs during refrigerated storage. Meatballs were stored at 4 in aerobic packaging for 0, 4, 8, 12 and 16 days under retail display conditions. Lipid oxidation was evaluated as thiobarbituric acid reactive substances, volatile compounds and cholesterol oxidation products. Colour stability was assessed through CIELab parameters. Microbiological spoilage was determined through total viable, mould and yeast and coliform counts. The samples containing green tea and grape seed extracts showed lower levels of thiobarbituric acid reacting substances, major volatile compounds and microbiological counts than the samples with sodium ascorbate. Formation of cholesterol oxidation products was also inhibited to a greater extent. Colour of meatballs and pork meatballs was not affected by refrigerated storage; however, the addition of extracts provided brown shades. The addition of antioxidants did not modify the sensory attributes except for the colour. Green tea and grape seed extracts were more effective than sodium ascorbate at preventing lipid oxidation. PMID- 23729425 TI - Related physicochemical properties to microstructure of hard and soft wheat grains with different kernel thickness and specific density. AB - Physicochemical properties of wheat grains with largest kernel thickness always was lowest than the other sections, examination of microstructure of wheat grains can help us understand this phenomena. Two varieties of wheat, soft white winter wheat Yangmai 11 and hard white winter wheat Zhengmai 9023, were fractionated into five sections by kernel thickness. Then the fractionated wheat grains in 2.7 3.0 mm section were separated into three fractions by kernel specific density sequentially. Microstructure of the fractured surface were evaluated at different scale level to two varieties wheat with different kernel thickness and specific density by using environmental scanning electron microscopy. Compactness and size of endosperm cell tended to decrease with decreasing wheat kernel thickness and specific density. Protein matrix tended to increase with decreasing wheat kernel thickness and specific density. Size of starch granules and proportion for different type starch granules also varied with different wheat kernel thickness and specific density. Those microstructure properties of the fractured surface, formation of endosperm cells, protein matrix and starch granules were close related to rheological properties and pasting properties of wheat grains. PMID- 23729426 TI - Improvement of cloud stability, yield and beta-carotene content of carrot juice by process modification. AB - This study investigated the effects of three processing factors, acid blanching, centrifugation and dynamic high pressure homogenization, on cloud stability of carrot juice. Results indicated that the optimum processing condition for stabilized carrot juice were with dynamic high pressure homogenization at 100 MPa combined with 2% citric acid blanching at 95-100 for 2 min followed by 2000 r/min centrifugation for 10 min. The improvement of juice yield was also investigated using a pre-treatment of three commercial enzymes: Pectinex 3XL(r) (pectinase), Celluclast 1.5 L(r) (cellulase) and Novozyme 188TM (beta glucosidase). The combination of 0.1 g/kg of Pectinex 3XL(r), 0.1 g/kg of Celluclast 1.5 L(r) and 0.1 g/kg of Novozyme 188TM at 50 and pH 4.0 for 90 min was the most effective condition to improve carrot juice yield from 49% to 67%. The enzymatic treatment increased juice total soluble solids from 7.5 to 8.9 degrees Brix and beta-carotene content from 21.4 to 33.7 mg/kg. PMID- 23729427 TI - Synthesis, properties, and dispersion of few-layer graphene fluoride. AB - We have fluorinated few-layer graphene (FLG) by using a low-temperature fluorination route with gaseous ClF3. The treatment process resulted in a new graphene derivative with a finite approximate composition of C2F. TEM studies showed that the product consisted of thin transparent sheets with no more than 10 fluorographene layers stacked together. Spectroscopic methods revealed a predominantly covalent nature of the C-F bonds in the as-synthesized product and we found no evidence for the existence of so-called "semi-ionic" C-F bonds, as observed in bulk C(x)F. In contrast to the case of graphite and typical (thick) expanded graphites, fluorination of FLG did not lead to the intercalation of ClF3 molecules, owing to the lack of a 3D layered structure. The approximate "critical" number of graphene layers that were necessary to form a phase of intercalated compound was estimated to be more than 12, thus providing a "chemical proof" of the difference between the properties of few-layered graphenes and bulk graphites. Fluorographene C2F was successfully delaminated into thinner layers in organic solvents, which is an important property for its integration into electronic devices, nanohybrids, etc. PMID- 23729428 TI - Unsafe abortion: why restricting abortive drugs only makes a bad situation worse. PMID- 23729429 TI - Proposed EU data protection regulation is a threat to medical research. PMID- 23729430 TI - Malnutrition linked to literacy problems in quarter of world's schoolchildren. PMID- 23729431 TI - Monitor investigates reasons behind closure of "popular" Darzi walk-in centres. PMID- 23729432 TI - Number of ambulances being turned away from full emergency departments increases by a quarter. PMID- 23729433 TI - Senior Canadian physician and hospital administrator wanted for fraud involving hospital contract arrested in Panama. PMID- 23729434 TI - Half a million people using food banks in UK as food poverty grows. PMID- 23729435 TI - Deaths from rare protozoan encephalitis in Karachi blamed on unchlorinated water. PMID- 23729436 TI - Indapamide lowers blood pressure by increasing production of epoxyeicosatrienoic acids in the kidney. AB - Diuretics are widely used in the treatment of hypertension, although the precise mechanisms remain unknown. Epoxyeicosatrienoic acids (EETs), cytochrome P450 (P450) epoxygenase metabolites of arachidonic acid, play critical roles in regulation of blood pressure. The present study was carried out to investigate whether EETs participate in the antihypertensive effect of thiazide diuretics [hydrochlorothiazide (HCTZ)] and thiazide-like diuretics (indapamide). Male spontaneously hypertensive rats (SHRs) were treated with indapamide or HCTZ for 8 weeks. Systolic blood pressure, measured via tail-cuff plethysmography and confirmed via intra-arterial measurements, was significantly decreased in indapamide- and HCTZ-treated SHRs compared with saline-treated SHRs. Indapamide increased kidney CYP2C23 expression, decreased soluble epoxide hydrolase expression, increased urinary and renovascular 11,12- and 14,15-EETs, and decreased production of 11,12- and 14,15-dihydroxyeicosatrienoic acids in SHRs. No effect on expression of CYP4A1 or CYP2J3, or on 20-hydroxyeicosatetraenoic acid production, was observed, suggesting indapamide specifically targets CYP2C23 derived EETs. Treatment of SHRs with HCTZ did not affect the levels of P450s or their metabolites. Increased cAMP activity and protein kinase A expression were observed in the renal microvessels of indapamide-treated SHRs. Indapamide ameliorated oxidative stress and inflammation in renal cortices by down regulating the expression of p47phox, nuclear factor-kappaB, transforming growth factor-beta1, and phosphorylated mitogen-activated protein kinase. Furthermore, the p47phox-lowering effect of indapamide in angiotensin II-treated rat mesangial cells was partially blocked by the presence of N-(methylsulfonyl)-2-(2 propynyloxy)-benzenehexanamide (MS-PPOH) or CYP2C23 small interfering RNA. Together, these results indicate that the hypotensive effects of indapamide are mediated, at least in part, by the P450 epoxygenase system in SHRs, and provide novel insights into the blood pressure-lowering mechanisms of diuretics. PMID- 23729437 TI - Leishmania-infected MHC class IIhigh dendritic cells polarize CD4+ T cells toward a nonprotective T-bet+ IFN-gamma+ IL-10+ phenotype. AB - A differential behavior among infected and bystander dendritic cells (DCs) has been explored in different infection models. We have analyzed both populations sorted on contact with visceral Leishmania infantum on a susceptible mice model evaluating the subsequent repercussions on adaptive immune response. Our results demonstrate a clear dichotomy between the immunomodulatory abilities of bystander and infected DCs. The bystander population presents increased levels of IL-12p40 and costimulatory molecules being capable to induce CD4(+) T cell activation with immune protective capabilities. In contrast, infected DCs, which express lower costimulatory molecules and higher levels of IL-10, promote the development of Leishmania Ag-specific, nonprotective T-bet(+)IFN-gamma(+)IL-10(+) CD4(+) T cells with an effector phenotype. This specific polarization was found to be dependent on IL-12p70. Splenic infected DCs recovered from chronic infected animals are similarly capable to polarize ex vivo syngeneic naive CD4(+) T cells toward a T bet(+)IFN-gamma(+)IL-10(+) phenotype. Further analysis revealed that only MHC class II(high)-infected DCs were responsible for this polarization. The adoptive transfer of such polarized CD4(+) T cells facilitates visceral leishmaniasis in BALB/c mice in a clear contrast with their counterpart generated with bystander DCs that significantly potentiate protection. Further, we demonstrated that CD4(+) T cells primed by infected DCs in an IL-10 free system, thus deprived of T bet(+)IFN-gamma(+)IL-10(+) population, restore the immune response and reduce parasite load, supporting a deleterious role of IFN-gamma(+)IL-10(+) T cells in the maintenance of infection. Overall, our results highlight novel subversion mechanisms by which nonprotective T-bet(+)IFN-gamma(+)IL-10(+) T cells are associated with chronicity and prolonged parasite persistence. PMID- 23729438 TI - CD166/ALCAM mediates proinflammatory effects of S100B in delayed type hypersensitivity. AB - Promiscuity of pattern recognition receptors, such as receptor for advanced glycation end products (RAGE), allows for a complex regulatory network controlling inflammation. Scavenging of RAGE ligands by soluble RAGE treatment is effective in reducing delayed-type hypersensitivity (DTH), even in RAGE(-/-) mice by 50% (p < 0.001). This has led to the hypothesis that molecules scavenged by soluble RAGE bind to receptors other than RAGE. This study identifies CD166/ALCAM (ALCAM) as a close structural and functional homolog of RAGE, and it shows that binding of S100B to CD166/ALCAM induces dose- and time-dependent expression of members of the NF-kappaB family in wild type (WT) and RAGE(-/-) mouse endothelial cells. Blocking CD166/ALCAM expression using small interfering RNA completely inhibited S100B-induced NF-kappaB activation in RAGE(-/-), but not in WT cells. The in vivo significance of these observations was demonstrated by attenuation of DTH in WT and RAGE(-/-) animals pretreated with CD166/ALCAM small interfering RNA by 50% and 40%, respectively (p < 0.001). Experiments in ALCAM(-/-) animals displayed an only slight reduction of 16% in DTH, explained by compensatory reciprocal upregulation of RAGE in animals devoid of CD166/ALCAM, and vice versa. Consistently, ALCAM(-/-) mice, but not WT mice treated with RAGE small interfering RNA show a 35% reduction in DTH, and ALCAM(-/-) RAGE(-/-) double knockout mice show a 27% reduction in DTH reaction. Thus, S100B is a proinflammatory cytokine bridging RAGE and CD166/ALCAM downstream effector mechanisms, both being compensatory upregulated after genetic deletion of its counterpart. PMID- 23729439 TI - Inhibition of histone deacetylase activity suppresses IFN-gamma induction of tripartite motif 22 via CHIP-mediated proteasomal degradation of IRF-1. AB - Tripartite motif (TRIM)22 plays an important role in IFN-mediated antiviral activity. We previously demonstrated that IFN regulatory factor (IRF)-1 was crucial for basal and IFN-induced TRIM22 transcription via binding to a novel cis element named 5' extended IFN-stimulating response element. In this study, we investigated the role of histone deacetylase (HDAC) activity in TRIM22 induction by IFN-gamma and its underlying mechanism. We found that the HDAC activity, especially that conferred by HDAC6, was required for IFN-gamma-induced TRIM22 transcription. Importantly, inhibition of HDAC activity by trichostatin A (TSA) enhanced the hyperacetylation of heat shock protein (HSP)90 and suppressed its chaperone activity for IRF-1. Further study showed that TSA treatment promoted the proteasomal degradation of IRF-1 protein via enhancing the association of IRF 1 with the ubiquitin E3 ligase carboxyl terminus of Hsc70-interacting protein. Moreover, carboxyl terminus of Hsc70-interacting protein was found to be involved in the TSA-mediated inhibitory effect on IFN-gamma induction of TRIM22 as well as other IRF-1-dependent IFN-stimulated genes. This study may provide novel insight into the role of HDAC activity in the transcriptional control of IFN-stimulated gene induction. PMID- 23729441 TI - Phosphatidylinositol 3-kinase-independent signaling pathways contribute to ICOS mediated T cell costimulation in acute graft-versus-host disease in mice. AB - We and others have previously shown that ICOS plays an important role in inducing acute graft-versus-host disease (GVHD) in murine models of allogeneic bone marrow transplantation. ICOS potentiates TCR-mediated PI3K activation and intracellular calcium mobilization. However, ICOS signal transduction pathways involved in GVHD remain unknown. In this study, we examined the contribution of ICOS-PI3K signaling in the pathogenic potential of T cells using a knock-in mouse strain, ICOS-YF, which selectively lost the ability to activate PI3K. We found that when total T cells were used as alloreactive T cells, ICOS-YF T cells caused less severe GVHD compared with ICOS wild-type T cells, but they induced much more aggressive disease than ICOS knockout T cells. This intermediate level of pathogenic capacity of ICOS-YF T cells was correlated with similar levels of IFN gamma-producing CD8 T cells that developed in the recipients of ICOS-WT or ICOS YF T cells. We further evaluated the role of ICOS-PI3K signaling in CD4 versus CD8 T cell compartment using GVHD models that are exclusively driven by CD4 or CD8 T cells. Remarkably, ICOS-YF CD8 T cells caused disease similar to ICOS wild type CD8 T cells, whereas ICOS-YF CD4 T cells behaved very similarly to their ICOS knockout counterparts. Consistent with their in vivo pathogenic potential, CD8 T cells responded to ICOS ligation in vitro by PI3K-independent calcium flux, T cell activation, and proliferation. Thus, in acute GVHD in mice, CD4 T cells heavily rely on ICOS-PI3K signaling pathways; in contrast, CD8 T cells can use PI3K-independent ICOS signaling pathways, possibly through calcium. PMID- 23729440 TI - Human plasmacytoid dendritic cells efficiently capture HIV-1 envelope glycoproteins via CD4 for antigen presentation. AB - Advances in HIV-1 vaccine clinical trials and preclinical research indicate that the virus envelope glycoproteins (Env) are likely to be an essential component of a prophylactic vaccine. Efficient Ag uptake and presentation by dendritic cells (DCs) is important for strong CD4(+) Th cell responses and the development of effective humoral immune responses. In this study, we examined the capacity of distinct primary human DC subsets to internalize and present recombinant Env to CD4(+) T cells. Consistent with their specific receptor expression, skin DCs bound and internalized Env via C-type lectin receptors, whereas blood DC subsets, including CD1c(+) myeloid DCs, CD123(+) plasmacytoid DCs (PDCs), and CD141(+) DCs exhibited a restricted repertoire of C-type lectin receptors and relied on CD4 for uptake of Env. Despite a generally poor capacity for Ag uptake compared with myeloid DCs, the high expression of CD4 on PDCs allowed them to bind and internalize Env very efficiently. CD4-mediated uptake delivered Env to EEA1(+) endosomes that progressed to Lamp1(+) and MHC class II(+) lysosomes where internalized Env was degraded rapidly. Finally, all three blood DC subsets were able to internalize an Env-CMV pp65 fusion protein via CD4 and stimulate pp65 specific CD4(+) T cells. Thus, in the in vitro systems described in this paper, CD4-mediated uptake of Env is a functional pathway leading to Ag presentation, and this may therefore be a mechanism used by blood DCs, including PDCs, for generating immune responses to Env-based vaccines. PMID- 23729442 TI - Ectopic expression of epidermal antigens renders the lung a target organ in paraneoplastic pemphigus. AB - Paraneoplastic pemphigus (PNP) is an autoimmune disease of the skin and mucous membranes that can involve fatal lung complications. IgG autoantibodies target the cell adhesion molecules desmoglein (Dsg)3 and plakins, but the nature and targets of infiltrating T cells are poorly characterized. Moreover, the lung involvement in this skin Ag-specific autoimmune condition represents a paradox. To mimic autoimmunity in PNP, we grafted wild-type skin onto Dsg3(-/-) mice, which resulted in graft rejection and generation of anti-Dsg3 IgG and Dsg3 specific T cells. Transfer of splenocytes from these mice into Rag2(-/-) mice induced a combination of suprabasilar acantholysis and interface dermatitis, a histology unique to PNP. Furthermore, the recipient mice showed prominent bronchial inflammation of CD4(+) and CD8(+) T cells with high mortality. Intriguingly, ectopic Dsg3 expression was observed in the lungs of PNP mice, mirroring the observation that squamous metaplasia is often found in the lungs of PNP patients. Dsg3 and other epidermal Ags were ectopically expressed in the lungs after pulmonary injuries by naphthalene, which was sufficient for recruitment of Dsg3-specific CD4(+) T cells. These findings demonstrate that squamous metaplasia after pulmonary epithelial injury may play a crucial role in redirecting the skin-specific autoimmune reaction to the lungs in PNP. PMID- 23729443 TI - Antibody-secreting cells with a phenotype of Ki-67low, CD138high, CD31high, and CD38high secrete nonspecific IgM during primary hepatitis A virus infection. AB - Although studies investigating the nature of Ab-secreting cells (ASCs) during acute infection with influenza or dengue virus found that the ASC response was dominated by virus-specific IgG secretion, the Ag specificity and phenotype of ASCs during primary acute viral infection were not identified. To this end, we investigated the nature of ASCs in direct ex vivo assays from patients with acute hepatitis A caused by primary infection with hepatitis A virus (HAV). We found that the frequency of CD27(high)CD38(high) ASCs was markedly increased in the peripheral blood during the acute phase of HAV infection. Moreover, substantial numbers of ASCs were non-HAV-specific and dominantly secreted IgM. We detected HAV-specific ASCs by staining with fluorochrome-tagged HAV-VP1 protein. As compared with HAV-specific ASCs, non-HAV-specific ASCs were Ki 67(low)CD138(high)CD31(high)CD38(high), demonstrating that non-HAV-specific ASCs had a bone marrow plasma cell-like phenotype whereas HAV-specific ASCs had a phenotype typical of circulating plasmablasts. These data suggest that non-HAV specific ASCs might be mobilized plasma cells from the bone marrow or the spleen, whereas HAV-specific ASCs were newly generated plasmablasts. In this study, we provide evidence that pre-existing plasma cells are released into the circulation and contribute to Ag-nonspecific secretion of IgM during primary HAV infection. PMID- 23729444 TI - GILZ overexpression inhibits endothelial cell adhesive function through regulation of NF-kappaB and MAPK activity. AB - Glucocorticoid-induced leucine zipper (GILZ) is an anti-inflammatory protein first identified in T lymphocytes. We recently observed that GILZ is highly expressed in synovial endothelial cells in rheumatoid arthritis. However, the function of GILZ in endothelial cells is unknown. To investigate the actions of GILZ in this cell type, we induced GILZ expression in HUVECs via transient transfection. GILZ overexpression significantly reduced the capacity of TNF stimulated HUVECs to support leukocyte rolling, adhesion, and transmigration. These effects were associated with decreased expression of E-selectin, ICAM-1, CCL2, CXCL8, and IL-6. Experiments in a human microvascular endothelial cell line demonstrated that TNF-inducible NF-kappaB activity was significantly inhibited by overexpression of GILZ. Exogenous GILZ inhibited TNF-induced NF-kappaB p65 DNA binding, although this occurred in the absence of an effect on p65 nuclear translocation, indicating that the mechanism of action of exogenous GILZ in endothelial cells differs from that reported in other cell types. GILZ overexpression also inhibited TNF-induced activation of p38, ERK, and JNK MAPKs, as well as increased expression of the MAPK inhibitory phosphatase, MKP-1. In contrast, silencing endogenous GILZ in glucocorticoid-treated HUVECs did not alter their capacity to support leukocyte interactions. These data demonstrate that exogenous GILZ exerts inhibitory effects on endothelial cell adhesive function via a novel pathway involving modulation of NF-kappaB p65 DNA binding and MAPK activity. Induction of GILZ expression in endothelial cells may represent a novel therapeutic modality with the potential to inhibit inflammatory leukocyte recruitment. PMID- 23729445 TI - MAPK kinase 3 potentiates Chlamydia HSP60-induced inflammatory response through distinct activation of NF-kappaB. AB - Chlamydia pneumonia (C. pneumonia) remains one of the leading causes of bacterial pneumonia and has been implicated in the pathogenesis of some inflammation related diseases, such as asthma, chronic obstructive pulmonary disease, and vascular diseases. Heat shock protein 60 is one of the pathogenic components of C. pneumonia that is closely associated with the inflammatory disorders. However, the molecular basis for the immunopathologic property of chlamydial heat shock protein (cHSP60) has not been elucidated. In this article, we report that MAPK kinase 3 (MKK3) is essential for cHSP60-induced lung inflammation, because MKK3 knockout mice displayed significantly reduced lung neutrophil accumulation and decreased production of proinflammatory mediators, correlating with the alleviated inflammatory response in lung tissues. Mechanistically, p38 kinase was selectively activated by MKK3 in response to cHSP60 and activated NF-kappaB by stimulating the nuclear kinase, mitogen- and stress-activated protein kinase 1. The specific knockdown of mitogen- and stress-activated protein kinase 1 in macrophages resulted in a defective phosphorylation of NF-kappaB/RelA at Ser(276) but had no apparent effect on RelA translocation. Furthermore, TGF-beta-activated kinase 1 was found to relay the signal to MKK3 from TLR4, the major receptor that sensed cHSP60 in the initiation of the inflammatory response. Thus, we establish a critical role for MKK3 signaling in cHSP60 pathology and suggest a novel mechanism underlying C. pneumonia-associated inflammatory disorders. PMID- 23729446 TI - Myeloid hypoxia-inducible factor-1alpha is essential for skeletal muscle regeneration in mice. AB - The outstanding regeneration ability of skeletal muscle is based on stem cells that become activated and develop to myoblasts after myotrauma. Proliferation and growth of myoblasts result in self-renewal of skeletal muscle. In this article, we show that myotrauma causes a hypoxic microenvironment leading to accumulation of the transcription factor hypoxia-inducible factor-1 (HIF-1) in skeletal muscle cells, as well as invading myeloid cells. To evaluate the impact of HIF-1 in skeletal muscle injury and repair, we examined mice with a conditional HIF-1alpha knockout targeted to skeletal muscle or myeloid cells in a model of soft tissue trauma. No differences in acute trauma size were detected between control and HIF 1alpha knockout mice. However, muscles of myeloid HIF-1alpha knockout mice showed a significant delay in myoblast proliferation and growth of regenerating myofibers, in association with decreased expression of cyclooxygenase-2 in HIF 1alpha-deficient myeloid cells. Moreover, the removal of necrotic cell debris and the regeneration of endothelial cell structure were impaired in myeloid HIF 1alpha knockout mice that showed delayed invasion of macrophages to the injury site. Our findings for the first time, to our knowledge, demonstrate that myeloid HIF-1alpha is required for adequate skeletal muscle regeneration. PMID- 23729447 TI - First, do no harm. PMID- 23729448 TI - Cements and composites. PMID- 23729449 TI - Author's response. PMID- 23729450 TI - Using a rubber dam. PMID- 23729451 TI - Proving its worth. PMID- 23729452 TI - Do no harm. PMID- 23729453 TI - Authors' response. PMID- 23729454 TI - Drs. Tiecke and Bernier: pioneers in oral pathology. PMID- 23729456 TI - Fabrication of customized tongue-displacing stents: considerations for use in patients receiving head and neck radiotherapy. AB - BACKGROUND: Conformal or intensity-modulated radiation therapy can be improved by using a customized tongue-displacing (CTD) stent. These stents are designed to either move healthy oral tissues out of the path of the radiation beam or stabilize mobile tissues to allow more precise field control. METHODS: The authors describe CTD stent construction for both tongue-deviating and tongue depressing applications. RESULTS: CTD stents enable clinicians to achieve more predictable and consistent radiation dosimetry planning while sparing greater volumes of healthy tissue from damage. They have been well tolerated by patients. CONCLUSIONS: Use of CTD stents results in increased oral mucosal sparing, ensures reproducible immobilization and is incorporated readily into the clinical practice of radiation oncology. Practical Implications. Clinicians can reduce or avoid significant morbidity to healthy oral tissues by using CTD stents. This can lead to better outcomes and improved quality of life for patients receiving head and neck radiation therapy. PMID- 23729455 TI - A 24-month evaluation of amalgam and resin-based composite restorations: Findings from The National Dental Practice-Based Research Network. AB - BACKGROUND: Knowing which factors influence restoration longevity can help clinicians make sound treatment decisions. The authors analyzed data from The National Dental Practice-Based Research Network to identify predictors of early failures of amalgam and resin-based composite (RBC) restorations. METHODS: In this prospective cohort study, the authors gathered information from clinicians and offices participating in the network. Clinicians completed a baseline data collection form at the time of restoration placement and annually thereafter. Data collected included patient factors, practice factors and dentist factors, and the authors analyzed them by using mixed-model logistic regression. RESULTS: A total of 226 practitioners followed up 6,218 direct restorations in 3,855 patients; 386 restorations failed (6.2 percent) during the mean (standard deviation) follow-up of 23.7 (8.8) months. The number of tooth surfaces restored at baseline helped predict subsequent restoration failure; restorations with four or more restored surfaces were more than four times more likely to fail. Restorative material was not associated significantly with longevity; neither was tooth type. Older patient age was associated highly with failure (P < .001). The failure rate for children was 4 percent, compared with 10 percent for people 65 years or older. Dentist's sex and practice workload were associated significantly with restoration longevity. CONCLUSIONS: In this prospective cohort study, these factors were significantly predictive of failure for amalgam and RBC restorations: patient's age, a higher number of surfaces restored at baseline, the dentist's sex and the practice workload. Material choice was not significantly predictive in these early results. Practical Implications. If clinicians can recognize and identify the risk factors associated with early restoration failure, more effective treatment plans may be offered to the patient. PMID- 23729457 TI - Management of ankylosed primary molars with premolar successors: a systematic review. AB - BACKGROUND: The authors conducted a systematic review to determine the clinical prognosis of and methods of managing ankylosed primary molars with permanent successors. METHODS: The authors searched electronic databases (PubMed, Scopus, MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Cochrane Database of Systematic Reviews and Google Scholar) up to April 2012 with the assistance of a librarian specializing in health sciences databases. They also searched the gray literature. They selected clinical studies in which investigators assessed the prognosis of ankylosed primary molars with permanent successors; they also hand searched references of the selected articles to identify any additional studies that the electronic search may have missed. RESULTS: The authors identified 3,529 original articles from the electronic database search and none from the hand search. Once selection criteria were applied, only four articles met all inclusion criteria and were included. The number of patients studied ranged from 15 to 107. The number of ankylosed primary molars investigated ranged from 26 to 263. CONCLUSIONS: Ankylosed primary molars often manifest with mild to moderate progressive infraocclusion. Conservative monitoring of ankylosed primary molars is recommended. The clinician should consider extraction if the permanent successor has an altered path of eruption, if the ankylosed primary molar is severely infraoccluded with the adjacent teeth tipping to prevent the successor from erupting, or both. The ankylosed molar often exfoliates spontaneously within six months; however, when exfoliation is more delayed, arch-length loss, occlusal disturbance, hooked roots or impaction of permanent successors may occur. Practical Implications. Ankylosed primary molars initially should be monitored closely for up to six months. If they do not exfoliate spontaneously, they should be removed, because arch-length loss, alveolar bone defects, impacted permanent successors and occlusal disturbances often occur when the removal is delayed. PMID- 23729458 TI - Topical medications for the effective management of neuropathic orofacial pain. PMID- 23729459 TI - The characteristics of hospital emergency department visits made by people with mental health conditions who had dental problems. AB - BACKGROUND: There is a paucity of knowledge regarding nationally representative estimates of hospital-based emergency department (ED) visits for dental problems made by people with mental health conditions. The authors conducted a study to provide nationwide estimates of hospital-based ED visits attributed to dental caries, pulpal and periapical lesions, gingival and periodontal lesions and mouth cellulitis/abscess made by people with mental health conditions. METHODS: The authors used the Nationwide Emergency Department Sample, which is a component of the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality. ED visits attributable to dental caries, pulpal and periapical lesions, gingival and periodontal lesions and mouth cellulitis/abscess were identified by the emergency care provider by using diagnostic codes in International Classification of Diseases, Ninth Revision, Clinical Modification. The authors examined outcomes, including hospital charges. They used simple descriptive statistics to summarize the data. RESULTS: In 2008, people with mental health conditions made 15,635,253 visits to hospital-based ED in the United States. A diagnosis of dental caries, pulpal and periapical lesions, gingival and periodontal lesions and mouth cellulitis/abscess represented 63,164 of these ED visits. The breakdown of the ED visits was 34,574 with dental caries, 25,352 with pulpal and periapical lesions, 9,657 with gingival and periodontal lesions, and 2,776 with mouth cellulitis/abscess. The total charge for ED visits in the United States was $55.46 million in 2008. CONCLUSIONS: In 2008, people with mental health conditions made 63,164 visits to hospital-based EDs and received a diagnosis of dental caries, pulpal and periapical lesions, gingival and periodontal lesions or mouth cellulitis/abscess. These ED visits incurred substantial hospital charges. Programs designed to reduce the number of ED visits made by this population for common dental problems could have a substantial impact in reducing the use of hospital resources. Practical Implications. Clinicians should implement preventive practices for patients with mental health conditions. The authors identified combinations of mental health conditions and dental problems that led to patients with mental health conditions making visits to hospital-based EDs for dental problems more frequently than did patients in the general population. PMID- 23729461 TI - Amoxicillin/metronidazole therapy may improve the effectiveness of scaling and root planing in patients with periodontitis. AB - SYSTEMATIC REVIEW CONCLUSION: Preliminary evidence suggests scaling and root planing (SRP) in combination with amoxicillin (AMX)/metronidazole (MET)(SRP + AMX/MET) therapy may be more effective in treating chronic periodontitis(CP) than is SRP alone. CRITICAL SUMMARY ASSESSMENT: Preliminary evidence from a meta analysis of four randomized clinical trials (RCTs) seems to support the effectiveness of systemic AMX/MET therapy as an adjunct to SRP alone in treating CP, although safety data are incomplete. EVIDENCE QUALITY RATING: Limited. PMID- 23729460 TI - Substance-use screening and interventions in dental practices: survey of practice based research network dentists regarding current practices, policies and barriers. AB - BACKGROUND: Dental visits represent an opportunity to identify and assist patients with unhealthy substance use, but little is known about how dentists are addressing patients' use of tobacco, alcohol and illicit drugs. The authors surveyed dentists to learn about the role their practices might play in providing substance-use screening and interventions. METHODS: The authors distributed a 41 item Web-based survey to all 210 dentists active in the Practitioners Engaged in Applied Research and Learning Network, a practice-based research network. The questionnaire assessed dental practices' policies and current practices, attitudes and perceived barriers to providing services for tobacco, alcohol and illicit drug use. RESULTS: One hundred forty-three dentists completed the survey (68 percent response rate). Although screening was common, fewer dentists reported that they were providing follow-up counseling or referrals for substance use. Insufficient knowledge or training was the most frequently cited barrier to intervention. Many dentists reported they would offer assistance for use of tobacco (67 percent) or alcohol or illicit drugs (52 percent) if reimbursed; respondents who treated publicly insured patients were more likely to reply that they would offer this assistance. CONCLUSIONS: Dentists recognize the importance of screening for substance use, but they lack the clinical training and practice based systems focused on substance use that could facilitate intervention. Practical Implications. The results of this study indicate that dentists may be willing to address substance use among patients, including use of alcohol and illicit drugs in addition to tobacco, if barriers are reduced through changes in reimbursement, education and systems-level support. PMID- 23729462 TI - Ohio dentists' awareness and incorporation of the dental home concept. AB - BACKGROUND: The authors measured the awareness of the dental home concept among pediatric dentists (PDs) and general practice dentists (GPs) in Ohio and determined whether they included dental home characteristics for children 5 years and younger into their practices. METHODS: The authors sent a pretested 20 question survey to all Ohio PDs and to a random sample of approximately 20 percent of GPs in Ohio. The authors designed the survey to elicit information about dental home awareness and the extent to which dental home characteristics were incorporated into dental practices. RESULTS: More than 90 percent of both GPs and PDs incorporated or intended to incorporate into their dental practices the specific dental home characteristics mentioned in 20 of 41 items related to dental home characteristics. Of the respondents who did not already incorporate dental home characteristics into their practices, however, most did not intend to do so. Less than 50 percent of respondents in both groups responded positively to some items in the culturally effective group, and GPs were less likely than were PDs to provide a range of behavior management services and to provide treatment for patients with complex medical and dental treatment needs. PDs were more likely than were GPs to accept Ohio Medicaid (64 versus 33 percent). PDs were more likely than were GPs (78 versus 18 percent) to be familiar with the term "dental home." More recent dental school graduates were more familiar with the term. CONCLUSIONS: Most Ohio PDs' and GPs' practices included characteristics found in the definition of dental home, despite a general lack of concept awareness on the part of GPs. Research is needed to provide an evidence base for the dental home. Practical Implications. Once an evidence base is developed for the important aspects of the dental home and the definition is revised, efforts should be made to incorporate these aspects more broadly into dental practice. PMID- 23729463 TI - Dealing with caries in the mature patient. PMID- 23729464 TI - Addressing bottlenecks in the dental practice. PMID- 23729465 TI - How should dentists address patients' after-hours emergencies? PMID- 23729466 TI - The use of antioxidants in radiotherapy-induced skin toxicity. AB - Radiation-induced skin damage is one of the most common complications of radiotherapy. In order to combat these side effects, patients often turn to alternative therapies, which often include antioxidants. Antioxidants such as those in the polyphenol chemical class, xanthine derivatives, tocepherol, sucralfate, and ascorbate have been studied for their use in either preventing or treating radiotherapy-induced skin damage. Apart from their known role as free radical scavengers, some of these antioxidants appear to alter cytokine release affecting cutaneous and systemic changes. We review the role of antioxidants in treating and preventing radiation-induced skin damage as well as the possible complications of using such therapy. PMID- 23729467 TI - Chemopreventive efficacy of Aegle marmelos on murine transplantable tumors. AB - Emerging trends for cancer chemotherapy show promising developments with the better understanding of molecules delivering more potent and powerful capabilities. But these are severely limited because of increased side effects and higher probability of tumor recurrence. In this scenario, putative exploration of the indigenous and untapped resources modulating immune system to deliver adequate but potent chemopreventive effects appeals considerable interest. However, these require rigorous scientific validation with regard to potency compared with the existing drugs. Aegle marmelos (Linnaeus) Correa (family Rutaceae), a plant component of polyherbal formulation, Indukantha Ghritha, is known for its widespread medicinal values. But the chemopreventive potential has not been explored in comparison to existing anticancer agents. Our attempt contributes the scientific evidence for beneficial immunoprophylactic and antitumor functions in mice challenged with ascites tumors, Dalton's lymphoma ascites, and Ehrlich's ascites carcinoma either alone or in combination with cyclophosphamide and 5-fluorouracil. Specifically, the petroleum ether extracts of this plant (AM(PE)) prophylactically activated a cascade of host defense mechanisms by stimulating or restoring total white blood cell count, macrophage phagocytosis, hematopoiesis, lymphocyte proliferation and functions (CD4+ and CD8+) either naturally or under conditions of impaired immunity like in ascites tumor or during standard agent chemotherapy. Overall, AM(PE) also elicited strong antitumor effects by increasing median survival time and life span, while reducing murine ascites tumor volume and viable tumor counts on par with cyclophosphamide and 5-fluorouracil especially when administered prophylactically. This study also identified 2 putative components, xanthorrhizol and marmelosin, which could be imparting the immunoprophylactic and antitumor effects in transplantable tumor models. Thus, our attempts provide sufficient proof to warrant further to test this drug in higher animal models or in patients with high risk for tumor recurrence and/or immunocompromised diseases. PMID- 23729468 TI - Comparison of pyogenic liver abscesses caused by hypermucoviscous Klebsiella pneumoniae and non-Klebsiella pneumoniae pathogens in Beijing: a retrospective analysis. AB - OBJECTIVE: To perform a retrospective comparison of the clinical and radiological features of Klebsiella pneumoniae (KP)-associated and non-KP-associated pyogenic liver abscesses (PLA) in Chinese patients. METHODS: Patients with confirmed diagnoses of bacterial liver abscess at three Beijing hospitals were enrolled. Clinical isolates from liver abscesses were used to determine serology and expression of hypermucoviscosity genes. Basic clinical, ultrasonographic (US) and computed tomography (CT) data were recorded and compared between patients with KP and non-KP-associated PLA. RESULTS: A total of 101 (77.10%) and 30 (22.90%) cases were due to KP and non-KP pathogens, respectively. Compared with the non-KP cohort, the KP cohort demonstrated a significantly higher incidence of underlying diabetes mellitus, and more gas-forming abscesses, as demonstrated by US and CT examinations. Prior abdominal surgery or chemoradiation therapy was significantly associated with non-KP cases. The non-KP group had a higher chance of a clear edge, compared with the KP group, on pre-contrast CT images. CONCLUSION: KP and non-KP-associated PLA have distinctive risk factors and unique US and CT features, in Chinese patients. PMID- 23729469 TI - PELE web server: atomistic study of biomolecular systems at your fingertips. AB - PELE, Protein Energy Landscape Exploration, our novel technology based on protein structure prediction algorithms and a Monte Carlo sampling, is capable of modelling the all-atom protein-ligand dynamical interactions in an efficient and fast manner, with two orders of magnitude reduced computational cost when compared with traditional molecular dynamics techniques. PELE's heuristic approach generates trial moves based on protein and ligand perturbations followed by side chain sampling and global/local minimization. The collection of accepted steps forms a stochastic trajectory. Furthermore, several processors may be run in parallel towards a collective goal or defining several independent trajectories; the whole procedure has been parallelized using the Message Passing Interface. Here, we introduce the PELE web server, designed to make the whole process of running simulations easier and more practical by minimizing input file demand, providing user-friendly interface and producing abstract outputs (e.g. interactive graphs and tables). The web server has been implemented in C++ using Wt (http://www.webtoolkit.eu) and MySQL (http://www.mysql.com). The PELE web server, accessible at http://pele.bsc.es, is free and open to all users with no login requirement. PMID- 23729470 TI - PlantLoc: an accurate web server for predicting plant protein subcellular localization by substantiality motif. AB - Knowledge of subcellular localizations (SCLs) of plant proteins relates to their functions and aids in understanding the regulation of biological processes at the cellular level. We present PlantLoc, a highly accurate and fast webserver for predicting the multi-label SCLs of plant proteins. The PlantLoc server has two innovative characters: building localization motif libraries by a recursive method without alignment and Gene Ontology information; and establishing simple architecture for rapidly and accurately identifying plant protein SCLs without a machine learning algorithm. PlantLoc provides predicted SCLs results, confidence estimates and which is the substantiality motif and where it is located on the sequence. PlantLoc achieved the highest accuracy (overall accuracy of 80.8%) of identification of plant protein SCLs as benchmarked by using a new test dataset compared other plant SCL prediction webservers. The ability of PlantLoc to predict multiple sites was also significantly higher than for any other webserver. The predicted substantiality motifs of queries also have great potential for analysis of relationships with protein functional regions. The PlantLoc server is available at http://cal.tongji.edu.cn/PlantLoc/. PMID- 23729471 TI - BeEP Server: Using evolutionary information for quality assessment of protein structure models. AB - The BeEP Server (http://www.embnet.qb.fcen.uba.ar/embnet/beep.php) is an online resource aimed to help in the endgame of protein structure prediction. It is able to rank submitted structural models of a protein through an explicit use of evolutionary information, a criterion differing from structural or energetic considerations commonly used in other assessment programs. The idea behind BeEP (Best Evolutionary Pattern) is to benefit from the substitution pattern derived from structural constraints present in a set of homologous proteins adopting a given protein conformation. The BeEP method uses a model of protein evolution that takes into account the structure of a protein to build site-specific substitution matrices. The suitability of these substitution matrices is assessed through maximum likelihood calculations from which position-specific and global scores can be derived. These scores estimate how well the structural constraints derived from each structural model are represented in a sequence alignment of homologous proteins. Our assessment on a subset of proteins from the Critical Assessment of techniques for protein Structure Prediction (CASP) experiment has shown that BeEP is capable of discriminating the models and selecting one or more native-like structures. Moreover, BeEP is not explicitly parameterized to find structural similarities between models and given targets, potentially helping to explore the conformational ensemble of the native state. PMID- 23729472 TI - QARIP: a web server for quantitative proteomic analysis of regulated intramembrane proteolysis. AB - Regulated intramembrane proteolysis (RIP) is a critical mechanism for intercellular communication and regulates the function of membrane proteins through sequential proteolysis. RIP typically starts with ectodomain shedding of membrane proteins by extracellular membrane-bound proteases followed by intramembrane proteolysis of the resulting membrane-tethered fragment. However, for the majority of RIP proteases the corresponding substrates and thus, their functions, remain unknown. Proteome-wide identification of RIP protease substrates is possible by mass spectrometry-based quantitative comparison of RIP substrates or their cleavage products between different biological states. However, this requires quantification of peptides from only the ectodomain or cytoplasmic domain. Current analysis software does not allow matching peptides to either domain. Here we present the QARIP (Quantitative Analysis of Regulated Intramembrane Proteolysis) web server which matches identified peptides to the protein transmembrane topology. QARIP allows determination of quantitative ratios separately for the topological domains (cytoplasmic, ectodomain) of a given protein and is thus a powerful tool for quality control, improvement of quantitative ratios and identification of novel substrates in proteomic RIP datasets. To our knowledge, the QARIP web server is the first tool directly addressing the phenomenon of RIP. The web server is available at http://webclu.bio.wzw.tum.de/qarip/. This website is free and open to all users and there is no login requirement. PMID- 23729473 TI - Diffusion tensor magnetic resonance imaging for single subject diagnosis in neurodegenerative diseases. AB - Although magnetic resonance imaging is a standard investigation in neurodegenerative disease, sensitive and specific markers for the underlying histopathological diagnosis are largely lacking. This report presents evidence to indicate that corticobasal degeneration and progressive supranuclear palsy, in particular, might be identifiable at a single subject level with diffusion tensor imaging. Patients with clinical diagnoses of Alzheimer's disease, semantic dementia and non-fluent primary progressive aphasia (n = 9 each) were contrasted with control subjects (n = 26) with the diffusion tensor imaging measures: fractional anisotropy, axial and radial diffusivity. At 1 year follow-up, all participants with non-fluent primary progressive aphasia had evolved either corticobasal degeneration (n = 5) or progressive supranuclear palsy (n = 4). The corticobasal degeneration/progressive supranuclear palsy set showed white matter abnormalities involving the entire cerebrum. Individual maps were similar to the group level results, even in the most minimally impaired patients. Fractional anisotropy was consistently the most sensitive metric. In Alzheimer's disease and semantic dementia, by contrast, group level and individual analyses revealed limited areas of abnormality centred on the posterior cingulate and rostral temporal lobes, respectively. In both groups radial diffusivity was the most sensitive metric. Scrutiny of the standard scores for each group's most sensitive metric revealed that, although the values for every patient with corticobasal degeneration or progressive supranuclear palsy fell outside 95% of the normal mean, none of the other two groups' members had values outside this range. Further underscoring the hypothesis that this finding relates specifically to a diffuse pathological process in the white matter of the tauopathies, and is not merely a function of disease severity, a grey matter analysis consisting of group level voxel-based morphometry revealed only focal areas of atrophy in all three groups. Consistent with past reports for the respective clinical syndromes, these were centred on the left frontal operculum and caudate nucleus in non-fluent primary progressive aphasia (the corticobasal degeneration/progressive supranuclear palsy set), anterior temporal lobes in semantic dementia, and hippocampus and posterior cingulate gyrus in Alzheimer's disease. Detection of this extensive white matter lesion in corticobasal degeneration and progressive supranuclear palsy-a pathologically proven feature of these conditions--in single subjects with diffusion tensor imaging appears to have strong diagnostic marker potential for these diseases. PMID- 23729475 TI - Reply: Small fibre neuropathy, fibromyalgia and dorsal root ganglia sodium channels. PMID- 23729474 TI - Storage of a naturally acquired conditioned response is impaired in patients with cerebellar degeneration. AB - Previous findings suggested that the human cerebellum is involved in the acquisition but not the long-term storage of motor associations. The finding of preserved retention in cerebellar patients was fundamentally different from animal studies which show that both acquisition and retention depends on the integrity of the cerebellum. The present study investigated whether retention had been preserved because critical regions of the cerebellum were spared. Visual threat eye-blink responses, that is, the anticipatory closure of the eyes to visual threats, have previously been found to be naturally acquired conditioned responses. Because acquisition is known to take place in very early childhood, visual threat eye-blink responses can be used to test retention in patients with adult onset cerebellar disease. Visual threat eye-blink responses were tested in 19 adult patients with cerebellar degeneration, 27 adult patients with focal cerebellar lesions due to stroke, 24 age-matched control subjects, and 31 younger control subjects. High-resolution structural magnetic resonance images were acquired in patients to perform lesion-symptom mapping. Voxel-based morphometry was performed in patients with cerebellar degeneration, and voxel-based lesion symptom mapping in patients with focal disease. Visual threat eye-blink responses were found to be significantly reduced in patients with cerebellar degeneration. Visual threat eye-blink responses were also reduced in patients with focal disease, but to a lesser extent. Visual threat eye-blink responses declined with age. In patients with cerebellar degeneration the degree of cerebellar atrophy was positively correlated with the reduction of conditioned responses. Voxel based morphometry showed that two main regions within the superior and inferior parts of the posterior cerebellar cortex contributed to expression of visual threat eye-blink responses bilaterally. Involvement of the more inferior parts of the posterior lobe was further supported by voxel-based lesion symptom mapping in focal cerebellar patients. The present findings show that the human cerebellar cortex is involved in long-term storage of learned responses. PMID- 23729476 TI - Small fibre neuropathy, fibromyalgia and dorsal root ganglia sodium channels. PMID- 23729477 TI - Metabolic labeling to characterize the overall composition of Francisella lipid A and LPS grown in broth and in human phagocytes. AB - A hallmark of Francisella tularensis, a highly virulent Gram-negative bacterium, is an unusual LPS that possesses both structural heterogeneity and characteristics that may contribute to innate immune evasion. However, none of the methods yet employed has been sufficient to determine the overall LPS composition of Francisella. We now demonstrate that metabolic labeling of francisellae with [(14)C]acetate, combined with fractionation of [(14)C]acetate labeled lipids by ethanol precipitation rather than hot phenol-water extraction, permits a more sensitive and quantitative appraisal of overall compositional heterogeneity in lipid A and LPS. The majority of lipid A of different francisellae strains grown in diverse bacteriologic media and within human phagocytes accumulated as very hydrophobic species, including free lipid A, with <10% of the lipid A molecules substituted with O-Ag polysaccharides. The spectrum of lipid A and LPS species varied in a medium- and strain-dependent fashion, and growth in THP-1 cells yielded lipid A species that were not present in the same bacteria grown in brain heart infusion broth. In summary, metabolic labeling with [(14)C]acetate greatly facilitates assessment of the effect of genotypic and/or environmental variables on the synthesis and accumulation of lipid A and LPS by Francisella, including during growth within the cytosol of infected host cells. PMID- 23729479 TI - Socio-economic inequalities in Norwegian health care utilization over 3 decades: the HUNT Study. AB - BACKGROUND: The aim of this study was to investigate socio-economic inequalities in health care utilization from the 1980s and through the last 3 decades in a Norwegian county population. METHODS: Altogether, 166 758 observations of 97 251 individuals during surveys in 1984-86 (83% eligible responses), 1995-97 (51% eligible responses) and 2006-08 (50% eligible responses) of the total population of adults (>= 20 years) from Nord-Trondelag county in Norway were included. Health care utilization was measured as at least one visit to general practitioner (GP), hospital outpatient services and inpatient care in the past year. Socio-economy was measured by both education and income and rescaled to measure relative indexes of inequality (RII). Relative and absolute inequalities were estimated from multilevel logistic regression. Estimates were adjusted for age, sex, municipality size and self-reported health. RESULTS: GP utilization was higher among individuals with higher education in 1984-86. Among men the RII was 0.54 (CI: 0.48-0.62), and among women RII was 0.67 (CI: 0.58-0.77). In 2006-08, the corresponding RII was 1.31 (CI: 1.13-1.52) for men and 1.00 (CI: 0.85-1.18) for women, indicating higher or equal GP utilization among those with lower education, respectively. The corresponding RIIs for outpatient consultations were 0.58 (CI: 0.49-0.68) for men and 0.40 (CI: 0.34-0.46) for women in 1984-86, and 0.53 (CI: 0.46-0.62) for men and 0.47 (CI: 0.41-0.53) for women in 2006-08. CONCLUSION: Through the last 3 decades, the previous socio-economic differences in GP utilization have diminished. Despite this, highly educated people were more prone to utilize hospital outpatient consultations throughout the period 1984 2008. PMID- 23729480 TI - Occurrence of violence among 12-18-year-old adolescents in 1999 and 2009 in Finland. AB - We examined whether the occurrence of violence changed among Finnish adolescents between 1999 and 2009. The study was based on the nationwide Adolescent Health and Lifestyle Survey from samples of 12- to 18-year-olds. The number of respondents was 8136 in 1999 and 5516 in 2009. The proportion of adolescents reporting violence was 7.9% in 1999 and 6.2% in 2009 (P < 0.000). In both of the study years, the violence occurrence rate varied by age and sex, with boys reporting higher rates in all age groups. The results did not support our hypothesis of a general increase in violence among adolescents. PMID- 23729478 TI - Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. AB - EGF receptor (EGFR)-targeted monoclonal antibodies are effective in a subset of metastatic colorectal cancers. Inevitably, all patients develop resistance, which occurs through emergence of KRAS mutations in approximately 50% of the cases. We show that amplification of the MET proto-oncogene is associated with acquired resistance in tumors that do not develop KRAS mutations during anti-EGFR therapy. Amplification of the MET locus was present in circulating tumor DNA before relapse was clinically evident. Functional studies show that MET activation confers resistance to anti-EGFR therapy both in vitro and in vivo. Notably, in patient-derived colorectal cancer xenografts, MET amplification correlated with resistance to EGFR blockade, which could be overcome by MET kinase inhibitors. These results highlight the role of MET in mediating primary and secondary resistance to anti-EGFR therapies in colorectal cancer and encourage the use of MET inhibitors in patients displaying resistance as a result of MET amplification. PMID- 23729481 TI - Using threshold messages to promote physical activity: implications for public perceptions of health effects. AB - BACKGROUND: The promotion of physical activity (PA) guidelines to the general public is an important issue that lacks empirical investigation. PA campaigns often feature participation thresholds that cite PA guidelines verbatim [e.g., 150 min/week moderate-to-vigorous physical activity (MVPA)]. Some campaigns instead prefer to use generic PA messages (e.g., do as much MVPA as possible). 'Thresholds' may disrupt understanding of the health benefits of modest PA participation. This study examined the perception of health benefits of PA after exposure to PA messages that did and did not contain a duration threshold. METHODS: Brief structured interviews were conducted with a convenience sample of adults (n = 1100). Participants received a threshold message (150 min/week MVPA), a message that presented the threshold as a minimum; a generic message or no message. Participants rated perceived health effects of seven PA durations. One way analyses of variance with post hoc tests for group differences were used to assess raw perception ratings for each duration of PA. RESULTS: Recipients of all three messages held more positive perceptions of >150 min/week of MVPA relative to those not receiving any message. For MVPA durations <150 min/week, the generic PA message group perceived the greatest health benefits. Those receiving the threshold message tended to have the least positive perceptions of durations <150 min/week. CONCLUSION: Threshold messages were associated with lower perceived health benefits for modest PA durations. Campaigns based on threshold messages may be limited when promoting small PA increases at a population level. PMID- 23729482 TI - Do sexual risk behaviour, risk perception and testing behaviour differ across generations of migrants? AB - BACKGROUND: Behaviour and related health outcomes of migrants have been suggested to shift towards the practices of the indigenous population of the host country. To investigate this, we studied generational differences in sexual behaviour between first- and second-generation migrants (FGMs and SGMs) in The Netherlands. METHODS: In 2003-05, persons aged 16-70 years with origins in Surinam, the Antilles and Aruba were interviewed on their sexual behaviour in The Netherlands and their country of origin. The relationship of generation, age at migration and sexual behaviour was studied by multinomial logistic regression analyses. RESULTS: Generational differences were observed regarding concurrent partnerships, anal sex and history of sexually transmitted infection. Compared with FGMs who migrated at an age >25 years, those who migrated between 10 and 25 years of age were more likely to report concurrency [odds ratio (OR): 1.52, 95% confidence interval (CI): 1.14-2.04], whereas SGMs were less likely to report concurrency (OR: 0.65, 95% CI: 0.43-0.98). FGMs who migrated before the age of 10 were more likely to have had anal sex (OR: 1.90, 95% CI: 1.34-2.71) or a sexually transmitted infection diagnosis (OR: 1.80, 95% CI: 1.20-2.71) than those who had migrated at >25 years of age. CONCLUSION: Our study shows that not only SGMs but also FGMs who migrated at an early age tend to differ from the sexual patterns of FGMs who migrated at an older age. Generational differences in sexual behaviour could be explained by acculturation and increased identity with the values of the host country. PMID- 23729483 TI - Myocardial infarction incidence and ischemic heart disease mortality: overall and trend results in repatriates, Germany. AB - BACKGROUND: The burden of cardiovascular diseases (CVDs) is much more pronounced in Eastern Europe, a spatial gradient within Europe still exists. However, former studies showed a significantly lower CVD mortality of German repatriates from the Former Soviet Union compared with the German population. METHODS: All-cause, CVD and ischemic heart disease (IHD) standardized mortality ratio (SMR), IHD standardized incidence ratio and annual age-standardized mortality and acute myocardial infarction (AMI) incidence rates were calculated in a retrospective cohort. Time trends were investigated by loess regression. RESULTS: A total of 6378 German repatriates were observed from 1990 to 2010, accumulating 92 149 person-years. We observed a lower all-cause mortality [SMR = 0.86 (0.75, 0.98)] in females and CVD mortality [International Statistical Classification of Diseases and Related Health Problems, version 10 (ICD) 10: I00-I99; SMR = 0.82 (0.65, 1.03)] and IHD mortality (I20-I25) [SMR = 0.84 (0.60, 1.15)] in males. In contrast, AMI incidence was significantly higher in male repatriates [standardized incidence ratio = 1.30 (1.02, 1.65)]. Whereas in the general population, mortality rates of CVD, IHD and AMI incidence have continuously decreased over time, the pattern in the repatriates was not as clear. In male repatriates, mortality rates seemed to be lower after immigration and remained rather constant. Incidence rates possibly exceed Germans rates by now. CONCLUSIONS: A possible historical repatriates' IHD advantage shown in former studies has disappeared. The increasing AMI incidence in (male) repatriates might demonstrate the delaying onset of the impact of changes in the CVD risk profile due to migration. Health politics and the health system should be sensitized and take care of the development of IHD mortality and AMI incidence among the repatriates. PMID- 23729484 TI - Disease presentation, treatment and survival for Italian colorectal cancer patients: a EUROCARE high resolution study. AB - We analysed presentation, treatment and survival in a representative population based sample of 3753 Italian colorectal cancer cases, diagnosed 2003-05: 70% were >65 years, 44% stage I-II, 27% stage IV and 92% received surgery. Chemotherapy was given to 58% of stage III colon cases, radiotherapy to 25% of rectal cases. Four percent of surgical cases underwent endoscopic polypectomy, and in 57% >=11 lymph nodes were examined. Five-year relative survival was good (60%), independent of sex and site. Adherence to treatment guidelines was satisfactory, but wider use of faecal blood testing and colonoscopy will anticipate stage at diagnosis and likely improve survival. PMID- 23729485 TI - Educational differences in estimated and measured physical fitness. AB - BACKGROUND: Available information about the association between education and physical fitness (PF) is scarce. The purpose of this study was to examine educational differences in PF in the working age population using different methods to assess PF. METHODS: The Health 2000 Survey was carried out for adults aged >= 30 years (n = 8028) in Finland. For this study, 30-54-year-old men and women with data on PF and physical activity (PA) were selected (n = 3724). PF was assessed by self-estimated overall physical fitness and running ability, a physician's estimation of a participant's working capacity, the trunk extensors' endurance and hand grip strength tests. The highest educational qualification taken by the participant was used as a measure of education. The analyses were adjusted for age, PA, BMI, smoking and chronic diseases. RESULTS: PF was best in the high-educated men and women. The educational differences were minor in self estimated overall PF. Adjusting for the covariates, the differences in self estimated running ability and working capacity decreased. The educational differences in the trunk extensors' endurance test were independent of covariates. PA and other health behaviours contributed most to the differences. CONCLUSION: People with high education had better PF irrespective of the method used to assess PF. A large amount of the educational differences could be explained by PA and other health behaviours. More research is needed to understand the determinants of educational differences in PF. PMID- 23729487 TI - Denis Jourdanet (1815-1892) and the early recognition of the role of hypoxia at high altitude. AB - Denis Jourdanet (1815-1892) was a French physician who spent many years in Mexico studying the effects of high altitude. He was a major benefactor of Paul Bert (1833-1886), who is often called the father of high-altitude physiology because his book La pression barometrique was the first clear statement that the harmful effects of high altitude are caused by the low partial pressure of oxygen. However, Bert's writings make it clear that the first recognition of the critical role of hypoxia at high altitude should be credited to Jourdanet. Jourdanet noted that some of his patients at high altitude had features that are typical of anemia at sea level, including rapid pulse, dizziness, and occasional fainting spells. These symptoms were correctly attributed to the low oxygen level in the blood and he coined the terms "anoxyhemie" and "anemie barometrique" to draw a parallel between the effects of high altitude on the one hand and anemia at sea level on the other. He also studied the relations between barometric pressure and altitude, and the characteristics of the native populations in Mexico at different altitudes. Jourdanet believed that patients with various diseases including pulmonary tuberculosis were improved if they went to altitudes above 2,000 m. This led him to recommend "aerotherapie" in which these patients were treated in low-pressure chambers. Little has been written about Jourdanet, and his work deserves to be better known. PMID- 23729488 TI - Insulin therapy attitudes and beliefs of physicians in Middle Eastern Arab countries. AB - BACKGROUND: Studies assessing attitudes and beliefs of physicians regarding insulin therapy in Arab countries are scant despite the high prevalence of type 2 diabetes mellitus (T2DM). OBJECTIVE: This study examines family physicians' attitudes and beliefs towards insulin therapy in T2DM patients in the East Mediterranean Region of the World Organization of National Colleges, Academies and Academic Associations of General Practitioners/Family Physicians. METHODS: This is a cross-sectional study conducted on 348 family physicians invited via email to fill an anonymous online questionnaire about their attitudes, beliefs and perceived barriers regarding insulin initiation in T2DM patients. RESULTS: One hundred and twenty-two physicians completed the questionnaire. Of the 122 physicians, 73.6% preferred to delay insulin initiation until it is absolutely essential and 59.0% initiated it themselves. The majority agreed that T2DM patients benefit from insulin prior to the development of complications (85.7%) and that patient education is important (99.1%) and uncomplicated (74.7%). Sixty three per cent expressed reluctance to start insulin mostly because of perceived patients' reluctance. Referral to endocrinologists to initiate insulin therapy was associated with inadequate experience and concern about risks, particularly in elderly patients (backward logistic regression, P < 0.05). Physicians' reluctance to initiate insulin therapy was associated with patients' perception of insulin initiation as a personal failure and threat to the quality of life (backward logistic regression, P < 0.05). CONCLUSIONS: Although family physicians in the Arab world believe in the benefits of insulin therapy, many are reluctant to initiate it themselves. Further studies are needed per country, as well as multiple measures to minimize the physicians' barriers to insulin prescription. PMID- 23729486 TI - Ezrin/radixin/moesin proteins differentially regulate endothelial hyperpermeability after thrombin. AB - Endothelial cell (EC) barrier disruption induced by inflammatory agonists such as thrombin leads to potentially lethal physiological dysfunction such as alveolar flooding, hypoxemia, and pulmonary edema. Thrombin stimulates paracellular gap and F-actin stress fiber formation, triggers actomyosin contraction, and alters EC permeability through multiple mechanisms that include protein kinase C (PKC) activation. We previously have shown that the ezrin, radixin, and moesin (ERM) actin-binding proteins differentially participate in sphingosine-1 phosphate induced EC barrier enhancement. Phosphorylation of a conserved threonine residue in the COOH-terminus of ERM proteins causes conformational changes in ERM to unmask binding sites and is considered a hallmark of ERM activation. In the present study we test the hypothesis that ERM proteins are phosphorylated on this critical threonine residue by thrombin-induced signaling events and explore the role of the ERM family in modulating thrombin-induced cytoskeletal rearrangement and EC barrier function. Thrombin promotes ERM phosphorylation at this threonine residue (ezrin Thr567, radixin Thr564, moesin Thr558) in a PKC-dependent fashion and induces translocation of phosphorylated ERM to the EC periphery. Thrombin induced ERM threonine phosphorylation is likely synergistically mediated by protease-activated receptors PAR1 and PAR2. Using the siRNA approach, depletion of either moesin alone or of all three ERM proteins significantly attenuates thrombin-induced increase in EC barrier permeability (transendothelial electrical resistance), cytoskeletal rearrangements, paracellular gap formation, and accumulation of phospho-myosin light chain. In contrast, radixin depletion exerts opposing effects on these indexes. These data suggest that ERM proteins play important differential roles in the thrombin-induced modulation of EC permeability, with moesin promoting barrier dysfunction and radixin opposing it. PMID- 23729489 TI - Chronic kidney disease is associated with increased platelet activation and poor response to antiplatelet therapy. AB - BACKGROUND: Chronic kidney disease (CKD) is a common co-morbidity of patients with atherosclerotic vascular disease, and may influence the response to antiplatelet therapy. We, therefore, sought to investigate its effect on platelet activation and on-treatment residual platelet reactivity. METHODS: We assessed platelet activation and the response to clopidogrel and aspirin in 316 patients after percutaneous intervention with stent implantation. CKD was defined as a glomerular filtration rate <60 mL/min/1.73 m(2) according to the Modification of Diet in Renal Disease formula. Surface expression of activated glycoprotein IIb/IIIa without the addition of agonists was determined to assess baseline platelet activation. GPIIb/IIIa in response to adenosine diphosphate (ADP) and arachidonic acid (AA), as well as the VerifyNow assays and light transmission aggregometry (LTA) were used to measure residual platelet reactivity. RESULTS: Baseline platelet activation was significantly increased in CKD patients compared with patients without renal insufficiency [3.1 versus 2.7 mean fluorescence intensity (MFI), P = 0.001]. Moreover, patients with CKD exhibited a more pronounced expression of GPIIb/IIIa in response to ADP (13 versus 9.6 MFI) and AA (6 versus 5.1 MFI; both P<= 0.02) than patients without CKD. In the VerifyNow assays, CKD patients showed significantly higher platelet reactivity than patients without CKD (P2Y12 assay: 239 versus 182 P2Y12 Reaction Units; aspirin assay: 415 versus 399 Aspirin Reaction Units; both P<= 0.03). Further, patients with CKD had significantly higher platelet reactivity by LTA in response to ADP (49.9 versus 43.2%, P = 0.01). Finally, high on-treatment residual ADP-inducible platelet reactivity by the VerifyNow P2Y12 assay and by LTA occurred significantly more frequent in patients with CKD (VerifyNow: 52.2 versus 26.2%, P < 0.001; LTA: 23.3 versus 12.1%, P = 0.01). CONCLUSIONS: Patients with CKD exhibit increased platelet activation, and an attenuated response to dual antiplatelet therapy compared with patients without renal insufficiency. PMID- 23729490 TI - Multiple imputation: dealing with missing data. AB - In many fields, including the field of nephrology, missing data are unfortunately an unavoidable problem in clinical/epidemiological research. The most common methods for dealing with missing data are complete case analysis-excluding patients with missing data--mean substitution--replacing missing values of a variable with the average of known values for that variable-and last observation carried forward. However, these methods have severe drawbacks potentially resulting in biased estimates and/or standard errors. In recent years, a new method has arisen for dealing with missing data called multiple imputation. This method predicts missing values based on other data present in the same patient. This procedure is repeated several times, resulting in multiple imputed data sets. Thereafter, estimates and standard errors are calculated in each imputation set and pooled into one overall estimate and standard error. The main advantage of this method is that missing data uncertainty is taken into account. Another advantage is that the method of multiple imputation gives unbiased results when data are missing at random, which is the most common type of missing data in clinical practice, whereas conventional methods do not. However, the method of multiple imputation has scarcely been used in medical literature. We, therefore, encourage authors to do so in the future when possible. PMID- 23729491 TI - Mutational analyses of the ATP6V1B1 and ATP6V0A4 genes in patients with primary distal renal tubular acidosis. AB - BACKGROUND: Mutations in the ATP6V1B1 and the ATP6V0A4 genes cause primary autosomal-recessive distal renal tubular acidosis (dRTA). Large deletions of either gene in patients with dRTA have not been described. METHODS: The ATP6V1B1 and ATP6V0A4 genes were directly sequenced in 11 Japanese patients with primary dRTA from nine unrelated kindreds. Large heterozygous deletions were analyzed by quantitative real-time polymerase chain reaction (PCR). The clinical features of the 11 patients were also investigated. RESULTS: Novel mutations in the ATP6V1B1 gene were identified in two kindreds, including frameshift, in-frame insertion and nonsense mutations. Large deletions in the ATP6V0A4 gene were identified in two kindreds. Exon 15 of ATP6V0A4 was not amplified in one patient, with a long PCR confirming compound heterozygous deletions of 3.7- and 6.9-kb nucleotides, including all of exon 15. Direct DNA sequencing revealed a heterozygous frameshift mutation in ATP6V0A4 in another patient, with quantitative real-time PCR indicating that all exons up to exon 8 were deleted in one allele. Clinical investigation showed that four of the six patients with available clinical data presented with hyperammonemia at onset. CONCLUSIONS: To our knowledge, these dRTA patients are the first to show large deletions involving one or more entire exons of the ATP6V0A4 gene. Quantitative PCR amplification may be useful in detecting heterozygous large deletions. These results expand the spectrum of mutations in the ATP6V0A4 and ATP6V1B1 genes associated with primary dRTA and provide insight into possible structure-function relationships. PMID- 23729492 TI - Can the Error-Monitoring System Differentiate ADHD From ADHD With Reading Disability? Reading and Executive Dysfunction as Reflected in Error Monitoring. AB - OBJECTIVES: ADHD and reading disability (RD) are distinct disorders that often appear together. Individuals with both disorders are currently diagnosed based on questionnaires/behavioral performance. The present study aimed to determine whether ADHD alone differs from ADHD with RD in error monitoring, which is part of the executive system, as measured while reading. METHOD: Event-related potentials were recorded during a lexical decision task performed by children with comorbid ADHD and RD and children with ADHD. RESULTS: Lower executive function and reading abilities were accompanied by decreased event-related potential components in participants with ADHD and RD, compared with participants with ADHD. CONCLUSION: Results suggest that the error monitoring activation can be used as a possible biomarker to objectively differentiate ADHD with RD from ADHD alone. PMID- 23729493 TI - Factorial Validity of the ADHD Adult Symptom Rating Scale in a French Community Sample: Results From the ChiP-ARD Study. AB - OBJECTIVE: Recent publications reported that a bifactor model better represented the underlying structure of ADHD than classical models, at least in youth. The Adult ADHD Symptoms Rating Scale (ASRS) has been translated into many languages, but a single study compared its structure in adults across Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) and International Classification of Diseases (ICD-10) classifications. METHOD: We investigated the factor structure, reliability, and measurement invariance of the ASRS among a community sample of 1,171 adults. RESULTS: Results support a bifactor model, including one general ADHD factor and three specific Inattention, Hyperactivity, and Impulsivity factors corresponding to ICD-10, albeit the Impulsivity specific factor was weakly defined. Results also support the complete measurement invariance of this model across gender and age groups, and that men have higher scores than women on the ADHD G-factor but lower scores on all three S-factors. CONCLUSION: Results suggest that a total ASRS-ADHD score is meaningful, reliable, and valid in adults. (J. of Att. Dis. 2016; 20(6) 530-541). PMID- 23729494 TI - Changes in indications and oncological outcomes of radical prostatectomy after 2000--data from 1268 Japanese patients treated with radical prostatectomy between 2000 and 2009. AB - OBJECTIVE: The aim of the study was to characterize trends in indications for and oncological outcomes of radical prostatectomy after 2000. METHODS: Data from 1268 patients undergoing radical prostatectomy without neoadjuvant therapy between 2000 and 2009 at four urological centers in Japan were retrospectively reviewed. Changes in age at radical prostatectomy, prostate-specific antigen level, biopsy Gleason score, clinical T stage, D'Amico risk classification, organ-confined disease and tumor volume in surgical specimens were analyzed over time. RESULTS: The median age at radical prostatectomy decreased from 68 years in 2000-2 to 65 years in 2009 (P < 0.001). Approximately 63.3% of patients were >=65 years old, and 31.4% of patients were >=70 years old during the whole study period. The median prostate-specific antigen level decreased from 8.61 ng/ml in 2000-2 to 6.90 ng/ml in 2009 (P < 0.001). The rate of organ-confined disease increased from 52.8% in 2000-2 to 72.5% in 2009 (P = 0.004). The median tumor volume decreased from 1.70 cc in 2000-2 to 1.28 cc in 2009 (P = 0.017). The proportion of biopsy Gleason score 7 increased from 40.6% in 2000-2 to 60.1% in 2009 (P < 0.001), and the proportion of the intermediate-risk group increased from 39.5% in 2000-2 to 59.5% in 2009 (P < 0.001). CONCLUSIONS: Age at radical prostatectomy for men with localized prostate cancer was higher in Japan than in the USA or Europe. Prostate specific antigen, non-organ-confined disease and tumor volume decreased during the study period, whereas Gleason score 7 and intermediate-risk disease increased during the study period. This information enables comparison of outcomes between various treatments, between various geographic regions and between various time periods. PMID- 23729495 TI - Diabetes mellitus with obesity is a predictor of recurrence in patients with non metastatic renal cell carcinoma. AB - OBJECTIVE: To investigate the associations of diabetes mellitus with recurrence and prognosis after surgery for non-metastatic renal cell carcinoma and the effect modification of obesity on the above relationships. METHODS: We retrospectively evaluated 543 patients with non-metastatic renal cell carcinoma (pT1-4N0M0) who underwent radical or partial nephrectomy. The association of diabetes mellitus with recurrence was analyzed using the Kaplan-Meier method and the Cox regression model. We also examined whether the above relationships were modified by obesity using subgroup analysis and tests of interaction. For subgroup analysis, the body mass index was categorized as non-obese (<25 kg/m(2)) and obese (>=25 kg/m(2)). RESULTS: Eighty-two patients (15.1%) had a history of diabetes mellitus. During the mean follow-up of 66.7 months, 68 patients (12.5%) developed recurrence. Although the body mass index was not associated with recurrence, diabetes mellitus was an independent predictor of recurrence in multivariate analysis (hazard ratio 2.43, P = 0.003), along with tumor diameter, grade and pathological T stage. In further subgroup analysis, the same relationship between diabetes mellitus and recurrence was clearly shown in the obese group (hazard ratio 4.07, P = 0.010), but not in the non-obese group (hazard ratio 1.95, P = 0.125). At the same time, obesity modified the effect of diabetes mellitus on recurrence with a trend (P-interaction = 0.086). In the obese group, 5-year recurrence-free survival rates were 75.3 and 91.9% for diabetes mellitus and non-diabetes mellitus patients, respectively (P < 0.001). Restricting analyses to patients with clear cell type histology did not materially change these results. CONCLUSIONS: Diabetes mellitus is a predictor of recurrence following surgery for non-metastatic renal cell carcinoma, especially in obese patients. PMID- 23729496 TI - First description of Mycobacterium heckeshornense infection in a feline immunodeficiency virus-positive cat. AB - A 13-year-old cat was presented to the veterinary clinic with poor condition, vomiting and a reduced appetite. A painful abdomen was diagnosed because of tension and defence reactions on palpation. Diagnostic laparotomy showed a thickening of the colon and caecal intestinal wall. Histopathological investigation of intestinal biopsies revealed focal severe granulomatous inflammation with numerous acid-fast bacilli in the tela submucosa. The complete blood count test showed a severe lymphopenia and anaemia, and the cat tested positive for feline immunodeficiency virus (FIV) antibodies by enzyme-linked immunosorbent assay. The cat was euthanased and necropsied. Multifocal granulomatous nodules were present in the intestines, liver and kidneys. The gastric lymph node was markedly enlarged and showed a caseous cut surface. Histopathology revealed a systemic mycobacteriosis affecting intestine, lymph nodes, liver and kidneys. The mycobacterial strain was cultured and determined by its unique 16S rRNA gene sequence as Mycobacterium heckeshornense. This is the first reported case of M heckeshornense in a cat. It was suspected that the disseminated mycobacteriosis was supported by the FIV infection. PMID- 23729497 TI - Ultra-distal large-bore intracranial access using the hyperflexible Navien distal intracranial catheter for the treatment of cerebrovascular pathologies: a technical note. AB - BACKGROUND: Successful neuroendovascular treatments rely on microcatheter stability from guide catheter support. We present our experience using a new large-bore 0.058 inch or 0.072 inch inner diameter (ID) hyperflexible access catheter placed deep within the intracranial circulation during the neurointervention. METHODS: We retrospectively reviewed all neurointerventions performed by the senior author during an 18-month period to identify patients in whom the Navien intracranial catheter was placed in an ultra-distal position, defined as beyond the clinoidal internal carotid artery (ICA) or V3 segment of the vertebral artery. Procedural data collected included parent artery tortuosity, technique for Navien advancement, intraprocedural Navien position and periprocedural complications. RESULTS: The Navien, either 6 F 0.072 inch ID or 5 F 0.058 inch ID, provided ultra-distal large-bore access in the following 11 intracranial interventions: anterior circulation aneurysm treatment with Pipeline embolization device (PED) (n=3); posterior circulation aneurysm single-stage stent coiling (n=5); liquid embolization of arteriovenous malformations (n=2); PED coiling of posterior circulation aneurysm (n=1). The Navien was tracked into position over a Marksman microcatheter in 10/11 cases and a Headway 27 microcatheter in one case. Intraprocedural Navien positions were as follows: supraclinoid ICA (n=2); mid M1 (n=1); V3-V4 junction (n=2) (both using 6 F Navien); distal V4 (n=3); proximal basilar (n=1); proximal-mid basilar (n=1); mid basilar (n=1). No significant catheter-related complications occurred. CONCLUSIONS: The Navien is the newest hyperflexible access catheter that is highly trackable into ultra-distal intracranial positions. It maneuvers atraumatically, providing improved distal intracranial support for a variety of complex cerebrovascular interventions and preserves necessary ID for quality intraprocedural roadmaps and angiography. PMID- 23729498 TI - Comparison of CT and fluoroscopic guidance for lumbar puncture in an obese population with prior failed unguided attempt. AB - BACKGROUND AND PURPOSE: In the past 50 years, fluoroscopic guidance has been used to improve upon lumbar puncture (LP) technique that was unchanged for over a century. Recently, CT has seen increasing use as a guidance modality due to its ability to demonstrate soft tissue contrast and provide millimeter accuracy with needle targeting. This study compared procedure time and radiation dosages for fluoroscopic and CT guided LP. MATERIALS AND METHODS: This institutional review board and Health Insurance Portability and Accountability Act (HIPAA) compliant study was a retrospective review of a consecutive cohort referred for image guided LP. For CT, 45 patients aged 49 years (range 20-78, SD 14) with body mass index (BMI) values of 33 kg/m(2) (range 20-50, SD 12) were included. For fluoroscopy, 100 patients aged 47 years (range 18-88, SD 17) with BMI values of 29 kg/m(2) (range 15-56, SD 9) were included. CT procedure time was determined using picture archiving and communication system (PACS) image time stamps. Radiation dose was determined using the CT dose report and effective dose conversion factors. Fluoroscopic procedure time was determined from nursing. Fluoroscopic radiation dose was calculated from dose-area product (DAP) and fluoroscopy times, with effective dosage calculated using simulation software. RESULTS: For CT, procedure time average was 14 min (range 5-42, SD 8.5). Average dose-length product was 120 mGy*cm (range 39-211, SD 43) and average effective dose was 1.98 mSv (range 0.2-8.18, SD 4.4). For fluoroscopy, procedure time averaged 12 min (range 12-30, SD 6). Average DAP was 10 Gy*cm(2) (range 0.1-70, SD 11) and effective dose estimate averaged 2.9 mSv (range 0.9-9.4, SD 1.9). There were no unsuccessful taps or complications. CONCLUSIONS: Both fluoroscopic and CT guidance may be used to perform an LP in an obese population with a short procedure time and low radiation dose. PMID- 23729499 TI - Regulatory T cell epitopes (Tregitopes) in IgG induce tolerance in vivo and lack immunogenicity per se. AB - Tregitopes are a set of epitopes, derived from IgG, that bind to MHCII, activate nTregs, and promote tolerance. We have now confirmed that coadministration of Tregitopes with a range of proteins (autoantigens and nominal antigens, such as OVA) in vitro and in vivo leads to suppression of T cell and antibody responses to the test antigens. In this study, we demonstrate that Tregitopes are not immunogenic in vivo even when emulsified with strong adjuvants, such as IFA or CFA. Moreover, in vivo administration of Tregitopes with IFA or CFA does not induce Th1 or Th2 cytokine expression under restimulation conditions in vitro. We investigated tolerance induction by codelivering Tregitopes with OVA using B cells. When B cells were pulsed with OVA plus Tregitopes and transferred into naive mice, we found that cellular and humoral immune responses to the OVA were suppressed. As a result of their ability to induce Tregs and the absence of immunogenicity in the context of strong adjuvants, Tregitopes might be considered a novel immunomodulatory approach for the suppression of immune responses to protein therapeutics (such as FVIII and mAb), as well as for treatment of autoimmune diseases. PMID- 23729500 TI - Noncanonical dendritic cell differentiation and survival driven by a bacteremic pathogen. AB - Maintenance of blood DC homeostasis is essential to preventing autoimmunity while controlling chronic infection. However, the ability of bacteremic pathogens to directly regulate blood DC homeostasis has not been defined. One such bacteremic pathogen, Porphyromonas gingivalis, is shown by our group to survive within mDCs under aerobic conditions and therein, metastasize from its oral mucosal niche. This is accompanied by expansion of the blood mDC pool in vivo, independently of canonical DC poietins. We presently know little of how this bacteremic pathogen causes blood DC expansion and the pathophysiological significance. This work shows that optimum differentiation of MoDCs from primary human monocytes, with or without GM-CSF/IL-4, is dependent on infection with P. gingivalis strains expressing the DC-SIGN ligand mfa-1. DC differentiation is lost when DC-SIGN is blocked with its ligand HIV gp120 or knocked out by siRNA gene silencing. Thus, we have identified a novel, noncanonical pathway of DC differentiation. We term these PDDCs and show that PDDCs are bona fide DCs, based on phenotype and phagocytic activity when immature and the ability to up-regulate accessory molecules and stimulate allo-CD4(+) T cell proliferation when matured. The latter is dependent on the P. gingivalis strain used to initially "educate" PDDCs. Moreover, we show that P. gingivalis-infected, conventional MoDCs become resistant to apoptosis and inflammatory pyroptosis, as determined by levels of Annexin V and caspase-8, -3/7, and -1. Taken together, we provide new insights into how a relatively asymptomatic bacteremia may influence immune homeostasis and promote chronic inflammation. PMID- 23729501 TI - Cigarette price minimization strategies in the United States: price reductions and responsiveness to excise taxes. AB - INTRODUCTION: Because cigarette price minimization strategies can provide substantial price reductions for individuals continuing their usual smoking behaviors following federal and state cigarette excise tax increases, we examined independent price reductions compensating for overlapping strategies. The possible availability of larger independent price reduction opportunities in states with higher cigarette excise taxes is explored. METHODS: Regression analysis used the 2006-2007 Tobacco Use Supplement of the Current Population Survey (N = 26,826) to explore national and state-level independent price reductions that smokers obtained from purchasing cigarettes (a) by the carton, (b) in a state with a lower average after-tax cigarette price than in the state of residence, and (c) in "some other way," including online or in another country. Price reductions from these strategies are estimated jointly to compensate for known overlapping strategies. RESULTS: Each strategy reduced the price of cigarettes by 64-94 cents per pack. These price reductions are 9%-22% lower than conventionally estimated results not compensating for overlapping strategies. Price reductions vary substantially by state. Following cigarette excise tax increases, the price reduction available from purchasing cigarettes by cartons increased. Additionally, the price reduction from purchasing cigarettes in a state with a lower average after-tax cigarette price is positively associated with state cigarette excise tax rates and border state cigarette excise tax rate differentials. CONCLUSIONS: Findings from this large, nationally representative study of cigarette smokers suggest that price reductions are larger in states with higher cigarette excise taxes, and increase as cigarette excise taxes rise. PMID- 23729502 TI - Contribution of the 7beta-hydroxysteroid dehydrogenase from Ruminococcus gnavus N53 to ursodeoxycholic acid formation in the human colon. AB - Bile acid composition in the colon is determined by bile acid flow in the intestines, the population of bile acid-converting bacteria, and the properties of the responsible bacterial enzymes. Ursodeoxycholic acid (UDCA) is regarded as a chemopreventive beneficial bile acid due to its low hydrophobicity. However, it is a minor constituent of human bile acids. Here, we characterized an UDCA producing bacterium, N53, isolated from human feces. 16S rDNA sequence analysis identified this isolate as Ruminococcus gnavus, a novel UDCA-producer. The forward reaction that produces UDCA from 7-oxo-lithocholic acid was observed to have a growth-dependent conversion rate of 90-100% after culture in GAM broth containing 1 mM 7-oxo-lithocholic acid, while the reverse reaction was undetectable. The gene encoding 7beta-hydroxysteroid dehydrogenase (7beta-HSDH), which facilitates the UDCA-producing reaction, was cloned and overexpressed in Escherichia coli. Characterization of the purified 7beta-HSDH revealed that the kcat/Km value was about 55-fold higher for the forward reaction than for the reverse reaction, indicating that the enzyme favors the UDCA-producing reaction. As R. gnavus is a common, core bacterium of the human gut microbiota, these results suggest that this bacterium plays a pivotal role in UDCA formation in the colon. PMID- 23729504 TI - CNVinspector: a web-based tool for the interactive evaluation of copy number variations in single patients and in cohorts. AB - OBJECTIVES: Many genetic disorders are caused by copy number variations (CNVs) in the human genome. However, the large number of benign CNV polymorphisms makes it difficult to delineate causative variants for a certain disease phenotype. Hence, we set out to create software that accumulates and visualises locus-specific knowledge and enables clinicians to study their own CNVs in the context of known polymorphisms and disease variants. METHODS: CNV data from healthy cohorts (Database of Genomic Variants) and from disease-related databases (DECIPHER) were integrated into a joint resource. Data are presented in an interactive web-based application that allows inspection, evaluation and filtering of CNVs in single individuals or in entire cohorts. RESULTS: CNVinspector provides simple interfaces to upload CNV data, compare them with own or published control data and visualise the results in graphical interfaces. Beyond choosing control data from different public studies, platforms and methods, dedicated filter options allow the detection of CNVs that are either enriched in patients or depleted in controls. Alternatively, a search can be restricted to those CNVs that appear in individuals of similar clinical phenotype. For each gene of interest within a CNV, we provide a link to NCBI, ENSEMBL and the GeneDistiller search engine to browse for potential disease-associated genes. CONCLUSIONS: With its user friendly handling, the integration of control data and the filtering options, CNVinspector will facilitate the daily work of clinical geneticists and accelerate the delineation of new syndromes and gene functions. CNVinspector is freely accessible under http://www.cnvinspector.org. PMID- 23729505 TI - Focus groups identify pressures to prescribe antimicrobials. PMID- 23729503 TI - Risk of childhood leukaemia and non-Hodgkin's lymphoma after parental occupational exposure to solvents and other agents: the SETIL Study. AB - AIM: In the context of the Italian Multicentric Epidemiological Study on Risk Factors for Childhood Leukaemia and Non-Hodgkin's Lymphoma (SETIL), the risk of childhood cancer was investigated in relation to parental occupational exposures. METHODS: All cases of childhood leukaemia and non-Hodgkin's lymphoma (NHL) in children aged 0-10 years were identified. Controls were chosen at random from the local population in each region. Parents were interviewed using a structured questionnaire. The collected data were blindly reviewed by expert industrial hygienists in order to estimate exposure to a list of agents. Statistical analyses were performed for each agent using unconditional multivariable logistic regression models, taking into account timing of exposure. RESULTS: 683 cases of acute childhood leukaemia, 97 cases of NHL and 1044 controls were identified. Increased risk of childhood leukaemia was found for maternal exposure to aliphatic (OR 4.3) or aromatic hydrocarbons (OR 3.8) in the preconception period, and for paternal exposure to diesel exhaust (OR 1.4), lead exposure (OR 1.7) and mineral oils (OR 1.4)[corrected]. Risk of NHL appeared to be related to paternal exposure to oxygenated solvents (OR 2.5) and petrol exhaust (OR 2.2). CONCLUSIONS: We found increased risk for childhood leukaemia associated with maternal occupational exposure to aromatic and aliphatic hydrocarbons, particularly in the preconception period; increased risks were also observed for paternal exposure to diesel exhaust fumes, mineral oils and lead. The risk of NHL appeared to be related to paternal exposure to oxygenated solvent and petrol exhausts. PMID- 23729506 TI - FAO warns Europe of the threat of African swine fever. PMID- 23729507 TI - Defra extends its badger vaccination fund. PMID- 23729508 TI - Survey suggests many pets do not receive preventive healthcare. PMID- 23729510 TI - Vet nurses' council discusses plans to change the Practice Standards Scheme. PMID- 23729511 TI - RCVS Charitable Trust joins All Trials campaign. PMID- 23729512 TI - UK horse passport rules--'a catalogue of misunderstanding'. PMID- 23729513 TI - New directions in teaching and research. PMID- 23729517 TI - Educating owners--the key to managing cat populations. PMID- 23729518 TI - Teaching dog owners new tricks. PMID- 23729519 TI - BVA policy on bovine TB and badger control. PMID- 23729520 TI - Importance of communication. PMID- 23729521 TI - History of veterinary science in Kenya. PMID- 23729522 TI - A vet not by any other name. PMID- 23729529 TI - Intraoperative optical imaging of functional brain areas for improved image guided surgery. AB - Intraoperative optical imaging of intrinsic signals can improve the localization of functional areas of the cortex. On the basis of a review of the current state of technology, a setup was developed and evaluated. The aim was to implement an easy-to-use and robust imaging setup that can be used in clinical routine with standard hardware equipment (surgical microscope, high-resolution camera, stimulator for peripheral nerve stimulation) and custom-made software for intraoperative and postoperative data analysis. Evaluation of different light sources (halogen, xenon) showed a sufficient temporal behavior of xenon light without using a stabilized power supply. Spatial binning (2*2) of the camera reduces temporal variations in the images by preserving a high spatial resolution. The setup was tested in eight patients. Images were acquired continuously for 9 min with alternating 30-s rest and 30-s stimulation conditions. Intraoperative measurement and visualization of high-resolution two dimensional activity maps could be achieved in <15 min. The detected functional regions corresponded with anatomical and electrophysiological validation. The integration of optical imaging in clinical routine could successfully be achieved using standard hardware, which improves guidance for the surgeon during interventions near the eloquent areas of the brain. PMID- 23729530 TI - Recommendations for accurate numerical blood flow simulations of stented intracranial aneurysms. AB - The number of scientific publications dealing with stented intracranial aneurysms is rapidly increasing. Powerful computational facilities are now available; an accurate computational modeling of hemodynamics in patient-specific configurations is, however, still being sought. Furthermore, there is still no general agreement on the quantities that should be computed and on the most adequate analysis for intervention support. In this article, the accurate representation of patient geometry is first discussed, involving successive improvements. Concerning the second step, the mesh required for the numerical simulation is especially challenging when deploying a stent with very fine wire structures. Third, the description of the fluid properties is a major challenge. Finally, a founded quantitative analysis of the simulation results is obviously needed to support interventional decisions. In the present work, an attempt has been made to review the most important steps for a high-quality computational fluid dynamics computation of virtually stented intracranial aneurysms. In consequence, this leads to concrete recommendations, whereby the obtained results are not discussed for their medical relevance but for the evaluation of their quality. This investigation might hopefully be helpful for further studies considering stent deployment in patient-specific geometries, in particular regarding the generation of the most appropriate computational model. PMID- 23729531 TI - In situ optical coherence tomography of percutaneous implant-tissue interfaces in a murine model. AB - Novel surface coatings of percutaneous implants need to be tested in biocompatibility studies. The use of animal models for testing usually involves numerous lethal biopsies for the analysis of the implant-tissue interface. In this study, optical coherence tomography (OCT) was used to monitor the reaction of the skin to a percutaneous implant in an animal model of hairless but immunocompetent mice. In vivo optical biopsies with OCT were taken at days 7 and 21 after implantation and post mortem on the day of noticeable inflammation. A Fourier-domain OCT was programmed for spoke pattern scanning schemes centered at the implant midpoint to reduce motion artifacts during in vivo imaging. Image segmentation allowed the automatic detection and morphometric analysis of the skin contour and the subcutaneous implant anchor. On the basis of the segmentation, the overall refractive index of the tissue within one OCT data set was estimated as a free parameter of a fitting algorithm, which corrects for the curved distortion of the planar implant base in the OCT images. OCT in combination with the spoke scanning scheme and image processing provided time resolved three-dimensional optical biopsies around the implants to assess tissue morphology. PMID- 23729532 TI - Evaluation of intraoperative optical imaging analysis methods by phantom and patient measurements. AB - Intraoperative optical imaging (IOI) is a localization method for functional areas of the human brain cortex during neurosurgical procedures. The aim of the current work was to develop of a new analysis technique for the computation of two-dimensional IOI activity maps that is suited especially for use in clinical routine. The new analysis technique includes a stimulation scheme that comprises 30-s rest and 30-s stimulation conditions, in connection with pixelwise spectral power analysis for activity map calculation. A software phantom was used for verification of the implemented algorithms as well as for the comparison with the commonly used relative difference imaging method. Furthermore, the analysis technique was tested using intraoperative measurements on eight patients. The comparison with the relative difference algorithm revealed an averaged improvement of the signal-to-noise ratio between 95% and 130% for activity maps computed from intraoperatively acquired patient datasets. The results show that the new imaging technique improves the activity map quality of IOI especially under difficult intraoperative imaging conditions and is therefore especially suited for use in clinical routine. PMID- 23729533 TI - Trends in twin pregnancies and mode of delivery during the last 30 years: inconsistency between guidelines and clinical practice. AB - AIM: To investigate the characteristics of twin pregnancies and their mode of delivery over a 30-year period, in order to define the current trends in clinical practice regarding twin deliveries and the factors that influence these practices. MATERIALS AND METHODS: A retrospective study of twin deliveries at >=24 weeks of gestation between January 1st, 1981 and December 31, 2010. Data concerning number of twin deliveries, mode of delivery, maternal age, use of ART techniques, parity, gestational age at delivery, birth weight and Apgar scores were collected from labor ward records. RESULTS: Over the years there has been a statistically significant increase in the number of twin deliveries, twins after IVF, cesarean section rate, maternal age, nulliparity and a statistically significant reduction in term deliveries, mean birth weight and assisted vaginal deliveries. Maternal age, gestational age, parity and conception after IVF are factors related to the risk of performing a cesarean section. CONCLUSIONS: Despite the lack of adequate scientific evidence concerning the optimal route of delivery in twin pregnancies it seems that over time cesarean section has become the standard of care in most of twin pregnancies. Changes in the demographic characteristics contribute among other factors to this practice. PMID- 23729534 TI - First trimester maternal serum placental protein 13 levels in singleton vs. twin pregnancies with and without severe pre-eclampsia. AB - AIMS: To determine first trimester maternal serum placental protein 13 (PP13) in singletons vs. twins with and without severe preeclampsia (PE). METHODS: Serum samples were prospectively collected at 8-14 weeks of gestation. PP13 was determined by solid-phase immunoassay. Patients were recruited in community clinics throughout the country, and from the twin antenatal assessment clinic in Assaf Harofeh Medical Center, Zerifin, Israel. Demographics, medical, and pregnancy history were obtained at enrollment. Pregnancy outcome was collected after delivery. PP13 was compared by the Wilcoxon rank sum test. RESULTS: In singletons, PP13 declined with maternal weight and was lower in in vitro fertilization. Levels were converted into multiples of the median (MoMs) accordingly. In twins, the median was 1.74 MoM (n=76) vs. 1.00 in singletons (n=676, P<0.0001). Among twins with severe PE (n=10), the median was 1.53 MoM vs. 1.74 in unaffected twins (P=0.10), and 2.26 (n=6) for mild PE (P=0.30). Among singletons with severe PE, the median was 0.44 MoM (n=26, P<0.0001), and for mild PE 0.62 (n=17, P<0.001). CONCLUSION: PP13 is higher in twins than singletons, corresponding to the larger placental mass. Among singletons with severe PE, levels were significantly reduced, however, among twins, only a non-significant tendency for a reduction was recorded, and warrants further investigation in a larger series. PMID- 23729535 TI - Effect of oxygen tension on bacteria-stimulated cytokine production by fetal membranes. AB - AIM: Tissue culture studies indicate that bacterial products stimulate the production of proinflammatory cytokines by reproductive tissues. However, most of these studies have been performed under room air conditions, supplemented with 5% CO2. In this study, we tested whether O2 tension affects bacteria-stimulated cytokine production by extra-placental fetal membranes. METHODS: Cultures of full thickness membranes, isolated choriodecidua, and isolated amnion were exposed to bacteria and incubated under 21% (room air) or 5% O2 for 18 h. Cytokine concentrations in conditioned medium was quantified by immunoassay. RESULTS: Culture under 5% O2 increased production of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, but reduced IL-10 and IL-6 production by full membranes. Isolated choriodecidua responded to 5% O2 with increased IL-1beta production and reduced IL-6 production, but had no effect on TNF-alpha and IL-10 production was not detected. No effect of O2 tension on IL-1beta or IL-6 production by isolated amnion was detected, however, Escherichia coli-stimulated IL-10, TNF-alpha and IL-8 production was enhanced by culture under 5% O2. CONCLUSIONS: Increased oxygen tension reduces the pro-inflammatory responsiveness of cell cultures to E. coli and promotes an anti-inflammatory cytokine profile. Differential effects of O2 tension on choriodecidua and amnion suggests a network of paracrine factors that regulate cytokine levels in response to changes in O2 tension. PMID- 23729536 TI - Association of vitamin D concentrations with adiposity indices among preadolescent children in Korea. AB - BACKGROUND AND OBJECTIVE: We aimed to investigate the association between serum 25-hydroxyvitamin D (25(OH)D) and anthropometric indicators of adiposity among Korean preadolescent children aged 7-9 years. SUBJECTS AND METHODS: Children aged 7 to 9 from the Ewha Birth & Growth Cohort were followed up from July to August 2011. Serum 25(OH)D concentration was measured using radio immunoassay. We assessed the magnitude of cross-sectional association with vitamin D concentrations and indicators of adiposity [body mass index (BMI), waist circumference (WC), mid-arm circumference (MAC), body fat mass (BFM), percent body fat (PBF), and triceps skinfold thickness (TSF)] using multiple linear and logistic regression analyses adjusted for sex, age, birth order, maternal education, and fruit/fruit juice intake. RESULTS: Thirty-two (16%) out of a total of 205 children showed an optimal level of serum 25(OH)D, but most children did not reach a sufficient level (<30 ng/mL) even in summer. The level of 25(OH)D was inversely associated with BMI (beta=-0.10, p<0.01), WC (beta=-0.28, p<0.01), and BFM (beta=-0.12, p=0.02) after adjusting for confounding factors and showed marginal boundary with PBF (beta=-0.20, p=0.06) and TSF (beta=-0.11, p=0.08). Regarding the risk of overweight, a 13% protective effect per 1 ng/mL increase of 25(OH)D was shown even after adjusting for relevant confounding factors (adjusted odds ratio=0.87, 95% confidence interval 0.78-0.98). CONCLUSIONS: We found that the 25(OH)D concentrations were inversely associated with adiposity indices in preadolescent children. This study suggests that adequate vitamin D intake in growing children is crucial to maintain an optimal vitamin D level to prevent obesity and obesity-related health problems later in life. PMID- 23729537 TI - Early presentation of bilateral gonadoblastomas in a Denys-Drash syndrome patient: a cautionary tale for prophylactic gonadectomy. AB - Mutation of the Wilms tumor gene (WT1) is associated with two well-described syndromes called Denys-Drash (DDS) and Frasier (FS). Both are associated with nephropathy and ambiguous genitalia and have overlapping clinical and molecular features. The known risk of Wilms tumor in DDS and gonadoblastoma (GB) in FS patients requires tumor surveillance. The literature reports the occurrence of GB in DDS as lower than FS. This case highlights a very early presentation of bilateral GB in DDS and the consideration of early prophylactic gonadectomy at the time of diagnosis with DDS. PMID- 23729538 TI - Clinical and molecular characterization of Chilean patients with Leri-Weill dyschondrosteosis. AB - AIM: Leri-Weill dyschondrosteosis (LWD) is a mesomelic dysplasia with disproportionate short stature associated with short stature homeobox-containing gene (SHOX) haploinsufficiency. The objective of this study was to improve the diagnosis of patients with suspected LWD through molecular analysis. METHODS: Twelve patients from 11 families with a clinical diagnosis of LWD were analyzed with multiplex ligation-dependent probe amplification to detect deletions and duplications of SHOX and its enhancer regions. High resolution melting and sequencing was employed to screen for mutations in SHOX coding exons. RESULTS: The molecular-based screening strategy applied in these patients allowed detection of five SHOX deletions and two previously unreported SHOX missense mutations. CONCLUSION: Molecular studies confirmed the clinical diagnosis of LWD in seven out of 12 patients, which provided support for therapeutic decisions and improved genetic counseling in their families. PMID- 23729539 TI - A rare association between Rathke's cyst and hypophysitis in a patient with delayed sex development and growth failure. AB - We report an 18-year-old Japanese male with a lack of secondary sex characterization and growth failure caused by a rare association between Rathke's cyst and hypophysitis. He was referred to us because of delayed secondary sex characterization. Endocrinological examination showed panhypopituitarism, and the replacement of hydrocortisone, levothyroxine, and desmopressin acetate (DDAVP) was initiated. Brain magnetic resonance imaging (MRI) showed a suprasellar region and a swollen pituitary stalk. The mass was partially resected using the transsphenoidal approach. The pathological diagnosis was hypophysitis and Rathke's cyst. Follow-up MRI performed 1 year after surgery showed that the size of sellar region had not changed. After surgery, in addition to pre-operative hormonal replacement, growth hormone and testosterone were initiated. Two years later, the size of sellar region remains unchanged. In conclusion, while an association between Rathke's cyst and hypophysitis is rare, we suggest that this condition should be included in differential diagnosis of the sellar region, even in adolescents. PMID- 23729540 TI - Abdominal aorta intima media thickness in obese children. AB - The aim of this study is to investigate whether abdominal aorta intima media thickness (aIMT), increases in obese children and to determine risk factors. Ninety-six children aged 5-16 (51 obese and 45 non-obese) were enrolled in this prospective and cross-sectional study. Age, gender, and relative body mass index (BMI) were recorded. Their serum lipids, thyrotropin, fasting glucose and insulin levels were analyzed. The homeostasis model assessment (HOMA-IR) score was calculated for insulin resistance. Anthropometric and biochemical data were assessed along with aIMT. Findings in obese children were compared with those of non-obese control subjects. The aIMT was significantly greater in obese children. Similar trends were observed in both prepubertal children and adolescents. In obese children, the mean aIMT (mm) was 0.021 (years of age) +0.519. In non-obese children, the mean aIMT (mm) was 0.017 (years of age) +0.381. Our data suggests a relationship between glucose metabolism and aIMT in obese children. BMI was an independent risk factor for increasing aIMT. In conclusion, when compared with non-obese controls, obese children demonstrated significantly increased aIMT. Higher BMI, insulin, HOMA-IR and increased systolic blood pressure seem to be the main factors contributing to increased aIMT and risk for developing vascular disease. Childhood obesity contributes to the development of an increased aIMT. PMID- 23729541 TI - Type 1 diabetes in women with endometriosis: What is the risk of occurrence? PMID- 23729542 TI - Homeostasis model assessment of insulin resistance may not be reliable to evaluate insulin sensitivity in young obese children. PMID- 23729543 TI - Pigmentary hypertrichosis and non-autoimmune insulin-dependent diabetes mellitus (PHID) syndrome is associated with severe chronic inflammation and cardiomyopathy, and represents a new monogenic autoinflammatory syndrome. AB - Mutations in SLC29A3 lead to pigmentary hypertrichosis and non-autoimmune insulin dependent diabetes mellitus (PHID) and H syndromes, familial Rosai-Dorfman disease, and histiocytosis-lymphadenopathy plus syndrome. We report a new association of PHID syndrome with severe systemic inflammation, scleroderma-like changes, and cardiomyopathy. A 12-year-old girl with PHID syndrome presented with shortness of breath, hepatosplenomegaly, and raised erythrocyte sedimentation rate and C-reactive protein. An echocardiogram showed biventricular myocardial hypertrophy, and cardiac magnetic resonance imaging showed circumferential late gadolinium enhancement of the myocardium. No systemic amyloid deposits were observed on a whole-body serum amyloid P scintigraphy scan. Abdominal ultrasound revealed intra-abdominal fat surrounding the solid organs, suggesting a possibility of evolving lipodystrophy with visceral adiposity. PHID syndrome is a novel monogenic autoinflammatory syndrome (AIS) associated with severe elevation of serum amyloid. Lipodystrophy, cutaneous sclerodermatous changes, and cardiomyopathy were also present in this case. In contrast to other AIS, blockade of interleukin-1 and tumor necrosis-alpha was ineffective. PMID- 23729544 TI - Wegener granulomatosis as an uncommon cause of panhypopituitarism in childhood. AB - Wegener granulomatosis (WG) is a cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA)-associated, multi-system, necrotizing granulomatous vasculitis. Inflammation of the nasal or oral mucosa, and lung and kidney involvements are typical in the course of the disease. In rare cases, pituitary involvement may occur and cause panhypopituitarism. Pituitary involvement is very rare, and only two pediatric case reports have been published to date out of a total of 24 cases. This is a case report of an adolescent patient who presented with panhypopituitarism symptoms and was later diagnosed with WG. A 16-year-old female patient complained of fever, headache, purulent nasal discharge and severe muscle and joint pain. Additionally, she had polyuria and polydipsia. Investigations revealed a pituitary mass and panhypopituitarism. Positivity of c-ANCA and renal biopsy result compatible with WG confirmed the diagnosis. PMID- 23729545 TI - Characteristics of infants at risk of hypoglycaemia secondary to being 'infant of a diabetic mother'. AB - BACKGROUND: Infants of diabetic mothers (IDMs) are at risk of hypoglycaemia in the neonatal period. The prediction of which of these infants are at higher risk of developing hypoglycaemia is complex. AIMS: To determine the characteristics of infants of diabetic mothers who are more likely to need an admission to the neonatal intensive care unit to manage their hypoglycaemia. METHODS: Retrospective chart review of maternal and infant characteristics of 'at-risk' infants. Electronic patient records and neonatal and obstetric database accessed to obtain data. RESULTS: A total of 326 infants were identified in a study period accessible to electronic patient records. Macrosomia was present in 15% of the infants. Hypoglycaemic episodes occurred in 109 (33.4%) infants. Maternal diabetes type, HbA1c, prematurity, macrosomia, and temperature instability were identified as risk factors most commonly associated in infants who actually went on to develop hypoglycaemia. CONCLUSIONS: A weighted risk score to predict hypoglycaemia in this at-risk population may serve to rationalise admission to the neonatal unit and management of IDMs. PMID- 23729546 TI - A family with Camurati-Engelman disease. The role of the missense p.R218C mutation in TGFB1 in bones and endocrine glands. AB - OBJECTIVES: Camurati-Engelmann disease (CED) is a rare form of progressive bone dysplasia due to mutations in the transforming factor gene TGFB1 on chromosome 19q13.1-q13.3. Endocrine complications such as osteoporosis, vitamin D deficiency, delayed puberty and hypogonadotrophic hypogonadism may be present. METHODS AND RESULTS: Genetic analysis of the TGFB1 gene revealed a heterozygous missense mutation p.R218C in exon 4 of chromosome 19q13.1-q13.3 in a 14-year-old girl who presented with typical symptoms of CED, hyperprolactinaemia and menstrual irregularity. The patient responded well to prednisone 5 mg/kg per day as well as calcium and vitamin D supplements. CONCLUSIONS: The role of p.R218C in TGFB1 on the mechanism of the disease itself and the complications of it in bones and endocrine glands remain unclear. Early recognition as well as a detailed understanding of the pathogenesis of the disease is important for future treatment options and better quality of life of such patients. PMID- 23729547 TI - How should we manage vitamin D-deficient adolescents? PMID- 23729548 TI - Identification of a novel homozygous mutation (S144I) in a Malay patient with maple syrup urine disease. AB - Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder of branched-chain amino acid metabolism caused by the defective function of branched-chain alpha-ketoacid dehydrogenase complex (BCKDH). It is characterised by increased plasma leucine, isoleucine, and valine levels, and mutations can be detected in any one of the BCKDHA, BCKDHB, and DBT genes. In this study, we describe the molecular basis of a novel mutation found in one MSUD Malay patient from consanguineous parents. A homozygous mutation has been detected in this patient whose both parents carried a heterozygous mutation at DNA coding region c.431G>T in exon 4, which resulted in a substitution of serine to isoleucine at codon 144 (p.S144I). In silico analysis predicted S144I to be potentially damaging. The mutation was located on the alpha helical region of the BCKDHA protein, and it is predicted to affect the stability of protein due to the loss of various polar interactions between local secondary structures. Homology analysis revealed that this mutation occurred in a highly conserved region (100%). This result indicates that S144I mutation is likely pathogenic and may contribute to the classic form of MSUD in this patient. PMID- 23729549 TI - Parental dyadic coping in families of children and adolescents with type 1 diabetes. AB - BACKGROUND: The strains of type 1 diabetes mellitus in children and adolescents pose a challenge to the minor and his/her parents. OBJECTIVE: The objective of this study was to identify parental dyadic coping patterns and explore their relation to psychosocial and disease variables. SUBJECTS: Parents (n=44 dyads) of children/adolescents with type 1 diabetes. METHODS: Cluster analysis employing Ward's method was conducted as a multivariate classification procedure without predetermined cluster centers. RESULTS: Three parental coping clusters were identified and labeled: avoiders, negotiators, and doers. Although not reaching statistical significance, the HbA1c levels of children/adolescents with parental dyads exhibiting the negotiator coping pattern were consistently lower than the levels of children with parents classified as avoiders or doers. CONCLUSIONS: Parental dyads were distinguishable based on their dyadic coping patterns with a substantial proportion employing avoidant coping and suboptimal communication strategies. These parental dyads may benefit from minimal psychosocial intervention. PMID- 23729550 TI - Influence of micronutrient status and socioeconomic gradient on growth indices of 2-18-year-old Indian girls. AB - Micronutrient deficiencies are common consequences of the plant-based diet in children from developing countries which may affect their linear and ponderal growth. The aim of the study was to investigate the association between micronutrient status and growth indices in Indian girls. In cross-sectional studies (2006-2010), data on weight, height and diet were collected on 1302 girls (2-18 years) from Pune city, India. Fasting hemoglobin was measured on 1118 girls and serum zinc was measured on 695 girls. Height-for-age Z-scores (HAZ) and body mass index for age Z-score (BMIZ) were computed using contemporary Indian references. HAZ >-1 was observed in 54% girls, and 18.1% were short (HAZ <-2). BMIZ was within the reference range (-2-1 than in short girls even after adjusting for socioeconomic status (SES). The mean serum zinc level of thin girls (BMIZ <-2) was significantly lower than those of both normal and overweight girls after adjusting for SES. Micronutrient sufficiency is of paramount importance for adequate growth in Indian girls. PMID- 23729551 TI - Effect of insulin therapy on IGF-1 level in children with new-onset type 1 diabetes mellitus: a comparison between DKA and non-DKA. AB - BACKGROUND AND OBJECTIVE: The issue of insulin-like growth factor 1 (IGF-1) and diabetes in adults and type 2 diabetes has been well investigated. A few studies have investigated the serum IGF-1 level at the onset of type 1 diabetes mellitus (T1DM) in children. In the present study, we investigated the IGF-1 level of T1DM children before and after insulin therapy. SUBJECTS AND METHODS: Between August 2011 and October 2012, 62 children with newly diagnosed T1DM were recruited. Serum IGF-1 levels were compared before and 1 month after insulin therapy between diabetic ketoacidosis (DKA) and non-DKA patients. RESULTS: Thirty-one patients without DKA (18 girls and 13 boys, mean age 8.8 +/- 3.01 years) and 31 patients with DKA (18 girls and 13 boys, mean age 8.3 +/- 3.7 years) were studied. The mean IGF-1 in the DKA group was lower than that in the non-DKA group; however, this difference was not statistically significant (p=0.10). Serum IGF-1 levels increased significantly 1 month after insulin therapy in both the DKA (p<0.001) and non-DKA (p<0.001) groups. CONCLUSION: Serum IGF-1 level is reduced in new onset T1DM children. A significant increase in serum IGF-1 level can occur with insulin therapy in both DKA and non-DKA children. PMID- 23729552 TI - Diabetes mellitus with Laron syndrome: case report. AB - There are different opinions concerning changes in glucose metabolism in patients with Laron syndrome. In this paper we discuss the treatment results of our patient with Laron syndrome who developed diabetes during late adolescence. A 19 year-old boy with Laron syndrome was referred to our clinic for follow-up. He had been diagnosed with Laron syndrome (LS) at 4 years old and rIGF-1 therapy was initiated. After 4 months the treatment was discontinued. At the age of 17, rIGF 1 therapy was restarted. A height gain of 8.8 cm. was observed during the 2-year treatment period. He was admitted to our hospital at the age of 19 years following discontinuation of the therapy. At that time, his height was 142 cm, and weight for height was 136%. His blood glucose was 85 mg/dL (4.72 mmol/L), insulin was 26.39 pmol/L, and HbA1c was 5.4%. At the age of 20, when he has not been receiving IGF-1 therapy for 1 year, his weight for height was 143 cm. Laboratory evaluation revealed that fasting blood glucose was 176 mg/dL (9.77 mmol/L), fasting insulin was 29.86 pmol/L, and HbA1c was 7.5%. Primary insulin therapy was then initiated. His parents both had a diagnosis of type 2 diabetes. Insulin therapy was switched to oral antidiabetic (OAD) therapy at the end of the second year because of a normal C-peptide level of 0.8 nmol/L under insulin therapy. After 6 months of OAD, HbA1c was 5.7%. The treatment was then switched to IGF-1 therapy, but his blood glucose profile was impaired and OAD therapy was restarted. In conclusion, we observed that genetic susceptibility and abdominal obesity caused type 2 diabetes in this patient. We believe that oral antidiabetic agents and life-style changes may be the appropriate approach when diabetes is developed in LS patients. PMID- 23729553 TI - Psychosexual outcomes in three siblings with partial androgen insensitivity syndrome: impact of nature versus nurture. AB - There are few reports of adults with disorders of sexual development (DSD). Here we describe the clinical profile and results of psychological assessment of three siblings with 46, XY DSD caused by partial androgen insensitivity syndrome (PAIS). The elder sibling (aged 22 years) was reared as female, while the middle and youngest siblings (17 and 18 years of age), were reared as males. The gender identity was concordant with the sex of rearing. There was no gender dysphoria. The psychological distress that our patients experienced was due to the limitations placed on them by their medical condition. It did not permit them to experience various facets of being either male or female completely. The younger siblings reared as males had additional problems of gynecomastia and lack of male secondary sexual development. PMID- 23729554 TI - Association of serum resistin levels with metabolic syndrome and early atherosclerosis in obese Chinese children. AB - AIM: To investigate the association of serum resistin levels with metabolic syndrome (MS) and early atherosclerosis in obese children. METHODS: A total of 176 obese children and 88 healthy children were enrolled in this study, and were gender and age matched. Obesity was defined as a body mass index (BMI) of >= the 95th percentile for age and sex. All children had a physical examination and routine hematology testing for fasting blood glucose, insulin, and lipids profile. Homeostasis model of assessment of insulin resistance (HOMA-IR) was calculated, as insulin resistance has a central role in the pathophysiology of MS. Non-invasive ultrasound measurement was obtained to investigate carotid intima-media thickness (IMT) as the markers of early atherosclerosis. Path analysis was used to evaluate the value of resistin levels to early atherosclerosis. RESULTS: The resistin levels were higher in obese children compared to healthy children (23.14 +/- 7.35 vs. 17.1 +/- 5.7 ng/mL, p<0.05), and it is positively correlated with BMI, waist circumference, systolic blood pressure, fasting insulin, HOMA-IR, IMT and high sensitive CRP (Hs-CRP), but not related to diastolic blood pressure, blood lipids and fasting glucose. A positive linear correlation was observed between resistin and the number of MS components. Path analysis indicated serum resistin can directly (beta=0.304, p=0.001), and indirectly via HOMA-IR (beta=0.085, p=0.008) and Hs-CRP (beta=0.047, p=0.029), contribute to early atherosclerosis. CONCLUSION: Resistin not only play a certain role in the presence of MS, but also indirectly via insulin resistance and Hs-CRP to contribute to early atherosclerosis in obese children. PMID- 23729555 TI - Cushing syndrome related to leukemic infiltration of the central nervous system: a case report and a possible role of LIF. AB - BACKGROUND: Adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome (CS) in the presence of leukemic central nervous system infiltration is very rare. CASE: A 3.8-year-old girl who had been treated for B-cell acute lymphoblastic leukemia (ALL) for 1.5 years was admitted to our hospital with excessive weight gain and depression for the last 2 months. Prior to her admission, she was on maintenance with the ALL-BFM95 study protocol for 10 months that does not contain corticosteroids. On physical examination, central obesity and moon face appearance were determined. Laboratory tests revealed high morning ACTH, cortisol level, and 24-h urinary free cortisol level. Morning cortisol level was 33.94 nmol/L after a 2-day (4 * 0.5 mg) dexamethasone suppression test. A lumbar puncture revealed leukemic cells in the cerebrospinal fluid. No pituitary adenoma was detected on magnetic resonance imaging. We diagnosed the patient with ACTH dependent CS related to leukemic infiltration of the central nervous system. CONCLUSION: Central nervous system infiltration should be considered in leukemic patients who have developed CS. We believe increased leukemia inhibitory factor levels may be a factor for CS in our patient with ALL. PMID- 23729556 TI - Does extracellular proteolysis control mammalian cognition? AB - Recent advances in neuroscience techniques for analyzing synaptic functions, have revealed that even in a fully developed nervous system, dynamic structural changes in synapses can modify a variety of interactions between the presynaptic and postsynaptic neuron. Accumulating evidence suggests that extracellular proteases are involved in the structural modification of synapses through various pathways, including proteolytic cleavage at specific amino acid residues of the extracellular matrix proteins, cell adhesion molecules, and neurotrophic factors. Limited proteolysis induces changes in the properties of substrate proteins or releases functional domains (such as ligands) of the substrate proteins, which activate a signal transduction cascade, and hence could serve to initiate a variety of physiological functions. Such morphological and functional synaptic plasticity might underlie cognitive processes, including learning and memory in animals and humans. Here, we review potential molecular mechanisms of cognition related focal proteolysis in the hippocampus. In addition, we developed a novel screening method to identify the physiological substrate for proteases. PMID- 23729557 TI - An update on the constitutive androstane receptor (CAR). AB - The constitutive androstane receptor (CAR; NR1I3) has emerged as one of the main drug- and xenobiotic-sensitive transcriptional regulators. It has a major effect on the expression of several oxidative and conjugative enzymes and transporters, and hence, CAR can contribute to drug/drug interactions. Novel functions for CAR are also emerging: it is able to modulate the metabolic fate of glucose, lipids, and bile acids, and it is also involved in cell-cell communication, regulation of the cell cycle, and chemical carcinogenesis. Here, we will review the recent information available on CAR and its target gene expression, its interactions with partner proteins and mechanisms of action, interindividual and species variation, and current advances in CAR ligand selectivity and methods used in interrogation of its ligands. PMID- 23729558 TI - Ospemifene metabolism in humans in vitro and in vivo: metabolite identification, quantitation, and CYP assignment of major hydroxylations. AB - BACKGROUND: The metabolism of ospemifene, a novel nonsteroidal selective estrogen receptor modulator, was investigated as part of its development. METHODS: Metabolite identification, tentative quantitation, and CYP assignment of ospemifene were performed in human liver microsomes or homogenate incubations and in plasma samples from volunteer humans. The potential contributions of CYP enzymes were determined by recombinant human CYPs. Metabolite identification and tentative quantification were performed by liquid chromatography-mass spectrometry. RESULTS: The relative abundances of metabolites produced were dependent on ospemifene concentration and liver preparation, but the largest quantities of 4- and 4'-hydroxy-ospemifene (and their glucuronides in smaller quantities) were produced in human liver microsomes at low ospemifene concentrations. Other metabolites were detected in in vitro incubation with human liver including a direct glucuronide of ospemifene and some metabolites with only minor abundance. In human plasma samples, 4-hydroxy-ospemifene was the most abundant metabolite, representing about 25% of the abundance of the parent compound. All the other metabolites detected in plasma, including 4'-hydroxy ospemifene, represented <7% of the abundance of ospemifene. Several CYP enzymes participated in 4-hydroxylation, including CYP2C9, CYP2C19, CYP2B6, and CYP3A4, whereas CYP3A enzymes were the only ones to catalyze 4'-hydroxylation. CONCLUSIONS: In vitro incubations with liver preparations provided a rather reliable starting point in the search for potential metabolites in clinical settings. The in vitro metabolite profile is informative for the in vivo metabolite profile, especially regarding the major hydroxylated metabolites. However, it is anticipated that extended in vivo exposures may result in an increased production of more distal metabolites from major metabolites. PMID- 23729559 TI - Utility of a column-switching LC/MS/MS method in cytochrome P450 inhibition assays using human liver microsomes. AB - BACKGROUND: Liquid chromatography-tandem mass spectrometry (LC/MS/MS)-based in vitro cytochrome P450 (CYP) inhibition assays in pooled human liver microsomes using therapeutically relevant probe drugs are recommended by the US Food and Drug Administration to assess the potential for drug-drug interactions. As these assays are used routinely in pharmaceutical drug discovery screening of new chemical entities for drug interaction liabilities, there is a need to have higher analytical throughput. Column-switching methods may offer increased chromatographic throughput while maintaining the quality of data generated. METHODS: In this study, the CYP3A4 inhibition assay was used as a potential application to demonstrate the performance of a dual-column parallel chromatographic system in a column-switching mode. Testosterone 6beta hydroxylation was monitored and IC50 values of known CYP3A4 inhibitors were determined using conventional as well as column-switching LC/MS/MS methods. RESULTS: Mean IC50 values of ketoconazole, itraconazole and verapamil were 0.056, 0.061 and 23 MUM (conventional method) compared to 0.05, 0.057 and 26 MUM (column switching method), respectively. The two different chromatographic methods resulted in IC50 values that were not statistically different and were within a twofold range, demonstrating reproducibility of results. Further, the column switching method saved nearly 50% of analytical time in comparison to the conventional chromatographic method, indicating increased throughput leading to better utilization of mass spectrometer time without compromising the quality of data. CONCLUSIONS: Similar column-switching methods may be used for other isoforms as well and offer a convenient increased analytical throughput in CYP inhibition assays. PMID- 23729560 TI - Antinociceptive, anti-inflammatory and antiulcerogenic activities of ethanol root extract of Strophanthus hispidus DC (Apocynaceae). AB - BACKGROUND: Strophanthus hispidus DC (Apocynaceae) is a medicinal plant widely used in traditional African medicine in the treatment of rheumatic afflictions, ulcer, conjunctivitis, leprosy and skin diseases. This study sought to investigate the antinociceptive, anti-inflammatory and antiulcer properties of the ethanol root extract of S. hispidus. METHODS: Antinociceptive activity was evaluated using acetic acid-induced writhing and formalin tests in mice. The carrageenan- and egg albumin-induced rat paw edema tests were used to investigate the anti-inflammatory actions, whereas the antiulcer activity was investigated using ethanol-, HCl- and pyloric ligation-induced gastric ulcer models in rats. RESULTS: S. hispidus [100-800 mg/kg orally (po)] produced significant (p<0.05) inhibition of writhing reflex with peak effect of 74.13% inhibition observed at 800 mg/kg. Similarly, S. hispidus significantly (p<0.05) attenuated formalin induced early and late phase of nociception with peak effect of 61.84% and 89.43%, respectively, at 200 mg/kg. S. hispidus (25-800 mg/kg po) caused significant (p<0.05) inhibition of edema development in the carrageenan and egg albumin models with peak effect (93.40% and 90.10% inhibition of edema formation) observed at 50 mg/kg. With respect to antiulcer activity, S. hispidus (100-800 mg/kg) showed potent antiulcer activity with respective peak effects of 96% (ethanol-induced), 99% (HCl-induced) and 70.60% inhibition of ulcer. CONCLUSIONS: The findings in this study suggest that the ethanol root extract of S. hispidus possesses antinociceptive, anti-inflammatory and antiulcerogenic activities. This justifies the use of the extract in folklore medicine for the treatment of ulcer and inflammatory disorders. PMID- 23729561 TI - Nephroprotective activity of Cocculus hirsutus leaf extract in 5/6 nephrectomized rat model. AB - BACKGROUND: Cocculus hirsutus, commonly known as broom creeper, belongs to the family Menispermaceae. It is widely used in folk medicine to treat leprosy, skin diseases, dyspepsia, etc. Hence, an effort has been made to investigate the nephroprotective potential of C. hirsutus. METHODS: The nephroprotective activity of ethanolic C. hirsutus leaf extract (ECHE) in the 5/6 nephrectomized rat model was investigated. Different parameters like postoperative survival rate, change in body weight and levels of red blood corpuscles (RBCs), hemoglobin (Hb), triglyceride, cholesterol, creatinine, urea and uric acid were estimated in experimental rats. RESULTS: The findings revealed the postoperative survival rate of rats in the investigated novel method to be 100%. Change in the body weight of ECHE-treated groups I and II was found to be 32 and 30 g, respectively. These values suggested that ECHE treatment normalized the elevated body weight levels in experimental rats. Furthermore, ECHE treatment normalized the decreased RBC levels and the elevated Hb, triglyceride, cholesterol, creatinine, urea and uric acid levels in experimental rats. CONCLUSIONS: The results indicate that C. hirsutus has strong nephroprotective activity. However, further scrutiny is essential for isolation and characterization of the active components that can be employed to allay various human maladies. PMID- 23729562 TI - Effect of Jobelyn(r) on intruder- and isolation-induced aggressive behavior in mice. AB - BACKGROUND: Aggression is a violent behavior emitted against another organism that may lead to its harm or death and thus is of public health significance, which necessitates the search for agents with anti-aggressive property. This study investigated the effect of Jobelyn(r) (JB), a unique African polyherbal formulation, on intruder- and isolation-induced aggressive behaviors in mice. METHODS: Male mice that showed aggression after being housed individually with female counterparts for 3 weeks or kept in isolation for 4 weeks were treated orally (p.o.) with JB (5, 10 or 50 mg/kg), haloperidol (HP) (1 mg/kg), fluoxetine (FL) (10 mg/kg), p-chlorophenylalanine (PCPA) (20 mg/kg), mianserin (MS) (50 mg/kg) or distilled water (10 mL/kg) 60 min before being tested for aggression. Interaction studies involving oral administration of PCPA (20 mg/kg), FL (10 mg/kg) or MS (50 mg/kg) to aggressive mice that had received JB (5 or 10 mg/kg, p.o.) 30 min earlier were assessed. The effect of JB (5, 10 or 50 mg/kg, p.o.) on defensive behaviors was also evaluated. RESULTS: JB (5, 10 or 50 mg/kg) decreased aggressive behaviors without impairing the defensive mechanisms of mice. PCPA (20 mg/kg), an inhibitor of 5-hydroxytryptamine (5-HT) biosynthesis, increased aggressive responses and reduced the anti-aggressive effect of JB. FL (10 mg/kg), a 5-HT reuptake inhibitor, significantly suppressed aggression but did not alter the effect of JB on aggression. MS (50 mg/kg), a 5-HT receptor antagonist, reduced aggression and enhanced the effect of JB on aggression. CONCLUSIONS: These findings suggest that JB has anti-aggressive activity, which may be related to the enhancement of serotonergic system. PMID- 23729563 TI - Testosterone promotes glucose intolerance, lipid disorder and oxidative stress in type 1 diabetic rats. AB - BACKGROUND: A bidirectional relationship has been established between testosterone deficiency (TD) and type 2 diabetes mellitus (T2DM). Low testosterone level has been reported to be a predisposing factor to T2DM, whereas recent clinical studies have shown a high prevalence of low testosterone in diabetic individuals. However, it is not known if any relationship exists between type 1 diabetes mellitus (T1DM) and testosterone level. This study was designed to investigate the effects of TD on T1DM. Twenty-four Sprague-Dawley rats were randomly divided into four groups designated as control, diabetic, orchiectomized and orchiectomized-diabetic. METHODS: Diabetes was induced with an intravenous injection of alloxan, and orchiectomy was done under sterile conditions. Fasting blood glucose (FBG), insulin level, lipid and oxidative parameters were determined in all experimental rats. RESULTS: The area under the curve during oral glucose tolerance test showed that the orchiectomized-diabetic group expressed an enhanced ability to metabolize glucose than the diabetic group. The malondialdehyde level in the diabetic group was significantly higher compared with that in the control and orchiectomized groups. Moreover, there was a significant decrease in glutathione (GSH) activity and an increase in superoxide dismutase activity in the diabetic group compared with control. Meanwhile, the activities of GSH and catalase were significantly reduced in the orchiectomized as well as the orchiectomized-diabetic group when compared with both control and diabetic groups. CONCLUSIONS: These data indicate that TD attenuates glucose intolerance under diabetic conditions and is equally associated with a considerable reduction in oxidative stress, which implies that testosterone may be a pro-oxidant. PMID- 23729564 TI - High level expression of the Drosophila Toll receptor ectodomain and crystallization of its complex with the morphogen Spatzle. AB - Drosophila Toll receptors are involved in embryonic development and in the immune response of adult flies. In both processes, the Toll receptor ligand is the NGF like cystine knot protein Spatzle. Here we present the expression of Toll receptor ectodomain in Schneider cells at high yields and demonstrate a high affinity interaction with the refolded and trypsin-processed Spatzle cystine knot domain dimer. Poorly and anisotropically diffracting crystals of the complex could be improved by deglycosylation and dehydration, paving the way for structural analyses of the Toll-Spatzle interaction. PMID- 23729565 TI - In vitro maturation of Drosophila melanogaster Spatzle protein with refolded Easter reveals a novel cleavage site within the prodomain. AB - Dorsoventral patterning during Drosophila melanogaster embryogenesis is mediated by a well-defined gradient of the mature NGF-like ligand Spatzle. Easter, the ultimate protease of a ventrally-restricted serine protease cascade, plays a key role in the regulation of the morphogenic gradient, catalyzing the activation cleavage of proSpatzle. As a result of alternative splicing, proSpatzle exists in multiple isoforms, almost all of which differ only in their prodomain. Although this domain is unstructured in isolation, it has a stabilizing influence on the mature cystine knot domain and is involved in the binding to the Toll receptor. Here, we report the expression and refolding of Easter, and show that the renatured enzyme performs the activation cleavage of two Spatzle isoforms. We determine the affinity of the prodomain for the cystine knot domain, and show that Easter performs a previously unknown secondary cleavage in each prodomain. PMID- 23729566 TI - The active form of goat insulin-like peptide 3 (INSL3) is a single-chain structure comprising three domains B-C-A, constitutively expressed and secreted by testicular Leydig cells. AB - Abstract Relaxin-like factor (RLF), also called insulin-like peptide 3 (INSL3), is a member of the insulin/relaxin gene family and is produced by testicular Leydig cells. While the understanding of its effects is accumulating, very little is known about the structural and functional properties of native INSL3. Here, we demonstrate that native INSL3 isolated from goat testes is a single-chain structure with full biological activity, and is constitutively expressed and secreted by Leydig cells. Using a series of chromatography steps, native INSL3 was highly purified as a single 12-kDa peak as revealed by SDS-PAGE. MS/MS analysis provided 72% sequence coverage and revealed a distinct single-chain structure consisting of the B-, C-, and A-domains deduced previously from the INSL3 cDNA sequence. Moreover, the N-terminal peptide was 6 amino acid residues longer than predicted. Native INSL3 exhibited full bioactivity in HEK-293 cells expressing the receptor for INSL3. Immunoelectron microscopy and Western blot analysis revealed that INSL3 was secreted by Leydig cells through the constitutive pathway into blood and body fluids. We conclude, therefore, that goat INSL3 is constitutively secreted from Leydig cells as a B-C-A single-chain structure with full biological activity. PMID- 23729567 TI - Sox appeal - Sox10 attracts epigenetic and transcriptional regulators in myelinating glia. AB - Sox10 belongs to the Sox family of high-mobility group-box transcription factors. It fulfils widespread and essential functions in myelinating glia at multiple stages of development such as glial specification, survival and terminal differentiation. To a large extent, these diverse activities can be attributed to its capacity to interact with different transcription factors in distinct regulatory networks. Beyond transcription factors, an increasing number of interaction partners are emerging with alternative impact on gene expression. These include components of the mediator complex, the Brahma-associated factor complex and histone deacetylases. Here, we discuss interactions with functional relevance in myelinating glia and link Sox10 function in these cells not only to gene transcription, but also to epigenetics and chromatin remodeling. PMID- 23729568 TI - Structure and allosteric regulation of eukaryotic 6-phosphofructokinases. AB - Although the crystal structures of prokaryotic 6-phosphofructokinase, a key enzyme of glycolysis, have been available for almost 25 years now, structural information about the more complex and highly regulated eukaryotic enzymes is still lacking until now. This review provides an overview of the current knowledge of eukaryotic 6-phosphofructokinase based on recent crystal structures, kinetic analyses and site-directed mutagenesis data with special focus on the molecular architecture and the structural basis of allosteric regulation. PMID- 23729569 TI - Cerebrospinal fluid analyses for the diagnosis of subarachnoid haemorrhage and experience from a Swedish study. What method is preferable when diagnosing a subarachnoid haemorrhage? AB - Subarachnoid haemorrhage (SAH) has a high mortality and morbidity rate. Early SAH diagnosis allows the early treatment of a ruptured cerebral aneurysm, which improves the prognosis. Diagnostic cerebrospinal fluid (CSF) analyses may be performed after a negative computed tomography scan, but the precise analytical methods to be used have been debated. Here, we summarize the scientific evidence for different CSF methods for SAH diagnosis and describe their implementation in different countries. The principle literature search was conducted using PubMed and Scopus with the search items "cerebrospinal fluid", "subarachnoid haemorrhage", and "diagnosis". CSF analyses for SAH include visual examination, red blood cell counts, spectrophotometry for oxyhaemoglobin or bilirubin determination, CSF cytology, and ferritin measurement. The methods vary in availability and performance. There is a consensus that spectrophotometry has the highest diagnostic performance, but both oxyhaemoglobin and bilirubin determinations are susceptible to important confounding factors. Visual inspection of CSF for xanthochromia is still frequently used for diagnosis of SAH, but it is advised against because spectrophotometry has a superior diagnostic accuracy. A positive finding of CSF bilirubin is a strong indicator of an intracranial bleeding, whereas a positive finding of CSF oxyhaemoglobin may indicate an intracranial bleeding or a traumatic tap. Where spectrophotometry is not available, the combination of CSF cytology for erythrophages or siderophages and ferritin is a promising alternative. PMID- 23729570 TI - Hemolysis-resistant reagent: another part of the puzzle for preventing errors in laboratory testing. PMID- 23729571 TI - Kidney stones in a southeast European population from Bulgaria. PMID- 23729572 TI - Trp64Arg (rs4994) polymorphism of beta3-adrenergic receptor gene is associated with hyperuricemia in a Chinese male population. AB - BACKGROUND: beta3-Adrenergic receptor (beta3-AR) gene is associated with insulin resistance and may affect serum uric acid levels. Our aim was to determine the possible association between beta3-AR gene Trp64Arg polymorphism (rs4994) and hyperuricemia in a Chinese male population. METHODS: A total of 410 hyperuricemic and 420 normouricemic male subjects were genotyped in this study. The genotypic and allelic frequencies were compared between the two groups. Body mass index (BMI), waist to hip ratio (WHR), systolic blood pressure (SBP), diastolic blood pressure (DBP), serum uric acid, urea nitrogen, creatinine, triglyceride, total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and fasting plasma glucose (FPG) were determined. RESULTS: The frequencies of CC genotype and C allele for Trp64Arg polymorphism were higher in hyperuricemic group than in normouricemic group (p<0.01 and p<0.05, respectively). In both hyperuricemic and normouricemic groups, subjects with mutated C allele of Trp64Arg polymorphism showed significantly higher average uric acid levels than TT genotype carriers (p<0.01 and p<0.01, respectively). Univariate and multivariate logistic regression showed that carrier of mutated C allele of Trp64Arg polymorphism was significantly associated with hyperuricemia occurrence (p=0.003, OR=1.587, 95% CI 1.175-2.145 and p=0.003, OR=1.676, 95% CI 1.051-3.617). CONCLUSIONS: Trp64Arg polymorphism was associated with hyperuricemia in a Chinese male population and should be an independent risk factor for hyperuricemia. PMID- 23729573 TI - Standardization and analytical goals for glycated hemoglobin measurement. AB - Glycated hemoglobin (HbA1c) plays a key role in diagnosing diabetes and monitoring the glycemic state. To guarantee the reliability of its measurement at the global level, the IFCC has defined a reference measurement system, based on the definition of the measurand as hemoglobin molecules having a special hexapeptide in common, which is the stable adduct of glucose to the N-terminal valine of the hemoglobin beta-chain. In addition to the traceability of HbA1c results to the reference system, the establishment of analytical goals to make HbA1c measurements clinically reliable becomes crucial. However, allowable goals will depend on the assay specificity (i.e., selectivity) and, consequently, on units in which HbA1c results are expressed [mmol/mol for IFCC-aligned systems or % for National Glycohemoglobin Standardization Program (NGSP) converted numbers]. In this regard, analytical goals derived from biological variability studies in which the determination of HbA1c has been carried out by an assay providing the same selectivity for the measurand as defined by the IFCC are recommended. Only these targets should be used for evaluating the performance of commercial assays traceable to the IFCC system and of clinical laboratories using them through appropriately structured quality assessment schemes. Analytical systems following different calibration hierarchies (e.g., the NGSP-aligned assays) will require different analytical goals, possibly derived from clinical outcome data. PMID- 23729574 TI - Risks of mortality associated with common laboratory tests: a novel, simple and meaningful way to set decision limits from data available in the Electronic Medical Record. AB - BACKGROUND: Laboratory tests provide objective measurements of physiologic functions, but are usually evaluated by demographic reference-intervals (RI), instead of risk-based decision-limits (DL). We show that hospital electronic medical record (EMR) data can be utilized to associate all-cause mortality risks with analyte test values, thereby providing more information than RIs and defining new DLs. METHODS: Our cohort was 39,964 patients admitted for any reason and discharged alive, during two 1-year periods, at Sarasota Memorial Hospital, Florida, USA. We studied five routinely-performed in-hospital laboratory tests: serum creatinine, blood urea nitrogen, serum sodium, serum potassium, and serum chloride. By associating a mortality odds ratio with small intervals of values for each analyte, we calculated relative risk of all-cause mortality as a function of test values. RESULTS: We found mortality risks below the population average within these proposed DLs: potassium 3.4-4.3 mmol/L; sodium 136-142 mmol/L; chloride 100-108 mmol/L; creatinine 0.6-1.1 mg/dL; blood urea nitrogen (BUN) 5-20 mg/dL. The DLs correspond roughly to the usually-quoted RIs, with a notable narrowing for electrolytes. Potassium and sodium have reduced upper limits, avoiding a "high-normal" area where the odds ratio rises 2 to 3 times the population average. CONCLUSIONS: Any clinical laboratory test can be transformed into a mortality odds ratio function, associating mortality risk with each value of the analyte. This provides a DL determined by mortality risk, instead of RI assumptions about distribution in a "healthy" population. The odds ratio function also provides important risk information for analyte values outside the interval. PMID- 23729575 TI - Falsely elevated cobalamin concentration in multiple assays in a patient with pernicious anemia: a case study. PMID- 23729576 TI - Preanalytical quality control in a university hospital in China. PMID- 23729577 TI - Survey of national guidelines, education and training on phlebotomy in 28 European countries: an original report by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) working group for the preanalytical phase (WG-PA). AB - BACKGROUND: European questionnaire survey was conducted by the European Federation of Clinical Chemistry and Laboratory Medicine Working Group for the Preanalytical Phase (EFLM WG-PA) to assess how phlebotomy is performed in EFLM countries, including differences in personnel, level of education and skills, and to investigate the presence and compliance of national phlebotomy guidelines on this matter. METHODS: A questionnaire was constructed containing questions elucidating different aspects of the organization behind the phlebotomy praxis on a national basis, including questions on the staff performing phlebotomy, the education of these staff members, and the existence of and adherence to national guidelines. All 39 EFLM member countries were invited to participate. RESULTS: In total 28/39 (72%) EFLM member countries responded. Seven out of the 28 (25%) have national phlebotomy guidelines and five have implemented other guidelines. The estimated compliance with phlebotomy guidance for the laboratories in the countries that have national guidelines available is poor, regardless to whether the phlebotomy was under the laboratory control or not. Most countries were interested in EFLM guidelines and to participate in a pilot EFLM preanalytical phase external quality assessment (EQA) scheme. In the responding EFLM member countries, the majority of phlebotomy is performed by nurses and laboratory technicians. Their basic education is generally 4-5 years of high school, followed by 2-5 years of colleague or university studies. Only a third (10/28; 36%) of the participating member countries has any specific training available as a continuous educational resource. A specific training for phlebotomy is not part of the education required to become qualified in 6/28 (21%) and 9/28 (32%) of countries for nurses and laboratory technicians, respectively. In countries and professions where training is required, most require more than 5 h of training. CONCLUSIONS: Based on the results of this survey we conclude the following: 1) There is a need to assess the quality of current practices, compliance to the CLSI H3-A6 guidelines and to identify some most critical steps which occur during phlebotomy, in different healthcare settings, across Europe; 2) Existing CLSI H3 A6 phlebotomy guidelines should be adapted and used locally in all European countries which do not have their own guidelines; 3) National EFLM societies need to be engaged in basic training program development and continuous education of healthcare phlebotomy staff (implementing the certification of competence). PMID- 23729578 TI - Multidisciplinarity and interdisciplinarity at work: the prenatal diagnosis. PMID- 23729579 TI - Molecular basis and clonal evolution of myeloproliferative neoplasms. AB - Myeloproliferative neoplasms (MPNs) represent a group of diseases that affect the myeloid lineage, characterized by the presence of an excess of terminally differentiated myeloid cells. Defects causing clonal hematopoiesis are a key factor in the emergence of these diseases. Throughout the years, a number of causative defects have been identified, predominantly affecting cytokine signaling and gene expression regulation. This review aims to provide an update on the current status of the MPN field in relation to identification of molecular defects involved in the disease and its clonal evolution. PMID- 23729580 TI - Nobelitis: a common disease among Nobel laureates? AB - Winning a Nobel Prize is a great personal achievement. Some Nobel laureates may consider that their award is a certificate of competence in any field. This may prompt them to undertake projects or accept positions which are beyond their capabilities. Since Nobels are awarded when the laureates have usually passed their prime, caution should be exercised when these individuals are offered highly influential positions in academia and elsewhere. PMID- 23729581 TI - Re-evaluation of laboratory predictors of response to current anemia treatment regimens of erythropoiesis stimulating agents in cancer patients. AB - BACKGROUND: Anemia is a major cause of morbidity in cancer. Erythropoiesis stimulating agents (ESA) are a mainstay of treatment, although some patients lack response for unknown reasons. Recently, ESA dosing recommendations have changed and iron is increasingly used as an adjunct. Due to these changes, potential laboratory predictors of response were re-evaluated. METHODS: This was a multi center, observational study in cancer outpatients developing anemia under standard chemotherapy without absolute iron deficiency. For up to 12 weeks, laboratory data was collected while patients were treated with darbepoetin alpha (DA) either alone or along with intravenous iron. Baseline erythropoietin (Epo), changes in soluble transferrin receptor (sTfR) and in hemoglobin (Hb) early after treatment initiation were re-evaluated as response predictors, based on logistic regression models. RESULTS: Overall, 279 patients (mean age 66.1 years, 59.5% female) entered the study; 171 (61%) received at least one iron dose along with DA. Response and its predictability hardly increased through adjunct iron, although baseline ferritin <100 mg/L resulted in a 10 times higher probability of response to the combination than to ESA alone. Baseline Epo had low predictive value, regardless of tumor type or use of adjunct iron, although it varied with sex and age. If criteria for all three - Epo, sTfR, and Hb - were met, probability of preventing transfusions was 97%, dropping to 44%, if all three failed. CONCLUSIONS: Changes in ESA treatment recommendations had no impact on the predictability of response. Best prediction is still based on the immediacy of Hb increase. PMID- 23729582 TI - Prenatal molecular diagnosis of inherited neuromuscular diseases: Duchenne/Becker muscular dystrophy, myotonic dystrophy type 1 and spinal muscular atrophy. AB - BACKGROUND: Neuromuscular disease is a broad term that encompasses many diseases that either directly, via an intrinsic muscle disorder, or indirectly, via a nerve disorder, impairs muscle function. Here we report the experience of our group in the counselling and molecular prenatal diagnosis of three inherited neuromuscular diseases, i.e., Duchenne/Becker muscular dystrophy (DMD/BMD), myotonic dystrophy type 1 (DM1), spinal muscular atrophy (SMA). METHODS: We performed a total of 83 DMD/BMD, 15 DM1 and 54 SMA prenatal diagnoses using a combination of technologies for either direct or linkage diagnosis. RESULTS: We identified 16, 5 and 10 affected foetuses, respectively. The improvement of analytical procedures in recent years has increased the mutation detection rate and reduced the analytical time. CONCLUSIONS: Due to the complexity of the experimental procedures and the high, specific professional expertise required for both laboratory activities and the related counselling, these types of analyses should be preferentially performed in reference molecular diagnostic centres. PMID- 23729583 TI - Tegillarca granosa extract Haishengsu (HSS) suppresses expression of mdr1, BCR/ABL and sorcin in drug-resistant K562/ADM tumors in mice. AB - PURPOSE: To evaluate the effect of Haishengsu (HSS), a protein extract from Tegillarca granosa, on multidrug-resistance genes mdr1, BCR/ABL and sorcin in transplanted tumors. MATERIAL/METHODS: Mice were inoculated subcutaneously with a drug resistant leukemia cell line K562/ADM. Tumor-bearing animals were divided into control, adriamycin, HSS and combination therapy (adriamycin plus HSS) groups. Flow cytometry was used to detect apoptosis of tumor cells, and RT-PCR was used to evaluate the expression of mdr1, BCR/ABL and sorcin. RESULTS: The apoptosis rate in the high (71.8%), medium (72.3%) and low doses HSS group (72.4%) was higher than in control (1.2%, p<0.01), adriamycin (34.4%, p<0.05) or combination therapy group (46.4%, p<0.05). The mean optical density of mdr1, BCR/ABL and sorcin in HSS groups was lower than in control, adriamycin and combination therapy group (p<0.01). The optical density of the three genes in high HSS group was lower than in medium and low HSS group (p<0.01). CONCLUSIONS: Haishengsu promotes apoptosis of drug-resistant K562/ADM tumors in mice in a dose dependent manner. The pro-apoptotic effect of Haishengsu may be related to a reduced expression of multidrug-resistance genes mdr1, BCR/ABL and sorcin. PMID- 23729584 TI - Expression of phosphatase of regenerating liver-3 (PRL-3) in endometrioid cancer and lymph nodes metastases. AB - PURPOSE: We identify the expression of PRL-3 in primary endometrioid endometrial cancer and metastases in relation to the clinicopathological characteristics. MATERIAL/METHODS: The study involved 30 patients with type I endometrial cancer. Twelve of them were diagnosed with metastases in various localization of abdomen. The PRL-3 expression was evaluated on the basis of immunohistochemistry results by the use of monoclonal antibody anti-PRL3 clone 3B6. RESULTS: The intensity of PRL-3 expression in correlation with tumor stage was statistically significant (p = 0.024). The strongest reaction was noted in cases classified as a 1a and 1b stage defined by FIGO. The strength of PRL-3 expression is significantly associated with the degree of histological tumor grade (p = 0.035). CONCLUSIONS: The strong expression of PRL-3 in the primary tumor that was significantly correlated with the grade and clinical stage suggest that PTP4A3 participates in the process of endometrial carcinogenesis. PMID- 23729585 TI - The influence of endurance training intensity on dynamics of post-exertional heart rate recovery adaptation in patients with ischemic heart disease. AB - PURPOSE: The intensity of post-exertion heart rate recovery, evaluated in the first minute of the recovery period (HRR60), is considered to be a strong predictor of risk for cardiac death. Intensification of physical activity performed as part of cardiac rehabilitation (CR) increases the HRR60 value in ischemic heart disease (IHD) patients. In this context, the impact of endurance training intensity (ETI) on change in HRR60 intensity seems to be an interesting issue. MATERIAL/METHODS: The study group consisted of 251 patients who were subjected to a CR cycle. 45 patients of this group participated in CR twice. The control group consisted of 35 patients who were not subjected to any CR. ETI was estimated by the training work. In all patients an exertion test on a treadmill was performed twice within six months, analyzing the initial and final HRR60 value and DeltaHRR60. RESULTS: After a six-month observation, there was a statistically significant increase in the HRR60 value (17.98+/-8.33/min vs. 22.72+/-7.72/min, p<0.01) in the test group, which was not observed in the control group. Mean DeltaHRR60 value in the test group was statistically significantly greater than in the control group. In the subgroup subjected to the two CR cycles, only the first cycle led to a statistically significant increase in the mean HRR60 value. CONCLUSIONS: A six-month CR cycle significantly increased the HRR60 value, while cardiac training intensity did not affect the exertion-evoked change in its intensity. Continuation of the CR cycle beyond 6 months no longer significantly affected the change in the HRR60 value. PMID- 23729586 TI - Changes in prion replication environment cause prion strain mutation. AB - Interspecies prion transmission often leads to stable changes in physical and biological features of prion strains, a phenomenon referred to as a strain mutation. It remains unknown whether changes in the replication environment in the absence of changes in PrP primary structure can be a source of strain mutations. To approach this question, RNA content was altered in the course of amplification of hamster strains in serial protein misfolding cyclic amplification (sPMCAb). On adaptation to an RNA-depleted environment and then readaptation to an environment containing RNA, strain 263K gave rise to a novel PrP(Sc) conformation referred to as 263K(R+), which is characterized by very low conformational stability, high sensitivity to proteolytic digestion, and a replication rate of 10(6)-fold/PMCAb round, which exceeded that of 263K by almost 10(4)-fold. A series of PMCAb experiments revealed that 263K(R+) was lacking in brain-derived 263K material, but emerged de novo as a result of changes in RNA content. A similar transformation was also observed for strain Hyper, suggesting that this phenomenon was not limited to 263K. The current work demonstrates that dramatic PrP(Sc) transformations can be induced by changes in the prion replication environment and without changes in PrP primary structure. PMID- 23729587 TI - CuZnSOD gene deletion targeted to skeletal muscle leads to loss of contractile force but does not cause muscle atrophy in adult mice. AB - We have previously shown that deletion of CuZnSOD in mice (Sod1(-/-) mice) leads to accelerated loss of muscle mass and contractile force during aging. To dissect the relative roles of skeletal muscle and motor neurons in this process, we used a Cre-Lox targeted approach to establish a skeletal muscle-specific Sod1-knockout (mKO) mouse to determine whether muscle-specific CuZnSOD deletion is sufficient to cause muscle atrophy. Surprisingly, mKO mice maintain muscle masses at or above those of wild-type control mice up to 18 mo of age. In contrast, maximum isometric specific force measured in gastrocnemius muscle is significantly reduced in the mKO mice. We found no detectable increases in global measures of oxidative stress or ROS production, no reduction in mitochondrial ATP production, and no induction of adaptive stress responses in muscle from mKO mice. However, Akt-mTOR signaling is elevated and the number of muscle fibers with centrally located nuclei is increased in skeletal muscle from mKO mice, which suggests elevated regenerative pathways. Our data demonstrate that lack of CuZnSOD restricted to skeletal muscle does not lead to muscle atrophy but does cause muscle weakness in adult mice and suggest loss of CuZnSOD may potentiate muscle regenerative pathways. PMID- 23729588 TI - Long-term application of the aldosterone antagonist spironolactone prevents stiff endothelial cell syndrome. AB - Aldosterone triggers the stiff endothelial cell syndrome (SECS), characterized by an up-regulation of epithelial sodium channels (ENaCs) and mechanical stiffening of the endothelial cell cortex accompanied by endothelial dysfunction. In vivo, aldosterone antagonism exerts sustained protection on the cardiovascular system. To illuminate the molecular mechanisms of this time-dependent effect, a study on endothelial cells in vitro and ex vivo was designed to investigate SECS over time. Endothelia (from human umbilical veins, bovine aortae, and explants of human arteries) were cultured in aldosterone-supplemented medium with or without the mineralocorticoid receptor (MR) antagonist spironolactone. MR expression, ENaC expression, cortical stiffness, and shear-mediated nitric oxide (NO) release were determined after 3 d (short term) and up to 24 d (long term). Over time, MR expression increased by 129%. ENaC expression and surface abundance increased by 32% and 42% (13.8 to 19.6 molecules per cell surface), paralleled by a 49% rise in stiffness. Spironolactone prevented this development and, after 3 wk of treatment, increased NO release by 50%. Thus, spironolactone improves endothelial function long-lastingly by preventing a time-dependent manifestation of SECS. This emphasizes the key role of vascular endothelium as a therapeutical target in cardiovascular disorders and might explain blood pressure independent actions of MR antagonism. PMID- 23729589 TI - A new role for histone deacetylase 5 in the maintenance of long telomeres. AB - Telomeres are major regulators of genome stability and cell proliferation. A detailed understanding of the mechanisms involved in their maintenance is of foremost importance. Of those, telomere chromatin remodeling is probably the least studied; thus, we intended to explore the role of a specific histone deacetylase on telomere maintenance. We uncovered a new role for histone deacetylase 5 (HDAC5) in telomere biology. We report that HDAC5 is recruited to the long telomeres of osteosarcoma- and fibrosarcoma-derived cell lines, where it ensures proper maintenance of these repetitive regions. Indeed, depletion of HDAC5 by RNAi resulted in the shortening of longer telomeres and homogenization of telomere length in cells that use either telomerase or an alternative mechanism of telomere maintenance. Furthermore, we present evidence for the activation of telomere recombination on depletion of HDAC5 in fibrosarcoma telomerase-positive cancer cells. Of potential importance, we also found that depletion of HDAC5 sensitizes cancer cells with long telomeres to chemotherapeutic drugs. Cells with shorter telomeres were used to control the specificity of HDAC5 role in the maintenance of long telomeres. HDAC5 is essential for the length maintenance of long telomeres and its depletion is required for sensitization of cancer cells with long telomeres to chemotherapy. PMID- 23729590 TI - Differential effects of maternal obesity and weight loss in the periconceptional period on the epigenetic regulation of hepatic insulin-signaling pathways in the offspring. AB - Our aim was to determine the effect of exposure to maternal obesity or to maternal weight loss around conception on the programming of hepatic insulin signaling in the offspring. We used an embryo transfer model in sheep to investigate the effects of exposure to either maternal obesity or to weight loss in normal and obese mothers preceding and for 1 wk after conception on the expression of hepatic insulin-signaling and gluconeogenic factors and key miRNAs involved in insulin signaling in the offspring. We found that exposure to maternal obesity resulted in increased hepatic miR-29b (P<0.05), miR-103 (P<0.01), and miR-107 (P<0.05) expression, a decrease in IR (P<0.05), phopsho-Akt (P<0.01), and phospho-FoxO1 (P<0.01) abundance, and a paradoxical decrease in 11betaHSD1 (P<0.05), PEPCK-C (P<0.01), and PEPCK-M (P<0.05) expression in lambs. These changes were ablated by a period of moderate dietary restriction imposed during the periconceptional period. Maternal dietary restriction alone also resulted in decreased abundance of a separate subset of hepatic insulin-signaling molecules, namely, IRS1 (P<0.05), PDK1 (P<0.01), phospho-PDK1 (P<0.05), and aPKCzeta (P<0.05) and in decreased PEPCK-C (P<0.01) and G6Pase (P<0.01) expression in the lamb. Our findings highlight the sensitivity of the epigenome to maternal nutrition around conception and the need for dietary interventions that maximize metabolic benefits and minimize metabolic costs for the next generation. PMID- 23729591 TI - Stress-inducible phosphoprotein 1 has unique cochaperone activity during development and regulates cellular response to ischemia via the prion protein. AB - Stress-inducible phosphoprotein 1 (STI1) is part of the chaperone machinery, but it also functions as an extracellular ligand for the prion protein. However, the physiological relevance of these STI1 activities in vivo is unknown. Here, we show that in the absence of embryonic STI1, several Hsp90 client proteins are decreased by 50%, although Hsp90 levels are unaffected. Mutant STI1 mice showed increased caspase-3 activation and 50% impairment in cellular proliferation. Moreover, placental disruption and lack of cellular viability were linked to embryonic death by E10.5 in STI1-mutant mice. Rescue of embryonic lethality in these mutants, by transgenic expression of the STI1 gene, supported a unique role for STI1 during embryonic development. The response of STI1 haploinsufficient mice to cellular stress seemed compromised, and mutant mice showed increased vulnerability to ischemic insult. At the cellular level, ischemia increased the secretion of STI1 from wild-type astrocytes by 3-fold, whereas STI1 haploinsufficient mice secreted half as much STI1. Interesting, extracellular STI1 prevented ischemia-mediated neuronal death in a prion protein-dependent way. Our study reveals essential roles for intracellular and extracellular STI1 in cellular resilience. PMID- 23729592 TI - Plasma zinc's alter ego is a low-molecular-weight humoral factor. AB - Mild dietary zinc deprivation in humans and rodents has little effect on blood plasma zinc levels, and yet cellular consequences of zinc depletion can be detected in vascular and other tissues. We proposed that a zinc-regulated humoral factor might mediate the effects of zinc deprivation. Using a novel approach, primary rat vascular smooth muscle cells (VSMCs) were treated with plasma from zinc-deficient (<1 mg Zn/kg) or zinc-adequate (35 mg Zn/kg, pair-fed) adult male rats, and zinc levels were manipulated to distinguish direct and indirect effects of plasma zinc. Gene expression changes were analyzed by microarray and qPCR, and incubation of VSMCs with blood plasma from zinc-deficient rats strongly changed the expression of >2500 genes, compared to incubation of cells with zinc-adequate rat plasma. We demonstrated that this effect was caused by a low-molecular-weight (~2-kDa) zinc-regulated humoral factor but that changes in gene expression were mostly reversed by adding zinc back to zinc-deficient plasma. Strongly regulated genes were overrepresented in pathways associated with immune function and development. We conclude that zinc deficiency induces the production of a low molecular-weight humoral factor whose influence on VSMC gene expression is blocked by plasma zinc. This factor is therefore under dual control by zinc. PMID- 23729593 TI - Hypoxia is not required for human endometrial breakdown or repair in a xenograft model of menstruation. AB - Menstrual endometrial breakdown induced by estradiol and progesterone withdrawal is regularly attributed to vasospasm of spiral arteries causing ischemia and hypoxia. We investigated whether hypoxia actually occurred in an in vivo model of menstruation. Three complementary approaches were used to look for signs of hypoxia in fragments of human functionalis xenografted to ovariectomized immunodeficient mice bearing pellets-releasing estradiol and progesterone, and then deprived of ovarian steroids. Hormone withdrawal 21 d after grafting induced menstrual breakdown and MMP expression within 4 d. Local partial oxygen pressure (pO2) was measured by electron paramagnetic resonance using implanted lithium phtalocyanine crystals. In mice with hormone maintenance until sacrifice, pO2 was low one week after grafting (14.8+/-3.4 mmHg) but increased twofold from the second week when tissue was largely revascularized. After 3 wk, pO2 was not modified by hormone withdrawal but was slightly increased on hormone reimpregnation 4 d after removal (34.7+/-6.1 mmHg) by comparison with hormone maintenance (27.1+/-8.6 mmHg). These results were confirmed using fluorescence quenching-based OxyLite measurements. In a further search for signs of hypoxia, we did not find significant HIF1-alpha immunostaining, nor pimonidazole adducts after hormone withdrawal. We conclude that hypoxia is not needed to trigger menstrual-like tissue breakdown or repair in human endometrial xenograft. PMID- 23729594 TI - Increased expression of STK25 leads to impaired glucose utilization and insulin sensitivity in mice challenged with a high-fat diet. AB - Partial depletion of serine/threonine protein kinase 25 (STK25), a member of the Ste20 superfamily of kinases, increases lipid oxidation and glucose uptake in rodent myoblasts. Here we show that transgenic mice overexpressing STK25, when challenged with a high-fat diet, develop reduced glucose tolerance and insulin sensitivity compared to wild-type siblings, as evidenced by impairment in glucose and insulin tolerance tests as well as in euglycemic-hyperinsulinemic clamp studies. The fasting plasma insulin concentration was elevated in Stk25 transgenic mice compared to wild-type littermates (4.9+/-0.8 vs. 2.6+/-0.4 ng/ml after 17 wk on high-fat diet, P<0.05). Overexpression of STK25 decreased energy expenditure during the dark phase of observation (P<0.05), despite increased spontaneous activity. The oxidative capacity of skeletal muscle of transgenic carriers was reduced, as evidenced by altered expression of Cpt1, Acox1, and ACC. Hepatic triglycerides and glycogen were elevated (1.6- and 1.4-fold, respectively; P<0.05) and expression of key enzymes regulating lipogenesis (Fasn), glycogen synthesis (Gck), and gluconeogenesis (G6pc, Fbp1) was increased in the liver of the transgenic mice. Our findings suggest that overexpression of STK25 in conditions of excess dietary fuels associates with a shift in the metabolic balance in peripheral tissues from lipid oxidation to storage, leading to a systemic insulin resistance. PMID- 23729596 TI - Heart valve engineering: decellularized allograft matrices in clinical practice. AB - The purpose of this review is to update the current clinical experience with tissue-engineered, nonseeded, allogenic matrices for pulmonary and aortic valve replacement. Allogenic heart valve replacement using an aortic root homograft was first performed 50 years ago on July 24, 1962, by Donald Ross at Guy's Hospital, London. Cryopreserved homografts have been the gold standard for many years in selected indications such as for pulmonary valve replacement in congenital heart disease, severe bacterial endocarditis, or for right ventricular outflow tract reconstruction during the Ross pulmonary autograft operation. However, there is evolving evidence that tissue-engineered decellularized homografts may be superior to conventional cryopreserved homografts. PMID- 23729597 TI - Calculation of the elastic properties of prosthetic knee components with an iterative finite element-based modal analysis: quantitative comparison of different measuring techniques. AB - With the aging but still active population, research on total joint replacements relies increasingly on numerical methods, such as finite element analysis, to improve wear resistance of components. However, the validity of finite element models largely depends on the accuracy of their material behavior and geometrical representation. In particular, material properties are often based on manufacturer data or literature reports, but can alternatively be estimated by matching experimental measurements and structural predictions through modal analyses and identification of eigenfrequencies. The aim of the present study was to compare the accuracy of common setups used for estimating the eigenfrequencies of typical components often used in prosthetized joints. Eigenfrequencies of cobalt-chrome and ultra-high-molecular weight polyethylene components were therefore measured with four different setups, and used in modal analyses of corresponding finite element models for an iterative adjustment of their material properties. Results show that for the low-damped cobalt chromium endoprosthesis components, all common measuring setups provided accurate measurements. In the case of high-damped structures, measurements were only possible with setups including a continuously excitation system such as electrodynamic shakers. This study demonstrates that the iterative back-calculation of eigenfrequencies can be a reliable method to estimate the elastic properties for finite element models. PMID- 23729595 TI - Perivascular macrophage-like melanocyte responsiveness to acoustic trauma--a salient feature of strial barrier associated hearing loss. AB - Tissue perivascular resident macrophages (PVM/Ms), a hybrid cell type with characteristics of both macrophages and melanocytes, are critical for establishing and maintaining the endocochlear potential (EP) required for hearing. The PVM/Ms modulate expression of tight- and adherens-junction proteins in the endothelial barrier of the stria vascularis (intrastrial fluid-blood barrier) through secretion of a signaling molecule, pigment epithelium growth factor (PEDF). Here, we identify a significant link between abnormalities in PVM/Ms and endothelial barrier breakdown from acoustic trauma to the mouse ear. We find that acoustic trauma causes activation of PVM/Ms and physical detachment from capillary walls. Concurrent with the detachment, we find loosened tight junctions between endothelial cells and decreased production of tight- and adherens-junction protein, resulting in leakage of serum proteins from the damaged barrier. A key factor in the intrastrial fluid-blood barrier hyperpermeability exhibited in the mice is down-regulation of PVM/M modulated PEDF production. We demonstrate that delivery of PEDF to the damaged ear ameliorates hearing loss by restoring intrastrial fluid-blood barrier integrity. PEDF up-regulates expression of tight junction-associated proteins (ZO-1 and VE cadherin) and PVM/M stabilizing neural cell adhesion molecule (NCAM-120). These studies point to the critical role PVM/Ms play in regulating intrastrial fluid blood barrier integrity in healthy and noise-damaged ears. PMID- 23729598 TI - Laser microstructured biodegradable scaffolds. AB - The two-photon polymerization technique (2PP) uses non-linear absorption of femtosecond laser pulses to selectively polymerize photosensitive materials. 2PP has the ability to fabricate structures with a resolution from tens of micrometers down to hundreds of nanometers. Three-dimensional microstructuring by the 2PP technique provides many interesting possibilities for biomedical applications. This microstructuring technique is suitable with many biocompatible polymeric materials, such as polyethylene glycol, polylactic acid, polycaprolactone, gelatin, zirconium-based hybrids, and others. The process of fabrication does not require clean room conditions and does not use hazard chemicals or high temperatures. The most beneficial property of 2PP is that it is capable of producing especially complex three-dimensional (3-D) structures, including devices with overhangs, without using any supportive structure. The flexibility in controlling geometries and feature sizes and the possibility to fabricate structures without the addition of new material layers makes this technique particularly appealing for fabrication of 3-D scaffolds for tissue engineering. PMID- 23729599 TI - Gonadal function of beta-thalassemics following stem cell transplantation conditioned with myeloablative and reduced intensity regimens. AB - Gonadal dysfunction is a complication following stem cell transplantation (SCT). There have been no reports of gonadal function in stem-cell-transplanted thalassemic survivors who received a reduced intensity conditioning regimen (RIC). We evaluated gonadal function in 47 beta-thalassemic patients following SCT with either myeloablative or reduced intensity regimen. Thirty-six patients received a myeloablative regimen, the remaining 11 patients had an RIC regimen. Their median (range) age was 13.2 (5.9-25.8) years. There were 29 patients (62%) with gonadal dysfunction (26 with primary gonadal dysfunction and three with gonadotropin deficiency). Comparisons between patients who received myeloablative and RIC regimens, revealed no differences in gonadal dysfunction (56% vs. 82%, p=0.113, respectively). In conclusion, our study demonstrated high frequency of gonadal dysfunction in these patients. Even after receiving RIC, gonadal dysfunction was very common. To our knowledge, this study is the first to report gonadal function in children and adolescents with beta-thalassemia disease who were pre-transplanted with RIC. PMID- 23729600 TI - Phosphotyrosine phosphatases in GH-stimulated skin fibroblasts from children with idiopathic short stature. AB - AIM: Some cases of idiopathic short stature (ISS) may be caused by defects in the modulation of the negative feedback regulation of the growth hormone receptor (GHR)/ Janus kinase (JAK)2/signal transducers and activators of transcription (STAT)5 signaling pathway. The cytosolic tyrosine phosphatases, protein tyrosine phosphatase 1B (PTP1B) and Src homology 2 (SH2) domain-containing protein tyrosine phosphatase-1 (SHP-1), the later which translocates to the nucleus after activation, interact with JAK2 in a GH-dependent manner. The possible contribution of PTP1B and SHP-1 to GH signaling in fibroblasts from ISS patients has not been studied. METHODS: We determined the basal protein content of PTP1B and SHP-1 in the presence of recombinant human GH (rhGH) for 24 h in skin fibroblast cultures, obtained from patients with ISS, and were compared with a normal height control children group. JAK2 activation was determined in both groups. RESULTS: JAK2 activation was delayed in fibroblasts from ISS patients compared to controls. Under basal conditions, the protein content of SHP-1 was lower in ISS, and after incubation with rhGH, it decreased in the non-nuclear and nuclear fraction of controls, but not in ISS patients. The protein content of PTP1B, however, increased in a similar fashion in fibroblasts from both ISS and control children. CONCLUSION: The delayed activation of JAK2 and the lack of response of SHP-1 after incubation with GH in fibroblasts from ISS patients, suggests that the growth retardation observed in some of these children may be mediated in part by this phosphotyrosine phosphatase. PMID- 23729601 TI - Mutation analysis of the SRD5A2, AR and SF-1 genes in 52 Chinese boys with hypospadias. AB - OBJECTIVES: To investigate the prevalence of genetic mutations in steroid 5alpha reductase-2 (SRD5A2), androgen receptor (AR) and steroidogenic factor-1 (SF-1) in Chinese children with hypospadias, and to also explore the possible underlying molecular mechanisms of this disease. METHODS: A total of 52 boys with hypospadias were enrolled. Mutational analyses of the SRD5A2, AR and SF-1 genes were performed by direct sequencing. RESULTS: SRD5A2 gene mutations were found in 13.5% (7/52 cases), including five compound heterozygotic and two homozygotic mutations. One novel heterozygotic SF-1 gene mutation was identified in a patient with perineal hypospadias and cryptorchidism, the patient's mother also had the same mutation. No mutation was found in the AR gene. The clinical manifestations of patients with mutations in SRD5A2 or SF-1 varied. CONCLUSIONS: In Chinese patients, SRD5A2 gene mutations were, relatively, frequently associated with hypospadias. The SF-1 gene may be another candidate gene for hypospadias. In contrast, AR gene mutations are not commonly associated with this condition. PMID- 23729602 TI - Should neonatal hyperparathyroidism associated with mucolipidosis II/III be treated pharmacologically? PMID- 23729603 TI - Tamoxifen therapy for the management of pubertal gynecomastia: a systematic review. AB - OBJECTIVE: A systematic review to assess the efficacy of tamoxifen in the management of idiopathic pubertal gynecomastia. DATA SOURCES: Searches were conducted using the databases of Medline (search engine PubMed) and Web of Science(r). STUDY SELECTION: Studies reporting the use of Tamoxifen for the treatment of gynecomastia in adolescents. OUTCOME MEASURE: Resolution of gynecomastia. RESULTS: A total of 164 publications were found; 59 were selected for retrieval and six were included in the review. There were no randomized controlled studies; the studies found have methodological flaws but show promising results. No clinical side-effects were reported or observed. CONCLUSION: Tamoxifen may be effective for the treatment of pubertal gynecomastia, and it seems safe to use. Randomized controlled studies are necessary to confirm this indication. PMID- 23729604 TI - Virilization in two pre-pubertal children exposed to topical androgen. AB - Androgen replacement therapy for male hypogonadism may be prescribed utilizing intramuscular, oral or more recently, topical formulations. With topical formulations, there is a risk of person-to-person transmission if appropriate precautions are not taken. We describe two cases of virilization in pre-pubertal children following passive transfer of paternal topical testosterone. A 21 month old male was referred with a 6 week history of pubic hair, phallic growth, and linear growth spurt. Genital examination revealed Tanner stage 2 pubic hair and Tanner stage 3 phallic development, which was discordant with the pre-pubertal testicular size (2 mL bilaterally). A 3 year 8 month old girl was referred for a 2 month history of increasing pubic hair development. Examination revealed Tanner stage 2 pubic hair and Tanner stage 1 breast development. Both of these patients had fathers who had been diagnosed with hypogonadism and were being treated with topical androgen gel therapy, which they applied to their arms and chest before bed. In addition, both patients often slept with their parents resulting in skin to-skin contact. Investigations were consistent with gonadotropin independent virilization with both patients demonstrating elevated testosterone levels. Testosterone levels returned to normal pre-pubertal levels with no further development of secondary sexual characteristics following discontinuation of exposure to topical testosterone. Precautions must be taken to prevent person-to person transfer of topical steroids. With the increasing popularity of topical steroids for the treatment of low testosterone, it is imperative that these therapies be prescribed and utilized judiciously to prevent harm, specifically gonadotropin-independent virilization. PMID- 23729605 TI - Assessment of contractility and myocardial function in small and appropriate for gestational age premature neonates using the stress-velocity relationship and tissue Doppler imaging immediately after birth. AB - Our aim was to determine whether small for gestational age (SGA) neonates exhibit reduced left ventricular contractility and diastolic dysfunction, through the assessment of tissue by Doppler imaging and investigation of the stress-velocity relationship (SVR). The study subjects were limited to 37 neonates just after birth. These patients were grouped into 14 SGA neonates with birth weights below the 10th percentile (aged 29-36 weeks, birth weight 860-2066 g) and 23 appropriate for age (AGA) neonates with birth weights between the 10th-90th percentile (aged 20-36 weeks, birth weight 954-2945 g). Although there were no significant differences in the SVR or diastolic function between the SGA and AGA neonates, wall stress correlated significantly and inversely with birth weight in all subjects with a higher E/Ew ratio by tissue Doppler imaging. In conclusion, there were no significant differences in cardiac function between SGA and AGA neonates. By contrast, the relationship between wall stress, diastolic dysfunction, and birth weight may be due to physiological alterations in neonates, including those with low birth weights, just after birth. PMID- 23729606 TI - The arginine stimulation test: timing of peak is not a helpful parameter in the diagnosis of growth hormone deficiency. AB - BACKGROUND: A typical peak timing in the glucagon stimulation test has been reported as an indication of growth hormone (GH) deficiency. Other stimulation tests have not been evaluated. OBJECTIVE: To evaluate the clinical usefulness of peak timing in the arginine stimulation test (AST) for growth hormone deficiency. METHODS: Retrospective review of 199 ASTs from one center. Outcomes included correlation of peak times with (a) frequency of deficient peak; (b) growth velocity standard deviation scores (GVSDSs); (c) other evidence of pituitary pathology; (d) results of confirmatory clonidine test; and (e) response to GH treatment. RESULTS: The peak in 83/109 (76.14%) sufficient tests occurred at typical times vs. 45/72 (62.5%) deficient tests (p<0.05). GVSDS on GH treatment was greater among patients with typical timing in the AST compared with atypical timing (2.67 +/- 0.59 vs. 0.46 +/- 1.17, p=0.021). No other variable correlated significantly with AST timing. CONCLUSIONS: Timing of peak in the AST is not a clinically useful parameter. PMID- 23729607 TI - Genetic diagnosis of one family with incomplete clinical data. AB - A 6-day-old female patient suddenly died of congestive heart failure, hepatomegaly and hypoglycemic encephalopathy. Tandem mass spectrometry (MS) analysis revealed a possibility of carnitine deficiency. However, many of the clinical symptoms had not yet occurred at that time, and the clinical data was incomplete. We aim to derive a systematic procedure of identifying pathogenic mutations for similar patients. Physicians could save patients' lives with effective treatment at a much earlier stage. Direct sequencing of the exons and exon-intron boundaries of GAA, SLC25A5, CPT1, CPT2, SLC25A20 and MUT genes were performed on the parents of the patient. DNA from the blood spots of the patient was analyzed for the MUT gene. The results revealed that the patient was a compound heterozygote with MUT. c. 729_730insTT and c. 1677-1G>A. cDNA sequence demonstrated MUT c. 1677-1G>A resulting in the deletion of eight nucleotides and the introduction of 13 novel amino acids before premature termination. PMID- 23729608 TI - Sexual development in prepubertal obese boys: a 4-year longitudinal study. AB - The objective of the study was to evaluate whether or not sexual development differs between boys with prepubertal obesity and boys of normal weight. We enrolled healthy obese and normoweight schoolboys from Shenyang City, Liaoning, China. Eligible boys were at Tanner stage 1 and 8 years of age at baseline. We measured testosterone and estradiol concentrations in the saliva and assessed auxology annually for 4 years. In all 56 obese and 56 normoweight boys, the height, weight, body composition, and sex organ volume increased with age. The percentages of body fat, fat mass, and lean mass were all higher in obese than in normoweight boys. The mean testicular volume was smaller in obese boys than in normoweight boys. The sex hormone concentrations increased with age, except for testosterone in obese boys in year 3 of follow-up. In year 4, estradiol concentrations were significantly higher in obese boys than in normoweight boys. Excessive adiposity in prepubertal boys might affect testicular volume, possibly because of high estradiol and low testosterone concentrations. PMID- 23729609 TI - Ambiguous genitalia in a 48, XXYY newborn: a casual relationship or a coincidence? AB - 48, XXYY is a very rare sex chromosome aneuploidy, characterized by both an extra X and Y chromosome with a prevalence of 1:18,000-1:40,000. Most patients are diagnosed prenatally by cytogenetic examination of amniotic fluid, or during the first years of life because of severe developmental delay, cognitive impairment and behavioural disorders. This syndrome shares two findings with Klinefelter syndrome, namely tall stature and hypergonadotropic hypogonadism but at this time no genital anomalies have been reported in patients with this tetrasomy. We describe a 48, XXYY neonate and a clinical picture characterized by small penis, bifid scrotum, scrotal hypospadias and testes palpable in the labioscrotal folds. PMID- 23729610 TI - The relationship between adiposity and stature in prepubertal children with celiac disease. AB - BACKGROUND AND AIM: The pathogenesis of short stature in celiac disease (CD) is unknown. Obese children are generally taller than their non-obese peers; however, the role of adiposity on stature in CD is unclear. Our aim was to determine the association between adiposity and stature in CD. SUBJECTS AND METHODS: We compared the anthropometric characteristics of prepubertal children of ages 3-12 years, with biopsy-proven CD (n=40) and who were not on gluten-free diet, to same aged, prepubertal non-CD children (n=50). Body mass index (BMI) was calculated using the formula weight/height2. Sex-adjusted midparental target height (MPTH) standard deviation score (SDS) was calculated using National Children Health Statistics data for 18-year-old adults. Data were expressed as mean +/- standard deviation. RESULTS: CD subjects had significantly lower BMI SDS than controls (0.61 +/- 1.22 vs. 1.28 +/- 1.60, p=0.027) but were not significantly shorter than the controls (-0.05 +/- 1.21 vs. 0.21 +/- 1.71, p=0.41). When the patients were subdivided into the normal-weight and overweight/obese groups, the normal weight CD patients were of similar height as the normal-weight controls (p=0.76) but were significantly shorter than both the overweight/obese controls (p<0.001) and overweight/obese CD children (p<0.001). Interestingly, the overweight/obese CD children were significantly taller than the normal-weight controls (p=0.003). The MPTH SDS did not differ between the groups. CONCLUSIONS: Overweight/obese prepubertal children with CD were taller than both their normal-weight CD peers and the normal-weight controls, but were of similar height as the overweight/obese control subjects. PMID- 23729611 TI - The influence of carbohydrate quality on cardiovascular disease, the metabolic syndrome, type 2 diabetes, and obesity - an overview. AB - There is compelling evidence that carbohydrate quality has important influences on cardiovascular disease, the metabolic syndrome, type 2 diabetes, and obesity. Cohort and interventional studies indicate that dietary fiber is an important determinant of satiation, satiety, and weight gain, and also protects against cardiovascular disease. Cohort studies have shown that vegetables and fruits protect against coronary heart disease, whereas whole grains provide protection against cardiovascular disease, type 2 diabetes, and weight gain. Dietary glycemia within the range eaten by most of the population seems not to have a significant influence on body weight, although it may influence waist circumference. There is strong evidence from interventional trials that dietary glycemia does influence insulin resistance and diabetes control. Moreover, replacing saturated fat with high-glycemic carbohydrate may increase cardiovascular risk. Soft drink consumption is a proven cause of weight gain, which may relate to the lack of satiation provided by these drinks. In large amounts, dietary fructose leads to greater adverse metabolic changes than equivalent amounts of glucose, although the extent to which fructose per se is contributing to many of the metabolic changes found in the obese, as distinct from the calories it provides, is still a matter of debate. PMID- 23729612 TI - Solitary median maxillary central incisor, a clinical predictor of hypoplastic anterior pituitary, ectopic neurohypophysis and growth hormone deficiency. PMID- 23729613 TI - A rare case of granuloma annulare in a 6-year-old child with type 1 diabetes. PMID- 23729614 TI - Type II vitamin D-dependent rickets with diabetic ketoacidosis. AB - The high prevalence of vitamin D deficiency in relation to diabetes mellitus is well reported in the literature. However, type I diabetes mellitus (T1DM) in association with resistant rickets is extremely rare and reported in only one previous case. The authors describe here a case of type II vitamin D-dependent rickets (VDDR type II) in a 10-year-old Indian girl who presented with diabetic ketoacidosis (DKA). DKA as a presenting manifestation of T1DM in a patient with VDDR type II has never been reported before in worldwide literature. PMID- 23729615 TI - Pituitary gigantism presenting with depressive mood disorder and diabetic ketoacidosis in an Asian adolescent. AB - Hyperglycemia is seldom described in young patients with pituitary gigantism. Here, we describe the case of a 17-year-old Taiwanese boy who developed depressive mood disorder and diabetic ketoacidosis (DKA) at the presentation of pituitary gigantism. The boy complained of lethargy and dysphoric mood in June 2008. He presented at the emergency department with epigastralgia and dyspnea in January 2009. Results of laboratory tests suggested type 1 diabetes mellitus with DKA. However, serum C-peptide level was normal on follow-up. Although he had no obvious features of acral enlargement, a high level of insulin-like growth factor 1 was detected, and a 75 g oral glucose suppression test showed no suppression of serum growth hormone levels. A pituitary macroadenoma was found on subsequent magnetic resonance imaging. The pituitary adenoma was surgically removed, followed by gamma-knife radiosurgery, and Sandostatin long-acting release treatment. He was then administered metformin, 500 mg twice daily, and to date, his serum glycohemoglobin has been <7%. PMID- 23729616 TI - Complete androgen insensitivity syndrome and discordant Mullerian remnants: two cases with novel mutation in the androgen receptor. AB - Complete androgen insensitivity syndrome (CAIS) associated with Mullerian remnant is rare during childhood. The Mullerian system usually regresses because of the presence of the anti-Mullerian hormone (AMH) originating from the Sertoli cells of the gonads. Rarely, residual Mullerian structures may exist. We present two cases from the same family, raised as females. They were 12 and 18 years old, respectively, and they had Tanner V breast development but Tanner I-II pubic hair. The older patient had primary amenorrhea. Both have a 46,XY genotype. Pelvic ultrasonography revealed no uterus and ovaries. The patients underwent bilateral laporoscopic gonadectomy. Both had residual Mullerian structures. Mutation analyses were performed, and both patients were found to be carrying a point mutation in exon 4 of the AR gene consisting of a G nucleotide deletion at position c.1890delG, followed by a frame-shift mutation and a stop codon. This mutation has not been described yet in the literature. Although the association with CAIS and Mullerian remnant is rare, no genetic defect specific to androgen insensitivity with Mullerian remnants has been identified so far. PMID- 23729618 TI - Histone lysine methylation: critical regulator of memory and behavior. AB - Histone lysine methylation is a well-established transcriptional mechanism for the regulation of gene expression changes in eukaryotic cells and is now believed to function in neurons of the central nervous system to mediate the process of memory formation and behavior. In mature neurons, methylation of histone proteins can serve to both activate and repress gene transcription. This is in stark contrast to other epigenetic modifications, including histone acetylation and DNA methylation, which have largely been associated with one transcriptional state in the brain. In this review, we discuss the evidence for histone methylation mechanisms in the coordination of complex cognitive processes such as long-term memory formation and storage. In addition, we address the current literature highlighting the role of histone methylation in intellectual disability, addiction, schizophrenia, autism, depression, and neurodegeneration. Further, we discuss histone methylation within the context of other epigenetic modifications and the potential advantages of exploring this newly identified mechanism of cognition, emphasizing the possibility that this molecular process may provide an alternative locus for intervention in long-term psychopathologies that cannot be clearly linked to genes or environment alone. PMID- 23729619 TI - Birth month and longevity: birth month of victims of sudden (SCD, <=1 h) and rapid (RCD, <=24 h) cardiac deaths. AB - BACKGROUND: After a publication of a study in the Proceedings of the National Academy of Sciences USA in 2001, we published three studies related to birth month and morbidity of patients that can affect longevity. The aim of this study is to check two groups of cardiac deaths, consisting of more than 50% of cardiovascular mortality in the industrial world, to examine this paradigm. METHODS: Patients suffering rapid cardiac death (RCD) (<=24 h) and sudden cardiac death (SCD) (<=1 h) in Lithuanian Medical Science University hospital, a tertiary 3000-bed facility, in 2000-2010 were studied. In total, 1239 RCDs and 324 SCDs were included in this study. Monthly, quarterly, trimester and half-year comparisons of the patients' birth month population were studied. RESULTS: A difference in birth month distribution of the study patients was observed. For RCDs (<=24 h), the highest numbers were found for January (11.0%) and May (10.3%), whereas for the SCDs (<=1 h), April (13.3%) and January (10.5%) dominated. The least numbers were in November (SCD, 5.6%; RCD, 6.2%) and December (5.2-6.1%). Those born in the first and second quarter and first trimester were significantly more than those born in the fourth quarter (I/IV, p=0.0023; I/III, p=0.0074; II/IV, p=0.047) or trimester [I/II, p=0.09 (trend); I/III p=0.014; II/III, p=0.079 (trend)]. In another study at the same location (number of newborns n=286,963), significant correlation between monthly newborn number and month of the year was not found. possible environmental effects related to the different monthly birth distributions of the studied group are discussed. CONCLUSIONS: Victims of SCD and RCD are unequally distributed according to month of birth. The highest numbers were found for January and March to May. The numbers are higher for the first and second quarter and first trimester in comparison with the months at the end of the year. The lowest numbers of study patients were born in November, December and October. This is in accord with the birth months of American centenarians (100-112 years old) found by colleagues from the University of Chicago. Possible mechanisms for predisposition to SCD and RCD need further elucidation. Our findings support the paradigm linking birth month and longevity. PMID- 23729617 TI - Prefrontal dopamine signaling and cognitive symptoms of Parkinson's disease. AB - Cognitive dysfunction is a common symptom of Parkinson's disease (PD) that causes significant morbidity and mortality. The severity of these symptoms ranges from minor executive symptoms to frank dementia involving multiple domains. In the present review, we will concentrate on the aspects of cognitive impairment associated with prefrontal dopaminergic dysfunction, seen in non-demented patients with PD. These symptoms include executive dysfunction and disorders of thought, such as hallucinations and psychosis. Such symptoms may go on to predict dementia related to PD, which involves amnestic dysfunction and is typically seen later in the disease. Cognitive symptoms are associated with dysfunction in cholinergic circuits, in addition to the abnormalities in the prefrontal dopaminergic system. These circuits can be carefully studied and evaluated in PD, and could be leveraged to treat difficult clinical problems related to cognitive symptoms of PD. PMID- 23729620 TI - ACE inhibition enhances bradykinin relaxations through nitric oxide and B1 receptor activation in bovine coronary arteries. AB - Bradykinin causes vascular relaxations through release of endothelial relaxing factors including prostacyclin, nitric oxide (NO) and epoxyeicosatrienoic acids (EETs). Bradykinin is metabolized by angiotensin converting enzyme (ACE) and ACE inhibition enhances bradykinin relaxations. Our goal was to characterize the role of bradykinin receptors and endothelial factors in ACE inhibitor-enhanced relaxations in bovine coronary arteries. In U46619 preconstricted arteries, bradykinin (10-11-10-8m) caused concentration-dependent relaxations (maximal relaxation >=100%, log EC50=-9.8+/-0.1). In the presence of the NO synthase inhibitor, N-nitro-L-arginine (L-NA, 30 MUm) and the cyclooxygenase inhibitor, indomethacin (10 MUm), relaxations were reduced by an inhibitor of EET synthesis, miconazole (10 MUm) (maximal relaxation=55+/-10%). Bradykinin relaxations were inhibited by the bradykinin 2 (B2) receptor antagonist, D-Arg0-Hyp3-Thi5,8-D-Phe7 bradykinin (1 MUm) (log EC50=-8.5+/-0.1) but not altered by the B1 receptor antagonist, des-Arg9[Leu8]bradykinin (1 MUm). Mass spectrometric analysis of bovine coronary artery bradykinin metabolites revealed a time-dependent increase in bradykinin (1-5) and (1-7) suggesting metabolism by ACE. ACE inhibition with captopril (50 MUm) enhanced bradykinin relaxations (log EC50=-10.3+/-0.1). The enhanced relaxations were eliminated by L-NA or the B1 receptor antagonist but not the B2 receptor antagonist. Our results demonstrate that ACE inhibitor enhanced bradykinin relaxations of bovine coronary arteries occur through endothelial cell B1 receptor activation and NO. PMID- 23729621 TI - Overexpression of miR-126 promotes the differentiation of mesenchymal stem cells toward endothelial cells via activation of PI3K/Akt and MAPK/ERK pathways and release of paracrine factors. AB - The endothelial cell (EC)-specific miRNA, miR-126, is known to promote angiogenesis in response to angiogenic factors by repressing negative regulators of signal transduction pathways; however, whether miR-126 might regulate the differentiation of stem cells toward endothelial lineage remains unknown. To answer this question, in this study mesenchymal stem cells (MSCs) harvested from C57BL/6 mouse bone marrow were transfected with miR-126 (MSCmiR-126) using recombinant lentiviral vectors. Results showed the para-secretion and the expression levels of phosphorylated PI3K p85, Akt, p38, ERK1 protein in the MSCmiR-126 group were dramatically increased when compared with the control group. With half culture medium refreshed every 3 days, a small number of 6-day cultured MSCmiR-126 differentiated into endothelial-like cells and most of 9-day cultured MSCmiR-126 formed a cobblestone-like structure. These differentiated cells evidently expressed EC-specific makers and possessed mature ECs function, while inhibition of paracrine factors suppressed the MSC-EC differentiation. Strikingly, the increased secretion of MSCmiR-126 and their endothelial differentiated potential were deprived by using a PI3K or MEK chemical inhibitor. Our results suggest that overexpression of miR-126 agumenting the endothelial differentiation of MSCs might in part be attributable to the activation of PI3K/Akt and MAPK/ERK pathways and an increased release of paracrine factors. PMID- 23729622 TI - Synthesis of a novel benzodifuran derivative and its molecular recognition of poly rA RNA. AB - In this manuscript, we describe a synthetic approach to a novel benzodifuran derivative as well as CD studies regarding its ability to interact with DNA and RNA. After the chemical synthesis and ESI-MS and NMR characterization, this heteroaromatic molecule was investigated by CD spectroscopy in order to evaluate it as a potential nucleic acid binder. Interestingly, the benzodifuran compound was found to be able to induce conformational changes in both DNA and RNA homoadenine molecules forming in the latter case a complex with a 6:1 benzodifuran/nucleobase stoichiometric ratio, as evidenced by CD titration experiments. PMID- 23729623 TI - Structure and function of MK5/PRAK: the loner among the mitogen-activated protein kinase-activated protein kinases. AB - Mitogen-activated protein kinase (MAPK) pathways are important signal transduction pathways that control pivotal cellular processes including proliferation, differentiation, survival, apoptosis, gene regulation, and motility. MAPK pathways consist of a relay of consecutive phosphorylation events exerted by MAPK kinase kinases, MAPK kinases, and MAPKs. Conventional MAPKs are characterized by a conserved Thr-X-Tyr motif in the activation loop of the kinase domain, while atypical MAPKs lack this motif and do not seem to be organized into the classical three-tiered kinase cascade. One functional group of conventional and atypical MAPK substrates consists of protein kinases known as MAPK-activated protein kinases. Eleven mammalian MAPK-activated protein kinases have been identified, and they are divided into five subgroups: the ribosomal-S6-kinases RSK1-4, the MAPK-interacting kinases MNK1 and 2, the mitogen- and stress activated kinases MSK1 and 2, the MAPK-activated protein kinases MK2 and 3, and the MAPK-activated protein kinase MK5 (also referred to as PRAK). MK5/PRAK is the only MAPK-activated protein kinase that is a substrate for both conventional and atypical MAPK, while all other MAPKAPKs are exclusively phosphorylated by conventional MAPKs. This review focuses on the structure, activation, substrates, functions, and possible implications of MK5/PRAK in malignant and nonmalignant diseases. PMID- 23729624 TI - Method-specific differences in plasma fibroblast growth factor 23 measurement using four commercial ELISAs. AB - BACKGROUND: There is growing interest in measuring plasma fibroblast growth factor 23 (FGF23) concentration in a number of clinical settings. However, data comparing current commercial intact and C-terminal FGF23 assays is lacking. METHODS: We used plasma samples collected from a cohort of healthy adults and patients undergoing chronic haemodialysis therapy (n=67) to compare the precision, recovery, linearity and pre-analytical stability characteristics of four commercial FGF23 assays from Kainos, Millipore and Immutopics Inc. Method agreement was evaluated using Passing-Bablok regression and difference plot analysis. RESULTS: Both Millipore and Immutopics intact FGF23 kits demonstrated marked negative proportional bias relative to Kainos assay readout, particularly in the haemodialysis group, and poor recovery of purified FGF23 standard at high spiking concentrations. Dilution of high-reading samples with saline as recommended by the Immutopics kit resulted in significant deviation from linearity. Immutopics C-terminal FGF23 concentrations displayed a strong association with intact FGF23 concentrations determined with all three intact assays in the haemodialysis group, but showed no significant correlation within the physiological range. Only intact FGF23 measurements made with the Immutopics assay demonstrated evidence of significant instability 8 h after venepuncture. CONCLUSIONS: Current ELISA kits for plasma intact FGF23 measurement show poor analytical agreement, and cannot be used interchangeably. This is mainly due to differences in calibration. Harmonisation of available assays using a common international standard would facilitate more meaningful interpretation of data from studies using different kits. Discordance between intact and C-terminal FGF23 assay measurements is more marked at physiological concentrations than in patients undergoing haemodialysis. PMID- 23729625 TI - Staging chronic kidney disease and estimating glomerular filtration rate: an opinion paper about the new international recommendations. AB - In January 2013, the international recommendations of the KDIGO (for "Kidney Disease: Improving Global Outcomes") to define chronic kidney disease (CKD) and classify patients in CKD stages have been published. In this opinion article, we will review and discuss the most important guidelines proposed about CKD staging and glomerular filtration rate (GFR) estimating. In particular, we question the choice of fixed knot values at 60 mL/min/1.73 m2 to define CKD. We also question the strategies proposed to measure and use cystatin C results. PMID- 23729627 TI - The influence of non-specificity of the creatinine assay on eGFR. PMID- 23729626 TI - Biomarkers in the treatment of cancer: opportunities and pitfalls. PMID- 23729628 TI - Glycogen phosphorylase isoenzyme BB plasma kinetics is not related to myocardial ischemia induced by exercise stress echo test. AB - BACKGROUND: Glycogen phosphorylase BB (GPBB) is released from cardiac cells during myocyte damage. Previous studies have shown contradictory results regarding the relation of enzyme release and reversible myocardial ischemia. The aim of this study was to determine the plasma kinetics of GPBB as a response to the exercise stress echocardiographic test (ESET), and to define the relationship between myocardial ischemia and enzyme plasma concentrations. METHODS: We studied 46 consecutive patients undergoing ESET, with recent coronary angiography. In all patients, a submaximal stress echo test according to Bruce protocol was performed. Concentration of GPBB was measured in peripheral blood that was sampled 5 min before and 10, 30 and 60 min after ESET. RESULTS: There was significant increase of GPBB concentration after the test (p=0.021). Significant increase was detected 30 min (34.9% increase, p=0.021) and 60 min (34.5% increase, p=0.016) after ESET. There was no significant effect of myocardial ischemia on GPBB concentrations (p=0.126), and no significant interaction between sampling intervals and myocardial ischemia, suggesting a similar release profile of GPBB in ischemic and non-ischemic conditions (p=0.558). Patients in whom ESET was terminated later (stages 4 or 5 of standard Bruce protocol; n=13) had higher GPBB concentrations than patients who terminated ESET earlier (stages 1, 2 or 3; n=33) (p=0.049). Baseline GPBB concentration was not correlated to any of the patients' demographic, clinical and hemodynamic characteristics. CONCLUSIONS: GPBB plasma concentration increases after ESET, and it is not related to inducible myocardial ischemia. However, it seems that GPBB release during ESET might be related to exercise load/duration. PMID- 23729629 TI - Investigation of apparent non-albuminuric proteinuria in a primary care population. AB - BACKGROUND: There is debate as to whether using the urinary albumin- or protein to-creatinine ratio (ACR or PCR) should be the primary test for proteinuria. Whilst albuminuria (increased ACR) in the absence of proteinuria (increased PCR) may be expected in some patients, the converse (i.e., proteinuria in the absence of albuminuria) is more unusual and its cause and significance are unclear. We investigated the nature of such apparent non-albuminuric proteinuria in a primary care population of patients. METHODS: ACR and PCR were measured in 569 urine samples from patients who either had chronic kidney disease or were at increased risk of the condition. Samples with apparent proteinuria (PCR >=23 mg/mmol/>=200 mg/g) but no albuminuria (ACR <3.4 mg/mmol/<30 mg/g) were classified as 'discrepant' (37% of proteinuric samples, 6% of all samples); 27 of these samples were available for further analyses. The further analyses included electrophoresis, repeat measurement, immunoassays for markers of tubular proteinuria and use of alternative albumin and total protein methods. RESULTS: Electrophoresis did not identify significant proteinuria in the discrepant samples. The only evidence of tubular proteinuria following measurement of three urinary markers of the condition was a mildly increased alpha1-microglobulin-to creatinine ratio in 10 of the 27 discrepant samples analysed, four of which also had a raised beta-trace protein-to-creatinine ratio. Use of an alternative urinary total protein method resulted in significantly lower PCRs and 17 of the 27 samples were no longer classified as proteinuric. CONCLUSIONS: We were unable to confirm the cause of a raised PCR without albuminuria in these patients and suspect that in most cases it is artefactual. PMID- 23729630 TI - New monoallelic combination of KRAS gene mutations in codons 12 and 13 in the lung adenocarcinoma. AB - PURPOSE: In a retrospective analysis of the prevalence of KRAS mutations in patients with advanced non-small cell lung cancer (NSCLC), we detected a unique and not earlier described case of a double combination of mutations at codons 12 and 13 of the KRAS gene in a patient with lung adenocarcinoma. MATERIAL/METHODS: To determine the molecular characteristics of the infrequent mutation and the mutational status of the KRAS gene in metastatic brain tumors in the same patient, we performed morphological and molecular tests. RESULTS: Molecular analysis of the nature of the double mutation showed that the unique combination of variants is a monoallelic mutation. This type of changes has not yet been registered in the Catalogue of Somatic Mutations in Cancer database. Molecular assessment of the KRAS mutation status in the brain metastatic site in the same patient, showed no mutations in codons 12 and 13. Moreover, we did not find mutation at exon 19 and 21 of EGFR gene, both in primary tumor as well as in secondary metastatic foci in the brain. CONCLUSIONS: The presented case shows an example of KRAS gene molecular mosaicism and heterogeneity of lung adenocarcinoma primary and metastatic tumors. Molecular heterogeneity of lung adenocarcinoma tumors can significantly affect eligibility of patients for targeted therapies. PMID- 23729631 TI - The influence of obesity on inflammation and clinical symptoms in asthma. AB - Obesity and asthma are both important public health issues. Increasing number of studies suggest the association between obesity and asthma which may be causal or accidental. The studies on animal models show innate enhancement of airway hyper responsiveness which suggest that chronic airway hyper-responsiveness may be related to chronic low-grade systemic inflammation occurring in obesity. These results are confirmed by studies on asthmatic patients which show that levels of inflammation markers were higher in obese asthma patients and are related to the parameters of obesity. However, adipokines secreted by adipose tissue have also been involved in the regulation of inflammation and allergic responses, and suggested to affect the risk of asthma, especially in obese female patients. The studies on the association between adiposity and atopy have conflicting results and the issue needs to be investigated in the future. Obesity also decreases lung volume and increases airway resistance inducing symptoms that could mimic asthma. Clinical studies suggest that asthma in obese subjects may differ from the classical phenotype of the disease. Obese patients referred for asthma exacerbation present a reduced response to standard asthma medications. The review indicates that mechanical and inflammatory effects of obesity may explain the influence on asthma. Further studies on the association between adiposity and atopy on airway inflammation may confirm the active role of fat tissue, not only simple mechanical impairment of the thorax movement. Longitudinal studies are needed to understand the association between asthma, and obesity, which may open new therapeutic options for asthma treatment in obese patients. PMID- 23729632 TI - Conserved miRNAs are candidate post-transcriptional regulators of developmental arrest in free-living and parasitic nematodes. AB - Animal development is complex yet surprisingly robust. Animals may develop alternative phenotypes conditional on environmental changes. Under unfavorable conditions, Caenorhabditis elegans larvae enter the dauer stage, a developmentally arrested, long-lived, and stress-resistant state. Dauer larvae of free-living nematodes and infective larvae of parasitic nematodes share many traits including a conserved endocrine signaling module (DA/DAF-12), which is essential for the formation of dauer and infective larvae. We speculated that conserved post-transcriptional regulatory mechanism might also be involved in executing the dauer and infective larvae fate. We used an unbiased sequencing strategy to characterize the microRNA (miRNA) gene complement in C. elegans, Pristionchus pacificus, and Strongyloides ratti. Our study raised the number of described miRNA genes to 257 for C. elegans, tripled the known gene set for P. pacificus to 362 miRNAs, and is the first to describe miRNAs in a Strongyloides parasite. Moreover, we found a limited core set of 24 conserved miRNA families in all three species. Interestingly, our estimated expression fold changes between dauer versus nondauer stages and infective larvae versus free-living stages reveal that despite the speed of miRNA gene set evolution in nematodes, homologous gene families with conserved "dauer-infective" expression signatures are present. These findings suggest that common post-transcriptional regulatory mechanisms are at work and that the same miRNA families play important roles in developmental arrest and long-term survival in free-living and parasitic nematodes. PMID- 23729634 TI - Intracranial pressure dynamics are not linked to aqueductal cerebrospinal fluid stroke volume. PMID- 23729633 TI - Genomic diversity of "deep ecotype" Alteromonas macleodii isolates: evidence for Pan-Mediterranean clonal frames. AB - We have compared genomes of Alteromonas macleodii "deep ecotype" isolates from two deep Mediterranean sites and two surface samples from the Aegean and the English Channel. A total of nine different genomes were analyzed. They belong to five clonal frames (CFs) that differ among them by approximately 30,000 single nucleotide polymorphisms (SNPs) over their core genomes. Two of the CFs contain three strains each with nearly identical genomes (~100 SNPs over the core genome). One of the CFs had representatives that were isolated from samples taken more than 1,000 km away, 2,500 m deeper, and 5 years apart. These data mark the longest proven persistence of a CF in nature (outside of clinical settings). We have found evidence for frequent recombination events between or within CFs and even with the distantly related A. macleodii surface ecotype. The different CFs had different flexible genomic islands. They can be classified into two groups; one type is additive, that is, containing different numbers of gene cassettes, and is very variable in short time periods (they often varied even within a single CF). The other type was more stable and produced the complete replacement of a genomic fragment by another with different genes. Although this type was more conserved within each CF, we found examples of recombination among distantly related CFs including English Channel and Mediterranean isolates. PMID- 23729635 TI - Heart rate and the assessment of changes in venous return after phenylephrine. PMID- 23729636 TI - Determination of MDMA and its three metabolites in the rat perfused liver. AB - 3,4-Methylenedioxymethamphetamine (MDMA) is one of the most commonly abused illicit drugs in the world. We developed a rapid and simple high-performance liquid chromatography with a fluorescence (FL) detector method to determine MDMA and its metabolites, such as 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3 methoxyamphetamine (HMA) and its main unstable metabolite 3,4 dihydroxymethamphetamine (HHMA) besides the internal standards, in a perfusion medium. The separation of analytes was performed at 25 degrees C on a Chromolith(r) C18 (100 * 4.6 mm) column from Merck (Darmstadt, Germany) without any derivatization. The FL detector wavelength was fixed at 285 nm for excitation and at 320 nm for emission. Acetonitrile:phosphate buffer (0.02 M) at pH = 3 (5:95 v/v) was used as the mobile phase. The elution order was HHMA, HMA, MDA and MDMA with a retention time of 1.7, 2.6, 6.1 and 7.4 min, respectively. The method was validated according to the FDA bioanalytical method validation guideline. The limits of quantifications (LOQs) obtained for MDMA, MDA, HMA and HHMA were 1, 1, 1.5 and 5 ng/mL, respectively. The repeatability of relative standard deviation was <11% (except for LOQs). This method was applied successfully to determine MDMA and its metabolites in rat liver perfusion samples. To our knowledge, this is the first method introduced for the determination of HHMA as a free form with an FL detector. PMID- 23729638 TI - MicroRNAs in the atherosclerotic plaque. AB - BACKGROUND: MicroRNAs (miRNA, miR) are noncoding RNAs that regulate gene expression by hindering translation. miRNA expression profiles have been shown to differ in vivo and in vitro in many cellular processes associated with cardiovascular diseases (CVDs). The progression of CVDs has also been shown to alter the blood miRNA profile in humans. CONTENT: We summarize the results of animal and cell experiments concerning the miRNA profile in the atherosclerotic process and the changes which occur in the blood miRNA profile of individuals with CVD. We also survey the relationship of these CVD-related miRNAs and their expression in the human advanced atherosclerotic plaque, thereby providing more insight into miRNA function in human atherosclerotic lesions. The miRNAs miR-126, -134, -145, -146a, -198, -210, -340*, and -92a were found to be expressed differently in the blood of individuals affected and unaffected by CVD. These differences paralleled those seen in tissue comparisons of miRNA expression in advanced atherosclerotic plaques and healthy arteries. Furthermore, several miRNAs associated with atherosclerosis in in vitro studies (such as miR-10a, 126, -145, -146a/b, -185, -210, and -326) were expressed in plaques in a similar pattern as was predicted by the in vitro experiments. The clinical implications of miRNAs in atherosclerosis as biomarkers and as possible drug targets are also reviewed. SUMMARY: miRNA profiles in in vitro and in vivo studies as well as in human peripheral blood are quite representative of the miRNA expression in human atherosclerotic plaques. miRNAs appear promising in terms of future clinical applications. PMID- 23729639 TI - Ancient DNA damage. AB - Under favorable conditions DNA can survive for thousands of years in the remains of dead organisms. The DNA extracted from such remains is invariably degraded to a small average size by processes that at least partly involve depurination. It also contains large amounts of deaminated cytosine residues that are accumulated toward the ends of the molecules, as well as several other lesions that are less well characterized. PMID- 23729641 TI - Application of Raman spectroscopy to identify microcalcifications and underlying breast lesions at stereotactic core needle biopsy. AB - Microcalcifications are a feature of diagnostic significance on a mammogram and a target for stereotactic breast needle biopsy. Here, we report development of a Raman spectroscopy technique to simultaneously identify microcalcification status and diagnose the underlying breast lesion, in real-time, during stereotactic core needle biopsy procedures. Raman spectra were obtained ex vivo from 146 tissue sites from fresh stereotactic breast needle biopsy tissue cores from 33 patients, including 50 normal tissue sites, 77 lesions with microcalcifications, and 19 lesions without microcalcifications, using a compact clinical system. The Raman spectra were modeled on the basis of the breast tissue components, and a support vector machine framework was used to develop a single-step diagnostic algorithm to distinguish normal tissue, fibrocystic change (FCC), fibroadenoma, and breast cancer, in the absence and presence of microcalcifications. This algorithm was subjected to leave-one-site-out cross-validation, yielding a positive predictive value, negative predictive value, sensitivity, and specificity of 100%, 95.6%, 62.5%, and 100% for diagnosis of breast cancer (with or without microcalcifications) and an overall accuracy of 82.2% for classification into specific categories of normal tissue, FCC, fibroadenoma, or breast cancer (with and without microcalcifications). Notably, the majority of breast cancers diagnosed are ductal carcinoma in situ (DCIS), the most common lesion associated with microcalcifications, which could not be diagnosed using previous Raman algorithm(s). Our study shows the potential of Raman spectroscopy to concomitantly detect microcalcifications and diagnose associated lesions, including DCIS, and thus provide real-time feedback to radiologists during such biopsy procedures, reducing nondiagnostic and false-negative biopsies. PMID- 23729642 TI - Cytomegalovirus contributes to glioblastoma in the context of tumor suppressor mutations. AB - To study the controversial role of cytomegalovirus (CMV) in glioblastoma, we assessed the effects of murine CMV (MCMV) perinatal infection in a GFAP-cre; Nf1(loxP/+); Trp53(-/+) genetic mouse model of glioma (Mut3 mice). Early on after infection, MCMV antigen was predominantly localized in CD45+ lymphocytes in the brain with active viral replication and local areas of inflammation, but, by 7 weeks, there was a generalized loss of MCMV in brain, confirmed by bioluminescent imaging. MCMV-infected Mut3 mice exhibited a shorter survival time from their gliomas than control Mut3 mice perinatally infected with mock or with a different neurotropic virus. Animal survival was also significantly shortened when orthotopic gliomas were implanted in mice perinatally infected with MCMV versus controls. MCMV infection increased phosphorylated STAT3 (p-STAT3) levels in neural stem cells (NSC) harvested from Mut3 mice subventricular zone, and, in vivo, there was increased p-STAT3 in NSCs in MCMV-infected compared with control mice. Of relevance, human CMV (HCMV) also increased p-STAT3 and proliferation of patient-derived glioblastoma neurospheres, whereas a STAT3 inhibitor reversed this effect in vitro and in vivo. These findings thus associate CMV infection to a STAT3-dependent modulatory role in glioma formation/progression in the context of tumor suppressor mutations in mice and possibly in humans. PMID- 23729643 TI - Opioid pharmacogenetics of alcohol addiction. AB - Alcohol addiction is one of the most common and devastating diseases in the world. Given the tremendous heterogeneity of alcohol-addicted individuals, it is unlikely that one medication will help nearly all patients. Thus, there is a clear need to develop predictors of response to existing medications. Naltrexone is a MU-opioid receptor antagonist, which has been approved in the United States for treatment of alcohol addiction since 1994. It has limited efficacy, in part because of noncompliance, but many patients do not respond despite high levels of compliance. There are reports that a missense single nucleotide polymorphism (rs179919 or A118G) in the MU-opioid receptor gene predicts a favorable response to naltrexone if an individual carries a "G" allele. This work will review the evidence for this hypothesis. The data are promising that the "G" allele predisposes to a beneficial naltrexone response among alcohol-addicted persons, but additional research is needed to prove this hypothesis in prospective clinical trials. PMID- 23729644 TI - Importance and determinants of induction of cold-induced DEAD RNA helicase in the hyperthermophilic archaeon Thermococcus kodakarensis. AB - Thermococcus kodakarensis, which grows optimally at 85 degrees C, expresses cold stress-inducible DEAD box RNA helicase (Tk-deaD) when shifted to 60 degrees C. A DDA1 deletion (DeltaTk-deaD) mutant exhibited decreased cell growth, and cells underwent lysis at 60 degrees C in nutrient broth in the absence of elemental sulfur. In contrast, cells in medium containing elemental sulfur at 60 degrees C did not undergo lysis, suggesting that Tk-deaD is necessary for cell growth in sulfur-free medium. To identify the element responsible for the cold response, a pTKR expression probe plasmid was constructed using thermostable catalase from Pyrobaculum calidifontis as a reporter. The plasmid pTKRD, which contained the transcription factor B recognition element, TATA region, and Shine-Dalgarno (SD) region, including the initiation codon of the Tk-deaD gene, exhibited cold inducibility. We also constructed a series of deletion and chimeric constructs with the glutamate dehydrogenase (gdh) promoter, whose expression is constitutive independent of culture temperatures and catalase expression. Reporter assay experiments indicated that the regulatory element is located in the region between the SD region and the initiation codon (ATG). Nucleotide sequences in the upstream regions of Tk-deaD and gdh were compared and revealed a five-adenosine (AAAAA) sequence between SD and ATG of Tk-deaD that was not present in gdh. Replacement of the repeated adenosine sequence with other sequences revealed that the AAAAA sequence is important for cold induction. This sequence-specific mechanism is unique and is one that has not been identified in other known cold inducible genes. PMID- 23729645 TI - Allelic variation in a simple sequence repeat element of neisserial pglB2 and its consequences for protein expression and protein glycosylation. AB - Neisseria species express an O-linked glycosylation system in which functionally distinct proteins are elaborated with variable glycans. A major source of glycan diversity in N. meningitidis results from two distinct pglB alleles responsible for the synthesis of either N,N'-diacetylbacillosamine or glyceramido-acetamido trideoxyhexose that occupy the reducing end of the oligosaccharides. Alternative modifications at C-4 of the precursor UDP-4-amino are attributable to distinct C terminal domains that dictate either acetyltransferase or glyceramidotransferase activity, encoded by pglB and pglB2, respectively. Naturally occurring alleles of pglB2 have homopolymeric tracts of either 7 or 8 adenosines (As) bridging the C terminal open reading frame (ORF) and the ORF encompassing the conserved N terminal domain associated with phosphoglycosyltransferase activity. In the work presented here, we explored the consequences of such pglB2 allele variation and found that, although both alleles are functional vis-a-vis glycosylation, the 7A form results in the expression of a single, multidomain protein, while the 8A variant elicits two single-domain proteins. We also found that the glyceramidotransferase activity-encoding domain is essential to protein glycosylation, showing the critical role of the C-4 modification of the precursor UDP-4-amino in the pathway. These findings were further extended and confirmed by examining the phenotypic consequences of extended poly(A) tract length variation. Although ORFs related to those of pglB2 are broadly distributed in eubacteria, they are primarily found as two distinct, juxtaposed ORFs. Thus, the neisserial pglB2 system provides novel insights into the potential influence of hypermutability on modular evolution of proteins by providing a unique snapshot of the progression of ongoing gene fusion. PMID- 23729646 TI - NO-induced biofilm dispersion in Pseudomonas aeruginosa is mediated by an MHYT domain-coupled phosphodiesterase. AB - Dispersion is a process used by bacteria to successfully transit from a biofilm to a planktonic growth state and to spawn novel communities in new locales. Alterations in bis-(3'-5')-cyclic dimeric GMP (c-di-GMP) levels have been shown to be associated with biofilm dispersal in a number of different bacteria. The signaling molecule nitric oxide (NO) is known to induce biofilm dispersion through stimulation of c-di-GMP-degrading phosphodiesterase (PDE) activity. However, no c-di-GMP modulating enzyme directly involved in NO-induced dispersion has yet been described in the opportunistic pathogen Pseudomonas aeruginosa. Here, we characterized MucR (PA1727) and NbdA (PA3311, NO-induced biofilm dispersion locus A), two membrane-bound proteins with identical domain organization consisting of MHYT-GGDEF-EAL, with respect to their role in NO induced dispersion. Inactivation of mucR impaired biofilm dispersion in response to NO and glutamate, whereas inactivation of nbdA only impaired biofilm dispersion upon exposure to NO. A specific role of NbdA in NO-induced dispersion was supported by increased PDE activity, resulting in decreased c-di-GMP levels in biofilms expressing nbdA upon exposure to NO, a response that was absent in the DeltanbdA strain. Moreover, increased PDE activity was mainly due to a transcriptional activation of nbdA upon addition of NO. Biochemical analyses of recombinant protein variants lacking the membrane-anchored MHYT domain support NbdA being an active PDE. In contrast, MucR displayed both diguanylate cyclase and PDE activity in vitro, which seemed regulated in a growth-dependent manner in vivo. This is the first description of a PDE specifically involved in NO-induced biofilm dispersion in P. aeruginosa. PMID- 23729647 TI - Activation of CpxRA in Haemophilus ducreyi primarily inhibits the expression of its targets, including major virulence determinants. AB - Haemophilus ducreyi causes chancroid, a genital ulcer disease that facilitates the transmission of human immunodeficiency virus type 1. In humans, H. ducreyi is surrounded by phagocytes and must adapt to a hostile environment to survive. To sense and respond to environmental cues, bacteria frequently use two-component signal transduction (2CST) systems. The only obvious 2CST system in H. ducreyi is CpxRA; CpxR is a response regulator, and CpxA is a sensor kinase. Previous studies by Hansen and coworkers showed that CpxR directly represses the expression of dsrA, the lspB-lspA2 operon, and the flp operon, which are required for virulence in humans. They further showed that CpxA functions predominantly as a phosphatase in vitro to maintain the expression of virulence determinants. Since a cpxA mutant is avirulent while a cpxR mutant is fully virulent in humans, CpxA also likely functions predominantly as a phosphatase in vivo. To better understand the role of H. ducreyi CpxRA in controlling virulence determinants, here we defined genes potentially regulated by CpxRA by using RNA-Seq. Activation of CpxR by deletion of cpxA repressed nearly 70% of its targets, including seven established virulence determinants. Inactivation of CpxR by deletion of cpxR differentially regulated few genes and increased the expression of one virulence determinant. We identified a CpxR binding motif that was enriched in downregulated but not upregulated targets. These data reinforce the hypothesis that CpxA phosphatase activity plays a critical role in controlling H. ducreyi virulence in vivo. Characterization of the downregulated genes may offer new insights into pathogenesis. PMID- 23729648 TI - Brucella BioR regulator defines a complex regulatory mechanism for bacterial biotin metabolism. AB - The enzyme cofactor biotin (vitamin H or B7) is an energetically expensive molecule whose de novo biosynthesis requires 20 ATP equivalents. It seems quite likely that diverse mechanisms have evolved to tightly regulate its biosynthesis. Unlike the model regulator BirA, a bifunctional biotin protein ligase with the capability of repressing the biotin biosynthetic pathway, BioR has been recently reported by us as an alternative machinery and a new type of GntR family transcriptional factor that can repress the expression of the bioBFDAZ operon in the plant pathogen Agrobacterium tumefaciens. However, quite unusually, a closely related human pathogen, Brucella melitensis, has four putative BioR-binding sites (both bioR and bioY possess one site in the promoter region, whereas the bioBFDAZ [bio] operon contains two tandem BioR boxes). This raised the question of whether BioR mediates the complex regulatory network of biotin metabolism. Here, we report that this is the case. The B. melitensis BioR ortholog was overexpressed and purified to homogeneity, and its solution structure was found to be dimeric. Functional complementation in a bioR isogenic mutant of A. tumefaciens elucidated that Brucella BioR is a functional repressor. Electrophoretic mobility shift assays demonstrated that the four predicted BioR sites of Brucella plus the BioR site of A. tumefaciens can all interact with the Brucella BioR protein. In a reporter strain that we developed on the basis of a double mutant of A. tumefaciens (the DeltabioR DeltabioBFDA mutant), the beta-galactosidase (beta Gal) activity of three plasmid-borne transcriptional fusions (bioBbme-lacZ, bioYbme-lacZ, and bioRbme-lacZ) was dramatically decreased upon overexpression of Brucella bioR. Real-time quantitative PCR analyses showed that the expression of bioBFDA and bioY is significantly elevated upon removal of bioR from B. melitensis. Together, we conclude that Brucella BioR is not only a negative autoregulator but also a repressor of expression of bioY and bio operons that separately function in biotin transport and the biosynthesis pathway. PMID- 23729649 TI - MtvR is a global small noncoding regulatory RNA in Burkholderia cenocepacia. AB - Burkholderia cenocepacia J2315 is a highly epidemic and transmissible clinical isolate of the Burkholderia cepacia complex (Bcc), a group of bacteria causing life-threatening respiratory infections among cystic fibrosis patients. This work describes the functional analysis of the 136-nucleotide (nt)-long MtvR small noncoding RNA (sRNA) from the Bcc member B. cenocepacia J2315, with homologues restricted to the genus Burkholderia. Bioinformatic target predictions revealed a total of 309 mRNAs to be putative MtvR targets. The mRNA levels corresponding to 17 of 19 selected genes were found to be affected when MtvR was either overexpressed or silenced. Analysis of the interaction between MtvR and the hfq mRNA, one of its targets, showed that the sRNA binds exclusively to the 5' untranslated region (UTR) of the hfq mRNA. This interaction resulted in decreased protein synthesis, suggesting a negative regulatory effect of MtvR on the RNA chaperone Hfq. Bacterial strains with MtvR silenced or overexpressed exhibited pleiotropic phenotypes related to growth and survival after several stresses, swimming and swarming motilities, biofilm formation, resistance to antibiotics, and ability to colonize and kill the nematode Caenorhabditis elegans. Together, the results indicate that the MtvR sRNA is a major posttranscriptional regulator in B. cenocepacia. PMID- 23729650 TI - Implication of the VirD4 coupling protein of the Lvh type 4 secretion system in virulence phenotypes of Legionella pneumophila. AB - The genome of the Philadelphia-1 strain of Legionella pneumophila, the causative organism of Legionnaires' disease, encodes two virulence-associated type 4 secretion systems (T4SSs), the Dot/Icm type 4B (T4BSS) and the Lvh type 4A (T4ASS). Broth stationary-phase cultures of most dot/icm mutants are defective in entry and evasion of phagosome acidification. However, those virulence defects can be reversed by incubating broth cultures of dot/icm mutants in water, termed water stress (WS). WS reversal requires the lvh T4ASS locus, suggesting an interaction between the two T4SSs in producing Legionella virulence phenotypes. In the current work, the loss of WS reversal in a dotA Deltalvh mutant of strain JR32 was shown to be attributable to loss of the lvh virD4 gene, encoding the putative coupling protein of the T4ASS. Transformation of a dotA Deltalvh mutant with virD4 also reversed entry and phagosome acidification defects in broth cultures. In addition, broth cultures of Deltalvh and DeltavirD4 mutants, which were dot/icm(+), showed 5-fold and >6-fold increases in translocation of the Dot/Icm translocation substrates, proteins RalF and SidD, respectively. These data demonstrate that the Lvh T4ASS functions in both broth stationary-phase cultures conventionally used for infection and cultures exposed to WS treatment. Our studies in a dotA Deltalvh mutant and in a dot/icm(+) background establish that VirD4 and the Lvh T4ASS contribute to virulence phenotypes and are consistent with independent functioning of Dot/Icm and Lvh T4SSs or functional substitution of the Lvh VirD4 protein for a component(s) of the Dot/Icm T4BSS. PMID- 23729651 TI - Discovery of catalases in members of the Chlamydiales order. AB - Catalase is an important virulence factor for survival in macrophages and other phagocytic cells. In Chlamydiaceae, no catalase had been described so far. With the sequencing and annotation of the full genomes of Chlamydia-related bacteria, the presence of different catalase-encoding genes has been documented. However, their distribution in the Chlamydiales order and the functionality of these catalases remain unknown. Phylogeny of chlamydial catalases was inferred using MrBayes, maximum likelihood, and maximum parsimony algorithms, allowing the description of three clade 3 and two clade 2 catalases. Only monofunctional catalases were found (no catalase-peroxidase or Mn-catalase). All presented a conserved catalytic domain and tertiary structure. Enzymatic activity of cloned chlamydial catalases was assessed by measuring hydrogen peroxide degradation. The catalases are enzymatically active with different efficiencies. The catalase of Parachlamydia acanthamoebae is the least efficient of all (its catalytic activity was 2 logs lower than that of Pseudomonas aeruginosa). Based on the phylogenetic analysis, we hypothesize that an ancestral class 2 catalase probably was present in the common ancestor of all current Chlamydiales but was retained only in Criblamydia sequanensis and Neochlamydia hartmannellae. The catalases of class 3, present in Estrella lausannensis and Parachlamydia acanthamoebae, probably were acquired by lateral gene transfer from Rhizobiales, whereas for Waddlia chondrophila they likely originated from Legionellales or Actinomycetales. The acquisition of catalases on several occasions in the Chlamydiales suggests the importance of this enzyme for the bacteria in their host environment. PMID- 23729652 TI - Role of the ribosomal P-site elements of m2G966, m5C967, and the S9 C-terminal tail in maintenance of the reading frame during translational elongation in Escherichia coli. AB - The ribosomal P-site hosts the peptidyl-tRNAs during translation elongation. Which P-site elements support these tRNA species to maintain codon-anticodon interactions has remained unclear. We investigated the effects of P-site features of methylations of G966, C967, and the conserved C-terminal tail sequence of Ser, Lys, and Arg (SKR) of the S9 ribosomal protein in maintenance of the translational reading frame of an mRNA. We generated Escherichia coli strains deleted for the SKR sequence in S9 ribosomal protein, RsmB (which methylates C967), and RsmD (which methylates G966) and used them to translate LacZ from its +1 and -1 out-of-frame constructs. We show that the S9 SKR tail prevents both the +1 and -1 frameshifts and plays a general role in holding the P-site tRNA/peptidyl-tRNA in place. In contrast, the G966 and C967 methylations did not make a direct contribution to the maintenance of the translational frame of an mRNA. However, deletion of rsmB in the S9Delta3 background caused significantly increased -1 frameshifting at 37 degrees C. Interestingly, the effects of the deficiency of C967 methylation were annulled when the E. coli strain was grown at 30 degrees C, supporting its context-dependent role. PMID- 23729653 TI - Key amino acid residues involved in the transitions of L- to R-type protofilaments of the Salmonella flagellar filament. AB - The flagellar filament enables bacteria to swim by functioning as a helical propeller. The filament is a supercoiled assembly of a single protein, flagellin, and is formed by 11 protofilaments arranged in a circle. Bacterial swimming and tumbling correlate with changes of the various helical structures, called polymorphic transformation, that are determined by the ratios of two distinct forms of protofilaments, the L and R types. The polymorphic transformation is caused by transition of the protofilament between L and R types. Elucidation of this transition mechanism has been addressed by comparing the atomic structures of L- and R-type straight filaments or using massive molecular dynamic simulation. Here, we found amino acid residues required for the transition of the protofilament using fliC-intragenic suppressor analysis. We isolated a number of revertants producing supercoiled filaments from mutants with straight filaments and identified the second-site mutations in all of the revertants. The results suggest that Asp107, Gly426, and Ser448 and Ser106, Ala416, Ala427, and Arg431 are the key residues involved in inducing supercoiled filaments from the R- and the L-type straight filaments, respectively. Considering the structures of the R- and L-type protofilaments and the relationship between the rotation of the flagellar motor and the polymorphic transformation, we propose that Gly426, Ala427, and Arg431 contribute to the first stage of the transition and that Ser106, Asp107, and Ala416 play a role in propagating the transitions along the flagellar filament. PMID- 23729654 TI - The human papillomavirus-16 E7 oncoprotein exerts antiapoptotic effects via its physical interaction with the actin-binding protein gelsolin. AB - The oncoprotein E7 from human papillomavirus-16 (HPV-16 E7) plays a pivotal role in HPV postinfective carcinogenesis, and its physical interaction with host cell targets is essential to its activity. We identified a novel cellular partner for the viral oncoprotein: the actin-binding protein gelsolin (GSN), a key regulator of actin filament assembly and disassembly. In fact, biochemical analyses, generation of a 3D molecular interaction model and the use of specific HPV-16 E7 mutants provided clear cut evidence supporting the crucial role of HPV-16 E7 in affecting GSN integrity and function in human immortalized keratinocytes. Accordingly, functional analyses clearly suggested that stable HPV-16 E7 expression induced an imbalance between polymeric and monomeric actin in favor of the former. These events also lead to changes of cell cycle (increased S phase), to the inhibition of apoptosis and to the increase of cell survival. These results provide support to the hypotheses generated from the 3D molecular interaction model and encourage the design of small molecules hindering HPV induced host cell reprogramming by specifically targeting HPV-16 E7-expressing cells. PMID- 23729655 TI - Suppression of colon carcinogenesis by targeting Notch signaling. AB - Recent studies have shown that aberrant Notch signaling contributes to the pathogenesis of colorectal cancer (CRC). However, the potential therapeutic benefits of Notch pathway inhibitors, including gamma-secretase inhibitors (GSIs) on colon carcinogenesis are still unclear. In this study, the effects of the GSI, N-[N-3,5-difluorophenacetyl]-L-alanyl-S-phenylglycine methyl ester (DAPM) on colon carcinogenesis were investigated. In vitro, DAPM suppressed cell proliferation and induced the expression of Kruppel-like factor 4 (KLF4) and p21 in human colon cancer cells. Interestingly, p21-null HCT 116 cells were largely resistant to the suppressive effects of DAPM on cell proliferation compared with the parental cells. To investigate the effects of DAPM in vivo, colonoscopy was performed to establish the presence of colon tumors 9 weeks after azoxymethane treatment. After tumors were identified, mice were injected intraperitoneally every other day with either DAPM or vehicle for 4 weeks. The frequency of both large (>4mm) and small (<1mm) colon tumors was significantly reduced by DAPM treatment. Colon tumors in the DAPM-treated mice displayed increased levels of KLF4 and p21, accompanied by reduced Ki-67 staining compared with controls. Notably, in human colon tumor biopsies, KLF4 and p21 expressions were present within hyperplastic polyps, but the levels of both proteins were markedly reduced in tubular adenomas. Our results suggest that inhibition of Notch signaling by DAPM provides a potential chemopreventive strategy for patients with tubular adenomas, in part via activation of the KLF4-p21 axis. PMID- 23729656 TI - BRIT1 regulates p53 stability and functions as a tumor suppressor in breast cancer. AB - In humans, the gene encoding the BRCA1 C terminus-repeat inhibitor of human telomerase expression 1 (BRIT1) protein is located on chromosome 8p23.1, a region implicated in the development of several malignancies, including breast cancer. Previous studies by our group and others suggested that BRIT1 might function as a novel tumor suppressor. Thus, identifying the molecular mechanisms that underlie BRIT1's tumor suppressive function is important to understand cancer etiology and to identify effective therapeutic strategies for BRIT1-deficient tumors. We thus investigated the role of BRIT1 as a tumor suppressor in breast cancer by using genetic approaches. We discovered that BRIT1 functions as a post-transcriptional regulator of p53 expression. BRIT1 regulates p53 protein stability through blocking murine double minute 2-mediated p53 ubiquitination. To fully demonstrate the role of BRIT1 as a tumor suppressor, we depleted BRIT1 in normal breast epithelial cells. We found that knockdown of BRIT1 caused the oncogenic transformation of normal mammary epithelial cells. Furthermore, ectopic expression of BRIT1 effectively suppressed breast cancer cell proliferation and colony formation in vitro and tumor growth in vivo. Taken together, our study provides new insights into the biological functions of BRIT1 as a tumor suppressor in human breast cancer. PMID- 23729657 TI - The non-obese diabetic mouse sequence, annotation and variation resource: an aid for investigating type 1 diabetes. AB - Model organisms are becoming increasingly important for the study of complex diseases such as type 1 diabetes (T1D). The non-obese diabetic (NOD) mouse is an experimental model for T1D having been bred to develop the disease spontaneously in a process that is similar to humans. Genetic analysis of the NOD mouse has identified around 50 disease loci, which have the nomenclature Idd for insulin dependent diabetes, distributed across at least 11 different chromosomes. In total, 21 Idd regions across 6 chromosomes, that are major contributors to T1D susceptibility or resistance, were selected for finished sequencing and annotation at the Wellcome Trust Sanger Institute. Here we describe the generation of 40.4 mega base-pairs of finished sequence from 289 bacterial artificial chromosomes for the NOD mouse. Manual annotation has identified 738 genes in the diabetes sensitive NOD mouse and 765 genes in homologous regions of the diabetes resistant C57BL/6J reference mouse across 19 candidate Idd regions. This has allowed us to call variation consequences between homologous exonic sequences for all annotated regions in the two mouse strains. We demonstrate the importance of this resource further by illustrating the technical difficulties that regions of inter-strain structural variation between the NOD mouse and the C57BL/6J reference mouse can cause for current next generation sequencing and assembly techniques. Furthermore, we have established that the variation rate in the Idd regions is 2.3 times higher than the mean found for the whole genome assembly for the NOD/ShiLtJ genome, which we suggest reflects the fact that positive selection for functional variation in immune genes is beneficial in regard to host defence. In summary, we provide an important resource, which aids the analysis of potential causative genes involved in T1D susceptibility. Database URLs: http://www.sanger.ac.uk/resources/mouse/nod/; http://vega previous.sanger.ac.uk/info/data/mouse_regions.html#Idd PMID- 23729658 TI - UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families. AB - Lynch syndrome is an autosomal dominant disease caused by germ line heterozygous mutations mainly involving the MSH2, MLH1 and MSH6 genes that belong to the DNA MisMatch Repair (MMR) genes family. The French network counting the 16 licensed laboratories involved in Lynch syndrome genetic testing developed three locus specific databases with the UMD software (www.umd.be/MLH1/, www.umd.be/MSH2/ and www.umd.be/MSH6/) that presently contain a total of 7047 sequence variations including 707 distinct variations of a priori unknown functional significance (VUS) that were identified through complete mutation screening or targeted predictive testing. Mutation carriers are at high risk for developing early-onset colorectal and endometrial adenocarcinomas. Consensus clinical guidelines have been proposed, allowing the efficient detection of curable lesions. The major challenge of genetic testing is to reliably classify the genomic variations in those patients who seek genetic counseling. Combining the interactive tools of the software, the relevant published data and mainly original information produced by the French MisMatch Repair network, the UMD-MLH1/MSH2/MSH6 databases provide interpretation data for the 707 VUS that were classified according to the IARC 5-Class system. These public databases are regularly updated to improve the classification of all registered VUS, exploring their role in cancer pre disposition based on structural and functional approaches. PMID- 23729660 TI - Lack of robustness of life extension associated with several single-gene P element mutations in Drosophila melanogaster. AB - The hypothesis tested in this study was that single-gene mutations found previously to extend the life span of Drosophila melanogaster could do so consistently in both long-lived y w and standard w (1118) genetic backgrounds. GAL4 drivers were used to express upstream activation sequence (UAS)-responder transgenes globally or in the nervous system. Transgenes associated with oxidative damage prevention (UAS-hSOD1 and UAS-GCLc) or removal (EP-UAS-Atg8a and UAS-dTOR (FRB) ) failed to increase mean life spans in any expression pattern in either genetic background. Flies containing a UAS-EGFP-bMSRA (C) transgene associated with protein repair were found not to exhibit life extension or detectable enhanced green fluorescent protein (EGFP) activity. The presence of UAS-responder transgenes was confirmed by PCR amplification and sequencing at the 5' and 3' end of each insertion. These results cast doubt on the robustness of life extension in flies carrying single-gene mutations and suggest that the effects of all such mutations should be tested independently in multiple genetic backgrounds and laboratory environments. PMID- 23729661 TI - In vitro characterization of axitinib interactions with human efflux and hepatic uptake transporters: implications for disposition and drug interactions. AB - Axitinib is an inhibitor of tyrosine kinase vascular endothelin growth factor receptors 1, 2, and 3. The ATP-binding cassette (ABC) and solute carrier (SLC) transport properties of axitinib were determined in selected cellular systems. Axitinib exhibited high passive permeability in all cell lines evaluated (Papp >= 6 * 10(-6) cm/s). Active efflux was observed in Caco-2 cells, and further evaluation in multidrug resistance gene 1 (MDR1) or breast cancer resistance protein (BCRP) transfected Madin-Darby canine kidney cells type 2 (MDCK) cells indicated that axitinib is at most only a weak substrate for P-glycoprotein (P gp) but not BCRP. Axitinib showed incomplete inhibition of P-gp-mediated transport of digoxin in Caco-2 cells and BCRP transport of topotecan in BCRP transfected MDCK cells with IC50 values of 3 MUM and 4.4 MUM, respectively. Axitinib (10 mg) did not pose a risk for systemic drug interactions with P-gp or BCRP per regulatory guidance. A potential risk for drug interactions through inhibition of P-gp and BCRP in the gastrointestinal tract was identified because an axitinib dose of 10 mg divided by 250 mL was greater than 10-fold the IC50 for each transporter. However, a GastroPlus simulation that considered the low solubility of axitinib resulted in lower intestinal concentrations and suggested a low potential for gastrointestinal interactions with P-gp and BCRP substrates. Organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3 transfected human embryonic kidney 293 (HEK293) cells transported axitinib to a minor extent but uptake into suspended hepatocytes was not inhibited by rifamycin SV suggesting that high passive permeability predominates. Mouse whole-body autoradiography revealed that [(14)C]axitinib-equivalents showed rapid absorption and distribution to all tissues except the brain. This suggests that efflux transport of axitinib may occur at the mouse blood-brain barrier. PMID- 23729662 TI - Oxysterol-induced apoptosis of smooth muscle cells is under the control of a soluble adenylyl cyclase. AB - AIMS: Apoptosis of vascular smooth muscle cells (VSMC) in advanced atherosclerotic plaques is an important cause of plaque instability. Oxysterols have been suggested as important inducers of apoptosis in VSMC, but the precise mechanism is still poorly understood. Here we aimed to analyse the role of the soluble adenylyl cyclase (sAC). METHODS AND RESULTS: VSMC derived from rat aorta were treated with either 25-hydroxycholesterol or 7-ketocholesterol for 24 h. Apoptosis was detected by TUNEL staining and caspases cleavage. Oxysterols treatment led to the activation of the mitochondrial pathway of apoptosis (cytochrome c release and caspase-9 cleavage) and mitochondrial ROS formation, which were suppressed by the pharmacological inhibition or knockdown of sAC. Scavenging ROS with N-acetyl-l-cysteine prevented oxysterol-induced apoptosis. Analyses of the downstream pathway suggest that protein kinase A (PKA)-dependent phosphorylation and the mitochondrial translocation of the pro-apoptotic protein Bax is a key link between sAC and oxysterol-induced ROS formation and apoptosis. To distinguish between intra-mitochondrial and extra-mitochondrial/cytosolic sAC pools, sAC was overexpressed in mitochondria or in the cytosol. sAC expression in the cytosol, but not in mitochondria, significantly promoted apoptosis and ROS formation during oxysterol treatment. CONCLUSION: These results suggest that the sAC/PKA axis plays a key role in the oxysterol-induced apoptosis of VSMC by controlling mitochondrial Bax translocation and ROS formation and that cytosolic sAC, rather than the mitochondrial pool, is involved in the apoptotic mechanism. PMID- 23729663 TI - HSPA12B attenuates cardiac dysfunction and remodelling after myocardial infarction through an eNOS-dependent mechanism. AB - AIMS: HSPA12B is a newly discovered and endothelial-cell-specifically expressed heat shock protein. We have reported recently that overexpression of HSPA12B increased endothelial nitric oxide synthase (eNOS) expression in mouse cardiac tissues during endotoxemia. Endothelial NOS has been shown to protect heart from ischaemic injury. We hypothesized that overexpression of HSPA12B will attenuate cardiac dysfunction and remodelling after myocardial infarction (MI) through an eNOS-dependant mechanism. METHODS AND RESULTS: MI was induced by permanent ligation of the left anterior descending coronary artery in the transgenic mice (Tg) overexpressing hspa12b gene and its wild-type (WT) littermates. Echocardiographic analysis revealed that Tg mice exhibited improvements in cardiac dysfunction and remodelling at 1 and 4 weeks after MI. These improvements were accompanied by a significant decrease in cardiomyocyte apoptosis and increase in capillary and arteriolar densities. Significant up-regulation of eNOS, VEGF, Ang-1, and Bcl-2 was also observed in Tg hearts compared with WT hearts after MI. However, pharmacological inhibition of eNOS abolished the HSPA12B-induced decrease in cardiomyocyte apoptosis and increase in capillary formation after MI. Most importantly, inhibition of eNOS abrogated the protection of HSPA12B against cardiac dysfunction and remodelling after MI. CONCLUSIONS: These data demonstrate for the first time that the overexpression of HSPA12B attenuates cardiac dysfunction and remodelling after MI. This action of HSPA12B was mediated, at least in part, by prevention of cardiomyocyte apoptosis and promotion of myocardial angiogenesis via an eNOS-dependent mechanism. HSPA12B could be a novel target for the management of patients with post-MI cardiac dysfunction and remodelling. PMID- 23729664 TI - Functional remodelling of arterial endothelium during early postnatal development in rats. AB - AIMS: Functional remodelling takes place permanently in the circulatory system. Whether this process also affects the anti-contractile effect of the endothelium during vasoconstrictor action is unknown. Therefore, the hypothesis was tested that the impact of the anti-contractile effect of the endothelium on agonist induced contractions changes during early postnatal development. METHODS AND RESULTS: We studied isometric contractions in saphenous arteries of young (1-2 weeks) and adult (2-3 months) rats. Real-time PCR and western blot were performed to evaluate the levels of mRNA expression and protein phosphorylation, respectively. In young but not in adult rats, methoxamine-induced contractions of endothelium-intact vessels exhibited a lower sensitivity compared with endothelium-denuded vessels. The endothelial influence on methoxamine-induced contractions in arteries of young rats was completely blocked by inhibition of endothelial NO-synthase (eNOS) and guanylate cyclase. NO-donor-induced vessel relaxations were not different in young and adult rats. The expression level of eNOS mRNA was prominently higher in arteries from young compared with adult rats. eNOS inhibition alone induced tonic contractions of endothelium-intact arteries from young but not from adult animals that were associated with corresponding changes in phosphorylation of the myosin regulatory light chains, the regulatory subunit of smooth muscle cell myosin light chain phosphatase, and vasodilator stimulated phosphoprotein, the latter two being considered to be good markers of NO/sGC/PKG pathway activity. CONCLUSION: We demonstrated that agonist-induced contractions in arteries of young rats are attenuated by the endothelium possessing an active NO-pathway. The active NO-pathway is due to a constitutive eNOS activity that disappears with age. PMID- 23729665 TI - Identification and functional analysis of the primary pantothenate transporter, PfPAT, of the human malaria parasite Plasmodium falciparum. AB - The human malaria parasite Plasmodium falciparum is absolutely dependent on the acquisition of host pantothenate for its development within human erythrocytes. Although the biochemical properties of this transport have been characterized, the molecular identity of the parasite-encoded pantothenate transporter remains unknown. Here we report the identification and functional characterization of the first protozoan pantothenate transporter, PfPAT, from P. falciparum. We show using cell biological, biochemical, and genetic analyses that this transporter is localized to the parasite plasma membrane and plays an essential role in parasite intraerythrocytic development. We have targeted PfPAT to the yeast plasma membrane and showed that the transporter complements the growth defect of the yeast fen2Delta pantothenate transporter-deficient mutant and mediates the entry of the fungicide drug, fenpropimorph. Our studies in P. falciparum revealed that fenpropimorph inhibits the intraerythrocytic development of both chloroquine- and pyrimethamine-resistant P. falciparum strains with potency equal or better than that of currently available pantothenate analogs. The essential function of PfPAT and its ability to deliver both pantothenate and fenpropimorph makes it an attractive target for the development and delivery of new classes of antimalarial drugs. PMID- 23729666 TI - Structural requirements for sterol regulatory element-binding protein (SREBP) cleavage in fission yeast. AB - Sterol regulatory element-binding proteins (SREBPs) are central regulators of cellular lipid synthesis and homeostasis. Mammalian SREBPs are proteolytically activated and liberated from the membrane by Golgi Site-1 and Site-2 proteases. Fission yeast SREBPs, Sre1 and Sre2, employ a different mechanism that genetically requires the Golgi Dsc E3 ligase complex for cleavage activation. Here, we established Sre2 as a model to define structural requirements for SREBP cleavage. We showed that Sre2 cleavage does not require the N-terminal basic helix-loop-helix zipper transcription factor domain, thus separating cleavage of Sre2 from its transcription factor function. From a mutagenesis screen of 94 C terminal residues of Sre2, we isolated 15 residues required for cleavage and further identified a glycine-leucine sequence required for Sre2 cleavage. Importantly, the glycine-leucine sequence is located at a conserved distance before the first transmembrane segment of both Sre1 and Sre2 and cleavage occurs in between this sequence and the membrane. Bioinformatic analysis revealed a broad conservation of this novel glycine-leucine motif in SREBP homologs of ascomycete fungi, including the opportunistic human pathogen Aspergillus fumigatus where SREBP is required for virulence. Consistent with this, the sequence was also required for cleavage of the oxygen-responsive transcription factor Sre1 and adaptation to hypoxia, demonstrating functional conservation of this cleavage recognition motif. These cleavage mutants will aid identification of the fungal SREBP protease and facilitate functional dissection of the Dsc E3 ligase required for SREBP activation and fungal pathogenesis. PMID- 23729667 TI - Ten-eleven translocation 1 (Tet1) is regulated by O-linked N-acetylglucosamine transferase (Ogt) for target gene repression in mouse embryonic stem cells. AB - As a member of the Tet (Ten-eleven translocation) family proteins that can convert 5-methylcytosine (5mC) to 5-hydroxylmethylcytosine (5hmC), Tet1 has been implicated in regulating global DNA demethylation and gene expression. Tet1 is highly expressed in embryonic stem (ES) cells and appears primarily to repress developmental genes for maintaining pluripotency. To understand how Tet1 may regulate gene expression, we conducted large scale immunoprecipitation followed by mass spectrometry of endogenous Tet1 in mouse ES cells. We found that Tet1 could interact with multiple chromatin regulators, including Sin3A and NuRD complexes. In addition, we showed that Tet1 could also interact with the O-GlcNAc transferase (Ogt) and be O-GlcNAcylated. Depletion of Ogt led to reduced Tet1 and 5hmC levels on Tet1-target genes, whereas ectopic expression of wild-type but not enzymatically inactive Ogt increased Tet1 levels. Mutation of the putative O GlcNAcylation site on Tet1 led to decreased O-GlcNAcylation and level of the Tet1 protein. Our results suggest that O-GlcNAcylation can positively regulate Tet1 protein concentration and indicate that Tet1-mediated 5hmC modification and target repression is controlled by Ogt. PMID- 23729668 TI - Circadian regulation of intestinal lipid absorption by apolipoprotein AIV involves forkhead transcription factors A2 and O1 and microsomal triglyceride transfer protein. AB - We have shown previously that Clock, microsomal triglyceride transfer protein (MTP), and nocturnin are involved in the circadian regulation of intestinal lipid absorption. Here, we clarified the role of apolipoprotein AIV (apoAIV) in the diurnal regulation of plasma lipids and intestinal lipid absorption in mice. Plasma triglyceride in apoAIV(-/-) mice showed diurnal variations similar to apoAIV(+/+) mice; however, the increases in plasma triglyceride at night were significantly lower in these mice. ApoAIV(-/-) mice absorbed fewer lipids at night and showed blunted response to daytime feeding. To explain reasons for these lower responses, we measured MTP expression; intestinal MTP was low at night, and its induction after food entrainment was less in apoAIV(-/-) mice. Conversely, apoAIV overexpression increased MTP mRNA in hepatoma cells, indicating transcriptional regulation. Mechanistic studies revealed that sequences between -204/-775 bp in the MTP promoter respond to apoAIV and that apoAIV enhances expression of FoxA2 and FoxO1 transcription factors and their binding to the identified cis elements in the MTP promoter at night. Knockdown of FoxA2 and FoxO1 abolished apoAIV-mediated MTP induction. Similarly, knockdown of apoAIV in differentiated Caco-2 cells reduced MTP, FoxA2, and FoxO1 mRNA levels, cellular MTP activity, and media apoB. Moreover, FoxA2 and FoxO1 expression showed diurnal variations, and their expression was significantly lower in apoAIV(-/-) mice. These data indicate that apoAIV modulates diurnal changes in lipid absorption by regulating forkhead transcription factors and MTP and that inhibition of apoAIV expression might reduce plasma lipids. PMID- 23729669 TI - Inducible interleukin 32 (IL-32) exerts extensive antiviral function via selective stimulation of interferon lambda1 (IFN-lambda1). AB - Interleukin (IL)-32 has been recognized as a proinflammatory cytokine that participates in responses to viral infection. However, little is known about how IL-32 is induced in response to viral infection and the mechanisms of IL-32 mediated antiviral activities. We discovered that IL-32 is elevated by hepatitis B virus (HBV) infection both in vitro and in vivo and that HBV induced IL-32 expression at the level of both transcription and post-transcription. Furthermore, microRNA-29b was found to be a key factor in HBV-regulated IL-32 expression by directly targeting the mRNA 3'-untranslated region of IL-32. Antiviral analysis showed that IL-32 was not sufficient to alter HBV replication in HepG2.2.15 cells. To mimic the viremic phase of viral infection, freshly isolated peripheral blood mononuclear cells were treated with IL-32gamma, the secretory isoform, and the supernatants were used for antiviral assays. Surprisingly, these supernatants exhibited extensive antiviral activity against multiplex viruses besides HBV. Thus, we speculated that the IL-32gamma-treated peripheral blood mononuclear cells produced and secreted an unknown antiviral factor. Using antibody neutralization assays, we identified the factor as interferon (IFN)-lambda1 and not IFN-alpha. Further studies indicated that IL 32gamma effectively inhibited HBV replication in a hydrodynamic injection mouse model. Clinical data showed that elevated levels of IFN-lambda1 both in serum and liver tissue of HBV patients were positively correlated to the increased levels of IL-32. Our results demonstrate that elevated IL-32 levels during viral infection mediate antiviral effects by stimulating the expression of IFN-lambda1. PMID- 23729670 TI - Insights into Okazaki fragment synthesis by the T4 replisome: the fate of lagging strand holoenzyme components and their influence on Okazaki fragment size. AB - In this study, we employed a circular replication substrate with a low priming site frequency (1 site/1.1 kb) to quantitatively examine the size distribution and formation pattern of Okazaki fragments. Replication reactions by the T4 replisome on this substrate yielded a patterned series of Okazaki fragments whose size distribution shifted through collision and signaling mechanisms as the gp44/62 clamp loader levels changed but was insensitive to changes in the gp43 polymerase concentration, as expected for a processive, recycled lagging-strand polymerase. In addition, we showed that only one gp45 clamp is continuously associated with the replisome and that no additional clamps accumulate on the DNA, providing further evidence that the clamp departs, whereas the polymerase is recycled upon completion of an Okazaki fragment synthesis cycle. We found no support for the participation of a third polymerase in Okazaki fragment synthesis. PMID- 23729672 TI - Who is not drinking less in Sweden? An analysis of the decline in consumption for the period 2004-2011. AB - AIMS: This study aimed to analyse if changes in drinking in Sweden have been similar in different population subgroups between 2004 and 2011, a period when per capita consumption declined significantly. METHOD: The analysis starts out from monthly alcohol survey data including 1500 telephone interviews every month. The population is divided into 20 equally large consumption groups separately for men and women and two broad age groups. Both absolute and relative changes in drinking are studied. RESULTS: Most findings confirmed a collectivity of change in drinking: a decline was found at all consumption levels overall, among men and women, and among those under 50 years of age. The decline was smaller in groups with the highest consumption, and among those over 50 years consumption rather increased among the heaviest drinkers. CONCLUSION: Support was obtained for the conception of a social component in recent consumption changes in Sweden. This finding has an important policy message in line with the total consumption model, namely that measures that reduce per capita consumption are likely to imply fewer heavy drinkers. Some exceptions from the collectivity theory that deserves attention in future studies were also noted, e.g. the development among heavier drinkers above 50 years of age. PMID- 23729671 TI - Regulation of Deinococcus radiodurans RecA protein function via modulation of active and inactive nucleoprotein filament states. AB - The RecA protein of Deinococcus radiodurans (DrRecA) has a central role in genome reconstitution after exposure to extreme levels of ionizing radiation. When bound to DNA, filaments of DrRecA protein exhibit active and inactive states that are readily interconverted in response to several sets of stimuli and conditions. At 30 degrees C, the optimal growth temperature, and at physiological pH 7.5, DrRecA protein binds to double-stranded DNA (dsDNA) and forms extended helical filaments in the presence of ATP. However, the ATP is not hydrolyzed. ATP hydrolysis of the DrRecA-dsDNA filament is activated by addition of single stranded DNA, with or without the single-stranded DNA-binding protein. The ATPase function of DrRecA nucleoprotein filaments thus exists in an inactive default state under some conditions. ATPase activity is thus not a reliable indicator of DNA binding for all bacterial RecA proteins. Activation is effected by situations in which the DNA substrates needed to initiate recombinational DNA repair are present. The inactive state can also be activated by decreasing the pH (protonation of multiple ionizable groups is required) or by addition of volume exclusion agents. Single-stranded DNA-binding protein plays a much more central role in DNA pairing and strand exchange catalyzed by DrRecA than is the case for the cognate proteins in Escherichia coli. The data suggest a mechanism to enhance the efficiency of recombinational DNA repair in the context of severe genomic degradation in D. radiodurans. PMID- 23729674 TI - The alcohol improvement programme: evaluation of an initiative to address alcohol related health harm in England. AB - AIMS: The evaluation aimed to assess the impact of The Alcohol Improvement Programme (AIP). This was a UK Department of Health initiative (April 2008-March 2011) aiming to contribute to the reduction of alcohol-related harm as measured by a reduction in the rate of increase in alcohol-related hospital admissions (ARHAs). METHODS: The evaluation (March 2010-September 2011) used a mix of qualitative and quantitative methods to assess the impact of the AIP on ARHAs, to describe and assess the process of implementation, and to identify elements of the programme which might serve as a 'legacy' for the future. RESULTS: There was no evidence that the AIP had an impact on reducing the rise in the rate of ARHAs. The AIP was successfully delivered, increased the priority given to alcohol related harm on local policy agendas and strengthened the infrastructure for the delivery of interventions. CONCLUSION: Although there was no measurable short term impact on the rise in the rate of ARHAs, the AIP helped to set up a strategic response and a delivery infrastructure as a first, necessary step in working towards that goal. There are a number of valuable elements in the AIP which should be retained and repackaged to fit into new policy contexts. PMID- 23729673 TI - MU-Opioid receptor gene (OPRM1) polymorphism A118G: lack of association in Finnish populations with alcohol dependence or alcohol consumption. AB - AIMS: The molecular epidemiological studies on the association of the opioid receptor u-1 (OPRM1) polymorphism A118G (Asn40Asp, rs1799971) and alcohol use disorders have given conflicting results. The aim of this study was to test the possible association of A118G polymorphism and alcohol use disorders and alcohol consumption in three large cohort-based study samples. METHODS: The association between the OPRM1 A118G (Asn40Asp, rs1799971) polymorphism and alcohol use disorders and alcohol consumption was analyzed using three different population based samples: (a) a Finnish cohort study, Health 2000, with 503 participants having a DSM-IV diagnosis for alcohol dependence and/or alcohol abuse and 506 age and sex-matched controls; (b) a Finnish cohort study, FINRISK (n = 2360) and (c) the Helsinki Birth Cohort Study (n = 1384). The latter two populations lacked diagnosis-based phenotypes, but included detailed information on alcohol consumption. RESULTS: We found no statistically significant differences in genotypic or allelic distribution between controls and subjects with alcohol dependence or abuse diagnoses. Likewise no significant effects were observed between the A118G genotype and alcohol consumption. CONCLUSION: These results suggest that A118G (Asn40Asp) polymorphism may not have a major effect on the development of alcohol use disorders at least in the Finnish population. PMID- 23729676 TI - Exposure to combat and traumatic events increases risk of violent offending among military personnel. PMID- 23729675 TI - Obesity accelerates Helicobacter felis-induced gastric carcinogenesis by enhancing immature myeloid cell trafficking and TH17 response. AB - OBJECTIVE: To investigate the role of obesity-associated inflammation and immune modulation in gastric carcinogenesis during Helicobacter-induced chronic gastric inflammation. DESIGN: C57BL/6 male mice were infected with H felis and placed on a high-fat diet (45% calories from fat). Study animals were analysed for gastric and adipose pathology, inflammatory markers in serum, stomach and adipose tissue, and immune responses in blood, spleen, stomach and adipose tissue. RESULTS: H felis-induced gastric carcinogenesis was accelerated in diet-induced obese mice compared with lean controls. Obesity increased bone marrow-derived immature myeloid cells in blood and gastric tissue of H felis-infected mice. Obesity also led to elevations in CD4 T cells, IL-17A, granulocyte macrophage colony stimulating factor, phosphorylated STAT3 and prosurvival gene expression in gastric tissue of H felis-infected mice. Conversely, in adipose tissue of obese mice, H felis infection increased macrophage accumulation and expression of IL-6, C-C motif ligand 7 (CCL7) and leptin. Finally, the combination of obesity and gastric inflammation synergistically increased serum proinflammatory cytokines, including IL-6. CONCLUSIONS: Here, we have established a model to study the molecular mechanism by which obesity predisposes individuals to gastric cancer. In H felis-infected mice, obesity increased proinflammatory immune responses and accelerated gastric carcinogenesis. Interestingly, gastric inflammation augmented obesity-induced adipose inflammation and production of adipose-derived factors in obese, but not lean, mice. Our findings suggest that obesity accelerates Helicobacter-associated gastric cancer through cytokine-mediated cross-talk between inflamed gastric and adipose tissues, augmenting immune responses at both tissue sites, and thereby contributing to a protumorigenic gastric microenvironment. PMID- 23729677 TI - An interesting case of acute, severe postoperative hyponatraemia following carotid endarterectomy. AB - A 62-year-old man with no major comorbidities became acutely hyponatraemic on the second postoperative day following a routine carotid endarterectomy. He developed a headache, became hypertensive and confused, and then had a seizure and required intubation and admission to the intensive care unit. A CT angiogram of his head and carotid arteries was normal, as was a subsequent MRI head. His serum and urine osmolality were low. He was treated by fluid restriction and his hyponatraemia resolved over 3 days. On discontinuation of sedation the patient woke up appropriately. The cause of his hyponatraemia was initially a mystery but when questioned by the medical team he admitted that he drank about 5 litres of water in the afternoon on the second postoperative day. At this point the diagnosis of dilutional hypervolaemic hyponatraemia secondary to water intoxication could be made. PMID- 23729678 TI - Late onset Ito's nevus. AB - Dermal melanocytoses include a variety of congenital and acquired melanocytic lesions characterised by the presence of multiple spindle-shaped dendritic melanocytes in the dermis. These lesions are commonly found in the skin of Asians, but they can also appear in Caucasians. The Mongolian spot, nevi of Ota and Ito are the most common morphological forms. We report a case of a 24-year old Caucasian woman presented with a 10-months history of progressive darkening of the right side of her upper back. Cutaneous examination revealed a macular blue-grey hyperpigmentation of the right side of her upper back. Biopsy specimen from the macule showed multiple darkly pigmented, spindle-shaped dendritic melanocytes in the superficial dermis, interstitially arranged between collagen bundles. The diagnosis of nevus of Ito was established. Our patient is maintaining vigilance in dermatology consultation. PMID- 23729679 TI - Parathyroid hormone (PTH)/PTH-related peptide type 1 receptor (PPR) signaling in osteocytes regulates anabolic and catabolic skeletal responses to PTH. AB - Parathyroid hormone (PTH) is the only Food and Drug Administration-approved anabolic agent to treat osteoporosis; however, the cellular targets of PTH action in bone remain controversial. PTH modulates bone turnover by binding to the PTH/PTH-related peptide (PTHrP) type 1 receptor (PPR), a G-protein-coupled receptor highly expressed in bone and kidneys. Osteocytes, the most abundant cells in adult bone, also express PPR. However, the physiological relevance of PPR signaling in osteocytes remains to be elucidated. Toward this goal, we generated mice with PPR deletion in osteocytes (Ocy-PPRKO). Skeletal analysis of these mice revealed a significant increase in bone mineral density and trabecular and cortical bone parameters. Osteoblast activities were reduced in these animals, as demonstrated by decreased collagen type I alpha1 mRNA and receptor activator of NF-kappaB ligand (RANKL) expression. Importantly, when subjected to an anabolic or catabolic PTH regimen, Ocy-PPRKO animals demonstrated blunted skeletal responses. PTH failed to suppress SOST/Sclerostin or induce RANKL expression in Ocy-PPRKO animals compared with controls. In vitro, osteoclastogenesis was significantly impaired in Ocy-PPRKO upon PTH administration, indicating that osteocytes control osteoclast formation through a PPR-mediated mechanism. Taken together, these data indicate that PPR signaling in osteocytes is required for bone remodeling, and receptor signaling in osteocytes is needed for anabolic and catabolic skeletal responses. PMID- 23729681 TI - How long should we treat this infection for? AB - Infection accounts for approximately half of all paediatric admissions to hospital and an even greater proportion of primary care. Guidelines on duration of antibiotic therapy exist, but antibiotic therapy for children needs to be individualised. If a child is not improving the clinical condition and treatment should be reviewed and/or discussed with an expert. However, slavishly completing the recommended course of antibiotics in a child who is well, may not be appropriate. Recent studies on treatment duration advocate shortened courses with certain caveats, but guidelines and clinical practice do not always follow the evidence from the few randomised trials of treatment duration of infection. PMID- 23729682 TI - Liver aminotransferases and risk of incident type 2 diabetes: a systematic review and meta-analysis. AB - We evaluated the associations of liver aminotransferases with risk of type 2 diabetes (T2D) in general populations by conducting a systematic review and meta analysis of published prospective studies. Studies were identified in a literature search of PubMed, EMBASE, and Web of Science from 1950 through October 2012. Of the 2,729 studies reviewed, 17 studies involving 60,359 participants and 3,890 incident T2D events were included. All of the studies assessed associations between alanine aminotransferase (ALT) level and T2D, with heterogeneous findings (I(2) = 88%, 95% confidence interval (CI): 82, 92; P < 0.001). The pooled fully adjusted relative risk of T2D was 1.26 (95% CI: 1.14, 1.41) per 1-standard deviation change in log baseline ALT level. This association became nonsignificant after trim-and-fill correction for publication bias. Nine studies evaluated associations between aspartate aminotransferase (AST) levels and T2D risk, with a corresponding relative risk of 1.02 (95% CI: 0.99, 1.04). The relative risk of T2D per 5-IU/L increase in ALT level was 1.16 (95% CI: 1.08, 1.25). Available data indicate moderate associations of ALT with risk of T2D events, which may be attributable to publication bias. There was no evidence for an increased risk of T2D with AST. Large prospective studies may still be needed to establish the magnitude and nature of these associations. PMID- 23729680 TI - STAT5 and prolactin participate in a positive autocrine feedback loop that promotes angiogenesis. AB - We have shown previously that the murine prolactin/growth hormone family member proliferin plays a pivotal role in angiogenesis induced by the FGF2/STAT5 signaling cascade. To delineate the signaling pathway downstream of STAT5 in the human system, where proliferin does not exist, we expressed constitutively active (CA) or dominant-negative (DN) mutant STAT5A in hCMEC/D3 human brain endothelial cells. We found that conditioned medium from CA-STAT5A- but not from DN-STAT5A overexpressing endothelial cells (EC) is sufficient to induce EC migration and tube formation but not proliferation, indicating that STAT5A regulates the secretion of autocrine proangiogenic factors. We identified prolactin (PRL) as a candidate autocrine factor. CA-STAT5A expression stimulates PRL production at the RNA and protein level, and STAT5A binds to the PRL promoter region, suggesting direct transcriptional regulation. Medium conditioned by CA-STAT5A-overexpressing EC induces phosphorylation of the PRL receptor and activates MAPK. Knockdown of PRL expression by shRNA or blocking of PRL activity with neutralizing antibodies removed the CA-STAT5A-dependent proangiogenic activity from the conditioned medium of EC. The addition of recombinant PRL restores this activity. STAT5A induced PRL in the conditioned medium can activate STAT5, STAT1, and to a lesser extent STAT3 in hCMEC/D3 cells, suggesting the existence of a positive feedback loop between STAT5 and PRL that promotes angiogenesis. Furthermore, we find that VEGF, a potent proangiogenic factor, is induced by activation of STAT5A, and VEGF induction depends on PRL expression. These observations demonstrate a STAT5/PRL/VEGF signaling cascade in human brain EC and implicate PRL and VEGF as autocrine regulators of EC migration, invasion, and tube formation. PMID- 23729683 TI - Coarse particles and respiratory emergency department visits in California. AB - Although respiratory disease has been strongly connected to fine particulate air pollution (particulate matter <2.5 MUm in diameter (PM2.5)), evidence has been mixed regarding the effects of coarse particles (particulate matter from 2.5 to 10 MUm in diameter), possibly because of the greater spatial heterogeneity of coarse particles. In this study, we evaluated the relationship between coarse particles and respiratory emergency department visits, including common subdiagnoses, from 2005 to 2008 in 35 California counties. A time-stratified case crossover design was used to help control for time-invariant confounders and seasonal influences, and the study population was limited to those residing within 20 km of pollution monitors to mitigate the influence of spatial heterogeneity. Significant associations between respiratory emergency department visits and coarse particle levels were observed. Asthma visits showed associations (for 2-day lag, excess risk per 10 MUg/m3 = 3.3%, 95% confidence interval: 2.0, 4.6) that were robust to adjustment by other common air pollutants (particles <2.5 MUm in diameter, ozone, nitrogen dioxide, carbon monoxide, and sulfur dioxide). Pneumonia and acute respiratory infection visits were not associated, although some suggestion of a relationship with chronic obstructive pulmonary disease visits was present. Our results indicate that coarse particle exposure may trigger asthma exacerbations requiring emergency care, and reducing exposures among asthmatic persons may provide benefits. PMID- 23729684 TI - Smoking status, snus use, and variation at the CHRNA5-CHRNA3-CHRNB4 locus in relation to obesity: the GLACIER study. AB - A genetic variant within the CHRNA5-CHRNA3-CHRNB4 region (rs1051730), previously associated with smoking quantity, was recently shown to interact with smoking on obesity predisposition. We attempted to replicate this finding in the Gene Lifestyle Interactions and Complex Traits Involved in Elevated Disease Risk (GLACIER) Study, a prospective cohort study of adults from northern Sweden (n = 16,426). We also investigated whether a similar interaction is apparent between rs1051730 and snus, a type of moist oral tobacco, to determine whether this interaction is driven by factors that cigarettes and snus have in common, such as nicotine. Main effects of smoking, snus, and the rs1051730 variant and pairwise interaction terms (smoking * rs1051730 and snus * rs1051730) were tested in relation to body mass index (BMI; calculated as weight (kg)/height (m)2) through the use of multivariate linear models adjusted for age and sex. Smoking status and BMI were inversely related (beta = -0.46 kg/m2, standard error (SE) = 0.08; P < 0.0001). Snus use and BMI were positively related (beta = 0.35 kg/m2, SE = 0.12; P = 0.003). The rs1051730 variant was not significantly associated with smoking status or snus use (P > 0.05); the T allele was associated with lower BMI in the overall cohort (beta = -0.10 kg/m2, SE = 0.05; P = 0.03) and with smoking quantity in those in whom this was measured (n = 5,304) (beta = 0.08, SE = 0.01; P < 0.0001). Neither smoking status (Pinteraction = 0.29) nor snus use (Pinteraction = 0.89) modified the association between the rs1051730 variant and BMI. PMID- 23729685 TI - Genotype misclassification in genetic association studies of the rs1042522 TP53 (Arg72Pro) polymorphism: a systematic review of studies of breast, lung, colorectal, ovarian, and endometrial cancer. AB - Preferential loss of heterozygosity at the rs1042522 locus of the tumor protein 53 gene (TP53) (Arg72Pro) is observed in several tumors. Genetic association studies in oncology often use tumor tissue rather than unaffected tissue for genotyping; in such cases, loss of heterozygosity at the TP53 locus could lead to differential misclassification and could bias estimates of association. We searched multiple databases (through March 8, 2011) for studies investigating the association of Arg72Pro with breast, lung, colorectal, ovarian, or endometrial cancer. Meta-analysis was performed with multilevel Bayesian models. Informative priors for the bias effect were derived from a meta-analysis of the same polymorphism in cervical cancer. Of 160 studies (68 breast, 42 lung, 26 colorectal, 16 ovarian, and 8 endometrial cancer), 22 used tumor tissue as the source of genotyping material for cases. Use of tumor tissue versus other sources of genotyping material was associated with an apparent protective effect of the proline allele (relative odds ratio = 0.78, 95% credible interval: 0.70, 0.88). The probability that use of tumor tissue induced bias was estimated to be higher than 99%. Use of tumor tissue as the source of genotyping material for cases is associated with significant bias in the estimate of the genetic effect in cancer genetic association studies. PMID- 23729686 TI - Influence of sex on the outcome of autologous chondrocyte implantation in chondral defects of the knee. AB - BACKGROUND: Sex-specific outcomes have been reported in anterior cruciate ligament reconstruction as well as in osteoarthrosis progression, but there are currently no related published data on autologous chondrocyte implantation (ACI). The present prospective study was performed to investigate sex-dependent differences in the results after ACI. HYPOTHESIS: The clinical and magnetic resonance imaging (MRI) results after ACI of the knee are influenced by the patient's sex. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: The midterm clinical and MRI results of a cell-based fibrin-polymer graft for the treatment of full-thickness cartilage defects were evaluated preoperatively and 6, 12, and 48 months after surgery in 52 patients (male:female ratio, 25:27; average age, 35.6 years). Depending on the sex and the location of the defects (femoral condyles, n = 32; patellofemoral compartment, n = 20), patients were assigned to 4 different groups. Baseline clinical scores were compared with follow-up data by paired Wilcoxon tests for the Lysholm score and the International Knee Documentation Committee (IKDC) scoring system. Sex-specific differences were evaluated with the Mann-Whitney U test. The MRI evaluation was performed with the Henderson score at final follow-up. RESULTS: Clinical scores improved in all groups over the whole study period (P < .05). Compared with female patients, male patients achieved significantly better results in the Lysholm score at all time intervals and in the IKDC score at 6 and 12 months after surgery (P < .05). In a subgroup analysis, female patients with patellar defects had the worst results in both clinical scores. With the available number of patients, MRI evaluation at 48 months after surgery revealed no significant difference in defect fill between male and female patients (P > .05). The Pearson correlation coefficient between both clinical scores and the MRI parameters of defect fill and cartilage signal was significant (P < .05). CONCLUSION: Autologous chondrocyte implantation is a promising treatment option for full thickness cartilage defects of male and female knee joints. Female patients with patellar defects have worse prognostic factors. PMID- 23729687 TI - Comparison of bone tunnel and suture anchor techniques in the modified Brostrom procedure for chronic lateral ankle instability. AB - BACKGROUND: The modified Brostrom procedure is frequently used to treat chronic lateral ankle instability. There are 2 common methods of the modified Brostrom procedure, which are the bone tunnel and suture anchor techniques. PURPOSE: To compare the clinical outcomes of the modified Brostrom procedure using the bone tunnel and suture anchor techniques. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Eighty-one patients (81 ankles) treated with the modified Brostrom procedure for chronic lateral ankle instability constituted the study cohort. The 81 ankles were divided into 2 groups, namely, a bone tunnel technique (BT group; 40 ankles) and a suture anchor technique (SA group; 41 ankles). The Karlsson score, American Orthopaedic Foot and Ankle Society (AOFAS) ankle hindfoot score, anterior talar translation, and talar tilt angle were used to evaluate clinical and radiographic outcomes. The BT group consisted of 32 men and 8 women with a mean age of 34.8 years at surgery and a mean follow-up duration of 34.2 months. The SA group consisted of 33 men and 8 women with a mean age of 33.3 years at surgery and a mean follow-up duration of 32.8 months. RESULTS: Mean Karlsson scores improved significantly from 57.0 points preoperatively to 94.9 points at final follow-up in the BT group and from 59.9 points preoperatively to 96.4 points at final follow-up in the SA group. Mean AOFAS scores also improved from 64.2 points preoperatively to 97.8 points at final follow-up in the BT group and from 70.3 points preoperatively to 97.4 points at final follow-up in the SA group. Mean anterior talar translations in the BT group and SA group improved from 9.0 mm and 9.2 mm preoperatively to 6.5 mm and 6.8 mm at final follow-up, respectively. Mean talar tilt angles were 12.0 degrees in the BT group and 12.5 degrees in the SA group preoperatively and 8.8 degrees at final follow-up for both groups. No significant differences were found between the 2 groups in terms of the Karlsson score, AOFAS score, anterior talar translation, and talar tilt angle. CONCLUSION: The bone tunnel and suture anchor techniques of the modified Brostrom procedure showed similar good functional and radiographic outcomes. Both techniques appear to be effective and reliable methods for the treatment of chronic lateral ankle instability. PMID- 23729688 TI - ST elevation myocardial infarction treated with bioresorbable vascular scaffold: rationale and first cases. PMID- 23729689 TI - Is myocardial revascularization safe in trainees' hands? PMID- 23729690 TI - Angiopoietin-like 4 and ischaemic stroke: a promising start. PMID- 23729691 TI - Risk stratification for implantable cardioverter defibrillator therapy: the role of the wearable cardioverter-defibrillator. AB - The benefit of implantable cardioverter-defibrillator (ICD) therapy depends upon appropriate evaluation of a persisting risk of sudden death and estimation of the patient's overall survival. Assessment of a stable and unchangeable arrhythmogenic substrate is often difficult. Structural abnormality and ventricular dysfunction, the two major risk parameters, may recover, and heart failure symptoms can improve so that ICD therapy may not be indicated. Risk stratification can take time while the patient continues to be at high risk of arrhythmic death, and patients may need temporary bridging by a defibrillator in cases of interrupted ICD therapy. The wearable cardioverter-defibrillator (WCD) combines a long-term electrocardiogram (ECG)-monitoring system with an external automatic defibrillator. The LIfeVest(r) (ZOLL, Pittsburgh, PA, USA) is composed of a garment, containing two defibrillation patch electrodes on the back, and an elastic belt with a front-defibrillation patch electrode and four non-adhesive ECG electrodes, connected to a monitoring and defibrillation unit. The WCD is a safe and effective tool to terminate ventricular tachycardia/ventricular fibrillation events, unless a conscious patient withholds shock delivery. It may be used in patients in the early phase after acute myocardial infarction with poor left ventricular function, after acute coronary revascularization procedures (percutaneous coronary intervention or coronary artery bypass grafting) and reduced left ventricular ejection fraction (<=35%), in patients with acute heart failure in non-ischaemic cardiomyopathy of uncertain aetiology and prognosis. The WCD may be helpful in subjects with syncope of assumed tachyarrhythmia origin or in patients with inherited arrhythmia syndromes. The WCD may replace ICD implantation in patients waiting for heart transplantation or who need a ventricular-assist device. This review describes the technical details and characteristics of the WCD, discusses its various potential applications, and reports the currently available experience with the wearable defibrillator. PMID- 23729693 TI - Multifocal pulmonary outflow tract primary sarcoma presenting as syncope. PMID- 23729692 TI - Secondary prevention by stroke subtype: a nationwide follow-up study in 46 108 patients after acute ischaemic stroke. AB - AIMS: Although use of antithrombotic agents is recommended after ischaemic stroke or transient ischaemic attack (TIA), long-term outcome of secondary prevention between stroke subtypes has not yet been explored. METHODS AND RESULTS: We used data from the Korean Stroke Registry (KSR), a nationwide, multicentre, prospective registry for acute stroke patients. Patients with acute ischaemic stroke or TIA within 7 days of onset were consecutively enrolled between January 2002 and September 2010. A total of 46 108 patients with ischaemic stroke and TIA were included in this study. Among the major stroke subtypes, stroke due to small vessel occlusion (SVO) showed the lowest mortality, whereas cardioembolic stroke (CE) was associated with the fatal prognosis during the follow-up [for SVO: hazard ratio (HR) 0.66, 95% CI 0.62-0.71; for CE: HR 1.41, 95% CI 1.30-1.53; large artery atherosclerosis (LAA) group as a reference]. Regarding secondary prevention, antiplatelet polytherapy was better than monotherapy in the patients with LAA-related stroke in prognosis [HR 0.89, 95% CI 0.80-0.98]. Anticoagulant therapy was associated with better outcome than antiplatelet monotherapy in CE related stroke [HR 0.66, 95% CI 0.59-0.74]. In SVO-related stroke group, antiplatelet polytherapy failed to show benefits over monotherapy. Additionally, the risk of death was higher with anticoagulant therapy in the patients with SVO related stroke [HR 1.44, CI 95% 1.06-1.97]. CONCLUSIONS: Our study demonstrated that stroke subtype affects prognosis and also determines the effectiveness of secondary prevention. PMID- 23729694 TI - Dogs don't bark at parked cars. PMID- 23729695 TI - Exome sequencing identifies a significant variant in methionyl-tRNA synthetase (MARS) in a family with late-onset CMT2. AB - Charcot-Marie-Tooth (CMT) disease is a genetically heterogeneous condition with >50 genes now being identified. Thanks to new technological developments, namely, exome sequencing, the ability to identify additional rare genes in CMT has been drastically improved. Here we present data suggesting that MARS is a very rare novel cause of late-onset CMT2. This is supported by strong functional and evolutionary evidence, yet the absence of additional unrelated cases warrant future studies to substantiate this conclusion. PMID- 23729696 TI - Longitudinal assessment of cerebral beta-amyloid deposition in mice overexpressing Swedish mutant beta-amyloid precursor protein using 18F florbetaben PET. AB - The progression of beta-amyloid deposition in the brains of mice overexpressing Swedish mutant beta-amyloid precursor protein (APP-Swe), a model of Alzheimer disease (AD), was investigated in a longitudinal PET study using the novel beta amyloid tracer (18)F-florbetaben. METHODS: Groups of APP-Swe and age-matched wild type (WT) mice (age range, 10-20 mo) were investigated. Dynamic emission recordings were acquired with a small-animal PET scanner during 90 min after the administration of (18)F-florbetaben (9 MBq, intravenously). After spatial normalization of individual PET recordings to common coordinates for mouse brain, binding potentials (BPND) and standardized uptake value ratios (SUVRs) were calculated relative to the cerebellum. Voxelwise analyses were performed using statistical parametric mapping (SPM). Histochemical analyses and ex vivo autoradiography were ultimately performed in a subset of animals as a gold standard assessment of beta-amyloid plaque load. RESULTS: SUVRs calculated from static recordings during the interval of 30-60 min after tracer injection correlated highly with estimates of BPND based on the entire dynamic emission recordings. (18)F-florbetaben binding did not significantly differ in APP-Swe mice and WT animals at 10 and 13 mo of age. At 16 mo of age, the APP-Swe mice had a significant 7.9% increase (P < 0.01) in cortical (18)F-florbetaben uptake above baseline and at 20 mo there was a 16.6% increase (P < 0.001), whereas WT mice did not show any temporal changes in tracer uptake during the interval of follow-up. Voxelwise SPM analyses revealed the first signs of increased cortical binding at 13 mo and confirmed progressive binding increases in both the frontal and the temporal cortices (P < 0.001 uncorrected) to 20 mo. The SUVR strongly correlated with percentage plaque load (R = 0.95, P < 0.001). CONCLUSION: In the first longitudinal PET study in an AD mouse model using the novel beta-amyloid tracer (18)F-florbetaben, the temporal and spatial progression of amyloidogenesis in the brain of APP-Swe mice were sensitively monitored. This method should afford the means for preclinical testing of novel therapeutic approaches to the treatment of AD. PMID- 23729697 TI - Validation of several SUV-based parameters derived from 18F-FDG PET for prediction of survival after SIRT of hepatic metastases from colorectal cancer. AB - (90)Y radioembolization (selective internal radiation therapy [SIRT]) is a valuable therapeutic option for unresectable hepatic metastases arising from primary colorectal cancer. The present study evaluated the prognostic value of (18)F-FDG PET/CT metabolic parameters for predicting survival after SIRT. METHODS: Eighty patients with hepatic metastases of colorectal cancer were treated with SIRT. (18)F-FDG PET/CT was performed at baseline and 3 mo after the treatment. Metabolic volume, total lesion glycolysis, and maximum and peak standardized uptake value (SUV(max) and SUV(peak), respectively) according to PET Response Criteria in Solid Tumors (PERCIST 1.0) were obtained from 3 liver lesions in each patient, and the corresponding percentage changes from baseline to follow-up were calculated. Tumor response was defined as more than a 30% decrease in these parameters. Furthermore, response was evaluated in accordance with Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Toxicity events and survival were recorded. RESULTS: Overall median survival after SIRT was 60 wk. Responders who had a change in metabolic volume or total lesion glycolysis had significantly longer survival (92 vs. 49 wk [P = 0.006] and 91 vs. 48 wk [P = 0.025], respectively). However, neither RECIST 1.1 criteria nor changes in SUV(peak) or SUV(max) after treatment predicted outcome (P = 0.086 for RECIST; P = 0.310 for change in SUV(peak); P = 0.155 for change in SUV(max)). CONCLUSION: Changes in metabolic volume and total lesion glycolytic rate as measured by (18)F FDG PET predicted survival in patients with hepatic metastases from colorectal cancer, whereas changes in SUV(peak) or SUV(max) and RECIST 1.1 criteria did not predict survival. PMID- 23729698 TI - ESC opens Brussels Bureau: the European Heart Agency. PMID- 23729699 TI - Hypovitaminosis D and severe hypocalcaemia: the rebirth of an old disease. AB - Vitamin D deficiency, once thought to be eradicated, is becoming a frequent occurence in children, caused mainly by dietary insufficiency. The classical manifestation is rickets, but in infants severe hypocalcaemia may present as stridor, tetany, seizures or, rarely, heart disease. Here, we describe four infants who presented with complications of severe hypocalcaemia secondary to nutritional vitamin D deficiency. (1) Female, 4 months old, several spasms. (2) Male, 8 days old, generalised tonic-clonic seizure. (3) Male, 9 months old, tetany. (4) Male, 4 months old, cardiogenic shock. The cases highlight the importance of child vitamin D supplementation from birth and throughout childhood. We also note that the vitamin D state should be evaluated by the 25(OH)-D value and not the 1,25(OH)2-D. PMID- 23729700 TI - Megacystis microcolon intestinal hypoperistalsis syndrome. AB - Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a multisystemic disorder in which impaired intestinal motor activity causes recurrent symptoms of intestinal obstruction in the absence of mechanical occlusion, associated with bladder distention without distal obstruction of the urinary tract. MMIHS and prune belly syndrome may overlap in most of the clinical features and discrimination of these two entities is important because the prognosis, management and consulting with parents are completely different. MMIHS outcome is very poor and in this article we present two neonates with MMIHS that both died in a few days. PMID- 23729701 TI - Systemic lupus erythematosus, pregnancy and carcinoma of the tongue. AB - We present a case which describes a 29-year-old woman with systemic lupus erythematosus who was treated aggressively with cytotoxic immunosuppression. Five years later and approximately 12 weeks pregnant, she is confirmed as having carcinoma of the tongue. Not wishing to consider termination of her pregnancy, she underwent surgical resection, which included partial glossectomy with microvascular reconstruction. Good oral function (speech and swallowing) was restored within 2 weeks. The pregnancy proceeded relatively uneventfully to 37 weeks gestation when proteinuric hypertension necessitated induction of labour. She remains well with no evidence of recurrence. This case highlights the options available in the treatment of carcinoma of the tongue during pregnancy together with the ethical considerations required, balanced against optimising maternal outcomes. PMID- 23729702 TI - Small bowel obstruction secondary to a liberated Meckel's enterolith. AB - A 30-year-old woman presented with a short history of abdominal pain which rapidly progressed to absolute constipation. An abdominal radiograph demonstrated a paucity of bowel gas and a 4 cm lesion with concentric laminar calcification projected over the pelvis. A CT scan revealed a 4 cm giant Meckel's diverticulum, downstream of which a laminated mass was impacted in the lumen of the distal ileum causing small bowel obstruction. Subsequent surgery confirmed small bowel obstruction secondary to impaction of a liberated enterolith from the giant Meckel's diverticulum. The history, imaging appearances and surgical findings in this case are classical of this unusual but treatable condition. PMID- 23729703 TI - Malignant fibrous histiocytoma. AB - Malignant fibrous histiocytoma (MFH) is a type of histiocytoma and is the most common soft tissue sarcoma of late adult life. However, it is relatively uncommon in the head and neck area. It usually occurs/develops in the lower extremities and in the retroperitonium. This tumour is difficult to distinguish histologically from other sarcomas and carcinomas. Surgery is the only treatment option. Prognosis is fairly poor; recurrence and local metastasis are common. In comparison with MFH of the extremities and the trunk, the 5-year survival rate for cases of this tumour in the head and neck is low. It is important to consider MFH in differential diagnosis of head and neck tumours because of its poor prognosis. We report a rare case of MFH in an 11-year-old girl. PMID- 23729704 TI - Renal calculi in pregnancy? The role of ultralow-dose CT. AB - Presented is a case of an acute, right flank, loin to groin pain in the third trimester of an otherwise uncomplicated pregnancy. Renal calculi was suspected clinically and supported by radiological evidence. Temporising treatment was undertaken successfully by retrograde ureteric stenting, which became blocked, secondarily resulting in a percutaneous nephrostomy. Good symptomatic control was achieved before the delivery at 38 weeks and 1 day gestation. Postpartum intravenous urogram and ureteroscopy did not reveal evidence of calculi. The patient does not recall passing a stone. With existing diagnostic modalities having poor sensitivity and specificity, the clinical role of ultralow-dose CT is explored, in light of recent new evidence. PMID- 23729705 TI - Vertebra collapse due to primary amyloidosis causing neurological compromise. AB - In primary amyloidosis (AL), a fibrillar protein (amyloid light chain) is deposited in many organs; however, it is rare to have involvement of the vertebral bodies. Multiple myeloma is a well-known systemic amyloid disease that frequently has vertebral involvement. However, the pathology of vertebral involvement of these two clinical entities differs significantly. We report a patient with L4 vertebral collapse because of primary AL, causing neurological compromise that improved with surgical treatment. Deposition of amyloid and following demineralisation caused the vertebral collapse. Primary AL needs to be taken into consideration as a cause of pathological vertebral fracture. PMID- 23729706 TI - Laryngeal leiomyosarcoma masquerading as laryngeal carcinoma. AB - Laryngeal leiomyosarcoma is an exceedingly rare malignant tumour, with fewer than 50 reported cases in scientific literature. Diagnosis is based on immunohistochemistry, supplemented with ultrastructural studies, if required. It is aggressive and associated with variable survival outcomes. A 63-year-old man presented with hoarseness for 7 months and breathlessness for 3 months. Imaging showed a well-defined 3 cm glottic mass. Total laryngectomy was performed. The histopathological examination showed features of leiomyosarcoma. The index case has been presented owing to its rarity, variable clinical manifestations and diagnostic dilemmas and to stress upon the importance of ancillary techniques for confirmation. PMID- 23729707 TI - Nitrofurantoin related pulmonary disease: a clinical reminder. AB - A 57-year-old woman presented to the admissions unit with a 2-month history of malaise, chest tightness and non-productive cough. An outpatient chest radiograph arranged by her general practitioner was reported as showing 'changes in keeping with a severe chest infection' and she had been started on oral antibiotics but her clinical condition subsequently deteriorated. On admission she was febrile (39.2 degrees C) and her oxygen saturation was 99% on 60% oxygen via facemask (rapidly desaturating when supplementary oxygen was removed). Auscultation revealed fine mid-late inspiratory crackles over both lung bases. It transpired that 4 months prior to the onset of symptoms she had been started on nitrofurantoin for prophylaxis against urinary tract infections. The nitrofurantoin was stopped and she was started on prednisolone. Her fever and oxygen saturation gradually improved and she was discharged home after 11 days in the hospital. Her improvement was sustained on outpatient review 8 months later. PMID- 23729708 TI - Analysis using histograms of muscle CT images in patients with Duchenne muscular dystrophy. AB - We showed that the shape of the thigh CT value histogram, which was reflecting muscle and fat, changed with the disease progression in a patient with Duchenne muscular dystrophy, and this shape of the histogram will employ a new analytical method. CT images of the middle part of the thigh were acquired in a patient with Duchenne muscular dystrophy once a year from 6 to 11 years of age. Regions apparently corresponding to subcutaneous fat, bone and bone marrow were manually excluded, and the CT values were calculated to prepare histograms. His motor disability was also evaluated employing Vignos functional rating scale. A single peak was noted in the muscle CT value range in the histogram at the youngest age. The muscle-to-fat ratio in muscle decreased with the worsening of his disease disability level and the peak of the histogram shifted from the muscle to the fat CT value. PMID- 23729709 TI - A late recurrence of renal cell carcinoma as pancreatic metastases: a rare disease. AB - A man presented with multifocal pancreatic metastases 9 years after nephrectomy for renal cell carcinoma. He was managed with oral sunitinib. He had favourable response to treatment with excellent compliance. PMID- 23729710 TI - Peripapillary and macular retinoschisis in a patient with pseudoexfoliation glaucoma. AB - A 55-year-old man was admitted with a 2-year history of pseudoexfoliation glaucoma. The best-corrected visual acuities were 10/10 in both eyes. Pseudoexfoliation material was noted on the iris and the lens capsule. Fundus examination evidenced cup-to-disc ratio of 0.7 OD and 0.9 OS with peripapillary atrophy. Gonioscopy revealed open angles. Optical coherence tomography demonstrated peripapillary retinoschisis extending to the nasal macula in the left eye and optic nerve head was almost fully excavated. Coexisting retinoschisis in a patient with glaucoma may interfere with the reliability of retinal nerve fibre layer and ganglion cell complex analysis and may change the treatment plan and follow-up intervals. PMID- 23729711 TI - Fracture of temporary femoral haemodialysis catheter: our experience. AB - We report two similar cases of fracture and proximal migration of temporary femoral haemodialysis catheters. The two cases were encountered 6 years apart. These types of occurrences, especially in centres where catheter reuse is practiced, are not uncommon but seldom reported in the literature. Alert dialysis staff on both the occasions took remedial steps in time, which prevented embolisation of the catheters into the inferior vena cava. Both the catheters were removed successfully by the surgical team. PMID- 23729712 TI - Idiopathic bilateral adrenal haemorrhage related to acute adrenal insufficiency. AB - A 54-year-old woman presented with sudden epigastralgia and left back pain. She had no significant history. Laboratory data showed mild inflammation and no liver or renal dysfunction. Abdominal CT showed left adrenal enlargement and haemorrhage. Hydrocortisone therapy was started to prevent adrenal insufficiency before laboratory findings for ACTH (adrenocorticotropic hormone) and cortisol levels. On the second hospital day, abdominal CT showed additional right adrenal enlargement and haemorrhage. The serum cortisol level suggested adrenal insufficiency. No specific findings were detected by bilateral adrenal angiography. 6 to 12 months later, abdominal CT showed decreased bilateral adrenal haemorrhage. This case illustrates the importance of prompt diagnosis and treatment of acute adrenal insufficiency, and shows sequential changes in the size of bilateral adrenal haemorrhage. Rapid corticosteroid replacement is important if acute adrenal insufficiency is suspected. In a case with unilateral adrenal haemorrhage, the possibility of additional adrenal haemorrhage on the opposite side should also be considered. PMID- 23729713 TI - Recognising compartment syndrome in the upper limbs of a patient with central cord syndrome: getting out of pitfalls. AB - This is a case where limb threatening compartment syndrome of the hand was masked by co-existing central cord syndrome following trauma. PMID- 23729715 TI - Viral and paraneoplastic encephalitis in a patient with liver transplant with unilateral temporoparietal lobe abnormalities: a diagnostic challenge. AB - We report a patient who recently had a liver transplant presented with increasing confusion and intermittent hallucinations. MRI of the brain revealed diffuse left temporal and parietal lobe swelling with cortical diffusion restriction suggestive of possible infectious aetiology, although stroke was also possible given the presence of left posterior cerebral arteries with fetal origin in the anterior circulation. An EEG demonstrated subclinical seizures, for which he was placed on an antiepileptic medication. Routine laboratory testing, lumbar puncture, serum and cerebrospinal fluid testing for viral and paraneoplastic encephalitis, and brain biopsy were performed on our patient. Our clinical diagnosis was viral encephalitis, and positive N-type voltage-gated calcium channel antibody titres were suggestive of paraneoplastic limbic encephalitis. Treatment with antiviral and antiepileptic medications for subclinical seizures resulted in the improvement of his mental status, language output and motor functioning. PMID- 23729714 TI - Guillain-Barre syndrome as a paraneoplastic manifestation of disseminated squamous cell carcinoma. AB - We describe a 65-year-old woman who developed ascending, symmetrical paraesthesia and weakness. This was on a background of metastatic disseminated squamous cell carcinoma, with a likely recurrent mandibular primary. Serum testing for antiganglioside antibodies was strongly positive. Despite a 5-day course of intravenous immunoglobulin, the patient passed away on day 34 of admission. This is the first case, to our knowledge, of Guillain-Barre syndrome in association with squamous cell carcimoma. PMID- 23729716 TI - Stable graft function on low-dose steroid monotherapy in spite of donor-specific antibodies in renal transplantation combined with stem cell infusion. AB - Transplantation using immunosuppression/induction therapies has controlled acute rejections; however, there is no answer for chronic graft attrition. Donor specific antibodies (DSA) are believed to cause antibody mediated rejections eventually causing chronic graft loss. Regulatory T cells (T-regs) are believed to protect the graft from immune injury. We report a 53-year-old woman transplanted with her son's kidney using donor-specific transfusion and stem cells (SC) under non-myeloablative conditioning of cyclophosphamide, anti-T and anti-B-cell antibodies and Bortezomib. The patient was on low-dose steroid monotherapy under immune monitoring of DSA and serum creatine. Graft biopsy at 1 and 3.5 years post-transplant was unremarkable in spite of the presence of DSA. Peripheral T-regs (pTregs) at 3.5 years post-transplant were 3.54%. This case shows that DSA are not necessarily detrimental to the renal allograft. We further hypothesise that pTregs were induced from SC and sustained to protect this graft from cytotoxic T cells and DSA. PMID- 23729717 TI - A case of putty kidney without pulmonary tuberculosis. AB - A 30-year-old woman presented with a 1-year history of a dull ache in her left flank along with recent onset of hypertension. There was no history suggestive of tuberculosis and examination was unremarkable. X-ray showed dense opacity in left renal area. Contrast-enhanced CT revealed a non-enhancing and non-excretory left kidney suggesting autonephrectomy. When a 6 week course of antituberculous therapy (ATT) failed to alleviate her symptoms, surgical nephroureterectomy was performed which resulted in complete resolution of symptoms and well-controlled blood pressure without any medication. PMID- 23729718 TI - Tuberous sclerosis presenting with spontaneous pneumothorax secondary to lymphangioleiomyomatosis; previously mistaken for asthma. AB - A middle-aged female patient, previously diagnosed with asthma, presented with a large spontaneous left pneumothorax. She had a history of nephrectomy for a ruptured renal angiomyolipoma (AML) with a postoperative spontaneous pneumothorax when she was an adolescent. High-resolution CT chest revealed multiple scattered thin-walled lung parenchyma cysts consistent with lymphangioleiomyomatosis (LAM). Hepatic AMLs and adenoma sebaceum skin lesions were also noted, consistent with an overall diagnosis of tuberous sclerosis. Her acute management included lung re expansion via chest tube insertion, antibiotics for concurrent chest infection, nebulisation and chest physiotherapy. Since discharge, the patient had only occasional shortness of breath, relieved by bronchodilators. She is considering expanded immunisation as well as enrolment in a clinical trial. Her hepatic AMLs will be monitored via ultrasound for growth. LAM treatment is generally aimed at its complications with lung transplantation reserved for severe disease; however, hormonal therapy and the mTOR inhibitor aim at targeting systemic disease. PMID- 23729719 TI - Neonatal heel-prick testing leading to dystrophic calcification. PMID- 23729720 TI - Occlusion of M1 segment after superficial temporal artery-middle cerebral artery bypass in a giant M1 aneurysm with Onyx-34 injected via a double-lumen balloon under balloon inflation. AB - A 29-year-old patient attended our institution for recurrent strokes related to a giant partially thrombosed M1 aneurysm. Superficial temporal artery-middle cerebral artery (STA-MCA) bypass and subsequent occlusion of both the aneurysm and the dysplastic M1 segment were planned. However, owing to the shortness of the non-dysplastic segment of M1 and the risk of occlusion of the lenticulostriate arteries, the use of a double-lumen balloon was considered for coiling and subsequent injection of Onyx. STA-MCA bypass was performed using a regular technique. Endovascular occlusion of both the aneurysm and the parent artery was subsequently performed by means of coils and Onyx-34 that was injected via the Ascent balloon under balloon inflation. No complications were recorded and no stroke was observed on control MRI. The injection of Onyx-34 through a double-lumen balloon under balloon inflation is a quick and safe technique for precise occlusion of a parent artery. PMID- 23729721 TI - Quality of life in higher resolution: the next generation of comparative effectiveness research in malignant hematology. PMID- 23729722 TI - Trithorax and polycomb cooperation in MLL fusion acute leukemia. PMID- 23729723 TI - Patients' needs in hematology: whose perspectives? PMID- 23729724 TI - Age and aging in blood disorders: EHA theme of the year 2013-2014. PMID- 23729725 TI - Non-transfusion-dependent thalassemias. AB - Non-transfusion-dependent thalassemias include a variety of phenotypes that, unlike patients with beta (beta)-thalassemia major, do not require regular transfusion therapy for survival. The most commonly investigated forms are beta thalassemia intermedia, hemoglobin E/beta-thalassemia, and alpha-thalassemia intermedia (hemoglobin H disease). However, transfusion-independence in such patients is not without side effects. Ineffective erythropoiesis and peripheral hemolysis, the hallmarks of disease process, lead to a variety of subsequent pathophysiologies including iron overload and hypercoagulability that ultimately lead to a number of serious clinical morbidities. Thus, prompt and accurate diagnosis of non-transfusion-dependent thalassemia is essential to ensure early intervention. Although several management options are currently available, the need to develop more novel therapeutics is justified by recent advances in our understanding of the mechanisms of disease. Such efforts require wide international collaboration, especially since non-transfusion-dependent thalassemias are no longer bound to low- and middle-income countries but have spread to large multiethnic cities in Europe and the Americas due to continued migration. PMID- 23729727 TI - A detailed evaluation of the current renal response criteria in AL amyloidosis: is it time for a revision? AB - Organ response correlates with overall survival in patients with immunoglobulin light chain amyloidosis and is the goal of treatment. This study evaluates the current renal response criteria and their ability to predict overall survival. Patients with immunoglobulin light chain amyloidosis who underwent autologous stem cell transplantation between 1995 and 2010 were recruited. Eligibility criteria included >1 g/dL of proteinuria, dialysis independence at baseline and within the first year of autologous stem cell transplantation, and a minimum follow-up of 1 year. Responses were assessed by the best values after autologous stem cell transplantation. The difference between involved and uninvolved serum free light chain levels was used to determine hematologic response. Increases in serum creatinine were calculated from the highest creatinine after autologous stem cell transplantation. Inclusion and exclusion criteria were met by 141 patients. These patients had a median follow-up of 52 months. Superior overall survival was observed in patients with a >75% reduction in proteinuria and those who had a >95% reduction had additional benefits. The overall survival of patients with >50% to <=75% proteinuria was similar to that of patients with <=50% reduction. A rise in serum creatinine >25% was not associated with a poorer outcome in patients with a >75% reduction in proteinuria. Deeper hematologic responses were associated with higher rates of proteinuria reduction. These results suggest that further evaluation of the current renal response criteria is needed. In particular, discrimination of the renal response into complete and partial categories and modification of the serum creatinine requirement seem justified. PMID- 23729726 TI - Iron refractory iron deficiency anemia. AB - Iron refractory iron deficiency anemia is a hereditary recessive anemia due to a defect in the TMPRSS6 gene encoding Matriptase-2. This protein is a transmembrane serine protease that plays an essential role in down-regulating hepcidin, the key regulator of iron homeostasis. Hallmarks of this disease are microcytic hypochromic anemia, low transferrin saturation and normal/high serum hepcidin values. The anemia appears in the post-natal period, although in some cases it is only diagnosed in adulthood. The disease is refractory to oral iron treatment but shows a slow response to intravenous iron injections and partial correction of the anemia. To date, 40 different Matriptase-2 mutations have been reported, affecting all the functional domains of the large ectodomain of the protein. In vitro experiments on transfected cells suggest that Matriptase-2 cleaves Hemojuvelin, a major regulator of hepcidin expression and that this function is altered in this genetic form of anemia. In contrast to the low/undetectable hepcidin levels observed in acquired iron deficiency, in patients with Matriptase 2 deficiency, serum hepcidin is inappropriately high for the low iron status and accounts for the absent/delayed response to oral iron treatment. A challenge for the clinicians and pediatricians is the recognition of the disorder among iron deficiency and other microcytic anemias commonly found in pediatric patients. The current treatment of iron refractory iron deficiency anemia is based on parenteral iron administration; in the future, manipulation of the hepcidin pathway with the aim of suppressing it might become an alternative therapeutic approach. PMID- 23729728 TI - Unusual low sickle cell hemoglobin level. PMID- 23729729 TI - Response to "Unusual low sickle cell hemoglobin level" Haematologica. 2012;98(6):e64. PMID- 23729730 TI - Phosphorylation of Crm1 by CDK1-cyclin-B promotes Ran-dependent mitotic spindle assembly. AB - Mitotic spindle assembly in animal cells is orchestrated by a chromosome dependent pathway that directs microtubule stabilization. RanGTP generated at chromosomes releases spindle assembly factors from inhibitory complexes with importins, the nuclear transport factors that facilitate protein import into the nucleus during interphase. In addition, the nuclear export factor Crm1 has been proposed to act as a mitotic effector of RanGTP through the localized assembly of protein complexes on the mitotic spindle, notably at centrosomes and kinetochores. It has been unclear, however, how the functions of nuclear transport factors are controlled during mitosis. Here, we report that human Crm1 is phosphorylated at serine 391 in mitosis by CDK1-cyclin-B (i.e. the CDK1 and cyclin B complex). Expression of Crm1 with serine 391 mutated to either non phosphorylated or phosphorylation-mimicking residues indicates that phosphorylation directs the localization of Crm1 to the mitotic spindle and facilitates spindle assembly, microtubule stabilization and chromosome alignment. We find that phosphorylation of Crm1 at serine 391 enhances its RanGTP-dependent interaction with RanGAP1-RanBP2 and promotes their recruitment to the mitotic spindle. These results show that phosphorylation of Crm1 controls its molecular interactions, localization and function during mitosis, uncovering a new mechanism for the control of mitotic spindle assembly by CDK1-cyclin-B. We propose that nuclear transport factors are controlled during mitosis through the selection of specific molecular interactions by protein phosphorylation. PMID- 23729731 TI - Membrane cholesterol modulates the hyaluronan-binding ability of CD44 in T lymphocytes and controls rolling under shear flow. AB - The adhesion of circulating lymphocytes to the surface of vascular endothelial cells is important for their recruitment from blood to secondary lymphoid organs and to inflammatory sites. CD44 is a key adhesion molecule for this interaction and its ligand-binding ability is tightly regulated. Here we show that the hyaluronan-binding ability of CD44 in T cells is upregulated by the depletion of membrane cholesterol with methyl-beta-cyclodextrin (MbetaCD), which disintegrates lipid rafts, i.e. cholesterol- and sphingolipid-enriched membrane microdomains. Increasing concentrations of MbetaCD led to a dose-dependent decrease in cellular cholesterol content and to upregulation of hyaluronan binding. Additionally, a cholesterol-binding agent filipin also increased hyaluronan binding. Cholesterol depletion caused CD44 to be dispersed from cholesterol-enriched membrane microdomains. Cholesterol depletion also increased the number of cells undergoing rolling adhesion under physiological flow conditions. Our results suggest that the ligand-binding ability of CD44 is governed by its cholesterol-dependent allocation to membrane microdomains at the cell surface. These findings provide novel insight into the regulation of T cell adhesion under blood flow. PMID- 23729732 TI - Late endosomal transport and tethering are coupled processes controlled by RILP and the cholesterol sensor ORP1L. AB - Late endosomes and lysosomes are dynamic organelles that constantly move and fuse to acquire cargo from early endosomes, phagosomes and autophagosome. Defects in lysosomal dynamics cause severe neurodegenerative and developmental diseases, such as Niemann-Pick type C disease and ARC syndrome, yet little is known about the regulation of late endosomal fusion in a mammalian system. Mammalian endosomes destined for fusion need to be transported over very long distances before they tether to initiate contact. Here, we describe that lysosomal tethering and transport are combined processes co-regulated by one multi-protein complex: RAB7-RILP-ORP1L. We show that RILP directly and concomitantly binds the tethering HOPS complex and the p150(Glued) subunit of the dynein motor. ORP1L then functions as a cholesterol-sensing switch controlling RILP-HOPS-p150(Glued) interactions. We show that RILP and ORP1L control Ebola virus infection, a process dependent on late endosomal fusion. By combining recruitment and regulation of both the dynein motor and HOPS complex into a single multiprotein complex, the RAB7-RILP-ORP1L complex efficiently couples and regulates the timing of microtubule minus-end transport and fusion, two major events in endosomal biology. PMID- 23729733 TI - Melanoma-associated mutations in protein phosphatase 6 cause chromosome instability and DNA damage owing to dysregulated Aurora-A. AB - Mutations in the PPP6C catalytic subunit of protein phosphatase 6 (PP6) are drivers for the development of melanoma. Here, we analyse a panel of melanoma associated mutations in PPP6C and find that these generally compromise assembly of the PP6 holoenzyme and catalytic activity towards a model substrate. Detailed analysis of one mutant, PPP6C-H114Y, in both primary melanoma and engineered cell lines reveals it is destabilized and undergoes increased proteasome-mediated turnover. Global analysis of phosphatase substrates by mass spectrometry identifies the oncogenic kinase Aurora-A as the major PP6 substrate that is dysregulated under these conditions. Accordingly, cells lacking PPP6C or carrying the PPP6C-H114Y allele have elevated Aurora-A kinase activity and display chromosome instability with associated Aurora-A-dependent micronucleation. Chromosomes mis-segregated to these micronuclei are preferentially stained by the DNA damage marker gamma-H2AX, suggesting that loss of PPP6C promotes both chromosome instability and DNA damage. These findings support the view that formation of micronuclei rather than chromosome instability alone explains how loss of PPP6C, and more generally mitotic spindle and centrosome defects, can act as drivers for genome instability in melanoma and other cancers. PMID- 23729734 TI - TEM4 is a junctional Rho GEF required for cell-cell adhesion, monolayer integrity and barrier function. AB - Signaling events mediated by Rho family GTPases orchestrate cytoskeletal dynamics and cell junction formation. The activation of Rho GTPases is tightly regulated by guanine-nucleotide-exchange factors (GEFs). In this study, we identified a novel Rho-specific GEF called TEM4 (tumor endothelial marker 4) that associates with multiple members of the cadherin-catenin complex and with several cytoskeleton-associated proteins. Depending on confluence, TEM4 localized to either actin stress fibers or areas of cell-cell contact. The junctional localization of TEM4 was independent of actin binding. Depletion of endogenous TEM4 by shRNAs impaired Madin-Darby canine kidney (MDCK) and human umbilical vein endothelial cell (HUVEC) cell junctions, disrupted MDCK acini formation in 3D culture and negatively affected endothelial barrier function. Taken together, our findings implicate TEM4 as a novel and crucial junctional Rho GEF that regulates cell junction integrity and epithelial and endothelial cell function. PMID- 23729735 TI - Abba is an essential TRIM/RBCC protein to maintain the integrity of sarcomeric cytoarchitecture. AB - Organized sarcomeric striations are an evolutionarily conserved hallmark of functional skeletal muscles. Here, we demonstrate that the Drosophila Abba protein, a member of the TRIM/RBCC superfamily, has a pivotal regulatory role in maintaining proper sarcomeric cytoarchitecture during development and muscle usage. abba mutant embryos initially form muscles, but F-actin and Myosin striations become progressively disrupted when the muscles undergo growth and endure increased contractile forces during larval development. Abnormal Myosin aggregates and myofiber atrophy are also notable in the abba mutants. The larval defects result in compromised muscle function, and hence important morphogenetic events do not occur properly during pupation, leading to lethality. Abba is localized at larval Z-discs, and genetic evidence indicates that abba interacts with alpha-actinin, kettin/D-titin and mlp84B, genes that encode important Z-disc proteins for stable myofibrillar organization and optimal muscle function. RNAi experiments and ultrastructural analysis reveal that Abba has an additional crucial role in sarcomere maintenance in adult muscles. Abba is required to ensure the integrity and function of Z-discs and M-lines. Rescue experiments further show that Abba function is dependent upon its B-box/coiled-coil domain, NHL repeats and RING finger domain. The importance of these presumed protein protein interactions and ubiquitin ligase-associated domains supports our hypothesis that Abba is needed for specific protein complex formation and stabilization at Z-discs and M-lines. PMID- 23729736 TI - microRNA regulation of skin pigmentation in fish. AB - MicroRNAs (miRNAs) are endogenous small non-coding RNAs that play crucial roles in numerous biological processes. However, the role of miRNAs in skin color determination in fish has not been completely determined. Here, we identified that 13 miRNAs are differentially expressed between red and white skin. The analysis of miRNA spatial and temporal expression patterns suggests that miR-429 is a potential regulator of skin pigmentation. miR-429 silencing results in an obvious change in skin pigmentation. Bioinformatics analysis and a luciferase reporter assay show that miR-429 directly regulates expression of Foxd3 by targeting its 3'-untranslated (3'-UTR) region. miR-429 silencing leads to a substantial increase in the expression of Foxd3 in vivo, thereby repressing the transcription of MITF and its downstream genes, such as TYR, TYRP1 or TYRP2. These findings would provide a novel insight into the determination of skin color in fish. PMID- 23729738 TI - In vivo interactions of TTDA mutant proteins within TFIIH. AB - Trichothiodystrophy group A (TTD-A) patients carry a mutation in the transcription factor II H (TFIIH) subunit TTDA. Using a novel in vivo tripartite split-GFP system, we show that TTDA interacts with the TFIIH subunit p52 and the p52-TTDA-GFP product is incorporated into TFIIH. p52-TTDA-GFP is able to bind DNA and is recruited to UV-damaged DNA. Furthermore, we show that two patient-mutated TTDA proteins can interact with p52, are able to bind to the DNA and can localize to damaged DNA. Our findings give new insights into the behavior of TTDA within the context of a living cell and thereby shed light on the complex phenotype of TTD-A patients. PMID- 23729737 TI - The Toxoplasma gondii centrosome is the platform for internal daughter budding as revealed by a Nek1 kinase mutant. AB - The pathology and severity of toxoplasmosis results from the rapid replication cycle of the apicomplexan parasite Toxoplasma gondii. The tachyzoites divide asexually through endodyogeny, wherein two daughter cells bud inside the mother cell. Before mitosis is completed, the daughter buds form around the duplicated centrosomes and subsequently elongate to serve as the scaffold for organellogenesis and organelle partitioning. The molecular control mechanism of this process is poorly understood. Here, we characterized a T. gondii NIMA related kinase (Nek) ortholog that was identified in a chemical mutagenesis screen. A temperature-sensitive mutant, V-A15, possesses a Cys316Arg mutation in TgNek1 (a novel mutant allele in Neks), which is responsible for growth defects at the restrictive temperature. Phenotypic analysis of V-A15 indicated that TgNek1 is essential for centrosome splitting, proper formation of daughter cells and faithful segregation of genetic material. In vitro kinase assays showed that the mutation abolishes the kinase activity of TgNek1. TgNek1 is recruited to the centrosome prior to its duplication and localizes on the duplicated centrosomes facing the spindle poles in a cell-cycle-dependent manner. Mutational analysis of the activation loop suggests that localization and activity are spatio-temporally regulated by differential phosphorylation. Collectively, our results identified a novel temperature-sensitive allele for a Nek kinase and highlight its essential function in centrosome splitting in Toxoplasma. Moreover, these results conclusively show for the first time that Toxoplasma bud assembly is facilitated by the centrosome because defective centrosome splitting results in single daughter cell budding. PMID- 23729740 TI - Nonsense-mediated mRNA decay of collagen -emerging complexity in RNA surveillance mechanisms. AB - Nonsense-mediated mRNA decay (NMD) is an evolutionarily conserved mRNA surveillance system that degrades mRNA transcripts that harbour a premature translation-termination codon (PTC), thus reducing the synthesis of truncated proteins that would otherwise have deleterious effects. Although extensive research has identified a conserved repertoire of NMD factors, these studies have been performed with a restricted set of genes and gene constructs with relatively few exons. As a consequence, NMD mechanisms are poorly understood for genes with large 3' terminal exons, and the applicability of the current models to large multi-exon genes is not clear. In this Commentary, we present an overview of the current understanding of NMD and discuss how analysis of nonsense mutations in the collagen gene family has provided new mechanistic insights into this process. Although NMD of the collagen genes with numerous small exons is consistent with the widely accepted exon-junction complex (EJC)-dependent model, the degradation of Col10a1 transcripts with nonsense mutations cannot be explained by any of the current NMD models. Col10a1 NMD might represent a fail-safe mechanism for genes that have large 3' terminal exons. Defining the mechanistic complexity of NMD is important to allow us to understand the pathophysiology of the numerous genetic disorders caused by PTC mutations. PMID- 23729739 TI - SA1 binds directly to DNA through its unique AT-hook to promote sister chromatid cohesion at telomeres. AB - Sister chromatid cohesion relies on cohesin, a complex comprising a tri-partite ring and a peripheral subunit Scc3, which is found as two related isoforms SA1 and SA2 in vertebrates. There is a division of labor between the vertebrate cohesin complexes; SA1-cohesin is required at telomeres and SA2-cohesin at centromeres. Depletion of SA1 has dramatic consequences for telomere function and genome integrity, but the mechanism by which SA1-cohesin mediates cohesion at telomeres is not well understood. Here we dissect the individual contribution of SA1 and the ring subunits to telomere cohesion and show that telomeres rely heavily on SA1 and to a lesser extent on the ring for cohesion. Using chromatin immunoprecipitation we show that SA1 is highly enriched at telomeres, is decreased at mitosis when cohesion is resolved, and is increased when cohesion persists. Overexpression of SA1 alone was sufficient to induce cohesion at telomeres, independent of the cohesin ring and dependent on its unique (not found in SA2) N-terminal domain, which we show binds to telomeric DNA through an AT hook motif. We suggest that a specialized cohesion mechanism may be required to accommodate the high level of DNA replication-associated repair at telomeres. PMID- 23729741 TI - Ca2+ signalling early in evolution--all but primitive. AB - Early in evolution, Ca(2+) emerged as the most important second messenger for regulating widely different cellular functions. In eukaryotic cells Ca(2+) signals originate from several sources, i.e. influx from the outside medium, release from internal stores or from both. In mammalian cells, Ca(2+)-release channels represented by inositol 1,4,5-trisphosphate receptors and ryanodine receptors (InsP3R and RyR, respectively) are the most important. In unicellular organisms and plants, these channels are characterised with much less precision. In the ciliated protozoan, Paramecium tetraurelia, 34 molecularly distinct Ca(2+) release channels that can be grouped in six subfamilies, based on criteria such as domain structure, pore, selectivity filter and activation mechanism have been identified. Some of these channels are genuine InsP3Rs and some are related to RyRs. Others show some--but not all--features that are characteristic for one or the other type of release channel. Localisation and gene silencing experiments revealed widely different--yet distinct--localisation, activation and functional engagement of the different Ca(2+)-release channels. Here, we shall discuss early evolutionary routes of Ca(2+)-release machinery in protozoa and demonstrate that detailed domain analyses and scrutinised functional analyses are instrumental for in-depth evolutionary mapping of Ca(2+)-release channels in unicellular organisms. PMID- 23729742 TI - Microtubule-based transport - basic mechanisms, traffic rules and role in neurological pathogenesis. AB - Microtubule-based transport is essential for neuronal function because of the large distances that must be traveled by various building blocks and cellular materials. Recent studies in various model systems have unraveled several regulatory mechanisms and traffic rules that control the specificity, directionality and delivery of neuronal cargos. Local microtubule cues, opposing motor activity and cargo-adaptors that regulate motor activity control microtubule-based transport in neurons. Impairment of intracellular transport is detrimental to neurons and has emerged as a common factor in several neurological disorders. Genetic approaches have revealed strong links between intracellular transport processes and the pathogenesis of neurological diseases in both the central and peripheral nervous system. This Commentary highlights recent advances in these areas and discusses the transport defects that are associated with the development of neurological diseases. PMID- 23729743 TI - Using fly genetics to dissect the cytoskeletal machinery of neurons during axonal growth and maintenance. AB - The extension of long slender axons is a key process of neuronal circuit formation, both during brain development and regeneration. For this, growth cones at the tips of axons are guided towards their correct target cells by signals. Growth cone behaviour downstream of these signals is implemented by their actin and microtubule cytoskeleton. In the first part of this Commentary, we discuss the fundamental roles of the cytoskeleton during axon growth. We present the various classes of actin- and microtubule-binding proteins that regulate the cytoskeleton, and highlight the important gaps in our understanding of how these proteins functionally integrate into the complex machinery that implements growth cone behaviour. Deciphering such machinery requires multidisciplinary approaches, including genetics and the use of simple model organisms. In the second part of this Commentary, we discuss how the application of combinatorial genetics in the versatile genetic model organism Drosophila melanogaster has started to contribute to the understanding of actin and microtubule regulation during axon growth. Using the example of dystonin-linked neuron degeneration, we explain how knowledge acquired by studying axonal growth in flies can also deliver new understanding in other aspects of neuron biology, such as axon maintenance in higher animals and humans. PMID- 23729745 TI - Complete avulsion of right coronary artery caused by acute type-A aortic dissection. PMID- 23729744 TI - Notch signaling at a glance. AB - Cell-cell interactions define a quintessential aspect of multicellular development. Metazoan morphogenesis depends on a handful of fundamental, conserved cellular interaction mechanisms, one of which is defined by the Notch signaling pathway. Signals transmitted through the Notch surface receptor have a unique developmental role: Notch signaling links the fate of one cell with that of a cellular neighbor through physical interactions between the Notch receptor and the membrane-bound ligands that are expressed in an apposing cell. The developmental outcome of Notch signals is strictly dependent on the cellular context and can influence differentiation, proliferation and apoptotic cell fates. The Notch pathway is conserved across species (Artavanis-Tsakonas et al., 1999; Bray, 2006; Kopan and Ilagan, 2009). In humans, Notch malfunction has been associated with a diverse range of diseases linked to changes in cell fate and cell proliferation including cancer (Louvi and Artavanis-Tsakonas, 2012). In this Cell Science at a Glance article and the accompanying poster we summarize the molecular biology of Notch signaling, its role in development and its relevance to disease. PMID- 23729746 TI - Pulmonary endarterectomy for chronic thrombo-embolic pulmonary hypertension: an institutional experience. AB - OBJECTIVE: Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thrombo-embolic pulmonary hypertension (CTEPH). The aim of this study was to review our initial experience since the implementation of our program. METHODS: Data were collected prospectively on all patients who underwent PEA between March 2011 and March 2012. RESULTS: Forty-nine patients (20 male, 29 female, mean age 47.7 years) underwent surgery. The preoperative New York Heart Association class distribution showed the majority to be in class III or IV (n = 40). Mortality rate was 14.2% (n = 7) and the morbidity rate was 26.5% (n = 13). After PEA, the durations of mechanical ventilation, intensive care stay and hospital stay before discharge were 49.7 +/- 46.1 h, 6.5 +/- 5.0 days and 12.9 +/ 7.5 days, respectively. The systolic and mean pulmonary artery pressure (PAP) fell significantly from 87.0 +/- 26.6 mmHg and 53.8 +/- 14.5 before, to 41.5 +/- 12.4 mmHg and 28.5 +/- 10.5 after surgery (P < 0.001 and P < 0.001, respectively). Pulmonary vascular resistance (PVR) also improved significantly from 808 +/- 352.0 to 308 +/- 91 dyn*s*cm(-5) (P < 0.001). Univariate analysis showed that preoperative systolic PAP, tricuspid annular plane systolic excursion, right atrial volume, right atrial pressure, forced expiratory volume in 1 s, forced vital capacity, preoperative PVR, postoperative PVR, the duration of circulatory arrest and postoperative use of extracorporeal membrane oxygenation were risk factors for mortality (P < 0.05). According to multivariate analyses, only prolonged mechanical ventilation was selected as predictive risk factor for morbidity (P = 0.005). After a median follow-up of 6.1 months, two patients died due to cerebrovascular disease and one patient needed targeted pulmonary hypertension therapy. The rest of the 39 patients showed marked improvements in their clinical status. CONCLUSIONS: Starting a pulmonary endarterectomy program with acceptable mortality and morbidity rates and satisfactory early-term outcomes increases awareness of the CTEPH and surgery. Preoperative factors can primarily predict postoperative outcome after PEA. Identifying the risk factors in order to achieve a good result is important for the success of a PEA program. Therefore all patients diagnosed with CTEPH should be referred for consideration of PEA in a specialized centre. PMID- 23729747 TI - Prognostic factors in pulmonary metastasectomy: spotlight on molecular and radiological markers. AB - Pulmonary metastasectomy is nowadays a common practice in thoracic surgery. Clinical prognostic markers for poor outcome after pulmonary metastasectomy have been proposed in the late 1970's of the last century. Despite new insights in molecular mechanisms and advances in imaging techniques, neither molecular markers nor radiological features of metastases are used as prognosticators in routine clinical practice. Biomarkers associated with aggressive tumour behaviour came into the focus of clinical research and are the basis of personalized medicine. In addition, non-invasive imaging modalities like positron emission tomography and high-resolution computed tomography can provide further information on tumour aggressiveness. Regardless of a myriad of studies assessing prognostic markers in primary tumours, little is known about these markers in metastatic lesions. Furthermore, it has been emphasized that tumour biology of the primary might not reflect the behaviour of the corresponding metastasis. Therefore, information on the biology of metastases is necessary to treat patients adequately. This work reviews potential prognostic biomarkers in patients with pulmonary metastases, grouped in soluble tumour markers, tumour suppressor genes/proto-oncogenes and proteins involved in cell adhesion, tumour growth, cell metabolism and tumour angiogenesis. PMID- 23729748 TI - Differences in the prognosis of resected lung adenocarcinoma according to the histological subtype: a retrospective analysis of Japanese lung cancer registry data. AB - OBJECTIVES: This study intended to assess the clinicopathological features of the histological subtypes of adenocarcinoma of the lung in a large registry population. METHODS: The Japanese Joint Committee of Lung Cancer Registry performed a nationwide retrospective registry study on the prognosis and clinicopathological profiles of 11 663 patients who underwent resection for primary lung neoplasm in 2004. The registry data of 7921 (62.5%) patients with adenocarcinoma were analysed regarding the prognosis and clinicopathological features according to the histological subtype of adenocarcinoma. The histological subtypes were defined according to the 1999 World Health Organization classification (third edition), where bronchioloalveolar carcinoma (BAC) is defined as adenocarcinoma with a pure bronchioloalveolar growth pattern without invasion. RESULTS: The distribution of the histological subtype was acinar in 471 patients (7.5%), papillary in 2004 (32.2%), BAC in 1385 (22.3%), solid adenocarcinoma with mucin in 103 (1.7%) and adenocarcinoma with mixed subtypes (AMS) in 2257 (36.3%). The 5-year overall survival rates according to histological subtype were 63.4% for acinar, 72.9% for papillary, 90.3% for BAC, 54.4% for solid adenocarcinoma with mucin and 73.7% for AMS. While the survival rate in patients with BAC was significantly better than those for the other histological subtypes, acinar and solid adenocarcinoma with mucin had significantly worse prognoses than the other histological subtypes. The histological subtype was an independent predictor of survival in a multivariate analysis (P < 0.001). Regarding BAC, the pathological stage included not only Stage IA/IB (n = 1275; 92.1%), but also Stage II-IV (n = 110; 7.9%). One hundred twenty-five patients (9.0%) with BAC had recurrence, including both local and distant recurrence. CONCLUSIONS: The histological subtype in adenocarcinoma significantly correlated with the prognosis. In BACs with recurrence or pathological stage II-IV, these tumours might have been classified as invasive adenocarcinoma rather than as BAC. The need for the rigorous pathological evaluation of adenocarcinomas that are considered to be a preinvasive or minimally invasive tumour should be addressed in the new lung adenocarcinoma classification to be proposed by the International Association for the Study of Lung Cancer, the American Thoracic Society and the European Respiratory Society. PMID- 23729749 TI - Two young women with soft tissue tumours of the heart. AB - Primary cardiac sarcomas often strike young, healthy patients and tend to have a dismal prognosis. Because of limited experience, the heterogeneous nature of cardiac sarcomas and different treatment results of patients with malignant primary tumours of the heart, the role of heart transplantation should be weighed on a case-by-case basis. PMID- 23729750 TI - Anaemia is a predictor of mortality in patients undergoing aortic valve surgery. PMID- 23729751 TI - Transplantation of lungs after ex vivo reconditioning in a patient on semi elective long-term veno-arterial extracorporeal life support. AB - We present the case of a 41-year old patient suffering from end-stage pulmonary hypertension secondary to veno-occlusive disease who underwent implantation of a veno-arterial extracorporeal membrane oxygenator as a bridge to lung transplantation (LTx) due to significant deterioration of myocardial pump and liver function. After 33 days on support, lungs with extended donor criteria were offered. Owing to the deteriorating clinical condition of the patient, the lungs were assessed using our ex vivo lung perfusion system. After reconditioning of the graft, a bilateral LTx was performed. PMID- 23729752 TI - Heterotopic heart transplant: is there an indication in the continuous flow ventricular assist device era? AB - OBJECTIVES: Heterotopic heart transplantation (HHTx) is a therapeutic option in heart failure patients with fixed elevated pulmonary hypertension. However, survival is poorer in HHTx recipients, and with improving results in continuous flow ventricular assist devices (VADs), many patients can be bridged to allow normalization of pulmonary artery pressures, making them orthotopic heart transplant (OHTx) candidates. Thus, the aim of this study was to analyse the survival of our HHTx cohort and compare them with our VAD bridge patients. METHODS: A retrospective review of 342 heart transplant patients (315 OHTx and 27 HHTx) performed at our institution over 15 years was compared with 124 bridge-to transplant VAD patients over the same time period, of whom 69 received an OHTx. Pulmonary artery pressures before and after VAD implant were analysed. Survival was analysed using both univariate and multivariate analyses. RESULTS: HHTx recipients were significantly older, and the donor allografts were older, smaller and had longer ischaemic times than the OHTx cohort. Comparison of the VAD types implanted (pulsatile vs continuous) showed significantly longer time supported on the continuous devices with significantly fewer deaths than the pulsatile devices. The continuous devices were successful in reducing pulmonary artery pressures pretransplant. The HHTx cohort had a significantly poorer survival than the OHTx cohort (P=0.002). Survival on a continuous device and then OHTx was significantly better than either HHTx or pulsatile device support. CONCLUSIONS: The main indication for HHTx, namely fixed elevated pulmonary hypertension in heart failure patients, can be safely and effectively treated by continuous flow bridge to transplant with superior survival. PMID- 23729753 TI - Editorial comment: The end of all our exploring ... PMID- 23729754 TI - Is type and screen only policy safe for patients undergoing elective lobectomy? AB - OBJECTIVE: The purpose of this study was to establish the safety and feasibility of a recently adopted policy to type and screen (TS) (group and save) only for selected patients who had low likelihood of transfusion requirement. METHODS: The TS only policy was applied to patients undergoing first-time elective lobectomy with Hb of >11 g/dl, aged <70 years, with no clotting abnormality and no history of neoadjuvant therapy. A retrospective analysis of prospectively collected data was made of 208 consecutive patients undergoing elective lobectomy from November 2009 to October 2010. The patients who were only type and screened (Group TS, n = 87) were compared with those who had preoperative cross matching (XM) (Group XM, n = 121). The perioperative characteristics, transfusion requirements and outcomes were compared between the two groups. RESULTS: Preoperative characteristics of the two groups were similar, except that the XM group were significantly older, with lower mean preoperative haemoglobin levels. Postoperative complications (9 vs 13%, P = 0.24) and hospital mortality (0 vs 0.8%, P = 0.5) were similar between TS and XM, respectively. On the day of operation, 16 patients (13%) required transfusion in the XM group. Six patients in the TS group were cross matched, of whom only 3 (3.4%) actually required transfusion. The mean postoperative Hb levels in XM were also significantly lower (12.96 vs 10.88 gm/dl). In the XM group, 260 units of blood were unnecessarily cross matched and had to be returned to the blood bank compared with zero units in the TS group. There was no delay caused by unavailability of blood at the time of clinical need. CONCLUSION: Our data suggest that it is safe and feasible to adopt a policy of type and screen only in selected patients undergoing elective lobectomy, who have low likelihood of transfusion requirement. PMID- 23729756 TI - A 39-year-old woman with silent endocarditis of a caged-ball mitral valve. PMID- 23729757 TI - The year 2012 in the European Heart Journal-Cardiovascular Imaging. Part II. AB - The part II of the best of the European Heart Journal - Cardiovascular Imaging in 2012 specifically focuses on studies of valvular heart diseases, heart failure, cardiomyopathies, and congenital heart diseases. PMID- 23729758 TI - Pediatric collaborative improvement networks: bridging quality gaps to improve health outcomes. PMID- 23729759 TI - Pediatric collaborative improvement networks: background and overview. AB - Multiple gaps exist in health care quality and outcomes for children, who receive <50% of recommended care. The American Board of Pediatrics has worked to develop an improvement network model for pediatric subspecialties as the optimal means to improve child health outcomes and to allow subspecialists to meet the performance in practice component of Maintenance of Certification requirements. By using successful subspecialty initiatives as exemplars, and features of the Institute for Healthcare Improvement's Breakthrough Series model, currently 9 of 14 pediatric subspecialties have implemented collaborative network improvement efforts. Key components include a common aim to improve care; national multicenter prospective collaborative improvement efforts; reducing unnecessary variation by identifying, adopting, and testing best practices; use of shared, valid, high-quality real-time data; infrastructure support to apply improvement science; and public sharing of outcomes. As a key distinguisher from time-limited collaboratives, ongoing pediatric collaborative improvement networks begin with a plan to persist until aims are achieved and improvement is sustained. Additional evidence from within and external to health care has accrued to support the model since its proposal in 2002, including the Institute of Medicine's vision for a Learning Healthcare System. Required network infrastructure systems and capabilities have been delineated and can be used to accelerate the spread of the model. Pediatric collaborative improvement networks can serve to close the quality gap, engage patients and caregivers in shared learning, and act as laboratories for accelerated translation of research into practice and new knowledge discovery, resulting in improved care and outcomes for children. PMID- 23729760 TI - Exemplar pediatric collaborative improvement networks: achieving results. AB - A number of pediatric collaborative improvement networks have demonstrated improved care and outcomes for children. Regionally, Cincinnati Children's Hospital Medical Center Physician Hospital Organization has sustained key asthma processes, substantially increased the percentage of their asthma population receiving "perfect care," and implemented an innovative pay-for-performance program with a large commercial payor based on asthma performance measures. The California Perinatal Quality Care Collaborative uses its outcomes database to improve care for infants in California NICUs. It has achieved reductions in central line-associated blood stream infections (CLABSI), increased breast-milk feeding rates at hospital discharge, and is now working to improve delivery room management. Solutions for Patient Safety (SPS) has achieved significant improvements in adverse drug events and surgical site infections across all 8 Ohio children's hospitals, with 7700 fewer children harmed and >$11.8 million in avoided costs. SPS is now expanding nationally, aiming to eliminate all events of serious harm at children's hospitals. National collaborative networks include ImproveCareNow, which aims to improve care and outcomes for children with inflammatory bowel disease. Reliable adherence to Model Care Guidelines has produced improved remission rates without using new medications and a significant increase in the proportion of Crohn disease patients not taking prednisone. Data driven collaboratives of the Children's Hospital Association Quality Transformation Network initially focused on CLABSI in PICUs. By September 2011, they had prevented an estimated 2964 CLABSI, saving 355 lives and $103,722,423. Subsequent improvement efforts include CLABSI reductions in additional settings and populations. PMID- 23729761 TI - Physician professionalism and accountability: the role of collaborative improvement networks. AB - The medical profession is facing an imperative to deliver more patient-centered care, improve quality, and reduce unnecessary costs and waste. With significant unexplained variation in resource use and outcomes, even physicians and health care organizations with "the best" reputations cannot assume they always deliver the best care possible. Going forward, physicians will need to demonstrate professionalism and accountability in a different way: to their peers, to society in general, and to individual patients. The new accountability includes quality and clinical outcomes but also resource utilization, appropriateness and patient centeredness of recommended care, and the responsibility to help improve systems of care. The pediatric collaborative improvement network model represents an important framework for helping transform health care. For individual physicians, participation in a multisite network offers the opportunity to demonstrate accountability by measuring and improving care as part of an approach that addresses the problems of small sample size, attribution, and unnecessary variation in care by pooling patients from individual practices and requiring standardization of care to participate. For patients and families, the model helps ensure that they are likely to receive the current best evidence-based recommendation. Finally, this model aligns with payers' goals of purchasing value based care, rewarding quality and improvement, and reducing unnecessary variation around current best evidenced-based, effective, and efficient care. In addition, within the profession, the American Board of Pediatrics recognizes participation in a multisite quality improvement network as one of the most rigorous and meaningful approaches for a diplomate to meet practice performance maintenance of certification requirements. PMID- 23729762 TI - Collaborative networks for both improvement and research. AB - Moving significant therapeutic discoveries beyond early biomedical translation or T1 science and into practice involves: (1) T2 science, identifying "the right treatment for the right patient in the right way at the right time" (eg, patient centered outcomes research) and tools to implement this knowledge (eg, guidelines, registries); and (2) T3 studies addressing how to achieve health care delivery change. Collaborative improvement networks can serve as large-scale, health system laboratories to engage clinicians, researchers, patients, and parents in testing approaches to translate research into practice. Improvement networks are of particular importance for pediatric T2 and T3 research, as evidence to establish safety and efficacy of therapeutic interventions in children is often lacking. Networks for improvement and research are also consistent with the Institute of Medicine's Learning Healthcare Systems model in which learning networks provide a system for improving care and outcomes and generate new knowledge in near real-time. Creation of total population registries in collaborative network sites provides large, representative study samples with high-quality data that can be used to generate evidence and to inform clinical decision-making. Networks use collaboration, data, and quality-improvement methods to standardize practice. Therefore, variation in outcomes due to unreliable and unnecessary care delivery is reduced, increasing statistical power, and allowing a consistent baseline from which to test new strategies. In addition, collaborative networks for improvement and research offer the opportunity to not only make improvements but also to study improvements to determine which interventions and combination of strategies work best in what settings. PMID- 23729763 TI - Roles for children's hospitals in pediatric collaborative improvement networks. AB - Children's hospitals represent a significant opportunity to reduce morbidity, mortality, and costs, particularly for children with complex chronic conditions (CCCs) who comprise a disproportionate and growing share of admissions, readmissions, and resource use. Most children with CCCs are in some way associated with a children's hospital, and the subspecialists who care for them are primarily concentrated in the ~ 200 children's hospitals in the United States. Children's hospitals and their associated subspecialty clinics are uniquely positioned to achieve significant outcomes and cost savings through coordinated quality-improvement efforts. However, even the largest children's hospital has relatively small volumes of patients with any given condition. Only by linking children's hospitals in networks can a sufficient "N" be achieved to build the evidence for what works for children. Large-scale pediatric collaborative network exemplars have demonstrated the ability to improve outcomes, reduce costs, and spread changes found to be effective. Substantial opportunities exist for networks to expand to additional conditions, improvement topics, and sites, but financial barriers exist. Although much of their participation has been funded as "pay to participate" efforts by the hospitals themselves, most financial benefits accrue to payers. As health care reform becomes a reality and financial pressures intensify, it will become increasingly difficult for children's hospitals to serve as the primary source of support for networks. Partnerships between children's hospitals and national payers to support collaborative networks are needed, and these partnerships have the potential to significantly improve pediatric care and outcomes, particularly for children with CCCs. PMID- 23729764 TI - Collaborative Chronic Care Networks (C3Ns) to transform chronic illness care. AB - Despite significant gains by pediatric collaborative improvement networks, the overall US system of chronic illness care does not work well. A new paradigm is needed: a Collaborative Chronic Care Network (C3N). A C3N is a network-based production system that harnesses the collective intelligence of patients, clinicians, and researchers and distributes the production of knowledge, information, and know-how over large groups of people, dramatically accelerating the discovery process. A C3N is a platform of "operating systems" on which interconnected processes and interventions are designed, tested, and implemented. The social operating system is facilitated by community building, engaging all stakeholders and their expertise, and providing multiple ways to participate. Standard progress measures and a robust information technology infrastructure enable the technical operating system to reduce unwanted variation and adopt advances more rapidly. A structured approach to innovation design provides a scientific operating system or "laboratory" for what works and how to make it work. Data support testing and research on multiple levels: comparative effectiveness research for populations, evaluating care delivery processes at the care center level, and N-of-1 trials and other methods to select the best treatment of individual patient circumstances. Methods to reduce transactional costs to participate include a Federated IRB Model in which centers rely on a protocol approved at 1 central institutional review board and a "commons framework" for organizational copyright and intellectual property concerns. A fully realized C3N represents a discontinuous leap to a self-developing learning health system capable of producing a qualitatively different approach to improving health. PMID- 23729765 TI - After Dr Google: peer-to-peer health care. AB - Although the majority of US adults has Internet access and gathers health information online, the Internet does not replace clinicians. People rate health professionals as their top source for technical questions such as diagnosis and treatment, but nonprofessionals (eg, friends and family) are rated higher for emotional support and quick remedies. For their most recent health issue, 21% of adults say they turned to others who have the same health condition; evidence of people's interest in connecting with and learning from each other. People living with chronic diseases (and their caregivers) are especially likely to say they look online for peer advice. They are pioneering new ways of pursuing health by banding together and sharing knowledge; so-called peer-to-peer health care. Practical tips from fellow patients and caregivers can have far-reaching implications for clinical outcomes. As a parent of a chronically ill child observed: "We all work collaboratively, but I notice that my doctor doesn't. After I've talked with my community online, I go back to him and ask, 'What do your colleagues say about this issue?' And it's clear it didn't occur to him to ask them." Clinicians might do well to look into online patient communities and consider recommending them as resources for their patients. Clinicians might look at patient networks as a model for their own collaborative learning process as well. Linking the expertise of patients, families, and clinicians holds promise for further improving care and outcomes. PMID- 23729766 TI - The path forward: collaborative networks and the future for children's health care. PMID- 23729767 TI - Motion-form interactions beyond the motion integration level: evidence for interactions between orientation and optic flow signals. AB - Motion and form encoding are closely coupled in the visual system. A number of physiological studies have shown that neurons in the striate and extrastriate cortex (e.g., V1 and MT) are selective for motion direction parallel to their preferred orientation, but some neurons also respond to motion orthogonal to their preferred spatial orientation. Recent psychophysical research (Mather, Pavan, Bellacosa, & Casco, 2012) has demonstrated that the strength of adaptation to two fields of transparently moving dots is modulated by simultaneously presented orientation signals, suggesting that the interaction occurs at the level of motion integrating receptive fields in the extrastriate cortex. In the present psychophysical study, we investigated whether motion-form interactions take place at a higher level of neural processing where optic flow components are extracted. In Experiment 1, we measured the duration of the motion aftereffect (MAE) generated by contracting or expanding dot fields in the presence of either radial (parallel) or concentric (orthogonal) counterphase pedestal gratings. To tap the stage at which optic flow is extracted, we measured the duration of the phantom MAE (Weisstein, Maguire, & Berbaum, 1977) in which we adapted and tested different parts of the visual field, with orientation signals presented either in the adapting (Experiment 2) or nonadapting (Experiments 3 and 4) sectors. Overall, the results showed that motion adaptation is suppressed most by orientation signals orthogonal to optic flow direction, suggesting that motion form interactions also take place at the global motion level where optic flow is extracted. PMID- 23729769 TI - A formula for the mean human optical modulation transfer function as a function of pupil size. AB - We have constructed an analytic formula for the mean radial modulation transfer function of the best-corrected human eye as a function of pupil diameter, based on previously collected wave front aberrations from 200 eyes (Thibos, Hong, Bradley, & Cheng, 2002). This formula will be useful in modeling the early stages of human vision. PMID- 23729768 TI - Dynamic brightness induction causes flicker adaptation, but only along the edges: evidence against the neural filling-in of brightness. AB - Is brightness represented in a point-for-point neural map that is filled in from the response of small, contrast-sensitive edge detector cells? We tested for the presence of this filled-in map by adapting to illusory flicker caused by a dynamic brightness-induction stimulus. Thereafter flicker sensitivity was reduced when our test region was the same size as the induced region, but not for smaller, inset regions. This suggests induced brightness is represented by either small edge-selective cells with no filling-in stage, or by contrast-sensitive spatial filters at many different scales, but not by a population of filled-in neurons arranged in a point-for-point map. PMID- 23729770 TI - Adaptation to interocular differences in blur. AB - Adaptation to a blurred image causes a physically focused image to appear too sharp, and shifts the point of subjective focus toward the adapting blur, consistent with a renormalization of perceived focus. We examined whether and how this adaptation normalizes to differences in blur between the two eyes, which can routinely arise from differences in refractive errors. Observers adapted to images filtered to simulate optical defocus or different axes of astigmatism, as well as to images that were isotropically blurred or sharpened by varying the slope of the amplitude spectrum. Adaptation to the different types of blur produced strong aftereffects that showed strong transfer across the eyes, as assessed both in a monocular adaptation task and in a contingent adaptation task in which the two eyes were simultaneously exposed to different blur levels. Selectivity for the adapting eye was thus generally weak. When one eye was exposed to a sharper image than the other, the aftereffects also tended to be dominated by the sharper image. Our results suggest that while short-term adaptation can rapidly recalibrate the perception of blur, it cannot do so independently for the two eyes, and that the binocular adaptation of blur is biased by the sharper of the two eyes' retinal images. PMID- 23729771 TI - A non-device-specific approach to display characterization based on linear, nonlinear, and hybrid search algorithms. AB - In almost all of the recent vision experiments, stimuli are controlled via computers and presented on display devices such as cathode ray tubes (CRTs). Display characterization is a necessary procedure for such computer-aided vision experiments. The standard display characterization called "gamma correction" and the following linear color transformation procedure are established for CRT displays and widely used in the current vision science field. However, the standard two-step procedure is based on the internal model of CRT display devices, and there is no guarantee as to whether the method is applicable to the other types of display devices such as liquid crystal display and digital light processing. We therefore tested the applicability of the standard method to these kinds of new devices and found that the standard method was not valid for these new devices. To overcome this problem, we provide several novel approaches for vision experiments to characterize display devices, based on linear, nonlinear, and hybrid search algorithms. These approaches never assume any internal models of display devices and will therefore be applicable to any display type. The evaluations and comparisons of chromaticity estimation accuracies based on these new methods with those of the standard procedure proved that our proposed methods largely improved the calibration efficiencies for non-CRT devices. Our proposed methods, together with the standard one, have been implemented in a MATLAB-based integrated graphical user interface software named Mcalibrator2. This software can enhance the accuracy of vision experiments and enable more efficient display characterization procedures. The software is now available publicly for free. PMID- 23729772 TI - When luminance increment thresholds depend on apparent lightness. AB - A fundamental question in visual perception research is whether the sensitivity to stimulus differences is limited by the sensory representation of the external stimulus, that is, the proximal stimulus, or by its perceptual representation, i.e., stimulus appearance. In the domain of lightness perception, the question translates into whether discrimination thresholds depend on the local luminance in the retinal image or on the apparent lightness of the corresponding image region. The majority of findings seem to indicate that sensitivity is limited by the sensory stimulus representation, which would imply different mechanisms for stimulus discrimination and appearance. We think this conclusion needs to be qualified. We report data suggesting that the relationship between discrimination and appearance judgments depends on how exactly they are being measured. We propose a theoretical account that provides a common mechanism for appearance and sensitivity. An interesting corollary of this model is that it also accounts for the perceptual phenomenon of assimilation. PMID- 23729774 TI - Anaphylaxis, urticaria, and angioedema. AB - OBJECTIVES: After completing this article, readers should be able to: 1. List the etiologic agents that commonly cause urticaria, angioedema, and anaphylaxis. 2. Recognize the signs and symptoms of anaphylaxis and be able to deliver rapid,effective treatment for anaphylaxis. 3. Distinguish between acute and chronic urticaria, and recognize the differences in their evaluation and treatment. 4. List the causes of papular urticaria. 5. Discuss the acute management of stinging insect anaphylaxis. PMID- 23729773 TI - Symmetry in context: salience of mirror symmetry in natural patterns. AB - Symmetry is a biologically relevant, mathematically involving, and aesthetically compelling visual phenomenon. Mirror symmetry detection is considered particularly rapid and efficient, based on experiments with random noise. Symmetry detection in natural settings, however, is often accomplished against structured backgrounds. To measure salience of symmetry in diverse contexts, we assembled mirror symmetric patterns from 101 natural textures. Temporal thresholds for detecting the symmetry axis ranged from 28 to 568 ms indicating a wide range of salience (1/Threshold). We built a model for estimating symmetry energy by connecting pairs of mirror-symmetric filters that simulated cortical receptive fields. The model easily identified the axis of symmetry for all patterns. However, symmetry-energy quantified at this axis correlated weakly with salience. To examine context effects on symmetry detection, we used the same model to estimate approximate symmetry resulting from the underlying texture throughout the image. Magnitudes of approximate symmetry at flanking and orthogonal axes showed strong negative correlations with salience, revealing context interference with symmetry detection. A regression model that included the context-based measures explained the salience results, and revealed why perceptual symmetry can differ from mathematical characterizations. Using natural patterns thus produces new insights into symmetry perception and its possible neural circuits. PMID- 23729775 TI - Pediatric pharmacokinetics. AB - OBJECTIVES: After reading this article, the reader should be able to 1. Realize that volume of distribution, elimination clearance, and elimination half-life are crucial parameters of pharmacokinetics that must be understood to determine clinical pharmacologic decisions.2. Know that drug disposition is a complicated process of absorption, distribution,metabolism, and excretion. 3. Understand that any abnormality in absorption, distribution, metabolism, and/or excretion can potentially affect the efficacy or toxicity of a drug. 4. Understand that the anatomical and physiologic changes during development must be considered in predicting age-dependent changes in drug disposition. PMID- 23729776 TI - Reducing sports heat illness risk. AB - OBJECTIVES: After reading this article, readers should 1. Appreciate that exertional heatstroke is the leading cause of preventable death in youth sports.2. Know the importance of progressive acclimatization to minimize the risk of exertional heat illness in youth sports.3. Be able to identify other contributing risk factors and effective ways to improve exercise-heat tolerance and reduce exertional heat illness risk in youth sports.4. Be prepared to educate others on their roles and responsibilities in improving safety and well-being of youth participating in outdoor sports in the heat. PMID- 23729777 TI - Index of suspicion. AB - Case 1: Facial and upper extremity weakness in a 16-year-old boy. Case 2: Hematochezia in a neonate. Case 3: bad body odor in a 13-year-old girl. PMID- 23729778 TI - Pediatrics in the community: Healthy Kids Zoo Adventure. PMID- 23729779 TI - Visual diagnosis: 13-year-old girl with pink papules. Allergic contact dermatitis with id reaction. PMID- 23729781 TI - Digestive physiology of the pig symposium: gut chemosensing: integrating nutrition, gut function, and metabolism in pigs. PMID- 23729780 TI - A common fungal associate of the spruce bark beetle metabolizes the stilbene defenses of Norway spruce. AB - Norway spruce (Picea abies) forests suffer periodic fatal attacks by the bark beetle Ips typographus and its fungal associate, Ceratocystis polonica. Norway spruce protects itself against fungal and bark beetle invasion by the production of terpenoid resins, but it is unclear whether resins or other defenses are effective against the fungus. We investigated stilbenes, a group of phenolic compounds found in Norway spruce bark with a diaryl-ethene skeleton with known antifungal properties. During C. polonica infection, stilbene biosynthesis was up regulated, as evidenced by elevated transcript levels of stilbene synthase genes. However, stilbene concentrations actually declined during infection, and this was due to fungal metabolism. C. polonica converted stilbenes to ring-opened, deglycosylated, and dimeric products. Chromatographic separation of C. polonica protein extracts confirmed that these metabolites arose from specific fungal enzyme activities. Comparison of C. polonica strains showed that rapid conversion of host phenolics is associated with higher virulence. C. polonica is so well adapted to its host's chemical defenses that it is even able to use host phenolic compounds as its sole carbon source. PMID- 23729782 TI - Digestive physiology of the pig symposium: intestinal bile acid sensing is linked to key endocrine and metabolic signaling pathways. AB - Bile acids have historically been considered to mainly function in cholesterol homeostasis and facilitate fat digestion in the gastrointestinal tract. Recent discoveries show that bile acids also function as signaling molecules that exert diverse endocrine and metabolic actions by activating G protein-coupled bile acid receptor 1 (GPBAR1/G-protein-coupled bile acid receptor 1 or TGR5), a membrane G protein-coupled receptor, and farnesoid X receptor (FXR), a member of the nuclear hormone receptor superfamily. These bile acid sensing receptors are expressed in intestinal epithelial cells, TGR5 in enteroendocrine cells and FXR in enterocytes, which line the mucosa of gut lumen. A dominant effect of intestinal FXR activation by bile acids is secretion of fibroblast growth factor (FGF) 19, a novel enterokine that functions as a central enterohepatic signal to maintain bile acid homeostasis in the liver. Activation of TGR5 on enteroendocrine cells stimulates secretion of glucagon-like peptides (GLP)-1 and -2, which function, respectively, as the major incretin hormone involved in glucose homeostasis and key trophic hormone in intestinal adaptation and growth in response to food ingestion. The biological actions induced by bile acid activation of intestinal FXR and TGR5 have important therapeutic implications for the pathogenesis and treatment of several metabolic diseases, such as cholestasis and diabetes. This review highlights these new developments in the biology of intestinal bile acid sensing and metabolic function and discusses the potential implications for the health and agricultural production of domestic swine. PMID- 23729784 TI - Unfinished epidemics. PMID- 23729783 TI - Prognostic value of the trichorhinophalangeal syndrome-1 (TRPS-1), a GATA family transcription factor, in early-stage breast cancer. AB - BACKGROUND: TRPS-1 is a new GATA transcription factor that is differentially expressed in breast cancer (BC) where it been found recently to regulate epithelial-to-mesenchymal transition (EMT). PATIENTS AND METHODS: We carried out a quantitative immunohistochemistry (qIHC) analysis of TRPS-1 expression in 341 primary-stage I-III BC samples in relation to patient clinical characteristics as well as its prognostic value, especially in an estrogen receptor-positive (ER+) subgroup. RESULTS: Higher TRPS-1 expression was significantly associated with a number of clinical and pathological characteristics as well as with improved overall survival (OS) and disease-free survival (DFS). Among stage I/II ER+ BC patients who received endocrine therapy alone, those with high TRPS-1 expression had significantly longer OS and DFS. There was also a strong association between TRPS-1 levels and the EMT marker E-cadherin in the ER+ invasive ductal carcinoma cases. Analysis of gene expression data on a panel of BC lines found that TRPS-1 expression was low or absent in BC lines having enriched mesenchymal features. CONCLUSIONS: Our data indicated that TRPS-1 is an independent prognostic marker in early-stage BC and a new EMT marker that can distinguish patients with ER+ BC who will respond longer to adjuvant endocrine therapy. PMID- 23729785 TI - Nursing the tropics: nurses as agents of imperial hygiene. AB - BACKGROUND: Mrs Francis Piggott proposed the Colonial Nursing Association in 1895 as a means of supplying Britain's colonies and dominions with trained professional nurses, who would support the health of white colonists abroad. Over 8400 nurses were placed between 1896 and the Association's end in 1966. Despite the burgeoning of scholarship on gender and empire over the last few decades, there is still more research to be done examining nurses as professional, working women, who present a fascinating variation on the figure of the woman traveler. METHODS: This essay focuses on 1896-1927, exploring how nurses were prepared for their labor abroad and how these skills were challenged and adapted within a foreign environment. We contextualize this discussion with examples from literary tales of exploration and adventure and discourses of empire. RESULTS/CONCLUSIONS: Though the sources of disease against which nurses fought changed during this period, we assert that the underlying role of the nurse continued the same: she was meant to use the tools of personal as well as public 'hygiene' to create both physical and cultural boundaries around her white patients and herself, setting colonists apart from their colonial setting. PMID- 23729786 TI - Beyond sanctions: a response to Sen et al. PMID- 23729787 TI - Syria: effects of conflict and sanctions on public health: response to Coutts correspondence. PMID- 23729788 TI - Increasing the utility of systematic reviews findings through strategic communication. PMID- 23729789 TI - NICE public health guidance update. PMID- 23729790 TI - CrossTalk proposal: there is added benefit to providing permissive hypercapnia in the treatment of ARDS. PMID- 23729791 TI - CrossTalk opposing view: there is not added benefit to providing permissive hypercapnia in the treatment of ARDS. PMID- 23729792 TI - Rebuttal from Gerard F. Curley, John G. Laffey and Brian P. Kavanagh. PMID- 23729793 TI - Rebuttal from Jeremy R. Beitler, Rolf D. Hubmayr and Atul Malhotra. PMID- 23729794 TI - 'Cold as ice', why do old coronary arteries pay the price? PMID- 23729795 TI - Sweating the details: what really drives eccrine output during exercise-heat stress. PMID- 23729796 TI - To resist or to endure: exercise mode matters in arterial structure and function. PMID- 23729797 TI - Unsupported assumption in model of salt-sensitive hypertension. PMID- 23729798 TI - Reply from V. A. Averina, H. G. Othmer, G. D. Fink and J. W. Osborn. PMID- 23729799 TI - Signal hyperintensities on brain magnetic resonance imaging in patients with primary Sjogren syndrome and frequent episodic tension-type headache: relation to platelet serotonin level and disease activity. AB - OBJECTIVE: To examine differences in number and size of signal hyperintensities (SH) on magnetic resonance imaging (MRI) between patients with primary Sjogren syndrome (pSS) and controls who all had frequent episodic tension-type headache (FETH), and to investigate their relation to platelet serotonin level (PSL), patient age, disease duration, and activity. METHODS: SH in 22 pSS patients with FETH were compared to 20 aged-matched controls with FETH, using the modified semiquantitative rating scale. Spectrofluorimetry was used for determination of PSL, and the European League Against Rheumatism SS Disease Activity Index (ESSDAI) for disease activity assessment. RESULTS: Statistically significant differences in the total number of SH were noted infratentorially (p = 0.025) and in the basal ganglia for lesions of diameter > 5 mm (p = 0.048). Significant correlations were found between disease duration and number of overall lesions > 5 mm (p = 0.04) and subcortical lesions of diameter 2-5 mm (p = 0.035). Number of periventricular SH inversely correlated to PSL (p = 0.019) and to patient age (p = 0.004), without association with markers of immunoinflammation and ESSDAI. CONCLUSION: Our study showed that SH on brain MRI are more common in specific regions of the brain in pSS patients with FETH than in controls with FETH, signifying a more widespread cerebral vasculopathy in SS patients with FETH. Periventricular SH seem to be associated to increased platelet serotonin release in pSS patients with FETH and correlated with disease duration, without correlation to the actual ESSDAI and markers of immunoinflammation, and might be linked with chronic immunoinflammation of low-grade intensity and vasculitis in pSS. PMID- 23729800 TI - Effect of genetic polymorphisms on development of gout. AB - OBJECTIVE: To validate the association between genetic polymorphisms and gout in Japanese patients, and to investigate the cumulative effects of multiple genetic factors on the development of gout. METHODS: Subjects were 153 Japanese male patients with gout and 532 male controls. The genotypes of 11 polymorphisms in the 10 genes that have been indicated to be associated with serum uric acid levels or gout were determined. The cumulative effects of the genetic polymorphisms were investigated using a weighted genotype risk score (wGRS) based on the number of risk alleles and the OR for gout. A model to discriminate between patients with gout and controls was constructed by incorporating the wGRS and clinical factors. C statistics method was applied to evaluate the capability of the model to discriminate gout patients from controls. RESULTS: Seven polymorphisms were shown to be associated with gout. The mean wGRS was significantly higher in patients with gout (15.2 +/- 2.01) compared to controls (13.4 +/- 2.10; p < 0.0001). The C statistic for the model using genetic information alone was 0.72, while the C statistic was 0.81 for the full model that incorporated all genetic and clinical factors. CONCLUSION: Accumulation of multiple genetic factors is associated with the development of gout. A prediction model for gout that incorporates genetic and clinical factors may be useful for identifying individuals who are at risk of gout. PMID- 23729801 TI - Subcutaneously administered ofatumumab in rheumatoid arthritis: a phase I/II study of safety, tolerability, pharmacokinetics, and pharmacodynamics. AB - OBJECTIVE: To investigate the safety and tolerability of a single subcutaneous (SC) dose of ofatumumab, a fully human anti-CD20 monoclonal antibody, in patients with rheumatoid arthritis (RA) taking background methotrexate (MTX). Secondary objectives included characterizing pharmacokinetics and pharmacodynamics. METHODS: In this single-blind, phase I/II study, 35 patients with RA were randomized in 5 cohorts to receive a single subcutaneous (SC) ofatumumab dose ranging from 0.3 to 100 mg, or placebo, following premedication with oral acetaminophen and antihistamine. Patients were followed for 24 weeks with extended followup to monitor B cell and immunoglobulin recovery for up to 2 years if required. RESULTS: Thirty-five patients received the following treatment: 0.3 mg, n = 4; 3 mg, n = 6; 30 mg, n = 8; 60 mg, n = 6; 100 mg, n = 3; placebo, n = 8. The most common adverse events in the combined ofatumumab groups were headache, nausea, and upper respiratory tract infection. Because of tolerability concerns, only 3 patients were given 100 mg. For the 30-100 mg doses, median maximum plasma concentration values ranged from 4.02 to 4.49 days. Mean elimination half-life values ranged from 5.20 to 6.83 days. Increasing peripheral median B cell depletion was observed from 0.3 mg up to 30 mg, and full target B cell depletion was achieved with 30 mg, 60 mg, and 100 mg. CONCLUSION: Treatment of RA patients with SC ofatumumab doses of 30 mg or higher resulted in profound and prolonged B cell depletion in blood. Single doses up to 60 mg were tolerated without glucocorticoid premedication. (ClinicalTrials.gov identifier NCT00686868). PMID- 23729802 TI - Serum pyridinoline levels and prediction of severity of joint destruction in rheumatoid arthritis. AB - OBJECTIVE: Previous studies indicated that pyridinoline, a collagen crosslink in cartilage and bone, might be a good marker to predict joint destruction in patients with rheumatoid arthritis (RA), although large prospective studies are lacking. We evaluated the predictive value of serum pyridinoline levels for joint destruction, both at baseline for longterm prediction and during the disease course for near-term prediction. METHODS: Patients with early RA from the Leiden Early Arthritis Clinic were studied. Radiographs at baseline and yearly during 7 years of followup were scored according to the Sharp-van der Heijde Scoring (SHS) method. Pyridinoline serum levels at baseline and during followup were measured by ELISA. The association between baseline pyridinoline levels and difference in SHS over 7 years was tested, with a multivariate normal regression model. Second, the association between pyridinoline levels determined during the disease course and progression of SHS over the next year was tested with a multivariable linear regression analysis. RESULTS: Studying baseline pyridinoline serum levels in 437 patients revealed that the mean SHS over 7 years was 6% higher for every higher pyridinoline level (nmol/l) at baseline (p = 0.001). Subsequently, during followup (n = 184 patients) the progression in SHS in the upcoming year was 17% higher for every higher nmol/l pyridinoline level (p = 0.001). The area under the receiver-operation characteristic curve for rapid radiological progression was 0.59. CONCLUSION: Increased pyridinoline serum levels, both at baseline and during the disease course, are associated with more severe joint destruction during the coming year(s), although the predictive accuracy as a sole predictor was moderate. PMID- 23729804 TI - Sustained clinical remission and rate of relapse after tocilizumab withdrawal in patients with rheumatoid arthritis. AB - OBJECTIVE: Data on when to stop use of biological agents in rheumatoid arthritis (RA) are scant. We assessed the length of remission and the rate of clinical relapse in patients with RA who had to discontinue treatment with tocilizumab (TCZ) because of the ending of longterm (5 yrs) open-label clinical trials. METHODS: All patients at 2 participating centers in Mexico were in remission, defined as Disease Activity Score 28 <= 2.6, with no swollen joints at the time of the last TCZ infusion. Patients were followed thereafter every 8 weeks for 12 months or until relapse. Relapse was defined as the presence of >= 1 swollen joint. Doses of methotrexate and antiinflammatory drugs were not changed during the followup period. RESULTS: Forty-five patients were analyzed, 87% were women (mean age 52 yrs, mean disease duration 14 yrs). During the 12 months of followup, 44% of patients maintained remission. Relapses occurred in 56% of patients: 14 during the first 3 months after the last TCZ administration. Retreatment using other agents achieved low disease activity or remission. CONCLUSION: Longterm clinical remission is possible in a number of patients with RA after suspension of TCZ. This effect has also been reported with other biologic agents. Additional data are required to support recommendations for discontinuing a biological agent after achieving remission. PMID- 23729803 TI - Should we redefine treatment targets in rheumatoid arthritis? Low disease activity is sufficiently strict for patients who are anticitrullinated protein antibody-negative. AB - OBJECTIVE: Clinical remission currently is the treatment target for all patients with rheumatoid arthritis (RA). At the same level of inflammation, the prognosis regarding joint damage is believed to be different for anticitrullinated protein antibody (ACPA)-negative and ACPA-positive patients. Our objective was to show the difference in prognosis at similar disease activity levels, and to illustrate how this could be translated to differentiation of treatment targets. METHODS: Data were used from the Nijmegen Early RA Cohort. The relation between the time averaged disease activity level (by Disease Activity Score; DAS) and joint damage progression over 3 years was analyzed, separately for ACPA-negative and ACPA positive patients. Joint damage was assessed as change in Ratingen score, and dichotomized as occurrence of erosions in joints that were unaffected at baseline. Linear and logistic multivariable regression models were used. RESULTS: The regression coefficient of DAS on change in Ratingen score was 3.9 (p < 0.001) for ACPA-negative and 4.7 (p < 0.001) for ACPA-positive patients, showing less joint damage progression at the same disease activity level in ACPA-negative patients. This difference became greater with increasing disease activity. The probability for erosions in joints unaffected at baseline was 0.35 in ACPA negative patients when time-averaged DAS was < 2.4 versus 0.80 in ACPA-positive patients. CONCLUSION: At the same level of inflammation, ACPA-negative patients have less joint damage and lower probability for damage in newly affected joints than ACPA-positive patients. Low disease activity might be a sufficiently strict treatment target for ACPA-negative patients to prevent progression of joint damage. PMID- 23729805 TI - Outcome of pregnancy in Italian patients with primary Sjogren syndrome. AB - OBJECTIVE: To investigate pregnancy and fetal outcomes in patients with primary Sjogren syndrome (pSS). METHODS: An obstetric history of 36 women with established diagnosis of pSS at pregnancy was obtained from a multicenter cohort of 1075 patients. In a subgroup case-control analysis, 12 deliveries in patients with pSS were compared with 96 control deliveries. RESULTS: Thirty-six women (31 with anti-SSA/Ro and/or anti-SSB/La antibodies) with an established diagnosis of pSS had 45 pregnancies with the delivery of 40 newborns. Two miscarriages, 2 fetal deaths, and 1 induced abortion were recorded. Mean age at the first pregnancy was 33.9 years; mean number of pregnancies was 1.25; 18/40 (45%) cesarean births were delivered; mean pregnancy length was 38.5 weeks (range 32 43), with 6 preterm deliveries. The mean Apgar score at 5 min was 8.9, mean birthweight was 2920 g (range 826-4060 g). Congenital heart block (CHB) occurred in 2/40 (5%) newborns. The reported rate of breastfeeding for at least 1 month was 60.5%. In 4/40 pregnancies (10%) a flare of disease activity was observed within a year from delivery. In the case-control subgroup analysis, 12 deliveries were compared with 96 controls and no significant differences were found. CONCLUSION: Patients with pSS can have successful pregnancies, which might be followed by a mild relapse. CHB was the only cause of death for offspring of mothers with pSS. PMID- 23729806 TI - Bilateral evaluation of the hand and wrist in untreated early inflammatory arthritis: a comparative study of ultrasonography and magnetic resonance imaging. AB - OBJECTIVE: To compare Doppler ultrasound (US) and 3.0-Tesla magnetic resonance imaging (3.0-T MRI) findings of synovial inflammation in the tendons and joints in an early polyarthritis cohort (patients who presented < 1 year after arthritis onset) using a bilateral hand and wrist evaluation. Also, to evaluate the diagnostic performance of US and MRI findings for rheumatoid arthritis (RA), their ability to predict RA as a diagnostic outcome, and their capacity to improve the accuracy of the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) RA classification criteria in early arthritis. METHODS: Forty-five patients (40 women, 5 men; mean age 45.6 yrs) with untreated recent-onset polyarthritis participated in this prospective study and were examined using an US and MRI approach including both wrists and hands. After a followup of 12 months, patients were classified as having RA if they fulfilled the criteria for RA. The proportion of synovitis identified by US and MRI for each joint and tendon region was compared by chi-square test. The diagnostic performance of US and MRI for RA identification was evaluated using receiver operating curve (ROC) analysis. Possible associations between synovitis for each joint and tendon region as identified by US or MRI and RA diagnosis at 12 months were tested by logistic regression analysis. The diagnostic performance of the ACR/EULAR RA classification criteria corrected by US and MRI joint and tendon counts was evaluated using ROC analysis. RESULTS: Thirty patients fulfilled the ACR/EULAR criteria [early RA (ERA) patients] and the remaining 15 failed to meet these criteria (non-RA). Carpal joint synovitis and tenosynovitis of the flexor tendons was found in 86.7% and 86.7% of patients with ERA on MRI compared with 63.3% and 50% on US, respectively (p < 0.05). The global MRI and US counts revealed a good diagnostic performance for RA diagnosis of both techniques, although MRI was statistically significantly better [area under the curve (AUC) = 0.959 and AUC = 0.853, respectively; z statistic = 2.210, p < 0.05]. MRI identification of carpal joint synovitis (OR 3.64, 95% CI 1.119-11.841), tenosynovitis of the flexor tendons (OR 5.09, 95% CI 1.620-16.051), and global joint and tendon count (OR 2.77, 95% CI 1.249-6.139) were in the multivariate logistic regression model the most powerful predictors of progression toward RA. In the group of ERA patients with US joint and tendon counts <= 10, a statistically significant difference was found between the diagnostic performance for RA of the ACR/EULAR criteria as previously described and the diagnostic performance of the MRI-corrected ACR/EULAR criteria (AUC = 0.898 and AUC = 0.986, respectively; z statistic = 2.181, p < 0.05). CONCLUSION: 3.0-T MRI identified a higher prevalence of synovitis in comparison to US in an early polyarthritis cohort. Both techniques have good diagnostic performance for RA although MRI reveals a significantly higher diagnostic capability. Synovitis of carpal joints and of flexor tendons as identified by MRI were the most powerful predictors of progression toward RA. In patients with US joint and tendon counts <= 10, MRI can significantly improve the diagnostic performance of the 2010 ACR/EULAR classification criteria. PMID- 23729807 TI - DcR3 mutations in patients with juvenile-onset systemic lupus erythematosus lead to enhanced lymphocyte proliferation. AB - OBJECTIVE: Previous studies suggested a role for the death decoy receptor 3 (DcR3) in the pathogenesis of adult systemic lupus erythematosus (SLE). We investigated the role of DcR3 in juvenile-onset SLE, to identify polymorphisms that might alter the function of this protein. METHODS: DcR3 was measured in the serum of 61 patients with juvenile SLE. The coding region of the DcR3 gene was sequenced in 100 juvenile and 103 adult patients with SLE, together with 500 healthy controls. RESULTS: DcR3 was elevated in the serum of juvenile patients with active SLE disease (440.8 +/- 169.1 pg/ml), compared to patients with inactive disease (122.6 +/- 28.05 pg/ml; p = 0.0014) and controls (69.27 +/- 20.23 pg/ml; p = 0.0009). DNA sequencing identified 2 novel missense mutations: c.C167T (p.T56I) in an adult SLE patient and c.C364T (p.H122Y) in a juvenile patient. Recombinant proteins containing these mutations exhibited altered binding kinetics to FasL and they significantly increased lymphocyte proliferation, compared to the wild-type protein (p < 0.05). The adult patient with SLE carrying the p.T56I mutation had significantly increased lymphocyte proliferation compared to 3 SLE controls matched for age, sex, and disease severity. CONCLUSION: DcR3 may play an etiologic role in SLE through either elevated serum levels of wild-type DcR3 or normal levels of gain-of-function DcR3 proteins that increase lymphocyte proliferation. PMID- 23729808 TI - Lumbar disc degeneration in osteoporotic men: prevalence and assessment of the relation with presence of vertebral fracture. AB - OBJECTIVE: The relationship between osteoarthritis (OA) and osteoporosis (OP) remains controversial. An inverse relationship between spine OA and the presence of prevalent vertebral fractures has been shown in osteoporotic women. Our objective was to assess this relationship in osteoporotic men. METHODS: All the patients had OP based on densitometric data and were aged >= 65 years. Spine radiographs were performed according to a standardized procedure. Vertebral fractures were assessed from T4 to L4 by a semiquantitative method. Disc degenerative changes were assessed by the presence and severity of osteophytes and disc narrowing at levels T12-L1 to L5-S1. Logistic regression was used to study the relationship between the presence of vertebral fracture and lumbar disc degeneration. RESULTS: The study included 261 osteoporotic men. The prevalence of vertebral fractures was 26.4% (69/261). At least 1 osteophyte was found in 91.6% (239/261) of patients, and at least 1 disc space narrowing in 63.5% (165/260). The prevalence of at least 1 osteophyte and/or at least 1 disc space narrowing was similar in patients with and those without vertebral fracture. No relationship was found between the presence and/or the severity of osteophytes and disc narrowings and the presence of prevalent vertebral radiographic fractures. CONCLUSION: In osteoporotic men, the prevalence of lumbar spine degeneration is high. There is no relationship between lumbar disc degeneration and the presence of vertebral fracture in osteoporotic men. PMID- 23729809 TI - Glutamate is an inhibitory neurotransmitter in the Drosophila olfactory system. AB - Glutamatergic neurons are abundant in the Drosophila central nervous system, but their physiological effects are largely unknown. In this study, we investigated the effects of glutamate in the Drosophila antennal lobe, the first relay in the olfactory system and a model circuit for understanding olfactory processing. In the antennal lobe, one-third of local neurons are glutamatergic. Using in vivo whole-cell patch clamp recordings, we found that many glutamatergic local neurons are broadly tuned to odors. Iontophoresed glutamate hyperpolarizes all major cell types in the antennal lobe, and this effect is blocked by picrotoxin or by transgenic RNAi-mediated knockdown of the GluClalpha gene, which encodes a glutamate-gated chloride channel. Moreover, antennal lobe neurons are inhibited by selective activation of glutamatergic local neurons using a nonnative genetically encoded cation channel. Finally, transgenic knockdown of GluClalpha in principal neurons disinhibits the odor responses of these neurons. Thus, glutamate acts as an inhibitory neurotransmitter in the antennal lobe, broadly similar to the role of GABA in this circuit. However, because glutamate release is concentrated between glomeruli, whereas GABA release is concentrated within glomeruli, these neurotransmitters may act on different spatial and temporal scales. Thus, the existence of two parallel inhibitory transmitter systems may increase the range and flexibility of synaptic inhibition. PMID- 23729810 TI - The cost of efficiency in energy metabolism. PMID- 23729811 TI - Simulating the pulling of stalled elongated peptide from the ribosome by the translocon. AB - The nature of the coupling between the stalling of the elongated nascent peptide chain in the ribosome and its insertion through the translocon is analyzed, focusing on the recently discovered biphasic force that overcomes the stalling barrier. The origin of this long-range coupling is explored by coarse-grained simulations that combine the translocon (TR) insertion profile and the effective chemical barrier for the extension of the nascent chain in the ribosome. Our simulation determined that the inserted H segment is unlikely to climb the TR barrier in parallel with the peptide synthesis chemical step and that the nascent chain should first overcome the chemical barriers and move into the ribosome-TR gap region before the insertion into the TR tunnel. Furthermore, the simulations indicate that the coupled TR-chemistry free energy profile accounts for the biphasic force. Apparently, although the overall elongation/insertion process can be depicted as a tug-of-war between the forces of the TR and the ribosome, it is actually a reflection of the combined free-energy landscape. Most importantly, the present study helps to relate the experimental observation of the biphasic force to crucial information about the elusive path and barriers of the TR insertion process. PMID- 23729812 TI - Multiple risk pathways for schizophrenia converge in serine racemase knockout mice, a mouse model of NMDA receptor hypofunction. AB - Schizophrenia is characterized by reduced hippocampal volume, decreased dendritic spine density, altered neuroplasticity signaling pathways, and cognitive deficits associated with impaired hippocampal function. We sought to determine whether this diverse pathology could be linked to NMDA receptor (NMDAR) hypofunction, and thus used the serine racemase-null mutant mouse (SR(-/-)), which has less than 10% of normal brain D-serine, an NMDAR coagonist. We found that D-serine was necessary for the maintenance of long-term potentiation in the adult hippocampal dentate gyrus and for full NMDAR activity on granule cells. SR(-/-) mice had reduced dendritic spines and hippocampal volume. These morphological changes were paralleled by diminished BDNF/Akt/mammalian target of rapamycin (mTOR) signaling and impaired performance on a trace-conditioning memory task. Chronic D-serine treatment normalized the electrophysiological, neurochemical, and cognitive deficits in SR(-/-) mice. These results demonstrate that NMDAR hypofunction can reproduce the numerous hippocampal deficits associated with schizophrenia, which can be reversed by chronic peripheral D-serine treatment. PMID- 23729814 TI - Direct electrolytic dissolution of silicate minerals for air CO2 mitigation and carbon-negative H2 production. AB - We experimentally demonstrate the direct coupling of silicate mineral dissolution with saline water electrolysis and H2 production to effect significant air CO2 absorption, chemical conversion, and storage in solution. In particular, we observed as much as a 10(5)-fold increase in OH(-) concentration (pH increase of up to 5.3 units) relative to experimental controls following the electrolysis of 0.25 M Na2SO4 solutions when the anode was encased in powdered silicate mineral, either wollastonite or an ultramafic mineral. After electrolysis, full equilibration of the alkalized solution with air led to a significant pH reduction and as much as a 45-fold increase in dissolved inorganic carbon concentration. This demonstrated significant spontaneous air CO2 capture, chemical conversion, and storage as a bicarbonate, predominantly as NaHCO3. The excess OH(-) initially formed in these experiments apparently resulted via neutralization of the anolyte acid, H2SO4, by reaction with the base mineral silicate at the anode, producing mineral sulfate and silica. This allowed the NaOH, normally generated at the cathode, to go unneutralized and to accumulate in the bulk electrolyte, ultimately reacting with atmospheric CO2 to form dissolved bicarbonate. Using nongrid or nonpeak renewable electricity, optimized systems at large scale might allow relatively high-capacity, energy-efficient (<300 kJ/mol of CO2 captured), and inexpensive (<$100 per tonne of CO2 mitigated) removal of excess air CO2 with production of carbon-negative H2. Furthermore, when added to the ocean, the produced hydroxide and/or (bi)carbonate could be useful in reducing sea-to-air CO2 emissions and in neutralizing or offsetting the effects of ongoing ocean acidification. PMID- 23729816 TI - Cortisol: ACTH ratio to test for primary hypoadrenalism: a pilot study. AB - INTRODUCTION: A standard short Synacthen test (SST) is the conventional diagnostic test for primary hypoadrenalism. Measuring simultaneous plasma cortisol and adrenocorticotrophin hormone (ACTH) and using the cortisol: ACTH ratio as a first-line test may be safer and more convenient than performing a SST. METHODS: A retrospective study of 349 patients who had a SST with simultaneous baseline plasma cortisol and ACTH performed between 2005 and 2010 in two separate Australian health centres. The plasma cortisol: ACTH ratio was calculated for each patient and their final diagnosis was determined based on their SST result and a review of their clinical notes. RESULTS: Eighteen patients had primary hypoadrenalism, 46 patients had secondary hypoadrenalism and 285 patients had normal adrenal function. All the patients with primary hypoadrenalism had a plasma cortisol: ACTH ratio <3, while none of the patients with normal adrenal function or secondary hypoadrenalism had a cortisol: ACTH ratio <3. Therefore, a cortisol: ACTH ratio <3 had a 100% sensitivity and specificity for the diagnosis of primary hypoadrenalism. Patients with secondary hypoadrenalism had a cortisol: ACTH ratio >3, while subjects with normal adrenal function had a cortisol: ACTH ratio >15. There was overlap in cortisol: ACTH ratios of patients with secondary hypoadrenalism and normal adrenal function. CONCLUSIONS: Although the cortisol: ACTH ratio predicts primary hypoadrenalism, its value is limited to diagnosing primary hypoadrenalism as it does not distinguish secondary hypoadrenalism from normal adrenal function. Larger prospective studies that include patients with early primary hypoadrenalism are needed to confirm the reliability of plasma cortisol: ACTH ratio as a diagnostic test for primary hypoadrenalism. PMID- 23729815 TI - Suspended microfluidics. AB - Although the field of microfluidics has made significant progress in bringing new tools to address biological questions, the accessibility and adoption of microfluidics within the life sciences are still limited. Open microfluidic systems have the potential to lower the barriers to adoption, but the absence of robust design rules has hindered their use. Here, we present an open microfluidic platform, suspended microfluidics, that uses surface tension to fill and maintain a fluid in microscale structures devoid of a ceiling and floor. We developed a simple and ubiquitous model predicting fluid flow in suspended microfluidic systems and show that it encompasses many known capillary phenomena. Suspended microfluidics was used to create arrays of collagen membranes, mico Dots (MUDots), in a horizontal plane separating two fluidic chambers, demonstrating a transwell platform able to discern collective or individual cellular invasion. Further, we demonstrated that MUDots can also be used as a simple multiplexed 3D cellular growth platform. Using the MUDot array, we probed the combined effects of soluble factors and matrix components, finding that laminin mitigates the growth suppression properties of the matrix metalloproteinase inhibitor GM6001. Based on the same fluidic principles, we created a suspended microfluidic metabolite extraction platform using a multilayer biphasic system that leverages the accessibility of open microchannels to retrieve steroids and other metabolites readily from cell culture. Suspended microfluidics brings the high degree of fluidic control and unique functionality of closed microfluidics into the highly accessible and robust platform of open microfluidics. PMID- 23729813 TI - Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance. AB - Obesity is an epidemic, calling for innovative and reliable pharmacological strategies. Here, we show that ShK-186, a selective and potent blocker of the voltage-gated Kv1.3 channel, counteracts the negative effects of increased caloric intake in mice fed a diet rich in fat and fructose. ShK-186 reduced weight gain, adiposity, and fatty liver; decreased blood levels of cholesterol, sugar, HbA1c, insulin, and leptin; and enhanced peripheral insulin sensitivity. These changes mimic the effects of Kv1.3 gene deletion. ShK-186 did not alter weight gain in mice on a chow diet, suggesting that the obesity-inducing diet enhances sensitivity to Kv1.3 blockade. Several mechanisms may contribute to the therapeutic benefits of ShK-186. ShK-186 therapy activated brown adipose tissue as evidenced by a doubling of glucose uptake, and increased beta-oxidation of fatty acids, glycolysis, fatty acid synthesis, and uncoupling protein 1 expression. Activation of brown adipose tissue manifested as augmented oxygen consumption and energy expenditure, with no change in caloric intake, locomotor activity, or thyroid hormone levels. The obesity diet induced Kv1.3 expression in the liver, and ShK-186 caused profound alterations in energy and lipid metabolism in the liver. This action on the liver may underlie the differential effectiveness of ShK-186 in mice fed a chow vs. an obesity diet. Our results highlight the potential use of Kv1.3 blockers for the treatment of obesity and insulin resistance. PMID- 23729817 TI - Design of Gas-phase Synthesis of Core-Shell Particles by Computational Fluid - Aerosol Dynamics. AB - Core-shell particles preserve the bulk properties (e.g. magnetic, optical) of the core while its surface is modified by a shell material. Continuous aerosol coating of core TiO2 nanoparticles with nanothin silicon dioxide shells by jet injection of hexamethyldisiloxane precursor vapor downstream of titania particle formation is elucidated by combining computational fluid and aerosol dynamics. The effect of inlet coating vapor concentration and mixing intensity on product shell thickness distribution is presented. Rapid mixing of the core aerosol with the shell precursor vapor facilitates efficient synthesis of hermetically coated core-shell nanoparticles. The predicted extent of hermetic coating shells is compared to the measured photocatalytic oxidation of isopropanol by such particles as hermetic SiO2 shells prevent the photocatalytic activity of titania. Finally the performance of a simpler, plug-flow coating model is assessed by comparisons to the present detailed CFD model in terms of coating efficiency and silica average shell thickness and texture. PMID- 23729818 TI - Analysing panel count data with informative observation times. AB - In this paper, we study panel count data with informative observation times. We assume nonparametric and semiparametric proportional rate models for the underlying event process, where the form of the baseline rate function is left unspecified and a subject-specific frailty variable inflates or deflates the rate function multiplicatively. The proposed models allow the event processes and observation times to be correlated through their connections with the unobserved frailty; moreover, the distributions of both the frailty variable and observation times are considered as nuisance parameters. The baseline rate function and the regression parameters are estimated by maximising a conditional likelihood function of observed event counts and solving estimation equations. Large-sample properties of the proposed estimators are studied. Numerical studies demonstrate that the proposed estimation procedures perform well for moderate sample sizes. An application to a bladder tumour study is presented. PMID- 23729820 TI - Pet wellness. PMID- 23729821 TI - An ethicist's commentary on the dog with Cushing's syndrome. PMID- 23729822 TI - Pilot evaluation of a novel test strip for the assessment of dissolved thiol levels, as an indicator of canine gingival health and periodontal status. AB - This study evaluated a novel test strip designed to assess thiol levels as they relate to gingival/periodontal health in dogs. The simple to use strip (similar in form to a pH test strip) provides a colorimetric signal which estimates the level of thiols dissolved in oral fluid. Among several oral sites tested (left and right lingual vestibules, lower buccal vestibule, and upper buccal gingival margin), fluid from the maxillary gingival margin gave results with the best dynamic range, and its thiol levels correlated well with several oral health parameters (Pearson coefficients between 0.55 and 0.84; P < 0.001), especially those relating directly to the gingiva. The strip, which can be used on animals which are awake, may be useful as a quick, objective assessment of periodontal health, potentially enhancing compliance for thorough examinations, and promoting earlier and better-sustained treatment programs. PMID- 23729824 TI - Ultrasonography of the liver and kidneys of healthy camels (Camelus dromedarius). AB - This study describes the ultrasonography of the liver and kidneys of healthy camels (Camelus dromedarius). Images of the liver were obtained from the 11th to 5th intercostal spaces (ICSs). The distance between the dorsal liver margin and the midline of the back was shortest (39.1 +/- 7.4 cm) at the 11th ICS and increased cranially to 5th ICS. The size of the liver was largest at the 9th ICS and smallest at the 5th ICS. In 6 camels the right kidney was visualized from the 10th and 11th ICSs and upper right flank and in the 10th and 11th ICSs in the remaining 16 camels. In all camels, the left kidney was imaged from the caudal left flank. In 21 camels, the differentiation between the renal cortex and medulla was clearly visible in the ultrasonograms. Ultrasonographic description of the liver and kidneys provides a basic reference for diagnosing hepatic and renal disorders in camels. PMID- 23729823 TI - Simple tube centrifugation for processing platelet-rich plasma in the horse. AB - This study evaluated the quality and bacteriologic safety of platelet-rich plasma (PRP) produced by 3 simple, inexpensive tube centrifugation methods and a commercial system. Citrated equine blood collected from 26 normal horses was processed by 4 methods: blood collection tubes centrifuged at 1200 and 2000 * g, 50-mL conical tube, and a commercial system. White blood cell (WBC), red blood cell (RBC), and platelet counts and mean platelet volume (MPV) were determined for whole blood and PRP, and aerobic and anaerobic cultures were performed. Mean platelet concentrations ranged from 1.55- to 2.58-fold. The conical method yielded the most samples with platelet concentrations greater than 2.5-fold and within the clinically acceptable range of > 250,000 platelets/MUL. White blood cell counts were lowest with the commercial system and unacceptably high with the blood collection tubes. The conical tube method may offer an economically feasible and comparatively safe alternative to commercial PRP production systems. PMID- 23729825 TI - Prospective medical evaluation of 7 dogs presented with fly biting. AB - Fly biting describes a syndrome in which dogs appear to be watching something and then snapping at it. Medical work-up of fly biting in dogs has never been reported. The aims of this case series were to characterize fly biting and perform a complete medical evaluation of dogs displaying fly biting. PMID- 23729826 TI - Measurement of vitamin A, vitamin E, selenium, and L-lactate in dogs with and without osteoarthritis secondary to ruptured cranial cruciate ligament. AB - This study compared vitamin A, vitamin E, selenium (Se), and L-lactate in blood and synovial fluid in 2 groups of 6 dogs; a control group (without OA) and an osteoarthritic group with spontaneous cranial cruciate ligament rupture and OA. Concentrations of vitamin E were significantly higher in serum than in synovial fluid in both OA (P = 0.006) and control (P = 0.0008) groups. Vitamin E concentration in synovial fluid was significantly higher in the OA group than in the control group (P = 0.009). Concentrations of Se were significantly higher in serum than in synovial fluid in both OA (P = 0.003) and control (P = 0.0006) groups. There were no significant differences in levels of Se, vitamin A, and L lactate between the 2 groups. This is the first study to show an increased concentration of vitamin E in the synovial fluid of dogs with OA compared with dogs that did not have OA. PMID- 23729827 TI - Review of antimicrobial therapy of selected bacterial diseases in broiler chickens in Canada. AB - This paper reviews common therapeutic applications of antimicrobials in broiler chicken production in relation to Canadian guidelines, surveillance data, and emerging public health concerns about antimicrobial use (AMU). Escherichia coli, Clostridium perfringens, and Staphylococcus spp., were reviewed because of their animal health and economic significance. Enterococcus cecorum and Salmonella were included because of their importance in antimicrobial resistance (AMR) surveillance. This review identified that i) antimicrobials are available in Canada to treat infections by these agents, but may be through over the counter or extra-label use, ii) prevalence rates for these diseases are unknown, iii) antimicrobial use estimates in broilers are lacking, and iv) AMR has emerged in clinical isolates, though data are very sparse. This review highlights the need for surveillance of AMU and AMR in broiler chickens in Canada. PMID- 23729829 TI - Anthelmintic resistance in a herd of alpacas (Vicugna pacos). AB - A herd of alpacas was examined because of a history of severe endoparasitism, anemia, hypoproteinemia, and weight loss. Resistance of gastrointestinal nematodes to albendazole, fenbendazole, and doramectin was documented. This report suggests that anthelmintic resistance may be an emerging problem in South American camelids in North America. PMID- 23729828 TI - Retrospective study and review of ocular radiation side effects following external-beam Cobalt-60 radiation therapy in 37 dogs and 12 cats. AB - This retrospective study evaluated the ocular side effects of cancer-bearing dogs and cats treated with external-beam Cobalt-60 (Co-60) radiation in which one or both orbit(s) were included in the radiation field. A total of 37 dogs and 12 cats presented to the Ontario Veterinary College during the 10-year study period (1999-2009) were evaluated. The radiation protocols ranged from a maximum of 60 Gray (Gy) in 24 fractions for curative intent to a minimum of 8 Gy in 1 fraction for palliative treatment. The main ocular side effect reported in both dogs and cats was conjunctivitis (79% and 55%, respectively). Other common ocular side effects included eyelid lesions in dogs (44%), ulcerative keratitis in cats (36%), and keratoconjunctivitis sicca in both dogs and cats (44% and 27%, respectively). The high incidence of ocular side effects in both patient populations indicates a need for regular ophthalmic examinations as a component of routine follow-up for radiation therapy involving the orbit. Radiation damage to ocular tissues is also reviewed. PMID- 23729830 TI - Cystocele and rectal prolapse in a female dog. AB - A case of cystocele and prolapsed rectum is reported. The urinary bladder and rectum were repositioned and fixed by cystopexy, colposuspension, and colopexy concurrently. There was no recurrence after 3 months. This is the first report to describe cystocele in a young female dog never having been pregnant. PMID- 23729831 TI - A colon-associated cystic mass occurring in conjunction with cecal dilatation in a Holstein cow. AB - A 7-year-old Holstein cow was presented for reduced appetite and decreased milk production. Based on physical examination, cecal dilatation was the primary differential diagnosis and was confirmed at surgery. However, in addition to the dilated cecum, 2 large cystic masses were found firmly attached to the proximal loop of the ascending colon. PMID- 23729832 TI - Assumed communication. PMID- 23729833 TI - Design of Aerosol Particle Coating: Thickness, Texture and Efficiency. AB - Core-shell particles preserve the performance (e.g. magnetic, plasmonic or opacifying) of a core material while modifying its surface with a shell that facilitates (e.g. by blocking its reactivity) their incorporation into a host liquid or polymer matrix. Here coating of titania (core) aerosol particles with thin silica shells (films or layers) is investigated at non-isothermal conditions by a trimodal aerosol dynamics model, accounting for SiO2 generation by gas phase and surface oxidation of hexamethyldisiloxane (HMDSO) vapor, coagulation and sintering. After TiO2 particles have reached their final primary particle size (e.g. upon completion of sintering during their flame synthesis), coating starts by uniformly mixing them with HMDSO vapor that is oxidized either in the gas phase or on the particles' surface resulting in SiO2 aerosols or deposits, respectively. Sintering of SiO2 deposited onto the core TiO2 particles takes place transforming rough into smooth coating shells depending on process conditions. The core-shell characteristics (thickness, texture and efficiency) are calculated for two limiting cases of coating shells: perfectly smooth (e.g. hermetic) and fractal-like. At constant TiO2 core particle production rate, the influence of coating weight fraction, surface oxidation and core particle size on coating shell characteristics is investigated and compared to pertinent experimental data through coating diagrams. With an optimal temperature profile for complete precursor conversion, the TiO2 aerosol and SiO2-precursor (HMDSO) vapor concentrations have the strongest influence on product coating shell characteristics. PMID- 23729834 TI - Finding a Civic Voice: Latino Immigrant Youths' Experiences in High School Social Studies. AB - Socialization into the dominant civic and political discourse lies at the heart of social studies. As they become proficient in the discourse of home and school, Latino immigrant youth demonstrate the potential to uniquely benefit from this socialization. This qualitative study explores ten Latino immigrant young adults' perceptions of how their social studies experiences shaped their young adult civic selves. Participants internalized not only their parents' high expectations for them, but also those of their teachers, highlighting the potentially instrumental role of schools in the civic fabric of the nation. In addition, the Latino young adults felt empowered by their social studies teachers via civic expectations and academic encouragement and perceived this empowerment to have facilitated the skill development necessary for later civic leadership. In closing, we reflect on immigrant students' incorporation of the discourse of the dominant culture with that of the home to develop their own civic voices. PMID- 23729835 TI - Limitations on the Importance of Self-Regulation in Old Age. PMID- 23729836 TI - Dynamic Active Contours for Visual Tracking. AB - Visual tracking using active contours is usually set in a static framework. The active contour tracks the object of interest in a given frame of an image sequence. A subsequent prediction step ensures good initial placement for the next frame. This approach is unnatural; the curve evolution gets decoupled from the actual dynamics of the objects to be tracked. True dynamical approaches exist, all being marker particle based and thus prone to the shortcomings of such particle-based implementations. In particular, topological changes are not handled naturally in this framework. The now classical level set approach is tailored for evolutions of manifolds of codimension one. However, dynamic curve evolution is at least a codimension two problem. We propose an efficient, level set based approach for dynamic curve evolution, which addresses the artificial separation of segmentation and prediction while retaining all the desirable properties of the level set formulation. It is based on a new energy minimization functional which, for the first time, puts dynamics into the geodesic active contour framework. PMID- 23729837 TI - Age and Race Differences in Racial Stereotype Awareness and Endorsement. AB - Age and race differences in race stereotype awareness and endorsement were examined in 382 Black and White fourth, sixth, and eighth graders. Youth reported their own beliefs and their perceptions of adults' beliefs about racial differences in ability in two domains: academics and sports. Children's own endorsement of race stereotypes was highly correlated with their perceptions of adults' race stereotypes. Blacks reported stronger traditional sports stereotypes than Whites, and fourth- and sixth-grade Blacks reported roughly egalitarian academic stereotypes. At every grade level, Whites reported academic stereotypes that favored Whites, and sixth and eighth grade Whites reported sports stereotypes that favored Blacks. Results support the tenets of status theory and have implications for identity development and achievement motivation in adolescents. PMID- 23729838 TI - Fear and Anger Responses to Local News Coverage of Alcohol-Related Crimes, Accidents, and Injuries: Explaining News Effects on Policy Support Using a Representative Sample of Messages and People. AB - An experiment investigated emotional reactions to news on policy support. Stimuli were selected from a nationally representative sample of local crime/accident news, and a nationally representative online panel of U.S. adults. Stories were manipulated to mention or not mention the role of alcohol. Anger elicited by stories increased blame of individuals, whereas fear increased consideration of contributing societal factors. Mention of alcohol increased likelihood of different emotional responses dominating--greater anger when alcohol was mentioned and greater fear when not mentioned. Such emotions influence policy support: enforcement of existing laws controlling individual behavior in addition to new laws when anger predominated, and, indirectly, support for new laws changing social context in which alcohol is promoted and sold when fear predominated. PMID- 23729839 TI - Patient-Specific Models of Cardiac Biomechanics. AB - Patient-specific models of cardiac function have the potential to improve diagnosis and management of heart disease by integrating medical images with heterogeneous clinical measurements subject to constraints imposed by physical first principles and prior experimental knowledge. We describe new methods for creating three-dimensional patient-specific models of ventricular biomechanics in the failing heart. Three-dimensional bi-ventricular geometry is segmented from cardiac CT images at end-diastole from patients with heart failure. Human myofiber and sheet architecture is modeled using eigenvectors computed from diffusion tensor MR images from an isolated, fixed human organ-donor heart and transformed to the patient-specific geometric model using large deformation diffeomorphic mapping. Semi-automated methods were developed for optimizing the passive material properties while simultaneously computing the unloaded reference geometry of the ventricles for stress analysis. Material properties of active cardiac muscle contraction were optimized to match ventricular pressures measured by cardiac catheterization, and parameters of a lumped-parameter closed-loop model of the circulation were estimated with a circulatory adaptation algorithm making use of information derived from echocardiography. These components were then integrated to create a multi-scale model of the patient-specific heart. These methods were tested in five heart failure patients from the San Diego Veteran's Affairs Medical Center who gave informed consent. The simulation results showed good agreement with measured echocardiographic and global functional parameters such as ejection fraction and peak cavity pressures. PMID- 23729840 TI - Multi-Scale Computational Model of Three-Dimensional Hemodynamics within a Deformable Full-Body Arterial Network. AB - In this article, we present a computational multi-scale model of fully three dimensional and unsteady hemodynamics within the primary large arteries in the human. Computed tomography image data from two different patients were used to reconstruct a nearly complete network of the major arteries from head to foot. A linearized coupled-momentum method for fluid-structure-interaction was used to describe vessel wall deformability and a multi-domain method for outflow boundary condition specification was used to account for the distal circulation. We demonstrated that physiologically realistic results can be obtained from the model by comparing simulated quantities such as regional blood flow, pressure and flow waveforms, and pulse wave velocities to known values in the literature. We also simulated the impact of age-related arterial stiffening on wave propagation phenomena by progressively increasing the stiffness of the central arteries and found that the predicted effects on pressure amplification and pulse wave velocity are in agreement with findings in the clinical literature. This work demonstrates the feasibility of three-dimensional techniques for simulating hemodynamics in a full-body compliant arterial network. PMID- 23729841 TI - Fluid-structure interaction of an aortic heart valve prosthesis driven by an animated anatomic left ventricle. AB - We develop a novel large-scale kinematic model for animating the left ventricle (LV) wall and use this model to drive the fluid-structure interaction (FSI) between the ensuing blood flow and a mechanical heart valve prosthesis implanted in the aortic position of an anatomic LV/aorta configuration. The kinematic model is of lumped type and employs a cell-based, FitzHugh-Nagumo framework to simulate the motion of the LV wall in response to an excitation wavefront propagating along the heart wall. The emerging large-scale LV wall motion exhibits complex contractile mechanisms that include contraction (twist) and expansion (untwist). The kinematic model is shown to yield global LV motion parameters that are well within the physiologic range throughout the cardiac cycle. The FSI between the leaflets of the mechanical heart valve and the blood flow driven by the dynamic LV wall motion and mitral inflow is simulated using the curvilinear immersed boundary (CURVIB) method [1, 2] implemented in conjunction with a domain decomposition approach. The computed results show that the simulated flow patterns are in good qualitative agreement with in vivo observations. The simulations also reveal complex kinematics of the valve leaflets, thus, underscoring the need for patient-specific simulations of heart valve prosthesis and other cardiac devices. PMID- 23729842 TI - Continuum-kinetic-microscopic model of lung clearance due to core-annular fluid entrainment. AB - The human lung is protected against aspirated infectious and toxic agents by a thin liquid layer lining the interior of the airways. This airway surface liquid is a bilayer composed of a viscoelastic mucus layer supported by a fluid film known as the periciliary liquid. The viscoelastic behavior of the mucus layer is principally due to long-chain polymers known as mucins. The airway surface liquid is cleared from the lung by ciliary transport, surface tension gradients, and airflow shear forces. This work presents a multiscale model of the effect of airflow shear forces, as exerted by tidal breathing and cough, upon clearance. The composition of the mucus layer is complex and variable in time. To avoid the restrictions imposed by adopting a viscoelastic flow model of limited validity, a multiscale computational model is introduced in which the continuum-level properties of the airway surface liquid are determined by microscopic simulation of long-chain polymers. A bridge between microscopic and continuum levels is constructed through a kinetic-level probability density function describing polymer chain configurations. The overall multiscale framework is especially suited to biological problems due to the flexibility afforded in specifying microscopic constituents, and examining the effects of various constituents upon overall mucus transport at the continuum scale. PMID- 23729843 TI - A CONTINUUM HARD-SPHERE MODEL OF PROTEIN ADSORPTION. AB - Protein adsorption plays a significant role in biological phenomena such as cell surface interactions and the coagulation of blood. Two-dimensional random sequential adsorption (RSA) models are widely used to model the adsorption of proteins on solid surfaces. Continuum equations have been developed so that the results of RSA simulations can be used to predict the kinetics of adsorption. Recently, Brownian dynamics simulations have become popular for modeling protein adsorption. In this work a continuum model was developed to allow the results from a Brownian dynamics simulation to be used as the boundary condition in a computational fluid dynamics (CFD) simulation. Brownian dynamics simulations were used to model the diffusive transport of hard-sphere particles in a liquid and the adsorption of the particles onto a solid surface. The configuration of the adsorbed particles was analyzed to quantify the chemical potential near the surface, which was found to be a function of the distance from the surface and the fractional surface coverage. The near-surface chemical potential was used to derive a continuum model of adsorption that incorporates the results from the Brownian dynamics simulations. The equations of the continuum model were discretized and coupled to a CFD simulation of diffusive transport to the surface. The kinetics of adsorption predicted by the continuum model closely matched the results from the Brownian dynamics simulation. This new model allows the results from mesoscale simulations to be incorporated into micro- or macro scale CFD transport simulations of protein adsorption in practical devices. PMID- 23729844 TI - Including fluid shear viscosity in a structural acoustic finite element model using a scalar fluid representation. AB - An approximate boundary condition is developed in this paper to model fluid shear viscosity at boundaries of coupled fluid-structure system. The effect of shear viscosity is approximated by a correction term to the inviscid boundary condition, written in terms of second order in-plane derivatives of pressure. Both thin and thick viscous boundary layer approximations are formulated; the latter subsumes the former. These approximations are used to develop a variational formation, upon which a viscous finite element method (FEM) model is based, requiring only minor modifications to the boundary integral contributions of an existing inviscid FEM model. Since this FEM formulation has only one degree of freedom for pressure, it holds a great computational advantage over the conventional viscous FEM formulation which requires discretization of the full set of linearized Navier-Stokes equations. The results from thick viscous boundary layer approximation are found to be in good agreement with the prediction from a Navier-Stokes model. When applicable, thin viscous boundary layer approximation also gives accurate results with computational simplicity compared to the thick boundary layer formulation. Direct comparison of simulation results using the boundary layer approximations and a full, linearized Navier Stokes model are made and used to evaluate the accuracy of the approximate technique. Guidelines are given for the parameter ranges over which the accurate application of the thick and thin boundary approximations can be used for a fluid structure interaction problem. PMID- 23729845 TI - The Development of Reasoning about Beliefs: Fact, Preference, and Ideology. AB - The beliefs people hold about the social and physical world are central to self definition and social interaction. The current research analyzes reasoning about three kinds of beliefs: those that concern matters of fact (e.g., dinosaurs are extinct), preference (e.g., green is the prettiest color), and ideology (e.g., there is only one God). The domain of ideology is of unique interest because it is hypothesized to contain elements of both facts and preferences. If adults' distinct reasoning about ideological beliefs is the result of prolonged experience with the physical and social world, children and adults should reveal distinct patterns of differentiating kinds of beliefs, and this difference should be particularly pronounced with respect to ideological beliefs. On the other hand, if adults' reasoning about beliefs is a basic component of social cognition, children and adults should demonstrate similar belief representations and patterns of belief differentiation. Two experiments demonstrate that 5-10 year old children and adults similarly judged religious beliefs to be intermediate between factual beliefs (where two disagreeing people cannot both be right) and preferences (where they can). From the age of 5 years and continuing into adulthood, individuals distinguished ideological beliefs from other types of mental states and demonstrated limited tolerance for belief-based disagreements. PMID- 23729846 TI - Dietary fibre in foods: a review. AB - Dietary fibre is that part of plant material in the diet which is resistant to enzymatic digestion which includes cellulose, noncellulosic polysaccharides such as hemicellulose, pectic substances, gums, mucilages and a non-carbohydrate component lignin. The diets rich in fibre such as cereals, nuts, fruits and vegetables have a positive effect on health since their consumption has been related to decreased incidence of several diseases. Dietary fibre can be used in various functional foods like bakery, drinks, beverages and meat products. Influence of different processing treatments (like extrusion-cooking, canning, grinding, boiling, frying) alters the physico- chemical properties of dietary fibre and improves their functionality. Dietary fibre can be determined by different methods, mainly by: enzymic gravimetric and enzymic-chemical methods. This paper presents the recent developments in the extraction, applications and functions of dietary fibre in different food products. PMID- 23729847 TI - Onion dehydration: a review. AB - Onion (Allium cepa), a very commonly used vegetable, ranks third in the world production of major vegetables. Apart from imparting a delicious taste and flavour due to its pungency in many culinary preparations, it serves several medicinal purposes also. Processing and preservation of onion by suitable means is a major thrust area since a long time. The various kinds of treatments followed for dehydration of onion such as convective air drying, solar drying, fluidized bed drying, vacuum microwave drying, infrared drying and osmotic drying are reviewed here. These techniques are mainly used for preservation and value addition of onion. Several researchers have tried for decades to model the drying kinetics and quality parameters, which are also compiled here briefly. PMID- 23729848 TI - Utilization of byproducts and waste materials from meat, poultry and fish processing industries: a review. AB - India is bestowed with vast livestock wealth and it is growing at the rate of 6% per annum. The contribution of livestock industry including poultry and fish is increasing substantially in GDP of country which accounts for >40% of total agricultural sector and >12% of GDP. This contribution would have been much greater had the animal by-products been also efficiently utilized. Efficient utilization of by-products has direct impact on the economy and environmental pollution of the country. Non-utilization or under utilization of by-products not only lead to loss of potential revenues but also lead to the added and increasing cost of disposal of these products. Non-utilization of animal by-products in a proper way may create major aesthetic and catastrophic health problems. Besides pollution and hazard aspects, in many cases meat, poultry and fish processing wastes have a potential for recycling raw materials or for conversion into useful products of higher value. Traditions, culture and religion are often important when a meat by-product is being utilized for food. Regulatory requirements are also important because many countries restrict the use of meat by-products for reasons of food safety and quality. By-products such as blood, liver, lung, kidney, brains, spleen and tripe has good nutritive value. Medicinal and pharmaceutical uses of by-product are also highlighted in this review. Waste products from the poultry processing and egg production industries must be efficiently dealt with as the growth of these industries depends largely on waste management. Treated fish waste has found many applications among with which the most important are animal feed, biodiesel/biogas, dietectic products (chitosan), natural pigments (after extraction) and cosmetics (collagen). Available information pertaining to the utilization of by-products and waste materials from meat, poultry and fish and their processing industries has been reviewed here. PMID- 23729849 TI - Optimization of extraction of antioxidants from wheat bran (Triticum spp.) using response surface methodology. AB - In this study, the optimal conditions for the extraction of antioxidants from hard winter wheat bran (WH711) were determined using response surface methodology (RSM). A central composite face centred design was used to investigate the effects of three independent variables, namely solvent composition (%v/v), extraction temperature ( degrees C) and time (minutes) on the responses; free phenolic content (FPC), total flavonoid content (TFC), total antioxidant activity (TAA), ferric reducing power (FRP), hydrogen peroxide scavenging activity (HPSA). Regression analysis showed that more than 90% of the variation was explained by the models of different responses. The optimal conditions for the antioxidantss extraction were found to be methanol concentration of 85%v/v, extraction temperature of 75 degrees C, extraction time of 45 min, for wheat bran. The experimental values of FPC, TFC, TAA, FRP and HPSA were 0.921 mg GAE/g bran (B), 0.4588 mg CE/g B, 0.01408 mM AAE/g B, 2.532 mM AAE/g B and 3.193 mM TE/g B, respectively which agreed with those predicted, thus indicating suitability of the model employed and the suitability of RSM in optimizing the extraction conditions. PMID- 23729850 TI - Characteristics of freeze-dried fish protein isolated from saithe (Pollachius virens). AB - Fish proteins isolated from by-products or low commercial/underutilized species using pH-shift process is a new source of proteins that may be used as wet or dried ingredients to develop value-added convenience foods. This paper reports the effects of freeze-drying on characteristics of fish protein isolates (FPI) from saithe (Pollachius virens) with or without lyoprotectants. Freeze-dried saithe mince from the same lot and without additives was used as a control. The resulting fish protein powders contained 71-93% protein, 1.5-3% moisture, 0-21% carbohydrate and 0.5-2% fat. Lipid oxidation (assessed by TBARS) of FPI powder groups was higher than that of fish mince powder. The results revealed that oxidation started during the pH-shift process and was increased by freeze-drying. Functional properties and sensory attributes were influenced by the advanced oxidation. However, the mince powder was less oxidized and had higher functional properties such as water binding capacity, gel forming ability, emulsification, foaming properties and colour and lower sensory scores for rancid odour and flavour than the FPI powders. Further studies on how to prevent oxidation of fish flesh during pH-shift and drying processes are recommended. PMID- 23729851 TI - A study on cations and color removal from thin sugar juice by modified sugar beet pulp. AB - This article describes the use of citric acid modified sugar beet pulp as new ion exchanger sorbent for the removal of metal cations and colorants from thin juice. The results of batch adsorption runs concerning the effects of contact time, material dosage, temperature and pH drop were presented and discussed. Experimental data on the removal of metal cations showed that the sorption process was rapid and reached equilibrium in 60 min. Modified material in acidic form caused to a significant pH drop in thin juice, which could result with sucrose inversion. Uptake of metal cations increased with temperature whereas that of color decreased. Neutralised type modified product gave more satisfying results. After six successive contacts, 49.7%, 37.5% and 43.7% removals for Ca Mg, K and color, respectively, were obtained by using neutralised form of modified sugar beet pulp. PMID- 23729852 TI - Application of principal component analysis (PCA) as a sensory assessment tool for fermented food products. AB - The objective of the work was to use the method of quantitative descriptive analysis (QDA) to describe the sensory attributes of the fermented food products prepared with the incorporation of lactic cultures. Panellists were selected and trained to evaluate various attributes specially color and appearance, body texture, flavor, overall acceptability and acidity of the fermented food products like cow milk curd and soymilk curd, idli, sauerkraut and probiotic ice cream. Principal component analysis (PCA) identified the six significant principal components that accounted for more than 90% of the variance in the sensory attribute data. Overall product quality was modelled as a function of principal components using multiple least squares regression (R (2) = 0.8). The result from PCA was statistically analyzed by analysis of variance (ANOVA). These findings demonstrate the utility of quantitative descriptive analysis for identifying and measuring the fermented food product attributes that are important for consumer acceptability. PMID- 23729853 TI - Development of shelf stable protein rich composite cereal bar. AB - Protein rich composite cereal bar based on cereal ingredients was prepared using semi automatic tablet making machine, packed in poly propylene (PP), paper aluminium foil polyethylene (PFP), metallised polyester (MP) followed by vacuum packing in metallized polyester films. Proximate composition, mineral contents as well as changes in peroxide value (PV), free fatty acid value (FFA), thiobarbituric acid value (TBA), browning, fatty acid profile, vitamins, effect of water activity on lipid peroxidation, fortification with vitamins and minerals, microbiological as well as sensory parameters during storage under ambient (15-34 degrees C) and 37 degrees C temperature conditions were studied. Composite cereal bar remained shelf stable for 3 months in PP and 6 months in PFP, MP and MP plus vacuum packing under ambient and 37 degrees C temperature conditions. PMID- 23729854 TI - Nondestructive methods for quality evaluation of livestock products. AB - The muscles derived from livestock are highly perishable. Rapid and nondestructive methods are essential for quality assurance of such products. Potential nondestructive methods, which can supplement or replace many of traditional time consuming destructive methods, include colour and computer image analysis, NIR spectroscopy, NMRI, electronic nose, ultrasound, X-ray imaging and biosensors. These methods are briefly described and the research work involving them for products derived from livestock is reviewed. These methods will be helpful in rapid screening of large number of samples, monitoring distribution networks, quick product recall and enhance traceability in the value chain of livestock products. With new developments in the areas of basic science related to these methods, colour, image processing, NIR spectroscopy, biosensors and ultrasonic analysis are expected to be widespread and cost effective for large scale meat quality evaluation in near future. PMID- 23729855 TI - Quality evaluation of stiff porridges prepared from Irish potato (Solanum tuberosum) and pigeon pea (Cajanus cajan) starch blends. AB - Quality attributes of stiff porridges prepared from Irish potato and pigeon pea starch blends were studied. Starches were extracted from Irish potato and pigeon pea using a wet extraction method. Various ratios of the starches were mixed and analyzed for chemical, functional and pasting properties. The starch blends were then prepared into stiff porridges for sensory evaluation using a 20-man sensory panel. Substitution of Irish potato starch with pigeon pea starch led to increases in protein (0.15 to 1.2%), fat (0.26 to 0.56%) and ash (0.30 to 0.69%) while the amylose content of the starch blends decreased (from 23.8 to 18.4%) respectively. Functional properties such as bulk density (0.75 to 0.60 g/cm(3)), water absorption capacity (3.1 to 2.6 g water/ g sample) and dispersibility (58.6 to 42.7%) decreased significantly (P < 0.05) at the highest concentration (50%) of pigeon pea starch respectively. Pasting properties such as peak, breakdown, final and setback viscosities increased with increasing levels of pigeon pea starch while peak time and pasting temperature decreased. The sensory attributes of stiff porridges were not adversely affected by pigeon pea starch inclusion. Therefore it should be possible to incorporate up to 50% of low digestible pigeon pea starch into Irish potato starch from legumes such as pigeon pea as alternatives to cassava starch in the preparation of stiff porridges. Such porridges made from Irish potato and legume starches could provide additional incentive for individuals requiring decreased and or slow starch digestibility such as diabetics. PMID- 23729856 TI - Comparative studies on the physicochemical and antioxidant properties of different tea extracts. AB - Tea is one of the most popular drinks next to water. Tea polyphenol is one of the main bioactive constituents of tea with health functions. In order to find the most bioactive tea polyphynols, polyphenol extracts from green tea, black tea and chemical oxidation products of green tea extracts were comparatively studied on the physicochemical and antioxidant properties. Results showed physicochemical and antioxidant properties of polyphenol extracts changed greatly after the chemical oxidation. Hydrogen peroxide induced oxidation products (HOP) possessed the highest antioxidant ability among the four tea polyphenol extracts. Thirteen phenolic compounds and one alkaloid in HOP were identified by reversed phase high performance liquid chromatography coupled to diode array detection and electrospray ionization mass spectrometry (RP-HPLC-DAD-ESI-MS). Hydrogen peroxide induced oxidation of tea polyphenol extracts could improve the antioxidant activity and could be used to produce antioxidants for food industry. PMID- 23729857 TI - Analysis of cream formation in green tea concentrates with different solid concentrations. AB - The formation of tea cream in the green tea concentrates of different solid concentrations (5, 10, 20, 30, 40, 50 and 60 degrees Brix) was investigated. The results showed a good positive correlation (gamma = 0.98, p <= 0.05) between the amount of tea cream and the solid concentrations from 5 to 40 degrees Brix, while the amount of tea cream in the tea concentrates of 50 and 60 degrees Brix decreased acutely. Total sugar, caffeine and catechins were found to be the main chemical components of tea cream in the green tea concentrate. The large decrease of the amount of tea cream in the tea concentrates of 50 and 60 degrees Brix may be induced by a sharp increase of the viscosity of the tea concentrates, which helped to improve the stability of tea concentrate. It may be indicated that the stability of green tea concentrate enhanced when the concentration higher than 50 degrees Brix, which helped to restrain the formation of tea cream. PMID- 23729858 TI - Effect of various process treatment conditions on the allyl isothiocyanate extraction rate from mustard meal. AB - Allyl isothiocyanate (AITC), which has the potential to be used as flavoring, antibacterial, antifungal, antifermentative and antibrowning agent in food industry, was extracted from the pretreated MM by distillation technique. The mustard meal was analyzed for the proximate composition and the metals Fe, Mg and Zn. At the optimum pretreatment conditions of temperature 60 degrees C, time 120 min and pH 4.5, the effect of fractional distillation, mesh size and different additives was studied. Considerable effect of mesh size was observed, as the mesh size was decreased from 1,690 to 400 MUm, the allyl isothiocyanate content was increased from 99.15 to 337.11 mg/100 ml. Addition of magnesium chloride (0.05 g/l to 0.2 g/l) and L-ascorbic acid (1 g/l to 5 g/l) increased allyl isothiocyanate from 257.79 to 317.28 mg/100 ml and 316.77 to 396.60 mg/100 ml respectively whereas the addition of the magnesium chloride and L-ascorbic acid in combination did not affect the AITC extraction rate as compare to their addition in single effect. PMID- 23729859 TI - Effect of different cooking methods on proximate and mineral composition of striped snakehead fish (Channa striatus, Bloch). AB - The effects of different cooking methods (boiling, baking, frying and grilling) on proximate and mineral composition of snakehead fish were investigated. The mean content of moisture, protein, fat and ash of raw fish was found to be 77.2 +/- 2.39, 13.9 +/- 2.89, 5.9 +/- 0.45 and 0.77 +/- 0.12% respectively. The changes in the amount of protein and fat were found to be significantly higher in frying and grilling fish. The ash content increased significantly whereas that of the minerals (Na, K, Ca, Mg, Fe, Zn and Mn) was not affected in all cooking methods. Increased in Cu contents and decreased in P contents were observed in all cooking methods except grilling. In the present study, the grilling method of cooking is found to be the best for healthy eating. PMID- 23729860 TI - Effect of drying temperature and slice size on quality of dried okra (Abelmoschus esculentus (L.) Moench). AB - Okra (Abelmoschus esculentus (L) Moench) is an important vegetable crop of India. Dried okra pods have wide use in snacks and are in great demand for domestic as well as export market. Hence, effect of four slice sizes (1, 2, 3 and 4 cm) and four drying temperatures (50, 60, 70 and 80 degrees C) on quality of hot air dried okra were studied. Okra pods were dried in the form of slices cut across the length at different temperatures. Quality assessment of okra was done on the basis of protein, ascorbic acid and fibre content. Okra slice sizes and drying temperatures affected all the quality parameters significantly (p < 0.05). Maximum retention of protein, ascorbic acid and fibre content were found in 2 cm long slices dried at 60 degrees C temperature. PMID- 23729862 TI - Young Adults' Fertility Expectations and Events: Associations With College Enrollment and Persistence. AB - The analyses described in this article investigated the association between adolescent fertility expectations and college enrollment (N = 7,838). They also explored the potential impact of fertility expectations and events on college persistence among 4-year (n = 2,605) and 2-year (n = 1,962) college students. The analysis, which used data from the National Longitudinal Survey of Youth 1997 cohort, showed a significant association between expectations for early parenthood and the likelihood of going to a 4-year college or 2-year college for both men and women. In addition, the authors found that pregnancies were associated with an increased risk of college dropout for women; however, if all of the estimated effect of pregnancies on the risk of dropout were causal, they would still not be a major factor contributing to educational attainment because fertile pregnancies among college women are so rare. PMID- 23729861 TI - Consequences of Teen Parents' Child Care Arrangements for Mothers and Children. AB - Using the nationally representative Early Childhood Longitudinal Study-Birth Cohort (2001 - 2006; N ~ 7900), we examined child care arrangements among teen parents from birth through prekindergarten. Four latent classes of child care arrangements at 9, 24, and 52 months emerged: "parental care," "center care," "paid home-based care," and "free kin-based care." Disadvantaged teen-parent families were overrepresented in the "parental care" class, which was negatively associated with children's preschool reading, math, and behavior scores and mothers' socioeconomic and fertility outcomes compared to some nonparental care classes. Nonparental care did not predict any negative maternal or child outcomes, and different care arrangements had different benefits for mothers and children. Time spent in nonparental care and improved maternal outcomes contributed to children's increased scores across domains. Child care classes predicted maternal outcomes similarly in teen-parent and nonteen-parent families, but the "parental care" class predicted some disproportionately negative child outcomes for teen-parent families. PMID- 23729863 TI - 1-3 piezoelectric composites for high temperature transducer applications. AB - High temperature Pb(Zr,Ti)O3 /epoxy 1-3 composites were fabricated using the dice and fill method. The epoxy filler was modified with glass spheres in order to improve the thermal reliability of the composites at elevated temperatures. Temperature dependent dielectric and electromechanical properties of the composites were measured after aging at 250 degrees C with different dwelling times. Obvious cracks were observed and the electrodes were damaged in the composite with unmodified epoxy after 200 hours, leading to the failure of the composite. In contrast, composites with >12 vol% glass sphere loaded epoxies were found to exhibit minimal electrical property variation after aging for 500 hours, with dielectric permittivity, piezoelectric coefficient and electromechanical coupling being on the order of 940, 310pC/N and 57%, respectively. This is due to the improved thermal expansion behavior of the modified filler. PMID- 23729864 TI - The Magic Number 70 (plus or minus 20): Variables Determining Performance in the Rodent Odor Span Task. AB - The olfactory span task (OST) uses an incrementing non-matching to sample procedure such that the number of stimuli to remember increases during the session. The number of consecutive correct responses (span length) and percent correct as a function of the memory load have been viewed as defining rodent working memory capacity limitations in several studies using the OST. However, the procedural parameters of the OST vary across experiments and their effects are not well understood. For example, in several studies, the number of stimuli to remember is confounded with the number of comparison stimuli displayed in the test arena. Experiment 1 addressed whether performance is influenced by the number of comparison choices available on any given trial (2, 5, 10) as well as the number of odor stimuli to remember during a session (12, 24, 36). Performance was most accurate when the number of stimuli to remember was low, as would be expected from a working memory interpretation of OST. However, accuracy was also affected by the number of comparison stimulus choices. High levels of accuracy were seen even with 36 odors, suggesting that the capacity for odor memory in rats was greater than suggested by previous research. Experiment 2 attempted to define this capacity by programming sessions with 36, 48 or 72 stimuli to remember in a group of rats that had previously received extensive OST training. Highly accurate performance (80% correct or better) was sustained throughout the session at even the greatest memory loads, arguing strongly against the notion that the OST models the limited capacity of human working memory. Experiment 3 explored the possibility that stimulus control in the OST is based on relative stimulus familiarity, rather than recognition of stimuli not yet presented during the current session. Number of odor cups visited increased with the number of comparisons in the arena, but rats rarely sampled all of the comparison odors before responding. However, on probe trials which included only stimuli that had been presented during the session, latency to respond and number of comparisons sampled was sharply increased. These data suggest that responding in the OST is determined not just by relative familiarity, but rather by a more specific "what when" or perhaps "how long ago" form of stimulus control. PMID- 23729865 TI - Effects of Knots on Ring Polymers in Solvents of Varying Quality. AB - We employ extensive computer simulations to investigate the conformations and the interactions of ring polymers under conditions of worsening solvent quality, in comparison with those for linear polymers. We determine the dependence of the Theta-temperature on knotedness by considering ring polymers of different topologies. We establish a clear decrease of the former upon changing the topology of the polymer from linear to an unknotted ring and a further decrease of the same upon introducing trefoil- or 5-fold knots but we find no difference in the Theta-point between the two knotted molecules. Our results are based on two independent methods: one considering the scaling of the gyration radius with molecular weight and one based on the dependence of the effective interaction on solvent quality. In addition, we calculate several shape-parameters of the polymers to characterize linear, unknotted, and knotted topologies in good solvents and in the proximity of the Theta-point. The shape parameters of the knotted molecules show an interesting crossover at a degree of polymerization that depends on the degree of knottedness of the molecule. PMID- 23729866 TI - Survival Analysis with Time-Varying Covariates Measured at Random Times by Design. AB - Ecological momentary assessment (EMA) is a method for collecting real-time data in subjects' environments. It often uses electronic devices to obtain information on psychological state through administration of questionnaires at times selected from a probability-based sampling design. This information can be used to model the impact of momentary variation in psychological state on the lifetimes to events such as smoking lapse. Motivated by this, a probability-sampling framework is proposed for estimating the impact of time-varying covariates on the lifetimes to events. Presented as an alternative to joint modeling of the covariate process as well as event lifetimes, this framework calls for sampling covariates at the event lifetimes and at times selected according to a probability-based sampling design. A design-unbiased estimator for the cumulative hazard is substituted into the log likelihood, and the resulting objective function is maximized to obtain the proposed estimator. This estimator has two quantifiable sources of variation, that due to the survival model and that due to sampling the covariates. Data from a nicotine patch trial are used to illustrate the proposed approach. PMID- 23729867 TI - Rural Agricultural Change and Fertility Transition in Nepal. AB - Using longitudinal panel data from the Western Chitwan Valley of Nepal, this study investigates the impact of the use of modern farm technologies on fertility transition-specifically, the number of births in a farm household. Previous explanations for the slow pace of fertility transition in rural agricultural settings often argued that the demand for farm labor is the primary driver of high fertility. If this argument holds true, the use of modern farm technologies that are designed to carry out labor-intensive farm activities ought to substitute for farm labor and discourage births in farm families. However, little empirical evidence is available on the potential influence of the use of modern farm technologies on the fertility transition. To fill this gap, the panel data examined in this study provides an unusual opportunity to test this long standing, but unexplored, argument. The results demonstrate that the use of modern farm technologies, particularly the use of a tractor and other modern farm implements, reduce subsequent births in farm households. This offers important insight for understanding the fertility transition in Nepal, a setting that is experiencing high population growth and rapidly changing farming practices. PMID- 23729868 TI - Insight into the palladium catalyzed oxidative arylation of benzofuran: Heteropoly acid oxidants evoke a Pd(II)/Pd(IV) mechanism. AB - The effects of oxidant and organic acid additives on the oxidative cross-coupling reactions of electron rich heterocycles such as benzofuran with benzene were studied. Both regioselectivity and reaction rate could be controlled by varying the condition parameters. Furthermore, mechanistic insight was achieved via kinetic studies which indicate that reactions that are oxidized by the heteropoly acid H4PMo11VO40 operate via a Pd(II)/Pd(IV) mechanisms, while reactions oxidized by either AgOAc or Cu(OAc)2 operate by a Pd(II)/Pd(0) mechanism. PMID- 23729869 TI - Coupled Particulate and Continuum Model for Nanoparticle Targeted Delivery. AB - Prediction of nanoparticle (NP) distribution in a vasculature involves transport phenomena at various scales and is crucial for the evaluation of NP delivery efficiency. A combined particulate and continuum model is developed to model NP transport and delivery processes. In the particulate model ligand-receptor binding kinetics is coupled with Brownian dynamics to study NP binding on a microscale. An analytical formula is derived to link molecular level binding parameters to particulate level adhesion and detachment rates. The obtained NP adhesion rates are then coupled with a convection-diffusion-reaction model to study NP transport and delivery at macroscale. The binding results of the continuum model agree well with those from the particulate model. The effects of shear rate, particle size and vascular geometry on NP adhesion are investigated. Attachment rates predicted by the analytical formula also agree reasonably well with the experimental data reported in literature. The developed coupled model that links ligand-receptor binding dynamics to NP adhesion rate along with macroscale transport and delivery processes may serve as a faster evaluation and prediction tool to determine NP distribution in complex vascular networks. PMID- 23729870 TI - Resuscitation promoting factors: a family of microbial proteins in survival and resuscitation of dormant mycobacteria. AB - Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is an extraordinarily successful pathogen of humankind. It has been estimated that up to one-third of the world's population is infected with M. tuberculosis, and this population is an important reservoir for disease reactivation. Resuscitation promoting factor (Rpf) is a secretory protein, which was first reported in Micrococcus luteus. There are five functionally redundant Rpf-like proteins found in M. tuberculosis. Rpf promotes the resuscitation of dormant bacilli to yield normal, viable colony forming bacteria. All Rpfs share a conserved domain of about 70 amino acids and possess a lysozyme-like activity. The structural studies of the conserved domain suggest that Rpfs could be considered as a c-type lysozyme and lytic transglycosylases. Recently a novel class of nitrophenylthiocyanates (NPT) inhibitors of the muralytic activity of Rpf were reported which opens a new approach in the study of cell-wall hydrolyzing enzymes. This review describes molecular and structural studies conducted on Rpf proteins, their role in the resuscitation of dormant bacteria, in the reactivation of latent infection and identification of low molecular weight inhibitors of resuscitation promoting factors. PMID- 23729871 TI - Biological pretreatment of lignocellulosic substrates for enhanced delignification and enzymatic digestibility. AB - Sheer enormity of lignocellulosics makes them potential feedstock for biofuel production but, their conversion into fermentable sugars is a major hurdle. They have to be pretreated physically, chemically, or biologically to be used by fermenting organisms for production of ethanol. Each lignocellulosic substrate is a complex mix of cellulose, hemicellulose and lignin, bound in a matrix. While cellulose and hemicellulose yield fermentable sugars, lignin is the most recalcitrant polymer, consisting of phenyl-propanoid units. Many microorganisms in nature are able to attack and degrade lignin, thus making access to cellulose easy. Such organisms are abundantly found in forest leaf litter/composts and especially include the wood rotting fungi, actinomycetes and bacteria. These microorganisms possess enzyme systems to attack, depolymerize and degrade the polymers in lignocellulosic substrates. Current pretreatment research is targeted towards developing processes which are mild, economical and environment friendly facilitating subsequent saccharification of cellulose and its fermentation to ethanol. Besides being the critical step, pretreatment is also cost intensive. Biological treatments with white rot fungi and Streptomyces have been studied for delignification of pulp, increasing digestibility of lignocellulosics for animal feed and for bioremediation of paper mill effluents. Such lignocellulolytic organisms can prove extremely useful in production of bioethanol when used for removal of lignin from lignocellulosic substrate and also for cellulase production. Our studies on treatment of hardwood and softwood residues with Streptomyces griseus isolated from leaf litter showed that it enhanced the mild alkaline solubilisation of lignins and also produced high levels of the cellulase complex when growing on wood substrates. Lignin loss (Klason lignin) observed was 10.5 and 23.5% in case of soft wood and hard wood, respectively. Thus, biological pretreatment process for lignocellulosic substrate using lignolytic organisms such as actinomycetes and white rot fungi can be developed for facilitating efficient enzymatic digestibility of cellulose. PMID- 23729872 TI - Molecular Variability in North Indian Isolates of Cylindrocladium quinquieseptatum Causing Eucalyptus Leaf and Seedling Blight. AB - Cylindrocladium quinqueseptatum has been considered as the most destructive pathogen of Eucalyptus nurseries and plantations in north India. Genetic resistance has not been determined against this disease in Eucalyptus and genetic diversity among the fungal population in northern India is not known. Seventy three isolates from infected leaves and twigs of Eucalyptus were collected from different northern Indian state and analyzed through RAPD-PCR for screening genetic diversity. The UPGMA cluster analysis score of 284 loci permitted identification of 11 population lines and an outlier. This molecular variability prevalent among the north Indian population of the pathogen can used in identifying Cylindrocladium leaf and seedling blight resistant Eucalyptus germplasm. PMID- 23729873 TI - Isolation and Characterization of Trichoderma spp. for Antagonistic Activity Against Root Rot and Foliar Pathogens. AB - Trichoderma, soil-borne filamentous fungi, are capable of parasitising several plant pathogenic fungi. Twelve isolates of Trichoderma spp. isolated from different locations of South Andaman were characterized for their cultural, morphological and antagonistic activity against soil borne and foliar borne pathogens. The sequencing of these isolates showed seven different species. The isolates revealed differential reaction patterns against the test pathogens viz., Sclerotium rolfsii, Colletotrichum gloeosporioides and C. capsici. However, the isolates, TND1, TWN1, TWC1, TGD1 and TSD1 were most effective in percentage inhibition of mycelial growth of test pathogens. Significant chitinase and beta 1,3-glucanase activities of all Trichoderma isolates has been recorded in growth medium. T. viride was found with highest chitinase whereas T. harzianum was recorded with highest beta-1,3-glucanase activities. PMID- 23729874 TI - Morpho-typing and molecular diversity of arbuscular mycorrhizal fungi in sub tropical soils of Coimbatore region, Tamil Nadu, India. AB - The diversity potential of arbuscular mycorrhizal fungi (AMF) in three different tropical soils of southern part of India was assessed by traditional morpho typing of AMF-spores and by culture-independent nested-PCR of internal transcribed spacer region of ribosomal genes. The population diversity of AMF in soil was strongly correlated with available P2O5 in soil. Among the three different soils, black-cotton soil had more diversified AMF species than alluvial and red sandy soils. Pooled data of morpho-typing and sequence-driven analysis revealed that Glomus, Gigaspora, Scutellospora and Acaulospora are the AMF genera present in these soils. The diversity of AMF in soil differs with the mycorrhiza colonizing the plant roots. PMID- 23729875 TI - Incidence of staphylococci and streptococci during winter in mastitic milk of sahiwal cow and murrah buffaloes. AB - Mastitis is a serious problem in dairy sector and among various aetiological agents, the incidence of staphylococci and streptococci remains high in milking animal. The present study was focused on detection of staphylococci and streptococci in winter season. Milk samples (117) of mastitic animals were tested for presence of staphylococci and streptococci using biochemical and PCR based assays. The testing revealed majority of animals (90.6%) were infected with more than one causative agent. Amongst 117 sample, 109 and 90 comprised of staphylococci and 90 streptococci, respectively. Distribution proportion of S. aureus, S. epidermidis, S. agalactiae, S. uberis and S. dysgalactiae among the mastitic cases was found as 64.9, 7.7, 5.1, 1.7, 48.7, 65.8 and 0.8%, respectively. Streptococci and staphylococci were observed in different combinations and the frequent were S. aureus/S. agalactiae/S. uberis, S. aureus/S. uberis, S. aureus/S. agalactiae and S. agalactiae/S. uberis which were accounted for 23.9, 19.7, 5.9 and 2.6%, respectively. Approximately half of the (52.1%) cases were observed for reoccurrence of mastitis. Reoccurrence of mastitis in winter season among these cases was significantly low as compared to summer (cattle-5 cases; buffaloes-2 cases). In addition, prevalence of S. aureus, S. agalactiae, S. uberis, and S. epidermidis in reoccurring mastitic cases was 73.7, 63.9, 45.9 and 6.6%, respectively. The observations revealed mastitis causing pathogens remains in hidden phase in winter season; however, cannot be neglected. The observation might be helpful in culling or segregation of cows for mastitis reduction programmes. PMID- 23729876 TI - Inhibition of Quorum Sensing Mediated Virulence Factors Production in Urinary Pathogen Serratia marcescens PS1 by Marine Sponges. AB - The focal intent of this study was to find out an alternative strategy for the antibiotic usage against bacterial infections. The quorum sensing inhibitory (QSI) activity of marine sponges collected from Palk Bay, India was evaluated against acyl homoserine lactone (AHL) mediated violacein production in Chromobacterium violaceum (ATCC 12472), CV026 and virulence gene expressions in clinical isolate Serratia marcescens PS1. Out of 29 marine sponges tested, the methanol extracts of Aphrocallistes bocagei (TS 8), Haliclona (Gellius) megastoma (TS 25) and Clathria atrasanguinea (TS 27) inhibited the AHL mediated violacein production in C. violaceum (ATCC 12472) and CV026. Further, these sponge extracts inhibited the AHL dependent prodigiosin pigment, virulence enzymes such as protease, hemolysin production and biofilm formation in S. marcescens PS1. However, these sponge extracts were not inhibitory to bacterial growth, which reveals the fact that the QSI activity of these extracts was not related to static or killing effects on bacteria. Based on the obtained results, it is envisaged that the marine sponges could pave the way to prevent quorum sensing (QS) mediated bacterial infections. PMID- 23729877 TI - Characterisation of phosphate solubilising bacteria in sandy loam soil under chickpea cropping system. AB - With the aim to explore the possible role of phosphate-solubilizing bacteria (PSB) in phosphorus (P) cycling in agricultural soils, we isolated PSB inhabiting naturally in the sandy loam soils under chickpea cropping of Patiala (Punjab State). A total of 31 bacterial isolates showing solubilizing activities were isolated on Pikovskaya agar plates. The potent phosphate solubilizers were selected for further characterization. These isolates were shown to belong to the genera Pseudomonas and Serratia by partial sequencing analysis of their respective 16S rDNA genes. ERIC-PCR based fingerprinting was done for tracking the survival of introduced populations of the PSB during mass inoculation of these strains under chickpea plots. The results showed positive correlation (r(2) = 0.853) among soil phosphatase activity and phosphate solubilizers population, which was also positively correlated (r(2) = 0.730) to available phosphorus. Identification and characterization of soil PSB for the effective plant growth promotion broadens the spectrum of phosphate solubilizers available for field application. PMID- 23729878 TI - Occurrence of Plasmid-Mediated AmpC beta-Lactamases Among Escherichia coli and Klebsiella pneumoniae Clinical Isolates in a Tertiary Care Hospital in Bangalore. AB - Therapeutic options for infections caused by gram-negative organisms expressing plasmid-mediated AmpC beta-lactamases are limited because these organisms are usually resistant to all the beta-lactam antibiotics, except for cefepime, cefpirome and the carbapenems. These organisms are a major concern in nosocomial infections and should therefore be monitored in surveillance studies. Hence, this study was aimed out to determine the prevalence of plasmid-mediated AmpC beta lactamases in E. coli and K. pneumoniae from a tertiary care in Bangalore. A total of 63 E. coli and 27 K. pneumoniae were collected from a tertiary care hospital in Bangalore from February 2008 to July 2008. The isolates with decreased susceptibility to cefoxitin were subjected to confirmation test with three dimensional extract tests. Minimum inhibitory concentrations (MICs) were determined by agar dilution method. Conjugation experiments, plasmid profiling and susceptibility testing were carried out to investigate the underlying mechanism of resistance. In our study, 52 (57.7%) isolates showed resistance to cefoxitin, the occurrence of AmpC was found to be 7.7% of the total isolates. Plasmid analysis of the selected isolates showed the presence of a single plasmid of 26 kb in E. coli and 2 Kb in K. pneumoniae. Plasmid-mediated AmpC beta lactamases were found in 11.1% of K. pneumoniae and in 6.3% of E. coli. Curing and conjugation experiments showed that resistance to cephamycins and cephalosporins was plasmid-mediated. Our study has demonstrated the occurrence of plasmid-mediated AmpC in E. coli and K. pneumoniae which illustrates the importance of molecular surveillance in tracking AmpC-producing strains at general hospitals and emphasizes the need for epidemiological monitoring. PMID- 23729879 TI - Novel whole-cell Reporter Assay for Stress-Based Classification of Antibacterial Compounds Produced by Locally Isolated Bacillus spp. AB - Reporter bacteria are beneficial for the rapid and sensitive screening of cultures producing peptide antibiotics, which can be an addition or alternative to the established antibiotics. This study was carried out to validate the usability of specific reporter strains for the target mediated identification of antibiotics produced by native Bacillus spp. isolated from different food sources. During preliminary classification, cell wall stress causing Bacillus isolates were screened by using reporter strain Bacillus subtilis BSF2470. The isolates which induced cell wall stress were further characterized for their specific mode of action by using other B. subtilis reporter strains (TMB 488, TMB 299 and TMB 279). The isolate B. licheniformis N12 was found to produce bacitracin confirmed by the response to reporter strain B. subtilis TMB 279 and by putative identification of bacitracin biosynthetic loci. The other isolate B. subtilis EC1 also induced B. subtilis TMB 279, but does not possess the bacitracin gene cluster indicating that it can be a novel, bacitracin like antibiotic. The different but related subsets of peptide antibiotics that bind the pyrophosphate moiety of the lipid carrier of cell wall biosynthesis can be identified using this whole cell based reporter strains. PMID- 23729880 TI - Nutritional and toxicological assessment of white-rot fermented animal feed. AB - The fungal fermented wheat straws as animal feeds have been evaluated for its toxicological and nutritional status in male rats (Holtzman strain). Digestibility of dry matter and other nutrients as well as fiber fractions were found significantly higher (P < 0.05) in straw fermented with either Ganoderma sp. rckk02 (T3) or Crinipellis sp. RCK-1 (T4) than unfermented straw (T1) or straw fermented with Pycnoporus cinnabarinus (T2). The aflatoxin B1, B2, G1 and G2 were either absent or present in permissive levels in T3 and T4 diets and exhibited normal stress enzyme activity in case of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) enzymes whereas, rats fed on T2 diet showed elevated levels of stress enzymes (ALT, AST and LDH activity), 100% high morbidity and 8.3% mortality. This study suggests that Ganoderma sp. rckk02 and Crinipellis sp. RCK-1 are efficient in improving the nutritive value of poor quality straw and do not posses any threat for their subsequent use as ruminant feed. PMID- 23729881 TI - Highly Expressed Recombinant SEB for Antibody Production and Development of Immunodetection System. AB - Staphylococcal enterotoxins (SEs) are the second most common causal agents of food poisoning throughout the world. Staphylococcal enterotoxin B (SEB) is one of the most potent and a listed biological warfare agent. Therefore, its quick, accurate and sensitive detection is of paramount importance. But availability of sensitive and specific antibodies against SEB is the major bottleneck in the development of an immunodetection system. Therefore, in the present study seb gene was cloned and expressed in a heterologous host resulting in a yield of 92 mg pure toxin per litre of culture broth after Ni-NTA affinity purification. Antibodies raised against the recombinant toxin did not cross react with related enterotoxins and organisms that can gain access in the food. Further, a sandwich ELISA was developed to detect SEB after extraction from artificially spiked food samples like milk, orange juice, skim milk and khoya. The sandwich ELISA was able to detect SEB in the range of 0.25 to 0.49 ng/ml or g of food. The detection system developed in the present study is at least as specific and sensitive as other commercially available kits which use monoclonal antibodies. PMID- 23729882 TI - Transformation of pWWO in Rhizobium leguminosarum DPT to Engineer Toluene Degrading Ability for Rhizoremediation. AB - Rhizoremediation of organic xenobiotics is based on interactions between plants and their associated micro-organisms. The present work was designed to engineer a bacterial system having toluene degradation ability along with plant growth promoting characteristics for effective rhizoremediation. pWWO harboring the genes responsible for toluene breakdown was isolated from Pseudomonas putida MTCC 979 and successfully transformed in Rhizobium DPT. This resulted in a bacterial strain (DPT(T)) which had the ability to degrade toluene as well as enhance growth of host plant. The frequency of transformation was recorded 5.7 * 10(-6). DPT produced IAA, siderophore, chitinase, HCN, ACC deaminase, solubilized inorganic phosphate, fixed atmospheric nitrogen and inhibited the growth of Fusarium oxysporum and Macrophomina phaseolina in vitro. During pot assay, 50 ppm toluene in soil was found to inhibit the germination of Cajanus cajan seeds. However when the seeds bacterized with toluene degrading P. putida or R. leguminosarum DPT were sown in pots, again no germination was observed. Non bacterized as well as bacterized seeds germinated successfully in toluene free soil as control. The results forced for an alternative mode of application of bacteria for rhizoremediation purpose. Hence bacterial suspension was mixed with soil having 50 ppm of toluene. Germination index in DPT treated soil was 100% while in P. putida it was 50%. Untreated soil with toluene restricted the seeds to germinate. PMID- 23729883 TI - Bacterial spectrum and antimicrobial susceptibility pattern of bloodstream infections in children with febrile neutropenia: experience of single center in southeast of Turkey. AB - Empirical antimicrobial therapy is usually started in febrile neutropenic patients without having culture results. The aim of this study was to help determine the policies of empirical antibiotic usage in febrile neutropenic children by detecting the antimicrobial susceptibility profile in this group of patients. In this study 811 blood cultures taken from neutropenic children hospitalized at the Department of Oncology of Gaziantep Children Hospital November 2007 and February 2010 were retrospectively evaluated. Blood cultures were routinely collected in aerobic and anaerobic media and incubated using the BACTEC system. Identification and antimicrobial susceptibility testing of the isolates to antimicrobial agents was performed using the Vitek2((r)) system according to the recommendations of the Clinical and Laboratory Standards Institute. Of 811 isolates analyzed, 128 (56.4%) were gram positive cocci, 43 (18.9%) were gram negative bacilli and fungi accounted for 56 (24.7%). The main isolated Gram-positive bacteria from blood were coagulase-negative staphylococcus (56.7%), followed by methicillin-resistant Staphylococcus aureus (14.1%). S. aureus and Streptococcus spp. were all susceptible to linezolid, vancomycin and teicoplanin. S aureus was still susceptible to few other antimicrobial agents such as tetracycline (82.4%), chloramphenicol (55.6%). Seven E. faecium, 7 E. fecalis and 1 E. hirae was isolated from blood cultures. Vancomycin resistance was detected in 6 out of 15 (40%) Enterococcus spp. isolates. Among gram-negative bacteria E. coli (30.2%) was followed by Klebsiella pneumoniae (20.9%) and Proteus spp. (18.6%). Imipenem (89.2%), meropenem (86.6%), chloramphenicol (88.9%), amicasin (82.4%) and fosfomycin (81.3%) showed highest susceptibility in vitro activity against all Gram-negative isolates. To know the antimicrobial susceptibility profile of the pathogens frequently isolated from febrile neutropenic children and to consider this profile before starting an empirical antibiotic therapy would help the clinics which have any role in the treatment of these patients to determine the empirical antibiotic usage policies. PMID- 23729884 TI - Homologous Recombination is Activated at Early Time Points Following Exposure to Cobalt Chloride Induced Hypoxic Conditions in Saccharomyces cerevisiae. AB - DNA repair functions are essential for the maintenance of genetic integrity and are regulated in response to both environmental and chemical stressors in mammalian and yeast cells in culture. The inhibitory effect of limited O2 availability on DNA repair functions in general and on homologous recombination (HR) in particular, correlates with increased chromosomal abnormalities in hypoxic cancer cells. Given the above, we have investigated the effects of CoCl2, -a hypoxia mimetic agent on HR and genetic aberrations in Saccharomyces cerevisiae. Our studies demonstrate that both acute and chronic exposure to CoCl2 activated HR and increased genetic aberrations in S. cerevisiae D7 cells. At early time points following addition of CoCl2 to the growth media, cells were briefly arrested in the G1-S boundary concomitant with a transient increase in Rad52-GFP foci formation and induction of low levels of DNA damage. The mode of action of CoCl2 is thus similar to that of DNA synthesis inhibitors, the later are known to induce HR and cause G1-S arrest. We propose that the activation of HR in the presence of the hypoxia mimetic agent may be attributed to the replication stress and/or DNA damage induced by the stressor. PMID- 23729885 TI - Effect of Extracellular Factors on Growth and Dimorphism of Rhizopus oryzae with Multiple Enzyme Synthesizing Ability. AB - Rhizopus oryzae PR7 MTCC 9642 was a dimorphic fungus that showed a regular 90 days cycle of filament (mycelium) to pellet (yeast) transformation through a distinct bottom dwelling intermediate state and the pellets never revert back to filamentous form. Apart from the normal cycle, high temperature (37 degrees C and above) and extreme pH also induced the yeast formation. Among the ions tested, calcium and chloride ions were found to restore the filamentous morphology, even in extreme pH and temperature. Cysteine HCl also played noteworthy role in maintaining mycelial growth even at adverse condition. Immobilized spores showed the appearance of intermediate form instead of typical yeast form even at high temperature. The strain could produce a number of extracellular hydrolytic enzymes like cellulolytic, xylanolytic, pectinolytic and amylolytic enzymes. The pellet and mycelial forms were found to be a better producer of cellulase lignocellulase enzymes and amylolytic enzymes respectively, which might be correlated with their infectivity. Increase in inoculum size, agitation during cultivation, change in carbon and nitrogen source failed to induce mycelial growth in extreme conditions, which might be explained as irreversible change of configuration of protein responsible for mycelial development. PMID- 23729886 TI - Application of Thermostable Xylanase of Bacillus pumilus in Textile Processing. AB - Desizing of cotton and micropoly fabrics was done using thermostable xylanase from Bacillus pumilus ASH. Micropoly fabric showed better desizing than cotton under same conditions. Violet scale readings from the TEGEWA test after enzymatic desizing for 90 min at pH 7.0 and at 60 degrees C showed the readings falling in the range of 4-5, indicating good desizing efficiency. During bioscouring the weight loss values and liberation of reducing sugars were highest when EDTA was used along with xylanase. The weight loss value of 1.5% was observed for dry cotton fabric after 1 h in case of agitated system at pH 7.0 and at an optimal enzyme dosage of 5 IU/g. The weight loss values and the liberation of reducing sugars were higher in case of cotton fabrics. Wetting time of fabrics was lowered significantly after 60 min of bioscouring using xylanase. Increase in temperature or concentration of surfactant led to further reduction in the wetting time. The whiteness values of fabrics after bioscouring were 0.9% higher than the chemically scoured fabrics indicating good efficacy of xylanase during the scouring process. PMID- 23729887 TI - Optimization of Antimicrobial Production by a Marine Actinomycete Streptomyces afghaniensis VPTS3-1 Isolated from Palk Strait, East Coast of India. AB - Totally 25 marine soil samples were collected from the region of Palk Strait of Bay of Bengal, Tamil Nadu, and were subjected to the isolation of actinomycetes. Sixty-eight morphologically distinct isolates were obtained and 37% (25) of them had antimicrobial activity. The potential producer was named as Streptomyces sp. VPTS3-1 and the phylogenetic evaluation on the basis of 16S rDNA sequence further categorized the organism as Streptomyces afghaniensis VPTS3-1. Further, the antimicrobial compound was extracted from the isolate using various solvents and the antimicrobial efficacies were tested against bacterial and fungal pathogens. In addition, in vitro optimization of parameters for the antimicrobial compound production revealed that the suitable pH as 7-8, the period of incubation as 9 days, temperature (30 degrees C), salinity (2%), and starch and KNO3 as the suitable carbon and nitrogen sources respectively in starch-casein medium. PMID- 23729888 TI - Production, Purification of Exo-Polygalacturonase from Soil Isolate Paecilomyces variotii NFCCI 1769 and Its Application. AB - The aim of the present study was to produce exo-polygalacturonase from potent soil isolate by submerged fermentation and its application for fruit juice treatment. Pectinase producing strains were selectively isolated from pectin industry waste. A selected isolate C2 was found to produce significant amount of exo-polygalacturonase. The isolate was identified as Paecilomyces variotii on the basis of morphological characteristics and 18S rRNA gene sequence analysis. The exo-polygalacturonase produced by the isolate was purified by ammonium sulphate precipitation, size exclusion chromatography and ion exchange chromatography. The purified enzyme had MW of 39.4 kD based on SDS PAGE. Under partially optimized conditions, purified exo-polygalacturonase showed specific activity of 98.49 U/mg protein at pH 6.0 and 30 degrees C. The enzyme was comparatively stable from 10 to 30 degrees C and the activity decreased with increasing temperature. Purified enzyme brought about considerable reduction in viscosity of fruit juice samples. PMID- 23729889 TI - Screening diverse fungi for laccases of varying properties. AB - Qualitative screening of 295 fungi for laccases yielded 125 laccase positive ones, mostly basidiomycetes. Fifty of these were tested for laccase activity at pH 3.0, 4.5 and 6.0. Most showed maximum activity at pH 4.5, a few showed a broad activity range, two were optimal at pH 3.0 and only the mitosporic fungus Beltraniella sp. was best at pH 6. Most of the 25 fungi assayed at three different temperatures had an optimum at 45 degrees C. The basidiomycete Auricularia sp. acted best at 30 degrees C, while three others showed best activity at 60 degrees C. This study shows the potential of screening diverse fungi for laccase with varying pH and temperature preferences for different applications. PMID- 23729890 TI - Prebiotic Activity of Purified Xylobiose Obtained from Ragi (Eleusine coracana, Indaf-15) Bran. AB - The role of prebiotics in improving human health has attracted global attention and the research is mostly focused on the strains belonging to the genera Bifidobacterium and Lactobacillus. Non-digestible oligosaccharides hold significant role in recent research due to their prebiotic nature. Soluble polysaccharides (SP, 14.4%), isolated from ragi bran consisted mainly of arabinose and xylose with minor quantities of rhamnose, mannose, galactose and glucose. Ragi bran SP subjected to purified endoxylanase (from 96 h ragi malt) treatment to obtain xylo-oligosaccharides which were further purified on Biogel P 2 followed by HPLC. The purified oligosaccharide yielded (RO-1; 17.9%) was identified as xylobiose by electrospray ionization mass spectrometry (282 + 23 = 305) and (1)HNMR. In vitro studies carried out using Bifidobacterium and Lactobacillus sp. proved the prebiotic nature of the crude xylo-oligosaccharides (XOs) and RO-1. Acetate was found to be the chief short chain fatty acid released during fermentation of both crude XOs and purified xylobiose and 24 h bacterial culture showed high xylanase activity (1020-1690 MUU min(-1)). PMID- 23729891 TI - Simultaneous Cellulase Production, Saccharification and Detoxification Using Dilute Acid Hydrolysate of S. spontaneum with Trichoderma reesei NCIM 992 and Aspergillus niger. AB - Bioethanol production from lignocellulosic materials has several limitations. One aspect is the high production cost of cellulases used for saccharification of substrate and inhibition of fermenting yeast due to inhibitors released in acid hydrolysis. In the present work we have made an attempt to achieve simultaneous cellulases production, saccharification and detoxification using dilute acid hydrolysate of Saccharum spontaneum with and without addition of nutrients, supplemented with acid hydrolyzed biomass prior to inoculation in one set and after 3 days of inoculation in another set. Organisms used were T. reesei NCIM 992, and Aspergillus niger isolated in our laboratory. Cellulase yield obtained was 0.8 IU/ml on fourth day with T. reesei. Sugars were found to increase from fourth to fifth day, when hydrolysate was supplemented with nutrients and acid hydrolyzed biomass followed by inoculation with T. reesei. Phenolics were also found to decrease by 67%. PMID- 23729892 TI - Computational Modeling Deduced Three Dimensional Structure of Cry1Ab16 Toxin from Bacillus thuringiensis AC11. AB - The first theoretical structural model of newly reported Cry1Ab16 delta-endotoxin produced by Bacillus thuringiensis AC11 was predicted using homology modeling technique. Cry1Ab16 resembles the Cry1Aa protein structure by sharing a common three domains structure responsible in pore forming and specificity determination along with few structural deviations. The main differences between the two is in the length of loops, absence of alpha7b, alpha9a, alpha10b, alpha11a and presence of additional beta12b, alpha13 components while alpha10a is spatially located at downstream position in Cry1Ab16. A better understanding of the 3D structure shall be helpful in the design of domain swapping and mutagenesis experiments aimed at improving toxicity. PMID- 23729893 TI - Profile of dermatophytic and other fungal infections in jaipur. AB - The common cause of skin infections are dermatophytes and opportunistic fungi. Aim of present study is to find predominant etiological agent of dermatophytoses and to isolate various fungal agents from clinical samples of patients with different mycoses and Clinical samples from 260 patients were subjected to potassium hydroxide (KOH) examination and culture isolation; causative agents were identified macroscopically and microscopically. One hundred sixty three (62.7%) were found to be positive by KOH examination while 132 (50.8%) were culture positive. Dermatophytes were isolated in 90/140 (64.3%) specimens. Trichophyton rubrum (75.5%) was the commonest isolate among the patients suffering from dermatophytoses. Candida spp. and Malassezia furfur were isolated from patient suffering from candidiasis and pityriasis versicolor. PMID- 23729894 TI - Effect of fungicides and insecticides on growth and enzyme activity of four cyanobacteria. AB - Cyanobacterial populations introduced into crop fields as biofertilizer become non-target organisms for the pesticides and fungicides applied in the field. Effect of four commonly used pesticides viz. Bagalol, Mancozeb (fungicides), Thiodan and Phorate (insecticides) was studied on growth and different enzymes of four cyanobacterial species viz. Nostoc ellipsosporum, Scytonema simplex, Tolypothrix tenuis, and Westiellopsis prolifica. EC 50 concentration of each pesticide was determined for all cyanobacteria. Bagalol and Thiodan were found to be the most toxic. Both the fungicides and insecticides inhibited the activity of nitrogenase and glutamine synthetase (GS) at EC 50 concentration in all the four species studied. Bagalol incurred maximum inhibition of nitrogenase and GS activity on N. ellipsosporum and S. simplex while Thiodan and Phorate had maximum effect on T. tenuis, and W. prolifica. Mancozeb had lesser effect on all the above enzymes. One catabolic enzyme of carbohydrate metabolism, isocitrate dehydrogenase (ICDH) and one anabolic enzyme isocitrate lyase (ICL), which is related to glyoxylate pathway as well as gluconeogenesis, were also assayed. Cell free extracts of cyanobacteria treated with pesticides for 7 days show a drastic reduction of ICDH activity. ICL activity was induced in the organisms when treated with pesticides. PMID- 23729895 TI - Effect of arbuscular mycorrhizal inoculations on seedling growth and biomass productivity of two bamboo species. AB - A study was conducted to identify suitable arbuscular mycorrhizal (AM) fungi for inoculation of Bambusa bambos and Dendrocalamus strictus at nursery stage for increasing growth and productivity. Twelve AM species, isolated from bamboo and other common trees of Bundelkhand were used for inoculations. In B. bambos, total dry weight and phosphorus (P) uptake were significantly increased by all studied fungi and shoot length was increased by eight AM inoculants. Maximum mycorrhizal dependency (MD) was recorded for Acaulospora scrobiculata (44.2%), followed by Glomus cerebriforme (41.6%) and G. intraradix (41.0%). In D. strictus, all tested AM inoculants significantly increased shoot length, dry shoot weight and P uptake, except Glomus 1. Dry root weight was significantly increased by only two inoculants namely, G. cerebriforme and G. etunicatum. Total dry weight was significantly increased by eight AM fungi. Maximum MD was recorded for G. cerebriforme (62.9%), followed by G. diaphanum (55.0%) and G. etunicatum (51.3%). Thus, the results showed that utilization of effective AM fungi can enhance the productivity of bamboo in the region. PMID- 23729896 TI - Analysis of Bacterial Community in the Ginseng Soil Using Denaturing Gradient Gel Electrophoresis (DGGE). AB - The objective of this work was to determine the shifts in the PCR-DGGE profiles of bacterial communities associated with the rhizosphere soil of ginseng at varying age levels. Differences in the dominance of intense DNA bands in the DGGE profile was observed over the age of the plants indicating the fluctuation in the microbial community structure. The bacterial orders of actinomycetales of Actinobacteria and Spingomonadales and Rhizobiales of alpha-Proteobacteria were predominant in the ginseng soil. PMID- 23729897 TI - Detection of Mycobacterium bovis and Mycobacterium tuberculosis from Cattle: Possible Public Health Relevance. AB - Mycobacterium bovis and Mycobacterium tuberculosis infect both animals and humans. The disease epidemiology by these agents differs in developed and developing countries due to the differences in the implementation of the prevention and control strategies. The present study describes the detection of M. bovis and M. tuberculosis from specimens of lungs and pulmonary lymph nodes of four cattle died in an organized herd of 183 cattle in the state of Himachal Pradesh, India, with inconclusive skin test results. Identification and distinction of these closely related mycobacterial species was done by PCR-RFLP targeting hsp65 gene followed by spacer oligonucleotide typing. Mixed infection of M. bovis and M. tuberculosis was detected in one cattle. PMID- 23729898 TI - Biotransformation of alpha-Pinene to Terpineol by Resting Cell Suspension of Absidia corulea. AB - Microbial biotransformation of monoterpenes results in the formation of many valuable compounds. Many microorganisms can be used to carry out extremely specific conversions using substrates of low commercial value. Absidia corulea MTCC 1335 was examined for its ability to transform alpha-Pinene enantiomers. The substrates (-)-alpha-Pinene and (+)-alpha-Pinene converted to alpha-terpineol and isoterpineol, were detected in gas chromatographic analysis. The Biotransformation kinetics of the oxidized products were analysed using GC-MS. With both the substrates the products formed were similar and not much difference in the rate of transformation was observed, suggesting no enantioselectivity of organism towards the substrate. PMID- 23729899 TI - Influence of Inoculation with the Endomycorrhizal Fungi and Trichoderma viride on Morphological and Physiological Growth Parameters of Rauwolfia serpentina Benth. Ex. Kurtz. AB - Two arbuscular mycorrhizal fungi, Glomus mosseae and Acaulospora laevis either alone or in combination with Trichoderma viride showed the dependence of Rauwolfia serpentina on endomycorrhizal fungi. After 60 days, G. mosseae singly or in combination with Trichoderma viride showed enhanced height increment compared to control plants. Maximum phosphorus content was shown by plants treated with G. mosseae plus T. viride (0.444 +/- 2.62) in roots and (0.437 +/- 4.71) in shoots. Phosphorus content in roots was more than that in shoots. Chlorophyll content and stomatal conductivity also showed similar trend. PMID- 23729900 TI - Bioremediation of organometallic compounds by bacterial degradation. AB - The use of organometallic compounds in the environment is constantly increasing with increased technology and progress in scientific research. But since these compounds are fairly stable, as metallic bonds are stable, they are difficult to degrade or decompose naturally. The aim of this work was to isolate and characterize heterotrophic bacteria that can degrade organometallic compounds (in this case 'ferrocene' and its derivatives). A Gram-negative coccobacillus was isolated from a rusting iron pipe draining into a freshwater lake, which could utilize ferrocene as a sole source of carbon. Phylogenetic analysis based on 16S rDNA sequence suggested that the isolated organism resembled an environmental isolate of Bordetella. Ferrocene degradation was confirmed by plotting the growth curve of the bacterium in a medium with ferrocene as the sole source of carbon. Further confirmation of degradation of ferrocene and its derivatives was done using Gas Chromatography Mass Spectroscopy. Since the bacterium degraded organometallic compounds and released the metal in liquid medium, it could be suggested that this organism can also be used for extracting metal ions from organo-metal containing wastes. PMID- 23729901 TI - Quality indicators of scientific research. PMID- 23729902 TI - Consumption, Retirement and Social Security: Evaluating the Efficiency of Reform that Encourages Longer Careers. AB - This paper proposes and analyzes a Social Security reform in which individuals no longer face the OASI payroll tax after, say, age 54 or a career of 34 years, and their subsequent earnings have no bearing on their benefits. We first estimate parameters of a life-cycle model. Our specification includes non-separable preferences and possible disability. It predicts a consumption-expenditure change at retirement. We use the magnitude of the expenditure change, together with households' retirement-age decisions, to identify key structural parameters. The estimated magnitude of the change in consumption-expenditure depends importantly on the treatment of consumption by adult children of the household. Simulations indicate that the reform could increase retirement ages one year or more, equivalent variations could average more than $4,000 per household, and income tax revenues per household could increase by more than $14,000. PMID- 23729904 TI - Using a reduced dimensionality model to compute the thermodynamic properties of finite polypeptide aggregates. AB - By implementing a simple reduced dimensionality model to describe the interactions in finite systems composed of two seven-amino-acid peptides, the thermodynamic properties of ordered and disordered aggregates were computed. Within this model, the hydrophobicity of each amino acid was varied, and the stability of the systems computed. Accurate averages in the canonical ensemble were obtained using various replica exchange Monte Carlo algorithms. Low and high temperature regions were encountered where the ordered and disordered aggregates were stabilized. It was observed that as the degree of hydrophobicity increased, the stability of the aggregates increased, with a significant energetic stabilization obtained for the ordered aggregates. Upon decreasing the concentration of the solution, the stability of the amorphous aggregates increased when compared to the ordered systems. PMID- 23729905 TI - Effects of the binding of calcium ions on the structure and dynamics of the PhiX174 virus investigated using molecular dynamics. AB - It is known that the presence of calcium ions (Ca(2 + )) is necessary for the enterobacterial virus PhiX174 to inject its DNA into the host cell, and that some mutations in the major capsid proteins lead to better survivability at higher temperatures. Our goal in the current study is to determine the physical changes in both the wild-type and mutant virus due to the binding of Ca(2 + ). Thus, we performed molecular dynamics simulations of the PhiX174 major capsid protein complex with and without Ca(2 + ) bound. Our results show that binding of Ca(2 + ) leads to energetic and dynamical changes in the virus proteins. In particular, the results suggest that binding of Ca(2 + ) is energetically favorable and that the mutation leads to increased fluctuations of the protein complex (especially with the calcium ions bound to the complex), which may increase the rate of genome packaging and ejection for PhiX174. PMID- 23729903 TI - Plasmodium-Mosquito Interactions: A Tale of Roadblocks and Detours. PMID- 23729906 TI - First principles investigation of L-alanine in terahertz region. AB - Terahertz absorption spectrum (0.5-4.0 THz) of L-alanine in the solid phase was measured by terahertz time-domain spectroscopy at room temperature. Simulations utilizing gaseous-state and solid-state theory were performed to determine the origins of the observed vibrational features. Our calculations showed that the measured features in solid-state materials could be well understood by considering the crystal packing interactions in a solid-state density functional theory calculation. Furthermore, intermolecular vibrations of L-alanine are found to be the dominating contributions to these measured spectral features in the range of 0.5-4.0 THz, except that located at 3.11 THz. PMID- 23729907 TI - Coupled oscillations of a protein microtubule immersed in cytoplasm: an orthotropic elastic shell modeling. AB - Revealing vibration characteristics of sub-cellular structural components such as membranes and microtubules has a principal role in obtaining a deeper understanding of their biological functions. Nevertheless, limitations and challenges in biological experiments at this scale necessitates the use of mathematical and computational models as an alternative solution. As one of the three major cytoskeletal filaments, microtubules are highly anisotropic structures built from tubulin heterodimers. They are hollow cylindrical shells with a ~ 25 nm outer diameter and are tens of microns long. In this study, a mechanical model including the effects of the viscous cytosol and surrounding filaments is developed for predicting the coupled oscillations of a single microtubule immersed in cytoplasm. The first-order shear deformation shell theory for orthotropic materials is used to model the microtubule, whereas the motion of the cytosol is analyzed by considering the Stokes flow. The viscous cytosol and the microtubule are coupled through the continuity condition across the microtubule-cytosol interface. The stress and velocity fields in the cytosol induced by vibrating microtubule are analytically determined. Finally, the influences of the dynamic viscosity of the cytosol, filament network elasticity, microtubule shear modulus, and circumferential wave-number on longitudinal, radial, and torsional modes of microtubule vibration are elucidated. PMID- 23729908 TI - Modeling temperature entrainment of circadian clocks using the Arrhenius equation and a reconstructed model from Chlamydomonas reinhardtii. AB - Endogenous circadian rhythms allow living organisms to anticipate daily variations in their natural environment. Temperature regulation and entrainment mechanisms of circadian clocks are still poorly understood. To better understand the molecular basis of these processes, we built a mathematical model based on experimental data examining temperature regulation of the circadian RNA-binding protein CHLAMY1 from the unicellular green alga Chlamydomonas reinhardtii, simulating the effect of temperature on the rates by applying the Arrhenius equation. Using numerical simulations, we demonstrate that our model is temperature-compensated and can be entrained to temperature cycles of various length and amplitude. The range of periods that allow entrainment of the model depends on the shape of the temperature cycles and is larger for sinusoidal compared to rectangular temperature curves. We show that the response to temperature of protein (de)phosphorylation rates play a key role in facilitating temperature entrainment of the oscillator in Chlamydomonas reinhardtii. We systematically investigated the response of our model to single temperature pulses to explain experimentally observed phase response curves. PMID- 23729910 TI - Role of methyl groups in dynamics and evolution of biomolecules. AB - Recent studies have discovered strong differences between the dynamics of nucleic acids (RNA and DNA) and proteins, especially at low hydration and low temperatures. This difference is caused primarily by dynamics of methyl groups that are abundant in proteins, but are absent or very rare in RNA and DNA. In this paper, we present a hypothesis regarding the role of methyl groups as intrinsic plasticizers in proteins and their evolutionary selection to facilitate protein dynamics and activity. We demonstrate the profound effect methyl groups have on protein dynamics relative to nucleic acid dynamics, and note the apparent correlation of methyl group content in protein classes and their need for molecular flexibility. Moreover, we note the fastest methyl groups of some enzymes appear around dynamical centers such as hinges or active sites. Methyl groups are also of tremendous importance from a hydrophobicity/folding/entropy perspective. These significant roles, however, complement our hypothesis rather than preclude the recognition of methyl groups in the dynamics and evolution of biomolecules.Electronic supplementary material The online version of this article (doi:10.1007/s10867-012-9268-6) contains supplementary material, which is available to authorized users. PMID- 23729909 TI - A mathematical model of the tripartite synapse: astrocyte-induced synaptic plasticity. AB - In this paper, we present a biologically detailed mathematical model of tripartite synapses, where astrocytes modulate short-term synaptic plasticity. The model consists of a pre-synaptic bouton, a post-synaptic dendritic spine head, a synaptic cleft and a peri-synaptic astrocyte controlling Ca(2 + ) dynamics inside the synaptic bouton. This in turn controls glutamate release dynamics in the cleft. As a consequence of this, glutamate concentration in the cleft has been modeled, in which glutamate reuptake by astrocytes has also been incorporated. Finally, dendritic spine-head dynamics has been modeled. As an application, this model clearly shows synaptic potentiation in the hippocampal region, i.e., astrocyte Ca(2 + ) mediates synaptic plasticity, which is in conformity with the majority of the recent findings (Perea and Araque (Science 317, 1083-1086, 2007); Henneberger et al. (Nature 463, 232-236, 2010); Navarrete et al. (PLoS Biol. 10, e1001259, 2012)). PMID- 23729911 TI - On a drug-resistant malaria model with susceptible individuals without access to basic amenities. AB - In this paper, a deterministic malaria transmission model in the presence of a drug-resistant strain is investigated. The model is studied using stability theory of differential equations, optimal control, and computer simulation. The threshold condition for disease-free equilibrium is found to be locally asymptotically stable and can only be achieved in the absence of a drug-resistant strain in the population. The existence of multiple endemic equilibria is also established. Both the Sensitivity Index (SI) of the model parameters and the Incremental Cost-Effectiveness Ratio (ICER) for all possible combinations of the disease-control measures are determined. Our results revealed among others that the most cost-effective strategy for drug-resistant malaria control is the combination of the provision of basic amenities (such as access to clean water, electricity, good roads, health care, and education) and treatment of infective individuals. Therefore, more efforts from policy-makers on the provisions of basic amenities and treatment of infectives would go a long way to combat the malaria epidemic. PMID- 23729912 TI - DNA fragmentation by gamma radiation and electron beams using atomic force microscopy. AB - Double-stranded pBS plasmid DNA was irradiated with gamma rays at doses ranging from 1 to 12 kGy and electron beams from 1 to 10 kGy. Fragment-size distributions were determined by direct visualization, using atomic force microscopy with nanometer-resolution operating in non-tapping mode, combined with an improved methodology. The fragment distributions from irradiation with gamma rays revealed discrete-like patterns at all doses, suggesting that these patterns are modulated by the base pair composition of the plasmid. Irradiation with electron beams, at very high dose rates, generated continuous distributions of highly shattered DNA fragments, similar to results at much lower dose rates found in the literature. Altogether, these results indicate that AFM could supplement traditional methods for high-resolution measurements of radiation damage to DNA, while providing new and relevant information. PMID- 23729913 TI - The Impact of Elections on Cooperation: Evidence from a Lab-in-the-Field Experiment in Uganda. AB - Communities often rely on sanctioning to induce public goods contributions. Past studies focus on how external agencies or peer sanctioning induce cooperation. In this article, we focus instead on the role played by centralized authorities, internal to the community. Combining "lab-in-the-field" experiments with observational data on 1,541 Ugandan farmers from 50 communities, we demonstrate the positive effect of internal centralized sanctioning authorities on cooperative behavior. We also show that the size of this effect depends on the political process by which authority is granted: subjects electing leaders contribute more to public goods than subjects who were assigned leaders through a lottery. To test the ecological validity of our findings, we relate farmers' behavior in the experiment to their level of cooperation in their community organization. We show that deference to authority in the controlled setting predicts cooperative behavior in the farmers' natural environment, in which they face a similar social dilemma. PMID- 23729915 TI - Care robots for the supermarket shelf: a product gap in assistive technologies. AB - The literature on the development of assistive robots is dominated by technological papers with little consideration of how such devices might be commercialised for a mass market at a price that is affordable for older people and their families as well as public services and care insurers. This article argues that the focus of technical development in this field is too ambitious, neglecting the potential market for an affordable device that is aleady in the realm of the 'adjacent possible' given current technology capabilities. It also questions on both ethical and marketing grounds the current effort to develop assistive robots with pet-like or human-like features. The marketing literature on 'really new products' has so far not appeared to inform the development of assistive robots but has some important lessons. These include using analogies with existing products and giving particular attention to the role of early adopters. Relevant analogies for care robots are not animals or humans but useful domestic appliances and personal technologies with attractive designs, engaging functionality and intuitive usability. This points to a strategy for enabling mass adoption - which has so far eluded even conventional telecare - of emphasising how such an appliance is part of older people's contemporary lifestyles rather than a sign of age-related decline and loss of independence. PMID- 23729916 TI - Rumination Mediates the Relationship Between Distress Tolerance and Depressive Symptoms Among Substance Users. AB - Distress tolerance has been implicated in the emergence of internalizing symptomatology, notably depressive symptoms. However, few studies have tested potential mechanisms underlying the relationship between distress tolerance and depressive symptoms, and further, this has not been tested among substance users, who commonly experience both low distress tolerance and elevated depressive symptoms. The current study focused on the construct of rumination, which has been suggested to be a coping response to stress associated with substance use and depression. Two forms of rumination, brooding and reflection, were tested as potential mediators of the relationship between distress tolerance and self reported depressive symptoms among 128 individuals entering substance abuse treatment. Brooding (i.e., to overly focus on symptoms of distress) mediated the relationship between distress tolerance and depressive symptoms. However, reflection (i.e., to attempt to gain insight into problems) was unrelated to distress tolerance. Findings suggest the important role of brooding as a mechanism underlying the relationship between distress tolerance and depressive symptomatology. PMID- 23729917 TI - Head Start, Pre-Kindergarten, and Academic School Readiness: A Comparison Among Regions in the U.S. AB - Child care programs (including Head Start, pre-Kindergarten [pre-K], and other center-based care) can differ, with patterns of use based on their location. Yet little research has examined how Head Start and pre-K programs affect children's academic school readiness, including vocabulary and reading skills at school entry, in the South as compared to other regions. To examine this further, secondary data (n = 2,803) collected in the Fragile Families and Child Wellbeing Study were examined. Overall findings suggest, regardless of region, that Head Start and pre-K participants had higher academic skills at school entry than their counterparts. In addition, when Head Start was compared to other center based care and pre-K was compared to other care arrangements, both had larger effects on improving academic skills in the South than in other regions. These findings imply that Head Start and pre-K programs should target children who otherwise would receive non-parental non-center-based care. Future research should focus on why the effects of Head Start and pre-K vary between the South and other regions. PMID- 23729918 TI - Organization and structure for sleep medicine programs at academic institutions: Part 1--current challenges. PMID- 23729919 TI - Organization and structure for sleep medicine programs at academic institutions: Part 2--goals and strategies to optimize patient care, education, and discovery. PMID- 23729920 TI - Sleep restriction in adolescents: forging the path towards obesity and diabetes? PMID- 23729921 TI - Two independent sources of short term memory problems during sleep deprivation. PMID- 23729922 TI - Reflex tachycardia with airway opening in obstructive sleep apnea. PMID- 23729923 TI - Overnight sleep loss and "executive" decision making-subtle findings. PMID- 23729924 TI - The spindles: are they still thalamic? PMID- 23729925 TI - Dietary intake following experimentally restricted sleep in adolescents. AB - STUDY OBJECTIVE: To examine the relationship between sleep and dietary intake in adolescents using an experimental sleep restriction protocol. DESIGN: Randomized crossover sleep restriction-extension paradigm. SETTING: Sleep obtained and monitored at home, diet measured during an office visit. PARTICIPANTS: Forty-one typically developing adolescents age 14-16 years. INTERVENTIONS: The 3-week protocol consisting of a baseline week designed to stabilize the circadian rhythm, followed randomly by 5 consecutive nights of sleep restriction (6.5 hours in bed Monday-Friday) versus healthy sleep duration (10 hours in bed), a 2-night washout period, and a 5-night crossover period. MEASUREMENTS: Sleep was monitored via actigraphy and teens completed validated 24-hour diet recall interviews following each experimental condition. RESULTS: Paired-sample t-tests examined differences between conditions for consumption of key macronutrients and choices from dietary categories. Compared with the healthy sleep condition, sleep restricted adolescents' diets were characterized by higher glycemic index and glycemic load and a trend toward more calories and carbohydrates, with no differences in fat or protein consumption. Exploratory analyses revealed the consumption of significantly more desserts and sweets during sleep restriction than healthy sleep. CONCLUSIONS: Chronic sleep restriction during adolescence appears to cause increased consumption of foods with a high glycemic index, particularly desserts/sweets. The chronic sleep restriction common in adolescence may cause changes in dietary behaviors that increase risk of obesity and associated morbidity. PMID- 23729926 TI - Comorbidity and mortality of narcolepsy: a controlled retro- and prospective national study. AB - STUDY OBJECTIVES: To identify the factual morbidity and mortality of narcolepsy in a controlled design. SETTING: National Patient Registry. PATIENTS: All national diagnosed patients (757) with health information at least 3 years prior to and after diagnose of narcolepsy. CONTROLS: Randomly selected four citizens (3,013) matched for age, sex, and socioeconomic status from the Danish Civil Registration System Statistics. RESULTS: Increased morbidity prior to narcolepsy diagnosis included (odds ratio, 95% confidence interval):- diseases of the endocrine, nutritional, and metabolic systems (2.10, 1.32-3.33); nervous system (5.27, 3.65-7.60); musculoskeletal system (1.59, 1.23-2.05); and other abnormal symptoms and laboratory findings (1.66, 1.25-2.22). After the diagnosis, narcolepsy patients experienced diseases of the endocrine, nutritional, and metabolic (2.31, 1.51-3.54), nervous (9.19, 6.80-12.41), musculoskeletal (1.70, 1.28-2.26), eye (1.67, 1.03-2.71), and respiratory systems (1.84, 1.21-2.81). Specific diagnoses were diabetes (2.4, 1,2-4.7, P < 0.01), obesity (13.4, 3.1 57.6, P < 0.001), sleep apnea (19.2, 7.7-48.3, P < 0.001), other sleep disorders (78.5, 11.8-523.3, P < 0.001), chronic obstructive pulmonary disease (2.8, 1.4 5.8, P < 0.01), lower back pain (2.5, 1.4-4.2, P < 0.001), arthrosis/arthritis (2.5, 1.3-4.8, P < 0.01), observation of neurological diseases (3.5, 1.9-6.5, P < 0.001), observation of other diseases (1.7, 1.2-2.5, P < 0.01), and rehabilitation (5.0, 1.5-16.5, P < 0.005). There was a trend towards greater mortality in narcolepsy (P = 0.07). CONCLUSIONS: Patients with narcolepsy present higher morbidity several years prior to diagnose and even higher thereafter. The mortality rate due to narcolepsy was slightly but not significantly higher. PMID- 23729927 TI - Adenotonsillectomy in obese children with obstructive sleep apnea syndrome: magnetic resonance imaging findings and considerations. AB - OBJECTIVE: The reasons why adenotonsillectomy (AT) is less effective treating obese children with obstructive sleep apnea syndrome (OSAS) are not understood. Thus, the aim of the study was to evaluate how anatomical factors contributing to airway obstruction are affected by AT in these children. METHODS: Twenty-seven obese children with OSAS (age 13.0 +/- 2.3 y, body mass index Z-score 2.5 +/- 0.3) underwent polysomnography and magnetic resonance imaging of the head during wakefulness before and after AT. Volumetric analysis of the upper airway and surrounding tissues was performed using commercial software (AMIRA(r)). RESULTS: Patients were followed for 6.1 +/- 3.6 mo after AT. AT improved mean obstructive apnea-hypopnea index (AHI) from 23.7 +/- 21.4 to 5.6 +/- 8.7 (P < 0.001). Resolution of OSAS was noted in 44% (12 of 27), but only in 22% (4 of 18) of those with severe OSAS (AHI > 10). AT increased the volume of the nasopharynx and oropharynx (2.9 +/- 1.3 versus 4.4 +/- 0.9 cm(3), P < 0.001, and 3.2 +/- 1.2 versus 4.3 +/- 2.0 cm(3), P < 0.01, respectively), reduced tonsils (11.3 +/- 4.3 versus 1.3 +/- 1.4 cm(3), P < 0.001), but had no effect on the adenoid, lingual tonsil, or retropharyngeal nodes. A small significant increase in the volume of the soft palate and tongue was also noted (7.3 +/- 2.5 versus 8.0 +/- 1.9 cm(3), P = 0.02, and 88.2 +/- 18.3 versus 89.3 +/- 24.4 cm(3), P = 0.005, respectively). CONCLUSIONS: This is the first report to quantify volumetric changes in the upper airway in obese children with OSAS after adenotonsillectomy showing significant residual adenoid tissue and an increase in the volume of the tongue and soft palate. These findings could explain the low success rate of AT reported in obese children with OSAS and are important considerations for clinicians treating these children. PMID- 23729928 TI - Sleep deprivation accelerates delay-related loss of visual short-term memories without affecting precision. AB - STUDY OBJECTIVES: Visual short-term memory (VSTM) is an important measure of information processing capacity and supports many higher-order cognitive processes. We examined how sleep deprivation (SD) and maintenance duration interact to influence the number and precision of items in VSTM using an experimental design that limits the contribution of lapses at encoding. DESIGN: For each trial, participants attempted to maintain the location and color of three stimuli over a delay. After a retention interval of either 1 or 10 seconds, participants reported the color of the item at the cued location by selecting it on a color wheel. The probability of reporting the probed item, the precision of report, and the probability of reporting a nonprobed item were determined using a mixture-modeling analysis. Participants were studied twice in counterbalanced order, once after a night of normal sleep and once following a night of sleep deprivation. SETTING: Sleep laboratory. PARTICIPANTS: Nineteen healthy college age volunteers (seven females) with regular sleep patterns. INTERVENTIONS: Approximately 24 hours of total SD. MEASUREMENTS AND RESULTS: SD selectively reduced the number of integrated representations that can be retrieved after a delay, while leaving the precision of object information in the stored representations intact. Delay interacted with SD to lower the rate of successful recall. CONCLUSIONS: Visual short-term memory is compromised during sleep deprivation, an effect compounded by delay. However, when memories are retrieved, they tend to be intact. PMID- 23729929 TI - Extended remediation of sleep deprived-induced working memory deficits using fMRI guided transcranial magnetic stimulation. AB - STUDY OBJECTIVES: We attempted to prevent the development of working memory (WM) impairments caused by sleep deprivation using fMRI-guided repetitive transcranial magnetic stimulation (rTMS). Novel aspects of our fMRI-guided rTMS paradigm included the use of sophisticated covariance methods to identify functional networks in imaging data, and the use of fMRI-targeted rTMS concurrent with task performance to modulate plasticity effects over a longer term. DESIGN: Between groups mixed model. SETTING: TMS, MRI, and sleep laboratory study. PARTICIPANTS: 27 subjects (13 receiving Active rTMS, and 14 Sham) completed the sleep deprivation protocol, with another 21 (10 Active, 11 Sham) non-sleep deprived subjects run in a second experiment. INTERVENTIONS: Our previous covariance analysis had identified a network, including occipital cortex, which demonstrated individual differences in resilience to the deleterious effects of sleep deprivation on WM performance. Five Hz rTMS was applied to left lateral occipital cortex while subjects performed a WM task during 4 sessions over the course of 2 days of total sleep deprivation. MEASUREMENTS AND RESULTS: At the end of the sleep deprivation period, Sham sleep deprived subjects exhibited degraded performance in the WM task. In contrast, those receiving Active rTMS did not show the slowing and lapsing typical in sleep deprivation, and instead performed similarly to non- sleep deprived subjects. Importantly, the Active sleep deprivation group showed rTMS-induced facilitation of WM performance a full 18 hours after the last rTMS session. CONCLUSIONS: Over the course of sleep deprivation, these results indicate that rTMS applied concurrently with WM task performance affected neural circuitry involved in WM to prevent its full impact. PMID- 23729930 TI - Association of sleep disordered breathing and cognitive deficit in APOE epsilon4 carriers. AB - STUDY OBJECTIVES: The aim of the study was to determine whether apolipoprotein E epsilon 4 genotype (APOE4) modifies the association of sleep disordered breathing (SDB) with cognitive function in a middle-aged population. DESIGN: Cross sectional analysis of a community-dwelling cohort. SETTINGS: Sleep laboratory at the Clinical Research Unit of the University of Wisconsin Hospitals and Clinics. PARTICIPANTS: There were 755 adults from the Wisconsin Sleep Cohort who provided a total of 1,843 polysomnography and cognitive evaluations (most participants were assessed multiple times at approximately 4-y intervals); 56% males, average age 53.9 years (range 30-81 years). INTERVENTIONS: None. MEASUREMENT AND RESULTS: In-laboratory overnight polysomnography was used to assess SDB. Cognition was evaluated by a battery of six neurocognitive tests assessing memory and learning, attention, executive function, and psychomotor efficiency. The APOE4 genotype (epsilon3/epsilon4 or epsilon4/ epsilon4) was identified in 200 participants. Data were analyzed using linear mixed-effects models, accounting for multiple observations per participant. Cognitive test scores were regressed on SDB categories (AHI < 5, 5 <= AHI < 15, AHI >= 15); APOE4 and their interaction; and age, education, sex, and body mass index. There was no statistically significant association between SDB and cognitive performance among APOE4-negative individuals. However, in APOE4-positive individuals, those with AHI >= 15 had significantly worse performance on the Auditory Verbal Learning Test and the Controlled Oral Word Association Test. CONCLUSIONS: In APOE4-positive individuals, moderate to severe sleep disordered breathing (AHI >= 15) was associated with poorer performance on cognitive tests that require both memory and executive function engagement. PMID- 23729931 TI - Contribution of arousal from sleep to postevent tachycardia in patients with obstructive sleep apnea. AB - STUDY OBJECTIVES: Heart rate increases after obstructive events in patients with obstructive sleep apnea (OSA). This response is generally attributed to arousal from sleep. Opening of the obstructed airway, however, is associated with ventilatory and hemodynamic changes that could result in physiologic responses unrelated to arousal. Our objective was to determine the contribution of these physiologic responses to postevent tachycardia. DESIGN: Analysis of data obtained during previous research protocols. SETTING: Academic sleep laboratory. PARTICIPANTS: Twenty patients with severe OSA. INTERVENTIONS: Patients were placed on a continuous positive airway pressure (CPAP) device. CPAP was reduced during sleep to different levels (dial-downs), producing obstructive events of varying severity. Some dial-downs with severe obstruction were maintained until spontaneous airway opening. In others, CPAP was increased after three obstructed breaths, terminating the events approximately 10 sec before spontaneous termination in long dial-downs. MEASUREMENT AND RESULTS: Beat-by-beat heart rate (HR) was measured for 20 sec following airway opening. Spontaneous opening during sustained dial-downs occurred 21.9 +/- 8.4 sec after dial-down, was associated with arousal, and resulted in the greatest postevent tachycardia (7.8 +/- 4.0 min(-1)). However, deliberate termination of events (12.2 +/- 2.6 sec after dial down) was also followed by tachycardia that, in the absence of cortical arousal, showed a dose-response behavior, increasing with severity of obstruction and without apparent threshold. DeltaHR following deliberately brief, severe obstruction (3.8 +/- 3.0 min(-1)) was approximately half the DeltaHR that followed spontaneous opening of equally severe obstructions despite the shorter duration and absence of cortical arousal. CONCLUSIONS: Postevent tachycardia is due in large part to physiologic (arousal-unrelated) responses that occur upon relief of obstruction. PMID- 23729932 TI - Sleep patterns as predictors for disability pension due to low back diagnoses: a 23-year longitudinal study of Finnish twins. AB - STUDY OBJECTIVES: Impaired sleep patterns are known to be associated with many chronic conditions and ultimately they may lead to permanent work incapacity. Less is known about the associations between sleep patterns and cause-specific disability pensions, such as low back diagnoses, or whether familial factors (genetics and family environment) can affect the associations. The objective of this study was to investigate sleep patterns as predictors of disability pension due to low back diagnoses with a 23-year follow-up. DESIGN AND SETTING: A prospective cohort study with comprehensive mailed questionnaires about sleep patterns, e.g., quality and length of sleep in 1975 and 1981. Follow-up from the national disability pension register data until 2004. INTERVENTIONS: Not applicable. PARTICIPANTS: There were 18,979 individuals (7,722 complete twin pairs) born before 1958. MEASUREMENTS AND RESULTS: Cox proportional hazards regression was used to calculate hazard ratios (HR) with 95% confidence intervals (95% CI). Disability pension due to low back diagnoses had been granted to 467 individuals during the follow-up. Sleeping moderately well (HR 1.25; 95% CI 1.02, 1.53), or fairly poorly/poorly (HR 2.05; 95% CI 1.53, 2.73) at baseline predicted a significantly higher risk for disability pension. Stable patterns of sleeping either fairly well (HR 1.29; 95% CI 1.01, 1.64), or stably fairly poorly/poorly (HR 2.29; 95% CI 1.49, 3.52) between 1975 and 1981 were associated with a higher risk as compared to a stable pattern of sleeping well. Furthermore, a decrease in quality of sleep from 1975 to 1981 was associated (HR 1.34; 95% CI 1.03, 1.76) with an increased risk of disability pension. CONCLUSIONS: Sleep quality and changes in sleep quality appear to be early predictors for disability pension due to low back diagnoses independently from other confounding factors. PMID- 23729933 TI - Sleep deprivation alters effort discounting but not delay discounting of monetary rewards. AB - STUDY OBJECTIVES: To determine whether sleep deprivation would affect the discounting of delayed rewards, of rewards entailing the expense of effort, or both. DESIGN: We measured rates of two types of reward discounting under conditions of rested wakefulness (RW) and sleep deprivation (SD). Delay discounting was defined as the willingness to accept smaller monetary rewards sooner rather than larger monetary rewards later. Effort discounting was defined as the willingness to accept smaller rewards that require less effort to obtain (e.g., typing a small number of letter strings backward) over larger but more effortful rewards (e.g., typing more letter strings to receive the reward). The first two experiments used a crossover design in which one session was conducted after a normal night of sleep (RW), and the other after a night without sleep (SD). The first experiment evaluated only temporal discounting whereas the second evaluated temporal and effort discounting. In the second experiment, the discounting tasks were repeatedly administered prior to the state comparisons to minimize the effects of order and/or repeated testing. In a third experiment, participants were studied only once in a between-subject evaluation of discounting across states. SETTING: The study took place in a research laboratory. PARTICIPANTS: Seventy-seven healthy young adult participants: 20 in Experiment 1, 27 in Experiment 2, and 30 in Experiment 3. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Sleep deprivation elicited increased effort discounting but did not affect delay discounting. CONCLUSIONS: The dissociable effects of sleep deprivation on two forms of discounting behavior suggest that they may have differing underlying neural mechanisms. PMID- 23729934 TI - Differential effects on fast and slow spindle activity, and the sleep slow oscillation in humans with carbamazepine and flunarizine to antagonize voltage dependent Na+ and Ca2+ channel activity. AB - STUDY OBJECTIVES: Sleep spindles play an important functional role in sleep dependent memory consolidation. They are a hallmark of non-rapid eye movement (NREM) sleep and are grouped by the sleep slow oscillation. Spindles are not a unitary phenomenon but are differentiated by oscillatory frequency and topography. Yet, it is still a matter of debate whether these differences relate to different generating mechanisms. As corticothalamic networks are known to be involved in the generation of spindles and the slow oscillation, with Ca2+ and Na+ conductances playing crucial roles, we employed the actions of carbamazepine and flunarizine to reduce the efficacy of Na+ and Ca2+ channels, respectively, for probing in healthy human subjects mechanisms of corticothalamocortical excitability. DESIGN: For each pharmacologic substance a within-design study was conducted on 2 experimental nights in young, healthy adults. MEASUREMENTS AND RESULTS: Results indicate differential effects for slow frontocortical (approximately 10 Hz) and fast centroparietal (approximately 14 Hz) spindles. Carbamazepine enhanced slow frontal spindle activity conjointly with an increment in slow oscillation power (approximately 0.75 Hz) during deep NREM sleep. In contrast, fast centroparietal spindle activity (approximately 14 Hz) was decreased by carbamazepine. Flunarizine also decreased fast-spindle electroencephalogram power, but affected neither slow frontal spindle nor slow oscillation frequency bands. CONCLUSIONS: Our findings indicate a differential pharmacologic response of the two types of sleep spindles and underscore a close linkage of the generating mechanisms underlying the sleep slow oscillation and the slow frontal sleep spindles for the signal transmission processes manipulated in the current study. PMID- 23729935 TI - Alterations in circulating T-cell lymphocyte populations in children with obstructive sleep apnea. AB - STUDY OBJECTIVES: Changes in lymphocyte phenotype and functionality have been described in adult patients with obstructive sleep apnea (OSA). We hypothesized that OSA is associated with T lymphocyte alterations in children, particularly in T regulatory lymphocytes (T regs), and aimed to characterize circulating T lymphocyte subsets in children with OSA. DESIGN: Cross-sectional. SETTING: Kosair Children's Hospital (Louisville, KY, USA) and Comer Children's Hospital (Chicago, IL, USA). PARTICIPANTS: Consecutively recruited children being evaluated for habitual snoring. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Overnight polysomnography (PSG) was performed and a fasting blood sample was obtained from the patients. Flow cytometry was performed on peripheral blood mononuclear cells stained for CD3, CD4, CD8, CD25, FOXP3, interleukin-4 (IL-4), interferon-gamma (IFN-gamma), and IL-17. Patients were divided into three groups based on their PSG: controls (apnea-hypopnea indices [AHI] < 1/h total sleep time [TST]), mild OSA (1 <= AHI < 5/hTST), moderate-severe OSA (AHI >= 5/h TST). The percentage of CD4+ and T reg lymphocytes differed across groups. Children with moderate-severe OSA had significantly reduced T reg than control children (median [interquartile range] 4.8 [3.8-5.7% CD4+] versus 7.8 [7.0-9.2% CD4+]; P < 0.001). There were also significant differences in the percentage of T helper 1 (Th1) lymphocytes and in Th1:Th2 ratios between groups. Children with moderate-severe OSA had increased Th1 cells (P = 0.001) and Th1:Th2 ratios (P = 0.0026) compared with children with mild OSA and control children. Associations between AHI and T reg (P = 0.0003; r = -0.46), CD4+ lymphocytes (P = 0.0047; r = -0.37), and Th1:Th2 ratios (P = 0.0009; r = 0.43) emerged. In addition, the percentage of T reg was inversely correlated with Th1:Th2 ratios (P = 0.029; r = -0.29). CONCLUSIONS: Pediatric OSA is associated with reduced T reg population and altered Th1:Th2 balance toward Th1 predominance, suggesting a shift to a proinflammatory state. The changes in lymphocytic phenotypes associated with OSA may contribute to the variance in systemic inflammation and downstream morbidities associated with this condition. PMID- 23729936 TI - TREM-1 and pentraxin-3 plasma levels and their association with obstructive sleep apnea, obesity, and endothelial function in children. AB - BACKGROUND: Obstructive sleep apnea (OSA) is a common health problem in children and increases the risk of cardiovascular disease (CVD). Triggering receptor expressed on myeloid cells-1 (TREM-1) plays an important role in innate immunity and amplifies inflammatory responses. Pentraxin-3 is predominantly released from macrophages and vascular endothelial cells, plays an important role in atherogenesis, and has emerged as a biomarker of CVD risk. Thus, we hypothesized that plasma TREM-1 and pentraxin-3 levels would be elevated in children with OSA. METHODS: ONE HUNDRED SIX CHILDREN (MEAN AGE: 8.3 +/- 1.6 y) were included after they underwent overnight polysomnographic evaluation and a fasting blood sample was drawn the morning after the sleep study. Endothelial function was assessed with a modified hyperemic test after cuff-induced occlusion of the brachial artery. Plasma TREM-1 and pentraxin-3 levels were assayed using commercial enzyme linked immunosorbent assay kits. Circulating microparticles (MPs) were assessed using flow cytometry after staining with cell-specific antibodies. RESULTS: Children with OSA had significantly higher TREM-1 and pentraxin-3 levels (versus controls: P < 0.01, P < 0.05, respectively). Plasma TREM-1 was significantly correlated with both body mass index (BMI)-z score and the obstructive apnea hypopnea index (AHI) in univariate models. Pentraxin-3 levels were inversely correlated with BMI-z score (r = -0.245, P < 0.01), and positively associated with endothelial MPs and platelet MPs (r = 0.230, P < 0.01 and r = 0.302, P < 0.01). Both plasma TREM-1 and pentraxin-3 levels were independently associated with AHI in multivariate models after controlling for age, sex, race, and BMI-z score (P < 0.001 for TREM-1 and P < 0.001 for pentraxin-3). However, no significant associations emerged between TREM-1, pentraxin-3, and endothelial function. CONCLUSIONS: Plasma TREM-1 and pentraxin-3 levels are elevated in pediatric OSA, and may play a role in modulating the degree of systemic inflammation. The short-term and long-term significance of elevated TREM-1 and pentraxin-3 in OSA-induced end-organ morbidity remains to be defined. PMID- 23729937 TI - Increased sympathetic and decreased parasympathetic cardiac tone in patients with sleep related alveolar hypoventilation. AB - OBJECTIVE: To assess autonomic function by heart rate variability (HRV) during sleep in patients with sleep related alveolar hypoventilation (SRAH) and to compare it with that of patients with obstructive sleep apnea (OSA) and control patients. DESIGN: Cross-sectional study. SETTING: Sleep Unit, University Hospital of University of Navarra. PATIENTS: Fifteen idiopathic and obesity related-SRAH patients were studied. For each patient with SRAH, a patient with OSA, matched in age, sex, body mass index (BMI), minimal oxygen saturation (SatO2), and mean SatO2 was selected. Control patients were also matched in age, sex, and BMI with patients with OSA and those with SRAH, and in apnea/hypopnea index (AHI) with patients with SRAH. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Time- and frequency-domain HRV measures (R-R, standard deviation of normal-to-normal RR interval [SDNN], very low frequency [VLF], low frequency [LF], high frequency [HF], LF/HF ratio) were calculated across all sleep stages as well as during wakefulness just before and after sleep during a 1-night polysomnography. In patients with SRAH and OSA, LF was increased during rapid eye movement (REM) when compared with control patients, whereas HF was decreased during REM and N1-N2 sleep stages. The LF/HF ratio was equally increased in patients with SRAH and OSA during REM and N1-N2. Correlation analysis showed that LF and HF values during REM sleep were correlated with minimal SatO2 and mean SatO2. CONCLUSIONS: Patients with SRAH exhibited an abnormal cardiac tone during sleep. This fact appears to be related to the severity of nocturnal oxygen desaturation. Moreover, there were no differences between OSA and SRAH, supporting the hypothesis that autonomic changes in OSA are primarily related to a reduced nocturnal oxygen saturation, rather than a consequence of other factors such as nocturnal respiratory events. PMID- 23729938 TI - Repetitive traumatic brain injury (or concussion) increases severity of sleep disturbance among deployed military personnel. AB - STUDY OBJECTIVES: Considerable research indicates that sleep disturbances and insomnia are more common and severe among individuals following a traumatic brain injury (TBI). It remains unclear, however, how the experience of multiple TBIs affect sleep disturbances and insomnia. The current study investigated the incidence and severity of insomnia and sleep complaints among active-duty military personnel who have sustained multiple TBIs. DESIGN AND SETTING: Upon intake at a military TBI clinic located in Iraq, 150 male military patients completed standardized self-report measures and clinical interviews. MEASUREMENTS AND RESULTS: Patients were categorized into three groups according to history of TBI: zero TBIs (n = 18), single TBI (n = 54), multiple TBIs (n = 78). Rates of clinical insomnia significantly increased across TBI groups (P < 0.001):- 5.6% for no TBIs, 20.4% for single TBI, and 50.0% for multiple TBIs. Insomnia severity significantly increased across TBI groups even when controlling for depression, posttraumatic stress disorder, and concussion symptom severity (B = 1.134, standard error = 0.577, P = 0.049). CONCLUSIONS: Multiple TBIs are associated with increased risk for and severity of sleep disturbance among male military personnel. PMID- 23729939 TI - Observer variation in drug-induced sleep endoscopy: experienced versus nonexperienced ear, nose, and throat surgeons. AB - STUDY OBJECTIVE: To determine variations in interobserver and intraobserver agreement of drug-induced sleep endoscopy (DISE) in a cohort of experienced versus nonexperienced ear, nose, and throat (ENT) surgeons. DESIGN: Prospective, blinded agreement study. SETTING: Ninety-seven ENT surgeons (90 nonexperienced with DISE; seven experienced) observed six different DISE videos and were asked to score the upper airway (UA) level (palate, oropharynx, tongue base, hypopharynx, epiglottis), direction (anteroposterior, concentric, lateral), and degree of collapse (none; partial or complete collapse). Findings were collected and analyzed, determining interobserver and intraobserver agreement [overall agreement (OA), specific agreement (SA)] and kappa values per UA level. MEASUREMENT AND RESULTS: In the nonexperienced group, overall interobserver agreement on presence of tongue base collapse (OA = 0.63; kappa = 0.33) was followed by the agreement on epiglottis (OA = 0.57; kappa = 0.23) and oropharynx collapse (OA = 0.45; kappa = 0.09). Low overall interobserver agreement in this group was found for hypopharyngeal collapse (OA = 0.33; kappa = 0.08). A similar ranking was found for degree of collapse. For direction of collapse, high interobserver agreement was found for the palate (OA = 0.57; kappa = 0.16). Among the experienced observers, overall interobserver agreement was highest for presence of tongue base collapse (OA = 0.93; kappa = 0.71), followed by collapse of the palate (OA = 0.80; kappa = 0.51). In this group, lowest agreement was also found for hypopharyngeal collapse (OA = 0.47; kappa = 0.03). Interob-server agreement on direction of collapse was highest for epiglottis collapse (OA = 0.97; kappa = 0.97). Concerning the degree of collapse, highest agreement was found for degree of oropharyngeal collapse (OA = 0.82; kappa = 0.66). Among the experienced observers a statistically significant higher interobserver agreement was obtained for presence, direction, and degree of oropharyngeal collapse, as well as for presence of tongue base collapse and degree of epiglottis collapse. Among the nonexperienced observers, high intraobserver agreement was found in particular for tongue base and epiglottis collapse. Among the experienced observers, high agreement was found for all levels but to a lesser extent for hypopharyngeal collapse. Intraobserver agreement was statistically significantly higher in the experienced group, for all UA levels expect for the hypopharynx. CONCLUSION: This study indicates that both interobserver and intraobserver agreement was higher in experienced versus nonexperienced ENT surgeons. Agreement ranged from poor to excellent in both groups. The current results suggest that experience in performing DISE is necessary to obtain reliable observations. PMID- 23729940 TI - Differences in insulin secretion and sensitivity in short-sleep insomnia. AB - OBJECTIVE: Short-sleep insomnia is associated with increased risk of diabetes. The role of altered insulin secretion and action in this association is poorly understood. DESIGN: Observational study. SETTING: Academic clinical research center. PARTICIPANTS: Nondiabetic individuals with insomnia (mean [standard deviation] age 48 [9] y, body mass index 25.6 [3.9] kg/m(2)) with <= 6 h (short sleep, n = 14) and > 6 h of sleep (n = 14) during overnight laboratory polysomnography. MEASUREMENTS AND RESULTS: Standard oral glucose testing was used to assess glucose tolerance, beta-cell function (homeostasis model assessment [HOMA-B]; second-phase insulin secretion) and insulin resistance (HOMA-IR; insulin sensitivity index). There was no significant difference in hemoglobin A1C and fasting or 2-h blood glucose concentrations between sleep groups. Short-sleep insomnia sufferers had lower fasting and postchallenge serum insulin concentrations associated with lower estimates of fasting and glucose-stimulated insulin secretion, and increased insulin sensitivity. CONCLUSIONS: Individuals with short-sleep insomnia appear to have higher indices of systemic insulin sensitivity and secrete less insulin without changes in overall glucose tolerance. PMID- 23729942 TI - Empirical Likelihood-Based Estimation of the Treatment Effect in a Pretest Posttest Study. AB - The pretest-posttest study design is commonly used in medical and social science research to assess the effect of a treatment or an intervention. Recently, interest has been rising in developing inference procedures that improve efficiency while relaxing assumptions used in the pretest-posttest data analysis, especially when the posttest measurement might be missing. In this article we propose a semiparametric estimation procedure based on empirical likelihood (EL) that incorporates the common baseline covariate information to improve efficiency. The proposed method also yields an asymptotically unbiased estimate of the response distribution. Thus functions of the response distribution, such as the median, can be estimated straightforwardly, and the EL method can provide a more appealing estimate of the treatment effect for skewed data. We show that, compared with existing methods, the proposed EL estimator has appealing theoretical properties, especially when the working model for the underlying relationship between the pretest and posttest measurements is misspecified. A series of simulation studies demonstrates that the EL-based estimator outperforms its competitors when the working model is misspecified and the data are missing at random. We illustrate the methods by analyzing data from an AIDS clinical trial (ACTG 175). PMID- 23729943 TI - How many people do you know?: Efficiently estimating personal network size. AB - In this paper we develop a method to estimate both individual social network size (i.e., degree) and the distribution of network sizes in a population by asking respondents how many people they know in specific subpopulations (e.g., people named Michael). Building on the scale-up method of Killworth et al. (1998b) and other previous attempts to estimate individual network size, we propose a latent non-random mixing model which resolves three known problems with previous approaches. As a byproduct, our method also provides estimates of the rate of social mixing between population groups. We demonstrate the model using a sample of 1,370 adults originally collected by McCarty et al. (2001). Based on insights developed during the statistical modeling, we conclude by offering practical guidelines for the design of future surveys to estimate social network size. Most importantly, we show that if the first names to be asked about are chosen properly, the simple scale-up degree estimates can enjoy the same bias-reduction as that from the our more complex latent non-random mixing model. PMID- 23729944 TI - Silica encapsulation of thiol-stabilized lead selenide (PbSe) quantum dots in aqueous solution. AB - Silica encapsulation of lead selenide quantum dots (PbSe QDs) in aqueous solution is reported. Thioglycolic acid (TGA) stabilized PbSe QDs were modified with 3 mercaptopropyl trimethoxysilane (MPS) through vigorous stirring in water for 18 24 h in alkaline solution (pH 10.4-10.6). Silica shell was developed by controlled deposition and precipitation of silicates from sodium silicate solution onto MPS modified QDs surfaces. TEM images showed multiple PbSe QDs encapsulated in silica shell. The size of PbSe-SiO2 core-shell nanocrystals was estimated to be 25-30 nm by TEM. Elemental compositions (Pb, Se and Si) were investigated by EDX analysis. The purified colloids of PbSe-SiO2 QDs were stable for months when kept at 4 degrees C. PMID- 23729945 TI - Methodological Guidelines for Reducing the Complexity of Data Warehouse Development for Transactional Blood Bank Systems. AB - Over time, data warehouse (DW) systems have become more difficult to develop because of the growing heterogeneity of data sources. Despite advances in research and technology, DW projects are still too slow for pragmatic results to be generated. Here, we address the following question: how can the complexity of DW development for integration of heterogeneous transactional information systems be reduced? To answer this, we proposed methodological guidelines based on cycles of conceptual modeling and data analysis, to drive construction of a modular DW system. These guidelines were applied to the blood donation domain, successfully reducing the complexity of DW development. PMID- 23729946 TI - Flame Aerosol Deposition of TiO2 Nanoparticle Films on Polymers and Polymeric Microfluidic Devices for On-Chip Phosphopeptide Enrichment. AB - Direct and fast (10s of seconds) deposition of flame-made, high surface-area aerosol films on polymers and polymeric microfluidic devices is demonstrated. Uniform TiO2 nanoparticle films were deposited on cooled Poly(methyl methacrylate) (PMMA) substrates by combustion of titanium(IV) isopropoxide (TTIP) - xylene solution sprays. Films were mechanically stabilized by in-situ annealing with a xylene spray flame. Plasma-etched microfluidic chromatography columns, comprising parallel microchannels were also coated with such nanoparticle films without any microchannel deformation. These microcolumns were successfully used in metal-oxide affinity chromatography (MOAC) to selectively trap phosphopeptides on these high surface-area nanostructured films. The chips had a high capacity retaining 1.2 MUg of standard phosphopeptide. A new extremely fast method is developed for MOAC microchip stationary phase fabrication with applications in proteomics. PMID- 23729947 TI - Foster care re-entry: Exploring the role of foster care characteristics, in-home child welfare services and cross-sector services. AB - This study seeks to advance our understanding of how modifiable and non modifiable factors may impact the likelihood of re-entry into foster care. Children who entered foster care for the first time following at least one report of maltreatment and were then reunified were followed from exit to re-entry, age 18 or the end of the study period using longitudinal administrative data. Risk of re-entry was explored according to a range of modifiable and non-modifiable case and service characteristics. Children removed from homes with parents who had multiple risk factors (e.g., no high school diploma, mental health diagnosis, criminal record, or teen parents) or were receiving AFDC prior to entry were more likely to re-enter. The receipt of in-home child welfare services during or after foster care was associated with reduced risk of re-entry. Having the longest placement with a relative was associated with decreased risk of re-entry. In conclusion, both modifiable and non-modifiable factors are associated with re entry into foster care. Among modifiable factors, services appear to have a particularly strong relationship to re-entry. Our data also suggest that in-home child welfare services provided during and after foster care may be associated with improved long-term permanency after return home. Given the continued import of caregiver risk factors even among reunified families, services provided to support reunification should include attention to caregiver needs outside parenting. PMID- 23729948 TI - "Discredited" Versus "Discreditable": Understanding How Shared and Unique Stigma Mechanisms Affect Psychological and Physical Health Disparities. AB - In his classic treatise, Goffman (1963) delineates between people who are discredited-whose stigma is clearly known or visible-and people who are discreditable-whose stigma is unknown and can be concealable. To what extent has research in the past 50 years advanced Goffman's original ideas regarding the impact of concealability on stigma management strategies and outcomes? In the current article, we outline a framework that articulates how stigma can "get under the skin" in order to lead to psychological and physical health disparities. Further, we consider when and to what degree concealability moderates these effects, creating divergent outcomes for the discredited and discreditable. Does the stigmatized individual assume his differentness is known about already or is evident on the spot, or does he assume it is neither known about by those present nor immediately perceivable by them? In the first case one deals with the plight of the discredited, in the second with that of the discreditable. This is an important difference.- Goffman (1963, p. 4). PMID- 23729949 TI - Protective Parenting, Relationship Power Equity, and Condom Use Among Rural African American Emerging Adult Women. AB - Sexually transmitted infections disproportionately affect African Americans, particularly young women. The influence of a set of interrelated protective parenting processes-instrumental and emotional support, sexual risk communication, and encouragement of goals for employment or education-on emerging adult women was examined. Parenting was hypothesized to affect consistent condom use through its association with women's reports of power equity in their intimate relationships. Hypotheses were tested with 135 sexually active women 18 to 21 years of age living in rural southern communities. Structural equation modeling indicated that (a) parenting processes predicted women's self-reported relationship power equity and consistent condom use, and (b) relationship power equity predicted consistent condom use. Limited support emerged for a mediational role of relationship power equity in explaining the influence of parenting on consistent condom use. Parental involvement and young women's establishment of personal control in their intimate relationships are important goals for sexual risk reduction programs. PMID- 23729950 TI - Two-Type Age-Dependent Branching Processes with Inhomogeneous Immigration as Models of Renewing Cell Populations. AB - Two-type reducible age-dependent branching processes with inhomogeneous immigration are considered to describe the kinetics of renewing cell populations. This class of processes can be used to model the generation of oligodendrocytes in the central nervous system in vivo or the kinetics of leukemia cells. The asymptotic behavior of the first and second moments, including the correlation, of the process is investigated. PMID- 23729951 TI - Is "Walkability" A Useful Concept for Gerontology? AB - The study tested two hypotheses. 1) In a walkable neighborhood, residents will exercise more, eat healthier, and suffer from less obesity. 2) That relation will be stronger for the elderly. Health was measured by physical activity, number of portions of fruits and vegetables eaten, and BMI. "Walkability" was measured by a set of environmental items that formed three distinct factors. The three health outcomes were related to the three environmental factors. Age was not a significant predictor. While environment does play a significant role in health outcomes the ways that role is expressed and its relation to age is complex. PMID- 23729952 TI - Junk Food in Schools and Childhood Obesity. AB - Despite limited empirical evidence, there is growing concern that junk food availability in schools has contributed to the childhood obesity epidemic. In this paper, we estimate the effects of junk food availability on BMI, obesity, and related outcomes among a national sample of fifth-graders. Unlike previous studies, we address the endogeneity of the school food environment by controlling for children's BMI at school entry and estimating instrumental variables regressions that leverage variation in the school's grade span. Our main finding is that junk food availability does not significantly increase BMI or obesity among this fifth grade cohort despite the increased likelihood of in-school junk food purchases. The results are robust to alternate measures of junk food availability including school administrator reports of sales during school hours, school administrator reports of competitive food outlets, and children's reports of junk food availability. Moreover, the absence of any effects on overall food consumption and physical activity further support the null findings for BMI and obesity. PMID- 23729953 TI - The Structure of Agglomerates consisting of Polydisperse Particles. AB - Agglomeration is encountered in many natural or industrial processes, like growth of aerosol particles in the atmosphere and during material synthesis or even flocculation of suspensions, granulation, crystallization and with colloidal particle processing. These particles collide by different mechanisms and stick together forming irregular or fractal-like agglomerates. Typically, the structure of these agglomerates is characterized with the fractal dimension, Df , and pre exponential factor, kn , of simulated agglomerates of monodisperse primary particles (PP) for ballistic or diffusion-limited particle-cluster and cluster cluster collision mechanisms. Here, the effect of PP polydispersity on Df and kn is investigated with agglomerates consisting of 16 - 1024 PP with closely controlled size distribution (geometric standard deviation, sigma g = 1-3). These simulations are in excellent agreement with the classic structure (Df and kn ) of agglomerates consisting of monodisperse PPs made by four different collision mechanisms as well as with agglomerates of bi-, tri-disperse and normally distributed PPs. Broadening the PP size distribution of agglomerates decreases monotonically their Df and for sufficiently broad PP distributions (sigma g > 2.5) the Df reaches about 1.5 and kn about 1 regardless of collision mechanism. Furthermore with increasing PP polydispersity, the corresponding projected area exponent, Dalpha , and pre-exponential factor, ka , decrease monotonically from their standard values for agglomerates with monodisperse PPs. So Df as well as Dalpha and ka can be an indication for PP polydispersity in mass-mobility and light scattering measurements, if the dominant agglomeration mechanism is known, like diffusion-limited and/or ballistic cluster-cluster coagulation in aerosols. PMID- 23729954 TI - Knowledge translation and behaviour change: patients, providers, and populations. PMID- 23729955 TI - Professional Satisfaction and Desire to Emigrate among Nigerian Physiotherapists. AB - PURPOSE: Physiotherapists from developing countries are attracted to developed countries, where health personnel are in high demand. We investigated Nigerian physiotherapists' desire to emigrate, explored the possible relationship between job satisfaction and emigration, and elucidated common reasons why physiotherapists emigrate to other countries. METHODS: Nigerian physiotherapists (n=181) were surveyed using a three-part questionnaire. Part 1 elicited socio demographic information; part 2 assessed satisfaction with work; and part 3 assessed the importance of some possible reasons that physiotherapists choose to emigrate. RESULTS: Close to half of the physiotherapists surveyed have plans to emigrate, but no relationship exists between job satisfaction level and desire to emigrate. An overwhelming majority felt that better or more realistic remuneration was the most important reason for them to leave their country, whereas age and practice experience were inversely related to physiotherapists' desire to emigrate. CONCLUSION: Policies aimed at mediating "brain drain" should take age and experience into consideration and should be geared toward creating opportunities for career advancement and continuing education. PMID- 23729956 TI - Clinician's Commentary on Oyeyemi et al.(1.). PMID- 23729957 TI - Fear and Avoidance of Movement in People with Chronic Pain: Psychometric Properties of the 11-Item Tampa Scale for Kinesiophobia (TSK-11). AB - PURPOSE: To determine the psychometric properties of the 11-item Tampa Scale for Kinesiophobia (TSK-11) in patients with heterogeneous chronic pain. METHODS: The study evaluated test-retest reliability (intra-class correlation coefficient), cross-sectional convergent construct validity (Pearson product-moment correlation between TSK-11 and the Pain Catastrophizing Scale [PCS] scores at admission), and sensitivity to change of the TSK-11 (area under the receiver operating characteristic [ROC] curve) in patients (n=74) with heterogeneous chronic pain. We used two data sets (retrospective, n=56; prospective, n=18). All patients attended the 4-week interdisciplinary chronic pain management programme at Chedoke Hospital, Hamilton Health Sciences, Hamilton, Ontario. RESULTS: The test retest reliability of the TSK-11 was 0.81 (95% CI, 0.58-0.93), the standard error of measurement was 2.41 (90% CI, 1.47-2.49), and the minimal detectible change score was 5.6. The correlation between TSK-11 and PCS at admission was 0.60 (95% CI, 0.43-0.73). The area under the ROC curve was 0.73 (95% CI, 0.57-0.88). CONCLUSIONS: The study results provide evidence for the test-retest reliability, cross-sectional convergent construct validity, and sensitivity to change of the TSK-11 in a population with heterogeneous chronic pain. PMID- 23729958 TI - The effect of previous loading cycles on the reliability of a clinical measure of hamstring flexibility. AB - PURPOSE: The aim of the study was to determine the effect of successive repetitions of a measure of hamstring flexibility-the passive unilateral straight leg raise (SLR)-on the reliability of this measure. METHOD: Ten repetitions of the SLR were performed on nine healthy adults. Measures were quantified using an electromagnetic tracking system and standardized using a handheld dynamometer by stopping the SLR at a set end-point force. The 10 repetitions were analyzed as two blocks of five, and intra-class correlation coefficients-models (2,1) and (3,k)-were calculated for each block of data. RESULTS: ICC values for both models were comparable between the two blocks of data. CONCLUSION: Previous loading cycles, to a set end-point force, are unlikely to improve the reliability of muscle flexibility assessment in a clinical setting. PMID- 23729960 TI - Clinician's Commentary on Montuno et al.(1.). PMID- 23729959 TI - Academic Dishonesty among Physical Therapy Students: A Descriptive Study. AB - PURPOSE: To examine academically dishonest behaviours based on physical therapy (PT) students' current practices and educators' prior behaviours as PT students. METHOD: A Web-based questionnaire was sent to 174 students and 250 educators from the PT programme at the University of Toronto. The questionnaire gathered data on demographics as well as on the prevalence of, seriousness of, and contributing factors to academic dishonesty (AD). RESULTS: In all, 52.4% of educators and 44.3% of students responded to the questionnaire over a 6-week data-collection period. Scenarios rated the most serious were the least frequently performed by educators and students. The impact of generation on attitudes and prevalence of AD was not significant. The factors most commonly reported as contributing to AD were school-related pressure, disagreement with evaluation methods, and the perception that "everyone else does it." CONCLUSION: This study parallels the findings of similar research conducted in other health care programmes: AD does occur within the PT curriculum. AD was more prevalent in situations associated with helping peers than in those associated with personal gain. The consistency in behaviours reported across generations suggests that some forms of cheating are accepted as the social norm and may be a function of the environment. PMID- 23729961 TI - Reliability of the jones patellofemoral osteoarthritis score for radiological assessment of patellofemoral degenerative changes: comparing a physiotherapist to doctors. AB - PURPOSE: Radiological measurement scores are used by orthopaedic physiotherapists in triage and surveillance of patients with degenerative changes of the tibiofemoral and patellofemoral joints. The purpose of this study was to estimate the intra- and inter-observer reliability of a radiological measurement score to assess patellofemoral joint osteoarthritis, the Jones Patellofemoral Osteoarthritis Score (JPOS), with an orthopaedic physiotherapist and three grades of junior surgeons/doctors. METHODS: A total of 390 skyline X-rays of the patellofemoral joint were reviewed on 2 occasions, 4 weeks apart, by an orthopaedic physiotherapist, 2 orthopaedic surgeons, and an orthopaedic doctor. Intra- and inter-observer reliability of the JPOS was calculated using a weighted kappa analysis. RESULTS: The results indicated that while there was good overall intra-observer agreement for this measurement score for all assessors, inter observer reliability was generally poor between the orthopaedic physiotherapist and the orthopaedic surgeons/doctor. CONCLUSION: Our findings call into question the use of the JPOS by orthopaedic physiotherapists working in triage or orthopaedic surveillance programmes with other orthopaedic clinicians. PMID- 23729962 TI - Management of early- and late-stage rheumatoid arthritis: are physiotherapy students' intended behaviours consistent with canadian best practice guidelines? AB - PURPOSE: This study examined whether physiotherapy students in a problem-based learning (PBL) curriculum intend to implement best practices for management of clients with rheumatoid arthritis (RA). METHOD: Physiotherapy students (n=49) completed a subsection of the ACREU Primary Care Survey to evaluate the concordance between intended behaviours and Canadian best practices for early- and late-stage RA, before and after completing the relevant PBL content. Changes in scores were assessed using McNemar's test for dependent proportions. RESULTS: Most students indicated that they would recommend treatments or referrals for physiotherapy/exercise, education, and occupational therapy or joint protection pre- and post-PBL (>83% and >95%, respectively). Post-PBL, more students recommended referral to a rheumatologist and disease-modifying anti-rheumatic drugs (DMARDs) for both early and late RA; however, the increase was significant only for early RA (p=0.013 and 0.031 for referral to rheumatologist and DMARDs, respectively). More students recommended psychosocial support at both stages of RA post-PBL (early RA: p<0.001; late RA: p=0.031). Although more students recommended DMARDs post-PBL, only 8 students in total made this recommendation (16%), and fewer students considered use of non-steroidal anti-inflammatory drugs. Most students (94%) did not recommend referral to a surgeon for early or late RA. CONCLUSION: Intended behaviour of physiotherapy students was more consistent with Canadian best practice guidelines for managing clients with early and late-stage RA following the PBL curriculum. Further study is required to determine whether the students were less aware of best practices related to pharmacologic interventions and timely referral to appropriate specialists, or whether they considered these issues to be outside their scope of practice. PMID- 23729963 TI - Survey of Canadian Physiotherapists: Entry-Level and Post-professional Education in Women's Health. AB - PURPOSE: The aims of this study were to identify (1) practice patterns of Canadian physiotherapists who consider themselves women's health providers or educators (WHPTs); (2) WHPTs' perception of the relative importance of entry level and post-professional education curricular content directed at women's health issues; and (3) WHPTs' patterns and preferences with respect to continuing education. METHOD: A survey link was sent via e-mail to all 429 members of the Women's Health Division of the Canadian Physiotherapy Association and to physiotherapist educators at the 14 Canadian physiotherapy programmes. RESULTS: A total of 114 WHPTs responded (27%), including 16 educators. Of the 114 respondents, 53% spent less than 25% of their practice specifically treating women's health issues. Over half of the 114 respondents felt that entry-level preparation must include aging issues, musculoskeletal dysfunction, osteoporosis, and sports injuries in women. Respondents' stated that post-professional education should also include female anatomy, obstetrics and gynecology, pelvic floor assessment, treatment of urogenital concerns, complications of cancer, wellness and health promotion, and research. Most respondents (63%) showed interest in achieving continuing-education credentials in women's health, preferably using a combined theoretical online and hands-on weekend-based format. CONCLUSIONS: The survey results suggest that WHPTs practising in Canada seek post professional training with an emphasis on pelvic floor assessment and treatment, obstetrics and gynecology, urogenital concerns, complications of cancer, wellness and health promotion, and research. Future research should focus on the barriers to devoting full-time practice hours to WHPTs. PMID- 23729964 TI - Standardizing foot-type classification using arch index values. AB - PURPOSE: The lack of a reliable classification standard for foot type makes drawing conclusions from existing research and clinical decisions difficult, since different foot types may move and respond to treatment differently. The purpose of this study was to determine interrater agreement for foot-type classification based on photo-box-derived arch index values. METHOD: For this correlational study with two raters, a sample of 11 healthy volunteers with normal to obese body mass indices was recruited from both a community weight-loss programme and a programme in physical therapy. Arch index was calculated using AutoCAD software from footprint photographs obtained via mirrored photo-box. Classification as high-arched, normal, or low-arched foot type was based on arch index values. Reliability of the arch index was determined with intra-class correlations; agreement on foot-type classification was determined using quadratic weighted kappa (kappaw). RESULTS: Average arch index was 0.215 for one tester and 0.219 for the second tester, with an overall range of 0.017 to 0.370. Both testers classified 6 feet as low-arched, 9 feet as normal, and 7 feet as high-arched. Interrater reliability for the arch index was ICC=0.90; interrater agreement for foot-type classification was kappaw=0.923. CONCLUSIONS: Classification of foot type based on arch index values derived from plantar footprint photographs obtained via mirrored photo-box showed excellent reliability in people with varying BMI. Foot-type classification may help clinicians and researchers subdivide sample populations to better differentiate mobility, gait, or treatment effects among foot types. PMID- 23729965 TI - The Relationship between Radial Bone Properties and Disease Activity and Physical Function in Individuals with Rheumatoid Arthritis. AB - PURPOSE: People with rheumatoid arthritis (RA) are at increased risk for osteoporosis. This study explored the relationships between compartment-specific (cortical and trabecular) bone properties in the distal radius, a common site for osteoporotic fracture, and RA-related pain, upper-limb disease activity, and hand function in adults diagnosed within the previous 8 years. METHODS: Cortical and trabecular bone properties (mass, density, and apparent trabecular structure) were assessed at the 4% site of the radius in 21 adults with RA using peripheral quantitative computed tomography (pQCT). Clinical measures included upper-limb active joint count; self-reported pain (AIMS-2 Arthritis Pain scale) and physical function (AIMS-2 Hand and Finger Function scale); and grip strength (modified sphygmomanometer). Associations were characterized using correlations (Pearson correlation coefficients or Spearman's rho). RESULTS: Cortical and trabecular bone mass and trabecular bone density were negatively associated with the number of active joints (r=-0.47, -0.54, and -0.47, respectively). Cortical bone density and mass were associated with grip strength (r=0.61 and 0.51, respectively). Cortical and trabecular bone density and cortical bone mass were negatively associated with scores on the Hand and Finger Function scale (r=-0.49, -0.45 and 0.56, respectively). CONCLUSIONS: Although the patterns differed slightly for cortical and trabecular bone, better bone health in both compartments was associated with fewer active joints and lower self-reported hand disability in adults with RA. PMID- 23729966 TI - Site-specific variance in radius and tibia bone strength as determined by muscle size and body mass. AB - PURPOSE: To investigate the predictive ability of muscle cross-sectional area (MCSA) and body mass on bone mineral content, compressive bone strength index (BSIc), and the polar stress-strain index (SSIp) of the forearms and lower legs of middle-aged adults. METHODS: A total of 53 healthy adults (37 male, 16 female; mean age 50.4; SD 2.1 y) were scanned with peripheral quantitative computed tomography (pQCT) to measure radius and tibia total and cortical bone mineral content, BSIc, SSIp, and forearm and lower-leg MCSA (BSIc: 4% distal; SSIp and MCSA at 65% and 66% radius and tibia shaft sites, respectively). Multiple regression models adjusted for sex and height were used to assess the relative variance in radius or tibia bone outcomes predicted by body mass and/or forearm or lower-leg MCSA. RESULTS: Forearm MCSA independently predicted total bone mineral content, BSIc, and SSIp in radius (r partial=0.59, 0.56, 0.42). Body mass was a negative predictor of radius BSIc (r partial=-0.32) and did not predict other radius outcomes when both body mass and MCSA were forced in the models. In the lower leg shaft, MCSA, and body mass predicted bone content and strength similarly when independently added to the models with sex and height. CONCLUSIONS: Forearm MCSA was a dominant predictor of radius bone content and estimated strength. In the tibia, both body mass and lower-leg MCSA contributed to predicting bone content and estimated strength. PMID- 23729968 TI - Clinician's Commentary on Arnold and Gyurcsik(1.). PMID- 23729967 TI - Risk factors for falls in older adults with lower extremity arthritis: a conceptual framework of current knowledge and future directions. AB - PURPOSE: As the numbers of Canadians aged 65 years and over increases over the next 20 years, the prevalence of chronic conditions, including arthritis, will rise as will the number of falls. Although known fall-risk factors are associated with hip and knee osteoarthritis (OA), minimal research has evaluated fall and fracture risk and/or rates in this population. Thus, the purpose was to summarize research on fall and fracture risk in older adults with hip or knee OA and to develop a conceptual framework of fall-risk screening and assessment. METHOD: The International Classification of Functioning, Disability and Health, clinical practice guidelines for fall-risk screening, and a selected literature review were used. RESULTS: Gaps exist in our knowledge of fall and fracture risk for this population. Muscle performance, balance, and mobility impairments have been identified, but little is known about whether personal and environmental contextual factors impact fall and fracture risk. Physical activity may help to prevent falls, but non-adherence is a problem. CONCLUSION: A need exists to assess fall risk in older adults with hip and knee OA. Promoting regular physical activity by focusing on disease- and activity-specific personal contextual factors may help direct treatment planning. PMID- 23729969 TI - Neuromuscular electrical stimulation and exercise for reducing trapezius muscle dysfunction in survivors of head and neck cancer: a case-series report. AB - PURPOSE: Damage to the spinal accessory nerve (SAN) can result in denervation of the trapezius muscle in patients undergoing surgery for head and neck cancer. Trapezius denervation leads to muscle weakness and dysfunction that, for some patients, persists despite the return of conduction along the SAN. This prospective case series describes an intervention involving a combination of a novel type of neuromuscular electrical stimulation (NMES) with bilateral exercise. METHODS: Three survivors of head and neck cancer participated in the 6 week program. NMES was applied over the region of the SAN on the affected side while subjects performed bilateral voluntary scapular retraction and elevation exercises against resistance. The NMES was delivered using relatively wide pulse widths and high frequencies to enhance the electrically evoked sensory volley and was triggered by the onset of trapezius muscle activity on the non-affected side. Shoulder range of motion (ROM) assessments and patient-rated outcomes were administered at baseline and 6 weeks. RESULTS: All patients showed improvements in shoulder flexion and abduction ROM and reported reductions in pain and disability. CONCLUSIONS: This combination of NMES and bilateral exercise may prove to be an effective component of a comprehensive shoulder rehabilitation program for patients with persistent trapezius muscle dysfunction as a result of SAN damage. PMID- 23729970 TI - What Does the Cochrane Collaboration Say about Rheumatoid Arthritis? PMID- 23729971 TI - Gender Affirmation: A Framework for Conceptualizing Risk Behavior among Transgender Women of Color. AB - Experiences of stigma, discrimination, and violence as well as extreme health disparities and high rates of sexual risk behavior and substance use have been well-documented among transgender women of color. Using an intersectional approach and integrating prominent theories from stigma, eating disorders, and HIV-related research, this article offers a new framework for conceptualizing risk behavior among transgender women of color, specifically sexual risk behavior and risky body modification practices. This framework is centered on the concept of 'gender affirmation,' the process by which individuals are affirmed in their gender identity through social interactions. Qualitative data from 22 interviews with transgender women of color from the San Francisco Bay Area in the United States are analyzed and discussed in the context of the gender affirmation framework. PMID- 23729972 TI - Logarithmic Lipschitz norms and diffusion-induced instability. AB - This paper proves that contractive ordinary differential equation systems remain contractive when diffusion is added. Thus, diffusive instabilities, in the sense of the Turing phenomenon, cannot arise for such systems. An important biochemical system is shown to satisfy the required conditions. PMID- 23729973 TI - Modeling Cell Kinetics using Branching Processes with Non-Homogeneous Poisson Immigration. AB - Age-dependent branching processes with non-homogeneous Poisson immigration are proposed as models of cell proliferation kinetics. The asymptotic behaviour of the first and second-order moments is investigated and the obtained results are use to develop a relevant statistical inference. PMID- 23729974 TI - NONPARAMETRIC BENCHMARK ANALYSIS IN RISK ASSESSMENT: A COMPARATIVE STUDY BY SIMULATION AND DATA ANALYSIS. AB - We consider the finite sample performance of a new nonparametric method for bioassay and benchmark analysis in risk assessment, which averages isotonic MLEs based on disjoint subgroups of dosages, and whose asymptotic behavior is essentially optimal (Bhattacharya and Lin (2010)). It is compared with three other methods, including the leading kernel-based method, called DNP, due to Dette et al. (2005) and Dette and Scheder (2010). In simulation studies, the present method, termed NAM, outperforms the DNP in the majority of cases considered, although both methods generally do well. In small samples, NAM and DNP both outperform the MLE. PMID- 23729975 TI - Mentoring-It's All Good, Right? PMID- 23729976 TI - Percutaneous portal vein access and transhepatic tract hemostasis. AB - Percutaneous portal vein interventions require minimally invasive access to the portal venous system. Common approaches to the portal vein include transjugular hepatic vein to portal vein access and direct transhepatic portal vein access. A major concern of the transhepatic route is the risk of postprocedural bleeding, which is increased when patients are anticoagulated or receiving pharmaceutical thrombolytic therapy. Thus percutaneous portal vein access and subsequent closure are important technical parts of percutaneous portal vein procedures. At present, various techniques have been used for either portal access or subsequent transhepatic tract closure and hemostasis. Regardless of the method used, meticulous technique is required to achieve the overall safety and effectiveness of portal venous procedures. This article reviews the various techniques of percutaneous transhepatic portal vein access and the various closure and hemostatic methods used to reduce the risk of postprocedural bleeding. PMID- 23729977 TI - Portal vein embolization: rationale, technique, and current application. AB - Portal vein embolization (PVE) is a technique used before hepatic resection to increase the size of liver segments that will remain after surgery. This therapy redirects portal blood to segments of the future liver remnant (FLR), resulting in hypertrophy. PVE is indicated when the FLR is either too small to support essential function or marginal in size and associated with a complicated postoperative course. When appropriately applied, PVE has been shown to reduce postoperative morbidity and increase the number of patients eligible for curative intent resection. PVE is also being combined with other therapies in novel ways to improve surgical outcomes. This article reviews the rationale, technical considerations, and current use of preoperative PVE. PMID- 23729978 TI - Update on islet cell transplantation for type 1 diabetes. AB - Despite modern medical breakthroughs, diabetes mellitus is a worldwide leading cause of morbidity and mortality. Definitive surgical treatment of diabetes mellitus was established with the advent and refinement of clinical pancreas transplantation in the 1960s. During the following decades, critical discoveries involving islet isolation and engraftment took place. Clinical islet cell transplantation represents the potential for reduced insulin requirements and debilitating hypoglycemic episodes without the morbidity of surgery. Unfortunately, islet cell transplantation was unable to achieve comparable results with solid organ transplantation. This was until the Edmonton protocol (steroid-free immunosuppression) was described, which demonstrated that islet cell transplantation could be a viable alternative to pancreas transplantation. Significant advances in islet purification techniques and novel immunomodulatory agents have since renewed interest in islet cell transplantation. Yet the field is still challenged by a limited supply of islet cells, inadequate engraftment, and the deleterious effects of chronic immunosuppression. This article discusses the history and the current status of clinical islet cell transplantation. PMID- 23729979 TI - Portal interventions in liver transplant recipients. AB - Portal vein interventions in liver transplant recipients represent a group of interventions in the management of several disease entities including portal vein stenosis, portal vein thrombosis, and recurrent liver cirrhosis with portal hypertension with and without gastric varices. The procedures performed in these patient populations include portal vein angioplasty with or without stent placement for portal vein stenosis, portal vein thrombolysis with or without stent placement for portal vein thrombosis, transjugular intrahepatic portosystemic shunts or splenic embolization for cirrhosis, and balloon-occluded retrograde transvenous obliteration for gastric varices. This article discusses these disease entities and the minimal invasive procedures used in their management. PMID- 23729980 TI - Arterioportal fistulas in liver transplant recipients. AB - Arterioportal fistulas (APFs) are classified into intrahepatic (>75% of all reported) and extrahepatic (<25% of all reported ). Anecdotally, investigators are more likely to report more sensational cases (typically extrahepatic APFs), so the actual prevalence of intrahepatic APFs is probably much higher (likely >90% of APFs). All reported APFs in liver transplant recipients have been intrahepatic. Hemodynamically significant APFs in liver transplant recipients are rare, occurring in 0.2%; however, APFs (hemodynamically significant or not) are not uncommonly seen in hepatic angiograms of liver transplant recipients (up to 5.4% of hepatic arteriograms in transplants). Interestingly, hemodynamically significant APFs warranting endovascular treatment are reported more commonly in the literature in native compared with transplanted livers (n >280-300 versus n = 13, respectively). This article discusses APFs that are specific to liver transplant recipients; their incidence, etiology, pathogenesis, natural history, clinical presentation, and endovascular management are discussed in detail. PMID- 23729981 TI - Transjugular liver biopsy. AB - Liver biopsy is considered the gold standard for the evaluation of acute and chronic liver disorders. Transjugular liver biopsy (TJLB) was described by Dotter in 1964 and clinically performed for the first time by Hanafee in 1967. TJLB consists of obtaining liver tissue through a rigid cannula introduced into one of the hepatic veins, typically using jugular venous access. The quality of the TJLB specimens has improved so much that the samples obtained by this method are comparable with those obtained with the percutaneous technique. TJLB is indicated for patients with coagulopathy, ascites, peliosis hepatis, morbid obesity, liver transplant, or in patients undergoing a transjugular intrahepatic portosystemic shunt procedure. The technical success rate for a TJLB procedure ranges from 87 to 97%. Sample fragmentation has been reported in 14 to 25% of the TJLB samples. The complication rates are low and range between 1.3% and 6.5%. The purpose of this article is to provide a review of the fundamental aspects of the TJLB procedure, including technique, indications, contraindications, results, and complications. PMID- 23729982 TI - Balloon-occluded retrograde transvenous obliteration of gastric varices: concept, basic techniques, and outcomes. AB - Patients with gastric variceal bleeding require a multidisciplinary team approach including hepatologists, endoscopists, diagnostic radiologists, and interventional radiologists. Upper gastrointestinal endoscopy is the first-line diagnostic and management tool for bleeding gastric varices, as it is in all upper gastrointestinal bleeding scenarios. In the United States when endoscopy fails to control gastric variceal bleeding, a transjugular intrahepatic portosystemic shunt (TIPS) traditionally is performed along the classic teachings of decompressing the portal circulation. However, TIPS has not shown the same effectiveness in controlling gastric variceal bleeding that it has with esophageal variceal bleeding. For the past 2 decades, the balloon-occluded retrograde transvenous obliteration (BRTO) procedure has become common practice in Asia for the management of gastric varices. BRTO is gaining popularity in the United States. It has been shown to be effective in controlling gastric variceal bleeding with low rebleed rates. BRTO has many advantages over TIPS in that it is less invasive and can be performed on patients with poor hepatic reserve and those with encephalopathy (and may even improve both). However, its by-product is occlusion of a spontaneous hepatofugal (TIPS equivalent) shunt, and thus it is contradictory to the traditional American doctrine of portal decompression. Indeed, BRTO causes an increase in portal hypertension, with potential aggravation of esophageal varices and ascites. This article discusses the concept, technique, and outcomes of BRTO within the broader management of gastric varices. PMID- 23729983 TI - Percutaneous placement and management of peritoneovenous shunts. AB - Peritoneovenous shunts are used in the treatment of recurrent ascites or recurrent pleural effusions. Generally speaking, the shunts allow passage of ascites or pleural effusions (by either passive or active means) back into the central venous system. The most recent development in peritoneovenous shunts, known as the Denver Shunt, is a modification of a shunt developed for the treatment of hydrocephalus. In recent years, the Denver shunt has been placed by interventional radiologists. It is used to treat both cirrhotic and malignant effusions in the peritoneal and pleural cavities. Reported complications of the shunt are shunt occlusion, infection, post-shunt coagulopathy, deep vein thrombosis, catheter breakage, and leaks. This article discusses the technical aspects related to the percutaneous placement and maintenance of the Denver Shunt. PMID- 23729984 TI - Splenic artery embolization as an adjunctive procedure for portal hypertension. AB - Splenic embolization is a technique that can be used alone or in conjunction with other treatments for the mitigation of portal hypertension and associated physiological effects of portal hypertension. This technique can be used safely when total embolization volume is ~50% and the procedural and periprocedural time periods are covered with antibiotics. In this patient population, partial splenic embolization can decrease the incidence of variceal bleeding, and protection can persist for at least a year. Additionally, liver function tests and serum cell counts can be expected to improve. Although not frequently used as primary therapy for patients with portal hypertension, splenic embolization can often be helpful as an alternative or adjunctive procedure. PMID- 23729985 TI - Nonocclusive hepatic artery hypoperfusion syndrome (splenic steal syndrome) in liver transplant recipients. AB - There are numerous causes of reduced arterial inline flow to the liver transplant despite a patent hepatic artery. These include causes of increased peripheral resistance in the hepatic arterial bed, siphoning of the hepatic arterial flow by a dominant splenic artery (splenic steal syndrome), functional reduction of hepatic arterial flow in response to hyperdynamic portal inline flow, and small hepatic graft relative to normal portal inline flow (relative increase of portal flow). These causes are incompletely understood, and perhaps the most controversial of all is the splenic steal syndrome, which is possibly an underrecognized cause of graft ischemia in the United States. Splenic steal syndrome presents nonspecifically as graft dysfunction; if overlooked, it may lead to graft failure. Its incidence is reported to be 0.6 to 10.1% in liver transplant recipients, with some institutions performing prophylactic and/or posttransplant treatment procedures in up to a quarter of their transplant recipients. This wide disparity in the incidence of the diagnosis is probably because there are no objective diagnostic imaging criteria. This article presents a review of the literature that addresses the differential diagnostic considerations of hepatic artery hypoperfusion (splenic steal syndrome included) in the absence of an anatomical defect (hepatic artery stenosis, thrombosis, and/or kinks). PMID- 23729986 TI - Splenic artery embolization in blunt trauma. PMID- 23729987 TI - Traversing the Renal Pelvis during Percutaneous Nephrostomy Tube Placement ("Kidney Kabob"). PMID- 23729988 TI - Measuring Social Support from Mother-Figures in the Transition from Pregnancy to Parenthood among Mexican-Origin Adolescent Mothers. AB - Social support for adolescent mothers, particularly from mother figures, can buffer risks and promote well-being. To date, no longitudinal research has investigated how the dimensions of social support may change during the transition from pregnancy to parenthood for adolescent mothers. This study examined stability and change in dimensions of social support from the third trimester of pregnancy to two years postpartum among 191 dyads of Mexican-origin adolescent first-time mothers and their mother figures. Perceptions of social support received from a mother figure shifted from a single dimension (i.e., global support) to three distinct factors (instrumental, emotional, and companionship support) during this transition; however, social support provision as reported by mother figures remained stable. Measurement equivalence was established across interview language (English and Spanish) and across two time points postpartum. Bivariate correlations provided support for the convergent and divergent validity of these measures. Implications for future research and practice are discussed. PMID- 23729989 TI - Trauma Exposure in Anxious Primary Care Patients. AB - The present study examined rates of trauma exposure, clinical characteristics associated with trauma exposure, and the effect of trauma exposure on treatment outcome in a large sample of primary care patients without posttraumatic stress disorder (PTSD). Individuals without PTSD (N = 1263) treated as part of the CALM program (Roy-Byrne et al., 2010) were assessed for presence of trauma exposure. Those with and without trauma exposure were compared on baseline demographic and diagnostic information, symptom severity, and responder status six months after beginning treatment. Trauma-exposed individuals (N = 662, 53%) were more likely to meet diagnostic criteria for Obsessive Compulsive Disorder and had higher levels of somatic symptoms at baseline. Individuals with and without trauma exposure did not differ significantly on severity of anxiety, depression, or mental health functioning at baseline. Trauma exposure did not significantly impact treatment response. Findings suggest that adverse effects of trauma exposure in those without PTSD may include OCD and somatic anxiety symptoms. Treatment did not appear to be adversely impacted by trauma exposure. Thus, although trauma exposure is prevalent in primary care samples, results suggest that treatment of the presenting anxiety disorder is effective irrespective of trauma history. PMID- 23729990 TI - Hybrid, silica-coated, Janus-like plasmonic-magnetic nanoparticles. AB - Hybrid plasmonic-magnetic nanoparticles possess properties that are attractive in bioimaging, targeted drug delivery, in vivo diagnosis and therapy. The stability and toxicity, however, of such nanoparticles challenge their safe use today. Here, biocompatible, SiO2-coated, Janus-like Ag/Fe2O3 nanoparticles are prepared by one-step, scalable flame aerosol technology. A nanothin SiO2 shell around these multifunctional nanoparticles leaves intact their morphology, magnetic and plasmonic properties but minimizes the release of toxic Ag+ ions from the nanosilver surface and its direct contact with live cells. Furthermore, this silica shell hinders flocculation and allows for easy dispersion of such nanoparticles in aqueous and biological buffer (PBS) solutions without any extra functionalization step. As a result, these hybrid particles exhibited no cytotoxicity during bioimaging and remained stable in suspension with no signs of agglomeration and sedimentation or settling. Their performance as biomarkers was explored by selectively binding them with live tagged Raji and HeLa cells enabling their detection under dark-filed illumination. Therefore, these SiO2 coated Ag/Fe2O3 nanoparticles do not exhibit the limiting physical properties of each individual component but retain their desired functionalities facilitating thus, the safe use of such hybrid nanoparticles in bio-applications. PMID- 23729991 TI - A linear optimal transportation framework for quantifying and visualizing variations in sets of images. AB - Transportation-based metrics for comparing images have long been applied to analyze images, especially where one can interpret the pixel intensities (or derived quantities) as a distribution of 'mass' that can be transported without strict geometric constraints. Here we describe a new transportation-based framework for analyzing sets of images. More specifically, we describe a new transportation-related distance between pairs of images, which we denote as linear optimal transportation (LOT). The LOT can be used directly on pixel intensities, and is based on a linearized version of the Kantorovich-Wasserstein metric (an optimal transportation distance, as is the earth mover's distance). The new framework is especially well suited for computing all pairwise distances for a large database of images efficiently, and thus it can be used for pattern recognition in sets of images. In addition, the new LOT framework also allows for an isometric linear embedding, greatly facilitating the ability to visualize discriminant information in different classes of images. We demonstrate the application of the framework to several tasks such as discriminating nuclear chromatin patterns in cancer cells, decoding differences in facial expressions, galaxy morphologies, as well as sub cellular protein distributions. PMID- 23729992 TI - Multiscale Aspects of Modeling Gas-Phase Nanoparticle Synthesis. AB - Aerosol reactors are utilized to manufacture nanoparticles in industrially relevant quantities. The development, understanding and scale-up of aerosol reactors can be facilitated with models and computer simulations. This review aims to provide an overview of recent developments of models and simulations and discuss their interconnection in a multiscale approach. A short introduction of the various aerosol reactor types and gas-phase particle dynamics is presented as a background for the later discussion of the models and simulations. Models are presented with decreasing time and length scales in sections on continuum, mesoscale, molecular dynamics and quantum mechanics models. PMID- 23729993 TI - Mother-Adolescent Conflict: Stability, Change, and Relations with Externalizing and Internalizing Behavior Problems. AB - Stability and change in mother-adolescent conflict reactions (CRs) and the prediction of CRs from adolescents' earlier behavior problems (and vice versa) were examined with 131 mothers and their adolescents (63 boys). Dyads engaged in a 6-minute conflict discussion twice, 2 years apart (M age was 13 at Time 1 (T1). Nonverbal expressive and verbal CRs during the conflict discussion were coded. Mothers, fathers, and teachers reported on adolescents' problem behaviors. There was inter-individual (rank-order) stability for adolescents' CRs whereas mothers' reactions were less stable. Mean levels of mothers' negativity, anger, and positive reactions and adolescents' negativity declined with time. Mothers' CRs predicted and were predicted by adolescents' problem behaviors more often than adolescents' CRs in zero-order correlations. In structural models with the stability of the constructs accounted for, adolescents' externalizing problems at T1 predicted higher maternal anger at T2. Mothers' anger and positive CRs at T1 predicted fewer T2 adolescents' internalizing problems. Stability and change in CRs are discussed. PMID- 23729994 TI - The relationship of area-level sociodemographic characteristics, household composition and individual-level socioeconomic status on walking behavior among adults. AB - Understanding the contextual factors associated with why adults walk is important for those interested in increasing walking as a mode of transportation and leisure. This paper investigates the relationships between neighborhood-level sociodemographic context, individual level sociodemographic characteristics and walking for leisure and transport. Data from two community-based studies of adults (n=550) were used to determine the association between the area sociodemographic environment (ASDE), calculated from U.S. Census variables, and individual-level SES as potential correlates of walking behavior. Descriptive statistics, mean comparisons and Pearson's correlations coefficients were used to assess bivariate relationships. Generalized estimating equations were used to model the relationship between ASDE, as quartiles, and walking behavior. Adjusted models suggest adults engage in more minutes of walking for transportation and less walking for leisure in the most disadvantaged compared to the least disadvantaged neighborhoods but adding individual level demographics and SES eliminated the significant results. However, when models were stratified for free or reduced cost lunch, of those with children who qualified for free or reduced lunch, those who lived in the wealthiest neighborhoods engaged in 10.7 minutes less of total walking per day compared to those living in the most challenged neighborhoods (p<0.001). Strategies to increase walking for transportation or leisure need to take account of individual level socioeconomic factors in addition to area-level measures. PMID- 23729995 TI - Emergence and reemergence of vaccinia-like viruses: global scenario and perspectives. AB - Among the members of the genus Orthopoxvirus (OPXV), vaccinia virus (VACV), the type species of the genus is a double-stranded DNA virus, belongs to the subfamily Chordopoxvirinae of the family Poxviridae. The causative agents of smallpox, VACV and Variola virus are mutually immunogenic and the type species of Orthopoxvirus, cause only mild complications in humans. Therefore, the VACV was used as a smallpox vaccine world over under mass immunization program promoted by World Health Organization, which lead to the variola eradication globally in 1979. Since then, no vaccination of human population has been carried out; however, vaccination has been continued for at-risk laboratory workers, military personnel and others working with recombinant VACV or other non-variola orthopoxviruses (OPXVs). There has now been a surge in the development of safer smallpox vaccines and understanding of the biology of VACV necessitating re-use of this vaccine in most vulnerable population, because of rise in bioterrorist threats globally. Also, globally there has been the emergence and re-emergence of vaccinia-like viruses (VLVs) in Brazil, buffalopox viruses in Egypt, Indonesia, India and its neighbouring countries like Nepal, Pakistan. Bioterrorism as well as emergence and re-emergence of the VLVs constitute a concern as 50 % of the population globally (40 % in USA) <30 years are unvaccinated and most vulnerable for smallpox reemergence. Thus, the search for new generation safer smallpox vaccine entails review of biology of VLVs in the smallpox-free world. In this review, we present occurrence of VLVs in the world with exhaustive discussion particularly on the emergence and re-emergence of these viruses in India and Brazil where VLVs are sufficiently studied. PMID- 23729996 TI - Pandemic Influenza A H1N1 (2009) Virus: Lessons from the Past and Implications for the Future. AB - The recent pandemic by novel influenza A (H1N1) 2009 (pH1N1) virus is an emerging viral infection, being of significant international concern and requires intensive research. The virus spread in pandemic proportions, and continues to be in the post-pandemic phase. Since, the pH1N1 is still circulating in the community, monitoring is required during the post-pandemic period. The pH1N1 defied influenza seasonality and rapidly became dominant over the seasonal influenza viruses. This new strain was antigenically different from the seasonal H1N1 influenza strains due to the genetic re-assortment. Surprisingly, this new reassortant virus emerged at the end of influenza season, caused a sudden toll of mild illness and is now co-circulating with the seasonal strains. The recent outbreak of pH1N1 consolidates the fact that a new reassortant virus may have originated in animal reservoirs and got transferred to human who were in close contact with these animals. There is a continued need for multisite surveillance to detect potentially dangerous influenza strains, which may emerge and establish themselves in human population. This review is an attempt to address the lessons learnt from the recent influenza pandemic and the future implications for prevention and control of influenza. PMID- 23729997 TI - Loop-Mediated Isothermal Amplification Assay for Rapid Detection of Hepatitis C virus. AB - Hepatitis C virus (HCV) is a major public health problem and a leading cause of chronic liver disease. An estimated 180 million people are infected worldwide. In this study, we developed a loop-mediated isothermal amplification (LAMP) assay for rapid detection of HCV genomic RNA and compared the sensitivity of LAMP with nested-PCR. A total of 30 blood samples from HCV-infected patients were analyzed with six primers targeting conserved sequences of the HCV 5'UTR within 70 min, under isothermal conditions at 62 degrees C. Then, visualized by gel electrophoresis with ethidium bromide staining and detected by the naked-eye after adding SYBR Green I. All samples positive for HCV by nested PCR were confirmed by LAMP method. When visualized by gel electrophoresis and ethidium bromide staining, the HCV LAMP assay products appeared in a ladder pattern, with many bands of different sizes. The HCV LAMP product could also be detected by the naked-eye after adding SYBR Green I to the reaction tube and observing a color change from orange to green in positive samples. The HCV LAMP had the same sensitivity as a nested-PCR assay, the detection limit for the both systems were found to be 10 copies/mL of HCV RNA. The LAMP assay reported here is superior for rapid amplification, simple operation, and easy detection and will be useful for rapid and reliable clinical diagnosis of HCV in areas with limited resources, such as developing countries. PMID- 23729998 TI - Prevalence and molecular genotyping of group a rotaviruses in Iranian children. AB - Rotavirus is the leading cause of acute gastroenteritis in worldwide young children. Effective vaccines to prevent rotavirus infection are currently available, although their clinical use is still limited, and rotavirus still causes many episodes of infantile gastroenteritis, mainly during the winter season. The aim of this study was to evaluate the prevalence of rotavirus infection in children aged <5-years-old who were hospitalised for gastroenteritis. One hundred and sixty-three stool samples from hospitalised children (<5-years-old) complicated with severe diarrhoea, in two hospitals in Jahrom City, Iran were collected from 2009 to 2010. Antigenic prevalence of rotavirus group A was distinguished by enzyme immunoassay. The antigen of group A rotavirus was diagnosed by EIA in 75 of 163 collected samples. The genotype of EIA-positive samples was determined by nested RT-PCR. The frequency of rotavirus genotypes G1, G2, G3, G4 and G9 was 17.33, 13.34, 2.67, 30.66 and 2.67 %, respectively. Also, the frequency of mixed and non-typable genotypes was detected in 2.67 and 30.66 %, respectively. G1/G8 mixed infection was the first of these rotavirus genotypes to be reported in Iran. Detection of high prevalence of group A rotavirus infection in hospitalised children with diarrhoea, and determination of circulating rotavirus genotypes in this region of Iran, provide useful data for formulating effective vaccines; especially for infants less than 5-years-old. PMID- 23729999 TI - Seroprevalence and Molecular Characterisation of Human Hepatitis A virus in Serum Samples of Tunisian Patients with Clinical Symptoms of Viral Hepatitis. AB - The aim of the present study was to investigate the seroprevalence of Hepatitis A virus antibodies in patients with clinical symptoms of viral hepatitis and molecular characterization of the detected isolates. The present study deals with the seroprevalence and the genetic diversity of HAV in 400 Tunisian patients presenting in dispensaries (160 patients) and in University Hospitals (240 patients) with hepatitis symptoms between 2006 and 2008. The patients with acute hepatitis were mainly from rural regions. However, the total number of patients was decreased over time. The collected samples were from patients with hepatitis symptoms occurring mainly during January-March (36.7, 26, and 35.5%) and September-December (39.4, 43.4, and 35.5%) during the three years of study, respectively. However, HAV infection was established for only 110 among 400 patients. The detected isolates were clustered within sub-genotype IA. The present study constituted another report of the continued surveillance of HAV infection in the region of Monastir and the molecular characterisation of the detected strains. PMID- 23730000 TI - Low Level of Cross-Reactive Antibodies to Pandemic Influenza (H1N1) 2009 Virus in Humans in Pre-Pandemic Period in Maharashtra, India. AB - In India, the first outbreak of pandemic influenza (H1N1) 2009 (H1N1pdm) was reported from Panchgani, Maharashtra, in June 2009. Studies from several countries have revealed different levels of pre-existing immunity to H1N1pdm 2009 in various age groups. This study was undertaken using age-stratified pre pandemic human sera to understand baseline cross-reactivity of antibodies against H1N1pdm. Using cut off antibody titers 20 and 40, overall cross-reactivity was 2.1 and 0.9% respectively by microneutralization assay; 1.2% and 0.7% by haemagglutination inhibition assay, respectively. Results showed higher baseline antibodies and cross-reactive antibodies in the 0-19 age group whereas the elderly age group (>=60) showed no cross-reactivity to H1N1pdm. The higher baseline and cross-reactive antibodies in 0-19 years age group could be because of higher positivity to seasonal H1N1 in that age group. Overall, low level of cross-reactive antibodies to H1N1pdm virus were found in humans in pre-pandemic period in Maharashtra, India. PMID- 23730001 TI - Evaluation of Reference Genes for the Relative Quantification of Apple stem grooving virus and Apple mosaic virus in Apple Trees. AB - A SYBR Green((r))-based one step RT-qPCR assay was developed for the detection and quantification of Apple stem grooving virus (ASGV) and Apple mosaic virus (ApMV). The RT-qPCR assay employed seven plant-expressed genes-glyceraldehyde 3 phosphate dehydrogenase (GAPDH), 18S ribosomal RNA, ubiquitin, ribosomal protein S19, Rubisco, RNA polymerase subunit II and beta-actin-as internal reference housekeeping genes in a relative quantification system in three apple cultivars (i.e. Idared, Champion, Fragrance). The average expression stability (M) found by GeNorm software suggest that GAPDH and S19 were the most stable reference genes. We propose employing GAPDH and S19 as housekeeping genes for accurate quantification of ASGV and ApMV in apple leaf samples. The detection limit for both viruses was found around 70 copies of viral genome by one-step RT-qPCR. PMID- 23730002 TI - Tomato leaf curl New Delhi virus is Associated With Pumpkin Leaf Curl: A New Disease in Northern India. AB - During 2006, pumpkin leaf curl-a new disease was observed in the experimental field at Indian Agricultural Research Institute. The disease was characterized by upward leaf curl with chlorotic patches and stunting of plant. Polymerase chain reaction (PCR) with coat protein specific primers to Tomato leaf curl New Delhi virus (ToLCNDV) indicated association of a begomovirus with the disease. The sequence comparison and phylogenetic analysis of the complete DNA genome further revealed the identity of the virus as ToLCNDV. The study provides evidence that ToLCNDV is associated with the leaf curl of pumpkin (Cucurbita moschata) in northern India. PMID- 23730003 TI - In Vitro Expression and Production of Antibody Against Cymbidium mosaic virus Coat Protein. AB - Polyclonal rabbit antisera were produced using coat protein of Cymbidium mosaic virus (CymMV) Indian isolate expressed in E. coli as GST fusion. The expressed protein was purified by GST-fusion protein purification kit for use as an immunogen in rabbits. Antisera prepared in this manner reacted in double antibody sandwich enzyme-linked immunosorbent assay (DAS ELISA) with extract from CymMV infected tissue. The results indicate that polyclonal antisera prepared from expressed CymMV coat proteins were useful for the detection of CymMV in an array of assays. The detection system developed is highly effective for detection of Indian strain of the virus in comparison to kits available in the international market. PMID- 23730004 TI - Molecular Characterization of Phylogenetically Distinct Isolates of Grapevine fanleaf virus from Iran Based on 2A(HP) Gene. AB - Movement and coat protein genes from Grapevine fanleaf virus (GFLV) isolates have been characterized previously from Iran. In this study, an optimized reverse transcription polymerase chain reaction protocol was established to amplify RNA2 genomic segment corresponding to the hypothetical protein (2A(HP)). The sequence of 2A(HP) was compared with that of previously reported GFLV strains/isolates from other countries which showed 82-86% sequence identities. The 2A(HP) gene from Iran appeared to be standing distinct from other isolates of GFLV when genetic distance- or parsimony-based phylogeneitc analyses were carried out. The present study for the first time reports characterization of Iranian isolate of GFLV based on 2A(HP) gene. PMID- 23730005 TI - Biological and Molecular Characterization of Cucumber mosaic virus Isolate Causing Shoestring Disease of Tomato in India which has Closer Affinity to European or East Asian Isolates of CMV. AB - An isolate of Cucumber mosaic virus (CMV) retrieved from tomato in India was characterized based on its transmission by sap inoculations, Western blot immuno assay and sequence analysis of RNA3 and 2b genome. The RNA3 genome was of 2,220 nucleotides (nt) which contained two ORFs: movement protein of 852 nt translating 283 amino acids and coat protein of 657 nt translating 218 amino acids. The complete sequence of RNA3 geneome (Acc. EF153734) shared highest 98-99% identities with P1-1, Tfn, and Nt9 strains of CMV infecting tomato reported from abroad. The 333 nucleotides long RNA2b gene (Acc. EF710773) also showed highest 98% identities with P1-1 and 97% with Tfn and NT9 strains of CMV but only 83-84% identities with Indian strains of CMV. Therefore, the isolate under study was identified as a new isolate of CMV of subgroup IB based on highest sequence similarities and closer affinity to European or East Asian isolates of CMV. PMID- 23730006 TI - Evidence of the Association of Radish leaf curl virus with Tobacco Yellow Leaf Curl Disease in Bihar, India. AB - A new disease of tobacco with characteristic mild leaf curl and yellowing symptoms was observed in 2007 in commercial plantings in Pusa, Bihar, India. A begomovirus and a betasatellite were found associated with the disease. The associated begomovirus was identified as a strain of Radish leaf curl virus (RaLCV) based on nucleotide sequence of the viral genome (2,761 nucleotides; EU194914). The betasatellite (HQ180397) associated with TbYLCD was identified as a variant of Chilli leaf curl betasatellite (ChLCB). Recombination events were detected both in the RaLCV and ChLCB sequences. This is the first report of yellow leaf curl disease of tobacco, and the association of RaLCV with a disease of tobacco. PMID- 23730007 TI - Detection of Corchorus golden mosaic virus Associated with Yellow Mosaic Disease of Jute (Corchorus capsularis). AB - Yellow mosaic disease, caused by a whitefly transmitted New World Begomovirus, named Corchorus golden mosaic virus (CoGMV), is emerging as a serious biotic constraint for jute fibre production in Asia. For rapid and sensitive diagnosis of the Begomovirus associated with this disease, a non-radiolabelled diagnostic probe, developed against the DNA A component of the east Indian isolate of CoGMV, detected the presence of the virus in infected plants and viruliferous whiteflies following Southern hybridization and nucleic acid spot hybridization tests. Presence of the virus was also confirmed when polymerase chain reaction amplification was performed using virus-specific primers on DNA templates isolated from infected plants and viruliferous whiteflies. PMID- 23730008 TI - Determination of major viral and sub viral pathogens incidence in apple orchards in himachal pradesh. AB - Apple is the major commercial horticulture crop in Himachal Pradesh and other hill states of Jammu & Kashmir, Uttarakhand and some parts of Northeastern states of India. In order to gather data on health status and incidence of virus and virus-like pathogens in apple orchards, survey was conducted in the month of June and September, 2010 in Hatkoti, Rohru, Kuthara, Jubbal and Khadapathar areas of major apple producing Shimla district of Himachal Pradesh. A total of 250 samples were collected and analyzed by DAS-ELISA, NASH and RT-PCR. NASH results indicated that a total of 117 samples were infected with Apple chlorotic leaf spot virus (ACLSV), Apple mosaic virus (ApMV), Apple stem grooving virus (ASGV), Apple stem pitting virus (ASPV) and Apple scar skin viroid (ASSVd). Results showed that ASSVd is predominant in these areas with highest infection rate of 27.6% followed by ASPV (17.2%), ACLSV (16.8%), ApMV (15.2%) and ASGV (12%). Mixed infection of these viruses and viroid was frequently detected in apple trees in Himachal Pradesh. The trees, which were positive for viruses and viroids, showed a variety of fruit deformation and rusting symptoms besides leaf deformation, mosaic and chlorosis. PMID- 23730009 TI - First Report of Tobacco streak virus Infecting Kenaf (Hibiscus cannabinus) in India. AB - The natural occurrence of Tobacco streak virus (TSV) in Hibiscus cannabinus was detected by enzyme-linked immunosorbent assay using an antiserum raised against TSV and reverse transcription polymerase chain reaction (PCR) using primers specific for the coat protein gene of the virus. Sequence analysis of the PCR products showed 99.6 and 99.5% of maximum identity at nucleotide and amino acid levels, respectively with TSV onion isolate from Kurnool (HM131490).This is the first report of the natural occurrence of TSV on kenaf in India. PMID- 23730010 TI - First report of association of a begomovirus with the leaf curl disease of a common weed, datura inoxia. PMID- 23730011 TI - Multiple myeloma in post nuclear accident crisis. AB - The problem of 2011 nuclear accident crisis draws attention of physicians and medical scientists around the world. The cancer induction is an important adverse effect of exposure to radionuclide. In this specific article, the multiple myeloma, an important hematological cancer, in the post nuclear accident crisis will be discussed. PMID- 23730012 TI - Treatment with Thalidomide and Cyclophosphamide (TCID) is Superior to Vincristine (VID) and to Vinorelbine (VRID) Regimens in Patients with Refractory or Recurrent Multiple Myeloma. AB - Treatment of relapsed or refractory multiple myeloma remains a challenge and novel treatment regimen are required. Here, a matched pair analysis was performed comparing TCID (thalidomide, cyclophosphamide, idarubicin, dexamethasone) treatment to the treatment of patients with VID (vincristine, idarubicin, dexamethasone) or with VRID (vinorelbine, idarubicin, dexamethasone) for relapsed or refractory multiple myeloma. In total, 197 patients were enrolled in multicenter trials. After matching for important prognostic variables 46 matched pairs (total of 138 patients) could be analysed with regard to survival, toxicity and efficacy. Interestingly, a significant improvement of overall response rate (ORR) for TCID treatment compared to VID and VRID was found. In addition, TCID treatment also led to a significantly higher overall survival (OS) as well as progression-free survival (PFS) compared to VID and VRID. In conclusion, TCID treatment appears to be superior to VRID and VID treatment in patients with progressive or refractory myeloma. PMID- 23730013 TI - Prevalence and characterization of thrombocytopenia in pregnancy in Indian women. AB - To find the prevalence and causes of thrombocytopenia during pregnancy. An analytical prospective observational study was conducted in Department of Obstetrics & Gynecology, CSMMU, Lucknow. 1079 antenatal women screened for thrombocytopenia and investigated for cause and management strategies and fetomaternal outcome were recorded. Prevalence of thrombocytopenia was 8.8%. Gestational thrombocytopenia was seen in 64.2%, obstetric in 22.1% and medical in 13.68% cases. Mean platelet count in controls was lower with a significant fall (P < 0.001) in the platelet count as pregnancy advanced. Hypertensive and hepatic disorders were the most common obstetric causes of thrombocytopenia. Mode of delivery was not affected by thrombocytopenia. Maternal morbidity and mortality was seen only in medical and obstetric thrombocytopenia. The low platelet counts and declining trend with increasing gestational age predispose Indian women to risk of thrombocytopenia and a routine platelet count is suggested. PMID- 23730014 TI - Imatinib mesylate therapy in patients of chronic myeloid leukemia with Philadelphia chromosome positive: an experience from eastern India. AB - Imatinib inhibits constitutively active BCR-ABL tyrosine kinase of chronic myeloid leukemia (CML). In a long term study it was found superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. However, till date there is no major study to evaluate eastern Indian CML patients treated with imatinib mesylate. The aim of our study was to see the efficacy, tolerability, toxicity and safety of imatinib in eastern Indian subset of CML population. The present study enrolled 831 patients with CML out of which 197 were excluded due to various reasons of noncompliance, death and not being fit to receive the drug. The rest, 634 (76% of total enrolled) were selected for the evaluation. In the beginning of the study, 603 patients were in chronic phase, 27 in accelerated phase and 4 patients in blast crisis phase. Among 634 patients, 280 patients (44%) received previously either interferon alpha or hydroxyurea and other 354 patients (56%) were previously untreated. Complete hematological remission and major cytogenetic response were 91 and 67%, respectively after 1 year of treatment. Complete molecular remission was 35% after 1 year of treatment. Sixty four patients (10.1%) were resistant to imatinib mesylate in 5 years. The disease free and overall survival at 60 months were 72.2 and 76.1% respectively. After 60 months of follow up, continuous treatment of chronic phase CML with imatinib as initial therapy was found to be safe and able to induce durable responses in a high proportion of patients. PMID- 23730015 TI - Flowcytometric immunophenotypic profile of acute leukemia: mansoura experience. AB - Acute leukemia (AL) displays characteristic patterns of antigen expression, which facilitate their identification and proper classification. The purpose of this study is to evaluate the diagnostic usefulness of commonly used immune-markers for immunophenotyping of AL and to define the best immune-markers to be used for proper diagnosis and classification of AL. Besides, to recognize the frequency of different AL subtypes and the antigen expression profile in our Egyptian patients. We retrospectively analyzed the immunophenotypic data of 164 de novo AL patients from our institution during 2009 and 2010. Among these patients, 68.9% were classified as acute myeloblastic leukemia (AML) while 31.1% classified as acute lymphoblastic leukemia (ALL). The commonest FAB subtype in AML group was AML-M4/5 (34.5%) which may differ from most published data. As regard ALL, there were 74.5% with B-ALL and 25.5% with T-ALL. It was found that combined use of HLADR and CD34 was much more helpful in distinguishing APL from non-APL AML than either of these antigens alone. It was found that cCD79a and CD19 were the most sensitive marker for B-ALL while cCD3, CD7 and CD5 were the most sensitive antigens for T-ALL. Our analysis of AL phenotypes proved that employed antibody panels are adequate for proper diagnosis and classification of AL. Flowcytometry was found to be especially useful in the identification of AML-M0 and differentiation of APL from non-APL AML. Immunophenotyping results and FAB classification of our AL patients were comparable to internationally published studies apart from predominance of AML-M4/5 and more frequent APL. PMID- 23730016 TI - Electrochemical assay of heparin to monitor anticoagulation action in cardiovascular patients. AB - Complications in anticoagulation therapy and long term consequences of the post thrombotic syndromes requires a fast and powerful therapy such as heparin therapy (anticoagulation) to minimize the thrombotic effects in patients. Thus, a simple approach via electrochemical method: Differential pulse polarography (DPP) has been developed for heparin analysis as a powerful clinical tool to monitor anticoagulation action in-patient undergoing heparin therapy. The method has been standardized for determination of heparin activity over the existing methods and a very well defined characteristic reduction peak at -1.25 V in 2 M NaOH was observed for heparin. A linear relation was observed with a regression equation as y = 0.3117x + 0.8069, for 0.1 to 2.0 units/ml heparin. The developed DPP method was observed with excellent precision, accuracy and recovery in human blood plasma samples and in pharmacological formulations. The limit of detection (LOD) and limit of quantification (LOQ) noticed to be 2.04 and 6.8 units/ml respectively. The DPP results compared with pharmacological screening through average thrombin time (TT) and applied to monitor invitro anticoagulation action of heparin in healthy human subjects. Statistical analysis done to validate developed DPP method for heparin analysis and its probable clinical use to monitor anticoagulation action to treat patients suffering from various cerebrovascular disorders (CVD) by proper dosing of heparin. PMID- 23730017 TI - A study of plasma fibrinogen level in type-2 diabetes mellitus and its relation to glycemic control. AB - The high prevalence of classic cardiac risk factors in patients with type 2 diabetes mellitus does not explain the increased cardiovascular related morbidity and mortality in these patients. Fibrinogen may have a role in this excess risk. This study is undertaken to know the fibrinogen levels in type 2 diabetes mellitus and its relations to glycemic control. In the present study fibrinogen levels (Clauss method) were estimated in 100 type 2 diabetic subjects and 100 age and sex matched controls. Fibrinogen was correlated with various parameters like glycosylated hemoglobin (cation exchange resin method), age, sex, smoking, body mass index (kg/m(2)), hypertension and ischemic heart disease. Higher plasma fibrinogen levels were found in type 2 diabetes mellitus patients (656 +/- 130 mg/dl) as compared to controls (324 +/- 139 mg/dl) which were statistically significant. Fibrinogen levels were associated with age (P < 0.01), hypertension (P < 0.01), body mass index (P < 0.01), smoking (P < 0.01), ischemic heart disease (P < 0.01), and glycosylated hemoglobin (r = 0.49) in diabetics in a significant manner. But no correlation was found with sex (P < 0.05) in diabetes. In controls, association was found between fibrinogen levels and smoking (P < 0.01) and body mass index (P < 0.01). Patients with type 2 diabetes mellitus had a high prevalence of hyperfibrinogenemia. Fibrinogen levels were independently associated with hemoglobin A1c values, which suggests that fibrinogen may be involved in the increased cardiovascular risk of patients with type 2 diabetes mellitus. PMID- 23730018 TI - Thrombocytopenia in HIV-Infected Patients. AB - Thrombocytopenia is a common feature among HIV-positive patients. However, there are few reports about this subject after highly active antiretroviral therapy (HAART) introduction. The authors show a retrospective description of epidemiology, clinical aspects, and treatment observed in 55 HIV-positive outpatients with thrombocytopenia treated in two reference centers for HIV treatment in Sao Paulo, Brazil. Thirty-four (62%) patients were male, 50 (91%) were Caucasian, with median of lymphocytes TCD4 of 394 cells/mm(3). In 63.6% patients, the cause of thrombocytopenia was classified as immune thrombocytopenic purpura and non immune in 25.5%. Regular use of HAART was present in 43.6% of the population studied. In 20% HAART was initiated for thrombocytopenia treatment with improvement in platelets count observed after 3 months. Platelet transfusion was needed in 23.7% of the patients and one patient died due to bleeding. Thrombocytopenia is still common among patients infected with HIV, considered a multifactor disorder, commonly due to immune mechanisms in our cases. In the clinical setting, a diagnostic approach related to the hematological consequences of HIV infection is needed for a better therapy option for this population. PMID- 23730019 TI - Case report on a child with paroxysmal cold haemoglobinuria. AB - PCH is one of the most common causes of acute AIHA in young children, although it affects patients of all ages. In children it is commonly seen following a viral illness or after immunization. Donath Landsteiner test is the diagnostic test. This is a case report of a child who presented with features of haemolysis and was diagnosed as PCH. PMID- 23730020 TI - Successful treatment of refractory idiopathic thrombocytopenic purpura and neutropenia with the monoclonal antibody, rituximab. AB - We describe a 22-year-old male with idiopathic autoimmune thrombocytopenia whose diagnosis was made at age of eight. He underwent splenectomy at age ten and ITP recurred at age 21 with episodes of infection and severe neutropenia (absolute count around 170/MUl). He showed no response to immunoglobulin, corticosteroids, danazol, cyclosporine and azathioprine. Anti-CD20 antibody was administered at a dose of 375 mg/m(2) once a week for 2 weeks. After the second infusion of rituximab, the platelet count increased from 4,000 to 516,000/mm(3) and neutrophils count raised from 180 to 545/mm(3). The response improvement persisted during follow up for 9 months (neutrophil count 4,390/mm(3)). This observation indicates that B-cells may play a central role in the pathogenesis of ITN. Anti-CD20 antibody therapy may be an efficient treatment for the patients with chronic or recurrent ITN. PMID- 23730021 TI - Hemophagocytic lymphohistiocytosis in a 19 year old critically ill patient. AB - Haemophagocytic lymphohistiocytosis (HLH) describes a clinical syndrome of hyperinflammation resulting in an uncontrolled and ineffective immune response. It presents with a clinical picture of likely sepsis, i.e., fever, laboratory evidence of inflammatory response, coagulopathy and thrombocytopaenia should be appropriately investigated and managed for sepsis, but the possible diagnosis of HLH should be borne in mind. Awareness of the clinical symptoms and of diagnostic criteria for HLH is crucial to starting immunosuppressive/immunomodulatory and cytotoxic drugs in time. We present a case of HLH in a 19 year old male who presented with fever, neurological symptoms, cytopaenias, laboratory markers of inflammation and bone marrow aspirate showed hemophagocytosis. PMID- 23730022 TI - Anti Rh Hemolytic Disease due to Anti C Antibody: Is Testing for Anti D Antibodies Enough? AB - Rh blood group system is a complex blood group system. Rh antibodies are produced in Rh negative individuals following exposure to foreign RBCs after transfusion or pregnancy. Anti C is a rare cause of hemolytic disease of newborn and is very scarcely reported in the literature. The aim of the present case report of Hemolytic disease caused by Anti C antibody is to bring out the fact that antibodies other than anti D should be considered in cases that give a suggestive history but no evidence of Anti D. PMID- 23730023 TI - Acute parvovirus b19 infection leading to severe aplastic anemia in a previously healthy adult female. AB - Human Parvovirus B19 has been linked to a variety of diseases. One of the most common complications is transient aplastic crisis in patients with chronic hemolytic anemia. Very few case reports have implicated this virus as a putative etiology behind hepatitis and severe aplastic anemia in immuno competent individuals. We report a case of severe aplastic anemia in a previously healthy adult female due to acute parvovirus B19 infection. Laboratory examination showed pancytopenia in peripheral blood and severe hypoplastic bone marrow on biopsy. Serological analysis (ELISA) revealed acute Parvovirus B19 infection. In the face of unavailable HLA matched bone marrow donor, immuno-supressive therapy was contemplated, but could not be given because of financial constraints. Pancytopenia persists till date, 4 months after the diagnosis, with the patient requiring repeated packed red cell and irradiated platelet transfusions. Thus, acute infection with this virus must be considered a cause of acquired aplastic anemia even in individuals without underlying disease. PMID- 23730024 TI - Hemolysis in E. coli O104:H4 Infection. PMID- 23730025 TI - Seroprevalence pattern in blood bank: further consideration. PMID- 23730026 TI - Hormone replacement therapy: an update. PMID- 23730027 TI - Indian contribution to obstetrics and gynecology. PMID- 23730028 TI - Pregnancy and skin. AB - INTRODUCTION: Skin changes occur in about 90 % pregnant women in one form or the other. The various skin changes maybe either physiological (hormonal), changes in pre-existing skin diseases or development of new pregnancy-specific dermatoses. All of these dermatoses can be attributed to the profound hormonal, vascular, metabolic, and immunological changes occurring during pregnancy. CLASSIFICATION: Pregnancy-specific dermatoses have now been classified into dermatoses which are definitively associated and dermatoses with uncertain association with pregnancy. Though most of these skin dermatoses are benign and resolve in postpartum period, a few can risk fetal life and require antenatal surveillance. Most of the dermatoses of pregnancy can be treated conservatively but a few require intervention in the form of termination of pregnancy. CONCLUSION: Careful history taking and examination will help us to identify each condition clinically and appropriate management can be instituted for the well-being of the mother and the fetus. PMID- 23730029 TI - Obstetric behavior and pregnancy outcome in overweight and obese women: maternal and fetal complications and risks in relation to maternal overweight and obesity. AB - OBJECTIVE: To perform analyses of maternal and fetal complications in overweight and obese women. METHODS: Eighty-seven women with singleton pregnancies with BMI > 25-29.9 kg/m(2) and 83 women with singleton pregnancies with BMI > 30 kg/m(2) were studied for maternal and fetal complications at Nehru Hospital, B.R.D. Medical College, Gorakhpur during June 2007-October 2008. Forty-five women with BMI 20-24.9 kg/m(2) were selected to serve as control. RESULTS: Compared with women with normal BMI, the outcomes which were more common in overweight and obese women were gestation hypertension (p < 0.05); pre-eclampsia (p < 0.001); preterm delivery (p < 0.05); induction of labor (p < 0.05); instrumental vaginal delivery (p > 0.05); cesarean section (p < 0.01); increased operative time (p < 0.01); still births (p < 0.05); early neonatal deaths (p < 0.05); Apgar score < 7 at 5 min (p < 0.05); and admission to NICU (p < 0.001). No significant differences were noted among groups regarding hypoglycemia hyperbilirubinemia and respiratory distress. CONCLUSION: Overweight and obesity are definite risk factors for adverse pregnancy outcomes. This may be due to altered metabolic state in obesity. PMID- 23730030 TI - Assessment of intravenous iron sucrose in the management of anemia in gynecological and obstetrical practice. AB - OBJECTIVE: The present study was undertaken to assess the impact of intravenous iron sucrose (Feronia IV) in the treatment of iron deficiency anemia observed in gynecological and obstetrical practice. METHODS: Seventy-seven practicing gynecologists and obstetricians throughout India collaborated in the recruitment of 145 women over a period of 1 year, of which 143 were analyzable cases. RESULTS: The overall mean rise in hemoglobin level was observed to be 2.43 gm % at the end of 4 weeks. The dose of iron sucrose administered ranged from 100 to 1,050 mg. In women who received 200 mg of the drug, and the mean Hb rise was found to be 2.21 +/- 1.06 gm %. The highest observable rise in hemoglobin level was 5.5 gm % with 800 mg of iron sucrose. No serious adverse reactions were reported during the observation period. CONCLUSION: Intravenous Iron sucrose is a safe and effective treatment for the rapid reversal of iron deficiency anemia, in obstetric and gynecological settings. PMID- 23730031 TI - Can community-based, low-cost antenatal care in the third trimester of pregnancy reduce the incidence of low birth weight newborns? AB - OBJECTIVE: To determine if community-based, low-cost interventions during third trimester of pregnancy can reduce the incidence of low birth weight babies. METHODS: In a case control study, 290 pregnant women from a slum area were registered in the beginning of third trimester of pregnancy and provided full antenatal care comprising fortnightly check up, one IFA tablet daily, counseling for minimum one-and-a-half hour post-lunch rest in left lateral position, additional diet to ensure minimum 2,200 kcal per day, and management of clinical conditions, if any. An equal number of pregnant women belonging to the same slum area were registered as control who received routine antenatal services from the existing health care facilities. The birth weight of the babies in the two groups were recorded and compared. Test of significance and correlation coefficient were applied to the data. RESULTS: Mean birth weight of the babies of the Subjects was 2.76 kg (SD 0.39) compared to mean birth weight of 2.57 kg (SD 0.36) of the babies in the Control group. Incidence of low birth weight babies among subjects who consumed minimum 2,400 kcal per day, had one-and-a-half hour post-lunch rest in left lateral position and who consumed one tablet of IFA (100 mg iron and 5 mg folic acid) per day during the last trimester of pregnancy was lower (17.6 %) as compared with women in the Control group (36.2 %). The difference in the mean birth weight of newborns of the two groups was statistically significant (t = 2.52, p < 0.01). CONCLUSIONS: Incidence of low birth weight babies can be significantly reduced by providing simple, low-cost care to pregnant women during the last trimester of pregnancy in the community setting. PMID- 23730032 TI - Obstetric emergencies: role of obstetric drill for a better maternal outcome. AB - OBJECTIVE: To evaluate factors contributing to obstetric emergencies, analyze the fetomaternal outcome and role of obstetric drill in facing these emergencies effectively. MATERIAL AND METHOD: Out of 10,892 deliveries, a total of 520 women were included in this prospective study. Analysis of emergency obstetric conditions was done by evaluating incidence, various contributing factors, and fetomaternal outcome. Obstetric drill was conducted among residents repetitively. Pre drill and post drill assessment of confidence in clinical, knowledge, and team work skills were compared by chi(2) test. Impact of drill on severe obstetric morbidities was noted. OBSERVATIONS: Incidence of obstetric emergencies was found to be 4.88 %. Maternal and perinatal mortality was seen in 4.23 and 37.11 %, respectively, of these emergency obstetric women. Impact of drill showed an increase in score in knowledge (p < 0.019), confidence (p, 0.001), and team work (p < 0.001). CONCLUSION: Active implementation of emergency obstetric care and incorporation of obstetric drill lays a strong foundation for safe fetomaternal outcome. PMID- 23730033 TI - Prediction of preeclampsia by midtrimester uterine artery Doppler velocimetry in high-risk and low-risk women. AB - OBJECTIVE: To observe the role of uterine artery Doppler flow velocimetry at midtrimester in prediction of preeclampsia. METHOD: 179 women carrying <16 weeks of pregnancy, with singleton fetus and without any fetal anomaly were recruited and were divided in high-risk and low-risk group. Doppler velocimetry of uterine artery was done at 24-26 weeks. Any notch in uterine artery, unilateral or bilateral, or RI > 0.6, was considered abnormal. Women were followed up and development of preeclampsia noted. RESULT: Sensitivity and specificity of abnormal uterine artery Doppler study for prediction of preeclampsia were 73.33 and 86.48 % in high-risk and 57.14 and 95.83 % in low-risk group, respectively. Relative risk with 95 % confidence interval was 5.427 (2.272-12.958) in high-risk and 13.65 (5.669-32.865) in low-risk women. CONCLUSION: Doppler velocimetry of uterine artery at 24 weeks can be used as a reliable screening test for prediction of preeclampsia in both high-risk and low-risk women. PMID- 23730034 TI - Pregnancy complicated by maternal heart disease: a review of 281 women. AB - OBJECTIVES: To study maternal heart disease in an Indian setting for: (1) different etiological factors, (2) different types of lesions, and (3) maternal and perinatal outcome. METHODS: 281 women with heart disease who delivered >=28 weeks of gestation at different teaching institutions (tertiary care centres) in India were studied. RESULTS: Rheumatic heart disease (n = 195; 69.4 %) with isolated mitral stenosis (n = 75; 26.7 %) were the commonest. Septal defect (n = 27; 9.6 %) was the predominant lesion among the congenital heart disease (n = 60; 21.3 %) patients, whereas in the miscellaneous group (n = 26; 9.2 %), ischemic heart disease (n = 10; 3.6 %) was the leading cause. Multiple cardiac lesions were also diagnosed in 100 (35.58 %) women. In 87 (31 %) women, diagnosis was made first time in labor. Majority n = 131, (46.6 %) had spontaneous vaginal delivery and few (n = 9; 3.3 %) required induction of labor. Cardiac complications were noted in 72 women (25.6 %). There were three (1.06 %) maternal deaths and perinatal mortality was 4 % (n = 11). CONCLUSION: In this study, rheumatic heart disease in pregnancy is still predominant though acquired cardiac lesions are rising. In rheumatic heart disease, mitral valve involvement was the commonest and multiple valve lesions were a major observation. Most common obstetric complication was small for gestation baby. Maternal morbidities in the unbooked women are high and congestive cardiac failure was the major cardiac complication. PMID- 23730035 TI - Trends in Maternal Mortality and Impact of Janani Suraksha Yojana (JSY) on Maternal Mortality Ratio in a Tertiary Referral Hospital. AB - OBJECTIVE: To analyse the impact of Janani Suraksha Yojana (JSY) on Maternal Mortality Ratio (MMR). DESIGN: Retrospective analysis of maternal mortality. METHODS: Analysis of all maternal deaths between January 2001 and December 2009. RESULTS AND DISCUSSION: The total number of deliveries has been steadily rising from 1,685 in 2001 to 3,957 in 2009. The MMR doubled from 1,500/100,000 live births in 2001 to 3,000/100,000 live births in 2006, then declined to 2,464/100,000 live births in 2009. Implementation of the various maternity benefit schemes has had no significant impact on the profile of dying mothers admission-to-death interval. Deaths due to anemia and eclampsia have significantly increased (P < 0.05), whereas due to sepsis (P < 0.001) and hemorrhage (P < 0.05), deaths have significantly decreased. Almost 96 % of dying subjects received inadequate antenatal care. However, significantly less number (P < 0.001) of women are delivering at home. CONCLUSIONS: There is a need to stress the importance of good antenatal care in reducing MMR. PMID- 23730036 TI - A prospective study for the prediction of preeclampsia with urinary calcium level. AB - OBJECTIVES: To assess the efficacy of calciuria as a diagnostic test for the prediction of preeclampsia, and also to determine the changes in urinary excretion of calcium in preeclampsia and normotensive women. METHODS: A prospective study was conducted on 60 primi mothers in the age group of 20-30 years, and all were enrolled at 16 weeks of gestation with clinical follow up by 4 weeks and 24 h urinary calcium and creatinine estimation. Ten mothers developed preeclampsia (study groups) and fifty remained normotensive (control groups). By means of Receiver-operator curve, a cut-off level of urinary calcium in 24 h was chosen for predicting preeclampsia. RESULTS: Preeclamptic women excreted significantly less total urine calcium (87.0 +/- 3.59 mg/24 h) than normotensive women (303.68 +/- 17.699 mg/24 h) (p < 0.0001) at 40 weeks of gestation. Urinary calcium and calcium/creatinine (Ca:Cr) ratio decreases progressively from 28 weeks to 40 weeks in the study group when compared to normotensive group. CONCLUSIONS: Preeclamptic women excrete less calcium than normotensive women. This parameter would predict preeclampsia earlier in pregnancy. PMID- 23730037 TI - Iron deficiency anemia in pregnancy: intravenous versus oral route. AB - OBJECTIVES: The aim of this study was to compare the efficacy and safety of intravenous iron with oral iron in the treatment of iron deficiency anemia of pregnancy. METHODS: A randomized experimental study was conducted at K. J. Somaiya Hospital involving 200 pregnant women with iron deficiency anemia. In the intravenous group iron dose was calculated from: Total iron dose required (mg) = 2.4 * weight kg * target hemoglobin - actual hemoglobin) g/dl + 500. Target hemoglobin was set at 12 g/dl. In the oral group patients received 200 mg oral ferrous ascorbate daily. Hemoglobin and serum ferritin were reviewed at 2, 4, and 6 weeks. Paired and independent t test was applied. RESULTS: The change in hemoglobin and ferritin levels from baseline was significantly higher in the intravenous group than the oral group at each measurement (P = 0.000). CONCLUSION: Intravenous iron elevates hemoglobin and restores iron stores faster than oral iron, with no severe adverse reactions. PMID- 23730038 TI - Granulosa cell tumours: a study of 37 cases. AB - OBJECTIVES: To evaluate the clinico-pathological features, surgical procedures and postoperative treatment and their relation to survival in women with granulosa cell tumours. METHODS: Data of 37 women with granulosa cell tumours were collected and reviewed retrospectively. Mann-Whitney test, log rank test and Kaplan-Meier survival analysis were applied appropriately. RESULTS: Thirty-seven women of median age 48.6 years were diagnosed in stage Ia (45.9 %), stage Ic (27 %), stage III (16.2 %) and unstaged (10.8 %). The median follow up was 5 years. Overall survival was 93 % at 5 years. Disease-free survival at 5 years was 63 %. Tumour stage and residual disease were associated with poor prognosis (p < 0.001). Mitotic rate and tumour grade were not of prognostic significance. CONCLUSIONS: Stage of disease and residual disease are valuable prognostic factors. Prospective studies with large sample sizes and long-term follow up are needed to confirm our findings. PMID- 23730039 TI - Massive fibrinoid debris in the uterus causing post partum hemorrhage. PMID- 23730040 TI - Total abdominal hysterectomy in a patient with uncorrected truncus arteriosus. PMID- 23730041 TI - The XY Female (Androgen Insensitivity Syndrome)-Runs in the Family. PMID- 23730042 TI - Giant haemangiopericytoma of the uterus. PMID- 23730043 TI - Sentinel lymph node biopsy in breast cancer-should it be the standard of care in India? PMID- 23730044 TI - Crucial controversies in surgery. PMID- 23730045 TI - Oophorectomy in breast cancer-controversies and current status. AB - The role of oophorectomy in the treatment of breast cancer is known for over 100 years. Ovarian ablation has a relatively large positive effect on both disease free survival (DFS) and overall survival (OS) in premenopausal women when compared to no adjuvant treatment. Today the standard of care in adjuvant therapy of endocrine responsive tumors in premenopausal women is tamoxifen with or without chemotherapy. The role of oophorectomy /ovarian ablation in current surgical practice is discussed and important issues highlighted in the article. PMID- 23730046 TI - Current Debates in Surgery - A Cross Sectional Study amongst Indian Surgeons. AB - Surgery like all fields of medicine is evolving rapidly and these new techniques are challenging to replace the existing 'standard of care'. Though some of these advances are here to stay, many of them are driven by a handful of surgeons influenced by market forces. In some controversial topics, there is a problem of plenty and it is difficult for a general surgeon to choose from the various options available. In order to address some of these contentious issues, a cross sectional, questionnaire based study was designed. The questionnaire was posted to surgeons across the country and it included 11 questions (single best answer format) on the current debates in surgery. The questionnaire was answered by 778 surgeons and gave rise to interesting observations. The practice of surgery is an interplay of patient- surgeon and market forces and more comprehensive studies are required to address these controversial topics in surgery. PMID- 23730047 TI - Controversies in fistula in ano. AB - Managing a complex fistula in ano can be a daunting task for most surgeons; largely due to the two major dreaded complications-recurrence & fecal incontinence. It is important to understand the anatomy of the anal sphincters & the aetiopathological process of the disease to provide better patient care. There are quite a few controversies associated with fistula in ano & its management, which compound the difficulty in treating fistula in ano. This article attempts to clear some of those major controversies. PMID- 23730048 TI - A review of controversies in the management of colorectal cancers. AB - Colorectal cancer (CRC) is one of the most common malignancies worldwide. Due to a higher incidence of CRC in the western hemisphere a significant amount of research was carried out and majority of the controversies could be resolved as far as management of CRC is concerned. Recently a number of significant advances were made in the field of CRC related to surgery, systemic therapy and radiotherapy. During the last decade we have witnessed introduction of minimally invasive surgery, incorporation of more effective newer chemotherapeutic regimes and targeted therapies and refinements in radiotherapy protocols. The demographics and clinical picture of CRC seems to be different in developing countries and there is paucity of CRC related studies from developing countries. In-order to update the practicing surgeons a review of conventional controversies of CRC surgery was performed and an update on the recent developments in the field of CRC was also presented in this article. PMID- 23730049 TI - A review of controversies in the management of soft tissue sarcomas. AB - Soft tissue sarcomas (STS) constitute a rare and challenging group of solid tumor in the field of oncology. Unlike other malignancies STS can affect a wide variety of anatomical regions in the body with varied histo-pathological variants and clinical outcomes. There are controversies in the diagnosis and management of STS due to rarity and heterogeneity of the disease entity. Due to dedicated research and advances made in the field of imaging, pathology, surgery, radiotherapy and chemotherapy certain controversies were laid to rest and treatment approach to STS could be standardized to a large extent in the recent past. A review of controversies related to STS was performed in this article and an attempt was made to present a balanced view pertaining to these issues. PMID- 23730051 TI - Current status of robotic surgery. AB - Surgery has increasingly become a technology-driven specialty. Robotic assistance is considered one innovation within abdominal surgery over the past decade that has the potential to compensate for the drawbacks of conventional laparoscopy. The dramatic evolution of robotic surgery over the past 10 years is likely to be eclipsed by even greater advances over the next decade. We review the current status of robotic technology in surgery. The Medline database was searched for the terms "robotic surgery, telesurgery, and laparoscopy." A total of 2,496 references were found. All references were considered for information on robotic surgery in advanced laparoscopy. Further references were obtained through cross referencing the bibliography cited in each work. There is a paucity of control studies on a sufficient number of subjects in robot-assisted surgeries in all fields. Studies that meet more stringent clinical trials criteria show that robot assisted surgery appears comparable to traditional surgery in terms of feasibility and outcomes but that costs associated with robot-assisted surgery are higher because of longer operating times and expense of equipment. While a limited number of studies on the da Vinci robotic system have proven the benefit of this approach in regard to patient outcomes, including significantly reduced blood loss, lower percentage of postoperative complications, and shorter hospital stays, there are mechanical and institutional risks that must be more fully addressed. Robotic assistance will remain an intensively discussed subject since clinical benefits for most procedures have not yet been proven. While the benefit still remains open to discussion, robotic systems are spreading and are available worldwide in tertiary centers. PMID- 23730052 TI - Incidentally detected gallbladder cancer- the controversies and algorithmic approach to management. AB - Incidentally discovered gallbladder cancer (IGBC) is defined as the gallbladder cancer (GBC) diagnosed during or after the cholecystectomy done for unsuspected benign gallbladder disease. Laparoscopic cholecystectomy (LC) is the most common procedure performed for benign gallbladder disease worldwide. Majority of GBC patients have associated gallstones. With the advent of ultrasonography more patients are being diagnosed with gallstones and are being subjected to cholecytectomy. IGBC is found in 0.2-2.9 % of all cholecytectomies done for gallstone disease. It represents 27-41 % of all GBC. Patients with IGBC having Tis and T1a stage, with negative cystic duct margin can be treated by simple cholecystectomy alone. Patients with stage T1b and beyond should undergo restaging, and should be treated with radical re - resection (R0). Residual disease is found in 40-76 % patients on re-exploration. The survival rates of patients undergoing re resection for IGBC is similar to those undergoing primary radical surgery. LC is contraindicated in patients with GBC. Patients presenting post LC should undergo radical re- resection and additional port site excision, as they have a high incidence of port site metastasis. At cholecystectomy for benign gallbladder disease all gallbladder specimens should be opened before closing abdomen and if available all suspicious specimens should be sent for immediate frozen section. All gallbladder specimens should be subjected to histopathology examination to avoid missing GBC. The surgeon should have a high index of suspicion for GBC if encountering difficult cholecystectomy for a benign disease, and in patients with atypical clinical and ultrasound findings in high incidence areas. PMID- 23730050 TI - Innovations in Endosurgery-Journey into the Past of the Future: To Ride the SILS Bandwagon or Not? AB - Progress in surgical practice has paralleled the civilizational evolution. Surgery has progressed from being the last resort in saving life to being form and function preserver. Post-renaissance Industrial age gave an impetus to this march of surgery. The currently on going digital technological revolution has further catalysed this march. Having achieved the stabilized and acceptable clinical outcomes, the surgeon has embarked on a journey of improving patient reported outcomes (PRO). Improvement in PROs with the advent of laparoscopic surgery with the attendant emphasis on minimising invasion has led to debates about invasion being just parietal or holistic in physiological sense. There is a concern that parietal invasiveness shouldn't be a trade-off for compromised clinical outcomes. Single Incision Laparoscopic Surgery (SILS) in its current avatar with current instrumentation seems to be an enthusiastic bandwagon rolling on with the cosmetic benefits acting as veil to hide the potential clinical concerns. History of surgical innovations is riddled with tales of vindictiveness and vicissitude. Lest the same fate befalls SILS we would do better to examine the SILS bandwagon in its current form till the emerging technologies address the current concerns. PMID- 23730053 TI - Oncoplastic breast surgery. AB - Breast Surgery is now a recognized subspecialty of General Surgery abroad with structured training for designated 'Oncoplastic Breast Surgeons'. Oncoplastic Breast surgery is probably one of the most interesting and challenging new developments over the past 20 years. The aims of Oncoplastic surgery are wide local excision of the cancer coupled with partial reconstruction of the defect to achieve a cosmetically acceptable result. Avoidance of mastectomy and consequent reduction of psychological morbidity are the principal goals in the development of various oncoplastic techniques. The use of plastic surgical techniques not only ensures good cosmetic outcome, but also allows the cancer surgeon to remove the tumour with greater volume of surrounding tissue, thus extending the boundaries of breast conserving surgery. Proper patient selection and careful planning after proper radiological and clinical assessment are the two essential prerequisites before undertaking oncoplastic breast surgery. Oncoplastic surgery involves both volume displacement and volume replacement techniques. Some commonly used volume displacement procedures are described in the article. The need for adjustment of contralateral breast should also be anticipated at the time of planning breast conserving surgery, which can be done either at the same time as breast cancer surgery or as a delayed setting. PMID- 23730054 TI - Management of common bile duct stones in the laparoscopic era. AB - There is no consensus regarding the ideal management of concurrent gallbladder and common bile duct (CBD) stones. Currently the treatment protocol involves most commonly a sequential approach consisting of endoscopic sphincterotomy followed by laparoscopic cholecystectomy or a single stage laparoscopic procedure, including cholecystectomy and exploration of the CBD. For this article literature search was performed using online search engines, Google, Pubmed, the online Springer link library and the Cochrane Database Systematic Review. Review articles, prospective and retrospective studies which detailed or compared the various treatment strategies for CBD stones were selected and analyzed. This review article aims to provide an insight into the optimal management of CBD stones in different clinical scenarios. Endoscopic sphincterotomy has inherent morbidity and complications like CBD stone recurrence whereas laparoscopic CBD exploration demands considerable expertise which is available only at specialized centres. The clinical presentation of the patient, number of stones, size of CBD, available resources and technical expertise at hand are an important consideration for the ideal management in different scenarios. PMID- 23730055 TI - Sils without Frills. AB - Historically, invasive, large incisions were necessary to perform "open" abdominal surgical procedures. While effective, this method increased the possibility of multiple complications, including post-operative pain, wound infection, incisional hernia and prolonged hospitalization. Concerns over the rate of complications and morbidities led surgeons to develop laparoscopic surgical techniques, in which operations in the abdomen are performed through small incisions as opposed to larger, open incisions across the surgical site. There was a continuous effort to minimize the number of ports, and finally single incision laparoscopic surgery (SILS) came into practice. Sils without frills is a concept where multiple ports are made in a curved 2.5 cm incision in a triangle. The chopstick method is used to minimize instrument and telescope clash during the procedure. Standard laparoscopic instruments are introduced along with a 30 degrees telescope. Instrument clashes are avoided by chop stick technique of crossing them at a proximal point so that ends are away from each other. Dissection takes place in forward backward movement after making lateral retraction by the other instrument. With experience the operative time is expected to become comparable with conventional laparoscopic cholecystectomy. But benefits regarding post operative pain in SILS has not been confirmed. It is felt that expertise and reduction of operative time may reduce post operative pain. No special telescopes, ports or hand instruments are needed for this procedure but may have a role in advanced laparoscopic procedures. PMID- 23730056 TI - Globalization and maxillofacial surgery: a strategy for the future. PMID- 23730057 TI - The use of the buccal fat pad for reconstruction of oral defects: review of the literature and report of cases. AB - Although the buccal fat pad (BFP) was originally used as an alternative method for the closure of small to medium-sized oroantral and oronasal communications, its use has now been extended to use after excision of oral pre malignant lesions. This report describes experience with this technique. PMID- 23730058 TI - Resorbable implants in maxillofacial surgery: a reality check. AB - BACKGROUND: Stability is the main feature of fixation techniques in fracture management modalities, in vogue today. One of the most significant landmarks in the armamentarium of maxillofacial fracture management has been the introduction of rigid internal fixation (RIF). The biomaterials used in RIF have seen a gradual change from Stainless steel to titanium due to the evidence based advantages of the latter. However, the inherent problems with metallic implants led to the introduction of resorbable polymers in RIF. MATERIALS AND METHOD: This article evaluates the efficacy of these polymers in fixation of bone segments as compared to titanium fixation implants in 40 patients of zygomatic complex fractures. The study compared the clinical efficacy, technique, cost and time factors in the use of these two biomaterials. RESULTS: The results showed very little difference after the use of these two biomaterials in spite of the increased time, technique sensitivity and cost of the resorbable system. CONCLUSION: The argument for use of the resorbable fixation implants as a better alternative to titanium in maxillofacial fracture management seems overstated considering the insignificant differences in the results obtained but significant differences in the time taken and economics of the two biomaterials. The resorbabale system should ideally be restricted for use in pediatric craniofacial surgery. PMID- 23730059 TI - Current perspectives in intra operative airway management in maxillofacial trauma. AB - OBJECTIVE: Maxillofacial trauma presents a complex problem due to the disruption of normal anatomy. In such cases, we anticipate a difficult oral intubation that may hinder intraoperative IMF. Nasal and skull base fractures do not advocate use of nasotracheal intubation. Hence, other anesthetic techniques should be considered in management of maxillofacial trauma patients with occlusal derangement and nasal deformity. This study evaluates the indications and outcomes of anesthetic management by retromolar, nasal, submental intubation and tracheostomy. METHODOLOGY: Of the 49 maxillofacial trauma cases reviewed, that required intraoperative IMF, 32 underwent nasal intubation, 9 patients had tracheostomy, 5 patients utilized submental approach and 3 underwent retromolar intubation. RESULTS: Among patients who underwent nasal intubation, eight cases needed fiberoptic assistance. In retromolar approach, though no complication was encountered, constant monitoring was mandatory to avoid risk of tube displacement. Consequently, submental intubation required a surgical procedure which could result in a cosmetically acceptable scar. Though invasive, tracheostomy has its benefits for long term ventilation. CONCLUSION: Intubation of any form performed in a maxillofacial trauma patient is complex and requires both sound judgement and considerable experience. PMID- 23730060 TI - A study of strategies for treating compensatory articulation in patients with cleft palate. AB - INTRODUCTION: Patients with cleft palate (PCP) frequently show compensatory articulation disorder (CAD). Compensatory errors require a prolonged period of speech intervention. Scaffolding strategies are used for correcting placement and manner of articulation. OBJECTIVE: To study whether some strategies commonly used in speech therapy for correcting compensatory articulation errors, can be more effective depending on severity of CAD in PCP. MATERIALS AND METHODS: Fifty PCP were studied. All patients showed velopharyngeal insufficiency (VPI) and CAD. Transcriptions of speech therapy sessions were revised in order to quantify positive changes in articulation. Correlation between effectiveness of each strategy and degree of severity of CAD was assessed. Also, different strategies were compared in order to determine whether some strategies were more appropriate for specific levels of severity of CAD. RESULTS: There was a significant relationship between the success of some strategies, as measured by the number of positive changes in articulation, and the degree of severity of CAD in PCP. CONCLUSION: There seems to be a relationship between effectiveness of some speech therapy strategies for correcting compensatory articulation errors and severity of CAD. Assessment of severity of CAD appears to be useful for planning speech intervention in PCP. Selected speech therapy strategies could be used according to severity of CAD. PMID- 23730061 TI - Three dimensional titanium mini plates in oral & maxillofacial surgery: a prospective clinical trial. AB - AIM: The purpose of the study was to evaluate the efficacy of three dimensional titanium miniplates as treatment modality for the stabilization of the fractured or osteotomized bone fragments in maxillofacial region. PATIENTS AND METHODS: 24 patients with maxillofacial trauma and one patient who underwent orthognathic surgery constituted the sample of the study. All the patients with maxillofacial injuries required open reduction internal fixation of the fractures and the orthognathic surgery patient required stabilization of the osteotomized segments. CONCLUSIONS: Three dimensional plates provide good stability of bone fragments due to closed quadrangular geometric shape, and the ease of contouring and adapting. Because of better inter fragmentary stability; supplemental fixation is not necessary, thereby enhancing the overall comfort, convenience and well being of the patient. PMID- 23730062 TI - Assessment of the Effects of Curacel and Bone Wax on the Acute Oroantral Opening Site by means of Computer Tomography and Histopathology. AB - PURPOSE: In this study, the effects of Curacel TM oxidized regenerated cellulose and bone wax on the healing bone were compared to each other by means of CT based bone density measurement and histopathological evaluation. METHODS: The bone density measurements of the control group were significantly higher than those of both Curacel and bone wax groups. RESULTS: There was no significant difference between Curacel and bone wax. Histopathologically, the bone wax group showed more osteoblastic activation than Curacel group. For all measurement parameters (osteoblastic activation, osteoclastic activation, fibrous connective tissue, osseous trabeculae), Curacel and bone wax groups had worse results than control group. It is concluded that Curacel has no superiority over bone wax in terms of osseous healing in the oroantral region. There is no need to use oxidized regenerated cellulose or bone wax for small oroantral openings since the healing is better without any intervention. In addition, bone density measurement and histopathological evaluation were consistent in terms of osseous healing of the oroantral opening. PMID- 23730063 TI - Role of collagen impregnated with dexamethasone and placentrix in patients with oral submucous fibrosis. AB - PURPOSE: To evaluate the versatility of the collagen membrane as both drug carrier and biologic dressing material to cover the raw wounds created after the surgical excision of fibrotic bands in oral submucous fibrosis. MATERIALS AND METHODS: The study comprises of ten patients. The patients of age group 20 to 50 years were selected. The collagen is reconstituted by injecting with dexamethasone and placentrix solution leaving a small overlap on to the remaining mucous membrane and the graft is sutured. Preoperative and post operative assessment was done regarding the improvement in mouth opening, decrease in burning sensation, change in colour of oral mucosa and clinically grading the extent of lesion. RESULTS: The results were found appreciable in seven patients while in the remaining three patients it showed relapse because of inadequate physiotherapy. All the ten patients were comfortable with intra oral collagen grafting. The collagen remained moist and supple intraorally, and remained in close contact with the underlying tissues, providing a strong mechanical barrier. The material was effective in attaining haemostasis, relieving pain and preventing extensive contracture. CONCLUSION: In this study of short duration, the nature of collagen membrane was observed as both biological dressing material and drug carrier. It was found as a very suitable alternative to the other graft material mentioned for the repair of defects in the mucous membrane created by surgical excision of fibrous bands in oral submucous fibrosis. PMID- 23730064 TI - Evaluation of treatment of zygomatic bone and zygomatic arch fractures: a retrospective study of 10 years. AB - OBJECTIVE: The aim of this study was to investigate the treatment of zygomatic bone and zygomatic arch fractures without other facial fractures. PATIENTS AND METHODS: A 10 year (2000-2010) retrospective study involving 310 patients admitted and treated for zygomatic bone and zygomatic arch fractures at the department of oral and maxillofacial surgery was done. The data collection protocol included: age, gender, site, type of fracture. Other data presented included clinical diagnosis, radiographic examination findings as well as preoperative and postoperative imaging for evaluation of the fracture. Descriptive statistics was performed with SPSS version 16. RESULTS: The ages of the patients ranged from 10 to 76 years old, mean age was 32.33 years. 237(80.6%) of the patients were males and 73 (19.4%) were females (Table 1). According to the site of fracture, the patients were divided into three groups: group A, with zygomatic bone fracture, group B with zygomatic arch fracture and group C with co existing zygomatic bone and zygomatic arch fracture. Regarding the site of fracture 57.7% of the patients had fractures of the zygomatic bone, 13.8% had fractures of the zygomatic arch and 28.4% had fractures of both zygomatic bone and zygomatic arch. [Table: see text] The treatment of both fractures was: closed reduction for isolated zygomatic arch fractures; open reduction and internal rigid fixation through a coronal incision was performed in comminuted arch fractures and displaced fractures. CONCLUSION: In this study, the majority of the patients were young adult men; road traffic accidents were the leading cause of fractures. According to the site of fracture, various modalities of treatment were used and all the patients achieved satisfactory results without any complications after operation. PMID- 23730065 TI - Retrospective analysis of 503 maxillo-facial trauma cases in odisha during the period of dec'04-nov'09. AB - This study involves mandibular and midface fractures recorded in the trauma reports of OMFS department, SCB dental college, Cuttack, Odisha. The reports were studied between December 2004 and November 2009. The 503 patients had 539 mandibular fractures and 117 midface fractures. Males accounted for 442 (87.87%) and females accounted for 61 (12.12%). Male to female ratio was 7.25:1. The most common cause of fracture was road traffic accident and accounted for 404 (80.31%). The most common site of fracture mandible was parasymphysis where as in middle third fracture it was zygomatic complex fracture. The most common age groups involved in fracture were 21-30 years and the incidence of head injury was 97(19.28%). Many of these variations may be related to socioeconomic, cultural and environmental conditions. PMID- 23730066 TI - Cricket related maxillofacial fractures. AB - BACKGROUND: Cricket is a popular sport in New Zealand, enjoyed both at social and competitive level. Although it is a non-contact sport and there is in place good facial protection, injury to the head and neck region is still frequently seen in the emergency department. METHODS: Data were collected from departmental records between 1996 and 2006. Variables examined included incidence, demographics, site of fracture and treatment method. RESULTS: Of the 561 patients with sports related maxillofacial fractures during the study period, 40 were cricket-related. Male to female ratio was 36:1. 45% of patients were in the 16-30 year age group. 55% of injuries were due to impact from cricket ball. 70% of injuries occurred at midface level, while 30% at the mandible. 38% of patients required surgery and hospitalization. CONCLUSION: Maxillofacial fracture from cricket playing is a frequent injury in patients presenting with sports-related injuries. Cricket players need to be educated on the safety measures in playing the sport, including facial protection devices. PMID- 23730067 TI - Cortical tibial bone graft for nasal augmentation. AB - BACKGROUND: This study sought to determine the efficacy of cortical tibial bone graft for nasal augmentation. Nine cases of augmentation rhinoplasty with cortical tibial bone graft are presented. METHODS: This prospective study evaluated the postoperative results of nine patients who underwent augmentation rhinoplasty using cortical tibial bone graft. There were six males and three females aged between 21 and 36 years (mean age 29). All the nine cases were treated through closed rhinoplasty incisions. RESULTS: Nine patients were operated on and the average follow up was 18 months. The results were favorable. The aesthetic results were gratifying; with good nasal projection in every case without any significant postoperative effects or complications requiring surgery were noted during the follow up. CONCLUSION: The findings of this study support the use of cortical tibial bone graft for nasal augmentation although further studies with more sample size are required. PMID- 23730068 TI - Blast injuries of mandible: a protocol for primary management. AB - OBJECTIVE: Purpose of this study is to introduce a new protocol for primary management of blast injuries of mandible with the aim of preserving maximum tissues at the same time achieving excellent aesthetics and function in the long term. METHOD: All cases were managed primarily using this protocol. Secondary reconstruction was carried out at least six months later. RESULTS: Excellent results were achieved in all cases. CONCLUSION: Management of blast injuries requires special consideration to achieve good aesthetics and function. The above protocol will give good results in the long term. PMID- 23730069 TI - Ptosis correction: a challenge following complex orbital injuries. AB - Ptosis occurs when the muscles that raise the upper eyelid (levator and Muller's muscle) get damaged. There are lot of ptosis correction surgery reported in the journals of oculoplastic surgery and opthalmic surgery. Most of these surgeries are cosmetic correction. Rarely ptosis can be seen as a complication following orbitozygomatic complex injuries. Cause of traumatic ptosis most often is levator detachment from the superior tarsal plate. Lacerations of the lid may sever the levator tendon leading to scarring and secondary mechanical ptosis. Challenge in surgical management lies in identification of Levator aponeurosis, posterior to orbital septum and preaponeuratic fat. Once the levator muscle is freed from scar tissue it should be reapproximated to tarsal plate. PMID- 23730070 TI - Autologous platelet rich plasma after third molar surgery: a comparative study. AB - PURPOSE: This study is an attempt to evaluate the use of autologous platelet rich plasma (PRP) to promote wound healing and osseous regeneration in human third molar extraction sockets. MATERIALS AND METHOD: PRP was prepared after two centrifugation and the gelling agent used was freshly prepared 10% calcium chloride.PRP gel was placed in one of the extracted sockets of bilateral impacted mandibular third molars. IOPA Xrays were used to evaluate the wound dehiscence, probing depth, bone density & alveolar bone level after 1st, 2nd and 7th day and 3rd & 6th month respectively. RESULTS: On evaluation, it was found that PRP grafted sockets showed dehiscence in 8% cases. The decrease in alveolar bone level was highly significant in PRP grafted sockets in 3rd and 6th month post operatively. There was significant difference between pre-operative density of adjacent bone and bone formed in extraction sockets at 3rd and 6th month in PRP grafted sockets. There was significant reduction in probing depth from initial period to 3 and 6 months in both the groups, but PRP grafted sockets showed greater decrease in probing depth. CONCLUSION: PRP is an inexpensive and widely available modality to minimize postoperative complication and enhance both hard and soft tissue healing potentials. This autologous product eliminates concern about immunogenic reaction and disease transmission. Its beneficial outcomes in dental clinic, including decrease in bleeding and rapid wound healing hold promise for further procedures.PRP is thus a new application in tissue engineering and developing area for clinician and researchers. PMID- 23730071 TI - Finite Element Analysis: A Maxillofacial Surgeon's Perspective. AB - The science of finite element analysis (FEA) is purely a mathematical way of solving complex problems in the universe. In medical field, this is an innovation in biomedical research and development, as it gives easier mathematical solution to biological problems. This article deals with the understanding of various basic material properties of bone like Young's modulus, yield strength, Bulk modulus, shear modulus, Poisson's ratio and density from a maxillofacial surgeon's perspective. Basic concepts in FEA, its application, advantages, disadvantages, and limitations in the field of maxillofacial surgery have been discussed. The importance of surgical fraternity to be in coordination with evolving technologies has been emphasized for the future of evidence based practice of oral and maxillofacial surgery. PMID- 23730072 TI - OraVerse: Reverses Numbness After Dental Procedures. AB - The lingering numbness that can last anywhere from 3 to 5 h after a routine dental procedure is often an unnecessary, inconvenient hassle. Patients may find that their ability to speak, smile, eat and drink is impaired, and may even have uncontrollable drooling. The effects of local dental anesthetics can now be reversed. That's because OraVerse, an anesthetic reversal agent, can return the patient to normal sensation and function in about half the time. OraVerse which is U.S. Food and Drug Administration approved is a safe and effective form of phentolamine mesylate, a vasodilator that has been used in several other medical applications since 1952. OraVerse injection - the first and only proven safe and effective product of its kind can quickly reverse the effects of local dental anesthetics, so patient can carry on without impairment of talk, smile and drink after dental procedures. Studies also have shown that there are no known drug interactions and no evident toxicity or contraindications for using OraVerse. PMID- 23730073 TI - Third molars: a threat to periodontal health?? AB - The third molars have received the fair amount of interest in literature. It has been blamed for problems such as-lower incisor crowding, atypical facial pain, caries etc. They are considered as 'waste bins' in dental practices as they are regarded as functionally non-essential. While making the clinical decision, they are given less importance and often extraction is considered to be the treatment option. Despite periodontal problems that can arise with extracted third molars, retention of third molars can also lead to periodontal problems with the adjacent teeth in addition to teeth farther to third molars. Of late, it is very important to consider the periodontal problems while making the clinical decision. This review paper has been discussed keeping this as prime objective. PMID- 23730074 TI - Biomechanics of cranio-maxillofacial trauma. AB - The forces to the cranium and facial skeleton can be applied from an anteroposterior, superior, inferior and lateral directions. These forces with level and location of point of impact will determine the pattern of injury. Fractures of the cranium rarely extend into the region of facial skeleton. On the other hand, fractures originating in the facial skeleton can extend into the cranium. This has got implications as facial fractures are associated with head injury. Understanding the biomechanics of craniomaxillofacial trauma gives an insight in understanding the pattern of injury. We have briefly reviewed the literature and discussed biomechanics of craniofacial trauma, and how it influences head injury. PMID- 23730075 TI - Evaluation of fractured condylar head along the sagittal plane: report of three cases. AB - There are case reports of sagittal fractures of the condylar head leading to bifid condyle. However bifid condyles maybe found in patients with no history of trauma. A split in the saggital plane of the condyle is not visible with a lateral, oblique or panaromic radiographs but only with anteriorposterior, transorbital projections or CT scan of the temperomandibular joint. The chances of condyle being split in the sagittal plane may be due to the medial pole extending beyond the condylar neck, moreover the condyle is composed of cancellous bone covered by a thin layer of cortical bone. Here we are presenting three case reports of Saggital split condyles and stress the need for inclusion of these type of fractures in the classification of condylar fractures. PMID- 23730076 TI - Giant sublingual dermoid cyst in floor of the mouth. AB - The dermoid cysts of the mouth are most frequently located on the median line of the mouth floor and are most likely caused by the retention of the germinal epithelium during the growth of the mandible and hyoid branchial arches. We report an unusual case of giant dermoid cyst of the floor of the mouth in a 17 year female who presented with progressively increasing swelling below her tongue and reviewed the relevant literature. PMID- 23730077 TI - Aneurysmal bone cyst, a lesion of the mandibular condyle. AB - Benign and malignant tumors of the temporomandibular joint are rare. An aneurysmal bone cyst (ABC) of the condyle is even more unusual and usually presents as a slowly enlarging firm swelling which occasionally may be associated with pain and tenderness. Surgical curettage or excision is the treatment of choice, in an attempt to reduce the potential problem of recurrence; we undertook surgical resection of the affected bone. Immediate mandibular reconstruction using autologous bone was deferred though it is generally recommended in such type of cases. PMID- 23730078 TI - Congenital facial teratoma. AB - Teratomas are neoplasm composed of three germinal layers of the embryo that form tissues not normally found in the organ in which they arise. These are most common in the sacrococcygeal region and are rare in the head and neck, which account for less than 6%. An unusual case of facial teratoma in a new born, managed successfully is described here with postoperative follow up of 2 years without any recurrence. PMID- 23730079 TI - A modified technique for post operative physiotherapy in edentulous patients. PMID- 23730080 TI - Recurrent carpal tunnel syndrome--analysis of the impact of patient personality in altering functional outcome following a vascularised hypothenar fat pad flap surgery. AB - We retrospectively analysed 25 patients (27 hands) who had both clinical and electrophysiological confirmation of true recurrent carpal tunnel syndrome from January 2004 to December 2009. In all the patients, after releasing the nerve a vascularised fat pad flap was mobilised from the hypothenar region and sutured to the lateral cut end of flexor retinaculum. The patient characteristics, co morbidities, duration of symptom, interval between first release and revision surgery and intra-operative findings were assessed against post-operative relief of pain, recovery of sensory and motor dysfunction. The average age of the patients was 58 years (43-81) and the dominant hand was involved in 22 patients. Intra-operatively the nerve was compressed by scar tissue connecting the previously divided ends of the retinaculum in 18 and nine had scar tissue and fibrosis around the nerve. Following surgery 16 patients had complete recovery (asymptomatic at the first follow-up), eight had delayed recovery (partial recovery of symptoms at final follow-up) and three had a poorer outcome (persistence of preoperative symptoms at the final follow-up). The patients with delayed recovery/poorer outcome had a) Early recurrence; b) Diabetes mellitus; c) Obesity; d) Cervical spine problems; e) Involvement of non-dominant hand; and f) Intraoperative scar tissue and fibrosis. The hypothenar fat pad transposition flap provides a reliable source of vascularised local tissue that can be used in patients with recurrent carpal tunnel syndrome. The factors that were associated with poorer/delayed recovery were involvement of non-dominant hand, recurrence within a year from the previous surgery, intra-operatively scar tissue in the carpal tunnel and associated co-morbidities, like obesity diabetes mellitus and cervical spine problems. PMID- 23730081 TI - Predictors of return after cast removal in patients with a nonoperatively treated distal radius fracture. AB - Patients with a nonoperatively treated fracture of the distal radius are often scheduled for a follow-up appointment after cast removal to assess function and outcome. Our experience is that, once the cast is off, many patients do not return. The purpose of this study was to determine which variables significantly influence return for a scheduled visit after cast removal. Thirty-seven patients enrolled in a prospective cohort study (27 men and 10 women) with an average age of 49 years (range, 19 to 82) had a distal radius fracture immobilized in a cast. During the visit at which the cast was removed, arm-specific disability, misinterpretation of nociception, and symptoms of depression were measured using validated questionnaires. Eleven of 37 patients did not attend the final scheduled office visit and the only predictor of a return visit was older age. PMID- 23730082 TI - Scaphoid nonunion advanced collapse classifications: a reliability study. AB - Watson & Ballet and Vender staging systems are widely known for classifying SNAC wrist osteoarthritis. Despite of its day-to-day use, no assessment for its agreement was performed. To Evaluate the intra and interobserver agreement for these classification systems. Forty-eight posteroanterior wrist radiographs from patients with osteoarthritis due to scaphoid nonunion were evaluated at two occasions-in a 1 week interval-by five observers with different expertise-hand surgeons, hand surgery residents, orthopedic surgeons and orthopedic surgery residents. They rated osteoarthritis stages according to the above-cited systems. Kappa statistics were performed for measuring agreement. Unsatisfactory (Cohen's Kappa <0.5) agreement was found for all intra and inter observer measures for both systems. There was no clear correlation between expertise and kappa values. Unsatisfactory agreement was found for both classifications, despite the evaluator expertise. A rationale of a more reliable classification is needed. PMID- 23730083 TI - Tensile strength of flexor tendon repair using barbed suture material in a dynamic ex vivo model. AB - The purpose of this study was to compare two sutures; a knotted polydioxane with a knotless barbed in a 4-strand Kirchmayr-Kessler suture technique. Human flexor digitorum tendons were separated into four groups. Group 1 - polydioxane; Group 2 - barbed suture; Group 3 and 4 - same as group 1 and 2 with an additional peripheral running suture. In each group the repaired tendons were subjected to linear and cyclical loads. No difference in maximum tensile strength after linear and cyclical force could be detected between the knotted polydioxane suture and the knotless barbed suture. On linear force tests an additional circumferential repair increased the maximum tensile strength of both sutures. Cyclical force loading did not lead to a reduction of maximum strength. Following linear and cyclical loading the 4-strand barbed suture achieved maximum tensile strengths comparable to the 4-strand repair using the polydioxane suture. Barbed suture repair may offer the advantage of knotless suture techniques. PMID- 23730084 TI - Evaluating the effectiveness of a wiki internet site for medical topics. AB - To evaluate the iterative process of a collaborative public database (a Wiki) as a reference for information on hand illnesses we tested the null hypothesis that the number and type of edits are comparable for web pages covering different topics. The history of 4 hand surgery related web pages on the English language Wikipedia (Trigger finger, Complex Regional Pain Syndrome (CRPS), Ganglion cyst, and de Quervain Syndrome) were analyzed from inception to July 2011. Each edit was classified as one of six types: an addition is an edit that adds material; a deletion removes material; a modification is a combination of addition and deletion, or any rearrangement; a minor edit is a correction of spelling, grammar, or formatting errors; vandalism is any edit that is intended to harm the page; a vandalism fixed is an edit that addresses harm. The edits were also rated as possibly controversial or not (defined as edits that present information with a clear bias or do not list reliable sources). For both the Ganglion cyst and Trigger Finger pages, readability was measured at 1 year increments. Our primary null hypothesis was that the proportion of constructive edits (addition, deletion or modification) did not differ between the 4 web pages. The percentage of constructive edits (additions, deletions, and modifications) was significantly different for each page: 121/234 (52 %) for de Quervain, 258/448 (58 %) for CRPS, 103/156 (66 %) for Trigger Finger, and 160/389 (41 %) for Ganglion cyst. The percentage of edits related to vandalism was also significantly different: 28/234 (12 %) for de Quervain, 33/156 (7 %) for CRPS, 21/156 (14 %) for Trigger Finger, and 135/389 (35 %) for Ganglion cyst. Vandalism was quickly identified and addressed. Twenty-six percent of all edits were classified as potentially controversial. Forty percent of possibly controversial edits were deletions. The topic of a Wiki web page for information on hand illness influences the degree to which edits are constructive. A Wiki for hand illness could be a very useful resource for patients with hand illness, but it requires careful moderation because only about half the edits are constructive. Cohort Study. PMID- 23730086 TI - Necessities in clinical photography. PMID- 23730085 TI - The flexor tendon pulley system and rock climbing. AB - Rock climbing has increased in popularity over the past two decades. Closed traumatic rupture of the finger flexor tendon pulleys is rare among the general population but is seen much more commonly in rock climbers. This article reviews the anatomy and biomechanics of the finger flexor tendon pulleys, how they may be injured in rock climbing and how these injuries are best diagnosed and managed. PMID- 23730087 TI - Voluntary anterior dislocation of the shoulder in a 10-year-old child treated surgically. PMID- 23730088 TI - Osteoblastoma of the capitate bone. PMID- 23730089 TI - Injection injury of an aberrant superficial radial artery requiring surgical intervention. PMID- 23730090 TI - Dynamic Ulnar Deviation Deformity of Wrist Due to Post Infective/Posttraumatic Contracture of Isolated Musculotendinous unit-A Report of Two Unusual Cases. PMID- 23730091 TI - From the desk of the editor. PMID- 23730092 TI - Uro-oncology: an evolution of past four decades in India. PMID- 23730093 TI - Computer assisted robotic surgery in urooncology. AB - Robotic surgery is a significant advance in the realm of urologic surgery esp. for uro genital cancers and reconstructive procedures. Robotic surgery is associated with precision and ease in dissection, incision and suturing with less steep learning curve in comparison to laparoscopy. It provides all benefits of minimally invasive surgery. At present, cost is a prohibitive factor. Robotic surgery is going to stay and is going to open new avenues for, image guided and telepresence surgery. PMID- 23730094 TI - The emergence of surgeon-controlled robotic surgery in urologic oncology. AB - The rise of robotic surgery is transforming medicine. In many ways, urology has taken charge in pioneering a new era of minimally invasive surgery with the emergence of the robot. The unprecedented dissecting precision and the dynamic three-dimensional, high definition view of the surgical field are undoubtedly revolutionizing the field of urology. These unique attributes of robotic surgery confer enormous advantages in dealing with uro-oncological surgery. The robotic revolution began nearly a decade ago with surgeon-controlled robotic radical prostatectomy and has since expanded to include radical cystectomies and partial nephrectomies. There have been numerous landmark studies published showing that robotic surgery provides comparable oncological and functional outcomes against traditional open or laparoscopic surgery. As a result, it becomes exceedingly imperative that urologists and the oncological community remain up-to-date regarding these developments and appreciate the oncological outcomes of surgeon controlled robotic surgery. This review will assess the impact surgeon-controlled robotic surgery has had in the field of urologic oncology. PMID- 23730095 TI - Status of Robot-Assisted Radical Cystectomy (RARC) in 2012. AB - Robot-assisted radical cystectomy (RARC) for bladder cancer is increasingly becoming popular in specialist centres around the world. RARC has the advantage of being minimally invasive and also the dexterity of the instruments allow reconstruction such as ileal conduit urinary diversion or neobladder formation. Starting from the initial series demonstrating the feasibility of RARC and extended pelvic lymph node dissection, we now have mature series demonstrating equal oncological and functional outcomes in the medium term follow-up. In addition, literature suggests decreased hospital stay, less blood loss equating to less blood transfusion and a trend towards decreased complications as well. In the near future we would anticipate further refinement and reduced operating times with increased benefits for the patient undergoing RARC. PMID- 23730096 TI - Current status of robot-assisted laparoscopic partial nephrectomy. AB - With increased incidence of diagnosis of small renal masses, partial nephrectomy has been preferred over radical nephrectomy as the surgical treatment of choice. The transition from open to laparoscopic partial nephrectomy had been challenging for many urologists. Robotic-assisted laparoscopic partial nephrectomy(RLPN) is increasingly used to facilitate this transition . In this review, we examine the recent technical advances and clinical outcomes in RLPN. Many series had successfully reported the feasibility of using the da Vinci Surgical (Intuitive Surgical Inc, Sunnyvale, CA) System in laparoscopic partial nephrectomy. Recent advances had focused on reducing risk of renal damage by shortening the warm ischaemia time. These techniques included unclamped excision, selective arterial clamping and improved renorrhaphy methods. Operative times and warm ischaemia times have also improved once the learning curve are overcome, which is less steep than conventional laparoscopy. With longer follow-up and more widespread experience, the outcome of RLPN could be favourable compared to conventional laparoscopy. Improving techniques had made this surgery a safe and efficacious treatment option for small renal masses. PMID- 23730097 TI - Robotic oncological surgery: our initial experience of 164 cases. AB - Minimal access surgery is an accepted modality for benign surgery. Despite the advantages of laparoscopy, its acceptance in oncology is slow. Robotic surgery is an emerging field with rapid acceptance because of the 3-dimensional image, dexterity of instruments and autonomy of camera control. We report here our experience of using the Da Vinci robot for various oncological procedures. We performed 164 oncological surgeries from November 2009 to June 2011. The surgeries performed included thoracic, colorectal, hepatobiliary, gynaecological and urological system. We could complete 163 cases robotically. We share our initial experience of robotic surgery in oncology with comparison with other series. PMID- 23730098 TI - Current update of management of clinical stage I non seminomatous germ cell tumors of testis. AB - The management of patients with testicular germ cell tumors (GCT) has evolved significantly over the past 30 years with cure rates approaching nearly 100% for low-stage disease and more than 80% for advanced disease. Controversy surrounds about ideal management of clinical stage I non seminomatous germ cell tumors (CS I NSGCT) of the testis due to multiple treatment options available with more or less equal efficacy. Nerve-sparing retroperitoneal lymph node dissection (RPLND), adjuvant chemotherapy with two cycles of bleomycin, etoposide, and cisplatin , or surveillance have all achieved long-term survival in nearly 100% of patients with clinical stage I NSGCT. Retroperitoneal lymph node dissection is still favoured as the therapy of choice for clinical stage I non-seminomatous germ cell tumors in many centres, but as risk factors for the primary tumor have become better understood, surveillance and risk-adapted therapy, including surveillance for low risk patients and adjuvant chemotherapy for the high-risk group, is now being considered a therapeutic option. The objective of this study is to review current developments in the management of CS I NSGCT testis with emphasis on risk stratification and treatment recommendations. PMID- 23730099 TI - IVC Thrombectomy in Renal Cell Carcinoma-Analysis of Out Come Data of 100 Patients and Review of Literature. AB - To review our experience of RCC with IVC thrombus in terms of clinical presentation, principles of surgical management in contemporary era, also an impact of clinico-pathological factors on prognosis. Total 100 patients who underwent radical nephrectomy and IVC thrombectomy between 1991-2008 were included in this retrospective analysis. Data was analysed in terms of clinical pathological factors, survivals and compared with contemporary literature. The extent tumour thrombus was infrahepatic in 58 retro hepatic in 28 and suprahepatic in 14 patients including 6 with right atrial thrombus. The immediate postoperative mortality was 2% and incidence of major postoperative non fatal complications was 38%, which were managed conservatively. The overall and disease free 5 year survival was 63% and 55%. Further amongst the histological types, patients with clear cell tumours had the best (DFS- 71.42%), and those with papillary had the poor (DFS- 30.76%) outcome. Grade II tumors had better survivals as compared to grade IV (DFS 75.39% vs 23.52%, p < 0.05). Loco- regional extent wise 74% patients without perinephric fat invasion were free from disease at 5 years as compared to 30% of those who had perinephric fat invasion (p < 0.01). Similarly 5 year DFS was 76.11% in patients with negative nodes as compared to 12% in positive nodes (p < 0.01). In conclusion radical nephrectomy with IVC thrombectomy still remains the most effective therapeutic option in management in this clinical setting. Although this is complicated surgery success with multi disciplinary approach excellent survival outcome can be obtained. Further pathological factors, such as loco-regional spread and grade of tumor, rather than clinical factors influence long term survival. PMID- 23730100 TI - Neo adjuvant treatment with targeted molecules for renal cell cancer in current clinical practise. AB - Target molecule Treatment (TMT) have emerged as the primary treatment in metastatic renal cell carcinoma. Majority of the patients in pivot trials were post nephrectomy cases. The benefit of cytoreductive nephrectomy in the era of TMT is debated. The role of these molecules in the adjuvant settings and in neo adjuvant/pre surgical role has evoked interest. In this review the different molecules used in the treatment of metastatic renal cancer and its effect on the primary renal tumour is discussed. Information available in the public domain about the presurgical/neoadjuvant targeted molecular treatment (TMT) is reviewed to understand the benefits and adverse effects of this modality of treatment. Sunitinib and sorafenib are the most commonly used and effective molecules in the neo adjuvant/re surgical treatment of renal cell carcinoma . Bevacizumab is less effective and has more chance of surgical complications in these settings mainly due to poor wound healing secondary to prolonged wash off period . The patent and the surgeon should be aware of the unpredictability and possible adverse effects before advising these molecule pre operatively. The response of the primary renal tumour to the target molecule is different from that of the metastatic tumour. The side effects of the molecules and its effect on the peri operative morbidity and mortality should also be considered when we advise these molecules as pre surgical/neo adjuvant treatment. PMID- 23730101 TI - A Review on the Clinical Utility of PSA in Cancer Prostate. AB - Prostate cancer has come to share the oncological centrestage among male cancers. The availability of Serum Prostate Specific Antigen, PSA, as a marker has encouraged it's use to diagnose both cancer and cancer recurrence. Some clarity is required about its precise role in clinical practice. The available literature on Prostate Specific Antigen was reviewed; Articles were reviewed for content, applicability to the problem at hand, availability of data about sensitivity and specificity of values, refinements in measurements and finally for impact of screening programmes using these values on survival and quality of life. The data in the literature was critically re-evaluated and analysed to draw reasonable conclusions. Serum PSA measurements show variable reliability when it comes to diagnosis of Prostate cancer, given the dynamics of PSA physiology. Surrogate measures like PSA density, PSA velocity, free-to-complexed PSA ratio, percentage Pro-PSA, etc., have been used to improve the predictive utility of this assay for Prostate cancer. The ability of PSA to detect those cancers that will cost life, and thereby permit early curative treatment, is as yet unclear. It's most definitive role appears to be in diagnosing recurrences after adequate surgical treatment, and in evaluating response to treatment. PMID- 23730102 TI - Reconstruction of groin defects following radical inguinal lymphadenectomy: an evidence based review. AB - Inguinal lymph node involvement is an important prognostic and predictive factor in various neoplasms of the genitalia and lower limb. As part of the multimodality approach, these patients undergo surgery and adjuvant radiotherapy. Morbidity of inguinal lymphadenectomy includes lymphedema, lymphorrhea and infection; however the most common distressing complication is skin necrosis. Myocutaneous flaps have been the most popular form of primary or delayed groin reconstruction. This paper aims to critically review the different myocutaneous flaps used in groin reconstruction, discuss evidence based data on the versatility and utility of these flaps and discuss ways in which modifications maybe incorporated in treatment and radiation planning following groin reconstruction. A comprehensive search of the scientific literature was carried out using PubMed to access all publications related to groin reconstruction. The search focused specifically on current management, technique, safety and complications of these procedures. Keywords searched included "inguinal lymphadenectomy", "primary reconstruction", "musculocutaneus flap", "myocutaneous flap", "tensor fascia lata flap", "anterolateral thigh flap", "rectus abdominis flap". Low to middle income countries witness a huge burden of locally advanced genital malignancies and melanoma of the lower extremity. Higher tumor burden both at the primary site as well as the inguinal basin requires surgery as the primary modality of treatment. Groin reconstruction is required not only to prevent femoral blowouts but also for early administration of adjuvant radiation. The versatility of tensor fascia lata, anterolateral thigh, and rectus abdominis flaps is useful to cover the defect, provide radiation, eradicate pain and achieve good palliation. Assessment of aesthetic and functional outcomes of one flap over the other and the "ideal" form of reconstruction for groin defects needs additional investigation. PMID- 23730103 TI - Accuracy of clinical examination of breast lumps in detecting malignancy: a retrospective study. AB - Clinical examination is a simple method to detect breast lumps and their nature as it is inexpensive and non-invasive and if found to be accurate, might be of great value as a diagnostic tool. The aim of this study was to evaluate the accuracy of clinical examination and its contribution towards the diagnosis of a palpable breast lump. The study was record based and conducted at a University Medical College Hospital and a tertiary referral centre of South India. Patient files of those women who presented with a breast lump between January to December 2011 were studied. A total of 120 patients were obtained following necessary exclusions. The accuracy of clinical assessment at an outpatient facility was determined by comparing the physician's diagnosis with the final histopathological diagnosis. The inter-observer agreement (kappa) for diagnosing a breast lump was 81 % (95 % Confidence Interval = 71 % to 92 %) indicating a good agreement between clinical and pathological diagnoses. McNemar test also indicated a high degree of concordance between the two diagnoses (4.17 % discordance). Sensitivity, specificity, positive and negative predictive values of clinical breast examination in comparison to histopathology were 95, 88, 87, and 95 % respectively, with an overall accuracy of 90.8 %. 11 lumps were wrongly diagnosed at the time of clinical examination. Clinical examination of breast lumps was found to have a high sensitivity (94.5 %) and specificity (87.7 %) and can be used as the diagnostic tool to identify the nature of the lump, however, its value in diagnosing breast malignancy remains contributory due to the possibility that malignant lumps could be overlooked and present as advanced cancer at a later stage. Histopathology is recommended in all cases unless clinical examination is supported with strong evidence of benignity based on repeated breast imaging via ultrasound or mammogram (>35 yrs). PMID- 23730104 TI - Regulation of SREBP-Mediated Gene Expression. AB - The sterol regulatory element-binding proteins (SREBPs) play an important role in regulating lipid homeostasis. Translated as inactive precursors that are localized in the endoplasmic reticulum (ER) membrane, SREBPs are activated through a proteolytic process in response to intracellular demands for lipids. The cleaved amino-terminal fragments of SREBPs then translocate into the nucleus as homodimers and stimulate the transcription of target genes by binding to the sterol response elements (SREs) in their promoters. Numerous studies using cell culture or genetically modified mouse models have demonstrated that the major target genes of SREBPs include rate-limiting enzymes in the pathways of fatty acid and cholesterol biosynthesis as well as the low-density lipoprotein (LDL) receptor. The proteolytic maturation of SREBPs has been well studied in the past. However, recent studies have also improved our understanding on the regulation of nuclear SREBPs. In the nucleus, SREBPs interact with specific transcriptional cofactors, such as CBP/p300 and the Mediator complex, resulting in stimulation or inhibition of their transcriptional activities. In addition, nuclear SREBP protein stability is dynamically regulated by phosphorylation and acetylation. Such protein-protein interactions and post-translational modifications elegantly link the extracellular signals, such as insulin, or intracellular signals, such as oxidative stress, to lipid biosynthesis by modulating the transcriptional activity of SREBPs. Under normal physiological states, lipid homeostasis is strictly maintained. However, the SREBP pathways are often dysregulated in pathophysiological conditions, such as obesity, type 2 diabetes, and fatty liver diseases. Thus, the novel regulatory mechanisms of SREBPs may provide new opportunities for fighting these metabolic diseases. PMID- 23730105 TI - Autologous tragal perichondrium transplantation: a novel approach for the management of painful bullous keratopathy. AB - PURPOSE: To introduce autologous tragal perichondrium transplantation as a novel surgical modality for the management of intractable symptomatic bullous keratopathy. METHODS: In three eyes of three patients with painful bullous keratopathy, autologous tragal perichondria were transplanted on the corneal surface with the human amniotic membrane transplanted above. We included an additional three eyes of three patients with painful bullous keratopathy who received amniotic membrane transplantation only to serve as controls. Clinical symptom outcomes were assessed using a visual analogue scale at postsurgical months 1, 3, 5, 7, and 9. In addition, transplanted tragal perichondrium and amniotic membrane complex tissue button obtained from one patient who underwent penetrating keratoplasty was evaluated by immunohistochemical analysis of CD34, vimentin, and alcian blue staining. RESULTS: All three patients who underwent autologous tragal perichondrium and human amniotic membrane co-transplantation showed improvements in pain and tearing. However, all three patients in the control group experienced aggravation of tearing and no further improvement of pain 3 months after surgery. In addition, one patient in the control group developed premature degradation of the amniotic membrane. Histopathologic and immunohistochemical analysis showed intact surface epithelization and positive CD34, vimentin and alcian blue staining of transplanted tragal perichondria. CONCLUSIONS: The tragal perichondrium has a high mechanical structural force and high potency due to well-organized epithelization and the presence of mesenchymal stem cells. Autologous tragal perichondrium transplantation may be an effective modality for the management of painful bullous keratopathy. PMID- 23730106 TI - Evaluation of plasma vitamin A and E levels and tear film changes in patients with psoriasis vulgaris. AB - PURPOSE: To evaluate whether alterations in plasma vitamin A and E levels in patients with psoriasis have an effect on tear film changes. METHODS: Sixty-two eyes of 31 patients with psoriasis vulgaris (Group A) and 74 eyes of 37 age- and gender-matched control subjects (Group B) were included in the study. Ocular and medical histories and dietary habits were obtained from each patient. The tear film break-up time (TBUT), the Schirmer 1 test results and plasma vitamin A and E levels were evaluated. RESULTS: The mean Schirmer 1 test score was 14.76 +/- 6.12 mm/5 min in Group A and 15.69 +/- 3.10 mm/5 min in Group B. The mean plasma levels of vitamins A and E in Groups A and B were 1.86 +/- 0.62 umol/L and 1.88 +/- 0.65 umol/L vs. 26.21 +/- 5.13 umol/L and 27.19 +/- 8.89 umol/L, respectively. The Schirmer 1 test results and plasma vitamin A and E levels were not found to be significantly different between the groups (p > 0.05). The mean TBUT was 9.94 +/- 6.18 seconds in Group A and 14.47 +/- 5.65 seconds in Group B, a significant difference (p < 0.05). No correlation existed between plasma vitamin A and E levels, TBUT or the severity and duration of the disease (p > 0.05). CONCLUSIONS: Plasma vitamin A and E levels do not seem to be related to tear film changes in patients with psoriasis vulgaris. PMID- 23730107 TI - Topographic progression of keratoconus in the Korean population. AB - PURPOSE: To develop a criterion for determining the topographic progression of keratoconus and to analyze the prognostic factors of progression. METHODS: Medical records of 211 eyes of 128 patients who had been followed up for more than 2 years on three or more occasions were retrospectively reviewed. Topographic parameters, including simulated K, corneal astigmatism, irregular astigmatism at 3 and 5 mm, thinnest-point pachymetry, anterior and posterior elevation, and inferior minus superior index, were used to determine topographic progression. Topographic progression was determined by the greatest kappa value associated with progression to corneal graft surgery. Eyes were separated into progressed and non-progressed groups on the basis of topographic progression. The association of clinical factors with topographic progression, including demographic factors, contact lens use, corneal erosion, and atopic history at the time of diagnosis, was assessed by logistic regression. RESULTS: When topographic progression was defined as five or more progressed topographic parameters, the greatest kappa value (0.354) was obtained. Ninety-four of the 211 keratoconic eyes (44.5%) were identified as topographically progressed. Age at diagnosis was significantly different between the progressed and non-progressed groups (22.2 vs. 24.7 years, p = 0.014). Logistic regression revealed that younger age at diagnosis was a risk factor for topographic progression (odds ratio, 0.948; 95% confidence interval, 0.907 to 0.991; p = 0.010). CONCLUSIONS: We developed a criterion for evaluating topographic progression of keratoconus using diverse topographic indices. Younger age at diagnosis was associated with topographic progression of keratoconus. PMID- 23730108 TI - The effect of topical cyclosporine 0.05% on dry eye after cataract surgery. AB - PURPOSE: To evaluate the effectiveness of cyclosporine 0.05% for dry eye after cataract surgery. METHODS: Thirty-two newly diagnosed patients with dry eye syndrome 1 week after cataract surgery received a twice-daily treatment of cyclosporine 0.05% for one eye and normal saline 0.9% for the other. Disease severity was measured at 2 weeks, 1 month, 2 months, and 3 months by Schirmer test I (ST-I), tear film break-up time (tBUT), corneal temperature and dry eye symptom questionnaire (Ocular Surface Disease Index). RESULTS: Both groups increased in ST-I and tBUT over time. ST-I in the cyclosporine 0.05% group showed a significant increase at 3 months and tBUT in the cyclosporine 0.05% group showed an increase at 2 and 3 months. The dry eye symptom score was significantly reduced in the cyclosporine 0.05% group. CONCLUSIONS: Cyclosporine 0.05% can also be an effective treatment for dry eye after cataract surgery. PMID- 23730109 TI - Simplified method to measure the peripapillary choroidal thickness using three dimensional optical coherence tomography. AB - PURPOSE: To evaluate a simplified method to measure peripapillary choroidal thickness using commercially available, three-dimensional optical coherence tomography (3D-OCT). METHODS: 3D-OCT images of normal eyes were consecutively obtained from the 3D-OCT database of Korea University Medical Center On the peripapillary images for retinal nerve fiber layer (RNFL) analysis, choroidal thickness was measured by adjusting the segmentation line for the retinal pigment epithelium to the chorioscleral junction using the modification tool built into the 3D-OCT image viewer program. Variations of choroidal thickness at 12 sectors of the peripapillary area were evaluated. RESULTS: We were able to measure the peripapillary choroidal thickness in 40 eyes of our 40 participants, who had a mean age of 41.2 years (range, 15 to 84 years). Choroidal thickness measurements had strong inter-observer correlation at each sector (r = 0.901 to 0.991, p < 0.001). The mean choroidal thickness was 191 +/- 62 um. Choroidal thickness was greatest at the temporal quadrant (mean +/- SD, 210 +/- 78 um), followed by the superior (202 +/- 66 um), nasal (187 +/- 64 um), and inferior quadrants (152 +/- 59 um). CONCLUSIONS: The measurement of choroidal thickness on peripapillary circle scan images for RNFL analysis using the 3D-OCT viewing program was highly reliable and efficient. PMID- 23730110 TI - Structural recovery of the detached macula after retinal detachment repair as assessed by optical coherence tomography. AB - PURPOSE: To investigate correlations between preoperative and postoperative foveal microstructures in patients with macula-off rhegmatogenous retinal detachment (RRD). METHODS: We reviewed the records of 31 eyes from 31 patients with macula-off RRD who had undergone successful re-attachment surgery. We analyzed data obtained from complete ophthalmologic examinations and optical coherence tomography (OCT) before and 9 to 12 months after surgery. All postoperative OCT measurements were taken with spectral-domain OCT, but a subset of preoperative OCT measurements were taken with time-domain OCT. RESULTS: The mean duration of macular detachment was 15.5 +/- 15.2 days, and mean preoperative best-corrected visual acuity (BCVA, logarithm of the minimum angle of resolution) was 1.03 +/- 0.68. Preoperative visual acuity was correlated with retinal detachment height (p < 0.001) and the existence of intraretinal separation (IRS) along with outer layer undulation (OLU) (p = 0.022), but not with macula-off duration. The final BCVA was significantly correlated with integrity of the junction between the photoreceptor inner and outer segments (IS/OS) combined with the continuity of external limiting membrane (ELM) (p = 0.025). The presence of IRS and OLU on a detached macula were highly correlated with the final postoperative integrity of the IS/OS junction and the ELM (p = 0.017). CONCLUSIONS: Eyes preoperatively exhibiting IRS and OLU showed a higher incidence of disruption to the photoreceptor IS/OS junction and the ELM at final follow-up. Such a close correlation between preoperative and postoperative structural changes may explain why ultimate visual recovery in such eyes is poor. PMID- 23730112 TI - A novel computerized visual acuity test for children. AB - PURPOSE: To investigate the efficacy of a computerized visual acuity test, the SNU visual acuity test for children. METHODS: Fifty-six children, ranging from 1 to 5 years of age, were included. In a dark room, children gazed at and followed a circular dot with 50% contrast moving at a fixed velocity of 10 pixels/sec on a computer monitor. Eye movement was captured using a charge coupled device camera and was expressed as coordinates on a graph. Movements of the eye and dot were superimposed on a graph and analyzed. Minimum visualized dot diameters were compared to the Teller visual acuity. RESULTS: Ten eyes (8.9%) of six children failed to perform the Teller visual acuity test, and two eyes (1.8%) of one patient failed to perform the SNU visual acuity test. The observed Teller visual acuity and SNU visual acuity were significantly correlated (p < 0.001). Visual angle degrees converted from the Teller visual acuity and SNU visual acuity were also significantly correlated (p < 0.001). CONCLUSION: The SNU visual acuity using moving targets correlated well with Teller visual acuity and was more applicable than the Teller acuity test. Therefore, the SNU visual acuity test has potential clinical applications for children. PMID- 23730111 TI - Vitrectomy combined with intravitreal triamcinolone acetonide injection and macular laser photocoagulation for nontractional diabetic macular edema. AB - PURPOSE: To evaluate the efficacy of vitrectomy combined with intravitreal injection of triamcinolone acetonide (IVTA) and macular laser photocoagulation for the treatment of nontractional diabetic macular edema (DME) refractory to anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Twenty-eight eyes from 28 subjects who were diagnosed with nontractional DME refractory to three or more sequential anti-VEGF injections underwent sequential vitrectomy, IVTA, and macular laser photocoagulation. Changes in best-corrected visual acuity (BCVA) and central subfield thickness (CST) during the six months following vitrectomy were evaluated. Additionally, the CST and BCVA outcomes were compared with those of 26 eyes treated with the same triple therapy for nontractional DME refractory to conventional treatment, such as IVTA or macular laser photocoagulation, or both. RESULTS: The mean logarithm of the minimum angle of resolution BCVAs before and one, three, and six months after vitrectomy were 0.44 +/- 0.15, 0.36 +/- 0.18, 0.31 +/- 0.14, and 0.34 +/- 0.22, respectively. The mean CSTs were 433.3 +/- 77.9, 329.9 +/- 59.4, 307.2 +/- 60.2, and 310.1 +/- 80.1 microns, respectively. The values of both BCVA and CST at one, three, and six months were significantly improved from baseline (p < 0.05). The extent of CST reduction during the first month after triple therapy was greater in eyes refractory to conventional treatment than in eyes refractory to anti-VEGF (p = 0.012). CONCLUSIONS: Vitrectomy combined with IVTA and macular laser photocoagulation had a beneficial effect on both anatomical and functional outcomes in eyes with nontractional DME refractory to anti-VEGF therapy. PMID- 23730113 TI - Anti-adenoviral effects of human cationic antimicrobial protein-18/LL-37, an antimicrobial peptide, by quantitative polymerase chain reaction. AB - PURPOSE: Antimicrobial peptides have an important role in self-protection of the ocular surface. Human cationic antimicrobial protein (hCAP)-18 is a linear, alpha helical peptide that consists of a conserved pro-sequence called a cathelin-like domain and a C-terminal peptide named LL-37. We investigated the in vitro anti adenoviral activity of hCAP-18/LL-37 in several adenovirus types, inducing keratoconjunctivitis. METHODS: A549 cells were used for viral cell culture, and human adenovirus (HAdV) types 3 (HAdV3, species B), 4 (species E), 8, 19a, and 37 (species D) were used. The cytotoxicity of LL-37 was evaluated by 3-(4,5 dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay to obtain 50% cytotoxic concentration. After pretreatment of A549 cells with serial dilutions of LL-37 for 24 hours, adenovirus was cultured for seven days, and adenoviral DNA was quantitatively measured by real-time polymerase chain reaction (PCR). RESULTS: The 50% effective concentration of LL 37 obtained by real-time PCR ranged between 118 and 270 uM. LL-37 showed a significant inhibitory effect on adenoviral proliferation in all adenovirus types except HAdV4 in a dose-dependent manner. CONCLUSIONS: LL-37 has significant inhibitory activity against HAdV3, 8, and 19, which induce keratoconjunctivitis. These results indicate that hCAP-18/LL-37 may be a possible candidate for the treatment of HAdV keratoconjunctivitis. PMID- 23730114 TI - A case of Muir-Torre syndrome with multiple cancers of bilateral eyelids and breast. AB - We report a case of Muir-Torre syndrome (MTS) with a very rare combination of cancers, involving bilateral eyelid cancers and breast cancer. A 71-year-old female with a history of breast cancer from 18 years prior presented with bilateral eyelid tumors. One of her siblings had lung cancer, and another had pancreatic cancer. She underwent excisional biopsy of the eyelid tumors and histopathology revealed sebaceous carcinoma of the right eyelid and basal cell carcinoma of the left. She was diagnosed with MTS: a skin cancer associated with visceral malignancy. Immunohistochemical tests for mutS homolog 2 showed a lack of expression in both eyelid carcinomas. PMID- 23730115 TI - The development of scleromalacia after regional conjunctivectomy with the postoperative application of mitomycin C as an adjuvant therapy. AB - A 40-year-old woman presented with ocular discomfort in both eyes that had persisted for several months. Six months ago, she had undergone a bilateral nasal and temporal conjunctivectomy using a bare scleral technique followed by a postoperative application of 0.02% mitomycin C (MMC) to treat her chronic hyperemic conjunctiva for cosmesis. Slit-lamp examination revealed that the patient had bilateral nasal and temporal scleral thinning, and a calcified plaque on her nasal conjunctiva. There was no episcleral tissue present around the wound area, and it was difficult to detect any normal conjunctival tissue in the adjacent area for covering the lesion. We believe that performing an aggressive conjunctival excision procedure followed with MMC application for cosmetic enhancement may be disastrous in certain cases. PMID- 23730116 TI - Partial visual rehabilitation using a toric implantable collamer lens in a patient with keratoconus: a case report with 20 months of follow-up. AB - We report the case of a 37-year-old man with a high myopic keratoconus eye that was treated with a posterior chamber toric implantable collamer lens (ICL) in Korea. The patient had a history of contact lens intolerance and did not want to have a corneal transplantation. His uncorrected visual acuity (UCVA) and best spectacle corrected visual acuity were 0.02 and 0.4 in the left eye, respectively. Preoperatively, the manifest refraction was -12.0 -3.5 * 30A. Postoperatively, the manifest refraction was -1.75 * 180A. UCVA improved markedly after implantation. No intraoperative or postoperative complications were observed during 20 months of follow-up. Toric ICL implantation may be a possible alternative surgical option for the visual rehabilitation of high myopic astigmatism in keratoconus patients with rigid gas permeable contact lens intolerance and in patients who do not want to get a corneal transplant. PMID- 23730117 TI - Papillary thyroid carcinoma: bilateral choroidal metastases with extrascleral extension. AB - Here, we present the case of a patient with bilateral choroidal metastases with extraocular extension in one eye. Metastasis of papillary thyroid carcinoma to the uvea is extremely rare, with only 6 patients reported in the literature. A 62 year-old man with a prior history of papillary thyroid carcinoma suffered the rapid loss of vision in his right eye. He had neovascular glaucoma, total retinal detachment, and a solitary choroidal mass. A month later, his left visual acuity also decreased because of a small macular choroidal mass. The right eye was enucleated and a nodular lesion over the sclera representing extraocular extension was observed. This tumor and the intraocular lesion were composed of papillary excrescences and cystic spaces and stained positively for thyroid transcription factor 1 and thyroglobulin, all confirming the diagnosis of metastatic papillary thyroid carcinoma. The tumor in the left eye was successfully treated with diode laser transpupillary thermotherapy. The patient expired within a month as a result of widespread pulmonary metastases. Papillary thyroid carcinoma may metastasize to the uvea bilaterally, cause rapid visual function loss, erode the sclera, and may extend outside the globe similar to choroidal melanoma. This aggressive ocular involvement was associated with a dismal prognosis in our patient. PMID- 23730118 TI - Differential diagnosis of Lemierre's syndrome in a patient with acute paresis of the abducens and oculomotor nerves. AB - Lemierre's syndrome is characterized by anaerobic septicemia, internal jugular vein thrombosis, and septic emboli associated with infections of the head and neck. We describe an unusual and clinically confusing case of a young woman with an acute paresis of the abducens nerve and partial paresis of the right oculomotor nerve. After an extensive imaging diagnostic procedure, we also documented a peritonsillar abscess and various types of thromboses in intracranial and extracranial veins. Furthermore, we found brain and lung abscesses, which led us to establish the diagnosis of Lemierre's syndrome. Despite intensive anti-coagulation and antibiotic therapy, the patient developed a mycotic aneurysm in the right internal carotid artery directly adjacent to the previously thrombosed cavernous sinus. In summary, we were able to confirm that Lemierre's syndrome may occur in conjunction with uncharacteristic symptoms. Due to the sometimes confusing clinical symptoms as well as clinical and radiological specialties, we had to work on an interdisciplinary basis to minimize the delay prior to establishing the diagnosis and therapy. PMID- 23730119 TI - Silent giant cell arteritis in an elderly Korean woman. AB - Giant cell arteritis (GCA) is a rare disease among Asians. Arteritic anterior ischemic optic neuropathy, which accompanies GCA, has not yet been reported in Koreans. Diagnosis of GCA is difficult if typical symptoms other than visual loss are absent. Here, we report a case of an 83-year-old Korean woman presenting with sudden visual loss in both eyes (oculus uterque, OU). Her visual acuities included perception of light in the right eye (oculus dexter, OD) and perception of hand motion in the left eye (oculus sinister, OS). The results of the Hardy Rand-Rittler test and Ishihara test showed total dyschromatopsia OU. The Goldmann perimetry test revealed a total field defect OD and paracentral island OS. Fundus examination revealed chalky-white disc swelling OU. Other systemic symptoms and signs were unremarkable. The erythrocyte sedimentation rate, C-reactive protein and platelet count were highly elevated. Temporal artery biopsy revealed multiple lymphocytes and multinucleated giant cells in the arterial media layer. To our knowledge, this is the first report of GCA in a Korean that has been confirmed with temporal artery biopsy. In conclusion, silent GCA can occur in Koreans, and hence, elderly patients presenting with chalky-white disc swelling, and corresponding laboratory findings must be evaluated for GCA. PMID- 23730120 TI - Long Distance Electron Transfer Across >100 nm Thick Au Nanoparticle/Polyion Films to a Surface Redox Protein. AB - Glutathione-decorated 5 nm gold nanoparticles (AuNPs) and oppositely charged poly(allylamine hydrochloride) (PAH) were assembled into {PAH/AuNP} n films fabricated layer-by-layer (LbL) on pyrolytic graphite (PG) electrodes. These AuNP/polyion films utilized the AuNPs as electron hopping relays to achieve direct electron transfer between underlying electrodes and redox proteins on the outer film surface across unprecedented distances >100 nm for the first time. As film thickness increased, voltammetric peak currents for surface myoglobin (Mb) on these films decreased but the electron transfer rate was relatively constant, consistent with a AuNP-mediated electron hopping mechanism. PMID- 23730121 TI - Child Maltreatment and Delinquency Onset Among African American Adolescent Males. AB - Child welfare and criminology research have increasingly sought to better understand factors that increase the likelihood that abused and neglected children will become involved in the juvenile justice system. However, few studies have addressed this relationship among African American male adolescents. The current study examines the relationship between child maltreatment (i.e., neglect, physical abuse, sexual abuse, and other/mixed abuse) and the likelihood of a delinquency petition using a sample of African American males (N = 2,335) born before 1990. Multivariable logistic regression models compared those with a delinquency-based juvenile justice petition to those without. Results indicate that African American males with a history of neglect, physical abuse, or other/mixed abuse were more likely to be involved in the juvenile justice system than those without any child maltreatment. Additionally, multiple maltreatment reports, a prior history of mental health treatment, victimization, and having a parent who did not complete high school also increased the likelihood of a delinquency petition. Implications for intervention and prevention are discussed. PMID- 23730122 TI - Beyond Homophily: A Decade of Advances in Understanding Peer Influence Processes. AB - This article reviews empirical and theoretical contributions to a multidisciplinary understanding of peer influence processes in adolescence over the past decade. Five themes of peer influence research from this decade were identified, including a broadening of the range of behaviors for which peer influence occurs, distinguishing the sources of influence, probing the conditions under which influence is amplified/attenuated (moderators), testing theoretically based models of peer influence processes (mechanisms), and preliminary exploration of behavioral neuroscience perspectives on peer influence. This review highlights advances in each of these areas, underscores gaps in current knowledge of peer influence processes, and outlines important challenges for future research. PMID- 23730124 TI - Jonah's Birth. AB - Rachel Goldstein shares her experience of exploring options related to care provider and place of birth early in her pregnancy. Goldstein and her husband, Marc, after reading and research, chose midwifery care and a home birth. She shares the story of a long labor at home supported by her husband, her doula, and her midwife. Her positive attitude, her ability to use various comfort strategies, and the support she received throughout labor contributed to being able to give birth naturally and ecstatically to her son Jonah. PMID- 23730123 TI - Use of a Direct Observational Measure in a Trial of Risperidone and Parent Training in Children with Pervasive Developmental Disorders. AB - A Structured Observational Analog Procedure (SOAP), an analogue measure of parent child interactions, was used to assess treatment outcome in children with Autism Spectrum Disorder and serious behavior problems. It served as a secondary outcome measure in a 24-week, randomized trial of risperidone (MED; N=49) versus risperidone plus parent training (COMB; n=75) (ages 4-13 years). At 24-weeks, there was 28 % reduction in child inappropriate behavior during a Demand Condition (p=.0002) and 12 % increase in compliance to parental requests (p=.004) for the two treatment conditions combined. Parents displayed 64 % greater use of positive reinforcement (p=.001) and fewer repeated requests for compliance (p<.0001). In the analysis of covariance (ANCOVA), COMB parents used significantly more positive reinforcement (p=.01) and fewer restrictive statements (p<.05) than MED parents. The SOAP is sensitive to change in child and parent behavior as a function of risperidone alone and in combination with PMT and can serve as a valuable complement to parent and clinician-based measures. PMID- 23730125 TI - Continuing education module transforming maternity care: implementing the blueprint for action. AB - In January 2010, Women's Health Issues published two direction-setting reports from the Transforming Maternity Care (TMC) Project: "2020 Vision for a High Quality, High-Value Maternity Care System" and "Blueprint for Action: Steps Toward a High-Quality, High-Value Maternity Care System." This guest editorial summarizes highlights of the implementation phase of what is now known as the TMC Partnership. Major progress has been made in elevating maternity care quality to a national policy priority, increasing the availability and use of maternity care performance measures, and developing shared decision making tools for childbearing women. PMID- 23730126 TI - A Realistic Evaluation of Two Training Programs on Implementing Skin-to-Skin as a Standard of Care. AB - The authors used realistic evaluation to examine the real-world effectiveness of two 5-day training techniques on sustained optimal skin-to-skin practices that support Step 4 of the revised Baby-Friendly Hospital Initiative (BFHI). The authors found that education alone was insufficient to effect sustainable practice change. Exposure to the 5-day immersion model (Practice, Reflection, Education and training, Combined with Ethnography for Sustainable Success, or PRECESS) alone or combined with education was an effective strategy to change and sustain the standard of care for skin-to-skin practice (p < 0.00001). The intended outcome of sustained practice change toward implementation of skin-to skin care through immersion or a combined approach shows promise and should be repeated in other localities. PMID- 23730127 TI - The Impact of Choice and Control on Women's Childbirth Experiences. AB - Women's choice and control impact birthing experiences. This study used a qualitative, descriptive approach to explore how women develop their initial birth plan and how changes made to the plan affect overall birth experiences. Narrative, semistructured interviews were conducted with 15 women who had given birth in Waterloo Region, Ontario, Canada, and data were analyzed using a phenomenological approach. Findings showed that women relied on many resources when planning a birth and that changes made to a woman's initial birth plan affected her recollection of the birth experience. Conclusions are that women's positive and negative recollections of their birth experiences are related more to feelings and exertion of choice and control than to specific details of the birth experience. PMID- 23730128 TI - Teaching physiologic birth in maternal-newborn courses in undergraduate nursing programs: current challenges. AB - For low-risk childbearing women, fewer technological interventions are associated with better physical and psychosocial outcomes; yet, the number of unmedicated physiologic births is decreasing. As a result, fewer undergraduate nursing students experience caring for women who choose physiologic birth, which presents a challenge for nurse educators and implications for preparing students to provide appropriate care for all childbearing women after the students graduate. This exploratory descriptive qualitative study was conducted among 150 randomly selected undergraduate nursing programs in the United States to explore the challenges of educating nursing students about low-intervention birth. Four themes described current challenges: lack of placement opportunities, education versus clinical practice, evidence-based support of physiologic birth, and the need for more research on pedagogical strategies that effectively educate future nurses to advocate for minimal intervention birth options for all women. PMID- 23730129 TI - Making friends at antenatal classes: a qualitative exploration of friendship across the transition to motherhood. AB - This study explored how friendships made at antenatal classes preserve new mothers' well-being, postnatally. Eight women from the United Kingdom who had attended antenatal classes in the third trimester were interviewed following the birth of their first baby. Transcripts were analyzed using a constant comparative method. Findings suggest that friendships made at antenatal classes are not only unique but also support women's mental health and enhance self-efficacy because the women give and gain reassurance that their babies are developing normally. Such friendships may reduce demands on overstretched social and health-care services. Childbirth educators, midwives, and nurses can be encouraged to capitalize on the opportunity provided by antenatal classes to facilitate the formation of friendships that can help mothers to find "a new equilibrium." PMID- 23730130 TI - Making the case for a physiologic approach to childbirth. AB - In this column, Optimal Care in Childbirth: The Case for a Physiologic Approach by Henci Goer and Amy Romano is reviewed. The book presents compelling evidence for the value and importance of a physiological approach to childbirth and provides a clear, exhaustive guide for making sense of the research in the context of the current maternity care system. The book is an invaluable resource for navigating the maze of contemporary obstetrics for both health-care professionals and childbearing families. PMID- 23730131 TI - Considerations when using videos in lamaze classes. AB - There are enough worthwhile videos available today so that a Lamaze Certified Childbirth Educator could literally teach an entire class series using only videos and feedback discussion. In this column, the author explores considerations in choosing videos for adult learners in Lamaze birth classes. Some things to consider when using videos should be the adult learner's attention span, whether the video increases fear of birth or empowers the learner, and if the video is appropriate for the culture of the class participants. Finally, the author provides a list of some of the many wonderful videos available to Lamaze birth educators. PMID- 23730132 TI - Olive Oil Polyphenols Differentially Inhibit Smooth Muscle Cell Proliferation through a G1/S Cell Cycle Block Regulated by ERK1/2. AB - We hypothesized that polyphenols contained in olive oil play a role in reducing the risk of atherosclerosis. The aim of this study was to determine if the polyphenols in olive oil, oleuropein (Ole), hydroxytyrosol (HT), and tyrosol (Tyr) could inhibit smooth muscle cell (SMC) proliferation through its influence on cell cycle regulation. Bovine vascular SMC were cultured in the presence of Ole, HT, or Tyr at concentration of 1, 10, or 100 MUmol/L. On days 1, 3, and 5, numbers of cells were counted. Cell cycle analysis was performed by flow cytometry on day 1 after SMC were stained with propidium iodide. Cell populations grown in the presence of Ole or HT at 100 MUmol/L concentration were significantly inhibited after 5 days of exposure. Tyr had a similar tendency but it did not attain significance. Cell cycle analysis revealed that 66% of cells were in G1 phase in Ole group, compared with 48% in control group. To examine the cell cycle block between G1 and S phases, we performed Western blotting and found that ERK1/2 activation was inhibited by Ole or HT. We conclude that olive oil polyphenols could inhibit SMC proliferation through a cell cycle block between G1 and S phases which may be regulated by ERK1/2. These results demonstrate a mechanism by which olive oil consumption may be atheroprotective by inhibiting SMC proliferation. PMID- 23730133 TI - How the dissection laboratory facilitates integration of learning: presence of abdominal aortic aneurysm with a large intracardiac thrombus: a rare cadaver finding. AB - There is a debate among medical education experts on the application of dissection or prosection for learning anatomy. However, the literature reveals that the majority of published articles are in favor of dissection. In this article, we present a case of an abdominal aortic aneurysm (AAA) with intracardiac thrombus in a cadaver on routine dissection. We will discuss possible explanations for such finding and provide some insight into how this finding can support the significance of the cadaver-based teaching of anatomy of the medical students. Initially, the abdomen was dissected and exposed to study the abdominal structures in an anatomy class and later the thoracic region was dissected and all the clinical abnormalities were examined and documented. Autopsy of the clot was obtained for histopathology analysis. The intracardiac thrombus was present in the right atrium characterized by its projection into the superior vena cava, inferior vena cava, and the right ventricle. The AAA was extensive and inferior to the renal arteries constricting the entire inferior vena cava. Moreover, associated findings included presence of numerous collaterals in the thoracic region near the superior vena cava; histological examination of the clot showed extensive population of leukocytes. There were enlarged mediastinal lymph nodes. Our cadaver showed an excellent model for integrating between clinical anatomy and pathology by triggering medical students to think of normal and abnormal structures: often called "thinking outside the box." Such an effort might help them in developing their thought processes and future medical careers. PMID- 23730134 TI - Molded Parallel Endografts for Branch Vessel Preservation during Endovascular Aneurysm Repair in Challenging Anatomy. AB - Parallel endografts (also known as snorkels or chimneys) are a proposed strategy for increasing the applicability of endovascular repair to aneurysms involving branch vessels. One major disadvantage of this strategy is the imperfect nature of seal inherent to having multiple side-by-side endografts. In this article, the use of odd-shaped parallel endografts to facilitate apposition and improve seal is proposed and a technique to mold a round stent graft into an "eye" shape using balloons is described. PMID- 23730135 TI - Partial closure of skin wounds after kidney transplantation decreases the incidence of postoperative wound infections. AB - Wound infections are a major cause of morbidity after kidney transplantation. The purpose of our study was to evaluate an improved technique of wound closure. Data corresponding to 104 consecutive live donor kidney recipients were prospectively collected and analyzed. Our routine standard technique involved closure of the abdominal wall muscle and fascia in one layer with interrupted nonabsorbable full thickness sutures. No drains were used. The skin was closed with interrupted 2-0 nylon sutures 4 to 5 cm apart, leaving the skin and subcutaneous tissue in between partially open. Patients were allowed to shower starting on the first postoperative day. Examination of the wounds was continued for at least 1 month postoperatively, and then routinely as needed. All patients were thoroughly informed preoperatively of our technique. There were no immediate postoperative wound infections. There were no instances of dehiscence, evisceration, or need for revision. All patients were able to continue with their routine daily activities. Cosmetic results were satisfactory in all cases. We did not experience any patient complaints with respect to our technique. Patient satisfaction scores conducted by Press Ganey and Associates ranked in the 99 percentile with respect to peers undergoing kidney transplantation. Three patients returned six months postoperatively with suture granulomas which were treated nonoperatively. Partial closure of the skin wound with no associated drains is an effective and cosmetically desirable way to decrease the incidence of postoperative infections in kidney transplantation. PMID- 23730136 TI - Reduced survival in patients with "coronary microvascular disease". AB - The syndrome of chest pain, abnormal stress test, and nonflow limiting coronary artery disease (CAD) is common and is attributed to coronary microvascular disease (uVD). It is associated with increased hospital admissions and health care costs. But its impact on long-term survival is not known. Of the 9941 consecutive patients who had an exercise stress test for evaluation of chest pain between May 1991 and July 2007, 935 had both a positive stress test and a coronary angiogram within 1 year of their stress test forming the study cohort. Significant angiographic CAD defined as >=70% stenosis of an epicardial coronary artery or >=50% stenosis of the left main coronary artery was present in 324 patients. Rest (n = 611) were considered to have coronary uVD. Compared with patients with significant epicardial CAD, patients with coronary uVD were younger (63 +/- 11 vs. 65 +/- 10 years, p = 0.002), and had lower left ventricular wall thickness (p < 0.02), systolic blood pressure (BP; p = 0.002), pulse pressure (0.0008), systolic BP with exercise (p = 0.0001), and pulse pressure with exercise (p < 0.0001). Those with coronary uVD had a better survival compared with those with significant epicardial CAD, but worse than that expected for age- and gender-matched population (p < 0.0001). Coronary uVD as a cause of chest pain and positive stress test is common. All-cause mortality in patients with coronary uVD is worse than in an age- and gender-matched population control, but better than those with significant epicardial CAD. PMID- 23730137 TI - Recurrent unprovoked venous thromboembolism in a young female patient with high levels of homocysteine. AB - Hyperhomocysteinemia is a rare condition which predisposes to atherothrombosis. Recurrent venous thromboembolism (VTE) with hyperhomocysteinemia is known but extremely uncommon. Homocysteine levels of more than 22 umol/L can predispose to VTE in a middle-aged women. We describe a case of a middle-aged woman, community ambulant with recurrent VTE with intermediately high homocysteine levels. She had no other risk factors for recurrent venous thrombosis. In our article, we also discuss hyperhomocysteinemia and its link to VTE. PMID- 23730138 TI - Isolated spontaneous renal artery dissection: a case report and review. AB - We report an interesting case of a 65-year-old gentleman who presented with hypertensive emergency and was found to have an isolated spontaneous dissection of the right renal artery. The dissection was stented via endovascular approach and resulted in marked improvement in blood pressure. Spontaneous renal artery dissection is a difficult condition to diagnose and treat, unless suspected early enough during the course of treatment. Endovascular intervention is the treatment of choice, as failure of conservative treatment may have long lasting clinical implications relating to decreased renal perfusion. Surgical intervention can be associated with high rate of complications. PMID- 23730139 TI - Inadvertent port: catheter placement in azygos vein. AB - Totally implantable ports are safe and effective means of venous access for administration of chemotherapy. One of the usual vessels accessed, through which the port is placed, is the subclavian. Herein, we report a case where the central access was obtained through the left subclavian vein. But the catheter when it was placed was found to be in the azygos vein. This was confirmed with dye study. This is the first report of such an occurrence with subclavian access. The catheter was later withdrawn and repositioned in the superior vena cava. We recommend that the entire procedure of catheter placement must be done under fluoroscopy guidance to ensure safe and error-free positioning. PMID- 23730140 TI - Treatment of Late Class II Antibody-Mediated Rejection Status Postkidney Transplantation: Two Case Reports. AB - We are describing the successful treatment of two cases of late Class II antibody mediated rejection status postkidney transplantation. The first patient was treated with a combination of plasmapheresis, intravenous immunoglobulin (IVIG), and stenting of the transplanted renal artery. The second was treated with IVIG and pulse steroids. PMID- 23730141 TI - Syncope as initial presentation of kommerell diverticulum. AB - Kommerell diverticulum (KD) is an aortic arch diverticulum at the origin of an aberrant subclavian artery. It is a rare anatomical anomaly that can be associated with a double aortic arc, a left aortic arch, and anomalous origin of the right subclavian artery or a right aortic arch with anomalous left subclavian artery. We present a case of KD presenting initially as syncope, as well as a review of the literature of this rare syndrome, including diagnosis, imaging techniques, and current surgical treatments. PMID- 23730142 TI - Endovascular repair of a blunt abdominal aortic injury. AB - Blunt abdominal aortic injury is an uncommon traumatic finding. In the past, treatment options have traditionally consisted of open operative repair; however, the development of endovascular surgery has created new interventional possibilities. This case is presented to demonstrate the applications of endovascular abdominal aortic repair for a blunt traumatic injury. PMID- 23730143 TI - Subclavian steal syndrome successfully treated with a novel application of embolic capture angioplasty. AB - Subclavian artery stenosis can lead to subclavian steal syndrome. Endovascular treatment of these lesions has become the preferred modality. We describe the successful use of embolic capture angioplasty for the treatment of a patient with subclavian artery stenosis resulting in subclavian steal syndrome. PMID- 23730144 TI - Prior Trauma Exposure for Youth in Treatment Foster Care. AB - Very little research has focused on rates of trauma exposure for youth in treatment foster care (TFC). Available research has utilized record review for assessing exposure, which presents limitations for the range of trauma types examined, as records are predominantly focused on abuse and neglect. The current study examines exposure rates and association with emotional and behavioral outcomes for 229 youth in 46 TFC agencies. The youth in this study had exceptionally high rates of trauma exposure by foster parent report, similar to youth in traditional foster care, with nearly half of the sample exposed to four or more types of traumatic events. A composite child abuse and neglect exposure variable was associated with child and adolescent emotional and behavioral outcomes. Implications for services provided as part of TFC are discussed. PMID- 23730145 TI - Estimating Velocity for Processive Motor Proteins with Random Detachment. AB - We show that, for a wide range of models, the empirical velocity of processive motor proteins has a limiting Pearson type VII distribution with finite mean but infinite variance. We develop maximum likelihood inference for this Pearson type VII distribution. In two simulation studies, we compare the performance of our MLE with the performance of standard Student's t-based inference. The studies show that incorrectly assuming normality (1) can lead to imprecise inference regarding motor velocity in the one-sample case, and (2) can significantly reduce power in the two-sample case. These results should be of interest to experimentalists who wish to engineer motors possessing specific functional characteristics. PMID- 23730146 TI - Intimate Partner Violence among West African Immigrants. AB - Although the number of African immigrants arriving to the United States has increased significantly, there has been little investigation regarding their experiences of intimate partner violence or coping strategies. This study used focus groups and individual interviews to explore intimate partner violence among 32 heterosexual West African immigrants. Results suggest that although cultural expectations influence their coping strategies, West African-born men and women face different realities, with women reporting multiple instances of abuse and a sense of frustration with the existing options for assistance. Although participants discussed multilevel support structures within the immediate West African community to address intimate partner violence, all of these options maintained a gender hierarchy, leaving women dissatisfied. Challenges and barriers to partner violence resolution and coping strategies are identified. Results are examined in terms of their implications for addressing the needs of this underserved population. Implications for future research and services are discussed and highlighted. PMID- 23730147 TI - Early Adult Outcomes of Male Arrest Trajectories: Propensity versus Causation Effects. AB - This study examined early adult outcomes of differing arrest trajectories across childhood through early adulthood that were identified in prior work for 197 at risk young men. Early adult outcomes were assessed at ages 27-28 to 29-30 years. Predictive effects of arrest trajectory membership on outcomes were examined after controlling for various factors, including prior levels and early antisocial propensity. As early adults, both chronic offender groups showed poorer adjustment in terms of deviant peer affiliation, education, and work domains than did the Rare Offenders; High-Level Chronic Offenders stood out from all other groups in terms of mental health problems and physical aggression toward a partner. These effects represent plausible causal effects of developmental pathways of offending on the outcomes. Evidence for propensity effects on the outcomes was more limited. Theoretical and prevention implications are discussed. PMID- 23730148 TI - Pain and endometriosis: Etiology, impact, and therapeutics. AB - The association of pain and endometriosis was recognized with the first definitive published reports of this disorder. Unfortunately, the precise etiologies and pathways leading to nociception and pain symptoms in endometriosis remain poorly understood, and as a result, effective therapeutic interventions are lacking with consequent profound effects on affected women's quality of life. In this opinion paper we summarize selected proceedings presented at the 28th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) in Istanbul, Turkey, and review the clinical and translational evidence of chronic pain, neurogenesis, and the pernicious impact of dyspareunia on women with symptomatic endometriosis. The effectiveness of medical treatments is critically assessed and the findings indicate that good therapeutic options are available with extant medications effective in some sub-groups of women with endometriosis, many of which are affordable globally. Nevertheless, new management strategies and drugs need to be developed to increase the options of all afflicted women to minimize and ideally eradicate painful symptoms of endometriosis. However, only by elucidating distinctions among sub-groups with specific symptoms, suggesting different mechanisms, are we likely to derive truly successful therapeutic strategies. PMID- 23730150 TI - Health economics: Why surgeons must embrace these concepts or be content with what politicians and administrators will leave us with. PMID- 23730149 TI - Role of grape seed polyphenols in Alzheimer's disease neuropathology. AB - Alzheimer's disease (AD) is an age-related neurodegenerative condition characterized by a progressive decline in cognitive function. AD affects approximately five million people in the US, creating a devastating financial burden on health care costs and an emotional burden on caregivers. To date, there is no cure for AD, so researchers are continually exploring novel avenues for the prevention and treatment of this condition. In this article, we present some findings from our laboratory and those of others on the potential benefits of a grape seed polyphenolic extract (GSPE) for the prevention and treatment of AD, including its chemical composition, bioactivity, bioavailability, safety, and tolerability, and the mechanisms by which it interferes with AD pathogenesis. Findings presented in this review article support the development of GSPE as a preventative and/or therapeutic agent in AD. PMID- 23730151 TI - Where have we arrived in the care of vascular anomalies a generation after Mulliken's classification system? PMID- 23730152 TI - The epidemiological profile of the Vascular Birthmark Clinic at the Alberta Children's Hospital. AB - BACKGROUND: The Vascular Birthmark (VBM) Clinic at the Alberta Children's Hospital (Calgary, Alberta) is a multidisciplinary clinic dedicated to the evaluation of children with vascular anomalies. OBJECTIVE: To review the characteristics of patients seen at the VBM Clinic. METHOD: A retrospective data analysis of all pediatric patients presenting to the VBM Clinic between 1998 and 2009 was performed. Data including demographic, referring, diagnostic and treatment information were obtained from the clinic's database. RESULTS: Of 932 patients, 621 with hemangiomas and 311 patients with vascular malformations were found in the database. Hemangiomas were more commonly found in girls (68.5%), and most commonly located on the head and neck (54%), with most patients (72.6%) having only one lesion. Of the patients with hemangiomas, 14.7% underwent diagnostic imaging investigation and 23.7% received treatment including medications, surgery, pulsed-dye laser or dressings. The sex distribution among the 311 patients with vascular malformations was almost equal. Venous malformations accounted for 38.9% of patients, isolated capillary malformations for 31.5%, lymphatic malformations for 11.6%, mixed low-flow malformations for 14.8% and arteriovenous malformations for 2.9%. Overall, 37.9% of patients underwent diagnostic imaging investigation and 42.4% received treatment - either pulsed-dye laser, surgical excision, sclerotherapy or other treatment. CONCLUSIONS: Hemangiomas and vascular malformations can occur at any anatomical site. There is a large variation in clinical presentation necessitating expertise in a variety of diagnostic approaches and treatment modalities. Vascular anomalies are best managed in a multidisciplinary setting. PMID- 23730153 TI - How acidic is the lidocaine we are injecting, and how much bicarbonate should we add? AB - BACKGROUND: The infiltration of local anesthetics can be painful, which is likely due, in part, to their acidity. In spite of a Cochrane study that recommended neutralizing lidocaine with bicarbonate to decrease the pain of injection, not many surgeons have adopted the practice, and there are many 'recipes' for how much bicarbonate one should add. OBJECTIVE: To determine the acidity of lidocaine and the correct ratio of bicarbonate that should be added to neutralize lidocaine to achieve body pH. METHODS: Fifty samples each of commonly used anesthetics (lidocaine 1% and 2%, with and without epinephrine 1:100,000) were obtained and tested for pH. Data were also analyzed according to whether the vials had been previously opened. Ten additional samples of lidocaine 1% with 1:100,000 epinephrine were titrated against sodium bicarbonate 8.4% and tested for pH and the presence of precipitate. RESULTS: A solution of 1% lidocaine with 1:100,000 epinephrine had a mean (+/- SD) pH of 4.24+/-0.42, and 2% lidocaine with 1:100,000 epinephrine had a mean pH of 3.93+/-0.43. Plain 1% lidocaine had a pH of 6.09+/-0.16, and plain 2% lidocaine had a pH of 6.00+/-0.27. Epinephrine containing solutions were more acidic when they had been previously opened. One per cent lidocaine with epinephrine required 8.4% sodium bicarbonate at a ratio of 1.1 mL:10 mL to 1.8 mL:10 mL to achieve the target tissue pH of 7.38 to 7.62. CONCLUSION: Lidocaine with epinephrine was approximately 1000 times more acidic than subcutaneous tissue. The addition of bicarbonate to the local anesthetic solution is simple to perform and is inexpensive. The proper volume ratio of 8.4% sodium bicarbonate to 1% lidocaine with 1:100,000 epinephrine is approximately 1 mL:10 mL. Surgeons should be more aware of the simplicity and value of buffering with bicarbonate to decrease the pain of injection. PMID- 23730154 TI - Acellular dermal matrices: Use in reconstructive and aesthetic breast surgery. AB - Acellular dermal matrices (ADMs) were first described for use in breast surgery in 2001. Since this initial report, ADMs have become an increasingly common component of implant-based breast procedures. ADMs have shown promise for use in both aesthetic and reconstructive breast surgery; however, concerns about their use remain because of the significant costs associated with these products. The present article reviews the history of ADM use in breast surgery and the outcomes reported to date. Common techniques for placement of ADMs in aesthetic revisionary and breast reconstruction surgery are provided, and use in the setting of chest wall irradiation and capsular contracture is discussed. Finally, the authors comment on the cost implications of these products in the Canadian and American health care systems. PMID- 23730155 TI - Diagnosis and management of eosinophilic cellulitis (Wells' syndrome): A case series and literature review. AB - INTRODUCTION: Eosinophilic cellulitis (Wells' syndrome) is an inflammatory dermatitis that is often misdiagnosed as infectious cellulitis due to its similarity in presentation. Misdiagnosis leads to delay of correct treatment and inappropriate use of antibiotics. METHODS: A case series of eosinophilic cellulitis and a literature review are presented. RESULTS: Patients with Wells' syndrome may present with a variety of nonspecific symptoms, such as fever, arthralgia and malaise, as well as myriad cutaneous lesions with associated erythema, presenting as blisters, bullae, papules and/or nodules. Several treatment modalities have been used to treat eosinophilic cellulitis and have been met with variable success rates; these include systemic corticosteroids, topical corticosteroids and antihistamines, with success rates of 91.7%, 50% and 25%, respectively. CONCLUSIONS: A high degree of clinical suspicion must be exercised to diagnose this rare condition. Cellulitis with an atypical presentation or not responding to appropriate antibiotic treatment should trigger suspicion of Wells' syndrome. To date, the most successful treatment method is a short course of systemic corticosteroids. PMID- 23730156 TI - The utility of the microvascular anastomotic coupler in free tissue transfer. AB - BACKGROUND: The microvascular anastomosis remains a technically sensitive and critical determinant of success in free tissue transfer. The microvascular anastomotic coupling device is an elegant, friction-fit ring pin device that is becoming more widely used. OBJECTIVE: To systematically review the literature to examine the utility of the microvascular coupler in free tissue transfer. METHODS: A comprehensive database search was performed to identify eligible publications. Inclusion criteria were anastomotic coupler utilization and free tissue transfer. Recorded information from eligible studies included patient age, follow-up, radiation history, number of free-flaps and failure rates, reconstruction subsites, number of coupled venous and arterial anastomoses, coupling time, conversion to sutured anastomosis, coupler size and thrombosis rates. RESULTS: Twenty-five studies reporting on 3207 patients were included in the analysis. A total of 3576 free-flaps were performed within the following subsites: 1103 head and neck, 2094 breast, 300 limb or body, and 79 nonspecified. There were only 26 reported flap failures (0.7%). A total of 3497 venous and 342 arterial coupled anastomoses were performed. The primary outcome measure was thrombosis rates, and there were 61 venous (1.7%) and 12 arterial (3.6%) thromboses reported. Mean coupling time was 5 min, and 30 anastomoses (0.8%) were converted to suture. CONCLUSION: Flap survival and revision-free application of the microvascular coupler occurred in more than 99% of cases. There is a substantial time savings with coupler use. Venous and arterial thrombosis rates are comparable with the best results achieved by sutured anastomosis and, when used by experienced surgeons, the coupler achieves superior results. PMID- 23730157 TI - Lower extremity anterior compartment syndrome complicating bilateral mastectomy and immediate breast reconstruction: A case report and literature review. AB - 'Well leg compartment syndrome' refers to compartment syndrome occurring in a nontraumatic setting. This occurs most commonly in the lower limb during surgery performed with the patient in an anatomically vulnerable position. While this complication is well documented in the setting of orthopedic, urological and gynecological surgeries, it is an exceptionally rare complication in plastic surgery; only seven cases have been published on compartment syndrome complicating an operation performed on a supine patient. A case involving a 56 year-old woman who developed an anterior compartment syndrome of her right lower leg following a bilateral mastectomy with immediate breast reconstruction is presented. A detailed literature review is also included. PMID- 23730158 TI - The practical benefits of planning. PMID- 23730159 TI - Oral exam. PMID- 23730160 TI - Revisiting Gavello's procedure for single-stage reconstruction of the earlobe: The vascular basis, technique and clinical uses. AB - BACKGROUND: Deformities or loss of the earlobe may be congenital, or acquired due to trauma, bites, burns or tumour excision. A variety of single-stage and two stage procedures have been described for earlobe reconstruction, of which Gavello's procedure was one of the earliest. OBJECTIVE: To revisit Gavello's procedure with reference to the vascular supply of the flap, and discuss the relevance of the technique in current practice. METHODS: The authors discuss the vascular basis of Gavello's flap, and describe the clinical application of the single-stage Gavello's procedure in diverse clinical situations, including congenital absence of earlobe, post-burn earlobe deformity and traumatic amputation of the earlobe. RESULTS: Excellent cosmetic results have been achieved in all different clinical situations in the authors' experience, with preservation of earlobe shape and volume, good colour match and a well-concealed scar in the donor area. DISCUSSION: Gavello's procedure is a simple, one-stage procedure that relies entirely on local tissue for earlobe reconstruction; the flap has a predictable vascular supply, skin grafting is not required and the procedure can be used for large defects. An intact donor area over the postauricular mastoid region is a prerequisite. CONCLUSION: The simple, century old Gavello's procedure is still of great value for reconstruction of earlobe defects of diverse etiology. PMID- 23730161 TI - Reconstruction with distally based dorsalis pedis fasciocutaneous flap for the coverage of distal toe-plantar defects. AB - Reconstruction of small defects in the distal portion of the foot has always been a difficult problem. A case involving a young man with a deep electric burn of the distal lateral side of the big toe, successfully treated with a distally based dorsalis pedis fasciocutaneous flap, is presented. The donor site area of the dorsum of the foot was grafted, and deambulation was reassumed three weeks later. Advantages, limits and anatomical consideration regarding the viability of the flap are also discussed. PMID- 23730162 TI - Helical advancement: Pearls and pitfalls. AB - BACKGROUND: Reconstruction of acquired auricular defects is a challenging procedure. Since its emergence, the helical advancement technique has proved to be an excellent method of repairing many auricle defects. This technique may occasionally result in an alteration in the dimensions of the neoauricle, with subsequent deformity. However, the advantages of this technique are well known, while the pitfalls are scarce. OBJECTIVE: To critically review the selection criteria of patients with acquired auricular defects to determine which are eligible for helical advancement technique without subsequent deformity. METHODS: From March 2004 to January 2006, 18 patients with three types of upper one-third auricle defects underwent the helical advancement procedure. All patients were male, with mean age of 33.5 years. The defects ranged from 1.2 cm to 4.3 cm in length. Two helical flaps (one on either side of the injury) were advanced along the helical margin to ensure closure. The vertical and horizontal auricular axes were measured before and after surgery, and the actual reduction in millimetres was calculated. Patients were followed up for three months postoperatively. Assessment of the surgical outcome was performed by surgeon (with patient feedback) in the final patient visit. RESULTS: The principle pitfall in the form of small neoauricle with or without cupping was reported in five patients (27.77%). The defects in these cases were >2.8 cm and the mean resultant reduction in vertical axes was >5 mm. Statistical analysis resulted in chi(2)=4.24 and P=0.04. CONCLUSION: The three varieties of upper one-third auricle defects can best be corrected by the helical advancement technique when the defect is <2.8 cm. Furthermore, perioperative reduction in the vertical axis of the neoauricle >5 mm was an important predictive factor in the development of subsequent deformity. PMID- 23730163 TI - From primary care to bird's eye view: A career in paediatrics. PMID- 23730164 TI - Navigating the stages of an academic career for paediatricians. PMID- 23730165 TI - Chaperoning adolescents: A bygone era or modern medical necessity? PMID- 23730166 TI - Case 2: 'I feel faint': An adolescent with recurrent dizziness and syncope. PMID- 23730167 TI - Case 1: A toddler with stridor. PMID- 23730168 TI - Gentamicin in neonates at risk for sepsis - peak serum concentrations are not necessary. AB - BACKGROUND: Serum gentamicin concentrations (GSCs) are frequently obtained before and after gentamicin administration to newborns with, or at high risk for, sepsis. OBJECTIVE: To determine whether performing a peak GSC assay when the trough GSC is within the guidelines for care would add clinically relevant information for health care workers. METHODS: A retrospective review of the IWK Health Centre (Halifax, Nova Scotia) laboratory database for peak and trough GSC for infants <28 days after birth was performed. RESULTS: Of 5253 paired samples of trough and peak GSCs, 3001 (57%) had trough GSCs <=2 MUg/mL. Of these, only nine (0.3%) had a peak GSC >10 MUg/mL. CONCLUSIONS: Performing a peak GSC measurement does not provide further clinically important data and increases patient morbidity and hospital costs. PMID- 23730169 TI - Ethics application protocols for multicentre clinical studies in Canada: A paediatric rheumatology experience. AB - INTRODUCTION: Individual institutions govern research ethics applications and each must administer and regulate their own protocols. Variations in ethics review procedures and expectations among centres impose impediments to efficiently conducting multicentre studies. METHODS: Observations relating to preparing multisite ethics documents for a study conducted by Canadian paediatric rheumatology investigators are described. Research ethics applications from the 12 participating centres were compared. RESULTS: Although the applications were similar in their content, they differed in their formatting. All applications shared a commitment to ensuring that the study conformed to exemplary ethical standards. CONCLUSIONS: There is wide variation in the multicentre clinical study ethics application process at the institutional level. Considering the common fundamental elements required by all ethics review boards, the present study conceptualized introducing a discipline-specific uniform ethics application process acceptable to all Canadian research ethics boards. This may be a more efficient strategy that could help lessen the burden of collaborative research. PMID- 23730171 TI - Preventing playground injuries. AB - With concerns increasing around childhood obesity and inactivity, playgrounds offer a chance for children to be active. But playgrounds also have risks, with injuries from falls being the most common. Research has shown that playground injuries can be reduced by lowering the heights of play equipment and using soft, deep surfaces to cushion falls. The Canadian Standards Association has published voluntary standards for playgrounds to address these risks for several years. Parents can further reduce injury risks by following simple playground strategies. This statement outlines the burden of playground injuries. It also provides parents and health care providers with opportunities to reduce injury incidence and severity through education and advocacy, and to implement evidence informed safety standards and safer play strategies in local playgrounds. This document replaces a previous Canadian Paediatric Society position statement published in 2002. PMID- 23730170 TI - The Baby-Friendly Initiative: Protecting, promoting and supporting breastfeeding. AB - Breastfeeding confers extensive and well-established benefits and is recognized as an extremely effective preventative health measure for both mothers and babies. Except in very few specific medical situations, breastfeeding should be universally encouraged for all mothers and infants. To improve worldwide breastfeeding initiation and duration rates, the WHO and UNICEF launched the Baby Friendly Initiative (BFI) in 1991. The goal was to protect, promote and support breastfeeding by adherence to the WHO's "Ten Steps to Successful Breastfeeding". Since then, more than 20,000 hospitals in 156 countries have achieved Baby Friendly status, with a resultant increase in both breastfeeding initiation and duration. Still, only 500 hospitals are currently designated Baby-Friendly in industrialized countries, including 37 health centres or health authorities in Canada. Health care practitioners have a unique and influential role in promoting and supporting breastfeeding. Provincial and territorial government leadership is essential to ensuring implementation of the BFI in all health care facilities delivering services to families with young children. PMID- 23730172 TI - Melatonin for the management of sleep disorders in children and adolescents. AB - Problems of sleep initiation and maintenance occur in 15% to 25% of children and adolescents. Studies of the benefits of melatonin for sleep disorders have been published for healthy populations, for children and adolescents with attention deficit hyperactivity disorder, for children and youth with autism, and for several other special populations. These studies demonstrate benefit with minimal side effects. However, all studies have involved small numbers of subjects and address only short-term use of melatonin. There are no good data concerning the safety and efficacy of long-term melatonin use. Further studies are needed to confirm the usefulness and safety of melatonin for sleep disorders in children and adolescents. PMID- 23730173 TI - Perinatal and childhood morbidity and mortality in congenital analbuminemia. AB - Albumin, a serum transport protein, provides 80% of colloid osmotic pressure. Congenital analbuminemia (CAA) is an autosomal recessive disorder characterized by absence of serum albumin. Fifty cases of CAA have been reported throughout the world; however, little is known about its clinical impact. Most reported cases have few clinical signs and symptoms. Twelve local cases from the northwestern central plains region in Saskatchewan were identified and reviewed to ascertain morbidity and mortality related with CAA. All the cases are from two remote First Nations communities. Cases had frequent hospital admissions and recurrent respiratory tract infections. Placental abnormalities included hydropic placentas, placental infarcts and microcalcifications. One-half of the cases were born preterm and one-quarter were small for their gestational age. There were three mortalities in the case series. The present case series suggests increased morbidity and mortality during infancy in patients with CAA. The long-term risks of CAA in this population are unknown and a longitudinal study is recommended. PMID- 23730174 TI - Contributions to the systematics of New World macro-moths IV. PMID- 23730175 TI - A new species of Palpita (Crambidae, Spilomelinae) from the coastal plains of southeastern United States. AB - A new species of Palpita Hubner (Crambidae, Spilomelinae), Palpita maritima, sp. n., is described from maritime forests of the coastal plains of southeastern United States. PMID- 23730176 TI - Cryptic species within cryptic moths: new species of Dunama Schaus (Notodontidae, Nystaleinae) in Costa Rica. AB - Based on almost 1,700 recently reared and wild-collected specimens, the genus Dunama Schaus (Notodontidae, Nystaelinae) in Costa Rica is reviewed. Eight species are recorded of which seven are newly described: Dunama jessiehillae Chacon, Dunama jessiebarronae Chacon, Dunama janewaldronae Chacon, Dunama jessiebancroftae Chacon, Dunama janecoxae Chacon, Dunama biosise Chacon, Dunama indereci Chacon. Dunama angulinea Schaus is redescribed and associated with its correct genitalia. Dunama tuna (Schaus), previously listed as ocurring in Costa Rica, is restricted to Colombia. Most species are described through their distinctive CO1 barcodes, genitalia and life histories. Dunama adults and caterpillars, their foodplants, and their parasites in Area de Conservacion Guanacaste (ACG) in northwestern Costa Rica are described where known. Many life history stages are illustrated. PMID- 23730177 TI - Four new Neotropical Lophocampa species with a redescription of Lophocampa atriceps (Hampson) (Lepidoptera, Erebidae, Arctiinae). AB - Four new species of Lophocampa Harris, are described and illustrated: Lophocampa flavodorsata sp. n., Lophocampa griseidorsata sp. n., Lophocampa herbini sp. n. and Lophocampa sullivani sp. n. Lophocampa atriceps (Hampson) is redescribed, illustrated and compared to the new species. PMID- 23730178 TI - Description of a new species and subspecies of Idalus Walker from Costa Rica, Honduras and Guatemala (Lepidoptera, Erebidae, Arctiinae, Arctiini). AB - A new species and subspecies of Idalus Walker are described from Costa Rica, Honduras and Guatemala. Images of males and females and their genitalia are provided. Locality information and distribution maps for Costa Rica and for Guatemala are included. The biology and phylogeny of Idalus are discussed. PMID- 23730179 TI - Five new species and three new subspecies of Erebidae and Noctuidae (Insecta, Lepidoptera) from Northwestern North America, with notes on Chytolita Grote (Erebidae) and Hydraecia Guenee (Noctuidae). AB - Several taxonomic issues in the moth families Erebidae and Noctuidae are addressed for Northwestern North America. Drasteria parallelaCrabo & Mustelin andCycnia oregonensis tristisCrabo in the Erebidae and Eudryas brevipennis bonneville Shepard & Crabo, Resapamea diluvius Crabo, Resapamea angelika Crabo, Resapamea mammuthus Crabo, Fishia nigrescens Hammond & Crabo, and Xestia perquiritata orcaCrabo & Hammond in the Noctuidae are described as new. The following new synonyms are proposed: Chytolita petrealis Grote with Herminea morbidalis Guenee; Gortyna columbia Barnes & Benjamin and Gortyna ximena Barnes & Benjamin with Gortyna obliqua Harvey; and Hydroecia pallescens Smith with Hydroecia medialis Smith. The type locality of Gortyna intermedia Barnes & Benjamin is restricted to Lundbreck, Municipality of Crowsnest Pass, Alberta, Canada. PMID- 23730180 TI - A review of the Paectes arcigera species complex (Guenee) (Lepidoptera, Euteliidae). AB - Five new species of Paectes Hubner [1818] related to Paectes arcigera (Guenee) (Puerto Rico, U.S. Virgin Islands, British Virgin Islands, Guadeloupe, Dominica, St. Lucia, Trinidad) and Paectes longiformis Pogue (Brazil) are described: Paectes asper sp. n. (Florida, Bahamas, Cuba, Cayman Islands, Jamaica, Haiti, Dominican Republic, Puerto Rico, British Virgin Islands, U.S. Virgin Islands, Dominica, Colombia), Paectes medialba sp. n. (Argentina), Paectes similis sp. n. (Brazil), Paectes sinuosa sp. n. (Argentina, Brazil, Paraguay), and Paectes tumida sp. n. (Colombia, Guyana, Suriname, French Guiana). Adults and genitalia are illustrated for all species. Taxonomic changes include the rev. stat. of Paectes nana (Walker) (Florida, Greater Antilles, Mexico, Guatemala, Galapagos) as a valid species and revised synonyms Paectes indefatigabilis Schaus and Paectes isabel Schaus as junior synonyms of Paectes nana instead of Paectes arcigera. New host records for Paectes sinuosa and Paectes nana reared on Brazilian peppertree (Schinus terebinthifolius Raddi, Anacardiaceae) are presented. The holotype and female genitalia of Paectes obrotunda (Guenee) are illustrated. PMID- 23730181 TI - A revision of the genus Ufeus Grote with the description of a new species from Arizona (Lepidoptera, Noctuidae, Noctuinae, Xylenini, Ufeina). AB - The genus Ufeus Grote is revised to include five species including Ufeus felsensteini,sp. n. in southern Arizona. A key to species, descriptions, illustrations of adults and genitalia are included. PMID- 23730182 TI - Comments on differences in classification of the superfamily Noctuoidea (Insecta, Lepidoptera) between Eurasia and North America. AB - An attempt is made to bring consensus between the classifications of the Noctuoidea in Europe and North America. Twelve points of disagreement between the check lists from the two regions are discussed and solutions recommended. PMID- 23730183 TI - Lepidoptera family-group names proposed by Thaddeus William Harris in 1841. AB - In 1841, T. W. Harris published "A Report on the Insects of Massachusetts, Injurious to Vegetation," a seminal work in North American Entomology and one of the first New World publications to describe Lepidoptera species. Although appearing in several subsequent editions, the eight family-group names proposed by Harris were largely overlooked. In summarizing Harris' family-group names, we show that authorship for two Noctuidae names in current usage require changes: Acronictinae Harris, 1841 (originally as Acronyctadae) has priority over Heinemann, 1859, and Agrotini Harris, 1841 (as Agrotitidae) has priority over Rambur, 1848. Mamestradae Harris, 1841 is also a senior synonym of Mamestrinae Hampson, 1902 (Type genus: Mamestra Ochsenheimer, 1816), an available name that is currently a junior subjective synonym of Noctuidae: Noctuinae: Hadenini Guenee, 1837 (Type genus: Hadena Schrank, 1802). Geometridae: Ennominae: Hyberniini Harris, 1841 (as Hyberniadae), based on Erranis Hubner, [1825] (= Hybernia Berthold, 1827), has precedence over two family-group names with long standing usage, Bistonini Stephens, 1850 and Boarmiini Duponchel, 1845, and a reversal of precedence for the latter two names over Hyberniini is proposed under ICZN guidelines. PMID- 23730184 TI - Additions and corrections to the check list of the Noctuoidea (Insecta, Lepidoptera) of North America north of Mexico. AB - A total of 64 additions and corrections are listed and discussed for the check list of the Noctuoidea of North America north of Mexico published in 2010. One family-group name is inserted, four are changed in rank, one is deleted, one is changed in name, and three are changed in authorship. Taxonomic changes to species are six new or revised synonymies, one new combination, and one revision in status from species to subspecies. PMID- 23730185 TI - Gondysia preceeded Neadysgonia (Lepidoptera, Erebidae, Erebinae), a new generic synonymy from Southeastern United States - Corrigendum. PMID- 23730186 TI - Two new species of the gorgonian inhabiting barnacle, Conopea (Crustacea, Cirripedia, Thoracica), from the Gulf of Guinea. AB - Two new species of Conopea (Say 1822) are described from the Gulf of Guinea: Conopea saotomensis sp. n.and Conopea fidelis sp. n. These two new species were collected from the historically isolated volcanic islands of Sao Tome and Principe. The relationship between Conopea saotomensis sp. n., Conopea fidelis sp. n.and two other Atlantic barnacle species, Conopea calceola (Ellis 1758) and Conopea galeata (Linnaeus 1771), is examined. The methods employed are the construction of a molecular phylogeny using mitochondrial COI and nuclear H3 gene sequence data along with morphological comparisons of calcareous and cuticular body parts. It is found that Conopea saotomensis sp. n., Conopea fidelis sp. n.and Conopea calceola are most closely related to each other but the relationship among them is unresolved. Gorgonian hosts are identified. Preliminary observations show species level host specificity for Conopea fidelis sp. n. PMID- 23730187 TI - A new Vaejovis C.L. Koch, 1836, the second known vorhiesi group species from the Santa Catalina Mountains of Arizona (Scorpiones, Vaejovidae). AB - A new species of the vorhiesi group of Vaejovis C.L. Koch, 1836, Vaejovis brysoni sp. n., is described from the Santa Catalina Mountains in southern Arizona. Vaejovis deboerae Ayrey also inhabits this mountain range, making this the first documented case of two vorhiesi group species distributed on the same mountain. When compared to all other vorhiesi group species, Vaejovis brysoni sp. n. is distinct based on several combinations of morphological characters and morphometric ratios. PMID- 23730188 TI - New spider flies from the Neotropical Region (Diptera, Acroceridae) with a key to New World genera. AB - Two new genera and five new species of spider flies (Diptera: Acroceridae) are described from the Neotropical Region. A new genus of Philopotinae (Neophilopota brevirostris Schlinger gen. et sp. n.) is described from Mexico, while an unusual new species of Sphaerops Philippi, 1865 (Acrocerinae: Sphaerops micella Schlinger sp. n.) is described from Chile. A new Panopinae genus near Lasia Wiedemann, 1824 (Coquena stangei Schlinger gen. et sp. n.), is described from Argentina and two new species of Pialea Erichson, 1840 (Pialea brunea Schlinger sp. n. and Pialea corbiculata Schlinger sp. n.)are described from Venezuela. Each genus is diagnosed and figured, and a key to species provided. The Neotropical fauna presently includes 19 genera, containing approximately 100 species. A key to New World genera is also included. PMID- 23730189 TI - A new species of Solanum sect. Acanthophora (Solanaceae) from Argentina and Brazil. AB - A new species of Solanum belonging to section Acanthophora (subgenus Leptostemonum) from Argentina and Brazil is described. Solanum neei Chiarini & L.A.Mentz, sp. nov. is found in clearings of semideciduous forests and in secondary formations, from the states of Parana, Rio Grande do Sul and Santa Catarina in Brazil to the Misiones province in Argentina. It is morphologically similar to Solanum incarceratum Ruiz & Pav. from Peru, Bolivia and Western Central Brazil, differing mainly by its pedunculate inflorescences. A key to related species is provided, as well a photograph of the holotype, a distribution map and illustration. PMID- 23730190 TI - Costus loangensis, an exciting new species from Gabon, Africa. AB - A new species of spiral ginger (Costus: Costaceae) from Gabon, Africa is described. Costus loangensis H. Maas & Maas is found in the coastal region on white sand soils under a tropical rain forest canopy. It is morphologically distinct from all other African species of Costus but shows some similarities in floral form with the savanna-inhabiting Costus spectabilis (Fenzl) K. Schum. and similarities in vegetative form with Costus ligularis Baker. Only one population of the new species is documented. Photographs of the new species are included as is a preliminary phylogeny indicating its position within the African Costaceae. PMID- 23730191 TI - Diatoms from Brazil: the taxa recorded by Christian Gottfried Ehrenberg. AB - The flora of diatoms from Brazil has been studied by several authors from the beginning of the 19(th) up to now. Some of the old lists and descriptions are unknown or have been ignored by Brazilian researchers and the situation of the names cited was not assessed. Here we compiled a list of 101 taxa of diatoms from Brazil registered by Christian Gottfried Ehrenberg during the 19(th) century. We checked the current nomenclatural status of those taxa and lectotypified species from Brazil described by this author. For this, we accessed the Ehrenberg collection in the Museum fur Naturkunde, Berlin, Germany, where 11 samples from Brazil studied by Ehrenberg are housed and published in different papers. Using these samples, we found 101 taxa (specific and infraspecific) published by Ehrenberg from Brazil. Five species (Eunotia bidens Ehrenb., Eunotia depressa Ehrenb., Eunotia elephas Ehrenb., Pinnularia microstauron Ehrenb., and Terpsinoe brasiliensis Ehrenb.) were new descriptions and were lectotypified here. The other species cited for Brazil were described initially from other places. However, 23 names were invalid and one illegitimate. PMID- 23730192 TI - Symphysodontella madhusoodananii (Pterobryaceae, Moss) a new species from the Western Ghats of India. AB - Symphysodontella madhusoodananii Manju & Rajesh, sp. nov. an epiphytic pendant moss, with flagellate branches and long acuminate leaves with two short costa is described and illustrated from the tropical wet evergreen forests of the Western Ghats of India. PMID- 23730193 TI - Melothria domingensis (Cucurbitaceae), an endangered Caribbean endemic, is a Cayaponia. AB - The Neotropical genus Melothria (Benincaseae, Cucurbitaceae) is a small group of yellow- or white-flowered climbers with small to medium-sized fruits. In 1899, Alfred Cogniaux described a species from montane rainforest in Haiti as Melothria domingensis, presumably based on the overall similarity in habit, leaf shape, and fruit morphology of his incomplete herbarium material to other Central American Melothria species. Melothria domingensis is still rare in European and American herbaria and the species has never been studied in detail. We here present molecular and morphological analyses, which show that the species is misplaced in Melothria and instead belongs in the distantly related tribe Cucurbiteae in the genus Cayaponia. We illustrate the species, provide the formal transfer and an extended description, and discuss the phylogenetic, biogeographic and ecological implications, including the finding that most likely bee- and not bat-pollination is ancestral in Cayaponia. PMID- 23730194 TI - Zyzyura, a new genus of Eupatorieae (Asteraceae) from Belize. AB - A new Genus, Zyzyura is named to accommodate Fleischmannia mayana Pruski that has an eximbricate involucre, a high-conical receptacle, a corolla with a slender base closely investing the style and with a broadly campanulate limb, enlarged elongate cells in the carpopodium, short and broad distally protruding cells in the corolla lobes, and broad rounded anther appendages. PMID- 23730195 TI - Murdannia saddlepeakensis (Commelinaceae) - a new species from Andaman and Nicobar Islands, India. AB - Murdannia saddlepeakensis (Commelinaceae), a new species from the Andaman and Nicobar Islands, India, is described and illustrated. The new species is remarkable for its narrowly linear leaves, two fertile stamens, single seeded locule and scorbiculate seeds. PMID- 23730196 TI - New and existing combinations in Palaeotropical Phlegmariurus (Lycopodiaceae) and lectotypification of the type species Phlegmariurus phlegmaria (L.) T.Sen & U.Sen. AB - The genus Phlegmariurus Holubis recognised more widely than originally proposed and is circumscribed to include both Neotropic and Palaeotropic epiphytic and terrestrial species of Huperzioid Lycopodiaceae that have isotomous shoots, lack bulbils in their sporophyllous shoots and have spores with convex lateral margins and foveolate-fossulate sculpture restricted to their distal surfaces. New combinations with Phlegmariurus are proposed for 81 species and existing combinations identified for 33 species originating from the Palaeotropics. This installs a generic circumscription that is consistent between the Neotropics and Palaeotropics. A lectotype is designated for the type species of the genus, Phlegmariurus phlegmaria (L.) T.Sen & U.Sen. PMID- 23730197 TI - Condition Number Regularized Covariance Estimation. AB - Estimation of high-dimensional covariance matrices is known to be a difficult problem, has many applications, and is of current interest to the larger statistics community. In many applications including so-called the "large p small n" setting, the estimate of the covariance matrix is required to be not only invertible, but also well-conditioned. Although many regularization schemes attempt to do this, none of them address the ill-conditioning problem directly. In this paper, we propose a maximum likelihood approach, with the direct goal of obtaining a well-conditioned estimator. No sparsity assumption on either the covariance matrix or its inverse are are imposed, thus making our procedure more widely applicable. We demonstrate that the proposed regularization scheme is computationally efficient, yields a type of Steinian shrinkage estimator, and has a natural Bayesian interpretation. We investigate the theoretical properties of the regularized covariance estimator comprehensively, including its regularization path, and proceed to develop an approach that adaptively determines the level of regularization that is required. Finally, we demonstrate the performance of the regularized estimator in decision-theoretic comparisons and in the financial portfolio optimization setting. The proposed approach has desirable properties, and can serve as a competitive procedure, especially when the sample size is small and when a well-conditioned estimator is required. PMID- 23730198 TI - Nanosilver on nanostructured silica: Antibacterial activity and Ag surface area. AB - Nanosilver is one of the first nanomaterials to be closely monitored by regulatory agencies worldwide motivating research to better understand the relationship between Ag characteristics and antibacterial activity. Nanosilver immobilized on nanostructured silica facilitates such investigations as the SiO2 support hinders the growth of nanosilver during its synthesis and, most importantly, its flocculation in bacterial suspensions. Here, such composite Ag/silica nanoparticles were made by flame spray pyrolysis of appropriate solutions of Ag-acetate or Ag-nitrate and hexamethyldisiloxane or tetraethylorthosilicate in ethanol, propanol, diethylene glucolmonobutyl ether, acetonitrile or ethylhexanoic acid. The effect of solution composition on nanosilver characteristics and antibacterial activity against the Gram negative Escherichia coli was investigated by monitoring their recombinantly synthesized green fluorescent protein. Suspensions with identical Ag mass concentration exhibited drastically different antibacterial activity pointing out that the nanosilver surface area concentration rather than its mass or molar or number concentration determine best its antibacterial activity. Nanosilver made from Ag acetate showed a unimodal size distribution, while that made from inexpensive Ag nitrate exhibited a bimodal one. Regardless of precursor composition or nanosilver size distribution, the antibacterial activity of nanosilver was correlated best with its surface area concentration in solution. PMID- 23730200 TI - Crosstalk Between DNA and Histones: Tet's New Role in Embryonic Stem Cells. AB - Embryonic stem (ES) cells are characterized by the expression of an extensive and interconnected network of pluripotency factors which are downregulated in specialized cells. Epigenetic mechanisms, including DNA methylation and histone modifications, are also important in maintaining this pluripotency program in ES cells and in guiding correct differentiation of the developing embryo. Methylation of the cytosine base of DNA blocks gene expression in all cell types and further modifications of methylated cytosine have recently been discovered. These new modifications, putative intermediates in a pathway to erase DNA methylation marks, are catalyzed by the ten-eleven translocation (Tet) proteins, specifically by Tet1 and Tet2 in ES cells. Surprisingly, Tet1 shows repressive along with active effects on gene expression depending on its distribution throughout the genome and co-localization with Polycomb Repressive Complex 2 (PRC2). PRC2 di- and tri-methylates lysine 27 of histone 3 (H3K27me2/3 activity), marking genes for repression. In ES cells, almost all gene loci containing the repressive H3K27me3 modification also bear the active H3K4me3 modification, creating "bivalent domains" which mark important developmental regulators for timely activation. Incorporation of Tet1 into the bivalent domain paradigm is a new and exciting development in the epigenetics field, and the ramifications of this novel crosstalk between DNA and histone modifications need to be further investigated. This knowledge would aid reprogramming of specialized cells back into pluripotent stem cells and advance understanding of epigenetic perturbations in cancer. PMID- 23730199 TI - Molecular mechanisms involved in the aging of the T-cell immune response. AB - T-lymphocytes play a central role in the effector and regulatory mechanisms of the adaptive immune response. Upon exiting the thymus they begin to undergo a series of phenotypic and functional changes that continue throughout the lifetime and being most pronounced in the elderly. The reason postulated for this is that the dynamic processes of repeated interaction with cognate antigens lead to multiple division cycles involving a high degree of cell differentiation, senescence, restriction of the T-cell receptor (TCR) repertoire, and cell cycle arrest. This cell cycle arrest is associated with the loss of telomere sequences from the ends of chromosomes. Telomere length is reduced at each cell cycle, and critically short telomeres recruit components of the DNA repair machinery and trigger replicative senescence or apoptosis. Repetitively stimulated T-cells become refractory to telomerase induction, suffer telomere erosion and enter replicative senescence. The latter is characterized by the accumulation of highly differentiated T-cells with new acquired functional capabilities, which can be caused by aberrant expression of genes normally suppressed by epigenetic mechanisms in CD4+ or CD8+ T-cells. Age-dependent demethylation and overexpression of genes normally suppressed by DNA methylation have been demonstrated in senescent subsets of T-lymphocytes. Thus, T-cells, principally CD4+CD28(null) T-cells, aberrantly express genes, including those of the KIR gene family and cytotoxic proteins such as perforin, and overexpress CD70, IFN-gamma, LFA-1 and others. In summary, owing to a lifetime of exposure to and proliferation against a variety of pathogens, highly differentiated T-cells suffer molecular modifications that alter their cellular homeostasis mechanisms. PMID- 23730201 TI - Planar cell polarity signaling in collective cell movements during morphogenesis and disease. AB - Collective and directed cell movements are crucial for diverse developmental processes in the animal kingdom, but they are also involved in wound repair and disease. During these processes groups of cells are oriented within the tissue plane, which is referred to as planar cell polarity (PCP). This requires a tight regulation that is in part conducted by the PCP pathway. Although this pathway was initially characterized in flies, subsequent studies in vertebrates revealed a set of conserved core factors but also effector molecules and signal modulators, which build the fundamental PCP machinery. The PCP pathway in Drosophila regulates several developmental processes involving collective cell movements such as border cell migration during oogenesis, ommatidial rotation during eye development, and embryonic dorsal closure. During vertebrate embryogenesis, PCP signaling also controls collective and directed cell movements including convergent extension during gastrulation, neural tube closure, neural crest cell migration, or heart morphogenesis. Similarly, PCP signaling is linked to processes such as wound repair, and cancer invasion and metastasis in adults. As a consequence, disruption of PCP signaling leads to pathological conditions. In this review, we will summarize recent findings about the role of PCP signaling in collective cell movements in flies and vertebrates. In addition, we will focus on how studies in Drosophila have been relevant to our understanding of the PCP molecular machinery and will describe several developmental defects and human disorders in which PCP signaling is compromised. Therefore, new discoveries about the contribution of this pathway to collective cell movements could provide new potential diagnostic and therapeutic targets for these disorders. PMID- 23730202 TI - On the structural plasticity of the human genome: chromosomal inversions revisited. AB - With the aid of novel and powerful molecular biology techniques, recent years have witnessed a dramatic increase in the number of studies reporting the involvement of complex structural variants in several genomic disorders. In fact, with the discovery of Copy Number Variants (CNVs) and other forms of unbalanced structural variation, much attention has been directed to the detection and characterization of such rearrangements, as well as the identification of the mechanisms involved in their formation. However, it has long been appreciated that chromosomes can undergo other forms of structural changes - balanced rearrangements - that do not involve quantitative variation of genetic material. Indeed, a particular subtype of balanced rearrangement - inversions - was recently found to be far more common than had been predicted from traditional cytogenetics. Chromosomal inversions alter the orientation of a specific genomic sequence and, unless involving breaks in coding or regulatory regions (and, disregarding complex trans effects, in their close vicinity), appear to be phenotypically silent. Such a surprising finding, which is difficult to reconcile with the classical interpretation of inversions as a mechanism causing subfertility (and ultimately reproductive isolation), motivated a new series of theoretical and empirical studies dedicated to understand their role in human genome evolution and to explore their possible association to complex genetic disorders. With this review, we attempt to describe the latest methodological improvements to inversions detection at a genome wide level, while exploring some of the possible implications of inversion rearrangements on the evolution of the human genome. PMID- 23730203 TI - Toll-like receptors and human disease: lessons from single nucleotide polymorphisms. AB - Toll-like receptors (TLRs), a large group of proteins which recognize various pathogen-associated molecular patterns, are critical for the normal function of the innate immune system. Following their discovery many single nucleotide polymorphisms within TLRs and components of their signaling machinery have been discovered and subsequently implicated in a wide range of human diseases including atherosclerosis, sepsis, asthma, and immunodeficiency. This review discusses the effect of genetic variation on TLR function and how they may precipitate disease. PMID- 23730206 TI - CDC25A protein stability represents a previously unrecognized target of HER2 signaling in human breast cancer: implication for a potential clinical relevance in trastuzumab treatment. AB - The CDC25A-CDK2 pathway has been proposed as critical for the oncogenic action of human epidermal growth factor receptor 2 (HER2) in mammary epithelial cells. In particular, transgenic expression of CDC25A cooperates with HER2 in promoting mammary tumors, whereas CDC25A hemizygous loss attenuates the HER2-induced tumorigenesis penetrance. On the basis of this evidence of a synergism between HER2 and the cell cycle regulator CDC25A in a mouse model of mammary tumorigenesis, we investigated the role of CDC25A in human HER2-positive breast cancer and its possible implications in therapeutic response. HER2 status and CDC25A expression were assessed in 313 breast cancer patients and we found statistically significant correlation between HER2 and CDC25A (P = .007). Moreover, an HER2-positive breast cancer subgroup with high levels of CDC25A and very aggressive phenotype was identified (P = .005). Importantly, our in vitro studies on breast cancer cell lines showed that the HER2 inhibitor efficacy on cell growth and viability relied also on CDC25A expression and that such inhibition induces CDC25A down-regulation through phosphatidylinositol 3 kinase/protein kinase B pathway and DNA damage response activation. In line with this observation, we found a statistical significant association between CDC25A overexpression and trastuzumab-combined therapy response rate in two different HER2-positive cohorts of trastuzumab-treated patients in either metastatic or neoadjuvant setting (P = .018 for the metastatic cohort and P = .021 for the neoadjuvant cohort). Our findings highlight a link between HER2 and CDC25A that positively modulates HER2-targeted therapy response, suggesting that, in HER2 positive breast cancer patients, CDC25A overexpression affects trastuzumab sensitivity. PMID- 23730204 TI - Progress in multiple sclerosis genetics. AB - A genetic component in the susceptibility to multiple sclerosis (MS) has long been known, and the first and major genetic risk factor, the HLA region, was identified in the 1970's. However, only with the advent of genome-wide association studies in the past five years did the list of risk factors for MS grow from 1 to over 50. In this review, we summarize the search for MS risk genes and the latest results. Comparison with data from other autoimmune and neurological diseases and from animal models indicates parallels and differences between diseases. We discuss how these translate into an improved understanding of disease mechanisms, and address current challenges such as genotype-phenotype correlations, functional mechanisms of risk variants and the missing heritability. PMID- 23730207 TI - Combination of oncolytic herpes simplex viruses armed with angiostatin and IL-12 enhances antitumor efficacy in human glioblastoma models. AB - Oncolytic herpes simplex virus (oHSV) can potentially spread throughout the tumor, reach isolated infiltrating cells, kill them, and deliver anticancer agents. However, the host responds to oHSV by inducing intratumoral infiltration of macrophages that can engulf the virus, limiting the potential of this therapeutic strategy. Hypervascularity is a pathognomonic feature of glioblastoma (GBM) and is a promising therapeutic target. Antiangiogenic treatments have multiple benefits, including the capacity to increase oHSV efficacy by suppressing macrophage extravasation and infiltration into the tumor. Angiostatin is an antiangiogenic polypeptide, and interleukin-12 (IL-12) is an immunostimulatory cytokine with strong antiangiogenic effects. Clinical use of each has been limited by delivery issues and systemic toxicity. We tested a combination treatment strategy using oHSVs expressing angiostatin (G47Delta mAngio) and IL-12 (G47Delta-mIL12) in two orthotopic human GBM models. Intratumoral injection of G47Delta-mAngio and G47Delta-mIL12 in mice bearing intracranial U87 or tumors derived from glioblastoma stem cells significantly prolonged survival compared to each armed oHSV alone. This was associated with increased antiangiogenesis and virus spread and decreased macrophages. These data support the paradigm of using oHSV expressing different antiangiogenic agents and show for the first time that oHSVs expressing angiostatin and IL-12 can improve efficacy in human GBM models. PMID- 23730208 TI - BRCA1 expression is epigenetically repressed in sporadic ovarian cancer cells by overexpression of C-terminal binding protein 2. AB - INTRODUCTION: Ovarian cancer is the leading cause of mortality from gynecological malignancy despite advancements in novel therapeutics. We have recently demonstrated that the transcriptional co-repressor C-terminal binding protein 2 (CtBP2) is overexpressed in epithelial ovarian carcinoma. MATERIALS AND METHODS: Reverse-transcribed cDNA from CtBP2 wild-type and knockdown ovarian cancer cell lines was hybridized to Affymetrix Gene 1.0 ST microarrays, and differentially expressed genes were studied. Immunohistochemical analysis of CtBP2 and BRCA1 staining of ovarian tissues was performed. Chromatin immunoprecipitation (ChIP) and luciferase assays were carried out. The effect of the drugs 4-methylthio-2 oxobutyric acid (MTOB) and poly(ADP-ribose) polymerase (PARP) inhibitor Olaparib on CtBP2 wild-type and knockdown cell lines was examined using methylthiazol tetrazolium assays and an xCELLigence System. RESULTS: Eighty-five genes involved in DNA repair, mitotic checkpoint, nucleosome assembly, and the BRCA1 network were differentially regulated by CtBP2 expression. ChIP and luciferase reporter assays using a BRCA1 promoter-regulated luciferase construct indicated that the CtBP2 complex binds the BRCA1 promoter and represses BRCA1 transcription. Immunohistochemistry illustrated a significant inverse CtBP2 and BRCA1 expression in a panel of malignant ovarian tumor tissues. The CtBP2 inhibitor MTOB suppressed ovarian cancer cell survival in a CtBP2-dependent manner. Ovarian cancer cells with CtBP2 knockdown did not display increased sensitivity to the PARP inhibitor Olaparib. CONCLUSION: CtBP2 is an ovarian cancer oncogene that may play a significant role in epigenetically silencing BRCA1 function in sporadic epithelial ovarian cancer. CtBP2-specific inhibitors, such as MTOB, may be effective adjunct therapies in the management of patients with CtBP2-positive ovarian carcinoma. PMID- 23730209 TI - Extracellular tissue transglutaminase activates noncanonical NF-kappaB signaling and promotes metastasis in ovarian cancer. AB - Tissue transglutaminase (TG2) is a multifunctional protein that binds to fibronectin and exerts protein transamidating activity in the presence of Ca(2+). We previously reported that TG2 is upregulated in ovarian tumors and enhances intraperitoneal (i.p.) metastasis. TG2 is secreted abundantly in ovarian cancer (OC) ascites as an active enzyme, yet its function in the extracellular compartment remains unknown. To study the distinct functions of secreted TG2, we used recombinant His6-tagged TG2 and catalytically inactive enzyme in vitro and in vivo. By using i.p. and orthotopic ovarian xenografts, we show that extracellular transglutaminase promoted OC peritoneal metastasis. The main pathway activated by extracellular TG2 was noncanonical nuclear factor-kappa B (NF-kappaB) signaling, and the enzymatic function of the protein was required to induce phosphorylation of IkappaB kinase alpha and processing of the precursor protein p100 into the active p52 subunit. A specific target of TG2-activated p52/RelB complex is the hyaluronan receptor, CD44. Noncanonical NF-kappaB activation by extracellular TG2 induced CD44 up-regulation and epithelial-to mesenchymal transition, contributing to increased cancer cell invasiveness and OC peritoneal dissemination. Taken together, our data support that noncanonical NF kappaB activation is the pathway through which extracellular TG2 promotes OC metastasis. PMID- 23730210 TI - Improved clearance during treatment of HPV-positive head and neck cancer through mTOR inhibition. AB - Human papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) incidence is increasing at a near epidemic rate. We investigated whether the mammalian (or mechanistic) target of rapamycin (mTOR) inhibitor, rapamycin, can be used as a concurrent agent to standard-of-care cisplatin/radiation therapy (CRT) to attenuate tumor lactate production, thus enhancing CRT-induced immune mediated clearance of this antigenic tumor type. A C57Bl/6-derived mouse oropharyngeal epithelial cell line retrovirally transduced with HPV type 16 E6/E7 and human squamous cell carcinoma cell lines were evaluated for their response to rapamycin in vitro with proliferation assays, Western blots, and lactate assays. Clonogenic assays and a preclinical mouse model were used to assess rapamycin as a concurrent agent to CRT. The potential of rapamycin to enhance immune response through lactate attenuation was assessed using quantitative tumor lactate bioluminescence and assessment of cell-mediated immunity using E6/E7-vaccinated mouse splenocytes. Rapamycin alone inhibited mTOR signaling of all cancer cell lines tested in vitro and in vivo. Furthermore, rapamycin administered alone significantly prolonged survival in vivo but did not result in any long-term cures. Given concurrently, CRT/rapamycin significantly enhanced direct cell killing in clonogenic assays and prolonged survival in immunocompromised mice. However, in immunocompetent mice, concurrent CRT/rapamycin increased long-term cures by 21%. Preliminary findings suggest that improved survival involves increased cell killing and enhanced immune-mediated clearance in part due to decreased lactate production. The results may provide rationale for the clinical evaluation of mTOR inhibitors concurrent with standard-of-care CRT for treatment of HPV-positive HNSCC. PMID- 23730211 TI - Curcumin triggers p16-dependent senescence in active breast cancer-associated fibroblasts and suppresses their paracrine procarcinogenic effects. AB - Activated cancer-associated fibroblasts (CAFs) or myofibroblasts not only facilitate tumor growth and spread but also affect tumor response to therapeutic agents. Therefore, it became clear that efficient therapeutic regimens should also take into account the presence of these supportive cells and inhibit their paracrine effects. To this end, we tested the effect of low concentrations of curcumin, a pharmacologically safe natural product, on patient-derived primary breast CAF cells. We have shown that curcumin treatment upregulates p16(INK4A) and other tumor suppressor proteins while inactivates the JAK2/STAT3 pathway. This reduced the level of alpha-smooth muscle actin (alpha-SMA) and the migration/invasion abilities of these cells. Furthermore, curcumin suppressed the expression/secretion of stromal cell-derived factor-1 (SDF-1), interleukin-6 (IL 6), matrix metalloproteinase-2 (MMP-2), MMP-9, and transforming growth factor beta, which impeded their paracrine procarcinogenic potential. Intriguingly, these effects were sustained even after curcumin withdrawal and cell splitting. Therefore, using different markers of senescence [senescence-associated beta galactosidase (SA-beta-gal) activity, Ki-67 and Lamin B1 levels, and bromodeoxyuridine incorporation], we have shown that curcumin markedly suppresses Lamin B1 and triggers DNA damage-independent senescence in proliferating but not quiescent breast stromal fibroblasts. Importantly, this curcumin-related senescence was p16(INK4A)-dependent and occurred with no associated inflammatory secretory phenotype. These results indicate the possible inactivation of cancer associated myofibroblasts and present the first indication that curcumin can trigger DNA damage-independent and safe senescence in stromal fibroblasts. PMID- 23730212 TI - Control of both myeloid cell infiltration and angiogenesis by CCR1 promotes liver cancer metastasis development in mice. AB - Expression of the CC chemokine receptor 1 (CCR1) by tumor cells has been associated with protumoral activity; however, its role in nontumoral cells during tumor development remains elusive. Here, we investigated the role of CCR1 deletion on stromal and hematopoietic cells in a liver metastasis tumor model. Metastasis development was strongly impaired in CCR1-deficient mice compared to control mice and was associated with reduced liver monocyte infiltration. To decipher the role of myeloid cells, sublethally irradiated mice were reconstituted with CCR1-deficient bone marrow (BM) and showed better survival rates than the control reconstituted mice. These results point toward the involvement of CCR1 myeloid cell infiltration in the promotion of tumor burden. In addition, survival rates were extended in CCR1-deficient mice receiving either control or CCR1-deficient BM, indicating that host CCR1 expression on nonhematopoietic cells also supports tumor growth. Finally, we found defective tumor-induced neoangiogenesis (in vitro and in vivo) in CCR1-deficient mice. Overall, our results indicate that CCR1 expression by both hematopoietic and nonhematopoietic cells favors tumor aggressiveness. We propose CCR1 as a potential therapeutical target for liver metastasis therapy. PMID- 23730213 TI - ERK5/BMK1 is a novel target of the tumor suppressor VHL: implication in clear cell renal carcinoma. AB - Extracellular signal-regulated kinase 5 (ERK5), also known as big mitogen activated protein kinase (MAPK) 1, is implicated in a wide range of biologic processes, which include proliferation or vascularization. Here, we show that ERK5 is degraded through the ubiquitin-proteasome system, in a process mediated by the tumor suppressor von Hippel-Lindau (VHL) gene, through a prolyl hydroxylation-dependent mechanism. Our conclusions derive from transient transfection assays in Cos7 cells, as well as the study of endogenous ERK5 in different experimental systems such as MCF7, HMEC, or Caki-2 cell lines. In fact, the specific knockdown of ERK5 in pVHL-negative cell lines promotes a decrease in proliferation and migration, supporting the role of this MAPK in cellular transformation. Furthermore, in a short series of fresh samples from human clear cell renal cell carcinoma, high levels of ERK5 correlate with more aggressive and metastatic stages of the disease. Therefore, our results provide new biochemical data suggesting that ERK5 is a novel target of the tumor suppressor VHL, opening a new field of research on the role of ERK5 in renal carcinomas. PMID- 23730214 TI - CD74-dependent deregulation of the tumor suppressor scribble in human epithelial and breast cancer cells. AB - The gamma subunit of the major histocompatibility complex (MHC) class II complex, CD74, is overexpressed in a significant proportion of metastatic breast tumors, but the mechanistic foundation and biologic significance of this phenomenon are not fully understood. Here, we show that when CD74 is overexpressed in human cancer and noncancerous epithelial cells, it interacts and interferes with the function of Scribble, a product of a well-known tumor suppressor gene. Furthermore, using epithelial cell lines expressing CD74 under the control of tetracycline-inducible promoter and quantitative high-resolution mass spectrometry, we demonstrate that, as a result of CD74 overexpression, the phosphorylation pattern of the C-terminal part of Scribble undergoes specific changes. This is accompanied with a translocation of the protein from the sites of cell-to-cell contacts at the plasma membrane to the cytoplasm, which is likely to effectively enhance the motility and invasiveness of the cancer cells. PMID- 23730216 TI - Masculinity and HIV Risk among Homeless Men in Los Angeles. AB - HIV continues to be a serious public health problem for men who have sex with women (MSW), especially homeless MSW. Although consideration of gender has improved HIV prevention interventions, most of the research and intervention development has targeted how women's HIV risk is affected by gender roles. The effect of gender roles on MSW has received relatively little attention. Previous studies have shown mixed results when investigating the association between internalization of masculine gender roles and HIV risk. These studies use a variety of scales that measure individual internalization of different aspects of masculinity. However, this ignores the dynamic and culturally constructed nature of gender roles. The current study uses cultural consensus analysis (CCA) to test for the existence of culturally agreed upon masculinity and gender role beliefs among homeless MSW in Los Angeles, as well as the relationship between these beliefs and HIV-related behaviors and attitudes. Interviews included 30 qualitative and 305 structured interviews with homeless MSW in Los Angeles's Skid Row area. Analysis identified culturally relevant aspects of masculinity not represented by existing masculinity scales, primarily related to barriers to relationships with women. Behaviors, attitudes, and knowledge related to HIV were significantly associated with men's level of agreement with the group about masculinity. The findings are discussed in light of implications for MSW HIV intervention development. PMID- 23730215 TI - Molecular and functional characterizations of the association and interactions between nucleophosmin-anaplastic lymphoma kinase and type I insulin-like growth factor receptor. AB - Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is aberrantly expressed in a subset of T cell lymphoma that commonly affects children and young adults. NPM ALK possesses significant oncogenic potential that was previously documented using in vitro and in vivo experimental models. The exact mechanisms by which NPM ALK induces its effects are poorly understood. We have recently demonstrated that NPM-ALK is physically associated with type I insulin-like growth factor receptor (IGF-IR). A positive feedback loop appears to exist between NPM-ALK and IGF-IR through which these two kinases interact to potentiate their effects. We have also found that a single mutation of the Tyr(644) or Tyr(664) residue of the C terminus of NPM-ALK to phenylalanine decreases significantly, but does not completely abolish, the association between NPM-ALK and IGF-IR. The purpose of this study was to determine whether the dual mutation of Tyr(644) and Tyr(664) abrogates the association and interactions between NPM-ALK and IGF-IR. We also examined the impact of this dual mutation on the oncogenic potential of NPM-ALK. Our results show that NPM-ALK(Y644,664F) completely lacks association with IGF IR. Importantly, we found that the dual mutation of Tyr(644) and Tyr(664) diminishes the oncogenic effects of NPM-ALK, including its ability to induce anchorage-independent colony formation and to sustain cellular transformation, proliferation, and migration. Furthermore, the association between NPM-ALK and IGF-IR through Tyr(644) and Tyr(664) appears to contribute to maintaining the stability of NPM-ALK protein. Our results provide novel insights into the mechanisms by which NPM-ALK induces its oncogenic effects through interactions with IGF-IR in this aggressive lymphoma. PMID- 23730218 TI - Jaime L. Bohl, m.d. PMID- 23730217 TI - Rhythmic grouping biases constrain infant statistical learning. AB - Linguistic stress and sequential statistical cues to word boundaries interact during speech segmentation in infancy. However, little is known about how the different acoustic components of stress constrain statistical learning. The current studies were designed to investigate whether intensity and duration each function independently as cues to initial prominence (trochaic-based hypothesis) or whether, as predicted by the Iambic-Trochaic Law (ITL), intensity and duration have characteristic and separable effects on rhythmic grouping (ITL-based hypothesis) in a statistical learning task. Infants were familiarized with an artificial language (Experiments 1 & 3) or a tone stream (Experiment 2) in which there was an alternation in either intensity or duration. In addition to potential acoustic cues, the familiarization sequences also contained statistical cues to word boundaries. In speech (Experiment 1) and non-speech (Experiment 2) conditions, 9-month-old infants demonstrated discrimination patterns consistent with an ITL-based hypothesis: intensity signaled initial prominence and duration signaled final prominence. The results of Experiment 3, in which 6.5-month-old infants were familiarized with the speech streams from Experiment 1, suggest that there is a developmental change in infants' willingness to treat increased duration as a cue to word offsets in fluent speech. Infants' perceptual systems interact with linguistic experience to constrain how infants learn from their auditory environment. PMID- 23730219 TI - Hereditary colon and rectal cancer. PMID- 23730220 TI - History and pathogenesis of lynch syndrome. AB - Lynch syndrome is the familial clustering of colorectal and endometrial cancers. This syndrome is passed in an autosomal dominant fashion within families with defective mismatch repair as the genetic basis for cancer development in these patients. There remains a group of patients who fit clinical diagnostic criteria for an autosomal dominant familial cancer syndrome, which is phenotypically similar to Lynch syndrome, but for which no mismatch repair mutation is identified. Identification of alternate genetic mutations such as EPCAM and CHEK2 may explain the cancer risk in a small subset of these patients, but continuing work into the genetic basis of colorectal familial cancer syndromes is needed. PMID- 23730222 TI - Familial adenomatous polyposis: challenges and pitfalls of surgical treatment. AB - Surgical management of familial adenomatous polyposis (FAP) is complex and requires both sound judgment and technical skills. Because colorectal cancer risk approaches 100%, prophylactic colorectal surgery remains a cornerstone of management. Both patient factors and disease characteristics influence surgical decision-making regarding the timing of prophylactic surgery, the extent of resection, and types of reconstruction. Making appropriate choices can be challenging and there is continued debate regarding optimal strategies. This chapter reviews the controversies in colorectal surgery for FAP. PMID- 23730223 TI - Endoscopic and surgical management of hereditary nonpolyposis colorectal cancer. AB - Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is a disease characterized by autosomal dominant clustering of colorectal cancer (CRC) as well as other cancers. It is critical for clinicians and surgeons caring for patients with HNPCC to be familiar with their management related to CRC. Based on retrospective studies, screening colonoscopy is recommended every 1 to 2 years beginning at age 20 to 25, or 10 years younger than the earliest CRC in the family (whichever is earlier). HNPCC patients with colon cancer should be considered for total abdominal colectomy rather than a more limited segmental colon resection due to the increased risk of metachronous neoplasia associated with the condition. Rectal cancer in HNPCC has not been well studied, but discussions with the patient regarding surgical management should weigh the risks of metachronous CRC with the morbidity and quality of life issues associated with proctocolectomy. Regardless of the procedure, a patient with HNPCC requires close postoperative endoscopic surveillance of any remaining at-risk mucosa. In terms of chemoprevention, aspirin has been shown to be effective in preventing colorectal neoplasia in prospective trials and should be considered in patients who do not have a contraindication to the drug. Trials for other chemopreventative agents in HNPCC are ongoing. As more is learned about particular genotype-phenotype correlations with Lynch syndrome, this will likely affect surgical decision making. Despite all of these efforts in the management of patients with HNPCC or Lynch syndrome, incident CRCs still occur, thus reinforcing the need for further studies to better understand the optimal management of these patients. PMID- 23730221 TI - Identification of patients at risk for hereditary colorectal cancer. AB - Diagnosis of hereditary colorectal cancer syndromes requires clinical suspicion and knowledge of such syndromes. Lynch syndrome is the most common cause of hereditary colorectal cancer. Other less common causes include familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome (PJS), juvenile polyposis syndrome, and others. There have been a growing number of clinical and molecular tools used to screen and test at risk individuals. Screening tools include diagnostic clinical criteria, family history, genetic prediction models, and tumor testing. Patients who are high risk based on screening should be referred for genetic testing. PMID- 23730224 TI - Endometrial and ovarian cancer in lynch syndrome. AB - Lynch syndrome (LS) is an autosomal dominant familial cancer risk syndrome that occurs due to a germline mutation in one of several mismatch repair genes and is associated with an increased risk of colorectal, endometrial, and ovarian cancer. The risk of endometrial cancer equals or exceeds that of colorectal cancer in women with LS. The diagnosis of gynecologic cancer precedes that of colorectal cancer in over half of women with metachronous gynecologic and colon cancers, making gynecologic cancer a "sentinel cancer" for LS. There are no studies addressing the effectiveness or safety of chemoprevention for women with LS. Surveillance with gynecologic examination including assessment of symptoms, transvaginal pelvic ultrasonography, endometrial biopsy, and CA125 tumor marker assessment can be offered, but has not been shown to improve outcomes for these patients. Prophylactic hysterectomy with bilateral salpingo-oophorectomy performed after the completion of childbearing may be offered for gynecologic cancer prevention. PMID- 23730225 TI - Extracolonic manifestations of lynch syndrome. AB - Lynch syndrome has classically been defined by several predominant malignancies. Initial clinical criteria for diagnosis of Lynch syndrome would miss 40% of affected individuals. As time has passed, our understanding of Lynch syndrome has evolved and will continue to do so. The number of cancer types that are included in the Lynch phenotype is growing. This has allowed clinicians to redefine Lynch syndrome, at risk populations, screening needs, and diagnostic criteria. Inclusion of extracolonic malignancies and alternative genetic pathways gives new insight into the true prevalence and penetrance of Lynch syndrome. PMID- 23730226 TI - Health behaviors in patients and families with hereditary colorectal cancer. AB - It is estimated that 5 to 10% of all colorectal cancer (CRC) cases are attributed to a hereditary cause. The primary hereditary cancer syndromes that confer an increased risk for colorectal cancers are Lynch syndrome/hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP). Through genetic testing, health care providers can identify patients and families who carry gene mutations and subsequently are at a substantially greater risk for developing colorectal cancer than the general population. Genetic testing provides risk information not only about an individual patient, but also his or her biological relatives. A variety of risk-reduction behaviors (including screening, surgery, and health and lifestyle behaviors) have been examined in Lynch syndrome and FAP populations. The research indicates that screening behaviors are less than optimal, although the rates vary from study to study. Prophylactic colectomy is the primary course of treatment for individuals who test positive for a FAP mutation, but the results are inconclusive for cancer unaffected Lynch syndrome mutation carriers. Although research suggests that the adoption of healthy lifestyles and behaviors (e.g., diet, physical activity, weight control, smoking cessation, limited alcohol consumption) could have a favorable impact on colon cancer burden, there is minimal data on how these behaviors may moderate cancer risk among those at risk of hereditary colon cancer. To date, we know very little about the actual health and lifestyle behaviors of those at risk of hereditary colon cancer. Genetic testing and counseling at risk individuals may resolve uncertainty about their personal and familial cancer risk and provide information to guide and personalize decisions about their future health care. PMID- 23730227 TI - Oncologic management of hereditary colorectal cancer. AB - Colorectal cancer (CRC) is the second most common cancer in females and the third most common cancer diagnosed in males. Familial CRC comprises ~20 to 30% of all CRC cases. Lynch syndrome (LS), previously called hereditary nonpolyposis CRC (HNPCC), is the most common of the hereditary CRC syndromes. In this review, the oncological management of hereditary colorectal cancer from the medical oncologist perspective is discussed with special emphasis on Lynch syndrome. Lynch syndrome is characterized by the presence of germline mutations in the mismatch repair genes (MMR)-MSH2, MLH1, MSH6, and PMS2. The available data regarding the prognostic role of mismatch repair genes (MMR), the predictive role of MMR genes, and the implications of that in the management of patients with deficient MMR genes (dMMR/MSI-H) tumors including Lynch syndrome patients are also discussed. PMID- 23730228 TI - DILI: New Insights into Diagnosis and Management. AB - Drug-induced liver injury continues to have a significant impact. With over 1000 drugs now registered as causing DILI, this form of liver injury is the most cited reason for withdrawal of a drug from the marketplace. Despite this, the diagnosis of DILI continues to rely on subjective measures and expert opinion with results that are both difficult to verify and reproduce. However, recent developments in DILI research may provide new insights to improve diagnosis and treatment in the future. PMID- 23730229 TI - Early versus delayed imaginal exposure for the treatment of posttraumatic stress disorder following accidental upper extremity injury. AB - BACKGROUND: The consequences following work-related injuries are far reaching, which are in part due to unrecognized and untreated posttraumatic stress disorder (PTSD). Imaginal exposure is a frequently used cognitive behavioral approach for the treatment of PTSD. This study examined the impact of early versus delayed treatment with imaginal exposure on amelioration of PTSD symptomatology in individuals who suffered upper extremity injuries. METHODS: Sixty individuals who suffered severe work-related injuries received standard, non-randomly assigned psychological treatment for PTSD (e.g., prolonged imaginal exposure) either early (30-60 days) or delayed (greater than 120 days) following severe work-related upper extremity injury. Nine measures of various components of PTSD symptomatology were administered at onset of treatment, end of treatment, and at 6-month follow-up evaluations. RESULTS: Patients showed significant treatment outcomes at all three measurement intervals in both the early and delayed groups demonstrating that Prolonged Imaginal Exposure is an appropriate treatment for persons diagnosed with PTSD. In addition, there was no difference in return to work status between the early and the delayed treatment groups. However, the early treatment group required significantly fewer treatment sessions than the delayed treatment group. CONCLUSIONS: Results supported the utility of imaginal exposure and the need for early assessment and referral for those diagnosed with PTSD following upper extremity injuries. PMID- 23730230 TI - Management of digital tendon avulsion at the musculotendinous junction of the forearm: a systematic review. AB - BACKGROUND: Tendon avulsion at the musculotendinous junction caused by digit avulsion amputation or closed injury is a challenging problem, for which the literature lacks definitive recommendations regarding treatment. We have provided a systematic review and developed an algorithm to delineate optimal management of this injury. METHODS: Two independent reviewers undertook a systematic review of the literature to identify articles discussing management of forearm tendons avulsed at their musculotendinous junction. Patient demographics, injury mechanism, injury pattern, type of repair, and outcome were investigated. These data were analyzed to reveal tendencies in management, which were then organized into an algorithm. RESULTS: Twenty articles fit our criteria for a total of 91 tendons. Cases were mostly males involved in work accidents. Treatment options were tendon resection, reattachment to muscle, tendon transfer, and side-to-side repair. When the digit was replanted, tendons avulsed through avulsion amputations were preferentially treated by reattachment in the case of the thumb, transfers for the index and long fingers, and resection for the ring and small fingers. Reattachment was favored for metacarpophalangeal level amputations, while transfer was selected for proximal phalanx levels. For closed avulsion injuries, flexors were preferentially treated with reattachment or transfer, while extensors underwent transfer or side-to-side repair. CONCLUSIONS: In the management of tendon avulsions at the musculotendinous junction, specific procedures are favored depending on the mechanism of injury, the type of tendon and digit involved, and the level of bone amputation. An algorithm is presented to facilitate optimal treatment based on these injury characteristics. PMID- 23730231 TI - Nonsurgical treatment of Dupuytren's contracture: 1-year US post-marketing safety data for collagenase clostridium histolyticum. AB - BACKGROUND: Collagenase clostridium histolyticum (CCH) is a Food and Drug Administration-approved treatment for adult patients with Dupuytren's contracture with a palpable cord that has been shown efficacious and safe in clinical trials. METHODS: This paper summarizes the most common post-marketing clinical adverse event (AE) reports received by the manufacturer of CCH and sponsor of the US Biologics License Application (Auxilium Pharmaceuticals, Malvern, PA, USA) during the first 12 months after drug approval and commercialization in the USA. RESULTS: Of the 115 AE reports describing 270 AEs voluntarily received from patients or health care providers after approximately 5,400 injections of CCH administered, the most common AEs involved local, nonserious reactions to treatment, including skin tears, peripheral edema, and contusion. There were few serious AEs observed (0.6% reporting rate per 1,000 injections), and two flexor tendon ruptures and one flexor pulley injury were reported. CONCLUSIONS: Analysis of post-marketing AEs received for CCH in the first year post-approval supports the safety profile reported earlier during clinical development and did not reveal additional clinical risks or concerns about CCH. PMID- 23730232 TI - Patient-reported outcomes after acute carpal tunnel release in patients with distal radius open reduction internal fixation. AB - BACKGROUND: Acute carpal tunnel syndrome (CTS) is a complication that can develop after distal radius fractures. Our hypothesis tested whether patient-reported outcomes after acute carpal tunnel release (CTR) performed in combination with distal radius fracture open reduction internal fixation (ORIF) are worse than patient-reported outcomes with only elective CTR as measured by the symptom severity and functional status scales of the Boston carpal tunnel questionnaire (BCTQ). METHODS: A retrospective assessment identified 26 patients treated with acute CTR at the same time as distal radius ORIF, no history of pre-existing CTS or CTR, no other injuries, and >12 months follow-up. Sixteen of these patients (Group A) could be contacted and answered the BCTQ. Group A was age- and sex matched to control patients (Group B) treated with only elective CTR. A case control study was performed comparing outcomes of both groups. RESULTS: The average age of patients was 51 +/- 15 years, with an average follow-up of Group A at 49 +/- 21 months versus Group B at 55 +/- 20 months. The mean symptom severity scale score for Group A was 1.4 +/- 0.4 and for Group B was 1.4 +/- 0.4. The mean functional status scale score for Group A was 1.4 +/- 0.5 and for Group B was 1.3 +/- 0.4. The mean total BCTQ score for Group A was 26.5 +/- 7.5 and for Group B was 24.9 +/- 7.5. There were no statistical or clinically significant differences between Group A and Group B for symptom severity, functional status, and total BCTQ scores. CONCLUSIONS: Patients with acute CTR performed at the same time with distal radius ORIF do as well in the long-term as those patients with only elective CTR as measured by the BCTQ. Patients should expect similar recovery of subjective nerve function from acute median nerve dysfunction when CTR is performed with distal radius ORIF as patients with only elective CTR. PMID- 23730234 TI - High-impact articles in hand surgery. AB - BACKGROUND: There have been few attempts to identify classic papers within the hand surgery literature. This study used citation analysis to identify and characterize the top 50 highly cited hand surgery articles published in six peer reviewed journals. METHODS: The 50 most highly cited hand surgery articles were identified in the Journal of Bone and Joint Surgery (JBJS) American, JBJS British, Plastic and Reconstructive Surgery, Journal of Hand Surgery (JHS) American, JHS British/European, and Hand. Articles were evaluated for citations per year, surgical/anatomical topic, and type of study. Clinical studies were further sub-categorized by level of evidence. The distribution of topics was compared with all indexed hand surgery articles. The educational relevance was assessed via comparison with lists of "classic" papers. RESULTS: The most common subjects were distal radius fracture, carpal tunnel syndrome, and flexor tendon repair. There was moderate correlation between the distribution of these topics and all indexed hand surgery articles (rho = 0.71). There were 31 clinical studies, of which 16 were therapeutic, ten were prognostic, and five were diagnostic. These articles assessed the outcomes of an intervention, described an anatomical/functional observation, introduced an innovation, presented a discovery/classification, or validated a questionnaire. There were only three randomized trials. Using citations per year to control for the influence of time since publication, 36 articles were consistently highly cited. Twenty-three articles were on Stern's Selected Readings in Hand Surgery, considered important in education. CONCLUSIONS: The top 50 highly cited articles in hand surgery reflect the most common clinical, scientific, and educational efforts of the field. PMID- 23730233 TI - Corticosteroid injection for carpal tunnel syndrome: a 5-year survivorship analysis. AB - BACKGROUND: The purpose of our study was to determine the rate of carpal tunnel decompression (CTD) following local corticosteroid injection for carpal tunnel syndrome (CTS), as well as identifying predictors of requiring further intervention and eventual decompression. METHODS: All patients diagnosed with CTS in our unit over a 6-year period were prospectively assessed. Patients were diagnosed using a combination of clinical presentation and nerve conduction studies. Patients were managed with open carpal tunnel decompression or corticosteroid injection. There were 1,564 consecutive patients diagnosed with CTS over the study period, of whom 824 (53%) underwent a corticosteroid injection as their primary treatment. We performed a survivorship analysis of these patients and used Kaplan-Meier survivorship methodology to determine the 5-year rate of re-intervention. Risk factors for re-intervention were also determined. RESULTS: The overall 5-year Kaplan-Meier rate of secondary CTD was 15% at 1 year and 33% at 5 years. The need for secondary CTD was independently associated with female gender, diabetes mellitus and positive nerve conduction studies at diagnosis. CONCLUSIONS: Steroid injection is an appropriate treatment in carefully selected patients. Those who are female, diabetic and have neurophysiological confirmation of diagnosis have the highest risk of relapse. These results may be used to guide initial treatment and counsel patients about the risk relapse. PMID- 23730235 TI - The free lateral arm flap-a reliable option for reconstruction of the forearm and hand. AB - BACKGROUND: This retrospective study was performed to verify the advantages and disadvantages of the free lateral arm flap for defect reconstruction of the forearm and hand. PATIENTS AND METHODS: Between 2001 and 2010, 21 patients underwent defect coverage of the forearm and hand with the free lateral arm flap. The mean patient age was 48 years (17-78). The results concerning defect origin, flap size, pedicle length, operative time, revisions of the anastomoses or other complications, donor site morbidity, and length of hospital stay were evaluated. RESULTS: The majority of defects were caused by infections or chronic wounds. The defects were localized at the forearm in 6 cases and at the hand in 15 cases. The flap width ranged from 3 to 8 cm, and the length was from 5 to 20 cm. All flaps survived. Only in one case, a revision of the anastomosis was necessary. Primary closure of the donor site was possible in all patients. No complications occurred during the healing procedure. The majority of the patients were satisfied with the aesthetic result at the recipient site as well as at the donor site. CONCLUSION: The free lateral arm flap is a very reliable option for defect coverage at the forearm and hand for small and medium size defects. A satisfactory aesthetic appearance, an excellent tissue quality, and frequent primary donor site closure are great advantages for selecting this flap. PMID- 23730236 TI - Psychological factors predict unexpected diagnoses. AB - BACKGROUND: Unexpected diagnoses and treatment recommendations can be awkward for both hand specialist and patient. We tested the hypothesis that psychological factors predict an unexpected hand specialist diagnosis after referral from a primary care provider (PCP) for management of an atraumatic hand condition. METHODS: One hundred and thirty patients referred to a hand surgeon by their PCP were asked to complete measures of symptoms of depression, catastrophic thinking, hypochondriacal attitudes and beliefs, and disability prior to the visit. Patients indicated their impression of the diagnosis and treatment recommendations. The hand specialist recorded a diagnosis and treatment recommendations after the visit. RESULTS: Patients receiving unexpected diagnoses had more psychological symptoms than patients receiving expected diagnoses. In logistic regression analysis, symptoms of depression were the sole predictor of an unexpected diagnosis. Patients receiving unexpected treatment recommendations had greater catastrophic thinking and hypochondriacal attitudes and beliefs than patients receiving expected treatment recommendations. In logistic regression analysis, catastrophic thinking was the sole predictor of unexpected treatment recommendations. CONCLUSIONS: Given that unexpected hand diagnoses or treatment recommendations are both inherently awkward and associated with greater symptoms of depression, catastrophic thinking, and hypochondriacal beliefs, a practiced, thoughtful, and empathetic communication strategy may improve patient satisfaction and health outcomes. PMID- 23730237 TI - Predictors of missed appointments in prospective hand surgery research. AB - BACKGROUND: Missed research appointments may bias the outcome of prospective clinical trials if the participants that miss appointments differ in important ways from those that do not. The purpose of this study was to determine the predictors of missed research appointments in patients enrolled in clinical trials. METHODS: We retrospectively evaluated 665 participants enrolled in ten prospective clinical trials conducted at our outpatient office between 2001 and 2010. Demographic data (sex, race, date of birth, date of enrollment, age at enrollment, educational level, and work status), study coordinator, and study type were analyzed for association with missed a research appointment in bivariate and multiple logistic regression analyses. RESULTS: One hundred and forty-four (21.7 %) participants missed research appointments during their follow up. There were no statistical differences between those who missed appointments and those who did not, regarding sex, race, and age at enrollment. Educational level and work status were independent predictors of missed appointments. CONCLUSIONS: This study suggests that educational level and work status are predictors of missed appointments in prospective clinical research. PMID- 23730238 TI - Psychopathological hand disorders: a rare somatoform reaction to psychological conflicts. PMID- 23730239 TI - Transfer of triceps motor branches of the radial nerve to the axillary nerve with or without other nerve transfers provides antigravity shoulder abduction in pediatric brachial plexus injury. PMID- 23730240 TI - Acquired trigger thumb vs. congenital clasped thumb: recognize the difference: a case report. PMID- 23730242 TI - Vascular malformation of the flexor tendon presenting as tenosynovitis. PMID- 23730241 TI - Spindle cell hemangioma reoccurrence in the hand: case report. PMID- 23730243 TI - Hand metastasis: an unusual presentation of renal cell carcinoma. PMID- 23730244 TI - Metallosis following silicone metacarpophalangeal joint arthroplasties with grommets: case report. PMID- 23730245 TI - Moberg modification using the first web space: thumb reconstruction following distal amputation. PMID- 23730246 TI - Epithelioid hemangioendothelioma of the pisiform. PMID- 23730247 TI - Volar perilunate dislocations: possible association with prior wrist injuries. PMID- 23730248 TI - Re: End-of-skin grafts in syndactyly release: description of a new flap for web space resurfacing and primary closure of finger defects. PMID- 23730249 TI - Review of Marjolin's ulcer arising at the elbow. PMID- 23730250 TI - Nerve and arterial supply to the hand in Vesalius's De Humani Corporis Fabrica. AB - BACKGROUND: Belgian anatomist Andreas Vesalius, in his groundbreaking medical atlas De Humani Corporis Fabrica, 1543, committed to paper two anatomical errors relating to the vascular and nervous system of the hand. In the diagrams, he depicts a highly irregular symmetrical sensory innervation of the median and ulnar nerves. He also fails to mention or illustrate the deep or superficial palmar arches. PMID- 23730251 TI - Wrong site surgery-where are we and what is the next step? AB - BACKGROUND: Wrong site surgery is estimated to occur 40 times per week in hospitals and clinics in USA. The universal protocol was implemented by the joint commission board of commissioners to address wrong site, wrong procedure, and wrong person surgery. DISCUSSION: The universal protocol has three principal components: preoperative verification, marking of the operative site, and a time out. Despite this organized approach to this problem, current data do not demonstrate any progress. In fact some data suggest that the problem may be getting worse. It is apparent that a process relying on surgeon and surgical team memory is doomed to ultimate failure. Recommendations are made for a more in depth checklist process based on the recommendations of the World Health Organization, reports in the literature of known areas of weakness in the current process, and personal experience in hopes of establishing a more bullet proof system to avoid wrong site procedure. PMID- 23730252 TI - Recognition of functional roles of free radicals. PMID- 23730253 TI - Redox processes in neurodegenerative disease involving reactive oxygen species. AB - Much attention has been devoted to neurodegenerative diseases involving redox processes. This review comprises an update involving redox processes reported in the considerable literature in recent years. The mechanism involves reactive oxygen species and oxidative stress, usually in the brain. There are many examples including Parkinson's, Huntington's, Alzheimer's, prions, Down's syndrome, ataxia, multiple sclerosis, Creutzfeldt-Jacob disease, amyotrophic lateral sclerosis, schizophrenia, and Tardive Dyskinesia. Evidence indicates a protective role for antioxidants, which may have clinical implications. A multifaceted approach to mode of action appears reasonable. PMID- 23730254 TI - Neuronal-glial Interactions Define the Role of Nitric Oxide in Neural Functional Processes. AB - Nitric oxide (NO) is a versatile cellular messenger performing a variety of physiologic and pathologic actions in most tissues. It is particularly important in the nervous system, where it is involved in multiple functions, as well as in neuropathology, when produced in excess. Several of these functions are based on interactions between NO produced by neurons and NO produced by glial cells, mainly astrocytes and microglia. The present paper briefly reviews some of these interactions, in particular those involved in metabolic regulation, control of cerebral blood flow, axonogenesis, synaptic function and neurogenesis. Aim of the paper is mainly to underline the physiologic aspects of these interactions rather than the pathologic ones. PMID- 23730255 TI - H2O2 Signalling Pathway: A Possible Bridge between Insulin Receptor and Mitochondria. AB - This review is focused on the mechanistic aspects of the insulin-induced H2O2 signalling pathway in neurons and the molecules affecting it, which act as risk factors for developing central insulin resistance. Insulin-induced H2O2 promotes insulin receptor activation and the mitochondria act as the insulin-sensitive H2O2 source, providing a direct molecular link between mitochondrial dysfunction and irregular insulin receptor activation. In this view, the accumulation of dysfunctional mitochondria during chronological ageing and Alzheimer's disease (AD) is a risk factor that may contribute to the development of dysfunctional cerebral insulin receptor signalling and insulin resistance. Due to the high significance of insulin-induced H2O2 for insulin receptor activation, oxidative stress-induced upregulation of antioxidant enzymes, e.g., in AD brains, may represent another risk factor contributing to the development of insulin resistance. As insulin-induced H2O2 signalling requires fully functional mitochondria, pharmacological strategies based on activating mitochondria biogenesis in the brain are central to the treatment of diseases associated with dysfunctional insulin receptor signalling in this organ. PMID- 23730256 TI - NADPH oxidase and neurodegeneration. AB - NADPH oxidase (Nox) is a unique, multi-protein, electron transport system that produces large amounts of superoxide via the reduction of molecular oxygen. Nox derived reactive oxygen species (ROS) are known to be involved in a variety of physiological processes, including host defense and signal transduction. However, over the past decade, the involvement of (Nox)-dependent oxidative stress in the pathophysiology of several neurodegenerative diseases has been increasingly recognized. ROS produced by Nox proteins contribute to neurodegenerative diseases through distinct mechanisms, such as oxidation of DNA, proteins, lipids, amino acids and metals, in addition to activation of redox-sensitive signaling pathways. In this review, we discuss the recent literature on Nox involvement in neurodegeneration, focusing on Parkinson and Alzheimer diseases. PMID- 23730257 TI - The role of reactive species in epileptogenesis and influence of antiepileptic drug therapy on oxidative stress. AB - Epilepsy is considered one of the most common neurological disorders. The focus of this review is the acquired form of epilepsy, with the development process consisting of three major phases, the acute injury phase, the latency epileptogenesis phase, and the phase of spontaneous recurrent seizures. Nowadays, an increasing attention is paid to the possible interrelationship between oxidative stress resulting in disturbance of physiological signalling roles of calcium and free radicals in neuronal cells and mitochondrial dysfunction, cell damage, and epilepsy. The positive stimulation of mitochondrial calcium signals by reactive oxygen species and increased reactive oxygen species generation resulting from increased mitochondrial calcium can lead to a positive feedback loop. We propose that calcium can pose both, physiological and pathological effects of mitochondrial function, which can lead in neuronal cell death and consequent epileptic seizures. Various antiepileptic drugs may impair the endogenous antioxidative ability to prevent oxidative stress. Therefore, some antiepileptic drugs, especially from the older generation, may trigger oxygen dependent tissue injury. The prooxidative effects of these antiepileptic drugs might lead to enhancement of seizure activity, resulting in loss of their efficacy or apparent functional tolerance and undesired adverse effects. Additionally, various reactive metabolites of antiepileptic drugs are capable of covalent binding to macromolecules which may lead to deterioration of the epileptic seizures and systemic toxicity. Since neuronal loss seems to be one of the major neurobiological abnormalities in the epileptic brain, the ability of antioxidants to attenuate seizure generation and the accompanying changes in oxidative burden, further support an important role of antioxidants as having a putative antiepileptic potential. PMID- 23730258 TI - Oxidative Stress in the Hypothalamus: the Importance of Calcium Signaling and Mitochondrial ROS in Body Weight Regulation. AB - A considerable amount of evidence shows that reactive oxygen species (ROS) in the mammalian brain are directly responsible for cell and tissue function and dysfunction. Excessive reactive oxygen species contribute to various conditions including inflammation, diabetes mellitus, neurodegenerative diseases, tumor formation, and mental disorders such as depression. Increased intracellular calcium levels have toxic roles leading to cell death. However, the exact connection between reactive oxygen production and high calcium stress is not yet fully understood. In this review, we focus on the role of reactive oxygen species and calcium stress in hypothalamic arcuate neurons controlling feeding. We revisit the role of NPY and POMC neurons in the regulation of appetite and energy homeostasis, and consider how ROS and intracellular calcium levels affect these neurons. These novel insights give a new direction to research on hypothalamic mechanisms regulating energy homeostasis and may offer novel treatment strategies for obesity and type-2 diabetes. PMID- 23730259 TI - Redox signaling pathways involved in neuronal ischemic preconditioning. AB - There is extensive evidence that the restoration of blood flow following cerebral ischemia contributes greatly to the pathophysiology of ischemia mediated brain injury. The initiating stimulus of reperfusion injury is believed to be the excessive production of reactive oxygen (ROS) and nitrogen (RNS) species by the mitochondria. ROS and RNS generation leads to mitochondrial protein, lipid and DNA oxidation which impedes normal mitochondrial physiology and initiates cellular death pathways. However not all ROS and RNS production is detrimental. It has been demonstrated that low levels of ROS production are protective and may serve as a trigger for activation of ischemic preconditioning. Ischemic preconditioning is a neuroprotective mechanism which is activated upon a brief sublethal ischemic exposure and is sufficient to provide protection against a subsequent lethal ischemic insult. Numerous proteins and signaling pathways have been implicated in the ischemic preconditioning neuroprotective response. In this review we examine the origin and mechanisms of ROS and RNS production following ischemic/reperfusion and the role of free radicals in modulating proteins associated with ischemic preconditioning neuroprotection. PMID- 23730261 TI - Pyruvate Dehydrogenase Kinases in the Nervous System: Their Principal Functions in Neuronal-glial Metabolic Interaction and Neuro-metabolic Disorders. AB - Metabolism is involved directly or indirectly in all processes conducted in living cells. The brain, popularly viewed as a neuronal-glial complex, gets most of its energy from the oxygen-dependent metabolism of glucose, and the mitochondrial pyruvate dehydrogenase complex (PDC) plays a key regulatory role during the oxidation of glucose. Pyruvate dehydrogenase kinase (also called PDC kinase or PDK) is a kinase that regulates glucose metabolism by switching off PDC. Four isoforms of PDKs with tissue specific activities have been identified. The metabolisms of neurons and glial cells, especially, those of astroglial cells, are interrelated, and these cells function in an integrated fashion. The energetic coupling between neuronal and astroglial cells is essential to meet the energy requirements of the brain in an efficient way. Accumulating evidence suggests that alterations in the PDKs and/or neuron-astroglia metabolic interactions are associated with the development of several neurological disorders. Here, the authors review the results of recent research efforts that have shed light on the functions of PDKs in the nervous system, particularly on neuron-glia metabolic interactions and neuro-metabolic disorders. PMID- 23730262 TI - mTOR Inhibitors in Tuberous Sclerosis Complex. AB - Tuberous sclerosis complex (TSC) is a genetic multiple organ system disorder that is characterized by the development of tumor-like lesions (hamartomas) and neurodevelopmental disorders. Mutations in the TSC1 and TSC2 tumor suppressor genes occur in the majority of patients with TSC, resulting in hyperactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for patients with TSC. Everolimus is the first mTOR inhibitor approved as a treatment option in the USA and in Europe for patients with subependymal giant-cell astrocytomas (SEGAs) associated with TSC. The clinical evidence to date supports the use of mTOR inhibitors in a variety of TSC-associated disease manifestations, including SEGAs, renal angiomyolipoma, skin manifestations, and epilepsy. Furthermore, ongoing clinical trials evaluating mTOR inhibitors in TSC are underway, and the results of these studies are expected to provide further evidence that will firmly establish their role in this setting. This article will discuss the role of the mTOR pathway in TSC and review the pharmacokinetics, pharmacodynamics, clinical efficacy, and tolerability of mTOR inhibitors, along with their current place in clinical practice. PMID- 23730260 TI - Revolutionary impact of nanodrug delivery on neuroscience. AB - Brain research is the most expanding interdisciplinary research that is using the state of the art techniques to overcome limitations in order to conduct more accurate and effective experiments. Drug delivery to the target site in the central nervous system (CNS) is one of the most difficult steps in neuroscience researches and therapies. Taking advantage of the nanoscale structure of neural cells (both neurons and glia); nanodrug delivery (second generation of biotechnological products) has a potential revolutionary impact into the basic understanding, visualization and therapeutic applications of neuroscience. Current review article firstly provides an overview of preparation and characterization, purification and separation, loading and delivering of nanodrugs. Different types of nanoparticle bioproducts and a number of methods for their fabrication and delivery systems including (carbon) nanotubes are explained. In the second part, neuroscience and nervous system drugs are deeply investigated. Different mechanisms in which nanoparticles enhance the uptake and clearance of molecules form cerebrospinal fluid (CSF) are discussed. The focus is on nanodrugs that are being used or have potential to improve neural researches, diagnosis and therapy of neurodegenerative disorders. PMID- 23730265 TI - Injecting drug users in Scotland, 2006: Listing, number, demography, and opiate related death-rates. AB - Using Bayesian capture-recapture analysis, we estimated the number of current injecting drug users (IDUs) in Scotland in 2006 from the cross-counts of 5670 IDUs listed on four data-sources: social enquiry reports (901 IDUs listed), hospital records (953), drug treatment agencies (3504), and recent Hepatitis C virus (HCV) diagnoses (827 listed as IDU-risk). Further, we accessed exact numbers of opiate-related drugs-related deaths (DRDs) in 2006 and 2007 to improve estimation of Scotland's DRD rates per 100 current IDUs. Using all four data sources, and model-averaging of standard hierarchical log-linear models to allow for pairwise interactions between data-sources and/or demographic classifications, Scotland had an estimated 31700 IDUs in 2006 (95% credible interval: 24900-38700); but 25000 IDUs (95% CI: 20700-35000) by excluding recent HCV diagnoses whose IDU-risk can refer to past injecting. Only in the younger age group (15-34 years) were Scotland's opiate-related DRD rates significantly lower for females than males. Older males' opiate-related DRD rate was 1.9 (1.24-2.40) per 100 current IDUs without or 1.3 (0.94-1.64) with inclusion of recent HCV diagnoses. If, indeed, Scotland had only 25000 current IDUs in 2006, with only 8200 of them aged 35+ years, the opiate-related DRD rate is higher among this older age group than has been appreciated hitherto. There is counter-balancing good news for the public health: the hitherto sharp increase in older current IDUs had stalled by 2006. PMID- 23730264 TI - Application of Electrode Methods in Studies of Nitric Oxide Metabolism and Diffusion Kinetics. AB - Nitric oxide (NO) has many important physiological roles in the body. Since NO electrodes can directly measure NO concentration in the nM range and in real time, NO electrode methods have been generally used in laboratories for measuring NO concentration in vivo and in vitro. This review focuses on the application of electrode methods in studies of NO diffusion and metabolic kinetics. We have described the physical and chemical properties that need to be considered in the preparation of NO stock solution, discussed the effect of several interfering factors on the measured curves of NO concentration that need to be eliminated in the experimental setup for NO measurements, and provided an overview of the application of NO electrode methods in measuring NO diffusion and metabolic kinetics in solution and in biological systems. This overview covers NO metabolism by oxygen (O2), superoxide, heme proteins, cells and tissues. Important conclusions and physiological implication of these studies are discussed. PMID- 23730266 TI - Non-toxic dry-coated nanosilver for plasmonic biosensors. AB - The plasmonic properties of noble metals facilitate their use for in-vivo bio applications such as targeted drug delivery and cancer cell therapy. Nanosilver is best suited for such applications as it has the lowest plasmonic losses among all such materials in the UV-visible spectrum. Its toxicity, however, can destroy surrounding healthy tissues and thus, hinders its safe use. Here, that toxicity against a model biological system (Escherichia coli) is "cured" or blocked by coating nanosilver hermetically with a about 2 nm thin SiO2 layer in one-step by a scalable flame aerosol method followed by swirl injection of a silica precursor vapor (hexamethyldisiloxane) without reducing the plasmonic performance of the enclosed or encapsulated silver nanoparticles (20 - 40 nm in diameter as determined by X-ray diffraction and microscopy). This creates the opportunity to safely use powerful nanosilver for intracellular bio-applications. The label-free biosensing and surface bio-functionalization of these ready-to-use, non-toxic (benign) Ag nanoparticles is presented by measuring the adsorption of bovine serum albumin (BSA) in a model sensing experiment. Furthermore, the silica coating around nanosilver prevents its agglomeration or flocculation (as determined by thermal annealing, optical absorption spectroscopy and microscopy) and thus, enhances its biosensitivity, including bioimaging as determined by dark field illumination. PMID- 23730267 TI - Intramural hematoma of the esophagus. AB - We report the case of a patient with an intramural hematoma of the esophagus. This rare condition is more common in elderly women and can be misdiagnosed as cardiovascular or other digestive emergent disease. The classical clinical triad includes chest pain, sudden dysphagia or odynophagia and minor hematemesis. Known precipitating factors are Valsalva maneuver, blunt, direct or iatrogenic injuries, but spontaneous cases have also been described. Chest imaging including computed tomography or magnetic resonance imaging as well as upper gastrointestinal endoscopy are useful tools for diagnosis. The treatment is conservative and the prognosis usually excellent with complete resolution within a few weeks. PMID- 23730268 TI - Automatic selection of resting-state networks with functional magnetic resonance imaging. AB - Functional magnetic resonance imaging (fMRI) during a resting-state condition can reveal the co-activation of specific brain regions in distributed networks, called resting-state networks, which are selected by independent component analysis (ICA) of the fMRI data. One of the major difficulties with component analysis is the automatic selection of the ICA features related to brain activity. In this study we describe a method designed to automatically select networks of potential functional relevance, specifically, those regions known to be involved in motor function, visual processing, executive functioning, auditory processing, memory, and the default-mode network. To do this, image analysis was based on probabilistic ICA as implemented in FSL software. After decomposition, the optimal number of components was selected by applying a novel algorithm which takes into account, for each component, Pearson's median coefficient of skewness of the spatial maps generated by FSL, followed by clustering, segmentation, and spectral analysis. To evaluate the performance of the approach, we investigated the resting-state networks in 25 subjects. For each subject, three resting-state scans were obtained with a Siemens Allegra 3 T scanner (NYU data set). Comparison of the visually and the automatically identified neuronal networks showed that the algorithm had high accuracy (first scan: 95%, second scan: 95%, third scan: 93%) and precision (90%, 90%, 84%). The reproducibility of the networks for visual and automatic selection was very close: it was highly consistent in each subject for the default-mode network (>=92%) and the occipital network, which includes the medial visual cortical areas (>=94%), and consistent for the attention network (>=80%), the right and/or left lateralized frontoparietal attention networks, and the temporal-motor network (>=80%). The automatic selection method may be used to detect neural networks and reduce subjectivity in ICA component assessment. PMID- 23730269 TI - Combinatorial brain decoding of people's whereabouts during visuospatial navigation. AB - Complex behavior typically relies upon many different processes which are related to activity in multiple brain regions. In contrast, neuroimaging analyses typically focus upon isolated processes. Here we present a new approach, combinatorial brain decoding, in which we decode complex behavior by combining the information which we can retrieve from the neural signals about the many different sub-processes. The case in point is visuospatial navigation. We explore the extent to which the route travelled by human subjects (N = 3) in a complex virtual maze can be decoded from activity patterns as measured with functional magnetic resonance imaging. Preliminary analyses suggest that it is difficult to directly decode spatial position from regions known to contain an explicit cognitive map of the environment, such as the hippocampus. Instead, we were able to indirectly derive spatial position from the pattern of activity in visual and motor cortex. The non-spatial representations in these regions reflect processes which are inherent to navigation, such as which stimuli are perceived at which point in time and which motor movement is executed when (e.g., turning left at a crossroad). Highly successful decoding of routes followed through the maze was possible by combining information about multiple aspects of navigation events across time and across multiple cortical regions. This "proof of principle" study highlights how visuospatial navigation is related to the combined activity of multiple brain regions, and establishes combinatorial brain decoding as a means to study complex mental events that involve a dynamic interplay of many cognitive processes. PMID- 23730270 TI - Response of striosomal opioid signaling to dopamine depletion in 6 hydroxydopamine-lesioned rat model of Parkinson's disease: a potential compensatory role. AB - The opioid peptide receptors consist of three major subclasses, namely, MU, delta, and kappa (MOR, DOR, and KOR, respectively). They are involved in the regulation of striatal dopamine functions, and increased opioid transmissions are thought to play a compensatory role in altered functions of the basal ganglia in Parkinson's disease (PD). In this study, we used an immunohistochemistry with tyramide signal amplification (TSA) protocols to determine the distributional patterns of opioid receptors in the striosome-matrix systems of the rat striatum. As a most striking feature of striatal opioid anatomy, MORs are highly enriched in the striosomes and subcallosal streak. We also found that DORs are localized in a mosaic pattern in the dorsal striatum (caudate-putamen), with heightened labeling for DOR in the striosomes relative to the matrix compartment. In the 6 hydroxydopamine-lesioned rat model of PD, lesions of the nigrostriatal pathways caused a significant reduction of striatal labeling for both the MOR and DOR in the striosomes, but not in the matrix compartment. Our results suggest that the activities of the striosome and matrix compartments are differentially regulated by the opioid signals involving the MORs and DORs, and that the striosomes may be more responsive to opioid peptides (e.g., enkephalin) than the matrix compartment. Based on a model in which the striosome compartment regulates the striatal activity, we propose a potent compensatory role of striosomal opioid signaling under the conditions of the striatal dopamine depletion that occurs in PD. PMID- 23730272 TI - Parallel fiber and climbing fiber responses in rat cerebellar cortical neurons in vivo. AB - Over the last few years we have seen a rapidly increasing interest in the functions of the inhibitory interneurons of the cerebellar cortex. However, we still have very limited knowledge about their physiological properties in vivo. The present study provides the first description of their spontaneous firing properties and their responses to synaptic inputs under non-anesthetized conditions in the decerebrated rat in vivo. We describe the spike responses of molecular layer interneurons (MLI) in the hemispheric crus1/crus2 region and compare them with those of Purkinje cells (PCs) and Golgi cells (GCs), both with respect to spontaneous activity and responses evoked by direct electrical stimulation of parallel fibers (PFs) and climbing fibers (CFs). In agreement with previous findings in the cat, we found that the CF responses in the interneurons consisted of relatively long lasting excitatory modulations of the spike firing. In contrast, activation of PFs induced rapid but short-lasting excitatory spike responses in all types of neurons. We also explored PF input plasticity in the short-term (10 min) using combinations of PF and CF stimulation. With regard to in vivo recordings from cerebellar cortical neurons in the rat, the data presented here provide the first demonstration that PF input to PC can be potentiated using PF burst stimulation and they suggest that PF burst stimulation combined with CF input may lead to potentiation of PF inputs in MLIs. We conclude that the basic responsive properties of the cerebellar cortical neurons in the rat in vivo are similar to those observed in the cat and also that it is likely that similar mechanisms of PF input plasticity apply. PMID- 23730273 TI - Linking enhancing and impairing effects of emotion-the case of PTSD. PMID- 23730271 TI - The cerebellar Golgi cell and spatiotemporal organization of granular layer activity. AB - The cerebellar granular layer has been suggested to perform a complex spatiotemporal reconfiguration of incoming mossy fiber signals. Central to this role is the inhibitory action exerted by Golgi cells over granule cells: Golgi cells inhibit granule cells through both feedforward and feedback inhibitory loops and generate a broad lateral inhibition that extends beyond the afferent synaptic field. This characteristic connectivity has recently been investigated in great detail and been correlated with specific functional properties of these neurons. These include theta-frequency pacemaking, network entrainment into coherent oscillations and phase resetting. Important advances have also been made in terms of determining the membrane and synaptic properties of the neuron, and clarifying the mechanisms of activation by input bursts. Moreover, voltage sensitive dye imaging and multi-electrode array (MEA) recordings, combined with mathematical simulations based on realistic computational models, have improved our understanding of the impact of Golgi cell activity on granular layer circuit computations. These investigations have highlighted the critical role of Golgi cells in: generating dense clusters of granule cell activity organized in center surround structures, implementing combinatorial operations on multiple mossy fiber inputs, regulating transmission gain, and cut-off frequency, controlling spike timing and burst transmission, and determining the sign, intensity and duration of long-term synaptic plasticity at the mossy fiber-granule cell relay. This review considers recent advances in the field, highlighting the functional implications of Golgi cells for granular layer network computation and indicating new challenges for cerebellar research. PMID- 23730274 TI - Gait analysis of teenagers and young adults diagnosed with autism and severe verbal communication disorders. AB - Both movement differences and disorders are common within autism spectrum disorders (ASD). These differences have wide and heterogeneous variability among different ages and sub-groups all diagnosed with ASD. Gait was studied in a more homogeneously identified group of nine teenagers and young adults who scored as "severe" in both measures of verbal communication and overall rating of Autism on the Childhood Autism Rating Scales (CARS). The ASD individuals were compared to a group of typically developing university undergraduates of similar ages. All participants walked a distance of 6-meters across a GAITRite (GR) electronic walkway for six trials. The ASD and comparison groups differed widely on many spatiotemporal aspects of gait including: step and stride length, foot positioning, cadence, velocity, step time, gait cycle time, swing time, stance time, and single and double support time. Moreover, the two groups differed in the percentage of the total gait cycle in each of these phases. The qualitative rating of "Body Use" on the CARS also indicated severe levels of unusual body movement for all of the ASD participants. These findings demonstrate that older teens and young adults with "severe" forms of Verbal Communication Impairments and Autism differ widely in their gait from typically developing individuals. The differences found in the current investigation are far more pronounced compared to previous findings with younger and/or less severely involved individuals diagnosed with ASD as compared to typically developing controls. As such, these data may be a useful anchor-point in understanding the trajectory of development of gait specifically and motor functions generally. PMID- 23730275 TI - Neural correlates of learning and trajectory planning in the posterior parietal cortex. AB - The posterior parietal cortex (PPC) is thought to play an important role in the planning of visually-guided reaching movements. However, the relative roles of the various subdivisions of the PPC in this function are still poorly understood. For example, studies of dorsal area 5 point to a representation of reaches in both extrinsic (endpoint) and intrinsic (joint or muscle) coordinates, as evidenced by partial changes in preferred directions and positional discharge with changes in arm posture. In contrast, recent findings suggest that the adjacent medial intraparietal area (MIP) is involved in more abstract representations, e.g., encoding reach target in visual coordinates. Such a representation is suitable for planning reach trajectories involving shortest distance paths to targets straight ahead. However, it is currently unclear how MIP contributes to the planning of other types of trajectories, including those with various degrees of curvature. Such curved trajectories recruit different joint excursions and might help us address whether their representation in the PPC is purely in extrinsic coordinates or in intrinsic ones as well. Here we investigated the role of the PPC in these processes during an obstacle avoidance task for which the animals had not been explicitly trained. We found that PPC planning activity was predictive of both the spatial and temporal aspects of upcoming trajectories. The same PPC neurons predicted the upcoming trajectory in both endpoint and joint coordinates. The predictive power of these neurons remained stable and accurate despite concomitant motor learning across task conditions. These findings suggest the role of the PPC can be extended from specifying abstract movement goals to expressing these plans as corresponding trajectories in both endpoint and joint coordinates. Thus, the PPC appears to contribute to reach planning and approach-avoidance arm motions at multiple levels of representation. PMID- 23730276 TI - Functional wiring of hypocretin and LC-NE neurons: implications for arousal. AB - To survive in a rapidly changing environment, animals must sense their external world and internal physiological state and properly regulate levels of arousal. Levels of arousal that are abnormally high may result in inefficient use of internal energy stores and unfocused attention to salient environmental stimuli. Alternatively, levels of arousal that are abnormally low may result in the inability to properly seek food, water, sexual partners, and other factors necessary for life. In the brain, neurons that express hypocretin neuropeptides may be uniquely posed to sense the external and internal state of the animal and tune arousal state according to behavioral needs. In recent years, we have applied temporally precise optogenetic techniques to study the role of these neurons and their downstream connections in regulating arousal. In particular, we have found that noradrenergic neurons in the brainstem locus coeruleus (LC) are particularly important for mediating the effects of hypocretin neurons on arousal. Here, we discuss our recent results and consider the implications of the anatomical connectivity of these neurons in regulating the arousal state of an organism across various states of sleep and wakefulness. PMID- 23730277 TI - Perceived stress predicts altered reward and loss feedback processing in medial prefrontal cortex. AB - Stress is a significant risk factor for the development of psychopathology, particularly symptoms related to reward processing. Importantly, individuals display marked variation in how they perceive and cope with stressful events, and such differences are strongly linked to risk for developing psychiatric symptoms following stress exposure. However, many questions remain regarding the neural architecture that underlies inter-subject variability in perceptions of stressors. Using functional magnetic resonance imaging (fMRI) during a Monetary Incentive Delay (MID) paradigm, we examined the effects of self-reported perceived stress levels on neural activity during reward anticipation and feedback in a sample of healthy individuals. We found that subjects reporting more uncontrollable and overwhelming stressors displayed blunted neural responses in medial prefrontal cortex (mPFC) following feedback related to monetary gains as well monetary losses. This is consistent with preclinical models that implicate the mPFC as a key site of vulnerability to the noxious effects of uncontrollable stressors. Our data help translate these findings to humans, and elucidate some of the neural mechanisms that may underlie stress-linked risk for developing reward-related psychiatric symptoms. PMID- 23730278 TI - Motor activation in literal and non-literal sentences: does time matter? AB - Despite the impressive amount of evidence showing involvement of the sensorimotor systems in language processing, important questions remain unsolved among which the relationship between non-literal uses of language and sensorimotor activation. The literature did not yet provide a univocal answer on whether the comprehension of non-literal, abstract motion sentences engages the same neural networks recruited for literal sentences. A previous TMS study using the same experimental materials of the present study showed activation for literal, fictive and metaphoric motion sentences but not for idiomatic ones. To evaluate whether this may depend on insufficient time for elaborating the idiomatic meaning, we conducted a behavioral experiment that used a sensibility judgment task performed by pressing a button either with a hand finger or with a foot. Motor activation is known to be sensitive to the action-congruency of the effector used for responding. Therefore, all other things being equal, significant differences between response emitted with an action-congruent or incongruent effector (foot vs. hand) may be attributed to motor activation. Foot related action verbs were embedded in sentences conveying literal motion, fictive motion, metaphoric motion or idiomatic motion. Mental sentences were employed as a control condition. foot responses were significantly faster than finger responses but only in literal motion sentences. We hypothesize that motor activation may arise in early phases of comprehension processes (i.e., upon reading the verb) for then decaying as a function of the strength of the semantic motion component of the verb. PMID- 23730280 TI - Measuring attention using the Posner cuing paradigm: the role of across and within trial target probabilities. AB - Numerous studies conducted within the recent decades have utilized the Posner cuing paradigm for eliciting, measuring, and theoretically characterizing attentional orienting. However, the data from recent studies suggest that the Posner cuing task might not provide an unambiguous measure of attention, as reflexive spatial orienting has been found to interact with extraneous processes engaged by the task's typical structure, i.e., the probability of target presence across trials, which affects tonic alertness, and the probability of target presence within trials, which affects voluntary temporal preparation. To understand the contribution of each of these two processes to the measurement of attentional orienting we assessed their individual and combined effects on reflexive attention elicited by a spatially nonpredictive peripheral cue. Our results revealed that the magnitude of spatial orienting was modulated by joint changes in the global probability of target presence across trials and the local probability of target presence within trials, while the time course of spatial orienting was susceptible to changes in the probability of target presence across trials. These data thus raise important questions about the choice of task parameters within the Posner cuing paradigm and their role in both the measurement and theoretical attributions of the observed attentional effects. PMID- 23730281 TI - Neural correlates of deception in social contexts in normally developing children. AB - Deception is related to the ability to inhibit prepotent responses and to engage in mental tasks such as anticipating responses and inferring what another person knows, especially in social contexts. However, the neural correlates of deception processing, which requires mentalizing, remain unclear. Using functional magnetic resonance imaging (fMRI), we examined the neural correlates of deception, including mentalization, in social contexts in normally developing children. Healthy right-handed children (aged 8-9 years) were scanned while performing interactive games involving deception. The games varied along two dimensions: the type of reply (deception and truth) and the type of context (social and less social). Participants were instructed to deceive a witch and to tell the truth to a girl. Under the social-context conditions, participants were asked to consider what they inferred about protagonists' preferences from their facial expressions when responding to questions. Under the less-social-context conditions, participants did not need to consider others' preferences. We found a significantly greater response in the right precuneus under the social-context than under less-social-context conditions. Additionally, we found marginally greater activation in the right inferior parietal lobule (IPL) under the deception than under the truth condition. These results suggest that deception in a social context requires not only inhibition of prepotent responses but also engagement in mentalizing processes. This study provides the first evidence of the neural correlates of the mentalizing processes involved in deception in normally developing children. PMID- 23730282 TI - Fast entrainment of human electroencephalogram to a theta-band photic flicker during successful memory encoding. AB - Theta band power (4-8 Hz) in the scalp electroencephalogram (EEG) is thought to be stronger during memory encoding for subsequently remembered items than for forgotten items. According to simultaneous EEG-functional magnetic resonance imaging (fMRI) measurements, the memory-dependent EEG theta is associated with multiple regions of the brain. This suggests that the multiple regions cooperate with EEG theta synchronization during successful memory encoding. However, a question still remains: What kind of neural dynamic organizes such a memory dependent global network? In this study, the modulation of the EEG theta entrainment property during successful encoding was hypothesized to lead to EEG theta synchronization among a distributed network. Then, a transient response of EEG theta to a theta-band photic flicker with a short duration was evaluated during memory encoding. In the results, flicker-induced EEG power increased and decreased with a time constant of several hundred milliseconds following the onset and the offset of the flicker, respectively. Importantly, the offset response of EEG power was found to be significantly decreased during successful encoding. Moreover, the offset response of the phase locking index was also found to associate with memory performance. According to computational simulations, the results are interpreted as a smaller time constant (i.e., faster response) of a driven harmonic oscillator rather than a change in the spontaneous oscillatory input. This suggests that the fast response of EEG theta forms a global EEG theta network among memory-related regions during successful encoding, and it contributes to a flexible formation of the network along the time course. PMID- 23730279 TI - The impact of anxiety upon cognition: perspectives from human threat of shock studies. AB - Anxiety disorders constitute a sizeable worldwide health burden with profound social and economic consequences. The symptoms are wide-ranging; from hyperarousal to difficulties with concentrating. This latter effect falls under the broad category of altered cognitive performance which is the focus of this review. Specifically, we examine the interaction between anxiety and cognition focusing on the translational threat of unpredictable shock paradigm; a method previously used to characterize emotional responses and defensive mechanisms that is now emerging as valuable tool for examining the interaction between anxiety and cognition. In particular, we compare the impact of threat of shock on cognition in humans to that of pathological anxiety disorders. We highlight that both threat of shock and anxiety disorders promote mechanisms associated with harm avoidance across multiple levels of cognition (from perception to attention to learning and executive function)-a "hot" cognitive function which can be both adaptive and maladaptive depending upon the circumstances. This mechanism comes at a cost to other functions such as working memory, but leaves some functions, such as planning, unperturbed. We also highlight a number of cognitive effects that differ across anxiety disorders and threat of shock. These discrepant effects are largely seen in "cold" cognitive functions involving control mechanisms and may reveal boundaries between adaptive (e.g., response to threat) and maladaptive (e.g., pathological) anxiety. We conclude by raising a number of unresolved questions regarding the role of anxiety in cognition that may provide fruitful avenues for future research. PMID- 23730283 TI - Advancing the science of spatial neglect rehabilitation: an improved statistical approach with mixed linear modeling. AB - VALID RESEARCH ON NEGLECT REHABILITATION DEMANDS A STATISTICAL APPROACH COMMENSURATE WITH THE CHARACTERISTICS OF NEGLECT REHABILITATION DATA: neglect arises from impairment in distinct brain networks leading to large between subject variability in baseline symptoms and recovery trajectories. Studies enrolling medically ill, disabled patients, may suffer from missing, unbalanced data, and small sample sizes. Finally, assessment of rehabilitation requires a description of continuous recovery trajectories. Unfortunately, the statistical method currently employed in most studies of neglect treatment [repeated measures analysis of variance (ANOVA), rANOVA] does not well-address these issues. Here we review an alternative, mixed linear modeling (MLM), that is more appropriate for assessing change over time. MLM better accounts for between-subject heterogeneity in baseline neglect severity and in recovery trajectory. MLM does not require complete or balanced data, nor does it make strict assumptions regarding the data structure. Furthermore, because MLM better models between-subject heterogeneity it often results in increased power to observe treatment effects with smaller samples. After reviewing current practices in the field, and the assumptions of rANOVA, we provide an introduction to MLM. We review its assumptions, uses, advantages, and disadvantages. Using real and simulated data, we illustrate how MLM may improve the ability to detect effects of treatment over ANOVA, particularly with the small samples typical of neglect research. Furthermore, our simulation analyses result in recommendations for the design of future rehabilitation studies. Because between-subject heterogeneity is one important reason why studies of neglect treatments often yield conflicting results, employing statistical procedures that model this heterogeneity more accurately will increase the efficiency of our efforts to find treatments to improve the lives of individuals with neglect. PMID- 23730284 TI - Insular Dysfunction Reflects Altered Between-Network Connectivity and Severity of Negative Symptoms in Schizophrenia during Psychotic Remission. AB - Schizophrenia is characterized by aberrant intrinsic functional connectivity (iFC) within and between intrinsic connectivity networks (ICNs), including the Default Mode- (DMN), Salience- (SN), and Central Executive Network (CEN). The anterior insula (AI) of the SN has been demonstrated to modulate DMN/CEN interactions. Recently, we found that the dependence of DMN/CEN interactions on SN's right AI activity is altered in patients with schizophrenia in acute psychosis and related to psychotic symptoms, indicating a link between aberrant AI, DMN, CEN, and psychosis. However, since structural alterations of the insula are also present during psychotic remission and associated with negative symptoms, impaired AI interaction might be relevant even for psychotic remission and corresponding symptoms. Twelve patients with schizophrenia during psychotic remission (SR) and 12 healthy controls were assessed using resting-state fMRI and psychometric examination. High-model-order independent component analysis of fMRI data revealed ICNs including DMN, SN, and CEN. Scores of iFC within (intra-iFC) and between (inter-iFC) distinct subsystems of the DMN, SN, and CEN were calculated, compared between groups and correlated with the severity of symptoms. Intra-iFC was altered in patients' SN, DMN, and CEN, including decreased intra iFC in the left AI within the SN. Patients' inter-iFC between SN and CEN was increased and correlated with the severity of negative symptoms. Furthermore, decreased intra-iFC of the left AI correlated with both severity of negative symptoms and increased inter-iFC between SN and CEN. Our result provides first evidence for a relationship between AI dysfunction and altered between-network interactions in schizophrenia during psychotic remission, which is related to the severity of negative symptoms. Together with our previous results, data suggest specific SN/DMN/CEN reorganization in schizophrenia with distinct insular pathways for distinct symptom dimensions. PMID- 23730285 TI - Evolutionary and developmental modules. AB - The identification of biological modules at the systems level often follows top down decomposition of a task goal, or bottom-up decomposition of multidimensional data arrays into basic elements or patterns representing shared features. These approaches traditionally have been applied to mature, fully developed systems. Here we review some results from two other perspectives on modularity, namely the developmental and evolutionary perspective. There is growing evidence that modular units of development were highly preserved and recombined during evolution. We first consider a few examples of modules well identifiable from morphology. Next we consider the more difficult issue of identifying functional developmental modules. We dwell especially on modular control of locomotion to argue that the building blocks used to construct different locomotor behaviors are similar across several animal species, presumably related to ancestral neural networks of command. A recurrent theme from comparative studies is that the developmental addition of new premotor modules underlies the postnatal acquisition and refinement of several different motor behaviors in vertebrates. PMID- 23730286 TI - Interactions between motion and form processing in the human visual system. AB - The predominant view of motion and form processing in the human visual system assumes that these two attributes are handled by separate and independent modules. Motion processing involves filtering by direction-selective sensors, followed by integration to solve the aperture problem. Form processing involves filtering by orientation-selective and size-selective receptive fields, followed by integration to encode object shape. It has long been known that motion signals can influence form processing in the well-known Gestalt principle of common fate; texture elements which share a common motion property are grouped into a single contour or texture region. However, recent research in psychophysics and neuroscience indicates that the influence of form signals on motion processing is more extensive than previously thought. First, the salience and apparent direction of moving lines depends on how the local orientation and direction of motion combine to match the receptive field properties of motion-selective neurons. Second, orientation signals generated by "motion-streaks" influence motion processing; motion sensitivity, apparent direction and adaptation are affected by simultaneously present orientation signals. Third, form signals generated by human body shape influence biological motion processing, as revealed by studies using point-light motion stimuli. Thus, form-motion integration seems to occur at several different levels of cortical processing, from V1 to STS. PMID- 23730288 TI - Impact of mitochondria on nitrite metabolism in HL-1 cardiomyocytes. AB - Apart from ATP synthesis mitochondria have many other functions, one being nitrite reductase activity. Nitric oxide (NO) released from nitrite has been shown to protect the heart from ischemia/reperfusion (I/R) injury in a cGMP dependent manner. However, the exact impact of mitochondria on the release of NO from nitrite in cardiomyocytes is not completely understood. Besides mitochondria, a number of non-mitochondrial metalloproteins have been suggested to facilitate this process. The aim of this study was to investigate the impact of mitochondria on the bioactivation of nitrite in HL-1 cardiomyocytes. The levels of nitrosyl complexes of hemoglobin (NO-Hb) and cGMP levels were measured by electron spin resonance spectroscopy and enzyme immunoassay. In addition the formation of free NO was determined by confocal microscopy as well as intracellular nitrite and S-nitrosothiols by chemoluminescence analysis. NO was released from nitrite in cell culture in an oxygen-dependent manner. Application of specific inhibitors of the respiratory chain, p450, NO synthases (NOS) and xanthine oxidoreductase (XOR) showed that all four enzymatic systems are involved in the release of NO, but more than 50% of NO is released via the mitochondrial pathway. Only NO released by mitochondria activated cGMP synthesis. Cardiomyocytes co-cultured with red blood cells (RBC) competed with RBC for nitrite, but free NO was detected only in HL-1 cells suggesting that RBC are not a source of NO in this model. Apart from activation of cGMP synthesis, NO formed in HL-1 cells diffused out of the cells and formed NO-Hb complexes. In addition nitrite was converted by HL-1 cells to S-nitrosyl complexes. In HL-1 cardiomyocytes, several enzymatic systems are involved in nitrite reduction to NO but only the mitochondrial pathway of NO release activates cGMP synthesis. Our data suggest that this pathway may be a key regulator of myocardial contractility especially under hypoxic conditions. PMID- 23730289 TI - Sampling rate dependence of correlation at long time lags in BOLD fMRI measurements on humans and gel phantoms. AB - The aim of this study is to investigate the effects of sampling rate on Hurst exponents derived from Blood Oxygenation Level Dependent functional Magnetic Resonance Imaging (BOLD fMRI) resting state time series. fMRI measurements were performed on 2 human subjects and a selection of gel phantoms. From these, Hurst exponents were calculated. It was found that low sampling rates induced non trivial exponents at sharp material transitions, and that Hurst exponents of human measurements had a strong TR-dependence. The findings are compared to theoretical considerations regarding the fractional Gaussian noise model and resampling, and it is found that the implications are problematic. This result should have a direct influence on the way future studies of low-frequency variation in BOLD fMRI data are conducted, especially if the fractional Gaussian noise model is considered. We recommend either using a different model (examples of such are referenced in the conclusion), or standardizing experimental procedures along an optimal sampling rate. PMID- 23730287 TI - Metal-induced neurodegeneration in C. elegans. AB - The model species, Caenorhabditis elegans, has been used as a tool to probe for mechanisms underlying numerous neurodegenerative diseases. This use has been exploited to study neurodegeneration induced by metals. The allure of the nematode comes from the ease of genetic manipulation, the ability to fluorescently label neuronal subtypes, and the relative simplicity of the nervous system. Notably, C. elegans have approximately 60-80% of human genes and contain genes involved in metal homeostasis and transport, allowing for the study of metal-induced degeneration in the nematode. This review discusses methods to assess degeneration as well as outlines techniques for genetic manipulation and presents a comprehensive survey of the existing literature on metal-induced degeneration studies in the worm. PMID- 23730290 TI - Brain dysfunction as one cause of CFS symptoms including difficulty with attention and concentration. AB - We have been able to reduce substantially patient pool heterogeneity by identifying phenotypic markers that allow the researcher to stratify chronic fatigue syndrome (CFS) patients into subgroups. To date, we have shown that stratifying based on the presence or absence of comorbid psychiatric diagnosis leads to a group with evidence of neurological dysfunction across a number of spheres. We have also found that stratifying based on the presence or absence of comorbid fibromyalgia leads to information that would not have been found on analyzing the entire, unstratified patient group. Objective evidence of orthostatic intolerance (OI) may be another important variable for stratification and may define a group with episodic cerebral hypoxia leading to symptoms. We hope that this review will encourage other researchers to collect data on discrete phenotypes in CFS to allow this work to continue more broadly. Finding subgroups of CFS suggests different underlying pathophysiological processes responsible for the symptoms seen. Understanding those processes is the first step toward developing discrete treatments for each. PMID- 23730291 TI - Small Saccades and Image Complexity during Free Viewing of Natural Images in Schizophrenia. AB - In schizophrenia, patients display dysfunctions during the execution of simple visual tasks such as antisaccade or smooth pursuit. In more ecological scenarios, such as free viewing of natural images, patients appear to make fewer and longer visual fixations and display shorter scanpaths. It is not clear whether these measurements reflect alterations in their proficiency to perform basic eye movements, such as saccades and fixations, or are related to high-level mechanisms, such as exploration or attention. We utilized free exploration of natural images of different complexities as a model of an ecological context where normally operative mechanisms of visual control can be accurately measured. We quantified visual exploration as Euclidean distance, scanpaths, saccades, and visual fixation, using the standard SR-Research eye tracker algorithm (SR). We then compared this result with a computation that includes microsaccades (EM). We evaluated eight schizophrenia patients and corresponding healthy controls (HC). Next, we tested whether the decrement in the number of saccades and fixations, as well as their increment in duration reported previously in schizophrenia patients, resulted from the increasing occurrence of undetected microsaccades. We found that when utilizing the standard SR algorithm, patients displayed shorter scanpaths as well as fewer and shorter saccades and fixations. When we employed the EM algorithm, the differences in these parameters between patients and HC were no longer significant. On the other hand, we found that image complexity plays an important role in exploratory behaviors, demonstrating that this factor explains most of differences between eye-movement behaviors in schizophrenia patients. These results help elucidate the mechanisms of visual motor control that are affected in schizophrenia and contribute to the finding of adequate markers for diagnosis and treatment for this condition. PMID- 23730292 TI - Behavioral, Biochemical, and Molecular Indices of Stress are Enhanced in Female Versus Male Rats Experiencing Nicotine Withdrawal. AB - Stress is a major factor that promotes tobacco use and relapse during withdrawal. Although women are more vulnerable to tobacco use than men, the manner in which stress contributes to tobacco use in women versus men is unclear. Thus, the goal of this study was to compare behavioral and biological indices of stress in male and female rats during nicotine withdrawal. Since the effects of nicotine withdrawal are age-dependent, this study also included adolescent rats. An initial study was conducted to provide comparable nicotine doses across age and sex during nicotine exposure and withdrawal. Rats received sham surgery or an osmotic pump that delivered nicotine. After 14 days of nicotine, the pumps were removed and controls received a sham surgery. Twenty-four hours later, anxiety like behavior and plasma corticosterone were assessed. The nucleus accumbens (NAcc), amygdala, and hypothalamus were examined for changes in corticotropin releasing factor (CRF) gene expression. In order to differentiate the effects of nicotine withdrawal from exposure to nicotine, a cohort of rats did not have their pumps removed. The major finding is that during nicotine withdrawal, adult females display higher levels of anxiety-like behavior, plasma corticosterone, and CRF mRNA expression in the NAcc relative to adult males. However, during nicotine exposure, adult males exhibited higher levels of corticosterone and CRF mRNA in the amygdala relative to females. Adolescents displayed less nicotine withdrawal than adults. Moreover, adolescent males displayed an increase in anxiety-like behavior and an up-regulation of CRF mRNA in the amygdala during nicotine exposure and withdrawal. These findings are likely related to stress produced by the high doses of nicotine that were administered to adolescents to produce equivalent levels of cotinine as adults. In conclusion, these findings suggest that intense stress produced by nicotine withdrawal may contribute to tobacco use in women. PMID- 23730293 TI - Syntactic computations in the language network: characterizing dynamic network properties using representational similarity analysis. AB - The core human capacity of syntactic analysis involves a left hemisphere network involving left inferior frontal gyrus (LIFG) and posterior middle temporal gyrus (LMTG) and the anatomical connections between them. Here we use magnetoencephalography (MEG) to determine the spatio-temporal properties of syntactic computations in this network. Listeners heard spoken sentences containing a local syntactic ambiguity (e.g., "... landing planes ..."), at the offset of which they heard a disambiguating verb and decided whether it was an acceptable/unacceptable continuation of the sentence. We charted the time-course of processing and resolving syntactic ambiguity by measuring MEG responses from the onset of each word in the ambiguous phrase and the disambiguating word. We used representational similarity analysis (RSA) to characterize syntactic information represented in the LIFG and left posterior middle temporal gyrus (LpMTG) over time and to investigate their relationship to each other. Testing a variety of lexico-syntactic and ambiguity models against the MEG data, our results suggest early lexico-syntactic responses in the LpMTG and later effects of ambiguity in the LIFG, pointing to a clear differentiation in the functional roles of these two regions. Our results suggest the LpMTG represents and transmits lexical information to the LIFG, which responds to and resolves the ambiguity. PMID- 23730294 TI - Attentional load and attentional boost: a review of data and theory. AB - Both perceptual and cognitive processes are limited in capacity. As a result, attention is selective, prioritizing items and tasks that are important for adaptive behavior. However, a number of recent behavioral and neuroimaging studies suggest that, at least under some circumstances, increasing attention to one task can enhance performance in a second task (e.g., the attentional boost effect). Here we review these findings and suggest a new theoretical framework, the dual-task interaction model, that integrates these findings with current views of attentional selection. To reconcile the attentional boost effect with the effects of attentional load, we suggest that temporal selection results in a temporally specific enhancement across modalities, tasks, and spatial locations. Moreover, the effects of temporal selection may be best observed when the attentional system is optimally tuned to the temporal dynamics of incoming stimuli. Several avenues of research motivated by the dual-task interaction model are then discussed. PMID- 23730295 TI - What is Bottom-Up and What is Top-Down in Predictive Coding? AB - Everyone knows what bottom-up is, and how it is different from top-down. At least one is tempted to think so, given that both terms are ubiquitously used, but only rarely defined in the psychology and neuroscience literature. In this review, we highlight the problems and limitations of our current understanding of bottom-up and top-down processes, and we propose a reformulation of this distinction in terms of predictive coding. PMID- 23730296 TI - Targeting the full length of the motor end plate regions in the mouse forelimb increases the uptake of fluoro-gold into corresponding spinal cord motor neurons. AB - Lower motor neuron dysfunction is one of the most debilitating motor conditions. In this regard, transgenic mouse models of various lower motor neuron dysfunctions provide insight into the mechanisms underlying these pathologies and can also aid the development of new therapies. Viral-mediated gene therapy can take advantage of the muscle-motor neuron topographical relationship to shuttle therapeutic genes into specific populations of motor neurons in these mouse models. In this context, motor end plates (MEPs) are highly specialized regions on the skeletal musculature that offer direct access to the pre-synaptic nerve terminals, henceforth to the spinal cord motor neurons. The aim of this study was two-folded. First, it was to characterize the exact position of the MEP regions for several muscles of the mouse forelimb using acetylcholinesterase histochemistry. This MEP-muscle map was then used to guide a series of intramuscular injections of Fluoro-Gold (FG) in order to characterize the distribution of the innervating motor neurons. This analysis revealed that the MEPs are typically organized in an orthogonal fashion across the muscle fibers and extends throughout the full width of each muscle. Furthermore, targeting the full length of the MEP regions gave rise labeled motor neurons that are organized into columns spanning through more spinal cord segments than previously reported. The present analysis suggests that targeting the full width of the muscles' MEP regions with FG increases the somatic availability of the tracer. This process ensures a greater uptake of the tracer by the pre-synaptic nerve terminals, hence maximizing the labeling in spinal cord motor neurons. This investigation should have positive implications for future studies involving the somatic delivery of therapeutic genes into motor neurons for the treatment of various motor dysfunctions. PMID- 23730297 TI - Differential roles of orexin receptors in the regulation of sleep/wakefulness. AB - Orexin A and orexin B are hypothalamic neuropeptides that play critical roles in the regulation of sleep/wakefulness, as well as in a variety of physiological functions such as emotion, reward, and energy homeostasis. The actions of orexins are mediated by two receptors, orexin 1 (OX1R) and orexin 2 (OX2R) receptors. OX1R and OX2R show partly overlapping but distinct distributions throughout the central nervous system, suggesting their differential roles. This review presents and discusses the current knowledge concerning the physiological roles of each orexin receptor subtype, focusing on the regulation of sleep/wakefulness. PMID- 23730298 TI - Abnormal Neurodevelopmental Outcomes are Common in Children with Transient Congenital Hyperinsulinism. AB - INTRODUCTION: Neuroglycopenia is recognized to be associated with abnormal neurodevelopmental outcomes in 26-44% of children with persistent congenital hyperinsulinism (P-CHI). The prevalence of abnormal neurodevelopment in transient CHI (T-CHI) is not known. We have aimed to investigate abnormal neurodevelopment and associated factors in T-CHI and P-CHI. MATERIALS AND METHODS: A cohort of children with CHI (n = 67, age 2.5-5 years) was assessed at follow-up review and noted to have normal or abnormal (mild or severe) neurodevelopmental outcomes for the domains of speech and language, motor, and vision. Children were classified as P-CHI (n = 33), if they had undergone surgery or remained on medical therapy, or T-CHI (n = 34), if medical treatment for hypoglycemia was stopped. RESULTS: Overall, abnormal neurodevelopment was present in 26 (39%) children with CHI, of whom 18 (69%) were severe. Importantly, the incidence of abnormal neurodevelopment in T-CHI was similar to that in P-CHI (30 vs. 47% respectively, p = 0.16). The prevalence of severe abnormal neurodevelopment in speech, motor, and vision domains was similar in both T-CHI and P-CHI children. For this cohort, we found that the severity of disease [based upon maximal diazoxide dose (odds ratio 95% confidence intervals) 1.3 (1.1; 1.5), p = 0.03], and early presentation of CHI <7 days following birth [5.9 (1.3; 27.8), p = 0.02] were significantly associated with abnormal neurodevelopment. There was no significant association with gender, genotype, or the histopathological basis of CHI. CONCLUSION: Abnormal neurodevelopment was evident in one third of children with both T-CHI and P-CHI, early presentation and severe CHI being risk factors. Early recognition and rapid correction of hypoglycemia are advocated to avoid abnormal neurodevelopment in children with CHI. PMID- 23730299 TI - Crinivirus replication and host interactions. AB - Criniviruses comprise one of the genera within the family Closteroviridae. Members in this family are restricted to the phloem and rely on whitefly vectors of the genera Bemisia and/or Trialeurodes for plant-to-plant transmission. All criniviruses have bipartite, positive-sense single-stranded RNA genomes, although there is an unconfirmed report of one having a tripartite genome. Lettuce infectious yellows virus (LIYV) is the type species of the genus, the best studied so far of the criniviruses and the first for which a reverse genetics system was developed. LIYV RNA 1 encodes for proteins predicted to be involved in replication, and alone is competent for replication in protoplasts. Replication results in accumulation of cytoplasmic vesiculated membranous structures which are characteristic of most studied members of the Closteroviridae. These membranous structures, often referred to as Beet yellows virus (BYV)-type vesicles, are likely sites of RNA replication. LIYV RNA 2 is replicated in trans when co-infecting cells with RNA 1, but is temporally delayed relative to RNA 1. Efficient RNA 2 replication also is dependent on the RNA 1-encoded RNA-binding protein, P34. No LIYV RNA 2-encoded proteins have been shown to affect RNA replication, but at least four, CP (major coat protein), CPm (minor coat protein), Hsp70h, and P59 are virion structural components and CPm is a determinant of whitefly transmissibility. Roles of other LIYV RNA 2-encoded proteins are largely as yet unknown, but P26 is a non-virion protein that accumulates in cells as characteristic plasmalemma deposits which in plants are localized within phloem parenchyma and companion cells over plasmodesmata connections to sieve elements. The two remaining crinivirus-conserved RNA 2 encoded proteins are P5 and P9. P5 is 39 amino acid protein and is encoded at the 5' end of RNA 2 as ORF 1 and is part of the hallmark closterovirus gene array. The orthologous gene in BYV has been shown to play a role in cell-to-cell movement and indicated to be localized to the endoplasmic reticulum as a Type III integral membrane protein. The other small protein, P9, is encoded by ORF 4 overlaps with ORF 3 that encodes the structural protein, P59. P9 seems to be unique to viruses in the genus Crinivirus, as no similar protein has been detected in viruses of the other two genera of the Closteroviridae. PMID- 23730300 TI - Epidemiology of criniviruses: an emerging problem in world agriculture. AB - The genus Crinivirus includes the whitefly-transmitted members of the family Closteroviridae. Whitefly-transmitted viruses have emerged as a major problem for world agriculture and are responsible for diseases that lead to losses measured in the billions of dollars annually. Criniviruses emerged as a major agricultural threat at the end of the twentieth century with the establishment and naturalization of their whitefly vectors, members of the genera Trialeurodes and Bemisia, in temperate climates around the globe. Several criniviruses cause significant diseases in single infections whereas others remain asymptomatic and only cause disease when found in mixed infections with other viruses. Characterization of the majority of criniviruses has been done in the last 20 years and this article provides a detailed review on the epidemiology of this important group of viruses. PMID- 23730301 TI - Rise and dissemination of aminoglycoside resistance: the aac(6')-Ib paradigm. AB - Enzymatic modification is a prevalent mechanism by which bacteria defeat the action of antibiotics. Aminoglycosides are often inactivated by aminoglycoside modifying enzymes encoded by genes present in the chromosome, plasmids, and other genetic elements. The AAC(6')-Ib (aminoglycoside 6'-N-acetyltransferase type Ib) is an enzyme of clinical importance found in a wide variety of gram-negative pathogens. The AAC(6')-Ib enzyme is of interest not only because of his ubiquity but also because of other characteristics, it presents significant microheterogeneity at the N-termini and the aac(6')-Ib gene is often present in integrons, transposons, plasmids, genomic islands, and other genetic structures. Excluding the highly heterogeneous N-termini, there are 45 non-identical AAC(6') Ib related entries in the NCBI database, 32 of which have identical name in spite of not having identical amino acid sequence. While some variants conserved similar properties, others show dramatic differences in specificity, including the case of AAC(6')-Ib-cr that mediates acetylation of ciprofloxacin representing a rare case where a resistance enzyme acquires the ability to utilize an antibiotic of a different class as substrate. Efforts to utilize antisense technologies to turn off expression of the gene or to identify enzymatic inhibitors to induce phenotypic conversion to susceptibility are under way. PMID- 23730303 TI - Arginase promotes skeletal muscle arteriolar endothelial dysfunction in diabetic rats. AB - Endothelial dysfunction is a characteristic feature in diabetes that contributes to the development of vascular disease. Recently, arginase has been implicated in triggering endothelial dysfunction in diabetic patients and animals by competing with endothelial nitric oxide synthase for substrate l-arginine. While most studies have focused on the coronary circulation and large conduit blood vessels, the role of arginase in mediating diabetic endothelial dysfunction in other vascular beds has not been fully investigated. In the present study, we determined whether arginase contributes to endothelial dysfunction in skeletal muscle arterioles of diabetic rats. Diabetes was induced in male Sprague Dawley rats by streptozotocin injection. Four weeks after streptozotocin administration, blood glucose, glycated hemoglobin, and vascular arginase activity were significantly increased. In addition, a significant increase in arginase I and II mRNA expression was detected in gracilis muscle arterioles of diabetic rats compared to age-matched, vehicle control animals. To examine endothelial function, first-order gracilis muscle arterioles were isolated, cannulated in a pressure myograph system, exposed to graded levels of luminal flow, and internal vessel diameter measured. Increases in luminal flow (0-50 MUL/min) caused progressive vasodilation in arterioles isolated from control, normoglycemic animals. However, flow-induced vasodilation was absent in arterioles obtained from streptozotocin-treated rats. Acute in vitro pretreatment of blood vessels with the arginase inhibitors N (omega)-hydroxy-nor-l-arginine or S-(2 boronoethyl)-l-cysteine restored flow-induced responses in arterioles from diabetic rats and abolished differences between diabetic and control animals. Similarly, acute in vitro pretreatment with l-arginine returned flow-mediated vasodilation in vessels from diabetic animals to that of control rats. In contrast, d-arginine failed to restore flow-induced dilation in arterioles isolated from diabetic animals. Administration of sodium nitroprusside resulted in a similar degree of dilation in arterioles isolated from control or diabetic rats. In conclusion, the present study identifies arginase as an essential mediator of skeletal muscle arteriolar endothelial dysfunction in diabetes. The ability of arginase to induce endothelial dysfunction in skeletal muscle arterioles may further compromise glucose utilization and facilitate the development of hypertension in diabetes. PMID- 23730302 TI - Food components and the immune system: from tonic agents to allergens. AB - The intestinal mucosa is the major site of contact with antigens, and it houses the largest lymphoid tissue in the body. In physiological conditions, microbiota and dietary antigens are the natural sources of stimulation for the gut associated lymphoid tissues (GALT) and for the immune system as a whole. Germ free models have provided some insights on the immunological role of gut antigens. However, most of the GALT is not located in the large intestine, where gut microbiota is prominent. It is concentrated in the small intestine where protein absorption takes place. In this review, we will address the involvement of food components in the development and the function of the immune system. Studies in mice have already shown that dietary proteins are critical elements for the developmental shift of the immature neonatal immune profile into a fully developed immune system. The immunological effects of other food components (such as vitamins and lipids) will also be addressed. Most of the cells in the GALT are activated and local pro-inflammatory mediators are abundant. Regulatory elements are known to provide a delicate yet robust balance that maintains gut homeostasis. Usually antigenic contact in the gut induces two major immune responses, oral tolerance and production of secretory IgA. However, under pathological conditions mucosal homeostasis is disturbed resulting in inflammatory reactions such as food hypersensitivity. Food allergy development depends on many factors such as genetic predisposition, biochemical features of allergens, and a growing array of environmental elements. Neuroimmune interactions are also implicated in food allergy and they are examples of the high complexity of the phenomenon. Recent findings on the gut circuits triggered by food components will be reviewed to show that, far beyond their role as nutrients, they are critical players in the operation of the immune system in health and disease. PMID- 23730304 TI - T cell aging: a review of the transcriptional changes determined from genome-wide analysis. AB - Age carries a detrimental impact on T cell function. In the past decade, analyses of the genome-scale transcriptional changes of T cells during aging have yielded a large amount of data and provided a global view of gene expression changes in T cells from aged hosts as well as subsets of T cells accumulated with age. Here, we aim to review the changes of gene expression in thymocytes and peripheral mature T cells, as well as the subsets of T cells accumulated with age, and discuss the gene networks and signaling pathways that are altered with aging in T cells. We also discuss future direction for furthering the understanding of the molecular basis of gene expression alterations in aged T cells, which could potentially provide opportunities for gene-based clinical interventions. PMID- 23730305 TI - The systems genetics resource: a web application to mine global data for complex disease traits. AB - The Systems Genetics Resource (SGR) (http://systems.genetics.ucla.edu) is a new open-access web application and database that contains genotypes and clinical and intermediate phenotypes from both human and mouse studies. The mouse data include studies using crosses between specific inbred strains and studies using the Hybrid Mouse Diversity Panel. SGR is designed to assist researchers studying genes and pathways contributing to complex disease traits, including obesity, diabetes, atherosclerosis, heart failure, osteoporosis, and lipoprotein metabolism. Over the next few years, we hope to add data relevant to deafness, addiction, hepatic steatosis, toxin responses, and vascular injury. The intermediate phenotypes include expression array data for a variety of tissues and cultured cells, metabolite levels, and protein levels. Pre-computed tables of genetic loci controlling intermediate and clinical phenotypes, as well as phenotype correlations, are accessed via a user-friendly web interface. The web site includes detailed protocols for all of the studies. Data from published studies are freely available; unpublished studies have restricted access during their embargo period. PMID- 23730306 TI - Converging Evidence for Epistasis between ANK3 and Potassium Channel Gene KCNQ2 in Bipolar Disorder. AB - Genome-wide association studies (GWAS) have implicated ANK3 as a susceptibility gene for bipolar disorder (BP). We examined whether epistasis with ANK3 may contribute to the "missing heritability" in BP. We first identified via the STRING database 14 genes encoding proteins with prior biological evidence that they interact molecularly with ANK3. We then tested for statistical evidence of interactions between SNPs in these genes in association with BP in a discovery GWAS dataset and two replication GWAS datasets. The most significant interaction in the discovery GWAS was between SNPs in ANK3 and KCNQ2 (p = 3.18 * 10(-8)). A total of 31 pair-wise interactions involving combinations between two SNPs from KCNQ2 and 16 different SNPs in ANK3 were significant after permutation. Of these, 28 pair-wise interactions were significant in the first replication GWAS. None were significant in the second replication GWAS, but the two SNPs from KCNQ2 were found to significantly interact with five other SNPs in ANK3, suggesting possible allelic heterogeneity. KCNQ2 forms homo- and hetero-meric complexes with KCNQ3 that constitute voltage-gated potassium channels in neurons. ANK3 is an adaptor protein that, through its interaction with KCNQ2 and KCNQ3, directs the localization of this channel in the axon initial segment (AIS). At the AIS, the KCNQ2/3 complex gives rise to the M-current, which stabilizes the neuronal resting potential and inhibits repetitive firing of action potentials. Thus, these channels act as "dampening" components and prevent neuronal hyperactivity. The interactions between ANK3 and KCNQ2 merit further investigation, and if confirmed, may motivate a new line of research into a novel therapeutic target for BP. PMID- 23730307 TI - Screening of the ito regulatory subunit klf15 in patients with early-onset lone atrial fibrillation. AB - Several studies have associated mutations in genes encoding potassium channels and accessory subunits involved in cardiac repolarization with increased susceptibility of atrial fibrillation (AF). Recently, the Kruppel-like factor 15 (Klf15) was found to transcriptionally control rhythmic expression of KChIP2, a critical subunit required for generating the transient outward potassium current (Ito), and that deficiency or excess of Klf15 increased the susceptibility of arrhythmias. On this basis we hypothesized that mutations in Klf15 could be associated with AF. A total of 209 unrelated Caucasian lone AF patients were screened for mutations in Klf15 by direct sequencing. No mutations in the lone AF cohort were found. In one patient we found a synonymous variant (c.36C > T). In NHLBI GO Exome Sequencing Project (ESP) the variant was present in 31 of 4269 Caucasian individuals and in 3 of 2200 African Americans. In our cohort Klf15 was not associated with lone AF. PMID- 23730308 TI - Fractional Flow in Cerebrovascular Disorders. AB - There is an urgent need for stroke experts to advance the care of their patients, yet current approaches are outmoded and have not been successful. The traditional emphasis on anatomical identification of disease, using percent luminal stenosis, results in suboptimal identification of lesions likely to produce recurrent ischemia and, consequently, results in poor patient selection and hampers the development of new aggressive treatments. The traditional emphasis on time since symptom onset and alleged need to achieve complete revascularization in patients with acute ischemic stroke ignores the very nature and degree of the underlying culprit lesion and hampers our understanding of the relationships between the patient's original ischemic state, revascularization, reperfusion, reperfusion injury and hemorrhagic transformation. The trajectory for the study and care of cerebrovascular patients needs to adapt, as it has in cardiology, employing hemodynamics and pathophysiology as the new guideposts for advancement. We introduce fractional flow as one hemodynamic parameter to be utilized to set a course on this new path for the care of stroke patients. PMID- 23730310 TI - Economic evaluation of posaconazole versus standard azole therapy as prophylaxis against invasive fungal infections in patients with prolonged neutropenia in Canada. AB - INTRODUCTION: Posaconazole prophylaxis in high-risk neutropenic patients prevents invasive fungal infection (IFI). An economic model was used to assess the cost effectiveness of posaconazole from a Canadian health care system perspective. METHODS: A decision-analytic model was developed based on data from a randomized trial comparing posaconazole with standard azole (fluconazole or itraconazole) therapy. The model was extrapolated to a lifetime horizon using one-month Markov cycles; lifetime survival was specific to the underlying disease. Drug and treatment costs associated with IFI were estimated using published literature. The model was used to estimate total costs, IFIs avoided, life-years gained and the incremental cost-effectiveness ratio of posaconazole versus standard azole therapy, in 2007 Canadian dollars. RESULTS: Based on the clinical trial data, posaconazole was associated with fewer cases of IFI (0.05 versus 0.11; P=0.003), increased life-years (2.52 years versus 2.43 years) and slightly lower costs ($6,601 versus $7,045) per patient relative to standard azole therapy over a lifetime horizon. Higher acquisition costs for posaconazole were offset by IFI associated inpatient costs for those prophylaxed with standard azoles. Probabilistic sensitivity analysis indicated a 59% probability that posaconazole was cost-saving versus standard azole therapy and a 96% probability that the incremental cost-effectiveness ratio for posaconazole was at or below the $50,000 per life-year saved threshold. DISCUSSION: In Canada, posaconazole appears to be cost-saving relative to standard azole therapy in IFI prevention among high-risk neutropenic patients. PMID- 23730311 TI - Serological survey of the novel influenza A H1N1 in inner city Winnipeg, Manitoba, 2009. AB - INTRODUCTION: Little is known about the determinants of pandemic H1N1 (pH1N1) infection in Canada among low-income, inner city populations. To inform future influenza planning, the seroprevalence of pH1N1 antibodies among inner city clinic attendees in Winnipeg (Manitoba) according to sociodemographic and risk factor characteristics were estimated and vaccination rates were explored. METHODS: Adults presenting to three inner city community clinics in Winnipeg from October 2009 to December 2009 were recruited as study participants (n=458). A questionnaire was administered to collect demographic, risk factor and symptom information, and a venous blood sample was collected for hemagglutination inhibition assay testing to detect the presence of antibodies against pH1N1. RESULTS: Approximately one-half (53%) of the study participants reported an annual household income of <$10,000/year, and 65% identified as Aboriginal. pH1N1 positivity was 5.7% among those enrolled early in the study and 15.5% among those enrolled later in the study. Positivity was higher among participants who were female, Aboriginal and in contact with children <=5 years of age. The overall pH1N1 vaccination rate was 28%. DISCUSSION: pH1N1 positivity was high among low income adults accessing clinics in Winnipeg's inner city compared with the general population. Of further concern were the low rates of uptake of both seasonal and pH1N1 influenza vaccinations. When planning for future influenza outbreaks, it is important to incorporate strategies for the prevention, control, and care of influenza among low-income and inner city adults. PMID- 23730312 TI - Cost effectiveness of infant vaccination for rotavirus in Canada. AB - INTRODUCTION: Rotavirus is the main cause of gastroenteritis in Canadian children younger than five years of age, resulting in significant morbidity and cost. The present study provides evidence on the cost effectiveness of two alternative rotavirus vaccinations (RotaTeq [Merck Frosst Canada Ltd, Canada] and Rotarix [GlaxoSmithKline, Canada]) available in Canada. METHODS: Analysis was conducted through a Markov model that followed a cohort of children from birth to five years of age. Analysis used pertinent data on the natural history of rotavirus and the effects of vaccination. Estimates of heath care costs for children requiring hospitalizations and emergency department visits were derived from the Canadian Immunization Monitoring Program, Active (IMPACT) surveillance, emergency department studies, as well as other Canadian studies. The model estimated the effect of vaccination on costs and quality-adjusted life years (QALYs). RESULTS: The incremental cost per QALY gained from the health care system perspective was $122,000 for RotaTeq and $108,000 for Rotarix. From the societal perspective, both vaccination strategies were dominant - both cost saving and more effective. The cost-effectiveness of vaccination is dependent on the mode of administration, the perspective adopted and the cost of the vaccine. CONCLUSIONS: From a societal perspective, a universal vaccination program against rotavirus will be both cost saving and more effective than no vaccination. Becasue the majority of rotavirus infections do not require emergency department visits or hospital admission, from a health care system perspective, a program would not be considered cost effective. PMID- 23730309 TI - Progress in Brucella vaccine development. AB - Brucella spp. are zoonotic, facultative intracellular pathogens, which cause animal and human disease. Animal disease results in abortion of fetuses; in humans, it manifests flu-like symptoms with an undulant fever, with osteoarthritis as a common complication of infection. Antibiotic regimens for human brucellosis patients may last several months and are not always completely effective. While there are no vaccines for humans, several licensed live Brucella vaccines are available for use in livestock. The performance of these animal vaccines is dependent upon the host species, dose, and route of immunization. Newly engineered live vaccines, lacking well-defined virulence factors, retain low residual virulence, are highly protective, and may someday replace currently used animal vaccines. These also have possible human applications. Moreover, due to their enhanced safety and efficacy in animal models, subunit vaccines for brucellosis show great promise for their application in livestock and humans. This review summarizes the progress of brucellosis vaccine development and presents an overview of candidate vaccines. PMID- 23730313 TI - The role of torovirus in nosocomial viral gastroenteritis at a large tertiary pediatric centre. AB - OBJECTIVE: To describe the viral etiology and epidemiology of nosocomial viral gastroenteritis (NVG) at a tertiary care pediatric hospital and identify any changes over the past two decades. METHODS: Retrospective review of all patients with laboratory-confirmed NVG at The Hospital for Sick Children (Toronto, Ontario), from January 1, 2004, to December 31, 2005. RESULTS: One hundred forty two episodes of NVG were found among 133 patients, occurring in 0.48 of 100 admissions. The median age was two years; 42% were <1 year of age and 41% were immunocompromised. The most commonly detected pathogen was torovirus (67% of episodes), followed by rotavirus (19%) and adenovirus (9%). Seventy-five cases (53%) were epidemiologically linked in 32 separate clusters (median cluster size two, range two to four). The NVG rate fell from 0.63 of 100 to 0.22 of 100 admissions after March 2005 (P<0.001) when enhanced infection control precautions were instituted in response to an outbreak of vancomycin-resistant Enterococcus. CONCLUSIONS: Torovirus remains the most commonly identified cause of NVG at The Hospital for Sick Children. Most NVG cases were epidemiologically linked, and a significant reduction in cases occurred after the institution of enhanced infection control practices following an outbreak of vancomycin-resistant Enterococcus. Improved education and surveillance for NVG should lead to further reduction in this problem. PMID- 23730314 TI - Control of Clostridium difficile-associated diarrhea by antibiotic stewardship in a small community hospital. PMID- 23730315 TI - Antimicrobial-resistant Escherichia coli in public beach waters in Quebec. AB - INTRODUCTION: Human exposure to antimicrobial-resistant bacteria may result in the transfer of resistance to commensal or pathogenic microbes present in the gastrointestinal tract, which may lead to severe health consequences and difficulties in treatment of future bacterial infections. It was hypothesized that the recreational waters from beaches represent a source of antimicrobial resistant Escherichia coli for people engaging in water activities. OBJECTIVE: To describe the occurrence of antimicrobial-resistant E coli in the recreational waters of beaches in southern Quebec. METHODS: Sampling occurred over two summers; in 2004, 674 water samples were taken from 201 beaches, and in 2005, 628 water samples were taken from 177 beaches. The minimum inhibitory concentrations of the antimicrobial-resistant E coli isolates against a panel of 16 antimicrobials were determined using microbroth dilution. RESULTS: For 2004 and 2005, respectively, 28% and 38% of beaches sampled had at least one water sample contaminated by E coli resistant to one or more antimicrobials, and more than 10% of the resistant isolates were resistant to at least one antimicrobial of clinical importance for human medicine. The three antimicrobials with the highest frequency of resistance were tetracycline, ampicillin and sulfamethoxazole. DISCUSSION: The recreational waters of these beaches represent a potential source of antimicrobial-resistant bacteria for people engaging in water activities. Investigations relating the significance of these findings to public health should be pursued. PMID- 23730316 TI - Supra-additive expression of interleukin-6, interleukin-8 and basic fibroblast growth factor in vascular smooth muscle cells following coinfection with Chlamydia pneumoniae and cytomegalovirus as a novel link between infection and atherosclerosis. AB - BACKGROUND: Chlamydia pneumoniae and human cytomegalovirus (HCMV) may be involved in the pathogenesis of atherosclerosis. Prospective studies indicate an increased risk for cardiovascular events in patients with evidence of multiple infections. OBJECTIVE: To determine whether there is a synergistic effect of coinfection with C pneumoniae and HCMV on expression of selected growth factors and cytokines. METHODS: The production of interleukin (IL)-6, IL-8, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and 'regulated on activation normal T-cell expressed and secreted' (RANTES) was measured in coinfected aortic smooth muscle cells (AoSMC). RESULTS: Using reverse transcription polymerase chain reaction and immunoassays, it was demonstrated that the expression of IL-6, IL-8, RANTES and bFGF was stimulated in a dose- and time-dependent fashion in C pneumoniae and also in HCMV-infected cultures. In contrast, the expression of PDGF-AA was only stimulated following HCMV infection. Coinfection with C pneumoniae and HCMV resulted in a supra-additive stimulation of IL-6 (30% increased expression, P<=0.05) at 48 h, IL-8 (137% increased expression, P<=0.001) at 24 h and bFGF (209% increased expression, P<=0.01) at 48 h following infection. CONCLUSIONS: The findings of the present study show that C pneumoniae and HCMV are able to act in synergy in coinfected AoSMC. The supra additive induction of AoSMC growth factors and cytokines indicates a novel molecular link between infection and vascular disease development. PMID- 23730317 TI - Prion disease risk perception in Canadian medical laboratories. AB - BACKGROUND: There are no national guidelines specific for handling prion associated specimens in Canadian medical laboratories. Medical laboratory workers may perceive themselves at risk of prion transmission and, on occasion, decline to process such specimens. OBJECTIVE: To examine the knowledge, attitudes and reported behaviours of medical laboratory workers in relation to prion disease to understand their risk perception and the need for national laboratory guidelines on prion infection control. DESIGN: Survey development and cross-sectional web based administration. METHODS: The survey was developed through key informant interviews and a modified Delphi process. Medical laboratory workers across Canada were invited by laboratory managers and national organizations to complete the web-based survey. RESULTS: Twelve key informant interviews were performed. Consensus for questionnaire content was reached through two rounds of the Delphi process. Responses were received from 426 Canadian medical laboratory workers; 37% of medical laboratory staff reported processing prion-associated specimens. Different protocols for specimen processing were followed, and 18% believed they were at risk when processing these specimens. Less than one-third of those receiving specimens believed they were adequately trained. The mean (+/-SD) knowledge score was 9.25+/-4.5/24; individuals who had received training scored significantly higher than those who were untrained (P<0.01). Eighty-one per cent of respondents would be more comfortable processing specimens if national guidelines existed and were used in their laboratory. CONCLUSION: There is a high perception of risk and few perceived benefits of processing prion-associated specimens. National guidelines for prion infection control in medical laboratories and adequate training would enable medical laboratory workers to process these specimens efficiently and confidently. PMID- 23730318 TI - The changing demographics of women living with HIV/AIDS in southern Alberta from 1982 to 2006. AB - INTRODUCTION: Women account for a growing proportion of HIV infections in Canada. This has implications with respect to prevention, diagnosis and treatment. OBJECTIVE: To describe the female population presenting for HIV care in southern Alberta and to examine the impact of opt-out pregnancy screening. METHODS: A retrospective review of demographic and clinical characteristics of all patients presenting to the Southern Alberta HIV Clinic (SAC) care program from 1982 to 2006, was performed. RESULTS: The proportion of newly diagnosed patients who were female increased from 7.5% before 1998 to 21.5% after 1998. Women were more likely to be from vulnerable populations, such as intravenous drug users (31.3% versus 13.7%, P<0.001), aboriginals/Metis (21.5% versus 8.7%, P<0.001), blacks (28.9% versus 4.9%, P<0.001) and immigrants (36.6% versus 14.7%, P<0.001). Heterosexual intercourse was the main risk factor for HIV acquisition (43.7%). Women were less likely than men to have requested HIV testing (20.9% versus 37.8%, P<0.001). Opt-out pregnancy screening accounted for 12.7% of HIV-positive tests in women, following its introduction in 1998. Of the women diagnosed by pregnancy screening, 62.1% were from HIV-endemic countries. There was an association between reason for testing and CD4 count at presentation; women who requested their HIV test had higher median CD4 counts than those diagnosed because of illness (478 cells/mL, interquartile range [IQR]=370 cells/mL versus 174 cells/mL, IQR=328 cells/mL, P<0.001) or pregnancy screening (478 cells/mL, IQR=370 cells/mL versus 271 cells/mL, IQR=256 cells/mL, P=0.001). CONCLUSIONS: Women were less likely than men to have requested HIV testing and were more likely to be diagnosed by population-based screening methods. Women, especially vulnerable groups, account for a growing number and proportion of newly diagnosed HIV infections in Alberta. The implications of expanded screening in this population merit further consideration. PMID- 23730319 TI - Enterocolic fistula: A rare presentation of cytomegalovirus infection. AB - In the present report, the first reported case of cytomegalovirus (CMV) associated enterocolic fistula in an HIV/AIDS patient is described. CMV colitis is the second most common presentation of CMV infection in immunocompromised patients. CMV-associated enteric fistulae are an exceedingly rare complication, with only four previous cases described: a gastrocolic, an enterocutaneous, a rectovaginal and a colocutaneous fistula. Management of these patient demonstrates the importance of treating the precipitating viral infection before considering surgical intervention of the enterocolic fistula. PMID- 23730320 TI - Successful use of posaconazole to treat invasive cutaneous fungal infection in a liver transplant patient on sirolimus. AB - Fungi are an important and common cause of cutaneous infections affecting solid organ transplant recipients. These infections can represent a primary site of infection with the potential for dissemination, or a manifestation of metastatic infection. The high morbidity and mortality associated with these infections necessitates urgent therapy with antifungal drugs; however, the interaction between these drugs and immunosuppressive therapies can be a major limitation because of drug toxicity. A case of soft tissue infection of the toe caused by Fusarium chlamydosporum and Candida guilliermondii in a liver transplant patient on sirolimus, who was successfully treated with the new antifungal agent posaconazole, is described. The pharmacokinetic interactions of sirolimus and the new triazoles, and their impact on treatment choices are briefly discussed. PMID- 23730321 TI - Daptomycin-nonsusceptible, vancomycin-intermediate, methicillin-resistant Staphylococcus aureus endocarditis. AB - Due to the emergence of Staphylococcus aureus with reduced vancomycin susceptibility, newer antibiotics, including daptomycin, have been used to treat methicillin-resistant S aureus infections. Daptomycin is a cyclic lipopeptide that is approved to treat S aureus bacteremia and right-sided endocarditis, and reports of S aureus with reduced susceptibility to daptomycin are infrequent. To our knowledge, the present report describes the first Canadian case of daptomycin nonsusceptible, vancomycin-intermediate S aureus infection. PMID- 23730323 TI - Contrasting causal pathways contribute to poorer health and nutrition outcomes in orphans in Zimbabwe. AB - Orphaned children have been found to be at greater risk of poor health and malnutrition compared to non-orphans in sub-Saharan African countries. However, levels of disadvantage vary by location and little is known about the causal pathways that lead from orphanhood to poorer health and malnutrition. Aggregate data from recent Demographic and Health Surveys in 22 countries were used to compare overall levels of ill-health and malnutrition by orphan status. Data from the Manicaland Child Cohort Study in Zimbabwe - a closed cohort study with detailed longitudinal information on orphan's experience - were used to describe how patterns of ill-health and malnutrition alter over the child's life-course and to test causal pathways between orphanhood and ill-health and malnutrition, hypothesized in a previously published theoretical frame-work. Modest increases in ill-health and malnutrition were found in orphans in the Demographic and Health Surveys data, with maternal and double orphans being worst affected. Non significant associations were found between orphanhood and ill-health in the Manicaland Child Cohort Study data, but no associations with malnutrition were found. None the less, smaller increases in body mass index with age were seen among orphans (ologit test for difference: adjusted odds ratio = 0.68; p = 0.07) and maternal orphans (ologit test for difference: adjusted odds ratio = 0.67; p = 0.03) than among non-orphans. Stigma and discrimination contributed to poor diet, malnutrition and ill-health in children whose mothers had died, while heightened poverty was a more important factor for paternal orphans. These results suggest social and psychological support for orphans and their families could be as important as material support in preventing malnutrition and ill-health. PMID- 23730322 TI - Using Drosophila as a tool to identify Pharmacological Therapies for Fragile X Syndrome. AB - Despite obvious differences such as the ability to fly, the fruit fly Drosophila melanogaster is similar to humans at many different levels of complexity. Studies of development, cell growth and division, metabolism, and even cognition, have borne out these similarities. For example, Drosophila bearing mutations in the fly gene homologue of the known human disease Fragile X, are affected in fundamentally similar ways as affected humans. The ramification of this degree of similarity is that Drosophila, as a model organism, is a rich resource for learning about human cells, development and even human cognition and behavior. Drosophila has a short generation time of ten days, is cheap to propagate and maintain and has a vast array of genetic tools available to it; making Drosophila an extremely attractive organism for the study of human disease. Here, we summarize research from our lab and others using Drosophila to understand the human neurological disease, called Fragile X. We focus on the Drosophila model of fragile X, its characterization, and use as a tool to identify potential drugs for the treatment of Fragile X. Several clinical trials are in progress now that were motivated by this research. PMID- 23730325 TI - Is there a role for ubiquitin or SUMO in human T-cell leukemia virus type 2 Tax induced NF-kappaB activation? AB - It is well established that the human T-cell leukemia virus type 1-encoded oncoprotein Tax (Tax1) undergoes polyubiquitination as part of its mechanism to persistently activate NF-kappaB. However, it remains unclear whether Tax2 encoded by the closely related human T-cell leukemia virus type 2 utilizes any post translational mechanisms to activate NF-kappaB. This study examines the role of ubiquitination and SUMOylation in Tax2 activation of NF-kappaB. The authors have demonstrated that, in contrast to Tax1, Tax2 is not conjugated by ubiquitin or SUMO proteins. Overexpression of the E2 ubiquitin-conjugating enzyme Ubc13 specifically enhances Tax1, but not Tax2, ubiquitination and NF-kappaB activation. Furthermore, a Tax2 lysineless mutant that is unable to be ubiquitinated, SUMOylated or acetylated retains NEMO/IKKgamma interactions and activation of the NF-kappaB pathway. Together, these results provide evidence that Tax1 and Tax2 utilize distinct mechanisms to activate NF-kappaB. PMID- 23730326 TI - Concealable Stigmatized Identities and Psychological Well-Being. AB - Many people have concealable stigmatized identities: Identities that can be hidden from others and that are socially devalued and negatively stereotyped. Understanding how these concealable stigmatized identities affect psychological well-being is critical. We present our model of the components of concealable stigmatized identities including valenced content - internalized stigma, experienced discrimination, anticipated stigma, disclosure reactions, and counter stereotypic/positive information - and magnitude - centrality and salience. Research has shown that negatively valenced content is related to increased psychological distress. However, smaller identity magnitude may buffer this distress. We review the research available and discuss important areas for future work. PMID- 23730327 TI - Enhancing the mental health promotion component of a health and personal development programme in Irish schools. AB - This study set out to examine the impact of a health and personal development programme (the Social, Personal and Health Education Programme) which had been 'enhanced' by the addition of a mental health promotion component. Students aged 12-16 years attending 17 secondary schools were randomly allocated as clusters to participate in either the standard programme (SP) or the enhanced programme (EP). Both programmes were delivered over an eight-month period. Questionnaires assessing help-seeking, emotional and behavioural difficulties and students' views of school social environment were completed by students in both groups at pre-intervention, post-intervention and at six-month follow-up. One thousand and seventy-two students participated. Analyses were carried out on the 782 students (72.9%) for whom data were available at all three time points. Both groups showed improvement over time in terms of emotional and behavioural difficulties, with male students identified as 'at risk' in the EP showing significantly greater improvements than males 'at risk' in the SP. Although there were few differences in outcomes between the groups, males identified as 'at risk' appeared to benefit selectively from the EP. PMID- 23730328 TI - Endoscopic spray cryotherapy for genitourinary malignancies: safety and efficacy in a porcine model. AB - OBJECTIVE: To examine the effects and safety of using endoscopic spray cryotherapy (ESC) on bladder, ureteral, and renal pelvis urothelium in a live porcine model. SUBJECTS AND METHODS: ESC treatments were systematically applied to urothelial sites in the bladder, ureter, and renal pelvis of eight female Yorkshire swine in a prospective trial. Freeze-thaw cycles ranged from 5 to 60 s/cycle for one to six cycles using a 7 French cryotherapy catheter. Tissue was evaluated histologically for treatment-related effects. Acute physiologic effects were evaluated with pulse oximetry, Doppler sonography, and postmortem findings. RESULTS: In bladder, treatment depth was inconsistent regardless of dose, demonstrating urothelial necrosis in one, muscularis propria depth necrosis in two, and full thickness necrosis in all remaining samples. In ureter, full thickness necrosis was seen in all samples, even with the shortest spray duration (5 s/cycle for six cycles or 30 s/cycle for one cycle). Treatment to the renal pelvis was complicated by adiabatic gas expansion of liquid nitrogen to its gaseous state, resulting in high intraluminal pressures requiring venting to avoid organ perforation, even at the lowest treatment settings. At a planned dose of 5 s/cycle for six cycles of the first renal pelvis animal, treatment was interrupted by sudden and unrecoverable cardiopulmonary failure after three cycles. Repeated studies replicated this event. Ultrasound and immediate necropsy confirmed the creation of a large gaseous embolism and reproducible cardiopulmonary effects. CONCLUSION: ESC in a porcine urothelial treatment model results in full-thickness tissue necrosis in bladder, ureter, and renal pelvis at a minimal treatment settings of 5 s/cycle for six cycles. Adiabatic gas expansion may result in fatal pyelovenous gas embolism and collateral organ injury, as seen in both animals receiving treatment to the renal pelvis in this study. These results raise safety concerns for use of ESC as a treatment modality in urothelial tissues with current device settings. PMID- 23730329 TI - Best practice in the diagnosis and management of urogenital tuberculosis. AB - Tuberculosis (TB) is a current public health problem, remaining the most common worldwide cause of mortality from infectious diseases. Urogenital tuberculosis (UGTB) is the second most common form of extrapulmonary TB in countries with severe epidemic situations and the third most common form in regions with a low incidence of TB. In this article we present the terminology, epidemiology and classification of UGTB, as well as describing the laboratory findings and clinical features and approaches to chemotherapy as well as surgery. PMID- 23730330 TI - Primary Ewing sarcoma of the kidney: a symptomatic presentation and review of the literature. AB - The objective of this review is to discuss the unique nature of primary renal Ewing sarcoma, including incidence, presentation and management. We also report on a common pattern of presentation, consisting of acute flank pain mimicking a renal stone colic, with or without hydronephrosis, and a renal mass discovered during imaging studies of renal Ewing sarcoma. We present our case of renal Ewing sarcoma along with imaging and pathological analysis. We also performed a retrospective review of all cases of renal Ewing sarcoma using PubMed. A total of 48 cases of renal EWS sarcoma have been reported and analyzed in this review. A mean age of 30.4 years was found along with a 61% male predominance. The mean survival was 26.14 months with a lower median survival in patients with advanced metastatic disease. Primary Ewing sarcoma of the kidney is rare. The diagnosis of primary renal EWS can be difficult and is based on a combination of electron microscopy, immunohistochemistry, chromosomal analysis, fluorescence in situ hybridization (FISH) and light microscopy. PMID- 23730331 TI - Primary prevention and vaccination for penile cancer. AB - The outcome of penile cancer is proportional to the stage at presentation. Strategies aimed at primary prevention would have a clear advantage, both for the individual and in terms of health economics. A number of preventative measures could be employed, including circumcision, smoking cessation, education on hygiene and human papillomavirus (HPV) prevention. There is a high prevalence of HPV infection associated with penile cancer worldwide. The recent development of HPV vaccines has facilitated interest in their use for the prevention of penile cancer. In this article we review the literature surrounding penile cancer prevention and HPV vaccination in men. PMID- 23730332 TI - Collaboration between general practitioners (GPs) and mental healthcare professionals within the context of reforms in Quebec. AB - Background In the context of the high prevalence and impact of mental disorders worldwide, and less than optimal utilisation of services and adequacy of care, strengthening primary mental healthcare should be a leading priority. This article assesses the state of collaboration among general practitioners (GPs), psychiatrists and psychosocial mental healthcare professionals, factors that enable and hinder shared care, and GPs' perceptions of best practices in the management of mental disorders. A collaboration model is also developed. Methods The study employs a mixed-method approach, with emphasis on qualitative investigation. Drawing from a previous survey representative of the Quebec GP population, 60 GPs were selected for further investigation. Results Globally, GPs managed mental healthcare patients in solo practice in parallel or sequential follow-up with mental healthcare professionals. GPs cited psychologists and psychiatrists as their main partners. Numerous hindering factors associated with shared care were found: lack of resources (either professionals or services); long waiting times; lack of training, time and incentives for collaboration; and inappropriate GP payment modes. The ideal practice model includes GPs working in multidisciplinary group practice in their own settings. GPs recommended expanding psychosocial services and shared care to increase overall access and quality of care for these patients. Conclusion As increasing attention is devoted worldwide to the development of optimal integrated primary care, this article contributes to the discussion on mental healthcare service planning. A culture of collaboration has to be encouraged as comprehensive services and continuity of care are key recovery factors of patients with mental disorders. PMID- 23730333 TI - Evaluation of collaborative models of care in the management of patients with depression: protocol and progress. AB - Introduction Depression is highly prevalent and has a considerable impact on the quality of life of affected individuals, and on healthcare resources. Evidence indicates that collaborative care models can improve patient outcomes within a primary care setting. The Primary Care Services Improvement Project (PCSIP) aims to investigate the costs and outcomes of different models of care for the management of patients with depression. These models have been defined based on the level of involvement of practice nurses in management processes within the primary care setting in Australia. This paper describes our study protocol and its progress. Methods PCSIP is an observational study that will link retrospective data from a range of sources to estimate costs and intermediate outcomes (such as relapse rate) over a 3-year time horizon. The main sources of primary data include the medical records of patients held at participating practices and Medicare Australia. Initial report We recruited 15 practices from a metropolitan area and allocated them to three models of care. Two hundred and sixty-one patients agreed to participate. Appropriate regression-based analyses will be used to evaluate the association between different models of care and patient-level outcomes while controlling for several covariates such as age and gender. Discussion/conclusions This project will generate the knowledge required to promote investment in the most cost-effective initiatives, and to ensure that waste of resources due to the implementation of comparatively inefficient interventions is minimised. Given the scarcity of resources, the increasing costs of providing healthcare and the increasing prevalence of chronic diseases, such research is essential. PMID- 23730334 TI - Depression remission after six months of collaborative care management: role of initial severity of depression in outcome. AB - Aim The impact of initial severity of depression on the rate of remission has not been well studied. The hypothesis for this study was that increased depression severity would have an inverse relationship on clinical remission at six months while in collaborative care management. Participants The study cohort was 1128 primary care patients from a south-eastern Minnesota practice and was a longitudinal retrospective chart review analysis. Results Clinical remission at six months was less likely in the severe depression group at 29.6% compared with 36.9% in the moderately severe group and 45.6% in the moderate depression group (P < 0.001). Multivariate analysis of a sub-group demonstrated that increased initial anxiety symptoms (odds ratio [OR] 0.9645, 95% confidence interval [CI] 0.9345-0.9954, P = 0.0248) and an abnormal screening for bipolar disorder (OR 0.4856, 95% CI 0.2659-0.8868, P = 0.0187) predicted not achieving remission at six months. A patient with severe depression was significantly less likely to achieve remission at six months (OR 0.6040, 95% CI 0.3803-0.9592, P = 0.0327) compared with moderate depression, but not moderately severe depression (P = 0.2324). There was no statistical difference in the adjusted means of the PHQ-9 score for those patients who were in remission at six months. However, in the unremitted patients, the six-month PHQ-9 score was significantly increased by initial depression severity when controlling for all other variables. Conclusion Multivariate analysis in our study demonstrated that patients with severe depression have a decreased OR for remission at six months compared with moderate depression. Also, there was a significant increase in the six-month PHQ-9 score for those unremitted patients in the severe vs. moderate depression groups. PMID- 23730335 TI - Longitudinal association of intimate partner violence and depressive symptoms. AB - Purpose The association between intimate partner violence (IPV) and depression has been well established in cross-sectional research, but how IPV is associated with depressive symptoms over time has not been well studied. Methods Using the Central Pennsylvania Women's Health Study, a population-based longitudinal survey of women aged 18-45 (N = 1,420), we performed a two-step logistic regression analysis. In step 1, the association of recent IPV exposure at baseline with depressive symptoms 2 years later was analysed adjusting for relevant covariates; in step 2, we additionally included positive coping strategies (social support, physical activity) and negative coping strategies (binge drinking/drug use, smoking) in the model. Results Baseline IPV was reported by 4.6 percent of the sample and was independently associated with depressive symptoms 2 years later (adjusted or 1.88, 95% confidence interval [CI] 1.02-3.45). The strongest predictor was depressive symptoms at baseline, which was associated with a fivefold increase in the likelihood of depressive symptoms at 2-year follow-up. Other predictors of future depressive symptoms were IPV at follow-up, older age, lower educational attainment, and lower household income. When we controlled for potential coping strategies in the model (step 2), the relationship between recent IPV and follow-up depressive symptoms was attenuated (adjusted OR 1.50, 95% CI 0.80-2.80). Conclusions Exposure to IPV increases the likelihood of depressive symptoms occurring two years later. Greater social support and binge drinking/drug use attenuates this association, suggesting that interventions focusing on coping mechanisms may serve to reduce the impact of IPV on future depression. PMID- 23730336 TI - 'Can he have the test for bipolar, doctor? His dad's got it': exploring the potential of general practitioners to work with children and young people presenting in primary care with common mental health problems - a clinical initiative. AB - Background General practitioners (GPs) play a key role in assessing and managing adult mental health problems, but this input is not seen in their management of child and adolescent mental health. Mental health problems in 5-19-year-olds are common, yet detection rates in primary care are low. The symptoms of most adult diagnoses of mental health problems are present by mid-adolescence, yet the typical time from onset to diagnosis is 5-15 years. The role of general practice in this area has been underexplored. Aim This pilot study explores the potential of GPs to respond to common mental health problems in children and adolescents. Design Children and young people who would have ordinarily been referred to Child and Adolescent Mental Health Services (CAMHS) were seen in a GP setting. In a UK general practice surgery serving a disadvantaged population. Method Children and young people were seen for an initial biopsychosocial assessment and formulation of the presenting concerns. GP-based interventions were offered as appropriate or referred to CAMHS. Results Data from the first 50 children (2-19 years) are presented. Twenty younger children (10 years and under) and 30 older children (11 years and above) were seen. Eighteen referrals were made to CAMHS. GP interventions included watchful waiting, brief behavioural interventions, non directive counselling, brief cognitive- behavioural therapy (CBT) and liaison with colleagues in education, CAMHS and the voluntary sector. Conclusion This clinical pilot demonstrates that with adequate time, access to supervision and practice support, children and young people experiencing emotional and behavioural problems associated with common mental health issues can be helped in primary care. PMID- 23730337 TI - Standardised measures of needs, stigma and informal care in schizophrenia using a bottom-up, cross-cultural approach. AB - Background There is a lack of instruments to measure the needs, stigma and informal care of people with schizophrenia that take account of sociocultural variation and patients' and formal and informal carers' opinions and experiences. Aims To develop questionnaires to measure stigma, needs and informal (non professional) care for people with schizophrenia. Method We undertook the study in seven countries and in English, Spanish and Portuguese. We first held focus group discussions with patients, formal carers (professionals) and informal carers (family and friends) in Spain, the UK, Argentina, Brazil, Chile and Venezuela to elicit the main dimensions of needs, stigma and informal care. We then held nominal group discussions about these dimensions with patients, family members and professionals in Spain, Portugal and the UK, to develop the instruments. Results Three hundred and three people participated in 46 focus groups and results were discussed in three nominal groups, each involving eight participants. Three instruments were developed in this iterative process: needs for care (46 items), stigma (38 items) and informal care (20 items). Conclusions These instruments are based on service users' and carers' views and experiences and have cross-cultural validity. They will have application in assessment of outcomes for people with schizophrenia and their families. PMID- 23730338 TI - Community Involvement among Residents of Second-Order Change Recovery Homes. AB - The present study investigated the process of second-order change among a group of individuals recovering from substance abuse problems. Data were collected from 56 individuals who were current or past members of Oxford Houses, which are democratically operated recovery homes that have no professional staff and where there is no limit on length of stay. We collected data on individual and house demographics, per week involvement in the community, house involvement in the community, and types of community involvement while residing in the Oxford House. Findings reveal a significant positive relationship between the length of time living in an Oxford House and level of participant involvement in the community. Participants reported multiple factors that increased their community involvement and reported the type of impact that their involvement had on their neighborhoods. Findings from the present study indicate that not only do residents help themselves stay abstinent by living in the Oxford Houses, but residents report that they also make important contributions to their neighborhoods and communities. PMID- 23730340 TI - Alternative technique for open reduction and fixation of displaced pediatric medial epicondyle fractures. AB - PURPOSE: To describe an alternative positioning technique for the fixation of pediatric medial epicondyle fractures which offers some significant advantages over traditional supine positioning. METHODS: At our institution, 27 patients with a displaced medial epicondyle fracture requiring open reduction and fixation were positioned prone for the procedure. The internally rotated operative arm lies on the hand table with the elbow in a natural flexed, pronated position. The elbow can be brought into extension and flexion for appropriate intraoperative radiographs. The fracture is then reduced with the arm in flexion and pronation, without having to pull excessively on the fragment. After reduction, the fragment is held easily in place for surgical fixation. A similar group of patients from the same time period positioned supine was also examined and compared to the patients who had the surgery prone. RESULTS: The average age of the 27 patients was 11.2 years (range 5.1-16.9 years). Indications for operative treatment were displaced medial epicondyle fracture (14), medial epicondyle fracture with associated elbow dislocation (12), and medial epicondyle fracture with ulnar nerve symptoms (1). At a mean of 4.5 months of follow up (1-11 months), 7 patients required the removal of hardware for screw irritation. There were no infections in the 27 surgeries and there were no other intraoperative or postoperative complications. Mild loss of flexion and extension was common in the group. Patients who had surgery in the supine position were similar with regards to patient demographics and postoperative complications, including the need for screw removal. CONCLUSIONS: While displaced medial epicondyle fractures can be treated successfully with traditional positioning, placing patients prone for the fixation of pediatric medial epicondyle fractures offers some significant advantages over supine positioning. PMID- 23730341 TI - Open reduction of proximal humerus fractures in the adolescent population. AB - PURPOSE: Proximal humerus fractures in the pediatric population are a relatively uncommon injury, with the majority of injuries treated in a closed fashion due to the tremendous remodeling potential of the proximal humerus in the skeletally immature. Yet, in adolescent patients, open treatment is, at times, necessary due to unsatisfactory alignment following a closed reduction, loss of previously achieved closed reduction, and limited remodeling when close to skeletal maturity. The purpose of our study was to examine the open reduction of adolescent proximal humerus fractures. METHODS: A retrospective review of the outcomes of proximal humerus fractures in the adolescent population which were consecutively treated at our institution with open reduction was performed. RESULTS: Ten children met the inclusion criteria, with a mean age of 14.3 years (+/-1.3) and a mean weight of 60.7 kg (+/-14.9) at the time of injury. There were seven Salter-Harris 2 fractures and three Salter-Harris 1 fractures. The largest mean angulation was 55.0 degrees (+/-33.9) and the largest mean displacement was 87.0 % (+/-22.8). Intra-operatively, impediments to closed reduction within the fracture site which were found included: periosteum (90.0 %), biceps tendon (90.0 %), deltoid muscle (70.0 %), and comminuted bone (10.0 %). K-wire fixation was most commonly used (70.0 %), followed by flexible nails (20.0 %) and cannulated screws (10.0 %) for fixation. All patients achieved radiographic union at a mean of 4.0 weeks (+/-0.7), had non-painful full shoulder range of motion and rotator cuff strength at final follow-up (mean 7.7 +/- 4.6 months), and returned to pre injury sporting activities. CONCLUSIONS: The operative treatment of proximal humerus fracture, particularly in adolescents with severe displacement/angulation having failed closed methods of treatment, is increasingly considered to be an acceptable modality of treatment. In addition to the long head of the biceps, periosteum, deltoid muscle, and bone fragments in combination can prevent fracture reduction. Surgeon preference and skill should dictate implant choice, and the risk of physeal damage utilizing these implants in this age group is low. PMID- 23730339 TI - Current concepts of leg lengthening. AB - Any lower limb discrepancy may be equalised by conservative means (insoles, prosthesis and orthosis). However, their long-term acceptance is low in regard to function, costs, expenditure and appearance. Timely epiphysiodesis is the best option in uniplanar deformities with adequate remaining growth and for patients whose predicted final body height is above the 50th percentile. However, many patients present late or with multi-planar deformities, which warrant more sophisticated operative approaches. The history of surgical bone lengthening comprises 100 exciting years of struggling, development and ongoing learning. The initial strategy of acute or rapid incremental distraction had lasted almost half a century until Ilizarov recognised the benefits of biological periosteum preserving osteotomies and incremental lengthening at slow rates (1 mm/day) at a 4 * 0.25-mm daily rhythm, well appreciated as callotasis. In parallel, ring and wire constructs made complex three-dimensional axial, translational and rotational bone moulding possible. Taylor Spatial Frames-built on hexapod strut linked platform technology as known from flight simulators-took limb correction to a more reliable, more precise and aesthetical level, all the more that the whole process became web-based. It represents state-of-the-art methodology and technology for complex, multi-plane deformities. Due to the significant risk of secondary malalignment, indications for lengthening by unilateral fixation have shrunken to moderate amounts of length disparity and uni- to bi-planar deformities in patients with still open physes. Mechanical or motorised, minimally invasively placed nails prevent muscle fixation and, therefore, ease rehabilitation, increase patient comfort and potentially shorten the overall time of sick leave and refrain from sports activities. Hence, they offer a valuable alternative for low-grade complexity situations. It remains to be proved if the significantly higher implant costs are compensated by lower treatment costs. Overall, limb lengthening, particularly in combination with multi-planar deformity correction, can still be an arduous endeavour. In any case, wise judgement of the patient's deformity, medical and biological situation, psychosocial environment, selection of the appropriate method and hardware, as well as meticulous operating technique by an experienced surgeon are the cornerstones of successful outcomes. PMID- 23730342 TI - Flexible intramedullary nailing for distal femoral fractures in patients with myopathies. AB - PURPOSE: Distal femoral fractures are quite common in nonambulating patients with myopathies, as they present marked osteoporosis. The deterioration of preexisting knee flexion contracture is a known problem, as these fractures are usually angulated posteriorly. The goals of treatment are to reduce immobilization and bed rest to a minimum, prevent function loss, and prevent refracture. The aim of our work was to investigate if these goals can be achieved by an operative treatment with closed reduction and flexible intramedullary nailing (FIN). METHODS: Six distal femoral fractures in four nonambulating patients with myopathies (three Duchenne muscular dystrophy and one nemaline myopathy) were treated with FIN between 2005 and 2011. Patient charts and radiographs were reviewed to determine if intra- or postoperative complications occurred and to detect the interval to wheelchair mobilization and hospital discharge. Pre- and postoperative knee flexion contracture was noted from the patient charts of our reeducation unit, where patients were already known preoperatively. RESULTS: Wheelchair mobilization without further immobilization after an interval of 2-3 days was possible. No aggravation of knee flexion contracture was detected in our patient series. No complications associated to the operative treatment itself and no refractures in the follow up occurred. CONCLUSION: Our experience showed that FIN is a low invasive and sufficiently stable osteosynthesis in such fractures. Left in place, nails will reinforce mechanical stability. PMID- 23730343 TI - Childhood metatarsal shaft fractures: treatment outcomes and relative indications for surgical intervention. AB - PURPOSE: Although the epidemiology of childhood metatarsal fractures is known, the appropriate treatment has not been elucidated. This study was undertaken to ascertain the outcomes of both non-operative and surgical treatment of these common childhood injuries and to discern any indications for treatment. METHODS: A retrospective review was performed of all children identified from 2006 to 2007 with a metatarsal fracture by the ICD-9 code, 825.25. After dividing the cohort into groups by age in years (0-5, 6-10, 11-15, 16 and older), we collected demographics, mechanism of injury, and associated injuries, as well as clinical information concerning metatarsal involvement, treatment, complications, return to activities/sports, and residual pain. Radiographic information was also collected, including fracture location, displacement, comminution, and union. RESULTS: We identified 337 children that met the criteria. The mean age was 10.5 years (range 1.8-20.6). Only ten children had surgery. Only age, multiplicity of metatarsal fracture, and fracture translation was statistically different between the non-surgical and surgical cohorts. None of the patients under the age of 12 years underwent surgical intervention (p = 0.005). Evidence of multiple metatarsal fractures was seen in only 28 % of the non-surgical group compared to 70 % of the surgical group (p = 0.009). The amount of fragment translation significantly correlated with a decision for surgery (p = 0.001), but not angulation. Logistic regression demonstrated that, for every year of age, the likelihood for surgery increased by 32 % and that children were 6.6 times more likely to have surgery if they had multiple metatarsal fractures. Complete union was achieved in 84.6 %, with no difference in treatment groups regarding the time of release to full activities, and of the 50 delayed unions, only two required subsequent operative interventions. Return to sports took longer in the operative group, with a mean of 4.0 compared to 2.1 months (p < 0.001). Only 14 children complained of residual post-treatment pain and all of those cases had been treated without surgery. The presence of post-treatment pain did not correlate with the mechanism of injury or the amount of displacement. CONCLUSION: Each metatarsal injury pattern is unique and surgeons should utilize their clinical judgment to determine appropriate treatment; however, there appears to be some relative indications for surgical treatment. Whereas open and articular fractures may be absolute indications for surgery, the relative indications for surgical intervention in metatarsal shaft fractures appear to be adolescent age and multiple fractures. Successful non-surgical management may consist of a short-leg walking cast for a mean of 4 weeks and activity restrictions for an additional month. However, children should be followed to radiographic union, since 15.4 % may have a delayed union and 4.3 % have short-term residual problems related to the injury. PMID- 23730344 TI - Posterior spinal fusion in patients with Ehlers-Danlos syndrome: a report of six cases. AB - PURPOSE: There is a paucity of literature describing posterior spinal fusion (PSF) in the Ehlers-Danlos syndrome (EDS) patient. The vast majority of these studies diagnosed EDS clinically. The purpose of this study is to discuss the management and complications of EDS patients with scoliosis treated with PSF at a single institution. METHODS: Clinical and radiographic data are presented describing six patients who had PSF for EDS. The diagnoses were confirmed by a geneticist. RESULTS: All of the patients in the current cohort underwent posterior fusion only, with no anterior approach. Neuromonitoring was also used in the majority. Half of our patients experienced complications. One patient had a hemoperitoneum that was initially treated nonoperatively but, unfortunately, they expired 1 month after discharge from abdominal bleeding. Another patient suffered neuropathic pain attributed to the type of implant used. A third underwent a total of seven procedures beginning at the age of 3 years in a different era of spinal surgery. The mean major curve, percentage correction, and estimated blood loss of the current cohort are similar to previous studies. CONCLUSION: The fragility of the EDS patient population cannot be overlooked. Despite a conservative surgical approach, half of our patients experienced complications. The surgeon choosing to operate on EDS patients must do so with extreme caution. PMID- 23730345 TI - Screws versus hooks: implant cost and deformity correction in adolescent idiopathic scoliosis. AB - OBJECTIVE: To compare the costs of two spinal implants-hook and hybrid constructs and pedicle screw constructs-in posterior spinal fusion for adolescent idiopathic scoliosis (AIS) as they relate to intraoperative deformity correction. STUDY DESIGN AND METHOD: This retrospective study examined 50 patients with AIS who were treated with posterior spinal fusion using segmental hook-hybrid constructs (23) or pedicle screws (27). Radiographic parameters measured on immediate preoperative and initial standing postoperative scoliosis films were the coronal Cobb angles of the upper thoracic, middle thoracic, lumbar, and instrumented curves; global coronal and sagittal balance; thoracic kyphosis; lumbar lordosis; and type and number of implants used. Current implant cost data were obtained from three major spinal implant manufacturers to determine the total cost of the constructs, cost per degree of correction, cost per level fused, and cost per degree of correction of the major curve. RESULTS: After surgery, the average percentage of correction for the middle thoracic curve or major curve was 57 % in the hook-hybrid group compared to 73 % in the pedicle screw group (P < 0.001). The average amount of correction of the major curve was 31.1 degrees in the hook hybrid group compared to 42.7 degrees in the pedicle screw group (P < 0.001). The average number of fused levels was 10.7 in the hook-hybrid group compared to 12.2 in the pedicle screw group (P < 0.001). The average number of implants was 14.8 in the hook-hybrid group compared to 23.3 in the pedicle screw group (P < 0.001). The average total cost of implants was $11,248 in the hook-hybrid group compared to $22,826 in the pedicle screw group (P < 0.001), and the average cost per fused level was $1,058 in the hook-hybrid group compared to $1,878 in the pedicle screw group (P < 0.001). The average cost per degree of correction of the major curve was $415 in the hook-hybrid group compared to $559 in the pedicle screw group (P = 0.0014). The global coronal balance, global sagittal balance, thoracic kyphosis, and lumbar lordosis did not differ significantly between the two groups. CONCLUSION: Pedicle screw instrumentation was shown to be more expensive overall, per fused level, and per degree of correction. Also, more implants were used and more levels were fused in the pedicle screw group than in the hook-hybrid group. Pedicle screws showed a statistically significantly greater percentage of correction of the major curve. Physicians must evaluate each patient individually and determine if the increased percentage of correction warrants the increased cost for pedicle screw constructs. PMID- 23730346 TI - Unilateral varus osteotomy of the proximal femur in children with cerebral palsy: a five-year follow-up of the development of both hips. AB - BACKGROUND: Varus osteotomy of the proximal femur (VOPF) is one treatment option to prevent hip dislocation in children with cerebral palsy (CP). It is questioned whether the osteotomy should be performed in the displaced hip only, or if it should be performed bilaterally to prevent later displacement of the contralateral hip. CPUP is a register and healthcare programme for children with CP that was initiated in 1994 in southern Sweden. In the programme, range-of motion and radiographic examination of the hips is performed regularly. These data have been analysed preoperatively and for 5 years postoperatively in children treated with unilateral VOPF. METHODS: Children with CP living in the counties of Skane and Blekinge in the south of Sweden, who were treated with unilateral VOPF at least 5 years ago, were included in the study. The degree of hip displacement and the range of hip motion were analysed preoperatively and after 5 years. Repeat hip operations after the index operation were recorded. RESULTS: Twenty-four children fulfilled the inclusion criteria. Mean age at index operation was 7.6 (2.8-13.2) years. No child died within 5 years postoperatively, and no child was lost from follow-up. At follow-up after 5 years, 2 of the 24 children had been operated on with VOPF in the contralateral hip. The range of motion in both hips decreased, but the difference between the index hip and the contralateral hip did not change significantly. CONCLUSION: Children with CP and unilateral hip displacement have a low risk of later contralateral displacement after being operated on with unilateral VOPF. This supports healthcare programmes that advocate unilateral VOPF in children with unilateral hip displacement. PMID- 23730347 TI - Scarf osteotomy in the management of symptomatic adolescent hallux valgus. AB - PURPOSE: This study was designed to assess the utility of the scarf osteotomy in the management of symptomatic adolescent hallux valgus. MATERIALS AND METHODS: This is a case series of 29 patients (39 feet) with a mean follow up of 38.6 months (range 6-60 months). The mean age at the time of surgery was 14.1 years (range 10-17 years). American Orthopaedic Foot and Ankle Society (AOFAS) scores were collected at final follow up, along with a rating of the overall satisfaction. Any complications were recorded. Pre- and post-surgical radiographic angles were measured and analysed using the Student's t-test. The angles measured were the hallux valgus angle (HVA), the inter-metatarsal angle (IMA) and the distal metatarsal articular angle (DMAA). A second surgeon independently reviewed the angles in order to assess the inter-rater reliability using the Pearson product moment correlation. RESULTS: The mean AOFAS score at final follow up was 94.2 (range 54-100). Of all patients, 93 % were either satisfied or very satisfied with their final outcome. One patient has been listed for revision surgery after symptomatic recurrence at 3 years follow up. The pre operative HVA, IMA and DMAA were 34.8 degrees , 15.9 degrees and 16.0 degrees , respectively. The post-operative values were 16.3 degrees , 8.8 degrees and 9.2 degrees , respectively (p < 0.001 for each). Pearson's r coefficient values demonstrated good inter-rater reliability of measurement. CONCLUSION: We have presented the results of the largest case series of scarf osteotomies for adolescent hallux valgus reported in the literature up to now, as far as we are aware. AOFAS scores at final follow up are comparable to the smaller studies previously reported and provide evidence that good outcomes and high levels of patient satisfaction can be achieved. Early follow up demonstrates a low level of symptomatic recurrence, but longer term data are still required. PMID- 23730348 TI - Manipulation of 3D Cluster Size and Geometry by Release from 2D Micropatterns. AB - A novel method to control three-dimensional cell cluster size and geometry using two-dimensional patterning techniques is described. Cells were first cultured on two-dimensional micropatterned collagen using conventional soft lithography techniques. Collagenase was used to degrade the micropatterned collagen and release cells from the micropatterns, forming clusters of cells which were then resuspended in a three-dimensional collagen matrix. This method facilitated the formation of uniformly sized clusters within a single sample. By systematically varying the geometry of the two-dimensional micropatterned islands, final cluster size and cell number in three dimensions could be controlled. Using this technique, we showed that proliferation of cells within collagen gels depended on the size of clusters, suggesting an important role for multicellular structure on biological function. Furthermore, by utilizing more complex two-dimensional patterns, non-spherical structures could be produced. This technique demonstrates a simple way to exploit two-dimensional micro-patterning in order to create complex and structured multicellular clusters in a three-dimensional environment. PMID- 23730349 TI - On Estimation of Allele Frequencies via Next-Generation DNA Resequencing with Barcoding. AB - Next Generation Sequencing (NGS) has revolutionized biomedical research in recent years. It is now commonly used to identify rare variants through re-sequencing individual genomes. Due to the cost of NGS, researchers have considered pooling samples as a cost-effective alternative to individual sequencing. In this article, we consider the estimation of allele frequencies of rare variants through the NGS technologies with pooled DNA samples with or without barcodes. We consider three methods for estimating allele frequencies from such data, including raw sequencing counts, inferred genotypes, and expected minor allele counts and compare their performance. Our simulation results suggest that the estimator based on inferred genotypes overall performs better than or as well as the other two estimators. When the sequencing coverage is low, biases and MSEs can be sensitive to the choice of the prior probabilities of genotypes for the estimators based on inferred genotypes and expected minor allele counts so that more accurate specification of prior probabilities is critical to lower biases and MSEs. Our study shows that the optimal number of barcodes in a pool is relatively robust to the frequencies of rare variants at a specific coverage depth. We provide general guidelines on using DNA pooling with barcoding for the estimation of allele frequencies of rare variants. PMID- 23730350 TI - Acute and chronic vascular responses to experimental focal arterial stroke in the neonate rat. AB - The presence of active developmental angiogenesis and vascular outgrowth in the postnatal brain may differentially affect vascular responses to stroke in newborns and adults, but very little is known about the dynamics of vascular injury and re-growth after stroke during the neonatal period. In this study we used a clinically relevant animal model of ischemic arterial stroke in neonate rats, a transient middle cerebral artery occlusion (MCAO) in postnatal day 7 (P7), to characterize the effects of injury on vascular density and angiogenesis from acute through the chronic phase. A marked vessel degeneration and suppressed endothelial cell proliferation occur in the ischemic regions early after neonatal stroke. In contrast to what has been described in adult animals, endothelial cell proliferation and vascular density are not increased in the peri-ischemic regions during the first week after MCAO in neonates. By two weeks after injury, endothelial cell proliferation is increased in the cortical peri-ischemic region but these changes are not accompanied by an increased vascular density. Suppressed angiogenesis in injured postnatal brain that we report may limit recovery after neonatal stroke. Thus, enhancement of angiogenesis after neonatal stroke may be a promising strategy for the long-term recovery of the affected newborns. PMID- 23730351 TI - Recommendations for preclinical research in hemorrhagic transformation. AB - Hemorrhagic transformation (HT) is an important complication of ischemic stroke and is responsible for most of the mortality associated with acute reperfusion therapy. Although many important publications address the preclinical models of ischemic stroke, there are no current recommendations on the conduct of research aimed at understanding the mechanisms and consequences of HT. The purpose of this review is to present the various models used in HT research, the clinical correlates, and the experimental variables known to influence the quantitation of HT in preclinical investigation. Lastly, recommendations for the conduct of preclinical research in HT are provided. PMID- 23730352 TI - Sleep, neuroengineering and dynamics. AB - Modeling of consciousness-related phenomena and neuroengineering are fields that are rapidly growing together. We review recent approaches and developments and point out some promising directions of future research: Understanding the dynamics of consciousness states and associated oscillations, pathological oscillations as well as their treatment by stimulation, neuroprosthetics and brain-computer-interface approaches, and stimulation approaches that probe, influence and strengthen memory consolidation. In all these fields, computational models connect theory, neurophysiology and neuroengineering research and pave a way towards medical applications. PMID- 23730353 TI - Gap junctions modulate seizures in a mean-field model of general anesthesia for the cortex. AB - During slow-wave sleep, general anesthesia, and generalized seizures, there is an absence of consciousness. These states are characterized by low-frequency large amplitude traveling waves in scalp electroencephalogram. Therefore the oscillatory state might be an indication of failure to form coherent neuronal assemblies necessary for consciousness. A generalized seizure event is a pathological brain state that is the clearest manifestation of waves of synchronized neuronal activity. Since gap junctions provide a direct electrical connection between adjoining neurons, thus enhancing synchronous behavior, reducing gap-junction conductance should suppress seizures; however there is no clear experimental evidence for this. Here we report theoretical predictions for a physiologically-based cortical model that describes the general anesthetic phase transition from consciousness to coma, and includes both chemical synaptic and direct electrotonic synapses. The model dynamics exhibits both Hopf (temporal) and Turing (spatial) instabilities; the Hopf instability corresponds to the slow (?8 Hz) oscillatory states similar to those seen in slow-wave sleep, general anesthesia, and seizures. We argue that a delicately balanced interplay between Hopf and Turing modes provides a canonical mechanism for the default non cognitive rest state of the brain. We show that the Turing mode, set by gap junction diffusion, is generally protective against entering oscillatory modes; and that weakening the Turing mode by reducing gap conduction can release an uncontrolled Hopf oscillation and hence an increased propensity for seizure and simultaneously an increased sensitivity to GABAergic anesthesia. PMID- 23730355 TI - Exploring the spectrum of dynamical regimes and timescales in spontaneous cortical activity. AB - Rhythms at slow (<1 Hz) frequency of alternating Up and Down states occur during slow-wave sleep states, under deep anaesthesia and in cortical slices of mammals maintained in vitro. Such spontaneous oscillations result from the interplay between network reverberations nonlinearly sustained by a strong synaptic coupling and a fatigue mechanism inhibiting the neurons firing in an activity dependent manner. Varying pharmacologically the excitability level of brain slices we exploit the network dynamics underlying slow rhythms, uncovering an intrinsic anticorrelation between Up and Down state durations. Besides, a non monotonic change of Down state duration is also observed, which shrinks the distribution of the accessible frequencies of the slow rhythms. Attractor dynamics with activity-dependent self-inhibition predicts a similar trend even when the system excitability is reduced, because of a stability loss of Up and Down states. Hence, such cortical rhythms tend to display a maximal size of the distribution of Up/Down frequencies, envisaging the location of the system dynamics on a critical boundary of the parameter space. This would be an optimal solution for the system in order to display a wide spectrum of dynamical regimes and timescales. PMID- 23730354 TI - The population firing rate in the presence of GABAergic tonic inhibition in single neurons and application to general anaesthesia. AB - Tonic inhibition has been found experimentally in single neurons and affects the activity of neural populations. This kind of inhibition is supposed to set the background or resting level of neural activity and plays a role in the brains arousal system, e.g. during general anaesthesia. The work shows how to involve tonic inhibition in population rate-coding models by deriving a novel transfer function. The analytical and numerical study of the novel transfer function reveals the impact of tonic inhibition on the population firing rate. Finally, a first application to a recent neural field model for general anaesthesia discusses the origin of the loss of consciousness during anaesthesia. PMID- 23730356 TI - Synaptic consolidation: an approach to long-term learning. AB - Synaptic plasticity is thought to be the basis of learning and memory, but it is mostly studied on the timescale of mere minutes. This review discusses synaptic consolidation, a process that enables synapses to retain their strength for a much longer time (days to years), instead of returning to their original value. The process involves specific plasticity-related proteins, and depends on the dopamine D1/D5 receptors. Here, we review the research on synaptic consolidation, describing electrophysiology experiments, recent modeling work, as well as behavioral correlates. PMID- 23730357 TI - A minimal mechanistic model for temporal signal processing in the lateral geniculate nucleus. AB - The receptive fields of cells in the lateral geniculate nucleus (LGN) are shaped by their diverse set of impinging inputs: feedforward synaptic inputs stemming from retina, and feedback inputs stemming from the visual cortex and the thalamic reticular nucleus. To probe the possible roles of these feedforward and feedback inputs in shaping the temporal receptive-field structure of LGN relay cells, we here present and investigate a minimal mechanistic firing-rate model tailored to elucidate their disparate features. The model for LGN relay ON cells includes feedforward excitation and inhibition (via interneurons) from retinal ON cells and excitatory and inhibitory (via thalamic reticular nucleus cells and interneurons) feedback from cortical ON and OFF cells. From a general firing-rate model formulated in terms of Volterra integral equations, we derive a single delay differential equation with absolute delay governing the dynamics of the system. A freely available and easy-to-use GUI-based MATLAB version of this minimal mechanistic LGN circuit model is provided. We particularly investigate the LGN relay-cell impulse response and find through thorough explorations of the model's parameter space that both purely feedforward models and feedback models with feedforward excitation only, can account quantitatively for previously reported experimental results. We find, however, that the purely feedforward model predicts two impulse response measures, the time to first peak and the biphasic index (measuring the relative weight of the rebound phase) to be anticorrelated. In contrast, the models with feedback predict different correlations between these two measures. This suggests an experimental test assessing the relative importance of feedforward and feedback connections in shaping the impulse response of LGN relay cells. PMID- 23730358 TI - Differential contributions of somatic and dendritic calcium-dependent potassium currents to the control of motoneuron excitability following spinal cord injury. AB - The hyperexcitability of alpha-motoneurons and accompanying spasticity following spinal cord injury (SCI) have been attributed to enhanced persistent inward currents (PICs), including L-type calcium and persistent sodium currents. Factors controlling PICs may offer new therapies for managing spasticity. Such factors include calcium-activated potassium (KCa) currents, comprising in motoneurons an after-hyperpolarization-producing current (I KCaN) activated by N/P-type calcium currents, and a second current (I KCaL) activated by L-type calcium currents (Li and Bennett in J neurophysiol 97:767-783, 2007). We hypothesize that these two currents offer differential control of PICs and motoneuron excitability based on their probable somatic and dendritic locations, respectively. We reproduced SCI induced PIC enhancement in a two-compartment motoneuron model that resulted in persistent dendritic plateau potentials. Removing dendritic I KCaL eliminated primary frequency range discharge and produced an abrupt transition into tertiary range firing without significant changes in the overall frequency gain. However, I KCaN removal mainly increased the gain. Steady-state analyses of dendritic membrane potential showed that I KCaL limits plateau potential magnitude and strongly modulates the somatic injected current thresholds for plateau onset and offset. In contrast, I KCaN had no effect on the plateau magnitude and thresholds. These results suggest that impaired function of I KCaL may be an important intrinsic mechanism underlying PIC-induced motoneuron hyperexcitability following SCI. PMID- 23730359 TI - Quantum-like model for the adaptive dynamics of the genetic regulation of E. coli's metabolism of glucose/lactose. AB - We developed a quantum-like model describing the gene regulation of glucose/lactose metabolism in a bacterium, Escherichia coli. Our quantum-like model can be considered as a kind of the operational formalism for microbiology and genetics. Instead of trying to describe processes in a cell in the very detail, we propose a formal operator description. Such a description may be very useful in situation in which the detailed description of processes is impossible or extremely complicated. We analyze statistical data obtained from experiments, and we compute the degree of E. coli's preference within adaptive dynamics. It is known that there are several types of E. coli characterized by the metabolic system. We demonstrate that the same type of E. coli can be described by the well determined operators; we find invariant operator quantities characterizing each type. Such invariant quantities can be calculated from the obtained statistical data. PMID- 23730360 TI - Microbial synthetic biology for human therapeutics. AB - The emerging field of synthetic biology holds tremendous potential for developing novel drugs to treat various human conditions. The current study discusses the scope of synthetic biology for human therapeutics via microbial approach. In this context, synthetic biology aims at designing, engineering and building new microbial synthetic cells that do not pre-exist in nature as well as re-engineer existing microbes for synthesis of therapeutic products. It is expected that the construction of novel microbial genetic circuitry for human therapeutics will greatly benefit from the data generated by 'omics' approaches and multidisciplinary nature of synthetic biology. Development of novel antimicrobial drugs and vaccines by engineering microbial systems are a promising area of research in the field of synthetic biology for human theragnostics. Expression of plant based medicinal compounds in the microbial system using synthetic biology tools is another avenue dealt in the present study. Additionally, the study suggest that the traditional medicinal knowledge can do value addition for developing novel drugs in the microbial systems using synthetic biology tools. The presented work envisions the success of synthetic biology for human therapeutics via microbial approach in a holistic manner. Keeping this in view, various legal and socio-ethical concerns emerging from the use of synthetic biology via microbial approach such as patenting, biosafety and biosecurity issues have been touched upon in the later sections. PMID- 23730361 TI - Gene network analysis of Aeromonas hydrophila for novel drug target discovery. AB - Increasing the multi-drug resistance Aeromonas hydrophila creates a health problem regularly thus, an urgent needs to develop and screen potent antibiotics for controlling of the infections. There are many studies have focused on interactions between specific drugs, little is known about the system properties of a full drug interaction in gene network. Thus, an attractive approach for developing novel antibiotics against DNA gyrase, an enzyme essential for DNA replication, transcription, repair and recombination mechanisms which is important for bacterial growth and cell division. Homology modeling method was used to generate the 3-D structure of B subunit of DNA gyrase (gyrB) using known crystal structure. The active amino acids in 3-D structure of gyrB were targeted for structure based virtual screening of potent drugs by molecular docking. Number of drugs and analogs were selected and used for docking against gryB. The drugs Cinodine I, Cyclothialidine and Novobiocin were found to be more binding affinity with gyrB-drug interaction. The homology of gyrB protein sequence of A. hydrophila resembles with other species of Aeromonas closely showed relationship in phylogenetic tree. We have also demonstrated the gene network interactions of gyrB with other cellular proteins which are playing the key role in gene regulation. These findings provide new insight to understand the 3-D structure of gyrB which can be used in structure-based drug discovery; and development of novel, potent and specific drug against B subunit of DNA gyrase. PMID- 23730362 TI - Systems biology beyond degree, hubs and scale-free networks: the case for multiple metrics in complex networks. AB - Modeling and topological analysis of networks in biological and other complex systems, must venture beyond the limited consideration of very few network metrics like degree, betweenness or assortativity. A proper identification of informative and redundant entities from many different metrics, using recently demonstrated techniques, is essential. A holistic comparison of networks and growth models is best achieved only with the use of such methods. PMID- 23730363 TI - On an infrastructure to support sharing and aggregating pre- and post-publication systems biology research data. AB - The move towards in silico experimentation has resulted in the use of computational models, in addition to traditional experimental models, to generate the raw data that is analysed and published as research findings. This change requires new methods to be introduced to facilitate independent validation of the underlying models and the reported results. The promotion of co-operative research has the potential to help to both validate results and explore wider problem areas. In this paper we leverage and extend two existing software frameworks to develop an infrastructure that has the potential to both promote the sharing of data between researchers pre-publication and enable access to the data for interested parties post-publication. The pre-publication sharing of data would enable larger problem spaces to be explored by distributed research groups; enabling access to the data post-publication would allow reviewers and the wider community to independently verify the published results which would, in the longer term, help to increase confidence in published results. The framework is used to perform reproducible and numerically validated individual-based computational experiments into the onset of colorectal cancer. Existing results are verified and new insights into the top-down versus bottom-up hypothesis of colorectal crypt invasion are given. PMID- 23730364 TI - Different redox response elicited by naturally occurring antioxidants in human endothelial cells. AB - Evidences that higher natural antioxidant (NA) intake provides protection against cardiovascular disease (CVD) are contradictory. Oxidative-induced endothelial cells (ECs) injury is the key step in the onset and progression of CVD and for this reason the cellular responses resulting from NA interaction with ECs are actively investigated. This study was designed to investigate the direct impact of different naturally occurring antioxidants on the intracellular ROS levels in cultured human ECs. NA-induced redox changes, in terms of modulation of the intracellular ROS levels, were assessed by using the ROS fluorescent probe 2',7' dichlorodihydrofluorescein diacetate (H2DCF-DA). While caffeic and caftaric acid exerted an anti-oxidant effect, both coumaric acid and resveratrol were pro oxidant. Anti- and pro-oxidant effects of the tested compounds were concentration dependent, showing the induction or the tendency to promote a pro-oxidant outcome with increasing concentrations. Interestingly, the anti- and pro-oxidant behavior of chlorogenic and ferulic acid was dependent on the basal intracellular redox state. Our data indicate that naturally occurring antioxidants are able to induce a rapid modification of the intracellular ROS levels in human ECs, which is dependent on both the applied concentration and the intracellular redox state. PMID- 23730365 TI - Width of 3. Ventricle: reference values and clinical relevance in a cohort of patients with relapsing remitting multiple sclerosis. AB - OBJECTIVES: To estimate the quantity of multiple sclerosis (MS) patients with brain atrophy as indicated by third ventricular enlargement using transcranial colourcoded ultrasound (TCCS). METHODS: The width of the 3. ventricle was assessed by TCCS in 70 healthy controls (male 31, female 39, mean age 41 +/- 15 years, age range 18 - 79 years), and in a cohort of 54 patients with relapsing remitting MS (male 16, female 38, mean age 40 +/- 10 years, median EDSS 2 [1-3]). RESULTS: In the controls, the width of the 3. ventricle increased with age (without any sex differences) from 3.0 +/- 0.76 mm in the age group < 40 years to 4.0 +/- 0.74 mm in the age group of 60 years or more (ANOVA p=0.0001). Derived from regression analysis, the upper limit of the 95% Confidence Interval for each year provided cutoff points according to which 14 of 54 patients (25%) exhibited an enlarged 3. ventricle. In a multivariate regression analysis, the width of the 3. ventricle over all MS patients was significantly related to EDSS (Spearman rho , r=0.446, p<0.005) and to MS duration (r=0.319, p<0.005). CONCLUSIONS: Even in MS patients in good clinical conditions the rate of patients with brain atrophy determined by TCCS is high. PMID- 23730366 TI - In vivo assessment of pulmonary arterial wall fibrosis by intravascular optical coherence tomography in pulmonary arterial hypertension: a new prognostic marker of adverse clinical follow-up. AB - BACKGROUND: The aim is to correlate pulmonary arterial (PA) remodeling estimated by PA fibrosis in PA hypertension (PAH) with clinical follow-up. Histology of PA specimens is also performed. METHODS: 19 patients, aged 54+/-16 (4 men), functional class II-III were studied with right heart catheterization, PA Intravascular Ultrasound and optical coherence tomography (OCT) in inferior lobe segment. PA wall fibrosis was obtained by OCT ( area of fibrosis/PA cross sectional area * 100). Patients follow-up was blind to OCT. Events were defined as mortality, lung transplantation, need of intravenous prostaglandins or onset of right ventricular failure. RESULTS: OCT measurements showed high intra- and interobserver agreement. There was a good correlation between OCT and histology in PA fibrosis from explanted lungs. Area of fibrosis was 1.4+/-0.8 mm(2), % fibrosis was 22.3+/-8. Follow-up was 3.5 years (2.5-4.5). OCT %Fib was significantly correlated with PA capacitance (r=-0.536) and with pulmonary vascular rsistance (r=0.55). Patients were divided according to the median value of PA fibrosis. There were 10 patients with a high (>= 22%) and 9 with a low fibrosis (<22%). Events occurred in 6 (1 death, 1 lung transplantation, 2 intravenous prostaglandins, 2 right heart failure) out of 10 patients with high and in 0 out of 9 patients with low fibrosis (p<0.01). CONCLUSIONS: In PAH, the severity of PA remodeling assessed by OCT wall fibrosis was significantly predictive of severely unfavorable clinical outcome. In vivo assessment of pulmonary arterial wall fibrosis by intravascular OCT in PAH is a promising new prognostic marker of adverse clinical outcome. PMID- 23730367 TI - Content Validity of the Comprehensive ICF Core Set for Chronic Obstructive Pulmonary Diseases: An International Delphi Survey. AB - INTRODUCTION: The "Comprehensive ICF Core Set for Chronic Obstructive Pulmonary Diseases (COPD)" is an application of the International Classification of Functioning, Disability and Health (ICF) and represents the typical spectrum of problems in functioning of patients with COPD. The objective of this study was to validate this ICF Core Set from the perspective of physicians. MATERIALS AND METHODOLOGY: Physicians experienced in COPD treatment were asked about the patients' problems treated by physicians in patients with COPD in a three-round electronic mail survey using the Delphi technique. Responses were linked to the ICF. RESULTS: Seventy-six physicians in 44 countries gave a total of 1330 responses that were linked to 148 different ICF categories. Nine ICF categories were not represented in the Comprehensive ICF Core Set for COPD although at least 75% of the participants have rated them as important. Nineteen concepts were linked to the not yet developed ICF component personal factors and seventeen concepts were not covered by the ICF. CONCLUSION: The high percentage of ICF categories represented in the ICF Core Set for COPD indicates satisfactory content validity from the perspective of the physicians. However, some issues were raised that were not covered and need to be investigated further. PMID- 23730368 TI - Adult Rat Bone Marrow-Derived Stem Cells Promote Late Fetal Type II Cell Differentiation in a Co-Culture Model. AB - Bronchopulmonary dysplasia develops in preterm infants due to a combination of lung immaturity and lung injury. Cultured pluripotent bone marrow stem cells (BMSC) are known to reduce injury and induce repair in adult and in immature lungs, possibly through paracrine secretion of soluble factors. The paracrine relationship between BMSC and primary fetal lung epithelial type II cells is unknown. We determined the effects of BMSC on type II cell and fibroblast behavior using an in vitro co-culture model. Rat BMSC were isolated and co cultured with primary fetal E21 rat type II cells or lung fibroblasts in a Transwell((r)) system without direct cell contact. Effects of BMSC conditioned media (CM) on type II cell and fibroblast proliferation and on type II cell surfactant phospholipid (DSPC) synthesis and mRNA expression of surfactant proteins B and C (sftpb and sftpc) were studied. We also determined the effect of fibroblast and type II cell CM on BMSC proliferation and surface marker expression. Co-culture with BMSC significantly decreased type II cell and fibroblast proliferation to 72.5% and 83.7% of controls, respectively. Type II cell DSPC synthesis was significantly increased by 21% and sftpb and sftpc mRNA expressions were significantly induced (2.1 fold and 2.4 fold, respectively). BMSC proliferation was significantly reduced during the co-culture. Flow cytometry confirmed that BMSC retained the expression of undifferentiated stem cell markers despite their exposure to fetal lung cell CM. We conclude that BMSC induce fetal type II cell differentiation through paracrine release of soluble factors. These studies provide clues for how BMSC may act in promoting alveolar repair following injury. PMID- 23730369 TI - Extended long-term (5 years) outcomes of triangle tilt surgery in obstetric brachial plexus injury. AB - OBJECTIVE: We evaluated the "extended" long-term (5 years) functional outcomes in obstetric brachial plexus injury (OBPI) patients, who underwent triangle tilt surgery between February 2005 and January 2008. METHODS: Twenty two children (9 girls and 13 boys, mean age at surgery was 5.8 years; ranging 2.1-11.8 years old), who initially presented with medial rotation contracture and scapula deformity secondary to obstetric brachial plexus injury were included in this study. Functional movements were evaluated pre-operatively, and 5 years following triangle tilt surgery by modified Mallet scale. RESULTS: Here, we report long term (5 years) follow-up of triangle tilt surgery for 22 OBPI patients. Upper extremity functional movements such as, external rotation (2.5+/-0.6 to 4.1+/ 0.8, p<0.0001), hand-to-spine (2.6+/-0.6 to 3.4+/-1.1, p<0.005), hand-to-neck (2.7+/-0.7 to 4.3+/-0.7, p<0.0001), hand-to-mouth (2.3+/-0.9 (92o+/-33) to 4.2+/ 0.5 (21o+/-16), p<0.0001), and supination (2.6+/-1.1 (-8.2o +/-51) to 4.1+/-0.7 (61+/-32)) were significantly improved (p<0.0001), and maintained over the extended long-term (5 years). Total modified Mallet functional score was also shown to improve from 14.1+/-2.7 to 20.3+/-2.5. CONCLUSIONS: The triangle tilt surgery improved all shoulder functions significantly, and maintained over the extended long-term (5 years) in these patients. PMID- 23730370 TI - The relationship between neuropathic pain, and the function of the upper limbs based on clinical severity according to electrophysiological studies in patients with carpal tunnel syndrome. AB - Carpal tunnel syndrome (CTS) is an entrapment neuropathy of the median nerve, and CTS can cause neuropathic pain. The aim of this study was to evaluate the relationship between neuropathic pain, function of the upper limb, and the electrophysiology in patients with CTS. The terminal latency of median nerve was measured in 34 patients diagnosed with CTS, and they were asked to fill out the Japanese Society for Surgery of the Hand version of the Disability of Arm, Shoulder, and Hand questionnaire (DASH-JSSH) as the patient's assessment of the function of upper limbs and pain DETECT as an assessment for neuropathic pain. There was no significant correlation between the terminal latency and the pain DETECT score, or the terminal latency and the DASH-JSSH score. However, there was a significant correlation between the pain DETECT and DASH-JSSH scores. Neuropathic pain affects the function of the upper extremities in patients with CTS. PMID- 23730371 TI - A Systematic Review and Meta-Analysis of En-Bloc vs Intralesional Resection for Giant Cell Tumor of Bone of the Distal Radius. AB - INTRODUCTION: Surgical management of Giant Cell Tumor of Bone of the distal radius (GCTDR) remains controversial due to risk of local recurrence (LR) offset by functional limitations which result from en-bloc resection. This study aims to determine the oncologic and functional outcomes of wide excision (WE) vs intralesional curettage (IC) of GCTDR. METHODS: A complete search of the applicable literature was done. Included studies reported on patients from the same cohort who were surgically treated for GCTDR with WE or IC. Two reviewers independently assessed all papers. The primary outcome measure was LR. RESULTS: One-hundred-forty-one patients from six studies were included: 60 treated with WE, and 81 with IC. Five WE patients (8%) suffered LR whereas 25 IC patients (31%) did. The odds of LR were three times less in the WE group vs the IC group. MSTS1993 scores, where available, were on average 'good' with WE and 'excellent' with IC. CONCLUSIONS: Within statistical limitations the data support an attempt, where feasible, at wrist joint preservation and superior function with IC. Intralesional curettage is reasonable when the functional benefit outweighs the risk of recurrence as is the case in many cases of GCT of the distal radius. PMID- 23730372 TI - Expressional Analysis of GFP-Tagged Cells in an In Vivo Mouse Model of Giant Cell Tumor of Bone. AB - Giant cell tumor of bone in a neoplastic stromal cell which survives for multiple passages in primary cell culture with a stable phenotype. In the pathological environment of GCT, the neoplastic nature of the mesenchymal stromal component drives local hematopoietic precursors to undergo fusion and form multinucleated osteoclast like giant cells. There is currently very limited knowledge about the pathogenesis of GCT due to the lack of suitable in vivo models for this tumor. Here we report stable gene transfer of Green fluorescence protein (GFP) in GCT stromal cells. In the present study, we have used GCT stromal cells that stably express enhanced green fluorescence protein (GFP) that are used in a new in vivo culture model. Our results show the utility of the GFP tagged cell lines that stably express GFP signals up to 52 weeks of continuous growth. The in vivo model described herein can serve as an excellent system for in vivo therapeutic and mechanistic evaluation of existing and novel targets for GCT. PMID- 23730373 TI - Hyperbaric oxygen for osteomyelitis in a compromised host. AB - Post-traumatic osteomyelitis is a rare but debilitating complication of closed fractures. Most infections can be resolved with aggressive debridement, intravenous antibiotics, and hardware removal. However, the eradication of infection can be challenging in a patient with multiple comorbidities. Refractory infection may require suppressive therapy or amputation to control the disease. Improvements in care have led to improved survival for this population, posing new challenges in their post-traumatic care. We report on the successful use of hyperbaric oxygen therapy as an adjunct in a compromised host with recurrent post traumatic osteomyelitis despite aggressive debridement, removal of instrumentation, and several courses of intravenous antibiotic therapy. Hyperbaric oxygen may be considered as an adjunct to standard treatment protocols for refractory osteomyelitis in compromised hosts. PMID- 23730374 TI - Editorial: technology advancement and research progress in orthopedic surgery. PMID- 23730375 TI - PRP for the treatment of cartilage pathology. AB - In recent years biological strategies are being more widely used to treat cartilage lesions. One of the most exploited novel treatments is Platelet-rich Plasma (PRP), whose high content of growth factors is supposed to determine a regenerative stimulus to cartilaginous tissue. Despite many promising in vitro and in vivo studies, when discussing clinical application a clear indication for the use of PRP cannot be assessed. There are initial encouraging clinical data, but only a few randomized controlled trials have been published, so it is not possible to fully endorse this kind of approach for the treatment of cartilage pathology. Furthermore, study comparison is very difficult due to the great variability in PRP preparation methods, cell content and concentration, storage modalities, activation methods and even application protocols. These factors partially explain the lack of high quality controlled trials up to now. This paper discusses the main aspects concerning the basic biology of PRP, the principal sources of variability, and summarizes the available literature on PRP use, both in surgical and conservative treatments. Based on current evidence, PRP treatment should only be indicated for low-grade cartilage degeneration and in case of failure of more traditional conservative approaches. PMID- 23730376 TI - Bilateral suprascapular nerve entrapment by ganglion cyst associated with superior labral lesion. AB - Suprascapular nerve compression is a rare cause of shoulder pain. We report the clinical features, radiological findings, arthroscopic management and outcome of three patients with suprascapular nerve compression caused by labral ganglion cyst associated with SLAP lesion. We performed simultaneous suture anchor SLAP repair and cyst decompression with a blunt probe. Upon a two-year follow-up, patients recovered full shoulder function without pain or limitations in activities of daily living. PMID- 23730377 TI - A Randomized, Controlled Trial Comparing Autologous Matrix-Induced Chondrogenesis (AMIC(r)) to Microfracture: Analysis of 1- and 2-Year Follow-Up Data of 2 Centers. AB - Microfracture (MFx) is currently the recommended option for the treatment of small cartilage defects but is not regarded as suitable for the treatment of defects larger than 2.5 cm(2). To extent its applicability to medium-sized defects MFx has been combined with a collagen type I/III matrix (Chondro Gide((r))). This technique is called Autologous Matrix-Induced Chondrogenesis (AMIC((r))) and meanwhile a clinically established treatment option for localized full-thickness small- to medium-sized cartilage defects. Despite its more spreading clinical use, clinical data published so far are limited to mainly case report series. In this study, we report the first results of a randomized, controlled trial assessing the efficacy and safety of AMIC((r)) versus MFx. Patients enrolled in 2 centers were included in this analysis. 38 patients (aged 21-50 years, mean defect size 3.4 cm(2)) were randomized and treated either with MFx, with sutured AMIC((r)) or glued AMIC((r)). Clinical outcomes (modified Cincinnati and ICRS score) could be assessed in 30 patients at 1-year and 27 patients at 2-years post-operation. Improvements in both scores were seen at 1 and 2-years post-operation, irrespective of the technique used. MRI assessment revealed a satisfactory and homogenous defect filling in the majority of patients. No treatment-related adverse events were reported. This interim analysis confirms the mid-term results for AMIC((r)) reported in literature. It demonstrates clearly that clinical outcomes at 1-year post-operation are maintained at 2-years. Therefore we consider enhancing MFx with Chondro-Gide ((r)) is a valid and safe cartilage repair option for small- to medium-sized cartilage defects of the knee. PMID- 23730378 TI - Functionality and Safety of an Ultra-Congruent Rotating Platform Knee Prosthesis at 5.6 Years: More than 5- Year Follow-Up of the e.motion (((r))) UC-TKA. AB - BACKGROUND: Mobile bearing TKA prostheses were designed to minimize polyethylene wear by increasing implant conformity and reducing stresses between the articulating prosthesis components. It is the purpose of this study to assess the mid-term functionality and clinical outcome associated with a highly congruent mobile platform design, the e.motion((r)) UC total knee prosthesis. MATERIAL AND METHODS: Functional and clinical outcomes were assessed after an average of 5.6 years (5.1 - 6.0 years) after total knee arthroplasty in 28 patients (24 women), aged 77.8+/-7.5 years. The Knee injury and Osteoarthritis Outcome Score (KOOS) was assessed. Secondary outcomes included the Knee Society Score (KSS), radiological evaluation of radiolucent lines and recording of adverse events. RESULTS: The average KOOS subscore for the activities of daily life was 77.8 points after 5.6 years. Both the clinical and functional KSS improved at 2.4 and 5.6 years. Two patients showed radiolucent lines at 5.6 years. Adverse events over 5.6 years included 3 subluxations, 1 tilting and 1 misalignment of the patella. None of the prostheses were revised. CONCLUSION: This pilot study shows promising outcomes for the e.motion((r)) UC prosthesis. In the small sample, the implant performed comparably to the LCS prosthesis (the gold standard). There were no loosenings or revisions observed at 5.6 years. PMID- 23730379 TI - Eleven year results of total hip arthroplasty in patients with secondary osteoarthritis due to slipped capital femoral epiphysis. AB - BACKGROUND: Total hip arthroplasty (THA) in patients with a history of Slipped Capital Femoral Epiphysis (SCFE), is typically indicated to address the consequent deformity of the proximal femur and/or acetabulum. It can be a challenging procedure for the orthopaedic surgeon. Previous studies have focused on prevention of osteoarthritis post-SCFE. However, there is a paucity of data on the outcomes of total hip arthroplasty in patients with osteoarthritis secondary to SCFE. This study was performed to assess the mid-term results of total hip arthroplasty in this patient cohort. MATERIALS AND METHODS: All patients with secondary osteoarthritis due to slipped capital femoral epiphysis, treated with total hip arthroplasty between 1987 and 2005, were included in this retrospective study (n=30). Thirty patients (17 male, 13 female) met the inclusion criteria with one patient lost to follow-up and one unrelated death one year before follow up examination, thereby leaving 28 patients (32 hips) eligible for the study with a mean follow-up time period of 11.2 years. The Harris Hip Score (HHS) and MOS 36 short form health survey (SF36) were determined preoperatively and at most recent follow-up for all patients. Complications were also noted for all cases. RESULTS: The mean Harris Hip Score increased significantly from 47 (32-59; SD=8.3) to 92.3 (65-100; SD=8.2) (p<0.0001). The SF-36 health survey showed an improvement of quality-of-life in all sub-scales. Overall, revision surgery was required in six cases (19 %). Aseptic loosening, leading to implant removal, was noted in five cases. A single-stage revision to address infection was performed in one case. The cumulative survival rate at latest follow-up was 81 %. No other complications were encountered during the study. CONCLUSIONS: Despite a higher failure rate, compared to total hip arthroplasty in the treatment of primary osteoarthritis, total hip arthroplasty can be considered a feasible option for patients with secondary osteoarthritis of the hip due to slipped capital femoral epiphysis. The current study demonstrates good outcomes in patients treated with a cementless column-preserving prosthesis, which is of particular relevance for this young patient cohort. However, further clinical prospective randomized studies are warranted to provide more definitive evidence. PMID- 23730380 TI - MIS Fusion of the SI Joint: Does Prior Lumbar Spinal Fusion Affect Patient Outcomes? AB - BACKGROUND: Sacroiliac (SI) joint pain is a challenging condition to manage as it can mimic discogenic or radicular low back pain, and present as low back, hip, groin and/or buttock pain. Patients may present with a combination of lumbar spine and SI joint symptoms, further complicating the diagnosis and treatment algorithm [1-3]. SI joint pain after lumbar spinal fusion has been reported in the literature. Both clinical and biomechanical studies show the SI joint to be susceptible to increased motion and stress at the articular surface with up to 40 75% of patients developing significant SI joint degeneration after 5 years. In a recent case series study of 50 patients who underwent minimally invasive SI joint arthrodesis, 50% had undergone previous lumbar spinal fusion and 18% had symptomatic lumbar spine pathology treated conservatively [4]. The purpose of this study is to determine if history of previous lumbar fusion or lumbar pathology affects patient outcomes after MIS SI joint fusion surgery. METHODS: We report on 40 patients with 24 month follow up treated with MIS SI joint fusion using a series of triangular porous plasma coated titanium implants (iFuse, SI Bone, Inc. San Jose, CA). Outcomes using a numerical rating scale (NRS) for pain were obtained at 3-, 6-, 12- and 24 month follow up intervals. Additionally, patient satisfaction was collected at the latest follow up interval. Patients were separated into 3 cohorts: 1) underwent prior lumbar spine fusion (PF), 2) no history of previous lumbar spine fusion (NF), 3) no history of previous lumbar spine fusion with symptomatic lumbar spine pathology treated conservatively (LP). A repeated measures analysis of variance (rANOVA) was used to determine if the change in NRS pain scores differed across timepoints and subgroups. A decrease in NRS by 2 points was deemed clinically significant [5]. RESULTS: Mean age was 54 (+/-13) years and varied slightly but not statistically between groups. All subgroups experienced a clinically and statistically significant reduction in pain at all time points (mean change >2 points, p<0.001). There was a statistically significant effect of cohort (p=0.045), with the NF cohort (no prior lumbar spinal fusion) having a somewhat greater decrease in pain (by approximately 1 point) compared to the other 2 groups (PF and LP).Patient reported satisfaction by cohort was: 89% (NF), 92% (PF) and 63% (LP).Overall satisfaction rate was 87%. DISCUSSION AND CONCLUSION: Patients with SI joint pain, regardless of prior lumbar spine fusion history, show significant improvement in pain after minimally invasive SI joint fusion. The presence of symptomatic lumbar spine pathology potentially confounds the treatment affect, as patients may not be able to discriminate between symptoms arising from the SI joint and the lumbar spine. These patients expressed a lower satisfaction with surgery. Patients without other confounding lumbar spine pathology and who have not undergone previous spine surgery tend to be younger and experience a greater reduction in pain. PMID- 23730381 TI - Intrapelvic dislocation of a femoral trial head during primary total hip arthroplasty requiring laparotomy for retrieval. AB - BACKGROUND AND PURPOSE: Total hip arthroplasty (THA) is a safe and reliable surgical procedure. However, THA also has intra- and postoperative complications. A dreaded and frustrating intraoperative complication during total hip arthroplasty is dislocation of the femoral trial head from the neck into the pelvis. METHODS: Here, we report on the case of a 71-year old female patient with osteoarthritis of the left hip. Total hip arthroplasty was performed in a lateral position through a standard posterior approach. During intraoperative trial reduction, the femoral trial head dissociated from the taper and dislocated into the psoas compartment. Several unsuccessful attempts, including an additional ventral approach, were made to immediately retrieve the femoral trial head. RESULTS AND INTERPRETATION: Postoperative a Computerized Tomography (CT) was performed to locate the trial head, a secondary explorative laparotomy was undertaken to retrieve it. The retrieval of the femoral trial head should be performed in a planned second surgical procedure to avoid possible complications during the manipulation necessary for retrieval. PMID- 23730382 TI - Mechanical quantification of local bone quality in the humeral head: a feasibility study. AB - OBJECTIVES: Surgical treatment of proximal humerus fractures can be challenging due to osteoporosis. The weak bone stock makes stable implant anchorage difficult, which can result in low primary stability. Accordingly, significant failure rates, even with modern locking plates, are reported in the literature. Intraoperative knowledge of local bone quality could be helpful in improving results. This study evaluates the feasibility of local bone quality quantification using breakaway torque measurements. MATERIALS AND METHODS: A torque measurement tool (DensiProbeTM) was developed to determine local resistance to breakaway offered by the cancellous bone in the humeral head to quantify local bone quality. The tool was adapted to a standard locking plate (PHILOS, Synthes), allowing measurement in the positions of the six humeral head screws, as provided by the aiming device of the plate. Two hundred and seventy measurements were performed in 44 fresh cadaveric human humeri. RESULTS: Handling of the tool was straight forward and provided reproducible results for the six different positions. The method allows discrimination between the respective positions with statistical significance, and thus provides reliable information on the local distribution of bone quality within the humeral head. DISCUSSION: This study introduces a new method using breakaway torque to determine local bone quality within the humeral head in real time. Because DensiProbe is adapted to a standard locking plate, there is the potential for intraoperative application. The information provided could enable the surgeon to improve fixation of osteoporotic proximal humerus fractures. PMID- 23730383 TI - Contrast enhanced ultrasound: Roles in immediate post-procedural and 24-h evaluation of the effectiveness of thermal ablation of liver tumors. AB - PURPOSE: To retrospectively assess the diagnostic accuracy of immediate post procedural CEUS, 24-h CEUS, and 24-h CT in verifying the effectiveness of thermal ablation of liver tumors ablation, using the combined results of 3-month post procedure CEUS and MDCT as the reference standard. MATERIALS AND METHODS: From our database, we selected patients who had immediate post-procedural CEUS and 24 h CEUS and MDCT examinations after undergoing thermal ablation of a liver tumor between January 2009 and March 2010. The study population consisted of 53 subjects and 55 tumors (44 HCC and 11 metastasis) were evaluated. Thirty-seven tumors were treated with radiofrequency and 18 with microwave ablation. Post procedural CEUS, 24-h CEUS and MDCT, and 3-month follow-up CEUS and MDCT images were blindly reviewed by two radiologists, who measured the size of the ablation area on the post-procedural and 24-h studies. They also evaluated the ability of each of these three index tests to predict the outcome (residual tumor vs. no residual tumor) using imaging studies done at the 3-month follow-up as the reference standard. RESULTS: Mean tumor diameter on preablation CEUS (the day before treatment) was 20 +/- 9 mm. Mean diameter of the necrotic area was 29 +/- 9 mm on post-procedural CEUS, 34 +/- 11 mm on 24-h CEUS, and 36 +/- 11 mm on 24-h MDCT. Diameters of the necrotic area (mean and maximum) on post-procedural CEUS were significantly smaller than those measured on 24-h CEUS or 24-h MDCT, which were not significantly different. For predicting the presence of residual tumor at the 3-month follow-up, post-procedural CEUS, 24-h CEUS, and 24-h MDCT displayed sensitivity of 33%, 33%, and 42%; specificity of 92%, 97%, and 97%; negative predictive value of 84%, 85%, and 83%. The accuracy parameters of these three imaging modalities were not significantly different from one another. CONCLUSIONS: In patients undergoing thermal ablation for liver tumors, the immediate post-procedural CEUS seems comparable to 24-h CEUS and MDCT in terms of detecting residual disease. PMID- 23730384 TI - Hepatic Kaposi's sarcoma in a patient affected by AIDS: Correlation between histology and imaging. AB - Kaposi's sarcoma (KS) is an aggressive, multifocal oncologic disease, which frequently involves skin and internal organs, predominantly affecting homosexual men with AIDS. Hepatic KS is rarely reported in living patients, while autopsies show liver involvement in 35% of patients with KS. Ultrasound (US) of the liver in AIDS patients shows hyperechoic nodules with periportal bands; CT shows a hypodense lesion before and after contrast administration, but in the late phase after iodinated contrast agent injection the nodules are enhanced. Those findings are considered indicative of hepatic KS [1-3]. PMID- 23730385 TI - Real-time elastography as a noninvasive technique for quantification of fibrosis in patients with chronic viral liver disease: Preliminary findings. AB - INTRODUCTION: Real-time elastography (RTE) is a novel technique for measuring tissue elasticity. The aims of this study were to prospectively measure liver stiffness with RTE in patients with chronic viral hepatitis and to evaluate the possible correlation between RTE data and the extent of fibrosis based on liver biopsy findings (Ishak score). MATERIAL AND METHODS: Between February and October 2011, 26 patients (18M, 8F, mean age 41 +/- 13 [standard deviation], range 22-62) with chronic viral hepatitis were prospectively evaluated with ultrasonography (US) that included RTE. All patients then underwent US-guided percutaneous liver biopsy (right lobe) for evaluation of fibrosis. Examinations were performed with a iU22 scanner (Philips, Bothell, WA, USA); a convex transducer (C5-1) was used for the US examination, and a linear transducer (L12-5) for RTE. In the RTE images, relative tissue stiffness is expressed according to a color scale with soft areas represented in green/red and hard areas in blue. Patients were examined in the supine position in suspended normal respiration; three loops of 20 RTE frames were recorded for each case. For each patient, we calculated the mean strain ratio (MSR) for the 3 loops. The Spearman correlation coefficient was used to assess correlation between the ASR and fibrosis stage (F) reflected by the Ishak score. RESULTS: The Spearman coefficient showed significant correlation between the MSR and F (Rho = 0.470, p = 0.015). CONCLUSIONS: RTE appears to be a useful tool for noninvasive evaluation of fibrosis in patients with chronic viral hepatitis although these findings need to be confirmed in larger case series. PMID- 23730386 TI - ARFI elastography in patients with chronic autoimmune liver diseases: A preliminary study. AB - OBJECTIVE: Acoustic radiation force impulse (ARFI) is a new software-based technique that evaluates liver stiffness during B-mode ultrasonography. The purpose of this study was to evaluate the accuracy of ARFI in distinguishing patients with chronic autoimmune liver disease from healthy subjects. MATERIAL AND METHODS: We enrolled 9 adult patients (8 women, 1 man; age 48.1 +/- 12.8 years) with chronic autoimmune disease (primary biliary cirrhosis (PBC, n = 3), autoimmune hepatitis (AIH, n = 2), primary sclerosing cholangitis (PSC, n = 1) and overlap syndromes, (n = 3) who underwent a liver biopsy and 11 healthy volunteers (age 34.7 +/- 10.4 years; 7 women, 4 men). Liver stiffness was evaluated and expressed as the shear wave velocity (SWV) in m/sec. We used a US scanner Siemens-Acuson S2000, evaluating the right liver lobe and the left liver lobe. RESULTS: THE SWV WAS SIGNIFICANTLY HIGHER IN CASES (RIGHT LOBE: 1.51 +/- 0.44; left lobe: 1.57 +/- 0.40) than in controls (right lobe: 1.08 +/- 0.10; left lobe: 1.12 +/- 0.13) (right lobe: P = 0.002; left lobe: P = 0.013). We found no significant correlation between right and left lobe SWVs in cases (P = 0.779) or controls (P = 0.385). The SWV cut-off that best distinguished cases from controls was 1.25 m/sec (accuracy: AUC=0.885; sensitivity: 70.6%; specificity: 95.5%). CONCLUSIONS: ARFI elastography is a noninvasive ultrasonographic technique that can differentiate healthy subjects from patients with fibrotic stages of chronic liver disease. PMID- 23730387 TI - Alpha-galactosidase versus active charcoal for improving sonographic visualization of abdominal organs in patients with excessive intestinal gas. AB - Intestinal gas is a frequent cause of poor visualization during gastrointestinal ultrasound (US). The enzyme alpha-galactosidase may reduce intestinal gas production, thereby improving abdominal US visualization. We compared the efficacies of alpha-galactosidase and active charcoal in improving US visualization in patients with previous unsatisfactory abdominal US scans caused by excessive intestinal gas. MATERIALS AND METHODS: 45 patients with poor visualization of at least one target organ: pancreas, hepatic lobes (score 0-2) or common bile duct (CBD) (score 0-1) were enrolled in a prospective randomized, crossover, observer-blinded study. The patients received alpha-galactosidase (Sinaire Forte, Promefarm, Milan, Italy) 600 GalU t.i.d. for 2 days before abdominal US plus 900 GalU the morning of exam or active charcoal 448 mg t.i.d., for 2 days before the exam plus 672 mg the morning of the exam. Visualization was graded as follows: 0 = none (complete gas interference); 1 = severe interference, 2 = moderate interference, 3 = mild interference; 4 = complete (no gas interference). RESULTS: 42 patients completed the study. Both alpha-galactosidase and active charcoal improved the visualization of target organs. Visualization of the right hepatic lobe, CBD and pancreatic tail was significantly improved (vs. baseline) only by alpha-galactosidase (p < 0.01). Scores >=3 for all parts of the pancreas and both hepatic lobes were achieved in only 12.5% of the patients after both treatments. Both products were well tolerated. CONCLUSION: Alpha galactosidase and active charcoal can improve US visualization of abdominal organs in patients whose scans are frequently unsatisfactory due to excessive intestinal gas. Visualization of the pancreatic tail and right hepatic lobe was significantly improved only by alpha-galactosidase. However, both treatments allowed adequate visualization of all target organs during the same examination only in a few patients. PMID- 23730388 TI - The renal resistive index as a predictor of acute hydronephrosis in patients with renal colic. AB - INTRODUCTION: The objective of this study was to determine whether the renal resistive index (RI) can predict hydronephrosis in patients with renal colic (RC) and whether or not its performance is time-dependent. MATERIALS AND METHODS: The study population was composed of 54 patients admitted for unilateral RC. At the time of the first observation (time point I, tpI), each patient underwent routine examinations, abdominal ultrasonography, and renal color Doppler ultrasound (CDUS) with measurement of the RI. The two imaging studies were repeated 6, 12, 18, 24, 36, and 48 h later (tpII, tpIII, tpIV, tpV, tpVI, tpVII). In addition, each patient underwent non-contrast urinary tract CT 48-60 h after admission. A mean renal RI of >0.70 (mRI+) for the symptomatic kidney was considered indicative of obstruction. Patients were retrospectively divided into two groups: those who developed dilatation (group A) and those who did not (group B). RESULTS: A mRI+ on CDUS predicted the onset of hydronephrosis with 100% sensitivity, 84% specificity, 92.6% accuracy, PPV and NPV of 87.9% and 100%, and diagnostic efficiency of 84%. In group A, mRI+ were always observed before onset of hydronephrosis in a time-dependent manner. In group B, mRI+ were observed occasionally in 4/25 patients (16%) and all were recorded at tpII. In these cases, the RI had returned to normal by tpIII. CONCLUSIONS: In our RC patients, renal RI obtained with CDUS predicted the onset of acute dilatation with higher sensitivity, specificity, accuracy, and diagnostic efficiency than ultrasonography, and it can be used routinely in the emergency department to supplement ultrasound findings. PMID- 23730389 TI - CEUS in the differentiation between low and high-grade bladder carcinoma. AB - INTRODUCTION: Bladder cancer ranks 4th overall in the number of newly diagnosed cancers and 10th in causes of cancer deaths. More than 90% of all cases of bladder cancer are transitional cell carcinoma (TCC). The goal of this study is to confirm the usefulness of low mechanical index contrast-enhanced ultrasonography (CEUS), also in association with time-intensity curves, in the differentiation between high- and low-grade bladder malignant lesions. MATERIALS AND METHODS: From February 2006 to February 2012 we recruited 144 patients. All patients underwent grayscale ultrasonography (US), color-Doppler ultrasonography (CDUS) and contrast-enhanced ultrasonography (CEUS). Subsequently all patients underwent cystoscopy and TURB. RESULTS: HISTOLOGICAL DIAGNOSES WERE: 88 high grade carcinomas (61.1%), and 56 low-grade carcinomas (38.9%). Sensitivity and specificity of CDUS were 87.5% (126/144) and 60%, respectively. Sensitivity and specificity of CEUS were 90.9% and 85.7%, respectively. Sensitivity and specificity of TIC were 91.6% (132/144) and 85.7%, respectively. DISCUSSION AND CONCLUSIONS: CEUS is a reliable noninvasive method for differentiating low- and high-grade bladder carcinomas since it provides typical enhancement patterns as well as specific contrast-sonographic perfusion curves. PMID- 23730390 TI - Echocardiography and right ventricular function in NKF stage III cronic kidney disease: Ultrasound nephrologists' role. AB - TAPSE measurement during echocardiography is a well known measure of right heart systo-diastolic function. Low TAPSE means reduced cranio-caudal excursion of tricuspidal annulus, sign of both reduced ejection fraction and reduced distensibility of right ventricle. It is a good prognostic index for cardiac mortality risk in CHF patients, adding significant prognostic information to NYHA stadiation. Nephrologists do not always fully aware of right ventricular function in their patients affected by chronic renal failure (CRF), even if this datum is probably crucial in vascular access policy. Our study was designed to study right ventricle function and TAPSE on 202 patients affected by moderate chronic renal failure, free from overt pulmonary hypertension. TAPSE, PAPs, right chambers diameters, classical Framingham factors, estimated glomerular filtration rate were recorded. TAPSE was reduced (<23 mm) in 43% of patients enrolled, while dilated right chambers were present in 24%. PAPs exceeded 30 mmHg in 29% of patients. Echocardiographic signs of left ventricular hypertrophy were found in 36% of patients. The ejection fraction was normal in all patients. Statistical analysis showed a significant indirect correlation between TAPSE and PAPs and between TAPSE and tele-diastolic diameters and volumes of the right ventricle, while a direct correlation was observed between TAPSE and Framingham score. TAPSE showed a bimodal distribution, with a subpopulation "low TAPSE - high PAPs", next to a population characterized by normal values ??for both parameters. A reduction in compliance and systolic function of the right heart chambers is quite early and frequent in course of CKD, a fact that the nephrologist should take in due consideration, managing blood volume or planning vascular access for hemodialysis. PMID- 23730391 TI - Retroperitoneal lipomas: A case report. AB - Lipomas are mesenchymal tumors characterized by the abnormal proliferation of adipocytes. We describe a case of retroperitoneal lipomas in a patient with chronic lymphatic leukemia, who was referred to our sonography unit for a regular (6-month) follow-up scan. She had no abdominal symptoms of note. The sonographic examination revealed two well-defined, hyperechoic, oval-shaped masses: the first situated between the posterior wall of the stomach, the duodenum, and the head of the pancreas; the second lying craniomedial to the left kidney. Neither of the masses exhibited intralesional vascularization on color Doppler imaging. Retrospective examination of previous CT scans revealed that the lesions had been present for the past 4 years. Their slow growth was consistent with the suspicion of retroperitoneal lipomas, and this diagnosis was confirmed by magnetic resonance imaging. CT and MRI are the imaging studies of choice for diagnosing retroperitoneal lipomas, but ultrasonography is ideal for the follow-up of these patients because it is repeatable and relatively low in cost. PMID- 23730392 TI - Ultrasound-guided injection of platelet-rich plasma in chronic Achilles and patellar tendinopathy. AB - PURPOSE: The efficacy of platelet-rich plasma (PRP) in the treatment and healing of chronic tendinopathy through stimulation of cell proliferation and total collagen production has been demonstrated by both in vitro and in vivo studies. The aim of this study is to evaluate the effectiveness of ultrasound (US)-guided autologous PRP injections in patellar and Achilles tendinopathy. MATERIALS AND METHODS: Autologous PRP was injected under US-guidance into the Achilles and patellar tendons (30 Achilles tendons, 28 patellar tendons) in 48 prospectively selected patients (30 males, 18 females, mean age 38 +/- 16 years, range 20-61 years). All patients were previously evaluated according to the Victoria Institute of Sport Assessment (VISA) scale, which assessed pain and activity level, and they all underwent US of the tendon before treatment and at follow-up after 20 days and 6 months. Statistical analysis was performed with Chi-square and Wilcoxon tests. RESULTS: 20 days after PRP injection the patients presented a non-significant improvement of clinical symptoms. At the 6-month follow-up VISA score increased from a mean value of 57-75.5 (p < .01). US evaluation revealed a reduction of hypoechoic areas in 26 tendons (p < .01) associated with a widespread improvement of fibrillar echotexture of the tendon and reduced hypervascularity at power Doppler. CONCLUSION: PRP injection in patellar and Achilles tendinopathy results in a significant and lasting improvement of clinical symptoms and leads to recovery of the tendon matrix potentially helping to prevent degenerative lesions. US-guidance allows PRP injection into the tendon with great accuracy. PMID- 23730393 TI - High-resolution ultrasound of the extrinsic carpal ligaments. AB - Thanks to its intrinsic high spatial resolution, ultrasound is an ideal imaging modality for examining very thin, superficial structures, and this makes it very helpful in the evaluation of extrinsic carpal ligaments. These structures, which arise from the radius and ulna and insert on the carpal bones, are extremely important for wrist stability. Previous studies have assessed the use of ultrasound to study the extrinsic carpal ligaments in cadavers, healthy asymptomatic subjects, and patients with rheumatoid arthritis. In the present report, we review the normal anatomy, biomechanics, and ultrasound appearance of these ligaments. PMID- 23730394 TI - We Should Do a Journal: a Brief History of the IJTMB. AB - This editorial tracks progress from informal conversations in 2001 to the fifth anniversary publication of the International Journal of Therapeutic Massage and Bodywork: Research Education and Practice, the only open-source, peer-reviewed journal specifically dedicated to the scientific exploration of therapeutic massage practice and education. PMID- 23730395 TI - Massage efficacy beliefs for muscle recovery from a running race. AB - BACKGROUND: Belief in efficacy of CAM therapies has been sparsely reported and may be different than reported use of the therapy. PURPOSE: The aim of this study was to identify efficacy beliefs of massage for muscle recovery following a 10-km running race. SETTING: Finish zone of a 10-km race. RESEARCH DESIGN: Participants completed a brief survey regarding running race characteristics, prior use of massage, and belief in efficacy of massage regarding muscle recovery from the race. PARTICIPANTS: The subject pool consisted of 745 individuals who completed a running race and were within 60 minutes of race completion. MAIN OUTCOME MEASURES: Subjects reported demographic information (age, gender), race information (finish time, perceived exertion, muscle soreness, fatigue), prior use of massage, and belief regarding efficacy of massage for postrace muscle recovery. RESULTS: Most study participants believed that massage would benefit muscle recovery following the running race (80.0%), even though only 43.9% had received a massage previously. Those who had received at least one massage were significantly more likely to believe that massage would benefit muscle recovery (91.9% vs. 70.4%, p < .001). Females were more likely than males to have had a massage (52.3% vs. 36.0%, p < .001) and to believe it would benefit recovery (83.1% vs. 77.1%, p = .046). CONCLUSIONS: Massage is well-accepted as a muscle recovery aid following a running race, but females and those who have used massage were significantly more likely to perceive it as advantageous. Belief in a therapeutic value of massage for muscle recovery exceeds its reported use. PMID- 23730397 TI - Facilitating case studies in massage therapy clinical education. AB - The integration of evidence into reflective health care practice has been on the rise in recent years and is a phenomenon that has affected all health care professions, including massage therapy. Clinical case studies are a research design that follows one patient or subject, making the studies ideal for use in clinical practice. They are valuable for communicating information from clinical practice to the broader community. Case studies have face validity that may be more valuable to individual practitioners than homogeneous randomized controlled trials, as the practitioner may recognize a complex patient in the case report. At Humber College, Student Massage Therapists (SMTs) create, conduct, and communicate results of a clinical case study prior to graduation. This article describes the process and experience. PMID- 23730396 TI - Developing Compassionate Self-care Skills in Persons Living with HIV: a Pilot Study to Examine Mindful Awareness in Body-oriented Therapy Feasibility and Acceptability. AB - BACKGROUND: Self-care skills for persons living with HIV (PLWH) are needed to better cope with the common symptoms and emotional challenges of living with this chronic illness. PURPOSE: The purpose of this study was to examine the feasibility and acceptability of Mindful Awareness in Body-oriented Therapy (MABT) for individuals receiving medical management for HIV at an outpatient program. SETTING: A nonprofit outpatient day program that provided medical management to low-income individuals with HIV. RESEARCH DESIGN: A one group pre post study design, nine participants were recruited to receive eight weekly MABT sessions of 1.25 hours each. INTERVENTION: MABT is designed to facilitate emotion regulation through teaching somatically-based self-care skills to respond to daily stressors. MAIN OUTCOME MEASURES: To assess participant characteristics and study feasibility, a battery of health questionnaires and one week of wrist actigraphy was administered pre- and postintervention. A satisfaction survey and written questionnaire was administered postintervention to assess MABT acceptability. RESULTS: The results demonstrated recruitment and retention feasibility. The sample had psychological and physical health symptoms that are characteristic of PLWH. MABT acceptability was high, and participants perceived that they learned new mind-body self-care skills that improved HIV symptoms and their ability to manage symptoms. CONCLUSION: The positive findings support a larger future study to examine MABT efficacy to improve coping with HIV symptoms among PLWH. PMID- 23730398 TI - Positive effects of massage therapy on a patient with narcolepsy. AB - PURPOSE: The purpose of this case report was to investigate the effects of massage therapy on the sleep patterns of a woman with narcolepsy. PARTICIPANT: The 23-year-old woman's primary symptoms included excessive daytime sleepiness and periodic leg movements (PLM), which were associated with her diagnoses of both narcolepsy and cataplexy. INTERVENTION: Five 45-minute massage therapy treatments were administered over a five-week period. The patient's sleep patterns were recorded each week before the treatment. A final measurement was recorded in the sixth week. The sleep patterns were monitored using the Leeds Sleep Evaluation Questionnaire, which included ten visual analogue scales. RESULTS: The results of this case report included an improvement in getting to sleep by 148%, an improvement in quality of sleep by 1100%, an improvement in awake following sleep by 121%, and an improvement in behaviour following wakening by 28% using the Leeds Sleep Evaluation Questionnaire. CONCLUSION: This case report suggests that massage therapy had a positive effect on this patient with narcolepsy. Further research is needed to investigate the effects of massage therapy on narcolepsy and sleep patterns. PMID- 23730399 TI - Targeting Mantle Cell Lymphoma with Anti-SYK Nanoparticles. AB - The pentapeptide mimic 1,4-bis(9-O-dihydroquinidinyl)phthalazine / hydroquinidine 1,4-phathalazinediyl diether ("compound 61") (C-61) is the first reported inhibitor targeting the P-site of SYK. Here we report a nanotechnology platform to target C-61 to mantle cell lymphoma (MCL) cells. Liposomal nanoparticles (NP) loaded with C-61 were prepared using the standard thin film evaporation method. The entrapment of C-61 was obtained using the pH gradient procedure with lactobionic acid (LBA) being used as a low pH buffer inside the NP. Formulation F6A was selected as a lead candidate for further biological testing. The average diameter, zeta potential and C-61 content of the F6A NP was 40 nm, 0.1 mV, and 12.6 mg/ml, respectively. F6A induces apoptosis in SYK+ but not SYK- leukemia/lymphoma cells. We also evaluated the cytotoxic activity of F6A in the context of an in vitro artificial bone marrow assay platform based on a 3D scaffold with inverted colloidal crystal geometry mimicking the structural topology of actual bone marrow matrix. The ability of C-61 to induce apoptosis in ALL-1 cells was not adversely affected by the scaffolds. F6A, but not the drug free NP formulation F6B, caused apoptosis of MCL cell lines MAVER-1 and MINO within 24h. Further development of rationally designed SYK inhibitors and their nanoscale formulations may provide the foundation for therapeutic innovation against a broad spectrum of lymphoid malignancies, including MCL. PMID- 23730400 TI - Sintering Rate and Mechanism of TiO2 Nanoparticles by Molecular Dynamics. AB - Titania is the dominant white pigment and photocatalytic material, a key component of sunscreens and has promising applications in photovoltaics and sensors of organic vapors. The growth of TiO2 nanoparticles by sintering, the critical step during their large scale manufacture and processing, is elucidated and quantified by molecular dynamics. Highly mobile ions from the particle surface fill in the initially concave space between nanoparticles (surface diffusion) forming the final, fully-coalesced, spherical-like particle with minimal displacement of inner Ti and O ions (grain boundary diffusion) revealing also the significance and sequence of these two sintering mechanisms of TiO2. A sintering rate for TiO2 nanoparticles is extracted that is much faster than that in the literature but nicely converges to it for increasing particle size. PMID- 23730401 TI - Color-tunable nanophosphors by co-doping flame-made Y2O3 with Tb and Eu. AB - Rare-earth phosphors with tunable optical properties are used in display panels and fluorescent lamps and have potential applications in lasers and bio-imaging. Here, non-aggregated Y2O3 nanocrystals either doped with Tb3+ (1-5 at%) or co doped with Tb3+ (2 at%) and Eu3+ (0.1-2 at%) ions are made in one-step by scalable flame spray pyrolysis. The morphology of these nanophosphors is investigated by X-ray diffraction, electron microscopy and N2 adsorption while their optical properties are monitored by photoluminescent spectroscopy. When yttria nanocrystals are doped with terbium, a bright green emission is obtained at an optimum Tb-content of 2 at%. When, however, europium is added, the emission color of these Tb-doped yttria nanophosphors can be tuned precisely from green to red depending on the Tb/Eu ratio. Furthermore, energy-transfer from Tb3+ to Eu3+ is observed, thus allowing the control of the excitation spectra of the co-doped nanophosphors. PMID- 23730402 TI - Anti-VEGFA Therapy Reduces Tumor Growth and Extends Survival in a Murine Model of Ovarian Granulosa Cell Tumor. AB - Although angiogenesis has been proposed as a therapeutic target for the treatment of ovarian granulosa cell tumor (GCT), its potential has not been evaluated in controlled studies. To do so, we used the Pten (tm1Hwu/tm1Hwu); Ctnnb1 (tm1Mmt/+);Amhr2 (tm3(cre)Bhr/+) (PCA) mouse model, which develops GCTs that mimic the advanced disease in women. A monoclonal anti-vascular endothelial growth factor A (VEGFA) antibody was administered weekly to PCA mice beginning at 3 weeks of age. By 6 weeks of age, anti-VEGFA therapy significantly decreased tumor weights relative to controls (P < .05) and increased survival, with all treated animals but none of the controls surviving to 8 weeks of age. Analyses of PCA tumors showed that anti-VEGFA treatment resulted in significant decreases in tumor cell proliferation and microvessel density relative to controls (P < .05). However, treatment did not have a significant effect on apoptosis or tumor necrosis. The VEGFA receptor 2 (VEGFR2) signaling effector p44/p42 mitogen activated protein kinase (MAPK), whose activity is associated with cell proliferation, was significantly less phosphorylated (i.e., activated) in tumors from the treated group (P < .05). Conversely, no significant difference was found in the activation of protein kinase B, a VEGFR2 signaling effector associated with cell survival. Together, these results suggest that anti-VEGFA therapy is effective at inhibiting GCT growth in the PCA model and acts by reducing microvascular density and cell proliferation through inhibition of the VEGFR2 MAPK pathway. Findings from this preclinical model therefore support the investigation of targeting VEGFA for the adjuvant treatment of GCT in women. PMID- 23730404 TI - Parameterizing the Logistic Model of Tumor Growth by DW-MRI and DCE-MRI Data to Predict Treatment Response and Changes in Breast Cancer Cellularity during Neoadjuvant Chemotherapy. AB - Diffusion-weighted and dynamic contrast-enhanced magnetic resonance imaging (MRI) data of 28 patients were obtained pretreatment, after one cycle, and after completion of all cycles of neoadjuvant chemotherapy (NAC). For each patient at each time point, the tumor cell number was estimated using the apparent diffusion coefficient and the extravascular extracellular (v e) and plasma volume (v p) fractions. The proliferation/death rate was obtained using the number of tumor cells from the first two time points in conjunction with the logistic model of tumor growth, which was then used to predict tumor cellularity at the conclusion of NAC. The Pearson correlation coefficient between the predicted and the experimental number of tumor cells measured at the end of NAC was 0.81 (P = .0043). The proliferation rate estimated after the first cycle of therapy was able to separate patients who went on to achieve pathologic complete response from those who did not (P = .021) with a sensitivity and specificity of 82.4% and 72.7%, respectively. These data provide preliminary results indicating that incorporating readily available quantitative MRI data into a simple model of tumor growth can lead to potentially clinically relevant information for predicting an individual patient's response to NAC. PMID- 23730405 TI - Genetic grouping of medulloblastomas by representative markers in pathologic diagnosis. AB - A recent analysis of the genetic features of medulloblastoma (MB) suggested classification into distinct subgroups according to gene expression profiles, including the Wingless signaling pathway-activated group (WNT group), the Sonic Hedgehog signaling pathway-activated group (SHH group), group 3, and group 4. To classify MB according to genetic features in practice, we analyzed 74 MBs using representative markers of each group. Based on immunohistochemistries (IHC), cytogenetic alterations, and a CTNNB1 mutation study, the patients were divided into the following three groups: cases showing nuclear beta-catenin and/or CTNNB1 mutation and/or monosomy 6 were included in the WNT group (14/74, 18.9%); cases expressing GAB1 were included in the SHH group (15/74, 20.2%); cases that did not show positivity for markers of the WNT or SHH group were included in the non WNT/SHH group (45/74, 60.6%). Immunoexpression of NPR3 seemed to lack sensitivity for classifying group 3, showing diffuse positivity in only two cases. KCNA1 was not specific to group 4 because it was expressed in all groups. Cases in the WNT group showed a slightly better survival than those in the SHH or non-WNT/SHH group, although additional cases are required for statistical significance. Isochromosome 17q (P = .002) and the large cell/anaplastic variant (P = .002) were demonstrated to be poor prognostic indicators in multivariate analysis. The representative IHC and cytogenetic data facilitated the division of MBs into the WNT and SHH groups; however, more specific markers should be added for the identification of group 3 and group 4 in practice. PMID- 23730403 TI - Chemoprevention of BBN-Induced Bladder Carcinogenesis by the Selective Estrogen Receptor Modulator Tamoxifen. AB - Bladder cancer is the fifth most frequent tumor in men and ninth in women in the United States. Due to a high likelihood of recurrence, effective chemoprevention is a significant unmet need. Estrogen receptors (ERs), primarily ERbeta, are expressed in normal urothelium and urothelial carcinoma, and blocking ER function with selective ER modulators such as tamoxifen inhibits bladder cancer cell proliferation in vitro. Herein, the chemoprotective potential of tamoxifen was evaluated in female mice exposed to the bladder-specific carcinogen, N-butyl-N-(4 hydroxybutyl) nitrosamine (BBN). Carcinogen treatment resulted in a 76% tumor incidence and increased mean bladder weights in comparison to controls. In contrast, mice receiving tamoxifen concurrent (8-20 weeks) or concurrent and subsequent (8-32 weeks) to BBN administration had no change in bladder weight and only 10% to 14% incidence of tumors. Non-muscle-invasive disease was present in animals treated with tamoxifen before (5-8 weeks) or after (20-32 weeks) BBN exposure, while incidence of muscle-invasive bladder carcinoma was reduced. ERbeta was present in all mice and thus is a potential mediator of the tamoxifen chemoprotective effect. Surprisingly, ERalpha expression, which was detected in 74% of the mice exposed to BBN alone but not in any controlmice, was correlated with tumor incidence, indicating a possible role for this receptor in carcinogen induced urothelial tumorigenesis. Thus, these data argue that both ERalpha and ERbeta play a role in modulating carcinogen-induced bladder tumorigenesis. Administration of tamoxifen should be tested as a chemopreventive strategy for patients at high risk for bladder cancer recurrence. PMID- 23730406 TI - The Histone Methyltransferase EZH2 Mediates Tumor Progression on the Chick Chorioallantoic Membrane Assay, a Novel Model of Head and Neck Squamous Cell Carcinoma. AB - Current in vivo models for head and neck squamous cell carcinoma (HNSCC) have limitations in simulating some essential tumorigenic phenotypes, such as invasion. Most mouse models of human HNSCC are inadequate because tumor cells are injected directly into the connective tissue, thereby bypassing the basement membrane of the surface epithelium, the first barrier to invasion. In this manuscript, we establish the chick chorioallantoic membrane (CAM) assay as an in vivomodel of human HNSCC tumor progression. Using the CAM model of HNSCC, we investigated the role of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase, in multiple aspects of HNSCC tumor progression. We found that knockdown of EZH2 reduced tumor size, angiogenesis, invasion, and metastasis of tumors produced by grafting human HNSCC cells onto the CAM. In addition, we demonstrate that EZH2 expression mediates a mesenchymal phenotype in HNSCC cell lines and mouse tumors. These findings demonstrate the advantages of the newly proposed CAM model of human HNSCC and highlight the emerging role of EZH2 in HSNCC tumor progression. PMID- 23730407 TI - Tumor-infiltrating PD1-Positive Lymphocytes and FoxP3-Positive Regulatory T Cells Predict Distant Metastatic Relapse and Survival of Clear Cell Renal Cell Carcinoma. AB - BACKGROUND: Clear cell renal cell carcinoma (CRCC) is the most common malignant tumor of the kidney, and the clinical outcome of CRCC is related with the metastatic potential of CRCC. A significant proportion of metastatic CRCC remains incurable. Recently, immunotherapy against specific targets such as programmed death 1 (PD1) has been adapted for fatal cases of CRCC. MATERIALS AND METHODS: In this study, we aimed to evaluate the potential of tumor-infiltrating PD1-positive lymphocytes or FoxP3-positive regulatory T cells (Tregs) as predictors of the metastatic potential or prognosis of CRCC and investigate possible correlations with Epstein-Barr virus (EBV) infection in 199 cases of CRCC. RESULTS: PD1 positivity, high Treg number, and EBV infection all predicted poor overall survival (OS) by univariate analysis. PD1 positivity and high Treg numbers were also significantly correlated with more distant metastatic relapse (DMR) and poor relapse-free survival (RFS) by univariate analysis. PD1 positivity and high Treg number were independent prognostic indicators for OS. In addition, PD1 positivity was an independent predictor of RFS and DMR. EBV infection was an independent predictor of OS of CRCC. CONCLUSION: This study demonstrates that intratumoral infiltration of PD1-positive or FoxP3-positive lymphocytes can be used as significant prognostic indicators of CRCC and PD1 positivity could be very helpful in the prediction of latent distant metastasis of CRCCs. Therefore, evaluation of the infiltration of PD-positive cells or Tregs in CRCC may be useful diagnostic tools for the selection of patients who could benefit from PD1- or Treg-based immunotherapy. PMID- 23730408 TI - Circulating methylated septin 9 nucleic Acid in the plasma of patients with gastrointestinal cancer in the stomach and colon. AB - BACKGROUND: Methylated Septin 9 (mSEPT9) in plasma has recently been suggested as a screening marker for colorectal cancer (CRC) with variable sensitivity. We aimed to determine the usefulness of plasma mSEPT9 for screening CRC and gastric cancer (GC) and its diagnostic role in postoperative CRC patients. METHODS: A total of 350 peripheral blood samples from 101 CRC patients, 153 GC patients, and 96 healthy persons were collected. In addition, we obtained 35 follow-up blood samples from 27 CRC patients after curative radical surgery. Plasma mSEPT9, serum carcinoembryonic antigen (CEA), and serum CA19-9 were evaluated with clinicopathologic features. RESULTS: The sensitivity of plasma mSEPT9 was 36.6% for detecting CRC and 17.7% for detecting GC, and the specificity was 90.6%. During follow-up periods, mSEPT9 showed negative conversion in eight of nine CRC patients (88.9%) whose plasma mSEPT9 had been positive before radical surgery. The patients with plasma mSEPT9 had a tendency of presence of distant metastasis and lower disease-free survival in both CRC and GC. In GC patients, plasma mSEPT9 was more frequently observed in intestinal (23.5%) and mixed type (40.0%) than diffuse type (7.3%; P =.009). Combined analysis of mSEPT9, CEA, and CA19-9 increased the sensitivity for diagnosing GC to 32.7% (P = .002). CONCLUSION: Considering the high incidence of plasma mSEPT9 in intestinal or mixed type GCs similar to CRCs, GC should be examined through the plasma mSEPT9 screening test. In addition, plasma mSEPT9 is proposed as a follow-up marker in CRC patients, but further validation is required. PMID- 23730409 TI - RASSF1A Promoter Methylation Levels Positively Correlate with Estrogen Receptor Expression in Breast Cancer Patients. AB - The aim of this study was to investigate the relationship between the promoter methylation in five cancer-associated genes and clinicopathologic features for identification of molecular markers of tumor metastatic potential and hormone therapy response efficiency in breast cancer. The methylation levels in paraffin embedded tumor tissues, plasma, and blood cells from 151 sporadic breast cancer patients and blood samples of 50 controls were evaluated by quantitative multiplex methylation-specific polymerase chain reaction. DNA methylation of RAS association domain family member 1 (RASSF1A), estrogen receptor 1 (ESR1), cadherin 1, type 1, E-cadherin (CDH1), TIMP metallopeptidase inhibitor 3 (TIMP3) and spleen tyrosine kinase (SYK) genes was detected in the tumors of 124, 19, 15, 15, and 6 patients with mean levels of 48.45%, 3.81%, 2.36%, 27.55%, and 10.81%, respectively. Plasma samples exhibited methylation in the same genes in 25, 10, 15, 17, and 3 patients with levels of 22.54%, 17.20%, 22.87%, 31.93%, and 27.42%, respectively. Cumulative methylation results confirmed different spectra in tumor and plasma samples. Simultaneous methylation in tumors and plasma were shown in less than 17% of patients. RASSF1A methylation levels in tumor samples statistically differ according to tumor size (P = .029), estrogen receptor (ER) and progesterone receptor (PR) status (P = .000 and P = .004), and immunohistochemical subtype (P = .000). Moreover, the positive correlation was found between RASSF1A methylation levels and percentage of cancer cells expressing ER and PR. The direct relationship between RASSF1A promoter methylation and expression of ER could aid the prognosis of hormonal therapy response. PMID- 23730410 TI - Evaluation of potentially predictive markers for anti-angiogenic therapy with sunitinib in recurrent ovarian cancer patients. AB - INTRODUCTION: In ovarian cancer, new therapeutic strategies are needed because the vast majority of patients develop a recurrence and resistance to platinum derivates. Attached to the AGO-OVAR2.11 study investigating the multityrosine kinase inhibitor sunitinib in recurrent platinum refractory ovarian cancers, this translational research project assesses the potential value of serum vascular endothelial growth factor (VEGF), soluble VEGF receptor-3 (sVEGFR-3), and angiopoietin-2 (Ang-2) levels for progression-free survival (PFS). MATERIALS AND METHODS: Longitudinal serum samples were taken while the patient was on study drugs. Serum concentration of VEGF, sVEGFR-3, and Ang-2 was determined by ELISA. The slope of the markers was correlated to the PFS. RESULTS: Patients showing a decrease in VEGF concentration had a median PFS of 10.5 months [confidence interval (CI), 2.89-12.25] compared to 2.9 months (CI, 1.48-5.32) in the case of an increase (P = .17). The stratified log-rank test showed a trend for longer PFS if a decrease of Ang-2 was observed (P = .089). Dichotomized in absolute decrease or increase, the PFS was 8.4 months (CI, 2.89-12.26) versus 2.7 months (CI, 1.05 5.32), respectively. Patients with a reduction of the sVEGFR-3 concentration had a median PFS of 4.76 months (CI 2.86-10.65) versus 8.61 months (CI, 1.05-not estimable) in patients with an increase of sVEGFR-3. This observation was statistically not significant in the log-rank test (P = .81). CONCLUSION: Ang-2 could potentially identify a patient population that might have a better PFS when under anti-angiogenic treatment, like the tyrosine kinase inhibitor sunitinib. PMID- 23730411 TI - High Serum Levels of the Interleukin-33 Receptor Soluble ST2 as a Negative Prognostic Factor in Hepatocellular Carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor, usually arises in the setting of liver cirrhosis (LC), and has a poor prognosis. The recently discovered Th2-cytokine interleukin-33 (IL-33) is a possible mediator in pancreatic and gastric carcinogeneses. IL-33 binds to its receptor and to soluble ST2 (sST2), which thereby acts as a regulator. The role of IL-33 and sST2 in HCC has not been elucidated yet. METHODS: We conducted a case-control study with 130 patients and 50 healthy controls (HCs). Sixty-five patients suffered from HCC and 65 patients had LC without HCC. We assessed serum IL-33 and sST2 levels and their association with established prognostic scores, liver function parameters, and overall survival (OS). RESULTS: No significant difference in IL-33 serum levels was found in HCC compared to LC and HCs. IL-33 levels did not correlate with OS, liver function parameters, the Model for End Stage Liver Disease (MELD) score, or the Cancer of the Liver Italian Program (CLIP) score. sST2 levels were significantly elevated in LC and HCC patients compared to HCs (P < .0001). Mean sST2 levels in LC were higher than in HCC (P < .0001), but a significant association with OS was only observed in the HCC group (P = .003). sST2 in HCC correlated with the CLIP score, the MELD score, and liver function parameters. CONCLUSION: In the present study, the serum concentration of sST2 was associated with OS of HCC. Therefore, sST2 may be considered as a new prognostic marker in HCC and is worth further evaluation. PMID- 23730412 TI - Circulating Cell-Free DNA from Colorectal Cancer Patients May Reveal High KRAS or BRAF Mutation Load. AB - We used a novel method based on allele-specific quantitative polymerase chain reaction (Intplex) for the analysis of circulating cell.free DNA (ccfDNA) to compare total ccfDNA and KRAS- or BRAF-mutated ccfDNA concentrations in blood samples from mice xenografted with the human SW620 colorectal cancer (CRC) cell line and from patients with CRC. Intplex enables single-copy detection of variant alleles down to a sensitivity of >=0.005 mutant to wild-type ratio. The proportion of mutant allele corresponding to the percentage of tumor-derived ccfDNA was elevated in xenografted mice with KRAS homozygous mutation and varied highly from 0.13% to 68.7% in samples from mutation-positive CRC patients (n = 38). Mutant ccfDNA alleles were quantified in the plasma of every patient at stages II/III and IV with a mean of 8.4% (median, 8.4%) and 21.8% (median, 12.4%), respectively. Twelve of 38 (31.6%) and 5 of 38 (13.2%) samples showed a mutation load higher than 25%and 50%, respectively. This suggests that an important part of ccfDNA may originate from tumor cells. In addition, we observed that tumor-derived (mutant) ccfDNA was more fragmented than ccfDNA from normal tissues. This observation suggests that the form of tumor-derived and normal ccfDNA could differ. Our approach revealed that allelic dilution is much less pronounced than previously stated, considerably facilitating the noninvasive molecular analysis of tumors. PMID- 23730413 TI - Molecular Magnetic Resonance Imaging of Tumors with a PTPu Targeted Contrast Agent. AB - Molecular magnetic resonance imaging (MRI) of tumors improves the specificity of MRI by using targeted probes conjugated to contrast-generating metals. The limitation of this approach is in the identification of a target molecule present in sufficient concentration for visualization and the development of a labeling reagent that can penetrate tumor tissue with the fast kinetics required for use in a clinical setting. The receptor protein tyrosine phosphatase PTPu is a transmembrane protein that is continuously proteolyzed in the tumor microenvironment to generate a high concentration of extracellular fragment that can be recognized by the SBK2 probe. We conjugated the SBK2 peptide to a gadolinium chelate [SBK2-Tris-(Gd-DOTA)3] to test whether the SBK2 probe could be developed as an MR molecular imaging probe. When intravenously injected into mice bearing flank tumors of human glioma cells, SBK2-Tris-(Gd-DOTA)3 labeled the tumors within 5 minutes with a high level of contrast for up to 2 hours post injection. The contrast enhancement of SBK2-Tris-(Gd-DOTA)3 was significantly higher than that observed with a current MRI macrocyclic gadolinium chelate (Gadoteridol, ProHance) alone or a scrambled control. These results demonstrate that SBK2-Tris-(Gd-DOTA)3 labeling of the PTPu extracellular fragment is a more specific MR molecular imaging probe than ProHance or a scrambled control. Consequently, the SBK2 probe may be more useful than the current gold standard reagent for MRI to identify tumors and to co-register tumor borders during surgical resection. PMID- 23730414 TI - Galanin has tumor suppressor activity and is frequently inactivated by aberrant promoter methylation in head and neck cancer. AB - PURPOSE: There is accumulating evidence that galanin receptors (GALRs) may be tumor suppressors in head and neck squamous cell carcinoma (HNSCC). Promoter methylation status and gene expression were assessed in a large panel of primary tumors, based on the hypothesis that CpG hypermethylation might silence the galanin gene. EXPERIMENTAL DESIGN: Galanin expression was examined using reverse transcription-polymerase chain reaction (PCR). The methylation status of the galanin promoter was studied using bisulfate sequencing and methylation-specific PCR. UM-SCC-54 was stably transfected to express galanin. RESULTS: Galanin expression was absent in 3/12 (25.0%) UM-SCC cell lines, whereas three nonmalignant cell lines had stable expression. Galanin methylation was found in 24/100 (24.0%) cases. HNSCC tumor specimens was significantly correlated with the GALR1 methylation status (P = 1.88E-06). The presence of galanin promoter hypermethylation was statistically correlated with a decrease in disease-free survival (log-rank test, P = 6.02E-05). A multivariate logistic regression analysis showed that methylation of galanin and methylation of the gene pair galanin and GALR1 had an odds ratio for recurrence of 8.95 [95% confidence interval (CI), 2.29-35.03] and 23.84 (95% CI, 2.74-207.17), respectively. UM-SCC 54 cells that are GALR1-proficient but have hypermethylated galanin exhibited suppressed cell proliferation following exogenous expression of galanin. CONCLUSIONS: Association of frequent promoter hypermethylation and gene silencing with poor survival, combined with growth suppression of HNSCC cells after forced gene expression, supports the hypothesis that galanin acts as a tumor suppressor. These data suggest that galanin and GALR1 are potential therapeutic targets and prognostic factors. PMID- 23730415 TI - MRI detection of nonproliferative tumor cells in lymph node metastases using iron oxide particles in a mouse model of breast cancer. AB - Cell tracking with magnetic resonance imaging (MRI) and iron nanoparticles is commonly used to monitor the fate of implanted cells in preclinical disease models. Few studies have employed these methods to study cancer cells because proliferative iron-labeled cancer cells will lose the label as they divide. In this study, we evaluate the potential for retention of the iron nanoparticle label, and resulting MRI signal, to serve as a marker for slowly dividing cancer cells. Green fluorescent protein-transfected MDA-MB-231 breast cancer cells were labeled with red fluorescent micron-sized superparamagnetic iron oxide (MPIO) nanoparticles. Cells were examined in vitro at multiple time points after labeling by staining for iron-labeled cells and by flow cytometric detection of the fluorescent MPIO. Severe combined immune deficiency (SCID) mice were implanted with 5 x 10(5) MPIO-labeled or unlabeled cells in the mammary fat pad and MRI was performed weekly until 28 days after injection. Microscopy was performed to validate MRI. In vitro assays revealed a very small percentage of cells that retained MPIO at 14 days after labeling. Regions of signal loss were observed in MRI of primary tumors that developed from iron-labeled cancer cells. Small focal regions of signal loss were detected in images of the axillary and brachial nodes in six of eight mice, at day 14 or later, with microscopy confirming the presence of iron-labeled cancer cells. Our data suggest an interesting role for cell tracking with iron particles since label retention leads to persistent signal void, allowing proliferative status to be determined. PMID- 23730416 TI - Competitive but Not Allosteric mTOR Kinase Inhibition Enhances Tumor Cell Radiosensitivity. AB - The mechanistic target of rapamycin (mTOR) is a critical kinase in the regulation of gene translation and has been suggested as a potential target for radiosensitization. The goal of this study was to compare the radiosensitizing activities of the allosteric mTOR inhibitor rapamycin with that of the competitive mTOR inhibitor PP242. On the basis of immunoblot analyses, whereas rapamycin only partially inhibited mTOR complex 1 (mTORC1) activity and had no effect on mTOR complex 2 (mTORC2), PP242 inhibited the activity of both mTOR containing complexes. Irradiation alone had no effect on mTORC1 or mTORC2 activity. Clonogenic survival was used to define the effects of the mTOR inhibitors on in vitro radiosensitivity. In the two tumor cell lines evaluated, PP242 treatment 1 hour before irradiation increased radiosensitivity, whereas rapamycin had no effect. Addition of PP242 after irradiation also enhanced the radiosensitivity of both tumor lines. To investigate the mechanism of radiosensitization, the induction and repair of DNA double-strand breaks were evaluated according gammaH2AX foci. PP242 exposure did not influence the initial level of gammaH2AX foci after irradiation but did significantly delay the dispersal of radiation-induced gammaH2AX foci. In contrast to the tumor cell lines, the radiosensitivity of a normal human fibroblast cell line was not influenced by PP242. Finally, PP242 administration to mice bearing U251 xenografts enhanced radiation-induced tumor growth delay. These results indicate that in a preclinical tumor model PP242 enhances tumor cell radiosensitivity both in vitro and in vivo and suggest that this effect involves an inhibition of DNA repair. PMID- 23730417 TI - Oxaliplatin-based Chemotherapy Might Provide Longer Progression-Free Survival in KRAS Mutant Metastatic Colorectal Cancer. AB - The identification of better regimens in currently available chemotherapeutic agents is crucial for treating patients with KRAS mutant metastatic colorectal cancer (mCRC). Records of mCRC patients who received first-line oxaliplatin-based or irinotecan-based regimens were reviewed retrospectively. Clinicopathologic features and treatment outcome of patients with first-line progression-free survival (PFS) and overall survival (OS) in association with KRAS mutation status were analyzed using the Cox proportional hazard model. Between 2007 and 2010, a total of 118 mCRC patients were enrolled. Among them, 67 were males and 51 were females. In patients who received first-line oxaliplatin-based regimens, the PFS was significantly longer in KRAS mutant patients (N = 32) than that in KRAS wild type patients (N = 51). The median PFS was 8.5 months in KRAS mutant versus 5.8 months in KRAS wild-type patients (P = .008). In contrast, in patients who received first-line irinotecan-based regimens, the PFS was shorter in KRAS mutant patients (N = 15) than that in KRAS wild-type patients (N = 20). Median PFS was 3.9 months in KRAS mutant versus 6.0 months in KRAS wild-type patients (P = .23). Median OS between KRAS mutant and wild-type patients was not significantly different in both oxaliplatin-based and irinotecan-based regimens. In multivariate analyses, KRAS mutation remains an independent predictive factor for longer PFS in first-line oxaliplatin-based regimens. In conclusion, oxaliplatin based chemotherapy in KRAS mutant mCRC might result in longer PFS than in KRAS wild-type mCRC. PMID- 23730418 TI - Expression of DBC1 and Androgen Receptor Predict Poor Prognosis in Diffuse Large B Cell Lymphoma. AB - BACKGROUND: Recently, deleted in breast cancer 1 (DBC1) has been suggested as a poor prognostic indicator of various human cancers and may possibly have a role as a coactivator of androgen receptor (AR). However, their roles in lymphoma are still unknown. MATERIALS AND METHODS: We investigated the effect of the expression of DBC1 and AR in diffuse large B cell lymphoma (DLBCL). Immunohistochemical expression of DBC1 and AR were evaluated in 101 DLBCL samples by tissue microarray. RESULTS: Positive expression of DBC1 and AR was seen in 73% and 70% of DLBCL, respectively. In total DLBCL patients, DBC1 and AR expression were significantly associated with high clinical stage, elevated serum lactate dehydrogenase levels, and high international prognostic index scores, and they predicted shorter overall survival (OS) and relapse-free survival (RFS) by univariate analysis. DBC1 expression was also an independent prognostic indicator by multivariate analysis (OS, P = .017; RFS, P = .004). Especially, both DBC1 and AR expression significantly correlated with shorter OS and RFS in non-germinal center B cell (non-GCB)-type DLBCL by univariate analysis. In multivariate analysis, DBC1 expression was an independent prognostic predictor for OS (P = .035) and AR expression significantly correlated with RFS (P = .005). CONCLUSION: We demonstrate that the expression of DBC1 and AR are significant prognostic indicators for DLBCL patients, especially for unfavorable non-GCB-type DLBCL. PMID- 23730420 TI - Surgical treatment of the atrophic mandibular fractures by locked plates systems: our experience and a literature review. AB - The management of atrophic mandibular fractures in edentulous patients represents an insidious issue for the maxillofacial surgeon due to the biological and biomechanical conditions that are unfavorable for fracture fixation and bone healing. The purpose of this study was to evaluate the results of the treatment of atrophic mandibular fractures and to compare the outcomes of different plating systems used for stabilization. We selected a study group of 16 patients with fractures of completely edentulous atrophic mandibles who were treated in our department between 2004 and 2010. All patients were surgically treated by open reduction and internal rigid fixation using 2.0-mm large-profile locking and 2.4 mm locking bone plates. All patients achieved a complete fracture healing and fast functional recovery of mandibular movements without intraoperative or postoperative surgical complications. The results of our study demonstrated the efficacy of this type of treatment in association with a low postoperative complication rate, a reduction in the recovery time, and the possibility to have an immediately functional rehabilitation. There were very similar results using each of the two bone plating methods considered: no case had hardware failure or nonunion of the fracture. The 2.0-mm large locking plate is thinner, exposes through the soft tissues less frequently, and is much easier to shape and adapt to the mandibular anatomy. However, the 2.4-mm locking plate system still represents the reference hardware in the condition of severe bone atrophy. PMID- 23730419 TI - High-throughput screening identifies aclacinomycin as a radiosensitizer of EGFR mutant non-small cell lung cancer. AB - The endoplasmic reticulum (ER) provides a specialized environment for the folding and modification of trans-membrane proteins, including receptor tyrosine kinases (RTKs), which are vital for the growth and survival of malignancies. To identify compounds which disrupt the function of the ER and thus could potentially impair cancer cell survival signaling, we adapted a set of glycosylation-sensitive luciferase reporters for the development and optimization of a cell-based high throughput screen (HTS). Secondary screens for false-positive luciferase activation and tertiary lectin-based and biochemical analyses were also devised for compound triage. Through a pilot screen of 2802 compounds from the National Cancer Institute (NCI) chemical libraries, we identified aclacinomycin (Acm) as a compound that preferentially affects ER function. We report that Acm reduces plasma membrane expression of glycoproteins including epidermal growth factor receptor (EGFR) and Met but does not inhibit N-linked glycosylation or generalized protein translation. Fluorescence microscopy co-localization experiments were also performed and demonstrated Acm accumulation in the ER in further support of the overall HTS design. The consequences of Acm treatment on cell survival were analyzed through clonogenic survival analysis. Consistent with the reduction of EGFR levels, pretreatment with Acm sensitizes the EGFR-mutant non-small cell lung cancer (NSCLC) cell lines HCC827 and HCC2935 to ionizing radiation and did not affect the sensitivity of the RTK-independent and KRAS mutant A549 NSCLC cell line. Thus, Acm and similar compounds targeting the ER may represent a novel approach for radiosensitizing tumor cells dependent on RTK function. PMID- 23730421 TI - Computer-aided design and rapid prototyping-assisted contouring of costal cartilage graft for facial reconstructive surgery. AB - Complex 3-D defects of the facial skeleton are difficult to reconstruct with freehand carving of autogenous bone grafts. Onlay bone grafts are hard to carve and are associated with imprecise graft-bone interface contact and bony resorption. Autologous cartilage is well established in ear reconstruction as it is easy to carve and is associated with minimal resorption. In the present study, we aimed to reconstruct the hypoplastic orbitozygomatic region in a patient with left hemifacial microsomia using computer-aided design and rapid prototyping to facilitate costal cartilage carving and grafting. A three-step process of (1) 3-D reconstruction of the computed tomographic image, (2) mirroring the facial skeleton, and (3) modeling and rapid prototyping of the left orbitozygomaticomalar region and reconstruction template was performed. The template aided in donor site selection and extracorporeal contouring of the rib cartilage graft to allow for an accurate fit of the graft to the bony model prior to final fixation in the patient. We are able to refine the existing computer aided design and rapid prototyping methods to allow for extracorporeal contouring of grafts and present rib cartilage as a good alternative to bone for autologous reconstruction. PMID- 23730422 TI - Maxillary artery injury associated with subcondylar mandible fractures: a novel treatment algorithm. AB - Mandible fractures commonly occur in patients who have sustained blunt facial trauma, and the subcondylar region is the most frequently fractured due to its intrinsic biomechanical weakness. The maxillary artery lies in close relation to the medial cortex of the subcondyle and is vulnerable to injury by the sharp edges of the fracture fragments during the initial trauma or during operative fracture reduction. Maxillary artery injuries and subcondylar fractures may be an underdiagnosed phenomenon. Yet, this is of clinical significance as the maxillary artery caliber is usually of significant caliber and may lead to substantial hemorrhage. Surgical access to the artery for hemostasis is challenging and is further compounded by small surgical incisions usually undertaken for fracture fixation, obscuring of the artery by the overlying fracture fragments, and vessel retraction following its transection. In cases where maxillary artery injury is suspected, an open surgical approach may be favored over an endoscopic one. The authors illustrate a case in which brisk hemorrhage from the maxillary artery encountered during a preauricular approach to fixation of the mandible subcondyle was successfully controlled with temporary pressure on the external carotid artery through a neck incision and direct ligation of the lacerated maxillary artery. The authors then discuss diagnosis and treatment of such maxillary artery injuries and propose a novel diagnostic and treatment algorithm. PMID- 23730423 TI - Vertical fracture of the mandibular posterior ramus border secondary to the stress of the rigid internal fixation material. AB - A unique case of a vertical fracture of the mandibular posterior ramus border secondary to the stress of the rigid internal fixation material is described in this study. We think that the surgeon's experience and awareness play a key role in avoidance of such a complication. PMID- 23730424 TI - The Use of 2.4-mm Locking Plate System in Treating Comminuted Mandibular Fracture by Firearm. AB - Maxillofacial trauma caused by firearms has considerably increased, in which the mandibular body is the site of highest incidence of firearm projectiles. In these cases, the use of titanium plates and screws allows the early restoration of form and function of the mandible with stable and predictable results. Recently, conventional plates have been extensively used to treat comminuted mandibular fractures. Nevertheless, the conventional system presents several limitations such as screw compression against the bone interface and the necessity of precise fit of plate to the bone. To overcome such drawbacks, the locking plates have emerged. The present clinical case reported the operative treatment of mandibular fracture caused by firearm projectiles with the use of locking plate. The indications, advantages, and disadvantages of this system are presented. PMID- 23730425 TI - Spiral intermaxillary fixation. AB - Intermaxillary fixation (IMF) remains an important component in the management of many facial fractures. During IMF, dental occlusion plays an important role as a guide and therapeutic tool. Since time immemorial there is a constant quest of oral and maxillofacial surgeons to find a quick way for IMF. The desire to develop an alternate interdental fixation technique, which not only would decrease the risk to the operator and gingival trauma but also accurately satisfy dental occlusion, lead to the development of this novel technique of "spiral IMF." PMID- 23730426 TI - External fixation of unstable, "flail" nasal fractures. AB - Nasal bone fractures are the most common among facial fractures. Usually these are adequately treated with closed reduction and internal and/or external stabilization with splints. However, there are clinical situations where the nasal bones are severely displaced, the nasal septum fractured and displaced, or there are external drape lacerations which preclude the use of nasal splints. If the nasal bones are reducible but unstable we consider them "flail" and in this case transmucosal, endonasal Kirschner wires are used for dorsal support until sufficient healing occurs. The technique is simple, quick, and predictable and causes minimal discomfort to the patients. PMID- 23730427 TI - The use of risdon cables in pediatric maxillofacial trauma: a technique revisited. AB - Although less common than adult fractures, fractures of the pediatric maxillofacial skeleton present unique challenges. Different considerations including variations of anatomy including tooth buds, dental variations, as well as considerations for future growth must be addressed. When traditional techniques to treat adult fractures are applied for securing intermaxillary fixation (IMF) such as arch bars, difficulty arises because the primary teeth are shorter and conventional arch bar techniques may slip off intra or postoperatively. We present a technique to achieve both IMF as well as interdental stability using a Risdon cable. Although this technique is not new, we present it as our preferred method for treating pediatric fractures of the facial skeleton where IMF must be accomplished. PMID- 23730428 TI - A safe and accurate method of assessing the size of implants required in orbital floor reconstruction. AB - Many methods to determine the size of an orbital floor implant depend on trial and error. However, this technique is imprecise and the repeated insertion and removal of the implant leads to soft tissue trauma and swelling. A method of measuring orbital floor dimensions intraoperatively using a waterproof paper ruler is presented in this study. This technique has the advantage of being simple, precise, safe, and expedient. PMID- 23730429 TI - Superior orbital fissure syndrome: a case report. AB - Superior orbital fissure syndrome is an infrequently encountered entity with a unique presentation and significant morbidity. This article reviews the background of the syndrome, treatments in the literature, and discusses a recent case with treatment strategy. PMID- 23730430 TI - Writing education studies for publication. PMID- 23730431 TI - Residents and authorship: rights, obligations, and avoiding the pitfalls. PMID- 23730432 TI - Fixing the "match": how to play the game. PMID- 23730433 TI - Changes in the national residency matching program policy: are internal medicine program directors "all-in"? PMID- 23730434 TI - Giving feedback on clinical skills: are we starving our young? AB - BACKGROUND: Feedback to clinical learners about their performance is crucial to their development into competent clinicians. Most feedback is provided by clinicians who have little or no formal training for this aspect of their teaching role. METHOD: Narrative review. FINDINGS: Feedback is most effective if provided by clinical mentors based on observations of behavior, with emphasis on correctable deficiencies. The difference between feedback, which is formative, and evaluation, which is summative, needs to be understood by both the giver and receiver. The ability to self-assess is an important related concept, with studies showing that self-assessment skills are lowest in individuals found to be the least competent in external assessments and in individuals with a high level of confidence. CONCLUSIONS: Feedback is an important component in learners' development, and clinical faculty should be educated about the importance of providing feedback, and the means to do so effectively must be provided to them. Despite several decades of accumulated knowledge in this area, the evidence from learners is that we continue to starve them of this critical nutrient for their growth. PMID- 23730435 TI - To match or not: factors influencing resident choice of graduate medical education program. AB - BACKGROUND: Little is known about the factors that influence applicants' decisions to select a graduate medical education training program. Programs may improve their recruitment by better understanding that process. METHODS: Following the Match for the years 2008 though 2010, an electronic survey was sent to 664 applicants to 15 Duke University graduate medical education programs. Those individuals were ranked high enough to match to Duke University but chose to match at another institution. We used quantitative and qualitative analyses to explore factors influencing candidates' decisions and to identify program and institutional improvements to better attract top candidates. RESULTS: Response rate was 63% (417/664). The quantitative analysis identified factors that were "very important" to applicants (current resident satisfaction, relationship between faculty and residents, collegiality of current residents, quantity and quality of faculty content/mentoring, faculty teaching expertise, diversity of patients and types of procedures, and location), and those that were "not important" to applicants (child care or education opportunities for children, salary, United States Medical Licensing Examination requirements, part-time training options, favorable environment for minorities or women). There were statistically significant differences among specialties. Qualitative analysis identified 3 themes as most influential in their choice: location, program relationships, and the interview experience. CONCLUSION: The collection of 3 years of data across specialties identified factors that are important to applicants' choice of a training program. Some factors can be addressed quickly and with little effort, such as the format of the interview day. Others require programs and institutions to revisit their mission, priorities, and training culture to improve relationships between residents and faculty. Programs may wish to be more tactical in selecting the residents and faculty who meet with applicants and be more focused in planning how the interview time is used. PMID- 23730436 TI - Postinterview Communication between Obstetrics and Gynecology Residency Programs and Candidates. AB - INTRODUCTION: Residency programs seek to match the best candidates with their positions. To avoid ethical conflicts in this process, the National Residency Matching Program (NRMP or Match) has rules regarding appropriate conduct, including guidelines on contact between candidates and programs. Our study examined communication between obstetrics and gynecology (Ob-Gyn) programs and residency candidates after interviewing and prior to ranking. METHODS: Ob-Gyn program directors in the United States were sent a self-administered survey via e mail. Data were collected and analyzed using descriptive methods to examine communication practices of these programs. RESULTS: The response rate was 40%. The findings showed that respondents had variable interpretations of the NRMP rules and suggest that programs may be communicating their match intentions especially to favored candidates. Respondents' open text comments highlighted program directors' frustrations with current NRMP rules. DISCUSSION: NRMP communication rules are intended to minimize pressure on residency candidates. Our findings suggest they may be leading to unforeseen stresses on program directors and candidates. CONCLUSIONS: As educational leaders in medicine, we must consider what professional communications are acceptable without increasing the pressure on candidates during the ranking and match process. PMID- 23730437 TI - A randomized controlled trial of the impact of a teaching procedure service on the training of internal medicine residents. AB - INTRODUCTION: Academic medical centers must provide safe inpatient procedures while balancing resident autonomy and education. We performed a randomized, controlled trial to evaluate the effect of a 2-week hospitalist procedure service (HPS) rotation on interns' self-perceived procedure ability, knowledge, and autonomy versus the standard curriculum. METHODS: We randomly selected 16 of 57 internal medicine interns (28%) to participate in the intervention group rotation, with 29 interns in the control group. All interns were surveyed before the start of residency and at the end of the postgraduate year-1 (PGY-1) and PGY 2 years to evaluate self-reported knowledge and ability to (1) safely perform procedures, (2) supervise procedures, and (3) use bedside ultrasound. RESULTS: Ninety-four percent of HPS interns (15/16) and 71% of control interns (29/41) completed all surveys. Baseline knowledge and experience did not differ significantly between the groups. The intervention group performed significantly more paracentesis (9 versus 4; P < .001), thoracentesis (6 versus 2; P < .001), and lumbar puncture (4 versus 3; P < .001) procedures than did the control group. After their first year, residents who completed the HPS rotation rated their ability to safely perform and supervise all of the assessed procedures as higher (P < .05 for all procedures) and were more likely to rate self-perceived knowledge as very good or excellent in all surveyed aspects of procedure performance (P < .05). DISCUSSION: A 2-week hospitalist-supervised procedure service rotation substantially improved residents' experience, confidence, and knowledge in performing bedside procedures early in their training, with this effect sustained through the PGY-2 year. Standardized procedure service rotations are a viable solution for programs seeking to improve their procedure-based education. PMID- 23730438 TI - Educational Experiences Residents Perceive As Most Helpful for the Acquisition of the ACGME Competencies. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) requires physicians in training to be educated in 6 competencies considered important for independent medical practice. There is little information about the experiences that residents feel contribute most to the acquisition of the competencies. OBJECTIVE: To understand how residents perceive their learning of the ACGME competencies and to determine which educational activities were most helpful in acquiring these competencies. METHOD: A web-based survey created by the graduate medical education office for institutional program monitoring and evaluation was sent to all residents in ACGME-accredited programs at the David Geffen School of Medicine, University of California-Los Angeles, from 2007 to 2010. Residents responded to questions about the adequacy of their learning for each of the 6 competencies and which learning activities were most helpful in competency acquisition. RESULTS: We analyzed 1378 responses collected from postgraduate year-1 (PGY-1) to PGY-3 residents in 12 different residency programs, surveyed between 2007 and 2010. The overall response rate varied by year (66%-82%). Most residents (80%-97%) stated that their learning of the 6 ACGME competencies was "adequate." Patient care activities and observation of attending physicians and peers were listed as the 2 most helpful learning activities for acquiring the 6 competencies. CONCLUSION: Our findings reinforce the importance of learning from role models during patient care activities and the heterogeneity of learning activities needed for acquiring all 6 competencies. PMID- 23730439 TI - Global Health Fellowships: A National, Cross-Disciplinary Survey of US Training Opportunities. AB - INTRODUCTION: Medical trainee interest and participation in global health programs have been growing at unprecedented rates, and the response has been increasing opportunities for medical students and residents. However, at the fellowship level, the number and types of global health training opportunities across specialties have not previously been characterized. METHODS: A cross sectional survey was conducted between November and December 2010 among all identified global health fellowship programs in the United States. Programs were identified through review of academic and institutional websites, peer-reviewed literature, web-based search engines, and epidemiologic snowball sampling. Identified global health fellowship programs were invited through e-mail invitation and follow-up telephone calls to participate in the web-based survey questionnaire. RESULTS: The survey identified 80 global health fellowship programs: 31 in emergency medicine, 14 in family medicine, 11 in internal medicine, 10 in pediatrics, 8 interdisciplinary programs, 3 in surgery, and 3 in women's health. Of these, 46 of the programs (57.5%) responded to the survey. Fellowship programs were most commonly between 19 and 24 months in duration and were nearly equally divided among 2 models: (1) fellowship integrated into residency, and (2) fellowship following completion of residency. Respondents also provided information on selection criteria for fellows, fellowship training activities, and graduates' career choices. Nearly half of fellowship programs surveyed were recently established and had not graduated fellows at the time of the study. CONCLUSION: Institutions across the nation have established a significant, diverse collection of global health fellowship opportunities. A public online database (www.globalhealthfellowships.org), developed from the results of this study, will serve as an ongoing resource on global health fellowships and best practices. PMID- 23730440 TI - Impact of the medical liability crisis on postresidency training and practice decisions in obstetrics-gynecology. AB - INTRODUCTION: The liability crisis may affect residency graduates' practice decisions, yet structured liability education during residency is still inadequate. The objective of this study was to determine the influence of medical liability on practice decisions and to evaluate the adequacy of current medical liability curricula. METHODS: All fourth-year residents (n = 1274) in 264 Accreditation Council for Graduate Medical Education-accredited allopathic and 25 osteopathic US obstetrics and gynecology residency training programs were asked to participate in a survey about postgraduate plans and formal education during residency regarding liability issues in 2006. Programs were identified by the Council on Resident Education in Obstetrics and Gynecology directory and the American College of Osteopathic Obstetricians and Gynecologists residency program registry. Outcome measures were the reported influence of liability/malpractice concerns on postresidency practice decision making and the incidence of formal education in liability/malpractice issues during residency. RESULTS: A total of 506 of 1274 respondents (39.7%) returned surveys. Women were more likely than men to report "region of the country" (P = .02) and "paid malpractice insurance as a salaried employee" (P = .03) as a major influence. Of the respondents, 123 (24.3%) planned fellowship training, and 229 (45.3%) were considering limiting practice. More than 20% had been named in a lawsuit. Respondents cited Pennsylvania, Florida, and New York as locations to avoid. In response to questions about medical liability education, 54.3% reported formal education on risk management, and 65.2% indicated they had not received training on "next steps" after a lawsuit. DISCUSSION: Residents identify liability-related issues as major influences when making choices about practice after training. Structured education on matters of medical liability during residency is still inadequate. PMID- 23730441 TI - Relationship Between Time of First Publication and Subsequent Publication Success Among Non-PhD Physician-Scientists. AB - BACKGROUND: Studies have shown that publication of work during medical school and residency is associated with higher numbers of later publications and citations of published research. However, it is unknown whether this association exists for non-PhD physician-scientists and whether the association persists later into their careers. METHODS: We extracted publication records from the curricula vitae (CVs) of 102 corresponding authors of articles published in 2008 in the New England Journal of Medicine and JAMA, and obtained those authors' citation records from Web of Science. We used regression models to examine the association between time of first publication and later publication and citation rates for the entire postgraduate career and a recent 2-year period. RESULTS: After adjusting for time since medical school graduation, sex, location of medical school (United States or not United States), and additional non-PhD degrees, we found that authors who first published before graduating from medical school had a greater mean number of publications after medical school and during the period from 2006 to 2007 (164 and 28, respectively) than those who first published during the 5 years afterward (111 and 19, respectively) and those who first published more than 5 years after graduation (59 and 13, respectively). Similarly, authors who first published before graduating from medical school had a greater mean number of citations of their published work since graduation and of publications from 2006 to 2007 (4634 and 333, respectively) than those who first published during the 5 years afterward (2936 and 183, respectively) and those who first published more than 5 years after graduation (1512 and 143, respectively). CONCLUSIONS: Early publication is associated with higher numbers of publications and more citations of published research among non-PhD physician scientists. This association persists well into a researcher's career. PMID- 23730442 TI - Baseline sleep dysfunction among matriculating interns. AB - BACKGROUND: Work hour limitations for graduate medical trainees, motivated by concerns about patient safety, quality of care, and trainee well-being, continue to generate controversy. Little information about sleep habits and the prevalence of sleep disorders among residents is available to inform policy in this area. OBJECTIVES: To evaluate the sleep habits of matriculating residents, postgraduate year-1 (PGY-1). DESIGN: An anonymous, voluntary, self-administered survey study was used with 3 validated questionnaires: the Pittsburgh Sleep Quality Index, the Insomnia Severity Index, and the Epworth Sleepiness Scale, which were fielded to PGY-1 residents entering the Accreditation Council for Graduate Medical Education accredited programs at Massachusetts General Hospital and/or Brigham and Women's Hospitals in June and July 2009. RESULTS: Of 355 eligible subjects, 310 (87%) participated. Mean sleep time for PGY-1 residents was 7 hours and 34 minutes, and 5.6% of PGY-1 residents had Pittsburgh Sleep Quality Index global scores greater than 5, indicating poor quality sleep. Using multiple linear and ordinal logistic regression models, men had higher Pittsburgh Sleep Quality Index sleep latency scores, whereas women and those with children had higher Epworth Sleepiness Scale daytime sleepiness scores, and 18% of PGY-1 residents had abnormal amounts of daytime sleepiness based on the Epworth Sleepiness Scale. The Insomnia Severity Index identified 4.2% of PGY-1 residents with moderate insomnia. CONCLUSIONS: Some PGY-1 residents may begin residency with sleep dysfunctions. Efforts to provide targeted help to selected trainees in managing fatigue during residency should be investigated. PMID- 23730443 TI - Effects of education on interns' verbal and electronic handoff documentation skills. AB - BACKGROUND: Improving handoff communications is a National Patient Safety Goal. Interns and residents are rarely taught how to safely handoff their patients. Our objective was to determine whether teaching safe handoff principles would improve handoff quality. METHODS: Our study was conducted on the inpatient services at 2 teaching hospitals. In this single-institution, randomized controlled trial, internal medicine interns (N = 44) and residents (N = 24) participated in a 45-minute educational session on safe handoff communication skills. Residents received additional education on effective feedback practices and were asked to provide each intern with structured feedback. Quality of interns' electronic and verbal handoffs was measured by using a Handoff Evaluation Tool created by the authors. The frequency of handoff communication failures was also assessed through semistructured phone interviews of postcall interns. RESULTS: Interns who received handoff education demonstrated superior verbal handoff skills than control interns (P < .001), while no difference was seen in electronic handoff skills. Communication failures related to code status (P < .001) and overnight tasks (P < .050) were less frequent in the intervention group. CONCLUSIONS: Interns' electronic handoff documentation skills did not improve with the intervention. This may reflect greater difficulty in changing physicians' electronic documentation habits. PMID- 23730444 TI - Use of a structured template to facilitate practice-based learning and improvement projects. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) requires residency programs to meet and demonstrate outcomes across 6 competencies. Measuring residents' competency in practice-based learning and improvement (PBLI) is particularly challenging. PURPOSE: We developed an educational tool to meet ACGME requirements for PBLI. The PBLI template helped programs document quality improvement (QI) projects and supported increased scholarly activity surrounding PBLI learning. METHODS: We reviewed program requirements for 43 residency and fellowship programs and identified specific PBLI requirements for QI activities. We also examined ACGME Program Information Form responses on PBLI core competency questions surrounding QI projects for program sites visited in 2008-2009. Data were integrated by a multidisciplinary committee to develop a peer-protected PBLI template guiding programs through process, documentation, and evaluation of QI projects. All steps were reviewed and approved through our GME Committee structure. RESULTS: An electronic template, companion checklist, and evaluation form were developed using identified project characteristics to guide programs through the PBLI process and facilitate documentation and evaluation of the process. During a 24 month period, 27 programs have completed PBLI projects, and 15 have reviewed the template with their education committees, but have not initiated projects using the template. DISCUSSION: The development of the tool generated program leaders' support because the tool enhanced the ability to meet program-specific objectives. The peer-protected status of this document for confidentiality and from discovery has been beneficial for program usage. The document aggregates data on PBLI and QI initiatives, offers opportunities to increase scholarship in QI, and meets the ACGME goal of linking measures to outcomes important to meeting accreditation requirements at the program and institutional level. PMID- 23730445 TI - The radar graph: the development of an educational tool to demonstrate resident competency. AB - BACKGROUND: Despite the movement toward competency-based assessment by accrediting bodies in recent years, there is no consensus on how to best assess medical competence. Direct observation is a useful tool. At the same time, a comprehensive assessment system based on direct observation has been difficult to develop. INTERVENTION: We developed a system that translates data obtained from checklists of observed behaviors completed during educational activities, including direct observation of clinical care, into a graphic tool (the "radar graph") usable for both formative and summative assessment. Using unique, observable behaviors to evaluate levels of competency on the Dreyfus scale, we assessed resident performance in 6 learning sites within our residency. Data are represented on a radar graph, which residents and faculty used to recognize both strengths and areas for growth to guide educational planning for the individual learner. RESULTS: Initial data show that the radar graphs have construct validity because the development process accurately reflects the desired construct, assessors were adequately trained, and the radar graphs demonstrated resident growth over time. A form completion rate of 90% for >1500 disseminated assessments suggests the feasibility of our process. CONCLUSIONS: The radar graph is a promising tool for use in resident feedback and competency assessment. Further research is needed to determine the full utility of the radar graphs, including a better understanding of the tool's reliability and construct validity. PMID- 23730446 TI - Impact of a computer-based diagnostic decision support tool on the differential diagnoses of medicine residents. AB - BACKGROUND: Computer-based medical diagnostic decision support systems have been used for decades, initially as stand-alone applications. More recent versions have been tested for their effectiveness in enhancing the diagnostic ability of clinicians. OBJECTIVE: To determine if viewing a rank-ordered list of diagnostic possibilities from a medical diagnostic decision support system improves residents' differential diagnoses or management plans. METHOD: Twenty first-year internal medicine residents at Massachusetts General Hospital viewed 3 deidentified case descriptions of real patients. All residents completed a web based questionnaire, entering the differential diagnosis and management plan before and after seeing the diagnostic decision support system's suggested list of diseases. In all 3 exercises, the actual case diagnosis was first on the system's list. Each resident served as his or her own control (pretest/posttest). RESULTS: For all 3 cases, a substantial percentage of residents changed their primary considered diagnosis after reviewing the system's suggested diagnoses, and a number of residents who had not initially listed a "further action" (laboratory test, imaging study, or referral) added or changed their management options after using the system. Many residents (20% to 65% depending on the case) improved their differential diagnosis from before to after viewing the system's suggestions. The average time to complete all 3 cases was 15.4 minutes. Most residents thought that viewing the medical diagnostic decision support system's list of suggestions was helpful. CONCLUSION: Viewing a rank-ordered list of diagnostic possibilities from a diagnostic decision support tool had a significant beneficial effect on the quality of first-year medicine residents' differential diagnoses and management plans. PMID- 23730447 TI - An alternative practice model: residents transform continuity clinic and become systems thinkers. AB - BACKGROUND: A changing health care environment has created a need for physicians trained in health system improvement. Residency programs have struggled to teach and assess practice-based learning and improvement and systems-based practice competencies, particularly within ambulatory settings. INTERVENTION: We describe a resident-created and resident-led quality and practice-improvement council in an internal medicine continuity clinic. We conducted focus groups and report on residents' perspectives on council membership, practice management experiences, quality improvement projects, and resident satisfaction. METHOD: Focus groups were held from May 2009 to March 2010 with internal medicine residents (N = 5/focus group) who participated in the Continuity Clinic Ownership in Resident Education (CCORE) council. Data were analyzed with a grounded theory approach. RESULTS: DURING THE FOCUS GROUPS, RESIDENTS RESPONDED TO THE QUESTION: "Do you have any new insights into delivering quality patient care in an outpatient clinic as a result of this experience (CCORE membership)?" The qualitative analysis resulted in 6 themes: systems thinking and systems-based care skills; improving quality of patient care; improved clinic efficiency; ownership of patients; need for improved communication of practice changes; and a springboard for research. CONCLUSIONS: CCORE residents participated in system changes and acquired leadership skills while working on practice-based and system problems in a clinic microsystem. We believe this model can be implemented by other residency programs to promote the development of systems thinking in residents, increase their ownership of continuity clinic, and empower them to implement system changes. PMID- 23730448 TI - Implementing a multifaceted quality-improvement curriculum in an obstetrics gynecology resident continuity-clinic setting: a 4-year experience. AB - BACKGROUND: Although many residency programs are instituting quality improvement (QI) curricula in response to both institutional and external mandates, there are few reports of successful integration of resident initiated projects into these QI curricula with documented impact on health care processes and measures. INTERVENTION: We introduced a multifaceted curriculum into an Obstetrics Gynecology continuity clinic. Following a needs assessment, we developed a didactic session to introduce residents to QI tools and the how to of a mentored resident-initiated project. Resident projects were presented to peers and faculty and were evaluated. A postgraduation survey assessed residents' satisfaction with the curriculum and preparedness for involvement in QI initiatives after residency. We also assessed whether this resulted in sustained improvement in health care measures. RESULTS: The curriculum was presented to 7 classes of residents (n = 25) and 17 resident initiated projects have been completed. Twenty-one residents (84%) completed the preintervention survey and 12 of 17 (71%) residents who completed the entire curriculum completed the postintervention survey. Sustained change in surrogate health measures was documented for 4 projects focused on improving clinical measures, and improvement in clinical systems was sustained in 9 of the remaining 13 projects (69%). Most of the respondents (75%, n = 9) agreed or strongly agreed that the projects done in residency provided a helpful foundation to their current QI efforts. CONCLUSION: This project successfully demonstrates that a multifaceted program in QI education can be implemented in a busy Obstetrics-Gynecology residency program, resulting in sustained improvement in surrogate health measures and in clinical systems. A longitudinal model for resident projects results in an opportunity for reflection, project revision, and a maintenance plan for continued clinical impact. PMID- 23730449 TI - Development of a Test of Residents' Ethics Knowledge for Pediatrics (TREK-P). AB - BACKGROUND: Professionalism is one of the Accreditation Council for Graduate Medical Education's core competencies. Residency programs must teach residents about ethical principles, which is an essential component of professionalism. OBJECTIVES: We aimed to formally develop a valid and reliable test of ethics knowledge that effectively discriminated among learners in pediatric residency training and to improve methods for measuring outcomes of resident education in medical ethics. METHODS: We created an instrument with 36 true/false questions that tested knowledge in several domains of pediatric ethics: professionalism, adolescent medicine, genetic testing and diagnosis, neonatology, end-of-life decisions, and decision making for minors. All questions and their correct answers were derived from published statements from the American Academy of Pediatrics Committee on Bioethics. We invited a range of participants from novices to experts to complete the test. We evaluated the instrument's reliability and explored item discrimination, omitting 13 items with the least discriminatory power. Score differences between the 3 categories of examinees were evaluated. RESULTS: The 23-item test, completed by 54 participants, demonstrated good internal reliability (Kuder-Richardson 20 statistic = 0.73). The test was moderately difficult and had a mean overall score of 17.3 (+/-3.3 standard deviation). Performance appropriately improved with degree of expertise: median scores for medical students, postgraduate year-3 residents, and ethicists were 15 (65%, range, 11-19), 19 (83%, range, 14-23), and 22 (96%, range, 20-23), respectively. Ethicists' scores were significantly higher than those of medical students (P < .001) and residents (P = .007). Moreover, residents performed significantly better than medical students (P = .001). CONCLUSIONS: We developed a standardized instrument, entitled Test of Residents' Ethics Knowledge for Pediatrics (TREK-P), to evaluate residents' knowledge of pediatric ethics. The TREK-P is easy to administer, reliably discriminates among learners, and highlights content areas in which knowledge may be deficient. PMID- 23730450 TI - Field trips as a novel means of experiential learning in ambulatory pediatrics. AB - BACKGROUND: Parents and caregivers look to pediatric health care providers for guidance on feeding, safety issues, and child-care products for children, but trainees have infrequent first-hand exposure to child products marketed to parents. OBJECTIVE: To conduct a pilot study to assess an experiential field trip as a novel method of enhancing medical knowledge in ambulatory pediatric feeding and safety. METHODS: Resident physicians and medical students visited a local children's store, where they took part in an interactive store tour, product discussions, and product demonstrations led by a physician educator. Participants also completed a 20-question pretest and a 20-question posttest related to common ambulatory pediatric feeding and safety issues, based on recent American Academy of Pediatrics (AAP) policy statements and practice guidelines. RESULTS: Sixty seven medical students and resident physicians participated in the study. Overall, participants' short-term knowledge significantly increased from 9.9 +/- 2.6 to 15.4 +/- 2.2 questions correct (P = .001), with statistically significant gains (P < .001) on both the feeding and safety sections of the test. There were no differences in improvement based on participant's student or resident status, residency program type, program year, sex, or parental status. Ninety-five percent of the participants believed that their knowledge was enhanced by this approach, and participants uniformly agreed that this field trip was valuable to their pediatric training and that such field trip sessions should continue. CONCLUSIONS: The inclusion of experiential learning through an interactive field trip in the curriculum of medical training was acceptable and feasible and showed short-term improvements in knowledge of AAP safety and feeding concepts. PMID- 23730451 TI - Use of an integrated, anatomic-based, orthopaedic resident education curriculum: a 5-year retrospective review of its impact on orthopaedic in-training examination scores. AB - INTRODUCTION: Experts have called for a comprehensive didactic curriculum in orthopaedic residency training. This study examined the effects of an anatomic based, integrated conference program on annual Orthopaedic In-Training Examination (OITE) scores at a single orthopaedic residency program. METHODS: We implemented a new, integrated, anatomic-based curriculum in January 2005. Differences between scores were analyzed by postgraduate year (PGY) of training. OITE scores (percentile ranking and raw scores) of year 1 (PGY-2) through year 4 (PGY-5) residents exposed to the curriculum (2005-2009) were compared to prior PGY-2 through PGY-5 residents (2000-2004) who had experienced the previous unstructured curriculum. To evaluate for cohort effects, United States Medical Licensing Examination (USMLE) Step I scores for these 2 groups were also compared. RESULTS: Eight residents were exposed to the new conference program and 8 to the prior conference program. All residents' percentile rankings improved after exposure to the curriculum, although improvement was not statistically significant for all participants. The most dramatic improvements in OITE scores were seen for PGY-4 and PGY-5 residents, which improved from 65th to 91st percentile (P = .03) and from 66th to 91st percentile (P = .06), respectively. There were no differences between the cohorts in USMLE Step I scores. DISCUSSION: Initiation of an integrated, anatomic-based, resident conference program had a positive impact on resident performance on the OITE. PMID- 23730452 TI - Correlation between self-reported resident duty hours and time-stamped parking data. AB - BACKGROUND: Failure to comply with Accreditation Council for Graduate Medical Education-mandated resident work hour limitations can result in citations and shortened accreditation cycles. Many programs assess compliance by collecting self-reports of work hours from each resident. OBJECTIVES: To examine residents' self-reported assessment of work hours recorded on a daily basis using a Web based product with electronically recorded times collected as residents entered and exited the parking garage. METHODS: Study participants consisted of 62 University of Colorado Denver internal medicine residents rotating at Denver Health Medical Center on a monthly basis over a 4-month period. Self-reported data submitted by 60 residents were compared with the times these residents entered and exited from the parking garage at Denver Health Medical Center, as assessed by an electronic badge reader. RESULTS: A high level of agreement was found between these two data sets. No significant difference was found between the time-stamped parking data and self-reported Web-based data for resident work hours. CONCLUSIONS: Residents accurately self-reported their work hours, using a daily Web-based duty hours log when compared to an independent, objective and blinded assessment of work hours. PMID- 23730453 TI - Residents make their lists and program directors check them twice: reviewing case logs. PMID- 23730454 TI - Examining the scale and outcomes of global health fellowship programs in the United States. PMID- 23730455 TI - Postinterview Communications Between Residency Programs and Candidates: What are the Rules? PMID- 23730456 TI - Why don't we dismiss residents? PMID- 23730457 TI - Intern olympics as a tool to reinforce surgical skills acquisition. PMID- 23730459 TI - Professional promises. PMID- 23730458 TI - The "hidden costs" of graduate medical education in the United States. PMID- 23730460 TI - Specialist training in obstetrics and gynecology in singapore: transition to structured residency program. AB - BACKGROUND: The article describes the experience of planning and implementing the transition of the residency program in obstetrics and gynecology at Singhealth, Singapore, from a model largely based on British training principles to a new model in accordance with the ACGME-International (ACGME-I) standards. INTERVENTION: Initial steps in transitioning to the new model entailed (1) identifying faculty with an interest in education to lead the various initiatives and programs and to ensure appropriate educational role models, (2) securing adequate funding, (3) holding focus groups with physicians to identify opportunities for improvement in the new system, and (4) developing a schedule for the phased implementation of key features of the structured system. RESULTS: The program started in July 2011, with 14 residents for a 4-year course of training. The curriculum consisted of 5 modules: (1) general obstetrics and gynecology and ambulatory care, (2) maternal fetal medicine, (3) urogynecology and minimally invasive surgery, (4) reproductive medicine, and (5) gynecology oncology. Faculty was assigned responsibility for teaching and assessing the 6 competencies, and appropriate training was provided through specially designed, professional-development programs. CONCLUSIONS: Challenges in the implementation of the new training program included the need to replace clinical service previously provided by trainees, a lack of fit between the traditional qualifying exam and the new model for training, and the need to adapt teaching strategies to new competencies not explicitly taught in the prior program, particularly practice-based learning and improvement and systems-based practice. The strength of the new obstetrics and gynecology residency lies in having a structured, competency-based, closely supervised approach to training with standardized evaluations, timely feedback, and a committed faculty. PMID- 23730461 TI - The next accreditation system: stakeholder expectations and dialogue with the community. AB - In February 2012, in an article in the New England Journal of Medicine,1 the Accreditation Council for Graduate Medical Education (ACGME) provided an initial description and the rationale for the Next Accreditation System (NAS). We follow up with this piece, which reflects on questions about the NAS, as a starting point for a dialogue with the community, and as the first in a series of articles that will describe key attributes of the NAS, offer practical guidance to programs and sponsoring institutions, and solicit stakeholder input. Dialogue with the community will be helpful in answering questions and in allowing the ACGME to clarify and refine certain elements of the NAS. This dialogue needs to be mindful that many details of the NAS are yet to be finalized. In communicating about the NAS, ACGME, thus, must balance a timely response to the community's desire to learn more and the need to have details well established to avoid a need to make changes after details have been released to stakeholders and the public. PMID- 23730462 TI - Evidence-based staff training: a guide for practitioners. AB - Behavior analysts in human service agencies are commonly expected to train support staff as one of their job duties. Traditional staff training is usually didactic in nature and generally has not proven particularly effective. We describe an alternative, evidence-based approach for training performance skills to human service staff. The description includes a specific means of conducting a behavioral skills training session with a group of staff followed by on-the-job training requirements. A brief case demonstration then illustrates application of the training approach and its apparent effectiveness for training staff in two distinct skill sets: use of most-to-least prompting within teaching procedures and use of manual signs. Practical issues associated with applying evidence-based behavioral training are presented with a focus on providing training that is effective, efficient, and acceptable to staff trainees. PMID- 23730463 TI - Training novice instructors to implement errorless discrete-trial teaching: a sequential analysis. AB - Discrete trial teaching (DTT) is a common instructional method incorporated into intensive behavioral intervention programs for children diagnosed with autism. Errorless learning strategies are frequently recommended during DTT because they often result in more efficient and effective instruction. The purpose of the present study was to conduct a sequential analysis of the efficacy of three methods for teaching errorless DTT procedures to novice instructors: (a) a self instruction manual, (b) an instructional video, (c) and brief performance feedback. Three participants mastered DTT following self-instruction and the remaining three participants required all three interventions. The present study extends the literature on training DTT skills by (a) illustrating an efficient, sequential method of staff training, (b) introducing an improved self-instruction manual, and (c) clearly delineating guidelines for implementing an errorless prompt fading strategy during DTT. PMID- 23730464 TI - Description of a practitioner training program on functional analysis and treatment development. AB - The current project examined the effectiveness of a functional analysis skills training package for practitioners with advanced degrees working within an applied setting. Skills included appropriately carrying out the functional analysis conditions as outlined by Iwata, Dorsey, Slifer, Bauman, and Richman (1982/1994), interpreting multielement functional analysis graphs using the methodology described by Hagopian et al. (1997), determining next steps when functional analysis data are undifferentiated, and selecting function-based interventions once functional analysis data are conclusive. The performance of three participants was examined within a multiple baseline design across participants. Although performance varied, baseline skill level was insufficient prior to intervention across participants and skill areas. Mastery was attained for all participants within four to eight training sessions per skill and the acquired skills were demonstrated effectively during generalization trials. Minimal retraining was required for some component skills at a 3-month follow up. PMID- 23730465 TI - Assessing preferences of individuals with developmental disabilities: a survey of current practices. AB - Although professionals working with individuals with developmental disabilities have much to gain from using systematic methods of reinforcer identification, practitioner knowledge and use of stimulus preference assessments (SPA) has rarely been examined. The purpose of this survey was to assess awareness and implementation of SPAs among professionals who serve people with developmental disabilities within and outside the field of applied behavior analysis. A total of 406 individuals responded to the survey; 246 respondents were recruited via direct email, and 160 respondents were recruited from Internet postings. Fewer than 60% of respondents across all disciplines (i.e., applied behavior analysis, psychology, and special education) reported knowledge of the term stimulus preference assessment. While nearly 90% of behavior analysts reported using at least one direct method of SPA (i.e., an assessment involving direct observation and measurement of behavior), many reported personal lack of knowledge (18.6%) and lack of time (81.4%) as barriers to conducting these assessments on a regular basis. Survey results are discussed in terms of (1) the need for greater awareness and acceptance of reinforcer identification methods among behavior analysts, educators, and other service providers and (2) barrier-specific solutions to potentially increase the regularity of SPA usage in the education and treatment of individuals with developmental disabilities. PMID- 23730466 TI - Teaching receptive discriminations to children with autism: a comparison of traditional and embedded discrete trial teaching. AB - Discrete trial teaching (DTT) procedures have proven effective in teaching language to children with autism. Discrete trial teaching uses a highly structured, fast-paced format of instruction that is typically conducted in a one to-one situation at a desk or table with minimal distractions. We compared this traditional model of DTT to a version of DTT in which instruction was embedded within the context of a more naturalistic, activity-based environment. However, all of the other characteristics of DTT (e.g., pacing, tight stimulus control, targets selected by the teacher) were retained. Receptive discriminations were taught to 2 4-year-old boys, diagnosed with autism in traditional or embedded DTT. Results showed that for both boys, traditional and embedded DTT were equally effective and efficient. Additionally, measures were collected on participant affect and a concurrent-chains preference evaluation was used to determine which teaching procedure was preferred by the participants. The two procedures produced similar levels of positive and negative affect and were equally preferred by 1 participant while embedded DTT produced more positive affect and was more preferred by the other. PMID- 23730467 TI - Toilet training children with autism and developmental delays: an effective program for school settings. AB - Current research literature on toilet training for children with autism or developmental delays focuses on smaller case studies, typically with concentrated clinical support. Limited research exists to support an effective school-based program to teach toileting skills implemented by public school staff. We describe an intervention program to toilet train 5 children with autism or developmental delays who demonstrated no prior success in the home or school setting. Intervention focused on (a) removal of diapers during school hours, (b) scheduled time intervals for bathroom visits, (c) a maximum of 3 min sitting on the toilet, (d) reinforcers delivered immediately contingent on urination in the toilet, and (e) gradually increased time intervals between bathroom visits as each participant met mastery during the preceding, shorter time interval. The program was effective across all 5 cases in a community-based elementary school. Paraprofessional staff implemented the program with minimal clinical oversight. PMID- 23730468 TI - Increasing the mand repertoire of children with autism through the use of an interrupted chain procedure. AB - Mand training is an essential component of verbal behavior training for any individual who lacks this skill. The current study replicates and extends, with some procedural differences, the work of Hall and Sundberg (1987) by using an interrupted chain procedure to teach mands for missing items to children with autism. The participants were 3 children with autism, ranging between 5 and 8 years of age, who would regularly mand for a wide variety of reinforcers when they were present but would rarely mand for items that were not in sight (i.e., missing items). Participants were first taught to complete 3 behavior chains. Subsequently, the chains were interrupted by removing 1 item needed to complete each chain to contrive motivating operations (MOs) as a means of teaching mands for missing items. Following mand training incorporating vocal prompt and prompt fading procedures, all participants emitted unprompted mands for the missing items within the context of the trained chains and within the context of novel, untrained chains. After teaching mands for missing items, probes were conducted to test for untrained tact acquisition. All participants also demonstrated tact responses relative to the missing items as a result of the mand training. PMID- 23730469 TI - Use of discontinuous methods of data collection in behavioral intervention: guidelines for practitioners. AB - Over the past three decades, researchers have examined the sensitivity and accuracy of discontinuous data-collection methods. Momentary-time sampling (MTS) and partial-interval recording (PIR) have received particular attention in regards to their ability to estimate the occurrence of behavior and their sensitivity to behavior change compared to continuous data collection. In this article, we summarize these findings and provide recommendations for designing a discontinuous measurement system with consideration of the dimensions of behavior to be measured and the expected direction of behavior change. PMID- 23730470 TI - Teaching and maintaining ethical behavior in a professional organization. AB - In addition to continuing education mandates by the Behavior Analyst Certification Board (BACB), behavior-analytic professional organizations may adopt systems that teach and maintain ethical behavior in its employees. Systems of ethical supervision and management may allow for an organization to customize training that prevents ethical misconduct by employees. These systems may also allow supervisors to identify ethical problems in their infancy, allowing the organization to mitigate concerns before they further develop. Systems of ethical management and supervision also may help to improve services and promote consumer protection. Additional benefits might include both avoiding litigation and loss of consumers and income. These systems may promote the field of Behavior Analysis as a desirable, consumer-friendly approach to solving socially significant behavior problems. PMID- 23730471 TI - Current biomechanical concepts for rotator cuff repair. AB - For the past few decades, the repair of rotator cuff tears has evolved significantly with advances in arthroscopy techniques, suture anchors and instrumentation. From the biomechanical perspective, the focus in arthroscopic repair has been on increasing fixation strength and restoration of the footprint contact characteristics to provide early rehabilitation and improve healing. To accomplish these objectives, various repair strategies and construct configurations have been developed for rotator cuff repair with the understanding that many factors contribute to the structural integrity of the repaired construct. These include repaired rotator cuff tendon-footprint motion, increased tendon-footprint contact area and pressure, and tissue quality of tendon and bone. In addition, the healing response may be compromised by intrinsic factors such as decreased vascularity, hypoxia, and fibrocartilaginous changes or aforementioned extrinsic compression factors. Furthermore, it is well documented that torn rotator cuff muscles have a tendency to atrophy and become subject to fatty infiltration which may affect the longevity of the repair. Despite all the aforementioned factors, initial fixation strength is an essential consideration in optimizing rotator cuff repair. Therefore, numerous biomechanical studies have focused on elucidating the strongest devices, knots, and repair configurations to improve contact characteristics for rotator cuff repair. In this review, the biomechanical concepts behind current rotator cuff repair techniques will be reviewed and discussed. PMID- 23730472 TI - Evaluation of associated carpal bone fractures in distal radial fractures. AB - BACKGROUND: The purpose of this study was to investigate the frequency and distribution of associated carpal bone fractures (CBFs) in distal radial fractures (DRFs). METHODS: Three hundred and thirteen patients who underwent surgical treatment for DRFs between March 2007 and January 2010 were reviewed retrospectively. In this study, 223 patients who had preoperative computed tomography (CT) were included. We investigated the frequency and distribution of associated CBFs on CT scans. The relationship between the frequency of associated CBFs and patient factors such as age, gender, body mass index, and the mechanism of injury was assessed. RESULTS: CBFs were complicated in 46 of 223 DRFs (20.9%). The distribution of CBFs was 23 cases in the triquetrum, 16 in the lunate, 12 in the scaphoid, five in the hamate, and four in the pisiform. Among the 46 cases, a fracture of one carpal bone occurred in 36 cases, two in seven cases, three in two cases, and four in one case. In 10 of the 46 cases, associated CBFs occurred in more than two carpal bones. No significant differences were observed for age, sex, body mass index, or the mechanism of injury between patients with DRFs and CBFs and those without CBFs. CONCLUSIONS: Because CBFs that mainly occur in the proximal carpal row are complicated in DRFs at a relatively high frequency, assessment of carpal bones using CT scans is beneficial. PMID- 23730473 TI - Microbiological culture findings of the femoral heads as a prognostic factor in the total hip replacement surgery. AB - BACKGROUND: In primary total hip replacements (THRs), the dissected femoral heads (FHs) are commonly used to make the bone-chips for the reconstruction in the orthopaedic surgery. The donated FHs are routinely microbiologically cultured to identify and contaminated FHs are discarded. This study examines whether a positive FH culture predicts an infection and prosthetic failure after primary THR. METHODS: The study sampled 274 donated FHs from patients with osteonecrosis (ON), hip joint osteoarthritis (OA), and femoral neck fracture (FNF) in THR to culture the microbes. The FH contamination rates were analyzed for ON, OA, and FNF groups. Proportion of the postoperative infection or prosthetic failure in the group of donors with a positive FH culture were compared to the proportion in the group of donors with a negative FH culture. RESULTS: The rates of the positive culture in the ON, OA, and FNF groups were 7.1%, 3.8%, and 4.0%, respectively. The infection rate was found to be non-significantly greater in the ON group than in the OA and FNF groups. In the negative culture group, one patient (0.63%) had a postoperative superficial infection, and five patients (3.2%) experienced additional surgeries including a fixation for a periprosthetic fracture, within a minimum follow-up of two years. However, no postoperative infection was encountered, and no revision surgery was required in the positive culture group. CONCLUSIONS: A positive FH culture is not always associated with elevated risks of infection or prosthetic failure after THR. Therefore, such finding cannot be used as a prognostic factor of THR. The FHs that return a positive culture may not lead to the orthopaedic assessment of an infection or other postoperative complication risks in primary THR. PMID- 23730474 TI - Fifteen-year results of precoated femoral stem in primary hybrid total hip arthroplasty. AB - BACKGROUND: There has been controversy whether methylmethacrylate precoating of the cemented femoral stem is a solution for aseptic loosening or rather contributes to increased failure rates in cemented total hip arthroplasties. METHODS: On a retrospective basis, we analyzed 76 primary hybrid total hip arthroplasties from 63 patients with precoated, cemented femoral stems between October 1990 and December 1995. The mean age of the patients was 46.8 years (range, 22 to 77 years) with a minimum follow-up of 14 years (mean, 15.5 years; range, 14 to 19.5 years). Third generation cementing techniques were employed in all cases. RESULTS: Twenty-four out of 76 cases (31.6%) showed aseptic loosening of the femoral stems, of which 23 stems were revised at an average revision time of 8 years (range, 3 to 14.8 years). The main mode of loosening was cement-stem interface failure in 22 hips (91.7%). Twenty-one out of 24 failed hips (87.5%) demonstrated C2 cementing grades (p < 0.001). Kaplan-Meier survivorship analysis using radiographic aseptic loosening of the femoral stem as the endpoint for failure showed survival rates of 76.5% at 10 years (95% confidence interval [CI], 71.4 to 81.6) and 63.2% at 19 years (95% CI, 57.3 to 69.1). CONCLUSIONS: An early failure of the precoated femoral stem in this study was mainly due to an insufficient cementing technique. Achievement of good cement mantle may improve the survival rates. PMID- 23730475 TI - Relations between long-term glycemic control and postoperative wound and infectious complications after total knee arthroplasty in type 2 diabetics. AB - BACKGROUND: The authors examined whether poor preoperative glucose control, as indicated by the hemoglobin A1c (HbA1c) level of more than 8%, is associated with postoperative wound and infectious complications in diabetic patients that have undergone total knee arthroplasty (TKA). METHODS: One hundred and sixty-seven TKAs performed in 115 patients with type 2 diabetes mellitus, from January 2001 through March 2007, were retrospectively reviewed. Logistic regression was used to identify the variables that had a significant effect on the risk of wound complications or early deep infection. The variables considered were age, gender, body mass index, comorbidities, operation time, antibiotic-impregnated cement use, amount of blood transfusion, close suction drain use, duration of diabetes, method of diabetes treatment, diabetes complications, and preoperative HbA1c level. RESULTS: The overall incidence of wound complications was 6.6% (n = 11) and there were seven cases (4.2%) of early postoperative deep infection. Logistic regression revealed that the independent risk factors of wound complications were preoperative HbA1C >= 8% (odds ratio [OR], 6.07; 95% confidence interval [CI], 1.12 to 33.0) and operation time (OR, 1.01; 95% CI, 1.00 to 1.03). No variable examined was found to be significantly associated with the risk of early postoperative deep infection. CONCLUSIONS: Poorly controlled hyperglycemia before surgery may increase the incidence of wound complications among diabetic patients after TKA. PMID- 23730476 TI - The outcome and complications of the locked plating management for the periprosthetic distal femur fractures after a total knee arthroplasty. AB - BACKGROUND: The osteosynthesis of the periprosthetic fractures following a total knee arthroplasty (TKA) can be technically difficult with the relatively small satisfactory outcomes and the high complication rates. The purpose of the study is to analyze the mid-term radiological and functional outcomes following the locked plating of the distal femur periprosthetic fractures after a TKA. METHODS: Records of 20 patients with a periprosthetic distal femur fracture following TKA treated by the locked plate osteosynthesis were retrospectively evaluated. The union rate, complications and functional outcome measures were analyzed. RESULTS: Successful union was achieved in 18 of the 19 patients available for the follow up. The mean follow-up was 39 +/- 10 months. Significant reductions (p < 0.05) in the range of motion and Western Ontario and McMaster Universities Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores were evident in the follow-up. Secondary procedures were required in 5 patients to address the delay in union and the reduced knee range of motion. The osteosynthesis failed in 1 patient who underwent a revision TKA. CONCLUSIONS: The satisfactory union rates can be achieved with the locked plate osteosynthesis in the periprosthetic distal femur fractures after TKA. Prolonged rehabilitation coupled with the un modifiable risk factors can decrease the activity and satisfaction levels, which can significantly alter the functional outcome. PMID- 23730477 TI - The efficacy of carotid tubercle as an anatomical landmark for identification of cervical spinal level in the anterior cervical surgery: comparison with preoperative C-arm fluoroscopy. AB - BACKGROUND: In cervical anterior approach, transverse skin incision is preferred due to cosmetic reasons. Precise skin incision is required to reach the surgery segment while minimizing soft tissue injury. Skin incision site is frequently identified using C-arm fluoroscopy or the carotid tubercle. Accordingly, this study was conducted to investigate the efficacy of skin incision using the carotid tubercle as a marker. METHODS: This study was retrospectively conducted on 114 patients who underwent anterior cervical surgery by the same surgeon from April 2004 to June 2012. The rate of the appropriate insertion of K-wire, which was inserted into the disc after anterior approach, into the surgery segment was compared between 62 patients where skin incision site was identified using C-arm fluoroscopy before skin incision and 52 patients where skin incision site was identified using carotid tubercle palpitation before surgery. RESULTS: The needle was shown to have been inserted into the planned site in 106 patients out of the total 114 patients. The appropriate insertion of the needle was shown in 59 patients of group I (95.2%) and in 47 patients of group II (90.4%). Although the success rate was higher in group I than group II, it was statistically insignificant. The success rate of one-segment surgery was shown to be 89.7% in group I and 82.6% in group II. Although the success rate was higher in group I than group II, it was statistically insignificant. The success rate of two segment surgery was shown to be 100% in group I, and 96.4% in group II due to one case of the failure at C3-4 and C5-6. The success rate of three- and four-segment surgeries was shown to be 100% in both groups. CONCLUSIONS: The identification of skin incision site via carotid tubercle palpation was useful for surgeries involving two or more segments. Furthermore, it could be useful for one-segment surgery if surgical site is identified using vertebral body or soft tissues such as longus collis rather than insertion into the disc. PMID- 23730478 TI - Postoperative urinary retention following anterior cervical spine surgery for degenerative cervical disc diseases. AB - BACKGROUND: Postoperative urinary retention (POUR) may cause bladder dysfunction, urinary tract infection, and catheter-related complications. It is important to be aware and to be able to identify patients at risk of developing POUR. However, there has been no study that has investigated the incidence and risk factors for the development of POUR following anterior cervical spine surgery for degenerative cervical disc disease. METHODS: We included 325 patients (164 male and 161 female), who underwent anterior cervical spine surgery for cervical radiculopathy or myelopathy due to primary cervical disc herniation and/or spondylosis, in the study. We did not perform en bloc catheterization in our patients before the operation. RESULTS: There were 36 patients (27 male and 9 female) that developed POUR with an overall incidence of 11.1%. The mean numbers of postoperative in-and-out catheterizations was 1.6 times and mean urine output was 717.7 mL. Thirteen out of 36 POUR patients (36%) underwent indwelling catheterization for a mean 4.3 days after catheterization for in-and-out surgery, because of persisting POUR. Seven out of 36 POUR patients (19%) were treated for voiding difficulty, urinary tract irritation, or infection. Chi-square test showed that patients who were male, had diabetes mellitus, benign prostate hypertrophy or myelopathy, or used Demerol were at higher risk of developing POUR. The mean age of POUR patients was higher than non-POUR patients (68.5 years vs. 50.8 years, p < 0.01). CONCLUSIONS: To avoid POUR and related complications as a result of anterior cervical spine surgery for degenerative cervical disc disease, we recommend that a catheter be placed selectively before the operation in at-risk patients, the elderly in particular, male gender, diabetes mellitus, benign prostate hypertrophy, and myelopathy. We recommend that Demerol not be used for postoperative pain control. PMID- 23730479 TI - A new examination method for anatomical variations of the flexor digitorum superficialis in the little finger. AB - BACKGROUND: Current examination methods to assess the anatomical variations of flexor digitorum superficialis (FDS) tendon in the little finger necessitate a strong external force applied by the examiner and cause false negatives. A new examination method was designed to detect the variations more accurately. METHODS: We examined the little fingers of 220 adult hands (110 subjects) by 2 methods: the expanded examination method advocated by Tan et al., and a new examination method. Variations of the FDS in the little finger were examined by both methods and categorized separately as having independent FDS function, FDS connection to the tendons of the ring finger or of the multiple adjacent fingers, and functional substitution of the flexor digitorum profundus (FDP) with or without tendinous connection to the ring or multiple adjacent fingers. By our new method, we could further divide the FDS connection or FDP substitution with connection to the ring finger into 2 subtypes: loose and close connections. Data were reported as case numbers and percent. Date on symmetry were statistically analyzed by matched case-control studies. RESULTS: Among 220 hands, 113 hands (51.4%) had independent FDS function by the new examination method, which was lower than the incidence (55.5%) detected with the existing expanded examination method. In the hands with connections between FDS tendons of the little and the ring fingers, 32 hands (14.5%) demonstrated loose and 37 (16.8%) close connections. Three hands (1.4%) had loose and 19 (8.6%) had close FDP substitution with tendinous connection to the ring finger. Among 110 hands without independent FDS function, variants of 42 hands (38.2%) were asymmetric. There was no statistical significance in symmetry of variations. CONCLUSIONS: This new examination method offers other assessment variations of FDS tendon in the little finger. We recommend using this test to assess the variations and function of the FDS of the little finger. PMID- 23730480 TI - Effects of Beraprost sodium on subjective symptoms in diabetic patients with peripheral arterial disease. AB - BACKGROUND: This study evaluated the effects of Beraprost sodium (Berasil) on subjective leg symptoms in patients with peripheral arterial disease caused by diabetes mellitus. METHODS: Ninety-four diabetic patients with peripheral arterial disease were treated with Beraprost in a fixed-dose, prospective, multicenter, cohort study. Beraprost (40 ug) was administered orally 3 times daily (120 ug/day) for 12 weeks. We developed a new disease-specific symptom questionnaire, which evaluated the effect of peripheral arterial disease on leg discomfort in daily life and assessed therapeutic responses to treatment. Patients were asked for their subjective assessment of symptoms on a written questionnaire before treatment and after 12 weeks of therapy. RESULTS: There was significant improvement in all estimated subjective symptoms (burning, coldness, edema, exertional pain, stabbing, and paresthesias) in the lower extremities at 12 weeks (p < 0.001). There were 18 patients with neuropathy in whom significant improvement was noted for 6 subjective symptoms at 12 weeks (p < 0.05). Adverse events considered to be drug-related were observed in 4 patients (4.3%), all of which were mild and resolved with discontinuation of the medication. CONCLUSIONS: Beraprost is effective as a treatment for improving various subjective symptoms in the lower extremities, such as burning, coldness, edema, exertional pain, stabbing, and paresthesias, in diabetic patients with peripheral arterial disease. PMID- 23730481 TI - Symptomatic os infranaviculare. AB - The author observed a new accessory bone of the foot in the distal portion of navicular, which articulated with the medial cuneiform and the intermediate cuneiform, and named it os infranaviculare. A degenerative change was observed between the accessory bone and the navicular; this caused midfoot pain to the patient during weight-bearing. Thus, the patient was treated by excision of the accessory bone. The symptom was relieved at one-year postoperative. PMID- 23730482 TI - Using patient medical records for medical research. PMID- 23730483 TI - Factors associated with persistent smoking after the diagnosis of cardiovascular disease. AB - BACKGROUND: Although cigarette smoking is a major modifiable risk factor for the occurrence of primary and secondary cardiovascular disease (CVD), not all survivors from CVD attacks can successfully stop smoking. However, little is known about the factors associated with the change in smoking behavior after CVD attack. METHODS: Study subjects included 16,807 participants (>=19 years) in the fourth Korean National Health and Nutrition Examination Surveys. From them, we selected 180 persons who had previous CVD diagnosis (angina pectoris, myocardial infarction, or stroke) and were smoking at the time of CVD diagnosis. Then, we categorized the 180 persons into two groups according to change in smoking status after the CVD: quitter and non-quitter. Logistic regression analysis was done to evaluate multivariable-adjusted association. RESULTS: Even after CVD diagnosis, 63.60% continued to smoke. Fully-adjusted analysis revealed that regular drinking (odds ratio [OR], 4.44) and presence of smokers among family members (OR, 5.86) were significantly (P < 0.05) associated with greater risk of persistent smoking, whereas lower education level (OR, 0.20), larger amount of smoking (OR, 0.95), longer time since diagnosis (OR, 0.88), and diabetes (OR, 0.36) were significantly (P < 0.05) associated with decreased risk of persistent smoking after CVD. CONCLUSION: A great proportion of CVD patients tended to continue smoking in the Korean population. In order to reduce smoking rates among CVD patients further, more aggressive efforts towards smoking cessation should be continuously made with consideration of individual socioeconomic, behavioral, and clinical characteristics of CVD patients. PMID- 23730484 TI - Relationship between Family Adaptability, Cohesion and Adolescent Problem Behaviors: Curvilinearity of Circumplex Model. AB - BACKGROUND: The Family Adaptability and Cohesion Evaluation Scale (FACES) III using the circumplex model has been widely used in investigating family function. However, the criticism of the curvilinear hypothesis of the circumplex model has always been from an empirical point of view. This study examined the relationship between adolescent adaptability, cohesion, and adolescent problem behaviors, and especially testing the consistency of the curvilinear hypotheses with FACES III. METHODS: We used the data from 398 adolescent participants who were in middle school. A self-reported questionnaire was used to evaluate the FACES III and Youth Self Report. RESULTS: According to the level of family adaptability, significant differences were evident in internalizing problems (P = 0.014). But, in externalizing problems, the results were not significant (P = 0.305). Also, according to the level of family cohesion, significant differences were in internalizing problems (P = 0.002) and externalizing problems (P = 0.004). CONCLUSION: The relationship between the dimensions of adaptability, cohesion and adolescent problem behaviors was not curvilinear. In other words, adolescents with high adaptability and high cohesion showed low problem behaviors. PMID- 23730485 TI - The Relationship between Smoking Status and Suicidal Behavior in Korean Adults: The 4th Korea National Health and Nutrition Examination Survey (2007-2009). AB - BACKGROUND: This study was performed to evaluate the relationship between smoking status and suicidal ideations or suicide attempts in Korean adults. METHODS: The study used data from the 4th Korea National Health and Nutrition Examination Survey, and involved 17,065 participants. We used multiple logistic regression analysis to evaluate the relationship between smoking status and suicidal behavior. The results were adjusted for covariates including depression and physical disease. RESULTS: After adjusting for covariates, current smokers (odds ratio [OR], 1.66; 95% confidence interval [CI], 1.34 to 2.05) and former smokers (OR, 1.39; 95% CI, 1.13 to 1.72) proved more likely to have suicidal ideations than non-smokers. Among women, current smokers (OR, 2.00; 95% CI, 1.47 to 2.72) and former smokers (OR, 1.48; 95% CI, 1.11 to 1.99) were more likely to have suicidal ideations than non-smokers. However, among the men there was no significant relationship between smoking status and suicidal ideations. Among all the participants who had had suicidal ideations, there was a significant relationship between current smoking and suicide attempts (OR, 1.80; 95% CI, 1.05 to 3.07). There was also a relationship between current smoking and suicide attempts among women (OR, 2.40; 95% CI, 1.31 to 4.37), but no significant relationship among men. CONCLUSION: There is a relationship between smoking status and suicidal ideations and suicide attempts in the general population of Korea. This relationship is particularly clear in women, and is independent of comorbid chronic disease and depression. Current smokers and former smokers are more likely to have suicidal ideations than non-smokers; current smokers are also more likely to have attempted suicide. PMID- 23730486 TI - Effects of brief smoking cessation education with expiratory carbon monoxide measurement on level of motivation to quit smoking. AB - BACKGROUND: Smoking rates among Korean adult males is still high despite multifaceted efforts to reduce it. In Korea, there have been several studies on the effectiveness of smoking cessation education for inpatients, health check ups, and smoking cessation clinics. However, there haven't been any studies on the effectiveness of smoking cessation education conducted outside the hospital. This study investigated effectiveness of brief education on smoking cessation with an expiratory carbon monoxide (CO) measurement outside the hospital among adult male office-workers in Korea. METHODS: From April 1st to May 10th, 2012, we conducted a controlled trial among 95 adult male office workers over the age of 19 who smoke outside, in a public place in Seoul by cluster sampling. For the education group, we provided smoking cessation education for about 5 to 10 minutes, measured the expiratory CO level, and made the subjects complete questionnaires, while only self-help materials on quitting smoking were given to the control group. After 4 weeks, we evaluated the change in the level of motivation or success to quit smoking in both groups via e-mail or mobile phone. RESULTS: In the education group, the level of motivation to quit smoking was improved significantly. A multiple logistic regression analysis showed that the odds ratio of improved motivation to quit smoking in the education group was 28.10 times higher than that of the control group. CONCLUSION: Brief education on smoking cessation with expiratory CO measurement conducted outside the hospital could enhance the level of motivation to quit smoking. PMID- 23730487 TI - Non-alcoholic Fatty Liver Disease and Chronic Kidney Disease in Koreans Aged 50 Years or Older. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) share common pathogenic mechanisms and many risk factors, and both are linked to an increased risk of cardiovascular diseases. The aim of this study was to assess the association between NAFLD and CKD according to the presence of hypertension and diabetes mellitus in Koreans aged 50 years or older. METHODS: A cross-sectional study of 1,706 subjects who received their routine health examination was conducted between May 2008 and April 2010 at Konkuk University medical center. Biochemical tests for liver and abdominal ultrasonography were performed. CKD was defined as either proteinuria or glomerular filtration rate <=60 mL/min per 1.73 m(2). RESULTS: Among the 1,706 subjects, There were 545 (31.9%) with non-alcoholic fatty liver disease and 424 (24.9%) with chronic kidney disease. In univariate logistic regression analysis, NAFLD was significantly associated with CKD (odds ratio [OR], 1.69; 95% confidence interval [CI], 1.34 to 2.12). In multivariate logistic regression analysis adjusted for age, sex, current smoking, abdominal obesity, aspartate aminotransferases, alanine aminotransferases, gamma-glutamyltransferase, hypertension, diabetes mellitus, hypertriglyceridemia, and low high-density lipoprotein cholesterol, NAFLD was associated with CKD (adjusted OR, 1.68; 95% CI, 1.27 to 2.24). This relationship remained significant after classification according to the presence of hypertension or diabetes mellitus. CONCLUSION: NAFLD diagnosed by ultrasonography was significantly associated with CKD in Koreans aged 50 years or older. PMID- 23730488 TI - Relationship between Family Meals and Depressive Symptoms in Children. AB - BACKGROUND: Recently, importance of family meals has been emphasized at home and abroad, and several journals reported that family meals had a big impact on children's development. In this paper, we would like to report the relationship between family meals and depressive symptoms in children. METHODS: This study was based on questionnaires distributed to 162 5th and 6th graders of one elementary school in the area of Daegu, Korea, in July, 2010. The questionnaire was about general characteristics, family characteristics, and quantity/quality of family meals. Family functions and depressive symptoms in children were evaluated with Smilkstein's family APGAR (adaptability, partnership, growth, affection, and resolve) score (FAS) and Kovac's Children's Depression Inventory (CDI). RESULTS: In one-way analyses of variance, there was no significant difference in FAS and CDI according to general and family characteristics (P > 0.05). CDI was significantly lower in the group having more frequent family meals (P < 0.05). Higher FAS and lower CDI was seen in the group having more conversation and better atmosphere during meals (P < 0.05). There were no significant differences in FAS and CDI according to the number of participants, duration, and watching television during meals (P > 0.05). CONCLUSION: The frequency of family meals, having more conversation and better atmosphere during family meals predicted less depressive symptoms in children. PMID- 23730489 TI - Association of abdominal aortic calcification with lifestyle and risk factors of cardiovascular disease. AB - BACKGROUND: Abdominal aortic calcification (AAC) is a marker of subclinical atherosclerotic disease and an independent predictor of subsequent vascular morbidity and mortality. This study was conducted to investigate the association of AAC with lifestyle and risk factors of cardiovascular disease. METHODS: The results of the abdominal computed tomography of 380 patients who visited Chungnam National University Hospital for a health checkup from January 1, 2008 to December 31, 2009 were reviewed. A six-point scale was used in grading the overall severity of the calcification in three areas of the abdominal aorta, including the area superior to the renal artery, the upper-half area inferior to the renal artery, and the lower-half area inferior to the renal artery, in addition to the common iliac artery. The association of the AAC severity with the age, lifestyle factors, and risk factors of cardiovascular disease was analyzed via multiple linear regression analysis. RESULTS: In the male subjects, the age, presence of dyslipidemia and smoking were positively related to AAC, but exercising was negatively related to AAC (total R(2) = 0.563). In the female subjects, the age and presence of diabetes mellitus, hypertension, and dyslipidemia were positively related to AAC, but exercising was negatively related to AAC (total R(2) = 0.547). CONCLUSION: AAC was related to both the male and female subjects' age, presence of dyslipidemia, and exercising, to smoking in the male subjects and to the presence of diabetes mellitus and hypertension in the female subjects. PMID- 23730491 TI - Comments on statistical issues in may 2013. PMID- 23730490 TI - Referred otalgia induced by a large tonsillolith. AB - Herein, we report an unusual case of large tonsillolith presented with acute otalgia. Since the tonsils and tonsillar fossa are supplied by the glossopharyngeal nerve, any irritation or pain can be referred to the ear along the tympanic branch of the glossopharyngeal (Jacobson's) nerve. Also, it is worth re-emphasizing that normal otoscopy must be followed by inspection of the nasal cavities, oral cavity, and oropharynx, with particular note given to the floor of mouth, teeth, tongue, and tonsils because the identification of a causative etiology is necessary to successfully treat referred otalgia. PMID- 23730492 TI - Educational interventions need to be defined precisely. PMID- 23730493 TI - Editorial. PMID- 23730494 TI - Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study. AB - OBJECTIVES: Bendamustine is a unique cytotoxic agent active against various human malignancies, including chronic lymphocytic leukemia (CLL). In vitro studies suggest that cytotoxic activity of bendamustine on CLL-derived cells is synergized by rituximab. A retrospective chart review was conducted to characterize treatment-naive outpatients and those with relapsed disease aged 70 years and over with CLL receiving bendamustine (with or without rituximab) and to evaluate real-world patterns of care, safety, and effectiveness. METHODS: Using McKesson Specialty Care/US Oncology Network iKnowMed databases, 91 outpatients with at least two recorded visits and at least two cycles of bendamustine monotherapy or bendamustine-rituximab combination therapy were identified and included. Mean age at diagnosis and start of first therapy was 70.3 and 77.4 years respectively, and 63.7% of patients were men. RESULTS: Observed overall response rate was 56.3% in pooled treatment-naive patients [n = 9; complete response (CR) 18.8%; partial response (PR) 37.5%; nodular partial response (nPR) 0%] and 58.7% in pooled patients with relapsed disease (n = 44; CR 13.3%; PR 44.0%; nPR 1.3%). Median time to progressive disease has not been reached for the 16 treatment-naive patients (median follow up 15.1 months), and was 18.4 months for those with relapsed disease (n = 73). No unexpected toxicities were observed. Overall rate of blood/bone marrow toxicities (all grades) was 40.7%; grade 3/4 rates were 18.8% in treatment-naive patients and 25.3% in those with relapsed disease. Most frequent nonhematologic adverse events were fatigue and rash. CONCLUSION: In this retrospective chart review of 91 outpatients with CLL aged 70 years and over, bendamustine (with or without rituximab) was an effective therapeutic option with manageable toxicity. PMID- 23730495 TI - Novel therapies for peripheral T-cell lymphomas. AB - Peripheral T-cell lymphomas (PTCLs) are a diverse family of lymphoid neoplasms with poor prognosis. They represent approximately 6-10% of non-Hodgkin lymphomas with significant geographic variation. The median age at diagnosis varies with histology, however the majority of patients with PTCL are in their fifth or sixth decade of life. Until recently clinical development of new agents for PTCL was slow due to difficulties in making the correct diagnosis, lack of uniform classification and combination of rarity and biologic diversity of the group. In the last 5 years, significant advances were made to overcome these obstacles, leading to the approval of three new agents for relapsed and refractory PTCL by the Food and Drug Administration, based on well conducted prospective studies. Pralatrexate, a unique antifol, was the first agent granted approval, followed by romidepsin, a histone deacetylase inhibitor, and brentuximab vedotin, an immunoconjugate. Owing to the unique nature of these agents, durable responses were seen in patients with highly refractory disease, and some of these responses are long lasting after discontinuation of therapy. Accumulating data indicate that these novel agents have little cumulative toxicity and can be administered continuously to patients who are not candidates for consolidative stem-cell transplantation (SCT), with little impact on quality of life. They might also provide a new salvage option for patients eligible for SCT with no impact on autologous stem-cell collection or subsequent engraftment. New studies are underway to evaluate efficacy and safety of new agents in combination regimens for both newly diagnosed and relapsed/refractory PTCL. Several other investigational drugs showed promise in recent trials. This review focuses on novel therapies for T-cell lymphomas, their place in current treatment paradigms and future directions. PMID- 23730496 TI - Clinical implications and prognostic role of minimal residual disease detection in follicular lymphoma. AB - The identification of patients at high risk of relapse is a critical goal of modern translational research in oncohematology. Minimal residual disease (MRD) detection by polymerase chain reaction-based methods is routinely employed in the management of patients with acute lymphoblastic leukemia. Current knowledge indicates that it is also a useful prognostic tool in several mature lymphoproliferative disorders and particularly in follicular lymphoma (FL). Based on this evidence clinical trials employing MRD-based risk stratification are currently ongoing in FL. In this review the 'state of the art' of MRD evaluation in FL is discussed. A short description of technical issues and recent methodological advances is provided. Then, the bulk of the review focuses on critical take-home messages for clinicians working in the field. Finally, we discuss future perspectives of MRD detection and more generally outcome prediction in FL. PMID- 23730498 TI - Pomalidomide and its clinical potential for relapsed or refractory multiple myeloma: an update for the hematologist. AB - Multiple myeloma is a common plasma cell neoplasm that is incurable with conventional therapy. The treatment paradigm of multiple myeloma is not standardized and is evolving. The advent of novel drugs, including the proteasome inhibitor bortezomib and the immunomodulatory agents, has resulted in increased median survival. Unfortunately, all patients eventually relapse and require further therapy. Pomalidomide is the newest immunomodulatory drug, created by chemical modification of thalidomide with the intention of increasing therapeutic activity while limiting toxicity. Its mechanism of action is incompletely understood but involves anti-angiogenic effects, immunomodulation, an effect on the myeloma tumor microenvironment, and the protein cereblon. It is more potent than thalidomide and lenalidomide. In phase II studies, it has shown significant activity in patients with relapsed and refractory multiple myeloma, including patients who are heavily pretreated, have disease refractory to lenalidomide and bortezomib, and those with high-risk cytogenetic or molecular markers. It is generally well tolerated, with adverse effects including fatigue, neutropenia, neuropathy, and thromboembolic disease. Pomalidomide is a promising new agent in the expanding arsenal of antimyeloma drugs. In this review, we discuss the clinical experience to date with pomalidomide in multiple myeloma. PMID- 23730497 TI - The NOTCH signaling pathway: role in the pathogenesis of T-cell acute lymphoblastic leukemia and implication for therapy. AB - T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is characterized by aberrant activation of NOTCH1 in over 60% of T-ALL cases. The high prevalence of activating NOTCH1 mutations highlights the critical role of NOTCH signaling in the pathogenesis of this disease and has prompted the development of therapeutic approaches targeting the NOTCH signaling pathway. Small molecule gamma secretase inhibitors (GSIs) can effectively inhibit oncogenic NOTCH1 and are in clinical testing for the treatment of T-ALL. Treatment with GSIs and glucocorticoids are strongly synergistic and may overcome the gastrointestinal toxicity associated with systemic inhibition of the NOTCH pathway. In addition, emerging new anti NOTCH1 therapies include selective inhibition of NOTCH1 with anti-NOTCH1 antibodies and stapled peptides targeting the NOTCH transcriptional complex in the nucleus. PMID- 23730499 TI - Voriconazole and its clinical potential in the prophylaxis of systemic fungal infection in patients with hematologic malignancies: a perspective review. AB - Invasive fungal infections (IFIs) have become high prevalence in patients with hematologic malignancies. Drug-based strategies for IFIs include various approaches such as prophylactic, empiric, preemptive, and directed treatment. Prophylaxis is an attractive strategy in high-risk patients, given the lack of reliable diagnostics and the high mortality rate associated with IFIs. Prophylaxis includes the use of antifungal drugs in all patients at risk. An ideal antifungal compound for prophylaxis should have a potent and broad activity, be available both orally and intravenously, and have a low toxicity profile. Voriconazole fulfills all these criteria. The clinical efficacy of voriconazole against the majority of fungal pathogens makes it potentially very useful for the prevention of IFIs in patients with hematologic malignancies. Voriconazole appears to be very effective for the primary and secondary prevention of IFIs in these patients and recipients of allogeneic hematopoietic stem-cell transplantation. Randomized controlled trials evaluating voriconazole as primary antifungal prophylaxis in patients with neutropenia treated for a variety of hematologic malignancies have been performed, confirming its value as a prophylactic agent. Voriconazole is generally safe and well tolerated; however, its use is also associated with a number of concerns. In most patients with hematologic malignancies there is the potential for pharmacokinetic drug-drug interactions given that voriconazole is metabolized through the P450 cytochrome system. PMID- 23730500 TI - Short-term in vivo biological and mechanical remodeling of porcine acellular dermal matrices. AB - The purpose of this study was to assess the biological revitalization and mechanical integrity of Strattice(TM) Reconstructive Tissue Matrix, a porcine derived acellular dermal matrix, in vivo over time. We expanded the traditional subcutaneous model to incorporate biologic matrix scaffolds large enough to allow evaluation of mechanical properties in addition to the assessment of histological changes. Hematoxylin and eosin histology staining was used to evaluate cellular and tissue changes, and a mechanical testing frame was used to measure the ultimate tensile stress and Young's modulus of the implanted material over time. Cell infiltration and blood vessel formation into the porcine-derived acellular dermal matrix were evident at 2 weeks and increased with implantation time. Mechanical remodeling resulted in an initial decrease in ultimate tensile stress, not associated with cell infiltration, followed by a significant increase in material strength, concurrent with histological evidence of new collagen synthesis. Young's modulus followed a similar trend. PMID- 23730501 TI - Experience with cinacalcet in primary hyperparathyroidism: results after 1 year of treatment. AB - OBJECTIVES: To assess the characteristics of patients with primary hyperparathyroidism (PHPT) treated with cinacalcet and to evaluate its efficacy in reducing serum calcium and parathyroid hormone (PTH) concentrations after 1 year of treatment. METHODS: The study included 20 patients with PHPT who had completed at least 12 months of treatment with cinacalcet (eight patients for refusal of parathyroidectomy, three for surgery not possible due to comorbidities and nine for progressive hypercalcemia prior to surgery). We recorded clinical and biochemical data at baseline, and after 3, 6 and 12 months of treatment. We also monitored adverse events. Cinacalcet was administered in increasing doses until normal serum calcium was reached or side effects preventing a further increase occurred. RESULTS: After 3 months of treatment, serum calcium significantly decreased (11.73 +/- 0.85 versus 10.71 +/- 1.63 mg/dl, p < 0.001) and serum phosphorus significantly increased (2.41 +/- 0.48 versus 2.63 +/- 0.70 mg/dl, p = 0.004) while no significant change occurred in PTH (181.91 +/- 102.37 versus 195.47 +/- 111.71 pg/ml, p = 0.695). No further variation was observed after 6 months compared with 3 months of follow up. However, after 12 months of treatment, there was a significant decrease in PTH concentrations compared with baseline (181.91 +/- 102.37 versus 152.47+/- 70.16 pg/ml, p = 0.028) as well as serum calcium (11.73 +/- 0.85 versus 10.20+/- 0.95 mg/dl, p < 0.001); serum phosphorus significantly increased (2.41 +/- 0.48 versus 2.71 +/- 0.43 mg/dl, p = 0.01). Normocalcemia (S-Ca < 10.2 mg/dl) was achieved in 55% of patients. The medication was usually well tolerated (83.4%). Most common adverse events were nausea and vomiting, especially at the beginning of therapy. CONCLUSION: Cinacalcet rapidly reduced serum calcium in patients with PHPT and this reduction remained stable after 1 year of treatment. We also observed a decrease in PTH. Cinacalcet is an effective alternative in nonsurgical treatment of PHPT and may be useful in the preoperative hypercalcemia management. PMID- 23730502 TI - Improving major amputation rates in the multicomplex diabetic foot patient: focus on the severity of peripheral arterial disease. AB - OBJECTIVE: Peripheral arterial disease (PAD), as well as diabetic neuropathy, is a risk factor for the development of diabetic foot ulcers. The aim of this study was to evaluate differences and predictors of outcome parameters in patients with diabetic foot by stratifying these subjects according to the severity of PAD. RESEARCH DESIGN AND METHODS: In a prospective study, patients with new diabetic foot ulcers have been treated and investigated by structured healthcare. Subjects were recruited between 1 January 2000 and 31 December 2007. All study participants underwent a 2-year follow-up observation period. The patients underwent a standardized examination and classification of their foot ulcers according to a modification of the University of Texas Wound Classification System. The severity of PAD was estimated by measurement of the ankle brachial index (ABI) and the continuous wave Doppler flow curve into undisturbed perfusion (0.9 < ABI < 1.3), compensated perfusion (0.5 < ABI < 0.9), decompensated perfusion (ABI < 0.5) and medial arterial calcification. RESULTS: A total of 678 patients with diabetic foot were consecutively included into the study (69% male, mean age 66.3 +/- 11.0 years, mean diabetes duration 15.8 +/- 10.2 years). Major amputations (above the ankle) were performed in 4.7% of the patients. 22.1% of these subjects had decompensated PAD. These subjects had delayed ulcer healing, higher risk for major amputation [odds ratio (OR) 7.7, 95% confidence interval (CI) 2.8-21.2, p < 0.001] and mortality (OR 4.9, 95 % CI 1.1-22.1, p < 0.05). CONCLUSION: This prospective study shows that the severity of PAD significantly influences the outcome of diabetic foot ulcers regarding to wound healing, major amputation and mortality. PMID- 23730503 TI - Safety and efficacy of linagliptin in type 2 diabetes patients with common renal and cardiovascular risk factors. AB - Dipeptidyl-peptidase-IV (DPP-4) inhibitors have become an important orally active drug class for the treatment of type 2 diabetes as second-line therapy after metformin failure or as monotherapy or combination therapy with other drugs when metformin is not tolerated or contraindicated. DPP-4 inhibitors act mainly by increasing endogenous incretin hormone concentrations. They stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner with a significantly lower risk for hypoglycaemia than sulfonylureas. Furthermore, DPP-4 inhibitors are weight neutral. Linagliptin is a DPP-4 inhibitor that is eliminated by a hepatobiliary route, whereas the other DPP-4 inhibitors available today show a renal elimination. Therefore, it can be used in normal kidney function as well as in all stages of chronic kidney disease to stage 5 (glomerular filtration rate <15 ml/min/1.73 m(2)) without dose adjustments. Linagliptin was noninferior to metformin and sulfonylureas in clinical studies. In recent studies, it showed a superior safety profile over sulfonylurea treatment regarding hypoglycaemia and weight gain. More patients reached an HbA1c <7% without hypoglycaemia and weight gain with linagliptin compared with glimepiride. The safety profile with respect to a composite cardiovascular endpoint and stroke was also favourable for linagliptin, most likely due to a higher incidence of hypoglycaemia associated with glimepiride therapy and titration. This review gives an overview on the efficacy and safety of linagliptin in comparison with other antidiabetic drugs in type 2 diabetes patients with renal and cardiovascular risk factors as well as an outlook on the perspective for linagliptin in this patient population in the future. PMID- 23730505 TI - The re-birth of hepatic arterial infusion for colorectal liver metastases. PMID- 23730504 TI - Nano- and microfabrication for overcoming drug delivery challenges. AB - This highlight article describes current nano- and microfabrication techniques for creating drug delivery devices. We first review the main physiological barriers to delivering therapeutic agents. Then, we describe how novel fabrication methods can be utilized to combine many features into a single physiologically relevant device to overcome drug delivery challenges. PMID- 23730506 TI - The role of Endoscopic Ultrasound (EUS) in the management of patients with pancreatic cancer: now bigger than ever. PMID- 23730507 TI - A comparison of three treatment strategies for locally advanced and borderline resectable pancreatic cancer. AB - BACKGROUND: The optimal treatment strategy for locally advanced and borderline resectable pancreatic cancer is not known. We compared overall survival (OS), local control (LC), metastasis free survival (MFS), and percent of patients who were able to undergo successful surgical resection for three treatment strategies. METHODS: We retrospectively reviewed 115 sequentially treated cases of locally advanced (T4) or borderline resectable (T3 but unresectable) pancreatic cancer. Patients were treated with either chemotherapy alone (C), concurrent chemoradiation therapy (CRT), or chemotherapy followed by chemoradiation therapy (CCRT). We compared survival between groups using Kaplan Meier analysis and Cox-proportional hazards models. RESULTS: Median follow-up was 18.7 months. Fifty-six (49%) patients had locally advanced disease. Of the patients who received chemotherapy up-front, 82/92 (89%) received gemcitabine based chemotherapy. Of the patients receiving C alone, 11/65 (17%) were diagnosed with distant metastases or died before 3 months. The rate of successful surgical resection was 6/50 (12%) in patients treated with radiation therapy (CRT or CCRT). Median survival times for patients undergoing C, CRT, and CCRT were 13.9, 12.5, and 21.5 months respectively. Patients treated with CCRT experienced statistically significant improved OS and MFS compared to C alone (P=0.003 and P=0.012 respectively). There was no difference in LC between treatment groups. On multivariable analysis younger age (P=0.009), borderline resectable disease (P=0.035), successful surgery (P=0.002), and receiving chemotherapy followed by chemoradiation therapy (P=0.035) were all associated with improved OS. CONCLUSIONS: Treatment with CCRT is associated with improved median OS and MFS compared with C alone. This strategy may select for patients who are less likely to develop early metastases and therefore have a better prognosis. PMID- 23730508 TI - Hepatosplenic alpha/beta T-cell lymphoma masquerading as cirrhosis. AB - A 59-year-old man with diabetes mellitus, prior hepatitis B infection and recently diagnosed cirrhosis with prior Babesiosis presented to our institution from an outside hospital with six months of worsening abdominal pain, myalgias and fevers. On admission, physical examination revealed jaundice, hepatosplenomegaly and diffuse lymphadenopathy. Laboratory investigations demonstrated mild anemia, thrombocytopenia, hyperbilirubinemia and elevated lactate dehydrogenase. Tests for human immunodeficiency virus, and active Babesia microti infection were negative, however Epstein-Barr virus DNA by quantitative PCR was markedly elevated. CT scan revealed features suggestive of a cirrhotic liver without focal mass lesions as well as massive splenomegaly with axillary, retroperitoneal and inguinal lymphadenopathy. Bone marrow and lymph node biopsies were obtained which ultimately revealed hepatosplenic T-cell lymphoma. The patient's initial liver biopsy from five months prior to presentation was re evaluated by our institution's pathologists. Histologic analysis showed hepatic sinusoidal and portal infiltration of atypical lymphocytes morphologically identical to those present on the more recently excised lymph node tissue. The hepatic sinusoidal lymphoid cells were strongly positive for CD2, CD3 and CD5 whereas CD4, CD8 stained only minor subsets of the T cells. Subsequent flow cytometric immunophenotypying of peripheral blood identified T-cell receptor alpha/beta positive cells that lacked CD4 and CD8 (double negative alpha/beta T cells). Given the established bone marrow involvement, he was diagnosed with stage IV disease and treated with chemotherapy. His clinical course involved multiple hospitalizations complicated by hyponatremia, neutropenic fevers and pulmonary emboli. Following his fourth cycle of chemotherapy, he developed worsening liver failure and expired approximately three months after initial diagnosis of lymphoma. Hepatosplenic lymphoma of alpha/beta T cells is a rare malignancy with largely unclear risk factors and varied clinical presentations. Notably, diffuse infiltration of liver parenchyma is a prominent feature and the disease can mimic cirrhosis clinically as well as radiographically. Early recognition of this aggressive lymphoma is important and should be considered in the evaluation of patients in whom the etiology of cirrhosis remains in question. PMID- 23730509 TI - Neoadjuvant chemoradiotherapy for esophageal/gastroesophageal carcinoma. AB - BACKGROUND: Esophageal/gastroesophageal junction (GEJ) adenocarcinoma is increasingly treated with trimodality therapy. We present our experience using carboplatin/paclitaxel and radiotherapy followed by surgery. METHODS: Consecutive patients with distal esophageal/GEJ adenocarcinoma (>=T2 or N+) treated from July 2010 to October 2011 were identified. Treatment included neoadjuvant carboplatin/paclitaxel with concurrent radiotherapy (CRT) to 50.4 Gy using an IMRT technique and then Ivor Lewis esophagogastrectomy (ILE). PET/CT was performed prior to and after CRT. Patient/treatment characteristics and tumor response were analyzed. RESULTS: Over this timeframe, 16 patients completed trimodality therapy. All were male, median age of 60 years (45-72 years). All tumors were grade 2-3 with mean tumor length of 4.4 cm (1-9 cm). A median of 6 cycles (5-9 cycles) neoadjuvant carboplatin/paclitaxel were administered. Average time from diagnosis to CRT completion was 76 days (44-141 days) and 60 days (35 92 days) from CRT end to surgery. Neoadjuvant CRT was well tolerated with mean weight loss of 3.9 kg. All pts had R0 resections. No anastomotic leaks or perioperative mortality occurred. Mean hospital stay was 13 days (8-28 days). Pathologic complete response (pCR) was seen in 38% of patients, microscopic residual disease (isolated tumor cells or <2 mm) in 31%, and macroscopic residual disease remained in 31%. Mean SUV reduction was 41% (0-100%). Of 11 patients with >=35% SUV decrease, 45% had pCR and 27% had microscopic residual disease. Three patients had signet ring features. Of these, 2 had no SUV reduction and all had gross residual disease, including the only patient with positive nodal disease. CONCLUSIONS: Trimodality therapy utilizing concurrent carboplatin/paclitaxel and radiotherapy to 50.4 Gy followed by surgery was well tolerated and resulted in significant pathologic complete response or minimal residual disease. Further investigation of predictive factors for response is needed to best tailor therapy in the management of esophageal/GEJ adenocarcinoma. PMID- 23730510 TI - Clinical applications of gene expression in colorectal cancer. AB - BACKGROUND: Despite developments in diagnosis and treatment, 20% of colorectal cancer (CRC) patients present with metastatic disease and 30% of cases recur after curative surgery. Furthermore, the molecular factors involved in prognosis and response to therapy in CRC is poorly understood. The aims of this study were to quantitatively examine the expression of target genes in colorectal cancer and to correlate their expression levels with clinico-pathological variables. METHODS: A detailed analysis of published CRC microarray data was performed to identify the most prominent genes. The selected genes were validated in fifty-two pairs of fresh colorectal tumour and associated normal tissue specimens by RQ-PCR using TaqMan((r)) assays. Statistical analysis and correlation with clinicopathological data was performed using SPSS software. RESULTS: Expression levels of CXCL12 (P=0.000), CDH17 (P=0.026), MUC2 (P=0.000), L-FABP (P=0.000) and PDCD4 (P=0.000) were down regulated and IL8 (P=0.000) was upregulated in tumours compared to normal colorectal tissues. No significant differences were noted in expression of CEACAM5, CXCR4, CXCR7, TGFB1, TGFBR1 and TGFBR2. Furthermore, we found significant associations of gene expression levels and clinicopathological variables such as tumour size, grade, invasion and lymph node status. CONCLUSIONS: We identified a comprehensive list of genes with highly differential expression patterns in colorectal cancer that could serve as molecular markers to complement existing histopathological factors in diagnosis, follow up and therapeutic strategies for individualised care of patients. PMID- 23730511 TI - Differential lymph node retrieval in rectal cancer: associated factors and effect on survival. AB - BACKGROUND: Recent publications have identified positive associations between numbers of lymph nodes pathologically examined and five-year overall survival (5 yr OS) in colon cancer. However, focused examinations of relationships between survival of rectal cancer and lymph node counts are less common. We conducted a single institution, retrospective review of rectal cancer resections to determine whether lymph node counts correlated with 5-yr OS and to explore the relationship between lymph node counts and various clinical and pathologic factors. METHODS: A retrospective review of our institutional tumor registry identified 159 patients with AJCC Stage 1, 2, or 3 rectal cancers that underwent surgical resection at our institution over eleven years. Univariate analysis was used to explore the relationship between lymph node counts and age, AJCC Stage, time period of diagnosis, preoperative radiotherapy, and performance of TME. Survival analysis was performed by the Kaplan-Meier method and the Cox proportional hazards model. RESULTS: In univariate analysis, there was an association between increased lymph node counts and age <70, higher stage, and diagnosis during the later portion of the study period [all P-values <0.05]. Lymph node counts were not associated with survival in Kaplan-Meier analysis or in multivariate Cox proportional hazards analysis. CONCLUSIONS: Increasing lymph node counts improve survival and the accuracy of colorectal cancer staging. The body of literature recommends identical minimum lymph node counts in both colon and rectal cancer. In our study, which exclusively examined rectal cancer, we could not demonstrate that increased lymph node counts were associated with improved survival. PMID- 23730512 TI - Recent advances and significance of intra-arterial infusion chemotherapy in non resectable colorectal liver metastasis. AB - In era of systemic chemotherapy for colorectal liver metastasis (CLM), role of hepatic intraarterial infusion chemotherapy (HAIC) remains important. We examined treatment effects of HAIC in 36 patients with non-resectable CLM using 5-FU or CPT-11. Tumor response was complete response (CR) in 4, partial response (PR) in 19, stable disease (SD) in 6, and progressive disease (PD) in 7. Tumor control rate was 81% and response rate was 64%. Six patients showed catheter-related complications. Median survival period was 62 months in CR, and 25 with PR. HAIC has a major impact in high chemotherapy response and prolonging survival. PMID- 23730513 TI - Carbohydrate antigen 19-9 (CA 19-9) is an independent prognostic indicator in pseudomyxoma peritonei post cytoreductive surgery and perioperative intraperitoneal chemotherapy. AB - INTRODUCTION: Pseudomyxoma peritonei (PMP) is characteristically divided into two histopathological subtypes; disseminated peritoneal adenomucinosis (DPAM) and peritoneal mucinous carcinomatosis (PMCA). The latter is associated with a worse prognosis. However, even within the DPAM group, there is a considerable variation in outcome. In this study we investigate the role of baseline serum tumor markers CA 19-9, CEA and CA-125 in further stratifying survival. METHODS: Over 16 years, 218 patients with PMP were treated with cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) at our institution. A CA-125 level of >35 U/L, CA 19-9 of >40 U/mL and CEA of >3 ng/mL were considered positive or elevated outside the laboratory reference range. The impact of clinicopathologic and treatment-related variables on overall survival (OS) was analyzed with the Kaplan Meier method. Survival curves were compared using the log-rank test. Variables deemed significant by univariate analyses were entered into multivariate analysis using the Cox proportional hazards model. RESULTS: Within the DPAM group, the 5-year survival of patients who were CA 19-9 positive versus those with normal values were 58% and 90% respectively (P<0.001). Other variables found to negatively impact on OS in univariate analyses were completeness of cytoreduction (CC) score 2/3 (P<0.001), peritoneal cancer index (PCI) >25 (P<0.001) and male gender (P=0.017). In the Cox regression model, only CA 19-9 positivity was found to be an independent prognostic factor for OS (P=0.034). In addition to marker positivity, the absolute level of CA 19-9 was also prognostically significant. In patients with CA 19-9>1,000 U/mL, the 5-year survival was 23%, in contrast to 90% in patients with CA 19-9<100 U/mL (P<0.001). In the PMCA cohort, only CC-score was found to be associated with OS (P<0.001). CONCLUSIONS: Our study provides relevant prognostic information for the DPAM subtype in staging and prioritizing surgery; as even in apparently indolent disease, some patients have poorer survival. CA 19-9 elevation may also be useful in identifying patients who would potentially benefit from adjuvant therapy and/or closer post-operative surveillance. The potential role of CA 19-9 in mediating tumor cell adhesion and disease progression in PMP should be further investigated to deepen our understanding of the disease's inherent biological behavior. If a true relationship exists, CA 19-9 may be a conceivable target for immunotherapy. PMID- 23730514 TI - Signature of microsatellite instability, KRAS and BRAF gene mutations in German patients with locally advanced rectal adenocarcinoma before and after neoadjuvant 5-FU radiochemotherapy. AB - BACKGROUND: Multiple activating mutations of the signal- and repair pathway, such as BRAF-, KRAS-mutations and microsatellite instabilities are involved in colorectal cancer pathogenesis. Molecular characterization of specifically locally advanced rectal cancers is scarce. Therefore the retrospective study addresses the intratumoral status of KRAS, BRAF and microsatellites loci with respect to tumor response and patients' antecedent including nicotine abusus, familial history, and health care to further molecularly identify rectal cancer patients. METHODS: The study assesses the molecular status of 50 rectal cancer samples (25 before and 25 after neoadjuvant 5-FU radiochemotherapy). KRAS and BRAF mutations were examined through two independent analytical methods (sequencing and SNaPshot) to ensure efficient mutation detection. The microsatellite analysis was conducted using a fluorescent multiplex PCR-based method. RESULTS: KRAS mutations were found in 9 of 25 (36%) rectal cancer patients and were not significantly associated with the response to therapy (P=0.577), age (P=0.249) or sex of the patient (P=0.566). No link exists between KRAS mutation status and nodal (P=0.371) or metastatic stage (P=0.216). For two patients, KRAS mutation status changed after application of neoadjuvant 5-FU radiochemotherapy. All tumor samples were diagnosed BRAF-negative. Two rectal cancer patients exhibited a MSI-H phenotype and showed no tumor response. CONCLUSIONS: So one can conclude that (I) KRAS mutations status may change after neoadjuvant 5-FU radiochemotherapy relevant for further therapeutic decisions; (II) MSI-H patients do not respond to neoadjuvant 5-FU radiochemotherapy. Further prospective studies are needed to validate these results. PMID- 23730515 TI - Can only chemoradiotherapy and chemotherapy treatment be applied to patients with rectal cancer who could not be operated? AB - OBJECTIVES: This study is aimed to evaluate patients with non-metastatic rectal cancer who could not be operated due to any reason and were treated with chemoradiotherapy alone or chemotherapy following chemoradiotherapy. METHODS: Patients with locally advanced non-metastatic rectal cancer, who were treated and followed-up were evaluated. RESULTS: Totally 263 patients with stage II and III rectal cancer were evaluated. It was determined that 14 (5.2%) of the patients with locally advanced stages received chemoradiotherapy alone or chemotherapy following chemoradiotherapy, and they were followed-up instead of undergoing operation. The baseline assessments revealed that 8 (57.1%) patients had clinical stage II, and 6 (42.9%) patients had clinical stage III diseases. Recurrence was detected in 3 (21.4%) patients. 6 (42.9%) patients died, and death due to rectal cancer progression was detected in 2 (14.3%) patients. Median progression-free survival was 25 months (8 to 68 months), median overall survival was 35 months (12 to 68 months), overall survival rates in 1, 3 and 5 years were 92.9%, 69.8% and 52.4%, respectively. CONCLUSIONS: Chemoradiotherapy alone or subsequent chemotherapy after chemoradiotherapy may be suitable for patients with non metastatic locally advanced rectal cancer who could not be operated due to any reason. PMID- 23730517 TI - The aspartate aminotransferase to platelet ratio before chemotherapy predicts adverse events for FOLFOX and XELOX regimens including bevacizumab as the first line therapy for stage IV, recurrent and metastatic colorectal cancer. AB - BACKGROUND: Oxaliplatin-based chemotherapy for colorectal liver metastasis can induce hepatotoxicity, which increases the risk of liver resection. We previously reported that the aspartate aminotransferase to platelet ratio (APR) before chemotherapy can indicate oxaliplatin-induced splenomegaly and also predict the occurrence of adverse events during chemotherapy. Bevacizumab (BEV) was recently reported to reduce oxaliplatin-induced splenomegaly. Therefore, the aim of the present study was to investigate whether the APR before chemotherapy can predict the splenomegaly and adverse events associated with FOLFOX/BEV or XELOX/BEV in patients with stage IV or recurrent colorectal cancer. METHODS: We performed CT volumetry of the spleen before and 12 weeks after FOLFOX/BEV and XELOX/BEV in 63 patients. The incidence of adverse events, haematological parameters, and biochemistry and urinalysis results were assessed during treatment. RESULTS: An increase in the splenic volume was not observed in the FOLFOX/BEV group, but was significant in the XELOX/BEV group (+5.0% vs. +18.8%, P=0.01). The APR before chemotherapy did not indicate the presence of splenomegaly in the 63 patients, however, it did significantly predict the development of grade 2 or higher adverse events during chemotherapy. CONCLUSIONS: An APR of 0.15 or higher before chemotherapy did not indicate the presence of splenomegaly, but could predict the development of adverse events due to FOLFOX/BEV and XELOX/BEV treatment. PMID- 23730516 TI - Treatment outcome of gastric extra-nodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue type in the Hong Kong Chinese population: a single centre experience. AB - OBJECTIVE: To analyze the clinical characteristics, treatment outcome of patients with gastric extra-nodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type (EMZBL-MALT). METHODS: Data of 30 patients with gastric EMZBL-MALT diagnosed in Caritas Medical Center between July 1997 and June 2009 were analyzed retrospectively. RESULTS: The median follow-up time was 6.4 years [interquartile range (IQR) 3.9 to 8.9 years] and the median age at time of diagnosis was 71.5 years (IQR 64 to 81 years). All subjects, with investigations done for disease staging, suffered from localized disease (stage I or II1). Helicobacter infection was identified in 67% of subjects. Twenty Helicobacter positive subjects received Helicobacter eradication treatment and seven Helicobacter-negative subjects received single-agent chemotherapy (cyclophosphamide), with disease remission rates at 85% and 71% respectively. Only one subject died apparently from disease progression. The 5-year and 10-year overall survival rates were 75% and 62.5% respectively. CONCLUSIONS: Helicobacter eradication and single-agent chemotherapy were effective treatment modalities for early stage gastric EMZBL-MALT with and without Helicobacter infection respectively. Survival was favorable. PMID- 23730518 TI - Cytopathology of the pancreatobiliary tract-the agony, and sometimes, the ease of it. AB - Pancreatic cytopathology is recognized as a rapid, reliable, safe and cost beneficial modality of investigation of pancreatic mass lesions. Optimal cytodiagnosis depends on multiple factors including sample quality, and expertise of the cytopathologist and endoscopist. This article discusses key cytologic features of specific tumor types, specimen handling, differential diagnoses and pitfalls. PMID- 23730519 TI - Endoscopic ultrasonography for pancreatic cancer: current and future perspectives. AB - A suspected pancreatic lesion can be a difficult challenge for the clinician. In the last years we have witnessed tumultuous technological improvements of the radiological and nuclear medicine imaging. Taking this into account, we will try to delineate the new role of endoscopic ultrasound (EUS) in pancreatic imaging and to place it in a shareable diagnostic and staging algorithm of pancreatic cancer (PC). To date the most accurate imaging techniques for the PC remain contrast-enhanced computed tomography (CT) and EUS. The latter has the highest accuracy in detecting small lesions, in assessing tumor size and lymph nodes involvement, but helical CT or an up-to-date magnetic resonance imaging (MRI) must be the first choice in patients with a suspected pancreatic lesion. After this first step there is place for EUS as a second diagnostic level in several cases: negative results on CT/MRI scans and persistent strong clinical suspicion of PC, doubtful results on CT/MRI scans or need for cyto-histological confirmation. In the near future there will be great opportunities for the development of diagnostic and therapeutic EUS and pancreatic pathology could be the best testing bench. PMID- 23730520 TI - Update on antiangiogenic therapy in colorectal cancer: aflibercept and regorafenib. AB - Angiogenesis plays an important role in colorectal carcinogenesis and approaches targeting the vascular growth factor receptor (VEGF) signaling such as bevacizumab yielded significant survival improvement for metastatic colorectal cancer patients. Recent evidence demonstrated the benefit of continuing angiogenic suppression after first-progression following bevacizumab-containing cytotoxic regimen though no benefit was observed with the use of bevacizumab in adjuvant setting. Aflibercept, a soluble fusion protein with high affinity for VEGF-A, -B and PlGF, administered in combination with irinotecan-containing regimen improved the survival of metastatic colorectal cancer patients in second line setting (VELOUR trial). Regorafenib, a small molecule multikinase inhibitor against various pro-angiogenic and -proliferation targets, improved the survival of metastatic colorectal cancer patients who had progressed on all standard therapy. These developments had renewed enthusiasm in the field and the role of aflibercept and regorafenib in other treatment settings will continue to be defined by on-going and future clinical trials. As other anti-angiogenic approaches are being tested clinically, other novel non-angiogenic targets deserve to be evaluated in our effort to improve the outcome of colorectal cancer patients. PMID- 23730521 TI - Small cell carcinoma of the anus in the setting of prior squamous dysplasia and carcinoma in situ. AB - Small cell carcinoma of the anus is a rare tumor that has been infrequently described in the literature. In contrast to squamous cell carcinoma, which is known to be associated with high-risk subtypes of human papillomavirus (HPV), the etiology of small cell carcinoma of the anal canal is not established. We present a case of a patient with small cell carcinoma of the anal canal in the setting of prior squamous dysplasia and carcinoma in situ. In conjunction with recently published data demonstrating the presence of HPV in tumor specimens from patients with small cell carcinoma of the anal canal, our patient's clinical course suggests a possible link between HPV and this rare malignancy. PMID- 23730522 TI - Solitary gastric metastasis from primary lung adenocarcinoma: a rare site of extra-thoracic metastatic disease. AB - Lung cancer metastasizing to gastrointestinal (GI)-tract is a rare event. Gastric metastasis is usually asymptomatic but when mucosal in location it may cause symptoms as demonstrated in the current case. This report describes a 60-year old male who was admitted for evaluation of a left upper lobe lung mass with associated bilateral nodular opacities and mediastinal lymphadenopathy. After thorough work-up the diagnosis of advanced lung adenocarcinoma was made. During hospitalization period and prior to starting chemotherapy, he exhibited upper gastrointentinal bleeding. Esophagogastroduodenoscopy revealed an ulcerative lesion in the gastric corpus representing metastasis of the primary lung carcinoma that ensued from immunohistochemical analysis. Clinical, pathological and therapeutic aspects of this uncommon site of extrathoracic metastatic disease are discussed, emphasizing the importance of the immunohistochemistry in the differential diagnosis of lung carcinomas whether primary or secondary to the lung. PMID- 23730523 TI - Gemcitabine plus Nab-Paclitaxel with chemoradiation in locally advanced pancreatic cancer (LAPC). AB - Gemcitabine (GEM) is a cytotoxic agent that is potent against pancreatic adenocarcinoma. Nab-paclitaxel (nab-P), an albumin-bound formulation of paclitaxel, appears to decrease levels of cytidine deaminase, which is the primary gemcitabine catabolic enzyme, this likely increases sensitivity to GEM when these agents are combined. Here we present a case of a 52 year old female with locally advanced pancreatic cancer with elevated CA19-9 at diagnosis who received GEM + nab-P followed by GEM based chemoradiation who underwent surgical resection despite persistent stable disease on radiographic studies and was found to have complete pathologic response. PMID- 23730524 TI - A patient who showed a pathologically complete response after undergoing treatment with XELOX plus bevacizumab for synchronous liver metastasis of grade H2 from sigmoid colon cancer. AB - We herein report the case of a patient who showed a pathological complete response after undergoing chemotherapy with capecitabine, oxaliplatin and bevacizumab. The patient presented with synchronous solitary liver metastasis from sigmoid colon cancer. The maximum diameter of the liver deposit was 5.7 cm and the grade of the liver metastasis was H2 according to the Japanese classification. Deferred hepatectomy after sigmoidectomy was performed, followed by the administration of neoadjuvant chemotherapy. After undergoing sigmoidectomy, the patient received 1,000 mg/m(2) of capecitabine and 130 mg/m(2) of oxaliplatin without bevacizumab as the first cycle of chemotherapy followed by eight cycles of chemotherapy with bevacizumab (7.5 mg/kg) every three weeks. The liver deposit was reduced to 2.2 cm in diameter and the patient showed a partial response to chemotherapy. The patient then underwent metastasectomy of segment 8 of the liver instead of the central hepatectomy that was possibly needed before chemotherapy. Histopathologically, the tumor consisted of fibrous tissue, and no cancer cells were detected in the resected specimen. A pathological complete response in a patient with H2 liver metastasis is considered rare and suggests that capecitabine, oxaliplatin and bevacizumab are efficacious as neoadjuvant chemotherapy. PMID- 23730526 TI - Nitric Oxide-Releasing Hybrid Drugs Target Cellular Processes Through S Nitrosylation. AB - Nitric oxide (NO)-releasing agents such as JS-K and NO-releasing hybrids such as NO- and NONO-nonsteroidal anti-inflammatory drugs are novel agents with great potential for controlling cancer. Although studied extensively, a key question pertaining to their molecular targets and mechanism of action remains unclear: the role of NO in the overall biological effect of these agents. It has been shown that NO can directly modify sulfhydryl residues of proteins through S nitrosylation and induce apoptosis. We showed that 3 structurally diverse NO nonsteroidal anti-inflammatory drugs S-nitrosylated nuclear factor-kappaB p65 in vitro and in vivo and also showed that these agents S-nitrosylated caspase-3 in vivo. JS-K reduced nuclear beta-catenin and cyclin D1 protein levels without affecting cytosolic beta-catenin expression. On the basis of a time course study, S-nitrsolyation of nuclear beta-catenin was determined to precede its degradation. These data provide a mechanistic role for NO and a rationale for the chemopreventive effects of these novel agents. PMID- 23730525 TI - Computer-Aided Approaches for Targeting HIVgp41. AB - Virus-cell fusion is the primary means by which the human immunodeficiency virus 1 (HIV) delivers its genetic material into the human T-cell host. Fusion is mediated in large part by the viral glycoprotein 41 (gp41) which advances through four distinct conformational states: (i) native, (ii) pre-hairpin intermediate, (iii) fusion active (fusogenic), and (iv) post-fusion. The pre-hairpin intermediate is a particularly attractive step for therapeutic intervention given that gp41 N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR) domains are transiently exposed prior to the formation of a six-helix bundle required for fusion. Most peptide-based inhibitors, including the FDA-approved drug T20, target the intermediate and there are significant efforts to develop small molecule alternatives. Here, we review current approaches to studying interactions of inhibitors with gp41 with an emphasis on atomic-level computer modeling methods including molecular dynamics, free energy analysis, and docking. Atomistic modeling yields a unique level of structural and energetic detail, complementary to experimental approaches, which will be important for the design of improved next generation anti-HIV drugs. PMID- 23730527 TI - Astroglial PTEN Loss Disrupts Neuronal Lamination by Dysregulating Radial Glia guided Neuronal Migration. AB - PTEN plays an important role not only in tumorigenesis but also in the normal development of central nervous system. PTEN loss in neural progenitor cells during embryogenesis disrupts migration and proper formation of the brain laminar structure. We generated a conditional PTEN knockout mouse by crossing mice that express Cre recombinase driven by the human GFAP promoter to a floxed PTEN gene to investigate the role of astroglial PTEN signaling pathway in neuronal patterning and lamination. We found PTEN loss not only in astroglial cells, but also in radial glia-derived neurons in hGFAP-Cre(+/-)/PTEN(loxp/loxp) transgenic mice. Homozygous hGFAP-Cre(+/-)/PTEN(loxp/loxp) transgenic mice showed progressive brain enlargement with cellular disorganization that occurred predominantly in hippocampus and cerebellum and died by postnatal day 20. Confocal images show that nestin-positive radial glial cells were observed in the hippocampus, cortex, and cerebellum at postnatal day 0 in homozygous hGFAP-Cre(+/ )/PTEN(loxp/loxp), but not in heterozygous hGFAP-Cre(+/-)/PTEN(loxp/-) and hGFAP Cre(-/-)/PTEN(loxp/loxp) mice. Homozygous hGFAP-Cre(+/-)/PTEN(loxp/loxp) transgenic mouse eyes, which lack radial glial lineage, were able to develop normal architectonics after birth. In addition, we also found that neuronal progenitor migration was defected at postnatal day 0 in homozygous hGFAP-Cre(+/ )/PTEN(loxp/loxp) mice. These results suggest that PTEN has a critical role in regulating radial glial differentiation, proliferation, maturation, and eventually neuronal patterning in central nervous system in a spatio-temporal dependent manner. PMID- 23730528 TI - Secondhand Smoke Exposure in Aging-related Cardiac Disease. AB - Exposure to secondhand smoke (SHS) exposure is increased the risk of heart disease included atherosclerosis and coronary disease. Aging is a physiology process involving progressive impairment of normal heart functions, due to an increasing vulnerability, which reduces the ability of survive. However, it is not clear pathological condition in aging exposure to SHS. The aim of this study was to examine SHS exposure in aging-related disease. The rats were placed in SHS exposure chamber and exposed to 10 cigarettes for 30 min, twice a day, 5 days/ one week for 1 month. After 4 weeks secondhand smoke exposure, rats left ventricular (LV) underwent morphological and function study with echocardiography. Histopathology of left ventricular sections were stained with Hematoxylin-Eosin staining and related left ventricular hypertrophy protein expression levels by Western blot analysis. After 4 weeks SHS exposure, LV weight showed significant increased. On the other hand, from echocardiography result, we found EF (%) and FS (%) were apparently decreased in aging SHS exposure. IVS, LVID and LVPW at diastolic diameters were increased in aging SHS exposure. However, in aging systolic diameters always preserved. Here we did not show that. Moreover, we observed enlargement morphology of the LV and LV well thickness of increase. In addition, we found LV hypertrophy marker protein, calcineurin/NFATc4, was only increased in aging and aging SHS exposure. Our study suggests that SHS exposure and aging will altercate left ventricular hypertrophy. PMID- 23730529 TI - Hippocampal oscillatory activity in Alzheimer's disease: toward the identification of early biomarkers? AB - Alzheimer's disease (AD) develops for a yet unknown period of time and can progress undiagnosed for years before its first clinical manifestation consisting of characteristic cognitive impairments. Current AD treatments offer only a small symptomatic benefit, likely because AD is diagnosed when the pathology is already well advanced, whereas treatments may be most efficient in the early phases of pathology. An accurate, early marker of AD is therefore needed to help diagnose AD earlier. It is now well documented that AD patients and animal models of AD exhibit reorganization of hippocampal and cortical networks. This reorganization is initiated by an early imbalance between excitation and inhibition, leading to altered network activity. The mechanisms underlying these changes are unknown but recent evidence suggests that either soluble amyloid-beta (Abeta) or fibrillar forms of Abeta are central to various network alterations observed in AD. However, recent evidence also suggests that Abeta over-production in animal models is not systematically linked to network over-excitation. We hypothesize here that early changes in the excitation-inhibition balance within the hippocampus occurs much earlier than currently believed and initially produces only slight changes in overall hippocampal activity. In this review, we introduce the concept according to which the subtle changes in theta and gamma rhythms might occur during the very first stages of AD and thus could be used as a possible predictor for the disease. PMID- 23730532 TI - Impact of an EMR-Based Daily Patient Update Letter on Communication and Parent Engagement in a Neonatal Intensive Care Unit. AB - OBJECTIVE: To evaluate the impact of using electronic medical record (EMR) data in the form of a daily patient update letter on communication and parent engagement in a level II neonatal intensive care unit (NICU). STUDY DESIGN: Parents of babies in a level II NICU were surveyed before and after the introduction of an EMR-generated daily patient update letter, Your Baby's Daily Update (YBDU). RESULTS: Following the introduction of the EMR-generated daily patient update letter, 89% of families reported using YBDU as an information source; 83% of these families found it "very useful", and 96% of them responded that they "always" liked receiving it. Rates of receiving information from the attending physician were not statistically significantly different pre- and post implementation, 81% and 78%, respectively (p = 1). Though there was no statistically significant improvement in parents' knowledge of individual items regarding the care of their babies, a trend towards statistical significance existed for several items (p <.1), and parents reported feeling more competent to manage information related to the health status of their babies (p =.039). CONCLUSION: Implementation of an EMR-generated daily patient update letter is feasible, resulted in a trend towards improved communication, and improved at least one aspect of parent engagement-perceived competence to manage information in the NICU. PMID- 23730530 TI - The effects of aging and electrical stimulation exercise on bone after spinal cord injury. AB - Age related bone loss predisposes adults to osteoporosis. This is especially true for individuals with spinal cord injury (SCI). The effects of decreased bone loading with older age and paralysis significantly contribute to decreased bone mass and increased risk for fragility fractures. Loading bone via volitional muscle contractions or by using electrical stimulation are common methods for helping to prevent and/or decrease bone loss. However the effectiveness and safety of electrical stimulation activities remain unclear. The purpose of this review is to investigate the factors associated with aging and osteoporosis after SCI, the accuracy of bone measurement, the effects of various forms of bone loading activities with a focus on electrical stimulation activities and the safety of physical exercise with a focus on electrical stimulation cycling. Osteoporosis remains a disabling and costly condition for older adults and for those with paralysis. Both dual energy x-ray absorptiometry and peripheral quantitative computed tomography are valuable techniques for measuring bone mineral density (BMD) with the latter having the ability to differentiate trabecular and cortical bone. Physical activities have shown to be beneficial for increasing BMD however, the extent of the benefits related to aging and paralysis remain undetermined. Electrical stimulation activities administered appropriately are assumed safe due to thousands of documented safe FES cycling sessions. However, specific documentation is needed to verify safety and to development formal guidelines for optimal use. PMID- 23730531 TI - Cholesterol and cardiovascular disease in the elderly. Facts and gaps. AB - Hypercholesterolemia is a major cardiovascular risk factor that increases the incidence of atherosclerotic diseases in adults, although the association is less well established in the elderly. The role of statins is well characterized for the reduction of myocardial infarction incidence or death in individuals with a history or high risk of cardiovascular diseases, regardless of age. Therapeutic measures recommended to prevent cardiovascular diseases and to reduce cholesterol levels in the elderly, such as lifestyle changes and lipid-lowering drugs, particularly statins, are based on studies conducted in younger adults. This narrative review aims to summarize the main observational studies and randomized clinical trials that have studied the relationship between cholesterol and cardiovascular diseases and the potential benefits and drawbacks of statins use in elderly patients. PMID- 23730533 TI - Incorporating digital health literacy into adult ESL education on the US-Mexico border. AB - The increasing digitization of information and communication has undoubtedly impacted the ways in which people in the United States access and interpret health information. Although the traditional emphasis of health literacy research has been the comprehension of health-related texts such as patient information forms, prescriptions, and medicine labels, the increased use of electronic means to locate health information requires more critical engagement with texts beyond basic comprehension. In accessing electronic health information, patients need to be able to navigate the vast amount of online health information and to interpret and synthesize health information across multiple sources (i.e. websites) while also evaluating the credibility of these sources. Recent health literacy research has examined the increased role of the media literacy in influencing health behaviors (Bergsma & Carney, 2008) and the role of increased access to computers (Salovey et al., 2009), but little (if any) research to date has provided recommendations for best practices related to meeting the health literacy demands required by digitization. This article attempts to fill this gap by exploring the use of the internet as a key source of health information and by looking at best practices in teaching digital health literacy. It describes the development of a digital literacy component within a community-based health literacy/ESL curriculum funded by the National Institutes of Health and implemented on the US Mexico border. PMID- 23730534 TI - Observations from the Balcony: Directions for Pediatric Health Disparities Research and Policy. PMID- 23730535 TI - Impaired Histatin-5 Levels and Salivary Antimicrobial Activity against C. albicans in HIV Infected Individuals. AB - HIV-infected individuals constitute a population highly susceptible to opportunistic infections, particularly oral candidiasis caused by the most pathogenic human fungal species Candida albicans. Host-produced salivary antimicrobial peptides are considered to be an important part of the host innate immune system involved in protection of the oral cavity against colonization and infection by microbial species. Histatin-5 (Hst-5) specifically has exhibited potent anti-candidal properties in vitro. However, its importance in protecting the oral mucosa against candidal colonization and importantly, its contribution to the observed enhanced susceptibility of HIV-infected individuals to candidiasis has not been previously investigated. To that end, a novel immunoassay was used to demonstrate significant decrease in salivary Hst-5 levels in HIV+ individuals concomitant with enhanced candidal prevalence. Further, saliva's anti-candidal potency was found to be proportional to Hst-5 concentration and significantly compromised in HIV+ subjects compared to controls. The key role for Hst-5 was further confirmed upon exposure to the Hst-5 specific antibody where saliva's initial killing activity was substantially compromised. Combined, these findings identify Hst-5 as a key anti-candidal salivary component and demonstrate its decreased levels in HIV infection providing new insights into oral Innate immune defense mechanisms and the enhanced susceptibility of HIV+ individuals to oral candidiasis. PMID- 23730538 TI - The worm sheds light on anesthetic mechanisms. AB - One hundred and sixty five years have passed since the first documented use of volatile anesthetics to aid in surgery, but we have yet to understand the underlying mechanism of action of these drugs. There is no question that, in vitro, volatile anesthetics can affect the function of numerous neuronal and non neuronal proteins. In fact, volatile anesthetics are capable of binding such diverse proteins as albumin and bacterial luciferase. The promiscuity of volatile anesthetic binding makes it difficult to determine which proteins are modulated by anesthetics to cause the state of anesthesia. Consequently, despite a great deal of in vitro data, the fundamental physiological process that volatile anesthetics perturb to effect neuronal silencing is not yet identified. Recently, data has increasingly indicated that membrane leak channels may play a role in the anesthetic response. Here we comment on the use of optogenetics to further support such a model. PMID- 23730539 TI - Evaluation of the Accuracy of a Triaxial Accelerometer Embedded into a Cell Phone Platform for Measuring Physical Activity. AB - BACKGROUND: Physical activity is important in health and weight management. Several cell phone platforms integrate an accelerometer onto the motherboard. Here we tested the validity of the cell phone accelerometer to assess physical activity in a controlled laboratory setting. METHODS: 31 subjects wore the cell phone on their waist along with the validated Physical Activity Monitoring System (PAMS) with different body postures and during graded walking. Energy expenditure was measured using indirect calorimetry. 11 subjects also wore the iPhone at different locations such as arm, hand, pant pocket, etc. RESULTS: The cell phone accelerometer was accurate and precise compared to the PAMS, with an intra-class correlation coefficient (r2> 0.98). The cell phone accelerometer showed excellent sequential increases with increased in walking velocity and energy expenditure (r2>0.9). CONCLUSION: An accelerometer embedded into a cell phone was accurate and reliable in measuring and quantifying physical activity in the laboratory setting. Data from free-living users shows promise for deployment of a comprehensive integrated physical activity promoting and weight loss platform using such mobile technologies. PMID- 23730536 TI - Mapping the New World of Necrotizing Enterocolitis (NEC): Review and Opinion. AB - A comprehensive review of necrotizing enterocolitis (NEC) is provided; including history, biological basis and frequently asked questions. In addition, a system of improved NEC classification is explained in detail (consisting of five NEC subsets and four NEC-like diseases), to aid the bedside clinician in therapy and prevention. The authors offer opinion for therapeutics in italics at the end of each definition. PMID- 23730540 TI - Chemical Exchange Saturation Transfer (CEST) Imaging: Description of Technique and Potential Clinical Applications. AB - Chemical exchange saturation transfer (CEST) is a magnetic resonance imaging (MRI) contrast enhancement technique that enables indirect detection of metabolites with exchangeable protons. Endogenous metabolites with exchangeable protons including many endogenous proteins with amide protons, glycosaminoglycans (GAG), glycogen, myo-inositol (MI), glutamate (Glu), creatine (Cr) and several others have been identified as potential in vivo endogenous CEST agents. These endogenous CEST agents can be exploited as non-invasive and non-ionizing biomarkers of disease diagnosis and treatment monitoring. This review focuses on the recent technical developments in endogenous in vivo CEST MRI from various metabolites as well as their potential clinical applications. The basic underlying principles of CEST, its potential limitations and new techniques to mitigate them are discussed. PMID- 23730542 TI - Expanded endoscopic endonasal approaches to skull base meningiomas. AB - Anterior cranial base meningiomas have traditionally been addressed via frontal or frontolateral approaches. However, with the advances in endoscopic endonasal treatment of pituitary lesions, the transphenoidal approach is being expanded to address lesions of the petrous ridge, anterior clinoid, clivus, sella, parasellar region, tuberculum, planum, olfactory groove, and crista galli regions. The expanded endoscopic endonasal approach (EEEA) has the advantage of limiting brain retraction and resultant brain edema, as well as minimizing manipulation of neural structures. Herein, we describe the techniques of transclival, transphenoidal, transplanum, and transcribiform resections of anterior skull base meningiomas. Selected cases are presented. PMID- 23730541 TI - Mechanisms for Structural Variation in the Human Genome. AB - It has been known for several decades that genetic variation involving changes to chromosomal structure (i.e., structural variants) can contribute to disease; however this relationship has been brought into acute focus in recent years largely based on innovative new genomics approaches and technology. Structural variants (SVs) arise from improperly repaired DNA double-strand breaks (DSB). DSBs are a frequent occurrence in all cells and two major pathways are involved in their repair: homologous recombination and non-homologous end joining. Errors during these repair mechanisms can result in SVs that involve losses, gains and rearrangements ranging from a few nucleotides to entire chromosomal arms. Factors such as rearrangements, hotspots and induced DSBs are implicated in the formation of SVs. While de novo SVs are often associated with disease, some SVs are conserved within human subpopulations and may have had a meaningful influence on primate evolution. As the ability to sequence the whole human genome rapidly evolves, the diversity of SVs is illuminated, including very complex rearrangements involving multiple DSBs in a process recently designated as "chromothripsis". Elucidating mechanisms involved in the etiology of SVs informs disease pathogenesis as well as the dynamic function associated with the biology and evolution of human genomes. PMID- 23730543 TI - Survival in Sinonasal Melanoma: A Meta-analysis. AB - Sinonasal melanoma is an uncommon tumor which carries a poor prognosis and high rates of local and regional recurrence and distant metastasis. While surgical resection is the mainstay of treatment, the utility of multimodality therapy has not been well studied or established. We sought to better evaluate the optimal treatment modality for sinonasal melanoma. We reviewed 39 case reports involving 423 patients with sinonasal melanoma and present a meta-analysis comparing survival by treatment modality. The two-tailed p-value for survival by treatment modality was determined. The number of primary site/local, regional, and distant recurrences was determined where data was available. There was a nonsignificant increase in survival for patients treated with surgery + radiotherapy versus surgery alone. There was a statistically significant increase in survival for surgery + chemotherapy versus chemotherapy alone and versus surgery alone. Patients treated with combined surgery, radiation, and chemotherapy had a statistically shorter survival interval than patients treated with surgery + chemotherapy, which may reflect more advanced disease in patients treated with triple therapy. There was no statistically significant increase in survival found for the addition of radiation to surgery. This meta-analysis demonstrates that multimodality therapy, particularly the addition of chemo-or immunotherapy to surgery, may increase survival in a subset of patients. Radiation therapy did not appear to increase survival. There may be a significant increase in overall survival with combined modality therapy with surgery and chemo/immunotherapy versus single modality therapy. LEVEL OF EVIDENCE: III. Grade of recommendation: C. PMID- 23730544 TI - Skull base approach to carotid artery lesions: technique, indications, and outcomes. AB - Operative approaches to lesions of the carotid artery at the skull base are challenging and place multiple cranial nerves at risk. Herein, we describe a preauricular approach utilizing anterior dislocation of the temporomandibular joint with microscopic drill-out of the medial glenoid and Eustachian tube to identify and skeletonize the carotid artery in the foramen lacerum. The facial nerve remains undissected during this approach. Nine of 10 patients presented with aneurysm, six spontaneous and three following blunt trauma, and one patient presented with carotid artery rupture after penetrating trauma. Three of the patients presented with cranial nerve (CN) deficits that persisted. One patient was unevaluable preoperatively due to trauma but awoke with multiple CN deficits. Only one of nine evaluable patients suffered a new long-term CN deficit (XI). One patient had persistent temporomandibular joint dysfunction. All patients had long term patency of the graft or anastamosis and no new neurologic symptoms were reported with a mean follow-up of 55 months. Open approaches to the carotid artery at the skull base are feasible and with careful anatomic dissection can be performed with minimal morbidity in most cases. We present full details and images of the operative approach. PMID- 23730545 TI - Outcome after translabyrinthine surgery for vestibular schwannomas: report on 1244 patients. AB - The objective of this article is to study the outcome after translabyrinthine surgery for vestibular schwannomas, with special focus on the facial nerve function. The study design is a case series from a national centralized database and it is set in two University Hospitals in Denmark. Participants were 1244 patients who underwent translabyrinthine surgery during a period of 33 years from 1976 to 2009. Main outcome measures were tumor removal, intraoperative facial nerve preservation, complications, and postoperative facial nerve function. In 84% patients, the tumor was totally resected and in ~85% the nerve was intact during surgery. During 33 years, 12 patients died from complications to surgery and ~14% had cerebrospinal fluid leakage. Before surgery, 74 patients had facial paresis and 46% of these improved after surgery. In patients with normal facial function, overall ~70% had a good outcome (House-Brackmann grade 1 or 2). The chance of a good outcome was related to tumor size with a higher the chance the smaller the tumor, but not to the degree of tumor removal. In ~78% of the patients with facial paresis at discharge the paresis improved over time, in ~42% from a poor to a good function. The translabyrinthine approach is generally efficient in tumor control and with satisfactory facial nerve outcome. With larger tumors the risk of a poor outcome is evident and more data on patients managed with alternative strategies are warranted. PMID- 23730546 TI - The superior transvelar approach to the fourth ventricle and brainstem. AB - Objective The superior transvelar approach is used to access pathologies located in the fourth ventricle and brainstem. The surgical path is below the venous structures, through the superior medullary velum. Following splitting the tentorial edge, near the tentorial apex, the superior medullary velum is split in the cerebello-mesencephalic fissure. Using the supracerebellar infratentorial, transtentorial or parietal interhemispheric routes, the superior medullary velum is approached. Splitting this velum provides a detailed view of the fourth ventricle and its floor. Materials and Methods A total of 10 formalin-fixed specimens were dissected in a stepwise manner to simulate the superior transvelar approach to the fourth ventricle. The exposure gained the distance from the craniotomy site and the ease of access was assessed for each of the routes. We also present an illustrative case, operated by the senior author (AN). Results The superior transvelar approach provides access to the entire length of the fourth ventricle floor, from the aqueduct to the obex, when using the parietal interhemispheric route. In addition, this approach provides access to the entire width of the floor of the fourth ventricle; however, this requires retracting the superior cerebellar peduncle. Using the supracerebellar infratentorial route gives a limited exposure of the superior part of the fourth ventricle. The occipital interhemispheric route is a compromise between these two. Conclusion The superior transvelar approach to the fourth ventricle provides a route for approaching the fourth ventricle from above. This approach does not require opening the posterior fossa in the traditional way, and provides a reasonable alternative for accessing the superior fourth ventricle. PMID- 23730547 TI - Dorello's Canal for Laymen: A Lego-Like Presentation. AB - Objective Dorello's canal was first described by Gruber in 1859, and later by Dorello. Vail also described the anatomy of Dorello's canal. In the preceding century, Dorello's canal was clinically important, in understanding sixth nerve palsy and nowadays it is mostly important for skull base surgery. The understanding of the three dimensional anatomy, of this canal is very difficult to understand, and there is no simple explanation for its anatomy and its relationship with adjacent structures. We present a simple, Lego-like, presentation of Dorello's canal, in a stepwise manner. Materials and Methods Dorello's canal was dissected in five formalin-fixed cadaver specimens (10 sides). The craniotomy was performed, while preserving the neural and vascular structures associated with the canal. A 3D model was created, to explain the canal's anatomy. Results Using the petrous pyramid, the sixth nerve, the cavernous sinus, the trigeminal ganglion, the petorclival ligament and the posterior clinoid, the three-dimensional structure of Dorello's canal was defined. This simple representation aids in understanding the three dimensional relationship of Dorello's canal to its neighboring structures. Conclusion Dorello's canal with its three dimensional structure and relationship to its neighboring anatomical structures could be reconstructed using a few anatomical building blocks. This method simplifies the understanding of this complex anatomical structure, and could be used for teaching purposes for aspiring neurosurgeons, and anatomy students. PMID- 23730548 TI - Endoscopic endonasal management of recurrent petrous apex cholesterol granuloma. AB - Introduction Petrous apex cholesterol granulomas (PACGs) are uncommon lesions. Recurrence following transcranial or endonasal approaches to aerate the cyst occurs in up to 60% of cases. We describe the technical nuances pertinent to the endonasal endoscopic management of a recurrent symptomatic PACG and review the literature. Results A 19-year-old woman presented with a recurrent abducens nerve paresis. Four months prior, she underwent an endonasal transsphenoidal surgery (TSS) for drainage of a symptomatic PACG. Current imaging documented recurrence of the right PACG. Transsphenoidal and infrapetrous approaches were performed to obtain a wider bony opening along the petrous apex and drain the cyst. A Doyle splint was inserted into the cyst's cavity and extended out into the sphenoid sinus, maintaining patency during the healing process. Three months after surgery, the splint was removed endoscopically, allowing visualization of a patent cylindrical communication between both aerated cavities. The patient remains symptom-free and recurrence-free. Conclusion Endoscopic endonasal surgery must be adapted to manage a recurrent PACG. A TSS may not be sufficient. An infrapetrous approach with wider bony opening, extensive removal of the cyst's anterior wall, and the use of a stent are indicated for the treatment of recurrent PACG and to prevent recurrences. PMID- 23730549 TI - Surgical management of giant transdural glomus jugulare tumors with cerebellar and brainstem compression. AB - Objective The objective of this study is to discuss the management of advanced glomus jugulare tumors (GJTs) presenting with intradural disease and concurrent brainstem compression. Study Design This is a retrospective case series. Results Over the last decade, four patients presented to our institution with large (Fisch D2; Glasscock-Jackson 4) primary or recurrent GJTs resulting in brainstem compression of varying severities. All patients underwent surgical resection through a transtemporal, transcervical approach resulting in adequate brainstem decompression; the average operative time was 12.75 hours and the estimated blood loss was 2.7 L. All four patients received postoperative adjuvant radiotherapy in the form of intensity-modulated radiation therapy or stereotactic radiosurgery. Combined modality treatment permitted tumor control in all patients (range of follow-up 5 to 9 years). Conclusion A small subset of GJTs may present with intracranial transdural extension with aggressive brainstem compression mandating surgical intervention. Surgical resection is extremely challenging; the surgical team must be prepared for extensive operating time and the patient for prolonged aggressive rehabilitation. Newly diagnosed and recurrent large GJTs involving the brainstem may be controlled with a combination of aggressive surgical resection and postoperative radiation. PMID- 23730550 TI - Craniofacial surgery for esthesioneuroblastoma: report of an international collaborative study. AB - Introduction Impact of treatment and prognostic indicators of outcome are relatively ill-defined in esthesioneuroblastomas (ENB) because of the rarity of these tumors. This study was undertaken to assess the impact of craniofacial resection (CFR) on outcome of ENB. Patients and Methods Data on 151 patients who underwent CFR for ENB were collected from 17 institutions that participated in an international collaborative study. Patient, tumor, treatment, and outcome data were collected by questionnaires and variables were analyzed for prognostic impact on overall, disease-specific and recurrence-free survival. The majority of tumors were staged Kadish stage C (116 or 77%). Overall, 90 patients (60%) had received treatment before CFR, radiation therapy in 51 (34%), and chemotherapy in 23 (15%). The margins of surgical resection were reported positive in 23 (15%) patients. Adjuvant postoperative radiation therapy was used in 51 (34%) and chemotherapy in 9 (6%) patients. Results Treatment-related complications were reported in 49 (32%) patients. With a median follow-up of 56 months, the 5-year overall, disease-specific, and recurrence-free survival rates were 78, 83, and 64%, respectively. Intracranial extension of the disease and positive surgical margins were independent predictors of worse overall, disease-specific, and recurrence-free survival on multivariate analysis. Conclusion This collaborative study of patients treated at various institutions across the world demonstrates the efficacy of CFR for ENB. Intracranial extension of disease and complete surgical excision were independent prognostic predictors of outcome. PMID- 23730551 TI - Engineering nanosilver as an antibacterial, biosensor and bioimaging material. AB - The capacity of nanosilver (Ag nanoparticles) to destroy infectious micro organisms makes it one of the most powerful antimicrobial agents, an attractive feature against "super-bugs" resistant to antibiotics. Furthermore, its plasmonic properties facilitate its employment as a biosensor or bioimaging agent. Here, the interaction of nanosilver with biological systems including bacteria and mammalian cells is reviewed. The toxicity of nanosilver is discussed focusing on Ag+ ion release in liquid solutions. Biomedical applications of nanosilver are also presented capitalizing on its antimicrobial and plasmonic properties and summarizing its advantages, limitations and challenges. Though a lot needs to be learned about the toxicity of nanosilver, enough is known to safely use it in a spectrum of applications with minimal impact to the environment and human health. PMID- 23730552 TI - Recommendation letter for Asian Pacific Journal of Tropical Biomedicine (APJTB). PMID- 23730553 TI - Acute pancreatitis in HIV/AIDS patients: an issue of concern. AB - Pancreatitis is a well-described complication of human immunodeficiency virus (HIV) itself and its combination antiretroviral therapy. Historically, this has been predominantly associated with the usage of nucleoside reverse transcriptase inhibitors such as didanosine and stavudine, but only rarely with the usage of protease inhibitors via the induction of hypertriglyceridemia. Pancreatitis rates in HIV/AIDS population may have been exceedingly high because of the comorbid conditions prevalent in HIV/AIDS patients (e.g. ethanol use and biliary disease), and the use of non-combination antiretroviral therapy medications such as pentamidine, corticosteroids, ketoconazole, sulphonamides, metronidazole, isoniazid and opportunistic infections (e.g. cytomegalovirus, cryptosporidiosis, mycobacterial disease). In resource limited settings, where didanosine and stavudine are widely available in cheaper generic fixed dose combinations it is likely that their usage will remain in the first line HIV treatment in common. In such settings management or estimation of a patient's risk of pancreatitis still remains an issue of concern. PMID- 23730554 TI - Isolation and characterization of potential antibiotic producing actinomycetes from water and sediments of Lake Tana, Ethiopia. AB - OBJECTIVE: To isolate, evaluate and characterize potential antibiotic producing actinomycetes from water and sediments of Lake Tana, Ethiopia. METHODS: A total of 31 strains of actinomycetes were isolated and tested against Gram positive and Gram negative bacterial strains by primary screening. In the primary screening, 11 promising isolates were identified and subjected to solid state and submerged state fermentation methods to produce crude extracts. The fermented biomass was extracted by organic solvent extraction method and tested against bacterial strains by disc and agar well diffusion methods. The isolates were characterized by using morphological, physiological and biochemical methods. RESULTS: The result obtained from agar well diffusion method was better than disc diffusion method. The crude extract showed higher inhibition zone against Gram positive bacteria than Gram negative bacteria. One-way analysis of variance confirmed most of the crude extracts were statistically significant at 95% confidence interval. The minimum inhibitory concentration and minimum bactericidal concentration of crude extracts were 1.65 mg/mL and 3.30 mg/mL against Staphylococcus aureus, and 1.84 mg/mL and 3.80 mg/mL against Escherichia coli respectively. The growth of aerial and substrate mycelium varied in different culture media used. Most of the isolates were able to hydrolysis starch and urea; able to survive at 5% concentration of sodium chloride; optimum temperature for their growth was 30 degrees C. CONCLUSIONS: The results of the present study revealed that freshwater actinomycetes of Lake Tana appear to have immense potential as a source of antibacterial compounds. PMID- 23730555 TI - The optimization of phenolic compounds extraction from cactus pear (Opuntia ficus indica) skin in a reflux system using response surface methodology. AB - OBJECTIVE: To extract, quantify, and evaluate the phenolic content in Opuntia ficus-indica skin for their antioxidant capacity with three different methods (ABTS, DPPH, and lipid oxidation) and to optimize the extraction conditions (time, temperature and ethanol concentration) in a reflux system. METHODS: The extraction process was done using a reflux system. A San Cristobal II experimental design with three variables and three levels was used. The variables evaluated were time of extraction (h), concentration of ethanol (%, v/v) and temperature ( degrees C). The extraction process was optimized using a response surface methodology. RESULTS: It was observed that at higher temperature more phenolic compounds were extracted, but the antioxidant capacity was decreased. The optimum conditions for phenolic compounds extraction and antioxidant capacity mixing the three methods were as follows: 45% of ethanol, 80 degrees C and 2 hours of extraction. Values obtained in our results are little higher that other previously reported. CONCLUSIONS: It can be concluded the by-products of Opuntia ficus-indica represent a good source of natural antioxidants with possible applications in food, cosmetics or drugs industries. PMID- 23730556 TI - Evaluation of antifungal activity of free fatty acids methyl esters fraction isolated from Algerian Linum usitatissimum L. seeds against toxigenic Aspergillus. AB - OBJECTIVE: The aim of this study was to evaluate the antifungal activity of the major fraction of fatty acids methyl esters (FAMEs) isolated from Linum usitatissimum L. seeds oil collected from Bechar department (Algeria). METHODS: The assessment of antifungal activity was carried out in terms of percentage of radial growth on solid medium (potatoes dextrose agar PDA) and biomass growth inhibition on liquid medium (potatoes dextrose broth PDB) against two fungi. RESULTS: The FAMEs was found to be effective in inhibiting the radial mycelial growth of Aspergillus flavus more than Aspergillus ochraceus on all tested concentrations. The highest antifungal index was found to be (54.19%) compared to Aspergillus ochraceus (40.48%). The results of the antifungal activity of the FAMEs inhibition of biomass on liquid medium gave no discounted results, but this does not exclude the antifungal activity. CONCLUSIONS: We can assume that the observed antifungal potency may be due to the abundance of linoleic and alpha linolenic acids in linseed oil which appears to be promising to treat fungal infections, storage fungi and food spoilage in food industry field. PMID- 23730557 TI - Antioxidant properties of aqueous extracts of unripe Musa paradisiaca on sodium nitroprusside induced lipid peroxidation in rat pancreas in vitro. AB - OBJECTIVE: To evaluate and compare antioxidant activities of the aqueous extracts of unripe plantain (Musa paradisiaca), assess their inhibitory action on sodium nitroprusside induced lipid peroxidation in rat pancreas in vitro and to characterize the main phenolic constituents of the plantain products using gas chromatography analysis. METHODS: Aqueous extracts of plantain products (raw, elastic pastry, roasted and boiled) flour of 0.1 g/mL (each) were used to determine their total phenol, total flavonoid, 1,1 diphenyl-2 picrylhydrazyl (DPPH) and hydroxyl (OH) radical scavenging ability. The inhibitory effect of the extracts on sodium nitroprusside induced lipid peroxidation was also determined. RESULTS: The results revealed that all the aqueous extracts showed antioxidant activity. The boiled flour had highest DPPH and OH radical scavenging ability while raw flour had the highest Fe(2+) chelating ability, sodium nitroprusside inhibitory effect and vitamin C content. The antioxidant results showed that elastic pastry had the highest total phenol and total flavonoid content. Characterization of the unripe plantain products for polyphenol contents using gas chromatography showed varied quantity of apigenin, myricetin, luteolin, capsaicin, isorhaemnetin, caffeic acid, kampferol, quercetin, p-hydroxybenzoic acid, shogaol, glycitein and gingerol per product on the spectra. CONCLUSIONS: Considering the antioxidant activities and ability to inhibit lipid peroxidation of unripe plantain, this could justify their traditional use in the management/prevention of diseases related to stress. PMID- 23730558 TI - Cyanobacteria, Lyngbya aestuarii and Aphanothece bullosa as antifungal and antileishmanial drug resources. AB - OBJECTIVE: To investigate two cyanobacteria isolated from different origins i.e. Lyngbya aestuarii (L. aestuarii) from brackish water and Aphanothece bullosa (A. bullosa) from fresh water paddy fields for antifungal and antileishmanila activity taking Candida albicans and Leishmania donovain as targets. METHODS: Biomass of L. aestuarii and A. bullosa were harvested after 40 and 60 d respectively and lyophilized twice in methanol (100%) and redissolved in methanol (5%) for bioassay. Antifungal bioassay was done by agar well diffusion method while antileishmanial, by counting cell numbers and flageller motility observation of promastigotes and amastigotes from L. donovani. Fluconazole and 5% methanol were used as control. RESULTS: Both the cyanobacteria were found to be potent source of antifungal activity keeping fluconazole as positive control, however, methanolic crude extract (15 mg/mL) of A. bullosa was found more potent (larger inhibition zone) over that of methanolic crude extract of L. aestuarii. Similarly antileishmanial activity of crude extract (24.0 mg/mL) of A. bullosa was superior over that of methanolic crude extract of L. aestuarii (25.6 mg/mL). CONCLUSIONS: Antifungal and antileishmanial drugs are still limited in the market. Screening of microbes possessing antifungal and antileishmanial activity drug is of prime importance. Cyanobacteria are little explored in this context because most of the drugs in human therapy are derived from microorganisms, mainly bacterial, fungal and actinomycetes. Thus in the present study two cyanobacterial strains from different origins showed potent source of antifungal and antileishmanial biomolecules. PMID- 23730559 TI - In vitro antioxidant, cytotoxic, thrombolytic activities and phytochemical evaluation of methanol extract of the A. philippense L. leaves. AB - OBJECTIVE: To study the leaves of Adiantum philippense L. for their antioxidant, cytotoxicity and thrombolytic activities and to perform phytochemical evaluation. METHODS: In-vitro antioxidant activity of extract was studied using DPPH radical scavenging, reducing power, total phenol and total flavonoid content determination assays. The cytotoxic activity was determined using brine shrimp lethality bioassay, thrombolytic activity by clot disruption and phytochemical potential by qualitative analysis. RESULTS: The antioxidant activity of the extracts was found promising. The reducing power of this crude extract increase with the increase of concentration; IC50 values of DPPH scavenging activity was (140.00+/-0.86) ug/mL as compared to ascorbic acid [IC50 (130.00+/-0.76) ug/mL]; Total phenol and total flavonoids content were (148.26+/-0.24) mg/mL and (163.06+/-0.56) mg/mL respectively. In cytotoxicity assay the LC50 values of the sample was (106.41+/-0.78) ug/mL where as for standard vincristin sulphate was (08.50+/-0.24) ug/mL as a positive control and the extract shows (12.86+/-1.02)% clot lytic whereas standard streptokinase shows (30.86+/-0.44% clot lytic activity in thrombolytic assay. The phytochemical evaluation indicates the presence of chemical constituents including carbohydrates, alkaloids, saponins, glycosides, flavonoids. CONCLUSIONS: This study shows that the methanol extract of leaves of Adiantum philippense L. has bioactivity but further compound isolation is necessary to confirm the activities of individual compounds. PMID- 23730560 TI - Modulatory effects of dietary inclusion of garlic (Allium sativum) on gentamycin induced hepatotoxicity and oxidative stress in rats. AB - OBJECTIVE: To investigate the ameliorative effect of dietary inclusion of garlic (Allium sativum) on gentamycin-induced hepatotoxicity in rats. METHODS: Adult male rats were randomly divided into four groups with six animals in each group. Groups 1 and 2 were fed basal diet while Groups 3 and 4 were fed diets containing 2% and 4% garlic respectively for 27 d prior to gentamycin administration. Hepatotoxicity was induced by the intraperitoneal administration of gentamycin (100 mg/kg body weight) for 3 d. The liver and plasma were studied for hepatotoxicity and antioxidant indices. RESULTS: Gentamycin induces hepatic damage as revealed by significant (P<0.05) elevation of liver damage marker enzymes (aspartate transaminase and alanine aminotransferase) and reduction in plasma albumin level. Gentamycin also caused a significant (P<0.05) alteration in plasma and liver enzymatic (catalase, glutathione and super oxygen dehydrogenises) and non-enzymatic (glutathione and vitamin C) antioxidant indices with concomitant increase in the malondialdehyde content; however, there was a significant (P<0.05) restoration of the antioxidant status coupled with significant (P<0.05) decrease in the tissues' malondialdehyde content, following consumption of diets containing garlic. CONCLUSIONS: These results suggest that dietary inclusion of garlic powder could protect against gentamycin-induced hepatotoxicity, improve antioxidant status and modulate oxidative stress; a function attributed to their phenolic constituents. PMID- 23730561 TI - Medicinal activities of the leaves of Musa sapientum var. sylvesteris in vitro. AB - OBJECTIVE: This study is to investigate the medicinal value of methanolic extract of the leaves of Musa sapientum var. sylvesteris in Bangladesh. METHODS: Several biochemical assays, thin layer chormatogarphy and ultra-violet spectroscopy were used to detect the presence of various types of compounds in this extract. Antioxidant effects were measured by DPPH scavenging assay, total reducing assay and hydrogen peroxide scavenging assay. Receptor binding activities and hydrogen peroxide induced hemolysis assay were performed by hemagglutination assay and hemolysis assay using erythrocytes. Disk diffusion assay was performed to show the antibacterial effect of the extract. RESULTS: Methanolic extract of the leaves showed antioxidant and antibacterial activity in vitro. The extract showed hemaglutination inhibition activities and hydrogen peroxide induced hemolysis inhibition activity of human red blood cells. CONCLUSION: Musa sapientum var. sylvesteris can be an useful medicinal plant. PMID- 23730562 TI - Retrospective study of clinical and hematological aspects associated with dogs naturally infected by Hepatozoon canis in Ludhiana, Punjab, India. AB - OBJECTIVE: To evaluate clinical and hematological aspects of dogs naturally infected with Hepatozoon canis (H. canis) presented at the Small Animal Clinics of Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana. METHODS: Blood films of 34 naturally infected dogs were examined for haematological alterations and parasitaemia. Signalment and clinical signs were recorded from the animals. Clinical histories were filled out during the consultation. RESULTS: Of the 34 positive dogs by Giemsa stained peripheral blood films, 88.23% presented parasitaemia by H. canis only, while 11.77% had the combination of H. canis, Babesia sp. and Ehrlichia sp. Young male dogs less than one-year-old, of non-descript breed, were the most commonly affected. And 26.47% were presented with anorexia/inappetence as the only clinical symptom. Other clinical symptoms were mild to moderate fever, pale mucosae and lethargy; a few were also showing the signs of vomiting and diarrhoea. Haematological alterations showed mainly normochromic-normocytic anaemia, leukocytosis and neutrophilia. CONCLUSIONS: The findings of this study substantiate that H. canis caused clinical and haematological alterations of the varied intensity in dogs, even with low parasitaemia, should be taken into consideration. PMID- 23730563 TI - Correlation between lipid profile and troponin I test results in patients with chest pain in Nepal. AB - OBJECTIVE: To study the usefulness of traditional lipid profile levels in screening subjects who had developed chest pain due to cardiac event as indicated by a positive troponin I test. METHODS: In this retrospective study data of the 430 patients presented to the emergency department with symptoms of cardiac ischemia who underwent both troponin and lipid profiles tests were compared with the lipid profiles of 165 normal healthy subjects (controls). The troponin was detected qualitatively when a specimen contains troponin I (cTnI) above the 99th percentile (TnI>0.5 ng/mL). The total cholesterol, high density lipoproteins cholesterol, very low density lipoproteins and triacyl glycerol levels were also analyzed and low density lipoprotein level was calculated using Friedewald's formula. RESULTS: Patients with chest pain and positive troponin test (with confirmed cardiac event) were found to have significantly elevated levels of total cholesterol, triacyl glycerol levels, low density lipoprotein level and significantly reduced high density lipoproteins cholesterol levels when compared to the patients who experienced only chest pain (negative troponin) and healthy controls. CONCLUSIONS: Traditional lipid profile levels is still can be used in screening populations to identify the subjects with high risk of developing cardiac event in case if the laboratory set up has not troponin test facilities. PMID- 23730564 TI - Seroepidemiology of bluetongue disease in small ruminants of north-east of Iran. AB - OBJECTIVE: To estimate the prevalence and distribution of bluetongue virus antibody in sheep and goats in 25 townships of Khorasan Razavi. Bluetongue is an infectious, non-contagious, arthropod born viral disease of ruminants and has been reported from most of the tropical and subtropical regions of the world. METHODS: A total number of 1 034 serum samples from sheep and goats were collected and transmitted to Serological Laboratory of Veterinary Council of Khorasan Razavi. Serums were screened for the presence of group-specific bluetongue virus antibody using competitive Enzyme Linked Immuno Sorbent Assay (c ELISA). RESULTS: The seropositivity of sheep and goats for bluetongue was found to be 89.2%. The highest prevalence rate was seen in Taybad, Khalil-abad and Torbat-jam (100%) and the least prevalence rate was seen in Jovein (55%). CONCLUSIONS: The results showed that the majority of animals in the north-east of Iran are infected with bluetongue virus. High correlation between abortion history and seroposivity emphasize the economical importance of bluetongue virus in the sheep herds of the region. PMID- 23730565 TI - Outbreaks of salmonellosis in three different poultry farms of Kerala, India. AB - Avian salmonellosis is an important disease causing serious impediment to the development of poultry industry especially in developing countries of Asia and Africa. Since no "effective" immunoprophylactic measures are available for the disease till date, strict biosecurity is the only alternative to preclude the disease. For formulating the control measures, an understanding of the epidemiology of the disease, proper diagnosis and identification of the causative agent is quintessential. This report sheds light on three different outbreaks of salmonellosis in three different farms in Kerala (India) describing the disease diagnosis, antibiotic resistance and the suggested control measures. All the three isolates were revealed to be Salmonella gallinarum and were resistant to at least three of the antimicrobial agents tested. PMID- 23730567 TI - Preimplantation genetic diagnosis and deafness. AB - Deafness in India ranges from 4.0 % in urban and 4.0-11 % in rural and slum areas, out of which 50 % are of conductive hearing loss hence curable. In the congenital hearing loss the incidence of syndromic hearing loss is only 30 %, rest 70 % are non syndromic. Genetic counseling is going to make aware the parents. Preimplantation genetic diagnosis can help to have a baby free from genetic deafness. Procedure is almost safe, harmless, non-invasive and ethically acceptable. While by genetic testing through prenatal genetic testing, amniocentesis and chorionic villous sampling is invasive and termination of pregnancy is difficult, social and ethical issue. The connexin 26 (CX26W 24X) has been observed as most common and easy to identify by polymerase chain reaction. There is always co morbidity after cochlear implantation and the person remains handicapped while baby after PGD shall be having healthy normal life and person prone to environmental factors may be counseled and guided to prevent deafness in next generation. Public must be made aware of noise pollution, tobacco toxicity and consanguinity. The obstetrician and pediatrician apart from ENT surgeon should be involved to prevent antenatal or neonatal deafness. PMID- 23730566 TI - Tegumental histological effects of Mirazid((r)) and myrrh volatile oil on adult Fasciola gigantica. AB - OBJECTIVE: To evaluated the histological changes within the tegument of adult Fasciola gigantica (F. gigantica) that led to the gross changes that were visible externally. METHODS: The effects of oleoresin extract of myrrh (Mirazid((r))), myrrh volatile oil and triclabendazole sulphoxide (reference drug) on the tegumental structure of adult F. gigantica following treatment in vitro had been determined by light microscopy. RESULTS: The internal changes in the tegument observed in this study were compatible with surface changes seen in the previous scanning electron microscopy study, using the same drugs. The swelling of tegumental syncytium was a particular feature of their action, but its level was much greater with myrrh volatile oil, in which vacuolization of the tegument and loss of spines were observed. CONCLUSIONS: The present study demonstrated the fasciocidal properties of Mirazid((r)) oleoresin extract, and it might be possible to reinforce its fasciocidal activity by increasing its content of myrrh volatile oil. PMID- 23730568 TI - Publications about hearing in otorhinolaryngology journals from chinese authors: a 11-year survey of the literature. AB - Hearing loss is a leading cause of disability in China. However, the research status in the field of hearing among Chinese individuals in the three major regions of China: Mainland (ML), Hong Kong (HK) and Taiwan (TW), are unknown. The output of hearing articles published in international otorhinolaryngology journals from these three regions were compared in this study. Articles published in 31 international otorhinolaryngology journals related to hearing originating from the ML, TW and HK from 2000 to 2011 were retrieved from the PubMed database search. The number of total articles, clinical trials, randomized controlled trials, case reports, and articles published in the top 5 international otorhinolaryngology journals were assessed in terms of quantity and quality comparisons. The total number of articles from the three regions increased significantly from 2000 to 2011. There were 379 articles from ML (143), TW (180) and HK (56) in the past 10 years. The number of articles published per year from the ML has exceeded those from TW in 2009 and HK in 2003. TW had the most articles (46) published in the top 5 international otorhinolaryngology journals among the three regions. The total number of articles from the three major regions of China increased significantly from 2000 to 2011. The numbers of articles published per year from the ML have exceeded those from TW and HK. However, the quality of articles from TW is better than that from ML. PMID- 23730569 TI - TEMPS-A Temperament Scale Before and After Septoplasty in Patients with Nasal Septum Deviation. AB - The present study aimed to evaluate whether patients undergoing an operation for septum deviation exhibited a change in affective status. The temperament evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) was administered to all patients at the pre-operative and post-operative periods. The mean age of the patients was 32.46 +/- 11.22 years. Of the patients, 34 (65.4%) were males and 18 (34.6%) were females. A significant difference was found between pre- and post-operative scores of the patients on all TEMPS-A subscales (p < 0.05). Patients with symptoms of upper airway obstruction may have mood disorders due to the decrease in blood oxygen levels. This condition can be corrected with septoplasty procedure. In the present study, it was demonstrated that patients had a better affective status post-operatively as compared to the pre-operative period. PMID- 23730570 TI - Conservative management of otogenic brain abscess with surgical management of attico antral ear disease: a review. AB - Otological intra cranial complications are still a major problem in developing countries. Otogenic brain abscess is a serious, life-threatening complication of otitis media and it usually occurs due to attico antral ear disease. Treatment of otogenic brain abscess is immediate surgical drainage, and mastoidectomy is done to remove the source of infection. This article describes three cases of otogenic brain abscess secondary to attico antral ear disease, which were less than 1.6 cm in size and were treated conservatively with antibiotic therapy. All the patients were started on intravenous antibiotic therapy and serial CT scan was done to monitor the progression of the brain abscess. Canal wall down mastoidectomy was done for the removal of otogenic source of infection. Antibiotic therapy was continued for 6 weeks. Post operative CT scan was done after 8 weeks and it showed complete resolution of the abscess. This study showed that small otogenic brain abscess, which are less than 1.6 cm in size responded to treatment with antibiotics, could be managed by medical therapy. Surgery was required only for the management of attico antral ear disease. To best of our knowledge this is the first review on conservative management of small otogenic brain abscess secondary to attico antral ear disease. PMID- 23730571 TI - Voice examination in patients with decreased high pitch after thyroidectomy. AB - Decreased high pitch after thyroidectomy due to injury of the external branch of superior laryngeal nerve (EBSLN) may be a critical, especially to professional voice users. The author studied the usefulness of VRP (voice range profile) and MDVP (multi-dimensional voice program) to evaluate patients who have decreased high pitch after thyroidectomy. A study was performed with 58 females and 9 males who underwent voice assessment between January 2008 and June 2009. The patients were classified as the group of female with no decreased high pitch (group A, n = 52), decreased high pitch (group B, n = 6) and the group of male with no decreased high pitch (group C, n = 9). VRP and laryngeal electromyogram (EMG) was performed in group B. RESULTS: The preoperative frequency range of group A and B were statistically not different. In Group B, the result of VRP showed that the frequency range was 443.11 +/- 83.97, 246.67 +/- 49.41, 181.37 +/- 80.13 Hz showing significant decrease after the surgery compared to that of the preoperative result. (P < 0.05) In addition, the intensity range was 22.25 +/- 2.87, 15.25 +/- 2.22, 16.25 +/- 2.63 dB respectively showing significant postoperative decrease. (P < 0.05) EMG of the cricothyroid muscle of group B showed decreased potential with 3 patients, normal potential in 2, and the other patient refused to take the examination. In group A and C, the result of VRP revealed no significant difference between the preoperative and postoperative result. VRP is a noninvasive, quick, and practical test to demonstrate decreased frequency range visually and helps to evaluate EBSLN injury in patient with thyroidectomy. PMID- 23730572 TI - Outcome of adenotonsillectomy for sleep and breathing difficulties in nigerian children with obstructive adenotonsillar enlargement. AB - The aim of this study was to examine improvements or otherwise, in sleep disturbance and breathing difficulties after adenotonsillectomy (AT) for chronic upper airway obstruction in children. In a prospective clinical study and tertiary referral center setting, the study population included consecutive children aged 1.5 through 12 years who underwent AT for chronic upper airway obstruction due to adenotonsillar enlargement, without any history of previous AT. The validated "Symptomatology score" (SS) parameters were used to grade the symptoms before and after AT. The extent of improvement of the symptoms after surgery were estimated by a standardized response mean (SRM). The study included 59 children, 40 of whom were males (68%). Their ages ranged from 1.5 to 12 years with a mean of 3.3 years and 63% were <4 years. The results showed that tonsillar size was correlated significantly with a high preoperative SS (P <= 0.001). The mean preoperative SS for the study population was 7.2, whereas the mean postoperative SS was 1.7. This change was highly significant (P < 0.001). The symptom domain with the greatest change in mean score was snoring, which improved by 2 points with SRM of 2.2. The changes in total score and in the scores for each symptom domain were highly significant (P < 0.002). We concluded that adenotonsillectomy is associated with remarkable improvement in breathing difficulties and sleep disturbances in children with obstructive adenotonsillar hypertrophy regardless of the condition whether it is mild or severe. PMID- 23730573 TI - The utility of second look microlaryngoscopy after trans oral laser resection of laryngeal cancer. AB - In the past few decades more and more number of tumors of the glottis and supraglottis are been treated with single stage transoral laser microsurgery (TOLS). TOLS for the treatment of glottic and supraglottic carcinoma with anterior commissure (A-com) and/paraglottic space involvement is associated with a high rate of recurrence. We prospectively evaluated the outcomes of laser microsurgery and the impact of second look operation in these patients. Twenty three patients with glottic and supraglottic carcinoma underwent transoral laser micro resection of the lesions. Subsequently five patients underwent second look microlaryngeal evaluation 6-8 months later for non-satisfactory healing, poor voice, and or suspicion of recurrent disease. Patients with A-com involvement and or paraglottic space involvement were followed up longitudinally for the effectiveness and timing of second look microsurgery. After initial transoral laser micro resection, all patients achieved microscopically clear resection margins. At second look microlaryngeal evaluation, local recurrence was found in four of 23 patients. Of these, two patients were salvaged by second look surgery and are disease free, whereas in two others, the larynx had to be subjected to open surgical intervention. One of two had extensive local recurrent tumor and underwent total laryngectomy with neck dissection followed by post-operative radiotherapy. Tracheohyoidopexy was done with successful functional and oncologic outcome for another patient who had local recurrence for the third time. Only the patient who underwent total laryngectomy with neck dissection was subjected to adjuvant post-operative radiotherapy. Finally, larynx was saved in 21 out of 23 patients. PMID- 23730574 TI - Trans-aditus approach: an alternative technique for cochlear implantation. AB - The objective of this study was to report our preliminary experience with an alternative technique for cochlear implantation. Twenty patients underwent cochlear implantation via a trans-aditus ad antrum approach to the round window. The main steps involved in the surgical procedure are cortical mastoidectomy, elevation of tympanomeatal flap, incudostapedial joint dislocation, incus removal, preparation of a bed for the implant, cochleostomy via the external auditory canal, and finally insertion of the electrode into the cochlea via the aditus. Twenty-five implants were performed on 20 patients, 18 children (mean age of 3.2 years) and 2 adults. Twelve patients were males and eight were females. All the children were pre-lingual while the adults were post-lingual. Nucleus freedom cochlear implant system (Cochlear, Lane Cover, NSW, Australia) was used in four patients and a cochlear Nucleus 5 was used in six patients. A Med-el SONATA implant (MED-EL, Innsbruck, Austria) was used in 15 patients. The minimum follow-up was 5 months. Here, we describe a new alternative technique for cochlear implantation and report our preliminary results. The procedure has advantages over the existing techniques and avoids the potential complications of posterior tympanotomy, transcanal, and transmeatal techniques. PMID- 23730575 TI - Extended high frequency audiometry in secretory otitis media. AB - The objective of the present study was to determine the status of extended high frequencies in subjects with secretory otitis media. The study evaluated 30 ears of 20 subjects with secretory otitis media in the age group of 15-30 years. This data was compared with 20 ears of 10 volunteers of the same age group with clinically normal hearing. Pure tone air conduction thresholds were analyzed in three frequency groups: low frequency (LF: 0.25, 0.5, and 1 kHz), high frequency (HF: 2, 4, and 8 kHz) and extended high frequency (EHF: 10, 12, and 16 kHz). The results showed elevated extended high frequency thresholds (EHFG) as compared to control group and comparatively better thresholds at high frequencies(HFG)s as compared to low (LFG)and extended high frequencies(EHFG) in the study group. This validates the importance of including an extended high frequency audiometry in the test battery of patients with secretory otitis media. PMID- 23730576 TI - Demographic and videostroboscopic assessment of vocal pathologies. AB - Successful treatment of bilateral vocal fold lesions depends on the accuracy of the diagnosis. The application of stroboscopy to the study of vocal fold vibration has led to dramatic advances in the understanding of vocal fold physiology. Laryngeal stroboscopy is the state of the art diagnostic tool and this technique provides valuable information about the nature of the vibration and a visual image that can be used both for immediate analysis and as a permanent record for comparison of repeated examination at a later date. In this study we are presenting demographic analysis and videostroboscopic assessment in 112 cases of different vocal pathologies. Stroboscopic parameters like glottic closure, amplitude, vocal fold edge, symmetry, periodicity and mucosal wave pattern were studied and statistically significant relationship with different vocal pathologies were obtained. PMID- 23730577 TI - Carotid body tumors and our surgical approaches. AB - Glomus tumors known as paragangliomas are neoplasms arising from the neural crest. They are named according to the place they originate from. Tumors originating from the carotid body at the carotid bifurcation are called Carotid Body Tumors (CBT). Surgical intervention is planned according to the Shamblin classification. 17 patients were operated after being diagnosed with CBT in our clinic between February 2007 and June 2010. 12 (70.5%) of the patients were male, and 5 (29.4%) of the patients were female. The average age was 42 (ages ranging between 32 and 47). Nine of the patients were diagnosed and treated with Shamblin type I tumor, seven of the patients with type II and one patient with type III. Only one patient had bilateral carotid tumor. In all patients with Shamblin type I and II, blunt dissection of the tumor was conducted smoothly by means of thermal cautery in the subadventitial plane. The patient with Shamblin type III had tumor invasion in the carotid artery and adjacent tissues were in an adherent state. Therefore mass resection was carried out by resecting 2 cm of the distal portion of the common carotid artery and 3 cm of the proximal portion of the internal carotid artery. 6 mm of synthetic polytetrafluoroethylene graft was interpositioned between the common carotid artery and the internal carotid artery. External carotid artery was anastomosed to this graft in an end-to-end fashion. The patient developed vocal cord paralysis postoperatively on the lesion side. The patient who underwent bilateral tumor excision developed Baroreflex Failure Syndrome. In the two patients thrombus developed in the internal carotid artery in the early postoperative period. These patients underwent thrombectomy and developed hemiplegia on the lesion side. One of them died on the seventh post operative day while in follow-up in the intensive care unit. Surgical resection is the recommended treatment for carotid body tumors. Shamblin I and II type tumors' dimensions and pathological characteristics allow dissection. However Shamblin III tumors may require carotid artery resection and reconstruction due to tissue invasion. The possibility of post-operative cranial nerve paralysis and arterial thrombosis should be taken into account. PMID- 23730578 TI - Virtual reality simulation in ear microsurgery: a pilot study. AB - Classically, teaching of otological micro procedures is achieved by cadaveric dissection of the temporal bones, achieved by attending expensive temporal bone dissection courses. The difficulty in acquiring cadaveric specimens and the cost of courses has led to the development of alternative techniques. The aim of this study is to evaluate the efficacy of using virtual reality temporal bone simulation in training otolaryngology residents for mastoidectomy procedures. Four senior residents were evaluated during six canal wall down mastoidectomy procedures. Three of these procedures were done conventionally. The other three procedures were preceded by virtual reality simulation 1 day before the operation. In simulated cases, the residents scored higher on the global rating scale and task-based checklist, and were faster and more confident. Further, fewer instructions were required during the actual operation. This outcome is encouraging for the utilization of virtual reality simulation in otolaryngology residency training. Further studies should be performed on a larger number of simulators and surgical procedures to validate our results. PMID- 23730579 TI - Endoscopic approach to middle turbinate squeeze syndrome. AB - Middle turbinate squeeze syndrome (MTSS) refers to sino-nasal headache due to intense contact between the middle turbinate and the nasal septum and/or between middle turbinate and other structures in the lateral nasal wall. This study was intended to evaluate the efficacy of precise endoscopic surgical treatment of MTSS. This is a prospective study of 126 patients with refractory cephalgia due to endoscopically confirmed MTSS who underwent functional endoscopic naso-sinus surgery (FENS) wherein the contact points and ostio-meatal complex obstruction were endoscopically relieved. 91% of cases reported improvement/resolution of headache and 95% of cases had relieved contact points as documented endoscopically. This surgery was also found to facilitate resolution of sinus disease, both radiologically (in 64% of cases) and endoscopically (in 94% of cases). Cephalgia caused by MTSS can be effectively treated by an ultra conservative endoscopic approach. PMID- 23730580 TI - Nasal breathing exercise and its effect on symptoms of allergic rhinitis. AB - Allergic rhinitis (AR) is a common and chronic health problem with a high prevalence and a significant effect on the health care expenditure. Intranasal steroid spray is recommended as the first line therapy for patients with moderate to severe AR. Our study clinically analysed the use of nasal breathing exercise (NBE) as an adjunct to intranasal steroid spray as a cheap and effective mode of management of AR. A 3 month, parallel, randomized study was carried out in a zonal and tertiary care referral center. In this study, participants (N = 60) with symptomatic AR were administered either a intranasal steroid spray fluticasone propionate (group A) or fluticasone propionate nasal spray and NBE (group B). Participants assessed their symptom severity daily over the 3 month treatment period. The mean total nasal symptom scores were lower in both the groups (5.1 vs. 3.8333 for group A and 5.2 vs. 2.6777 for group B) and the difference was statistically significant (P < 0.05). The patients showed a definite improvement in overall and individual symptoms for both groups with significantly greater reduction in individual symptoms in the group B (P < 0.05). In our study we have found that both treatments provided clinically meaningful responses, but the overall results favored fluticasone propionate and the NBE group. Hence NBE is a simple and cost effective measure to reduce symptoms of AR and improve patient satisfaction. PMID- 23730581 TI - Schwannomas of head and neck and review of literature. AB - Benign nerve cell tumours have been given various names like schwannoma, neurilemmoma, neurinoma, neurofibroma, spindle cell tumours etc. Extra cranial head and neck schwannomas usually present as solitary and well-demarcated lesions. The lesion can cause secondary symptoms, such as nasal obstruction, dysphasia, and hoarseness, depending upon the location of the lesion. Fine needle aspiration cytology, CT scans, and MRI may be of limited help in the diagnosis of schwannomas. The treatment is complete surgical excision of the benign tumour and postoperative histopathological examination establishes the final diagnosis. PMID- 23730583 TI - Modified incision for maxillectomy: our experience. AB - Radical maxillectomy has usually been done by the classical Weber Ferguson incision since age old times and still is being used widely due to its advantage of excellent exposure and minimal scarring as the incision follows the natural skin crease. In our modification of radical maxillectomy incision we avoid a scar on the midface by performing a midface degloving and combining it with a subconjunctival eye incision thus avoiding any cosmetic deformity and associated eye complication. It also avoids the late complication of cutaneous fistula following radiotherapy to these areas and due to early healing of the wound, early radiotherapy can be started. PMID- 23730582 TI - The effect of adenotonsillectomy on quality of life in adults and pediatric patients. AB - The aim of this study was to evaluate the benefits, impact, and overall efficacy of tonsillectomy or adenotonsillectomy on quality of life in patients with recurrent, chronic tonsillitis or adenotonsillar hypertrophy before and after surgery in adults and children. A multi-center, observational, retrospective study of all adults and children who had undergone tonsillectomy in adults (14 years or older) and adenotonsillectomy in children for chronic, recurrent tonsillitis or adenotonsillar hypertrophy between September 2003-September 2008 in Ahwaz Imam and Apadana Hospitals. Patients were asked by questionnaire to compare their symptoms 6-months period before and after tonsillectomy or adenotonsillectomy. Outcome measures included the frequency of tonsillitis per year, days off work (or school), doctor visits and feelings of well-being. 812 adults and children were sent a questionnaire regarding their symptoms in the 6 months before and 6 months after surgery. A total of 812 patients (81 adults and 731 children) were enrolled in the study. The age of the patients ranged from 3 to 42 years. In adults group there were 34 men and 47 women. In child group there were 325 boys and 406 girls. The mean age of the children patients was 8.6 years and adults 26.5 years. The mean duration of symptoms was 3.6 years. The mean frequency of tonsillitis per year, days off work (or school), doctor visits decreased postoperatively. We concluded that tonsillectomy in adult and adenotonsillectomy in children is benefit for patients with adenotonsillar hypertrophy and/or recurrent, chronic tonsillitis and results in significant improvement in overall quality of life, physical health and general well-being. PMID- 23730585 TI - Combined laryngocele secondary to localized laryngeal amyloidosis. AB - Laryngocele is a benign condition due to abnormal dilatation of the laryngeal saccule. Localized amyloidosis causing laryngocele is a rare entity with few reports in the literature. We present a young male patient with a large combined laryngocele secondary to laryngeal amyloidosis. PMID- 23730584 TI - Endoscopic repair of lateral sphenoid recess cerebrospinal fluid leaks. AB - Endoscopic repair of anterior cranial base has been widely reported. However there is still no uniformity in the technique of endoscopic repair of lateral sphenoid cerebrospinal fluid (CSF) leaks. To highlight the management of CSF leak or encephalocele in the lateral sphenoid recess and relate our experiences. We retrospectively reviewed the medical records of all our patients who underwent an endoscopic repair of CSF leaks in the lateral sphenoid recess during the period from September 2003 to January 2010 at our tertiary hospital. Fifteen cases with CSF leaks/encephalocele that were repaired by the endoscopic approach were included. The majority of our cases were spontaneous leaks. In all our cases we approached the site of defect by an end on approach. All our patients were successfully treated in the first attempt. Endoscopic repair of lateral sphenoid recess has shown better surgical outcome with reduced morbidity. PMID- 23730586 TI - Oro-pharyngo-laryngeal foreign bodies: some interesting cases. AB - Ingestion of variety of foreign bodies causing respiratory distress and/or dysphagia is worldwide among all age groups. Securing airway by tracheostomy is important and direct laryngoscopy provides immediate diagnosis. The importance of contributory history and its visualization is emphasized in the diagnosis and early management in the described six cases. PMID- 23730587 TI - Role of CT Scan in Decision Making Prior to Approximation Laryngoplasty. AB - To evaluate the role of CT scan prior to approximation laryngoplasty (AL). Occasionally, postoperative results in AL are unsatisfactory. The reasons for failure may be an incomplete closure of the phonatory gap or improper size of the implant or implant migration. The role of CT scan in planning the steps of surgery in cases of AL especially in revision cases is discussed in three cases of unilateral vocal fold paralysis. Preoperative CT larynx, especially in revision AL cases, helps plan steps of surgery by deciphering implant material, size, shape and position used in previous surgery. PMID- 23730588 TI - The Need for a Reviewer to Play Devil's Advocate. PMID- 23730589 TI - An algorithmic approach to total breast reconstruction with free tissue transfer. AB - As microvascular techniques continue to improve, perforator flap free tissue transfer is now the gold standard for autologous breast reconstruction. Various options are available for breast reconstruction with autologous tissue. These include the free transverse rectus abdominis myocutaneous (TRAM) flap, deep inferior epigastric perforator flap, superficial inferior epigastric artery flap, superior gluteal artery perforator flap, and transverse/vertical upper gracilis flap. In addition, pedicled flaps can be very successful in the right hands and the right patient, such as the pedicled TRAM flap, latissimus dorsi flap, and thoracodorsal artery perforator. Each flap comes with its own advantages and disadvantages related to tissue properties and donor-site morbidity. Currently, the problem is how to determine the most appropriate flap for a particular patient among those potential candidates. Based on a thorough review of the literature and accumulated experiences in the author's institution, this article provides a logical approach to autologous breast reconstruction. The algorithms presented here can be helpful to customize breast reconstruction to individual patient needs. PMID- 23730590 TI - The effects of polydeoxyribonucleotide on the survival of random pattern skin flaps in rats. AB - BACKGROUND: Partial or complete necrosis of a skin flap is a common problem. Polydeoxyribonucleotide (PDRN) can be extracted from trout sperm and used as a tissue repair agent. The aim of this study was to investigate whether PDRN could improve the survival of random pattern skin flaps in rats. METHODS: Twenty-two male Sprague-Dawley rats were randomly divided into two groups: the PDRN treatment group (n=11) and the control group (n=11). Caudally pedicled random pattern skin flaps were elevated on their dorsal skin and resutured. The treatment group received daily intraperitoneal administration of PDRN (8 mg/kg/day), and the control group received fluid vehicle (NaCl 0.9%, 8 mg/kg/day) from day 0 to day 6. On day 7, the flap survival was evaluated and the harvested tissue surrounding the demarcation line of the necrotic area was stained with H&E, anti-rat vascular endothelial cell growth factor (VEGF) antibody, and PECAM 1/CD31 antibody. RESULTS: The average necrotic area of the flap in the PDRN group was significantly smaller when compared with that of the control group. Histologic and immunohistochemical evaluation showed that granulation thickness score and VEGF-positive staining cells were marked higher in the PDRN group than in the control group. PECAM-1/CD31-positive microvascular densities were significantly higher in the PDRN group when compared with the control group. CONCLUSIONS: This study confirms that PDRN improves the survival of random pattern skin flaps in rats. These results may represent a new therapeutic approach to enhancing flap viability and achieving faster wound repair. PMID- 23730591 TI - The deep inferior epigastric perforator and pedicled transverse rectus abdominis myocutaneous flap in breast reconstruction: a comparative study. AB - BACKGROUND: Our objective was to compare the complication rates of two common breast reconstruction techniques performed at our hospital and the cost effectiveness for each test group. METHODS: All patients who underwent deep inferior epigastric perforator (DIEP) flap and transverse rectus abdominis myocutaneous (TRAM) flap by the same surgeon were selected and matched according to age and mastectomy with or without axillary clearance. Patients from each resultant group were selected, with the patients matched chronologically. The remainder were matched for by co-morbidities. Sixteen patients who underwent immediate breast reconstruction with pedicled TRAM flaps and 16 patients with DIEP flaps from 1999 to 2006 were accrued. The average total hospitalisation cost, length of hospitalisation, and complications in the 2 year duration after surgery for each group were compared. RESULTS: Complications arising from both the pedicled TRAM flaps and DIEP flaps included fat necrosis (TRAM, 3/16; DIEP, 4/16) and other minor complications (TRAM, 3/16; DIEP, 1/16). The mean hospital stay was 7.13 days (range, 4 to 12 days) for the pedicled TRAM group and 7.56 (range, 5 to 10 days) for the DIEP group. Neither the difference in complication rates nor in hospital stay duration were statistically significant. The total hospitalisation cost for the DIEP group was significantly higher than that of the pedicled TRAM group (P<0.001). CONCLUSIONS: Based on our study, the pedicled TRAM flap remains a cost-effective technique in breast reconstruction when compared to the newer, more expensive and tedious DIEP flap. PMID- 23730592 TI - The importance of a conchal bowl element in the fabrication of a three dimensional framework in total auricular reconstruction. AB - BACKGROUND: To construct a sophisticated three-dimensional framework, numerous modifications have been reported in the literature. However, most surgeons have paid little attention to the anatomical configuration of the concha and more to its deepness and hollowness, leading to unsatisfactory outcomes. METHODS: For a configuration of the concha that is definitely anatomical, the author further developed and employed the conchal bowl element, which has been used by several surgeons although the results have not been published elsewhere. The author constructed the conchal bowl element in one of three patterns according to the amount of available cartilages: one block, two-pieces, or a cymba bowl element only. A total of 20 patients underwent auricular reconstruction using a costal cartilage framework between 2009 and 2012. The 8 earliest reconstructions were performed without a conchal bowl element and the latter 12 with a conchal bowl element. The patients were followed up for more than 1 year. The aesthetic results were scored by evaluating characteristics involving the stability of the crus helicis, the conchal definition, and the smoothness of the helical curve. RESULTS: The ears reconstructed early without a conchal bowl element showed a shallow and one or two incompletely separated concha with an obliterated cymba conchal space. They also did not have a realistic or smooth curve of the helix because of an unstable crus helicis. However, ears reconstructed later with the concha bowl element showed a definite crus helicis, deep cymba conchal space, and smooth helical curve. CONCLUSIONS: The construction of the conchal bowl element is simple, not time-consuming procedure. It is suggested that the conchal bowl element must be constructed and attached to the main framework for natural configuration of the reconstructed ear. PMID- 23730593 TI - Impact of Disturbed Wound Healing after Surgery on the Prognosis of Marjolin's Ulcer. AB - BACKGROUND: Marjolin's ulcer is known to present a high proportion of recurrence and poor prognosis compared to other kinds of skin cancer. Based on our experience, Marjolin's ulcer patients who have received reconstructive surgery present a higher proportion of recurrence when there was disturbed wound healing after surgery. The impact of disturbed wound healing after surgery on the prognosis was examined in this study. METHODS: A retrospective study was carried out on 26 patients who were diagnosed with Marjolin's ulcer and received surgery in this hospital from 1996 to 2011. Histologic grading, lymph node metastasis at diagnosis, and the wound healing process were evaluated and chi-squared analysis applied in order to determine the correlation with recurrence. RESULTS: The proportion of recurrence increases in patients with a low histologic grade or lymph node metastasis at diagnosis. The proportion of recurrence is even higher when the problem occurs during the wound healing process after surgery. CONCLUSIONS: Disturbed wound healing after surgery could be used as a sign to quickly identify the recurrence of carcinoma. Therefore, in the event a problem occurs in the wound healing process after surgery, one should keep in mind that this could be a sign of the possibility of recurrence and proceed with careful observation and active diagnosis through additional physical examinations, general X-ray tests, computed tomographys, magnetic resonance imagings, and so on, to obtain an early diagnosis of recurrence. PMID- 23730594 TI - Magnetic resonance imaging-based volumetric analysis and its relationship to actual breast weight. AB - BACKGROUND: Preoperative volume assessment is useful in breast reconstruction. Magnetic resonance imaging (MRI) and mammography are commonly available to reconstructive surgeons in the care of a patient with breast cancer. This study aimed to verify the accuracy of breast volume measured by MRI, and to identify any factor affecting the relationship between measured breast volume and actual breast weight to derive a new model for accurate breast volume estimation. METHODS: From January 2012 to January 2013, a retrospective review was performed on a total of 101 breasts from 99 patients who had undergone total mastectomy. The mastectomy specimen weight was obtained for each breast. Mammographic and MRI data were used to estimate the volume and density. A standard statistical analysis was performed. RESULTS: The mean mastectomy specimen weight was 340.8 g (range, 95 to 795 g). The mean MRI-estimated volume was 322.2 mL(3). When divided into three groups by the "difference percentage value", the underestimated group showed a significantly higher fibroglandular volume, higher percent density, and included significantly more Breast Imaging, Reporting and Data System mammographic density grade 4 breasts than the other groups. We derived a new model considering both fibroglandular tissue volume and fat tissue volume for accurate breast volume estimation. CONCLUSIONS: MRI-based breast volume assessment showed a significant correlation with actual breast weight; however, in the case of dense breasts, the reconstructive surgeon should note that the mastectomy specimen weight tends to overestimate the volume. We suggested a new model for accurate breast volume assessment considering fibroglandular and fat tissue volume. PMID- 23730595 TI - Onlay rib bone graft in elevation of reconstructed auricle: 17 years of experience. AB - BACKGROUND: A cartilage wedge block and covering flap are standard procedures for firm elevation of the ear in microtia correction. However, using costal cartilage for elevation of the reconstructed auricle can be insufficient, and the fixed cartilage wedge block may be absorbed or may slip out. Furthermore, elevating covering flaps is time-consuming and uses up fascia, a potential source of reconstruction material. Therefore, we propose an innovative method using autologous onlay rib bone graft for auricular elevation of microtia. METHODS: From February 1995 to August 2012, 77 patients received a first stage operation with a rib cartilage framework graft. In the second stage operation, a small full thickness of rib bone was harvested through the previous donor scar. The bihalved rib bone was inserted into the subperiosteal pocket beneath the cartilage framework. RESULTS: The follow-up time ranged from 1 month to 17 years, with a mean of 3 years. All of the patients sustained the elevation of their ears very well during the follow-up period. Donor site problems, except for hypertrophic scars, were not observed. Surgery-related complications, specifically skin necrosis, infection, or hematoma, occurred in 4 cases. CONCLUSIONS: Onlay rib bone graft used to elevate the reconstructed auricle is a more anatomically appropriate material than cartilage, due to the bone-to-bone contact between the bone graft and the temporal bone. Postoperative minor correction of the elevation degree is straightforward and the skin graft survives better. Therefore, reconstructed auricle elevation using onlay rib bone graft is a useful and valuable method. PMID- 23730596 TI - Evaluation of the microvascular research center training program for assessing microsurgical skills in trainee surgeons. AB - BACKGROUND: We established the Microvascular Research Center Training Program (MRCP) to help trainee surgeons acquire and develop microsurgical skills. Medical students were recruited to undergo the MRCP to assess the effectiveness of the MRCP for trainee surgeons. METHODS: Twenty-two medical students with no prior microsurgical experience, who completed the course from 2005 to 2012, were included. The MRCP comprises 5 stages of training, each with specific passing requirements. Stages 1 and 2 involve anastomosing silicone tubes and blood vessels of chicken carcasses, respectively, within 20 minutes. Stage 3 involves anastomosing the femoral artery and vein of live rats with a 1-day patency rate of >80%. Stage 4 requires replantation of free superficial inferior epigastric artery flaps in rats with a 7-day success rate of >80%. Stage 5 involves successful completion of one case of rat replantation/transplantation. We calculated the passing rate for each stage and recorded the number of anastomoses required to pass stages 3 and 4. RESULTS: The passing rates were 100% (22/22) for stages 1 and 2, 86.4% (19/22) for stage 3, 59.1% (13/22) for stage 4, and 55.0% (11/20) for stage 5. The number of anastomoses performed was 17.2+/-12.2 in stage 3 and 11.3+/-8.1 in stage 4. CONCLUSIONS: Majority of the medical students who undertook the MRCP acquired basic microsurgical skills. Thus, we conclude that the MRCP is an effective microsurgery training program for trainee surgeons. PMID- 23730597 TI - Versatility of the distally-based sural artery fasciocutaneous flap on the lower leg and foot in patients with chronic disease. AB - BACKGROUND: A recent advancement in microsurgery, the free flap is widely used in the reconstruction of the lower leg and foot. The simple and effective methods of local flaps, including transposition and advancement flaps, have been considered for patients with chronic debilitation who are unable to endure long surgical procedures or general anesthesia. However, the location and size of the wound may restrict the clinical application of a local flap. Under these circumstances, a sural flap can be an excellent alternative, rendering satisfying clinical outcomes in chronically debilitated patients. METHODS: Between 2008 and 2012, 39 patients underwent soft tissue defect treatment by sural artery flap as a final method. All of the patients had at least one chronic disease or more (diabetes, hypertension, vascular disease, etc.). Also, all of the patients had a history of chronic lower extremity ulceration, which revealed no response to several months of conservative treatment. RESULTS: The results of the 39 cases had a success rate of 100% with 39 complete recoveries. Nine cases suffered complications: partial necrosis (n=4), wound dehiscence without necrosis (n=3), hematoma (n=1), and infection (n=1). CONCLUSIONS: The sural artery flap is not only useful for the lower leg but also for the heel, and other various parts. Furthermore, it is a relatively simple surgical technique for reconstructing the defect area for patients with various chronic conditions with a high surgical risk or contraindications to surgery. PMID- 23730598 TI - Second toe plantar free flap for volar tissue defects of the fingers. AB - BACKGROUND: The reconstruction of volar surface defects is difficult because of the special histologic nature of the tissue involved. The plantar surface is the most homologous in shape and function and could be considered the most ideal of reconstructive options in select cases of volar surface defects. In this paper, we evaluate a single institutional case series of volar tissue defects managed with second toe plantar free flaps. METHODS: A single-institution retrospective review was performed on 12 cases of reconstruction using a second toe plantar free flap. The mean age was 33 years (range, 9 to 54 years) with a male-to-female ratio of 5-to-1. The predominant mechanism was crush injury (8 cases) followed by amputations (3 cases) and a single case of burn injury. Half of the indications (6 cases) were for soft-tissue defects with the other half for scar contracture. RESULTS: All of the flaps survived through the follow-up period. Sensory recovery was related to the time interval between injury and reconstruction-with delayed operations portending worse outcomes. There were no postoperative complications in this series. CONCLUSIONS: Flexion contracture is the key functional deficit of volar tissue defects. The second toe plantar free flap is the singular flap whose histology most closely matches those of the original volar tissue. In our experience, this flap is the superior reconstructive option within the specific indications dictated by the defect size and location. PMID- 23730599 TI - New classification of polydactyly of the foot on the basis of syndactylism, axis deviation, and metatarsal extent of extra digit. AB - BACKGROUND: Polydactyly of the foot is one of the most frequent anomalies of the limbs. However, most classification systems are based solely on morphology and tend to be inaccurate and less relevant to surgical methods and results. The purpose of this study is to present our new classification of polydactyly of the foot, which can serve as a predictor of treatment and prognosis. METHODS: To find a correlation between the various morphologic traits of polydactyly of the foot and the treatment plan and outcomes, we reviewed 532 cases of polydactyly of the foot in 431 patients treated in our hospital, expanding on our previous study that described polydactyly based on the importance of metatarsal bone status and varus deformity. The records of patients were evaluated and compared with previous studies at other centers. RESULTS: Unsatisfactory results were seen in 36 cases, which included 5 cases of incomplete separation due to syndactylism, 23 cases of axis deviation, and 8 cases of remnants of extra-digit metatarsal bones. The locus of the polydactyly, or the digit which was involved, did not seem to affect the final postoperative outcomes in our study. Three factors-syndactylism, axis deviation, and metatarsal extension-are the major factors related to treatment strategy and prognosis. Therefore, we developed a new classification system using three characters (S, A, M) followed by three groups (0, 1, 2), to describe the complexity of polydactyly of the foot, such as S1A2M2. CONCLUSIONS: Our new classification could provide a communicable description to help determine the surgical plan and predict outcomes. PMID- 23730600 TI - Surgical options for malignant skin tumors of the hand. AB - BACKGROUND: Primary malignant tumors of the hand, although unusual, may present varied and often complex clinical problems. The main treatment modality of skin cancer of the hand has changed. METHODS: We retrospectively reviewed the medical records of 43 patients who underwent surgery for malignant skin tumors of the hand during an 18-year period, from September 1994 to February 2012. The characteristics of the tumor, methods of reconstruction, and long-term results were reviewed. RESULTS: We had 43 patients with 27 melanomas, 14 squamous cell carcinomas, and 2 sarcomas. Their ages ranged from 19 to 74 years (mean, 53.4+/ 14.5 years), from 46 to 79 years (mean, 59.7+/-9.6 years), and from 15 to 43 years (mean, 29+/-19.8 years), respectively. Thirty-four cases occurred on the fingertip (16 of those cases on the thumb), 5 cases occurred on the palm, and 4 cases on the dorsum of the hand. Amputation was most frequently used in early cases, but recently, tissue-sparing excision has been performed frequently. The incidence of local recurrence was 3 cases and distant metastasis was 1 case, and the 5-year survival rate was 100%, except in 4 cases due to follow-up loss. CONCLUSIONS: The principles of treatment-to be curative and to preserve function and appearance-are important points. "Preservative surgery" preserves function and cosmesis of the involved finger or hand dorsum or palm. Preservative surgery not only emphasizes less resection and surgery of a smaller scale, but also optimal reconstruction of the soft tissue defect of the digit. PMID- 23730601 TI - Giant lipoma of the breast. AB - Lipomas are benign mesenchymal tumors that develop in areas of abundant adipose tissue. Due to the fatty composition of the breast, difficulties in diagnosis, treatment, and reconstruction are often encountered. We report a case of a 55 year-old female with a giant tumor of the right breast that comprised most of its mass, causing breast asymmetry. A thorough preoperative evaluation, followed by an uneventful difficult surgical resection and reconstruction, resulted in diagnosis of a benign lipoma. The case prompted this report because of its challenging size, location, diagnosis, and reconstructive solution. PMID- 23730602 TI - A salvage operation for total penis amputation due to circumcision. AB - Circumcision is one of the most common rituals in Jewish and Islamic cultures. It may also be performed for phimosis correction or the treatment of recurrent balanitis. Although circumcision is considered to be a technically easy and safe surgical procedure with no significant risk, it may lead to severe complications such as necrotizing fasciitis or total penis amputation. In this report, we present a case of penis amputation at two levels occurring with third-degree burns due to electrocautery during circumcision. Although penile replantation was attempted, it was unsuccessful due to burn damage to the veins. After restoration of the functional structures, the penis was buried in the inguinal area by reepithelization to maintain blood circulation. The recovery of the penis was successful. This case is presented as a novel example of groin flap surgery to achieve a functionally and aesthetically acceptable outcome in a salvage operation for a penis with significant traumatic injury, which has not been previously reported in the literature. PMID- 23730603 TI - Anterograde intra-arterial urokinase injection for salvaging fibular free flap. AB - We present a case of a 57-year-old male patient who presented with squamous cell carcinoma on his mouth floor with cervical and mandibular metastases. Wide glossectomy with intergonial mandibular ostectomy, and sequential reconstruction using fibular osteomyocutaneous free flap were planned. When the anastomosis between the peroneal artery of the fibular free flap and the right lingual artery was performed, no venous flow was observed at the vena comitans. Then re anastomosis followed by topical application of papaverine and lidocaine was attempted. However, the blood supply was not recovered. Warm saline irrigation over 30 minutes was also useless. Microvascular thromboses of donor vessels were clinically suspected, so a solution of 100,000 units of urokinase was infused once through a 26-gauge angiocatheter inserted into the recipient artery just at the arterial anastomotic site, until the solution gushed out through the flap vena comitans. Immediately after the application of urokinase, arterial flow and venous return were restored. There were no complications during the follow-up period of 11 months. We believe that vibrating injuries from the reciprocating saw during osteotomies and flap insetting might be the cause of microvascular thromboses. The use of urokinase may provide a viable option for the treatment of suspicious intraoperative arterial thrombosis. PMID- 23730604 TI - Subcision using a spinal needle cannula and a thread for prominent nasolabial fold correction. AB - Deepening of the nasolabial crease is an esthetically unpleasing aging phenomenon occurring in the midface. Various treatment modalities have been introduced to improve the appearance of prominent nasolabial folds, all of which have pros and cons. Currently, a minimally invasive technique using synthetic dermal fillers is most commonly used. A simple and easy subcision procedure using a wire scalpel has also been used and reported to be effective for prominent nasolabial fold correction, with minimal complications. As an alternative to the wire scalpel, we used a 20-gauge metal type spinal needle cannula (Hakko Co.) and 4-0 Vicryl suture (Ethicon Inc.) for subcision of nasolabial folds. This technique is less expensive than the use of a wire scalpel and easily available when needed. Therefore, on the basis of favorable results, our modified subcision technique may be considered effective for prominent nasolabial fold correction. PMID- 23730605 TI - Redoable tie-over dressing using multiple loop silk threads. AB - After skin grafting, to prevent hematoma or seroma collection at the graft site, a tie-over dressing has been commonly used. However, although the conventional tie-over dressing by suture is a useful method for securing a graft site, refixation is difficult when repeated tie-over dressing is needed. Therefore, we recommend a redoable tie-over dressing technique with multiple loops threads and connecting silk threads. After the raw surface of each of our cases was covered with a skin graft, multiple loop silk thread attached with nylon at the skin graft margin. We applied the ointment gauze and wet cotton/fluffy gauze over the skin graft, then fixed the dressing by connecting cross-counter multiple loop thread with connecting silk threads. When we opened the tie-over dressing by cutting the connecting silk threads, we repeated the tie-over dressing with the same method. The skin graft was taken successfully without hematoma or seroma collection or any other complications. In conclusion, we report a novel tie-over dressing enabling simple fixation of the dressing to maintain proper tension for wounds that require repetitive fixation. Further, with this reliable method, the skin grafts were well taken. PMID- 23730606 TI - A comparative study to evaluate a simple method for the management of postoperative bleeding following palatoplasty. AB - Bleeding, is one of the most common postoperative complications after palatoplasty in patients with cleft palate. The purpose of this article is to present our experience using a Foley catheter balloon for perioperative palatoplasty bleeding management. A retrospective data analysis was performed for all cases of palatoplasty performed by the author from 1999 to 2012 that experienced postoperative hemorrhage. These patients were managed by utilizing posterior nasal compression with a Foley catheter balloon for the period 2006 to 2012. We have compared two methods (we use before 2006 the reoperative method) with regards to the later development of palatal fistulae and cases with reoperative hemostasis. The study found no statistically significant differences between the conventional and proposed method in relation to the development of palatal fistulae (P=0.7). These findings suggest that nasal packing using a Foley balloon is a safe and effective method for postoperative bleeding control after palatoplasty in patients with cleft palate. PMID- 23730607 TI - Nicolau's Syndrome Complicated by Atypical Necrotizing Fasciitis. PMID- 23730608 TI - Aesthetic refinement of the dog ear correction: the 90 degrees incision technique and review of the literature. PMID- 23730609 TI - Macrodystrophia lipomatosa. PMID- 23730610 TI - Malignant peripheral nerve sheath tumor arising from neurofibromatosis. PMID- 23730611 TI - Clinical experience of stewart-treves syndrome in the lower leg. PMID- 23730612 TI - Treatment of Refractory Lower Extremity Ulcer Associated with Sneddon's Syndrome. PMID- 23730613 TI - Giant epidermal cyst on posterior scalp. PMID- 23730614 TI - Primary intraosseous hemangioma in the frontal bone. PMID- 23730615 TI - An unusual case of a malignant peripheral nerve sheath tumor. PMID- 23730616 TI - Nonslip breast retractors with cautery tip cleaners. PMID- 23730617 TI - Basal cell carcinoma presenting as a hypertrophic scar. PMID- 23730618 TI - Reconstruction of a rare palate defect originating from extranodal natural killer/t-cell lymphoma. PMID- 23730619 TI - My Trip to the XXI Congress of the European Association for Cranio-Maxillo-Facial Surgery. PMID- 23730620 TI - Ovarian tumor attachment, invasion, and vascularization reflect unique microenvironments in the peritoneum: insights from xenograft and mathematical models. AB - Ovarian cancer relapse is often characterized by metastatic spread throughout the peritoneal cavity with tumors attached to multiple organs. In this study, interaction of ovarian cancer cells with the peritoneal tumor microenvironment was evaluated in a xenograft model based on intraperitoneal injection of fluorescent SKOV3.ip1 ovarian cancer cells. Intra-vital microscopy of mixed GFP red fluorescent protein (RFP) cell populations injected into the peritoneum demonstrated that cancer cells aggregate and attach as mixed spheroids, emphasizing the importance of homotypic adhesion in tumor formation. Electron microscopy provided high resolution structural information about local attachment sites. Experimental measurements from the mouse model were used to build a three dimensional cellular Potts ovarian tumor model (OvTM) that examines ovarian cancer cell attachment, chemotaxis, growth, and vascularization. OvTM simulations provide insight into the relative influence of cancer cell-cell adhesion, oxygen availability, and local architecture on tumor growth and morphology. Notably, tumors on the mesentery, omentum, or spleen readily invade the "open" architecture, while tumors attached to the gut encounter barriers that restrict invasion and instead rapidly expand into the peritoneal space. Simulations suggest that rapid neovascularization of SKOV3.ip1 tumors is triggered by constitutive release of angiogenic factors in the absence of hypoxia. This research highlights the importance of cellular adhesion and tumor microenvironment in the seeding of secondary ovarian tumors on diverse organs within the peritoneal cavity. Results of the OvTM simulations indicate that invasion is strongly influenced by features underlying the mesothelial lining at different sites, but is also affected by local production of chemotactic factors. The integrated in vivo mouse model and computer simulations provide a unique platform for evaluating targeted therapies for ovarian cancer relapse. PMID- 23730621 TI - Immune responses to cancer: are they potential biomarkers of prognosis? AB - Recent technical improvements in evaluations of immune cells in situ and immune monitoring of patients with cancer have provided a wealth of new data confirming that immune cells play a key role in human cancer progression. This, in turn, has revived the expectation that immune endpoints might serve as reliable biomarkers of outcome or response to therapy in cancer. The recent successes in linking the T-cell signature in human colorectal carcinoma (CRC) with prognosis have provided a strong motive for searching for additional immune biomarkers that could serve as intermediate endpoints of response to therapy and outcome in human cancers. A number of potentially promising immune biomarkers have emerged, but most remain to be validated. Among them, the B-cell signature, as exemplified by expression of the immunoglobulin G kappa chain (IGKC) in tumor-infiltrating lymphocytes (TIL), has been validated as a biomarker of response to adjuvant therapy and better survival in patients with breast carcinoma and several other types of human solid tumors. Additional immune endpoints are being currently tested as potentially promising biomarkers in cancer. In view of currently growing use of immune cancer therapies, the search for immune biomarkers of prognosis are critically important for identifying patients who would benefit the most from adjuvant immunotherapy. PMID- 23730623 TI - Clinical grade purification and expansion of NK cell products for an optimized manufacturing protocol. AB - Allogeneic natural killer (NK) cells are used for adoptive immunotherapy after stem cell transplantation. In order to overcome technical limitations in NK cell purification and activation, the following study investigates the impact of different variables on NK cell recovery, cytotoxicity, and T-cell depletion during good manufacturing practice (GMP)-grade NK cell selection. Forty NK cell products were derived from 54 unstimulated donor leukaphereses using immunomagnetic CD3 T-cell depletion, followed by a CD56 cell enrichment step. For T-cell depletion, either the depletion 2.1 program in single or double procedure (D2.11depl, n = 18; D2.12depl, n = 13) or the faster depletion 3.1 (D3.1, n = 9) was used on the CliniMACS instrument. Seventeen purified NK cell products were activated in vitro by IL-2 for 12 days. The whole process resulted in a median number of 7.59 * 10(8) CD56(+)CD3(-) cells with both purity and viability of 94%, respectively. The T-cell depletion was significantly better using D2.11depl/2depl compared to D3.1 (log 4.6/log 4.9 vs. log 3.7; p < 0.01) and double procedure in two stages led always to residual T cells below 0.1%. In contrast D3.1 was superior to D2.11depl/2depl with regard to recovery of CD56(+)CD3(-) NK cells (68% vs. 41%/38%). Concomitant monocytes and especially IL-2 activation led to increased NK cell activity against malignant target cells compared to unstimulated NK cells, which correlated with both up-regulation of natural cytotoxicity receptors and intracellular signaling. Overall, wide variations in the NK cell expansion rate and the distribution of NK cell subpopulations were found. In conclusion, our results indicate that GMP-grade purification of NK cells might be improved by a sequential processing of T-cell depletion program D2.1 and D3.1. In addition NK cell expansion protocols need to be further optimized. PMID- 23730622 TI - Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors. AB - Gastrointestinal stromal tumors (GISTs) in adults are generally driven by somatic gain-of-function mutations in KIT or PDGFRA, and biological therapies targeted to these receptor tyrosine kinases comprise part of the treatment regimen for metastatic and inoperable GISTs. A minority (10-15%) of GISTs in adults, along with ~85% of pediatric GISTs, lacks oncogenic mutations in KIT and PDGFRA. Not surprisingly these wild type (WT) GISTs respond poorly to kinase inhibitor therapy. A subset of WT GISTs shares a set of distinguishing clinical and pathological features, and a flurry of recent reports has convincingly demonstrated shared molecular characteristics. These GISTs have a distinct transcriptional profile including over-expression of the insulin-like growth factor-1 receptor, and exhibit deficiency in the succinate dehydrogenase (SDH) enzyme complex. The latter is often but not always linked to bi-allelic inactivation of SDH subunit genes, particularly SDHA. This review will summarize the molecular, pathological, and clinical connections that link this group of SDH deficient neoplasms, and offer a view toward understanding the underlying biology of the disease and the therapeutic challenges implicit to this biology. PMID- 23730624 TI - Frameless fractionated stereotactic radiosurgery for vestibular schwannomas: a single-institution experience. AB - OBJECTIVE: To examine tumor control, hearing preservation, and complication rates after frameless fractionated stereotactic radiosurgery (SRS) in patients with vestibular schwannomas (VS). METHODS: Thirty-seven patients treated with fractionated SRS from 2002 to 2011 were retrospectively analyzed. Ninety-five percent were treated with 25 Gy in five fractions, targeting a median tumor volume of 1.03 cc (range 0.14-7.60). RESULTS: With a median follow-up of 4.25 years (range, 15 months-9 years), no tumors required an additional treatment resulting in 100% tumor control rate. Radiographic control rate was 91% in 32 patients at a median follow-up of 3 years. Of the 14 patients with serviceable hearing and with audiograms, the hearing preservation rate was 78% at a median follow-up of 18 months. Twenty-six patients with serviceable hearing pretreatment, were evaluated by a phone survey with a hearing preservation rate of 73% at a 5 year median follow-up. There were two cases that developed both new increased trigeminal parasthesias and facial spasms but there were no cases of facial weakness. Patient had 96% of good to excellent satisfaction rate with the treatment at a median follow-up of 5 years. CONCLUSION: Frameless fractionated SRS treatment of VS results in good rate of tumor control. Hearing preservation rate and rates of cranial nerve toxicity are comparable to what is reported in the literature. Patients choose this modality because of its non-invasive nature and are generally very satisfied with their long term outcome. PMID- 23730625 TI - New Strategies to Direct Therapeutic Targeting of PML to Treat Cancers. AB - The tumor suppressor function of the promyelocytic leukemia (PML) protein was first identified as a result of its dysregulation in acute promyelocytic leukemia, however, its importance is now emerging far beyond hematological neoplasms, to an extensive range of malignancies, including solid tumors. In response to stress signals, PML coordinates the regulation of numerous proteins, which activate fundamental cellular processes that suppress tumorigenesis. Importantly, PML itself is the subject of specific post-translational modifications, including ubiquitination, phosphorylation, acetylation, and SUMOylation, which in turn control PML activity and stability and ultimately dictate cellular fate. Improved understanding of the regulation of this key tumor suppressor is uncovering potential opportunities for therapeutic intervention. Targeting the key negative regulators of PML in cancer cells such as casein kinase 2, big MAP kinase 1, and E6-associated protein, with specific inhibitors that are becoming available, provides unique and exciting avenues for restoring tumor suppression through the induction of apoptosis and senescence. These approaches could be combined with DNA damaging drugs and cytokines that are known to activate PML. Depending on the cellular context, reactivation or enhancement of tumor suppressive PML functions, or targeted elimination of aberrantly functioning PML, may provide clinical benefit. PMID- 23730626 TI - Stereotactic body radiotherapy for treatment of squamous cell carcinoma of the tongue associated with human papilloma virus: a case report. AB - Stereotactic body radiotherapy (SBRT) has emerged as a treatment for recurrent squamous cell carcinoma of the head and neck in the field of prior radiation. We report a case of its use in an human papilloma virus (HPV) positive patient with squamous cell carcinoma of the right base of tongue. The patient had complete response to treatment and modest toxicities were noted. This represents encouraging results that SBRT is also useful for salvage in patients with HPV positive disease. PMID- 23730627 TI - Bacillus anthracis co-opts nitric oxide and host serum albumin for pathogenicity in hypoxic conditions. AB - Bacillus anthracis is a dangerous pathogen of humans and many animal species. Its virulence has been mainly attributed to the production of Lethal and Edema toxins as well as the antiphagocytic capsule. Recent data indicate that the nitric oxide (NO) synthase (baNOS) plays an important pathogenic role at the early stage of disease by protecting bacteria from the host reactive species and S-nytrosylating the mitochondrial proteins in macrophages. In this study we for the first time present evidence that bacteria-derived NO participates in the generation of highly reactive oxidizing species which could be abolished by the NOS inhibitor L - NAME, free thiols, and superoxide dismutase but not catalase. The formation of toxicants is likely a result of the simultaneous formation of NO and superoxide leading to a labile peroxynitrite and its stable decomposition product, nitrogen dioxide. The toxicity of bacteria could be potentiated in the presence of bovine serum albumin. This effect is consistent with the property of serum albumin to serves as a trap of a volatile NO accelerating its reactions. Our data suggest that during infection in the hypoxic environment of pre-mortal host the accumulated NO is expected to have a broad toxic impact on host cell functions. PMID- 23730628 TI - Dioxin-like compounds are not associated with bone strength measured by ultrasonography in Inuit women from Nunavik (Canada): results of a cross sectional study. AB - BACKGROUND: Bone strength in Inuit people appears lower than that of non Aboriginals. Inuit are exposed to persistent organic pollutants including dioxin like compounds (DLCs) through their traditional diet that comprises predatory fish and marine mammal fat. Results from experimental and population studies suggest that some DLCs can alter bone metabolism and increase bone fragility. OBJECTIVE: This cross-sectional descriptive study was conducted to examine the relationship between the stiffness index (SI) and plasma concentrations of total DLCs or specific dioxin-like polychlorinated biphenyls (DL-PCBs) in Inuit women of Nunavik (Northern Quebec, Canada). METHODS: SI was determined by ultrasonography at the right calcaneus of 194 Inuit women aged 35-72 years who participated to Qanuippitaa? How Are We? Nunavik Inuit Health Survey in 2004. Plasma total DLC levels were quantified by measuring the aryl hydrocarbon receptor-mediated transcriptional activity elicited by plasma sample extracts in a cell-based reporter gene assay. Plasma concentrations of DL-PCBs nos. 105, 118, 156, 157, 167 and 189 were measured by gas chromatography-mass spectrometry. We used multiple linear regression analyses to investigate relations between total DLCs or specific DL-PCBs and SI, taking into consideration several potential confounders. RESULTS: Neither total plasma DLCs nor specific DL-PCBs were associated with SI after adjustment for several confounders and covariates. CONCLUSION: Our results do not support a relation between exposure to DLCs and bone strength measured by ultrasonography in Inuit women of Nunavik. PMID- 23730629 TI - A cross-sectional study on the palmar dermatoglyphics in relation to carcinoma breast patients. AB - INTRODUCTION: Dermatoglyphics is a collective term for all the integumentary features (skin patterning of the fingers, toes, palms and soles) and it applies to the division of the anatomy which embraces their study. AIMS AND OBJECTIVES: The purpose of this study was to examine the predominant finger tip patterns in the patients of carcinoma breast. An attempt is also being made to devise a score to assess the risk variables. MATERIALS AND METHODS: The fingerprints of 100 carcinoma breast patients were obtained and they were compared with those of 100 females who were not suffering from any malignancy till date. The different quantitative parameters of each hand of both the cancer patients and the controls were studied. The parameters which were included were the fingertip ridge pattern, the ridge count in the individual fingers, the Total Finger Ridge Count (TFRC) and the Absolute Finger Ridge Count (AFRC). RESULTS: There was a significant increase in the arch pattern and a decrease in the radial loops in the right thumb (p<0.001), the left thumb (p<0.001), the left index finger (p<0.001) and the left middle finger (p<0.001). A comparison of all the five fingers of both the left and right hands of the cancer patients with the controls showed an arch pattern (p<0.001) with the highest frequency. The lower values of the TFRC (below 50) were associated with carcinoma breast .The lower values of the AFRC (below 100) were associated with the cancer patients. CONCLUSION: This study was able to establish a specific finger tip predominance in the Carcinoma breast patients. PMID- 23730630 TI - A study on the serum adenosine deaminase activity in patients with typhoid Fever and other febrile illnesses. AB - BACKGROUND: Adenosine Deaminase (ADA) has been suggested to be an important enzyme which is associated with the cell mediated immunity, but its clinical significance in typhoid fever has not yet been characterized. The present study was taken up to evaluate the serum ADA activity in patients of typhoid fever. The levels of ADA were also measured in the patients who were suffering from other febrile illnesses. MATERIAL AND METHOD: This was a case control study. The subjects who were included in this study were divided into 3 groups. Group A consisted of 50 normal healthy individuals who served as the controls. Group B consisted of 50 patients, both males and females of all age groups, who were suffering from culture positive typhoid fever. Group C consisted of 50 patients who were suffering from febrile illnesses other than typhoid fever like viral fever, gastro enteritis, malaria, tonsillitis, upper respiratory tract infections, etc. The serum levels of ADA were estimated in all the subjects who were under study. RESULTS: The serum ADA level was found to be increased in the patients of typhoid fever as compared to that in those with other febrile illnesses and in the controls. CONCLUSION: From the present study, it can be concluded that there was a statistically significant increase in the serum ADA levels in the patients with typhoid. PMID- 23730631 TI - The clinical and biochemical parameters in relation to the serum neopterin levels in Indian children and adolescents. AB - INTRODUCTION: An adverse pattern of blood lipids and cardiovascular abnormalities starts in obese children during childhood and neopterin serves as a marker for cardiovascular disease. Unfortunately, the data for children and adolescents, particularly, in the Indian population, are scarce. The present study aimed at evaluating the levels of serum neopterin in obese and overweight children and adolescents of the Indian population. METHODS: The study groups included 296 school going children and adolescents. (96 obese and 97 overweight subjects were compared with 103 normal controls who were aged between 10-17 years). The anthropometric variables, the lipid profile, the fasting serum glucose which was analyzed by using an autoanalyzer and the serum neopterin levels were assayed by HPLC (Shimazdu) by using the method of Palfrey et al., 1993. The serum insulin levels were measured by using ELISA kits. RESULTS: The serum neopterin levels (nmol/l) were elevated significantly in the obese (7.4+/-1.4) and overweight (6.4+/-0.8) (p<0.001) children and adolescents than in the controls (4.9+/-0.9). The serum neopterin levels showed a positive correlation with the BMI (r=0.79), WHR (r=0.5), systolic (r=0.44) and diastolic blood pressures (r= 0.25), insulin (r=0.57), HOMAIR (r=0.55), total cholesterol (r=0.35), triglycerides (r=0.20) and LDL-C (r=0.27) and they showed a negative correlation with HDL-C (r=-0.15) and fasting glucose (r= -0.3). CONCLUSION: This study revealed a good relationship between serum neopterin and the anthropometric and biochemical parameters. We, therefore, aim to conduct regular camps at schools to counsel and advise the identified overweight and obese children to go for physical exercise and a balanced diet. The implementation of preventive measures from early childhood will have far reaching benefits, as even the prevalence of other obesity related disorders could decline. PMID- 23730632 TI - Comparison of urinary protein: creatinine index and dipsticks for detection of microproteinuria in diabetes mellitus patients. AB - BACKGROUND: Proteinuria has been recognized as one of the earliest signs of renal function deterioration in Diabetes mellitus. Proteinuria occurs due to alterations in the glomerular permeability and later, due to a failure in the reabsorption of filtered protein by the tubular cells. Normally, most of the healthy adults excrete 20-150 mg of protein in urine over 24 hours. OBJECTIVES: To find out the normal urinary Protein Creatinine Index (PCI) in healthy subjects, to compare the urinary PCI of diabetic patients with that of healthy subjects and to compare the urinary PCI with dipsticks for the detection of microproteinuria. MATERIAL AND METHODS: This study was conducted on 28 type 2 Diabetes mellitus patients and 40 age and sex matched healthy controls. Freshly collected urine samples were tested qualitatively for the presence of proteinuria by Heller's test, the sulfosalicylic acid test, heat-coagulation tests and urine dipsticks. Later on, the results were compared by performing a quantitative analysis of the protein in the spot urine samples by the sulfosalicylic acid method. A quantitative analysis of creatinine was done by the modified Jaffe's test. The PCI was calculated for each of the participant in the study. The Mean and Standard Deviation (SD) of the PCI was calculated and it was compared between the two groups. RESULTS: The normal range of the PCI which was established in this study was 60 to 220. Significantly higher amount of proteins were found to be excreted in urine in diabetic patients (25.37 +/- 12.51 mg/dl) as compared to those in normal subjects (8.93 +/- 3.54 mg/dl). On comparison of the PCI between the controls and the diabetic subjects, it was found to be significantly elevated in the Diabetes mellitus patients (controls = 114.65 +/-47.97 and in the diabetic patients =373.04 +/- 98.53) (p < 0.001). CONCLUSION: The PCI of a random urine sample can provide a very useful, simple and convenient method for the quantitative assessment of proteinuria, to judge the extent of kidney damage and for avoiding the drawbacks of the 24 - hr urine collections. PMID- 23730633 TI - A comparative study on the fasting and the postprandial dyslipidaemia in type 2 diabetes mellitus. AB - BACKGROUND AND OBJECTIVES: Type 2 Diabetes Mellitus (Type 2 DM), which is characterized by a relative insulin deficiency or insulin resistance is associated with a cluster of metabolic abnormalities, which includes glucose intolerance, hypertension, a unique dyslipidaemia, a procoagulant state, and an increase in macrovascular diseases. The present study was conducted to assess the significance of postprandial dyslipidaemia with respect to fasting dyslipidaemia, in the pathogenesis of atherosclerotic changes and possible cardiovascular diseases (CVD) and complications. Methods and Statistical Analysis: Fifty diagnosed cases of type 2 DM which were in the age group of 35-65 years, which had a duration of diabetes of more than five years, were included in the study and 50 age and sex matched healthy subjects were taken as the controls. In both the study groups, we measured the serum levels of fasting as well as the postprandial lipid profile, which was comprised of the total Cholesterol (TC), triglycerides (TGs), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and the waist-hip ratio (WHI) as the cardiovascular risk factors. The statistical analysis was done by using the Students unpaired 't'-test. RESULTS: The results of this study showed significantly increased levels of serum total cholesterol, TGs, LDL-C and VLDL-C in the postprandial state as compared to those in the fasting state (p<0.001) and as compared to those in the fasting and the postprandial states of the controls (p<0.001). The serum HDL-C level was significantly lower in the postprandial state as compared to that in the fasting state (p<0.001). Also, the postprandial and the fasting HDL-C levels were significantly lower as compared to the levels in their respective control groups (p<0.001). CONCLUSION: The findings of the present study indicated that the lipid profile, as a cardiovascular risk factor, was significantly elevated in the postprandial state as compared to that in the fasting state and that it was significantly elevated in the postprandial and the fasting states in the Type 2 DM patients as compared to the levels in their respective control groups. This signified a routine estimation of the postprandial lipid profile, rather than the fasting lipid parameters, in the cardiovascular risk assessment in Type 2 DM. PMID- 23730634 TI - Association Between Waist Circumference and Serum Triacylglcerol Status in Type 2 Diabetes Mellitus (T2DM): A Study Performed on a Rural Population in Puducherry. AB - INTRODUCTION: India is on the verge of being the diabetic capital of the world, owing to the increasing prevalence of diabetes in India. The aim of this study was to find the association between anthropometry and dyslipidaemia, with a particular reference to the triacylglycerol levels, besides suggesting a better anthropometric variable. METHOD: A group of eighty diabetic patients took part in the study. The Waist Circumference (WC), the waist to hip ratio, the serum triacylglycerol (TAG) levels and the glycated haemoglobin (HbA1c) levels were measured and studied. RESULTS: We found out that there was a significant association between the WC and the TAG levels (p-value = 0.030), between high TAG levels and high HbA1c values (p-value = 0.038) with greater accuracy, in favour of the waist circumference. CONCLUSION: This depicted the fact that a simple measuring tape which is used in measuring the WC, could prove to be a useful and a cost-effective diagnostic approach for monitoring the metabolic complications of type 2 DM. PMID- 23730635 TI - The stress-induced cardiovascular reactivity in the fasting and fed States of healthy young Indian males. AB - BACKGROUND AND OBJECTIVES: Low blood glucose levels have been associated with a hostile behaviour. The individuals who show aggressiveness and hostility are more likely to develop hypertension and cardiac diseases. The future hypertension has been linked with a high cardiovascular reactivity to stress. We have investigated the association of the blood glucose levels with the Cardio Vascular Reactivity (CVR) to stress. METHODS: Fourty six volunteers were subjected to stress (which was induced by the cold pressor task) in the fasting state and again, half an hour after the ingestion of 75 grams of glucose. The CVR in both conditions was compared in terms of an increase in the heart rate and the blood pressure. RESULTS: The resting pulse was lower and the blood pressure was higher in the fasting condition, as compared to the values which were obtained in the 1/2 hour post-prandial condition. The CVR to stress was significantly higher in the fasting condition. INTERPRETATION AND CONCLUSION: The increased resting heart rate and the decreased resting blood pressure in the 1/2 hourPost-Prandial (PP) condition was due to the higher levels of histamine in the post-prandial state. Low blood glucose levels are associated with a higher CVR to stress. This suggests that the persons are prone to develop future hypertension, those with frank hypertension, and the chronic pain sufferers should avoid prolonged fasts, in order to lower their CVR to the stress stimuli which are encountered in the daily life. PMID- 23730636 TI - The aetiology of the bloodstream infections in the patients who presented to a tertiary care teaching hospital in kathmandu, Nepal. AB - BACKGROUND: Bloodstream infections are associated with a significant patient morbidity and mortality. The detection of microorganisms in the patients' blood has a great diagnostic and prognostic significance. The early positive results provide valuable diagnostic information, based on which the appropriate antimicrobial therapy can be initiated. OBJECTIVE: To know the aetiology of the bloodstream infections in the Kathmandu Medical College, Nepal and the antibiotic sensitivity patterns of the causative organisms. MATERIALS AND METHODS: The blood specimens which were received from May 2010 to October 2010 in Kathmandu Medical College and Teaching Hospital, Kathmandu, Nepal, were processed and all the positive isolates were included in the study. The isolates were identified by the standard laboratory procedures. The antibiotic susceptibility patterns were determined by the modified Kirby Bauer antibiotic sensitivity method. RESULT: Of the 1089 blood cultures which were received with the suspected cases of blood stream infections, 138 (12.6 %) were bacteriologically positive. Salmonella serotypes were isolated in 42.7% cases of blood stream infections, followed by Klebsiella pneumoniae in 19.5%, Staphylococcus aureus in 15.9% and others in the rest of the cases. All the gram-negative bacilli isolates showed lower degrees of resistance to amikacin and ofloxacin. All the gram positive isolates were sensitive to amikacin, oxacillin and vancomycin. CONCLUSION: This study stresses on the need for a continued screening and surveillance in the routine blood culture technique for starting with the empiric therapy for blood borne infections. PMID- 23730637 TI - Occurrence of the CTX-M, SHV and the TEM Genes Among the Extended Spectrum beta Lactamase Producing Isolates of Enterobacteriaceae in a Tertiary Care Hospital of North India. AB - PURPOSE: The present study was carried out to assess the prevalence of the Extended Spectrum Beta Lactamases (ESBLs) and to characterize the ESBL types which were prevalent in our hospital. MATERIAL METHODS: Five hundred gram negative isolates which belonged to the family, Enterobacteriaceae, which were isolated during the study period of 2009 to 2011, were investigated for ESBL production. Clinical isolates from urine (344), pus (109), blood (15), IV/ central line tip (10), sputum (12) and body fluid (10) specimens were processed. The organisms which were identified, included E.coli (351), Klebsiella pneumoniae (74), Klebsiella oxytoca (21), Proteus mirabilis (15), Proteus vulgaris (9), Enterobacter spp (15) and Citrobacterspp (15). Antimicrobial susceptibility testing was done. The ESBL detection was carried out for all the isolates by the CLSI confirmatory method. The MIC of ceftazidime and ceftazidime plus clavulanic acid was determined by the E-test. Molecular typing of the ESBLs was performed by multiplex PCR among 93 ESBL isolates. RESULTS: 45.8% isolates were found to be ESBL producers by the CLSI confirmatory method and they were confirmed by the E test ESBL strips. A majority of E.coli in the study possessed the CTX-M genes (59.32%). Among the Klebsiella isolates, a majority were co producers of the ESBL genes; either 2 or all the 3 genes co-existed together. CONCLUSION: An indiscriminate use of the higher antibiotics should be restricted as far as possible. The infection control programmes should be monitored continuously in hospitals, to contain these ESBL producers. We are reporting the presence of all types of ESBL genes among the Enterobacteriaceae isolates from our hospital setting. PMID- 23730638 TI - Optimization of PCR-RFLP Directly from the Skin and Nails in Cases of Dermatophytosis, Targeting the ITS and the 18S Ribosomal DNA Regions. AB - PURPOSE: A pan fungal primer targeting the Internal Transcribed Spacer (ITS) region and optimization of PCR-RFLP using a dermatophyte specific primer targeted the 18S ribosomal DNA (rDNA) region were performed for the identification of dermatophyte species and strains directly from clinical specimens. MATERIALS AND METHODS: One hundred and thirty eight specimens (129 skin scrapings and 9 nail clippings) from clinically suspected cases of dermatophytosis were collected and subjected to direct microscopy and culture. Among them, 66 skin scrapings and 3 nail clippings were processed for genotyping by PCR-RFLP analysis using the Mva I, Hae III and the Dde I restriction enzymes. RESULTS: Of the 138 specimens, 81 specimens were positive for dermatophytosis, the most common one being Trichophyton rubrum (47), followed by Trichophyton mentagrophytes (25) and Epidermophyton floccosum (9). Of the 47 T. rubrum isolates, 10 were T. rubrum var. raubitschekii which were identified phenotypically as urease positive and by DNA sequencing. Since they exhibited minor morphological and physiological features, they have currently been synonymized with T. rubrum. Of the 25 T. mentagrophytes isolates, three were Trichophyton interdigitale, which were identified by DNA sequencing. Among the 66 skin specimens smear, culture and PCR showed the presence of dermatophytes in 36 (54.54%), 42 (63.63%) and 47 (71.21%) cases respectively. Among the three nail specimens, only one was found to be positive for dermatophytosis by smear, culture and PCR. CONCLUSION: Amplification of the dermatophyte specific primer is appropriate in the identification of dermatophytes directly from the clinical material. PCR targeting the ITS region by using the Mva I and the Dde I enzymes was equally good for the RFLP analysis. However, by using the above three restriction enzymes, no strain variations were detected among the T. rubrum and the T. mentagrophytes strains. PMID- 23730639 TI - Prevalence of Hypertension Amongst Adult Patients Attending Out Patient Department of Urban Health Training Centre, Department of Community Medicine, Era's Lucknow Medical College and Hospital, Lucknow. AB - BACKGROUND: Hypertension is the most common disorder which is encountered in outdoor patients. The existing data suggests that there is an increase in the prevalence of pre-hypertension and hypertension in India. The prevalence of hypertension will increase even further, unless broad and effective preventive measures are implemented. The main objective of this study was to find out the prevalence of hypertension amongst the adult outdoor patients of an urban health centre of Lucknow district. MATERIALS AND METHODS: This observational, Out Patients Department based study involved a survey on 306 male and 1203 female respondents who were aged 18 years, who attended the Urban Health Training Centre of the Department of Community Medicine, Era's Lucknow Medical College and Hospital, Lucknow, India. A structured, pretested schedule was used to collect the data with regards to the demographic characteristics and the blood pressure pattern. The Chi- square test and ANOVA were used to analyze the data. RESULTS: The prevalence of hypertension was found to be 44.46%. The proportion of hypertension showed an increasing trend with age. The mean systolic as well as diastolic blood pressure patterns were found to be higher, with an increase in age. CONCLUSION: Hypertension was found to be highly prevalent among the outdoor patients of an urban health centre of Lucknow. An early detection of hypertension can be facilitated by periodically screening people regularly. PMID- 23730640 TI - A Study to Assess Economic Burden and Practice of Cell Phone Disposal among Medical Students. AB - CONTEXT: Our country India is having 919.17 million cell phone users; currently this is the second largest number of cell phone users after China. The youth spend a good amount on talk time and purchasing cell phone handsets. Discarding of cell phone is another issue which needs attention because of generation of e wastes, which leads to environmental pollution. AIM: To assess economic burden and practice of cell phone disposal among medical students. METHODOLOGY: It is a cross-sectional study where self filled questionnaire were given to randomly chosen students. RESULTS: Out of total 311 participants, 133 were males and 178 were females. Mean monthly expenditure of students was Rs. 2787. Out of 311 students only 2 (0.64%) boys were not using cell phones. It was observed that boys are more inclined towards cell phone than girls, as number of previous handsets, money spent on buying handsets and therefore average monthly costs of handsets were significantly higher among boys than girls. Most common reason for frequent changing of handsets was that they were outdated (46.14%). 47.13% of handsets were disposed by exchanging or giving to somebody for use, but 36.57% of handsets were lying waste or thrown away. CONCLUSION: As noticed that a good amount of money was spent on cell phones, students and parents should be counseled regarding cost effective use of cell phone. An effort should be made to dispose off handset in environment friendly way, which can be done by creating awareness about collection centers and strengthening collection chain. PMID- 23730641 TI - Compliance to anti-diabetic drugs: observations from the diabetic clinic of a medical college in kolkata, India. AB - BACKGROUND: The poor glycaemic control among the patients with type 2 diabetes constitutes a major public health problem and a major risk factor for the development of diabetes complications. AIM OF THE STUDY: To study the compliance rate of the patients with type 2 diabetes to the prescribed medications, to find out its correlation with different socio-demographic factors and other patient characteristics and to find out the reasons behind the non-compliance, if any. SETTINGS AND DESIGN: This cross sectional study was conducted on the patients with type 2 diabetes, who Attended the Diabetic Clinic of a Medical College in Kolkata, India. METHODS AND MATERIAL: The patients of type 2 diabetes who attended the diabetes clinic between April to August 2012 were recruited in the study by systematic random sampling and they were interviewed by using the help of a structured interview schedule. The patients who reported taking less than 80% of their prescribed anti-diabetes medicines in the preceding week and had HbA1C of < 7% were considered to be non-compliant. STATISTICAL ANALYSIS USED: The data was analyzed by using the SPSS software. The Chi-square test was used to assess the association of the compliance with the different study variables. A binary logistic regression analysis helped in identifying the factors which contributed to the non-compliance. RESULTS: The compliance rate to the anti diabetic drugs was found to be 57.7%. A univariate analysis showed that it decreased significantly with increasing age and that it was also significantly lower among males, illiterates, those with a poor per capita monthly income and those who had a longer duration of diabetes. It varied significantly with the type of drugs, being lowest with an oral drug and insulin combination (43.4%). No knowledge on the complications of diabetes was significantly associated with a lower compliance. The binary logistic regression also helped in identifying these as the significant contributory factors. The common reasons behind the non compliance were forgetfulness (44.7%) and financial constraints (32.7%). CONCLUSION: It can be concluded that the compliance to anti-diabetic drugs was quite poor among the participants. Increasing age, the male sex, illiteracy, a low monthly income and a longer duration of diabetes were significantly associated with the non compliance. A more concerning fact was the significant association of the non-compliance with the types of drug regimens and a lack of knowledge on the complications of diabetes, which emphasized the role of a repeated patient education regarding the basic aspects of diabetes. PMID- 23730642 TI - A study on the drug utilization trends in the cardiovascular emergencies in a tertiary care hospital. AB - OBJECTIVES: To observe the cardiovascular emergencies which were most frequently treated and to quantify the drug utilization trends in the cardiovascular emergencies, in terms of the Defined Daily Doses [DDD] and the prescribing prevalence in the cardiovascular emergencies. METHODS: This prescription based study was undertaken in the Medicine ICU of the government medical hospital. The age, sex, diagnosis (only cardiovascular) and the drugs which were prescribed, were recorded for each patient. Also, the brand names and the generic names of the prescribed drugs were noted. The collected data was analyzed to study the drug utilization trends. RESULTS: It was observed that the most commonly treated cardiovascular disease was IHD. The IHD was more in males than in females who were below 50 years of age and it was nearly equal in the age groups which were above 50 years. The use of Angiotensin Converting Enzyme (ACE) inhibitors was higher than that of the beta blockers and the calcium channel blockers. The patients with cardiovascular emergencies also had preceding associated diseases like diabetes mellitus and hypertension. CONCLUSIONS: The protocol of the management which was followed by the college in the treatment of cardiovascular emergencies was competent enough, as the clinical outcomes of the patients were favourable. But there was a guideline incongruent prescribing behaviour which was statistically significant, for which there is a need to undertake large scale studies. PMID- 23730643 TI - A Study on the Usage Pattern of Antimicrobial Agents for the Prevention of Surgical Site Infections (SSIs) in a Tertiary Care Teaching Hospital. AB - CONTEXT: Inappropriate antimicrobial use increases the incidence of drug resistance, drug toxicity and superinfections, thereby increasing the healthcare costs. Various approaches for rationalizing the antimicrobial therapy, have been suggested. Collection of baseline data on the pattern of the antimicrobial use is usually suggested as the first step in this direction, which will help in identifying the problem areas, which demand our attention. AIMS: To study the usage pattern of prophylactic antimicrobials in surgical patients, in order to detect any inappropriateness concerning the selection, timing, redosing and the duration of antimicrobial administration. SETTINGS AND DESIGN: A retrospective review of the randomly selected medical records of general surgical cases over an 8 month period in a tertiary care teaching hospital. METHODS AND MATERIAL: The medical records of 258 patients who had undergone surgical procedures were verified for the appropriateness of the antimicrobial prophylaxis, with respect to the choice of the antimicrobial agent, the time of its administration, the intraoperative dosing, and the duration of the postoperative use. The obtained data was analyzed and conclusions were drawn with the help of descriptive statistics. RESULTS: Third generation cephalosporins were used preoperatively in all the 258(100%) patients through the intravenous route. In addition, 77(30%) patients received metronidazole or amikacin. The antimicrobials were administered half an hour to one hour before the surgery. No intraoperative redosing was given. The duration of the postoperative prophylaxis was extended to 36 hours or more in 248(96%) of the cases. CONCLUSIONS: The timing of administration of the preoperative dose was appropriate and well delegated to the operating room nurse. The intra operative dose was appropriately omitted. The main concern was the increasing use of the third generation cephalosporins and the unnecessary prolonged duration of the postoperative prophylaxis, which needed to be addressed. PMID- 23730644 TI - The knowledge, attitude and the perception of prescribers on the rational use of antibiotics and the need for an antibiotic policy-a cross sectional survey in a tertiary care hospital. AB - BACKGROUND: Antibiotics are prescribed frequently and there is always an overuse with a risk of resistance and increasing costs. Rational drug prescribing is essential for minimizing the health care costs and for reducing the resistance. The implementation of a strict antibiotic policy by all the health care institutes is being made mandatory nowadays. An improving awareness among the prescribers which can be created through educational interventions, can promote the rational use of antibiotics. Hence, we considered it worthwhile to study the knowledge, attitude and the perception of the practitioners towards a rational antibiotic use. MATERIALS AND METHODS: All the registered practitioners who were working in the hospital setting and were willing to give written informed consents, were enrolled in the study. All the participants who were enrolled in the study during a one month period, had to fill up a predesigned, structured and validated questionnaire which was used to assess the knowledge, attitude and the perception among physicians towards the rational use of antibiotics. RESULTS: About 65% of the participants who provided complete information in the questionnaire, were included in analysis. Among them, more than 50 % agreed on the existence of an essential drug list, on the knowledge about new antibiotics and on prescribing antibiotics rationally and on the interpretation of the culture and the sensitivity results. A majority strongly agreed that they ensured that their patients completed the course, that they provided counselling and that they took special interest in the proper use of antibiotics. There was a consensus on the overuse, issues of resistance, and on the input from fellow colleagues. CONCLUSION: The participants in our study had knowledge about the rational use of antibiotics, an attitude to prescribe drugs as per the essential drug list and a perception that antibiotics were being overused and that rational drug prescribing had an important role in the antibiotic resistance. PMID- 23730645 TI - To analyze the Impact of Serial Prescription Audits with Active Feedback on Quality of Prescription Behaviour. AB - MATERIAL AND METHODS: A serial prescription audit in four cycles (three months each) was conducted at Jhalawar Medical College and Hospital and at Chintpurni Medical College and Hospital for two years, one year in each hospital. One cycle included the prescriptions which were collected by using a digital camera from the outdoor patients department every month (n=250 per month), for three months regularly. A baseline prescription audit, as a cross-sectional survey, was done on the last date of the first month. Re-audits were done on the last date of the 2(nd) and 3(rd) months, which concluded one cycle. One cycle was followed by three months of no prescription audit. In total, four cycles were completed in two years. The parameters which were observed were- (a) the formats of the prescriptions (b) the WHO drug core indicators and (c) the legibility of the prescriptions. The clarity of the prescriptions was decided upon by the consensus group. A continuous evaluation and a feedback process were carried out every month by analyzing the prescriptions, based on the extent of conformity to the "WHO Guide to Good Prescribing" and the updated list of the "WHO Essential Medicines." The data was analyzed by using the Chi-square test. RESULTS: There was a significant improvement in the formats of the prescriptions in terms of the quality of the completeness and the rationality at the end of the 2nd and 3rd months of each cycle. Similarly, the WHO drug core indicators improved with every re-audit in each cycle (p < 0.05). Overall, the total percentage of the core indicators significantly improved in the 2nd and 3rd months as compared to the 1st month in all the cycles (p < 0.05). The clarity of the prescriptions improved in the successive re-audits. There was a sudden decline in the improvement in all the parameters in the first month of the 2nd, 3rd and the 4th cycles as compared to that in the 2(nd) and 3(rd) months of the previous cycles. CONCLUSION: Serial prescription audits and an active feedback definitely improve the prescription behaviours in the therapeutic decision making. But discontinuing the prescription audits begins to reverse the improvement in the prescription behaviours. PMID- 23730646 TI - Psychosocial morbidities in school going adolescent girls: a study from a South Indian city. AB - INTRODUCTION: Adolescents form about 20-30% of our population. Like the children of any other ages, adolescents have the so called usual problems and problems which are specific for their age and developmental peculiarities. The present study was undertaken to assess the prevalence of the psycho-social problems of adolescent girls and to counsel the girls with problems or those who were problem prone. METHODS: This was a cross-sectional study in which 500 adolescent girls from 6 higher secondary schools were selected via a simple random sampling method. A psychiatrist was consulted before the study was undertaken. A pre designed profoma was given to be filled up and the data was analyzed later. RESULTS: Sixty percent of the girls were in the age group of 14 to 15 years. Depression was noted in 10 girls (2%), symptoms of anxiety were noted in 5 girls (1%), stuttering and a poor concentration were observed in 10 girls ( 1% each), 2 girls (0.4%) came from broken families, 5 girls (1%) were suffering from anorexia nervosa, 3 girls (0.6%) were suffering from bulimia nervosa and 10 girls (2%) had pychosomatic symptoms. 5 girls (1%) reported interpersonal violence among their hostelmates. CONCLUSION: Finding out the prevalence of the psychosocial problems among adolescent girls and counselling them appropriately can decrease the major psychosocial morbidities which are prevalent in the community. PMID- 23730647 TI - The Antihypertensive Efficacy of Chlorthalidone and Telmisartan in Indian Hypertensive Patients who were Uncontrolled with Hydrochlorothiazide and Telmisartan Combination-A Prospective and an Open Label Study. AB - OBJECTIVE: The primary objective of this study was to evaluate the antihypertensive efficacy of the chlorthalidone and telmisartan combination in Indian hypertensive patients who remained uncontrolled after taking the hydrochlorothiazide and telmisartan combination. METHODS: A total of 100 eligible patients were enrolled in this prospective, open label study. The patients were given telmisartan (40 mg) and chlorthalidone (12.5 mg), who had not achieved the target blood pressure (140/90 mmHg) despite taking the combination of telmisartan (40 mg) and hydrochlorothiazide (12.5 mg). The assessment was done at the end of 4 weeks and 8 weeks. RESULTS: The mean SBP and DBP after taking telmisartan (40 mg) and hydrochlorothiazide (12.5 mg) were 154.88+/-9.57 (range 144 to 160) mmHg and 99.37+/-2.78 (range 92 to 106). At the end of 4 weeks of being on telmisartan (40 mg) and chlorthalidone (12.5 mg), the mean SBP and DBP were 145.56+/-5.12 (range 134 to 158) mmHg and 95.14+/-4.27 (range 84 to 100) mmHg. Significant falls in the SBP (5.32+/-2.64) and DBP (4.18+/-2.48) were noted at the end of the 4 week therapy. They were sustained at the end of 8 weeks also. The SBP target (<140 mmHg) was achieved in 24 % patients. The DBP target (<90 mmHg) was achieved in 19% patients. The combined SBP and DBP target (<140/90 mmHg) was achieved in 15% patients. No significant clinical adverse events were reported. Similar falls in the SBP and DBP were noted in the subgroups (smokers, females, diabetics, etc). CONCLUSIONS: The hypertensive patients who do not achieve the target blood pressures on telmisartan and hydrochlorothiazide can be switched on to the telmisartan and chlorthalidone combination. This combination is effective and well tolerated. PMID- 23730648 TI - The Serum Gamma Glutamyl Transpeptidase - A Non invasive Diagnostic Bio Marker of Chronic Anicteric Non Alcoholic Liver Diseases. AB - BACKGROUND: The serum gamma glutamyl transpeptidase (GGT) levels rise and return to normal levels later in the chronic anicteric non alcoholic liver diseases than the transaminases levels. So, the estimation of GGT is of some value in monitoring the progress of acute to chronic hepatitis, when the values persist in high levels. AIMS AND OBJECTIVES: To evaluate the serum GGT levels in patients with chronic anicteric non alcoholic liver diseases and to show that it can be used as a noninvasive diagnostic biomarker for the diagnosis of chronic anicteric non alcoholic liver disorders. MATERIALS AND METHODS: This was a case control study, in which 50 cases and 50 controls were selected.The liver function tests with a special reference to the serum level of GGT were measured in the laboratory for both the cases and the controls and the serum GGT levels of the cases were compared with those of the controls. The Chi-square and the Fisher exact tests were used to find the significance of the proportions of the study parameters between the cases and the controls. The Student's t test (two tailed) was used to find the significance mean pattern of the study parameters between the cases and the controls. RESULTS: The mean serum GGT level was 38.73+/-11 IU/L in the cases and in the controls, it was 20.42+/-9 IU/L(p<0.001).The mean value of serum ALT was 41.37+/-12.5 vs 16.3+/-8iu/l(p<0.001), that of AST was 28.14+/-8 vs 17.56+/-8.5iu/l(p<0.05), that of total bilirubin was 0.9+/-0.3 vs 0.5+/ 0.2mg/dl and that of serum albumin was 4.17+/-0.6 vs 4.5+/-0.75gm/dl, as were seen in the cases and the controls respectively. CONCLUSION: The serum gamma glutamyl transpeptidase level was elevated more consistently along with the alanine transaminase level in all types of anicteric nonalcoholic chronic liver diseases. The alanine transminase level has already been proved to be a marker in the diagnosis of chronic anicteric nonalcoholic liver diseases. So, in view of the persistent elevation, along with the high sensitivity, the elevated gamma glutamyl transpeptidase level can also be used as a noninvasive bio marker of chronic anicteric nonalcoholic liver diseases for both diagnostic and therapeutic purposes. PMID- 23730649 TI - The Correlation Between Psychiatric Disorders and Women's Lives. AB - OBJECTIVE: Psychiatric disorders are important factors which affect the quality of life: employment rates, interpersonal and intrafamilial communications, marriage, child-bearing, parental skills and many other social - cognitive areas in different ways. Psychiatric disorders like schizophrenia, bipolar affective disorder and depressive disorder have a negative impact on women's lives. This study has compared the relationship between these mental illnesses and the liabilities of women's lives. METHODS: For the purpose of this study, 61 schizophrenics, 35 bipolar and 40 unipolar female patients and 60 healthy controls from a university hospital of eastern Turkey were evaluated with SCID- I, a family environmental scale and a personal information questionnaire. RESULTS: The women with psychiatric disorders had higher rates of unemployment, shorter durations of marriage and lower numbers of parity, as compared to their healthy counterparts, especially after the onset of their illnesses. The schizophrenia and bipolar groups are at risk due to the psychotropic medications which they take during pregnancy. The onset or the exacerbations of illnesses during the postpartum period are also seen more in the schizophrenia and the bipolar groups. However, the patients did not use medicines more than the healthy controls during lactation. The schizophrenia and bipolar groups seem to be failing in using reliable methods of contraception. This data is important due to the traditional and the socio-economical structure of eastern Turkey, which may interrelate with the results. CONCLUSION: Women have to play various roles in life and they have various challenges which are related to these roles. The female psychiatric patients should be evaluated in the special perspective of 'being women', along with other clinical parameters. The evaluation of the social, cultural and the economic aspects and the collaborative teams of different clinical disciplines which are related to women's mental health would be beneficial. PMID- 23730650 TI - Association between Oro-Facial Defects and Systemic Alterations in Children Affected by Marfan Syndrome. AB - BACKGROUND: It is important to establish an early diagnosis of the Marfan Syndrome (MFS) for providing an adequate pharmacological or surgical therapy. Nevertheless, this diagnosis may be complex, given the multi-organic involvement of this disease. AIMS: In this work, we evaluated the oral phenotype in a group of paediatric patients with a clinical diagnosis of MFS, to quantify the association of the oro-facial defects with other systemic alterations. SETTINGS AND DESIGN: Paediatric subjects who were aged, with a clinical diagnosis of MFS, were selected from our regional Marfan monitoring unit. METHODS AND MATERIAL: All the patients were subjected to Paediatric Dentistry examinations and a radiological screening with Panoramic and Cephalometric X-Rays. The aortic dilation (Aortic Z-score value), the hyperlaxity of the ligaments and scoliosis were evaluated by cardio-surgical and orthopaedics specialists. STATISTICAL ANALYSIS: The correlations between the oral and systemic alterations were analyzed by using the chi square test for the nominal variables. RESULTS AND CONCLUSIONS: We found a significant correlation of the Aortic Z - score with multiple oral defects which included retrognathia, malar hypoplasia, cross bite, oral respiration and an ogival palate. An association of the oral defects with hyperlaxity of the ligaments and scoliosis was also found. Thus, the data suggested that dentists should be more involved in a multidisciplinary approach, to provide an early MFS diagnosis in paediatric patients. PMID- 23730651 TI - A two trunked brachial plexus: a case report. AB - The brachial plexus is a major and a complicated plexus at the root of the neck. It is formed by the ventral primary rami of the C5, C6, C7, C8 and the T1 spinal nerves. During the routine under graduate dissection of the right upper limb of an adult female cadaver, a variant pattern of a two trunked brachial plexus was encountered. The upper trunk was formed by the fusion of the C5 and the C6 roots. The C7 root, instead of continuing as the middle trunk, joined with the roots of C8 and T1 to form the lower trunk. On the left side, the usual pattern of the brachial plexus was seen. The knowledge on such variations are of interest to anatomists, clinicians, anesthesiologists and especially, to surgeons. These are of immense importance during surgical explorations of the axilla and the arm region and also during nerve blocks. It also helps the clinicians in getting a proper understanding of some previously unexplained clinical symptoms. Further, the ontogeny and the phylogeny of this entity have been discussed in detail. PMID- 23730652 TI - A rare finding of the superficial palmar arch-developmental and clinical significance. AB - The ulnar artery provides a major blood supply to the hand in the form of the superficial palmar arch, with the assistance of the radial artery. A rare pattern of the superficial palmar arch was observed in a formalin fixed, male cadaveric left hand. The ulnar artery was only involved in the formation of this arch, which provided three common palmar digital arteries which ran into the second, third and the fourth spaces between the corresponding digits and one proper palmar digital artery which ran along the ulnar side of the little finger. The main trunk of the ulnar artery bifurcated to supply the thumb and the index finger. The superficial branch of the radial artery did not participate in the arch formation. The arch was completed by the radial artery proper on the dorsolateral surface of the hand, after joining the point of bifuracation of the ulnar artery. PMID- 23730653 TI - Pleural tuberculosis mimicking inflammatory pseudotumour. AB - A pseudotumour is a rare presentation of bronchopulmonary tuberculosis which occurs in immunocompetent patients, which can simulate malignancy, both clinically and radiologically, and may cause delay in its diagnosis and treatment. The incidence of bronchopulmonary pseudotumours was found to vary from 2-4%, as was seen in various studies. A mycobacterial pseudotumour of the pleura is a rare entity. We are reporting a case of a pleura based tubercular pseudotumour in a 59 years old patient who presented with a four month history of the nonspecific symptoms of cough and chest pain. The radiological investigations showed that a pleural based mass lesion was occupying the right lower hemithorax. The initial biopsy was suggestive of a hyalinizing variant of an inflammatory pseudotumour. The follow-up surgical resected mass was consistent with the features of a tubercular granuloma. The clinical presentation and the histopathological findings have been presented, with a brief review of the literature. Due to its varied and unusual presentation, bronchopulmonary tuberculosis should always be kept in mind when a patient with a similar clinical and a radiological picture is being evaluated. PMID- 23730654 TI - Pleomorphic adenoma of the lacrimal gland in an eleven years old girl. AB - We are presenting a case of pleomorphic adenoma of the lacrimal gland in a 11 years old girl. This is a rare presentation. Pleomorphic adenoma is the most common epithelial tumour of the lacrimal gland, which represents 12% of all the lacrimal fossa lesions. It typically presents in middle age and is rare in children who are under the age of sixteen years, with only a few previously reported cases. PMID- 23730655 TI - Post thyroidectomy suture granuloma: a cytological diagnosis. AB - There are known post thyroidectomized complications, a suture granuloma being less frequent, with its late complication mimicking recurrent thyroid cancer. A suture granuloma is a benign, granulomatous inflammatory reaction that occurs due to the use of non absorbable suture. It constitutes one of the late complications which altogether make up less than 2% of its incidence. A suture granuloma is similar to a foreign body reaction and it usually develops slowly as a painless, palpable asymptomatic mass over the years. It mimics a cancer recurrence or a lymph node metastasis. Here, we are reporting a case of a post thyroidectomy suture granuloma in a 46 years old lady who presented with a painless swelling in the lateral neck, with a past history of thyroidectomy 5 years back. PMID- 23730656 TI - Extragenital aggressive angiomyxoma of the axilla and the chest wall. AB - Aggressive angiomyxomas are uncommon mesenchymal tumours which most often arise in the perineal and the pelvic regions in women. Extragenital aggressive angiomyxonas are extremely rare. We are reporting a young male with an aggressive angiomyxoma which involved the axillary region and extended into the anterior chest wall, which demonstrated its characteristic histomorphological features. The diagnosis was confirmed by immunohistochemistry. A careful histological examination, along with immunohistochemistry, aids in diagnosing this lesion and differentiating it from tumours which have similar histologies. PMID- 23730657 TI - The cytological diagnosis of extra-oral plasmablastic lymphoma: a rare entity. AB - Non-Hodgkin's Lymphomas (NHLs) which are associated with the Acquired Immunodeficiency Syndrome (AIDS) are heterogeneous. Plasmablastic Lymphoma (PBL) was first recognized as an aggressive, invariably fatal subtype of Non-Hodgkin's Lymphoma which occurred mostly in patients with AIDS, with distinct histomorphologic and immunophenotypic findings, which affected the jaw and the oral mucosa exclusively. Subsequently, there have been case reports which have described extra-oral plasmablastic lymphomas in the lung, jejunum, caecum, nasal mucosa, etc. We are reporting a case of this rare subtype of diffuse large B-cell lymphoma which presented as a soft tissue mass, which we believe is the first case to be diagnosed by FNAC. PMID- 23730658 TI - An Idiopathic Membranous IVC Obstruction: Presenting as a Variant of the BCS. AB - An Inferior Venacaval (IVC) lumen obstruction, whether it is partial or complete, is not a common phenomenon and it may be caused by the thrombosis or compression which may result from neoplastic or non neoplastic masses. There are cases which are idiopathic and which are typically referred to as membranous obstructions of the IVC. Here, we are presenting a 40 years old male with multiple tortuous veins over the abdomen, with non healing ulcers in the leg for 12 years, without ascites, who underwent a successful percutaneous transluminal balloon dilatation of the IVC membrane which was located above the hepatic veins, which resulted in a successful palliation of his symptoms. PMID- 23730659 TI - Bilateral primary fallopian tube carcinoma with the classical clinical features: a case report. AB - Bilateral primary fallopian tube carcinoma is a rare diagnosis in our gynaecological practice. Very often, the diagnosis is mistaken for an ovarian carcinoma or a tubo-ovarian mass. A correct, preoperative diagnosis is made only in 4% of the cases. This is due to the nonspecific symptoms. The Latzko's triad of a watery vaginal discharge, a colicky lower abdominal pain and a pelvic mass is typical of a fallopian tube carcinoma, but this triad is noted only in less than 15% of the patients. Here, we are reporting such a case where the patient presented with all the classical features of a primary fallopian tube carcinoma. This case is also being reported for it's extreme rarity. PMID- 23730660 TI - A Case Report on A Myomectomy which was Done During A Caesarean Section. AB - Uterine myomas are being observed in pregnancy more frequently now than in the past, because many women are delaying child bearing till their late thirties, which is the time for the greatest risk of the myoma growth. Traditionally, obstetricians are trained to avoid myomectomies during caesarean sections as severe haemorrhages can occur, which may often necessitate hysterectomies. Pedunculated fibroids which can be easily removed are an exception. Here, we are reporting one case of a myomectomy which was done during a caesarean section. PMID- 23730661 TI - Torsion of the fallopian tube and the haematosalpinx in perimenopausal women- a case report. AB - An isolated fallopian tube torsion is a rare, often difficult to diagnose, but significant cause of acute lower abdominal pain in women of the reproductive age group. It is rare in the perimenopausal age group. We are presenting a literature review and the case of a 47 years old woman who presented with a sudden onset of acute lower abdominal pain . Her clinical examination revealed an 8x8 cm, tender, cystic mass in the left lower quadrant, with positive cervical movement tenderness. MRI revealed a gross hydrosalpinx with a small left ovarian cyst. With a diagnosis of left adnexal torsion, an emergency laparotomy was performed, which revealed an isolated left fallopian tube torsion which necessitated a left salpingo-oophorectomy. A tubal torsion should be suspected in females with acute lower abdominal pain, of any age group, especially in those with predisposing factors like pelvic infections, tumours and surgeries which include tubal ligation. Laparoscopy is the preferred modality for the diagnosis and treatment of a tubal torsion. PMID- 23730662 TI - An interesting case of eosinophilic meningitis. AB - Angiostrongylus cantonensis is one of the causative agents of eosinophilic meningitis. Humans get infected when they ingest raw or partially cooked snails or monitor lizards (Varanus bengalensis). There is a popular belief that the tongue and the liver of the monitor lizard has aphrodisiac properties. A 20-year old man was admitted to our hospital with a history of fever, headache and vomiting. His cerebrospinal fluid revealed eosinophilia. He gave a history of the ingestion of a monitor lizard, ten days prior to the onset of the symptoms. So, a diagnosis of eosinophilic meningitis due to Angiostrongylus cantonensis was made. He was treated with oral albendazole and prednisolone. His symptoms improved gradually within two weeks from his admission. PMID- 23730663 TI - A delayed traumatic diaphragmatic hernia presenting with a bowel obstruction 20 years postinjury. AB - A delayed Traumatic Diaphragmatic Hernia is a rare diagnosis. A 38 years old male presented to our emergency department with an acute bowel obstruction. He had a prior trauma laparotomy twenty year's prior, which was reportedly negative. He required preoperative resuscitation for his severe hypokalaemic, hypochloraemic metabolic alkalosis, and acute renal failure. He underwent operative reduction of the incarcerated contents, and a primary permanent suture repair of the defect. The principles of the diagnosis of the delayed traumatic diaphragmatic hernia, and the operative repair of this entity have been reviewed. PMID- 23730664 TI - Colon Obstruction due to an Anticoagulant Induced Intramural Haematoma; A Rare Case Report. AB - A spontaneous, intramural, intestinal haematoma is a rare complication of the anticoagulant therapy. We are reporting here, a rare case of a 63-years-old male, who presented with intestinal obstruction which was caused by an intramural and a submucosal colonic haematoma, which had resulted from warfarin administration. This patient rapidly improved after taking conservative treatment. A history of anticoagulant use with a prolonged INR value in patients who present with abdominal pain, should alert the physicians or surgeons to search for this entity. It is extremely important to recognize this syndrome at its early stages, to avoid an unnecessary operation, since the outcome is usually excellent after a conservative treatment. PMID- 23730665 TI - Syringocystadenoma papilliferum of the scalp in an adult male - a case report. AB - Syringocystadenoma papilliferum is a benign adnexal skin tumour of the apocrine or the eccrine type with characteristic histological features and varied and non distinct clinical findings. It is relatively a rare neoplasm, which is called as a childhood tumour, since it usually appears at birth or during puberty. A case of syringocystadenoma papilliferum of the scalp in an adult male has been presented, which was clinically diagnosed at first as keratocanthoma of the scalp but was later histologically confirmed as syringocystadenoma papilliferum. PMID- 23730666 TI - Bullous fixed drug eruption to ciprofloxacin: a case report. AB - Adverse reactions to medications are extremely common and display a characteristic clinical morphology such as fixed drug eruption (FDE), Stevens Johnson syndrome, urticaria, morbilliform exanthem, hypersensitivity syndrome, pigmentary changes, lichenoid, dermatitis, acute generalized exanthematous pustulosis, photosensitivity, vasculitis etc. Here we report a case of a 60 year old male who presented to us with multiple bullous eruptions over both the hands and feet after oral ingestion of ciprofloxacin. PMID- 23730667 TI - Melioidosis with a Pericardial Effusion, which Relapsed as a Chest Wall Abscess: A Rare Presentation. AB - Melioidosis, which is caused by a soil saprophyte, Burkholderia pseudomallei, is most prevalent in the south-west coast of India. Although it is frequently seen in immunocompromised patients, melioidosis can occur in apparently normal individuals. Melioidosis can involve almost any organ. A relapse of melioidosis is usually associated with a poor adherence to the eradication therapy, a multifocal involvement and bacteraemia. A relapsing melioidosis is usually known to follow a similar pattern of organ involvement in the first and second episodes of the infection. We are discussing here, a rare case of melioidosis in a 38-year old construction-worker, with no risk factors, who presented initially with a pericardial effusion. It relapsed 6 months after he completed the prescribed eradication therapy for 3 months, as an anterior chest wall abscess. The author recommends a high index of suspicion for the relapsed melioidosis cases, inspite of the primary episode being non-bacteraemic and compliant with the recommended therapy, in order to avoid further complications. PMID- 23730668 TI - Alveolar Soft Part Sarcoma-A Histological Surprise in a Male Patient who was Suspected to have Breast Cancer. AB - Alveolar Soft Part Sarcoma (ASPS) is a very rare type of soft tissue sarcoma. Its cell of origin is unclear. It usually presents in the second to fourth decade of life. The most common reported sites of ASPS are the lower extremities, the head and the neck. Because of the rarity of this disease, there is no standard treatment plan. Surgical excision with negative margins is considered as the treatment of choice. We are reporting a rare presentation of ASPS as a male breast lump. PMID- 23730669 TI - SLE Developing in a Follow-Up Patient of Kikuchi's Disease: A Rare Disorder. AB - Kikuchi's disease or the Kikuchi-Fujimoto Disease (KFD) is a very rare, self limiting, benign form of histiocytic necrotizing lymphadenitis, which is mostly seen in young females. We are presenting a case of Systemic Lupus Erythematosus (SLE) which occurred after 2 years in a patient of Kikuchi's disease during a follow-up examination. PMID- 23730670 TI - Adherence and non-adherence to treatments: focus on pharmacy practice in Nepal. AB - Nepal is one of the developing countries having many limitations in providing the quality health services to its population. In many countries, improvement in patients' adherence to the pharmacotherapy had been one of major outcome of quality pharmaceutical services. Till date, very less thing has been done in this area in Nepal; so it seems mandatory to improve the patient adherence to the treatment plans. Adherence to the medical therapy can be explained by the extent of the behavioral coincidence to the medication and non-medication regimen by a patient whereas compliance and concordance are two different models of patient adherence to the therapy. Compliance model suggests that patients have been brought responsible for being unable to follow 'doctor's order and concordance tempts to measure the degree of agreement between patient and his or her clinician about the nature of illness and the best possible therapy for the welfare of the patient. Non-adherence to the therapy may lead to different problems as consequences of non-adherence in four different level- individual, institutional, societal and national levels. Although some programs like, "Direct Observation Treatment, Short-course (DOTS) for tuberculosis, implementation of antiretroviral treatment schedules for HIV patients and pediatric vaccination models," are the examples of attention towards the cases of noncompliance in Nepal. It has long been faced its limitations in the forms of either untrained manpower or lack of good documentation of patients' adherence to therapy or high illiteracy rate or unaffordibility of patients to their treatment or lack of pharmaceutical care services. PMID- 23730671 TI - The relationship between periodontitis and systemic diseases - hype or hope? AB - Investigations have definitely acknowledged a clinically relevant two-way relationship between periodontitis and certain systemic diseases and conditions, which are significant for the dentist in the daily practice and for a physician as well. This review article yields the most up-to-date information on the role of periodontal diseases in systemic diseases, that include cardiovascular diseases and atherosclerosis, diabetes mellitus, respiratory diseases and unfavourable pregnancy outcomes. It debates the role of diabetes and smoking in the periodontal tissues. PMID- 23730672 TI - The malnutrition inflammation complex syndrome-the micsing factor in the perio chronic kidney disease interlink. AB - The patients who undergo Maintenance Haemodialysis (MHD) have a high prevalence of Protein-Energy Malnutrition (PEM) and inflammation. Because these two conditions often occur concomitantly in the MHD patients, they have been referred to together as the Malnutrition-Inflammation Complex Syndrome (MICS) or Malnutrition-inflammation atherosclerosis, to underscore the atherosclerotic complications of this entity. MICS is also reported to correlate with a poor outcome, including a decreased quality of life, refractory anaemia and significantly greater rates of hospitalization and mortality in the MHD patients .Indeed, MICS may be the major cause of the paradoxical exposure-outcome association, which is also known as reverse epidemiology of the cardiovascular disease risk factors in the maintenance dialysis patients. Periodontitis is a chronic inflammatory disease of the supporting tissues from the dentition, which results from the infection of and the interaction of selected bacterial species with the components of the host response in disease-susceptible individuals as the haemodialysis (HD) patients. Only in recent years, did an emerging evidence link the dental infection, especially periodontitis, to an increased risk of atherosclerosis and thrombosis. In the HD patients, studies have been showing a positive link between periodontal disease and systemic inflammation on correlation between the levels of CRP and immunoglobulin G of Porphyromonas gingivalis. Recent researches have confirmed that the periodontal health is poor in haemodialysis patients and that it correlates with the markers of malnutrition and inflammation. PMID- 23730673 TI - Awareness and knowledge of common oral diseases among primary care physicians. AB - OBJECTIVE: The objectives of this study were to examine the level of awareness of the common oral disease amongst the primary care physicians in Chennai, India and to study the proportion of the routine oral examination among them. METHOD: This study was a cross-sectional, self administered, questionnaire survey which was done among 70 primary care physicians of Chennai, India. The questionnaire assessed the proportion of the routine oral examination and the knowledge and the awareness about the common dental problems among the primary care physicians. RESULT: This study showed moderate awareness about the signs and symptoms of the common oral diseases. There appeared to be a low awareness about the treatment of limited mouth opening and the causes of white patches. 85.9% of the doctors said that they routinely examined the oral cavity; 4.2% said that they sometimes did so. 4.2% of the sample said that they did not perform a routine oral examination, whilst another 4.2% said that they examined the throat only. CONCLUSION: The information which was gleaned from this study can help in developing a focused module which is aimed at the practising primary care physicians, and to suggest appropriate additions to the curriculum of the medical graduates, so as to enable an early detection, an appropriate referral, and an ultimately improved oral and general health of our population. PMID- 23730674 TI - Creating a Single-Visit, Fibre-Reinforced, Composite Resin Bridge by Using a Natural Tooth Pontic: A Viable Alternative to a PFM Bridge. AB - BACKGROUND: The rehabilitation of an anterior tooth space presents a confronting situation. Several modalities are presently available to address the challenge of an immediate replacement of a missing anterior tooth. These include a removable temporary acrylic prosthesis or resin-bonded bridges. Fibre-Reinforced Composite (FRC) bridges are preferable if they are fixed and if a cost-effective tooth replacement is desired. Also, they provide an aesthetic and a conservative treatment choice as the abutment teeth require a minimal or no preparation. METHODS: This article is describing two cases with an immediate replacement of the maxillary incisor teeth by a single visit technique, with the use of FRC Resin (Ribbond) bridges and natural tooth crowns as pontics. RESULTS AND CONCLUSIONS: The procedure was completed at the chair side, thereby avoiding the laboratory costs. A two year follow up of the cases has shown a successful outcome. Creating an adhesive FRC bridge by using a natural tooth pontic is a successful treatment option for the direct aesthetic replacement of missing anterior teeth. PMID- 23730675 TI - Non-syndromic oligodontia of primary and permanent dentition: 5 year follow up- a rare case report. AB - Oligodontia designates the congenital absence of six or more permanent teeth, excluding the third molars. Oligodontia of primary and permanent dentition is a rare observance. This case report describes the missing teeth in primary and permanent dentition of an 8 year old boy. Early diagnosis, and comprehensive treatment planning with good coordination and timing of the individual treatment phases are decisive for a successful treatment outcome. PMID- 23730676 TI - Incidentally detected isolated unilateral pulmonary artery agenesis. AB - We are reporting here, a case of an incidentally detected, isolated, unilateral pulmonary artery agenesis on contrast enhanced Computed Tomography (CT) of the chest in a 39-year-old male patient. PMID- 23730677 TI - The perspectives on including palliative care in the Indian undergraduate physiotherapy curriculum. AB - According to the guidelines which were published by WHO in 2008, palliative care has been defined as "An approach that improves the quality of life of the patients and their families who face the problems which are associated with life threatening illnesses, through the prevention and relief of suffering by means of an early identification, an impeccable assessment and the treatment of pain and other problems, physical, psychosocial and spiritual". The intervention which is provided as a part of the palliative care has to be provided by health professionals who strictly work as a part of multidisciplinary team and have been specifically trained to an optimal level of competency in the field. The impairment of the physical function and pain are two key problem areas in palliative care, which a physiotherapist deals with. Is a physiotherapist who is trained in India, trained to work as an efficient member of the team in this field? THIS ARTICLE DEALS WITH THE FOLLOWING: What is palliative care and what is its importance?A multidisciplinary approach to palliative careThe scenario of palliative care in IndiaThe role of physiotherapy in palliative care.The current scenario of physiotherapy education vis a vis palliative care. PMID- 23730678 TI - Unusual 'Tick Mark' Calcification on Chest Radiograph in Rheumatic Heart Disease CT Imaging Revealing Pericardial Calcification. AB - The identification and the interpretation of subtle opacities on chest radiographs are challenging for clinicians. At times, especially when they are found incidentally, some opacities may be considered as artefacts or insignificant and they are neglected. In the present case, an unusual 'tick mark' - shaped dense opacity was incidentally found over the cardiac shadow, and CT imaging revealed pericardial calcification. Pericardial, valvular and atrial calcifications in rheumatic heart disease have been described in the literature. PMID- 23730679 TI - Bypassing Bypass Surgery and Other Success Stories from the National Institutes of Health. AB - After a heart attack, patients often undergo a procedure to open up the clogged artery and install a tiny meshlike device called a stent to keep the artery propped open. In most cases, the body reacts to this foreign object with scar tissue formation, and the artery narrows again. To combat this re-clogging process, National Institutes of Health inventors developed paclitaxel-coated stents and later licensed it to Angiotech. Approved by the Food and Drug Administration in March 2004, these stents are expected to substantially reduce the use of coronary artery bypass surgery, an expensive operation now performed annually on 350,000-plus Americans. This and three other examples of NIH licensing success stories are described in this paper: (a) Kepivance, which improves the quality of life for cancer patients by eliminating mouth sores, (b) AIDS drug ddI, an important component of many combination drug therapies, and (c) Vitravene, the first and only antisense drug to be approved by FDA. These four examples will illustrate the success not only of the NIH licensing program, but also the innovative approaches taken by NIH inventors and the persistence of its commercial partners. This paper also highlights the business and legal lessons learned from these four cases. PMID- 23730680 TI - Congenital disorders of glycosylation. Part I. Defects of protein N glycosylation. AB - Glycosylation is the most common chemical process of protein modification and occurs in every living cell. Disturbances of this process may be either congenital or acquired. Congenital disorders of glycosylation (CDG) are a rapidly growing disease family, with about 50 disorders reported since its first clinical description in 1980. Most of the human diseases have been discovered recently. CDG result from defects in the synthesis of the N- and O-glycans moiety of glycoproteins, and in the attachment to the polypeptide chain of proteins. These defects have been found in the activation, presentation, and transport of sugar precursors, in the enzymes responsible for glycosylation, and in proteins that control the traffic of component. There are two main types of protein glycosylation: N-glycosylation and O-glycosylation. Most diseases are due to defects in the N-glycosylation pathway. For the sake of convenience, CDG were divided into 2 types, type I and II. CDG can affect nearly all organs and systems. The considerable variability of clinical features makes it difficult to recognize patients with CDG. Diagnosis can be made on the basis of abnormal glycosylation display. In this paper, an overview of CDG with a new nomenclature limited to the group of protein N-glycosylation disorders, clinical phenotype and diagnostic approach, have been presented. The location, reasons for defects, and the number of cases have been also described. This publication aims to draw attention to the possibility of occurrence of CDG in each multisystem disorder with an unknown origin. PMID- 23730681 TI - Detailed characterization of the substrate specificity of mouse wax synthase. AB - Wax synthases are membrane-associated enzymes catalysing the esterification reaction between fatty acyl-CoA and a long chain fatty alcohol. In living organisms, wax esters function as storage materials or provide protection against harmful environmental influences. In industry, they are used as ingredients for the production of lubricants, pharmaceuticals, and cosmetics. Currently the biological sources of wax esters are limited to jojoba oil. In order to establish a large-scale production of desired wax esters in transgenic high-yielding oilseed plants, enzymes involved in wax esters synthesis from different biological resources should be characterized in detail taking into consideration their substrate specificity. Therefore, this study aims at determining the substrate specificity of one of such enzymes -- the mouse wax synthase. The gene encoding this enzyme was expressed heterologously in Saccharomyces cerevisiae. In the in vitro assays (using microsomal fraction from transgenic yeast), we evaluated the preferences of mouse wax synthase towards a set of combinations of 11 acyl-CoAs with 17 fatty alcohols. The highest activity was observed for 14:0 CoA, 12:0-CoA, and 16:0-CoA in combination with medium chain alcohols (up to 5.2, 3.4, and 3.3 nmol wax esters/min/mg microsomal protein, respectively). Unsaturated alcohols longer than 18 degrees C were better utilized by the enzyme in comparison to the saturated ones. Combinations of all tested alcohols with 20:0-CoA, 22:1-CoA, or Ric-CoA were poorly utilized by the enzyme, and conjugated acyl-CoAs were not utilized at all. Apart from the wax synthase activity, mouse wax synthase also exhibited a very low acyl-CoA:diacylglycerol acyltransferase activity. However, it displayed neither acyl-CoA:monoacylglycerol acyltransferase, nor acyl-CoA:sterol acyltransferase activity. PMID- 23730682 TI - Cohesin Irr1/Scc3 is likely to influence transcription in Saccharomyces cerevisiae via interaction with Mediator complex. AB - The evolutionarily conserved proteins forming sister chromatid cohesion complex are also involved in the regulation of gene transcription. The participation of SA2p (mammalian ortholog of yeast Irr1p, associated with the core of the complex) in the regulation of transcription is already described. Here we analyzed microarray profiles of gene expression of a Saccharomyces cerevisiae irr1-1/IRR1 heterozygous diploid strain. We report that expression of 33 genes is affected by the presence of the mutated Irr1-1p and identify those genes. This supports the suggested role of Irr1p in the regulation of transcription. We also indicate that Irr1p may interact with elements of transcriptional coactivator Mediator. PMID- 23730683 TI - A novel tantalum-based sol-gel packed microextraction syringe for highly specific enrichment of phosphopeptides in MALDI-MS applications. AB - A new tantalum-based sol-gel material was synthesized using a unique sol-gel synthesis pathway by PEG incorporation into the sol-gel structure without performing a calcination step. This improved its chemical and physical properties for the high capacity and selective enrichment of phosphopeptides from protein digests in complex biological media. The specificity of the tantalum-based sol gel material for phosphopeptides was evaluated and compared with tantalum(V) oxide (Ta2O5) in different phosphopeptide enrichment applications. The tantalum based sol-gel and tantalum(V) oxide were characterized in detail using FT-IR spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy (SEM), and also using a surface area and pore size analyzer. In the characterization studies, the surface morphology, pore volume, crystallinity of the materials and PEG incorporation into the sol-gel structure to produce a more hydrophilic material were successfully demonstrated. The X-ray diffractograms of the two different materials were compared and it was noted that the broad signals of the tantalum-based sol-gel clearly represented the amorphous structure of the sol-gel material, which was more likely to create enough surface area and to provide more accessible tantalum atoms for phosphopeptides to be easily adsorbed when compared with the neat and more crystalline structure of Ta2O5. Therefore, the phosphopeptide enrichment performance of the tantalum-based sol-gels was found to be remarkably higher than the more crystalline Ta2O5 in our studies. Phosphopeptides at femtomole levels could be selectively enriched using the tantalum-based sol-gel and detected with a higher signal-to-noise ratio by matrix assisted laser desorption/ionization-mass spectrometer (MALDI-MS). Moreover, phosphopeptides in a tryptic digest of non-fat bovine milk as a complex real world biological sample were retained with higher yield using a tantalum-based sol-gel. Additionally, the sol-gel material was packed into a standard syringe (0.5 mL) to enhance the ease of use of the sol-gel material and for the elimination of additional mixing and separation procedures during the adsorption, washing and elution steps of the enrichment procedure. It was found that up to 28 phosphopeptides in milk digest were easily detectable by MALDI-MS at femtomole levels (around 20 fmol) using the microextraction syringe within less than one minute. PMID- 23730684 TI - Total viable bacterial count using a real time all-fibre spectroscopic system. AB - Rapid, accurate and sensitive enumeration of bacterial populations in the natural environment is an essential task for many research fields. Widely used standard methods for counting bacteria such as heterotrophic plate count require 1 to 8 days of incubation time for limited accuracy, while more accurate and rapid techniques are often expensive and may require bulky equipment. In the present study, we have developed a computerized optical prototype for bacterial detection. The goal of this research was to estimate the potential of this optical system for Total Viable Bacterial Count in water. For this purpose, we tested water batches with different microbiological content. Bacterial detection was based on fluorescence enhanced by nucleic acid staining. High sensitivity was achieved by a stable diode pumped solid state laser, sensitive CCD spectrometer and in situ excitation and signal collection. The results have shown that the bacterial count from different water origins using our optical setup along with multivariate analysis presents a higher accuracy and a shorter detection time compared to standard methods. For example, in a case where the fluorescence signal is calibrated to the water batch regression line, the relative standard deviation of the optical system enumeration varies between 21 and 36%, while that of the heterotropic plate count counterpart varies between 41 and 59%. In summary, we conclude that the all-fibre optical system may offer the following advantages over conventional methods: near real time examinations, portability, sensitivity, accuracy and ability to detect 10(2) to 10(8) CFU per ml bacterial concentrations. PMID- 23730685 TI - Non-invasive analysis of hormonal variations and effect of postmenopausal Vagifem treatment on women using in vivo high wavenumber confocal Raman spectroscopy. AB - This study aims to evaluate the feasibility of applying high wavenumber (HW) confocal Raman spectroscopy for non-invasive assessment of menopause-related hormonal changes in the cervix as well as for determining the effect of Vagifem((r)) treatment on postmenopausal women with atrophic cervix. A rapid HW confocal Raman spectroscopy system coupled with a ball lens fiber-optic Raman probe was utilized for in vivo cervical tissue Raman measurements at 785 nm excitation. A total of 164 in vivo HW Raman spectra (premenopausal (n = 104), postmenopausal-prevagifem (n = 34), postmenopausal-postvagifem (n = 26)) were measured from the normal cervix of 26 patients undergoing colposcopy. We established the biochemical basis of premenopausal, postmenopausal-prevagifem and postmenopausal-postvagifem cervix using semiquantitative biomolecular modeling derived from Raman-active biochemicals (i.e., lipids, proteins and water) that play a critical role in HW Raman spectral changes associated with the menopausal process. The diagnostic algorithms developed based on partial least squares discriminant analysis (PLS-DA) together with leave-one patient-out, cross validation yielded the diagnostic sensitivities of 88.5%, 91.2% and 88.5%, and specificities of 91.7%, 90.8% and 99.3%, respectively, for non-invasive in vivo discrimination among premenopausal, postmenopausal-prevagifem and postmenopausal postvagifem cervix. This work demonstrates for the first time that HW confocal Raman spectroscopy in conjunction with biomolecular modeling can be a powerful diagnostic tool for identifying hormone/menopause-related variations in the native squamous epithelium of normal cervix, as well as for assessing the effect of Vagifem treatment on postmenopausal atrophic cervix in vivo during clinical colposcopic inspections. PMID- 23730686 TI - Peroxynitrite activity of hemin-functionalized reduced graphene oxide. AB - Conducting interfaces modified with reduced graphene oxide (rGO) have shown improved electrochemical response for different analytes. The efficient formation of functionalized rGO based materials is thus of current interest for the development of sensitive and selective biosensors. Herein, we report a simple and environmentally friendly method for the formation of a hemin-functionalized rGO hybrid nanomaterial that exhibits remarkable sensitivity to peroxynitrite (ONOO( )) in solution. The hemin-functionalized rGO hybrid nanomaterial was formed by mixing an aqueous solution of graphene oxide (GO) with hemin and sonicating the suspension for 5 h at room temperature. In addition to playing a key role in biochemical and electrocatalytic reactions, hemin has been proven to be a good reducing agent for GO. The sensitivity of the peroxynitrite sensor is ~7.5 +/- 1.5 nA mM(-1) with a detection limit of 5 +/- 1.5 nM. PMID- 23730687 TI - Nanoparticle embedded enzymes for improved lateral flow sensors. AB - In this study, combining the nanoparticle embedded sensors with lateral flow assays, a novel strategy for ensuring the quality of signalling in lateral flow assays (LFAs) was developed. A LFA for reactive oxygen species (ROS) is reported that is based on horse radish peroxidase (HRP) which is co-entrapped with Texas Red dextran inside porous polyacrylamide nanoparticles. In this system, enzymes are protected in the porous matrix of polyacrylamide which freely allows the diffusion of the analyte. The sensor is rapid and sensitive for quantification of hydrogen peroxide concentrations. A test solution of hydrogen peroxides was quantified with this novel LFA-ROS sensor to obtain a linear range between 1 and 25 MUM. Nanoparticle embedding of enzymes is proposed here as a general strategy for developing enzyme-based lateral flow assays, eliminating adverse effects associated with biological samples. PMID- 23730688 TI - Nitrogen-doped zinc oxide thin films biosensor for determination of uric acid. AB - Nitrogen-doped zinc oxide thin films (ZnO:N) have been realized as a potential matrix for the development of a uric acid biosensor. The correlation between the change in property of the ZnO film with N doping concentration and its biosensing response has been studied. The nitrogen dopant in a ZnO film alters its defects profile, thus improving the charge transfer characteristics and resulting in an enhanced peak oxidation current in the cyclic voltammogram in comparison to that of the pure ZnO film. The studies reveal that the bio-electrode based on the nitrogen-doped ZnO thin film matrix exhibits better sensitivity (1.1 mA mM(-1) cm(-2)) with linearity over a wide range (0.05 mM to 1.0 mM) of uric acid concentration. A comparatively low value (0.10 mM) of the Michaelis-Menten constant (Km) indicates high affinity of the immobilized uricase towards uric acid. The proposed ZnO:N thin films matrix-based uric acid-biosensor has good reproducibility, a long shelf-life (20 weeks) and high selectivity. PMID- 23730690 TI - [3,3]Paracyclophanes as planar chiral scaffolds for the synthesis of new phosphoric acids. AB - Cyclic phosphoric acids displaying planar chiral paracyclophane structures, which include a 1,1'-ferrocenediyl unit, have been designed as a new class of chiral organocatalysts. Their synthesis, optical resolution, structural characterization and preliminary catalytic tests are reported. PMID- 23730689 TI - Copper-catalyzed sulfonamides formation from sodium sulfinates and amines. AB - A new and convenient method for the construction of sulfonamides via a copper catalyzed oxidative coupling between sodium sulfinates and amines with 1 atm O2 or DMSO as the oxidant was described. This method provides efficient and robust synthesis of functional sulfonamides in good yields and excellent chemoselectivity. And detailed mechanistic studies showed that this transformation may go through a single electron transfer (SET) pathway. PMID- 23730691 TI - Iterative method for mass spectra recalibration via empirical estimation of the mass calibration function for Fourier transform mass spectrometry-based petroleomics. AB - We describe a mass spectra recalibration method, which enables analysis of petroleum samples with Orbitrap FTMS. In this method, the mass calibration function is estimated on the basis of mass-to-charge ratios and abundances of internal calibrants without a need for theoretical description of residual mass errors. Importantly, to maximize the estimation accuracy of the mass calibration function, an iterative approach is implemented to obtain sufficiently high number of internal calibrants covering the entire ranges of mass-to-charge ratios and abundances of interest. For petroleomic samples, the method routinely provides root-mean-square (RMS) mass accuracies at sub-ppm level and hence allows for reliable assignment of elemental compositions. Moreover, since the achieved mass accuracies are normally limited only by random errors of low-abundance analytes, the method maximizes the range of abundances of assignable species for a given signal-to-noise ratio of experimental data. Additionally, despite being initially developed for Orbitrap FTMS, the method is likewise applicable for ion cyclotron resonance FTMS. PMID- 23730692 TI - siRNA-based nanomedicine. PMID- 23730693 TI - Major toxicities of carbon nanotubes induced by reactive oxygen species: should we worry about the effects on the lungs, liver and normal cells? PMID- 23730695 TI - Targeting specific receptors on dendritic cells. PMID- 23730697 TI - Aptamer-conjugated gold nanoparticles for bioanalysis. AB - Aptamers are single-stranded oligonucleotides synthesized through an in vitro selection and amplification process that involves systematic evolution of ligands by exponential enrichment. Based on their high binding affinity and specificity towards other molecules, aptamers generated during the final rounds of selection can be utilized in applications ranging from biosensing to diagnostics and therapeutics. Meanwhile, advances in nanotechnology have led to new and improved materials for biomedical applications. Specifically, nanoparticles can readily interact with both intra- and extra-cellular biomolecules to yield improved signal amplification and target recognition. By combining both technologies, aptamer-conjugated nanoparticles, especially gold nanoparticles (Apt-AuNPs), offer great promise for applications in bioanalysis and biomedicine, including early diagnosis and drug delivery. This review summarizes recent methodologies that have increased the application of Apt-AuNPs in biomedicine, and discusses the potential of Apt-AuNPs in bioanalysis. PMID- 23730696 TI - Nanoparticles and the blood coagulation system. Part II: safety concerns. AB - Nanoparticle interactions with the blood coagulation system can be beneficial or adverse depending on the intended use of a nanomaterial. Nanoparticles can be engineered to be procoagulant or to carry coagulation-initiating factors to treat certain disorders. Likewise, they can be designed to be anticoagulant or to carry anticoagulant drugs to intervene in other pathological conditions in which coagulation is a concern. An overview of the coagulation system was given and a discussion of a desirable interface between this system and engineered nanomaterials was assessed in part I, which was published in the May 2013 issue of Nanomedicine. Unwanted pro- and anti-coagulant properties of nanoparticles represent significant concerns in the field of nanomedicine, and often hamper the development and transition into the clinic of many promising engineered nanocarriers. This part will focus on the undesirable effects of engineered nanomaterials on the blood coagulation system. We will discuss the relationship between the physicochemical properties of nanoparticles (e.g., size, charge and hydrophobicity) that determine their negative effects on the blood coagulation system in order to understand how manipulation of these properties can help to overcome unwanted side effects. PMID- 23730698 TI - Advances in the understanding of nanomaterial-biomembrane interactions and their mathematical and numerical modeling. AB - The widespread application of nanomaterials (NMs), which has accompanied advances in nanotechnology, has increased their chances of entering an organism, for example, via the respiratory system, skin absorption or intravenous injection. Although accumulating experimental evidence has indicated the important role of NM-biomembrane interaction in these processes, the underlying mechanisms remain unclear. Computational techniques, as an alternative to experimental efforts, are effective tools to simulate complicated biological behaviors. Computer simulations can investigate NM-biomembrane interactions at the nanoscale, providing fundamental insights into dynamic processes that are challenging to experimental observation. This paper reviews the current understanding of NM biomembrane interactions, and existing mathematical and numerical modeling methods. We highlight the advantages and limitations of each method, and also discuss the future perspectives in this field. Better understanding of NM biomembrane interactions can benefit various fields, including nanomedicine and diagnosis. PMID- 23730699 TI - Nanobodies and their potential applications. AB - Nanobodies are recombinant, antigen-specific, single-domain, variable fragments of camelid heavy chain-only antibodies. The innate supremacy of nanobodies as a renewable source of affinity reagents, together with their high production yield in a broad variety of expression systems, minimal size, great stability, reversible refolding and outstanding solubility in aqueous solutions, and ability to specifically recognize unique epitopes with subnanomolar affinity, have combined to make them a useful class of biomolecules for research and various medical diagnostic and therapeutic applications. This article speculates on a number of technological innovations that might be introduced in the nanobody identification platform to streamline the generation of more potent nanobodies and to expand their application range. PMID- 23730702 TI - Broadband light absorption with multiple surface plasmon polariton waves excited at the interface of a metallic grating and photonic crystal. AB - Light incident upon a periodically corrugated metal/dielectric interface can generate surface plasmon polariton (SPP) waves. This effect is used in many sensing applications. Similar metallodielectric nanostructures are used for light trapping in solar cells, but the gains are modest because SPP waves can be excited only at specific angles and with one linear polarization state of incident light. Here we report the optical absorptance of a metallic grating coupled to silicon oxide/oxynitride layers with a periodically varying refractive index, i.e., a 1D photonic crystal. These structures show a dramatic enhancement relative to those employing a homogeneous dielectric material. Multiple SPP waves can be activated, and both s- and p-polarized incident light can be efficiently trapped. Many SPP modes are weakly bound and display field enhancements that extend throughout the dielectric layers. These modes have significantly longer propagation lengths than the single SPP modes excited at the interface of a metallic grating and a uniform dielectric. These results suggest that metallic gratings coupled to photonic crystals could have utility for light trapping in photovoltaics, sensing, and other applications. PMID- 23730706 TI - Acute presentation of autoimmune hepatitis: How to find and manage still remains unsolved. PMID- 23730707 TI - Oxaliplatin-related sinusoidal obstruction syndrome mimicking metastatic liver tumors. AB - A 40-year-old woman who had undergone a curative low anterior resection for advanced rectal cancer was admitted to our hospital. She had been administrated oxaliplatin-based chemotherapy as postoperative adjuvant chemotherapy. The contrast-enhanced computed tomography revealed three hypovascular tumors, 3.0, 1.5 and 1.0 cm in diameter, located in the right hepatic lobe. The hepatocyte phase of the gadoxetic acid-enhanced magnetic resonance imaging demonstrated these lesions as hypointense tumors relative to the surrounding hepatic parenchyma. All these findings of the preoperative imaging modalities were compatible to metastatic liver tumors from the rectal cancer, and right hepatic lobectomy was successfully performed. Histopathologically, the tumors revealed sinusoidal dilation and severe congestion outlined by atrophic hepatocyte trabeculae, which was known as peliosis hepatis. The perisinusoidal space of Disse was extensively dilated and contained many erythrocytes. Taking these findings into account, the hepatic tumors were considered to be the space occupying lesions resulting from the sinusoidal obstruction syndrome. We herein report the first case of focal sinusoidal obstruction syndrome mimicking metastatic liver tumors. PMID- 23730703 TI - Risk patterns preceding diagnosis among newly HIV-diagnosed men who have sex with men in New York City. AB - Men who have sex with men (MSM) are at high risk for contracting and transmitting HIV. They are increasingly encouraged to get tested, but understanding of the interplay between HIV testing and risk behavior is limited. One hundred fifty newly HIV-diagnosed (within past 3 months) MSM were recruited from a community clinic in New York City. Participants completed an interview assessing sexual behavior and substance use during the 3 months pre-diagnosis, current depressive symptoms, and prior HIV testing. HIV-related health characteristics at diagnosis were abstracted from medical records. Analyses examined factors associated with unprotected anal intercourse (UAI) in the 3 months pre-diagnosis, and with a negative HIV test in the 12 months pre-diagnosis. The sample was young (mean age=32.5, SD=8.8), ethnically diverse (62% racial/ethnic minority), low-income (71%<=$30,000/year), and educated (48% college/advanced degree). Most (95%) had a prior negative HIV test, 55% within the last 12 months. Significant risk behavior was reported, with 79% reporting UAI. UAI was associated with recent testing and use of substances during sexual behavior. Recent testing was associated with being employed/a student, having had UAI, and higher CD4 count. Implications for future research addressing perceived HIV risk, HIV testing utilization, and risk behavior are discussed. PMID- 23730708 TI - Naphthoxanthenyl, a new stable phenalenyl type radical stabilized by electronic effects. AB - Naphthoxanthenyl 1 is a new stable phenalenyl-type radical. Electrochemical studies indicate that 1 has two reversible redox processes that occur on comparatively short time scales. Crystals containing 1 can be grown by electrocrystallization, suggesting that they are conductive. PMID- 23730709 TI - Spatio-temporal changes in the structure of archaeal communities in two deep freshwater lakes. AB - In this study, we evaluated the driving forces exerted by a large set of environmental and biological parameters on the spatial and temporal dynamics of archaeal community structure in two neighbouring peri-alpine lakes that differ in terms of trophic status. We analysed monthly data from a 2-year sampling period at two depths corresponding to the epi- and hypolimnetic layers. The archaeal communities seemed to be mainly composed of ammonia-oxidizing archaea belonging to the thaumarchaeotal phylum. The spatio-temporal dynamics of these communities were very similar in the two lakes and were characterized by (1) disparities in archaeal community structure in both time and space and (2) no seasonal reproducibility between years. The archaeal communities were regulated by a complex combination of abiotic factors, including temperature, nutrients, chlorophyll a and dissolved oxygen, and biotic factors such as heterotrophic nanoflagellates and ciliates. However, in most cases, these factors explained < 52% of the variance in archaeal community structure, while we showed in a previous study that these factors explained 70-90% of the temporal variance for bacteria. This suggests that Bacteria and Archaea may be influenced by different factors and could occupy different ecological niches despite similar spatio temporal dynamics. PMID- 23730710 TI - Acquired reactive perforating collagenosis associated with urticarial vasculitis in pregnancy. PMID- 23730711 TI - Chiral induction in the ionothermal synthesis of a 3D chiral heterometallic metal organic framework constructed from achiral 1,4-naphthalenedicarboxylate. AB - A chiral heteometallic compound, [(EMIM)NaCu(1,4-ndc)2]n (1), constructed from the achiral 1,4-naphthalenedicarboxylate (1,4-ndc) ligand has been ionothermally synthesized and structurally and magnetically characterized. The chiral induction effect of the enantiopure 1-ethyl-3-methylimidazolium (EMIM) L-lactate additive in the ionothermal reaction is briefly discussed. PMID- 23730712 TI - Structural insights into the inhibition of type VI effector Tae3 by its immunity protein Tai3. AB - The recently described T6SS (type VI secretion system) acts as a needle that punctures the membrane of the target cells to deliver effector proteins. Type VI amidase effectors can be classified into four divergent families (Tae1-Tae4). These effectors are secreted into the periplasmic space of neighbouring cells via the T6SS and subsequently rupture peptidoglycan. However, the donor cells are protected from damage because of the presence of their cognate immunity proteins [Tai1 (type VI amidase immunity 1)-Tai4]. In the present paper, we describe the structure of Tae3 in complex with Tai3. The Tae3-Tai3 complex exists as a stable heterohexamer, which is composed of two Tae3 molecules and two Tai3 homodimers (Tae3-Tai34-Tae3). Tae3 shares a common NlpC/P60 fold, which consists of N terminal and C-terminal subdomains. Structural analysis indicates that two unique loops around the catalytic cleft adopt a closed conformation, resulting in a narrow and extended groove involved in the binding of the substrate. The inhibition of Tae3 is attributed to the insertion of the Omega-loop (loop of alpha3-alpha4) of Tai3 into the catalytic groove. Furthermore, a cell viability assay confirmed that a conserved motif (Gln-Asp-Xaa) in Tai3 members may play a key role in the inhibition process. Taken together, the present study has revealed a novel inhibition mechanism and provides insights into the role played by T6SS in interspecific competition. PMID- 23730713 TI - After breast cancer: sexual functioning of sexual minority survivors. AB - Research on sexual difficulties after cancer has neglected sexual minority women (SMW); for example, lesbian and bisexual women. Clinicians treating these women are therefore at a disadvantage as they lack information about sexual problems in this population. This study tested the hypothesis that SMW with breast cancer have poorer sexual function than SMW without breast cancer, distinguishing partnered from unpartnered women. Using convenience sample recruitment, we conducted a case-control study to compare survivors of breast cancers who are SMW, in other words, cases to controls, that is, SMW without cancer. Anonymous survey data were collected from 85 cases after they had completed active cancer treatment and 85 age- and partner-status matched controls with no history of any cancer. Participants' self-reported sexual frequency and sexual function measured by the Female Sexual Function Index were evaluated. Cases and controls did not differ in risk of sexual dysfunction or the level of overall sexual functioning; however, cases had lower sexual frequency and scored lower on desire and ability to reach orgasm, and higher on pain compared to controls. Results inform clinicians about sexual minority survivors' sexual domains affected by cancer. When discussing sexual problems and therapeutic options, sexual orientation should be ascertained. PMID- 23730714 TI - Correlation between local structural dynamics of proteins inferred from NMR ensembles and evolutionary dynamics of homologues of known structure. AB - Conformational changes in proteins are extremely important for their biochemical functions. Correlation between inherent conformational variations in a protein and conformational differences in its homologues of known structure is still unclear. In this study, we have used a structural alphabet called Protein Blocks (PBs). PBs are used to perform abstraction of protein 3-D structures into a 1-D strings of 16 alphabets (a-p) based on dihedral angles of overlapping pentapeptides. We have analyzed the variations in local conformations in terms of PBs represented in the ensembles of 801 protein structures determined using NMR spectroscopy. In the analysis of concatenated data over all the residues in all the NMR ensembles, we observe that the overall nature of inherent local structural variations in NMR ensembles is similar to the nature of local structural differences in homologous proteins with a high correlation coefficient of .94. High correlation at the alignment positions corresponding to helical and beta-sheet regions is only expected. However, the correlation coefficient by considering only the loop regions is also quite high (.91). Surprisingly, segregated position-wise analysis shows that this high correlation does not hold true to loop regions at the structurally equivalent positions in NMR ensembles and their homologues of known structure. This suggests that the general nature of local structural changes is unique; however most of the local structural variations in loop regions of NMR ensembles do not correlate to their local structural differences at structurally equivalent positions in homologues. PMID- 23730715 TI - Spatial and temporal genetic structure of Symbiodinium populations within a common reef-building coral on the Great Barrier Reef. AB - The dinoflagellate photosymbiont Symbiodinium plays a fundamental role in defining the physiological tolerances of coral holobionts, but little is known about the dynamics of these endosymbiotic populations on coral reefs. Sparse data indicate that Symbiodinium populations show limited spatial connectivity; however, no studies have investigated temporal dynamics for in hospite Symbiodinium populations following significant mortality and recruitment events in coral populations. We investigated the combined influences of spatial isolation and disturbance on the population dynamics of the generalist Symbiodinium type C2 (ITS1 rDNA) hosted by the scleractinian coral Acropora millepora in the central Great Barrier Reef. Using eight microsatellite markers, we genotyped Symbiodinium in a total of 401 coral colonies, which were sampled from seven sites across a 12-year period including during flood plume-induced coral bleaching. Genetic differentiation of Symbiodinium was greatest within sites, explaining 70-86% of the total genetic variation. An additional 9-27% of variation was explained by significant differentiation of populations among sites separated by 0.4-13 km, which is consistent with low levels of dispersal via water movement and historical disturbance regimes. Sampling year accounted for 6 7% of total genetic variation and was related to significant coral mortality following severe bleaching in 1998 and a cyclone in 2006. Only 3% of the total genetic variation was related to coral bleaching status, reflecting generally small (8%) reductions in allelic diversity within bleached corals. This reduction probably reflected a loss of genotypes in hospite during bleaching, although no site-wide changes in genetic diversity were observed. Combined, our results indicate the importance of disturbance regimes acting together with limited oceanographic transport to determine the genetic composition of Symbiodinium types within reefs. PMID- 23730716 TI - Early adversity and health outcomes in young adulthood: the role of ongoing stress. AB - OBJECTIVE: The current study examined the prospective effects of exposure to stressful conditions in early childhood on physical health in young adulthood, and explored continuing exposure to stressors, as well as depression, in adolescence as possible mechanisms of this relationship. METHOD: A prospective longitudinal design was used to examine 705 mother-child pairs from a community based sample, followed from offspring birth through age 20 years. Mothers provided contemporaneous assessments of early adverse conditions from offspring birth through age 5. Offspring responses to the UCLA Life Stress Interview, Structured Clinical Interview for DSM Disorders, Physical Functioning subscale of the SF-36 Health Survey, and questions about the presence of chronic disease were used to assess youth stress at age 15, depression from ages 15-20, and physical health at age 20. RESULTS: Early adversity conferred risk for elevated levels of social and nonsocial stress at youth age 15, as well as depression between ages 15 and 20. Social and nonsocial stress, in turn, had effects on physical health at age 20, directly and indirectly via depression. CONCLUSION: Findings suggest that early adverse conditions have lasting implications for physical health, and that continued exposure to increased levels of both social and nonsocial stress in adolescence, as well as the presence of depression, might be important mechanisms by which early adversity impacts later physical health. PMID- 23730717 TI - Does theory influence the effectiveness of health behavior interventions? Meta analysis. AB - OBJECTIVE: To systematically investigate the extent and type of theory use in physical activity and dietary interventions, as well as associations between extent and type of theory use with intervention effectiveness. METHODS: An in depth analysis of studies included in two systematic reviews of physical activity and healthy eating interventions (k = 190). Extent and type of theory use was assessed using the Theory Coding Scheme (TCS) and intervention effectiveness was calculated using Hedges's g. Metaregressions assessed the relationships between these measures. RESULTS: Fifty-six percent of interventions reported a theory base. Of these, 90% did not report links between all of their behavior change techniques (BCTs) with specific theoretical constructs and 91% did not report links between all the specified constructs with BCTs. The associations between a composite score or specific items on the TCS and intervention effectiveness were inconsistent. Interventions based on Social Cognitive Theory or the Transtheoretical Model were similarly effective and no more effective than interventions not reporting a theory base. CONCLUSIONS: The coding of theory in these studies suggested that theory was not often used extensively in the development of interventions. Moreover, the relationships between type of theory used and the extent of theory use with effectiveness were generally weak. The findings suggest that attempts to apply the two theories commonly used in this review more extensively are unlikely to increase intervention effectiveness. PMID- 23730718 TI - Autonomy support, self-regulation, and weight loss. AB - OBJECTIVE: Social support is believed to contribute to weight loss success, yet the type of support received is rarely assessed. To develop more effective weight loss interventions, examinations of the types of support that are associated with positive outcomes are needed. Self-Determination Theory suggests that support for an individual's autonomy is beneficial and facilitates internalization of autonomous self-regulation. We examined whether autonomy support and directive forms of support were associated with weight loss outcomes in a larger randomized controlled trial. METHOD: Adults (N = 201; 48.9 +/- 10.5 years; 78.1% women) participating in a weight loss trial were assessed at 0, 6, and 18 months. Autonomy support (AS), directive support, and autonomous self-regulation (ASR) were measured at 0 and 6 months and examined in relation to 18-month weight loss outcomes. RESULTS: Baseline AS and ASR did not predict outcomes; however, AS and ASR at 6 months positively predicted 18-month weight losses (ps < .05), encouragement of healthy eating at 6 months was negatively related to 18-month weight losses (p < .01), and other forms of directive support were not associated with outcomes. CONCLUSIONS: Autonomy support predicted better weight loss outcomes while some forms of directive support hindered progress. Weight loss trials are needed to determine whether family members and friends can be trained to provide autonomy support and whether this is more effective than programs targeting more general or directive forms of support. PMID- 23730719 TI - Intervention to improve follow-up for abnormal Papanicolaou tests: a randomized clinical trial. AB - OBJECTIVE: To evaluate the effect of a theory-based, culturally targeted intervention on adherence to follow-up among low-income and minority women who experience an abnormal Pap test. METHOD: 5,049 women were enrolled and underwent Pap testing. Of these, 378 had an abnormal result and 341 (90%) were randomized to one of three groups to receive their results: Intervention (I): culturally targeted behavioral and normative beliefs + knowledge/skills + salience + environmental constraints/barriers counseling; Active Control (AC): nontargeted behavioral and normative beliefs + knowledge/skills + salience + environmental constraints/barriers counseling; or Standard Care Only (SCO). The primary outcome was attendance at the initial follow-up appointment. Secondary outcomes included delay in care, completion of care at 18 months, state anxiety (STAI Y-6), depressive symptoms (CES-D), and distress (CDDQ). Anxiety was assessed at enrollment, notification of results, and 7-14 days later with the CDDQ and CES-D. RESULTS: 299 women were included in intent-to-treat analyses. Adherence rates were 60% (I), 54% (AC), and 58% (SCO), p = .73. Completion rates were 39% (I) and 35% in the AC and SCO groups, p = .77. Delay in care (in days) was (M +/- SD): 58 +/- 75 (I), 69 +/- 72 (AC), and 54 +/- 75 (SCO), p = .75. Adherence was associated with higher anxiety at notification, p < .01 and delay < 90 days (vs. 90+) was associated with greater perceived personal responsibility, p < .05. Women not completing their care (vs. those who did) had higher CES-D scores at enrollment, p < .05. CONCLUSIONS: A theory-based, culturally targeted message was not more effective than a nontargeted message or standard care in improving behavior. PMID- 23730720 TI - Systemic racism moderates effects of provider racial biases on adherence to hypertension treatment for African Americans. AB - OBJECTIVE: The purpose of the current study was to examine perceived exposure to systemic racism as a moderator of the effects of perceived exposure to provider racial biases on treatment adherence and mistrust of health care for a sample of African American hypertensive patients. We hypothesized that patients who endorsed high levels of systemic racism would exhibit poor adherence to hypertension treatment and increased mistrust in health care in relation to perceptions of exposure to provider racial biases. METHOD: The sample consisted of 100 African American patients who ranged in age from 24 to 82 years. All were diagnosed with hypertension and were recruited from an outpatient clinic located in the Southeastern region of the United States. Moderated regression analyses were performed to test the study hypotheses. RESULTS: Findings revealed a positive, significant main effect for perceived provider racial biases in predicting mistrust of care. This finding suggested that an increase in mistrust of health care was associated with increased perceptions of provider biases. In predicting treatment adherence, a significant interaction revealed that patients who endorsed low and moderate degrees of exposure to systemic racism displayed poor adherence to treatment in relation to greater perceptions of provider racial biases. CONCLUSIONS: The overall findings suggest that patients who perceive themselves as infrequently exposed to systemic racism possess the greatest risk for nonadherence to hypertension treatment in relation to increased perceptions of provider racial biases. Implications of the findings are discussed. PMID- 23730721 TI - Objective and subjective socioeconomic gradients exist for sleep in children and adolescents. AB - OBJECTIVE: Socioeconomic position (SEP) is inversely associated with many health outcomes, yielding a socioeconomic gradient in health. In adults, low SEP is associated with short sleep duration, poorer sleep quality, and difficulty initiating and maintaining sleep. Relatively little is known about this relation in youth. The aim of the present study was to examine whether socioeconomic gradients exist for various sleep indices among a healthy sample of children and adolescents. METHOD: Participants took part in the larger Healthy Heart Project and included 239 youth (69.6% Caucasian; 45.6% female), aged 8-17 years (M = 12.6, SD = 1.9). Parental income and education were used to measure objective SEP. The Subjective Social Status Scale-Youth Version was used to measure subjective SEP. Sleep duration, sleep quality, daytime sleepiness, and sleep disturbances were assessed through self- and parent-report. RESULTS: In children, objective SEP was related with sleep duration (beta = .35, p < .01), although subjective SEP was related with daytime sleepiness (betaavg = .33, p < .01) and parent-reported sleep duration (beta = .23, p < .05). In adolescents, subjective SEP was related with sleep quality (beta = .28, p < .01) and parent-reported sleep duration (beta = -.18, p < .05), even after controlling for objective SEP. CONCLUSIONS: Socioeconomic gradients were observed for multiple sleep measures in youth. Objective parental SEP was related with sleep complaints (e.g., sleep disturbances), and subjective SEP was related with sleep quality and daytime sleepiness. Findings suggest sleep may be one pathway underlying the socioeconomic gradient in health. Future research should aim to elucidate how distinct sleep constructs may explain how socioeconomic status "gets under the skin" to affect health. PMID- 23730722 TI - Depressive symptoms in Latina breast cancer survivors: a barrier to cancer screening. AB - OBJECTIVE: Depressed mood limits vigilance, risk avoidance or risk reduction. This may reflect inability to follow health care provider recommendations for screening for other cancers. We determined prevalence of depressive symptoms and its role in screening for other cancers in Latina breast cancer survivors. METHOD: A convenience sample of 117 Latina breast cancer survivors completed a questionnaire including the Center for Epidemiologic Studies Depression scale (CES-D) and substantive barriers to following health care provider recommendations. A threshold score of 16 or greater on the CESD was considered elevated symptoms in the past week. Chi-square and T tests were used to evaluate bivariate associations and multiple logistic regression to identify barriers to compliance with recommendations regarding ovarian and colorectal screening. RESULTS: The results showed 31.6% had CESD scores above the threshold, about three times the general population. Cancer screening rates were very low with only five women (4.2%) screened for both ovarian and colorectal cancer. Elevated symptoms were present in 38% of those without colorectal cancer screening and 42% of those without ovarian cancer screening. It is inversely related to screening for colorectal (aOR = 0.44, p = .04), ovarian (aOR = 0.44, p = .09), or either screening (aOR = 0.38, p = .035). CONCLUSIONS: Depressive symptom rates are higher among breast cancer survivors than the general population; rates of screening for other cancers are low. This indicates general failure to comply with recommendations for screening for other cancers among breast cancer survivors. Depressive symptoms may be a barrier to screening. Affective components of survivorship must be addressed in order to make interventions more effective. PMID- 23730723 TI - A randomized trial to promote physical activity among breast cancer patients. AB - OBJECTIVE: Physical activity (PA) has been shown to provide health benefits for breast cancer patients. The effects of augmenting oncology health care provider (HCP) advice for PA with 3 months of telephone counseling versus contact control were evaluated in a randomized trial. METHODS: After receiving brief HCP advice to become physically active, 192 women (age in years: M = 60.0, SD = 9.9) who had completed treatment for Stage 0-IV breast cancer were randomized to telephone counseling to support PA (n = 106) or contact control (n = 86). Their PA, motivational readiness, fatigue, and physical functioning were assessed at baseline (before receiving HCP advice), 3, 6, and 12 months. RESULTS: Telephone counseling produced significant effects on the primary outcome of moderate intensity PA of about 30 min/week at both 3 months (95% CI = 0.44, 57.32) and 6 months (95% CI = 3.06, 61.26). Intervention participants were also more than twice as likely as control participants to report improvements in achieving PA guidelines of at least 150 min/week at 3 (OR = 2.43, 95% CI = 1.18, 4.98) and 6 months (OR = 2.11, 95% CI = 1.00-4.48). Telephone counseling was significantly more effective than contact control in increasing motivational readiness for PA at all follow-ups (ORs = 3.93-6.28, all ps <.003). No between-groups differences were found for fatigue, while differential improvements in physical functioning did not remain significant past 3 months (p = .01). CONCLUSION: HCP advice plus telephone counseling improved PA among breast cancer patients at 3 and 6 months and also differentially improved patients' motivational readiness at all follow ups, suggesting the potential for exercise promotion in cancer follow-up care. PMID- 23730724 TI - Biocompatibility, absorption and safety of protein nanoparticle-based delivery of doxorubicin through oral administration in rats. AB - Doxorubicin, a potent anticancer drug associated with cardiotoxicity and low oral bioavailability, was loaded into apotransferrin nanoparticles to improve its pharmacological performance. Here, doxorubicin (doxo)-loaded apotransferrin nanoparticles were termed as Apodoxonano, and they were prepared by sol-oil chemistry. The pH-dependent stability of nanoparticles in simulated fluids was evaluated, and the in vitro release was investigated in phosphate-buffered saline. The pharmacokinetic and toxicity studies were conducted in Wistar rats. Nanoparticles have an average size of 75 nm, with 63% entrapment efficiency, at 10 mg w/w of apotransferrin. The particles displayed good pH-dependent stability in the pH range 1.1-7.4, but sensitive at endosomal pH of 5.5, thus facilitating intracellular drug release in endosomes. Multiplex assay showed high transport ability of nano form across epithelial cells (caco-2) when compared to doxo. Moreover, during oral administration, Apodoxonano localizes significantly in esophagus, stomach and small intestine, suggesting that it was absorbed in GI tract through epithelial lining. The drug localization was shown to be significantly lower in the heart reflecting its decreased cardiotoxic nature. The Apodoxonano with a longer bioavailability and a negligible cardiotoxicity can serve as an effective and safe vehicle of drug delivery. PMID- 23730725 TI - Using the Haemophilia Joint Health Score for assessment of teenagers and young adults: exploring reliability and validity. AB - Outcome assessment in haemophilia is important to assess results of prophylactic treatment. Recently, the Haemophilia Joint Health Score (HJHS) was developed to assess early joint damage in children with haemophilia. Thus, the aim of this study was to assess reliability and explore validity of the HJHS in teenagers and young adults with haemophilia. Twenty-two patients with haemophilia (mean age 20.4, range 14-30, including 15 severe) were assessed by the HJHS1.0, Haemophilia Activities List (HAL), SF36 and self-evaluation was performed using a Visual Analogue Scale (VAS) scale. A subset of 12 patients were assessed by three physiotherapists to establish interobserver reliability (intraclass correlation coefficient: ICC). Total HJHS1.0 scores were calculated without overall global gait. Validity was explored by the assessment of Pearson's correlation with all outcome parameters and recent Pettersson scores. Overall outcome was good, with median HJHS score of 5.5 of a maximum 144 (range 0-34), median patients' VAS of 96.5 and maximum scores for HAL and SF36 physical functioning for the majority of patients. Pettersson scores were low (median 3.5 of 78, N = 18). Interobserver reliability was good (ICC 0.84), with limits of agreement of +/-7.2 points. ICC was unaffected by different score calculation methods. Exploration of validity in 22 patients showed weak correlations of HJHS scores with patients' VAS (0.33) and HAL (-0.40) and strong correlations with SF36-PF (-0.66) and Pettersson scores (0.86). These results suggest that interobserver reliability of the HJHS1.0 in teenagers and young adults with limited joint damage is excellent. Preliminary data on validity were similar or better than those in children. PMID- 23730726 TI - 'It depends on how the relationship was before you became ill': black South African women's experiences of life partner support through the trajectory of cervical cancer. AB - Spouses are the primary source of support for married patients and patients suffering from gynaecological cancers and play a major role in the positive, or negative, management of the disease and treatment. The purpose of the study was to explore the experiences of life partner support among hospitalised women receiving treatment for cervical cancer at an academic hospital in Tshwane, South Africa. An exploratory, qualitative study was conducted using a convenience sampling method. Seventeen (n = 17) women were interviewed. The data were analysed using open coding and a template analysis style. The support women treated for cervical cancer received from their life partner varied. Some were fully supported while others received limited support and some were even abandoned. Both the women and their life partners were challenged in terms of giving and receiving support. How the support they received from their life partners influenced their quality of life is not known and should be the next exploratory step before designing and testing a support intervention to maximise the outcomes for these patients. PMID- 23730728 TI - Naphthoxazole-based singlet oxygen fluorescent probes. AB - In this study, we report the synthesis and photochemical behavior of a new family of photoactive compounds to assess its potential as singlet oxygen ((1)O2) probes. The candidate dyads are composed by a (1)O2 trap plus a naphthoxazole moiety linked directly or through an unsaturated bond to the oxazole ring. In the native state, the inherent great fluorescence of the naphthoxazole moiety is quenched; but in the presence of (1)O2, generated by the addition and appropriate irradiation of an external photosensitizer, a photooxidation reaction occurs leading to the formation of a new chemical entity whose fluorescence is two orders of magnitude higher than that of the initial compound, at the optimal selected wavelength. The presented dyads outperform the commonly used indirect fluorescent (1)O2 probes in terms of fluorescence enhancement maintaining the required specificity for (1)O2 detection in solution. PMID- 23730727 TI - Clinical and epidemiological characterization of a lymphogranuloma venereum outbreak in Madrid, Spain: co-circulation of two variants. AB - The lymphogranuloma venereum (LGV) outbreak described in the Netherlands in 2003, increased the interest in the genotyping of Chlamydia trachomatis. Although international surveillance programmes were implemented, these studies slowly decreased in the following years. Now data have revealed a new accumulation of LGV cases in those European countries with extended surveillance programmes. Between March 2009 and November 2011, a study was carried out to detect LGV cases in Madrid. The study was based on screening of C. trachomatis using commercial kits, followed by real-time pmpH-PCR discriminating LGV strains, and finally ompA gene was sequenced for phylogenetic reconstruction. Ninety-four LGV infections were identified. The number of cases increased from 10 to 30 and then to 54 during 2009-2011. Incidence of LGV was strongly associated with men who have sex with men; but in 2011, LGV cases were described in women and heterosexual men. Sixty-nine patients were also human immunodeficiency virus (HIV) positive, with detectable viral loads at the moment of LGV diagnosis, suggesting a high-risk of co-transmission. In fact, in four patients the diagnosis of HIV was simultaneous with LGV infection. The conventional treatment with doxycycline was prescribed in 75 patients, although in three patients the treatment failed. The sequencing of the ompA gene permitted identification of two independent transmission nodes. One constituted by 25 sequences identical to the L2b variant, and a second node including 37 sequences identical to L2. This epidemiological situation characterized by the co-circulation of two LGV variants has not been previously described, reinforcing the need for screening and genotyping of LGV strains. PMID- 23730729 TI - TaEIL1, a wheat homologue of AtEIN3, acts as a negative regulator in the wheat stripe rust fungus interaction. AB - Transcription factors (TFs) play crucial roles in the transcriptional regulation of plant development and defence responses. Increasing evidence has implicated ETHYLENE INSENSITIVE3 (EIN3) in the plant defence response to pathogen infection and environmental stimuli. However, the role of EIN3 in wheat resistance to Puccinia striiformis f. sp. tritici (Pst) is not clear. Here, TaEIL1 was isolated by rapid amplification of cDNA ends (RACE) based on a sequence fragment from a wheat-Pst interaction cDNA library. The TaEIL1 protein contains a typical EIN3 binding domain, and transient expression analyses indicated that TaEIL1 is localized in the nucleus. Yeast one-hybrid assay revealed that TaEIL1 exhibits transcriptional activity, and its C-terminus is necessary for the activation of transcription. TaEIL1 transcripts were regulated by environmental stress stimuli and were decreased under salicylic acid (SA) treatment. When wheat leaves were challenged with Pst, the transcript level of TaEIL1 in the compatible interaction was approximately three times higher than that in the incompatible interaction. Knocking down TaEIL1 through the Barley stripe mosaic virus (BSMV) virus-induced gene silencing (VIGS) system attenuated the growth of Pst, with shortened hyphae and reduced hyphal branches, haustorial mother cells and colony size. Moreover, enhanced necrosis was triggered by the Pst avirulent race CYR23, indicating that the hypersensitive response was strengthened in TaEIL1-silenced wheat plants. Thus, the up-regulation of defence-related genes and increased sucrose abundance might contribute to the enhanced disease resistance of wheat to the virulent race CYR31. Taken together, the results suggested that the suppression of TaEIL1 transcripts could enhance the resistance of wheat to stripe rust fungus. PMID- 23730730 TI - Alefacept combined with tacrolimus, mycophenolate mofetil and steroids in de novo kidney transplantation: a randomized controlled trial. AB - Memory T cells play a central role in mediating allograft rejection and are a rational target for immunosuppressive therapy. Alefacept is a recombinant LFA3/IgG1 fusion protein that reduces the number of memory T cells in both psoriatic lesions and the peripheral circulation of psoriasis patients. This study evaluated the efficacy and safety of alefacept compared with placebo when combined with tacrolimus, mycophenolate mofetil and corticosteroids in de novo renal transplant recipients. Between December 2007 and March 2009 patients were randomized in a double-blind fashion to receive alefacept (n = 105) or placebo (n = 107) for 3 months and were then followed for a further 3 months. The primary efficacy endpoint was the incidence of biopsy-confirmed acute T cell mediated rejection (Banff grade >= 1) through Month 6. Memory T cell counts were significantly reduced in the alefacept group from Week 3 to study end compared with placebo. However, there was no significant difference between the alefacept and placebo groups for the primary efficacy endpoint (alefacept, 11.0% vs. placebo, 7.0%, p = 0.3). Patient and graft survival as well as renal function was similar between treatment groups. Safety and tolerability were generally similar between the treatment arms. Malignancy was higher in the alefacept treatment arm. PMID- 23730731 TI - Electrohysterography of labor contractions: propagation velocity and direction. AB - OBJECTIVE: Electrohysterographic assessment of the propagation velocity of uterine depolarization has been introduced as a promising predictor of preterm labor. Therefore, the objectives of this study were to characterize the uterine electrohysterographic signals during labor and to determine the propagation velocity and propagation direction of electrohysterographic signals. DESIGN: Descriptive study. SETTING: Department of Obstetrics and Gynecology, Aarhus University Hospital, Denmark. POPULATION: Eight women in active labor at term. METHODS: Electrohysterograms (three channels) were recorded using surface electrodes placed abdominally along the vertical median axis with an inter electrode distance of 6.5-11.2 cm. In total, 89 contractions were analyzed. RESULTS: Electrohysterographic characteristics: The duration of the contractions was 61.0 +/- 18.0 s (mean +/- SD). The median frequency of the power spectrum density was 0.51 (0.44; 0.51) Hz (median; 10th; 90th percentile). The greatest signal magnitude was obtained by the electrode in the centermost position. The propagation velocity: 2.15 (0.66; 13.8) cm/s in the upper part and 1.53 (0.58; 6.7) cm/s in the lower part of the uterus. Propagation direction: Both downward (58%) and upward (42%) propagation of the electrohysterographic signals occurred. Moreover, downward and upward propagations were recorded simultaneously in the upper and lower part of the uterus, suggesting a multidirectional propagation pattern. CONCLUSIONS: Labor contractions, expressed by electrohysterographic signals, propagate both in the downward and upward direction, a phenomenon that must be taken into account when determining the propagation velocity for preterm labor diagnostics. PMID- 23730732 TI - Intermolecular CH...O/N H-bonds in the biologically important pairs of natural nucleobases: a thorough quantum-chemical study. AB - This study aims to cast light on the physico-chemical nature and energetic of the non-conventional CH...O/N H-bonds in the biologically important natural nucleobase pairs using a comprehensive quantum-chemical approach. As a whole, the 36 biologically important pairs, involving canonical and rare tautomers of nucleobases, were studied by means of all available up-to-date state-of-the-art quantum-chemical techniques along with quantum theory "Atoms in molecules" (QTAIM), Natural Bond Orbital (NBO) analysis, Grunenberg's compliance constants theory, geometrical and vibrational analyses to identify the CH...O/N interactions, reveal their physico-chemical nature and estimate their strengths as well as contribution to the overall base-pairs stability. It was shown that all the 38 CH...O/N contacts (25 CH...O and 13 CH...N H-bonds) completely satisfy all classical geometrical, electron-topological, in particular Bader's and "two molecule" Koch and Popelier's, and vibrational criteria of H-bonding. The positive values of Grunenberg's compliance constants prove that the CH...O/N contacts in nucleobase pairs are stabilizing interactions unlike electrostatic repulsion and anti-H-bonds. NBO analysis indicates the electron density transfer from the lone electron pair of the acceptor atom (O/N) to the antibonding orbital corresponding to the donor group sigma(*)(CH). Moreover, significant increase in the frequency of the out-of-plane deformation modes gamma (CH) under the formation of the CH...O (by 17.2/81.3/10.8/84.7 cm(-1)) and CH...N (by 32.7/85.9/9.0/77.9 cm(-1)) H-bonds at the density functional theory (DFT)/second order Moller-Plesset (MP2) levels of theory, respectively, and concomitant changes of their intensities can be considered as reliable indicators of H bonding. The strengths of the CH...O/N interactions, evaluated by means of Espinosa-Molins-Lecomte formula, lie within the range 0.45/3.89/0.62/4.10 kcal/mol for the CH...O H-bonds and 1.45/3.17/1.70/3.43 kcal/mol for the CH...N H bonds at the DFT/MP2 levels of theory, respectively. We revealed high linear mutual correlations between the H-bond energy and different physico-chemical parameters of the CH...O/N H-bonds. Based on these observations, the authors asserted that the most reliable descriptors of the H-bonding are the electron density rho at the SN...O/N H-bond critical points and the NBO calculated stabilization energy E((2)). The linear dependence of the H-bond energy ECH...O/N (in kcal/mol) on the electron density rho (in atomic units) was established (DFT/MP2): ECH...O = 248.501[Formula: see text]rho-0.367/260.518[Formula: see text]rho-0.373 and ECH...N = 218.125[Formula: see text]rho-0.339/243.599[Formula: see text]rho-0.441. Red-shifted and blue-shifted CH...O/N H-bonds behave in a similar way and can be described with the same fit parameters. It was found that the A-U HH2 and U-U3 nucleobase pairs are stabilized solely by the CH...O/N H bonds. At the same time, in the A-U HH1, A-U HH2, A-Asyn 1, A-Asyn 2, A-Asyn 3, A A4, A-G1, A-G2, G-U1, G-U2, G-U3, G-C HH1, U-U1, U-U2, U-U3 and A-C nucleobase pairs the CH...O/N H-bonds play a prominent role (>30%) in their stabilization. We suppose that unconventional CH...O/N H-bond plays the role of the third "fulcrum", ensuring structurally dynamic similarity of the isomorphic base pairs of different origin, which are incorporated equally well into the structure of the DNA double helix. PMID- 23730733 TI - "Becoming bold": alcohol use and sexual exploration among Black and Latino young men who have sex with men (YMSM). AB - Alcohol use is correlated with unprotected sex, which may place young men who have sex with men (YMSM) who use alcohol with sex at increased risk for contracting HIV. However, little is known about how this link develops. This study used qualitative interviews to explore how alcohol became associated with sex and sexual risk among YMSM. We purposively sampled 20 Black and 20 Latino YMSM (N = 40), ages 21 to 24, who used substances (alcohol, marijuana, and crystal methamphetamine) with sex. Interviews focused on participants' personal histories to trace how these associations developed for each individual. Drawing on sexual script, emotion regulation, and alcohol expectancy theories, analyses followed a modified grounded theory approach. Participants stated that alcohol enabled them to engage in sexual behaviors with men that they wanted to try, allowing them to be more "bold," overcome stigma about homosexuality, and feel increased comfort with their sexual desires and identities. The use of alcohol during sex was helpful to some of the participants but could also lead to sexual risk behaviors. Intervention programs seeking to reduce alcohol misuse and sexual risk should take into account how YMSM conceptualize associations between alcohol and sex. These programs may be more effective if they provide support for sexual identity exploration. PMID- 23730735 TI - Clinical application of total parenteral nutrition in patients with peritoneal carcinomatosis. AB - Cancer patients with terminal stage peritoneal carcinomatosis are often unable to eat, rendering total parenteral nutrition (TPN) as the only option to avoid starvation. In this retrospective study, we reviewed the medical records of 46 patients with peritoneal carcinomatosis and compared them to the records of 51 patients who had gastrointestinal malignancy without evidence of peritoneal carcinomatosis. The factors evaluated include demographic data, cause of primary malignancy, ascites formation, anthropometric measurements, laboratory tests, and outcome measurements as well as factors associated with greater than 90-day survival. In-hospital mortality was observed in 31 of the 46 patients with peritoneal carcinomatosis, with a median survival time of 40 days (4-148 days) for all 46 patients. The median duration of TPN administration in the peritoneal carcinomatosis group was 24.1 +/- 27.4 days (3-68 days). Severe infection related to TPN application was seen in 5/46 (10.7%) patients with peritoneal carcinomatosis and 6/51 (9.8%) patients without peritoneal carcinomatosis. The length of survival varied widely among terminal patients with peritoneal carcinomatosis. The average survival time in peritoneal carcinomatosis patients receiving TPN was short, indicating that the nutrition support of TPN was relatively suboptimal. Ascites was not a prognostic factor for peritoneal carcinomatosis, while body mass index was a predictor for 90-day survival. PMID- 23730736 TI - Analysis of Fe(III) heme binding to cysteine-containing heme-regulatory motifs in proteins. AB - Regulatory heme binds to specific motifs in proteins and controls a variety of biochemical processes. Several of these proteins were recently shown to form complexes with ferric and/or ferrous heme via a cysteine residue as axial ligand. The objective of this study was to examine the heme-binding properties of a series of cysteine-containing peptides with focus on CP motif sequences. The peptides displayed different binding behavior upon Fe(III) heme application with characteristic wavelength shifts of the Soret band to 370 nm or 420-430 nm and in some cases to both wavelengths. Whereas for most of the peptides containing a cysteine only a shift to 420-430 nm was observed, CP-containing peptides exhibited a preference for a shift to 370 nm. Detailed structural investigation using Raman and NMR spectroscopy on selected representatives revealed different binding modes with respect to iron ion coordination, which reflected the results of the UV-vis studies. A predicted short sequence stretch derived from dipeptidyl peptidase 8 was additionally examined with respect to CP motif binding to heme on the peptide as well as on the protein level. The heme association was confirmed with the first solution structure of a CP-peptide-heme complex and, moreover, an inhibitory effect of Fe(III) heme on the enzyme's activity. The relevance of both the use of model compounds to elucidate the molecular mechanism underlying regulatory heme binding and its potential for the investigation of regulatory heme control is discussed. PMID- 23730737 TI - A simple genetic basis for complex social behaviour mediates widespread gene expression differences. AB - A remarkable social polymorphism is controlled by a single Mendelian factor in the fire ant Solenopsis invicta. A genomic element marked by the gene Gp-9 determines whether workers tolerate one or many fertile queens in their colony. Gp-9 was recently shown to be part of a supergene with two nonrecombining variants, SB and Sb. SB/SB and SB/Sb queens differ in how they initiate new colonies, and in many physiological traits, for example odour and maturation rate. To understand how a single genetic element can affect all these traits, we used a microarray to compare gene expression patterns between SB/SB and SB/Sb queens of three different age classes: 1-day-old unmated queens, 11-day-old unmated queens and mated, fully reproductive queens collected from mature field colonies. The number of genes that were differentially expressed between SB/SB and SB/Sb queens of the same age class was smallest in 1-day-old queens, maximal in 11-day-old queens and intermediate in reproductive queens. Gene ontology analysis showed that SB/SB queens upregulate reproductive genes faster than SB/Sb queens. For all age classes, genes inside the supergene were overrepresented among the differentially expressed genes. Consistent with the hypothesized greater number of transposons in the Sb supergene, 13 transposon genes were upregulated in SB/Sb queens. Viral genes were also upregulated in SB/Sb mature queens, consistent with the known greater parasite load in colonies headed by SB/Sb queens compared with colonies headed by SB/SB queens. Eighteen differentially expressed genes between reproductive queens were involved in chemical signalling. Our results suggest that many genes in the supergene are involved in regulating social organization and queen phenotypes in fire ants. PMID- 23730738 TI - Crateriform papule on the left knee in a 7-year-old boy. PMID- 23730739 TI - Correspondence between Henry A. Murray and Siegen K. Chou. AB - Siegen K. Chou received his PhD under the supervision of Walter R. Miles and conducted psychological research in China afterward. During 1930-1949, he kept close communication and cooperated with American psychologists. In 1945, Chou and his colleagues cooperated with Murray, Lyman, and others to test paratroop candidates for the Chinese Nationalist Army. Correspondence between Henry A. Murray and Siegen K. Chou, which reveals their friendship and cooperation relation to Chou's goal to develop Chinese psychology, was reviewed briefly. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23730740 TI - 1,4-Naphthoquinones in H-bond-directed trienamine-mediated strategies. AB - The synthesis of optically active, carboannulated dihydronaphthoquinone and naphthoquinone derivatives with up to four stereogenic centers is demonstrated by H-bond-directed, trienamine-mediated [4 + 2]-cycloadditions. The outcome of the reaction between 2,4-dienals and 1,4-naphthoquinones is controlled by the substituent in the 2-position of the 1,4-naphthoquinone. In the case of sterically demanding 2-substituted derivatives, dihydronaphthoquinones are obtained. However, when a hydrogen atom is present in the 2-position, a subsequent oxidation of the initially formed cycloadducts occurs yielding naphthoquinones. PMID- 23730741 TI - Test of memory malingering: cutoff scores for psychometrically defined malingering groups in a military sample. AB - This research examined cutoffs for the Test of Memory Malingering (TOMM) in a military sample composed primarily of mTBI patients. The results are consistent with previous research and provide additional evidence that cutoffs higher than those originally recommended for the TOMM can produce excellent classification and diagnostic statistics when a psychometrically defined non-malingering group is compared with three psychometrically defined malingering groups: Probable, Probable to Definite, and Definite Malingering. The groups were formed based on the number of symptom and performance validity tests passed or failed. Cutoffs that were 4-5 points higher for Trial 2 and the Retention Trial than originally recommended produced very low false positive rates (.0 to .06) and excellent positive predictive values (.75 to 1.00) for a base rate of malingering commonly found in TBI patients. Positive likelihood ratios were all above 10 for these two trials indicating excellent ability to rule in malingering. A range of cutoffs for Trial 1 were also examined, and classification and diagnostic statistics are presented for cutoffs ranging from 40 to 44 with results similar to the other TOMM trials. PMID- 23730742 TI - Treatment failure in automated peritoneal dialysis and double-bag continuous ambulatory peritoneal dialysis. AB - AIM: Automated peritoneal dialysis (APD) and double-bag continuous ambulatory peritoneal dialysis (CAPD) are the two current standard modalities of peritoneal dialysis (PD). Outcomes of these two modalities have not been well described. METHODS: A single-centre, retrospective review was carried out to compare the treatment failure rate of APD and double-bag CAPD. Treatment failure was a combined endpoint including death and technique failure. Cox regression was used to compare risk (hazard ratio, HR) of treatment failure in APD and CAPD. RESULTS: There were 121 patients included in this study, 55 with APD and 66 with CAPD. APD patients had significantly lower risk of treatment failure (death and technique failure) than CAPD patients (HR 0.58, 95% confidence interval [CI]: 0.37-0.91, P=0.02). The lower risk of treatment failure in APD compared to CAPD was mainly caused by the significantly lower risk of technique failure (HR 0.30, 95%CI: 0.10 0.93, P=0.04). The mortality rates of the two modalities were not significantly different (HR 0.69, 95%CI: 0.42-1.12, P=0.13). CONCLUSION: Our data suggest that APD may have lower risk of treatment failure compared with double-bag CAPD. These potential benefits of APD might justify the use of this modality despite its higher cost. PMID- 23730743 TI - Gene use restriction technologies for transgenic plant bioconfinement. AB - The advances of modern plant technologies, especially genetically modified crops, are considered to be a substantial benefit to agriculture and society. However, so-called transgene escape remains and is of environmental and regulatory concern. Genetic use restriction technologies (GURTs) provide a possible solution to prevent transgene dispersal. Although GURTs were originally developed as a way for intellectual property protection (IPP), we believe their maximum benefit could be in the prevention of gene flow, that is, bioconfinement. This review describes the underlying signal transduction and components necessary to implement any GURT system. Furthermore, we review the similarities and differences between IPP- and bioconfinement-oriented GURTs, discuss the GURTs' design for impeding transgene escape and summarize recent advances. Lastly, we go beyond the state of the science to speculate on regulatory and ecological effects of implementing GURTs for bioconfinement. PMID- 23730744 TI - Development and in vitro characterization of floating sustained-release drug delivery systems of polyphenols. AB - The aim of this study was to develop and characterize floating stomach-retentive matrix tablets that will deliver polyphenols in a controlled release manner. The tablets were prepared by direct compression. A number of polymers were examined and egg albumin was chosen in light of a better performance in terms of floating behavior and decomposition time. Dissolution studies for three representative polyphenols loaded into a number of formulations were performed using the "f2" factor in order to compare release profiles of different polyphenols and formulations. The release data showed a good fit into the power law equation and zero-order kinetics has been determined for some of the systems. Erosion and textural analysis studies revealed that higher concentration of egg albumin results in a higher gel strength that is less susceptible to erosion, potentially leading to a prolonged delivery time of drug. The ability of egg albumin-based tablets to resist high mechanical forces was also determined, while comparison to cellulose-derived polymers revealed that the latter have a much lower ability to resist the same forces. The developed delivery system has the potential to increase the efficacy of the therapy for various pathological stomach conditions and to improve patient compliance. PMID- 23730745 TI - Active and total prokaryotic communities in dryland soils. AB - The relationship between total and metabolically active soil microbial communities can change drastically with environment. In dry lands, water availability is a key factor limiting cells' activity. We surveyed the diversity of total and active Archaea and Bacteria in soils ranging from arid desert to Mediterranean forests. Thirty composited soil samples were retrieved from five sites along a precipitation gradient, collected from patches located between and under the dominant perennial plant at each site. Molecular fingerprinting was used to site-sort the communities according of their 16S rRNA genes (total community) and their rRNA (active community) amplified by PCR or RT-PCR from directly extracted soil nucleic acids. The differences between soil samples were much higher in total rather than active microbial communities: differences in DNA fingerprints between sites were 1.2 and 2.5 times higher than RNA differences (for Archaea and Bacteria, respectively). Patch-type discrepancies between DNA fingerprints were on average 2.7-19.7 times greater than RNA differences. Moreover, RNA-based community patterns were highly correlated with soil moisture but did not necessarily follow spatial distribution pattern. Our results suggest that in water-limited environments, the spatial patterns obtained by the analysis of active communities are not as robust as those drawn from total communities. PMID- 23730746 TI - Prolonged effect of a new O-glycoPEGylated FVIII (N8-GP) in a murine saphenous vein bleeding model. AB - Prophylaxis in severe haemophilia significantly increases health-related quality of life for patients, but the dosing frequency still constitutes a challenge. Thus, there is a need for new treatment options, utilizing compounds with longer duration of action, while still maintaining potency. The objective of this study was to evaluate the acute and prolonged effects of a new glycoPEGylated recombinant factor VIII (rFVIII) (N8-GP) in a venous bleeding model in haemophilia A mice and to compare the efficacy and potency to turoctocog alfa (rFVIII). Following intravenous administration of turoctocog alfa or N8-GP to normal and FVIII-deficient mice, bleeding time and blood loss from a saphenous vein incision were evaluated in an acute dose-response study and a duration of action study. In the acute setting, N8-GP dose dependently reduced the number and duration of bleeding episodes as well as blood loss compared to FVIII-deficient mice, reaching statistical significance at doses as low as 5-10 U kg(-1) . In the duration of action study, a significantly prolonged and maintained effect of N8 GP was found for up to 48 h after dosing, whereas the effect of rFVIII was no longer present for any end-points 24 h after dosing. Seventy-two hours after dosing, no significant effect of either compound was found. This study shows a prolonged haemostatic effect of N8-GP compared to rFVIII supporting other recent studies that N8-GP may hold a potential to increase the quality of life for patients with haemophilia A by reducing dosing frequency. PMID- 23730747 TI - Validation and limitation of age-period-cohort model in simulating mortality due to hepatocellular carcinoma from 1940 to 2010 in Japan. AB - AIM: We aimed to simulate the mortality due to hepatocellular carcinoma (HCC) by the age-period-cohort (APC) model with use of sex- and age-specific mortality data, for the purpose of validating the utility and assessing the limitation of this model. METHODS: Age-specific mortality due to HCC was gleaned from people aged 20-84 years during 1940 through 2010 in Japan. RESULTS: The APC model had a high performance in reproducing HCC mortality (modified determination coefficient R(2) COR >= 0.99). Risk of HCC increased with age in both sexes, while risk of period barely changed in both sexes. The birth cohort factor in the APC model in males highlighted the maximum point within birth years 1931-1935. The observed HCC mortality in 2010 in males (19 444) was lower than the predicted, and corresponded to 72.3% of the predicted 26 883.4, and in all age groups by 5-year increments (55.6-90.9%). In females, the observed mortality was lower than that predicted in those aged 64 years or less, but not in those aged 65 years or more. CONCLUSION: We applied the APC model to predict HCC mortality rate, and it reproduced the observed mortality rate faithfully. However, in the recent past, the observed morality rate in males was only 72.3% that of the predicted. Such differences would be attributed to combined effects of medical interventions, such as antiviral treatments and screening for hepatitis viruses implemented in the early 1990s in Japan. PMID- 23730748 TI - Learning from the closure of clinical programs: a case series from the Hospital Elder Life Program. AB - Clinical programs in geriatrics face a challenging fiscal environment. Although recent research offers lessons from successful programs to help others like them sustain operations, it is not clear whether these lessons apply to programs that are beginning to fail. This study takes an approach that is frequently recommended, but rarely applied: examining failed programs to develop guidance for those at risk. It uses the example of an evidence-based, cost-effective geriatrics program that has been successfully implemented at more than 200 sites: the Hospital Elder Life Program (HELP). Data come from 14 in-depth interviews conducted between January and May 2011 with staff and hospital administrators affiliated with the six fully operational sites that closed between 2006 and 2011. Using the constant comparative method, researchers identified major themes suggesting that former HELP sites closed because of two interrelated problems centered on a major financial crisis or restructuring at the hospital or health system level. First, the crisis created challenges, such as the removal of program champions and a new focus on revenue-generating programs. Second, there were on-going vulnerabilities that the crisis revealed but that had not previously posed a threat to program viability. These included problems such as insufficient support from physicians and nursing leaders and limited documentation of program outcomes. Results suggest that, to protect against closure, clinical programs need to prepare for major crises at the hospital or health system level by ensuring support from multiple senior champions, with a special emphasis on nursing and physician leaders. PMID- 23730749 TI - On multilevel selection and kin selection: contextual analysis meets direct fitness. AB - When Hamilton defined the concept of inclusive fitness, he specifically was looking to define the fitness of an individual in terms of that individual's behavior, and the effects of its' behavior on other related individuals. Although an intuitively attractive concept, issues of accounting for fitness, and correctly assigning it to the appropriate individual make this approach difficult to implement. The direct fitness approach has been suggested as a means of modeling kin selection while avoiding these issues. Whereas Hamilton's inclusive fitness approach assigns to the focal individual the fitness effects of its behavior on other related individuals, the direct fitness approach assigns the fitness effects of other actors to the focal individual. Contextual analysis was independently developed as a quantitative genetic approach for measuring multilevel selection in natural populations. Although the direct fitness approach and contextual analysis come from very different traditions, both methods rely on the same underlying equation, with the primary difference between the two approaches being that the direct fitness approach uses fitness optimization modeling, whereas with contextual analysis, the same equation is used to solve for the change in fitness associated with a change in phenotype when the population is away from the optimal phenotype. PMID- 23730750 TI - When hawks give rise to doves: the evolution and transition of enforcement strategies. AB - The question of how altruism can evolve despite its local disadvantage to selfishness has produced a wealth of theoretical and empirical research capturing the attention of scientists across disciplines for decades. One feature that has remained consistent through this outpouring of knowledge has been that researchers have looked to the altruists themselves for mechanisms by which altruism can curtail selfishness. An alternative perspective may be that just as altruists want to limit selfishness in the population, so may the selfish individuals themselves. These alternative perspectives have been most evident in the fairly recent development of enforcement strategies. Punishment can effectively limit selfishness in the population, but it is not free. Thus, when punishment evolves among altruists, the double costs of exploitation from cheaters and punishment make the evolution of punishment problematic. Here we show that punishment can more readily invade selfish populations when associated with selfishness, whereas altruistic punishers cannot. Thereafter, the establishment of altruism because of enforcement by selfish punishers provides the ideal invasion conditions for altruistic punishment, effectively creating a transition of punishment from selfishness to altruistic. Thus, from chaotic beginnings, a little hypocrisy may go a long way in the evolution and maintenance of altruism. PMID- 23730751 TI - Towards a general theory of group selection. AB - The longstanding debate about the importance of group (multilevel) selection suffers from a lack of formal models that describe explicit selection events at multiple levels. Here, we describe a general class of models for two-level evolutionary processes which include birth and death events at both levels. The models incorporate the state-dependent rates at which these events occur. The models come in two closely related forms: (1) a continuous-time Markov chain, and (2) a partial differential equation (PDE) derived from (1) by taking a limit. We argue that the mathematical structure of this PDE is the same for all models of two-level population processes, regardless of the kinds of events featured in the model. The mathematical structure of the PDE allows for a simple and unambiguous way to distinguish between individual- and group-level events in any two-level population model. This distinction, in turn, suggests a new and intuitively appealing way to define group selection in terms of the effects of group-level events. We illustrate our theory of group selection by applying it to models of the evolution of cooperation and the evolution of simple multicellular organisms, and then demonstrate that this kind of group selection is not mathematically equivalent to individual-level (kin) selection. PMID- 23730752 TI - Tempo and mode of multicellular adaptation in experimentally evolved Saccharomyces cerevisiae. AB - Multicellular complexity is a central topic in biology, but the evolutionary processes underlying its origin are difficult to study and remain poorly understood. Here we use experimental evolution to investigate the tempo and mode of multicellular adaptation during a de novo evolutionary transition to multicellularity. Multicelled "snowflake" yeast evolved from a unicellular ancestor after 7 days of selection for faster settling through liquid media. Over the next 220 days, snowflake yeast evolved to settle 44% more quickly. Throughout the experiment the clusters evolved faster settling by three distinct modes. The number of cells per cluster increased from a mean of 42 cells after 7 days of selection to 114 cells after 227 days. Between days 28 and 65, larger clusters evolved via a twofold increase in the mass of individual cells. By day 227, snowflake yeast evolved to form more hydrodynamic clusters that settle more quickly for their size than ancestral strains. The timing and nature of adaptation in our experiment suggests that costs associated with large cluster size favor novel multicellular adaptations, increasing organismal complexity. PMID- 23730753 TI - Allelopathy as an emergent, exploitable public good in the bloom-forming microalga Prymnesium parvum. AB - Many microbes cooperatively secrete extracellular products that favorably modify their environment. Consistent with social evolution theory, structured habitats play a role in maintaining these traits in microbial model systems, by localizing the benefits and separating strains that invest in these products from 'cheater' strains that benefit without paying the cost. It is thus surprising that many unicellular, well-mixed microalgal populations invest in extracellular toxins that confer ecological benefits upon the entire population, for example, by eliminating nutrient competitors (allelopathy). Here we test the hypotheses that microalgal exotoxins are (1) exploitable public goods that benefit all cells, regardless of investment, or (2) nonexploitable private goods involved in cell level functions. We test these hypotheses with high-toxicity (TOX+) and low toxicity (TOX-) strains of the damaging, mixotrophic microalga Prymnesium parvum and two common competitors: green algae and diatoms. TOX+ actually benefits from dense populations of competing green algae, which can also be prey for P. parvum, yielding a relative fitness advantage over coexisting TOX-. However, with nonprey competitors (diatoms), TOX- increases in frequency over TOX+, despite benefiting from the exclusion of diatoms by TOX+. An evolutionary unstable, ecologically devastating public good may emerge from traits selected at lower levels expressed in novel environments. PMID- 23730754 TI - Phase III of Wright's shifting balance process and the variance among demes in migration rate. AB - Interdemic selection by the differential migration of individuals out from demes of high fitness and into demes of low fitness (Phase III) is one of the most controversial aspects of Wright's Shifting Balance Theory. I derive a relationship between Phase III migration and the interdemic selection differential, S, and show its potential effect on FST . The relationship reveals a diversifying effect of interdemic selection by Phase III migration on the genetic structure of a metapopulation. Using experimental metapopulations, I explored the effect of Phase III migration on FST by comparing the genetic variance among demes for two different patterns of migration: (1) island model migration and (2) Wright's Phase III migration. Although mean migration rates were the same, I found that the variance among demes in migration rate was significantly higher with Phase III than with island model migration. As a result, FST for the frequency of a neutral marker locus was higher with Phase III than it was with island model migration. By increasing FST , Phase III enhanced the genetic differentiation among demes for traits not subject to interdemic selection. This feature makes Wright's process different from individual selection which, by reducing effective population size, decreases the genetic variance within demes for all other traits. I discussed this finding in relation to the efficacy of Phase III and random migration for effecting peak shifts, and the contribution of genes with indirect effects to among-deme variation. PMID- 23730755 TI - Multilevel selection with kin and non-kin groups, experimental results with Japanese quail (Coturnix japonica). AB - An experiment was conducted comparing multilevel selection in Japanese quail for 43 days weight and survival with birds housed in either kin (K) or random (R) groups. Multilevel selection significantly reduced mortality (6.6% K vs. 8.5% R) and increased weight (1.30 g/MG K vs. 0.13 g/MG R) resulting in response an order of magnitude greater with Kin than Random. Thus, multilevel selection was effective in reducing detrimental social interactions, which contributed to improved weight gain. The observed rates of response did not differ significantly from expected, demonstrating that current theory is adequate to explain multilevel selection response. Based on estimated genetic parameters, group selection would always be superior to any other combination of multilevel selection. Further, near optimal results could be attained using multilevel selection if 20% of the weight was on the group component regardless of group composition. Thus, in nature the conditions for multilevel selection to be effective in bringing about social change maybe common. In terms of a sustainability of breeding programs, multilevel selection is easy to implement and is expected to give near optimal responses with reduced rates of inbreeding as compared to group selection, the only requirement is that animals be housed in kin groups. PMID- 23730756 TI - Species selection and the macroevolution of coral coloniality and photosymbiosis. AB - Differences in the relative diversification rates of species with variant traits are known as species selection. Species selection can produce a macroevolutionary change in the frequencies of traits by changing the relative number of species possessing each trait over time. But species selection is not the only process that can change the frequencies of traits, phyletic microevolution of traits within species and phylogenetic trait evolution among species, the tempo and mode of microevolution can also change trait frequencies. Species selection, phylogenetic, and phyletic processes can all contribute to large-scale trends, reinforcing or canceling each other out. Even more complex interactions among macroevolutionary processes are possible when multiple covarying traits are involved. Here I present a multilevel macroevolutionary framework that is useful for understanding how macroevolutionary processes interact. It is useful for empirical studies using fossils, molecular phylogenies, or both. I illustrate the framework with the macroevolution of coloniality and photosymbiosis in scleractinian corals using a time-calibrated molecular phylogeny. I find that standing phylogenetic variation in coloniality and photosymbiosis deflects the direction of macroevolution from the vector of species selection. Variation in these traits constrains species selection and results in a 200 million year macroevolutionary equilibrium. PMID- 23730757 TI - A demographic transition altered the strength of selection for fitness and age specific survival and fertility in a 19th century American population. AB - Modernization has increased longevity and decreased fertility in many human populations, but it is not well understood how or to what extent these demographic transitions have altered patterns of natural selection. I integrate individual-based multivariate phenotypic selection approaches with evolutionary demographic methods to demonstrate how a demographic transition in 19th century female populations of Utah altered relationships between fitness and age-specific survival and fertility. Coincident with this demographic transition, natural selection for fitness, as measured by the opportunity for selection, increased by 13% to 20% over 65 years. Proportional contributions of age-specific survival to total selection (the complement to age-specific fertility) diminished from approximately one third to one seventh following a marked increase in infant survival. Despite dramatic reductions in age-specific fertility variance at all ages, the absolute magnitude of selection for fitness explained by age-specific fertility increased by approximately 45%. I show that increases in the adaptive potential of fertility traits followed directly from decreased population growth rates. These results suggest that this demographic transition has increased the adaptive potential of the Utah population, intensified selection for reproductive traits, and de-emphasized selection for survival-related traits. PMID- 23730758 TI - Multi-level sexual selection: individual and family-level selection for mating success in a historical human population. AB - Precopulatory sexual selection is the association between fitness and traits associated with mate acquisition. Although sexual selection is generally recognized to be a powerful evolutionary force, most investigations are limited to characters belonging to individuals. A broader multilevel perspective acknowledges that individual fitness can be affected by aspects of mating success that are characters of groups, such as families. Parental mating success in polygynous or polyandrous human societies may exemplify traits under group-level sexual selection. Using fitness measures that account for age-structure, I measure multilevel selection for mate number over 55 years in a human population with declining rates of polygyny. Sexual selection had three components: individual-level selection for ever-mating (whether an individual mated) and individual- and family-level selection for polyandry and polygyny. Family- and individual-level selection for polygyny was equally strong, three times stronger than family-level selection for polyandry and more than an order of magnitude stronger than individual-level selection for polyandry. However, individual-level selection for polyandry and polygyny was more effective at explaining relative fitness variance than family-level selection. Selection for ever-mating was the most important source of sexual selection for fitness; variation for ever-mating explained 23% of relative fitness variance. PMID- 23730759 TI - The effect of collective dispersal on the genetic structure of a subdivided population. AB - Correlated dispersal paths between two or more individuals are widespread across many taxa. The population genetic implications of this collective dispersal have received relatively little attention. Here we develop two-sample coalescent theory that incorporates collective dispersal in a finite island model to predict expected coalescence times, genetic diversities, and F-statistics. We show that collective dispersal reduces mixing in the system, which decreases expected coalescence times and increases FST . The effects are strongest in systems with high migration rates. Collective dispersal breaks the invariance of within-deme coalescence times to migration rate, whatever the deme size. It can also cause FST to increase with migration rate because the ratio of within- to between-deme coalescence times can decrease as migration rate approaches unity. This effect is most biologically relevant when deme size is small. We find qualitatively similar results for diploid and gametic dispersal. We also demonstrate with simulations and analytical theory the strong similarity between the effects of collective dispersal and anisotropic dispersal. These findings have implications for our understanding of the balance between drift-migration-mutation in models of neutral evolution. This has applied consequences for the interpretation of genetic structure (e.g., chaotic genetic patchiness) and estimation of migration rates from genetic data. PMID- 23730760 TI - Genetic drift and collective dispersal can result in chaotic genetic patchiness. AB - Chaotic genetic patchiness denotes unexpected patterns of genetic differentiation that are observed at a fine scale and are not stable in time. These patterns have been described in marine species with free-living larvae, but are unexpected because they occur at a scale below the dispersal range of pelagic larvae. At the scale where most larvae are immigrants, theory predicts spatially homogeneous, temporally stable genetic variation. Empirical studies have suggested that genetic drift interacts with complex dispersal patterns to create chaotic genetic patchiness. Here we use a co-ancestry model and individual-based simulations to test this idea. We found that chaotic genetic patterns (qualified by global FST and spatio-temporal variation in FST's between pairs of samples) arise from the combined effects of (1) genetic drift created by the small local effective population sizes of the sessile phase and variance in contribution among breeding groups and (2) collective dispersal of related individuals in the larval phase. Simulations show that patchiness levels qualitatively comparable to empirical results can be produced by a combination of strong variance in reproductive success and mild collective dispersal. These results call for empirical studies of the effective number of breeders producing larval cohorts, and population genetics at the larval stage. PMID- 23730761 TI - The joint evolution of dispersal and dormancy in a metapopulation with local extinctions and kin competition. AB - Dispersal and dormancy are two strategies that allow recolonization of empty patches and escape from kin competition. Because they presumably respond to similar evolutionary forces, it is tempting to consider that these strategies may substitute for each other. Yet in order to predict the outcome of the evolution of dispersal and dormancy, and to characterize the emerging covariation between both traits, it is necessary to consider models where dispersal and dormancy evolve jointly. Here, we analyze the evolution of dispersal and dormancy as a function of direct fitness costs, environmental variation, and competition among relatives. We consider two scenarios depending on whether the rates of dormancy for philopatric and dispersed individuals are constrained to be the same (unconditional dormancy) or allowed to be different (conditional dormancy). We show that only philopatric individuals should enter dormancy, at a rate increasing with increasing rates of local extinction and decreasing population sizes. When dormancy and dispersal evolve jointly, we observe a wide range of evolutionary outcomes. In particular, we find that the pattern of covariation between the evolutionarily stable rates of dispersal and dormancy is molded by the rate of extinction and the local population size. PMID- 23730762 TI - Parental frequencies and spatial configuration shape bumblebee behavior and floral isolation in hybridizing Rhinanthus. AB - To shed light on the role played by pollinators in the diversification of angiosperms, focus is needed on how floral isolation varies locally in the early stages of plant divergence. The few studies performed so far have often used species pairs with distinct pollination syndromes and contrasting floral displays. Here, we focus on a hybridizing pair (Rhinanthus minor and Rhinanthus angustifolius) with strong similarities in flower morphology and pollinators (bumblebees). We examined how ethological isolation changes locally in relation to relative Rhinanthus frequencies, spatial configurations, and pollinator assemblages. Interestingly, floral divergence based on adaptation to different pollinators is unlikely in Rhinanthus: no relationship was found between floral isolation and the local pollinator assemblage. In contrast, species frequency and spatial arrangement strongly influenced bumblebee behavior, ethological isolation, and thus potentially hybrid formation. When both Rhinanthus were present in equal proportions, bees generally preferred the more rewarding and conspicuous species. However, when the Rhinanthus frequencies were unbalanced, the more abundant species was preferred, although this was less pronounced when the less rewarding R. minor predominated. Ethological isolation is highly sensitive to site characteristics, and can be as high as in species with contrasting floral displays and pollinator suites, even though flowers are similar. PMID- 23730763 TI - The influence of pollinator phylogeography and mate preference on floral divergence in a sexually deceptive daisy. AB - Divergent mate preferences and subsequent genetic differentiation between populations has been demonstrated, but its effects on interspecific interactions are unknown. Associated species exploiting these mate preferences, for example, may diverge to match local preferences. We explore this idea in the sexually deceptive, fly-mimicking daisy, Gorteria diffusa, by testing for association between genetic structure in the fly pollinator (a proxy for mate preference divergence) and geographic divergence in floral form. If genetic structure in flies influences interactions with G. diffusa, we expect phylogeographically distinct flies to be associated with different floral forms. Flies associated with forms exploiting only feeding behavior often belonged to several phylogeographic clades, whereas flies associated with forms exploiting male mating behavior always belonged to distinct clades, indicating the possibility of pollinator-mediated floral divergence through phylogeographic variation in mating preferences of male flies. We tested this hypothesis with reciprocal presentations using male flies from distinct clades associated with separate floral forms. Results show that males from all clades exhibit similar preferences, making pollinator driven divergence through geographic variation in mate preference unlikely. Males, however, showed evidence of learned resistance to deceptive traits, suggesting antagonistic interactions between plants and pollinators may drive deceptive floral trait evolution in G. diffusa. PMID- 23730764 TI - Diversity and niche evolution along aridity gradients in north american lizards (phrynosomatidae). AB - Deserts occupy approximately 12% of the Earth's land surface, and are thought to have species poor but highly specialized biotas. However, few studies have examined the evolutionary origins of desert biotas and of diversity patterns along aridity gradients. Further, it is unclear if species occurring in more extreme conditions on a given niche axis (i.e., precipitation) are more specialized for those conditions (i.e., have narrower niche breadths). We address these questions here using a time-calibrated phylogeny and climatic data for 117 species of phrynosomatid lizards. Phrynosomatids are the most species-rich family of lizards in North America, and are found from deserts to rainforests. Surprisingly, we find that phrynosomatids have higher richness in more arid environments. This pattern occurs seemingly because they have been present in more arid habitats longer (~55 million years), and lineages in mesic environments are recently derived from more arid-dwelling ancestors. We find little support for the hypothesis that species in more extreme environments are more specialized. Instead, many desert-dwelling species are broadly distributed, and species in the most mesic environments have the broadest niche breadths. In summary, phrynosomatids offer a counterexample to the idea that arid regions are inhabited by a small number of recent and highly specialized lineages. PMID- 23730765 TI - Strong selection barriers explain microgeographic adaptation in wild salamander populations. AB - Microgeographic adaptation occurs when populations evolve divergent fitness advantages across the spatial scales at which focal organisms regularly disperse. Although an increasing number of studies find evidence for microgeographic adaptation, the underlying causes often remain unknown. Adaptive divergence requires some combination of limited gene flow and strong divergent natural selection among populations. In this study, we estimated the relative influence of selection, gene flow, and the spatial arrangement of populations in shaping patterns of adaptive divergence in natural populations of the spotted salamander (Ambystoma maculatum). Within the study region, A. maculatum co-occur with the predatory marbled salamander (Ambystoma opacum) in some ponds, and past studies have established a link between predation risk and adaptive trait variation in A. maculatum. Using 14 microsatellite loci, we found a significant pattern of genetic divergence among A. maculatum populations corresponding to levels of A. opacum predation risk. Additionally, A. maculatum foraging rate was strongly associated with predation risk, genetic divergence, and the spatial relationship of ponds on the landscape. Our results indicate the sorting of adaptive genotypes by selection regime and strongly suggest that substantial selective barriers operate against gene flow. This outcome suggests that microgeographic adaptation in A. maculatum is possible because strong antagonistic selection quickly eliminates maladapted phenotypes despite ongoing and substantial immigration. Increasing evidence for microgeographic adaptation suggests a strong role for selective barriers in counteracting the homogenizing influence of gene flow. PMID- 23730766 TI - What can multiple phylogenies say about the latitudinal diversity gradient? A new look at the tropical conservatism, out of the tropics, and diversification rate hypotheses. AB - We reviewed published phylogenies and selected 111 phylogenetic studies representing mammals, birds, insects, and flowering plants. We then mapped the latitudinal range of all taxa to test the relative importance of the tropical conservatism, out of the tropics, and diversification rate hypotheses in generating latitudinal diversity gradients. Most clades originated in the tropics, with diversity peaking in the zone of origin. Transitions of lineages between latitudinal zones occurred at 16-22% of the tree nodes. The most common type of transition was range expansions of tropical lineages to encompass also temperate latitudes. Thus, adaptation to new climatic conditions may not represent a major obstacle for many clades. These results contradict predictions of the tropical conservatism hypothesis (i.e., few clades colonizing extratropical latitudes), but support the out-of-the-tropics model (i.e., tropical originations and subsequent latitudinal range expansions). Our results suggest no difference in diversification between tropical and temperate sister lineages; thus, diversity of tropical clades was not explained by higher diversification rates in this zone. Moreover, lineages with latitudinal stasis diversified more compared to sister lineages entering a new latitudinal zone. This preserved preexisting diversity differences between latitudinal zones and can be considered a new mechanism for why diversity tends to peak in the zone of origin. PMID- 23730767 TI - Syndrome-driven diversification in a Mediterranean ecosystem. AB - Phylogenetic methods to detect lineage diversification have been traditionally used within a particular taxonomic clade, but rarely applied to detect local diversification. For understanding in situ diversification triggered by novel conditions it is necessary to focus on the time slice where such conditions occur. These new conditions may differentially affect the diversification rate of lineages with different morpho-functional syndromes. A prominent example of these processes occurs in the Mediterranean Basin, where climate arising along the Tertiary/Quaternary transition acted as an environmental filter. In this context, lineages with different syndromes (sclerophyllous and nonsclerophyllous) are hypothesized to have different local diversification rates after the rise of the Mediterranean conditions. We used macroevolutionary methods of time-dependent diversification on a calibrated local phylogeny accommodating topological and chronological uncertainty to test syndrome-driven diversification in Mediterranean shrublands from the eastern Iberian Peninsula. We found phylogenetic evidence of higher speciation associated with the nonsclerophyllous syndrome, although extinction rates were similar between syndromes. Consequently a syndrome-driven local diversification has occurred in shrublands under Mediterranean conditions. The results provide an example of how the integration of the environmental filter in a dated phylogeny may recreate the local history of lineages and help to explain assembly processes in Mediterranean ecosystems. PMID- 23730768 TI - Evolution of resistance to a multiple-herbivore community: genetic correlations, diffuse coevolution, and constraints on the plant's response to selection. AB - Although plants are generally attacked by a community of several species of herbivores, relatively little is known about the strength of natural selection for resistance in multiple-herbivore communities-particularly how the strength of selection differs among herbivores that feed on different plant organs or how strongly genetic correlations in resistance affect the evolutionary responses of the plant. Here, we report on a field study measuring natural selection for resistance in a diverse community of herbivores of Solanum carolinense. Using linear phenotypic-selection analyses, we found that directional selection acted to increase resistance to seven species. Selection was strongest to increase resistance to fruit feeders, followed by flower feeders, then leaf feeders. Selection favored a decrease in resistance to a stem borer. Bootstrapping analyses showed that the plant population contained significant genetic variation for each of 14 measured resistance traits and significant covariances in one third of the pairwise combinations of resistance traits. These genetic covariances reduced the plant's overall predicted evolutionary response for resistance against the herbivore community by about 60%. Diffuse (co)evolution was widespread in this community, and the diffuse interactions had an overwhelmingly constraining (rather than facilitative) effect on the plant's evolution of resistance. PMID- 23730769 TI - Adaptation of diploid and tetraploid chamerion angustifolium to elevation but not local environment. AB - Polyploid organisms often have different geographic ranges than their diploid relatives. However, it is unclear whether this divergence is maintained by adaptation or results from historical differences in colonization. Here, we conducted a reciprocal transplant experiment with diploid and autotetraploid Chamerion angustifolium to test for adaptation at the ploidy and population level. In the Rocky Mountains, pure diploid populations occur at high elevations and pure autotetraploid populations occur at low elevations with mixed ploidy populations between. We planted 3134 seedlings in 2004 and 3890 juveniles (bolting) in 2005 among nine plots, three in each of the diploid, mixed ploidy, and tetraploid zones, and monitored survival until 2008. For both seedlings and juvenile plants, elevation significantly influenced survival. The juvenile plants also showed a significant ploidy by elevation interaction, indicating that diploids and tetraploids survived best at their native elevations. In contrast, we found no evidence of local adaptation to plot within elevation. This suggests that the current distribution of diploids and tetraploids across elevations is the result of adaptation and that genome duplication may have facilitated the invasion of lower elevation habitats by limiting the movement of maladapted alleles from diploid populations at higher elevations. PMID- 23730770 TI - Under pressure? Dental adaptations to termitophagy and vermivory among mammals. AB - The extant mammals have evolved highly diversified diets associated with many specialized morphologies. Two rare diets, termitophagy and vermivory, are characterized by unusual morphological and dental adaptations that have evolved independently in several clades. Termitophagy is known to be associated with increases in tooth number, crown simplification, enamel loss, and the appearance of intermolar diastemata. We observed similar modifications at the species level in vermivorous clades, although interestingly the vermivorous mammals lack secondarily derived tools that compensate for the dentition's reduced function. We argue that the parallel dental changes in these specialists are the result of relaxed selection on occlusal functions of the dentition, which allow a parallel cascade of changes to occur independently in each clade. Comparison of the phenotypes of Rhynchomys, a vermivorous rat, and strains of mice whose ectodysplasin (EDA) pathway has been mutated revealed several shared dental features. Our results point to the likely involvement of this genetic pathway in the rapid, parallel morphological specializations in termitophagous and vermivorous species. We show that diets or feeding mechanisms in other mammals that are linked to decreased reliance on complex can lead to similar cascades of change. PMID- 23730771 TI - Tropics accelerate the evolution of hybrid male sterility in Drosophila. AB - Understanding the evolutionary mechanisms that facilitate speciation and explain global patterns of species diversity has remained a challenge for decades. The most general pattern of species biodiversity is the latitudinal gradient, whereby species richness increases toward the tropics. Although such a global pattern probably has a multitude of causes, recent attention has focused on the hypothesis that speciation and the evolution of reproductive isolation occur faster in the tropics. Here, I tested this prediction using a dataset on premating and postzygotic isolation between recently diverged Drosophila species. Results showed that while the evolution of premating isolation was not greater between tropical Drosophila relative to nontropical species, postzygotic isolation evolved faster in the tropics. In particular, hybrid male sterility was much greater among tropical Drosophila compared to nontropical species pairs of similar genetic age. Several testable explanations for the novel pattern are discussed, including greater role for sterility-inducing bacterial endosymbionts in the tropics and more intense sperm-sperm competition or sperm-egg sexual conflict in the tropics. The results imply that processes of speciation in the tropics may evolve at different rates or may even be somewhat different from those at higher latitudes. PMID- 23730773 TI - Microevolutionary processes generate phylogenomic discordance at ancient divergences. AB - Stochastic population processes may cause differences between species histories and gene histories. These processes are assumed to only influence the most recent divergences in the tree of life; however, there may be underappreciated potential for microevolutionary processes to impact deep divergences. I used multispecies coalescent models to determine the impact of stochastic processes on deep phylogenomic histories. Here I show phylogenomic discordance between gene histories and species histories is expected at deep divergences for many eukaryotic taxa, and the probability of discordance increases with population size, generation time, and the number of species in the tree. Five eukaryotic clades (angiosperms, birds, harpaline beetles, mammals, and nymphalid butterflies) demonstrate significant discordance potential at divergences over 50 million years old, and this discordance potential is independent of the age of divergence. These findings demonstrate population processes acting over very short timescales will leave a lasting impact on genomic histories, even for divergence events occurring tens to hundreds of millions of years ago. PMID- 23730774 TI - Sex-specific evolutionary potential of pre- and postcopulatory reproductive interactions in the field cricket, Teleogryllus commodus. AB - Mate choice often depends on the properties of both sexes, such as the preference and responsiveness of the female and the sexual display traits of the male. Quantitative genetic studies, however, traditionally explore the outcome of an interaction between males and females based solely on the genotype of one sex, treating the other sex as a source of environmental variance. Here, we use a half sib breeding design in the field cricket, Teleogryllus commodus, to estimate the additive genetic contribution of both partners to three steps of the mate choice process: the time taken to mate; the duration of spermatophore attachment; and the intensity of mate guarding. Rather than each sex contributing equally to the interactions, we found that genetic variation for latency to mate and spermatophore attachment was sex-specific, and in the case of mate-guarding intensity, largely absent. For a given interaction, genetic variation in one sex also appears to be largely independent of the other, and is also uncorrelated with the other traits. We discuss how pre- and postcopulatory interactions have the potential to evolve as an interacting phenotype, but that any coevolution between these traits, due to sexual selection or sexual conflict, may be limited. PMID- 23730772 TI - Intergenerational phenotypic mixing in viral evolution. AB - Viral particles (virions) are made of genomic material packaged with proteins, drawn from the pool of proteins in the parent cell. It is well known that when virion concentrations are high, cells can be coinfected with multiple viral strains that can complement each other. Viral genomes can then interact with proteins derived from different strains, in a phenomenon known as phenotypic mixing. But phenotypic mixing is actually far more common: viruses mutate very often, and each time a mutation occurs, the parent cell contains different types of viral genomes. Due to phenotypic mixing, changes in viral phenotypes can be shifted by a generation from the mutations that cause them. In the regime of evolutionary invasion and escape, when mutations are crucial for the virus to survive, this timing can have a large influence on the probability of emergence of an adapted strain. Modeling the dynamics of viral evolution in these contexts thus requires attention to the mutational mechanism and the determinants of fitness. PMID- 23730775 TI - Postcopulatory sexual selection increases ATP content in rodent spermatozoa. AB - Sperm competition often leads to increase in sperm numbers and sperm quality, and its effects on sperm function are now beginning to emerge. Rapid swimming speeds are crucial for mammalian spermatozoa, because they need to overcome physical barriers in the female tract, reach the ovum, and generate force to penetrate its vestments. Faster velocities associate with high sperm competition levels in many taxa and may be due to increases in sperm dimensions, but they may also relate to higher adenosine triphosphate (ATP) content. We examined if variation in sperm ATP levels relates to both sperm competition and sperm swimming speed in rodents. We found that sperm competition associates with variations in sperm ATP content and sperm-size adjusted ATP concentrations, which suggests proportionally higher ATP content in response to sperm competition. Moreover, both measures were associated with sperm swimming velocities. Our findings thus support the idea that sperm competition may select for higher ATP content leading to faster sperm swimming velocity. PMID- 23730776 TI - Prognosis of implants and abutment teeth under combined tooth-implant-supported and solely implant-supported double-crown-retained removable dental prostheses. AB - OBJECTIVE: Objective of this study was to evaluate the incidence of complications in dental implants and abutment teeth used for combined tooth-implant- and solely implant-supported double crown-retained removable dental prostheses (RDPs). MATERIAL AND METHODS: Patients were selected from a prospective clinical study. Seventy-three RDPs retained by 234 implants and 107 abutment teeth were placed in 39 men and 22 women with a mean age of 65 years. Forty-five RDPs were located in the maxilla and 28 in the mandible. Thirty-four RDPs were solely implant supported and 39 were combined tooth-implant-supported. Kaplan-Meier analysis was used to estimate success defined as survival without severe abutment-related complications, and Cox regression was used to isolate the most relevant prognostic risk factors. RESULTS: After a median observation period of 2.7 years for the RDPs, six implants failed and eleven implants were diagnosed with peri implantitis. Four abutment teeth were extracted, and three abutment teeth showed severe complications requiring extended interventions. For both abutment teeth and implants, Kaplan-Meier analyses revealed a 5-year probability of success of 85% for solely implant-supported RDPs and 92% for combined tooth-implant supported RDPs. Multiple Cox regression identified RDP location (P = 0.01), age (P = 0.01), and gender (P = 0.04) as prognostic risk factors for severe implant related complications. Solely implant-supported RPDs showed a poorer prognosis, but the risk difference did not reach statistical significance. CONCLUSIONS: Preliminary data suggest that the combination of teeth and implants to support double crown-retained RDPs may result in a prognostic advantage. The present findings should be validated in independent studies. PMID- 23730777 TI - Combined kidney and intestinal transplantation in patients with enteric hyperoxaluria secondary to short bowel syndrome. AB - Kidney transplantation is the treatment of choice for end-stage renal disease whereas indications for intestinal transplantation are currently restricted to patients with irreversible small bowel failure and severe complications of total parenteral nutrition (mostly shortage and infection of venous accesses, major electrolyte disturbances and liver failure). Enteric hyperoxaluria is secondary to certain intestinal diseases like intestinal resections, chronic inflammatory bowel disease and other malabsorption syndromes and can lead to end-stage renal disease requiring kidney transplantation. We report two patients suffering from renal failure due to enteric hyperoxaluria (secondary to extensive intestinal resection) in whom we elected to replace not only the kidney but also the intestine to prevent recurrence of hyperoxaluria in the transplanted kidney. PMID- 23730779 TI - AOTJ celebrates 10 years of critically appraised papers. PMID- 23730778 TI - Microchip emitter for solid-phase extraction-gradient elution-mass spectrometry. AB - A microchip electrospray emitter with a magnetic bead trap has been designed for solid-phase extraction-gradient elution-mass spectrometry (SPE-GEMS). The goal of this method is the detection of analytes at low concentrations and it is here demonstrated using reverse phase coated magnetic beads (Mbs) for the preconcentration and detection of the peptides. The sample is passed through the chip, and the peptides are retained and enriched in the trap. After washing, the peptides are released sequentially by stepwise gradient elution and electrosprayed for mass spectrometry analysis. This approach allows effective sample desalting, enrichment, sequential elution, and MS detection without the introduction of an additional separation step after SPE. Efficient preconcentration of model peptides by SPE and sequential release and analysis of peptides by GEMS were demonstrated for diluted sample solutions within the range of 1 MUM to 10 nM. Fortified human blood serum, protein digest and fractions collected after protein digest OFFGEL separation were analyzed by SPE-GEMS allowing the detection of low abundance peptides usually not observed by direct mass spectrometry analysis. A mathematical model for gradient elution is proposed. PMID- 23730780 TI - Sustainable enhancement in clients who perceive the Tree Theme Method((r)) as a positive intervention in psychosocial occupational therapy. AB - BACKGROUND/AIM: The Tree Theme Method((r)) is an intervention based on creative activities and occupational storytelling. The Tree Theme Method((r)) implies that the clients draw and paint trees symbolising various periods in their life. The pictures are then used as a starting point to tell their life story to enhance their wellbeing and management of their everyday life. This study aimed to evaluate if changes observed among clients regarding their wellbeing and everyday occupations, between baseline and the end of their term of the Tree Theme Method((r)) therapy, persisted three years after the completion of the intervention. METHODS: This study had a quantitative design. Thirty-one former clients were recruited to a follow-up three years after completing the intervention. Self-rating questionnaires were used regarding psychological symptoms, self-mastery, sense of coherence, activity level, occupational performance and satisfaction with occupational performance. Non-parametric methods were used for the data analysis. RESULTS: The findings revealed positive significant changes regarding sense of coherence and occupational performance and satisfaction with occupational performance, measured between the end of the intervention and at the time of the three-year follow-up. Furthermore, the respondents' ratings regarding psychological symptoms, self-mastery, activity level and the extent of satisfaction with performed occupations were found to be stable. CONCLUSIONS: The Tree Theme Method((r)) appeared to function well as an intervention in psychosocial occupational therapy, where the aim was that a client would enhance their wellbeing and management of their everyday life. However, there is need for further evaluation to assess the effects of the Tree Theme Method((r)) intervention. PMID- 23730781 TI - Perspectives of occupational therapists working in primary health promotion. AB - BACKGROUND/AIM: Given a global reorientation of health services towards upstream, or primary health promotion, there is a need to explore the role of occupational therapy in this area of practice. This study aimed to explore and describe the primary health promotion practice of community health workers with an occupational therapy background. The study highlights their practice working at a community or population (macro) level, rather than at the client service (micro) level, and explores related enablers and barriers to this practice. METHODS: The study utilised the qualitative methodology of narrative enquiry. Five workers with an occupational therapy background were recruited from community health services within Victoria. Data were gathered via in-depth interviews. Individual participant interview data were ordered to form a narrative detailing each participant's experience. These narratives were then analysed to generate themes representing important aspects of participant's experiences. RESULTS: Although some practitioners with an occupational therapy background perform primary health promotion, the findings indicate that a number of barriers deter occupational therapists from engaging in this type of practice, including lack of funding, preparation and limited understanding of the role of occupational therapy in health promotion. Enablers to engagement included undertaking further education, gaining clinical experience and establishing a professional identity. CONCLUSION: This study provides insights into the experiences of occupational therapists who work at a macro rather than micro-level of practice, and emphasises some of the barriers and enablers to embracing the sorts of roles that are emerging as part of a changing health system. PMID- 23730782 TI - Understanding the sensory experiences of young people with autism spectrum disorder: a preliminary investigation. AB - BACKGROUND/AIM: Unusual responses to sensations can impact upon the daily activities for individuals with autism spectrum disorder. Current understandings of these sensory experiences have been drawn from the proxy reports from parents/caregivers, standardised self-report questionnaires and autobiographical accounts. As sensory experiences are intensely personal, the first-hand accounts of people with autism spectrum disorder may have greater validity than caregiver reports, but these have never been systematically researched. This study explored the utility of using a semi-structured interview protocol augmented with visual cues to facilitate our understanding of the way people with autism spectrum disorder experience sensory input, and use coping strategies to manage sensory issues that interfere with participation. METHOD: A semi-structured interview augmented by visual cues was used to investigate the sensory experiences of three adolescent males with autism spectrum disorder. As is common in this population, two of the participants also had a diagnosis of Attention Deficit Hyperactivity Disorder and were taking stimulant medication. RESULTS: Participants shared a preference for expected, predictable and controllable sensory input, whereas unexpected, unpredictable and uncontrollable sensations were perceived as unpleasant. A heightened awareness of and difficulty filtering extraneous sensory input, high levels of movement seeking and an over-focus on salient sensory input were also described. Strategies employed to manage sensory challenges included avoiding, increasing predictability and control and meta-cognitive adaptations. CONCLUSIONS: Further research involving a larger sample of participants is recommended to determine the utility of using a semi-structured interview protocol augmented with visual cues to understand the sensory experiences of individuals with high-functioning autism spectrum disorder. PMID- 23730783 TI - Re-visioning practice through action research. AB - BACKGROUND/AIM: Ongoing knowledge development calls on health professionals to explore strategies to disseminate new or updated theoretical frameworks to practitioners. To date few researchers have explored effective means to do this or how the dissemination of professional ideas impacts on effective service delivery. The study described in this article aimed to identify strategies senior occupational therapists adopted to disseminate new concepts that have the potential to re-vision and transform practice. METHODS: Six occupational therapists were recruited as co-researchers to become part of a collaborative community of practice. Over a 9-month period they engaged in a project based on action research cycles where they had access to a newly revised theoretical framework. During each cycle the co-researchers participated in a teleconference which was audio-recorded where they reflected on concepts in relation to their own practice. FINDINGS: As understanding of the theoretical framework increased, they discussed which aspects of their practice could change, particularly in relation to processes they used to disseminate knowledge to the staff they supervised or managed. CONCLUSION/SIGNIFICANCE: The co-researchers described a range of ideas for dissemination which included individual and group strategies. In addition, they became aware of the transformative potential of their new knowledge as a way to better understand and create change within their organisations. The co-researchers also described a sense of increased confidence, not only in terms of conceptualising practice but in terms of supervising staff and challenging service delivery. PMID- 23730784 TI - The competency of New Zealand new graduate occupational therapists: perceived strengths and weaknesses. AB - BACKGROUND/AIM: There is a paucity of research examining the issues faced by New Zealand new graduate occupational therapists entering practice, including understanding graduates' abilities to translate knowledge and skills gained in their professional training, into the clinical setting. This study sought to explore the perceived strengths and weaknesses of newly graduated occupational therapists in New Zealand. METHODS: A mixed methods approach was used including: (i) online survey completed by 458 New Zealand registered occupational therapists, and (ii) five focus groups, in four cities, with occupational therapists, educators and managers. Survey and focus group questions explored new graduates' preparedness for practice based on the Occupational Therapy Board of New Zealand competencies for registration. RESULTS: New graduates were perceived to be strong in the competencies of 'communication' and 'continuing professional development', and weaker in the areas of 'implementation of occupational therapy' and 'management of environment and resources'. Perceptions of graduates' preparedness in relation to 'culturally safe practice', 'safe, ethical and legal practice' and 'management of self and people' were mixed. CONCLUSION: The profession has not raised any serious concerns about new graduates' preparedness for practice; however, there were some identified weaknesses. Currently, there is no clear evidence that increasing undergraduate training time would address these weaknesses and some indication that postgraduate focus may be preferable. Furthermore, the findings highlight the inconsistency in previous studies regarding perceptions of graduate preparedness. Further research regarding new graduates preparedness for practice, from multiple perspectives and taking into consideration length and stage of education, is recommended. PMID- 23730785 TI - Barriers to the use of Information and Communication Technology by occupational therapists working in a rural area of New South Wales, Australia. AB - BACKGROUND/AIM: This qualitative study formed part of a large-scale, multi-phase study into the delivery of therapy services to people with a disability, living in one rural area of New South Wales, Australia. The study's purpose was to identify the impact of Information and Communication Technology on the workforce practices of occupational therapists' working in a rural area of New South Wales. METHODS: Individual semi-structured telephone interviews were conducted with 13 occupational therapists working in disability, health and private practice in a rural area of New South Wales. Participants were asked about access to, skills and limitations of using Information and Communication Technology. A modified grounded theory approach, based on thematic analysis and constant comparison, was used to analyse the interview transcripts. RESULTS: This study found widespread use of technology by rurally based occupational therapists working in the disability sector in New South Wales. However, Information and Communication Technology was primarily used for client contact, professional development and professional networking rather than therapy provision. The study identified individual, workplace and community barriers to greater uptake of Information and Communication Technology by this group. The individual barriers included: age cohort, knowledge and personal preferences. The workplace barriers included: support and training and availability of resources. The community barriers included: infrastructure and perceptions of clients' acceptance. CONCLUSION: The potential exists for Information and Communication Technology to supplement face to-face therapy provision, enhance access to professional development and reduce professional isolation thereby addressing the rural challenges of large distances, travel times and geographic isolation. To overcome these challenges, individual, workplace and community Information and Communication Technology barriers should be addressed concurrently. PMID- 23730786 TI - Towards a definition of professionalism in Australian occupational therapy: using the Delphi technique to obtain consensus on essential values and behaviours. AB - BACKGROUND/AIM: Professionalism involves practitioners applying the values of their profession and demonstrating essential professional behaviours and attitudes. Within the Australian occupational therapy profession, there is little research on the values, behaviours and attitudes that constitute professionalism. As a result, there is limited understanding of professionalism, and the approaches used to enhance the professionalism of future practitioners are not evidence based. This study aimed to contribute to the understanding of professionalism within the Australian occupational therapy profession, by obtaining consensus among Australian occupational therapists on the professional values and behaviours essential for practice. METHOD: A constructivist paradigm guided this study. The Delphi technique was used to obtain consensus on essential professional values and behaviours among 68 occupational therapists. Consensus was identified by numerical and content analysis. RESULTS: After two Delphi rounds, 61 professional values were identified as essential for practice. These values related to ethical practice, client-centred practice, contemporary practice and to the foundational beliefs of the profession. Seven professional behaviours also achieved consensus, but there was clear disparity in participants' opinions. CONCLUSION: The results provide insight into several professional values and behaviours perceived as essential for practice. Consequently, these professional values need to be taken into consideration when defining the values of the profession. The professional behaviours need to be taken into account when finalising the essential behaviours that constitute professionalism in the profession. This study takes an initial but fundamental step towards defining professionalism within the Australian occupational therapy profession. PMID- 23730787 TI - Transition to practice in supercomplex environments: are occupational therapy graduates adequately prepared? PMID- 23730788 TI - Response from Bundy et al. to sensory interventions for children: where does our profession stand? PMID- 23730789 TI - Response from Burrows to sensory interventions for children: where does our profession stand? PMID- 23730790 TI - Reply from Rodger et al. to response from Bundy et al. to sensory interventions for children: where does our profession stand? PMID- 23730791 TI - Feedback provided to people with brain injury as an intervention improves self awareness, task completion and satisfaction with performance. PMID- 23730792 TI - Eight weeks of individual compensatory memory training improved memory performance and diary use in people with severe traumatic brain injury. PMID- 23730793 TI - Nanofilm processors controlled by electrolyte flows of femtoliter volume. AB - Nanofilm processors are a new kind of smart system based on the lateral self oxidation of nanoscale aluminum films. The time dependency of these devices is controlled by electrolyte flows of femtoliter volume which can be modulated by different mechanisms. In this paper, we provide a deeper investigation of the electrolyte transport in the nanofilm processor and the different possibilities to control the aluminum oxidation velocity. A method for the in situ investigation of the acidic characteristic of the channel electrolyte is demonstrated. The obtained results form a set of instruments for constructing more complex electrolyte circuits and should allow the creation of nanofilm processors of arbitrary time dependence. Because the nanofilm processor combines different functional blocks and can operate in a self-sustained manner, without requiring batteries, this smart system may serve as a basis for many potential applications. PMID- 23730794 TI - The suitability of teff flour in bread, layer cakes, cookies and biscuits. AB - A niche market in alternative foods has emerged in response to interest in a health conscientious diet. The purpose of this study was to evaluate the baking characteristics of teff to determine whether teff could produce satisfactory baked products. Cakes, cookies, biscuits and bread were made in triplicate from composites of wheat flour with 0, 10, 20, 30, 40 and 100% teff flour. Objective tests on size, shape, color and texture were used to evaluate the quality of the baked products. Increases in percent teff resulted in decreases in bread and cake volume (p > 0.05). The fracture strength of the cookies were not significantly different (p > 0.05) but spread was significantly greater for cookies made with 40% and 100% teff flour (p <= 0.05). There was also significant difference (p <= 0.05) in biscuit height and color among teff treatments. Overall, this study showed that teff flour is best suited for use in cookies and biscuits. PMID- 23730795 TI - Complementary medicine and recovery from cancer: the importance of post-traumatic growth. AB - Many users of Complementary and Alternative Medicines (CAMs) claim that participation leads to improved well-being; however, contradictory evidence exists, with some studies linking CAM use with poorer quality of life (QoL) or increased distress. This study explored whether an individual's experience of post-traumatic growth (PTG) following cancer may play a role in explaining these disparate outcomes. One hundred and sixty-one cancer survivors (mean age = 58.96, SD = 12.12) completed measures comprised of PTG (Post-Traumatic Growth Inventory), CAM use, QoL (Functional Assessment of Cancer Therapy scale + Functional Assessment of Chronic Illness Therapy Spiritual Well-Being Scale), post-traumatic stress disorder symptoms (Impact of Event Scale Revised) and depression, anxiety and stress (21-item short-form Depression Anxiety Stress Scale). A multiple regression controlling for gender, age, general and cancer specific distress indicated support for PTG as a mediator of the relationship between CAM and QoL. An individual's experience of PTG following cancer may be an important determinant of gaining benefit from participation in CAMs. Future research aimed at identifying potential facilitators of PTG may result in increased benefits of interventions aimed at improving adjustment among cancer survivors. PMID- 23730796 TI - Donor assists acceptor binding and catalysis of human alpha1,6 fucosyltransferase. AB - alpha1,6-Core-fucosyltransferase (FUT8) is a vital enzyme in mammalian physiological and pathophysiological processes such as tumorigenesis and progress of, among others, non-small cell lung cancer and colon carcinoma. It was also shown that therapeutic antibodies have a dramatically higher efficacy if the alpha1,6-fucosyl residue is absent. However, specific and potent inhibitors for FUT8 and related enzymes are lacking. Hence, it is crucial to elucidate the structural basis of acceptor binding and the catalytic mechanism. We present here the first structural model of FUT8 in complex with its acceptor and donor molecules. An unusually large acceptor, i.e., a hexasaccharide from the core of N glycans, is required as minimal structure. Acceptor substrate binding of FUT8 is being dissected experimentally by STD NMR and SPR and theoretically by molecular dynamics simulations. The acceptor binding site forms an unusually large and shallow binding site. Binding of the acceptor to the enzyme is much faster and stronger if the donor is present. This is due to strong hydrogen bonding between O6 of the proximal N-acetylglucosamine and an oxygen atom of the beta-phosphate of GDP-fucose. Therefore, we propose an ordered Bi Bi mechanism for FUT8 where the donor molecule binds first. No specific amino acid is present that could act as base during catalysis. Our results indicate a donor-assisted mechanism, where an oxygen of the beta-phosphate deprotonates the acceptor. Knowledge of the mechanism of FUT8 is now being used for rational design of targeted inhibitors to address metastasis and prognosis of carcinomas. PMID- 23730797 TI - Lacrimal gland uptake of (67)Ga-gallium citrate correlates with biopsy results in patients with suspected sarcoidosis. AB - PURPOSE: To investigate whether lacrimal gland uptake on (67)Ga-gallium citrate scintigraphy correlates with histopathologic evidence of sarcoidosis. METHODS: A retrospective, pilot study of 31 patients with suspected sarcoidosis who underwent gallium scintigraphy and lacrimal gland biopsy. Lacrimal gland gallium uptake was assessed by subjective visual scoring (SVS) and lacrimal uptake ratio (LUR). RESULTS: Eleven (36%) patients had lacrimal gland biopsies containing noncaseating granulomas. A statistically significant correlation was found between lacrimal gland gallium uptake and biopsy positivity using SVS (p = 0.03) or LUR (p = 0.01). Using SVS, biopsy positivity rate increased from 0 to 50% in patients with mild to intense uptake. Using LUR, biopsy positivity rate increased linearly as the ratio increased from 13% (LUR < 4) to 100% (LUR > 8). CONCLUSIONS: Lacrimal biopsy positivity rate significantly correlated with gallium uptake on scintigraphy. Both SVS and LUR methods appear to correlate with histologic results and may potentially aid in patient selection for biopsy. PMID- 23730798 TI - Discovery of novel insomnia leads from screening traditional Chinese medicine database. AB - Insomnia is a prominent modern disease that affects an increasing population. Undesirable side effects of commercial drugs highlight the need to develop novel insomnia drugs. Virtual screening of traditional chinese medicine Database@Taiwan (TCM Database@Taiwan) identified 2-O-Caffeoyl tartaric acid (1), 2-O-Feruloyl tartaric acid (2), and Mumefural (3) as potential agonists for both gamma-amino butyric acid (GABA) or benzodiazepine (BZ) binding sites. The TCM candidates exhibited higher affinity than GABA and Zolpidem, a phenomenon that could be attributed to higher quantity of stabilizing H-bonds. Efficacy profiles using support vector machines and pharmacophore contour also suggest drug potential of the TCM candidates. Fragments added to the de novo derivatives 3a, 3b, 3c for GABA binding site, and 1a, 2a, and 3d for BZ binding site contributed to new binding sites and structural stability, further optimizing binding to GABA or BZ binding sites. Increased opening of the ion channel by candidate ligands provide strong support for their potential biological functions. The dual binding properties of the TCM candidates present a unique opportunity to develop twin targeting drugs with less side effects. Derivative structures can be used as starting points for developing high affinity GABAA receptor agonists with specificity towards GABA binding site and BZ binding site. PMID- 23730799 TI - A case of anaplastic large-cell lymphoma mimicking preseptal cellulitis. PMID- 23730800 TI - Using multilevel models to identify drivers of landscape-genetic structure among management areas. AB - Landscape genetics offers a powerful approach to understanding species' dispersal patterns. However, a central obstacle is to account for ecological processes operating at multiple spatial scales, while keeping research outcomes applicable to conservation management. We address this challenge by applying a novel multilevel regression approach to model landscape drivers of genetic structure at both the resolution of individuals and at a spatial resolution relevant to management (i.e. local government management areas: LGAs) for the koala (Phascolartos cinereus) in Australia. Our approach allows for the simultaneous incorporation of drivers of landscape-genetic relationships operating at multiple spatial resolutions. Using microsatellite data for 1106 koalas, we show that, at the individual resolution, foliage projective cover (FPC) facilitates high gene flow (i.e. low resistance) until it falls below approximately 30%. Out of six additional land-cover variables, only highways and freeways further explained genetic distance after accounting for the effect of FPC. At the LGA resolution, there was significant variation in isolation-by-resistance (IBR) relationships in terms of their slopes and intercepts. This was predominantly explained by the average resistance distance among LGAs, with a weaker effect of historical forest cover. Rates of recent landscape change did not further explain variation in IBR relationships among LGAs. By using a novel multilevel model, we disentangle the effect of landscape resistance on gene flow at the fine resolution (i.e. among individuals) from effects occurring at coarser resolutions (i.e. among LGAs). This has important implications for our ability to identify appropriate scale dependent management actions. PMID- 23730801 TI - Synthesis of alkyl aryl ketones by Pd/light induced carbonylative cross-coupling of alkyl iodides and arylboronic acids. AB - Alkyl aryl ketones were synthesized by the carbonylative cross-coupling reaction of alkyl iodides and arylboronic acids under combined Pd/light conditions. In this reaction, it is likely that an acylpalladium species would be formed via carbonylation of the alkyl radical, which would then undergo transmetalation of an arylboronic acid to give the corresponding acyl(aryl)palladium species, ready to undergo reductive elimination to yield the alkyl aryl ketone. PMID- 23730803 TI - Measurement development and validation of the Family Supportive Supervisor Behavior Short-Form (FSSB-SF). AB - Recently, scholars have demonstrated the importance of Family Supportive Supervisor Behaviors (FSSB), defined as behaviors exhibited by supervisors that are supportive of employees' family roles, in relation to health, well-being, and organizational outcomes. FSSB was originally conceptualized as a multidimensional, superordinate construct with four subordinate dimensions assessed with 14 items: emotional support, instrumental support, role modeling behaviors, and creative work-family management. Retaining one item from each dimension, two studies were conducted to support the development and use of a new FSSB-Short Form (FSSB-SF). Study 1 draws on the original data from the FSSB validation study of retail employees to determine whether the results using the 14-item measure replicate with the shorter 4-item measure. Using data from a sample of 823 information technology professionals and their 219 supervisors, Study 2 extends the validation of the FSSB-SF to a new sample of professional workers and new outcome variables. Results from multilevel confirmatory factor analyses and multilevel regression analyses provide evidence of construct and criterion-related validity of the FSSB-SF, as it was significantly related to work-family conflict, job satisfaction, turnover intentions, control over work hours, obligation to work when sick, perceived stress, and reports of family time adequacy. We argue that it is important to develop parsimonious measures of work family specific support to ensure supervisor support for work and family is mainstreamed into organizational research and practice. PMID- 23730804 TI - Comment on Constraining nitrogen inputs to urban streams from leaking sewers using inverse modeling: implications for dissolved inorganic nitrogen (DIN) retention in urban environments. PMID- 23730805 TI - Assessment of the reproducibility of the indirect ultrasound method of measuring diaphragm mobility. AB - The aim of this study was to assess the reproducibility of the ultrasound (US) measurement of craniocaudal displacement of the left branch of the portal vein as an indirect method of measuring right hemidiaphragm mobility in healthy young adults. Forty-one healthy participants were selected, ranging from 20 to 30 years of age. The US tests were conducted and interpreted by two observers (A and B) on two separate occasions (Test 1 and Test 2). Intra-observer and interobserver reproducibility and repeatability of US measurements were determined by the intraclass correlation coefficient (ICC[2,1] ) using a 95% confidence interval (CI). Interobserver reproducibility assessment showed 'high correlation' for Test 1 and Test 2 (ICC[2,1] = 0.83, 95% CI = 0.70-0.91, and ICC[2,1] = 0.79, 95% CI = 0.61-0.89, respectively). Intra-observer reproducibility assessment showed 'moderate correlation' for observer A (ICC[2,1] = 0.69, 95% CI = 0.45-0.84) and for observer B (ICC[2,1] = 0.65, 95% CI = 0.39-0.81). Repeatability assessment showed 'high correlation' for all tests performed (ICC[2,1] = 0.86, 0.80, 0.74, 0.79, P<0.001). In conclusion, US measurement of craniocaudal displacement of the left branch of the portal vein is a reproducible method of measuring right hemidiaphragm mobility in healthy young adults. PMID- 23730806 TI - Clinical and pathologic characteristics of hereditary apolipoprotein A-I amyloidosis in Ireland. AB - AIM: Apolipoprotein A-I amyloidosis is a rare, autosomal dominant disorder characterized by progressive accumulation of amyloid fibrils in tissues, leading to renal and hepatic disease. We describe the clinical manifestations and pathologic features of kidney disease in three Irish families. METHODS: This observational study examines all known cases of chronic kidney disease due to hereditary apolipoprotein A-I amyloidosis in Ireland. Patients were identified by physician interview. In all of the affected individuals the disease was caused by the Gly26Arg heterozygous mutation. Immunohistochemistry confirmed that amyloid deposits were composed of apolipoprotein A-I fibrils. Family trees and clinical data were obtained via analysis of patient medical records. RESULTS: The vast majority of affected cases had demonstrable kidney disease, with variable liver disease. Renal disease most commonly manifested as slowly progressive renal impairment with mild proteinuria. In one kindred, a severe, debilitating peripheral neuropathy was common among affected family members. Histology demonstrated tubulointerstitial fibrosis with amyloid deposition in the medulla. There was very high penetrance within affected families. Of five patients who were transplanted, one transplant was lost after 5 years due to recurrent disease. One patient died from sepsis shortly after transplant. CONCLUSION: Hereditary apolipoprotein A-I amyloidosis is characterized by slowly progressive renal disease. Amyloid is deposited in the renal medulla highlighting the need to examine the medulla on renal biopsy. Overall, kidney transplantation conferred a survival advantage. PMID- 23730807 TI - Fracture resistance of single-tooth implant-supported zirconia-based indirect composite-layered molar restorations. AB - OBJECTIVES: This study evaluated the fracture resistance of single-tooth implant supported zirconia-based indirect composite-layered molar restorations. MATERIAL AND METHODS: Forty-four titanium abutments (GingiHue Post) were placed on dental implants (Osseotite Implant). Standardized single-tooth cement-retained implant supported mandibular molar restorations were fabricated for each of four test groups (n = 11) as follows: porcelain-fused-to-metal crowns (PFM), zirconia-based all-ceramic crowns (ZAC), zirconia-based indirect composite-layered crowns primed with Estenia Opaque Primer for zirconia frameworks (ZIC-E), and zirconia-based indirect composite-layered crowns (ZIC). The crowns were luted with a glass ionomer cement (Ketac Cem Easymix). Fracture resistance (N) was determined by force application of a perpendicular load to the crowns with a universal testing machine. One-way analysis of variance (ANOVA) and the Tukey's HSD test were used to assess differences in fracture resistance values (alpha = 0.05). RESULTS: Mean fracture resistances (SD) were 3.09 (0.22) kN, 3.11 (0.34) kN, 2.84 (0.21) kN, and 2.50 (0.36) kN for the PFM, ZAC, ZIC-E, and ZIC groups, respectively. Fracture resistance in the ZIC specimens was significantly lower (P < 0.044) than that in the other groups, which did not significantly differ. CONCLUSIONS: The fracture resistance of single-tooth implant-supported zirconia-based indirect composite-layered molar crowns primed with Estenia Opaque Primer for zirconia frameworks (ZIC-E) is comparable to that of porcelain-fused-to-metal (PFM) and zirconia-based all-ceramic (ZAC) restorations. Application of Estenia Opaque Primer to zirconia ceramic framework provides superior fracture resistance in implant-supported zirconia-based indirect composite-layered molar crowns. PMID- 23730808 TI - Mechanical muscle function and lean body mass during supervised strength training and testosterone therapy in aging men with low-normal testosterone levels. AB - OBJECTIVES: To examine the effect of strength training and testosterone therapy on mechanical muscle function and lean body mass (LBM) in aging men with low normal testosterone levels in a randomized, double-blind, placebo-controlled 24 week study. DESIGN: Randomized, double-blind, placebo-controlled. SETTING: Odense, Denmark. PARTICIPANTS: Men aged 60 to 78, with bioavailable testosterone levels of less than 7.3 nmol/L and a waist circumference greater than 94 cm were randomized to testosterone (50-100 mg/d, n = 22) placebo (n = 23) or strength training (n = 23) for 24 weeks. The strength training group was randomized to addition of testosterone or placebo after 12 weeks. Subjects performed supervised strength training (2-3 sets with 6- to 10-repetition maximum loads, 3 times per week). MEASUREMENTS: Testosterone levels, maximal voluntary contraction and rate of force development, and LBM were obtained at 0 and at Weeks 12 and 24 of the intervention. RESULTS: No changes in any variables were recorded with placebo. In the strength training group, maximal voluntary contraction increased 8% after 12 weeks (P = .005). During the following 12 weeks of strength training rate of force development increased by 10% (P = .04) and maximal voluntary contraction further increased (P < .001). Mechanical muscle function was unchanged in men receiving only testosterone for 24 weeks. LBM increased only in men receiving testosterone (P = .004). CONCLUSION: Strength training in aging men with low normal testosterone levels may improve mechanical muscle function, but this effect occurs without a significant increase in LBM. Clinically, only the combination of testosterone therapy and strength training resulted in an increase in mechanical muscle function and LBM. PMID- 23730809 TI - Comparison of a new chemiluminescent immunoassay for von Willebrand factor activity with the ristocetin cofactor-induced platelet agglutination method. AB - Measuring von Willebrand factor (VWF) activity is essential for the diagnosis of von Willebrand disease (VWD). The VWF activity is usually assessed based on measurement of the ristocetin cofactor (VWF:RCo). However, that test is technically challenging and has high intra- and inter-assay variabilities. A new automated chemiluminescent immunoassay VWF activity has recently become commercially available (HemosIL AcuStar von Willebrand Factor Ristocetin Cofactor Activity). The main objective of this study was to evaluate this new method and to compare it with the VWF:RCo assay as the reference method. We studied 91 samples, 18 healthy volunteers samples and 73 samples from patients (VWF:RCo level <50 IU dL(-1) ): 29 type 1 VWD, 13 type 2A, 5 type 2B, 5 type 2M, 3 type 2N, 5 type 3, 4 type 3 under treatment, 5 type 3 carriers and 4 samples with other pathologies. The HemosIL AcuStar VWF:RCo assay was 96% sensitive and 100% specific for detecting VWF abnormalities. The good analytical performance, and the sensitivity and specificity of HemosIL AcuStar VWF:RCo to detect VWF deficiency renders it a suitable method for VWD screening. PMID- 23730810 TI - Foraging currencies, metabolism and behavioural routines. AB - A fundamental issue in foraging theory is whether it is possible to find a simple currency that characterizes foraging behaviour. If such a currency exists, then it is tempting to argue that the selective forces that have shaped the evolution of foraging behaviour have been understood. We review previous work on currencies for the foraging behaviour of an animal that maximizes total energy gained. In many circumstances, it is optimal to maximize a suitably modified form of efficiency. We show how energy gain, predation and damage can be combined in a single currency based on reproductive value. We draw attention to the idea that hard work may have an adverse effect on an animal's condition. We develop a model of optimal foraging over a day when a forager's state consists of its energy reserves and its condition. Optimal foraging behaviour in our model depends on energy reserves, condition and time of day. The pattern of optimal behaviour depends strongly on assumptions about the probability that the forager is killed by a predator. If condition is important, no simple currency characterizes foraging behaviour, but behaviour can be understood in terms of the maximization of reproductive value. It may be optimal to adopt a foraging option that results in a rate of energy expenditure that is less than the rate associated with maximizing efficiency. PMID- 23730811 TI - Laser in caries treatment--patients' experiences and opinions. AB - OBJECTIVES: The aim of this study was to obtain a deeper understanding of patient's experiences and perspectives after dental caries treatment with Er:YAG laser technology. METHODS: Twelve patients aged 15-30 years who had undergone at least one laser caries excavation agreed to participate in an interview study. All the interviews were tape recorded and transcribed by a transcription agency. The transcribed texts were analysed using manifest and latent qualitative content analysis. RESULTS: The categories in this study were identified as choosing laser, understanding laser, encouraging dental care and my oral health. The motivation for laser treatment was described as dental fear in general, specific fear of needles or discomfort with the drill. The informants described the dentist's role as initiators of treatment and willing or unwilling facilitators. Laser treatment was described as safer and more carefully considered treatment. They felt generally safe with laser and were able to relax during the treatment. All interviewers described a positive impression of the laser, and words like 'up to date' and 'future-oriented' were used to describe laser. Laser treatment was considered less painful. CONCLUSIONS: The results indicate that patients find laser a feasible and convenient treatment option. PMID- 23730812 TI - Evaluation of 1H NMR metabolic profiling using biofluid mixture design. AB - A strategy for evaluating the performance of quantitative spectral analysis tools in conditions that better approximate background variation in a metabonomics experiment is presented. Three different urine samples were mixed in known proportions according to a {3, 3} simplex lattice experimental design and analyzed in triplicate by 1D (1)H NMR spectroscopy. Fifty-four urinary metabolites were subsequently quantified from the sample spectra using two methods common in metabolic profiling studies: (1) targeted spectral fitting and (2) targeted spectral integration. Multivariate analysis using partial least squares (PLS) regression showed the latent structure of the spectral set recapitulated the experimental mixture design. The goodness-of-prediction statistic (Q(2)) of each metabolite variable in a PLS model was calculated as a metric for the reliability of measurement, across the sample compositional space. Several metabolites were observed to have low Q(2) values, largely as a consequence of their spectral resonances having low s/n or strong overlap with other sample components. This strategy has the potential to allow evaluation of spectral features obtained from metabolic profiling platforms in the context of the compositional background found in real biological sample sets, which may be subject to considerable variation. We suggest that it be incorporated into metabolic profiling studies to improve the estimation of matrix effects that confound accurate metabolite measurement. This novel method provides a rational basis for exploiting information from several samples in an efficient manner and avoids the use of multiple spike-in authentic standards, which may be difficult to obtain. PMID- 23730813 TI - Beverage and water intake of healthy adults in some European countries. AB - INTRODUCTION: Nutritional surveys frequently collect some data of consumption of beverages; however, information from different sources and different methodologies raises issues of comparability. The main objective of this review was to examine the available techniques used for assessing beverage intake in European epidemiological studies and to describe the most frequent method applied to assess it. MATERIALS AND METHODS: Information of beverage intake available from European surveys and nutritional epidemiological investigations was obtained from gray literature. RESULTS: Twelve articles were included and relevant data were extracted. The studies were carried out on healthy adults by different types of assessments. The most frequent tool used was a 7-d dietary record. Only Germany used a specific beverage assessment tool (Beverage Dietary History). CONCLUSION: From the limited data available and the diversity of the methodology used, the results show that consumption of beverages is different between countries. Current epidemiological studies in Europe focusing on beverage intake are scarce. Further research is needed to clarify the amount of beverage intake in European population. PMID- 23730814 TI - Discovery of high potency, single-chain insulin analogs with a shortened B-chain and nonpeptide linker. AB - A series of novel, single chain insulin analogs containing polyethylene glycol based connecting segments were synthesized by native chemical ligation and tested for biological activity. While the full length single chain insulin analogs exhibited low potency, deletion of amino acids B26-B30 unexpectedly generated markedly higher activity. This observation is unprecedented in all previous studies of single chain insulin analogs and is consistent with the presumption that in the native hormone this sequence must translocate to achieve high potency insulin receptor interaction. Optimization of the sequence yielded an insulin analog with potency and selectivity comparable to that of native insulin. These results establish a basis for discovery of novel higher potency, single chain insulin analogs of shortened length. PMID- 23730815 TI - Age-related changes in ERP correlates of visuospatial and motor processes. AB - Although previous ERP studies have demonstrated slowing of visuospatial and motor processes with age, such studies frequently included only young and elderly participants, and lacked information about age-related changes across the adult lifespan. The present research used a Simon task with two irrelevant dimensions (position and direction of an arrow) to study visuospatial (N2 posterior contralateral, N2pc) and motor (response-locked lateralized readiness potential, LRP-r) processes in young, middle-aged, and elderly adults. The reaction time and motor execution stage (LRP-r) increased gradually with age, while visuospatial processes (N2pc latency) were similarly delayed in the older groups. No age related increase in interference was observed, probably related to a delay in processing the symbolic meaning of the direction in older groups, which was consistent with age-related differences in distributional analyses and N2pc amplitude modulations. PMID- 23730816 TI - Differential diagnosis of behcet uveitis. AB - The diagnosis of Behcet disease is clinical and based on the presence of characteristic ocular and systemic inflammatory manifestations. Patients may present with anterior, posterior, or panuveitis in one or both eyes. The differential diagnosis includes a variety of infectious and noninfectious causes of acute nongranulomatous anterior uveitis, intermediate uveitis, occlusive retinal vasculitis, focal or multifocal retinitis, and necrotizing retinitis. A course characterized by sudden onset with improvement followed by recurrence of inflammatory signs is most typical for Behcet uveitis. PMID- 23730817 TI - Laparoscopic findings of congenital hepatic fibrosis: A case report and review of the published work. AB - A 33-year-old man visited a hospital after vomiting blood. Emergent esophagogastroduodenoscopy revealed the presence of varices in the lower esophagus. The patient did not have a past history of alcohol consumption and was negative for hepatitis B and C viruses. He was referred to our hospital for closer examination. Portal hypertension was detected by conventional imaging modalities, but signs of liver cirrhosis, thrombosis, stenosis, malformation of the portal vein and bile duct abnormalities were not observed. We performed laparoscopy-guided liver biopsy to examine the cause of portal hypertension. In addition to prominent development of collateral vessels on hepatic ligaments and the omenta, marbled whitish markings with black-green spots were dispersed over the liver surface, but nodular formation and lymphatic vesicles were not found. Biopsied specimen demonstrated severe dense fibrosis in portal areas and von Meyenburg complexes (vMC). Based on these findings, the diagnosis of congenital hepatic fibrosis (CHF) was made. Post-biopsy hemostasis was confirmed under laparoscopy and no major complications occurred after biopsy. We reviewed 11 cases of CHF which had undergone laparoscopy in Japan, including our case. Marbled whitish markings, black-green spots and collateral vessels were seen in 11, five and seven cases, respectively. When we encounter the patients having portal hypertension of unknown etiology, laparoscopy-guided liver biopsy should be considered as a safe and useful diagnostic procedure. Black-green spots in marbled whitish markings, which reflect vMC in broad fibrotic areas, are laparoscopic characteristics of CHF. PMID- 23730818 TI - Low electric field parameters required to induce death of cancer cells. AB - Irreversible electroporation (IRE) is a novel technique that deals with killing undesirable cells, mainly cancer cells, directly without using any cytotoxic drugs. Commonly in this technique very high electric field up to 1000 V/cm is used but for very short exposure time (nanoseconds). Low electric fields (LEFs) are used before to internalize molecules and drugs inside the cells (electroendocytosis) but mainly not in killing the cells. The aim of this work is to determine the ability of using LEFs to kill cancer cells (Hela cells). The Physics idea is in making LEFs energy equivalent to IRE energy. Four IRE protocols were selected to represent very high, high, moderate and mild voltages IRE, then we make equivalent energy for each of these protocols using different LEFs' parameters of different amplitudes (7, 10, 14 and 20 V), different pulse numbers (40, 80, 160 and 320 pulses), different frequencies from 0.5 to 106.86 Hz and different pulse widths from 9.38 to 2000 ms. Each of the calculated LEF equivalent to IRE was applied on Hela cell line. The results show complete destruction of the cancer cells for all the tested exposure protocols. This damage was not due to thermal effect because the measured temperature was not changed before and after the exposure. The possible effect mechanism is discussed. It was concluded that the lethal effect on the cancer cells can be achieved using LEFs if the same energy equivalent to IRE is used. This work will help in using low-risk drug-free techniques in cancer treatment. PMID- 23730819 TI - Self-reported symptoms associated with exposure to electromagnetic fields: a questionnaire study. AB - Abstract In the last years, it has been discussed frequently whether there are any harmful effects of electromagnetic fields on human health. Electromagnetic fields are generated by several natural and man-made sources. Part of the electromagnetic spectrum called Radiofrequency is used in communication systems such as mobile (cellular) phone and computer. The aim of our study was to explore different self-reported symptoms that may be associated with exposure to electromagnetic fields. This survey study was conducted, using a questionnaire, on 350 people aged +9 years in Turkey. The chi-square test was used for data analysis. Self-reported symptoms were headache, vertigo/dizziness, fatigue, forgetfulness, sleep disturbance-insomnia, tension-anxiety, joint and bone pain, lacrimation of the eyes, hearing loss and tinnitus. As a result of the survey, the study has shown that users of mobile phone and computer more often complained of headache, joint and bone pain, hearing loss, vertigo/dizziness, tension anxiety symptoms according to time of daily usage (p < 0.05). In users of mobile phone and computer, women significantly (p < 0.05) complained more often of headache, vertigo/dizziness, fatigue, forgetfulness and tension-anxiety than men. PMID- 23730820 TI - Possibility of using near infrared irradiation for early cancer diagnosis. AB - Penetration of near infrared radiation (NIR) through biological tissues (human wrist, muscle and skin of hen, muscle of mollusk) was studied. The possibilities of visualizing various objects within biological tissues were examined. It is found that: (a) it is possible to see small objects with millimeter and sub millimeter dimensions; and (b) by using NIR rays it is possible to distinguish different parts of small homogeneous biological tissues. NIR can be a possible tool in the near future to visualize millimeter size cancerous outgrowths located inside human body cavities. It will enable diagnosis of cancer at an early stage of development. PMID- 23730821 TI - Childhood cancer survivors' school (re)entry: Australian parents' perceptions. AB - Starting or returning to school after intense medical treatment can be academically and socially challenging for childhood cancer survivors. This study aimed to evaluate the school (re)entry experience of children who had recently completed cancer treatment. Forty-two semi-structured telephone interviews were conducted to explore parents' perceptions of their child's (re)entry to school after completing treatment (23 mothers, 19 fathers, parent mean age 39.5 years; child mean age 7.76 years). Interviews were analysed using the framework of Miles and Huberman and emergent themes were organised using QSR NVivo8. Parents closely monitored their child's school (re)entry and fostered close relationships with their child's teacher to ensure swift communication of concerns should they arise. The most commonly reported difficulty related to aspects of peer socialisation; survivors either displayed a limited understanding of social rules such as turn taking, or related more to older children or teachers relative to their peers. Additionally, parents placed a strong emphasis on their child's overall personal development, above academic achievement alone. Improved parent, clinician and teacher awareness of the importance of continued peer socialisation during the treatment period is recommended in order to limit the ongoing ramifications this may have on school (re)entry post-treatment completion. PMID- 23730822 TI - A combined theoretical and experimental study of solid octyl and decylammonium chlorides and of their aqueous solutions. AB - The analysis of the thermal behavior of octyl- (OAC) and decylammonium chloride (DAC) has provided relevant new information. OAC shows a polymorphic phase transition that starts at 308 K and is completed at 313 K, between a monoclinic and a tetragonal structure, which belongs to a space group different from what was observed for other alkylammonium chlorides. At the melting temperature (463 K), the growing of a strong first sharp diffraction peak (FSDP) occurring at a d spacing of ca. 21.0 A was observed. DAC is characterized by two phase transitions at 318 (T(d1)) and 323 K (T(d2)). At T(d1), the LT polymorph coexists with a new formed phase. At T(d2) the LT polymorph is replaced by a further polymorphic modification of DAC that becomes the only one at 328 K. This second phase transition signals the occurrence of a phase, closely related to the LT polymorph of HeAC, that crystallizes in the tetragonal crystal system a = ca. 5.00 A and c = ca. 28.5 A, P4/nmm space group. DAC melting starts at 458 K and is accompanied, as in the case of OAC, by the growing of a strong FSDP at a d-spacing of ca. 24.8 A. A parallel DSC study confirmed the above-mentioned transitions. In addition, the structural properties of OAC/water and DAC/water mixtures were studied using an integrated approach, which combines X-ray diffraction and molecular dynamics (MD) techniques. A very good agreement between theoretical and experimental diffraction patterns has been obtained for both investigated mixtures. A thorough analysis of the MD trajectories shows that strong anion-water interactions are present in the mixtures, where Cl(-) forms a rather unstructured first hydration shell of water molecules bound to the anion in a linear Cl...H-O configuration. Moreover, cations and anions were found to interact with each other, and to form "solvent-shared ion pairs", in which one or more water molecules are shared between Cl(-) and the alkylammonium cation. PMID- 23730823 TI - Role of proton pump inhibitors in the occurrence and the prognosis of spontaneous bacterial peritonitis in cirrhotic patients with ascites. AB - BACKGROUND: Proton pump inhibitors (PPIs) facilitate intestinal bacterial translocation. No robust data exist demonstrating that PPIs increase the risk of spontaneous bacterial peritonitis (SBP) and that PPIs worsen the prognosis of SBP patients. PPI use might be unsuitable for cirrhotic patients. AIMS: To analyse: (i) the role of PPIs in the occurrence of SBP in cirrhotic patients; (ii) their impact on the prognosis of SBP patients; and (iii) the suitability of their use. METHODS: In this retrospective case-control study, PPI use was first assessed in cirrhotic patients consecutively admitted with SBP (group I) and in a control group that included the same number of uninfected cirrhotic patients with ascites (group II). Afterwards, the impact of PPIs on SBP was assessed in group I by comparing survival of patients with and without PPIs. RESULTS: A total of 102 patients were included, 51 in each group. (i) SBP patients were more frequently treated by PPIs than controls (49 vs. 25%, P = 0.014). (ii) In group I, patients with (n = 25) and without (n = 26) PPIs had similar survival rates at 1 month (64.0 +/- 9.6% vs. 59.4 +/- 10.0%), 3 months (41.2 +/- 10.2% vs. 44.6 +/- 10.6%), and 1 year (26.6 +/- 9.6% vs. 28.9 +/- 10.1%), and similar median age at death (53 vs. 57 years). (iii) The reason for PPI use was inappropriate or undocumented in 34% of group I and II. CONCLUSIONS: Proton pump inhibitors were more frequently used in SBP patients than in controls, but did not influence the prognosis in SBP. Overuse of PPIs was encountered in one-third of cirrhotic patients and should be avoided. PMID- 23730824 TI - Efficacy of a functionally-based neurorehabilitation programme: a retrospective case-matched study of rehabilitation outcomes following traumatic brain injury. AB - OBJECTIVE: To investigate the efficacy of a functionally-based neurorehabilitation programme. DESIGN: Retrospective, case-matched cohort design. SETTING: An inpatient acquired brain injury (ABI) service at a post-acute rehabilitation facility. In 2001, a functionally-based rehabilitation model was introduced that streams patients into neurocognitive (NC) and neurophysical (NP) treatment groups based on predominant functional deficits. METHODS: Sixty-nine patients with TBI admitted to the ABI service before implementation of the functionally-based programme comprised a historical control group. These patients were individually case-matched to 69 participants admitted after the functionally based programme began. Rehabilitation outcomes were compared between matched patients treated before and after implementation of the programme. OUTCOME MEASURES: Rehabilitation length of stay (RLOS), Functional Independence Measure (FIM) and Disability Rating Scale (DRS) at rehabilitation discharge and FIM efficiency. RESULTS: At discharge, the NP-stream had a significantly higher FIM motor efficiency compared to the historical control (0.41 vs. 0.29; p = 0.01). The NC-stream had significantly less disability, as measured by the DRS, compared to its control (3.63 vs. 5.05; p = 0.01). CONCLUSIONS: This study presents preliminary evidence that a rehabilitation programme that targets functional needs rather than diagnosis may be useful in improving function after traumatic brain injury. PMID- 23730825 TI - Psychological features of North Korean female refugees on the MMPI-2: latent profile analysis. AB - This study examined the heterogeneity in the Minnesota Multiphasic Personality Inventory-2nd Edition (MMPI-2; Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989) profiles of North Korean female refugee population (N = 2,163) using latent profile analysis (LPA). The North Korean female refugee sample arrived at Hanawon, South Korea's resettlement center for North Korean refugees in 2008 and 2009 and took the MMPI-2 as part of an initial psychological screen. The analysis, which included the T scores of the 6 validity scales and the 10 standard clinical scales, identified 4 classes with distinctive psychological features: Class 1 (nonclinical), Class 2 (demoralized), Class 3 (somatized), and Class 4 (detached). The 4 covariates entered into the model (age, education, affiliation with a religion, and the number of forced repatriations) impacted the likelihood of belonging to certain classes. As hypothesized, older age, fewer years of education, and more incidents of forced repatriation predicted higher proneness to psychopathology. However, contrary to our expectation, having a religious faith did not emerge as a salient protective factor. The current LPA results revealed distinct heterogeneous subgroups that previous research on the MMPI and MMPI-2 profiles of refugee populations overlooked with the assumption of a homogeneous sample. Clinical implications for the treatment of North Korean female refugees and the limitations of the study are discussed. PMID- 23730826 TI - Assessing clinical significance of treatment outcomes using the DASS-21. AB - Standard clinical significance classifications are based on movement between the "dysfunctional" and "functional" distributions; however, this dichotomy ignores heterogeneity within the "dysfunctional" population. Based on the methodology described by Tingey, Lambert, Burlingame, and Hansen (1996), the present study sought to present a 3-distribution clinical significance model for the 21-item version of the Depression Anxiety Stress Scales (DASS-21; P. F. Lovibond & Lovibond, 1995) using data from a normative sample (n = 2,914), an outpatient sample (n = 1,000), and an inpatient sample (n = 3,964). DASS-21 scores were collected at pre- and post-treatment for both clinical samples, and patients were classified into 1 of 5 categories based on whether they had made a reliable change and whether they had moved into a different functional range. Evidence supported the validity of the 3-distribution model for the DASS-21, since inpatients who were classified as making a clinically significant change showed lower symptom severity, higher perceived quality of life, and higher clinician rated functioning than those who did not make a clinically significant change. Importantly, results suggest that the new category of recovering is an intermediate point between recovered and making no clinically significant change. Inpatients and outpatients have different treatment goals and therefore use of the concept of clinical significance needs to acknowledge differences in what constitutes a meaningful change. PMID- 23730827 TI - Factor structure of the Social Experience Questionnaire across time, sex, and grade among early elementary school children. AB - Ample research suggests that peer victimization predicts social and psychological maladjustment, including emotional (e.g., anxiety, low self-esteem, and depression) and behavioral (e.g., aggression) problems among children. Thus, a reliable measure of peer victimization for research with young children is needed. The Social Experience Questionnaire-Self-Report (SEQ-S) has been widely used in existing research to assess children's victimization (Crick & Grotpeter, 1996). However, empirical support for the psychometric properties of the SEQ-S is limited by the methods used to evaluate it (i.e., exploratory as opposed to confirmatory analyses), by the lack of longitudinal data, and by the limited age ranges studied. This study examined the underlying factor structure of SEQ-S ratings across 3 time points in a sample of 830 early elementary school children using confirmatory factor analysis. The hypothesized model included 3 latent factors: overt victimization, relational victimization, and receipt of prosocial acts from peers. This model provided a good fit to the data at each time point. Although it is not clear that there is invariance, results indicate that invariance across time, sex, and grade could be present. Recommendations for continued use of the SEQ-S in future research on peer victimization with young children are discussed. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23730828 TI - Detecting well-being via computerized content analysis of brief diary entries. AB - Two studies evaluated the correspondence between self-reported well-being and codings of emotion and life content by the Linguistic Inquiry and Word Count (LIWC; Pennebaker, Booth, & Francis, 2011). Open-ended diary responses were collected from 206 participants daily for 3 weeks (Study 1) and from 139 participants twice a week for 8 weeks (Study 2). LIWC negative emotion consistently correlated with self-reported negative emotion. LIWC positive emotion correlated with self-reported positive emotion in Study 1 but not in Study 2. No correlations were observed with global life satisfaction. Using a co occurrence coding method to combine LIWC emotion codings with life-content codings, we estimated the frequency of positive and negative events in 6 life domains (family, friends, academics, health, leisure, and money). Domain-specific event frequencies predicted self-reported satisfaction in all domains in Study 1 but not consistently in Study 2. We suggest that the correspondence between LIWC codings and self-reported well-being is affected by the number of writing samples collected per day as well as the target period (e.g., past day vs. past week) assessed by the self-report measure. Extensions and possible implications for the analyses of similar types of open-ended data (e.g., social media messages) are discussed. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23730830 TI - The behavioral avoidance task using imaginal exposure (BATIE): a paper-and-pencil version of traditional in vivo behavioral avoidance tasks. AB - Behavioral avoidance tasks (BATs) have been used for decades in the assessment of specific phobias, but they also involve a number of prohibitive difficulties. This study investigated a new imaginal/self-report instrument, the Behavioral Avoidance Task Using Imaginal Exposure (BATIE), and evaluated whether it was an efficient paper-and-pencil alternative. Forty-nine adults diagnosed with specific phobias were matched to 49 participants without those particular phobias who served as control participants. The participants were 89.8% female and 79.6% Caucasian and had a mean age of 20.81 years (SD = 3.62). Diagnosis was determined using the Anxiety Disorders Interview Schedule (Brown, DiNardo, & Barlow, 1994). Participants completed a BAT following a BATIE. Results indicated BATIE ratings significantly correlated with BAT performance and ratings. Significant differences were also found between the phobic and control groups on all BATIE ratings (all differences indicated poorer performance or more fear in those with specific phobias). Also, the BATIE scores demonstrated good evidence of convergent and discriminant validity compared to other self-reports, significantly predicted BAT performance even when controlling for those measures of fear and anxiety, and significantly predicted diagnostic severity ratings. Overall, results indicated that the BATIE may be a reasonable alternative to in vivo BATs in certain situations (e.g., clinical practice, unavailability of BAT stimuli). PMID- 23730829 TI - Interpreting multiple risk scales for sex offenders: evidence for averaging. AB - This study tested 3 decision rules for combining actuarial risk instruments for sex offenders into an overall evaluation of risk. Based on a 9-year follow-up of 940 adult male sex offenders, we found that Rapid Risk Assessment for Sex Offender Recidivism (RRASOR), Static-99R, and Static-2002R predicted sexual, violent, and general recidivism and provided incremental information for the prediction of all 3 outcomes. Consistent with previous findings, the incremental effect of RRASOR was positive for sexual recidivism but negative for violent and general recidivism. Averaging risk ratios was a promising approach to combining these risk scales, showing good calibration between predicted (E) and observed (O) recidivism rates (E/O index = 0.93, 95% CI [0.79, 1.09]) and good discrimination (area under the curve = 0.73, 95% CI [0.69, 0.77]) for sexual recidivism. As expected, choosing the lowest (least risky) risk tool resulted in underestimated sexual recidivism rates (E/O = 0.67, 95% CI [0.57, 0.79]) and choosing the highest (riskiest) resulted in overestimated risk (E/O = 1.37, 95% CI [1.17, 1.60]). For the prediction of violent and general recidivism, the combination rules provided similar or lower discrimination compared with relying solely on the Static-99R or Static-2002R. The current results support an averaging approach and underscore the importance of understanding the constructs assessed by violence risk measures. PMID- 23730831 TI - The Forms of Bullying Scale (FBS): validity and reliability estimates for a measure of bullying victimization and perpetration in adolescence. AB - The study of bullying behavior and its consequences for young people depends on valid and reliable measurement of bullying victimization and perpetration. Although numerous self-report bullying-related measures have been developed, robust evidence of their psychometric properties is scant, and several limitations inhibit their applicability. The Forms of Bullying Scale (FBS), with versions to measure bullying victimization (FBS-V) and perpetration (FBS-P), was developed on the basis of existing instruments, for use with 12- to 15-year-old adolescents to economically, yet comprehensively measure both bullying perpetration and victimization. Measurement properties were estimated. Scale validity was tested using data from 2 independent studies of 3,496 Grade 8 and 783 Grade 8-10 students, respectively. Construct validity of scores on the FBS was shown in confirmatory factor analysis. The factor structure was not invariant across gender. Strong associations between the FBS-V and FBS-P and separate single-item bullying items demonstrated adequate concurrent validity. Correlations, in directions as expected with social-emotional outcomes (i.e., depression, anxiety, conduct problems, and peer support), provided robust evidence of convergent and discriminant validity. Responses to the FBS items were found to be valid and concurrently reliable measures of self-reported frequency of bullying victimization and perpetration, as well as being useful to measure involvement in the different forms of bullying behaviors. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23730832 TI - A dispositional trait framework elucidates differences between interview and questionnaire measurement of childhood attention problems. AB - At present, no single attention-deficit/hyperactivity disorder (ADHD) measure completely and comprehensively captures all ADHD diagnostic criteria (Anastopoulos, 2001). This represents a notable limitation in the assessment of attention problems and suggests the need for research that reconciles differences in information across measures purporting to measure the same or similar constructs. For example, by analyzing differences in measures in relation to a third construct, the third construct can provide an illuminative backdrop against which to view and ultimately reconcile differences between measures of the same attention problem construct. Thus, the purpose of the present study was to draw on a dispositional trait framework to illustrate differences in the ADHD construct assessed by 2 widely used attention problem measures. Parents of 346 children (51% girls) ranging in age from 7 to 12 years (M = 9.92 years, SD = 0.83 years) completed the Child Behavior Checklist (CBCL; Achenbach & Rescorla, 2001), a structured clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000), and dispositional trait questionnaires about their child. Both low Conscientiousness/Effortful Control and high Neuroticism/Negative Affect showed strong, unique associations with the CBCL Attention Problem score, whereas only low Conscientiousness/Effortful Control showed a strong, unique association with DSM-IV-TR ADHD symptoms assessed by clinical interview. These discriminant dispositional trait correlates help us understand the nature of the attention problem construct as assessed by each measure, with important implications for the practice of cross-measure integration in both research and applied settings. PMID- 23730833 TI - Estimation of population allele frequencies from next-generation sequencing data: pool-versus individual-based genotyping. AB - Molecular markers produced by next-generation sequencing (NGS) technologies are revolutionizing genetic research. However, the costs of analysing large numbers of individual genomes remain prohibitive for most population genetics studies. Here, we present results based on mathematical derivations showing that, under many realistic experimental designs, NGS of DNA pools from diploid individuals allows to estimate the allele frequencies at single nucleotide polymorphisms (SNPs) with at least the same accuracy as individual-based analyses, for considerably lower library construction and sequencing efforts. These findings remain true when taking into account the possibility of substantially unequal contributions of each individual to the final pool of sequence reads. We propose the intuitive notion of effective pool size to account for unequal pooling and derive a Bayesian hierarchical model to estimate this parameter directly from the data. We provide a user-friendly application assessing the accuracy of allele frequency estimation from both pool- and individual-based NGS population data under various sampling, sequencing depth and experimental error designs. We illustrate our findings with theoretical examples and real data sets corresponding to SNP loci obtained using restriction site-associated DNA (RAD) sequencing in pool- and individual-based experiments carried out on the same population of the pine processionary moth (Thaumetopoea pityocampa). NGS of DNA pools might not be optimal for all types of studies but provides a cost-effective approach for estimating allele frequencies for very large numbers of SNPs. It thus allows comparison of genome-wide patterns of genetic variation for large numbers of individuals in multiple populations. PMID- 23730834 TI - Chiral-auxiliary-mediated asymmetric synthesis of ruthenium polypyridyl complexes. AB - An octahedral metal complex with 6 different monodentate ligands can form 15 diastereomers as pairs of enantiomers. As a result, the elaborate stereochemistry of octahedral coordination geometries provides tremendous opportunities in the fields of catalysis, the materials sciences, and the life sciences. The demand for enantiomerically pure coordination complexes for tasks related to the selective molecular recognition of biomacromolecules led us to develop synthetic methods to control the absolute stereochemistry at octahedral metal centers. A few years ago our laboratory therefore embarked on a project exploring new and general synthetic strategies for the asymmetric synthesis of inert octahedral transition metal complexes. We initially used the example of thermally inert ruthenium polypyridyl complexes and developed a family of chiral bidentate ligands, including salicyloxazolines, (mercaptophenyl)oxazolines, sulfinylphenols, N-acetylsulfinamides, a phosphinohydroxybinaphthyl, and even the amino acid proline to serve as chiral auxiliaries for asymmetric coordination chemistry. All these chiral auxiliaries strongly coordinate to ruthenium(II) in a bidentate, deprotonated fashion, allowing them to control the absolute metal centered configuration in the course of subsequent ligand exchange reactions. Finally, we can remove them from the metal without any loss of chiral information and without leaving a chemical trace. A key feature of these chiral auxiliary ligands is their switchable binding strength. A chelate effect ensures that the chiral ligands coordinate very tightly to the metal center, placing their carbon based, sulfur-based, or axial chirality in a well-defined position close to the metal center to efficiently establish the absolute metal-centered configuration. At the same time a coordinating phenolate, carboximidate, carboxylate, or thiophenolate moiety makes the coordination reversible by weakening the binding strength through protonation or methylation. Following this strategy, we synthesized a large number of homoleptic, bis-heteroleptic, and tris-heteroleptic ruthenium polypyridyl complexes in an asymmetric fashion with enantiomeric ratios that routinely reached or exceeded 96:4. Our approach should serve as a blueprint for the asymmetric synthesis of different classes of ruthenium complexes and chiral coordination complexes of other metals. PMID- 23730835 TI - The influence of epigenetics in relation to oral health. AB - The immune response is influenced by genetic and epigenetic factors, as well as disease and environmental factors. The term 'epigenetics' describes changes in the genome that influence the gene expression without altering the DNA sequence. In contrast to genetic changes in the DNA, epigenetic changes are reversible and are influenced by environmental factors. The aim of this study is to review the literature on epigenetic modifications with respect to oral health and inflammatory conditions in the oral cavity and to discuss the potential use of this new research field for the dental hygienists' and/or dentists' clinical work. Relevant publications were identified using the PubMed database without limits. The searches were conducted during January to March 2012 and resulted in articles published between 1912 and 2012. Key factors such as environment, diet, smoking, bacteria and inflammation were identified to be relevant to oral health. The result of this review article shows that there is a void in the research on epigenetics in relation to oral health. Identification of epigenetic modifications correlating with oral health may not only present a link between the influence of genetics and that of the environment on oral diseases but also provide new treatment models and tools for the dental professionals. PMID- 23730836 TI - Assessment of driving-related skills prediction of unsafe driving in older adults in the office setting. AB - OBJECTIVES: To examine the sensitivity and specificity of the Assessment of Driving-Related Skills (ADReS), a clinical tool recommended by the American Medical Association for identifying potentially unsafe older drivers that includes tests of vision, motor function, and cognition. DESIGN: Cross-sectional observation study. SETTING: Memory assessment outpatient clinic of a university hospital. PARTICIPANTS: Drivers with normal cognition (n = 47) and cognitive impairment (n = 75). MEASUREMENTS: A neurologist completed the ADReS during an office visit. Additional cognitive tests of executive, visuospatial, and visuomotor function were also performed. On a separate day, participants completed a standardized on-road test, assessed by a professional driving instructor using a global safety rating and a quantitative driving score. RESULTS: In this sample of currently active older drivers with and without cognitive impairment, measures of cognition-particularly the Trail-Making Test Part B-were more highly correlated with driving scores than other measures of function. Using recommended scoring procedures, the ADReS had a sensitivity of 0.81 for detecting impaired driving on the road test, with a specificity of 0.32 and an area under the receiver operating characteristic curve (AUC) of 0.57. A logistic regression model that incorporated computerized maze task and Mini Mental State Examination scores improved overall classification accuracy, yielding a sensitivity of 0.61, a specificity of 0.84, and an AUC of 0.80. CONCLUSION: In its present form, the ADReS has limited utility as an office screen for individuals who should undergo formal driving assessment. Improved scoring methods and screening tests with greater diagnostic accuracy than the ADReS are needed for general office practice. PMID- 23730837 TI - Anti-HBV effect of individual traditional Chinese herbal medicine in vitro and in vivo: an analytic review. AB - Traditional Chinese herbal medicine (TCHM) has been widely used in the treatment of chronic hepatitis B (CHB) in China. The systematic analysis of clinical research of TCHM against CHB revealed its potential but not confirmed its therapeutic effect. To understand the detailed antiviral effect of TCHM against HBV infection, we systematically analysed the anti-HBV effect of individual Chinese herbs on the basis of the research on individual TCHM in vitro and in vivo, which were published from 1995 to 2012. Among 171 herbal components isolated from 76 Chinese herbs, we found 13 compounds and 9 extracts isolated from 18 Chinese herbs showing strong inhibitory effect on HBV DNA, HBeAg or HBsAg release with low cytotoxicity in HepG2.2.15 cells, and agents from 12 Chinese herbs showing the highest inhibition rates of plasma DHBV DNA of more than 50% in DHBV-infected ducks. In addition, the two compounds chrysophanol 8-O-beta-D glucoside isolated from Rheum palmatum and wogonin isolated from Scutellaria baicalensis were found to display strong anti-HBV activity. Interestingly, compounds isolated from 5 of these effective anti-HBV Chinese herbs were found to show strong antibacterial or antifungal activity also. This review summarizes and analyses the studies on the anti-HBV effect of individual TCHM in cell and animal models, providing potential perspective in the understanding of TCHM in the treatment of hepatitis B and the development of new anti-HBV drugs from TCHM. PMID- 23730839 TI - Hepatitis C virus treatment and survival in patients with hepatitis C and human immunodeficiency virus co-infection and baseline anaemia. AB - The impact of pretreatment anaemia on survival in individuals with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection is not known. Moreover, HCV treatment is offered less frequently to individuals with anaemia, due to haematological side effects of the treatment regimen. This study aimed to determine the effect of HCV treatment on survival among HCV/HIV co-infected individuals with pretreatment anaemia using the Electronically Retrieved Cohort of HCV-Infected Veterans (ERCHIVES). Individuals with HCV/HIV co-infection were included in current analyses. Participants were considered treated if they were prescribed >= 4 weeks of HCV treatment. All-cause mortality data were obtained using record linkage. Survival analyses were performed using Cox proportional hazard models. Among 5000 HCV/HIV co-infected individuals, 1671 (33.4%) had pretreatment anaemia. In a follow-up period of up to 7 years (19,500 person years), individuals with anaemia had significantly higher mortality rate compared with those without anaemia [144.2 (95% CI: 134.5-154.7) vs 47.5 (44.0-51.2) per 1000 person-years, respectively]. Among individuals with anaemia, HCV treatment was associated with significantly lower mortality rate [66.6 (44.3-100.2) vs 149.6 (139.2-160.5) per 1000 person-years, for treated vs untreated, respectively]. Treatment remained associated with substantial survival benefit after taking into account the effect of multiple comorbidities (hazards ratio: 0.34, 95% CI: 0.21-0.62). These data suggest that HCV/HIV co-infected individuals with pretreatment anaemia have significantly higher mortality compared with those without anaemia. HCV treatment is associated with substantial survival benefit in this group. Additional studies are needed to determine strategies to improve HCV treatment rates among this group. PMID- 23730838 TI - Impact of oral silymarin on virus- and non-virus-specific T-cell responses in chronic hepatitis C infection. AB - Silymarin displays anti-inflammatory effects on T lymphocytes in vitro. The immunomodulatory properties of oral silymarin in vivo in humans with chronic hepatitis C have not previously been characterized. We hypothesized that silymarin would suppress T-cell proliferation and pro-inflammatory cytokine production of virus- and non-virus-specific T cells while increasing anti inflammatory IL-10 production in vivo. Patients from one site of the SyNCH-HCV double-masked, placebo-controlled study of oral silymarin in prior interferon nonresponders with chronic hepatitis C provided blood samples at baseline and treatment week 20. Mononuclear cells were stimulated with recombinant HCV proteins and controls in (3) H-thymidine proliferation assays, IFNgamma ELISPOT and IL-10 ELISPOT. The frequency of CD4(+) CD25(hi) and CD4(+) foxp3(+) regulatory T cells, serum cytokine levels, serum IP-10 and lymphocyte interferon stimulated gene expression were also quantified at baseline and week 20. Thirty two patients were recruited (10; placebo, 11; 420 mg three times a day, 11; 700 mg three times a day). Serum ALT and HCV RNA titres did not change in any group. HCV-specific CD4(+) T-cell proliferation and the frequency of IFNgamma- and IL-10 producing T cells were not significantly changed in silymarin-treated subjects. However, C. albicans-induced T-cell IFNgamma and phytohaemagglutinin-induced T cell proliferation were suppressed by silymarin therapy. A trend towards augmentation of interferon-induced ISG15 expression was present in the high-dose silymarin group. While no effect on HCV-specific T cells was identified, these data confirm that high-dose oral silymarin exerts modest nonspecific immunomodulatory effects in vivo. The impact of this anti-inflammatory effect on long-term liver health in chronic hepatitis C merits future clinical investigation. PMID- 23730840 TI - Role of IL28B and inosine triphosphatase polymorphisms in the treatment of chronic hepatitis C virus genotype 6 infection. AB - IL28B and inosine triphosphatase (ITPA) polymorphisms are able to predict treatment response and degree of ribavirin-related anaemia, respectively, in the treatment of chronic hepatitis C virus (HCV) infection. However, their roles in the treatment of chronic HCV genotype 6 remain undetermined. Sixty patients who were infected with HCV genotype 6 were commenced on 48 weeks of combination pegylated interferon and ribavirin therapy. Response to therapy, profiles of haemoglobin changes and platelet counts during therapy and their associations with IL28B rs8099917 and ITPA rs1127354 polymorphisms were analysed. The overall sustained virologic response (SVR) rate was 91.7%. 18 patients (30.0%) required a reduction in ribavirin dosage. The distribution of IL28B rs8099917 TT/TG genotypes and ITPA rs1127354 CC/CA genotypes were in Hardy-Weinberg equilibrium. IL28B rs8099917 TT genotype, when compared to TG genotype, was significantly associated with an increased SVR rate (96.2% and 62.5%, respectively) and was the only clinical parameter that predicted SVR (P = 0.014). The same significant association was observed when analysing allelic frequencies (T vs G, P = 0.001). ITPA rs1127354 CA genotype, when compared to CC genotype, was associated with lesser degree of anaemia throughout therapy (P < 0.05 for all time points). ITPA polymorphisms showed no association with changes in platelet count throughout therapy (P > 0.05 for all time points) and was not associated with SVR (P = 0.640). In chronic HCV genotype 6 infection, IL28B polymorphisms were associated with response to therapy. ITPA polymorphisms influenced the degree of anaemia but not thrombocytopenia during therapy. PMID- 23730841 TI - Thermostability of seven hepatitis C virus genotypes in vitro and in vivo. AB - Hepatitis C virus (HCV) is transmitted primarily through percutaneous exposure to contaminated blood especially in healthcare settings and among people who inject drugs. The environmental stability of HCV has been extrapolated from studies with the bovine viral diarrhoea virus or was so far only addressed with HCV genotype 2a viruses. The aim of this study was to compare the environmental and thermostability of all so far known seven HCV genotypes in vitro and in vivo. Incubation experiments at room temperature revealed that all HCV genotypes showed similar environmental stabilities in suspension with viral infectivity detectable for up to 28 days. The risk of HCV infection may not accurately be reflected by determination of HCV RNA levels. However, viral stability and transmission risks assessed from in vitro experiments correlated with viral infectivity in transgenic mice containing human liver xenografts. A reduced viral stability for up to 2 days was observed at 37 degrees C with comparable decays for all HCV genotypes confirmed by thermodynamic analysis. These results demonstrate that different HCV genotypes possess comparable stability in the environment and that noninfectious particles after incubation in vitro do not cause infection in an HCV in vivo model. These findings are important for estimation of HCV cross transmission in the environment and indicate that different HCV genotypes do not display an altered stability or resistance at certain temperatures. PMID- 23730842 TI - Association of vitamin D serum levels and its common genetic determinants, with severity of liver fibrosis in genotype 1 chronic hepatitis C patients. AB - Lower 25-hydroxyvitamin D [25(OH)D] serum levels have been associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients (G1CHC). In addition, a recent genome-wide study identified genetic variants (rs12785878, near dehydrocholesterol reductase, DHCR7; rs10741657, near CYP2R1; and rs7041, near vitamin D-binding protein, GC) affecting 25(OH)D serum levels in healthy populations. We aimed to assess the association between vitamin D serum levels and its genetic determinants, with the severity of liver fibrosis. Two hundred and sixty patients with biopsy-proven G1CHC were consecutively evaluated. The 25(OH)D serum levels were measured by high-pressure liquid chromatography. All patients were genotyped for DHCR7 rs12785878, CYP2R1 rs10741657 and GC rs7041 single nucleotide polymorphisms. DHCR7 GG genotype (P = 0.003) and the severity of fibrosis (P = 0.03) were independent factors associated with lower 25(OH)D serum levels in multiple linear regression analysis. Interestingly, 53.8% (7/13) of patients with DHCR7 GG genotype had severe liver fibrosis, compared to 27.1% (67/247) of those with DHCR7 TT/TG genotype (P = 0.03). By multivariate logistic regression analysis, severe fibrosis was independently associated with older age (OR, 1.056; 95% CI, 1.023-1.089, P = 0.001), low cholesterol (OR, 0.984; 95% CI, 0.974-0.994, P = 0.002), high triglycerides (OR, 1.008; 95% CI, 1.002-1.015, P = 0.01), low 25(OH)D (OR, 0.958; 95% CI, 0.919-0.999, P = 0.04), DHCR7 GG genotype (OR, 4.222; 95% CI, 1.106-16.120; P = 0.03), moderate-severe steatosis (OR, 2.588; 95% CI, 1.355-4.943; P = 0.004) and moderate-severe necroinflammatory activity (grading) (OR, 2.437; 95% CI, 1.307-4.763; P = 0.001). No associations were found between liver fibrosis and both CYP2R1 and GC genotypes. In patients with G1CHC, GG homozygosis for DHCR7 gene and lower 25(OH)D levels are independently associated with the severity of liver fibrosis. PMID- 23730843 TI - Hepatitis B virus surface protein mutations clustered mainly in CTL immune epitopes in chronic carriers: results of an Iranian nationwide study. AB - Mutations within the coding region of hepatitis B surface antigen (HBsAg) have been found naturally in chronic carriers. To characterize the mutations of HBsAg from Iranian chronic carriers who were vaccine and/or medication naive. The surface genes from 360 patients were amplified and directly sequenced. The distribution of amino acid substitutions was classified according to different immune epitopes of the surface protein. All isolates belonged to genotype D. 222 (61.6%) of 360 patients contained at least one amino acid substitution. 404 (74.5%) of 542 amino acid changes occurred in different immune epitopes of HBsAg, of which 112 (27.7%) in 32 residues of B-cell epitopes (62 in the 'a' determinant); 111 (27.4%) in 32 residues of T helper; and 197 (48.7%) in 32 residues inside cytotoxic T lymphocyte (CTL) epitopes. One Th (186-197) and two CTL (28-51 and 206-215) epitopes were found to be hotspot motifs for the occurrence of 213 (52.7%) substitutions. 20 stop codons were identified in different epitopes. There was a significant association between amino acid substitutions and anti-HBe seropositivity; however, the correlation between such changes with viral load and ALT levels was not significant. In chronic hepatitis B virus(HBV) carriers, positive selection in particular outside the 'a' determinant appeared to exert influence on the surface proteins. These changes could be immune escape mutations naturally occurring due to the host immune surveillance especially at the T-cell level. PMID- 23730844 TI - Long-term outcome of hepatitis B virus-related Chronic Hepatitis under protracted nucleos(t)ide analogues. AB - Long-term outcome of patients with chronic hepatitis B virus (HBV) infection under continuous nucleos(t)ide analogues (NUCs) has been poorly elucidated. We enrolled 121 anti-HBe-positive patients into a prospective surveillance programme while on (>36 months) NUCs therapy. HBV-DNA clearance, add-on therapy and safety were evaluated. Development of cirrhosis, events of liver decompensation and hepatocellular carcinoma (HCC) during the follow-up were the main endpoints, as the complication-free survival. At baseline, 74 patients (61%) had chronic hepatitis, the remainders a cirrhotic liver. HBV-DNA levels >38 000 IU/mL were discovered in 103 patients. At enrolment, 79 patients were naive to NUCs treatment. Lamivudine monotherapy (n = 70) or a different NUC (n = 51) was administered. At month 6 of therapy, HBV-DNA clearance was documented in 88 patients (73%). Treatment schedule was modified in 52 patients due to breakthrough or suboptimal response. During a mean follow-up of 6 +/- 3 years, viral clearance was achieved in the majority of patients. Ten of 74 patients (13.5%) with chronic hepatitis progressed to cirrhosis, 1 patient developed a HCC. In the 47 patients with cirrhosis at presentation, HCC occurred in 14 (30%) and liver decompensation in 5 (11%). The 5 and 10-year event-free survivals were, respectively, 89.3% (95% CI, 81.7 -96.9) and 75.6% (95% CI, 61.5 -89.7) for patients with chronic hepatitis, and 70.2% (95% CI, 56.3 -84.1) and 40.4% (95% CI, 16.9 -63.9) for those with cirrhosis. Protracted, effective treatment with oral NUCs affects the natural history of chronic HBV infection by reducing the incidence of cirrhosis and risk of complications, but does not guarantee against the development of HCC in cirrhosis at presentation. PMID- 23730845 TI - Incidence of diabetes mellitus in a population-based cohort of persons with chronic hepatitis B virus infection. AB - To investigate the effect of hepatitis B virus (HBV) infection on the development of diabetes mellitus (DM), we compared DM incidence and characteristics of Alaska Native persons with and without HBV infection. From 1990 to 2010, there were 52 incident DM cases among 1309 persons with infection vs 4557 DM cases among 85 698 persons without infection (log-rank test, P = 0.20). Compared to infected persons without DM, those with DM were significantly older (57.0 vs 47.4 years, P < 0.001) and had higher body mass index (34.5 vs 28.4 kg/m(2) , P < 0.001). Genotype, immune active disease and the presence of cirrhosis were not associated with DM. In this population-based cohort with over 20 years of follow-up, there was no effect of HBV infection on DM development. PMID- 23730846 TI - Hepatocellular carcinoma screening among hepatitis B-infected Asian Americans. PMID- 23730847 TI - Hepatocellular screening in hepatitis-B infected Asian Americans. PMID- 23730848 TI - Muscle size and arterial stiffness after blood flow-restricted low-intensity resistance training in older adults. AB - Previous studies have shown that blood flow-restricted low-intensity resistance training (BFR-RT) causes muscle hypertrophy while maintaining arterial function in young adults. We examined the effects of BFR-RT on muscle size and arterial stiffness in older adults. Healthy subjects (ages 61-84 years) were divided into BFR-RT (n = 9) or non-training control (CON; n = 10) groups. The BFR-RT group performed 20% and 30%, respectively, of one-repetition maximal (1-RM) knee extension and leg press exercises, 2 days/wk for 12 weeks. The BFR-RT group wore elastic cuffs (120-270 mmHg) on both legs during training. Magnetic resonance imaging-measured muscle cross-sectional area (CSA), 1-RM strength, chair stand (CS) test, and cardio-ankle vascular index testing (CAVI), an index of arterial stiffness, were measured before and 3-5 days after the final training session. Muscle CSA of the quadriceps (8.0%), adductors (6.5%), and gluteus maximus (4.4%), leg extension and leg press 1-RM strength (26.1% and 33.4%), and CS performance (18.3%) improved (P < 0.05) in the BFR-RT group, but not in the CON group. In CAVI testing, there were no changes in both two groups. In conclusion, BFR-RT improves muscle CSA as well as maximal muscle strength, but does not negatively affect arterial stiffness or humeral coagulation factors in older adults. PMID- 23730849 TI - Modelling and analysis of early aggregation events of BMHP1-derived self assembling peptides. AB - Despite the increasing use and development of peptide-based scaffolds in different fields including that of regenerative medicine, the understanding of the factors governing the self-assembly process and the relationship between sequence and properties have not yet been fully understood. BMHP1-derived self assembling peptides (SAPs) have been developed and characterized showing that biotinylation at the N-terminal cap corresponds to better performing assembly and scaffold biomechanics. In this study, the effects of biotinylation on the self assembly dynamics of seven BMHP1-derived SAPs have been investigated by molecular dynamics simulations. We confirmed that these SAPs self-assemble into beta structures and that proline acts as a beta-breaker of the assembled aggregates. In biotinylated peptides, the formation of ordered beta-structured aggregates is triggered by both the establishment of a dense and dynamic H-bonds network and the formation of a 'hydrophobic wall' available to interact with other peptides. Such conditions result from the peculiar chemical composition of the biotinyl cap, given by the synergic cooperation of the uracil function of the ureido ring with the high hydrophobic portion consisting of the thiophenyl ring and valeryl chain. The inbuilt propensity of biotinylated peptides towards the formation of ordered small aggregates makes them ideal precursors of higher hierarchically organized self-assembled nanostructures as experimentally observed. PMID- 23730850 TI - Light-driven transformation processes of anisotropic silver nanoparticles. AB - The photoinduced formation of silver nanoprisms from smaller silver seed particles in the presence of citrate anions is a classic example of a photomorphic reaction. In this case, light is used as a convenient tool to dynamically manipulate the shape of metal nanoparticles. To date, very little is known about the prevailing reaction mechanism of this type of photoreaction. Here we provide a detailed study of the shape transformation dynamics as a function of a range of different process parameters, such as photon energy and photon flux. For the first time, we provide direct evidence that the photochemical synthesis of silver nanoprisms from spherical seed nanoparticles proceeds via a light activated two-dimensional coalescence mechanism. On the other hand, we could show that Ostwald ripening becomes the dominant reaction mechanism when larger silver nanoprisms are grown from photochemically synthesized smaller nanoprisms. This two-step reaction proceeds significantly faster and yields more uniform, sharper nanoprisms than the classical one-step photodevelopment process from seeds. The ability to dynamically control nanoparticle shapes and properties with light opens up novel synthesis avenues but also, more importantly, allows one to conceive new applications that exploit the nonstatic character of these nanoparticles and the ability to control and adjust their properties at will in a highly dynamic fashion. PMID- 23730852 TI - Differential roles of serum hepatitis B virus DNA and hepatitis B surface antigen level in predicting virological breakthrough in patients receiving lamivudine therapy. AB - BACKGROUND AND AIM: The role of serum hepatitis B surface antigen (HBsAg) level in determining virological breakthrough (VB) for patients with hepatitis B virus (HBV) infection receiving lamivudine remains unclear. The study aimed to evaluate the impact of serum HBsAg levels on VB among patients receiving lamivudine therapy, especially in a setting of low HBV viral load. METHODS: Two hundred sixty-eight consecutive treatment-naive patients who underwent lamivudine therapy for chronic hepatitis B were enrolled. Factors in terms of VB were analyzed by multivariate analysis. RESULTS: After a median treatment duration of 67.1 weeks, 102 patients had VB. Multivariate analysis showed that positive hepatitis B e antigen (HBeAg) (hazard ratio 2.165, P = 0.026) and HBV DNA levels >= 2000 IU/mL after 6 months of lamivudine therapy (hazard ratio 5.236, P = 0.001) were independent risk factors predicting VB. The cumulative VB rates stratified by HBeAg-positive and -negative at 3 years were 44.7% and 26.3%, respectively. At 3 years, the cumulative VB rates stratified by the HBV DNA < 2000 and >= 2000 IU/mL after 6 months of therapy were 25.5% and 79.4%, respectively. For HBeAg-positive patients with serum HBV DNA < 2000 IU/mL after 6 months of therapy, baseline HBsAg levels >= 20,000 IU/mL was the only risk factor associated with VB. CONCLUSIONS: For chronic hepatitis B patients treated with lamivudine, serum HBV DNA level > 2000 IU/mL after 6 months of therapy could predict subsequent VB. In patients with lower on-treatment viral load, baseline serum HBsAg level is associated with the emergence of VB, especially for those with serum positive HBeAg. PMID- 23730853 TI - Rhodium-catalyzed highly regioselective hydroaminomethylation of styrenes with tetraphosphorus ligands. AB - The highly linear-selective hydroaminomethylation of styrenes is very challenging. Herein, an efficient, highly chemoselective, and linear-selective hydroaminomethylation (l/b up to >99:1) of styrenes using Rh(nbd)2SbF6 with a pyrrole-based 3,3',5,5'-substituted tetraphosphorus ligand is documented. This is in sharp contrast to other available processes leading to branched amines and provides a novel atom economic approach to 3-arylpropylamines. PMID- 23730854 TI - Health status of hearing-impaired children and adolescents. AB - This descriptive study was conducted to identify factors that affect the general health status of hearing-impaired children and adolescents aged 6-18. One hundred six hearing-impaired students were sampled from two primary schools and a high school in Izmir, Turkey. The data were collected utilizing the Child Health Questionnaire (CHQ). Children and adolescents' physical health mean score and psychological health mean score were M = 47.4 +/- 10.2 and M = 49.4 +/- 9.5, respectively. Statistically significant differences in health status were found between the categories of age, mother's educational level and economic status of the family. The general health status of children and adolescents was found to be positive. PMID- 23730855 TI - Psychological and organizational impact of bullying over and above negative affectivity: a survey of two nursing contexts. AB - Limited research exists on the impact of bullying across psychological and/or organizationally orientated outcomes for nurses working within different nursing contexts. Research that has explored these outcomes has not considered the potential confounding effects of negative affectivity (NA). This study's aim was to examine the extent hospital and aged care nurses are impacted by bullying on these outcomes, while considering NA. A total of 267 hospital nurses/midwives and 168 aged care nurses from an Australian healthcare organization responded to a survey. The results revealed hospital nurses/midwives who experienced bullying reported higher levels of psychological distress, as well as lower commitment and job satisfaction levels. Aged care nurses who experienced bullying reported lower levels of well-being and commitment. NA was a significant covariate for most analyses. Thus, nurses across these contexts are affected by bullying in relation to psychological and organizational-orientated outcomes over and above the effects of NA, particularly for commitment. PMID- 23730856 TI - Evaluating a community-based stroke nursing education and rehabilitation programme for patients with mild stroke. AB - This study evaluated whether mild stroke patients who received a community-based stroke nursing intervention had better stroke knowledge, behaviour and self efficacy than those who were exposed to traditional education programmes. The intervention group consisted of sixty five stroke patients randomly selected from seven communities who received three 2-hour stroke interventions per week for 8 weeks. The normal care group consisted of sixty two stroke patients randomly selected from a medical centre who received a general stroke education programme. The stroke patients in two groups were assessed at baseline, after intervention and at the 6-month follow-up. At the 6-month follow-up, the intervention group demonstrated an improvement in the knowledge of stroke risk factors compared with the normal care group. Three months after education, the intervention group exhibited changes in the knowledge of stroke, social participation and self efficacy compared with those at baseline. Also, self-efficacy was correlated with the knowledge of stroke risk factors after intervention and at the 6-month follow up; self-efficacy was correlated with social participation after the 6-month follow-up. A community-based stroke nursing intervention might have effects on changes in the knowledge of stroke risk factors, social participation and self efficacy. PMID- 23730857 TI - Infusion volume control and calculation using metronome and drop counter based intravenous infusion therapy helper. AB - This study assessed the method of fluid infusion control using an IntraVenous Infusion Controller (IVIC). Four methods of infusion control (dial flow controller, IV set without correction, IV set with correction and IVIC correction) were used to measure the volume of each technique at two infusion rates. The infused fluid volume with a dial flow controller was significantly larger than other methods. The infused fluid volume was significantly smaller with an IV set without correction over time. Regarding the concordance correlation coefficient (CCC) of infused fluid volume in relation to a target volume, IVIC correction was shown to have the highest level of agreement. The flow rate measured in check mode showed a good agreement with the volume of collected fluid after passing through the IV system. Thus, an IVIC could assist in providing an accurate infusion control. PMID- 23730858 TI - The effect of reflexology applied on haemodialysis patients with fatigue, pain and cramps. AB - The research was conducted to evaluate the effect of foot reflexology on fatigue, pain and cramps in haemodialysis patients. The sample consisted of 80 patients in total, 40 intervention and 40 control patients, receiving treatment in the haemodialysis units of two institutions. Data were collected by using a questionnaire, Piper Fatigue Scale and visual analogue scale for measuring the severity of cramp and pain. The intervention group received reflexology treatment for 1 week in three sessions following haemodialysis, each session lasting approximately 30 min. Parametric and non-parametric tests were used in data analysis. It was determined that reflexology reduced the fatigue subscale scores and total scale scores as well as pain and cramp mean scores in the intervention group. The research results revealed that the severity of fatigue, pain and cramp decreased in patients receiving reflexology. PMID- 23730859 TI - Social support: the most important need of young Iranian single-parent widows on their path to widowhood. AB - Few researchers specifically focus on the sociocultural problems facing single parent widows in the process of becoming widow after spousal death. Scant research has also been done on the effects that these problems have on their well being. This study aims to investigate the sociocultural problems, responses and consequences experienced by Iranian widow/single-mothers. A qualitative exploratory study with a non-structured interview was used to collect the data from participants who consisted of 24 young Iranian single-parent widows. Using the constant comparative analysis method, the achieved results were summarized in three main categories: the facing of social problems, self-restriction and the consequences of social wearing, with some subcategories for the first and third categories. The findings could assist nurses in becoming aware of the sociocultural problems and their unhealthy psychosocial consequences so as to help them to better focus on them in their assessments and treatment, which in turn would empower the widows to adapt positively to widowhood and live hopefully. PMID- 23730860 TI - Construct validity and reliability of the Single Checking Administration of Medications Scale. AB - Research indicates that single checking of medications is as safe as double checking; however, many nurses are averse to independently checking medications. To assist with the introduction and use of single checking, a measure of nurses' attitudes, the thirteen-item Single Checking Administration of Medications Scale (SCAMS) was developed. We examined the psychometric properties of the SCAMS. Secondary analyses were conducted on data collected from 503 nurses across a large Australian health-care service. Analyses using exploratory and confirmatory factor analyses supported by structural equation modelling resulted in a valid twelve-item SCAMS containing two reliable subscales, the nine-item Attitudes towards single checking and three-item Advantages of single checking subscales. The SCAMS is recommended as a valid and reliable measure for monitoring nurses' attitudes to single checking prior to introducing single checking medications and after its implementation. PMID- 23730861 TI - Quality of life and anticipatory grieving among parents living with a child with cerebral palsy. AB - The purpose of this study was to describe the quality of life and anticipatory grieving among Jordanian parents living with a child with cerebral palsy. A cross sectional, descriptive, correlational design was used with 204 Jordanian parents. Both mothers and fathers were recruited from health-care centres that provided comprehensive care for children with cerebral palsy in Jordan and from schools for special education. Structured interviews were conducted using the Marwit and Meuser Caregiver Grief Inventory Cerebral Palsy and Quality of Life Index. The majority of the parents reported that providing care for a child with cerebral palsy is requiring more emotional energy and determination than ever expected. There was a significant negative correlation between total anticipatory grief score and total quality of life score and all subscales. This indicates that parents with high level of intensity of anticipatory grief had lower quality of life. No statistically significant differences were found in anticipatory grief and quality of life responses between mothers and fathers. The outcomes of this study have important implications for encouraging family-centred care and inform policy to improve the lives of children with cerebral palsy and their parents. PMID- 23730862 TI - Effects of a psychoeducational intervention for secondary prevention in Korean patients with coronary artery disease: a pilot study. AB - This intervention study was designed to examine whether a 12-week psychoeducational intervention influenced recurrent cardiac events, symptom experience and treatment adherence of patients with coronary artery disease. Fifty-eight patients were randomized to either the intervention or the control group. Measures were taken at baseline, after intervention, and at 6-month follow up. Recurrent cardiac events included revascularization, rehospitalization, emergency room visits and mortality. Symptom experiences were measured using the Seattle Angina Questionnaire-Korean and Hospital Anxiety and Depression Scale. Treatment adherence included health behaviours, routine check-up and medication adherence. At 6-month follow-up, the intervention group had significantly better physical functions and lower anxiety and depressive symptoms. Treatment adherence was also significantly higher in the intervention group than the control group. No significant difference was noticed in the incidence of recurrent cardiac events between the groups. A longer follow-up study is needed to determine the long-term effects on the prevention of recurrent cardiac events. PMID- 23730863 TI - Comparison of health-related quality of life and emotional distress among Chinese cancer survivors. AB - The purpose of this study is to compare health-related quality of life (HRQoL) and emotional distress among diverse cancer survivors who had completed all treatment within the previous year. A convenience sample of 353 cancers survivors (lung, head and neck, breast and prostate cancers) were recruited to complete a survey, which consisted of (i) Hospital Anxiety and Depression Scales; (ii) Chinese version of the Functional Assessment of Cancer Therapy-General version; and (iii) demographic and clinical data. The HRQoL scores were similar among the four types of survivors. Mild anxiety and depression levels were reported, but no significant difference was noted. Younger females with financial burdens and uncertain prognosis were particularly associated with HRQoL and emotional distress. Further studies are essential to identify specific problems that cancer patients experience after cancer diagnosis that might lead to the early detection of those most at risk of ongoing problems. PMID- 23730864 TI - The nature and course of illness perception following cardiac pacemaker implantation: a self-regulatory approach. AB - This study was designed to explore the relationship between illness perceptions and educational intervention based on the Leventhal's model in pacemaker patients. Fifty-one consecutive patients who were admitted for implantation of permanent cardiac pacemaker were recruited to receive an educational intervention, which consisted of two sessions delivered in the hospital and clinic, respectively. Participants completed a pacemaker-specific Brief Illness Perception Questionnaire (BIPQ) twice, one prior to educational intervention and the other 10 weeks following the pacemaker implantation. Data regarding the dimensions of cognitive and emotional representations based on the Leventhal's model have demonstrated the relationship between the patients' perception before and after the educational intervention. Overall, after the educational intervention, the patients have considered the illness as having a moderate impact on their life and have known their illness as a chronic condition that was responsive to treatment and influenced by personal behavior. Participants believed they had a good understanding of their illness and had less 'concern' and 'emotional representation'. Based on the results of the present study, pacemaker patients had a more benign view about their illness after educational intervention compared with before this intervention. These explanations might affect the acceptance and treatment seeking and even lead to lower complications. PMID- 23730865 TI - Patients' satisfaction with the care offered by advanced practice nurses: a new role in Swedish primary care. AB - The aim of this study is to describe patients' satisfaction with the new role of advanced practice nurses (APNs) in Swedish primary care. A questionnaire pertaining to patient satisfaction with the care offered by APNs was sent to respondents. Descriptive statistics, a chi-squared test and manifest qualitative content analysis were used during analysis. Although the results show an overall high level of patient satisfaction as regards APN-led care, those patients informed of the APN role prior to a consultation were significantly more satisfied. Respondents' comments indicate that professional treatment and competence are characteristic of the care offered by APNs and also relate the concepts of increased availability of and continuity in health care to the APN role. In order to guarantee the positive development of the APN role in Sweden, continued research is needed from patient, organizational and interprofessional perspectives, including intervention studies of cost effectiveness and the quality of care. PMID- 23730866 TI - Korean nurses' perceived facilitators and barriers in provision of end-of-life care. AB - This study examined nurses' perceived facilitators and barriers to end-of-life (EOL) care in clinical settings. The study participants were 383 Korean nurses working at tertiary hospitals. The nurses had an average of 7.6 years of clinical experience. The three highest-scoring facilitating items were 'family member acceptance of patient death', 'having time to prepare the family for the patient's expected death' and 'having the physician meet with the family after the patient's death to offer support and validate the given care'. The top two perceived barriers were 'families not accepting what the physician is telling them about the patient's prognosis' and 'dealing with angry family members'. Nurses who had received EOL care education showed a higher score in perception of facilitators than nurses who did not receive that education. EOL care for patients and their families is a challenge; thus, continuing education should be provided to improve nursing practice. PMID- 23730867 TI - Community nurses' perceptions of providing bereavement care. AB - This study explored the perceptions of bereavement support offered to clients and their carers and family by community nurses (CNs) in three community health centres located in a single area health service. In the context of an ageing population, it is pertinent to review CNs' perceptions in providing bereavement services. Early assessment and intervention is likely to prevent complicated grief occurring in the community. The bereavement support provided by CNs, considered here within a person-centred framework, enables identification of complicated grief. Semistructured interviews were held with 10 CNs and were transcribed verbatim. Transcriptions were analysed for major themes, and responses were grouped in relation to the study aims and themes emerging from the interviews. The themes discussed in this paper are as follows: the carer as a focus of palliative care; bereavement support as an outlet for carers; and the ending of the relationship between carers and CNs that is facilitated through bereavement support. The study provides evidence that supports the adoption of a model of bereavement support delivered by CNs as a means of reducing the likelihood of complicated grief occurring in the community. Further, the visits provide an important opportunity for nurses and carers to satisfactorily complete their relationship. PMID- 23730868 TI - The relationship between patient-provider communication and quality of life for children with asthma and their caregivers. AB - OBJECTIVE: This study examined whether patient-provider communication is associated with asthma-related quality of life (QOL) and asthma outcomes among children with asthma and their caregivers. METHODS: Children ages 8-16 years with asthma and their caregivers (n = 296) were recruited at five pediatric practices in North Carolina. Children and caregivers reported demographic and clinical characteristics immediately after an audio-taped medical visit with their health care provider. During a home visit that took place 1 month after the medical visit, children and caregivers reported asthma-related QOL, and caregivers reported child asthma outcomes, including asthma symptom days and missed school days. Generalized estimating equations were used to determine whether patient provider communication during the medical visit was associated with child and caregiver QOL and child asthma outcomes 1 month later. RESULTS: On average, providers asked caregivers 4.5 questions and asked children 3 questions per visit, whereas caregivers and children asked less than 1 question per visit. Providers asked children more asthma-related questions, caregivers reported better QOL and fewer asthma symptom days 1 month later. Children and caregivers with higher asthma-management self-efficacy at the office visit reported better QOL 1 month later. CONCLUSIONS: Mirroring national guideline recommendations, our results suggest that providers should ask children about their asthma during medical visits. Future longitudinal studies should conduct mediation analyses to determine whether asking children asthma-related questions during medical visits increases children's asthma management self-efficacy and ultimately improve outcomes, such as QOL, health care utilization, symptom days and missed school days. PMID- 23730869 TI - Ion mobility-mass spectrometry with a radial opposed migration ion and aerosol classifier (ROMIAC). AB - The first application of a novel differential mobility analyzer, the radial opposed migration ion and aerosol classifier (ROMIAC), is demonstrated. The ROMIAC uses antiparallel forces from an electric field and a cross-flow gas to both scan ion mobilities and continuously transmit target mobility ions with 100% duty cycle. In the ROMIAC, diffusive losses are minimized, and resolution of ions, with collisional cross-sections of 200-2000 A(2), is achieved near the nondispersive resolution of ~20. Higher resolution is theoretically possible with greater cross-flow rates. The ROMIAC was coupled to a linear trap quadrupole mass spectrometer and used to classify electrosprayed C2-C12 tetra-alkyl ammonium ions, bradykinin, angiotensin I, angiotensin II, bovine ubiquitin, and two pairs of model peptide isomers. Instrument and mobility calibrations of the ROMIAC show that it exhibits linear responses to changes in electrode potential, making the ROMIAC suitable for mobility and cross-section measurements. The high resolution of the ROMIAC facilitates separation of isobaric isomeric peptides. Monitoring distinct dissociation pathways associated with peptide isomers fully resolves overlapping peaks in the ion mobility data. The ability of the ROMIAC to operate at atmospheric pressure and serve as a front-end analyzer to continuously transmit ions with a particular mobility facilitates extensive studies of target molecules using a variety of mass spectrometric methods. PMID- 23730870 TI - Crystal engineering of green tea epigallocatechin-3-gallate (EGCg) cocrystals and pharmacokinetic modulation in rats. AB - The most abundant polyphenol in green tea, epigallocatechin-3-gallate (EGCg), has recently received considerable attention due to the discovery of numerous health promoting bioactivities. Despite reports of its poor oral bioavailability, EGCg has been included in many dietary supplement formulations. Conventional preformulation methods have been employed to improve the bioavailability of EGCg. However, these methods have limitations that hinder the development of EGCg as an effective therapeutic agent. In this study, we have utilized the basic concepts of crystal engineering and several crystallization techniques to screen for various solid crystalline forms of EGCg and evaluated the efficacy of crystal engineering for modulating the pharmacokinetics of EGCg. We synthesized and characterized seven previously undescribed crystal forms of EGCg including the pure crystal structure of EGCg. The aqueous solubility profiles of four new EGCg cocrystals were determined. These cocrystals were subsequently dosed at 100 mg EGCg per kg body weight in rats, and the plasma levels were monitored over the course of eight hours following the single oral dose. Two of the EGCg cocrystals were found to exhibit modest improvements in relative bioavailability. Further, cocrystallization resulted in marked effects on pharmacokinetic parameters including Cmax, Tmax, area under curve, relative bioavailability, and apparent terminal half-life. Our findings suggest that modulation of the pharmacokinetic profile of EGCg is possible using cocrystallization and that it offers certain opportunities that could be useful during its development as a therapeutic agent. PMID- 23730871 TI - Patterns of top-down control in a seagrass ecosystem: could a roving apex predator induce a behaviour-mediated trophic cascade? AB - 1. The loss of large-bodied herbivores and/or top predators has been associated with large-scale changes in ecosystems around the world, but there remain important questions regarding the contexts in which such changes are most likely and the mechanisms through which they occur, particularly in marine ecosystems. 2. We used long-term exclusion cages to examine the effects of large grazers (sea cows, Dugong dugon; sea turtles Chelonia mydas) on seagrass community structure, biomass and nutrient dynamics. Experiments were conducted in habitats with high risk of predation (interior of shallow banks) and lower risk (edges of banks) to elucidate whether nonconsumptive (risk) effects of tiger sharks (Galeocerdo cuvier), a roving predator, structure herbivore impacts on seagrasses. 3. In lower-risk habitats, excluding large herbivores resulted in increased leaf length for Cymodocea angustata and Halodule uninervis. C. angustata shoot densities nearly tripled when released from herbivory, while H. uninervis nearly disappeared from exclusion cages over the course of the study. 4. We found no support for the hypothesis that grazing increases seagrass nutrient content. Instead, phosphorus content was higher in seagrasses within exclosures. This pattern is consistent with decreased light availability in the denser C. angustata canopies that formed in exclosures, and may indicate that competition for light led to the decrease in H. uninervis. 5. Impacts of large grazers were consistent with a behaviour-mediated trophic cascade (BMTC) initiated by tiger sharks and mediated by risk-sensitive foraging by large grazers. 6, Our results suggest that large-bodied grazers likely played important roles in seagrass ecosystem dynamics historically and that roving predators are capable of initiating a BMTC. Conservation efforts in coastal ecosystems must account for such interactions or risk unintended consequences. PMID- 23730872 TI - The psychophysiology of mixed emotional states. AB - How to conceptualize mixed emotional states is a central issue in the field of affective science. Nondifferentiation, additive, and emergence accounts of mixed emotions make divergent predictions regarding physiological responses in mixed emotions. To test these predictions, 43 women watched film clips that elicited amusement, disgust, or mixed emotions while feeling self-report, facial electromyography, cardiovascular, electrodermal, and respiratory measures were assessed. Simultaneous self-reports of amusement and disgust confirmed elicitation of a mixed emotional state. Physiologically, mixed emotions differed from pure amusement and pure disgust both in intensity and pattern. This suggests a distinct physiological response of the mixed emotional state, as predicted by the emergence account of mixed emotions. Implications for emotion theory and research are discussed. PMID- 23730873 TI - Refractory autoimmune hemolytic anemia after intestinal transplant responding to conversion from a calcineurin to mTOR inhibitor. AB - AIHA is a rare and serious complication of solid organ transplantation. Herein, we report four cases of warm or mixed AIHA in pediatric patients following combined liver, small bowel and pancreas transplant. The hemolysis was refractory to multiple treatment modalities including steroids, rituximab, IVIG, plasmapheresis, cytoxan, discontinuation of prophylactic penicillin, and a change in immunosuppression from tacrolimus to cyclosporine. All patients had resolution or marked improvement of hemolysis after discontinuation of maintenance of CNI and initiation of sirolimus immunosuppression. One patient developed nephrotic syndrome but responded to a change in immunosuppression to everolimus. Three of the four patients continue on immunosuppression with sirolimus or everolimus without further hemolysis, evidence of rejection or medication side effects. Based on our experience and review of similar cases in the literature, we have proposed a treatment algorithm for AIHA in the pediatric intestinal transplant patient population that recommends an early change in immunosuppressive regimen from CNIs to sirolimus therapy. PMID- 23730874 TI - Laser capture microdissection shows HPV11 as both a causal and a coincidental infection in cervical cancer specimens with multiple HPV types. AB - AIMS: To identify, by laser capture microdissection (LCM), the cellular localization of HPV11 when present with carcinogenic HPV in invasive cervical cancer (ICC) specimens, and to relate this to p16(INK) (4a) expression. METHODS AND RESULTS: Three squamous cell ICC specimens showing coinfection with HPV11 and carcinogenic HPV16 or HPV31 were selected from the Institut Catala d'Oncologia international survey of anogenital carcinomas, and coinfection was confirmed by SPF10 -DEIA-LiPA25 analysis. In two cases LCM-PCR identified HPV11 in low-grade and high-grade squamous intraepithelial lesions (SILs) adjacent to the ICC, and HPV16 or HPV31 in the ICC. In one case, HPV11 was the only genotype found in the ICC. P16(INK) (4a) expression was diffuse in ICC associated with carcinogenic HPV, but focal in ICC with HPV11. CONCLUSIONS: Our results confirm that a single cervical, cancerous or precancerous lesion is associated with a single HPV type. Detecting low-risk HPV as a coinfection in whole tissue from ICC does not prove a causal association. HPV11 may be found only in an adjacent SIL with carcinogenic HPV in the ICC. It is also found alone in carcinoma. LCM-PCR and differential P16(INK) (4a) expression can clarify the causal role of each type when multiple HPVs are present in whole tissue from carcinomas. PMID- 23730875 TI - Behavior of drug excited states within macromolecules: binding of colchicine and derivatives to albumin. AB - The aqueous solutions of colchicine (COL) and analogues such as colchiceine (CEI), and N-deacetylcolchiceine (DCEI) have been studied by laser flash photolysis (LFP) with and without the presence of human serum albumin (HSA) to determine the possible interactions between the drugs and the albumin. When irradiation of these drugs was performed in aqueous media, transient absorption species were not detected. However, triplet excited states of CEI and DCEI were detected when the experiments were carried out in the presence of albumin. Contrary to expectations, in the case of COL, no transient absorption species was observed. A deep study of COL triplet excited-state properties has revealed that intersystem crossing quantum yield (phi(ISC)) decreases from organic media such as dichloromethane to water with phi(ISC) values ca. 0.035 and <0.001 respectively. This fact together the inappreciable reactivity of (3)COL with tyrosine and tryptophan agree with the unbinding of COL to HSA. This study will show for the first time a way to determine the association constant (K(a)) using the LFP technique. Thus, for CEI and DCEI binding to HSA, K(a) values of 8 +/- 3 * 10(4) M(-1) and 2 +/- 1 * 10(4) M(-1) were obtained, respectively. Moreover, it was also established that these drugs are mainly placed into site II of the albumin using this technique. Therefore, this study validates the LFP as a useful methodology to study the interactions of COL and its analogues with serum albumins, and consequently it could be applied to others proteins such as tubulin. PMID- 23730876 TI - Scaling up epidemics of acute hepatitis C and syphilis in HIV-infected men who have sex with men in Spain. AB - BACKGROUND: Outbreaks of acute hepatitis C in HIV-positive men who have sex with men (MSM) are being reported in large cities in western countries along with increasing rates of sexually transmitted diseases. METHODS: All HIV individuals attended at a large outclinic in Madrid within the last 5 years were examined. Incident syphilis was diagnosed based on rapid plasma reagin (RPR) reactivity, being negative previously or showing >4-fold increase. Acute hepatitis C was diagnosed based on HCV antibody seroconversion and/or positive serum HCV-RNA after being negative within the last year. RESULTS: A total of 859 episodes of syphilis and 19 of acute hepatitis C were diagnosed during the study period. Syphilis was recognized in 65/2,094 (3.1%) individuals attended in 2008 and rose up to 261/2,512 (10.4%) in 2012 (P < 0.001). Acute hepatitis C was diagnosed in only one subject in 2008 but rose up to 7 in 2012 (P = 0.12). All 19 HIV patients with acute hepatitis C were MSM. Syphilis was diagnosed concomitantly in seven. All eight individuals who were treated with peginterferon/ribavirin were cured, whereas only one untreated experienced spontaneous clearance (P = 0.004). Two clusters of infections by HCV genotypes 4 and 1a were identified by phylogenetic analyses. CONCLUSIONS: The incidence of acute hepatitis C is low but steadily increasing in HIV-positive MSM in Madrid (<1% yearly), despite the very high rates of syphilis (currently 20% yearly in HIV-positive MSM). Preventive measures for sexually transmitted infections and periodic HCV screening are warranted in this population as treatment of acute hepatitis C is very effective. PMID- 23730877 TI - Lipoxin A4: a new direction in asthma therapy? PMID- 23730878 TI - Ibrutinib: a strong candidate for the future of mantle cell lymphoma treatment. PMID- 23730880 TI - Rescue therapy: ciclosporin or infliximab? AB - Severe active refractory ulcerative colitis is a potentially life-threatening disease. The introduction of intensive steroid treatment and early surgery has reduced mortality in recent years. Ciclosporin and infliximab are effective rescue therapies in steroid refractory colitis. A head-to-head study proposed by Laharie et al. failed to demonstrate the superiority of ciclosporin but confirmed the efficacy and safety of infliximab to control active disease and to maintain remission. PMID- 23730881 TI - Beyond anti-TNF-alpha agents in psoriatic arthritis. AB - The IL-23/IL-17 pathway may be a novel therapeutic target for the treatment of psoriatic arthritis (PsA). The potential beneficial effect of Th-17A antagonism has been investigated by a randomized controlled trial in PsA patients with secukinumab, a fully human, high-affinity, monoclonal antibody in a cohort of patients with active PsA. Although this Phase II study presents bias that limits the ability of this drug to meet the primary and some secondary end points, the authors suggest that secukinumab may have biological effects and some clinical benefits in PsA patients. Further studies are required to demonstrate if the rationale to use drugs acting on the IL-23/IL-17 pathway is associated with relevant efficacy and safety in the treatment of PsA. PMID- 23730882 TI - Spondyloarthritis and smoking: towards a new insight into the disease. AB - In spondyloarthritis, smoking was found in several studies from the literature to be associated with earlier onset, more severe disease in activity, function, quality of life and imaging (inflammatory and structural lesions), sometimes in a dose-dependent manner. Smoking is also associated with elevated inflammatory biologic parameters (e.g., C-reactive protein). Periodontitis, associated with smoking, is more frequent in patients with ankylosing spondylitis as compared with controls. This periodontal disease may favor citrullination, as in rheumatoid arthritis. Citrullinated vimentin has been demonstrated to be associated with radiographic damage. In this line, smoking was found to be associated with matrix metalloproteinase levels, which is also a predictive factor for spinal radiographic progression. Finally, smoking has a negative influence on bronchopulmonary and cardiovascular outcomes, already impaired by the disease itself. Smoking represents a target for therapeutic impact and disease modification in spondyloarthritis. PMID- 23730883 TI - 1,25-dihydroxyvitamin D in the pathogenesis of Barrett's esophagus and esophageal adenocarcinoma. AB - The incidence of reflux-related esophageal disease - Barrett's esophagus and esophageal adenocarcinoma - is rising, and the prognosis remains poor. Evidence exists that 1,25-dihydroxyvitamin D may augment the course of colon, breast and prostate cancer but little knowledge exists regarding its impact on disease of the esophagus. Important immune cells involved in reflux-related esophageal disease include CD4(+) T cells, macrophages and dendritic cells, and key signaling pathways include Wnt, Hedgehog, NFkappa-B and IL-6-JAK-STAT. There is an inter-relationship between these entities and 1,25-dihydroxyvitamin D, which has been described in animal models and some human tissue. Despite this, there is an incomplete understanding of how the immune cell population and signaling pathways contribute to the course and prognosis of Barrett's esophagus and esophageal adenocarcinoma. More investigation with a focus on the clinical outcomes of patients with Barrett's esophagus and esophageal adenocarcinoma and the immune cell population and cell signaling activity in the diseased esophagus is necessary to determine the immunomodulatory role of 1,25-dihydroxyvitamin D in the pathogenesis of esophageal diseases. PMID- 23730884 TI - The road to remyelination in demyelinating diseases: current status and prospects for clinical treatment. AB - Within CNS disorders, demyelinating diseases are among the most devastating and cost intensive due to long-term disabilities affecting relatively young patients. Multiple sclerosis, a chronic inflammatory demyelinating disease in which the persistent inhibitory microenvironment of the resident oligodendrocyte precursor cells abrogates regeneration of myelin sheaths, is the most prominent disease in the spectrum of demyelinating diseases. The essential goal is to stimulate creation of new myelin sheaths on the demyelinated axons, leading to restoration of saltatory conduction and resolving functional deficits. The past few decades witnessed significant efforts to understand the cellular interactions at the lesion site with studies suggesting efficient remyelination as a prerequisite for functional repair. Despite its proven efficacy in experimental models, immunosuppression has not had profound clinical consequences in multiple sclerosis, which argued for a paradigm shift in the design of therapeutics aiming to achieve remyelination. For example, targeting oligodendrocytes themselves may drive remyelination in the CNS. This group and others have demonstrated that natural autoreactive antibodies directed at oligodendrocyte progenitors participate in remyelination. Accordingly, the authors developed a recombinant autoreactive natural human IgM antibody with therapeutic potential for remyelination. PMID- 23730885 TI - Recent advances in the diagnosis and therapy of peanut allergy. AB - Peanut allergy is a life-threatening, IgE-mediated allergic disease. In developed countries, the prevalence rate of peanut allergy in school-aged children is reported to be in excess of 1% and continues to rise, representing a major public health concern. Peanut allergy is diagnosed on the basis of a relevant clinical history combined with results of skin-prick testing and/or peanut-specific IgE levels. A double-blind placebo-controlled oral food challenge is the gold standard for diagnosis. Currently, there is no approved treatment or disease modifying therapy for peanut allergy. This review discusses recent advances in molecular diagnostic techniques for peanut allergy and highlights advances in peanut allergy therapeutics, discussing allergen-specific and allergen nonspecific treatments that are currently in Phase I/II clinical trials. PMID- 23730886 TI - A review on guidelines for management and treatment of common variable immunodeficiency. AB - Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency in adults. As symptoms of CVID are usually heterogeneous and unspecific, diagnosis and follow-up of CVID can be challenging. In light of this, a broad review of advances in management and treatment of CVID is performed here in order to reach a distinct protocol. However, it should be noted that owing to the nature of the disease, it can only be treated symptomatically but not cured. There is little evidence to guide appropriate or universal guidelines to improve the current status of management of the disease. The most satisfactory treatments of CVID could be achieved by the use of immunoglobulin replacement, antibiotics, immunosuppressants and hematopoietic stem cell transplantation. This review is written based on the importance of clinical surveillance of asymptomatic CVID cases and early recognition of different clinical complications. Moreover, for each complication, appropriate interventions for improving outcomes are mentioned. PMID- 23730887 TI - Improving patient tolerability in immunoglobulin treatment: focus on stabilizer effects. AB - Various types of excipients are added to immunoglobulin preparations to stabilize the product and prevent aggregation and dimer formation. These excipients, which are also called stabilizers or additives, are not inert chemicals and may have clinical implications. This is one reason why immunoglobulin products are not interchangeable. Herein, immunoglobulin preparation, excipient types and the differences among sugar stabilizers and the amino acids, glycine and proline as excipients, are presented. Preclinical studies that unravel the complexities of dimer reduction are summarized. Details of patient considerations with respect to excipient content are outlined focusing on patients with renal insufficiency, diabetes, corn allergy, hereditary fructose intolerance, inborn errors of proline metabolism, DiGeorge Syndrome and neuropsychiatric disorders associated with hyperprolinemia. Excipients are essential components of immunoglobulin preparations and their presence should be a consideration when matching patient needs to product characteristics. PMID- 23730889 TI - Risk factors for developing heterotopic ossification in patients with traumatic brain injury. AB - OBJECTIVE: To evaluate the possible risk factors of heterotopic ossification (HO) in traumatic brain injury (TBI) patients. METHODS: A total of 151 patients with TBI were included. Demographical variables, laboratory investigations and risk factors for HO including spasticity, walking ability (using Functional Ambulation Category (FAC)), pressure ulcer, neurogenic bladder and systemic infection were recorded. RESULTS: Fifty-six patients (37.1%) had HO. Time since injury and serum ALP and ESR levels were significantly higher in HO patients than in non-HO patients. Hip (73.2%) and knee (44.6%) were the most commonly involved joints. This study has detected significant associations between FAC scores (FAC 0-1-2 vs. FAC 3-4-5, p < 0.001), degree of spasticity (p = 0.01), pressure ulcer (Absent/Grade 1 vs. Grade 2, 3 and 4, p = 0.001), presence of neurogenic bladder (p < 0.001) and systemic infection (p = 0.002) with the development of HO. According to the final logistical regression analysis, only lower FAC score was independently associated with HO development (p = 0.006). CONCLUSION: As lower scores of FAC is an independent risk factor for HO formation and is related to the severity and consequences of injury, ambulation and regular/cautious mobilization of the joints are of paramount importance in the early period of the rehabilitation in TBI patients. PMID- 23730890 TI - Feeling like me again: a grounded theory of the role of breast reconstruction surgery in self-image. AB - The present study aimed to develop a theoretical understanding of the role of breast reconstruction in women's self-image. Semi-structured interviews were conducted with 10 women from breast cancer support groups who had undergone breast reconstruction surgery. A grounded theory methodology was used to explore their experiences. The study generated a model of 'breast cancer, breast reconstruction and self-image', with a core category entitled 'feeling like me again' and two principal categories of 'normal appearance' and 'normal life'. A further two main categories, 'moving on' and 'image of sick person' were generated. The results indicated a role of breast reconstruction in several aspects of self-image including the restoration of pre-surgery persona, which further promoted adjustment. PMID- 23730891 TI - Hybrid artificial photosynthetic systems comprising semiconductors as light harvesters and biomimetic complexes as molecular cocatalysts. AB - Solar fuel production through artificial photosynthesis may be a key to generating abundant and clean energy, thus addressing the high energy needs of the world's expanding population. As the crucial components of photosynthesis, the artificial photosynthetic system should be composed of a light harvester (e.g., semiconductor or molecular dye), a reduction cocatalyst (e.g., hydrogenase mimic, noble metal), and an oxidation cocatalyst (e.g., photosystem II mimic for oxygen evolution from water oxidation). Solar fuel production catalyzed by an artificial photosynthetic system starts from the absorption of sunlight by the light harvester, where charge separation takes place, followed by a charge transfer to the reduction and oxidation cocatalysts, where redox reaction processes occur. One of the most challenging problems is to develop an artificial photosynthetic solar fuel production system that is both highly efficient and stable. The assembly of cocatalysts on the semiconductor (light harvester) not only can facilitate the charge separation, but also can lower the activation energy or overpotential for the reactions. An efficient light harvester loaded with suitable reduction and oxidation cocatalysts is the key for high efficiency of artificial photosynthetic systems. In this Account, we describe our strategy of hybrid photocatalysts using semiconductors as light harvesters with biomimetic complexes as molecular cocatalysts to construct efficient and stable artificial photosynthetic systems. We chose semiconductor nanoparticles as light harvesters because of their broad spectral absorption and relatively robust properties compared with a natural photosynthesis system. Using biomimetic complexes as cocatalysts can significantly facilitate charge separation via fast charge transfer from the semiconductor to the molecular cocatalysts and also catalyze the chemical reactions of solar fuel production. The hybrid photocatalysts supply us with a platform to study the photocatalytic mechanisms of H2/O2 evolution and CO2 reduction at the molecular level and to bridge natural and artificial photosynthesis. We demonstrate the feasibility of the hybrid photocatalyst, biomimetic molecular cocatalysts, and semiconductor light harvester for artificial photosynthesis and therefore provide a promising approach for rational design and construction of highly efficient and stable artificial photosynthetic systems. PMID- 23730892 TI - Comparable effects of capsaicin-containing red pepper sauce and hydrochloric acid on secondary peristalsis in humans. AB - BACKGROUND AND AIM: We aimed to evaluate whether acute esophageal instillation of capsaicin and hydrochloric acid had different effects on distension-induced secondary peristalsis. METHODS: Secondary peristalsis was induced by slow and rapid air injections into the mid-esophagus after the evaluation of baseline motility in 16 healthy subjects. The effects on secondary peristalsis were determined by esophageal instillation with capsaicin-containing red pepper sauce (pure capsaicin, 0.84 mg) and hydrochloric acid (0.1 N). RESULTS: The administration of capsaicin induced a significant increase in the visual analogue scale score for heartburn as compared with hydrochloric acid (P = 0.002). The threshold volume for generating secondary peristalsis during slow and rapid air distensions did not differ between capsaicin and hydrochloric acid infusions. Hydrochloric acid significantly increased the frequency of secondary peristalsis in response to rapid air distension compared with capsaicin infusion (P = 0.03). Pressure wave amplitude during slow air distension was greater with the infusion of hydrochloric acid than capsaicin infusion (P = 0.001). The pressure wave duration during rapid air distension was longer after capsaicin infusion than hydrochloric acid infusion (P = 0.01). The pressure wave amplitude during rapid air distension was similar between capsaicin and hydrochloric acid infusions. CONCLUSIONS: Despite subtle differences in physiological characteristics of secondary peristalsis, acute esophageal instillation of capsaicin and hydrochloric acid produced comparable effects on distension-induced secondary peristalsis. Our data suggest the coexistence of both acid- and capsaicin sensitive afferents in human esophagus which produce similar physiological alterations in secondary peristalsis. PMID- 23730893 TI - Leveraging tobacco control research in India: the need for setting up a tobacco control research network. PMID- 23730894 TI - Biomembrane simulations of 12 lipid types using the general amber force field in a tensionless ensemble. AB - The AMBER family of force fields is one of the most commonly used alternatives to describe proteins and drug-like molecules in molecular dynamics simulations. However, the absence of a specific set of parameters for lipids has been limiting the widespread application of this force field in biomembrane simulations, including membrane protein simulations and drug-membrane simulations. Here, we report the systematic parameterization of 12 common lipid types consistent with the General Amber Force Field (GAFF), with charge-parameters determined with RESP at the HF/6-31G(d) level of theory, to be consistent with AMBER. The accuracy of the scheme was evaluated by comparing predicted and experimental values for structural lipid properties in MD simulations in an NPT ensemble with explicit solvent in 100:100 bilayer systems. Globally, a consistent agreement with experimental reference data on membrane structures was achieved for some lipid types when using the typical MD conditions normally employed when handling membrane proteins and drug-membrane simulations (a tensionless NPT ensemble, 310 K), without the application of any of the constraints often used in other biomembrane simulations (such as the surface tension and the total simulation box area). The present set of parameters and the universal approach used in the parameterization of all the lipid types described here, as well as the consistency with the AMBER force field family, together with the tensionless NPT ensemble used, opens the door to systematic studies combining lipid components with small drug-like molecules or membrane proteins and show the potential of GAFF in dealing with biomembranes. PMID- 23730895 TI - Spontaneous phase transformation and exfoliation of rectangular single-crystal zinc hydroxy dodecylsulfate nanomembranes. AB - Free-standing two-dimensional (2D) nanostructures, exemplified by graphene and semiconductor nanomembranes, exhibit exotic electrical and mechanical properties and have great potential in electronic applications where devices need to be flexible or conformal to nonplanar surfaces. Based on our previous development of a substrate-free synthesis of large-area, free-standing zinc hydroxy dodecylsulfate (ZHDS) hexagonal nanomembranes, herein, we report a spontaneous phase transformation of ZHDS nanomembranes under extended reaction time. The hexagonal ZHDS sheets transformed into rectangular single crystal nanomembranes with sizes of hundreds of micrometers. They contain long-range-ordered zinc vacancies that can be fitted into an orthorhombic superlattice. A surplus of dodecylsulfate ions and a deficit of Zn(2+) diffusion near the water surface are believed to be the factors that drive the phase transformation. The phase transformation starts with the formation of zinc vacancies at the topmost layer of the hexagonal hillock, and propagates along the spiral growth path of the initial hexagonal sheets, which bears a great resemblance to the classic "periodic slip process". Mechanical property characterization of ZHDS nanomembranes by nanoindentation shows they behave much like structural polymers mechanically due to the incorporation of surfactant molecules. We also developed a one-step exfoliation and dehydration method that converts ZHDS nanomembranes to ZnO nanosheets using n-butylamine. This work provides a further understanding of the growth and stability of ZnO-based nanomembranes, as well as advisory insight for the further development on solution-based synthesis of free-standing, single crystalline 2D nanostructures. PMID- 23730896 TI - Control of transient aluminum-aminals for masking and unmasking reactive carbonyl groups. AB - A new reagent, the dimethylaluminum N,O-dimethylhydroxylamine complex, is effective at masking reactive carbonyl groups in situ from nucleophilic addition. This reagent allows chemoselective addition of reducing reagents, Grignard reagents, organolithiums, Wittig reagents, and enolates into substrates with multiple carbonyl groups. Moreover, the trapped carbonyl group, a stable aminal, can be unmasked in situ for additional synthetic manipulations. PMID- 23730897 TI - Response to comment on "Constraining nitrogen inputs to urban streams from leaking sewers using inverse modeling: implications for DIN retention in urban environments". PMID- 23730898 TI - A new indicator of the oral hygiene habits of disabled persons: relevance of the carer's personal appearance and interest in oral health. AB - OBJECTIVE: To investigate whether there is a relationship between the oral hygiene habits of individuals with severe disability the carer's personal appearance and interest in oral health. PATIENTS AND METHODS: The study group was formed of 60 disabled persons and their respective carers who came for the first time to consultation in the Special-Needs Dentistry Unit of the University of Santiago de Compostela, Spain. All the carers answered a standardised questionnaire of 28 questions divided into four sections: disabled individual's demographic data, disabled individual's general medical details, social aspects of the carer (personal appearance of the carer and interest in oral health), and disabled individual's oral hygiene habits. The personal appearance of the carers and their interest in the disabled individual's oral health were evaluated using independent scales designed specifically for the study, with five binary items in each scale. RESULTS: The carer's personal appearance and interest in the disabled individual's oral health showed a statistically significant relationship with the individual's oral hygiene habits, particularly with respect to the frequency and duration of toothbrushing, need for physical restraint during toothbrushing, use of a manual toothbrush and use of toothpaste. CONCLUSIONS: The carer's personal appearance and interest in the disabled individual's oral health are good indicators of the oral hygiene habits of an individual with severe disability. Consideration should be given to the inclusion of these aspects as a complementary element of the dental record. PMID- 23730899 TI - Effect of a school environment intervention on adolescent adiposity and physical fitness. AB - The aim of this study was to evaluate the effect of an intervention targeting the physical and organizational school environment for noncurricular physical activity (SPACE) on adiposity, aerobic fitness, and musculo-skeletal strength in Danish adolescents. The study used a cluster randomized controlled design. Fourteen schools and 1348 adolescents aged 11-14 years were included at baseline. Seven schools were randomized to the intervention, which was designed to change the organizational and physical environment of the school. The analysis revealed no significant differences between the adolescents in the intervention group compared to the comparison group after a 2-year follow-up. Adjusted for baseline, sex, age, and clustering within schools, the difference between the intervention schools compared to the comparison schools was 6 m in the shuttle run test [95% confidence interval (CI): -21; 33], 0.2 cm in waist circumference (95% CI: -2.6; 3.1), and -1.1 kg in handgrip strength (95% CI: -2.2; -0.1). The results did not provide evidence for the effect of the intervention on adiposity, aerobic fitness, or musculo-skeletal strength in adolescents. Reasons for not finding an effect could be related to both the design and the implementation of the intervention. PMID- 23730900 TI - Cyclin D1-induced proliferation is independent of beta-catenin in head and neck cancer. AB - OBJECTIVE: Head and neck squamous cell carcinoma (HNSCC) progression and metastasis have previously been associated with the activation of phosphatidylinositol 3-kinase-protein kinase B (PI3K-Akt) and Wnt signalling pathways, which lead to the activation of pro-proliferative genes, such as cyclin D1. The current study aims to investigate whether there is a crosstalk between these pathways in HNSCC and which pathway is more likely to regulate cyclin D1. MATERIAL AND METHODS: Two HNSCC and a control keratinocyte cell lines were treated with EGF and wortmannin to respectively activate and block the PI3K-Akt and Wnt pathways. Partial and total levels of cyclin D1, beta-catenin and Akt were evaluated by Western blotting and immunofluorescence. Twenty-four paraffin embedded samples of human HNSCC, as well as normal oral mucosa biopsies, were also immunohistochemically evaluated for beta-catenin and cyclin D1 expression. RESULTS: Following both treatments, change in cyclin D1 protein was correlated with Akt levels only. Cytoplasmic staining for beta-catenin and loss of its membranous expression in the HNSCC invasive areas were found in 92% of the HNSCC biopsies. CONCLUSION: Taken together, we show that the change in cyclin D1 levels is more likely to be due to the EGFR-Akt pathway activation than due to beta catenin nuclear translocation. PMID- 23730901 TI - Causes and prevalence of unplanned readmissions after colorectal surgery: a systematic review and meta-analysis. AB - A systematic review and meta-analysis of the current literature was conducted to compare the overall and cause-specific readmission rates after colorectal surgery of older adults with those of younger individuals. Potential predictors of unplanned readmission were also identified. Estimated pooled readmission rates were calculated and reported as pooled proportions with associated 95% confidence intervals (CI) in 60,131 total readmissions; 11.0% (95% CI = 10.0-12.0) of all admissions after colorectal surgery resulted in unplanned readmission at 30 days. Older adults had a lower rate of readmission than younger individuals. Bowel obstruction was the most common cause of unplanned readmission, accounting for 33.4% of all unplanned readmissions, followed by surgical site infection (15.7%) and intraabdominal abscess (12.6%). Several age-related predictors of unplanned readmission were identified, such as poor functional capacity, multiple comorbidities, chronic obstructive pulmonary disease, and discharge to a nonhome destination. The findings of this review will help guide the development of future interventions to reduce preventable readmissions after colorectal surgery in older adults. PMID- 23730902 TI - Determination of tear and serum inflammatory cytokines in patients with rosacea using multiplex bead technology. AB - PURPOSE: To compare serum and tear inflammatory and anti-inflammatory cytokine levels of rosacea patients with the healthy controls and evaluate the correlation of tear cytokine levels with tear function parameters. METHODS: Tear and serum interleukin (IL)-1alpha, IL-6, IL-8, IL-10, monocyte chemotactic protein-1 (MCP 1), macrophage inflammatory protein-1alpha (MIP-1alpha), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) levels were measured using multiplex bead (Luminex) technology in 12 rosacea patients without ocular involvement (group 1), 20 rosacea patients with ocular involvement (group 2), and 22 healthy subjects (group 3). The correlation of the cytokines with tear function parameters was analyzed using Spearman correlation test. RESULTS: Tear IL-10 and VEGF levels were significantly lower in group 1 (median: 35.78 pg/mL and 427.29, respectively) and group 2 (median: 26.25 pg/mL and 348.31, respectively) than in group 3 (median: 75.96 pg/mL and 480.12, respectively) (p < 0.05). Mean serum IL-8 level was significantly lower in group 2 (median = 0) compared to group 3 (median = 3.98) (p = 0.02). Tear breakup time was found to be positively correlated with IL-10 (r = 0.46, p = 0.013) and inversely correlated with MCP-1 (r = -0.52, p = 0.004). CONCLUSIONS: Tear and serum levels of cytokines and growth factors measured with Luminex technology showed a large variation in rosacea and healthy subjects. Decreased levels of tear IL-10, an anti-inflammatory cytokine, may lead to an inflammatory ocular surface environment, exacerbate ocular surface inflammation, and deteriorate tear function tests. A bigger sample size, including rosacea patients with corneal involvement, is needed to confirm the role of cytokines in the pathogenesis of rosacea-associated ocular inflammation. PMID- 23730903 TI - Synergistic interaction of paclitaxel and curcumin with cyclodextrin polymer complexation in human cancer cells. AB - The use of cytotoxic chemotherapic agents is the most common method for the treatment of metastatic cancers. Poor water solubility and low efficiency of chemotherapic agents are among the major hurdles of effective chemotherapy treatments. Curcumin and paclitaxel are well-known chemotherapic agents with poor water solubility and undesired side effects. In this study, a novel drug nanocarrier system was formulated by encapsulating curcumin and paclitaxel in poly(beta-cyclodextrin triazine) (PCDT) for the therapy of four cancer models; ovarian, lung, prostate, and breast cancer. Cell viability and colony formation assays revealed enhanced curcumin cytotoxicity upon complexation. Annexin V apoptotic studies showed that the PCDT complexation improved curcumin induced apoptosis in human ovarian cancer cell lines A2780 and SKOV-3, human nonsmall cell lung carcinoma cell line H1299, and human prostate cancer line DU-145, while no significant effect was observed with paclitaxel/PCDT complexation. The bioactivity of combining curcumin and paclitaxel was also investigated. A synergism was found between curcumin and paclitaxel, particularly when complexed with PCDT on A2780, SKOV-3, and H1299 cancer cell lines. PMID- 23730904 TI - Exploring united airways. PMID- 23730905 TI - Different models of transition to adult care after pediatric kidney transplantation: a comparative study. AB - Transition from pediatric to adult care is a critical and difficult step for young people with transplants and for the multidisciplinary team involved. In our retrospective study, we investigated the clinical course in a two-yr period of transition. Data from 66 teenagers were collected one yr before and after their transfer to three different adult care settings: (i) a specialized transition clinic, (ii) a general transplantation clinic, and (iii) a nephrologist. Patient survival rate was 100%. Three patients developed graft loss. GFR development was comparable in the three settings (DeltaGFR 1.4 +/- 8.7 vs. 3.1 +/- 10.6 vs. 0.8 +/- 4.4 mL/min/1.73 m2 , p = ns). Immunosuppressive therapy was stable in setting 1, whereas the number of changes increased in setting 2 and even more in setting 3. The percentage of patients with steroids increased from 36% to 38% and 52% in settings 1-3. Patient satisfaction was highest in setting 1 (100% vs. 64% and 78%, p < 0.05). Setting 1 was associated with fewer changes in therapy (13% vs. 91% and 45%, p < 0.05). The use of a specialized transition clinic is associated with fewer changes in medication and care and a higher level of patient satisfaction. This was not associated with a lower increase in GFR one yr after transition. Long-term results are awaited. PMID- 23730906 TI - Expression of the tumour-suppressor maspin in temporal bone carcinoma. AB - AIMS: Although it accounts for fewer than 0.2% of all head and neck tumours, temporal bone squamous cell carcinoma (SCC) is an aggressive malignancy with a poor prognosis in advanced cases. Novel therapeutic strategies should be developed focusing on specific targeted therapies. Maspin is a serpin showing tumour-suppressing activity which has therapeutic potential. The present study is the first to investigate maspin expression in temporal bone SCCs, using a series of 29 cases. METHODS AND RESULTS: Cytoplasmic maspin expression was significantly higher in the group of patients whose SCC did not recur than in the group experiencing recurrences (P = 0.029), and in G1-G2 SCCs than in G3 cases (P = 0.001). cT correlated with recurrence rate (P = 0.05), disease-free survival (DFS) (P = 0.008) and disease-specific survival (DSS) (P = 0.0043), and pT and pathological regional lymph node status correlated with recurrence rate (P = 0.008 and P = 0.03, respectively), DFS (P = 0.017 and P = 0.0049, respectively) and DSS (P = 0.008 and P = 0.0009, respectively). CONCLUSIONS: Although further studies using larger series are required, our preliminary findings suggest that cytoplasmic maspin expression has promise as a prognostic indicator of disease recurrence in temporal bone SCC, and that reactivating maspin functions in association with apoptosis-inducing or anti-angiogenic chemotherapeutic agents might be an important goal in the treatment of temporal bone SCC. PMID- 23730907 TI - How do people adhere to goals when willpower is low? The profits (and pitfalls) of strong habits. AB - Across 5 studies, we tested whether habits can improve (as well as derail) goal pursuit when people have limited willpower. Habits are repeated responses automatically triggered by cues in the performance context. Because the impetus for responding is outsourced to contextual cues, habit performance does not depend on the finite self-control resources required for more deliberative actions. When these resources are limited, people are unable to deliberatively choose or inhibit responses, and they become locked into repeating their habits. Thus, depletion increases habit performance. Furthermore, because the habit-cuing mechanism is blind to people's current goals, depletion should boost the performance of both desirable and undesirable habits. This habit boost effect emerged consistently across experiments in the field (Studies 1-2) and in the laboratory (Studies 3-4), as well as in a correlational study using a trait measure of self-control (Study 5). Given that many of people's habits in daily life are congruent with their goals, habit processes can improve goal adherence when self-control is low. PMID- 23730909 TI - Total synthesis of aplyronine C. AB - A highly stereocontrolled total synthesis of the cytotoxic marine macrolide aplyronine C is described. The route exploits aldol methodology to install the requisite stereochemistry and features a crucial boron-mediated aldol coupling of an N-vinylformamide-bearing methyl ketone with a macrocyclic aldehyde to introduce the full side chain. The synthesis of two novel C21-C34 side chain analogs is also reported. PMID- 23730910 TI - Compound aggregation in drug discovery: implementing a practical NMR assay for medicinal chemists. AB - The pharmaceutical industry has recognized that many drug-like molecules can self aggregate in aqueous media and have physicochemical properties that skew experimental results and decisions. Herein, we introduce the use of a simple NMR strategy for detecting the formation of aggregates using dilution experiments that can be performed on equipment prevalent in most synthetic chemistry departments. We show that (1)H NMR resonances are sensitive to large molecular size entities and to smaller multimers and mixtures of species. Practical details are provided for sample preparation and for determining the concentrations of single molecule, aggregate entities, and precipitate. The critical concentrations above which aggregation begins can be found and were corroborated by comparisons with light scattering techniques. Disaggregation can also be monitored using detergents. This NMR assay should serve as a practical and readily available tool for medicinal chemists to better characterize how their compounds behave in aqueous media and influence drug design decisions. PMID- 23730911 TI - Coarse-grained simulations of RNA and DNA duplexes. AB - Although RNAs play many cellular functions, little is known about the dynamics and thermodynamics of these molecules. In principle, all-atom molecular dynamics simulations can investigate these issues, but with current computer facilities, these simulations have been limited to small RNAs and to short times. HiRe-RNA, a recently proposed high-resolution coarse-grained RNA that captures many geometric details such as base pairing and stacking, is able to fold RNA molecules to near native structures in a short computational time. So far, it had been applied to simple hairpins, and here we present its application to duplexes of a couple dozen nucleotides and show how with replica exchange molecular dynamics (REMD) we can easily predict the correct double helix from a completely random configuration and study the dissociation curve. To show the versatility of our model, we present an application to a double stranded DNA molecule as well. A reconstruction algorithm allows us to obtain full atom structures from the coarse grained model. Through atomistic molecular dynamics (MD), we can compare the dynamics starting from a representative structure of a low temperature replica or from the experimental structure, and show how the two are statistically identical, highlighting the validity of a coarse-grained approach for structured RNAs and DNAs. PMID- 23730912 TI - Normative data of high-resolution impedance manometry in the Chinese population. AB - BACKGROUND AND AIM: Current normative data of high-resolution manometry have been obtained from Western populations, and esophageal motility disorders have been categorized using Chicago classification. However, the utility of high-resolution impedance manometry (HRiM) in the Chinese population has not been evaluated. The study aimed to investigate the normal reference of esophageal motility in healthy volunteers (as defined by Chicago classification) using HRiM. METHODS: Healthy, fasted volunteers underwent HRiM in a supine position with 10 liquid swallows and 10 viscous swallows. Integrated relaxation pressure (IRP), distal contractile integral (DCI), contractile front velocity (CFV), and distal latency were calculated. The interquartile ranges and the 95th percentile range for each metric were obtained. RESULTS: Forty-two healthy volunteers were enrolled with 411 total liquid swallows and 398 viscous swallows available for analysis. A 20.5 mmHg of IRP and a 3195 mmHg.s.cm of DCI as the 95th percentile for liquid swallows were established. Using the reference range defined by Chicago classification, 6.3% (26/411) weak peristalsis and 0.7% (3/411) failed peristalsis for liquid swallows were observed; 12 (28.6%, 12/42) and 2 (4.7%, 2/42) individuals were diagnosed as esophagogastric junction outflow obstruction and weak peristalsis for liquid swallows. Compared with liquid swallows, viscous swallows had a decreased IRP (P = 0.000) and CFV (P = 0.000), and an unchanged DCI (P = 0.211). CONCLUSIONS: HRiM normative data of both liquid and viscous swallows from healthy Chinese volunteers were established. The IRP and CFV were significantly decreased in the viscous swallows compared with those of the liquid swallows. PMID- 23730913 TI - Asthma and attention-deficit/hyperactivity disorder: a nationwide population based prospective cohort study. AB - BACKGROUND: Previous cross-sectional studies have suggested an association between asthma and attention-deficit/hyperactivity disorder (ADHD), but the temporal relationship was not determined. Using a nationwide population-based prospective case-control cohort study (1:4, age-/gender-matched), we hypothesized that asthma in infanthood or early childhood would increase the risk of ADHD in later life. METHODS: In all, 2,294 children with asthma and 9,176 controls aged between 0 and 3 years in 2000 were included in our study. Cases of ADHD that occurred to the end of follow-up (31 December 2010) were identified. RESULTS: Children with asthma had a higher incidence of developing ADHD (7% vs. 4.6%, p < .001) than control cohort during the follow-up period. After adjusting for age at enrollment, gender, level of urbanization, and comorbid allergic diseases (allergic rhinitis and atopic dermatitis), children with asthma had an elevated risk (HR: 1.31, 95% CI: 1.07-1.59) of developing ADHD compared with control group. DISCUSSION: Our prospective study supported a temporal relationship between asthma and ADHD. Asthma in very early life increased the risk of developing ADHD during the school years. Further studies are required to investigate whether the prompt treatment of asthma and comorbid allergic diseases could prevent the development of ADHD or decrease ADHD symptoms. PMID- 23730917 TI - Ion conductivity and transport by porous coordination polymers and metal-organic frameworks. AB - Ion conduction and transport in solids are both interesting and useful and are found in widely distinct materials, from those in battery-related technologies to those in biological systems. Scientists have approached the synthesis of ion conductive compounds in a variety of ways, in the areas of organic and inorganic chemistry. Recently, based on their ion-conducting behavior, porous coordination polymers (PCPs) and metal-organic frameworks (MOFs) have been recognized for their easy design and the dynamic behavior of the ionic components in the structures. These PCP/MOFs consist of metal ions (or clusters) and organic ligands structured via coordination bonds. They could have highly concentrated mobile ions with dynamic behavior, and their characteristics have inspired the design of a new class of ion conductors and transporters. In this Account, we describe the state-of-the-art of studies of ion conductivity by PCP/MOFs and nonporous coordination polymers (CPs) and offer future perspectives. PCP/MOF structures tend to have high hydrophilicity and guest-accessible voids, and scientists have reported many water-mediated proton (H(+)) conductivities. Chemical modification of organic ligands can change the hydrated H(+) conductivity over a wide range. On the other hand, the designable structures also permit water-free (anhydrous) H(+) conductivity. The incorporation of protic guests such as imidazole and 1,2,4-triazole into the microchannels of PCP/MOFs promotes the dynamic motion of guest molecules, resulting in high H(+) conduction without water. Not only the host-guest systems, but the embedding of protic organic groups on CPs also results in inherent H(+) conductivity. We have observed high H(+) conductivities under anhydrous conditions and in the intermediate temperature region of organic and inorganic conductors. The keys to successful construction are highly mobile ionic species and appropriate intervals of ion-hopping sites in the structures. Lithium (Li(+)) and other ions can also be transported. If we can optimize the crystal structures, this could offer further improvements in terms of both conductivity and the working temperature range. Another useful characteristic of PCP/MOFs is their wide application to materials fabrication. We can easily prepare heterodomain crystal systems, such as core-shell or solid solution. Other anisotropic morphologies (thin film, nanocrystal, nanorod, etc.,) are also possible, with retention of the ion conductivity. The flexible nature also lets us design morphology-dependent ion conduction behaviors that we cannot observe in the bulk state. We propose (1) multivalent ion and anion conductions with the aid of redox activity and defects in structures, (2) control of ion transport behavior by applying external stimuli, (3) anomalous conductivity at the hetero-solid-solid interface, and (4) unidirectional ion transport as in the ion channels in membrane proteins. In the future, scientists may use coordination polymers not only to achieve higher conductivity but also to control ion behavior, which will open new avenues in solid-state ionics. PMID- 23730918 TI - Face-centered-cubic lithium crystals formed in mesopores of carbon nanofiber electrodes. AB - In the foreseeable future, there will be a sharp increase in the demand for flexible Li-ion batteries. One of the most important components of such batteries will be a freestanding electrode, because the traditional electrodes are easily damaged by repeated deformations. The mechanical sustainability of carbon-based freestanding electrodes subjected to repeated electrochemical reactions with Li ions is investigated via nanotensile tests of individual hollow carbon nanofibers (HCNFs). Surprisingly, the mechanical properties of such electrodes are improved by repeated electrochemical reactions with Li ions, which is contrary to the conventional wisdom that the mechanical sustainability of carbon-based electrodes should be degraded by repeated electrochemical reactions. Microscopic studies reveal a reinforcing mechanism behind this improvement, namely, that inserted Li ions form irreversible face-centered-cubic (FCC) crystals within HCNF cavities, which can reinforce the carbonaceous matrix as strong second-phase particles. These FCC Li crystals formed within the carbon matrix create tremendous potential for HCNFs as freestanding electrodes for flexible batteries, but they also contribute to the irreversible (and thus low) capacity of HCNFs. PMID- 23730919 TI - Sexual stigma, psychological well-being and social engagement among men who have sex with men in Beirut, Lebanon. AB - This qualitative study sought to explore sexual identity development among men who have sex with men in Beirut, Lebanon; the stigma experienced by these men; and how their psychological well-being and social engagement are shaped by how they cope with this stigma. Semi-structured interviews were conducted with 31 men who have sex with men and content analysis was used to identify emergent themes. While many men reported feeling very comfortable with their sexual orientation and had disclosed their sexual orientation to family, most men struggled at least somewhat with their sexuality, often because of perceived stigma from others and internal religious conflict about the immorality of homosexuality. Most participants described experiencing verbal harassment or ridicule or being treated as different or lesser than in social relationships with friends or family. Mechanisms for coping with stigma included social avoidance (trying to pass as heterosexual and limiting interaction with men who have sex with men to the internet) or withdrawal from relationships in an attempt to limit exposure to stigma. Findings suggest that effective coping with both internal and external sexual stigma is central to the psychological well-being and social engagement of men who have sex with men in Beirut, much as has been found in Western gay communities. PMID- 23730921 TI - Vitis vinifera canes, a new source of antifungal compounds against Plasmopara viticola, Erysiphe necator, and Botrytis cinerea. AB - Methanolic and ethanolic crude extracts of Vitis vinifera canes exhibited significant antifungal activity against the three major fungal pathogens affecting grapevines, Plasmopara viticola, Erysiphe necator and Botrytis cinerea. The active extracts were analyzed by LC-PDA-ESI-MS, and selected compounds were identified. Efficient targeted isolation using medium-pressure liquid chromatography afforded six pure constituents in one step. The structures of the isolated compounds were elucidated by NMR and HRMS. Six identified compounds (ampelopsin A, hopeaphenol, trans-resveratrol, ampelopsin H, epsilon-viniferin, and E-vitisin B) presented antifungal activities against P. viticola. epsilon Viniferin also exhibited a low antifungal activity against B. cinerea. None of the identified compounds inhibited the germination of E. necator. The potential to develop a novel natural fungicide against the three major fungal pathogens affecting V. vinifera from viticulture waste material is discussed. PMID- 23730920 TI - Incidence of chemotherapy-induced neutropenia and current practice of prophylaxis with granulocyte colony-stimulating factors in cancer patients in Spain: a prospective, observational study. AB - We aimed to describe the incidence of neutropenia in breast cancer and lymphoma patients and granulocyte colony-stimulating factors (G-CSF) use in clinical practice. We conducted a multicentre, prospective, observational study including breast cancer and lymphoma patients initiating chemotherapy (>= 10% febrile neutropenia risk). We included 734 patients with breast cancer and 291 with lymphoma. Over the first four chemotherapy cycles, patients had an incidence of 11.0% grade 3-4 neutropenia (absolute neutrophil count <1.0 * 10(9) /L) and 4.3% febrile neutropenia (absolute neutrophil count <0.5 * 10(9) /L and fever >= 38 degrees C) in the breast cancer cohort, and 40.5% and 14.8% in the lymphoma cohort. Full dose on schedule (>85% of planned chemotherapy dose and <= 3 days delay) was achieved by 85.6% of breast cancer and 68.9% of lymphoma patients. Hospitalisation due to febrile neutropenia was required in 2.0% and 12.0% of breast cancer and lymphoma patients respectively. G-CSF was administered to 70.0% of breast cancer and 83.8% of lymphoma patients, and initiated from the first chemotherapy cycle (primary prophylaxis) in 60.6% and 64.2% of cases. Severe neutropenia affects approximately one in 10 breast cancer patients and one in two lymphoma patients receiving chemotherapy with moderate or greater risk of febrile neutropenia. Most patients received treatment with G-CSF in Spanish clinical practice. PMID- 23730922 TI - Clinical features of post-polypectomy bleeding associated with heparin bridge therapy. AB - BACKGROUND: Heparin is given to patients undergoing colonoscopic polypectomy at high risk for thromboembolism. Little is known, however, about how heparin bridge therapy (HB) affects post-polypectomy bleeding (PPB). The present study aimed to identify the clinical features of PPB associated with HB. PATIENTS AND METHODS: Data of consecutive inpatients who underwent colonoscopic polypectomy with antithrombotic therapy at Osaka University Hospital were retrospectively collected and categorized into a HB group or a non-HB group. The incidence and characteristics of PPB were analyzed. RESULTS: A total of 117 patients with 279 lesions were identified, and the HB group included 45 patients. Nine of 10 patients with PPB were in the HB group, and the incidence of PPB was significantly higher in the HB group than in the non-HB group (20.0% vs 1.4%, respectively). PPB onset was later in the HB group than inthe non-HB group (median postoperative day: 4 vs 1, respectively). Five of the nine patients with PPB (55.6%) in the HB group experienced recurrent bleeding. One patient in the HB group required a blood transfusion as a result of massive PPB. All bleeding was eventually controlled endoscopically. Hospitalization was significantly longer in the HB group than in the non-HB group (median hospitalization: 14 vs 4 days, respectively). The univariate analysis showed that the predictors of PPB were warfarin use, HB and pedunculated polyps. CONCLUSIONS: PPB associated with HB is characterized by high incidence, late onset and recurrent bleeding, resulting in long hospitalization. PMID- 23730923 TI - Interleukin-6 prevents NMDA-induced neuronal Ca2+ overload via suppression of IP3 receptors. AB - PRIMARY OBJECTIVE: The mechanism underlying interleukin-6 (IL-6) prevention of N methyl-D-aspartate (NMDA)-induced neuronal Ca(2+) overload was explored at the profile of Ca(2+) channel receptors, including NMDA, inositol 1,4,5-trisphosphate and ryanodine receptors (NMDAR, IP3R and RyR, respectively). METHODS: Cerebellar granule neurons from 8-day-old rats were exposed to IL-6 (40 or 120 ng ml(-1)) for 8 days and stimulated with NMDA (100 MUM) for 15 or 30 minutes. RESULTS: NMDA evoked an acute and sustained enhancement of intracellular Ca(2+) fluorescence intensity in the entire 15-minute NMDA application period. IL-6 prevented the acute and sustained intracellular Ca(2+) elevation triggered by NMDA in a concentration-dependent manner. MK-801, an NMDAR antagonist, completely suppressed NMDA-evoked neuronal Ca(2+) overload in the absence or presence of IL 6. IP3R antagonist 2-APB lessened NMDA-evoked acute and sustained cytosolic Ca(2+) overload and IL-6 further reduced the acute 2-APB-dependent Ca(2+) component. Dissimilarly, after RyR antagonist DAN treatment, NMDA still induced an acute and sustained elevation of intracellular Ca(2+) levels, and the elevated Ca(2+) was significantly suppressed by IL-6. Moreover, IL-6 down-regulated NMDAR1 and IP3R1 but did not alter RyR2 expression. CONCLUSION: The present results suggest that IL-6 suppresses NMDA-induced neuronal Ca(2+) overload by inhibiting NMDAR and IP3R activities. PMID- 23730924 TI - Pharmaceutical applications of the Calu-3 lung epithelia cell line. AB - INTRODUCTION: The Calu-3 lung cell line has been shown to be a promising in vitro model of airway epithelia due to its similarity to in vivo physiology. Hence, over the past decade, it has found increasing applications in the pharmaceutical industry. AREAS COVERED: This review focuses on the pharmaceutical applications of the Calu-3 cell line in areas such as mechanisms of drug transport, studying aerosol deposition, controlled release studies and identification of possible drug-drug interactions. The main findings of various studies, as well as the predictive potential of this model, are presented and discussed in this review. EXPERT OPINION: There is still a lack of mechanistic knowledge regarding transport of inhaled therapeutics across the lungs. Cell culture models such as Calu-3 provide a simple and reproducible system to study the underlying mechanisms by which inhaled therapeutics interact with the lungs. However, more complex systems that integrate particle deposition onto different cell culture systems may be useful in addressing some fundamental questions to generate a better understanding of determinants that influences pulmonary drug dissolution, absorption, metabolism and efficacy. Ultimately the use of the Calu-3 cell line provides a basic research tool that enables the development of safer and more effective inhaled therapeutics. PMID- 23730925 TI - Association of bilateral acute anterior uveitis with a capsaicin patch. AB - PURPOSE: To report a case of bilateral acute anterior uveitis in association with the application of an analgesic transdermal capsaicin patch. METHODS: Case report and review of literature. RESULTS: A 38-year-old woman suffered from bilateral acute anterior uveitis, manifesting 12-24 h after application of an analgesic capsaicin patch (Isola Capsicum N Plus) that served to alleviate muscular neck pain. Systemic immune-mediated and infectious diseases were excluded by medical history and laboratory testing. Control of inflammation was achieved with topical corticosteroid treatment within 1 week. Over the course of a 1-year follow-up, no further recurrence of uveitis was observed. CONCLUSIONS: The case suggests a possible association of capsaicin-containing transdermal patches and acute anterior uveitis. PMID- 23730926 TI - Preventing intercostal vessel trauma: ultrasound to the rescue once more? PMID- 23730927 TI - Post-transplant lymphoproliferative disorders and other malignancies after pediatric intestinal transplantation: incidence, clinical features and outcome. AB - PTLDs are a well-recognized and potentially fatal complication after intestinal transplantation. We analyzed the incidence, clinical features, and outcome in a 63 intestinal transplantation series performed in our unit between October 1999 and July 2011. Types of graft included ISB (n = 23), LSB (n = 20), and MV (n = 20). Patients were categorized into three groups of immunosuppression: I (n = 43) received basiliximab, tacrolimus, and steroids; II (n = 11) thymoglobulin and tacrolimus, and III (n = 9) alemtuzumab and tacrolimus. EBV status was serially assessed. All PTLD cases were biopsied to establish histopathological diagnosis. The incidence of PTLD was 14.2% (9/63). Median onset of PTLD after transplant was four months (range: 0.5-28), within first postoperative year in 6 (66.6%) patients. Fever was the most common symptom. Graft removal was needed in four patients (44%). The patient survival rate was 66.6% (6/9). We have not found any association between PTLD and immunosuppression regimen or transplant type. However, there was a statistical association with EBV active infection. PMID- 23730928 TI - Feasibility and validity of dementia assessment by trained community health workers based on Clinical Dementia Rating. AB - OBJECTIVES: To determine the level of agreement between dementia rating by trained community health workers (CHWs) based on the Clinical Dementia Rating (CDR) and the criterion standard: physician diagnosis. DESIGN: Cross-sectional validation study. SETTING: Community gathering places such as ethnic churches, senior centers, low-income elderly apartments, and ethnic groceries in the Baltimore-Washington metropolitan area. PARTICIPANTS: Ninety community-dwelling Korean-American individuals aged 60 and older. MEASUREMENTS: The CDR is a standardized clinical dementia staging instrument used to assess cognitive and functional performance using a semistructured interview protocol. Six CHWs trained and certified as CDR raters interviewed and rated study participants. A bilingual geriatric psychiatrist evaluated participants independently for dementia status. RESULTS: CHWs rated 61.1% of the participants as having mild cognitive impairment (MCI; CDR = 0.5) or dementia (CDR>=1), versus 56.7% diagnosed by the clinician. A receiver operating characteristic (ROC) curve analysis demonstrated good predictive ability of CDR rating by trained CHWs (area under the ROC curve = 0.86, 95% confidence interval = 0.78-0.93, sensitivity = 85.5%, specificity = 88.6%) in detecting MCI and dementia. CONCLUSION: The findings provide preliminary evidence that trained CHWs can effectively identify community-dwelling elderly Korean adults with MCI and dementia for early follow up assessment and care in a community with scarce bilingual caregivers and programs. PMID- 23730929 TI - FX enzyme and GDP-L-Fuc transporter expression in colorectal cancer. AB - AIMS: Fucosylation is regulated by fucosyltransferases, the guanosine diphosphate L-fucose (GDP-L-Fuc) synthetic pathway, and the GDP-L-fucose transporter (GDP-L Fuc Tr). We have reported previously an increased level of alpha(1,6)fucosyltransferase activity and expression in colorectal cancer (CRC). The present study aimed to analyse the expression profiles of the FX enzyme and GDP-L-Fuc Tr in a cohort of operated CRC patients to elucidate their role in alpha(1,6)fucosylation in this neoplasm. METHODS AND RESULTS: We assessed the immunohistochemical expression of FX and GDP-L-Fuc Tr in a series of tumour samples and healthy tissues from CRC specimens. FX expression was observed in 58 of 91 (63.7%) tumours and 23 of 28 (82.1%) corresponding healthy samples. GDP-L Fuc Tr expression was detected in 86 of 102 (84.3%) colorectal tumours, and 13 of 27 (48.1%) healthy tissue specimens. The expression of GDP-L-Fuc Tr was statistically higher in tumours than in healthy tissues (P < 0.001). A correlation was found between FX and GDP-L-Fuc Tr expression in tumour samples (P = 0.003). CONCLUSION: GDP-L-Fuc Tr overexpression in the tumour tissue of CRC patients suggests that GDP-L-Fuc transport to the Golgi apparatus may be an important factor associated with increased alpha(1,6)fucosylation in CRC. PMID- 23730930 TI - Photoresponsive coumarin-tethered multifunctional magnetic nanoparticles for release of anticancer drug. AB - Recently, photoresponsive nanoparticles have received significant attention because of their ability to provide spatial and temporal control over the drug release. In the present work, we report for the first time photoresponsive multifunctional magnetic nanoparticles (MNPs) fabricated using coumarin-based phototrigger and Fe/Si MNPs for controlled delivery of anticancer drug chlorambucil. Further, newly fabricated photoresponsive multifunctional MNPs were also explored for cell luminescence imaging. In vitro biological studies revealed that coumarin tethered Fe/Si MNPs of ~9 nm size efficiently delivered the anticancer drug chlorambucil into cancer cells and thereby improving the drug action to kill the cancer cells upon irradiation. Such multifunctional MNPs with strong fluorescence, good biocompatibility and efficient photocontrolled drug release ability will be of great benefit in the construction of light-activated multifunctional nano drug delivery systems. PMID- 23730931 TI - Malignant odontogenic tumors: a multicentric Latin American study of 25 cases. AB - OBJECTIVE: The aim of this study was to show the epidemiological features of 25 malignant odontogenic tumors (MOT) in Latin America. MATERIALS AND METHODS: We retrieved 25 cases of MOT out of 2142 odontogenic tumors, from four oral diagnostic centers in Latin America, and described the main clinical and pathological characteristics. RESULTS: A total of 19 cases were carcinomas, including eight ameloblastic carcinomas, five primary intra-osseous squamous cell carcinomas, three clear cell odontogenic carcinomas and three ghost cell odontogenic carcinomas. All six sarcomas corresponded to ameloblastic fibrosarcoma. Thirteen cases occurred in men and 12 in women, age ranged from 7 to 77 years old, with a mean of 41.4 years. The average age of patients with carcinomas and sarcomas were 48.53 and 19 years old, respectively. CONCLUSION: As malignant odontogenic tumors are very rare, this series helps to better clarify their relative frequency, predominant subtypes, and clinical characteristics in Latin America. PMID- 23730932 TI - Skin care. Sun care. A successful symbiosis? PMID- 23730934 TI - Asymmetric construction of spirocyclopentenebenzofuranone core structures via highly selective phosphine-catalyzed [3 + 2] cycloaddition reactions. AB - An efficient organocatalytic asymmetric [3 + 2] cycloaddition reaction between 3 substituted methylenebenzofuranone derivatives and diverse Morita-Baylis-Hillman carbonates to provide complex polysubstituted spirocyclopentenebenzofuranone scaffolds in a single step is reported. C2-symmetric phospholanes were efficient nucleophilic catalysts of this transformation under mild conditions, providing reaction products comprised of three consecutive stereocenters, including one all carbon center, with excellent enantioselectivity. PMID- 23730933 TI - Young adults with coeliac disease may be at increased risk of early atherosclerosis. AB - BACKGROUND: Accelerated progression of atherosclerosis and increased cardiovascular risk have been described in immune-mediated disorders, but few data are available in coeliac disease. AIM: To evaluate instrumental and biochemical signs of atherosclerosis risk in 20 adults at first diagnosis of coeliac disease and after 6-8 months of gluten-free diet with mucosal recovery. METHODS: We analysed total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, triglycerides, homocysteine, C-reactive protein, folate and vitamin B12; ultrasound measurement of carotid intima-media thickness (IMT) and endothelium-dependent dilatation were both carried on at diagnosis and after gluten withdrawal. Twenty-two healthy members of the hospital staff served as matched controls for vascular examinations. RESULTS: At baseline, mean total and HDL-cholesterol (HDL-C) were both within normal range, while mean LDL cholesterol concentration was slightly increased; diet was associated with an increment in total and HDL-C (68.2 +/- 17.4 vs. 51.4 +/- 18.6 mg/dL; P < 0.001) and a significant improvement in total/HDL-C ratio (3.05 +/- 0.71 vs. 3.77 +/- 0.92; P < 0.02). Mean plasma homocysteine was elevated and not influenced by diet. C-reactive protein significantly decreased with diet (1.073 +/- 0.51 vs. 1.92 +/- 1.38 mg/dL; P < 0.05). At baseline, in coeliacs, IMT was increased (0.082 +/- 0.011 vs. 0.058 +/- 0.012 cm; P < 0.005), while endothelium-dependent dilatation was decreased (9.3 +/- 1.3 vs. 11.2 +/- 1.2%; P < 0.05). Both parameters improved after gluten abstinence. CONCLUSIONS: Adults with coeliac disease seem to be at potentially increased risk of early atherosclerosis as suggested by vascular impairment and unfavourable biochemical risk pattern. Chronic inflammation might play a determining role. Gluten abstinence with mucosal normalisation reverts to normal the observed alterations. PMID- 23730935 TI - Isopiestic investigations of the interactions of water-soluble polymers with imidazolium-based ionic liquids in aqueous solutions. AB - To provide insight into the salting effects produced by the addition of hydrophilic ionic liquids to aqueous solutions of water-soluble polymers and to obtain a relation between the vapor-liquid and liquid-liquid equilibrium behavior of ionic liquid-polymer aqueous-biphasic systems, the isopiestic equilibrium molalities of some ternary ionic liquid-polymer-water systems in both the one- and two-phase areas together with the liquid-liquid equilibrium phase diagrams for systems capable of inducing phase separation were determined at 298.15 K. The polymers are poly(ethylene glycol) 400 (PEG400), poly(ethylene glycol) 2000 (PEG2000), poly(ethylene glycol) 6000 (PEG6000), poly(ethylene glycol) 10,000 (PEG10,000), poly(propylene glycol) 400 (PPG400), and poly(propylene glycol) 725 (PPG725), and the investigated ionic liquids are 1-butyl-3-methylimidazolium bromide ([C4mim][Br]) and 1-butyl-3-methylimidazolium hydrogen sulfate ([C4mim][HSO4]). It was found that aqueous solutions of [C4mim][HSO4] form aqueous biphasic systems with PPG400 and PPG725 (salting-out effect); however, other investigated systems do not form aqueous biphasic systems (salting-in effect). A relationship was found between the salting-out and salting-in effects of ionic liquids on aqueous polymer solutions and the slopes of the constant water-activity lines for ternary ionic liquid-polymer aqueous solutions so that in the case of the salting-out effect the constant water-activity lines had a concave slope, but in the case of the salting-in effect the constant water activity lines had a convex slope. PMID- 23730936 TI - Suppressive effect of RAS inhibitor manumycin A on aberrant crypt foci formation in the azoxymethane-induced rat colorectal carcinogenesis model. AB - BACKGROUND AND AIM: The chemopreventive effect of RAS inhibitors on colorectal cancer is unknown. Because aberrant crypt foci (ACF), earliest preneoplastic lesions, are highly positive for K-RAS mutation, RAS inhibitors are likely to be effective for chemoprevention. Therefore, in the present study, the suppressive effect of a RAS inhibitor, manumycin A, on ACF formation in an azoxymethane (AOM) induced rat colorectal carcinogenesis model was investigated. METHODS: Rats injected with AOM were administered manumycin A (30 mg/kg) subcutaneously thrice weekly for 8 weeks or for 4 weeks (latter half), sacrificed at 8 weeks, and examined for ACF in the colorectum. Phosphorylated ERK and Ki-67 expression was evaluated by immunohistochemistry. Apoptosis was assessed by TUNEL staining. RESULTS: The mean number of ACF in the 8-week manumycin A group (72.9 +/- 20.1) was significantly lower than in the vehicle group (155.6 +/- 56.7, P < 0.01), and it was significantly lower even in the 4-week manumycin A group than in the vehicle group (92.2 +/- 13.0 vs 222.3 +/- 83.3, P < 0.01). The positive rate for phosphorylated ERK in the manumycin A group (13.5 +/- 19.2%) was significantly lower than in the vehicle group (50.2 +/- 19.8%, P < 0.01). The positive rate for Ki-67 in the manumycin A group (2.2 +/- 3.4%) was significantly lower than in the vehicle group (14.7 +/- 8.2%, P < 0.01). There were significantly more terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling positive cells in tissue samples from the manumycin A group versus the vehicle group (8.6 +/- 9.7% vs 2.9 +/- 2.0%, P < 0.05). CONCLUSION: Manumycin A suppressed ACF formation in the AOM-induced colorectal carcinogenesis model, demonstrating that RAS inhibitors may be very effective for chemoprevention of colorectal cancers. PMID- 23730937 TI - Functionally selective dopamine D2/D3 receptor agonists comprising an enyne moiety. AB - Dopaminergics of types 1 and 2 incorporating a conjugated enyne as an atypical catechol-simulating moiety were synthesized in enantiomerically pure form and investigated for their metabolic stability. Radioligand binding studies indicated high affinity to D2-like receptors. The test compounds were evaluated for their ability to differentially activate distinct signaling pathways. Measurement of D(2L)- and D(2S)-mediated [(35)S]GTPgammaS incorporation in the presence of coexpressed Galpha(o) and Galpha(i) subunits showed significantly biased receptor activation for several test compounds. Thus, the 2-azaindolylcarboxamide (S)-2a exhibited substantial functional selectivity for D(2S)-promoted G(o) activation over G(i) coupling. The most significant bias was determined for the triazolylalkoxy-substituted benzamide (S)-2c that displayed higher potency for G(o) activation than for G(i) coupling at the D(2L) subtype. Functional selectivity for beta-arrestin recruitment over G(i) activation was observed for the biphenylcarboxamide (R)-1 and the 2-benzothiophenylcarboxamide (S)-2d, whereas the 2-substituted azaindole (S)-2a preferred beta-arrestin recruitment compared to G(o) coupling. PMID- 23730938 TI - Modelling stomatal conductance in response to environmental factors. AB - Stomata are an attractive system for modellers for many reasons, and the literature contains a large number of papers describing models that predict stomatal conductance as a function of environmental factors. The approaches and goals of these models vary considerably. This review summarizes these different approaches and discusses their strengths and weaknesses with a focus on mechanistically based models. The critical unresolved questions are highlighted and placed in the context of current research on stomatal physiology. Finally, directions for future research are considered. PMID- 23730940 TI - Reversible, long-range radical transfer in E. coli class Ia ribonucleotide reductase. AB - Ribonucleotide reductases (RNRs) catalyze the conversionof nucleotides to 2' deoxynucleotides and are classified on the basis of the metallo-cofactor used to conduct this chemistry. The class Ia RNRs initiate nucleotide reduction when a stable diferric-tyrosyl radical (Y*, t1/2 of 4 days at 4 degrees C) cofactor in the beta2 subunit transiently oxidizes a cysteine to a thiyl radical (S*) in the active site of the alpha2 subunit. In the active alpha2beta2 complex of the class Ia RNR from E. coli , researchers have proposed that radical hopping occurs reversibly over 35 A along a specific pathway comprised of redox-active aromatic amino acids: Y122* <-> [W48?] <-> Y356 in beta2 to Y731 <-> Y730 <-> C439 in alpha2. Each step necessitates a proton-coupled electron transfer (PCET). Protein conformational changes constitute the rate-limiting step in the overall catalytic scheme and kinetically mask the detailed chemistry of the PCET steps. Technology has evolved to allow the site-selective replacement of the four pathway tyrosines with unnatural tyrosine analogues. Rapid kinetic techniques combined with multifrequency electron paramagnetic resonance, pulsed electron-electron double resonance, and electron nuclear double resonance spectroscopies have facilitated the analysis of stable and transient radical intermediates in these mutants. These studies are beginning to reveal the mechanistic underpinnings of the radical transfer (RT) process. This Account summarizes recent mechanistic studies on mutant E. coli RNRs containing the following tyrosine analogues: 3,4 dihydroxyphenylalanine (DOPA) or 3-aminotyrosine (NH2Y), both thermodynamic radical traps; 3-nitrotyrosine (NO2Y), a thermodynamic barrier and probe of local environmental perturbations to the phenolic pKa; and fluorotyrosines (FnYs, n = 2 or 3), dual reporters on local pKas and reduction potentials. These studies have established the existence of a specific pathway spanning 35 A within a globular alpha2beta2 complex that involves one stable (position 122) and three transient (positions 356, 730, and 731) Y*s. Our results also support that RT occurs by an orthogonal PCET mechanism within beta2, with Y122* reduction accompanied by proton transfer from an Fe1-bound water in the diferric cluster and Y356 oxidation coupled to an off-pathway proton transfer likely involving E350. In alpha2, RT likely occurs by a co-linear PCET mechanism, based on studies of light initiated radical propagation from photopeptides that mimic the beta2 subunit to the intact alpha2 subunit and on [(2)H]-ENDOR spectroscopic analysis of the hydrogen-bonding environment surrounding a stabilized NH2Y* formed at position 730. Additionally, studies on the thermodynamics of the RT pathway reveal that the relative reduction potentials decrease according to Y122 < Y356 < Y731 ~ Y730 <= C439, and that the pathway in the forward direction is thermodynamically unfavorable. C439 oxidation is likely driven by rapid, irreversible loss of water during the nucleotide reduction process. Kinetic studies of radical intermediates reveal that RT is gated by conformational changes that occur on the order of >100 s(-1) in addition to the changes that are rate-limiting in the wild-type enzyme (~10 s(-1)). The rate constant of one of the PCET steps is ~10(5) s(-1), as measured in photoinitiated experiments. PMID- 23730941 TI - The British Chinese Adoption Study: orphanage care, adoption and mid-life outcomes. AB - BACKGROUND: While studies of ex-orphanage care show adverse effects on development, the longer-term impact on mid-life psychosocial functioning and physical health has not been established. METHODS: Orphanage records provided baseline data on a sample of 100 Hong Kong Chinese girls who were subsequently adopted into the UK. A mid-life follow-up using standardised questionnaires and face-to-face interviews assessed current circumstances, life satisfaction and mental and physical health outcomes. Comparisons were made with age-matched UK born adopted and nonadopted women. RESULTS: Half the group spent between 1 and 2 years in orphanages, average age at adoptive placement was 23 months and 72% participated in the follow-up. Despite this poor early start, mid-life outcomes were commensurate with the comparison groups in terms of mental and physical health measures. Serious psychiatric and social difficulties were largely absent. Although the timing and extent of exposure to orphanage care did not influence outcome, participants' reports of poorer quality adoptive family experience and a negative view of their adoption were significantly associated with poorer mental health outcomes (difference in means = 0.76, 95% CI 1.33-0.19, p = .01; difference in means = 1.2, 95% CI 0.68-1.73, p = .01, respectively). CONCLUSIONS: Moderately depriving orphanage care did not predict enduring adverse consequences in mid-life but subsequent poor adoption experience was associated with outcome. PMID- 23730942 TI - Cost-effectiveness of distributing naloxone to heroin users for lay overdose reversal in Russian cities. AB - OBJECTIVE: To evaluate the cost-effectiveness of distributing naloxone to illicit opioid users for lay overdose reversal in Russian cities. METHOD: This study adapted an integrated Markov and decision analytic model to Russian cities. The model took a lifetime, societal perspective, relied on published literature, and was calibrated to epidemiologic findings. RESULTS: For each 20% of heroin users reached with naloxone distribution, the model predicted a 13.4% reduction in overdose deaths in the first 5 years and 7.6% over a lifetime; on probabilistic analysis, one death would be prevented for every 89 naloxone kits distributed (95% CI = 32-260). Naloxone distribution was cost-effective in all deterministic and probabilistic sensitivity analyses and cost-saving if resulting in a reduction in overdose events. Naloxone distribution increased costs by US$13 (95% CI = US$3-US$32) and QALYs by 0.137 (95% CI = 0.022-0.389) for an incremental cost of US$94 per QALY gained (95% CI = US$40-US$325). In a worst-case scenario where overdose was rarely witnessed and naloxone was rarely used, minimally effective, and expensive, the incremental cost was US$1987 per QALY gained. If national expenditures on drug-related HIV, tuberculosis, and criminal justice were applied to heroin users, the incremental cost was US$928 per QALY gained. CONCLUSIONS: Naloxone distribution to heroin users for lay overdose reversal is highly likely to reduce overdose deaths in target communities and is robustly cost-effective, even within the constraints of this conservative model. PMID- 23730943 TI - Association between drug tolerability and medical resource use in prophylaxis of invasive fungal infections after allogeneic hematopoietic stem cell transplant. AB - OBJECTIVES: To conduct a retrospective analysis of the association between drug tolerability and potential economic impact measured by medical resource utilization (MRU) for prophylaxis of invasive antifungal infections (IFI) after allogeneic hematopoietic stem cell transplantation (alloHCT). METHODS: An open label, multi-center study (IMPROVIT) included patients (>=12-years old) who were randomized to receive oral voriconazole (VOR) or oral itraconazole (ITR) from the alloHCT day for at least 100 days and up to 180 days. Trial data on discontinuation and MRU for the first 100 days were analyzed. RESULTS: Two hundred and twenty-four patients were in VOR and 241 in ITR, with similar demographic distributions (average age of 43 years, 58% male, 92% Caucasian). All cause and study drug intolerance discontinuations were less frequent with VOR than ITR (50% vs 63%, p = 0.0137; 7% vs 22%, p < 0.0001). VOR patients had longer study drug exposure (median = 96 vs 68 days, p < 0.0001; mean = 68 vs 60 days, p = 0.0044). ITR patients were 2-times more likely (p = 0.0110) to use other antifungals vs VOR patients. Controlling for treatment and key baseline variables, longer IFI prophylaxis was associated with fewer hospital days (p < 0.0001) and less other antifungal use (p < 0.0001). Patients who discontinued prophylaxis during the first 100 days incurred 10 more hospital days (p < 0.0001) and 17 more other antifungal days (p < 0.0001) compared to their counterparts. Eight more prophylaxis days were associated with ~1 less hospital day and 3.6 less other antifungal days (p < 0.0001). Key limitation: MRU data collection was limited to the first 100 days post-transplant, which may not fully capture the real-world utilization and outcomes. CONCLUSIONS: Patients' ability to tolerate and continue their antifungal prophylaxis after alloHCT is associated with less use of MRU such as other antifungals and hospital days. In the current resource constrained healthcare environment, it is important to consider the potential economic impact of the tolerability of antifungal prophylaxis. PMID- 23730944 TI - A discrete choice experiment to determine patient preferences for injection devices in multiple sclerosis. AB - OBJECTIVE: Relapsing-remitting multiple sclerosis (MS) is usually managed with disease modifying drugs (DMDs), most commonly administered via self-injection. The aim of this study was to estimate the influence that different treatment related attributes have for MS patients on their choice of MS DMD device. By establishing the relative importance of these characteristics for patients it should be possible to better understand the acceptability of a given device and to optimize the development of future devices. METHODS: A discrete choice experiment (DCE) survey was developed on the basis of a review of published literature. Attributes identified for inclusion in the survey were: ease of use; comfort of use; presence of additional functions, needle visibility; practicality and efficacy. Choice sets were presented as pairs of hypothetical treatments based upon a fractional factorial design. One-hundred device-using MS patients completed the survey online. Analysis was conducted using a mixed-logit approach. RESULTS: Analysis of the DCE data revealed that all attributes significantly predicted treatment choice. Efficacy exhibited the largest effect on treatment selection and this provided context for understanding the magnitude of impact for the other attributes. Reducing the discomfort associated with device use and eliminating the necessity for assembly or drug reconstitution were highly valued. The addition of reminder and time-stamping functions, improved needlestick injury prevention, and reduction in device size were secondary concerns but still deemed desirable. CONCLUSION: Efficacy is of primary importance to MS patients, but characteristics of drug delivery devices can play an important role in treatment decision-making. Not all device characteristics could be included, and results are based upon 100 participants only. Findings suggest there is significant potential value in developing self-injection devices that are not only efficacious but also convenient and comfortable to use. Reducing barriers to adherence could potentially translate into improved treatment outcomes for patients with MS. PMID- 23730945 TI - Atomic-scale observation of lithiation reaction front in nanoscale SnO2 materials. AB - In the present work, taking advantage of aberration-corrected scanning transmission electron microscopy, we show that the dynamic lithiation process of anode materials can be revealed in an unprecedented resolution. Atomically resolved imaging of the lithiation process in SnO2 nanowires illustrated that the movement, reaction, and generation of b = [1[overline]1[overline]1] mixed dislocations leading the lithiated stripes effectively facilitated lithium-ion insertion into the crystalline interior. The geometric phase analysis and density functional theory simulations indicated that lithium ions initial preference to diffuse along the [001] direction in the {200} planes of SnO2 nanowires introduced the lattice expansion and such dislocation behaviors. At the later stages of lithiation, the Li-induced amorphization of rutile SnO2 and the formation of crystalline Sn and LixSn particles in the Li2O matrix were observed. PMID- 23730947 TI - The experiences of gay and bisexual men diagnosed with prostate cancer: results from an online focus group. AB - Research concerning gay and bisexual men diagnosed with prostate cancer is sparse. An online focus group was conducted over a 4-week period with participants responding to a range of discussion questions concerning their experiences following a prostate cancer diagnosis. Emerging themes were identified and consensus reached. A summary of each of the themes was produced which the coders agreed conveyed the essence of the online discussion. All men who took part in the online focus group reported that prostate cancer significantly impacted their lives. Unexpectedly, some participants actually gained a positive perspective and adopted a sense of empowerment. Participants spoke about emotional responses to a diagnosis of prostate cancer, accessing help and support, the impact of incontinence, the impact of sexual changes on identity, a re-evaluation of life, changed sexual relationships, the need to find the most suitable healthcare professionals and identification of current needs to improve quality of care. These areas of disquiet suggest that the psychological impact of this disease may be quite significant over an extended time-frame. Further research needs to be undertaken to assess the degree of distress accompanying the treatment of gay and bisexual men with prostate cancer. PMID- 23730946 TI - Three-dimensional microfluidic collagen hydrogels for investigating flow-mediated tumor-endothelial signaling and vascular organization. AB - Hyperpermeable tumor vessels are responsible for elevated interstitial fluid pressure and altered flow patterns within the tumor microenvironment. These aberrant hydrodynamic stresses may enhance tumor development by stimulating the angiogenic activity of endothelial cells lining the tumor vasculature. However, it is currently not known to what extent shear forces affect endothelial organization or paracrine signaling during tumor angiogenesis. The objective of this study was to develop a three-dimensional (3D), in vitro microfluidic tumor vascular model for coculture of tumor and endothelial cells under varying flow shear stress conditions. A central microchannel embedded within a collagen hydrogel functions as a single neovessel through which tumor-relevant hydrodynamic stresses are introduced and quantified using microparticle image velocimetry (MU-PIV). This is the first use of MU-PIV in a tumor representative, 3D collagen matrix comprised of cylindrical microchannels, rather than planar geometries, to experimentally measure flow velocity and shear stress. Results demonstrate that endothelial cells develop a confluent endothelium on the microchannel lumen that maintains integrity under physiological flow shear stresses. Furthermore, this system provides downstream molecular analysis capability, as demonstrated by quantitative RT-PCR, in which, tumor cells significantly increase expression of proangiogenic genes in response to coculture with endothelial cells under low flow conditions. This work demonstrates that the microfluidic in vitro cell culture model can withstand a range of physiological flow rates and permit quantitative measurement of wall shear stress at the fluid collagen interface using MU-PIV optical flow diagnostics, ultimately serving as a versatile platform for elucidating the role of fluid forces on tumor-endothelial cross talk. PMID- 23730949 TI - Efficacy of video capsule endoscopy with flexible spectral imaging color enhancement at setting 3 for differential diagnosis of red spots in the small bowel. AB - BACKGROUND: Red spots on the small bowel mucosa are observed in patients with angioectasia and enteritis. The present study investigated the effectiveness of capsule endoscopy (CE)-flexible spectral imaging color enhancement (FICE) as a method for differential diagnosis of the two conditions. PATIENTS AND METHODS: The subjects were 30 patients who underwent CE and double-balloon endoscopy at Dokkyo Medical University Hospital between February 2007 and January 2013. Of these 30 patients, those diagnosed with angioectasia were assigned to Group A (n = 13) and those diagnosed with enteritis were assigned to Group E (n = 17). RESULTS: Using FICE at setting 3 and comparing the color intensity of the red spots on a four-step scale (0-3), no statistically significant (P = 0.712) difference was found between the twogroups (Group A: 2.69 +/- 0.48, Group E: 2.76 +/- 0.56). Subjects were considered to show a positive blue sign when areas of blue were observed against the yellow-green background and surrounding the red spots. A comparison of the ratio of positive blue sign for both groups (Group A: 15.4% +/- 37.6%, Group E: 94.1% +/- 24.2%) showed a statistically significant increase in the ratio in Group E (P < 0.001). CONCLUSION: The results of the present study suggest that blue sign may be effective in the differential diagnosis of angioectasia and enteritis in patients with red spots. PMID- 23730950 TI - Antiretroviral drug-related toxicities - clinical spectrum, prevention, and management. AB - INTRODUCTION: The number of HIV patients receiving antiretroviral therapy is increasing worldwide, as new infections continue to occur and access to drugs is scaling up in most developing regions. Due to the efficacious nature of combination antiretroviral therapy in most drug-adherent patients, the concerns on the safety profile of these lifelong medicines have attracted great attention. AREAS COVERED: Side effects of antiretroviral agents can be clinically symptomatic or manifest only as laboratory abnormalities. Drug-related toxicities can be grouped by antiretroviral drug class or damage of distinct body organs/systems. By mechanism, antiretroviral-associated adverse events generally result from hypersensitivity reactions, direct cytopathic effect, or idiosyncratic phenomena. EXPERT OPINION: A good knowledge of the toxicity profile of antiretroviral agents is warranted for HIV care providers in order to prevent and avoid unwanted complications. PMID- 23730948 TI - Predictive factors for 1-year outcome of a cohort of patients with severe traumatic brain injury (TBI): results from the PariS-TBI study. AB - OBJECTIVES: To assess outcome and predicting factors 1 year after a severe traumatic brain injury (TBI). METHODS: Multi-centre prospective inception cohort study of patients aged 15 or older with a severe TBI in the Parisian area, France. Data were collected prospectively starting the day of injury. One-year evaluation included the relatives-rating of the Dysexecutive Questionnaire (DEX R), the Glasgow Outcome Scale-Extended (GOSE) and employment. Univariate and multivariate tests were computed. RESULTS: Among 257 survivors, 134 were included (mean age 36 years, 84% men). Good recovery concerned 19%, moderate disability 43% and severe disability 38%. Among patients employed pre-injury, 42% were working, 28% with no job change. DEX-R score was significantly associated with length of education only. Among initial severity measures, only the IMPACT prognostic score was significantly related to GOSE in univariate analyses, while measures relating to early evolution were more significant predictors. In multivariate analyses, independent predictors of GOSE were length of stay in intensive care (LOS), age and education. Independent predictors of employment were LOS and age. CONCLUSIONS: Age, education and injury severity are independent predictors of global disability and return to work 1 year after a severe TBI. PMID- 23730951 TI - Kidney transplantation in children weighing less than 15 kg: extraperitoneal surgical access-experience with 62 cases. AB - Small children are a challenging group in whom to perform KT. This retrospective study analyzed the results of 62 KTs in children weighing <15 kg, performed between 1998 and 2010, using extraperitoneal access and anastomosis of the renal vessels of donors to the aorta and IVC or iliac vessels of the recipients. Thirty two (51.6%) grafts were LRDTs and 30 (48.4%) were DDRTs-28 of them pediatric. The mean age at KT was 3.7 +/- 2.2 yr (1-12), and the mean weight was 12.3 +/- 2.1 kg (5.6-14.9). Ten children weighed <10 kg, and five (8.1%) children presented previous thrombosis of the venous system. At one and five yr, patient survival was 93.2% and 84.2%, and graft survival was 85.2% and 72.7%. There were no differences between the rates for LRDT and DDRT. There were six vascular complications (four vascular thromboses, one laceration, and one renal artery stenosis) and two perirenal collections. Extraperitoneal access is a valid KT technique in children weighing <15 kg. PMID- 23730953 TI - Insights, attitudes and perceptions about asthma and its treatment: findings from a multinational survey of patients from 8 Asia-Pacific countries and Hong Kong. AB - BACKGROUND AND OBJECTIVE: The Asthma Insight and Management (AIM) survey was conducted in North America, Europe, the Asia-Pacific region and Latin America to characterize patients' insights, attitudes and perceptions about their asthma and its treatment. We report findings from the Asia-Pacific survey. METHODS: Asthma patients (>=12 years) from Australia, China, Hong Kong, India, Malaysia, Singapore, South Korea, Taiwan and Thailand were surveyed. Patients answered 53 questions exploring general health, diagnosis/history, symptoms, exacerbations, patient burden, disease management, medications/treatments and patient's attitudes. The Global Initiative for Asthma guidelines were used to assess asthma control. The survey was conducted by random digit telephone dialling (Australia, China and Hong Kong) or by random face-to-face interviews (India, Malaysia, Singapore, South Korea, Taiwan and Thailand). RESULTS: There were 80 761 households screened. Data from 3630 patients were collected. Wide disparity existed between objective measures of control and patient perception. Reported exacerbations during the previous year ranged from 19% (Hong Kong) to 67% (India). Reported unscheduled urgent/emergency visits to a doctor's office/hospital/clinic in the previous year ranged from 15% (Hong Kong) to 46% (Taiwan). Patients who reported having controlled asthma in the previous month ranged from 27% (South Korea) to 84% (Taiwan). Substantial functional and emotional limitations due to asthma were identified by 13% (South Korea) to 78% (India) of patients. CONCLUSIONS: Asthma has a profound impact on patients' well being despite the availability of effective treatments and evidence-based management guidelines. Substantial differences across the surveyed countries exist, suggesting unmet, country-specific cultural and educational needs. A large proportion of asthma patients overestimate their level of control. PMID- 23730954 TI - The relationship between nurse-patient interaction and meaning-in-life in cognitively intact nursing home patients. AB - AIM: To investigate the associations between nurse-patient interaction and meaning-in-life in a nursing home population. BACKGROUND: Meaning has been found to be a strong individual predictor of successful ageing and life satisfaction as well as an important psychological variable that promotes well-being. Meaning seems to serve as a mediating variable in both psychological and physical health. Connecting and communicating with others have been seen to facilitate meaning-in life among older individuals. DESIGN: Cross-sectional descriptive study. METHODS: The data were collected in 2008-2009 using the Nurse-Patient Interaction Scale and the Purpose-in-Life test. A total of 250 cognitively intact nursing home patients met the inclusion criteria and 202 (81%) participated. A structural equation model of the hypothesized relationship between nurse-patient interaction and meaning was tested by means of LISREL 8.8. FINDINGS: The structural equation model fit well with the data. A significant direct relationship between nurse patient interaction and meaning-in-life in cognitively intact nursing home patients was displayed. CONCLUSION: Nurse-patient interaction significantly relates to meaning and purpose-in-life among cognitively intact nursing home patients and might be an important resource in relation to the patient's mental health and global well-being. High-quality nurse-patient interaction and in-house activities aiming to increase patients' meaning might increase psychological and physical health, well-being and psycho-spiritual functioning in this vulnerable population. PMID- 23730955 TI - Association between a low ankle-brachial index and dementia in a general elderly population in Central Africa (Epidemiology of Dementia in Central Africa Study). AB - OBJECTIVES: To investigate the association between peripheral arterial disease (PAD) and dementia in native elderly African populations. DESIGN: Two successive door-to-door cross-sectional surveys in the general population. SETTINGS: Representative districts of Bangui (Central African Republic) and Brazzaville (Republic of Congo). PARTICIPANTS: Population aged 65 and older. MEASUREMENTS: Peripheral arterial disease was defined as an ankle-brachial index (ABI) of 0.90 or less. Cognitive screening was performed using the Community Screening Interview for Dementia and the Five-Word Test. Diagnosis of dementia was confirmed after further neuropsychological tests and neurological examination according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria. Multivariate logistic regression models were used to quantify the association between PAD and dementia in those populations, with adjustments for cardiovascular disease (CVD) and other variables. RESULTS: A significant association was observed between PAD and prevalent dementia (odds ratio (OR) = 2.43, 95% confidence interval (CI) = 1.44-4.13, P = .001), even after adjustment for age, city, sex, CVD risk factors, education, and depressive disorders (OR = 2.37, 95% CI = 1.31-4.26, P = .004). This association was stronger with lower ABI. CONCLUSION: These findings support the hypothesis of a link between atherosclerosis (represented by a low ABI) and cognitive disorders in native Africans and are similar to previous reports in African Americans and other ethnic groups. PMID- 23730957 TI - Quantitative orientation analysis by sum frequency generation in the presence of near-resonant background signal: acetonitrile on rutile TiO2 (110). AB - Sum frequency generation (SFG) spectroscopic techniques are used to investigate the molecular orientation of adsorbed acetonitrile on rutile TiO2 (110) at the solid-vapor interface. Generally, most molecular orientation analyses using SFG have been performed on dielectric substrates, to avoid the spectral interference between resonant and the near-resonant background signal. Although rutile crystal can be treated as a dielectric substrate, its electronic state contributes to the intensity and interferes with the resonant signal when the SFG frequency is close to its band gap energy. In addition, the rutile crystal is a uniaxial birefringent material, and the (110) surface is anisotropic, which further complicates the spectral analysis. In this study, various SFG measurement techniques were applied, and quantitative analytical methods were established to interpret the surface orientation of an adsorbed molecule. SFG vibrational spectra of acetonitrile on rutile TiO2 (110) surface have been measured using distinct polarization combinations, polarization mapping, and null angle method. By varying the polarization combinations of SFG, the magnitude and shape of the spectra undergo substantial change, which originate from the interference between the near-resonant signal from the rutile substrate and the resonance signal from the acetonitrile. Theory, simulation, and analytical methods for obtaining quantitative orientation information of a molecule on an anisotropic semiconductor substrate in the presence of a near-resonant signal are presented. PMID- 23730956 TI - Randomised clinical trial: the safety and tolerability of Trichuris suis ova in patients with Crohn's disease. AB - BACKGROUND: Recent evidence suggests that embryonated eggs of the porcine whipworm Trichuris suis ova (TSO) may be an effective treatment for inflammatory bowel disease (IBD). AIM: To assess the safety and tolerability of TSO following a single dose in patients with Crohn's disease. METHODS: This was a sequential dose-escalation (500, 2500 and 7500 viable embryonated TSO), randomised, double blind, placebo-controlled study to evaluate the safety of a single dose of oral suspension TSO in patients with Crohn's disease. Twelve patients were randomised into each of three cohorts. Patients were assessed 1, 3, 5, 7, 9, 11 and 14 days following dosing (via a telephone call and diary symptom collection through 14 days postdose) for adverse events, changes to concomitant medications and gastrointestinal (GI) signs and symptoms. Patients were again assessed at Months 1, 2 and 6. RESULTS: Eighteen males and 18 females were enrolled, ages 20 to 54 years. All patients were dosed and completed the initial 2-month follow-up period (five patients did not attend their 6-month study visit). GI disorders were reported with the highest frequency; 7 (25.9%) TSO-treated patients and 3 (33.3%) placebo-treated patients. No dose-dependent relationship was observed, with 3 (33.3%) placebo, 4 (44.4%) TSO 500, 0 (0.0%) TSO 2500 and 3 (33.3%) TSO 7500 patients experiencing at least one GI event, and no clinically meaningful changes in GI signs and symptoms. CONCLUSIONS: A single dose of Trichuris suis ova up to 7500 ova was well tolerated and did not result in short- or long-term treatment related side effects. Clinicaltrials.gov NCT01576461. PMID- 23730958 TI - Total syntheses of cannabicyclol, clusiacyclol A and B, iso-eriobrucinol A and B, and eriobrucinol. AB - Total syntheses of a series of chromane natural products that contain a cyclobutane ring are described. A unified theme in the strategy employed for all these syntheses is an oxa-[3 + 3] annulation for constructing the chromane nucleus and a stepwise cationic [2 + 2] cycloaddition for the cyclobutane formation. More importantly, the two reactions could be rendered in tandem, thereby providing an expeditious approach to this family of natural products. PMID- 23730959 TI - Elevated serum IgE in recurrent aphthous stomatitis and associations with disease characteristics. AB - OBJECTIVES: To characterize demographic, clinical and serological parameters in recurrent aphthous stomatitis (RAS) patients and analyse their association with serum immunoglobulin E (IgE) levels. SUBJECTS AND METHODS: Forty-nine patients with RAS responded to a questionnaire that included demographic background, stress status, smoking habits, history and course of RAS episodes. They were also subjected to relevant laboratory tests, including determination of serum IgE levels. RESULTS: A familial history of RAS was reported by 47.9% of the patients, stress in the previous year by 51.1% and smoking by 18.4%. Non-Caucasian origin, familial history of RAS, stress and smoking were associated with increased severity of RAS episodes. Haematological deficiencies were observed in 18.7% of RAS patients. Average IgE levels were increased and were significantly associated with younger age, <=12 years of schooling, female gender, RAS episode frequency of every 2 weeks, early onset of RAS episodes and elevated C reactive protein levels. CONCLUSION: Immunoglobulin E levels may be considered as part of the RAS patient's work-up. Further research is needed to identify biological mechanisms that account for the observed associations. PMID- 23730960 TI - Predictors of mental health care use among male and female veterans deployed in support of the wars in Afghanistan and Iraq. AB - What factors predict whether Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) veterans who need mental health care receive that care? The present research examined factors associated with a need for care, sociodemographic characteristics, deployment experiences, and perceptions of care as gender-specific predictors of overall mental health care use and Veterans Affairs (VA) mental health care use for male and female OEF/OIF veterans (N = 1,040). Only veterans with a probable need for mental health care, as determined by scores on self-report measures of mental health symptomatology, were included in the sample. Overall, predictors of service use were similar for women and men. A notable exception was the finding that lower income predicted use of both overall and VA mental health care for women, but not men. In addition, sexual harassment was a unique predictor of VA service use for women, whereas non-White race was predictive of VA service use for men only. Knowledge regarding the factors that are associated with use of mental health care (broadly and at VA) is critical to ensuring that veterans who need mental health care receive it. PMID- 23730961 TI - Postdeployment military mental health training: cross-national evaluations. AB - Deployments increase risk for adjustment problems in service members. To mitigate this increased risk, mental health training programs have been developed and implemented in several nations. As part of a coordinated effort, three nations adapted a U.S. mental health training program that had been validated by a series of group randomized trials demonstrating improvement in postdeployment adjustment. Implementation of evidence-based programs in a new context is challenging: How much of the original program needs to remain intact in order to retain its utility? User satisfaction rates can provide essential data to assess how well a program is accepted. This article summarizes service member ratings of postdeployment mental health training and compares ratings from service members across four nations. The participating nations (Canada, New Zealand, United Kingdom, and the United States) administered mental health training to active duty military personnel in their respective nations. Following the training, military personnel completed an evaluation of the training. Overall, across the four nations, more than 70% of military personnel agreed or strongly agreed that they were satisfied with the mental health training. Although some differences in evaluations were observed across nations, components of training that were most important to overall satisfaction with the training were strikingly similar across nations. Fundamentally, it appears feasible that despite cultural and organizational differences, a mental health training program developed in one nation can be successfully adapted for use in other nations. PMID- 23730962 TI - Influence of trauma history on panic and posttraumatic stress disorder in returning veterans. AB - The current study examined the role of predeployment sexual and physical abuse, combat exposure, and postdeployment social support in predicting panic disorder and PTSD diagnoses in a large sample of returning veterans. A chart review was conducted for 1740 OEF/OIF veterans who received mental health screenings at a large VA hospital between May 24, 2004 and March 26, 2008. Assessments included psychosocial evaluations conducted by psychiatrists, psychologists, and social workers in addition to self-report measures. Results suggested that the prevalence of panic disorder (6.1%) and PTSD (28.7%) are elevated among OEF/OIF veterans. Veterans reporting higher levels of combat experience were likely to be diagnosed with PTSD (odds ration [OR], 1.17; 95% confidence interval [CI], 1.10 1.25; p < .001) or comorbid panic disorder and PTSD (OR, 1.18; 95% CI, 1.04-1.33; p < .001). Veterans endorsing predeployment sexual abuse were likely to be diagnosed with comorbid panic disorder and PTSD (OR, 3.05; 95% CI, 1.15-8.08; p < .05), as were veterans endorsing predeployment physical abuse (OR, 0.47; 95% CI, 0.22-1.00; p < .05). Panic disorder was also found to be associated with greater risk for suicide attempts than PTSD (chi2 = 16.38, p = .001). These findings indicate a high prevalence of panic disorder among returning veterans and highlight the importance for clinicians to assess returning veterans routinely for panic disorder in addition to PTSD. PMID- 23730963 TI - Perceived military organizational support and peacekeeper distress: a longitudinal investigation. AB - Many professions vital to the safety of society require workers to face high magnitude and potentially traumatizing events. Because this routine exposure can cause high levels of stress in workers, it is important to investigate factors that contribute to both risk of posttraumatic stress disorder (PTSD), and healthy responses to stress. Although some research has found social support to mitigate the effects of posttraumatic stress symptoms, scant research has investigated organizational support. The aim of the present study is to investigate the temporal relationship between stress symptoms and perceived organizational support in a sample of 1,039 service members deployed to the peacekeeping mission to Kosovo. Participants completed self-report measures of stress symptoms and perceived organizational support at 4 study time points. Bivariate latent difference score structural equation modeling was utilized to examine the temporal relationship among stress and perceived organizational support. In general, across the 4 time points, latent PCL scores evidenced a salient and negative relationship to subsequent POS latent difference scores. However, no significant relationship was found between latent POS variables and subsequent PCL latent difference scores. Findings suggest that prior stress symptoms are influencing service member's perceptions of the supportiveness of their organization such that increased prior stress is associated with worsening perceptions of support. These results illustrate that targeting stress directly may potentiate the positive influence of organizational support and that institutional support programs should be adapted to better account for the negative biases increased distress may encourage. PMID- 23730964 TI - Barriers to care for women veterans with posttraumatic stress disorder and depressive symptoms. AB - As the number of women veterans continues to rise, an issue of concern is whether those with mental health symptoms experience disproportionate barriers to care. The purpose of this study was to examine unmet medical needs and barriers to health care among women veterans who screened positive for lifetime posttraumatic stress disorder (PTSD), current depressive symptoms, both or neither. Using the National Survey of Women Veterans dataset (N = 3,593), we compared women veterans corresponding to these 4 groups on whether they had unmet medical needs in the past year, reasons for unmet needs, and barriers to using VA care for those not currently doing so. The majority of women veterans who screened positive for both PTSD and depressive symptoms had unmet medical care needs in the prior 12 months (59%), compared to 30% of women with PTSD symptoms only, 18% of those with depressive symptoms only, and 16% of women with neither set of symptoms. Among those reporting unmet medical needs (n = 840), those with both PTSD and depressive symptoms were more likely than the other groups to identify affordability as a reason for going without or delaying care. Among women veterans not using VA health care (n = 1,677), women with both PTSD and depressive symptoms were more likely to report not knowing if they were eligible for VA benefits and were less likely to have health insurance to cover care outside of the VA. These data highlight specific areas of vulnerability of women veterans with comorbid PTSD and depressive symptoms and identify areas of concern as VA and other health facilities work to ensure equitable access to care. PMID- 23730965 TI - Veterans administration health care utilization among sexual minority veterans. AB - According to recent census reports, nearly a million veterans have a same-sex partner, yet little is known about them or their use of Veterans Health Care Administration (VHA) services. Gay, lesbian, and bisexual (GLB) veterans recruited from the community (N = 356) completed an on-line survey to assess their rates of VHA utilization and whether they experience specific barriers to accessing VHA services. Andersen's model of health care utilization was adapted to provide an analytic and conceptual framework. Overall, 45.5% reported lifetime VHA utilization and 28.7% reported past-year VHA utilization. Lifetime VHA health care utilization was predicted by positive service connection, positive screen for both posttraumatic stress disorder (PTSD) and depression, and history of at least one interpersonal trauma during military service related to respondent's GLB status. Past-year VHA health care utilization was predicted by female gender, positive service connection, positive screen for both PTSD and depression, lower physical functioning, a history of military interpersonal trauma related to GLB status, and no history of stressful experiences initiated by the military to investigate or punish GLB status. Rates of VHA utilization by GLB veterans in this sample are comparable to those reported by VHA Central Office for all veterans. Of those who utilized VHA services, 33% reported open communication about their sexual orientation with VHA providers. Twenty-five percent of all participants reported avoiding at least one VHA service because of concerns about stigma. Stigma and lack of communication between GLB veterans and their providers about sexual orientation are areas of concern for VHA. PMID- 23730966 TI - The impact of current alcohol and drug use on outcomes among homeless veterans entering supported housing. AB - Permanent supported housing has increasingly been identified as a central approach to helping homeless individuals with disabilities exit from homelessness. Given that one third or more of homeless individuals actively use substances, it is important to determine the extent to which individuals who report using alcohol and/or drugs at the time of housing benefit from such programs. The current study examines data from the evaluation of the United States Department of Housing and Urban Development-Veterans Affairs (HUD-VA) Supported Housing (HUD-VASH) program to determine differences in housing and clinical outcomes among participants with two different levels of active alcohol or drug use at time of housing entry. Whereas veterans with 1-15 days of active use and 15-30 days of active use had significantly more days homeless than abstainers, albeit with small effect sizes (.06 and .19, respectively), there were no significant differences in days housed or days in institutions. Interaction analysis suggests that the highest frequency substance users who spent time in residential treatment prior to housing had the poorest housing outcomes, while those who were not in residential treatment had outcomes comparable to abstainers. Although active substance users clearly benefit from supportive housing with small differences in outcomes from abstainers, high frequency substance users who were admitted to residential treatment before housing placement, may be an especially vulnerable population. PMID- 23730967 TI - Endoscopic closure of experimental iatrogenic gastric fundus perforation using over-the-scope clips in a surviving canine model. AB - BACKGROUND AND AIM: To evaluate the effectiveness and outcomes of endoscopic closure of a gastric fundus perforation using over-the-scope clips (OTSCs) system in a surviving canine model. METHODS: Gastric fundus perforations (20-mm diameter) were created by an endoscopic needle-knife in six dogs. The perforations then were closed by the OTSC system. Gastroscopy was performed to evaluate the postoperative perforation healing every week. The animals were sacrificed 4 weeks later to examine the possible intraperitoneal complications, and the healing of the perforation was examined histopathologically. RESULTS: The gastric fundus perforations could primarily be closed using one OTSC in each experimental dog, and the mean time of the procedure was 17.3 +/- 7.6 min (9-26 min). All animals survived without postoperative complications. The OTSC retention was observed in one dog at the end of 4 weeks, and the apparent foreign body reaction was examined pathologically. CONCLUSIONS: Our surviving animal study demonstrated that the OTSC clip system could reliably close gastric fundus perforations without complications. PMID- 23730970 TI - Modulation of protonation-deprotonation processes of 2-(4'-pyridyl)benzimidazole in its inclusion complexes with cyclodextrins. AB - 2-(4'-Pyridyl)benzimidazole (4PBI) can exist in several states of protonation, having three basic nitrogen atoms. The equilibria involving these states, in ground as well as in excited states, are found to be affected significantly by cyclodextrins (CDs). The formation of inclusion complexes of this compound with all three varieties of cyclodextrins is observed to be more favorable at pH 9 than at pH 4, due to the predominance of the neutral form of dye at pH 9. The binding affinity of 4PBI to CDs is found to be governed by two factors: (i) the size of the host and (ii) the mode of insertion of 4PBI. We find that, for the host with a smaller cavity (alpha-CD), insertion of the dye with a pyridyl face is favored, whereas, for gamma-CD, the preference is shifted toward the benzimidazole face of the dye. For beta-CD, the binding affinity of the dye is maximum due to perfect cavity matching with the guest. A combination of steric factor and hydrogen bonding interaction is found to be responsible for modulation of the protonation-deprotonation equilibria of the guest molecule in the inclusion complex. Surprisingly, a protonated form is found to be promoted upon inclusion in cyclodextrins, under certain conditions. This is an unusual behavior and has been rationalized by prototropism involving the hydroxyl protons of cyclodextrin molecules. PMID- 23730968 TI - Phytotoxic activity and metabolism of Botrytis cinerea and structure-activity relationships of isocaryolane derivatives. AB - Research has been conducted on the biotransformation of (8S,9R)-isocaryolan-9-ol (4a) and (1S,2S,5R,8S)-8-methylene-1,4,4-trimethyltricyclo[6.2.1.0(2,5)]undecan 12-ol (5a) by the fungal phytopathogen Botrytis cinerea. The biotransformation of compound 4a yielded compounds 6-9, while the biotransformation of compound 5a yielded compounds 10-13. The activity of compounds 4a and 5a against B. cinerea has been evaluated. (8R,9R)-Isocaryolane-8,9-diol (6), a major metabolite of compound 4a, shows activity compared to its parent compound 4a, which is inactive. The effect of isocaryolanes 3, 4a, and 5a, together with their biotransformation products 6-8, 10, and 14-17, on the germination and radicle and shoot growth of Lactuca sativa (lettuce) has also been determined. Compounds 7-13 are described for the first time. PMID- 23730969 TI - ML297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in mice. AB - The G-protein activated, inward-rectifying potassium (K(+)) channels, "GIRKs", are a family of ion channels (Kir3.1-Kir3.4) that has been the focus of intense research interest for nearly two decades. GIRKs are comprised of various homo- and heterotetrameric combinations of four different subunits. These subunits are expressed in different combinations in a variety of regions throughout the central nervous system and in the periphery. The body of GIRK research implicates GIRK in processes as diverse as controlling heart rhythm, to effects on reward/addiction, to modulation of response to analgesics. Despite years of GIRK research, very few tools exist to selectively modulate GIRK channels' activity and until now no tools existed that potently and selectively activated GIRKs. Here we report the development and characterization of the first truly potent, effective, and selective GIRK activator, ML297 (VU0456810). We further demonstrate that ML297 is active in two in vivo models of epilepsy, a disease where up to 40% of patients remain with symptoms refractory to present treatments. The development of ML297 represents a truly significant advancement in our ability to selectively probe GIRK's role in physiology as well as providing the first tool for beginning to understand GIRK's potential as a target for a diversity of therapeutic indications. PMID- 23730971 TI - Executive function in children and adolescents with posttraumatic stress disorder 4 and 12 months after the Sichuan earthquake in China. AB - BACKGROUND: While several studies have found executive function deficits in adults and maltreated children with posttraumatic stress disorder (PTSD), there are few data on executive function in children and adolescents with PTSD related to natural disasters. The objective of this study was to test executive function changes over time in children and adolescents with PTSD after a magnitude 8.0 earthquake in Sichuan, China. METHOD: A sample of 34 children and adolescents with diagnosed PTSD following the Sichuan earthquake and 66 matched controls exposed to the same earthquake but without PTSD participated in the study. Executive function was assessed using a battery of interviewer-rated neuropsychological tests and the guardian-rated Behavior Rating Scale of Executive Function (BRIEF) at 4- and 12-month after the earthquake. RESULTS: Children and adolescents with PTSD performed similar to controls in executive function at 4-months after the earthquake. Both groups improved significantly in similar domains of cognition during the following 8 months. The PTSD group exhibited daily deficits in emotional control compared with the controls at the 4 month assessment, but the differences disappeared during the following 8 months. CONCLUSIONS: Children and adolescents with PTSD related to a natural disaster have deficits only in the emotional control domain of executive function compared with controls exposed to the same disaster, but even these deficits did not persist. PMID- 23730972 TI - How do trees die? A test of the hydraulic failure and carbon starvation hypotheses. AB - Despite decades of research on plant drought tolerance, the physiological mechanisms by which trees succumb to drought are still under debate. We report results from an experiment designed to separate and test the current leading hypotheses of tree mortality. We show that pinon pine (Pinus edulis) trees can die of both hydraulic failure and carbon starvation, and that during drought, the loss of conductivity and carbohydrate reserves can also co-occur. Hydraulic constraints on plant carbohydrate use determined survival time: turgor loss in the phloem limited access to carbohydrate reserves, but hydraulic control of respiration prolonged survival. Our data also demonstrate that hydraulic failure may be associated with loss of adequate tissue carbohydrate content required for osmoregulation, which then promotes failure to maintain hydraulic integrity. PMID- 23730973 TI - Altered gene expression in gingival tissues and enhanced bone loss in rats with diabetes with experimental periodontitis. AB - BACKGROUND: Systemic hyperglycemia is clearly related to severity of periodontitis, meaning that periodontitis can be exacerbated by diabetes mellitus (DM). However, the biologic mechanisms responsible for this relationship remain unclear. Thus, in this study, the global gene expression in gingival tissue with periodontitis is profiled in Zucker diabetic fatty (ZDF) rats compared with Zucker normoglycemic littermates (Lean). METHODS: At age 8 weeks, ZDF and Lean rats received ligature placement around the maxillary right second molar. At 0, 14, 28, 42, and 56 days after ligature placement, the maxilla around the molar was analyzed using microcomputed tomography. Two and 7 days after ligature placement, total RNA in the gingival tissue was isolated, and gene expression analysis was conducted using a rat oligo array. To validate the microarray findings, the selected genes were analyzed using real-time quantitative polymerase chain reaction assays. RESULTS: There was a significant difference regarding the average amount of bone resorption between ZDF and Lean rats from days 14 to 56. On day 2, it was found that 113 genes were regulated (20 upregulated, 93 downregulated) in the presence of DM. Lipopolysaccharide binding protein (LBP) messenger RNA (mRNA) expression was significantly higher in gingival tissue with periodontitis from ZDF rats compared with that from Lean rats. On day 7, interleukin (IL)-10 and IL-24 mRNA levels were significantly lower, whereas IL-2 level was significantly elevated. CONCLUSION: The results of this study indicate that the role of DM in modulating bone breakdown related to periodontitis may involve an increased level of LBP and reduced levels of T helper 2 cytokines. PMID- 23730974 TI - Drying-mediated assembly of colloidal nanoparticles into large-scale microchannels. AB - Large-scale highly ordered microchannels were spontaneously and rapidly created by simply drying the colloidal nanoparticle suspension on a rigid substrate. Interestingly, free evaporation of colloidal suspension yielded radially aligned microchannels, while constrained evaporation that was rendered by the use of confined geometries composed of either two nearly parallel plates or a slide placed perpendicular to a rigid substrate imparted the formation of periodic arrays of parallel microchannels in a controllable manner. The microchannels were formed as a result of the competition between stress relaxation due to crack opening that ruptured the film and stress increase due to the loss of solvent. Quite intriguingly, these patterned microchannels can be exploited as templates to craft well-ordered metallic stripes. This facile and scalable approach may offer a new paradigm of producing microscopic patterns over large areas with unprecedented regularity at low cost that can serve as scaffolds for use in microelectronics and microfluidic-based biochips, among other areas. PMID- 23730975 TI - The changes of lumbar muscle flexion-relaxation response due to laterally slanted ground surfaces. AB - Lifting tasks performed on uneven ground surfaces are common in outdoor industries. Previous studies have demonstrated that lifting tasks performed on laterally slanted ground surfaces influence lumbar muscle activation and trunk kinematics. In this study, the effect of laterally slanted ground surfaces on the lumbar muscle flexion-relaxation responses was investigated. Fourteen participants performed sagittal plane, trunk flexion-extension tasks on three laterally slanted ground surfaces (0 degrees (flat ground), 15 degrees and 30 degrees ), while lumbar muscle activities and trunk kinematics were recorded. Results showed that flexion-relaxation occurred up to 6.2 degrees earlier among ipsilateral lumbar muscles with an increase in laterally slanted ground angle; however, the contralateral side was not affected as much. Our findings suggest that uneven ground alters the lumbar tissue load-sharing mechanism and creates unbalanced lumbar muscle activity, which may increase the risk of low back pain with repeated exposure to lifting on variable surfaces. PRACTITIONER SUMMARY: Uneven ground surfaces are ubiquitous in agriculture, construction, fishing and other outdoor industries. A better understanding of the effects of laterally slanted ground surfaces on the interaction between passive and active lumbar tissues during lifting tasks could provide valuable knowledge in the design of preventive strategies for low back injuries. PMID- 23730976 TI - Can flat-type brownish microlesions in the orohypopharynx be followed up without biopsy or endoscopic resection? AB - BACKGROUND: Narrow-band imaging (NBI) is useful for detecting superficial oropharyngeal lesions. However, the diagnostic and treatment guidelines for NBI are not established. The aim of the present study was to evaluate the treatment strategy for these microlesions. METHODS: From October 2008 to September 2009, 68 flat-type brownish microlesions were observed in the orohypopharynx using NBI. Lesions were examined via magnifying NBI (M-NBI) and followed up without biopsy or endoscopic resection for >12 months. To clarify the characteristics, lesions were compared with the endoscopic characteristics of flat-type lesions diagnosed by biopsy and endoscopic resection as squamous cell carcinoma and high-grade intraepithelial neoplasia. RESULTS: The average diameter of the 68 lesions was 1.6 mm (range, 0.5-5 mm). At the 1-year follow up, 19 lesions had disappeared. No size increases or morphological changes wereobserved among 49 lesions followed for >1 year. At 2 years, 10 patients had dropped out and 11 lesions had disappeared. No changes were observed among 28 lesions followed for >2 years. Of the flat-type lesions as squamous cell carcinoma and high-grade intraepithelial neoplasia, a distinct border and irregular distribution of atypical vessels were observed in all cases using M-NBI. These findings were observed in two of 68 flat type brownish microlesions during follow up. CONCLUSION: Although there is some possibility of squamous cell carcinoma or high-grade intraepithelial neoplasia, flat-type microlesions of <=5 mm diameter in the orohypopharynx may be followed for up to 2 years without biopsy or endoscopic resection. PMID- 23730977 TI - Dietary Chinese quince polyphenols suppress generation of alpha-dicarbonyl compounds in diabetic KK-A(y) mice. AB - Many dietary polyphenols can provide health benefits, such as antioxidant and antidiabetic effects, and can down-regulate the progression of glycation (one cause of diabetic complications). Chinese quince (CQ) is rich in polyphenols, especially procyanidins. A few studies have indicated that CQ has an effect on diabetes. In this study, a procyanidin-rich extract was prepared from Chinese quince fruit (CQE), and its effects were investigated and compared with those of green tea extract (GTE) in type 2 diabetes model KK-A(y) mice. Mice were provided one of two high-fat (HF) diets for 4 weeks: a HF diet containing 0.5% CQE or a HF diet containing 0.5% GTE. Blood glucose was suppressed in mice fed CQE and GTE during the experimental period (p < 0.05), although the effect of CQE was weaker than that of GTE. Intake of CQE had no effect on the blood insulin level, whereas GTE decreased the insulin level. Body weight gain was suppressed in mice fed CQE similarly to mice fed GTE (p < 0.05). Hepatic lipid content and alpha-dicarbonyl compounds in the kidney were reduced in mice fed CQE and GTE (p < 0.05). These results suggest that intake of CQE could moderate type 2 diabetes and diabetic complications. PMID- 23730978 TI - Retroclival subdural haematoma secondary to pituitary apoplexy. AB - Retroclival haematomas are rare entity and they are mostly caused by trauma. There has been only one case published to have a retroclival haematoma following pituitary apoplexy. We present a patient diagnosed with pituitary apoplexy who was found to have acute subdural retroclival haematoma on the MRI. PMID- 23730979 TI - Evaluation of the impact of the Canadian subarachnoid haemorrhage clinical decision rules on British practice. AB - INTRODUCTION: Acute headache is among the commonest presenting complaints to emergency departments. While it is estimated that only 1-3% result from subarachnoid haemorrhage (SAH), because the disease carries such significant morbidity and mortality if missed, most clinicians have a low threshold for investigation. A recent prospective cohort study in Canada determined a number of high-risk clinical characteristics for SAH in patients with acute headache. We investigated the potential impact of incorporating the Canadian clinical decision rules on British practice. METHODS: A retrospective case note review on all adult patients presenting to our emergency department with acute headache between August and October 2011 was conducted. The Canadian decision rules for SAH were applied retrospectively to the cases identified, and the sensitivity, specificity and negative predictive values calculated. The two-tailed McNemar test was used to evaluate differences between proportions of patients undergoing investigations using the clinical decision rules against current practice. RESULTS: In all, 112 patients met the inclusion criteria in a 3-month period, of which 41 patients (36.6%) underwent unenhanced computed tomography and 4 (3.6%) were found to have SAH. Nine patients subsequently had a lumbar puncture and none demonstrated xanthochromia. None of the patients who were not fully investigated were readmitted to the regional neurosurgical centre within 6 months of discharge with missed SAH. Application of the Canadian clinical decision rules would have led to an investigation rate between 59% and 74%, compared to an actual rate of 37% (p < 0.05). CONCLUSION: The present study shows that application of the Canadian clinical decision rules for SAH would lead to more patients with acute headache being investigated than current British practice. However, much larger prospective studies are required to determine whether such clinical decision rules may identify patients at risk who would otherwise have been missed. PMID- 23730980 TI - Support after the completion of cancer treatment: perspectives of Australian adolescents and their families. AB - Young people recovering from cancer may lack adequate support post-treatment, yet little is known about the types of support and information young Australians and their families need. This study investigated adolescent/young adult cancer survivors' and their families' perceptions of care and support needs after completing cancer treatment. Seventy semi-structured interviews were conducted with 19 survivors (mean age 16.1 years), 21 mothers, 15 fathers and 15 siblings. Interviews were recorded, transcribed and analysed using the conceptual framework of Miles and Huberman. Post-treatment, participants regarded medical staff positively but were reluctant to ask for their help fearing it may deflect resources away from patients still receiving treatment. Appraisals of social workers' and psychologists' support post-treatment were mixed. Formal emotional support was rarely accessed and participants reported that any additional funds should be directed to greater psychological support in this period. Participants also reported the need for additional financial support post-treatment. Clinicians need to be aware that while young people and their families may not demand support post-treatment, they may 'suffer in silence' or burden family members and friends with the responsibility of providing emotional support, though they may be experiencing distress also. PMID- 23730981 TI - Determining the relative antihypertensive potency and relative cardiovascular risk reduction associated with different thiazide and thiazide-type diuretics. PMID- 23730982 TI - Improving approaches to hypertension treatment in African Americans: lessons learned from the Jackson Heart Study. PMID- 23730983 TI - Therapeutic inertia and measurement inertia in hypertension: a call to action. PMID- 23730985 TI - Prevalence of true therapeutic inertia in blood pressure control in an academic chronic kidney disease clinic. AB - Therapeutic inertia (TI) in blood pressure (BP) control has been traditionally defined as failure to initiate or intensify therapy when treatment goals are not met. The fallacy with this definition is that TI may be overestimated because it includes hypertensive patients deliberately uncontrolled. This is a retrospective chart review study that evaluated physicians' response to an uncontrolled clinic BP reading in a population of patients with stage 3 to 5 chronic kidney disease (CKD) and hypertension. Of 429 patients screened, 166 had controlled BP and 263 did not. Of these 263 patients, 115 patients had no clear reason documented for the absence of changes in medication regimen. This population was defined as cases with true TI. In the remaining 148 patients, the medication regimen was changed in 81 patients. In the rest of the patients, there was a reason documented for not changing the medication regimen. The prevalence of true TI rate (defined as percentage of uncontrolled hypertension as a result of physician inaccountability) in our study was 44% as compared with 69% if the traditional TI definition is applied. Thus, we conclude that the prevalence of TI in the literature overestimates the rate of true TI as it does not account for physician decision making. The current definition of TI in BP control needs to be revised, as it underestimates a provider's care to improve BP control and is misleading. The TI definition should include some mechanism to account for interventions beyond medication titration. PMID- 23730984 TI - Treatment of hypertension among African Americans: the Jackson Heart Study. AB - Hypertension treatment regimens used by African American adults in the Jackson Heart Study were evaluated at the first two clinical examinations (2415 treated hypertensive persons at examination I [exam I], 2000-2004; 2577 at examination II [exam II], 2005-2008). Blood pressure (BP) was below 140/90 mm Hg for 66% and 70% of treated participants at exam I and exam II, respectively. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure treatment targets were met for 56% and 61% at exam I and exam II, respectively. Persons with diabetes or chronic kidney disease were less likely to have BP at target, as were men compared with women. Thiazide diuretics were the most commonly used antihypertensive medication, and persons taking a thiazide were more likely to have their BP controlled than persons not taking them; thiazides were used significantly less among men than women. Although calcium channel blockers are often considered to be effective monotherapy for African Americans, persons using calcium channel blocker monotherapy were significantly less likely to be at target BP than persons using thiazide monotherapy. PMID- 23730986 TI - Telmisartan/Hydrochlorothiazide combination therapy for the treatment of hypertension: a pooled analysis in older and younger patients. AB - Older patients frequently receive angiotensin II receptor blocker/diuretic combinations to control blood pressure (BP), although there have been relatively few trials specifically examining this patient population. A pooled analysis was performed of data from 7 randomized trials of telmisartan/hydrochlorothiazide combinations or telmisartan monotherapy in older (65 years and older) and younger (younger than 65 years) patients to better understand the response of older patients to a telmisartan/hydrochlorothiazide combination. Telmisartan doses were 40 mg and 80 mg (T40 and T80). Hydrochlorothiazide doses were 12.5 mg and 25 mg (H12.5 and H25). A total of 3654 patients were included and the mean treatment duration was approximately 8 weeks. BP reductions with telmisartan/hydrochlorothiazide combinations were broadly similar in older and younger patients. In older patients, mean BP reductions from baseline were -30.1/ 19.0 mm Hg with the T80/H25 combination and -21.7/-13.0 mm Hg with T80 monotherapy. Tolerability was similar regardless of age, and the incidence of adverse events in both older and younger patients was similar to placebo. The telmisartan/hydrochlorothiazide combination, particularly high-dose T80/H25, is effective and well tolerated in patients 65 years and older as well as in younger patients. PMID- 23730987 TI - Health behaviors for hypertension management in people with and without coexisting diabetes. AB - Since blood pressure (BP) control is less often achieved by individuals with diabetes, the authors sought to determine whether receipt of and adherence to health behavior advice for hypertension control differs between people with and without diabetes, using data from the 2009 Survey on Living With Chronic Diseases in Canada. Individuals with coexisting diabetes were more likely to report receiving advice to control/lose weight (81% vs 66%), be physically active (79% vs 68%), limit alcohol consumption (78% vs 55%), and modify diet (70% vs 61%) but not limit dietary salt (65% vs 64%) compared with individuals with hypertension alone (n=4.965). People with and without diabetes were equally likely to report following the advice they received, with receipt of advice positively associated with engagement in healthy behaviors. Since receipt of advice appears to influence behavior, health professionals should be encouraged to further promote BP self-management strategies. PMID- 23730988 TI - Rationale for establishing a mechanism to increase reimbursement to hypertension specialists. AB - Hypertension is an important public health problem both in the United States and worldwide, contributing to many forms of cardiovascular and renal diseases. Although great strides have been made in the proportion of the US population that achieves recommended blood pressure targets, many Americans still have undertreated and uncontrolled blood pressure that increases the risk of expensive strokes, heart attacks, heart failure, and dialysis. Because hypertension is a common but heterogeneous and sometimes complex condition, the American Society of Hypertension (ASH) has, since 1999, designated physicians as "ASH Hypertension Specialists." Such Hypertension Specialists (as defined by ASH's Specialist Program) are fully licensed physicians with a primary board certification who are competent in all aspects of the diagnosis and treatment of hypertension, as evidenced by passing a specific examination on these topics offered by ASH's Specialist Program. These physicians have a proven track record of controlling blood pressure in "resistant hypertensive" patients, the general population whom they serve, and educating other physicians to help them achieve higher blood pressure control rates among their patient populations. This report sets out a rationale for increased reimbursement for care of hypertensive patients by ASH Designated Hypertension Specialists. PMID- 23730989 TI - Similar blood pressure values across racial and economic groups: baseline data from a group randomized clinical trial. AB - This paper examines baseline characteristics from a prospective, cluster randomized trial in 32 primary care offices. Offices were first stratified by percentage of minorities and level of clinical pharmacy services and then randomized into 1 of 3 study groups. The only differences between randomized arms were for marital status (P=.03) and type of insurance coverage (P<.001). Blood pressures (BPs) were similar in Caucasians and minority patients, primarily blacks, who were hypertensive at baseline. On multivariate analyses, patients who were 65 years and older had higher systolic BP (152.4 +/- 14.3 mm Hg), but lower diastolic BP (77.3 +/- 11.8 mm Hg) compared with those younger than 65 years (147.4 +/- 15.0/88.6 +/- 10.6 mm Hg, P<.001 for both systolic and diastolic BP). Other factors significantly associated with higher systolic BP were a longer duration of hypertension (P=.04) and lower basal metabolic index (P=.011). Patients with diabetes or chronic kidney disease had a lower systolic BP than those without these conditions (P<.0001). BP was similar across racial and socioeconomic groups for patients with uncontrolled hypertension in primary care, suggesting that patients with uncontrolled hypertension and an established primary care relationship likely have different reasons for poor BP control than other patient populations. PMID- 23730990 TI - Association of B2 receptor polymorphisms and ACE activity with ACE inhibitor induced angioedema in black and mixed-race South Africans. AB - Angiotensin-converting enzyme (ACE) inhibitors are first-line therapy for the treatment of hypertension, congestive heart failure, and diabetic nephropathy. ACE inhibitors are associated with adverse side effects such as persistent dry cough (ACE-cough) and, rarely, life-threatening angioedema (ACE-AE). The authors investigated the influence of ACE I/D polymorphism in combination with serum ACE activity, B2 receptor -9/+9 polymorphism, and B2 receptor C-58T single nucleotide polymorphism (SNP) on the development of ACE-AE and ACE-cough. The frequencies of ACE I/D as well as B2 receptor +9/-9 and C-58T polymorphisms were compared in patients with ACE-AE, ACE-cough, and ACE inhibitor-exposed controls, and serum ACE activity was measured. There were 52 cases of ACE-AE, 36 cases of ACE-cough, and 77 controls. The genotyping revealed a significant association between the B2 -9 allele and ACE inhibitor-induced AE (62% vs 38%, P=.008), and ACE inhibitor induced cough (61% vs 38%, P=.02) when compared with controls. There was no significant association between ACE I/D polymorphism as well as the B2 C-58T SNP with both ACE-induced AE and cough. ACE activity was significantly higher in controls compared with patients with ACE-AE (34.5 +/- 1.14 mU/mL vs 17.8 +/- 0.86 mU/mL, P=.0001) and ACE-cough (34.5 +/- 1.14 mU/mL vs 23.3 +/- 1.88 mU/mL, P=.0001). Thus, our data suggest that the B2 -9 allele and reduced ACE activity are associated with both ACE-AE and ACE-cough. PMID- 23730991 TI - Effects of intensive antihypertensive treatment on Chinese hypertensive patients older than 70 years. AB - This study was performed to investigate whether intensive antihypertensive treatment with achieved blood pressure (BP) <=140/90 mm Hg, as compared with standard treatment with achieved BP <=150/90 mm Hg, could further improve cardiovascular outcomes in Chinese hypertensive patients older than 70 years. A total of 724 participants were randomly assigned to intensive or standard antihypertensive treatment. After a mean follow-up of 4 years, the mean achieved BP was 135.7/76.2 mm Hg in the intensive treatment group and 149.7/82.1 mm Hg in the standard treatment group. The visit-to-visit variability in systolic BP and diastolic BP was lower in the intensive group than that in the standard group. Intensive antihypertensive treatment, compared with the standard treatment, decreased total and cardiovascular mortality by 41.7% and 50.3%, respectively, and reduced fatal/nonfatal stroke by 42.0% and heart failure death by 62.7%. Cox regression analysis indicated that the mean systolic BP (P=.020; 95% confidence interval, 1.006-1.069) and the standard deviation of systolic BP (P=.033; 95% confidence interval, 1.006-1.151) were risk factors for cardiovascular endpoint events. Intensive antihypertensive treatment with achieved 136/76 mm Hg was beneficial for Chinese hypertensive patients older than 70 years. Long-term visit to-visit variability in systolic BP was positively associated with the incidence of cardiovascular events. PMID- 23730992 TI - Pheochromocytoma/Paraganglioma: Review of perioperative management of blood pressure and update on genetic mutations associated with pheochromocytoma. AB - Pheochromocytomas and paragangliomas are rare tumors with high morbidity rates caused by excessive catecholamine secretion, even though the majority of tumors are benign. The use of perioperative blockade regimens, together with improved surgical techniques, has greatly impacted the perioperative morbidity associated with these tumors. The old dogma of the "tumor of tens" no longer holds true. For example, at least one third of all pheochromocytomas and paragangliomas are hereditary, with mutations in 1 of 10 well-characterized susceptibility genes, and one quarter of all tumors are malignant. This review focuses on the perioperative management of pheochromocytoma and paragangliomas and the clinical implications of the associated genetic mutations. PMID- 23730993 TI - Effect of allopurinol on blood pressure: a systematic review and meta-analysis. AB - Allopurinol is a potent xanthine oxidase inhibitor that is used in hyperuricemic patients to prevent gout. It has also been shown to decrease cardiovascular complications in a myriad of cardiovascular conditions. However, studies have reported conflicting evidence on its effects on blood pressure (BP). A systematic review was conducted using Medline, PubMed, Embase, and the Cochrane Library for all the longitudinal studies that assessed the efficacy of allopurinol on systolic and diastolic BP. A total of 10 clinical studies with 738 participants were included in the analysis. Compared with the control group, systolic BP decreased by 3.3 mm Hg (95% confidence interval [CI], 1.4-5.3 mm Hg; P=.001) and diastolic BP decreased by 1.3 mm Hg (95% CI, 0.1-2.5 mm Hg; P=.03) in patients treated with allopurinol. When analysis was restricted to the higher-quality randomized controlled trials, similar changes in systolic and diastolic BPs were found: 3.3 mm Hg (95% CI, 0.8-5.8 mm Hg; P<.001) and 1.4 mm Hg (95% CI, 0.1-2.7 mm Hg; P=.04), respectively. Allopurinol is associated with a small but significant reduction in BP. This effect can be potentially exploited to aid in controlling BP in hypertensive patients with hyperuricemia. PMID- 23730994 TI - Inflammatory markers should be assessed together with cardiovascular risk factors by clinicians in masked hypertension. PMID- 23730995 TI - Effect of granulocyte-macrophage colony-stimulating factor on neutrophil function in idiopathic bronchiectasis. AB - BACKGROUND AND OBJECTIVE: Neutrophils are consistently found in inflamed and infected airways in idiopathic bronchiectasis, but relatively little is known about the function of blood neutrophils in this condition. We hypothesized that peripheral blood neutrophil (PBN) phagocytosis and superoxide generation are impaired in bronchiectasis, and that granulocyte-macrophage colony-stimulating factor (GM-CSF) is capable of improving neutrophil function. METHODS: Neutrophils were isolated from the peripheral blood of patients with idiopathic bronchiectasis who were free of exacerbation, and from healthy controls of similar age (n = 21 in both groups). Ingestion of serum-opsonized zymosan by neutrophils was used to quantify phagocytic capacity. Superoxide generation in neutrophils was measured in response to addition of platelet activating factor and formyl-methionyl-leucyl-phenylalanine. Experiments were performed in the presence or absence of GM-CSF. RESULTS: No differences were observed in either phagocytic capacity (P = 0.99) or superoxide generation (P = 0.81) when comparing patients and controls. However, a significant increase in phagocytic capacity above baseline levels in both patients (P < 0.005) and controls (P < 0.005) was induced by GM-CSF. Similarly, the superoxide generation in patients (P < 0.005) and controls (P = 0.001) was significantly increased by GM-CSF. CONCLUSIONS: PBN function was preserved in idiopathic bronchiectasis. Enhancement of neutrophil phagocytosis and superoxide generation by GM-CSF requires further study. PMID- 23730996 TI - A randomized trial comparing the rate of hypoglycemia--assessed using continuous glucose monitoring--in 125 preschool children with type 1 diabetes treated with insulin glargine or NPH insulin (the PRESCHOOL study). AB - BACKGROUND: Avoidance of hypoglycemia is a key consideration in treating young children with type 1 diabetes (T1DM). KEY OBJECTIVE: To evaluate hypoglycemia with insulin glargine vs. neutral protamine Hagedorn (NPH) insulin in young children, using continuous glucose monitoring (CGM). SUBJECTS: Children of 1 to <6 yr treated with once-daily glargine vs. once- or twice-daily NPH, with bolus insulin lispro/regular human insulin provided to all. METHODS: Twenty-four week, multicenter, randomized, open-label study. Primary endpoint was event rate of composite hypoglycemia [symptomatic hypoglycemia, low CGM excursions (<3.9 mmol/L) or low fingerstick blood glucose (FSBG; <3.9 mmol/L)]. Noninferiority of glargine vs. NPH was assessed for the primary endpoint. RESULTS: One hundred and twenty-five patients (mean age, 4.2 yr) were randomized to treatment (glargine, n = 61; NPH, n = 64). At baseline, mean HbA1c was 8.0 and 8.2% with glargine and NPH, respectively. Composite hypoglycemia episodes/100 patient-yr was 1.93 for glargine and 1.69 for NPH; glargine noninferiority was not met. Events/100 patient-yr of symptomatic hypoglycemia were 0.26 for glargine vs. 0.33 for NPH; low CGM excursions 0.75 vs. 0.72; and low FSBG 1.93 vs.1.68. There was a slight difference in between-group severe/nocturnal/severe nocturnal hypoglycemia and glycemic control. All glargine-treated patients received once-daily injections; on most study days NPH-treated patients received twice-daily injections. CONCLUSIONS: While glargine noninferiority was not achieved, in young children with T1DM, there was a slight difference in hypoglycemia outcomes and glycemic control between glargine and NPH. Once-daily glargine may therefore be a feasible alternative basal insulin in young populations, in whom administering injections can be problematic. PMID- 23730997 TI - Autoimmune retinopathies: a report of 3 cases. AB - PURPOSE: To describe 3 representative cases of autoimmune retinopathy (AIR). METHODS: Clinical records of patients with a diagnosis of AIR were analyzed for demographic data, clinical findings, ancillary and laboratory tests, and treatment employed. RESULTS: Three female patients diagnosed with AIR had bilateral reduction of electroretinogram amplitudes and elevation of visual field threshold within the central 30 degrees of the visual field that was disproportionately more severe than the clinical findings of retinal degeneration. The diagnoses were cancer-associated retinopathy, non-neoplastic AIR, and hereditary retinal dystrophy with secondary inflammation. Optic nerve involvement was also present in all cases. The patient with non-neoplastic AIR was successfully treated with systemic corticosteroids and immunomodulatory agents. CONCLUSION: High index of suspicion is essential for an early diagnosis of AIR. Visual function and electrophysiological tests should be included in the initial workup of patients who present with suggestive clinical signs and symptoms of AIR. PMID- 23730999 TI - Proteomics as a methodology for the characterization of potential new markers of stress elicited by strenuous exercise in sporting dogs--a preliminary study. PMID- 23731000 TI - The many faces of Mott cells. PMID- 23731001 TI - Botryoid nuclei in the peripheral blood of a dog with heatstroke. AB - An EDTA-anticoagulated blood sample collected from a 1.5-year-old, intact male, English Bulldog was submitted for a CBC. The CBC data and blood smear evaluation revealed borderline high hematocrit (54%, reference interval 37-55%), inappropriate rubricytosis, moderate leukopenia due to both mature neutropenia and lymphopenia, and mild thrombocytopenia. Numerous leukocytes showed evidence of karyolysis, pyknosis, and karyorhexis, and apoptotic bodies were frequent in the background. Many neutrophils had botryoid nuclei characterized by increased numbers of nuclear segments radially arranged with spoke-like, delicate chromatin filaments connecting the segments centrally. The finding of botryoid nuclei and inappropriate rubricytosis was indicative of severe hyperthermia, such as heatstroke. The dog had been exercised a long time during conditions of high temperature and humidity until he collapsed. The dog was diagnosed with severe heatstroke, hypovolemic shock, disseminated intravascular coagulation, and multiorgan dysfunction syndrome. Despite aggressive treatment, the patient died of cardiopulmonary arrest. Botryoid nuclei are frequent in people with heatstroke. In the authors' experience, botryoid nuclei are seen commonly in dogs with heatstroke, but they have never been reported in veterinary medicine. The presence of petechiation with only mild thrombocytopenia and inappropriate rubricytosis also is suggestive of heatstroke and manifests ongoing life threatening vascular derangement. PMID- 23731002 TI - Candida peritonitis in dogs: report of 5 cases. AB - Candida peritonitis is reported in people and is associated with significant morbidity and mortality compared with sterile or bacterial peritonitis. Recognized predisposing risk factors include peritoneal dialysis, hollow viscous organ perforation, abdominal surgery, inflamed intestinal mucosa, antimicrobial administration, and immunosuppression. In this report, we describe 5 cases of dogs with peritonitis complicated by Candida spp; 3 dogs with C albicans, one dog with C albicans and C glabrata, and one dog with C glabrata only. The 3 dogs with C albicans peritonitis presented with duodenal perforation due to NSAID therapy, intestinal resection and anastomosis following postspay-surgery dehiscence, and intestinal foreign body removal. The 2 dogs with C glabrata peritonitis had undergone cholecystectomy due to gall bladder rupture and dehiscence of intestinal biopsy removal sites following exploratory laparatomy. In all cases, initial diagnosis of fungal peritonitis was made via cytologic examination of peritoneal effusions, which revealed marked pyogranulomatous inflammation with numerous 3-8 MUm oval, deeply basophilic yeast organisms with thin clear capsules noted within phagocytes and extracellularly. In addition, germ tube formation, hyphae, and pseudohyphae were rarely seen in some of the cases with pure C albicans. Identity of the organisms was determined by culture in all cases and confirmed by PCR in 3 cases. Candida spp. are commensals normally inhabiting the alimentary, the upper respiratory, and the lower urogenital tracts of mammals. They are opportunistic pathogens that can invade and colonize tissue when a patient is immune-compromised or there is disruption of the mucosal barrier. Candida peritonitis should be considered in patients with peritoneal contamination with gastrointestinal or biliary contents. PMID- 23731004 TI - A cultural change in the management of mental illness. PMID- 23731003 TI - The consequences of poor communication during transitions from hospital to skilled nursing facility: a qualitative study. AB - OBJECTIVES: To examine how skilled nursing facility (SNF) nurses transition the care of individuals admitted from hospitals, the barriers they experience, and the outcomes associated with variation in the quality of transitions. DESIGN: Qualitative study using grounded dimensional analysis, focus groups, and in-depth interviews. SETTING: Five Wisconsin SNFs. PARTICIPANTS: Twenty-seven registered nurses. MEASUREMENTS: Semistructured questions guided the focus group and individual interviews. RESULTS: SNF nurses rely heavily on written hospital discharge communication to transition individuals into the SNF effectively. Nurses cited multiple inadequacies of hospital discharge information, including regular problems with medication orders (including the lack of opioid prescriptions for pain), little psychosocial or functional history, and inaccurate information regarding current health status. These communication inadequacies necessitated repeated telephone clarifications, created care delays (including delays in pain control), increased SNF staff stress, frustrated individuals and family members, contributed directly to negative SNF facility image, and increased risk of rehospitalization. SNF nurses identified a specific list of information and components that they need to facilitate a safe, high quality transition. CONCLUSION: Nurses note multiple deficiencies in hospital-to SNF transitions, with poor quality discharge communication being identified as the major barrier to safe and effective transitions. This information should be used to refine and support the dissemination of evidence-based interventions that support transitions of care, including the Interventions to Reduce Acute Care Transfers program. PMID- 23731005 TI - The aesthetic and cultural interests of patients attending an acute hospital--a phenomenological study. AB - AIM: To describe the aesthetic and cultural pursuits of older patients in hospital. BACKGROUND: Although there is much discussion of the importance of arts - used in this paper to refer to all art forms, as currently listed by the Arts Council of Ireland www.artscouncil.ie - in health, little is known about the salience of aesthetic and cultural pursuits of hospital patients. DESIGN: A qualitative, hermeneutic phenomenological study examined artistic and cultural interests and experiences of older hospital patients and their perceptions of aesthetics of hospital. METHODS: A phenomenological study was carried out in 2011, using purposeful sampling with 20 inpatients aged over 65. Patients were selected from the geriatric medicine day hospital of a university teaching hospital, 10 had experience of the hospital arts programme. RESULTS: Seven themes identified: loss and the impact of illness on leisure activities; patients' interests and passions; a lack of expectation of arts in hospital; the positive impact of arts in hospital for those who had experienced them; varying preference between receptive and participative arts activity according to phase of illness; aesthetic aspects of the hospital experience; recommendations for changes to improve arts in hospital. CONCLUSIONS: Aesthetic and cultural interests are important in the lives of older patients admitted to hospital. Illness can create barriers to artistic engagement. Participation in arts activities may be more important during recovery and rehabilitation, with receptive arts being more popular during the acute phase of illness in hospital. Further research recommended on the role of the aesthetic environment for patients' health and well-being as well as receptive arts in hospital. PMID- 23731006 TI - Can the active component U.S. military achieve tuberculosis elimination? PMID- 23731007 TI - Tuberculosis trends in the U.S. Armed Forces, active component, 1998-2012. AB - Members of the Armed Forces represent a segment of the U.S. population that may be at increased risk for tuberculosis (TB) infection, disease, and transmission due to overseas service in endemic areas and residence in congregate settings. The purpose of this study was to examine recent surveillance trends and risk factors associated with TB disease in the active component U.S. military. The rate of TB in the U.S. military -0.6 per 100,000 population (n=128) over the interval from 1998 to 2012 - was lower than the age-adjusted rate among the U.S. population (adjusted rate ratio=0.20) over the same time interval. During the last five years of the surveillance period, the most common factor associated with the diagnosis of TB disease during military service was latent infection at time of accession; also, as many as nine (24%) cases of TB were associated with deployment to Iraq or other military exposures. TB control activities should continue to mitigate unique military exposures such as crowding during recruit training and deployments to TB endemic areas. PMID- 23731008 TI - Using the tuberculosis cohort review to evaluate and improve the U.S. Army's tuberculosis control program. AB - The challenges of tuberculosis (TB) control in the U.S. military are similar to those in other low-incidence populations; in addition, the U.S. Military Health System must account for geographic separation, frequent staff turnover, deployments to TB-endemic areas, and residence in congregate settings. The objective of this evaluation was to use a TB cohort review process to assess indicators of the quality and effectiveness of the TB control program in the U.S. Army. Ten cases of TB disease occurred at U.S. Army installations in 2011; all were pulmonary. Two cases occurred among the active component U.S. Army, a rate of 0.4 per 100,000 population; no case was attributable to infection acquired during deployment. Eight (80%) were foreign born. Seven (70%) were smear positive and one (10%) had multi-drug resistant TB. One (10%) case died. All (100%) of the nine remaining cases completed therapy. The median time from onset of symptoms to diagnosis was 98 days, but there was substantial variability (range 21-444). This is the first report of the cohort review methodology being applied to a military population. Most performance indicators in the U.S. Army met or approached national standards. PMID- 23731009 TI - Incidence of acute respiratory illnesses among enlisted service members during their first year of military service: did the 2011 resumption of adenovirus vaccination of basic trainees have an effect? AB - This study analyzed the incidence of acute respiratory illnesses (i.e., upper respiratory illnesses, bronchitis and bronchiolitis, and pneumonias) during the first 12 months of service among enlisted members of the active components of the U.S. Armed Forces. Subjects were assigned to cohorts designated 1999 through 2012 corresponding to the years during which they entered service. The objective was to determine if the late 2011 resumption of administration of adenovirus vaccines to basic trainees was associated with a reduction in acute respiratory illnesses among the 2012 cohort. Because acute respiratory illness rates were considerably higher during the first three months than the rest of the first year of service, rates during the first three months and the next nine months of service were compared separately among the cohorts. In the 2012 compared to the prior year cohorts, incidence rates of hospitalizations for pneumonia and of outpatient diagnoses of the other two acute respiratory illness types of interest were lower during the first three months but not the next nine months of enlisted service. The findings suggest a protective effect of adenovirus vaccines during recruit training. Reasons for cautious interpretation of the results are discussed. PMID- 23731010 TI - Epilepsy in active component service members, 1998-2012. AB - Epilepsy is defined as a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures without any immediate identified cause. During the surveillance period there were 11,295 incident cases of epilepsy among active component service members (incidence rate: 52.8 per 100,000 person-years). Incidence rates increased 23 percent from 1999 to 2006, increased 52 percent from 2006 to 2010, and then decreased 38 percent from 2010 to 2012. Epilepsy incidence rates were higher among females, in the youngest age group (>20), and among white, non-Hispanics. A majority (85.8%) had no predisposing condition identified in their medical record. The number of epilepsy cases with a traumatic brain injury preceding their epilepsy diagnosis could not account for the increases in epilepsy during the period. However, the upward trend may be attributable to increased screening and evaluation of service members with possible head injuries, with subsequent detection of epileptic seizures. PMID- 23731011 TI - MiR-99a exerts anti-metastasis through inhibiting myotubularin-related protein 3 expression in oral cancer. AB - OBJECTIVE: We aimed at studying the role of the most deregulated miR-99a, identifying its downstream targets, and exploring the clinical potential of miR 99a and its target(s) in oral cancer. SUBJECTS AND METHODS: Following confirmation of miR-99a deregulation in nine oral lines and 26 pairwise clinical specimens, miR-99a-manipulated oral cancer cells were subjected to cell proliferation, migration, invasion, and in vivo murine metastasis assays. We characterized putative miR-99a target(s) using luciferase reporter assays and genetic manipulation. The inverse relation of miR-99a and its target(s) was examined in clinical specimens using real-time PCR and Western blot analysis. RESULTS: MiR-99a down-regulation was confirmed both in tested oral cancer cell lines and clinical specimens. Ectopic miR-99a expression inhibited oral cancer cell migration and invasion. Anti-miR-99a, silencing miR-99a functions, had the opposite effect. Myotubularin-related protein 3 (MTMR3) with one evolutionarily conserved seed region in the 3'-untranslated region was a novel miR-99a target. Depleting MTMR3 expression significantly reduced cell proliferation, migration, or invasion. There was an inverse expression of miR-99a and MTMR3 protein in oral cancer lines and clinical specimens. CONCLUSION: miR-99a repressed oral cancer cell migration and invasion partly through decreasing MTMR3 expression. MTMR3 may serve as a therapeutic target for oral cancer treatment. PMID- 23731012 TI - Enzymatic AND logic gate with sigmoid response induced by photochemically controlled oxidation of the output. AB - We report a study of a system which involves an enzymatic cascade realizing an AND logic gate, with an added photochemical processing of the output, allowing the gate's response to be made sigmoid in both inputs. New functional forms are developed for quantifying the kinetics of such systems, specifically designed to model their response in terms of signal and information processing. These theoretical expressions are tested for the studied system, which also allows us to consider aspects of biochemical information processing such as noise transmission properties and control of timing of the chemical and physical steps. PMID- 23731013 TI - Evidence for shared genetic risk between ADHD symptoms and reduced mathematics ability: a twin study. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) symptoms and mathematics ability are associated, but little is known about the genetic and environmental influences underlying this association. METHODS: Data came from more than 6,000 twelve-year-old twin pairs from the UK population-representative Twins Early Development Study. Parents rated each twin's behaviour using a DSM-IV based 18-item questionnaire of inattentive and hyperactive-impulsive ADHD symptoms. Mathematics tests based on the UK National Curriculum were completed by each twin. The twins also completed standardised tests of reading and general cognitive ability. Multivariate twin model fitting was applied. RESULTS: Inattentive and hyperactive-impulsive ADHD symptoms were highly heritable (67% and 73% respectively). Mathematics ability was moderately heritable (46%). Mathematics ability and inattentiveness showed a significantly greater phenotypic correlation (r(p) = -.26) and genetic correlation (r(A) = -.41) than mathematics ability and hyperactivity-impulsivity (r(p) = -.18; r(A) = -.22). The genetic correlation between inattentiveness and mathematics ability was largely independent from hyperactivity-impulsivity, and was only partially accounted for by genetic influences related to reading and general cognitive ability. CONCLUSIONS: Results revealed the novel finding that mathematics ability shows significantly stronger phenotypic and genetic associations with inattentiveness than with hyperactivity-impulsivity. Genetic associations between inattentiveness and mathematics ability could only partially be accounted for by hyperactivity impulsivity, reading and general cognitive ability. Results suggest that mathematics ability is associated with ADHD symptoms largely because it shares genetic risk factors with inattentiveness, and provide further evidence for considering inattentiveness and hyperactivity-impulsivity separately. DNA markers for ADHD symptoms (especially inattentiveness) may also be candidate risk factors for mathematics ability and vice versa. PMID- 23731014 TI - Inducers of hypoxic response: marine sesquiterpene quinones activate HIF-1. AB - The hypoxia-inducible factor-1 (HIF-1) transcription factor regulates cellular oxygen homeostasis. Agents that activate HIF-1 and downstream HIF targets represent potential drug leads for the prevention and/or treatment of ischemic disorders. In a search for small-molecule HIF-1 activators, 1936 marine invertebrate and algal extract samples (U.S. National Cancer Institute's Open Repository) were evaluated for HIF-1 activation activity in a cell-based reporter assay. Bioassay-guided fractionation of two active extracts of the sponge Dactylospongia elegans afforded four new sesquiterpene quinones (2-5), one new sesquiterpene phenol (6), the known Golgi disruptor ilimaquinone (1), and three previously reported ilimaquinone analogues (7-9). While antiproliferative activity was observed at higher concentrations, the sesquiterpene quinones (1-3) possessing a 2-hydroxy-5-methoxy-1,4-benzoquinone moiety activated HIF-1 and increased the expression of HIF-1 target gene vascular endothelial growth factor (VEGF) in T47D cells. PMID- 23731017 TI - Is surgery necessary for patients with hepatic angiomyolipoma? Retrospective analysis from eight Chinese cases. AB - BACKGROUND AND AIM: Hepatic angiomyolipoma (AML) is a rare, hepatic mesenchymal neoplasm. Its preoperative diagnosis is very difficult, and the treatment is still controversial. The aim is to summarize experience in diagnosis and management of hepatic AML from a cancer center. METHODS: We retrospectively reviewed the clinical presentation, histopathological, features and treatment of the tumors encountered at our institute from January 2000 to December 2012. RESULTS: The patients included six females and two males, with female preponderance. Six patients are asymptomatic. Laboratory tests lack specificity. Combining imaging modality, only one patient obtained the accurate diagnosis of hepatic AML and was confirmed by fine-needle aspiration biopsy combined with homatropine methylbromide-45 staining. All other patients received hepatic resection. There was no tumor recurrence or increase of tumor size within the follow-up period. CONCLUSION: We suggest fine-needle aspiration combined with homatropine methylbromide-45 staining should be performed in all patients who are asymptomatic and without serological abnormalities. Surgical resection might be considered only if the malignant potential of the lesion cannot be ruled out or the tumor size is increasing during observation. PMID- 23731016 TI - Evaluation of NHS carbamates as a potent and selective class of endocannabinoid hydrolase inhibitors. AB - Monoacylglycerol lipase (MAGL) is a principal metabolic enzyme responsible for hydrolyzing the endogenous cannabinoid (endocannabinoid) 2-arachidonoylglycerol (2-AG). Selective inhibitors of MAGL offer valuable probes to further understand the enzyme's function in biological systems and may lead to drugs for treating a variety of diseases, including psychiatric disorders, neuroinflammation, and pain. N-Hydroxysuccinimidyl (NHS) carbamates have recently been identified as a promising class of serine hydrolase inhibitors that shows minimal cross reactivity with other proteins in the proteome. Here, we explore NHS carbamates more broadly and demonstrate their potential as inhibitors of endocannabinoid hydrolases and additional enzymes from the serine hydrolase class. We extensively characterize an NHS carbamate 1a (MJN110) as a potent, selective, and in-vivo active MAGL inhibitor. Finally, we demonstrate that MJN110 alleviates mechanical allodynia in a rat model of diabetic neuropathy, marking NHS carbamates as a promising class of MAGL inhibitors. PMID- 23731015 TI - The impact of environmental stress on male reproductive development in plants: biological processes and molecular mechanisms. AB - In plants, male reproductive development is extremely sensitive to adverse climatic environments and (a)biotic stress. Upon exposure to stress, male gametophytic organs often show morphological, structural and metabolic alterations that typically lead to meiotic defects or premature spore abortion and male reproductive sterility. Depending on the type of stress involved (e.g. heat, cold, drought) and the duration of stress exposure, the underlying cellular defect is highly variable and either involves cytoskeletal alterations, tapetal irregularities, altered sugar utilization, aberrations in auxin metabolism, accumulation of reactive oxygen species (ROS; oxidative stress) or the ectopic induction of programmed cell death (PCD). In this review, we present the critically stress-sensitive stages of male sporogenesis (meiosis) and male gametogenesis (microspore development), and discuss the corresponding biological processes involved and the resulting alterations in male reproduction. In addition, this review also provides insights into the molecular and/or hormonal regulation of the environmental stress sensitivity of male reproduction and outlines putative interaction(s) between the different processes involved. PMID- 23731018 TI - Stilbenes and anthocyanins reduce stress signaling in BV-2 mouse microglia. AB - Blueberries contain an array of phytochemicals that may decrease both inflammatory and oxidative stress. This study determined if pterostilbene, resveratrol, and two anthocyanins commonly found in blueberries, delphinidin-3-O glucoside and malvidin-3-O-glucoside, would be efficacious in protecting microglia from inflammatory-induced stress signaling. Microglia that were pretreated with blueberry extract (0.25, 0.5, 1, 2 mg/mL) or its components (1, 10, 20, 30 MUM pterostilbene, resveratrol, delphinidin-3-O-glucoside, or malvidin 3-O-glucoside) prior to exposure to lipopolysaccharide (100 ng/mL) demonstrated concentration-dependent reductions in nitric oxide and tumor necrosis factor alpha release and decreased expression of inducible nitric oxide synthase and cyclooxygenase-2. However, much higher concentrations of the individual components than those found in blueberries were needed to demonstrate the effects. For example, 1 mg/mL blueberry extract significantly reduced LPS-induced nitric oxide release; this concentration of blueberry extract contains 2.6 MUM malvidin-3-O-glucoside, but when malvidin-3-O-glucoside was tested individually, 20 MUM was necessary to observe a significant reduction in nitric oxide release. Therefore the protective effects of blueberries may not be due to any one component, but rather a synergism of the activity of the compounds tested and/or other blueberry compounds not tested here. These results lend further support that blueberry and its active components are able to combat some of the inflammatory mediators of aging at the cellular level. PMID- 23731019 TI - Metabolic effects of telmisartan in subjects with abdominal obesity: a prospective randomized controlled trial. AB - BACKGROUND. Abdominal obesity, characterized by ectopic fat deposition in skeletal muscle and liver tissue, has been associated with insulin resistance and increased risk for type 2 diabetes mellitus. The aim of this study was to evaluate whether treatment with the angiotensin II type 1 (AT-1) receptor blocker telmisartan can reduce intramyocellular lipid (IMCL) and hepatic fat storage, thereby improving insulin sensitivity among individuals with abdominal obesity. METHODS. Ninety-five adults with abdominal obesity (body mass index >= 30 kg/m(2) and waist circumference > 102 cm in men and > 88 cm in women) were randomized to double-blind treatment with telmisartan or placebo for 24 weeks. Following 4 weeks of 80 mg telmisartan per day, the dose was increased to 160 mg telmisartan for the duration of the study. Soleus muscle IMCL and liver fat content were assessed by (1)H-magnetic resonance imaging ((1)H-MRI) spectroscopy. Secondary outcomes included changes in body composition, plasma lipids, glucose profiles, insulin sensitivity, beta-cell function and total adiponectin levels. RESULTS. There was no significant effect of telmisartan in abdominally obese individuals consuming either a low or high glycemic diet, on IMCL content (5.73 +/- 1.11 vs 6.11 +/- 1.11; p = 0.13) or liver fat (0.08 +/- 0.05 vs 0.09 +/- 0.05; p = 0.60). Body composition, lipid and glucose profiles, insulin sensitivity and adiponectin were likewise unaffected. Beta-cell function, as determined by the insulinogenic index (IGI), improved significantly (19.3 +/- 13.7 vs 22.5 +/- 17.6; p = 0.03; 16.5% increase from baseline in the telmisartan group). CONCLUSIONS. Telmisartan increased beta-cell function but did not decrease IMCL or liver fat content or other metabolic parameters among individuals with abdominal obesity. PMID- 23731020 TI - Cancer risk comparative perception and overscreening behaviours of non-carriers from BRCA1/2 families. AB - Cancer-free women who are from families with an inherited form of breast and/or ovarian cancer (BRCA1/2) are referred to as 'unaffected non-carriers' when the results of genetic testing for the inherited gene are negative. Recent studies have identified overscreening behaviours (undergoing more screening tests for cancer than are medically warranted) among these women, even though they do not require specific cancer monitoring. Overscreening behaviours deserve particular attention due to their potential psychological drivers and implications. The principal objective of this study was to examine the factors, including state anxiety, feelings of self-vulnerability, and the comparative perception of cancer risk that might explain these overscreening behaviours. Unaffected non-carriers women (n = 77) were asked about these different variables. Overscreening was associated with and determined by feelings of self-vulnerability and the comparative perception of cancer risk, but was not associated with anxiety. An increase in feelings of self-vulnerability or elevated comparative pessimism (CP) was related to the participants' decision to be frequently screened. Patients' perceptions of the risk should be considered in measures or information aimed at preventing inappropriate overscreening behaviours. PMID- 23731021 TI - Low-dimensional nanoparticle clustering in polymer micelles and their transverse relaxivity rates. AB - One- or two-dimensional arrays of iron oxide nanoparticles were formed in colloidal assemblies of amphiphilic polymers. Electron tomography imaging revealed that nanoparticles are arranged into one-dimensional strings in magneto micelles or two-dimensional sheets in magneto-core/shell assemblies. The distinct directional assembly behavior was attributed to the interparticle interaction relative to the nanoparticle-polymer interaction, which was modulated by varying the cosolvent used for the solution phase self-assembly. Magneto-core/shell assemblies with varying structural parameters were formed with a range of different sized as-synthesized nanoparticles. The transverse magnetic relaxivity rates (r2) of a series of different assemblies were determined to examine the effect of nanoparticle arrangement on the magnetic relaxivity for their potential applications in MRI. The results indicated that the assembly structure of nanoparticles in polymer micelles significantly affects the r2 of surrounding water, providing a way to control magnetic relaxivity. PMID- 23731022 TI - Update of studies on drug-related problems in older adults. PMID- 23731023 TI - Genetic variants in HHIP are associated with FEV1 in subjects with chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a complex disease in which multiple genes and their interaction with environmental factors contribute to disease development. Recent genome-wide association studies in COPD revealed the chromosome 4 region near hedgehog interacting protein (HHIP). However, these studies were mostly performed in Caucasians, and additional studies in multiple ethnic groups are needed. We investigated genetic associations of HHIP in Korean COPD and control subjects. METHODS: Two separate case-control studies were performed. Firstly, 139 subjects with COPD and 199 control subjects were selected from the Soonchunhyang University Bucheon Hospital Biobank. Secondly, 219 individuals with COPD were recruited from the Korean Obstructive Lung Disease (KOLD) cohort. The control subjects consisted of 305 smokers or ex-smokers with normal lung function who were registered in the Korean Genome Epidemiology Study. Associations between COPD susceptibility and single nucleotide polymorphism (SNP) genotypes were tested by logistic regression. Associations between lung function and SNP genotypes were tested by linear regression. RESULTS: In the first study, the mean forced expiratory volume in 1 s (FEV1 ) of these COPD subjects was 1.32 L. None of 15 SNP was significantly associated with COPD susceptibility. However, four SNP associated significantly with FEV1 in subjects with COPD. In the KOLD cohort study, two SNPs (rs11938704 and rs10013495) near HHIP were significantly associated with FEV1 (P = 0.0001 and 0.001, respectively) in subjects with COPD. CONCLUSIONS: Genetic variants in HHIP are associated with lung function in subjects with COPD. PMID- 23731024 TI - Parapagus conjoined twin calf: a case study - focused on CT and cardiac abnormalities. AB - Congenital duplication anomalies occasionally occur in both humans and animals. Although various forms of classification of these conjoined twins exist, each case should be considered as an individual. In the case study presented a Holstein Frisian calf, born alive after 281 days of normal gravidity was investigated by computed tomography (CT) and subsequent dissection. The calf could be classified as a parapagus dicephalus tetrabrachius. It exhibited two heads each of them with a complete cervical spine leading to a complete thoracic and lumbar spine and separate tails. Looking at the point of fusion, the twin was conjoined in the ventrolateral thoracic part of the body. The calf had two thoraces with four forelimbs and two pelvic limbs on a single pelvis. As two heads and thoraces were present, beginning at the oral cavity, two intestinal systems were observable leading to a fusion point at the ascending part of the duodenum been continued caudally as a single system. Within each thorax, two lungs and a heart were present. However, only the heart in the left thorax was normal shape, exhibiting a strong myocardium and increased size. In contrast, the heart within the right thorax was considerably smaller, round shaped, and it appeared to be spongy and not fully developed during the foetal period. Commonly, classification of conjoined twins is only based on the appearance of the skeletal system. However, in the case presented, the point of fusion of the skeletal system did not allow conclusions regarding the intestinal or cardiovascular system. PMID- 23731025 TI - High resolution chromosomal microarray in undiagnosed neurological disorders. AB - AIM: Despite advances in medical investigation, many children with neurological conditions remain without a diagnosis, although a genetic aetiology is often suspected. Chromosomal microarray (CMA) screens for copy number variants (CNVs) and long continuous stretches of homozygosity (LCSH) and may further enhance diagnostic yield. Although recent studies have identified pathogenic CNVs in intellectual disability, autism and epilepsy, the utility of CMA testing in a broader cohort of children with neurologic disorders has not been reported. METHODS: Two hundred fifteen patients with neurological conditions of unknown aetiology were seen over a 6-month period and were prospectively tested by CMA using high-resolution single nucleotide polymorphism (SNP) microarrays (Illumina HumanCytoSNP-12 v2.1 or Affymetrix 2.7M). RESULTS: Thirty of 215 (14%) patients tested had an abnormal CMA. Twenty-nine had CNVs (13%) and one (0.5%) a clinically significant stretch of homozygosity. Twenty (9.3%) had a CMA finding considered to be pathogenic or involved in susceptibility to the condition of interest, and 10 (4.7%) had findings of unknown significance. Their phenotypes included infantile spasms and other epilepsies, neuromuscular conditions, ataxia, movement disorders, microcephaly and malformations of cortical development. At least one third of patients did not meet national funding criteria for CMA at the time of presentation. CONCLUSIONS: CMA detected clinically significant abnormalities in a broad range of neurologic phenotypes of unknown aetiology. This test should be considered a first-tier investigation of children with neurologic disorders in whom the initial clinical assessment does not indicate a likely aetiology, especially those with severe epilepsies and neurologically abnormal neonates. PMID- 23731026 TI - Response to competition of bulbous geophyte Allium oleraceum differing in ploidy level. AB - Experimental studies that explore the possible causes of ploidy distributions and niche differentiation are rare. Increased competitive ability may be advantageous for survival in dense vegetation and may strongly affect local and regional abundances of cytotypes and potentially contribute to invasion success. We compared survival, growth and reproduction of plants originating from bulbils of three cytotypes (2n = 4x, 5x, 6x) of Allium oleraceum growing with and without a competitor (Arrhenatherum elatius). There was a strong negative effect of competition but no effect of ploidy or ploidy * competition on survivorship, height and total dry mass of A. oleraceum, i.e. no support for different competitive abilities of the ploidy levels. However, slightly different responses of populations to competition treatments within all cytotypes suggest differentiation within cytotypes. Under competition, plant survivorship was low, surviving plants were small, had low dry mass and produced neither sexual nor asexual propagules. Without competition, plant survivorship was high, and cytotypes differed in three traits after 2 year's growth: dry mass of flowers, number of flowers and ratio of the dry mass of sexual to asexual propagules all decreased with increasing ploidy level. We additionally tested tetra- and pentaploids as to whether plants originating from different types of propagule (bulbils, seeds) differ in survivorship, growth and reproduction when growing with and without a competitor. Plants originating from bulbils had higher survivorship, were more robust, flowered earlier and produced more propagules when compared to plants originating from seeds and grown without competition. Under competition, differences in performance between plants originating from seeds and bulbils mostly disappeared, with higher survivorship only for plants originating from bulbils. PMID- 23731027 TI - Moving beyond relationship and task conflict: toward a process-state perspective. AB - Teams are formed to benefit from an expanded pool of expertise and experience, yet 2 aspects of the conflict stemming from those core differences will ultimately play a large role in determining team viability and productivity: conflict states and conflict processes. The current study theoretically reorganizes the literature on team conflict--distinguishing conflict states from conflict processes--and details the effects of each on team effectiveness. Findings from a meta-analytic cumulation of 45 independent studies (total number of teams = 3,218) suggest states and processes are distinct and important predictors of team performance and affective outcomes. Controlling for conflict states (i.e., task and relationship conflict), conflict processes explain an additional 13% of the variance in both team performance and team affective outcomes. Furthermore, findings reveal particular conflict processes that are beneficial and others detrimental to teams. The truth about team conflict: conflict processes, that is, how teams interact regarding their differences, are at least as important as conflict states, that is, the source and intensity of their perceived incompatibilities. PMID- 23731028 TI - Reducing job insecurity and increasing performance ratings: does impression management matter? AB - Prior research on job insecurity has demonstrated its detrimental effects on both employees and the organization, yet no research has detailed how people actively deal with it. Drawing from proactivity research, this article argues that job insecurity prompts a proactive use of impression management tactics in the workplace. The effectiveness of these tactics depends on the level of supervisory liking for the employee and the attributions supervisors make regarding the employee's motives for the impression management behaviors (i.e., for the good of the organization or for self-interest). A 3-wave survey study of 271 Chinese employees and their supervisors showed that employees experiencing job insecurity in Time 1 reported using a variety of tactics to impress their supervisors at Time 2 and that these tactics curbed the affect associated with job insecurity and enhanced supervisor rated performance, through supervisor's liking and attributed motives. The relationship between impression management and increased supervisor-rated performance was moderated by supervisor attributions; the relationship between impression management and reduced affective job insecurity depended on supervisor liking. PMID- 23731029 TI - A meta-analysis of sex differences in physical ability: revised estimates and strategies for reducing differences in selection contexts. AB - Despite the wide use of physical ability tests for selection and placement decisions in physically demanding occupations, research has suggested that there are substantial male-female differences on the scores of such tests, contributing to adverse impact. In this study, we present updated, revised meta-analytic estimates of sex differences in physical abilities and test 3 moderators of these differences-selection system design, specificity of measurement, and training-in order to provide insight into possible methods of reducing sex differences on physical ability test scores. Findings revealed that males score substantially better on muscular strength and cardiovascular endurance tests but that there are no meaningful sex differences on movement quality tests. These estimates differ in several ways from past estimates. Results showed that sex differences are similar across selection systems that emphasize basic ability tests versus job simulations. Results also showed that sex differences are smaller for narrow dimensions of muscular strength and that there is substantial variance in the sex differences in muscular strength across different body regions. Finally, we found that training led to greater increases in performance for women than for men on both muscular strength and cardiovascular endurance tests. However, training reduced the male-female differences on muscular strengths tests only modestly and actually increased male-female differences on cardiovascular endurance. We discuss the implications of these findings for research on physical ability testing and adverse impact, as well as the practical implications of the results. PMID- 23731030 TI - Influence of annealing temperature of WO3 in photoelectrochemical conversion and energy storage for water splitting. AB - The current work demonstrates the importance of WO3 crystallinity in governing both photoenergy conversion efficiency and storage capacity of the flower structured WO3 electrode. The degree of crystallinity of the WO3 electrodes was varied by altering the calcination temperature from 200 to 600 degrees C. For the self-photochargeability phenomenon, the prevailing flexibility of the short range order structure at low calcination temperature of 200 degrees C favors the intercalation of the positive cations, enabling more photoexcited electrons to be stored within WO3 framework. This leads to a larger amount of stored charges that can be discharged in an on-demand manner under the absence of irradiation for H2 generation. The stability of the electrodes calcined at 200 degrees C, however, is compromised because of the structural instability caused by the abundance insertion of cations. On the other hand, films that were calcined at 400 degrees C displayed the highest stability toward both intercalation of the cations and photoelectrochemical water splitting performance. Although crystallinty of WO3 was furthered improved at 600 degrees C heat treatment, the worsened contact between the WO3 platelets and the conducting substrate as induced by the significant sintering has been more detrimental toward the charge transport. PMID- 23731031 TI - Investigational therapies for acromegaly. AB - INTRODUCTION: The treatment of acromegaly aims at normalizing growth hormone (GH) and insulin-like growth factor (IGF-I) levels and controlling tumor growth. The approaches to therapy are essentially three: surgery and pharmacotherapy, alone or in combination, and radiotherapy, generally used in more aggressive tumors. AREAS COVERED: This review focuses on the novel drug formulations being developed for medical therapy of acromegaly. Even though many efficient treatments have been made available to manage acromegaly in the last two decades, a significant number of patients remain still uncontrolled. Medical therapy represents an important therapeutic option and can be used as the first-line treatment in many patients. However, roughly 25% of patients might be considered as poor responsive or resistant to conventional long-acting somatostatin analogs (SSA) treatment. Therefore, new longer-acting SSA, oral SSA formulations, new combined therapies with weekly doses of pegvisomant, combination therapy with pegvisomant (PEG) and cabergoline (CAB) or SSA and new approaches have been proposed. New molecules are currently under investigation in clinical trials, such as the SSA multi-receptor ligand, pasireotide, which represents a promising option therapy, especially in patients not adequately controlled with currently available SSA. Further, temozolomide has been suggested as an efficient drug for treating GH-aggressive pituitary tumors resistant to conventional therapy. EXPERT OPINION: All these novel SSA formulations and new molecules implement the available options in therapies of acromegaly to improve disease control. However, further studies are needed to define the exact role of these newer agents. The predicting factors for response to these new therapies should also be determined. PMID- 23731032 TI - Psychosocial health of infertile Ghanaian women and their infertility beliefs. AB - PURPOSE: The purpose of this study was to describe infertile women's psychosocial health problems and their infertility-related beliefs and examine the relationships between their beliefs about infertility and psychosocial health problems. DESIGN: The study was a descriptive correlational cross-sectional survey. Women (N = 203) who were receiving treatment for fertility problems in two public hospitals in Ghana were recruited. METHODS: Participants completed a Fertility Belief Questionnaire; measures of infertility-related stress, anxiety, social isolation, perceived stigma, and depressive symptoms; and sociodemographic and infertility-related health questions. Descriptive statistics, Pearson's correlations, and hierarchical regression analyses were performed. FINDINGS: The women reported high levels of infertility-related stress, low levels of anxiety, some social isolation, low levels of perceived stigma, and high levels of depressive symptoms. Beliefs that infertility has negative consequences and that one has a poor understanding of infertility were significantly related to infertility-related stress, social isolation, and depressive symptoms. Belief that infertility could be managed by personal control was significantly related to lower levels of anxiety and perceived stigma. Beliefs about consequences, illness coherence, and personal control explained significant proportions of the variances in anxiety, stress, social isolation, perceived stigma, and depressive symptoms. CONCLUSIONS: Infertile women in Ghana have psychosocial health problems that are associated with their beliefs about infertility. CLINICAL RELEVANCE: Findings have implications for nursing care of infertile women in Ghana. PMID- 23731033 TI - Characterization of organic phosphorus in lake sediments by sequential fractionation and enzymatic hydrolysis. AB - The role of sediment-bound organic phosphorus (Po) on lake eutrophication was studied using sequential extraction and enzymatic hydrolysis by collecting sediments from Dianchi Lake, China. Bioavailable Po species including labile monoester P, diester P, and phytate-like P were identified in the sequential extractions by H2O, NaHCO3, and NaOH. For the H2O-Po, 36.7% (average) was labile monoester P, 14.8% was diester P, and 69.9% was phytate-like P. In NaHCO3-Po, 19.9% was labile monoester P, 17.5% was diester P, and 58.8% was phytate-like P. For NaOH-Po, 25.6% was labile monoester P, 7.9% was diester P, and 35.9% was phytate-like P. Labile monoester P was active to support growth of algae to form blooms. Diester P mainly distributed in labile H2O and NaHCO3 fractions was readily available to cyanobacteria. Phytate-like P represents a major portion of the Po in the NaOH fractions, also in the more labile H2O and NaHCO3 fractions. Based on results of sequential extraction of Po and enzymatic hydrolysis, lability and bioavailability was in decreasing order as follows: H2O-Po > NaHCO3 Po > NaOH-Po, and bioavailable Po accounted for only 12.1-27.2% of total Po in sediments. These results suggest that the biogeochemical cycle of bioavailable Po might play an important role in maintaining the eutrophic status of lakes. PMID- 23731034 TI - Ability of a novel blue laser imaging system for the diagnosis of colorectal polyps. AB - BACKGROUND: A new endoscope system with a laser light source, blue laser imaging (BLI), has been developed by Fujifilm that allows for narrow-band light observation. The aim of the present study was to evaluate the utility of BLI for the diagnosis of colorectal polyps. METHODS: We retrospectively analyzed 314 colorectal polyps that were examined with BLI observation at Kyoto Prefectural University of Medicine between September 2011 and January 2013. The surface and vascular patterns of polyps detected by published narrow-band imaging magnification: Hiroshima classification were used. Correlations were determined between the classifications and the histopathological diagnoses. Additionally, the ability of BLI without magnification to differentiate between neoplastic or non-neoplastic polyps was analyzed. RESULTS: A total of 41 hyperplastic polyps, 168 adenomas, 80 intramucosal cancer, 11 shallowly invaded submucosal cancer, and 14 deeply invaded submucosal cancer were analyzed.Hyperplastic polyp was observed in 100% of Type A lesions (39 lesions), adenoma was observed in 89.3% of Type B lesions (159 lesions), intramucosal cancer and shallowly invaded submucosal cancer was observed in 69.6% of Type C1 (92 lesions) and in 84.6% of Type C2 (13 lesions), and deeply invaded submucosal cancer was observed in 81.8% of Type C3 lesions (11 lesions). The overall diagnostic accuracy of BLI with magnification was 84.3%. Additionally, the diagnostic accuracy of BLI without magnification for differentiating between neoplastic and non-neoplastic polyps <10 mm in diameter was 95.2%, which was greater than that of white light (83.2%). CONCLUSION: BLI was useful for the diagnosis of colorectal polyps. PMID- 23731035 TI - Self-reported neck symptoms and use of personal computers, laptops and cell phones among Finns aged 18-65. AB - The purpose of this study was to investigate the possible relation between self reported neck symptoms (aches, pain or numbness) and use of computers/cell phones. The study was carried out as a cross-sectional study by posting a questionnaire to 15,000 working-age persons, and 15.1% of all respondents (6121) reported that they very often experienced physical symptoms in the neck. The results showed that they also had many other symptoms very often, and 49% used a computer daily at work and 83.9% used cell phones. We compared physical/mental symptoms of persons with symptoms in the neck quite often or more, with others. We found significant differences in the physical/mental symptoms and use of cell phones and computers. The results suggest taking into account in the future that those persons' symptoms in the neck can be associated with use of cell phones or computers. PRACTITIONER SUMMARY: We investigated the possible relation between neck symptoms and use of computers/cell phones. We found that persons, who very often had symptoms in the neck, had also other symptoms very often (e.g. exhaustion at work). Their use of information and communication technology (e.g. computers) can associate with their symptoms. PMID- 23731036 TI - The relevance bias: valence-specific, relevance-modulated performance in a two choice detection task. AB - The aim of this study was to test the hypothesis that relevance modulates subsequent non-emotional behaviour, using a personalised mental-imagery-cued relevance manipulation paradigm. Participants had to build positive, negative and neutral mental images based on personalised scenarios that had been selected during an earlier picture-cued imagery phase. Participants imagined situations that were highly relevant for them and situations that were moderately relevant for them, depending on the effects the situations could exert on them. After each mental image, the effect of the relevance manipulation was tested in a two-choice detection task. The interaction of relevance and valence was found to be predictive of the response times. Moreover, in the high-relevance condition, longer response times were observed for positive scenarios compared to negative ones, whereas in the low-relevance condition, shorter response times were observed for positive scenarios compared to negative ones. Results are consistent with the motivational theory of emotions, which posits that low-relevance stimuli trigger valence-specific attention modulations, whereas high-relevance stimuli trigger valence-specific action tendencies. PMID- 23731037 TI - Hydrazino-Pictet-Spengler ligation as a biocompatible method for the generation of stable protein conjugates. AB - Aldehyde- and ketone-functionalized biomolecules have found widespread use in biochemical and biotechnological fields. They are typically conjugated with hydrazide or aminooxy nucleophiles under acidic conditions to yield hydrazone or oxime products that are relatively stable, but susceptible to hydrolysis over time. We introduce a new reaction, the hydrazino-Pictet-Spengler (HIPS) ligation, which has two distinct advantages over hydrazone and oxime ligations. First, the HIPS ligation proceeds quickly near neutral pH, allowing for one-step labeling of aldehyde-functionalized proteins under mild conditions. Second, the HIPS ligation product is very stable (>5 days) in human plasma relative to an oxime-linked conjugate (~1 day), as demonstrated by monitoring protein-fluorophore conjugates by ELISA. Thus, the HIPS ligation exhibits a combination of product stability and speed near neutral pH that is unparalleled by current carbonyl bioconjugation chemistries. PMID- 23731039 TI - Bone biomarkers of ovariectomised rats after leptin therapy. AB - BACKGROUND AND AIM: Under physiological conditions, maintenance of skeletal mass is the result of a tightly coupled process of bone formation and bone resorption. Disease states, osteoporosis included, arise when this delicate balance is disrupted, such as in menopause. The aim of the present work was to study the effect of leptin supplementation on bone metabolism in ovariectomized adult female rats by measuring indices of bone biomarkers. METHODS: Forty adult female albino rats were chosen as an animal model for this study and divided into the four equal groups (n=10/group): Group I (control SHAM-operated group) received a single dose of buffer solution i.p. daily for eight weeks. Group II (ovariectomy group) received a single dose of buffer solution i.p. daily for eight weeks. Group III (alendronate group): Ovariectomized rats that received alendronate 0.1 mg/kg body weight i.p. daily for eight weeks. Group IV (leptin group): Ovariectomized rats that received leptin (10 ug/kg body weight) i.p. daily for eight weeks. The obtained serum is required for determination of: Serum osteocalcin, alkaline phosphatase, calcium and phosphorous levels. RESULTS: The obtained data revealed that treatment with alendronate or leptin caused a significant decrease of serum osteocalcin, specific bone alkaline phosphatase and urinary deoxypyridinoline levels compared to ovariectomy group, and there was no significant difference between both drugs. CONCLUSION: Leptin prevents ovariectomy induced increases in bone turnover in rats. Leptin therapy has a significant effect in treatment of ovariectomy induced osteoporosis in rats (Tab. 1, Ref. 32). PMID- 23731038 TI - Genetic contributions to continuity and change in attachment security: a prospective, longitudinal investigation from infancy to young adulthood. AB - BACKGROUND: Longitudinal research has demonstrated that individual differences in attachment security show only modest continuity from infancy to adulthood. Recent findings based on retrospective reports suggest that individuals' genetic variation may moderate the developmental associations between early attachment relevant relationship experiences and adult attachment security. The purpose of this study was to use a prospective, longitudinal design to investigate genetic contributions to continuity and changes in attachment security from infancy to young adulthood in a higher risk sample. METHODS: Infant attachment security was assessed using the Strange Situation Procedure at 12 and 18 months. Adults' general attachment representations were assessed using the Adult Attachment Interview at ages 19 and 26. Romantic attachment representations were assessed with the Current Relationship Interview (CRI) at ages 20-21 and ages 26-28. Individuals were genotyped for variants within the oxytocin receptor (OXTR), dopamine D4 receptor (DRD4), and serotonin transporter linked polymorphic region (5-HTTLPR). RESULTS: The continuity of attachment security from infancy into young adulthood was consistently moderated by OXTR genetic variation. Infant attachment security predicted the security of adults' general and romantic attachment representations only for individuals with the OXTR G/G genotype. This interaction was significant when predicting adult attachment security as measured by the Adult Attachment Interview at ages 19 and 26 and the CRI at ages 26-28. Dopamine D4 receptor and 5-HTTLPR genetic variation did not consistently moderate the longitudinal associations between attachment security during infancy and adulthood. CONCLUSIONS: This study provides initial longitudinal evidence for genetic contributions to continuity and change in attachment security from infancy to young adulthood. Genetic variation related to the oxytocin system may moderate the stability of attachment security across development. PMID- 23731040 TI - Donepezil-induced response of Spirulina supplemented rat urinary bladder. AB - OBJECTIVE: At present, very little is known about the effects of donepezil on vascular reactivity. The aim of the present study was to evaluate the responses of rat urinary bladder to donepezil (10-10-3x10-4 M) and the role of Spirulina supplementation in these effects. MATERIAL AND METHODS: Animals were divided into the two groups of six animals in each group. The first group received only distilled water daily as vehicle for six weeks and served as the control. The second group received Spirulina 750 mg kg -1 orally, daily for six weeks and served as the spirulina group. Preparations of rat urinary bladder were used from both groups. RESULTS: Donepezil produced concentration dependent relaxation of rat urinary bladder preparations pre-contracted with KCl.The pIC50 value, but not the maximal response of donepezil, was significantly lower (p<0.05) in the Spirulina supplemented group. CONCLUSIONS: These results demonstrated for the first time that spirulina treatment can affect urinary bladder activity (Fig. 1, Ref. 20). PMID- 23731041 TI - Subthalamic electrode implantation using the MicroDrive system and the importance of microrecording data. AB - OBJECTIVE: The aim of the paper was to describe the relationship of the anatomical and electrophysiological target for the subthalamic electrode implantation in Parkinson's disease patients defined as the best electrophysiological recordings from multiple paralel electrodes tracts with a target discrepancy explanation. BACKGROUND: Although microrecording is the standard in subthalamic stimulation, microelectrode monitoring prolongs surgical time and may increase the risk of haemorrhagic complications. The main purpose for the electrophysiological mapping is to overcome the discrepancy between the anatomical and electrophysiological targets. METHODS: Subthalamic electrodes were stereotactically implanted in 58 patients using microrecording by means of parallel electrodes at defined distances. The relationship of the final electrode to the anatomical trajectory, the subthalamic nucleus electrical activity length, and the relationship of right and left electrodes were analysed. RESULTS: The final electrode placement matched the anatomical trajectory in 53.4 % of patients on the right side, and 43.1 % of patients on the left side. The electrode position was symmetrical in 38.3 % of patients. The analysis of left and right electrode positions did not prove brain shift as the sole factor responsible for anatomy-functional discrepancy. Further, neither age, Parkinson's disease duration, or L-DOPA adverse effects were confirmed as responsible factors. CONCLUSIONS: The difference between the anatomical trajectory and the final electrode placement underlined the need for functional microelectrode monitoring. Brain shift is not the only causative factor for the difference (Tab. 7, Ref. 27). PMID- 23731042 TI - The effects of nitrous oxide on vitamin B12 and homocysteine levels in methyltetrahydrofolate reductase gene mutation. AB - BACKGROUND: We aimed to investigate the effects of nitrous oxide on plasma total homocysteine and vitamin B12 levels in patients with or without methyltetrahydrofolate reductase (MTHRF) gene mutation. METHODS: After obtaining the ethics committee approval and written informed consents of patients, 93 patients between 18-70 years of age scheduled for surgery anticipated to last 1-4 hours were enrolled in the study. Patients with contraindications for nitrous oxide use were excluded. Preoperatively, blood samples were obtained from all patients for the determination of MTHFR gene mutation. Anesthesia induction was achieved with 3 mg.kg-1 of propofol and 1 ug.kg-1 of fentanyl. Anesthesia maintenance was performed with sevoflurane and with a carrier gas composed of 40 % O2 and 60 % N2O. Venous blood samples were obtained after venous canulation, and 24 hours after extubation for the analysis of plasma total homocysteine, vitamin B12 levels. RESULTS: Eighty-one patients were included in the study. Postoperative vitamin B12 levels were found to be significantly lower when compared with their preoperative levels (p<0.05). It was found that MTHRF gene polymorphism had no significant effect on postoperative plasma total homocysteine and serum vitamin B12 levels (p>0.05). Postoperative plasma total homocysteine levels were found to be significantly different between patients with operation times under and over 3 hours (p=0.028). CONCLUSIONS: We conclude that MTHRF gene polymorphism had no significant effects on postoperative plasma total homocysteine levels. However, we found that homocysteine levels might rise in patients who received general anesthesia with nitrous oxide for longer than 3 hours (Tab. 7, Ref. 26). PMID- 23731043 TI - TUGENDHAT: a pilot randomized study on effects of biventricular pacing in patients with bradycardia pacing indication and normal systolic function on heart failure, atrial fibrillation and quality of life (results of 12 month follow-up). AB - BACKGROUND: Since the late 1990s, a growing number of clinical studies have indicated that long-term permanent right ventricular (RV) apical pacing will induce severe complications such as development of heart failure, increased burden of atrial fibrillation leading to decreased quality of life. AIM OF THE STUDY: To investigate whether cardiac resynchronization therapy (CRT) using biventricular (BiV) pacing can prevent the development of left ventricular (LV) dysfunction, LV remodelling, worsening of the clinical status and quality of life in chronically RV paced patients with normal LV ejection fraction (EF). METHODS AND RESULTS: A total of 127 patients with Class I indication for permanent cardiac pacing and without established indication for CRT were subjected to 6 months of RV and BiV pacing in a patient-blinded, randomized crossover trial. Treatment effects of BiV pacing were evaluated for LV function, LV remodelling and clinical status. As compared with RV pacing, BiV pacing did not significantly prevent the decrease of LV function [LVEF 61.0 % (36.0; 68.0) vs 60.5 % (38.5; 67.5) in RV pacing], did not change the functional class according to the New York Heart Association [52 % in Class II vs 53.9 % in Class II in RV pacing, and 3.9 % in Class III vs 6.9 % in Class III in RV pacing], and did not present any changes in quality of life [32.5 (18.0; 80.0) vs 32.0 (21.0; 47.0) indexes in RV pacing]. CONCLUSION: BiV pacing, compared to RV pacing, did not change LV function and quality of life in patients with the absence of LV dysfunction or remodelling, standard bradycardia pacing indications in a pilot phase (12- month follow-up) of the TUGENDHAT trial. The final report will be published after 60 month follow-up termination (Tab. 5, Fig. 3, Ref. 30). PMID- 23731044 TI - Prevalence of mutations in thiopurine S-methyltransferase gene among Slovak IBD patients. AB - BACKGROUND: Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurines. It has been suggested that TPMT genetic polymorphisms lead to dose-related hematopoietic toxicity. Since there are major ethnic differences in the prevalence of particular TPMT variants, it is important for each country to study their own prevalence in order to estimate the role of TPMT variants-related thiopurines toxicity in population suffering from particular inflammatory bowel disease (IBD). AIMS: The aim of this study was to determine the frequency of the four most common allelic variants of TPMT gene in the population of Slovak IBD patients. METHODS: TPMT genetic polymorphisms (TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C) were amplified using PCR and consequently genotyped with genetic analyzer. The allele frequencies of particular allelic variants were calculated and compared with other Caucasian populations reported so far. RESULTS: Three hundred and thirty IBD patients were included; 196/132/2 cases of Crohn's disease/ulcerative colitis/unclassified colitis; 180 (55 %) males. Ninety three percent of patients were homozygous for wild-type TPMT variant. Heterozygous genotype of any of the studied polymorphisms was present in 6 % of patients while only one patient was homozygous for TPMT*3A allele (0.3 %). The most prevalent mutant allele was that of TPMT*3A (3.2 %). The distribution of most common allelic variants of TPMT gene among Slovak IBD patients was in accordance with previously reported prevalence in Caucasian populations. CONCLUSION: This study shows the prevalence of TPMT genetic polymorphisms in population of Slovak IBD patients. As in other Caucasian populations, the most common mutant allelic variant is that of TPMT*3A while the prevalence of homozygosity is relatively low (Tab. 3, Ref. 22). PMID- 23731045 TI - Wildflower (Hyoscyamus reticulatus) causes QT prolongation. AB - INTRODUCTION: In the environment, there are hundreds of poisonous and injurious plants with a wide variety of toxicity. Among all plants with anticholinergic effect, Hyoscyamus reticulatus is a species whose clinicopathological effects have been poorly described in literature. The paper is especially aimed at drawing attention to the possibly fatal syndrome of prolonged QT, as well as to clinical and laboratory changes in six members of a single family poisoned with this plant. CASES: Six female patients aged from 19 to 49 presented to our emergency room with a suspicion of being poisoned after having ingested a plant known as 'the mad axe plant' (Hyoscyamus reticulatus). At least one of anticholinergic symptoms including flushing, mydriasis, dry mouth and tachycardia was present in all of the patients. In addition, different levels of agitation were observed in four of the patients. A euphoric emotional state was present in two patients. The corrected QT distances were found to be prolonged in three of the patients. DISCUSSION AND CONCLUSION: Based on economical, social and cultural reasons, it is a very common habit in our country, especially in our region in spring and summer months, to consume some plants growing spontaneously in rural areas as food. Intoxication with Hyoscyamus reticulatus is a plant poisoning that is poorly described in literature. Its classical symptoms are predominantly anticholinergic. Although it is commonly self-limited and can be corrected with close observation and supportive treatments, it should be kept in mind that the prolongation of QT interval can accompany the symptoms of poisoning with this plant (Tab. 1, Fig. 3, Ref. 19). PMID- 23731046 TI - Alcoholic cardiomyopathy and cardiovascular events - an insight from the Liptov region. AB - AIM: This study was conducted to study the association between alcohol consumption and cardiovascular events and echocardiographical parameters in 100 consumers with the average daily dose <120 g and >=120 g of alcohol per day during a 4-year follow-up. METHODS: 100 patients/heavy alcohol consumers (on average >= 80 g daily), with no cardiovascular disease, divided into 2 groups, underwent a baseline echocardiographic and clinical evaluation and were followed up for cardiovascular events, biochemical analysis and rhythm disorder for 4 years. RESULTS: Data regarding the dose and duration of alcohol consumption showed a low correlation and nonlinear character between the duration of alcohol consumption and monitored parameters. There were no differences between the groups in the echo-parameters ejection fraction EF (p=0.43), in the diameter of left atrium LA (p=0.51). Left chamber - LVEDD - was slightly bigger in the group with a heavier drinking pattern (p=0.09). There were no differences in biochemical parameters between the groups. When comparing these two groups of consumers the percentage of diabetes mellitus (p=0.283), episodes of heart failure (p=0.308), atrial fibrillation (p=0.652), cerebral vascular accident (p=0.722) and delirium (p=0.559) were not significantly different; only 2 subjects suffered from myocardial infarction during the follow-up. CONCLUSION: We conclude, that no significant differences (p<0.05) between the two groups of heavy alcohol consumers were observed in echo parameters, biochemical values and cardiovascular events (Tab. 4, Ref. 28). PMID- 23731047 TI - Morphology of intestinal microcirculation in colitis ulcerosa and Crohn's disease. AB - AIM OF THE WORK: To describe the state of microcirculation in the intestinal wall in ulcerative colitis and Crohn's disease in own material. MATERIALS AND METHODS: For morphological examination, we obtained tissue samples from both diseases during bioptic bowel examination from 11 patients. We fixed the samples with 10% buffered formalin, de-hydrated and covered with paraffin. From paraffin blocks, we made histological sections about 5MUm thick with a microtome. They were always stained with haematoxylin and eosin. For immunohistochemistry sections, we either did or did not revitalise the sections according to the manufacturer's recommendations for specific to-reagents. For immunohistochemic examinations, we revitalised the sections by acquiring the heat-induced epitope in DakoCytomation Target Retrieval Solution, Code No S 1700, or in mmol.l-1 citrate buffer, pH 6.0. We did not dry the sections during such procedure. We used antibodies as follows: Monoclonal mouse antibodies against human von Willebrand factor, Clone F8/86 (DakoCytomation, Denmark), Monoclonal mouse antibodies against smooth muscle actine, Clone HHF35 (DakoCytomation, Denmark). We used detection system Dako EnVisionTM + Dual Link System-HPR (Dako, Denmark) or Dako Liquid DAB + Substrate Chromogen System (Dako, Denmark) to display areas of specific connection of antibodies. Antibodies against von Willebrand factor react in our samples with the endothelium of vessels and with precursors in the lining of peaks of villi. We have also seen a diffuse positive reaction. Lymphatic vessels do not display monoclonal antibodies (Fig. 4, Ref. 8). PMID- 23731048 TI - Role of human papilloma virus infection and oral-genital contact in oral cancer ethiopathogenesis. AB - Head and neck squamous cell carcinoma and especially oropharyngeal squamous cell carcinoma is a very significant cause of morbidity and mortality. The majors risk factors of these tumors are tobacco smoking, chewing and alcohol consumption. But there is a group, non-drinking and non-smoking, patients with oropharyngeal squamous cell carcinoma. In these patients may be oral-genital contact and human papillomavirus infection the major risk factor for oral carcinogenesis. Aim of this review is to point out this fact in correlation with clinical studies and clinical conclusion for medical practice (Fig. 1, Ref. 32). PMID- 23731049 TI - Changes in metabolic syndrome parameters after liposuction. AB - Liposuction - one of the most frequent procedures in cosmetic surgery - is the surgical aspiration of fat from the subcutaneous layer leaving a more desirable body contour and leaving a smooth transition between the suctioned and nonsuctioned areas. Metabolic syndrome is epidemiologically important medical condition that includes insulin resistance, dyslipidemia, central obesity, hypertension, impaired glucose tolerance or diabetes mellitus, and high rates of atherosclerotic disease. According to the latest findings, liposuction reduces the amount of subcutaneous fat, which changes the abdominal - superficial adipose tissue ratio and thus might affect the potential of metabolic syndrome by the means of its separate parameters and clinical manifestations. Results that can be found in the published literature remain controversial and often contradictory, thus leaving enough space for further investigations regarding the relation of these two clinical entities (Ref. 33). PMID- 23731050 TI - Vasculitides as a rare cause of intermittent claudication. AB - Intermittent claudication of the lower extremities is a common symptom described in older patients with atherosclerotic peripheral arterial disease. Peripheral arterial disease due to atherosclerosis is known to be associated with a higher risk of myocardial infarction, stroke and all-cause mortality. However, if intermittent claudication appears in a younger group of patients or older patients in absence of traditional risk factors for atherosclerosis such as smoking, dyslipidemia, arterial hypertension and diabetes mellitus other causes than atherosclerosis must be considered. These conditions include vasculitides, fibromuscular dysplasia, cystic adventitial disease, excentric vascular compression by tumor, popliteal artery entrapment syndrome, trauma or dissection. Vasculitides present a heterogenous group of disorders characterized by inflammatory destruction of blood vessels. Although often not a leading symptom intermittent claudication could be a part of a clinical picture in giant-cell arteritis, Takayasu's arteritis, Buerger's disease, polyarteritis nodosa or Behcet disease. Limb claudication is usually of rapid onset, progressive and bilateral. Each of the mentioned vasculitides is specific in ethiology and clinical manifestation with a variable prognosis for the patient. Increased awareness of the presence of different causes of limb claudication and their early diagnosis with a prompt initiation of appropriate treatment may help to avoid clinical progression that can lead to vascular surgery or even limb loss (Ref. 37). PMID- 23731051 TI - Evaluation of the oblique fissure on lateral chest radiographs in coal workers pneumoconiosis. AB - OBJECTIVE: The oblique fissure separates the upper lobe from the lower lobe in the left lung and the upper lobe from the lower and middle lobes in the right lung. The aim of the present study was to compare the projection of the oblique fissure observed on lateral chest radiographs of retired coal mine workers who had coal worker's pneumoconiosis (CWP) with that of healthy men. MATERIALS AND METHODS: The study included 120 men divided into three groups: retired coal miner patients diagnosed with CWP (group 1), men >=38 years of age with no CWP (group 2, first control group), and men <=37 years of age with no CWP (group 3, second control group). The projection of the oblique fissure observed on lateral chest radiographs (left side) were evaluated using geometric morphometrics. Geometric morphometric analysis of each sample was performed using 11 pre-specified landmarks designated on X-ray images, using tpsDig2 software. A text file containing the landmark coordinates of the 120 samples was created, and the data in the text file was statistically analyzed using Morpheus software. RESULTS: The projection of the oblique fissure differed significantly between the CWP patients and the control groups (p<0.05). CONCLUSION: We suggest that the difference in the projection of the oblique fissure between men with and without CWP was attributable to a protrusion in the fissure caused by nodules that developed in the lungs of coal miners after years of dust inhalation (Tab. 4, Fig. 4, Ref. 30). PMID- 23731052 TI - Solubility of helium in ice Ih at pressures up to 2000 bar: experiment and calculations. AB - The solubility of helium in ice Ih has been examined both experimentally and theoretically. It has been demonstrated that the calculations are in good accord with the experimental data. The tested calculation method has been used for deriving the helium solubility in ice Ih at pressures up to 2000 bar and at temperatures of 0-50 degrees C. Obtained data may be useful in some practical applications (storage of enriched with helium natural gas in permafrost, extraction of helium from natural gas). PMID- 23731053 TI - Epidemiological survey and risk factor analysis of fatty liver disease of adult residents, Beijing, China. AB - BACKGROUND AND AIM: With the changes in diet structure and lifestyle, the incidence of fatty liver disease is increasing in China, especially in cities. The goal of the present study was to accurately determine the prevalence and risk factors of fatty liver disease in Beijing residents, China. METHODS: By using random multistage stratification and cluster sampling, residents aged > 20 years in Dongcheng District and Tongzhou District were recruited, and questionnaire survey, physical examination, detection of fasting glucose, blood lipids and liver biochemistry, and ultrasonography of the liver, gallbladder, and spleen were carried out. Database EpiData 3.0 was employed for data input, followed by statistical analysis with SPSS version 11.0. RESULTS: A total of 3762 residents were included in the present study including 2328 males and 1434 females with a mean age of 46.37 +/- 14.28 years (range 20-92 years). Ultrasonography revealed fatty liver in 1486 residents with a prevalence of 39.5%. Moreover, non-alcoholic fatty liver disease (NAFLD) and alcoholic fatty liver disease were found in 1177 (31.3%) and 309 (8.2%) residents, respectively. After adjustment of prevalence based on the age and gender constituents of Beijing residents, the standardized prevalence of overall fatty liver disease, NAFLD, and alcoholic fatty liver disease was 35.1%, 31.0%, and 4.1%, respectively. Binary logistic regression analysis revealed waist-to-hip ratio, diastolic pressure, fasting blood glucose, triglyceride, high-density lipoprotein cholesterol, and low density lipoprotein cholesterol were closely related to NAFLD. CONCLUSIONS: The Beijing residents have a high prevalence of fatty liver disease as much as 35.1%, which is characterized by NAFLD. Obesity, and glucose and lipid metabolism disorders are the main risk factors of fatty liver disease. PMID- 23731054 TI - Auxin-mediated nitrate signalling by NRT1.1 participates in the adaptive response of Arabidopsis root architecture to the spatial heterogeneity of nitrate availability. AB - To optimize their nitrogen nutrition, plants are able to direct root growth in nitrate-rich patches. This depends in Arabidopsis on the NRT1.1 nitrate transporter/sensor. NRT1.1 was shown to display on homogenous medium, an auxin transport activity that lowers auxin accumulation in lateral roots and inhibits their growth at low nitrate. Using a split-root system, we explored the hypothesis that preferential lateral root growth in the nitrate-rich side involves the NRT1.1-dependent repression of lateral root growth in the low nitrate side. Data show that NRT1.1 acts locally to modulate both auxin levels and meristematic activity in response to the low nitrate concentration directly experienced by lateral roots leading to a repression of their growth. A stimulatory role of NRT1.1 in the high nitrate side, which does not rely on changes in auxin levels, is also observed. Altogether, our data suggest that NRT1.1 allows preferential root colonization of nitrate-rich patches by both preventing root growth in response to low nitrate, through modulation of auxin traffic, and stimulating root growth in response to high nitrate, through a yet uncharacterized mechanism. In addition, transcriptional regulation of NRT1.1 affects both mechanisms allowing plants to modulate the effect of nitrate on root branching. PMID- 23731055 TI - Mouse ES cells have a potential to differentiate into odontoblast-like cells using hanging drop method. AB - OBJECTIVES: We examined whether mouse embryonic stem (ES) cells can differentiate into odontoblast-like cells without epithelial-mesenchymal interaction. MATERIALS AND METHODS: Cells were cultured by the 'hanging drop' method using a collagen type-I scaffold (CS) combined with bone morphogenetic protein (BMP)-4 (CS/BMP-4). Expression of odontoblast-related mRNA and protein, and cell proliferation were performed by reverse transcription-polymerase chain reaction (RT-PCR), immunofluorescence staining and WST-1 assay, respectively. RESULTS: Cells potently expressed odontoblast-related cell marker mRNAs following induction of odontoblastic differentiation. Dentin sialophosphoprotein, a marker of mature odontoblasts, was strongly expressed in differentiated ES cells. The cells also acquired an odontoblast-like functional phenotype, as evidenced by the appearance of alkaline phosphatase activity and calcification. The cell-surface expression of alpha2, alpha6, alphaV and alphaVbeta3 integrin proteins was rapidly upregulated in differentiated cells. Finally, anti-alpha2 integrin antibody suppressed the expression of odontoblastic markers in cells grown using this culture system, suggesting that alpha2 integrin expression in ES cells triggers their differentiation into odontoblast-like cells. CONCLUSIONS: Mouse ES cells cultured by the 'hanging drop' method are able to differentiate into cells with odontoblast-specific physiological functions and cell-surface integrin protein expression. PMID- 23731056 TI - Enhanced water dispersibility of coenzyme Q10 by complexation with albumin hydrolysate. AB - The biologically important coenzyme Q10 (CoQ10) is widely used as a drug for chronic heart failure, as a nutritional supplement, and in cosmetics. However, the oral bioavailability of CoQ10 is poor due to its extremely low solubility in aqueous media. In this study, complexation of CoQ10 with albumin hydrolysate as a peptide mixture (Pep) was shown to enhance the water dispersibility of CoQ10. An aqueous solution of Pep and an acetone solution of CoQ10 were mixed and lyophilized to obtain a white-yellow powder containing peptides and CoQ10 complex (Q10-Pep). The water dispersibility of Q10-Pep was much higher than that of CoQ10 alone and increased with the quantity of Pep. The particle size of Q10-Pep in aqueous media was 170-280 nm, suggesting that Q10-Pep was present as a hydrocolloidal material. Characterization of Q10-Pep using differential scanning calorimetry showed that CoQ10 was incorporated in the hydrocolloid in an amorphous state. PMID- 23731057 TI - Objectively measured light and moderate-to-vigorous physical activity is associated with lower depression levels among older US adults. AB - OBJECTIVES: We have a limited understanding of the epidemiological association between objectively measured physical activity and depression among older adults. Therefore, the purpose of this study was to examine the association between accelerometer-assessed physical activity and depression symptoms among a nationally representative sample of US older adults. METHODS: Data from the 2005 2006 National Health and Nutrition Examination Survey was used. 708 older adults (65+ years) wore an ActiGraph 7164 accelerometer for at least 4 days, and completed data on the study covariates along with depression, as assessed by the Patient Health Questionnaire-9. RESULTS: After controlling for age, gender, race ethnicity, body mass index, marital status, education, comorbidity index, and physical functioning, for every 60-minute increase in light-intensity physical activity, participants were 20% (OR = 0.80; 95% CI: 0.67-0.95; p = 0.01) less likely to be depressed. Moderate-to-vigorous physical activity was also inversely associated with depression (OR = 0.78; 95% CI: 0.64-0.94; p = 0.01). CONCLUSION: These findings suggest that promoting physical activity, even light-intensity physical activity, may have positive mental health effects among older adults. Future prospective and experimental studies are warranted. PMID- 23731058 TI - Phenotype versus genotype methods for copy number variant analysis of glutathione S-transferases M1. AB - Several variants have been identified for genes encoding Glutathione S transferase (GST) enzymes; some are associated with significant alteration of protein function. One of the most extensively studied is a copy number variant (CNV) in the GSTM1 gene. In this study, we compared phenotype (positive, null) and genotype (1/1, 1/0, 0/0) methods in order to assess dissimilarities obtained using these two different approaches to evaluate possible methodology-related bias. We analyzed a sample of 1947 individuals belonging to 18 human populations with different ethnic origins. We also evaluated whether the presence of missense substitutions in the GSTM1 gene might influence the association of the CNV with phenotype distribution. Through the comparison of GSTM1 CNV frequencies in phenotype and genotype among human populations, we observed that differences increase in high heterogeneous populations. Furthermore, we identified two missense variants (rs199816990 and rs202002774) that may distort the outcome of genetic association studies on Asian populations. These results indicate that the phenotype analysis may strongly alter the genetic association. Therefore, genotype discrimination analysis should be used to analyze GSTM1 CNV. To understand the role of GSTM1 in human health, the analysis of CNV should be combined with the investigation of single nucleotide polymorphisms with functional effect. PMID- 23731059 TI - How does the radiation therapist affect the cancer patients' experience of the radiation treatment? AB - Previous studies of head and neck cancer patients going through radiation treatment have shown the treatment causes great physical as well as psychosocial problems. Although previous research acknowledges the needs of cancer patients, there is a lack of literature regarding the patient's perspective about radiation therapy. Studies have rarely focused on the whole experience of radiation treatment. The aim of this study was to illuminate how head and neck cancer patients' encounters with radiation therapists influence patients' experiences going through radiation therapy. The study was conducted via qualitative interviews, using a phenomenological hermeneutic approach. Eleven cancer patients were treated with radiation therapy. This study showed that encounters with radiation therapists have a significant influence on patients' experiences. Cancer patients' contact with radiation therapists can lead to increases or decreases in existential anxiety. When patients experience that the radiation therapist is professionally competent, the existential anxiety decreases. When the radiation therapist make time to build relationships and take responsibility for treatment and side effects, this creates a feeling of security and the treatment is easier to review. The study may indicate that the patients' existential anxiety increases when the radiation therapist shows professional incompetence. PMID- 23731060 TI - Coaxial fiber supercapacitor using all-carbon material electrodes. AB - We report a coaxial fiber supercapacitor, which consists of carbon microfiber bundles coated with multiwalled carbon nanotubes as a core electrode and carbon nanofiber paper as an outer electrode. The ratio of electrode volumes was determined by a half-cell test of each electrode. The capacitance reached 6.3 mF cm(-1) (86.8 mF cm(-2)) at a core electrode diameter of 230 MUm and the measured energy density was 0.7 MUWh cm(-1) (9.8 MUWh cm(-2)) at a power density of 13.7 MUW cm(-1) (189.4 MUW cm(-2)), which were much higher than the previous reports. The change in the cyclic voltammetry characteristics was negligible at 180 degrees bending, with excellent cycling performance. The high capacitance, high energy density, and power density of the coaxial fiber supercapacitor are attributed to not only high effective surface area due to its coaxial structure and bundle of the core electrode, but also all-carbon materials electrodes which have high conductivity. Our coaxial fiber supercapacitor can promote the development of textile electronics in near future. PMID- 23731061 TI - Immunolocalization of intermediate filaments and laminin in the oviduct of the immature and mature Japanese quail (Coturnix coturnix japonica). AB - This study describes the distribution of vimentin, desmin, smooth muscle actin (SMA) and laminin in the oviduct of the immature and mature Japanese quail. The cytoskeletal proteins vimentin, desmin and SMA have been shown to be involved in cellular support, differentiation, migration and contractility. Laminin is a major component of basement membranes. Luminal epithelia in the infundibular and magnal regions of immature and mature birds exhibited strong vimentin immunoreactivity. Luminal epithelial cells exhibiting strong vimentin immunoreactivity were present in the isthmus and shell gland regions of only mature quails. Infundibular glandular grooves displayed strong vimentin immunostaining. In contrast, the glandular epithelia of the magnum, isthmus and shell gland were vimentin immunonegative. Fibroblasts and vascular endothelial cells in the lamina propria of the oviductal regions studied exhibited strong vimentin immunostaining. Smooth muscle cells forming the tunica muscularis and vascular tunica media displayed strong desmin and SMA immunostaining. Strong laminin immunostaining was demonstrated in the basement membranes associated with smooth muscle cells, as well as in the basement membranes underlying the luminal and glandular epithelia. In conclusion, this study has shown that the immunolocalization of desmin, SMA and laminin in the oviduct of the Japanese quail is similar to that in the domestic fowl. However, differences in the immunoexpression of vimentin in the LE of the two avian species were shown to exist. In addition, the study has shown that the immunolocalization of vimentin in the Japanese quail varies depending on the oviductal region, as well as the developmental stage of the oviduct. PMID- 23731062 TI - Cardiovascular mortality in obstructive sleep apnoea treated with continuous positive airway pressure or oral appliance: an observational study. AB - BACKGROUND AND OBJECTIVE: The objective of this study was to evaluate the long term cardiovascular mortality in patients with severe obstructive sleep apnoea (OSA) treated with either continuous positive airway pressure (CPAP) or mandibular advancing device (MAD). METHODS: A non-concurrent cohort study of 570 subjects with severe OSA (apnoea/hypopnoea index (AHI) >= 30/h) and a control group of 269 subjects (AHI < 5/h) were followed up for a median of 79 months (interquartile range 76-88 months). All patients received CPAP initially. MAD was offered for those who were non-adherent to CPAP. The endpoint was cardiovascular death. RESULTS: Two hundred and eight control subjects, 177 patients treated with CPAP, 72 with MAD and 212 who declined treatment were analysed. Forty-two patients had a fatal cardiovascular event during the course of the study. The non apnoeic group had the lowest cardiovascular death rate (0.28 per 100 person-years (95% confidence interval (CI): 0.08-0.71)) followed by the CPAP-treated (0.56 per 100 person-years (95% CI: 0.20-1.23)) and the MAD-treated OSA group (0.61 per 100 person-years (95% CI: 0.13-1.78)), with the highest cardiovascular mortality rate observed in the untreated OSA group (2.1 per 100 person-years (95% CI: 1.37 2.92)). Although residual AHI for MAD-treated patients was significantly higher than CPAP-treated patients (16.3 +/- 5.1/h vs. 4.5 +/- 2.3/h; P < 0.001), there was no difference in cardiovascular death rate between the two groups (hazard ratio 1.08 (95% CI: 0.55-1.74); P = 0.71). CONCLUSIONS: Both CPAP and MAD may be equally effective therapy in reducing the risk of fatal cardiovascular events in patients with severe OSA. PMID- 23731063 TI - Repeated thermo-sterilisation further affects the reliability of positive end expiratory pressure valves. AB - AIM: Positive end-expiratory pressure (PEEP) valves are used together with self inflating bags (SIB) to provide a preset PEEP during manual ventilation. It has recently been shown that these valves deliver highly variable levels of PEEP. We hypothesised that material fatigue due to repeated thermo-sterilisation (TS) may contribute to varying reliability of PEEP valves. METHODS: In a laboratory study 10 new PEEP valves were tested before and after 10, 20 and 30 cycles of routine TS (7 min at 134 degrees C) by using a neonatal lung model (compliance 0.2 mL/kPa). Settings were positive inflation pressure = 20 and 40 cm H(2)O, PEEP = 5 and 10 cm H(2)O, respiratory rate = 40 and 60/min, flow = 8l/min. PEEP was recorded using a respiratory function monitor. RESULTS: Before TS, a mean (standard deviation) PEEP of 4.0 (0.9) and 7.7 (1.0) cm H(2)O was delivered by the 10 valves when the PEEP was set to 5 and 10 cm H(2)O, respectively. One new valve only delivered 2.0 (0.0) and 5.0 (0.0) cm H(2)O when the PEEP was adjusted to 5 and 10 cm H(2)O, respectively. Four of the 10 investigated valves showed significant variations in PEEP (coefficient of variation >10%) throughout the autoclaving process. One valve completely lost its function after the 20th TS. Common defects were tears in the softer materials or displacement of the rubber seal. Six of the 10 valves continued to provide PEEP in spite of repeated TS. CONCLUSION: The reliability of PEEP valves is affected by repeated TS. Multi-use PEEP valves should be tested for reliable PEEP provision following TS. PMID- 23731064 TI - New candidates for mechano-sensitive channels potentially involved in gravity sensing in Arabidopsis thaliana. AB - The mechano-sensitive channels of plants may sense increases in tension induced by mechanical stimuli, such as touch, wind and turgor pressure, and a gravitational stimulus. Recent studies have identified plant homologues of the bacterial mechano-sensitive channel MscS, which is gated by membrane tension and reduces intracellular osmolality by releasing small osmolytes from bacterial cells. However, the physiological roles of these homologues have not yet been clearly elucidated, and only two of them have been shown to be involved in the protection of osmotically stressed plastids in Arabidopsis thaliana. We identified another group of candidates for mechano-sensitive channels in Arabidopsis, named MCA1 and MCA2, whose homologues are exclusively found in plant genomes. MCA1 and MCA2 are composed of 421 and 416 amino acid residues, respectively, share 73% homology in their amino acid sequences, and are not homologous to any known ion channels or transporters. Our structural study revealed that the N-terminal region (one to 173 amino acids) of both proteins was necessary and sufficient for Ca(2+) influx activity. Interestingly, this region had one putative transmembrane segment containing an Asp residue whose substitution mutation abolished this activity. Our physiological study suggested that MCA1 expressed at the root tip was required for sensing the hardness of the agar medium or soil. In addition, MCA1 and MCA2 were shown to be responsible for hypo-osmotic shock-induced increases in [Ca(2+) ]cyt . Thus, both proteins appear to be involved in the process of sensing mechanical stresses. We discussed the possible role of both proteins in sensing mechanical and gravitational stimuli. PMID- 23731065 TI - Translation of oral care practice guidelines into clinical practice by intensive care unit nurses. AB - PURPOSE: The purpose of this study was to determine whether there was a change in the oral care practices of intensive care unit (ICU) nurses for ventilated patients after a national effort to increase evidence-based oral care practices. DESIGN: Descriptive comparison of ICU nurses in 2004-2005 and 2012. METHOD: Two convenience national surveys of ICU nurses were collected in 2004-2005 (n = 218) and 2012 (n = 233). After the results of the initial survey were reported, a national effort to increase awareness of evidence-based oral care practices was conducted that included in-service presentations; publication of an evidence based protocol in a national nursing journal; publication of the survey findings in an international nursing journal; and reports to the local press. A repeat survey was conducted 7 to 8 years later. The same survey instrument was used for both periods of data collection. This questionnaire included questions about demographic and personal characteristics and a checklist of oral care practices. Nurses rated their perceived priority level concerning oral care on a scale from 0 to 100. An evidence-based practice (EBP)[O4] score was computed representing the sum of 14 items related to equipment, solutions, assessments, and techniques associated with the evidence. The EBP score, priority score, and oral care practices were compared between the two samples. A regression model was built based on those variables that were associated with the EBP score in 2012. FINDINGS: There was a statistically significant increase in the use of EBPs as shown by the EBP score and in the perceived priority level of oral care. Increased EBPs were found in the areas of teeth brushing and oral assessment. Decreases were found in the use of non-evidence-based practices, such as the use of gauze pads, tongue depressors, lemon water, and sodium bicarbonate. No differences were found in the use of chlorhexidine, toothpaste, or the nursing documentation of oral care practices. A multiple regression model was found to be significant with the time of participation (2004-2005 vs. 2012) and priority level of oral care significantly contributing to the regression model. CONCLUSIONS: The national effort was partially successful in improving evidence based oral care practices; however, increased awareness to EBP also might have come from other sources. Other strategies related to knowledge translation need to be attempted and researched in this clinical setting such as the use of opinion leaders, audits and feedback, small group consensus, provider reminder systems, incentives, clinical information systems, and computer decision support systems. CLINICAL RELEVANCE: This national effort to improve EBP did reap some rewards; however, other knowledge translation strategies should be used to further improve clinical practice. PMID- 23731066 TI - Synthesis and photoresponse of large GaSe atomic layers. AB - We report the direct growth of large, atomically thin GaSe single crystals on insulating substrates by vapor phase mass transport. A correlation is identified between the number of layers and a Raman shift and intensity change. We found obvious contrast of the resistance of the material in the dark and when illuminated with visible light. In the photoconductivity measurement we observed a low dark current. The on-off ratio measured with a 405 nm at 0.5 mW/mm(2) light source is in the order of 10(3); the photoresponsivity is 17 mA/W, and the quantum efficiency is 5.2%, suggesting possibility for photodetector and sensor applications. The photocurrent spectrum of few-layer GaSe shows an intense blue shift of the excitation edge and expanded band gap compared with bulk material. PMID- 23731067 TI - Theoretical analysis of weak adjacent substituent effect on the overtone intensities of XH (X = C, O) stretching vibrations. AB - It is known that the overtone intensities of some set of OH and CH stretching vibrations show only a weak dependence on the adjacent substituent, in sharp contrast to the much stronger dependence of their fundamental intensities. To understand this characteristic, we calculated the fundamental and overtone intensities of the Deltav = 1-6 transitions for the OH stretching of alcohols and acids and the CH stretching of hydrocarbons with different types of hybridization. Based on the local-mode model, from the three components of the dipole moment function (DMF) of each molecule, a one-component effective DMF that recovered about 95% of the total intensity for the Deltav = 1-6 transitions was constructed and expressed as a sixth-order polynomial of the bond displacement DeltaR, with the leading expansion coefficients M1, M2, and M3 for the linear, quadratic, and cubic terms, respectively. When these coefficients for each molecule were represented as points in the coordinate system O-M1M2M3, the points for some set of molecules were found to lie on a straight line. Interestingly, the line had a direction cosine such that the resultant transition moments exhibited a small substituent dependence of the overtone intensities. Moreover, the slope of the line could be well approximated by the Morse exponential parameter and the bond distance. These characteristics of the DMFs can be rationalized by using the calculated transition moments and the wave function expansion method with the eigenfunction of the Morse potential. It was also verified by the quasiclassical method of Medvedev that these characteristics of the DMFs are the intrinsic reason for the weak substituent dependence of the overtone intensities. It is emphasized that the graphical representation of the DMF parameters provides a comprehensive tool for discussing various aspects of vibrational intensities. PMID- 23731068 TI - Interaction between territoriality, spatial environment, and hippocampal neurogenesis in male side-blotched lizards. AB - Differences in an animal's spatial environment can have dramatic effects on the hippocampus, an area of the brain involved with spatial processing. Animals in spatially impoverished environments have decreased hippocampal attributes. However, we do not know if differences in the spatial environment differentially interact with territorial status, which also covaries with hippocampal attributes. Here, we asked whether territoriality and differential spatial-area use interact to generate different effects on cortical attributes (reptilian hippocampal homologue) in lizards. We compared medial and dorsal cortical attributes between territorial and nonterritorial morphotypes of side-blotched lizards, Uta stansburiana, in larger versus smaller (i.e., spatially impoverished) enclosures. We found that territorial males had increased neurogenesis rates in their medial cortices in larger enclosures when compared with their siblings in smaller enclosures; nonterritorial males had low levels of neurogenesis regardless of enclosure size. Enclosure size had no significant effect on cortical volumes or the total number of neurons in either cortical region. These results suggest that territorial morphotypes may be more sensitive to changes in the spatial environment, thus leading to increases in regulation of neurogenesis in the face of increased spatial processing and physical activity demands. PMID- 23731069 TI - Lesions of the dorsal tegmental nuclei disrupt control of navigation by distal landmarks in cued, directional, and place variants of the Morris water task. AB - Navigation depends on a network of neural systems that accurately monitor an animal's spatial orientation in an environment. Within this navigation system are head direction (HD) cells which discharge as a function of an animal's directional heading, providing an animal with a neural compass to guide ongoing spatial behavior. Experiments were designed to test this hypothesis by damaging the dorsal tegmental nucleus (DTN), a midbrain structure that plays a critical role in the generation of the rodent HD cell signal, and evaluating landmark based navigation using variants of the Morris water task. In Experiments 1 and 2, shams and DTN-lesioned rats were trained to navigate toward a cued platform in the presence of a constellation of distal landmarks located outside the pool. After reaching a training criteria, rats were tested in three probe trials in which (a) the cued platform was completely removed from the pool, (b) the pool was repositioned and the cued platform remained in the same absolute location with respect to distal landmarks, or (c) the pool was repositioned and the cued platform remained in the same relative location in the pool. In general, DTN lesioned rats required more training trials to reach performance criterion, were less accurate to navigate to the platform position when it was removed, and navigated directly to the cued platform regardless of its position in the pool, indicating a general absence of control over navigation by distal landmarks. In Experiment 3, DTN and control rats were trained in directional and place navigation variants of the water task where the pool was repositioned for each training trial and a hidden platform was placed either in the same relative location (direction) in the pool or in the same absolute location (place) in the distal room reference frame. DTN-lesioned rats were initially impaired in the direction task, but ultimately performed as well as controls. In the place task, DTN-lesioned rats were severely impaired and displayed little evidence of improvement over the course of training. Together, these results support the conclusion that the DTN is required for accurate landmark navigation. PMID- 23731070 TI - Rapid effects of 17beta-estradiol on male copulatory behaviors are not elicited by the novel membrane active estrogenic compound STX. AB - Estrogens have been shown to rapidly promote male copulatory behaviors with a time-course that suggests rapid signaling events are involved. The present study tested the hypothesis that estrogen acts through a novel Gq protein-coupled membrane estrogen receptor (ER). Thus, either estradiol (E2), STX (a diphenylacrylamide compound that selectively activates a membrane ER pathway), or vehicle were administered acutely to castrated male rats that bore subcutaneous (sc) dihydrotestosterone implants to maintain genital sensitivity. Appetitive (level changes, genital investigation) and consummatory (mounts, intromissions, ejaculations) components of male sexual behavior were measured in a bilevel testing apparatus. Testing showed that E2 treatment promoted olfactory and mounting behaviors, but had no effect on motivation as measured by anticipatory level changes. STX treatment showed no effect on either component of male sexual behavior. These results support previous results that showed that E2 can rapidly affect male sexual behaviors but fail to support a role for the specific membrane initiated pathway activated by STX. PMID- 23731071 TI - Social defeat stress switches the neural system mediating benzodiazepine conditioned motivation. AB - Benzodiazepines have been demonstrated to have a high abuse liability in persons suffering from anxiety but have demonstrated mixed abuse liability findings in preclinical models. We hypothesized that by modeling anxiety in a male C57BL/6 mouse model it would be possible to reveal a preference for benzodiazepines within this subpopulation through negative reinforcement. Using the Tube Test of Social Dominance and the Resident/Intruder Paradigm we investigated whether animals identified as dominant or submissive/defeated would differentially display a preference for midazolam (a short acting benzodiazepine) in a conditioned place preference paradigm. Consistent with our hypotheses, benzodiazepine conditioned motivation was mediated by negative reinforcement as submissive but not dominant mice displayed a preference for midazolam. Furthermore, different neural systems mediated midazolam conditioned motivation depending on the stress status of the animal (single vs. repeated stress-as induced by the Resident/Intruder Paradigm). Singly stressed animals showed midazolam place preferences through a dopamine-independent pathway, whereas the place preferences of repeatedly stressed animals were mediated through a dopamine dependent pathway. This demonstrates that stress is sufficient for switching the neural system mediating midazolam conditioned motivation. Finally, midazolam reinforcement in the conditioned place preference paradigm was shown to be predictive for dominance/submission status. PMID- 23731072 TI - Age and apolipoprotein E epsilon4 effects on neural correlates of odor memory. AB - Alzheimer's disease (AD) affects 5.4 million Americans. Evidence suggests that individuals who are positive for the apolipoprotein E (ApoE) epsilon4 allele are at higher risk for developing the disease. Studies have also shown that the epsilon4 allele is linked to olfactory decline. Olfactory functioning may be investigated using olfactory event-related potentials (OERPs). The high temporal resolution of OERPs enables an understanding of the neural correlates of olfactory processing and functioning. This study investigated the effects of age, ApoE epsilon4 status, response type, and electrode site on OERP latency and amplitude during encoding and retrieval in an odor recognition memory task. The 60 participants were equally divided into 3 age groups matched on epsilon4 status: younger, middle, and older. Odors were presented using a computer controlled olfactometer. Participants were notified during encoding that this was a task of odor memory. Results indicated differences in OERP activity as a function of age, ApoE epsilon4 status, response type, and electrode site. These findings highlight the potential of OERPs to distinguish epsilon4- and epsilon4+ individuals and to contribute to an earlier diagnosis of AD. PMID- 23731073 TI - Dissociation between implicit and explicit responses in postconditioning UCS revaluation after fear conditioning in humans. AB - The nature of the relationship between explicit and implicit learning is a topic of considerable debate. To investigate this relationship we conducted two experiments on postconditioning revaluation of the unconditional stimulus (UCS) in human fear conditioning. In Experiment 1, the intensity of the UCS was decreased after acquisition for one group (devaluation) and held constant for another group (control). A subsequent test revealed that even though both groups exhibited similar levels of UCS expectancy, the devaluation group had significantly smaller conditional skin conductance responses. The devaluation effect was not explained by differences in the explicit estimates of UCS probability or explicit knowledge that the UCS intensity had changed. In Experiment 2, the value of the UCS was increased after acquisition for one group (inflation) and held constant for another group (control). Test performance revealed that UCS inflation did not alter expectancy ratings, but the inflation group exhibited larger learned skin conductance responses than the control group. The inflation effect was not explained by differences in the explicit estimates of UCS probability or explicit knowledge that the UCS intensity had changed. The SCR revaluation effect was not dependent on explicit memory processes in either experiment. In both experiments we found differences on an implicit measure of learning in the absence of changes in explicit measures. Together, the differences observed between expectancy measures and skin conductance support the idea that these responses might reflect different types of memory formed during the same training procedure and be supported by separate neural systems. PMID- 23731074 TI - Dissociation of neuronal, electrodermal, and evaluative responses in disgust extinction. AB - Disgust extinction is an important mechanism relevant for the treatment of psychiatric disorders. However, only a few studies have investigated disgust extinction. Moreover, because disgust sensitivity (DS) is considered as a relevant factor for learning processes, this study also investigated the potential relationship between DS and disgust extinction learning. The aim of this study was to explore the neuronal correlates of disgust extinction, as well as changes in skin conductance responses (SCRs) and evaluative conditioning. Twenty subjects were exposed to a differential extinction paradigm, in which a previous conditioned, and now unreinforced, stimulus (conditioned stimulus, CS+) was compared to a second stimulus (CS-), which was previously not associated with the unconditioned stimulus (UCS). Extinction learning was measured on three different response levels (BOLD responses, SCRs, and evaluative conditioning). Regarding evaluative conditioning, the CS+ was rated as more unpleasant than the CS-. Interestingly, significantly increased amygdala responses and SCRs toward to the CS- were observed. Finally, a (negative) trend was found between DS scores and BOLD responses of the prefrontal cortex. The present findings showed a dissociation of different response levels. The increased CS- responses could be explained by the assumption that the increased amygdala activity may reflect a safety learning signal during the first extinction trials and the subjective focus may therefore shift from the CS+ to the CS-. The correlation finding supports previous studies postulating that DS hampers extinction processes. The present results point toward dissociations between the response levels in context of extinction processes. PMID- 23731076 TI - Dissociation of recognition and recency memory judgments after anterior thalamic nuclei lesions in rats. AB - The anterior thalamic nuclei form part of a network for episodic memory in humans. The importance of these nuclei for recognition and recency judgments remains, however, unclear. Rats with anterior thalamic nuclei lesions and their controls were tested on object recognition, along with two types of recency judgment. The spontaneous discrimination of a novel object or a novel odor from a familiar counterpart (recognition memory) was not affected by anterior thalamic lesions when tested after retention delays of 1 and 60 min. To measure recency memory, rats were shown two familiar objects, one of which had been explored more recently. In one condition, rats were presented with two lists (List A, List B) of objects separated by a delay, thereby creating two distinct blocks of stimuli. After an additional delay, rats were presented with pairs of objects, one from List A and one from List B (between-block recency). No lesion-induced deficit was apparent for recency discriminations between objects from different lists, despite using three different levels of task difficulty. In contrast, rats with anterior thalamic lesions were significantly impaired when presented with a continuous list of objects and then tested on their ability to distinguish between those items early and late in the same list (within-block recency). The contrasting effects on recognition and recency support the notion that interlinked hippocampal-anterior thalamic interconnections support aspects of both spatial and nonspatial learning, although the role of the anterior thalamic nuclei may be restricted to a subclass of recency judgments (within-block). PMID- 23731077 TI - Interoceptive conditioning with a nicotine stimulus is susceptible to reinforcer devaluation. AB - Pavlovian conditioning processes contribute to the etiology of nicotine dependence. Conditioning involving interoceptive stimuli is increasingly recognized as playing a role in many diseases and psychopathologies, including drug addiction. Previous animal research on diminishing the influence of interoceptive conditioning has been limited to antagonism and nonreinforced exposures to the drug stimulus. The goal of the present research was to determine whether interoceptive conditioning with a nicotine stimulus could be diminished through an unconditioned stimulus (US) devaluation procedure. In two separate experiments, male Sprague-Dawley rats received nicotine injections (0.4 mg base/kg) followed by intermittent sucrose (26%) access in a conditioning chamber. On intermixed saline sessions, sucrose was withheld. Conditioning was demonstrated by a reliable increase in head entries in the dipper receptacle on nicotine versus saline sessions. After conditioning, rats in a devaluation condition were given access to sucrose in their home cages immediately followed by a lithium chloride (LiCl) injection on 3 consecutive days. On subsequent test days, nicotine-evoked conditioned responding was significantly attenuated. Within subject (Experiment 1) and between-subjects (Experiment 2) controls revealed that the diminished responding was not attributable to mere exposure to the sucrose US in the devaluation phase. Experiment 2 included a LiCl-alone control group. Repeated illness induced by LiCl did not reduce later nicotine-evoked responding. These findings suggest that there is a direct association between the interoceptive stimulus effects of nicotine and the appetitive sucrose US (i.e., stimulus-stimulus) rather than a stimulus-response association. PMID- 23731078 TI - IL-17 targeted therapies for psoriasis. AB - INTRODUCTION: Psoriasis is a chronic, disabling, inflammatory skin disease whose pathogenesis still remains to be fully elucidated. Genetic and environmental factors induce an immune response mediated by several cytokines and chemokines, including IL-17A. AREAS COVERED: Emerging evidence now suggests that IL-17A is central in the pathogenesis of psoriasis. Three agents neutralizing IL-17 (i.e., secukinumab and ixekizumab) or antagonizing its receptor (i.e., brodalumab) are in development and are being studied in Phase III clinical trials to evaluate their overall efficacy and safety. However, Phase II results of IL-17 blockade with each of these agents has shown a marked improvement of disease severity, thus confirming the pathogenic relevance of IL-17 in mediating crucial inflammatory circuits in psoriasis. EXPERT OPINION: Anti-IL-17 agents are likely to become important future therapeutics in this disease and the may potentially impact on cardiovascular diseases, arthritis and other comorbidities associated with psoriasis. PMID- 23731079 TI - Comment on advances in urologic surgery special edition. PMID- 23731080 TI - Robot-assisted surgery: current status evaluation in abdominal and urological pediatric surgery. AB - PURPOSE: The last two decades have witnessed a dramatic development of minimally invasive surgery (MIS). Robotic-assisted surgery is currently the latest step in the evolution of MIS. MIS was initially developed for adult surgery, but its use has progressively been extended to pediatrics. As for all new technologies, an objective evaluation is essential to adopt the robot in the practice of pediatrics. MATERIALS AND METHODS: This article reviews the spectrum of evidence regarding the feasibility, safety, benefits, and limitations of abdominal and urological robot-assisted surgery in children. This analysis was performed using the PubMed database, using key words such as "robot," "robotic surgery," "robot assisted," "da Vinci," and "computer-enhanced surgery" combined with "child," "children," "infants," and "pediatric." RESULTS: In total, 88 studies met the selection criteria for our review. Only 10 studies comparing robotic surgery with open or conventional laparoscopic surgery are available for abdominal or urological pediatric procedures. Fundoplication for gastroesophageal reflux and pyeloplasty for hydronephrosis represent the most frequent procedures performed with robotic assistance in children. CONCLUSIONS: Robotic surgery is suitable in the pediatric practice, which necessitates fine dissections and sutures in narrow anatomical spaces. The initial results of robotic surgery in the field of pediatrics are encouraging. Further prospective and comparative studies, especially between robotic and laparoscopic approaches, are required to confirm these preliminary results. PMID- 23731081 TI - Patient scar assessment after single-incision versus four-port laparoscopic cholecystectomy: long-term follow-up from a prospective randomized trial. AB - BACKGROUND: The single-incision laparoscopic approach for cholecystectomy has been reported to be cosmetically superior in the traditional four-port technique in several case series; however, prospective comparative data are lacking. We conducted a 60-patient, prospective, randomized trial comparing single-incision laparoscopic cholecystectomy with standard four-port cholecystectomy, including validated scar assessment evaluation around 6 weeks and 18 months after the operation in an effort to determine if a cosmetic advantage existed. PATIENTS AND METHODS: Patients over 12 years of age and parents of patients under 12 years of age enrolled in the trial were asked to complete the validated Patient Scar Assessment Questionnaire (PSAQ). The PSAQ consists of four subscales: Appearance, Consciousness, Satisfaction with Appearance, and Satisfaction with Symptoms. The Symptoms subscale is omitted from analysis per PSAQ instructions because of insufficient reliability. Each subscale is a set of items with 4-point categorical responses (from 1=most favorable to 4=least favorable). The sum of the questions quantifies each subscale. Data are expressed as mean+/-standard deviation values. RESULTS: Eighteen single-site patients and 8 four-port patients completed early questionnaires, in which there was no difference in overall scar assessment (P=.17). Telephone follow-up was accomplished for 17 single-site patients and 24 four-port patients and revealed that the overall scar assessment significantly favored the single-site approach (P=.04). CONCLUSIONS: Patients or parents of patients do not identify an overall superior scar assessment at early follow-up after single-site laparoscopic versus four-port cholecystectomy. However, they do perceive a superior scar assessment at long-term follow-up, suggesting that there is a cosmetic benefit favoring the single-site approach. PMID- 23731082 TI - Thoracoscopic thymectomy in children: our preliminary experience. AB - INTRODUCTION: The aim of this study is to present a preliminary series of six children affected by an anterior mediastinal mass, resulting in a thymoma. We treated this pediatric population by a video-assisted thoracoscopic thymectomy. PATIENTS AND METHODS: We performed a retrospective study from January 2000 to January 2012 of all children affected by an anterior mediastinal mass, resulting in a thymoma. Data included sex, age at surgery, clinical and radiological features, surgical procedure, follow-up, and complications. RESULTS: Video assisted thoracoscopic thymectomy was performed in six children (five boys and one girl). Four patients presented with dyspnea and/or thoracic pain treated with analgesic and corticosteroid therapy without any benefits. Two patients were asymptomatic. Preoperatively, exams included radiological imaging, blood, and immunological test. All 6 patients were treated with a thoracoscopic approach; of these patients, 5 were treated with a thoracoscopic right-side thymectomy and 1 with a left-side approach. Patients were treated by a three-trocar technique, and thymectomy was performed using Valleylab (now Covidien) (Boulder, CO) LigaSureTM. The mean operative time was 120 minutes. The mean hospital stay was 5 days. In all cases histological findings revealed no malignancy. The mean follow-up was 38 months. DISCUSSION: Thoracoscopic thymectomy facilitated the goal of early thymectomy. The right-side approach is preferred because it gains a good visualization of the venous anatomy for dissection. The left side allows a good extended resection of both the thymus and perithymic fat. Thoracoscopic thymectomy should be consider a valid, less invasive alternative to the most radical open approach. PMID- 23731083 TI - Determination of 20 coccidiostats in milk, duck muscle and non-avian muscle tissue using UHPLC-MS/MS. AB - In this paper, methods were developed to measure coccidiostats in bovine milk, duck muscle and non-avian species. The methods were validated to the maximum levels and MRLs laid down in European Union legislation. A simple sample preparation procedure was developed for the isolation of coccidiostat residues from bovine, ovine, equine, porcine and duck muscle tissue, based on solvent extraction with acetonitrile and concentration. An alternative method had to be developed for milk samples based on the QuEChERS sample preparation approach because of the high water content in this matrix. Milk samples were adjusted to basic pH with sodium hydroxide and extracted by using a slurry of acetonitrile, MgSO4 and NaCl. Purified sample extracts were subsequently analysed by using UHPLC-MS/MS in a 13.2-min chromatographic run. It was found that the use of rapid polarity switching enabled both negatively and positively charged ions to be analysed from a single injection. By using this approach, solvent usage was reduced significantly and sample throughput improved. The method was validated for the analysis of 20 coccidiostats (arprinocid, clopidol, decoquinate, diclazuril, diaveridine, ethopabate, halofuginone, laidlomycin, lasalocid, maduramicin, monensin, narasin, nequinate, nicarbazin, robenidine, salinomycin, semduramicin, toltrazuril, toltrazuril sulphoxide and toltrazuril sulphone) in muscle and milk. The method is quantitative for toltrazurils, but it cannot be used for confirmation because only the precursor ion is monitored. Accuracy values for muscle ranged from 80% to 125%, while CCalpha ranged from 2.2 ug kg( 1) for clopidol to 122 ug kg(-1) for toltrazuril sulphoxide. Bovine milk accuracy ranged from 84% to 120% for all analytes except maduramicin, semduramicin and salinomycin, for which the values were higher. CCalpha values achieved ranged from 1.1 ug kg(-1) for arprinocid, nequinate and lasalocid to 27 ug kg(-1) for toltrazuril. PMID- 23731084 TI - Reducible hyaluronic acid-siRNA conjugate for target specific gene silencing. AB - Despite wide applications of polymer-drug conjugates, there are only a few polymer-siRNA conjugates like poly(ethylene glycol) conjugated siRNA. In this work, reducible hyaluronic acid (HA)-siRNA conjugate was successfully developed for target specific systemic delivery of siRNA to the liver. The conjugation of siRNA to HA made it possible to form a compact nanocomplex of siRNA with relatively nontoxic linear polyethyleneimine (LPEI). After characterization of HA siRNA conjugate by size exclusion chromatography (SEC) and gel electrophoresis, its complex formation with LPEI was investigated with a particle analyzer. The HA siRNA/LPEI complex had a mean particle size of ca. 250 nm and a negative or neutral surface charge at physiological condition. The reducible HA-siRNA/LPEI complex showed a higher in vitro gene silencing efficiency than noncleavable HA siRNA/LPEI complex. Furthermore, after systemic delivery, apolipoprotein B (ApoB) specific HA-siApoB/LPEI complex was target specifically delivered to the liver, which resulted in statistically significant reduction of ApoB mRNA expression in a dose dependent manner. The HA-siRNA conjugate can be effectively applied as a model system to the treatment of liver diseases using various siRNAs and relatively nontoxic polycations. PMID- 23731085 TI - Comparison of nanomilling and coprecipitation on the enhancement of in vitro dissolution rate of poorly water-soluble model drug aripiprazole. AB - The aim of this study was to evaluate the effect of coprecipitation and nanomilling on the crystallinity of a model drug, aripiprazole and evaluate the in vitro dissolution rate (IDR). Aripiprazole compositions were prepared by physical mixing, coprecipitation and nanomilling using hydroxypropylcellulose (HPC), polyvinylpyrrolidone (PVP) K17 and pluronic F127. The particle size, solubility, IDR and drug crystallinity were studied. Aripiprazole pluronic compositions were compressed into tablets and dissolution rate was evaluated. The particle size of nanomilled compositions was significantly smaller than that of the other compositions. The saturation solubility of aripiprazole from nanoparticle (NP) and coprecipitate (CP) from PVP and Pluronic was comparable, however, NP of HPC containing composition showed higher solubility when compared to its CP compositions. The crystallinity of aripiprazole decreased from physical mixtures to coprecipitates and further in NPs. The increased aripiprazole IDR was due to decreased crystallinity from coprecipitate compositions and disruption of crystallinity from nanomilled compositions. Aripiprazole tablets prepared from nanomilled powder dissolved >75% within 10 min compared with 17% and 20% for tablets prepared from physical mixture and coprecipitate powders, respectively. The increase in IDR due to nanomilling was more significant than coprecipitation and NPs retained the IDR after compression into tablets. PMID- 23731086 TI - Kinetics of homogeneous and surface-catalyzed mercury(II) reduction by iron(II). AB - Production of elemental mercury, Hg(0), via Hg(II) reduction is an important pathway that should be considered when studying Hg fate in environment. We conducted a kinetic study of abiotic homogeneous and surface-catalyzed Hg(0) production by Fe(II) under dark anoxic conditions. Hg(0) production rate, from initial 50 pM Hg(II) concentration, increased with increasing pH (5.5-8.1) and aqueous Fe(II) concentration (0.1-1 mM). The homogeneous rate was best described by the expression, r(hom) = k(hom) [FeOH(+)] [Hg(OH)2]; k(hom) = 7.19 * 10(+3) L (mol min)(-1). Compared to the homogeneous case, goethite (alpha-FeOOH) and hematite (alpha-Fe2O3) increased and gamma-alumina (gamma-Al2O3) decreased the Hg(0) production rate. Heterogeneous Hg(0) production rates were well described by a model incorporating equilibrium Fe(II) adsorption, rate-limited Hg(II) reduction by dissolved and adsorbed Fe(II), and rate-limited Hg(II) adsorption. Equilibrium Fe(II) adsorption was described using a surface complexation model calibrated with previously published experimental data. The Hg(0) production rate was well described by the expression r(het) = k(het) [>SOFe((II))] [Hg(OH)2], where >SOFe((II)) is the total adsorbed Fe(II) concentration; k(het) values were 5.36 * 10(+3), 4.69 * 10(+3), and 1.08 * 10(+2) L (mol min)(-1) for hematite, goethite, and gamma-alumina, respectively. Hg(0) production coupled to reduction by Fe(II) may be an important process to consider in ecosystem Hg studies. PMID- 23731087 TI - Hyaluronic acid solution injection for upper and lower gastrointestinal bleeding after failed conventional endoscopic therapy. AB - Hyaluronic acid solution injection can be an additional endoscopic modality for controlling bleeding in difficult cases when other techniques have failed. We evaluated 12 cases in which we used hyaluronic acid solution injection for stopping bleeding. Immediately following hyaluronic acid solution injection, bleeding was controlled in 11 out of 12 cases. There was no clinical evidence of renewed bleeding in 11 cases during follow up.Hyaluronic acid solution injection can be a simple and efficient additional method for controlling upper and lower gastrointestinal bleeding after failed endoscopic therapy. PMID- 23731088 TI - Rural generalism and the Queensland Health pathway--implications for rural clinical supervisors, placements and rural medical education providers. AB - The lifeline for country medicine' was the description by the Rural Doctors Association of Australia of the Queensland Health Rural Generalist Pathway (RGP). The program promises to redress rural medical workforce issues in Queensland. It may fulfil these promises, but only with the support of rural clinical supervisors and medical educators adapting to new expectations of competencies, of training structure and endpoints of training. These adaptations will be a key element of the RGP success, particularly as other states adopt the approach. This article outlines the lessons learnt and adaptations made by clinical supervisors and medical educators in the Queensland Rural Medical Education group, to deliver the Rural Pathway of the Australian General Practice Training program since the first registrars identifying as RGP appeared in this program in 2006. PMID- 23731089 TI - The molecular second hyperpolarizability of the light-harvesting chlorophyll a/b pigment-protein complex of photosystem II. AB - Photosynthetic structures when imaged with nonlinear optical microscopy give rise to high third harmonic generation (THG) signal intensity due to the presence of chlorophylls and xanthophylls which have large second hyperpolarizabilitiy (gamma) values. The gamma value of trimers of the light-harvesting chlorophyll a/b pigment-protein complex of photosystem II (LHCII) isolated from pea (Pisum sativum) plants was investigated by the THG ratio technique at 1028 nm wavelength and found to have the value (-1600 +/- 400) * 10(-41) m(2) V(-2). The large negative gamma value of trimeric LHCII is due to the presence of chlorophyll a and chlorophyll b which have large negative gamma values, while positive gamma values of xanthophylls reduce the magnitude of the THG signal. Variation was observed between the measured gamma value of LHCII and the approximated gamma value of LHCII obtained by adding individual gamma values of chlorophylls and xanthophylls. This difference can be attributed to the differing inter-pigment interactions of oriented chlorophylls and xanthophylls in the pigment-protein complex compared to randomly oriented non-interacting pigments in solution, as well as a differing dielectric environment of the pigments within LHCII versus the surrounding organic solvent. PMID- 23731090 TI - Maternal warmth and directiveness jointly moderate the etiology of childhood conduct problems. AB - BACKGROUND: Prior studies exploring gene-environment interactions (GxE) in the development of youth conduct problems (CP) have focused almost exclusively on single-risk experiences, despite research indicating that the presence of other risk factors and or the absence of protective factors can accentuate the influence of a given risk factor on CP. The goal of the current study was to fill this gap in the literature, evaluating whether risky and protective aspects of parenting might combine to jointly moderate the etiology of CP. METHODS: The sample consisted of 500 child twin pairs from the Michigan State University Twin Registry (MSUTR). Child CP was assessed using multiple informant reports. Maternal warmth and directiveness were assessed via videotaped dyadic interactions between mothers and each of their twins. RESULTS: Biometric GxE analyses revealed that directiveness and warmth did appear to jointly moderate the etiology of CP. In particular, shared environmental influences were accentuated by colder, less directive or 'less engaged' mothering, whereas genetic influences were strongest when the child was experiencing warmer, more directive or 'more authoritative' mothering. CONCLUSIONS: Such findings serve to highlight the synergistic effects of risky and protective experiences on child outcomes. They also provide additional empirical support for the bioecological form of GxE, which postulates that, in some cases, genetic influences may be most strongly expressed in the presence of low-risk environments. PMID- 23731091 TI - Mulberry anthocyanins inhibit oleic acid induced lipid accumulation by reduction of lipogenesis and promotion of hepatic lipid clearance. AB - Mulberry (Morus alba L.) has been considered to possess different benefits such as protecting liver; improving fever, urine excretion disorder, hypertension, and diabetic syndrome; and preventing cardiovascular diseases. Recently, mounting evidence has shown that mulberry anthocyanin extract (MAE) is beneficial to hyperlipidemia; however, the mechanisms remain unclear. The present study was aimed to investigate the protective effects of MAE on hepatocyte cultured with high fatty acid and the underlying mechanisms. By using human hepatoma cell HepG2 as cell model, the results showed that MAE suppressed fatty acid synthesis and enhanced fatty acid oxidation, contributing to amelioration of lipid accumulation induced by oleic acid (OA). Moreover, MAE also inhibited acetyl coenzyme A carboxylase (ACC) activities by stimulating adenosine monophosphate-activated protein kinase (AMPK). MAE attenuated the expression of sterol regulatory element binding protein-1 (SREBP-1) and its target molecules, such as fatty acid synthase (FAS). Similar results were also found in the expressions of enzymes involved in triglyceride and cholesterol biosyntheses including glycerol-3-phosphate acyltransferase (GPAT), 3-hydroxy-3-methyl-glutaryl CoA reductase (HMGCoR), adipocyte-specific fatty acid binding protein (A-FABP), and SREBP-2. In contrast, the lipolytic enzyme expressions of peroxisome proliferator activated receptor alpha (PPARalpha) and carnitinepalmitol- transferase-1 (CPT1) were increased. This study suggests the hypolipidemic effects of MAE occur via phosphorylation of AMPK and inhibition of lipid biosynthesis and stimulation of lipolysis. Therefore, the mulberry anthocyanins may actively prevent nonalcoholic fatty liver disease. PMID- 23731092 TI - Carcass characteristics, composition, physico-chemical, microbial and sensory quality of emu meat. AB - 1. In order to investigate whether emu meat is a potential red meat alternative, this work was carried out with the objective of studying the carcass characteristics, proximate composition, physico-chemical and microbial characteristics and sensory attributes of emu meat. 2. Carcass characteristics clearly indicate that emus are a significant source of lean meat, fat, skin and edible by-products and these findings confirm earlier reports. 3. Proximate composition of emu meat indicated higher protein and ash content and lower fat, total lipids and cholesterol content than meat from other meat animals. 4. The pH, water holding capacity, collagen content and solubility, protein extractability, muscle fibre diameter and Warner-Bratzler shear force values of emu meat are similar to the earlier reports for meats from other food animals. 5. Emu meat is dark, cherry red in colour with significantly higher myoglobin content and the myoglobin is more prone to oxidation as evidenced by higher initial metmyoglobin percentage. The initial thiobarbituric acid reactive substances (TBARS) values and free fatty acids percentage in emu meat were higher than those in meats from other species. 6. Sensory evaluation of cooked emu meat curry revealed highly acceptable scores relative to goat meat curry, the most preferred meat in India. 7. The study shows the potential of emu meat as a new source of low fat, quality meat proteins. However, more studies are required to elucidate the effect of age, sex, muscles, pre-slaughter and post-slaughter factors on different carcass and meat quality characteristics. PMID- 23731094 TI - Congenital viral infections: available strategies to decrease their prevalence. PMID- 23731093 TI - Prazosin reduces alcohol drinking throughout prolonged treatment and blocks the initiation of drinking in rats selectively bred for high alcohol intake. AB - BACKGROUND: This study examined whether prazosin reduces alcohol drinking over the course of prolonged treatment and whether it blocks the initiation of alcohol drinking in rats with a genetic predisposition toward high alcohol drinking, that is alcohol-preferring (P) rats. METHODS: In study one, alcohol-experienced P rats that had been drinking alcohol for 2 h/d for several months were treated daily with prazosin (0, 0.5, 1.0, or 2.0 mg/kg body weight [BW]) for 7 weeks. In study two, alcohol-naive P rats were treated daily with prazosin (0, 1.0, or 2.0 mg/kg BW) for 2 weeks prior to, or concomitantly with, the initiation of alcohol access and throughout 3 weeks of alcohol availability. Prazosin treatment and alcohol access were then discontinued for 2 weeks followed by reinstatement of alcohol access without prazosin treatment for 4 weeks, followed by resumption of daily prazosin treatment (2.0 mg/kg BW) for 3 weeks. RESULTS: Prazosin reduced alcohol drinking throughout 7 weeks of treatment in P rats accustomed to drinking alcohol. Following termination of prazosin treatment, alcohol drinking slowly returned to pretreatment baseline. Reduced alcohol intake was accompanied by increased water intake. In alcohol-naive P rats, prazosin administration prior to the first opportunity to drink alcohol and throughout 3 weeks of alcohol access retarded acquisition of alcohol drinking and reduced the amount of alcohol consumed. When prazosin was administered concomitantly with the first opportunity to drink alcohol, it abolished acquisition of alcohol drinking. Discontinuation of prazosin treatment allowed expression of a genetic predisposition toward high alcohol drinking to gradually emerge. Prazosin retained the ability to reduce alcohol intake with repeated treatments. CONCLUSIONS: Prazosin decreased alcohol drinking during prolonged treatment and may be useful for treating alcoholism and alcohol-use disorders. Prazosin may also be useful for deterring the initiation of drinking in individuals with a family history of alcoholism. PMID- 23731095 TI - Evaluation of the frequency and obstetric risk factors associated with term neonatal admissions to special care units. AB - INTRODUCTION: Approximately 10-15% of term babies may require admission to neonatal special care units. This level of care is frequently an unexpected event for parents. AIMS: To review the frequency and obstetric risk factors associated with the admission of term neonates to a tertiary hospital special care unit (SCN). MATERIALS AND METHODS: All babies born >=37-weeks gestation admitted to the SCN at King Edward Memorial Hospital between 2004 and 2006 were identified from the institutional maternity and neonatal databases. Maternal and obstetric factors were reviewed to identify potential predictors of admission to the SCN. RESULTS: During the study period, 1671 term neonates born to 1624 women were admitted to the SCN (14.4% of term deliveries). Neonatal intensive care unit admissions accounted for 10.6% of the term admissions. The most common reasons for SCN admission were respiratory complications (n = 421, 25.2%), observation postresuscitation (n = 402, 24.1%) and hypoglycaemia (n = 152, 9.1%). Elective caesarean delivery was significantly associated with admission to the special care unit for respiratory complications compared with all other delivery modes (37 vs 23%, P < 0.001), particularly if the birth occurred at <39-weeks gestation (38 vs 24%, P < 0.001). CONCLUSIONS: In our population of women delivering at a tertiary maternity facility, approximately 1:8 term babies were admitted to the neonatal special care unit. Elective caesarean delivery was associated with a significant risk of admission for respiratory complications compared with other birth modes, especially when <39-weeks gestation. PMID- 23731096 TI - Urinary retention following laparoscopic gynaecological surgery with or without 4% icodextrin anti-adhesion solution. AB - BACKGROUND: Urinary retention is a recognised complication of laparoscopic surgery. Previous work showed an association with 4% icodextrin solution and urinary retention. AIMS: To determine the incidence of urinary retention following laparoscopic gynaecological surgery with or without the use of 4% icodextrin. METHODS: A prospective observational study of 147 women undergoing laparoscopic gynaecological surgery for benign pathology. Women had their planned laparoscopic procedure and either received icodextrin solution or nothing as determined by their treating surgeon at the time of the operation. RESULTS: From May 2011 to February 2012, 147 women were approached to participate in the study; of whom, 124 women were included: 62 received icodextrin and 62 did not. The women in the non-icodextrin group were significantly older (P = 0.007) and had a higher BMI (P = 0.03) than those in the icodextrin group. Following surgery, 27/124 (21.8%) women had post-operative urinary retention. Icodextrin was associated with significantly more urinary retention (P = 0.017), but did not extend hospital admission significantly (P = 0.14). The administration of icodextrin was associated with resection of moderate- or severe-stage endometriosis involving multiple surgical sites, whereas women in the non icodextrin group were more likely to be having a hysterectomy. CONCLUSIONS: In this non-randomised study, there were significantly more women with post operative urinary retention when icodextrin was used; however, this did not contribute to an extended hospital admission. While there may be confounding factors, women receiving icodextrin should be warned of the possibility of urinary retention post-operatively, but that this is unlikely to affect their stay in hospital. PMID- 23731097 TI - Re: Chronic pelvic pain in Australia and New Zealand. PMID- 23731098 TI - Cure of chronic pelvic pain by reinforcing the uterosacral ligaments. PMID- 23731099 TI - Re: P Petros. Pelvic pain may be caused by laxity in the uterosacral ligaments as part of 'posterior fornix syndrome'. PMID- 23731100 TI - "... solitary, poore, nasty, brutish, and short". PMID- 23731101 TI - Cost-effectiveness of asthma clinic approach in the management of chronic asthma in Australia. AB - OBJECTIVES: To compare cost-effectiveness of an asthma clinic that would provide education, promotion of self-monitoring of symptoms, regular review of treatment by a medical practitioner and a written asthma action plan to current practice in Australia. METHODS: A decision tree model was used to compare treatment and improved management using asthma clinics under three scenarios: 1) intervention reduces only emergency department visits; 2) in addition, it leads to a reduction in days out of role; and 3) it also reduces unplanned general practitioner visits and hospitalisations. Evidence from existing published studies was used for asthma incidence, duration, treatment practices and health seeking behaviours. Costs for one year were estimated based on an asthma clinic trial in Australia. RESULTS: The estimated $274 million annual cost of asthma clinics is much greater than the potential cost savings of $11 million resulting from reduced emergency department visits, and an overall potential cost saving of $85 million resulting from decreased GP visits and hospitalisations. The incremental cost-effective ratio (ICER) is $24,000 if a reduction in days out of role is quantified as a health benefit in estimating disability-adjusted life years (DALY). If a potential $85 million in cost-savings from decreased emergency department visits, GP visits and hospitalisation is taken into account, the ICER drops to $17,000 per DALY averted. CONCLUSIONS: An asthma clinic as an intervention for improving self-management may be cost-effective in Australia if multiple benefits can be achieved. IMPLICATIONS: A large-scale asthma clinic trial and long-term evaluation of benefits are necessary to obtain stronger evidence on the benefit of asthma clinic approach in Australia. PMID- 23731102 TI - Income-related health inequalities in working age men and women in Australia and New Zealand. AB - Objective : To examine income-related inequalities in health in working age men and women in Australia and New Zealand. Methods : We used data from two longitudinal surveys, Wave 8 (2008) of the Household Income and Labour Dynamics in Australia (HILDA) Survey and Wave 7 (2008/2009) of the New Zealand Survey of Family Income and Employment (SoFIE). We compared concentration indices (a measure of income-related health inequality) that examined the distribution of general and mental health-related quality of life scores (from the SF-36) across income in working age (20-65 year old) men and women. Decomposition analyses of the concentration indices were done to identify the relative contribution of various determinants to the income-related health inequality. Results : General health (GH) scores generally decline with age, and mental health (MH) scores increase with age, in both surveys. Income-related health inequalities were present in both the HILDA and SoFIE samples, with better health in high income groups. Decomposition analyses found that income, area deprivation and being inactive in the labour force were major contributors to income-related health inequality, in both surveys, and for both health outcomes. Conclusions and implications : Despite some baseline differences in income-related health inequalities using Australian and New Zealand surveys, we found similar modifiable determinants, which could be targeted to improve health inequalities in both countries. PMID- 23731103 TI - The burden of cancer in New Zealand: a comparison of incidence and DALY metrics and its relevance for ethnic disparities. AB - AIM: Cancer burden measured in disability adjusted life years (DALYs) captures survival and disability impacts of incident cancers. In this paper, we estimate the prospective burden of disease arising from 27 cancer sites diagnosed in 2006, by sex and ethnicity; and determine how its distribution differs from that for incidence rates alone. METHODS: Using a prospective approach, Markov and cancer disease models were used to estimate DALYs with inputs of population counts, incidence and excess mortality rates, disability weights, and background mortality. DALYs were discounted at 3.5% per year. RESULTS: The age standardised Maori:non-Maori incidence rate ratios were 1.00 for males and 1.19 for females, whereas for DALYs they were greater at 1.42 for males and 1.68 for females. The total burden of cancer for 2006 incident cases (i.e. not age standardised) was estimated to be approximately 127,000 DALYs. Breast (27%), lung (14%) and colorectal (13%) cancers for females and lung (16%), colorectal (14%), and prostate (16%) cancers for males were the top contributors. By ethnicity, Maori experienced a substantially higher burden from lung cancer (around 25% for both sexes). CONCLUSIONS: Due to Maori both having higher rates of cancers with a worse survival (e.g. lung cancer), and tending to have worse survival for each cancer site, ethnic disparities in the age-standardised DALY burden were greater than those for incidence (rate ratios of 1.52 and 1.07 respectively, sexes pooled). PMID- 23731104 TI - Socioeconomic status and quality of life in population-based Australian men: data from the Geelong Osteoporosis Study. AB - OBJECTIVE: To investigate the relationship between socioeconomic status (SES) and reported perceptions of quality of life (QOL) in a cross-sectional population based analysis of a representative sample of Australian men. METHODS: In 917 randomly recruited men aged 24-92 years, we measured QoL in the domains of physical health, psychological health, environment and social relationships, using the Australian World Health Organization Quality of Life Instrument (WHOQOL BREF). Residential addresses were cross-referenced with Australian Bureau of Statistics 2006 census data to ascertain SES. Participants were categorised into lower, mid, or upper SES based on the Index of Relative Socioeconomic Disadvantage and Advantage (IRSAD), the Index of Economic Resources (IER), and the Index of Education and Occupation (IEO). Lifestyle and health information was self-reported. RESULTS: Males of lower SES reported poorer satisfaction with physical health (OR=0.6, 95%CI 0.4-0.9, p=0.02), psychological health (OR=0.4, 95%CI 0.3-0.7, p<0.001) and environment (OR=0.5, 95%CI 0.3-0.7, p<0.001), although not social relationships (p=0.59). The poorest QOL for each domain was observed in the lower and upper SES groups, representing an inverse U-shaped pattern of association; however, statistical significance was only observed for psychological health (OR=0.5, 95%CI 0.4-0.7, p<0.001). These relationships were similar for IEO and IER. CONCLUSIONS: Men from lower and upper SES groups have lower QOL compared to their counterparts in the mid SES group. PMID- 23731105 TI - Blood lead levels in the adult Victorian population: results from the Victorian Health Monitor. AB - OBJECTIVE: To estimate blood lead levels (BLLs) in the adult Victorian population and compare the distribution of BLLs with the current national reference level to better inform public health prevention and management of lead toxicity. METHODS: Population-based cross-sectional health measurement survey of 50 randomly selected Census Collection Districts (CDs) throughout Victoria. The Victorian Health Monitor (VHM) was conducted over 12 months from May 2009 to April 2010. One eligible person (aged 18-75 years) from each household selected within each CD was randomly selected to participate. Persons with an intellectual disability and pregnant women were excluded from the sampling frame. BLLs were obtained from 3,622 of the 3,653 (99%) VHM participants. RESULTS: The geometric mean and median BLLs from the adult sample were 0.070 MUmol/L (95%CI, 0.068-0.073) and 0.05 MUmol/L (range: 0.05 to 1.22 MUmol/L), respectively. Elevated BLLs (>=0.483 MUmol/L or >=10 MUg/dL) were identified in 19 participants (0.7%; 95%CI, 0.3 1.6). Additionally, 86 participants (1.8%; 95%CI, 1.3-2.4) were identified with BLLs between 0.242 and <0.483 MUmol/L (5 to <10 MUg/dL). The geometric mean BLL was significantly higher for males, compared with females (0.077 MUmol/L vs 0.064 MUmol/L; p<0.001). BLLs increased significantly with age for both sexes. CONCLUSIONS: The first population estimates of BLLs in Victorian adults indicate the average adult BLL to be well below the current national reference level. However, some groups of the population have BLLs at which adverse effects may occur. Implications : The results provide baseline estimates for future population health surveillance and comparison with studies of at-risk groups. PMID- 23731106 TI - Air pollution from bushfires and their association with hospital admissions in Sydney, Newcastle and Wollongong, Australia 1994-2007. AB - OBJECTIVE: We examined the association between validated bushfire smoke pollution events and hospital admissions in three eastern Australian cities from 1994 to 2007. METHODS: Smoke events were defined as days on which bushfire smoke caused the 24-hour citywide average concentration of airborne particles to exceed the 99(th) percentile of the daily distribution for the study period. We used a time stratified case-crossover design to assess the association between smoke events and hospital admissions. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for cardiovascular and respiratory conditions on event days compared with non-event days. Models were adjusted for daily meteorology, influenza epidemics and holidays. RESULTS: Smoke events occurred on 58 days in Sydney (population: 3,862,000), 33 days in Wollongong (population: 406,000) and 50 days in Newcastle (population: 278,000). In Sydney, events were associated with a 6% (OR=1.06, 95%CI=1.02-1.09) same day increase in respiratory hospital admissions. Same day chronic obstructive pulmonary disease admissions increased 13% (OR=1.13, 95%CI=1.05-1.22) and asthma admissions by 12% (OR=1.12, 95%CI=1.05-1.19). Events were also associated with increased admissions for respiratory conditions in Newcastle and Wollongong. CONCLUSIONS: Smoke events were associated with increased hospital admissions for respiratory but not cardiovascular conditions. Large populations are needed to assess the impacts of brief exposures. Implications : Public health impacts from bushfire pollution events are likely to increase in association with a warming climate and more frequent severe fire weather. PMID- 23731107 TI - How the factoid of wind turbines causing 'vibroacoustic disease' came to be 'irrefutably demonstrated'. AB - OBJECTIVE: In recent years, claims have proliferated in cyberspace that wind turbines cause a large variety of symptoms and diseases. One of these, "vibroacoustic disease" (VAD) is frequently mentioned. The aim of this study is to examine the quality of the evidence on how VAD came to be associated with wind turbine exposure by wind farm opponents. METHODS: Searches of the web (Google advanced) and major research databases for papers on VAD and wind turbines. Self citation analysis of research papers on VAD. RESULTS: Google returned 24,700 hits for VAD and wind turbines. Thirty-five research papers on VAD were found, none reporting any association between VAD and wind turbines. Of the 35 papers, 34 had a first author from a single Portuguese research group. Seventy-four per cent of citations to these papers were self-citations by the group. Median self-citation rates in science are around 7%. Two unpublished case reports presented at conferences were found asserting that VAD was "irrefutably demonstrated" to be caused by wind turbines. The quality of these reports was abject. CONCLUSIONS: VAD has received virtually no scientific recognition beyond the group who coined and promoted the concept. There is no evidence of even rudimentary quality that vibroacoustic disease is associated with or caused by wind turbines. IMPLICATIONS: The claim that wind turbines cause VAD is a factoid that has gone 'viral' in cyberspace and may be contributing to nocebo effects among those living near turbines. PMID- 23731108 TI - An investigation of culturally competent terminology in healthcare policy finds ambiguity and lack of definition. AB - OBJECTIVE: This research explored how the concept of cultural competence was represented and expressed through health policies that were intended to improve the quality and efficacy of healthcare provided to families from culturally marginalised communities, particularly women and children with refugee backgrounds. METHOD: A critical document analysis was conducted of policies that inform healthcare for families from culturally marginalised communities in two local government areas in South Australia. RESULTS: The analysis identified two major themes: lack of, or inconsistent, definitions of 'culture' and 'cultural competency' and related terms; and the paradoxical use of language to determine care. CONCLUSIONS: Cultural competence within health services has been identified as an important factor that can improve the health outcomes for families from marginalised communities. However, inconsistency in definitions, understanding and implementation of cultural competence in health practice makes it difficult to implement care using these frameworks. IMPLICATIONS: Clearly defined pathways are necessary from health policy to inform culturally competent service delivery. The capacity for policy directives to effectively circumvent the potential deleterious outcomes of culturally incompetent services is only possible when that policy provides clear definitions and instructions. Consultation and partnership are necessary to develop effective definitions and processes relating to cultural competence. PMID- 23731109 TI - Health shocks adversely impact participation in the labour force in a working age population: a longitudinal analysis. AB - BACKGROUND: It is well understood that health affects labour force participation (LFP). However, much of the published research has been on older (retiring age) populations and using subjective health measures. This paper aims to assess the impact of an objective measure of 'health shock' (cancer registration or hospitalisation) on LFP in a working age population using longitudinal panel study data and fixed effect regression analyses. METHODS: Seven waves of data from 2002-09 from the longitudinal Survey of Family, Income and Employment (SoFIE) were used, including working aged individuals who consented to have their survey information linked to health records (n=6,780). Fixed effect conditional logistic regression was used to model the impact of health shocks (hospitalisation or cancer registration) in the previous year on labour force participation at date of annual interview. Models were stratified by gender, age group (25-39 years, 40-54 years) and gender by age group. RESULTS: A health shock was associated with a significantly increased risk of subsequent non participation in the labour force (odds ratio 1.54, 95%CI 1.30-1.82). Although interactions of age, sex and age by sex with health shock were not statistically significant, the association was largest in younger men and women. CONCLUSION: Using an objective measure of health, we have shown that a health shock adversely affects subsequent labour force participation. There are a number of policy and practice implications relating to support for working age people who have hospitalisations. PMID- 23731110 TI - Reports of the proportion of older people living in long-term care: a cautionary tale from New Zealand. AB - OBJECTIVE: Population ageing is driving many countries to review health and social care policies. For many, an important component is residential long-term care (LTC). This study uses New Zealand to ascertain the extent different reports provide consistent and accurate estimates of LTC use. METHODS: We searched for available cross-sectional information about use of LTC by people aged 65 years or over in NZ's population since 1988. In addition, for one geographic region, Auckland, we compared research survey data at three time-points with the nearest census estimates. RESULTS: Fifty-eight national-level estimates (census, subsidy payments and population surveys) were found. Since 2000, estimates of the proportion of older people reportedly living in long-term care ranged from 3.4% to 9.2%. Comparisons with Auckland studies demonstrated improved reporting in the 2006 census. CONCLUSION: Estimates of the proportion of people living in residential LTC varied widely. OECD reports, often used for cross-national comparisons, were particularly inconsistent. IMPLICATIONS: While estimates of the proportion of people living in residential LTC in NZ are inconsistent, improvements are evident in census and subsidy data. Reconciling new data with previous reports prior to publication may reduce variations in reporting. Improved reliability will assist understanding of within-country trends and international comparisons, and better inform decisions shaping health services for older people. PMID- 23731111 TI - Increase in best practice child car restraint use for children aged 2-5 years in low socioeconomic areas after introduction of mandatory child restraint laws. AB - OBJECTIVES: To examine changes in child car restraint practices in low socioeconomic areas following the introduction of mandatory child car restraint legislation in New South Wales (NSW), Australia. METHODS: Data from two cross sectional studies of child car restraint use at pre-schools, early childhood centres and primary schools before and after the introduction of legislating mandatory age-appropriate car restraint use for children up to the age of seven years was used in this analysis. All included observations were from local government areas with socioeconomic status in the lowest 30% of urban Sydney. Children aged 2-5 years were observed in their vehicles as they arrived at observation sites (107 pre-legislation, 360 post-legislation). Multilevel logistic regression was used to examine changes in observed age-appropriate and correct use of car restraints. RESULTS: Age-appropriate car restraint use was higher post-legislation than pre-legislation. After controlling for child's age, parental income, language spoken at home and adjusting for clustering, the odds of children being appropriately restrained post-legislation were 2.3 times higher than in the pre-legislation sample, and the odds of them being correctly restrained were 1.6 times greater. CONCLUSIONS: Results indicate an improvement in car restraint practices among children aged 2-5 in low socioeconomic areas after introduction of child restraint laws. Implications : Despite improvements observed with enhanced legislation, further efforts are required to increase optimal child car restraint use. PMID- 23731112 TI - Traffic lights and health claims: a comparative analysis of the nutrient profile of packaged foods available for sale in New Zealand supermarkets. AB - OBJECTIVE: To assess the application of Multiple Traffic Light (MTL) nutrition labels and the Food Standards Australia New Zealand (FSANZ) Nutrient Profiling Standard Calculator (NPSC) to foods and their agreement in classification of foods. METHODS: MTL and NPSC criteria were applied to selected packaged food products available in New Zealand (NZ) supermarkets in 2011: 157 breakfast cereals; 128 cereal bars; 40 pizzas; 69 sausages and hotdogs; and 13 burgers. A points-based system combined MTL criteria into an overall score to enable comparison of food classification by the two systems. RESULTS: Based on NPSC criteria, 156 (38%) NZ packaged food products were eligible to carry a health claim and thus classified as 'healthy'; 251 were 'less healthy'. Based on MTL criteria most 'healthy' products (61%) would also receive one red light. Using the MTL score, only 14% of products were classified as 'healthy'. Percentage agreement between the two systems was 73%. CONCLUSIONS: More than half of NZ packaged foods are 'less healthy' according to criteria underpinning two front-of pack labelling systems. A number of foods eligible to carry health claims would display at least one red traffic light if MTL were introduced. PMID- 23731113 TI - Investigating the media power of a population health monitoring survey: case study of the NSW Schools Physical Activity and Nutrition Survey (SPANS). AB - OBJECTIVE: To examine the extent and nature of news coverage of a government funded population monitoring survey of children and the potential implications of this coverage for public health advocacy. METHODS: Case study of the NSW Schools Physical Activity and Nutrition Survey (SPANS), a population monitoring survey of school-aged children's weight and weight-related behaviours, conducted in 1997, 2004 and 2010. Printed news items from all Australian newspapers between January 1997 and December 2011 mentioning the survey findings were identified from the Factiva database and a descriptive analysis of the content conducted. RESULTS: Overall, 144 news items were identified. The news angles focused mainly on physical activity/sedentary behaviour; overweight/obesity and nutrition; however these angles changed between 1997 and 2011, with angles focused on physical activity/sedentary behaviour increasing, compared with overweight/obesity and nutrition angles (p=0.001). Responsibility for obesity and weight-related behaviours was most frequently assigned to parents and food marketing, and the most common solutions were policy strategies and parental/child education and support. CONCLUSIONS: Population health surveys are newsworthy and when coupled with strategic dissemination, media can contribute to communicating health issues and interpreting findings in ways that are relevant for consumers, policy makers and stakeholders. Implications : This case study emphasises the news value of government-funded population surveys, while providing a cautionary note about media focus on individual studies rather than a larger body of research evidence. PMID- 23731114 TI - A trichiasis screening program in the Kimberley 2008-2010. PMID- 23731115 TI - 'Whole of system' intervention points for obesity prevention: a case study from a long day care setting. PMID- 23731116 TI - Monitoring public interest in solariums: variations in internet search volumes over time in Victoria. PMID- 23731117 TI - SCOPE childhood obesity project bridges policy/practice gap. PMID- 23731118 TI - Pre-service primary school teachers' experiences of physical education. PMID- 23731119 TI - Risk factors for chronic disease in young, midlife and older adults: the PATH Through Life study. PMID- 23731120 TI - User satisfaction with the Western Australian Vaccine Safety Surveillance (WAVSS) System. PMID- 23731121 TI - Construction of a spirooxindole amide library through nitrile hydrozirconation acylation-cyclization cascade. AB - A library of spirooxindoles containing varied elements of structural and stereochemical diversity has been constructed via a three step, one pot nitrile hydrozirconation-acylation-cyclization reaction sequence from common acyclic indole intermediates. The resulting library was evaluated for novelty through comparison with MLSMR and Maybridge compound collections. PMID- 23731123 TI - Prenatal development of the eye tunics in the dromedary camel (Camelus dromedarius). AB - Studies of ocular development in the dromedary camel (Camelus dromedarius) have not been reported previously. The aim of the present investigation was therefore to document the major landmarks and the time course in the prenatal development of the eye tunics in dromedary camel and its accommodation with the surrounding hard environment of the desert. Serial histological sections of dromedary camel embryos and foetuses were used. Age estimation was made on the basis of gestational size, crown vertebral-rump length (CVRL), which ranged 1.2-110 cm. The eye of the dromedary camel developed in a similar manner to that of the human and domestic animals eyes; the principal differences were in the time of occurrence of certain developmental events, pigmented peripheral cornea near the limbus, a remarkably thickened Descemet's membrane and pigmentation in the corneo scleral junction, which represent an adaptive modification in relation to a severe environment. PMID- 23731124 TI - Association between the MDR1 gene variant C3435T and risk of leukaemia: a meta analysis. AB - Although a number of genetic studies have attempted to link the multidrug resistance (MDR1) C3435T polymorphism to risk of leukaemia, the results were often inconsistent. The present study aimed at investigating the pooled association using a meta-analysis on the published studies. 1933 cases and 2215 controls of 11 published studies in English before June 2012 were involved in the updated meta-analysis. Furthermore, subgroup analysis was performed in different ethnic and leukaemia subtype groups. This meta-analysis suggests that the MDR1 C3435T polymorphism associate with risk of leukaemia. The effect of the variant on the expression levels and the possible functional role of the variant in leukaemia should be addressed in further studies. PMID- 23731122 TI - Effect of injection routes on the biodistribution, clearance, and tumor uptake of carbon dots. AB - The emergence of photoluminescent carbon-based nanomaterials has shown exciting potential in the development of benign nanoprobes. However, the in vivo kinetic behaviors of these particles that are necessary for clinical translation are poorly understood to date. In this study, fluorescent carbon dots (C-dots) were synthesized and the effect of three injection routes on their fate in vivo was explored by using both near-infrared fluorescence and positron emission tomography imaging techniques. We found that C-dots are efficiently and rapidly excreted from the body after all three injection routes. The clearance rate of C dots is ranked as intravenous > intramuscular > subcutaneous. The particles had relatively low retention in the reticuloendothelial system and showed high tumor to-background contrast. Furthermore, different injection routes also resulted in different blood clearance patterns and tumor uptakes of C-dots. These results satisfy the need for clinical translation and should promote efforts to further investigate the possibility of using carbon-based nanoprobes in a clinical setting. More broadly, we provide a testing blueprint for in vivo behavior of nanoplatforms under various injection routes, an important step forward toward safety and efficacy analysis of nanoparticles. PMID- 23731125 TI - Coordinated action of beta-galactosidases in the cell wall of embryonic axes during chickpea germination and seedling growth. AB - The plant cell wall is a dynamic structure whose constant modification is necessary for plant cells to grow and divide. In the cell walls of chickpea (Cicer arietinum) there are at least four beta-galactosidases, whose presence and location in embryonic axes during the first 48 h of seed imbibition are discussed in this paper. We examined their roles as cell wall-modifying enzymes in germinative and/or post-germinative events. At the start of germination, only betaV-Gal, and to a lesser extent betaIV-Gal, appear in the axes before rupture of the testa, suggesting they are related to germination sensu stricto. Once the testa has broken, the four beta-galactosidases are involved in growth and differentiation of the axes. Immunolocation of the different proteins in axes, which in part confirms previous results in seedlings and plants, allows assignment of post-germinative roles to betaI-Gal and betaIII-Gal as cell wall modifiers in vascular tissue elements. betaIV-Gal and betaV-Gal participate in the initial events of germination in which cell walls are involved: betaV-Gal in cell proliferation, detachment of root cap cells and initial vascular tissue differentiation; both of them in xylem maturation; and betaIV-Gal in thickening of the primary cell wall. Together with other cell wall-modifying enzymes, such as expansins and XTH, chickpea galactosidases might function in a sequential order in turnover of the primary cell wall, allowing the elongation of embryonic axes during seed germination. PMID- 23731126 TI - Subjective cognitive complaint in healthy older adults: identification of major domains and relation to objective performance. AB - This study analyzed complaints across a range of memory domains in middle-aged and older adults, as well as assessed their relationship with objective cognitive performance and personal characteristics. A total of 115 community-dwelling, healthy adults between the ages of 45 and 87 completed the Self-Evaluation Questionnaire (QAM) and were tested with a comprehensive neuropsychological battery. A principal component analysis identified seven dimensions of complaint. Difficulty inhibiting internal and external sources of interference when learning or remembering something was the main area of complaint and it was correlated with word-list recall and Digit Symbol. We identified complaints related to a set of memory failures that appear to be more detrimental to autonomy and safety. These were correlated with a measure of functional autonomy and might, therefore, indicate more severe difficulties. Overall, this study provides indications regarding the main domains of memory complaints and identifies which complaints are most reflective of objective cognitive problems. PMID- 23731127 TI - Atomic-scale mapping of thermoelectric power on graphene: role of defects and boundaries. AB - The spatially resolved thermoelectric power is studied on epitaxial graphene on SiC with direct correspondence to graphene atomic structures by a scanning tunneling microscopy (STM) method. A thermovoltage arises from a temperature gradient between the STM tip and the sample, and variations of thermovoltage are distinguished at defects and boundaries with atomic resolution. The epitaxial graphene has a high thermoelectric power of 42 MUV/K with a big change (9.6 MUV/K) at the monolayer-bilayer boundary. Long-wavelength oscillations are revealed in thermopower maps which correspond to the Friedel oscillations of electronic density of states associated with the intravalley scattering in graphene. On the same terrace of a graphene layer, thermopower distributions show domain structures that can be attributed to the modifications of local electronic structures induced by microscopic distortions (wrinkles) of graphene sheet on the SiC substrate. The thermoelectric power, the electronic structure, the carrier concentration, and their interplay are analyzed on the level of individual defects and boundaries in graphene. PMID- 23731128 TI - Clinical utility of endoscopic ultrasound elastography for identification of malignant pancreatic masses: a meta-analysis. AB - BACKGROUND AND AIM: Endoscopic ultrasound (EUS) elastography is not used for detection but rather for characterization of solid pancreatic masses. A meta analysis was used to assess the accuracy of EUS elastography for identification of malignant pancreatic masses. METHODS: PubMed, the Cochrane Library, and the ISI Web of Knowledge were searched. The studies relating to evaluation accuracy of qualitative or quantitative EUS elastography for identification of malignant pancreatic masses were collected. Language was limited to English. The sensitivity and specificity were used to examine the accuracy. Clinical utility was evaluated by likelihood ratio scattergram. RESULTS: A total of 10 studies including 893 pancreatic masses (646 malignant, 72.3%) were analyzed. The summary sensitivity and specificity for the diagnosis of malignant pancreatic masses were 0.98 (95% confidence interval [CI] 0.93-1.00) and 0.69 (95% CI 0.52-0.82) for qualitative EUS elastography, and 0.96 (95% CI 0.86-0.99) and 0.76 (95% CI 0.58 0.87) for quantitative EUS elastography, respectively. The hierarchical summary receiver operating characteristic curves were 0.94 and 0.93 for qualitative and quantitative EUS elastography. The accuracy of quantitative methods was similar to qualitative methods. The positive and negative likelihood ratios were 3.15 and 0.03 for qualitative EUS elastography, and 3.94 and 0.05 for quantitative EUS elastography, respectively. Both qualitative and quantitative methods were useful for exclusion of presence of malignant pancreatic masses and not for its confirmation. CONCLUSIONS: EUS elastography could be used as a good identification tool for benign and malignant pancreatic masses, with its good performance for exclusion of presence of malignant pancreatic masses. PMID- 23731129 TI - Antioxidant support in composite musculo-adipose-fasciocutaneous flap applications: an experimental study. AB - Free radicals are chemicals that play roles in the etio-pathogenesis of ischaemia reperfusion injury. Various antioxidants have been used in an attempt to mitigate the damage induced by these chemicals. In the present study, the antioxidative effects of grape seed extract (proanthocyanidin), tomato extract (lycopene), and vitamin C (ascorbic acid) on a composite re-established-flow inferior epigastric artery based rectus abdominis muscle-skin flap model on which experimental ischaemia was induced were investigated. The rats have been administered antioxidants for 2 weeks prior to the surgery and for 2 more weeks thereafter. Macroscopic, histopathological, and biochemical analyses were carried out at the decision of the experiment. It was found that flap skin island necrosis was significantly reduced in the proanthocyanidin, lycopene, vitamin C groups (p < 0.001). Statistical analyses showed significant decreases in inflammation, oedema, congestion, and granulation tissue in the proanthocyanidin and lycopene groups compared to the vitamin C and control groups (p < 0.001). When the viability rates of fat and muscle tissues were examined, significant improvements were found in the proanthocyanidin and lycopene groups in comparison to the other groups (p < 0.001). Serum antioxidant capacity measurements revealed significant differences in the lycopene group compared to all other groups (p < 0.001). It is concluded that lycopene and proanthocyanidin are protective antioxidants in rat composite muscle-skin flap ischaemia-reperfusion models. PMID- 23731130 TI - Positive compared with negative margins in a single-centre retrospective study on 3957 consecutive excisions of basal cell carcinomas. Associated risk factors and preferred surgical management. AB - The rate of margins involvement and the associated recurrence risk in basal cell carcinomas (BCCs) varies widely in published works (7%-25% and 26%-67%, respectively). This study investigated the risk factors associated with incomplete excision and their relevance in surgical management when positive margins occur in 3957 BCCs excised in 2358 patients. This study performed a multivariate analysis on the database collected from all patients operated for BCCs in the Plastic Surgery Department between 1 January 1992 and 1 September 2007. All data collected (3957 excisions; 2358 individuals) were divided into complete and incomplete excisions groups and analyzed according to 14 variables. The overall rate of incomplete excisions was 14%. Mean age (68), size of the lesion (< 0.5 cm), BCC subtype (nodular with sclerosant aspects, sclerosant and basosquamous), location (face), infiltration depth (hypodermis and deep tissues), recurrent BCC and re-excised BCC were significantly associated with a higher rate of incomplete excision. The recurrence rate for incompletely excised tumours was 26.8%, while only 5.9% for completely excised tumours. Most of the risk factors associated to incomplete excision can be identified before surgery (by simple anamnesis and clinical examination) and successfully overcome by appropriate surgical margins. The high recurrence rate after incomplete excision and the low patient compliance towards follow-up should lead the surgeon to early re-excise residual cancer. PMID- 23731132 TI - Long-term results after vascularised bone graft as treatment of Kienbock disease. AB - The aim of this study was to present the long-term results in a small series of patients with Kienbock disease treated with a pedicled vascularised bone graft from the 4/5 extensor compartment of the distal radius as the only surgical treatment. In the period 2002-2006, five patients, three men and two women, mean age 41 years (22-54) were operated on using a pedicled vascularised bone graft from the 4/5 extensor compartment of the distal radius as described by Sheetz et al. Four patients were staged as Lichtman stage 2 and one as Lichtman stage 3. At the follow-up examination with radiographs and clinical examination at a mean of 7.4 years (5-9) after the operation, they all stated that they were satisfied with the operation. None of the patients had any further surgery in the observation period. Four patients were fully employed, and only one had changed employment due to his hand. The last patient was on a medical pension due to other medical causes. In all patients, no sign of progression was found of the radiological changes in the lunate and in all patients the arches of Gilula were unchanged without signs of carpal collapse. So, in this small series, a pedicled vascularised bone graft from the 4/5 extensor compartment of the distal radius as the only surgical treatment provided good long-term results in patients with stage 2 and 3 Kienbock disease. PMID- 23731131 TI - Cosmetic closure of pilonidal sinus defects with bilateral transpositional adipofascial flaps. AB - The optimal treatment of the pilonidal sinus has not currently been defined. This study described the use of a modified bilateral transpositional adipofascial flap technique that effectively serves to flatten the deep natal cleft while keeping the scar limited to the intergluteal fold for good cosmesis. Between June 2007 and September 2011, 83 patients (61 men, 22 women) were included in the study. Duration of pilonidal sinus symptoms ranged from 1-15 (median 5) years; 15 patients had recurrent disease. Before the operation, perforating branches of the four pairs of lateral sacral arteries were identified with a Doppler audioscope. After complete excision of the sinus cavity and adequate undermining of the skin, bilateral adipofascial flaps were raised in order to realise a Yin-Yang pattern, with the lateral sacral artery perforators at the base of each flap. Complementary flaps were then transposed into the defect and inset to completely obliterate dead space. Skin was closed primarily in two layers. The median (range) defect size after total excision of the sinus cavity was 38 (19-60) cm2. All flaps survived. There was no wound infection or dehiscense. Median (range) follow-up was 26 (6-52) months. No recurrences were observed. Extensive scarring or asymmetry in the gluteal prominences was not observed. Transient paraesthesia over the flap donor region occurred in 14 cases (16%) and resolved completely within 6 months. The bilateral adipofascial transpositional flap method is an alternative to previously described treatment options in pilonidal sinus surgery. It is a safe, reliable, and easily applicable method, which provides cosmetically acceptable coverage of pilonidal sinus defects of moderate size. PMID- 23731133 TI - Volar A1 pulley sparing technique for fixation of avulsion fractures of the base of the proximal phalanx. AB - For open reduction and internal fixation of the displaced avulsion fractures of the base of the proximal phalanx of the fingers, the volar A1 pulley approach was introduced instead of the dorsal approach. Although this procedure is quite useful, the A1 pulley and volar plate need to be divided. As a less invasive alternative, the authors developed the volar A1 pulley sparing technique and treated six patients with the median follow-up period of 14 months. All fractures healed without displacement, and all patients regained full range of motion without any evidence of instability. The volar A1 pulley sparing technique is minimally invasive and provides good visualization of the fracture site without damage to the metacarpophalangeal joint and flexor tendon structure. PMID- 23731135 TI - Editorial on writing equations and mathematical expressions: some basic principles. PMID- 23731134 TI - Microwave heating for the rapid generation of glycosylhydrazides. AB - Conditions for simple derivatization of reducing carbohydrates via adipic acid dihydrazide microwave-assisted condensation are described. We demonstrate with a diverse set of oligo- and polysaccharides how to improve a restrictive and labor intensive conventional conjugation protocol by using microwave-assisted chemistry. We show that 5 min of microwave heating in basic or acidic conditions are adequate to generate, in increased yields, intact and functional glycosylhydrazides, whereas hours to days and acidic conditions are generally required under conventional methods. PMID- 23731136 TI - Recurrent facial taste neurons of sea catfish Plotosus japonicus: morphology and organization in the ganglion. AB - This study investigated the morphology of the recurrent facial taste neurons and their organization in the recurrent ganglion of the sea catfish Plotosus japonicus. The recurrent ganglion is independent of the anterior ganglion, which consists of trigeminal, facial and anterior lateral line neurons that send peripheral fibres to the head region. The recurrent taste neurons are round or oval and bipolar, with thick peripheral and thin central fibres, and completely wrapped by membranous layers of satellite cells. Two peripheral nerve branches coursing to the trunk or pectoral fin originate from the recurrent ganglion. The results presented here show that the trunk and pectoral-fin neurons are independently distributed to form various sizes of groups, and the groups are intermingled throughout the ganglion. No distinct topographical relationship of the two nerve branches occurs in the ganglion. Centrally, the trunk and pectoral fin branches project somatotopically in the anterolateral and intermediate medial regions of the trunk tail lobule of the facial lobe, respectively. PMID- 23731137 TI - Beaufort trout MicroPlex: a high-throughput multiplex platform comprising 38 informative microsatellite loci for use in resident and anadromous (sea trout) brown trout Salmo trutta genetic studies. AB - A flexible panel consisting of 38 informative microsatellite markers for Salmo trutta is described. These markers were selected from a pool of over 150 candidate loci that can be readily amplified in four multiplex PCR groups but other permutations are also possible. The basic properties of each markers were assessed in six population samples from both the Burrishoole catchment, in the west of Ireland, and Lough Neagh, in Northern Ireland. A method to assess the relative utility of individual markers for the detection of population genetic structuring is also described. Given its flexibility, technical reliability and high degree of informativeness, the use of this panel of markers is advocated as a standard for S. trutta genetic studies. PMID- 23731138 TI - Dietary partitioning by five sympatric species of stingray (Dasyatidae) on coral reefs. AB - Dietary characteristics and the degree of dietary partitioning by five species of sympatric stingray were assessed using stomach content and sediment analyses within a coral reef lagoon at Ningaloo Reef, Western Australia (the cowtail Pastinachus atrus, blue-spotted fantail Taeniura lymma, blue-spotted mask Neotrygon kuhlii, porcupine Urogymnus asperrimus rays and the reticulate whipray Himantura uarnak). A total of 2804 items were recovered from the stomachs of 170 rays and 3215 individual taxa from the environment, which were used in selectivity analyses. Twenty-four prey taxa were identified from stomach contents and pooled into 10 taxonomic categories for analysis, of which annelids, prawns, brachyurans and bivalves were the most abundant, together accounting for 96% of the diet. Himantura uarnak had the greatest interspecific dissimilarity in diet, consuming a larger proportion of crustaceans, notably penaeids (41% of total diet) than the other four species of rays, all of which had diets dominated by annelids (71-82% of total diet). Crustacean specialization by H. uarnak may exist to maximize resources and reduce competition among sympatric species. The remaining species may partition resources on the basis of space, rather than diet. PMID- 23731139 TI - Marine fish communities in shallow volcanic habitats. AB - This survey of the marine ichthyofauna of the Piton de La Fournaise volcano at Reunion Island is the first explanatory study of fish community structures in this area. It describes and analyses the main qualitative descriptors of the fish communities (i.e. species richness, diet, life history and geographical distribution) and their spatio-temporal organization. This investigation in 2011 examined lava flows of different ages, including the most recent flows that entered the ocean between 1977 and 2007. In all, 263 species belonging to 45 families were observed. Overall, the fish community was notable for an absence of top predators and a predominance of opportunistic small-bodied species, with dietary flexibility and high reproductive rates, characteristic of the early stages of ecological succession. Between-site analysis indicated that the fish assemblages differed essentially according to the intensity of the last volcanic disturbances. Fish communities in the most disturbed sites showed the highest numbers of Serranidae and the highest proportions of omnivores and small-bodied opportunistic carnivores, including a high proportion of endemic south-western Indian Ocean species. The spatial pattern of this last category of species could be the result of convergent biological traits, and their adaptation to unstable environments at the expense of their competitiveness in more biodiverse, mature communities. Conversely, fish communities in the less disturbed sites showed the highest number of Holocentridae and the highest proportion of browsers of sessile invertebrates. This last characteristic could be a consequence of higher ecological maturity, illustrated by a more specialized trophic network, for assemblages in areas with less intense disturbances. Otherwise, high structural complexity, either in unconsolidated lava boulders, rocks and rubble or high coral-covered sites, could favour the increase of the total number of species independent of disturbance intensity. Regarding the broader effects, this study helps better understand how ecosystems can resist or recover from acute disturbances and the process of ecological succession that leads to the establishment of fish communities in newly submerged habitats. PMID- 23731140 TI - Telemetry tag effects on juvenile lingcod Ophiodon elongatus movement: a laboratory and field study. AB - This study tested the behavioural effects of tagging subyearling and yearling lingcod Ophiodon elongatus with acoustic telemetry tags in laboratory tanks and in the natural environment (Puget Sound, WA). In the laboratory, tagged individuals showed less movement and feeding behaviour soon after tagging than untagged controls. The effect dissipated after c. 1 week, presumably as the tagged O. elongatus recovered from surgery or adjusted to the presence of the tags. This dissipation enabled a field study that compared early-tagged individuals with a long recovery period after tagging to recently-tagged individuals with a short recovery period after tagging. Consistent with findings from the laboratory experiment, recently tagged individuals showed less movement away from three release sites in Puget Sound than early-tagged individuals. Together, the laboratory and field results provide evidence of temporary tag effects on actual movement in the natural environment and provide a method for testing tag effects in the field. This study suggests that subyearling and yearling O. elongatus should be held for a recovery period before release. If holding after tagging is not an option, then movement data collected during the first week should be interpreted cautiously. PMID- 23731141 TI - Natural sex change in the temperate protogynous Ballan wrasse Labrus bergylta. AB - Wild Ballan wrasse Labrus bergylta were sampled monthly over 2 years in western Norway to identify the natural process of sex change in this species. Light microscopy of standard histological-stained and immunohistochemistry-treated gonad tissue showed that spermatogonial germ cells tended to proliferate around the periphery of the lamellae before filling into the slowly receding, apoptotic central areas of the lamellae. Sex change occurred following the breeding season. From July to September, fish were most often in an early state of gonadal transition (ET), characterized by degenerating previtellogenic oocytes and pockets of proliferating spermatogonia in the germinative epithelia. The majority of fish with late transitional gonads, that were typically dominated by spermatogenic cells, developing efferent ducts and the beginning of lobule formation, were found between October and November. Sex steroid profiles of fish representing the different sexual phases showed that breeding females had the highest concentrations of 17beta oestradiol (E2 ) and the lowest concentration of 11 ketotestosterone (11KT). Concentrations of E2 decreased greatly in ET fish at the beginning of sex change and remained low in all subsequent phases. The opposite trend was demonstrated in 11KT profiles. Initial-phase female fish had minimal concentrations of 11KT, but these increased during subsequent transitions. Sex change occurred most often in fish 34-41 cm total length (L(T)) and the median of fish in the size-frequency overlap of female and male fish was 36 cm L(T). PMID- 23731142 TI - Migration behaviour of twaite shad Alosa fallax assessed by otolith Sr:Ca and Ba:Ca profiles. AB - Individual migration behaviour during the juvenile and adult life phase of the anadromous twaite shad Alosa fallax in the Elbe estuary was examined using otolith Sr:Ca and Ba:Ca profiles. Between hatching and the end of the first year of life, juveniles showed two migration patterns. Pattern one exhibited a single downstream migration from fresh water to the sea with no return into fresh water. In contrast, pattern two showed a first migration into the sea, then a return into fresh water and, finally, a second downstream migration into marine water. This first report of migration plasticity for A. fallax points to different exposure times to estuarine threats depending on the migration strategy. In adults, high Sr:Ca and low Ba:Ca in the majority of individuals confirmed prior reports of a primarily marine habitat use. Patterns reflecting spawning migrations were rarely observed on otoliths, possibly due to the short duration of visits to fresh water. PMID- 23731143 TI - Characterization of a novel cell line from the caudal fin of koi carp Cyprinus carpio. AB - A continuous cell line (KF-101) derived from the caudal fin of the koi carp Cyprinus carpio was established and characterized. The KF-101 cell line multiplied abundantly in Leibovitz's L-15 medium containing 10% foetal bovine serum at 25 degrees C, and was subcultured for >90 passages over a period of 3 years. Immunocytochemistry revealed that the KF-101 cells contain keratin, junction proteins connexin-43 and occludin, and ectodermal stem-cell marker Pax 6, but not vimentin. Furthermore, the KF-101 cells reacted with anti-human DARPP 32 and anti-human GATA-4 antibodies, and the labelling was regulated according to the cell cycle. The labels of the DARPP-32 and GATA-4 antibodies in the KF-101 cells were the suggested phosphatase-1 inhibitor-1 and GATA-3, respectively. In addition, the KF-101 cells were susceptible to koi herpesvirus but were resistant to eel herpesvirus, iridovirus, grouper nodavirus and chum salmon (Oncorhynchus keta) virus. The results indicate that the KF-101 cells are suitable materials for investigating biological and virological development. PMID- 23731144 TI - Species-specific ontogenetic diet shifts among Neotropical Crenicichla: using stable isotopes and tissue stoichiometry. AB - Ontogenetic diet shifts were compared among five sympatric pike cichlids Crenicichla in a subtropical South American stream using stable C and N isotopes and tissue stoichiometry (C:N). Within species, stable N isotopes were positively related to body size while C:N showed negative relationships. Stable C isotopes, however, were not related to body size in any species. By modelling the switch to piscivory using gut content-isotope-body size relationships, diet shifts were shown to be species-specific with regard to both rate and degree of piscivory. Compared to other piscivorous lineages, Crenicichla appear to be unusually small bodied (based on maximum body size). Because of their diversity, abundance and dynamic size-structured functional roles, Crenicichla may exert broad and complex predation pressures on the aquatic community. PMID- 23731145 TI - Species compositions and ecology of the riverine ichthyofaunas in two Sulawesian islands in the biodiversity hotspot of Wallacea. AB - This account of the riverine ichthyofaunas from the islands of Buton and Kabaena, off south-eastern mainland Sulawesi, represents the first detailed quantitative checklist and ecological study of the riverine fish faunas in the biological hotspot of Wallacea. The results are based on analysis of samples collected by electrofishing at a wide range of sites from July to September in both 2001 and 2002. While the fauna was diverse, with the 2179 fishes caught comprising 64 species representing 43 genera and 22 families, the catches were dominated by the Gobiidae (26 species and 25% by numbers), Eleotridae (seven species and 27% by numbers), Zenarchopteridae (three species and 22% by numbers) and Anguillidae (two species and 12% by numbers). The most abundant species were the eleotrids Eleotris aff. fusca-melanosoma and Ophieleotris aff. aporos, the anguillid Anguilla celebesensis, the zenarchopterids Nomorhamphus sp. and Nomorhamphus ebrardtii and the gobiids Sicyopterus sp. and Glossogobius aff. celebius-kokius. The introduced catfish Clarias batrachus was moderately abundant at a few sites. Cluster analysis, allied with the similarity profiles routine SIMPROF, identified seven discrete groups, which represented samples from sites entirely or predominantly in either Buton (five clusters) or Kabaena (two clusters). Species composition was related to geographical location, distance from river mouth, per cent contribution of sand and silt, altitude and water temperature. The samples from the two islands contained only one species definitively endemic to Sulawesi, i.e. N. ebrardtii and another presumably so, i.e. Nomorhamphus sp., contrasting starkly with the 57 species that are endemic to Sulawesi and, most notably, its large central and deep lake systems on the mainland. This accounts for the ichthyofaunas of these two islands, as well as those of rivers in northern mainland Sulawesi and Flores, being more similar to each other than to those of the central mainland lake systems. This implies that the major adaptive radiation of freshwater fishes in Sulawesi occurred in those lacustrine environments rather than in rivers. PMID- 23731146 TI - Life-history traits of the common snook Centropomus undecimalis in a Caribbean estuary and large-scale biogeographic patterns relevant to management. AB - The ecology of common snook Centropomus undecimalis in Amatique Bay, a tropical estuary in eastern Guatemala, was investigated and life-history traits were used to conduct a meta-analysis of the species from Florida to Brazil. The reproduction cycle of C. undecimalis in Amatique was strongly related to the precipitation cycle, with a lag of 2 months. Spawning occurred from April to November with a peak spawning after the onset of the summer rains. Protandric sex reversal occurred early in the dry season (December) before somatic recovery from spawning. The growth cycle preceded that of body condition by c. 1 month, and was out of phase with the reproductive cycle. Growth was fast, as many individuals reached >70% of the maximum observed total length (LT , 102 cm) after 3 years. Sex transition occurred within a relatively narrow LT range (70-79 cm), but over a wide range of ages, indicating plasticity in this respect. The meta-analysis indicated a latitudinal-temperature gradient in life-history traits, as well as different seasonal patterns relative to temperature and hydrographical cycles. Centropomus undecimalis from cooler winter waters (e.g. Florida) reach larger maximum LT and LT at sex change, as well as greater gonado-somatic indices and longer life spans. Further, increased fishing mortality results in younger age at sex reversal and male predominance in the populations compared. Recognition of large-scale biogeographic patterns in this important, but little studied, fish species helps in the formulation of management advice in other areas of its occurrence. PMID- 23731147 TI - Metabolic divergence between sibling species of cichlids Pundamilia nyererei and Pundamilia pundamilia. AB - This study compared Pundamilia nyererei and Pundamilia pundamilia males in routine metabolic rate (R(R)) and in the metabolic costs males pay during territorial interactions (active metabolic rate, R(A)). Pundamilia nyererei and P. pundamilia males housed in social isolation did not differ in RR . In contrast to expectation, however, P. nyererei males used less oxygen than P. pundamilia males, for a given mass and level of agonistic activity. This increased metabolic efficiency may be an adaptation to limit the metabolic cost that P. nyererei males pay for their higher rate of aggressiveness compared to P. pundamilia males. Thus, the divergence between the species in agonistic behaviour is correlated with metabolic differentiation. Such concerted divergence in physiology and behaviour might be widespread in the dramatically diverse cichlid radiations in East African lakes and may be an important factor in the remarkably rapid speciation of these fishes. The results did not support the hypothesis that higher metabolic rates caused a physiological cost to P. nyererei males that would offset their dominance advantage. PMID- 23731148 TI - Early development of marine catfishes (Ariidae): from mouth brooding to the release of juveniles in nursery habitats. AB - The development and allometric growth patterns of the ariid catfishes Cathorops spixii and Cathorops agassizii were studied from neurula embryos to juveniles. The ontogenetic sequence revealed that prior to hatching, embryos of both species are well developed, and their axial and appendicular skeletons are well ossified. Embryos of both species grow slowly longitudinally, but positively allometric growth (growth coefficient, beta1 > 1) was observed in head width and eye diameter. It is hypothesized that these growth patterns might be related to functional priorities for the development of sensory organs, such as the inner ears (otoliths), the Weberian apparatus, eyes and nostrils, during the embryonic period. The first appearance of vertebrae and otoliths, as well as the ossification of otoliths and the Weberian apparatus, occur earlier in embryos of C. agassizii than in embryos of C. spixii. After hatching, mouth-brooded free embryos of both species grow isometrically. Negatively allometric growth was observed in head width and eye diameter during the yolk-sac period, which is expected given that the sensory organs are already formed. Free embryos of C. agassizii are distinguishable from those of C. spixii by their larger eyes, longer snouts, longer heads and heavier yolk sacs. The end of the yolk-sac period is characterized by a direct change from free embryo to juvenile, without a true larval period. The juveniles of the two species can also be distinguished from each other by the larger eyes of C. agassizii compared with C. spixii, as in adult fishes. PMID- 23731149 TI - Genetic and morphometric differences demonstrate fine-scale population substructure of the yellow perch Perca flavescens: need for redefined management units. AB - Whole-body morphometrics and 15 nuclear DNA microsatellite loci were analysed for 158 Perca flavescens collected during the spawning season from four spawning locations in central Lake Erie, two along the northern shore and two along the southern shore, to evaluate fine-scale variation (spanning 17-94 km). Results showed significant morphological and genetic differences among P. flavescens from the four locations. The magnitudes of differences were unrelated to geographic distance, demonstrating spatially heterogeneous levels of genetic divergence. These results linked morphometric and genetic variation, showing a discontinuity of scale between currently defined management units and population structure of P. flavescens in Lake Erie, and support that P. flavescens might exist as one or more metapopulations. Findings demonstrate the value of using complementary techniques for evaluating population structure. PMID- 23731150 TI - Pair formation in the herbivorous rabbitfish Siganus doliatus. AB - This study investigated the basis of pair formation in the abundant herbivorous rabbitfish Siganus doliatus on Orpheus Island, Great Barrier Reef. Pair formation was the most common social system in S. doliatus, with 67.4% of all individuals occurring in pairs. Pairs were stable (i.e. individuals remained with the same partner throughout the study) and pair members were found within 5 m of each other 82.9% of the time. Of the examined pairs, 25% were homosexual resulting in a proportion of heterosexual pairs (75%) that was significantly lower than expected if pairs were formed solely for reproductive reasons. Therefore, although reproduction appears to be the main driver of pair formation in S. doliatus, other factors are likely to influence this behaviour. The high density of individuals on the reef crest (5.7 +/- 0 .9 individuals 200 m(-2); mean +/- s.e.) and extensively overlapping home ranges of pairs indicated that the defence of territories plays no role in pair formation. Instead, it appears that pair formation in S. doliatus is driven, in part, by other, non-reproductive, ecological factors. It is suggested that pair formation allows for increased vigilance against predation and enables S. doliatus to execute a novel feeding behaviour. PMID- 23731151 TI - Identification of a uniquely southern African clade of coastal pipefishes Syngnathus spp. AB - The taxonomic status of two southern African coastal pipefish species, Syngnathus temminckii and Syngnathus watermeyeri, was investigated using a combination of morphological and genetic data. Morphological data showed that S. temminckii is distinct from the broadly distributed European pipefish Syngnathus acus, and a molecular phylogeny reconstructed using mitochondrial DNA recovered S. temminckii and S. watermeyeri as sister taxa. The southern African species share an evolutionary origin with north-eastern Atlantic Ocean and Mediterranean Sea species, including S. acus. These data support the existence of a distinct southern African clade of Syngnathus pipefishes that has diverged in situ to form the two species present in the region today. PMID- 23731152 TI - Effects of sampling techniques on population assessment of invasive round goby Neogobius melanostomus. AB - In this study, a comparison of point abundance sampling (PAS) electrofishing, angling with two different hook sizes and trap-based fishing was performed in a non-wadeable river to analyse their effects on catch per unit effort (CPUE) and population characteristics of invasive round goby Neogobius melanostomus. PAS electrofishing was identified as the most effective (mean +/- s.e. CPUE = 57 +/- 4 N. melanostomus min(-1) ) and least selective method in terms of size, feeding status and species composition. Angling had the second highest CPUE, but was more size selective and resulted in a higher proportion of males compared to electrofishing [overall sex ratio angling (female:male) = 1:0.92, electrofishing 1:0.65]. Owing to low CPUE (0.012 +/- 0.004) and low frequency of occurrence, minnow traps were least suitable for N. melanostomus population assessment. The results of this study suggest that a higher degree of standardization and inter calibration is useful to achieve better comparability of population data of invasive N. melanostomus and other benthic fish species. PMID- 23731153 TI - An analysis of genetic stock identification on a small geographical scale using microsatellite markers, and its application in the management of a mixed-stock fishery for Atlantic salmon Salmo salar in Ireland. AB - A genetic stock identification (GSI) study was undertaken in a fishery for Atlantic salmon Salmo salar to determine the effects of restrictive fishery management measures on the stock composition of the fishery, and if accurate and precise stock composition estimates could be achieved on the small geographical scale where this fishery operates, using a suite of only seven microsatellite loci. The stock composition of the Foyle fishery was shown to comprise almost exclusively of Foyle origin fish in the 3 years after restrictive measures were introduced in 2007, compared to 85% the year before. This showed that the restrictive measures resulted in the Foyle fishery being transformed from a mixed stock fishery to an almost exclusively single-stock fishery, and showed how GSI studies can guide and evaluate management decisions to successfully manage these fisheries. Highly accurate and precise stock composition estimates were achieved in this study, using both cBAYES and ONCOR genetic software packages. This suggests accurate and precise stock composition is possible even on small geographical scales. PMID- 23731154 TI - Variation in social information use: the influences of information reliability and mass on decision making in a group-living fish Gambusia affinis. AB - The effect of the reliability of available social information was assessed by examining whether the age of social information changes its effects on a foraging decision in a group-living fish Gambusia affinis. Individuals switched their patch preference when faced with social information that conflicted with personal information in general; the age of the social information, however, did not significantly influence preference for feeding patch. The mass of decision makers was positively correlated with their use of available social information, with heavier individuals exhibiting a greater difference in patch preference than lighter individuals, suggesting that large and small G. affinis trade-off the benefits of information acquisition and the costs of competition from conspecifics differently. PMID- 23731155 TI - Low cardiac and aerobic scope in a coastal population of sockeye salmon Oncorhynchus nerka with a short upriver migration. AB - This study showed that a coastal population (Harrison) of Fraser River sockeye salmon Oncorhynchus nerka had a lower aerobic and cardiac scope compared with interior populations with more challenging upriver spawning migrations, providing additional support to the idea that Fraser River O. nerka populations have adapted physiologically to their local migratory environment. PMID- 23731156 TI - The shore fishes of the Trindade-Martin Vaz insular complex: an update. AB - A compilation of historical and recent collections and observations of shore fishes yielded 154 recorded species for Trindade and 67 for Martin Vaz. Twelve taxa, mostly small cryptobenthic species with limited dispersal capabilities and low ecological amplitude, are endemic to this insular complex. In several cases, the seamounts of the Vitoria-Trindade Chain appear to have acted as stepping stones between the mainland and islands in periods of low sea level. PMID- 23731157 TI - First evidence for interspecific hybridization between invasive goby species Neogobius fluviatilis and Neogobius melanostomus (Teleostei: Gobiidae: Benthophilinae). AB - Two hybrids between the monkey goby Neogobius fluviatilis and the round goby Neogobius melanostomus from the Rhine River were identified by genotyping and morphological comparison. These are the first records of goby-hybrids outside the parent species' native ranges worldwide. PMID- 23731158 TI - Vertical and horizontal distributions of coral-reef fish larvae in open water immediately prior to reef colonization. AB - To explore the vertical and horizontal distributions of fish larvae near the end of their pelagic period, six light traps were set up over four lunar months at different depths (sub-surface, midwater and bottom) and different habitat types (reef slope: 50 m horizontal distance from the reef crest; frontier zone: 110 m horizontal distance; sandy zone: 200 m horizontal distance) on the outer reef slope of Moorea Island, French Polynesia. The highest captures were in sub surface traps on the reef slope and the frontier zone, and in bottom traps on the sandy zone and the frontier zone. It is hypothesized that fish larvae move towards the surface near the reef slope to avoid reef-based planktivores and to get into a favourable position for surfing over the reef crest. PMID- 23731160 TI - Variability in energy density of forage fishes from the Bay of Biscay (north-east Atlantic Ocean): reliability of functional grouping based on prey quality. AB - Energy densities of 670 fishes belonging to nine species were measured to evaluate intraspecific variability. Functional groups based on energy density appeared to be sufficiently robust to individual variability to provide a classification of forage fish quality applicable in a variety of ecological fields including ecosystem modelling. PMID- 23731159 TI - Habitat complexity affects how young of the year Atlantic cod Gadus morhua perceive predation threat from older conspecifics. AB - The response of age 0+ year juvenile Atlantic cod Gadus morhua to the presence of age 1+ and age 3+ year conspecifics was measured with and without cover available. Juveniles reacted by aggregating more closely and maintaining distance from older conspecifics in an experimental setting without cover but only to age 3+ year conspecifics when cover was available. The results indicate that prior residence of older juveniles can affect age 0+ year juveniles during benthic settlement and highlights the conservation value of structurally complex nursery habitats. PMID- 23731161 TI - (H2O)20 water clusters at finite temperatures. AB - We have performed an exhaustive study of energetics of (H2O)20 clusters. Our goal is to study the role that various free-energy terms play in this popular model system and see their effects on the distribution of the (H2O)20 clusters and in the infrared spectrum at finite temperatures. In more detail, we have studied the electronic ground-state structure energy and its long-range correlation (dispersion) part, vibrational zero-point corrections, vibrational entropy, and proton configurational entropy. Our results indicate a delicate competition between the energy terms; polyhedral water clusters are destabilized by dispersion interaction, while vibrational terms (zero-point and entropic) together with proton disorder entropy favor them against compact structural motifs, such as the pentagonal edge- or face-sharing prisms. Apart from small water clusters, our results can be used to understand the influence of these energy terms in water/ice systems in general. We have also developed energy expressions as a function of both earlier proposed and novel hydrogen-bond connectivity parameters for prismatic water clusters. PMID- 23731162 TI - Phosphatidylethanol: the potential role in further evaluating low positive urinary ethyl glucuronide and ethyl sulfate results. AB - BACKGROUND: Whereas urinary ethyl glucuronide (EtG) levels above 1,000 ng/ml reflect with a high probability ethanol (EtOH) consumption, levels below this cutoff are difficult to interpret as both extraneous (nonbeverage) EtOH exposure, recent drinking, and more distant high EtOH intake (several days ago) might yield similar results. This might be of particular relevance in medico-legal cases. To overcome this dilemma, phosphatidylethanol (PEth) might be a promising marker, because blood PEth is only positive following significant alcohol use. The aim of our study was therefore to employ PEth as a marker to differentiate between the different conditions. METHODS: Subjects included were 252 participants in monitoring with the Alabama Physician Health Program. All subjects testing positive for EtG and/or ethyl sulfate (EtS) who denied drinking after routine supportive confrontation were subject to information about PEth testing. If they still denied drinking, PEth testing was performed and the result communicated. EtG, EtS, and PEth testing was performed in a commercial laboratory using liquid chromatography tandem mass spectrometry methods. RESULTS: Of a total of 18 subjects who tested positive for EtG and/or EtS, 10 denied drinking. Of the 7 who denied drinking after PEth explanation, in 5 cases, their claim was supported by a negative PEth result. In 2 cases, a positive PEth result was in contrast to their claim. CONCLUSIONS: PEth results in combination with previous low positive EtG/EtS results allow differentiating between innocent/extraneous exposure and drinking. Negative PEth testing following low positive EtG/EtS results helps to further elucidate the findings and support the claim of the patient of recent alcohol abstinence. Positive PEth testing following positive EtG/EtS results confirms recent drinking. PMID- 23731163 TI - Cell-specific analysis of the tomato pollen proteome from pollen mother cell to mature pollen provides evidence for developmental priming. AB - Tomato is a globally important crop grown and consumed worldwide. Its reproductive activity is highly sensitive to environmental fluctuations, for instance temperature and drought. Here, pollen development is one of the most decisive processes. The present study aims for the identification of cell specific proteins during pollen developmental stages of tomato. We have setup a protocol for stage-specific pollen isolation including microsporocytes (pollen mother cells), tetrads, microspores, polarized microspores, and mature pollen. Proteins were extracted using phenol and prefractionated using SDS-PAGE followed by protein digestion, peptide extraction, and desalting. Identification and quantification of proteins were performed using nanoHPLC coupled to LTQ-Orbitrap MS. In total, 1821 proteins were identified. Most of these proteins were classified based on their homology and designated functions of orthologs. Cluster and principal components analysis revealed stage-specific proteins and demonstrated that pollen development of tomato is a highly controlled sequential process at the proteome level. Intermediate stages such as tetrad and polarized microspore are clearly distinguished by different functionality compared to other stages. From the predicted functions, energy-related proteins are increased during the later stages of development, which indicates that pollen germination depends upon presynthesized proteins in mature pollen. In contrast, heat stress related proteins are highly abundant in very early developmental stages, suggesting a dominant role in stress protection. Taken together, the data provide a first cell-specific protein reference set for tomato pollen development from pollen mother cells to the mature pollen and give evidence for developmentally controlled processes that might help to prepare the cells for specific developmental programs and environmental stresses. PMID- 23731164 TI - Socio-cultural differences in Australian primary school children's weight and weight-related behaviours. AB - AIM: To examine whether there are socio-cultural differences in overweight/obesity and weight-related behaviours of Australian primary school children. METHODS: Secondary data analysis of the 2010 NSW Schools Physical Activity and Nutrition Survey (n = 4898). Height and weight were measured. Parents of Year K, 2, 4 children and Year 6 students completed a questionnaire on demographics and weight-related behaviours. Cardio-respiratory fitness was assessed by the 20-meter shuttle run test and categorised as adequately fit or unfit. Children were categorised according to the main cultural/ethnic backgrounds (Middle-Eastern, Asian and English-speaking backgrounds) and socio economic status (SES) tertile. RESULTS: Within ethnic groups, SES was associated with weight-related behaviours, but not consistently, and not with body mass index status. Within ethnic groups, the odds were higher among low SES, compared with high SES to be inactive, unfit and have poorer dietary habits. Weight related behaviours among each ethnic group also differed by gender. Compared with low SES children from English-speaking backgrounds, ethnic boys were two times as likely to be overweight/obese, and the odds were significantly higher among ethnic children to be inactive, unfit and have poor dietary patterns. CONCLUSION: The results indicate the need for obesity prevention initiatives to specifically target and reach children from low SES and Asian and Middle-Eastern backgrounds, and the importance of ensuring that such initiatives are culturally appropriate and address relevant issues. PMID- 23731165 TI - Collaborative validation of an event-specific quantitative real-time PCR method for genetically modified rice event TT51-1 detection. AB - In this study, a collaborative trial of validating a real-time PCR method for the TT51-1 rice event was organized, including six participating laboratories. In this validation, serially diluted solutions from homogeneous genomic DNA of the TT51-1 event were used to construct standard curves of the TT51-1 event and phospholipase D (PLD) assays. The PCR efficiency was 95%, and the R(2) coefficient was 0.99 for the TT51-1 system. The mean quantitative values for blind samples containing 0.1%, 0.5% 1%, 5%, and 10% (w/w) TT51-1 corresponded to 0.1%, 0.51%, 1.06%, 4.83%, and 9.62%, respectively, with a bias (%) ranging from 3.77% to 5.87%. The repeatability and reproducibility were all below 25% across the entire dynamic range. Furthermore, the measurement uncertainties of the quantitative results were estimated to be 0.10%, 0.20%, 0.40%, 1.76%, and 3.52% (w/w) for the tested samples. Both the LOD and LOQ were calculated to be 0.22%. This collaborative trial demonstrated that the TT51-1 method produces reliable, comparable, and reproducible results for a given sample set and can be adopted as a detection standard for testing laboratories. PMID- 23731166 TI - Naive hypothesis testing for case series analysis with time-varying exposure onset measurement error: inference for infection-cardiovascular risk in patients on dialysis. AB - The case series method is useful in studying the relationship between time varying exposures, such as infections, and acute events observed during the observation periods of individuals. It provides estimates of the relative incidences of events in risk periods (e.g., 30-day period after infections) relative to the baseline periods. When the times of exposure onsets are not known precisely, application of the case series model ignoring exposure onset measurement error leads to biased estimates. Bias-correction is necessary in order to understand the true directions and effect sizes associated with exposure risk periods, although uncorrected estimators have smaller variance. Thus, inference via hypothesis testing based on uncorrected test statistics, if valid, is potentially more powerful. Furthermore, the tests can be implemented in standard software and do not require additional auxiliary data. In this work, we examine the validity and power of naive hypothesis testing, based on applying the case series analysis to the imprecise data without correcting for the error. Based on simulation studies and theoretical calculations, we determine the validity and relative power of common hypothesis tests of interest in case series analysis. In particular, we illustrate that the tests for the global null hypothesis, the overall null hypotheses associated with all risk periods or all age effects are valid. However, tests of individual risk period parameters are not generally valid. Practical guidelines are provided and illustrated with data from patients on dialysis. PMID- 23731167 TI - Progress towards TB control in East Kwaio, Solomon Islands. PMID- 23731168 TI - Silodosin versus naftopidil for the treatment of benign prostatic hyperplasia: a multicenter randomized trial. AB - This was a multicenter randomized trial to investigate the clinical efficacy and the impact on sexual function of alpha-1A selective silodosin and alpha-1D selective naftopidil for treatment of benign prostatic hyperplasia. A total of 97 patients with lower urinary tract symptoms/benign prostatic hyperplasia who had an International Prostate Symptom Score of 8 or more were randomly assigned to receive silodosin (8 mg/day, n = 53) or naftopidil (75 mg/day, n = 44). Before and 4, 8 and 12 weeks after treatment, International Prostate Symptom Score and its quality of life score were used to assess lower urinary tract symptoms. Also, International Index of Erectile Function-5, and an original questionnaire were used to evaluate erectile function and ejaculation for sexually active patients, respectively. The silodosin group showed advantages in terms of voiding symptoms and quality of life of International Prostate Symptom Score when compared with the naftopidil group. Both silodosin and naftopidil showed no significant effect on International Index of Erectile Function-5. A total of 23 sexually active patients in the silodosin group experienced more ejaculatory impairment than 21 patients in the naftopidil group, with a decrease of ejaculation volume (87% vs 40%, P = 0.003), prolonged time to ejaculation (56% vs 33%, P = 0.027) and decrease of orgasm (50% vs 39%, P = 0.027). These results suggest that alpha-1A selective blockers are more effective for voiding symptoms, whereas alpha-1D selective blockers offer a minor degree of ejaculatory dysfunction. PMID- 23731169 TI - Sunlight-driven reduction of silver ions by natural organic matter: formation and transformation of silver nanoparticles. AB - Photobiogeochemical reactions involving metal species can be a source of naturally occurring nanoscale materials in the aquatic environment. This study demonstrates that, under simulated sunlight exposure, ionic Ag is photoreduced in river water or synthetic natural water samples that contain natural organic matter (NOM), forming Ag nanoparticles (AgNPs) that transform in size and shape and precipitate out upon extended irradiation. We show that the dissolved oxygen concentration does not appear to affect AgNP formation rates, indicating that reactive transients such as superoxide, hydrated electron, and triplet NOM do not play a large role. By varying pH and NOM concentrations and adding competing cations on the AgNP formation, we present three lines of evidence to show that Ag ion photoreduction likely involves ionic Ag binding to NOM. Our work suggests that photochemical reactions involving ionic Ag and NOM can be a source of nanosized Ag in the environment. PMID- 23731170 TI - Therapeutic targeting of EGFR-activated metabolic pathways in glioblastoma. AB - INTRODUCTION: The highly divergent histological heterogeneities, aggressive invasion and extremely poor response to treatment make glioblastoma (GBM) one of the most lethal and difficult cancers in humans. Among key elements driving its behavior is epidermal growth factor receptor (EGFR), however, neither traditional therapy including neurosurgery, radiation, temozolomide, nor targeted EGFR therapeutics in clinic has generated promising results to date. Strategies are now focusing on blocking the downstream EGFR-activated metabolic pathways and the key phosphorylated kinases. AREAS COVERED: Here, we review two major EGFR activated downstream metabolic pathways including the PI3K/AKT/mTOR and RAS/RAF/MAPK pathways and their key phosphorylated kinase alterations in GBMs. This review also discusses potential pharmacological progress from bench work to clinical trials in order to evaluate specific inhibitors as well as therapeutics targeting PI3K and RAS signaling pathways. EXPERT OPINION: Several factors impede clinical progress in targeting GBM, including the high rates of acquired resistance, heterogeneity within and across the tumors, complexity of signaling pathways and difficulty in traversing the blood-brain barrier (BBB). Substantial insight into genetic and molecular pathways and strategies to better tap the potential of these agents include rational combinatorial regimens and molecular phenotype-based patient enrichment, each of which will undoubtedly generate new therapeutic approaches to combat these devastating disabilities in the near future. PMID- 23731171 TI - Utility of the phylotoxigenic relationships among trichothecene-producing Fusarium species for predicting their mycotoxin-producing potential. AB - Species of the genus Fusarium are well-known plant pathogens and mycotoxigenic fusaria are associated with health hazards to humans and animals. There is a need to understand the mechanisms of mycotoxin production by Fusarium species and to predict which produce mycotoxins. In this study, the Fusarium phylogenetic tree was first inferred among trichothecene producers and related species. We reconstructed the maximum likelihood (ML) tree based on the combined data from nucleotide sequences of rDNA cluster regions, the beta-tubulin gene (beta-tub) and the elongation factor 1alpha gene (EF-1alpha). Second, based on this tree topology, the ancestral states of the producing potential of type A and B trichothecenes (TriA and TriB), zearalenone (ZEN), moniliformin (MON), beauvericin (BEA) and enniatins (ENN) were reconstructed using the maximum parsimony (MP) method based on the observed production by extant species as reported in the literature. Finally, the species having the potential to produce each of these six mycotoxins was predicted on the basis of the parsimonious analysis. The ML tree indicated that the Fusarium species analysed in this study could be divided into two major clades. Clade I was divided into four distinct subclades: I-a, I-b, I-c and I-d. Furthermore, the parsimony reconstruction suggested that the potential for producing MON and ZEN was gained or lost only once, and that the producing potential for TriA and TriB, BEA and ENN was repeatedly gained and lost during the evolutionary history of the Fusarium species analysed in this study. Interestingly, the results showed the possibility that several species, about which reports were scarce with regard to mycotoxin production, have the potential to produce one or more of the six evaluated in this study. The phylogenetic information therefore helps one to predict the mycotoxin-producing potential by Fusarium species, and these "phylotoxigenic relationships" may be useful for predicting the pathogenicity of fungi. PMID- 23731172 TI - Seasonal changes in temperature response of photosynthesis and its contribution to annual carbon gain in Daphniphyllum humile, an evergreen understorey shrub. AB - We evaluated seasonal variation in photosynthetic temperature dependence and its contribution to annual carbon gain in an evergreen understorey shrub, Daphniphyllum humile Maxim, growing at the forest border and in the understorey of a deciduous forest. Plants at both sites exhibited similar optimal temperatures for photosynthesis (T(opt)). The activation energy for ribulose-1,5 bisphosphate (RuBP) carboxylation (HaV) at both sites tended to be higher in summer than in spring or autumn, suggesting that HaV may be the controlling factor in the T(opt) shift in D. humile. In contrast to the seasonal changes in T(opt ), the maximum photosynthetic rate at the optimal temperature (P(opt)) differed between the two sites: it was lower in autumn than in summer at the forest border, but was the same in summer and autumn in the understorey. In the understorey plants, nitrogen content (Narea) increased in autumn, but this was not the case for forest border plants. In addition, Rubisco content increased significantly in autumn in the understorey leaves but decreased distinctly in forest border leaves. Increased Narea and Rubisco in understorey leaves resulted in increased in photosynthesis in autumn. Annual carbon gain was 30.8 mol . m(-2) in forest border leaves and 5.8 mol . m(-2) in understorey leaves. Carbon gain in understorey leaves during the short period after overstorey leaf fall and before snow accumulation was approximately 49% of annual carbon gain. Furthermore, autumn carbon gain calculated using activation energy of summer with autumn photosynthetic parameters underestimated the autumn carbon gain by as much as 31%. In conclusion, photosynthetic temperature acclimation may be a key factor in increasing annual carbon gain in understorey D. humile. PMID- 23731173 TI - Effects of exercise on angiogenesis and apoptosis-related molecules, quality of life, fatigue and depression in breast cancer patients. AB - The aim of this study was to explore the effects of exercise on angiogenesis and apoptosis-related molecules, quality of life, fatigue and depression in patients who completed breast cancer treatment. Sixty breast cancer patients were randomised into three groups, as supervised exercise group, home exercise group and education group. Angiogenesis and apoptosis-related cytokine levels and quality of life (EORTC QOL-C30: European Organisation for Research and Treatment of Cancer Quality of Life C30), fatigue (Brief Fatigue Inventory) and depression (BDI: Beck Depression Inventory) scores were compared before and after a 12-week exercise programme. After the exercise programme, statistically significant decreases were found in interleukin-8 and neutrophil activating protein-78 levels in the home exercise group (P < 0.05). The education group showed a statistically significant increase in monocyte chemoattractant protein-1 level (P < 0.05). Functional score and global health score of EORTC QOL-C30 in the supervised exercise group and functional score of EORTC QOL-C30 in the home exercise group increased significantly after exercise programme (P < 0.05). BDI score was significantly lower in the supervised exercise group after the exercise programme (P < 0.05). Changes in angiogenesis and apoptosis-related molecules in the study groups suggest a possible effect of exercise on these parameters. Exercise programmes are safe and effective on quality of life and depression in breast cancer patients whose treatments are complete. PMID- 23731174 TI - A critical comparison of discrete-state and continuous models of recognition memory: implications for recognition and beyond. AB - Multinomial processing tree (MPT) models such as the single high-threshold, double high-threshold, and low-threshold models are discrete-state decision models that map internal cognitive events onto overt responses. The apparent benefit of these models is that they provide independent measures of accuracy and response bias, a claim that has motivated their frequent application in many areas of psychological science including perception, item and source memory, social cognition, reasoning, educational testing, eyewitness testimony, and psychopathology. Before appropriate conclusions about a given analysis can be drawn, however, one must first confirm that the model's assumptions about the underlying structure of the data are valid. The current review outlines the assumptions of several popular MPT models and assesses their validity using multiple sources of evidence, including receiver operating characteristics, direct model fits, and experimental tests of qualitative predictions. We argue that the majority of the evidence is inconsistent with these models and that, instead, the evidence supports continuous models such as those based on signal detection theory (SDT). Hybrid models that incorporate both SDT and MPT processes are also explored, and we conclude that these models retain the limitations associated with their threshold model predecessors. The potentially severe consequences associated with using an invalid model to interpret data are discussed, and a simple tutorial and model-fitting tool is provided to allow implementation of the empirically supported SDT model. PMID- 23731175 TI - Does heightening risk appraisals change people's intentions and behavior? A meta analysis of experimental studies. AB - Several theories construe risk appraisals as key determinants of decisions and actions, and this idea has been supported in correlational studies. However, correlational data cannot answer the question, "Does heightening risk appraisals change people's intentions and behavior?" The present review meta-analyzed experimental evidence in order to address this issue. We identified 4 elements of risk appraisal-risk perception, anticipatory emotion, anticipated emotion, and perceived severity-and located experiments that (a) engendered a statistically significant increase in risk appraisal among treatment compared to control participants and (b) measured subsequent intention or behavior. Heightening risk appraisals had effects of d+ = .31 (k = 217) and d+ = .23 (k = 93) on intention and behavior, respectively. There was evidence that the elements of risk appraisal combined to influence outcomes. For instance, heightening risk perceptions had larger effects on outcomes when anticipatory emotions or perceived severity was also increased. Crucially, risk appraisal effects were augmented by coping appraisals: Risk appraisals had larger effects on outcomes when response efficacy and self-efficacy were enhanced or when response costs were reduced. The largest effect sizes were observed when risk appraisals, response efficacy, and self-efficacy were simultaneously heightened (d+ = .98 and .45, for intention and behavior, respectively). These findings indicate that heightening risk appraisals changes intentions and behavior. However, the direct effects of risk appraisals were generally small. Exploiting synergies among the elements of risk appraisal, and between risk appraisals and coping appraisals, should make for more effective behavior change interventions. PMID- 23731176 TI - Ascending aortic aneurysm treatment with linear plication and external wrapping technique: mid-term results. AB - OBJECTIVE: The aim of this study is to assess mid-term outcomes of reduction aortoplasty and wrapping technique which is an alternative method to replacement of the aorta in ascending aortic aneurysms. We aimed to show the efficacy of this technique especially when used for patients with increased perioperative mortality or morbidity due to their concomitant pathologies. MATERIALS AND METHODS: From March 2009 to May 2011, 22 patients underwent reduction aortoplasty and wrapping for ascending aortic aneurysm. The study group consisted of 16 male and six female patients with a mean age of 68 +/- 13.1 years. Linear plication with wrapping was performed as concomitant surgery in 20 patients and as a primary procedure in two patients. The diameter of the aorta was measured using a computed tomography scan 12 months after surgery and was compared with the preoperative value. RESULTS: Mean aortic clamp and cardiopulmonary bypass times were 91.0 +/- 58.1 and 150.7 +/- 80.9 minutes, respectively. Mortality was 9.1%. In no case was the postoperative death related to the aortoplasty procedure. The mean postoperative ascending diameter was 29.5 +/- 1.04 mm (vs. preoperative 49.1 +/- 4.1 mm, p < 0.001). Mean follow-up time was 17.2 +/- 8.88 months. During the follow-up period we observed that there were no findings to suggest redilatation. CONCLUSION: Linear plication with external wrapping is a therapeutic option with promising mid-term results, in carefully selected, high surgical risk patients with an ascending aortic aneurysm. PMID- 23731177 TI - Parasympathetic vasoactive intestinal peptide (VIP): a likely contributor to clozapine-induced sialorrhoea. AB - OBJECTIVE: The parasympathetic transmitter vasoactive intestinal peptide (VIP) increases salivary gland blood flow and evokes protein secretion and, in some species, such as rats, a small fluid secretion. It interacts synergistically with muscarinics for protein and fluid output. Human salivary acini are supplied with VIP-containing nerves. We hypothesise that VIP and clozapine, acting together, evoke a volume of saliva greater than the sum of those induced by each drug given separately. It was further considered whether, in the current test situation, circulatory events influenced the magnitude of the secretory response. MATERIAL AND METHODS: Saliva from parotid glands deprived of their autonomic innervation, and saliva and blood from innervated submandibular glands were collected in adrenoceptor antagonist-pretreated pentobarbitone-anaesthetised rats. Initially, the individual and then the combined effects of intravenous doses of VIP and clozapine were established. RESULTS: The submandibular volume response to the combination was 2-3 times higher, while blood pressure and glandular blood flow did not differ from those to VIP alone. The synergism occurred independent of nerves as shown in denervated parotid glands. CONCLUSIONS: From the current preclinical data, we speculate that VIP of parasympathetic origin, by its synergistic interaction with clozapine, may contribute to the clozapine (muscarinic M1-receptor)-induced sialorrhoea in schizophrenics. PMID- 23731178 TI - [3,3]-Sigmatropic rearrangement versus carbene formation in gold-catalyzed transformations of alkynyl aryl sulfoxides: mechanistic studies and expanded reaction scope. AB - Gold-catalyzed intramolecular oxidation of terminal alkynes with an arenesulfinyl group as the tethered oxidant is a reaction of high impact in gold chemistry, as it introduced to the field the highly valued concept of gold carbene generation via alkyne oxidation. The proposed intermediacy of alpha-oxo gold carbenes in these reactions, however, has never been substantiated. Detailed experimental studies suggest that the involvement of such reactive intermediates in the formation of dihydrobenzothiepinones is highly unlikely. Instead, a [3,3] sigmatropic rearrangement of the initial cyclization intermediate offers a reaction path that can readily explain the high reaction efficiency and the lack of sulfonium formation. With internal alkyne substrates, however, the generation of a gold carbene species becomes competitive with the [3,3]-sigmatropic rearrangement. This reactive intermediate, nevertheless, does not proceed to afford the Friedel-Crafts-type cyclization product. Extensive density functional theory studies support the mechanistic conclusion that the cyclized product is formed via an intramolecular [3,3]-sigmatropic rearrangement instead of the previously proposed Friedel-Crafts-type cyclization. With the new mechanistic insight, the product scope of this versatile formation of mid-sized sulfur containing cycloalkenones has been expanded readily to various dihydrobenzothiocinones, a tetrahydrobenzocyclononenone, and even those without the entanglement of a fused benzene ring. Besides gold, Hg(OTf)2 can be an effective catalyst, thereby offering a cheap alternative for this intramolecular redox reaction. PMID- 23731179 TI - Coupling supported lipid bilayer electrophoresis with matrix-assisted laser desorption/ionization-mass spectrometry imaging. AB - Herein, we describe a new analytical platform utilizing advances in heterogeneous supported lipid bilayer (SLB) electrophoresis and matrix-assisted laser desorption/ionization-mass spectrometry (MALDI-MS) imaging. This platform allowed for the separation and visualization of both charged and neutral lipid membrane components without the need for extrinsic labels. A heterogeneous SLB was created using vesicles containing monosialoganglioside GM1, disialoganglioside GD1b, POPC, as well as the ortho and para isomers of Texas Red-DHPE. These components were then separated electrophoretically into five resolved bands. This represents the most complex separation by SLB electrophoresis performed to date. The SLB samples were flash frozen in liquid ethane and dried under vacuum before imaging with MALDI-MS. Fluorescence microscopy was employed to confirm the position of the Texas Red labeled lipids, which agreed well with the MALDI-MS imaging results. These results clearly demonstrate this platform's ability to isolate and identify nonlabeled membrane components within an SLB. PMID- 23731180 TI - Mutant IDH1 enhances the production of 2-hydroxyglutarate due to its kinetic mechanism. AB - The human, cytosolic enzyme isocitrate dehydrogenase 1 (IDH1) reversibly converts isocitrate to alpha-ketoglutarate (alphaKG). Cancer-associated somatic mutations in IDH1 result in a loss of this normal function but a gain in a new or neomorphic ability to convert alphaKG to the oncometabolite 2-hydroxyglutarate (2HG). To improve our understanding of the basis for this phenomenon, we have conducted a detailed kinetic study of wild-type IDH1 as well as the known 2HG producing clinical R132H and G97D mutants and mechanistic Y139D and (newly described) G97N mutants. In the reductive direction of the normal reaction (alphaKG to isocitrate), dead-end inhibition studies suggest that wild-type IDH1 goes through a random sequential mechanism, similar to previous reports on related mammalian IDH enzymes. However, analogous experiments studying the reductive neomorphic reaction (alphaKG to 2HG) with the mutant forms of IDH1 are more consistent with an ordered sequential mechanism, with NADPH binding before alphaKG. This result was further confirmed by primary kinetic isotope effects for which saturating with alphaKG greatly reduced the observed isotope effect on (D)(V/K)NADPH. For the mutant IDH1 enzyme, the change in mechanism was consistently associated with reduced efficiencies in the use of alphaKG as a substrate and enhanced efficiencies using NADPH as a substrate. We propose that the sum of these kinetic changes allows the mutant IDH1 enzymes to reductively trap alphaKG directly into 2HG, rather than allowing it to react with carbon dioxide and form isocitrate, as occurs in the wild-type enzyme. PMID- 23731181 TI - Executive functioning in individuals with a history of ASDs who have achieved optimal outcomes. AB - Executive functioning (EF) is examined among children and adolescents once diagnosed with an autism spectrum disorder (ASD), but who no longer meet diagnostic criteria. These individuals have average social and language skills, receive minimal school support and are considered to have achieved "optimal outcomes" (OOs). Since residual impairments in these individuals might be expected in deficits central to autism, and in developmentally advanced skills, EF was examined in 34 individuals who achieved OOs, 43 individuals with high functioning autism (HFA), and 34 typically developing (TD) peers. Groups were matched on age (M = 13.49), gender, and nonverbal IQ (NVIQ) but differed on verbal IQ (VIQ; HFA < TD, OO). On direct assessment, all three groups demonstrated average EF; however, the OO and HFA groups exhibited more impulsivity and less efficient planning and problem-solving than the TD group, and more HFA participants exhibited below average inhibition than did OO and TD participants. Parent-report measures revealed average EF among the OO and TD groups; however, the OO group exhibited more difficulty than the TD group on set shifting and working memory. HFA participants demonstrated more difficulty on all parent-reported EF domains, with a clinical impairment in attention-shifting. Results suggest that EF in OO appears to be within the average range, even for functions that were impaired among individuals with HFA. Despite their average performance, however, the OO and TD groups differed on measures of impulsivity, set-shifting, problem-solving, working memory, and planning, suggesting that the OO group does not have the above-average EF scores of the TD group despite their high-average IQs. PMID- 23731182 TI - A sacro-caudal spinal cord choroid plexus papilloma in a shar-pei dog. AB - A seven-year-old shar-pei dog was referred because of severe lumbosacral pain and faecal incontinence of 20 days' duration. Neurological examination was characterised by plegic tail, absence of perineal reflex, dilated anus, perineum and tail analgesia, and severe lumbosacral pain. The neurological clinical signs were suggestive of a selective lesion involving sacral and caudal spinal cord segments and/or related nerve roots. A magnetic resonance imaging of lumbosacral spine was performed and was suggestive of an intradural lesion. Primary or secondary neoplasia was considered as the most probable differential diagnosis. The dog was euthanased upon the owner's request. Histopathological examination confirmed the presence of an intradural-extramedullary neoplastic tissue enveloping intradural tract of spinal nerve roots. On the basis of histological and immunohistochemical findings, a diagnosis of well-differentiated choroid plexus papilloma was made. To the authors's knowledge, this is the first case of primary or metastatic spinal choroid plexus papilloma in dogs. PMID- 23731184 TI - Colloidal luminescent silicon nanorods. AB - Silicon nanorods are grown by trisilane decomposition in hot squalane in the presence of tin (Sn) nanocrystals and dodecylamine. Sn induces solution-liquid solid nanorod growth with dodecylamine serving as a stabilizing ligand. As prepared nanorods do not luminesce, but etching with hydrofluoric acid to remove residual surface oxide followed by thermal hydrosilylation with 1-octadecene induces bright photoluminescence with quantum yields of 4-5%. X-ray photoelectron spectroscopy shows that the ligands prevent surface oxidation for months when stored in air. PMID- 23731183 TI - Use of theoretical peptide distributions in phosphoproteome analysis. AB - The high mass accuracy and resolution of modern mass spectrometers provides new opportunities to employ theoretical peptide distributions in large-scale proteomic studies. We used theoretical distributions to study noise filtering and mass measurement errors and to examine mass-based differentiation of phosphorylated and nonphosphorylated peptides. Only the monoisotopic mass of the experimental precursor ion was necessary for this analysis. We found that peak deviations can be used to characterize the modification states of peptides in a sample. When applied to large-scale proteomic data sets, the peak deviation distribution can be used to filter chemical/electronic noise for singly charged species. Using peak deviation distributions, it is possible to separate the phosphorylated peptides from the nonphosphorylated peptides, enabling evaluation of the phosphoproteome content of a sample. Because this approach is simple, with light computational requirements, the analysis of theoretical peptide distributions has a significant potential for application to phosphoproteome analyses. For our studies we used publicly available data sets from three large scale proteomic studies. PMID- 23731185 TI - What kind of memory has evolution wrought? Introductory article for the special issue of memory: adaptive memory: the emergence and nature of proximate mechanisms. AB - It is without question that our memory system evolved through a process of natural selection. However, basic research into the evolutionary foundations of memory has begun in earnest only recently. This is quite peculiar as the majority, perhaps even all, of memory research relates to whether memory is adaptive or not. In this Special Issue of Memory we have assembled a variety of papers that represent the cutting edge in research on the evolution of memory. These papers are centred on issues about the ultimate and proximate explanations of memory, the development of the adaptive functions of memory, as well as the positive consequences that arise from the current evolutionary form that our memory has taken. In this introductory article we briefly outline these different areas and indicate why they are vital for a more complete theory of memory. Further we argue that, by adopting a more applied stance in the area of the evolution of memory, one of the many future directions in this field could be a new branch of psychology that addresses questions in evolutionary legal psychology. PMID- 23731186 TI - Risky single-occasion drinking and disadvantaged men: will recruitment through primary care miss hazardous drinkers? AB - BACKGROUND: Men who are socially disadvantaged are at a substantially higher risk of developing alcohol-related diseases. People from deprived areas are known to be more difficult to recruit to research studies. As part of a feasibility assessment for an intervention study, 2 recruitment strategies were investigated. This article compares the drinking patterns of the disadvantaged men identified by the 2 strategies. METHODS: A cross-sectional survey compared 2 strategies for recruiting disadvantaged men to a study on alcohol consumption: recruitment through general practice (GP) registers and through a community outreach strategy, respondent-driven sampling (RDS). Men aged 25 to 44 years were recruited from deprived areas in the community. The entry criterion was binge drinking (>=8 units in a single session) at least twice in the previous 4 weeks. Demographic characteristics, total consumption of alcohol, frequency of binge drinking (>=8 units in a session), and heavy binge drinking (>=16 units in a session) were measured. RESULTS: Men recruited by RDS drank more than twice as much as the men recruited through GP (137 units in the previous 30 days compared with 62 units; p = 0.003). They also had many more binge drinking days: more than half (57%) of men from RDS had 6 or more binge drinking days in the previous 30 days, whereas only 16% of the GP sample had 6 or more binge drinking days (p = 0.001). Many more men recruited by RDS (37% vs. 5%; p = 0.002) had more than 5 very heavy drinking sessions in the previous month (>=16 units in a session). The RDS group also had fewer alcohol-free days. CONCLUSIONS: The 2 sampling strategies recruited different types of drinkers. The men recruited through RDS were much more likely to engage in frequent harmful drinking. The results indicate that the 2 methods recruit different samples of disadvantaged men. Intervention studies that are only conducted through primary care may miss many harmful drinkers. PMID- 23731187 TI - Near-IR spectrum of NO(X2Pi)-Xe: a joint experimental-theoretical investigation. AB - Employing the method of constant photon energy sum (CONPHOENERS) scans, we measure the near-IR spectrum of NO-Xe in the region of the first vibrational overtone of the NO monomer. Three bands are detected, which are assigned as the origin band located at 3722.60 cm(-1) and as bands with excitation of one quantum of z-axis rotation (3726.07 cm(-1)) and one quantum of bending vibration (3739.02 cm(-1)), respectively. The partially resolved rotational and electronic fine structures of the bands are analyzed with the help of a full quantum mechanical bound-state calculation using the ab initio potential energy surfaces of Klos et al. (J. Chem. Phys. 2012, 137, 014312/1-014312/14). We perform a linear least squares fit to the calculated energy levels to determine a set of spectroscopic constants that describe not only the overall rotation of the complex but also the electrostatic splitting due to the sum potential and the P-type doubling due to the difference potential. Using these results as guidance, we are able to simulate the experimental spectra. The comparison with the results from the theoretical treatment confirms the high quality of the ab initio treatment. The position of the excited bands is predicted with sub-wavenumber accuracy. Also, the rotational constants for all bands are found within less than 5%. Some differences are found for the amount of P-type doubling, which is overestimated by the theoretical treatment. Constants for the electrostatic splitting are in reasonable agreement for the origin band. Larger deviations are found for the vibrationally excited band, which points toward some inaccuracies in the potential energy surfaces. PMID- 23731189 TI - Pink discoloration of canned pears: role of procyanidin chemical depolymerization and procyanidin/cell wall interactions. AB - After canning, pear pieces turn occasionally from whitish-beige to pink. Conditions were set up to obtain this discoloration systematically and investigate its mechanism. Canned pears showed a significantly lower L* coordinate compared with fresh pears, and the L* coordinate of canned pears decreased with decreasing pH. The values of the a* and b* coordinates increased significantly after processing, the increase being greater for the more acidic pH values, with corresponding redder colors. After canning, polyphenol concentrations decreased significantly, mainly due to loss of procyanidins. This supported the hypothesis of conversion of procyanidins to anthocyanin-like compounds. However, no soluble product was detected at 520 nm, the characteristic wavelength of anthocyanins. When purified procyanidins were treated at 95 degrees C at three different pH values (2.7, 3.3, and 4.0), procyanidin concentrations decreased after treatment, the more so as the pH was lower, and a pinkish color also appeared, attributed to tannin-anthocyanidin pigment. The pink color was bound to cell walls. Extraction of the neoformed pink entities was attempted by successive solvent extractions followed by cell wall degrading enzymes. The pink color persisted in the residues, and canned pears gave significantly higher amounts of residues after solvent and enzyme treatments than fresh pears. Procyanidins were the entities responsible for the appearance of pink discoloration. However, it seems that this pink discoloration also involved the formation of strong, probably covalent, bonds to the cell wall. PMID- 23731190 TI - Dual neurohormonal intervention in CV disease: angiotensin receptor and Neprilysin inhibition. AB - INTRODUCTION: Cardiovascular disease is the leading cause of death worldwide, accounting for 30% of all deaths, with elevated blood pressure probably the most important modifiable risk factor. Worldwide, elevated blood pressure is estimated to cause 7.5 million deaths, about 12.8% of the total of all annual deaths. New drugs with different efficacy and effectiveness to control cardiovascular and renal disease are always welcomed. AREAS COVERED: Adequate control of arterial hypertension is needed in order to reduce the consequences of cardiovascular and renal disease. A novel compound, LCZ696 , is currently in development based on the concept of comprising in the same entity a Neprilysin inhibitor, with a renin angiotensin-aldosterone system inhibitor, in this case an angiotensin receptor blocker. This review, performed in PubMed including the last five years under the keywords cited below, presents the available data about LCZ696, the first-in class angiotensin receptor Neprilysin inhibitor. EXPERT OPINION: Available data show that positive efficacy and a good tolerability profile of LCZ696 in the treatment of arterial hypertension as well as preliminary data indicate that it can also be useful in the treatment of cardiovascular disease. These data are particularly promising in the treatment of arterial hypertension. PMID- 23731191 TI - A simple method for the determination of fluoroquinolone residues in tilapia (Oreochromis niloticus) and pacu (Piaractus mesopotamicus) employing LC-MS/MS QToF. AB - The use of antimicrobials in livestock production is a powerful resource applied throughout the world to guarantee high yield and control bacterial diseases in aquaculture. However, residues of these substances in animal products represent a potential risk to consumer health when residue levels are above the established maximum residue limits (MRLs). Fluoroquinolones (FQs) are antimicrobials commonly used worldwide in aquaculture. The aim of this work was to develop and validate a simple analytical method for the simultaneous determination of norfloxacin, danofloxacin, enrofloxacin and ciprofloxacin levels in tilapia (Oreochromis niloticus) and pacu (Piaractus mesopotamicus) fillets using liquid chromatography tandem mass spectrometry (LC-MS/MS) quadrupole time of flight (QToF). The FQs were extracted from the fillets with 1% acetic acid-methanol and 1% acetic acid acetonitrile solutions using ultrasonic assistance. The clean-up was performed with hexane. Chromatographic separation was conducted in an XTerra RP18 column (2.1 * 150 mm, 5 um) at 25 degrees C with a flow of 0.2 mL min-1. The mobile phase consisted of 0.1% aqueous formic acid and acetonitrile, with gradient elution. The validation parameters for all FQs were linearity (>0.99), intra-day precision (CV of 1%-9%), inter-day precision (CV of 3%-17%), decision limit (63 126 ng g-1), detection capability (76 -152 ng g-1) and accuracy (90%-111%). The limit of quantification was lower than the MRL for each FQ, indicating that the method is suitable for the determination of the FQ levels in the fish fillets. The mass analyser of the QToF type was able to confirm the identities of the FQs with an error of the accuracy of the mass (reasons m/z) of less than 10 ppm. PMID- 23731193 TI - Acne--what counts! PMID- 23731192 TI - Development of thin-film composite forward osmosis hollow fiber membranes using direct sulfonated polyphenylenesulfone (sPPSU) as membrane substrates. AB - This study investigates a new approach to fabricate thin-film composite (TFC) hollow fiber membranes via interfacial polymerization for forward osmosis (FO) applications. Different degrees of sulfonation of polyphenylenesulfone (PPSU) were adopted as membrane substrates to investigate their impact on water flux. It has been established that the degree of sulfonation plays a role in both creating a macrovoid-free structure and inducing hydrophilicity to bring about higher water fluxes. The fabricated membranes exhibit extremely high water fluxes of 30.6 and 82.0 LMH against a pure water feed using 2.0 M NaCl as the draw solution tested under FO and pressure retarded osmosis (PRO) modes, respectively, while maintaining low salt reverse fluxes below 12.7 gMH. The structural parameter (S) displays remarkable decreases of up to 4.5 times as the membrane substrate is switched from a nonsulfonated to sulfonated one. In addition, the newly developed TFC-FO membranes containing 1.5 mol % sPPSU in the substrate achieves a water flux of 22 LMH in seawater desalination using a 3.5 wt % NaCl model solution and 2.0 M NaCl as the draw solution under the PRO mode. To the best of our knowledge, this value is the highest ever reported for seawater desalination using flat and hollow fiber FO membranes. The use of sulfonated materials in the FO process opens up a frontier for sustainable and efficient production of potable water. PMID- 23731194 TI - Acne treatment in the field: how guidelines and other sources can be included in daily practice. AB - BACKGROUND: Acne is a complex disease ranging from mild to very severe. Quality of life can be considerably affected although the impact on the quality of life does not necessarily correlate with the severity of the disease. AIM: To show how good external evidence can be used in individual treatment decisions. METHODS: Description of four typical case secenarios usining the recommendation of the recent evidence based guidelines and other sources. RESULTS: The four quite typical patients presented here (i) a young boy with comedonal acne; (ii) a young black girl with papulopustular acne; (iii) an older boy with conglobate acne; and (iv) a young women with postadolescent papulopustular acne give a range of the possible challenges a dermatologist may face. CONCLUSION: How can the best treatment be selected for our patients? By keeping a clear mind, using the available best evidence and taking of course into account individual factors. PMID- 23731188 TI - Tetraspanins as regulators of the tumour microenvironment: implications for metastasis and therapeutic strategies. AB - One of the hallmarks of cancer is the ability to activate invasion and metastasis. Cancer morbidity and mortality are largely related to the spread of the primary, localized tumour to adjacent and distant sites. Appropriate management and treatment decisions based on predicting metastatic disease at the time of diagnosis is thus crucial, which supports better understanding of the metastatic process. There are components of metastasis that are common to all primary tumours: dissociation from the primary tumour mass, reorganization/remodelling of extracellular matrix, cell migration, recognition and movement through endothelial cells and the vascular circulation and lodgement and proliferation within ectopic stroma. One of the key and initial events is the increased ability of cancer cells to move, escaping the regulation of normal physiological control. The cellular cytoskeleton plays an important role in cancer cell motility and active cytoskeletal rearrangement can result in metastatic disease. This active change in cytoskeletal dynamics results in manipulation of plasma membrane and cellular balance between cellular adhesion and motility which in turn determines cancer cell movement. Members of the tetraspanin family of proteins play important roles in regulation of cancer cell migration and cancer-endothelial cell interactions, which are critical for cancer invasion and metastasis. Their involvements in active cytoskeletal dynamics, cancer metastasis and potential clinical application will be discussed in this review. In particular, the tetraspanin member, CD151, is highlighted for its major role in cancer invasion and metastasis. LINKED ARTICLES: This article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-24. PMID- 23731195 TI - A double-blind, randomized, vehicle-controlled efficacy assessment study of a skin care formulation for improvement of mild to moderately severe acne. AB - BACKGROUND: Inflammation, increased sebum production and P. acnes colonization are key factors in acne pathogenesis. Cosmetic formulations based on a combination of active compounds with in vitro proven anti-inflammatory, sebum regulating and P. acnes reducing properties may therefore contribute to improve the clinical signs and associated burden of disease. OBJECTIVE: To provide in vivo proof-of-concept, we performed a 9-week, double-blind, randomized, vehicle controlled study to assess the stand-alone efficacy of a skin care formulation containing licochalcone A, l-carnitine and 1,2-decanediol in volunteers with mild to moderately severe acne (10-25 inflammatory lesions) involving the face. MATERIALS AND METHODS: After enrolment followed by a 1-week standardization of the cleansing procedure, 60 volunteers aged 14-40 years (40 women and 20 men, mean age 22.4 years) were randomized into two groups of 30 volunteers each, to apply either the active formulation or the vehicle twice daily on the face for 8 weeks. Reduction in the lesion count, P. acnes and sebum levels, stratum corneum hydration, Dermatology Life Quality Index (DLQI) and skin tolerability, assessed after 4 and 8 weeks were defined as outcomes. RESULTS: Compared to baseline, the active formulation group showed at the end of the study a reduction in the mean total lesions count and papular lesions, significant reduction in the pustules (P < 0.05) and sebum levels (P < 0.01), marked reduction in P. acnes and improvement of DLQI. No significant changes in the respective parameters were found in the vehicle group. At the end of the study, greater reduction in the total lesion count, papules and pustules, P. acnes colonization, sebum production and more pronounced improvement of life quality in the active formulation group compared to the vehicle were found. CONCLUSIONS: Our results provide evidence for improved outcomes in result of the application of the active formulation compared to the vehicle from both physician's and patient's perspective. PMID- 23731196 TI - Characterization of IBS-like symptoms in patients with ulcerative colitis in clinical remission. AB - BACKGROUND: Gastrointestinal symptoms compatible with Irritable Bowel Syndrome (IBS) are common in patients with inflammatory bowel disease. It has been suggested that these symptoms are a reflection of occult inflammation rather than coexisting IBS. The aim of this study was to characterize IBS-like symptoms in patients with Ulcerative Colitis (UC) in clinical remission by assessing inflammatory markers, psychological symptoms, and quality of life. METHODS: Ninety-four patients with new onset of UC were followed prospectively during 3 years with yearly follow-up visits. The patients completed self-administrated questionnaires. Fecal calprotectin was used as an inflammatory biomarker. Remission was defined as a total Mayo-score <=2 and an endoscopic subscore <=1, with no relapse during the 3-month period prior to visit. KEY RESULTS: The prevalence of patients that fulfilled Rome II criteria for IBS among UC patients in remission was 11% at visit 1, 23% at visit 2, and 17% at visit 3. When comparing UC patients in remission with and without IBS-like symptom, patients with IBS-like symptoms had more severe gastrointestinal symptoms, tendencies toward more severe psychological symptoms and reduced levels of quality of life, but the calprotectin levels did not differ between the two groups. CONCLUSIONS & INFERENCES: IBS-like symptoms are common in patients with UC in clinical remission and these fluctuate over time. The symptoms are associated with poor psychological well-being and reduced quality of life, and do not seem to be a reflection of low-grade inflammatory activity. PMID- 23731197 TI - Efficacy of a supersaturated calcium phosphate oral rinse for the prevention and treatment of oral mucositis in patients receiving high-dose cancer therapy: a review of current data. AB - Oral mucositis (OM) is a painful and debilitating complication of cancer therapy that can adversely affect patients' treatment regimens and quality of life. It is also considered to be a substantial burden on the financial and human resources of health services. Despite progress in the understanding of the pathophysiology of OM and the number of new treatments that have been developed, there remains an unmet need for effective preventative measures in clinical practice. Literature on oral healthcare management in oncology patients suggests that a preventative approach consisting of a supersaturated Ca2+ / PO4(3-) oral rinse (Caphosol((r))) aimed at maintaining oral hygiene, moistening and lubricating the oral cavity, effectively reduces the incidence and severity of OM. This review looked at data from all known adult and paediatric studies investigating the use of Caphosol((r)) in patients receiving high-dose cancer therapy in order to evaluate its efficacy for both the prevention and treatment of OM. Thirty studies were identified. The majority of these studies (n = 24) found Caphosol((r)) to be efficacious at reducing the grade and/or duration, as well as pain associated with OM. Despite important limitations, these data warrant serious consideration for the inclusion of Caphosol((r)) in regimens for preventing or reducing the debilitating effects of OM. PMID- 23731198 TI - Plant cell gravisensitivity and adaptation to microgravity. AB - A short overview on the effects of real and simulated microgravity on certain cell components and processes, including new information obtained recently, is presented. Attention is focused on the influence of real and simulated microgravity on plant cells that are not specialised to gravity perception and on seed formation. The paper considers the possibility of full adaptation of plants to microgravity, and suggests some questions for future plant research in order to make decisions on fundamental and applied problems of plant space biology. PMID- 23731199 TI - Reply: Cost and returns related to medical education in rural and remote locations. PMID- 23731200 TI - Does midline shift predict postoperative nausea in brain tumor patients undergoing awake craniotomy? A retrospective analysis. AB - BACKGROUND: The presence of midline shift on neuroradiologic studies in brain tumor patients represents mass effect from the tumor and surrounding edema. We hypothesized that baseline cerebral edema as measured by midline shift would increase postoperative nausea (PON). We studied the incidence of PON in brain tumor patients, with and without midline shift on preoperative magnetic resonance (MRI) or computed tomographic (CT) imaging, undergoing awake craniotomy. METHODS: After IRB approval, we retrospectively extracted data from perioperative records between January 2005 and December 2010. Post-craniotomy nausea and pain scores were collected. Intraoperative anti-emetic, anesthetic, and analgesic regimens were assessed. Both the rescue anti-emetic and cumulative postoperative analgesic requirements were collected up to 12 hours postoperatively. The amount of midline shift on preoperative neuroimaging was gathered from radiology reports. Univariate comparisons between groups (no midline shift vs. midline shift) were made with t-tests for continuous variables, and chi-square tests for categorical variables. A multivariable analysis was performed to identify predictors of postoperative nausea. Limitations of this study include the retrospective design and the inability to gather accurate data regarding vomiting from the medical record. RESULTS: Data from 386 patients were available for analysis. Patients were divided into two groups: no midline shift (n = 283) and midline shift (n = 103). The mean midline shift distance was 5.96 mm (95% CI [5.32, 6.59]). There was no difference in the incidence of nausea or pain scores between the two groups. More malignant brain tumor patients were in the midline shift group, as determined by the postoperative histopathological diagnosis (P < 0.05). Patients in the midline shift group also had longer anesthesia and surgical times (P < 0.05). CONCLUSION: In patients undergoing a standardized anesthetic for awake craniotomy for tumor resection, the presence of preoperative midline shift did not correlate with postoperative nausea. PMID- 23731201 TI - Comparison of postoperative nausea between benign and malignant brain tumor patients undergoing awake craniotomy: a retrospective analysis. AB - BACKGROUND: Benign and malignant brain tumors have different histopathological characteristics, including different degrees of tissue infiltration and inflammatory response. The aim of this retrospective study was to compare the incidence of postoperative nausea between the two categories of brain tumors in patients undergoing awake craniotomy. METHODS: After IRB approval, we retrospectively extracted data from perioperative records between January 2005 and December 2010. Patients were divided based on the postoperative histopathological diagnosis into two groups, benign and malignant. The incidence of nausea, rescue anti-emetics, pain scores and postoperative analgesic requirements were compared between the two groups up to 12 hours postoperatively. Intraoperative anti-emetic, anesthetic, and analgesic regimens were also assessed. Limitations of this study include the retrospective design, the arbitrary dichotomization of tumors as benign or malignant, and the inability to gather accurate data regarding vomiting from the medical record. RESULTS: Data from 415 patients were available for analysis, with 115 patients in the benign group and 300 patients in the malignant tumor group. A higher postoperative mean pain score was found in the benign brain tumor group compared to the malignant brain tumor group (P < 0.05). However, there was no difference in the incidence of nausea between the two groups. CONCLUSION: The different histopathological characteristics of brain tumors have no association with postoperative nausea in patients undergoing awake craniotomy. Patients with benign brain tumors experience more pain than patients with malignant brain tumors. This difference in postoperative pain may be due to the younger age of the patients in the benign group. PMID- 23731202 TI - Quantum dot light-emitting diode with quantum dots inside the hole transporting layers. AB - We report a hybrid, quantum dot (QD)-based, organic light-emitting diode architecture using a noninverted structure with the QDs sandwiched between hole transporting layers (HTLs) outperforming the reference device structure implemented in conventional noninverted architecture by over five folds and suppressing the blue emission that is otherwise observed in the conventional structure because of the excess electrons leaking towards the HTL. It is predicted in the new device structure that 97.44% of the exciton formation takes place in the QD layer, while 2.56% of the excitons form in the HTL. It is found that the enhancement in the external quantum efficiency is mainly due to the stronger confinement of exciton formation to the QDs. PMID- 23731203 TI - Mechanisms of lactone hydrolysis in acidic conditions. AB - The acid-catalyzed hydrolysis of linear esters and lactones was studied using a hybrid supermolecule-polarizable continuum model (PCM) approach including up to six water molecules. The compounds studied included two linear esters, four beta lactones, two gamma-lactones, and one delta-lactone: ethyl acetate, methyl formate, beta-propiolactone, beta-butyrolactone, beta-isovalerolactone, diketene (4-methyleneoxetan-2-one), gamma-butyrolactone, 2(5H)-furanone, and delta valerolactone. The theoretical results are in good quantitative agreement with the experimental measurements reported in the literature and also in excellent qualitative agreement with long-held views regarding the nature of the hydrolysis mechanisms at molecular level. The present results help to understand the balance between the unimolecular (A(AC)1) and bimolecular (A(AC)2) reaction pathways. In contrast to the experimental setting, where one of the two branches is often occluded by the requirement of rather extreme experimental conditions, we have been able to estimate both contributions for all the compounds studied and found that a transition from A(AC)2 to A(AC)1 hydrolysis takes place as acidity increases. A parallel work addresses the neutral and base-catalyzed hydrolysis of lactones. PMID- 23731204 TI - Left atrial ejection fraction assessed by real-time 3-dimensional echocardiography in normal dogs and dogs with myxomatous mitral valve disease. AB - BACKGROUND: Real-time 3-dimensional (RT3D) echocardiography provides a novel technique for assessing left atrial ejection fraction (LAEF) in dogs. HYPOTHESIS: Left atrial ejection fraction is associated with severity of myxomatous mitral valve disease (MMVD). ANIMALS: Privately owned dogs; 101 with MMVD and 52 healthy control dogs. METHODS: Prospective observational study using RT3D echocardiographic estimations of LA volumes at atrial end-diastole and atrial end systole to calculate LAEF in comparison with conventional 2-dimensional echocardiographic variables. RESULTS: Left atrial ejection fraction decreased with increasing LA to aortic ratio (LA/Ao), percentage increase in left ventricular (LV) internal dimension, corrected for body weight (BW), in diastole (LVIDd inc%) and systole (LVIDs inc%), and age for MMVD dogs, and with BW for control dogs. The final models in the multiple regression analyses included LVIDd inc% and age for MMVD dogs, and BW alone for control dogs. LAEF varied widely in both MMVD dogs and control dogs. CONCLUSION AND CLINICAL IMPORTANCE: The wide variation of LAEF and the fact that LAEF does not appear to be an independent marker of disease severity suggest that the clinical importance of determining LAEF in dogs with MMVD might be limited. PMID- 23731205 TI - Chronic sleep disturbances and borderline personality disorder symptoms. AB - OBJECTIVE: Few studies have examined the experience of chronic sleep disturbances in those with borderline personality disorder (BPD), and further establishing this association may be pertinent to enhancing current treatments, given the relevance of sleep to emotion regulation and stress management. METHOD: Data were analyzed (N = 5,692) from Part II of the National Comorbidity Survey-Replication (NCS-R) sample (Kessler & Merikangas, 2004), which assessed personality disorders and sleep problems. Rates of chronic sleep disturbances (difficulty initiating sleep, difficulty maintaining sleep, and waking earlier than desired), as well as the consequences of poor sleep, were examined. Indices for BPD diagnosis and symptoms were used in logistic and linear regression analyses to predict sleep and associated problems after accounting for chronic health problems, Axis I comorbidity, suicidal ideation over the last year, and key sociodemographic variables. RESULTS: BPD was significantly associated with all 3 chronic sleep problems assessed, as well as with the consequences of poor sleep. The magnitude of the association between BPD and sleep problems was comparable to that for Axis I disorders traditionally associated with sleep problems. BPD symptoms interacted with chronic sleep problems to predict elevated social/emotional, cognitive, and self-care impairment. CONCLUSIONS: Sleep disturbances are consistently associated with BPD symptoms, as are the daytime consequences of poor sleep. There may also be a synergistic effect where BPD symptoms are aggravated by poor sleep and lead to higher levels of functional impairment. Sleep in patients with BPD should be routinely assessed, and ameliorating chronic sleep problems may enhance treatment by improving emotion regulation and implementation of therapeutic skills. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23731206 TI - Real-time monitoring of intracellular cAMP during acute ethanol exposure. AB - BACKGROUND: In previous studies, we have shown that ethanol (EtOH) enhances the activity of stimulatory G protein (Gs)-stimulated membrane-bound adenylyl cyclase (AC). The effect is AC isoform specific, and the type 7 AC (AC7) is most responsive to EtOH. In this study, we employed a fluorescence resonance energy transfer (FRET)-based cyclic AMP (cAMP) sensor, Epac1-camps, to examine real-time temporal dynamics of EtOH effects on cAMP concentrations. To our knowledge, this is the first report on real-time detection of the EtOH effect on intracellular cAMP. METHODS: Hela cells were transfected with Epac1-camps, dopamine (DA) receptor D1a , and 1 isoform of AC (AC7 or AC3). Fluorescent images were captured using a specific filter set for cyan fluorescent protein (CFP), yellow fluorescent protein (YFP), and FRET, respectively, and FRET intensity was calculated on a pixel-by-pixel basis to examine changes in cAMP. RESULTS: During 2-minute stimulation with DA, the cytoplasmic cAMP level quickly increased and then decreased to a plateau, where the cAMP level was higher than the level prior to stimulation with DA. EtOH concentration dependently increased cytoplasmic cAMP in cells transfected with AC7, while EtOH did not have effect on cells transfected with AC3. Similar trends were observed for cAMP at the plasma membrane and in the nucleus during 2-minute stimulation with DA. Unexpectedly, when cells expressing AC7 were stimulated with DA or other Gs-coupled receptor's ligand plus EtOH for 5 seconds, EtOH reduced cAMP concentration. CONCLUSIONS: These results suggest that EtOH has 2 opposing effects on the cAMP-generating system in an AC isoform-specific manner, the enhancing effect on AC activity and the short-lived inhibitory effect. Thus, EtOH may have a different effect on cAMP depending on not only AC isoform but also the duration of exposure. PMID- 23731207 TI - Conflicts of interest and the quality of recommendations in clinical guidelines. AB - BACKGROUND: There is increasing concern that conflicts of interest affect the development process of clinical practice guidelines. We evaluated The American Psychiatric Association's Practice Guideline for the Treatment of Patients with Major Depressive Disorder to determine the existence of financial and intellectual conflicts of interest and examine their possible effects. We selected this guideline because of its influence on clinical practice and because this guideline recommends pharmacotherapy for all levels of depression, despite controversies over the evidence base. METHODS AND FINDINGS: We determined the number and type of financial conflicts of interest for members of the guideline development group as well as for the independent panel charged with mitigating any effect of these conflicts. We also quantified the potential for intellectual conflicts of interest. We examined the quality of references used to support recommendations, as well as the degree of congruence between the research results and the recommendations. Fewer than half (44.4%) of the studies supporting the recommendations met criteria for high quality. Over one-third (34.2%) of the cited research did not study outpatients with major depressive disorder, and 17.2% did not measure clinically relevant results. One-fifth (19.7%) of the references were not congruent with the recommendations. Financial ties to industry were disclosed by all members (100%) of the guideline development committee with members reporting a mean 20.5 relationships (range 9-33). The majority of the committee participated on pharmaceutical companies' speakers' bureaus. Members of the independent panel that reviewed the guidelines for bias had undeclared financial relationships. As a marker of intellectual conflict of interest, 9.1% of all cited research and 13% of references supporting the recommendations were co-authored by the six guideline developers. CONCLUSIONS: The prevalence of conflicts of interest among panel members was high. The quality of the evidence cited raises questions about the validity of the recommendations. Attention to the quality of cited studies and to the risk of bias resulting from conflicts of interest should be a priority for guideline development groups. PMID- 23731208 TI - Shedding of soluble epidermal growth factor receptor (sEGFR) is mediated by a metalloprotease/fibronectin/integrin axis and inhibited by cetuximab. AB - Soluble epidermal growth factor receptor (sEGFR) is a circulating serum biomarker in cancer patients. Recent studies suggest that baseline serum sEGFR concentrations may predict responsiveness to EGFR-targeted therapy. Here, we demonstrate that sEGFR is generated through proteolytic cleavage of a cell surface precursor of an alternately spliced EGF receptor isoform and that sEGFR binds to EGF with high affinity. Proteolytic cleavage is stimulated by an anti alpha5/beta1 integrin antibody and 4-aminophenylmercuric acetate, and inhibited by fibronectin. Two FDA-approved therapeutic anti-EGFR antibodies also inhibit shedding of sEGFR, thus implicating the cell surface precursor of sEGFR as a competing target for anti-EGFR antibodies in human tissues. These observations parallel trastuzumab regulation of HER2 shedding and have implications for patient stratification in future clinical trials of EGFR-targeted antibodies. PMID- 23731209 TI - Verbal fluency in children with ADHD: strategy using and temporal properties. AB - Verbal fluency tasks are commonly used in cognitive and developmental neuropsychology in assessing executive functions, language skills as well as divergent thinking. Twenty-two typically developing children and 22 children with ADHD between the ages of 8 and 12 years were examined using verbal fluency tasks, prepotent response inhibition, and working memory tests. The clinical group showed impaired inhibitory and spatial working memory processes. We used different qualitative analyses of verbal fluency tasks to explore the lexical and executive strategies (word clustering and switching), and the temporal properties of the responses. Children with ADHD had a leeway in applying relevant lexical or executive strategies related to difficulties in strategy using. The reduced efficiency of children with ADHD in semantic fluency task is based on suboptimal shifting between word clusters and is related to the lack of ability of producing new clusters of items. The group difference appeared at the level of accessing and/or activating common words; however, the executive process of searching the lexicon extensively is intact. PMID- 23731210 TI - Use of negative contrast computed tomography for diagnosis of a colonic duplication in a dog. AB - A 24-week-old dog was presented with recurrent rectal prolapse because of colonic duplication. Colonic duplication is an extremely uncommon congenital abnormality, with only six cases reported in veterinary medicine, one diagnosed at necropsy and five after barium enema, colonoscopy, abdominal ultrasound, exploratory laparotomy either alone or in combination. In this case, these techniques failed to identify the abnormality and diagnosis was ultimately achieved via negative contrast computed tomography. The evaluation generated by the computed tomography images allowed a refined surgical approach. To the authors' knowledge, negative contrast computed tomography has not yet been reported in the veterinary literature to diagnose gastrointestinal pathologies. Colonic duplication in this case was treated by removal of the intercolonic septum via colotomy. PMID- 23731211 TI - Spectroscopy of colloidal semiconductor core/shell nanoplatelets with high quantum yield. AB - Free standing two-dimensional materials appear as a novel class of structures. Recently, the first colloidal two-dimensional heterostructures have been synthesized. These core/shell nanoplatelets are the first step toward colloidal quantum wells. Here, we study in detail the spectroscopic properties of this novel generation of colloidal nanoparticles. We show that core/shell CdSe/CdZnS nanoplatelets with 80% quantum yield can be obtained. The emission time trace of single core/shell nanoplatelets exhibits reduced blinking compared to core nanoplatelets with a two level emission time trace. At cryogenic temperatures, these nanoplatelets have a quantum yield close to 100% and a stable emission time trace. A solution of core/shell nanoplatelets has emission spectra with a full width half-maximum close to 20 nm, a value much lower than corresponding spherical or rod-shaped heterostructures. Using single particle spectroscopy, we show that the broadening of the emission spectra upon the shell deposition is not due to dispersity between particles but is related to an intrinsic increased exciton-phonon coupling in the shell. We also demonstrate that optical spectroscopy is a relevant tool to investigate the presence of traps induced by shell deposition. The spectroscopic properties of the core/shell nanoplatelets presented here strongly suggest that this new generation of objects will be an interesting alternative to spherical or rod-shaped nanocrystals. PMID- 23731212 TI - Moving pieces in a venomic puzzle: unveiling post-translationally modified toxins from Tityus serrulatus. AB - Besides being a public health problem, scorpion venoms have a potential biotechnological application since they contain peptides that may be used as drug leads and/or to reveal novel pharmacological targets. A comprehensive Tityus serrulatus venom proteome study with emphasis on the phosphoproteome and N glycoproteome was performed to improve our knowledge on the molecular diversity of the proteinaceous toxins. We combined two peptide identification methodologies, i.e., database search and de novo sequencing, to achieve a more comprehensive overview of the molecular diversity of the venoms. A total of 147 proteins were identified, including neurotoxins, enzymes, bradykinin-potentiating peptides, and molecules with antimicrobial and diuretic activities. Among those, three proteins were found to be phosphorylated, and one N-glycosylated. Finally, cleavage of toxin polypeptide chains seems to be a common post-translational modification in the venom since 80% of the identified molecules were, in fact, products of toxins proteolysis. PMID- 23731213 TI - Histotripsy effects on the bladder trigone: functional and histologic consequences in the canine model. AB - BACKGROUND: Histotripsy is an extracorporeal therapeutic ultrasound (US) technology, where high-amplitude acoustic energy is applied to targeted tissue. Previous research has demonstrated the feasibility, safety, and effectiveness of histotripsy tissue homogenization and debulking of the prostate in the canine model. Before translating this technology for human use, it is prudent to examine the susceptibility of critical periprostatic structures to cavitation injury in the event of histotripsy mistargeting. In this study, we sought to characterize the tissue effects and biologic response of directly treating the bladder trigone with histotripsy. MATERIALS AND METHODS: In eight anesthetized canines, 750,000 histotripsy pulses were applied uniformly across a 2*1.5-cm area encompassing the bladder trigone and ureteral orifices. Prostate and bladder trigone were harvested immediately after treatment (2 subjects) or at 14 days (6 subjects). Flexible cystourethroscopy, US imaging, and creatinine levels were obtained at intervals until harvest, 14 days after treatment. In one control subject, harvested at 2 days, the same treatment algorithm was applied to the prostate. RESULTS: Transrectal US imaging revealed a cavitation bubble cloud on the surface of the bladder trigone and progressive development of tissue edema during treatment. Flexible cystourethroscopy immediately after treatment confirmed edema and erythema of the trigone. In the six subjects survived 2 weeks after treatment, one incidence of transient, self-limited ureteral obstruction was noted based on hydronephrosis and creatinine levels. At harvest, ureteral orifices were confirmed patent by passage of a guide wire. Histologic evaluation revealed hemorrhage acutely with mild localized fibrosis at 14 days. CONCLUSIONS: In this study, designed along the lines of a worst-case, destructive testing scenario, direct targeting of the bladder trigone with supratherapeutic histotripsy failed to induce significant tissue damage or clinical complication. These results are reassuring and will guide treatment strategy in upcoming human clinical trials of histotripsy treatment for benign prostatic hyperplasia. PMID- 23731214 TI - Retrospective analysis of quality improvement throughput measures at a high volume community emergency department. AB - OBJECTIVE: To assess the effect of having a physician or physician's assistant (PA) as patients' first point of contact in our emergency department (ED) on the rate of leaving without being seen (LWBS) and wait time. METHODS: In before and after intervention conducted in the ED at a 265-bed community hospital, data were collected on all patients presenting to the ED during a 70-month period. A physician or PA was stationed in triage 16 hr a day. The screening process included measurement of vital signs, a brief history and physical examination, and computerized physician order entry. RESULTS: During the study period, volume increased from 86,000 to 102,000 patients per year. Monthly averages for ED visits increased 16%, admissions increased 5%, and ambulance visits increased 18%. The rate of LWBS decreased from 3.1% to 1.7%. Door-to-doctor time decreased by 14 min. CONCLUSIONS: Despite an increase in patient census, the LWBS rate and door-to-doctor time decreased. This study of one solution to the issue of ED crowding demonstrates how a process redesign can lead to successful changes in throughput metrics. PMID- 23731215 TI - Analysis of the gas phase reactivity of chlorosilanes. AB - Trichlorosilane is the most used precursor to deposit silicon for photovoltaic applications. Despite of this, its gas phase and surface kinetics have not yet been completely understood. In the present work, it is reported a systematic investigation aimed at determining what is the dominant gas phase chemistry active during the chemical vapor deposition of Si from trichlorosilane. The gas phase mechanism was developed calculating the rate constant of each reaction using conventional transition state theory in the rigid rotor-harmonic oscillator approximation. Torsional vibrations were described using a hindered rotor model. Structures and vibrational frequencies of reactants and transition states were determined at the B3LYP/6-31+G(d,p) level, while potential energy surfaces and activation energies were computed at the CCSD(T) level using aug-cc-pVDZ and aug cc-pVTZ basis sets extrapolating to the complete basis set limit. As gas phase and surface reactivities are mutually interlinked, simulations were performed using a microkinetic surface mechanism. It was found that the gas phase reactivity follows two different routes. The disilane mechanism, in which the formation of disilanes as reaction intermediates favors the conversion between the most stable monosilane species, and the radical pathway, initiated by the decomposition of Si2HCl5 and followed by a series of fast propagation reactions. Though both mechanisms are active during deposition, the simulations revealed that above a certain temperature and conversion threshold the radical mechanism provides a faster route for the conversion of SiHCl3 into SiCl4, a reaction that favors the overall Si deposition process as it is associated with the consumption of HCl, a fast etchant of Si. Also, this study shows that the formation of disilanes as reactant intermediates promotes significantly the gas phase reactivity, as they contribute both to the initiation of radical chain mechanisms and provide a catalytic route for the conversion between the most stable monosilanes. PMID- 23731217 TI - Co-treatment with quercetin and 1,2,3,4,6-penta-O-galloyl-beta-D-glucose causes cell cycle arrest and apoptosis in human breast cancer MDA-MB-231 and AU565 cells. AB - Breast cancer is the most universal cancer in women, but the medications for breast cancer usually cause serious side effects and offer no effective treatment for triple-negative breast cancer. Here, we investigated the growth inhibitory effects of gallic acid (GA), (-)-epigallocatechin gallate (EGCG), or 1,2,3,4,6 penta-O-galloyl-beta-D-glucose (5GG) combined with quercetin (Que) on breast cancer cells. In this study, we tested the combined effects of these compounds on estrogen receptor (ER)/human epidermal growth factor 2 (Her2)-negative (MDA-MB 231), ER-positive/Her2-negative (BT483), and ER-negative/Her2-positive (AU565) breast cancer cells. After treatment of each cell line with these compounds, we found that Que combined with 5GG induced S-phase arrest and apoptosis in MDA-BM 231 cells through downregulation of S-phase kinase protein 2 expression, but induced G2/M-phase arrest and apoptosis in AU565 cells through downregulation of Her2 expression. Additionally, Que combined with 5GG was more effective in inhibiting MDA-MB-231 cell growth than Que combined with EGCG (5GG analogue) or GA. The combination of 5GG and Que can offer great potential for the chemoprevention of ER-negative breast cancer. PMID- 23731218 TI - Moniliformin analysis in maize samples from North-West Italy using multifunctional clean-up columns and the LC-MS/MS detection method. AB - A fast clean-up method has been developed to purify maize extracts and to detect moniliformin (MON) in maize samples from North-West Italy over a four-year period (2008-2011). The method is based on the use of MycoSep(r) 240 Mon clean-up columns (Romer Labs(r)). Samples were extracted using acetonitrile/water (84:16, v/v), and the extracts were purified with previously described clean-up columns. The liquid chromatography-tandem mass spectrography (LC-MS/MS) analysis has been carried out by means of hydrophilic interaction chromatography (HILIC), combined with negative electrospray mass spectrometry. The method has a recovery of 76-91% (relative standard deviation, RSD%: 6-14%), a limit of detection (LOD) of 1 ug kg 1 and a limit of quantification (LOQ) of 4 ug kg-1. Naturally contaminated maize (108 samples) was analysed for MON content. The average percentages of positive samples was 93% with the following ranges (ug kg-1): 33-2606 (2008); 2 h = 0.021), greater for LBW babies, particularly for more than 2 h of SSC (Pinteraction = 0.050). CONCLUSION: Newhints successfully promoted the uptake of SSC in rural Ghana. Although findings are encouraging, promotion in rural community settings in sub-Saharan Africa is challenging. Lessons learned can help shape SSC promotion in efforts to increase adoption and save newborn lives. PMID- 23731229 TI - Restructuring transition metal oxide nanorods for 100% selectivity in reduction of nitric oxide with carbon monoxide. AB - Transition metal oxide is one of the main categories of heterogeneous catalysts. They exhibit multiple phases and oxidation states. Typically, they are prepared and/or synthesized in solution or by vapor deposition. Here we report that a controlled reaction, in a gaseous environment, after synthesis can restructure the as-synthesized transition metal oxide nanorods into a new catalytic phase. Co3O4 nanorods with a preferentially exposed (110) surface can be restructured into nonstoichiometric CoO1-x nanorods. Structure and surface chemistry during the process were tracked with ambient pressure X-ray photoelectron spectroscopy (AP-XPS) and environmental transmission electron microscopy (E-TEM). The restructured nanorods are highly active in reducing NO with CO, with 100% selectivity for the formation of N2 in temperatures of 250-520 degrees C. AP-XPS and E-TEM studies revealed the nonstoichiometric CoO1-x nanorods with a rock-salt structure as the active phase responsible for the 100% selectivity. This study suggests a route to generate new oxide catalysts. PMID- 23731230 TI - ?Y ahora que? Anticipated immigration status barriers and Latina/o high school students' future expectations. AB - Latina/o high school students without documentation face a challenging situation when they graduate from high school, with pathways to work and postsecondary education stymied by their immigration status. We examined the effects of anticipated barriers associated with immigration status, age, and sex on the dependent variables of vocational outcome expectations, anticipated external and internal barriers, and postsecondary schooling plans in a sample of 475 Latina/o high school students. Findings include that students anticipating immigration status problems had lower vocational outcome expectations and anticipated more external barriers to pursuing their postsecondary plans. Latina girls and older high school students anticipating immigration status problems were more likely to plan to attend 2-year rather than 4-year colleges, and less likely to plan on postsecondary education, respectively. Implications for practice, policy, and research are discussed. PMID- 23731231 TI - Investigation of the structural invariance of the Ethnic Identity Scale with Native American youth. AB - This study examined the structural invariance of the 17-item Ethnic Identity Scale (EIS; Umana-Taylor, Yazedjian, & Bamaca-Gomez, 2004) with a Native American sample. Participants were 144 students (55% female) enrolled in a Native American boarding school in the south-central U.S. Participants ranged in age from 13 to 19 years (M = 15.9, SD = 1.49). Confirmatory factor analysis was performed using maximum likelihood estimation. The original model was a poor fit for the data set. Removal of Items 1 and 2 and modeling the covariation between Items 6 and 11 resulted in an overall chi square value of Chi2(86, N = 144) = 152.21, p < .0001 (CFI = .936; RMSEA = .073; 90% CI on RMSEA = .054, .092), suggesting an acceptable fit. Substantial factor loadings were evident for the remaining 15 items. Analyses for the most part replicated Umana-Taylor, Yazedjian, and Bamaca Gomez's (2004) original 3-factor structure. We hypothesize that the minor differences between the present structure and that of Umana-Taylor et al. (2004) may be an artifact of this particular sample. PMID- 23731232 TI - Health consequences of racist and antigay discrimination for multiple minority adolescents. AB - Individuals who belong to a marginalized group and who perceive discrimination based on that group membership suffer from a variety of poor health outcomes. Many people belong to more than one marginalized group, and much less is known about the influence of multiple forms of discrimination on health outcomes. Drawing on literature describing the influence of multiple stressors, three models of combined forms of discrimination are discussed: additive, prominence, and exacerbation. The current study examined the influence of multiple forms of discrimination in a sample of African American lesbian, gay, or bisexual (LGB) adolescents ages 14-19. Each of the three models of combined stressors were tested to determine which best describes how racist and antigay discrimination combine to predict depressive symptoms, suicidal ideation, and substance use. Participants were included in this analysis if they identified their ethnicity as either African American (n = 156) or African American mixed (n = 120). Mean age was 17.45 years (SD = 1.36). Results revealed both forms of mistreatment were associated with depressive symptoms and suicidal ideation among African American LGB adolescents. Racism was more strongly associated with substance use. Future intervention efforts should be targeted toward reducing discrimination and improving the social context of multiple minority adolescents, and future research with multiple minority individuals should be attuned to the multiple forms of discrimination experienced by these individuals within their environments. PMID- 23731233 TI - Do measures commonly used in body image research perform adequately with African American college women? AB - This study examines reliability and validity estimates for 3 widely used measures in body image research in a sample of African American college women (N = 278). Internal consistency estimates were adequate (alpha coefficients above .70) for all measures, and evidence of convergent and discriminant validity was found. Confirmatory factor analyses failed to replicate the hypothesized factor structures of these measures. Exploratory factor analyses indicated that 4 factors found for the Sociocultural Attitudes Toward Appearance Questionnaire were similar to the hypothesized subscales, with fewer items. The factors found for the Multidimensional Body-Self Relations Questionnaire-Appearance Scales and the Body Dissatisfaction subscale of the Eating Disorders Inventory-3 were not similar to the subscales developed by the scale authors. Validity and reliability evidence is discussed for the new factors. PMID- 23731234 TI - A new hemostatic agent (Ankaferd Blood Stopper((r))) in tubeless percutaneous nephrolithotomy: a prospective randomized study. AB - PURPOSE: The present study evaluates the efficiency and reliability of a hemostatic agent ABS (Ankaferd Blood Stopper((r))) in tubeless percutaneous nephrolithotomy (PCNL). PATIENTS AND METHODS: A total of 90 patients were divided into two subgroups. The first group had ABS applied during the intervention, whereas the control group underwent regular tubeless PCNL in this prospective randomized study. Age, stone size, operative time, postoperative hemoglobin change, renal parenchyma thickness, postoperative ureteral catheter removal time, access number, nephroscope time, blood transfusion rate, serum creatinine change, complication rate, visual analogue scale (VAS), and hospitalization time were compared between the two groups. RESULTS: Preoperative and postoperative data obtained from both groups were compared. No statistically meaningful differences were found related to variables of mean age, stone size, access number, serum creatinine change, operative time, renal parenchyma thickness, VAS scores, and hospitalization period. Whereas the nephroscope time (minutes) was longer in the ABS group (Group 1 [G1]:3, 33+/-1, 72 vs G2:2, 62+/-1, 43, P=0.035), hemoglobin (Hb) decrease, and urine clarity time were statistically lower compared with the control group. Hb decrease was (mg/dL) (G1: 1.40+/-1.04 vs G2: 1.84+/-1.15, P=0.034), and urine clarity time was (hour) (G1: 9.60+/-5.50 vs G2: 11.95+/-4.71, P=0.012), respectively. Complications were encountered in three (6.6%) patients of the ABS group and in four (8.8%) of the control group. CONCLUSION: ABS is an efficient and reliable hemostatic agent in tubeless PCNL. Comparative studies are needed, however, with other hemostatic agents that might be applied in tubeless PCNL. PMID- 23731235 TI - Sustaining nurse-rapid HIV testing in the U.S. Department of Veterans Affairs: lessons learned from a comparative evaluation. AB - Routine HIV testing in primary care is now recommended in the United States. The U.S. Department of Veterans Affairs (VA) has increased the number of patients tested for HIV, but overall HIV testing rates remain low. A promising intervention for increasing HIV testing is nurse-initiated rapid testing (NRT). The purpose of this study was to build upon our previous research by implementing NRT in primary care clinics at two geographically distinct VA medical centers, and then conduct an evaluation to identify the barriers and facilitators to implementing and sustaining it. Semistructured telephone interviews were conducted with providers and stakeholders at two VA medical centers, one each on the East Coast and in the Southwest. Fieldnotes were developed following each interview and qualitatively coded for emerging themes. Findings indicate NRT was well integrated in both settings. NRT took little time to conduct, was well received by patients, and did not disrupt clinical scheduling. However, there were some sustainability challenges, including difficulties using the electronic medical record, and the challenges of new care practice structures. Implementing NRT is feasible in VA primary care settings. However, organizational challenges should be taken into account for subsequent efforts to implement NRT in VA primary care settings. PMID- 23731237 TI - Tracing the evolution of angucyclinone monooxygenases: structural determinants for C-12b hydroxylation and substrate inhibition in PgaE. AB - Two functionally distinct homologous flavoprotein hydroxylases, PgaE and JadH, have been identified as branching points in the biosynthesis of the polyketide antibiotics gaudimycin C and jadomycin A, respectively. These evolutionarily related enzymes are both bifunctional and able to catalyze the same initial reaction, C-12 hydroxylation of the common angucyclinone intermediate prejadomycin. The enzymes diverge in their secondary activities, which include hydroxylation at C-12b by PgaE and dehydration at C-4a/C-12b by JadH. A further difference is that the C-12 hydroxylation is subject to substrate inhibition only in PgaE. Here we have identified regions associated with the C-12b hydroxylation in PgaE by extensive chimeragenesis, focusing on regions surrounding the active site. The results highlight the importance of a hairpin-beta motif near the dimer interface, with two nonconserved residues, P78 and I79 (corresponding to Q89 and F90, respectively, in JadH), and invariant residue H73 playing key roles. Kinetic characterization of PgaE variants demonstrates that the secondary C-12b hydroxylation and substrate inhibition by prejadomycin are likely to be interlinked. The crystal structure of the PgaE P78Q/I79F variant at 2.4 A resolution confirms that the changes do not alter the conformation of the beta strand secondary structure and that the side chains of these residues in effect point away from the active site toward the dimer interface. The results support a catalytic model for PgaE containing two binding modes for C-12 and C-12b hydroxylations, where binding of prejadomycin in the orientation for C-12b hydroxylation leads to substrate inhibition. The presence of an allosteric network is evident based on enzyme kinetics. PMID- 23731236 TI - Inosine induces presynaptic inhibition of acetylcholine release by activation of A3 adenosine receptors at the mouse neuromuscular junction. AB - BACKGROUND AND PURPOSE: The role of inosine at the mammalian neuromuscular junction (NMJ) has not been clearly defined. Moreover, inosine was classically considered to be the inactive metabolite of adenosine. Hence, we investigated the effect of inosine on spontaneous and evoked ACh release, the mechanism underlying its modulatory action and the receptor type and signal transduction pathway involved. EXPERIMENTAL APPROACH: End-plate potentials (EPPs) and miniature end plate potentials (MEPPs) were recorded from the mouse phrenic-nerve diaphragm preparations using conventional intracellular electrophysiological techniques. KEY RESULTS: Inosine (100 MUM) reduced MEPP frequency and the amplitude and quantal content of EPPs; effects inhibited by the selective A3 receptor antagonist MRS-1191. Immunohistochemical assays confirmed the presence of A3 receptors at mammalian NMJ. The voltage-gated calcium channel (VGCC) blocker Cd(2+) , the removal of extracellular Ca(2+) and the L-type and P/Q-type VGCC antagonists, nitrendipine and omega-agatoxin IVA, respectively, all prevented inosine-induced inhibition. In the absence of endogenous adenosine, inosine decreased the hypertonic response. The effects of inosine on ACh release were prevented by the Gi/o protein inhibitor N-ethylmaleimide, PKC antagonist chelerytrine and calmodulin antagonist W-7, but not by PKA antagonists, H-89 and KT-5720, or the inhibitor of CaMKII KN-62. CONCLUSION AND IMPLICATIONS: Our results suggest that, at motor nerve terminals, inosine induces presynaptic inhibition of spontaneous and evoked ACh release by activating A3 receptors through a mechanism that involves L-type and P/Q-type VGCCs and the secretory machinery downstream of calcium influx. A3 receptors appear to be coupled to Gi/o protein. PKC and calmodulin may be involved in these effects of inosine. PMID- 23731238 TI - Dissociation of the fluorine molecule. AB - The primary purpose of the present study is to resolve the discrepancy that exists between the two most recently published dissociation energies for the fluorine molecule [D0(F2)] and, consequently, for the associated heats of formation of the fluorine atom [DeltafH0 degrees (F)]. We hope to provide a reliable, well-established theoretical estimate for these thermochemical quantities. To this end, a high-accuracy coupled-cluster-based composite ab initio model chemistry has been utilized. The protocol involves contributions of up to pentuple excitations in coupled-cluster theory augmented with basis set extrapolation techniques and additional corrections beyond the nonrelativistic and Born-Oppenheimer approximations. The augmented core-valence correlation consistent basis set families, aug-cc-pCVXZ, have been successively used, in some cases, up to octuple-zeta quality. Our best theoretical results for D0(F2) and DeltafH0 degrees (F) obtained in this study are 154.95 +/- 0.48 and 77.48 +/- 0.24 kJ/mol, respectively. Because conflicting theoretical results are also reported about the existence of a barrier along the dissociation curve of F2, extensive multireference configuration interaction and coupled-cluster calculations have been performed using reference orbitals taken from all-electron complete active space self-consistent field computations. Extrapolations from the results obtained with the aug-cc-pCVXZ (X = T, Q, 5) basis sets clearly indicate that the barrier indeed exists. It is located at 3.80 +/- 0.20 A along the dissociation curve with a height of 42 +/- 10 MUEh (~0.11 +/- 0.03 kJ/mol). Because of the neglect of this effect during the evaluation of the raw experimental data used to obtain D0(F2) = 154.52 +/- 0.12 kJ/mol and DeltafH0 degrees (F) = 77.26 +/- 0.06 kJ/mol [Stevens; et al. J. Phys. Chem. A 2010, 114, 13134], an additional error should be attached to these latter values. Obviously, the barrier does not affect either the experimental results, D0(F2) = 154.92 +/- 0.10 kJ/mol and DeltafH0 degrees (F) = 77.46 +/- 0.05 kJ/mol [Yang; et al. J. Chem. Phys. 2005, 122, 134308; 2007, 127, 209901], which are based on the ion pair dissociation of the molecule, or the data calculated theoretically. It is also noteworthy that our best estimates are in excellent agreement with those obtained from the ion-pair dissociation experiment. PMID- 23731239 TI - Ethnic identity, region and attitudes towards male circumcision in a high HIV prevalence country. AB - We study how considerations of male circumcision (MC) as both a favourable practice and as protective against HIV are linked with ethnicity in sub-Saharan Africa, where many ethnic groups do not traditionally circumcise. We focus on Malawi, a country with a high HIV prevalence but low MC prevalence. Survey data from a population-based random sample in rural Malawi (N =3400) were analysed for ethnoregional patterns in attitudes towards MC. We used logit regression models to measure how reported circumcision status, region of residence and ethnic identity relate to attitudes towards circumcision. Overall, Malawians reported more negative than positive opinions about MC, but attitudes towards circumcision varied by ethnicity and region. The implications for agencies and governments aggressively scaling up the provision of MC are clear; acceptance of circumcision as a tool for HIV prevention could be low in societies divided by ethnoregional identities that also shape the practice of circumcision. PMID- 23731240 TI - Elucidating the breathing of the metal-organic framework MIL-53(Sc) with ab initio molecular dynamics simulations and in situ X-ray powder diffraction experiments. AB - Ab initio molecular dynamics (AIMD) simulations have been used to predict structural transitions of the breathing metal-organic framework (MOF) MIL-53(Sc) in response to changes in temperature over the range 100-623 K and adsorption of CO2 at 0-0.9 bar at 196 K. The method has for the first time been shown to predict successfully both temperature-dependent structural changes and the structural response to variable sorbate uptake of a flexible MOF. AIMD employing dispersion-corrected density functional theory accurately simulated the experimentally observed closure of MIL-53(Sc) upon solvent removal and the transition of the empty MOF from the closed-pore phase to the very-narrow-pore phase (symmetry change from P2(1)/c to C2/c) with increasing temperature, indicating that it can directly take into account entropic as well as enthalpic effects. We also used AIMD simulations to mimic the CO2 adsorption of MIL-53(Sc) in silico by allowing the MIL-53(Sc) framework to evolve freely in response to CO2 loadings corresponding to the two steps in the experimental adsorption isotherm. The resulting structures enabled the structure determination of the two CO2-containing intermediate and large-pore phases observed by experimental synchrotron X-ray diffraction studies with increasing CO2 pressure; this would not have been possible for the intermediate structure via conventional methods because of diffraction peak broadening. Furthermore, the strong and anisotropic peak broadening observed for the intermediate structure could be explained in terms of fluctuations of the framework predicted by the AIMD simulations. Fundamental insights from the molecular-level interactions further revealed the origin of the breathing of MIL-53(Sc) upon temperature variation and CO2 adsorption. These simulations illustrate the power of the AIMD method for the prediction and understanding of the behavior of flexible microporous solids. PMID- 23731241 TI - HR-MAS NMR tissue metabolomic signatures cross-validated by mass spectrometry distinguish bladder cancer from benign disease. AB - Effective diagnosis and surveillance of bladder cancer (BCa) is currently challenged by detection methods that are of poor sensitivity, particularly for low-grade tumors, resulting in unnecessary invasive procedures and economic burden. We performed HR-MAS NMR-based global metabolomic profiling and applied unsupervised principal component analysis (PCA) and hierarchical clustering performed on NMR data set of bladder-derived tissues and identified metabolic signatures that differentiate BCa from benign disease. A partial least-squares discriminant analysis (PLS-DA) model (leave-one-out cross-validation) was used as a diagnostic model to distinguish benign and BCa tissues. Receiver operating characteristic curve generated either from PC1 loadings of PCA or from predicted Y-values resulted in an area under curve of 0.97. Relative quantification of more than 15 tissue metabolites derived from HR-MAS NMR showed significant differences (P < 0.001) between benign and BCa samples. Noticeably, striking metabolic signatures were observed even for early stage BCa tissues (Ta-T1), demonstrating the sensitivity in detecting BCa. With the goal of cross-validating metabolic signatures derived from HR-MAS NMR, we utilized the same tissue samples to analyze 8 metabolites through gas chromatography-mass spectrometry (GC-MS) targeted analysis, which undoubtedly complements HR-MAS NMR-derived metabolomic information. Cross-validation through GC-MS clearly demonstrates the utility of a straightforward, nondestructive, and rapid HR-MAS NMR technique for clinical diagnosis of BCa with even greater sensitivity. In addition to its utility as a diagnostic tool, these studies will lead to a better understanding of aberrant metabolic pathways in cancer as well as the design and implementation of personalized cancer therapy through metabolic modulation. PMID- 23731242 TI - Photodynamic therapy in the treatment of class II furcation: a randomized controlled clinical trial. AB - AIM: To investigate the effect of photodynamic therapy (PDT) as adjunct to mechanical therapy in furcations. MATERIALS AND METHODS: A double-blind, parallel, randomized controlled clinical trial was conducted in subjects presenting class II furcations. The subjects were randomly allocated to a test (PDT; n = 16) or control group (non-activated laser/only photosensitizer; n = 21). At baseline, 3 and 6 months, clinical, microbiological and cytokine pattern evaluation was performed. Clinical attachment level was defined as the primary outcome variable. RESULTS: Clinical parameters improved after both therapies (p < 0.05) with no differences between groups at any time point (p > 0.05). At 6 months, real-time PCR evaluation showed a decrease in Porphyromonas gingivalis and Tannerella forsythia only in the PDT group (p < 0.05) with no inter-group differences. Regarding cytokines, IL-4 and IL-10 levels increased in both groups at 6 months. GM-CSF, IL-8, IL-1beta and IL-6 levels decreased only in the PDT group after 3 months (p < 0.05). At 3 months, inter-group analyses showed that GM CSF, IFN-gamma, IL-6 and IL-8 levels were lower in the PDT group. At 6 months, lower IL-1beta levels were also observed in the PDT group (p < 0.05). CONCLUSION: Photodynamic therapy did not promote clinical benefits for class II furcations; however, advantages in local levels of cytokines and a reduction in periodontopathogens were demonstrated. PMID- 23731243 TI - Ultrasonographic findings of the pancreas in cats with elevated serum pancreatic lipase immunoreactivity. AB - BACKGROUND: Pancreatitis is a common disease in cats that is difficult to diagnose. HYPOTHESIS/OBJECTIVES: To determine the sensitivity and specificity of ultrasonographic changes of the pancreas with serum feline pancreatic lipase immunoreactivity (fPLI) as the standard for diagnosis of pancreatitis. ANIMALS: 35 cats with clinical signs consistent with pancreatitis with an abdominal ultrasound examination and serum fPLI concentration measured within 3 days of the ultrasound. METHODS: Retrospective study: Pancreatic thickness, pancreatic margination, pancreatic echogenicity, and peripancreatic fat echogenicity were evaluated. Sensitivity and specificity were calculated with an elevated serum fPLI concentration indicative of pancreatitis as the standard for diagnosis. RESULTS: Serum fPLI was elevated and diagnostic for pancreatitis in 19 of 35 cats. The single ultrasound characteristic with the highest sensitivity was hyperechoic peripancreatic fat at 68% (95% confidence interval = 44-87%), indicating a moderate probability that cats with pancreatitis will have this abnormality on ultrasonographic examination. Specificity was >90% for each of increased pancreatic thickness, abnormal pancreatic margin, and hyperechoic peripancreatic fat. The sensitivity and specificity of ultrasound were 84% (95% confidence interval = 60-97%) and 75% (95% confidence interval = 48-93%), respectively, in cats with elevated serum fPLI indicative of pancreatitis. CONCLUSIONS AND CLINICAL IMPORTANCE: The presence of a thick left limb of the pancreas, severely irregular pancreatic margins, and hyperechoic peripancreatic fat in cats with appropriate clinical signs and elevated serum fPLI are highly supportive of pancreatitis. PMID- 23731244 TI - Nonvacuum, maskless fabrication of a flexible metal grid transparent conductor by low-temperature selective laser sintering of nanoparticle ink. AB - We introduce a facile approach to fabricate a metallic grid transparent conductor on a flexible substrate using selective laser sintering of metal nanoparticle ink. The metallic grid transparent conductors with high transmittance (>85%) and low sheet resistance (30 Omega/sq) are readily produced on glass and polymer substrates at large scale without any vacuum or high-temperature environment. Being a maskless direct writing method, the shape and the parameters of the grid can be easily changed by CAD data. The resultant metallic grid also showed a superior stability in terms of adhesion and bending. This transparent conductor is further applied to the touch screen panel, and it is confirmed that the final device operates firmly under continuous mechanical stress. PMID- 23731245 TI - Monascin and AITC attenuate methylglyoxal-induced PPARgamma phosphorylation and degradation through inhibition of the oxidative stress/PKC pathway depending on Nrf2 activation. AB - Abnormal cellular accumulation of the dicarbonyl metabolite methylglyoxal (MG) results in cell damage, inflammation, and oxidative stress. It is also associated with increased protein linkage to form advanced glycation end products (AGEs) or induce DNA strand breaks. The association between peroxisome proliferator activated receptor-gamma (PPARgamma) and nuclear factor-erythroid 2-related factor 2 (Nrf2) is unclear. This study investigated Nrf2 activator protection against PPARgamma phosphorylation and degradation to maintain pancreatic function. MG was used at a noncytotoxic concentration (200 MUM) to induce protein kinase C (PKC) and PPARgamma phosphorylation in pancreatic RINm5F cells. For in vivo studies, MG (60 mg/kg bw) was intraperitoneally (IP) injected into Balb/C mice for 28 d to induce pancreas damage, at which point we investigated the effect of monascin protection (PPARgamma and Nrf2 activator), rosiglitazone (PPARgamma activator), allyl isothiocyanate (AITC; Nrf2 activator), or N acetylcysteine (NAC) on pancreatic function. The in vitro and in vivo results indicated that MG leads to marked PPARgamma phosphorylation (serine 82); this effect led to reduction in pancreatic and duodenal homeobox-1 (PDX-1), glucokinase (GCK), and insulin expression. However, monascin and rosiglitazone may protect PPARgamma degradation by elevating PDX-1, GCK, and as a result, insulin expression. Monascin and AITC can attenuate PKC activation to suppress PPARgamma phosphorylation caused by oxidative stress through the Nrf2 pathway. Similarly, the N-acetylcysteine (NAC) antioxidant also improved oxidative stress and pancreatic function. This study examined whether MG caused impairment of PDX 1, GCK, and insulin through PPARgamma phosphorylation and degradation. MG and AGE accumulation improved on Nrf2 activation, thereby protecting against pancreas damage. Taken together, PPARgamma activation maintained pancreatic PDX-1, GCK, and insulin expression levels to regulate blood glucose levels. PMID- 23731246 TI - Health-related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: results from the Pro-FEIBA study. AB - Patients with haemophilia A and inhibitors are at high risk for severe bleeding, progression of joint disease and deterioration of health-related quality of life (HRQoL). To determine the impact of prophylaxis with an activated prothrombin complex concentrate (aPCC) on HRQoL, HRQoL was assessed using the Short-Form (SF) 36 Health Survey and the EQ-5D questionnaire in subjects >= 14 years participating in a prospective, randomized, crossover study comparing 6 months of aPCC prophylaxis with 6 months of on-demand therapy. Eighteen of 19 patients completed the survey or questionnaire before and after the on-demand therapy and prophylaxis periods. A general trend towards improved HRQoL after prophylaxis was observed for the 18 evaluable patients in all SF-36 dimensions except for vitality/energy and physical functioning. After prophylaxis, 'good responders,' defined as patients experiencing >= 50% reduction in bleeding, exhibited statistically and clinically significant differences in the physical component score (P = 0.021), role - physical (P = 0.042), bodily pain (P = 0.015), and social functioning (P = 0.036). Similarly, the EQ-5D health profile showed a trend towards improvement after prophylaxis in all evaluable patients. Among the good responders, improvements did not differ from those observed after on-demand treatment. EQ visual analogue scale values were slightly improved following prophylaxis for all evaluable patients and the EQ-5D utility index improved in the good responders only. During prophylaxis, patients missed significantly fewer days from school or work because of bleeding than during on-demand treatment (P = 0.01). In conclusion, by significantly reducing bleeding frequency in good responders, aPCC prophylaxis improved HRQoL compared with on-demand treatment. PMID- 23731247 TI - NaBa2Cu3S5: a doped p-type degenerate semiconductor. AB - Mixed S(2-/)S(1-) oxidation states have been discovered in the new quaternary compound NaBa2Cu3S5. Synthesized from the reaction of Cu in a molten alkali metal/polysulfide flux, the compound crystallizes in monoclinic space group C2/m with a = 16.5363(7) A, b = 5.5374(5) A, c = 10.3717(10) A, beta = 98.535(8) degrees . The Na(+) Ba2(+2) [Cu(+)3S3](3-)S2(2-) crystal structure contains layers of edge sharing CuS4 tetrahedra and sheets of S2(2-) dimers. These layers are separated by mixed Ba/Na cation layers. The conductivity of the single crystals of NaBa2Cu3S5 is ~450 S cm(-1) at room temperature, and increasing conductivity with decreasing temperature is observed, indicating metallic behavior despite the optical band gap of 0.45 eV. A small positive thermopower (45-55 MUV K(-1) from 300 K to 500 K) and Hall effect measurements also confirm p type conductivity with carrier concentration at 200 K of ~1.6 * 10(21) cm(-3) and a hole mobility of ~2 cm(2) V(-1) s(-1). NaBa2Cu3S5 exhibits temperature independent Pauli paramagnetism. PMID- 23731248 TI - Citrate-free synthesis of silver nanoplates and the mechanistic study. AB - We report a citrate-free synthesis of Ag nanoplates with an edge length of 50 nm that involved the reduction of AgNO3 by poly(vinyl pyrrolidone) (PVP) in ethanol at 80 degrees C under a solvothermal condition. Within a period of 4 h, greater than 99% of the initially added AgNO3 could be converted into Ag nanoplates with excellent stability. To understand this remarkably simple and efficient process, we systematically investigated the roles played by various reaction parameters, which include the type of precursor, reducing powers of PVP and ethanol, molar ratio of PVP to AgNO3, solvent, involvement of O2, and effects of pressure and temperature. Our results suggest a plausible mechanism that involves (i) fast reduction of AgNO3 to generate Ag multiple twinned particles (MTPs) via a thermodynamically controlled process, (ii) kinetically controlled formation of plate-like seeds and their further growth into small nanoplates in the presence of Ag(+) ions at a low concentration, and (iii) complete transfer of Ag atoms from the MPTs to nanoplates via O2-mediated Ostwald ripening. We demonstrated that the molar ratio of PVP to AgNO3 in ethanol plays an essential role in controlling the reduction rate for the formation of MTPs and plate-like seeds under the solvothermal condition, transformation kinetics, and final morphology taken by the Ag nanoplates. In particular, when the reaction temperatures were above the boiling point of ethanol, the pressure induced by a solvothermal process accelerated the oxidative etching of Ag MTPs to facilitate their complete conversion into nanoplates. The mechanistic insight could serve as a guideline to optimize the experimental parameters of a solvothermal synthesis to control the reduction kinetics and thus the formation of metallic nanocrystals with controlled shapes and in high yields and large quantities. PMID- 23731249 TI - Microbial and functional diversity of a subterrestrial high pH groundwater associated to serpentinization. AB - Microbial and functional diversity were assessed, from a serpentinization-driven subterrestrial alkaline aquifer - Cabeco de Vide Aquifer (CVA) in Portugal. DGGE analyses revealed the presence of a stable microbial community. By 16S rRNA gene libraries and pyrosequencing analyses, a diverse bacterial composition was determined, contrasting with low archaeal diversity. Within Bacteria the majority of the populations were related to organisms or sequences affiliated to class Clostridia, but members of classes Acidobacteria, Actinobacteria, Alphaproteobacteria, Betaproteobacteria, Deinococci, Gammaproteobacteria and of the phyla Bacteroidetes, Chloroflexi and Nitrospira were also detected. Domain Archaea encompassed mainly sequences affiliated to Euryarchaeota. Only form I RuBisCO - cbbL was detected. Autotrophic carbon fixation via the rTCA, 3-HP and 3 HP/4H-B cycles could not be confirmed. The detected APS reductase alpha subunit - aprA sequences were phylogenetically related to sequences of sulfate-reducing bacteria belonging to Clostridia, and also to sequences of chemolithoautothrophic sulfur-oxidizing bacteria belonging to Betaproteobacteria. Sequences of methyl coenzyme M reductase - mcrA were phylogenetically affiliated to sequences belonging to Anaerobic Methanotroph group 1 (ANME-1). The populations found and the functional key markers detected in CVA suggest that metabolisms related to H2 , methane and/or sulfur may be the major driving forces in this environment. PMID- 23731251 TI - Perceptions of coronary heart disease: the development and psychometric testing of a measurement scale. AB - Individuals' perceptions of coronary heart disease (CHD) have implications for the ways in which they respond to the disease, process risks, make decisions, and take action to reduce CHD risks. This study aimed to develop and evaluate the psychometric properties of the perceptions of coronary heart disease scale (PCS) among a Hong Kong Chinese population. A cross-sectional study was conducted using a convenient sample (n = 232) of participants recruited from a variety of catchments including public domains, a cardiac unit, and a cardiac rehabilitation and prevention center. Exploratory factor analysis identified a nine-item, two factor model that accounted for 52.5% of the total explained variance. The two factors were the perceived risk (five items) and perceived seriousness (four items) of CHD. The PCS demonstrated good content validity; acceptable total, and subscale internal consistency (.73, .61 - .81); and significant contrast-group differences with higher levels of CHD perceptions among males (p = .002), younger participants (p < .001), and those with higher educational levels (p < .001), suggesting excellent construct validity. The newly developed PCS demonstrates acceptable psychometric properties as a short measurement scale, which supports its use in future research. Future validation of this scale is warranted. PMID- 23731250 TI - Inhibition of tumorigenesis by the thyroid hormone receptor beta in xenograft models. AB - BACKGROUND: Previous studies showed a close association between several types of human cancers and somatic mutations of thyroid hormone receptor beta (TRbeta) and reduced expression of TRbeta due to epigenetic inactivation and/or deletion of the THRB gene. These observations suggest that TRbeta could act as a tumor suppressor in carcinogenesis. However, the mechanisms by which TRbeta could function to inhibit tumorigenesis are less well understood. METHODS: We used the human follicular thyroid cancer cell lines (FTC-133 and FTC-236 cells) to elucidate how functional expression of the THRB gene could affect tumorigenesis. We stably expressed the THRB gene in FTC cells and evaluated the effects of the expressed TRbeta on cancer cell proliferation, migration, and tumor growth in cell-based studies and xenograft models. RESULTS: Expression of TRbeta in FTC-133 cells, as compared with control FTC cells without TRbeta, reduced cancer cell proliferation and impeded migration of tumor cells through inhibition of the AKT mTOR-p70 S6K pathway. TRbeta expression in FTC-133 and FTC-236 led to less tumor growth in xenograft models. Importantly, new vessel formation was significantly suppressed in tumors induced by FTC cells expressing TRbeta compared with control FTC cells without TRbeta. The decrease in vessel formation was mediated by the downregulation of vascular endothelial growth factor in FTC cells expressing TRbeta. CONCLUSIONS: These findings indicate that TRbeta acts as a tumor suppressor through downregulation of the AKT-mTOR-p70 S6K pathway and decreased vascular endothelial growth factor expression in FTC cells. The present results raise the possibility that TRbeta could be considered as a potential therapeutic target for thyroid cancer. PMID- 23731252 TI - Electrical failure of an ICD lead due to a presumed insulation defect only diagnosed by a maximum output shock. AB - A 55-year-old male patient presented after a single shock caused by oversensing of isolated nonphysiologic signals on both the distal HV and pace-sense channels. No other abnormalities were found. He subsequently returned complaining of device "vibration" and his St. Jude implantable defibrillator (ICD; St. Jude Medical, St. Paul, MN, USA) was found to be in VVI backup mode and could not be interrogated. Direct testing in the electrophysiology lab showed normal lead impedances and thresholds with an inability to reproduce the abnormal signals. Detailed cine fluoroscopy of the leads found no abnormalities. A new ICD was connected and successfully delivered a 20-joule shock but failed to deliver a maximum output (39-joule) shock. The new ICD was again found to be in backup mode. A new Endotak Reliance G lead (Boston Scientific, Natick, MA, USA) was implanted and a maximum-output shock was successful using a new Fortify DR ICD. This case likely represents a Durata lead insulation defect in the form of an inside-out abrasion under the distal HV coil. Increased awareness of this defect is warranted, particularly since routine interrogation and submaximum-output shocks may fail to detect the problem. PMID- 23731253 TI - Disengagement from care in a decentralised primary health care antiretroviral treatment programme: cohort study in rural South Africa. AB - OBJECTIVE: To determine rates of, and factors associated with, disengagement from care in a decentralised antiretroviral programme. METHODS: Adults (>=16 years) who initiated antiretroviral therapy (ART) in the Hlabisa HIV Treatment and Care Programme August 2004-March 2011 were included. Disengagement from care was defined as no clinic visit for 180 days, after adjustment for mortality. Cumulative incidence functions for disengagement from care, stratified by year of ART initiation, were obtained; competing-risks regression was used to explore factors associated with disengagement from care. RESULTS: A total of 4,674 individuals (median age 34 years, 29% male) contributed 13 610 person-years of follow-up. After adjustment for mortality, incidence of disengagement from care was 3.4 per 100 person-years (95% confidence interval (CI) 3.1-3.8). Estimated retention at 5 years was 61%. The risk of disengagement from care increased with each calendar year of ART initiation (P for trend <0.001). There was a strong association between disengagement from care and higher baseline CD4+ cell count (subhazard ratio (SHR) 1.94 (P < 0.001) and 2.35 (P < 0.001) for CD4+ cell count 150-200 cells/MUl and >200 cells/MUl respectively, compared with CD4 count <50 cells/MUl). Of those disengaged from care with known outcomes, the majority (206/303, 68.0%) remained resident within the local community. CONCLUSIONS: Increasing disengagement from care threatens to limit the population impact of expanded antiretroviral coverage. The influence of both individual and programmatic factors suggests that alternative service delivery strategies will be required to achieve high rates of long-term retention. PMID- 23731254 TI - Knowledge of and opinions on HIV preexposure prophylaxis among front-line service providers at Canadian AIDS service organizations. AB - Oral daily tenofovir/emtricitabine (Truvada) is approved in the United States for HIV preexposure prophylaxis (PrEP) but has generated controversy in the media and within HIV-affected communities. We conducted an online survey about PrEP-related knowledge, experience, opinions, and learning needs, and received 160 responses from service providers at Canadian AIDS Service Organizations. Respondents were cautiously optimistic about PrEP and 48.8% believed that PrEP warranted Health Canada approval. In multivariable logistic regression, support for PrEP approval was associated with more years working in HIV (odds ratio=1.89 per decade, 95% CI=1.10, 3.25), low baseline familiarity with PrEP (OR=3.24, 95% CI=1.01, 14.41), and knowing someone who had used PrEP (OR=4.39, 95% CI=1.28,15.08). Participants major concerns about PrEP were similar to those highlighted in other publications, and some issues specific to certain target populations were raised. Several participants (26.2%) had been asked about PrEP in the past year and 10.6% knew of one or more Canadian who had used PrEP. Despite clients' interest, most participants thought that they (60.6%) or their organization (63.1%) did not have enough current knowledge about PrEP, highlighting the need for further education on this novel HIV prevention strategy. PMID- 23731255 TI - Chloroform as a hydrogen atom donor in Barton reductive decarboxylation reactions. AB - The utility of chloroform as both a solvent and a hydrogen atom donor in Barton reductive decarboxylation of a range of carboxylic acids was recently demonstrated (Ko, E. J. et al. Org. Lett. 2011, 13, 1944). In the present work, a combination of electronic structure calculations, direct dynamics calculations, and experimental studies was carried out to investigate how chloroform acts as a hydrogen atom donor in Barton reductive decarboxylations and to determine the scope of this process. The results from this study show that hydrogen atom transfer from chloroform occurs directly under kinetic control and is aided by a combination of polar effects and quantum mechanical tunneling. Chloroform acts as an effective hydrogen atom donor for primary, secondary, and tertiary alkyl radicals, although significant chlorination was also observed with unstrained tertiary carboxylic acids. PMID- 23731256 TI - The effect of subambient to elevated atmospheric CO2 concentration on vascular function in Helianthus annuus: implications for plant response to climate change. AB - Plant gas exchange is regulated by stomata, which coordinate leaf-level water loss with xylem transport. Stomatal opening responds to internal concentrations of CO2 in the leaf, but changing CO2 can also lead to changes in stomatal density that influence transpiration. Given that stomatal conductance increases under subambient concentrations of CO2 and, conversely, that plants lose less water at elevated concentrations, can downstream effects of atmospheric CO2 be observed in xylem tissue? We approached this problem by evaluating leaf stomatal density, xylem transport, xylem anatomy and resistance to cavitation in Helianthus annuus plants grown under three CO2 regimes ranging from pre-industrial to elevated concentrations. Xylem transport, conduit size and stomatal density all increased at 290 ppm relative to ambient and elevated CO2 concentrations. The shoots of the 290-ppm-grown plants were most vulnerable to cavitation, whereas xylem cavitation resistance did not differ in 390- and 480-ppm-grown plants. Our data indicate that, even as an indirect driver of water loss, CO2 can affect xylem structure and water transport by coupling stomatal and xylem hydraulic functions during plant development. This plastic response has implications for plant water use under variable concentrations of CO2, as well as the evolution of efficient xylem transport. PMID- 23731258 TI - Patient participation in the medical decision-making process in haemato-oncology- a qualitative study. AB - Cancer patients are showing increased interest in shared decision-making. Patients with haematological illnesses, however, express considerably less desire for shared decision-making as compared with other oncological patient groups. The goal of the current project was to identify the reasons for the lower desire for shared decision-making among patients with haematological illness. We conducted qualitative, semi-structured interviews with 11 haematological patients (39-70 years old) after the beginning of therapy concerning the course and evaluation of medical shared decision-making. The patients were often overwhelmed by the complexity of the illness and the therapy and did not want to assume any responsibility in medical decision-making. They reported a great deal of distress and very traditional paternalistic role expectations with regards to their health care providers, which limited the patients' ability to partake in the decision making process. In contrast to the socio-cultural support for many other oncological diseases, haematological diseases are not as well supported, e.g. there is a lack of self-help materials, systematic provision of information and support groups for patients, which may be related to a lower empowerment of this patient population. Results show the limits of patient participation in the context of highly complicated medical conditions. In addition to already researched preferences of the physicians and patients for shared decision-making, future research should pay greater attention to the process and other variables relevant to this aspect of the doctor-patient relationship. PMID- 23731259 TI - Clinical Research Office Of The Endourology Society-giving developing countries the opportunity to be involved in research. PMID- 23731257 TI - Intracranial pressure monitoring in severe traumatic brain injury: results from the American College of Surgeons Trauma Quality Improvement Program. AB - Although existing guidelines support the utilization of intracranial pressure (ICP) monitoring in patients with traumatic brain injury (TBI), the evidence suggesting benefit is limited. To evaluate the impact on outcome, we determined the relationship between ICP monitoring and mortality in centers participating in the American College of Surgeons Trauma Quality Improvement Program (TQIP). Data on 10,628 adults with severe TBI were derived from 155 TQIP centers over 2009 2011. Random-intercept multilevel modeling was used to evaluate the association between ICP monitoring and mortality after adjusting for important confounders. We evaluated this relationship at the patient level and at the institutional level. Overall mortality (n=3769) was 35%. Only 1874 (17.6%) patients underwent ICP monitoring, with a mortality of 32%. The adjusted odds ratio (OR) for mortality was 0.44 [95% confidence interval (CI), 0.31-0.63], when comparing patients with ICP monitoring to those without. It is plausible that patients receiving ICP monitoring were selected because of an anticipated favorable outcome. To overcome this limitation, we stratified hospitals into quartiles based on ICP monitoring utilization. Hospitals with higher rates of ICP monitoring use were associated with lower mortality: The adjusted OR of death was 0.52 (95% CI, 0.35-0.78) in the quartile of hospitals with highest use, compared to the lowest. ICP monitoring utilization rates explained only 9.9% of variation in mortality across centers. Results were comparable irrespective of the method of case-mix adjustment. In this observational study, ICP monitoring utilization was associated with lower mortality. However, variability in ICP monitoring rates contributed only modestly to variability in institutional mortality rates. Identifying other institutional practices that impact on mortality is an important area for future research. PMID- 23731262 TI - Liver transplantation using DCD donors: the current strategy to expand the organ donor pool in China. PMID- 23731263 TI - Magnetocaloric effect in AlFe2B2: toward magnetic refrigerants from earth abundant elements. AB - AlFe2B2 was prepared by two alternative synthetic routes, arc melting and synthesis from Ga flux. In the layered crystal structure, infinite chains of B atoms are connected by Fe atoms into two-dimensional [Fe2B2] slabs that alternate with layers of Al atoms. As expected from the theoretical analysis of electronic band structure, the compound exhibits itinerant ferromagnetism, with the ordering temperature of 307 K. The measurement of magnetocaloric effect (MCE) as a function of applied magnetic field reveals isothermal entropy changes of 4.1 J kg(-1) K(-1) at 2 T and 7.7 J kg(-1) K(-1) at 5 T. These are the largest values observed near room temperature for any metal boride and for any magnetic material of the vast 122 family of layered structures. Importantly, AlFe2B2 represents a rare case of a lightweight material prepared from earth-abundant, benign reactants which exhibits a substantial MCE while not containing any rare-earth elements. PMID- 23731264 TI - High pressure-high temperature polymorphism and decomposition of pentaerythritol tetranitrate (PETN). AB - To elucidate the behavior of PETN at thermo-mechanical conditions relevant for shock initiation, Raman spectroscopy, and optical imaging were used to examine its static high pressure and high temperature (HP-HT) response. Experiments were performed on single crystals in a heated diamond anvil cell at pressures to 14 GPa and temperatures ranging from room temperatures to 550 K. Regarding the pressure-induced PETN-I transition to PETN-III at room temperature, our results show that nonhydrostaticity plays an important role in driving this transition. Furthermore, we found that PETN-III transforms to PETN-IV at high temperatures, and this transformation can involve lowering of molecular symmetry from C2 to C1. The HP-HT phase diagram for PETN presented here includes the melting/decomposition curve and boundaries between three PETN phases: PETN-I, PETN-III, and PETN-IV. The relevance of static compression results for shock initiation of PETN is discussed. PMID- 23731265 TI - Sterols of the green-pigmented, freshwater raphidophyte, Gonyostomum semen, from Scandinavian lakes. AB - Sterols are a class of membrane-reinforcing, ringed lipids which have a long history of examination in algae as a means of deriving chemotaxonomic relationships and as potential lipidic biomarkers. The Raphidophyceae represent a class of harmful, bloom-forming, marine and freshwater algae. To date, there have been four published examinations of their sterol composition, focusing primarily on brown-pigmented, marine species within the genera, Chattonella, Fibrocapsa, and Heterosigma. Lacking in these examinations has been the species Gonyostomum semen Ehrenb., which is a green-pigmented, freshwater raphidophyte with a worldwide distribution. The goal of this study was to examine the sterol composition of this nuisance alga, determine the potential of using its sterol profile as a biomarker, and finally to determine if there is any intraspecific variability between isolates. We have examined 21 isolates of G. semen from a number of Scandinavian lakes, and all were found to produce two major sterols, 24 ethylcholesta-5,22E-dien-3beta-ol and 24-ethylcholest-5-en-3beta-ol, and 24 methylcholest-5-en-3beta-ol as a minor sterol; the presence of 24-ethylcholesta 5,22E-dien-3beta-ol differentiates G. semen from brown-pigmented, marine raphidophytes which generally lack it. The results of this study indicate that isolates of G. semen from geographically separate lakes across Finland and Scandinavia have the same sterol biosynthetic pathway, and that there is no evolutionary divergence between the isolates with regard to sterol composition. The sterols of G. semen are not considered to be useful biomarkers for this particular organism because they are commonly found in other algae and plants. PMID- 23731266 TI - British Dietetic Association evidence-based guidelines for the protein requirements of adults undergoing maintenance haemodialysis or peritoneal dialysis. AB - BACKGROUND: Existing nutritional guidelines suggest that protein requirements of adults with stage five chronic kidney disease undergoing haemodialysis (HD) or peritoneal dialysis (PD) are increased as a result of protein losses during dialysis. The present review aimed to update previous guidance and develop evidence-based practice guidelines on the protein requirements of adults undergoing maintenance dialysis. METHODS: Following a PICO approach (Participants or Population, Intervention or Exposure, Comparison and Outcome), four research questions were formulated to investigate the total protein requirement and protein quality required by adults undergoing HD and PD. A comprehensive, systematic review was undertaken using the databases Medline, EMBASE and the Cochrane Library from 2005 to September 2009 for HD studies and from 1997 to September 2009 for PD studies. RESULTS: The literature search yielded 2931 studies, which were assessed for inclusion. Following appraisal, 19 studies in HD and 18 studies in PD met the inclusion criteria and were systematically reviewed. Limited good quality evidence supports the recommendations that: (i) adults undergoing maintenance HD require a minimum protein intake of 1.1 g kg(-1) ideal body weight (IBW) per day; and (ii) adults undergoing maintenance PD require a minimum protein intake of 1.0-1.2 kg(-1) IBW per day, in conjunction with an adequate energy intake. There were no studies that addressed the quality of protein for either HD or PD. CONCLUSIONS: Evidence suggests that nutritional status may be maintained with lower protein intakes than previously recommended. However, the evidence base is limited and further randomised controlled trials are required to establish the optimal protein intake for dialysis patients. PMID- 23731267 TI - Glucose impairs B-1 cell function in diabetes. AB - B-1 lymphocytes produce natural immunoglobulin (Ig)M, among which a large proportion is directed against apoptotic cells and altered self-antigens, such as modified low-density lipoprotein (LDL). Thereby, natural IgM maintains homeostasis in the body and is also protective against atherosclerosis. Diabetic patients have an increased risk of developing certain infections as well as atherosclerosis compared with healthy subjects, but the underlying reason is not known. The aim of this study was to investigate whether diabetes and insulin resistance affects B-1 lymphocytes and their production of natural IgM. We found that diabetic db/db mice had lower levels of peritoneal B-1a cells in the steady state-condition compared to controls. Also, activation of B-1 cells with the Toll like receptor (TLR)-4 agonist Kdo2-Lipid A or immunization against Streptococcus pneumoniae led to a blunted IgM response in the diabetic db/db mice. In-vitro experiments with isolated B-1 cells showed that high concentrations of glucose, but not insulin or leptin, caused a reduced secretion of total IgM and copper oxidized (CuOx)-LDL- and malondialdehyde (MDA)-LDL-specific IgM from B-1 cells in addition to a decreased differentiation into antibody-producing cells, proliferation arrest and increased apoptosis. These results suggest that metabolic regulation of B-1 cells is of importance for the understanding of the role of this cell type in life-style-related conditions. PMID- 23731268 TI - Conductance of molecular junctions formed with silver electrodes. AB - We compare the conductance of a series of amine-terminated oligophenyl and alkane molecular junctions formed with Ag and Au electrodes using the scanning tunneling microscope based break-junction technique. For these molecules that conduct through the highest occupied molecular orbital, junctions formed with Au electrodes are more conductive than those formed with Ag electrodes, consistent with the lower work function for Ag. The measured conductance decays exponentially with molecular backbone length with a decay constant that is essentially the same for Ag and Au electrodes. However, the formation and evolution of molecular junctions upon elongation are very different for these two metals. Specifically, junctions formed with Ag electrodes sustain significantly longer elongation when compared with Au due to a difference in the initial gap opened up when the metal point-contact is broken. Using this observation and density functional theory calculations of junction structure and conductance we explain the trends observed in the single molecule junction conductance. Our work thus opens a new path to the conductance measurements of a single molecule junction in Ag electrodes. PMID- 23731269 TI - Successful management of bilateral total hip replacement in a patient with von Willebrand's disease and developmental hip dysplasia. PMID- 23731270 TI - Transmission network of an HIV type 1 strain with K103N in young Belgian patients from different risk groups. AB - Transmitted drug resistance (TDR) influencing nonnucleoside reverse transcriptase inhibitor (NNRTI) activity is increasing among new HIV-1 patients in several countries. As we recently observed an increase of K103N prevalence among new diagnoses in Belgium, we mined the Belgian national sequence database for homologous sequences. The earliest reverse transcriptase (RT) sequences available for drug-naive patients as well as sequences related to treatment failure were included. Fifty-five sequences were aligned and subjected to phylogenetic analysis, revealing the presence of a cluster of 29 virus sequences. All except one of those sequences were from antiretroviral (ARV)-naive patients at the time of sampling, and 22 had the K103N mutation. Epidemiological data of clustered patients were collected through the Institute of Public Health. Seventy-two percent of the clustered patients were infected through homosexual or bisexual contacts while the others reported heterosexual contacts only. All patients reside and were infected in Belgium. Sixteen were diagnosed between January 2011 and June 2012; 14 were aged between 18 and 29 years at the time of diagnosis. Nearly 60% of the clustered patients live close to the city of Namur, where HIV incidence substantially increased in the past 2 years. The identification of this transmission network advocates for local prevention reinforcement and underscores the need for continuous TDR monitoring. The spread of NNRTI TDR could affect ARV initiation schemes and prophylaxis strategies. PMID- 23731271 TI - Effective learning among elite football players: the development of a football specific self-regulated learning questionnaire. AB - The present study aimed to develop a football-specific self-report instrument measuring self-regulated learning in the context of daily practice, which can be used to monitor the extent to which players take responsibility for their own learning. Development of the instrument involved six steps: 1. Literature review based on Zimmerman's (2006) theory of self-regulated learning, 2. Item generation, 3. Item validation, 4. Pilot studies, 5. Exploratory factor analysis (EFA), and 6. Confirmatory factor analysis (CFA). The instrument was tested for reliability and validity among 204 elite youth football players aged 13-16 years (Mage = 14.6; s = 0.60; 123 boys, 81 girls). The EFA indicated that a five-factor model fitted the observed data best (reflection, evaluation, planning, speaking up, and coaching). However, the CFA showed that a three-factor structure including 22 items produced a satisfactory model fit (reflection, evaluation, and planning; non-normed fit index [NNFI] = 0.96, comparative fit index [CFI] = 0.95, root mean square error of approximation [RMSEA] = 0.067). While the self regulation processes of reflection, evaluation, and planning are strongly related and fit well into one model, other self-regulated learning processes seem to be more individually determined. In conclusion, the questionnaire developed in this study is considered a reliable and valid instrument to measure self-regulated learning among elite football players. PMID- 23731272 TI - Multiple pathways promote dynamical coupling between catalytic domains in Escherichia coli prolyl-tRNA synthetase. AB - Aminoacyl-tRNA synthetases are multidomain enzymes that catalyze covalent attachment of amino acids to their cognate tRNA. Cross-talk between functional domains is a prerequisite for this process. In this study, we investigate the molecular mechanism of site-to-site communication in Escherichia coli prolyl-tRNA synthetase (Ec ProRS). Earlier studies have demonstrated that evolutionarily conserved and/or co-evolved residues that are engaged in correlated motion are critical for the propagation of functional conformational changes from one site to another in modular proteins. Here, molecular simulation and bioinformatics based analysis were performed to identify dynamically coupled and evolutionarily constrained residues that form contiguous pathways of residue-residue interactions between the aminoacylation and editing domains of Ec ProRS. The results of this study suggest that multiple pathways exist between these two domains to maintain the dynamic coupling essential for enzyme function. Moreover, residues in these interaction networks are generally highly conserved. Site directed changes of on-pathway residues have a significant impact on enzyme function and dynamics, suggesting that any perturbation along these pathways disrupts the native residue-residue interactions that are required for effective communication between the two functional domains. Free energy analysis revealed that communication between residues within a pathway and cross-talk between pathways are important for coordinating functions of different domains of Ec ProRS for efficient catalysis. PMID- 23731273 TI - Prognosis of differentiated thyroid cancer in relation to serum thyrotropin and thyroglobulin antibody status at time of diagnosis. AB - BACKGROUND: Serum thyrotropin (TSH) concentration and thyroid autoimmunity may be of prognostic importance in differentiated thyroid cancer (DTC). Preoperative serum TSH level has been associated with higher DTC stage in cross-sectional studies; data are contradictory on the significance of thyroid autoimmunity at the time of diagnosis. OBJECTIVE: We sought to assess whether preoperative serum TSH and perioperative antithyroglobulin antibodies (TgAb) were associated with thyroid cancer stage and outcome in DTC patients followed by the National Thyroid Cancer Treatment Cooperative Study, a large multicenter thyroid cancer registry. METHODS: Patients registered after 1996 with available preoperative serum TSH (n=617; the TSH cohort) or perioperative TgAb status (n=1770; the TgAb cohort) were analyzed for tumor stage, persistent disease, recurrence, and overall survival (OS; median follow-up, 5.5 years). Parametric tests assessed log transformed TSH, and categorical variables were tested with chi square. Disease free survival (DFS) and OS was assessed with Cox models. RESULTS: Geometric mean serum TSH levels were higher in patients with higher-stage disease (Stage III/IV=1.48 vs. 1.02 mU/L for Stages I/II; p=0.006). The relationship persisted in those aged >=45 years after adjusting for sex (p=0.01). Gross extrathyroidal extension (p=0.03) and presence of cervical lymph node metastases (p=0.003) were also significantly associated with higher serum TSH. Disease recurrence and all cause mortality occurred in 37 and 38 TSH cohort patients respectively, which limited the power for survival analysis. Positive TgAb was associated with lower stage on univariate analysis (positive TgAb in 23.4% vs. 17.8% of Stage I/II vs. III/IV patients, respectively; p=0.01), although the relationship lost significance when adjusting for age and sex (p=0.34). Perioperative TgAb was not an independent predictor of DFS (hazard ratio=1.12 [95% confidence interval=0.74 1.69]) or OS (hazard ratio=0.98 [95% confidence interval=0.56-1.72]). CONCLUSIONS: Preoperative serum TSH level is associated with higher DTC stage, gross extrathyroidal extension, and neck node metastases. Perioperative TgAb is not an independent predictor of DTC prognosis. A larger cohort is required to assess whether preoperative serum TSH level predicts recurrence or mortality. PMID- 23731274 TI - GM2 gangliosidosis (B variant) in two Japanese Chins: clinical, magnetic resonance imaging and pathological characteristics. PMID- 23731275 TI - MicroRNA-503 suppresses proliferation and cell-cycle progression of endometrioid endometrial cancer by negatively regulating cyclin D1. AB - MicroRNAs (miRNAs) are post-transcriptional inhibitor regulators of gene expression that act by directly binding complementary mRNA and are key determinants of cancer initiation and progression. In this study, we revealed a role for the tumor-suppressor miRNA miR-503 in endometrioid endometrial cancer (EEC) cells. The miR-503 expression level gradually decreases across normal endometrial tissues, endometrial tissues with complex atypical hyperplasia, and EEC tissues. A relatively high level of miR-503 in EEC tissues indicates a longer survival time in EEC patients. The expression of a cell cycle-associated oncogene encoding cyclin D1 (CCND1) was inversely correlated with miR-503 expression in EEC tissues and cell lines. CCND1 has a binding sequence of miR-503 within its 3' untranslated region, and was confirmed to be a direct target of miR-503 by the fluorescent reporter assays. Increasing the miR-503 level in EEC cells suppressed cell viability, colon formation activity and cell-cycle progression, and the inhibited oncogenic phenotypes induced by miR-503 were alleviated by ectopic expression of CCND1 without the untranslated region sequence. Furthermore, in vivo studies also suggested a suppressive effect of miR-503 on EEC cell-derived xenografts. miR-503 increased in cell cycle-arrested EEC cells, and was restored to a normal level in EEC cells after cell cycle re-entry, while CCND1 displayed the opposite expression pattern. Collectively, this study suggested that miR-503 plays a tumor-suppressor role by targeting CCND1. Abnormal suppression of miR-503 leads to an increase in the CCND1 level, which may promote carcinogenesis and progression of EEC. PMID- 23731276 TI - Selective growth of silver nanoparticle arrays on nanoimprinted sol-gel silica patterns. AB - Selective growth of silver nanoparticles on ~100 nm thick silica patterns produced by nanoimprint method has been successfully demonstrated using either (1) thermo-induced reduction or (2) room temperature electroless deposition (ELD) without removing the ~25 nm thick residual layer left by nanoimprint process. This selectivity was achieved by silane additive, (3 mercaptopropyl)trimethoxysilane (3-MTS), which was added to the silica matrix to control nucleation and growth of silver. The presence of silver nanoparticles was confirmed by EDX and UV-vis spectrum, and the density, distribution, and size of silver particles were examined by atomic force microscopy (AFM) and scanning electron microscopy (SEM). Silica film heat-treated between 400 and 600 degrees C resulted in silver particles of 100-120 nm diameter with a linear density of 2.63-3.36 MUm(-1), while the film treated by room temperature ELD produced silver particles of 67 nm diameter with a linear density of 5.65 MUm(-1). The selective growth ratio based on particle density on pattern area versus residual layer is 12.92 and 20.31 for high- and room-temperature processes, respectively, whereas the samples without 3-MTS shows low selective growth ratio of 1.22 and 1.04. These results prove that both approaches are fast and effective, suggesting their potential to produce other type of nanoparticle arrays directly on nanoimprinted patterns. PMID- 23731277 TI - Early parental physical punishment and emotional and behavioural outcomes in preschool children. AB - OBJECTIVE: To determine whether there is an association between being smacked by your main caregiver in the first two years and emotional and behavioural problems at age four. METHODS: DESIGN: Secondary analysis of data from the Growing Up in Scotland Prospective Study (GUS). SETTING: Scotland, UK. PARTICIPANTS: GUS birth cohort children, whose main caregiver had no concerns about their behaviour at 22 months. EXPOSURE: Ever smacked by main caregiver in first 22 months, as measured by caregiver self-report at 22 months. MAIN OUTCOME: Emotional and behavioural problems as measured by parental assessment and the Strengths and Difficulties Questionnaire (SDQ) at 46 months. RESULTS: Preschool children exposed to main caregiver smacking in the first two years were twice as likely to have emotional and behavioural problems as measured by parental assessment [odds ratio (OR) 2.5, 95% confidence interval (CI) 1.9-3.2; absolute risk reduction (ARR) 17.8%, 95% CI 12.1-23.5] and SDQ (OR 2.5, 95% CI 1.7-3.7; ARR 7.5%, 95% CI 3.7-11.5), as children never smacked by their main caregiver. The association remained significant after adjusting for child age and sex, caregiver age, sex, ethnicity, educational attainment and mental health status, sibling number, structural family transitions and socioeconomic status (adj. OR 2.4, 95% CI 1.8-3.2 for parental assessment and adj. OR 2.2, 95% CI 1.4-3.5 for SDQ). CONCLUSIONS: Parental use of physical punishment in the first two years may be a modifiable risk factor for emotional and behavioural difficulties in preschool children. PMID- 23731279 TI - The role of emotions in UV protection intentions and behaviors. AB - Two studies examined the role of emotions, relative to cognitions, in predicting sun protection intentions and practices. In Study 1, 106 females were assessed for baseline sun protection, ultraviolet (UV) radiation exposure-related cognitions (perceived susceptibility to skin damage, self-efficacy for regular sunscreen use, perceived costs of sun protection use, perceived rewards of tanning), anticipated negative mood following future risky UV behavior, and future sun protection intentions. Self-reported sun protection behavior was then assessed in the same participants five weeks later. The results of Study 1 demonstrated that the extent to which participants' expected to experience negative feelings if they engaged in future risky UV behavior predicted their intentions to sun protect and their subsequent sun protection behaviors independent of their UV radiation exposure-related cognitions. In Study 2, in addition to the assessments collected in Study 1, participants were exposed to an appearance-based intervention that included visual images of their existing skin damage and were then assessed for their emotional reactions to the intervention. The results replicated those of Study 1 and, in addition, showed that negative emotional reactions to the intervention predicted future sun protection intentions and self-reported behaviors at follow-up, independent of the various cognitive factors that are central to prominent models of health behavior. These studies provide preliminary support for the development of expanded health behavior models that incorporate anticipated and experienced emotions. PMID- 23731278 TI - HvLUX1 is a candidate gene underlying the early maturity 10 locus in barley: phylogeny, diversity, and interactions with the circadian clock and photoperiodic pathways. AB - Photoperiodic flowering is a major factor determining crop performance and is controlled by interactions between environmental signals and the circadian clock. We proposed Hvlux1, an ortholog of the Arabidopsis circadian gene LUX ARRHYTHMO, as a candidate underlying the early maturity 10 (eam10) locus in barley (Hordeum vulgare L.). The link between eam10 and Hvlux1 was discovered using high throughput sequencing of enriched libraries and segregation analysis. We conducted functional, phylogenetic, and diversity studies of eam10 and HvLUX1 to understand the genetic control of photoperiod response in barley and to characterize the evolution of LUX-like genes within barley and across monocots and eudicots. We demonstrate that eam10 causes circadian defects and interacts with the photoperiod response gene Ppd-H1 to accelerate flowering under long and short days. The results of phylogenetic and diversity analyses indicate that HvLUX1 was under purifying selection, duplicated at the base of the grass clade, and diverged independently of LUX-like genes in other plant lineages. Taken together, these findings contribute to improved understanding of the barley circadian clock, its interaction with the photoperiod pathway, and evolution of circadian systems in barley and across monocots and eudicots. PMID- 23731280 TI - The influence of social factors on help-seeking for people with lung cancer. AB - While there has been no clear consensus on the potential for earlier diagnosis of lung cancer, recent research has suggested that the time between symptom onset and consultation can be long enough to plausibly affect prognosis. In this article, we present a review of the literature concerning help-seeking delays in lung cancer presentation, and more specifically, the role and influence that social factors may play in determining when and how people decide to seek medical help. We also consider how these factors contribute to patients' understanding of symptoms and illness indicators. We suggest that while there is research highlighting the importance of psychosocial influences on the general help seeking behaviour of people with concerns about cancer, existing studies are mainly retrospective, and very little work has focused on identifying triggers and barriers specific to lung cancer. Further, we propose that while there have been a number of recent initiatives to raise awareness of the early signs of lung cancer, aimed at both patients and health professionals, little information provision has been targeted specifically at the formal and informal network level. This may be a useful avenue to pursue in future initiatives. PMID- 23731281 TI - Palladium-catalyzed Z-selective oxidative amination of ortho-substituted primary anilines with olefins under an open air atmosphere. AB - The Pd-catalyzed oxidative amination of olefins with primary anilines has been achieved using molecular dioxygen as the sole oxidant. The use of ortho substituted primary anilines such as ortho-toluidine was the key to the successful development of this reaction, providing the corresponding N-alkenyl substituted anilines in high yields with unusually high levels of Z-selectivity. PMID- 23731283 TI - An improved cell separation technique for marine subsurface sediments: applications for high-throughput analysis using flow cytometry and cell sorting. AB - Development of an improved technique for separating microbial cells from marine sediments and standardization of a high-throughput and discriminative cell enumeration method were conducted. We separated microbial cells from various types of marine sediment and then recovered the cells using multilayer density gradients of sodium polytungstate and/or Nycodenz, resulting in a notably higher percent recovery of cells than previous methods. The efficiency of cell extraction generally depends on the sediment depth; using the new technique we developed, more than 80% of the total cells were recovered from shallow sediment samples (down to 100 meters in depth), whereas ~50% of cells were recovered from deep samples (100-365 m in depth). The separated cells could be rapidly enumerated using flow cytometry (FCM). The data were in good agreement with those obtained from manual microscopic direct counts over the range 10(4)-10(8) cells cm(-3). We also demonstrated that sedimentary microbial cells can be efficiently collected using a cell sorter. The combined use of our new cell separation and FCM/cell sorting techniques facilitates high-throughput and precise enumeration of microbial cells in sediments and is amenable to various types of single-cell analyses, thereby enhancing our understanding of microbial life in the largely uncharacterized deep subseafloor biosphere. PMID- 23731282 TI - Toward an international initiative for traumatic brain injury research. AB - The European Commission (EC) and the National Institutes of Health (NIH) jointly sponsored a workshop on October 18-20, 2011 in Brussels to discuss the feasibility and benefits of an international collaboration in the field of traumatic brain injury (TBI) research. The workshop brought together scientists, clinicians, patients, and industry representatives from around the globe as well as funding agencies from the EU, Spain, the United States, and Canada. Sessions tackled both the possible goals and governance of a future initiative and the scientific questions that would most benefit from an integrated international effort: how to optimize data collection and sharing; injury classification; outcome measures; clinical study design; and statistical analysis. There was a clear consensus that increased dialogue and coordination of research at an international level would be beneficial for advancing TBI research, treatment, and care. To this end, the EC, the NIH, and the Canadian Institutes of Health Research expressed interest in developing a framework for an international initiative for TBI Research (InTBIR). The workshop participants recommended that InTBIR initially focus on collecting, standardizing, and sharing clinical TBI data for comparative effectiveness research, which will ultimately result in better management and treatments for TBI. PMID- 23731284 TI - End-of-life care in patients with implantable cardioverter defibrillators: a MADIT-II substudy. AB - BACKGROUND: Implantable cardioverter defibrillator (ICD)-delivered shocks can cause substantial distress, warranting consideration of ICD deactivation at end of life. This study was designed to describe the patterns of end-of-life management in patients with ICDs. METHODS: There was a retrospective chart review of 98 patients who died in the ICD arm of multicenter automated defibrillator implantation trial II (MADIT II). The pattern of ICD management and the frequency of ICD shocks delivered before death were reviewed. RESULTS: We identified three groups: Group 1 consisting of individuals who underwent ICD, deactivation, 15 (15%); Group 2 patients without ICD deactivation who were in hospice or with "do not resuscitate" (DNR) orders, 36 (37%); and Group 3 patients without ICD deactivation who were not in hospice care and did not have DNR orders, 47 (48%). Out of 15 deactivations, 11 (73%) occurred in the week before death. None of the patients in Group 1 received an ICD shock in the 24-hour period before death. However, one (3%) patient from Group 2 and nine (19%) patients from Group 3 had shocks during the 24 hours before death (P = 0.03). In the last week before death, three (20%), two (6%), and six (13%) patients received ICD shocks in the three groups, respectively (P = 0.28). CONCLUSIONS: In patients with terminal conditions who are at risk for imminent death, active management of the patient's ICD, including timely discussions regarding ICD deactivation, may reduce the risk of ICD shocks during the end of life. PMID- 23731285 TI - Altered expression of sialylated glycoproteins in ovarian cancer sera using lectin-based ELISA assay and quantitative glycoproteomics analysis. AB - Herein, we identify and confirm differentially expressed sialoglycoproteins in the serum of patients with ovarian cancer. On the basis of Sambucus nigra (SNA) lectin enrichment and on an isobaric chemical labeling quantitative strategy, clusterin (CLUS), leucine-rich alpha-2-glycoprotein (LRG1), hemopexin (HEMO), vitamin D-binding protein (VDB), and complement factor H (CFH) were found to be differentially expressed in the serum of patients with ovarian cancer compared to benign diseases. The abnormal sialylation levels of CLUS, CFH, and HEMO in serum of ovarian cancer patients were verified by a lectin-based ELISA assay. ELISA assays were further applied to measure total protein level changes of these glycoproteins. Protein levels of CLUS were found to be down-regulated in the serum of ovarian cancer patients, while protein levels of LRG1 were increased. The combination of CLUS and LRG1 (AUC = 0.837) showed improved performance for distinguishing stage III ovarian cancer from benign diseases compared to CA125 alone (AUC = 0.811). In differentiating early stage ovarian cancer from benign diseases or healthy controls, LRG1 showed comparable performance to CA125. An independent sample set was further used to confirm the ability of these candidate markers to detect patients with ovarian cancer. Our study provides a comprehensive strategy for the identification of candidate biomarkers that show the potential for diagnosis of ovarian cancer. Further studies using a large number of samples are necessary to validate the utility of this panel of proteins. PMID- 23731286 TI - Diatomic silylynes, germylynes, stannylynes, and plumbylynes: structures, dipole moments, dissociation energies, and quartet-doublet gaps of EH and EX (E = Si, Ge, Sn, Pb; X = F, Cl, Br, I). AB - Systematic theoretical studies of the carbyne and halocarbyne analogues E-H and E X (E = Si, Ge, Sn, Pb; X = F, Cl, Br, I) were carried out with ab initio coupled cluster methods using very large basis sets. The (2)Pi state is the ground electronic state for all these compounds. The quartet-doublet energy separations, equilibrium distances, and dissociation energies for these species are predicted. The quartet-doublet splittings fall in the order EF > ECl > EBr > EI > EH for a given metal E; and PbX > GeX > SnX > SiX for the same halogen atom X. The dipole moments span a large range, from 0.08 debye (GeH) to 3.58 debye (PbCl). The dissociation energies range from 1.84 eV (PbH) to 6.15 eV (SiF). PMID- 23731288 TI - Four-month-old infants' visual investigation of cats and dogs: relations with pet experience and attentional strategy. AB - We assessed the eye-movements of 4-month-old infants (N = 38) as they visually inspected pairs of images of cats or dogs. In general, infants who had previous experience with pets exhibited more sophisticated inspection than did infants without pet experience, both directing more visual attention to the informative head regions of the animals, particularly when comparing stimuli, and maintaining their attention to an individual animal, resisting the pull on their attention by the other visible animal. Individual differences in general attentional strategies as assessed during a pretest had similar but weaker relations to visual scanning patterns. There was some evidence that the 2 factors were interactively associated with visual inspection, supporting the findings of Kovack-Lesh and colleagues (Kovack-Lesh, Horst, & Oakes, 2008; Kovack-Lesh, Oakes, & McMurray, 2012) that infants' learning about and memory for this type of stimuli is jointly determined by pet experience and attentional style. PMID- 23731287 TI - Own- and other-race face identity recognition in children: the effects of pose and feature composition. AB - We used a matching-to-sample task and manipulated facial pose and feature composition to examine the other-race effect (ORE) in face identity recognition between 5 and 10 years of age. Overall, the present findings provide a genuine measure of own- and other-race face identity recognition in children that is independent of photographic and image processing. The current study also confirms the presence of an ORE in children as young as 5 years of age using a recognition paradigm that is sensitive to their developing cognitive abilities. In addition, the present findings show that with age, increasing experience with familiar classes of own-race faces and further lack of experience with unfamiliar classes of other-race faces serves to maintain the ORE between 5 and 10 years of age rather than exacerbate the effect. All age groups also showed a differential effect of stimulus facial pose in their recognition of the internal regions of own- and other-race faces. Own-race inner faces were remembered best when three quarter poses were used during familiarization and frontal poses were used during the recognition test. In contrast, other-race inner faces were remembered best when frontal poses were used during familiarization and three-quarter poses were used during the recognition test. Thus, children encode and/or retrieve own- and other-race faces from memory in qualitatively different ways. PMID- 23731289 TI - The development of prosocial moral reasoning and a prosocial orientation in young adulthood: concurrent and longitudinal correlates. AB - We examined stability and change in prosocial moral reasoning (PRM) assessed longitudinally at ages 20/21, 22/23, 24/25, 26/27, and 31/32 years (N = 32; 16 female) using a pencil-and-paper measure of moral reasoning and examined relations of PRM and prosocial behavior with one another and with empathy, sympathy measured with self- and friend reports in adulthood, self- and mother reports of prosocial tendencies in adolescence, and observed prosocial behavior in preschool. Proportions of different types of PRM (hedonistic, approval, stereotypic, internalized) exhibited high mean-level stability across early adulthood, although stereotypic PMR increased with age and hedonistic PRM (a less sophisticated type of PRM) declined over time for males. More sophisticated PMR was positively related to friends' reports of a prosocial orientation concurrently and at age 24/25, as well as self-reports of sympathy in adolescence. Specific modes of PMR related to spontaneous or compliant sharing in preschool. Women used more sophisticated PMR than men across the entire study period. Self-reported and friend-reported prosociality at age 27/28 and 31/32 (combined) was related to numerous prior measures of a prosocial orientation, including spontaneous, relatively costly prosocial behavior in preschool (for self-reports and friend-reported sympathy/consideration for others). Donating/volunteering at T13/T14 was related to concurrent self- and friend reported prosociality and to self-reported prosocial orientation in earlier adulthood and mother-reported helping in adolescence. PMID- 23731291 TI - Predicting which childhood memories persist: contributions of memory characteristics. AB - This investigation identified memory-level predictors of the survivability of 4- to 13-year-old children's earliest recollections over a 2-year period. Data previously reported by Peterson, Warren, and Short (2011) were coded for inclusion of emotion terms and thematic, chronological, and contextual narrative coherence. In addition, the uniqueness and content of the reported events were classified, and the presence or absence of event reminders was recorded. The use of logistic multilevel modeling indicated that emotion and each dimension of coherence added to the prediction of a memory's survivability over and above age related variance. In contrast, event uniqueness, content category, reminders, and word count were not associated with retention. The findings help explain why particular early memories endure over time. PMID- 23731290 TI - Relating dopaminergic and cholinergic polymorphisms to spatial attention in infancy. AB - Early selective attention skills are a crucial building block for cognitive development, as attention orienting serves as a primary means by which infants interact with and learn from the environment. Although several studies have examined infants' attention orienting using the spatial cueing task, relatively few studies have examined neurodevelopmental factors associated with attention orienting during infancy. The present study examined the relationship between normative genetic polymorphisms affecting dopamine and acetylcholine signaling and attention orienting in 7-month-old infants during a spatial cueing task. We focused on 3 genes, including the CHRNA4 C1545T SNP (rs10344946), DAT1 3'UTR VNTR, and COMT Val158Met SNP (rs4680), as previous adult research has linked spatial attention skills to these polymorphisms. Behavioral measures included both facilitation of orienting at the cued location as well as inhibition of return (IOR), in which attention orienting is suppressed at the cued location. Results indicated that COMT Val carriers showed robust IOR relative to infants with the Met/Met genotype. However, COMT was unrelated to infants' facilitation responses, and there were no effects of CHRNA4 or DAT1 on either facilitation or IOR. Overall, this study suggests that variations in dopamine signaling, likely in prefrontal cortex, contribute to individual differences in orienting during early development. PMID- 23731293 TI - Early and midterm outcomes after endovascular treatment of degenerative aneurysms of the descending thoracic aorta: a Finnish multicenter study. AB - PURPOSE: To evaluate results of endovascular stent-graft placement for aneurysms of the descending aorta in 3 Finnish university hospitals during 1998-2010. METHODS: Among 158 consecutive patients treated with stent-graft placement for disease of the descending thoracic aorta, all 69 patients (58 men; mean age 71.7 years, range 54-90) with an aneurysm were included in the analysis. Medical records, radiological images, and national death records were collected and analyzed on an intention-to-treat basis. RESULTS: The 30-day mortality rate was 3.7% in 54 elective patients and 46.7% in 15 urgently treated acute patients. The paraparesis rate was 4.3%, and the major stroke rate was 4.3% after the operation. There were 4 aneurysm ruptures, all in the urgent group, two of whom had access failure. The other two died despite seemingly good initial results. The mean follow-up was 34.8+/-29 months. Two late ruptures occurred in patients who were lost to follow-up. In all, 12 type I (10 early, 2 late) and 1 late type III endoleaks were encountered in the observation period. CONCLUSION: Based on our findings, endovascular treatment of aneurysms of the descending aorta is relatively safe. To reduce the risk of postoperative complications, optimal preoperative imaging is mandatory. Postoperative regular imaging controls are indicated for early detection and prompt treatment of late type I or III endoleaks and to reduce the risk of late ruptures. PMID- 23731295 TI - Endovascular repair of the descending thoracic aorta: a tale of two nations. PMID- 23731294 TI - Endovascular aortic repair of thoracic aortic disease: early and 1-year results from a German multicenter registry. AB - PURPOSE: To report a "real-world" multicenter experience in the use of thoracic endovascular aortic repair (TEVAR) for diseases of the descending thoracic aorta. METHODS: A prospective, multicenter, German TEVAR Registry was established in October 2008 and enrolled 191 patients (134 men; mean age 64.5+/-13.2 years) from 7 hospitals up to March 2011. Stent-graft implantation was performed for Stanford type B aortic dissection (104, 55.3%), true thoracic aortic aneurysm (91, 48.7%), intramural hematoma (20, 10.7%), penetrating aortic ulcer (16, 8.6%), and traumatic aortic rupture (6, 3.2%). RESULTS: Per patient, a mean of 1.2+/-0.7 stent-grafts were implanted. Technical success was 92.1% (164/178); 15 (8.5%) endoleaks (types I-III) were reported. Intervention duration was a mean 107+/-122 minutes. During the hospital stay, stroke occurred in 3.9% of patients (7/180) and paraplegia in 1.7% (3/180). Reintervention was performed in 3.3% (6/180). The mortality was 5.5% (10/181) in-hospital and 5.6% at 30 days. The mean follow-up was 24.5+/-27.7 months. The Kaplan-Meier estimates of 1-year reintervention and death rates were 7.2% and 11.4%, respectively. CONCLUSION: In this real-world TEVAR registry for acute or chronic descending aortic diseases, technical success was high and the short-term complication rate was acceptable. However, the high reintervention rate observed in the present study mandates thorough clinical and imaging follow-up after an initially successful procedure. PMID- 23731296 TI - Midterm results of intentional celiac artery coverage during TEVAR for type B aortic dissection. AB - PURPOSE: To report the outcome of intended celiac artery coverage during thoracic endovascular aortic repair (TEVAR) for type B aortic dissection with an intimal tear near the celiac artery (CA) orifice. METHODS: Between 2007 and 2011, 13 patients (10 men; mean age 61.3 years, range 46-70) with type B aortic dissection underwent primary (n=9) or secondary (n=4) TEVAR with intentional CA coverage. Preoperative imaging was performed to confirm the existence of collateral circulation between the celiac artery and superior mesenteric artery. A short stent-graft was then deployed to cover both the entry tear and the CA. Follow-up was at 2 weeks; 1, 3, and 6 months; and every year thereafter. Preoperative diameters of the true and false lumens at the CA level, 8 cm above the CA, and at the aortic bifurcation, along with the maximum aortic diameter in the dissected segment, were compared to similar measurements at 6 months. RESULTS: All stent graft procedures were successful and without complication. No immediate or delayed endoleak was identified in 8 of 13 patients over a mean 25-month follow up (range 3-38). The other 5 patients had type II endoleak on completion imaging; these all resolved within 3 months after operation. Postoperative blood liver function and amylase assays were normal in all patients. No abdominal symptoms or signs of spinal cord ischemia were discovered. Expansion of the true lumen after TEVAR was statistically significant vs. at baseline in both groups (primary p<0.001, secondary p=0.023). Both the false lumen and the entire aorta showed signs of shrinkage after TEVAR in the 2 groups as well, although only the secondary group showed significant change (p<0.005) vs. baseline. CONCLUSION: TEVAR with intentional CA coverage is effective in excluding an infradiaphragmatic entry tear near the CA level. The incidence of abdominal ischemia is low if collateral circulation has been confirmed preoperatively. Type II endoleak is a major complication, yet most cease under observation. PMID- 23731297 TI - Endovascular repair with the chimney technique for Stanford type B aortic dissection involving right-sided arch with mirror image branching. AB - PURPOSE: To report endovascular repair with the chimney technique of type B aortic dissection involving a right-sided aortic arch (RAA). CASE REPORTS: Two hypertensive men aged 48 and 42 years with symptoms of aortic dissection resistant to medical therapy underwent emergent thoracic endovascular aortic repair with the chimney technique to extend the proximal landing zones. Both patients had right-sided arches with mirror image branching. One patient required a bare metal chimney stent to maintain perfusion to the right subclavian artery, while the other patient had a chimney stent to revascularize the right common carotid artery. Short-term follow-up (1 year and 1 month, respectively) showed that there was positive aortic remodeling, and the chimney stents were patent. CONCLUSION: Chimney TEVAR seems safe and effective for Stanford type B dissection in patients having RAA with mirror image branching and no sufficient proximal fixation zone. PMID- 23731298 TI - Antegrade in situ stent-graft fenestration for the renal artery following inadvertent coverage during EVAR. AB - PURPOSE: To report the use of antegrade in situ fenestration as a bailout technique to rescue a renal artery after inadvertent coverage during endovascular aneurysm repair (EVAR). TECHNIQUE: The technique is demonstrated in a patient with a 6-cm infrarenal abdominal aortic aneurysm (AAA) and a short, angulated proximal neck. A type I endoleak persisted on completion angiography after implantation of a bifurcated Zenith stent-graft despite dilation with a compliant balloon. A Giant Palmaz stent mounted on a large compliant balloon successfully resolved the endoleak. After placing the stent, the left renal artery was covered completely by the main aortic graft material, leading to only marginal opacification on angiography. To preserve flow to the renal artery, a transseptal sheath and transseptal needle were introduced from the right femoral artery and used to puncture the abdominal stent-graft antegrade at the site of the left renal artery. A 0.018-inch guidewire could then be introduced into the left renal artery; following a number of maneuvers, a balloon-expandable stent was placed through the fenestration into the target vessel. On computed tomographic angiography 4 days postoperatively, the AAA remained excluded and both renal arteries were patent, with all side branches fully preserved. Renal function was completely restored. CONCLUSION: Antegrade in situ fenestration can facilitate immediate revascularization of inadvertently covered side branches in EVAR using a transseptal sheath and needle. If the anatomical features are supportive, antegrade in situ fenestration can be a useful bailout technique. PMID- 23731299 TI - Renal artery rescue after EVAR. PMID- 23731300 TI - Crossover chimney technique to preserve the internal iliac artery in abdominal aortic aneurysm with common iliac artery aneurysms. AB - PURPOSE: To report a new technique to preserve the internal iliac artery (IIA) in cases of aortoiliac aneurysms. TECHNIQUE: Under bilateral common femoral artery (CFA) exposure, a crossover sheath was inserted from the contralateral CFA to the ipsilateral IIA involved in the common iliac artery (CIA) aneurysm. A Viabahn stent-graft was positioned 2 cm inside the IIA. The main body abdominal stent graft was inserted through the ipsilateral CFA with distal sealing in the external iliac artery (EIA). The gate was cannulated, and the limb extension was positioned in the contralateral CIA near the IIA orifice. After the first Viabahn deployment, a second device was deployed with a minimum 1-cm overlap inside the first Viabahn and 2 mm distal to the limb extension. For bilateral CIA aneurysms, the Viabahn and extension limb were landed in the EIA with IIA embolization. In the past year, this technique has been used in 5 patients with success. There was no acute branch occlusion or type I endoleak from the IIA or chimney graft gutters on imaging studies up to 6 months. CONCLUSION: This technique is easy to use and avoids the brachial access of the sandwich technique and the additional cost of an iliac branch device. PMID- 23731301 TI - New endovascular strategy to overcome anatomical constraints when dealing with aortoiliac aneurysms. PMID- 23731302 TI - Open and endovascular repair of primary mycotic aortic aneurysms: a 10-year single-center experience. AB - PURPOSE: To report early and midterm outcomes after open or endovascular repair of primary mycotic aortic aneurysms treated over a 10-year period in a single center. METHODS: The records of all 12 patients (10 men; 72.9 years, range 59-83) treated for primary mycotic aortic aneurysms from September 2001 to December 2010 were retrospectively reviewed. The aneurysms were located in the abdominal aorta in 10 cases and in the thoracic aorta in 2. Preoperative signs of infection, such as leukocytosis or elevated C-reactive protein, were found in all patients, and fever was apparent in 7. Three patients had primary open surgery with extensive debridement and extra-anatomical bypass, while 9 patients underwent endovascular aneurysm repair. At the time of operation, 10 mycotic aneurysms were already ruptured. All patients were prescribed lifelong antibiotics after discharge. RESULTS: Positive microbial cultures were found in 8 patients, including Salmonella species in 2, S. aureus in 3, E. coli in 1, and Streptococcus in 1. Mean follow-up was 29.9 months (range 1-98). Five patients took lifelong oral antibiotics after discharge with a mean medication duration of 17 months (range 1 65). Two of the 3 open surgery patients died (1 early). In the 9 endovascular repair patients, there was no early mortality, but 1 patient died at 6 months of an unknown cause. Additionally, 6 patients had a late relapse and underwent either secondary open surgical debridement (n=2) or computed tomography-guided drainage and antibiotic flush; 3 of the 6 died. CONCLUSION: Endovascular aneurysm repair is a reasonable short-term management for patients with hemodynamic instability or high surgical risk. However, the late relapse rate after endovascular repair was very high in this series, despite adjunctive drainage and aggressive antibiotic treatment. PMID- 23731303 TI - Following the short-term benefit of endovascular repair of mycotic aortic aneurysm: what is the next step? PMID- 23731304 TI - Acute kidney injury after endovascular repair of abdominal aortic aneurysm. AB - Acute kidney injury (AKI) after any type of intervention negatively impacts mortality, length of hospitalization, and perhaps long-term survival. In the case of endovascular aneurysm repair (EVAR), the incidence of AKI ranges from 1% to 23% for elective and emergency procedures and is lower compared to open repair. The pathophysiology of AKI in EVAR is complex: contrast-induced nephropathy, renal microembolization, and acute tubular necrosis are all implicated. Prevention strategies include hydration, ischemic preconditioning, regional anesthesia, and pharmacological agents. There is no level I evidence regarding the prevention of AKI in EVAR, so this review sought to examine the mechanisms and prevention strategies for this potentially fatal complication. PMID- 23731305 TI - Renal dysfunction after EVAR: time for a standard definition. PMID- 23731306 TI - Analysis of effects of fixation type on renal function after endovascular aneurysm repair. AB - PURPOSE: To report a prospective nonrandomized study comparing the effects of suprarenal (SR) vs. infrarenal (IR) stent-graft fixation on renal function in patients undergoing endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA). METHODS: Patients with AAA undergoing elective EVAR between June 2008 and June 2010 were eligible for the comparative study of fixation method on renal function. Patients with impaired renal function [estimated creatinine clearance (eCrCl) <30 mL/min] or a history of renal impairment were not eligible. Renal function was assessed by measuring serum creatinine (SCr) and total proteins and microalbumin in the urine preoperatively, on postoperative day 1, and at 1, 6, and 12 months. The eCrCl was calculated using the Cockcroft-Gault formula. A standard preoperative hydration protocol was followed in all patients, and stent-graft choice was at the operator's discretion. Of 116 patients undergoing elective EVAR in the study period, 16 were ineligible, leaving 100 patients (95 men; median age 74 years) enrolled in the study (49 SR and 51 IR). RESULTS: There was no statistically significant difference between the groups in the prevalence of any risk factor, the baseline SCr and eCrCl values, contrast usage, or procedure duration. At the postoperative measurement, there was no significant deterioration of renal function in either group, although total urinary proteins increased significantly in both groups (IR p=0.01, SR p<0.001). At the 12-month follow-up, patients in the IR group had no significant alteration in any marker vs. baseline, while patients in the SR group had significant alterations in SCr (p=0.001), eCrCl (p<0.001), and microalbumin (p=0.04) in urine. The number of patients with a >20% decrease in eCrCl was not significantly different between the groups. No patient had an adverse renal event. CONCLUSION: Deterioration in renal function was observed 12 months after EVAR in patients receiving a stent-graft with suprarenal fixation, even though this did not seem to increase the likelihood of postoperative renal impairment. Furthermore, suprarenal fixation may be responsible for progressively significant proteinuria. Further studies are needed to determine the long-term impact of suprarenal fixation on renal function and investigate the potential risk of progressive renal disease in relation to type of fixation. PMID- 23731307 TI - Combined cardiac surgery and endovascular repair of abdominal aortic aneurysms. AB - PURPOSE: To report an initial experience of concomitant endovascular repair of abdominal aortic aneurysms (AAA) and cardiac surgery. METHODS: Records for 10 consecutive patients (all men; median age 68 years, range 60-79) with AAA treated by a multidisciplinary team at a tertiary specialist center were retrospectively reviewed. Each patient had independent indications for surgical correction of their cardiac disease and AAAs. The patients underwent endovascular aneurysm repair (EVAR) followed by cardiac surgery under the same anesthesia. Eight patients had concomitant coronary artery bypass grafting (CABG; 4 off-pump), 1 patient had CABG and left ventricular aneurysmectomy, and 1 patient required aortic root replacement. RESULTS: All combined procedures were performed successfully under a single general anesthesia and took a median of 508 minutes (range 425-625). Median intensive care stay was 3 days (range 2-4), while hospital stay was 8 days (range 7-21) days. There were no deaths in-hospital or within 30 days. Complications were minor and self-limiting; there were no instances of renal failure. At a median follow-up of 29 months (range 14-38), no EVAR-related secondary interventions were required. CONCLUSION: Concomitant EVAR and cardiac surgery delivered by a multidisciplinary team is feasible, appears safe, and eliminates the risk associated with staged operations. Improved patient satisfaction and efficient use of resources are potential advantages. PMID- 23731308 TI - Efficacy and safety of the preclose technique following percutaneous aortic stent graft implantation. AB - PURPOSE: To evaluate in a large patient cohort the 6-F Perclose ProGlide in conjunction with the preclose technique to seal puncture sites after percutaneous endovascular aortic repairs. METHODS: The medical records were reviewed of 367 patients (303 men; mean age 68.5+/-10.8 years) having 599 access site closures with the 6-F Perclose ProGlide performed in conjunction with percutaneous endovascular aortic repairs. Procedure success was defined as hemostasis with the preclose technique without the need for any ancillary procedure. Access-related major adverse events included infection, bleeding, lower leg ischemia, hematoma, pseudoaneurysm, arteriovenous fistula, embolization, laceration, femoral artery thrombosis, nerve injury, or death owing to an access site injury. RESULTS: Procedure success was achieved in 359 (97.8%) of 367 patients and in 591 (98.7%) of 599 femoral sites. Access-related major adverse events developed in 25 (6.8%) of 367 patients [26/599 (4.3%) sites]. The most frequent adverse event was a hematoma [16/367 (4.4%) patients; 17/599 (2.8%) sites], followed by pseudoaneurysm [7/367 (1.9%) patients; 7/599 (1.2%) sites]. Bleeding occurred in 6 (1.6%) of 367 patients [6/599 (1.0%) sites]. There were 2 infections, 2 distal embolizations, 1 acute femoral thrombosis, and 1 laceration at the puncture site. CONCLUSION: The preclose technique can be used to achieve hemostasis with remarkable success and low rates of adverse events. PMID- 23731309 TI - Association between the SVS/AAVS anatomical severity grading score and operative outcomes in fenestrated endovascular repair of juxtarenal aortic aneurysm. AB - PURPOSE: To evaluate the association between the Society for Vascular Surgery/American Association for Vascular Surgery (SVS/AAVS) anatomical severity grading (ASG) score and operative outcomes in fenestrated endovascular repair (f EVAR) for juxtarenal aortic aneurysm. METHODS: A review was conducted of all patients treated at our clinic with commercially available, custom-made f-EVAR devices between June 2007 and December 2011. Preoperative computed tomography (CT) scans were analyzed in a dedicated vascular 3-dimensional workstation for calculation of the ASG score. Of the 100 patients treated with f-EVAR during the study period, 88 (69 men; mean age 70 years, range 50-82) had high quality CT scans available for generating semiautomatic centerline-of-flow reconstructions needed to calculate the ASG score. The mean score was used to divide the patients into high and low score groups for comparison of operative outcomes. RESULTS: A total ASG score >=24 was associated with longer procedure time (357+/-121 vs. 298+/-131 minutes, p=0.03) and more frequent intraoperative adjunctive maneuvers (48% vs. 29% of patients, p=0.05). An ASG neck score >=7 was associated with longer procedure time (365+/-126 vs. 288+/-119 minutes, p<0.01), more operative adverse events (31% vs. 14% of patients, p=0.05), higher radiation exposure (53828+/-37341 vs. 38788+/-25846 MUGym(2), p=0.04), and more frequent postoperative complications (46% vs. 18% of patients, p<0.01). An ASG aneurysm score >=5 was associated with operative adverse events (44% vs. 19% of patients, p=0.04). No relationship was found between the ASG score and blood loss, contrast volume, fluoroscopy time, or hospital stays. CONCLUSION: The ASG score is associated with operative adverse events, intraoperative adjunctive maneuvers, radiation exposure, and postoperative complications in patients treated with f EVAR for juxtarenal aortic aneurysm. PMID- 23731310 TI - One-year results of the multilayer flow modulator stent in the management of thoracoabdominal aortic aneurysms and type B dissections. AB - PURPOSE: To report 1-year results from the first subgroup of patients treated with the Multilayer Flow Modulator (MFM) stent for aortic aneurysm and dissection. METHODS: Up to December 2012, 243 patients have been treated worldwide for aortic aneurysm and dissection with the Cardiatis MFM under the established indications for use. This retrospective review encompasses the first 55 of these patients (41 men; mean age 64.5+/-18 years), who were treated on a compassionate basis in 11 countries. There were 31 thoracoabdominal aortic aneurysms (8 Crawford type I, 3 type II, 9 type III, and 11 type IV), 7 arch aneurysms, 3 infrarenal abdominal aortic aneurysms, 8 suprarenal aortic aneurysms, and 6 type B dissections. Mean aneurysm diameter was 6.04+/-1.66 cm, and the mean length was 11.58+/-7.62 cm. The primary endpoint at 1 year was a composite of rupture and aneurysm-related death. The secondary endpoints were all cause mortality, visceral branch occlusion, adverse events (i.e., stroke and paraplegia), and reintervention. RESULTS: Technical success was 98.2%; there was no paraplegia or perioperative visceral or renal insult. The mean number of side branches covered was 3.7+/-1.3 per case (range 0-6); 108 stents were deployed (range 1-5). At 1 year, aneurysm-related survival was 93.7%, all-cause survival was 84.8%, intervention-free survival was 92.4%, and all of the 202 side branches were patent. There were no stent fractures. At 6 months, the mean rate of sac volume increase was 0.36% per month, resulting in a mean volume increase of 2.14%. At 12 months, the rate of increase had slowed to 0.28% per month, resulting in a total average increase in sac volume of 3.26%. The ratio of thrombus to total volume stayed almost constant over the 12 months at 0.48, while the ratio of flow to total volume fell from 0.21 to 0.12 at 12 months. CONCLUSION: MFM implantation instigates a process of aortic remodeling involving initial thrombus deposition, which slowed between 6 and 12 months. Increasing sac size did not herald rupture, and the MFM was not associated with loss of native side branches. With physiological modulation of the aneurysm, the MFM offers promise for resolution of complex thoracoabdominal pathology with off-the-shelf availability, but this disruptive technology requires further development and technical refinement. Long-term follow-up of the registry patients is mandatory before establishing a randomized controlled study. PMID- 23731311 TI - Flow-diverting multilayer stents: a promising but questionable solution for aortic pathologies. PMID- 23731312 TI - Early experience with the multilayer aneurysm repair stent in the endovascular treatment of trans/infragenicular popliteal artery aneurysms: a mixed bag. AB - PURPOSE: To present a preliminary experience using a multilayer flow-modulating stent for trans/infragenicular popliteal endovascular aneurysm repair. METHODS: Five men (mean age 76 years, range 62-86) with 6 popliteal artery aneurysms (PAAs) measuring 22 to 39 mm in diameter (mean 30) underwent endovascular repair using the Cardiatis Multilayer Aneurysm Repair System (MARS) between June and August 2011. Radiological assessments post procedure using duplex ultrasonography and biplanar knee radiographs (additional contrast studies as necessary) sought evidence of aneurysm exclusion, graft patency, and preservation of branches and runoff vessels. RESULTS: Technical success was achieved in each case. There was one symptomatic stent occlusion requiring thrombectomy at 4 days, with reocclusion, and one leak via the stent struts into the sac with no branch outflow identified. Two further symptomatic stent occlusions were identified within a 6-week follow-up period, totaling 3 occlusions among the 6 devices deployed. CONCLUSION: No firm conclusion can be reached on the efficacy of the MARS in PAAs due to the inherent limitations of this small series, although a 50% thrombosis rate is a poor outcome. The risk of early thrombosis in flow modulating stents deployed in the popliteal artery exists, as it does with earlier generation stent-grafts. Larger prospective trials and the influence of more aggressive antithrombotic/anticoagulant therapy should be considered to enable accurate evaluation of this device in popliteal artery aneurysms. PMID- 23731313 TI - Popliteal artery aneurysms and the multilayer stent: are there problems ahead? PMID- 23731314 TI - Disconnection of multilayer stents 2 years after treatment of a hepatic artery aneurysm. AB - PURPOSE: To report midterm failure of tandem peripheral multilayer stents used to treat a common hepatic artery aneurysm (HAA) that had a good early result. CASE REPORT: A 71-year-old man with multiple comorbidities had a 3.4-cm HAA treated with 2 Cardiatis peripheral multilayer stents (8*100 and 9*60 mm) that overlapped by 3 cm. At the 12-month follow-up, the stents were patent, with signs of collateral patency and full thrombosis of the aneurysm sac without expansion. At the 18-month visit, the sac had expanded to 4.5 cm without signs of revascularization, but there was an initial stent dislocation; a wait and watch approach was elected. On the 24-month imaging, the HAA had enlarged to 6 cm, with disconnection of the 2 stents. A new multilayer stent (9*100 mm) was positioned to "bridge" the gap; however, the proximal part of the new stent did not correctly expand despite multiple attempts to overcome the infolding. The 3 stents became completely thrombosed, but thanks to rich mesenteric collaterals, perfusion of the proper hepatic artery was adequate. CONCLUSION: The multilayer peripheral stent appears to be an alternative for the treatment of visceral aneurysms in patients with a high surgical risk, but it is not a conventional stent. There are unknowns about its function, behavior, and application. Therefore, more experience is needed to validate the effectiveness of the multilayer stent. PMID- 23731315 TI - Intracranial hemodynamic stabilization patterns after stenting of severe stenosis in the proximal internal carotid artery. AB - PURPOSE: To evaluate intracranial hemodynamic stabilization patterns after carotid artery stenting (CAS) in patients having variable collateral developments before CAS. METHODS: The hemodynamic and angiographic data of 62 patients (58 men; mean age 68.0+/-8.4 years) who underwent CAS for unilateral proximal internal carotid artery stenosis were analyzed. The patients had transcranial Doppler examinations before and at 1 and 90 days after CAS. Patients were classified according to pre-CAS mean blood flow velocity (MBFV) of the ipsilateral middle cerebral artery (MCA): low (<30 cm/s; n=17), normal (30 to 48 cm/s; n=26), or high (>48 cm/s; n=19). The collaterals from contralateral anterior and/or posterior circulations prior to CAS, the stabilization pattern of MBFV, and the pulsatility index (PI) after CAS were compared across the 3 groups. RESULTS: The presence of collaterals was lowest in the low MBFV group (17.6% of patients) than in the normal (38.5%) or high (68.4%) MBFV groups (p=0.008). The low MBFV group exhibited an increase in MBFV and PI in the ipsilateral MCA at 1 and 90 days after CAS (p<0.05). By contrast, the high MBFV group exhibited a decrease in MBFV and no change in PI in the ipsilateral MCA up to 90 days after CAS (p<0.05). The normal MBFV group showed an increase in MBFV at post-CAS day 1 but a subsequent decrease at 90 days and an increase in PI in the ipsilateral MCA at 1 and 90 days post-CAS (p<0.05). CONCLUSION: The pattern of post-CAS intracranial hemodynamic stabilization differs according to the pre-CAS MBFV in the ipsilateral MCA. PMID- 23731316 TI - Impact of carotid stenting on the intracranial circulation in patients with internal carotid artery stenosis. PMID- 23731317 TI - New approach to protected percutaneous transluminal angioplasty in the lower limbs. AB - PURPOSE: To provide evidence for the safety and efficacy of the Proteus embolic capture balloon in lower limb interventions and to evaluate its indications for use. METHODS: The study was designed as a prospective, multicenter, non randomized, single arm study enrolling 123 patients (78 men; mean age 68 years). The primary endpoint was rate of freedom from death, amputation, and target vessel revascularization (TVR) at 30 days post procedure. Follow-up was performed at 30 days and at 12 months. RESULTS: The freedom from death, amputation, and TVR rate was 95.9% (118/123). Procedure and device success rates were 98.7% (218/223) and 97.8% (156/158), respectively. TVR and death rates at 12 months were 18.8% and 4.1%, respectively. Histological analysis identified particles in 100% of the balloons. The median number of particles per subject was 339 (range 63-4361). Medians of particle size and total particle area were 0.8 (range 0.3-8.3) and 1.0 mm(2) (range 0.1-237) per balloon, respectively. Particles >1 mm were found in 37% (53/143) of the balloons analyzed. Higher mean number, length, and surface area of particles were found in long lesions (909+/-1057, 2.6+/-2.3 mm, and 18.2+/-44.2 mm(2), respectively; all p<0.0001 vs. short lesions). Additionally, longer particles were found in total occlusions (2.5+/-2.5 mm, p<0.0001), and a higher mean particle count was found in thrombotic lesions (1785+/-1821, p<0.05). De novo lesions had more thrombotic material than any other type of lesion. CONCLUSION: Proteus demonstrated good particle capture ability, making it a useful tool in situations where embolism is anticipated, such as complex lesions with calcified or thrombotic material and/or lesions with high plaque burden (i.e., long and totally occluded). PMID- 23731318 TI - Protected PTA in the lower limbs: a step forward in preventing distal embolization. PMID- 23731319 TI - Acute peripheral arterial occlusion: prospective study evaluating intra-arterial thrombolysis with a micro-porous balloon catheter. AB - PURPOSE: To assess the efficacy of a new in situ thrombolysis method using a low pressure micro-porous balloon catheter (MPBC) compared to a traditional in situ infusion (ISI) of a fibrinolytic agent in the treatment of acute limb ischemia. METHODS: Between January 2010 and December 2011, 21 patients (14 men; mean age 64.6 years, range 40-92) treated for acute lower limb ischemia were prospectively enrolled in the study. Seven patients underwent in situ thrombolysis using the ISI method and 14 patients the MPBC method to deliver urokinase. The total urokinase dose injected and the length of stay in an intermediate care unit were compared between the groups. RESULTS: Recanalization was successful in 90% of cases (6/7 patients in the ISI group; 13/14 patients in the MPBC group). The morbidity was 7% (1 pseudoaneurysm). The dose of urokinase needed was significantly lower (p<0.001) in the MPBC group (0.7+/-0.44 IU, range 0.15-1.6) vs. the ISI group (1.66+/-0.71 IU, range 0.2-2). The average length of stay in the intermediate care unit was significantly shorter in the MPBC group (1.2 vs. 3.9 days, p<0.002). The overall 6-month limb salvage rate after recanalization was 90% (83% for the ISI patients vs. 93% for the MPBC group). CONCLUSIONS: Intra arterial thrombolysis using a balloon catheter is an effective method in the treatment of acute peripheral arterial occlusions. In the case of occlusion caused by embolism, primarily in very elderly patients, it may reduce the risk of hemorrhage. A randomized study on high-risk patients is needed to confirm these initial results. PMID- 23731320 TI - Local delivery of thrombolysis using the ClearWay irrigating balloon catheter in acute limb ischemia. PMID- 23731321 TI - Efficacy of the S.M.A.R.T. Control vs. other stents for aortoiliac occlusive disease in contemporary clinical practice. AB - PURPOSE: To compare the safety and efficacy of the S.M.A.R.T. Control stent vs. other stents in patients with symptomatic aortoiliac occlusive disease (AIOD) followed for up to 4 years. METHODS: A subgroup analysis of data from a retrospective multicenter registry examined 2036 symptomatic patients (1659 men; mean age 71+/-8 years) who received stent-supported endovascular therapy for 2541 AIOD lesions between April 2005 and December 2009. The cohort was divided into the S.M.A.R.T. stent group (955 patients/1196 lesions) and the "other" stent group (1081 patients/1345 lesions). The main study outcomes of primary patency and event-free survival at 4 years were compared before and after propensity matching analysis. The rates for freedom from major amputation, surgical conversion, target lesion revascularization (TLR), and major adverse limb events were also assessed. RESULTS: The S.M.A.R.T. Control stent group had greater frequency of critical limb ischemia (CLI), TASC C/D lesions, and chronic total occlusions. The mean follow-up was 25+/-17 months in the S.M.A.R.T. group vs. 29+/-19 months in the other stent group. After propensity matching, 4-year primary patency (86% vs. 76%, p<0.001) and freedom from adverse limb events (93% vs. 90%, p=0.04) were greater in the S.M.A.R.T. Control stent group, while event free survival rates (75% vs. 77%, p=0.50) were similar between groups. Univariate subgroup analysis showed that use of the S.M.A.R.T. stent was associated with greater primary patency in patients with renal insufficiency (serum creatinine >1.5 mg/dL) and CLI. CONCLUSION: After propensity matching analysis, the durability of the S.M.A.R.T. stent was superior to that of other stents, which might reflect differing design characteristics. PMID- 23731322 TI - Re: "Retrograde recanalization technique for use after failed antegrade angioplasty in chronic femoral artery occlusions". PMID- 23731323 TI - Re: "The enigma of lesion morphology in peripheral arterial occlusive disease". PMID- 23731324 TI - The first simultaneous kidney-adrenal gland-pancreas transplantation: outcome at 1 year. AB - Adrenal insufficiency is a rare but life-threatening disease. Replacement therapy sometimes fails to prevent an acute adrenal crisis and most often does not lead to restoration of well-being. We report here the 1-year outcome of the first simultaneous kidney-adrenal gland-pancreas transplantation in a 33-year-old patient with type 1 diabetes and concomitant autoimmune adrenal insufficiency. En bloc left adrenal gland and kidney grafts were anastomosed on the left iliac vessels in normal vascular conditions and the pancreas graft was anastomosed on the right iliac vessels. The immunosuppressive regimen was not modified by the addition of the adrenal gland. We observed no additional morbidity due to the adrenal gland transplantation, as there were no surgical complications. One-year kidney and pancreas graft functions were satisfactory (estimated glomerular filtration rate: 55 mL/min/1.73 m(2) and HbA1c: 4.8%). The adrenal graft functioned well at 12 months with a normalization of cortisol and aldosterone baseline levels. Functional imaging at 3 months showed good uptake of [(123) I] metaiodobenzylguanidine by the adrenal graft. Transplantation of the adrenal gland en bloc with the left kidney appears to be a good therapeutic option in patients with adrenal insufficiency awaiting kidney or kidney-pancreas transplantation. PMID- 23731325 TI - Neuromodulation for spasticity and dystonia. PMID- 23731327 TI - Synthesis of eukaryotic translation elongation inhibitor lactimidomycin via Zn(II)-mediated Horner-Wadsworth-Emmons macrocyclization. AB - An enantioselective synthesis of potent eukaryotic translation elongation inhibitor lactimidomycin has been accomplished in 21 linear steps. This synthesis features a Zn(II)-mediated Horner-Wadsworth-Emmons reaction that could be executed on a large scale to provide the highly strained 12-membered lactimidomycin macrolactone. PMID- 23731328 TI - Transitional B cell subsets in human bone marrow. AB - B cells originate from precursors in the bone marrow, and the first cells which migrate to the peripheral blood have been classified as 'transitional B cells'. Transitional B cells have been characterized in human blood with stage 1 (T1) and stage 2 (T2) subsets being proposed. In the present study, 27 normal human bone marrow samples were analysed for transitional B cell markers by eight-colour flow cytometry. T1 transitional B cells (CD45(+)CD19(+)CD10(+)IgM(+)IgD(lo)) and T2 transitional B cells (CD45(+)CD19(+)CD10(+)IgM(+)IgD(+)) were identified in normal bone marrow samples at a mean frequency of 3.2 and 3.1% of total B lineage cells, respectively. A majority of the bone marrow transitional B cells were CD24(hi)CD38(hi) , the phenotype of blood transitional B cells. Consistent with recent peripheral blood data, T2 B cells had a significantly higher CD21 expression compared with T1 B cells (72.4 versus 40.9%) in the bone marrow. These data raise the possibility that transitional B cells are capable of differentiating from T1 to T2 B cells within the bone marrow. Furthermore, transitional cells at either stages 1 or 2 might be capable of migrating out of the bone marrow. PMID- 23731329 TI - A contemporary view of applied relaxation for generalized anxiety disorder. AB - Applied relaxation (AR), originally developed by Lars-Goran Ost, is a long standing, efficacious treatment for generalized anxiety disorder (GAD). While newer treatments are continuing to be developed, AR remains one of the most efficacious treatments for GAD. However, AR has received less in-depth attention more recently, particularly in terms of potential mechanisms of action. This article is written to honor the development and history of AR and to highlight the ways that it has continued to be adapted. In this article, AR treatment strategies are presented, which include: noticing early signs of anxiety, learning relaxation skills, and applying relaxation at the first sign of anxiety. Then, additional adaptations to AR are presented along with recommendations of how AR may be enhanced by understanding potential mechanisms of change. Finally, recommendations are made for the continued evolution of AR as a powerful and efficacious treatment for GAD. PMID- 23731331 TI - A quasi-quantum well sensitized solar cell with accelerated charge separation and collection. AB - Semiconductor-sensitized solar cell (SSSC) represents a new generation of device aiming to achieve easy fabrication and cost-effective performance. However, the power of the semiconductor sensitizers has not been fully demonstrated in SSSC, making it actually overshadowed by dye-sensitized solar cell (DSSC). At least part of the problem is related to the inefficient charge separation and severe recombination with the current technologies, which calls on rethinking about how to better engineer the semiconductor sensitizer structure in order to enhance the power conversion efficiency (PCE). Herein we report on using for the first time a quasi-quantum well (QW) structure (ZnSe/CdSe/ZnSe) as the sensitizer, which is quasi-epitaxially deposited on ZnO tetrapods. Such a novel photoanode architecture has attained 6.20% PCE, among the highest reported to date for this type of SSSCs. Impedance spectra have revealed that the ZnSe/CdSe/ZnSe QW structure has a transport resistance only a quarter that of, but a recombination resistance twice that of the ZnSe/CdSe heterojunction (HJ) structure, yielding much longer electron diffusion length, consistent with the resulting higher photovoltage, photocurrent, and fill factor. Time-resolved photoluminescence spectroscopy indicates dramatically reduced electron transfer from ZnO to the QW sensitizer, a feature which is conducive to charge separation and collection. This study together with the impedance spectra and intensity modulated photocurrent spectroscopies supports a core/shell two-channel transport mechanism in this type of solar cells and further suggests that the electron transport along sensitizer can be considerably accelerated by the QW structure employed. PMID- 23731330 TI - Safety and immunovirologic outcomes with maraviroc combination regimens in patients with a history of past treatment failures and virologic resistance in Brazil: an open-label, multicenter phase 3b study. AB - Maraviroc is a first-in-class chemokine coreceptor type-5 (CCR5) antagonist with demonstrated immunovirologic activity in treatment-experienced (TE) patients with CCR5 (R5)-tropic HIV-1; however, experience in regimens containing newer antiretroviral agents is limited. The primary objective of this 96-week open label, noncomparative, multicenter Phase 3b study (NCT00478231) was to assess the safety of maraviroc in combination with optimized background therapy (OBT), which could include recently introduced agents such as darunavir and raltegravir in TE patients in Brazil with R5 HIV-1 and limited therapeutic options. Immunovirologic activity was a secondary endpoint. Of 638 patients screened, 206 were treated and 125 completed the study. Approximately 70% were male; the mean age was 43.2 years. Most patients (65.0%) received an OBT combination of protease inhibitor plus nucleoside reverse transcriptase inhibitor. Adverse event (AE) and treatment related AE incidence was 91.3% and 36.9%, respectively. The most common AEs were diarrhea, nasopharyngitis, and headache. Serious AEs and treatment-related serious AEs occurred in 16.5% and 4.4% of patients. Only eight patients (3.9%) discontinued due to AEs. Few AIDS-defining events were observed (4.9%). The proportion of patients with viral load <400 copies/ml increased from 2.4% at baseline to 43.9% at week 8, remaining >40% until week 48. At the end of treatment, 26.7% of patients had a viral load <400 copies/ml. Median CD4(+) cell count increased throughout the study; the mean change from baseline to end of treatment was 174.1 cells/MUl. In conclusion, maraviroc, combined with different agents from multiple classes, was well tolerated in highly TE patients. Maraviroc plus OBT was associated with an immunovirologic response in this population. PMID- 23731333 TI - Metabolic syndrome profiles, obesity measures and intake of dietary fatty acids in adults: Tehran Lipid and Glucose Study. AB - BACKGROUND: To determine the association between fatty acid intake and the prevalence of risk factors for the metabolic syndrome. METHODS: In this population-based cross-sectional study, a sample of 2750 Tehranian subjects (44% men and 56% women) aged 20-74 years, who completed a validated food frequency questionnaire, was studied. The metabolic syndrome (MetS) was defined in accordance with the modified guidelines of the National Cholesterol Education Program Adults Treatment Panel III, and waist circumference was coded according to the newly-introduced cut-off points for Iranian adults (>=95 cm for both sexes). Metabolic risk factors across quartile categories of each type of dietary fat [total fat intake, total poly-unsaturated fatty acid (PUFA) intake, total MUFA intake, total saturated fatty acid (SFA) intake expressed as percentage of energy and quartiles of the ratio of polyunsaturated fat to saturated fat (P : S)] were compared. RESULTS: The mean (SD) ages of participants were 40.8 (14.6) and 38.6 (12.9) years, respectively, for men and women. The mean contribution of fat to energy intake was approximately 26% in men and women. A positive trend over successive quartiles of SFA intake with low-density lipoprotein-cholesterol (LDL-C) and triglyceride, as well as P/S ratio intake with high-density lipoprotein-cholesterol (HDL-C), was found. An inverse association between HDL-C with SFA and PUFA intake and a positive association with MUFA and the P/S ratio was found. A significant association of fatty acid consumption and risk of the MetS in this population was observed, except for total PUFA intake. CONCLUSIONS: Special dietary fatty acids are associated with metabolic risk factors among the Iranian population. Because of the high prevalence of cardiovascular disease and MetS, national nutrition policies must be developed accordingly for the modification of dietary fatty acid intake with respect to causation and prevention. PMID- 23731332 TI - Genotype and phenotype relationships in 10 Pakistani unrelated patients with inherited factor VII deficiency. AB - Inherited factor VII (FVII) deficiency is one of the commonest rare bleeding disorders. It is characterized by a wide molecular and clinical heterogeneity and an autosomal recessive pattern of inheritance. Factor VII-deficient patients are still scarcely explored in Pakistan although rare bleeding disorders became quite common as a result of traditional consanguineous marriages. The aim of the study was to give a first insight of F7 gene mutations in Pakistani population. Ten unrelated FVII-deficient patients living in Pakistan were investigated (median FVII:C = 2%; range = 2-37%). A clinical questionnaire was filled out for each patient and direct sequencing was performed on the coding regions, intron/exon boundaries and 5' and 3' untranslated regions of the F7 gene. Nine different mutations (eight missense mutations and one located within the F7 promoter) were identified on the F7 gene. Five of them were novel (p.Cys82Tyr, p.Cys322Ser, p.Leu357Phe, p.Thr410Ala, c-57C>T, the last being predicted to alter the binding site of transcription factor HNF-4). Half of the patients had single mutations in Cys residues involved in disulfide bridges. The p.Cys82Arg mutation was the most frequent in our series. Six of seven patients with FVII:C levels below 10% were homozygous in connection with the high percentage of consanguinity in our series. In addition, we graded the 10 patients according to three previously published classifications for rare bleeding disorders. The use of the bleeding score proposed by Tosetto and co-workers in 2006 appears to well qualify the bleeding tendency in our series. PMID- 23731334 TI - A novel phospholipase B from Streptomyces sp. NA684--purification, characterization, gene cloning, extracellular production and prediction of the catalytic residues. AB - A novel metal ion-independent phospholipase B (PLB684) from Streptomyces sp. strain NA684 was purified 264-fold from the culture supernatant with 2.85% recovery (6330 U.mg protein-1). The enzyme functions as a monomer with a molecular mass of 38.9 kDa. Maximum activity was found at pH 8.4 and 50 degrees C. The substrate specificity was in the order: phosphatidylcholine >= phosphatidic acid >= lysophosphatidylcholine > phosphatidylserine > phosphatidylinositol > phosphatidylglycerol. The enzyme did not hydrolyze phosphatidylethanolamine, tristearin and dipalmitin. PLB684 hydrolyzed lysophosphatidylcholine and diacylphosphatidylcholine, and lysophosphatidylcholine was primarily produced during the early stages of phosphatidylcholine hydrolysis. The apparent K(m), V(max) and k(cat) for hydrolysis of dimyristoyl phosphatidic acid were 14.5 mm, 15.8 mmol.min-1.mg protein-1 and 1.02 * 104 s-1, respectively. The positional specificity of 1 palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine hydrolysis was investigated using GC. In the reaction equilibrium, the molar ratio of released fatty acids (sn-1: sn-2) was 45 : 55. The ORF of the gene is 1239 bp in length and codes for a 30 amino acid signal peptide and a 382-amino acid mature enzyme. The deduced amino acid sequence of PLB684 shows 60% identity to a uncharacterized protein of Streptomyces auratus AGR0001(UniProt accession number: J1RQY0). The extracellular production of PLB684 was achieved using a pUC702 expression vector and Streptomyces lividans as the host. Mutagenesis analysis showed that Ser12 is essential for the catalytic function of PLB684 and that the active site may include residues Ser330 and His332. PMID- 23731335 TI - Adequate levothyroxine doses for the treatment of hypothyroidism newly discovered during pregnancy. AB - BACKGROUND: Recent guidelines recommend thyrotropin (TSH) target levels of <=2.5 mIU/L for the first trimester and <=3 mIU/L for the subsequent trimesters. Euthyroidism should be attained as soon as possible, but there are no precise indications about the initial levothyrorine (LT4) dose. The aim of our study was to determine the appropriate LT4 doses in order to normalize TSH levels in patients with newly discovered subclinical hypothyroidism (SCH) during pregnancy, and to correlate them with basal TSH levels. The adequate LT4 doses for women with SCH were also compared to those required in pregnant women with overt hypothyroidism (OH). METHODS: Seventy-seven patients with newly diagnosed hypothyroidism during pregnancy were retrospectively analyzed. Patients were assigned to group 1 (n = 64) with SCH or group 2 (n = 13) with OH. SCH patients were subdivided into two groups: group 1a serum TSH >2.5 (1st trimester) or >3 (2nd or 3rd trimester) to 4.2 mIU/L; and group 1b TSH level > 4.21-10 mIU/L. All patients were treated with LT4 as soon as hypothyroidism was diagnosed. The dose that allowed a TSH of <=2.5 mIU/L to be reached in the first trimester or one that allowed a TSH of <=3 mIU/L to be reached during the second and third trimesters was considered the appropriate one. RESULTS: A significant difference (p < 0.0001) in the appropriate LT4 dose (mean +/- SD, MUg/kg/day) was observed between group 1 and group 2: 1.31 +/- 0.36 versus 2.33 +/- 0.59. Patients in group 1a required a significantly lower LT4 dose (p < 0.014) than group1b: 1.20 +/- 0.39 versus 1.42 +/- 0.31 MUg/kg/day. In 57 of the 64 (89.06%) women with SCH and in 10/13 (76.92%) women with OH, the appropriate LT4 dose coincided with the initial dose. Only 11% and 23% respectively required additional adjustments. Once the appropriate dose of LT4 was prescribed, the time at which euthyroidism (mean +/- SD, weeks) was confirmed was similar in patients with SCH (6.06 +/- 3.3) and OH (5.3 +/- 1.8). There were no miscarriages or premature deliveries. CONCLUSIONS: When hypothyroidism is newly discovered during pregnancy, we suggest initiating the treatment with the following LT4 doses: 1.20 MUg/kg/day for SCH with TSH <= 4.2 mIU/L, 1.42 MUg/kg/day with TSH > 4.2-10, and 2.33 MUg/kg/day for OH. By taking this approach, patients will promptly attain the euthyroid state avoiding additional increments and, probably, obstetric risks. PMID- 23731336 TI - Sustainable mesoporous carbons as storage and controlled-delivery media for functional molecules. AB - Here, we report the synthesis of surfactant-templated mesoporous carbons from lignin, which is a biomass-derived polymeric precursor, and their potential use as a controlled-release medium for functional molecules such as pharmaceuticals. To the best of our knowledge, this is the first report on the use of lignin for chemical-activation-free synthesis of functional mesoporous carbon. The synthesized carbons possess the pore widths within the range of 2.5-12.0 nm. In this series of mesoporous carbons, our best result demonstrates a Brunauer-Emmett Teller (BET) surface area of 418 m(2)/g and a mesopore volume of 0.34 cm(3)/g, which is twice the micropore volume in this carbon. Because of the dominant mesoporosity, this engineered carbon demonstrates adsorption and controlled release of a representative pharmaceutical drug, captopril, in simulated gastric fluid. Large-scale utilization of these sustainable mesoporous carbons in applications involving adsorption, transport, and controlled release of functional molecules is desired for industrial processes that yield lignin as a coproduct. PMID- 23731338 TI - Do not hesitate to use Tversky-and other hints for successful active analogue searches with feature count descriptors. AB - This study is an exhaustive analysis of the neighborhood behavior over a large coherent data set (ChEMBL target/ligand pairs of known Ki, for 165 targets with >50 associated ligands each). It focuses on similarity-based virtual screening (SVS) success defined by the ascertained optimality index. This is a weighted compromise between purity and retrieval rate of active hits in the neighborhood of an active query. One key issue addressed here is the impact of Tversky asymmetric weighing of query vs candidate features (represented as integer-value ISIDA colored fragment/pharmacophore triplet count descriptor vectors). The nearly a 3/4 million independent SVS runs showed that Tversky scores with a strong bias in favor of query-specific features are, by far, the most successful and the least failure-prone out of a set of nine other dissimilarity scores. These include classical Tanimoto, which failed to defend its privileged status in practical SVS applications. Tversky performance is not significantly conditioned by tuning of its bias parameter alpha. Both initial "guesses" of alpha = 0.9 and 0.7 were more successful than Tanimoto (at its turn, better than Euclid). Tversky was eventually tested in exhaustive similarity searching within the library of 1.6 M commercial + bioactive molecules at http://infochim.u strasbg.fr/webserv/VSEngine.html , comparing favorably to Tanimoto in terms of "scaffold hopping" propensity. Therefore, it should be used at least as often as, perhaps in parallel to Tanimoto in SVS. Analysis with respect to query subclasses highlighted relationships of query complexity (simply expressed in terms of pharmacophore pattern counts) and/or target nature vs SVS success likelihood. SVS using more complex queries are more robust with respect to the choice of their operational premises (descriptors, metric). Yet, they are best handled by "pro query" Tversky scores at alpha > 0.5. Among simpler queries, one may distinguish between "growable" (allowing for active analogs with additional features), and a few "conservative" queries not allowing any growth. These (typically bioactive amine transporter ligands) form the specific application domain of "pro candidate" biased Tversky scores at alpha < 0.5. PMID- 23731337 TI - Associations of family meal frequency with family meal habits and meal preparation characteristics among families of youth with type 1 diabetes. AB - BACKGROUND: While benefits of family mealtimes, such as improved dietary quality and increased family communication, have been well-documented in the general population, less is known about family meal habits that contribute to more frequent family meals in youth with type 1 diabetes. METHODS: This cross sectional study surveyed 282 youth ages 8-18 years with type 1 diabetes and their parents on measures regarding diabetes-related and dietary behaviours. T-tests determined significant differences in youth's diet quality, adherence to diabetes management and glycaemic control between those with and without regular family meals (defined as >= 5 meals per week). Logistic regression analyses determined unadjusted and adjusted associations of age, socio-demographics, family meal habits, and family meal preparation characteristics with regular family meals. RESULTS: 57% of parents reported having regular family meals. Families with regular family meals had significantly better diet quality as measured by the Healthy Eating Index (P < 0.05) and the NRF9.3 (P < 0.01), and adherence to diabetes management (P < 0.001); the difference in glycaemic control approached statistical significance (P = 0.06). Priority placed on, pleasant atmosphere and greater structure around family meals were each associated with regular family meals (P < 0.05). Meals prepared at home were positively associated with regular family meals, while convenience and fast foods were negatively associated (P < 0.05). Families in which at least one parent worked part-time or stayed at home were significantly more likely to have regular family meals than families in which both parents worked full-time (P < 0.05). In the multivariate logistic regression model, greater parental priority given to family mealtimes (P < 0.001) and more home-prepared meals (P < 0.001) predicted occurrence of regular family meals; adjusting for parent work status and other family meal habits. CONCLUSIONS: Strategies for promoting families meals should not only highlight the benefits of family meals, but also facilitate parents' skills for and barriers to home-prepared meals. PMID- 23731339 TI - Key workers in cancer care: patient and staff attitudes and implications for role development in cancer services. AB - The role of the key worker in cancer services was developed in the UK and is now being adopted more widely. Although this role arose out of national guidance, little is known about how it has been implemented, and there been no systematic attempt to investigate how the role is viewed by either patients or staff. This study used a qualitative approach to explore views of the impact of the key worker role in cancer care. Interviews were conducted with 15 staff and 15 patients. Generally, patients were very positive about the role, while staff felt it was just a renaming of their role, which they thought unnecessary. Several differences in the views of staff and patients emerged from the interviews. For example, staff felt the role should transfer to other members of the care team while patients wanted to keep the same worker. Potential reasons for this divergence in attitudes are discussed, and suggestions for the future development of the role made. PMID- 23731340 TI - Microbial community adaptation to quaternary ammonium biocides as revealed by metagenomics. AB - Quaternary ammonium compounds (QACs) represent widely used cationic biocides that persist in natural environments. Although microbial degradation, sensitivity and resistance to QACs have been extensively documented, a quantitative understanding of how whole communities adapt to QAC exposure remain elusive. To gain insights into these issues, we exposed a microbial community from a contaminated river sediment to varied levels of benzalkonium chlorides (BACs, a family of QACs) for 3 years. Comparative metagenomic analysis showed that the BAC-fed communities were dramatically decreased in phylogenetic diversity compared with the control (no BAC exposure), resulting presumably from BAC toxicity, and dominated by Pseudomonas species (> 50% of the total). Time-course metagenomics revealed that community adaptation occurred primarily via selective enrichment of BAC-degrading Pseudomonas populations, particularly P. nitroreducens, and secondarily via amino acid substitutions and horizontal transfer of a few selected genes in the Pseudomonas populations, including a gene encoding a PAS/PAC sensor protein and ring-hydroxylating dioxygenase genes. P. nitroreducens isolates were reproducibly recoverable from communities after prolonged periods of no-BAC exposure, suggesting that they are robust BAC-degraders. Our study provides new insights into the mechanisms and tempo of microbial community adaptation to QAC exposure and has implications for treating QACs in biological engineered systems. PMID- 23731341 TI - Exploring the effect of depressive symptoms and ageing on metamemory in an Italian adult sample. AB - The current study aimed to investigate the effect of depression and age-related factors on metamemory measures in an Italian adult sample. Fifty-eight healthy participants were recruited in Northern Italy and were, respectively, assigned to the following groups: Young (20-30 years old), old (60-70 years old), and Very Old (71-84 years old). Participants were administered a battery of tests, including a word recall task, self-referent mnestic efficiency scales, general beliefs about memory, and depression measures. General beliefs about memory, self efficacy, and beliefs about the control of personal memory were predicted by age, education, depression, and mnestic and cognitive efficiency. Finally, age-related differences were found in metamemory measures: the accuracy of mnestic control processes is thought to be lower by very old adults than by old and young individuals. PMID- 23731342 TI - Histological effects of residual compression sustained for 60 minutes at different depths in a novel rat spinal cord injury contusion model. AB - Spinal cord injuries are frequently accompanied by persisting residual compression of the spinal cord; however, it remains controversial as to what effect the sustained compression has on neurological damage. The objective of this study was to determine the influence of post-traumatic residual spinal cord compression on the extent and progression of tissue damage within a dynamic thoracic contusion rat model. Twenty-nine male Wistar rats were distributed into one of four groups: spinal cord contusion only, contusion with 40% residual compression, contusion with 90% residual compression, and a surgical control group. A moderate injury was performed (1 mm, 700 mm/sec) with our custom University of British Columbia (UBC) multimechanism apparatus, and the residual compression groups had the impactor tip maintained at 40% or 90% of the initial impact depth (1.0 mm) for 60 min post-injury. All animals were killed at 3 h post injury, when the spinal cord was harvested and stained for hemorrhage, neuronal damage in the gray matter, and axonal disruption in the white matter. The initial contusion injury immediately damaged tissue beneath the impactor as evidenced by rapid relaxation of the reaction force on the spinal cord during the subsequent compression. Importantly, the rostral-caudal extent of intramedullary hemorrhage was 66% larger after 90% residual spinal cord compression compared to the 40% group (p=0.016). Similarly, the extent of neuronal nuclei lost in different gray matter regions was 60-86% greater after 90% residual compression compared with 40% (p<0.001). Thus, a high level of residual compression of the spinal cord following a moderate contusion injury has the potential to adversely increase the extent of tissue damage, whereas a lower level of residual compression may have little to no effect. PMID- 23731343 TI - Nucleocytoplasmic partitioning of tobacco N receptor is modulated by SGT1. AB - SGT1 (Suppressor of G2 allele of SKP1) is required to maintain plant disease Resistance (R) proteins with Nucleotide-Binding (NB) and Leucine-Rich Repeat (LRR) domains in an inactive but signaling-competent state. SGT1 is an integral component of a multi-protein network that includes RACK1, Rac1, RAR1, Rboh, HSP90 and HSP70, and in rice the Mitogen-Activated Protein Kinase (MAPK), OsMAPK6. Tobacco (Nicotiana tabacum) N protein, which belongs to the Toll-Interleukin Receptor (TIR)-NB-LRR class of R proteins, confers resistance to Tobacco Mosaic Virus (TMV). Following transient expression in planta, we analyzed the functional relationship between SGT1, SIPK - a tobacco MAPK6 ortholog - and N, using mass spectrometry, confocal microscopy and pathogen assays. Here, we show that tobacco SGT1 undergoes specific phosphorylation in a canonical MAPK target-motif by SIPK. Mutation of this motif to mimic SIPK phosphorylation leads to an increased proportion of cells displaying SGT1 nuclear accumulation and impairs N-mediated resistance to TMV, as does phospho-null substitution at the same residue. Forced nuclear localization of SGT1 causes N to be confined to nuclei. Our data suggest that one mode of regulating nucleocytoplasmic partitioning of R proteins is by maintaining appropriate levels of SGT1 phosphorylation catalyzed by plant MAPK. PMID- 23731344 TI - Magnesium adjunctive therapy in atrial arrhythmias. AB - Magnesium (Mg) is an important intracellular ion with cardiac metabolism and electrophysiologic properties. A large percentage of patients with arrhythmias have an intracellular Mg deficiency, which is out of line with serum Mg concentrations, and this may explain the rationale for Mg's benefits as an atrial antiarrhythmic agent. A current limitation of antiarrhythmic therapy is that the potential for cardiac risk offsets some of the benefits of therapy. Mg enhances the balance of benefits to harms by enhancing atrial antiarrhythmic efficacy and reducing antiarrhythmic proarrhythmia potential as well as providing direct antiarrhythmic efficacy when used as monotherapy in patients undergoing cardiothoracic surgery. PMID- 23731345 TI - Two patients with history of STEC-HUS, posttransplant recurrence and complement gene mutations. AB - Hemolytic uremic syndrome (HUS) is a disease of microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. About 90% of cases are secondary to infections by Escherichia coli strains producing Shiga-like toxins (STEC-HUS), while 10% are associated with mutations in genes encoding proteins of complement system (aHUS). We describe two patients with a clinical history of STEC-HUS, who developed end-stage renal disease (ESRD) soon after disease onset. They received a kidney transplant but lost the graft for HUS recurrence, a complication more commonly observed in aHUS. Before planning a second renal transplantation, the two patients underwent genetic screening for aHUS-associated mutations that revealed the presence of a heterozygous CFI mutation in patient #1 and a heterozygous MCP mutation in patient #2, and also in her mother who donated the kidney. This finding argues that the two cases originally diagnosed as STEC HUS had indeed aHUS triggered by STEC infection on a genetic background of impaired complement regulation. Complement gene sequencing should be performed before kidney transplantation in patients who developed ESRD following STEC-HUS since they may be undiagnosed cases of aHUS, at risk of posttransplant recurrence. Furthermore, genetic analysis of donors is mandatory before living related transplantation to exclude carriers of HUS-predisposing mutations. PMID- 23731346 TI - Formal total synthesis of lactimidomycin. AB - A concise synthesis of an intermediate of lactimidomycin, a glutarimide containing macrocyclic polyketide produced by an actinomycete, has been accomplished in 35% overall yield from a known vinylketene silyl N,O-acetal by a 10-step sequence that involves two types of asymmetric aldol reactions to install all the stereocenters, the Stille coupling to set up the whole carbon famework, and the Yamaguchi lactonization to construct the 12-membered macrolactone ring. PMID- 23731347 TI - Spatial waves in synthetic biochemical networks. AB - We report the experimental observation of traveling concentration waves and spirals in a chemical reaction network built from the bottom up. The mechanism of the network is an oscillator of the predator-prey type, and this is the first time that predator-prey waves have been observed in the laboratory. The molecular encoding of the nonequilibrium behavior relies on small DNA oligonucleotides that enforce the network connectivity and three purified enzymes that control the reactivity. Wave velocities in the range 80-400 MUm min(-1) were measured. A reaction-diffusion model in quantitative agreement with the experiments is proposed. Three fundamental parameters are easy to tune in nucleic acid reaction networks: the topology of the network, the rate constants of the individual reactions, and the diffusion coefficients of the individual species. For this reason, we expect such networks to bring unprecedented opportunities for assaying the principles of spatiotemporal order formation in chemistry. PMID- 23731348 TI - An integrator circuit in cerebellar cortex. AB - The brain builds dynamic models of the body and the outside world to predict the consequences of actions and stimuli. A well-known example is the oculomotor integrator, which anticipates the position-dependent elasticity forces acting on the eye ball by mathematically integrating over time oculomotor velocity commands. Many models of neural integration have been proposed, based on feedback excitation, lateral inhibition or intrinsic neuronal nonlinearities. We report here that a computational model of the cerebellar cortex, a structure thought to implement dynamic models, reveals a hitherto unrecognized integrator circuit. In this model, comprising Purkinje cells, molecular layer interneurons and parallel fibres, Purkinje cells were able to generate responses lasting more than 10 s, to which both neuronal and network mechanisms contributed. Activation of the somatic fast sodium current by subthreshold voltage fluctuations was able to maintain pulse-evoked graded persistent activity, whereas lateral inhibition among Purkinje cells via recurrent axon collaterals further prolonged the responses to step and sine wave stimulation. The responses of Purkinje cells decayed with a time-constant whose value depended on their baseline spike rate, with integration vanishing at low (< 1 per s) and high rates (> 30 per s). The model predicts that the apparently fast circuit of the cerebellar cortex may control the timing of slow processes without having to rely on sensory feedback. Thus, the cerebellar cortex may contain an adaptive temporal integrator, with the sensitivity of integration to the baseline spike rate offering a potential mechanism of plasticity of the response time-constant. PMID- 23731349 TI - Attentional bias modification in people with chronic pain: a proof of concept study. AB - The purpose of this proof of concept study was to explore the role of attentional bias modification (ABM) in improving clinically relevant outcomes in chronic pain. Eight participants with chronic pain completed eight ABM sessions, which featured a modified version of the visual-probe task implicitly training attention away from pain-related stimuli towards neutral stimuli. Training sessions included a variety of linguistic and pictorial pain-related stimuli, which were presented at two presentation times (500 and 1250 ms). Participants also completed a standard version of the visual-probe task pre- and post-ABM to assess changes in bias. The primary outcome measure was pain intensity, and secondary outcome measures were anxiety, depression severity and pain interference. Statistically and clinically significant change was shown pre- to post-ABM in pain intensity, anxiety, depression and pain interference. Attentional bias scores did not statistically differ across time. These results support the continued exploration of ABM in chronic pain and the modifications we made to the intervention (i.e. the inclusion of pictorial stimuli and a longer presentation time). Future research is needed to explore the optimal form of ABM and whether improvements are maintained over time. PMID- 23731350 TI - Potentiometric sensors with ion-exchange Donnan exclusion membranes. AB - Potentiometric sensors that exhibit a non-Hofmeister selectivity sequence are normally designed by selective chemical recognition elements in the membrane. In other situations, when used as detectors in separation science, for example, membranes that respond equally to most ions are preferred. With so-called liquid membranes, a low selectivity is difficult to accomplish since these membranes are intrinsically responsive to lipophilic species. Instead, the high solubility of sample lipids in an ionophore-free sensing matrix results in a deterioration of the response. We explore here potentiometric sensors on the basis of ion-exchange membranes commonly used in fuel cell applications and electrodialysis, which have so far not found their way into the field of ion-selective electrodes. These membranes act as Donnan exclusion membranes as the ions are not stripped of their hydration shell as they interact with the membrane. Because of this, lipophilic ions are no longer preferred over hydrophilic ones, making them promising candidates for the detection of abundant ions in the presence of lipophilic ones or as detectors in separation science. Two types of cation-exchanger membranes and one anion-exchange membrane were characterized, and potentiometric measuring ranges were found to be Nernstian over a wide range down to about 10 MUM concentrations. Depending on the specific membrane, lipophilic ions gave equal response to hydrophilic ones or were even somewhat discriminated. The medium and long-term stability and reproducibility of the electrode signals were found to be promising when evaluated in synthetic and whole blood samples. PMID- 23731351 TI - Population pharmacokinetics of recombinant factor IX: implications for dose tailoring. AB - The principles of pharmacokinetic (PK) dose tailoring in clinical practice, using limited blood sampling and Bayesian PK analysis, have been described for factor VIII (FVIII). This study applied the same procedure to recombinant FIX (rFIX), i.e. population PK modelling and the use of a simplified (one-compartment) model to describe only the terminal part of the coagulation factor vs. time curve. Data from a previous study on rFIX in 56 patients (4-56 years, 18-133 kg) were used to define a three-compartment population PK model. The average FIX clearance was 8.4 mL h(-1) kg(-1) . Elimination half-life ranged between 14 and 27 h. Data obtained from 24 h after the infusion were found to define the terminal phase of FIX disposition. Doses to produce a target trough FIX level (set at 0.01 IU mL(-1) ) at 72 h predicted by the Bayesian analysis, with blood sampling at either 24, 48 and 72 h or at only 24 and 48 h, were within -40% to +67% of those predicted using the three-compartment model, and within -57% to +125% for targeting a level at 96 h. These errors were lower than the overall interindividual variance in dose requirements. As three-compartment models are needed to characterize the PK of both plasma-derived FIX and rFIX, simplification to a one-compartment model is less straightforward than for FVIII, and the methodology should be investigated further before clinical application. Limited blood sampling and Bayesian analysis could still, however, be potentially useful for targeting rFIX trough levels during prophylaxis. PMID- 23731352 TI - Pnicogen-bonded cyclic trimers (PH2X)3 with X = F, Cl, OH, NC, CN, CH3, H, and BH2. AB - Ab initio MP2/aug'-cc-pVTZ calculations have been carried out to determine the structures and binding energies of cyclic trimers (PH2X)3 with X = F, Cl, OH, NC, CN, CH3, H, and BH2. Except for [PH2(CH3)]3, these complexes have C3h symmetry and binding energies between -17 and -63 kJ mol(-1). Many-body interaction energy analyses indicate that the two-body terms are dominant, accounting for 97-103% of the total binding energy. Except for the trimer [PH2(OH)]3, the three-body terms are stabilizing. Charge transfer from the lone pair on one P atom to an antibonding sigma* orbital of the P atom adjacent to the lone pair plays a very significant role in stabilization. The charge-transfer energies correlate linearly with the trimer binding energies. NBO, AIM, and ELF analyses have been used to characterize bonds, lone pairs, and the degree of covalency of the P...P pnicogen bonds. The NMR properties of chemical shielding and (31)P-(31)P coupling constants have also been evaluated. Although the (31)P chemical shieldings in the five most strongly bound trimers increase relative to the corresponding isolated monomers, there is no correlation between the chemical shieldings and the charges on the P atoms. EOM-CCSD (31)P-(31)P spin-spin coupling constants computed for four (PH2X)3 trimers fit nicely onto a plot of (1p)J(P-P) versus the P-P distance for (PH2X)2 dimers. A coupling constant versus distance plot for the four trimers has a second-order trendline which has been used to predict the values of (1p)J(P P) for the remaining trimers. PMID- 23731353 TI - A unifying quantitative framework for exploring the multiple facets of microbial biodiversity across diverse scales. AB - Recent developments of molecular tools have revolutionized our knowledge of microbial biodiversity by allowing detailed exploration of its different facets and generating unprecedented amount of data. One key issue with such large datasets is the development of diversity measures that cope with different data outputs and allow comparison of biodiversity across different scales. Diversity has indeed three components: local (alpha), regional (gamma) and the overall difference between local communities (beta). Current measures of microbial diversity, derived from several approaches, provide complementary but different views. They only capture the beta component of diversity, compare communities in a pairwise way, consider all species as equivalent or lack a mathematically explicit relationship among the alpha, beta and gamma components. We propose a unified quantitative framework based on the Rao quadratic entropy, to obtain an additive decomposition of diversity (gamma = alpha + beta), so the three components can be compared, and that integrate the relationship (phylogenetic or functional) among Microbial Diversity Units that compose a microbial community. We show how this framework is adapted to all types of molecular data, and we highlight crucial issues in microbial ecology that would benefit from this framework and propose ready-to-use R-functions to easily set up our approach. PMID- 23731354 TI - Predicting depression with temperament and character in lung cancer patients. AB - Depression is highly prevalent in cancer patients. Variations in intensity and frequency of depression in cancer patients may be attributed, in part, to differences in personality dimensions. Our aim was to asses if dimensions of temperament and character could predict depression in lung cancer patients. Ninety newly diagnosed non-small cell lung cancer patients were assessed in the oncology unit with the Centre for Epidemiologic Studies Depression Scale (CES-D), pain subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30 and the Temperament and Character Inventory (TCI). Fifty out of 90 patients (55.6%) fulfilled the cut-off criteria for depression on the CES-D scale. Logistic regression performed to assess if depression was predicted by personality dimensions, revealed dimension of temperament Harm Avoidance and pain as significant predictors of depression. Depressive reactions are highly prevalent in lung cancer patients and related to patients' personality. These findings may be helpful in planning preventive, as well as psychoeducational and treatment programmes for newly diagnosed, and depression prone patients. PMID- 23731355 TI - Parents of children with physical disabilities - perceived health in parents related to the child's sleep problems and need for attention at night. AB - BACKGROUND: Approximately half of all children with moderate to severe physical disabilities have persistent sleep problems and many of these children need parental attention at night. AIM: To study whether sleep problems and need for night-time attention among children with physical disabilities are associated with perceived parental health, headache, psychological exhaustion, pain due to heavy lifting, night-time wakefulness and disrupted sleep. METHODS: We asked parents of 377 children with physical disabilities aged 1-16 years to complete a questionnaire about their own health. The children all lived at home with both parents. RESULTS: Both parents reported poor health, psychological exhaustion, more night-time wakefulness and disrupted sleep when the child had sleep problems (P < 0.05). Mothers also reported more headache when the child had sleep problems (P = 0.001). Both parents reported more night-time wakefulness and disrupted sleep when the child needed night-time attention (P < 0.01). In general, mothers reported significantly poorer health, more night-time wakefulness, disrupted sleep, headache and psychological exhaustion than fathers (P < 0.001). CONCLUSIONS: Sleep problems need to be acknowledged within the paediatric setting in order to prevent psychological exhaustion and poor health in mothers and fathers of children with physical disabilities. PMID- 23731357 TI - Mild hypothermia increases pulmonary anti-inflammatory response during protective mechanical ventilation in a piglet model of acute lung injury. AB - BACKGROUND: The effects of mild hypothermia (HT) on acute lung injury (ALI) are unknown in species with metabolic rate similar to that of humans, receiving protective mechanical ventilation (MV). We hypothesized that mild hypothermia would attenuate pulmonary and systemic inflammatory responses in piglets with ALI managed with a protective MV. METHODS: Acute lung injury (ALI) was induced with surfactant deactivation in 38 piglets. The animals were then ventilated with low tidal volume, moderate positive end-expiratory pressure (PEEP), and permissive hypercapnia throughout the experiment. Subjects were randomized to HT (33.5 degrees C) or normothermia (37 degrees C) groups over 4 h. Plasma and tissue cytokines, tissue apoptosis, lung mechanics, pulmonary vascular permeability, hemodynamic, and coagulation were evaluated. RESULTS: Lung interleukin-10 concentrations were higher in subjects that underwent HT after ALI induction than in those that maintained normothermia. No difference was found in other systemic and tissue cytokines. HT did not induce lung or kidney tissue apoptosis or influence lung mechanics or markers of pulmonary vascular permeability. Heart rate, cardiac output, oxygen uptake, and delivery were significantly lower in subjects that underwent HT, but no difference in arterial lactate, central venous oxygen saturation, and coagulation test was observed. CONCLUSIONS: Mild hypothermia induced a local anti-inflammatory response in the lungs, without affecting lung function or coagulation, in this piglet model of ALI. The HT group had lower cardiac output without signs of global dysoxia, suggesting an adaptation to the decrease in oxygen uptake and delivery. Studies are needed to determine the therapeutic role of HT in ALI. PMID- 23731358 TI - Ploidy-specific symbiotic interactions: divergence of mycorrhizal fungi between cytotypes of the Gymnadenia conopsea group (Orchidaceae). AB - Polyploidy is widely recognized as a major mechanism of sympatric speciation in plants, yet little is known about its effects on interactions with other organisms. Mycorrhizal fungi are among the most common plant symbionts and play an important role in plant nutrient supply. It remains to be understood whether mycorrhizal associations of ploidy-variable plants can be ploidy-specific. We examined mycorrhizal associations in three cytotypes (2x, 3x, 4x) of the Gymnadenia conopsea group (Orchidaceae), involving G. conopsea s.s. and G. densiflora, at different spatial scales and during different ontogenetic stages. We analysed: adults from mixed- and single-ploidy populations at a regional scale; closely spaced adults within a mixed-ploidy site; and mycorrhizal seedlings. All Gymnadenia cytotypes associated mainly with saprotrophic Tulasnellaceae (Basidiomycota). Nonetheless, both adults and seedlings of diploids and their autotetraploid derivatives significantly differed in the identity of their mycorrhizal symbionts. Interploidy segregation of mycorrhizal symbionts was most pronounced within a site with closely spaced adults. This study provides the first evidence that polyploidization of a plant species can be associated with a shift in mycorrhizal symbionts. This divergence may contribute to niche partitioning and facilitate establishment and co-existence of different cytotypes. PMID- 23731359 TI - Role of aspirin and non-aspirin NSAIDs in preventing melanoma. PMID- 23731361 TI - Organopalladium complexes of oxacalixarenes: selecting the lid for the three dimensional scaffold. AB - The first organometallic (palladium) complexes of oxacalixarene molecules were prepared via oxidative addition of the C-I bond at the lower rim. The unique geometry of the oxacalixarene scaffold allowed for the selective introduction of new ligands at the top of the calixarene scaffold. Such coordination can be used to coordinatively link the opposing aromatic rings. PMID- 23731362 TI - Prophylactic high-dose oral-N-acetylcysteine does not prevent atrial fibrillation after heart surgery: a prospective double blind placebo-controlled randomized clinical trial. AB - AIMS: Postoperative atrial fibrillation (POAF) following cardiac surgery is a frequent complication with multifactorial etiologies. Recently inflammation due to enhanced oxidative stress has been implicated in its pathogenesis. N acetylcysteine (NAC) is a promising and novel antioxidant agent. The purpose of this study was to evaluate the efficacy of high-dose oral-NAC for prevention of POAF. METHODS: Two hundred and forty patients were randomized in this prospective, double blind placebo-controlled trial to either 1,200-mg oral-NAC two times a day (n = 120) or placebo (n = 120) starting 48 hours before and up to 72 hours after open heart surgery. RESULTS: The mean age was about 60 years, and 75% were male. Patients in the NAC group were older, with higher percentage of acute coronary syndrome, hypercholesterolemia, and left internal mammary artery use. Coronary involvement and hypertension were more prevalent in the placebo group. All other baseline patient characteristics were similar between groups. Overall POAF developed in 13.8% of the patients. There was no difference in the incidence of POAF between the NAC vs placebo groups (11.7% vs 15.8%, respectively; P = 0.34). Postoperative hospital stay, morbidity, and mortality were similar in both groups. CONCLUSIONS: Prophylactic high-dose oral-NAC begun 2 days before open heart surgery and continued for 5 days, and had no significant effect on the incidence of POAF, in-hospital stay, and postoperative morbidity or mortality. PMID- 23731360 TI - Synthesis of mixed (E,Z)-, (E)-, and (Z)-norendoxifen with dual aromatase inhibitory and estrogen receptor modulatory activities. AB - The first synthesis of the tamoxifen metabolite norendoxifen is reported. This included syntheses of (E)-norendoxifen, (Z)-norendoxifen, and (E,Z)-norendoxifen isomers. (Z)-Norendoxifen displayed affinity for aromatase (Ki 442 nM), estrogen receptor-alpha (EC50 17 nM), and estrogen receptor-beta (EC50 27.5 nM), while the corresponding values for (E)-norendoxifen were aromatase (Ki 48 nM), estrogen receptor-alpha (EC50 58.7 nM), and estrogen receptor-beta (EC50 78.5 nM). Docking and energy minimization studies were performed with (E)-norendoxifen on aromatase, and the results provide a foundation for structure-based drug design. The oral pharmacokinetic parameters for (E,Z)-norendoxifen were determined in mice, and (Z)-norendoxifen was found to result in significantly higher plasma concentrations and exposures (AUC values) than (E)-norendoxifen. The affinities of both isomers for aromatase and the estrogen receptors, as well as the pharmacokinetic results, support the further development of norendoxifen and its analogues for breast cancer treatment. PMID- 23731363 TI - Nanoparticles produced by ring-opening metathesis polymerization using norbornenyl-poly(ethylene oxide) as a ligand-free generic platform for highly selective in vivo tumor targeting. AB - We described a norbornenyl-poly(ethylene oxide) nanoparticles ligand-free generic platform, made fluorescent with straightforward preparation by ring-opening metathesis polymerization (ROMP). Our method allowed to easily obtain a drug delivery system (DDS) with facilitated functionalization by means of azide-alkyne click chemistry and with a high selectivity for the tumor in vivo, while cellular internalization is obtained without cell targeting strategy. We demonstrated that our nanoparticles are internalized by endocytosis and colocalized with acidic intracellular compartments in two models of aggressive tumoral cell lines with low prognostic and limited therapeutic treatments. Our nanoparticles could be of real interest to limit the toxicity and to increase the clinical benefit of drugs suffering rapid clearance and side effects and an alternative for cancers with poorly efficient therapeutic solutions by associating the drug delivery in the tumor tissue with an acid-sensitive release system. PMID- 23731365 TI - Validity and reliability of radiological methods to assess proximal hip geometry in children with cerebral palsy: a systematic review. AB - AIM: The aim of this systematic review was to assess the current validity and reliability of radiological methods used to measure proximal hip geometry in children with cerebral palsy. METHOD: A search was conducted using relevant keywords and inclusion/exclusion criteria of the MEDLINE, CINALH Plus, Embase, Web of Science, Academic Search Premier, The Cochrane Library, and PsychINFO databases. RESULTS: The migration percentage using X-rays showed excellent reliability and concurrent validity with three-dimensional (3D) measurements from computed tomography (CT) scans. The acetabular index, measured using X-rays had good reliability but moderate concurrent validity with 3D CT measurements; 3D CT scan indexes had greater reliability. The measurement of the neck shaft angle using X-rays showed excellent concurrent validity with measurements from 3D CT scans and excellent reliability. Regarding femoral anteversion, one study found an excellent correlation between two-dimensional CT and clinical assessment and excellent reliability. Two others showed less evidence for the use of CT ultrasounds. INTERPRETATION: Most of the X-ray-based measurements showed good to excellent metrological properties. More metrological evidence is needed for the assessment of femoral anteversion. Magnetic resonance imaging and ultrasound based measurements have great potential although very little metrological evidence is available. PMID- 23731366 TI - Interfacially polymerized layers for oxygen enrichment: a method to overcome Robeson's upper-bound limit. AB - Interfacial polymerization of four aqueous phase monomers, diethylenetriamine (DETA), m-phenylenediamine (mPD), melamine (Mela), and piperazine (PIP), and two organic phase monomers, trimethyl chloride (TMC) and cyanuric chloride (CC), produce a thin-film composite membrane of polymerized polyamide layer capable of O2/N2 separation. To achieve maximum efficiency in gas permeance and O2/N2 permselectivity, the concentrations of monomers, time of interfacial polymerization, number of reactive groups in monomers, and the structure of monomers need to be optimized. By controlling the aqueous/organic monomer ratio between 1.9 and 2.7, we were able to obtain a uniformly interfacial polymerized layer. To achieve a highly cross-linked layer, three reactive groups in both the aqueous and organic phase monomers are required; however, if the monomers were arranged in a planar structure, the likelihood of structural defects also increased. On the contrary, linear polymers are less likely to result in structural defects, and can also produce polymer layers with moderate O2/N2 selectivity. To minimize structural defects while maximizing O2/N2 selectivity, the planar monomer, TMC, containing 3 reactive groups, was reacted with the semirigid monomer, PIP, containing 2 reactive groups to produce a membrane with an adequate gas permeance of 7.72 * 10(-6) cm(3) (STP) s(-1) cm(-2) cm Hg(-1) and a high O2/N2 selectivity of 10.43, allowing us to exceed the upper-bound limit of conventional thin-film composite membranes. PMID- 23731364 TI - Engineered proteins with Pumilio/fem-3 mRNA binding factor scaffold to manipulate RNA metabolism. AB - Pumilio/fem-3 mRNA binding factor proteins are characterized by a sequence specific RNA-binding domain. This unique single-stranded RNA recognition module, whose sequence specificity can be reprogrammed, has been fused with functional modules to engineer protein factors with various functions. We summarize the advances made with respect to developing RNA regulatory tools, as well as opportunities for the future. PMID- 23731367 TI - Prediction of kidney graft failure using clinical scoring tools. AB - BACKGROUND: Donor organ quality is a key determinant of graft function, and considerable efforts have been made to identify donor and transplant factors predicting inferior outcomes. This has resulted in the development of various scoring tools to aid in allocation of kidneys. METHODS: The performance of four donor quality scoring systems in predicting delayed graft function, and death censored graft failure was examined in a single-center cohort of 730 consecutive deceased donor kidneys transplanted between 1990 and 2004. The predictive accuracy of the variables was analyzed with receiver operating characteristic curves and graft survival distribution. RESULTS: The three outcome tools, that is, deceased donor score (DDS; Am J Transplant, 3, 2003, 715), donor risk score (DRS; Am J Transplant, 5, 2005, 757) and kidney donor risk index (KDRI; Transplantation, 88, 2009, 231) provided a significant and equivalent prediction of graft failure by using variables available at time of transplantation (p < 0.01). The risk of delayed graft function was predicted by the (DGF) nomogram (J Am Soc Nephrol, 14, 2003, 2967; Am J Transplant 10, 2010, 2279) with a high degree of discrimination (concordance index of 0.69, p < 0.01). CONCLUSIONS: Our findings validate four pre-operative clinical scoring tools to predict early and late graft outcome in an independent, single-center set of kidney transplants. PMID- 23731368 TI - CMV infection in the donor and increased kidney graft loss: impact of full HLA-I mismatch and posttransplantation CD8(+) cell reduction. AB - Despite a large body of literature, the impact of chronic cytomegalovirus (CMV) infection in donor on long-term graft survival remains unclear, and factors modulating the effect of CMV infection on graft survival are presently unknown. In this retrospective study of 1279 kidney transplant patients, we analyzed long term graft survival and evolution of CD8(+) cell population in donors and recipients by CMV serology and antigenemia status. A positive CMV serology in the donor was an independent risk factor for graft loss, especially among CMV positive recipients (R(+) ). Antigenemia was not a risk factor for graft loss and kidneys from CMV-positive donors remained associated with poor graft survival among antigenemia-free recipients. Detrimental impact of donor's CMV seropositivity on graft survival was restricted to patients with full HLA-I mismatch, suggesting a role of CD8(+) cells. In R(+) patients with positive CMV antigenemia during the first year, CD8(+) cell count did not increase at 2 years posttransplantation, in contrast to R(-) recipients. In addition, marked CD8(+) cell decrease was a risk factor of graft failure in these patients. This study identifies HLA-I full mismatch and a decrease of CD8(+) cell count at 2 years as important determinants of CMV-associated graft loss. PMID- 23731369 TI - The bone disease associated with factor VIII deficiency in mice is secondary to increased bone resorption. AB - Osteopenia and osteoporosis have increasingly become a recognized morbidity of factor VIII (FVIII) deficiency. Recently, we demonstrated that FVIII knockout (KO) mice had significantly decreased bone mass and bone strength despite the fact that they did not have haemarthroses. The aim of this study was to explore the mechanism of bone disease associated with FVIII deficiency. We compared biochemical markers of bone formation and osteoclastogenesis, inflammatory cytokines, as well as static and dynamic histomorphometry of genetically engineered FVIII KO male mice to those of wild-type (WT) controls. At 20 weeks of age, FVIII KO mice, as well as WT controls, were sacrificed. Serum and bones were obtained at the time of sacrifice to study biochemical markers of bone formation (osteocalcin) and osteoclastogenesis (receptor activator of nuclear factor kappa beta and osteoprotegerin), levels of inflammatory cytokines (interleukin-1alpha and interferon-beta) and to perform static and dynamic histomorphometry of tibia cancellous bone. There was no difference in the biochemical markers of bone formation or osteoclastogenesis. However, there were differences in the two bone associated cytokines studied. In addition, histomorphometric examination revealed cancellous osteopenia in FVIII KO mice as evidenced by decreased bone area and trabecular number and increased trabecular separation. Bone formation parameters were normal in FVIII KO mice. In contrast, osteoclast-lined bone perimeter was increased. These data demonstrate that bone disease in FVIII KO mice is due to an increased rate of bone resorption. PMID- 23731370 TI - Health-related quality of life in traumatic brain injury: is a proxy report necessary? AB - Despite its importance to care, clinicians and researchers often discount patient reported outcomes in favor of proxy reports, in persons with traumatic brain injury (TBI). The rationale relates to concerns about lack of awareness of patients regarding their functioning. However, although lack of awareness occurs in some patients with severe TBI, or in TBI involving certain lesion locations, or very soon after injury, this conclusion has been overgeneralized. The objective of this study is to determine the validity of patient-reported health related quality of life by evaluating its relationship to injury severity and more objective indices of outcome, in a representative series of adults with TBI. A consecutive sample of 374 persons with TBI at least 14 years old, and having a post-resuscitation Glasgow Coma Scale score <=12, an acute seizure, or a CT scan showing TBI- related findings. Seventy-six percent (374/491) of the eligible survivors were assessed at 6 months post-injury on the Life Satisfaction Survey. The greatest decrease in satisfaction was in the ability to think and remember, work, receive adequate income, and participate in leisure and recreational activities. Dissatisfaction significantly related to the functional limitation in that area as judged by the patients themselves (p<0.001) or by someone who knew them well (p<=0.001). The most severely injured group reported the most dissatisfaction for 13 out of 17 areas assessed. Patients with TBI, in general, do not need a proxy to report on their behalf regarding their functional limitations or health-related quality of life. PMID- 23731371 TI - "A rare ingestion of the black locust tree". PMID- 23731372 TI - Outcome of children with melamine-induced urolithiasis: results of a two-year follow-up. AB - OBJECTIVE: Our purpose is to describe the characteristics and the outcome of melamine-induced renal and urinary tract injury in young children who consumed melamine-contaminated infant formula. METHODS: This is a descriptive longitudinal study over 2 years in 240 children with melamine-induced urolithiasis screened in our hospital from September 15 to October 31, 2008. Ultrasonography and serum creatinine (SCr), urea, beta2-microglobulin (MG), cystatin C (Cys C), urinary Cr (UCr), microalbumin (mALB), alpha1-MG, beta2-MG, n-acetyl-beta-d-glucosaminidase (NAG) and retinol-binding protein (RBP) measurements were performed. RESULTS: The children ranged in age from 1 to 82 months, and 145 were males. The largest calculus was 33 mm in diameter. X-ray diffraction pattern of the calculi displayed two diffraction peaks at 10.9 degrees and 27.7 degrees (2theta). Surgical management was performed in 14 patients. In 226 patients without surgical management, the calculi were passed in 59.63% patients within 1 month, in 85.40% within 6 and in 91.15% within 24 months. Increased SCr and urea levels were noted in three and six patients, respectively, at the time of diagnosis. The SCr, serum beta2-MG, and Cys C levels at the time of diagnosis were higher than those at 3 and 6 months after diagnosis (P < 0.05, respectively). The levels of mALB/UCr, NAG/UCr, and RBP/UCr at the time of diagnosis were higher than those at 3, 6, 12, and 24 months after diagnosis (P < 0.05, respectively). alpha1-MG/UCr and beta2-MG/UCr levels at the time of diagnosis were similar to those at 3 months after diagnosis, and significantly higher than those in the follow-up period (P < 0.05, respectively). CONCLUSION: Melamine might injure both the renal glomerulus and the tubule, and that the predominant lesion is urolithiasis. The compositions of melamine-induced urolithiasis are melamine and cyanuric acid crystals. The urolithiasis might persist for over 2 years and cause irreversible damage. Therefore, a long-term follow-up for all patients is required. PMID- 23731373 TI - Severe clinical toxicity associated with analytically confirmed recreational use of 25I-NBOMe: case series. AB - CONTEXT: 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a N-methoxybenzyl-substituted phenethylamine with potent serotoninergic effects. We describe seven cases of analytically confirmed toxicity due to the recreational use of 25I-NBOMe in the United Kingdom. CASE SERIES: Seven patients, all young adult males, presented to hospitals in the northeast of England with clinical toxicity after recreational drug use in January 2013. Clinical features included tachycardia (n = 7), hypertension (4), agitation (6), aggression, visual and auditory hallucinations (6), seizures (3), hyperpyrexia (3), clonus (2), elevated white cell count (2), elevated creatine kinase (7), metabolic acidosis (3), and acute kidney injury (1). LC-MS/MS analysis identified 25I-NBOMe as the main active substance in the plasma of all seven cases. CONCLUSIONS: Severe clinical toxicity may occur following recreational use of 25I-NBOMe, with stimulant and serotoninergic features predominating. Clinicians should be alert to this substance, in view of its emergence in Europe as well as in the United States. PMID- 23731374 TI - Acute disseminated encephalomyelitis following biting by a scolopendra subspinipes mutilans. PMID- 23731375 TI - The administration of N-acetylcysteine reduces oxidative stress and regulates glutathione metabolism in the blood cells of workers exposed to lead. AB - CONTEXT AND OBJECTIVE: The aim of the study was to investigate whether treatment with N-acetylcysteine (NAC) is able to restore erythrocyte glutathione (GSH) content in workers exposed to lead. Additionally, we measured the leukocyte and erythrocyte activities of GSH-related enzymes, such as glutathione reductase (GR), glutathione-S-transferase (GST), and glucose-6-phosphate dehydrogenase (G6PD), and estimated the influence of NAC administration on oxidative stress intensity, which was measured as the lipofuscin (LPS) level in erythrocytes. METHODS: The exposed population consisted of 171 healthy males randomly divided into four groups. Workers in the first group (n = 49) were not administered any antioxidants, drugs, vitamins, or dietary supplements, while workers in the remaining groups were treated with NAC at three doses for 12 weeks (1 * 200 mg per day, 2 * 200 mg per day, and 2 * 400 mg per day). All workers continued to work during the study. The blood of all examined workers was drawn two times: at the beginning of the study and after 12 weeks of treatment. RESULTS AND CONCLUSION: Blood lead levels decreased significantly in all groups receiving NAC compared to those in baseline. Erythrocyte GSH concentrations were significantly elevated in workers receiving 400 and 800 mg of NAC compared to those in baseline by 5% and 6%, respectively. Erythrocyte G6PD activity was significantly elevated in workers receiving 200, 400, and 800 mg of NAC compared to those in baseline by 24%, 14%, and 14%, respectively. By contrast, there were no significant differences in leukocyte G6PD or leukocyte and erythrocyte glutathione reductase (GR) activities before and after treatment. Leukocyte GST activities decreased significantly after treatment in workers receiving 200 mg of NAC by 34%, while LPS levels decreased significantly in workers receiving 200, 400, and 800 mg of NAC compared to those in baseline by 5%, 15%, and 13%, respectively. In conclusion, NAC decreases oxidative stress in workers exposed to lead via stimulating GSH synthesis. PMID- 23731376 TI - Clinical toxicology in Edinburgh, two centuries of progress. AB - The Scottish Poisons Information Bureau was established in Edinburgh in September 1963 and shortly afterwards one of the wards of the city's Royal Infirmary was designated a Regional Poisoning Treatment Centre. Both units were soon to be brought under one roof. To mark this 50th anniversary, we review how they built upon a history dating from the early 19th century and highlight their influence on current clinical toxicological practice and the delivery of poisons information. While many centres worldwide seek to improve the care of poisoned patients, the contribution of Edinburgh over the past 50 years has been notable. PMID- 23731377 TI - Regioselective synthesis of multisubstituted benzenes by palladium-catalyzed intermolecular reaction of beta-iodo-beta-silylstyrenes with alkynes. AB - The Pd-catalyzed reaction between beta-iodo-beta-silylstyrenes and terminal alkynes in i-Pr2NEt gave 1,2,3,5-tetrasubstituted benzenes with complete regioselection. The use of certain silylacetylenes as alkynes enabled efficient synthesis of 1,3,5-trissilyl-2-arylbenzenes, which could be transformed into other multisubstituted benzenes by displacement of the silyl groups. PMID- 23731378 TI - Clinical correlates of alexithymia among patients with personality disorder. AB - The literature portrays patients with alexithymia as unusual and difficult to treat; research to date has not clarified the nature of this condition. This study addressed associations between alexithymia and constructs relevant to clinical intervention, namely attachment, quality of object relations, emotion regulation, defense style, personality disorder, and treatment outcome. Fifty-one patients admitted to an intensive group-oriented day treatment program were recruited. Prior to therapy, patients were administered self-report and structured interview measures of predictor and outcome variables; outcome measures were re-administered at completion of the 18-week program. Alexithymia was common in this sample, with four of five patients endorsing moderate or greater problems. Associations with attachment avoidance, primitive object relations, suppression of emotional expression, use of immature defenses, and severity of borderline personality disorder were identified. Alexithymia did not, however, predict outcome. Findings are considered in terms of how the construct informs views of personality disorder. PMID- 23731379 TI - Microporous aluminophosphate nanosheets and their nanomorphic zeolite analogues tailored by hierarchical structure-directing amines. AB - Multiamines with amphiphilic structures have been synthesized to serve as simultaneous structure-directing agents in micro- and meso-structural levels for aluminophosphate materials (AlPOs) and their analogues, such as silicoaluminophosphate, cobalt aluminophosphate, and gallium phosphate. The amine molecules are assembled into a micelle with a specific morphology to function as a meso-level structure director. Individual amine groups in the micelle are able to direct the formation of microporous crystalline AlPO structure. The resultant meso-level morphologies of the AlPOs are typically nanosheets of uniform thickness, which can be tailored in the range of 2-5 nm by the number of amine groups. Sponge-like disordered mesoporous morphologies can be generated, depending on the amine structures. Using such multiamines provides a versatile route to various phosphate materials with a structural hierarchy for enhanced porous functionalities. PMID- 23731380 TI - Enabling quantitative analysis in ambient ionization mass spectrometry: internal standard coated capillary samplers. AB - We describe a sampling method using glass capillaries for quantitative analysis of trace analytes in small volumes of complex mixtures (~1 MUL) using ambient ionization mass spectrometry. The internal surface of a sampling glass capillary was coated with internal standard then used to draw liquid sample and so transfer both the analyte and internal standard in a single fixed volume onto a substrate for analysis. The internal standard was automatically mixed into the sample during this process and the volumes of the internal standard solution and sample are both fixed by the capillary volume. Precision in quantitation is insensitive to variations in length of the capillary, making the preparation of the sampling capillary simple and providing a robust sampling protocol. Significant improvements in quantitation accuracy were obtained for analysis of 1 MUL samples using various ambient ionization methods. PMID- 23731381 TI - Generation of functional hepatocyte-like cells from human pluripotent stem cells in a scalable suspension culture. AB - Recent advances in human embryonic and induced pluripotent stem cell-based therapies in animal models of hepatic failure have led to an increased appreciation of the need to translate the proof-of-principle concepts into more practical and feasible protocols for scale up and manufacturing of functional hepatocytes. In this study, we describe a scalable stirred-suspension bioreactor culture of functional hepatocyte-like cells (HLCs) from the human pluripotent stem cells (hPSCs). To promote the initial differentiation of hPSCs in a carrier free suspension stirred bioreactor into definitive endoderm, we used rapamycin for "priming" phase and activin A for induction. The cells were further differentiated into HLCs in the same system. HLCs were characterized and then purified based on their physiological function, the uptake of DiI-acetylated low density lipoprotein (LDL) by flow cytometry without genetic manipulation or antibody labeling. The sorted cells were transplanted into the spleens of mice with acute liver injury from carbon tetrachloride. The differentiated HLCs had multiple features of primary hepatocytes, for example, the expression patterns of liver-specific marker genes, albumin secretion, urea production, collagen synthesis, indocyanin green and LDL uptake, glycogen storage, and inducible cytochrome P450 activity. They increased the survival rate, engrafted successfully into the liver, and continued to present hepatic function (i.e., albumin secretion after implantation). This amenable scaling up and outlined enrichment strategy provides a new platform for generating functional HLCs. This integrated approach may facilitate biomedical applications of the hPSC-derived hepatocytes. PMID- 23731382 TI - Protein-serine/threonine/tyrosine kinases in bacterial signaling and regulation. AB - In this review, we address some recent developments in the field of bacterial protein phosphorylation, focusing specifically on serine/threonine and tyrosine kinases. We present an overview of recent studies outlining the scope of physiological processes that are regulated by phosphorylation, ranging from cell cycle, growth, cell morphology, to metabolism, developmental phenomena, and virulence. Specific emphasis is placed on Mycobacterium tuberculosis as a showcase organism for serine/threonine kinases, and Bacillus subtilis to illustrate the importance of protein phosphorylation in developmental processes. We argue that bacterial serine/threonine and tyrosine kinases have a distinctive feature of phosphorylating multiple substrates and might thus represent integration nodes in the signaling network. Some open questions regarding the evolutionary benefits of relaxed substrate selectivity of these kinases are treated, as well as the notion of nonfunctional 'background' phosphorylation of cellular proteins. We also argue that phosphorylation events for which an immediate regulatory effect is not clearly established should not be dismissed as unimportant, as they may have a role in cross-talk with other post-translational modifications. Finally, recently developed methods for studying protein phosphorylation networks in bacteria are briefly discussed. PMID- 23731383 TI - Small peptide-modified nanostructured lipid carriers distribution and targeting to EGFR-overexpressing tumor in vivo. AB - Ala-Glu-Tyr-Leu-Arg (AEYLR) was identified as a small peptide ligand targeting epidermal growth factor receptors (EGFR) in vitro in our previous study. The in vivo targeting ability of AEYLR and AEYLR-conjugated nanostructured lipid carriers (NLC) was studied in this paper. Near-infrared fluorescent (NIFR) dye 1,1'-dioctadecyltetramethyl indotricarbocyanine iodide (DiR)-loaded and AEYLR modified NLC (A-D-NLC) were prepared. The average diameter, zeta potential, coupling efficiency between AEYLR and NLC and the amount of DiR released from A-D NLC were used to evaluate their in vivo characteristics. AEYLR was labeled by Cy7 and A549 xenograft tumor-bearing mice model were establish. The in vivo distribution in tumor-bearing mice of A-D-NLC and Cy7-AEYLR was examined using NIRF imaging experiments at different times post-injection. AEYLR and AEYLR conjugated NLC showed obvious targeting to A549 xenograft tumor compared with the control group. These results suggested that AEYLR-modified NLC could be considered as a promising targeted delivery system for combination cancer chemotherapy to improve therapeutic efficacy and to minimize adverse effects. PMID- 23731384 TI - Building foundations for an open perspective on synthetic biology research and innovation. PMID- 23731385 TI - The expanding role of PARPs in the establishment and maintenance of heterochromatin. AB - Poly(ADP-ribose) polymerases (PARPs) are enzymes that transfer poly(ADP-ribose) (PAR) groups to target proteins, and thereby affect various nuclear and cytoplasmic processes. The activity of PARP family members, such as PARP1 and PARP2, is tied to cellular signalling pathways, and, through poly(ADP ribosyl)ation, they ultimately promote changes in chromatin architecture, gene expression, and the location and activity of proteins that mediate signalling responses. A growing body of evidence suggest that PARPs, particularly PARP1 and PARP2, also operate at heterochromatic regions such as the inactive X chromosome, telomeres, pericentric heterochromatin and silent ribosomal RNA (rRNA) genes. Both proteins localize to heterochromatic sites and often associate with or poly(ADP-ribosyl)ate histones and heterochromatin-binding proteins, thereby modulating their activities. In this review, we describe current knowledge concerning the role of PARPs in establishment and inheritance of heterochromatic structures, and highlight how their contribution affects biological outcomes. PMID- 23731386 TI - Hemin therapy suppresses inflammation and retroperitoneal adipocyte hypertrophy to improve glucose metabolism in obese rats co-morbid with insulin-resistant type 2 diabetes. AB - AIM: Visceral adiposity and impaired glucose metabolism are common patho physiological features in patients co-morbid with obesity and type-2 diabetes. We investigated the effects of the heme-oxygenase (HO) inducer hemin and the HO blocker stannous-mesoporphyrin (SnMP) on glucose metabolism, adipocyte hypertrophy and pro-inflammatory cytokines/mediators in Zucker diabetic fatty (ZDF) rats, a model characterized by obesity and type-2 diabetes. METHODS: Histological, morphological/morphometrical, Western immunoblotting, enzyme immunoassay, ELISA and spectrophotometric analysis were used. RESULTS: Treatment with hemin enhanced HO-1, HO activity and cGMP, but suppressed retroperitoneal adiposity and abated the elevated levels of macrophage-chemoattractant protein-1 (MCP-1), ICAM-1, tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), IL-1beta, NF-kappaB, c-Jun-NH2-terminal-kinase (JNK) and activating-protein (AP 1), with parallel reduction of adipocyte hypertrophy. Correspondingly, important proteins of lipid metabolism and insulin-signalling such as lipoprotein lipase (LPL), insulin-receptor substrate-1 (IRS-1), GLUT4, PKB/Akt, adiponectin, the insulin-sensitizing and anti-inflammatory protein and adenosine-monophosphate activated protein kinase (AMPK) were significantly enhanced in hemin-treated ZDF rats. CONCLUSION: Elevated retroperitoneal adiposity and the high levels of MCP 1, ICAM-1, TNF-alpha, IL-6, IL-1beta, NF-kappaB, JNK and AP-1 in untreated ZDF are patho-physiological factors that exacerbate inflammatory insults, aggravate adipocyte hypertrophy, with corresponding reduction of adiponectin and deregulation of insulin-signalling and lipid metabolism. Therefore, the suppression of MCP-1, ICAM-1, TNF-alpha, IL-6, IL-1beta, NF-kappaB, JNK, AP-1 and adipocyte hypertrophy, with the associated enhancement of LPL, adiponectin, AMPK, IRS-1, GLUT4, PKB/Akt and cGMP in hemin-treated ZDF are among the multifaceted mechanisms by which the HO system combats inflammation to potentiate insulin signalling and improve glucose and lipid metabolism. Thus, HO inducers may be explored in the search of novel remedies against the co-morbidities of obesity, dysfunctional lipid metabolism and impaired glucose metabolism. PMID- 23731387 TI - Cytomegalovirus infection post-pancreas-kidney transplantation--results of antiviral prophylaxis in high-risk patients. AB - BACKGROUND: Cytomegalovirus (CMV) is a major pathogen affecting solid organ transplant (SOT) recipients. Prophylactic strategies have decreased the rate of CMV infection/disease among SOT. However, data on the effect of current prophylactic strategies for simultaneous pancreas-kidney (SPK) or pancreas after kidney (PAK) transplant remain limited. We report our experience of CMV prophylaxis in SPK/PAK recipients. METHODS: A total of 130 post-SPK/PAK patients were analyzed retrospectively for the rate of CMV and the risk factors associated with the acquisition of CMV. All patients received antiviral prophylaxis. The follow-up period was one yr post-transplant or until death. RESULTS: The rate of CMV post-SPK/PAK transplant was 24%, 44%, and 8.2% among the whole cohort, the D+/R- and the R+ groups, respectively. Median time of prophylaxis was 49 (0-254) d. In the whole cohort, risk factors for CMV infection/diseases were D+/R- CMV status (odds ratio [OR] = 16.075), preceding non-CMV (infection caused by bacteria or fungi and other viruses) infection (OR = 6.362) and the duration of prophylaxis (OR = 0.984). Among the CMV D+/R- group, non-CMV infection was the only risk factor for CMV disease (OR = 10.7). CONCLUSIONS: Forty-four per cent (25/57) of the D+/R- recipients developed CMV infection/disease despite CMV prophylaxis. Current CMV prophylaxis failed to prevent CMV infection/disease in this group of patients. PMID- 23731388 TI - A novel assay to measure B cell responses to keyhole limpet haemocyanin vaccination in healthy volunteers and subjects with systemic lupus erythematosus. AB - The aim of the study was to characterize performance of a complementary set of assays to measure antigen-specific immune responses in subjects immunized with a neoantigen. Healthy volunteers (HV) (n = 8) and patients with systemic lupus erythematosus (SLE) (n = 6) were immunized with keyhole limpet haemocyanin (KLH) on days 1 and 29. Serum antibodies were detected using a flow cytometric bead array (CBA) that multiplexed the KLH response alongside pre-existing anti-tetanus antibodies. Peripheral blood mononuclear cells were studied by B cell ELISPOT. These assays were built upon precedent assay development in cynomolgus monkeys, which pointed towards their utility in humans. Primary anti-KLH IgG responses rose to a mean of 65-93-fold above baseline for HV and SLE patients, respectively, and secondary responses rose to a mean of 260-170-fold above baseline. High levels of anti-tetanus IgG were detected in pre-immunization samples and their levels did not change over the course of study. Anti-KLH IgG1-4 subclasses were characterized by a predominant IgG1 response, with no significant differences in subclass magnitude or distribution between HV and SLE subjects. Anti-KLH IgM levels were detectable, although the overall response was lower. IgM was not detected in two SLE subjects whodid generate an IgG response. All subjects responded to KLH by B cell ELISPOT, with no significant differences observed between HV and SLE subjects. The CBA and B cell ELISPOT assays reliably measured anti-KLH B cell responses, supporting use of this approach and these assays to assess the pharmacodynamic and potential safety impact of marketed/investigational immune-therapeutics. PMID- 23731390 TI - Phylogeny and assemblage composition of Frankia in Alnus tenuifolia nodules across a primary successional sere in interior Alaska. AB - In nitrogen (N) fixing symbioses, host-symbiont specificity, genetic variation in bacterial symbionts and environmental variation represent fundamental constraints on the ecology, evolution and practical uses of these interactions, but detailed information is lacking for many naturally occurring N-fixers. This study examined phylogenetic host specificity of Frankia in field-collected nodules of two Alnus species (A. tenuifolia and A. viridis) in interior Alaska and, for A. tenuifolia, distribution, diversity, spatial autocorrelation and correlation with specific soil factors of Frankia genotypes in nodules collected from replicated habitats representing endpoints of a primary sere. Frankia genotypes most commonly associated with each host belonged to different clades within the Alnus-infective Frankia clade, and for A. tenuifolia, were divergent from previously described Frankia. A. tenuifolia nodules from early and late succession habitats harboured distinct Frankia assemblages. In early succession, a single genotype inhabited 71% of nodules with no discernable autocorrelation at any scale, while late succession Frankia were more diverse, differed widely among plants within a site and were significantly autocorrelated within and among plants. Early succession Frankia genotype occurrence was strongly correlated with carbon/nitrogen ratio in the mineral soil fraction, while in late succession, the most common genotypes were correlated with different soil variables. Our results suggest that phylogenetic specificity is a significant factor in the A. tenuifolia-Frankia interaction and that significant habitat-based differentiation may exist among A. tenuifolia-infective genotypes. This is consistent with our hypothesis that A. tenuifolia selects specific Frankia genotypes from early succession soils and that this choice is attenuated in late succession. PMID- 23731389 TI - Racial and ethnic differences in pediatric access to preemptive kidney transplantation in the United States. AB - Preemptive kidney transplantation is the optimal treatment for pediatric end stage renal disease patients to avoid increased morbidity and mortality associated with dialysis. It is unknown how race/ethnicity and poverty influence preemptive transplant access in pediatric. We examined the incidence of living donor or deceased donor preemptive transplantation among all black, white, and Hispanic children (<18 years) in the United States Renal Data System from 2000 to 2009. Adjusted risk ratios for preemptive transplant were calculated using multivariable-adjusted models and examined across health insurance and neighborhood poverty levels. Among 8,053 patients, 1117 (13.9%) received a preemptive transplant (66.9% from LD, 33.1% from DD). In multivariable analyses, there were significant racial/ethnic disparities in access to LD preemptive transplant where blacks were 66% (RR = 0.34; 95% CI: 0.28-0.43) and Hispanics 52% (RR = 0.48; 95% CI: 0.35-0.67) less likely to receive a LD preemptive transplant versus whites. Blacks were 22% less likely to receive a DD preemptive transplant versus whites (RR = 0.78, 95% CI: 0.57-1.05), although results were not statistically significant. Future efforts to promote equity in preemptive transplant should address the critical issues of improving access to pre-ESRD nephrology care and overcoming barriers in living donation, including obstacles partially driven by poverty. PMID- 23731392 TI - Utility of unsedated transnasal endoscopy for pharyngeal observation during esophagogastroduodenoscopy. A prospective study to assess cardiopulmonary function. AB - OBJECTIVES: Emergence of image-enhanced endoscopy has enabled an early detection of pharyngeal carcinoma. Pharyngeal observation during esophagogastroduodenoscopy (EGD) is sometimes difficult because of excessive reflexes and is a great burden to the patients and impacts on their cardiopulmonary function. In this study, the authors aimed to evaluate the utility of transnasal EGD (TN-EGD) in comparison with sedated and unsedated transoral EGD (TO-EGD) in pharyngeal observation using a continuous monitoring device. METHODS: A total of 70 patients receiving diagnostic EGD (unsedated TN-EGD, sedated TO-EGD, and unsedated TO-EGD) were enrolled in this study and were evaluated by the following three criteria: (1) numbers of patients with excessive gag and/or cough reflex, (2) vital signs before and during the pharyngeal observation, and (3) response to the request for vocalization or breath-holding. RESULTS: Unsedated TN-EGD, sedated TO-EGD, and unsedated TO-EGD were performed in 30, 20, and 20 patients, respectively. The rate of gag reflex was significantly lower in TN-EGD than in both types of TO-EGD (0% vs. 30%, chi-square test, p < 0.005). The changes in average values of both arterial oxygen saturation (SpO2) and pulse rate (PR) in TN-EGD were smaller than those in sedated TO-EGD (-0.23% vs. -1.23% in SpO2 and 1.57 vs. 8.11 bpm in PR, p < 0.01, respectively). Unsedated TN-EGD patients could respond to the instructions of utterance and breath-holding during the observation (p < 0.05, p < 0.001, respectively). CONCLUSION: Unsedated TN-EGD is safe and feasible for pharyngeal observation during normal EGD examination. PMID- 23731391 TI - tPA-S(481)A prevents impairment of cerebrovascular autoregulation by endogenous tPA after traumatic brain injury by upregulating p38 MAPK and inhibiting ET-1. AB - Traumatic brain injury (TBI) is associated with loss of cerebrovascular autoregulation, which leads to cerebral hypoperfusion. Mitogen activated protein kinase (MAPK) isoforms ERK, p38, and JNK and endothelin-1 (ET-1) are mediators of impaired cerebral hemodynamics after TBI. Excessive tissue plasminogen activator (tPA) released after TBI may cause loss of cerebrovascular autoregulation either by over-activating N-methyl-D-aspartate receptors (NMDA-Rs) or by predisposing to intracranial hemorrhage. Our recent work shows that a catalytically inactive tPA variant (tPA-S(481)A) that competes with endogenous wild type (wt) tPA for binding to NMDA-R through its receptor docking site but that cannot activate it, prevents activation of ERK by wt tPA and impairment of autoregulation when administered 30 min after fluid percussion injury (FPI). We investigated the ability of variants that lack proteolytic activity but bind/block activation of NMDA-Rs by wt tPA (tPA-S(481)A), do not bind/block activation of NMDA-Rs but are proteolytic (tPA-A(296-299)), or neither bind/block NMDA-Rs nor are proteolytic (tPA-A(296-299)S(481)A) to prevent impairment of autoregulation after TBI and the role of MAPK and ET-1 in such effects. Results show that tPA-S(481)A given 3 h post-TBI, but not tPA-A(296-299) or tPA-A(296-299)S(481)A prevents impaired autoregulation by upregulating p38 and inhibiting ET-1, suggesting that tPA S(481)A has a realistic therapeutic window and focuses intervention on NMDA-Rs to improve outcome. PMID- 23731393 TI - Organocatalytic asymmetric annulation of 1,3-bis(alkoxycarbonyl)buta-1,3-dienes and aldehydes. AB - Asymmetric organocatalytic annulation of E/Z isomeric mixtures of bis(alkyl carboxylate)buta-1,3-dienes and aldehydes has been realized via enamine catalysis. In the presence of alpha,alpha-diphenyl-2-pyrrolidinemethanol trimethylsilyl ether, excellent stereo- and enantioselectivities were achieved for a broad spectrum of substrates. PMID- 23731394 TI - Frequencies, costs, and complications of catheter ablation for tachyarrhythmias in children: 2000-2009. AB - BACKGROUND: Over the past two decades, catheter ablation (CA) has revolutionized the treatment of tachyarrhythmias in children by providing a relatively safe and effective alternative to open heart surgery or lifelong pharmacotherapy. This study (1) described national trends in pediatric CAs and their associated costs and complications and (2) predicted the likelihood of major complications based on patient and hospital characteristics. METHODS: Inpatient data were obtained from the Kids' Inpatient Database for the years 2000, 2003, 2006, and 2009. Outpatient data were obtained from the California, Maryland, and New Jersey State Ambulatory Surgery Databases for the years 2006 and 2009. Logistic regression was used to predict the odds of major complications from CA. RESULTS: There was a 20% increase (4,134-4,967) in the number of pediatric CAs performed from 2006 to 2009 that was concomitant with a decrease in the percentage of those procedures being performed as inpatient procedures (2,254-1,846). In 2009, a complication rate of 4.81% was estimated. For inpatient CAs, higher risk patients (with congenital heart disease, congestive heart failure, or heart transplant), ablations for ventricular tachycardias, and low-CA-volume hospitals were associated with increased risk of complications. In 2009, the mean cost of a hospitalization involving CA, but no cardiac surgery, was $17,204 (standard error = $1,015). CONCLUSIONS: CA has increasingly been used over the past decade for pediatric patients with a multitude of tachycardia mechanisms. There continues to be a small risk of major complications, especially for higher risk children and in hospitals with more limited experience with the procedure. PMID- 23731395 TI - Epilepsia and the rough seas of medical publishing. PMID- 23731396 TI - Cardiopulmonary complications during pediatric seizures: a prelude to understanding SUDEP. AB - PURPOSE: Sudden unexpected death in epilepsy (SUDEP) is an important, unexplained cause of death in epilepsy. Role of cardiopulmonary abnormalities in the pathophysiology of SUDEP is unclear in the pediatric population. Our objective was to assess cardiopulmonary abnormalities during epileptic seizures in children, with the long-term goal of identifying potential mechanisms of SUDEP. METHODS: We prospectively recorded cardiopulmonary functions using pulse oximetry, electrocardiography (ECG), and respiratory inductance plethysmography (RIP). Logistic regression was used to evaluate association of cardiorespiratory findings with seizure characteristics and demographics. KEY FINDINGS: We recorded 101 seizures in 26 children (average age 3.9 years). RIP provided analyzable data in 78% and pulse-oximetry in 63% seizures. Ictal central apnea was more prevalent in patients with younger age (p = 0.01), temporal lobe (p < 0.001), left-sided (p < 0.01), symptomatic generalized (p = 0.01), longer duration seizures (p < 0.0002), desaturation (p < 0.0001), ictal bradycardia (p < 0.05), and more antiepileptic drugs (AEDs; p < 0.01), and was less prevalent in frontal lobe seizures (p < 0.01). Ictal bradypnea was more prevalent in left-sided (p < 0.05), symptomatic generalized seizures (p < 0.01), and in brain magnetic resonance imaging (MRI) lesions (p < 0.1). Ictal tachypnea was more prevalent in older-age (p = 0.01), female gender (p = 0.05), frontal lobe (p < 0.05), right-sided seizures (p < 0.001), fewer AEDs (p < 0.01), and less prevalent in lesional (p < 0.05) and symptomatic generalized seizures (p < 0.05). Ictal bradycardia was more prevalent in male patients (p < 0.05) longer duration seizures (p < 0.05), desaturation (p = 0.001), and more AEDs (p < 0.05), and was less prevalent in frontal lobe seizures (p = 0.01). Ictal and postictal bradycardia were directly associated (p < 0.05). Desaturation was more prevalent in longer-duration seizures (p < 0.0001), ictal apnea (p < 0.0001), ictal bradycardia (p = 0.001), and more AEDs (p = 0.001). SIGNIFICANCE: Potentially life-threatening cardiopulmonary abnormalities such as bradycardia, apnea, and hypoxemia in pediatric epileptic seizures are associated with predictable patient and seizure characteristics, including seizure subtype and duration. PMID- 23731397 TI - Should consciousness be included in the classification of focal (partial) seizures? AB - The ILAE 2010 report does not classify focal seizures and instead uses "descriptors" to distinguish focal seizures with versus without impaired consciousness. Below, we recall a recent informal conversation that took place while traveling a back road in Australia (true story), discussing problems with the old terms as well as new biological and practical evidence separating events formerly known as complex partial versus simple partial seizures. Impaired level of consciousness is a core distinguishing feature of focal seizures, which arises from established physiological mechanisms and can be readily determined based on behavior in most cases. After some debate, we arrive at succinct terms compatible with the old as well as the new ILAE classification report: Focal Impaired Consciousness Seizures (FICS), and Focal Aware Conscious Seizures (FACS). We hope that this discussion will bring impaired consciousness off the back roads of epilepsy classification, and provide useful names for these two very common seizure types. PMID- 23731398 TI - Consciousness and aura: two controversial concepts on epilepsy. PMID- 23731399 TI - Focal seizures and consciousness. PMID- 23731400 TI - The concept of consciousness and its relevance to the classification of seizures and epilepsies. PMID- 23731401 TI - New terminologies: the downsides. PMID- 23731402 TI - Commentary on Standardized computer-based organized reporting of EEG: SCORE. PMID- 23731403 TI - A commentary on SCORE. PMID- 23731404 TI - Commentary on standardized computer-based organized reporting of EEG. PMID- 23731405 TI - A modeling approach for orthogonality of comprehensive two-dimensional separations. AB - A novel method is developed for orthogonality evaluation of comprehensive two dimensional separations (C2DS). Utilization of efficiency measures such as peak capacity (n(c)) can be critically evaluated for C2DS analysis to describe an orthogonal separation of the analytes in a 2D plane. Unlike most previous methods focusing on "bin coverage" over 2D space, rather than taking into account the distribution based on accurate peak retention, in the proposed method, the separation orthogonality of C2DS is divided into two parts (i.e., C(pert) and C(peaks)). These correspond to peak coverage percent, and 2D distribution correlation of compounds, respectively. Bin occupation and a simple-linear regression model, on the basis of normalized retention times in 2D separation space ((1)t(R) and (2)t(R)), are further introduced to quantitatively define the two terms. Orthogonality ranges from 0 to 1 correspond to perfectly correlated and orthogonal separations, respectively, which are presented based on both C(pert) and C(peaks) considerations. The advantage of this method is the use of separation properties of C2DS to characterize practical 2D peak distribution and does not rely on assumptions or any imposed limitations. Simulation of comprehensive two-dimensional gas chromatography (GC * GC) was achieved by using the Abraham solvation parameter model, and applied to generate examples for orthogonality assessment. In this work, 225 compounds comprising a range of chemical classes were simulated for separation on two column set pairs comprising low polarity/polar and moderately polar/polar combinations. Results illustrate that the proposed method applied to GC * GC provides a reasonable assessment of 2D separation performance and may be used to derive optimal experimental conditions when used with an experimental design strategy. PMID- 23731406 TI - Factors affecting enzymatic degradation of microgel-bound peptides. AB - Proteolytic degradation and release of microgel-bound peptides was investigated for trypsin, poly(acrylic acid-co-acrylamide) microgels (70-90 MUm in diameter), and oppositely charged polylysine, using a method combination of confocal microscopy and micromanipulator-assisted light microscopy. Results show that trypsin-induced release of polylysine increased with increasing trypsin concentration, decreasing microgel charge density and decreasing peptide molecular weight. While the microgel offered good protection against enzymatic degradation at high microgel charge density, it was also observed that the cationic peptide enabled trypsin to bind throughout the peptide-loaded microgels, even when it did not bind to the peptide-void ones. With the exception of highly charged microgels, proteolytic degradation throughout the peptide-loaded microgel resulted in the generation of short and non-adsorbing peptide stretches, giving rise to the concentration and peptide length dependence observed. A simple random scission model was able to qualitatively capture these experimental findings. Collectively, the results demonstrate that microgel charge density, peptide molecular weight, and enzyme concentration greatly influence degradation/release of microgel-bound peptides and need to be considered in the use of microgels, e.g., as carriers for protein and peptide drugs. PMID- 23731407 TI - Tamoxifen for recurrent bleeds due to angiodysplasia in von Willebrand's disease. PMID- 23731408 TI - Dynamic combinatorial libraries: from exploring molecular recognition to systems chemistry. AB - Dynamic combinatorial chemistry (DCC) is a subset of combinatorial chemistry where the library members interconvert continuously by exchanging building blocks with each other. Dynamic combinatorial libraries (DCLs) are powerful tools for discovering the unexpected and have given rise to many fascinating molecules, ranging from interlocked structures to self-replicators. Furthermore, dynamic combinatorial molecular networks can produce emergent properties at systems level, which provide exciting new opportunities in systems chemistry. In this perspective we will highlight some new methodologies in this field and analyze selected examples of DCLs that are under thermodynamic control, leading to synthetic receptors, catalytic systems, and complex self-assembled supramolecular architectures. Also reviewed are extensions of the principles of DCC to systems that are not at equilibrium and may therefore harbor richer functional behavior. Examples include self-replication and molecular machines. PMID- 23731409 TI - Co-infections with hepatitis B and C viruses in human immunodeficiency virus infected patients in Morocco. AB - Human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are major public health concerns. We aimed to determine the prevalence of HBV and HCV infections among HIV-infected patients, and to identify the main circulating hepatitis strains in Morocco. The study was carried out in 503 HIV infected patients. Our survey indicated that the prevalence of HIV/hepatitis co infection was 10.6%; 5.2% of patients were HBV surface antigen positive, and 5.4% of patients were anti-HCV positive. Among the HBV surface antigen-positive group, HBV DNA sequencing identified exclusively genotype D (D1: 26.7%; D7: 73.3%) in accordance with what is found in the general population. In contrast, sequencing of HCV isolates produced an unusual subtype distribution with a decreasing order of prevalence: 1a, 3a (both 23.5%), 1b, 4a (both 17.6%), 1c (11.8%) and 6h (6%). PMID- 23731410 TI - The many roles of social workers in the prevention and treatment of alcohol and drug addiction: a major health and social problem affecting individuals, families, and society. Introduction. PMID- 23731412 TI - The impact of alcohol on society: a brief overview. AB - Alcohol is the most common drug used among adults in the United States. The use of alcohol is associated with an increased risk of injuries and accidents. Even a single episode of excessive drinking can lead to a negative outcome. Alcoholism and chronic use of alcohol are associated with numerous medical, psychiatric, social, and family problems. Family members, including children, exposed to a first-degree relative's alcohol problem are at risk for problems. Children of parents with alcohol addiction, for example, show higher rates of alcoholism than children who do not have parents with an alcohol addiction. It is important for social workers to keep in mind that alcohol and alcohol problems affect the health, safety, and well-being of people. PMID- 23731411 TI - Treatment for substance use disorder: opportunities and challenges under the affordable care act. AB - Addiction is a chronic brain disease with consequences that remain problematic years after discontinuation of use. Despite this, treatment models focus on acute interventions and are carved out from the main health care system. The Patient Protection and Affordable Care Act (2010) brings the opportunity to change the way substance use disorder (SUD) is treated in the United States. The treatment of SUD must adapt to a chronic care model offered in an integrated care system that screens for at-risk patients and includes services needed to prevent relapses. The partnering of the health care system with substance abuse treatment programs could dramatically expand the benefits of prevention and treatment of SUD. Expanding roles of health information technology and nonphysician workforces, such as social workers, are essential to the success of a chronic care model. PMID- 23731413 TI - Genetics of alcohol dependence and social work research: do they mix? AB - Since completion of the mapping of the human genome in early 2000, tremendous progress has been made in the identification of many different genes associated with our health and across diseases. Although social work researchers are not expected to conduct genetic research at the molecular level, it is imperative that we are able to understand the basic genetic findings related to behavioral problems and are able to translate and integrate this information into psychosocial treatment approaches and program development. This article is an introduction and overview of genetic approaches, using studies of the genetics of alcoholism to exemplify important issues. The literature review is not comprehensive and focuses primarily on the Collaborative Study on the Genetics of Alcoholism project as an example of a multidisciplinary and integrative approach to the genetic study of a major health problem often encountered in social work practice. PMID- 23731414 TI - The impact of substance use disorders on families and children: from theory to practice. AB - The effects of a substance use disorder (SUD) are felt by the whole family. The family context holds information about how SUDs develop, are maintained, and what can positively or negatively influence the treatment of the disorder. Family systems theory and attachment theory are theoretical models that provide a framework for understanding how SUDs affect the family. In addition, understanding the current developmental stage a family is in helps inform assessment of impairment and determination of appropriate interventions. SUDs negatively affect emotional and behavioral patterns from the inception of the family, resulting in poor outcomes for the children and adults with SUDs. Social workers can help address SUDs in multiple ways, which are summarized in this article. PMID- 23731415 TI - Brief strategic family therapy: engaging drug using/problem behavior adolescents and their families in treatment. AB - Despite the efficacy of family-based interventions for improving outcomes for adolescent behavior problems such as substance use, engaging and retaining whole families in treatment is one of the greatest challenges therapists confront. This article illustrates how the Brief Strategic Family Therapy model, a family-based, empirically validated intervention designed to treat children and adolescents' problem behaviors, can be used to increase engagement, improve retention, and bring about positive outcomes for families. Research evidence for efficacy and effectiveness is also presented. PMID- 23731416 TI - CHOICES: an integrated behavioral intervention to prevent alcohol-exposed pregnancies among high-risk women in community settings. AB - CHOICES is an integrated behavioral intervention for prevention of prenatal alcohol exposure in women at high risk for alcohol-exposed pregnancies. The intervention uses motivational interviewing and cognitive-behavioral strategies, and targets adoption of effective contraception and reduction of alcohol use. The CHOICES intervention includes four manual-guided counseling sessions delivered by behavioral health counselors and one contraceptive session with a family planning clinician. CHOICES's efficacy has been established through a series of randomized controlled trials in settings including primary care, university hospital-based obstetrical/gynecology practices, urban jails, substance abuse treatment settings, and a media-recruited sample in three large cities. This article describes the CHOICES line of research including the epidemiology, feasibility, and efficacy studies. It also details the CHOICES intervention and the components of each session. In addition, the authors describe current studies testing modifications of the CHOICES intervention, the dissemination efforts to date, and implications for social work practice. PMID- 23731417 TI - Treating substance abuse: partner and family approaches. AB - Historically, alcohol and other substance use disorders were viewed as individual based problems that were most effectively treated by focusing on the diagnosed individual. However, in response to numerous clinical trials demonstrating the efficacy (and often superiority) of couple and family treatments for alcoholism and drug abuse, this emphasis on treating the individual has slowly given way to a greater awareness of family members' crucial roles in the etiology, maintenance, and long-term course of substance use and addictive behavior. As a result, clinicians are increasingly interested in understanding substance misuse from a systemic perspective and exploring how partner- and family-involved interventions may be used to address individuals' substance abuse. PMID- 23731418 TI - Brief intervention and social work: a primer for practice and policy. AB - Most individuals in need of help for alcohol use disorders do not receive care. Screening and brief intervention (SBI) is an evidence-based practice for reducing at-risk drinking and alcohol-related risk behaviors. Health care reform sets the stage for a large expansion of SBI to individuals in the United States. Social workers have the opportunity to play an important role in helping establish SBI nationally, but they must become more involved in its delivery, educating new social workers with respect to SBI practice, and taking part in research to expand the field's knowledge of this service. PMID- 23731419 TI - Medications for substance use disorders. AB - In this article, the authors briefly review the pharmacotherapeutic agents that are currently available for the treatment of substance use disorders. Nicotine replacement therapies are most effective for tobacco cessation. Naltrexone, acamprosate, and disulfiram are effective for reducing alcohol use. The most effective pharmacotherapies for opiate use disorders are agonist therapies, including methadone and buprenorphine. The authors also examine recent advances in medication development for other substance use disorders such as stimulant addiction. The role of medication adherence and behavioral treatments and the integration of behavioral and pharmacotherapeutic interventions are also discussed. PMID- 23731421 TI - Blending research and practice: an evolving dissemination strategy in substance abuse. AB - Substance abuse is a leading cause of death and disability throughout the world. The mission of the National Institute on Drug Abuse (NIDA) is to lead the United States in bringing the power of science to bear on drug abuse and addiction. This charge has two critical components: (a) strategic support of research across a broad range of disciplines and (b) rapid, effective dissemination of research results that can improve prevention and treatment efforts, with potential to inform policy. The NIDA Clinical Trials Network and the Blending Initiative are critical elements of this strategy, and the social work field is poised to use these resources to expand its role in the dissemination and implementation of NIDA's mission. PMID- 23731420 TI - Social workers and delivery of evidence-based psychosocial treatments for substance use disorders. AB - Social workers encounter individuals with substance use disorders (SUDs) in a variety of settings. With changes in health care policy and a movement toward integration of health and behavioral health services, social workers will play an increased role vis-a-vis SUD. As direct service providers, administrators, care managers, and policy makers, they will select, deliver, or advocate for delivery of evidence-based SUD treatment practices. This article provides an overview of effective psychosocial SUD treatment approaches. In addition to describing the treatments, the article discusses empirical support, populations for whom the treatments are known to be efficacious, and implementation issues. PMID- 23731422 TI - 12-step interventions and mutual support programs for substance use disorders: an overview. AB - Social workers and other behavioral health professionals are likely to encounter individuals with substance use disorders in a variety of practice settings outside of specialty treatment. 12-Step mutual support programs represent readily available, no cost community-based resources for such individuals; however, practitioners are often unfamiliar with such programs. The present article provides a brief overview of 12-Step programs, the positive substance use and psychosocial outcomes associated with active 12-Step involvement, and approaches ranging from ones that can be utilized by social workers in any practice setting to those developed for specialty treatment programs to facilitate engagement in 12-Step meetings and recovery activities. The goal is to familiarize social workers with 12-Step approaches so that they are better able to make informed referrals that match clients to mutual support groups that best meet the individual's needs and maximize the likelihood of engagement and positive outcomes. PMID- 23731423 TI - Substance use disorders and HIV/AIDS prevention and treatment intervention: research and practice considerations. AB - Social workers are often on the front lines of the HIV/AIDS epidemic delivering prevention education and interventions, offering or linking individuals to HIV testing, and working to improve treatment access, retention, and adherence, especially among vulnerable populations. Individuals with substance use disorders face additional challenges to reducing sexual and drug risk behaviors, as well as barriers to testing, treatment, and antiretroviral therapy adherence. This article presents current data on HIV transmission and research evidence on prevention and intervention with substance abusers and highlights how individual social workers can take advantage of this knowledge in practice and through adoption and implementation within organizations. PMID- 23731424 TI - Science-based prevention through communities that care: a model of social work practice for public health. AB - This article describes a public health orientation to drug and alcohol abuse prevention; reviews the state of the science underlying a risk and protective factor approach to alcohol and drug abuse prevention; describes Communities That Care, a community practice model that makes use of this evidence; and considers how this model reflects four important principles of social work practice. The intent of this article is to provide guidance to social workers who support the National Association of Social Work's intention to make prevention practice central to the provision of alcohol and drug abuse services by social workers. PMID- 23731425 TI - Substance use disorder in the context of LGBT health: a social work perspective. AB - The impacts of public and private funding of lesbian, gay, bisexual, and transgender (LGBT) health research, the state of integration of LGBT health issues into the academic and professional training programs of health care practitioners, and the larger social reality experienced by LGBT people profoundly affect substance use and substance use disorders in those populations. This analysis uses a social work perspective and considers the current state of research, professional training, and social oppression as they affect the health of LGBT people. Suggestions for action are offered that may improve the health of LGBT peoples and the practice of social work. PMID- 23731426 TI - Just say know: an examination of substance use disorders among older adults in gerontological and substance abuse journals. AB - This article examines the extent to which studies of alcohol abuse, illicit drug use, and prescription drug abuse among older adults appear in the leading gerontological and substance abuse journals. The authors reviewed articles published in the 10 social science gerontological journals and the 10 social science substance abuse journals with the highest 5-year impact factors in PubMed from 2000 to 2010. Articles were selected that presented original research on alcohol, substance, or prescription abuse with older adults aged 50 and older; and were identified through aging and substance abuse-related Medical Subject Headings and word searches of titles and abstracts (N = 634). Full text of each article was reviewed by the authors, and consensus determined inclusion in the final sample. Of the 19,953 articles published respectively in the top 10 gerontological and substance abuse journals, 181 articles met the inclusion criteria of reporting findings related to substance use disorders among older adults. Specifically, 0.9% (102 of 11,700) of articles from the top 10 gerontology journals and 1.0% (79 of 8,253) of articles from the top 10 substance abuse journals met the criteria. Most published articles addressed alcohol misuse/abuse or polysubstance abuse with few articles addressing illicit drug use or the misuse of prescription medications. Less than 1% of articles published in the 10 gerontology journals and the 10 substance abuse journals with the highest 5-year impact scores addressed substance abuse in older adults. Practitioners treating health and/or mental health problems are at a disadvantage in accurately identifying and treating these conditions in older adult populations without a proper understanding of the role of comorbid substance use disorders. PMID- 23731427 TI - Integrated treatment of substance use and psychiatric disorders. AB - Epidemiological studies find that psychiatric disorders, including mental disorders and substance use disorders, are common among adults and highly comorbid. Integrated treatment refers to the focus of treatment on two or more conditions and to the use of multiple treatments such as the combination of psychotherapy and pharmacotherapy. Integrated treatment for comorbidity has been found to be consistently superior compared to treatment of individual disorders with separate treatment plans. This article focuses on a review of the risks for developing comorbid disorders and the combinations of treatments that appear to be most effective for clients with particular comorbid disorders. PMID- 23731428 TI - Substance use disorders and anxiety: a treatment challenge for social workers. AB - Converging evidence from epidemiologic and treatment studies indicate that anxiety disorders and substance use disorders commonly co-occur, and the interaction is multifaceted and variable. Epidemiological studies and investigations within clinical substance abuse populations have found an association between anxiety disorders and substance use disorders. Specific anxiety disorders including generalized anxiety disorder, panic disorder, and post traumatic stress disorder have all been associated with substance use. The association with obsessive-compulsive disorder is less robust, and some research has found a negative association. The risk of nicotine dependence is significantly higher among individuals with an anxiety disorder, and conversely, smoking has been found to be associated with trait anxiety and anxiety disorders. A review of the current literature and the relationship between specific anxiety disorders and alcohol and substance use disorders is discussed in detail. This article, written for social workers in a variety of practice settings, reviews the prevalence, diagnostic, and treatment issues at the interface of substance use disorders and anxiety disorders. PMID- 23731429 TI - Treatment of co-occurring psychotic and substance use disorders. AB - People with psychotic disorders and other serious mental illnesses, such as schizophrenia, bipolar disorder, and severe major depression, have high rates of co-occurring substance use disorder, which can wreak havoc in their lives. In this article the authors describe strategies for assessing substance use problems in people with serious mental illnesses, and then address the treatment of these co-occurring disorders. The authors review principles of treatment of co occurring disorders, including integration of mental health and substance abuse services, adopting a low-stress and harm-reduction approach, enhancing motivation, using cognitive-behavioral therapy strategies to teach more effective interpersonal and coping skills, supporting functional recovery, and engaging the social network. The authors include a section on how social workers may play a key role in assessment, treatment, or referral for co-occurring disorders in a variety of settings. Throughout the article the authors emphasize that belief in the possibility of recovery from co-occurring disorders and instilling hope in clients, their family members, and other treatment providers, are vital to the effective treatment of co-occurring disorders. PMID- 23731430 TI - Does cultural adaptation have a role in substance abuse treatment? AB - The changing ethnic composition of the nation and increasing requirements to use evidence-based treatments (EBTs) challenge mental health professionals to adapt treatments and interventions to be appropriate for their clients. This article applies the available information on cultural adaptation to substance abuse. The authors' review suggests that the most common approaches for adapting substance use interventions include some combination of either community involvement in the adaptation, existing research and literature, and/or consultation from experts to adapt EBTs. The challenges facing the development of culturally adapted interventions include the need for additional research to determine which specific EBTs warrant adaptation, the responsibility of maintaining the balance between fidelity and adaptation, and the challenge of intragroup diversity. PMID- 23731432 TI - Negative emotional experiences arouse rumination and affect working memory capacity. AB - Following an emotional experience, individuals are confronted with the persistence of ruminative thoughts that disturb the undertaking of other activities. In the present study, we experimentally tested the idea that experiencing a negative emotion triggers a ruminative process that drains working memory (WM) resources normally devoted to other tasks. Undergraduate participants of high versus low WM capacity were administered the operation-word memory span test (OSPAN) as a measure of availability of WM resources preceding and following the presentation of negative emotional versus neutral material. Rumination was assessed immediately after the second OSPAN session and at a 24-hr delay. Results showed that both the individual's WM capacity and the emotional valence of the material influenced WM performance and the persistence of ruminative thoughts. Following the experimental induction, rumination mediated the relationship between the negative emotional state and the concomitant WM performance. Based on these results, we argue that ruminative processes deplete WM resources, making them less available for concurrent tasks; in addition, rumination tends to persist over time. These findings have implications for the theoretical modeling of the long-term effects of emotions in both daily life and clinical contexts. PMID- 23731433 TI - Too much of a good thing? Cardiac vagal tone's nonlinear relationship with well being. AB - Parasympathetic regulation of heart rate through the vagus nerve--often measured as resting respiratory sinus arrhythmia or cardiac vagal tone (CVT)--is a key biological correlate of psychological well-being. However, recent theorizing has suggested that many biological and psychological processes can become maladaptive when they reach extreme levels. This raises the possibility that CVT might not have an unmitigated positive relationship with well-being. In line with this reasoning, across 231 adult participants (Mage = 40.02 years; 52% female), we found that CVT was quadratically related to multiple measures of well-being, including life satisfaction and depressive symptoms. Individuals with moderate CVT had higher well-being than those with low or high CVT. These results provide the first direct evidence of a nonlinear relationship between CVT and well-being, adding to a growing body of research that has suggested some biological processes may cease being adaptive when they reach extreme levels. PMID- 23731434 TI - The social functions of the emotion of gratitude via expression. AB - Recent theory posits that the emotion of gratitude uniquely functions to build a high-quality relationship between a grateful person and the target of his or her gratitude, that is, the person who performed a kind action (Algoe et al., 2008). Therefore, gratitude is a prime candidate for testing the dyadic question of whether one person's grateful emotion has consequences for the other half of the relational unit, the person who is the target of that gratitude. The current study tests the critical hypothesis that being the target of gratitude forecasts one's relational growth with the person who expresses gratitude. The study employed a novel behavioral task in which members of romantic relationships expressed gratitude to one another in a laboratory paradigm. As predicted, the target's greater perceptions of the expresser's responsiveness after the interaction significantly predicted improvements in relationship quality over 6 months. These effects were independent from perceptions of responsiveness following two other types of relationally important and emotionally evocative social interactions in the lab, suggesting the unique weight that gratitude carries in cultivating social bonds. PMID- 23731436 TI - The regulation of negative and positive affect in daily life. AB - Emotion regulation has primarily been studied either experimentally or by using retrospective trait questionnaires. Very few studies have investigated emotion regulation in the context in which it is usually deployed, namely, the complexity of everyday life. We address this in the current paper by reporting findings of two experience-sampling studies (Ns = 46 and 95) investigating the use of six emotion-regulation strategies (reflection, reappraisal, rumination, distraction, expressive suppression, and social sharing) and their associations with changes in positive affect (PA) and negative affect (NA) in daily life. Regarding the relative use of emotion-regulation strategies, a highly similar ordering was found across both studies with distraction being used more than sharing and reappraisal. While the use of all six strategies was positively correlated both within- and between-persons, different strategies were associated with distinct affective consequences: Suppression and rumination were associated with increases in NA and decreases in PA, whereas reflection was associated with increases in PA across both studies. Additionally, reappraisal, distraction, and social sharing were related to increases in PA in Study 2. Discussion focuses on how the current findings fit with theoretical models of emotion regulation and with previous evidence from experimental and retrospective studies. PMID- 23731435 TI - Can older adults resist the positivity effect in neural responding? The impact of verbal framing on event-related brain potentials elicited by emotional images. AB - Older adults have demonstrated an avoidance of negative information, presumably with a goal of greater emotional satisfaction. Understanding whether avoidance of negative information is a voluntary, motivated choice or an involuntary, automatic response will be important to differentiate, as decision making often involves emotional factors. With the use of an emotional framing event-related potential (ERP) paradigm, the present study investigated whether older adults could alter neural responses to negative stimuli through verbal reframing of evaluative response options. The late positive potential (LPP) response of 50 older adults and 50 younger adults was recorded while participants categorized emotional images in one of two framing conditions: positive ("more or less positive") or negative ("more or less negative"). It was hypothesized that older adults would be able to overcome a presumed tendency to down-regulate neural responding to negative stimuli in the negative framing condition, thus leading to larger LPP wave amplitudes to negative images. A similar effect was predicted for younger adults, but for positively valenced images, such that LPP responses would be increased in the positive framing condition compared with the negative framing condition. Overall, younger adults' LPP wave amplitudes were modulated by framing condition, including a reduction in the negativity bias in the positive frame. Older adults' neural responses were not significantly modulated, even though task related behavior supported the notion that older adults were able to successfully adopt the negative framing condition. PMID- 23731437 TI - Stimulus fear-relevance and the vicarious learning pathway to childhood fears. AB - Enhanced fear learning for fear-relevant stimuli has been demonstrated in procedures with adults in the laboratory. Three experiments investigated the effect of stimulus fear-relevance on vicarious fear learning in children (aged 6 11 years). Pictures of stimuli with different levels of fear-relevance (flowers, caterpillars, snakes, worms, and Australian marsupials) were presented alone or together with scared faces. In line with previous studies, children's fear beliefs and avoidance preferences increased for stimuli they had seen with scared faces. However, in contrast to evidence with adults, learning was mostly similar for all stimulus types irrespective of fear-relevance. The results support a proposal that stimulus preparedness is bypassed when children observationally learn threat-related information from adults. PMID- 23731438 TI - Emotion regulation and emotion coherence: evidence for strategy-specific effects. AB - One of the central tenets of emotion theory is that emotions involve coordinated changes across experiential, behavioral, and physiological response domains. Surprisingly little is known, however, about how the strength of this emotion coherence is altered when people try to regulate their emotions. To address this issue, we recorded experiential, behavioral, and physiological responses while participants watched negative and positive pictures. Cross-correlations were used to quantify emotion coherence. Study 1 tested how two types of suppression (expressive and physiological) influence coherence. Results showed that both strategies decreased the response coherence measured in negative and positive contexts. Study 2 tested how multichannel suppression (simultaneously targeting expressive and physiological responses) and acceptance influence emotion coherence. Results again showed that suppression decreased coherence. By contrast, acceptance was not significantly different from the unregulated condition. These findings help to clarify the nature of emotion response coherence by showing how different forms of emotion regulation may differentially affect it. PMID- 23731439 TI - Alpha suppression following performance errors is correlated with depression, affect, and coping behaviors. AB - This study tested the hypothesis that enhanced neural arousal in response to performance errors would predict poor affect and coping behaviors in everyday life. Participants were preselected as either low-depressed (LD) or high depressed (HD) based on a screening questionnaire, and they then completed a laboratory Stroop task while EEG was recorded, followed by a 2-week period of daily reports of affect and coping behaviors. The EEG measure of arousal response to errors was the degree of error-related alpha suppression (ERAS) in the intertrial interval, that is the reduction in alpha power following errors compared with correct responses. ERAS was relatively heightened at frontal sites for the HD versus the LD group, and frontal ERAS predicted lower positive affect, higher negative affect, and less adaptive coping behaviors in the daily reports. Together, the results imply that heightened arousal following mistakes is associated with suboptimal emotion and coping with stressors. PMID- 23731440 TI - Evaluation of nutritional and physical stress conditions during vegetative growth on conidial production and germination in Ophiocordyceps sinensis. AB - The influence of nutritional and physical stress on sporulation, conidial germination and vegetative biomass of Ophiocordyceps sinensis, one of the most important medicinal fungi in China and now globally, was evaluated using a two stage culture method. All the treatments, except nutrient deprivation, enhanced conidial production and vegetative biomass to some extent. However, conidia produced under stress showed decreased germination in comparison with those continuously cultured on the enriched potato dextrose agar (PDA; as the control). Among 10 treatments tested, the physical stress of frozen-shock produced the largest number of conidia, 7.5 times higher than that of the control, followed by heat-shock treatment. These results demonstrate that the fungus has strong physiological adaptations to environmental stress that may have evolved because it is endemic to the Tibetan Plateau. This report will be relevant to the study of the pathogenicity and artificial cultivation of this endangered fungus. PMID- 23731442 TI - Increased glycemic variability at the onset and during progression of type 2 diabetes-commentary. PMID- 23731441 TI - Real-time and in situ drug release monitoring from nanoporous implants under dynamic flow conditions by reflectometric interference spectroscopy. AB - Herein, we present an innovative approach to monitoring in situ drug release under dynamic flow conditions from aluminum implants featuring nanoporous anodic alumina (NAA) covers used as a model of drug-releasing implants. In this method, reflectometric interference spectroscopy (RIfS) is used to monitor in real-time the diffusion of drug from these nanoporous implants. The release process is carried out in a microfluidic device, which makes it possible to analyze drug release under dynamic flow conditions with constant refreshing of eluting medium. This setup mimics the physiological conditions of biological milieu at the implant site inside the host body. The release of a model drug, indomethacin, is established by measuring the optical thickness change with time under four different flow rates (i.e. 0, 10, 30, and 50 MUL min(-1)). The obtained data are fitted by a modified Higuchi model, confirming the diffusion-controlled release mechanism. The obtained release rate constants demonstrate that the drug release depends on the flow rate and the faster the flow rate the higher the drug release from the nanoporous covers. In particular, the rate constants increase from 2.23 +/- 0.02 to 12.47 +/- 0.04 MUg min(-1/2) when the flow rate is increased from 10 to 50 MUL min(-1), respectively. Therefore, this method provides more reliable and relevant information than conventional in vitro drug release methods performed under static conditions. PMID- 23731443 TI - Bioavailability of vitamin E in humans: an update. AB - Vitamin E is essential for human health and may play a role in the prevention of some degenerative diseases. Its bioavailability, however, is wide ranging and is affected by numerous factors. Recent findings showing that the intestinal absorption of vitamin E involves proteins have raised new relevant questions about factors that can affect bioavailability. It is, therefore, opportune to present a current overview of this topic. This review begins by exploring what is known, as well as what is unknown, about the metabolization of vitamin E in the human upper gastrointestinal tract and then presents a methodical evaluation of factors assumed to affect vitamin E bioavailability. Three main conclusions can be drawn. First, the proteins ABCA1, NPC1L1, and SR-BI are implicated in the absorption of vitamin E. Second, the efficiency of vitamin E absorption is widely variable, though not accurately known (i.e., between 10% and 79%), and is affected by several dietary factors (e.g., food matrix, fat, and fat-soluble micronutrients). Finally, numerous unanswered questions remain about the metabolization of vitamin E in the intestinal lumen and about the factors affecting the efficiency of vitamin E absorption. PMID- 23731444 TI - Use of dual X-ray absorptiometry to measure body mass during short- to medium term trials of nutrition and exercise interventions. AB - Dual X-ray absorptiometry (DXA) has a range of clinical applications, from assessing associations between adipose or lean body mass and the risk of disease to measuring the effects of dietary interventions on adipose deposition and oxidation and/or muscle accumulation. Many lifestyle-related studies, however, are short- to medium-term interventions, and inter- or intradevice variation between DXA scanners can facilitate type I and type II errors during data analysis. Studies demonstrate that variation in body composition measurements exist not only between DXA instruments using fan-beam and pencil-beam technologies but also between DXA instruments produced by different manufacturers. Moreover, studies show inter- and intrainstrument variation between identical DXA instruments. Such inter- and intrascan variability between instruments can be compounded by the particular patient population being investigated. The objective of this review is to discuss inter- and intradevice variation of DXA instruments and to outline quality control procedures that should be implemented prior to initiating short-term single or multicenter clinical trials that use DXA to investigate the effects of an intervention on loss or accretion of lean or fat mass. PMID- 23731445 TI - Association between weight gain during pregnancy and postpartum weight retention and obesity: a bias-adjusted meta-analysis. AB - Gestational weight gain (GWG) is associated with postpartum weight retention (PPWR) in women. The strength of the association between GWG and long-term PPWR and body mass index (BMI), however, is still unclear. Publications from different databases were systematically extracted and the articles relevant to this study were reviewed to quantify the effect estimate of GWG on PPWR and BMI using a bias adjusted method. The Institute of Medicine categories of "inadequate," "adequate," and "excess" were used to define GWG. The time span for PPWR was divided into three periods (<1 year, 1 year to 9 years, and >=15 years) to determine outcome at different times postpartum. Twelve studies met the eligibility criteria and were included in the analyses. Women with an inadequate GWG had a significantly lower mean PPWR of -2.14 kg (95%CI, -2.61 to -1.66) than women with an adequate GWG, who had a mean PPWR of 3.15 kg (95%CI, 2.47 to 3.82) up to 21 years postpartum. Over the postpartum time span, a U-shaped relationship was observed between the weighted mean difference calculated for women with excess GWG and the weighted mean difference calculated for women with adequate GWG, and this relationship was time independent between these two groups. Postpartum BMI showed a similar relationship and magnitude of change, but the exact loss or gain was difficult to assess due to fewer studies (n = 5) with considerable heterogeneity of BMI measurements. The findings of this study suggest that GWG outside of the Institute of Medicine recommendations can lead to both short-term and long-term postpartum weight imbalance. PMID- 23731448 TI - Effect of iron intervention on growth during gestation, infancy, childhood, and adolescence: a systematic review with meta-analysis. AB - To evaluate the effect of iron intervention on physical growth in fetuses, infants, children, and adolescents up to 18 years of age, a systematic review with meta-analysis of randomized controlled trials (RCTs) was conducted. Structured electronic searches were conducted to February 2010 using MEDLINE, Embase, and the Cochrane Library databases. RCTs that included iron-fortified foods, iron-fortified formula, or iron supplements and in which height, weight, mid-arm circumference (MAC), head circumference, birth weight, or length of gestation was evaluated were analyzed for inclusion. In total, 21 RCTs in infants, children, and adolescents and 7 studies in pregnant women met the inclusion criteria. The overall pooled result (random-effects model) showed no significant effects of iron intervention on any of the parameters measured. To accommodate wide heterogeneity, studies were stratified according to dose of iron, duration of intervention, age, and baseline iron status. However, only doses of 40-66 mg of supplemental iron and intervention in children >= 6 years of age showed a slight but significant association with weight and MAC. PMID- 23731447 TI - Evidence of health benefits of canola oil. AB - Canola oil-based diets have been shown to reduce plasma cholesterol levels in comparison with diets containing higher levels of saturated fatty acids. Consumption of canola oil also influences biological functions that affect various other biomarkers of disease risk. Previous reviews have focused on the health effects of individual components of canola oil. Here, the objective is to address the health effects of intact canola oil, as this has immediate practical implications for consumers, nutritionists, and others deciding which oil to consume or recommend. A literature search was conducted to examine the effects of canola oil consumption on coronary heart disease, insulin sensitivity, lipid peroxidation, inflammation, energy metabolism, and cancer cell growth. Data reveal substantial reductions in total cholesterol and low-density lipoprotein cholesterol, as well as other positive actions, including increased tocopherol levels and improved insulin sensitivity, compared with consumption of other dietary fat sources. In summary, growing scientific evidence supports the use of canola oil, beyond its beneficial actions on circulating lipid levels, as a health-promoting component of the diet. PMID- 23731449 TI - Dietary sodium, potassium, and alcohol: key players in the pathophysiology, prevention, and treatment of human hypertension. AB - Western industrialized societies are currently experiencing an epidemic expansion of hypertension (HTN), which extends alarmingly even to children and adolescents. HTN constitutes an independent risk factor for cardiorenal disease and represents an extremely common comorbidity of diabetes and obesity. Numerous randomized clinical trials and meta-analyses have provided robust scientific evidence that reduced dietary salt intake, increased dietary potassium intake, moderation of alcohol consumption, optimal weight maintenance, and the adoption of "heart friendly" dietary patterns such as the Dietary Approaches to Stop Hypertension or the Mediterranean diet can effectively lower blood pressure. Interestingly, the susceptibility of blood pressure to nutritional interventions is greatly variable among individuals, depending on age, race, genetic background, and comorbidities. The purpose of this review is to provide a comprehensive overview of currently available scientific evidence in the constantly evolving field of diet and HTN, placing particular emphasis on the key role of dietary sodium, dietary potassium, and alcohol intake in the pathophysiology, prevention, and treatment of human hypertension. PMID- 23731446 TI - Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders. AB - The aim of this review is to discuss research involving ligands for the aryl hydrocarbon receptor (AhR) and their role in immunomodulation. While activation of the AhR is well known for its ability to regulate the biochemical and toxic effects of environmental chemicals, more recently an exciting discovery has been made indicating that AhR ligation can also regulate T-cell differentiation, specifically through activation of Foxp3(+) regulatory T cells (Tregs) and downregulation of the proinflammatory Th17 cells. Such findings have opened new avenues of research on the possibility of targeting the AhR to treat inflammatory and autoimmune diseases. Specifically, this review will discuss the current research involving natural and dietary AhR ligands. In addition, evidence indicating the potential use of these ligands in regulating inflammation in various diseases will be highlighted. The importance of the AhR in immunological processes can be illustrated by expression of this receptor on a majority of immune cell types. In addition, AhR signaling pathways have been reported to influence a number of genes responsible for mediating inflammation and other immune responses. As interest in the AhR and its ligands increases, it seems prudent to consolidate current research on the contributions of these ligands to immune regulation during the course of inflammatory diseases. PMID- 23731450 TI - Total and unbound darunavir pharmacokinetics in pregnant women infected with HIV 1: results of a study of darunavir/ritonavir 600/100 mg administered twice daily. AB - OBJECTIVES: Antiretroviral therapy during pregnancy is recommended to reduce the risk of mother-to-child transmission of HIV and for maternal care management. Physiological changes during pregnancy can affect pharmacokinetics, potentially altering pharmacological activity. We therefore evaluated the pharmacokinetics of twice-daily (bid) darunavir in HIV-1-infected pregnant women. METHODS: HIV-1 infected pregnant women receiving an antiretroviral regimen containing darunavir/ritonavir 600/100 mg bid were enrolled in this study. Total and unbound darunavir and total ritonavir plasma concentrations were obtained over 12 h during the second and third trimesters and postpartum. Total darunavir and ritonavir plasma concentrations were determined using a validated high performance liquid chromatography tandem mass spectrometry assay and unbound darunavir was determined using (14) C-darunavir-fortified plasma. Pharmacokinetic parameters were derived using noncompartmental analysis. RESULTS: Data were available for 14 women. The area under the plasma concentration-time curve from 0 to 12 h (AUC12h) for total darunavir was 17-24% lower during pregnancy than postpartum. The AUC12h for unbound darunavir was minimally reduced during pregnancy vs. postpartum. The minimum plasma concentration (Cmin) of total and unbound darunavir was on average 43-86% and 10-14% higher, respectively, during pregnancy vs. postpartum. The antiviral response (< 50 HIV-1 RNA copies/mL) was 33% at baseline and increased to 73-90% during treatment; the percentage CD4 count increased over time. One serious adverse event was reported (increased transaminase). All 12 infants born to women remaining in the study at delivery were HIV-1-negative; four of these infants were premature. CONCLUSIONS: Total darunavir exposure decreased during pregnancy. No clinically relevant change in unbound (active) darunavir occurred during pregnancy, suggesting that no dose adjustment is required for darunavir/ritonavir 600/100 mg bid in pregnant women. PMID- 23731451 TI - Preliminary investigation of topical nitroglycerin formulations containing natural wound healing agent in diabetes-induced foot ulcer. AB - Nitroglycerin (NTG) is an organic nitrate rapidly denitrated by enzymes to release free radical nitric oxide and shows improved wound healing and tissue protection from oxidative damage. The purpose of this study was to evaluate whether topical application of NTG in the form of gel/ointment along with a natural wound healing agent, aloe vera, would bring about wound healing by using diabetes-induced foot ulcer model and rat excision wound model. All these formulations were evaluated for pH, viscosity, drug content and ex vivo diffusion studies using rat skin. Based on ex vivo permeation studies, the formulation consisting of carbopol 974p as a gelling agent and aloe vera was found to be suitable. The in vivo study used streptozotocin-induced diabetic foot ulcer and rat excision wound models to analyse wound healing activity. The wound size in animals of all treated groups was significantly reduced compared with that of the diabetic control and marketed treated animals. This study showed that the gel formed with carbopol 974p (1%) and aloe vera promotes significant wound healing and closure in diabetic rats compared with the commercial product and provides a promising product to be used in diabetes-induced foot ulcer. PMID- 23731452 TI - Linking people with long-term health conditions to healthy community activities: development of Patient-Led Assessment for Network Support (PLANS). AB - OBJECTIVE: To combine insights from service users with long-term conditions (LTCs) to assist the development of a community referral intervention designed to promote engagement and improve access to health-relevant resources. BACKGROUND: Social deprivation and reduced access to resources have been causally linked with social isolation and the ability to manage LTCs. Participation in meaningful activity has been associated with positive health benefits, and strategies to promote access to community activities have shown some potential to improve outcomes for people with LTCs. This suggests the need to develop an engagement and referral intervention in partnership with service users and community groups as part of mainstream self-care support. METHOD: A series of focus groups and interviews with members of community groups in Greater Manchester designed as an iterative and collaborative approach to elicit the role of personal and community networks that support long-term condition management (LTCM) to develop a community referral tool. RESULTS: Participants reported a broad range of resources relevant to LTCM that often went beyond the usual concerns associated with self-care. This helped to inform a tool (PLANS) to tailor access to types of community-based resources which can support LTCM. CONCLUSIONS: Understanding the everyday challenges of living with a LTC highlighted the importance of connecting and engaging with localized support for people. In response to this, we developed an intervention (PLANS) which tailors access to local resources based on personal preferences, needs and acceptability to encourage service users to engage with sustainable health choices. PMID- 23731453 TI - Sildenafil in the treatment of pressure ulcer: a randomised clinical trial. AB - Pressure ulcer (PrU)-related hospitalisation and mortality are critical issues in medical and surgical patients. Although animal studies have suggested the beneficial effects of sildenafil on wound healing, related clinical data are lacking. This is the first clinical study that has evaluated the effects of topical sildenafil on PrU healing in human subjects. Enrolled patients were randomly allocated to receive topical sildenafil (10%) ointment or placebo daily. Wound healing was assessed visually and photographically by the change in wound score according to two-digit Stirling scale. Decreases in grades of the PrUs were significantly higher in sildenafil group compared with placebo group (P < 0.001). In addition, surface areas of ulcers in sildenafil group were significantly reduced compared to the control group at day 14 of intervention (P = 0.007). It appears that these effects may be mediated by improvement of microvascular reperfusion in the skin and soft tissue. Further study to emphasise the role of topical sildenafil in the prevention or treatment of PrUs in hospitalised patients is required. PMID- 23731454 TI - Evaluation of the efficacy of low-level light therapy using 1072 nm infrared light for the treatment of herpes simplex labialis. AB - BACKGROUND: Recent research has shown that low-level light therapy (LLLT) using 1072 nm infrared light is effective in reducing the duration of herpes simplex labialis (HSL) episodes and enhancing the healing process. METHODS: This was a prospective, randomized, placebo-controlled, clinical trial to evaluate the efficacy of a 1072 nm light-emitting diode device for the treatment of HSL. In total, 87 patients with recurrent HSL were recruited and randomly divided into two groups. Subjects received a 3-min treatment with either 1072 nm infrared light therapy or placebo (sham) light therapy three times/day for 2 days. The devices used for both groups were identical in appearance and could not be differentiated by volunteers or researchers, and 1072 nm light is invisible to the human eye. The primary endpoint was healing time, which was taken as the time for the HSL lesions to resolve fully and for the underlying skin to become completely re-epithelialized, and the secondary endpoint was lesion crusting. RESULTS: The median time to healing for the active group was 129 h, compared with 177 h for the control group, which was significant (P = 0.01). There was no difference between the two groups for median time to lesion crusting (P = 0.66). CONCLUSIONS: Compared with placebo treatment, the treatment of HSL lesions with 1072 nm infrared light significantly reduced healing time. PMID- 23731455 TI - Serum hepcidin and growth differentiation factor-15 (GDF-15) levels in polycythemia vera and essential thrombocythemia. AB - OBJECTIVES: Hepcidin plays a regulatory role in systemic iron homeostasis. GDF-15 has been found to be expressed from matured erythroblasts and very high levels of GDF-15 suppresses hepcidin secretion. In this study, we evaluated hepcidin and GDF-15 levels in polycythemia vera (PV) and essential thrombocythemia (ET). METHODS: The study included 29 patients and 21 healthy controls. The patient group included 13 patients with ET and 16 patients with PV. Serum hepcidin and GDF-15 levels were measured at the time of diagnosis, before the initiation of any therapy. RESULTS: Hepcidin levels did not differ significantly in patients with chronic myeloproliferative disease (CMPD) and healthy controls. However, GDF 15 levels were significantly increased in patients with CMPD (P = 0.038). No difference could be found between patients with PV and ET in terms of hepcidin and GDF-15 levels. Patients with JAK2-V617F mutation had increased GDF-15 levels when compared with patients without this mutation (P: 0.006). CONCLUSIONS: The levels of GDF-15 were higher in CMPD, which are characterized by increased erythropoiesis, and this effect was more pronounced particularly in individuals with JAK2-V617F mutation. Hepcidin levels were not suppressed despite the increased erythroid activity and GDF-15 levels may be protective against the clinical complications of the disease such as thrombosis. This study revealed that, hepcidin levels were not suppressed despite increased erythroid activity and high GDF-15 levels in CMPD. We hypothesized that, this may be an attempt to prevent further amplification of erythropoietic activity by reducing iron utilization. PMID- 23731456 TI - Cellular communication via nanoparticle-transporting biovesicles. AB - AIMS: Endothelial cells are dynamic cells tasked with selective transport of cargo from blood vessels to tissues. Here we demonstrate the potential for nanoparticle transport across endothelial cells in membrane-bound vesicles. MATERIALS & METHODS: Cell-free endothelial-derived biovesicles were characterized for cellular and nanoparticle content by electron microscopy. Confocal microscopy was used to evaluate biovesicles for organelle-specific proteins, and to monitor biovesicle engulfment by naive cells. RESULTS: Nanoparticle-laden biovesicles containing low-density polyethyleneimine nanoparticles appear to be predominately of endosomal origin, combining features of multivesicular bodies, lysosomes and autophagosomes. Conversely, high-density polyethyleneimine nanoparticles stimulate the formation of biovesicles associated with cellular apoptotic breakdown. Secreted LAMP-1-positive biovesicles are internalized by recipient cells, either of the same origin or of novel phenotype. CONCLUSION: Cellular biovesicles, rich in cellular signals, present an important mode of cell-to-cell communication either locally or through broadcasting of biological messages. PMID- 23731457 TI - Combating Helicobacter pylori infections with mucoadhesive nanoparticles loaded with Garcinia mangostana extract. AB - AIM: To combat the resistance of Helicobacter pylori to antibiotics through the use of Garcinia mangostana extract (GME) in the form that can be localized at stomach mucosa. MATERIALS & METHODS: GME and its major active component, alpha mangostin, are encapsulated into the moderately acid stable mucoadhesive nanocarriers, and tested for anti-H. pylori and antiadhesion activities in vitro and their ability to eradicate H. pylori in infected mice. RESULTS: The two in vitro activities are observed and are enhanced when the materials are encapsulated into nanocarriers. Preliminary in vivo tests revealed the ability to combat H. pylori in mice following oral administration of the encapsulated GME, but not the unencapsulated GME. CONCLUSION: Nanoencapsulated GME is a potential anti-H. pylori agent. PMID- 23731458 TI - Nanoparticle-induced photocatalytic head and neck squamous cell carcinoma cell death is associated with autophagy. AB - AIM: To characterize molecular mechanisms underlying photocatalytic cell death of head and neck squamous cell carcinoma (HNSCC) by zinc oxide nanoparticles (ZnO NPs). MATERIALS & METHODS: Human HNSCC-derived FaDu cells were incubated with ZnO NPs followed by UVA-1 irradiation. Cytotoxicity was assessed by MTT assay and annexin-V propidium iodide test. Autophagy was detected by autophagosome accumulation, conversion of light chain 3 I to II, and lysosomal activity. The generation of reactive oxygen species was measured using the 2',7' dichlorofluorescein-diacetate test. RESULTS: Apoptosis-independent cytotoxic effects were induced by 0.2- and 2-ug/ml ZnO-NPs and UVA-1. FaDu cells promoted autophagosome formation. Significantly elevated light chain 3 II and reactive oxygen species were seen after the combined application of both ZnO-NPs and UVA-1 as photocatalytic treatment. Autophagy probably mediates cell survival under UVA 1 or ZnO-NP exposure alone but induces self-digestive cell death after combined treatment. CONCLUSION: The effect of autophagy on HNSCC viability after nanoparticle-induced photocatalytic treatment seems to depend on the impact of the physicochemical trigger. PMID- 23731459 TI - How diverse is Mitopus morio? Integrative taxonomy detects cryptic species in a small-scale sample of a widespread harvestman. AB - Mitopus morio is a widespread harvestman species occurring in most of Europe and in moderate and cold-moderate zones of Asia and North America. The species is characterized by extreme variability in body size and leg length. As leg length is correlated with habitat temperature, M. morio has been considered as an example of Allen's rule. Recently, observations for a single location in Tyrol, Austria, indicated the absence of mating between short- and long-legged individuals. This study examines for signs of putative cryptic species in M. morio using an integrative approach that combines mating trials, amplified fragment length polymorphism whole-genome scans, mitochondrial sequences and morphometrics. The mating trials did not corroborate the initial hypothesis of a reproductive barrier associated with leg size. Both types of genetic data revealed the existence of three distinct groups, in line with the mating results but largely unrelated to leg morphology and geographical origin of specimens. Morphometric characters supporting the findings of the other disciplines were identified using a supervised approach. We infer from all data together the existence of strongly diverged cryptic lineages among the analysed individuals, cautiously interpret them as three sympatric species and conclude that in these harvestmen Allen's rule applies at different levels. Due to the unexpected amount of differentiation found within a geographical scale very small compared with the distribution of M. morio, we suggest a thorough revision of the genus prior to formal taxonomic changes. Our case study underlines the general applicability of the integrative taxonomic protocol used and highlights the relevance of several rationales implemented in the protocol. PMID- 23731460 TI - Anti-biofilm activity of silver nanoparticles against different microorganisms. AB - Biofilms confer protection from adverse environmental conditions and can be reservoirs for pathogenic organisms and sources of disease outbreaks, especially in medical devices. The goal of this research was to evaluate the anti-biofilm activities of silver nanoparticles (AgNPs) against several microorganisms of clinical interest. The antimicrobial activity of AgNPs was tested within biofilms generated under static conditions and also under high fluid shears conditions using a bioreactor. A 4-log reduction in the number of colony-forming units of Pseudomonas aeruginosa was recorded under turbulent fluid conditions in the CDC reactor on exposure to 100 mg ml(-1) of AgNPs. The antibacterial activity of AgNPs on various microbial strains grown on polycarbonate membranes is reported. In conclusion, AgNPs effectively prevent the formation of biofilms and kill bacteria in established biofilms, which suggests that AgNPs could be used for prevention and treatment of biofilm-related infections. Further research and development are necessary to translate this technology into therapeutic and preventive strategies. PMID- 23731461 TI - Frailty and early hospital readmission after kidney transplantation. AB - Early hospital readmission (EHR) after kidney transplantation (KT) is associated with increased morbidity and higher costs. Registry-based recipient, transplant and center-level predictors of EHR are limited, and novel predictors are needed. We hypothesized that frailty, a measure of physiologic reserve initially described and validated in geriatrics and recently associated with early KT outcomes, might serve as a novel, independent predictor of EHR in KT recipients of all ages. We measured frailty in 383 KT recipients at Johns Hopkins Hospital. EHR was ascertained from medical records as >=1 hospitalization within 30 days of initial post-KT discharge. Frail KT recipients were much more likely to experience EHR (45.8% vs. 28.0%, p = 0.005), regardless of age. After adjusting for previously described registry-based risk factors, frailty independently predicted 61% higher risk of EHR (adjusted RR = 1.61, 95% CI: 1.18-2.19, p = 0.002). In addition, frailty improved EHR risk prediction by improving the area under the receiver operating characteristic curve (p = 0.01) as well as the net reclassification index (p = 0.04). Identifying frail KT recipients for targeted outpatient monitoring and intervention may reduce EHR rates. PMID- 23731462 TI - Postsynthetic modification of dicarbene-derived metallacycles via photochemical [2 + 2] cycloaddition. AB - Molecular squares obtained from two olefin-bridged bis(NHC) ligands, NHC-Ar-C?C Ar-NHC, and two Ag(+) or Au(+) ions undergo postsynthetic modifications via a UV irradiation-initiated [2 + 2] cycloaddition reaction to yield the corresponding cyclobutane-bridged dinuclear tetrakis(NHC) complexes. The tetrakis(NHC) ligand can be liberated from the Ag(I) complexes as the tetraimidazolium salt. For the Au(I) complexes, the substituents at N3 and N3' of the dicarbene ligands determine the outcome of the reaction in the solid state. PMID- 23731463 TI - Mechanical evaluation of adjunctive fixation for prevention of periprosthetic femur fracture with the Zurich cementless total hip prosthesis. AB - OBJECTIVE: To evaluate whether cerclage wire or a lateral plate increases the peak-torque load to failure, compared to femora without adjunctive fixation, in femora implanted with Zurich Cementless stems. STUDY DESIGN: In vitro biomechanical study. SAMPLE POPULATION: Paired femora from adult dogs (n = 24) weighing 28-35 kg. METHODS: Pairs of femora were implanted with a stem and randomly assigned to 2 treatment groups: cerclage or plate. Within each pair, either 3 loop cerclage wires or a laterally applied 12-hole Advanced Locking Plate System 10-mm plate (ALPS 10) were implanted in a femur, whereas the contralateral femur acted as control with no adjunctive fixation. After application of a static axial load each specimen was loaded to failure in torsion. Peak torque load at failure was compared between femora with each adjunctive fixation and the control using a paired t-test; P < .05 was considered significant. RESULTS: In both treatment groups, femora with adjunctive fixation failed at higher loads compared to the femora without fixation; however, significant difference in peak torque at failure between treated femora and control was found only in the plated group (P < .05). Femora implanted with plates and with cerclage were 13.9% and 7.2% stronger in torsion than the femora without fixation, respectively. CONCLUSIONS: Adjunctive fixation with a laterally applied ALPS 10 may aid in the prevention of peri-prosthetic fractures associated with Zurich Cementless medium stems. PMID- 23731464 TI - The suppressive effect of IL-27 on encephalitogenic Th17 cells induced by multiwalled carbon nanotubes reduces the severity of experimental autoimmune encephalomyelitis. AB - BACKGROUND: Both Th1 and Th17 cells specific for neuroantigen are described as encephalitogenic in the experimental autoimmune encephalomyelitis (EAE) model. AIM: The proposal of this study was to investigate how carbon nanotubes internalized by antigen-presenting cells (APCs) affect the development of encephalitogenic CD4(+) T cells. METHODS: Therefore, we stimulated encephalitogenic T cells in the presence or not of multiwalled carbon nanotube (MWCNT). After the incubation, we analyzed the expression profile of the encephalitogenic T cells and their capacity to induce EAE. RESULTS: Encephalitogenic CD4(+) T cells cultured with APCs that were previously incubated with MWCNTs do not express IL-17. The adoptive transfer of these cells causes less severe EAE than the transfer of both Th1 and Th17 cells that are not incubated with MWCNTs. These results suggest that the increased IL-27 level produced by the APCs incubated with the carbon nanotubes inhibits the development of Th17 cells. This observation is confirmed by the concomitant reduction in the level of RORgammat, which is a transcription factor essential for the development of Th17 cells. Moreover, the incubation of encephalitogenic T cells devoid of Th17 cells with neutralizing anti-IL-27 antibodies restored the production of IL 17. CONCLUSION: This finding confirms the suppressive effect of IL-27 on encephalitogenic Th17 cells. The results presented suggest that the stimulation of APCs with carbon nanoparticles prior to neuroantigen presentation affects the development of the Th17 subset of encephalitogenic CD4(+) T lymphocytes and results in less severe EAE. PMID- 23731465 TI - Prevalence and characterization of verotoxigenic-Escherichia coli isolates from pigs in Malaysia. AB - BACKGROUND: Postweaning diarrhea caused by pathogenic Escherichia coli, in particular verotoxigenic E. coli (VTEC), has caused significant economic losses in the pig farming industry worldwide. However, there is limited information on VTEC in Malaysia. The objective of this study was to characterize pathogenic E. coli isolated from post-weaning piglets and growers with respect to their antibiograms, carriage of extended-spectrum beta-lactamases, pathotypes, production of hemolysins and fimbrial adhesins, serotypes, and genotypes. RESULTS: PCR detection of virulence factors associated with different E. coli pathotypes (ETEC, EPEC, EHEC, and VTEC) revealed that VTEC was the only pathotype identified from six swine farms located at north-western Peninsular Malaysia. A low prevalence rate of VTEC was found among the swine samples (n = 7/345) and all 7 VTEC isolates were multidrug resistant. Five of these isolates from different hosts raised in the same pen were likely to be of the same clone as they shared identical sero-pathotypes (O139:H1, VT2e/alpha-hly/F18), resistance profiles and DNA fingerprinting profiles. Two other serotypes, O130: H26 (n = 1) and O168: H21 (n = 1) carrying virulence factors were also identified. O168: H21 is possibly a new serotype as this has not been previously reported. CONCLUSIONS: The occurrence of VTEC with infrequently encountered serotypes that are multidrug resistant and harbouring virulence factors may be of public health concern. The detection of possible clones in this study also showed that the combination of different typing tools including phenotyping and genotyping methods is useful for molecular epidemiologic surveillance and studies. PMID- 23731466 TI - Microarray analysis of microRNA expression in peripheral blood mononuclear cells of critically ill patients with influenza A (H1N1). AB - BACKGROUND: With concerns about the disastrous health and economic consequences caused by the influenza pandemic, comprehensively understanding the global host response to influenza virus infection is urgent. The role of microRNA (miRNA) has recently been highlighted in pathogen-host interactions. However, the precise role of miRNAs in the pathogenesis of influenza virus infection in humans, especially in critically ill patients is still unclear. METHODS: We identified cellular miRNAs involved in the host response to influenza virus infection by performing comprehensive miRNA profiling in peripheral blood mononuclear cells (PBMCs) from critically ill patients with swine-origin influenza pandemic H1N1 (2009) virus infection via miRNA microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) assays. Receiver operator characteristic (ROC) curve analysis was conducted and area under the ROC curve (AUC) was calculated to evaluate the diagnostic accuracy of severe H1N1 influenza virus infection. Furthermore, an integrative network of miRNA-mediated host influenza virus protein interactions was constructed by integrating the predicted and validated miRNA-gene interaction data with influenza virus and host-protein protein interaction information using Cytoscape software. Moreover, several hub genes in the network were selected and validated by qRT-PCR. RESULTS: Forty-one significantly differentially expressed miRNAs were found by miRNA microarray; nine were selected and validated by qRT-PCR. QRT-PCR assay and ROC curve analyses revealed that miR-31, miR-29a and miR-148a all had significant potential diagnostic value for critically ill patients infected with H1N1 influenza virus, which yielded AUC of 0.9510, 0.8951 and 0.8811, respectively. We subsequently constructed an integrative network of miRNA-mediated host-influenza virus protein interactions, wherein we found that miRNAs are involved in regulating important pathways, such as mitogen-activated protein kinase signaling pathway, epidermal growth factor receptor signaling pathway, and Toll-like receptor signaling pathway, during influenza virus infection. Some of differentially expressed miRNAs via in silico analysis targeted mRNAs of several key genes in these pathways. The mRNA expression level of tumor protein T53 and transforming growth factor beta receptor 1 were found significantly reduced in critically ill patients, whereas the expression of Janus kinase 2, caspase 3 apoptosis-related cysteine peptidase, interleukin 10, and myxovirus resistance 1 were extremely increased in critically ill patients. CONCLUSIONS: Our data suggest that the dysregulation of miRNAs in the PBMCs of H1N1 critically ill patients can regulate a number of key genes in the major signaling pathways associated with influenza virus infection. These differentially expressed miRNAs could be potential therapeutic targets or biomarkers for severe influenza virus infection. PMID- 23731467 TI - A screening for antimicrobial activities of Caribbean herbal remedies. AB - BACKGROUND: The TRAMIL program aims to understand, validate and expand health practices based on the use of medicinal plants in the Caribbean, which is a "biodiversity hotspot" due to high species endemism, intense development pressure and habitat loss. The antibacterial activity was examined for thirteen plant species from several genera that were identified as a result of TRAMIL ethnopharmacological surveys or were reported in ethnobotanical accounts from Puerto Rico. The aim of this study was to validate the traditional use of these plant species for the treatment of bacterial infections, such as conjunctivitis, fever, otitis media and furuncles. METHODS: An agar disc diffusion assay was used to examine five bacterial strains that are associated with the reported infections, including Staphylococcus saprophyticus (ATCC 15305), S. aureus (ATCC 6341), Escherichia coli (ATCC 4157), Haemophilus influenzae (ATCC 8142), Pseudomonas aeruginosa (ATCC 7700) and Proteus vulgaris (ATCC 6896), as well as the fungus Candida albicans (ATCC 752). The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values were determined for each of the extracts that showed inhibitory activity. RESULTS: The decoctions of Pityrogramma calomelanos, Tapeinochilus ananassae, and Syzygium jambos, as well as the juice of Gossypium barbadense, showed > 20% growth inhibition against several bacteria relative to the positive control, which was the antibiotic Streptomycin. Extracts with the best antimicrobial activities were S. jambos that showed MIC = 31 MUg/mL and MBC = 1.0 mg/mL against P. vulgaris and T. ananassae that showed MIC = 15 MUg/mL against S. aureus. CONCLUSION: This report confirms the traditional use of P. calomelanos for the treatment of kidney infections that are associated with stones, as well as the antimicrobial and bactericidal effects of T. ananassae against P. vulgaris and S. saprophyticus and the effects of S. jambos against S. aureus and S. saprophyticus. PMID- 23731469 TI - Comments on Margolis et al. Lack of effectiveness of hyperbaric oxygen therapy for the treatment of diabetic foot ulcer and the prevention of amputation. PMID- 23731470 TI - The re-emergence of tuberculosis: what have we learnt from molecular epidemiology? AB - Tuberculosis (TB) has re-emerged over the past two decades: in industrialized countries in association with immigration, and in Africa owing to the human immunodeficiency virus epidemic. Drug-resistant TB is a major threat worldwide. The variable and uncertain impact of TB control necessitates not only better tools (diagnostics, drugs, and vaccines), but also better insights into the natural history and epidemiology of TB. Molecular epidemiological studies over the last two decades have contributed to such insights by answering long-standing questions, such as the proportion of cases attributable to recent transmission, risk factors for recent transmission, the occurrence of multiple Mycobacterium tuberculosis infection, and the proportion of recurrent TB cases attributable to re-infection. M. tuberculosis lineages have been identified and shown to be associated with geographical origin. The Beijing genotype is strongly associated with multidrug resistance, and may have escaped from bacille Calmette-Guerin induced immunity. DNA fingerprinting has quantified the importance of institutional transmission and laboratory cross-contamination, and has helped to focus contact investigations. Questions to be answered in the near future with whole genome sequencing include identification of chains of transmission within clusters of patients, more precise quantification of mixed infection, and transmission probabilities and rates of progression from infection to disease of various M. tuberculosis lineages, as well as possible variations in vaccine efficacy by lineage. Perhaps most importantly, dynamics in the population structure of M. tuberculosis in response to control measures in high-prevalence areas should be better understood. PMID- 23731468 TI - Patient and service user engagement in research: a systematic review and synthesized framework. AB - BACKGROUND: There is growing attention towards increasing patient and service user engagement (PSUE) in biomedical and health services research. Existing variations in language and design inhibit reporting and indexing, which are crucial to comparative effectiveness in determining best practices. OBJECTIVE: This paper utilizes a systematic review and environmental scan to derive an evidence-based framework for PSUE. DESIGN: A metanarrative systematic review and environmental scan/manual search using scientific databases and other search engines, along with feedback from a patient advisory group (PAG). ELIGIBLE SOURCES: English-language studies, commentaries, grey literature and other sources (including systematic and non-systematic reviews) pertaining to patient and public involvement in biomedical and health services research. DATA EXTRACTED: Study description (e.g. participant demographics, research setting) and design, if applicable; frameworks, conceptualizations or planning schemes for PSUE-related endeavours; and methods for PSUE initiation and gathering patients'/service users' input or contributions. RESULTS: Overall, 202 sources were included and met eligibility criteria; 41 of these presented some framework or conceptualization of PSUE. Sources were synthesized into a two-part framework for PSUE: (i) integral PSUE components include patient and service user initiation, reciprocal relationships, colearning and re-assessment and feedback, (ii) sources describe PSUE at several research stages, within three larger phases: preparatory, execution and translational. DISCUSSION AND CONCLUSIONS: Efforts at developing a solid evidence base on PSUE are limited by the non standard and non-empirical nature of much of the literature. Our proposed two part framework provides a standard structure and language for reporting and indexing to support comparative effectiveness and optimize PSUE. PMID- 23731471 TI - mRNA nuclear export in yeast. PMID- 23731473 TI - Psychosocial predictors of parental participation in ultrasound screening for developmental dysplasia of the hip. AB - Ultrasound screening for developmental dysplasia of the hip (DDH) is an innovation in preventive child health care in the Netherlands. Parental participation in the screening will be essential for the success of implementation of the screening. The aim of the current study was to investigate whether psychosocial factors (attitude, subjective norm, self-efficacy, perceived susceptibility, perceived severity, perceived effectiveness) predicted parental participation in the screening. A cross-sectional survey was conducted. Using a questionnaire, several background variables (organization, sociodemographic variables, and knowledge) and psychosocial variables were collected. Blockwise logistic regression was used to analyze the relations. A total of 703 questionnaires of participating parents (response 61.7%) and 393 questionnaires of nonparticipating parents were received (response 37.2%). When controlling for the background variables, attitude, subjective norm, self-efficacy, perceived susceptibility, and perceived effectiveness predicted parental participation in the screening (p < .05). Perceived severity of the dysplasia did not predict participation (p > .05). Psychosocial determinants influenced parental participation in the ultrasound screening for DDH. Emphasizing the positive aspects of the screening, highlighting the effectiveness, removing practical barriers, and being conscious of the influential role of child health care professionals on decision making are areas to focus on when organizing the ultrasound screening for DDH. Health care policy decision makers and child health care professionals should consider these determinants in order to stimulate parental participation. PMID- 23731472 TI - Working memory deficits in high-functioning adolescents with autism spectrum disorders: neuropsychological and neuroimaging correlates. AB - Working memory is a temporary storage system under attentional control. It is believed to play a central role in online processing of complex cognitive information and may also play a role in social cognition and interpersonal interactions. Adolescents with a disorder on the autism spectrum display problems in precisely these domains. Social impairments, communication difficulties, and repetitive interests and activities are core domains of autism spectrum disorders (ASD), and executive function problems are often seen throughout the spectrum. As the main cognitive theories of ASD, including the theory of mind deficit hypotheses, weak central coherence account, and the executive dysfunction theory, still fail to explain the broad spectrum of symptoms, a new perspective on the etiology of ASD is needed. Deficits in working memory are central to many theories of psychopathology, and are generally linked to frontal-lobe dysfunction. This article will review neuropsychological and (functional) brain imaging studies on working memory in adolescents with ASD. Although still disputed, it is concluded that within the working memory system specific problems of spatial working memory are often seen in adolescents with ASD. These problems increase when information is more complex and greater demands on working memory are made. Neuroimaging studies indicate a more global working memory processing or connectivity deficiency, rather than a focused deficit in the prefrontal cortex. More research is needed to relate these working memory difficulties and neuroimaging results in ASD to the behavioral difficulties as seen in individuals with a disorder on the autism spectrum. PMID- 23731474 TI - Adiponectin levels in patients with psoriasis: a meta-analysis. AB - Conflicting results regarding adiponectin levels in patients with psoriasis have been reported. We carried out a meta-analysis on studies which compared adiponectin levels of psoriatic patients with controls. A published work search was performed through PubMed (MEDLINE), EMBASE and the Cochrane Library for articles published in English. Pooled standardized mean difference (SMD) and 95% confidence intervals (95% CI) were calculated by using random effects and fixed effect models. Heterogeneity between studies was assessed using the Cochran's Q and I(2) statistics. A total of nine studies were enrolled (389 cases and 360 controls) for adiponectin, and three studies were included (132 cases and 132 controls) for high-molecular weight (HMW) adiponectin. Adiponectin and HMW adiponectin levels were not significantly different in patients with psoriasis compared with controls (SMD, -0.151 [95% CI, -0.616 to 0.315]; P = 0.526 for adiponectin; SMD, 0.999 [95% CI, -2.626 to 4.624]; P = 0.589 for HMW adiponectin). The associations were borderline significantly different in the stratum of those with a mean age of less than 40 years (SMD, -0.516 [95% CI: 1.032 to 0]; P = 0.050). Sensitivity analyses were not substantially altered in the direction of effect when any one study was excluded. No publication bias was detected. The level of adiponectin and HMW adiponectin may not be associated with psoriasis. The relationship between psoriasis and adipokines needs more in-depth studies with larger sample sizes. PMID- 23731475 TI - Development of miliary tuberculosis related to anti-tumor necrosis factor-alpha inhibitor therapy for pustular psoriasis. PMID- 23731476 TI - Folliculosebaceous cystic hamartoma presenting as a subcutaneous nodule on the thigh. PMID- 23731477 TI - Case of metastatic malignant melanoma associated with hypertrophic osteoarthropathy. PMID- 23731478 TI - Chronic active Epstein-Barr virus infection with progression to large granular lymphocytic leukemia. PMID- 23731479 TI - Adult case of Stevens-Johnson syndrome possibly induced by Chlamydophila pneumoniae infection with severe involvement of bronchial epithelium resulting in constructive respiratory disorder. PMID- 23731480 TI - Second report of FLG R501X mutation in Japanese patients with atopic dermatitis. PMID- 23731481 TI - Cutaneous sarcoidosis with livedoid lesions: evidence of the involvement of Propionibacterium acnes. PMID- 23731482 TI - Molecular structure differences between the antiviral Nucleoside Analogue 5-iodo 2'-deoxyuridine and the natural nucleoside 2'-deoxythymidine using MP2 and DFT methods: conformational analysis, crystal simulations, DNA pairs and possible behaviour. AB - 5-iodo-2'-deoxyuridine Nucleoside Analogue (IUdR) was the first selective antiviral nucleoside against herpes simplex virus type 1 and 2, and it was also a meaningful anticancer drug. Within a full study of this drug and its possible behaviour, previously, a comprehensive theoretical conformational analysis by MP2 and B3LYP was carried out, and all the possible stable structures were determined with full relaxation of all geometrical parameters. The search located 45 stable structures, and in all them, the whole conformational parameters ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], P, [Formula: see text]max) were analyzed as well as the NBO natural atomic charges. Comparisons of the conformers with those of the natural Nucleoside 2'-deoxythymidine (dT) were carried out, and the main differences between IUdR and dT were analyzed. The accuracy of the methods used was probed with the simulation of the X-ray crystal data by a tetramer form. Watson-Crick (WC) IUdR/dT...2'-deoxyadenosine pairs were analyzed for the first time using quantum chemical calculations, as well as the mispairing IUdR/dT...2' deoxyguanosine. As result, it is observed that IUdR give rises to a slightly stronger WC pair and weaker mispairing than those with dT, therefore deforming slightly the DNA axis and difficulting the growth of the DNA virus and consequently, killing it. PMID- 23731484 TI - Abstracts of the 29th Annual Scientific Meeting of the Australasian College for Emergency Medicine. November 19-22, 2012. Hobart, Australia. PMID- 23731483 TI - Machine learning and genome annotation: a match meant to be? AB - By its very nature, genomics produces large, high-dimensional datasets that are well suited to analysis by machine learning approaches. Here, we explain some key aspects of machine learning that make it useful for genome annotation, with illustrative examples from ENCODE. PMID- 23731485 TI - In vivo study of effects of artesunate nanoliposomes on human hepatocellular carcinoma xenografts in nude mice. AB - To investigate the effect of artesunate nanoliposomes on cultured cells in vitro and hepatocellular carcinoma xenografts in BALB/c-nu mice. Fluorescence polarization was applied for measurement of mitochondrial membrane fluidities; inhibition test of tumor cell proliferation in vitro was performed and nude mice xenograft model from human hepatocellular carcinoma (HCC) was established. Cytotoxicity of these compounds was evaluated by MTT assay on hepatocellular carcinoma xenografts in nude mice. Anisotropy (r-value) of blank nanoliposomes didn't change, it had no statistically significance between the blank nanoliposomes group and the control group, it indicated that artesunate had no obvious effect on L-O2 human normal liver cells. IC50 values of artesunate nanoliposomes and artesunate API (active pharmaceutical ingredient) against HepG 2 cells were 15.997 and 19.706 MUg/ml; IC50 values of the same drugs against L-O2 normal human liver cells were 100.23 and 105.54 MUg/ml, respectively. Tumor growth inhibitory effect of artesunate nanoliposomes was 32.7%, and artesunate API was 20.5%, respectively. HepG-2 cells treated with artesunate nanoliposomes showed dose-dependent apoptosis. The antitumor effect of artesunate nanoliposomes on human hepatoma HepG2 cells were stronger than that of artesunate API at the same concentration. PMID- 23731486 TI - Heterometallic derivatives of the unsaturated ditungsten hydride [W2(eta(5) C5H5)2(H)(MU-PCy2)(CO)2]. AB - The title complex reacted with different transition-metal (M) complexes to give heterometallic clusters with W2M and W2M2 metal cores. The reaction with [Fe2(CO)9] in THF at room temperature gave a mixture of the heterodinuclear compound [FeWCp(MU-PCy2)(CO)6] and the tetrahedral clusters [Fe2W2Cp2(MU3-H)(MU PCy2)(CO)8] (W-W = 2.704(1) A) and [Fe2W2Cp2(MU-H)(MU-PCy2)(MU-CO)(CO)8] (W-W = 3.058(5) A). In contrast, its reaction with [Ru3(CO)12] under ultraviolet-visible (UV-Vis) irradiation gave only the heterodinuclear complex [RuWCp(MU-PCy2)(CO)6]. The title complex also reacted readily with [M(CO)6] (M = Cr, Mo, W) in toluene solution under UV-Vis irradiation, but the main product was the known tetracarbonyl complex [W2Cp2(MU-H)(MU-PCy2)(CO)4], except in the reaction with [W(CO)6], the latter also yielding the expected 46-electron cluster [W3Cp2(MU3 H)(MU-PCy2)(CO)7] in 40% yield. The title complex reacted under visible-UV irradiation with different metal-metal bonded dimers in toluene solution, but only with [Ru2Cp2(CO)4] an heterometallic cluster was obtained, with composition [RuW2Cp3(MU-PCy2)(CO)4]. Its reaction with the tetrahydroborate complex [Cu(BH4)(PPh3)2] led to the insertion of two CuH(PPh3) fragments and release of BH3.PPh3, to give the tetranuclear cluster [Cu2W2Cp2(MU-H)3(MU PCy2)(CO)2(PPh3)2], which exists in solution as an equilibrium mixture of two isomers. PMID- 23731487 TI - Linear IgA bullous dermatosis induced by moxifloxacin. PMID- 23731488 TI - The involvement of autophagy pathway in exaggerated ischemic brain damage in diabetic mice. AB - BACKGROUND: Patients with Diabetes are at greater risk for ischemic stroke and usually suffer more severe ischemic brain damage than nondiabetic patients. However, the underlying mechanism of the exaggerated injury is not well defined. AIMS: Macroautophagy (hereafter called autophagy in this report) plays a key role in cellular homeostasis and may contribute to cell death as well. Our aim was to determine whether autophagy was involved in the enhanced susceptibility of diabetic brain cells to ischemic injury and explore it as a possible target for the treatment of stroke in a diabetic condition. RESULTS: A type II diabetic mouse model generated by combined administration of streptozotocin and nicotinamide showed enlarged infarct volume, increased cell death and excessive blood-brain barrier (BBB) disruption compared with nondiabetic stroke mice. After ischemic stroke, both diabetic and nondiabetic mice showed enhanced autophagosome formation and autophagic flux as demonstrated by increased expression of autophagy signals Beclin 1, microtubule-associated protein light-chain II (LC3 II), and decreased autophagy-specific substrate p62. The increased autophagic activity was significantly higher in diabetic stroke mice than that in nondiabetic stroke mice. The autophagy inhibitor 3-methyladenine (3-MA) attenuated the exaggerated brain injury and improved functional recovery. CONCLUSIONS: These data suggest that autophagy contributes to exacerbated brain injury in diabetic condition, and autophagy-mediated cell death may be a therapeutic target in diabetic stroke. PMID- 23731489 TI - Determination of water-soluble vitamins in multivitamin dietary supplements and in artichokes by micellar electrokinetic chromatography. AB - Several procedures of extraction with solvents for the simultaneous determination of vitamin C and some vitamins belonging to the B group (thiamine, riboflavine, nicotinic acid and nicotinamide) in multivitamin preparations and in artichokes (Cynara cardunculus subsp. scolymus [L.] Hegi) were developed. Different experimental conditions were used, in terms of heat treatment, composition and pH of the extraction mixture, with particular attention to high-temperature steps; purification of the extracts with solid phase extraction and stabilisation through lyophilisation were discussed. Analyses of the extracts were conducted by capillary electrophoresis in micellar electrokinetic chromatography modality. Borate buffer at pH 8.2 was used, and sodium dodecyl sulphate was added to the background electrolyte as surfactant. A range of linearity was determined and calibration curves were plotted for all the analytes. PMID- 23731490 TI - Safety and utility of passive peritoneal drainage following Fontan palliation. AB - OBJECTIVE: Placement of peritoneal drainage catheters intra-operatively has been shown to help prevent fluid overload in children recovering from surgery for two ventricle heart disease. We aimed to determine whether this practice is also helpful in children recovering from Fontan palliation. MATERIAL AND METHODS: A retrospective review was performed on children with single-ventricle anatomy undergoing Fontan palliation at our institution from 2007 to 2011. Variables in those with peritoneal drainage were compared with those without using t-tests, Mann-Whitney U-tests, chi-square tests, or analysis of variance for repeated measures as appropriate. Data were represented as mean with standard deviation unless otherwise noted. RESULTS: A total of 43 children were reviewed, 21 (49%) with peritoneal drainage catheters. No complications from catheter placement occurred. The groups did not differ with regard to cardiopulmonary bypass duration, dominant ventricle, pre-operative haemodynamic data, fenestration use, and initial intensive care unit ventilation index. Central venous pressures, vasoactive medication use, and diuretic use during the first 48 hours were also not statistically different. At 48 hours, the median fluid balance was -9 (interquartile range : -50, +20) in those with peritoneal drainage and +77 cc/kg (interquartile range : +22, +96) in those without (p < 0.001), yet median duration of mechanical ventilation was 40 hours (range: 19-326) in those with peritoneal drainage and 23 hours (range: 9-92) in those without, p = 0.01. CONCLUSION: Patients with peritoneal drainage recovering from Fontan palliation achieved negative fluid balance as compared with those without peritoneal drainage, although this difference was associated with a longer duration of mechanical ventilation. PMID- 23731491 TI - Phylogenetic analysis based on 18S rRNA gene sequences of Schellackia parasites (Apicomplexa: Lankesterellidae) reveals their close relationship to the genus Eimeria. AB - In the present study we detected Schellackia haemoparasites infecting the blood cells of Lacerta schreiberi and Podarcis hispanica, two species of lacertid lizards from central Spain. The parasite morphometry, the presence of a refractile body, the type of infected blood cells, the kind of host species, and the lack of oocysts in the fecal samples clearly indicated these blood parasites belong to the genus Schellackia. Until now, the species of this genus have never been genetically characterized and its taxonomic position under the Lankesterellidae family is based on the lack of the exogenous oocyst stage. However, the phylogenetic analysis performed on the basis of the 18S rRNA gene sequence revealed that species of the genus Schellackia are clustered with Eimeria species isolated from a snake and an amphibian species but not with Lankesterella species. The phylogenetic analysis rejects that both genera share a recent common ancestor. Based on these results we suggest a revision of the taxonomic status of the family Lankesterellidae. PMID- 23731493 TI - How academic labs can approach the drug discovery process as a way to synergize with big pharma. AB - While the pharmaceutical industry is facing highly challenging times, the academic drug discovery sector has the potential to contribute meaningfully to the discovery of novel drug targets and to the development of new mode-of-action therapeutics against a range of diseases, including rare and neglected diseases. PMID- 23731494 TI - The hospital cost of road traffic accidents at a South African regional trauma centre: a micro-costing study. AB - BACKGROUND: Road traffic crashes are responsible for a vast amount of death and disability in developing countries. This study uses a bottom up, micro-costing approach to determine the cost of road traffic related crashes in South Africa. METHODS: Using the data from one hundred consecutive RTC related admissions to a regional hospital in South Africa we performed a bottom up costing study. To calculate costs patients were reviewed every 48 h and all interventions were recorded for each individual patient. Prices of interventions were obtained from hospital pricelists. A total cost was calculated on an individual basis. RESULTS: The total cost of in-patient care for these patients was US $6,98,850. Upper limb injuries were the most expensive, and the total cost increased with the number of body regions injured. The biggest expenditure was on ward overheads ($2,81,681). Ninety operations were performed - the total cost of theatre time was $1,48,230 and the cost of orthopaedic implants was $1,26,487. CONCLUSION: The cost of care of a RTC victim is significant. In light of the high numbers of RTC victims admitted over the course of the year this is a significant cost burden for a regional hospital to bear. This cost must be taken into account when allocating hospital budgets. PMID- 23731492 TI - Epigenetic layers and players underlying neurodevelopment. AB - Epigenetic mechanisms convey information above and beyond the sequence of DNA, so it is predicted that they are critical in the complex regulation of brain development and explain the long-lived effects of environmental cues on pre- and early post-natal brain development. Neurons have a complex epigenetic landscape that changes dynamically with transcriptional activity in early life. Here, we summarize progress in our understanding of the discrete layers of the dynamic methylome, chromatin proteome, noncoding RNAs, chromatin loops, and long-range interactions in neuronal development and maturation. Many neurodevelopmental disorders have genetic alterations in these epigenetic modifications or regulators, and these human genetics lessons have demonstrated the importance of these epigenetic players and the epigenetic layers that transcriptional events lay down in the early brain. PMID- 23731495 TI - Compact platelet-rich fibrin scaffold to improve healing of patellar tendon defects and for medial collateral ligament reconstruction. AB - BACKGROUND: Platelets are one of the most biocompatible and cost-effective sources of growth factors. Attention is being paid to autologous platelets and platelet-rich plasma. We developed a novel compact platelet-rich fibrin scaffold (CPFS) that was produced from blood and calcium gluconate only. The objective of this study was to investigate the potential of CPFS as a provisional scaffold in two rabbit models. METHODS: In the first rabbit model, the central half of the patellar tendon was resected bilaterally. Allogenic CPFS was attached to the defect in the right knee, while the left knee was untreated. In the other model, the medial collateral ligament was removed bilaterally. The ligament of the right knee was reconstructed with allogenic CPFS, whereas the left knee was untreated. RESULTS: After 12weeks, the ultimate failure load and stiffness were higher for the right patellar tendon than for the left patellar tendon in the former model. It was found that CPFS promoted ligament repair tissue in contrast with that on the untreated side in the latter model. The ultimate failure load of the CPFS repair tissue at 20weeks was 78% of that in healthy controls of the same age. CONCLUSIONS: CPFS enhanced the healing of tendons and ligaments. CLINICAL RELEVANCE: CPFS has the potential to accelerate healing of tendons and ligaments as a provisional bioscaffold or a material for graft augmentation. PMID- 23731496 TI - Probability of mechanical loosening of the femoral component in high flexion total knee arthroplasty can be reduced by rather simple surgical techniques. AB - BACKGROUND: Some follow-up studies of high flexion total knee arthoplasties report disturbingly high incidences of femoral component loosening. Femoral implant fixation is dependant on two interfaces: the cement-implant and the cement-bone interface. The present finite-element model (FEM) is the first to analyse both the cement-implant interface and cement-bone interface. The cement bone interface is divided into cement-cancellous and cement-cortical bone interfaces, each having their own strength values. The research questions were: (1) which of the two interfaces is more prone to failure? and (2) what is the effect of different surgical preparation techniques for cortical bone on the risk of early failure.? METHODS: FEM was used in which the posterior-stabilized PFC Sigma RP-F (DePuy) TKA components were incorporated. A full weight-bearing squatting cycle was simulated (ROM=50 degrees -155 degrees ). An interface failure index (FI) was calculated for both interfaces. RESULTS: The cement-bone interface is more prone to failure than the cement implant interface. When drilling holes through the cortex behind the anterior flange instead of unprepared cortical bone, the area prone to early interface failure can be reduced from 31.3% to 2.6%. CONCLUSION: The results clearly demonstrate high risk of early failure at the cement-bone interface. This risk can be reduced by some simple preparation techniques of the cortex behind the anterior flange. CLINICAL RELEVANCE: High-flexion TKA is currently being introduced. Some reports show high failure rates. FEM can be helpful in understanding failure of implants. PMID- 23731497 TI - Low dopamine transporter occupancy by methylphenidate as a possible reason for reduced treatment effectiveness in ADHD patients with cocaine dependence. AB - Methylphenidate (MPH) occupies brain striatal dopamine transporters (DATs) and is an effective treatment for attention deficit hyperactivity disorder (ADHD). However, patients with ADHD and comorbid cocaine dependence do not benefit significantly from treatment with MPH. To better understand the neurobiology of this phenomenon, we examined DAT availability and the effects of MPH treatment on DAT occupancy in ADHD patients with and without cocaine dependence. ADHD patients without a comorbid substance use disorder (N=16) and ADHD patients with comorbid cocaine dependence (N=8) were imaged at baseline and after two weeks MPH treatment using single photon emission computed tomography (SPECT) with the DAT tracer [(123)I]FP-CIT. Changes in ADHD symptoms were measured with the ADHD symptom rating scale (ASRS). At baseline, we observed lower striatal DAT availability in ADHD patients with cocaine dependence. Following fixed MPH treatment, MPH occupied significantly less striatal DATs in cocaine-dependent than in non-cocaine dependent ADHD patients. There were no significant correlations between baseline DAT availability or DAT occupancy by MPH and ADHD symptom improvement. However, we did find significant correlations between DAT occupancy by MPH and decreases in impulsivity scores and years of cocaine use. These preliminary findings suggest that low DAT occupancy is not the reason why ADHD patients with cocaine dependence do not benefit from MPH treatment. It also suggests that higher dosages of MPH in these patients are probably not the solution and that medications directed at other pharmacological targets should be considered in these comorbid ADHD patients. This trial is registered at the Dutch Trial Register, www.trialregister.nl, under Trial ID number NTR3127. PMID- 23731498 TI - Does pharmacogenetic testing for CYP450 2D6 and 2C19 among patients with diagnoses within the schizophrenic spectrum reduce treatment costs? AB - The effect of pharmacogenetic testing for CYP450 2D6 and 2C19 on treatment costs have not yet been documented. This study used Danish patient registers to calculate healthcare costs of treating patients with diagnoses within the schizophrenic spectrum for 1 year with or without pharmacogenetic testing for polymorphisms in the genes for the CYP2D6 and CYP2C19 enzymes. In a randomized, controlled trial, stratified with respect to metabolizer genotype, 104 patients were assigned to treatment based on pharmacogenetic testing and 103 patients to treatment as usual. Random exclusion of extensive and intermediate metabolizers was used to increase the frequency of extreme metabolizers (poor metabolizers and ultrarapid metabolizers for CYP2D6) to 20% in both groups. Cost differences were analysed at several levels including (i) overall healthcare expenditure, (ii) psychiatric hospital cost (iii) nonpsychiatric hospital cost, (iv) primary care spending and (v) pharmaceuticals. Statistically significant differences in costs of psychiatric care dependent on metabolizer status were found between intervention groups. Pharmacogenetic testing significantly reduced costs among the extreme metabolizers (poor metabolizers and ultrarapid metabolizers) to 28%. Use of primary care services and pharmaceuticals was also affected by the intervention.This study confirms earlier findings that extreme metabolizers (poor and ultrarapid metabolizers) incur higher costs than similar patients with a normal metabolizer genotype. However, this study shows that these excess costs can be reduced by pharmacogenetic testing. Pharmacogenetic testing for CYP2D6 and CYP2C19 could thus be considered as a means of curtailing high psychiatric treatment costs among extreme metabolizers. PMID- 23731499 TI - ADC normalization: a promising research track for diffusion-weighted MR imaging of the abdomen. PMID- 23731500 TI - Internal hernia through the omental foramen. Answer to the e-quid "Epigastric pain with sudden onset". PMID- 23731501 TI - Epidermoid cyst. Answer to the e-quid "A testicular mass". PMID- 23731502 TI - [Assessment of patient needs to design a patient education program in systemic lupus erythematosus]. AB - PURPOSE: The aim of this study was to collect information to design a patient education program (PEP) for patients with systemic lupus erythematosus (SLE), based as much as possible on their expectations. PATIENTS AND METHODS: Three different approaches were used for addressing patients' needs: 1) A questionnaire on their expectations in terms of a PEP was sent to the members of SLE associations and offered to patients at the French reference center for SLE, 2) A patients' focus group was conducted, and 3) After the teaching sessions, satisfaction questionnaires were also evaluated. RESULTS: The patients who answered the expectation questionnaire (n=422, women/men sex-ratio: 12.6) indicated a major interest in the PEP (70.4%). Their expectations were broad, and covered the topics of pregnancy (90% of the women under the age of 40), the outcome of the disease (80.8%), the respective roles of the different treatments (70.4%), and also the management of everyday symptoms: fatigue and pain (66.4%). The focus group (eight people) highlighted the need for improving how the diagnosis of the disease was delivered, and also revealed the loneliness and the guilty feeling experienced by some patients toward their relatives. Satisfaction questionnaires confirmed these expectations for the PEP, and even extended them to new topics: the mechanisms behind SLE, travel and leisure, and possible accommodations in the workplace. CONCLUSIONS: The direct consultation of patients with SLE targeted by a specific PEP program allowed us to confirm and adapt the topics and the content of a program designed by medical staff. PMID- 23731503 TI - Impaired dynamic cerebral autoregulation in moyamoya disease. PMID- 23731504 TI - Livestock-associated methicillin-resistant Staphylococcus aureus responsible for human colonization and infection in an area of Italy with high density of pig farming. AB - BACKGROUND: Livestock-Associated MRSA (LA-MRSA) belonging to ST398 lineage, common among pigs and other animals, emerged in Central and Northern Europe, becoming a new risk factor for MRSA among farm workers. Strains belonging to ST398 can be responsible for human colonization and infection, mainly in areas with high livestock-farming. The aim of this study was to investigate the occurrence of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) human colonization and infections in an area of the Lombardy Region (Italy), the Italian region with the highest density of pig farming. METHODS: In the period March-April 2010, 879 nasal swabs were taken from subjects at admission to a local hospital serving an area of the Lombardy Region devoted to agriculture and farming. In the period March 2010-February 2011, all MRSA strains from community-acquired infection (CAI) observed in the same hospital, were collected. Molecular characterization of the isolates included SCCmec typing, spa typing and multilocus sequence typing (MLST). RESULTS: Out of 879 nasal swabs examined, 9 (1%) yielded MRSA. Five strains were assigned to sequence type (ST)398 (spa t899, 3 isolates; t108 and t2922, 1 isolate each) and were therefore categorized as LA-MRSA. The other 4 isolates were likely of hospital origin. No strains were positive for Panton-Valentine Leukocidin genes. Twenty MRSA isolates were detected from CAI, 17 were from skin and soft-tissue infections and 3 from other infections. An MRSA isolate from otitis externa was t899/ST398 and PVL negative, hence categorized as LA-MRSA. Four isolates were assigned to t127/ST1. Eight strains were PVL-positive community acquired (CA)-MRSA and belonged to different clones, the most frequent being ST8. CONCLUSIONS: In an area of Italy with high density of pig farming, LA-MRSA is able to colonize the population and rarely to produce infections. Typical CA-MRSA is more common than LA-MRSA among CAI. PMID- 23731505 TI - [Regarding: Benefit/risk ratio analysis from a possible anticoagulation of asymptomatic deep venous thrombosis in major orthopedic surgery]. PMID- 23731506 TI - Results of a community-based cervical cancer screening pilot project using human papillomavirus self-sampling in Kampala, Uganda. AB - OBJECTIVE: To examine the feasibility of a community-based screening program using human papillomavirus (HPV) self-sampling in a low-income country with a high burden of cervical cancer. METHODS: A pilot study was conducted among 205 women aged 30-69years in the Kisenyi district of Kampala, Uganda, from September 5 to October 30, 2011. Women were invited to provide a self-collected specimen for high-risk oncogenic HPV testing by outreach workers at their homes and places of gathering in their community. Specimens were tested for HPV, Neisseria gonorrhoeae and Chlamydia trachomatis. Women who tested positive for HPV were referred for colposcopy, biopsy, and treatment at a regional hospital. RESULTS: Of the 199 women who provided a specimen, 35 (17.6%) tested positive for HPV. The outreach workers were able to provide results to 30 women (85.7%). In all, 26 (74.3%) of the women infected with HPV attended their colposcopy appointments and 4 (11.4%) women were diagnosed with grade 3 cervical intraepithelial neoplasia. CONCLUSION: Self-collection of samples for community-based HPV testing was an acceptable option; most women who tested positive attended for definitive treatment. Self-sampling could potentially allow for effective recruitment to screening programs in limited-resource settings. PMID- 23731507 TI - Prospective cohort study and meta-analysis of cyclic bleeding after laparoscopic supracervical hysterectomy. AB - OBJECTIVE: To evaluate a modified technique of laparoscopic supracervical hysterectomy (LSH) on rates of postoperative cyclic bleeding (PCB). METHODS: A retrospective study was conducted of 173 women who underwent LSH with bipolar electrocoagulation of the endocervical canal at Landeskrankenhaus Wolfsberg, Wolfsberg, Austria, between January 1, 2005, and December 31, 2009. Long-term follow-up was assessed using a questionnaire. A systematic literature review and a meta-analysis of 13 studies that reported on PCB after LSH were also conducted. RESULTS: In all, 164 women (94.8%) had uneventful intraoperative and postoperative courses. By contrast, 9 of 146 premenopausal women (6.2%) experienced PCB. The meta-analysis (n=1822) revealed an overall PCB rate of 7.1%. Bipolar electrocoagulation of the endocervical canal was the most effective method for prevention of PCB (bleeding rate, 2.9%) followed by unipolar electrocoagulation (bleeding rate, 9.9%). Uterine resection below the internal cervical orifice was more effective for preventing PCB (13 of 633 women; 2.1%) than either amputation at this site or above this site (27 of 537 women [5.0%] and 88 of 640 women [13.8%]). CONCLUSION: Bipolar coagulation of the endocervical canal and extensive resection with amputation below the level of the internal cervical orifice were effective for reducing rates of PCB. PMID- 23731508 TI - Obstetric care for resident immigrant women in Argentina compared with Argentine women. AB - OBJECTIVE: To evaluate inequities in obstetric care in Argentina between women from Argentina and resident immigrants. METHODS: A secondary analysis was performed using data generated from a prospective, multicenter, descriptive study conducted in 2008 that assessed perinatal care in 12 public hospitals in the city of Buenos Aires and 70 public hospitals in Buenos Aires Province. In the original study, eligible women answered questions about their obstetric history, sociodemographic characteristics, and prenatal and intrapartum care within 48hours of delivery. In the present analysis, the associations between nationality and prenatal care, intrapartum care, and perinatal outcome were determined. RESULTS: The study included 10898 women. The sociodemographic characteristics were similar between the groups, although the proportion of adolescents was higher among Argentines than among immigrants (20.1% versus 12.5%), whereas immigrant women were less educated (30.7% of the immigrant women reported 0-6years of education compared with 7.3% of Argentines). Likewise, there were few differences in obstetric care during pregnancy and delivery, and the pregnancy outcomes were also similar between the groups. CONCLUSION: There were few clinically significant differences in medical care between Argentine women and resident immigrant women during the prepartum and intrapartum periods. PMID- 23731510 TI - The impact of the Nitrates Directive on nitrogen emissions from agriculture in the EU-27 during 2000-2008. AB - A series of environmental policies have been implemented in the European Union (EU) to decrease nitrogen (N) emissions from agriculture. The Nitrates Directive (ND) is one of the main policies; it aims to reduce nitrate leaching from agriculture through a number of measures. A study was carried out to quantify the effects of the ND in the EU-27 on the leaching and runoff of nitrate (NO3(-)) to groundwater and surface waters, and on the emissions of ammonia (NH3), nitrous oxide (N2O), nitrogen oxides (NO(x)) and dinitrogen (N2) to the atmosphere. We formulated a scenario with and a scenario without implementation of the ND. The model MITERRA-Europe was used to calculate N emissions on a regional level in the EU-27 for the period 2000-2008. The calculated total N loss from agriculture in the EU-27 was 13 Mton N in 2008, with 53% as N2, 22% as NO3, 21% as NH3, 3% as N2O, and 1% as NO(x). The N emissions and leaching in the EU-27 slightly decreased in the period 2000-2008. Total emissions in the EU in 2008 were smaller with implementation of the ND than without the ND, by 3% for NH3, 6% for N2O, 9% for NO(x), and 16% for N leaching and runoff in 2008. However, regional differences were large. The lower emissions with ND were mainly due to the lower N inputs by fertilizers and manures. In conclusion, implementation of the ND decreased both N leaching losses to ground and surface waters, and gaseous emissions to the atmosphere. It is expected that the ND will result in a further decrease in N emissions in EU-27 in the near future, because the implementation of the measures for the ND is expected to become more strict. PMID- 23731512 TI - Reflection on the International Society for the Study of Women's Sexual Health. PMID- 23731509 TI - The genome sequence of the most widely cultivated cacao type and its use to identify candidate genes regulating pod color. AB - BACKGROUND: Theobroma cacao L. cultivar Matina 1-6 belongs to the most cultivated cacao type. The availability of its genome sequence and methods for identifying genes responsible for important cacao traits will aid cacao researchers and breeders. RESULTS: We describe the sequencing and assembly of the genome of Theobroma cacao L. cultivar Matina 1-6. The genome of the Matina 1-6 cultivar is 445 Mbp, which is significantly larger than a sequenced Criollo cultivar, and more typical of other cultivars. The chromosome-scale assembly, version 1.1, contains 711 scaffolds covering 346.0 Mbp, with a contig N50 of 84.4 kbp, a scaffold N50 of 34.4 Mbp, and an evidence-based gene set of 29,408 loci. Version 1.1 has 10x the scaffold N50 and 4x the contig N50 as Criollo, and includes 111 Mb more anchored sequence. The version 1.1 assembly has 4.4% gap sequence, while Criollo has 10.9%. Through a combination of haplotype, association mapping and gene expression analyses, we leverage this robust reference genome to identify a promising candidate gene responsible for pod color variation. We demonstrate that green/red pod color in cacao is likely regulated by the R2R3 MYB transcription factor TcMYB113, homologs of which determine pigmentation in Rosaceae, Solanaceae, and Brassicaceae. One SNP within the target site for a highly conserved trans-acting siRNA in dicots, found within TcMYB113, seems to affect transcript levels of this gene and therefore pod color variation. CONCLUSIONS: We report a high-quality sequence and annotation of Theobroma cacao L. and demonstrate its utility in identifying candidate genes regulating traits. PMID- 23731511 TI - Histological and molecular characterisation of feline humeral condylar osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is a clinically important and common disease of older cats. The pathological changes and molecular mechanisms which underpin the disease have yet to be described. In this study we evaluated selected histological and transcriptomic measures in the articular cartilage and subchondral bone (SCB) of the humeral condyle of cats with or without OA. RESULTS: The histomorphometric changes in humeral condyle were concentrated in the medial aspect of the condyle. Cats with OA had a reduction in articular chondrocyte density, an increase in the histopathological score of the articular cartilage and a decrease in the SCB porosity of the medial part of the humeral condyle. An increase in LUM gene expression was observed in OA cartilage from the medial part of the humeral condyle. CONCLUSIONS: Histopathological changes identified in OA of the feline humeral condyle appear to primarily affect the medial aspect of the joint. Histological changes suggest that SCB is involved in the OA process in cats. Differentiating which changes represent OA rather than the aging process, or the effects of obesity and or bodyweight requires further investigation. PMID- 23731513 TI - Sexual health for people with disabilities. PMID- 23731514 TI - What are the benefits of early patient contact?--A comparison of three preclinical patient contact settings. AB - BACKGROUND: Despite increasing attention to providing preclinical medical students with early patient experiences, little is known about associated outcomes for students. The authors compared three early patient experiences at a large American medical school where all preclinical students complete preceptorships and weekly bedside clinical-skills training and about half complete clinical, community-based summer immersion experiences. The authors asked, what are the relative outcomes and important educational components for students? METHODS: Medical students completed surveys at end of second year 2009 2011. In 2009, students compared/contrasted two of three approaches; responses framed later survey questions. In 2010 and 2011, students rated all three experiences in relevant areas (e.g., developing comfort in clinical setting). Investigators performed qualitative and quantitative analyses. RESULTS: Students rated bedside training more highly for developing comfort with clinical settings, one-on-one clinical-skills training, feedback, active clinical experience, quality of clinical training, and learning to be part of a team. They rated community clinical immersion and preceptorships more highly for understanding the life/practice of a physician and career/specialty decisions. CONCLUSIONS: Preclinical students received different benefits from the different experiences. Medical schools should define objectives of early clinical experiences and offer options accordingly. A combination of experiences may help students achieve clinical and team comfort, clinical skills, an understanding of physicians' lives/practices, and broad exposure for career decisions. PMID- 23731515 TI - Pancreaticoduodenectomy: ERAS recommendations. PMID- 23731516 TI - Decreased tryptophan metabolism in patients with autism spectrum disorders. AB - BACKGROUND: Autism spectrum disorders (ASDs) are relatively common neurodevelopmental conditions whose biological basis has been incompletely determined. Several biochemical markers have been associated with ASDs, but there is still no laboratory test for these conditions. METHODS: We analyzed the metabolic profile of lymphoblastoid cell lines from 137 patients with neurodevelopmental disorders with or without ASDs and 78 normal individuals, using Biolog Phenotype MicroArrays. RESULTS: Metabolic profiling of lymphoblastoid cells revealed that the 87 patients with ASD as a clinical feature, as compared to the 78 controls, exhibited on average reduced generation of NADH when tryptophan was the sole energy source. The results correlated with the behavioral traits associated with either syndromal or non-syndromal autism, independent of the genetic background of the individual. The low level of NADH generation in the presence of tryptophan was not observed in cell lines from non ASD patients with intellectual disability, schizophrenia or conditions exhibiting several similarities with syndromal autism except for the behavioral traits. Analysis of a previous small gene expression study found abnormal levels for some genes involved in tryptophan metabolic pathways in 10 patients. CONCLUSIONS: Tryptophan is a precursor of important compounds, such as serotonin, quinolinic acid, and kynurenic acid, which are involved in neurodevelopment and synaptogenesis. In addition, quinolinic acid is the structural precursor of NAD+, a critical energy carrier in mitochondria. Also, the serotonin branch of the tryptophan metabolic pathway generates NADH. Lastly, the levels of quinolinic and kynurenic acid are strongly influenced by the activity of the immune system. Therefore, decreased tryptophan metabolism may alter brain development, neuroimmune activity and mitochondrial function. Our finding of decreased tryptophan metabolism appears to provide a unifying biochemical basis for ASDs and perhaps an initial step in the development of a diagnostic assay for ASDs. PMID- 23731517 TI - Crystal structures of S6K1 provide insights into the regulation mechanism of S6K1 by the hydrophobic motif. AB - The activity of S6K1 (p70 ribosomal protein subunit 6 kinase 1) is stimulated by phosphorylation of Thr389 in the hydrophobic motif by mTORC1 (mammalian target of rapamycin complex 1) and phosphorylation of Thr229 in the activation loop by PDK1 (phosphoinositide-dependent kinase 1); however, the order of the two events is still ambiguous. In the present paper we report six crystal structures of the S6K1 kinase domain alone or plus the hydrophobic motif in various forms, in complexes with a highly specific inhibitor. The structural data, together with the biochemical data, reveal in vivo phosphorylation of Thr389 in the absence of Thr229 phosphorylation and demonstrate the importance of two conserved residues, Gln140 and Arg121, in the establishment of a hydrogen-bonding network between the N-lobe (N-terminal lobe) and the hydrophobic motif. Phosphorylation of Thr389 or introduction of a corresponding negatively charged group leads to reinforcement of the network and stabilization of helix alphaC. Furthermore, comparisons of S6K1 with other AGC (protein kinase A/protein kinase G/protein kinase C) family kinases suggest that the structural and sequence differences in the hydrophobic motif and helix alphaC account for their divergence in PDK1 dependency. Taken together, the results of the present study indicate that phosphorylation of the hydrophobic motif in S6K1 is independent of, and probably precedes and promotes, phosphorylation of the activation loop. PMID- 23731518 TI - Interview with Nancy Kopell. PMID- 23731519 TI - Mitochondrial phylogeny of the genus Echinococcus (Cestoda: Taeniidae) with emphasis on relationships among Echinococcus canadensis genotypes. AB - The mitochondrial genomes of the genus Echinococcus have already been sequenced for most species and genotypes to reconstruct their phylogeny. However, two important taxa, E. felidis and E. canadensis G10 genotype (Fennoscandian cervid strain), were lacking in the published phylogeny. In this study, the phylogeny based on mitochondrial genome sequences was completed with these taxa. The present phylogeny highly supports the previous one, with an additional topology showing sister relationships between E. felidis and E. granulosus sensu stricto and between E. canadensis G10 and E. canadensis G6/G7 (closely related genotypes referred to as camel and pig strains, respectively). The latter relationship has a crucial implication for the species status of E. canadensis. The cervid strain is composed of two genotypes (G8 and G10), but the present phylogeny clearly suggests that they are paraphyletic. The paraphyly was also demonstrated by analysing the complete nucleotide sequences of mitochondrial cytochrome c oxidase subunit 1 (cox1) of E. canadensis genotypes from various localities. A haplotype network analysis using the short cox1 sequences from worldwide isolates clearly showed a close relatedness of G10 to G6/G7. Domestic and sylvatic life cycles based on the host specificity of E. canadensis strains have been important for epidemiological considerations. However, the taxonomic treatment of the strains as separate species or subspecies is invalid from a molecular cladistic viewpoint. PMID- 23731520 TI - An unusual but important cause of biliary obstruction. PMID- 23731521 TI - Competency in chaos: lifesaving performance of care providers utilizing a competency-based, multi-actor emergency preparedness training curriculum. AB - OBJECTIVE: Providing comprehensive emergency preparedness training (EPT) to care providers is important to the future success of disaster operations in the US. Few EPT programs possess both competency-driven goals and metrics to measure performance during a multi-patient simulated disaster. METHODS: A 1-day (8-hour) EPT course for care providers was developed to enhance provider knowledge, skill, and comfort necessary to save lives during a simulated disaster. Nine learning objectives, 18 competencies, and 34 performance objectives were developed. During the 2-year demonstration of the curriculum, 24 fourth-year medical students and 17 Veterans Hospital Administration (VHA) providers were recruited and volunteered to take the course (two did not fully complete the research materials). An online pre-test, two post-tests, course assessment, didactic and small group content, and a 6-minute clinical casualty scenario were developed. During the scenario, trainees working in teams were confronted with three human simulators and 10 actor patients simultaneously. Unless appropriate performance objectives were met, the simulators "died" and the team was exposed to "anthrax." After the scenario, team members participated in a facilitator-led debriefing using digital video and then repeated the scenario. RESULTS: Trainees (N = 39) included 24 (62%) medical students; seven (18%) physicians; seven (18%) nurses; and one (3%) emergency manager. Forty-seven percent of the VHA providers reported greater than 16 annual hours of disaster training, while 15 (63%) of the medical students reported no annual disaster training. The mean (SD) score for the pre test was 12.3 (3.8), or 51% correct, and after the training, the mean (SD) score was 18.5 (2.2), or 77% (P < .01). The overall rating for the course was 96 out of 100. Trainee self-assessment of "Overall Skill" increased from 63.3 out of 100 to 83.4 out of 100 and "Overall Knowledge" increased from 49.3 out of 100 to 78.7 out of 100 (P < .01). Of the 34 performance objectives during the disaster scenario, 23 were completed by at least half of the teams during their first attempt. All teams except one (8 of 9) could resuscitate two simulators and all teams (9 of 9) helped prevent anthrax exposure during their second scenario attempt. CONCLUSIONS: The 1-day EPT course for novice and experienced care providers recreated a multi-actor clinical disaster and enhanced provider knowledge, comfort level, and EPT skill. A larger-scale study, or multi-center trial, is needed to further study the impact of this curriculum and its potential to protect provider and patient lives. PMID- 23731523 TI - Metabolically re-modeling the drug pipeline. AB - Costs for drug development have soared, exposing a clear need for new R&D strategies. Systems biology has meanwhile emerged as an attractive vehicle for integrating omics data and other post-genomic technologies into the drug pipeline. One of the emerging areas of computational systems biology is constraint-based modeling (CBM), which uses genome-scale metabolic models (GSMMs) as platforms for integrating and interpreting diverse omics datasets. Here we review current uses of GSMMs in drug discovery, focusing on prediction of novel drug targets and promising lead compounds. We then expand our discussion to prediction of toxicity and selectivity of potential drug targets. We discuss successes as well as limitations of GSMMs in these areas. Finally, we suggest new ways in which GSMMs may contribute to drug discovery, offering our vision of how GSMMs may re-model the drug pipeline in years to come. PMID- 23731522 TI - Oestrogen and immunomodulation: new mechanisms that impact on peripheral and central immunity. AB - The regulation of the immune response to infection or tissue damage is a complex interplay of multiple factors, but it has long been recognised that steroid hormones can exert powerful modulatory effects at all levels of the innate and adaptive immune systems. Although most attention has been paid to glucocorticoids given their widespread clinical use, it is becoming increasingly clear that sex steroid hormones, and in particular the principle female sex steroid oestrogen, exerts potent effects upon the immune response. In this review, we will discuss the latest findings on the impact of oestrogen upon various cellular components of the immune system, and how this hormone can offer new opportunities to pharmacologically harness the immune response. PMID- 23731524 TI - Maintenance immunosuppression in renal transplantation. AB - The need to maintain allograft recipients on immunosuppression is nearly universal. Immunosuppressive agents used in organ transplantation target one or more steps of the host alloimmune response, specifically processes related to CD4 positive T lymphocytes. Calcineurin-inhibitor based steroid-containing regimens have been the mainstay of maintenance immunosuppression over the last two decades. Newer agents have shown efficacy in this role in recent trials with comparable allograft and patient outcomes. These agents have permitted calcineurin-inhibitor minimization and steroid-sparing strategies in selected groups of patients. PMID- 23731525 TI - A hand hygiene intervention to decrease infections among children attending day care centers: design of a cluster randomized controlled trial. AB - BACKGROUND: Day care center attendance has been recognized as a risk factor for acquiring gastrointestinal and respiratory infections, which can be prevented with adequate hand hygiene (HH). Based on previous studies on environmental and sociocognitive determinants of caregivers' compliance with HH guidelines in day care centers (DCCs), an intervention has been developed aiming to improve caregivers' and children's HH compliance and decrease infections among children attending DCCs. The aim of this paper is to describe the design of a cluster randomized controlled trial to evaluate the effectiveness of this intervention. METHODS/DESIGN: The intervention will be evaluated in a two-arm cluster randomized controlled trial among 71 DCCs in the Netherlands. In total, 36 DCCs will receive the intervention consisting of four components: 1) HH products (dispensers and refills for paper towels, soap, alcohol-based hand sanitizer, and hand cream); 2) training to educate about the Dutch national HH guidelines; 3) two team training sessions aimed at goal setting and formulating specific HH improvement activities; and 4) reminders and cues to action (posters/stickers). Intervention DCCs will be compared to 35 control DCCs continuing usual practice. The primary outcome measure will be observed HH compliance of caregivers and children, measured at baseline and one, three, and six months after start of the intervention. The secondary outcome measure will be the incidence of gastrointestinal and respiratory infections in 600 children attending DCCs, monitored over six months by parents using a calendar to mark the days their child has diarrhea and/or a cold. Multilevel logistic regression will be performed to assess the effect of the intervention on HH compliance. Multilevel poisson regression will be performed to assess the incidence of gastrointestinal and respiratory infections in children attending DCCs. DISCUSSION: This is one of the first DCC intervention studies to assess HH compliance of both caregivers and children, as well as the incidence of gastrointestinal and respiratory infections in children, as outcome measures. When an effect of the intervention on improving HH compliance and/or reducing incidence of infections is shown, (inter)national dissemination of the intervention in other DCCs may be considered. TRIAL REGISTRATION: Netherlands trial registry: NTR3000. PMID- 23731526 TI - Prediabetes is not an independent risk factor for incident heart failure, other cardiovascular events or mortality in older adults: findings from a population based cohort study. AB - BACKGROUND: Whether prediabetes is an independent risk factor for incident heart failure (HF) in non-diabetic older adults remains unclear. METHODS: Of the 4602 Cardiovascular Health Study participants, age>=65 years, without baseline HF and diabetes, 2157 had prediabetes, defined as fasting plasma glucose (FPG) 100-125 mg/dL. Propensity scores for prediabetes, estimated for each of the 4602 participants, were used to assemble a cohort of 1421 pairs of individuals with and without prediabetes, balanced on 44 baseline characteristics. RESULTS: Participants had a mean age of 73 years, 57% were women, and 13% African American. Incident HF occurred in 18% and 20% of matched participants with and without prediabetes, respectively (hazard ratio {HR} associated with prediabetes, 0.90; 95% confidence interval {CI}, 0.76-1.07; p=0.239). Unadjusted and multivariable-adjusted HRs (95% CIs) for incident HF associated with prediabetes among 4602 pre-match participants were 1.22 (95% CI, 1.07-1.40; p=0.003) and 0.98 (95% CI, 0.85-1.14; p=0.826), respectively. Among matched individuals, prediabetes had no independent association with incident acute myocardial infarction (HR, 1.02; 95% CI, 0.81-1.28; p=0.875), angina pectoris (HR, 0.93; 95% CI, 0.77-1.12; p=0.451), stroke (HR, 0.86; 95% CI, 0.70-1.06; p=0.151) or all cause mortality (HR, 0.99; 95% CI, 0.88-1.11; p=0.840). CONCLUSIONS: We found no evidence that prediabetes is an independent risk factor for incident HF, other cardiovascular events or mortality in community-dwelling older adults. These findings question the wisdom of routine screening for prediabetes in older adults and targeted interventions to prevent adverse outcomes in older adults with prediabetes. PMID- 23731527 TI - The role of C-reactive protein genetic variability in the onset of carotid artery disease and renal function impairment in patients with diabetes mellitus type 2. PMID- 23731528 TI - Resveratrol protects vascular endothelial cells from high glucose-induced apoptosis through inhibition of NADPH oxidase activation-driven oxidative stress. AB - INTRODUCTION: Hyperglycemia-induced oxidative stress has been implicated in diabetic vascular complications in which NADPH oxidase is a major source of reactive oxygen species (ROS) generation. Resveratrol is a naturally occurring polyphenol, which has vasoprotective effects in diabetic animal models and inhibits high glucose (HG)-induced oxidative stress in endothelial cells. AIMS: We aimed to examine whether HG-induced NADPH oxidase activation and ROS production contribute to glucotoxicity to endothelial cells and the effect of resveratrol on glucotoxicity. RESULTS: Using a murine brain microvascular endothelial cell line bEnd3, we found that NADPH oxidase inhibitor (apocynin) and resveratrol both inhibited HG-induced endothelial cell apoptosis. HG-induced elevation of NADPH oxidase activity and production of ROS were inhibited by apocynin, suggesting that HG induces endothelial cell apoptosis through NADPH oxidase-mediated ROS production. Mechanistic studies revealed that HG upregulated NADPH oxidase subunit Nox1 but not Nox2, Nox4, and p22(phox) expression through NF-kappaB activation, which resulted in elevation of NADPH oxidase activity and consequent ROS production. Resveratrol prevented HG-induced endothelial cell apoptosis through inhibiting HG-induced NF-kappaB activation, NADPH oxidase activity elevation, and ROS production. CONCLUSIONS: HG induces endothelial cell apoptosis through NF-kappaB/NADPH oxidase/ROS pathway, which was inhibited by resveratrol. Our findings provide new potential therapeutic targets against brain vascular complications of diabetes. PMID- 23731529 TI - Inferring human history in East Asia from Y chromosomes. AB - East Asia harbors substantial genetic, physical, cultural and linguistic diversity, but the detailed structures and interrelationships of those aspects remain enigmatic. This question has begun to be addressed by a rapid accumulation of molecular anthropological studies of the populations in and around East Asia, especially by Y chromosome studies. The current Y chromosome evidence suggests multiple early migrations of modern humans from Africa via Southeast Asia to East Asia. After the initial settlements, the northward migrations during the Paleolithic Age shaped the genetic structure in East Asia. Subsequently, recent admixtures between Central Asian immigrants and northern East Asians enlarged the genetic divergence between southern and northern East Asia populations. Cultural practices, such as languages, agriculture, military affairs and social prestige, also have impacts on the genetic patterns in East Asia. Furthermore, application of Y chromosome analyses in the family genealogy studies offers successful showcases of the utility of genetics in studying the ancient history. PMID- 23731530 TI - Primary preventive services in patients with systemic lupus erythematosus: study from a population-based sample in Southeast U.S. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) patients are at risk for complications that can be mitigated by appropriate preventive care. We examined the receipt of immunizations, cancer screening, and cardiovascular risk preventive services in a predominantly Black cohort of SLE patients from the Southeast U.S. To identify gaps in primary preventive services (PPS) that might be specific to SLE as opposed to local health system factors, we used as reference a population-based sample from the same area. METHODS: A cross sectional design was used to characterize the percentage of PPS received by 751 SLE patients from Atlanta, GA, and 9040 subjects from the same community, of whom 938 had diabetes. Factors associated with the receipt of PPS were examined with multivariable analysis of variance. RESULTS: Approximately 65% of recommended PPS were provided to the SLE, overall community (OC), and diabetes samples. However, only 22.5%, 45.7%, and 27.6% of SLE, OC, and diabetes subjects, respectively, received all recommended services. Factors associated with a higher percentage of PPS received by SLE patients included older age (63.6% if age >=65 years, 45.8% if age between 18 and 35 years), having medical insurance (61.1% for insured, 49.7% for uninsured), having a primary care physician (PCP) (59.0% if patient had PCP, 51.8% if patient did not have PCP), and being a non-smoker (61.9% for non smokers, 49.9% for smokers). CONCLUSIONS: Less than one-quarter of SLE patients from a southeast U.S. community received all the recommended services that were studied. Further research is warranted to unravel the barriers that prevent SLE patients from reaching appropriate standards of preventive care. PMID- 23731531 TI - Role of neuroendocrine and neuroimmune mechanisms in chronic inflammatory rheumatic diseases--the 10-year update. AB - BACKGROUND: Neuroendocrine immunology in musculoskeletal diseases is an emerging scientific field. It deals with the aspects of efferent neuronal and neurohormonal bearing on the peripheral immune and musculoskeletal systems. This review aims to add new information that appeared since 2001. SEARCH STRATEGY: The following PubMed search sentence was used to find a total of 15,462 references between 2001 and March 2013: "(rheum* OR SLE OR vasculitis) AND (nerve OR hormone OR neurotransmitter OR neuropeptide OR steroid)." In a continuous process, year by year, this search strategy yielded relevant papers that were screened and collected in a database, which build the platform of this review. RESULTS: The main findings are the anti-inflammatory role of androgens, the loss of androgens (androgen drain), the bimodal role of estrogens (support B cells and inhibit macrophages and T cells), increased conversion of androgens to estrogens in inflammation (androgen drain), disturbances of the gonadal axis, inadequate amount of HPA axis hormones relative to inflammation (disproportion principle), biologics partly improve neuroendocrine axes, anti-corticotropin-releasing hormone therapies improve inflammation (antalarmin), bimodal role of the sympathetic nervous system (proinflammatory early, anti-inflammatory late-most probably due to catecholamine-producing local cells), anti-inflammatory role of alpha melanocyte-stimulating hormone, vasoactive intestinal peptide, and the Vagus nerve via alpha7 nicotinergic receptors. Circadian rhythms of hypothalamic origin are responsible for circadian rhythms of symptoms (neuroimmune link revealed). Important new pain-sensitizing immunological pathways were found in the last decade. CONCLUSIONS: The last decade brought much new information that gave birth to the first therapies of chronic inflammatory diseases on the basis of neuroendocrine immune targets. In addition, a new theory linked evolutionary medicine, neuroendocrine regulation of distribution of energy-rich fuels, and volume regulation that can explain many disease sequelae in patients with chronic inflammatory diseases. PMID- 23731532 TI - Enthesitis in psoriatic arthritis. AB - OBJECTIVES: It is increasingly recognized that enthesitis in patients with psoriatic arthritis (PsA) is of clinical importance. We review data on the detection, assessment, and treatment of enthesitis and its related dactylitis in PsA. METHODS: We searched Pubmed with the search terms psoriatic arthritis or psoriasis in combination with enthesitis, enthesopathy, and treatment, or enthesitis in combination with imaging. RESULTS: One hundred fifty-seven papers were selected. Enthesitis occurs frequently in PsA and may be asymptomatic or painful. It can also affect patient's function and quality of life. New imaging modalities, such as ultrasonography and magnetic resonance imaging, have revealed that enthesitis may be the initial osteoarticular inflammatory site in patients with PsA. Enthesitis indices have been developed and should be incorporated in clinical trials. Dactylitis, a characteristic and frequent manifestation of PsA can be tender or not tender and is prognostic of disease progression. Treatment of enthesitis includes non-steroidal anti-inflammatory drugs, classical DMARDs, and adjunctive local steroid injections. In inadequate response, TNFalpha inhibitors are used. CONCLUSIONS: Enthesitis and dactylitis are important manifestations of PsA, and their evaluation is increasingly used in drug trials and clinical practice. PMID- 23731533 TI - The time consuming nature of phenylketonuria: a cross-sectional study investigating time burden and costs of phenylketonuria in the Netherlands. AB - BACKGROUND: Phenylketonuria (PKU) is a rare inborn error of metabolism that affects the ability of patients to metabolise phenylalanine (Phe). Lifelong management of blood Phe levels is required in order to avoid the complications associated with PKU. This constitutes a severely protein restricted diet, and regular monitoring of Phe levels. Management of PKU may be costly and time consuming for adult patients or caregivers of PKU-affected children. A cross sectional study was performed with patients or their caregivers in the Netherlands to gain insight into the personal time burden and cost of living with PKU. METHODS: A systematic literature review was performed to identify all aspects of PKU management that may pose a financial or time burden on patients or caregivers. Findings were confirmed through interviews with PKU experts and feedback from patients and caregivers, and consolidated into a questionnaire that aimed to evaluate the impact of each of these factors. Early and continuously treated adult patients and caregivers from seven metabolic centres were recruited to complete the questionnaire online. RESULTS: 22 adult patients and 24 caregivers participated in the study. Managing a Phe-restricted diet represented an extra time burden of 1 h and 24 min for caregivers and 30 min for adult patients per day. Caregivers reported a significantly higher time burden than adult patients. The median total out-of-pocket cost (OOPC) for patients was ?604 annually, with 99% of expenditure on low-protein food products. Greater disease severity was significantly associated with increased OOPC and time burden for both adult patients and caregivers. CONCLUSIONS: Management of PKU is associated with a considerable time burden for both caregivers of children with PKU and adult patients. Caregivers of PKU-affected children reported a significantly higher time burden than adult patients. The OOPC of caregivers and patients was mainly driven by the expenditure on low protein food. PMID- 23731534 TI - Atlas-based and DTI-guided quantification of human brain cerebral blood flow: feasibility, quality assurance, spatial heterogeneity and age effects. AB - Accurate and noninvasive quantification of regional cerebral blood perfusion (CBF) of the human brain tissue would advance the study of the complex interplay between human brain structure and function, in both health and disease. Despite the plethora of works on CBF in gray matter, a detailed quantitative white matter perfusion atlas has not been presented on healthy adults using the International Consortium for Brain Mapping atlases. In this study, we present a host of assurance measures such as temporal stability, spatial heterogeneity and age effects of regional and global CBF in selected deep, cortical gray matter and white matter tracts identified and quantified using diffusion tensor imaging (DTI). We utilized whole brain high-resolution DTI combined with arterial spin labeling to quantify regional CBF on 15 healthy adults aged 23.2-57.1years. We present total brain and regional CBF, corresponding volume, mean diffusivity and fractional anisotropy spatial heterogeneity, and dependence on age as additional quality assurance measures to compare with published trends using both MRI and nuclear medicine methods. Total CBF showed a steady decrease with age in gray matter (r=-0.58; P=.03), whereas total CBF of white matter did not significantly change with age (r=0.11; P=.7). This quantitative report offers a preliminary baseline of CBF, volume and DTI measurements for the design of future multicenter and clinical studies utilizing noninvasive perfusion and DT-MRI. PMID- 23731535 TI - Physiological assessment of in vivo human knee articular cartilage using sodium MR imaging at 1.5 T. AB - Osteoarthritis is a common joint disorder that is most prevalent in the knee joint. Knee osteoarthritis (OA) can be characterized by the gradual loss of articular cartilage (AC). Formation of lesion, fissures and cracks on the cartilage surface has been associated with degenerative AC and can be measured by morphological assessment. In addition, loss of proteoglycan from extracellular matrix of the AC can be measured at early stage of cartilage degradation by physiological assessment. In this case, a biochemical phenomenon of cartilage is used to assess the changes at early degeneration of AC. In this paper, a method to measure local sodium concentration in AC due to proteoglycan has been investigated. A clinical 1.5-T magnetic resonance imaging (MRI) with multinuclear spectroscopic facility is used to acquire sodium images and quantify local sodium content of AC. An optimised 3D gradient-echo sequence with low echo time has been used for MR scan. The estimated sodium concentration in AC region from four different data sets is found to be ~225+/-19mmol/l, which matches the values that has been reported for the normal AC. This study shows that sodium images acquired at clinical 1.5-T MRI system can generate an adequate quantitative data that enable the estimation of sodium concentration in AC. We conclude that this method is potentially suitable for non-invasive physiological (sodium content) measurement of articular cartilage. PMID- 23731536 TI - Diffusion-weighted imaging (DWI) of the spleen in patients with liver cirrhosis and portal hypertension. AB - OBJECTIVE: The purpose of this study was to assess the influence of liver cirrhosis and portal hypertension on diffusion coefficients of the spleen. MATERIAL AND METHODS: We retrospectively evaluated 50 patients with liver cirrhosis and 50 patients without any history of liver disease who underwent magnetic resonance imaging of the upper abdomen, including echo planar diffusion weighted imaging using b values of 50, 300 and 600mm(2)/s. Spleen apparent diffusion coefficient (ADC), liver ADC, muscle ADC and normalized spleen ADC (defined as the ratio of spleen ADC to muscle ADC) were compared between cirrhotic patients and patients in the control group and correlated with Child Pugh stages. Reproducibility was assessed by measuring interclass correlation coefficient (n=11). Additionally, in eight patients, ADC measurements were performed 1 day before and 3 days after transjugular intrahepatic portosystemic shunt (TIPSS) implantation. RESULTS: Compared with control subjects, patients with cirrhosis and portal hypertension had significantly higher spleen ADCs (P=.0001). There was a statistically significant correlation between Child-Pugh grade and spleen ADC (Pearson correlation coefficient, observer 1 r=0.6, P=.0001; observer 2 r=0.5, P=.0001). After TIPSS implantation, we observed a reduction in spleen ADC values. Spleen ADC measurements showed a high reproducibility (interclass correlation coefficient 0.75, P=.001). CONCLUSION: Our data suggest that different stages of liver cirrhosis and portal hypertension correlate with ADC values of the spleen. Furthermore, ADC values of the spleen decrease after TIPSS implantation. Further studies are required to understand the potential clinical values of these observations. PMID- 23731537 TI - A recurrent PDGFRB mutation causes familial infantile myofibromatosis. AB - Infantile myofibromatosis (IM) is the most common benign fibrous tumor of soft tissues affecting young children. By using whole-exome sequencing, RNA sequencing, and targeted sequencing, we investigated germline and tumor DNA in individuals from four distinct families with the familial form of IM and in five simplex IM cases with no previous family history of this disease. We identified a germline mutation c.1681C>T (p.Arg561Cys) in platelet-derived growth factor receptor beta (PDGFRB) in all 11 affected individuals with familial IM, although none of the five individuals with nonfamilial IM had mutations in this gene. We further identified a second heterozygous mutation in PDGFRB in two myofibromas from one of the affected familial cases, indicative of a potential second hit in this gene in the tumor. PDGFR-beta promotes growth of mesenchymal cells, including blood vessels and smooth muscles, which are affected in IM. Our findings indicate p.Arg561Cys substitution in PDGFR-beta as a cause of the dominant form of this disease. They provide a rationale for further investigations of this specific mutation and gene to assess the benefits of targeted therapies against PDGFR-beta in aggressive life-threatening familial forms of the disease. PMID- 23731538 TI - Hypermethylation of the CpG island near the G4C2 repeat in ALS with a C9orf72 expansion. AB - The G4C2 repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We tested the hypothesis that the repeat expansion causes aberrant CpG methylation near the G4C2 repeat, which could be responsible for the downregulation of gene expression. We investigated the CpG methylation profile by two methods using genomic DNA from the blood of individuals with ALS (37 expansion carriers and 64 noncarriers), normal controls (n = 76), and family members of 7 ALS probands with the expansion. We report that hypermethylation of the CpG island 5' of the G4C2 repeat is associated with the presence of the expansion (p < 0.0001). A higher degree of methylation was significantly correlated with a shorter disease duration (p < 0.01), associated with familial ALS (p = 0.009) and segregated with the expansion in 7 investigated families. Notably, we did not detect methylation for either normal or intermediate alleles (up to 43 repeats), bringing to question the current cutoff of 30 repeats for pathological alleles. Our study raises several important questions for the future investigation of large data sets, such as whether the degree of methylation corresponds to clinical presentation (ALS versus FTLD). PMID- 23731539 TI - Network-based multiple sclerosis pathway analysis with GWAS data from 15,000 cases and 30,000 controls. AB - Multiple sclerosis (MS) is an inflammatory CNS disease with a substantial genetic component, originally mapped to only the human leukocyte antigen (HLA) region. In the last 5 years, a total of seven genome-wide association studies and one meta analysis successfully identified 57 non-HLA susceptibility loci. Here, we merged nominal statistical evidence of association and physical evidence of interaction to conduct a protein-interaction-network-based pathway analysis (PINBPA) on two large genetic MS studies comprising a total of 15,317 cases and 29,529 controls. The distribution of nominally significant loci at the gene level matched the patterns of extended linkage disequilibrium in regions of interest. We found that products of genome-wide significantly associated genes are more likely to interact physically and belong to the same or related pathways. We next searched for subnetworks (modules) of genes (and their encoded proteins) enriched with nominally associated loci within each study and identified those modules in common between the two studies. We demonstrate that these modules are more likely to contain genes with bona fide susceptibility variants and, in addition, identify several high-confidence candidates (including BCL10, CD48, REL, TRAF3, and TEC). PINBPA is a powerful approach to gaining further insights into the biology of associated genes and to prioritizing candidates for subsequent genetic studies of complex traits. PMID- 23731540 TI - Detecting and characterizing genomic signatures of positive selection in global populations. AB - Natural selection is a significant force that shapes the architecture of the human genome and introduces diversity across global populations. The question of whether advantageous mutations have arisen in the human genome as a result of single or multiple mutation events remains unanswered except for the fact that there exist a handful of genes such as those that confer lactase persistence, affect skin pigmentation, or cause sickle cell anemia. We have developed a long range-haplotype method for identifying genomic signatures of positive selection to complement existing methods, such as the integrated haplotype score (iHS) or cross-population extended haplotype homozygosity (XP-EHH), for locating signals across the entire allele frequency spectrum. Our method also locates the founder haplotypes that carry the advantageous variants and infers their corresponding population frequencies. This presents an opportunity to systematically interrogate the whole human genome whether a selection signal shared across different populations is the consequence of a single mutation process followed subsequently by gene flow between populations or of convergent evolution due to the occurrence of multiple independent mutation events either at the same variant or within the same gene. The application of our method to data from 14 populations across the world revealed that positive-selection events tend to cluster in populations of the same ancestry. Comparing the founder haplotypes for events that are present across different populations revealed that convergent evolution is a rare occurrence and that the majority of shared signals stem from the same evolutionary event. PMID- 23731541 TI - Large sample size, wide variant spectrum, and advanced machine-learning technique boost risk prediction for inflammatory bowel disease. AB - We performed risk assessment for Crohn's disease (CD) and ulcerative colitis (UC), the two common forms of inflammatory bowel disease (IBD), by using data from the International IBD Genetics Consortium's Immunochip project. This data set contains ~17,000 CD cases, ~13,000 UC cases, and ~22,000 controls from 15 European countries typed on the Immunochip. This custom chip provides a more comprehensive catalog of the most promising candidate variants by picking up the remaining common variants and certain rare variants that were missed in the first generation of GWAS. Given this unprecedented large sample size and wide variant spectrum, we employed the most recent machine-learning techniques to build optimal predictive models. Our final predictive models achieved areas under the curve (AUCs) of 0.86 and 0.83 for CD and UC, respectively, in an independent evaluation. To our knowledge, this is the best prediction performance ever reported for CD and UC to date. PMID- 23731543 TI - Cloning and molecular analysis of the aspartic protease Sc-ASP110 gene transcript in Steinernema carpocapsae. AB - Many protease genes have previously been shown to be involved in parasitism and in the development of Steinernema carpocapsae, including a gene predicted to encode an aspartic protease, Sc-ASP110, which was cloned and was analysed in this study. A cDNA encoding Sc-ASP110 was cloned based on an expressed sequence tag (EST) fragment from our EST library. The full-length cDNA of Sc-ASP110 consists of 1112 nucleotides with a catalytic aspartic domain (aa18-337). The putative 341 amino acid residues have a calculated molecular mass of 37.1 kDa and a theoretical pI of 4.7. BLASTp analysis of the Sc-ASP110 amino acid sequence showed 45-77% amino acid sequence identity to parasitic and non-parasitic nematode aspartic proteases. An expression analysis showed that the sc-asp110 gene was upregulated during the late parasitic stage, L4, and 24 h after induction of in vitro nematodes. A sequence comparison revealed that Sc-ASP110 was a member of an aspartic protease family; additionally, a phylogenetic analysis indicated that Sc-ASP110 was clustered with the closely related nematode Steinernema feltiae. In situ hybridization showed that sc-asp110 was expressed in the body walls of dorsal cells. The upregulated Sc-ASP110 expression revealed that this protease could play a role in the late parasitic process. In this study, we have cloned and analysed the gene transcript of Sc-ASP110 in S. carpocapsae. PMID- 23731544 TI - Abstracts of the 14th Biennial Meeting of the Asia-Pacific Society for Sexual Medicine. Kanazawa, Japan. May 31-June 2, 2013. PMID- 23731542 TI - Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. AB - Infantile myofibromatosis (IM) is a disorder of mesenchymal proliferation characterized by the development of nonmetastasizing tumors in the skin, muscle, bone, and viscera. Occurrence within families across multiple generations is suggestive of an autosomal-dominant (AD) inheritance pattern, but autosomal recessive (AR) modes of inheritance have also been proposed. We performed whole exome sequencing (WES) in members of nine unrelated families clinically diagnosed with AD IM to identify the genetic origin of the disorder. In eight of the families, we identified one of two disease-causing mutations, c.1978C>A (p.Pro660Thr) and c.1681C>T (p.Arg561Cys), in PDGFRB. Intriguingly, one family did not have either of these PDGFRB mutations but all affected individuals had a c.4556T>C (p.Leu1519Pro) mutation in NOTCH3. Our studies suggest that mutations in PDGFRB are a cause of IM and highlight NOTCH3 as a candidate gene. Further studies of the crosstalk between PDGFRB and NOTCH pathways may offer new opportunities to identify mutations in other genes that result in IM and is a necessary first step toward understanding the mechanisms of both tumor growth and regression and its targeted treatment. PMID- 23731545 TI - Using a cloud-based electronic health record during disaster response: a case study in Fukushima, March 2011. AB - Following the Great East Japan Earthquake on March 11, 2011, the Japan Medical Association deployed medical disaster teams to Shinchi-town (population: approximately 8,000), which is located 50 km north of the Fukushima Daiichi nuclear power plant. The mission of the medical disaster teams sent from Fukuoka, 1,400 km south of Fukushima, was to provide medical services and staff a temporary clinic for six weeks. Fear of radiation exposure restricted the use of large medical teams and local infrastructure. Therefore, small volunteer groups and a cloud-hosted, web-based electronic health record were implemented. The mission was successfully completed by the end of May 2011. Cloud-based electronic health records deployed using a "software as a service" model worked well during the response to the large-scale disaster. PMID- 23731547 TI - Hunting for cancer in the microbial jungle. PMID- 23731546 TI - Driving and legal status of Spanish opioid-dependent patients. AB - BACKGROUND: Opioid dependent patients have legal problems, driving violations and accidents more frequently than the general population. We have hypothesized that those patients currently driving may have better legal outcomes than those who do not possess a valid driving license. With this aim we have analyzed the information gathered in the PROTEUS study regarding the legal and driving statuses and assessed the possible association between them. The PROTEUS study was an observational, cross-sectional, descriptive, multicenter nationwide representative study, conducted in Spanish healthcare centers for opioid dependent patients. FINDINGS: The driving and legal statuses of a population of opioid dependent patients >= 18 years and enrolled in Opioid Agonist Therapy treatment centers in Spain, were assessed using a short specific questionnaire and the EuropASI questionnaire to highlight distinct individual clinical needs. 621 patients were evaluable (84% men, 24.5% active workers). 321 patients (52%) drove on a regular basis. Nineteen percent of patients had some problem with the criminal justice system. There was a significant difference (p = 0.0433) in status, according to the criminal justice system, between patients who drove on a regular basis and those who did not, with a higher percentage of patients with non-pending charges among usual drivers. CONCLUSIONS: Regular drivers showed fewer legal problems than non-regular drivers, with the exception of those related to driving (driving violations and drunk driving). Driving is a good prognostic factor for the social integration of the patients and policies should be implemented to enable these patients to drive safely under medical authorization. The legal description will be useful to assess treatment efficacy. PMID- 23731548 TI - Experimental aspect of solid-state nuclear magnetic resonance studies of biomaterials such as bones. AB - Solid-state nuclear magnetic resonance (SSNMR) spectroscopy is increasingly becoming a popular technique to probe micro-structural details of biomaterial such as bone with pico-meter resolution. Due to high-resolution structural details probed by SSNMR methods, handling of bone samples and experimental protocol are very crucial aspects of study. We present here first report of the effect of various experimental protocols and handling methods of bone samples on measured SSNMR parameters. Various popular SSNMR experiments were performed on intact cortical bone sample collected from fresh animal, immediately after removal from animal systems, and results were compared with bone samples preserved in different conditions. We find that the best experimental conditions for SSNMR parameters of bones correspond to preservation at -20 degrees C and in 70% ethanol solution. Various other SSNMR parameters were compared corresponding to different experimental conditions. Our study has helped in finding best experimental protocol for SSNMR studies of bone. This study will be of further help in the application of SSNMR studies on large bone disease related animal model systems for statistically significant results. PMID- 23731549 TI - 13C and 15N spectral editing inside histidine imidazole ring through solid-state NMR spectroscopy. AB - Histidine usually exists in three different forms (including biprotonated species, neutral tau and pi tautomers) at physiological pH in biological systems. The different protonation and tautomerization states of histidine can be characteristically determined by (13)C and (15)N chemical shifts of imidazole ring. In this work, solid-state NMR techniques were developed for spectral editing of (13)C and (15)N sites in histidine imidazole ring, which provides a benchmark to distinguish the existing forms of histidine. The selections of (13)Cgamma, (13)Cdelta2, (15)Ndelta1, and (15)Nepsilon2 sites were successfully achieved based on one-bond homo- and hetero-nuclear dipole interactions. Moreover, it was demonstrated that (1)H, (13)C, and (15) chemical shifts were roughly linearly correlated with the corresponding atomic charge in histidine imidazole ring by theoretical calculations. Accordingly, the (1)H, (13)C and (15)N chemical shifts variation in different protonation and tautomerization states could be ascribed to the atomic charge change due to proton transfer in biological process. PMID- 23731550 TI - Decreased expression of SOX6 confers a poor prognosis in hepatocellular carcinoma. AB - BACKGROUND AND AIM: SOX6, a member of the D subfamily of sex determining region y related transcription factors, plays critical roles in cell fate determination, differentiation and proliferation. It has been identified as a tumor suppressor or an oncogene in different human cancers. However, the role of SOX6 in the development and progression of hepatocellular carcinoma (HCC) has not been explored. The aim of this study was to investigate the expression of SOX6 in HCC and determine its correlation with tumor progression and prognosis. METHODS: 130 HCC patients who had undergone curative liver resection were selected and immunohistochemistry, Western blotting, and quantitative real time polymerase chain reaction (Q-PCR) were performed to analyze SOX6 expression in the respective tumors. RESULTS: Q-PCR, immunohistochemistry and Western blotting consistently confirmed the decreased expression of SOX6 at both mRNA and protein levels in HCC tissues compared with their adjacent nonneoplastic tissues (P<0.01). Additionally, the expression of SOX6, determined by immunohistochemistry, was negatively correlated with the tumor stage (P=0.003) and serum AFP (P=0.02). Moreover, HCC patients with lower SOX6 expression had worse 5-year disease-free survival and 5-year overall survival than those with high SOX6 expression (P=0.006 and 0.001, respectively). Furthermore, the Cox proportional hazards model showed that the decreased expression of SOX6 was an independent poor prognostic factor for both 5-year disease-free survival (hazards ratio [HR]=2.398, 95% confidence interval [CI]=1.601-5.993, P=0.01) and 5-year overall survival (HR=3.569, CI=1.381-7.290, P=0.008) in HCC. CONCLUSION: These findings provide evidence for the first time that SOX6 expression was decreased in HCC, which correlated with poor prognosis, suggesting that SOX6 may be a novel and potential prognostic marker for HCC. PMID- 23731551 TI - What is different about medical students interested in non-clinical careers? AB - BACKGROUND: The proportion of medical school graduates who pursue careers other than full-time clinical practice has increased in some countries as the physician's role has evolved and diversified with the changing landscape of clinical practice and the advancement of biomedicine. Still, past studies of medical students' career choices have focused on clinical specialties and little is known about their choice of non-clinical careers. The present study examined backgrounds, motivation and perceptions of medical students who intended non clinical careers. METHODS: A questionnaire was administered to students at six Korean medical schools distributed across all provinces in the nation. The questionnaire comprised 40 items on respondents' backgrounds, their motivation for and interest in the study of medicine, their perceptions of medical professions, and their career intentions. Data was analyzed using various descriptive and inferential statistics. RESULTS: In total, 1,388 students returned the questionnaire (60% response rate), 12.3% of whom intended non clinical careers (i.e., basic sciences, non-clinical medical fields, and non medical fields). Those who planned non-clinical careers were comparable with their peers in their motivation for studying medicine and in their views of medical professions, but they were less interested in the study of medicine (P < 0.01). The two groups also differed significantly on their perceptions of what was uninteresting about the study of medicine (P < 0.01). The two groups were comparable in gender and entry-level ratios but their distributions across ages and years of study differed significantly (P < 0.01). A majority of respondents agreed with the statements that "it is necessary for medical school graduates to pursue non-clinical careers" and that "medical schools need to offer programs that provide information on such careers." Still, our finding indicates that medical school curricula do not address such needs sufficiently. CONCLUSIONS: Our study found some differences in backgrounds and perceptions of the study of medicine in medical students interested in non-clinical careers from their peers. Future studies are suggested to enhance our understanding of medical students" choice of non-clinical careers. PMID- 23731553 TI - A systematic review-meta-analysis and meta-regression on the effect of selected competitive exclusion products on Salmonella spp. prevalence and concentration in broiler chickens. AB - The effectiveness of various competitive exclusion (CE) products for reducing Salmonella colonization in broiler chickens was evaluated using systematic review meta-analysis-meta-regression (SR-MA-MR). Relevance screening identified 201 relevant studies that were subjected to methodological assessment. Of these studies, 159 were suitable for data extraction, 66 were presented in a number of MAs and 130 were examined in a meta-regression (MR). Fourteen different CE products were identified, 9 of them commercial products, and the most common route of administration was oral gavage (63.7% of trials). Meta-analyses indicated that a number of CE products reduce Salmonella colonization in broilers, the most effective one being PreemptTM which was formerly known as CF 3. Five study characteristics (publication year, CE type, CE route, sample origin, and Salmonella serovar administered/recovered) and three methodological soundness characteristics (treatment assignment, intervention and laboratory methods description) were retained as statistically significant (p<0.05) in the final MR model. The MR analysis indicated that, undefined CE products outperformed all commercial products, except for: PreemptTM and Broilact((r)). Both were considered comparable to the undefined chicken source CE culture products in effectiveness. The administration of CE through spraying the chicks at the hatchery was determined to be just as effective as the oral gavage treatment, and more practical for farmers to administer. The results of this study could be useful in decision-making concerning the on-farm use of CE products in broiler chickens, and as inputs for risk assessments as the industry pushes for more antibiotic-free alternatives. Out of the various interventions to reduce Salmonella colonization in broilers on-farm, CE was the most studied; its inability to be licenced in certain countries and proof of consistent efficacy remains a barrier. PMID- 23731552 TI - Synthesis and preclinical evaluation of [11C-carbonyl]PF-04457845 for neuroimaging of fatty acid amide hydrolase. AB - INTRODUCTION: Fatty acid amide hydrolase (FAAH) has a significant role in regulating endocannabinoid signaling in the central nervous system. As such, FAAH inhibitors are being actively sought for pain, addiction, and other indications. This has led to the recent pursuit of positron emission tomography (PET) radiotracers targeting FAAH. We report herein the preparation and preclinical evaluation of [(11)C-carbonyl]PF-04457845, an isotopologue of the potent irreversible FAAH inhibitor. METHODS: PF-04457845 was radiolabeled at the carbonyl position via automated [(11)C]CO(2)-fixation. Ex vivo brain biodistribution of [(11)C-carbonyl]PF-04457845 was carried out in conscious rats. Specificity was determined by pre-administration of PF-04457845 or URB597 prior to [(11)C-carbonyl]PF-04457845. In a separate experiment, rats injected with the title radiotracer had whole brains excised, homogenized and extracted to examine irreversible binding to brain parenchyma. RESULTS: The title compound was prepared in 5 +/- 1% (n = 4) isolated radiochemical yield based on starting [(11)C]CO(2) (decay uncorrected) within 25 min from end-of-bombardment in >98% radiochemical purity and a specific activity of 73.5 +/- 8.2 GBq/MUmol at end-of synthesis. Uptake of [(11)C-carbonyl]PF-04457845 into the rat brain was high (range of 1.2-4.4 SUV), heterogeneous, and in accordance with reported FAAH distribution. Saturable binding was demonstrated by a dose-dependent reduction in brain radioactivity uptake following pre-treatment with PF-04457845. Pre treatment with the prototypical FAAH inhibitor, URB597, reduced the brain radiotracer uptake in all regions by 71-81%, demonstrating specificity for FAAH. The binding of [(11)C-carbonyl]PF-04457845 to FAAH at 40 min post injection was irreversible as 98% of the radioactivity in the brain could not be extracted. CONCLUSIONS: [(11)C-carbonyl]PF-04457845 was rapidly synthesized via an automated radiosynthesis. Ex vivo biodistribution studies in conscious rodents demonstrate that [11C PF-04457845 is a promising candidate radiotracer for imaging FAAH in the brain with PET. These results coupled with the known pharmacology and toxicology of PF-04457845 should facilitate clinical translation of this radiotracer. PMID- 23731554 TI - Estimating the transmissibility of H5N1 and the effect of vaccination in Indonesia. AB - The spread of H5N1 avian influenza continues to pose an economic burden and a public health risk worldwide. Despite this, estimates of the transmissibility of infection exist in only a handful of settings and vary considerably. Using final size methods and flock-level infection data from a field trial of mass vaccination, we obtained the first estimates of the transmissibility of infection between and within flocks in Indonesia. We also found that outbreaks in areas designated as vaccination zones were less transmissible than in non-vaccination zones. However, this reduction is only comparable with a limited degree of protective vaccination coverage. Quantifying the overall effect of vaccination in these zones remains challenging. However, this result would appear to imply that, although the interventions applied in vaccination zones were not sufficient to completely prevent transmission in all areas, when outbreaks occur, they are less transmissible than those in areas where vaccination was not applied. This could be either a direct or an indirect effect of vaccination. Given the dynamism of small-scale poultry production in Indonesia, more regular vaccination may be required to ensure that infection is fully controlled in vaccination zones. PMID- 23731555 TI - Impact of toxigenic Clostridium difficile polymerase chain reaction testing on the clinical microbiology laboratory and inpatient epidemiology. AB - Conversion from Clostridium difficile toxin A/B EIA to tcdB polymerase chain reaction for diagnosis of C. difficile infection (CDI) resulted in significant decreases in laboratory testing volume and largely unchanged C. difficile toxin detection rates. Decreases in healthcare-associated CDI rates (P <= 0.05) reflected a clinical practice benefit of this conversion. PMID- 23731556 TI - Association between large strongyle genera in larval cultures--using rare-event poisson regression. AB - Decades of intensive anthelmintic treatment has caused equine large strongyles to become quite rare, while the cyathostomins have developed resistance to several drug classes. The larval culture has been associated with low to moderate negative predictive values for detecting Strongylus vulgaris infection. It is unknown whether detection of other large strongyle species can be statistically associated with presence of S. vulgaris. This remains a statistical challenge because of the rare occurrence of large strongyle species. This study used a modified Poisson regression to analyse a dataset for associations between S. vulgaris infection and simultaneous occurrence of Strongylus edentatus and Triodontophorus spp. In 663 horses on 42 Danish farms, the individual prevalences of S. vulgaris, S. edentatus and Triodontophorus spp. were 12%, 3% and 12%, respectively. Both S. edentatus and Triodontophorus spp. were significantly associated with S. vulgaris infection with relative risks above 1. Further, S. edentatus was associated with use of selective therapy on the farms, as well as negatively associated with anthelmintic treatment carried out within 6 months prior to the study. The findings illustrate that occurrence of S. vulgaris in larval cultures can be interpreted as indicative of other large strongyles being likely to be present. PMID- 23731557 TI - Reliability of the Siemens Enzygnost and Novagnost Epstein-Barr virus assays for routine laboratory diagnosis: agreement with clinical diagnosis and comparison with the Merifluor Epstein-Barr virus immunofluorescence assay. AB - BACKGROUND: Diagnosis of Epstein-Barr virus (EBV) infection is routinely conducted by clinical laboratories, especially to diagnose infectious mononucleosis. At an estimated general population incidence of 1:200, this represents a potentially significant testing burden. We evaluated the reliability of the Siemens Novagnost(r) and Enzygnost(r) EBV microtiter assays measuring VCA IgM and IgG, and EBNA-1 IgG for clinical diagnosis of EBV-related infectious mononucleosis. METHODS: Remnant sera from 537 patients tested for EBV infection were used to compare the Siemens assays to each other and to the Merifluor assay. The Siemens assays are qualitative/semiquantitative, automatable enzyme immunoassays. The Merifluor assays are manual, qualitative indirect immunofluorescent assays. Testing was conducted on the Siemens and Merifluor assays in parallel. All assays were conducted and interpreted according to each manufacturer's specifications. Agreement of serostatus between each of the three assays was assessed. Discrepant results were resolved using a third method (Mikrogen recomLine). RESULTS: Final EBV serostatus indicated 2.9% of the population had an acute infection, 89.6% had a past infection, and 7.5% were EBV naive. All three assays demonstrated 100% agreement with acute infection. Agreement with past-infection serostatus was 99.1% for Enzygnost, between 86% and 98.8% for Novagnost, and 98.1% for Merifluor. Seronegative agreement was 100% for Enzygnost, 89.7% for Novagnost, and 92.3% for Merifluor. CONCLUSIONS: The Siemens Enzygnost and Novagnost EBV microtiter assays are suitable for clinical rule-in of acute EBV infection and for identifying EBV-naive individuals. Both assays also adequately identify remote EBV infections. Because these assays can be automated, they can improve speed and efficiency of EBV testing, especially in high-volume laboratories. PMID- 23731558 TI - Coil embolization of ruptured frontopolar artery aneurysm: case report. AB - Distal anterior cerebral artery aneurysms are infrequent. The most common location is at the bifurcation of the pericallosal and callosomarginal arteries. Cerebral artery anomalies can sometimes, at least partially, explain aneurysm formation in less common locations in relation to hemodynamic stress caused on the vascular wall. We report a very rare case of subarachnoid hemorrhage due to a ruptured frontopolar artery aneurysm as a part of an anomalous anterior cerebral artery complex that was, for the first time, treated with endovascular coiling. PMID- 23731559 TI - [Sacral metastasis simulating aneurysmal bone cyst]. AB - Cystic spinal lesions with characteristic patterns, such as the presence of haematic fluid-fluid levels (H-FFL), have been associated with many tumoral lineages, more frequently with aneurysmal bone cyst (ABC) and exceptionally with metastasis. We present the case of a 60-year-old man with the finding of a sacral cystic bone lesion with H-FFL, with initial suspicion of ABC and confirmed diagnosis of metastasis. The case presented is, to our knowledge, the second case published of spinal cystic bone metastasis with H-FFL pattern with unknown primary tumour at the time of diagnosis and the only one that received resective surgical treatment, achieving pulmonary and metastatic disease control with good quality of life after 1 year of follow up. PMID- 23731560 TI - Response to Letter to Editor on publication: "Mandibular condylectomy with osteoarthrectomy with and without temporalis muscle transfer". PMID- 23731561 TI - Endoscopic septoplasty in primary cases using electromechanical instruments: surgical technique, efficacy and results. AB - INTRODUCTION AND OBJECTIVES: The microdebrider is a surgical tool which has been used successfully in many endoscopic surgical procedures in otolaryngology. In this study, we analysed our experience using this powered instrument in the resection of obstructive nasal septum deviations. SUBJECTS AND METHODS: This was a longitudinal, prospective, descriptive study conducted between January and June 2007 on 141 patients who consulted for chronic nasal obstruction caused by a septal deviation or deformity and underwent powered endoscopic septoplasty (PES). RESULTS: The mean age was 39.9 years (15-63 years); 60.28% were male (n=85) The change in nasal symptom severity decreased after surgery from 6.12 (preoperative) to 2.01 (postoperative). Patients undergoing PES had a significant reduction of nasal symptoms in the pre- and postoperative period, which was statistically significant (P<.05). There were no statistically significant differences between the results at the 2 nd week, 6th week and 5th year after surgery. The 100% of patients were satisfied with the results of surgery and no patient answered "No" to the question added to compare patient satisfaction after surgery. Minor complications in the postoperative period were present in 4.96% of the cases. CONCLUSIONS: Powered endoscopic septoplasty allows accurate, conservative repair of obstructive nasal septum deviations, with fewer complications and better functional results. In our experience, this technique offered significant perioperative advantages with high postoperative patient satisfaction in terms of reducing the severity of nasal symptoms. PMID- 23731562 TI - Health-related quality of life in men with corrected hypospadias: an explorative study. AB - OBJECTIVE: The aim of the study was to evaluate health-related quality of life (HRQoL) of men with a corrected hypospadias in comparison to circumcised controls. Furthermore, determinants of HRQoL were examined. PATIENTS AND METHODS: In a cross-sectional study, HRQoL of 45 men with corrected hypospadias (mean age: 26.2 years +/- 5.1) was compared with a control group of 46 circumcised men (mean age: 25.5 years +/- 4.9). Participants answered three questionnaires: The Medical Outcomes Study Short Form-36 item questionnaire (SF-36), the International Index of Erectile Function (IIEF), and the Penile Perception Score (PPS). RESULTS: Physical and mental dimensions of HRQoL were not impaired among men with corrected hypospadias if compared to circumcised men. Neither socio-demographic and medical variables nor erectile function (EF) predicted HRQoL. However, a negative genital self-perception (PPS) and a lower orgasmic function (OF) were risk factors for an impaired mental HRQoL. CONCLUSIONS: Our data suggest that the HRQoL of adult hypospadias patients is comparable to that of circumcised men. However, patients should be supported in developing a positive genital self perception, because poor genital self-perception correlated with an impaired mental HRQoL. Since studies with non-operated men suggest that some adapt well to their penile condition, further studies should also include non-operated hypospadias. PMID- 23731563 TI - Is intraoperative surgeon's opinion an accurate tool to assess the outcome of endoscopic treatment for vesicoureteral reflux? AB - OBJECTIVE: Our experience in the endoscopic treatment of vesicoureteral reflux (VUR) has significantly increased during the last decade. To help develop diagnostic tests to check the success of this procedure, we evaluated the accuracy of surgeons' intraoperative observations as a predictor of treatment results. METHOD: We performed a prospective study of patients with VUR who were endoscopically treated during 1 year (106 renal units). Patients' age and gender, laterality, material used, grade of reflux, presence of ureteral duplication or associated pathology, and morphology of ureteral orifice were recorded as predictive factors related to the success rate. Surgeon and assistant indicated at the end of the endoscopic procedure whether the VUR was cured or not for each renal unit. These estimations were compared with postoperative voiding cystourethrogram results. RESULTS: Overall cure rate was 75.5%. Positive predictive value (PPV) for surgeon's opinion was 0.79 and negative predictive value (NPV) was 0.40. Statistical analysis demonstrated that the association between the surgeon's opinion and the cure rate was low with a Kappa value of 0.171 (p = 0.30). PPV of assistant's opinion was 0.80 and NPV was 0.40, with a Kappa value of 0.2 (p = 0.13). Concordance of surgeon and assistant's opinion resulted in PPV of 0.79 and NPV of 0.53 (Kappa = 0.261). Kappa value did not improve when surgeon's opinion was related to other factors such as the material employed, grade of reflux, presence of ureteral duplication or associated pathology and morphology of the ureteral orifice. CONCLUSION: In our experience, surgeon's opinion is not an accurate tool to predict the outcome of endoscopic treatment of VUR. PMID- 23731564 TI - Platelet tissue factor: to be or not to be. PMID- 23731565 TI - Pharmacodynamics of recombinant activated factor VII and plasma-derived factor VII in a cohort of severe FVII deficient patients. AB - Recombinant activated factor VII (rFVIIa) and plasma-derived factor VII (pdFVII) are used to prevent bleedings in severe FVII deficient patients, despite their short half-lifes. It is suggested that FVII levels of 15-20 IU/dL are sufficient to maintain hemostasis. We analyzed the pharmacodynamic effects of FVII substitution therapy in the Nijmegen Hemostasis Assay (NHA) that simultaneously measures thrombin and plasmin generation. Ten severe FVII deficient patients were treated with 20 MUg/kg rFVIIa or 25 IU/kg pdFVII in a cross-over design. Thrombin generation lag-time (TG-LT) was identified as an effect-response parameter. Pharmacodynamic analysis using a maximum effect model showed 50% reduction of the TG-LT effect at ~2 IU/dL FVII activity for both rFVIIa and pdFVII. The FVII activity to obtain TG-LT comparable to the upper limit of normal range in healthy controls (4 min) was given by the effective concentration (ECnormal), showing sufficient hemostasis at 3-4 IU/dL FVII activity. No association was seen between FVII activity and other thrombin or plasmin generation parameters as measured by NHA. In conclusion, 3-4 IU/dL FVII activity seems sufficient to maintain hemostasis in patients with severe FVII deficiency during prophylaxis. These data may suggest a potential value for measurement of TG-LT in the monitoring of FVII(a) therapy. PMID- 23731566 TI - HDL function and cardiovascular risk: debate continues... PMID- 23731567 TI - Expedited electronic entry: a new way to manage mass-casualty radiology order workflow. AB - One of the important tenets of emergency preparedness is that planning for disaster response should resemble standard operating procedure whenever possible. Electronic order entry has become part of the standard operating procedures of most institutions but many of these systems are either too cumbersome for use during a surge or can even be rendered non-functional during a sudden patient surge such as a mass-casualty incident (MCI). Presented here is an experience with delayed radiology order entry during a recent MCI and the after action programming of the system based on this real experience. In response to the after action analysis of the MCI, a task force was assigned to solve the MCI radiology order entry problem and a solution to streamline disaster image ordering was devised. A "browse page" was created that lists every x-ray and every CT scan that might be needed in such an event with all required information defaulted to "Disaster." This created a way to order multiple images for any one patient, with 40% time saving over standard electronic order entry. This disaster radiology order entry solution is an example of the surge preparedness needed to promote patient safety and efficient care delivery as the widespread deployment of electronic health records and order entry continues across the United States. PMID- 23731568 TI - A quantitative reference transcriptome for Nematostella vectensis early embryonic development: a pipeline for de novo assembly in emerging model systems. AB - BACKGROUND: The de novo assembly of transcriptomes from short shotgun sequences raises challenges due to random and non-random sequencing biases and inherent transcript complexity. We sought to define a pipeline for de novo transcriptome assembly to aid researchers working with emerging model systems where well annotated genome assemblies are not available as a reference. To detail this experimental and computational method, we used early embryos of the sea anemone, Nematostella vectensis, an emerging model system for studies of animal body plan evolution. We performed RNA-seq on embryos up to 24 h of development using Illumina HiSeq technology and evaluated independent de novo assembly methods. The resulting reads were assembled using either the Trinity assembler on all quality controlled reads or both the Velvet and Oases assemblers on reads passing a stringent digital normalization filter. A control set of mRNA standards from the National Institute of Standards and Technology (NIST) was included in our experimental pipeline to invest our transcriptome with quantitative information on absolute transcript levels and to provide additional quality control. RESULTS: We generated >200 million paired-end reads from directional cDNA libraries representing well over 20 Gb of sequence. The Trinity assembler pipeline, including preliminary quality control steps, resulted in more than 86% of reads aligning with the reference transcriptome thus generated. Nevertheless, digital normalization combined with assembly by Velvet and Oases required far less computing power and decreased processing time while still mapping 82% of reads. We have made the raw sequencing reads and assembled transcriptome publically available. CONCLUSIONS: Nematostella vectensis was chosen for its strategic position in the tree of life for studies into the origins of the animal body plan, however, the challenge of reference-free transcriptome assembly is relevant to all systems for which well annotated gene models and independently verified genome assembly may not be available. To navigate this new territory, we have constructed a pipeline for library preparation and computational analysis for de novo transcriptome assembly. The gene models defined by this reference transcriptome define the set of genes transcribed in early Nematostella development and will provide a valuable dataset for further gene regulatory network investigations. PMID- 23731569 TI - HLA-A, HLA-B, HLA-DRB1 allele and haplotype frequencies in 6384 umbilical cord blood units and transplantation matching and engraftment statistics in the Zhejiang cord blood bank of China. AB - Umbilical cord blood (UCB) is a widely accepted source of progenitor cells, and now, many cord blood banks were established. Here, we analysed the HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies, HLA matching possibilities for searching potential donors and outcome of UCB transplantations in Zhejiang cord blood bank of China. A total of 6384 UCB units were characterized for 17 HLA-A, 30 HLA-B and 13 HLA-DRB1 alleles at the first field resolution level. Additionally, B*14, B*15 and B*40 were typed to the second field level. A total of 1372 distinct A-B-DRB1 haplotypes were identified. The frequencies of 7 haplotypes were more than 1%, and 439 haplotypes were <0.01%. A*02-B*46-DRB1*09, A*33-B*58-DRB1*03 and A*30-B*13-DRB1*07 were the most common haplotypes, with frequencies of 4.4%, 3.3%, and 2.9%, respectively. Linkage disequilibrium(LD) analysis showed that there were 83 A-B, 106 B-DRB1, 54 A-DRB1 haplotypes with positive LD, in which 51 A-B, 60 B-DRB1, 32 A-DRB1 haplotypes exhibited a significant LD (P < 0.05). In 682 search requests, 12.9%, 40.0% and 42.7% of patients were found to have 6 of 6, 5 of 6 and 4 of 6 HLA-A, HLA-B and HLA-DRB1 matching donors, respectively. A total of 30 UCB units were transplanted to 24 patients (3 patients not evaluated due to early death); 14 of 21 patients (66.7%) engrafted. This study reveals the HLA distribution and its transplantation application in the cord blood bank of Zhejiang province. These data can help to select potential UCB donors for transplantation and used to assess the scale of new cord blood banking endeavours. PMID- 23731570 TI - Bridging the gap between the economic evaluation literature and daily practice in occupational health: a qualitative study among decision-makers in the healthcare sector. AB - BACKGROUND: Continued improvements in occupational health can only be ensured if decisions regarding the implementation and continuation of occupational health and safety interventions (OHS interventions) are based on the best available evidence. To ensure that this is the case, scientific evidence should meet the needs of decision-makers. As a first step in bridging the gap between the economic evaluation literature and daily practice in occupational health, this study aimed to provide insight into the occupational health decision-making process and information needs of decision-makers. METHODS: An exploratory qualitative study was conducted with a purposeful sample of occupational health decision-makers in the Ontario healthcare sector. Eighteen in-depth interviews were conducted to explore the process by which occupational health decisions are made and the importance given to the financial implications of OHS interventions. Twenty-five structured telephone interviews were conducted to explore the sources of information used during the decision-making process, and decision-makers' knowledge on economic evaluation methods. In-depth interview data were analyzed according to the constant comparative method. For the structured telephone interviews, summary statistics were prepared. RESULTS: The occupational health decision-making process generally consists of three stages: initiation stage, establishing the need for an intervention; pre-implementation stage, developing an intervention and its business case in order to receive senior management approval; and implementation and evaluation stage, implementing and evaluating an intervention. During this process, information on the financial implications of OHS interventions was found to be of great importance, especially the employer's costs and benefits. However, scientific evidence was rarely consulted, sound ex post program evaluations were hardly ever performed, and there seemed to be a need to advance the economic evaluation skill set of decision-makers. CONCLUSIONS: Financial information is particularly important at the front end of implementation decisions, and can be a key deciding factor of whether to go forward with a new OHS intervention. In addition, it appears that current practice in occupational health in the healthcare sector is not solidly grounded in evidence-based decision-making and strategies should be developed to improve this. PMID- 23731571 TI - Migraine and epilepsy: progress towards preemptive therapy. PMID- 23731572 TI - Contributions of the soleus and gastrocnemius muscles to the anterior cruciate ligament loading during single-leg landing. AB - The aim of this study was to identify the contribution of the Soleus and Gastrocnemius (Gastroc) muscles' forces to anterior cruciate ligament (ACL) loading during single-leg landing. Although Quadriceps (Quads) and Hamstrings (Hams) muscles were recognized as the main contributors to the ACL loading, less is known regarding the role of ankle joint plantarflexors during landing. Eight healthy subjects performed single-landing tasks from 30 and 60cm heights. Scaled generic musculoskeletal models were developed in OpenSim to calculate lower limb muscle forces. The model consisted of 10 segments with 23 degrees of freedom and 92 lower body muscle-tendon units. Knee joint reaction forces were calculated based on the estimated muscle forces and used to predict ACL forces. We hypothesized that Soleus and Gastrocs muscle forces have opposite effects on tibial loading in the anterior/posterior directions. In situations where greater landing height would lead to an increase in GRF and risk of ACL injury, we further hypothesized that posterior forces of the Soleus and Hams would increase correspondingly to help protect the ACL during a safe landing maneuver. Our results demonstrated the antagonistic and agonistic roles of Gastrocs and Soleus respectively in ACL loading. The posterior force of Soleus reached 28-32% of Ham's posterior force for both landing heights at peak GRF while the posterior force of Gastrocs on femur was negligible. ACL injury risk during single-leg landing is not only dependent on knee musculature but also influenced by muscles that do not span the knee joint, such as the Soleus. In conclusion, the role of the ankle plantarflexors should be considered when developing training strategies for ACL injury prevention. PMID- 23731573 TI - N-acetylcysteine does not prevent contrast nephropathy in patients with renal impairment undergoing emergency CT: a randomized study. AB - BACKGROUND: Patients admitted to the emergency room with renal impairment and undergoing a contrast computed tomography (CT) are at high risk of developing contrast nephropathy as emergency precludes sufficient hydration prior to contrast use. The value of an ultra-high dose of intravenous N-acetylcysteine in this setting is unknown. METHODS: From 2008 to 2010, we randomized 120 consecutive patients admitted to the emergency room with an estimated clearance lower than 60 ml/min/1.73 m2 by MDRD (mean GFR 42 ml/min/1.73 m2) to either placebo or 6000 mg N-acetylcysteine iv one hour before contrast CT in addition to iv saline. Serum cystatin C and creatinine were measured one hour prior to and at day 2, 4 and 10 after contrast injection. Nephrotoxicity was defined either as 25% or 44 MUmol/l increase in serum creatinine or cystatin C levels compared to baseline values. RESULTS: Contrast nephrotoxicity occurred in 22% of patients who received placebo (13/58) and 27% of patients who received N-acetylcysteine (14/52, p = 0.66). Ultra-high dose intravenous N-acetylcysteine did not alter creatinine or cystatin C levels. No secondary effects were noted within the 2 groups during follow-up. CONCLUSIONS: An ultra-high dose of intravenous N acetylcysteine is ineffective at preventing nephrotoxicity in patients with renal impairment undergoing emergency contrast CT. TRIAL REGISTRATION: The study was registered as Clinical trial (NCT01467154). PMID- 23731574 TI - [Health personnel assessment about medical order entry systems of pharmacologic treatments in hospitalized patients]. AB - OBJECTIVE: to evaluate health personnel perceptions about medical order entry systems concerning the effect on workflow, medication errors risk and assessment of its potential advantages. MATERIAL AND METHODS: A cross-section opinion interview was conducted in a tertiary care hospital. Questionnaire consisted of three sections: perception of its effect on workflow, influence on medication error risk and assessment of potential advantages. We also asked them to assess drawbacks and provide suggestions about this prescription system. RESULTS: 76 health professionals were interviewed (58 physicians, 9 pharmacists and 9 nurses). They were satisfied mainly due to decrease the workload (85.5%; IC 95%: 75.58-92.55). They thought that the main characteristics that contribute to reduce medication errors are clinical decision supports related to predefined aspects which the program provided by default. Among potential benefits of medical order entry systems, legibility and warnings triggered by the program (98.7%; IC 95%: 92.90-99.97 and 97,4%; IC 95%: 90.81-99.68 respectively) were the most valuable. High technology dependence, IT failures and lack of infrastructure and medication therapy discontinuities at times of transition between different hospitals' units were the main drawbacks considered. The most repeated suggestion was related to the improvement of links between other health informatics applications used in the hospital. CONCLUSION: health personnel were highly satisfied with the CPOE system, which is considered to be effective and safe. Technology dependence and IT failures were the main disadvantages reported. According to them, a greater coordination and unification of all software applications available in the hospital would be desirable. PMID- 23731575 TI - [Assessment of the patient-safety culture in a healthcare district]. AB - OBJECTIVES: 1) To describe the frequency of positive attitudes and behaviours, in terms of patient safety, among the healthcare providers working in a healthcare district; 2) to determine whether the level of safety-related culture differs from other studies; and 3) to analyse negatively valued dimensions, and to establish areas for their improvement. MATERIAL AND METHODS: A descriptive, cross sectional study based on the results of an evaluation of the safety-related culture was conducted on a randomly selected sample of 247 healthcare providers, by using the Spanish adaptation of the Hospital Survey on Patient Safety Culture (HSOPSC) designed by the Agency for Healthcare Research and Quality (AHRQ), as the evaluation tool. Positive and negative responses were analysed, as well as the global score. Results were compared with international and national results. RESULTS: A total of 176 completed survey questionnaires were analysed (response rate: 71.26%); 50% of responders described the safety climate as very good, 37% as acceptable, and 7% as excellent. Strong points were: "Teamwork within the units" (80.82%) and "Supervisor/manager expectations and actions" (80.54%). Dimensions identified for potential improvement included: "Staffing" (37.93%), "Non-punitive response to error" (41.67%), and "Frequency of event reporting" (49.05%). CONCLUSIONS: Strong and weak points were identified in the safety related culture of the healthcare district studied, together with potential improvement areas. Benchmarking at the international level showed that our safety related culture was within the average of hospitals, while at the national level, our results were above the average of hospitals. PMID- 23731576 TI - Genomic disorders: complexity at multiple levels. AB - A report on the 7(th) Wellcome Trust Genomic Disorders conference held at the Homerton College, Cambridge, UK, April 10-12, 2013. PMID- 23731577 TI - The necessity of nuclear reactors for targeted radionuclide therapies. AB - Nuclear medicine has been contributing towards personalized therapies. Nuclear reactors are required for the working horses of both diagnosis and treatment, i.e., Tc-99m and I-131. In fact, reactors will remain necessary to fulfill the demand for a variety of radionuclides and are essential in the expanding field of targeted radionuclide therapies for cancer. However, the main reactors involved in the global supply are ageing and expected to shut down before 2025. Therefore, the fields of (nuclear) medicine, nuclear industry and politics share a global responsibility, faced with the task to secure future access to suitable nuclear reactors. At the same time, alternative production routes should be industrialized. For this, a coordinating entity should be put into place. PMID- 23731578 TI - Medial canthopexy of old unrepaired naso-orbito-ethmoidal (noe) traumatic telecanthus. AB - INTRODUCTION: Traumatic telecanthus resulting from injuries to the naso-orbito ethmoidal (NOE) complex is a difficult deformity to treat and involves both esthetic and functional aspects. Delayed or inadequate primary treatment often results in scarring and secondary deformities that are severe and make them extremely problematic to correct. The intricate anatomy of this area makes NOE injuries one of the most challenging areas of facial reconstruction. Several techniques were described to reconstruct the medial canthal tendon (MCT) and repair the telecanthus deformity. Transnasal wiring remains the gold standard. However, the procedure is technically difficult. It necessitates wide exposure sufficient to allow transverse passage of wires through bony fenestrations deep within the orbit, and involves dissection of the contralateral orbit. AIM: This study proposes a minor modification to simplify transnasal-wiring technique in the difficult cases presenting with telecanthus following unrepaired NOE fractures. PATIENTS & METHODS: The study included 13 patients (11 males and 2 females) presenting with telecanthus, at least six months after sustaining NOE fractures. Transnasal canthopexy was the fundamental step in reconstruction. Two wires held independently the anterior and posterior limbs of the MCT to ensure an adequate grip. They were delivered in a single pass through a single hole instead of two to avoid weakening of the thin lacrimal bones. The wires were then secured to a titanium mesh fixed to the contralateral medial orbital rim to guarantee a stable fixation. RESULTS: The technique restored the normal canthal position along the lacrimal crest. Good functional and esthetic results are reported based on the measurement of pre- and postoperative intercanthal & canthal-midline distances over a period of 2-years, with an average follow-up period of 12 months. CONCLUSION: The results reveal the simplicity and reliability of this technique in restoring palpebral shape and intercanthal distance without any recoded functional complications throughout the follow-up. PMID- 23731579 TI - Effect of rocker shoe design features on forefoot plantar pressures in people with and without diabetes. AB - BACKGROUND: There is no consensus on the precise rocker shoe outsole design that will optimally reduce plantar pressure in people with diabetes. This study aimed to understand how peak plantar pressure is influenced by systematically varying three design features which characterise a curved rocker shoe: apex angle, apex position and rocker angle. METHODS: A total of 12 different rocker shoe designs, spanning a range of each of the three design features, were tested in 24 people with diabetes and 24 healthy participants. Each subject also wore a flexible control shoe. Peak plantar pressure, in four anatomical regions, was recorded for each of the 13 shoes during walking at a controlled speed. FINDINGS: There were a number of significant main effects for each of the three design features, however, the precise effect of each feature varied between the different regions. The results demonstrated maximum pressure reduction in the 2nd-4th metatarsal regions (39%) but that lower rocker angles (<20 degrees ) and anterior apex positions (>60% shoe length) should be avoided for this region. The effect of apex angle was most pronounced in the 1st metatarsophalangeal region with a clear decrease in pressure as the apex angle was increased to 100 degrees . INTERPRETATION: We suggest that an outsole design with a 95 degrees apex angle, apex position at 60% of shoe length and 20 degrees rocker angle may achieve an optimal balance for offloading different regions of the forefoot. However, future studies incorporating additional design feature combinations, on high risk patients, are required to make definitive recommendations. PMID- 23731580 TI - The modern minimally invasive face lift: has it replaced the traditional access approach? AB - Because modern facelift patients desire a less-invasive approach or minimally invasive approach to reduce visible scarring and decrease the recovery phase, achieving the surgeon's goal of optimal, reliable, and long-term aesthetic results with few complications becomes a challenge. The authors use the terms minimal access and traditional access to describe rhytidectomy approaches based solely on incision size. A short-incision, minimal-access approach with a deep plane extended dissection is presented. A preoperative physical examination maneuver to evaluate a patient's candidacy for a minimal-access approach and guidelines for when to include platysmaplasty with the procedure to further improve cervicomental contour are described. PMID- 23731581 TI - Endoscopic brow lifts: have they replaced coronal lifts? AB - This article describes the use of the endoscopic brow-lifting technique in addressing periorbital aging. This article discusses the advantages and disadvantage of the endoscopic versus traditional techniques of brow lifting and gives our treatment algorithm depending on patient needs. PMID- 23731582 TI - The role of fillers in facial implant surgery. AB - Alloplastic facial implants and injectable fillers are currently used for facial rejuvenation and augmentation. Their respective roles in augmentation and volume replacement of the chin and midface are discussed. Treatment goals, patient selection, procedures, and patient recovery are detailed. In addition, there is a segment for surgeons presenting a decision algorithm for selecting surgical versus less-invasive or nonsurgical approaches for midface rejuvenation. PMID- 23731583 TI - Fractional CO2 resurfacing: has it replaced ablative resurfacing techniques? AB - The author uses the pulsed ablative CO2 laser regularly for skin rejuvenation. This decision is based on the gold standard status of the CO2 modality and an innovative aftercare treatment shown in the author's practice to greatly reduce the complications of ablative pulsed CO2 laser treatment. Depending on the patient and the severity of the skin condition, the author customizes each treatment, which may also include fractional CO2 lasers, fat grafting, facelifting, or any combination of these techniques. This article presents a detailed description of the evolution of skin rejuvenation with lasers and the current role of lasers as an adjunct to face and necklift surgery. PMID- 23731584 TI - Midface injectable fillers: have they replaced midface surgery? AB - This article examines the increasing role of injectable fillers to treat midface aging and our approach to decision making regarding the use of fillers versus surgery. We discuss the volume changes of the aging midface and advocate taking an anatomic approach to correct these changes. We discuss our approach to patient selection and injection technique. Finally, we review potential complications from injectable fillers and discuss the management of complications. PMID- 23731585 TI - Nonsurgical rhinoplasty using dermal fillers. AB - With the advent of newer injectables with less immunogenicity and greater longevity, nonsurgical rhinoplasty has become a viable alternative to surgery. An understanding of the surgical anatomy of the nose, particularly in a postrhinoplasty patient, affords the physician injector the opportunity to better plan the injectable treatment. This article outlines the evolution of nonsurgical rhinoplasty and identifies properties to consider when selecting which dermal filler to use. It includes a description of the types of nasal deformities that can be treated with injectables, as well as the role of nonsurgical rhinoplasty in a comprehensive regimen for correction of nasal deformities. PMID- 23731586 TI - Fat grafting: an alternative or adjunct to facelift surgery? AB - Fat transfer is a cornerstone to managing facial aging and can represent a stand alone procedure or be used in conjunction with other surgical treatments. Fat can also be used with fillers or as an alternative to fillers both for the benefit of educating surgeons and for improved patient communication to establish clear expectations of results. The surgeon should discuss these aspects with a patient in a preoperative setting to avoid false expectations. Fat is a bioactive substance and fat transfer should be avoided in very young patients, in those with weight instability, and in cases of asymmetric placement. PMID- 23731587 TI - Minimally invasive neck lifts: have they replaced neck lift surgery? AB - The aging neck is accompanied by an increase in submental fat, platysmal banding, and redundant dyspigmented skin. Creating a more acute cervicomental angle, distinct mandibular border, homogeneous skin tone, and smoother texture helps to achieve a more youthful appearance. The aesthetic provider's armamentarium has long had surgical techniques in the highest regard, but a new wave of minimally invasive procedures looks to offer a nonsurgical approach to cervicomental rejuvenation. Selecting the appropriate procedure for appropriate patients that will effectively meet their aesthetic goals and expectations is the core of successful neck rejuvenation. PMID- 23731588 TI - Poly-L-lactic acid facial rejuvenation: an alternative to autologous fat? AB - Facial volume loss is an important component of facial aging and tends to present at an earlier age than other aspects of aging. Several surgical and nonsurgical products and techniques are available to replace volume loss associated with aging. One surgical technique uses a patient's fat cells to replace or augment volume deficiency. Poly-L-lactic acid (PLLA) injection is a nonsurgical option. This article compares these 2 volume augmentation procedures and discusses characteristics of facial aging, the consultation process involved in assessing individual volume loss, procedure details of autologous fat grafting and PLLA injection, the decision of PLLA versus autologous fat, and patient outcomes. PMID- 23731589 TI - Cosmetic botulinum toxin: has it replaced more invasive facial procedures? AB - Botulinum toxin (BoNTA) has become the modern generation's treatment of choice for facial aging. Advanced uses of neurotoxin have treated specific areas of the face, in addition to the glabella, which is the only site for injection approved by the Food and Drug Administration. This article suggests that BoNTA has replaced surgical procedures that treat oral commissures, mild brow ptosis and brow asymmetries, and hypertrophic orbicularis oculi muscles. It is becoming increasingly used for lip asymmetry, platysmal banding, and necklift, although it has not replaced traditional procedures for the correction of these areas. PMID- 23731590 TI - Autologous cell therapy: will it replace dermal fillers? AB - This article discusses autologous cell therapy for wrinkles in the face. Autologous fibroblast therapy is compared with dermal fillers. Study outcomes of LaViv are detailed, including a summary of adverse events. The technique for injection of autologous cells is described in addition to the duration of effect of treatment. PMID- 23731591 TI - Minimal facial plastic surgery procedures... maximal results? PMID- 23731592 TI - Diabetes and the millennium development goals. PMID- 23731593 TI - Cytological, molecular and life cycle characterization of Anostracospora rigaudi n. g., n. sp. and Enterocytospora artemiae n. g., n. sp., two new microsporidian parasites infecting gut tissues of the brine shrimp Artemia. AB - Two new microsporidia, Anostracospora rigaudi n. g., n. sp., and Enterocytospora artemiae n. g., n. sp. infecting the intestinal epithelium of Artemia parthenogenetica Bowen and Sterling, 1978 and Artemia franciscana Kellogg, 1906 in southern France are described. Molecular analyses revealed the two species belong to a clade of microsporidian parasites that preferentially infect the intestinal epithelium of insect and crustacean hosts. These parasites are morphologically distinguishable from other gut microsporidia infecting Artemia. All life cycle stages have isolated nuclei. Fixed spores measure 1.3*0.7 MUm with 5-6 polar tube coils for A. rigaudi and 1.2*0.9 MUm with 4 polar tube coils for E. artemiae. Transmission of both species is horizontal, most likely through the ingestion of spores released with the faeces of infected hosts. The minute size of these species, together with their intestinal localization, makes their detection and identification difficult. We developed two species-specific molecular markers allowing each type of infection to be detected within 3-6 days post-inoculation. Using these markers, we show that the prevalence of these microsporidia ranges from 20% to 75% in natural populations. Hence, this study illustrates the usefulness of molecular approaches to study prevalent, but cryptic, infections involving microsporidian parasites of gut tissues. PMID- 23731594 TI - Systems intervention to promote colon cancer screening in safety net settings: protocol for a community-based participatory randomized controlled trial. AB - BACKGROUND: Colorectal cancer is a leading cause of cancer mortality. Screening can be effective but is underutilized. System- or multi-level interventions could be effective at increasing screening, but most have been implemented and evaluated in higher-resource settings such as health maintenance organizations. Given the disparities evident for colorectal cancer and the potential for screening to improve outcomes, there is a need to expand this work to include diverse settings, including those who treat economically disadvantaged patients. This paper describes the study protocol for a trial designed to increase colorectal cancer screening in those 'safety-net' health centers that serve underinsured and uninsured patients. This trial was designed and is being implemented using a community-based participatory approach. METHODS/DESIGN: We developed a practical clinical cluster-randomized controlled trial. We will recruit 16 community health centers to this trial. This systems-level intervention consists of a menu of evidence-based implementation strategies for increasing colorectal cancer screening. Health centers in the intervention arm then collaborate with the study team to tailor strategies to their own setting in order to maximize fit and acceptability. Data are collected at the organizational level through interviews, and at the provider and patient levels through surveys. Patients complete a survey about their healthcare and screening utilization at baseline, six months, and twelve months. OUTCOMES: The primary outcome is colorectal cancer screening by patient self-report, supplemented by a chart-audit in a subsample of patients. Implementation outcomes informed by the Reach, Efficacy/Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) conceptual framework will be measured at patient, provider, and practice levels. DISCUSSION: Our study is one of the first to integrate community participatory strategies to a randomized controlled trial in a healthcare setting. The multi level approach will support the ability of the intervention to affect screening through multiple avenues. The participatory approach will strengthen the chance that implementation strategies will be maintained after study completion and, supports external validity by increasing health center interest and willingness to participate. TRIAL REGISTRATION: NCT01299493. PMID- 23731595 TI - Both infected and uninfected mosquitoes are attracted toward malaria infected birds. AB - BACKGROUND: The biting behaviour of mosquitoes is crucial for the transmission of malaria parasites. This study focuses on the feeding behaviour of Culex pipiens mosquitoes with regard to the infection status by the avian malaria parasite Plasmodium relictum (lineage SGS1). METHODS: Uninfected and sporozoite-infected mosquitoes were provided with a choice between an uninfected bird and a bird undergoing a chronic P. relictum infection. Mosquito choice is assessed by microsatellite typing of the ingested blood. RESULTS: Chronically infected birds are more attractive to mosquitoes. This choice is not altered by the infection status of the mosquitoes: both infected and uninfected mosquitoes have similar host choice behaviours and are more attracted towards infected birds. CONCLUSIONS: These results support some, but not all predictions derived from the hypothesis that malaria parasites can manipulate the behaviour of their mosquito vectors to enhance their transmission. The possible mechanisms driving this manipulation, the evolutionary dynamics leading to the modification of the biting behaviour of mosquitoes by Plasmodium sp. as well as the implications for malaria epidemiology are discussed. PMID- 23731596 TI - Multiscale mechanobiology: mechanics at the molecular, cellular, and tissue levels. AB - Mechanical force is present in all aspects of living systems. It affects the conformation of molecules, the shape of cells, and the morphology of tissues. All of these are crucial in architecture-dependent biological functions. Nanoscience of advanced materials has provided knowledge and techniques that can be used to understand how mechanical force is involved in biological systems, as well as to open new avenues to tailor-made bio-mimetic materials with desirable properties.In this article, we describe models and show examples of how force is involved in molecular functioning, cell shape patterning, and tissue morphology. PMID- 23731597 TI - Epidemiology of the Foot-and-Mouth Disease Serotype O Epidemic of November 2010 to April 2011 in the Republic Of Korea. AB - The largest epidemic of foot-and-mouth disease (FMD) in Korea since the first record in 1911 occurred between November 2010 and April 2011. The outbreak was confirmed in 153 farms, and more than three million animals were destroyed. This study presents the temporal and spatial distribution patterns, epidemiological investigation and the control measures for the 2010/2011 epidemic in Korea. The index case of this 2010/2011 FMD epidemic was reported in a pig-farming complex with five piggeries in Andong, GyeongBuk Province, on 28 November 2010, and the outbreak lasted 145 days. The largest number of new detection of the infected farms per day was recorded in mid-January. Epidemiological investigation revealed that the FMD virus had spread from farm to farm through routine movements associated with animal husbandry operations. In contrast to FMD epidemics in other countries in which movement of the infected animals largely contributed to the spread of the disease, human behaviours were major factors in the spread of the FMD virus in the Korean epidemic. The 2010/2011 epidemic was first confirmed in a local small and medium city where share of smallholder producers is higher than that of other provinces. Although Korea had a well-developed emergent response system with the experience of controlling infection and re-obtaining FMD free status after the previous epidemics, Korea was prompted to revise their contingency plan by tailoring it to its unique livestock environment. Practical contingency plans tailored to Korea for control of FMD can be fully effective when farmers, livestock-related agencies, veterinary service providers and the general public work together. PMID- 23731598 TI - Pregabalin versus gabapentin in the management of peripheral neuropathic pain associated with post-herpetic neuralgia and diabetic neuropathy: a cost effectiveness analysis for the Greek healthcare setting. AB - BACKGROUND: The anticonvulsants pregabalin and gabapentin are both indicated for the treatment of peripheral neuropathic pain. The decision on which treatment provides the best alternative, should take into account all aspects of costs and outcomes associated with the two therapeutic options. The objective of this study was to examine the cost - effectiveness of the two agents in the management of patients with painful diabetic neuropathy or post - herpetic neuralgia, under the third party payer perspective in Greece. METHODS: The analysis was based on a dynamic simulation model which estimated and compared the costs and outcomes of pregabalin and gabapentin in a hypothetical cohort of 1,000 patients suffering from painful Diabetic Peripheral Neuropathy (DPN) or Post-Herpetic Neuralgia (PHN). In the model, each patient was randomly allocated an average pretreatment pain score, measured using an eleven-point visual analogue scale (0 - 10) and was "run through" the model, simulating their daily pain intensity and allowing for stochastic calculation of outcomes, taking into account medical interventions and the effectiveness of each treatment. RESULTS: Pregabalin demonstrated a reduction in days with moderate to severe pain when compared to gabapentin. During the 12 weeks the pregabalin arm demonstrated a 0.1178 (SE 0.0002) QALY gain, which proved to be 0.0063 (SE 0.0003) higher than that in the gabapentin arm. The mean medication cost per patient was higher for the pregabalin arm when compared to the gabapentin arm (i.e. ?134.40) over the 12 week treatment period. However, this higher cost was partially offset by the reduced direct medical costs (i.e. the cost of specialist visits, the cost of diagnostic tests and the other applied interventions). Comparing costs with respective outcomes, the ICERs for pregabalin versus gabapentin were ?13 (95%CI: 8 - 18) per additional day with no or mild pain and ?19,320 (95%CI: 11,743 - 26,755) per QALY gained. CONCLUSIONS: Neuropathic pain carries a great disease burden for patients and society and, is also, associated with a significant economic burden. The treatment of pain associated with DPN and PHN with pregabalin is a cost-effective intervention for the social security in Greece compared to gabapentin. Thus, these findings need to be taken into consideration in the decision - making process when considering which therapy to use for the treatment of neuropathic pain. PMID- 23731599 TI - Pediatric cardiology fellowship--the future. PMID- 23731600 TI - The frail brain. PMID- 23731601 TI - Virus-induced humoral immunity: on how B cell responses are initiated. AB - Most antiviral vaccines are based on viral particles, which are efficient inducers of B cell responses. In addition to their ability to replicate, several features associated with the structure and content of the viral particles are responsible for this high immunogenicity. First, viral particles usually have dimensions between 20 and 200 nm, a size optimal for drainage to lymph nodes and direct interaction with B cells. Second, the surface of most viral particles is highly repetitive, causing efficient cross-linking of B cell receptors, an early and key step of B cell activation. In addition, such repetitive structures bind natural antibodies and fix complement, further enhancing B cell activation as well as transport to and deposition on follicular dendritic cells. Third, viral particles carry ligands for toll-like receptor 7/8 or 9 which activate B cells directly for isotype switching as well as dendritic cells for T cell priming. In this review, we will highlight recent insights in these mechanisms and discuss their impact on antiviral antibody responses. PMID- 23731602 TI - [Links between obesity and diabetes mellitus. Reply from the authors]. PMID- 23731603 TI - [Analgesic efficacy of topical lidocaine for vaso-occlusive crisis in children with sickle cell disease]. AB - Pain associated with vaso-occlusive crisis is the main cause of hospitalization in children with sickle cell disease. Recent studies have suggested that pain might have a neuropathic component. Lidocaine patches are commonly prescribed as a topical analgesic in adult neuropathic pain. This study reports the efficacy and safety of such treatment in 6 patients with sickle cell disease, aged 6-18 years, who had been hospitalized for vaso-occlusive crisis after failure of the standard analgesic treatment. These data have led to setting up a confirmatory phase II trial, which is currently underway. PMID- 23731604 TI - [Admissions for pediatric asthma in France]. AB - INTRODUCTION: Most hospital admissions for asthma exacerbation are avoidable with adequate disease management. The objective of this study was to describe admissions for asthma in children in France using data from the French nationwide hospital database. METHODS: We selected admissions having either a main diagnosis of asthma or a main diagnosis of acute respiratory failure (ARF) with asthma as an associated diagnosis, occurring in children (age<15years) between 2002 and 2010 in France (excluding French Guyana). RESULTS: In 2010, 35,004 asthma admissions and 1381 cases of asthma-related ARF were recorded (crude admission rate, 30.1/10,000 children); the mean length of stay was 2days. The in-hospital lethality rate ranged from 0.01% to 0.03% depending on the year. The annual age standardized admission rate increased between 2002 and 2010 (+2.5% per year on average in metropolitan France). In 2010, 11.8% of children admitted for asthma or asthma-related ARF were readmitted for asthma or asthma-related ARF at least once within the same calendar year, and 1.3% were readmitted within the week following admission. The proportion of children aged less than 5 years who were readmitted within the same calendar year increased between 2002 and 2010. CONCLUSION: The increase in admission and readmission rates indicates non-optimal management of asthma in children in France. PMID- 23731605 TI - [Childhood onset schizophrenia: current data and therapeutic approach]. AB - Childhood schizophrenia is a rare but serious developmental disorder affecting most of the fields involved in the child's adaptive functioning: motor, emotional, cognitive, and social. The clinical expression of the disorder mainly depends on the child's age and the IQ level at the time the first clinical symptoms appear. The progression of childhood schizophrenia is generally poor, with different outcome studies suggesting a continuity of the process between childhood and adulthood. This stresses the importance of diagnosing the disorder early and initiating the adapted therapeutic measures as quickly as possible, including cognitive remediation (a new therapeutic tool to correct or anticipate cognitive disorders), which can prevent pejorative development. PMID- 23731606 TI - Ventricular assist device implant in the elderly is associated with increased, but respectable risk: a multi-institutional study. AB - BACKGROUND: There are an increasing number of elderly patients with end-stage heart failure. Destination mechanical circulatory support is often the only therapy available for these patients who are not transplant candidates. The outcomes after continuous flow left ventricular assist device (CF LVAD) implant in older patients remains unclear. We undertook this multi-institutional study to quantify short-term and midterm outcomes after CF LVAD implant in the elderly. METHODS: We retrospectively analyzed all patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) national registry that underwent implant of a CF LVAD (June 2006 to April 2012). Patients were divided into 2 cohorts based upon age (<70 years [n = 4,439] and >= 70 years (n = 590]). Preoperative, intraoperative, and postoperative variables were analyzed. The primary endpoint, survival, was compared between cohorts. RESULTS: Patients age 70 and older were more hemodynamically stable pre-VAD implant as evidenced by INTERMACS profile and inotrope dependence. Perioperative outcomes, including median bypass time (89 vs 89 minutes) and length of stay (0.657 vs 0.657 months) were similar between cohorts (p = not significant). Kaplan-Meier analysis revealed a significant difference in 2-year survival between patients aged 70 years or greater (63%) and less than 70 (71%, p < 0.001). Multivariable Cox proportional hazard analysis revealed age as an independent predictor of mortality during follow-up (p < 0.001). Nonetheless, midterm cumulative survival in the older cohort was still reasonable (63% at 2 years). CONCLUSIONS: Multi institutional analysis revealed advanced age as a predictor of increased mortality after CF LVAD implantation. Careful patient selection is critical in the elderly to optimize long-term outcomes after CF LVAD implantation. PMID- 23731607 TI - Periarteritis in lung from a continuous-flow right ventricular assist device: role of the local Renin-Angiotensin system. AB - BACKGROUND: We previously reported renal arterial periarteritis after implantation of a continuous-flow left ventricular assist device in calves. The purpose of the present study was to investigate whether the same periarteritis changes occur in the intrapulmonary arteries after implantation of a continuous flow right ventricular assist device (CFRVAD) in calves and to determine the mechanism of those histologic changes. METHODS: Ten calves were implanted with a CFRVAD for 29 +/- 7 days, and we compared pulmonary artery samples and hemodynamic data before and after CFRVAD implantation prospectively. RESULTS: After implantation, the pulsatility index (pulmonary arterial pulse pressure/pulmonary arterial mean pressure) significantly decreased (0.88 +/- 0.40 before vs 0.51 +/- 0.22 after; p < 0.05), with severe periarteritis of the intrapulmonary arteries in all animals. Periarterial pathology included hyperplasia and inflammatory cell infiltration. The number of inflammatory cells positive for the angiotensin II type 1 receptor was significantly higher after implantation (7.8 +/- 6.5 pre-CFRVAD vs 313.2 +/- 145.2 at autopsy; p < 0.01). Serum angiotensin-converting enzyme activity significantly decreased after implantation from 100% to 49.7 +/- 17.7% at week 1 (p = 0.01). Tissue levels of angiotensin-converting enzyme also demonstrated a significant reduction (0.381 +/ 0.232 before implantation vs 0.123 +/- 0.096 at autopsy; p = 0.043). CONCLUSIONS: Periarteritis occurred in the intrapulmonary arteries of calves after CFRVAD implantation. The local renin-angiotensin system (not the angiotensin-converting enzyme pathway) plays an important role in such changes. PMID- 23731608 TI - Evaluation of the reliability of clinical staging of T2 N0 esophageal cancer: a review of the Society of Thoracic Surgeons database. AB - BACKGROUND: Clinical staging of esophageal cancer has improved with positron emission tomography/computed tomography and endoscopic ultrasound imaging. Despite such progress, small single-center studies have questioned the reliability of clinical staging of T2 N0 esophageal cancer. This study broadly examines the adequacy of clinical staging of T2 N0 disease using The Society of Thoracic Surgeons database. METHODS: We retrospectively studied 810 clinical stage T2 N0 patients from 2002 to 2011, with 58 excluded because of incomplete pathologic staging data. Clinical stage, pathologic stage, and preoperative characteristics were recorded. Logistic regression analysis was used to identify factors associated with upstaging at the time of surgical intervention. RESULTS: Among 752 clinical stage T2 N0 patients, 270 (35.9%) received induction therapy before the operation. Of 482 patients who went directly to surgical intervention, 132 (27.4%) were confirmed as pathologic T2 N0, 125 (25.9%) were downstaged (ie, T0-1 N0), and 225 (46.7%) were upstaged at the operation (T3-4 N0 or Tany N1-3). Exclusive tumor upstaging (ie, pathologic T3-4 N0) accounted for 41 patients (18.2%), whereas exclusive nodal upstaging (ie, pathological T1-2 N1-3) accounted for 100 (44.5%). Combined tumor and nodal upstaging (ie, pathological T3-4 N1-3) accounted for 84 patients (37.3%). Among patients who received induction therapy, 103 (38.1%) were upstaged vs 225 (46.7%) without induction therapy (p = 0.026). Comparing the induction therapy group and the primary surgical group, postoperative 30-day mortality (3.7% vs 3.7%, p > 0.99) and morbidity (46.3% vs 45%, p = 0.76) were similar. CONCLUSIONS: Despite advances in staging techniques, clinical staging of T2 N0 esophageal cancer remains unreliable. Recognizing T2 N0 as a threshold for induction therapy in esophageal cancer, many surgeons have opted to treat T2 N0 disease with induction therapy, even though one-quarter of these patients will be pathologic T1 N0. Although this study demonstrated similar perioperative morbidity and mortality with and without induction therapy, further study is needed to examine the effect of upstaging on long-term survival. PMID- 23731609 TI - Early and long-term patency of in situ skeletonized gastroepiploic artery after off-pump coronary artery bypass graft surgery. AB - BACKGROUND: There is at present no accurate figure for the long-term patency rate of the skeletonized gastroepiploic artery (GEA). METHODS: From January 2002 to July 2012, 956 consecutive patients underwent isolated off-pump coronary artery bypass graft (OPCABG) surgery at our institution. Of these, the 424 who underwent GEA grafting and postoperative GEA graft evaluation were the subjects of the present study. Of these 424 subjects, 155 (36.6%) underwent long-term outpatient evaluation using multidetector computed tomography angiography. RESULTS: No patient was converted from off pump to on pump surgery. Overall 30-day mortality was 0.5% (2 of 424). The overall early (4 to 21 days after surgery) patency rate of the skeletonized GEA was 98.2% (599 of 610 anastomoses). A total of 215 GEA anastomoses, including 55 sequential bypasses, were followed for long-term evaluation, of which 12, including three sequential bypasses, were found to be occluded. The overall patency rate in skeletonized GEA grafting over a mean follow-up period of 73 months was 94.4% (203 of 215). The cumulative patency rate of the skeletonized GEA was 97.8% at 30 days, 96.7% at 1 year, 96.0% at 3 years, 94.7% at 5 years, and 90.2% at 8 years after surgery. Multivariate Cox proportional hazard regression analysis showed that target vessel stenosis (p = 0.008, hazard ratio 0.086, 95% confidence interval: 0.014 to 0.53) was the only independent predictor of late graft occlusion. CONCLUSIONS: We demonstrated an accurate long-term patency rate for the skeletonized GEA superior to that for pedicled GEA or saphenous vein graft. A low-grade degree of target vessel stenosis was the only risk factor for late GEA occlusion. PMID- 23731610 TI - Variation in ventilation time after coronary artery bypass grafting: an analysis from the society of thoracic surgeons adult cardiac surgery database. AB - BACKGROUND: Short postoperative ventilation times are accepted as a marker of quality. This analysis assesses center level variation in postoperative ventilation time in a subset of patients undergoing isolated coronary artery bypass grafting (CABG). METHODS: In 2009 and 2010, 325,129 patients in the STS Adult Cardiac Surgery Database underwent isolated CABG. Patients were excluded if they were intubated before entering the operating room, required ventilation for greater than 24 hours, or had missing data on key covariates. The final study cohort was 274,231 isolated CABG patients from 1,008 centers. Bayesian hierarchical models were used to assess between-center variation in ventilation time and to explore the effect of center-level covariates. Analyses were performed with and without adjusting for case mix. RESULTS: After adjusting for case mix, the ratio of median ventilator time at the 90th percentile of the center-level distribution compared with the tenth percentile was 9.0:5.0=1.8 (95% credible interval: 1.79 to 1.85). This ratio illustrates the scale of between center differences: centers above the 90th percentile have a ventilation time of at least 1.8 times that of centers below the tenth percentile. Smaller hospital volume, presence of a residency program, and some census regions were associated with longer ventilation times. CONCLUSIONS: After adjustment for severity of illness, substantial inter-center variation exists in postoperative ventilation time in this subset of patients undergoing isolated CABG. This finding represents an opportunity for multi-institutional quality improvement initiatives designed to limit variations in ventilator management and achieve the shortest possible ventilation times for all patients, thus benefiting both clinical outcomes and resource utilization. PMID- 23731611 TI - Rapid on-site pathologic evaluation does not increase the efficacy of endobronchial ultrasonographic biopsy for mediastinal staging. AB - BACKGROUND: Endobronchial ultrasonography with transbronchial needle aspiration (EBUS-TBNA) has been shown to be equivalent to mediastinoscopy in lung cancer staging for mediastinal node involvement. Rapid on-site evaluation (ROSE) to determine the adequacy of nodal sampling has been claimed to be beneficial. METHODS: A retrospective evaluation was performed in 170 patients who underwent EBUS-TBNA from July 2008 to May 2011. The patients were classified as having either high or low pretest probability for mediastinal disease based on history and radiographic imaging. ROSE was compared with the final pathology reports based on slides and cell blocks. RESULTS: One hundred thirty-one (77%) patients were classified as being in the high pretest cohort based on clinical staging. Of these, 101 (77%) patients had adequate tissue sampling based on ROSE, with 70 (69%) patients having positive mediastinal disease. In the 30 (23%) patients who had inadequate tissue by ROSE, the final analysis of all the prepared slides and cell blocks allowed for a diagnosis in all but 8 patients. The sensitivity and specificity of ROSE in the high pretest probability cohort were 89.5% and 96.4%, respectively, whereas the overall sensitivity and specificity of EBUS-TBNA was 92.1% and 100%, respectively. Despite having inadequate tissue on ROSE in 30 of 131 patients, sufficient tissue was available on final analysis for diagnosis in 22 of 30 patients. CONCLUSIONS: ROSE does not impact clinical decision making if a thorough mediastinal staging using EBUS is performed. Despite inadequate tissue sampling assessment by ROSE, a final diagnosis was made in most patients, potentially avoiding an additional surgical procedure to prove mediastinal disease. PMID- 23731612 TI - Hypoxemia during one-lung ventilation for robot-assisted coronary artery bypass graft surgery. AB - BACKGROUND: Robot-assisted coronary artery bypass grafting requires continuous one-lung ventilation (OLV) to evacuate the thoracic cavity. Whether this ventilatory mode subjects patients to serious hypoxemia remains underinvestigated. METHODS: From 2005 to 2010, all patients receiving robot assisted coronary artery bypass graft surgery using OLV with active capnothorax for internal mammary artery harvesting and then passive pneumothorax for minithoracotomy direct-vision coronary bypass graft surgery were included. Patients' variables of oxygenation were monitored and compared throughout the whole surgical period. Persistent oxygen desaturation (arterial oxygen pressure <70 mm Hg) refractory to primary managements was defined as a hypoxemic event, and predictors of such events were identified by multivariate regression analysis. RESULTS: A total of 255 consecutive patients were enrolled. Average oxygen saturation decreased modestly during the first stage of OLV with active capnothorax, causing hypoxemic events in 9 patients (4.3%) leading to death in 2 (0.8%), whereas it dropped drastically in the second stage of OLV with passive pneumothorax, resulting in hypoxemic events in 32 patients (12.6%) and death in 1 (0.4%). Multivariate regression analysis identified high pulmonary vascular resistance and low left ventricular ejection fraction as predictors of hypoxemia during internal mammary artery takedown, whereas prolonged procedure and chronic obstructive pulmonary disease were identified as predictors during minithoracotomy bypass grafting. CONCLUSIONS: Robot-assisted two-stage coronary artery bypass surgery employing OLV could be complicated by serious hypoxemia especially at the minithoracotomy grafting stage and in patients with specific risk factors. Thus, when managing such patients, invasive monitoring and aggressive treatment of arterial desaturation are mandatory to ensure the patient's safety and procedural smoothness. PMID- 23731613 TI - Biomechanical properties of human ascending thoracic aortic aneurysms. AB - BACKGROUND: Surgical management of ascending thoracic aortic aneurysms (aTAAs) relies on maximum diameter, growth rate, and presence of connective tissue disorders. However, dissection and rupture do occur in patients who do not meet criteria for surgical repair. This study investigated the mechanical properties of aTAAs compared with normal human ascending aortas for eventual development of biomechanical aTAA risk models. METHODS: aTAA specimens (n = 18) were obtained from patients undergoing surgical aneurysm repair, and fresh, healthy ascending aortas (n = 19) as controls were obtained from the transplant donor network. Biaxial stretch testing was performed to obtain tissue mechanical properties. Patient-specific aTAA physiologic stress was calculated based on preoperative computed tomography diameter. aTAA and ascending aorta tissue stiffness at respective physiologic stress were determined. RESULTS: Physiologic stress of aTAA was significantly greater (241.6 +/- 59.4 kPa) than the 74 kPa for normal controls. Tissue stiffness of aTAAs was significantly greater than that of the ascending aortas at their respective physiologic stresses in the circumferential (3041.4 +/- 1673.7 vs 905.1 +/- 358.9 kPa, respectively; p < 0.001) and longitudinal (3498.2 +/- 2456.8 vs 915.3 +/- 368.9 kPa, respectively; p < 0.001) directions. Tissue stiffness of aTAAs positively correlated with aTAA diameter but did not correlate with patient age. No correlation was found between aTAA physiologic stress level and maximum aTAA diameter. CONCLUSIONS: aTAAs are much stiffer than normal ascending aortas at their respective physiologic stress, which was also significantly greater in ATAAs than ascending aortas. Patient specific physiologic stress did not correlate with maximum aTAA diameter, and patient-specific aTAA wall stress may be a useful variable to predict adverse aTAA events. PMID- 23731614 TI - Hypertensive changes within the aortic arch of infants and children with isolated coarctation. AB - BACKGROUND: Despite repair, a significant proportion of patients with coarctation of the aorta (CoA) present with late hypertension. Increased gene expression of aortic wall collagen and vascular smooth muscle cell markers occurs in the presence of hypertension. Before repair, a patent ductus arteriosus (PDA) limits hypertension proximal to the coarctation. We hypothesize that preoperative collagen and vascular smooth muscle expression from the aortic arch in children is variable, depending on the presence or absence of a PDA. METHODS: We analyzed the expression patterns of collagen and vascular smooth muscle cell markers in 25 children with CoA using a quantitative polymerase chain reaction. Aortic arch tissue proximal to the CoA was normalized to descending aortic tissue distal to the coarctation. Collagen-I, transforming growth factor-beta, elastin, and calponin were analyzed. RESULTS: At repair, 19 patients were aged younger than 3 months (14 with a PDA, 5 with a ligamentum arteriosum), and the remaining 6 were older than 1 year. There was no difference in age or weight between infants with or without a PDA. Infants without a PDA had the greatest difference in collagen-I expression compared with infants with a PDA (7.0 +/- 1.6-fold vs 0.8 +/- 1.1 fold, p = 0.01). Expression of transforming growth factor-beta (4.3 +/- 1.4 vs 2.6 +/- 2.3, p = 0.01) and calponin (3.7 +/- 0.7 vs 0.6 +/- 1.1, p = 0.05) was lower from infants with vs without a PDA. CONCLUSIONS: Our findings provide evidence of preoperative changes in the aortic arch before repair, particularly in the absence of a PDA. PMID- 23731615 TI - Metastasectomy with standardized lymph node dissection for metastatic renal cell carcinoma: an 11-year single-center experience. AB - BACKGROUND: Pulmonary metastasectomy (PM) for metastatic renal cell carcinoma is an established method of treatment for selected patients. The incidence of intrathoracic lymph node metastases (ITLNM) and outcomes remain controversial. The purpose of this study was to determine the incidence of ITLNM and long-term outcome of PM for metastatic kidney cancer. METHODS: From January 1999 to December 2009, 116 patients (82 men, age 61.7 +/- 9.0 years) with metastases from kidney cancer underwent PM and systematic lymph node dissection with curative intent. Kaplan-Meier analyses, log-rank test, and Cox regression analyses were used to estimate survival and to determine prognosticators of survival. RESULTS: Overall survival rates were 49% at 5 years and 21% at 10 years (median survival, 56.6 +/- 9.2 months). Complete resections could be achieved in 108 patients (93.1%). Forty patients (34.5%) had systematic therapy before metastasectomy. Partial regression was observed in 11 patients (27.5%). Surgical morbidity and mortality rates were 13.8% (16 of 116) and 0.9% (1 of 116), respectively. ITLNM were found in 54 (46.6%). Patient age (>= 70 years; p = 0.003), female gender (p = 0.016), and number of metastases (>= 2 metastases; p = 0.012) were associated with inferior survival after PM in the univariate analysis. The presence of ITLNM and type of lung resection did not significantly affect survival. Patient age remained the only significant prognostic factor when a multivariate Cox proportional hazards model was applied. CONCLUSIONS: PM and systematic lymph node dissection can be performed safely with low morbidity and mortality. Long-term survival is achievable in selected patients even with ITLNM. We recommend that systematic lymph node dissection should be demanded in every patient due to the high prevalence of ITLNM. Patients aged 70 years or older should be selected carefully for PM. PMID- 23731616 TI - Personal medication preparedness among veteran and nonveteran men and women in the California population. AB - INTRODUCTION: The health of people with chronic medical conditions is particularly vulnerable to the disruptions caused by public health disasters, especially when there is massive damage to the medical infrastructure. Government agencies and national organizations recommend that people with chronic illness prepare for disasters by stockpiling extra supplies of medications. PROBLEM: A wide range of chronic illnesses has long been documented among veterans of the US armed forces. Veterans with chronic illness could be at great risk of complications due to disaster-related medication disruptions; however, the prevalence of personal medication preparedness among chronically ill veterans is not currently known. METHODS: Data was used from the 2009 California Health Interview Survey on 28,167 respondents who reported taking daily medications. After adjusting for differences in age, health status, and other characteristics, calculations were made of the percentage of respondents who had a two-week supply of emergency medications and, among respondents without a supply, the percentage who said they could obtain one. Veteran men, veteran women, nonveteran men, and nonveteran women were compared. RESULTS: Medication supplies among veteran men (81.9%) were higher than among nonveteran women (74.8%; P < .0001) and veteran women (81.1%; P = 0.014). Among respondents without medication supplies, 67.2% of nonveteran men said that they could obtain a two-week supply, compared with 60.1% of nonveteran women (P = .012). Discussion Among adults in California with chronic illness, veteran men are more likely to have personal emergency medication supplies than are veteran and nonveteran women. Veteran men may be more likely to be prepared because of their training to work in combat zones and other emergency situations, which perhaps engenders in them a culture of preparedness or self-reliance. It is also possible that people who choose to enlist in the military are different from the general population in ways that make them more likely to be better prepared for emergencies. CONCLUSION: Veterans in California have a relatively high level of emergency medication preparedness. Given the health complications that can result from disaster-related medication disruptions, this is a promising finding. Disasters are a national concern, however, and the personal preparedness of veterans in all parts of the nation should be assessed; these findings could serve as a useful reference point for such work in the future. PMID- 23731617 TI - Synchrotron microbeam radiation therapy induces hypoxia in intracerebral gliosarcoma but not in the normal brain. AB - PURPOSE: Synchrotron microbeam radiation therapy (MRT) is an innovative irradiation modality based on spatial fractionation of a high-dose X-ray beam into lattices of microbeams. The increase in lifespan of brain tumor-bearing rats is associated with vascular damage but the physiological consequences of MRT on blood vessels have not been described. In this manuscript, we evaluate the oxygenation changes induced by MRT in an intracerebral 9L gliosarcoma model. METHODS: Tissue responses to MRT (two orthogonal arrays (2 * 400Gy)) were studied using magnetic resonance-based measurements of local blood oxygen saturation (MR_SO2) and quantitative immunohistology of RECA-1, Type-IV collagen and GLUT-1, marker of hypoxia. RESULTS: In tumors, MR_SO2 decreased by a factor of 2 in tumor between day 8 and day 45 after MRT. This correlated with tumor vascular remodeling, i.e. decrease in vessel density, increases in half-vessel distances (*5) and GLUT-1 immunoreactivity. Conversely, MRT did not change normal brain MR_SO2, although vessel inter-distances increased slightly. CONCLUSION: We provide new evidence for the differential effect of MRT on tumor vasculature, an effect that leads to tumor hypoxia. As hypothesized formerly, the vasculature of the normal brain exposed to MRT remains sufficiently perfused to prevent any hypoxia. PMID- 23731618 TI - CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma. AB - Signaling lymphocytic activation molecule (SLAM) family receptors have been implicated in normal immunity, immunodeficiencies and autoimmunity. CS1 (also known as CRACC, CD319 and SLAMF7) is a member of the SLAM family expressed on several normal hematopoietic cell types. It is also highly and nearly universally expressed on multiple myeloma (MM) cells. This review focuses on the biology of CS1, both in normal hematopoietic cells and in MM cells. It also discusses the preclinical and clinical data on the use of a humanized anti-CS1 monoclonal antibody, elotuzumab, for the treatment of MM. Based on current knowledge, CS1 is a compelling new target for the treatment of MM. PMID- 23731619 TI - Energy management - a critical role in cancer induction? AB - The variety of genes implicated in cancer induction is extensive but paradoxically all cancer cells behave in an identical and highly predictable fashion. This behaviour is closely correlated with a group of cellular morphological criteria termed Anaplasticity which involves increases/changes in: motility; invasion; replication; nuclear and chromosomal fragmentation; structural degradation; and phenotypic fluidity. Anaplasticity is so predictive it is a universal clinical yardstick for assessment and treatment. To understand this paradox, perceived mechanisms of cancer induction are reviewed and a new proposal made, namely that cancer is a diversion of energy required for structural organisation into maximum energy dissipation (entropy) through increased dynamic activities. This process is driven by oncogenic mutations or a variety of other permanent molecular alterations which re-direct "channels" distributing energy dissipation. These are organised along fractal networks (Fractal Entropy) and are not necessarily structure-dependent. "Oncogenic" alterations of any kind create cumulative effects by permanently stabilising parts of the fractal network, resulting in fractured co-ordination and re direction of entropy into increased dynamic activity, which is the universal hallmark of cancer. The mechanism of Fractal Entropy employs Chaos and Fractal theories and is illustrated with Mandelbrot figures for fractal distributions and Chaos theory for its influence in creating fractal distributions and their behaviours. The proposal is examined in an in vitro heamatopoietic model (IL3 dependent cells) concerning regulation by growth factors of metabolism, apoptosis, oncogenesis and cell dormancy, and suggests new avenues of multi disciplinary research. Summary While a genetic basis for cancer is well established, the mechanism(s) by which it is induced remain obscure. Paradoxically, although the spectrum of oncogenic mutations is extremely wide, all cancer cells universally exhibit a characteristic profile regardless of origin, whose progression is extremely predictable: increased proliferation, invasion and migration, loss in architectural integrity (anaplasticity), apoptotic inactivation etc. To understand this discrepancy, an extensive review was performed from the standpoint that since all oncogenes directly or indirectly alter enzyme pathways which control energy management, this may be a critical component of the induction process; alterations in management divert energy away from the construction and maintenance of stable complex structure into dynamic activity such as continuing replication, motility and migration, and architectural fluidity, ie. anaplasticity. This diversion would flow from the laws of thermodynamics which require energy to be dissipated (entropy). The review prompted a model (Fractal Entropy) whereby cellular entropic dissipation follows structure-independent fractal distributions rather than the linearly ordered, sequential pathways currently modelled for signal transduction. "Malignant" behaviour arises from disturbances which bias this fractal network to achieve maximum entropy. Because replication, motility and architectural plasticity all actively dissipate more energy through kinetic activity than by structure-building in which energy becomes "locked in", these routes are preferred eventually generating a universal malignant phenotype independent of the types of mutations and pathways initially affected. A proposed mechanism for the model is based on Chaos and Fractal theories illustrated in the Appendix. These present examples of dynamic fractal behaviour through Mandelbrot figures and of how Chaos theory can initiate and guide distribution of entropy fractals. This proposal accords fully with established physical laws and the most recent research, and reconciles many of the unresolved problems concerning genetic heterogeneity, the universality of malignant cell behaviour, cancer progression, and the well-known, but still unexplained, metabolic Warburg effect. An established in vitro cell model offers evidence for the hypothesis which suggests new directions for multi-disciplinary research into the origin of cancer. PMID- 23731621 TI - Assessment of using fingerstick blood sample with i-STAT point-of-care device for cardiac troponin I assay. AB - PURPOSES: The purpose of this study is to compare fingerstick point-of-care (POC) testing for cardiac troponin I to conventional venipuncture POC testing using the i-STAT device. BASIC PROCEDURES: This study was conducted with institutional review board approval in the emergency department (ED) of a 535-bed suburban level I trauma center from June to August 2011. Fingerstick blood samples were collected from consenting patients for whom standard-of-care venipuncture POC troponin (POCT) testing had been ordered as part of their workup. Cardiac troponin I (cTnI) assays were performed using the i-STAT 1 device (Abbott Point of Care, Princeton, NJ). The data were subjected to categorical comparison, linear regression, and Bland-Altman agreement analysis using SAS 9.2 software (SAS, Cary, NC). MAIN FINDINGS: Eighty-nine cTnI levels were measured by both fingerstick and standard venipuncture ED POC testing. Four resulted in cartridge error; the remaining 85 were analyzed. Fingerstick testing, compared with standard ED POCT, has a positive predictive value of 1.00 (0.48, 1.00), negative predictive value of 0.96 (0.89, 0.99), sensitivity of 0.625 (0.24, 0.91), and specificity of 1.00 (0.95, 1.00). The relationship between methods appears linear, with linear regression equation ED POCT level = 0.0062 + 1.3752 * fingerstick level (P < 0.0001). Bland-Altman agreement analysis yielded a mean difference between fingerstick and ED POCT of -0.0095 with limits of agreement of -0.0625 to 0.0435. PRINCIPAL CONCLUSIONS: Fingerstick cTnI testing using the i STAT device is not accurate enough to determine the exact troponin level without the application of a corrective term. Fingerstick testing is, however, accurate in qualifying troponin levels as negative, borderline, or positive and is, therefore, capable of providing clinical information that may guide diagnostic and therapeutic decision making. PMID- 23731622 TI - Increased body mass index makes an impact on brain white-matter integrity in adults with remitted first-episode mania. AB - BACKGROUND: Obesity is increasingly prevalent in bipolar disorder (BD) but data about the impact of elevated body mass index (BMI) on brain white-matter integrity in BD are sparse. Based on extant literature largely from structural magnetic resonance imaging (MRI) studies, we hypothesize that increased BMI is associated with decreased fractional anisotropy (FA) in the frontal, temporal, parietal and occipital brain regions early in the course of BD. METHOD: A total of 26 euthymic adults (12 normal weight and 14 overweight/obese) with remitted first-episode mania (FEM) and 28 controls (13 normal weight and 15 overweight/obese) matched for age, handedness and years of education underwent structural MRI and diffusion tensor imaging scans. RESULTS: There are significant effects of diagnosis by BMI interactions observed especially in the right parietal lobe (adjusted F(1,48) = 5.02, p = 0.030), occipital lobe (adjusted F(1,48) = 10.30, p = 0.002) and temporal lobe (adjusted F(1,48) = 7.92, p = 0.007). Specifically, decreased FA is found in the right parietal (F(1,48) = 5.864, p = 0.023) and occipital lobes (F(1,48) = 4.397, p = 0.047) within overweight/obese patients compared with normal-weight patients with FEM. Compared with overweight/obese controls, decreased FA is observed in right parietal (F(1,48) = 6.708, p = 0.015), temporal (F(1,48) = 10.751, p = 0.003) and occipital (F(1,48) = 9.531, p = 0.005) regions in overweight/obese patients with FEM. CONCLUSIONS: Our findings suggest that increased BMI affects temporo parietal-occipital brain white-matter integrity in FEM. This highlights the need to further elucidate the relationship between obesity and other neural substrates (including subcortical changes) in BD which may clarify brain circuits subserving the association between obesity and clinical outcomes in BD. PMID- 23731623 TI - Miniaturized cardiopulmonary bypass: the Hammersmith technique. AB - BACKGROUND: Conventional Cardiopulmonary Bypass (cCPB) is a trigger of systemic inflammatory reactions, hemodilution, coagulopathy, and organ failure. Miniaturised Cardiopulmonary Bypass (mCPB) has the potential to reduce these deleterious effects. Here, we describe our standardised 'Hammersmith' mCPB technique, used in all types of adult cardiac operations including major aortic surgery. METHODS: The use of mCPB remains limited by the diversity of technologies which range from extremely complex, micro systems to ones very similar to cCPB. Our approach is designed around the principle of balancing the benefits of miniaturisation; reducing foreign surface area while maintaining patient safety. RESULTS: From January 2010 to March 2011, a single surgeon performed 184 consecutive operations (Euro score Logistic 8.4+/-9.9): 61 aortic valve replacements, 78 CABGs, 25 aortic valve replacement and CABG and 17 other procedures (major aortic surgery, re-do operations or double/triple valve replacements).Our clinical experience suggests that: i. Venous drainage is optimally maintained using kinetic energy. ii. Venous collapse pressure depends on the patient's anatomy and cannula size, but most importantly on the negative pressure generated by venous drainage. iii. The patient-prime interaction is optimised with antegrade and retrograde autologous priming, which mixes the blood and prime away from the tissues and results in a reduced oncotic destabilization. iv. mCPB is a safe and reproducible technique CONCLUSION: The Hammersmith mCPB is a "next generation" system which uses standard commercially available components. It aims to maintain safety margin and the benefit of miniaturised system whilst reducing the human factor demands. PMID- 23731620 TI - Genome-wide approaches for identifying genetic risk factors for osteoporosis. AB - Osteoporosis, the most common type of bone disease worldwide, is clinically characterized by low bone mineral density (BMD) and increased susceptibility to fracture. Multiple genetic and environmental factors and gene-environment interactions have been implicated in its pathogenesis. Osteoporosis has strong genetic determination, with the heritability of BMD estimated to be as high as 60%. More than 80 genes or genetic variants have been implicated in risk of osteoporosis by hypothesis-free genome-wide studies. However, these genes or genetic variants can only explain a small portion of BMD variation, suggesting that many other genes or genetic variants underlying osteoporosis risk await discovery. Here, we review recent progress in genome-wide studies of osteoporosis and discuss their implications for medicine and the major challenges in the field. PMID- 23731624 TI - Natural Plasmodium infection in monkeys in the state of Rondonia (Brazilian Western Amazon). AB - BACKGROUND: Simian malaria is still an open question concerning the species of Plasmodium parasites and species of New World monkeys susceptible to the parasites. In addition, the lingering question as to whether these animals are reservoirs for human malaria might become important especially in a scenario of eradication of the disease. To aid in the answers to these questions, monkeys were surveyed for malaria parasite natural infection in the Amazonian state of Rondonia, Brazil, a state with intense environmental alterations due to human activities, which facilitated sampling of the animals. METHODS: Parasites were detected and identified in DNA from blood of monkeys, by PCR with primers for the 18S rRNA, CSP and MSP1 genes and sequencing of the amplified fragments. Multiplex PCR primers for the 18S rRNA genes were designed for the parasite species Plasmodium falciparum and Plasmodium vivax, Plasmodium malariae/Plasmodium brasilianum and Plasmodium simium. RESULTS: An overall infection rate of 10.9% was observed or 20 out 184 monkey specimens surveyed, mostly by P. brasilianum. However, four specimens of monkeys were found infected with P. falciparum, two of them doubly infected with P. brasilianum and P. falciparum. In addition, a species of monkey of the family Aotidae, Aotus nigriceps, is firstly reported here naturally infected with P. brasilianum. None of the monkeys surveyed was found infected with P. simium/P. vivax. CONCLUSION: The rate of natural Plasmodium infection in monkeys in the Brazilian state of Rondonia is in line with previous surveys of simian malaria in the Amazon region. The fact that a monkey species was found that had not previously been described to harbour malaria parasites indicates that the list of monkey species susceptible to Plasmodium infection is yet to be completed. Furthermore, finding monkeys in the region infected with P. falciparum clearly indicates parasite transfer from humans to the animals. Whether this parasite can be transferred back to humans and how persistent the parasite is in monkeys in the wild so to be efficient reservoirs of the disease, is yet to be evaluated. Finding different species of monkeys infected with this parasite species suggests indeed that these animals can act as reservoirs of human malaria. PMID- 23731626 TI - Case studies of mental models in home heat control: searching for feedback, valve, timer and switch theories. AB - An intergroup case study was undertaken to determine if: 1) There exist distinct mental models of home heating function, that differ significantly from the actual functioning of UK heating systems; and 2) Mental models of thermostat function can be categorized according to Kempton's (1986) valve and feedback shared theories, and others from the literature. Distinct, inaccurate mental models of the heating system, as well as thermostat devices in isolation, were described. It was possible to categorise thermostat models by Kempton's (1986) feedback shared theory, but other theories proved ambiguous. Alternate control devices could be categorized by Timer (Norman, 2002) and Switch (Peffer et al., 2011) theories. The need to consider the mental models of the heating system in terms of an integrated set of control devices, and to consider user's goals and expectations of the system benefit, was highlighted. The value of discovering shared theories, and understanding user mental models, of home heating, are discussed with reference to their present day relevance for reducing energy consumption. PMID- 23731625 TI - The effect of depression symptoms and social support on black-white differences in health-related quality of life in early pregnancy: the health status in pregnancy (HIP) study. AB - BACKGROUND: Lower physical and social functioning in pregnancy has been linked to an increased risk of preterm delivery and low birth weight infants, butt few studies have examined racial differences in pregnant women's perception of their functioning. Even fewer studies have elucidated the demographic and clinical factors contributing to racial differences in functioning. Our objective was to determine whether there are racial differences in health-related quality of life (HRQoL) in early pregnancy; and if so, to identify the contributions of socio demographic characteristics, depression symptoms, social support and clinical factors to these differences. METHODS: Cross-sectional study of 175 women in early pregnancy attending prenatal clinics in urban setting. In multivariate analysis, we assessed the independent relation of black race (compared to white) to HRQoL scores from the eight domains of the Medical Outcomes (SF-36) SURVEY: Physical Functioning, Role-Physical, Bodily Pain, Vitality, General Health, Social Functioning, Role-Emotional, and Mental Health. We compared socio demographic and clinical factors and depression symptoms between black and white women and assessed the relative importance of these factors in explaining racial differences in physical and social functioning. RESULTS: Black women comprised 59% of the sample; white women comprised 41%. Before adjustment, black women had scores that were 14 points lower in Physical Function and Bodily Pain, 8 points lower in General Health, 4 points lower in Vitality and 7 points lower in Social Functioning. After adjustment for depression symptoms, social support and clinical factors, black women still had HRQoL scores that were 4 to 10 points lower than white women, but the differences were no longer statistically significant. Level of social support and payment source accounted for most of the variation in Physical Functioning, Bodily Pain and General Health. Social support accounted for most of the differences in Vitality and Social Functioning. CONCLUSIONS: Payment source and social support accounted for much of the racial differences in physical and social function scores. Efforts to reduce racial differences might focus on improving social support networks and Socio-economic barriers. PMID- 23731627 TI - Effects of child restraint system features on installation errors. AB - This study examined how child restraint system (CRS) features contribute to CRS installation errors. Sixteen convertible CRS, selected to include a wide range of features, were used in volunteer testing with 32 subjects. Subjects were recruited based on their education level (high or low) and experience with installing CRS (none or experienced). Each subject was asked to perform four child restraint installations in the right-rear passenger seat of a 2006 Pontiac G6 sedan using a crash dummy as a child surrogate. Each subject installed two CRS forward-facing (FF), one with LATCH and one with the vehicle seatbelt, and two CRS rear-facing (RF), one with LATCH and one with the seatbelt. After each installation, the experimenter evaluated 42 factors for each installation, such as choice of belt routing path, tightness of installation, and harness snugness. Analyses used linear mixed models to identify CRS installation outcomes associated with CRS features. LATCH connector type, LATCH strap adjustor type, and the presence of belt lockoffs were associated with the tightness of the CRS installation. The type of harness shoulder height adjuster was associated with the rate of achieving a snug harness. Correct tether use was associated with the tether storage method. In general, subject assessments of the ease-of-use of CRS features were not highly correlated with the quality of their installation, suggesting a need for feedback with incorrect installations. The data from this study provide quantitative assessments of some CRS features that were associated with reductions in CRS installation errors. These results provide child restraint designers with design guidelines for developing easier-to-use products. Research on providing effective feedback during the child restraint installation process is recommended. PMID- 23731628 TI - Lineages of Streptococcus equi ssp. equi in the Irish equine industry. AB - BACKGROUND: Streptococcus equi ssp. equi is the causative agent of 'Strangles' in horses. This is a debilitating condition leading to economic loss, yard closures and cancellation of equestrian events. There are multiple genotypes of S. equi ssp. equi which can cause disease, but to date there has been no systematic study of strains which are prevalent in Ireland. This study identified and classified Streptococcus equi ssp. equi strains isolated from within the Irish equine industry. RESULTS: Two hundred veterinary isolates were subjected to SLST (single locus sequence typing) based on an internal sequence from the seM gene of Streptococcus equi ssp equi. Of the 171 samples which successfully gave an amplicon, 162 samples (137 Irish and 24 UK strains) gave robust DNA sequence information. Analysis of the sequences allowed division of the isolates into 19 groups, 13 of which contain at least 2 isolates and 6 groups containing single isolates. There were 19 positions where a DNA SNP (single nucleotide polymorphism) occurs, and one 3 bp insertion. All groups had multiple (2-8) SNPs. Of the SNPs 17 would result in an amino acid change in the encoded protein. Interestingly, the single isolate EI8, which has 6 SNPs, has the three base pair insertion which is not seen in any other isolate, this would result in the insertion of an Ile residue at position 62 in that protein sequence. Comparison of the relevant region in the determined sequences with the UK Streptococcus equi seM MLST database showed that Group B (15 isolates) and Group I (2 isolates), as well as the individual isolates EI3 and EI8, are unique to Ireland, and some groups are most likely of UK origin (Groups F and M), but many more probably passed back and forth between the two countries. CONCLUSIONS: The strains occurring in Ireland are not clonal and there is a considerable degree of sequence variation seen in the seM gene. There are two major clades causing infection in Ireland and these strains are also common in the UK. PMID- 23731629 TI - MF59-adjuvanted and virosomal influenza vaccines for preventing influenza hospitalization in older people: comparative effectiveness using the Valencia health care information system. AB - BACKGROUND: Adjuvanted influenza vaccines offer greater and broader immunogenicity to older adults than conventional vaccines. Studies assessing the comparative effectiveness of adjuvanted influenza vaccines in this age group are lacking. METHODS: We conducted a retrospective cohort study to estimate the comparative effectiveness of MF59-adjuvanted trivalent influenza vaccine (TIV) and virosomal-TIV for prevention of influenza hospitalization in adults aged >=65 years. We obtained administrative data on immunization status and influenza hospitalization for the 2010-2011 influenza season. We used Cox regression models to assess comparative effectiveness; crude and adjusted by age, sex, comorbidity, deprivation, type of insurance, and travel time to hospital. We accounted for data clustering at the hospital level by using a multilevel random effects model. RESULTS: Overall, 373,798 vaccinated subjects were evaluated. There were 40 hospitalizations for influenza among 176,618 subjects, contributing 4,288,109 person-weeks at risk in the virosomal-TIV group, and 37 hospitalizations for influenza among 197,180 subjects, contributing 4,786,360 person-weeks at risk in the MF59-TIV group. The crude hazard ratio (HR) was 0.83 (0.53-1.30), and the adjusted Cox estimated HR of MF59-TIV relative to virosomal-TIV was 0.86 (0.55 1.35). After accounting for data clustering, the HR of influenza hospitalization associated with MF59-TIV relative to virosomal-TIV was 0.94 (0.37-2.38). CONCLUSION: During the 2010-2011 influenza season, we found no differences in the risk of influenza hospitalization in subjects aged >=65 years vaccinated with MF59-TIV compared with those vaccinated with virosomal-TIV. PMID- 23731630 TI - Bordetella pertussis iron regulated proteins as potential vaccine components. AB - Bordetella pertussis is the etiologic agent of whooping cough, an illness whose incidence has been increasing over the last decades. Pertussis reemergence despite high vaccination coverage, together with the recent isolation of circulating strains deficient in some of the vaccine antigens, highlight the need for new vaccines. Proteins induced under physiological conditions, such as those required for nutrient acquisition during infection, might represent good targets for better preventive strategies. By mean of serological proteome analysis we identified two novel antigens of B. pertussis potentially involved in iron acquisition during host colonization. We had previously demonstrated that one of them, designated IRP1-3, is protective against pertussis infection in mice. In the present study, we show that the other antigen, named AfuA (BP1605), is a highly antigenic protein, exposed on the bacterial surface, conserved among clinical isolates and expressed during infection. Immunization of mice with the recombinant AfuA induced opsonophagocytic antibodies which could explain the protection against B. pertussis infection conferred by mice immunization with rAfuA. Importantly, we found that the addition of rAfuA and rIRP1-3 proteins to the commercial three pertussis components acellular vaccine significantly increased its protective activity. Taken together, our results point at these two antigens as potential components of a new generation of acellular vaccines. PMID- 23731631 TI - Immunogenicity and safety of the vaccinia virus LC16m8Delta vector expressing SIV Gag under a strong or moderate promoter in a recombinant BCG prime-recombinant vaccinia virus boost protocol. AB - We compared the effect of the very strong pSFJ1-10 and moderately strong p7.5 promoters on the immunogenicity and pathogenicity of the replication-competent vaccinia virus (VV) LC16m8Delta (m8Delta) vector harboring the SIV gag gene in a vaccination regimen consisting of a recombinant BCG-SIVGag (rBCG-SIVGag) prime followed by a recombinant vaccinia boost. m8Delta/pSFJ/SIVGag synthesized more Gag protein than m8Delta/p7.5/SIVGag but replicated less efficiently in vitro. In addition, m8Delta/pSFJ/SIVGag was less pathogenic and elicited Gag-specific IFN gamma(+), CD107a(+), CD8(+) cells more efficiently than m8Delta/p7.5/SIVGag. Vaccination by this regimen elicited long-lasting Gag-specific CD8(+) T cells, the majority of which showed a CCR7(-) phenotype at over 8 weeks post-boost. Tetramer staining analyses revealed maintenance of Gag specific tetramer(+), CD62L(-), CD8(+) T cells for long time in vaccinated mice. However, Gag expression increased the neurotoxicity of the vaccinia vector, indicating the necessity of safety testing for each recombinant VV. We propose that this recombinant BCG prime-m8Delta/pSFJ/HIVGag boost regimen would be a promising vaccination procedure for preventing HIV infection. PMID- 23731632 TI - Coronary vasculitis associated with T-cell prolymphocytic leukemia. PMID- 23731633 TI - Overdiagnosing early spondyloarthritis: what are the risks? PMID- 23731634 TI - Online home self-assessment: a tool for improving future treatment trials... and daily practice: comments on the editorial by Berthelot JM, et al. "Online home self-assessment: a tool for improving future treatment trials?", Joint Bone Spine 2013;80:5-7. PMID- 23731635 TI - Osteoclasts in RA: diverse origins and functions. AB - Osteoclasts were recognized in the late 1990s as the cells responsible for generalized and focal bone loss in rheumatoid arthritis (RA). Concepts about osteoclast biology have changed radically based on recent evidence of considerable diversity in both the origins and the functions of osteoclasts. In addition, the role for osteoclasts is not confined to bone resorption but may also include active contributions to inflammatory and autoimmune responses. Thus, in RA, osteoclast progenitors may arise from both circulating cells and cells developed within the rheumatoid synovium or subchondral bone. Within the inflamed synovium, osteoclasts are activated by factors such as cytokines, immune complexes, or activators of the toll-like receptors, which are not found in healthy bone tissue. Finally, recent data suggest that osteoclasts may be capable of antigen presentation to T cells via major histocompatibility complex class I and class II molecules. Confirmation of this suggestion by future studies would indicate that osteoclasts might be involved not only in bone resorption, but also in autoimmune responses and antigen presentation. These data highlight the considerable complexity of interactions between bone tissue and the immune system. Research into these interactions may identify new targets for treatments against the bone abnormalities associated with chronic inflammatory disease. PMID- 23731636 TI - Usefulness and limitations of rapid urine dipstick testing for joint-fluid analysis. Prospective single-center study of 98 specimens. AB - OBJECTIVE: To evaluate the diagnostic performance of rapid urine reagent strip testing of joint fluid in separating mechanical from inflammatory disease. METHODS: In a prospective single-center 12-month study of joint fluid specimens, leukocyte esterase reagent strip testing (LERST) was compared to leukocyte counts used as the reference standard. Leukocyte counts greater than 2000/mm(3) were taken to indicate inflammation. Reproducibility of LERST was evaluated by testing 73 specimens twice and computing Cohen's kappa coefficient. RESULTS: Ninety-eight joint fluid specimens (26 with mechanical and 72 with inflammatory characteristics) were evaluated. LERST had 79.2% sensitivity, 92.3% specificity, 96.6% positive predictive value, 61.5% negative predictive value, a positive likelihood ratio of 10.3, and a negative likelihood ratio of 0.23. The kappa coefficient was 0.70 (0.53-0.87). Two negative LERSTs a few minutes apart had 80% negative predictive value and a negative likelihood ratio of 0.08. CONCLUSION: LERST of joint fluid is a rapid means of satisfactorily separating mechanical from inflammatory joint fluids. PMID- 23731637 TI - Cardiovascular risk profile in patients with spondyloarthritis. AB - OBJECTIVES: The spondyloarthritides (SpA) are associated with an increased cardiovascular risk. We studied cardiovascular risk factors in patients with SpA. METHODS: The following risk factors were assessed in SpA patients and healthy controls: smoking, family history of premature ischemic heart disease, obesity, serum lipids, apolipoproteins, urate and carotid intima media thickness (IMT). RESULTS: Overall 150 patients (73 with ankylosing spondylitis [AS], 71 with psoriatic arthritis [PsA] and six with other SpA types) were included. Generally SpA patients were significantly more often smokers, while PsA patients had greater values of abdominal obesity. AS patients had significantly lower levels of triglyceride, HDL, ApoB, ApoE and Lp(a) and a higher atherogenic index (total cholesterol/HDL). PsA patients had significantly lower levels of HDL, ApoAI and ApoE, an elevated atherogenic index and higher serum urate. In multivariate analysis the atherogenic index was positively associated with SpA across all patient groups independently of smoking and other lipid parameters. Carotid IMT in SpA patients (0.71 mm) was higher than controls (0.63 mm, P=0.017), although after adjusting for smoking this ceased to be significant. Treatment of patients with previously untreated disease resulted in a small but significant decline in ApoB levels at 6 months (P=0.045), which, however, was no longer evident at 12 months. CONCLUSION: Spondyloarthritis patients are at a greater cardiovascular risk owing to the higher prevalence of smoking and a higher atherogenic index. PsA patients have more abdominal fat and higher urate levels. Immunosuppressive treatment of SpA produces minor and temporary effects on the lipid profile. PMID- 23731638 TI - Predictors of response to anti-TNF therapy in RA patients with moderate or high DAS28 scores. AB - OBJECTIVES: To identify the clinical factors predicting a good clinical response to anti-TNF therapy in rheumatoid arthritis (RA) patients entered in the LORHEN registry after 5years of treatment with anti-TNF agents and divided into two groups on the basis of their baseline DAS28 scores (moderate>3.2-5.1 [MDA] and high>5.1 [HDA]). METHODS: Disease activity at baseline and after 12months was assessed using the DAS28, and response was evaluated using the EULAR improvement criteria. RESULTS: The study involved 1300 patients with established RA: 975 with HDA and 325 with MDA. After a mean 36-month, 29.6% of the patients had a DAS28 score of less or equal to 2.6 (HDA 25.8% vs. MDA 43.0%; P<0.001) and were considered to be in remission. A higher probability of a good EULAR response in patients with HDA was associated with male gender (F vs. M - OR 0.45, 95% CI 0.26 0.78; P: 0.004), lower age at the start of treatment (OR 0.98, 95% CI 0.96-0.99; P: 0.002), the absence of comorbidities (OR 0.18, 95% CI 0.06-0.52; P: 0.002) or no previous use of corticosteroids (OR 1.92, 95% CI 1.14-3.22; P: 0.015) and the use of adalimumab vs. infliximab (OR 2.21, 95% CI 1.37-3.57; P 0.001); in patients with MDA, the probability of a good EULAR response was associated with male gender (F vs. M - OR 0.39, 95% CI 0.17-0.90; P: 0.027). CONCLUSIONS: With the exception of male gender, the factors predicting a good EULAR response are different in patients with MDA and those with HDA. PMID- 23731639 TI - Psoriasis onset with tocilizumab. PMID- 23731640 TI - Avascular necrosis in a patient with systemic lupus erythematosus. PMID- 23731641 TI - Association of microRNAs genes polymorphisms with rheumatoid arthritis in Egyptian female patients. AB - OBJECTIVE: To investigate whether miRNA-499 (rs3746444) and miRNA-146a (rs2910164) genes polymorphisms are independent factors for rheumatoid arthritis (RA) in Egyptians, and whether they influence disease severity and activity. METHODS: Two hundred and seventeen RA patients and 245 healthy controls were enrolled in this study. Polymorphisms of miRNA-146a and miRNA-499 genes were detected using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS: The miRNA-499 CT genotype was an independent factor of RA. The miRNA-499 CT, CC genotypes and C allele frequencies were significantly increased in erosive RA group. Moreover, the heterozygote CT had more severe and more active form of the disease compared with homozygote CC or TT. However, we did not find any significant association of miRNA-146a polymorphism with RA risk, severity, and activity. CONCLUSION: The miRNA-499 polymorphism is an independent factor of RA, and influences disease severity and activity. PMID- 23731642 TI - Coexistence of seropositive rheumatoid arthritis and SAPHO syndrome. PMID- 23731643 TI - WITHDRAWN: Ivory vertebra and systemic mastocytosis. Comments on the article by Frenzel et al. AB - L'editeur a le regret de vous informer que cet article ayant deja ete publie dans: , 80/5 (2013) 553-554, doi:10.1016/< S1297 319X(13)00186-3 >, cette seconde publication faite par erreur a ete retiree. PMID- 23731644 TI - Rheumatoid factor and response to TNF antagonists in rheumatoid arthritis: systematic review and meta-analysis of observational studies. AB - OBJECTIVE: To systematically analyze literature with the aim of examining whether rheumatoid factor (RF) is a predictor of response to tumor necrosis factor (TNF) antagonists in rheumatoid arthritis (RA). METHODS: A systematic review and meta analysis of observational studies were conducted. All studies on the association of baseline RF (titer and/or status) and response to any TNF antagonists, or with enough information to estimate this association were included. Qualitative analysis and meta-analysis using random-effects approach by type of outcome response and RF test was performed. Risk of publication bias was also evaluated. RESULTS: The systematic review included 18 studies of 4163 identified articles, involving 5703 patients with homogeneous baseline characteristics. The most common outcome to assess response was European League Against Rheumatism (EULAR) response criteria, normally merging good and moderate categories as response. The weighted mean difference (WMD) of baseline IgM RF titer in meta-analysis was higher in the non-responders group [-101.58 (95% CI -156.58,-46.59) I2=0.0]. Combined odds ratios (ORs) of positive IgM RF, positive IgA RF, and positive IgG RF to achieve good/moderate response were 1.08 (0.80, 1.47), I2=40.9%; 0.83 (0.39, 1.73), I2=39.8%, and 1.30 (0.48, 3.51), I2=62.9%, respectively. We did not find an association between a positive IgM RF and EULAR good response or remission. CONCLUSIONS: This meta-analysis does not support baseline IgM RF titer as a predictor of response to TNF antagonists in RA. However, this conclusion is hampered by high heterogeneity in the studies included in this meta-analysis. PMID- 23731645 TI - Pathogenesis of hyperostosis: a key role for mesenchymatous cells? AB - The similarities between diffuse idiopathic skeletal hyperostosis (DISH) and some forms of ankylosing spondylitis suggest shared pathogenic mechanisms. Entheseal ossification progresses at the same rate in the two conditions, and spondyloarthritis was the first diagnosis considered in several families with genetically determined early-onset DISH. However, DISH may be a heterogeneous condition, as the presence of peripheral calcifications in some families suggests pathogenic similarities with several animal models combining entheseal ossification and peripheral calcifications, as well as with X-linked familial hypophosphatemia and dentin-matrix-protein mutations. In the far more common presentation of hyperostosis without calcifications, entheseal ossification may be related to abnormal osteoblastic differentiation of mesenchymatous stem cells normally found around the intervertebral disks, in the vertebral periosteum, and in the anterior and posterior longitudinal ligaments. The many factors suspected of promoting this abnormal differentiation include bone morphogenetic proteins (BMPs), retinoids, and various hormonal factors; in addition, adipokines such as leptin are the focus of growing interest based on the well-documented association between DISH and obesity. Confirmation of the role for mesenchymatous cells in DISH should encourage investigations of mesenchymatous cells as possible pathogenic contributors to the entheseal abnormalities seen in spondyloarthritis. These cells normally exert immunosuppressive effects, which may be subverted in spondyloarthritis, notably by a T-cell population that homes specifically to the entheses. PMID- 23731646 TI - Adolescents and mothers value referral to a specialist service for chronic fatigue syndrome or myalgic encephalopathy (CFS/ME). AB - BACKGROUND: Paediatric chronic fatigue syndrome or myalgic encephalopathy (CFS/ME) is relatively common and disabling. Current guidance recommends referral to specialist services, although some general practitioners believe the label of CFS/ME is harmful and many are not confident about diagnosing CFS/ME. Aim Explore whether or not adolescents and their mothers value referral to a specialist service for young people with CFS/ME. METHODS: A qualitative study nested within a feasibility study of interventions for CFS/ME [Specialist Medical Intervention and Lightning Evaluation (SMILE)]. In-depth interviews were undertaken with 13 mothers and 12 adolescents participating in the SMILE study. Transcripts were systematically assigned codes using the qualitative data organisation package NVivo and analysed thematically using techniques of constant comparison. RESULTS: Gaining access to the specialist service was difficult and took a long time. Mothers felt that they needed to be proactive and persistent, partly because of a lack of knowledge in primary and secondary care. Having gained access, mothers felt the CFS/ME service was useful because it recognised and acknowledged their child's condition and opened channels of dialogue between health-care professionals and education providers. Adolescents reported that specialist medical care resulted in better symptom management, although some adolescents did not like the fact that the treatment approach limited activity. CONCLUSIONS: Adolescents and their mothers value receiving a diagnosis from a specialist service and making progress in managing CFS/ME. General practitioners should support adolescents with CFS/ME in accessing CFS/ME specialist services, consistent with current guidance. PMID- 23731647 TI - Chemoradiotherapy for N2 head and neck squamous cell carcinoma - outcomes without a planned neck dissection: our experience in two hundred and seven patients. PMID- 23731648 TI - International aspirations for speech-language pathologists' practice with multilingual children with speech sound disorders: development of a position paper. AB - A major challenge for the speech-language pathology profession in many cultures is to address the mismatch between the "linguistic homogeneity of the speech language pathology profession and the linguistic diversity of its clientele" (Caesar & Kohler, 2007, p. 198). This paper outlines the development of the Multilingual Children with Speech Sound Disorders: Position Paper created to guide speech-language pathologists' (SLPs') facilitation of multilingual children's speech. An international expert panel was assembled comprising 57 researchers (SLPs, linguists, phoneticians, and speech scientists) with knowledge about multilingual children's speech, or children with speech sound disorders. Combined, they had worked in 33 countries and used 26 languages in professional practice. Fourteen panel members met for a one-day workshop to identify key points for inclusion in the position paper. Subsequently, 42 additional panel members participated online to contribute to drafts of the position paper. A thematic analysis was undertaken of the major areas of discussion using two data sources: (a) face-to-face workshop transcript (133 pages) and (b) online discussion artifacts (104 pages). Finally, a moderator with international expertise in working with children with speech sound disorders facilitated the incorporation of the panel's recommendations. The following themes were identified: definitions, scope, framework, evidence, challenges, practices, and consideration of a multilingual audience. The resulting position paper contains guidelines for providing services to multilingual children with speech sound disorders (http://www.csu.edu.au/research/multilingual-speech/position-paper). The paper is structured using the International Classification of Functioning, Disability and Health: Children and Youth Version (World Health Organization, 2007) and incorporates recommendations for (a) children and families, (b) SLPs' assessment and intervention, (c) SLPs' professional practice, and (d) SLPs' collaboration with other professionals. LEARNING OUTCOMES: Readers will 1. recognize that multilingual children with speech sound disorders have both similar and different needs to monolingual children when working with speech language pathologists. 2. Describe the challenges for speech-language pathologists who work with multilingual children. 3. Recall the importance of cultural competence for speech-language pathologists. 4. Identify methods for international collaboration and consultation. 5. Recognize the importance of engaging with families and people within their local communities for supporting multilingual children in context. PMID- 23731649 TI - Subpopulation-specific confidence designation for more informative biomedical classification. AB - OBJECTIVE: Although classification algorithms are promising tools to support clinical diagnosis and treatment of disease, the usual implicit assumption underlying these algorithms, that all patients are homogeneous with respect to characteristics of interest, is unsatisfactory. The objective here is to exploit the population heterogeneity reflected by characteristics that may not be apparent and thus not controlled, in order to differentiate levels of classification accuracy between subpopulations and further the goal of tailoring therapies on an individual basis. METHODS AND MATERIALS: A new subpopulation based confidence approach is developed in the context of a selective voting algorithm defined by an ensemble of convex-hull classifiers. Populations of training samples are divided into three subpopulations that are internally homogeneous, with different levels of predictivity. Two different distance measures are used to cluster training samples into subpopulations and assign test samples to these subpopulations. RESULTS: Validation of the new approach's levels of confidence of classification is carried out using six publicly available datasets. Our approach demonstrates a positive correspondence between the predictivity designations derived from training samples and the classification accuracy of test samples. The average difference between highest- and lowest confidence accuracies for the six datasets is 17.8%, with a minimum of 11.3% and a maximum of 24.1%. CONCLUSION: The classification accuracy increases as the designated confidence increases. PMID- 23731650 TI - Individual risk factors for Mycoplasma hyopneumoniae infections in suckling pigs at the age of weaning. AB - BACKGROUND: In recent years, the occurrence and the relevance of Mycoplasma hyopneumoniae infections in suckling pigs has been examined in several studies. Whereas most of these studies were focused on sole prevalence estimation within different age groups, follow-up of infected piglets or assessment of pathological findings, none of the studies included a detailed analysis of individual and environmental risk factors. Therefore, the aim of the present study was to investigate the frequency of M. hyopneumoniae infections in suckling pigs of endemically infected herds and to identify individual risk factors potentially influencing the infection status of suckling pigs at the age of weaning. RESULTS: The animal level prevalence of M. hyopneumoniae infections in suckling pigs examined in three conventional pig breeding herds was 3.6% (41/1127) at the time of weaning. A prevalence of 1.2% was found in the same pigs at the end of their nursery period. In a multivariable Poisson regression model it was found that incidence rate ratios (IRR) for suckling pigs are significantly lower than 1 when teeth grinding was conducted (IRR: 0.10). Moreover, high temperatures in the piglet nest during the first two weeks of life (occasionally >40 degrees C) were associated with a decrease of the probability of an infection (IRR: 0.23-0.40). Contrary, the application of PCV2 vaccines to piglets was associated with an increased infection risk (IRR: 9.72). CONCLUSIONS: Since single infected piglets are supposed to act as initiators for the transmission of this pathogen in nursery and fattening pigs, the elimination of the risk factors described in this study should help to reduce the incidence rate of M. hyopneumoniae infections and thereby might contribute to a reduced probability of high prevalences in older pigs. PMID- 23731651 TI - CCL17/thymus and activation-regulated chemokine induces calcitonin gene-related peptide in human airway epithelial cells through CCR4. AB - BACKGROUND: Calcitonin gene-related peptide (CGRP) is a potent arterial and venous vasodilator. Increased airway epithelial cell expression of CGRP, together with increased CCL17 expression, was previously observed in a model of provoked asthma in atopic human subjects. OBJECTIVE: We sought to determine whether CCL17 induces CCR4-dependent CGRP synthesis and secretion by human airway epithelial cells. METHODS: Human airway epithelial cell lines (BEAS-2B and A549) and human primary airway cells were cultured with CCL17 or various other cytokines, and CGRP expression was measured by using RT-PCR, quantitative immunofluorescence, and enzyme immunoassay. CCR4 expression was determined in cultured cells by using flow cytometry and in bronchial biopsy specimens by using immunohistochemistry. RESULTS: CCL17 induced a several thousand-fold increase in CGRP mRNA expression and released peptide product from BEAS-2B and A549 cells in a time- and concentration-dependent fashion. Concentration-dependent CCL17-induced release of CGRP by primary human airway epithelial cells was also observed. Under comparable conditions, CCL17 induced greater CGRP release from BEAS-2B cells than either IL 13, a cytokine mixture (TNF-alpha, GM-CSF, and IL-1), or CCL22. CCR4 was expressed by BEAS-2B and A549 cells and internalized after ligation with CCL17. CCL17-induced CGRP release was inhibited by a specific anti-CCR4 blocking antibody. Bronchial biopsy specimens obtained from healthy volunteers and asthmatic patients before and after provoked asthma all exhibited CCR4 staining of equivalent intensity, indicating that the receptor is constitutively expressed. CONCLUSIONS: CCL17-induced, CCR4-dependent release of CGRP by human airway epithelial cells represents a novel inflammatory pathway and a possible target in patients with asthma and allergic disease. PMID- 23731652 TI - Effects of short-chain fatty acids on Actinomyces naeslundii biofilm formation. AB - Actinomyces naeslundii is an early colonizer and has important roles in the development of the oral biofilm. Short-chain fatty acids (SCFA) are secreted extracellularly as a product of metabolism by gram-negative anaerobes, e.g. Porphyromonas gingivalis and Fusobacterium nucleatum; and the SCFA may affect biofilm development with interaction between A. naeslundii and gram-negative bacteria. Our aim was to investigate the effects of SCFA on biofilm formation by A. naeslundii and to determine the mechanism. We used the biofilm formation assay in 96-well microtiter plates in tryptic soy broth without dextrose and with 0.25% sucrose using safranin stain of the biofilm monitoring 492 nm absorbance. To determine the mechanism by SCFA, the production of chaperones and stress-response proteins (GrpE and GroEL) in biofilm formation was examined using Western blot fluorescence activity with GrpE and GroEL antibodies. Adding butyric acid (6.25 mm) 0, 6 and 10 h after beginning culture significantly increased biofilm formation by A. naeslundii, and upregulation was observed at 16 h. Upregulation was also observed using appropriate concentrations of other SCFA. In the upregulated biofilm, production of GrpE and GroEL was higher where membrane damaged or dead cells were also observed. The upregulated biofilm was significantly reduced by addition of anti-GroEL antibody. The data suggest biofilm formation by A. naeslundii was upregulated dependent on the production of stress proteins, and addition of SCFA increased membrane-damaged or dead cells. Production of GroEL may physically play an important role in biofilm development. PMID- 23731654 TI - Improved coverage and accuracy with strand-conserving sequence enrichment. AB - Targeted next-generation sequencing is becoming a common tool in the molecular diagnostic laboratory. However, currently available methods to enrich for regions of interest in the DNA sequence suffer from drawbacks such as high cost, complex protocols, lack of clinical-level accuracy and uneven target coverage. A target enrichment approach using complementary long padlock probes described in a recent article significantly improves on previous methods in most of these areas. SEE RELATED RESEARCH: http://genomemedicine.com/content/5/5/50. PMID- 23731653 TI - The issue of African ancestry in Caribbean Hispanics and salt sensitivity of blood pressure. PMID- 23731655 TI - Molecular cloning and biologically active production of IpaD N-terminal region. AB - Shigella is known as pathogenic intestinal bacteria in high dispersion and pathogenic bacteria due to invasive plasmid antigen (Ipa). So far, a number of Ipa proteins have been studied to introduce a new candidate vaccine. Here, for the first time, we examined whether the N-terminal region of IpaD(72-162) could be a proper candidate for Shigella vaccine. Initially, the DNA sequence coding N terminal region was isolated by PCR from Shigella dysenteriae type I and cloned into pET-28a expression vector. Then, the heterologous protein was expressed, optimized and purified by affinity Ni-NTA column. Western blot analysis using, His-tag and IpaD(72-162) polyclonal antibodies, confirmed the purity and specificity of the recombinant protein, respectively. Subsequently, the high immunogenicity of the antigen was shown by ELISA. The results of the sereny test in Guinea pigs showed that IpaD(72-162) provides a protective system against Shigella flexneri 5a and S. dysenteriae type I. PMID- 23731658 TI - Willow bark extract STW 33-I in the long-term treatment of outpatients with rheumatic pain mainly osteoarthritis or back pain. AB - STUDY OBJECTIVE: Efficacy and safety of willow bark extract for pain reduction in patients suffering from musculoskeletal disorders (MSD) has been shown in clinical short term trials. Therefore this observational study over 6 months should evaluate patterns of treatments like mono- or combinations therapy, dosage and safety during long-term treatment under pragmatic conditions with the aqueous willow bark extract STW 33-I, (Proaktiv((r)); drug-extract-ratio 16-23:1). PATIENTS AND METHODS: The patients were treated with STW 33-I; comedication with other NSAIDs and opioids was allowed. An extensive case report form including pain questionnaires and patient diary was used for outcome evaluation. RESULTS: Four hundred and thirty-six patients with rheumatic pain mainly due to osteoarthritis (56.2%) and back pain (59.9%) were included. During the study the mean reductions from baseline value 58.4+/-22.6-31.8+/-22.5 after 24 weeks in the pain intensity scale (VAS 0-100mm) were significant even after 3 weeks with a reduction by 26 mm (45.6% of the baseline value) at the end of the study. The relative reductions of the weekly means of the daily patient self-rated scores of the pain (6-point Likert-scales) were between 33% and 44% of the baseline values during the course of the study. We present results of subgroups according their analgetic/antiphlogistic comedication. The distribution and specification of the main adverse events and the ratings of the treatment showed a good tolerability. No relevant drug interactions were reported. CONCLUSION: These data suggest that STW 33-I can be used as a basic treatment in the long-term therapy of painful musculoskeletal disorders and that it can be combined with NSAIDs and opioids if necessary. PMID- 23731657 TI - In vitro to in vivo evidence of the inhibitor characteristics of Schisandra lignans toward P-glycoprotein. AB - Concomitant administration of herbal medicines with drugs that are P-glycoprotein (P-gp) substrates may produce significant herb-drug interactions. The purpose of this study was to evaluate the effects of Schisandra lignans extract (SLE) on P gp thoroughly in vitro and in vivo, and to investigate the possible P-gp-based herb-drug interactions. In the in vitro experiments, the effect of SLE on the uptake and transport for P-gp substrates in Caco-2, LLC-PK1 and L-MDR1 cells were carefully investigated. Verapamil, a known P-gp inhibitor, was used as a positive control drug. Results shown that, 10 MUM verapamil and SLE (0.5, 2.0, and 10.0 MUg/ml) were observed to significantly enhance the uptake and inhibit the efflux ratio of P-gp substrates in Caco-2 and L-MDR1 cells. In vivo experiments showed that single-dose SLE at 500 mg/kg could increase the area under the plasma concentration time curve of digoxin and vincrisine significantly without affecting terminal elimination half-time. Long-term treatment with SLE for continuous 10 days could also increase the absorption of P-gp substrates with greatly down regulation of P-gp expression in rat intestinal and brain tissues. In conclusion, SLE was a strong P-gp inhibitor, which indicated a potential herb drug interaction when SLE was co-administered with P-gp substrate drugs. PMID- 23731659 TI - Clinical and genetic evaluation of a Chinese family with isolated oligodontia. AB - OBJECTIVES: Oligodontia is defined as the congenital absence of 6 or more permanent teeth excluding the third molar. Tooth agenesis may be classified as syndromic/non-syndromic and as familial/sporadic. To date, more than 300 genes have been found to be involved in tooth development, but only a few of these genes, such as MSX1, PAX9 and AXIN2, are related to the condition of non syndromic oligodontia. The objective of the present work was to investigate the disease-causing gene of non-syndromic oligodontia in a Han Chinese family and analyse the pathogenesis of mutations that result in oligodontia. DESIGN: We examined all individuals of the oligodontia family by clinical and radiographic examinations. Based on the clinical manifestations, the candidate genes MSX, PAX9 and AXIN2 were selected to analyse and screen for mutations. RESULTS: The clinical evaluation suggested that the family might show non-syndromic oligodontia. DNA sequencing of the MSX1 gene revealed two mutations in the two patients with oligodontia: a heterozygotic silent mutation, c.348C>T (P.Gly116=), in exon 1 and a homozygotic deletion of 11 nucleotides (c.469+56delins GCCGGGTGGGG) in the intron. However, the silent mutation and the deletion mutation were thought to be known polymorphisms (rs34165410 and rs34341187) by bioinformatics analysis. We did not detect any mutations in the PAX9 and AXIN2 genes of oligodontia patients. CONCLUSION: Our finding suggests that identified polymorphisms (c.348C>T and c.469+56delins GCCGGGTGGGG) may be responsible for the oligodontia phenotype in this Chinese family, but the association requires further study. PMID- 23731660 TI - pLDH level of clinically isolated Plasmodium vivax and detection limit of pLDH based malaria rapid diagnostic test. AB - BACKGROUND: The malaria rapid diagnostic tests (RDTs) are now widely used in the world. Compared to Plasmodium falciparum, a poor sensitivity of RDTs was reported against Plasmodium vivax based on the adopted antibody against pan-Plasmodium antigen lactate dehydrogenase (pLDH) or aldolase. Levels of pLDH were measured from patient with P. vivax, and the correlations between the levels of pLDH and the sensitivities of RDTs were analysed among Republic of Korea (ROK) isolates. METHODS: Three RDTs, OptiMAL test, SD BIOLINE Malaria Ag P.f/Pan test, Humasis Malaria Pf/Pan antigen test, and the Genedia pLDH antigen ELISA were performed with blood samples from 152 febrile patients and 100 healthy controls. RESULTS: Three malaria RDTs revealed sensitivities between 85.5 (131/152) and 86.8% (132/152) with highest sensitivity for the detection of P.vivax by pLDH antigen ELISA test (145/152, 95.4%) in comparison to traditional microscopy using Giemsa stained slides. None of the healthy control tested positive by three RDTs or ELISA, indicating 100% specificity in their respective test. Levels of pLDH among Korean P. vivax isolates ranged between 0 ng/mL and 22,387.2 ng/mL (mean +/- standard deviation 3,917.5 +/- 6,120.9 ng/mL). The lower detection limits of three RDTs were between 25 and 50 ng/mL with artificially diluted samples. The moderate degree of correlation was observed between parasitaemia and concentrations of pLDH (r = 0.4, p < 0.05). CONCLUSION: The pLDH levels of P. vivax are the main explanation for the variations in the performance of pLDH based RDTs. Therefore, comparing sensitivities of RDT may need to include targeted biomarker value of patients. PMID- 23731661 TI - Cancer testis antigens and NY-BR-1 expression in primary breast cancer: prognostic and therapeutic implications. AB - BACKGROUND: Cancer-testis antigens (CTA) comprise a family of proteins, which are physiologically expressed in adult human tissues solely in testicular germ cells and occasionally placenta. However, CTA expression has been reported in various malignancies. CTAs have been identified by their ability to elicit autologous cellular and or serological immune responses, and are considered potential targets for cancer immunotherapy. The breast differentiation antigen NY-BR-1, expressed specifically in normal and malignant breast tissue, has also immunogenic properties. Here we evaluated the expression patterns of CTAs and NY BR-1 in breast cancer in correlation to clinico-pathological parameters in order to determine their possible impact as prognostic factors. METHODS: The reactivity pattern of various mAbs (6C1, MA454, M3H67, 57B, E978, GAGE #26 and NY-BR-1 #5) were assessed by immunohistochemistry in a tissue micro array series of 210 randomly selected primary invasive breast cancers in order to study the diversity of different CTAs (e.g. MAGE-A, NY-ESO-1, GAGE) and NY-BR-1. These expression data were correlated to clinico-pathological parameters and outcome data including disease-free and overall survival. RESULTS: Expression of at least one CTA was detectable in the cytoplasm of tumor cells in 37.2% of the cases. NY-BR-1 expression was found in 46.6% of tumors, respectively. Overall, CTA expression seemed to be linked to adverse prognosis and M3H67 immunoreactivity specifically was significantly correlated to shorter overall and disease-free survival (p=0.000 and 0.024, respectively). CONCLUSIONS: Our findings suggest that M3H67 immunoreactivity could serve as potential prognostic marker in primary breast cancer patients. The exclusive expression of CTAs in tumor tissues as well as the frequent expression of NY-BR-1 could define new targets for specific breast cancer therapies. PMID- 23731662 TI - Peritrabecular clefting in fibrous dysplasia of the jaws: how soon is now? PMID- 23731663 TI - Health-care utilization for primary headache disorders in China: a population based door-to-door survey. AB - BACKGROUND: In order to know the status quo of health care for primary headache disorders in China, questions about headache consultation and diagnosis were included in a nationwide population-based survey initiated by Lifting The Burden: the Global Campaign against Headache. METHODS: Throughout China, 5,041 unrelated respondents aged 18-65 years were randomly sampled from the general population and visited unannounced at their homes. After basic sociodemographic and headache diagnostic questions, respondents with headache answered further questions about health-care utilization in the previous year. RESULTS: Significantly higher proportions of respondents with migraine (239/452; 52.9%) or headache on >=15 days per month (23/48; 47.9%) had consulted a physician for headache than of those with tension-type headache (TTH) (218/531; 41.1%; P < 0.05). Multivariate analysis showed associations between disability and probability of consultation in those with migraine (mild vs. minimal: AOR 3.4, 95% CI: 1.6-7.4; moderate vs. minimal: 2.5, 1.2-5.4; severe vs. minimal: 3.9, 1.9-8.1) and between rural habitation and probability of consulting in those with TTH (AOR: 3.5; 95% CI: 1.9 6.3, P < 0.001). Married respondents with TTH were less likely than unmarried to have consulted (AOR: 0.26; 95% CI: 0.07-0.93; P = 0.038). About half of consultations (47.8-56.5%) for each of the headache disorders were at clinic level in the health system. Consultations in level-3 hospitals were relatively few for migraine (5.9%) but more likely for headache on >=15 days/month (8.7%) and, surprisingly, for TTH (13.3%). Under-diagnosis and misdiagnosis were common in consulters. More than half with migraine (52.7%) or headache on >=15 days/month (51.2%), and almost two thirds (63.7%) with TTH, reported no previous diagnosis. Consulters with migraine were as likely (13.8%) to have been diagnosed with "nervous headache" as with migraine. "Nervous headache" (9.8%) and "vascular headache" (7.6%) were the most likely diagnoses in those with TTH, of whom only 5.6% had previously been correctly diagnosed. These were also the most likely diagnoses (14.0% each) in consulters with headache on >=15 days/month. CONCLUSIONS: This picture of the status quo shows limited reach of headache services in China, and high rates of under-diagnosis and misdiagnosis in those who achieve access to them. This is not a picture of an efficient or cost effective response to major causes of public ill-health and disability. PMID- 23731664 TI - A modified uvulopalatal flap with lateral pharyngoplasty for treatment in 92 adults with obstructive sleep apnoea syndrome. PMID- 23731666 TI - Sphingosine-1-phosphate inhibits ceramide-induced apoptosis during murine preimplantation embryonic development. AB - Sphingolipids are a complex family of naturally occurring molecules enriched with lipid rafts that contribute to their unique biochemical properties. Sphingolipid metabolites, including ceramide (Cer) and sphingosine-1-phosphate (S1P), are bioactive signaling molecules that regulate cell movement, differentiation, survival, and apoptosis, but their effects on preimplantation development of murine embryos are not well-characterized. In this study, murine zygotes were collected, cultured in vitro, and treated with 50 MUM C2-Cer plus various concentrations of S1P. The blastocyst formation rate was decreased in the C2-Cer treated group, compared with that in the control group and the group treated with 50 MUM C2-Cer plus 25, 50, or 100 nM S1P (P < 0.05), respectively. The total cell number of the blastocysts from various treatment groups was similar at 110 hours post-hCG treatment, but that from the group treated with 50 MUM C2-Cer was significantly decreased at 120 hours post-hCG treatment, compared with the control group and the group treated with 50 MUM C2-Cer plus 50 nM S1P. However, the apoptotic cell number of blastocysts from the group treated with 50 MUM C2 Cer was significantly increased at 110 and 120 hours post-hCG treatment, compared with the control group and the group treated with 50 MUM C2-Cer plus 50 nM S1P. Moreover, expression of p53 in the group treated with 50 MUM C2-Cer was higher than that in the control group and the group treated with 50 MUM C2-Cer plus 50 nM S1P (P < 0.05). In conclusion, Cer decreases the blastocyst formation rate and induces embryonic cell apoptosis, but S1P partly inhibits the effects of Cer during preimplantation development of murine embryos. PMID- 23731665 TI - Chronic lymphocytic leukemia: molecular heterogeneity revealed by high-throughput genomics. AB - Chronic lymphocytic leukemia (CLL) has been consistently at the forefront of genetic research owing to its prevalence and the accessibility of sample material. Recently, genome-wide technologies have been intensively applied to CLL genetics, with remarkable progress. Single nucleotide polymorphism arrays have identified recurring chromosomal aberrations, thereby focusing functional studies on discrete genomic lesions and leading to the first implication of somatic microRNA disruption in cancer. Next-generation sequencing (NGS) has further transformed our understanding of CLL by identifying novel recurrently mutated putative drivers, including the unexpected discovery of somatic mutations affecting spliceosome function. NGS has further enabled in-depth examination of the transcriptional and epigenetic changes in CLL that accompany genetic lesions, and has shed light on how different driver events appear at different stages of disease progression and clonally evolve with relapsed disease. In addition to providing important insights into disease biology, these discoveries have significant translational potential. They enhance prognosis by highlighting specific lesions associated with poor clinical outcomes (for example, driver events such as mutations in the splicing factor subunit gene SF3B1) or with increased clonal heterogeneity (for example, the presence of subclonal driver mutations). Here, we review new genomic discoveries in CLL and discuss their possible implications in the era of precision medicine. PMID- 23731667 TI - Single-molecule photobleaching reveals increased MET receptor dimerization upon ligand binding in intact cells. AB - BACKGROUND: The human receptor tyrosine kinase MET and its ligand hepatocyte growth factor/scatter factor are essential during embryonic development and play an important role during cancer metastasis and tissue regeneration. In addition, it was found that MET is also relevant for infectious diseases and is the target of different bacteria, amongst them Listeria monocytogenes that induces bacterial uptake through the surface protein internalin B. Binding of ligand to the MET receptor is proposed to lead to receptor dimerization. However, it is also discussed whether preformed MET dimers exist on the cell membrane. RESULTS: To address these issues we used single-molecule fluorescence microscopy techniques. Our photobleaching experiments show that MET exists in dimers on the membrane of cells in the absence of ligand and that the proportion of MET dimers increases significantly upon ligand binding. CONCLUSIONS: Our results indicate that partially preformed MET dimers may play a role in ligand binding or MET signaling. The addition of the bacterial ligand internalin B leads to an increase of MET dimers which is in agreement with the model of ligand-induced dimerization of receptor tyrosine kinases. PMID- 23731668 TI - Isolated fracture of the capitate with rotation of the proximal fragment. Case report. AB - A case of capitate fracture in a 28-year-old man, with a 180-degree rotation (volar dislocation) of the proximal fragment is reported. Due to a late diagnosis, the patient presented 2 weeks after trauma. Open reduction and internal fixation with Kirschner wires provided good bone alignment, uneventful healing and a good range of wrist motion was achieved. The authors remind the reader the possibility of capitate fracture, a rare but troublesome event among wrist traumas, requiring a prompt diagnosis and treatment to relief important wrist pain and to restore function. Moreover, in consideration of important vascular complications, producing non-union and arthritis, the emerging role of imaging in detecting even minor signs of bone necrosis, leading to correct surgical indications, has to be taken into account. PMID- 23731669 TI - Hinged elbow fixator: an extracorporeal technique to position the hinge based on an original guidewire device. AB - INTRODUCTION: The application of a hinged elbow external fixator is technically demanding because the hinge axis must coincide exactly with the flexion-extension axis of the elbow. The standard technique involves inserting a 3-mm K-wire freehand into the distal humerus to materialize the flexion-extension axis. We designed a guidewire device for extracorporeal hinge positioning without K-wire insertion. In a cadaver study, we compared freehand K-wire insertion and our extracorporeal technique. METHODS: In 12 cadaveric elbows, we induced acute elbow instability by sectioning the medial collateral ligament complex and the anterior and posterior capsule. A hinged external fixator was applied to each elbow using both techniques. The outcome measures were procedure duration, number of image intensifier shots (as a measure of radiation exposure), and passive motion range after fixator implantation. RESULTS: Compared with the freehand K-wire technique, the extracorporeal technique provided greater range of motion and significantly lower values for procedure duration and number of image-intensifier shots. Data dispersion was less marked with the extracorporeal technique, indicating better reproducibility. CONCLUSION: The extracorporeal technique based on a guidewire device enabled non-invasive positioning of a hinged elbow external fixator. This technique was faster, less irradiating, and more reproducible than the freehand K wire technique. PMID- 23731670 TI - [Functional magnetic resonance imaging. What are the benefits expected in hand surgery?]. AB - Functional MRI (fMRI) allowed considerable advances upon understanding of cerebral functioning. Cortical plasticity, which allows the voluntary command of a restored function by a transferred muscle remains to be investigated in its intimacy. The authors present here the round table held at the 48th annual meeting of the French Society for Surgery of the Hand on December 22nd, 2012. It tries to review the analysis of the phenomenon observed during multiple tendinous transfers for restoration of proximal radial nerve palsy. Were successively approached: 1) Methods of acquisition and analysis of the signals (C. D-M.); 2) Movement reorganization (O.M.); 3) Motor plasticity after hand allograft (A. S.); 4) The potential interest of the fMRI in hand rehabilitation (F. D.); 5) The analysis of cerebral plasticity in general (H. B.). A rather philosophical conclusion opens other fields to f MRI (A.M.). PMID- 23731671 TI - Quinazoline derivatives: synthesis and bioactivities. AB - Owing to the significant biological activities, quinazoline derivatives have drawn more and more attention in the synthesis and bioactivities research. This review summarizes the recent advances in the synthesis and biological activities investigations of quinazoline derivatives. According to the main method the authors adopted in their research design, those synthetic methods were divided into five main classifications, including Aza-reaction, Microwave-assisted reaction, Metal-mediated reaction, Ultrasound-promoted reaction and Phase transfer catalysis reaction. The biological activities of the synthesized quinazoline derivatives also are discussed. PMID- 23731672 TI - The Cedar Project: impacts of policing among young Aboriginal people who use injection and non-injection drugs in British Columbia, Canada. AB - BACKGROUND: Policing has profound health implications for people who use illicit drugs. Among Aboriginal communities, distrust of police is common, due partly to legacies of colonial policing. In response to the paucity of research among Aboriginal people who use drugs, this paper aims to: (1) Describe the policing experiences of young Aboriginal people who use drugs; (2) Identify policing activities associated with unsafe injection practices; and (3) Elucidate barriers to positive police relations. METHODS: The Cedar Project is a cohort study involving young Aboriginal people in Vancouver and Prince George, British Columbia, who use illicit drugs. This mixed-methods study (N=372) used period prevalence from 2007 to 2010 to describe policing experiences, mixed effects regression models to identify correlates of policing activities, and thematic qualitative analysis to assess attitudes to police relations. RESULTS: Many participants were stopped by police (73%), experienced physical force by police (28%), had drug equipment confiscated (31%), and changed location of drug use because of police (43%). Participants who reported dealing drugs (40%) were significantly more likely to experience police engagement. Among participants in Prince George, 4% reported to have had non-consensual sex with members of the criminal justice system. Policing activity was significantly associated with syringe sharing, rushed injection, and reused syringe. Due to personal experience, practical concerns, and intergenerational legacies of unfair policing practices, most participants did not want a positive relationship with police (57%). Desire for a positive relationship with police was directly associated with being helped by police, and inversely associated with being stopped by police and experiencing physical force by police. CONCLUSION: Policing activities may be impacting the well-being of Aboriginal people who use drugs. Due to focused prosecution of street-level drug dealing, some police may favor enforcement over harm reduction. Positive police engagement and less aggressive policing may enhance perceptions of police among young Aboriginal people who use drugs. PMID- 23731673 TI - Patching plus extended exposure and tacking of the common carotid cuff may reduce the late incidence of recurrent stenosis after carotid endarterectomy. AB - OBJECTIVE: The safety and durability of carotid endarterectomy (CEA) require attention to certain technical details that may evolve over time. The objective of this study was to determine whether routine patch angioplasty and precautions related to the common carotid cuff could reduce the risks for perioperative stroke, internal carotid artery (ICA) thrombosis, or recurrent carotid stenosis. METHODS: The senior author (N.H.) performed 1959 consecutive isolated CEAs at the Cleveland Clinic from 1976 to 2004. This series can be divided into three distinct eras with respect to patching and management of the proximal common carotid cuff: (1) primary arteriotomy closure with selective patching in only 38 of 653 CEAs (5.8%) from 1976 to 1983 (group 1); (2) routine patching without any special precautions related to the common carotid cuff in 568 CEAs from 1983 to 1990 (group 2); and (3) routine patching with extended exposure and tacking sutures to secure the carotid cuff in 738 CEAs from 1990 to 2004 (group 3). RESULTS: Although vein patching alone seemed to have less risk for perioperative stroke (1.2% vs 2.4%) or ICA thrombosis (0.6% vs 1.8%) than primary closure, these differences did not attain statistical significance. There also were no significant differences in the perioperative stroke and ICA thrombosis rates among the three eras in which changes occurred in patch use and in the management of the carotid cuff. After adjusting for the various lengths of follow-up in the study groups, however, group 3 had a significantly lower risk for recurrent 60% to 99% stenosis or ICA occlusion at >5 years after CEA (odds ratio [OR], 0.09; 95% confidence interval [CI], 0.04-0.22; P < .001). On multivariable analysis, group 3 (OR, 0.23; 95% CI, 0.09-0.60; P = .003) and advancing age (OR, 0.89 per year; 95% CI, 0.85-0.92 per year; P < .001) had less risk for late recurrent stenosis, whereas this risk was higher in women (OR, 2.23; 95% CI, 1.23-4.06; P = .009) and in patients who had undergone previous ipsilateral CEA (OR, 6.02; 95% CI, 1.63-22.2; P = .007). CONCLUSIONS: Routine patching plus extended exposure and tacking of the common carotid cuff appear to significantly reduce the long term incidence of recurrent 60% to 99% stenosis or ICA occlusion after CEA. PMID- 23731674 TI - Influence of a six month endurance exercise program on the immune function of prostate cancer patients undergoing Antiandrogen- or Chemotherapy: design and rationale of the ProImmun study. AB - BACKGROUND: Exercise seems to minimize prostate cancer specific mortality risk and treatment related side effects like fatigue and incontinence. However the influence of physical activity on the immunological level remains uncertain. Even prostate cancer patients undergoing palliative treatment often have a relatively long life span compared to other cancer entities. To optimize exercise programs and their outcomes it is essential to investigate the underlying mechanisms. Further, it is important to discriminate between different exercise protocols and therapy regimes. METHODS/DESIGN: The ProImmun study is a prospective multicenter patient preference randomized controlled trial investigating the influence of a 24 week endurance exercise program in 80-100 prostate cancer patients by comparing patients undergoing Antiandrogen therapy combined with exercise (AE), Antiandrogen therapy without exercise (A), Chemotherapy with exercise(CE) or Chemotherapy without exercise (C). The primary outcome of the study is a change in prostate cancer relevant cytokines and hormones (IL-6, MIF, IGF-1, Testosterone). Secondary endpoints are immune cell ratios, oxidative stress and antioxidative capacity levels, VO2 peak, fatigue and quality of life. Patients of the intervention group exercise five times per week, while two sessions are supervised. During the supervised sessions patients (AE and CE) exercise for 33 minutes on a bicycle ergometer at 70-75% of their VO2 peak. To assess long term effects and sustainability of the intervention two follow-up assessments are arranged 12 and 18 month after the intervention. DISCUSSION: The ProImmun study is the first trial which primarily investigates immunological effects of a six month endurance exercise program in prostate cancer patients during palliative care. Separating patients treated with Antiandrogen therapy from those who are additionally treated with Chemotherapy might allow a more specific view on the influence of endurance training interventions and the impact of different therapy protocols on the immune function. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00004739. PMID- 23731675 TI - Blue roses. PMID- 23731676 TI - AICDA single nucleotide polymorphism in common variable immunodeficiency and selective IgA deficiency. AB - BACKGROUND: Primary antibody deficiencies (PADs) are a heterogeneous group of disorders, characterised by increased susceptibility to recurrent bacterial infections. Common variable immunodeficiency (CVID) is the most important PAD from the clinical point of view and selective IgA deficiency (IgAD) is the most common PAD. However, the underlying gene defect in both is still unknown. As a recent study in Europe showed an association between a single nucleotide polymorphism (SNP) of AICDA gene with PADs, this study was performed to evaluate such an association in Iranian patients. METHODS: Fifty-eight patients with PAD, including 39 CVID and 19 IgAD, as well as 34 healthy volunteers, were enrolled in this study. Genotyping was done in all groups for an intronic SNP in AICDA (rs2580874), using real-time PCR genotyping assay. RESULTS: The less frequent genotype of AICDA in IgAD patients was AA, seen in 10.5% of the patients, which was much lower than the 30.8% in CVID patients and 38.2% in the controls. However, these differences were not significant. Indeed the GG genotype in the patients with PADs was seen in 20.7%, compared to 8.8% in the controls without any significant difference. CONCLUSIONS: There was no significant association between the previously reported genetic variant of AICDA gene and the development of CVID or IgAD, but further multi-center studies are also needed. PMID- 23731678 TI - Assessing multiple foodborne, waterborne and environmental exposures of healthy people to potential enteric pathogen sources: effect of age, gender, season, and recall period. AB - Information is lacking in Canada on the frequency of exposures of healthy people to enteric pathogen sources (i.e. water, food, animal contact) at the community level. This information is critical to develop more robust risk assessments and prioritize control measures. A 12-month-long cross-sectional telephone survey of 1200 healthy individuals in a sentinel community was performed. Survey respondents were divided into three recall period groups (3, 7, 14 days). The occurrence of 46 exposures (including water, animal contact, environmental contact and high-risk foods) was assessed per recall period. Effect of age, gender, and season on exposures was modelled and frequencies of exposure were extrapolated. Thirty-five exposures had similar occurrences across recall periods. Age was significant for 23 exposures, season for 18, and gender for three. Exposures that vary by age and season (i.e. bottled water, swimming, etc.) warrant consideration when investigating and analysing cases of enteric illness. PMID- 23731679 TI - Prevalence and antibiotic susceptibility pattern of methicillin-resistant Staphylococcus aureus (MRSA) among primary school children and prisoners in Jimma Town, Southwest Ethiopia. AB - BACKGROUND: Staphylococcus aureus infections are increasingly reported from both health institutions and communities around the world. In particular, infections due to methicillin-resistant Staphylococcus aureus (MRSA) strains have been detected worldwide. If MRSA becomes the most common form of S. aureus in a community, it makes the treatment of common infections much more difficult. But, report on the current status of community acquired MRSA in the study area is scanty. METHODS: Community-based cross sectional study was conducted to evaluate the current prevalence and antibiotic susceptibility pattern of MRSA among primary school children and prisoners in Jimma town. MRSA was detected using Cefoxitin (30MUg) disc; and epidemiologic risk factors were assessed using pre designed questionnaires distributed to the children's parents and prisoners. A total of 354 nasal swabs were collected from primary school children and prisoners from December 2010 to March 2011 following standards microbiological methods. RESULTS: A total of 169 S. aureus isolates were recovered. The overall prevalence of MRSA among the study population was 23.08 % (39/169). Specifically, the prevalence of MRSA among primary school children and prisoners were 18.8% (27/144) and 48% (12/25), respectively. The isolated S. aureus and MRSA displayed multiple drug resistance (MDR) to 2 to 10 antibiotics. The most frequent MDR was Amp/Bac/Ery/Pen/Fox (resistance to Ampicillin, Bacitracin, Erythromycin, Penicillin, and Cefoxitin). CONCLUSION: The present study revealed that MRSA could be prevalent in the healthy community, transmitted from hospital to the community. The high distribution of MRSA could be favored by potential risk factors. Thus, for comprehensive evaluation of the current prevalence of MRSA and design control measures, consideration need to be given to the healthy community besides data coming from health institutions. PMID- 23731680 TI - Deletion of regulatory T cells supports the development of intestinal ischemia reperfusion injuries. AB - BACKGROUND: Ischemia-reperfusion injury (IRI) of the intestine is associated with high morbidity and mortality in surgical and trauma patients. T cells participate in the pathogenesis of intestinal IRI, and T-cell depletion has been shown to inhibit inflammatory responses and diminish intestinal damage. However, the mechanism by which T cells contribute to intestinal IRI is not completely understood. Regulatory T cells (Tregs) are a specific subset of T cells that suppress immune responses and protect against tissue injuries. We hypothesized that Tregs might be involved in intestinal IRI. MATERIALS AND METHODS: We subjected C57/Bl6 mice to 30 min of ischemia by clamping the superior mesenteric artery followed by reperfusion. Animals were pretreated with the anti-CD25 monoclonal antibody or adoptive transfer of Tregs before induction of IRI. The number of inflammatory cells, the level of inflammatory factors, and intestinal permeability were assessed. RESULTS: Partial depletion of Tregs with an anti-CD25 monoclonal antibody potentiated intestinal permeability induced by IRI. The Treg depleted mice showed more neutrophils and CD4(+) T cells. In addition, depletion of Tregs led to enhanced secretion of tumor necrosis factor-alpha, interferon gamma, and interleukin (IL)-4 and reduced levels of IL-10. Furthermore, we performed adoptive transfer of Tregs and found that transfer of Tregs significantly inhibited the ischemia-reperfusion-induced increase in intestinal permeability. CONCLUSIONS: Our study indicated that Tregs participate in intestinal inflammatory responses induced by IRI and that targeting Tregs could be a novel therapeutic approach to intestinal IRI. PMID- 23731681 TI - Protective effects of selective mineralocorticoid receptor antagonist against aortic aneurysm progression in a novel murine model. AB - BACKGROUND: The optimal medical management to delay the progression of aortic aneurysms has not been fully clarified, and the only standard treatment at present is antihypertensive therapy. Previous studies have shown beneficial effects of selective mineralocorticoid receptor (MR) antagonists on cardiovascular remodeling. The aim of the present study was to investigate the effect of a selective MR antagonist on aortic aneurysm progression. METHODS: Seven-week-old C57BL/6J male mice were administered with angiotensin II and beta aminopropionitrile for 4 weeks. The mice received either vehicle or eplerenone, a selective MR antagonist (100 mg/kg daily) every day by gavage, starting at 7 weeks of age. The production of inflammatory cytokines in cultures of high mobility group box-1-stimulated macrophages with or without a MR antagonist was also analyzed using an enzyme-linked immunosorbent assay. RESULTS: Although no differences were found in the peak systolic blood pressure between the experimental groups, the mice in the eplerenone group showed a significant reduction in aneurysm development. On histologic analysis, coarse and stretched elastic fibers were markedly improved in the aortic wall in the eplerenone group. Real-time polymerase chain reaction of both aortic wall and perivascular adipose tissue demonstrated the expression of tumor necrosis factor-alpha, interleukin-6, and matrix metalloproteinase-2 was significantly decreased in eplerenone group, and that of monocyte chemoattractant protein-1 in the aortic wall was also significantly decreased. Macrophage infiltration in the aortic wall and perivascular adipose tissue in the eplerenone group was also significantly decreased. The production of tumor necrosis factor-alpha and interleukin-6 in macrophage culture, which was stimulated by high mobility group box-1 and CpG oligodeoxynucleotides, was also significantly decreased in the eplerenone group. CONCLUSIONS: Eprelenone suppressed aortic aneurysm progression through an anti inflammatory effect. Thus, selective MR antagonists might be effective in preventing the progression of aortic aneurysms. PMID- 23731682 TI - Benefits of active oxygenation during hypothermic machine perfusion of kidneys in a preclinical model of deceased after cardiac death donors. AB - BACKGROUND: Deceased after cardiac death donors (DCDs) represent a valuable source of organs; however, preventing poor outcome is difficult, even with the use of machine perfusion (MP). It is of paramount importance to improve this method. We proposed to evaluate the benefits of active oxygenation during kidney graft hypothermic MP using a novel perfusion machine: Kidney Assist (KA). METHODS: We used a pig model of DCD transplantation in Large White pigs. Cold preservation was performed by conventional non-oxygenated MP (KAnoO2) or oxygenated MP (KA). RESULTS: In the first 2 wk post-transplant, KA grafts displayed a lower serum creatinine peak and a faster return to normal levels compared with KAnoO2 animals, translating into a smaller area under the curve. Urinary neutrophil gelatinase-associated lipocalin levels and serum aspartate amino transferase levels were lower in KA animals compared with the non oxygenated group. These correlated with better chronic function. Longer follow-up of the animals (3 mo) permitted evaluation of chronic outcome lesions. Interstitial fibrosis was reduced in the KA group, and these kidneys also displayed significantly lower levels of vimentin staining. Further histologic investigation also showed a trend toward decreased chronic inflammation in kidneys preserved with oxygen. CONCLUSIONS: This new MP system is efficient in preserving DCD kidneys, greatly enhancing the capacity of the graft to withstand preservation stress and improving outcome. Oxygen delivery during preservation is thus valuable for highly damaged organs and offers an important therapeutic tool for transplant teams faced with decreased quality of donor organs. PMID- 23731683 TI - Evaluating the effectiveness of a discharge protocol for children with advanced appendicitis. AB - BACKGROUND: In 2006, an evidence-based protocol for the management of children with appendicitis was established at our institution. Discharge criteria for patients with advanced appendicitis were based on a combination of clinical parameters and laboratory values. The purpose of this study is to evaluate the utility of laboratory values in guiding patient management with a discharge protocol for advanced appendicitis. MATERIALS AND METHODS: We reviewed charts of patients with advanced appendicitis as defined by the surgeon intraoperatively from 2008-2009. We evaluated the sensitivity and specificity of the laboratory values at discharge for predicting postoperative intra-abdominal abscess (IAA) formation using a receiver operator curve. A logistic regression analysis was performed to identify predictors of IAA formation. RESULTS: We identified 450 patients (mean age 8.9 +/- 3.9 y). The postoperative IAA rate was 25%. The sensitivity and specificity for developing an abscess with a white blood cell count >12,000/UL were 52% and 82%, respectively (AUC 0.72, 95% CI 0.67-0.78, P < 0.001). The sensitivity and specificity for bands >3% were 47% and 70% (AUC 0.60, 95% CI 0.53-0.67, P = 0.002), respectively. On logistic regression analysis, an elevated white blood cell count was independently associated with an increased likelihood of a postoperative IAA (OR 1.27, 95% CI 1.19-1.35, P < 0.001). CONCLUSIONS: The absence of leukocytosis is useful for identifying children with a decreased risk of postappendectomy IAA formation who otherwise meet clinical discharge parameters. A band count is not as predictive of risk. The use of laboratory evaluation as a component of discharge criteria in advanced appendicitis can stratify a subset of patients who are at increased IAA risk and may benefit from continued antibiotic therapy. PMID- 23731684 TI - Pulmonary acute respiratory distress syndrome: positive end-expiratory pressure titration needs stress index. AB - BACKGROUND: The heterogeneity of lung injury in pulmonary acute respiratory distress syndrome (ARDS) may have contributed to the greater response of hyperinflated area with positive end-expiratory pressure (PEEP). PEEP titrated by stress index can reduce the risk of alveolar hyperinflation in patients with pulmonary ARDS. The authors sought to investigate the effects of PEEP titrated by stress index on lung recruitment and protection after recruitment maneuver (RM) in pulmonary ARDS patients. MATERIALS AND METHODS: Thirty patients with pulmonary ARDS were enrolled. After RM, PEEP was randomly set according to stress index, oxygenation, static pulmonary compliance (Cst), or lower inflection point (LIP) + 2 cmH2O strategies. Recruitment volume, gas exchange, respiratory mechanics, and hemodynamic parameters were collected. RESULTS: PEEP titrated by stress index (15.1 +/- 1.8 cmH2O) was similar to the levels titrated by oxygenation (14.5 +/- 2.9 cmH2O), higher than that titrated by Cst (11.3 +/- 2.5 cmH2O) and LIP (12.9 +/- 1.6 cmH2O) (P < 0.05). Compared with baseline, PaO2/FiO2 and recruitment volume were significantly improved after PEEP titration with the four strategies (P < 0.05). PaO2/FiO2 and recruitment volume were similar when using PEEP titrated by stress index and oxygenation but higher than that titrated by Cst and LIP. Compared with baseline, lung compliance increased significantly when PEEP determined by Cst, but there was no difference of Cst in these four strategies. There was no influence of PEEP titration with the four strategies on hemodynamic parameters. CONCLUSIONS: PEEP titration by stress index might be more beneficial for pulmonary ARDS patients after RM. PMID- 23731685 TI - Blocking the P2X7 receptor improves outcomes after axonal fusion. AB - BACKGROUND: Activation of the P2X7 receptor on peripheral neurons causes the formation of pannexin pores, which allows the influx of calcium across the cell membrane. Polyethylene glycol (PEG) and methylene blue have previously been shown to delay Wallerian degeneration if applied during microsuture repair of the severed nerve. Our hypothesis is that by modulating calcium influx via the P2X7 receptor pathway, we could improve PEG-based axonal repair. The P2X7 receptor can be stimulated or inhibited using bz adenosine triphosphate (bzATP) or brilliant blue (FCF), respectively. METHODS: A single incision rat sciatic nerve injury model was used. The defect was repaired using a previously described PEG methylene blue fusion protocol. Experimental animals were treated with 100 MUL of 100 MUM FCF solution (n = 8) or 100 MUL of a 30 MUM bzATP solution (n = 6). Control animals received no FCF, bzATP, or PEG. Compound action potentials were recorded prior to transection (baseline), immediately after repair, and 21 d postoperatively. Animals underwent behavioral testing 3, 7, 14, and 21 d postoperatively. After sacrifice, nerves were fixed, sectioned, and immunostained to allow for counting of total axons. RESULTS: Rats treated with FCF showed an improvement compared with control at all time points (n = 8) (P = 0.047, 0.044, 0.014, and 0.0059, respectively). A statistical difference was also shown between FCF and bzATP at d 7 (P < 0.05), but not shown with d 3, 14, and 21 (P > 0.05). CONCLUSIONS: Blocking the P2X7 receptor improves functional outcomes after PEG mediated axonal fusion. PMID- 23731687 TI - General surgeon workforce in Tennessee in the era of the Affordable Care Act. AB - BACKGROUND: The Affordable Care Act of (ACA) 2010 may result in an increase in demand for surgery and may exacerbate any existing surgeon shortage. The purpose of this study was to examine factors associated with general surgeon workforce within counties in Tennessee in light of the ACA. MATERIALS AND METHODS: The Area Resource File for 2011 was utilized for this study. Counties with less than 3 active surgeons/100,000 persons were classified as shortage counties (SC). Counties with more than 6 active surgeons/100,000 persons were considered over supply counties (OC). Demographic factors for each county were determined. Univariate and multivariable analysis was used to determine factors associated with SC. RESULTS: There are 95 counties in the state and 45.3% were SC and 33.7% were OC. Sixty-nine (72.6%) of the counties had at least one hospital and 57 (60%) were in non-metro counties. Multivariable logistic regression analysis revealed that increasing percent uninsured in a county was positively associated with a SC. No other factors were associated with SC. To meet the cutoff of three surgeons per 100,000 in SC 23 general surgeons would be required. There was an excess of 219 general surgeons in OCs. CONCLUSIONS: There appears to be an adequate supply of general surgeons but a maldistribution exists, particularly if demand increases with the implementation of the ACA. If redistribution of surgeons does not occur through natural changes in supply and demand, careful policy changes may be considered to encourage redistribution of surgeon resources to meet demand in counties that are currently underserved. PMID- 23731686 TI - Regulation of tumor necrosis factor-alpha-induced microvascular endothelial cell hyperpermeability by recombinant B-cell lymphoma-extra large. AB - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha), a cytotoxic cytokine, induces endothelial cell barrier dysfunction and microvascular hyperpermeability, leading to tissue edema, a hallmark of traumatic injuries. The objective of the present study was to determine whether B-cell lymphoma-extra large (Bcl-xL), an antiapoptotic protein, would regulate and protect against TNF-alpha-mediated endothelial cell barrier dysfunction and microvascular hyperpermeability. METHODS: Rat lung microvascular endothelial cells were grown as monolayers on Transwell membranes, and fluorescein isothiocyanate-bovine albumin flux (5 mg/mL) across the monolayer was measured fluorometrically to indicate changes in monolayer permeability. The rat lung microvascular endothelial cell adherens junctional integrity and actin cytoskeleton was studied using beta-catenin immunofluorescence and rhodamine phalloidin dye, respectively. Pretreatment of caspase-8 inhibitor (Z-IETD-FMK, 100 MUM) for 1 hour and transfection of Bcl-2 homology domain 3-interacting domain death agonist small interfering RNA (10 MUM) for 48 hours were performed to study their respective effects on TNF-alpha induced (10 ng/mL; 1-hour treatment) monolayer permeability. Recombinant Bcl-xL protein (2.5 MUg/ml) was transfected in rat lung microvascular endothelial cells for 1 hour, and its effect on permeability was demonstrated using a permeability assay. Caspase-3 activity was assayed fluorometrically. RESULTS: Z-IETD-FMK pretreatment protected the adherens junctions and decreased TNF-alpha-induced monolayer hyperpermeability. Bcl-2-homology domain 3-interacting domain death agonist small interfering RNA transfection attenuated the TNF-alpha-induced increase in monolayer permeability. Recombinant Bcl-xL protein showed protection against TNF-alpha-induced actin stress fiber formation, an increase in caspase-3 activity, and monolayer hyperpermeability. CONCLUSIONS: Our results have demonstrated the protective effects of recombinant Bcl-xL protein against TNF alpha-induced endothelial cell adherens junction damage and microvascular endothelial cell hyperpermeability. These findings support the potential for Bcl xL-based drug development against microvascular hyperpermeability and tissue edema. PMID- 23731688 TI - Innovative, simplified orthotopic lung transplantation in rats. AB - BACKGROUND: Various techniques of orthotopic single lung transplantation in rats have been reported; however, their widespread use has been limited owing to the complexity of the procedure. We report a novel microsurgical lung transplantation model in rats with a high survival rate that can be performed by one surgeon alone. METHODS: A total of 90 left lung allografts were transplanted from Fischer to Wistar Kyoto rats. We developed a triple axis precision system to place and stabilize the vascular clips intrathoracically to clamp the bronchovascular structures, thereby avoiding interference with the heart and contralateral lung movement. A single-suture bronchial anastomosis technique and proximal cuffing approach for vascular anastomosis was used, rendering surgical assistance unnecessary. RESULTS: In our recent series, both short-term (12 h) and long-term (21 d) survival was 100%. The lungs showed excellent perfusion and ventilation immediately on transplantation. Blood gas samples drawn from the left pulmonary vein and the histologic sections revealed excellent graft function. The donor operation lasted 20 +/- 2 min, donor left lung dissection required 20 +/- 2 min, and implantation required 90 +/- 5 min. CONCLUSIONS: The present innovative method of left orthotopic single lung transplantation can be performed by one experienced surgeon alone, with excellent results and a high degree of reproducibility. PMID- 23731689 TI - Supratherapeutic vancomycin levels after trauma predict acute kidney injury and mortality. AB - INTRODUCTION: High-dose vancomycin is increasingly prescribed for critically ill trauma patients at risk for methicillin-resistant Staphylococcus aureus pneumonia. Although trauma patients have multiple known risk factors for acute kidney injury (AKI), a link between vancomycin and AKI or mortality has not been established. We hypothesize that high vancomycin trough concentration (VT) after trauma is associated with AKI and increased mortality. METHODS: This was a retrospective analysis from a single institution Level I trauma center. Data were reviewed for all adult trauma patients who were admitted between 2006 and 2010. Patients were included if they received intravenous vancomycin, had serum creatinine levels before and after vancomycin administration, and had at least one recorded VT. Patients were stratified by VT into four groups: VT1 = 0-10 mg/L, VT2 = 10.1-15 mg/L, VT3 = 15.1-20 mg/L, VT4 >20 mg/L. Multivariable logistic regression was performed to determine the association between VT, AKI, and mortality. RESULTS: Of the 6781 trauma patients reviewed, 263 (3.9%) fit inclusion criteria. Ninety-seven (36.9%) patients developed AKI and 25 (9.5%) died. AKI and mortality increased progressively with VT. Ninety-one patients (34.6%) had troughs >20 mg/L and VT4 was independently associated with AKI (AOR 4.7, P < 0.01) and mortality (AOR 4.8, P = 0.05). CONCLUSION: AKI is common in trauma patients who receive intravenous vancomycin. A supratherapeutic trough level of >20 mg/L is an independent predictor of AKI and mortality in trauma patients. PMID- 23731690 TI - Healing outcomes of large (>50%) traumatic membrane perforations with inverted edges following no intervention, edge approximation and fibroblast growth factor application; a sequential allocation, three-armed trial. AB - OBJECTIVE: The goal of this study was to evaluate the effects of perforation edge approximation and direct application of basic fibroblast growth factor (bFGF) each alone on the healing of large traumatic tympanic membrane perforations with inverted edges in humans. STUDY DESIGN: Prospective, sequential allocation, three armed, controlled clinical study. SETTING: University-affiliated teaching hospital. PARTICIPANTS: Fifty-eight patients with large traumatic tympanic membrane perforations (i.e. affecting >50% of the surface area) with inverted edges were recruited. They were sequentially allocated to three groups: no intervention (n = 18), edge approximation alone (n = 20) and direct application of bFGF (n = 20). Otoscopy were performed before the treatment and at follow-up visits. MAIN OUTCOME MEASURES: The closure rate, closure time and rate of otorrhoea. RESULTS: Application of bFGF yielded a significantly higher average rate of perforation closure (100%) than edge approximation (60%) and no intervention (56%) (P < 0.05). It also significantly shortened the average closure time (12.4 +/- 3.6 days) as compared to edge approximation (46.3 +/- 8.7 days) and no intervention control (48.2 +/- 5.3 days) (P < 0.05). Purulent otorrhoea was observed in none of the three groups. CONCLUSION: Edge approximation of inverted edges has little benefit in improving the healing outcome of large traumatic tympanic membrane perforations and thus is not an ideal treatment option for large traumatic tympanic membrane perforations. Application of bFGF materially improves the closure rate of large traumatic tympanic membrane perforations and significantly shortens the closure time. PMID- 23731691 TI - Activation of signaling receptors: do ligands bind to receptor monomer, dimer, or both? AB - A recent study by Dietz et al. using single-molecule fluorescence microscopy techniques demonstrates that, in the absence of the ligand InlB, the MET receptor exists as both a monomer and a dimer on the cell membrane, and addition of the ligand leads to increased MET dimerization. Under the crowded conditions of the cell membrane, dimer formation may be a common phenomenon for cell surface receptors. Ligand binding to both monomeric and dimeric receptors may provide parallel routes to receptor activation. PMID- 23731693 TI - Nuanced but significant: how ethanol perturbs avian cranial neural crest cell actin cytoskeleton, migration and proliferation. AB - Children with fetal alcohol syndrome (FAS) display striking craniofacial abnormalities. These features are proposed to result from perturbations in the morphology and function of cranial neural crest cells (cNCCs), which contribute significantly to the craniofacial complex. While certain pathways by which this may occur have been suggested, precise teratogenic mechanisms remain intensely investigated, as does the question of the teratogenic dose. The present study focused on examining how avian cNCC actin cytoskeleton, migratory distance, and proliferation are affected ex vivo by exposure to ethanol concentrations that simulate maternal intoxication. Chick cNCCs were cultured in 0.2% and 0.4% v/v ethanol. Distances migrated by both ethanol-treated and control cells at 24 and 48 h were recorded. Following phalloidin immunocytochemistry, treated and control cNCCs were compared morphologically and quantitatively. Apoptosis and proliferation in control versus treated cNCCs were also studied. Chick cNCCs cultured in ethanol lost their spindle-like shapes and their ordered cytoskeleton. There was a significant stage-dependent effect on cNCC migration at 24 h (p = 0.035), which was greatest at stage 10 (HH). Ethanol treatment for 48 h revealed a significant main effect for ethanol, chiefly at the 0.4% level. There was also an interaction effect between ethanol dose and stage of development (stage 9 HH). Actin microfilament disruption was quantitatively increased by ethanol at the doses studied while cNCC proliferation was increased but not significantly. Ethanol had no effect on cNCC apoptosis. At ethanol levels likely to induce human FAS, avian cNCCs exhibit various subtle, potentially significant changes in morphology, migration, and proliferation, with possible consequences for fated structures. PMID- 23731692 TI - Protracted withdrawal from ethanol and enhanced responsiveness stress: regulation via the dynorphin/kappa opioid receptor system. AB - Although recent work suggests that the dynorphin/kappa opioid receptor (DYN/KOR) system may be a key mediator in the stress-related effects of alcohol, the regulation of long-term changes associated with protracted withdrawal from ethanol via the DYN/KOR system has yet to be explored. The objective of the present study was to determine the role of the DYN/KOR system in the regulation of anxiety-related behaviors during an extended period of abstinence from ethanol in animals with a history of ethanol dependence. Male Wistar rats (n = 94) were fed an ethanol or control liquid diet for 25-30 days. Six weeks after its removal, rats were exposed to 20 min of immobilization, and the ability of the KOR antagonist nor-binaltorphimine (nor-BNI) (0-20 mg/kg, intraperitoneal [i.p.]) to attenuate the enhanced responsiveness to stress observed in rats chronically exposed to ethanol was investigated using the elevated plus maze. In addition, the ability of U50,488 (0-10 mg/kg, i.p.) to prime anxiety-like behavior during protracted withdrawal was also examined. Rats with a history of ethanol dependence showed a significant decrease in open-arm exploration after exposure to restraint, indicating an anxiety-like state, compared to similarly treated controls, an effect that was blocked by nor-BNI. nor-BNI also selectively decreased center time and open-arm approaches in ethanol-exposed rats. The highest dose of U50,488 decreased open-arm exploration and the total number of arm entries in ethanol-exposed and control rats. Although lower doses of U50,488 did not affect open-arm exploration in either group, the 0.1 mg/kg dose selectively decreased motor activity in the ethanol-exposed rats when compared to similarly pretreated controls. These findings further support the hypothesis that behaviors associated with withdrawal from ethanol are in part regulated by the DYN/KOR system, and suggest that these effects may be long lasting in nature. PMID- 23731694 TI - Nicotine enhances ethanol-induced fat accumulation and collagen deposition but not inflammation in mouse liver. AB - INTRODUCTION: Alcohol and tobacco are frequently co-abused. Tobacco smoke increases alcoholic steatosis in apoE(-/-) mice. Tobacco smoke contains more than 4000 chemicals, but it is unknown which compounds in tobacco smoke play a major role in increasing alcoholic steatosis. METHODS: C57BL/J6 mice were intraperitoneally injected with nicotine at 1 mg/kg every day or saline at the same volume as a control and the mice were fed dextrose-control or ethanol Lieber DeCarli liquid diets. Three weeks later the mice were sacrificed after overnight fasting. RESULTS: Neither nicotine injection nor ethanol feeding alone increased serum levels of triglyceride, but the combination of nicotine and ethanol increased serum levels of triglyceride. Both nicotine injection alone and ethanol feeding alone increased hepatic collagen type I deposition, and nicotine injection and ethanol feeding combined further increased hepatic collagen type I deposition. The combination of nicotine and ethanol also activated hepatic stellate cells, a principal liver fibrogenic cell. Hepatic fat accumulation was induced by ethanol feeding, which was further enhanced by nicotine injection. Ethanol feeding caused an increase in serum ALT, but nicotine did not further increase serum ALT levels. Lipid droplets and inflammatory foci were observed in liver sections from ethanol-fed mice; nicotine treatment increased the number and size of lipid droplets, but not the number and size of inflammatory foci. Nicotine did not further increase ethanol-induced hepatic neutrophil infiltration. CONCLUSIONS: These results suggest that nicotine enhances ethanol induced steatosis and collagen deposition, but nicotine has no effect on ethanol induced inflammation. PMID- 23731696 TI - [Placental MRI: physiology and pathology]. AB - The placenta is essential for fetal development but its in vivo study, including the study of placental perfusion is still very limited to date. MRI is a safe examination that offers new perspectives for the study of placental function that is altered in many conditions (IUGR, preeclampsia...) and placental anatomy (placenta accreta...). The different MRI sequences (DCE, IVIM, BOLD, ASL...) are new tools that may soon allow us to assess precisely placental function and anatomy, in vivo and non-invasively. PMID- 23731697 TI - [Urogenital bleeding revealing urethral prolapse in a prepubertal girl]. AB - Urethral prolapse is a complete eversion of the distal urethral mucosa through the external meatus. It occurs primarily in prepubertal, primarly Black girls. Its pathophysiology has not been clearly identified. We report a case of a 5-year old girl who came to the Emergency Department with a 1-day history of genital pain and "vaginal bleeding". Early recognition makes differential diagnosis with sexual abuse and staging allows prompt management under general anesthesic like prolapse reduction or surgical excision. PMID- 23731695 TI - Pathology and tissue tropism of natural West Nile virus infection in birds: a review. AB - West Nile virus (WNV) is a globally distributed arthropod-borne flavivirus capable of infecting a wide variety of vertebrates, with birds as its natural reservoir. Although it had been considered a pathogen of little importance for birds, from the 1990's, and especially after its introduction in the North American continent in 1999, thousands of birds have succumbed to West Nile infection. This review summarizes the pathogenesis and pathology of WNV infection in birds highlighting differences in lesion and antigen distribution and severity among bird orders and families. Despite significant species differences in susceptibility to infection, WNV associated lesions and viral antigen are present in the majority of organs of infected birds. The non-progressive, acute or more prolonged course of the disease accounts for part of the differences in lesion and viral antigen distribution and lesion severity. Most likely a combination of host variables and environmental factors in addition to the intrinsic virulence and pathogenicity of the infecting WNV strain influence the pathogenesis of the infection. PMID- 23731698 TI - [Elective cryopreservation of all embryos in women at risk of ovarian hyperstimulation syndrome: prevention and efficiency]. AB - OBJECTIVE: To evaluate the benefits, regarding prevention and clinical pregnancy rates, of embryos cryopreservation in patients at high risk of ovarian hyper stimulation. PATIENTS AND METHODS: Retrospective study with 66 patients divided into two groups. Group 1 (n=24), cryopreservation of all the embryos due to high risk of OHSS. Group 2 (n=42), fresh embryo transfer despite of ovarian hyper response (E2>4000/mL, hCG day). We performed a comparative analysis for group 1 and 2 regarding implantation, pregnancy, live birth and spontaneous abortion rates. RESULTS: No case of OHSS was observed in group 1 and 40.5 % in group 2. Fresh embryo transfer in group 2 gave the following results: 12.9 % implantation rate, 21.4 % pregnancy rate per transfer and 22.2 % spontaneous abortion. Identical implantation and pregnancy rates after frozen ET cycles were observed in both groups. Whereas live birth rates were significantly better in group 1 (15.4 % vs. 67 %, P=0.04) with a significant lower rate of spontaneous abortion (27 % vs. 11.4 %, P<0,01). DISCUSSION AND CONCLUSION: The negative impact of hyperestrogenic state seems to be limited to endometrial receptivity with no effect on oocyte or embryo quality. In situation of ovarian hyper-response, cryopreservation of all embryos with subsequent transfer of thawed embryos is an efficient strategy to avoid OHSS without decreasing pregnancy and live birth rates. PMID- 23731699 TI - Simultaneous recovery of Zn and MnO2 from used batteries, as raw materials, by electrolysis. AB - High purity electrolytic manganese dioxide (EMD) is the main raw material used for manufacturing of zinc and manganese based portable batteries (alkaline with manganese AlMn and zinc carbon Zn-C). Lately, due to the progressive depletion of MnO(2) natural resources, the quantity of artificially electrolytic produced MnO(2) has started to increase to satisfy the demand. This paper describes an electrolytic process for the simultaneous production of the following components:The electrolysis process was conducted in a specialized laboratory facility. The study was particularly focused on the following electrolysis process parameters: PMID- 23731700 TI - Sex differences in the kinematics and neuromuscular control of landing: biological, environmental and sociocultural factors. AB - Potential sex differences in patterns of movement of recreational and competitive athletes were investigated in a systematic review of lower limb kinematics, muscle activation and stiffness during landing and hopping tasks. Little support for sex-specific lower limb kinematic patterns was found in 17 studies retrieved on landing and hopping. Ten studies retrieved on muscle activation during landing provided no support for sex-specific patterns. Four articles retrieved on leg stiffness established that absolute stiffness was lower in females, but differences in stiffness normalized to body mass were less clear. The wider literature indicates that a combination of biological, environmental and sociocultural constraints may shape movement patterns differently in females and males. Sociocultural factors differentially affect accumulated motor experience, practice opportunities and focus of attention in females, leading to differences in motor skill that confound the comparison of female and male movements. The findings of the review support the hypothesis that such sex differences in athletic performance are likely to diminish or disappear with increasing skill. In everyday movement tasks, however, where level of skill is a less meaningful dimension than in sport, differences in movement patterns observed between females and males point instead to the influence of subtle societal expectations on movement patterns. PMID- 23731701 TI - From community pharmacy to healthy living pharmacy: positive early experiences from Portsmouth, England. AB - BACKGROUND: Research has shown the potential for community pharmacies to promote better health and prevent disease by providing individual services in a limited range of settings. In the UK, the healthy living pharmacy (HLP) framework has been developed to allow pharmacies to provide a portfolio of such services tailored to local need. This paper reports an evaluation of the uptake and success of HLP introduction in Portsmouth, the original pathfinder site for a national program. OBJECTIVES: To assesses the impact on service provision and staff engagement at an early stage in HLP program development. METHODS: Quantitative data, derived from pharmacy records, on service provision by HLPs (n = 17) and non-HLPs (n = 19) during April 2011-March 2012 was evaluated for trends and differences. Face-to-face interviews were conducted during November 2011 and February 2012, to gauge staff opinion on HLP development and sustainability, using interpretative phenomenological analysis. RESULTS: Significantly more clients per pharmacy were seen in HLPs than non-HLPs for the following services: targeted respiratory medicine use reviews (medians: 29 vs 11; P = 0.0167); smoking cessation at initiation (62 vs 18; P < 0.001) and at 4-week (26 vs 10; P < 0.001) and 12-week (5 vs 1; P = 0.023) follow-ups. Medians for alcohol awareness and weight management were appreciably higher in HLP pharmacies, but the differences did not reach statistical significance. Medians for clients seeking emergency hormonal contraception were comparable. Interviews with 38 staff from 32 pharmacies revealed a positive impact on service development in HLPs, largely engineered through revision of skill mix and additional training of non-pharmacist staff to become healthy living champions. Obstacles to HLP development were managing the increased workload, raising awareness of clients and other healthcare professionals of the services available, and receiving remuneration for service provision. CONCLUSIONS: These data point to a largely successful introduction of the HLP program in Portsmouth and the potential for improving client health. Staff interviews suggest that adoption and sustainability of the scheme depend on achieving the right skill mix, including the introduction of healthy living champions, motivation of the entire staff team and the provision of adequate funding for services offered. PMID- 23731703 TI - ENT's part in the UK's 'Medical Oscars'. PMID- 23731702 TI - Celecoxib alleviates tamoxifen-instigated angiogenic effects by ROS-dependent VEGF/VEGFR2 autocrine signaling. AB - BACKGROUND: Tamoxifen (TAM) is widely used in the chemotherapy of breast cancer and as a preventive agent against recurrence after surgery. However, extended TAM administration for breast cancer induces increased VEGF levels in patients, promoting new blood vessel formation and thereby limiting its efficacy. Celecoxib (CXB), a selective COX-2 inhibitor, suppresses VEGF gene expression by targeting the VEGF promoter responsible for its inhibitory effect. For this study, we had selected CXB as non-steroidal anti-inflammatory drug in combination with TAM for suppressing VEGF expression and simultaneously reducing doses of both the drugs. METHODS: The effects of CXB combined with TAM were examined in two human breast cancer cell lines in culture, MCF7 and MDA-MB-231. Assays of proliferation, apoptosis, angiogenesis, metastasis, cell cycle distribution, and receptor signaling were performed. RESULTS: Here, we elucidated how the combination of TAM and CXB at nontoxic doses exerts anti-angiogenic effects by specifically targeting VEGF/VEGFR2 autocrine signaling through ROS generation. At the molecular level, TAM-CXB suppresses VHL-mediated HIF-1alpha activation, responsible for expression of COX-2, MMP-2 and VEGF. Besides low VEGF levels, TAM CXB also suppresses VEGFR2 expression, confirmed through quantifying secreted VEGF levels, luciferase and RT-PCR studies. Interestingly, we observed that TAM CXB was effective in blocking VEGFR2 promoter induced expression and further 2 fold decrease in VEGF levels was observed in combination than TAM alone in both cell lines. Secondly, TAM-CXB regulated VEGFR2 inhibits Src expression, responsible for tumor progression and metastasis. FACS and in vivo enzymatic studies showed significant increase in the reactive oxygen species upon TAM-CXB treatment. CONCLUSIONS: Taken together, our experimental results indicate that this additive combination shows promising outcome in anti-metastatic and apoptotic studies. In a line, our preclinical studies evidenced that this additive combination of TAM and CXB is a potential drug candidate for treatment of breast tumors expressing high levels of VEGF and VEGFR2. This ingenious combination might be a better tailored clinical regimen than TAM alone for breast cancer treatment. PMID- 23731704 TI - The relationship between the number of CGG repeats and serum level of anti Mullerian hormone in women without FMR1 premutation. AB - OBJECTIVE: To investigate the relationship between the number of CGG repeats in the fragile X mental retardation 1 (FMR1) gene and serum levels of anti-Mullerian hormone (AMH) in Korean infertility patients without premutation. STUDY DESIGN: A retrospective study of 228 infertile women who received fertility treatment in a single private in vitro fertilization (IVF) clinic from May 2010 to August 2012 was performed. Serum FSH and AMH were measured on menstrual day 3 and the number of CGG repeats was evaluated. RESULTS: The mean age of the study population was 33.3+/-3.8 years. No significant correlation was observed between CGG repeat count in both alleles and the serum FSH, AMH or multiples of median (MoM) of AMH in whole study subjects. In women with age >=35 years, however, there was an increasing tendency in the MoM of AMH with increasing number of CGG repeats in allele 2 (R(2)=0.075, p=0.008). This correlation was not observed in patients aged less than 35 years. CONCLUSION: We observed a positive correlation between MoM of AMH and number of CGG repeats in allele 2 in women aged over 35 years. Our findings are discordant with other reports, and therefore further studies are needed to determine whether this discrepancy is due to ethnic differences. PMID- 23731705 TI - Parallel improvement of left ventricular geometry and filling pressure after transcatheter aortic valve implantation in high risk aortic stenosis: comparison with major prosthetic surgery by standard echo Doppler evaluation. AB - PURPOSE: The effect of Transcatheter Aortic Valve Implantation (TAVI) on left ventricular (LV) geometry and function was compared to traditional aortic replacement (AVR) by major surgery. METHODS: 45 patients with aortic stenosis (AS) undergoing TAVI and 33 AVR were assessed by standard echo Doppler the day before and 2 months after the implantation. 2D echocardiograms were performed to measure left ventricular (LV) mass index (LVMi), relative wall thickness (RWT), ejection fraction (EF) and the ratio between transmitral E velocity and early diastolic velocity of mitral annulus (E/e' ratio). Valvular-arterial impedance (Zva) was also calculated. RESULTS: At baseline, the 2 groups were comparable for blood pressure, heart rate, body mass index mean transvalvular gradient and aortic valve area. TAVI patients were older (p<0.0001) and had greater LVMi (p<0.005) than AVR group. After 2 months, both the procedures induced a significant reduction of transvalvular gradient and Zva but the decrease of LVMi and RWT was significant greater after TAVI (both p<0.0001). E/e' ratio and EF were significantly improved after both the procedure but E/e' reduction was greater after TAVI (p<0.0001). TAVI exhibited greater percent reduction in mean transvalvular gradient (p<0.05), Zva (p<0.02), LVMi (p<0.0001), RWT (p<0.0001) and E/e' ratio (p<0.0001) than AVR patients. Reduction of E/e' ratio was positively related with reduction of RWT (r = 0.46, p<0.002) only in TAVI group, even after adjusting for age and percent reduction of Zva (r =0.43, p<0.005). CONCLUSIONS: TAVI induces a greater improvement of estimated LV filling pressure in comparison with major prosthetic surgery, due to more pronounced recovery of LV geometry, independent on age and changes of hemodynamic load. PMID- 23731706 TI - Artificial neural network modeling of p-cresol photodegradation. AB - BACKGROUND: The complexity of reactions and kinetic is the current problem of photodegradation processes. Recently, artificial neural networks have been widely used to solve the problems because of their reliable, robust, and salient characteristics in capturing the non-linear relationships between variables in complex systems. In this study, an artificial neural network was applied for modeling p-cresol photodegradation. To optimize the network, the independent variables including irradiation time, pH, photocatalyst amount and concentration of p-cresol were used as the input parameters, while the photodegradation% was selected as output. The photodegradation% was obtained from the performance of the experimental design of the variables under UV irradiation. The network was trained by Quick propagation (QP) and the other three algorithms as a model. To determine the number of hidden layer nodes in the model, the root mean squared error of testing set was minimized. After minimizing the error, the topologies of the algorithms were compared by coefficient of determination and absolute average deviation. RESULTS: The comparison indicated that the Quick propagation algorithm had minimum root mean squared error, 1.3995, absolute average deviation, 3.0478, and maximum coefficient of determination, 0.9752, for the testing data set. The validation test results of the artificial neural network based on QP indicated that the root mean squared error was 4.11, absolute average deviation was 8.071 and the maximum coefficient of determination was 0.97. CONCLUSION: Artificial neural network based on Quick propagation algorithm with topology 4-10-1 gave the best performance in this study. PMID- 23731708 TI - Intermittent pneumatic compression in patients with stroke. PMID- 23731707 TI - Do community-level predictors of pneumococcal carriage continue to play a role in the conjugate vaccine era? AB - This paper examined whether previously identified community-level factors (high proportion of crowded households and/or persons below the poverty level) remained associated with childhood pneumococcal carriage in the heptavalent pneumococcal conjugate vaccine (PCV7) era. Using logistic regression, individual factors were used to develop base models to which community-level factors were added to evaluate impact on pneumococcal carriage within two paediatric study cohorts from Massachusetts (urban Boston, outside Boston). Six years after introduction of universal childhood PCV7 vaccination, we found no consistent evidence that census tract characteristics (e.g. population size and density, age and race distribution, percent participating in group childcare, parental education, percent lacking in-unit plumbing, poverty, and community stability) affected odds of pneumococcal carriage when added to individual predictors (e.g. younger age, current respiratory tract infections, and attendance in group childcare). How community-level factors influence pneumococcal carriage continues to change in the era of increasing immunization coverage. PMID- 23731709 TI - Improved visualisation of blood while wearing KTP laser protective eyewear using digital manipulation of endoscopic images: seventeen surgeons experience on simulation testing. PMID- 23731710 TI - Screening of osteoprotegerin-related feature genes in osteoporosis and functional analysis with DNA microarray. AB - BACKGROUND: Osteoporosis affects 200 million people worldwide and places an enormous economic burden on society. We aim to identify the feature genes that are related to osteoprotegerin in osteoporosis and to perform function analysis with DNA microarray from human bone marrow. METHODS: We downloaded the gene expression profile GSE35957 from Gene Expression Omnibus database including nine gene chips from bone marrow mesenchymal stem cells of five osteoporotic and four non-osteoporotic subjects. The differentially expressed genes between normal and disease samples were identified by LIMMA package in R language. The interactions among the osteoprotegerin gene (OPG) and differentially expressed genes were searched and visualized by Cytoscape. MCODE and Bingo were used to perform module analysis. Finally, GENECODIS was used to obtain enriched pathways of genes in an interaction network. RESULTS: A total of 656 genes were identified as differentially expressed genes between osteoporotic and non-osteoporotic samples. IL17RC, COL1A1, and ESR1 were identified to interact with OPG directly from the protein-protein interaction network. A module containing ERS1 was screened out, and this module was most significantly enriched in organ development. Pathway enrichment analysis suggested genes in the interaction network were related to focal adhesion. CONCLUSIONS: The expression pattern of IL17RC, COL1A1, and ESR1 can be useful in osteoporosis detection, which may help in identifying those populations at high risk for osteoporosis, and in directing treatment of osteoporosis. PMID- 23731711 TI - Inhibition of P-glycoprotein and glutathione S-transferase-pi mediated resistance by fluoxetine in MCF-7/ADM cells. AB - Chemotherapy is important in the systematic treatment of breast cancer. While multidrug resistance (MDR) is the main obstacle in chemotherapy, a reversal reagent with high reversal effect but low toxicity is the hotspot issue at present to overcome MDR. Antidepressant fluoxetine (FLX) is a potential new highly effective chemosensitizer, however, the possible mechanism is unclear. In this study, the effect of FLX on multidrug resistance mediated by P-glycoprotein (P-gp) and glutathione S-transferase-pi (GST-pi) were researched in resistant/sensitive breast cancer cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) was used to determine the cells viability after being incubated with FLX/Adriamycin (ADM)/Paclitaxel (PTX) alone or FLX-ADM, FLX PTX combination. Western blot was performed to assay the expression of P-gp and GST-pi proteins. Reverse transcriptase polymerase chain reaction (RT-PCR) and quantitative real-time PCR (qRT-PCR) were performed to assay the level of MDR1 mRNA. The results showed that pre-treatment with FLX enhance cytotoxicity significantly both on resistant and sensitive cells, downregulated the expression of P-gp and GST-pi proteins in resistance cells, decreased the MDR1 mRNA by FLX PTX combination only. No P-gp and GST-pi were detected in sensitive cells. Our research thus indicated that FLX reverse the breast cancer cell's resistance and enhance the chemosensitivity by regulating P-gp and GST-pi levels. PMID- 23731712 TI - The effects of preoperative renin-angiotensin system inhibitors on outcomes in patients undergoing cardiac surgery. AB - OBJECTIVE: The effects of preoperative (pre-op) renin-angiotensin system (RAS) inhibitors on outcomes in patients undergoing cardiac surgery remain uncertain. The aim of this study was to evaluate whether the use of pre-op RAS inhibitors affected major outcomes of cardiac surgery. DESIGN: A retrospective cohort study. SETTING: A university teaching hospital. PARTICIPANTS: Patients undergoing cardiac surgery between January 1, 2001 and December 31, 2011. INTERVENTIONS: One thousand two hundred thirty-nine patients who received pre-op RAS inhibitors were compared with those who did not (control group, n = 1,083). MEASUREMENTS AND MAIN RESULTS: Acute kidney injury (AKI) was defined using Acute Kidney Injury Network classification. Patients in the RAS inhibitors group presented with higher comorbidities. Pre-op RAS inhibitors therapy was associated with the reduction in the incidence of AKI (27.2% v 34.0%, p<0.001), septicemia (1.9% v 3.5%, p = 0.019), and operative mortality (2.99% v 4.62%, p = 0.039). After adjusted propensity scores and multivariate logistic regression, the pre-op RAS inhibitors were found to have protective effects against AKI (odds ratio [OR]: 0.764, 95% confidence interval [CI]: 0.670-0.873, p<0.001), septicemia (OR: 0.515, 95% CI: 0.348-0.761, p>0.001), and operative mortality (OR: 0.539, 95% CI: 0.348-0.758, p<0.001). CONCLUSION: The results suggested that pre-op RAS inhibitor therapy was associated with significant reductions in the risk of AKI, operative mortality, and septicemia. PMID- 23731713 TI - Doppler-based renal resistive index can assess progression of acute kidney injury in patients undergoing cardiac surgery. AB - OBJECTIVES: The objective of this study was to test whether assessment of renal resistive index measured after cardiac surgery (RRI(T0)) can diagnose persistent acute kidney injury (AKI). The predictive value was evaluated using a gray-zone approach. DESIGN: A prospective observational study. SETTING: A teaching university hospital. PARTICIPANTS: Eighty-two patients following cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Measurements of hemodynamic parameters and RRI were obtained before surgery, on admission to the intensive care unit, 6 hours after admission, and on the first postoperative day. AKI was defined according to the renal risk, injury, failure, loss of kidney function, end-stage of kidney disease (RIFLE) classification during the first postoperative week. Persistent AKI was defined as AKI lasting >3 days. MEASUREMENTS AND MAIN RESULTS: Out of the 82 patients, 15 (18%) developed persistent AKI, and 6 (7%) developed transient AKI. The median value and time-course of RRI were significantly different between patients with transient AKI and persistent AKI. Doppler-based RRI(T0) predicted persistent AKI with an area under the receiver operating characteristic curve of 0.93 (95% confidence interval: 0.85-0.98, p<0.0001). The optimal cut-off of RRI was 0.73 (95% confidence interval: 0.73 0.75). The gray-zone approach identified a range of RRI values between 0.72 and 0.75 in 14% of patients. CONCLUSIONS: Doppler-based RRI can be helpful for noninvasive assessment of renal function recovery after cardiac surgery by using RRI(T0) to predict persistent AKI. The optimal cut-off was 0.73 with a gray zone ranging between 0.72 and 0.75. PMID- 23731714 TI - Early detection of gut ischemia-reperfusion injury during aortic abdominal aneurysmectomy: a pilot, observational study. AB - OBJECTIVE: D-lactate is the enantiomer of L-lactate, which is measured routinely in clinical practice to assess cell hypoxia. D-lactate has been proposed as a specific marker of gut ischemia-reperfusion (IR), particularly during surgery for ruptured abdominal aortic aneurysms. The aim of this study was to compare the use of D-lactate measurement and colonic tonometry (taken as a reference method) for gut IR detection during elective infrarenal aortic aneurysm (IrAA) surgery. DESIGN: Prospective, monocenter, observational study. SETTING: Vascular surgery unit, university hospital. PARTICIPANTS: Candidates for elective IrAA surgery. INTERVENTIONS: Patients without (controls) and with gut IR (defined as DeltaCO2>2.6 kPa) were compared retrospectively. MEASUREMENT AND MAIN RESULTS: D lactate levels were compared with colonic perfusion levels (DeltaCO2), as assessed by colonic tonometry, at 7 time points during surgery and until 24 hours after surgery. D-lactate also was measured in mesenteric vein blood before and after gut reperfusion. Plasma TNF-alpha level was measured at the same time points to assess systemic inflammatory response. Eighteen patients requiring elective IrAA surgery were included. The DeltaCO2 and TNF-alpha level varied significantly over time. There was a significant DeltaCO2 peak at the end of clamping (2.6+/-1.8 kPa, p = 0.006) and a significant peak in TNF-alpha level after 1 hour of reperfusion (183+/-53 ng/L, p = 0.05). D-lactate levels were undetectable in systemic and mesenteric blood in all the patients throughout the study period. Gut IR patients (n = 6) experienced a longer overall duration of intraoperative hypotensive episodes and received more catecholamines than the controls (n = 12). CONCLUSIONS: Compared with colonic tonometry, D-lactate was not a reliable biomarker of gut IR during elective IrAA surgery. PMID- 23731715 TI - Meta-omic characterization of prokaryotic gene clusters for natural product biosynthesis. AB - Microorganisms produce a remarkable selection of bioactive small molecules. The study and exploitation of these secondary metabolites have traditionally been restricted to the cultivable minority of bacteria. Rapid advances in meta-omics challenge this paradigm. Breakthroughs in metagenomic library methodologies, direct sequencing, single cell genomics, and natural product-specific bioinformatic tools now facilitate the retrieval of previously inaccessible biosynthetic gene clusters. Similarly, metaproteomic developments enable the direct study of biosynthetic enzymes from complex microbial communities. Additional methods within and beyond meta-omics are also in development. This review discusses recent reports in these arenas and how they can be utilized to characterize natural product biosynthetic gene clusters and pathways. PMID- 23731716 TI - Conjugation, characterization and toxicity of lipophosphoglycan-polyacrylic acid conjugate for vaccination against leishmaniasis. AB - Research on the conjugates of synthetic polyelectrolytes with antigenic molecules, such as proteins, peptides, or carbohydrates, is an attractive area due to their highly immunogenic character in comparison to classical adjuvants. For example, polyacrylic acid (PAA) is a weak polyelectrolyte and has been used in several biomedical applications such as immunological studies, drug delivery, and enzyme immobilization. However, to our knowledge, there are no studies that document immune-stimulant properties of PAA in Leishmania infection. Therefore, we aimed to develop a potential vaccine candidate against leishmaniasis by covalently conjugating PAA with an immunologically vital molecule of lipophosphoglycan (LPG) found in Leishmania parasites. In the study, LPG and PAA were conjugated by a multi-step procedure, and final products were analyzed with GPC and MALDI-TOF MS techniques. In cytotoxicity experiments, LPG-PAA conjugates did not indicate toxic effects on L929 and J774 murine macrophage cells. We assume that LPG-PAA conjugate can be a potential vaccine candidate, and will be immunologically characterized in further studies to prove its potential. PMID- 23731717 TI - Associations between oral health-related impacts and rate of weight gain after extraction of pulpally involved teeth in underweight preschool Filipino children. AB - BACKGROUND: Severe dental caries in young children is associated with underweight and failure to thrive. One possible mechanism for severe caries affecting growth is that the resulting pain and discomfort influences sleeping and eating, and that affects growth and weight. The objective of this study was to assess whether rate of weight gain after extraction of severely decayed teeth in underweight preschool Filipino children was related to reductions in oral health-related impacts and dental pain from severe dental caries affecting eating and sleeping. METHODS: Data are from the Weight Gain Study, a stepped wedge cluster randomized clinical trial where underweight Filipino children with severe dental decay had their pulpally involved teeth extracted. Day care centers were randomly divided into two groups; A and B. Group A children received treatment first and Group B children were treated four months after Group A. Clinical oral examinations used WHO criteria and the pufa-index. Self-reported oral health-related impacts and anthropometric measurements were collected for both groups at baseline, four months after treatment of Group A children and four months after treatment of Group B children. Weight-for-age z-scores were calculated using 2006 and 2007 WHO standards. Data were converted to a one-group pre-test post-test study design, where all children received treatment. Associations between changes in oral health-related impacts and weight-for-age z-scores after dental treatment were assessed. RESULTS: Data on 145 children (mean age 61.4 months) were analyzed. There was a significant association between oral health-related impacts and rate of weight gain after extraction of pulpally involved teeth (p=0.02). Children free of impacts on sleeping related to having severely decayed teeth extracted gained significantly more weight compared to children who reported sleeping problems after dental treatment (p<0.01). CONCLUSIONS: After extraction of severely decayed teeth in underweight Filipino children, levels of oral health related impacts were associated with rate of weight gain. Decreases in oral health impacts on sleeping appeared to be most strongly associated with weight gain. TRIAL REGISTRATION: ISRCTN: ISRCTN90779069. PMID- 23731718 TI - Pushing the science forward: chitosan nanoparticles and functional repair of CNS tissue after spinal cord injury. AB - BACKGROUND: We continue our exploration of the large polysaccharide polymer Chitosan as an acute therapy for severe damage to the nervous system. We tested the action of subcutaneously injected nanoparticles (~ 100 - 200 nanometers in diameter; 1 mg per ml) against control injections (silica particle of the same size and concentration) in a standardized in vivo spinal cord injury model. These functional tests used standardized physiological measurements of evoked potentials arriving at the sensorimotor cortex subsequent to stimulation of the tibial nerve of the contralateral hindlimb. We further explored the degree of acetylation and molecular weight of chitosan on the success of sealing cell damage using specific probes of membrane integrity. RESULTS: Not one of the control group showed restored conduction of evoked potentials stimulated from the tibial nerve of the hindleg - through the lesion - and recorded at the sensorimotor cortex of the brain. Investigation if the degree of acetylation and molecular weight impacted "membrane sealing" properties of Chitosan were unsuccessful. Dye - exchange membrane probes failed to show a difference between the comparators in the function of Chitosan in ex vivo injured spinal cord tests. CONCLUSIONS: We found that Chitosan nanoparticles effectively restore nerve impulse transmission through the crushed adult guinea pig spinal cord in vivo after severe crush/compression injury. The tests of the molecular weight (MW) and degree of acetylation did not produce any improvement in Chitosan's membrane sealing properties. PMID- 23731719 TI - Biomechanical simulation of the fetal descent without imposed theoretical trajectory. AB - The medical training concerning childbirth for young obstetricians involves performing real deliveries, under supervision. This medical procedure becomes more complicated when instrumented deliveries requiring the use of forceps or suction cups become necessary. For this reason, the use of a versatile, configurable childbirth simulator, taking into account different anatomical and pathological cases, would provide an important benefit in the training of obstetricians, and improve medical procedures. The production of this type of simulator should be generally based on a computerized birth simulation, enabling the computation of the reproductive organs deformation of the parturient woman and fetal interactions as well as the calculation of efforts produced during the second stage of labor. In this paper, we present a geometrical and biomechanical modeling of the main parturient's organs involved in the birth process, interacting with the fetus. Instead of searching for absolute precision, we search to find a good compromise between accuracy and model complexity. At this stage, to verify the correctness of our hypothesis, we use finite element analysis because of its reliability, precision and stability. Moreover, our study improves the previous work carried out on childbirth simulators because: (a) our childbirth model takes into account all the major organs involved in birth process, thus potentially enabling different childbirth scenarios; (b) fetal head is not treated as a rigid body and its motion is computed by taking into account realistic boundary conditions, i.e. we do not impose a pre-computed fetal trajectory; (c) we take into account the cyclic uterine contractions as well as voluntary efforts produced by the muscles of the abdomen; (d) a slight pressure is added inside the abdomen, representing the residual muscle tone. The next stage of our work will concern the optimization of our numerical resolution approach to obtain interactive time simulation, enabling it to be coupled to our haptic device. PMID- 23731720 TI - Micro-Analyzer: automatic preprocessing of Affymetrix microarray data. AB - A current trend in genomics is the investigation of the cell mechanism using different technologies, in order to explain the relationship among genes, molecular processes and diseases. For instance, the combined use of gene expression arrays and genomic arrays has been demonstrated as an effective instrument in clinical practice. Consequently, in a single experiment different kind of microarrays may be used, resulting in the production of different types of binary data (images and textual raw data). The analysis of microarray data requires an initial preprocessing phase, that makes raw data suitable for use on existing analysis platforms, such as the TIGR M4 (TM4) Suite. An additional challenge to be faced by emerging data analysis platforms is the ability to treat in a combined way those different microarray formats coupled with clinical data. In fact, resulting integrated data may include both numerical and symbolic data (e.g. gene expression and SNPs regarding molecular data), as well as temporal data (e.g. the response to a drug, time to progression and survival rate), regarding clinical data. Raw data preprocessing is a crucial step in analysis but is often performed in a manual and error prone way using different software tools. Thus novel, platform independent, and possibly open source tools enabling the semi-automatic preprocessing and annotation of different microarray data are needed. The paper presents Micro-Analyzer (Microarray Analyzer), a cross-platform tool for the automatic normalization, summarization and annotation of Affymetrix gene expression and SNP binary data. It represents the evolution of the MU-CS tool, extending the preprocessing to SNP arrays that were not allowed in MU-CS. The Micro-Analyzer is provided as a Java standalone tool and enables users to read, preprocess and analyse binary microarray data (gene expression and SNPs) by invoking TM4 platform. It avoids: (i) the manual invocation of external tools (e.g. the Affymetrix Power Tools), (ii) the manual loading of preprocessing libraries, and (iii) the management of intermediate files, such as results and metadata. Micro-Analyzer users can directly manage Affymetrix binary data without worrying about locating and invoking the proper preprocessing tools and chip specific libraries. Moreover, users of the Micro-Analyzer tool can load the preprocessed data directly into the well-known TM4 platform, extending in such a way also the TM4 capabilities. Consequently, Micro Analyzer offers the following advantages: (i) it reduces possible errors in the preprocessing and further analysis phases, e.g. due to the incorrect choice of parameters or due to the use of old libraries, (ii) it enables the combined and centralized pre-processing of different arrays, (iii) it may enhance the quality of further analysis by storing the workflow, i.e. information about the preprocessing steps, and (iv) finally Micro-Analzyer is freely available as a standalone application at the project web site http://sourceforge.net/projects/microanalyzer/. PMID- 23731721 TI - OnabotulinumtoxinA for idiopathic overactive bladder symptoms: many answers but more questions. PMID- 23731722 TI - Male lower urinary tract symptoms: a riddle waiting to be solved. PMID- 23731723 TI - The Mussel Watch California pilot study on contaminants of emerging concern (CECs): synthesis and next steps. AB - A multiagency pilot study on mussels (Mytilus spp.) collected at 68 stations in California revealed that 98% of targeted contaminants of emerging concern (CECs) were infrequently detectable at concentrations <= 1 ng/g. Selected chemicals found in commercial and consumer products were more frequently detected at mean concentrations up to 470 ng/g dry wt. The number of CECs detected and their concentrations were greatest for stations categorized as urban or influenced by storm water discharge. Exposure to a broader suite of CECs was also characterized by passive sampling devices (PSDs), with estimated water concentrations of hydrophobic compounds correlated with Mytilus concentrations. The results underscore the need for focused CEC monitoring in coastal ecosystems and suggest that PSDs are complementary to bivalves in assessing water quality. Moreover, the partnership established among participating agencies led to increased spatial coverage, an expanded list of analytes and a more efficient use of available resources. PMID- 23731725 TI - Reduced fractional shortening of right ventricular outflow tract is associated with adverse outcomes in patients with left ventricular dysfunction. AB - BACKGROUND: Recent studies suggest the significance of right ventricular (RV) function in the outcome in patients with left ventricular dysfunction (LVSD); however, global assessment of RV remains to be determined by echocardiogram because of its complex geometry. This study aimed to validate RV outflow tract fractional shortening (RVOT-FS) in the evaluation of RV function and its prognostic value in patients with LVSD. METHODS: This study included eighty-one patients (62 +/- 17 years, mean +/- SD, male 79%) with reduced LV ejection fraction (LVEF) (<=40%). Two-dimensional echocardiogram of the parasternal short axis view was obtained at the level of the aortic root, and RVOT-FS was calculated as the ratio of end-diastole minus end-systole dimension to end diastole dimension. RESULTS: RVOT-FS ranged from 0.04 to 0.8 (0.3 +/- 0.2, mean +/- SD), and correlated with LVEF (r = 0.33, p = 0.0028), RV fractional area change (r = 0.37, p = 0.0008) and brain natriuretic peptide level (r = -0.38, p = 0.0005). In Cox multivariate regression analysis, RVOT-FS [hazard ratio (HR) 0.028, 95% confidence interval (CI): 0.002-0.397]; p = 0.008] and New York Heart Association functional class III-IV [HR 2.233, 95% CI: 1.048-4.761]; p = 0.037] were independent factors to predict the events. During a median follow-up period of 319 days (1 to 1862 days), patients with RVOT-FS >= 0.2 showed a higher event free rate than those < 0.2 by Kaplan-Meier analysis (log-rank test, p = 0.0016). CONCLUSIONS: Our data suggest that RVOT-FS is a simple parameter reflecting the severity of both ventricular function in patients with LVSD. In addition, RVOT-FS might be useful to predict adverse outcomes in such a patient population. PMID- 23731726 TI - Early fibroblast progenitor cell migration to the AngII-exposed myocardium is not CXCL12 or CCL2 dependent as previously thought. AB - Fibroblast progenitor cells (fibrocytes) are important to the development of myocardial fibrosis and are suggested to migrate to the heart via CXCL12 and chemokine ligand (CCL) 2. We hypothesized that if these chemokines are recruiting fibrocytes, disrupting their signaling will reduce early (3-day) fibrocyte infiltration and, consequently, fibrosis in the myocardium. C57/Bl6 and CCR2(-/-) mice were infused with saline or angiotensin (Ang) II, with or without CXC receptor 4 blockade (AMD3100). Hearts were assessed for chemokine up-regulation, immunofluorescence, and histological features. AngII caused early myocardial up regulation of CXCL12 and CCL2, which corresponded to significant myocardial infiltration and fibrosis compared with controls. Animals receiving AMD3100 and/or with the genotype CCR2(-/-) failed to demonstrate reductions in infiltrate or fibrosis after 3 days of AngII, and AngII + AMD3100 animals showed exacerbated fibrocyte infiltration and fibrosis compared with AngII alone. CCR2(-/-) mice demonstrated significant reductions in myocardial fibrosis relative to wild type, but this was after 28 days of AngII infusion and was the result of reduced infiltrating cell proliferation. An alternative CCR2 ligand, CCL12, was found to be increasing infiltrating cell proliferation in the heart after AngII infusion, which we confirmed in vitro. In conclusion, early fibrocyte recruitment cannot be inhibited through modulating CXCL12 or CCL2, as previously thought. Ablating CCR2 signaling did confer myocardial fibrosis reductions, but these benefits were not observed until much later and were likely the result of modulated proliferation through ablating the CCL12-CCR2 interaction. PMID- 23731727 TI - Inhibition of CCR7/CCL19 axis in lesional skin is a critical event for clinical remission induced by TNF blockade in patients with psoriasis. AB - Despite the evidence that tumor necrosis factor (TNF) inhibitors block TNF and the downstream inflammatory cascade, their primary mechanism of action in inhibiting the self-sustaining pathogenic cycle in psoriasis is not completely understood. This study has the aim to identify early critical events for the resolution of inflammation in skin lesions using anti-TNF therapy. We used a translational approach that correlates gene expression fold change in lesional skin with the Psoriasis Area and Severity Index score decrease induced by TNF blockade after 4 weeks of treatment. Data were validated by immunofluorescence microscopy on skin biopsy specimens. We found that the anti-TNF-modulated genes that mostly associated with the clinical amelioration were Ccr7, its ligand, Ccl19, and dendritic cell maturation genes. Decreased expression of T-cell activation genes and Vegf also associated with the clinical response. More important, the down-regulation of Ccr7 observed at 4 weeks significantly correlated with the clinical remission occurring at later time points. Immunofluorescence microscopy on skin biopsy specimens showed that reduction of CCR7(+) cells and chemokine ligand (CCL) 19 was paralleled by disaggregation of the dermal lymphoid-like tissue. These data show that an early critical event for the clinical remission of psoriasis in response to TNF inhibitors is the inhibition of the CCR7/CCL19 axis and support its role in psoriasis pathogenesis. PMID- 23731728 TI - Algorithm based on eighteen patients with acquired traumatic earlobe defects not associated with jewellery. PMID- 23731729 TI - The drug efflux pump Pgp1 in pro-inflammatory lymphocytes is a target for novel treatment strategies in COPD. AB - BACKGROUND: Pro-inflammatory/cytotoxic T cells (IFNgamma, TNFalpha, granzyme B+) are increased in the peripheral circulation in COPD. NKT-like and NK cells are effector lymphocytes that we have also shown to be major sources of pro inflammatory cytokines and granzymes. P-glycoprotein 1 (Pgp1) is a transmembrane efflux pump well characterised in drug resistant cancer cells. We hypothesized that Pgp1 would be increased in peripheral blood T, NKT-like and NK cells in patients with COPD, and that this would be accompanied by increased expression of IFNgamma, TNFalpha and granzyme B. We further hypothesized that treatment with cyclosporine A, a Pgp1 inhibitor, would render cells more sensitive to treatment with corticosteroids. METHODS: Pgp1, granzyme B, IFNgamma and TNFalpha expression were measured in peripheral blood T, NK and NKT-like cells from COPD patients and control subjects (+/- cyclosporine A and prednisolone) following in vitro stimulation and results correlated with uptake of efflux dye Calcein-AM using flow cytometry. RESULTS: There was increased Pgp1 expression by peripheral blood T, NKT-like and NK cells co-expressing IFNgamma, TNFalpha and granzyme B in COPD patients compared with controls (e.g. %IFNgamma/Pgp1 T, NKT-like, NK for COPD (Control): 25(6), 54(27), 39(23)). There was an inverse correlation between Pgp1 expression and Calcein-AM uptake. Treatment with 2.5 ng/ml cylosporin A and10-6 M prednisolone resulted in synergistic inhibition of pro-inflammatory cytokines in Pgp1 + cells (p < 0.05 for all). CONCLUSIONS: Treatment strategies that target Pgp1 in T, NKT-like and NK cells may reduce systemic inflammatory mediators in COPD and improve patient morbidity. PMID- 23731730 TI - Measuring the effect of influenza A(H1N1)pdm09: the epidemiological experience in the West Midlands, England during the 'containment' phase. AB - The West Midlands was the first English region to report sustained community transmission during the 'containment' phase of the influenza A(H1N1)pdm09 pandemic in England. To describe the epidemiological experience in the region, West Midlands and national datasets containing laboratory-confirmed A(H1N1)pdm09 virus cases in the region during the 'containment' phase were analysed. The region accounts for about 10.5% of England's population, but reported about 42% of all laboratory-confirmed cases. Altogether 3063 cases were reported, with an incidence rate of 56/100 000 population. School-associated cases accounted for 25% of cases. Those aged <20 years, South Asian ethnic groups, and residents of urban and socioeconomically deprived areas were disproportionately affected. Imported cases accounted for 1% of known exposures. Regional R 0 central estimates between 1.41 and 1.43 were obtained. The West Midlands experience suggests that interpretation of transmission rates may be affected by complex interactions within and between sub-populations in the region. PMID- 23731731 TI - The appropriateness of the mouse model for ataxia-telangiectasia: neurological defects but no neurodegeneration. AB - Patients with ataxia-telangiectasia (A-T) are characterised by genome instability, cancer predisposition and a progressive neurodegeneration. A number of model systems have been developed for A-T but none recapitulate all the phenotype. The majority of these models have been generated in mice. While Atm deficient mouse models exhibit much of the phenotype described in patients with A T, the broad consensus is that they do not display the most debilitating aspect of A-T, i.e. neurodegeneration. Cerebellar atrophy is one of the neuronal characteristics of A-T patients due to defects in neuronal development and progressive loss of Purkinje and granule cells. This is not evident in Atm deficient mutants but there are multiple reports on neurological abnormalities in these mice. The focus of this review is to evaluate the appropriateness of Atm mutant mouse models for A-T, particularly with reference to neurological abnormalities and how they might relate to neurodegeneration. PMID- 23731732 TI - Role of PCNA and TLS polymerases in D-loop extension during homologous recombination in humans. AB - Homologous recombination (HR) is essential for maintaining genomic integrity, which is challenged by a wide variety of potentially lethal DNA lesions. Regardless of the damage type, recombination is known to proceed by RAD51 mediated D-loop formation, followed by DNA repair synthesis. Nevertheless, the participating polymerases and extension mechanism are not well characterized. Here, we present a reconstitution of this step using purified human proteins. In addition to Pol delta, TLS polymerases, including Pol eta and Pol kappa, also can extend D-loops. In vivo characterization reveals that Pol eta and Pol kappa are involved in redundant pathways for HR. In addition, the presence of PCNA on the D loop regulates the length of the extension tracks by recruiting various polymerases and might present a regulatory point for the various recombination outcomes. PMID- 23731733 TI - Peripheral blood pressure by Dinamap and central blood pressure by applanation tonometry in outpatient general practice. AB - INTRODUCTION: Central blood pressure (CBP) is the pressure exerted by the blood column at any given moment on the aortic and carotid artery walls, which is a close proxy for the blood pressure inside the brain and the heart, and is thus a better marker of cardiovascular morbidity and mortality than peripheral blood pressure (PBP). OBJECTIVE: To assess how the augmentation index (AI), peripheral pulse pressure (pPP), central pulse pressure (cPP) and subendocardial viability ratio (SEVR) vary in hypertensive patients according to level of control of CBP and PBP. METHODS: We performed an observational, cross-sectional study in a convenience sample from a general practice in Central Portugal over a period of four days in May 2010. Measurements were taken after a four-minute resting period. The following values were considered to reflect controlled pressures: PBP <140/90 mmHg, CBP <130/80 mmHg, pPP <55 mmHg and cPP <45 mmHg. RESULTS: The sample included 92 patients, 38 male (41.3%), mean age 62.3+/-11.1 years, with no significant difference in gender distribution. PBP was controlled in 55 (59.8%), and CBP in 53 (57.6%). Both PBP and CBP were controlled in 50 patients (54.3%) and neither was controlled in 34 (37.9%). pPP and cPP were significantly lower in those with controlled PBP (p<0.001) and CBP (p<0.001). AI was non-significantly lower in those with controlled PBP (78+/-9 vs. 80.7) and those with controlled CBP (78+/-9 vs.81+/-7) (p=0.02). SEVR was within the desirable range in 92 patients (92.2%). 78.4% of individuals were taking drugs acting on the renin angiotensin aldosterone system (RAAS). CONCLUSIONS: In a convenience sample of 92 patients, PBP and CBP were controlled in 59.8% and 57.6%, respectively. Those with controlled PBP had significantly better peripheral systolic and diastolic blood pressure, CBP, pPP and cPP; the same was true of those with controlled CBP, who also had a significantly better AI. The percentage of the cardiac cycle in diastole had a desirable value for 92,2% of the subjects. PMID- 23731734 TI - Iodine-123-metaiodobenzylguanidine scintigraphy in risk stratification of sudden death in heart failure. AB - Metaiodobenzylguanidine (MIBG) is a false neurotransmitter noradrenaline analogue that is taken up by the 'uptake 1' transporter mechanism in the cell membrane of presynaptic adrenergic neurons and accumulates in catecholamine storage vesicles. Since it is practically unmetabolized, it can be labeled with a radioisotope (iodine-123) in scintigraphic exams to noninvasively assess the functional status of the sympathetic innervation of organs with a significant adrenergic component, including the heart. Studies of its application in nuclear cardiology appear to confirm its value in the assessment of conditions such as coronary artery disease, heart failure, arrhythmias and sudden death. Heart failure is a global problem, with an estimated prevalence of 2% in developed countries. Sudden cardiac death is the main cause of its high mortality. The autonomic nervous system dysfunction, including sympathetic hyperactivity, that accompanies chronic heart failure is associated with progressive myocardial remodeling, declining left ventricular function and worsening symptoms, and contributes to the development of ventricular arrhythmias and sudden death. Since 123I-MIBG cardiac scintigraphy can detect changes in the cardiac adrenergic system, there is considerable interest in its role in obtaining diagnostic and prognostic information in patients with heart failure. In this article we present a literature review on the use of 123I-MIBG scintigraphy for risk stratification of sudden death in patients with heart failure. PMID- 23731735 TI - What is the future for left atrial appendage closure? PMID- 23731736 TI - A case of pulmonary thromboembolism and aortic dissection: the role of echocardiography. PMID- 23731737 TI - Extensor Pollicis Brevis tendon damage presenting as de Quervain's disease following kettlebell training. AB - Kettlebell exercises are more efficient for an athlete to increase his or her muscle strength. However it carries the risk of injury especially in the beginners. A 39 year old gentleman came to our clinic with radial sided wrist pain following kettlebell exercises. Clinically patient had swelling and tenderness over the tendons in the first dorsal wrist compartment, besides Finklesten test was positive. Patient had a decreased excursion of the thumb when compared to the opposite side. Ultrasound/MRI scan revealed asymmetric thickening of the 1st compartment extensors extending from the base of the thumb to the wrist joint. Besides injury to the Extensor Pollicis Brevis (EPB) tendon by repetitive impact from kettlebell, leading to its split was identified. Detailed history showed that the injury might be due to off-centre handle holding during triceps strengthening exercises. Our report stresses the fact that kettlebell users should be taught about problems of off-center handle holding to avoid wrist injuries. Also, in Kettlebell users with De Quervains disease clinical and radiological evaluation should be done before steroid injection as this might lead to complete tendon rupture. PMID- 23731738 TI - Upsizing of a Berlin Heart EXCOR pediatric left ventricular assist device to achieve adequate flow requirement. PMID- 23731739 TI - A case of lung adenocarcinoma harboring exon 19 EGFR deletion and EML4-ALK fusion gene. AB - We report a man with advanced adenocarcinoma who harboring exon 19 (E746-A750del) epidermal growth factor receptor (EGFR) deletion and echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) gene translocation in the re-biospy specimen. The patient was treated with erlotinib with a stable disease but progressed slowly, while crizotinib showed a complete response. PMID- 23731740 TI - Extra-thoracic tumor burden but not thoracic tumor burden on (18)F-FDG PET/CT is an independent prognostic biomarker for extensive-disease small cell lung cancer. AB - PURPOSE: The aim of this study was to evaluate the relationship and difference in prognostic significance between whole-body tumor burden, thoracic tumor burden, and extra-thoracic tumor burden on (18)F-FDG PET/CT for patients with extensive disease small cell lung cancer (ED-SCLC). MATERIALS AND METHODS: We performed a retrospective, two-center analysis for patients with ED-SCLC who underwent pretreatment (18)F-FDG PET/CT. Metabolic tumor burden was estimated using whole body metabolic tumor volume (MTV(WB)), thoracic metabolic tumor volume (MTV(TRX)), extra-thoracic metabolic tumor volume (MTV(EXT)), and the number of extra-thoracic tumor foci. Uni- and multivariate analyses were performed using various clinical factors and the metabolic indices. RESULTS: A total of 91 patients were eligible for this study. MTV(WB) showed stronger correlation with MTV(EXT) than MTV(TRX) (r(2) = 0.804 vs. 0.132, p < 0.001, both), whereas no correlation was observed between MTV(EXT) and MTV(TRX) (r(2) = 0.007, p = 0.428). Patients with smaller MTV(WB), MTV(EXT), and extra-thoracic tumor foci showed longer survival than patients with larger MTV(WB), MTV(EXT), and extra-thoracic tumor foci, respectively, whereas the survival difference between patients with smaller MTV(TRX) and those with larger MTV(TRX) was not significant. Results of uni- and multivariate analyses showed that ECOG performance status (HR = 2.31, p = 0.015), initial chemotherapy cycles (HR = 0.24, p < 0.001), and the number of extra-thoracic tumor foci (HR = 2.75, p < 0.001) were independent prognostic factors for overall survival, and initial chemotherapy cycles (HR = 0.25, p < 0.001), and MTV(EXT) (HR = 2.04, p = 0.013) were independent prognostic factors for progression-free survival. CONCLUSION: These data provide evidence indicating that extra-thoracic tumor burden but not thoracic tumor burden is an independent prognostic biomarker for ED-SCLC, and support further exploration of novel treatment strategies targeting extra-thoracic tumor burden in order to improve the clinical outcomes of patients with ED-SCLC. PMID- 23731741 TI - Neurofunctional effects of methylphenidate and atomoxetine in boys with attention deficit/hyperactivity disorder during time discrimination. AB - BACKGROUND: The catecholamine agonists methylphenidate and atomoxetine effectively treat attention-deficit/hyperactivity disorder (ADHD). Furthermore, dopamine agonists have shown to improve time estimation in ADHD, a core cognitive deficit. However, few have compared the effects of methylphenidate and atomoxetine on brain function in ADHD, and none during time estimation. Using single dose challenges, we investigated shared and drug-specific effects in ADHD adolescents on the neural substrates of time discrimination (TD). METHODS: Twenty ADHD adolescent male subjects were compared in a randomized double-blind cross over design after single doses of methylphenidate, atomoxetine, and placebo in functional magnetic resonance imaging during TD. Normalization effects were assessed by comparing brain activation under each drug condition with that of 20 healthy age-matched control subjects. RESULTS: Relative to control subjects, patients under placebo showed TD deficits and reduced activation of ventrolateral prefrontal cortex (VLPFC)/insula, inferior frontal cortex, and supplementary motor area. Performance differences were normalized only by methylphenidate, relative to both atomoxetine and placebo. Both medications, however, significantly upregulated right VLPFC/insula activation within patients and normalized its underactivation in ADHD boys under placebo relative to control subjects. The supplementary motor area and inferior frontal cortex activation differences that were observed under placebo were reduced by methylphenidate and atomoxetine, respectively, but neither survived rigorous testing for normalization. CONCLUSIONS: While only methylphenidate had a drug-specific effect of improving TD performance deficits, both drugs significantly upregulated and normalized right VLPFC underactivation in ADHD boys under placebo relative to control subjects, suggesting shared effects of stimulants and nonstimulants on a key prefrontal dysfunction during timing. PMID- 23731742 TI - How to assess common somatic symptoms in large-scale studies: a systematic review of questionnaires. AB - OBJECTIVE: Many questionnaires for assessment of common somatic symptoms or functional somatic symptoms are available and their use differs greatly among studies. The prevalence and incidence of symptoms are partially determined by the methods used to assess them. As a result, comparison across studies is difficult. This article describes a systematic review of self-report questionnaires for somatic symptoms for use in large-scale studies and recommends two questionnaires for use in such studies. METHODS: A literature search was performed in the databases Medline, PsycINFO and EMBASE. Articles that reported the development, evaluation, or review of a self-report somatic symptom measure were included. Instrument evaluation was based on validity and reliability, and their fitness for purpose in large scale studies, according to the PhenX criteria. RESULTS: The literature search identified 40 questionnaires. The number of items within the questionnaires ranged from 5 to 78 items. In 70% of the questionnaires, headaches were included, followed by nausea/upset stomach (65%), shortness of breath/breathing trouble (58%), dizziness (55%), and (low) back pain/backaches (55%). Data on validity and reliability were reported and used for evaluation. CONCLUSION: Questionnaires varied regarding usability and burden to participants, and relevance to a variety of populations and regions. Based on our criteria, the Patient Health Questionnaire-15 and the Symptom Checklist-90 somatization scale seem the most fit for purpose for use in large-scale studies. These two questionnaires have well-established psychometric properties, contain relevant symptoms, are relatively short, and are available in multiple languages. PMID- 23731743 TI - Rasch scalability of the somatosensory amplification scale: a mixture distribution approach. AB - OBJECTIVE: Somatosensory amplification refers to a person's tendency to experience somatic sensations as inappropriately intense and involves hypervigilance concerning bodily sensations. We applied the Somatosensory Amplification Scale (SSAS) in an Internet sample of young adults (N=3031) to test whether the SSAS is Rasch scalable. METHODS: We applied mixture distribution extensions of the partial credit and rating scale models to identify possible subgroups that use the response set of the SSAS in different ways. RESULTS: A partial credit model, with two latent classes, showed a superior fit to all other models. Still, one of the SSAS items had to be removed because it showed severe underfit. Overall fit of the remaining items was acceptable, although the differentiation between at least two of the five item categories was questionable in both classes. Class 1 was characterized by a higher SSAS sum score, female gender, more somatic complaints, more anxiety, more psychosocial stress, and slightly higher depressiveness. Further exploratory analyses showed that the three mid categories of the SSAS can be collapsed without a large loss of information. CONCLUSIONS: Our results show that a shortened version of the SSAS is Rasch scalable but also reveal that there is a lot of room for further improvements of the scale. Based on our results, Item 1 should be removed from the scale and a reduction of the number of response categories is probably warranted. PMID- 23731744 TI - Somatization is associated with deficits in affective Theory of Mind. AB - OBJECTIVE: To determine whether deficits in mental representation of emotion may constitute a mechanism for somatization. METHODS: In this case-control study, we obtained measures of cognitive and affective Theory of Mind, emotional awareness, positive and negative affect, depression, anxiety, and physical symptoms and determined psychiatric diagnoses in consecutive outpatients, aged 19 to 60, with Conversion Disorder (n=29), Functional Somatic Syndromes (n=30), or "explained" Medical Disorders (Controls) (n=30). Main outcome measure was the Animations-L score, i.e., use of words describing emotional content while performing the Frith Happe Animations (video) Task, an established Theory of Mind measure in which the emotional content of a story is conveyed through movement. RESULTS: Groups were similar in number of physical symptoms, negative affect, and ability to describe emotional experiences on a written measure that specifically solicited such descriptions. Conversion Disorder and Functional Somatic Syndrome groups scored lower on Animations-L, endorsed significantly less positive affect, and had more anxiety than Medical Controls. Animations-L and positive affect scores were predictive of group membership, with lower scores predicting somatizing conditions. CONCLUSIONS: Relative to Medical Controls, a deficit in the encoding and reporting of emotion when the emotional content of the stimulus is conveyed in action occurs equally in Conversion Disorder and Functional Somatic Syndrome patients and is consistent with previous findings in somatoform disorder inpatients. Difficulty with "conversion" from implicit (action, somatic) to explicit (representational) processing of emotions, exacerbated by anxiety, may constitute a mechanism for somatization. PMID- 23731745 TI - Which psychological factors exacerbate irritable bowel syndrome? Development of a comprehensive model. AB - OBJECTIVE: There is evidence that psychological factors affect the onset, severity and duration of irritable bowel syndrome (IBS). However, it is not clear which psychological factors are the most important and how they interact. The aims of the current study are to identify the most important psychological factors predicting IBS symptom severity and to investigate how these psychological variables are related to each other. METHODS: Study participants were 286 IBS patients who completed a battery of psychological questionnaires including neuroticism, abuse history, life events, anxiety, somatization and catastrophizing. IBS severity measured by the IBS Severity Scale was the dependent variable. Path analysis was performed to determine the associations among the psychological variables, and IBS severity. RESULTS: Although the hypothesized model showed adequate fit, post hoc model modifications were performed to increase prediction. The final model was significant (Chi(2)=2.2; p=0.82; RMSEA<.05) predicting 36% of variance in IBS severity. Catastrophizing (standardized coefficient (beta)=0.33; p<.001) and somatization (beta=0.20; p<.001) were the only two psychological variables directly associated with IBS severity. Anxiety had an indirect effect on IBS symptoms through catastrophizing (beta=0.80; p<.001); as well as somatization (beta=0.37; p<.001). Anxiety, in turn, was predicted by neuroticism (beta=0.66; p<.001) and stressful life events (beta=0.31; p<.001). CONCLUSION: While cause-and-effect cannot be determined from these cross-sectional data, the outcomes suggest that the most fruitful approach to curb negative effects of psychological factors on IBS is to reduce catastrophizing and somatization. PMID- 23731746 TI - Negative aspects of close relationships are more strongly associated than supportive personal relationships with illness burden of irritable bowel syndrome. AB - OBJECTIVE: This study assessed the relative magnitude of associations between IBS outcomes and different aspects of social relationships (social support, negative interactions). METHOD: Subjects included 235 Rome III diagnosed IBS patients (M age=41yrs, F=78%) without comorbid GI disease. Subjects completed a testing battery that included the Interpersonal Support Evaluation List (Social Support or SS), Negative Interaction (NI) Scale, IBS Symptom Severity Scale (IBS-SSS), IBS-QOL, BSI Depression, STAI Trait Anxiety, SOMS-7 (somatization), Perceived Stress Scale, and a medical comorbidity checklist. RESULTS: After controlling for demographic variables, both SS and NI were significantly correlated with all of the clinical variables (SS r's=.20 to .36; NI r's=.17 to .53, respectively; ps<.05) save for IBS symptom severity (IBS-SSS). NI, but not SS, was positively correlated with IBS-SSS. After performing r-to-z transformations on the correlation coefficients and then comparing z-scores, the correlation between perceived stress, and NI was significantly stronger than with SS. There was no significant difference between the strength of correlations between NI and SS for depression, somatization, trait anxiety, and IBSQOL. A hierarchical linear regression identified both SS and NI as significant predictors of IBS-QOL. CONCLUSIONS: Different aspects of social relationships - support and negative interactions - are associated with multiple aspects of IBS experience (e.g. stress, QOL impairment). Negative social relationships marked by conflict and adverse exchanges are more consistently and strongly related to IBS outcomes than social support. PMID- 23731747 TI - Decreased levels of kynurenic acid in the intestinal mucosa of IBS patients: relation to serotonin and psychological state. AB - OBJECTIVE: Irritable bowel syndrome (IBS) has been associated with psychiatric comorbidity and alterations in serotonergic metabolism. Tryptophan is the precursor of serotonin (5-HT), but it is mainly catabolized through the kynurenine pathway. This pathway may also be involved in the pathogenesis of IBS by virtue of deviating tryptophan from the 5-HT pathway resulting in 5-HT deficiency. We therefore aimed to ascertain the mucosal and systemic concentrations of 5-HT and kynurenic acid (KYNA), a principal kynurenine metabolite. METHODS: Duodenal mucosal biopsy specimens and platelet poor plasma samples were obtained from 15 healthy volunteers and 15 IBS patients. Psychological state was assessed using the Hospital Anxiety and Depression Scale and the Symptom Checklist-90. RESULTS: IBS patients showed significantly lower mucosal and higher systemic concentrations of both 5-HT and KYNA compared to healthy controls. Also, significant correlation between mucosal but not plasma concentrations of KYNA and 5-HT and psychological state in IBS was observed. CONCLUSION: The observation that mucosal KYNA and 5-HT are both decreased in IBS does not support the hypothesis that increased activation along the kynurenic pathway results in relative 5-HT deficiency. However, an increased release of these substances from the intestine to the systemic compartment may lead to a decrease in intestinal KYNA and 5-HT levels, resulting in disturbance of intestinal homeostasis. Thus, changes in psychological states observed in IBS patients may be secondary to alterations in gastrointestinal function, and in particular kynurenine and/or 5-HT metabolism. PMID- 23731748 TI - The link between asthma and smoking explained by depressive feelings and self efficacy. AB - OBJECTIVE: Adolescents with asthma consistently smoke at higher or similar rates as non-asthmatic peers, although smoking might involve more health risks. This study examined possible mechanisms (i.e. depressive feelings and self-efficacy to refrain from smoking) explaining the association between asthma and smoking initiation. METHODS: An indirect path from asthma to self-efficacy through depressive feelings was examined in two independent samples. Sample 1 consisted of 4531 adolescents (mean age 12.8) and sample 2 consisted of 1289 children (late childhood, mean age 10.1). Data were gathered from maternal and self-report. In the adolescent sample, whether the relationship between depressive feelings at baseline and smoking initiation two years post-baseline runs via self-efficacy was also examined. RESULTS: Higher amounts of depressive feelings decreased adolescents' self-efficacy to refrain from smoking, which subsequently increased the risk to initiate smoking. A diagnosis of asthma was also associated with higher levels of depressive feelings which in turn decreased self-efficacy. A marginal significant indirect effect was found in the childhood sample. CONCLUSION: Smoking prevention efforts should start as early as mid to late childhood. The results indicate that focus should be placed on preventing depressive feelings with the aim of increasing children's self-efficacy to refrain from smoking. This is especially important for children and adolescents with asthma. PMID- 23731750 TI - Development and measurement properties of the self assessment version of the INTERMED for the elderly to assess case complexity. AB - OBJECTIVES: The INTERMED for the Elderly Self Assessment (IM-E-SA) was developed to support health care professionals in providing demand driven elderly care. It assesses case complexity and health care needs as perceived by older adults themselves. By applying this instrument tailored care can be provided as it supports professionals in their allocation decisions. The aim was to evaluate the measurement properties of the IM-E-SA. METHODS: In this cross-sectional study 338 elderly people completed a postal questionnaire and participated in an interview. Feasibility of the IM-E-SA was assessed by determining the percentages of missing values per item. Reliability of the IM-E-SA was expressed as Cronbach's alpha. Intraclass correlation coefficients (ICCs) were calculated between the IM-E-SA and IM-E. Nonparametric tests were applied to assess if the IM-E-SA could distinguish between subgroups of elderly adults who differed on demographic characteristics and the prevalence of diseases/disorders. Convergent validity and discriminant validity were assessed using Spearman rank correlations between the IM-E-SA and IM-E, life satisfaction (Cantril's Ladder of Life), activities of daily living (Katz extended), quality of life (EQ-5D), mental health (SF-36) and prevalence of diseases/disorders. RESULTS: Percentages of missing values per IM-E SA item ranged from 0 to 5%. Cronbach's alpha was .78. The ICC between the total scores of the IM-E-SA and the IM-E was .68. The IM-E-SA yielded statistically significant differences between subgroups (known-group validity). Correlations evaluating the convergent validity were moderate to strong (.50-.70). Those correlations assessing the discriminant validity were moderate (.38-.53). CONCLUSION: This study supports the feasibility, reliability and validity of the IM-E-SA. PMID- 23731749 TI - How baseline, new-onset, and persistent depressive symptoms are associated with cardiovascular and non-cardiovascular mortality in incident patients on chronic dialysis. AB - OBJECTIVE: Depressive symptoms are associated with mortality among patients on chronic dialysis therapy. It is currently unknown how different courses of depressive symptoms are associated with both cardiovascular and non cardiovascular mortality. METHODS: In a Dutch prospective nation-wide cohort study among incident patients on chronic dialysis, 1077 patients completed the Mental Health Inventory, both at 3 and 12months after starting dialysis. Cox regression models were used to calculate crude and adjusted hazard ratios (HRs) for mortality for patients with depressive symptoms at 3months only (baseline only), at 12months only (new-onset), and both at 3 and 12months (persistent), using patients without depressive symptoms at 3 and 12months as reference group. RESULTS: Depressive symptoms at baseline only seemed to be a strong marker for non-cardiovascular mortality (HRadj 1.91, 95% CI 1.26-2.90), whereas cardiovascular mortality was only moderately increased (HRadj 1.41, 95% CI 0.85 2.33). In contrast, new-onset depressive symptoms were moderately associated with both cardiovascular (HRadj 1.66, 95% CI 1.06-2.58) and non-cardiovascular mortality (HRadj 1.46, 95% CI 0.97-2.20). Among patients with persistent depressive symptoms, a poor survival was observed due to both cardiovascular (HRadj 2.14, 95% CI 1.42-3.24) and non-cardiovascular related mortality (HRadj 1.76, 95% CI 1.20-2.59). CONCLUSION: This study showed that different courses of depressive symptoms were associated with a poor survival after the start of dialysis. In particular, temporary depressive symptoms at the start of dialysis may be a strong marker for non-cardiovascular mortality, whereas persistent depressive symptoms were associated with both cardiovascular and non cardiovascular mortality. PMID- 23731751 TI - A questionnaire-wide association study of personality and mortality: the Vietnam Experience Study. AB - OBJECTIVE: We examined the association between the Minnesota Multiphasic Personality Inventory (MMPI) and all-cause mortality in 4462 middle-aged Vietnam era veterans. METHODS: We split the study population into half-samples. In each half, we used proportional hazards (Cox) regression to test the 550 MMPI items' associations with mortality over 15years. In all participants, we subjected significant (p<.01) items in both halves to principal-components analysis (PCA). We used Cox regression to test whether these components predicted mortality when controlling for other predictors (demographics, cognitive ability, health behaviors, and mental/physical health). RESULTS: Eighty-nine items were associated with mortality in both half-samples. PCA revealed Neuroticism/Negative Affectivity, Somatic Complaints, Psychotic/Paranoia, and Antisocial components, and a higher-order component, Personal Disturbance. Individually, Neuroticism/Negative Affectivity (HR=1.55; 95% CI=1.39, 1.72), Somatic Complaints (HR=1.66; 95% CI=1.52, 1.80), Psychotic/Paranoid (HR=1.44; 95% CI=1.32, 1.57), Antisocial (HR=1.79; 95% CI=1.59, 2.01), and Personal Disturbance (HR=1.74; 95% CI=1.58, 1.91) were associated with risk. Including covariates attenuated these associations (28.4 to 54.5%), though they were still significant. After entering Personal Disturbance into models with each component, Neuroticism/Negative Affectivity and Somatic Complaints were significant, although Neuroticism/Negative Affectivity's were now protective (HR=0.73; 95% CI=0.58, 0.92). When the four components were entered together with or without covariates, Somatic Complaints and Antisocial were significant risk factors. CONCLUSIONS: Somatic Complaints and Personal Disturbance are associated with increased mortality risk. Other components' effects varied as a function of variables in the model. PMID- 23731752 TI - The "depression" of mental health care in general hospitals in Greece in the era of recession. PMID- 23731753 TI - Health reform and the Affordable Care Act: the importance of mental health treatment to achieving the triple aim. PMID- 23731754 TI - Lipopolysaccharide induces the expression of an autocrine prolactin loop enhancing inflammatory response in monocytes. AB - BACKGROUND: Prolactin from pituitary gland helps maintain homeostasis but it is also released in immune cells where its function is not completely understood. Pleiotropic functions of prolactin (PRL) might be mediated by different isoforms of its receptor (PRLr). METHODS: The aim of this study was to investigate the relationship between the eventual synthesis of PRL and PRLr isoforms with the inflammatory response in monocytes. We used THP-1 and monocytes isolated from healthy subjects stimulated with lipopolysaccharide (LPS). Western blot, real time PCR and immunocytochemistry were performed to identify both molecules. The bioactivity of the PRL was assessed using a bioassay and ELISA to detect pro inflammatory cytokines. RESULTS: PRLr mRNA and PRL mRNA were synthesized in THP-1 monocytes activated with LPS with peaks of 300-fold and 130-fold, respectively. The long (100 kDa) and the intermediate (50 kDa) isoforms of PRLr and big PRL (60 kDa) were time-dependent upregulated for monocytes stimulated with LPS. This expression was confirmed in monocytes from healthy subjects. The PRLr intermediate isoform and the big PRL were found soluble in the culture media and later in the nucleus in THP-1 monocytes stimulated with LPS. Big PRL released by monocytes showed bioactivity in Nb2 Cells, and both PRL and PRLr, synthesized by monocytes were related with levels of nitrites and proinflammatory citokines. CONCLUSIONS: Our results suggest the expression of a full-autocrine loop of PRL enhances the inflammatory response in activated monocytes. This response mediated by big PRL may contribute to the eradication of potential pathogens during innate immune response in monocytes but may also contribute to inflammatory disorders. PMID- 23731755 TI - Phospho-Rb (Ser780) as a biomarker in patients with cervical lymph node metastases from an unknown primary tumour: a retrospective cohort study. AB - OBJECTIVES: Cervical lymph node metastases from an unknown primary tumour are a heterogeneous disease entity with various clinical features. There are many controversies regarding treatment methods and treatment response predictions. Therefore, we examined the prognostic significance of biomarkers in patients with cervical metastasis of unknown primary tumour. DESIGN: A molecular study of retrospective cohorts. SETTING: University teaching hospital. MAIN OUTCOME MEASURES: Metastatic cervical lymph nodes of 36 patients with cervical unknown primary metastasis of squamous cell carcinoma were assessed by in situ hybridisation for human papillomavirus and immunohistochemistry for p16, retinoblastoma protein (phospho-Ser780), hypoxia-inducible factor-1alpha, glucose transporter 1 and carbonic anhydrase 9 expression. Clinicopathological factors and biomarkers were analysed for their associations with disease-free survival and overall survival. RESULTS: Univariate analysis showed that nodal extracapsular spread was associated with poor overall survival (P = 0.049), nodal positive retinoblastoma protein staining were significantly associated with poor outcomes of both disease-free survival (P = 0.035) and overall survival (P = 0.019), Multivariate analysis revealed that nodal positivity of retinoblastoma protein and nodal extracapsular spread were the significant predictors of overall survival (P = 0.049, hazard ratio = 6.21, 95% confidence interval = 1.01-38.35 and P = 0.037, hazard ratio = 4.34, 95% confidence interval = 1.09-17.21, respectively). CONCLUSION: The retinoblastoma protein expression of metastatic lymph nodes represents an independent prognostic indicator in patients with cervical metastasis of unknown primary tumour. PMID- 23731756 TI - Metabolic engineering of Caldicellulosiruptor bescii yields increased hydrogen production from lignocellulosic biomass. AB - BACKGROUND: Members of the anaerobic thermophilic bacterial genus Caldicellulosiruptor are emerging candidates for consolidated bioprocessing (CBP) because they are capable of efficiently growing on biomass without conventional pretreatment. C. bescii produces primarily lactate, acetate and hydrogen as fermentation products, and while some Caldicellulosiruptor strains produce small amounts of ethanol C. bescii does not, making it an attractive background to examine the effects of metabolic engineering. The recent development of methods for genetic manipulation has set the stage for rational engineering of this genus for improved biofuel production. Here, we report the first targeted gene deletion, the gene encoding lactate dehydrogenase (ldh), for metabolic engineering of a member of this genus. RESULTS: A deletion of the C. bescii L lactate dehydrogenase gene (ldh) was constructed on a non-replicating plasmid and introduced into the C. bescii chromosome by marker replacement. The resulting strain failed to produce detectable levels of lactate from cellobiose and maltose, instead increasing production of acetate and H2 by 21-34% relative to the wild type and DeltapyrFA parent strains. The same phenotype was observed on a real-world substrate - switchgrass (Panicum virgatum). Furthermore, the ldh deletion strain grew to a higher maximum optical density than the wild type on maltose and cellobiose, consistent with the prediction that the mutant would gain additional ATP with increased acetate production. CONCLUSIONS: Deletion of ldh in C. bescii is the first use of recently developed genetic methods for metabolic engineering of these bacteria. This deletion resulted in a redirection of electron flow from production of lactate to acetate and hydrogen. New capabilities in metabolic engineering combined with intrinsic utilization of lignocellulosic materials position these organisms to provide a new paradigm for consolidated bioprocessing of fuels and other products from biomass. PMID- 23731758 TI - Improved location features for linkage of regions across ipsilateral mammograms. AB - Improved performance has been reported for computer aided detection (CADe) methods using information from multiple mammographic views over single-view CADe approaches. Linkage across the views is based on assuming that location and image features from the same lesion depicted in both views will be similar. In this study we investigate if the location features can be improved and what effect such an improvement has on the linkage of lesions across ipsilateral views. Performance of different methods to define the location features was first assessed with respect to the location of 137 manually annotated and linked masses. Taking the median result from five complementary methods (based on pectoral muscle boundary, breast shape and intensity signature) increased the mean accuracy compared to the current standard (7.1 vs. 6.3 mm). Thereafter the impact of this best method on the automatic linkage of detected regions across views was assessed for a second, independent dataset of 131 mammogram pairs. Linkage was based on the combination of location and single-view image features by a linear discriminate analysis classifier trained to differentiate between links of corresponding true-positive (TP) regions versus links including TP and false-positive (FP) regions. Nested cross-validation results showed that using the improved location features significantly increased the classification performance and the percentage of correctly linked regions. PMID- 23731757 TI - Tropical species at the northern limit of their range: composition and distribution in Bermuda's benthic habitats in relation to depth and light availability. AB - Surveys were undertaken on the shallow Bermuda marine platform between 2006 and 2008 to provide a baseline of the distribution, condition and environmental characteristics of benthic communities. Bermuda is located in temperate latitudes but coral reefs, tropical seagrasses and calcareous green algae are common in the shallow waters of the platform. The dominant organisms of these communities are all living at or near their northern latitudinal range limits in the Atlantic Ocean. Among the major benthic autotrophs surveyed, seagrasses were most restricted by light availability. We found that the relatively slow-growing and long-lived seagrass Thalassia testudinum is restricted to habitats with much higher light availability than in the tropical locations where this species is commonly found. In contrast, the faster growing tropical seagrasses in Bermuda, Syringodium filiforme, Halodule sp. and Halophila decipiens, had similar ecological compensation depths (ECD) as in tropical locations. Increasing sea surface temperatures, concomitant with global climate change, may either drive or allow the poleward extensions of the ranges of such tropical species. However, due to latitudinal light limitations at least one abundant and common tropical autotroph, T. testudinum, is able to occupy only shallower depths at the more temperate latitudes of Bermuda. We hypothesize that the poleward shift of seagrass species ranges would be accompanied by restrictions to even shallower depths of T. testudinum and by very different seagrass community structures than in tropical locations. PMID- 23731759 TI - Mesenchymal stromal cells: filling the void of immunosuppressive therapy in aplastic anemia? PMID- 23731760 TI - Efficacy and safety of mesenchymal stromal cell treatment from related donors for patients with refractory aplastic anemia. AB - BACKGROUND AIMS: This study evaluated the feasibility, safety and immunological effects of the intravenous administration of mesenchymal stromal cells (MSCs) from a related donor in patients with refractory aplastic anemia (AA). METHODS: A mean of 6 * 10(5)/kg (range, 5.0-7.1 * 10(5)) MSCs were injected intravenously to 18 patients, including 14 patients with nonsevere AA and four patients with severe AA who were refractory to prior immunosuppressive treatment. The outcomes of patients treated with MSCs were evaluated and compared with a historic control cohort, including 18 patients with refractory AA. RESULTS: Two patients had injection-related adverse events, including transient fever and headache. No major adverse events were reported during the follow-up period. An immunological analysis revealed an increased proportion of CD4(+)CD25(+) FOXP3(+)regulatory T cells in peripheral mononuclear cells. Following up for 1 year, six of 18 patients (33.3%) achieved a complete response or a partial response to MSC treatment. In six patients, two achieved a complete response including a recovery of three hematopoietic cell lines after MSCs therapy at days 88 and 92, two patients achieved only a red cell recovery with hemoglobin levels >100 g/L at days 30 and 48 and two patients had only a platelet recovery with a platelet count of >60 * 10(9)/L at days 54 and 81. In the control cohort, only one patient (5.56%) achieved a partial response during the follow-up period. CONCLUSIONS: The data from the present study suggest that treatment with MSCs from a related donor may be a promising therapeutic strategy for patients with refractory AA. The trial has been registered at ClinicalTrials.gov: identifier NCT01305694. PMID- 23731761 TI - Safety and possible outcome assessment of autologous Schwann cell and bone marrow mesenchymal stromal cell co-transplantation for treatment of patients with chronic spinal cord injury. AB - BACKGROUND AIMS: Cell replacement therapy has become a promising issue that has raised much hope in the regeneration of central nervous system injury. Evidence indicates that successful functional recovery in patients with spinal cord injury will not simply emphasize a single therapeutic strategy. Therefore, many recent studies have used combination strategies for spinal cord regeneration. METHODS: We assessed the safety and feasibility of a bone marrow mesenchymal stromal cell and Schwann cell combination for the treatment of patients with chronic spinal cord injury. Eight subjects who received a complete traumatic spinal cord injury (American Spinal Injury Association [ASIA] classification A) enrolled in this study. The patients received this autologous combination of cells directly into the injury site. The mean duration of follow-up was approximately 24 months. RESULTS: No magnetic resonance imaging evidence of neoplastic tissue overgrowth, syringomyelia or psuedomeningocele in any of the patients was seen during the study. There was no deterioration in sensory or motor function in any of the patients during the course of the study. Three patients had negligible improvement in ASIA sensory scale. No motor score improvement and no change in ASIA classification was seen. The patients had widely subjective changes in the course of the study such as urination and defecation sensation and more stability and trunk equilibrium in the sitting position. CONCLUSIONS: There were no adverse findings at least 2 years after autologous transplantation of Schwann cell and mesenchymal stromal cell combination into the injured spinal cord. It appears that the use of this combination of cells is safe for clinical application to spinal cord regeneration. PMID- 23731762 TI - Combined treatment with platelet-rich plasma and brain-derived neurotrophic factor-overexpressing bone marrow stromal cells supports axonal remyelination in a rat spinal cord hemi-section model. AB - BACKGROUND AIMS: Combining biologic matrices is becoming a better choice to advance stem cell-based therapies. Platelet-rich plasma (PRP) is a biologic product of concentrated platelets and has been used to promote regeneration of peripheral nerves after injury. We examined whether PRP could induce rat bone marrow stromal cells (BMSCs) differentiation in vitro and whether a combination of BMSCs, PRP and brain-derived neurotrophic factor (BDNF) could provide additive therapeutic benefits in vivo after spinal cord injury (SCI). METHODS: BMSCs and BDNF-secreting BMSCs (BDNF-BMSCs) were cultured with PRP for 7 days and 21 days, respectively, and neurofilament (NF)-200, glial fibrillary acidic protein (GFAP), microtubule-associated protein 2 (MAP2) and ribosomal protein S6 kinase (p70S6K) gene levels were assessed. After T10 hemi-section in 102 rats, 15-MUL scaffolds (PRP alone, BMSCs, PRP/BMSCs, BDNF-BMSCs or PRP/BDNF-BMSCs) were transplanted into the lesion area, and real-time polymerase chain reaction, Western blot, immunohistochemistry and ultrastructural studies were performed. RESULTS: The messenger RNA expression of NF-200, GFAP, MAP2 and p70S6K was promoted in BMSCs and BDNF-BMSCs after culture with PRP in vitro. BDNF levels were significantly higher in the injured spinal cord after implantation of BDNF-BMSCs. In the PRP/BDNF-BMSCs group at 8 weeks postoperatively, more GFAP was observed, with less accumulation of astrocytes at the graft-host interface. Rats that received PRP and BDNF-BMSC implants showed enhanced hind limb locomotor performance at 8 weeks postoperatively compared with control animals, with more axonal remyelination. CONCLUSIONS: A combined treatment comprising PRP and BDNF overexpressing BMSCs produced beneficial effects in rats with regard to functional recovery after SCI through enhancing migration of astrocytes into the transplants and axonal remyelination. PMID- 23731763 TI - Preparation method and growth factor content of platelet concentrate influence the osteogenic differentiation of bone marrow stromal cells. AB - BACKGROUND AIMS: An extensive debate about the clinical benefits of autologous platelet concentrates used as a treatment option for patients with orthopedic injuries is ongoing. The aim of this study was to determine whether different compositions of platelet concentrates may affect the osteogenic differentiation of bone marrow stromal cells (BMSC). METHODS: Pure platelet-rich plasma (P-PRP) and leukocyte-PRP (L-PRP) were characterized for platelet and leukocyte content. As an indicative marker of the delivery of growth factors (GFs), the release of basic fibroblast growth factor (bFGF) from platelet gel (PG) was measured at 1, 18, 48 and 72 h and at 7 d. The ability of different PGs to induce proliferation and differentiation of BMSC was evaluated by using bioactivity assays. RESULTS: The platelet recovery was significantly higher in L-PRP, either fresh or frozen. PGs derived from L-PRP and P-PRP showed significant differences in terms of bFGF release and biological activity. bFGF release was faster both in fresh and frozen L-PRP preparations. Moreover, L-PRP samples were able to induce a significantly higher proliferation of BMSC compared with P-PRP or PPP samples. Even though all PG preparations allowed the deposition of mineral nodules in BMSC cultures, the mineralization activity correlated significantly with bFGF levels. CONCLUSIONS: The biological activity of platelet concentrates differs according to preparation technique, which affects platelet and leukocyte content and GF availability. Because GF levels are not always optimal in subjects with defective bone healing, composition and bioactivity of PRP should be analyzed to test the reliability and potential effectiveness of the regenerative treatment. PMID- 23731764 TI - Characterization of peripheral blood stem cell grafts mobilized by granulocyte colony-stimulating factor and plerixafor compared with granulocyte colony stimulating factor alone. AB - BACKGROUND AIMS: This study aimed to characterize the immune effectors contained in apheresis samples obtained from patients with grafts mobilized with plerixafor and granulocyte colony-stimulating factor (G-CSF) (P+G) compared with grafts mobilized with G-CSF alone (G). METHODS: Aliquots of apheresis samples were obtained from 36 patients with malignant diseases after mobilization with G (n = 18) or P+G (n = 18). The phenotype and cytokine secretion profile of T cell and dendritic cell subsets were characterized by multicolor cytometry including intracellular cytokine staining. RESULTS: In grafts collected after mobilization with P+G, there was a significantly higher percentage of CD3(+) T cells compared with samples collected after mobilization with G alone. On a functional level, a significant increase of interferon-gamma and tumor necrosis factor-alpha secreting CD8(+) T cells was observed in the P+G group compared with the G group. CD4(+)Foxp3(+) regulatory T cells were similar in both groups but exhibited a lower expression of inducible costimulatory molecule and a significantly higher expression of CD127 in the P+G group. Myeloid dendritic cells (MDCs) and BDCA3(+) dendritic cells were similar in both groups. In contrast, plasmacytoid dendritic cells (PDCs) (CD123(+)BDCA2(+)HLA-DR(+)) were significantly increased in the P+G grafts, leading to a higher PDC-to-MDC ratio. PDCs mobilized by P+G displayed different functional markers--a higher percentage of ILT7(+) PDCs and decreased expression of CD86--suggesting a potential regulatory capacity of PDCs mobilized by P+G. CONCLUSIONS: Grafts mobilized with P+G exhibited major different functional features compared with grafts mobilized with G alone, suggesting that such grafts may have an impact on patient outcome after autologous stem cell transplantation. PMID- 23731765 TI - Smooth muscle cell transplantation improves bladder contractile function in streptozocin-induced diabetic rats. AB - BACKGROUND AIMS: Damage to smooth muscle has been the primary cause of dysfunction in diabetic bladders. Major changes in the filling phase of the bladder result in the loss of compliance and incomplete emptying in patients. METHODS: Cell-based therapies in the lower urinary tract have shown promising results. We argue that because diabetic bladder dysfunction is primarily a problem arising out of altered smooth muscle cells (SMCs), it would be an interesting approach to introduce healthy SMCs into the bladder wall. RESULTS: Furthering this hypothesis, in this experiment, we were successful in introducing syngeneic, healthy SMCs into diabetic bladders. We attempted a method wherein bladder function can be improved in streptozocin-induced diabetes mellitus. Ex vivo-cultured healthy SMCs were introduced into the diabetic bladders of syngeneic Sprague-Dawley rats during the hypercontractile phase after induction of diabetes. Cystometry, metabolic cage evaluation, organ bath studies and histological analyses were performed on the healthy control, the diabetic and the diabetic group transplanted with SMCs. CONCLUSIONS: During the 2-week follow-up period after transplantation, we noticed an increase in contractile response of the bladder correlating to a decrease in residual urine. Cell survival studies revealed a cell survival rate close to 1.5%. PMID- 23731766 TI - Point-of-sale tobacco advertising in Beirut, Lebanon following a national advertising ban. AB - BACKGROUND: The objective of this study was to conduct an audit of point-of-sale (POS) tobacco advertising and assess compliance with an advertising ban in a large district of Beirut, Lebanon. METHODS: The audit was conducted 3 months following the ban on tobacco advertising. Trained students observed all tobacco retail outlets (n = 100) and entered data into a web-based form using iPad((r)) technology. Presence of tobacco advertisements was assessed to determine compliance with the national advertising ban. RESULTS: Among the 100 tobacco retail outlets, 62% had tobacco advertisements, including 7% with a tobacco brand logo as part of the main exterior store sign. CONCLUSIONS: POS tobacco advertising is widespread in Beirut despite the national advertising ban. These findings point to an urgent need for the enforcement of the advertisement ban with tobacco retail outlets in Lebanon. PMID- 23731767 TI - Dual-energy X-ray absorptiometry of human metatarsals: precision, least significant change and association to ex vivo fracture force. AB - BACKGROUND: Fractures are common in foot bones, but clinicians lack adequate indices of bone strength. OBJECTIVES: We used dual-energy X-ray absorptiometry (DXA) to measure bone mineral density (BMD) and content (BMC) of excised human metatarsals, determined intra- and inter-rater measurement precision, and assessed associations between BMD/BMC and ex vivo bone fracture strength. METHODS: Two raters each made two measurements of whole-bone and sub-regional BMD and BMC in both second and third metatarsals from 10 cadavers. Variance components analysis was used to assess variability attributable to repeat measurements, raters, sub-regions, bones, sides, and cadavers. Root-mean-square standard deviation (RMS-SD) and least-significant change (LSC) were used to assess rater precision and ultimate forces during 3-point bending were tested for correlations with BMD and BMC. RESULTS: Variation due to repeat measurements and rater was low (<1% combined) for BMD and BMC. RMS-SD for whole metatarsal BMD of both metatarsals ranged from 0.004 to 0.010 g/cm(2) and 0.062 to 0.086 g for BMC. Whole metatarsal and sub-region BMD and BMC were strongly correlated to ex vivo fracture force (r(2)=0.67-0.93). CONCLUSIONS: DXA measurements of BMD and BMC have high intra- and inter-rater precision and are strongly correlated to ex vivo bone strength. PMID- 23731768 TI - Efficacy and safety of AZD3199 vs formoterol in COPD: a randomized, double-blind study. AB - BACKGROUND: We investigated the efficacy and safety of AZD3199, a novel inhaled ultra-LABA, with the main aim of establishing a dose that would maintain 24-hour bronchodilation in patients with COPD. METHODS: Patients (n = 329) were randomized to AZD3199 (200, 400 or 800 MUg o.d.), formoterol (9 MUg b.i.d.) or placebo via Turbuhaler(r) in a parallel group study. The primary objective of the study was to compare the clinical efficacy of three doses of AZD3199 inhaled once daily with 9 MUg formoterol twice daily and placebo, over a 4-week treatment period in adults with moderate-to-severe COPD. After 4 weeks, peak (0-4 h) and trough (24-26 h) forced expiratory volume in 1 second (FEV1) were assessed as the primary efficacy outcome variables. RESULTS: All AZD3199 doses significantly increased mean peak and trough FEV1 versus placebo (106-171 ml and 97-110 ml increases, respectively), but with no clear dose-response; the level of bronchodilation was comparable to or greater than that achieved with formoterol. Forced vital capacity (FVC) at peak bronchodilation also significantly increased with AZD3199 versus placebo (153-204 ml). COPD symptom scores and reliever use were reduced with AZD3199, while FEV1 reversibility was unaltered. Adverse events were mild-to-moderate, with no safety concerns identified. Drug exposure was dose proportional, but lower than predicted from healthy volunteers. CONCLUSIONS: All three doses of AZD3199 produced 24-hour bronchodilation, but with no clear dose response, suggesting that doses of 200 MUg or less may be sufficient to maintain bronchodilation over 24 hours in patients with COPD. No safety concerns were identified. Further studies are required to determine the once-daily AZD3199 dose for COPD. TRIAL REGISTRATION: Clinicaltrials.gov, NCT00929708. PMID- 23731769 TI - Foveal visual acuity is worse and shows stronger contour interaction effects for contrast-modulated than luminance-modulated Cs. AB - Contrast-modulated (CM) stimuli are processed by spatial mechanisms that operate at larger spatial scales than those processing luminance-modulated (LM) stimuli and may be more prone to deficits in developing, amblyopic, and aging visual systems. Understanding neural mechanisms of contour interaction or crowding will help in detecting disorders of spatial vision. In this study, contour interaction effects on visual acuity for LM and CM C and bar stimuli are assessed in normal foveal vision. In Experiment 1, visual acuity is measured for all-LM and all-CM stimuli, at ~3.5* above their respective modulation thresholds. In Experiment 2, visual acuity is measured for Cs and bars of different type (LM C with CM bars and vice versa). Visual acuity is degraded for CM compared with LM Cs (0.46 +/- 0.04 logMAR vs. 0.18 +/- 0.04 logMAR). With nearby bars, CM acuity is degraded further (0.23 +/- 0.01 logMAR or ~2 lines on an acuity chart), significantly more than LM acuity (0.11 +/- 0.01 logMAR, ~1 line). Contour interaction for CM stimuli extends over greater distances (arcmin) than it does for LM stimuli, but extents are similar with respect to acuities (~3.5* the C gap width). Contour interaction is evident when the Cs and bars are defined differently: it is stronger when an LM C is flanked by CM bars (0.17 +/- 0.03 logMAR) than when a CM C is flanked by LM bars (0.08 +/- 0.02 logMAR). Our results suggest that contour interaction for foveally viewed acuity stimuli involves feature integration, such that the outputs of receptive fields representing Cs and bars are combined. Contour interaction operates at LM and CM representational stages, it can occur across stage, and it is enhanced at the CM stage. Greater contour interaction for CM Cs and bars could hold value for visual acuity testing and earlier diagnosis of conditions for which crowding is important, such as in amblyopia. PMID- 23731770 TI - Pilot study of PET imaging of 124I-iodoazomycin galactopyranoside (IAZGP), a putative hypoxia imaging agent, in patients with colorectal cancer and head and neck cancer. AB - BACKGROUND: Hypoxia within solid tumors confers radiation resistance and a poorer prognosis. 124I-iodoazomycin galactopyranoside (124I-IAZGP) has shown promise as a hypoxia radiotracer in animal models. We performed a clinical study to evaluate the safety, biodistribution, and imaging characteristics of 124I-IAZGP in patients with advanced colorectal cancer and head and neck cancer using serial positron emission tomography (PET) imaging. METHODS: Ten patients underwent serial whole-torso (head/neck to pelvis) PET imaging together with multiple whole body counts and blood sampling. These data were used to generate absorbed dose estimates to normal tissues for 124I-IAZGP. Tumors were scored as either positive or negative for 124I-IAZGP uptake. RESULTS: There were no clinical toxicities or adverse effects associated with 124I-IAZGP administration. Clearance from the whole body and blood was rapid, primarily via the urinary tract, with no focal uptake in any parenchymal organ. The tissues receiving the highest absorbed doses were the mucosal walls of the urinary bladder and the intestinal tract, in particular the lower large intestine. All 124I-IAZGP PET scans were interpreted as negative for tumor uptake. CONCLUSIONS: It is safe to administer 124I-IAZGP to human subjects. However, there was insufficient tumor uptake to support a clinical role for 124I-IAZGP PET in colorectal cancer and head and neck cancer patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00588276. PMID- 23731771 TI - The prognostic role of PRUNE2 in leiomyosarcoma. AB - PRUNE2 plays an important role in regulating tumor cell differentiation, proliferation, and invasiveness in neuroblastoma. Our previous study revealed that PRUNE2/OBSCN two-gene relative expression classifer accurately differentiated leiomyosarcoma from gastrointestinal stromal tumor. However, the association between PRUNE2 expression and prognosis in leiomyosarcoma is poorly understood. In this study, we evaluated the prognostic role of PRUNE2 in leiomyosarcoma. PRUNE2 expression was detected using immunohistochemistry in 30 formalin-fixed, paraffin-embedded leiomyosarcoma tissues from MD Anderson Cancer Center, and high expression was detected in 36.7% (11/30) of the samples. To validate these results, immunohistochemistry was performed on another cohort of 45 formalin-fixed, paraffin-embedded leiomyosarcoma tissues from Tianjin Medical University Cancer Institute & Hospital, and high PRUNE2 protein expression was detected in 37.8% (17/45) of the samples. Moreover, elevated PRUNE2 expression was significantly associated with tumor size (P = 0.03) and hemorrhage/cyst (P = 0.014), and was an independent favorable prognostic factor for overall survival in leiomyosarcoma patients from Tianjin Medical University Cancer Institute & Hospital (P < 0.05). These data suggest that increased PRUNE2 protein expression may serve as a favorable prognostic marker in human leiomyosarcoma. PMID- 23731772 TI - Allergic asthma and omalizumab--the experience at the Centro Hospitalar da Cova da Beira. PMID- 23731773 TI - Patients with a high risk for obstructive sleep apnea syndrome: postoperative respiratory complications. AB - BACKGROUND: STOP-BANG score (snore; tired; observed apnea; arterial pressure; body mass index; age; neck circumference and gender) can predict the risk of a patient having Obstructive Syndrome Apnea (OSA). The aim of this study was to evaluate the incidence STOP-BANG score>=3, in surgical patients admitted to the Post-Anesthesia Care Unit (PACU). METHODS: Observational, prospective study conducted in a post-anesthesia care unit (PACU) during three weeks (2011). The study population consisted of adult patients after noncardiac and non neurological surgery. Patients were classified as high risk of OSA (HR-OSA) if STOP-BANG score>=3 and Low-risk of OSA (LR-OSA) if STOP-BANG score<3 (LR-OSA). Patient demographics, intraoperative and postoperative data were collected. Patient characteristics were compared using Mann-Whitney U-test, t-test for independent groups, and chi-square or Fisher's exact test. RESULTS: A total of 357 patients were admitted to PACU; 340 met the inclusion criteria. 179 (52%) were considered HR-OSA. These patients were older, more likely to be masculine, had higher BMI, higher ASA physical status, higher incidence of ischemic heart disease, heart failure, hypertension, dyslipidemia and underwent more frequently insulin treatment for diabetes. These patients had more frequently mild/moderated hypoxia in the PACU (9% vs. 3%, p=0.012) and had a higher incidence of residual neuromuscular blockade (NMB) (20% vs. 16%, p=0.035). Patients with HR-OSA had a longer hospital stay. CONCLUSIONS: Patients with HR-OSA had an important incidence among patients scheduled for surgery in our hospital. These patients had more co-morbidities and were more prone to post-operative complications. PMID- 23731774 TI - Crosstalk between B16 melanoma cells and B-1 lymphocytes induces global changes in tumor cell gene expression. AB - The analysis of gene expression patterns in cancers has improved the understanding of the mechanisms underlying the process of metastatic progression. However, the acquisition of invasive behavior in melanoma is poorly understood. In melanoma, components of the immune system can contribute to tumor progression, and inflammatory cells can influence almost all aspects of cancer progression, including metastasis. Recent studies have attributed an important role to B-1 cells, a subset of B lymphocytes, in melanoma progression. In vitro interactions between B16 melanoma cells and B-1 lymphocytes lead to increased B16 cell metastatic potential, but the molecular changes induced by B-1 lymphocytes on B16 cells have not yet been elucidated. In this study, we used a microarray approach to assess the gene expression profile of B16 melanoma cells following contact with B-1 lymphocytes (B16B1). The microarray analysis identified upregulation in genes involved with metastatic progression, such as ctss, ccl5, cxcl2 and stat3. RT-qPCR confirmed this increase in mRNA expression in B16B1 samples. As previous studies have indicated that the ERK1/2 MAPK cascade is activated in melanoma cells following contact with B-1 lymphocytes, RT-qPCR was performed with RNA from melanoma cells before and after contacting B-1 cells and untreated or treated with ERK phosphorylation inhibitors. The results showed that the expression of stat3, ctss and cxcl2 increased in B16B1 but decreased following ERK1/2 MAPK inhibition. Ccl5 gene expression increased after contacting B-1 cells and was maintained at the same level following inhibitor treatment. Stat3 was verified and validated at the protein level by Western blot analysis. STAT3 expression was also significantly increased in B16B1, suggesting that this pathway can also contribute to the increased metastatic phenotype observed in our model. These results indicated that B-1 cells induce important global gene expression changes in B16 melanoma cells. We also evaluated the relationship of some of the genes identified as differentially expressed and the ERK1/2 MAPK cascade. This work may have important implications for understanding the role of B-1 lymphocytes and the ERK/MAPK cascade in the metastatic process. PMID- 23731775 TI - Angiotensin II blockade, YKL-40 and maintenance of sinus rhythm after electrical cardioversion for atrial fibrillation. AB - High levels of the novel inflammatory marker YKL-40 have been demonstrated in inflammatory environments and in remodeling of the extracellular matrix. Both are key components in atrial wall remodeling in atrial fibrillation (AF). We studied the relation between rhythm outcome after electrical cardioversion (ECV) for persistent AF and serum levels of YKL-40. A secondary point of interest was a potential effect of the angiotensin receptor blocker candesartan on YKL-40 levels. In the Candesartan in the Prevention of Relapsing Atrial Fibrillation (CAPRAF) study, 171 patients with persistent AF were randomized to receive candesartan 8mg once daily or placebo for 3-6 weeks before ECV and candesartan 16mg once daily or placebo for 6 months after ECV. Serum levels of YKL-40 were measured in fasting blood samples collected at baseline and at end of the study. Mean age was 64+/-11 years, and 39 (22.8%) were women. Sinus rhythm was maintained for 6 months after ECV in 41 (23.9%). Baseline levels of YKL-40 were significantly correlated to age (Spearmans rho; rs=0.442; p<0.001), CHA2DS2 VASc(1) score (rs=0.256; p<0.001) and left atrial diameter (rs=0.185; p=0.017). By use of Kaplan-Meier quartile analysis of baseline YKL-40 levels, no relation between YKL-40 levels and risk of AF recurrence was found. End of study YKL-40 levels were unchanged from baseline, both in patients with AF recurrence and those maintaining sinus rhythm for 6 months. Treatment with candesartan had no influence on serum YKL-40 levels. PMID- 23731776 TI - The second "time-out": a surgical safety checklist for lengthy robotic surgeries. AB - Robotic surgeries of long duration are associated with both increased risks to patients as well as distinct challenges for care providers. We propose a surgical checklist, to be completed during a second "time-out", aimed at reducing peri operative complications and addressing obstacles presented by lengthy robotic surgeries. A review of the literature was performed to identify the most common complications of robotic surgeries with extended operative times. A surgical checklist was developed with the goal of addressing these issues and maximizing patient safety. Extended operative times during robotic surgery increase patient risk for position-related complications and other adverse events. These cases also raise concerns for surgical, anesthesia, and nursing staff which are less common in shorter, non-robotic operations. Key elements of the checklist were designed to coordinate operative staff in verifying patient safety while addressing the unique concerns within each specialty. As robotic surgery is increasingly utilized, operations with long surgical times may become more common due to increased case complexity and surgeons overcoming the learning curve. A standardized surgical checklist, conducted three to four hours after the start of surgery, may enhance perioperative patient safety and quality of care. PMID- 23731777 TI - Health-related quality of life associated with daytime and nocturnal hypoglycaemic events: a time trade-off survey in five countries. AB - BACKGROUND: Hypoglycaemic events, particularly nocturnal, affect health-related quality of life (HRQoL) via acute symptoms, altered behaviour and fear of future events. We examined the respective disutility associated with a single event of daytime, nocturnal, severe and non-severe hypoglycaemia. METHODS: Representative samples were taken from Canada, Germany, Sweden, the United States and the United Kingdom. Individuals completed an internet-based questionnaire designed to quantify the HRQoL associated with different diabetes- and/or hypoglycaemia related health states. HRQoL was measured on a utility scale: 1 (perfect health) to 0 (death) using the time trade-off method. Three populations were studied: 8286 respondents from the general population; 551 people with type 1 diabetes; and 1603 with type 2 diabetes. Respondents traded life expectancy for improved health states and evaluated the health states of well-controlled diabetes and diabetes with non-severe/severe and daytime/nocturnal hypoglycaemic events. RESULTS: In the general population, non-severe nocturnal hypoglycaemic events were associated with a 0.007 disutility compared with 0.004 for non-severe daytime episodes, equivalent to a significant 63% increase in negative impact. Severe daytime and nocturnal events were associated with a 0.057 and a 0.062 disutility, respectively, which were not significantly different. CONCLUSIONS: This study applies an established health economic methodology to derive disutilities associated with hypoglycaemia stratified by onset time and severity using a large multinational population. It reveals substantial individual and cumulative detrimental effects of hypoglycaemic events - particularly nocturnal - on HRQoL, reinforcing the clinical imperative of avoiding hypoglycaemia. PMID- 23731778 TI - Visualizing molecular diffusion through passive permeability barriers in cells: conventional and novel approaches. AB - Diffusion barriers are universal solutions for cells to achieve distinct organizations, compositions, and activities within a limited space. The influence of diffusion barriers on the spatiotemporal dynamics of signaling molecules often determines cellular physiology and functions. Over the years, the passive permeability barriers in various subcellular locales have been characterized using elaborate analytical techniques. In this review, we will summarize the current state of knowledge on the various passive permeability barriers present in mammalian cells. We will conclude with a description of several conventional techniques and one new approach based on chemically inducible diffusion trap (CIDT) for probing permeable barriers. PMID- 23731779 TI - Circadian timekeeping and output mechanisms in animals. AB - Daily rhythms in animal behavior, physiology and metabolism are driven by cell autonomous clocks that are synchronized by environmental cycles, but maintain ~24 hours rhythms even in the absence of environmental cues. These clocks keep time and control overt rhythms via interlocked transcriptional feedback loops, making it imperative to define the mechanisms that drive rhythmic transcription within these loops and on a genome-wide scale. Recent work identifies novel post transcriptional and post-translational mechanisms that govern progression through these feedback loops to maintain a period of ~24 hours. Likewise, new microarray and deep sequencing studies reveal interplay among clock activators, chromatin remodeling and RNA Pol II binding to set the phase of gene transcription and drive post-transcriptional regulatory systems that may greatly increase the proportion of genes that are under clock control. Despite great progress, gaps in our understanding of how feedback loop transcriptional programs maintain ~24 hours cycles and drive overt rhythms remain. PMID- 23731780 TI - Efficiency of high molecular weight backbone degradable HPMA copolymer prostaglandin E1 conjugate in promotion of bone formation in ovariectomized rats. AB - Multiblock, high molecular weight, linear, backbone degradable HPMA copolymer prostaglandin E1 (PGE1) conjugate has been synthesized by RAFT polymerization mediated by a new bifunctional chain transfer agent (CTA), which contains an enzymatically degradable oligopeptide sequence flanked by two dithiobenzoate groups, followed by postpolymerization aminolysis and thiol-ene chain extension. The multiblock conjugate contains Asp8 as the bone targeting moiety and enzymatically degradable bonds in the polymer backbone; in vivo degradation produces cleavage products that are below the renal threshold. Using an ovariectomized (OVX) rat model, the accumulation in bone and efficacy to promote bone formation was evaluated; low molecular weight conjugates served as control. The results indicated a higher accumulation in bone, greater enhancement of bone density, and higher plasma osteocalcin levels for the backbone degradable conjugate. PMID- 23731781 TI - Radiotherapy for T1-2N0 glottic cancer: a multivariate analysis of predictive factors for the long-term outcome in 1050 patients and a prospective assessment of quality of life and voice handicap index in a subset of 233 patients. AB - OBJECTIVES: To evaluate the outcomes of patients with early stage glottic cancer (GC) treated with radiotherapy (RT). DESIGN, SETTING AND PARTICIPANTS: The current study report on a retrospective analysis of oncologic outcome of 1050 patients with T1-2N0 glottic cancer treated with radiotherapy. Prospective assessment of quality of life (QoL) and voice handicap index (VHI) was performed in all patients treated from 2006 onwards (n = 233). MAIN OUTCOME MEASURES: Local control (LC), regional control (RC), disease-free survival (DFS), overall survival (OS), quality of life and voice handicap index. RESULTS: After a median follow-up of 90 months (range 3-309), the actuarial rates of local control, regional control, disease-free survival and overall survival were 85%, 99%, 84% and 81% at 5 years and 82%, 98%, 80% and 61% at 10 years, respectively. On multivariate analysis, T2 tumours, smoking after radiotherapy and conventional radiation scheme correlated significantly with poor local control. Patients who continued smoking after radiotherapy had also significantly lower overall survival rates (OR 4.3, P < 0.001). Hypothyroidism was reported in 18% of patients. Slight and temporary deterioration of quality of life scores was reported. Patient-reported xerostomia and dysphagia at 48 months were -7.1 and 6.5, compared with baseline, respectively. Voice handicap index improved significantly from 37 at baseline to 18 at 48 months. Patients with T2b and those who continued smoking had significantly worse voice handicap index. CONCLUSIONS: In the current study, excellent outcome with good quality of life and voice handicap index scores were reported. T2 tumours, in particular T2b, and continuing smoking after radiotherapy correlated significantly with poor local control and worse voice handicap index. PMID- 23731782 TI - The association between physical fitness and depressive symptoms among young adults: results of the Northern Finland 1966 birth cohort study. AB - BACKGROUND: The effect of physical activity on mental health has been the subject of research for several decades. However, there is a lack of studies investigating the association between physical fitness, including both cardiorespiratory and muscular fitness and depressive symptoms among general population. The aim of this study was to determine the association between physical fitness and depressive symptoms among young adults. METHODS: The study population consists of 5497 males and females, members of the Northern Finland birth cohort of 1966, who at age 31 completed fitness tests and filled in a questionnaire including questions about depressive symptoms (Hopkins' Symptom Checklist-25) and physical activity. Cardiorespiratory fitness was measured by a 4-min step test and muscular fitness by tests of maximal isometric handgrip and isometric trunk extension. The odds ratios (OR) with 95% confidence intervals (95% CI) for having depressive symptoms were calculated for quintiles groups of physical fitness using the third, median quintile as reference group, and the results were adjusted for potential confounding variables. RESULTS: Depressive symptoms were most common among males and females in the lowest quintile group of trunk extension test (OR 1.58 and 95% CI 1.07-2.32 in males and OR 1.43 and 95% CI 1.03-2.0 in females) and among males in the lowest quintile group of handgrip strength (OR 1.64 95% CI 1.11-2.42) compared to the reference group. Level of self-reported physical activity was inversely associated with depressive symptoms both in males (OR 1.74 95% CI 1.25-2.36) and females (OR 1.36 95% CI 1.05-1.75). The cardiorespiratory fitness was not associated with depressive symptoms (OR 1.01 95% CI 0.68-1.49 in males and 0.82 95% CI 0.57-1.16 in females). CONCLUSIONS: The results indicate that low level of isometric endurance capacity of trunk extensor muscles is associated with high level of depressive symptoms in both sexes. In males, also poor handgrip strength is associated with increased levels of depressive symptoms. The physical activity level is inversely associated with the prevalence of depressive symptoms among young adults. PMID- 23731783 TI - Stability of reference genes for normalization of reverse transcription quantitative real-time PCR (RT-qPCR) data in bovine blastocysts produced by IVF, ICSI and SCNT. AB - Reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) is a sensitive and accurate tool for quantitative estimation of gene transcription levels in preimplantation embryos. To control for possible experimental variations, gene expression data must be normalized using internal control genes commonly known as reference genes. However, the stability of reference genes can vary depending on the state of development and/or experimental conditions; hence the assessment of their stability is essential before initiating a gene expression analysis. In the present study, we used RT qPCR to measure the transcript levels of 10 commonly used reference genes and analyzed their expression stability in bovine blastocysts produced by in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and somatic cell nuclear transfer (SCNT). Using the geNorm program, we found the best combination of genes to normalize gene expression data in bovine embryos at the blastocyst stage produced by IVF (HMBS, SF3A1, and HPRT1), ICSI (H2A, HMBS, and GAPDH), SCNT (ACTB, SF3A1, and SDHA) and/or between blastocysts produced by these methods (GAPDH, HMBS and EEF1A2). We also demonstrated that not only the culture conditions may affect the expression patterns in bovine blastocysts but also the choice of embryo production method may have an important effect. PMID- 23731784 TI - Removal of bisphenol A (BPA) from water by various nanofiltration (NF) and reverse osmosis (RO) membranes. AB - The removal of an endocrine disrupting compound, bisphenol A (BPA), from model solutions by selected nanofiltration (NF) and reverse osmosis (RO) membranes was studied. The commercially available membranes NF 90, NF 270, XLE BWRO, BW 30 (Dow FilmTech), CE BWRO and AD SWRO (GE Osmonics) were used to compare their performances for BPA removal. The water permeability coefficients, rejection of BPA and permeate flux values were calculated for all membranes used. No significant changes in their BPA removal were observed for all tight polyamide based NF and RO membranes tested except for loose NF 270 membrane. The polyamide based membranes exhibited much better performance than cellulose acetate membrane for BPA removal. Almost a complete rejection (>= 98%) for BPA was obtained with three polyamide based RO membranes (BW 30, XLE BWRO and AD SWRO). But cellulose acetate based CE BWRO membrane offered a low and variable (10-40%) rejection for BPA. PMID- 23731785 TI - Wide coverage biomedical event extraction using multiple partially overlapping corpora. AB - BACKGROUND: Biomedical events are key to understanding physiological processes and disease, and wide coverage extraction is required for comprehensive automatic analysis of statements describing biomedical systems in the literature. In turn, the training and evaluation of extraction methods requires manually annotated corpora. However, as manual annotation is time-consuming and expensive, any single event-annotated corpus can only cover a limited number of semantic types. Although combined use of several such corpora could potentially allow an extraction system to achieve broad semantic coverage, there has been little research into learning from multiple corpora with partially overlapping semantic annotation scopes. RESULTS: We propose a method for learning from multiple corpora with partial semantic annotation overlap, and implement this method to improve our existing event extraction system, EventMine. An evaluation using seven event annotated corpora, including 65 event types in total, shows that learning from overlapping corpora can produce a single, corpus-independent, wide coverage extraction system that outperforms systems trained on single corpora and exceeds previously reported results on two established event extraction tasks from the BioNLP Shared Task 2011. CONCLUSIONS: The proposed method allows the training of a wide-coverage, state-of-the-art event extraction system from multiple corpora with partial semantic annotation overlap. The resulting single model makes broad-coverage extraction straightforward in practice by removing the need to either select a subset of compatible corpora or semantic types, or to merge results from several models trained on different individual corpora. Multi corpus learning also allows annotation efforts to focus on covering additional semantic types, rather than aiming for exhaustive coverage in any single annotation effort, or extending the coverage of semantic types annotated in existing corpora. PMID- 23731786 TI - Medial unicompartmental knee arthroplasty in patients less than 55 years old: minimum of two years of follow-up. AB - Eighty-five fixed bearing medial unicompartmental arthroplasties were performed in 42 men and 33 women with a mean age of 49 years (range, thirty-three to fifty five years old) at the time of surgery. At a mean of 4.0 years (range two to twelve years), the mean pre-operative Knee Society score improved from 49 to 95.1 points (P<0.0001) and the mean UCLA activity score was 7.5 (range 5 to 9). Three knees underwent revision to a total knee arthroplasty; two for arthritic progression in the lateral compartment and one for pain. At the time of final follow-up, two knees (2.4%) demonstrated progressive Grade 4 arthritis of the patellofemoral compartment but were asymptomatic. There was no radiographic evidence of loosening, osteolysis, or premature polyethylene wear. Estimated survivorship was 96.5% at 10 years. UKA offered excellent early outcomes in this cohort of younger, active patients. PMID- 23731787 TI - Minimum two-year outcomes of modular bicompartmental knee arthroplasty. AB - The purpose of this study was to determine the results of modular unlinked bicompartmental knee arthroplasty (BiKA) for medial (or lateral) and patellofemoral arthritis. Twenty-nine modular BiKAs were followed prospectively, for a mean of 31 months (range, 24-46 months). Outcome measures included Knee Society Knee and Function Scores, KOOS, SF-12, and WOMAC, as well as radiographic assessments and implant survivorship. Two tail paired Student's t test was used to determine statistical differences between preoperative and postoperative scores. Mean range of motion (ROM) improved from 122 degrees to 133 degrees (P<0.001). There was a statistically significant improvement across all functional scores. One patient underwent conversion to total knee arthroplasty at 3 years for knee instability. There were no cases of patellar instability, implant loosening or wear, or progressive arthritis. PMID- 23731788 TI - Cell culture and electron microscopy for identifying viruses in diseases of unknown cause. AB - During outbreaks of infectious diseases or in cases of severely ill patients, it is imperative to identify the causative agent. This report describes several events in which virus isolation and identification by electron microscopy were critical to initial recognition of the etiologic agent, which was further analyzed by additional laboratory diagnostic assays. Examples include severe acute respiratory syndrome coronavirus, and Nipah, lymphocytic choriomeningitis, West Nile, Cache Valley, and Heartland viruses. These cases illustrate the importance of the techniques of cell culture and electron microscopy in pathogen identification and recognition of emerging diseases. PMID- 23731789 TI - Cortical florbetapir-PET amyloid load in prodromal Alzheimer's disease patients. AB - BACKGROUND: Florbetapir (AV-45) has been shown to be a reliable tool to assess amyloid load in patients with Alzheimer's disease (AD) at demential stages. Longitudinal studies also suggest that AV-45 has the ability to bind amyloid in the early stages of AD. In this study, we investigated AV-45 binding and its relation with cognitive performance in a group of patients at the prodromal stage of Alzheimer's disease, recruited according to strict inclusion criteria. METHODS: We recruited patients at the prodromal stage of AD and matched control subjects. AV-45 binding was assessed using an innovative extraction method allowing quantifying uptake in the cortex only. AV-45 uptake was compared between groups in the precuneus, posterior cingulate, anterior cingulate, and orbito frontal regions. Correlations between AV-45 uptake and cognitive performance were assessed. RESULTS: Twenty-two patients and 17 matched control subjects were included in the study. We report a significant increase of cortical AV-45 uptake in the patients compared to the control subjects in all regions of interest. Specific correlations were found within the patient group between mean global amyloid cortical load and cognitive performance in three different memory tests. CONCLUSIONS: These findings suggest that at the prodromal stage of AD, memory decline is linked to an increase of cortical beta-amyloid load. PMID- 23731790 TI - [Epithelial basement membrane dystrophy diagnosed following LASIK surgery]. AB - A 48-year-old woman with no significant past history underwent bilateral simultaneous laser in situ keratomileusis for correction of her myopia. On the tenth postoperative day, the patient complained of visual decrease and photophobia. Slit lamp exam showed corneal epithelial irregularities. Confocal microscopy was performed and revealed a characteristic appearance of epithelial basement membrane dystrophy (EBMD). The patient was successfully treated with artificial tears and autologous serum eyedrops. EBMD may be missed before LASIK surgery, even after a careful pre-operative examination. Exacerbation of EBMD after LASIK surgery is rare. It should be considered when unexplained corneal epithelial defects or irregularities occur following LASIK. Confocal microscopy is very useful to confirm the diagnosis. PMID- 23731791 TI - [Sixth, seventh and tenth cranial nerve palsies associated with pseudotumor cerebri in a 13-year-old boy]. AB - We describe the case of a 13-year-old boy who presented to the emergency department with an acute onset paresis of the left abducens, facial and vagus nerves. Bilateral papilledema was seen on fundoscopy. Blood tests and brain magnetic resonance imaging and angiography showed no abnormalities. A lumbar puncture revealed an elevated intracranial pressure (575mmH2O) and clear cerebrospinal fluid. The diagnosis of pseudotumor cerebri (PTC) associated with multiple cranial nerve palsies was made. Treatment with acetazolamide was initiated, resulting in progressive improvement with no sequelae and no clinical recurrence over an 8-month follow-up period. PTC in children can present with a wide spectrum of neurological signs, especially cranial nerve palsies which are most likely related to a pressure-dependent stretching mechanism. In 2007, distinctive diagnostic criteria for pediatric PTC were established, including the presence of any cranial nerve palsy in the absence of an identifiable etiology. PMID- 23731792 TI - [Cilioretinal artery occlusion and central retinal vein occlusion complicating hyperhomocysteinemia: a case report]. AB - INTRODUCTION: Hyperhomocysteinemia is known to be a risk factor in both retinal artery and retinal vein occlusions. We report the case of a young patient with combined occlusion of the cilioretinal artery and the central retinal vein due to hyperhomocysteinemia. PATIENTS AND METHODS: A 23-year-old patient without significant medical history, presented for sudden, painless visual loss in the right eye. Ophthalmologic examination revealed best-corrected visual acuity of the right eye 8/10 P2, and 10/10 P2 on the left. Anterior segment exam was normal in both eyes, while the right fundus revealed white, ischemic edema, centered around a cilioretinal artery, sparing the fovea, with some hemorrhagic spots and disc edema. Fluorescein angiography confirmed delayed filling of the right cilioretinal artery and revealed a normal disc on the left. Two weeks later, the clinical picture had evolved into a right ischemic CRVO, confirmed by a second angiogram, with a decrease in visual acuity to 3/10. RESULTS: A work-up was performed, including: a full lipid profile, serum electrolytes, ESR, CRP, a complete blood count (leukocytes, platelets, hemoglobin were normal), a coagulation work-up (PT, PTT, protein C, protein S, antithrombin III, factor V Leiden were normal), ANCA, antiphospholipid antibodies and antinuclear antibodies were negative, and finally cardiology studies (cardiac echo, carotid Doppler) and neurology (brain MRI) were ordered and came back normal. Otherwise, plasma homocysteine was moderately high on two samples, at 18.3 MUmol/L and 17.78 MUmol/L. Thyroid and renal work-ups were ordered. Urgent PRP was performed, and vitamin therapy (vitB12, vitB6, folic acid) was instituted. The subsequent course was remarkable for recovery of visual acuity to 10/10, P2 with persistence of an inferior altitudinal central scotoma. MTHFR C677T polymorphism was negative. DISCUSSION: Retinal vascular occlusions (RVO) are serious events, which require investigation for underlying systemic disease, which can be life-threatening. The clinical picture is variable depending on the location of the occlusion, the extent of the ischemic area and the degree of macular involvement. The etiologies of RVO are varied, requiring a thorough biological assessment in young subjects. The association between hyperhomocysteinemia and RVO is proven, while this association with the MTHFR C677T polymorphism was not found. Vitamin therapy reduces plasma levels of homocysteine by 25% but its role in the treatment and prevention of RVO remains to be demonstrated. CONCLUSION: Several cases of occlusion of the central retinal vein or one of its branches have been published. Combined occlusion of the central retinal vein and cilioretinal artery secondary to hyperhomocysteinemia does not appear to have been published, which would make our case unique. PMID- 23731793 TI - [Intracystic spherical exudate upon rapid regression of macular edema]. PMID- 23731794 TI - Neutrophil roles in left ventricular remodeling following myocardial infarction. AB - Polymorphonuclear granulocytes (PMNs; neutrophils) serve as key effector cells in the innate immune system and provide the first line of defense against invading microorganisms. In addition to producing inflammatory cytokines and chemokines and undergoing a respiratory burst that stimulates the release of reactive oxygen species, PMNs also degranulate to release components that kill pathogens. Recently, neutrophil extracellular traps have been shown to be an alternative way to trap microorganisms and contain infection. PMN-derived granule components are also involved in multiple non-infectious inflammatory processes, including the response to myocardial infarction (MI). In this review, we will discuss the biological characteristics, recruitment, activation, and removal of PMNs, as well as the roles of PMN-derived granule proteins in inflammation and innate immunity, focusing on the MI setting when applicable. We also discuss future perspectives that will direct research in PMN biology. PMID- 23731796 TI - 2013 International Congress on Ultrasonics. PMID- 23731795 TI - Tea consumption and the risk of oral cancer incidence: a case-control study from China. AB - OBJECTIVES: To evaluate the relation of tea consumption with the risk of oral cancer incidence. SUBJECTS AND METHODS: A multicenter case-control study based on hospitalized population was conducted for evaluating the association of tea consumption with oral cancer risk in China. Black tea and green tea were separately analyzed. 723 cases and 857 controls were included. Unconditional multiple logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) of oral cancer for tea consumption. RESULTS: The ORs for green tea consumption?8g/day compared with<4g/day were 0.72 (95% CI 0.54, 0.93) for men, and 0.93 (95% CI 0.74, 1.26) for women. The ORs for black tea consumption?6g/day compared with<2g/day were 0.97 (95% CI 0.74, 1.20) for men, and 0.91 (95% CI 0.68, 1.23) for women. Green tea intake was significantly associated with reduced risk of oral cancer in men, but not in women, and the association was stronger in heavily smoking men. There was no indication that black tea consumption was associated with decreased oral cancer risk. CONCLUSION: The results of this study indicated that green tea consumption may decrease the risk of oral cancer in men especially for those smoking heavily. PMID- 23731797 TI - Comparison of lipopolysaccharide structures of Bordetella pertussis clinical isolates from pre- and post-vaccine era. AB - Endotoxins are lipopolysaccharides (LPS), and major constituents of the outer membrane of Gram-negative bacteria. Bordetella pertussis LPS were the only major antigens, of this agent of whooping-cough, that were not yet analyzed on isolates from the pre- and post-vaccination era. We compared here the LPS structures of four clinical isolates with that of the vaccine strain BP 1414. All physico chemical analyses, including SDS-PAGE, TLC, and different MALDI mass spectrometry approaches were convergent. They helped demonstrating that, on the contrary to some other B. pertussis major antigens, no modification occurred in the dodecasaccharide core structure, as well as in the whole LPS molecules. These results are rendering these major antigens good potential vaccine components. Molecular modeling of this conserved LPS structure also confirmed the conclusions of previous experiments leading to the production of anti-LPS monoclonal antibodies and defining the main epitopes of these major antigens. PMID- 23731798 TI - Memb-roller: an effective way of making membrane rolls for pathological examination and studies of human placenta. AB - For the pathological evaluation of the chorioamniotic membranes, a membrane roll is made to give an orientation to the sections and to cover more extended planes. We designed a new instrument, Annie's memb-roller, for easy preparation of membrane rolls. Annie's memb-roller has two non-toothed arms which are 2 mm wide, 1 mm thick, and 8 cm long. To test its effectiveness in making a membrane roll, the placentas obtained from pregnant women (n = 10) with various obstetrical conditions were used. Preparation of the membrane rolls using Annie's memb-roller was easy and successful in all cases tested. The lengths of the membranes measured from fresh placentas and paraffin sections showed a very good correlation (p < 0.001; r = 0.941). Application of the memb-roller would be very helpful in the semi-quantitative analysis of the chorioamniotic membranes and the standardization of placental pathology and research practice. PMID- 23731799 TI - Maternal cotyledons at birth predict blood pressure in childhood. AB - INTRODUCTION: A small placental surface at birth has been shown to be associated with the development of hypertension in later life. In this study we extend this observation by looking at the relationship between the number of placental cotyledons and blood pressure in childhood. Because the number of cotyledons is correlated with the surface area, we hypothesized that fewer cotyledons would be associated with higher blood pressure. METHODS: The Alspac study is a longitudinal study of 13,971 children born in Bristol. Their placentas were stored in formalin. We photographed the placentas of a sample of the children and related the number of maternal cotyledons to their blood pressure levels at age 9 years. RESULTS: Contrary to our hypothesis, a greater number of maternal cotyledons was associated with higher blood pressure. Among boys, a greater number of cotyledons was associated with higher systolic and diastolic pressure but not with higher pulse pressure. Diastolic pressure rose by 2.2 mmHg (95% CI 0.6 to 3.7, p = 0.007) for every 10 additional cotyledons. Among girls, a greater number of cotyledons was associated with higher systolic pressure and pulse pressure but not with higher diastolic pressure. Pulse pressure rose by 2.7 mmHg (1.1-4.3, p < 0.001) for every 10 additional cotyledons. These associations were little changed by adjustment for placental surface area. CONCLUSION: Our study has shown that a large number of maternal cotyledons is associated with raised blood pressure in childhood. The associations differ in the two sexes. PMID- 23731801 TI - Advances in recombinant protein expression for use in pharmaceutical research. AB - Protein production for structural and biophysical studies, functional assays, biomarkers, mechanistic studies in vitro and in vivo, but also for therapeutic applications in pharma, biotech and academia has evolved into a mature discipline in recent years. Due to the increased emphasis on biopharmaceuticals, the growing demand for proteins used for structural and biophysical studies, the impact of genomics technologies on the analysis of large sets of structurally diverse proteins, and the increasing complexity of disease targets, the interest in innovative approaches for the expression, purification and characterisation of recombinant proteins has steadily increased over the years. In this review, we summarise recent developments in the field of recombinant protein expression for research use in pharma, biotech and academia. We focus mostly on the latest developments for protein expression in the most widely used expression systems: Escherichia coli (E. coli), insect cell expression using the Baculovirus Expression Vector System (BEVS) and, finally, transient and stable expression of recombinant proteins in mammalian cells. PMID- 23731800 TI - Strategies to control the binding mode of de novo designed protein interactions. AB - There has been significant recent progress in the computational design of protein interactions including the creation of novel heterodimers, homodimers, nanohedra, fibril caps and a protein crystal. Essential to these successes has been the use of innovative strategies for finding binding modes that are achievable, that is, identifying binding partners and docked conformations that can be successfully stabilized via sequence optimization and backbone refinement. In many cases this has involved the use of structural motifs commonly found at naturally occurring interfaces including alpha helices inserted into hydrophobic grooves, beta-strand pairing, metal binding, established helix packing motifs, and the use of symmetry to form cooperative interactions. Future challenges include the creation of hydrogen bond networks and antibody-like interactions based on the redesign of protein surface loops. PMID- 23731802 TI - Microtubule assembly and in vitro development of bovine oocytes with increased intracellular glutathione level prior to vitrification and in vitro fertilization. AB - Although vitrification is a useful technique for preservation of bovine oocytes, the yield of blastocysts derived from the vitrified oocytes is still low. We have recently reported a new type of cryoinjury, multiple aster formation, by which pronuclear migration and development of vitrified-warmed and in vitro-fertilized bovine oocytes are impaired. The aim of the present study was to investigate the effect of glutathione (GSH) content of vitrified bovine oocytes on multiple aster formation and subsequent in vitro development. Treatment of bovine cumulus-oocyte complexes with beta-mercaptoethanol (betaME) and L-cysteine (Cys) during in vitro maturation resulted in 2.5-fold higher GSH content not only in fresh control but also in vitrified-warmed oocytes. The percentage of normally fertilized zygotes exhibiting sperm aster(s) was >95% in all four groups (with or without betaME/Cys * fresh control or vitrified). The frequency of multiple aster formation in vitrified oocytes (three-fold higher than that in fresh control oocytes) was not affected by the increased level of intracellular GSH with betaME/Cys. Consequently, the migration and development of pronuclei as well as the yield of blastocysts from vitrified-warmed oocytes (17 versus 41%) were not improved. In addition, there was no effect of increased GSH level on the yield of blastocysts in fresh control groups. PMID- 23731803 TI - From policy to practice: implementation of physical activity and food policies in schools. AB - PURPOSE: Public policies targeting the school setting are increasingly being used to address childhood obesity; however, their effectiveness depends on their implementation. This study explores the factors which impeded or facilitated the implementation of publicly mandated school-based physical activity and nutrition guidelines in the province of British Columbia (BC), Canada. METHODS: Semi structured interviews were conducted with 50 school informants (17 principals - 33 teacher/school informants) to examine the factors associated with the implementation of the mandated Daily Physical Activity (DPA) and Food and Beverage Sales in Schools (FBSS) guidelines. Coding used a constructivist grounded theory approach. The first five transcripts and every fifth transcript thereafter were coded by two independent coders with discrepancies reconciled by a third coder. Data was coded and analysed in the NVivo 9 software. Concept maps were developed and current theoretical perspectives were integrated in the later stages of analysis. RESULTS: The Diffusion of Innovations Model provided an organizing framework to present emergent themes. With the exception of triability (not relevant in the context of mandated guidelines/policies), the key attributes of the Diffusion of Innovations Model (relative advantage, compatibility, complexity, and observability) provided a robust framework for understanding themes associated with implementation of mandated guidelines. Specifically, implementation of the DPA and FBSS guidelines was facilitated by perceptions that they: were relatively advantageous compared to status quo; were compatible with school mandates and teaching philosophies; had observable positive impacts and impeded when perceived as complex to understand and implement. In addition, a number of contextual factors including availability of resources facilitated implementation. CONCLUSIONS: The enactment of mandated policies/guidelines for schools is considered an essential step in improving physical activity and healthy eating. However, policy makers need to: monitor whether schools are able to implement the guidelines, support schools struggling with implementation, and document the impact of the guidelines on students' behaviors. To facilitate the implementation of mandated guidelines/policies, the Diffusion of Innovations Model provides an organizational framework for planning interventions. Changing the school environment is a process which cannot be undertaken solely by passive means as we know that such approaches have not resulted in adequate implementation. PMID- 23731804 TI - [DiabeTIC website: a pilot study of satisfaction and impact on metabolic control]. AB - OBJECTIVES: To evaluate satisfaction and short-term impact on metabolic control of diabetes monitoring through the DiabeTIC website. PATIENTS AND METHODS: A prospective, uncontrolled intervention study was conducted in 32 patients aged 29.7+/-9.7 years (65% female) incorporated to the telemedicine platform DiabeTIC between March and September 2012. All patients completed a satisfaction questionnaire in the first month, and impact on metabolic control was evaluated at three and six months. RESULTS: In the satisfaction survey conducted in the first month of follow-up, the following mean scores (0-10) were obtained: overall impression with the platform: 8.6+/-1.8; ease of use: 8.1+/-1.5; intuitive navigation: 6.7+/-3.0; value of measurements: 9.1+/-1.1; importance of the platform in diabetes management: 9.5+/-0.9; sense of security: 9.5+/-0.8; value of the library: 9.4+/-1.1; value of messages: 9.1+/-1.4, and recommendation to use the platform: 9.4+/-0.9. Glycosilated hemoglobin concentrations significantly improved at six months as compared to study start (7.0+/-0.8 versus 8.1+/-1.9; p=0.007). Nine patients were discharged from DiabeTIC before completing six months of follow-up. CONCLUSIONS: Patients with diabetes monitored through the DiabeTIC website report a high degree of satisfaction, showing improved metabolic control at short-term follow-up. PMID- 23731805 TI - [Estimated glucose disposal rate in patients under 18 years of age with type 1 diabetes mellitus and overweight or obesity]. AB - OBJECTIVE: To assess the estimated glucose disposal rate (eGDR), insulin dose, and lipoprotein profile in children with type 1 diabetes mellitus (T1DM) and overweight or obesity as compared to children with T1DM and normal weight. METHODS: A total of 115 patients (aged 5-16 years) with T1DM on intensive insulin therapy were recruited. The following parameters were measured: weight, height, body mass index, waist and hip circumference, insulin dose, eGDR, glycosylated hemoglobin, blood pressure, and lipoprotein profile. Results were stratified by sex and age. RESULTS: No significant differences were found in eGDR between children with normal weight, overweight, and obesity. However, obese children older than 11 years had lower eGDR values (9.3+/-1.3 vs 10.1+/-0.8 mg kg(-1)min( 1); p<0.01). Insulin dose was higher in overweight and obese children, especially in IU/m2/day (37.7 vs 36.1 vs. 29.4 respectively; p<0.01). Obese children had higher low-density lipoprotein cholesterol levels than children with overweight and normal weight (106.5 vs 91.7 vs 91.5mg/dL respectively; p<0.01). No correlation was found between waist circumference and the different markers of insulin resistance. CONCLUSIONS: Values of eGDR values were lower in obese children with T1DM older than 11 years, and this may therefore be considered a marker of insulin resistance. Insulin dose was higher in diabetic patients with overweight or obesity, specially in IU/m2/day. Obese children with T1DM had a lipoprotein profile of cardiovascular risk. PMID- 23731806 TI - A matter of authority. PMID- 23731807 TI - Obesity among Ghanaian women: past prevalence, future incidence. PMID- 23731808 TI - Biological Consequences of Global Change: past and future. PMID- 23731809 TI - Applying various algorithms for species distribution modelling. AB - Species distribution models have been used extensively in many fields, including climate change biology, landscape ecology and conservation biology. In the past 3 decades, a number of new models have been proposed, yet researchers still find it difficult to select appropriate models for data and objectives. In this review, we aim to provide insight into the prevailing species distribution models for newcomers in the field of modelling. We compared 11 popular models, including regression models (the generalized linear model, the generalized additive model, the multivariate adaptive regression splines model and hierarchical modelling), classification models (mixture discriminant analysis, the generalized boosting model, and classification and regression tree analysis) and complex models (artificial neural network, random forest, genetic algorithm for rule set production and maximum entropy approaches). Our objectives are: (i) to compare the strengths and weaknesses of the models, their characteristics and identify suitable situations for their use (in terms of data type and species-environment relationships) and (ii) to provide guidelines for model application, including 3 steps: model selection, model formulation and parameter estimation. PMID- 23731810 TI - Biological consequences of global change for birds. AB - Climate is currently changing at an unprecedented rate; so also human exploitation is rapidly changing the Earth for agriculture, forestry, fisheries and urbanization. In addition, pollution has affected even the most remote ecosystems, as has the omnipresence of humans, with consequences in particular for animals that keep a safe distance from potential predators, including human beings. Importantly, all of these changes are occurring simultaneously, with increasing intensity, and further deterioration in both the short and the long term is predicted. While the consequences of these components of global change are relatively well studied on their own, the effects of their interactions, such as the combined effects of climate change and agriculture, or the combined effects of agriculture through nutrient leakage to freshwater and marine ecosystems and fisheries, and the effects of climate change and urbanization, are poorly understood. Here, I provide a brief overview of the effects of climate change on phenology, diversity, abundance, interspecific interactions and population dynamics of birds. I address whether these effects of changing temperatures are direct, or indirect through effects of climate change on the phenology, distribution or abundance of food, parasites and predators. Finally, I review interactions between different components of global change. PMID- 23731811 TI - Review and synthesis of the effects of climate change on amphibians. AB - Considerable progress has been made in understanding the responses of amphibians to climate change, with successful research carried out on climate change associated shifts in amphibian phenology, elevational distributions and amphibian parasite interactions. We review and synthesize the literature on this topic, emphasizing acutely lethal, sublethal, indirect and positive effects of climate change on amphibians, and major research gaps. For instance, evidence is lacking on poleward shifts in amphibian distributions and on changes in body sizes and morphologies of amphibians in response to climate change. We have limited information on amphibian thermal tolerances, thermal preferences, dehydration breaths, opportunity costs of water conserving behaviors and actual temperature and moisture ranges amphibians experience. Even when much of this information is available, there remains little evidence that climate change is acutely lethal to amphibians. This suggests that if climate change is contributing to declines, it might be through effects that are not acutely lethal, indirect, or both, but evidence in support of this suggestion is necessary. In fact, evidence that climate change is directly contributing to amphibian declines is weak, partly because researchers have not often ruled out alternative hypotheses, such as chytrid fungus or climate-fungus interactions. Consequently, we recommend that amphibian-climate research shift from primarily inductive, correlational approach as to studies that evaluate alternative hypotheses for declines. This additional rigor will require interdisciplinary collaborations, estimates of costs and benefits of climate change to amphibian fitness and populations, and the integration of correlative field studies, experiments on 'model' amphibian species, and mathematical and functional, physiological models. PMID- 23731812 TI - Climate warming increases biodiversity of small rodents by favoring rare or less abundant species in a grassland ecosystem. AB - Our Earth is facing the challenge of accelerating climate change, which imposes a great threat to biodiversity. Many published studies suggest that climate warming may cause a dramatic decline in biodiversity, especially in colder and drier regions. In this study, we investigated the effects of temperature, precipitation and a normalized difference vegetation index on biodiversity indices of rodent communities in the current or previous year for both detrended and nondetrended data in semi-arid grassland of Inner Mongolia during 1982-2006. Our results demonstrate that temperature showed predominantly positive effects on the biodiversity of small rodents; precipitation showed both positive and negative effects; a normalized difference vegetation index showed positive effects; and cross-correlation function values between rodent abundance and temperature were negatively correlated with rodent abundance. Our results suggest that recent climate warming increased the biodiversity of small rodents by providing more benefits to population growth of rare or less abundant species than that of more abundant species in Inner Mongolia grassland, which does not support the popular view that global warming would decrease biodiversity in colder and drier regions. We hypothesized that higher temperatures might benefit rare or less abundant species (with smaller populations and more folivorous diets) by reducing the probability of local extinction and/or by increasing herbaceous food resources. PMID- 23731813 TI - Experimental evaluation of reproductive response to climate warming in an oviparous skink. AB - The impact of climate warming on organisms is increasingly being recognized. The experimental evaluation of phenotypically plastic responses to warming is a critical step in understanding the biological effects and adaptive capacity of organisms to future climate warming. Oviparous Scincella modesta live in deeply shaded habitats and they require low optimal temperatures during embryonic development, which makes them suitable subjects for testing the effects of warming on reproduction. We raised adult females and incubated their eggs under different thermal conditions that mimicked potential climate warming. Female reproduction, embryonic development and hatchling traits were monitored to evaluate the reproductive response to warming. Experimental warming induced females to lay eggs earlier, but it did not affect the developmental stage of embryos at oviposition or the reproductive output. The high temperatures experienced by gravid females during warming treatments reduced the incubation period and increased embryonic mortality. The locomotor performance of hatchlings was not affected by the maternal thermal environment, but it was affected by the warming treatment during embryonic development. Our results suggest that climate warming might have a profound effect on fitness-relevant traits both at embryonic and post-embryonic stages in oviparous lizards. PMID- 23731814 TI - Influence of geography and climate on patterns of cell size and body size in the lizard Anolis carolinensis. AB - Geographic patterns in body size are often associated with latitude, elevation, or environmental and climatic variables. This study investigated patterns of body size and cell size of the green anole lizard, Anolis carolinensis, and potential associations with geography or climatic variables. Lizards were sampled from 19 populations across the native range, and body size, red blood cell size and size and number of muscle cells were measured. Climatic data from local weather stations and latitude and longitude were entered into model selection with Akaike's information criterion to explain patterns in cell and body sizes. Climatic variables did not drive any major patterns in cell size or body size; rather, latitude and longitude were the best predictors of cell and body size. In general, smaller body and cell sizes in Florida anoles drove geographic patterns in A. carolinensis. Small size in Florida may be attributable to the geological history of the peninsular state or the unique ecological factors in this area, including a recently introduced congener. In contrast to previous studies, we found that A. carolinensis does not follow Bergmann's rule when the influence of Florida is excluded. Rather, the opposite pattern of larger lizards in southern populations is evident in the absence of Florida populations, and mirrors the general pattern in squamates. Muscle cell size was negatively related to latitude and red blood cell size showed no latitudinal trend outside of Florida. Different patterns in the sizes of the 2 cell types confirm the importance of examining multiple cell types when studying geographic variation in cell size. PMID- 23731815 TI - Extreme developmental temperatures result in morphological abnormalities in painted turtles (Chrysemys picta): a climate change perspective. AB - Increases in extreme environmental events are predicted to be major results of ongoing global climate change and may impact the persistence of species. We examined the effects of heat and cold waves during embryonic development of painted turtles (Chrysemys picta) in natural nests on the occurrence of abnormal shell morphologies in hatchlings. We found that nests exposed to extreme hot temperatures for >60 h produced more hatchlings with abnormalities than nests exposed to extreme hot temperatures for shorter periods, regardless of whether or not nesting females displayed abnormal morphologies. We observed no effect of extreme cold nest temperatures on the occurrence of hatchlings with abnormalities. Moreover, the frequency of nesting females with abnormal shell morphologies was approximately 2-fold lower than that of their offspring, suggesting that such abnormalities are negatively correlated with survival and fitness. Female turtles could potentially buffer their offspring from extreme heat by altering aspects of nesting behavior, such as choosing shadier nesting sites. We addressed this hypothesis by examining the effects of shade cover on extreme nest temperatures and the occurrence of hatchling abnormalities. While shade cover was negatively correlated with the occurrence of extreme hot nest temperatures, it was not significantly correlated with abnormalities. Therefore, female choice of shade cover does not appear to be a viable target for selection to reduce hatchling abnormalities. Our results suggest that increases in the frequency and intensity of heat waves associated with climate change might perturb developmental programs and thereby reduce the fitness of entire cohorts of turtles. PMID- 23731816 TI - Artificial nesting habitats as a conservation strategy for turtle populations experiencing global change. AB - Diamondback terrapins (Malaclemys terrapin) inhabit estuaries in eastern USA and may tolerate salinity of sea-water for short durations. Many North American estuaries are adversely affected by anthropogenic impacts, such as pollution, dredging and invasion by non-native plants. Many nesting areas have been altered or destroyed, causing terrapins to nest on roadsides and artificial islands made of dredged substrate from bottom sediments. Shading by non-native plants may suppress development and reduce survival of embryos. In Barnegat Bay, New Jersey, USA, there is a mosaic of natural and degraded terrapin nesting habitats. We investigated the effects of dredge soil and shade on the hatching success of diamondback terrapins to determine whether nesting habitat could be increased by using dredged bottom sediments. In year 1, unshaded nests in natural loamy-sand had the highest hatching success (55.2%), while nests in dredge soil produced no hatchlings. In year 2, nests in unshaded loamy-sand had a hatching success of 85.3%, whereas those in dredge soil, aged 1 year, had a hatching success of 59.4%. Dredge soil improved as an incubation substrate after aging 1 year by the washout of salt. Nest temperatures were generally cool and produced mostly male hatchlings. Uncontaminated dredge soil may provide suitable nesting substrates for diamondback terrapins if used after one year, and may be particularly beneficial if used for constructing islands that provide new nesting sites with reduced access of mammalian predators. PMID- 23731817 TI - Effect of acute endotoxemia on analog estimates of mean systemic pressure. AB - Dynamic estimates of mean systemic pressure based on a Guytonian analog model (Pmsa) appear accurate under baseline conditions but may not remain so during septic shock because blood volume distribution and resistances between arterial and venous beds may change. Thus, we examined the effect of acute endotoxemia on the ability of Pmsa, estimated from steady-state cardiac output, right atrial pressure, and mean arterial pressure, to reflect our previously validated instantaneous venous return measure of mean systemic pressure (Pmsi), derived from beat-to-beat measures of right ventricular stroke volume and right atrial pressure during positive pressure ventilation. We studied 6 splenectomized pentobarbital-anesthetized close chested dogs. Right ventricular stroke volume was measured by a pulmonary arterial electromagnetic flow probe. Instantaneous venous return measure of mean systemic pressure and Pmsa were calculated during volume loading and removal (+/-100-mL bolus increments*5) both before (control) and 30 minutes after endotoxin infusion (endo). Cardiac output increased (2628+/ 905 vs 3560+/-539 mL/min; P<.05) and mean arterial pressure decreased (107+/-16 vs 56+/-12 mm Hg; P<.01) during endo. Changes in Pmsi and Pmsa correlated during both control and endo (r2=0.7) with minimal bias by Bland-Altman analysis (mean difference+/-95% confidence interval, 0.47+/-5.04 mm Hg). We conclude that changes in Pmsa accurately tracts Pmsi under both control and endo. PMID- 23731818 TI - Previous antibiotic exposure and evolution of antibiotic resistance in mechanically ventilated patients with nosocomial infections. AB - PURPOSE: This study aimed to evaluate the impact of previous antibiotic exposure and the influence of time interval since exposure on the evolution of antibiotic resistant infections. METHODS: We retrospectively analyzed 167 mechanically ventilated patients with nosocomial infections over a 3-year period, with focus on infections in the bloodstream, urinary tract, lower respiratory tract, and surgical sites. RESULTS: Of 167 patients, 62% were confirmed as antibiotic resistant. The most common isolated pathogen was extended-spectrum beta-lactamase Enterobacteriaceae (43.9%), followed by methicillin-resistant Staphylococcus aureus (22.8%), and carbapenem-resistant Acinetobacter baumannii (17.5%). Multivariate analysis revealed that the association between resistance and the time interval increased within 10 days (odds ratio [OR], 2.45; P=.133) and peaked at 11 to 20 days (OR, 7.17; P=.012). The data were categorized into 2 groups: when the time interval was more than 20 days, there was a 23.9% reduction in resistance rate compared with when the time interval was 20 days or less (OR, 0.36; P=.002). CONCLUSIONS: Although antibiotic exposure increased resistance rate in nosocomial infections, this association decreased as time interval increased. Antibiotic stewardship should consider the significance of time interval while investigating the evolution of subsequent antibiotic-resistant infections. PMID- 23731819 TI - Coagulopathy, catecholamines, and biomarkers of endothelial damage in experimental human endotoxemia and in patients with severe sepsis: a prospective study. AB - PURPOSE: The aim of this study was to investigate associations between circulating catecholamines, endothelial damage, and coagulopathy in experimental human endotoxemia and septic patients. MATERIALS AND METHODS: Nine healthy male volunteers undergoing endotoxemia (4-hour 0.5 ng/kg/hour infusion of E. coli lipopolysaccharide, blood sampling at 0, 4, and 6 hours) and 20 patients with severe sepsis. Analysis of plasma biomarkers (adrenaline, noradrenaline, thrombomodulin, syndecan-1, soluble vascular endothelial cadherin, histone complexed DNA fragments, soluble CD40 ligand [sCD40L], protein C, tissue-type plasminogen activator, plasminogen activator inhibitor 1) and routine coagulation tests. RESULTS: Endotoxemia increased heart rate, temperature, white blood cell count, C-reactive protein and procalcitonin, decreased blood pressure and induced a hemostatic response with platelet consumption, reduced protein C and sCD40L levels and enhanced tissue-type plasminogen activator release (all P<.05). Septic patients had increased levels of noradrenaline, syndecan-1, thrombomodulin, histone-complexed DNA and sCD40L but reduced soluble vascular endothelial cadherin and plasminogen activator inhibitor 1 (all P<.05) and plasma catecholamines correlated positively with syndecan-1 (adrenaline and noradrenaline) and sTM (only noradrenaline) (all P<.05), biomarkers reflecting endothelial damage. Furthermore, noradrenaline, syndecan-1 and thrombomodulin levels correlated with INR and disease severity scores (noradrenaline and thrombomodulin) (all P<.05). CONCLUSIONS: Experimental endotoxemia induced a discrete hemostatic response without sympathoadrenal activation or endothelial damage. Septic patients had high levels of catecholamines and endothelial damage biomarkers that correlated with each other and with markers of hypocoagulability and disease severity. PMID- 23731821 TI - What boxing tells us about repetitive head trauma and the brain. AB - Boxing and other combat sports may serve as a human model to study the effects of repetitive head trauma on brain structure and function. The initial description of what is now known as chronic traumatic encephalopathy (CTE) was reported in boxers in 1928. In the ensuing years, studies examining boxers have described the clinical features of CTE, its relationship to degree of exposure to fighting, and an array of radiologic findings. The field has been hampered by issues related to study design, lack of longitudinal follow-up, and absence of agreed-upon clinical criteria for CTE. A recently launched prospective cohort study of professional fighters, the Professional Fighters Brain Health Study, attempts to overcome some of the problems in studying fighters. Here, we review the cross-sectional results from the first year of the project. PMID- 23731820 TI - Impact of a smoking ban in hospitality venues on second hand smoke exposure: a comparison of exposure assessment methods. AB - BACKGROUND: In May 2010, Switzerland introduced a heterogeneous smoking ban in the hospitality sector. While the law leaves room for exceptions in some cantons, it is comprehensive in others. This longitudinal study uses different measurement methods to examine airborne nicotine levels in hospitality venues and the level of personal exposure of non-smoking hospitality workers before and after implementation of the law. METHODS: Personal exposure to second hand smoke (SHS) was measured by three different methods. We compared a passive sampler called MoNIC (Monitor of NICotine) badge, to salivary cotinine and nicotine concentration as well as questionnaire data. Badges allowed the number of passively smoked cigarettes to be estimated. They were placed at the venues as well as distributed to the participants for personal measurements. To assess personal exposure at work, a time-weighted average of the workplace badge measurements was calculated. RESULTS: Prior to the ban, smoke-exposed hospitality venues yielded a mean badge value of 4.48 (95%-CI: 3.7 to 5.25; n = 214) cigarette equivalents/day. At follow-up, measurements in venues that had implemented a smoking ban significantly declined to an average of 0.31 (0.17 to 0.45; n = 37) (p = 0.001). Personal badge measurements also significantly decreased from an average of 2.18 (1.31-3.05 n = 53) to 0.25 (0.13-0.36; n = 41) (p = 0.001). Spearman rank correlations between badge exposure measures and salivary measures were small to moderate (0.3 at maximum). CONCLUSIONS: Nicotine levels significantly decreased in all types of hospitality venues after implementation of the smoking ban. In-depth analyses demonstrated that a time weighted average of the workplace badge measurements represented typical personal SHS exposure at work more reliably than personal exposure measures such as salivary cotinine and nicotine. PMID- 23731822 TI - Routine performance and errors of 454 HLA exon sequencing in diagnostics. AB - BACKGROUND: Next-generation sequencing (NGS) has changed genomics significantly. More and more applications strive for sequencing with different platforms. Now, in 2012, after a decade of development and evolution, NGS has been accepted for a variety of research fields. Determination of sequencing errors is essential in order to follow next-generation sequencing beyond research use only. This study describes the overall 454 system performance of using multiple GS Junior runs with an in-house established and validated diagnostic assay for human leukocyte antigen (HLA) exon sequencing. Based on this data, we extracted, evaluated and characterized errors and variants of 60 HLA loci per run with respect to their adjacencies. RESULTS: We determined an overall error rate of 0.18% in a total of 118,484,408 bases. 31.3% of all reads analyzed (n=349,503) contain one or more errors. The largest group are deletions that account for 50% of the errors. Incorrect bases are not distributed equally along sequences and tend to be more frequent at sequence ends. Certain sequence positions in the middle or at the beginning of the read accumulate errors. Typically, the corresponding quality score at the actual error position is lower than the adjacent scores. CONCLUSIONS: Here we present the first error assessment in a human next generation sequencing diagnostics assay in an amplicon sequencing approach. Improvements of sequence quality and error rate that have been made over the years are evident and it is shown that both have now reached a level where diagnostic applications become feasible. Our presented data are better than previously published error rates and we can confirm and quantify the often described relation of homopolymers and errors. Nevertheless, a certain depth of coverage is needed, in particular with challenging areas of the sequencing target. Furthermore, the usage of error correcting tools is not essential but might contribute towards the capacity and efficiency of a sequencing run. PMID- 23731823 TI - New Delhi metallo-beta-lactamase-producing Enterobacteriaceae, United States. AB - We characterized 9 New Delhi metallo-beta-lactamase-producing Enterobacteriaceae (5 Klebsiella pneumoniae, 2 Escherichia coli, 1 Enterobacter cloacae, 1 Salmonella enterica serovar Senftenberg) isolates identified in the United States and cultured from 8 patients in 5 states during April 2009-March 2011. Isolates were resistant to beta-lactams, fluoroquinolones, and aminoglycosides, demonstrated MICs <=1 ug/mL of colistin and polymyxin, and yielded positive metallo-beta-lactamase screening results. Eight isolates had blaNDM-1, and 1 isolate had a novel allele (blaNDM-6). All 8 patients had recently been in India or Pakistan, where 6 received inpatient health care. Plasmids carrying blaNDM frequently carried AmpC or extended spectrum beta-lactamase genes. Two K. pneumoniae isolates and a K. pneumoniae isolate from Sweden shared incompatibility group A/C plasmids with indistinguishable restriction patterns and a common blaNDM fragment; all 3 were multilocus sequence type 14. Restriction profiles of the remaining New Delhi metallo-beta-lactamase plasmids, including 2 from the same patient, were diverse. PMID- 23731824 TI - A study of the influence of task familiarity on user behaviors and performance with a MeSH term suggestion interface for PubMed bibliographic search. AB - PURPOSE: Previous research has shown that information seekers in biomedical domain need more support in formulating their queries. A user study was conducted to evaluate the effectiveness of a metadata based query suggestion interface for PubMed bibliographic search. The study also investigated the impact of search task familiarity on search behaviors and the effectiveness of the interface. METHODS: A real user, user search request and real system approach was used for the study. Unlike tradition IR evaluation, where assigned tasks were used, the participants were asked to search requests of their own. Forty-four researchers in Health Sciences participated in the evaluation - each conducted two research requests of their own, alternately with the proposed interface and the PubMed baseline. Several performance criteria were measured to assess the potential benefits of the experimental interface, including users' assessment of their original and eventual queries, the perceived usefulness of the interfaces, satisfaction with the search results, and the average relevance score of the saved records. RESULTS: The results show that, when searching for an unfamiliar topic, users were more likely to change their queries, indicating the effect of familiarity on search behaviors. The results also show that the interface scored higher on several of the performance criteria, such as the "goodness" of the queries, perceived usefulness, and user satisfaction. Furthermore, in line with our hypothesis, the proposed interface was relatively more effective when less familiar search requests were attempted. CONCLUSIONS: Results indicate that there is a selective compatibility between search familiarity and search interface. One implication of the research for system evaluation is the importance of taking into consideration task familiarity when assessing the effectiveness of interactive IR systems. PMID- 23731825 TI - The effects of an electronic medical record on the completeness of documentation in the anesthesia record. AB - OBJECTIVES: The purpose of this study is to evaluate the completeness of anesthesia recording before and after the introduction of an electronic anesthesia record. METHODS: The study was conducted in a Korean teaching hospital where the EMR was implemented in October 2008. One hundred paper anesthesia records from July to September 2008 and 150 electronic anesthesia records during the same period in 2009 were randomly sampled. Thirty-four essential items were selected out of all the anesthesia items and grouped into automatically transferred items and manual entry items. 1, .5 and 0 points were given for each item of complete entry, incomplete entry and no entry respectively. The completeness of documentation was defined as the sum of the scores. The influencing factors on the completeness of documentation were evaluated in total and by the groups. RESULTS: The average completeness score of the electronic anesthesia records was 3.15% higher than that of the paper records. A multiple regression model showed the type of the anesthesia record was a significant factor on the completeness of anesthesia records in all items (beta=.98, p<.05) and automatically transferred items (beta=.56, p<.01). The type of the anesthesia records had no influence on the completeness in manual entry items. CONCLUSIONS: The completeness of an anesthesia record was improved after the implementation of the electronic anesthesia record. The reuse of the data from the EMR was the main contributor to the improved completeness. PMID- 23731826 TI - Improving patient safety through surgical site infection surveillance: response to Tanner et al. PMID- 23731828 TI - Proceedings of the 2013 Rheumatology Winter Clinical Symposia. AB - Advances in rheumatology occur at a rapid pace and staying abreast of important changes is a challenge for all. Both novel drug development and enhanced understanding of conventional or historic therapies have molded current day rheumatologic practice. Rheumatology has led the way in the use of outcome measures and imaging modalities in common disorders like rheumatoid arthritis, osteoarthritis, and gout. The expertise of the rheumatologist has widened such that knowledge of economics, legal issues, related disorders and extraarticular disease is essential. In February 2013, the 6th annual Rheumatology Winter Clinical Symposium was held. At this meeting, faculty and participants held discussions and exchanged knowledge about new scientific data and how it may impact the care of rheumatology patients. Excerpts from some of the lectures from the Rheumatology Winter Clinical Symposium 2013 are included in this review. These and other presentations can be viewed in their entirety at http://www.r-w-c s.com. PMID- 23731827 TI - Obesity and hyperlipidemia are risk factors for early diabetic neuropathy. AB - The Utah Diabetic Neuropathy Study (UDNS) examined 218 type 2 diabetic subjects without neuropathy symptoms, or with symptoms of<5 years, in order to evaluate risk factors for neuropathy development. Each subject completed symptom questionnaires, the Utah Early Neuropathy Scale (UENS), nerve conduction studies (NCS), quantitative sensory testing (QST) for vibration and cold detection, quantitative sudomotor axon reflex testing (QSART), and skin biopsy with measurement of intraepidermal nerve fiber density (IENFD). Those with abnormalities of>=3 were classified as having probable, and those with 1-2 as possible neuropathy. The relationship between glycemic control, lipid parameters (high density lipoprotein and triglyceride levels), blood pressure, and obesity, and neuropathy risk was examined. There was a significant relationship between the number of abnormalities among these features and neuropathy status (p<0.01). Hypertriglyceridemia, obesity and 3 or more abnormalities increased neuropathy risk (risk ratios 2.1 p<0.03, 2.9 p>0.02 and 3.0 p<0.004 respectively). Multivariate analysis found obesity and triglycerides were related to loss of small unmyelinated axons based on IENFD whereas elevated hemoglobin A1c was related to large myelinated fiber loss (motor conduction velocity). These findings indicate obesity and hypertriglyceridemia significantly increase risk for peripheral neuropathy, independent of glucose control. Obesity/hypertriglyceridemia and hyperglycemia may have differential effects on small versus large fibers. PMID- 23731829 TI - In-depth interviews with state public health practitioners on the United States National Physical Activity Plan. AB - BACKGROUND: The United States National Physical Activity Plan (NPAP; 2010), the country's first national plan for physical activity, provides strategies to increase population-level physical activity to complement the 2008 physical activity guidelines. This study examined state public health practitioner awareness, dissemination, use, challenges, and recommendations for the NPAP. METHODS: In 2011-2012, we interviewed 27 state practitioners from 25 states. Interviews were recorded and transcribed verbatim. Transcripts were coded using a standard protocol, verified and reconciled by an independent coder, and input into qualitative software to facilitate development of common themes. RESULTS: NPAP awareness was high among state practitioners; dissemination to local constituents varied. Development of state-level strategies and goals was the most frequently reported use of the NPAP. Some respondents noted the usefulness of the NPAP for coalitions and local practitioners. Challenges to the plan included implementation cost, complexity, and consistency with other policies. The most frequent recommendation made was to directly link examples of implementation activities to the plan. CONCLUSIONS: These results provide early evidence of NPAP dissemination and use, along with challenges encountered and suggestions for future iterations. Public health is one of eight sectors in the NPAP. Further efforts are needed to understand uptake and use by other sectors, as well as to monitor long-term relevance, progress, and collaboration across sectors. PMID- 23731830 TI - Response to the letter to editor from Richard A. Anderson and co-workers. PMID- 23731831 TI - Induction of puberty by autograft of cryopreserved ovarian tissue in a patient previously treated for Ewing sarcoma. PMID- 23731832 TI - A phase 2, multicentre, single-arm, open-label study to evaluate the safety and efficacy of single-agent lenalidomide (Revlimid) in subjects with relapsed or refractory peripheral T-cell non-Hodgkin lymphoma: the EXPECT trial. AB - BACKGROUND: This multicentre, single-arm, open-label phase 2 trial investigated the efficacy and safety of lenalidomide monotherapy in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL). METHODS: Patients received oral lenalidomide 25mg once daily on days 1-21 of each 28-day cycle for a maximum of 24 months, until disease progression or development of unacceptable adverse events (AEs). The primary end-point was efficacy; safety was evaluated as a secondary end-point. This study was registered with ClinicalTrials.gov, number NCT00655668. FINDINGS: A total of 54 patients with PTCL were treated. The overall response rate was 22% (12 of 54), including complete response (CR) or unconfirmed CR (CRu) in 11% of patients; 31% of patients with angioimmunoblastic T-cell lymphoma (AITL) responded (CR/CRu in 15% of patients). The median progression free survival and median response duration were 2.5 and 3.6 months, respectively, in the intent-to-treat population, and 4.6 and 3.5 months, respectively, in patients with AITL. Thrombocytopenia and neutropenia were the most common grade 3 or 4 haematological AEs, in 11 (20%) and 8 (15%) patients, respectively. Overall, 19 patients (35%) experienced at least 1AE leading to study dose interruption or reduction (commonly neutropenia or thrombocytopenia). Serious AEs were observed in 54% of patients and 12 patients died during the study; lymphoma progression (n=6); and acute respiratory distress syndrome, dyspnea, lung infiltration, neutropenic sepsis, pneumonia and cerebral ischaemia (n=1 each). INTERPRETATION: Lenalidomide exhibited single-agent activity in heavily pretreated patients with PTCL, particularly in patients with AITL. Future development is warranted in specific histologies, such as AITL, and in combination with chemotherapy or other agents considered active in PTCL. FUNDING: Celgene Corporation. PMID- 23731833 TI - Comprehensive chromosome analysis of blastocysts before implantation using array CGH. AB - BACKGROUND: Chromosomal abnormalities are common in embryos produced in vitro and cause implantation failure, miscarriage, and serious medical problems in infants. Because preimplantation genetic screening (PGS) is increasingly being used to detect aneuploidy in embryos with the purpose of improving implantation rates after IVF (in vitro fertilization), we aimed to validate the usefulness of array CGH for the preimplantation genetic screening (PGS) of embryos at the blastocyst stage of development. RESULTS: A total of 150 blastocysts were biopsied from couples undergoing IVF and analyzed using array CGH. We found that 54.5% (73/134) of the blastocysts were euploid embryos, whereas 45.5% of the embryos (61/134) had chromosomal abnormalities. Multiple chromosome abnormality was most frequently observed (34.4%), and dual aneuploidy was observed in 26.2% of the embryos. Monosomy (21.3%) appeared more frequently than trisomy (18%). CONCLUSION: Chromosomal microarray analysis provided clinically significant cytogenetic information regarding the frequency and variety of chromosomal abnormalities observed in embryos at the blastocyst stage, suggesting that this is a useful tool for comprehensive aneuploidy screening in IVF. PMID- 23731834 TI - The distribution of galanin-immunoreactive nerve fibers in the rat pharynx. AB - Galanin (GAL) consists of a chain of 29/30 amino acids which is widely distributed in the central and peripheral nervous systems. In this study, the distribution of GAL-immunoreactive (-IR) nerve fibers was examined in the rat pharynx and its adjacent regions. GAL-IR nerve fibers were located beneath the epithelium and taste bud-like structure of the pharynx, epiglottis, soft palate and larynx. These nerve fibers were abundant in the laryngeal part of the pharynx, and were rare in other regions. Mucous glands were mostly devoid of GAL IR nerve fibers. In the musculature of pharyngeal constrictor muscles, many GAL IR nerve fibers were also located around small blood vessels. However, intrinsic laryngeal muscles contained only a few GAL-IR nerve fibers. The double immunofluorescence method demonstrated that the distribution pattern of GAL-IR nerve fibers was partly similar to that of calcitonin gene-related peptide-IR nerve fibers in the pharyngeal mucosa and muscles. The present findings suggest that the pharynx is one of main targets of GAL-containing nerves in the upper digestive and respiratory systems. These nerves may have sensory and autonomic origins. PMID- 23731835 TI - Combination of a reduced dose of an intrathecal local anesthetic with a small dose of an opioid: a meta-analysis of randomized trials. AB - We tested whether the combination of a reduced dose of a local anesthetic (LA) with an opioid compared with a standard dose of the same LA alone guaranteed adequate intraoperative anesthesia and postoperative analgesia and decreased LA related adverse effects. We systematically searched (to November 2012) for randomized comparisons of combinations of a reduced dose of an LA with a concomitant opioid (experimental) with a standard dose of the LA alone (control) in adults undergoing surgery with single-injection intrathecal anesthesia without general anesthesia. We included 28 trials (1393 patients). In experimental groups, the median decrease in LA doses was 40% (range, 12%-70%). There was no difference between experimental and control groups in the need for intraoperative opioids or general anesthesia for failed block or in the duration of postoperative analgesia. With experimental interventions, there was evidence of a reduction in the duration of motor blockade postoperatively (average, -50 minutes), time to discharge from hospital or PACU (-33 minutes), time to ambulation (-28 minutes), and time to urination (-14 minutes). There was also evidence of a decrease in the risk of shivering (risk ratio [RR]: 0.26; 95% confidence interval [CI]: 0.12-0.56), nausea (RR: 0.45; 95% CI: 0.31-0.66), and arterial hypotension (RR: 0.52; 95% CI: 0.35-0.78). The risk of pruritus was increased (RR: 11.7; 95% CI: 6.2-21.9). Adding an opioid to a reduced dose of an intrathecal LA can decrease LA-related adverse effects and improve recovery from the spinal block without compromising intraoperative anesthesia or duration of postoperative analgesia. PMID- 23731836 TI - Progress in Alzheimer's disease research circa 2013: Is the glass half empty or half full? PMID- 23731837 TI - [Extracorporeal membrane oxygenation in primary graft dysfunction in a paediatric double lung transplant: presentation of a case]. AB - Primary graft dysfunction is a leading cause of morbimortality in the immediate postoperative period of patients undergoing lung transplantation. Among the treatment options are: lung protective ventilatory strategies, nitric oxide, lung surfactant therapy, and supportive treatment with extracorporeal membrane oxygenation (ECMO) as a bridge to recovery of lung function or re-transplant. We report the case of a 9-year-old girl affected by cystic fibrosis who underwent double-lung transplantation complicated with a severe primary graft dysfunction in the immediate postoperative period and refractory to standard therapies. Due to development of multiple organ failure, it was decided to insert arteriovenous ECMO catheters (pulmonary artery-right atrium). The postoperative course was satisfactory, allowing withdrawal of ECMO on the 5th post-surgical day. Currently the patient survives free of rejection and with an excellent quality of life after 600 days of follow up. PMID- 23731838 TI - Gastroesophageal reflux in bronchiectasis and the effect of anti-reflux treatment. AB - BACKGROUND: Bronchiectasis is a progressive and fatal disease despite the available treatment regimens. Gastroesophageal reflux (GER) may play an important role in the progression of bronchiectasis. However, active anti-reflux intervention such as Stretta radiofrequency (SRF) and/or laparoscopic fundoplication (LF) have rarely been used to treat Bronchiectasis. CASE PRESENTATION: Seven patients' clinical outcomes for treating GER-related deteriorated bronchiectasis were retrospective reviewed. All patients were treated by SRF and/or LF, and had follow-up periods ranging from one to five years. Typical GER symptoms, respiratory symptoms, medication consumption and general health status were assessed during the follow-ups. At the latest follow up all patients were alive. The typical GER symptoms disappeared in five people and were significantly improved in the other two. Two had complete remissions of both respiratory symptoms and bronchiectasis exacerbations; four had significantly improved respiratory symptoms to mild/moderate degrees as well as reduced or zero bronchiectasis exacerbations, which allowed them to resume the physical and social functions; one's respiratory symptoms and bronchiectasis exacerbations were not much improved, yet she was in stable condition and satisfied with the results. CONCLUSIONS: Potentially, GER plays an important role in some patients with bronchiectasis, and active anti-reflux treatments can be beneficial. Future clinical studies are suggested to clarify GER's role in bronchiectasis and to further determine whether anti-reflux interventions for GER can improve the outcomes of patients with bronchiectasis. PMID- 23731839 TI - Pandemic influenza planning, United States, 1978-2008. AB - During the past century, 4 influenza pandemics occurred. After the emergence of a novel influenza virus of swine origin in 1976, national, state, and local US public health authorities began planning efforts to respond to future pandemics. Several events have since stimulated progress in public health emergency planning: the 1997 avian influenza A(H5N1) outbreak in Hong Kong, China; the 2001 anthrax attacks in the United States; the 2003 outbreak of severe acute respiratory syndrome; and the 2003 reemergence of influenza A(H5N1) virus infection in humans. We outline the evolution of US pandemic planning since the late 1970s, summarize planning accomplishments, and explain their ongoing importance. The public health community's response to the 2009 influenza A(H1N1)pdm09 pandemic demonstrated the value of planning and provided insights into improving future plans and response efforts. Preparedness planning will enhance the collective, multilevel response to future public health crises. PMID- 23731840 TI - Full scale demonstration of air-purifying pavement. AB - Experiments concerning a full-scale demonstration of air purifying pavement in Hengelo, The Netherlands, are reported. The full width of the street was provided with concrete pavement containing TiO2 over a length of 150 m ("DeNOx street"). Another part of the street, about 100 m, was paved with normal paving blocks ("Control street"). The outdoor monitoring was done during 26 days for a period exceeding one year, and measured parameters included traffic intensity, NO, NO2 and ozone concentrations, temperature, relative humidity, wind speed and direction, and the visible and UV light irradiance. Prior and parallel to these field measurements, the used blocks were also measured in the lab to assess their performance. The NOx concentration was, on average, 19% (considering the whole day) and 28% (considering only afternoons) lower than the obtained values in the Control street. Under ideal weather conditions (high radiation and low relative humidity) a NOx concentration decrease of 45% could be observed. PMID- 23731842 TI - Small bowel capsule endoscopy for management of Crohn's disease: where do we stand? PMID- 23731841 TI - Mitogenomic sequences and evidence from unique gene rearrangements corroborate evolutionary relationships of myctophiformes (Neoteleostei). AB - BACKGROUND: A skewed assemblage of two epi-, meso- and bathypelagic fish families makes up the order Myctophiformes - the blackchins Neoscopelidae and the lanternfishes Myctophidae. The six rare neoscopelids show few morphological specializations whereas the divergent myctophids have evolved into about 250 species, of which many show massive abundances and wide distributions. In fact, Myctophidae is by far the most abundant fish family in the world, with plausible estimates of more than half of the oceans combined fish biomass. Myctophids possess a unique communication system of species-specific photophore patterns and traditional intrafamilial classification has been established to reflect arrangements of photophores. Myctophids present the most diverse array of larval body forms found in fishes although this attribute has both corroborated and confounded phylogenetic hypotheses based on adult morphology. No molecular phylogeny is available for Myctophiformes, despite their importance within all ocean trophic cycles, open-ocean speciation and as an important part of neoteleost divergence. This study attempts to resolve major myctophiform phylogenies from both mitogenomic sequences and corroborating evidence in the form of unique mitochondrial gene order rearrangements. RESULTS: Mitogenomic evidence from DNA sequences and unique gene orders are highly congruent concerning phylogenetic resolution on several myctophiform classification levels, corroborating evidence from osteology, larval ontogeny and photophore patterns, although the lack of larval morphological characters within the subfamily Lampanyctinae stands out. Neoscopelidae is resolved as the sister family to myctophids with Solivomer arenidens positioned as a sister taxon to the remaining neoscopelids. The enigmatic Notolychnus valdiviae is placed as a sister taxon to all other myctophids and exhibits an unusual second copy of the tRNA-Met gene - a gene order rearrangement reminiscent of that found in the tribe Diaphini although our analyses show it to be independently derived. Most tribes are resolved in accordance with adult morphology although Gonichthyini is found within a subclade of the tribe Myctophini consisting of ctenoid scaled species. Mitogenomic sequence data from this study recognize 10 reciprocally monophyletic lineages within Myctophidae, with five of these clades delimited from additional rearranged gene orders or intergenic non-coding sequences. CONCLUSIONS: Mitogenomic results from DNA sequences and unique gene orders corroborate morphology in phylogeny reconstruction and provide a likely scenario for the phylogenetic history of Myctophiformes. The extent of gene order rearrangements found within the mitochondrial genomes of myctophids is unique for phylogenetic purposes. PMID- 23731843 TI - Diagnostic and therapeutic role of endoscopy in gastroenteropancreatic neuroendocrine neoplasms. AB - Gastroenteropancreatic neuroendocrine neoplasms have substantially increased over the last decades. Because of the indolent clinical course of the disease even in advance stages and the rise in the incidental diagnosis of small asymptomatic lesions, the prevalence of gastroenteropancreatic neuroendocrine neoplasms is higher than that of pancreatic, gastric and oesophageal adenocarcinomas, making them the second most prevalent cancer type of the gastrointestinal tract. This increase in the overall prevalence of gastroenteropancreatic neuroendocrine neoplasms has been paralleled by a growth in the importance of the endoscopist in the care of these patients, who usually require a multidisciplinary approach. In this manuscript the diagnostic and therapeutic role of endoscopic for gastroenteropancreatic neuroendocrine neoplasms will be reviewed. PMID- 23731844 TI - Clinical correlates of herpes simplex virus type 1 loads in the lower respiratory tract of critically ill patients. AB - BACKGROUND: The significance of isolation of herpes simplex virus (HSV) type 1 from the lower respiratory tract in critically ill patients on mechanical ventilation is still unclear. In the current study, we used polymerase chain reaction techniques to quantify HSV-1 to further evaluate its role. OBJECTIVES: The hypothesis was that high loads reflect invasive pulmonary disease related to prolonged mechanical ventilation and increased mortality, as opposed to shedding from the upper respiratory tract, which leads to lower viral loads. STUDY DESIGN: We prospectively studied 77 consecutive patients admitted to the intensive care unit and analyzed 136 tracheal aspirates or bronchoalveolar lavage fluids, taken when clinically indicated in the diagnostic workup of fever, radiologic pulmonary infiltrates, progressive respiratory insufficiency or combinations. Samples were cultured for bacteria and yeasts according to routine microbiological methods and HSV-1 loads were determined by real time quantitative PCR. Viral loads were expressed per number of cells recovered. RESULTS: HSV-1 load was directly related to the simplified acute physiology score II (rs=0.47, P=0.04) when the first specimen taken proved positive for HSV-1. HSV-1 positivity concurred with Candida spp. colonization. Patients with and without a HSV-1 load did not differ with respect to pulmonary and systemic courses and vital outcomes. CONCLUSIONS: The data suggest that HSV-1 in the lower respiratory tract originates from shedding in the upper respiratory tract in about 30% of critically ill patients, following immune suppression and reactivation, without invasively infecting the lung. No attributable mortality was observed. PMID- 23731845 TI - Phenotypic and genotypic characterization of acyclovir-resistant corneal HSV-1 isolates from immunocompetent patients with recurrent herpetic keratitis. AB - Herpes simplex virus type 1 (HSV-1) is a leading cause of corneal blindness. Acyclovir (ACV) constitutes the standard treatment of HSV infections including herpetic keratitis (HK). HSV resistance to ACV is mainly described in immunocompromised patients. We describe two cases of ACV-resistant corneal HSV-1 in immunocompetent individuals with recurrent HK. PMID- 23731846 TI - Fatal encephalitis due to BK virus in a patient with common variable immunodeficiency: a case report. AB - Encephalitis due to BK virus is a rare condition. Here, we describe a young male patient with common variable immunodeficiency who developed fatal encephalitis due to BK virus. The patient presented initially with ocular symptoms that were followed by behavioral changes and spastic quadriparesis. Diagnosis was made by the compatible clinical findings and detection of viral DNA by polymerase chain reaction in the cerebrospinal fluid. To the best of our knowledge, this is the first report of BK virus encephalitis in a patient with common variable immunodeficiency. We suggest that BK virus should be suspected in cases of encephalitis; particularly in patients with immunodeficiency. PMID- 23731847 TI - Accuracy of a commercially available assay for HCV genotyping and subtyping in the clinical practice. AB - BACKGROUND: Hepatitis C virus (HCV) genotyping is mandatory for tailoring dose and duration of pegylated interferon-alpha plus ribavirin treatment and for deciding on triple therapy eligibility. Additionally, subtyping may play a role in helping to select future treatment regimens that include directly-acting antivirals. However, commercial assays for HCV genotyping fail to identify the genotype/subtype in some cases. OBJECTIVE: Our aims were (i) to determine the success rate of the commercial genotyping assay Abbott RealTime HCV Genotype II at identifying the genotype and the HCV-1 subtype; and (ii) to phylogenetically characterise the obtained indeterminate results. STUDY DESIGN: HCV genotyping results obtained between 2009 and 2012 in a Spanish reference hospital were reviewed. A total of 896 people were genotyped with the Abbott RealTime HCV Genotype II assay. Specimens with an indeterminate result were retrospectively genotyped using the reference method based on the phylogenetic analysis of HCV NS5B sequences. RESULTS: Using the commercially available assay, an indeterminate HCV genotype result was obtained in 20 of 896 patients (2.2%); these corresponded to genotypes 3a, 3k and 4d. Importantly, 8.6% of all cases where genotype 3 was detected were indeterminate. In addition, the HCV-1 subtype was not assigned in 29 of 533 cases (5.4%). CONCLUSIONS: The implementation in the clinical microbiology laboratory of the reference method for HCV genotyping allows indeterminate genotype/subtype results to be interpreted and may lead to the identification of previously uncharacterised subtypes. PMID- 23731848 TI - Clinical significance of serum HBsAg levels and association with liver histology in HBeAg positive chronic hepatitis B. AB - BACKGROUND: Despite its recognized role as a prognostic marker for antiviral treatment, the clinical significance of serum hepatitis B surface antigen (HBsAg) level in the immune-clearance stage of chronic hepatitis B remains unclear. OBJECTIVES: To characterize how HBsAg level and various clinical and virological factors are related and analyze the correlation of HBsAg with liver histology. STUDY DESIGN: A total of 198 treatment-naive HBeAg-positive chronic hepatitis B patients were enrolled. Serum HBV DNA and HBsAg were determined quantitatively. Mutations of precore or basal core promoter (BCP) were also determined. Finally, liver necroinflammation grading and fibrosis stage were evaluated by Knodell score and Ishak score, respectively. RESULTS: Lower HBsAg levels were found in patients with genotype C HBV infection, or in the presence of precore or mutations, or Knodell necroinflammation grading >= 7, or advanced fibrosis (Ishak stage 4-6). HBsAg level displayed a strong correlation with HBV DNA (r = 0.727, P < 0.001) and also exhibited a positive correlation with intrahepatic HBcAg expression in either cytoplasm (r = 0.420, P < 0.001) or nucleus (r = 0.401, P < 0.001). Examining the correlation with advanced liver fibrosis revealed that HBsAg level is a significant factor in univariate analysis and is the only independent factor in multivariate analysis (Coefficient: -0.975, P = 0.039, OR: 0.377, 95% CI: 0.149-0.953). CONCLUSIONS: HBsAg level varied with different clinical or virological categories. Lower baseline levels of HBsAg might reflect the status of advanced liver fibrosis in HBeAg positive chronic hepatitis B patients. PMID- 23731849 TI - Nasal pH in patients with chronic rhinosinusitis before and after endoscopic sinus surgery. AB - PURPOSE: Physiologically acidic nasal pH depends on intact nasal mucosal function. The aim of this study was to determine nasal pH in patients with chronic rhinosinusitis and to investigate the changes in pH related to mucosal healing after endoscopic sinus surgery. MATERIALS AND METHODS: Normal subjects and the patients with chronic rhinosinusitis who showed no recurrence after endoscopic sinus surgery were enrolled. Using a portable pH meter and a glass tipped probe, nasal pH was measured in the inferior meatus in normal subjects and patients before and after surgery at 3 months. RESULTS: The mean (+/-SD) nasal pH was 6.5 +/- 0.5 (5.9 to 7.3) in 19 normal subjects, and 6.7 +/- 0.6 (5.3 to 7.6) in 19 CRS patients before surgery, which showed no significant difference between the groups. The nasal pH values were in the range of 3.8-7.7 (mean +/- SD 5.7 +/- 0.9) at 3 months after surgery, and significantly lower than the preoperative values in patients (P=.004). The patients showing pH lower than 6.0 accounted for 10.5% before surgery, but 68.4% after surgery. CONCLUSIONS: Normal nasal pH was in the slightly acidic range, and the mean nasal pH of patients with chronic rhinosinusitis fell within normal limits as well, which indicates that chronic rhinosinusitis may not disturb the electrolyte milieu of the nasal mucosa. The average nasal pH measured at 3 months after endoscopic sinus surgery exhibited acidity of pH5.7. The factors causing a fall in nasal pH during the healing period after the sinus surgery remain to be elucidated. PMID- 23731850 TI - Taste and smell function in chronic disease: a review of clinical and biochemical evaluations of taste and smell dysfunction in over 5000 patients at The Taste and Smell Clinic in Washington, DC. AB - PURPOSE: To describe systematic methods developed over 40 years among over 5000 patients at The Taste and Smell Clinic in Washington, DC to evaluate taste and smell dysfunction. MATERIALS AND METHODS: A tripartite methodology was developed. First, methods to determine clinical pathology underlying the multiple disease processes responsible for taste and smell dysfunction were developed. Second, methods to determine biochemical parameters responsible for these pathologies were developed. Third, methods to implement these techniques were developed to form a unified basis upon which treatment strategies can be developed to treat these patients. RESULTS: Studies were performed in 5183 patients. Taste loss was present in 62% of patients, smell loss in 87%. Most patients with taste loss (52%) exhibited Type II hypogeusia; most patients with smell loss (56%) exhibited Type II hyposmia. Sensory distortions were present in 60%. Four common diagnostic entities were found: post influenza-type hyposmia and hypogeusia (27% of patients), idiopathic causes (16%), allergic rhinitis (15%) and post head injury (14%). Regardless of clinical diagnosis the major biochemical abnormality found in most patients (~70%) was diminished parotid salivary and nasal mucus secretion of cAMP and cGMP. CONCLUSIONS: Taste and smell dysfunctions are common clinical problems associated with chronic disease processes. These symptoms require a systematic, integrated approach to understand their multiple and complex components. The approach presented here can and has led to effective treatment. PMID- 23731851 TI - Management of sinonasal teratocarcinosarcoma: a systematic review. AB - PURPOSE: Sinonasal teratocarcinosarcoma (SNTCS) is a rare and highly malignant neoplasm that often involves the anterior skull base. This study reviews the published literature related to SNTCS. Clinical presentation, demographics, radiographic diagnosis, pathology, treatment, and management outcomes of this uncommon disease are reported. METHODS: A systematic review in the published English literature was conducted. A MEDLINE/PubMed search and bibliographic examination of articles pertaining to SNTCS were performed. Each case was analyzed for patient demographics, clinical presentation, tumor location, diagnosis, treatment, and survival outcome. RESULTS: A total of 49 journal articles were included. Individual patient data were reported in 86 cases. The average age of the patients was 54.5 years (range, 0.1 to 85 years), with a strong male predilection (7:1). Average follow-up was found to be 38.9 months (range, 2 to 372 months). The most common treatment method was surgery with radiation therapy, utilized in 59.3% of patients. Out of 71 cases with reported outcome and follow-up, there were 21 cases of recurrence, 8 cases with metastasis, and 6 cases reporting both recurrence and metastasis. Forty-two out of 71 (59.2%) patients survived at the time of follow-up. CONCLUSIONS: This study describes the largest pool of SNTCS patients to date. SNTCS is a rare and aggressive malignant skull base tumor with a poor prognosis with frequent recurrence and metastasis. Although a variety of treatment paradigms have been reported in the literature, radical surgical resection followed by radiation therapy appears to be the most commonly used treatment option. PMID- 23731852 TI - Quadrupedal head position enhances recovery from chronic maxillary sinusitis. AB - OBJECTIVES: The position of human maxillary ostia is high on their superomedial walls, which may be suboptimal for natural drainage. Human maxillary sinuses exhibit better passive drainage through their ostia when tilted anteriorly to mimic a quadrupedal head position. We all know that sufficient drainage is very important for the treatment of chronic rhinosinusitis (CRS). Chronic maxillary sinusitis (CMS) is the high incidence of CRS. The aim of this study was to investigate the efficacy of quadrupedal head position in patients with CMS. METHODS: One hundred six patients diagnosed with CMS were enrolled. Patients were randomized to quadrupedal head position group and non-quadrupedal head position group for 6 weeks of treatment. Treatment outcomes were measured using 1) Lund Mackay scoring system of pre-and post-treatment computer tomography (CT); and 2) Sinonasal Quality-of-Life (QoL) Survey completed at baseline and 6 weeks of therapy. RESULTS: There were statistically significant differences in QoL scores and CT scores between quadrupedal head position group and non-quadrupedal head position group. The quadrupedal head position group had much more improvements in QoL scores and CT scores than that of non-quadrupedal head position group. One patient in the quadrupedal head position group required functional endoscopic sinus surgery (ESS) due to persistent symptoms, and nine patients in non quadrupedal head position group needed ESS. There were less patients that required ESS in the quadrupedal head position group than in the non-quadrupedal head position group. CONCLUSIONS: The improvements of QoL scores and CT scores were significantly better in the quadrupedal head position group than that in the non-quadrupedal head position group. Quadrupedal head position can be valuable adjuvant therapy for patients with CMS. PMID- 23731853 TI - Differential expression of microRNAs in 2-cell and 4-cell mouse embryos. AB - In vitro fertilized (IVF) human embryos have a high incidence of developmental arrest before the blastocyst stage, therefore characterization of the molecular mechanisms that regulate embryo development is urgently required. Post transcriptional control by microRNAs (miRNAs) is one of the most investigated RNA control mechanisms, and is hypothesized to be involved actively in developmental arrest in preimplantation embryos. In this study, we extracted total RNA from mouse 2-cell and 4-cell embryos. Using a miRNA microarray, 192 miRNAs were found to be differentially expressed in 4-cell embryos and 2-cell embryos; 122 miRNAs were upregulated and 70 were downregulated in 4-cell embryos. The microarray results were confirmed by real-time quantitative RT-PCR for six miRNAs (mmu-miR 467h, mmu-miR-466d-3p, mmu-miR-292-5p, mmu-miR-154, mmu-miR-2145, and mmu-miR 706). Cdca4 and Tcf12 were identified as miR-154 target genes by target prediction analysis. This study provides a developmental map for a large number of miRNAs in 2-cell and 4-cell embryos. The function of these miRNAs and the mechanisms by which they modulate embryonic developmental arrest require further study. The results of this study have potential applications in the field of reproductive medicine. PMID- 23731856 TI - Paratrichodina africana (Ciliophora): a pathogenic gill parasite in farmed Nile tilapia. AB - Trichodinids are ciliated protozoa that are widely known as one of the main groups of fish parasites. The genus Trichodina presents the greatest species diversity. However, records of Paratrichodina species are scarce, and little is known about their pathogenicity in hosts. The present study provides new records of Paratrichodina africana Kazubski and El-Tantawy (1986) in Nile tilapia from South America and descriptions of pathological changes and seasonality. A total of 304 farmed fish were examined. From gill scraping, parasites were identified using Klein's nitrate impregnation method. Gill samples were fixed for histopathological analysis. Small trichodinid found in this study have a prominent blade apophysis and narrow central part and blade shape that corresponds to the characteristics of P. africana Kazubski and El-Tantawy (1986). Gill lesions were proportional to parasite intensity, in which the gill tissue was compromised in heavy infestation. Proliferative disturbances were found, including epithelial hyperplasia, desquamation, and mononuclear and eosinophilic infiltrate that culminated in necrosis. We did not observe a seasonality effect on the occurrence of P. africana. This ciliated protozoan causes compromised respiratory capacity that leads to severe gill lesions and currently is an important pathogen that afflicts intensive tilapia cultures in Brazil. PMID- 23731855 TI - Hospice caregivers' experiences with pain management: "I'm not a doctor, and I don't know if I helped her go faster or slower". AB - CONTEXT: Those caring for their loved ones in hospice experience tremendous stress, being faced with numerous decisions as they work to manage the pain experienced by their loved one. Although hospice care teams create pain management strategies, it is the role of the caregiver to implement these plans. OBJECTIVES: The purpose of this study was to further understand the hospice caregiver experience relating to pain management. METHODS: Semistructured interviews with 146 caregivers provided data for the study. Responses to seven questions asking for a ranking of end-of-life pain management indicated a less than ideal experience. Available narratives from 38 caregivers were analyzed for themes related to further understanding of the concerns. RESULTS: Five themes were identified in the data including difficulty with administration of pain medicines, concerns about side effects of medications, insecurity with pain assessment, frustrations with communication among health care team members, and memories of unrelieved pain. CONCLUSION: These findings should raise concern among hospice professionals, whose commitment is to the management of pain, including emotional pain, with a focus on both the patient and the family as a unit of care. These data clearly suggest that hospice providers have an opportunity to be sensitive to perceptions held by caregivers regarding pain management. Effective planning for pain control must incorporate the values and beliefs not only of each patient but also of the family caregiver. PMID- 23731854 TI - Future perspectives in melanoma research. Meeting report from the "Melanoma Bridge. Napoli, December 2nd-4th 2012". AB - Recent insights into the genetic and somatic aberrations have initiated a new era of rapidly evolving targeted and immune-based treatments for melanoma. After decades of unsuccessful attempts to finding a more effective cure in the treatment of melanoma now we have several drugs active in melanoma. The possibility to use these drugs in combination to improve responses to overcome the resistance, to potentiate the action of immune system with the new immunomodulating antibodies, and identification of biomarkers that can predict the response to a particular therapy represent new concepts and approaches in the clinical management of melanoma. The third "Melanoma Research: "A bridge from Naples to the World" meeting, shortened as "Bridge Melanoma Meeting" took place in Naples, December 2 to 4th, 2012. The four topics of discussion at this meeting were: advances in molecular profiling and novel biomarkers, combination therapies, novel concepts toward integrating biomarkers and therapies into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage, and the knowledge gained from the biology of tumor microenvironment across different tumors as a bridge to impact on prognosis and response to therapy in melanoma. This international congress gathered more than 30 international faculty members who in an interactive atmosphere which stimulated discussion and exchange of their experience regarding the most recent advances in research and clinical management of melanoma patients. PMID- 23731857 TI - First isolation of Hammondia heydorni from dogs in China. AB - Fecal samples of 945 dogs were examined microscopically in 2 refuge facilities in China from March 2010 to November 2011. In 8 dogs, oocysts, 9-14 MUm in size, were found. Their morphology was similar to those of Hammondia heydorni and Neospora caninum. Sporulated Hammondia/Neospora-like oocysts were fed to 2 dogs, 2 gerbils, 2 guinea pigs, and 2 KM mice; tissues from these inoculated animals were then fed to coccidia-free dogs to determine species susceptibility to these oocysts. Oocysts were not excreted in the feces of dogs or rodents inoculated with oocysts. However, the dogs fed the tissues of gerbils or guinea pigs that were inoculated orally with oocysts excreted fresh oocysts. Dogs fed tissues from guinea pigs inoculated with brain and muscular homogenate from guinea pigs that were fed sporulated Hammondia/Neospora-like oocysts did not excrete oocysts. These findings indicated that the oocysts from naturally infected dogs had an obligatory 2-host life cycle, with gerbils and guinea pigs as intermediate hosts. DNA isolated from these oocysts could not be amplified using N. caninum- and Toxoplasma gondii-specific primers. However, positive amplification with the H. heydorni-specific primers confirmed the presence of H. heydorni DNA in the samples. A comparison of the intron 1 sequence of the alpha tubulin gene with those from H. heydorni from dogs and H. triffittae from foxes showed that dog derived oocysts possessed a different alpha tubulin gene. Both our dog-derived sequence and 2 previous alpha tubulin gene sequences from H. triffittae from foxes contained a 9-bp insertion relative to 3 sequences of H. heydorni from dogs. However, when the 9-bp insertion from H. triffittae sequences were compared, the 9-bp insertion in our dog-derived sequence had a nucleotide substitution. The present study, therefore, provides new evidence of genetic diversity among isolates from dogs. This is the first survey for H. heydorni in dogs from China. PMID- 23731858 TI - Equine cryptosporidial infection associated with Cryptosporidium hedgehog genotype in Algeria. AB - Faecal samples from two horse farms in Algeria keeping Arabian, Thoroughbred, and Barb horses were examined for the presence of Cryptosporidium in 2010-2011. A total of 138 faecal samples (16 from a farm keeping 50 animals and 122 from a farm with 267 horses) were screened for Cryptosporidium spp. infection using molecular tools. DNA was extracted from all samples. Nested PCR was performed to amplify fragments of the SSU rDNA and gp60 genes to determine the presence of Cryptosporidium species and genotypes. Sequence analyses of SSU and gp60 genes revealed four animals positive for the presence of subtype XIIIa A22R9 of the Cryptosporidium hedgehog genotype. The infections were not associated with diarrhoea. This study reports, for the first time, the occurrence of Cryptosporidium in Algeria and the first occurrence of the hedgehog genotype in horses. These findings support the potential role of infected horses in sylvatic domestic transmission of Cryptosporidium. PMID- 23731859 TI - Postpyloric decompression tube placement through a gastrostomy for malignant bowel obstruction. AB - BACKGROUND: Malignant bowel obstruction affect a patient's quality of life, but, management of MBO is controversial. CASE PRESENTATION: A 51-year-old woman who had been diagnosed as uterine cervix cancer 2 years ago and had undergone surgery, chemotherapy and radiotherapy, was admitted to our hospital. She was diagnosed as having a recurrence of peritoneal metastasis and bowel obstruction. For her nasal pain, we considered insertion of a postpyloric decompression tube through the gastrostomy instead of via the nasal cavity. After insertion of a percutaneous gastrostomy tube was performed endoscopically, we introduced a postpyloric decompression tube through her gastrostomy. She could be discharged home, and 91 days later, she died in her home under hospice care, as she had wished. CONCLUSIONS: Insertion of a postpyloric decompression tube through a gastrostomy might be useful in the management of advanced cancer patients with bowel obstruction. PMID- 23731860 TI - Nuclear magnetic resonance investigations on electrochemical reactions of low temperature fuel cells operating in acidic conditions. PMID- 23731861 TI - Conformational dynamics and distribution of nitroxide spin labels. AB - Long-range distance measurements based on paramagnetic relaxation enhancement (PRE) in NMR, quantification of surface water dynamics near biomacromolecules by Overhauser dynamic nuclear polarization (DNP) and sensitivity enhancement by solid-state DNP all depend on introducing paramagnetic species into an otherwise diamagnetic NMR sample. The species can be introduced by site-directed spin labeling, which offers precise control for positioning the label in the sequence of a biopolymer. However, internal flexibility of the spin label gives rise to dynamic processes that potentially influence PRE and DNP behavior and leads to a spatial distribution of the electron spin even in solid samples. Internal dynamics of spin labels and their static conformational distributions have been studied mainly by electron paramagnetic resonance spectroscopy and molecular dynamics simulations, with a large body of results for the most widely applied methanethiosulfonate spin label MTSL. These results are critically discussed in a unifying picture based on rotameric states of the group that carries the spin label. Deficiencies in our current understanding of dynamics and conformations of spin labeled groups and of their influence on NMR observables are highlighted and directions for further research suggested. PMID- 23731862 TI - Early detection of iron deficiency in elite athletes: could microcytic anemia factor (Maf) be useful? AB - INTRODUCTION: The aim of this study was to establish the sensitivity and specificity of the microcytic anemia factor (Maf((r))), which is generated by the Coulter LH 750 analyzer in the evaluation of iron depletion and iron-deficient erythropoiesis in athletes. METHODS: A total of 142 athletes were divided into three groups: with iron depletion, with iron-deficient erythropoiesis, and controls. The following parameters were measured: RBCs (red blood cells), Hb (hemoglobin), Hct (hematocrit), MCV (mean cellular volume), MCH (mean cell hemoglobin), MCHC (mean cell hemoglobin corpuscular), RDW (red cell distribution width), Maf((r)), Reticulocytes, Ferritin, sTfR (soluble transferrin receptor), Transferrin, Haptoglobin, IL- 6 (Interleukin-6), hs-CRP (high-sensitivity C reactive protein). RESULTS: The best Maf((r)) value to exclude iron depletion in athletes was 130.3, showing a sensitivity of 72.6% and a specificity of 57.3%. The AUC was 0.690 (CI 95% 0.607-0.765, P < 0.001). ROC curve analysis for Maf((r)) in the diagnosis of iron-deficient erythropoiesis indicates sensitivity of 61.5%, and specificity of 93.0%, with AUC = 0.826 (CI 95% 0.754-0.885, P < 0.001) and on cutoff value 114. CONCLUSIONS: This study shows that Maf((r)) generated by the Coulter LH 700 Series hematology analyzers, performs very well in discriminating healthy athletes and those with different stages of iron deficiency. Also, in cost/benefit terms, monitoring of Maf((r)) is justified as a low cost, effective screening parameter for determining iron status in athletes. PMID- 23731863 TI - Content and fractionation of Cu, Zn and Cd in size fractionated municipal solid waste incineration bottom ash. AB - Municipal solid waste incinerator (MSWI) bottom ash was size fractionated into six fractions, with the respective particle size of <0.45 mm, 0.45-1 mm, 1-2 mm, 2-4 mm, 4-8 mm and >8 mm. The contents and fractionation of Cu, Zn, Cd in the size fractionated MSWI bottom ash were investigated. The results showed the contents and fractionation of Cu, Zn and Cd varied among the different particle sizes, which were related to their thermodynamic characteristics. High content of Cu was found in the bottom ash with the particle size of <0.45 mm and >4 mm, due to its lithophilic property and the function of entrainment. The content of Zn showed a relatively even distribution among the various particles. The content of Cd showed a decreasing trend with the increase of the particle size, due to its high volatility. Besides, the carbonate bound fraction of Cd showed a decreasing trend with the increase of the particle size, while the carbonate bound fraction of Cu showed an increasing trend. The organic matter bound fraction of Cu increased when the particle size increased. The results also showed the fine ash contained a higher level of unstable Cd than the large ash, while the large ash had a higher level of unstable Cu comparatively. PMID- 23731864 TI - Toxicity cutoff of aromatic hydrocarbons for luminescence inhibition of Vibrio fischeri. AB - Effects of individual petroleum hydrocarbons on the luminescence inhibition of Vibrio fischeri were evaluated according to a standard protocol to develop a quantitative structure-activity relationship and identify the apparent toxicity cutoff. Eighteen aromatic hydrocarbons, including benzene and its derivatives and polycyclic aromatic hydrocarbons (PAHs), were chosen as model compounds with their log K(ow) values between 2.7 and 6.4. The obtained values of 50 percent luminescence inhibition (EC50) showed a good linear correlation with log K(ow) up to ~5. However, toxic effects were not observed for more hydrophobic chemicals with log K(ow) value >5. The calculated chemical activities that caused EC50 were mostly between 0.01 and 0.1. This agrees with an earlier hypothesis concerning a chemical activity resulting the critical membrane concentration of aromatic hydrocarbons. The highest chemical activities for aromatic hydrocarbons with log K(ow) value >5 or melting point >100 degrees C are <0.01 when they are spiked at their water solubility level according to the standard test protocol; this occurs for two primary reasons: (1) partitioning between organism and the test solution and (2) decreasing fugacity ratio with increasing melting point. Accordingly, luminescence inhibition by petroleum hydrocarbons is well explained by the baseline toxicity model. However, the apparent toxicity cutoff observed for single chemicals is not necessarily valid in a complex mixture, because baseline toxicity is regarded concentration additive. PMID- 23731865 TI - Development of a larval bioassay using the calanoid copepod, Eurytemora affinis to assess the toxicity of sediment-bound pollutants. AB - Hydrophobic pollutants, in particular sediment-sorbed organic compounds, are widespread in the aquatic environment and could represent a threat to living organisms. Estuarine species, which live in turbulent ecosystems, are particularly exposed to this mode of contamination. For precise evaluation of the toxicity of hydrophobic contaminants desorbed from particles, a new larval assay using nauplii of the estuarine calanoid copepod Eurytemora affinis was developed. It consists of the direct exposure of copepods during naupliar development to elutriates of an unpolluted sediment spiked with different model contaminants. This bioassay measures the toxicity of the bioavailable fraction of particle sorbed pollutants on the naupliar stage of copepods. Mortality and growth (non invasive endpoints) in nauplii were analysed after six days of exposure. This approach was validated using six pollutants with different modes of action: benzo[a]pyrene (BaP), dimethylbenzo[a]anthracene (DMBA), phenanthrene (PHE), polychlorinated biphenyls (PCB 126, PCB 153) and 4-nonylphenol (4-NP). All these compounds induced a dose-dependent increase in toxic effects. Lethal effects only occurred at the highest tested concentrations: 58,541 and 6092 ng g(-1) dry weight sediment (dws), for PHE and DMBA, respectively. Sublethal effects (growth inhibition) were observed at lower concentrations for all tested compounds except PCB 153, from 8, 142, 297, 6092 and 8453 ng g(-1) dws for PCB 126, BaP, PHE, DMBA and 4-NP, respectively. PMID- 23731866 TI - Occurrence of PCDD/PCDFs and PCBs in soil and comparison with CYP1A response in PLHC-1 cell line. AB - The responsiveness of CYP1A (gene transcription and EROD enzyme activity) in the cell line Poeciliopsis lucida hepatoma (PLHC-1) upon exposure to extracts of contaminated soil samples was investigated and compared to levels of PCDD/PCDFs and PCBs including non-ortho obtained by GC/MS analysis. Soil samples A and B were collected in sites A and B. Two fractions, not purified (np) and purified (p), were obtained from each sample and analyzed for PCDD/PCDF and PCB content by GC/MS; in parallel they were tested for 24 h with PLHC-1. CYP1A response was investigated at gene (RT-qPCR) level and as 7-ethoxyresorufin-O-deethylase (EROD) enzyme activity. Chem-TEQs and Bio-TEQs were then calculated. ?TEQ calculated for PCDD/Fs and PCBs was 0.081 pg/g and 20.32 pg/g for samples A and B, respectively. PLHC-1 showed less up-regulation of cyp1a gene on exposure to the two purified fractions (Ap 2.1-fold and Bp 1.8-fold) than to non-purified fractions (up to 15 fold for Anp and 13-fold for Bnp). EROD was also induced 2.38- and 9.44-fold in the two purified fractions (Ap and Bp) compared to model inducer 2,3,7,8-TCDD, and up to 16.03-fold for non-purified Anp and 33.79-fold for Bnp. The combination of CYP1A response, obtained in a PLHC-1 cell-based bioassay, with contaminant residue analysis provided a better description of the presence and toxicity of dioxin-like compounds in an environmental matrix. PMID- 23731867 TI - Cadmium-tolerant bacteria reduce the uptake of cadmium in rice: potential for microbial bioremediation. AB - We selected 24 bacterial isolates that could tolerate up to 2500 uM CdCl2 from the soil of rice fields downstream from a zinc-mineralized area contaminated with a high level of cadmium (Cd). In the presence of 500 uM CdCl2, all isolates grew slower and with a prolonged lag-phase compared to in the absence of Cd. Cd binding capacity was high and ranged from 6.38 to 9.38 log[Cd(atom)]/cell. The stability of Cd complexes in bacteria was affected by 1mM EDTA. In 500 uM CdCl2, all isolates produced 0.7 to 4.8-fold more inorganic sulfide and 0.6 to 2.2-fold more thio-rich compounds containing SH groups. Out of 24 Cd-tolerant bacterial isolates, KKU2500-3, -8, -9 and -20 were able to promote the growth of Thai jasmine rice (Kao Hom Mali 105) seedlings in the presence of 200 uM CdCl2, and KKU2500-3 produced the highest numbers of fibrous root. Interestingly, these 4 isolates increased Cd tolerance and decreased the accumulation of Cd in rice by 61, 9, 6, and 17% when grown in the presence of 200 uM CdCl2. Of the 4 isolates, KKU2500-3 produced more inorganic sulfide when grown in CdCl2 at 500-2000 uM. XANES analyses indicated that this isolate precipitated a detectable amount of cadmium sulfide (CdS) when grown in 500 uM CdCl2. Thus, the isolate KKU2500-3 could possibly transform toxic, soluble CdCl2 into non-toxic, insoluble CdS. These 4Cd-tolerant bacterial isolates were identified via 16S rDNA sequencing and classified as Cupriavidus taiwanensis KKU2500-3 and Pseudomonas aeruginosa KKU2500-8, -9, and -20. PMID- 23731868 TI - Differences in classification of COPD group using COPD assessment test (CAT) or modified Medical Research Council (mMRC) dyspnea scores: a cross-sectional analyses. AB - BACKGROUND: The GOLD 2011 document proposed a new classification system for COPD combining symptom assessment by COPD assessment test (CAT) or modified Medical Research Council (mMRC) dyspnea scores, and exacerbation risk. We postulated that classification of COPD would be different by the symptom scale; CAT vs mMRC. METHODS: Outpatients with COPD were enrolled from January to June in 2012. The patients were categorized into A, B, C, and D according to the GOLD 2011; patients were categorized twice with mMRC and CAT score for symptom assessment, respectively. Additionally, correlations between mMRC scores and each item of CAT scores were analyzed. RESULTS: Classification of 257 patients using the CAT score vs mMRC scale was as follows. By using CAT score, 60 (23.3%) patients were assigned to group A, 55 (21.4%) to group B, 21 (8.2%) to group C, and 121 (47.1%) to group D. On the basis of the mMRC scale, 97 (37.7%) patients were assigned to group A, 18 (7.0%) to group B, 62 (24.1%) to group C, and 80 (31.1%) to group D. The kappa of agreement for the GOLD groups classified by CAT and mMRC was 0.510. The mMRC score displayed a wide range of correlation with each CAT item (r = 0.290 for sputum item to r = 0.731 for dyspnea item, p < 0.001). CONCLUSIONS: The classification of COPD produced by the mMRC or CAT score was not identical. Care should be taken when stratifying COPD patients with one symptom scale versus another according to the GOLD 2011 document. PMID- 23731869 TI - Application of fungal laccase fused with cellulose-binding domain to develop low lignin rice plants. AB - We observed a reduction of lignin content linked to the expression of fungal laccase in rice plants. The lignin content of L-4, which showed the highest LAC activity among transgenic lines produced, was lower than that of the control line. However, this change was not reflected to the saccharification efficiency. PMID- 23731871 TI - Progress in global surveillance and response capacity 10 years after severe acute respiratory syndrome. AB - Ten years have elapsed since the World Health Organization issued its first global alert for an unexplained illness named severe acute respiratory syndrome (SARS). The anniversary provides an opportunity to reflect on the international response to this new global microbial threat. While global surveillance and response capacity for public health threats have been strengthened, critical gaps remain. Of 194 World Health Organization member states that signed on to the International Health Regulations (2005), <20% had achieved compliance with the core capacities required by the deadline in June 2012. Lessons learned from the global SARS outbreak highlight the need to avoid complacency, strengthen efforts to improve global capacity to address the next pandemic using all available 21st century tools, and support research to develop new treatment options, countermeasures, and insights while striving to address the global inequities that are the root cause of many of these challenges. PMID- 23731872 TI - Obesity. Preface. PMID- 23731870 TI - Cardiovascular risk in pediatric-onset rheumatological diseases. AB - Cardiovascular morbidity and mortality are becoming major health concerns for adults with inflammatory rheumatic diseases. The enhanced atherogenesis in this patient population is promoted by the exposure to traditional risk factors as well as nontraditional cardiovascular insults, such as corticosteroid therapy, chronic inflammation and autoantibodies. Despite definite differences between many adult-onset and pediatric-onset rheumatologic diseases, it is extremely likely that atherosclerosis will become the leading cause of morbidity and mortality in this pediatric patient population. Because cardiovascular events are rare at this young age, surrogate measures of atherosclerosis must be used. The three major noninvasive vascular measures of early atherosclerosis--namely, flow mediated dilatation, carotid intima-media thickness and pulse wave velocity--can be performed easily on children. Few studies have explored the prevalence of cardiovascular risk factors and even fewer have used the surrogate vascular measures to document signs of early atherosclerosis in children with pediatric onset rheumatic diseases. The objective of this review is to provide an overview on cardiovascular risk and early atherosclerosis in pediatric-onset systemic lupus erythematosus, juvenile idiopathic arthritis and juvenile dermatomyositis patients, and to review cardiovascular preventive strategies that should be considered in this population. PMID- 23731873 TI - Economic costs of overweight and obesity. AB - Obesity has substantially increased in recent decades and is now one of the major global health problems. The large obesity-related health burden negatively impacts many relevant health outcomes (e.g. quality of life, disability, mortality) and leads to increased healthcare utilization. This excess service use is the main driver behind high healthcare costs of obese individuals. Findings indicate that costs rise curvilinearly with increasing body mass index, especially among the obese. As more individuals of a country's population become obese, a larger share of total annual national healthcare expenditure is spent on obesity and obesity-related health problems. In addition to escalating healthcare costs, obesity goes along with indirect costs through decreases in workforce productivity. The empirical evidence has shown beyond doubt that obesity negatively impacts individuals, healthcare systems, employers, and the economy as a whole. This article provides a brief overview of selected economic consequences associated with excess-weight. PMID- 23731874 TI - Weight discrimination and bullying. AB - Despite significant attention to the medical impacts of obesity, often ignored are the negative outcomes that obese children and adults experience as a result of stigma, bias, and discrimination. Obese individuals are frequently stigmatized because of their weight in many domains of daily life. Research spanning several decades has documented consistent weight bias and stigmatization in employment, health care, schools, the media, and interpersonal relationships. For overweight and obese youth, weight stigmatization translates into pervasive victimization, teasing, and bullying. Multiple adverse outcomes are associated with exposure to weight stigmatization, including depression, anxiety, low self-esteem, body dissatisfaction, suicidal ideation, poor academic performance, lower physical activity, maladaptive eating behaviors, and avoidance of health care. This review summarizes the nature and extent of weight stigmatization against overweight and obese individuals, as well as the resulting consequences that these experiences create for social, psychological, and physical health for children and adults who are targeted. PMID- 23731875 TI - Obesity, functional mobility and quality of life. AB - Obesity is a health condition that, through a complex interaction of biopsychosocial and environmental factors, is associated with mobility disability. The mobility disability experienced by persons with obesity is associated with reduced health related quality of life (HRQoL) compared to persons without obesity. This paper will review and discuss functional mobility and its relationship to HRQoL for persons living with obesity. This will be done by conducting a review of the literature in the area of obesity and functional mobility and it's association with HRQoL. Recommendations to address the known factors that contribute to mobility disability and reduced quality of life are outlined while suggestions for research to contribute to best practice to enable mobility for persons with obesity are made. PMID- 23731876 TI - The impact of obesity on quality of life. AB - An important association exists between obesity and mental illness that impacts all aspects of an individual's quality of life. This association can begin early in the developmental trajectory and we do not yet completely understand all the mechanisms linking obesity and mental illness. What we e do know is that physical health factors that often occur secondary to obesity, combined with societal attitudes toward those that are obese coupled with iatrogenic treatment factors linked to psychiatric pharmacotherapy and a number of biologic mediators result in an important and increasing common comorbidity. Recognizing this association is essential for the proper management of both conditions. The following review addresses this issue and provides clinical pearls to help deal with this issue. PMID- 23731877 TI - Impact of obesity on cardiovascular health. AB - This review examines the impact of obesity on cardiovascular health. We will review first, relationship between obesity and hypertension. Second, we will describe obesity-related subclinical abnormalities in cardiovascular function and structure. Third, we will summarize evidence linking obesity to overt cardiovascular disease including coronary artery disease, congestive heart failure, stroke, arrhythmias and sudden cardiac death. Fourth, we will discuss the potential mechanisms underlying increased cardiovascular risk in obese subjects. Last, we will discuss contribution of sleep apnea to the link between obesity and cardiovascular disease. Despite recent progress in understanding epidemiologic and pathophysiological links between obesity and cardiovascular disease, several issues remain to be addressed in the future studies. There is a clear need to identify better markers of obesity-related subclinical cardiovascular damage. Furthermore, we should improve identification of obese subjects at highest cardiovascular risk. PMID- 23731878 TI - Respiratory physiology and pulmonary complications in obesity. AB - Obesity is generally accepted as a global epidemic and the most common metabolic disorder in the world. Obesity affects every organ system but the consequences on the respiratory system are often underappreciated. While the respiratory consequences of being overweight are predominantly mechanical, an inflammatory element has also been proposed. For this discussion, the components of the respiratory system can be divided into the airways, pulmonary parenchyma, pulmonary vasculature, and the upper respiratory tract. This section will discuss respiratory physiology and the mechanisms leading to breathing difficulties in obesity followed by the impact of obesity on commonly occurring pulmonary disorders. PMID- 23731879 TI - Adipose tissue dysfunction contributes to obesity related metabolic diseases. AB - Obesity significantly increases the risk of developing type 2 diabetes, hypertension, coronary heart disease, stroke, fatty liver disease, dementia, obstructive sleep apnea and several types of cancer. Adipocyte and adipose tissue dysfunction represent primary defects in obesity and may link obesity to metabolic and cardiovascular diseases. Adipose tissue (AT) dysfunction manifests by a proinflammatory adipokine secretion pattern that mediate auto/paracrine and endocrine communication and by inflammatory cell infiltration, particularly in intra-abdominal fat. Impaired AT function is caused by the interaction of genetic, behavioral and environmental factors which lead to adipocyte hypertrophy, ectopic fat accumulation, hypoxia, AT stresses, impaired AT mitochondrial function and inflammatory processes within adipose tissue. Recently, increased autophagy has been linked to obesity and AT dysfunction and may represent a mechanism to compensate for AT stresses. A better understanding of mechanisms causing or maintaining AT dysfunction may provide new therapeutic strategies in the treatment of obesity-induced metabolic diseases. PMID- 23731880 TI - Metabolic complications of obesity. AB - Obesity is a risk factor for several metabolic complications, with insulin resistance being the common denominator in these conditions. Impaired blood glucose regulation is one of the most important of these complications, and includes type 2 diabetes mellitus (T2DM), prediabetes, and gestational diabetes. Metabolic syndrome describes a constellation of features including insulin resistance, hypertension, dyslipidemia, and abdominal obesity. Polycystic ovary syndrome is a condition characterized by ovulatory dysfunction and clinical evidence of hyperandrogenism. As many of these complications can go unnoticed for years without overt clinical complications, awareness of both patients and health care professionals is essential such that appropriate screening and diagnostic strategies can be undertaken. Aggressive management strategies of diabetic and prediabetic states are essential for prevention of complications over time. Strategies for identification of vascular risk factors must be implemented such that appropriate risk reduction strategies can be undertaken to minimize the risk of development of cardiovascular complications. PMID- 23731881 TI - Gastrointestinal complications of obesity: non-alcoholic fatty liver disease (NAFLD) and its sequelae. AB - Obesity is a major risk factor for malign and non-malign diseases of the gastrointestinal tract. Non-alcoholic fatty liver disease (NAFLD) is an outstanding example for the complex pathophysiology of the metabolic system and represents both source and consequence of the metabolic syndrome. NAFLD has a growing prevalence and will become the leading cause of advanced liver disease and cirrhosis. Obesity has a negative impact on NAFLD at all aspects and stages of the disease. The growing epidemic will strain health care resources and demands new concepts for prevention, screening and therapeutic approaches. A better understanding of the interplay of liver, gut and hormonal system is necessary for new insights in the underlying mechanisms of NAFLD and the metabolic syndrome including obesity. Identification of patients at risk for progressive liver disease will allow a better adaption of treatment strategies. PMID- 23731882 TI - Urogenital complications of obesity. AB - We performed a critical review focused on the main non-oncologic disorders that have a strong, direct association with obesity: chronic kidney disease, kidney stones and female and male lower urinary tract symptoms/disorders. We discuss the epidemiology, pathogenesis and therapeutic aspects regarding the association between obesity and non-diabetic and non-hypertensive forms of chronic kidney disease directly caused or worsened by weight excess, with particular attention on obesity-related glomerulopathy (ORG), which is typical of severe obesity, and the consequences of intentional weight loss on proteinuria and glomerular filtration rate. The associations of obesity with kidney stones and lower urinary tract conditions are also discussed from the epidemiological, physiopathological and therapeutical points of view, with emphasis on the principal concerns raised by the heterogeneity of study designs and outcome definitions typical of research in these fields. We also call attention to important clinical and scientific questions that should be addressed by future research. PMID- 23731883 TI - Obesity and cancer--the update 2013. AB - Progress of the last five years regarding "Obesity and Cancer" with preference to cohort studies was reviewed for cancer of the colorectum, breast, endometrium, renal cell, and adenocarcinomas of the esophagus and compared to the knowledge reviewed in the year 2008. The new studies are mostly confirming what has been known also 5 years ago. Gender seems to play a role in colorectal cancer in that risk due to body fatness is much lower in women than in men. Body fatness at young adulthood is particularly related to risk of renal cancer whereas attained body fatness at a later stage of adulthood is driving the risk for postmenopausal breast and endometrial cancer. Fat distribution is playing a strong role for risk of adenocarcinoma of the esophagus and to a lesser extent also for colon cancer. Prediagnostic body fatness plays also a role in cancer recurrence and survival. PMID- 23731884 TI - Health impact in children and adolescents. AB - Obesity in children and adolescents is associated with multiple comorbidities, including metabolic, cardiovascular, gastrointestinal, pulmonary, orthopedic and psychological disorders. In fact, cardiovascular and metabolic impairments in childhood and adolescence constitute major risk factors for developing cardiovascular disease in adulthood. Thus, obesity in childhood and adolescence leads to a higher morbidity and mortality in adulthood. Therefore, strong emphasis must be laid on the prevention and therapy of childhood obesity. Treatment requires a multidisciplinary and multiphase approach including dietary management, physical activity, pharmacotherapy and bariatric surgery. This paper reviews the different comorbidities of childhood obesity supporting the notion of a multidisciplinary therapy concept. PMID- 23731885 TI - Surgical interventions for obesity and metabolic disease. AB - Obesity continues to be a growing problem in both the developed and the developing world. Its strong link with co-morbid conditions such as type 2 diabetes, hypertension, obstructive sleep apnea, and depression presents an increasing strain on health care systems around the world. Diet and exercise alone has been shown to be largely ineffective at managing obesity. Surgery is the only evidence-based method of allowing morbidly obese patients to lose weight and to maintain this weight loss. Weight-reduction in obese individuals from bariatric surgery has also been found to markedly improve obesity-related co morbid conditions, particularly, type 2-diabetes. Diabetic remission from bariatric surgery has resulted in the inclusion of bariatric surgery, by the International Diabetes Taskforce, as a treatment modality for type-2 diabetes. This consensus statement named four surgical options that have been found to be effective in both weight-loss and in inducing diabetes remission. These four surgical procedures lead to weight-loss through restrictive and malabsorptive mechanisms. Each specific operation has a different level of efficacy in inducing weight-loss and diabetic remission, as well as distinct types and rates of complications. This article reviews the best evidence that exists for the effectiveness and complications of these four operations. PMID- 23731886 TI - Obesity in anesthesia and intensive care. AB - Obesity is a global epidemic increasingly affecting management of anesthesia as well as intensive care medicine. Possible improvements in therapy require consideration of the specific pathophysiology of the obese, their concomitant diseases, and the complications associated with morbid obesity. Systematic assessment of perioperative risk factors is essential for an appropriate management. Paradoxically, overweight and moderately obese patients undergoing surgery have a lower risk when compared to patients with normal weight. The highest mortality and morbidity rates in this setting are reported for underweight and morbidly obese patients. The better chance of survival when compared to normal-weight individuals in the perioperative setting has been described the obesity paradox. In particular, the commitment of all involved physicians to improve all aspects of care will reduce the perioperative risk in obese patients. Physiological and pharmacological characteristics of the obese should also be considered. Furthermore, adequate technical equipment and practical skills of all members of the anesthesia team significantly contribute to risk reduction and therapeutic success in obese patients. PMID- 23731887 TI - Diagnostic imaging in obesity. AB - Magnetic resonance of the body offers different techniques for mapping fat deposits (MR Imaging) and analysis of organs with small amounts of lipids (MR Spectroscopy). Possible approaches for whole-body assessment of adipose tissue are presented and discussed and spectroscopic examinations in different organs are depicted. With magnetic resonance imaging (MRI) it has been shown that obesity per se is not a marker for metabolic failure, but depends on regional variations of body composition and ectopic lipid accumulation. In addition MRI of the brain is a powerful research tool to understand the brain's role in the development and maintenance of obesity and the overconsumption of foods in obese individuals. Sonography has a low accuracy in estimating hepatic steatosis until now. New sonographic methods have been evaluated to detect hepatic steatosis by physical properties of fatty tissue as tissue stiffness, sound absorption or sound speed. Nuclear medicine and in particular Positron Emission Tomography (PET) methods are used to explore central pathophysiology, brown adipose tissue activity and alterations in homeostatic feedback and gut-brain communication. PMID- 23731889 TI - Degeneration and regeneration of motor and sensory nerves: a stereological study of crush lesions in rat facial and mental nerves. AB - The aim of this study was to evaluate the degeneration and regeneration of a sensory nerve and a motor nerve at the histological level after a crush injury. Twenty-five female Wistar rats had their mental nerve and the buccal branch of their facial nerve compressed unilaterally against a glass rod for 30s. Specimens of the compressed nerves and the corresponding control nerves were dissected at 3, 7, and 19 days after surgery. Nerve cross-sections were stained with osmium tetroxide and toluidine blue and analysed using two-dimensional stereology. We found differences between the two nerves both in the normal anatomy and in the regenerative pattern. The mental nerve had a larger cross-sectional area including all tissue components. The mental nerve had a larger volume fraction of myelinated axons and a correspondingly smaller volume fraction of endoneurium. No differences were observed in the degenerative pattern; however, at day 19 the buccal branch had regenerated to the normal number of axons, whereas the mental nerve had only regained 50% of the normal number of axons. We conclude that the regenerative process is faster and/or more complete in the facial nerve (motor function) than it is in the mental nerve (somatosensory function). PMID- 23731888 TI - Drosophila GAGA factor polyglutamine domains exhibit prion-like behavior. AB - BACKGROUND: The Drosophila GAGA factor (GAF) participates in nucleosome remodeling to activate genes, acts as an antirepressor and is associated with heterochromatin, contributing to gene repression. GAF functions are intimately associated to chromatin-based epigenetic control, linking basic transcriptional regulation to heritable long-term maintenance of gene expression. These diverse functions require GAF to interact with different partners in different multiprotein complexes. The two isoforms of GAF depict highly conserved glutamine rich C-terminal domains (Q domain), which have been implicated in complex formation. RESULTS: Here we show that the Q domains exhibit prion-like properties. In an established yeast test system the two GAF Q domains convey prion activities comparable to well known yeast prions. The Q domains stably maintain two distinct conformational states imposing functional constraints on the fused yeast reporter protein. The prion-like phenotype can be reversibly cured in the presence of guanidine HCl or by over-expression of the Hsp104 chaperone protein. Additionally, when fused to GFP, the Q domains form aggregates in yeast cells. CONCLUSION: We conclude that prion-like behavior of the GAF Q domain suggests that this C-terminal structure may perform stable conformational switches. Such a self-perpetuating change in the conformation could assist GAF executing its diverse epigenetic functions of gene control in Drosophila. PMID- 23731890 TI - Integration of image guidance and rapid prototyping technology in craniofacial surgery. AB - This technical note demonstrates the benefits of preoperative planning, involving the use of rapid prototype models and rehearsal of the surgical procedure, using image-guided navigational surgery. Optimum reconstruction of large defects can be achieved with this technique. PMID- 23731891 TI - Deterioration in donepezil-induced PR prolongation after a coadministration of memantine in a patient with Alzheimer's disease. AB - The side effects and interaction of memantine and donepezil hydrochloride when used concomitantly are currently unknown. We encountered a case of a 77-year-old female with Alzheimer's disease in which the concomitant use of memantine exacerbated the prolonged electrocardiogram PR interval which appeared while donepezil hydrochloride was being orally administered. In terms of the cardiac circulation system side effects caused by donepezil hydrochloride and memantine, bradycardia has been reported. However, clinicians should be also aware of PR prolongation associated with the concomitant use of donepezil and memantine. PMID- 23731892 TI - Delirium with manic and psychotic features associated with amantadine. AB - While clinicians are familiar with psychosis as a complication in the long-term treatment with amantadine, rapid psychiatric complications are of much less concern. In the case presented, severe decompensation in mental status occurred within 48 h of initiation of standard doses of amantadine hydrochloride. Clinicians should be alert not only for delayed complications but also for early onset mental decompensation in elderly patients with influenza A treated with amantadine. PMID- 23731893 TI - The development and expression of pluripotency genes in embryos derived from nuclear transfer and in vitro fertilization. AB - Somatic cell nuclear transfer can be used to produce embryonic stem (ES) cells, cloned animals, and can even increase the population size of endangered animals. However, the application of this technique is limited by the low developmental rate of cloned embryos, a situation that may result from abnormal expression of some zygotic genes. In this study, sheep-sheep intra-species cloned embryos, goat sheep inter-species cloned embryos, or sheep in vitro fertilized embryos were constructed and cultured in vitro and the developmental ability and expression of three pluripotency genes, SSEA-1, Nanog and Oct4, were examined. The results showed firstly that the developmental ability of in vitro fertilized embryos was significantly higher than that of cloned embryos. In addition, the percentage of intra-species cloned embryos that developed to morula or blastocyst stages was also significantly higher than that of the inter-species cloned embryos. Secondly, all three types of embryos expressed SSEA-1 at the 8-cell and morula stages. At the 8-cell stage, a higher percentage of in vitro fertilized embryos expressed SSEA-1 than occurred for cloned embryos. However, at the morula stage, all detected embryos could express SSEA-1. Thirdly, the three types of embryos expressed Oct4 mRNA at the morula and blastocyst stages, and embryos at the blastocyst stage expressed Nanog mRNA. The rate of expression of Oct4 and Nanog mRNA at these developmental stages was higher in in vitro fertilized embryos than in cloned embryos. These results indicated that, during early development, the failure to reactivate some pluripotency genes maybe is a reason for the low cloning efficiency found with cloned embryos. PMID- 23731894 TI - The difference in the attitude of Chinese and Japanese college students regarding deceased organ donation. AB - BACKGROUND: Under the influence of traditional oriental culture, the lack of organ donation is especially serious in China and Japan. The aim of this study was to compare Chinese and Japanese college students' attitudes and analyze contributing factors toward deceased donation. METHODS: An anonymous, self administered questionnaire comprising 15 questions was distributed to approximately 400 college students at Liaoning University, China, and Kyushu University, Japan. Statistical analysis used SPSS software. RESULTS: Japanese students' attitude towards deceased organ donation was more favorable than that of Chinese students (43.6% versus 35.9%, P = .001). Several factors contributed to positive responses by students from both countries: family perspective on organ donation and transplantation; decision to donate to family members; prior blood donation; living liver or kidney donation; possibility of needing a transplant; and willingness to receive a deceased or a living donor organ. CONCLUSIONS: More efforts must emphasize awareness and up-to-date knowledge regarding organ donation among citizens and should be undertaken by the Chinese and Japanese governments. PMID- 23731895 TI - Body weight difference between donor and recipient is an important affector of early graft function after renal transplantation. AB - BACKGROUND: Poor early graft function (EGF), a frequent complication of kidney transplantation, can be caused by many risk factors, including donor kidney and body weights. METHODS: We studied the relationship to early graft function in a rat kidney transplantation model among 3 indices: ratio of graft to body weight; ratio of native kidney to body weight, and weight difference/body weight of the recipient. We categorized 2 groups based on contralateral nephrectomy at day 1 (G1) or day 3 (G2) after transplantation. EGF was evaluated by measuring serum creatinine levels at day 1 after bilateral nephrectomy. RESULTS: The 3 indices, ie, weight difference/body weight of recipient (G1 and G2: P < .0001), ratio of native kidney to body weight (G1: P < .0001; G2: P = .0013), and ratio of graft to body weight (G1: P = .0064; G2: P = .014) strongly correlated with EGF regardless of the time of contralateral nephrectomy. CONCLUSIONS: The index of weight difference/body weight of recipient sensitively and predominantly influenced EGF, which probably reflects the systemic metabolic profile. PMID- 23731896 TI - Dendritic cells play an essential role in transplantation responses via myeloid differentiation factor 88 signaling. AB - BACKGROUND: DCs (dendritic cells), play an important role in allo-recognition, but there is no direct evidence that DCs trigger and control allo-responses. In this study, we investigated the role of DCs by using a self-created MyD88 (myeloid differentiation factor 88) inhibitor and a minor antigen-mismatched (HY mismatched) skin transplantation model in mice. METHODS: An HY-mismatched skin allograft model (BALB/c ? -> BALB/c ?) using MyD88-knockout mice was employed in this study. WT (Wild-type) BALB/c immature BMDCs (bone marrow dendritic cells) were co-cultured with or without TJ-M2010 in vitro for 12 hours before transfusion of DCs (2* 10(7)/mouse) into recipients of skin transplantations. Wild-type BALB/c BMDCs were stimulated by the TLR9 (Toll-like receptor 9) agonist, CpG (cytidine-phosphate-guanosine), in the presence of TJ-M2010 or not for 12 hours in vitro. Costimulatory molecules CD80/CD86 were analyzed by flow cytometry. WT C57BL/6 naive T cells stained with CFSE (carboxyfluorescein diacetate succinimidyl ester) were co-cultured with WT BALB/c DCs for 3 days in the presence or absence of TJ-M2010. CD3(+)/CFSE(+) cells were analyzed by flow cytometry. RESULTS: TJ-M2010 inhibited DC maturation and T cell proliferation. Permanent survival of the skin allografts was observed in MyD88 knockout (MyD88- KO) mice. However, skin allografts were rejected by MyD88-KO mice infused with wild-type (WT) DCs. More interestingly, after treating the WT DCs with TJ-M2010, the DC infusion could not reverse the tolerance to skin allografts. CONCLUSION: This study provided evidence that DCs play an essential role in alloresponses. PMID- 23731897 TI - Validation of a functional remission threshold for the Functional Remission of General Schizophrenia (FROGS) scale. AB - OBJECTIVE: The aim of this study was to develop a functional remission threshold for the Functional Remission Of General Schizophrenia (FROGS) scale, and test its validity regarding clinical and quality of life outcomes. METHODS: DESIGN: Cross sectional study. INCLUSION CRITERIA: Schizophrenia according to DSM-IV-TR criteria. DATA COLLECTION: Functioning was assessed using the FROGS and the Global Assessment of Functioning (GAF) scales; psychotic symptoms using the Positive and Negative Syndrome Scale; memory, attention, and executive functions were assessed using the California Verbal Learning Test, the D2 attention task, the Stroop color-word test, the verbal fluency test, the Trail Making Test A and B and the Wechsler Adult Intelligence Scale; and quality of life using the schizophrenia quality of life (S-QoL 18) scale. ANALYSIS: A logistic regression analysis including the different dimensions of the FROGS was used to create a composite score to classify patients into remitted and non-remitted according a gold standard (cut-off: GAF>= 61). Receiver operating characteristics analyses were then performed to determine the area under the curve (AUC). RESULTS: Of 137 patients enrolled, 26 were functionally remitted and 111 were not remitted according to GAF score. The AUC for the combination of the FROGS's dimensions to detect functional remission was 0.903 (p<0.001). Sensitivity and specificity for the combination of the FROGS dimensions using the Youden index were 88.5 [69.8; 97.6] and 81.1 [72.5; 87.9], respectively. Validity of this combination was satisfactory. Patients in functional remission had a lower severity of the disease, especially for PANSS negative (p<0.001) and general psychopathology (p<0.001) symptoms. Only two cognitive functions (i.e. fluency and episodic memory) were improved in remitted patients. Higher quality of life levels were globally associated with better functioning. CONCLUSIONS: These findings provide for first accurate FROGS thresholds to detect functional remission in schizophrenia. PMID- 23731898 TI - Influence of temperament and character on resilience. AB - OBJECTIVE: The purpose of this study was to examine the influence of temperament and character on resilience. METHODS: A total of 4355 participants completed two questionnaires: the Conner-Davison Resilience Scale (CD-RISC) and the Temperament and Character Inventory-Revised Short (TCI-RS). We used Pearson's correlations to evaluate the correlation between the dimensions of the TCI and the CD-RISC. To determine the most influential TCI dimension with respect to the CD-RISC, a backward multiple regression analysis was performed. RESULTS: The resilience of both men and women was positively correlated with persistence, self-directedness, and cooperativeness. Conversely, harm avoidance was negatively correlated with resilience. In addition, reward dependence in men and self-transcendence in women were positively correlated with resilience. In the multiple regression analysis, persistence, self-directedness, and harm avoidance significantly predicted resilience after adjusting for age and gender. CONCLUSION: This results show that social support is affected by personality, which consists of both temperament and character. High persistence and self-directedness as well as low harm avoidance are found to contribute to a better stress response. PMID- 23731899 TI - Enhancement of ANAMMOX activity by low-intensity ultrasound irradiation at ambient temperature. AB - This paper aims to investigate the enhancement effect of low intensity intermittent ultrasound irradiation on the efficiency of anaerobic ammonium oxidation (ANAMMOX) process at ambient temperature. With intermittently irradiated (ultrasound intensity of 0.19 w/cm(2), exposure time of 0.2 min), the reactor (RU) had a nitrogen removal rate (NRR) of 5.49 kgTN/m(3)/d at 14.8 degrees C, while the NRR was 1.53 kgTN/m(3)/d in the control reactor (RC). At the end of operation, the contents of polysaccharide, protein, TTC-dehydrogenase and VSS were 6.82 mg/mgVSS, 26.79 mg/mgVSS, 0.58 mgTF/L/H and 10.11 gVSS/L in RU, higher than the levels in the RC. These results demonstrated that it is possible to achieve stable and highly efficient operation in an ANAMMOX reactor at low ambient temperature by implementation of ultrasonication. PMID- 23731900 TI - What are the immunological consequences of long-term use of biological therapies for juvenile idiopathic arthritis? AB - This review summarizes the immunological consequences of biological therapies used in juvenile idiopathic arthritis (JIA). For every frequently used biological agent the characteristics are clearly specified (molecular target, isotype, registered indication for JIA, route of administration, half-life, contraindication, very common side effects, expected time of response and average cost in the first year). The emphasis of this review is on the immunological side effects that have been encountered for every separate agent in JIA populations. For each agent these adverse events have been calculated as incidence per 100 patient-years for the following categories: serious infections, tuberculosis, malignancies, response to vaccination, new-onset autoimmune diseases and development of anti-drug antibodies. There are large differences in side effects between various agents and there is a clear need for an international and standardized collection of post-marketing surveillance data of biologicals in the vulnerable group of JIA patients. Such an international pharmacovigilance database, called Pharmachild, has now been started. PMID- 23731901 TI - Incidence of human herpesvirus 6 in clinical samples from Swedish patients with demyelinating diseases. AB - BACKGROUND: Human herpesvirus 6 (HHV-6) has been reported to be associated with multiple sclerosis (MS) and Guillain-Barre syndrome (GBS). METHODS: We analyzed cell-free HHV-6 DNA as an indication of active infection in the peripheral blood and cerebrospinal fluid (CSF) of Swedish patients with GBS, patients with chronic inflammatory demyelinating polyradiculoneuropathy, treatment-naive patients with possible MS, interferon-beta treated MS patients [with or without neutralizing antibodies (NAbs)], and control patients with headache. RESULTS: One of 14 GBS patients and one of eight patients with chronic inflammatory demyelinating polyradiculoneuropathy were positive for HHV-6 DNA in serum. Of the 27 treatment naive possible MS patients, two were positive in plasma and one in CSF. HHV-6 DNA was detected in the serum of three of 79 NAb+ patients and one of 102 NAb interferon-beta treated MS patients. HHV-6 DNA could not be detected in the plasma or CSF of any of the 33 controls, although the differences were not statistically significant. CONCLUSION: Our results do not suggest active HHV-6 infection to be a common phenomenon in any of the patient groups studied. PMID- 23731902 TI - Diabetes mellitus and decompensated cirrhosis: risk of hepatic encephalopathy in different age groups. AB - BACKGROUND: The aim of the present study was to examine the association of diabetes mellitus (DM) with the prevalence and severity of hepatic encephalopathy (HE) in patients with decompensated cirrhosis (DC) and determine the impact of age and gender on this relationship. METHODS: West Haven criteria was used to prospectively evaluate 352 consecutive patients with DC for the presence of HE. Detailed clinicobiochemical profiling of patients was performed. Categorical data and ordered categorical variables were evaluated using the Chi-squared test for independence and trend, respectively. Continuous normal and non-parametric data were evaluated using the t-test and Mann-Whitney U-test, respectively. RESULTS: At the time of admission, HE was present in 50.3% of patients. In all, 118 patients had DM (33.5%). Patients with DM had a significantly higher prevalence (58.5% vs 42.6%; P = 0.03) and severity of HE (P(trend) = 0.01) than patients without DM. However, there were no significant differences between the two groups in terms of Child-Pugh class, MELD scores, the presence of ascites and esophageal varices. Patients with DM had higher platelet counts than those without DM (P(trend) = 0.003). In age and gender subgroup analyses, older patients and men with DM had significantly greater evidence of HE (P = 0.02 and 0.03, respectively). Multivariate analysis showed that DM (P = 0.03) and older age (P = 0.006) were independently related to HE, whereas the association of gender was non-significant. CONCLUSION: Both DM and older age are independently associated with HE in patients with cirrhosis. PMID- 23731903 TI - Sodium supplementation has no effect on endurance performance during a cycling time-trial in cool conditions: a randomised cross-over trial. AB - BACKGROUND: Sodium ingestion during exercise may exert beneficial effects on endurance performance by either its ability to attenuate the decrease in plasma volume or reduce the risk of Exercise Associated Hyponatremia (EAH). This study aimed to investigate the effect of sodium supplements on endurance performance during a 72 km road cycling time-trial in cool conditions (13.8 +/- 2.0 degrees C). METHODS: Nine well-trained cyclists (5 male, 4 female) participated in this randomized, double-blinded cross-over study, receiving either a 700 mg(.)h(-1) salt capsule, or a corn flour placebo during the time trial. Water was ingested ad-libitum throughout the time trial. Measurements were taken pre, post, and 40 min following time-trials, analysing blood, sweat, and urinary hydration and sodium concentration. RESULTS: Sodium supplements had no effect on time-trial performance (overall time = 171 min sodium vs. 172 min placebo; p = 0.46). There was also no effect on the change in plasma sodium concentration from pre to post time trial between trials (relative plasma [Na(+)] change (pre-post): sodium = 0.56%, placebo = 0.47%; p = 0.60). The greatest difference observed was a significantly change in plasma volume from pre to post exercise between the salt and the placebo trial (p = 0.02), which corresponded with an increased thirst with sodium supplementation. CONCLUSION: Sodium supplements therefore do not improving performance during exercise of approximately 3 h duration in cool conditions. PMID- 23731904 TI - The P-type ATPase Spf1 is required for endoplasmic reticulum functions and cell wall integrity in Candida albicans. AB - Endoplasmic reticulum (ER) is crucial for protein folding, glycosylation and secretion in eukaryotic organisms. These important functions are supported by high levels of Ca(2+) in the ER. We have recently identified a putative ER Ca(2+) pump in Candida albicans, called Spf1, which plays key roles in maintenance of cellular Ca(2+) homeostasis, morphogenesis and virulence. In this study, we purified Spf1 and confirmed that it is a P-type ATPase, suggesting its role in maintaining high levels of ER Ca(2+). Disruption of SPF1 caused severe defects in glycosylation of the ER-localized protein Cdc101 and secretory acid phosphatase, and a decrease in expression of SEC61 which encodes an important ER protein. Moreover, the spf1Delta/Delta mutant showed increased sensitivity to cell wall stresses, abnormal cell wall composition, delayed cell wall reconstruction and decreased flocculation and adherence, indicating its defect in cell wall integrity (CWI). We also revealed that disruption of SPF1 has an impact on gene expression related to CWI and morphogenesis. This study provides evidence that Spf1, as a P-type ATPase, is essential for ER functions and consequent CWI, implicating a role of ER Ca(2+) homeostasis in C. albicans physiology. PMID- 23731906 TI - Differences in gait characteristics between total hip, knee, and ankle arthroplasty patients: a six-month postoperative comparison. AB - BACKGROUND: The recovery of gait ability is one of the primary goals for patients following total arthroplasty of lower-limb joints. The aim of this study was to objectively compare gait differences of patients after unilateral total hip arthroplasty (THA), total knee arthroplasty (TKA) and total ankle arthroplasty (TAA) with a group of healthy controls. METHODS: A total of 26 TAA, 26 TKA and 26 THA patients with a mean (+/- SD) age of 64 (+/- 9) years were evaluated six months after surgery and compared with 26 matched healthy controls. Subjects were asked to walk at self-selected normal and fast speeds on a validated pressure mat. The following spatiotemporal gait parameters were measured: walking velocity, cadence, single-limb support (SLS) time, double-limb support (DLS) time, stance time, step length and step width. RESULTS: TAA and TKA patients walked slower than controls at normal (p<0.05) and fast speeds (p<0.01). The involved side of TAA and TKA patients showed shorter SLS compared to controls at both normal and fast speeds (p<0.01). Regardless of walking speed, the uninvolved side of TAA and TKA patients demonstrated longer stance time and shorter step length than controls (p<0.01). TAA patients showed shorter SLS of the involved side, longer stance time and shorter step length of the uninvolved side compared to the contralateral side at both normal and fast speeds (p<0.001). CONCLUSIONS: Gait disability after unilateral lower-limb joint arthroplasty was more marked for distal than for proximal joints at six months after surgery, with a proximal to-distal progression in the impairment (TAA>TKA>THA). THA patients demonstrated no gait differences compared with controls. In contrast, TAA and TKA patients still demonstrated gait differences compared to controls, with slower walking velocity and reduced SLS in the involved limb. In addition, TAA patients presented marked side-to-side asymmetries in gait characteristics. PMID- 23731907 TI - Therapeutic effects of mesenchymal stem cells on renal ischemia-reperfusion injury: a matter of genetic transfer? AB - Accumulating evidence indicates that the protective effect of mesenchymal stem cells in models of tissue injury is related to the endocrine/pcrine release of factors. The delivery of growth factors, cytokines, prostaglandins, enzymes or extracellular vesicles from mesenchymal stem cells to target cells may induce cell reprogramming and de novo expression of factors involved in tissue proliferation and repair. A recent paper showed that Wharton jelly-derived mesenchymal stem cells interact with injured renal tubular epithelial cells, inducing the expression of native and foreign hepatocyte growth factor necessary for renal repair and fibrogenesis inhibition. The genetic exchange between resident and mesenchymal stem cells, probably mediated through microvesicles, therefore appears instrumental in mesenchymal stem cell therapeutic effects. PMID- 23731905 TI - Immunogenicity of Pasteurella multocida and Mannheimia haemolytica outer membrane vesicles. AB - Pasteurella multocida is able to cause disease in humans and in a wide range of animal hosts, including fowl cholera in birds, atrophic rhinitis in pigs, and snuffles in rabbits. Together with Mannheimia haemolytica, P. multocida also represents a major bacterial causative agent of bovine respiratory disease (BRD), which is one of the most important causes for economic losses for the cattle backgrounding and feedlot industry. Commercially available vaccines only partially prevent infections caused by P. multocida and M. haemolytica. Thus, this study characterized the immunogenicity of P. multocida and M. haemolytica outer membrane vesicles (OMVs) upon intranasal immunization of BALB/c mice. Enzyme-linked immunosorbent assays (ELISA) revealed that OMVs derived from P. multocida or M. haemolytica are able to induce robust humoral and mucosal immune responses against the respective donor strain. In addition, also significant cross-immunogenic potential was observed for both OMV types. Colonization studies showed that a potential protective immune response against P. multocida is not only achieved by immunization with P. multocida OMVs, but also by immunization with OMVs derived from M. haemolytica. Immunoblot and immunoprecipitation analyses demonstrated that M. haemolytica OMVs induce a more complex immune response compared to P. multocida OMVs. The outer membrane proteins OmpA, OmpH, and P6 were identified as the three major immunogenic proteins of P. multocida OMVs. Amongst others, the serotype 1-specific antigen, an uncharacterized outer membrane protein, as well as the outer membrane proteins P2 and OmpA were found to be the most important antigens of M. haemolytica OMVs. These findings are useful for the future development of broad-spectrum OMV based vaccines against BRD and other infections caused by P. multocida or M. haemolytica. PMID- 23731908 TI - Hypothesis for intracranial hypertension in slit ventricle syndrome: new concept of capillary absorption laziness in the hydrocephalic patients with long-term shunts. AB - Many theories have been postulated to date regarding mechanisms involved in intracranial hypertension in patients with long-term, shunt-induced slit ventricle syndrome (SVS), but it still seems difficult to define this entity more clearly. Many hypotheses have attempted to explain the causes of SVS as chronic or intermittent catheter obstruction, brain compliance change, and ventricular herniation and distortion, but this theory does not explain clearly the reason why extraventricular pressure (EVP) is increased and intraventricular pressure (IVP) is low or frequently negative. The authors attempt to postulate a hypothesis by addressing new concept of capillary absorption laziness which results in dissociation of EVP with IVP. We, the authors, propose a concept of 'capillary absorption laziness', which is a tendency of the brain parenchymal extracellular fluid (ECF) not to be absorbed through the brain parenchymal capillary absorption system (BPCAS) that results from the bypass of ECF to shunt in the low or even negative ECF pressure and IVP. If this continues for a prolonged period, the tendency not to be absorbed through the BPCAS, even when the IVP and extracellular fluid pressures increases more than the intracranial pressure (ICP), may be established. This leads to situations of the brain such as parenchymal accumulation of the ECF which results in brain edema or swelling, and eventually distortion or herniation which can act as a functional obstruction and consequent dissociation between the IVP and EVP. Hypothesis of capillary absorption laziness may explain several common phenomena of the SVS such as low or even negative IVP in coexistence with high EVP and high ICP, and in these cases, we expect serious complications of SVS such as brain distortion and herniation. From this hypothesis we attempt to find new shunt management protocols to prevent long-term shunt induced complications. PMID- 23731909 TI - From bench to bedside: the importance for neurodegenerative disorders of crosstalk between basic and clinical research. PMID- 23731910 TI - The effectiveness of habit reversal therapy in the treatment of Tourette syndrome and other chronic tic disorders: a systematic review. AB - Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple tics, which can require active intervention. It is recognized that behavioral techniques, especially habit reversal therapy (HRT), can offer an effective alternative or complement to pharmacotherapy in this setting. We conducted a systematic literature review to evaluate the efficacy of HRT in TS and other chronic tic disorders (CTDs). Our search was restricted to randomized controlled trials that used standardized diagnostic and outcome measures to compare the efficacy of HRT against a control treatment. We identified five relevant studies, which included 353 patients. Significant post-treatment reductions in tic severity scores (range: 18.3%-37.5%) were seen in the HRT groups across all studies. Current evidence suggests that HRT can significantly reduce tic severity in both adults and children with TS and other CTDs. Further head-to-head studies are needed to compare the efficacy of HRT with other behavioral interventions for tic management. PMID- 23731911 TI - The effect of dopamine agonists on cognitive functions in non-demented early-mild Parkinson's disease patients. AB - The effect of dopamine agonists (DAs) on cognition in Parkinson's disease (PD) is not yet completely established. Previous papers reported a worsening effect on some cognitive functions with some DAs, but not with others, suggesting that DAs may differently affect cognition in PD patients according to their pharmacological characteristics. We set out to test the effect of rotigotine and cabergoline on cognitive functions in a group of forty non-demented early-mild PD patients (H &Y <2). Subjects were randomly divided into two groups and evaluated in a randomized cross-over study using neuropsychological tests; at the same time, motor function was monitored under three different treatment conditions: DA (rotigotine or cabergoline), L-dopa, and off therapy. Rotigotine and cabergoline were chosen because while they share a mixed D1 and D2 receptor profile, the former is non-ergolinic and the latter ergolinic. No significant differences were found in cognitive function between the basal condition and the DA treatments. On the basis of the present data, which we compare with previous findings regarding pramipexole IR and pergolide, we hypothesize that combined stimulation of both dopamine receptor families, as occurs with rotigotine, cabergoline, L-dopa and pergolide, may preserve cognitive functions more than pure D2 family stimulation. PMID- 23731912 TI - Whole-brain voxel-based morphometry study of children and adolescents with Down syndrome. AB - In order to investigate alterations in brain morphology and a possible temporal pattern of neuroanatomical abnormalities in the gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) of young patients with Down syndrome (DS), high-resolution magnetic resonance imaging (MRI) voxel-based morphometry (VBM) was performed on 21 children and adolescents with this chromosomal aberration and 27 age-matched participants as controls. In comparison with control subjects, children and adolescents with DS showed not only an overall smaller whole-brain volume, but also volume reductions of the GM in the cerebellum, frontal lobes, frontal region of the limbic lobe, parahippocampal gyri and hippocampi and of the WM in the cerebellum, frontal and parietal lobes, sub-lobar regions and brainstem. By contrast, volume preservation was observed in the GM of the parietal lobes, temporal lobe and sub-lobar regions and in the WM of the temporal lobe and temporal regions of the limbic lobe. A lower volume of CSF was also detected in the frontal lobes. This study is the first to use the high-resolution MRI VBM method to describe a whole-brain pattern of abnormalities in young DS patients falling within such a narrow age range and it provides new information on the neuroanatomically specific regional changes that occur during development in these patients. PMID- 23731913 TI - Evaluation of autonomies in the severely brain injured: the Progression of Autonomies Scale. AB - The aim of this study was to validate the Progression of Autonomies Scale (PAS) for the evaluation of autonomies in severe acquired brain injury patients. The PAS design is based on a model of progressive recovery of autonomies and is organized in three domains (Personal, Domestic and Extra-domestic). Scores assigned range from zero to three. The PAS items gather information about the patient's perception and awareness of his/her disability(ies) on admission and perception of his/her improvement at the end of a rehabilitation process. The PAS was administered to 127 inpatients on admission to and at discharge from a rehabilitation program. All 127 inpatients, recruited in a prospective multicenter study, completed the rehabilitation program. The statistical analysis identified a total of 38 items to be retained in the PAS, out of an initial 82 items. The results provide evidence of the validity and reliability of the PAS in its final version. PMID- 23731914 TI - Comparison of active standing test, head-up tilt test and 24-h ambulatory heart rate and blood pressure monitoring in diagnosing postural tachycardia. AB - Protocols for the assessment of postural tachycardia differ in both type of orthostatic challenge and test duration. We therefore compared heart rate (HR) and blood pressure responses during an active standing test (AST) and a head-up tilt test (HUT) in 34 patients with orthostatic intolerance and 31 asymptomatic subjects. A subset also performed 24-h ambulatory blood pressure monitoring (ABPM). HR responses were similar between AST and HUT both in asymptomatic and in orthostatic intolerant subjects. Specificity of HR increase >=30 bpm for orthostatic intolerance was high (above 0.85) with both AST and HUT and was similar at 3 minutes and at 9 minutes. HR changes recorded during self-performed AST (in the context of 24-h ABPM) and circadian HR difference corresponded well to changes recorded during AST in the autonomic laboratory. We conclude that AST and HUT are comparable methods for the assessment of postural tachycardia, that 3 min and 9-min tests are appropriate, and that ABPM is a useful ancillary test in the assessment of orthostatic responses. PMID- 23731915 TI - Sleep in ring chromosome 20 syndrome: a peculiar electroencephalographic pattern. AB - Ring chromosome 20 [r(20)] syndrome is a chromosomal disorder characterized by epilepsy and intellectual disability. Distinctive electroclinical features and wakefulness EEG patterns have been described. The EEG features of sleep have not yet been evaluated. We studied the pattern of sleep in six patients aged 2-59 years who underwent at least one polysomnographic recording. Their sleep pattern evolution is described as deterioration ranging from normal to destructured NREM/REM sleep. NREM sleep alterations were observed from childhood and were more evident in adulthood. EEG abnormalities detected during wakefulness persisted, with morphological changes, during sleep. During NREM sleep all the subjects presented high amplitude delta sequences with a sharply contoured or notched appearance, prevalent over frontal regions. The theta rhythm of wakefulness was seen to persist during REM sleep. Ring chromosome 20 syndrome shows sleep alterations that seem to be age-related. A potential role of cortical and thalamocortical dysfunction is discussed. PMID- 23731916 TI - Atypical language lateralization: an fMRI study in patients with cerebral lesions. AB - Differences in the lateralization of language processes between healthy subjects and patients with neurological complaints other than epilepsy have been less documented than those between healthy subjects and epilepsy patients. Moreover, the contribution of factors such as the location and type of lesion in determining interhemispheric shift of language function is poorly understood. Sixty-seven patients who underwent presurgical evaluations at the Medical Imaging Center of the Imam Khomeini University Hospital, Tehran, and the same number of healthy controls, were recruited. The laterality index (LI) of language activation, calculated from two separate functional magnetic resonance imaging tasks, was compared between the patients and the age-/gender-/handedness-matched controls. Chi square testing showed that the percentages of subjects with "typical" and "atypical" language dominance in the patient group were significantly different from the percentages recorded in the matched healthy controls for both tasks (p<0.005). Lesion type, lesion location, lesion hemisphere, presenting symptom and patient gender had no statistically significant effect on the hemispheric LI (p>0.05). In a logistic regression model including all potential determinants of atypical LI, age emerged as the only independent predictor (p<0.05, odds ratio=0.9). Abnormal language lateralization is found in patients with a variety of cerebral lesions and with a diversity of clinical manifestations. In our selected population, symptom duration, lesion hemisphere and anatomical site of the lesion were not found to impact significantly on the development of an abnormal LI while patient age can independently predict the presence of an atypical LI. PMID- 23731917 TI - Two cases of cluster headache effectively treated with levetiracetam. PMID- 23731918 TI - Beneficial effects of tadalafil on left ventricular dysfunction in doxorubicin induced cardiomyopathy. AB - BACKGROUND: It is not clear yet how tadalafil affects nonischemic cardiomyopathy, although its beneficial effects on acute myocardial infarction are well-known. We investigated tadalafil's beneficial effects on nonischemic cardiomyopathy and the specific mechanisms of its effects. METHODS: Cardiomyopathy was induced in mice by a single intraperitoneal injection of doxorubicin (15 mg/kg). In some cases, tadalafil (4 mg/kg/day, p.o., 14 days) was started simultaneously. After two weeks, cardiac function was evaluated by echocardiography and cardiac catheterization, then all of the mice were killed and cardiac specimens were subjected for hemotoxylin and eosin staining, Masson's trichrome staining, terminal deoxynucleotidyltransferase dUTP nick-end labeling assay, enzyme-linked immunosorbent assay, and Western blot. RESULTS: Two weeks later, left ventricular dilatation and dysfunction were apparent in mice given doxorubicin but were significantly attenuated by tadalafil treatment. Tadalafil also protected hearts against doxorubicin-induced cardiomyocyte atrophy/degeneration and myocardial fibrosis. No doxorubicin-induced apoptotic effects were seen between groups. Cardiac cGMP level was lower in the doxorubicin-treated group, however it was significantly increased with tadalafil treatment. Compared to the control group, the myocardial expression of 3 sarcomeric proteins, myosin heavy chain, troponin I, and desmin were significantly decreased in the doxorubicin-treated group, which were restored by the tadalafil treatment. CONCLUSIONS: The present study indicates a protective effect of tadalafil mainly through cGMP signaling pathway against doxorubicin-induced nonischemic cardiomyopathy. PMID- 23731919 TI - Comparison of clinical outcomes between octogenarians and non-octogenarians with acute myocardial infarction in the drug-eluting stent era: analysis of the Korean Acute Myocardial Infarction Registry. AB - BACKGROUND AND PURPOSE: Octogenarians (age >= 80 years) with coronary artery disease constitute a high-risk group. However, octogenarian patients with acute myocardial infarction (AMI) in the drug-eluting stents (DES) era have not been widely reported. We aimed to identify clinical outcomes in octogenarian compared with non-octogenarian AMI patients. METHODS AND SUBJECTS: We retrospectively analyzed 9877 patients who underwent percutaneous coronary intervention (PCI) with drug-eluting stents (DES) and who were enrolled in the Korean Acute Myocardial Infarction Registry (KAMIR). They were divided into 2 groups, octogenarians (n=1494) and non-octogenarians (n=8383), in order to compare the incidence of 1-year all-cause death and 1-year major adverse cardiac events (MACE), where MACE included all-cause death, recurrent myocardial infarction, target vessel revascularization (TVR), target lesion revascularization (TLR), and coronary artery bypass grafting (CABG). RESULTS: The clinical status was significantly inferior in octogenarians compared to non-octogenarians: Killip class >= II (34.8% vs. 22.5%, p<0.001), multivessel disease (65.8% vs. 53.7%, p<0.001). Rates of 1-year all-cause death were significantly higher in octogenarians than in non-octogenarians (22.3% vs. 6.5%, p<0.001). However, the rates of 1-year recurrent myocardial infarction (1.3% vs. 0.9%, p=0.68), TLR (2.4% vs. 3.1%, p=0.69), TVR (3.6% vs. 4.3%, p=0.96), and CABG (0.9% vs. 0.9%, p=0.76) did not differ significantly between the 2 groups. CONCLUSIONS: Octogenarian AMI patients have higher rates of mortality and MACE even in the DES era. According to KAMIR subgroup analysis, the TLR/TVR rates in octogenarians were comparable to those in non-octogenarian AMI patients. PMID- 23731920 TI - Diagnostic value of automated quantification of nuclear cardiology in Japanese patients with single vessel coronary artery disease: comparison between Japanese and American normal databases. AB - BACKGROUND: The Japanese diagnostic assessment of nuclear cardiology has usually been based on semi-quantitative visual analyses but not on automated quantification with a total perfusion deficit (TPD). We, therefore, aimed to determine whether automated TPD quantification is useful to detect coronary artery disease (CAD) in Japanese patients in comparison with conventional visual segmental analysis, and to compare results from the automated assessment between the Japanese and American normal databases (NDBs). METHODS: Patients with suspected CAD underwent rest (201)Tl and stress (99m)Tc-tetrofosmin myocardial perfusion single photon emission computed tomography (SPECT) and coronary angiography within three months. The TPD was automatically derived from the SPECT image through quantitative perfusion SPECT software with the Japanese and American NDBs. The visual summed stress scores (SSS) were estimated with the 5 point visual scoring model for 20 segments of SPECT images. An abnormal criteria for the stress TPD and SSS were defined as >= 5% and >= 4, respectively. RESULTS: Detection sensitivity of CAD was 87% with the stress TPD score derived from the Japanese NDB and 85% with the SSS in visual analysis. In contrast, the detection sensitivity with the stress TPD score derived from the American NDB was 75%, which was significantly lower than that with the Japanese TPD (p=0.0004). Specificity of the automated Japanese TPD assessment was similar to that of the visual SSS assessment (87% vs. 80%). Thus, sensitivity and specificity of the automated quantitative assessment based on the TPD scores derived from the Japanese NDB were consistent with that of visual quantification based on the segmental defect scores. CONCLUSION: The automated quantitative assessment with the Japanese NDB is useful for the detection of CAD when experts in visual interpretation of a myocardial perfusion SPECT image were absent in a clinical setting. PMID- 23731921 TI - Relation of estimated glomerular filtration rate and body mass index to mortality in non-dialysis patients with coronary artery disease: a report from the ET-CHD registry, 1997-2003. AB - BACKGROUND: Low estimated glomerular filtration rate (eGFR) and body mass index (BMI) have been known as poor prognostic factors in patients with coronary artery disease (CAD). Besides, high BMI was associated with higher survival rate in patients on dialysis as well. However, the relation of eGFR and BMI to mortality has not been clarified in non-dialysis CAD patients. METHODS: We studied a cohort of 1243 non-dialysis patients with angiographic CAD from the ET-CHD registry during 1997-2003 in Taiwan. To evaluate the relation of eGFR and BMI to mortality, the subjects were categorized into 4 groups by BMI higher or lower than 25 kg/m2 and eGFR higher or lower than 60 mL/min/1.73 m2, a cut-off value for chronic kidney disease (CKD). At a mean follow-up of 5.4 years, cardiac and all-cause deaths were the primary end points. RESULTS: In the high BMI group, CKD was a strong predictor of cardiac and overall mortality [hazard ratio (HR): 1.63 (95% CI: 1.05-2.53) and 2.17 (95% CI: 1.54-3.07), respectively]. Besides, CKD marginally elevated the mortality risk in the low BMI group. Among CKD patients, BMI was not associated with mortality except for a high death rate in patients with BMI lower than 21 kg/m2. In contrast, in non-CKD patients, high BMI group had a lower cardiac and overall mortality than the low BMI group [HR: 0.75 (95% CI: 0.48-1.16) and 0.55 (95% CI: 0.39-0.77), respectively]. CONCLUSIONS: Among non-dialysis CAD patients in eastern Taiwan, lower eGFR was associated with worse prognosis regardless of BMI levels. Notably, in patients with high BMI, the relationship between CKD and mortality was extremely remarkable. Moreover, the obesity-mortality paradox phenomenon was not present in non-dialysis CKD patients. PMID- 23731922 TI - Effect on periprocedural myocardial infarction of intra-coronary nicorandil prior to percutaneous coronary intervention in stable and unstable angina. AB - BACKGROUND: Intravenous nicorandil infusion dilates the coronary artery and reduces inflammation, coronary spasm, and arrhythmia. Periprocedural myocardial infarction (PMI) is a frequent and prognostically important complication of percutaneous coronary intervention (PCI). This prospective randomized study was designed to evaluate the efficacy of intracoronary nicorandil on PMI after elective PCI. METHODS AND RESULTS: Eighty-one patients with stable or unstable angina undergoing PCIs of the left anterior descending artery were randomly assigned to the nicorandil group (n=41) or the control group (n=40). In the nicorandil group, 4 mg of intracoronary nicorandil was infused prior to PCI. Post PCI, peak levels of creatine kinase (CK)-MB and troponin I were measured and angiographic findings were analyzed. Side branch status was also assessed. All PCIs were successful. One cerebrovascular infarction and one acute ST segment elevation myocardial infarction with acute stent thrombosis occurred in the nicorandil group. No deaths occurred, and no other major cardiac adverse events were observed in either group over 6 months follow-up. The post-PCI peak CK-MB and troponin I levels were not significantly different between the two groups. There were no significant differences between the nicorandil and control subjects in side branch occlusion or flow reduction, or in the jail index. CONCLUSIONS: Intra-coronary nicorandil infusion had no significant effect on PMI and cardiac enzymes after PCI in patients with stable or unstable angina. PMID- 23731923 TI - Clinical characteristics and long-term clinical outcomes of Japanese heart failure patients with preserved versus reduced left ventricular ejection fraction: a prospective cohort of Shinken Database 2004-2011. AB - BACKGROUND: Clinical data on the mortality and morbidity of unselected Japanese patients with heart failure (HF) are limited. In this study, we aimed to determine the clinical characteristics, long-term outcomes, and prognostic factors of Japanese HF patients with preserved or reduced left ventricular ejection fraction (LVEF). METHODS AND RESULTS: We used a single hospital-based cohort from the Shinken Database 2004-2011 that comprised all new patients (n=17,517) visiting the Cardiovascular Institute Hospital. A total of 1,525 patients diagnosed with symptomatic HF at the initial visit were included in the analysis. Of these, 1121 patients (74%) exhibited a preserved LVEF (>50%) and 404 patients (26%) had a reduced LVEF (<= 50%). HF patients with preserved LVEF (HFpEF) were older and more often female than patients with reduced LVEF (HFrEF). Kaplan-Meier curves and log-rank test results showed that HFpEF patients had a better prognosis than HFrEF patients. However, there were no significant differences in clinical outcomes between HFpEF and HFrEF patients when the analysis was limited to inpatients. Cox regression analysis showed that HFpEF patients had a significantly lower risk of all-cause death (p=0.027; hazard ratio, 0.547, 95% confidence interval, 0.321-0.933). Multivariate analyses performed separately showed that the independent predictors of all-cause death in HFrEF were advanced age, lower body mass index, diabetes mellitus, and the absence of statin treatment, whereas those for HFpEF were advanced age, absence of dyslipidemia, anemia, and left ventricular hypertrophy. CONCLUSIONS: This prospective cohort study identified the clinical characteristics, long-term outcomes, and prognostic factors of Japanese HF patients with reduced and preserved ejection fractions in a real-world clinical setting. PMID- 23731924 TI - Impairment of platelet retention rate in patients with severe aortic valve stenosis. AB - BACKGROUND: Recent reports revealed the presence of acquired von Willebrand syndrome type 2A in patients with aortic valve stenosis (AS). von Willebrand factor (vWF) has been shown to play a vital role in platelet adhesion. Therefore, we measured the platelet retention rates, which reflect platelet adhesion, in patients with severe AS. METHODS: In addition to echocardiography, routine blood screening tests were performed and the platelet retention rates were measured using collagen-coated bead columns in 21 patients with severe AS and in 21 control subjects. RESULTS: Patients with severe AS showed the maximum aortic valve pressure gradients of 110.9+/-22.7 mmHg, and effective orifice areas of 0.59+/-0.20 cm2. The results of routine blood tests in patients with severe AS were comparable to those of control subjects; however, the platelet retention rates in the AS patients (7.3+/-5.0%) were significantly lower than those in control subjects (30.5+/-11.8%, p<0.001). A significant negative correlation was observed between maximum aortic valve pressure gradients and platelet retention rates (r = -0.81, p<0.001). In 8 patients with severe AS, the platelet retention rates increased from 5.8+/-3.6% to 16.0+/-2.4% after aortic valve replacement (p<0.001). CONCLUSION: These findings suggest that impairment of platelet retention rate is seen in almost all patients with severe AS. Clinicians should be aware of the possibilities of vWF-mediated platelet dysfunction and bleeding tendency in patients with severe AS. PMID- 23731925 TI - Non-invasively measured aortic wave reflection and pulse pressure amplification are related to the severity of coronary artery disease. AB - BACKGROUND: Augmentation index (AIx) and pulse pressure amplification (PPA, here the aortic/brachial pulse pressure ratio) are an age-related emerging risk factor for cardiovascular disease. However, it has not been clearly shown that AIx and PPA predict a high risk of coronary artery disease (CAD). OBJECTIVES: The aim of the study was to investigate the association between non-invasively measured aortic wave reflection (AWR) and PPA and CAD. METHODS: The study group consisted of 80 patients who were admitted to our institute for elective coronary angiography. We non-invasively measured augmentation pressure (AP), AIx, and PPA using radial applanation tonometry. RESULTS: When the extent of CAD was divided by no or minimal CAD, 1- or 2- and 3-vessel disease (VD), there was a significant association between the extent of CAD and AIx and PPA in patients aged <65 years, but not in patients aged >= 65 years. In multivariate regression analysis after controlling the traditional risk factors, the odds ratio of having 3VD was significant in patients aged <65 years: 2.15 (1.04-4.44; p=0.039) per 5% increase of AIx and 2.02 (1.15-3.55; p=0.015) per 0.05 increase of PPA, but not in patients aged >= 65 years. The severity of CAD expressed as a Gensini score showed a significant correlation with AP, AIx, and PPA in patients aged <65 years, but not in patients aged >= 65 years. CONCLUSION: Increasing of non invasively measured AWR and PPA is related to the severity of CAD, particularly in younger patients up to 65 years of age. PMID- 23731927 TI - Learning, teaching and evaluation of rheumatological skills. PMID- 23731926 TI - Smoking and alcohol consumption patterns among elderly Canadians with mobility disabilities. AB - BACKGROUND: Mobility disability is a major adverse health outcome associated with aging and an impediment to older adults' well-being and behaviors in social and leisure activities. It has been shown that lifestyle factors, including smoking and alcohol consumption, have been used as coping strategies to deal with the negative impact of disability. The aim of this study was to determine the prevalence of smoking and alcohol consumption among older Canadians with different levels of mobility disabilities and to examine factors associated with these two lifestyle patterns among those with disabilities. METHODS: Secondary data analysis was performed using individuals (n = 6,038) aged 65 years and older from both the 2001 Participation and Activity Limitation Survey and the 2003 Canadian Community Health Survey. Multivariate logistic regressions examined the relationship between disability severity and smoking as well as alcohol consumption while controlling for potential confounding socioeconomic factors. RESULTS: The proportion of current smokers among seniors with less-severe and more-severe mobility disabilities and those in the general population was comparable with 12.55%, 11.57% and 11.93%, respectively. Forty-eight percent of seniors in the general population consumed alcohol regularly, compared to only 12.85% with more-severe mobility disabilities. No significant association was shown between the severity level of mobility disabilities and smoking (odds ratio = 0.90, 95% confidence interval: 0.75, 1.08). However, seniors having more-severe disability were less likely to consume alcohol regularly (odds ratio = 0.76, 95% confidence interval: 0.65, 0.89). Other variables including age, gender, income, living status, and social participation also impacted these lifestyle patterns among the study population. CONCLUSIONS: Smoking and alcohol patterns present different associations with the severity level of mobility disabilities. Compared with the general population, elderly Canadians with mobility disabilities had similar smoking prevalence but differ significantly in terms of alcohol consumption. Results from this research will be relevant to decision makers involved in program planning, health education, and policy development as it pertains to the prevention and management of age-related disability. PMID- 23731928 TI - Developing a professional approach to work-based assessments in rheumatology. AB - This chapter discusses how doctors in key European countries develop and maintain professional standards of clinical knowledge in their specialism, rheumatology, with particular reference to how they are assessed in the workplace. The authors discuss key educational theories related to learning and assessment, including experiential learning, reflective practice, how formative and summative assessments drive experiential learning and the essential principles of reliability and validity. This chapter also considers the challenge of ensuring that professional attitudes towards assessment and reflective practice are developed alongside cognitive and practical skills, with reference to current frameworks, including the UK and North America. The chapter lists, describes and explains the main summative assessments used in postgraduate medicine in the UK. We advocate the development of the professional reflective-practitioner attitude as the best way of approaching the range of work-based assessments that trainees need to engage in. Our account concludes by briefly discussing the barriers that may impede professional approaches to assessing competence in rheumatology. A summary states how individual practitioners may contribute to a more effective process in their roles as assessors and trainees. PMID- 23731929 TI - Joint aspiration and injection and synovial fluid analysis. AB - Joint aspiration/injection and synovial fluid (SF) analysis are both invaluable procedures for the diagnosis and treatment of joint disease. This chapter addresses (1) the indications, technical principles, expected benefits and risks of aspiration and injection of intra-articular corticosteroid and (2) practical aspects relating to SF analysis, especially in relation to crystal identification. Intra-articular injection of long-acting insoluble corticosteroids is a well-established procedure that produces rapid pain relief and resolution of inflammation in most injected joints. The knee is the most common site to require aspiration although any non-axial joint is accessible for obtaining SF. The technique involves only knowledge of basic anatomy and should not be unduly painful for the patient. Provided sterile equipment and a sensible, aseptic approach are used, it is very safe. Analysis of aspirated SF is helpful in the differential diagnosis of arthritis and is the definitive method for diagnosis of septic arthritis and crystal arthritis. The gross appearance of SF can provide useful diagnostic information in terms of the degree of joint inflammation and presence of haemarthrosis. Microbiological studies of SF are the key to the confirmation of infectious conditions. Increasing joint inflammation associates with increased SF volume, reduced viscosity, increasing turbidity and cell count and increasing ratio of polymorphonuclear:mononuclear cells, but such changes are non-specific and must be interpreted in the clinical setting. However, detection of SF monosodium urate and calcium pyrophosphate dihydrate crystals, even from un-inflamed joints during intercritical periods, allows a precise diagnosis of gout and calcium pyrophosphate crystal-related arthritis. PMID- 23731930 TI - How to perform local soft-tissue glucocorticoid injections? AB - Inflammation of periarticular soft-tissue structures such as tendons, tendon sheaths, entheses, bursae, ligaments and fasciae is the hallmark of many inflammatory rheumatic diseases, but inflammation or rather irritation of these structures also occurs in the absence of an underlying rheumatic disease. In both these primary and secondary soft-tissue lesions, local glucocorticoid injection often is beneficial, although evidence in the literature is limited. This chapter reviews local injection therapy for these lesions and for nerve compression syndromes. PMID- 23731931 TI - How to perform and analyse synovial biopsies. AB - Although most of the rheumatologic diseases can be diagnosed based on clinical examination combined with additional laboratory and radiographic tests, histological examination of synovial tissue may lead to the correct diagnosis and adjustment of therapy when neoplastic or granulomatous disease, deposition disease or infection in spite of negative synovial fluid culture is suspected. For research purposes synovial tissue analysis is used to investigate the pathological changes of the synovium in studies aimed at elucidating the aetiology and pathogenetic mechanisms involved in arthritis. In addition, the use of synovial biomarkers has been shown to be instrumental in the developmental process of new therapeutics. In this chapter, several minimally invasive techniques for acquiring synovial tissue samples, handling of the tissue and the analysis thereof are described. PMID- 23731932 TI - When and how to perform biopsies in a patient with a (suspected) connective tissue disease. AB - In the differential diagnostic process for rheumatic inflammatory and/or connective tissue diseases (CTDs), history taking and physical examination are of main importance, more than additional investigations, as many diagnoses are clinical diagnoses with specific clinical/patterns and gold standards are often lacking. In rheumatic diseases and, especially, CTD, many organ systems apart from the joints may be involved. These include the skin and underlying tissues, muscles, salivary glands, nerves, kidneys and blood vessels. Biopsy specimens of these tissues may be helpful in establishing a diagnosis, in assessing the extent and severity of organ involvement and sometimes in monitoring therapy. In this chapter, practical information is described regarding which clinical practice might indicate a need for biopsy, and on how to prepare the patient, how to perform the biopsy and handle the biopsy specimen. In addition, the limitations and complications one should be cautious of are described. For full details of the clinical spectrum of the diseases and the histopathology, the reader is kindly referred to relevant textbooks. PMID- 23731933 TI - How to perform and interpret capillaroscopy. AB - The essence of capillaroscopy is to examine, noninvasively and safely the morphology of nailfold dermal papillary capillaries using a magnification system (microscopical lenses). Capillaroscopy may be performed with lenses with low (*20) and with high magnification (*200 up to *600). The video-capillaroscope consists of an optical/digital probe which is moved to the finger of the patient and allows direct contact with the nailfold. Through qualitative assessment a normal capillaroscopy can be distinguished from a pathognomonic abnormal one due most frequently to systemic sclerosis (SSc). This pattern recognition relies on evaluating the morphology of the capillaries, their density (number) and dimensions 'at sight' of the capillaries and their architecture. In SSc three progressive capillaroscopic patterns have been described ('early', 'active' and 'late'). Quantitative assessment (quantitation of certain characteristics and semi-quantitative scoring) of the capillaroscopic pictures may also be performed. Qualitative and semi-quantitative assessments are used to predict SSc clinical complications. In other connective tissue diseases (CTDs) prospective clinical studies resulting in indices which can predict future clinical complications have not been published, as yet. PMID- 23731934 TI - How to interpret plain radiographs in clinical practice. AB - In this article I will consider the basic principles of requesting, acquiring, interpreting and reporting plain radiographs of joints, including assessment of the distribution of joint abnormalities, and specific pathological changes that may occur in bone, cartilage and soft tissues. I will then move on to a more specific discussion of the major arthropathies and the role of radiographs in the diagnosis and assessment in each condition as well as reviewing the combined abnormalities that may be visible on radiographs and how these relate to underlying pathological processes. PMID- 23731935 TI - Becoming a musculoskeletal ultrasonographer. AB - Over the last decade, increasing numbers of rheumatologists have incorporated musculoskeletal ultrasound (MSUS) as a valuable diagnostic tool into their clinical practice. Some countries have established training programmes for MSUS. The European League Against Rheumatism has developed education guidelines for the content and conductance of MSUS courses and it would be useful to standardise rheumatology MSUS training worldwide. A thorough knowledge of anatomy, US physics and technology, US scanning methods, US pattern of normal and pathological musculoskeletal tissues, definitions for US pathology, artefacts and pitfalls in both greyscale and Doppler modalities is necessary to perform efficient MSUS. MSUS training includes attending theoretical-practical and online courses, as well as studying textbooks and using digital video discs (DVDs). Having access to US equipment and performing supervised normal and pathological MSUS examinations for a training period are mandatory for consolidating MSUS learning. A proposal to accredit and certificate competence in MSUS is now being discussed. PMID- 23731936 TI - Ultrasound-guided injections in rheumatology: actual knowledge on efficacy and procedures. AB - Ultrasound allows one to detect easily joint involvement. In addition to its primary use as a diagnostic tool, ultrasound is increasingly used by rheumatologists to guide musculoskeletal interventions. The correct position of the needle in the target area offers the chance to improve efficacy of the local procedure. Knowledge of anatomy and probe positioning as well as the ability to coordinate probe and needle are necessary when injecting patients with ultrasound guidance. Lack of training and of clear guidelines on their practice is demonstrated by recent surveys and by the high variability of the literature results evaluating practice and outcome of ultrasound-guided injections. This chapter deals with actual knowledge and practical suggestions for the indications and procedures of ultrasound guidance in rheumatology daily practice. PMID- 23731937 TI - How to perform a systematic search. AB - All medical practice and research must be evidence-based, as far as this is possible. With medical knowledge constantly growing, it has become necessary to possess a high level of information literacy to stay competent and professional. Furthermore, as patients can now search information on the Internet, clinicians must be able to respond to this type of information in a professional way, when needed. Here, the development of viable systematic search strategies for journal articles, books, book chapters and other sources, selection of appropriate databases, search tools and selection methods are described and illustrated with examples from rheumatology. The up-keep of skills over time, and the acquisition of localised information sources, are discussed. PMID- 23731938 TI - Nationwide continuous monitoring of end-of-life care via representative networks of general practitioners in Europe. AB - BACKGROUND: Although end-of-life care has become an issue of great clinical and public health concern in Europe and beyond, we lack population-based nationwide data that monitor and compare the circumstances of dying and care received in the final months of life in different countries. The European Sentinel GP Networks Monitoring End of Life Care (EURO SENTIMELC) study was designed to describe and compare the last months of life of patients dying in different European countries. We aim to describe how representative GP networks in the EURO SENTIMELC study operate to monitor end of life care in a country, to describe used methodology, research procedures, representativity and characteristics of the population reached using this methodology. METHODS: Nationwide representative Networks of General Practitioners (GPs)--ie epidemiological surveillance systems representative of all GPs in a country or large region of a country--in Belgium, The Netherlands, Italy and Spain continuously registered every deceased patient (>18 year) in their practice, using weekly standardized registration forms, during two consecutive years (2009-2010). RESULTS: A total of 6858 deaths were registered of which two thirds died non-suddenly (from 62% in The Netherlands to 69% in Spain), representative for the GP populations in the participating countries. Of all non-sudden deaths, between 32% and 44% of deaths were aged 85 or older; between 46% and 54% were female, and between 23% and 49% died at home. Cancer was cause of death in 37% to 53% of non-sudden death cases in the four participating countries. CONCLUSION: Via the EURO SENTI-MELC methodology, we can build a descriptive epidemiological database on end-of-life care provision in several EU countries, measuring across setting and diseases. The data can serve as baseline measurement to compare and monitor end-of-life care over time. The use of representative GP networks for end-of-life care monitoring has huge potential in Europe where several of these networks are operational. PMID- 23731939 TI - Addressing elder abuse: review of societal responses in India and selected Asian countries. AB - In India, during the last two decades, significant developments in societal responses to address elder abuse have emerged. There is greater emphasis on recognizing that older people may be subjected to abuse and neglect by family members and the community as well. Although there is growing interest in the collection of valid statistics on the incidence and prevalence of elder abuse, there is still a need for bringing better clarity on the conceptual understanding and refining definitions of elder abuse. The government, academic community, and the civil society are working toward understanding the underlying causes of elder abuse and neglect and are focusing on appropriate interventions to address it. This paper notes the developments in recognizing elder abuse and reviews the responses in addressing the issue from a legal, social, and public health perspective in India compared with some of the Asian countries, namely China, Hong Kong, Philippines, Singapore, and Thailand. While the paper highlights the Indian experience, it is also put in an Asian context where emerging demographics are raising many concerns related to the aging of the population, and the new dynamics of relationships at the family, community, and societal levels demand fresh approaches and thoughts toward improving the quality of life of older people and reducing their vulnerability toward the risk of abuse and neglect. PMID- 23731941 TI - Diaphyseal tibiofibular synostosis in a runner. AB - Diaphyseal tibiofibular synostosis is a very rare cause of shin and ankle pain. A 35-year-old male presented with complaints of left shin and ankle pain of 3 years duration that was sometimes worse after running a few miles. One year before presenting to our hospital, the actual cause for his pain was missed when only lumbar radiographs were taken at another institution. A full-length tibia film revealed a diaphyseal tibiofibular synostosis at our hospital. The presence of a synostosis should alert the surgeon to search for the various abnormalities usually associated with this condition. Magnetic resonance imaging and enhanced 3 dimensional computed tomography are essential to rule out the possibility of a neoplastic process and to determine its relation to the neurovascular structures. Simple excision of the synostosis can provide excellent symptomatic relief with a minimal risk of complications. PMID- 23731940 TI - Late-life depressive symptoms: prediction models of change. AB - BACKGROUND: Depression is a well-recognised problem in the elderly. The aim of this study was to determine the factors associated with predictors of change in depressive symptoms, both in subjects with and without baseline significant depressive symptoms. METHODS: Longitudinal study of community-dwelling elderly people (>60 years or older), baseline evaluations, and two additional evaluations were reported. Depressive symptoms were measured using a 30-item geriatric depression scale, and a score of 11 was used as cut-off point for significant depressive symptoms in order to stratify the analyses in two groups: with significant depressive symptoms and without significant depressive symptoms. Sociodemographic data, social support, anxiety, cognition, positive affect, control locus, activities of daily living, recent traumatic life events, physical activity, comorbidities, and quality of life were evaluated. Multi-level generalised estimating equation model was used to assess the impact on the trajectory of depressive symptoms. RESULTS: A number of 7882 subjects were assessed, with 29.42% attrition. At baseline assessment, mean age was 70.96 years, 61.15% were women. Trajectories of depressive symptoms had a decreasing trend. Stronger associations in those with significant depressive symptoms, were social support (OR.971, p<.001), chronic pain (OR 2.277, p<.001) and higher locus of control (OR.581, p<.001). In contrast for those without baseline significant depressive symptoms anxiety and a higher locus of control were the strongest associations. CONCLUSIONS: New insights into late-life depression are provided, with special emphasis in differentiated factors influencing the trajectory when stratifying regarding basal status of significant depressive symptoms. LIMITATIONS: The study has not included clinical evaluations and nutritional assessments. PMID- 23731942 TI - Treatment of acute Achilles tendon rupture in Scandinavia does not adhere to evidence-based guidelines: a cross-sectional questionnaire-based study of 138 departments. AB - The best treatment of acute Achilles tendon rupture has been discussed for decades. During the past half decade, evidence has increased in favor of nonoperative treatment and dynamic and weightbearing rehabilitation. We hypothesized that the treatment strategies would show great variation and that adherence to evidence-based recommendations would not be as good as desired. The purpose of the present study was to investigate how acute Achilles tendon rupture is treated in Scandinavia. A questionnaire was distributed to all orthopedic departments treating acute Achilles tendon ruptures in Denmark, Sweden, Norway, and Finland. The questionnaire was returned by 138 of 148 departments (response rate 93%). Two-way tables with Fisher's exact test were used for statistical analysis. In Denmark, Norway, Sweden, and Finland, 19 of 23 (83%), 44 of 48 (92%), 26 of 40 (65%), and 8 of 27 (30%) departments recommended surgical treatment (p < .001). Dynamic rehabilitation was used significantly less often in Denmark (5 of 23 [22%]), Norway (17 of 45 [38%]), and Sweden (11 of 40 [28%]) than in Finland (15 of 26 [58%]; p = .015). A significant difference was found among the countries in the educational level of the performing surgeons (p < .001). Surgical treatment was the treatment of choice in Danish, Norwegian, and Swedish hospitals regardless of the increasing evidence favoring nonoperative treatment. Although increasing evidence has favored dynamic rehabilitation, it has gained limited use across Scandinavia. Weightbearing was used in most hospitals. Surgery was performed by junior surgeons in most hospitals across Scandinavia. Treatment algorithms showed considerable variation and often did not adhere to the clinical evidence. PMID- 23731943 TI - Response to 'TNF/TNFR signal transduction pathway-mediated anti-apoptosis and anti-inflammatory effects of sodium ferulate on IL-1beta-induced rat osteoarthritis chondrocytes in vitro'--authors' reply. PMID- 23731944 TI - Synthesis and antiprotozoal activity of novel 2-{[2-(1H-imidazol-1 yl)ethyl]sulfanyl}-1H-benzimidazole derivatives. AB - A series of 19 new 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}-1H-benzimidazole derivatives was synthesized starting from the properly substituted 1,2 phenylendiamine. These compounds have hydrogen or methyl at position 1; while hydrogen, chlorine, ethoxy or methoxycarbonyl group is at position 5 and/or 6. The novel compounds were tested against protozoa Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Experimental evaluations revealed strong activity for all tested compounds, having IC50 values in the nanomolar range, which were even better than metronidazole, the drug of choice for these parasites. PMID- 23731945 TI - Design, synthesis and antibacterial activity studies of thiazole derivatives as potent ecKAS III inhibitors. AB - Two series of thiazole derivatives containing amide skeleton were synthesized and developed as potent Escherichia coli beta-ketoacyl-(acyl-carrier-protein) synthase III (ecKAS III) inhibitors. All the 24 new synthesized compounds were assayed for antibacterial activity against the respective Gram-negative and Gram positive bacterial strains, including E. coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus. In which, 10 compounds with broad-spectrum antibacterial activities were further tested for their ecKAS III inhibitory activity. Last, we have successfully found that compound 4e showed both the promising broad antibacterial activity with MIC of 1.56-6.25MUg/mL against the representative bacterial stains, and also processed the most potent ecKAS III inhibitory activity with IC50 of 5.3MUM. In addition, docking simulation also carried out in this study to give a potent prediction binding mode between the small molecule and ecKAS III (PDB code: 1hnj) protein. PMID- 23731946 TI - Discovery of new PPARgamma agonists based on arylopeptoids. AB - In this study we present the design, synthesis and biological evaluation of a small, first-generation library of small molecule aromatic amides based on the arylopeptoid skeleton. The compounds were efficiently synthesized using a highly convenient submonomer solid-phase methodology which potentially allows for access to great product diversity. The synthesized compounds were tested for their ability to activate peroxisome proliferator-activated receptors (PPARs) and they all acted as PPARgamma agonists in the MUM range spanning from 2.5- to 14.7-fold activation of the receptor. This is the first discovery of bioactive molecules based on the arylopeptoid architecture. PMID- 23731947 TI - Effect of endocannabinoids on IgE-mediated allergic response in RBL-2H3 cells. AB - Recently, some endocannabinoids were reported to show anti-inflammatory and anti allergic activities. In this respect, various arachidonoyl endocannabinoids were screened for the inhibition of allergic response in IgE-activated RBL-2H3 cells. Among arachidonoyl endocannabinoids with a low cytotoxicity, only NA-5HT remarkably inhibited the release of beta-hexosaminidase (IC(50), 13.58 MUM), a marker of degranulation, and tumor necrosis factor-alpha (IC(50), 12.52 MUM), a pro-inflammatory cytokine, in IgE-activated RBL-2H3 cells. Additionally, NA-5HT markedly suppressed the formation of prostaglandin D(2) (PGD(2)) with IC(50) value of 1.27 MUM and leukotriene B(4) (LTB(4)) with IC(50) value of 1.20 MUM, and slightly LTC4. When effect of NA-5HT on early stage of FcepsilonRI cascade was investigated, it significantly inhibited phosphorylation of Syk, but not Lyn. Furthermore, NA-5HT suppressed phosphorylation of PLCgamma1/2 and PKCdelta, related to degranulation process, as well as phosphorylation of LAT, ERK1/2, p38, JNK, Gab2, PI3K and Akt, implicated in the expression of pro-inflammatory cytokines. Relative to its effect on the late stage, NA-5HT slightly reduced phosphorylation of 5-lipoxygenase (5-LO) and cyclooxygenase-2 (COX-2). Additionally, NA-5HT significantly reduced the level of p40(phox), and partially inhibited the expression of p47(phox) and p67(phox). From these results, it is suggested that NA-5HT expresses anti-allergic action by suppressing the activation of Syk, LAT, p38, JNK, PI3K and Akt, as well as the expression of ERK1/2 and NADPH oxidase subunits. Further, a strong inhibition of PGD(2) or LTB(4) biosynthesis by NA-5HT may be an additional mechanism for its anti allergic action. Such anti-allergic actions of NA-5HT may contribute to further information about its biological functions. PMID- 23731948 TI - Classification of flaw severity using pattern recognition for guided wave-based structural health monitoring. AB - In this paper, the authors present a formal classification routine to characterize flaw severity in an aircraft-grade aluminum plate using Lamb waves. A rounded rectangle flat-bottom hole is incrementally introduced into the plate, and at each depth multi-mode Lamb wave signals are collected to study the changes in received signal due to mode conversion and scattering from the flaw. Lamb wave tomography reconstructions are used to locate and size the flaw at each depth, however information about the severity of the flaw is obscured when the flaw becomes severe enough that scattering effects dominate. The dynamic wavelet fingerprint is then used to extract features from the raw Lamb wave signals, and supervised pattern classification techniques are used to identify flaw severity with up to 80.7% accuracy for a training set and up to 51.7% accuracy on a series of validation data sets extracted from independent plate samples. PMID- 23731949 TI - Strategy for successful expression of the Pseudomonas putida nitrile hydratase activator P14K in Escherichia coli. AB - BACKGROUND: Activators of Nitrile hydratase (NHase) are essential for functional NHase biosynthesis. However, the activator P14K in P. putida is difficult to heterogeneously express, which retards the clarification of the mechanism of P14K involved in the maturation of NHase. Although a strep tag containing P14K (strep P14K) was over-expressed, its low expression level and low stability affect the further analysis. RESULTS: We successfully expressed P14K through genetic modifications according to N-end rule and analyzed the mechanism for its difficult expression. We found that mutation of the second N-terminal amino-acid of the protein from lysine to alanine or truncating the N-terminal 16 amino-acid sequence resulted in successful expression of P14K. Moreover, fusion of a pelB leader and strep tag together (pelB-strep-P14K) at the N-terminus increased P14K expression. In addition, the pelB-strep-P14K was more stable than the strep-P14K. CONCLUSIONS: Our results are not only useful for clarification of the role of P14K involved in the NHase maturation, but also helpful for heterologous expression of other difficult expression proteins. PMID- 23731950 TI - Effect of the parental origin of the X-chromosome on the clinical features, associated complications, the two-year-response to growth hormone (rhGH) and the biochemical profile in patients with turner syndrome. AB - BACKGROUND: It is possible that genes on the X chromosome are expressed differently depending of its parental origin. The objective of this study was to determine the influence of the parental origin of the X-chromosome on phenotypic variability, response to rhGH and on the biochemical profile of TS patients. METHODS: This was a cross-sectional multicenter correlational study carried out over three years in six Latin-American university hospitals. Unrelated 45,X TS patients (n = 93; 18.3 +/- 8.5 years )) were evaluated. A subgroup (n = 34) of the patients were prospectively treated with rhGH over two years. DNA profiles of patients and their mothers were compared to determine the parental origin of the retained X-chromosome through 10 polymorphic X-chromosome-STRs. The association with clinical features, biochemical profiles and anthropometric data at the beginning and after two years of rhGH treatment was determined. RESULTS: Seventy two percent of patients retained the maternal X chromosome (Xm). A trend towards significance between maternal height and patients final height (p <= 0.07) in 45,Xm subjects was observed. There was no correlation between paternal height and patient height. No differences were detected between both groups in regard to dysmorphic features, classical malformations or increase in the height-SDS after rhGH. There were higher levels of triglycerides, total and LDL cholesterol in patients >20 years who retained the Xm. CONCLUSIONS: The parental origin of the retained X chromosome may influence lipid metabolism in TS patients, but its effect on growth seems to be minimal. No parental-origin-effect on the phenotypic features, associated anomalies and on the growth response to rhGH was found in 45,X TS individuals. PMID- 23731951 TI - Seroprevalence and risk factors for Rickettsia felis exposure in dogs from Southeast Queensland and the Northern Territory, Australia. AB - BACKGROUND: The recent detection of Rickettsia felis DNA in dogs in Australia suggests that dogs are potential mammalian reservoir hosts for this emerging rickettsia. To date, there is no published report addressing the seroprevalence of R. felis in dogs in Australia. METHODS: Antigens for R. felis were produced by inoculating confluent XTC-2 monolayer cell cultures with three pools of cat flea (Ctenocephalides felis) homogenates. Infection was confirmed by real-time (qPCR), conventional or nested PCRs targeting the ompB, gltA, 17 kDa and ompA genes. Two hundred and ninety-two dogs from Southeast Queensland and the Northern Territory were tested for the presence of R. felis antibodies using a microimmunofluorescence (IF) test and the seroprevalence and associated risk factors for exposure were determined using both uni- and multi-variate analyses. RESULTS: Rickettsia felis was successfully isolated in cell culture from all three cat-flea pools. One hundred and forty-eight dogs (50.7%) showed seropositivity with titres >=64 and 54 (18.5%) with titres >=128. At antibody titres >=64, dogs with active ectoparasite control were less likely to be seropositive to R. felis (OR: 2.60; 95% CI: 1.20 - 5.56). CONCLUSIONS: This first reported isolation of R. felis in cell culture in Australia allowed for the production of antigen for serological testing of dogs. Results of this serological testing reflects the ubiquitous exposure of dogs to R. felis and advocate for owner vigilance with regards to ectoparasite control on domestic pets. PMID- 23731952 TI - Specific risk factors for microbleeds and white matter hyperintensities in Alzheimer's disease. AB - We investigated whether microbleeds and white matter hyperintensities (WMH) in Alzheimer's disease (AD) associate more with conventional vascular risk factors or with risk factors that reflect amyloid burden. A total of 371 patients with probable AD were included. WMH (Fazekas 2 or 3) were present in 107 (29%) patients and microbleeds were seen in 98 (26%). Patients with both microbleeds and WMH were older and presented more frequently with lacunes and multiple microbleeds than patients with microbleeds in isolation (all p < 0.05). Using multivariate regression models, we found that WMH presence showed independent associations with age, hypertension, current smoking, and lacune presence. Microbleeds were independently associated with male gender, higher blood pressure, lower cerebrospinal fluid Abeta42, and apolipoprotein E epsilon4 homozygosity. Separate analyses for microbleeds according to their location showed that these associations were driven by microbleeds in lobar locations. Our results suggest that, unlike WMH, microbleeds in AD are particularly associated with additional amyloid burden, and as such, may relate to cerebral amyloid angiopathy. PMID- 23731953 TI - Fused in Sarcoma (FUS) gene mutations are not a frequent cause of essential tremor in Europeans. AB - FUS/TLS (denoting fused in sarcoma/translocated in liposarcoma [MIM 137070]) codifies an RNA binding protein. Mutations in this gene cause amyotrophic lateral sclerosis (ALS; MIM 608030). Essential tremor (ET [MIM 190300]) is the most frequent movement disorder. Despite its strong familiar aggregation, recently a whole exome sequencing study has identified FUS mutations as a cause of familial ET. To determine whether mutations in FUS are also common in other populations, we sequenced FUS gene in 178 unrelated Spanish subjects with ET. We detected only an intronic single-pair nucleotide deletion (c.1293-37delC), which was predicted to affect mRNA splicing. However, leukocyte mRNA analysis showed no changes in FUS expression. In conclusion, coding or splicing FUS mutations are not a frequent cause of ET in the Spanish population. PMID- 23731954 TI - Improvement of cognitive function and physical activity of aging mice by human neural stem cells over-expressing choline acetyltransferase. AB - Aging is characterized by progressive loss of cognitive and memory functions as well as decrease in physical activities. In the present study, a human neural stem cell line (F3 NSC) over-expressing choline acetyltransferase (F3.ChAT), an enzyme responsible for acetylcholine synthesis, was generated and transplanted in the brain of 18-month-old male ICR mice. Four weeks post-transplantation, neurobehavioral functions, expression of ChAT enzyme, production of acetylcholine and neurotrophic factors, and expression of cholinergic nervous system markers in transplanted animals were investigated. F3.ChAT NSCs markedly improved both the cognitive function and physical activity of aging animals, in parallel with the elevation of brain acetylcholine level. Transplanted F3 and F3.ChAT cells were found to differentiate into neurons and astrocytes, and to produce ChAT proteins. Transplantation of the stem cells increased brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), enhanced expression of Trk B, and restored host microtubule-associated protein 2 and cholinergic nervous system. The results demonstrate that human NSCs over-expressing ChAT improve cognitive function and physical activity of aging mice, not only by producing ACh directly but also by restoring cholinergic neuronal integrity, which might be mediated by neurotrophins BDNF and NGF. PMID- 23731955 TI - Whey protein isolate counteracts the effects of a high-fat diet on energy intake and hypothalamic and adipose tissue expression of energy balance-related genes. AB - The intake of whey protein isolate (WPI) is known to reduce high-fat diet (HFD) induced body-weight gain and adiposity. However, the molecular mechanisms are not fully understood. To this end, we fed C57BL/6J mice for 8 weeks with diets containing 10 % energy as fat (low-fat diet, LFD) or 45 % energy as fat (HFD) enriched with either 20 % energy as casein (LFD and HFD) or WPI (high-fat WPI). Metabolic parameters and the hypothalamic and epididymal adipose tissue expression of energy balance-related genes were investigated. The HFD increased fat mass and plasma leptin levels and decreased the dark-phase energy intake, meal number, RER, and metabolic (VO2 and heat) and locomotor activities compared with the LFD. The HFD increased the hypothalamic tissue mRNA expression of the leptin receptor, insulin receptor (INSR) and carnitine palmitoyltransferase 1b (CPT1b). The HFD also reduced the adipose tissue mRNA expression of GLUT4 and INSR. In contrast, WPI reduced fat mass, normalised dark-phase energy intake and increased meal size in HFD-fed mice. The dietary protein did not have an impact on plasma leptin, insulin, glucose or glucagon-like peptide 1 levels, but increased plasma TAG levels in HFD-fed mice. At a cellular level, WPI significantly reduced the HFD-associated increase in the hypothalamic tissue mRNA expression of the leptin receptor, INSR and CPT1b. Also, WPI prevented the HFD induced reduction in the adipose tissue mRNA expression of INSR and GLUT4. In comparison with casein, the effects of WPI on energy intake and hypothalamic and adipose tissue gene expression may thus represent a state of reduced susceptibility to weight gain on a HFD. PMID- 23731956 TI - Regulation of the expression of Th17 cells and regulatory T cells by IL-27 in patients with unexplained early recurrent miscarriage. AB - In normal pregnancy, tolerance of the maternal immune system with regard to the genetically incompatible fetus depends on the interactions of an array of cytokines secreted by maternal and fetal cells at the site of implantation. Earlier research indicating that altered immunity exists in unexplained recurrent miscarriage (RM) has been dominated by the Th1/Th2 hypothesis. Recently, the Th1/Th2 paradigm has been expanded into the Th1/Th2/Th17 and regulatory T cells paradigm. We recently demonstrated a prevalence of Th17 cells, an inverse relationship between Th17 cells and regulatory T cells and deregulation of Th17 cells by regulatory T cells in early pregnancy in unexplained RM patients. In this study, we investigated the expression of IL-27 and the role of the cytokine IL-27 in the regulation of Th17/Treg expression. Quantitative real-time RT-PCR and Western blot analyses were performed to evaluate IL-27 expression in deciduas from unexplained RM patients, spontaneous miscarriage (SM) patients and healthy women following elective abortion in the early stages of normal pregnancy (control). Regulation of IL-17, TGF-beta and IL-10 expression in CD4(+) T cells in unexplained RM patients by IL-27 was assessed using enzyme-linked immunosorbent assay (ELISA). Expression of IL-27 was lower in deciduas of patients with unexplained RM compared with SM and control subjects. IL-27 inhibited IL-17 expression and enhanced IL-10 expression in a dose-dependent manner. IL-27 had no effect on TGF-beta expression. IL-27 regulates the expression of IL-17 and IL-10, which are predominantly secreted by Th17 cells and regulatory T cells in unexplained RM patients. PMID- 23731957 TI - No role for glutathione S-transferase genotypes in Caucasian esophageal squamous cell or adenocarcinoma etiology: an European case-control study. AB - BACKGROUND: Identifying and monitoring high-risk patients can aid the prevention of esophageal cancer (EC). The interaction of environmental risk factor exposure and genetic susceptibility may contribute to the etiology of EC. Biotransformation enzymes such as Glutathione S-Transferases (GSTs ) detoxify mutagenic and genotoxic compounds and therefore control the rate of detoxification of carcinogens. Functional polymorphisms in the genes coding for GSTs alter their enzyme activity in vitro, and were reported to modify EC risk in Asians. We hypothesized that altered enzyme activity GST genotypes influence the susceptibility for esophageal adeno- (EAC) and squamous cell carcinoma (ESCC) in Caucasians. METHODS: We performed a case-control study including 440 Caucasian patients with EC and 592 healthy Caucasian controls matched for age and sex. Functional polymorphisms were selected and genotypes were determined in GST classes Alpha, Mu, Theta and Pi by means of polymerase chain reaction. Genotypes were classified into predicted high, intermediate and low enzyme activity categories based on in vitro activity data. The distribution of the activity genotypes were compared between patients with EAC or ESCC, and controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated by logistic regression analyses. Gene-gene interactions were tested and for comparison purposes, the predicted low and intermediate activity genotypes were combined. Genotypes with similar risks for EAC or ESCC were combined and analyzed for multiplicative effects. RESULTS: Our analyses includes 327 patients with EAC and 106 patients with ESCC. Low or intermediate activity enzyme genotypes for GSTM1, GSTA1, GSTP1 I105V and A114V as well as for GSTT1, did not significantly modify the risk for ESCC or EAC in our Dutch population. CONCLUSION: Functional genotypes in GST genes are not involved in EAC or ESCC susceptibility in Caucasians, in contrast to results on ESCC from Asia or Africa. PMID- 23731958 TI - Effect of concentric and eccentric velocity during heavy-load non-ballistic elbow flexion resistance exercise. AB - OBJECTIVES: Mechanical and neuromuscular benefits arise during ballistic stretch shortening cycle muscle activation, yet resistance training regimens are typically non-ballistic, and in contrast to ballistic movement, require a concentric deceleration phase. DESIGN: Twelve healthy males performed a unilateral, six repetition maximum non-ballistic elbow flexion-extension task during; (i) rapid shortening (RS), (ii) stretch-shortening cycle (SSC) and (iii) a 2-s eccentric and 2-s concentric control (C). METHODS: A load cell and shaft encoder recorded respectively force and velocity. Surface electromyographic root mean square amplitude (EMGRMS) was recorded in the biceps and triceps brachii, and is reported as the relative (%) difference, normalised to control (C). RESULTS: The average lengthening and shortening velocity of SSC (0.57 +/- 0.03 ms(-1); 0.43 +/- 0.02 ms(-1)) was significantly greater than RS (0.22 +/- 0.01 ms(-1); 0.35 +/- 0.01 ms(-1)), and C (0.17 +/- 0.00 ms(-1), 0.20 +/- 0.00 ms( 1)). Peak eccentric force was increased (P<0.0001) and in the first 5% of concentric movement during SSC, in the first and last repetitions respectively (194.7 +/- 8.4N, 164.1 +/- 7.5 N) when compared to RS (163.3 +/- 8.9 N, 152.4 +/- 7.5 N) and C (155.9 +/- 8.5 N, 152.2 +/- 8.7 N). Eccentric EMGRMS in the biceps brachii was significantly increased during the first three and final repetitions of SSC (31.9 +/- 10.9%, 46.7 +/- 12.4, 69.3 +/- 13.6%, 92.0 +/- 16.4%), and the third and last repetitions of RS (35.9 +/- 7.4%, 50.3 +/- 10.9%), compared to C (0.00%, 15.8 +/- 4.0%, 23.7 +/- 4.1%, 39.2 +/- 8.6%). CONCLUSIONS: In the current study, eccentric limb velocity potentiated eccentric and concentric force, concentric velocity, and eccentric EMG amplitude during non-ballistic exercise. PMID- 23731959 TI - Making activity-based funding work for mental health. AB - The implementation of activity-based funding (ABF) in mental health from 1 July 2013 has significant risks and benefits. It is critical that the process of implementation is consistent with Australia's cherished goal of establishing a genuine and effective model of community-based mental health care. The infrastructure to support the application of ABF to mental health is currently weak and requires considerable development. States and territories are struggling to meet existing demand for largely hospital-based acute mental health care. There is a risk that valuable ABF-driven Commonwealth growth funds may be used to prop up these systems rather than drive the emergence of new models of community based care. Some of these new models exist now and this article provides a short description. The aim is to help the Independent Hospital Pricing Authority better understand the landscape of mental health into which it now seeks to deploy ABF. PMID- 23731960 TI - Using a public hospital funding model to strengthen a case for improved nutritional care in a cancer setting. AB - OBJECTIVE: This study aimed to measure the prevalence of malnutrition risk and assessed malnutrition in patients admitted to a cancer-specific public hospital, and to model the potential hospital funding opportunity associated with implementing routine malnutrition screening. METHODS: A point-prevalence audit of malnutrition risk and diagnosable malnutrition was conducted. A retrospective audit of hospital funding associated with documented cases of malnutrition was conducted. Audit results were used to estimate annual malnutrition prevalence, associated casemix-based reimbursement potential and the clinical support resources required to adequately identify and treat malnutrition. RESULTS: Sixty four percent of inpatients were at risk of malnutrition. Of these, 90% were assessed as malnourished. Twelve percent of malnourished patients produced a positive change in the diagnosis-related group (DRG) and increased allocated financial reimbursement. Identifying and diagnosing all cases of malnutrition could contribute an additional AU$413644 reimbursement funding annually. CONCLUSIONS: Early identification of malnutrition may expedite appropriate nutritional management and improve patient outcomes in addition to contributing to casemix-based reimbursement funding for health services. A successful business case for additional clinical resources to improve nutritional care was aided by demonstrating the link between malnutrition screening, hospital reimbursements and improved nutritional care. What is known about the topic? It is known that between 20 and 50% of hospital patients are malnourished and oncology patients are 1.7 times more likely to be malnourished than are other hospitalised patients. Despite the existence of practice guidelines for malnutrition screening of at-risk oncology patients, these are not routinely implemented. Identification of malnutrition in hospitalised patients is linked to casemix funding via DRG. Casemix reimbursement for malnutrition can be enhanced if: (1) malnutrition risk is identified; (2) malnutrition is diagnosed; (3) the word 'malnutrition' and an associated action plan is documented in the medical record; and (4) malnutrition is recognised and recorded by the clinical coder. Amendments to the ICD-10-AM in 2008 allowing malnutrition to be recognised as a complication for coding when it is documented by a dietitian in the medical history has hospital reimbursement implications for dietetic practice. Reimbursement potential for malnutrition has been calculated in public hospitals in Australia with varying results. What does this paper add? This paper reports the components of a successful business case made to enhance resources for identification and treatment of malnutrition on the basis of improved treatment as well as enhanced reimbursement potential resulting from changes to the ICD-10-AM. The present study adds to the body of literature showing that malnutrition coding contributes to casemix funding in Australian public hospitals, as well as internationally, and highlights the previously unreported opportunity for a cancer-specific health service. This work demonstrated that reassignment of a DRG based on a diagnosis of malnutrition altered the overall casemix funding value for 12% of audited patients. This compares with the findings of other authors who demonstrated hypothetical DRG changes and financial reallocation. What are the implications for practitioners? This paper highlights that practitioner-centred strategies are needed to enhance malnutrition identification, diagnosis, documentation and coding to maximise casemix reimbursement and better treat malnutrition in hospitals. Strategies include education of the dietetics, medical and health-information workforce. This manuscript provides a description of the conduct of quality-improvement activities that may support successful business cases for increased dietetic resources in future. PMID- 23731961 TI - Influenza pandemic 2009/A/H1N1 management policies in primary care: a comparative analysis of three countries. AB - BACKGROUND: During the influenza pandemic 2009/A/H1N1, the main burden of managing patients fell on primary care physicians (PCP). This provided an excellent opportunity to investigate the implications of pandemic policies for the PCP role. AIM: To examine policies affecting the role of PCP in the pandemic response in Australia (in the state of Victoria), Israel and England. METHODS: Content analysis of the documents published by the health authorities in Australia, Israel and England during the pandemic 2009/A/H1N1. RESULTS: The involvement of PCP in the pandemic response differed among the countries in timing and allocated responsibilities. The Israeli approach during the containment phase was to maximise the protection of PCP at the expense of putting pressure on hospitals where the suspected cases were tested and treated. In Australia and England, PCP managed the suspected patients from the beginning of the pandemic. The work of PCP in England was supported by the introduction of the National Pandemic Flu Service during the mitigation phase, whereas Australian PCP had no additional support structures and their role was constant and intensive throughout the pandemic period. CONCLUSION: Health authorities need to engage with representatives of PCP to evaluate policies for pandemic planning and management. Adequate support and protection for PCP during different stages of pandemic management should be provided. What is known about the topic? During the influenza pandemic 2009/A/H1N1, the main burden of diagnosing and managing the patients fell on PCP. The prominent role of PCP in the 2009/A/H1N1 pandemic presents an excellent opportunity to investigate implications of pandemic policies for primary care and to tackle the possible problems that these policies may impose on the ability of PCP to effectively participate in the public health response. What does this paper add? This paper examines policies that affected the roles of PCP in managing the influenza pandemic 2009/A/H1N1 in three countries: Australia, Israel and England. Although general evaluations of the pandemic response in different countries have previously been reported, this is the first study that focuses on policies for pandemic management at the primary care level. What are the implications for practitioners? Practitioners (PCP and primary care workers in general) would benefit if pandemic preparedness plans were constructed to provide an adequate system of support and protection to primary care workers during different stages of pandemic management. For policy makers, this analysis may help to overhaul the strategies for primary care engagement in the pandemic response. PMID- 23731962 TI - The carbon footprint of an Australian satellite haemodialysis unit. AB - OBJECTIVES: This study aimed to better understand the carbon emission impact of haemodialysis (HD) throughout Australia by determining its carbon footprint, the relative contributions of various sectors to this footprint, and how contributions from electricity and water consumption are affected by local factors. METHODS: Activity data associated with HD provision at a 6-chair suburban satellite HD unit in Victoria in 2011 was collected and converted to a common measurement unit of tonnes of CO2 equivalents (t CO2-eq) via established emissions factors. For electricity and water consumption, emissions factors for other Australian locations were applied to assess the impact of local factors on these footprint contributors. RESULTS: In Victoria, the annual per-patient carbon footprint of satellite HD was calculated to be 10.2t CO2-eq. The largest contributors were pharmaceuticals (35.7%) and medical equipment (23.4%). Throughout Australia, the emissions percentage attributable to electricity consumption ranged from 5.2% to 18.6%, while the emissions percentage attributable to water use ranged from 4.0% to 11.6%. CONCLUSIONS: State-by-state contributions of energy and water use to the carbon footprint of satellite HD appear to vary significantly. Performing emissions planning and target setting at the state level may be more appropriate in the Australian context. What is known about the topic? Healthcare provision carries a significant environmental footprint. In particular, conventional HD uses substantial amounts of electricity and water. In the UK, provision of HD and peritoneal dialysis was found to have an annual per-patient carbon footprint of 7.1t CO2-eq. What does this paper add? This is the first carbon-footprinting study of HD in Australia. In Victoria, the annual per-patient carbon footprint of satellite conventional HD is 10.2t CO2-eq. Notably, the contributions of electricity and water consumption to the carbon footprint varies significantly throughout Australia when local factors are taken into account. What are the implications for practitioners? We recommend that healthcare providers consider local factors when planning emissions reduction strategies, and target setting should be performed at the state, as opposed to national, level. There is a need for more comprehensive and current emissions data to enable healthcare providers to do so. PMID- 23731963 TI - Understanding the drivers on medical workloads: an analysis of spectators at the Australian Football League. AB - OBJECTIVE: The present study was designed to further understand the psychosocial drivers of crowds impacting on the demand for healthcare. This involved analysing different spectator crowds for medical usage at mass gatherings; more specifically, did different football team spectators (of the Australian Football League) generate different medical usage rates. METHODS: In total, 317 games were analysed from 10 venues over 2 years. Data were analysed by the ANOVA and Pearson correlation tests. RESULTS; Spectators who supported different football teams generated statistically significant differences in patient presentation rates (PPR) (F15, 618=1.998, P=0.014). The present study confirmed previous findings that there is a positive correlation between the crowd size and PPR at mass gatherings but found a negative correlation between density and PPR (r = -0.206, n=317, P<0.0005). CONCLUSIONS: The present study has attempted to scientifically explore psychosocial elements of crowd behaviour as a driver of demand for emergency medical care. In measuring demand for emergency medical services there is a need to develop a more sophisticated understanding of a variety of drivers in addition to traditional metrics such as temperature, crowd size and other physical elements. In this study we saw that spectators who supported different football teams generated statistically significant differences in PPR. What is known about this topic? Understanding the drivers of emergency medical care is most important in the mass gathering setting. There has been minimal analysis of psychological 'crowd' variables. What does this paper add? This study explores the psychosocial impact of supporting a different team on the PPR of spectators at Australian Football League matches. The value of collecting and analysing these types of data sets is to support more balanced planning, better decision support and knowledge management, and more effective emergency medical demand management. What are the implications for practitioners? This information further expands the body of evidence being created to understand the drivers of emergency medical demand and usage. In addition, it supports the planning and management of emergency medical and health-related requirements by increasing our understanding of the effect of elements of 'crowd' that impact on medical usage and emergency healthcare. PMID- 23731967 TI - Medication adherence survey of drugs useful in prevention of dementia of Alzheimer's type among Indian patients. AB - BACKGROUND: Good medication adherence is the cornerstone of therapeutic success. Alzheimer's disease (AD) is the most common type of dementia and most patients are old and on multiple drugs, and good compliance therefore is even more important in this population. Dementia of Alzheimer's type (DAT) at present is yet to find a cure. Anticholinesterases and N-methyl-D-aspartate blockers are specific anti-AD therapies available. Hypertension, diabetes, and dyslipidemia can contribute to cognitive worsening. Keeping hypertension, diabetes, and dyslipidemia in control can therefore possibly prevent further cognitive decline. METHODS: Patients with subjective memory complaints (n = 75) were chosen randomly. Upon thorough neurological diagnostic work up for dementia, those with mild cognitive impairment/questionable dementia (Clinical Dementia Rating = 0.5) or those with AD were recruited in this study (n = 67). Those with hypertension, diabetes, and deranged lipid profile were further interviewed if they were able to take medicines regularly or not. An attempt was made to know causes of non compliance. RESULTS: Forty-one percent of patients were not taking the drugs that have potential to prevent cardiovascular complications or ability to slow down cognitive decline in AD on regular basis. The lack of awareness, ignorance, medicines being "too expensive," and the pressure of taking medicines regularly were cited as the reasons for non-compliance. Being illiterate and having low education contributed majorly to poor compliance in this study. CONCLUSION: Compliance to drugs that have potential or real ability to slow down cognitive decline is low in elderly people with DAT. PMID- 23731968 TI - Selecting patients for acute normovolemic hemodilution during hepatic resection: a prospective randomized evaluation of nomogram-based allocation. AB - BACKGROUND: Acute normovolemic hemodilution (ANH) decreases transfusion rates but adds to the complexity of anesthetic management during hepatectomy. A randomized controlled trial was conducted to determine if selecting patients for ANH using a transfusion nomogram improves management and resource use compared with selection using extent of resection. STUDY DESIGN: One hundred fourteen patients undergoing partial hepatectomy were randomized to a clinical arm (ANH used for resection of >= 3 liver segments) or a nomogram arm (ANH used for predicted probability of transfusion >= 50% based on a previously validated nomogram). The primary end point was appropriate management, defined as avoidance of ANH in patients at low risk or use of ANH in patients at high risk for allogeneic red blood cell transfusions. RESULTS: Between September 2009 and May 2011, 58 patients were randomized to the clinical arm and 56 to the nomogram arm. Demographics, diagnoses, extent of resection, blood loss, and incidence and grade of complications did not differ between the 2 groups. There were no differences in perioperative transfusions or laboratory values. Nomogram-based allocation did not change appropriate management overall (80% vs 76% in the clinical arm; p = 0.65), but did result in comparable perioperative outcomes and a trend toward decreased ANH use (30% vs 47%; p = 0.09), particularly in low blood loss (estimated blood loss <= 400 mL) cases (12% vs 25%; p = 0.04). CONCLUSIONS: Although allocation of intraoperative management using a transfusion nomogram did not improve appropriate management overall, it more effectively identified low blood loss cases and reduced ANH use in patients least likely to benefit. PMID- 23731969 TI - Utilization of cholecystokinin cholescintigraphy in clinical practice. PMID- 23731970 TI - Individualised medicine from the perspectives of patients using complementary therapies: a meta-ethnography approach. AB - BACKGROUND: Personalised (or individualised) medicine in the days of genetic research refers to molecular biologic specifications in individuals and not to a response to individual patient needs in the sense of person-centred medicine. Studies suggest that patients often wish for authentically person-centred care and personal physician-patient interactions, and that they therefore choose Complementary and Alternative medicine (CAM) as a possibility to complement standard care and ensure a patient-centred approach. Therefore, to build on the findings documented in these qualitative studies, we investigated the various concepts of individualised medicine inherent in patients' reasons for using CAM. METHODS: We used the technique of meta-ethnography, following a three-stage approach: (1) A comprehensive systematic literature search of 67 electronic databases and appraisal of eligible qualitative studies related to patients' reasons for seeking CAM was carried out. Eligibility for inclusion was determined using defined criteria. (2) A meta-ethnographic study was conducted according to Noblit and Hare's method for translating key themes in patients' reasons for using CAM. (3) A line-of-argument approach was used to synthesize and interpret key concepts associated with patients' reasoning regarding individualized medicine. RESULTS: (1) Of a total of 9,578 citations screened, 38 studies were appraised with a quality assessment checklist and a total of 30 publications were included in the study. (2) Reasons for CAM use evolved following a reciprocal translation. (3) The line-of-argument interpretations of patients' concepts of individualised medicine that emerged based on the findings of our multidisciplinary research team were "personal growth", "holism", "alliance", "integrative care", "self-activation" and "wellbeing". CONCLUSIONS: The results of this meta-ethnographic study demonstrate that patients' notions of individualised medicine differ from the current idea of personalised genetic medicine. Our study shows that the "personal" patients' needs are not identified with a specific high-risk group or with a unique genetic profile in the sense of genome-based "personalised" or "individualised" medicine. Thus, the concept of individualised medicine should include the humanistic approach of individualisation as expressed in concepts such as "personal growth", "holistic" or "integrative care", doctor-patient "alliance", "self-activation" and "wellbeing" needs. This should also be considered in research projects and the allocation of healthcare resources. PMID- 23731973 TI - Dexmedetomidine use in the ICU: are we there yet? AB - CITATION: Jakob SM, Ruokonen E, Grounds RM, Sarapohja T, Garratt C, Pocock SJ, Bratty JR, Takala J; Dexmedeto midine for Long-Term Sedation Investigators: Dexmedetomidine vesus midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA 2012, 307:1151 1160. BACKGROUND: Long-term sedation with midazolam or propofol in intensive care units (ICUs) has serious adverse effects. Dexmedetomidine, an alpha-2 agonist available for ICU sedation, may reduce the duration of mechanical ventilation and enhance patient comfort. METHODS: OBJECTIVE: The objective was to determine the efficacy of dexmedetomidine versus midazolam or propofol (preferred usual care) in maintaining sedation, reducing duration of mechanical ventilation, and improving patients' interaction with nursing care. DESIGN: Two phase 3 multicenter, randomized, double-blind trials were conducted. SETTING: The MIDEX (Midazolam vs. Dexmedetomidine) trial compared midazolam with dexmedetomidine in ICUs of 44 centers in nine European countries. The PRODEX (Propofol vs. Dexmedetomidine) trial compared propofol with dexmedetomidine in 31 centers in six European countries and two centers in Russia. SUBJECTS: The subjects were adult ICU patients who were receiving mechanical ventilation and who needed light to moderate sedation for more than 24 hours.Intervention: After enrollment, 251 and 249 subjects were randomly assigned midazolam and dexmedetomidine,respectively, in the MIDEX trial, and 247 and 251 subjects were randomly assigned propofol and dexmedetomidine, respectively, in the PRODEX trial. Sedation with dexmedetomidine dexmedetomidine,midazolam, or propofol; daily sedation stops; and spontaneous breathing trials were employed. OUTCOMES: For each trial, investigators tested whether dexmedetomidine was noninferior to control with respect to proportion of time at target sedation level(measured by Richmond Agitation Sedation Scale) and superior to control with respect to duration of mechanical ventilation. Secondary end points were the ability of the patient to communicate pain (measured by using a visual analogue scale [VAS]) and length of ICU stay. Time at target sedation was analyzed in per protocol(midazolam, n=233, versus dexmedetomidine, n=227; propofol, n=214, versus dexmedetomidine, n=223) population. RESULTS: Dexmedetomidine/midazolam ratio in time at target sedation was 1.07 (95% confidence interval (CI) 0.97 to 1.18), and dexmedetomidine/propofol ratio in time at target sedation was 1.00 (95% CI 0.92 to 1.08). Median duration of mechanical ventilation appeared shorter with dexmedetomidine (123 hours, interquartile range (IQR) 67 to 337) versus midazolam (164 hours, IQR 92 to 380; P=0.03) but not with dexmedetomidine (97 hours, IQR 45 to 257) versus propofol (118 hours, IQR 48 to 327; P=0.24). Patient interaction (measured by using VAS) was improved with dexmedetomidine (estimated score difference versus midazolam 19.7, 95% CI 15.2 to 24.2; P<0.001; and versus propofol 11.2, 95% CI 6.4 to 15.9; P<0.001). Lengths of ICU and hospital stays and mortality rates were similar. Dexmedetomidine versus midazolam patients had more hypotension (51/247 [20.6%] versus 29/250 [11.6%]; P=0.007) and bradycardia (35/247 [14.2%] versus 13/250 [5.2%]; P<0.001). CONCLUSIONS: Among ICU patients receiving prolonged mechanical ventilation, dexmedetomidine was not inferior to midazolam and propofol in maintaining light to moderate sedation. Dexmedetomidine reduced duration of mechanical ventilation compared with midazolam and improved the ability of patients to communicate pain compared with midazolam and propofol. Greater numbers of adverse effects were associated with dexmedetomidine. PMID- 23731974 TI - Induction of immune tolerance and reduction of aggravated lung eosinophilia by co exposure to Asian sand dust and ovalbumin for 14 weeks in mice. AB - BACKGROUND: Atmospheric contamination caused by Asian sand-dust (ASD) storms aggravates asthma in both human adults and children. This study aims to investigate a series of manifestations in allergic airway disease caused by co exposure to allergens and ASD for 6 weeks and 14 weeks. METHODS: CD-1 Mice were instilled intratracheally with 0.1 mg of ASD/mouse four times (6 weeks) or eight times (14 weeks) at 2-week intervals (total dose of 0.4 mg or 0.8 mg/mouse) with or without ovalbumin (OVA). The pathologic changes in the airway, cytological alteration in bronchoalveolar lavage fluid (BALF), and levels of inflammatory cytokines/chemokines in BALF, and OVA-specific IgE and IgG1 antibodies in serum were measured in the treated CD-1 mice. RESULTS: Four-time co-exposure to OVA and ASD aggravates allergic airway inflammation along with Th2-cytokine IL-13 and eosinophil-relevant cytokine/chemokines IL-5, Eotaxin and MCP-3 in BALF, and fibrous thickening of the subepithelial layer in the airway. On the other hand, eight-time co-exposure attenuates these changes along with a significant increase of TGF-beta1 in BALF. Adjuvant effects of ASD toward IgG1 and IgE production in sera were, however, still seen in the eight-time co-exposure. CONCLUSIONS: These results indicate that the immune responses in airways are exacerbated by four time co-exposure to ASD with OVA, but that there is a shift to suppressive responses in eight-time co-exposure, suggesting that the responses are caused by TGF-beta1-related immune tolerance. PMID- 23731975 TI - Phenotypes of intermediate forms of Fasciola hepatica and F. gigantica in buffaloes from Central Punjab, Pakistan. AB - Fascioliasis is an important food-borne parasitic disease caused by the two trematode species, Fasciola hepatica and Fasciola gigantica. The phenotypic features of fasciolid adults and eggs infecting buffaloes inhabiting the Central Punjab area, Pakistan, have been studied to characterize fasciolid populations involved. Morphometric analyses were made with a computer image analysis system (CIAS) applied on the basis of standardized measurements. Since it is the first study of this kind undertaken in Pakistan, the results are compared to pure fasciolid populations: (a) F. hepatica from the European Mediterranean area; and (b) F. gigantica from Burkina Faso; i.e. geographical areas where both species do not co-exist. Only parasites obtained from bovines were used. The multivariate analysis showed that the characteristics, including egg morphometrics, of fasciolids from Central Punjab, Pakistan, are between F. hepatica and F. gigantica standard populations. Similarly, the morphometric measurements of fasciolid eggs from Central Punjab are also between F. hepatica and F. gigantica standard populations. These results demonstrate the existence of fasciolid intermediate forms in endemic areas in Pakistan. PMID- 23731976 TI - Assessment of a symptomatic Duchenne muscular dystrophy carrier 20 years after myoblast transplantation from her asymptomatic identical twin sister. AB - Because it is due to a mutation on the X-chromosome, Duchenne muscular dystrophy rarely affects women, unless there is an unequal lyonisation of the X-chromosome containing the normal dystrophin gene. We report here the unique situation of a symptomatic Duchenne muscular dystrophy woman who was transplanted with myoblasts received from her asymptomatic monozygotic twin sister 20 years ago. Specific dynamometry was performed to possibly detect a long-term effect of this cell therapy. Long-term safety of myoblast transplantation was established by this exceptional case. However, long-term efficacy could not be definitively asserted for this patient, in spite of several clues suggesting beneficial effects. PMID- 23731971 TI - The E5 proteins. AB - The E5 proteins are short transmembrane proteins encoded by many animal and human papillomaviruses. These proteins display transforming activity in cultured cells and animals, and they presumably also play a role in the productive virus life cycle. The E5 proteins are thought to act by modulating the activity of cellular proteins. Here, we describe the biological activities of the best-studied E5 proteins and discuss the evidence implicating specific protein targets and pathways in mediating these activities. The primary target of the 44-amino acid BPV1 E5 protein is the PDGF beta receptor, whereas the EGF receptor appears to be an important target of the 83-amino acid HPV16 E5 protein. Both E5 proteins also bind to the vacuolar ATPase and affect MHC class I expression and cell-cell communication. Continued studies of the E5 proteins will elucidate important aspects of transmembrane protein-protein interactions, cellular signal transduction, cell biology, virus replication, and tumorigenesis. PMID- 23731977 TI - Impact of obesity and insulin-resistance on cirrhosis and portal hypertension. AB - Obesity is sharply rising worldwide and is increasingly recognized in patients with cirrhosis. This review summarizes the available data documenting a detrimental role of obesity and insulin-resistance on the risk of appearance of clinical events in patients with cirrhosis. Molecular pathways explaining the harmful effect of obesity and insulin resistance in the natural history of cirrhosis are largely unknown. Increasing knowledge of mechanisms leading to white adipose tissue dysfunction on one side, and to portal hypertension on the other side, allow hypothesizing that a link between the pathophysiology of obesity, insulin resistance and portal hypertension in cirrhosis exists. Mechanisms likely involved in this interplay are discussed in this article. PMID- 23731978 TI - [Arterial embolization in the treatment of massive lower gastrointestinal bleeding in patients with Crohn's disease]. PMID- 23731979 TI - [De novo hepatitis B due to vaccine-escape mutants in a liver transplant recipient]. PMID- 23731980 TI - Targeted therapy for HER2 positive breast cancer. AB - INTRODUCTION: Breast cancer is the second most common cause of death for women behind lung cancer and the most common cause of cancer deaths for women aged 45 55 years old (CDC.gov 2012). Although there continue to be enormously large numbers of disease incidence, deaths have been declining due to the disease with two hallmark time frames. The first occurred during the mid to late 1980's when hormonal therapy was introduced as a treatment for ER/PR positive breast cancer. The second occurred in the late 1990's when trastuzumab was introduced in treating HER2 positive breast cancer. These remarkable accomplishments in developing novel targeted therapies for breast cancer, along with a better understanding of the disease biology have improved disease outcome over the past 20 years.This article reviews the data presented at 2012 American Society of Clinical Oncology and 2012 San Antonio Breast Cancer Symposium regarding progress made in the field of HER2 positive breast cancer and examines the future of HER2 targeted therapy. PMID- 23731981 TI - How to do it?: percutaneous treatment of a severely stenosed and calcified left main stem bifurcation. AB - CASE SUMMARY: A frail 87 year-old lady presented with rest angina associated with widespread ECG change and troponin release. She failed attempts at medical therapy and therefore was referred for coronary intervention on the basis that she was not a surgical candidate. INVESTIGATION: Coronary angiography demonstrated heavily calcified coronary arteries with critical disease at the distal left main stem bifurcation extending into the proximal segments of both LAD and circumflex. DIAGNOSIS: Acute coronary syndrome with extensive calcific coronary artery disease in the left main stem bifurcation. MANAGEMENT: Sequential rotational atherectomy of the left main stem bifurcation followed by 'Y'-stenting using three Xience Prime drug eluting stents. PMID- 23731972 TI - The papillomavirus E7 proteins. AB - E7 is an accessory protein that is not encoded by all papillomaviruses. The E7 amino terminus contains two regions of similarity to conserved regions 1 and 2 of the adenovirus E1A protein, which are also conserved in the simian vacuolating virus 40 large tumor antigen. The E7 carboxyl terminus consists of a zinc-binding motif, which is related to similar motifs in E6 proteins. E7 proteins play a central role in the human papillomavirus life cycle, reprogramming the cellular environment to be conducive to viral replication. E7 proteins encoded by the cancer-associated alpha human papillomaviruses have potent transforming activities, which together with E6, are necessary but not sufficient to render their host squamous epithelial cell tumorigenic. This article strives to provide a comprehensive summary of the published research studies on human papillomavirus E7 proteins. PMID- 23731982 TI - Idiopathic ventricular tachycardia cured by radiofrequency application from the distal great cardiac vein and the left coronary cusp. AB - A 79 year-old male without structural heart disease suffered from drug refractory ventricular tachycardia (VT). VTs and premature ventricular complexes (PVCs) with the same morphology occurred incessantly with a concordant R pattern in chest leads and a tall R in Lead II, III, and aVF. The origin was expected to be near the left epicardial ventricular outflow tract (LVOT), which was termed the left ventricular summit area. Pace-mapping from the LVOT and the left coronary cusp (LCC) did not match well with the QRS morphology of the PVC. A good match was obtained from the distal great cardiac vein (GCV), and radiofrequency (RF) delivery eliminated the PVC and VT. However, the PVC recurred four times upon cessation of RF delivery. By placing an ablation catheter at the LCC, we obtained pace-mapping showing two different types of QRS morphologies; one was an rS pattern in V1, and the other was an R pattern in V1 with a longer stimulus to QRS interval, which was a nearly perfect match to the PVC. RF application to the LCC permanently eliminated PVCs and VTs. Several VTs from the epicardial LVOT can be cured by RF application from both the distal GCV and the LCC. PMID- 23731983 TI - The CLOSER survey: impact of postmenopausal vaginal discomfort on relationships between women and their partners in Northern and Southern Europe. AB - OBJECTIVES: CLOSER investigated how postmenopausal vaginal atrophy ('vaginal discomfort') affects relationships between women and their partners. STUDY DESIGN: CLOSER involved postmenopausal women (55-65 years) with vaginal discomfort, and male partners of women with the condition. MAIN OUTCOME MEASURES: Structured questionnaire collecting information on impact of vaginal discomfort and local oestrogen treatment on intimacy and relationships, and symptoms and impact of menopause. RESULTS: 1600 women and 1600 men from Northern Europe and 1000 women and 1000 men from Southern Europe were included. Worry that vaginal discomfort would never go away was expressed by 28% and 38% of women in Northern and Southern Europe, respectively (p<0.05), while 21% and 27% worried that vaginal discomfort would ruin their future sex life (p<0.05). Half of women who avoided intimacy worried about painful sex. Among men, 86% wanted their partner to talk about symptoms; two-thirds felt comfortable with this. In Northern and Southern Europe, 15% and 11% of men, respectively, feared that discussing vaginal discomfort would ruin intimacy, while 29% and 19% believed that vaginal discomfort was a big problem in their sex life. Men with partners who avoided intimacy recognised that worry about painful sex was the main reason. Vaginal discomfort impaired self-esteem and emotional wellbeing among women, while local oestrogen treatment improved relationships, particularly in Southern Europe. CONCLUSIONS: Vaginal discomfort impairs quality of life in postmenopausal women and their partners. Southern European women were generally more worried about long-term effects on their relationship, and were more likely to report benefits after treatment. PMID- 23731985 TI - [Vascular medicine and psychiatric care: towards an active partnership]. PMID- 23731984 TI - Abnormalities in the fatty acid composition of the postmortem entorhinal cortex of patients with schizophrenia, bipolar disorder, and major depressive disorder. AB - Previous studies of postmortem orbitofrontal cortex have shown abnormalities in levels of n-3 polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), in individuals with schizophrenia, bipolar disorder, and major depressive disorder (MDD). We have previously measured PUFA levels in the postmortem hippocampus from patients with schizophrenia or bipolar disorder and control subjects; however, we found no significant differences between the groups except for small changes in n-6 PUFAs. Furthermore, our study of the postmortem amygdala showed no significant differences in major PUFAs in individuals with schizophrenia, bipolar disorder, or MDD in comparison with controls. In the present study, we investigated whether there were any changes in PUFAs in the entorhinal cortexes of patients with schizophrenia (n=15), bipolar disorder (n=15), or MDD (n=15) compared with unaffected controls (n=15) matched for characteristics including age and sex. In contrast to previous studies of the orbitofrontal cortex and hippocampus, we found no significant differences in major PUFAs. However, we found a 34.3% decrease in docosapentaenoic acid (DPA) (22:5n-3) in patients with MDD and an 8.7% decrease in docosatetraenoic acid (22:4n-6) in those with schizophrenia, compared with controls. Changes in PUFAs in patients with these psychiatric disorders may be specific to certain brain regions. PMID- 23731986 TI - A comparison of Irish set dancing and exercises for people with Parkinson's disease: a phase II feasibility study. AB - BACKGROUND: People with idiopathic Parkinson's disease (PD) frequently have low activity levels, poor mobility and reduced quality of life. Although increased physical activity may improve mobility, balance and wellbeing, adherence to exercises and activity programs over the longer term can be challenging, particularly for older people with progressive neurological conditions such as PD. Physical activities that are engaging and enjoyable, such as dancing, might enhance adherence over the long term. The objective of this study was to evaluate the feasibility of a randomized controlled trial of Irish set dancing compared with routine physiotherapy for people with mild to moderately severe PD. METHODS: Twenty-four people with idiopathic PD referred for movement rehabilitation were randomized to receive standard physiotherapy exercises or Irish set dancing classes once per week plus a weekly home program for 6 months (12 in each group). The feasibility and safety of the proposed RCT protocol was the main focus of this evaluation. The primary outcome was motor disability measured by the motor component of the UPDRS, which was assessed prior to and after therapy by trained assessors blinded to group assignment. The Timed Up and Go, the Berg Balance Scale and the modified Freezing of Gait Questionnaire were secondary measures. Quality of life of the people with PD was evaluated using the PDQ-39. RESULTS: Both the Irish set dancing and physiotherapy exercise program were shown to be feasible and safe. There were no differences between groups in the rate of adverse events such as falls, serious injuries, death or rates of admission to hospital. The physiotherapists who provided usual care remained blind to group allocation, with no change in their standard clinical practice. Compliance and adherence to both the exercise and dance programs were very high and attrition rates were low over the 6 months of therapy. Although improvements were made in both groups, the dance group showed superior results to standard physiotherapy in relation to freezing of gait, balance and motor disability. CONCLUSIONS: Irish dancing and physiotherapy were both safe and feasible in this sample from Venice, with good adherence over a comparatively long time period of 6 months. A larger multi-centre trial is now warranted to establish whether Irish set dancing is more effective than routine physiotherapy for enhancing mobility, balance and quality of life in people living with idiopathic PD. TRIAL REGISTRATION: EudraCT number 2012-005769-11. PMID- 23731987 TI - Membership and management: structures of inter-professional working in community mental health teams for older people in England. AB - BACKGROUND: Community mental health services are regarded as the preferred first tier of specialist psychogeriatric support, with integrated multidisciplinary teams believed to offer improved decision-making and greater continuity of care than separate single-profession services. In England over 400 community mental health teams (CMHTs) form the cornerstone of such support, yet research has neither assessed progress toward integrating key professional disciplines nor the nature of their membership and management arrangements. METHODS: A self administered questionnaire was sent to all CMHTs for older people in England, seeking a combination of objective and subjective information on team structure and management. RESULTS: Responses from 376 (88%) teams highlighted broader multidisciplinary membership than found in a 2004 survey, with particular growth in the number of support workers and other unqualified practitioners. Only modest progress was found in the integration of psychologists and social workers within CMHTs. The data also revealed a trend toward "core" team membership, and away from "sessional" membership in which staff may have divided loyalties between services. Multidisciplinary working was reported as beneficial by many respondents, but examples of "silo working" were also found, which may have hampered service delivery in a minority of teams. CONCLUSIONS: The reported growth in the number of practitioners without professional registration raises issues about the appropriate skill mix and substitution within CMHTs, while local agencies should review barriers to the integration of psychologists and social workers. Further research is required to explore the quality of multidisciplinary team working. PMID- 23731988 TI - [New MRI techniques in prostate cancer]. PMID- 23731989 TI - [Magnetic resonance imaging in management of prostate cancer]. AB - The development of multiparametric magnetic resonance imaging (MRI) offers new possibilities in management of prostate cancer due to its high-resolution and soft-tissue contrast. By combining high-resolution anatomical imaging with functional imaging techniques multiparametric MRI is now proven to be the most sensitive and specific imaging tool for detection, localization and staging of prostate cancer. PMID- 23731990 TI - [Magnetic resonance imaging facilitate appropriate treatment selection of prostate cancer patients]. AB - Recent scientific work supports the rapidly growing use of multiparametric magnetic resonance imaging (MRI) as the most sensitive and specific imaging tool for detection, staging and treatment planning of prostate cancer. Its use can improve many aspects of prostate cancer management. By increasing the detection rate of clinically significant tumours with less biopsy-cores and improving the evaluation of tumours, localization, volume, extend and biological aggressiveness multiparametric MRI facilitate appropriate treatment selection of prostate cancer patients. PMID- 23731991 TI - [Institutionalisation of medical innovations exemplified with percutaneous vertebroplasty]. AB - Institutionalisation of medical innovations is often based on low scientific evidence. According to McKinlay a medical innovation follows a process of seven typical stages from a promising report to either implementation or denunciation. This process is exemplified with percutaneous vertebroplasty, an invasive procedure for painful vertebral fracture in patients with osteoporosis. PMID- 23731992 TI - [Pulmonary hypertension--classification, work-up and treatment]. AB - Pulmonary hypertension (PH) is classified into five groups. It is an important cause of dyspnoea. Echocardiography is the best non-invasive method for detecting PH and should be part of the evaluation of patients with dyspnoea. If signs of PH are detected on echocardiography, a number of other examinations should be undertaken to verify the diagnosis and classify PH correctly, as the treatment depends on the subtype of PH. The prognosis of PH is poor, but early detection and treatment can improve the course for some of the patients. Surgery can often cure chronic thromboembolic pulmonary hypertension. PMID- 23731993 TI - [Video recordings can be used for easier and faster evaluations of the performances of postgraduate trainees]. AB - Evaluating post-graduate trainees under direct observation is troublesome, and there are concerns about rater-variability. The aim of this study was to explore if video recordings could be used for evaluation. The performances of five trainees were video recorded. The videos were assessed by six supervisors watching either the complete recording or approximately 20 min. Video recording was well tolerated by the patients and the supervisors, but not the trainees. Watching part of the videos was sufficient for assessment. Video recording seems to provide a feasible method of assessing postgraduate trainees. PMID- 23731994 TI - [Endovascular treatment of cerebral thrombosis in patient on dabigatran]. AB - We report a case of severe acute ischaemic stroke in a patient who could not receive treatment with thrombolysis due to concomitant treatment with dabigatran (new anticoagulant drug). Endovascular treatment was the only treatment of choice. Due to well-organized prehospital logistics, including helicopter transport, the patient arrived at hospital shortly after onset of symptoms and was treated successfully with thrombectomy. PMID- 23731995 TI - [Cerebral cysticerc is a rare cause of hydrocephalus]. AB - We present a case of a 39-year-old woman from Thailand. She presented with dizziness and signs of raised intracranial pressure. Magnetic resonance scanning revealed multiple cysticercs in cerebrum and cerebellum, and one of the cysticercs compressed the cerebral aqueduct resulting in hydrocephalus. The patient was transferred to an infectious disease department, where appropriate treatment with albendazol was initiated. Surprisingly she was found HIV-positive with a CD4 count of approx. 10 m/l. The patient deteriorated over the following week and died due to raised intracranial pressure. PMID- 23731996 TI - Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases in vitro fertilization implantation and delivery rates: a randomized controlled trial. AB - OBJECTIVE: To determine whether blastocyst biopsy and rapid quantitative real time polymerase chain reaction (qPCR)-based comprehensive chromosome screening (CCS) improves in vitro fertilization (IVF) implantation and delivery rates. DESIGN: Randomized controlled trial. SETTING: Academic reproductive medicine center. PATIENT(S): Infertile couples in whom the female partner (or oocyte donor) is between the ages of 21 and 42 years who are attempting conception through IVF. INTERVENTION(S): Embryonic aneuploidy screening. MAIN OUTCOME MEASURE(S): Sustained implantation and delivery rates. RESULT(S): We transferred 134 blastocysts to 72 patients in the study (CCS) group and 163 blastocysts to 83 patients in the routine care (control) group. Sustained implantation rates (probability that an embryo will implant and progress to delivery) were statistically significantly higher in the CCS group (89 of 134; 66.4%) compared with those from the control group (78 of 163; 47.9%). Delivery rates per cycle were also statistically significantly higher in the CCS group. Sixty one of 72 treatment cycles using CCS led to delivery (84.7%), and 56 of 83 (67.5%) control cycles ultimately delivered. Outcomes were excellent in both groups, but use of CCS clearly improved patient outcomes. CONCLUSION(S): Blastocyst biopsy with rapid qPCR-based comprehensive chromosomal screening results in statistically significantly improved IVF outcomes, as evidenced by meaningful increases in sustained implantation and delivery rates. CLINICAL TRIAL REGISTRATION NUMBER: NCT01219283. PMID- 23731997 TI - How to locate and appraise qualitative research in complementary and alternative medicine. AB - BACKGROUND: The aim of this publication is to present a case study of how to locate and appraise qualitative studies for the conduct of a meta-ethnography in the field of complementary and alternative medicine (CAM). CAM is commonly associated with individualized medicine. However, one established scientific approach to the individual, qualitative research, thus far has been explicitly used very rarely. This article demonstrates a case example of how qualitative research in the field of CAM studies was identified and critically appraised. METHODS: Several search terms and techniques were tested for the identification and appraisal of qualitative CAM research in the conduct of a meta-ethnography. Sixty-seven electronic databases were searched for the identification of qualitative CAM trials, including CAM databases, nursing, nutrition, psychological, social, medical databases, the Cochrane Library and DIMDI. RESULTS: 9578 citations were screened, 223 articles met the pre-specified inclusion criteria, 63 full text publications were reviewed, 38 articles were appraised qualitatively and 30 articles were included. The search began with PubMed, yielding 87% of the included publications of all databases with few additional relevant findings in the specific databases. CINHAL and DIMDI also revealed a high number of precise hits. Although CAMbase and CAM-QUEST(r) focus on CAM research only, almost no hits of qualitative trials were found there. Searching with broad text terms was the most effective search strategy in all databases. CONCLUSIONS: This publication presents a case study on how to locate and appraise qualitative studies in the field of CAM. The example shows that the literature search for qualitative studies in the field of CAM is most effective when the search is begun in PubMed followed by CINHAL or DIMDI using broad text terms. Exclusive CAM databases delivered no additional findings to locate qualitative CAM studies. PMID- 23731998 TI - Crystalloids vs. colloids: KO at the twelfth round? AB - CITATION: Myburgh JA, Finfer S, Bellomo R, Billot L, Cass A, Gattas D, Glass P, Lipman J, Liu B, McArthur C, McGuinness S, Rajbhandari D, Taylor CB, Webb SA; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group: Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med 2012, 367:1901-1911. BACKGROUND: The safety and efficacy of hydroxyethyl starch (HES) for fluid resuscitation have not been fully evaluated, and adverse effects of HES on survival and renal function have been reported. METHODS: We randomly assigned 7,000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kDa and a molar substitution ratio of 0.4 (130/0.4, Voluven; Fresenius Kabi AG, Bad Homburg vor der Hohe, Germany) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal replacement therapy. OBJECTIVE: We conducted a large-scale randomized controlled trial to evaluate the safety and efficacy of 6% HES(130/0.4) in 0.9% saline as compared with 0.9% saline alone for fluid resuscitation in a heterogeneous population of adult patients in the ICU. DESIGN: The Crystalloid versus Hydroxyethyl Starch Trial (CHEST) was an investigator initiated, multicenter,prospective, blinded, parallel-group, randomized controlled trial. SETTING: The study was set at 32 hospitals in Australia and New Zealand. SUBJECTS: The subjects were adult patients (>18 years) who were admitted to the ICU and who required intravenous fluid above maintenance requirements determined by the treating clinician and supported by at least one objective physiological criterion. Patients were excluded if they received more than 1 L of 6% HES within 24 hours of screening or had one of the following:dialysis dependent or impending dialysis renal failure,computed tomography evidence of non traumatic intracranial hemorrhage (ICH) or severe traumatic ICH, creatinine of more than 3.9 mg/dL or urine output of less than 10 mL/hour for 12 hours, sodium of more than 160 meq/L, or chloride of more than 130 meq/L. Also excluded were females of childbearing age (unless proven not to be pregnant) and patients who had post-cardiac surgery status, liver transplant, or burns and those whose death was judged to be imminent or whose underlying disease process indicated a life expectancy of less than 90 days. INTERVENTION: If fluid was deemed necessary by the treating clinician by the parameters described above, the patient received 'study' fluid with identical packaging and appearance. The fluid was either 6% HES (130/0.4) in saline (Voluven) or 0.9% saline. OUTCOMES: Th e primary outcome was death within 90 days. Secondary outcomes were acute kidney injury (AKI) and failure and treatment with renal replacement therapy. RESULTS: A total of 597 (18.0%) of 3,315 patients in the HES group and 566 (17.0%) of 3,336 in the saline group died (relative risk (RR) in the HES group 1.06, 95% confidence interval (CI) 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. AKI--defined by RIFLE (Risk, Injury, Failure, Loss, and End-stage kidney disease) criteria--occurred in few patients receiving HES (34.6%) compared with saline (38%) (RR 0.91, 95% CI 0.85 to 0.97). However, renal replacement therapy was used in 235 (7.0%) of 3,352 patients in the HES group and 196 (5.8%) of 3,375 in the saline group (RR 1.21, 95% CI 1.00 to 1.45; P=0.04). HES was significantly associated with more adverse events (5.3% versus 2.8%; P<0.001). CONCLUSIONS: In patients in the ICU, there was no significant difference in 90-day mortality between patients resuscitated with 6% HES (130/0.4) or saline. However, despite a lower overall rate of AKI, more patients who received resuscitation with HES were given renal replacement therapy. (The study was supported by the National Health and Medical Research Council of Australia; the Ministry of Health, New South Wales Government, Australia; and Fresenius Kabi; and by a Practitioner Fellowship from the National Health and Medical Research Council of Australia (to Drs Myburgh and Bellomo), by a Principal Research Fellowship from the National Health and Medical Research Council of Australia (to Dr Cass), and by a Practitioner Fellowship from the Medical Research Foundation of the Royal Perth Hospital (to Dr Webb); CHEST ClinicalTrials.gov number NCT00935168.). PMID- 23731999 TI - Beyond symmetry-breaking: competition and negative feedback in GTPase regulation. AB - Cortical domains are often specified by the local accumulation of active GTPases. Such domains can arise through spontaneous symmetry-breaking, suggesting that GTPase accumulation occurs via positive feedback. Here, we focus on recent advances in fungal and plant cell models - where new work suggests that polarity controlling GTPases develop only one 'front' because GTPase clusters engage in a winner-takes-all competition. However, in some circumstances two or more GTPase domains can coexist, and the basis for the switch from competition to coexistence remains an open question. Polarity GTPases can undergo oscillatory clustering and dispersal, suggesting that these systems contain negative feedback. Negative feedback may prevent polarity clusters from spreading too far, regulate the balance between competition and coexistence, and provide directional flexibility for cells tracking gradients. PMID- 23732000 TI - Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in cervical cancer. AB - BACKGROUND: Multiple studies proved that miRNAs have a causal role in tumorigenesis. Some miRNAs are regulated by epigenetic alterations in their promoter regions and can be activated by chromatin- modifying drugs. METHODS: We treated cervical cancer cells with 5-aza-2'-deoxycytidine and get a microarray analysis. Dysregulation of miRNAs was measured by qPCR in cervical cell lines and methylation status of them in cervical cancer tissue were performed with MeDIP qPCR assay. RESULTS: We found hypermethylation of miR-432, miR-1286, miR-641, miR 1290, miR-1287 and miR-95 may have some relationship with HPV infection in cervical cell lines. In primary tumors of cervix with paired normal tissue, expression levels of miRNAs were inversely correlated with their DNA methylation status in the cervical cancer cell lines treated with 5-AZA. CONCLUSIONS: Our results indicate that miRNAs might play a role in the pathogenesis of human cervical cancer with HPV and identify altered miRNA methylation as a possible epigenetic mechanism involved in their aberrant expression. PMID- 23732001 TI - Occlusion of the round window: a novel way to treat hyperacusis symptoms in superior semicircular canal dehiscence syndrome. AB - BACKGROUND: Conductive hyperacusis in superior semicircular canal dehiscence syndrome occurs due to the presence of a 'third window' created by the dehiscence. Reversible blocking of the round window can, in theory, cause a reduction in the compression-related volume displacement, and thereby minimise symptoms of conductive hyperacusis. This study describes a technique of permeatal blocking of the round window. METHOD: The tympanomeatal flap is elevated and the round window niche is identified. The round window membrane is subsequently identified and occluded with bone wax, muscle and fascia, in three separate layers. Finally, the tympanomeatal flap is reflected, and an ear wick is inserted. RESULTS: Two patients who underwent the procedure reported a reduction in symptoms. Importantly, no Tullio phenomenon was reported post-operation. CONCLUSION: Blocking of the round window can be used to control symptoms of superior semicircular canal dehiscence syndrome in patients who present solely with symptoms of conductive hyperacusis. This technique provides an alternative to resurfacing techniques. The procedure is simple to perform, reversible and can be undertaken as day-case surgery. PMID- 23732002 TI - Postnatal epigenetic reprogramming in the germline of a marsupial, the tammar wallaby. AB - BACKGROUND: Epigenetic reprogramming is essential to restore totipotency and to reset genomic imprints during mammalian germ cell development and gamete formation. The dynamic DNA methylation change at DMRs (differentially methylated regions) within imprinted domains and of retrotransposons is characteristic of this process. Both marsupials and eutherian mammals have genomic imprinting but these two subgroups have been evolving separately for up to 160 million years. Marsupials have a unique reproductive strategy and deliver tiny, altricial young that complete their development within their mother's pouch. Germ cell proliferation in the genital ridge continues after birth in the tammar wallaby (Macropus eugenii), and it is only after 25 days postpartum that female germ cells begin to enter meiosis and male germ cells begin to enter mitotic arrest. At least two marsupial imprinted loci (PEG10 and H19) also have DMRs. To investigate the evolution of epigenetic reprogramming in the marsupial germline, here we collected germ cells from male pouch young of the tammar wallaby and analysed the methylation status of PEG10 and H19 DMR, an LTR (long terminal repeat) and a non-LTR retrotransposons. RESULTS: Demethylation of the H19 DMR was almost completed by 14 days postpartum and de-novo methylation started from 34 days postpartum. These stages correspond to 14 days after the completion of primordial germ cell migration into genital ridge (demethylation) and 9 days after the first detection of mitotic arrest (re-methylation) in the male germ cells. Interestingly, the PEG10 DMR was already unmethylated at 7 days postpartum, suggesting that the timing of epigenetic reprogramming is not the same at all genomic loci. Retrotransposon methylation was not completely removed after the demethylation event in the germ cells, similar to the situation in the mouse. CONCLUSIONS: Thus, despite the postnatal occurrence of epigenetic reprogramming and the persistence of genome-wide undermethylation for 20 days in the postnatal tammar, the relative timing and mechanism of germ cell reprogramming are conserved between marsupials and eutherians. We suggest that the basic mechanism of epigenetic reprogramming had already been established before the marsupial-eutherian split and has been faithfully maintained for at least 160 million years and may reflect the timing of the onset of mitotic arrest in the male germline. PMID- 23732003 TI - A novel mechanism of bisphenol A removal during electro-enzymatic oxidative process: chain reactions from self-polymerization to cross-coupling oxidation. AB - The catalyzed removal of bisphenol A (BPA) by a horseradish peroxidase (HRP) cathode in the presence of humic acid (HA) was investigated. At an optimal condition, the removal of BPA achieved 100% within 2min reaction. In the electro enzymatic process, products were analyzed by high performance liquid chromatography with diode array detector (HPLC-DAD) and high performance size exclusion chromatography (HPSEC). HPLC-DAD results showed that BPA was oxidized into self-polymers and then self-polymers as important intermediate products decreased and disappeared. HPSEC results showed the order of molecular weight (MW): HA+BPA cross-coupling products>HA self-coupling products>initial HA. According to above results, a novel mechanism of BPA transformation in the presence of HA was proposed in electro-enzymatic process. In summary, under oxidation of in situ hydrogen peroxide on HRP electrode, the BPA first are polymerized into self-polymers, and then, the polymers may be incorporated into HA matrix and finally larger MW of BPAn-HA might be formed. The presence of HA can provide chain reactions from BPA self-polymerization to cross-coupling oxidation. Therefore, in the presence of HA, the electro-enzymatic oxidation is an effective way to improve BPA removal. PMID- 23732004 TI - Occurrence of PAOI in a low temperature EBPR system. AB - The occurrence of Accumulibacter Type I (a known phosphorus-accumulating organism, PAO) has received increased attention due to the potential operating benefits associated with their denitrifying activity in enhanced biological phosphorus removal (EBPR) wastewater treatment plants. In this study, after a shift from an enriched glycogen-accumulating organism (GAO) culture (competitors of PAO) to a PAO-enriched system, Accumulibacter Type I (PAO I) became dominant in an anaerobic-aerobic EBPR system fed with acetate and operated at 10 degrees C with a net aerobic solids retention time (SRT) of 6 d. Since Accumulibacter Type II (PAO II) were not detected, the low temperature in combination with the net aerobic SRT applied appeared to have suppressed their growth as well. The stoichiometry of PAO I was in agreement with previous metabolic models, suggesting that it was the main PAO organisms present in previous studies operated under similar conditions. Moreover, under poly-P limiting conditions, PAO I were unable to switch to a GAO-like metabolism at low temperatures. These results contribute to increase the understanding of the physiology, microbial metabolism and microbial ecology of PAO I. PMID- 23732005 TI - A new procedure of determination of alcohol sulfates and alcohol ethoxysulfates in agricultural soils. AB - The number of analytical methodologies that focus in the determination of alcohol sulfates (AS) and alcohol ethoxysulfates (AES) in terrestrial environment is very limited. In the present work, a new methodology to improve the extraction and determination of AS and AES in agricultural soil samples has been developed. Prior to instrumental analysis, an extraction procedure using pressurized liquid extraction with methanol (PLE) was carried out in order to obtain the highest recoveries and improve sensitivity. The most influential variables affecting the PLE procedure were optimized. Then, the separation and quantification of analytes were performed by liquid chromatography coupled to tandem mass spectrometry (LC MS/MS). The limits of detection (LOD) ranged from 0.03 to 0.08MUgg(-1) for AS homologues and in the case of AES ethoxymers from 0.03 to 0.09MUgg(-1) for AES C12Ex and from 0.03 to 0.08MUgg(-1) for AES-C14Ex. Matrix-matched calibration was used. Trueness was evaluated by using a spike recovery assay with spiked blank samples, and the recoveries ranged from 98.3% to 101.0% for AS and from 99.9% to 100.1% for AES. The method was satisfactorily applied in a field study designed to evaluate the environmental behavior of these compounds in agricultural soil. PMID- 23732006 TI - Aqueous pesticide mitigation efficiency of Typha latifolia (L.), Leersia oryzoides (L.) Sw., and Sparganium americanum Nutt. AB - Agricultural pesticide use is necessary to help meet the increased demand for a safe and secure food supply for the United States, as well as the global community. Even with proper application and careful management, the possibility of pesticide leaching and detachment in runoff still exists following certain storm events. Several different management practices have been designed to reduce the impacts of pesticides on aquatic receiving systems. Many such practices focus on the use of vegetation to slow runoff and allow for sorption of the various contaminants. Three common drainage ditch macrophytes, Leersia oryzoides (cutgrass), Typha latifolia (cattail), and Sparganium americanum (bur-reed) were assessed for their ability to reduce effluent loads of atrazine, diazinon, and permethrin in simulated agricultural runoff water in 379L individual mesocosms. Of the three macrophytes examined, L. oryzoides was the most effective at mitigating atrazine, and permethrin. L. oryzoides and T. latifolia significantly reduced overall atrazine loads (45+/-7%, p=0.0073 and 35+/-8%, p=0.0421, respectively) when compared to unvegetated controls (13+/-20%). No significant differences in overall diazinon load retention were noted between plant species. Each plant species significantly decreased the initial load (after 6h) of trans permethrin, while both L. oryzoides and T. latifolia significantly reduced the overall trans-permethrin loads (88+/-5%, p=0.0022 and 88+/-5%, p=0.0020, respectively) when compared to unvegetated controls (68+/-8%). Reversible adsorption of atrazine and diazinon to plants, noted during the flushing events, was greater than that observed in either cis- or trans-permethrin. These results demonstrate the ability of native ditch vegetation to mitigate pesticides associated with agricultural runoff. Likewise, they provide farmers and action agencies with supportive data for selection of vegetation in drainage ditches used as management practices. PMID- 23732007 TI - Comment on "degradation of organic molecules in advanced oxidation processes: relation between chemical structure and degradability [Chemosphere 91 (2013) 383 389]". PMID- 23732008 TI - Anion exchange of organic carboxylate by soils responsible for positive Km-fc relationship from methanol mixture. AB - The cosolvency model was not applicable for predicting the sorption of organic carboxylic acids. The reason of inapplicability was investigated by analyzing the solubility (Sm) and sorption (Km) of benzoic acid, 2,4-dichlorophenoxyacetic acid (2,4-D), and 2,4,6-trichlorophenol (2,4,6-TCP). The Sm and Km by two iron-rich soils was measured as a function of methanol volume fraction (fc), electrolyte compositions, and pH(app). For 2,4,6-TCP, the Km of both neutral and anion species was well-explainable by the cosolvency model, exemplifying the knowledge of cosolvency power (sigma) being sufficient to describe its sorption. However, for benzoic acid and 2,4-D, the Km of organic anions increased with fc, illustrating the organic carboxylate to be responsible for the deviation. The Sm of organic anions was not affected by the ionic valence (Ca(2+) vs. K(+)) of liquid phase. Among hydrophilic quantities of the 2,4-D sorption, the fraction of anion exchange increased with fc while the fraction of Ca-bridge decreased in the same range. Adding solvent in soil-water system is likely to render soil surface charge more positive, fortifying the anion exchange, but opposing the formation of Ca-bridging. Therefore, it can be concluded that the positive Km-fc relationship is due to the anion exchange of organic carboxylate with positively charged soil surface, whose contribution is >50% of overall sorption at solvent free system and becomes greater with fc up to 82%. PMID- 23732009 TI - The impact of size on the fate and toxicity of nanoparticulate silver in aquatic systems. AB - The increased use of silver nanomaterials presents a risk to aquatic systems due to the high toxicity of silver. The stability, dissolution rates and toxicity of citrate- and polyvinylpyrrolidone-coated silver nanoparticles (AgNPs) were investigated in synthetic freshwater and natural seawater media, with the effects of natural organic matter investigated in freshwater. When sterically stabilised by the large PVP molecules, AgNPs were more stable than when charge-stabilised using citrate, and were even relatively stable in seawater. In freshwater and seawater, citrate-coated AgNPs (Ag-Cit) had a faster rate of dissolution than PVP coated AgNPs (Ag-PVP), while micron-sized silver exhibited the slowest dissolution rate. However, similar dissolved silver was measured for both AgNPs after 72h in freshwater (500-600MUgL(-1)) and seawater (1300-1500MUgL(-1)), with higher concentrations in seawater attributed to chloride complexation. When determined on a mass basis, the 72-h IC50 (inhibitory concentration giving 50% reduction in algal growth rate) for Pseudokirchneriella subcapitata and Phaeodactylum tricornutum and the 48-h LC50 for Ceriodaphnia dubia exposure to Ag(+) (1.1, 400 and 0.11MUgL(-1), respectively), Ag-Cit (3.0, 2380 and 0.15MUgL( 1), respectively) and Ag-PVP (19.5, 3690 and 2.0MUgL(-1), respectively) varied widely, with toxicity in the order Ag(+)>Ag-Cit>Ag-PVP. Micron-sized silver treatments elicited much lower toxicity than ionic Ag(+) or AgNP to P. subcapitata. However, when related to the dissolved silver released from the nanoparticles the toxicities were similar to ionic silver treatments. The presence of natural organic matter stabilised the particles and reduced toxicity in freshwater. These results indicate that dissolved silver was responsible for the toxicity and highlight the need to account for matrix components such as chloride and organic matter in natural waters that influence AgNP fate and mitigate toxicity. PMID- 23732010 TI - (1)H NMR-based metabolomics investigation of Daphnia magna responses to sub lethal exposure to arsenic, copper and lithium. AB - Metal and metalloid contamination constitutes a major concern in aquatic ecosystems. Thus it is important to find rapid and reliable indicators of metal stress to aquatic organisms. In this study, we tested the use of (1)H nuclear magnetic resonance (NMR) - based metabolomics to examine the response of Daphnia magna neonates after a 48h exposure to sub-lethal concentrations of arsenic (49MUgL(-1)), copper (12.4MUgL(-1)) or lithium (1150MUgL(-1)). Metabolomic responses for all conditions were compared to a control using principal component analysis (PCA) and metabolites that contributed to the variation between the exposures and the control condition were identified and quantified. The PCA showed that copper and lithium exposures result in statistically significant metabolite variations from the control. Contributing to this variation was a number of amino acids such as: phenylalanine, leucine, lysine, glutamine, glycine, alanine, methionine and glutamine as well as the nucleobase uracil and osmolyte glycerophosphocholine. The similarities in metabolome changes suggest that lithium has an analogous mode of toxicity to that of copper, and may be impairing energy production and ionoregulation. The PCA also showed that arsenic exposure resulted in a metabolic shift in comparison to the control population but this change was not statistically significant. However, significant changes in specific metabolites such as alanine and lysine were observed, suggesting that energy metabolism is indeed disrupted. This research demonstrates that (1)H NMR based metabolomics is a viable platform for discerning metabolomic changes and mode of toxicity of D. magna in response to metal stressors in the environment. PMID- 23732011 TI - Partition, sorption and structure activity relation study of dialkoxybenzenes that modulate insect behavior. AB - Some dialkoxybenzenes are promising new insect control agents. These compounds mimic naturally occurring odorants that modulate insect behavior. Before applying these compounds, however, their persistence and biodegradability at the application site and in the environment should be understood. The fate of organic compounds in the environment is a complex phenomenon which is influenced by many processes such as sorption to soil components, sedimentation, volatilization, and uptake by plants, as well as biotic and abiotic chemical degradation. In this study, the octanol-water partition coefficient, volatility and sorption on soil components (sand, clay and organic matter) of selected dialkoxybenzenes as well as structure activity relationships with regard to partition, volatility and sorption were investigated. Additionally, calculations of partition, molar volume and molecular surface areas were done, to understand structure-activity relationships of the physical properties. PMID- 23732012 TI - Patients' experiences of supportive care from a long-term perspective after oesophageal cancer surgery - a focus group study. AB - After oesophageal cancer surgery quality of life (QOL) is severely reduced for a long time. Even though this is a well-documented fact no previous studies have focused on the patients' experiences of supportive care after surgery. PURPOSE: To illuminate patients' experiences of supportive care from a long-term perspective after oesophagectomy or oesophagogastrectomy for cancer. METHOD: Data collection was carried out using semi-structured focus-group interviews. Seventeen patients were included in the study, divided into 4 focus groups. Data was analysed with conventional qualitative content analysis. RESULTS: The patients' experiences of supportive care were captured in the theme "The need for a guiding light in the new life situation" and it was shown that support from the healthcare system as well as from the social network was experienced as important. The patients need support that starts at the hospital and that continues throughout the transition to out-patient care. This support should focus on developing a plan for the future and on providing the patients with information that will enable them to understand their new life situation. CONCLUSION: The findings indicated that the patients need a plan for the future, help in navigating the healthcare system and the provision of clear and honest information as well as a healthcare system that better overarches the gap between in and out-patient care. This suggests the need of developing and testing a supportive care programme that is designed according to the patients' needs and with focus on the potential to enhance the patients QOL after this life-changing surgery. PMID- 23732013 TI - The Patients Concerns Inventory in head and neck cancer: comparison between self completed paper and touch screen versions in the clinic setting. AB - BACKGROUND: The Patients Concerns Inventory (PCI) is a practical tool for patients to highlight their concerns and needs for discussion in consultations. OBJECTIVE: To use paper and touch-screen technology (TST) versions of the PCI, to see if there were differences in issues raised by patients before consultation and in issues discussed during consultation. METHODS: Two consultants participated. Also 105 of their post-operative head and neck cancer patients in 122 consultations completed paper or TST versions of the PCI before consultation, April 2010 to April 2012. RESULTS: There were no statistically significant differences between paper and TST in how many PCI concerns were selected by patients or discussed in consultation, nor in length of consultation. Fear of recurrence, chewing/eating, dental health, swallowing, salivation, head & neck pain, speech and sleeping issues were common concerns across both paper and TST. Fewer than 10% of patients encountered any problems when completing either form of PCI. Interestingly, the two consultants used the PCI differently, reflected in different levels of agreement between items highlighted on the PCI and items subsequently discussed - kappaappa-coefficients of agreement were 0.68 for the paper and 0.66 for the TST version of the PCI (consultant A) and 0.55 for the paper and 0.32 for the TST version of the PCI (consultant B). CONCLUSIONS: This study found that the paper version of the PCI was an acceptable alternative to the TST version. PMID- 23732014 TI - Exploring the relationship between coping, social support and health-related quality of life for prostate cancer survivors: a review of the literature. AB - OBJECTIVE: Men affected by prostate cancer can experience profound physical and psychological sequalae; and unmet support needs are prevalent in men affected by this disease. Social support has been linked to improved health-related quality of life (HRQoL) and coping strategies, but little is known about the relationship between social support, coping and HRQoL for prostate cancer survivors. This review aims to identify the mechanism through which social support influences the relationship between coping and HRQoL for prostate cancer survivors. METHODS: A literature review was conducted from the earliest date available to January 2013. Medline, CINAHL, PsycInfo, and ASSIA databases were searched using terms relevant to coping, social support and prostate cancer. Studies that explored the relationship between coping, social support and HRQoL were included. RESULTS: 175 studies were assessed for potential inclusion with 11 publications included in this review. Studies predominately reported main effects of perceived social support on HRQoL, and few studies assessed moderation and mediation effects of coping and social support on HRQoL. Perceived social support was frequently assessed, but few studies evaluated the effects of received social support or satisfaction with social support on HRQoL. CONCLUSIONS: The evidence base is under-developed at present. Future research should use a multidimensional inventory of the social support constructs to examine how each of the constructs influences the relationship between coping and HRQoL over time. This may facilitate the development of appropriately targeted social support interventions that are theoretically driven to address the unmet support needs of prostate cancer survivors. PMID- 23732015 TI - The Cognitive Biases Questionnaire for Psychosis (CBQ-P) and the Davos Assessment of Cognitive Biases (DACOBS): validation in a Flemish sample of psychotic patients and healthy controls. AB - OBJECTIVE: A large body of research has demonstrated the importance of cognitive biases in the development and maintenance of psychosis. Self-report scales for routine clinical practice have been developed only recently. Two new instruments on cognitive biases are evaluated: the Cognitive Biases Questionnaire for Psychosis and the Davos Assessment of Cognitive Biases Scale. METHODS: In a Flemish sample of 98 patients diagnosed with schizophrenia and 152 healthy controls, we investigated (1) the factor structure, (2) the reliability (internal consistency), (3) the discriminative power and (4) the convergent validity of the Dutch CBQ-P and the DACOBS. RESULTS: Using Confirmatory Factor Analysis, a 1 factor solution provided the best fit for the CBQ-P, and a 3-factor solution for the DACOBS. The CBQ-P Total Scale and the three scales of the DACOBS showed good internal consistencies. The CBQ-P Total Scale and all three DACOBS subscales were able to differentiate between healthy controls and patients diagnosed with schizophrenia, when controlling for age and years of education. The CBQ-P and DACOBS scales showed moderate correlations, confirming the convergent validity of both scales. CONCLUSIONS: The CPQ-P and DACOBS appear to be psychometrical sound instruments to assess general thinking bias in psychosis within a Flemish population. Implications for future research are discussed. PMID- 23732016 TI - A two-factor structure of first rank symptoms in patients with a psychotic disorder. AB - Kurt Schneider defined 'first rank symptoms' (FRS) of psychosis. Previous research found two clusters of FRS: 'loss of ego bound' symptoms (e.g., delusions of external control) and auditory hallucinations (e.g, commenting voices). In patients with a psychosis we investigated whether FRS are a separate cluster within the group of positive symptoms, consisting of two underlying factors that are stable over time. We conducted a principal axis factor analysis (PAF) at baseline (n = 857) and a confirmative factor analysis (CFA) at three-year follow up (n = 414) on (FRS) symptom score. Also, we investigated the stability of the two-factor structure of FRS over the interval. PAF on 16 items representing positive symptoms at baseline revealed two factors with eigenvalues > 1. FRS delusional self experience (thought withdrawal, thought broadcasting, thought insertion, and beliefs that impulses and/or actions are controlled by an outside force) clustered in one factor and FRS-auditory hallucinations (auditory hallucinations, conversational voices, and voices commenting on one's actions) in the second factor. Furthermore, CFA on the FRS-items at follow-up confirmed the two-factor structure of FRS. FRS delusional self experience and FRS-auditory hallucinations at baseline were significantly associated with the same factors at three-year follow-up (FRS-delusional self experience: r = 0.38; FRS-auditory hallucinations r = 0.47). Hence, our findings confirm a two-factor structure of first rank symptoms, i.e. FRS-delusional self experience and FRS-auditory hallucinations, with a moderate to large internal coherence within each factor and relative stability over time. Future studies on self-processes may contribute to our understanding of the pathophysiology of first rank symptoms. PMID- 23732017 TI - Social and neuro-cognition as distinct cognitive factors in schizophrenia: a systematic review. AB - Social cognition (SC) and neuro-cognition (NC) have emerged as predictors of functional outcome and possible endophenotype-markers in schizophrenia. The distinctiveness of these two domains is not well established. Factor analysis is used to identify distinct cognitive dimensions. This paper aims to systematically review studies reporting factor analysis of SC and NC in schizophrenia to provide empirical evidence for (a) distinctiveness of SC and NC; and (b) factor structure of SC. The review comprised 20 studies. Most of the studies were cross-sectional, involving variably defined 'stable' schizophrenia patients, using objective assessments of SC and NC. A quality check on reporting practices of factor analytic studies showed important deficiencies in reporting both exploratory and confirmatory factor analyses. There was fairly consistent evidence for the existence of distinct SC and NC factors, with eight out of nine studies supporting this separateness of the two cognitive dimensions. The results were inconsistent regarding factor structure of SC. Unitary, binary and multi factorial constructs were reported, possibly due to variability and lack of comprehensiveness of the SC measures used. This review highlights distinctiveness of SC and NC dimensions in schizophrenia. It thus provides construct validity for cognition in schizophrenia and offers clues regarding the potential neural processes underlying these cognitive dimensions. Future studies exploring the factor structure of SC should be guided by more careful theoretical work and use comprehensive measures of SC in large homogeneous samples of schizophrenia patients. PMID- 23732018 TI - Human corneal epithelial subpopulations: oxygen dependent ex vivo expansion and transcriptional profiling. AB - Corneal epithelium is being regenerated throughout life by limbal epithelial stem cells (LESCs) believed to be located in histologically defined stem cell niches in corneal limbus. Defective or dysfunctional LESCs result in limbal stem cell deficiency (LSCD) causing pain and decreased visual acuity. Since the first successful treatment of LSCD by transplantation of ex vivo expanded LESCs in 1997, many attempts have been carried out to optimize culture conditions to improve the outcome of surgery. To date, progress in this field of bioengineering is substantially hindered by both the lack of specific biomarkers of LESCs and the lack of a precise molecular characterization of in situ epithelial subpopulations. The aim of this dissertation was to optimize culture systems with regard to the environmental oxygen concentration for selective ex vivo expansion of LESCs and to analyse in situ subpopulations in human corneal epithelium using a combination of laser capture microdissection and RNA sequencing for global transcriptomic profiling. We compared dissociation cultures, using either expansion on gamma-irradiated NIH/3T3 feeder cells in serum-rich medium or expansion directly on plastic in serum-free EpiLife medium, using a range of physiologically relevant oxygen concentrations (2%, 5%, 10%, 15% and 20%). Using immunocytochemistry and advanced fluorescence microscopy, cells were characterized regarding growth, cell cycle distribution, colony-forming efficiency (CFE), phenotypes and cytomorphometry. Limbal epithelial cells expanded in 2% O2 exhibited slow growth, low fraction of cells in S/G2 , high CFE, high expression of stem cell markers ABCG2 and p63alpha, and low fraction of differentiation marker CK3 resembling a LESC phenotype. The effect of hypoxia to maintain LESCs in culture was not dependent on the system used for propagation (Bath et al. 2013a). Laser capture microdissection was used to isolate cellular subpopulations in situ from the spatially defined differentiation pathway in human corneal epithelium according to an optimized protocol for maintenance of expression profiles. Isolated total RNA from basal limbal crypts (BLCs), superficial limbal crypts (SLCs), paracentral/central cornea and limbal stroma was amplified and converted to fragmented cDNA libraries for use in deep paired end next-generation sequencing. Global transcriptional profiling was carried out using bioinformatics. The location of primitive cells in BLCs, migratory and activated cells in SLCs and differentiated cells in paracentral/central cornea was evident from mapping of significantly upregulated genes in each compartment to the gene ontology (GO). Interestingly, many GO terms in BLCs were also involved in neurogenic processes, whereas many GO terms in SLCs were related to vasculature. Mapping upregulated genes in BLCs to pathway annotations in Kyoto Encyclopedia of Genes and Genomes described many active pathways as signalling and cancer-associated pathways. We supply extensive information on possible novel biomarkers, reveal insight into both active pathways and novel regulators of LESCs such as Lrig1 and SOX9 and provide an immense amount of data for future exploration (Bath et al. 2013b). Selective ex vivo expansion of LESCs in hypoxia and the comprehensive molecular characterization of corneal epithelial subpopulations in situ are expected to be beneficial for the future treatment of LSCD by cultured limbal epithelial transplantation. PMID- 23732019 TI - End stage renal disease in six patients with beta-thalassemia intermedia. PMID- 23732020 TI - Lymphangioma circumscriptum of the tongue in children: successful treatment using intralesional bleomycin. AB - Lymphangioma circumscriptum is an uncommon congenital skin disorder occurring commonly in limbs and genitals, and is extremely rare in tongue. Although complete surgical excision is the most widely used treatment, more conservative procedures such as sclerotherapy are being increasingly used for treatment of lymphangiomas. We present a series of two cases of lymphangioma circumscriptum of tongue which were treated successfully with intralesional bleomycin injection. PMID- 23732021 TI - Usefulness of desaturation index for the assessment of obstructive sleep apnea syndrome in children. AB - OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) can result in learning, behavioral, and even growth problems in children. Overnight polysomnography (PSG) is the gold standard for the diagnosis of OSAS, but this diagnostic technique is time consuming and inconvenient. It is well documented that patients with OSAS experience oxygen desaturation during sleep. The purpose of this study was to determine if the level of oxygen desaturation can be used to predict OSAS in children. METHODS: This retrospective study included 148 children aged from 3 to 12 years; all were snorers and were suspected of having OSAS. Objective PSG parameters, nocturnal pulse oximeter data and subjective modified Epworth Sleepiness Scale (ESS) scores were assessed. Mild, moderate, and severe OSAS was classified as apnea-hypopnea index (AHI)>=1 and <5, AHI>=5 and <10, and AHI>=10, respectively. RESULTS: Of the 148 children, 130 (87.8%) were diagnosed with OSAS. There was no correlation between the AHI and the modified ESS score (r = -0.048, p = 0.563). The desaturation index (DI) had the highest correlation with AHI (r = 0.886, p < 0.001). Using the DI cut-off values of 2.05 to predict OSAS in children had good positive predictive value of 98.1%. The optimal DI cut-off values for predicting the occurrence of mild, moderate, and severe OSAS were 2.05 (sensitivity: 77.7%; specificity: 88.9%), 3.50 (sensitivity: 83.8%; specificity: 86.5%) and 4.15 (sensitivity: 89.1%; specificity: 86.0%), respectively. CONCLUSIONS: These findings suggest that DI, as determined using a nocturnal pulse oximeter, may be a good tool for predicting both the presence and the severity of OSAS in children. PMID- 23732022 TI - Juvenile nasopharyngeal angiofibroma: Timisoara ENT Department's experience. AB - Juvenile nasopharyngeal angiofibroma is a histologically benign, but very aggressive and destructive tumor found exclusively in young males. The management of juvenile nasopharyngeal angiofibroma has changed in recent years, but it still continues to be a challenge for the multidisciplinary head and neck surgical team. OBJECTIVE: The purpose of this study was to review a series of 30 patients describing the treatment approach used and studying the outcome of juvenile nasopharyngeal angiofibroma in the ENT Department Timisoara, Romania for a period of 30 years. METHODS: The patients were diagnosed and treated during the years 1981-2011. All patients were male. Tumors were classified using Radkowski's staging system. Computed tomography and magnetic resonance imaging allowed for accurate diagnosis and staging of the tumors. Biopsies were not performed. Surgery represented the gold standard for treatment of juvenine nasopharyngeal angiofibroma. All patients had the tumor removed by an external approach, endoscopic surgical approach not being employed in this series of patients. RESULTS: All patients were treated surgically. Surgical techniques performed were: Denker-Rouge technique in 13 cases (43.33%), paralateronasal technique in 7 cases (23.33%), retropalatine technique in 5 cases (16.66%) and transpalatine technique in 5 cases (16.66%). No preoperative tumor embolization was performed. The recurrence rate was 16.66%. The follow-up period ranged from 1 year to 12 years. CONCLUSIONS: Management of juvenile nasopharyngeal angiofibroma remains a surgical challenge. Clinical evaluation and surgical experience are very important in selecting the proper approach. A multidisciplinary team, with an experienced surgeon and good collaboration with the anesthesiologist are needed for successful surgical treatment. PMID- 23732023 TI - The natural history of cervical human papillomavirus infections and cervical cancer: gaps in knowledge and future horizons. AB - Genital human papillomavirus (HPV) infection is the most common sexually transmitted infection. Most HPV infections are benign and resolve on their own, but some women develop persistent HPV infections. Persistent HPV infection with certain high-risk HPV genotypes is the necessary cause of most epithelial lesions of the uterine cervix. The importance of latent or quiescent HPV, waning immunity, hormonal milieu, microbiota, and other factors modifying the natural history of HPV infections across a woman's lifetime deserves further study. Promising biomarkers are emerging that may aid in defining which HPV-infected women are at risk of developing invasive cervical cancer. PMID- 23732025 TI - The modern cytology laboratory: moving beyond the Pap test. AB - New recommendations for screening intervals across different age groups is leading to a diminished role for the cytology laboratory and an increased role for the human papillomavirus (HPV) testing laboratory. With the introduction of the liquid-based Papanicolaou test, high-risk HPV testing, and computer-assisted screening, the cytology laboratory is at the forefront of efforts to improve screening for the provision of better patient care. Cytology laboratories are ideally positioned to facilitate important basic and applied research involving cervical cancer. PMID- 23732024 TI - Human papillomavirus vaccination: current indications and future directions. AB - Human papillomavirus (HPV) is one of the most common sexually transmitted infections affecting both men and women worldwide. The development of the prophylactic HPV vaccines is a significant pharmaceutical innovation with potential to reduce HPV-related morbidity. However, barriers to the universal use and acceptability of the HPV vaccines continue to exist in both economically privileged and disadvantaged countries. It may be decades before the impact of preventive vaccines on HPV-related diseases caused by the considerable burden of HPV infections will be seen. Collaborative efforts must continue to promote vaccine implementation. PMID- 23732026 TI - New cervical cancer screening guidelines, again. AB - Guidelines for cervical cancer screening have continued to evolve as we have accumulated new information about the pathogenesis of cervical cancer and the role of the human papilloma virus. Most recently, the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology issued revised joint recommendations for the prevention and early detection of cervical cancer. In addition, the US Preventative Services Task Force revised its guidelines, and the American College of Obstetricians and Gynecologists updated its practice bulletin. PMID- 23732027 TI - The Lower Anogenital Squamous Terminology Project and its implications for clinical care. AB - Based on a growing need for unified terminology to describe the pathologic and clinical spectrum of lesions, the American Society for Colposcopy and Cervical Pathology and the College of American Pathologists Pathology and Laboratory Quality Center convened the Lower Anogenital Squamous Terminology (LAST) Project to reassess and harmonize the terminology used to describe human papillomavirus associated squamous lesions of the lower anogenital tract as manifested in a variety of end organs. The distinction between cancer precursors and those without malignant potential leads to consistency in the interpretation of management guidelines and the therapeutic options. PMID- 23732028 TI - Colposcopy: a global perspective: introduction of the new IFCPC colposcopy terminology. AB - This article describes the current nomenclature of colposcopic findings in the lower genital tract as defined by the International Federation for Cervical Pathology and Colposcopy (IFCPC) and agreed at their Triennial General Meeting in July 2012 in Rio de Janeiro. It builds on previous nomenclature published by the IFCPC over the last two decades and introduces for the first time the concept of transformation zone excision types. Vulval and vaginal colposcopic terminology is described. PMID- 23732029 TI - Cervical cancer prevention: new guidelines in the United States and new opportunities for low- and middle-income countries. AB - Developments from late 2011 to early 2013, including consensus conferences and the introduction of low-cost, rapid-turnaround testing of human papillomavirus, will change prevention strategies for cervical cancer in the United States and in low- and middle-income countries. PMID- 23732031 TI - Cervical cancer screening in pregnancy. AB - Cervical cancer is the most commonly diagnosed malignancy during pregnancy with an incidence of 1.5 to 12 per 100,000 pregnancies. In the United States between 2% and 7% of all pregnant women will have an abnormal Pap test. The management of these abnormal results during pregnancy can present a challenge to the practitioner. This article reviews recently published guidelines and current evidence for evaluation and management of abnormal cervical cytology and cervical cancer in pregnancy. PMID- 23732030 TI - Screening adolescents and young women. AB - Recent guidelines from multiple organizations stress screening initiation no earlier than the age of 21 years and increased screening intervals for women aged 21 to 29 years. Primary prevention with human papillomavirus vaccination has the potential to significantly affect the development of high-grade cervical lesions, including cancer, and will likely affect screening guidelines in the future. PMID- 23732032 TI - LSIL: definition and management. AB - The management of low-grade squamous intraepithelial lesions (LSIL) has changed greatly over the past 2 decades. The most recent recommendations propose avoiding treatment while continuing to monitor patients for clearance of disease or a change to a more severe diagnosis. Knowledge of the correct way to manage LSIL is important because LSIL is a relatively common diagnosis found on cervical cytology. Especially since the introduction of liquid-based cytology, the diagnosis of LSIL has become more frequent. The College of American Pathologists estimated in 2003 that the reporting rate for LSIL was 2.9%. PMID- 23732033 TI - Treatment options for high-grade squamous intraepithelial lesions. AB - The introduction of testing for high-risk HPV types and P16 immunostaining of CIN2 histologic specimens allows for determination of the risk of progression versus regression for a woman with a particular cytologic or histologic specimen. Observation with serial cytological or colposcopic examinations is now appropriate for women with low-grade histologic lesions as well as pregnant and young women with certain high-grade histologic lesions. Current recommendations for management of high-grade lesions, the efficacy of treatment options (cryotherapy and LEEP), and the immediate (bleeding, infection) and longer term complications (cervical incompetence, preterm delivery) of cervical dysplasia treatment are presented. PMID- 23732034 TI - Nongenital human papillomavirus disease. AB - Human papillomavirus (HPV) is the most common viral cause of cancer, and is responsible for 5% of cancers worldwide. Following demonstration of the causative link between HPV and cervical cancer, HPV has been shown to be associated with several anogenital malignancies and with oral pharyngeal cancers. HPV-related anal and oral pharyngeal disease is rising in incidence and includes anal warts and neoplasia, recurrent respiratory papillomatosis, and oral pharyngeal neoplasia. This article presents an overview of the epidemiology, clinical manifestations, diagnosis, and treatment of nongenital HPV-related disease. PMID- 23732035 TI - Cervical cancer screening in immunocompromised women. AB - Human papillomavirus (HPV) is a sexually transmitted virus that is associated with increased risk of anogenital cancers in immunosuppressed hosts. The behavior of HPV infection is controlled by the systemic immune system response as well as the local tissue immune system to the HPV virus. Individuals with a depressed immune system, either by viral infection (such as human immunodeficiency virus) or by chronic immunosuppressive agents (such as transplant recipients or patients with autoimmune disease) are at an increased risk of HPV-associated malignancies. This article addresses the data and limitations in developing evidence-driven guidelines for cervical cancer screening in immunocompromised women. PMID- 23732036 TI - Vulvar and vaginal HPV disease. AB - Human papilloma virus is associated with a multitude of lower genital tract diseases in women in addition to cervical cancer, including genital warts, vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia, and some vulvar, vaginal, and anal cancers that are associated with oncogenic subtypes. The degree to which HPV manifests pathology depends on viral type, host immune response, and local environmental factors. This article reviews the evaluation and management of the following vulvar and vaginal human papilloma virus diseases: condyloma, vulvar intraepithelial neoplasia, and vaginal intraepithelial neoplasia. Included is a brief discussion of the association with vulvar and vaginal cancer. PMID- 23732037 TI - Human papillomavirus testing in cervical cancer screening. AB - Human papillomavirus (HPV) testing is more reliable and sensitive but less specific than Papanicolaou (Pap) testing/cervical cytology for the detection of cervical precancer and cancer. HPV-negative women are at lower risk of cervical cancer than Pap-negative women. In high-resource settings, HPV testing can be used to make cervical cancer prevention programs more efficient by focusing clinical attention on women who have HPV. In lower-resource settings, where Pap testing has not been sustained or widespread, new, lower-cost HPV tests may make cervical cancer screening feasible. PMID- 23732038 TI - Counseling the patient with HPV disease. AB - This article reviews common clinical scenarios involving human papillomavirus (HPV) infections. The diagnosis, evaluation, and treatment of HPV disease can provoke anxiety and distress, and have a negative psychosocial impact on patients' lives. The article provides a platform on which the clinician can build counseling strategies. It is paramount to relay accurate, timely, and clear information in a reassuring manner. Emphasis is placed on encouraging patients to adopt healthy and protective measures, such as lifestyle changes, testing for other sexually transmitted diseases, compliance with surveillance and screening visits, and vaccination against HPV in age-appropriate individuals. PMID- 23732039 TI - Obstetrics and Gynecology Clinics of North America. HPV, colposcopy, and prevention of squamous anogenital tract malignancy. Foreword. PMID- 23732040 TI - Obstetrics and Gynecology Clinics of North America. HPV, colposcopy, and prevention of squamous anogenital tract malignancy. Preface. PMID- 23732041 TI - Deep C diving: mapping the low-abundance modifications of the DNA demethylation pathway. AB - Two new studies imply that the reprogramming of 5-methylcytosine via TET- and TDG family enzymes is both widespread throughout the genome and functionally significant. PMID- 23732042 TI - Nerve-sparing subcapsular resection of head and neck schwannomas: technique evaluation and literature review. AB - BACKGROUND: The head and neck region harbours crucial structures and hence the surgical technique used to remove schwannomas from this region should cause minimal damage to these structures, with complete removal of pathology. METHODS: This study entailed a retrospective analysis of 10 patients with head and neck schwannomas that were excised using a nerve-sparing subcapsular dissection technique. The primary aims were to assess the functional impact of the surgical technique on the structure of origin and to evaluate local control. RESULTS: One patient with parapharyngeal schwannoma developed symptoms suggestive of 'first bite syndrome' in the late post-operative period. Another patient with facial nerve schwannoma had House-Brackmann grade II weakness in the immediate post operative period, which subsequently resolved. None of the patients developed recurrence during a median follow-up period of two years. CONCLUSION: The nerve sparing subcapsular dissection technique provided effective local control of tumour pathology, with relative preservation of neural function post-operatively. PMID- 23732043 TI - Factors affecting antiretroviral pharmacokinetics in HIV-infected women with virologic suppression on combination antiretroviral therapy: a cross-sectional study. AB - BACKGROUND: Although some studies show higher antiretroviral concentrations in women compared to men, data are limited. We conducted a cross-sectional study of HIV-positive women to determine if protease inhibitor (PI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) C(min) and Cmax values were significantly different than historical general population (predominantly male) averages and to evaluate correlates of higher concentrations. METHODS: HIV-positive women with virologic suppression (viral load < 50copies/mL) on their first antiretroviral regimen were enrolled. Timed blood samples for C(min) and Cmax were drawn weekly for 3 weeks. The ratio of each individual's median C(min) and Cmax to the published population mean values for their PI or NNRTI was calculated and assessed using Wilcoxon sign-rank. Intra- and inter-patient variability of antiretroviral drug levels was assessed using coefficient of variation and intra class correlation. Linear regression was used to identify correlates of the square root-transformed C(min) and Cmax ratios. RESULTS: Data from 82 women were analyzed. Their median age was 41 years (IQR=36-48) and duration of antiretrovirals was 20 months (IQR=9-45). Median antiretroviral C(min) and Cmax ratios were 1.21 (IQR=0.72-1.89, p=0.003) (highest ratios for nevirapine and lopinavir) and 0.82 (IQR=0.59-1.14, p=0.004), respectively. Nevirapine and efavirenz showed the least and unboosted atazanavir showed the most intra- and inter-patient variability. Higher CD4+ count correlated with higher C(min). No significant correlates for Cmax were found. CONCLUSIONS: Compared to historical control data, C(min) in the women enrolled was significantly higher whereas Cmax was significantly lower. Antiretroviral C(min) ratios were highly variable within and between participants. There were no clinically relevant correlates of drug concentrations. TRIAL REGISTRATION: NCT00433979. PMID- 23732044 TI - LINE-1 and Alu retrotransposition exhibit clonal variation. AB - BACKGROUND: The non-long terminal repeat (non-LTR) retrotransposons, long interspersed element-1 (LINE-1) and Alu are currently active retroelements in humans. We, and others, have observed that different populations of HeLa cells from different laboratories support retrotransposition of LINE-1 and Alu to varying degrees. We therefore tested whether individual cell clones of HeLa and HCT116 cell lines supported different levels of LINE-1 and Alu retrotransposition, and whether these variations were stable upon re-cloning. FINDINGS: Standard retrotransposition tissue culture assays were used to measure a cell's ability to support LINE-1 and Alu retrotransposition in clonal HeLa and HCT116 cell lines. We observed that both LINE-1 and Alu retrotransposition exhibited clonal variation in HeLa cells, with certain HeLa cell clones supporting high levels of LINE-1 and Alu retrotransposition and other cell clones being essentially retrotransposition-dead. This clonal variation was similarly observed in HCT116 cells, although possibly not to the same extent. These patterns of clonal variation are relatively consistent upon re-cloning. CONCLUSIONS: Observations of the variability of LINE-1 and Alu retrotransposition in different populations of the same cell line are supported by our results that indicate in some cell types, individual cell clones can have dramatically differing capacity for retrotransposition. The mixed populations of cells commonly used in laboratories have often been passaged for many generations and accumulated significant genetic and epigenetic diversity. Our results suggest that the clonal variability observed by our cloning experiments may lead to a homogenization of retrotransposition capacity, with the resulting mixed population of cells being composed of individual variants having either increased or decreased retrotransposition potential compared to the starting population. PMID- 23732045 TI - [Methicillin-resistant Staphylococus aureus and health-care workers]. PMID- 23732046 TI - Do dietary patterns influence cognitive function in old age? AB - BACKGROUND: Evidence from observational studies to date suggests that healthy dietary patterns are associated with better cognitive performance in later life. We examined the extent to which childhood intelligence quotient (IQ) and socioeconomic status account for this association. METHODS: Analyses were carried out on 882 participants in the Lothian Birth Cohort 1936 Study. Four dietary patterns were extracted using principal components analysis of a food frequency questionnaire, namely "Mediterranean-style," "health aware," "traditional," and "sweet foods." Cognitive function was assessed at the age of 70 years, including general (g) cognitive ability, processing speed, memory, and verbal ability. RESULTS: Before adjustment for childhood IQ and socioeconomic status, the "Mediterranean-style" dietary pattern was associated with significantly better cognitive performance (effect size as partial eta-square (etap(2)) range = 0.005 to 0.055), and the "traditional" dietary pattern was associated with poorer performance on all cognitive domains measured in old age (etap(2) = 0.009 to 0.103). After adjustment for childhood IQ (measured at the age of 11 years) and socioeconomic status, statistical significance was lost for most associations, with the exception of verbal ability and the "Mediterranean-style" pattern (National Adult Reading Test (NART) etap(2) = 0.006 and Wechsler Test of Adult Reading (WTAR) etap(2) = 0.013), and the "traditional" pattern (NART etap(2) = 0.035 and WTAR etap(2) = 0.027). CONCLUSIONS: Our results suggest a pattern of reverse causation or confounding; a higher childhood cognitive ability (and adult socioeconomic status) predicts adherence to a "healthy" diet and better cognitive performance in old age. Our models show no direct link between diet and cognitive performance in old age; instead they are related via the lifelong-stable trait of intelligence. PMID- 23732047 TI - Evidence for crossing the blood barrier of adult rat brain by human adipose derived mesenchymal stromal cells during a 6-month period of post transplantation. AB - BACKGROUND AIMS: Therapeutic promises of adult stem cells have been overshadowed by an elicited immune response, low maintenance of implanted cells or concerns regarding their migration to non-target sites. These problems might be lessened by the use of immune privilege cells and tissues for implantation. METHODS: In this study, human adipose-derived mesenchymal stromal cells (hADMSCs) were stably transfected with a vector containing Turbo green fluorescent protein (GFP) and JRed, which allows tracing the cells after transplantation. Labeled hADMSCs were transplanted into the adult rat brain followed by assessment of their survival and migration during 6 months after transplantation. RESULTS: Results indicate that there were no postsurgical complications, and the animals thrived after transplantation. The lesions of the surgical process were remarkable at the first weeks, and a high number of transplanted cells were accumulated around them. Cell populations declined over time as they partly migrated away from the injection sites; nonetheless, they were detectable at each examination time point. Although the cells could survive and remain at the injection site for up to 6 months, some of them drifted to spleen, which is an indication of their ability to cross the blood-brain barrier. CONCLUSIONS: Despite the high survival rate of hADMSCs in the xenogenic condition, which is an ideal criterion in cell therapy, irregular migration tendency must be handled with caution. PMID- 23732048 TI - Modulation of glucose and lipid metabolism by porcine adiponectin receptor 1 transgenic mesenchymal stromal cells in diet-induced obese mice. AB - BACKGROUND AIMS: Obesity and its associated diseases demand better therapeutic strategies. Regenerative medicine combined with gene therapy has emerged as a promising approach in various clinical applications. Adiponectin (ApN) and its receptors have been demonstrated to play beneficial roles in modulating glucose and lipid homeostasis. In the current study, we tested such an approach by transplanting mesenchymal stromal cells (MSCs) from porcine ApN receptor (pAdipoR) 1-transgenic mice into high-fat/sucrose diet (HFSD)-fed mice. METHODS: Twenty 6-week-old Friend virus B/NJNarl male mice were randomly assigned into four groups with the control fed a chow diet (chow) and others HFSD for 10 months. The HFSD groups were then intraperitoneally injected once per week for 8 weeks with placebo (200 MUL phosphate-buffered saline), wild-type MSC (WT-MSC, 2 * 10(6) cells/200 MUL phosphate-buffered saline) or pAdipoR1-transgenic MSC (pR1 tMSC, 2 * 10(6) cells/200 MUL phosphate-buffered saline), respectively. Body weights, blood samples, tissue histology, and gene expression and protein levels of metabolism-associated genes were analyzed. RESULTS: Both WT-MSC and pR1-tMSC transplantations restored the messenger RNA expression of AdipoR1, with those of glucose transporter 4 and 5'-adenosine monophosphate-activated protein kinase catalytic subunit alpha-1 and protein levels of pyruvate kinase induced by pR1 tMSC in the muscles of HFSD-fed mice. In the liver, both WT-MSC and pR1-tMSC ameliorated HFSD-induced hepatosteatosis, with the gene expression of lipoprotein lipase and hormone-sensitive lipase upregulated by the latter. Lastly, pR1-tMSC transplantation reduced fatty acid synthase mRNA levels in the adipose tissues of HFSD-fed mice. CONCLUSIONS: This study demonstrates the modulatory actions of MSC and pR1-tMSC on genes associated with glucose and lipid metabolism and provides insights into its therapeutic application for obesity-associated metabolic complication. PMID- 23732049 TI - Development and validation of a decision tree early warning score based on routine laboratory test results for the discrimination of hospital mortality in emergency medical admissions. AB - AIM OF STUDY: To build an early warning score (EWS) based exclusively on routinely undertaken laboratory tests that might provide early discrimination of in-hospital death and could be easily implemented on paper. MATERIALS AND METHODS: Using a database of combined haematology and biochemistry results for 86,472 discharged adult patients for whom the admission specialty was Medicine, we used decision tree (DT) analysis to generate a laboratory decision tree early warning score (LDT-EWS) for each gender. LDT-EWS was developed for a single set (n=3496) (Q1) and validated in 22 other discrete sets each of three months long (Q2, Q3...Q23) (total n=82,976; range of n=3428 to 4093) by testing its ability to discriminate in-hospital death using the area under the receiver-operating characteristic (AUROC) curve. RESULTS: The data generated slightly different models for male and female patients. The ranges of AUROC values (95% CI) for LDT EWS with in-hospital death as the outcome for the validation sets Q2-Q23 were: 0.755 (0.727-0.783) (Q16) to 0.801 (0.776-0.826) [all patients combined, n=82,976]; 0.744 (0.704-0.784, Q16) to 0.824 (0.792-0.856, Q2) [39,591 males]; and 0.742 (0.707-0.777, Q10) to 0.826 (0.796-0.856, Q12) [43,385 females]. CONCLUSIONS: This study provides evidence that the results of commonly measured laboratory tests collected soon after hospital admission can be represented in a simple, paper-based EWS (LDT-EWS) to discriminate in-hospital mortality. We hypothesise that, with appropriate modification, it might be possible to extend the use of LDT-EWS throughout the patient's hospital stay. PMID- 23732050 TI - Ionic status, calcium uptake, and Ca2+-ATPase activity during early development in the purple sea urchin (Strongylocentrotus purpuratus). AB - Ionic status during early development was investigated in the purple sea urchin. Whole body cation concentrations (Ca(2+), Na(+), K(+), Mg(2+)), unidirectional Ca(2+) uptake rates measured with (45)Ca(2+), Ca(2+)-ATPase activity, and growth were examined at 12h intervals over the first 96h of development. Whole body Ca(2+) concentration was low initially but increased steadily by >15-fold through to the pluteus stage. Whole body Mg(2+), K(+) and Na(+) levels exhibited diverse patterns, but all increased at 72-96h. Ca(2+) uptake rates were low during initial cell cleavages at 12h but increased greatly at blastulation (24h) and then again at gastrulation (48h), declining thereafter in the pluteus stage, but increasing slightly at 96h. Ca(2+)-ATPase activity was initially low but increased at blastulation through gastrulation (24-48h) but declined thereafter in the pluteus stage. Embryonic weights did not change over most of development, but were significantly higher at 96h. Overall, the gastrulation stage displayed the most pronounced changes, as Ca(2+) uptake and accumulation and Ca(2+)-ATPase levels were the highest at this stage, likely involved in mineralization of the spicule. Biomarkers of Ca(2+) metabolism may be good endpoints for potential future toxicity studies. PMID- 23732053 TI - Ethical authorship and the Ingelfinger rule in the digital age. PMID- 23732057 TI - Second reflective band intensity in age-related macular degeneration. PMID- 23732054 TI - Conjunctival thickness measured by optical coherence tomography. PMID- 23732055 TI - An unusual case of epidermal iris cyst. PMID- 23732056 TI - Intraocular pressure in patients with muscular dystrophies. PMID- 23732051 TI - Oral flucloxacillin and phenoxymethylpenicillin versus flucloxacillin alone for the emergency department outpatient treatment of cellulitis: study protocol for a randomised controlled trial. AB - BACKGROUND: Oral flucloxacillin, either alone or in combination with phenoxymethylpenicillin, is a commonly prescribed antibiotic for the treatment of cellulitis, particularly in Ireland and the United Kingdom. This study aims to establish the non-inferiority of oral monotherapy (flucloxacillin alone) to dual therapy (flucloxacillin and phenoxymethylpenicillin) for the outpatient treatment of cellulitis in adults. METHODS/DESIGN: This study is a multicentre, randomised, double-blind, placebo-controlled trial of adults who present to the emergency department (ED) with cellulitis that is deemed treatable on an outpatient basis with oral antibiotics. After fulfilling specified inclusion and exclusion criteria, informed consent will be taken. Patients will be given a treatment pack containing 7 days of treatment with flucloxacillin 500 mg four times daily and placebo or flucloxacillin 500 mg four times daily and phenoxymethylpenicillin 500 mg four times daily. The primary outcome measure under study is the proportion of patients in each group in which there is greater than or equal to a 50% reduction in the area of diameter of infection from the area measured at enrolment at the end-of-treatment visit (7 to 10 days). Secondary endpoints include a health related quality of life measurement as rated by the SF-36 score and the Extremity Soft Tissue Infection Score (not validated), compliance and adverse events. Patients will be followed up by telephone call at 3 days, end-of-treatment visit (EOT) at 7 to 10 days and test-of-cure (TOC) visit at 30 days. To achieve 90% power, a sample size of 172 patients per treatment arm is needed. This assumes a treatment success rate of 85% with oral flucloxacillin and phenoxymethylpenicillin, an equivalence threshold Delta = 12.5% and an alpha = 0.025. Non-inferiority will be assessed using a one-sided confidence interval on the difference of proportions between the two groups. Standard analysis including per-protocol and intention-to-treat will be performed. DISCUSSION: This trial aims to establish the non-inferiority of flucloxacillin monotherapy to dual therapy in the treatment of uncomplicated cellulitis among ED patients. In doing so, this trial will bridge a knowledge gap in this understudied and common condition and will be relevant to clinicians across several different disciplines. PMID- 23732058 TI - MRI in retinoblastoma with orbital cellulitis. PMID- 23732059 TI - Fire risk during ophthalmic plastic surgery. PMID- 23732052 TI - Short telomeres: from dyskeratosis congenita to sporadic aplastic anemia and malignancy. AB - Telomeres are DNA-protein structures that form a protective cap on chromosome ends. As such, they prevent the natural ends of linear chromosomes from being subjected to DNA repair activities that would result in telomere fusion, degradation, or recombination. Both the DNA and protein components of the telomere are required for this essential function, because insufficient telomeric DNA length, loss of the terminal telomeric DNA structure, or deficiency of key telomere-associated factors may elicit a DNA damage response and result in cellular senescence or apoptosis. In the setting of failed checkpoint mechanisms, such DNA-protein defects can also lead to genomic instability through telomere fusions or recombination. Thus, as shown in both model systems and in humans, defects in telomere biology are implicated in cellular and organismal aging as well as in tumorigenesis. Bone marrow failure and malignancy are 2 life threatening disease manifestations in the inherited telomere biology disorder dyskeratosis congenita. We provide an overview of basic telomere structure and maintenance. We outline the telomere biology defects observed in dyskeratosis congenita, focusing on recent discoveries in this field. Last, we review the evidence of how telomere biology may impact sporadic aplastic anemia and the risk for various cancers. PMID- 23732060 TI - Author reply: To PMID 22796308. PMID- 23732061 TI - Oral acyclovir for herpes simplex blepharoconjunctivitis in children. PMID- 23732062 TI - Cataract extraction and the iris configuration. PMID- 23732063 TI - Orbital cerebrospinal fluid space in glaucoma. PMID- 23732064 TI - Predictive value of confocal scanning laser for the onset of visual field loss. PMID- 23732065 TI - Author reply: To PMID 22749084. PMID- 23732066 TI - Recognition of Henle's fiber layer on OCT images. PMID- 23732067 TI - Author reply: To PMID 22584019. PMID- 23732068 TI - Macular hole and choroidal thickness. PMID- 23732069 TI - Brow ptosis after temporal artery biopsy. PMID- 23732070 TI - Author reply: To PMID 22986114. PMID- 23732071 TI - Multiple synostoses syndrome in three members of a family displaying a novel mutation in NOGGIN gene. PMID- 23732072 TI - Conventional vs. micro-fat harvesting: how fat harvesting technique affects tissue-engineering approaches using adipose tissue-derived stem/stromal cells. AB - BACKGROUND: Biocompatible scaffolds as dermal substitutes are used commonly in soft tissue reconstruction and tissue-engineering approaches. The combination of these scaffolds with mesenchymal stem and stromal cells would have additional benefits in multilayer soft tissue reconstruction. In addition, the use of lipoaspirate may be beneficial for this purpose containing high levels of regenerative cells and relevant growth factors. However there are many factors, which may impact the lipoaspirate content of isolated cells, cell behaviour and growth factors. There is a lack of data as to whether fat-harvesting procedures using different cannulas of small diameter will impact these parameters, which are relevant not only for tissue engineering but also for clinical outcome. METHODS: Abdominal liposuctions were performed on 10 patients using the conventional fat harvesting by the Coleman cannula (3 mm, one-hole blunt tip) and the micro-fat-harvesting technique by the st'RIM cannula (2 mm, multi-perforated hole blunt tip) on contralateral area. Lipoaspirate contents of insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) were measured by enzyme-linked immunosorbent assay (ELISA). The in vitro viability of lipoaspirates was tested by the alamarBlueTM assay. Adipose-derived stem/stromal cells (ASCs) were isolated and the yields determined. Furthermore, ACSs were seeded on collagen elastin matrices (MatridermTM) and cell migration/adhesion rate was examined by the alamarBlueTM assay and visualised by two-photon microscopy. RESULTS: Conventionally obtained lipoaspirates were found to contain significantly higher concentrations of IGF and VEGF, but not PDGF or bFGF. No significant effects on the yields of ASCs or the in vitro viability of lipoaspirates obtained from different cannula sizes were observable. However, the viability and migration of isolated ASCs obtained from micro-harvested lipoaspirates were significantly higher. Moreover, a significant high adherence rate of isolated ASCs from the micro-fat-harvesting technique onto matrices was observed. CONCLUSION: The different sizes and surface/volume ratios of pieces of fatty tissue obtained by using different cannula sizes may be responsible for the observed differences and effects. Thus, micro-fat harvesting may be more suitable for tissue-engineering and -regenerative approaches using ASCs and collagen elastin matrices. PMID- 23732074 TI - Care pathways for managing invasive mould diseases. AB - In the last decade, there have been some favourable developments in the management of invasive fungal diseases, including definitions, diagnosis and drugs for treatment. This has led to a gradual awareness that caring for patients at risk need not solely rely on an empirical therapy approach but that a degree of individualisation is possible, provided certain prerequisites are met. PMID- 23732073 TI - Tensor tenopexy: a clinical study to assess its effectiveness in improving Eustachian tube function and preventing hearing loss in patients with cleft palate. AB - There is a consensus about the occurrence of otitis media in children with cleft palate before repair. However, controversy continues regarding the recovery of Eustachian tube function and level of hearing loss in the patients after cleft palate repair. Levator sling palatoplasty is an important component of the cleft repair. Most surgeons would routinely transect the tensor tendon (tensor tenotomy) during the course of palatoplasty. However, this procedure may pose a risk to Eustachian tube function. Some authorities feel that addition of tensor tenopexy during palatoplasty would maintain the Eustachian tube in an open conformation, thereby improving middle ear ventilation. The present study assesses the effectiveness of tensor tenopexy in improving Eustachian tube function and preventing hearing loss in cleft palate patients treated with palatoplasty. A prospective randomised controlled trial was conducted in the Department of Plastic Surgery at a tertiary care institute in India. A total of 17 children in the age group of 9-24 months were assigned to one of two groups: palatoplasty with either tensor tenotomy (n = 8) or tensor tenotomy with tensor tenopexy (n = 9). All patients were subjected to tympanometry, otoscopy and brainstem evoked response audiometry before surgery and at 3, 6, 9 and 12 months after surgery. Of these, 52.9% of patients already had hearing loss at the time of presentation. Hearing loss and middle ear effusion persisted even after palatoplasty. There was no significant difference in hearing loss and middle ear effusion between the two groups of patients. Thus, tensor tenopexy was not found to be helpful in maintaining Eustachian tube function or preventing hearing loss in cleft palate patients. However, further long-term studies are needed to confirm this study. PMID- 23732075 TI - Molecular cloning and tumour suppressor function analysis of canine REIC/Dkk-3 in mammary gland tumours. AB - REIC/Dkk-3, a member of the human Dickkopf (Dkk) family, plays a role as a suppressor of growth in several human cancers. In this study, the tumour suppression function of canine REIC/Dkk-3 was investigated. The full-length open reading frame of the canine REIC/Dkk-3 homologue was cloned and the tissue distribution of REIC/Dkk-3 mRNA was determined, along with the subcellular localisation of the REIC/Dkk-3 protein in canine cancer cell lines. Expression of REIC/Dkk-3 was lower in mammary gland tumours and in canine mammary carcinoma cell lines than in normal mammary gland tissue. Overexpression of REIC/Dkk-3 induced apoptosis in canine mammary carcinoma cell lines. These results show that expression of REIC/Dkk-3 is downregulated in canine mammary tumours and that one of the functions of this gene is induction of apoptosis. PMID- 23732076 TI - The welfare of livestock transported by sea: Australia's experience. PMID- 23732077 TI - Can Theileria equi be eliminated from carrier horses? PMID- 23732079 TI - Physiologically-based pharmacokinetic model for Fentanyl in support of the development of Provisional Advisory Levels. AB - Provisional Advisory Levels (PALs) are tiered exposure limits for toxic chemicals in air and drinking water that are developed to assist in emergency responses. Physiologically-based pharmacokinetic (PBPK) modeling can support this process by enabling extrapolations across doses, and exposure routes, thereby addressing gaps in the available toxicity data. Here, we describe the development of a PBPK model for Fentanyl - a synthetic opioid used clinically for pain management - to support the establishment of PALs. Starting from an existing model for intravenous Fentanyl, we first optimized distribution and clearance parameters using several additional IV datasets. We then calibrated the model using pharmacokinetic data for various formulations, and determined the absorbed fraction, F, and time taken for the absorbed amount to reach 90% of its final value, t90. For aerosolized pulmonary Fentanyl, F=1 and t90<1 min indicating complete and rapid absorption. The F value ranged from 0.35 to 0.74 for oral and various transmucosal routes. Oral Fentanyl was absorbed the slowest (t90~300 min); the absorption of intranasal Fentanyl was relatively rapid (t90~20-40 min); and the various oral transmucosal routes had intermediate absorption rates (t90~160-300 min). Based on these results, for inhalation exposures, we assumed that all of the Fentanyl inhaled from the air during each breath directly, and instantaneously enters the arterial circulation. We present model predictions of Fentanyl blood concentrations in oral and inhalation scenarios relevant for PAL development, and provide an analytical expression that can be used to extrapolate between oral and inhalation routes for the derivation of PALs. PMID- 23732080 TI - Inhibition of inflammatory mediators contributes to the anti-inflammatory activity of KYKZL-1 via MAPK and NF-kappaB pathway. AB - KYKZL-1, a newly synthesized compound with COX/5-LOX dual inhibition, was subjected to the anti-inflammatory activity test focusing on its modulation of inflammatory mediators as well as intracellular MAPK and NF-kappaB signaling pathways. In acute ear edema model, pretreatment with KYKZL-1 (p.o.) dose dependently inhibited the xylene-induced ear edema in mice with a higher inhibition than diclofenac. In a three-day TPA-induced inflammation, KYKZL-1 also showed significant anti-inflammatory activity with inhibition ranging between 20% and 64%. In gastric lesion test, KYKZL-1 elicited markedly fewer stomach lesions with a low index of ulcer as compared to diclofenac in rats. In further studies, KYKZL-1 was found to significantly inhibit the production of NO, PGE2, LTB4 in LPS challenged RAW264.7, which is parallel to its attenuation of the expression of iNOS, COX-2, 5-LOX mRNAs or proteins and inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-kappaB. Taken together, our data indicate that KYKZL-1 comprises dual inhibition of COX and 5-LOX and exerts an obvious anti inflammatory activity with an enhanced gastric safety profile via simultaneous inhibition of phosphorylation of p38 and ERK MAPKs and activation of NF-kappaB. PMID- 23732081 TI - Phycocyanobilin promotes PC12 cell survival and modulates immune and inflammatory genes and oxidative stress markers in acute cerebral hypoperfusion in rats. AB - Since the inflammatory response and oxidative stress are involved in the stroke cascade, we evaluated here the effects of Phycocyanobilin (PCB, the C-Phycocyanin linked tetrapyrrole) on PC12 cell survival, the gene expression and the oxidative status of hypoperfused rat brain. After the permanent bilateral common carotid arteries occlusion (BCCAo), the animals were treated with saline or PCB, taking samples 24h post-surgery. Global gene expression was analyzed with GeneChip Rat Gene ST 1.1 from Affymetrix; the expression of particular genes was assessed by the Fast SYBR Green RT-PCR Master Mix and Bioplex methods; and redox markers (MDA, PP, CAT, SOD) were evaluated spectrophotometrically. The PCB treatment prevented the H2O2 and glutamate induced PC12 cell injury assessed by the MTT assay, and modulated 190 genes (93 up- and 97 down-regulated) associated to several immunological and inflammatory processes in BCCAo rats. Furthermore, PCB positively modulated 19 genes mostly related to a detrimental pro-inflammatory environment and counteracted the oxidative imbalance in the treated BCCAo animals. Our results support the view of an effective influence of PCB on major inflammatory mediators in acute cerebral hypoperfusion. These results suggest that PCB has a potential to be a treatment for ischemic stroke for which further studies are needed. PMID- 23732082 TI - Safety pharmacology--current and emerging concepts. AB - Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds. PMID- 23732083 TI - Disruption of canonical TGFbeta-signaling in murine coronary progenitor cells by low level arsenic. AB - Exposure to arsenic results in several types of cancers as well as heart disease. A major contributor to ischemic heart pathologies is coronary artery disease, however the influences by environmental arsenic in this disease process are not known. Similarly, the impact of toxicants on blood vessel formation and function during development has not been studied. During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types including smooth muscle cells which contribute to the coronary vessels. The TGFbeta family of ligands and receptors is essential for developmental cardiac epithelial to mesenchymal transition (EMT) and differentiation into coronary smooth muscle cells. In this in vitro study, 18hour exposure to 1.34MUM arsenite disrupted developmental EMT programming in murine epicardial cells causing a deficit in cardiac mesenchyme. The expression of EMT genes including TGFbeta2, TGFbeta receptor-3, Snail, and Has-2 are decreased in a dose-dependent manner following exposure to arsenite. TGFbeta2 cell signaling is abrogated as detected by decreases in phosphorylated Smad2/3 when cells are exposed to 1.34MUM arsenite. There is also loss of nuclear accumulation pSmad due to arsenite exposure. These observations coincide with a decrease in vimentin positive mesenchymal cells invading three-dimensional collagen gels. However, arsenite does not block TGFbeta2 mediated smooth muscle cell differentiation by epicardial cells. Overall these results show that arsenic exposure blocks developmental EMT gene programming in murine coronary progenitor cells by disrupting TGFbeta2 signals and Smad activation, and that smooth muscle cell differentiation is refractory to this arsenic toxicity. PMID- 23732087 TI - [Responding to risks: between specialization and systemic integration]. PMID- 23732088 TI - [Role of the nucleus of the solitary tract in the detection and integration of multiple metabolic signals]. PMID- 23732085 TI - Health risks from lead-based ammunition in the environment. PMID- 23732084 TI - The role of renal proximal tubule P450 enzymes in chloroform-induced nephrotoxicity: utility of renal specific P450 reductase knockout mouse models. AB - The kidney is a primary target for numerous toxic compounds. Cytochrome P450 enzymes (P450) are responsible for the metabolic activation of various chemical compounds, and in the kidney are predominantly expressed in proximal tubules. The aim of this study was to test the hypothesis that renal proximal tubular P450s are critical for nephrotoxicity caused by chemicals such as chloroform. We developed two new mouse models, one having proximal tubule-specific deletion of the cytochrome P450 reductase (Cpr) gene (the enzyme required for all microsomal P450 activities), designated proximal tubule-Cpr-null (PTCN), and the other having proximal tubule-specific rescue of CPR activity with the global suppression of CPR activity in all extra-proximal tubular tissues, designated extra-proximal tubule-Cpr-low (XPT-CL). The PTCN, XPT-CL, Cpr-low (CL), and wild type (WT) mice were treated with a single oral dose of chloroform at 200mg/kg. Blood, liver and kidney samples were obtained at 24h after the treatment. Renal toxicity was assessed by measuring BUN and creatinine levels, and by pathological examination. The blood and tissue levels of chloroform were determined. The severity of toxicity was less in PTCN and CL mice, compared with that of WT and XPT-CL mice. There were no significant differences in chloroform levels in the blood, liver, or kidney, between PTCN and WT mice, or between XPT-CL and CL mice. These findings indicate that local P450-dependent activities play an important role in the nephrotoxicity induced by chloroform. Our results also demonstrate the usefulness of these novel mouse models for studies of chemical-induced kidney toxicity. PMID- 23732089 TI - [A molecular machine mimicking the ribosome: a molecule that makes molecules]. PMID- 23732090 TI - [Lipopolysaccharide of Coxiella burnetii controls bacterial phagolysosome degradation]. PMID- 23732091 TI - [Vaccine-like effects of antiviral monoclonal antibodies: a novel therapeutic perspective?]. PMID- 23732092 TI - [miR-199a-5p in idiopathic pulmonary fibrosis]. PMID- 23732093 TI - [Medical perspectives of metabolomics: the example of renal carcinoma]. PMID- 23732094 TI - [Dynamics of red blood cells in shear flow]. PMID- 23732095 TI - [Haemoglobin alpha regulates nitric oxide in endothelial cells]. PMID- 23732096 TI - [Mesolimbic dopaminergic firing and depression]. PMID- 23732097 TI - [The piRNAs forge an immune system for the genome]. AB - Genome integrity of germline is essential for the survival of any species. A dedicated defence mechanism based on small RNA called piRNA (PIWI-interacting RNA) has evolved to protect the germline from the deleterious effects of transposon mobility in genomes such as mutations, deletions or chromosomal rearrangements. The piRNA machinery ensures genomic integrity to germ cells by setting a response similar to the immune system. The recognition of the threat is mediated by sequence complementarity between a vast repertoire of piRNAs and the intruders, and initiates a rapid and efficient degradation of the targets. Akin to acquired immunity, the response is memorized throughout generations thanks to epigenetic modifications. Investigations are progressing to unravel the mysterious mechanisms of this exciting class of non coding RNAs. This review summarizes some of the recent advances on this exceptional immunity that protects transmission of genetic information. PMID- 23732098 TI - [The lipid droplet: a new organelle?]. AB - Lipid droplets (LD) are depots of neutral lipids that exist virtually in all cells. Until recently, they were considered to be in the same category as glycogen granules, simple inert storage sites for energy. There is now increasing evidence that LD interact dynamically with different organelles, probably as means of providing these organelles with lipids for their membrane expansion. However, most of the mechanisms driving LD biogenesis, growth and intracellular movement remain unknown. Recent data suggest that LD remain functionally connected to the endoplasmic reticulum (ER) membrane and represent specialized ER domains rather than independent organelles. Nevertheless, they represent important cellular structures for which dysfunctions may lead to human diseases such as lypodystrophies or neurodegenerative diseases. PMID- 23732099 TI - [Pathology and viral metagenomics, a recent history]. AB - Human, animal and plant viral diseases have greatly benefited from recent metagenomics developments. Viral metagenomics is a culture-independent approach used to investigate the complete viral genetic populations of a sample. During the last decade, metagenomics concepts and techniques that were first used by ecologists progressively spread into the scientific field of viral pathology. The sample, which was first for ecologists a fraction of ecosystem, became for pathologists an organism that hosts millions of microbes and viruses. This new approach, providing without a priori high resolution qualitative and quantitative data on the viral diversity, is now revolutionizing the way pathologists decipher viral diseases. This review describes the very last improvements of the high throughput next generation sequencing methods and discusses the applications of viral metagenomics in viral pathology, including discovery of novel viruses, viral surveillance and diagnostic, large-scale molecular epidemiology, and viral evolution. PMID- 23732100 TI - [P2X4 or P2X7: which of these two receptors is the best target to promote salivation?]. AB - P2X purinergic receptors are receptors which, after ATP binding, form a channel permeant to monovalent and divalent cations. Acinar and ductal cells from salivary glands express P2X4 and P2X7 receptors. The P2X4 receptor has a high affinity for ATP, rapidly desensitizes and is mostly located on the basal membrane of acinar cells. The P2X7 receptor has a very low affinity for ATP. After a sustained activation, the permeability of the channel formed by this receptor increases eventually leading to the death of the cell. This receptor is located mostly on the apical membrane of acinar and ductal cells. It is suggested that the sequential activation of the two receptors contributes to the secretory response to ATP. A low concentration of ATP released by nerve endings transiently activates the P2X4 receptors and promotes the release of secretory granules containing ATP. The local increase of the concentration of the nucleotide at the vicinity of P2X7 receptors accounts for their activation. This further increases the exocytosis. PMID- 23732101 TI - [The glideosome, a unique machinery that assists the Apicomplexa in gliding into host cells]. AB - Protozoan parasites belonging to the phylum Apicomplexa are of considerable medical and veterinary significance. These obligate intracellular parasites use a unique form of locomotion to traverse biological barriers and actively invade in and egress from host cells. An actin-myosin-based complex named "glideosome" drives this unusual substrate-dependent motility, which is essential for the establishment of the infection. The mechanisms involved in motility, invasion and egress are conserved throughout the phylum. This article describes the current knowledge on the invasion process of two experimentally tractable apicomplexan parasites: Toxoplasma gondii and Plasmodium falciparum. PMID- 23732102 TI - [From cannabis to selective CB2R agonists: molecules with numerous therapeutical virtues]. AB - Originally used in Asia for the treatment of pain, spasms, nausea and insomnia, marijuana is the most consumed psychotropic drug worldwide. The interest of medical cannabis has been reconsidered recently, leading to many scientific researches and commercialization of these drugs. Natural and synthetic cannabinoids display beneficial antiemetic, anti-inflammatory and analgesic effects in numerous diseases, however accompanied with undesirable effects due to the CB1 receptor. Present researches focus on the design of therapeutical molecules targeting the CB2 receptors, and thus avoiding central side effects and therefore psychotropic effects caused by the CB1 receptor. PMID- 23732103 TI - [A technological platform for cerebral palsy - the ICT4Rehab project]. AB - The musculoskeletal system (MSS) is essential to allow us performing every-day tasks, being able to have a professional life or developing social interactions with our entourage. MSS pathologies have a significant impact on our daily life. It is therefore not surprising to find MSS-related health problems at the top of global statistics on professional absenteeism or societal health costs. The MSS is also involved in central nervous conditions, such as cerebral palsy (CP). Such conditions show complex etiology that complicates the interpretation of the observable clinical signs and the establishment of a wide consensus on the best practices to adopt for clinical monitoring and patient follow-up. These elements justify the organization of fundamental and applied research projects aiming to develop new methods to help clinicians to cope with the complexity of some MSS disorders. The ICT4Rehab project (www.ict4rehab.org) developed an integrated platform providing tools that enable easier management and visualization of clinical information related to the MSS of CP patients. This platform is opened to every interested clinical centre. PMID- 23732104 TI - [The clinical trials of the rob Laffecteur: a secret remedy of the XVIII(th) century]. PMID- 23732105 TI - [Bisphenol A and hormone-dependent cancers: potential risk and mechanism]. AB - Being concerned by the increasing incidence of breast, prostate and testicular cancers, we overviewed the literature on the potential carcinogenic effect of endocrine disruptors (ED). It is extremely difficult to obtain the epidemiological proof of a carcinogenic effect of one ED in human for multi factorial diseases and the high number of confusing factors. However, many experimental studies in rodents on bis-phenol A (BPA) and its assay in human blood and urine, strongly suggest that BPA might increase the risk of hormone dependant cancers. Contrary to the mitogenic effect of estradiol, directly mediated in mammary cells by the classical nuclear estrogen receptor alpha, the mechanisms of the deleterious effect of BPA at low doses and in utero remain unknown since the molecular and cellular target(s) have not been defined. Based on all deleterious effects of BPA, France has banned the use of BPA in all food packaging. This should force the food industry to collaborate with members of public research to rapidly find safer substitutes to BPA. PMID- 23732106 TI - [Non-random randomness]. AB - Whole-genome sequencing of monozygotic twin pairs and of their parents brings new and surprising insights into the rate and distribution of de novo mutations. PMID- 23732107 TI - Facile synthesis of bimetallic Cu-Ag nanoparticles under microwave irradiation and their oxidation resistance. AB - Air-stable bimetallic Cu-Ag nanoparticles in the range of 12-30 nm have been synthesized at gram scale by a facile alcohol reduction in the absence of surfactants with the assistance of microwave irradiation. The synthesized nanoparticles were analyzed by x-ray powder diffraction (XRD), transmission electron microscopy (TEM), scanning TEM, ultraviolet-visible spectroscopy, x-ray photoelectron spectroscopy and thermogravimetry (TG). The stability of the bimetallic nanoparticles against oxidation was examined by TG and in situ temperature-programmed XRD analyses in the atmosphere. No oxidation of copper was confirmed by XRD after storing for longer than 6 months in the atmosphere at room temperature. No oxidation took place below 118 degrees C and the Cu(200) diffraction peak decreased by only 7% after heating at 100 degrees C for 30 min. The oxidation resistance has been ascribed to a Cu core-Ag shell structure, probably owing to the suppressive effect of Ag on the surface through the electronic interaction with Cu and a physical barrier of oxygen. PMID- 23732108 TI - Non-canonical ubiquitylation: mechanisms and consequences. AB - Post-translational protein modifications initiate, regulate, propagate and terminate a wide variety of processes in cells, and in particular, ubiquitylation targets substrate proteins for degradation, subcellular translocation, cell signaling and multiple other cellular events. Modification of substrate proteins is widely observed to occur via covalent linkages of ubiquitin to the amine groups of lysine side-chains. However, in recent years several new modes of ubiquitin chain attachment have emerged. For instance, covalent modification of non-lysine sites in substrate proteins is theoretically possible according to basic chemical principles underlying the ubiquitylation process, and evidence is building that sites such as the N-terminal amine group of a protein, the hydroxyl group of serine and threonine residues and even the thiol groups of cysteine residues are all employed as sites of ubiquitylation. However, the potential importance of this "non-canonical ubiquitylation" of substrate proteins on sites other than lysine residues has been largely overlooked. This review aims to highlight the unusual features of the process of non-canonical ubiquitylation and the consequences of these events on the activity and fate of a protein. PMID- 23732109 TI - Carbonyl reductase 1 is an essential regulator of skeletal muscle differentiation and regeneration. AB - It is well established that reactive oxygen species (ROS) are essential signaling molecules for muscle differentiation. Carbonyl reductase 1 (CBR1) reduces highly reactive lipid aldehydes and catalyzes a variety of endogenous and xenobiotic carbonyl compounds. However, the role of CBR1 in muscle differentiation remains unclear. In this study, we found that CBR1 plays a crucial role in differentiation of muscle-derived C2C12 cells. Our results clearly show that CBR1 is upregulated at the transcript level during differentiation. Consistently, CBR1 was increased during skeletal muscle regeneration in tibialis anterior muscle after injury induced by cardiotoxin. The transcriptional upregulation of CBR1 was found to be controlled by nuclear factor erythroid 2-related factor 2 (Nrf2), and Nrf2 knockdown with specific siRNA inhibited muscle differentiation. Furthermore, intracellular ROS levels and lipid peroxidation were increased in cells transfected with CBR1 siRNA, or in cells treated with the selective CBR1 inhibitor, Hydroxy-PP-Me. Subsequently, the increased ROS levels diminished muscle cell differentiation. All together, we conclude that CBR1 plays a critical role in controlling redox balance and detoxifying lipid peroxidation during muscle differentiation and regeneration. PMID- 23732110 TI - Detergent resistant membrane fractions are involved in calcium signaling in Muller glial cells of retina. AB - Compartmentalization of the plasma membrane into lipid microdomains promotes efficient cellular processes by increasing local molecular concentrations. Calcium signaling, either as transients or propagating waves require integration of complex macromolecular machinery. Calcium waves represent a form of intercellular signaling in the central nervous system and the retina. We hypothesized that the mechanism for calcium waves would require effector proteins to aggregate at the plasma membrane in lipid microdomains. The current study shows that in Muller glia of the retina, proteins involved in calcium signaling aggregate in detergent resistant membranes identifying rafts and respond by redistributing on stimulation. We have investigated Purinoreceptor-1 (P2Y1), Ryanodine receptor (RyR), and Phospholipase C (PLC-beta1). P2Y1, RyR and PLC beta1, redistribute from caveolin-1 and flotillin-1 positive fractions on stimulation with the agonists, ATP, 2MeS-ATP and Thapsigargin, an inhibitor of sarcoplasmic-endoplasmic reticulum Ca-ATPase (SERCA). Redistribution is absent on treatment with cyclopiazonic acid, another SERCA inhibitor. Disruption of rafts by removing cholesterol cause proteins involved in this machinery to redistribute and change agonist-induced calcium signaling. Cholesterol depletion from raft lead to increase in time to peak of calcium levels in agonist-evoked calcium signals in all instances, as seen by live imaging. This study emphasizes the necessity of a sub-population of proteins to cluster in specialized lipid domains. The requirement for such an organization at the raft-like microdomains may have implications on intercellular communication in the retina. Such concerted interaction at the rafts can regulate calcium dynamics and could add another layer of complexity to calcium signaling in cells. PMID- 23732111 TI - Osmotic stress transcription factor 1b (Ostf1b) promotes migration properties with the modulation of epithelial mesenchymal transition (EMT) phenotype in human embryonic kidney cell. AB - Osmoregulation is an essential mechanism for euryhaline fish. Gill cells undergo rapid mechanism to maintain the cellular homeostasis during osmotic stress. Reports have suggested that gill cells may be able to migrate between primary filament and secondary lamella during seawater acclimination. However, the factor that can trigger such process is not well-known. Previously, we identified the osmotic stress transcription factor 1b (Ostf1b) in medaka and found that it is an early hypertonic responsive gene and can activate the c-Jun N-terminal kinase (JNK) pathway. In this report, we aim to know if Ostf1b plays the role in the migration. Ostf1b was ectopic expressed in the human embryonic kidney cell line (HEK293) to understand the Ostf1b function. Results clearly demonstrated that Ostf1b could constitutively activate the Rho kinase 1 (ROCK1) and myosin light chain 2 (MLC2) signalling pathway that promotes cell migration, epithelial mesenchymal transition (EMT) and cytoskeletal dynamics through stress fibre formation. The study supports the notion of cell migration and cytoskeleton rearrangement theories in osmoregulation. PMID- 23732112 TI - The p38 MAPK NF-kappaB pathway, not the ERK pathway, is involved in exogenous HIV 1 Tat-induced apoptotic cell death in retinal pigment epithelial cells. AB - The mechanism through which human immunodeficiency virus (HIV) infection causes retinal disease and the loss of vision in AIDS patients remains unknown. The HIV 1 transactivator protein Tat (HIV-1 Tat) plays a pivotal role in the pathogenesis of HIV-1 infection and is often described as pleiotropic at different concentrations. In a previous study, we demonstrated that the HIV-1 Tat protein can disrupt the barrier function of retinal pigment epithelium (RPE) at 100 nM without affecting cell viability. The present study was undertaken to determine if HIV-1 Tat can induce RPE cell death at different concentrations and to determine the mechanism of any observed cell death. The results demonstrated that two RPE cell lines (ARPE-19 and D407) treated with Tat at concentrations of 200 nM and above exhibited reduced growth and apoptosis in a dose- and time-dependent manner. The disruption of mitochondrial outer membrane permeabilisation, the activation of caspase-3/7 and 9, the downregulation of Bcl-2, the upregulation of Bax, and the activation of p38 MAPK, ERK and NF-kappaB were all observed in HIV-1 Tat-treated RPE cells. When exposed to an inhibitor or transfected with siRNA of p38 MAPK and NF-kappaB, the level of cell death and deregulation of the expression of the apoptotic protein were attenuated. These effects were not observed with an ERK inhibitor or siRNA. Based on these results, we suggest that the induction of apoptosis by HIV-1 Tat in RPE cells may be mediated by p38 MAPK and NF-kappaB activation and involve the mitochondrial pathway. Therefore, these pathways may provide clues leading to novel therapeutic approaches for the retinopathy induced by HIV infection. PMID- 23732114 TI - Aberrant subclavian artery origin in tetralogy of Fallot with pulmonary stenosis is associated with chromosomal or genetic abnormality. AB - We determined the relationship between aortic arch anatomy in tetralogy of Fallot with pulmonary stenosis and chromosomal or genetic abnormality, by performing analysis of 257 consecutive patients undergoing surgical repair from January, 2003 to March, 2011. Chromosomal or genetic abnormality was identified in 49 of the 257 (19%) patients. These included trisomy 21 (n = 14); chromosome 22q11.2 deletion (n = 16); other chromosomal abnormalities (n = 9); CHARGE (n = 2); Pierre Robin (n = 2); and Kabuki, Alagille, Holt-Oram, Kaufman McKusick, Goldenhar, and PHACE (n = 1 each). Aortic anatomy was classified as left arch with normal branching, right arch with mirror image branching, left arch with aberrant right subclavian artery, or right arch with aberrant left subclavian artery. Associated syndromes occurred in 33 of 203 (16%) patients with left arch and normal branching (odds ratio 1); three of 36 (8%) patients with right arch and mirror image branching (odds ratio 0.4, 95% confidence interval 0.1-1.6); seven of eight (88%) patients with left arch and aberrant right subclavian artery (odds ratio 36, 95% confidence interval 4-302); and six of 10 (60%) patients with right arch and aberrant left subclavian artery (odds ratio 8, 95% confidence interval 2-26). Syndromes were present in 13 of 18 (72%) patients with either right or left aberrant subclavian artery (odds ratio 15, 95% confidence interval 4-45). Syndromes in patients with an aberrant subclavian artery included trisomy 21 (n = 4); chromosome 22q11.2 deletion (n = 5); and Holt-Oram, PHACE, CHARGE, and chromosome 18p deletion (n = 1 each). Aberrant right or left subclavian artery in tetralogy of Fallot with pulmonary stenosis is associated with an increased incidence of chromosomal or genetic abnormality, whereas right aortic arch with mirror image branching is not. The assessment of aortic arch anatomy at prenatal diagnosis can assist counselling. PMID- 23732113 TI - Expression and cytoprotective activity of the small GTPase RhoB induced by the Escherichia coli cytotoxic necrotizing factor 1. AB - RhoB is the only member of the Rho subfamily of small GTPases, which is classified as an immediate early gene product. RhoB is up-regulated in response to growth factors as well as cytotoxic and genotoxic agents. Clostridial glucosylating toxins have been reported to evoke pronounced RhoB expression, based on the inactivation of Rho/Ras proteins. In this study, we report on a long lasting expression of RhoB in cultured cells upon activation of Rho proteins by the cytotoxic necrotizing factor 1 (CNF1) from Escherichia coli. The observations of this study highlight a new pathway involving Rac1, which positively regulates the activity of the rhoB promoter and RhoB expression. Conversely, the isomeric cytotoxic necrotizing factor from Yersinia pseudotuberculosis (CNFy) drives GTP loading of basal RhoB but fails to cause activation of the rhoB promoter and thus its expression. CNF1 inhibits cytokinesis and induces the formation of bi nucleated (tetraploid) cells. Upon long term treatment with CNF1, RhoB(-/-) mouse embryonic fibroblasts (MEFs) exhibit DNA fragmentation, phosphatidylserine exposure, and loss of membrane integrity, while RhoB(+/-) MEFs persist as bi nucleated (tetraploid) cells without any signs of cell death. In conclusion, the cytoprotective RhoB response is not only evoked by bacterial protein toxins inactivating Rho/Ras proteins but also by the Rac1-activating toxin CNF1. PMID- 23732115 TI - A PROP1-binding factor, AES cloned by yeast two-hybrid assay represses PROP1 induced Pit-1 gene expression. AB - PROP1 mutation causes combined pituitary hormone deficiency (CPHD). Several mutations are located in a transactivation domain (TAD) of Prop1, and the loss of TAD binding to cofactors is likely the cause of CPHD. PROP1 cofactors have not yet been identified. In the present study, we aimed to identify the PROP1 interacting proteins from the human brain cDNA library. Using a yeast two-hybrid assay, we cloned nine candidate proteins that may bind to PROP1. Of those nine candidates, amino-terminal enhancer of split (AES) was the most abundant, and we analyzed the AES function. AES dose-dependently decreased the PROP1-induced Pit-1 reporter gene expression. An immunoprecipitation assay revealed the relationship between AES and PROP1. In a mammalian two-hybrid assay, a leucine zipper-like motif of the AES Q domain was identified as a region that interacted with TAD. These results indicated that AES was a corepressor of PROP1. PMID- 23732116 TI - Hepatic ERK activity plays a role in energy metabolism. AB - Mitogen activated protein kinases (MAPKs), such as c-Jun N-terminal kinase (JNK) and P38, have been reported to play important roles in energy homeostasis. In this study, we show that the activity of extracellular signal-regulated kinase (ERK) is increased in the livers of diet induced and genetically obese mice. Activation of ERK in the livers of lean mice by over-expressing the constitutively active MAPK kinase 1 (MEK CA) results in decreased energy expenditure, lowered expression of genes involved in fatty acid oxidation, increases fasting hyperglycemia and causes systemic insulin resistance. Interestingly, hepatic glycogen content is markedly increased and expression of G6Pase gene is decreased in mice over-expressing MEK CA compared to control mice expressing green fluorescent protein (GFP), therefore hepatic glucose output is not likely the major contributor of hyperglycemia. One potential mechanism of decreased expression of G6Pase gene by MEK CA is likely due to ERK mediated phosphorylation and cytosolic retention of FOXO1. Adipocytes isolated from MEK CA mice display increased lipolysis. Circulating levels of free fatty acids (FFAs) in these mice are also increased, which possibly contribute to systemic insulin resistance and subsequent hyperglycemia. Consistent with these results, knocking down ERK expression in the liver of diet induced obese (DIO) mice improves systemic insulin and glucose tolerance. These results indicate that increased hepatic ERK activity in DIO mice may contribute to increased liver glycogen content and decreased energy expenditure in obesity. PMID- 23732117 TI - A study of immunomodulatory genes responses to macrophages of Schistosoma japonicum infection during different stages by microarray analysis. AB - Macrophages initiate, modulate, and also serve as final effector cells in immune responses during the course of schistosomal infections. In this study, we investigated the gene expression profile and functional changes of macrophages in immune responses against the Schistosoma japonicum by microarray analysis. Hierarchical clustering analysis demonstrated that a significant switch in gene transformation associated with a type-1 response and linked with a type-2 cytokine phenotype occurs between 4.5 and 8 weeks post-infection. Moreover, the gene profiles at 3 later time-points following egg challenge were similar in complexity and magnitude. The data also showed that there were mostly inhibition of gene expression related TLR, IFN, MHC and TNFrsf at the switch between 4.5 and 8 weeks post-infection, It is suggested that these immunomodulatory genes may be down-regulated in defense against S. japonicum eggs and granuloma pathology. The induction of alternatively activated macrophage (AAMphi) was important for dampening the inflammation in hepatic granulomas and contributing to a decrease in cytotoxicity. The gene expressions involved in repair/remodeling during liver fibrosis were also observed after egg production. Understanding the immune mechanisms associated with parasitic resistance, pathology of parasite infection, and parasite growth will provide useful insight on host-schistosome interactions and for the control of schistosomiasis. PMID- 23732118 TI - Categorical sensitivity to color differences. AB - Categorical perception provides a potential link between color perception and the linguistic categories that correspond to the basic color terms. We examined whether the sensory information of the second-stage chromatic mechanisms is further processed so that sensitivity for color differences yields categorical perception. In this case, sensitivity for color differences should be higher across than within category boundaries. We measured discrimination thresholds (JNDs) and color categories around an isoluminant hue circle in Derrington Krauskopf-Lennie (DKL) color space at three levels of lightness. At isoluminant lightness, the global pattern of JNDs coarsely followed an ellipse. Deviations from the ellipse coincided with the orange-pink and the blue-green category borders, but these minima were also aligned with the second-stage cone-opponent mechanisms. No evidence for categorical perception of color was found for any other category borders. At lower lightness, categories changed substantially, but JNDs did not change accordingly. Our results point to a loose relationship between color categorization and discrimination. However, the coincidence of some boundaries with JND minima is not a general property of color categorical boundaries. Hence, our basic ability to discriminate colors cannot fully explain why we use the particular set of categories to communicate about colors. Moreover, these findings seriously challenge the idea that color naming forms the basis for the categorical perception of colors. With respect to previous studies that concentrated on the green-blue boundary, our results highlight the importance of controlling perceptual distances and examining the full set of categories when investigating category effects on color perception. PMID- 23732119 TI - Posing for awareness: proprioception modulates access to visual consciousness in a continuous flash suppression task. AB - The rules governing the selection of which sensory information reaches consciousness are yet unknown. Of our senses, vision is often considered to be the dominant sense, and the effects of bodily senses, such as proprioception, on visual consciousness are frequently overlooked. Here, we demonstrate that the position of the body influences visual consciousness. We induced perceptual suppression by using continuous flash suppression. Participants had to judge the orientation a target stimulus embedded in a task-irrelevant picture of a hand. The picture of the hand could either be congruent or incongruent with the participants' actual hand position. When the viewed and the real hand positions were congruent, perceptual suppression was broken more rapidly than during incongruent trials. Our findings provide the first evidence of a proprioceptive bias in visual consciousness, suggesting that proprioception not only influences the perception of one's own body and self-consciousness, but also visual consciousness. PMID- 23732120 TI - A method of comparing effectiveness of mattresses for pressure management for pediatric patients. AB - A systematic review of the pressure management performance of support surfaces (beds, mattresses, overlays, and the utilization of linens), using a standardized testing methodology, provided qualitative and quantitative information needed to support cost-effective purchasing decisions and resulted in the reduction of hospital-acquired pressure ulcers. In the 30 months since implementation of the new surfaces, use guidelines, and educational programs, zero surface-related stage 3, 4 and unstaged pressure ulcers have occurred despite a high-risk patient population. PMID- 23732121 TI - Using appreciative inquiry during care transitions: an exploratory study. AB - The purpose of the study was to evaluate the effectiveness of a transitional care coaching intervention offered to chronically ill medical patients during the transition from hospital to home. This 2-arm randomized pilot study uses a coaching framework based on appreciative inquiry theory. This article reviews the appreciative inquiry literature and identifies the characteristics of patients who participated in appreciative inquiry coaching. Lessons learned are summarized, and suggestions for future research are offered. PMID- 23732122 TI - The larynx in cough. AB - About 40% of the population will experience chronic cough at some point during their lives and it tends to be more common in women (Thorax 58:901-7, 2003). Post nasal drip (or upper airway cough syndrome), gastro-esophageal reflux disease and asthma are considered the most common causes. Yet only a small percentage of patients with these common conditions experience chronic cough. Also there is no agreed measure of post-nasal drip and controversy exists about the diagnosis of reflux above the upper esophageal sphincter (laryngopharyngeal reflux) based on observable changes to the larynx. The approach of the otolaryngologist is to consider the upper and lower airways as a continuum and that a common pathology can have an impact on all these anatomical sites.A multidisciplinary approach is advocated, utilising the skills of the respiratory physician, otolaryngologist, gastroenterologist and speech pathologist. PMID- 23732124 TI - Cloning and characterisation of three novel disintegrin precursors from the venoms of three Atheris species: Atheris chlorechis, Atheris nitschei and Atheris squamigera. AB - Snake venom constitutes one of the most complex mixtures of naturally-occurring toxic proteins/polypeptides and a large number of these possess very profound biological activities. Disintegrins, that are commonly found in viper venoms, are low molecular weight proteins that usually contain an -Arg-Gly-Asp- (-RGD-) motif that is known to be involved in cell adhesion ligand recognition, binding specifically to cell surface integrin receptors and also exhibiting platelet anti aggregation activity. Here, we report for the first time, the successful cloning of three cDNAs encoding disintegrin precursors from lyophilised venom-derived libraries of Atheris chlorechis, Atheris nitschei and Atheris squamigera, respectively. All of these disintegrins belong to the short-coding class and all exhibit high degrees of structural identity, both in their amino acid sequences and in the arrangement of their functional domains. Mass spectrometric analyses of the HPLC-separated/in-gel digested venom proteins was performed to characterise the mature disintegrins as expressed in the venom proteome. Studies on both the structures and conserved sites within these disintegrins are of considerable theoretical interest in the field of biological evolution and in the development of new research tools or novel templates for drug design. PMID- 23732123 TI - Bothropic antivenom based on monoclonal antibodies, is it possible? AB - Neutralizing monoclonal antibodies against three major toxic components of Bothrops atrox venom were produced and tested. The mAbs against phospholipase A2, hemorrhagic metalloprotease, and thrombin-like enzymes were produced in large amounts and purified with caprylic acid followed by ammonium sulfate precipitation. Purified mAbs were analyzed by SDS-PAGE and their ability to neutralize the respective toxins was tested. Five Swiss mice were injected i.p. with 13.5 mg of pooled mAbs and challenged via s.c. route with venom. Survival rate was recorded for the next 48 h. All mice treated and challenged with venom survived, whereas only one mouse in the control group survived. Bleeding time in mice treated with mAbs was similar to that observed in control mice. Our results show that monoclonal antibodies neutralized the lethal toxicity of Bothrops venom and indicate that there is a reasonable possibility of developing antivenoms based on humanized mAbs to treat victims of venomous animals in the future. PMID- 23732125 TI - Different types of toxins targeting TRPV1 in pain. AB - The transient receptor potential vanilloid 1(TRPV1) channels are members of the transient receptor potential (TRP) superfamily. Members of this family are expressed in primary sensory neurons and are best known for their role in nociception and sensory transmission. Multiple painful stimuli can activate these channels. In this review, we discussed the mechanisms of different types of venoms that target TRPV1, such as scorpion venom, botulinum neurotoxin, spider toxin, ciguatera fish poisoning (CFP) and neurotoxic shellfish poisoning (NSP). Some of these toxins activate TRPV1; however, some do not. Regardless of TRPV1 inhibition or activation, they occur through different pathways. For example, BoNT/A decreases TRPV1 expression levels by blocking TRPV1 trafficking to the plasma membrane, although the exact mechanism is still under debate. Vanillotoxins from tarantula (Psalmopoeus cambridgei) are proposed to activate TRPV1 via interaction with a region of TRPV1 that is homologous to voltage dependent ion channels. Here, we offer a description of the present state of knowledge for this complex subject. PMID- 23732126 TI - Comparison of venom composition and biological activities of the subspecies Crotalus lepidus lepidus, Crotalus lepidus klauberi and Crotalus lepidus morulus from Mexico. AB - The rock rattlesnakes Crotalus lepidus comprise a group (lepidus, klauberi, morulus and maculosus) of poorly known mountain cold-tolerant snakes in Mexico. In particular, Crotalus lepidus morulus is a snake endemic of the northeast of Mexico, whereas Crotalus lepidus klauberi and C. l. lepidus are distributed in some regions of the north and central Mexico and southern U. S. Until now very little data are available from C. lepidus subspecies from Mexico, as the terrain inhabited by these snakes is generally steep and rugged. In this work, we have determined some biochemical and biological properties of C. l. morulus, C. l. klauberi and C. l. lepidus crude venoms. Some minor differences in venoms were noted in SDS-PAGE, HPLC profile and MALDI-TOF mass spectrometry analysis. Partial sequences of metalloproteinases, phospholipases A2 (PLA2) and galactose-specific lectins were identified in the venoms. Venoms of C. l. klauberi and C. l. lepidus had significantly higher hemorrhagic and lethal activities than C. l. morulus venom. Proteolytic activity in azocasein was higher in C. l. morulus venom, whereas gelatin hydrolysis was higher in C. l. klauberi. Fibrinogenolytic and PLA2 activities were very similar in all venoms tested. The histological observations in the gastrocnemius muscle damaged by venoms from all the subspecies confirmed myonecrotic and hemorrhagic activities (at 3 and 24 h), which resulted in a poor regenerative response after 14 days. However, C. l. lepidus and C. l. klauberi venom induced a higher increase in the plasma activity of creatine kinase (CK), evidencing higher myotoxicity, whereas paw edema inducing activity was higher in C. l. lepidus venom. The results indicate that the venoms from the three subspecies have similar protein profiles in electrophoresis, HPLC and molecular weight determinations. However, differences were found in the biological activities in mice. Notably, the venoms of C. l. lepidus and C. l. klauberi present higher toxicity (lower LD50) and hemorrhagic activity than C. l. morulus venom. PMID- 23732127 TI - Crystal structure of a Trimeresurus mucrosquamatus venom metalloproteinase providing new insights into the inhibition by endogenous tripeptide inhibitors. AB - The crystal structure of TM-1, a P-I class snake-venom metalloproteinase (SVMP) from the Trimeresurus mucrosquamatus venom, was determined at 1.8-A resolution. The structure exhibits the typical feature of SVMPs and is stabilized by three disulfide linkages. The active site shows a deep S1' substrate-binding pocket limited by the non-conserved Pro174 at the bottom. Further comparisons with other SVMPs suggest that the deep S1' site of TM-1 correlates with its high inhibition sensitivity to the endogenous tripeptide inhibitors. Proteolytic specificity analysis revealed that TM-1 prefers substrates having a moderate-size and hydrophobic residue at the P1' position, consistent with our structural observation. PMID- 23732128 TI - Toxicity of harmful cyanobacterial blooms to bream and roach. AB - Aquatic ecosystems are facing increasing environmental pressures, leading to an increasing frequency of cyanobacterial Harmful Algal Blooms (cHABs) that have emerged as a worldwide concern due to their growing frequency and their potential toxicity to the fauna that threatens the functioning of ecosystems. Cyanobacterial blooms raise concerns due to the fact that several strains produce potent bioactive or toxic secondary metabolites, such as the microcystins (MCs), which are hepatotoxic to vertebrates. These strains of cyanobacteria may be potentially toxic to fish via gastrointestinal ingestion and also by direct absorption of the toxin MC from the water. The purpose of our study was to investigate toxic effects observed in fish taken from several lakes in the Ile-de France region, where MCs-producing blooms occur. This study comprises histological studies and the measurement of MC concentrations in various organs. The histological findings are similar to those obtained following laboratory exposure of medaka fish to MCs: hepatic lesions predominate and include cell lysis and cell detachment. MC concentrations in the organs revealed that accumulation was particularly high in the digestive tract and the liver, which are known to be classical targets of MCs. In contrast concentrations were very low in the muscles. Differences in the accumulation of MC variants produced by blooms indicate that in order to more precisely evaluate the toxic potential of a specific bloom it is necessary not only to consider the concentration of toxins, but also the variants produced. PMID- 23732129 TI - A day in the life of the AMU--the Society for Acute Medicine's benchmarking audit 2012 (SAMBA '12). AB - BACKGROUND: The absence of published data for benchmarking serves as a disincentive for Acute Medical Units to improve care. AIM: To test feasibility of a national audit in Acute Medicine for compliance with common standards. METHODS: On line questionnaire with summary data for patients admitted to participating Acute Medicine Units over a 24-hour-period. RESULTS: 30 units submitted summary data. The mean number of admission was 36 (SD 14). Compliance with standards around timing of junior and senior review was highly variable. In almost all other standards only a small number of units achieved high reliability with compliance of more than 90%. CONCLUSION: SAMBA provides a data set that can be used for local and national benchmarking and quality improvement work. Annual audit might be beneficial to track improvements. PMID- 23732130 TI - The ability of frailty to predict outcomes in older people attending an acute medical unit. AB - BACKGROUND: This study assessed the role of frailty assessment in the AMU. METHODS: Patients were assessed for frailty and their outcomes ascertained at 90 days. RESULTS: The Canadian Study on Health and Aging Clinical Frailty Scale categorised 29% of patients as moderately-severely frail. Frailty did not differentially identify those likely to be discharged within one day, nor with long stays. Mortality at 90 days was 32%; frailty was associated with the risk of dying, odds ratio 1.4. 21% of patients were readmitted at 30 days, and 33% at 90 days, but frailty was not predictive. DISCUSSION: Moderate-severe frailty in people aged 70+ was common and was predictive of higher mortality, but did not appear to predict admission, length of stay or readmission. PMID- 23732131 TI - Severe sepsis, social media and the #Sepsis 6: 'Tweeting' national innovations. AB - The Surviving Sepsis Campaign (SSC) was launched in 2002 with guidelines created to help manage severe sepsis and septic shock. In response to poor compliance with the SSC guidelines in the UK, the 'Sepsis 6' model of delivery was created. We report some of the innovative methods hospitals from around the UK are using to help deliver the 'Sepsis 6' care bundle. The use of social media, such as Twitter, for disseminating these innovations is also explored. PMID- 23732132 TI - Elemental mercury toxicity due to aspiration following intentional massive ingestion. AB - Deliberate poisoning with intentional ingestion of elemental mercury is reported not to result in systemic toxicity due to minimal absorption from the gastrointestinal tract. We report a case of a 43 year old male who intentionally ingested 200 ml elemental mercury which resulted in abdominal pain and vomiting. The patient subsequently aspirated globules of mercury which was confirmed on chest x-ray and his blood mercury levels were markedly raised. He was treated with chelating agents and managed in a negative pressure room to reduce the risk of staff being exposed to exhaled mercury vapour from the patient. PMID- 23732133 TI - An unusual complication of cocaine toxicity. AB - A 25-year man presented to the Accident and Emergency Department complaining of dizziness and shortness of breath after taking 70 grams of cocaine over 10 hours. He said a friend had noticed that his skin had turned dark blue. On examination the patient was severely centrally and peripherally cyanosed. His pulse oximeter oxygen saturations were 88% on air. An arterial blood gas showed a methaemoglobin level of 45.6%. The patient was diagnosed with cocaine-induced methaemoglobinaemia and given methyl thioninium chloride (methylene blue). He made an uneventful recovery. PMID- 23732134 TI - Infectious mononucleosis hepatitis; an unwelcome present for Father Christmas. AB - We describe a case of infectious mononucleosis (IM) hepatitis occurring in an elderly thespian, who had recently played the role of 'Father Christmas'. We discuss the importance of differing clinical manifestations in older and younger age groups, the changing epidemiology of Epstein Barr (EB) infection within the United Kingdom and the role of different virology tests in establishing a diagnosis. Raised awareness of this changing pattern of disease could prevent unnecessary investigation and consequent potential iatrogenic complications. PMID- 23732135 TI - A case of newly diagnosed primary hypothyroidism with deteriorating consciousness that did not respond to thyroxine--what else should be considered? AB - We present an unusual case of a 60 year old male who was noted to have primary hypothyroidism and decreased consciousness which did not respond to Levothyroxine. Further investigations revealed a diagnosis of Hashimoto's Encephalopathy which responded well to steroids. We describe the case in detail and discuss the available relevant literature on this topic. PMID- 23732136 TI - Problem based review: The patient with a pyrexia of unknown origin. AB - Pyrexia of unknown origin (PUO) is a frequent presentation to the Acute Medical Unit, and is a source of significant morbidity, both the psychological burden of an uncertain diagnosis and prognosis and untreated complications of the underlying pathology. We present a problem based review of the management of PUO, illustrated by a patient who recently presented to our unit with fever and systemic malaise after returning from abroad and in whom no cause could be found for more than two months. We describe a structured approach making use of complex modern techniques such as Positron Emission Tomography-Computed Tomography (PET CT) which ultimately provided the diagnosis for our patient. PMID- 23732137 TI - Problem based review: The patient with acute monoarthritis. AB - Acute monoarthritis is a common medical emergency with wide differential diagnosis. Common underlying causes include trauma, septic arthritis, crystal induced arthritis (gout and pseudogout), and reactive arthritis. Of these, septic arthritis is the diagnosis not to miss because of its association with significant morbidity and mortality. Precise diagnosis of the underlying cause of monoarthritis relies on a good history, physical examination findings, and results of focussed investigations. In this article, a practical approach to diagnosis and initial management of patients presenting with acute monoarthritis is described with the aid of a case vignette. PMID- 23732138 TI - Charting new frontiers in interventional medicine. PMID- 23732139 TI - Renal denervation: expanding the indication. PMID- 23732140 TI - Obstructive sleep apnoea, resistant hypertension and renal denervation. AB - Sleep apnoea occurs in 5% to 10% of the general population. Obstructive sleep apnoea (OSA) is the most common disease associated with resistant hypertension. In a paper published by Pedrosa et al, OSA - defined as an apnoea-hypopnoea index (AHI) >15 events/hour measured in polysomnography -was diagnosed in 64% of patients with resistant hypertension. OSA is also considered as an independent risk factor for cardiovascular events: ischaemic heart disease, heart failure, stroke and death. Several mechanisms, including oxidative stress, inflammation and endothelial dysfunction may be responsible for the association between OSA and cardiovascular disease. Continuous positive airway pressure (CPAP) is a treatment of choice to reverse severe OSA and its consequences. PMID- 23732141 TI - Potential role of renal sympathetic denervation for the treatment of cardiac arrhythmias. AB - The autonomic nervous system (ANS) has a pivotal role in the pathogenesis and maintenance of atrial and ventricular arrhythmias. Catheter-based renal denervation (RDN) is associated with a reduction of central sympathetic activity, muscle sympathetic nerve activity, and blood pressure in resistant hypertension. As renal afferent nerves are regulators of central sympathetic tone, RDN opens the possibility to modulate sympathetic activity, but without affecting peripheral chemoreceptors and mechanoreceptors in the heart and other organs. RDN was shown to reduce heart rate in humans and to reduce inducibility of atrial fibrillation (AF) as well as ventricular rate during AF in experimental studies. First evidence indicates that pulmonary vein isolation in combination with RDN increases the rate of AF freedom in patients with resistant hypertension. Furthermore, RDN may have a beneficial impact on ventricular arrhythmia, in particular in patients with coronary artery disease or heart failure. PMID- 23732143 TI - The burden of hypertension. AB - Arterial hypertension is among the leading global risks for mortality, being responsible for 9.4 million deaths in 2010. The reason for this enormous burden has been documented in multiple studies. Hypertension is strongly associated with overall cardiovascular risk. Increased blood pressure contributes to cardiovascular and cerebrovascular endpoints, such as myocardial infarction, heart failure, cardiovascular death and stroke. In addition, an age-dependent positive correlation exists between systolic blood pressure (SBP)/ diastolic blood pressure (DBP) and stroke, as well as between SBP/DBP and ischaemic heart disease. All these data suggest that hypertension is the number one risk for mortality because of its dominant role in cardiovascular pathogenesis. Despite a recently documented fall in blood pressure levels during the last decade in Europe, it appears very likely that hypertension, as a strong age-dependent risk factor, will remain one of the most crucial cardiovascular risk factors in an ageing world population. Along these lines, the well-known suboptimal hypertension control rates should be of great concern, and the identification and study of new strategies for an improvement in awareness and effective treatment for hypertension are absolutely essential. PMID- 23732142 TI - Expanding the indication spectrum: renal denervation in diabetes. AB - Catheter-based renal denervation (RDN) has been shown to reduce sympathetic nerve activity and blood pressure in patients with resistant hypertension. Increased central sympathetic activity is a main contributor to the pathophysiology of several important chronic cardiovascular diseases, including diabetes and the metabolic syndrome. Indeed several recently published pilot studies and case reports suggest beneficial effects of RDN on glucose metabolism in patients with resistant hypertension. This review highlights the background of approaching the renal sympathetic nerves as a potential new therapeutic option to improve glycaemic control in patients with resistant hypertension. PMID- 23732144 TI - Therapeutic potential of renal sympathetic denervation in patients with chronic heart failure. AB - Chronic heart failure is associated with sympathetic activation characterised by elevated circulating norepinephrine levels linked to cardiovascular morbidity and mortality. Norepinephrine induces phenotype changes of the cardiomyocyte, fibrosis and beta-adrenergic signal transduction defects implicated in the dysregulation of contractility. Renal denervation reduces left ventricular hypertrophy and improves diastolic dysfunction, partly blood pressure independently. Also, exercise tolerance and cardiac arrhythmias are positively influenced. Furthermore, there is evidence that common comorbidities like sleep apnoea, metabolic disease and microalbuminuria are improved following renal denervation. The available evidence suggests performing randomised controlled trials to scrutinise whether renal sympathetic denervation might be able to improve morbidity and mortality in chronic heart failure with preserved or reduced ejection fraction. PMID- 23732145 TI - Chronic kidney disease: role of sympathetic nervous system activation and potential benefits of renal denervation. AB - The prevalence of chronic kidney disease (CKD) and end-stage renal disease continues to increase worldwide. Hypertension and diabetes are recognised as two major factors contributing to further progression of CKD. Importantly, progressive renal impairment increases cardiovascular morbidity and mortality. Despite advances in pharmacological antihypertensive and anti-diabetic approaches, the alarming number of patients developing nephropathy indicates the failure of the available treatment strategies. The relevance of sympathetic activation for the development and progression of chronic kidney disease is well established. Likewise, progressive renal failure results in exaggerated sympathetic activation leading to a vicious cycle, providing the rationale for the use of renal denervation to modulate directly the mechanisms underlying disease progression. While initial data on the safety and effectiveness of the procedure to lower BP were obtained in patients with resistant hypertension and preserved renal function, there are now preliminary data to suggest that this approach can also be applied safely in patients with stage 3-4 CKD. Similarly, first reports applying renal denervation in patients with end-stage renal disease on dialysis demonstrate favourable effects. If appropriately designed clinical trials can confirm these initial observations, renal denervation may become a valuable new treatment option for the large cohort of patients with CKD. PMID- 23732146 TI - Efficacy of baroreflex activation therapy for the treatment of resistant hypertension. AB - The contribution of sympathetic activation in the development of hypertension is supported by early experimental evidence based on surgical denervation of sino aortic baroreceptors or lesions of the central relay station of the baroreflex, the nucleus tractus solitarii. Disruption of this area of the brain was associated with an immediate increase in blood pressure. Sympathetic overactivity can also be triggered by impairment of the inhibitory function physiologically exerted by reflexogenic areas (arterial baroreceptors, cardiopulmonary receptors, and chemoreceptors) on adrenergic drive. Metabolic and humoral mechanisms are also thought to be involved in the development and progression of hypertension related sympathetic overdrive. PMID- 23732148 TI - Pulmonary arterial hypertension: pharmacologic therapies and potential pulmonary artery denervation treatment. AB - Pulmonary arterial hypertension (PAH) is a group of diseases related to progressively increasing pulmonary vascular resistance, a high incidence of right ventricular failure and premature death. Only a limited number of pharmaceutical therapies have proven to be beneficial for PAH. These therapies improve symptoms, exercise capacity, and haemodynamics; however, the clinical relevance of these effects has been challenged. Therefore, the effect of currently approved treatment options remains inconclusive. Conversely, several new drugs for various aetiologies and clinical stages are expected to provide significant advances for the treatment of PAH. Moreover, percutaneous pulmonary artery denervation treatment may lead to a new therapeutic orientation in patients with PAH. The aim of this review is to present the new developments in PAH treatment, provide a brief overview of future directions in the field and discuss the potential future prospects of these innovative therapies. PMID- 23732147 TI - Restoring autonomic balance: future therapeutic targets. AB - Our aim was to highlight the very recent and rapid expansion of a number of contemporary, pioneering and projected interventional approaches for resistant hypertension. Our discussions of each approach centre on a new model of the cardiovascular system that emphasises the importance of the sympathetic nervous system, its differential control and reflex activation. Four interventional therapeutic strategies are discussed including targeted sympathectomies and carotid body ablation. Harnessing endogenous homeostatic control systems looks promising as a means to correct autonomic balance. The challenge will be in deciding which interventional approach should be selected. PMID- 23732149 TI - Potential new indications and future studies. AB - Despite lifestyle modification and pharmacological approaches, the rates of control of blood pressure are still not optimal. Experimental and clinical studies suggest that renal denervation therapy is an effective and safe treatment for patients with therapy-resistant hypertension leading to a reduction in blood pressure and in systemic and renal sympathetic nervous activation, which plays an important role in the development, progression and prognosis of arterial hypertension. Moreover, besides blood pressure reduction, renal denervation improves glucose metabolism, left ventricular hypertrophy and diastolic function in patients with resistant hypertension. Actually, many small clinical studies suggest that renal denervation may also be useful in diseases other than hypertension such as metabolic syndrome, sleep-related breathing disorders, chronic kidney disease and renal failure, chronic heart failure and polycystic ovary syndrome. PMID- 23732150 TI - A global approach to hypertension. AB - Hypertension is an extremely common condition and quantitatively the most important risk factor for cardiovascular disease and mortality. Cardiovascular risk factors other than hypertension occur more frequently in hypertensive subjects and contribute to the elevated cardiovascular risk. Management of hypertensive subjects includes lifestyle modification and, usually, treatment with antihypertensive agents. Due to the limited blood pressure lowering effect of a single antihypertensive agent, more than 2/3 of hypertensive patients require at least two or more antihypertensive agents to achieve target blood pressure. For combination therapy combining an agent that interferes with the renin-angiotensin system with an agent that does not is recommended. Treatment adherence and persistence can be improved by using fixed-dose combinations instead of single agents. PMID- 23732151 TI - Ruling out secondary causes of hypertension. AB - In the majority of hypertensive patients, no particular cause for abnormal blood pressure is evident (primary or essential hypertension). In contrast, in the minority of patients with secondary hypertension a specific underlying cause is responsible for the elevated blood pressure. The prevalence of secondary hypertension is higher in patients with resistant hypertension than in the general hypertensive population and increases with age. The list of secondary forms of hypertension is long and prevalence of the individual causes of secondary hypertension varies. Hence, this review divides them into two categories: common causes and rare causes. If appropriately diagnosed and treated, patients with a secondary form of hypertension might be cured, or at least show an improvement in their blood pressure control. Consequently, screening for secondary causes of hypertension plays an essential part in the care of patients with arterial hypertension. If the basal work-up raises the suspicion of a secondary cause of hypertension, specific diagnostic procedures become necessary, some of which can be performed by primary care physicians, while others require specialist input. PMID- 23732152 TI - Assessment of drug compliance in patients with high blood pressure resistant to antihypertensive therapy. AB - The persistence of high blood pressure under antihypertensive treatment (resistant hypertension) entails an increased cardiovascular risk. It occurs in three of ten treated hypertensive patients, and has several possible contributing factors, notably insufficient therapeutic adherence. There are a number of ways to evaluate whether patients take their medication as prescribed. These include interviewing the patient, pill counting, prescription follow-up, assay of drugs in blood or urine, and use of electronic pill dispensers. None is perfect. However, the essential is to discuss with the patient the importance of complying with the treatment as soon as it is prescribed for the first time, and not waiting for the appearance of resistant hypertension. The measurement of blood pressure outside the medical office and the monitoring of adherence may help to identify patients in whom hypertension is truly resistant and so to tailor the measures required to improve the control of blood pressure in the most appropriate manner. PMID- 23732153 TI - Home and ambulatory blood pressure in resistant hypertension. AB - Since their introduction in the clinical setting home and ambulatory blood pressure measurements have gained growing popularity in the diagnosis and treatment of essential hypertension for a number of reasons. These reasons include: 1) the lack of the so-called "white-coat effect", 2) the ability of the two approaches to provide information on blood pressure phenomena of prognostic value, and 3) the close relationship of the derived values with the risk of developing fatal and non-fatal cardiovascular events. These features also apply to resistant hypertension, in which these approaches allow a precise definition of the diagnosis of this clinical condition, by excluding the presence of white coat hypertension. Assessment of "out-of-office" blood pressure also allows us to define the patterns of blood pressure variability in this clinical condition as well as its relationships with target organ damage. Finally, home as well as ambulatory blood pressure measurements allow us to investigate the effects of therapeutic interventions, including those associated with the radiofrequency ablation of renal nerves. The present paper will provide a critical review of the main features of home and ambulatory blood pressure measurement in resistant hypertension, highlighting their main advantages as compared to office blood pressure. The prognostic significance, relationships with target organ damage and implications for treatment will also be discussed. PMID- 23732154 TI - Pathophysiology I: the kidney and the sympathetic nervous system. AB - Recently, catheter-based renal denervation (RDN) has become available. In order to understand better the possible role of RDN as a treatment modality, we first discuss the anatomy and function of the renal nerves in this brief review. Secondly, we address the question - what is the clinical evidence for the involvement of the kidneys and renal nerves in the pathogenesis of sympathetic hyperactivity. Finally, we will discuss how this sympathetic hyperactivity can be reduced, specifically addressing the possible role of RDN. PMID- 23732155 TI - The "resistant hypertension team": focus on a multidisciplinary approach to hypertension. AB - Renal denervation (RDN) as a catheter-based procedure was introduced in 2009. As a reinvention of an old concept this approach in treating resistant hypertension has been gathering an unprecedented momentum in the world of hypertension. The incredible success in introducing this technique, followed by its quick and wide distribution, introduced new challenges and requirements for hypertension centres in offering optimal patient care. The challenges of these new parameters and requirements have to be met not only by a multidisciplinary team of doctors who can provide excellent evaluation, treatment and follow-up of these patients, but also by the hypertension centres themselves, who wish to provide this treatment option to their patients. PMID- 23732156 TI - Response and non-response to renal denervation: who is the ideal candidate? AB - Catheter-based renal denervation (RDN) leads to a considerable decrease of blood pressure in the vast majority of patients with resistant hypertension. However, only minor or no blood pressure change is achieved in some patients. This non reponse is defined as a reduction of office systolic blood pressure of less than 10 mmHg following RDN. The rates of non-response vary between 8-37%. Here several causes are discussed such as inappropriate patient selection, an ineffective procedure, the subordinate contribution of sympathetic activation for the maintenance of hypertension, and patient conditions such as non-adherence to drug therapy. Based on current evidence, an ideal candidate for RDN has high baseline blood pressure, which is known to be the best predictor for blood pressure reduction after RDN. In order to ensure treatment success further criteria have to be fulfilled, such as exclusion of secondary hypertension and optimised medical therapy. PMID- 23732157 TI - Updated ESH position paper on interventional therapy of resistant hypertension. AB - Out of the overall hypertensive population it is estimated that approximately 10% have treatment resistant hypertension (TRH). Percutaneous catheter-based transluminal renal ablation (renal denervation [RDN] by delivery of radiofrequency energy) has emerged as a new approach to achieve sustained blood pressure reduction in patients with TRH. This innovative interventional technique is now available across Europe for severe TRH for those patients in whom pharmacologic strategies and lifestyle changes have failed to control blood pressure below target (usually <140/90 mmHg). In 2012, the "ESH position paper: renal denervation - an interventional therapy of resistant hypertension" was published to facilitate a better understanding of the effectiveness, safety, limitation and unresolved issues. We have now updated this position paper since numerous studies have been published over the last year providing more data about the rationale, therapeutic efficacy and safety of RDN. In the upcoming ESH/ESC guidelines for the management of arterial hypertension, therapeutic options of treatment resistant hypertension will be addressed, but only briefly, and thus it is the focus of this paper to provide detailed and updated information on this innovative interventional technique. PMID- 23732158 TI - Challenging anatomy, how to treat or not to treat? AB - Several position statements provided recommendations regarding the anatomical conditions qualifying for renal denervation catheter application based on the HTN 1 and HTN-2 trials. This manuscript summarises anatomical access artery and renal artery conditions which qualify for catheter-based renal denervation according to the instructions for use and those where treatment is not yet generally recommended, mostly due to limitations of the catheter technologies currently available, e.g., no current device is approved for brachial or radial access. PMID- 23732159 TI - Treatment resistant hypertension and renal sympathetic denervation: drug adherence and the consolidation of blood pressure lowering effects. PMID- 23732160 TI - Current technologies: an introduction. PMID- 23732161 TI - Renal denervation: tips and tricks to perform a technically successful procedure. AB - To most practitioners involved in catheter-based interventions, percutaneous renal sympathetic denervation is not technically challenging. However, under specific clinical circumstances (e.g., renal insufficiency) or when faced with more complex abdominal aortic anatomy (e.g., tortuosity) some procedural tips may come in handy. Here we review the equipment, antiplatelet and anticoagulant strategy as well as the procedural technique, including tips and tricks for the successful performance of catheter-based renal denervation. Among other topics, carbon dioxide angiography and brachial artery access are discussed. PMID- 23732162 TI - Pathophysiology of renal denervation procedures: from renal nerve anatomy to procedural parameters. AB - Endovascular renal denervation techniques have been clinically adopted for the treatment of resistant arterial hypertension with great success. Despite the favourable early results achieved with this technology, a clear understanding of the pathophysiology underlying this novel treatment is lacking. In addition, non responsiveness to renal denervation remains a nidus for treatment failure in distinct patients. In search of meaningful surrogate parameters relating to treatment responsiveness, the current article reviews the existing knowledge on renal nerve anatomy, changes occurring after denervation and procedural parameters collected during denervation. From preclinical experience, the most reliable morphological parameter reflecting successful renal denervation is the presence of axonal degeneration. Most procedural and clinical parameters need extended investigation before adopting them as potential surrogate parameters for successful renal denervation. As a consequence, there is an imperative need for dedicated research revealing the pathophysiology of renal denervation procedures. In this regard, close co-operation of engineers, researchers and clinicians is warranted to turn renal denervation into a milestone treatment of arterial hypertension. PMID- 23732163 TI - Follow-up, study design and outcome parameters. AB - Renal sympathetic denervation has shown promise in treating hypertension resistant to drug therapy. This procedure lowers blood pressure via targeted attenuation of renal sympathetic tone. Up to now, it has also shown a favourable safety profile. Despite this, there is reason for cautious optimism, since longer follow-up is needed to address whether these effects may be considered definitive and to detect long-term side effects. To assess this, patients who have undergone this procedure should be submitted to a specific follow-up in centres of excellence in treating resistant hypertension. PMID- 23732164 TI - Functional outcomes in traumatic disorders of consciousness: 5-year outcomes from the National Institute on Disability and Rehabilitation Research Traumatic Brain Injury Model Systems. AB - OBJECTIVE: To characterize the 5-year outcomes of patients with traumatic brain injury (TBI) not following commands when admitted to acute inpatient rehabilitation. DESIGN: Secondary analysis of prospectively collected data from the National Institute on Disability and Rehabilitation Research-funded Traumatic Brain Injury Model Systems (TBIMS). SETTING: Inpatient rehabilitation hospitals participating in the TBIMS program. PARTICIPANTS: Patients (N=108) with TBI not following commands at admission to acute inpatient rehabilitation were divided into 2 groups (early recovery: followed commands before discharge [n=72]; late recovery: did not follow commands before discharge [n=36]). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FIM items. RESULTS: For the early recovery group, depending on the FIM item, 8% to 21% of patients were functioning independently at discharge, increasing to 56% to 85% by 5 years postinjury. The proportion functioning independently increased from discharge to 1 year, 1 to 2 years, and 2 to 5 years. In the late recovery group, depending on the FIM item, 19% to 36% of patients were functioning independently by 5 years postinjury. The proportion of independent patients increased significantly from discharge to 1 year and from 1 to 2 years, but not from 2 to 5 years. CONCLUSIONS: Substantial proportions of patients admitted to acute inpatient rehabilitation before following commands recover independent functioning over as long as 5 years, particularly if they begin to follow commands before hospital discharge. PMID- 23732165 TI - Rationale and design of the prospective German registry of outcome in patients with severe disorders of consciousness after acute brain injury. AB - OBJECTIVE: To describe the rationale and design of a new patient registry (Koma Outcome von Patienten der Fruhrehabilitation-Register [KOPF-R; Registry for Coma Outcome in Patients Undergoing Acute Rehabilitation]) that has the scope to examine determinants of long-term outcome and functioning of patients with severe disorders of consciousness (DOC). DESIGN: Prospective multicenter neurologic rehabilitation registry. SETTING: Five specialized neurologic rehabilitation facilities. PARTICIPANTS: Patients (N=42) with DOC in vegetative state or minimally conscious state (MCS) as defined by the Coma Recovery Scale-Revised (CRS-R) after brain injury. Patients are being continuously enrolled. The data presented here cover the enrollment period from August 2011 to January 2012. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: CRS-R, FIM, and emergence from MCS. RESULTS: The registry was set up in 5 facilities across the state of Bavaria/Germany with a special expertise in the rehabilitation of acquired brain injury. Inclusion of patients started in August 2011. Measures include sociodemographic and clinical characteristics, course of acute therapy, electrophysiologic measures (evoked potentials, electroencephalogram), neuron specific enolase, current medication, functioning, cognition, participation, quality of life, quantity and characteristics of rehabilitation therapy, caregiver burden, and attitudes toward end-of-life decisions. Main diagnoses were traumatic brain injury (24%), intracerebral or subarachnoid hemorrhage (31%), and anoxic-ischemic encephalopathy (45%). Mean CRS-R score +/- SD at admission to rehabilitation was 5.9 +/- 3.3, and mean FIM score +/- SD at admission was 18 +/- 0.4. CONCLUSIONS: The KOPF-R aspires to contribute prospective data on prognosis in severe DOC. PMID- 23732166 TI - Specialized early treatment for persons with disorders of consciousness: program components and outcomes. AB - OBJECTIVES: To describe a specialized early treatment program for persons with disorders of consciousness (DOC) that includes family education; to identify rates of secondary conditions, imaging used, and selected interventions; and to evaluate outcomes. DESIGN: A single-center, retrospective, pre-post design using electronic medical record data. SETTING: A Commission on Accreditation of Rehabilitation Facilities-accredited, long-term acute care hospital that provides acute medical and inpatient rehabilitation levels of care for people with catastrophic injuries. PARTICIPANTS: Persons (N=210) aged 14 to 69 years with DOC of primarily traumatic etiology admitted at a mean +/- SD of 41.0 +/- 27.2 days postinjury; 2% were in coma, 41% were in the vegetative state, and 57% were in the minimally conscious state. INTERVENTIONS: An acute medical level of care with >=90 minutes of daily interdisciplinary rehabilitation and didactic and hands-on caretaking education for families. MAIN OUTCOME MEASURES: Coma Recovery Scale Revised, Modified Ashworth Scale, and discharge disposition. RESULTS: Program admission medical acuity included dysautonomia (15%), airway modifications (79%), infections (eg, pneumonia, 16%; urinary tract infection, 14%; blood, 11%), deep vein thrombosis (17%), pressure ulcers (14%), and marked hypertonia (30% in each limb). There were 168 program interruptions (ie, 139 surgeries, 29 nonsurgical intensive care unit transfers). Mean length of stay +/- SD was 39.1 +/- 29.4 days (range, 6-204d). Patients showed improved consciousness and respiratory function and reduced presence or severity of pressure ulcers and upper extremity hypertonia. At discharge, 54% showed sufficient emergence from a minimally conscious state to transition to mainstream inpatient rehabilitation, and 29% did not emerge but were discharged home to family with ongoing programmatic support; only 13% did not emerge and were institutionalized. CONCLUSIONS: Persons with DOC resulting primarily from a traumatic etiology who receive specialized early treatment that includes acute medical care and >=90 minutes of daily rehabilitation are likely to show improved consciousness and body function; more than half may transition to mainstream inpatient rehabilitation. Families who receive comprehensive education and hands-on training with ongoing follow-up support may be twice as likely to provide care for medically stable persons with DOC in their homes versus nursing facility placement. PMID- 23732167 TI - Interstitial cystitis: another IgG4-related inflammatory disease? AB - Interstitial cystitis (IC) is a disease of undetermined etiology and pathogenesis. Inflammation is thought to play a key role in many patients, characteristically with an increase in mast cells within the detrusor muscle of the bladder. We observed that some patients with IC had prominent plasma cells in bladder tissue, which elicited our interest in their possible pathogenic role in patients with IC. A total of 44 cases of IC were collected, including 42 bladder biopsies and 2 cystectomies. Patient age ranged from 18 to 92 years (average age of 49.5 years) and included 7 male and 37 female patients. The histology and immunostains for IgG, IgG4 and tryptase were examined, and the results were correlated with clinical and cystoscopic findings. Four cases showed a significant increase in IgG4-positive plasma cells, with greater than 30 IgG4 plasma cells per high-power field and an IgG4/IgG ratio greater than 0.5. In addition, statistically significant differences were found between IC with IgG4 positive plasma cells vs IgG4-negative cases. The IgG4-positive patients were of older age and had increased severe inflammation and decreased bladder capacity as compared with the IgG4-negative patients. We propose that a subset of patients with IC may have an IgG4-related disease, and further study including serum IgG4 measurement is required to better define this relationship. PMID- 23732168 TI - Inhibition of water absorption and selective damage to human colonic mucosa are induced by subtilase cytotoxin produced by Escherichia coli O113:H21. AB - Shiga toxin-producing Escherichia coli O157:H7 (STEC) is by far the most prevalent serotype associated with hemolytic uremic syndrome (HUS) although many non-O157 STEC strains have been also isolated from patients with HUS. The main virulence factor of STEC is the Shiga toxin type 2 (Stx2) present in O157 and non O157 strains. Recently, another toxin, named subtilase cytotoxin (SubAB), has been isolated from several non-O157 strains and may contribute to the pathogenesis of HUS. Here, we have demonstrated that an O113:H21 STEC strain expressing SubAB and Stx2 inhibits normal water absorption across human colon and causes damage to the surface epithelium, necrosis, mononuclear inflammatory infiltration, edema, and marked mucin depletion. This damage was less marked, but nevertheless significant, when purified SubAB or E. coli O113:H21 expressing only SubAB was assayed. This is the first study showing that SubAB may directly participate in the mechanisms of diarrhea in children infected with non-O157 STEC strains. PMID- 23732169 TI - Gallbladder epithelium as a niche for chronic Salmonella carriage. AB - Although typhoid fever has been intensively studied, chronic typhoid carriage still represents a problem for the transmission and persistence of the disease in areas of endemicity. This chronic state is highly associated with the presence of gallstones in the gallbladder of infected carriers upon which Salmonella can form robust biofilms. However, we hypothesize that in addition to gallstones, the gallbladder epithelium aids in the establishment/maintenance of chronic carriage. In this work, we present evidence of the role of the gallbladder epithelium in chronic carriage by a mechanism involving invasion, intracellular persistence, and biofilm formation. Salmonella was able to adhere to and invade polarized gallbladder epithelial cells apically in the absence and presence of bile in a Salmonella pathogenicity island 1 (SPI-1)-dependent manner. Intracellular replication of Salmonella was also evident at 12 and 24 h postinvasion. A flowthrough system revealed that Salmonella is able to adhere to and form extensive bacterial foci on gallbladder epithelial cells as early as 12 h postinoculation. In vivo experiments using a chronic mouse model of typhoid carriage showed invasion and damage of the gallbladder epithelium and lamina propria up to 2 months after Salmonella infection, with an abundant presence of macrophages, a relative absence of neutrophils, and extrusion of infected epithelial cells. Additionally, microcolonies of Salmonella cells were evident on the surface of the mouse gallbladder epithelia up to 21 days postinfection. These data reveal a second potential mechanism, intracellular persistence and/or bacterial aggregation in/on the gallbladder epithelium with luminal cell extrusion, for Salmonella maintenance in the gallbladder. PMID- 23732172 TI - The right ingredients: essential if you want to bake the cake right! PMID- 23732171 TI - The RNA chaperone Hfq promotes fitness of Actinobacillus pleuropneumoniae during porcine pleuropneumonia. AB - Actinobacillus pleuropneumoniae is the etiological agent of porcine pleuropneumonia, an economically important disease of pigs. The hfq gene in A. pleuropneumoniae, encoding the RNA chaperone and posttranscriptional regulator Hfq, is upregulated during infection of porcine lungs. To investigate the role of this in vivo-induced gene in A. pleuropneumoniae, an hfq mutant strain was constructed. The hfq mutant was defective in biofilm formation on abiotic surfaces. The level of pgaC transcript, encoding the biosynthesis of poly-beta 1,6-N-acetylglucosamine (PNAG), a major biofilm matrix component, was lower and PNAG content was 10-fold lower in the hfq mutant than in the wild-type strain. When outer membrane proteins were examined, cysteine synthase, implicated in resistance to oxidative stress and tellurite, was not found at detectable levels in the absence of Hfq. The hfq mutant displayed enhanced sensitivity to superoxide generated by methyl viologen and tellurite. These phenotypes were readily reversed by complementation with the hfq gene expressed from its native promoter. The role of Hfq in the fitness of A. pleuropneumoniae was assessed in a natural host infection model. The hfq mutant failed to colonize porcine lungs and was outcompeted by the wild-type strain (median competitive index of 2 * 10(-5)). Our data demonstrate that the in vivo-induced gene hfq is involved in the regulation of PNAG-dependent biofilm formation, resistance to superoxide stress, and the fitness and virulence of A. pleuropneumoniae in pigs and begin to elucidate the role of an in vivo-induced gene in the pathogenesis of pleuropneumonia. PMID- 23732170 TI - Persistence, immune response, and antigenic variation of Mycoplasma genitalium in an experimentally infected pig-tailed macaque (Macaca nemestrina). AB - Mycoplasma genitalium is a sexually transmitted pathogen associated with several acute and chronic reproductive tract disease syndromes in men and women. To evaluate the suitability of a pig-tailed macaque model of M. genitalium infection, we inoculated a pilot animal with M. genitalium strain G37 in the uterine cervix and in salpingeal pockets generated by transplanting autologous Fallopian tube tissue subcutaneously. Viable organisms were recovered throughout the 8-week experiment in cervicovaginal specimens and up to 2 weeks postinfection in salpingeal pockets. Humoral and cervicovaginal antibodies reacting to MgpB were induced postinoculation and persisted throughout the infection. The immunodominance of the MgpB adhesin and the accumulation of mgpB sequence diversity previously observed in persistent human infections prompted us to evaluate sequence variation in this animal model. We found that after 8 weeks of infection, sequences within mgpB variable region B were replaced by novel sequences generated by reciprocal recombination with an archived variant sequence located elsewhere on the chromosome. In contrast, mgpB region B of the same inoculum propagated for 8 weeks in vitro remained unchanged. Notably, serum IgG reacted strongly with a recombinant protein spanning MgpB region B of the inoculum, while reactivity to a recombinant protein representing the week 8 variant was reduced, suggesting that antibodies were involved in the clearance of bacteria expressing the original infecting sequence. Together these results suggest that the pig-tailed macaque is a suitable model to study M. genitalium pathogenesis, antibody-mediated selection of antigenic variants in vivo, and immune escape. PMID- 23732173 TI - Individually optimized hemodynamic therapy reduces complications and length of stay in the intensive care unit: a prospective, randomized controlled trial. AB - BACKGROUND: The authors hypothesized that goal-directed hemodynamic therapy, based on the combination of functional and volumetric hemodynamic parameters, improves outcome in patients with cardiac surgery. Therefore, a therapy guided by stroke volume variation, individually optimized global end-diastolic volume index, cardiac index, and mean arterial pressure was compared with an algorithm based on mean arterial pressure and central venous pressure. METHODS: This prospective, controlled, parallel-arm, open-label trial randomized 100 coronary artery bypass grafting and/or aortic valve replacement patients to a study group (SG; n = 50) or a control group (CG; n = 50). In the SG, hemodynamic therapy was guided by stroke volume variation, optimized global end-diastolic volume index, mean arterial pressure, and cardiac index. Optimized global end-diastolic volume index was defined before and after weaning from cardiopulmonary bypass and at intensive care unit (ICU) admission. Mean arterial pressure and central venous pressure served as hemodynamic goals in the CG. Therapy was started immediately after induction of anesthesia and continued until ICU discharge criteria, serving as primary outcome parameter, were fulfilled. RESULTS: Intraoperative need for norepinephrine was decreased in the SG with a mean (+/-SD) of 9.0 +/- 7.6 versus 14.9 +/- 11.1 ug/kg (P = 0.002). Postoperative complications (SG, 40 vs. CG, 63; P = 0.004), time to reach ICU discharge criteria (SG, 15 +/- 6 h; CG, 24 +/- 29 h; P < 0.001), and length of ICU stay (SG, 42 +/- 19 h; CG, 62 +/- 58 h; P = 0.018) were reduced in the SG. CONCLUSION: Early goal-directed hemodynamic therapy based on cardiac index, stroke volume variation, and optimized global end diastolic volume index reduces complications and length of ICU stay after cardiac surgery. PMID- 23732174 TI - Effect of deep tissue incision on pH responses of afferent fibers and dorsal root ganglia innervating muscle. AB - BACKGROUND: Understanding the mechanisms underlying deep tissue pain in the postoperative period is critical to improve therapies. Using the in vitro plantar flexor digitorum brevis muscle-nerve preparation and patch clamp recordings from cultured dorsal root ganglia neurons innervating incised and unincised muscle, the authors investigated responses to various pH changes. METHODS: Incision including the plantar flexor digitorum brevis muscle or sham operation was made in the rat hind paw. On postoperative day 1, in vitro single-fiber recording was undertaken. On the basis of previous studies, the authors recorded from at least 40 fibers per group. Also DiI-labeled dorsal root ganglia innervating muscle from rats undergoing incision and a sham operation were cultured and tested for acid responses, using whole cell patch clamp recordings. RESULTS: The prevalence of responsive group IV afferents to lactic acid pH 6.5 in the incision group (15 of 67; 22.3%) was greater than that in the control group (2 of 35; 5.7%; P=0.022). In dorsal root ganglia neurons innervating muscle, incision increased mean current amplitudes of acid-evoked currents; the acid-sensing ion channel blocker, amiloride 300 MUM, inhibited more than 75% of the acid-evoked current, whereas, the transient receptor vanilloid receptor 1 blocker (AMG9810 1 MUM) did not cause significant inhibition. CONCLUSION: The authors' experiments demonstrated that incision increases the responses of flexor digitorum brevis muscle afferent fibers to weak acid solutions, and increased acid-evoked currents in dorsal root ganglia innervating muscle. The authors' data suggest that up-regulation of acid sensing ion channels might underlie this increased chemosensitivity caused by surgery. PMID- 23732175 TI - Growth control, structure, chemical state, and photoresponse of CuO-CdS core shell heterostructure nanowires. AB - The growth of single-crystal CuO nanowires by thermal annealing of copper thin films in air is studied. We show that the density, length, and diameter of the nanowires can be controlled by tuning the morphology and structure of the copper thin films deposited by DC magnetron sputtering. After identifying the optimal conditions for the growth of CuO nanowires, chemical bath deposition is employed to coat the CuO nanowires with CdS in order to form p-n nanojunction arrays. As revealed by high-resolution TEM analysis, the thickness of the polycrystalline CdS shell increases when decreasing the diameter of the CuO core for a given time of CdS deposition. Near-edge x-ray absorption fine-structure spectroscopy combined with transmission x-ray microscopy allows the chemical analysis of isolated nanowires. The absence of modification in the spectra at the Cu L and O K edges after the deposition of CdS on the CuO nanowires indicates that neither Cd nor S diffuse into the CuO phase. We further demonstrate that the core-shell nanowires exhibit the I-V characteristic of a resistor instead of a diode. The electrical behavior of the device was found to be photosensitive, since increasing the incident light intensity induces an increase in the collected electrical current. PMID- 23732176 TI - The Tox21 robotic platform for the assessment of environmental chemicals--from vision to reality. AB - Since its establishment in 2008, the US Tox21 inter-agency collaboration has made great progress in developing and evaluating cellular models for the evaluation of environmental chemicals as a proof of principle. Currently, the program has entered its production phase (Tox21 Phase II) focusing initially on the areas of modulation of nuclear receptors and stress response pathways. During Tox21 Phase II, the set of chemicals to be tested has been expanded to nearly 10,000 (10K) compounds and a fully automated screening platform has been implemented. The Tox21 robotic system combined with informatics efforts is capable of screening and profiling the collection of 10K environmental chemicals in triplicate in a week. In this article, we describe the Tox21 screening process, compound library preparation, data processing, and robotic system validation. PMID- 23732177 TI - NIPTE: a multi-university partnership supporting academic drug development. AB - The strategic goal of academic translational research is to accelerate translational science through the improvement and development of resources for moving discoveries across translational barriers through 'first in humans' studies. To achieve this goal, access to drug discovery resources and preclinical IND-enabling infrastructure is crucial. One potential approach of research institutions for coordinating preclinical development, based on a model from the National Institute for Pharmaceutical Technology and Education (NIPTE), can provide academic translational and medical centers with access to a wide variety of enabling infrastructure for developing small molecule clinical candidates in an efficient, cost-effective manner. PMID- 23732178 TI - Cell-specific delivery of biologicals: problems, pitfalls and possibilities of antifibrotic compounds in the liver. AB - Liver fibrosis is a complex disease affecting millions of people world-wide. It involves the activation of several cell types whose activities are tightly controlled by endogenous mediators. No pharmacotherapy is available for this disease, despite the fact that many experimental drugs are very effective in vitro and the liver is easily accessible for most drugs. Our review provides arguments showing that cell-selectivity is essential for most antifibrotics. Several cell-specific drug carriers targeting the key pathogenic liver cells are discussed with special focus on hepatic stellate cells and fibroblast-like cells. Since endogenous mediators represent a powerful set of tools to modify the pathogenic process, this review focuses on these mediators as therapeutics and the problems and pitfalls associated with the use of such biologicals. PMID- 23732179 TI - Complications and Outcomes for Surgical Approaches to Cervical Kyphosis. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The primary objective of this study is to report the safety and efficacy of the different surgical approaches to cervical deformity correction surgery. SUMMARY OF BACKGROUND DATA: Cervical subaxial deformity surgery has been shown to be an effective means to alleviate pain and improve neurological function in symptomatic patients. The reported outcomes and complications for the different surgical approaches (ventral, dorsal, and combined) are limited to small retrospective studies. The appropriate surgical approach is at times unclear, which is likely attributed to the overlap in indications for the ventral and combined approach. MATERIALS AND METHODS: A retrospective review of 76 patients who underwent cervical deformity surgery for cervical kyphosis at 1 institution was performed. The authors reviewed the complications, radiographic outcomes, and long-term functional outcomes for all patients. RESULTS: The majority of patients in all groups reported excellent (15%) or good (50%) outcomes, with a mean improvement in modified Japanese orthopedic association score of 1.3. There were 26 perioperative complications (34%) for 19 patients (25%). We found the ventral alone and combined approaches to achieve similar degrees of correction (23.1 and 23.2 degrees, respectively). The combined approach had the highest complication rate of the 3 approaches (combined: 40%, ventral: 30%, dorsal: 27%). The dorsal, ventral, and combined approaches had a mean neurological improvement in modified Japanese orthopedic association scores of 1.95, 3.00, and 1.26, respectively, and mean pain improvement of 0.8, 2.0, and 1.4. CONCLUSIONS: Given the moderate improvements in long-term outcomes, and the risks for perioperative complications, we recommend a careful selection process for patients eligible for cervical deformity surgery. We found that the ventral approach has reduced complications, similar degree of correction capability, and potentially higher improved neurological outcomes compared to the combined approach. PMID- 23732180 TI - Comparison of 2 kinds of pedicle screws in primary spinal instrumentation: biomechanical and interfacial evaluations in sheep vertebrae in vitro. AB - STUDY DESIGN: Expansive pedicle screw (EPS) and polymethylmethacrylate-augmented pedicle screw (PMMA-PS) were inserted in sheep vertebrae in vitro and were evaluated by performing biomechanical tests, radiographic examinations and histological observations. OBJECTIVE: The objective of the study was to compare the biomechanical and interfacial performances of EPS and PMMA-PS in sheep lumbar vertebrae in vitro. SUMMARY OF BACKGROUND DATA: It is a great challenge for orthopedic surgeons performing transpedicular fixation in the osteoporotic spine. It was reported that either the EPS or PMMA-PS could increase the screw stability. However, there are no studies comparing the 2 kinds of screws especially in primary spinal instrumentation. METHODS: A total of 60 sheep lumbar vertebrae were randomly divided into 3 groups. A pilot hole was made in advance in all samples using the same method. Thereafter, the conventional pedicle screw (CPS) was inserted directly into the pilot hole in the CPS group; the hole in PMMA-PS group was first filled with polymethylmethacrylate (PMMA; 1.0 mL) and then inserted with CPS; and the EPS was inserted directly into the vertebrae in EPS group. After a period of 24 hours, biomechanical tests were performed to evaluate screw stability, and x-ray examination, micro-computerized tomography analysis, and histologic observation were performed to evaluate the interface between screw and bone. RESULTS: Compared with the stability of CPS, those of EPS and PMMA-PS were significantly enhanced. However, no significant differences were detected between the stabilities of EPS and PMMA-PS. The PMMA surrounding the screw blocked direct contact between bone and screw and formed a "screw-PMMA bone" interface in the PMMA-PS group. There was a "screw-bone" interface in both CPS and EPS groups. Nevertheless, the expanded anterior part of EPS formed a claw like structure pressing the surrounding bone trabeculae, which made the local bone tissue more compacted and denser than that in the CPS group. CONCLUSIONS: EPS can enhance the screw stability as markedly as the traditional PMMA-PS in primary surgery, and EPS can form a better immediate interface between screw and bone compared with PMMA-PS. EPS also can effectively avoid thermal injury, leakage, and compression caused by PMMA. A great feasibility was proved in this study to perform comparisons between the 2 kinds of pedicle screws in osteoporotic sheep vertebrae in vivo in the further research. In conclusion, we propose that EPS has a great application potential in augmentation of screw stability in the clinic. PMID- 23732181 TI - Radiographic risk factors and surgical outcomes for retroodontoid pseudotumors. AB - STUDY DESIGN: Retrospective review. OBJECTIVE: The aim of this study is to assess the radiographic characteristics of patients with a retroodontoid pseudotumor and to evaluate the efficacy of posterior fusion. SUMMARY OF BACKGROUND DATA: Retroodontoid pseudotumors are usually caused by chronic atlantoaxial instability in patients with rheumatoid arthritis (RA). However, the pathomechanism and optimum treatment are unknown. METHODS: We reviewed the charts and radiographs of 11 patients (5 RA and 6 non-RA) with a retroodontoid pseudotumor who underwent posterior fusion. Preoperative radiographs were evaluated for atlantodental interval; Redlund-Johnell criterion; O-C1, C1-2, C2-3, and C2-7 angles. The Japanese Orthopaedic Association (JOA) score was used to evaluate clinical outcomes. RESULTS: All RA patients and 1 non-RA patient displayed atlantoaxial subluxation. Three patients underwent occipitocervical fusion and 8 patients atlantoaxial fusion. The JOA score improved significantly from 10.0 to 12.8 at follow-up (P<0.01). The retroodontoid pseudotumor regressed in 10 patients. Maximal thickness of the pseudotumor decreased from 8.9 mm preoperatively to 5.3 mm (P<0.01) at follow-up. In non-RA patients, the mean differences (Delta) between flexion and extension were 7.8, 13.4, 3.5, and 18.5 degrees for DeltaO C1, DeltaC1-2, DeltaC2-3, and DeltaC2-7, respectively. CONCLUSIONS: In RA patients, a retroodontoid pseudotumor may develop because of atlantoaxial subluxation. In non-RA patients, excessive atlantoaxial angular motion because of the limited range of motion of O-C1 and/or subaxial vertebra may cause a pseudotumor. Atlantoaxial fusion to suppress atlantoaxial instability is one of the optimum treatments. PMID- 23732182 TI - Application of the hemi-semi-laminectomy approach in the microsurgical treatment of C2 schwannomas. AB - STUDY DESIGN: Retrospective analysis of 9 cases of C2 schwannomas who were treated microsurgically with hemi-semi-laminectomy approach. OBJECTIVE: To review the clinical data and describe several operative nuances and pearls from our experience about the hemi-semi-laminectomy approach that provided successful resection of C2 schwannomas. SUMMARY OF BACKGROUND DATA: Compared with hemi laminectomy, the hemi-semi-laminectomy is a more minimally invasive approach for excising spinal neurinomas, which can preserve as much of the mechanically relevant bone structures and facet joints as possible. There are no previous reports about the resection of C2 schwannomas with the hemi-semi-laminectomy approach. METHODS: Between June 2006 and February 2011, a consecutive series of 9 patients underwent surgery for C2 schwannomas. All patients were treated microsurgically with a midline posterior hemi-semi-laminectomy approach. Data regarding age, sex, duration and type of symptoms, topographical locations, and surgical results were investigated retrospectively. RESULTS: Of the 9 C2 schwannomas, 8 were located both intradurally and extradurally (dumbbell shaped), and 1 was located extradurally. The initial symptom was numbness of the extremity in 7 patients, neck pain in 1 patient, and clumsiness of the upper extremity in 1 patient. The average duration from initial symptom to surgery was 7.9 months. The average follow-up time was 39.6 months. There were no major surgical complications and tumor recurrence during the follow-up period. Remarkable neurological recovery was observed in 9 patients. CONCLUSIONS: The hemi-semi laminectomy is a more minimally invasive approach that can preserve as much of the mechanically relevant bone structures as possible, so that the integrity of the arch of the atlas and the lamina of C2 can be maintained. This approach can provide sufficient field for the resection of the C2 schwannomas that do not extend to the ventral side of the vertebral artery in the anterolateral direction. The minimally invasive access and the remarkable results associated with this approach make it a valid alternative in selected cases. PMID- 23732183 TI - Research on safety of single-stage multisegmental thoracolumbar percutaneous balloon vertebroplasty. AB - STUDY DESIGN: This is a prospective study evaluating the safety of single-stage multisegmental thoracolumbar percutaneous balloon vertebroplasty (PVP). OBJECTIVE: To discuss the safety of single-stage multisegmental thoracolumbar PVP. SUMMARY OF BACKGROUND DATA: The PVP is a minimally invasive surgery. It is mainly used in the treatment of individuals with serious back pain caused by osteoporotic compression fracture, vertebral metastatic tumors, symptomatic vertebral hemangioma, and multiple myeloma. METHODS: A total of 50 patients underwent the PVP on 3 or more vertebras compared with 50 cases of PVP on 1 or 2 vertebras. Assessment indexes of safety were: operation time, intraoperative blood pressure change, intraoperative oxyhemoglobin saturation change, intraoperative mental state of patients, postoperative x-ray examination, and results of computed tomography and complications. RESULTS: (1) Average operation time of group A was 125 minutes and that of group B was 56 minutes. (2) Change in arterial pressure of group A was more significant compared with group B, when assessed using the chi test. (3) Pain intensity of group A was compared with group B and a statistical difference was seen only in the patients who underwent PVP on 3 or more vertebras on the first day after surgery. (4) Change in oxyhemoglobin saturation (decreased under 90%) of group A was found to be more significant compared with group B, when assessed using the chi test. (5) No statistical difference in emotional state was found between the 2 groups. (6) There were 4 cases of perivertebral leakage, 1 case of intrapulmonary leakage, and 2 cases of symptoms of intercostal nerve stimulation in group A and 3 cases of perivertebral leakage, 1 case of intrapulmonary leakage, and 1 case of symptoms of intercostal nerve stimulation in group B. CONCLUSIONS: High risk exists in single-stage multisegmental thoracolumbar percutaneous vertebroplasty, especially during puncture and bone cement injection, which may cause wide fluctuation of blood pressure and reduce oxygen saturation sharply; however, the surgery is safe to a certain extent, although it requires close intraoperative supervision and shortened operation time. PMID- 23732184 TI - The validity and reliability of noninvasive methods for measuring kyphosis. AB - STUDY DESIGN: This is a cross-sectional study. OBJECTIVE: To examine the interrater and intrarater reliability and validity of tools for measuring thoracic kyphosis, namely the digital inclinometer and the flexicurve. SUMMARY OF BACKGROUND DATA: Various methods are used to measure kyphosis, and each has its own advantages and disadvantages. Radiography is common, highly reliable, and valid but unsuitable for regular use because of radiation exposure and cost. Other clinical methods allow safe and rapid assessment of spinal curvature. The validity and reliability of some nclinometers have been confirmed; however, there are no data that compare inclinometers and flexicurves using radiography for measuring thoracic kyphosis. METHODS: We enrolled 105 patients with hyperkyphosis, aged between 10 and 80 years. The Cobb angle was measured radiographically by a spine specialist. Two other examiners, blinded to the Cobb angles, measured thoracic kyphosis using the flexicurve and digital inclinometer. RESULTS: Comparing the kyphosis angle with the radiographic Cobb angle, as a gold standard, revealed that the digital inclinometer was reasonably valid for patients aged below 30 and above 50 years, whereas the validity of the flexicurve in both age ranges was poor. On the intrarater evaluation, the digital inclinometer provided a high reliability in patients aged below 30 and above 50 years; however, the flexicurve was also acceptable in this regard. In contrast, on the interrater evaluation, the digital inclinometer provided a high reliability in subjects aged below 30 and above 50 years. The flexicurve provided a poor interrater reliability in subjects aged below 30 years and an acceptable level of reliability in those aged above 50 years. CONCLUSIONS: The digital inclinometer is a valid and reliable instrument for measuring thoracic kyphosis and can be used for regular screening. In contrast, the flexicurve has poor interrater and intrarater reliability. PMID- 23732185 TI - Acrylic kyphoplasty in recent nonosteoporotic fractures of the thoracolumbar junction: a prospective clinical and 3D radiologic study of 54 patients. AB - STUDY DESIGN: Prospective clinical and radiological study. OBJECTIVES: To evaluate the impact of stand-alone acrylic kyphoplasty in the treatment of recent traumatic fractures of the thoracolumbar spine in young patients. SUMMARY OF BACKGROUND DATA: The management of fractures of the thoracolumbar spine without neurological deficit remains controversial. For a long time clinicians could only chose between functional treatment, orthopedic treatment, and traditional surgery. The recent advent of minimally invasive surgical techniques is an interesting alternative. MATERIALS AND METHODS: Fifty-four patients with a mean age of 45.8+/-18.2 years and who had recently sustained a fracture of the thoracolumbar junction were enrolled into the study. Balloon kyphoplasty was performed using acrylic cement. Radiologic assessments (computed tomography scans) and clinical assessments (including Visual Analog Scale and Oswestry Disability Index scores) were used to determine kyphoplasty success and measure patient recovery over 2 years. RESULTS: Kyphoplasty reduced mean vertebral kyphosis from 12.8+/-5.0 degrees at trauma to 8.2+/-5.1 degrees at 2-year follow up. Mean vertebral kyphosis was corrected by -5.7+/-4.7 degrees (P=0.0001) at the point of first verticalization, with no significant change at the 2-year follow up visit (+1.1+/-4.3 degrees, P=0.1058). Kyphoplasty significantly augmented the height of the 6 anterior and intermediate segments. Maximum mean augmentation of intermediate vertebral height after 6 months was (11.6%+/-15.5%, P<0.0001). Patients tolerated the procedure well and 56% of them returned to work 3 months after kyphoplasty. CONCLUSION: Kyphoplasty is safe and effective in the correction of nonosteoporotic fractures of the thoracolumbar junction in young patients, and remains stable for at least 2 years postsurgery. PMID- 23732186 TI - Do CT scans overestimate the fusion rate after anterior cervical discectomy and fusion? AB - DESIGN: This study is a radiographic analysis. OBJECTIVE: To compare the fusion rates after anterior cervical discectomy and fusion (ACDF) using x-rays versus computerized tomography (CT). BACKGROUND: Although fusion status may be obvious when evaluating ACDFs performed in the remote past, determining the presence of a solid fusion at earlier time points after ACDF is often ambiguous but a necessary part of practice. Commonly used tools include radiographs and CT scans. Currently, there is no gold standard imaging modality to determine fusion status. METHODS: Twenty-two patients status post-ACDF (cortical allograft with anterior plates) at 34 levels with CT scans and dynamic x-rays obtained at 3, 6, and 12 months postoperatively were included. Four spine surgeons blinded to the time point independently determined fusion status according to the criteria. RESULTS: On the basis of the x-ray criteria, the fusion rates were 26%, 41%, and 65% at 3, 6, and 12 months, respectively, postoperatively. On the basis of CT criteria, the fusion rates were 79%, 79%, and 91% at 3, 6, and 12 months, respectively. There was a significant difference in the predicted fusion rate at each time point comparing x-ray versus CT criteria. In addition, at 3 months, 41% of the levels (11/27) thought to be fused by CT criteria demonstrated >1 mm motion on dynamic x rays. At 6 months, 33% (9/27) of the levels thought to be fused by CT demonstrated persistent motion of >=1 mm. At 12 months, 23% (7/31) of the levels considered fused by CT still had persistent motion. DISCUSSION: X-ray criteria for fusion, which incorporate both static and dynamic factors, predicted lower fusion rates at each time point when compared with CT scans, which evaluate only static factors. Depending on the time point, anywhere from 23% to 41% of levels thought to be fused by CT criteria demonstrated persistent motion on dynamic x rays. Although <1 mm motion is not a sufficient criteria for fusion by itself, levels demonstrating >1 mm motion are less likely to be solidly fused. Thus, we conclude that CT scans may overestimate the fusion rate during the early stages of ACDF healing with cortical allograft, and that CT scans alone may not accurately determine fusion status. Reliable determination of fusion may thus require dynamic information obtained from flexion-extension x-ray in association with high-resolution static information from CT. PMID- 23732188 TI - Anger, injustice, and the continuing search for psychological mechanisms of pain, suffering, and disability. PMID- 23732190 TI - Unravelling intention: distal intentions increase the subjective sense of agency. AB - Experimental studies investigating the contribution of conscious intention to the generation of a sense of agency for one's own actions tend to rely upon a narrow definition of intention. Often it is operationalized as the conscious sensation of wanting to move right before movement. Existing results and discussion are therefore missing crucial aspects of intentions, namely intention as the conscious sensation of wanting to move in advance of the movement. In the present experiment we used an intentional binding paradigm, in which we distinguished between immediate (proximal) intention, as usually investigated, and longer standing (distal) intention. The results showed that the binding effect was significantly enhanced for distal intentions compared to proximal intentions, indicating that the former leads to stronger sense of agency. Our finding provides empirical support for a crucial distinction between at least two types of intention when addressing the efficacy of conscious intentions. PMID- 23732189 TI - Duloxetine and pregabalin: high-dose monotherapy or their combination? The "COMBO DN study"--a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. AB - This multicentre, double-blind, parallel-group study in diabetic peripheral neuropathic pain addressed whether, in patients not responding to standard doses of duloxetine or pregabalin, combining both medications is superior to increasing each drug to its maximum recommended dose. For initial 8-week therapy, either 60 mg/day duloxetine (groups 1, 2) or 300 mg/day pregabalin (groups 3, 4) was given. Thereafter, in the 8-week combination/high-dose therapy period, only nonresponders received 120 mg/day duloxetine (group 1), a combination of 60 mg/day duloxetine and 300 mg/day pregabalin (groups 2, 3), or 600 mg/day pregabalin (group 4). Primary outcome (Brief Pain Inventory Modified Short Form [BPI-MSF] 24-hour average pain change after combination/high-dose therapy) was analyzed comparing combination (groups 2, 3 pooled) with high-dose monotherapy (groups 1, 4 pooled). Secondary end points included response rates, BPI-MSF severity items, and comparison of duloxetine and pregabalin in BPI-MSF average pain. Eight hundred four patients were evaluated for initial therapy and 339 for combination/high-dose therapy. There were no significant differences between combination and high-dose monotherapy regarding BPI-MSF average pain (mean change: combination: -2.35; high-dose monotherapy: -2.16; P = 0.370) and most secondary end points, which, however, consistently favoured combination therapy. Fifty-percent response rates were 52.1% for combination and 39.3% for high-dose monotherapy (P = 0.068). In exploratory analyses of the initial 8-week therapy uncorrected for multiple comparisons, 60 mg/day duloxetine was found superior to 300 mg/day pregabalin (P < 0.001). Both drugs and their combination were well tolerated. Although not significantly superior to high-dose monotherapy, combination therapy was considered to be effective, safe, and well tolerated. PMID- 23732191 TI - The influence of total solids content and initial pH on batch biohydrogen production by solid substrate fermentation of agroindustrial wastes. AB - Hydrogen is a valuable clean energy source, and its production by biological processes is attractive and environmentally sound and friendly. In Mexico 5 million tons/yr of agroindustrial wastes are generated; these residues are rich in fermentable organic matter that can be used for hydrogen production. On the other hand, batch, intermittently vented, solid substrate fermentation of organic waste has attracted interest in the last 10 years. Thus the objective of our work was to determine the effect of initial total solids content and initial pH on H2 production in batch fermentation of a substrate that consisted of a mixture of sugarcane bagasse, pineapple peelings, and waste activated sludge. The experiment was a response surface based on 2(2) factorial with central and axial points with initial TS (15-35%) and initial pH (6.5-7.5) as factors. Fermentation was carried out at 35 degrees C, with intermittent venting of minireactors and periodic flushing with inert N2 gas. Up to 5 cycles of H2 production were observed; the best treatment in our work showed cumulative H2 productions (ca. 3 mmol H2/gds) with 18% and 6.65 initial TS and pH, respectively. There was a significant effect of TS on production of hydrogen, the latter decreased with initial TS increase from 18% onwards. Cumulative H2 productions achieved in this work were higher than those reported for organic fraction of municipal solid waste (OFMSW) and mixtures of OFMSW and fruit peels waste from fruit juice industry, using the same process. Specific energetic potential due to H2 in our work was attractive and fell in the high side of the range of reported results in the open literature. Batch dark fermentation of agrowastes as practiced in our work could be useful for future biorefineries that generate biohydrogen as a first step and could influence the management of this type of agricultural wastes in Mexico and other countries and regions as well. PMID- 23732192 TI - Geochemical baseline level and function and contamination of phosphorus in Liao River Watershed sediments of China. AB - The quantitative assessment of P contamination in sediments is a challenge due to sediment heterogeneity and the lacking of geochemical background or baseline levels. In this study, a procedure was proposed to determine the average P background level and P geochemical baseline level (GBL) and develop P geochemical baseline functions (GBF) for riverbed sediments of the Liao River Watershed (LRW). The LRW has two river systems - the Liao River System (LRS) and the Daliao River System (DRS). Eighty-eight samples were collected and analyzed for P, Al, Fe, Ca, organic matter, pH, and texture. The results show that Fe can be used as a better particle-size proxy to construct the GBF of P (P (mg/kg) = 39.98 + 166.19 * Fe (%), R(2) = 0.835, n = 66). The GBL of P was 675 mg/kg, while the average background level of P was 355 mg/kg. Noting that many large cities are located in the DRS watershed, most of the contaminated sites were located within the DRS and the riverbed sediments were more contaminated by P in the DRS watershed than in the LRS watershed. The geochemical background and baseline information of P are of great importance in managing P levels within the LRW. PMID- 23732193 TI - Integrated assessment of policy interventions for promoting sustainable irrigation in semi-arid environments: a hydro-economic modeling approach. AB - Sustaining irrigated agriculture to meet food production needs while maintaining aquatic ecosystems is at the heart of many policy debates in various parts of the world, especially in arid and semi-arid areas. Researchers and practitioners are increasingly calling for integrated approaches, and policy-makers are progressively supporting the inclusion of ecological and social aspects in water management programs. This paper contributes to this policy debate by providing an integrated economic-hydrologic modeling framework that captures the socio economic and environmental effects of various policy initiatives and climate variability. This modeling integration includes a risk-based economic optimization model and a hydrologic water management simulation model that have been specified for the Middle Guadiana basin, a vulnerable drought-prone agro ecological area with highly regulated river systems in southwest Spain. Namely, two key water policy interventions were investigated: the implementation of minimum environmental flows (supported by the European Water Framework Directive, EU WFD), and a reduction in the legal amount of water delivered for irrigation (planned measure included in the new Guadiana River Basin Management Plan, GRBMP, still under discussion). Results indicate that current patterns of excessive water use for irrigation in the basin may put environmental flow demands at risk, jeopardizing the WFD's goal of restoring the 'good ecological status' of water bodies by 2015. Conflicts between environmental and agricultural water uses will be stressed during prolonged dry episodes, and particularly in summer low-flow periods, when there is an important increase of crop irrigation water requirements. Securing minimum stream flows would entail a substantial reduction in irrigation water use for rice cultivation, which might affect the profitability and economic viability of small rice-growing farms located upstream in the river. The new GRBMP could contribute to balance competing water demands in the basin and to increase economic water productivity, but might not be sufficient to ensure the provision of environmental flows as required by the WFD. A thoroughly revision of the basin's water use concession system for irrigation seems to be needed in order to bring the GRBMP in line with the WFD objectives. Furthermore, the study illustrates that social, economic, institutional, and technological factors, in addition to bio-physical conditions, are important issues to be considered for designing and developing water management strategies. The research initiative presented in this paper demonstrates that hydro-economic models can explicitly integrate all these issues, constituting a valuable tool that could assist policy makers for implementing sustainable irrigation policies. PMID- 23732194 TI - [Utility of 11C-methionine PET/CT in neuro-oncology]. AB - Positron emission tomography (PET) with 11C-methionine (11C-methionine PET/CT) is a new technique used to evaluate primary central nervous system (CNS) tumors. We describe our experience regarding the first 4 patients with glial tumors and 11C methionine PET/CT. This is a descriptive, observational and prospective study of 4 patients between 38-50 years of age, with different gliomas (WHO classification). MRI and 11C-methionine PET/CT were performed in all cases. Case 1, gliomatosis cerebri grade II post-radiotherapy. Case 2, oligodendroglioma grade II diagnosed and treated with radiotherapy in 1993. Case 3, glioblastoma grade IV post-radiotherapy + temozolomide. Case 4, anaplastic oligoastrocytoma grade III post-radiotherapy + temozolomide. The pattern of 11C-methionine uptake compared with MRI showed tumor progression in cases 1, 3 and 4, and in case 2 showed uptake although the final diagnosis was pseudoprogression. Unlike 18fluordeoxiglucose PET/TC, 11C-methionine uptake in normal brain tissue and pseudoprogression is low, and gliomas are displayed as metabolically active areas. The 11C-methionine PET/CT provided valuable information on the tumoral behavior and extension, although in one case presented did not differentiate tumor progression from pseudoprogression. 11C-methionine PET/CT could be a useful tool in the study and follow-up to patients with gliomas. PMID- 23732195 TI - Prevalence of myopic shifts among patients seeking cataract surgery. AB - Modern cataract surgery by phacoemulsification is a widely accepted procedure with a rapid recovery time. The prescription of specific intraocular lens, implanted during surgery, makes it possible to anticipate whether the patient will need reading glasses after the procedure. The present study analyses a sample of cataract surgery patients to show the frequency of myopic shifts related to nuclear opacity, which can result in clear near vision before surgery. A non-selected sample of consecutive patients who underwent elective cataract surgery in a private clinic was studied retrospectively. The myopic shift in refraction was assessed by comparing the old prescription with the spectacle correction at the time of interviewing.The mean age of the 229 subjects studied was 71.5 +/- 10.4 years (109, 47.6%, males). A myopic shift in refraction, defined as at least - 0.5 diopters, was present in 37.1% of subjects (95% CI: 30.8%-43.4%). The mean change in refraction in these subjects was -2.52 +/- 1.52 diopters. The percentage of subjects who had developed a myopic shift was significantly greater in those who presented greater nuclear opalescence. There were also differences in the mean myopic shift by refractive group, with the emmetropes having the greatest myopic shift. In this study of patients seeking cataract surgery in a clinical setting, more than one third had myopic shifts in refraction. This must be taken into account in order that patients maintain the benefit of clear near vision after surgery. PMID- 23732196 TI - [Drugs used for cognitive impairment. Analysis of 1.5 million prescriptions in Argentina]. AB - Cognitive impairment and dementia treatment costs are significant for health systems. According to national and international guidelines, recommended drugs for treatment of dementias are cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and memantine. Despite these guidelines recommendations, other nootropics, vasodilators and antioxidants are often used in Argentina. The purpose of this study was to describe and compare the prescription pattern of commonly used drugs for the treatment of cognitive disorders and dementia in different regions of Argentina. An observational, retrospective study of 1814108 recipes prescribed to National Institute of Social Services for Retired and Pensioners outpatients during the during the second half of 2008 and the first and second half of 2009 was performed, taking in count the whole country and also different Argentina's regions. Demographic variables, quantity and rate of prescriptions, dosage forms and strengths were analyzed. Considering the entire country, memantine was the most prescribed drug in these periods (570893 packages). An increase in the memantine, donepezil, rivastigmine and idebenone rates of prescription was observed. Prescription rate of memantine increased in the North-West and North-East regions, that of idebenone in the North-East region and Patagonia and donepezil in the North-East region. Non recommended drugs were highly prescribed in all the analyzed regions. Some of them were indicated to young and middle-aged patients. PMID- 23732197 TI - [Pulmonary disease due to asbestos in steel industry workers]. AB - Asbestos-related diseases are caused by the inhalation of asbestos fibers in their variety chrysotile or white asbestos. Although the ban in Argentina dates from 2003, there are numerous industries where work continues with this mineral, including iron and steel industries. It is currently known the high pathogenicity of this material, so that in many countries there are programs to monitoring the exposed workers. Here we describe the general characteristics and pulmonary manifestations in 27 patients who had worked in a very huge steel factory in South America. The diagnosis of asbestos-related diseases was made by a medical occupational record, history of asbestos exposure, additional studies of lung function and chest images. Then the sources of exposure (occupational, domestic and environmental), exposure time and latency period were analyzed, in those patients in whom a related disease was detected. Smoking history was also taken into account. Twenty-two patients had benigns pathologies (81.4%), sixteen of them with lesions localyzed in pleura, and other six pulmonary asbestosis. The malignant pathologies occurred in five patients (18.5%), in four of them mesothelioma and in other one lung cancer. The problem of asbestos exposure has contemporary relevance. Hence the need for a surveillance program in workers exposed to asbestos in the past or currently, to detect, report, record and investigate the characteristics of these pathologies. PMID- 23732198 TI - [Impact of thoracic and abdominopelvic surgery on the functional status in the elderly]. AB - The quality of life of older people is determined by their functional capacity, rather than by the number or type of disease suffered. We analyzed 43 patients over 65 years undergoing major surgery. Longitudinally continued evolution of functional status by analyzing six variables, activities of daily living (ADLs), instrumental activities of daily living (IADL), the get up and walk test, functional reach test of arm, strength of handgrip and walking speed, measured before surgery (baseline measurement) and at 1, 2, 3 and 4 months after discharge. The objectives were to estimate the impact that surgery has on functional status in the elderly, determine how long each of the measurements returned to preoperative values at 4 months follow-up. Recovery curves compared the baseline AIVD, grip strength and hand speed on the fly, between two groups defined by baseline walking speed in slow (< 0.8 m/s) and fast (> 0.8 m/s). The impact of surgery on physical fitness showed a statistically significant decrease in ADL, IADL, and the get up and walk test and walking speed, with variable time recovery beyond convalescence. All return to baseline at 4 months except test walking speed that exceeded the baseline. Functional status can be evaluated quickly and should be included in the preoperative evaluation, since it allows planning strategies to meet the needs and limitations of patients and their families, in the immediate postoperative period. PMID- 23732199 TI - [Prevention of congenital toxoplasmosis in a Buenos Aires hospital]. AB - The prevention of congenital toxoplasmosis is based on providing information to women, serologic diagnosis and treatment of the infected mother and child. In this article we present the results of 12 years of implementation of a congenital toxoplasmosis prevention program in which we measured the mother's infection incidence rate, the transmission rate and the number and severity of infection in newborns. The study was performed on 12035 pregnant women in the period 2000 2011. The prevalence rate of antibodies against Toxoplasma gondii was 18.33% (2206/12035). Thirty-seven out of 9792 susceptible women presented acute infection and the mother's infection incidence rate was 3.78 per 1000 births. The transplacental transmission rate was 5.4% (2/37). Two newborns presented congenital toxoplasmosis infection, one had no clinical signs while the other presented strabismus and chorioretinitis. Thirty-five infected mothers and the two children with congenital infection were treated. The transmission rates obtained allow consider this prevention program as a valid resource to minimize the impact of congenital toxoplasmosis. PMID- 23732200 TI - [Metabolic abnormalities in young offsprings of parents with essential hypertension]. AB - The familiar history of hypertension in healthy young offsprings is associated with hyperinsulinemia, which could lead to increased serum cortisol, resulting in renal endothelial damage and the presence of microalbuminuria. The aim of this study was to evaluate, in healthy young offsprings of hypertensive parents, association between insulin levels, serum cortisol and microalbuminuria attending to its relationship with increased cardiovascular risk. We performed a cross sectional correlational study in Santa Fe, Argentina, including 145 healthy individuals aged over 18 years, allocated to two groups: those with a history of essential hypertensive parents (study group) and those without such history (control group). We evaluated fasting serum insulin, cortisol, and microalbuminuria levels in the first morning urine. The mean age was 20 +/- 2.9 years, and 58% were women. The study group included 48% (n = 69) of the sample. 4.8% had insulin resistance, microalbuminuria 13.8% and 52% hipercortisolinemia, with no significant differences in serum insulin, cortisol, or microalbuminuria between groups. No correlation was found between these variables. In this study there was no association between a history of first degree hypertension and impaired insulin or cortisol homoeostasis. PMID- 23732201 TI - [Sleep difficulties and psychological symptoms in medicine students in Mexico]. AB - The purpose of this study was to describe sleep difficulties in first year medical students associated with psychopathological symptoms. A cross-sectional study in 572 Medicine students, who were assessed by the Symptom Check List-90 (SCL-90), was performed. A 3.5% of students reported having a hard time sleeping, 6.3% had difficulty staying asleep and 11.4% waking up very early. Sleep difficulties were significantly associated with all psychopathological symptoms. The best predictors of sleep difficulties were anxiety, hostility and interpersonal sensitivity. In conclusion, the symptoms associated with stress, anger, worry, cognitive hyperarousal and hypervigilance are the best predictors for sleep difficulties in this population. PMID- 23732202 TI - [Response to thalidomide in scleromyxedema]. AB - The scleromyxedema is a rare condition characterized by hyperproliferation of fibroblasts with increased dermal deposition of mucin and frequently associated with monoclonal gammopathy of undetermined significance. Various treatments have been reported, with inconsistent results. In addition, the rarity of the disease and the lack of randomized controlled trials results in treatment options derived from anecdotal reports. We describe the case of a 52 year-old female patient diagnosed with scleromyxedema who developed a monoclonal gammopathy, with adequate response to thalidomide. The follow up of these patients is important due to the risk of progression to multiple myeloma and complications related to systemic treatments. PMID- 23732203 TI - [Secondary hemophagocytic syndrome due to recurrent infections in a severely burned patient]. AB - The hemophagocytic syndrome represents an infrequent, occasionally misdiagnosed and usually fatal heterogeneous entity. Infections, drugs, autoimmune diseases and cancer are often triggers of the secondary hemophagocytic syndrome. Its physiopathogenic mechanism is explained by an impaired and inefficacious function of the NK and T cytotoxic cells that leads to an ineffective and uncontrolled immune response, inducing cellular damage, multiorganic failure with macrophage proliferation and hemophagocytosis. The main objective of the different therapeutic options, commonly combinations of steroids and chemotherapy, is the suppression of the uncontrolled immune response. Occasionally, the clinical condition of some patients represents a contraindication for intensive treatment. We report a case of a severely burned patient that fulfilled the revised criteria for the hemophagocytic syndrome and was successfully treated with the combination of intravenous immunoglobulins and steroids. PMID- 23732205 TI - [Xanthogranulomatous pyelonephritis]. PMID- 23732204 TI - [Chronic inflammatory sensory polyradiculopathy]. AB - Chronic inflammatory sensory polyradiculopathy is a defined entity, frequently underdiagnosed, and potentially treatable. It must be suspected in patients with sensory ataxia, normal nerve conduction studies, and MRI with thickened lumbosacral nerve roots and gadolinium enhancement. We present the case of a 57 year-old man with marked sensory ataxia on his left leg. Examination showed normal strength, decreased knee and ankle jerks. Light touch and pinprick sensations were reduced below the knees. Vibration and joint position sense were absent at the feet. Nerve conduction studies were normal. Tibial sensory evoked potentials disclosed absent responses bilaterally. CSF was acellular with elevated protein. Lumbosacral magnetic resonance showed thickening of roots, with gadolinium enhancement. The patient was treated with IV-Ig, 2 g/kg, for 5 days with improvement of symptoms. The clinical course, elevated CSF protein, the evidence of root enhancement on the MRI, good response to immunotherapy, and the exclusion of other causes of sensory ataxia, were compatible with the diagnosis of chronic inflammatory sensory polyradiculopathy. To diagnose this disease the identification of isolated involvement of the sensory roots is required. PMID- 23732206 TI - [Oblito]. PMID- 23732207 TI - [Diet in the treatment of renal lithiasis. Pathophysiological basis]. AB - The composition of urine is influenced by diet and changes in dietary factors have been proposed to modify the risk of recurrent nephrolithiasis. Nutrients that have been implicated include calcium, oxalate, sodium, animal protein, magnesium and potassium. There is significant evidence showing that a high calcium diet is associated with a reduction of lithogenic risk. One of the possible mechanisms to explain this apparent paradox is that the higher intake of calcium in the intestine binds with dietary oxalate, reducing its absorption and urinary excretion. Oxalate from the diet seems to provide only a small contribution to excretion and dietary restriction is appropriate only in those with hyperoxaluria and hyperabsorption. Observational studies have shown a positive and independent association between sodium intake and the formation of new kidney stones. Consumption of animal protein creates an acid load that increases urinary excretion of calcium and uric acid and reduced citrate, all factors that could participate in the genesis of stones. Potassium-rich foods increase urinary citrate because of its alkali content. In prospective observational studies, diets rich in magnesium were associated with a lower risk of kidney stone formation in men. In conclusion, diet is a key element in the management of the patient with kidney stones but always subordinated to present metabolic risk factors. PMID- 23732208 TI - [Use of growth hormone in children and adolescents]. AB - Growth hormone treatment for children and adolescents with growth disorders has been used for more than five decades. Since 1985 recombinant human growth hormone (rhGH) is the only drug approved for treatment. In most of the countries rhGH is licensed for the treatment of children with growth hormone deficiency, Turner syndrome, Prader-Willi syndrome, chronic renal failure, and children born small for gestational age. The objective of the treatment is to improve the growth of these patients. The efficacy of rhGH treatment based on auxologic parameters has shown that growth response is variable and mostly dependent on each particular indication. Most of the reports on drug safety obtained from different databases that included thousands of patients, have shown that rhGH is a safe drug and that serious adverse events are rare. Regarding new indications to improve height in children, data on efficacy remains controversial, so we believe their ultimate indication must take into account potential risk versus benefits of this treatment. PMID- 23732209 TI - [Fifteen women received the Nobel Prize in science]. PMID- 23732210 TI - [Nobel Prize in Chemistry 2012. Solving the enigma of cellular receptors]. PMID- 23732211 TI - [Animal regeneration (reconstitution)]. PMID- 23732212 TI - [The unusual attire of Dr. Lejeune]. PMID- 23732213 TI - [Educational impact of performance appraisal: the case of the Mini-Clinical Evaluation Exercise (Mini-CEX)]. PMID- 23732214 TI - [Acute focal bacterial nephritis by methicillin-resistant Staphylococcus aureus]. PMID- 23732215 TI - [Emphysema and pulmonary fibrosis]. PMID- 23732216 TI - Highly electron deficient pyrido[3',2':4,5]furo[2,3-b]pyridine as a core structure of a triplet host material for high efficiency green phosphorescent organic light-emitting diodes. AB - Highly electron deficient pyrido[3',2':4,5]furo[2,3-b]pyridine (PFP) was developed as a core structure of a triplet host material and a derivative of PFP, 3-(3-(carbazole-9-yl)phenyl) pyrido[3',2':4,5]furo[2,3-b]pyridine (CzPFP), was synthesized as a bipolar host material. The CzPFP host material showed similar hole and electron densities in single charge devices, and a high quantum efficiency of 27.7% and a high power efficiency of 86.8 lm W(-1) in green phosphorescent organic light-emitting diodes. PMID- 23732217 TI - The company they keep: background similarity influences transfer of aftereffects from second- to first-order stimuli. AB - A wealth of studies has found that adapting to second-order visual stimuli has little effect on the perception of first-order stimuli. This is physiologically and psychologically troubling, since many cells show similar tuning to both classes of stimuli, and since adapting to first-order stimuli leads to aftereffects that do generalize to second-order stimuli. Focusing on high-level visual stimuli, we recently proposed the novel explanation that the lack of transfer arises partially from the characteristically different backgrounds of the two stimulus classes. Here, we consider the effect of stimulus backgrounds in the far more prevalent, lower-level, case of the orientation tilt aftereffect. Using a variety of first- and second-order oriented stimuli, we show that we could increase or decrease both within- and cross-class adaptation aftereffects by increasing or decreasing the similarity of the otherwise apparently uninteresting or irrelevant backgrounds of adapting and test patterns. Our results suggest that similarity between background statistics of the adapting and test stimuli contributes to low-level visual adaptation, and that these backgrounds are thus not discarded by visual processing but provide contextual modulation of adaptation. Null cross-adaptation aftereffects must also be interpreted cautiously. These findings reduce the apparent inconsistency between psychophysical and neurophysiological data about first- and second-order stimuli. PMID- 23732218 TI - V5+ degradation of sulfonated Radel membranes for vanadium redox flow batteries. AB - Insight into the degradation mechanisms of aromatic proton conducting membrane separators for vanadium redox flow batteries (VRFBs) is urgently needed for the development of long lifetime VRFBs. Other than in-cell observations of performance degradation, there is little fundamental evidence on the specific degradation pathways of aromatic ion exchange membranes for VRFBs. Herein we investigated a sulfonated Radel(r) membrane (S-Radel) as the degradation target to study the degradation mechanism of aromatic polymers by V(V) (or generally V(5+)) oxidation. It was found that the ductile S-Radel membrane, which has a similar aromatic backbone structure to the most-studied polyaromatic VRFB membranes that have shown high performance, became brittle and discolored after 3 days of immersion in 1.7 M V(V) + 3.3 M H2SO4 solution at 40 degrees C. The membrane's intrinsic viscosity was reduced to about half of its original value after this exposure to V(V) while the ion exchange capacity did not change. In addition to chain scission, it was found that -OH groups were introduced to the backbone of S-Radel as the major degradation product. Quinone groups were also observed at 1677 cm(-1) in FTIR measurements. While the V(V) species in VRFBs is usually denoted as VO2(+), V(V)=O in VOCl3 was found to not have degradation activity for S-Radel. Therefore, we hypothesized that there were other reactive forms of V(V) species that first attacked the S-Radel by incorporating hydroxyl groups into the polymer's aromatic backbone, followed by the oxidation of these hydroxyl groups to quinone functionalities through a redox mechanism. PMID- 23732219 TI - Molecular and evolutionary aspects of microbial sensory rhodopsins. AB - Retinal proteins (~rhodopsins) are photochemically reactive membrane-embedded proteins, with seven transmembrane alpha-helices which bind the chromophore retinal (vitamin A aldehyde). They are widely distributed through all three biological kingdoms, eukarya, bacteria and archaea, indicating the biological significance of the retinal proteins. Light absorption by the retinal proteins triggers a photoisomerization of the chromophore, leading to the biological function, light-energy conversion or light-signal transduction. This article reviews molecular and evolutionary aspects of the light-signal transduction by microbial sensory receptors and their related proteins. This article is part of a Special Issue entitled: Retinal Proteins - You can teach an old dog new tricks. PMID- 23732220 TI - Naringin inhibits high glucose-induced cardiomyocyte apoptosis by attenuating mitochondrial dysfunction and modulating the activation of the p38 signaling pathway. AB - Recently, naringin (NAR; 4',5,7-trihydroxyflavanone-7-rhamnoglucoside) has been shown to have cardioprotective properties. However, the specific mechanisms underlying its cardioprotective effects remain unclear. In this study, we aimed to investigate the cardioprotective effects of NAR and the possible underlying molecular mechanisms in cardiomyocytes using high glucose (HG) to induce apoptosis in H9c2 cells. The effect of NAR on apoptosis was assessed by Annexin V and propidium iodide staining, and by determining the levels of active caspase-3, -8 and -9. The effect of NAR on mitochondrial dysfunction was assessed by the loss of mitochondrial membrane potential (MMP). Our results demonstrated that exposure to HG induced apoptosis and mitochondrial dysfunction in cardiomyocytes. Treatment with NAR significantly increased MMP and inhibited the activation of caspase-3, -8 and -9. NAR attenuated the HG-induced p38 and p53 phosphorylation, decreased mitochondrial Bax and Bak expression, prevented the release of cytochrome c and increased Bcl-2 expression. Pre-treatment with SB203580, a p38 inhibitor, also suppressed p53 phosphorylation and prevented the loss of MMP, as well as apoptosis in the HG-treated H9c2 cells. Taken together, these data demonstrate that NAR inhibits HG-induced apoptosis by attenuating mitochondrial dysfunction and modulating the activation of the p38 signaling pathway. PMID- 23732221 TI - Influence of the reaction stoichiometry on the mechanical and thermal properties of SWCNT-modified epoxy composites. AB - Previous studies suggest that carbon nanotubes (CNTs) have a considerable influence on the curing behavior and crosslink density of epoxy resins. This invariably has an important effect on different thermal and mechanical properties of the epoxy network. This work focuses on the important role of the epoxy/hardener mixing ratio on the mechanical and thermal properties of a high temperature aerospace-grade epoxy (MY0510 Araldite as an epoxy and 4,4' diaminodiphenylsulfone as an aromatic hardener) modified with single-walled carbon nanotubes (SWCNTs). The effects of three different stoichiometries (stoichiometric and off-stoichiometric) on various mechanical and thermal properties (fracture toughness, tensile properties, glass transition temperature) of the epoxy resin and its SWCNT-modified composites were obtained. The results were also supported by Raman spectroscopy and scanning electron microscopy (SEM). For the neat resin, it was found that an epoxy/hardener molar ratio of 1:0.8 provides the best overall properties. In contrast, the pattern in property changes with the reaction stoichiometry was considerably different for composites reinforced with unfunctionalized SWCNTs and reduced SWCNTs. A comparison among composites suggests that a 1:1 molar ratio considerably outperforms the other two ratios examined in this work (1:0.8 and 1:1.1). This composition at 0.2 wt% SWCNT loading provides the highest overall mechanical properties by improving fracture toughness, ultimate tensile strength and ultimate tensile strain of the epoxy resin by 40%, 34%, 54%, respectively. PMID- 23732222 TI - Risk factors and outcomes for respiratory syncytial virus-related infections in immunocompromised children. AB - BACKGROUND: Respiratory syncytial virus (RSV) is associated with significant morbidity and mortality in immunocompromised children. Data on the risk factors for acquisition and outcomes from RSV infections in this population are limited. METHODS: This cohort study (2006 to 2011) included RSV-positive immunocompromised pediatric inpatients. Nasopharyngeal swabs were tested for RSV by direct immunofluorescence. Purposeful multiple regression was used to assess risk factors associated with community-acquired RSV (CA-RSV) infections and their outcomes compared with nosocomial (N-RSV) infections. Means and medians were compared using Student's t test and a nonparametric test, respectively. Proportions were compared using chi(2) or Fisher's exact test, as appropriate. RESULTS: There were 117 RSV-positive patients of whom 42 (35.9%) presented with (N-RSV) infection. Overall, more than a third presented with lower respiratory tract infections, which resulted in a 28% admission rate to the intensive care unit and a mortality rate of 5%; the latter solely among patients with community acquired infection. Subjects with CA-RSV presented with more advanced clinical evidence of lower tract disease with respiratory distress (eg, intercostal recession; odds ratio 2.5; 95% confidence interval: 1.1-5.6; P = 0.03) compared with those with N-RSV. Subjects with CA-RSV infections were less likely to have a prolonged hospital admission (odds ratio 0.7; 95% confidence interval: 0.5-0.8; P < 0.0001) relative to those with N-RSV infections. CONCLUSIONS: RSV-related infections in immunocompromised children may result in poor outcomes, including mortality. Differences in mortality rates among those with CA-RSV compared with N RSV warrant further study, with enhanced opportunities for prevention and early detection of infection. PMID- 23732223 TI - Mass balance evaluation of polybrominated diphenyl ethers in landfill leachate and potential for transfer from e-waste. AB - Previous research on brominated flame retardants (BFRs), including polybrominated diphenyl ethers (PBDEs) has largely focussed on their concentrations in the environment and their adverse effects on human health. This paper explores their transfer from waste streams to water and soil. A comprehensive mass balance model is developed to track polybrominated diphenyl ethers (PBDEs), originating from e waste and non-e-waste solids leaching from a landfill. Stepwise debromination is assumed to occur in three sub-systems (e-waste, aqueous leachate phase, and non-e waste solids). Analysis of landfill samples and laboratory results from a solid liquid contacting chamber are used to estimate model parameters to simulate an urban landfill system, for past and future scenarios. Sensitivity tests to key model parameters were conducted. Lower BDEs require more time to disappear than high-molecular weight PBDEs, since debromination takes place in a stepwise manner, according to the simplified reaction scheme. Interphase mass transfer causes the decay pattern to be similar in all three sub-systems. The aqueous phase is predicted to be the first sub-system to eliminate PBDEs if their input to the landfill were to be stopped. The non-e-waste solids would be next, followed by the e-waste sub-system. The model shows that mass transfer is not rate-limiting, but the evolution over time depends on the kinetic degradation parameters. Experimental scatter makes model testing difficult. Nevertheless, the model provides qualitative understanding of the influence of key variables. PMID- 23732224 TI - Contribution of hospital effluents to the load of pharmaceuticals in urban wastewaters: identification of ecologically relevant pharmaceuticals. AB - The impact of effluent wastewaters from four different hospitals: a university (1456 beds), a general (350 beds), a pediatric (110 beds) and a maternity hospital (96 beds), which are conveyed to the same wastewater treatment plant (WWTP), was evaluated in the receiving urban wastewaters. The occurrence of 78 pharmaceuticals belonging to several therapeutic classes was assessed in hospital effluents and WWTP wastewaters (influent and effluent) as well as the contribution of each hospital in WWTP influent in terms of pharmaceutical load. Results indicate that pharmaceuticals are widespread pollutants in both hospital and urban wastewaters. The contribution of hospitals to the input of pharmaceuticals in urban wastewaters widely varies, according to their dimension. The estimated total mass loadings were 306 g d(-1) for the university hospital, 155 g d(-1) for the general one, 14 g d(-1) for the pediatric hospital and 1.5 g d(-1) for the maternity hospital, showing that the biggest hospitals have a greater contribution to the total mass load of pharmaceuticals. Furthermore, analysis of individual contributions of each therapeutic group showed that NSAIDs, analgesics and antibiotics are among the groups with the highest inputs. Removal efficiency can go from over 90% for pharmaceuticals like acetaminophen and ibuprofen to not removal for beta-blockers and salbutamol. Total mass load of pharmaceuticals into receiving surface waters was estimated between 5 and 14 g/d/1000 inhabitants. Finally, the environmental risk posed by pharmaceuticals detected in hospital and WWTP effluents was assessed by means of hazard quotients toward different trophic levels (algae, daphnids and fish). Several pharmaceuticals present in the different matrices were identified as potentially hazardous to aquatic organisms, showing that especial attention should be paid to antibiotics such as ciprofloxacin, ofloxacin, sulfamethoxazole, azithromycin and clarithromycin, since their hazard quotients in WWTP effluent revealed that they could pose an ecotoxicological risk to algae. PMID- 23732225 TI - Lone atrial fibrillation: a disease threatened with extinction. PMID- 23732226 TI - The reverse mode switch algorithm: how well does it work? AB - BACKGROUND: The performance of the Reverse Mode Switch (RMS) algorithm, aimed at minimizing right ventricular pacing by operating in the AAI(R) mode with switch to the DDD(R) mode if atrioventricular (AV) conduction loss is detected, is not well known. OBJECTIVE: To determine the appropriateness of the RMS episodes available from patient follow-up data at our center. METHODS: Patients with the TELIGEN dual-chamber implantable cardioverter-defibrillator and the RMS algorithm activated were identified. The RMS episodes with available electrograms were analyzed and classified as appropriate (AV conduction loss) or inappropriate (non AV conduction loss) events. Cumulative percentage of ventricular pacing and amount of premature ventricular complexes (PVCs) were recorded. RESULTS: Of 21 patients, RMS episodes had occurred in 19 of them, with a mean of 527 episodes per month. Of the 172 RMS episodes available for analysis, 27 (16%) were classified as appropriate and 145 (84%) as inappropriate. Almost all (91%) inappropriate RMS episodes were due to PVC, and there was a positive correlation between the number of total RMS episodes per month and the number of PVCs per month (P < .0005). Considering patients with only inappropriate RMS episodes (n = 11), there was a positive correlation between the percentage of ventricular pacing and the number of RMS episodes per month (P < .05). CONCLUSIONS: A large majority of the RMS episodes available for analysis inappropriately triggered switch from the AAI(R) mode to the DDD(R) mode owing to PVCs. Patients with the RMS algorithm and elevated PVC burden are probably at risk of a high percentage of unnecessary right ventricular pacing. PMID- 23732227 TI - Instability of ventricular repolarization in long QT syndrome: is the corrected QT interval sufficient for risk assessment? PMID- 23732228 TI - Insight into the mechanism of Brugada syndrome: epicardial substrate and modification during ajmaline testing. PMID- 23732229 TI - Acute and chronic effects of selective serotonin reuptake inhibitor treatment on fear conditioning: implications for underlying fear circuits. AB - Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of a spectrum of anxiety disorders, yet paradoxically they may increase symptoms of anxiety when treatment is first initiated. Despite extensive research over the past 30 years focused on SSRI treatment, the precise mechanisms by which SSRIs exert these opposing acute and chronic effects on anxiety remain unknown. By testing the behavioral effects of SSRI treatment on Pavlovian fear conditioning, a well characterized model of emotional learning, we have the opportunity to identify how SSRIs affect the functioning of specific brain regions, including the amygdala, bed nucleus of the stria terminalis (BNST) and hippocampus. In this review, we first define different stages of learning involved in cued and context fear conditioning and describe the neural circuits underlying these processes. We examine the results of numerous rodent studies investigating how acute SSRI treatment modulates fear learning and relate these effects to the known functions of serotonin in specific brain regions. With these findings, we propose a model by which acute SSRI administration, by altering neural activity in the extended amygdala and hippocampus, enhances both acquisition and expression of cued fear conditioning, but impairs the expression of contextual fear conditioning. Finally, we review the literature examining the effects of chronic SSRI treatment on fear conditioning in rodents and describe how downregulation of N-methyl-d aspartate (NMDA) receptors in the amygdala and hippocampus may mediate the impairments in fear learning and memory that are reported. While long-term SSRI treatment effectively reduces symptoms of anxiety, their disruptive effects on fear learning should be kept in mind when combining chronic SSRI treatment and learning-based therapies, such as cognitive behavioral therapy. PMID- 23732231 TI - Keep your head on straight: facilitating sensori-motor transformations for eye hand coordination. AB - In many day-to-day situations humans manifest a marked tendency to hold the head vertical while performing sensori-motor actions. For instance, when performing coordinated whole-body motor tasks, such as skiing, gymnastics or simply walking, and even when driving a car, human subjects will strive to keep the head aligned with the gravito-inertial vector. Until now, this phenomenon has been thought of as a means to limit variations of sensory signals emanating from the eyes and inner ears. Recent theories suggest that for the task of aligning the hand to a target, the CNS compares target and hand concurrently in both visual and kinesthetic domains, rather than combining sensory data into a single, multimodal reference frame. This implies that when sensory information is lacking in one modality, it must be 'reconstructed' based on information from the other. Here we asked subjects to reach to a visual target with the unseen hand. In this situation, the CNS might reconstruct the orientation of the target in kinesthetic space or reconstruct the orientation of the hand in visual space, or both. By having subjects tilt the head during target acquisition or during movement execution, we show a greater propensity to perform the sensory reconstruction that can be achieved when the head is held upright. These results suggest that the reason humans tend to keep their head upright may also have to do with how the brain manipulates and stores spatial information between reference frames and between sensory modalities, rather than only being tied to the specific problem of stabilizing visual and vestibular inputs. PMID- 23732232 TI - Hyperbaric oxygen-induced seizures cause a transient decrement in cognitive function. AB - Hyperbaric oxygen-induced seizures are classified as brief, generalized tonic clonic seizures. They are believed to cause no residual cognitive damage, although this has not been investigated in depth. In the present study, we examined whether hyperbaric oxygen-induced seizures cause impairment of behavioral and cognitive abilities. Cognitive status was assessed using four behavioral tests: Y-maze, novel object recognition, the elevated plus maze, and a passive avoidance task. Three time intervals were examined: 24h, and 7 and 30 days after the seizures. We found transient impairment of performance in the compressed group on three tests (the novel object recognition paradigm, the Y maze paradigm, and the passive avoidance task). On the elevated plus maze test, the impairment persisted. The time interval to the appearance of deficits and to eventual recovery was not the same for the different tests. We conclude that hyperbaric oxygen-induced seizures result in transient impairment of performance on behavioral tests in a mouse model. Further investigation is required to establish the mechanism and location of injury, and to determine whether the performance decrement on the elevated plus maze test represents permanent damage or transient damage with slow resolution. These new findings should be taken into account when planning hyperbaric oxygen treatments, to ensure that the chosen protocol is therapeutic yet minimizes the risk of CNS oxygen toxicity. PMID- 23732230 TI - Regulation of dopamine D3 receptor in the striatal regions and substantia nigra in diffuse Lewy body disease. AB - The regulation of D3 receptor has not been well documented in diffuse Lewy body disease (DLBD). In this study, a novel D3-preferring radioligand [(3)H]WC-10 and a D2-preferring radioligand [(3)H]raclopride were used and the absolute densities of the dopamine D3 and D2 receptors were determined in the striatal regions and substantia nigra (SN) from postmortem brains from five cases of DLBD, which included dementia with Lewy bodies (DLB, n=4) and Parkinson disease dementia (PDD, n=1). The densities of the dopamine D1 receptor, vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT) were also measured by quantitative autoradiography using [(3)H]SCH23390, [(3)H]dihydrotetrabenazine, and [(3)H]WIN35428, respectively. The densities of these dopaminergic markers were also measured in the same brain regions in 10 age-matched control cases. Dopamine D3 receptor density was significantly increased in the striatal regions including caudate, putamen and nucleus accumbens (NAc). There were no significant changes in the dopamine D1 and D2 receptor densities in any brain regions measured. VMAT2 and DAT densities were reduced in all the brain regions measured in DLB/PDD, however, the significant reduction was found in the putamen for DAT and in the NAc and SN for VMAT2. The decrease of dopamine pre-synaptic markers implies neuronal loss in the substantia nigra pars compacta (SNpc) in these DLB/PDD cases, while the increase of D3 receptors in striatal regions could be attributed to dopaminergic medication history and psychiatric states such as hallucinations. Whether it also reflects compensatory regulation upon dopaminergic denervation warrants further confirmations on larger populations. PMID- 23732233 TI - Critical evaluation of the anatomical location of the Barrington nucleus: relevance for deep brain stimulation surgery of pedunculopontine tegmental nucleus. AB - Deep brain stimulation (DBS) has become the standard surgical procedure for advanced Parkinson's disease (PD). Recently, the pedunculopontine tegmental nucleus (PPN) has emerged as a potential target for DBS in patients whose quality of life is compromised by freezing of gait and falls. To date, only a few groups have published their long-term clinical experience with PPN stimulation. Bearing in mind that the Barrington (Bar) nucleus and some adjacent nuclei (also known as the micturition centre) are close to the PPN and may be affected by DBS, the aim of the present study was to review the anatomical location of this structure in human and other species. To this end, the Bar nucleus area was analysed in mouse, monkey and human tissues, paying particular attention to the anatomical position in humans, where it has been largely overlooked. Results confirm that anatomical location renders the Bar nucleus susceptible to influence by the PPN DBS lead or to diffusion of electrical current. This may have an undesirable impact on the quality of life of patients. PMID- 23732234 TI - Membrane protein interactions between different Arabidopsis thaliana MRS2-type magnesium transporters are highly permissive. AB - Membrane proteins of the Arabidopsis thaliana MRS2 (MGT) family have been characterised as magnesium transporters. Like their bacterial CorA homologues, the plant MRS2 proteins are characterised by an invariable GMN tripeptide motif terminating the first of two closely spaced transmembrane domains at the carboxy termini. The functional Mg(2+) transport channel is assembled as a pentamer in the case of CorA. However, in contrast to the single CorA genes of bacteria, plant genomes encode up to 10 highly divergent MRS2 proteins. To elucidate structure-function relationships and the possibility of plant MRS2 hetero pentamer formation, we performed protein-protein interaction studies in the yeast mating-based split-ubiquitin system (mbSUS) and concomitant protein modelling using I-TASSER. Despite very restricted sequence similarities and variable polypeptide insertions all AtMRS2 proteins feature the key structural elements determined for the CorA crystal structure. The mbSUS setup conclusively demonstrates protein-protein interactions of any given AtMRS2 protein not only with itself but also highly permissive interactions to varying degrees among all AtMRS2 proteins. AtMRS2-3 seems particularly prone to non-selective, strong interactions with the other homologues. Deletion constructs show that six amino acids may be deleted from the carboxy-terminus and 27 (but not 41) from the amino terminus of AtMRS2-7 without impairment of homologous or heterologous protein interactions. Despite significant diversification, the plant MRS2 proteins have obviously retained an ancient CorA/MRS2 core structure and the capacity for protein-protein interactions. Plant magnesium homeostasis may be influenced by hetero-oligomer channel formation where different plant MRS2 proteins meet in the same membrane naturally or in transgenic approaches. PMID- 23732235 TI - CLIC proteins, ezrin, radixin, moesin and the coupling of membranes to the actin cytoskeleton: a smoking gun? AB - The CLIC proteins are a highly conserved family of metazoan proteins with the unusual ability to adopt both soluble and integral membrane forms. The physiological functions of CLIC proteins may include enzymatic activity in the soluble form and anion channel activity in the integral membrane form. CLIC proteins are associated with the ERM proteins: ezrin, radixin and moesin. ERM proteins act as cross-linkers between membranes and the cortical actin cytoskeleton. Both CLIC and ERM proteins are controlled by Rho family small GTPases. CLIC proteins, ERM and Rho GTPases act in a concerted manner to control active membrane processes including the maintenance of microvillar structures, phagocytosis and vesicle trafficking. All of these processes involve the interaction of membranes with the underlying cortical actin cytoskeleton. The relationships between Rho GTPases, CLIC proteins, ERM proteins and the membrane:actin cytoskeleton interface are reviewed. Speculative models are proposed involving the formation of localised multi-protein complexes on the membrane surface that assemble via multiple weak interactions. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Herve. PMID- 23732237 TI - Complexation behavior of two-coordinated carbon compounds containing fluorenyl ligands. AB - DFT calculations using BP86 in conjunction with the SVP and TZVPP basis sets as well as ab initio calculations at SCS-MP2 have been carried out for six dicoordinated carbon molecules CLL' where L is a fluorenyl carbene while L' is a phosphine PH3 (1) or PPh3 (2) or a carbene, i.e. NHCMe (3), benzannulated NHCMe (4), cycloheptatrienylidene (5) and benzannulated cycloheptatrienylidene (6). The complexes of these compounds with one and two AuCl moieties were also calculated. The monoaurated adducts of 1-4 have the AuCl fragment eta(1) coordinated to the central carbon atom. The complexes 5(AuCl) and 6(AuCl) have AuCl eta(2) bonded across a C=C double bond. Three different bonding modes are found as energy minima for the diaurated species LL'C-(AuCl)2. The AuCl fragments are found to be either both coordinated eta(1), both coordinated eta(2) across double bonds, or a combination of the two. According to the electronic structure analysis of the free compounds, 1 and 2 might best be classified as carbenes, 3 and 4 as bent allenes while 5 and 6 are typical allenes. The complexation with AuCl reveals that 1-4 may exhibit chemical behaviour which is typical for carbones and thus, they may be termed "hidden carbones". The AuCl complexes show that compounds 5 and 6 are classical allenes. PMID- 23732236 TI - Defective interactions of protein partner with ion channels and transporters as alternative mechanisms of membrane channelopathies. AB - The past twenty years have revealed the existence of numerous ion channel mutations resulting in human pathology. Ion channels provide the basis of diverse cellular functions, ranging from hormone secretion, excitation-contraction coupling, cell signaling, immune response, and trans-epithelial transport. Therefore, the regulation of biophysical properties of channels is vital in human physiology. Only within the last decade has the role of non-ion channel components come to light in regard to ion channel spatial, temporal, and biophysical regulation in physiology. A growing number of auxiliary components have been determined to play elemental roles in excitable cell physiology, with dysfunction resulting in disorders and related manifestations. This review focuses on the broad implications of such dysfunction, focusing on disease causing mutations that alter interactions between ion channels and auxiliary ion channel components in a diverse set of human excitable cell disease. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Herve PMID- 23732238 TI - Mortality attributable to smoking in Vietnamese men in 2008. AB - OBJECTIVE: Smoking prevalence among Vietnamese men is among the highest in the world. Our aim was to provide estimates of tobacco attributable mortality to support tobacco control policies. METHOD: We used the Peto-Lopez method using lung cancer mortality to derive a Smoking Impact Ratio (SIR) as a marker of cumulative exposure to smoking. SIRs were applied to relative risks from the Cancer Prevention Study, Phase II. Prevalence-based and hybrid methods, using the SIR for cancers and chronic obstructive pulmonary disease and smoking prevalence for all other outcomes, were used in sensitivity analyses. RESULTS: When lung cancer was used to measure cumulative smoking exposure, 28% (95% uncertainty interval 24-31%) of all adult male deaths (>35 years) in Vietnam in 2008 were attributable to smoking. Lower estimates resulted from prevalence-based methods [24% (95% uncertainty interval 21-26%)] with the hybrid method yielding intermediate estimates [26% (95% uncertainty interval 23-28%)]. CONCLUSION: Despite uncertainty in these estimates of attributable mortality, tobacco smoking is already a major risk factor for death in Vietnamese men. Given the high current prevalence of smoking, this has important implications not only for preventing the uptake of tobacco but also for immediate action to adopt and enforce stronger tobacco control measures. PMID- 23732239 TI - Screening patterns within organized programs and survival of Italian women with invasive cervical cancer. AB - OBJECTIVES: To evaluate screening patterns within organized cervical screening programs (OCSPs) and survival of women with invasive cervical cancer (ICC). METHODS: A population-based study was conducted in Italian areas covered by cancer registries and OCSPs. The study included all women aged 25-65 years diagnosed with ICC between 1995 and 2008, and their screening histories within OCSPs were retrieved. Hazard ratios (HR) of death and 95% confidence intervals (CI) were computed according to screening pattern, using Cox models adjusted for age, ICC stage, and major confounders. RESULTS: Among 3268 women with ICC, 20% were never-invited to OCSP, 36% were never-compliant with OCSP's invitation, 33% were compliant and had a screen-detected ICC within OCSP (i.e., after a positive cytology), and 11% were compliant but had a non-screen-detected ICC. Screen detected ICCs were more frequently micro-invasive (42%) compared to non-screen detected ones (14%). Compared to women with screen-detected ICC, the adjusted HRs of death were 1.9 (95% CI 1.5-2.4) for those never-invited, 2.0 (95% CI 1.6-2.5) for never-compliant, and 1.7 (95% CI 1.3-2.4) for compliant women having non screen-detected ICC. CONCLUSION: Prolonged survival, beyond down-staging, of women with ICC detected within OCSPs in Italy, further calls for improvements of OCSPs' invitational coverage and participation. PMID- 23732241 TI - Prospective cohort study of compliance with faecal immunochemical tests for colorectal cancer screening in Hong Kong. AB - OBJECTIVE: This study aims to examine the rate and determinants of faecal immunochemical test (FIT) compliance over a four-year period among asymptomatic participants in a colorectal cancer (CRC) screening programme in Hong Kong. METHOD: Self-referred screening participants aged between 50 and 70 years who chose FIT for annual screening were followed up for four years (2008-2012). All participants were reminded up to three times yearly for FIT retrieval within two months of the expected screening date. The proportions of screening participants who failed to adhere to annual FIT tests in 1, 2, 3 and 4-years, respectively, after the initial screening uptake were evaluated. The factors associated with non-compliance with FITs in any year were assessed by a binary logistic regression analysis. RESULTS: From 5700 consecutive screening participants, the compliance rates to FIT were 95.1%, 79.9%, 66.2% and 68.4% at years one to four, respectively. The proportions of people missing one, two and three tests were 6.2%, 19.6% and 2.1%, respectively. From multivariate regression analysis, male subjects, younger participants, smokers and those with positive family history of CRC were more likely to be non-compliant. CONCLUSION: Participants identified as at higher risk for screening non-compliance should be especially considered for individual reminders to enhance screening effectiveness. PMID- 23732242 TI - Leisure-time physical activity and psychotropic medication: a prospective cohort study. AB - BACKGROUND: Physical inactivity is a major public health problem associated with an increased risk of mental health problems. The aim of this study was to examine the associations of leisure-time physical activity with subsequent psychotropic medication among middle-aged people employed at baseline. METHODS: Questionnaire survey data collected in 2000-02 among 40-60-year-old employees of the City of Helsinki (N = 8960) were linked with register data on prescribed psychotropic medication (74% gave permission to linkage). The mean follow-up time was 4.2 years. The analysis included 5961 respondents (78% women). The participants were classified into four groups according to physical activity recommendations. Cox regression analysis was used to calculate hazard ratios (HR) for the first psychotropic medication purchase. RESULTS: Leisure-time physical activity was associated with decreased risk of any psychotropic medication. After adjusting for prior psychotropic medication conditioning exercisers (HR = 0.65, 95% CI, 0.53-0.80), the vigorously active (HR = 0.83, 95% CI, 0.71-0.98) and the moderately active (HR = 0.85, 95% CI, 0.74-0.97) all showed a reduced risk of medication compared with the inactive. The associations were similar for the two main groups of psychotropic medication: antidepressants as well as sedatives and sleep medication. CONCLUSIONS: Leisure-time physical activity is potentially important for preventing mental health problems among the middle-aged. PMID- 23732240 TI - Neighborhood safety and green space as predictors of obesity among preschool children from low-income families in New York City. AB - BACKGROUND: Neighborhood safety, green space, walkability, and sociodemographics may influence physical activity and childhood obesity. METHODS: Data on measured height and weight, demographic characteristics, and home ZIP code were collected from year 2004 enrollees in a means-tested preschool program in New York City. Each ZIP code was surrounded by a 400-m buffer and characterized using data from the US census, local government departments, New York Times website, and Transportation Alternatives. Linear and Poisson models were constructed using cluster robust standard errors and adjusting for child's sex, race, ethnicity, age, and neighborhood characteristics. RESULTS: Analyses included 11,562 children ages 3-5 years living in 160 residential ZIP codes. A higher homicide rate (at the 75th vs 25th percentile) was associated with a 22% higher prevalence of obesity (95% CI for the prevalence ratio (PR): 1.05 to 1.41). A higher density of street trees (at the 75th vs 25th percentile) was associated with 12% lower prevalence of obesity (95% CI for the PR: 0.79 to 0.99). Other neighborhood characteristics did not have significant associations with childhood obesity. CONCLUSIONS: Among preschool children from low-income families, neighborhood homicide rate was associated with more obesity and street tree density was associated with less obesity. PMID- 23732243 TI - Influence of gender role attitudes on smoking and drinking among girls from Jujuy, Argentina. AB - OBJECTIVE: Evaluate effect of gender role attitudes on tobacco and alcohol use among Argentinean girls. METHOD: Cross-sectional survey of 10th grade students attending 27 randomly selected schools in Jujuy, Argentina. Questions about tobacco and alcohol use were adapted from global youth surveys. Five items with 5 point response options of agreement-disagreement assessed attitude towards egalitarian (higher score) gender roles. RESULTS: 2133 girls, aged 13-18 years, 71% Indigenous, 22% mixed Indigenous/European, and 7% European responded. Of these, 60% had ever smoked, 32% were current smokers, 58% ever drinkers, 27% drank in previous month, and 13% had >=5 drinks on one occasion. Mean response to the gender role scale was 3.49 (95% Confidence Intervals = 3.41-3.57) out of 5 tending toward egalitarian attitudes. Logistic regression models using the gender role scale score as the main predictor and adjusting for demographic and social confounders showed that egalitarian gender role was associated with ever smoking (Odds Ratio = 1.25; 95% Confidence Intervals 1.09-1.44), ever drinking (Odds Ratio = 1.24; 95% Confidence Intervals 1.10-1.40), drinking in prior month (Odds Ratio = 1.21; 95% Confidence Intervals 1.07-1.37) and >=5 drinks on one occasion (Odds Ratio = 1.15; 95% Confidence Intervals 1.00-1.33), but was not significant for current smoking. CONCLUSION: Girls in Jujuy who reported more egalitarian gender role attitudes had higher odds of smoking or drinking. PMID- 23732244 TI - Objectively measured physical activity, cardiorespiratory fitness and cardiometabolic risk factors in the Health Survey for England. AB - OBJECTIVES: The study aims to test the hypothesis that physical activity (PA) and cardiorespiratory fitness (CRF) are associated with cardiometabolic risk factors; and to test the hypothesis that CRF modifies (changes the direction and/or strength of) the associations between PA and cardiometabolic risk factors. METHODS: PA and CRF were objectively measured in the 2008 Health Survey for England and the present study included 536 adults who completed at least 4 min of the eight-minute sub-maximal step test and wore an accelerometer for at least 10 h on at least four days. Linear regression models were fitted to examine the relationship between PA and cardiometabolic risk factors and between CRF and cardiometabolic risk factors. A test of interaction was performed to examine whether CRF modifies the associations between PA and cardiometabolic risk factors. RESULTS: PA and CRF were associated with HDL cholesterol, the ratio of total to HDL cholesterol, glycated haemoglobin and BMI after adjustment for potential confounders. There was little evidence that CRF changed the direction or strength of associations between PA and cardiometabolic risk factors. CONCLUSIONS: PA and CRF are associated with cardiometabolic risk factors. A larger sample is required to determine if CRF modifies associations between PA and cardiometabolic risk factors. PMID- 23732246 TI - An analysis of the suitability of public spaces to physical activity practice in Rio de Janeiro, Brazil. AB - OBJECTIVES: To assess the physical characteristics of public spaces designed for sport/physical activity/leisure in Rio de Janeiro, Brazil, and their relationship to the socioeconomic indicators. METHODS: Public spaces (n = 38) spread across the city were evaluated between December 2011 and January 2012 using the Physical Activity Resource Assessment (PARA) instrument. Based on PARA results, a Quality Indicator (QI) was prepared and the sample was grouped into "High QI" and "Low QI" using a k-means clustering algorithm. The association between QI and the local Social Development Index (SDI) was tested using a Chi-square test. RESULTS: The average QI was 13.6 +/- 4.91 and the median was equal to 13 points. The High QI group, composed of sites with a QI above median, reached 17.9 +/- 2.35 points, while the Low QI group reached 9.3 +/- 2.16 points. Pearson's Chi-square tests identified a significant association between QI and SDI when the value of SDI 0.7 was used as a criterion for separation (chi(2) = 17.84, p < 0.001). In neighborhoods with lower levels of SDI, public spaces usually had a lower QI. CONCLUSIONS: Policies to encourage physical activity need to focus attention on the built environment also, particularly in socially vulnerable areas. PMID- 23732245 TI - Initiating and maintaining recreational walking: a longitudinal study on the influence of neighborhood green space. AB - OBJECTIVE: This study examined prospective relationships of green space attributes with adults initiating or maintaining recreational walking. METHODS: Postal surveys were completed by 1036 adults living in Adelaide, Australia, at baseline (two time points in 2003-04) and follow-up (2007-08). Initiating or maintaining recreational walking was determined using self-reported walking frequency. Green space attributes examined were perceived presence, quality, proximity, and the objectively measured area (total and largest) and number of green spaces within a 1.6 km buffer drawn from the center of each study neighborhood. Multilevel regression analyses examined the odds of initiating or maintaining walking separately for each green space attribute. RESULTS: At baseline, participants were categorized into non-regular (n = 395), regular (n = 286), and irregular walkers (n = 313). Among non-regular walkers, 30% had initiated walking, while 70% of regular walkers had maintained walking at follow up. No green space attributes were associated with initiating walking. However, positive perceptions of the presence of and proximity to green spaces and the total and largest areas of green space were significantly associated with a higher likelihood of walking maintenance over four years. CONCLUSION: Neighborhood green spaces may not assist adults to initiate walking, but their presence and proximity may facilitate them to maintain recreational walking over time. PMID- 23732247 TI - A multicentre randomized trial of combined individual and telephone counselling for smoking cessation. AB - OBJECTIVE: The present study assessed the effectiveness of smoking cessation programs combining individual and telephone counselling, compared to individual or telephone counselling alone. METHOD: A randomized, multicentre, open-label trial was performed between January 2009 and July 2011 at six smoking cessation clinics in Spain. Of 772 smokers assessed for eligibility, 600 (77%) met inclusion criteria and were randomized. Smokers were randomized to receive individual counselling, combined telephone and individual counselling, or telephone counselling. The primary outcome was biochemically validated continuous abstinence at 52 weeks. RESULTS: The 52-week abstinence rate was significantly lower in the telephone group compared to the combined group (20.1% vs. 29.0%; OR, 1.32; 95% CI, 1.1-2.7) and to the individual counselling group (20.1% vs. 27.9%; OR, 1.37; 95% CI, 1.0-2.8). The 52-week abstinence rates were not significantly higher in the combined group than the individual group (OR, 0.97; 95% CI, 0.7 1.4). CONCLUSION: Individual counselling and combined individual and telephone counselling were associated with higher 52-week abstinence rates than telephone counselling alone. A combined approach may be highly useful in the clinical treatment of smokers, as it involves less clinic visits than individual counselling alone, thus reducing the program cost, and it increases patient compliance compared to telephone counselling alone. PMID- 23732249 TI - The correlates of preschoolers' compliance with screen recommendations exist across multiple domains. AB - OBJECTIVE: To investigate the individual, social and physical environment correlates of preschool children's compliance with Australian/Canadian and American Academy of Pediatrics (AAP) screen recommendations. METHOD: An Ecological Model (EM) was used to identify constructs potentially associated with children's screen time. In 2008-2009, parents in Melbourne, Australia, reported their child's screen time and on a range of potential correlates. Children (n = 935; 54% boys, mean age 4.54 +/- 0.70 years) were assessed as meeting or not meeting each of the screen recommendations. Logistic regression assessed bivariable and multivariable associations. RESULTS: In total, 15 explanatory variables, across the three domains of the EM were associated with boys' and/or girls' compliance with either Australian/Canadian or AAP recommendations. Correlates varied by sex and recommendation. Maternal television viewing time was the only consistent correlate for both boys' and girls' compliance with both recommendations. No demographic groups were identified as being less likely to comply with screen recommendations. CONCLUSION: Public health programs should take account of the sex-specific nature of correlates of preschool children's screen time. Preschool children across all demographic groups need support to engage in less screen use. Parents may benefit from education and parenting skills to minimize potentially harmful effects of excessive screen time for their child. PMID- 23732250 TI - Hypertension identification via emergency responders: a randomized controlled intervention study. AB - OBJECTIVE: The objective was to test the effectiveness of a mail campaign that included blood pressure (BP) measurements from patients treated by emergency medical technicians (EMTs) to motivate them to (re)check their BP at a fire station. The mailing used a 2*2 research design tailoring on risk and source personalization. METHOD: In this randomized controlled trial, participants were randomized into a control group or one of four experimental groups. Participants residing in one of four fire departments in a Pacific Northwest metropolitan area were eligible if they had a systolic BP>=160 mm Hg and/or diastolic BP>=100 mm Hg when seen by EMTs during the study period (July 2007-September 2009). RESULTS: Of 7106 eligible participants, 40.7% were reached for a follow-up interview. Multivariable logistic regression analysis showed that although the absolute number of fire station BP checks was low (4%), participants who received any mailed intervention had a 3 to 5-fold increase in the odds of reporting a fire station BP check over controls. Fire station visits did not differ by type of tailored mailing. CONCLUSION: Partnering with Emergency Medical Services is an innovative way to identify high-risk community members for population health interventions. PMID- 23732252 TI - Beliefs, behaviors and HPV vaccine: correcting the myths and the misinformation. AB - OBJECTIVE: Human papillomavirus (HPV) vaccine uptake in many countries has been sub-optimal. We examine several issues associated with non-vaccination that have received particular attention, including fears about sexual risk compensation, concerns about vaccine safety, inadequate vaccination recommendations by health care providers (HCPs), and distrust due to the perceived "newness" of HPV vaccines. METHODS: Selective review of behavioral and social science literature on HPV vaccine attitudes and uptake. RESULTS: There is no evidence of post vaccination sexual risk compensation, HPV vaccines are quite safe, and they can no longer be considered "new". Nonetheless, research findings point to these issues and, most importantly, to the failure of HCPs to adequately recommend HPV vaccine as major drivers of non-vaccination. CONCLUSION: Most fears related to HPV vaccine are more related to myth than reality. In the absence of major health policy initiatives, such as those implemented in Canada, the U.K., and Australia, a multi-level, multi-faceted approach will be required to achieve high rates of HPV vaccination. It will be essential to focus on the education of HCPs regarding indications for HPV vaccination and approaches to communicating most effectively with parents and patients about the safety and benefits of vaccination and the risks associated with non-vaccination. PMID- 23732251 TI - Trends in influenza vaccine coverage among primary healthcare workers in Spain, 2008-2011. AB - OBJECTIVE: To evaluate trends in seasonal influenza vaccination coverage in primary healthcare workers (PHCWs) in Spain between 2008 and 2011. METHODS: We made an anonymous web survey of PHCWs in 2012. Information on attitudes towards and knowledge of influenza vaccine, and immunization in previous seasons was collected. Self-reported vaccination coverage and factors related to vaccination continuity were analysed. RESULTS: Of 5433 workers contacted, 2625 (48.3%) responded to the survey: 47.0% were general practitioners, 10.3% paediatricians and 42.7% nurses. Their reported vaccination rates from seasons 2008-2009 to 2011 2012 decreased over time: 58.4%, 57.4%, 53.2% and 49.3% (linear trend, p < 0.001). Among workers vaccinated in any previous season, 70.2% were vaccinated again in 2011-2012, compared with 5.2% among those not previously vaccinated (p < 0.001). Continuity of vaccination increased with age and with the worker or cohabitant having a major chronic condition. Vaccination was higher in workers who recognized vaccination as effective and those worried about being infected or infecting patients. CONCLUSION: Influenza vaccination coverage in PHCWs has declined, especially after the pandemic. Intensive interventions are needed to change this trend. Knowledge of vaccination should be reinforced by stressing the effectiveness of the vaccine and the risks of influenza for workers and patients. PMID- 23732253 TI - The oncology phone: an innovative program for the management of the oncology population in an academic medical center. AB - The Oncology Nursing Leadership Team at the Hospital of the University of Pennsylvania designed and implemented a phone consultation and intervention service to address increasing needs for specialty oncology nursing consultation and care for patients located on nononcology units. This article describes the planning, implementation, and evaluation of this service, which the team named the oncology phone. The service is available 24 hours per day, seven days per week by members of the Oncology Nursing Leadership Team and designated senior members of the clinical nursing staff. Consultation is initiated by any clinical nurse throughout the hospital who determines the need for oncology nursing expertise. Those needs include support for chemotherapy administration, symptom management, and care coordination. Data are collected from each call as well as subsequent face-to-face consultations and interventions. Evaluation of the data reveals important areas for education. A similar program may be valuable to other inpatient settings in addressing the needs of patients and staff. PMID- 23732254 TI - Towards a Casa Segura: a consumer product study of the effect of insecticide treated curtains on Aedes aegypti and dengue virus infections in the home. AB - The home, or domicile, is the principal environment for transmission of dengue virus (DENV) between humans and mosquito vectors. Community-wide distribution of insecticide-treated curtains (ITCs), mimicking vector control program-driven interventions, has shown promise to reduce DENV infections. We conducted a Casa Segura consumer product intervention study in Merida, Mexico to determine the potential to reduce intradomicillary DENV transmission through ITC use in individual homes. Dengue virus infections in mosquitoes and in humans were reduced in homes with ITCs in one of two study subareas. Overall, ITCs reduced intradomicillary DENV transmission; ITC homes were significantly less likely to experience multiple DENV infections in humans than NTC homes. Dengue virus infected Aedes aegypti females were reduced within the ITC homes where curtain use was highest. Some homes yielded up to nine infected Ae. aegypti females. This study provides insights regarding best practices for Casa Segura interventions to protect homes from intradomicillary DENV transmission. PMID- 23732255 TI - A stepped wedge, cluster-randomized trial of a household UV-disinfection and safe storage drinking water intervention in rural Baja California Sur, Mexico. AB - In collaboration with a local non-profit organization, this study evaluated the expansion of a program that promoted and installed Mesita Azul, an ultraviolet disinfection system designed to treat household drinking water in rural Mexico. We conducted a 15-month, cluster-randomized stepped wedge trial by randomizing the order in which 24 communities (444 households) received the intervention. We measured primary outcomes (water contamination and diarrhea) during seven household visits. The intervention increased the percentage of households with access to treated and safely stored drinking water (23-62%), and reduced the percentage of households with Escherichia coli contaminated drinking water (risk difference (RD): -19% [95% CI: -27%, -14%]). No significant reduction in diarrhea was observed (RD: -0.1% [95% CI: -1.1%, 0.9%]). We conclude that household water quality improvements measured in this study justify future promotion of the Mesita Azul, and that future studies to measure its health impact would be valuable if conducted in populations with higher diarrhea prevalence. PMID- 23732256 TI - A prospective evaluation of real-time PCR assays for the detection of Orientia tsutsugamushi and Rickettsia spp. for early diagnosis of rickettsial infections during the acute phase of undifferentiated febrile illness. AB - One hundred and eighty febrile patients were analyzed in a prospective evaluation of Orientia tsutsugamushi and Rickettsia spp. real-time polymerase chain reaction (PCR) assays for early diagnosis of rickettsial infections. By paired serology, 3.9% (7 of 180) and 6.1% (11 of 180) of patients were confirmed to have acute scrub or murine typhus, respectively. The PCR assays for the detection of O. tsutsugamushi and Rickettsia spp. had high specificity (99.4% [95% confidence interval (CI): 96.8-100] and 100% [95% CI: 97.8-100], respectively). The PCR results were also compared with immunoglobulin M (IgM) immunofluorescence assay (IFA) on acute sera. For O. tsutsugamushi, PCR sensitivity was twice that of acute specimen IgM IFA (28.6% versus 14.3%; McNemar's P = 0.3). For Rickettsia spp., PCR was four times as sensitive as acute specimen IgM IFA (36.4% versus 9.1%; P = 0.08), although this was not statistically significant. Whole blood and buffy coat, but not serum, were acceptable specimens for these PCRs. Further evaluation of these assays in a larger prospective study is warranted. PMID- 23732257 TI - Melioidosis as a consequence of sporting activity. AB - In the tropical city of Darwin, Northern Territory, Australia, dry season soil sampling cultured Burkholderia pseudomallei from 7 (70%) of 10 sports fields. However, during the 23 years of the Darwin Prospective Melioidosis Study, only 5 (0.6%) of 785 melioidosis cases have been attributed to infection from sports fields. In one soccer player with cutaneous melioidosis, B. pseudomallei cultured from the player was identical by multilocus sequence typing and multilocus variable-number tandem repeat analysis with an isolate recovered from soil at the location on the sports field where he was injured. Melioidosis is uncommon in otherwise healthy sports persons in melioidosis-endemic regions but still needs consideration in persons with abrasion injuries that involve contact with soil. PMID- 23732258 TI - Limberg flap versus Bascom cleft lift techniques for sacrococcygeal pilonidal sinus: prospective, randomized trial. AB - BACKGROUND: Although various methods have been described for surgical treatment of pilonidal sinus disease, which is best is under debate. Tension-free techniques seem to be most ideal. We aimed to evaluate the effects of two tension free methods in terms of patient satisfaction, postoperative complications, and early recurrence. METHODS: A group of 122 patients were prospectively included in the study. Patients were divided into two groups based on the operative method used: Limberg flap or Bascom cleft lift. Quality of life scores, pain scores, length of time for healing, hospital stay, surgical area-related complications, excised tissue weight, and early recurrence information were evaluated. RESULTS: Follow-up of patients in each group was completed. Patients in the Bascom cleft lift group had shorter operation duration, less excised tissue weight, better bodily pain score, and less role limitation due to physical problems score on postoperative day 10. There was no statistically significant difference between groups for the other criteria. CONCLUSIONS: Although both techniques provided good results during the early period, the Bascom cleft lift procedure is a reliable technique that provides shorter operation duration and better quality of life during the early postoperative period. PMID- 23732259 TI - Structural isomerism leading to variable proton conductivity in indium(III) isophthalic acid based frameworks. AB - Proton conductivity has been studied thoroughly in two isomeric In(III) isophthalate based MOFs. In-IA-2D-1 is capable of showing proton conductivity (3.4 * 10(-3) S cm(-1)) under humidified conditions (98% RH), whereas In-IA-2D-2 can conduct protons (2.6 * 10(-5) S cm(-1)) under humidified as well as anhydrous conditions. PMID- 23732260 TI - HEARTSTRING enabled no-touch proximal anastomosis for off-pump coronary artery bypass grafting: current evidence and technique. AB - Surgical revascularization remains the standard of care for many patients. Off pump coronary artery bypass grafting (OPCAB) without cardiopulmonary bypass (CPB) has evolved during the past 20 years, and as such can significantly reduce the occurrence of neurological complications. While avoiding the aortic cross clamping required in conventional on-pump techniques, OPCAB results in a lower incidence of stroke. However, clamp-related risk of stroke remains if partial or side-biting clamps are applied for proximal anastomoses. Others and we have demonstrated that no-touch 'anaortic' approaches avoiding any clamping during off pump procedures via complete in situ grafting result in significantly reduced stroke rates when compared with partial clamping. Therefore, OPCAB in situ grafting has been proposed as the 'standard of care' to reduce neurological complications. However, this technique may not be applicable to for every patient as the use of free grafts (arterial or venous) requiring proximal anastomosis is often still necessary to achieve complete revascularization. In these situations, proximal anastomosis can be performed without a partial clamp by using the HEARTSTRING device, and over the last few years, considerable evidence has arisen supporting the impact of HEARTSTRING-enabled anastomosis to significantly minimize atheroembolism and neurological complications when compared with partial or side-bite clamping. This paper provides a systematic overview and technical information about the combination of OPCAB and clampless strategies using the HEARTSTRING for proximal anastomosis to reduce stroke to levels reported for percutaneous coronary intervention. PMID- 23732261 TI - One-millimeter cancer-free margin is curative for colorectal liver metastases: a propensity score case-match approach. AB - OBJECTIVE: To investigate the influence of clear surgical resection margin width on disease recurrence rate after intentionally curative resection of colorectal liver metastases. BACKGROUND: There is consensus that a histological positive resection margin is a predictor of disease recurrence after resection of colorectal liver metastases. The dispute, however, over the width of cancer-free resection margin required is ongoing. METHODS: Analysis of observational prospectively collected data for 2715 patients who underwent primary resection of colorectal liver metastases from 2 major hepatobiliary units in the United Kingdom. Histological cancer-free resection margin was classified as positive (if cancer cells present at less than 1 mm from the resection margin) or negative (if the distance between the cancer and the margin is 1 mm or more). The negative margin was further classified according to the distance from the tumor in millimeters. Predictors of disease-free survival were analyzed in univariate and multivariate analyses. A case-match analysis by a propensity score method was undertaken to reduce bias. RESULTS: A 1-mm cancer-free resection margin was sufficient to achieve 33% 5-year overall disease-free survival. Extra margin width did not add disease-free survival advantage (P > 0.05). After the propensity case-match analysis, there is no statistical difference in disease free survival between patients with negative narrow and wider margin clearance [hazard ratio (HR) 1.0; 95% (confidence interval) CI: 0.9-1.2; P = 0.579 at 5-mm cutoff and HR 1.1; 95% CI: 0.96-1.3; P = 0.149 at 10-mm cutoff]. Patients with extrahepatic disease and positive lymph node primary tumor did not have disease free survival advantage despite surgical margin clearance (9 months for <1-mm vs 12 months for >=1-mm margin clearance; P = 0.062). CONCLUSION: One-mm cancer-free resection margin achieved in patients with colorectal liver metastases should now be considered the standard of care. PMID- 23732262 TI - Effects of Roux-en-Y gastric bypass or diabetes support and education on insulin sensitivity and insulin secretion in morbidly obese patients with type 2 diabetes. AB - OBJECTIVE: The long-term changes in insulin sensitivity and beta-cell function in morbidly obese patients with type 2 diabetes mellitus who undergo Roux-en-Y gastric bypass (RYGB) surgery or standard medical care remain unclear. We prospectively studied longitudinal changes of glucostatic parameters in morbidly obese patients with type 2 diabetes mellitus undergoing RYGB surgery or diabetes support and education (DSE). RESEARCH METHODS AND DESIGN: Sixty-one morbidly obese subjects (41.7 +/- 0.6 kg/m) with type 2 diabetes mellitus were assigned to RYGB surgery (n = 30) or DSE (n = 31). They were matched for sex, age, and body weight. Insulin sensitivity index (Si) and acute insulin response (AIR) were derived from frequently sampled intravenous glucose tolerance test. Body composition was measured using dual-energy x-ray absorptiometry. General linear model with repeated measures was used to examine the longitudinal changes (baseline, 6 months, 12 months) in these parameters. RESULTS: At 12-month follow up, significant improvement in obesity measures, body composition, glucose homeostasis, Si, and AIR was observed after RYGB surgery and weight loss. These outcomes were not influenced by preoperative insulin use. Although there were no significant changes in the body composition among DSE subjects, they experienced a decline in the Si and AIR, along with an increase in fasting glucose and HbA1c. The between-group differences in Si and AIR at 12-month follow-up were completely attenuated with adjustment to changes in body weight. CONCLUSIONS: The long-term effects of RYGB surgery on glucostatic parameters are partly dependent on weight loss. In morbidly obese patients with diabetes who were offered DSE, a progressive decline in the glucose homeostasis and glucostatic parameters is observed despite absence of weight gain. (NCT00787670). PMID- 23732263 TI - CONSORT compliance in surgical randomized trials: are we there yet? A systematic review. AB - OBJECTIVE: We performed a systematic review assessing the reporting quality of trials of surgical interventions, and explored associated trial level variables. BACKGROUND: Randomized controlled trials (RCTs) provide clinicians with the best evidence for the effects of interventions, but may not be reported with necessary detail. METHODS: In May 2009, 3 databases (MEDLINE, EMBASE, and CENTRAL) were searched for RCTs that assessed a surgical intervention using a comprehensive electronic strategy developed by the Cochrane Collaboration. The Consolidated Standards of Reporting Trials (CONSORT) checklist was used as a measure of reporting quality. An overall CONSORT score was calculated and expressed as a proportion. This was supplemented with domains related to external validity. We also collected data on characteristics hypothesized to improve reporting quality, and exploratory regression was performed to determine associations. RESULTS: One hundred fifty recently published RCTs were included. The most commonly represented surgical subspecialties were general (29%), orthopedic (23%), and cardiothoracic (13%). Most (65%) were published in subspecialty surgical journals. Overall reporting quality was low, with only 55% of CONSORT items addressed. Less than half of trials described adequate methods for sample size calculation (45%), random sequence generation (43%), allocation concealment (45%), and blinding (37%). The strongest associations with reporting quality were adequate methods related to methodological domains, an author with an epidemiology/statistics degree, and a longer report length. CONCLUSIONS: There remains much room for improvement for the reporting of surgical intervention trials. Authors and journal editors should apply existing reporting guidelines, and guidelines specific to the reporting of surgical interventions should be developed. PMID- 23732264 TI - Saline versus Plasma-Lyte A in initial resuscitation of trauma patients: a randomized trial. AB - OBJECTIVE: We sought to compare resuscitation with 0.9% NaCl versus Plasma-Lyte A, a calcium-free balanced crystalloid solution, hypothesizing that Plasma-Lyte A would better correct the base deficit 24 hours after injury. BACKGROUND: Sodium chloride (0.9%) (0.9% NaCl), though often used for resuscitation of trauma patients, may exacerbate the metabolic acidosis that occurs with injury, and this acidosis may have detrimental clinical effects. METHODS: We conducted a randomized, double-blind, parallel-group trial (NCT01270854) of adult trauma patients requiring blood transfusion, intubation, or operation within 60 minutes of arrival at the University of California Davis Medical Center. Based on a computer-generated, blocked sequence, subjects received either 0.9% NaCl or Plasma-Lyte A for resuscitation during the first 24 hours after injury. The primary outcome was mean change in base excess from 0 to 24 hours. Secondary outcomes included 24-hour arterial pH, serum electrolytes, fluid balance, resource utilization, and in-hospital mortality. RESULTS: Of 46 evaluable subjects (among 65 randomized), 43% had penetrating injuries, injury severity score was 23 +/- 16, 20% had admission systolic blood pressure less than 90 mm Hg, and 78% required an operation within 60 minutes of arrival. The baseline pH was 7.27 +/- 0.11 and base excess -5.9 +/- 5.0 mmol/L. The mean improvement in base excess from 0 to 24 hours was significantly greater with Plasma-Lyte A than with 0.9% NaCl {7.5 +/- 4.7 vs 4.4 +/- 3.9 mmol/L; difference: 3.1 [95% confidence interval (CI): 0.5-5.6]}. At 24 hours, arterial pH was greater [7.41 +/- 0.06 vs 7.37 +/- 0.07; difference: 0.05 (95% CI: 0.01-0.09)] and serum chloride was lower [104 +/- 4 vs 111 +/- 8 mEq/L; difference: -7 (95% CI: -10 to 3)] with Plasma-Lyte A than with 0.9% NaCl. Volumes of study fluid administered, 24-hour urine output, measures of resource utilization, and mortality did not significantly differ between the 2 arms. CONCLUSIONS: Compared with 0.9% NaCl, resuscitation of trauma patients with Plasma-Lyte A resulted in improved acid base status and less hyperchloremia at 24 hours postinjury. Further studies are warranted to evaluate whether resuscitation with Plasma-Lyte A improves clinical outcomes. PMID- 23732265 TI - Outpatient versus hospitalization management for uncomplicated diverticulitis: a prospective, multicenter randomized clinical trial (DIVER Trial). AB - OBJECTIVE: We compare the results of 2 different strategies for the management of patients with uncomplicated left colonic diverticulitis and to analyze differences in quality of life and economic costs. BACKGROUND: The most frequent standard management of acute uncomplicated diverticulitis still is hospital admission both in Europe and United States. METHODS: This multicenter, randomized controlled trial included patients older than 18 years with acute uncomplicated diverticulitis. All the patients underwent abdominal computed tomography. There were 2 strategies of management: hospitalization (group 1) and outpatient (group 2). The first dose of antibiotic was given intravenously to all patients in the emergency department and then group 1 patients were hospitalized whereas patients in group 2 were discharged. The primary end point was the treatment failure rate of the outpatient protocol and need for hospital admission. The secondary end points included quality-of-life assessment and evaluation of costs. RESULTS: A total of 132 patients were randomized: 4 patients in group 1 and 3 patients in group 2 presented treatment failure without differences between the groups (P=0.619). The overall health care cost per episode was 3 times lower in group 2, with savings of ?1124.70 per patient. No differences were observed between the groups in terms of quality of life. CONCLUSIONS: Outpatient treatment is safe and effective in selected patients with uncomplicated acute diverticulitis. Outpatient treatment allows important costs saving to the health systems without negative influence on the quality of life of patients with uncomplicated diverticulitis. Trial registration ID: EudraCT number 2008-008452-17. PMID- 23732266 TI - The impact of general surgeon supply on the risk of appendiceal rupture in North Carolina. AB - OBJECTIVE: To determine whether individuals from surgery-specific service areas with a low supply of general surgeons (GSs) are at increased risk for ruptured appendicitis (ruptured appendicitis is an indicator of surgical access). BACKGROUND: The increased health care costs and morbidity linked to appendiceal rupture are considered preventable in most cases with timely access to surgery. Among the factors thought to affect an individual's access to surgery for appendicitis is the relative supply of GSs. The maldistribution of GSs is targeted by a Medicare bonus payment although the impact of GS supply on surgical access has yet to be fully described. METHODS: Patients discharged from acute care and ambulatory surgery facilities in North Carolina from 2007 to 2009 were pooled for observational analysis. Using ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) codes, cases were identified as ruptured or unruptured. GS shortage levels based on supply were calculated at the surgical service area level and tested for an association with an individual's risk of rupture using logistic regression. RESULTS: Living in a service area with less than 3 GSs per 100,000 people significantly increases the probability of rupture in individuals with appendicitis, compared with living in a service area with at least 5 GSs per 100,000. CONCLUSIONS: The supply of GSs does affect access to surgical services for appendicitis. Expanding on this finding, the recently instituted HPSA (health professional shortage area) surgical incentive payment from the Affordable Care Act should be evaluated closely for its effectiveness. Enhancing supply in critical shortage areas could reduce appendiceal rupture and improve surgical access more generally. PMID- 23732267 TI - Incidence of groin hernia repair after radical prostatectomy: a population-based nationwide study. AB - OBJECTIVE: To assess the incidence of groin hernia repair after radical prostatectomy for prostate cancer compared with the incidence in a control population without prostate cancer in a nationwide, population-based study. BACKGROUND: Recent reports indicate an increase in the incidence of groin hernia repair after radical prostatectomy. Inadequate knowledge of the incidence of groin hernia in the general population makes this information hard to interpret. METHODS: Information was retrieved from the Prostate Cancer Database (PCBaSe) and Swedish Hernia Register for events between 1998 and 2010. The incidence of groin hernia surgery was calculated for a group of men treated with radical prostatectomy (open and minimally invasive) and for a group treated with radiation therapy, and these were compared with the incidence in a control cohort of men matched for age and county of residence. Multivariate analysis was used to assess the hazard ratio (HR) of groin hernia repair according to age, tumor risk category, and Charlson Comorbidity Index. RESULTS: A total of 28,608 cases and 105,422 controls were included in the study. Men treated with radical prostatectomy and radiation therapy had a significantly higher incidence of groin hernia repair than the control cohort: HR: 3.95 (95% confidence interval: 3.70 4.21) for retropubic prostatectomy, HR: 3.37 (95% confidence interval: 2.95-3.87) for minimally invasive prostatectomy, and HR: 1.84 (95% confidence interval: 1.66 2.04) for radiation therapy. CONCLUSIONS: An almost 4-fold increase in groin hernia repair was observed after radical prostatectomy compared with controls, and men who received radiation therapy had an almost 2-fold increase in incidence. As well as postoperative changes in the abdominal wall, increased vigilance for groin hernia seems to be important for the increased incidence of groin hernia repair seen after radical prostatectomy or radiation therapy for prostate cancer. PMID- 23732268 TI - Preoperative alcohol consumption and postoperative complications: a systematic review and meta-analysis. AB - OBJECTIVE: To systematically review and summarize the evidence of the association between preoperative alcohol consumption and postoperative complications elaborated on complication type. BACKGROUND: Conclusions in studies on preoperative alcohol consumption and postoperative complications have been inconsistent. METHODS: A systematic review and meta-analysis based on a search in MEDLINE, EMBASE, CINAHL, and PsycINFO citations. Included were original studies of the association between preoperative alcohol consumption and postoperative complications occurring within 30 days of the operation. In total, 3676 studies were identified and reviewed for eligibility, and data were extracted. Forest plots and pooled relative risks (RRs), including 95% confidence intervals (CIs), were estimated for several complication types. RESULTS: Fifty-five studies provided data for estimates. Preoperative alcohol consumption was associated with an increased risk of various postoperative complications, including general morbidity (RR = 1.56; 95% CI: 1.31-1.87), general infections (RR = 1.73; 95% CI: 1.32-2.28), wound complications (RR = 1.23; 95% CI: 1.09-1.40), pulmonary complications (RR = 1.80; 95% CI: 1.30-2.49), prolonged stay at the hospital (RR = 1.24; 95% CI: 1.18-1.31), and admission to intensive care unit (RR = 1.29; 95% CI: 1.03-1.61). Clearly defined high alcohol consumption was associated with increased risk of postoperative mortality (RR = 2.68; 95% CI: 1.50-4.78). Low to moderate preoperative alcohol consumption and postoperative complications did not seem to be associated; however, very few studies were included in the analyses hereof. CONCLUSIONS: Preoperative alcohol consumption was associated with an increased risk of general postoperative morbidity, general infections, wound complications, pulmonary complications, prolonged stay at the hospital, and admission to intensive care unit. PMID- 23732269 TI - Attentional capacity: an essential aspect of surgeon performance. PMID- 23732270 TI - Registration rates, adequacy of registration, and a comparison of registered and published primary outcomes in randomized controlled trials published in surgery journals. AB - OBJECTIVE: To determine the proportion of registered trials published in the surgical literature, to compare, in registered trials, the primary outcomes registered with those published and to determine whether outcome-reporting bias favored significant primary outcomes. BACKGROUND: Trial protocol registration before patient enrolment for randomized controlled trials (RCTs) is a perquisite for many journals in attempt to decrease publication and selective reporting bias. Analysis of the medical literature demonstrates poor registration rates with discrepancies between reported and registered primary outcomes. This has not been evaluated in contemporary surgical journals. METHODS: RCTs were identified for 2009 and 2010 from 10 high-impact factor surgical journals. One investigator identified all RCTs and extracted primary and secondary outcomes, dates of commencement and completion of study, funding source, and trial registration number. Trial registers were searched using the trial registration number for primary and secondary outcomes, dates of commencement and completion of study, and date of registration. Trial registration rates and registration adequacy were recorded. Register and published primary outcomes were then compared. RESULTS: A total of 246 papers were analyzed, among which 86 (34.9%) were not registered and 52 (21%) were inadequately registered. Of the 108 adequately registered trials, 32 (29%) had a discrepancy between the published primary outcome and that registered in trial register. In the 24 published studies where it was possible to assess, the discrepancy favored a statistically significant primary outcome in 22 (91.7%) whereas in 2 (8.3%) the discrepancy produced a statistically insignificant result. CONCLUSIONS: Less than half of all RCTs published in general surgical journals were adequately registered, and approximately 30% had discrepancies in the registered and published primary outcome with 90% of those assessable favoring a statistically positive result. PMID- 23732271 TI - Surveillance endoscopy at five or more years after cardiomyotomy for achalasia. AB - OBJECTIVE: To perform long-term histopathological and clinical assessment of patients who have previously undergone cardiomyotomy for achalasia. BACKGROUND: There are few studies on long-term outcome for patients treated by cardiomyotomy for achalasia. Recent publications suggest that these patients may be at high risk of both squamous cell carcinoma and adenocarcinoma of the esophagus. METHODS: All patients, in whom at least 5 years had elapsed since laparoscopic cardiomyotomy for achalasia, were identified from a prospective database. Patients were invited to attend for endoscopy and clinical outcome was assessed by questionnaire. RESULTS: Out of 171 patients identified, 2 had died from esophageal carcinoma. Of the remainder, 68 were recruited [mean age 52 years (range 26-72)]. Fifty-six percent reported minimal symptoms and 6% experienced frequent reflux symptoms. Almost all patients (93%) reported some dysphagia, but dysphagia scores remained significantly lower than preoperatively (P < 0.0001). Quality of life was comparable to normal subjects, and 97% of patients indicated they had made the correct decision to undergo surgery. At endoscopy 83% had evidence of chronic inflammation in the distal esophagus on histopathology, including 22% with moderate to severe esophagitis and 7% with Barrett's esophagus. Five patients showed esophageal candidiasis, and 2 had eosinophilic esophagitis. No dysplasia or malignancy was identified. CONCLUSIONS: The clinical outcome remains excellent in most patients at long-term follow-up after cardiomyotomy for achalasia. Surveillance endoscopy might identify high-risk patients but routine endoscopy in all patients is probably not necessary, particularly early after surgery. PMID- 23732273 TI - SPANNER: taxonomic assignment of sequences using pyramid matching of similarity profiles. AB - BACKGROUND: Homology-based taxonomic assignment is impeded by differences between the unassigned read and reference database, forcing a rank-specific classification to the closest (and possibly incorrect) reference lineage. This assignment may be correct only to a general rank (e.g. order) and incorrect below that rank (e.g. family and genus). Algorithms like LCA avoid this by varying the predicted taxonomic rank based on matches to a set of taxonomic references. LCA and related approaches can be conservative, especially if best matches are taxonomically widespread because of events such as lateral gene transfer (LGT). RESULTS: Our extension to LCA called SPANNER (similarity profile annotater) uses the set of best homology matches (the LCA Profile) for a given sequence and compares this profile with a set of profiles inferred from taxonomic reference organisms. SPANNER provides an assignment that is less sensitive to LGT and other confounding phenomena. In a series of trials on real and artificial datasets, SPANNER outperformed LCA-style algorithms in terms of taxonomic precision and outperformed best BLAST at certain levels of taxonomic novelty in the dataset. We identify examples where LCA made an overly conservative prediction, but SPANNER produced a more precise and correct prediction. CONCLUSIONS: By using profiles of homology matches to represent patterns of genomic similarity that arise because of vertical and lateral inheritance, SPANNER offers an effective compromise between taxonomic assignment based on best BLAST scores, and the conservative approach of LCA and similar approaches. AVAILABILITY: C++ source code and binaries are freely available at http://kiwi.cs.dal.ca/Software/SPANNER. CONTACT: beiko@cs.dal.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23732272 TI - Cerebrospinal fluid abeta to tau ratio and postoperative cognitive change. AB - OBJECTIVE: Determination of biomarker and neuropathogenesis of postoperative cognitive change (POCC) or postoperative cognitive dysfunction. BACKGROUND: POCC is one of the most common postoperative complications in elderly patients. Whether preoperative cerebrospinal fluid (CSF) beta-amyloid protein (Abeta) to tau ratio, an Alzheimer disease biomarker, is a biomarker for risk of POCC remains unknown. We therefore set out to assess the association between preoperative CSF Abeta42 or Abeta40 to tau ratio and POCC. METHODS: Patients who had total hip/knee replacement were enrolled. The CSF was obtained during the administration of spinal anesthesia. Cognitive tests were performed with these participants at 1 week before and at 1 week and 3 to 6 months after the surgery. Z scores of the changes from preoperative to postoperative on several key domains of the cognitive battery were determined. We then examined the association between preoperative CSF Abeta42/tau or Abeta40/tau ratio and the outcome measures described earlier, adjusting for age and sex. RESULTS: Among the 136 participants (mean age = 71 +/- 5 years; 55% men), preoperative CSF Abeta42/tau ratio was associated with postoperative Hopkins Verbal Learning Test Retention [Z score = 8.351; age, sex-adjusted (adj.) P = 0.003], and the Benton Judgment of Line Orientation (Z score = 1.242; adj. P = 0.007). Abeta40/tau ratio was associated with Brief Visuospatial Memory Test Total Recall (Z score = 1.045; adj. P = 0.044). CONCLUSIONS: Preoperative CSF Abeta/tau ratio is associated with postoperative changes in specific cognitive domains. The presence of the Alzheimer's disease biomarker, specifically the Abeta/tau ratio, may identify patients at higher risk for cognitive changes after surgery. PMID- 23732274 TI - AuthorReward: increasing community curation in biological knowledge wikis through automated authorship quantification. AB - SUMMARY: Community curation-harnessing community intelligence in knowledge curation, bears great promise in dealing with the flood of biological knowledge. To exploit the full potential of the scientific community for knowledge curation, multiple biological wikis (bio-wikis) have been built to date. However, none of them have achieved a substantial impact on knowledge curation. One of the major limitations in bio-wikis is insufficient community participation, which is intrinsically because of lack of explicit authorship and thus no credit for community curation. To increase community curation in bio-wikis, here we develop AuthorReward, an extension to MediaWiki, to reward community-curated efforts in knowledge curation. AuthorReward quantifies researchers' contributions by properly factoring both edit quantity and quality and yields automated explicit authorship according to their quantitative contributions. AuthorReward provides bio-wikis with an authorship metric, helpful to increase community participation in bio-wikis and to achieve community curation of massive biological knowledge. AVAILABILITY: http://cbb.big.ac.cn/software. CONTACT: zhangzhang@big.ac.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23732275 TI - Relating genes to function: identifying enriched transcription factors using the ENCODE ChIP-Seq significance tool. AB - MOTIVATION: Biological analysis has shifted from identifying genes and transcripts to mapping these genes and transcripts to biological functions. The ENCODE Project has generated hundreds of ChIP-Seq experiments spanning multiple transcription factors and cell lines for public use, but tools for a biomedical scientist to analyze these data are either non-existent or tailored to narrow biological questions. We present the ENCODE ChIP-Seq Significance Tool, a flexible web application leveraging public ENCODE data to identify enriched transcription factors in a gene or transcript list for comparative analyses. IMPLEMENTATION: The ENCODE ChIP-Seq Significance Tool is written in JavaScript on the client side and has been tested on Google Chrome, Apple Safari and Mozilla Firefox browsers. Server-side scripts are written in PHP and leverage R and a MySQL database. The tool is available at http://encodeqt.stanford.edu. CONTACT: abutte@stanford.edu SUPPLEMENTARY INFORMATION: Supplementary material is available at Bioinformatics online. PMID- 23732276 TI - Informed and automated k-mer size selection for genome assembly. AB - MOTIVATION: Genome assembly tools based on the de Bruijn graph framework rely on a parameter k, which represents a trade-off between several competing effects that are difficult to quantify. There is currently a lack of tools that would automatically estimate the best k to use and/or quickly generate histograms of k mer abundances that would allow the user to make an informed decision. RESULTS: We develop a fast and accurate sampling method that constructs approximate abundance histograms with several orders of magnitude performance improvement over traditional methods. We then present a fast heuristic that uses the generated abundance histograms for putative k values to estimate the best possible value of k. We test the effectiveness of our tool using diverse sequencing datasets and find that its choice of k leads to some of the best assemblies. AVAILABILITY: Our tool KmerGenie is freely available at: http://kmergenie.bx.psu.edu/. PMID- 23732277 TI - Gene-set analysis is severely biased when applied to genome-wide methylation data. AB - MOTIVATION: DNA methylation is an epigenetic mark that can stably repress gene expression. Because of its biological and clinical significance, several methods have been developed to compare genome-wide patterns of methylation between groups of samples. The application of gene set analysis to identify relevant groups of genes that are enriched for differentially methylated genes is often a major component of the analysis of these data. This can be used, for example, to identify processes or pathways that are perturbed in disease development. We show that gene-set analysis, as it is typically applied to genome-wide methylation assays, is severely biased as a result of differences in the numbers of CpG sites associated with different classes of genes and gene promoters. RESULTS: We demonstrate this bias using published data from a study of differential CpG island methylation in lung cancer and a dataset we generated to study methylation changes in patients with long-standing ulcerative colitis. We show that several of the gene sets that seem enriched would also be identified with randomized data. We suggest two existing approaches that can be adapted to correct the bias. Accounting for the bias in the lung cancer and ulcerative colitis datasets provides novel biological insights into the role of methylation in cancer development and chronic inflammation, respectively. Our results have significant implications for many previous genome-wide methylation studies that have drawn conclusions on the basis of such strongly biased analysis. CONTACT: cathal.seoighe@nuigalway.ie SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23732278 TI - Differential expression of long non-coding RNAs in bleomycin-induced lung fibrosis. AB - Recent studies suggest that long non-coding RNAs (lncRNAs) are more involved in human diseases than previously realized. A growing body of evidence links lncRNA mutation and dysregulation to diverse human diseases. However, the association of lncRNAs with the pathogenesis of lung fibrosis remains poorly understood. In this study, we detected changes in hydroxyproline and collagen levels, as well as the ultrastructure of lung tissue to develop a rat model of lung fibrosis. The differentially expressed lncRNAs and mRNA profiles between fibrotic lung and normal lung tissue were analyzed using microarrays. Gene Ontology analysis and pathway analysis were performed for further research. Two differentially expressed lncRNAs, namely, AJ005396 and S69206, were detected by in situ hybridization to validate the microarray data. The results revealed that the number of collagen fibers in the interstitial lung tissue significantly increased in the model group compared with the normal group. In total, 210 and 358 lncRNAs were upregulated and downregulated, respectively, along with 415 upregulated and 530 downregulated mRNAs in the rats with lung fibrosis. AJ005396 and S69206 were upregulated in the fibrotic lung tissue, consistent with the microarray data, and were located in the cytoplasm of the interstitial lung cells. In conclusion, the expression profile of the lncRNAs was significantly altered in the fibrotic lung tissue and these transcripts are potential molecular targets for inhibiting the development of lung fibrosis. PMID- 23732279 TI - beta-elemene decreases cell invasion by upregulating E-cadherin expression in MCF 7 human breast cancer cells. AB - Inactivation of E-cadherin results in cell migration and invasion, hence leading to cancer aggressiveness and metastasis. Downregulation of E-cadherin is closely correlated with a poor prognosis in invasive breast cancer. Thus, re-introducing E-cadherin is a novel strategy for cancer therapy. The aim of the present study was to determine the effects of the traditional Chinese medicine, beta-elemene (ELE), on E-cadherin expression, cell migration and invasion in the breast cancer cell line MCF-7. MCF-7 cells were treated with 50 and 100 ug/ml ELE. E-cadherin mRNA was analyzed by reverse transcription-polymerase chain reaction. E-cadherin protein levels were determined by immunofluorescence and western blot assays. Cell motility was measured by a Transwell assay. ELE increased both the protein and mRNA levels of E-cadherin, accompanied by decreased cell migration and invasion. Further analysis demonstrated that ELE upregulated estrogen receptor alpha (ERalpha) and metastasis-associated protein 3 (MTA3), and decreased the nuclear transcription factor Snail. In conclusion, our results demonstrate that ELE decreases cell migration and invasion by upregulating E-cadherin expression via controlling the ERalpha/MTA3/Snail signaling pathway. PMID- 23732280 TI - Therapy: Immunotherapy for T1DM--targeting innate immunity. PMID- 23732281 TI - Diabetes: hypertension during pregnancy and future diabetes mellitus. AB - Pregnancy is described as the window to a woman's future health. A study by Feig et al. has found an increased risk of diabetes mellitus later in life in women with a history of pre-eclampsia or gestational hypertension, which suggests the need for screening and preventative measures in these women. PMID- 23732282 TI - Therapy: Blockade of IGF-1R-not effective in neuroendocrine tumours. PMID- 23732283 TI - Reproductive endocrinology: AS101 might prevent chemotherapy-induced infertility. PMID- 23732285 TI - Effect of laser-induced temperature field on the characteristics of laser sintered silver nanoparticle ink. AB - Laser sintering of metal nanoparticles is a key technology for high-performance printed electronics fabricated on heat-sensitive substrates such as glass or plastic. Although laser-sintered electronic devices have been successfully fabricated, the role of the induced temperature field in the laser sintering process has not been reported thus far. In this work, the effect of temperature on the laser sintering process is described for the first time using a two dimensional transient heat conduction equation for inkjet-printed silver nanoparticle ink. The in situ electrical resistance was measured to estimate the transient thermal conductivity and hence the temperature of the sintered ink during the laser sintering process. To verify the estimated laser sintering temperature, the morphology of furnace-sintered silver nanoparticle ink was compared with that of laser-sintered ink. The electrical characteristics and surface morphology of laser-sintered ink are found to be related to the process temperature. PMID- 23732286 TI - Pervaporation behavior and integrated process for concentrating lignocellulosic ethanol through polydimethylsiloxane (PDMS) membrane. AB - The effects of by-products from ethanol fermentation and hydrolysates of lignocelluloses on ethanol diffusion through polydimethylsiloxane (PDMS) membranes with/without silicalite-1 were investigated. A pervaporation process was integrated with lignocellulosic fermentation to concentrate bioethanol using bare PDMS membranes. Results showed that yeasts, solid particles, and salts increased ethanol flux and selectivity through the membranes (PDMS with/without silicalite-1), whereas glucose exerted negative effects on the performance. On bare PDMS membrane, the performance was not obviously affected by the existence of aliphatic acids. However, on PDMS-silicalite-1 membrane, a remarkable decrease in ethanol selectivity and a rapid growth of total flux in the presence of aliphatic acids were observed. These phenomena were due to the interaction of acids with silanol (Si-OH) groups to break the dense membrane surface. On the PDMS membranes with/without silicalite-1, degradation products of lignocellulosic hydrolysates such as furfural and hydroxyacetone slightly influenced separation performance. These results revealed that an integrated process can effectively eliminate product inhibition, improve ethanol productivity, and enhance the glucose conversion rate. PMID- 23732284 TI - The obesogenic effect of high fructose exposure during early development. AB - Obesogens are compounds that disrupt the function and development of adipose tissue or the normal metabolism of lipids, leading to an increased risk of obesity and associated diseases. Evidence for the adverse effects of industrial and agricultural obesogens, such as tributyltin, bisphenol A and other organic pollutants is well-established. Current evidence suggests that high maternal consumption of fat promotes obesity and increased metabolic risk in offspring, but less is known about the effects of other potential nutrient obesogens. Widespread increase in dietary fructose consumption over the past 30 years is associated with chronic metabolic and endocrine disorders and alterations in feeding behaviour that promote obesity. In this Perspectives, we examine the evidence linking high intakes of fructose with altered metabolism and early obesity. We review the evidence suggesting that high fructose exposure during critical periods of development of the fetus, neonate and infant can act as an obesogen by affecting lifelong neuroendocrine function, appetite control, feeding behaviour, adipogenesis, fat distribution and metabolic systems. These changes ultimately favour the long-term development of obesity and associated metabolic risk. PMID- 23732287 TI - Do cryopreserved regulatory T cells retain their suppressive potency? PMID- 23732288 TI - Racial differences between solid organ transplant donors and recipients in British Columbia 2005-2009: a follow-up study since the last analysis in 1993 1997. PMID- 23732289 TI - Comparison of dynamics of wildtype and V94M human UDP-galactose 4-epimerase-A computational perspective on severe epimerase-deficiency galactosemia. AB - UDP-galactose 4'-epimerase (GALE) catalyzes the interconversion of UDP-galactose and UDP-glucose, an important step in galactose catabolism. Type III galactosemia, an inherited metabolic disease, is associated with mutations in human GALE. The V94M mutation has been associated with a very severe form of type III galactosemia. While a variety of structural and biochemical studies have been reported that elucidate differences between the wildtype and this mutant form of human GALE, little is known about the dynamics of the protein and how mutations influence structure and function. We performed molecular dynamics simulations on the wildtype and V94M enzyme in different states of substrate and cofactor binding. In the mutant, the average distance between the substrate and both a key catalytic residue (Tyr157) and the enzyme-bound NAD+ cofactor and the active site dynamics are altered making substrate binding slightly less stable. However, overall stability or dynamics of the protein is not altered. This is consistent with experimental findings that the impact is largely on the turnover number (kcat), with less substantial effects on Km. Active site fluctuations were found to be correlated in enzyme with substrate bound to just one of the subunits in the homodimer suggesting inter-subunit communication. Greater active site loop mobility in human GALE compared to the equivalent loop in Escherichia coli GALE explains why the former can catalyze the interconversion of UDP-N acetylgalactosamine and UDP-N-acetylglucosamine while the bacterial enzyme cannot. This work illuminates molecular mechanisms of disease and may inform the design of small molecule therapies for type III galactosemia. PMID- 23732290 TI - Molecular cloning and characterization of perlucin from the freshwater pearl mussel, Hyriopsis cumingii. AB - Perlucin is an important functional protein that regulates shell and pearl formation. In this study, we cloned the perlucin gene from the freshwater pearl mussel Hyriopsis cumingii, designated as Hcperlucin. The full-length cDNA transcribed from the Hcperlucin gene was 1460 bp long, encoding a putative signal peptide of 20 amino acids and a mature protein of 141 amino acids. The mature Hcperlucin peptide contained six conserved cysteine residues and a carbohydrate recognition domain, similar to other members of the C-type lectin families. In addition, a "QPS" and an invariant "WND" motif near the C-terminal region were also found, which are extremely important for polysaccharide recognition and calcium binding of lectins. The mRNA of Hcperlucin was constitutively expressed in all tested H. cumingii tissues, with the highest expression levels observed in the mantle, adductor, gill and hemocytes. In situ hybridization was used to detect the presence of Hcperlucin mRNA in the mantle, and the result showed that the mRNA was specifically expressed in the epithelial cells of the dorsal mantle pallial, an area known to express genes involved in the biosynthesis of the nacreous layer of the shell. The significant Hcperlucin mRNA expression was detected on day 14 post shell damage and implantation, suggesting that the Hcperlucin might be an important gene in shell nacreous layer and pearl formation. The change of perlucin expression in pearl sac also confirmed that the mantle transplantation results in a new expression pattern of perlucin genes in pearl sac cells that are required for pearl biomineralization. These findings could help better understanding the function of perlucin in the shell and pearl formation. PMID- 23732291 TI - Transcriptomic analysis of purple leaf determination in birch. AB - 'Purple Rain', a purple cultivar of Betula pendula, has dark purple leaves throughout the vegetative period. In this study, B. pendula 'Purple Rain' was found to have a higher anthocyanidin level compared with B. pendula, Transcriptome analysis revealed numerous changes in gene expression that could be attributed to color change, including the upregulation of 2467 unigenes and the downregulation of 2299 unigenes in 'Purple Rain'. Furthermore, anthocyanidin synthesis and transcriptional regulation were altered in 'Purple Rain', which may have contributed to phenotypic changes. These results provide unique molecular insights into the biochemical pathways and regulatory networks that function in a purple variety of B. pendula. PMID- 23732292 TI - Molecular cloning and characterization of TNFSF14 (LIGHT) and its receptor TNFRSF14 (HVEM) in guinea pig (Cavia porcellus). AB - LIGHT (lymphotoxin-related inducible ligand that competes with herpes simplex virus (HSV) glycoprotein D for herpesvirus entry mediator on T cells) is a member of the tumor necrosis factor (TNF) ligand superfamily, which plays important roles in inflammatory and immune responses. In the present study, the cDNAs of guinea pig (Cavia porcellus) LIGHT (designated as gpLIGHT) and its receptor herpes virus entry mediator (designated as gpHVEM) were amplified from spleen by reverse transcription polymerase chain reaction (RT-PCR). The ORFs of gpLIGHT and gpHVEM cover 726 and 861 bp, encoding predicted proteins with 241 and 286 aas, respectively. The three-dimensional (3D) structure, phylogenetic relationships, and characterization of both genes were also analyzed. We also generated a 3D model to verify interaction between the two proteins. Real-time quantitative PCR (qPCR) analysis revealed that both LIGHT and HVEM are constitutively expressed in guinea pig various tissues. A fusion protein SUMO (Small Ubiquitin-like Modifier) gpsLIGHT (the soluble mature part of gpLIGHT) was efficiently expressed in Escherichia coli BL21 (DE3) and purified using metal chelate affinity chromatography (Ni-NTA). Laser scanning confocal microscopy (LSCM) showed that gpsLIGHT can bind its receptors on T cells. The LIGHT-HVEM signaling pathway plays an important role in the immune system, and our results might provide a platform for further research into the effects of LIGHT and HVEM. PMID- 23732293 TI - Next generation sequencing as a useful tool in the diagnostics of mosaicism in Alport syndrome. AB - Alport syndrome (ATS) is a progressive hereditary nephropathy characterized by hematuria and/or proteinuria with structural defects of the glomerular basement membrane. It can be associated with extrarenal manifestations (high-tone sensorineural hearing loss and ocular abnormalities). Somatic mutations in COL4A5 (X-linked), COL4A3 and COL4A4 genes (both autosomal recessive and autosomal dominant) cause Alport syndrome. Somatic mosaicism in Alport patients is very rare. The reason for this may be due to the difficulty of detection. We report the case of a boy and his mother who presented with Alport syndrome. Mutational analysis showed the novel hemizygote pathogenic mutation c.2396-1G>A (IVS29-1G>A) at the splice acceptor site of the intron 29 exon 30 boundary of the COL4A5 gene in the boy. The mutation in the mother would not have been detected by Sanger sequencing without the knowledge of the mutational analysis result of her son. Further investigation of the mother using next generation sequencing showed somatic mosaicism and implied potential germ cell mosaicism. The mutation in the mother has most likely occurred during early embryogenesis. Analysis of tissue of different embryonic origin in the mother confirmed mosaicism in both mesoderm and ectoderm. Low grade mosaicism is very difficult to detect by Sanger sequencing. Next generation sequencing is increasingly used in the diagnostics and might improve the detection of mosaicism. In the case of definite clinical symptoms of ATS and missing detection of a mutation by Sanger sequencing, mutational analysis should be performed by next generation sequencing. PMID- 23732294 TI - CYP2C9 genotype and association with bone mineral density: a pilot study. AB - BACKGROUND: In recent years reduced bone mineral density (BMD) and osteoporosis have become major public health problems. Single nucleotide polymorphisms (SNPs) in the cytochrome P450 2C9 (CYP2C9) gene influence the response to oral anticoagulant drugs, which are positively associated with the risk to develop osteoporosis. The aim of the present investigation was to clarify a potential role of CYP2C9 sequence variations and susceptibility to develop osteoporosis. SUBJECTS AND METHODS: Ninety two consecutive angiologic outpatients, mean age: 60.3+/-14.4, without secondary causes of bone loss were genotyped and classified as patients with normal BMD, osteopenia and osteoporosis according to WHO criteria by dual-energy X-ray absorptiometry at the lumbar spine and/or the femoral neck. Potential association between the CYP2C9 genotype and BMD was tested. RESULTS: 59% of the patients (n=54) presented with reduced BMD and were compared to 38 age-matched persons with normal BMD. The genotype distribution showed 15% heterozygous for CYP2C9*2 p.Arg144Cys, 14% for CYP2C9*3 p.IIe359Leu, 2% for both polymorphisms, and 69% had wildtype genotypes. Patients with CYP2C9 mutations had significantly lower BMD values at the femoral neck and displayed a four-fold higher adjusted risk to suffer from reduced BMD than individuals with wildtype genotypes (p=0.02). DISCUSSION: Oral anticoagulant treatment is common in angiologic outpatients. The gene variants CYP2C9*2 and CYP2C9*3 have been shown to require lower maintenance doses of oral anticoagulant drugs. An association between oral anticoagulant drugs and the susceptibility to develop osteoporosis in relation to sequence variations in the CYP2C9 gene is suggested to be mediated via the glucocorticoid synthesis pathway. CONCLUSION: The CYP2C9*2/CYP2C9*3 variants were significantly associated with femoral BMD in a selected elderly Austrian population. These variants could contribute to the complex risk to develop osteoporosis. PMID- 23732295 TI - The unclassified variant: c.2044AD>G, p.T682A (het.) in exon 12 of the GLI3 gene in a patient with oral-facial-digital syndrome type II (Mohr syndrome) phenotype. AB - The gene mutation for oral-facial digital syndrome type II (Mohr syndrome) is unknown. We describe a Saudi female infant with Mohr syndrome. An unclassified variant: c.2044 A>G, p.T682A in exon 12 of the GLI3 gene in a heterozygous state was identified in the infant. Mutation Taster (http://www.mutationtaster.org) considers this variant as "disease causing". However, when the unaffected parents were tested, the father was found to have the same variant, also in a heterozygous state. Hence, the pathogenic role of this variant seems unlikely; although apparent non-penetrance remains a possibility. PMID- 23732297 TI - Drug-drug interactions and metabolism in cytochrome P450 2C knockout mice: application to troleandomycin and midazolam. AB - Drug-drug interactions (DDIs) may cause serious drug toxicity and delay development of candidate drugs. Screening using human liver microsomes and hepatocytes can help predict DDIs but do not always provide the degree of certainty required for confident progression of a candidate drug. Thus a suitable in vivo test system could be of great value. Here a Cyp2c knockout (KO) mouse was investigated for studying DDIs using midazolam (MDZ) a standard human CYP3A4 substrate and troleandomycin (TAO) a potent human CYP3A4 inhibitor. Pharmacokinetics (PK) and biotransformation of MDZ were investigated following dosing to Cyp2c KO and wild type mice before and after TAO treatment. The noteworthy differences in the metabolism of MDZ in Cyp2c KO compared to wild type mice confirms the important role that Cyp2c enzymes play in the murine metabolism of MDZ in vivo. The impact of Cyp3a inhibition produced a further increase in circulating MDZ concentrations in all individuals from both strains of mice though the impact of the elimination of the Cyp2c pathway in the KO mice on the AUC was less than perhaps expected. We have shown that TAO produces an increase in the MDZ concentration and a reduction in the 1'hydroxymidazolam/midazolam formation ratio but the expected difference in the magnitude of this effect between the wild type and the Cyp2c KO mice was not seen. The magnitude of the TAO effect was also smaller than is reported in humans. Hence further work is required before this animal model could be used to predict clinical interactions. PMID- 23732298 TI - Dual roles of nuclear receptor liver X receptor alpha (LXRalpha) in the CYP3A4 expression in human hepatocytes as a positive and negative regulator. AB - CYP3A4 is a major drug-metabolizing enzyme in humans, whose expression levels show large inter-individual variations and are associated with several factors such as genetic polymorphism, physiological and disease status, diet and xenobiotic exposure. Nuclear receptor pregnane X receptor (PXR) is a key transcription factor for the xenobiotic-mediated transcription of CYP3A4. In this study, we have investigated a possible involvement of liver X receptor alpha (LXRalpha), a critical regulator of cholesterol homeostasis, in the hepatic CYP3A4 expression since several recent reports suggest the involvement of CYP3A enzymes in the cholesterol metabolism in humans and mice. Reporter assays using wild-type and mutated CYP3A4 luciferase reporter plasmids and electrophoretic mobility shift assays revealed that LXRalpha up-regulated CYP3A4 through the known DNA elements critical for the PXR-dependent CYP3A4 transcription, suggesting LXRalpha as a positive regulator for the CYP3A4 expression and a crosstalk between PXR and LXRalpha in the expression. In fact, reporter assays showed that LXRalpha activation attenuated the PXR-dependent CYP3A4 transcription. Moreover, a PXR agonist treatment-dependent increase in CYP3A4 mRNA levels was suppressed by co-treatment with an LXRalpha agonist in human primary hepatocytes and HepaRG cells. The suppression was not observed when LXRalpha expression was knocked-down in HepaRG cells. In conclusion, the present results suggest that sterol-sensitive LXRalpha positively regulates the basal expression of CYP3A4 but suppresses the xenobiotic/PXR-dependent CYP3A4 expression in human hepatocytes. Therefore, nutritional, physiological and disease conditions affecting LXRalpha might be one of the determinants for the basal and xenobiotic-responsive expression of CYP3A4 in human livers. PMID- 23732296 TI - Effects of neuronal nicotinic acetylcholine receptor allosteric modulators in animal behavior studies. AB - Nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation-conducting transmembrane channels from the cys-loop receptor superfamily. The neuronal subtypes of these receptors (e.g. the alpha7 and alpha4beta2 subtypes) are involved in neurobehavioral processes such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and a number of cognitive functions like learning and memory. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders, and behavioral studies in animals are useful models to assess the effects of compounds that act on these receptors. Allosteric modulators are ligands that bind to the receptors at sites other than the orthosteric site where acetylcholine, the endogenous agonist for the nAChRs, binds. While conventional ligands for the neuronal nAChRs have been studied for their behavioral effects in animals, allosteric modulators for these receptors have only recently gained attention, and research on their behavioral effects is growing rapidly. Here we will discuss the behavioral effects of allosteric modulators of the neuronal nAChRs. PMID- 23732299 TI - Anti-proliferative actions of N'-desmethylsorafenib in human breast cancer cells. AB - The multi-kinase inhibitor sorafenib is used for the treatment of renal and hepatic carcinomas and is undergoing evaluation for treatment of breast cancer in combination with other agents. Cytochrome P450 (CYP) 3A4 converts sorafenib to multiple metabolites that have been detected in patient plasma. However, recent clinical findings suggest that combination therapy may elicit inhibitory pharmacokinetic interactions involving sorafenib that increase toxicity. While sorafenib N-oxide is an active metabolite, information on the anti-tumor actions of other metabolites is unavailable. The present study evaluated the actions of sorafenib and its five major metabolites in human breast cancer cell lines. All agents, with the exception of N'-hydroxymethylsorafenib N-oxide, decreased ATP formation in four breast cancer cell lines (MDA-MB-231, MDA-MB-468, MCF-7 and T 47D). Prolonged treatment of MDA-MB-231 cells with N'-desmethylsorafenib, N' desmethylsorafenib N-oxide and sorafenib (10 MUM, 72 h) produced small increases in caspase-3 activity to 128-139% of control. Sorafenib and its metabolites, again with the exception of N'-hydroxymethylsorafenib N-oxide, impaired MEK/ERK signaling in MDA-MB-231 cells and modulated the expression of cyclin D1 and myeloid cell leukemia sequence-1, which regulate cell viability. When coadministered with doxorubicin (0.5 or 1 MUM), sorafenib and N' desmethylsorafenib (25 MUM) produced greater effects on ATP production than either treatment alone. Thus, it emerges that, by targeting the MEK/ERK pathway, multiple sorafenib metabolites may contribute to the actions of sorafenib in breast cancer. Because N'-desmethylsorafenib is not extensively metabolized and does not inhibit major hepatic CYPs, this metabolite may have a lower propensity to precipitate pharmacokinetic drug interactions than sorafenib. PMID- 23732300 TI - Protective role of functionalized single walled carbon nanotubes enhance ex vivo expansion of hematopoietic stem and progenitor cells in human umbilical cord blood. AB - In this study, carboxylic acid functionalized single walled carbon nanotubes (f SWCNT-COOH) was shown to support the viability and ex vivo expansion of freeze thawed, non-enriched hematopoietic stem and progenitor cells (HSPC) in human umbilical cord blood-mononucleated cells (UCB-MNC). Our in vitro experiments showed that f-SWCNT-COOH increased the viability of the CD45(+) cells even without cytokine stimulation. It also reduced mitochondrial superoxides and caspase activity in CD45(+) cells. f-SWCNT-COOH drastically reduced the proportions of CD45(-) cells in the non-enriched UCB-MNC. Phenotypic expression analysis and functional colony forming units (CFU) showed significant ex vivo expansion of HSPC, particularly of CD45(+)CD34(+)CD38(-) population and granulocyte-macrophage (GM) colonies, in f-SWCNT-COOH augmented cultures supplemented with basal cytokines. In vivo data suggested that f-SWCNT-COOH expanded UCB-MNC could repopulate immunodeficient mice models with minimal acute or sub-acute symptoms of graft-versus-host disease (GVHD) and f-SWCNT-COOH dependent toxicity. FROM THE CLINICAL EDITOR: In this paper a novel method is presented by using single wall functionalized carbon nanotubes to enhance viability and ex vivo expansion of freeze-thawed, non-enriched hematopoietic stem and progenitor cells in human umbilical cord blood -mononucleated cells. Detailed data is presented about enhanced viability, including improved repopulation of immunodeficient mice models with minimal acute or sub-acute symptoms of graft versus-host disease. PMID- 23732301 TI - In silico bioremediation of polycyclic aromatic hydrocarbon: a frontier in environmental chemistry. AB - In recent years, the number of studies in the field of bioremediation has been growing steadily. Although a large number of studies provide information that is highly detailed and offer great amounts of knowledge on a given subject, the downside is that the hunt for more information requires the combined efforts of researchers from many areas, which are becoming increasingly difficult to attain. In this review, we present an overview of recent work investigating enzyme degradation of polycyclic aromatic hydrocarbons. In the first part, this review examines several of the new enzymes able to degrade pollutants, with special attention being given to those with a well-resolved structure. The second part explores some of the most recent work in which computational approaches, such as molecular dynamics, docking, density functional theory and database retrieval, have been employed to study enzymes with specific bioremediation activities. PMID- 23732302 TI - Theoretical study on the proton shuttle mechanism of saccharopine dehydrogenase. AB - Saccharopine dehydrogenase (SDH) is the last enzyme in the AAA pathway of l lysine biosynthesis. On the basis of crystal structures of SDH, the whole catalytic cycle of SDH has been studied by using density functional theory (DFT) method. Calculation results indicate that hydride transfer is the rate-limiting step with an energy barrier of 25.02kcal/mol, and the overall catalytic reaction is calculated to be endothermic by 9.63kcal/mol. Residue Lys77 is proved to be functional only in the process of saccharopine deprotonation until the formation of product l-lysine, and residue His96 is confirmed to take part in multiple proton transfer processes and can be described as a proton transfer station. From the point of view of energy, the SDH catalytic reaction for the synthesis of l lysine is unfavorable compared with its reverse reaction for the synthesis of saccharopine. These results are essentially consistent with the experimental observations from pH dependence of kinetic parameters and isotope effects. PMID- 23732303 TI - TDDFT studies on electronic structures, chiroptical properties and solvent effect on the CD spectra of diphosphonate-functionalized polyoxomolybdates. AB - The ultraviolet-visible and electronic circular dichroism (UV-vis/ECD) spectra of diphosphonate-functionalized asymmetric cantilever-type chiral polyoxomolybdate (POM) enantiomer R-{Mo2O5[(Mo2O6)NH3CH2CH2CH2C(O)(PO3)2]2}(6-) (R) were systematically investigated using time-dependent density functional theory (TDDFT) method. From the view of molecular structure and relative energy, we inferred that there is likely a structural conversion from enantiomers R to S {Mo2O5[(Mo2O6)NH3CH2CH2CH2C(O)(PO3)2]2}(6-) (S) via the intermediate configuration (IN). The ECD spectra of the enantiomer R were produced over the range of 3.0-6.3eV. The UV-vis and ECD spectra of enantiomer R in the gas phase and different solvents were calculated. The results reveal that the UV-vis and ECD spectra of the chiral POM in gas phase, polar solvent, or non-polar solvent are different. The calculated electron density difference maps (EDDMs) display that the POM cluster is a chiroptical chromophore in studied compound. PMID- 23732304 TI - Molecular dynamics simulation of single-walled silicon carbide nanotubes immersed in water. AB - The structure and dynamics of water confined in single-walled silicon carbon nanotubes (SWSiCNTs) are investigated using molecular dynamics (MD) simulations. The density of water inside SWSiCNTs is reported, and an equation is suggested to predict the density of water inside SWSiCNTs. Interestingly, the water diffusion coefficients (D) here are larger compared with those in SWCNTs and single-walled boron-nitride nanotubes (SWBNNTs). Furthermore, water inside zigzag SWCNTs has a lower diffusion coefficient than water inside armchair SWCNTs. A thorough analysis of the density profiles, hydrogen bonding, and water molecule orientation inside SWSiCNTs is presented to explore the mechanism behind the diffusive behavior of water observed here. It is shown here, by mean square displacement (MSD) analysis, that water molecules inside SWSiCNTs diffuse with a ballistic motion mechanism for up to 500ps. Additionally it is confirmed here for the first time that water molecules confined in the SWSiCNTs with diameters of less than 10A obey the single-file diffusion mechanism at time scales in excess of 500ps. The orientation of water molecules inside SWSiCNTs could be a good explanation for the difference between the diffusion coefficient in (6,6) and (10,0) SWSiCNTs. Finally, a PMF analysis explains the difficulty of water entrance into SWSiCNTs and also the different water self-diffusion inside armchair and zigzag SWSiCNTs. These results are motivating reasons to use SWSiCNTs in nanoscale biochannels, for instance, in drug-delivery applications. PMID- 23732305 TI - Quantum polarized ligand docking investigation to understand the significance of protonation states in histone deacetylase inhibitors. AB - The effects of different protonation states of the hydroxamic acid (HA) inhibitors against the class I histone deacetylase enzymes (HDACs) have been studied using the state of the art quantum polarized ligand docking (QPLD) and molecular mechanics-generalized Born surface area (MM-GBSA) approaches. The binding modes of the inhibitors and their inter-molecular interactions with class I HDACs, in response to the protonation states of the inhibitors, are explored. Our results indicate that the different protonation states of the inhibitors exhibit significant differences in their interactions with the catalytic zinc metal ion and the other active site residues in the HDAC enzymes, which in turn affect the 'Histidine-Aspartate' charge relay mechanism. The QPLD calculations show that the protonated states of the inhibitors display higher scores in all the class I HDACs in this study, while the deprotonated forms present lower scores. The molecular electrostatic potentials and the other physico-chemical descriptors support the results. The MM-GBSA approach employed in the present work has been able to accurately calculate the relative binding free energies of the neutral and the protonated HA inhibitors; those were close to the experimental values. However, the MM-GBSA approach breaks down while calculating the binding free energies of the deprotonated inhibitors, which resulted in unrealistic values. Large energetic differences were found in the polar electrostatic solvation energy terms and the coulombic contributions in the deprotonated inhibitors. Thus improvements in the present solvation models and force fields become inevitable for the inclusions of charged states of inhibitors in computational drug discovery. PMID- 23732306 TI - Conserved water mediated H-bonding dynamics of Ser117 and Thr119 residues in human transthyretin-thyroxin complexation: inhibitor modeling study through docking and molecular dynamics simulation. AB - Transthyretin (TTR) is a protein whose aggregation and deposition causes amyloid diseases in human beings. Amyloid fibril formation is prevented by binding of thyroxin (T4) or its analogs to TTR. The MD simulation study of several solvated X-ray structures of apo and holo TTR has indicated the role of a conserved water molecule and its interaction with T4 binding residues Ser117 and Thr119. Geometrical and electronic consequences of those interactions have been exploited to design a series of thyroxin analogs (Mod1-4) by modifying 5' or 3' or both the iodine atoms of thyroxin. Binding energy of the designed ligands has been calculated by docking the molecules in tetrameric structure of the protein. Theoretically investigated pharmacological parameters along with the binding energy data indicate the potentiality of 3',5'-diacetyl-3,5-dichloro-l-thyronine (Mod4) to act as a better inhibitor for TTR-related amyloid diseases. PMID- 23732307 TI - Laninamivir octanoate for post-exposure prophylaxis of influenza in household contacts: a randomized double blind placebo controlled trial. AB - Laninamivir octanoate, a long-acting neuraminidase inhibitor, is an effective treatment for influenza. However, its effectiveness for the prevention of influenza has not yet been demonstrated. We conducted a double-blind, multicenter, randomized, placebo-controlled trial to determine whether laninamivir octanoate was superior to a placebo for post-exposure prophylaxis of influenza in household contacts. Eligible participants, who were household members who did not have influenza and were in contact with an influenza-infected index patient, were randomly assigned (1:1:1) to one of three groups: 20 mg of laninamivir octanoate once daily for 2 days (LO-2), 20 mg of laninamivir octanoate once daily for 3 days (LO-3), or a placebo. The primary endpoint was the proportion of participants who developed clinical influenza during a 10-day period. A total of 1711 participants were enrolled, and 1451 participants were included in the primary analysis. The proportion of participants with clinical influenza was 3.9 % (19/487) in the LO-2 group, 3.7 % (18/486) in the LO-3 group, and 16.9 % (81/478) in the placebo group (P < 0.001 for each of the laninamivir octanoate group). The relative risk reductions, compared with the placebo group, were 77.0 % [95 % confidence interval (CI) 62.7-85.8] and 78.1 % (95 % CI 64.1 86.7 %) for the LO-2 and LO-3 groups, respectively. The incidences of adverse events in the laninamivir octanoate groups were similar to that in the placebo group. The inhalation of 20 mg of laninamivir octanoate once daily for 2 or 3 days was well tolerated and effectively prevented the development of influenza in household contacts. PMID- 23732308 TI - Distribution and drug susceptibilities of Candida species causing candidemia from a medical center in central Taiwan. AB - Invasive fungal infections have increased significantly in the past few decades because of the increase in high-risk populations. To investigate the distribution and drug susceptibilities of such infections, we analyzed all 152 Candida isolates causing candidemia from 2004 to 2006 at the China Medical University Hospital, a medical center in central Taiwan. Candida albicans was the most common species, accounting for 52.6% of the isolates, followed by C. tropicalis (19.7%), C. parapsilosis (14.5%), C. glabrata (8.6%), C. guilliermondii (3.9%), and C. pelliculosa (0.7%). All isolates were susceptible to amphotericin B, anidulafungin, micafungin, and voriconazole according to minimum inhibitory concentrations (MICs) after a 24-h incubation; 0.7%, 6.6%, and 7.9% of isolates were resistant to amphotericin B, fluconazole, and voriconazole, respectively, after 48-h incubation. Both C. albicans and C. parapsilosis had high degrees of agreement for azoles between 24- and 48-h incubation periods, whereas C. glabrata (38.5-46.2%) and C. tropicalis (56.7-63.3%) did not. The majority of the isolates with high azole MICs displayed a trailing growth phenotype. Hence, the MICs of different drugs after 24-h incubation may be considered for prognosis of candidemia. PMID- 23732309 TI - Nationwide survey of treatment for pediatric patients with invasive fungal infections in Japan. AB - In Japan, only a few antifungal agents have been approved for children, but in actual clinical practice, various antifungal agents used in adults are administered to pediatric patients with invasive fungal infections (IFIs). However, the pediatric dosages of some antifungal agents are not indicated in the package inserts or mentioned in the Japanese Mycology Study Group 2007 Guidelines for Management of Deep-seated Mycoses. We conducted a nationwide survey to determine how antifungal agents are being used to treat pediatric patients with IFIs in Japan. We sent a questionnaire to 792 medical centers that train pediatricians and received 250 (31.6%) responses. In the past 5 years, 65 (26.0%) of 250 facilities reported treating a total of 232 cases of IFIs. The characteristics of pediatric patients with IFIs were almost the same as adult patients except that immunological diseases and neonatal diseases are common as underlying diseases. Antifungal agents used in adults were all used in children. However, the dosages of some antifungal agents deviated from the package insert or guideline recommendations. As for the reasons for selecting a particular antifungal agent, strong antifungal activity (including potency, broad spectrum, and clinical efficacy) was favored over safety. These results can be used to revise guidelines for the management of children with IFIs. PMID- 23732310 TI - Measuring the lateral size of liquid-exfoliated nanosheets with dynamic light scattering. AB - We have developed an in situ method to estimate the lateral size of exfoliated nanosheets dispersed in a liquid. Using standard liquid exfoliation and size selection techniques, we prepared a range of dispersions of graphene, MoS2 and WS2 nanosheets with different mean lateral sizes. The mean nanosheet length was measured using transmission electron microscopy (TEM) to vary from ~40 nm to ~1 MUm. These dispersions were characterized using a standard dynamic light scattering (DLS) instrument. We found a well-defined correlation between the peak of the particle size distribution as outputted by the DLS instrument and the nanosheet length as measured by TEM. This correlation is consistent with the DLS instrument outputting the radius of a sphere with volume equal to the mean nanosheet volume. This correlation allows the mean nanosheet length to be extracted from DLS data. PMID- 23732311 TI - Mixed-ligand copper(II)-sulfonamide complexes: effect of the sulfonamide derivative on DNA binding, DNA cleavage, genotoxicity and anticancer activity. AB - Four ternary complexes, [Cu(L1)2(bipy)] (1) [HL1 = N-(6-chlorobenzo[d]thiazol-2 yl)-4-methylbenzenesulfonamide], [Cu(L2)2(bipy)] (2) [HL2 = N-(benzo[d]thiazol-2 yl)-4-methylbenzenesulfonamide], [Cu(L3)2(bipy)].1/2H2O (3) [HL3 = N-(5,6 dimethylbenzo[d]thiazol-2-yl)-4-methylbenzenesulfonamide] and [Cu(L4)2(bipy)] (4) [HL4 = N-(5,6-dimethylbenzo[d]thiazol-2-yl)benzenesulfonamide], were prepared and then characterized by X-ray crystallography, spectroscopy and magnetic measurements. Whereas the molecular structure of 1 and 2 consists of a discrete monomeric copper(II) species with a distorted square planar geometry, that of 3 and 4 consists of two independent molecules. In 3, both molecules present a different coordination geometry (distorted square planar and distorted square pyramidal) while in 4 they have an identical coordination environment (distorted square planar). The propensity for binding of 1-4 to calf thymus DNA was studied by thermal denaturation, viscosimetry, and fluorescence measurements. Results indicated that the N-sulfonamide derivative plays an important role in governing the type of interaction with DNA. The ability of the complexes to cleave DNA was studied in vitro with ascorbate activation and was tested by monitoring the expression of the yEGFP gene containing the RAD54 reporter. Moreover, their antiproliferative activity was verified in two cellular models: yeast and human tumor cells in culture. Their DNA cleavage efficiency at the cellular level was found to be: 1 < 3 ~ 4 < 2. The higher propensity of 2 for inflicting DNA damage was related with its higher binding affinity to DNA. The biological studies carried out with human tumor cells, colon adenocarcinoma Caco-2 cells and leukemia Jurkat T lymphocytes confirmed that the compounds produce cell death mainly by apoptosis, the complex 2 being the most effective. PMID- 23732312 TI - [The Gretchen question - implementing results of health and nursing research]. PMID- 23732313 TI - [German hospital nurses' attitudes concerning evidence-based nursing practice]. AB - The relevance of nurses' attitudes for establishing an evidence-based nursing practice (EBP) has been proven internationally. For German-speaking countries so far only few data are available. The present survey aims at assessing nurses' perceptions of relevant context factors for implementing an EBP. Therefore, 1384 nurses in 21 hospitals in Northern-Germany received a self-developed questionnaire based on established instruments in March and April 2012. 1023 (74 %) nurses responded. In principal, results show a positive attitude towards EBP. The majority of participants regards research as relevant for nursing practice. Support from superiors and colleagues is seen as important prerequisite. However, implementation remains a challenge. Nurses are not informed about recent research results. Original articles are hardly used. Only a minority is prepared to spend own money on congresses or to start academic nursing training in the near future. For the first time in German-speaking countries, the study provides meaningful data on nurses' attitudes towards EBP. Nurses confirm the value of research for their own practice. However, there is a lack of basic requirements to identify and implement relevant research findings as for example the use of recent scientific evidence. Nursing education in Germany should therefore focus more strongly on building competencies required for EBP, for example through properly designed academic nursing training. PMID- 23732314 TI - [From bedside to evidence - and back to bedside. 5 years evidence-based guidelines in South Tyrol: methods and experiences]. AB - In South Tyrol we developed guidelines with two different methodological approaches: one relates to the autonomous development of a nursing guideline for oral care using GRADE, and the other relates to the adaptation process of the NICE guideline on the prevention of venous thromboembolism. Both methods do have advantages and disadvantages: by autonomously developing guidelines the guideline panel identifies more with the product but time and effort is much higher than adapting and amending existing (high quality) guidelines. On the other hand there are only few high quality nursing guidelines. Additionally, the experiences in South Tyrol show that nursing guidelines seem to be not really suitable for a 1:1 application into practice because nearly half of the nurses have not changed their practice - although they knew the content of the guideline. Therefore, in order to promote the implementation process multimodal strategies on different organisational levels were adopted. Amongst these was the involvement of management through the negotiations of objectives, training and active participation of staff in the development of user-friendly application tools. PMID- 23732315 TI - [Development of an evidence-based self-management programme for patients in the first year after renal transplantation with a focus on prevention of weight gain, physical exercise and drug adherence]. AB - In the first year after kidney transplantation patients are challenged with incorporating new behaviour patterns into their daily lives. Due to the higher risk of cardiovascular disease amongst kidney transplant recipients, behaviours such as preventing undesired weight gain, exercising, avoiding smoking, and managing medications take on crucial importance. The aim of the project was to develop a programme based on prevailing evidence to promote self-management skills in this patient population. To this end a participatory action research approach was chosen. The programme was developed with inter-professional collaboration under the direction of an advanced practice nurse. As theoretical framework for the development of the intervention models of behaviour change and self-management were chosen. The content is based on current literature and includes the viewpoints of both patients and nursing experts. The programme consists of three elements: 1) Educational brochures developed through inter professional collaboration and evaluated in a pilot survey. These brochures provide a framework for appointments with nursing professionals. 2) The appointments are a forum in which the patient can gain access to relevant information and can be supported in putting sustainable health-related behaviours into practice in daily life. 3) A peer programme that uses treatment plans to encourage patients deviating from preferred health-related behaviours to make changes in their behaviour. The programme evaluation started in May of 2012. Results of the pilot study are expected in 2014. PMID- 23732316 TI - Development of clinically meaningful complex interventions - the contribution of qualitative research. AB - The debate about the "right" methods and designs for nursing research is on going. According to international surveys, studies on the effectiveness and safety of nursing interventions are rare. Since nursing practice deals daily with interventions, nurses ostensibly expose hospital patients and nursing home residents frequently to unproven therapeutic and preventive nursing interventions. Nursing interventions are predominately of a complex nature, consisting of several components depending on and interacting with each other and their complex contextual factors. Thus, evaluation studies are often challenging and need especially careful development, ambitious designs and systematic evaluations. The UK Medical Research Council (MRC) has proposed a framework, where qualitative and quantitative research rely on each other in order to develop theory-based complex interventions, prepare and conduct their optimal delivery, explain how the interventions work and which conditions contributed in case they did not work. The present essay outlines the points where qualitative research contributes towards the development and evaluation of complex interventions. First, the UK MRC framework is introduced, and secondly it is illustrated where qualitative research should necessarily be located using examples from a handful of qualitative studies. Future clinically meaningful and implementable nursing interventions should best be developed by research groups with both excellent qualitative and quantitative research skills. PMID- 23732317 TI - [Patient centered care and patient satisfaction]. PMID- 23732318 TI - [Effect of peer to peer interventions on recovery relevant attitudes: evaluation of a project in psychiatric institutions]. PMID- 23732325 TI - Cyclometalated metal-organic frameworks as stable and reusable heterogeneous catalysts for allylic N-alkylation of amines. AB - Metal-organic frameworks (MOFs) functionalized via Ir(I) cyclometalation are shown to be effective as heterogeneous catalysts for the allylic N-alkylation of various amines. The MOF catalysts are one of the first and most effective MOF based heterogeneous organometallic catalysts for the direct formation of C-N bonds. In addition, these MOFs represent a rare, stable and reusable, class of reactive Ir catalysts. PMID- 23732326 TI - The immunological adjuvant activity of gypenosides liposome against Newcastle disease vaccine. AB - The adjuvant activity of gypenosides liposome (GPSL) encapsulated with liposome was investigated in vitro and in vivo. In vitro, different concentrations of GPSL were added into chicken's peripheral blood lymphocytes and splenic lymphocyte. The results showed that GPSL could significantly enhance T and B lymphocytes proliferation singly or synergistically with PHA and LPS and the efficacy were superior to those of gypenosides (GPS) and blank liposome (BL) at most of concentrations. In vivo, three hundred and fifty 14-day-old chickens were assigned to 7 groups randomly and vaccinated with Newcastle disease (ND) vaccine. Simultaneously, the chickens in experimental groups were, respectively, oral administration with the GPSL at three doses, GPS and BL. The results showed that GPSL could significantly enhance lymphocyte proliferation, increase antibody titer, and promote cytokine secretion in vitro and in vivo, moreover, the adjuvant activity of GPSL was better than those of GPS and BL. These indicated that formulations of GPS and liposome can further enhance the immune response against ND vaccine compared with the adjuvant alone. PMID- 23732327 TI - Quaternized N-substituted carboxymethyl chitosan derivatives as antimicrobial agents. AB - Introduction of quaternary ammonium moieties into N-substituted carboxymethyl chitosan (N-substituted CMCh) derivatives enhances their biological activity. Several derivatives of CMCh having a variety of N-aryl substituents bearing either electron-donating or electron withdrawing groups have been synthesized by the reaction between amino group of CMCh with various aromatic aldehydes under acidic conditions, followed by reduction of the produced Schiff base derivatives with sodium cyanoborohydride. Each of the reduced derivatives was further quaternized using N-(3-chloro-2-hydroxy-propyl)trimethylammonium chloride (Quat 188). The resulting quaternized materials were characterized by FTIR and (1)H NMR spectroscopy. Their antibacterial activities against Streptococcus pneumoniae (S. pneumonia, RCMB 010010), Bacillis subtilis (B. subtilis, RCMB 010067), as Gram positive bacteria and against Escherichia coli (E. coli, RCMB 010052) as Gram negative bacteria and their antifungal activities against Aspergillus fumigatus (A. fumigates, RCMB 02568), Geotricum candidum (G. candidum, RCMB 05097), and Candida albicans (C. albicans, RCMB 05031) were examined using agar disk diffusion method. The results indicated that all the quaternized derivatives showed better antimicrobial activities than that of CMCh. These derivatives are highly potent against Gram positive bacteria compared to Gram negative bacteria. This is illustrated for example as the values of minimum inhibitory concentration (MIC) of Q4NO2-BzCMCh against B. subtilis and S. pneumonia were 6.25 and 12.5 MUg/mL, respectively corresponded to 20.0 MUg/mL against E. coli. The antimicrobial activity of quaternized N-aryl CMCh derivatives affected by not only the nature of the microorganisms but also by the nature, position and number of the substituent groups on the phenyl ring. Thus while the derivatives with groups of electron withdrawing nature show higher inhibition zone diameter and lower MIC values relative to that of those having electron-donating nature, the non-substituted derivative lies between these two extremes. Antibacterial activities of Q4NO2-BzCMCh, Q3Cl-BzCMCh and Q3Br-BzCMCh against E. coli are nearly equivalent to that of the standard drug Gentamycin. Q3Br-BzCMCh emerged almost equivalent antibacterial activity to Ampicillin against S. pneumonia. PMID- 23732328 TI - Screening of seeds prepared from retrograded potato starch to increase retrogradation rate of maize starch. AB - In this paper, retrograded potato starches treated by oxalic, hydrochloric and citric acids and/with amylase respectively, as seed crystals, are added into maize starch paste to increase maize starch retrogradation rate. The results show that addition of seed accelerates maize starch retrogradation greatly. Seed prepared from retrograded potato starch treated by oxalic acid increases maize starch retrogradation rate most, from 1.5% to 49%. The results of IR spectra of retrograded maize starch derived from different seeds show that double helix, not hydrogen bond, probably forms at stage of seed growth during retrogradation. The results of IR spectra, X-ray and SEM indicate that treatment of retrograded potato starch with oxalic acid leads to formation of more hydrogen bonds and an increase of seed crystal planes, which markedly promotes the growth of the seed. Retrogradation of maize starch by seeding method surely includes a stage of crystal growth through double helix in a way different from normal maize starch retrogradation. PMID- 23732329 TI - Effects of microcrystalline cellulose based comilled powder on the compression and dissolution of ibuprofen. AB - Ibuprofen is a poorly soluble and poorly compressible drug and is unsuitable for "direct tableting". Microcrystalline cellulose (Avicel((r)) PH 101) based ibuprofen powder formulations have been comilled in presence of Aerosil((r)) (colloidal silicon dioxide) as lubricant, and the total compression behavior was evaluated using the Cooper-Eaton equation. Scanning electron microscopy (SEM) revealed about the damage of crystal geometry of the crystalline drug after comilling. Differential scanning calorimetry (DSC) indicated decrease of melting endotherm (partially) attributing to the decrease in crystalline intensity of ibuprofen upon comilling. Small changes in the infrared spectra such as shift of characteristic bands, reduction in intensity, and appearance of new bands are mainly related to the possible physical interaction and/or amorphization of the drug in the comilled mixtures. Increased compaction can be achieved after milling of the microcrystalline cellulose based blends. Milling decreased particle size and improved wettability of the drug and increased dissolution. Microcrystalline cellulose based comilled ibuprofen powder with improved compression and dissolution may be taken as a future scope of scale up for "direct tableting". PMID- 23732330 TI - Structural investigation of idarubicin-DNA interaction: spectroscopic and molecular docking study. AB - Mechanistic understanding of interaction of drugs with their target molecule is important for development of new drug therapy regimes. Idarubicin (IDR) is a potent chemotherapeutic agent used to treat variety of cancers. Structural and conformational studies associated with binding of IDR on DNA double helix were investigated through spectroscopic techniques and molecular docking studies. Interaction studies were done by preparing different molar ratios of IDR with constant DNA concentration under physiological conditions. FTIR spectroscopy, UV vis spectroscopy, CD spectroscopy were used to analyze interaction between IDR and DNA. FTIR results suggest IDR binds at major groove of DNA duplex via guanine and cytosine bases. UV-vis spectroscopy result indicates IDR gets intercalated between the DNA bases. The calculated binding constant shows that IDR is a moderate binder. Slight perturbation in the native B-conformation of DNA was observed in all IDR-DNA molar ratios examined. In silico investigation of IDR binding with DNA is in agreement with our experimental results, providing structural insight into DNA binding properties of IDR. PMID- 23732331 TI - Antioxidant and antimicrobial activities of Lycium shawii fruits extract. AB - Crude extracts from the fruit of Lycium shawii, a plant collected from the south of Tunisia, were screened for their in vitro antioxidant, antimicrobial and antifungal activities. The dried fruits were extracted with EtOH and an aqueous suspension of the obtained EtOH extract was partitioned successively with CHCl3, CH2Cl2, EtOAc and n-BuOH, leaving residual water extract. Total phenolic content of extracts from these fruits were also determined. beta-Carotene bleaching assay and Folin-Ciocalteu reagent were used to determine total antioxidant activity and total phenols of fruit extracts. Total phenolic and flavonoid contents varied from 100 to 377 mg GAE/g DW and 3.3-110.6 mg quercetin/gDW, respectively. Several extracts showed high antioxidant capacity and an antimicrobial activity against different strains. This is, to our knowledge, the first report on the detail chemical composition, antioxidant and antimicrobial activities of L. shawii extracts. The results provided evidence that the studied fruit might indeed be potential sources of natural antioxidant and antimicrobial agents. PMID- 23732332 TI - Synthesis and antifungal evaluation of (1,2,3-triazol-4-yl)methyl nicotinate chitosan. AB - With an aim to discover novel chitosan derivatives with significant activities against crop-threatening fungi, (1,2,3-triazol-4-yl)methyl nicotinate chitosan (TAMNCS) was prepared via azide-alkyne click reaction. Its structure was characterized by FT-IR, (1)H NMR, elemental analysis, DSC, and SEM. In vitro antifungal properties of TAMNCS against Rhizoctonia solani Kuhn (R. solani), Stemphylium solani weber (S. solani), and Alternaria porri (A. porri) were studied at the concentrations ranged from 0.25 mg/mL to 1.0 mg/mL. Experiments conducted displayed the derivative had obviously enhanced antifungal activity after chemical modification compared with original chitosan. Moreover, it was shown that TAMNCS can 94.2% inhibit growth of A. porri at 1.0 mg/mL, while dose at which the fungicide triadimefon had lower inhibitory index (62.2%). The primary antifungal results described here indicate this derivative may be a promising candidate as an antifungal agent. PMID- 23732333 TI - Microbial production of levanase for specific hydrolysis of levan. AB - A newly isolated bacterial strain from Tunisian thermal source was selected for its ability to produce extracellular levanase when grown on levan substrate. The optimization of carbon source, nitrogen source, temperature and initial pH of the growth medium in submerged liquid cultures were investigated. In fact, levan was found to be a good inducer of levanase enzymes. The optimal temperature and pH of the levanase activity were 40 degrees C and 6.4, respectively. This enzyme exhibited a remarkable stability and retained 75% of its original activity at 55 degrees C for more than 1 h at pH 6.4. Crude enzyme of the strain rich in levanase was established for the hydrolysis of levan in order to produce fructooligosaccharides with variable degrees of polymerization which could be used in important fields such medicine, food-processing industry and cosmetic. The extracellular levanase of the strain was then, partially purified as determined by SDS-PAGE. The purification was achieved by ammonium sulfate precipitation, gel filtration and DEAE cellulose chromatographies. PMID- 23732334 TI - Ageing: an ageing balancing act. PMID- 23732336 TI - Genomics: Sprucing up forest tree genomics. PMID- 23732335 TI - Argonaute proteins: functional insights and emerging roles. AB - Small-RNA-guided gene regulation has emerged as one of the fundamental principles in cell function, and the major protein players in this process are members of the Argonaute protein family. Argonaute proteins are highly specialized binding modules that accommodate the small RNA component - such as microRNAs (miRNAs), short interfering RNAs (siRNAs) or PIWI-associated RNAs (piRNAs) - and coordinate downstream gene-silencing events by interacting with other protein factors. Recent work has made progress in our understanding of classical Argonaute mediated gene-silencing principles, such as the effects on mRNA translation and decay, but has also implicated Argonaute proteins in several other cellular processes, such as transcriptional regulation and splicing. PMID- 23732337 TI - HIF-1alpha knockdown by miRNA decreases survivin expression and inhibits A549 cell growth in vitro and in vivo. AB - The present study examined the downregulation of survivin expression by hypoxia inducible factor-1alpha (HIF-1alpha) miRNA and its effect in the inhibition of A549 cell growth in vitro and in vivo. Survivin expression, apoptosis, proliferation and migration under normoxic and hypoxic conditions were assessed by standard methods. Cotransfection and chromatin immunoprecipitation were used to observe the effects of HIF-1alpha on survivin transcription. HIF-1alpha knockdown in A549 cells were injected into nude mice to examine survivin expression and suppression of tumorigenicity. Transfection of A549 cells with HIF 1alpha miRNA led to decreased expression of HIF-1alpha and survivin mRNA and protein. Survivin overexpression is mediated by HIF-1alpha by direct binding to a putative binding site in the survivin core promoter. HIF-1alpha-miRNA induced apoptosis and inhibited proliferation of A549 cells under hypoxic, but not normoxic, conditions, whereas transfection by survivin expression vectors partly rescued the apoptotic phenotype and revived cell proliferation under hypoxic conditions. However, cell migration was substantially suppressed by HIF-1alpha silencing under normoxic and hypoxic conditions. After A549 cells were xenografted in nude mice, survivin expression in mice treated with HIF-1alpha miRNA was downregulated, and tumor growth was significantly inhibited. Silenced HIF-1alpha gene expression induced apoptosis and suppressed growth of A549 cells by downregulating survivin expression in vitro and in vivo. Our results also provide a basis to target the HIF-1alpha pathway in lung cancer therapy. PMID- 23732338 TI - Personality traits modulate neural responses to emotions expressed in music. AB - Music communicates and evokes emotions. The number of studies on the neural correlates of musical emotion processing is increasing but few have investigated the factors that modulate these neural activations. Previous research has shown that personality traits account for individual variability of neural responses. In this study, we used functional magnetic resonance imaging (fMRI) to investigate how the dimensions Extraversion and Neuroticism are related to differences in brain reactivity to musical stimuli expressing the emotions happiness, sadness and fear. 12 participants (7 female, M=20.33 years) completed the NEO-Five Factor Inventory (NEO-FFI) and were scanned while performing a passive listening task. Neurofunctional analyses revealed significant positive correlations between Neuroticism scores and activations in bilateral basal ganglia, insula and orbitofrontal cortex in response to music expressing happiness. Extraversion scores were marginally negatively correlated with activations in the right amygdala in response to music expressing fear. Our findings show that subjects' personality may have a predictive power in the neural correlates of musical emotion processing and should be considered in the context of experimental group homogeneity. PMID- 23732340 TI - "Can waiting awaken the resting brain?" A comparison of waiting- and cognitive task-induced attenuation of very low frequency neural oscillations. AB - The default mode network (DMN) is characterised by coherent very low frequency (VLF) neural oscillations in the resting brain. The attenuation of this activity has been demonstrated following the transition from rest to performance of a broad range of cognitive goal-directed tasks. Whether the activity of resting state VLF oscillations is attenuated during non-cognitive goal-directed tasks such as waiting for rewarding outcomes is not known. This study examined the VLF EEG power from resting to performance of attention demanding task and two types of goal-directed waiting tasks. The association between the attenuation of VLF EEG power and Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms was examined. Direct current EEG (DC-EEG) data were collected from 32 healthy young adults (half high and half low ADHD symptom scorers) during (i) a rest state, (ii) while performing a cognitive demanding reaction time task (2CRT), and (iii) while undertaking each of two different goal-directed waiting conditions: "forced to-wait (FW)" and "choose-to-wait (CW)" tasks. The spatial distribution of VLF EEG power across scalp was similar to that seen in previous resting VLF EEG studies. Significant rest-to-task attenuation of VLF EEG power occurred during the 2CRT and the CW task, but not during the FW task. The association between self-ratings of ADHD symptoms and waiting-induced attenuation was not significant. This study suggests VLF EEG power attenuation that occurs following rest-to-task transition is not simply determined by changes in cognitive load. The goal-directed nature of a task, its motivated nature and/or the involvement of effortful attention may also contribute. Future studies should explore the attenuation of resting state VLF oscillations during waiting and impulsive choice. PMID- 23732341 TI - Smoke-free legislation and prematurity. PMID- 23732339 TI - Regional mRNA expression of GABAergic receptor subunits in brains of C57BL/6J and 129P3/J mice: strain and heroin effects. AB - C57BL/6J and 129 substrains of mice are known to differ in their basal levels of anxiety and behavioral response to drugs of abuse. We have previously shown strain differences in heroin-induced conditioned place preference (CPP) between C57BL/6J (C57) and 129P3/J (129) mice, and in the regional expression of several receptor and peptide mRNAs. In this study, we examined the contribution of the GABAergic system in the cortex, nucleus accumbens (NAc), caudate putamen (CPu) and the region containing the substantia nigra and ventral tegmental area (SN/VTA) to heroin reward by measuring mRNA levels of 7 of the most commonly expressed GABA-A receptor subunits, and both GABA-B receptor subunits, in these same mice following saline (control) or heroin administration in a CPP design. Using real-time PCR, we studied the effects of strain and heroin administration on GABA-A alpha1, alpha2, alpha3, beta2, and gamma2 subunits, which typically constitute synaptic GABA-A receptors, GABA-A alpha4 and delta subunits, which typically constitute extrasynaptic GABA-A receptors, and GABA-B R1 and R2 subunits. In saline-treated animals, we found an experiment-wise significant strain difference in GABA-Aalpha2 mRNA expression in the SN/VTA. Point-wise significant strain differences were also observed in GABA-Aalpha2, GABA-Aalpha3, and GABA-Aalpha4 mRNA expression in the NAc, as well as GABA-BR2 mRNA expression in the NAc and CPu, and GABA-BR1 mRNA expression in the cortex. For all differences, 129 mice had higher mRNA expression compared to C57 animals, with the exception of GABA-BR1 mRNA in the cortex where we observed lower levels in 129 mice. Therefore, it may be possible that known behavioral differences between these two strains are, in part, due to differences in their GABAergic systems. While we did not find heroin dose-related changes in mRNA expression levels in C57 mice, we did observe dose-related differences in 129 mice. These results may relate to our earlier behavioral finding that 129 mice are hyporesponsive to the rewarding effects of heroin. PMID- 23732342 TI - Wheezing in infants: can we separate the wheat from the chaff? PMID- 23732343 TI - Association between the Asthma Predictive Index and levels of exhaled nitric oxide in infants and toddlers with recurrent wheezing. AB - It is difficult to make an early identification of which children with recurrent wheezing will develop asthma in the following years. The Asthma Predictive Index (API) is a questionnaire based on clinical and laboratory parameters used for this end. The measurement of fractional exhaled nitric oxide (FE NO) has been used as a marker of eosinophilic airway infammation in asthma patients. Objective. To determine the association between the Asthma Predictive Index and FE NO levels in children younger than 3 years old with recurrent wheezing. Materials and methods. Observational, cross sectional study. Children younger than 36 months old with 3 or more episodes of bronchial obstruction in the past year who were inhaled corticosteroid-naive or leukotriene receptor antagonist naive were included. After recording clinical data, FE NO was measured by a chemiluminescence analyzer during tidal breathing (online method). Results. A total of 52 children aged 5-36 months old were included. Patients with a positive API accounted for 60% of the population and had higher levels of FE NO than those with a negative API, with a median (range) of 13.5 ppb (0.7-31) versus 5.6 ppb (0.1-20.8), respectively (p <0.01). A high FE NO (>8 ppb) was observed in 74% of children with a positive API and in 26% of those with a negative API (p <0.01). Conclusions. This study found an association between high levels of exhaled nitric oxide and a positive Asthma Predictive Index in children younger than 3 years old with recurrent wheezing. PMID- 23732344 TI - Pulse oximetry recording in children with adenotonsillar hypertrophy: usefulness in the diagnostic of obstructive sleep apnea syndrome. AB - INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is the most serious consequence of adenotonsillar hypertrophy (ATH). The gold standard diagnostic method is polysomnography (PSG) with nocturnal oximetry, but it requires expensive equipment, the presence of a technician and a specialized doctor, and is very time consuming, making the procedure difficult. The recording of pulse oximetry monitoring during sleep may serve as a diagnostic approach. In pediatrics, few studies have been published, and their results have been controversial. OBJECTIVE: To establish the diagnostic value of the visual analysis of the recorded nocturnal oximetry monitoring vs. the PSG. POPULATION: Children with clinical suspicion of OSAS secondary to ATH referred to PSG. Children with other associated diagnoses (myopathy, craniofacial malformations, etc.) were excluded. METHODS: 1) A visual analysis (using our own algorithm) of the oximetry recorded simultaneously with the PSG was performed; 2) the diagnostic value of the pulse oximetry vs. the PSG was established. Both tests were conducted in a blinded and random fashion by two doctors. RESULTS: A total of 167 PSGs were included; the PSG showed OSAS in 75 children and simple snoring in 92; 65 oximetries were considered pathological and in agreement with the PSG in relation to OSAS; 10 children with mild OSAS in the PSGs had normal oximetries. The recorded pulse oximetry showed a sensitivity of 86.6% and a specificity of 98.9% for detecting OSAS. CONCLUSIONS: The visual analysis of recorded pulse oximetry monitoring during sleep is highly useful for the diagnosis and management of these patients. PMID- 23732345 TI - Invasive infections caused by Streptococcus pneumoniae in a tertiary-level children's hospital before the introduction of the conjugate vaccine: clinical characteristics and serotypes involved. AB - Invasive pneumococcal diseases are the main cause of morbidity and mortality in children. In the Hospital "Prof. Dr. Juan P. Garrahan", between October 1st , 2008 and September 30th, 2011 all invasive pneumococcal diseases with positive blood cultures were retrospectively studied before the implementation of the universal immunization schedule with the 13-valent pneumococcal conjugate vaccine. A total of 124 patients were identified, and their mean age was 48.3 months (range: 1-216). In this population, 58.9% (n: 73) were OVER 2 years old and 89% (n: 65) of them had an underlying disease. The most frequent clinical presentation was pneumonia. The most frequent S. pneumoniae serotypes identified were: 14 (22.5%, n: 25), 6 (14.4%, n: 16), 19 (8.1%, n: 9), 23 (7.2%, n: 8), 1 (6.3%, n: 7), 5 (4.5%, n: 5), and 7 (7.2%, n: 8). Of the S. pneumoniae serotypes in this series, 82.2% is included in the 13-valent pneumococcal conjugate vaccine. Continuous epidemiological surveillance is essential to further identify the epidemiology and study the evolution of invasive pneumococcal disease in Argentina. PMID- 23732346 TI - Relationship between P wave dispersion, left ventricular mass index and blood pressure. AB - INTRODUCTION: The study of arterial hypertension risk factors in children guarantees the establishment of health policies to avoid complications associated with this illness in the future. The highest values of P-wave dispersion during sinus rhythm are pointed as predictors of atrial fibrillation in adulthood since there is an association between arterial hypertension, P-wave dispersion and left ventricular hypertrophy. The aim of this study was to determine the relationship between blood pressure, left ventricular mass index and P-wave dispersion in the pediatric population. POPULATION AND METHODS: In the frame of the PROCDEC II project, children from 8 to 11 years old, without known heart conditions were studied. Arterial blood pressure was measured in all the children; a 12-lead surface ECG and an echocardiogram were done as well. RESULTS: Left ventricular mass index mean values for normotensive (25.21 +/- 5.96 g/m2) and hypertensive (30.38 +/- 7.39 g/m2) children showed significant differences (p= 0.000). The mean value of the left atrial area was significantly different (p= 0.000) when comparing prehypertensive (10.98 +/- 2.23 cm2) and hypertensive (12.21 +/- 1.27 cm2) children to normotensive ones (10.66 +/- 2.38 cm2). The correlation of P wave dispersion and the left ventricular mass index showed an r= 0.87 and p= 0.000. CONCLUSIONS: P-wave dispersion is increased in pre- and hypertensive children compared to normotensive ones. A dependence of the P-wave dispersion of the left ventricular mass index was found in hypertensive children. PMID- 23732347 TI - Migrant population and perinatal health. AB - INTRODUCTION: The number of foreign migrants tends to grow. The situation of people living away from their own country is complex and has an impact on the public health system. The objective of this article was to analyze the perinatal risk of migrant mothers and their newborn infants in comparison to native Argentine mothers and their newborn infants. METHODS: Cohort study that included 2000 mothers and their newborn infants (1000 migrants and 1000 natives) assisted at a public maternity hospital. RESULTS: Native mothers had a higher rate of low birth weight newborn infants (9.9% versus 5.3%; p <0.01), primiparity (42% versus 37%; p= 0.012), and adolescent pregnancy (6% versus 1.3%; p <0.001). Migrant women had a higher rate of poorly controlled pregnancies (21.7% versus 13.4%; p <0.01), positive serology for Chagas disease (3.2% versus 0.4%; p <0.01), and newborn infants requiring phototherapy (20.5% versus 14.3%; p =0.04). CONCLUSION: In our study, Argentine mothers had a higher rate of low birth weight newborn infants, primiparity and adolescent pregnancies, while immigrant women had higher rate of positive serology for Chagas disease, poor antenatal controls and more newborn infants requiring phototherapy. PMID- 23732348 TI - Epidemiological and clinical characteristics of acute gastroenteritis according to their etiology (rotavirus or other) in children younger than 5 years old at a private institution in the city of Buenos Aires. AB - INTRODUCTION: Acute gastroenteritis is a common disease in children. Rotavirus is the major etiologic agent. OBJECTIVES: To describe the epidemiological and clinical characteristics of acute gastroenteritis according to their etiology (rotavirus or other) in children younger than 5 years old in a private institution in the City of Buenos Aires. SECONDARY OBJECTIVE: to analyze related costs. MATERIAL AND METHODS: Cross sectional, descriptive, observational study conducted during one year in children younger than 5 years old with gastroenteritis. The presence of rotavirus was diagnosed with the VIKIA(r) Rota Adeno test. Demographic, clinical and immunization data were collected. A univariate data analysis was performed. RESULTS: A total of 275 patients were included; 18.5% of them were R+. Rotavirus was more common in children younger than 2 years old and in the period between March and June. The cases of rotavirus gastroenteritis were more severe, required more hospitalizations (OR 2.07; 95% CI 1.17-7.13), and resulted in higher costs. In the sample studied, the immunization outcome measure reduced the risk of rotavirus infection. CONCLUSIONS: Acute gastroenteritis caused by rotavirus were different from other etiologies in that they had a seasonal peak and in relation to the median age of patients, the severity of the condition, the association with hospitalization and the increase in costs. PMID- 23732349 TI - [Pediatrics and the social construction of childhood: review and outlooks]. PMID- 23732350 TI - Detection of illicit drugs in urine in the Division of Neonatology, Hospital Molas in La Pampa. AB - There are few studies on the use of illicit drugs during pregnancy with a variable prevalence depending on the year, maternal age, region and diagnostic methods. Mothers' and newborn infants' urine samples were tested for illegal drugs in cases where the mother reported consumption, lack of antenatal care and neonatal signs and symptoms, from 2009 to 2011. A rapid strip test for simultaneous qualitative detection of multiple drugs and metabolites in urine was used. In 19 out of 39 (49%) cases in which urine samples were collected, an illicit drug was detected in the mother and/or the newborn infant. Cocaine was the most frequently detected drug. There was a high coexistence of social and familiar risk factors, smoking (84%) and alcohol consumption (47%). PMID- 23732351 TI - Autoinflammatory diseases in pediatrics. AB - Monogenic autoinflammatory syndromes are caused by mutations in protein-coding genes that have a pivotal role in the regulation of the inflammatory response. Due to their genetic nature, most of these syndromes usually begin during childhood. They are clinically characterized by recurrent episodes of systemic inflammation (fever with different clinical manifestations, such as skin rash, serositis or arthritis) associated with elevation of acute phase reactants. During symptom-free intervals, patients achieve clinical well-being and normalize infammatory parameters. Amyloidosis is a serious long-term complication. In this update we will discuss the clinical presentation and therapeutic strategies for these diseases in pediatrics. PMID- 23732352 TI - [What pediatricians should know about car seats?: car safety seats]. AB - In Argentina more than 7,000 people die each year due to traffic injuries. It is an endemic disease, a serious public health problem. There are evidence-based recommendations about how children should ride safety in cars; children through 8 years or 4 feet 9 inches cannot be fastened by the seat belt so they should ride in a child restraint system. These devices significantly reduce the chances of suffering serious injuries and fatalities. Although in our country the use of car safety seats is not yet legislated nor compulsory, pediatricians should recommend parents how and why to use them. PMID- 23732354 TI - [Follow-up of infants with bronchopulmonary dysplasia after NICU discharge: part II: oxygen administration, farmacological treatment and follow-up]. PMID- 23732355 TI - [Atrioventricular canal defect, single atrium and tricuspid atresia as part of a case of Ellis-Van Creveld syndrome]. AB - Ellis-Van Creveld Syndrome or chondrectodermal dysplasia is produced by an autosomal recessive inheritance secondary to mutation in the short arm of chromosome 4. The syndrome affects multiple organs. It is described as a clinical tetrad that involves chondrodysplasia, ectodermal dysplasia, polydactyly and congenital heart defects. It is only known from reports and case series. We present a three months old male, without relevant family history, who presented chondrodysplasia, upper lip merged to palate, bilateral sinpolydactyly in the hands, developmental dysplasia of the hip, narrow chest with short ribs, and heart defects. This case is the first report of EVC in Peruvian literature. PMID- 23732356 TI - [Foreign bodies in esophagus in children: case series]. AB - Ingestion of foreign bodies is an avoidable accident that is seen mainly in children under 3 years-old. Most of them pass through the digestive tract without causing clinical manifestations or complications, but a significant percentage is impacted in the esophagus causing vomiting, sore throat, dysphagia and drooling. The most common foreign bodies are coins. Complications usually occur when there is a delay in diagnosis or with large, sharp or potentially toxic objects, as the button battery. It is essential to make differential diagnosis between coin and button battery, since the latter requires urgent removal due to the earliness of the injury caused. We report 115 cases of foreign bodies in the esophagus, and we alert the pediatrician in recognizing and preventing this problem. PMID- 23732357 TI - [Contact Paederus dermatitis in a 12 years old boy]. AB - Paederus dermatitis is a peculiar contact dermatitis caused by pederine contained in the hemolimph of a small insect of the genus Paederus. It is characterized by vesico-pustulous eruption arising over an erythematous background, of sudden onset, over exposed areas of the body, and the history of outdoor activities. Diagnosis is based on the typical clinical features and the epidemiological context. The aim of this publication is to report a case and evaluate the epidemiological and clinical characteristics of Paederus dermatitis. PMID- 23732358 TI - [Delayed diagnosis of foreign body in the airway in children: case series]. AB - Aspiration of foreign bodies is an important and preventable cause of morbidity and mortality in childhood. The early diagnosis and treatment are essential for risk of mortality in the acute and complications arising from the continuance of a foreign body in the airway. The clinical presentation may mimic different diseases, delaying the correct diagnosis. Pediatricians should be aware of the possibility of foreign body in children with persistent respiratory symptoms, even in the absence of a history of choking. Bronchoscopy is indicated in all patients with suspected aspiration, even when the physical and radiological examination is inconclusive. We evaluate in 90 cases the time between the aspiration of foreign body and the removal, and emphasize the need for preventive measures and greater dissemination of knowledge in the community and health professionals about this problem. PMID- 23732359 TI - [Adolescent with chest pain: the importance of clinical suspicion]. AB - Introduction. Chest pain is a common complaint in children visiting the emergency department and is mostly associated with benign conditions. Although genuine cardiac causes are uncommon, potentially life threatening conditions such as the pulmonary embolism should be suspected by clinical symptoms such as dyspnoea, chest pain and syncope, either singly or in combination. CASE PRESENTATION: The authors report a case of a pulmonary embolism with deep venous thrombosis following immobilization in a 15- year-old adolescent with limb fracture. CONCLUSIONS: This case illustrates the importance of considering pulmonary embolism in the differential diagnosis of a patient who presents at a paediatric emergency department with sudden onset of chest pain and dyspnoea. PMID- 23732360 TI - [Ocular involvement in congenital Chagas disease]. AB - Ophthalmic compromise is infrequent in children with congenital Chagas disease. We present 3 patients under 2 months of age, with ocular involvement, all of them referred to the hospital for ophthalmic evaluation of the premature newborn. The ophthalmic finding was bilateral severe vitreitis (posterior uveitis) related to Chagas disease. They received antiparasitic therapy with a good outcome in all cases. Chagas disease must be considered as differential diagnosis of ocular pathology in those countries where the pathology is endemic, and fundoscopic evaluation must be done in those children with the diagnosis, especially those symptomatic and prematurely born. PMID- 23732361 TI - IL6 trans-signaling promotes functional recovery of hypofunctional phagocytes through STAT3 activation during peritonitis. AB - OBJECTIVE: The role of high interleukin 6 (IL6) levels has not been clearly explained in severe sepsis. We show that the augmentation of the IL6 signal by recombinant IL6 receptors (rIL6R) delivery allows the functional recovery of phagocytes in a peritonitis mouse model. MATERIALS AND METHODS: Mice were challenged intraperitoneally (i.p.) with live Staphylococcus aureus for effect of IL6R delivery on the 24 h-survival, bacterial clearance and cellular responses. In additional experiments to assess the effect of IL6R delivery on phagocytosis, the model was i.p. inoculated with heat-killed S. aureus with or without rIL6R and the peritoneal lavage fluid and cells were collected at 1 h after the i.p. inoculation of S. aureus. RESULTS: The IL6R delivery tended to improve 24 h survival and increase bacteria clearance from the septic mice. The rIL6R treatment to heat-killed bacteria challenged mice augmented the uptake of bacteria and phagosome acidification, inducing the phosphorylation of STAT3 in peritoneal cells within 1 h after the IL6R delivery. Furthermore, the rIL6R delivery prevented the extracellular release of neutrophil elastase activity and myeloperoxidase (harmful factors). CONCLUSIONS: These results indicate that augmentation of IL6 signaling appears to be critical for the effective management of hypofunctional neutrophils during severe inflammation, such as sepsis. PMID- 23732362 TI - Nrf2 inducibility of aldo-keto reductases. PMID- 23732363 TI - Diallyl disulfide impairs hippocampal neurogenesis in the young adult brain. AB - Garlic and garlic extracts are used as seasonings and are generally considered beneficial to human health, which include antioxidant and neuroprotective properties in neurological disorders. In the present study, we examined the effects of garlic sulfur components on the proliferation of neural progenitor cells (NPCs) and hippocampal neurogenesis. Of the sulfur compounds extracted, diallyl disulfide (DADS) significantly suppressed the proliferation of NPCs, whereas other sulfur containing components had no effect. In order to investigate the effect of DADS on adult hippocampal neurogenesis, DADS was administered orally to young (6 week-old) male C57BL/6 mice for 2 weeks. It was found that 10 mg/kg of DADS significantly decreased the proliferation of NPCs in the dentate gyrus without affecting the survival of newly generated cells. Furthermore, DADS decreased levels of hippocampal BDNF, phosphorylated CREB signaling, and phosphorylated ERKs, which are known to be related to hippocampal neurogenesis and NPCs proliferation. In addition, DADS induced significant memory defects as compared with controls. We report that DADS may have adverse effects on hippocampal neurogenesis and neurocognitive functions by modulating ERK and BDNF CREB signaling, and suggest that the advisability of consuming large amounts of garlic products should be considered, particularly during the period of neural growth. PMID- 23732364 TI - Neovascularization prevalence in the supraspinatus of patients with rotator cuff tendinopathy. AB - OBJECTIVE: A high prevalence of neovascularity in lower extremity tendinopathies has been reported. Neovascularity in those with rotator cuff tendinopathy exclusively has not been examined. The objective was to determine the prevalence of neovascularization in patients with rotator cuff tendinopathy compared with asymptomatic controls. DESIGN: Single-blind cross-sectional study. SETTING: Research laboratory. PARTICIPANTS: Participants (n = 40; age = 44.9 years, 23-62 years; 20 females) with rotator cuff tendinopathy (n = 20) but without full thickness rotator cuff tears, and asymptomatic controls that were age, gender, and hand dominance matched (n = 20) to the patients. INTERVENTIONS: The participants laying in supine had their shoulder positioned in internal rotation and extension. Ultrasound images were collected of the supraspinatus tendon and subacromial bursae in the transverse and longitudinal planes using a linear transducer in color Doppler mode. MAIN OUTCOME MEASURES: Images were assessed for neovascularization by 2 trained raters who were blinded to group (rotator cuff tendinopathy or asymptomatic group). RESULTS: No statistically significant difference in neovascularization was identified between participants with and without rotator cuff tendinopathy (chi = 0.13, df = 1, P = 0.72). Neovascularization was identified in 6 of 20 patients with rotator cuff tendinopathy (30%) and 5 of 20 asymptomatic control participants (25%). CONCLUSIONS: The authors found no differences in neovascularization rate in patients with rotator cuff tendinopathy (30%) and asymptomatic controls (25%). The study indicates that neovascularization is not related to presence of symptomatic tendinopathy in those with rotator cuff tendinopathy. Neovascularization may not be a relevant sonographic finding to aid the clinical assessment of those with rotator cuff tendinopathy. PMID- 23732365 TI - Electrocardiographic and echocardiographic manifestations of cardiac involvement in leptospirosis. AB - BACKGROUND: Cardiac involvement is known to occur in leptospirosis, however, data on the significance of electrocardiographic and echocardiographic findings is very limited. METHODS: Electrocardiographic and echocardiographic changes were studied in serologically confirmed patients with leptospirosis. RESULTS: Of 22 patients, 45% (10) had cardiac symptoms; 59% (13) had abnormalities on the ECG; 90% (9/10) of patients with cardiac symptoms had at least one electrocardiographic abnormality. Echocardiographic abnormalities were seen in 41% (9). Clinical and echocardiographic evidence of myocarditis was seen in two patients, but left ventricular function was preserved. CONCLUSIONS: Echocardiographic changes may be useful in identifying patients with myocarditis in leptospirosis, especially in symptomatic patients. PMID- 23732366 TI - Contribution of spoligotyping and MIRU-VNTRs to characterize prevalent Mycobacterium tuberculosis genotypes infecting tuberculosis patients in Morocco. AB - In the present study, Mycobacterium tuberculosis complex (MTBC) clinical isolates from culture-positive TB patients in Morocco were studied by spoligotyping and 12 loci MIRU-VNTR typing methods to characterize prevalent genotypes (n = 219 isolates from 208 patients). Spoligotyping resulted in 39 unique patterns and 167 strains in 30 clusters (2-50 strains per cluster). Comparison with international database showed that 29 of 39 unique patterns matched existing shared spoligotype international types (SITs). Nine shared types containing 10 strains were newly created (SIT 2891 to SIT 2899); this led to the description of 69 SITs with 206 strains and two orphan patterns. The most prevalent spoligotype was SIT42 (LAM; n = 50 or 24% of isolates). The repartition of strains according to major MTBC clades was as follows LAM (46.1%)> Haarlem (26%) >ill-defined T superfamily (22.6%) and S clade (0.96%). On the other hand, Beijing, CAS (Central Asian) and EAI (East-African Indian) strains were absent in this setting. Subsequent 12-Loci MIRU typing resulted in a total of 25 SIT/MIT clusters (n = 66 isolates, 2-6 isolates per cluster), with a resulting recent transmission rate of 22.3%. The MIRU-VNTR patterns corresponded to 69 MITs for 138 strains and 46 orphan patterns. The most frequent patterns were MIT43 (n = 8), MIT9 (n = 7) and MIT42 (n = 7). HGDI analysis of the 12 MIRU loci showed that loci 10, 23 and 40 were highly discriminative in our setting. The results also underlined the usefulness of spoligotyping and MIRU-VNTR to detect mixed infections among certain of our TB patients. Globally, the results obtained showed that TB is almost exclusively transmitted in Morocco through evolutionary-modern MTBC lineages belonging to principal genetic groups 2/3 strains (Haarlem, LAM, T), with a high level of biodiversity seen by MIRU typing. This study provides with a 1st global snapshot of MTBC population structure in Morocco, and validates the potential use of spoligotyping in conjunction with minisatellites for future investigations in Morocco that should in future ideally include optimized 15- or 24-loci MIRU VNTRs. PMID- 23732367 TI - Managing type 1 diabetes - a journey from starvation to insulin pump. AB - With the discovery of insulin in 1921, hopes were high that type 1 diabetes mellitus would soon be cured. However, this goal has remained elusive. Nevertheless, technological advances have improved the management of diabetes and the quality of life of patients with diabetes. One of these advances has been the development of the insulin pump. This article reviews the development of insulin pumps and outlines the advantages and disadvantages of insulin pumps currently available. PMID- 23732368 TI - Clinical update on insulin pump therapy in combination with continuous glucose monitoring. AB - In recent years, the treatment of type 1 diabetes has changed significantly. An important diagnostic and therapeutic support tool is the continuous glucose monitoring (CGM) showing its best performance when used in combination with an insulin pump therapy. Before the availability of CGM the consideration of glucose regulation and therapeutic success was based solely on selectively measured blood glucose levels and HbA1c. In contrast to the blood glucose measurements CGM measures in the interstitial fluid and opens a new dimension of diabetes therapy, we call it "glucose dynamics". The knowledge of the continuous glucose course and its trends has proved to be a highly relevant additional parameter which in practical terms has a particularly stabilizing influence on blood glucose profiles. CGM therefore offers the option of a fine-tuning of metabolic control by experienced heath care professionals and the patient, making blood glucose control in general and unplanned activities and problems in everyday life better controllable. However, despite the tremendous potential of CGM in combination with a pump therapy the basic settings of an effective pump therapy are crucial. Particularly the right basal insulin coverage as the first step is the key issue for success. With support of CGM there is an enormous potential to facilitate the adjustment and optimization of insulin pump therapy. PMID- 23732370 TI - New technologies for treating obesity. AB - Obesity has become a national epidemic and a disease of global magnitude. The numbers of patients with obesity have grown exponentially in the last 10 years to the degree that the Centers for Disease Control and Prevention reports that one third of the US population is obese. The prevalence of diabetes has grown by more than 50% in that same time period. Unfortunately, the traditional therapies of diets, exercise, behavioral modification and medications have had little effect, especially in the severely obese. The introduction of bariatric surgery has changed the natural history of the super obese. Operative approaches now provide the most effective treatment of obesity but carry with them possible risks. Only 1% of patients who are estimated to benefit from bariatric surgery have undergone a procedure. The burgeoning field of endoluminal therapy has now allowed us to consider even more minimally invasive procedures to reach a larger patient population. This article will review the most recent advances in innovative technologies to treat the growing numbers of obese patients. PMID- 23732369 TI - Treating type 1 diabetes: from strategies for insulin delivery to dual hormonal control. AB - Type 1 diabetes is a disorder where slow destruction of pancreatic beta-cells occurs through autoimmune mechanisms. The result is a progressive and ultimately complete lack of endogenous insulin. Due to beta-cell lack, secondary abnormalities in glucagon and likely in incretins occur. These multiple hormonal abnormalities cause metabolic instability and extreme glycemic variability, which is the primary phenotype. As the disease progresses patients often develop hypoglycemia unawareness and defects in their counterregulatory defenses. Intensive insulin therapy may thus lead to 3-fold excess of severe hypoglycemia and severely hinder the effective and safe control of hyperglycemia. The main goal of the therapy for type 1 diabetes has long been physiological mimicry of normal insulin secretion based on monitoring which requires considerable effort and understanding of the underlying physiology. Attainment of this goal is challenged by the nature of the disease and our current lack of means to fully repair the abnormal endocrine pancreas interactive functions. As a result, various insulin preparations have been developed to partially compensate for the inability to deliver timely exogenous insulin directly to the portal/intrapancreatic circulation. It remains an ongoing task to identify the ideal routes and regimens of their delivery and potentially that of other hormones to restore the deficient and disordered hormonal environment of the pancreas to achieve a near normal metabolic state. Several recent technological advances help addressing these goals, including the rapid progress in insulin pumps, continuous glucose sensors, and ultimately the artificial pancreas closed loop technology and the recent start of dual-hormone therapies. PMID- 23732371 TI - Intraorbital injection of rituximab: a new approach for active thyroid-associated orbitopathy, a prospective case series. AB - AIM: The aim of this paper was to examine the efficacy and the safety of intraorbital administration of the monoclonal anti-CD20 antibody rituximab (RTX) to treat patients affected by thyroid-associated orbitopathy (TAO) unresponsive to conventional therapy. METHODS: Five patients with active moderately-severe TAO unresponsive to systemic glucocorticoids were studied. After a complete ophthalmological examination, disease activity and severity were assessed by the clinical activity score (CAS) and the NO SPECS scoring system. Computed tomography scans were performed in all patients. Patients were treated with intraorbital injection of RTX 10 mg once a week for one month repeated once one month apart. The patients were followed every three months until 18 months. RESULTS: In all patients treated with RTX, CAS was significantly reduced (p< 0,005), inactive phase of TAO was reached in four out of five patients. No patients experienced major side effects, minor side effects were reported in two patients. CONCLUSION: Intraorbital injection of RTX is a safe and useful promising therapeutic option for active TAO. PMID- 23732372 TI - Diet and physical activity "defeated" Tuberil(r) in treatment of childhood obesity. AB - AIM: Childhood obesity is remarkably spreading worldwide, involving both industrialized and low-income countries. Its prevalence, outcome and socioeconomic impact call for the attention of medical community. We conducted a monocentric, open, two-arm, parallel-group study to evaluate the efficacy at reducing appetite and increasing dietary compliance of obese children of Tuberil(r), a weight-loss supplement derived from potato and devoid of side effects. METHODS: We recruited participants, children with BMI >= 85th, through direct referrals in pediatrician's surgeries. Children were randomized to receive Tuberil(r) (group A) or nothing (group B), following a chronological order (A-B-A B). Every child received a nutritionally balanced diet and had to record their appetite and to describe their meals in a diary. RESULTS: Even if we found a significant reduction in BMI, weight and waist circumference in both groups, no statistically significant differences between groups were noted. We did not found any significant differences in appetite between group A and B. CONCLUSION: Our data show that Tuberil(r) has no efficacy neither in reducing appetite in children nor in increasing dietary compliance. We believe that only a nutritionally balanced diet and our attention in verifying their compliance led to the reduction in BMI, weight and waist circumferences noted in our series. PMID- 23732373 TI - Mortality in hyperglycemic crisis: a high association with infections and cerebrovascular disease. AB - AIM: Aim of the present study was to determine syndrome specific mortality rates and the precipitating factors associated with deaths following admission for hyperglycemic crisis to a high care unit. METHODS: Retrospective review of medical records for hyperglycemic crisis at Nelson Mandela Academic Hospital, Mthatha, Eastern Cape Province of South Africa from February 1 2010 to January 31 2011. All admissions were initially into the high care unit. RESULTS: The overall mortality rates (per admissions) was 13.9% (N.=15/108) with syndrome specific mortality rates (per admissions) of 11.9% (N.=8/67), 0% (N.=0/8) and 21.2% (N.=7/33) respectively for diabetic ketoacidosis (DKA), hyperglycemic hyperosmolar state (HHS) and hyperglycemia with dehydration (HD). The precipitating factors that were mainly associated with mortality were infections and cerebrovascular disease (CVD). The patients with CVD who died were all unconscious. There were no deaths where non-compliance with hypoglycaemic agents (14.8%, N.=16/108) was the precipitating factor. CONCLUSION: The overall mortality rates (per admissions) following high care unit admissions for hyperglycemic crisis was 13.9% with infections and CVD as the precipitating factors most associated with deaths. PMID- 23732374 TI - Vitamin D receptor gene ApaI, TaqI, FokI and BsmI polymorphisms in a group of Turkish patients with Hashimoto's thyroiditis. AB - AIM: Previous studies have suggested an influence of vitamin D receptor polymorphisms on the development of autoimmune thyroid disease in different ethnic populations. We aimed to investigate the distribution of vitamin D receptor (VDR) alleles in a group of Turkish patients with Hashimoto's thyroiditis (HT). METHODS: One hundred and eleven patients (male/female: 5/106, 47.9+/-12.8 years) and 159 healthy controls (male/female: 21/138, 30.5+/-6.3 yrs) were included in the study. VDR gene FokI, BsmI, ApaI TaqI polymorphisms were examined using a polymerase chain reaction (PCR) -based restriction analysis. Serum levels of (thyroid-stimulating hormone) TSH, anti-thyroid peroxidase and anti-thyroglobulin levels were determined. RESULTS: The VDR TaqI "TT" (59.5% in patients vs. 27.6% in controls; 95% confidence interval [CI]: 0.14-0.46) and FokI 'FF' genotypes (67.6% in patients vs. 44.6% in controls; 95% CI: 0.46-0.81) occurred more frequently in patients, while VDR "Tt" (56.6% in patients vs. 32.4% in controls 95% CI: 1.22-2.14) and "Ff" genotypes (25.2% in patients vs. 49.1% in controls 95% CI: 1.27-2.18) were more common in controls. There were no differences in the genotype frequencies of the ApaI and BsmI polymorphisms in cases and controls. The most common genotypes were "bbAaTTFF" in the thyroiditis group (12.6% patients vs. 5.6% in controls, P>0.05) and "BbAaTtFf" in the control group (6.3% patients vs. 22.2% in controls, P=0.002). CONCLUSION: VDR gene TaqI TT and FokI FF genotypes are associated with increased risk of HT disease in our group of Turkish patients. BbAaTtFf genotype seems to be protective for HT disease in our population. PMID- 23732375 TI - Adipocytokines and aging: adiponectin and leptin. AB - Adipose tissue is an active metabolic organ secreting adipocytokines which are involved in the energy homeostasis and regulation of glucose and lipid metabolism. Aging is associated with fat redistribution, which is characterized by loss of peripheral subcutaneous fat and accumulation of visceral fat. Visceral adipose tissue is more involved in the developement of metabolic diseases than subcutaneous adipose tissue. Aging also alters the function, proliferation, size, and number of adipose cells which leads to alterations in the secretion, synthesis and function of the adipocytokines. Adiponectin is an insulin sensitizing, anti-inflammatory, and antiathoregenic adipokine. Centarians have higher adiponectin levels associated with longevity. However, in older individuals - age 65 or more - adiponectin is associated with higher mortality. Dysregulation of adiponectin in older individuals may be due to loss of function of circulating adiponectin or a response to increased inflammatory process. Longitidunal increase in adiponectin levels 5with aging rather than genetically high adiponectin levels may translate to increased mortality in older patients. The adipocytokine leptin is traditionally viewed as a product of adipocytes that can exert endocrine effects. There have been conflicting reports of not only the effects of aging on leptin, but also the effects of leptin on age-related diseases including sarcopenia, Alzheimer's disease and cardiovascular diseases. Aging is also associated with resistance to leptin and/or to a decrease of receptors for this hormone. In this review, we briefly discuss the role of two major adipocytokines adiponectin and leptin in the aging process and age-related diseases. PMID- 23732376 TI - Impaired gonadal function in a woman with multiple symmetric lipomatosis. AB - Multiple symmetric lipomatosis (MSL, OMIM 151800), is a rare disease characterised by the growth of uncapsulated masses of abnormal adipose tissue around the neck, shoulders or other parts of the trunk and typically associated with high ethanol intake. We describe the case of a 33 year-old woman with MSL and secondary amenorrhea. Despite the presence of an ovarian failure confirmed by undetectable serum levels of inhibin B and anti-Mullerian hormone, the patient had normal serum levels of estrone and gonadotropins coexisting with a biological adrenal hyperandrogenism. We suggest that the adrenal hyperandrogenism observed in our patient could be attributed to an impairment of the cytochrome p450 function, inducing a relative 21-hydroxylase deficiency/insufficiency, related to alcohol abuse and that the increased peripheral aromatization of androgens in estrogens lead to normal circulating levels of estrone. The result is the absence of gonadotropin elevation despite primary ovarian failure. The peculiar functional pattern of brown adipocytes in patients with MSL may contribute to this biological phenomenon with an additive effect related to alcohol consumption. Altogether, these data could help to better define the peculiar pituitary-gonadal profile observed in this rare syndrome and in some cases of women with heavy alcohol consumption. PMID- 23732377 TI - Severe hypocalcemia associated with zoledronic acid treatment in a patient with a risk of fracture due to drug-induced osteopenia. PMID- 23732378 TI - [Specialized knowledge divisions--for our common goal]. PMID- 23732379 TI - Species distribution and resistance profiles of coagulase-negative staphylococci isolated from bovine mastitis in Switzerland. AB - Coagulase-negative staphylococci (CNS) are the predominant cause of bovine intra mammary infections. They can lead to chronic infections and were reported to significantly increase milk somatic cell counts. The goal of our study was to determine the species distribution and antimicrobial susceptibility profiles of CNS in bovine mastitis milk samples in Switzerland. Between March 2011 and February 2012, a total of 120 CNS were isolated from mastitis milk samples from 117 different animals at 77 farms. The isolates were identified by matrix assisted laser desorption ionization - time of flight mass spectrometry (MALDI TOF MS) and subsequently tested for sensitivity to various antibiotic agents by disk diffusion. Antimicrobial agents were selected mainly based on their relevance to the treatment of bovine mastitis in Switzerland. MALDI-TOF MS assigned the 120 isolates to 12 different staphylococcal species - S. chromogenes (33 %), S. xylosus (28 %), S. sciuri (13 %), S. haemolyticus (9 %), S. epidermidis (4 %), S. simulans (4 %), S. warneri (3 %), S. equorum (2 %), S. hyicus (2 %), S. cohnii (1 %), S. succinus (1 %), and S. fleuretti (1 %). Resistance rates in CNS were high, with 39% of isolates exhibiting resistance to ampicillin and penicillin, 6% of isolates being resistant to amoxicillin with clavulanic acid, ceftiofur, cephalothin, and cefoxitin, and 5 % being resistant to erythromycin. In rare cases resistance to gentamicin (2 %), kanamycin (2 %), and kanamycin-cefalexin (1 %) was detected. PMID- 23732380 TI - Antimicrobial susceptibility of gram-positive udder pathogens from bovine mastitis milk in Switzerland. AB - We evaluated the susceptibility of the gram-positive mastitis pathogens S. aureus, Str. uberis, Str. dysgalactiae, E. faecalis and L. garviae to antibiotics that are of epidemiological interest or are critically important for mastitis therapy and human medicine. Penicillin resistance was found to be most frequent in S. aureus, and nearly 5 % of the Str. uberis strains displayed a decreased susceptibility to this antibiotic. Resistance to aminoglycosides and macrolides was also detected in the strains tested. The detection of methicillin-resistant S. aureus (MRSA) and of a ciprofloxacin-resistant Str. dysgalactiae isolate corroborated the emergence of mastitis pathogens resistant to critically important antibiotics and underscores the importance of susceptibility testing prior to antibiotic therapy. The monitoring of antibiotic susceptibility patterns and antibiogram analyses are strongly recommended for targeted antimicrobial treatment and to avoid the unnecessary use of the latest generation of antibiotics. PMID- 23732381 TI - Resistance profiles and genetic diversity of Escherichia coli strains isolated from acute bovine mastitis. AB - Between March 2011 and February 2012 83 E. coli strains were isolated from mastitis milk samples from 83 different animals (67 farms) and tested for their sensitivity to various antibiotics by means of disk diffusion method and genotyped by determination of the phylogenetic groups as well as by pulsed field gel electrophoresis (PFGE). The antibiotics were chosen on the basis of their licenses for intramammary application in Switzerland. As many as 16.9 % of the isolates were resistant to one or more antimicrobial agents. Amoxicillin clavulanic acid, gentamicin and third generation cephalosporins proved effective against the majority of these strains. Nevertheless, one blaCTX-M-14 harbouring extended-spectrum-beta-lactamase producing strain was found. Genetic analysis grouped most of the strains (87 %) into phylogenetic groups A and B1. PFGE genotyping demonstrated that E. coli from cows with mastitis even from the same farm were genotypically very diverse. PMID- 23732382 TI - Function impairing mutations in blaZ and blaR genes of penicillin susceptible Staphylococcus aureus strains isolated from bovine mastitis. AB - Molecular based approaches have gained increasing importance in routine mastitis diagnostics for typing and antibiotic resistance testing of Staphylococcus aureus. Out of 78 S. aureus strains isolated from bovine mastitis milk 10 of them harbored blaZ, blaI and blaR genes. Although 5 strains were phenotypically resistant to penicillin, the other 5 (all belonging the clonal complex 8) were penicillin susceptible. PCR amplification confirmed the presence of the blaZ, blaR and blaI genes in all 5 strains. Sequencing of these genes uncovered a 29 base deletion within the blaZ gene in all these strains that causes a translational frame shift, which is predicted to induce abrogation of BlaZ expression. Additionally single nucleotide insertions and deletions were detected in blaR of 3 strains. These insertions cause translation reading frame shifts and premature stop codons that are predicted to induce expression of truncated BlaR proteins. Using the genetically altered blaZ genes detected as targets, a real time PCR system for detecting CC8 associated blaZ positive S. aureus strains that still remain susceptible to penicillin was developed. Such strains are part of detection challenges that must be considered in routine application of genotypic resistance testing of bovine mastitis S. aureus. PMID- 23732383 TI - [Calculation of therapeutic intensity for piglets and fattening pigs during the use of antibiotics in feed]. AB - Oral treatments for groups of pigs via medicated feed must be prescribed on specific forms submitted to veterinary authorities. We analyzed 869 such prescription forms for the year 2009 representing the treatment of 69'863 piglets and 31'506 fattening pigs. Parameters under investigation were indication and quantity of antimicrobials prescribed. Most of the treatments took place at weaning with 10 - 14 kg and again at the beginning of the fattening period with 20 - 29 kg body weight. The average body weights at treatment were 16 kg (piglets) and 29 kg (fatteners). In analogy with the indicator DID of human medicine, we developed PIDvet describing the prescribed dose per 1000 individuals on given day in veterinary medicine. Calculated PIDvet on a given day was 180.9 for the whole population, 297.6 for piglets and 83.2 for fatteners. This shows PIDvet to be useful to stratify therapeutic intensity in different age classes and could represent a new tool to monitor the use of antibiotics. PMID- 23732384 TI - Arcanobacterium pluranimalium leading to a bovine mastitis: species identification by a newly developed pla gene based PCR. AB - We are describing a clinical case of bovine mastitis due to Arcanobacterium pluranimalium in a Holstein-Friesian heifer, delivering bloody milk on the left hindquarter. Moreover, we report on the development and evaluation of PCR primers based on the pluranimaliumlysin (pla) gene for the identification of this species. With the primer pair PlaF/PlaR the A. pluranimalium type strain as well as the mastitis isolate 704 revealed a correctly sized amplification product (458 bp), whereas no amplification product was obtained for all non-target strains. The established PCR provides a new and convenient tool for the mastitis diagnostic to differentiate between A. pluranimalium and Trueperella pyogenes. PMID- 23732389 TI - [Dependents' allowance: self-employed recruiting likewise comes under the obligation]. PMID- 23732390 TI - Tuning stoichiometry and supramolecular assembly in perfluorinated indazolato coinage metal complexes. AB - The reaction of 3-pentafluoroethyl-4,5,6,7-tetrafluoro-1-H-indazole [3 (C2F5)IndF4]H with Ag2O or [Cu(CH3CN)4]BF4 leads to the formation of two different types of complexes: a trinuclear {[3-(C2F5)IndF4]Ag}3 complex (1) in the case of silver, and an unprecedented type of pentanuclear complex [Et3NH]{Cu5[3-(C2F5)IndF4]6} (2) in the case of copper. When crystallised from Et2O, appears as a dimer with d(10)-d(10) interactions. When crystallized from toluene, affords the [(toluene)(1)(toluene)] adduct, testifying to its strong pi acid properties. The formation and the aggregation pattern of 1 and 2 can be traced to the extended aromaticity and high electron withdrawing properties of the perfluorinated [3-(C2F5)IndF4](-) indazolate. PMID- 23732391 TI - Biomechanical origin of the Denonvilliers' fascia. AB - INTRODUCTION: Since 1836 and the first description of the recto-genital fascia by Charles Denonvilliers, many anatomists have shown interest in this subject. Recently, pelvic surgeons have in turn shown similar interest, for they consider that perfect knowledge of this anatomical domain is crucial for optimal nerve conservation during surgery. Thanks to new anatomical description techniques, fascia location and relationships with pelvic nerves now appear clearer. OBJECTIVES: To describe and represent Denonvilliers' fascia and its relationships in the female foetus at different stages of gestation and in three-dimensional space (3D). MATERIEL/PATIENTS AND METHODS: Computer-assisted anatomical dissection technique was used. Serial histological sections were made from four human female foetuses. Sections were treated with conventional staining, as well as with nerve and smooth muscle immunostaining. Finally, the sections were digitalized and reconstructed in 3D. RESULTS: Denonvilliers' fascia was clearly located and visualized in three dimensions. It was present in the female foetus, being distinct from the fascia propria of the rectum. It appeared to be composed of multiple parallel layers situated between the vagina and the rectum. From a lateral view, it had an asymmetrical "Y-shaped" aspect that seemed to play the role of a protective sheet for the neurovascular bundles. CONCLUSION: This study betters our comprehension of the Denonvilliers' fascia in the female foetus and of its connections with pelvic nerves. It also provides a better understanding of safe planes during pelvic dissection. These findings also suggest a biomechanical theory for embryological origin of the Denonvilliers' fascia. PMID- 23732392 TI - A new contrast agent for radiological and dissection studies of the arterial network of anatomic specimens. AB - PURPOSE: The aim of the present study is to propose a new contrast agent that can be easily applied both to CT and dissection studies to replace lead oxide based formulas for comparative anatomical analyses of the vascularisation of cadaveric specimens. METHODS: The infusion material was an epoxy resin, especially modified by the addition of barium sulphate to enhance its radiopacity. The final copolymer was toxicologically safe. To test the properties of the new material, several cadaveric limb injections were performed. The injected specimens were both CT scanned to perform 3D vascular reconstructions and dissected by anatomical planes. RESULTS: There was a perfect correspondence between the image studies and the dissections: even the smallest arteries on CT scan can be identified on the specimen and vice versa. The properties of the epoxy allowed an easy dissection of the vessels. CONCLUSIONS: The new imaging techniques available today, such as CT scan, can evaluate the vascular anatomy in high detail and 3D. This new contrast agent may help realising detailed vascular studies comparing CT scan results with anatomical dissections. Moreover, it may be useful for teaching surgical skills in the field of plastic surgery. PMID- 23732393 TI - Development and characterization of micellar systems for application as insect repellents. AB - N,N-diethyl-meta-toluamide (DEET) is a widely used insect repellent due to its high efficacy. In this work, micellar systems based on poly(ethylene oxide) poly(propylene oxide)-poly(ethylene oxide) triblock copolymer were developed and studied for the purpose of controlling the release and cutaneous permeation of DEET, using concentrated solutions of the copolymer Pluronic F127 to form thermoreversible gels. The formulations presented thermoreversible gelation above 5 degrees C and altered rheological behavior at 15 and 25 degrees C. The presence of the drug drastically changed the sol-gel transition temperatures. The micrographs suggest that DEET induced the formation of anisotropic structures, and Maltese Crosses were observed. The formulation containing 10wt% DEET and 15wt% Pluronic F127 presented sustained drug release for up to 7h. DEET release profile followed the Higuchi kinetics model. There was a reduction of approximately 35% in the amount of DEET absorbed through the skin after 6h. About 62% of DEET from the formulation consisting of Pluronic F127 and DEET remain retained on the skin. The anisotropic structure may constitute a barrier to diffusion and thereby controlling the drug release effectively. These tests suggest that the tested samples exhibit safety profile greater than some commercially available products. PMID- 23732394 TI - Silencing of miR-21 by locked nucleic acid-lipid nanocapsule complexes sensitize human glioblastoma cells to radiation-induced cell death. AB - The recent discovery of microRNA (miRNA) as major post-transcriptional repressors prompt the interest of developing novel approaches to target miRNA pathways to improve therapy. In this context, although the most significant barrier to their widespread clinical use remains delivery, nuclease-resistant locked nucleic acid (LNA) that bind specifically and irreversibly to miRNA represent interesting weapons. Thus, by focusing on oncongenic miR-21 miRNA, which participate to cancer cell resistance to apoptotic signals, the aim of the present study was to investigate the possibility of silencing miRNA by LNA conjugated to lipid nanocapsules (LNCs) as miRNA-targeted nanomedicines in U87MG glioblastoma (GBM) cells. After synthesis of an amphiphilic lipopeptide affine for nucleic acids, a post-insertion procedure during the LNC phase inversion formulation process allowed to construct peptide-conjugated LNCs. Peptide-conjugated LNCs were then incubated with LNAs to allow the formation of complexes characterized in gel retardation assays and by their physicochemical properties. U87MG cell treatment by LNA-LNC complexes resulted in a marked reduction of miR-21 expression as assessed by RTqPCR. In addition, exposure of U87MG cells to LNA-LNC complexes followed by external beam radiation demonstrated a significant improvement of cell sensitivity to treatment and emphasizes the interest to investigate further this miRNA-targeted strategy. PMID- 23732395 TI - A new quantum dot-platinum conjugate for self-assembled nanoconjugates by coordination bonding mediated recognition. AB - A new binding strategy of linking quantum dots (QDs) to magnetic nanoparticles (MNPs) using DNA interaction with metal coordination bonding was developed. Platinum was selected for binding QDs to DNA. This novel self-assembled nanoconjugate would be a new probe for diagnosing a specific disease more accurately with its double modalities, fluorescence and magnetic property. PMID- 23732396 TI - Rapid head growth in a baby with autosomal dominant polycystic kidney disease (ADPKD): questions. PMID- 23732397 TI - The innate immune response during urinary tract infection and pyelonephritis. AB - Despite its proximity to the fecal flora, the urinary tract is considered sterile. The precise mechanisms by which the urinary tract maintains sterility are not well understood. Host immune responses are critically important in the antimicrobial defense of the urinary tract. During recent years, considerable advances have been made in our understanding of the mechanisms underlying immune homeostasis of the kidney and urinary tract. Dysfunctions in these immune mechanisms may result in acute disease, tissue destruction and overwhelming infection. The objective of this review is to provide an overview of the innate immune response in the urinary tract in response to microbial assault. In doing so, we focus on the role of antimicrobial peptides-a ubiquitous component of the innate immune response. PMID- 23732398 TI - Plasma homocysteine and folate levels and dietary folate intake in adolescents and young adults who underwent kidney transplantation during childhood. AB - BACKGROUND: Hyperhomocysteinemia (hyper-Hcy) is an important and reversible cardiovascular disease risk factor. We examined the prevalence of hyper-Hcy, plasma folate levels, and dietary folate intake in adolescents and young adults who had undergone kidney transplantation during childhood to assess the necessity for managing dietary folate. METHODS: This cross-sectional study was performed in 89 kidney transplant recipients (age at kidney transplantation: 12.6 +/- 4.1 years; age during study: 21.2 +/- 5.5 years). Hyper-Hcy and plasma folate deficiency were defined as plasma homocysteine (Hcy) >15 nmol/ml and plasma folate <3.0 ng/ml, respectively. RESULTS: Of the patients, 60 (67.4 %) had hyper Hcy and 14 (15.7 %) had plasma folate deficiency. Plasma homocysteine levels correlated negatively with estimated glomerular filtration rate (eGFR; r = 0.565, p < 0.01) and plasma folate levels (r = -0.434, p < 0.01). For determinants of plasma homocysteine levels, a priori selected variables included kind of calcineurin inhibitor, age at kidney transplantation, pretransplant duration of dialysis, time since transplantation, age at examination, eGFR, and plasma folate. Stepwise multiple linear regression analysis revealed eGFR and plasma folate levels as significant independent variables influencing plasma homocysteine levels. Dietary folate intake in 11 of 16 patients (66.8 %) with eGFR >= 60 ml/min/1.73 m(2) was below the recommended dietary allowance for Japanese. CONCLUSIONS: The prevalence of hyper-Hcy and plasma folate deficiency, as well as the low dietary folate intake, suggest that dietary management of folate is necessary for adolescents and young adults who have undergone kidney transplantation during childhood. PMID- 23732399 TI - Uncertainty in assessment of radiation-induced diffusion index changes in individual patients. AB - The purpose of this study is to evaluate repeatability coefficients of diffusion tensor indices to assess whether longitudinal changes in diffusion indices were true changes beyond the uncertainty for individual patients undergoing radiation therapy (RT). Twenty-two patients who had low-grade or benign tumors and were treated by partial brain radiation therapy (PBRT) participated in an IRB-approved MRI protocol. The diffusion tensor images in the patients were acquired pre-RT, week 3 during RT, at the end of RT, and 1, 6, and 18 months after RT. As a measure of uncertainty, repeatability coefficients (RC) of diffusion indices in the segmented cingulum, corpus callosum, and fornix were estimated by using test retest diffusion tensor datasets from the National Biomedical Imaging Archive (NBIA) database. The upper and lower limits of the 95% confidence interval of the estimated RC from the test and retest data were used to evaluate whether the longitudinal percentage changes in diffusion indices in the segmented structures in the individual patients were beyond the uncertainty and thus could be considered as true radiation-induced changes. Diffusion indices in different white matter structures showed different uncertainty ranges. The estimated RC for fractional anisotropy (FA) ranged from 5.3% to 9.6%, for mean diffusivity (MD) from 2.2% to 6.8%, for axial diffusivity (AD) from 2.4% to 5.5%, and for radial diffusivity (RD) from 2.9% to 9.7%. Overall, 23% of the patients treated by RT had FA changes, 44% had MD changes, 50% had AD changes, and 50% had RD changes beyond the uncertainty ranges. In the fornix, 85.7% and 100% of the patients showed changes beyond the uncertainty range at 6 and 18 months after RT, demonstrating that radiation has a pronounced late effect on the fornix compared to other segmented structures. It is critical to determine reliability of a change observed in an individual patient for clinical decision making. Assessments of the repeatability and confidence interval of diffusion tensor measurements in white matter structures allow us to determine the true longitudinal change in individual patients. PMID- 23732400 TI - Leiomyosarcoma of the pulmonary veins extending into the left atrium. AB - Primary tumors of the great vessels are very rare. Primary leiomyosarcomas of the pulmonary vein are extremely rare and little is known about their clinical manifestation and treatment. We report the case of a 34-year-old patient with primary leiomyosarcoma of the pulmonary vein extending into the left atrium. A review of the clinical manifestation and treatment of 24 cases including our own is provided. PMID- 23732401 TI - Establishing benchmarks and metrics for disruptive technologies, inappropriate and obsolete tests in the clinical laboratory. AB - Benchmarks and metrics related to laboratory test utilization are based on evidence-based medical literature that may suffer from a positive publication bias. Guidelines are only as good as the data reviewed to create them. Disruptive technologies require time for appropriate use to be established before utilization review will be meaningful. Metrics include monitoring the use of obsolete tests and the inappropriate use of lab tests. Test utilization by clients in a hospital outreach program can be used to monitor the impact of new clients on lab workload. A multi-disciplinary laboratory utilization committee is the most effective tool for modifying bad habits, and reviewing and approving new tests for the lab formulary or by sending them out to a reference lab. PMID- 23732402 TI - Undetected hypoglycemia in a patient receiving TPN. AB - CASE REPORT: A 58-year-old female was admitted to the hospital in a severely malnourished state. She was treated for Crohn's disease with total parental nutrition (TPN). The patient's blood glucose was monitored by point of care (POC) testing every 4h, and a specimen is also drawn daily for metabolic assessment. The POC blood glucose values were consistently much higher than the lab values. Humalog insulin (5 U) was given to the patient to decrease high blood glucose levels that developed following administration of TPN. The patient then became hypoglycemic as a result of this insulin treatment. POC glucose testing, performed every 4h, did not detect the iatrogenic hypoglycemia, while lab glucose results were not given close attention. The lab sample was always drawn 1-2h after insulin was given to the patient and resulted in a lower blood glucose value. In addition, the symptoms of hypoglycemia such as shaking and dizziness were masked by the patient's poor health status, supine position, and the continuously given TPN. CONCLUSIONS: These findings highlighted the importance of the correct sampling time following insulin administration and the consideration of the lab results in addition to POC. The patient's insulin regimen was modified to prevent further hypoglycemic events. PMID- 23732403 TI - Achieving recommended daily physical activity levels through commuting by public transportation: unpacking individual and contextual influences. AB - This paper estimates the amount of daily walking associated with using public transportation in a large metropolitan area and examines individual and contextual characteristics associated with walking distances. Total walking distance to and from transit was calculated from a travel diary survey for 6913 individuals. Multilevel regression modelling was used to examine the underlying factors associated with walking to public transportation. The physical activity benefits of public transportation varied along gender and socio-economic lines. Recommended minutes of daily physical activity can be achieved for public transportation users, especially train users living in affluent suburbs. PMID- 23732404 TI - Introduction to the special issue of ageing research reviews on synaptic global positioning systems. PMID- 23732405 TI - Developmental regulation and antifungal activity of a growth-blocking peptide from the beet armyworm Spodoptera exigua. AB - Insect cytokine growth-blocking peptides (GBPs) are involved in growth regulation and the innate immune response. However, the microbial binding and antimicrobial activities of GBPs remain unclear. Here, we investigate the developmental role and antifungal activity of a GBP from the beet armyworm Spodoptera exigua (SeGBP). Sequence analysis predicted that mature SeGBP consists of 24 amino acid residues, including 2 cysteine residues. During S. exigua development, SeGBP is constitutively expressed in the fat body during the larval and adult stages but not in pupae. SeGBP expression is up-regulated by 20-hydroxyecdysone and down regulated by juvenile hormone analog. Recombinant SeGBP purified from baculovirus infected insect cells retards the growth of S. exigua larvae. Additionally, SeGBP expression is acutely induced in the fat body after injection with Escherichia coli, Bacillus thuringiensis, or Beauveria bassiana. Recombinant SeGBP can bind to B. bassiana but not to E. coli or B. thuringiensis. Consistent with these findings, SeGBP shows antifungal activity against B. bassiana. Therefore, these results provide insight into the role of SeGBP during the innate immune response following microbial infection, and furthermore, they suggest a novel function for SeGBP as a direct antifungal agent against entomopathogenic fungi, such as B. bassiana. PMID- 23732406 TI - Immune competence in insect eggs depends on the extraembryonic serosa. AB - Innate immunity is common to all metazoans and serves as a first line of defense against pathogens. Although the immune response of adult and larval insects has been well characterized, it remains unknown whether the insect egg is able to mount an immune response. Contrary to Drosophila, Tribolium eggs develop an extraembryonic epithelium, the serosa. Epithelia are well known for their ability to fight infection, so the serosa has the potential to protect the embryo against pathogens. To test this hypothesis we created serosa-less eggs by Tc-zen1 parental RNAi. We found that the Tribolium egg upregulates several immune genes to comparable levels as adults in response to infection. Drosophila eggs and serosa-less Tribolium eggs, however, show little to no upregulation of any of the tested immune genes. We conclude that the extraembryonic serosa is crucial for the early immune competence of the Tribolium egg. PMID- 23732407 TI - Identification and functional characterizations of a novel TRIF gene from grass carp (Ctenopharyngodon idella). AB - Toll/interleukin-1 receptor (TIR) domain containing adapter inducing interferon beta (TRIF) is an adapter in responding to activation of some toll-like receptors (TLRs), which provides early clearance of viral and bacterial pathogens. Here we identified and characterized a full-length genomic sequence of TRIF gene from grass carp Ctenopharyngodon idella (designated as CiTRIF). CiTRIF genomic sequence consists of 3534 base pairs (bp), containing 5' flank sequence (496 bp) and unique intron (815 bp). The full-length cDNA sequence is 2241 bp, including 5' untranslated region (UTR) of 352 bp, 3' UTR of 209 bp, and an open reading frame of 1680 bp encoding a polypeptide of 559 amino acids with an estimated molecular weight of 62.643 kDa and a predicted isoelectric point of 5.71. The deduced amino acid sequence just contains TIR domain, and is most similar to the zebrafish (Danio rerio) TRIF sequence with an identity of 64%. CiTRIF exhibits sequence divergence from its orthologs. Promoter region was predicted and promoter activity was verified. mRNA expression of CiTRIF gene is widespread in 15 tissues investigated, highly in foregut and skin physiological immune barrier. The transcripts of CiTRIF were significantly and rapidly induced in spleen and head kidney tissues at early stage post grass carp reovirus (GCRV) challenge. The modulations are significant but mild in CIK (C. idella kidney) cells post GCRV infection or poly(I:C) stimulation. The over-expression vector was constructed and transfected into CIK cell line to get stably expressing recombinant proteins. In CiTRIF transfected cells, mRNA expressions of CiTRIF, CiRIG-I, CiIRF7 and CiIFN-I were up-regulated. After GCRV infection, the transcripts of CiTRIF, CiRIG I, CiIRF7 and CiIFN-I fell a little bit after a rapidly and strongly rise. In CiTRIF over-expression cells, virus load and titer were significantly lower than those in controls post GCRV challenge, and virus replication was inhibited obviously. The results indicate that the novel TRIF gene from grass carp plays important roles in modulating antiviral innate immune responses, and serve the further functional studies on TRIF gene in teleosts and immune evolution. PMID- 23732408 TI - [Transcatheter aortic valve implantation: experience in 17 patients]. AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) is taking a leading role in the management of patients with severe aortic stenosis. Valve replacement surgery prolongs survival and is the technique of choice considering its historical background and long experience worldwide. Recently however, TAVI has positioned itself as the only standard therapy for symptomatic patients who are not candidates for surgery. AIM: To report the experience with this new technique comparing our results with those reported in the literature. MATERIAL AND METHODS: Between May 2010 and December 2011,17 patients aged 81 +/- 7.3 years (58.8% men with an Euro SCORE 29 +/- 22.4%) underwent a TAVI. RESULTS: The median transvalvular gradient was 54 +/- 15.7 mmHg. All patients received a CoreValveTM. Technical success was 100%, with a post implant gradient of 6.29 +/- 3.3 mmHg. Residual aortic regurgitation was observed in 94%, none greater than grade II. There were no complications at the vascular access site. One patient developed cardiac tamponade during the procedure. Permanent pacemaker implantation was required in 35.2%. Hospital mortality rate was 5.8%, a figure that remained unchanged at 30 days of follow-up. CONCLUSIONS: In high-risk patients with aortic stenosis, TAVI has a high success rate and a low rate of complications. Besides an appropriate patient selection, a trained multidisciplinary team and technical conditions to solve possible complications of the procedure are required. PMID- 23732409 TI - [Relationship between self-directed learning and value profile in Chilean medical students]. AB - BACKGROUND: Medical education should prepare students to face a dynamic environment, through competencies that allow them to learn independently. AIM: To evaluate the relationship between self-directed learning and value profile of undergraduate first year students in a medical school in Chile. MATERIAL AND METHODS: Self-Directed Learning Scale and Schwartz's Values Questionnaire were applied to 235 medical students from the University of Concepcion, Chile. RESULTS: Self-direction and Security are value types that correlate directly and significantly with the overall scale and with the five subscales of Self-Directed Learning. CONCLUSIONS: In first year medical students ofUniversity of Concepcion, Chile, Self-direction and Security are values that facilitate Self-directed Learning. PMID- 23732410 TI - [Effects of smoking on plasma antimullerian hormone concentrations among infertile women]. AB - BACKGROUND: Smoking may hamper female fertility, probably modifying ovarian reserve. Antimullerian hormone (AMH) is an accurate marker for ovarian reserve. AIM: To look for an association between smoking status and plasma AMH concentration. PATIENTS AND METHODS: A cohort of 141 infertile women in a university setting in Santiago, Chile was studied. Demographic and smoking data, including the number of cigarettes smoked during the last week, were collected. A blood sample was obtained and kept frozen until determination of AMH by ELISA and follicle stimulating hormone (FSH) and estradiol at day three of the menstrual cycle, by radioimmunoanalysis. RESULTS: Thirty two participants smoked (23%). There were no significant differences in age, parity, body mass index, causes of infertility and day three FSH and estradiol between smokers and nonsmokers. According to a regression analysis, there was a significant decrease in AMH concentration with age and active cigarette smoking. A drop in AMH of -0.189 ng/mL with a unitary change in age and a decrease of -2.29 ng/mL when everything else remains constant, except the smoking status, were established (p < 0.001 and r2 = 0.134). However, no dose response was observed when the number of cigarettes smoked during the last week were introduced in the model. Furthermore, no significant association of plasma AMH with day three plasma FSH and estradiol concentrations was observed. CONCLUSIONS: Cigarette smoking is associated with decreased AMH plasma concentrations among infertile women. However there was no dose response relationship. The mechanisms underlying this association are unknown and further investigation is required. PMID- 23732411 TI - [Factor analysis of abbreviated versions of the WHOQoL-Old in Chilean older people]. AB - BACKGROUND: The increase in elderly population demands the need for new health measures that are reliable and valid. AIM: To compare the factor structure of the Quality of Life Scale WHOQoL-Old of the World Health Organization with the three proposed abbreviated versions of the scale. MATERIAL AND METHODS: We performed confirmatory factor analysis on data collected from 804 older people, aged 70 +/- 6 years (66% females). RESULTS: One of the unifactorial models that incorporate six questions had goodness of fit values greater than 0.95 in the non-normed fit index and below .05 in the root-mean square error of approximation. CONCLUSIONS: The abbreviated version tested is a valid and reliable questionnaire to be used in Chilean older people. PMID- 23732412 TI - [Postoperative survival among nonagenarians: a retrospective study]. AB - BACKGROUND: As the Chilean population ages, anesthesiologists are regularly faced with elderly and even nonagenarian people undergoing surgical procedures. AIM: To determine the postoperative survival time in nonagenarians and its risk factors at a private clinic. MATERIAL AND METHODS: Review of medical records of the clinic, searching for patients aged 90 years or older, which were subjected to a surgical procedure between 2001 and 2012. Certification of survival or death was obtained from the clinical records or death certification at the National Identification Service. Survival analysis was made using Kaplan-Meier and Gompertz regression. RESULTS: The medical records of 167 patients, aged 90 to 101 years (64% women), were reviewed. Sixty four percent had an underlying cardiovascular disease; in 37%, cognitive impairment. Hip fracture surgery was the most common procedure. One intraoperative death occurred. Five percent of patients died one month after surgery. The median survival time was two years and the longest, seven years. According to Gompertz probability regression, the predictors of death were the presence of cardiac disease (Hazard ratio (HR): 1.91, 95% confidence intervals (95% CI): 1.16; 3.16), cognitive impairment (HR: 2.10,95% CI: 1.32; 3,22), cancer (HR:2.10,95% CI: 1.32; 3.22), requirement of transfusion (HR: 1.79, 95% CI: 1.13; 2.83) and an American Society of Anesthesiologists (ASA) Class III classification (HR: 1.95, IC95%: 1.21; 3.15). CONCLUSIONS: In nonagenarian patients undergoing surgery; 50% mortality was observed 2 years after surgery. The presence of cardiac disease, cognitive impairment, cancer, transfusion and a Class IIIASA classification were predictors of death. PMID- 23732413 TI - [Prognostic value of PET/CT in lung cancer: retrospective analysis of 47 patients]. AB - BACKGROUND: PET/CT (Positron emission tomography/computed tomography) is a hybrid image modality widely used in oncology, for staging, therapy evaluation or follow up. AIM: To evaluate the prognostic value of PET/CT in lung cancer. MATERIAL AND METHODS: Retrospective review of PET/CT records, selecting 51 patients with a lung malignancy, mass or nodule referred for PET/CT between December 2008 and December 2010. All had pathological confirmation of malignancy and had not been treated previously. Age, gender, body mass index, radiological features of lung tumor and metastases, and lung tumor 18F-fluoro-2-deoxy-d-glucose uptake using the SUV (Standardized uptake value) index were recorded. Survival was analyzed using Kaplan-Meier curves and a Cox proportional regression analysis. RESULTS: Pathology confirmed the presence of lung cancer in 47 patients aged 30 to 88 years. Four patients (7.8%) had other type of tumors such as carcinoid or lymphoma. Fifty percent of lung cancer patients died during a mean observation lapse of 18 months (range: 2-34 months). Patients with metastases, local lymph node involvement, a lung tumor size > 3 cm and high tumor uptake (SUVmax > 6) had significantly lower survival. Occurrence of metastases was the only independent prognostic factor in the Cox regression. A lung lesion with a SUVmax >= 12 was always associated to hilar/mediastinal lymph node involvement. CONCLUSIONS: PET/CT imaging gives important prognostic information in lung cancer patients. PMID- 23732414 TI - [Diffusion and adoption of health care innovations in cardiology, in Argentina]. AB - BACKGROUND: Medicine is changing rapidly and diagnostic and therapeutic innovations are common. Not all professionals adopt these innovations in the same way. AIM: To survey the physicians' opinions on adopting innovations in cardiovascular health care, to classify individuals from an innovative to a conservative behavior, and to individualize opinion leaders among them, in order to build a social network of influence. MATERIAL AND METHODS: Between November and December 2008, 765 Argentine cardiologists were surveyed via e-mail in Argentina, to assess the way they adopt and disseminate innovations in cardiovascular health care. RESULTS: The survey was answered by 537 professionals (70.2%). Fifty three percent of respondents were "Early adopters". However, 63 to 79.3% of respondents preferred to wait for a full demonstration of the usefulness of innovation before adopting it. The opinion leaders' distribution adopted a scale-free network pattern, where few leaders had many connections and influence on the whole network. The giant component of the network included 41% of physicians; growth simulation of the network showed that the four most popular leaders influenced over 44% of the giant component. CONCLUSIONS: Among surveyed physicians there was an attitude towards rapid acceptance of innovations in health care. However, when analyzing the direct opinion of physicians, most cases preferred usefulness demonstrated before accepting innovations. The social network including respondents and opinion leaders showed a scale-free topology with a big influence of a few over the whole network. PMID- 23732415 TI - [Pulmonary hypertension associated with connective tissue diseases]. AB - BACKGROUND: Pulmonary arterial hypertension is an important cause of complications among patients with connective tissue diseases. AIM: To describe the clinical and echocardiographic characteristics of patients with pulmonary hypertension associated with connective tissue diseases. MATERIAL AND METHODS: Retrospective, observational and descriptive study. We analyzed 35 patients with pulmonary hypertension associated with connective tissue diseases. All patients were evaluated and diagnosed by at least one medical specialist in rheumatology. Pulmonary arterial hypertension was defined as a pulmonary artery systolic pressure >= 40 mmHg by echocardiography. The group was divided as not severe when pressures ranged from 40 to 64 mmHg and severe, when pressures were >= 65 mmHg. RESULTS: The most common connective tissue disease associated with pulmonary arterial hypertension was diffuse scleroderma in 46% of cases. Eighty nine percent of patients were female. Time of evolution of the pulmonary hypertension was 18.8 +/- 21.8 months. The distance walked in the six minute walk test was < 400 m both in patients with and without severe pulmonary hypertension. Fifty one percent of patients had pulmonary restriction. No differences in gas exchange parameters were observed between groups. Comparing echo cardio-graphic findings in patients with and without severe hypertension, the former had a higher frequency of right ventricular dilatation (85.7 and 52.3% respectively, p = 0.04), right ventricular hypertrophy (42.8 and 0% respectively, p = 0.02) and right ventricular hypokinesia (71.4 and 9.5% respectively p = < 0.01). CONCLUSIONS: Patients with severe pulmonary arterial hypertension associated to connective tissue diseases have more commonly dilated, hypertrophic and hypokinetic right ventricles. PMID- 23732416 TI - [Protection against ionizing radiation by leaded glass googles during interventional cardiology]. AB - BACKGROUND: It is not known whether leaded glass goggles with 0.25 mm Pb equivalency, used in interventional cardiology procedures, attenuate radiation below the levels established by the latest recommendation of the International Commission on Radiological Protection (ICRP). AIM: To assess if the degree of attenuation of the secondary ionizing radiation achieved by the use of 0.25 mm Pb leaded glass goggles, in occupationally exposed workers in interventional cardiology procedures, meets the latest ICRP recommendations. MATERIAL AND METHODS: A prospective investigation was carried out to compare the eye exposure to secondary ionizing radiation received by occupationally exposed personnel in a 9 months period. A set of two thermo luminescent dosimeters was arranged in the front and back of leaded glass goggles in a cohort of seven members of an interventional cardiology service, exposed to 1057 consecutive procedures. RESULTS: The monthly dose equivalent measurement performed in front of the goggles ranged between 1.1 and 6.5 mSv, for paramedics and interventional cardiologists. The radiation measured in the back of the glass varied between 0.66 and 2.75 mSv, respectively. The degree of attenuation of the dose at eye level ranged from 40% to 57.7%, respectively. The projected annual exposure would reach 33 mSv for the interventional cardiologist. CONCLUSIONS: With a similar load of work and wearing 0.25 mm Pb equivalent glass goggles, interventional cardiologists will exceed the crystalline equivalent dose limit recommended by the ICRP (20 mSv/year averaged over the past 5 years). PMID- 23732417 TI - [Simulation in medical education: a synopsis]. AB - Clinical simulation is defined as a technique (not a technology) to replace or amplify real experiences with guided experiences that evoke or replicate substantial aspects of the real world in a fully interactive fashion. Over the past few years, there has been a significant growth in its use, both as a learning tool and as an assessment for accreditation. Example of this is the fact that simulation is an integral part of medical education curricula abroad. Some authors have cited it as an unavoidable necessity or as an ethical imperative. In Chile, its formal inclusion in Medical Schools' curricula has just begun. This review is an overview of this important educational tool, presenting the evidence about its usefulness in medical education and describing its current situation in Chile. PMID- 23732418 TI - [Recommendations for health care of people with Down syndrome from 0 to 18 years of age]. AB - People born with Down syndrome have an increased risk of birth defects and are more vulnerable to certain illnesses. Health care for them should emphasize prevention, early diagnosis and early treatment of their most common health conditions. A healthy lifestyle promotes future physical and intellectual development. The purpose of this review is to update health care recommendations for individuals with Down syndrome from 0 to 18 years of age. The health professionals members involved in the care of these patients should be aware of these guidelines. PMID- 23732419 TI - [Ministry of Health Intensive Care Medicine Commission: proposals for the development of the discipline]. AB - Intensive care medicine in Chile is still in its dawn. It has experienced a progressive growth in the last decade, but continues to be weak. Although investments in the discipline have increased fivefold, there is still a severe deficiency of intensive care specialists. This issue will represent a serious problem in the near future. The Ministry of Health gathered an expert committee to study the problem and propose solutions for the future development of the discipline. PMID- 23732420 TI - [Thyroid stimulating hormone reference values derived from the 2009-2010 Chilean National Health Survey]. AB - BACKGROUND: The determination of thyroid stimulating hormone (TSH) reference values is critical for the diagnosis of thyroid diseases. AIM: To explore and discuss different definitions to establish TSH reference values using a Chilean national survey sample. MATERIAL AND METHODS: The 2009-2010 Chilean National Health Survey recruited 5,416 participants between the ages of 15 and 96 years, from all geographic regions of Chile, including urban and rural zones. TSH was measured in a random subsample of 2,785 adults. Median value, 2.5 and 97.5 percentiles were described in three different populations: total survey population, "disease-free population" and the "laboratory kit disease free population". RESULTS: TSH values were higher among women, the elderly and the less educated population. The 97.5 percentile value in the disease-free population was 7.46 uUl/ml. Using this value as a cut-off, hypothyroidism prevalence would be 4.8% in Chile and estimated pharmacological treatment coverage would be 58%. When laboratory kit cut-offs are used, prevalence rises to 22% and treatment coverage drops to 12%. The 2.5 percentile value in the disease free population was 0.83 uUl/ml, which yields an estimated hyperthyroidism prevalence of 3.89%. CONCLUSIONS: Median TSH concentration values in the Chilean "disease-free population" are higher than those proposed by laboratory kits and those of developed countries. TSH values in the general population of Chile are also higher in women, the elderly and the less educated population. PMID- 23732421 TI - [Cerebral salt wasting syndrome associated with Listeria monocytogenes encephalitis. Report of one case]. AB - Hyponatremia is common in patients with severe neurological diseases and is often secondary to a syndrome of inappropriate antidiuretic hormone secretion (SIADH). However, in some patients, hyponatremia is due to cerebral salt wasting syndrome (CSWS). SIADH and CSWS treatments are opposite and misdiagnosis can lead to increased morbidity and mortality. We report a 52 years old female with a rhom boencephalitis caused by Listeria Monocytogenes (LM), ventriculitis and abscesses in cerebellum and brainstem. It was associated with hyponatremia, hypotension, increased natriuresis, hypouricemia, and low creatinine and blood urea nitrogen levels. Large amounts of sodium were needed and the condition persisted after hospital discharge. Hyponatremia is common in central nervous system involvement by LM, however we are not aware of CSWS reports of this condition. PMID- 23732422 TI - [Bifrontal cerebritis and brain abscess caused by Sreptococcus anginosus group: report of one case]. AB - The etiology of brain abscesses is mostly polymicrobial. Streptococci and anaerobic bacteria are the most commonly isolated pathogens. We report a previously healthy female without predisposing factors, presenting with a bifrontal cerebritis caused by a Streptococcus anginosus group infection. The patient developed a brain abscess and a subdural collection with severe intracranial hypertension of fatal evolution. The etiologic diagnosis was made culturing the material obtained from the subdural collection. It is presumed that, within the Streptococcus anginosus group, Streptococus intermedius could have been the causing bacteria, given its central nervous system tissue tropism and its predisposition to form brain abscesses. PMID- 23732423 TI - Neuro-Behcet: differential diagnosis of recurrent meningitis. AB - Behcet disease is a systemic inflammatory perivasculitis characterized by recurrent episodes of oral and genital ulcers associated with skin and ocular lesions. Neurological involvement occurs in 5 to 10% of the cases, and isolated meningeal involvement is very uncommon. We report a 21 years old man with a Behcet disease and a history of acute meningeal syndrome in two previous crises and meningoencephalitis in three others. He reported a history of conjunctivitis and oral and genital ulcers. On examination, he presented oral aphthoid lesions, macular edema, involvement of cranial nerves, pyramidal signs and meningeal irritation. The cell count in cerebrospinal fluid was 1800 cells/mm3, with polymorphonuclear predominance. Magnetic resonance imaging showed lesions in basal ganglia and the brainstem. The patient improved dramatically after intravenous steroid therapy. PMID- 23732424 TI - [Parochial hospital of San Bernardo, Chile: serving the community for over a century]. AB - The Parochial Hospital of San Bernardo is an intermediate complexity hospital that functions in its original 115- year- old building. It is one of the oldest hospitals in the country. Driven by the local Catholic Church and despite multiple difficulties, the hospital has uninterruptedly served a progressively growing community, with medical care and spiritual support. In the last two decades, it also has incorporated teaching activities with Universidad de los Andes Medical School. PMID- 23732425 TI - [The new law on patient rights: changing the relationship between patient and physician]. PMID- 23732426 TI - [Medical students' scientific societies: a driving force for research]. PMID- 23732427 TI - [When was the term Internal Medicine born?]. PMID- 23732428 TI - Mandibular alveolar reconstruction using three-dimensional planning. AB - PURPOSE OF REVIEW: Resection of malignant disease often results in full-thickness segmental defects of the mandible and loss of dentition. Ideal rehabilitation of the patient requires replacement of the missing segment with vascularized bone that will receive dental implants, and allow osseointegrated prosthetic rehabilitation and restoration of dentition and proper occlusion. Inexact contouring of the bony reconstruction can result in both cosmetic and functional defects that can diminish the future quality of life of the patient. This review summarizes recent advances in preoperative planning and intraoperative techniques that can maximize the success of proper alveolar reconstruction and dental restoration of the patient suffering a segmental maxillary or mandibular defect. RECENT FINDINGS: Preoperative modeling can be achieved with computer software that utilizes patient imaging. From this imaging, anticipated surgical defects can be planned, models can be generated, and intraoperative templates can be produced. These can be used to improve reconstructive plate bending, relative positioning of bone to opposing jaw, contouring of the reconstructive bone, and even placement of osseointegrated implants in a single operative setting. SUMMARY: In patients with complex mandibular defects, the use of computer assisted three-dimensional planning and modeling can result in time-saving and improved outcomes during maxillary and mandibular reconstruction. PMID- 23732429 TI - Triage in accident and emergency departments and possible outlets for patients with less-than-urgent medical problems. PMID- 23732430 TI - Clinical Epidemiology Workshop 12--Appraising a systematic review with meta analysis. PMID- 23732431 TI - Spontaneous carotid cavernous fistula complicating pregnancy. AB - Carotid cavernous fistula is a well-documented but rare condition in pregnancy, about which there are a limited number of reports in the literature. We report such a case in a 41-year-old woman presenting with right-sided headache, proptosis, and diplopia at 37 weeks of gestation. She was subsequently diagnosed to have carotid cavernous fistula based on angiography. Embolisation was performed in the postpartum period. Carotid cavernous fistula has the potential of serious morbidity including visual loss and intracranial haemorrhage. It can be treated effectively by endovascular embolisation, which confers a good prognosis. Although headache is a common complaint during pregnancy, obstetrician should be aware of this condition if the clinical presentation is suspicious. PMID- 23732432 TI - Hand, foot and mouth disease in an immunocompetent adult due to Coxsackievirus A6. AB - Hand, foot and mouth disease most commonly occurs in children less than 10 years old, but can occur in immunocompetent adults. We describe a 37-year-old immunocompetent man who presented with multiple painful papules and vesicles on his palms and feet together with vesicles inside the mouth. Real-time polymerase chain reaction revealed Coxsackievirus A6 in the vesicle fluid from the feet, throat swab, and rectal swab. Since the disease is highly contagious, to contain the infection it is prudent to recognise that hand, foot and mouth disease can occur in immunocompetent adults. PMID- 23732433 TI - Congenital pseudarthrosis of the clavicle: a rare and challenging diagnosis. AB - Congenital pseudarthrosis of the clavicle is a rare clinical entity, first described in 1910. We report on a newborn baby girl who presented with a painless lump over mid-portion of right clavicle at her routine newborn examination, which was subsequently diagnosed as a congenital pseudarthrosis. Here we explore its pathogenesis, elaborate on its differential diagnoses in paediatric patients, and comment on its distinct radiological features. PMID- 23732434 TI - Late presentation of simple virilising 21-hydroxylase deficiency in a Chinese woman with Turner's syndrome. AB - Classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a well-known disorder of sexual development (previously known as ambiguous genitalia) in genotypic female neonates. We report on a 66-year-old Chinese, brought up as male, with a simple virilising form of congenital adrenal hyperplasia associated with Turner's syndrome (karyotype 45,X/47,XXX/46,XX). His late presentation was recognised due to his exceptionally short stature and persistent sexual ambiguity. His condition was only brought to medical attention as he developed a huge abdominal mass, which later turned out to be a benign ovarian mucinous cyst. It is therefore important to look out for co-existing congenital adrenal hyperplasia in patients with Turner's syndrome and virilisation, after the presence of Y chromosome material has been excluded. PMID- 23732435 TI - Diagnosis of dihydropyrimidinase deficiency in a Chinese boy with dihydropyrimidinuria. AB - Dihydropyrimidinase deficiency is an autosomal recessive inborn error of metabolism characterised by the presence of dihydropyrimidinuria. Its clinical presentation is variable and has also been reported in asymptomatic subjects. We report the first case of dihydropyrimidinase deficiency in Hong Kong, which is also the first reported in a Chinese subject. The patient was a 32-month-old boy who presented with language development delay. Biochemical analysis confirmed markedly increased urinary excretion of dihydrouracil and dihydrothymine, whilst DNA testing confirmed that the patient was compound heterozygous for two missense mutations, one known (p.R302Q) and the other was novel (p.N16K). PMID- 23732436 TI - Eyelid tumours and pseudotumours in Hong Kong. PMID- 23732437 TI - Authors' reply. PMID- 23732438 TI - Sonographic characteristics of hepatic schistosomiasis: a rare cause of diffuse liver parenchymal disease. PMID- 23732440 TI - Participation by different stakeholders in participatory evaluation of health promotion: a literature review. AB - Participatory evaluation has been increasingly used in health promotion (HP) and various forms of participatory evaluation have been put into practice. Simultaneously, the concept of participation has become more important for evaluation research in general, which is equally diverse and the subject of various discourses. This study addresses the issue of how the concept of participation has been established in HP evaluation practice. An analytical framework was developed, which served as a basis for a literature review, but can also be used as a general framework for analyzing and planning the scope of participation by various stakeholders within different phases of participatory evaluation. Three dimensions of participation, which refer to decision making (decision power, deliberation) and action processes are distinguished. The results show that only a few articles discussed participatory evaluation processes and participatory (evaluation) research was largely put forth by participatory (action) research in communities. The articles analyzed referred mostly to three stakeholder groups - evaluators, program staff and beneficiaries and to participation processes in the initial evaluation phases. The application of the framework revealed that decision power seems to be held predominantly by program staff, evaluators seem to be more involved in action processes and beneficiaries in deliberation processes. PMID- 23732439 TI - A young woman with mucocutaneous pigmentation and intestinal polyps. PMID- 23732441 TI - Analysis of an alternative to the H-atom abstraction mechanism in methane C-H bond activation by nonheme iron(IV)-oxo oxidants. AB - The triplet delta-mechanism different from the previously reported ones, i.e., the pi-channel with the unoccupied pi(xz/yz)* (FeO) orbital and the sigma-channel involving the unoccupied alpha-spin Fe(z2)*-sigma orbital, has been theoretically described for the methane hydroxylation by [Fe(IV) = O(TMC)(SR)](+) and its derivative [Fe(IV) = O(TMC)(OH)](+) complex for the first time, and we have undertaken a detailed DFT study on the nature of this state by probing its geometry, electronic property and reactivity in comparison to all other possibilities. DFT calculations indicate that the electron transfer for the (3)delta-channel from the sigma(C-H) orbital of the substrate to the final acceptor sigma(x2-y2)* orbital of the catalyst occurs through a complex mechanism, which is initiated by the original alpha-spin electron transfer from the pi* orbital of the catalyst to the sigma(x2-y2)* orbital, where the alpha spin electron from the sigma(C-H) orbital of the substrate shifts to the just empty alpha-spin pi* orbital of the catalyst via the O-p(x/y) based pi(xz/yz)* orbital concomitantly. It is also found that the electron-donating ability of the axial ligand could influence the reaction channels, evident by the distinction that the electron-deficient F(-) and CF3CO2(-) ligands react via the (3)sigma channel, whereas the electron-rich SR(-) and OH(-) ligands proceed by the (3)delta-channel. With respect to reactivity, the (3)delta-pathway has a comparable barrier to the (3)pi and (5)pi-pathways, which may offer a new approach for the specific control of C-H bond activation by the iron(IV)-oxo species. PMID- 23732442 TI - Myelodysplastic syndrome with ider(20q) and prominent emperipolesis. PMID- 23732443 TI - The spatial pattern of leaf phenology and its response to climate change in China. AB - Leaf phenology has been shown to be one of the most important indicators of the effects of climate change on biological systems. Few such studies have, however, been published detailing the relationship between phenology and climate change in Asian contexts. With the aim of quantifying species' phenological responsiveness to temperature and deepening understandings of spatial patterns of phenological and climate change in China, this study analyzes the first leaf date (FLD) and the leaf coloring date (LCD) from datasets of four woody plant species, Robinia pseudoacacia, Ulmus pumila, Salix babylonica, and Melia azedarach, collected from 1963 to 2009 at 47 Chinese Phenological Observation Network (CPON) stations spread across China (from 21 degrees to 50 degrees N). The results of this study show that changes in temperatures in the range of 39-43 days preceding the date of FLD of these plants affected annual variations in FLD, while annual variations in temperature in the range of 71-85 days preceding LCD of these plants affected the date of LCD. Average temperature sensitivity of FLD and LCD for these plants was -3.93 to 3.30 days degrees C(-1) and 2.11 to 4.43 days degrees C-1, respectively. Temperature sensitivity of FLD was found to be stronger at lower latitudes or altitude as well as in more continental climates, while the response of LCD showed no consistent pattern. Within the context of significant warming across China during the study period, FLD was found to have advanced by 5.44 days from 1960 to 2009; over the same period, LCD was found to have been delayed by 4.56 days. These findings indicate that the length of the growing season of the four plant species studied was extended by a total of 10.00 days from 1960 to 2009. They also indicate that phenological response to climate is highly heterogeneous spatially. PMID- 23732444 TI - [Swissness]. PMID- 23732445 TI - [Travel medicine -- more than an immunization checklist]. PMID- 23732446 TI - [Pre travel advice - a study among Swiss general practitioners]. AB - Up to 65 % of travellers seek pre-travel advice at their general practitioner. Professionals should inform about the most common and most dangerous health threats, requiring up-to-date knowledge about epidemiology of respective disorders. The aim of the present study was to investigate the content of pre travel advice given by general practitioners in order to provide them with better expert support from travel medicine specialists. One third of them perform pre travel advice weekly, and some two thirds do so at least monthly. The most frequently discussed topics are malaria, immunisation, insect bite prevention and travellers' diarrhoea. Less than half of the advice sessions included talking about the risk of accidents. Apart from the need for yellow fever vaccination, referral to travel medicine experts was highest for immunocompromised and pregnant travellers, and for trips to "high risk" countries. A considerable number of practitioners do not comply with the Swiss recommendations, continuously updated in the Bulletin of the Federal Office of Public Health, possibly because only 21 % consult them at regular intervals. PMID- 23732447 TI - [Accidents in travellers - the hidden epidemic]. AB - The risk of malaria and other communicable diseases is well addressed in pre travel advice. Accidents are usually less discussed. Thus, we aimed at assessing accident figures for the Swiss population, based on data of the register from 2004 to 2008 of the largest Swiss accident insurance organization (SUVA). More than 139'000 accidents over 5 years showed that 65 % of the accidents overseas are injuries, and 24 % are caused by poisoning or harm by cold, heat or air pressure. Most accidents happened during leisure activities or sports. More than one third of the non-lethal and more than 50 % of the fatal accidents happened in Asia. More than three-quarters of non-lethal accidents take place in people between 25 and 54 years. One out of 74 insured persons has an accident abroad per year. Despite of many analysis short-comings of the data set with regard to overseas travel, the figures document the underestimated burden of disease caused by accidents abroad and should affect the given pre-health advice. PMID- 23732448 TI - [Malaria and children who travel - prophylaxis and therapy]. AB - Children account for between 15 - 20 % of all imported malaria cases worldwide. Immigrant children visiting their families in the country of origin in sub Saharan Africa are at highest risk. Prevention of malaria in children who travel to endemic areas is guided by the ABCD principles - Awareness of risk, Bite prevention, Chemoprophylaxis for high risk areas and rapid Diagnosis and treatment when malaria is suspected. The use of anti-malarial medication in small children is hampered by a paucity of dosage, pharmcokinetic and tolerability data. In the pre-travel consultation parents should be provided with practical advice on anti-mosquito measures, exact, (weight-based) dosages of chemoprophylaxis medication and/or stand-by treatment as indicated. A paediatric formulation is available for daily atovaquone-proguanil chemoprophylaxis (children > 11 kg) and mefloquine is a cost-effective, once weekly prophylaxis that is useful for children > 5 kg who travel for longer periods. The bitter taste of mefloquine should be disguised to increase adherence. When a Stand-by Emergency Treatment (SBET) is indicated, artemether-lumefantrine cherry flavoured dispersible tablets are a good choice for small children. Post-travel to endemic areas, malaria should always be suspected if a child becomes ill. Paediatric malaria is an emergency requiring prompt diagnosis and appropriate treatment. PMID- 23732449 TI - [Skin diseases in travellers returning from tropical countries]. AB - The most frequently observed skin lesions in travellers returning from tropical countries are insect bite reactions, bacterial skin diseases, creeping eruption and allergic reactions. The article describes these most relevant diseases and their differential diagnosis focussing on the diseases, which are potentially dangerous and which should not be missed, such as resistant staphylococci, chancre of rickettsia or sleeping sickness, cutaneous leishmaniasis or worms, which are not limited to the skin. PMID- 23732450 TI - [Special souvenirs after a trip to the tropics - the diagnosis of tissue helminths]. AB - A case history after a trip to a tropical country documents the diagnostic tools (parasitology, PCR, serology) to detect a tissue helminth infection. PMID- 23732451 TI - [High altitude related health problems in travel medicine]. AB - Giving travel advice to travellers visiting high-altitude destinations around the globe is daily routine in travel clinics. However, with the classical focus on vaccinations, traveller's diarrhoea, mosquito protection and malaria prophylaxis, altitude-related health problems are often neglected at counselling. The importance to communicate these problems when giving travel advice is impressively reflected by the high prevalence of altitude-related health problems among tourists visiting high-lying tourist destinations. This article aims at providing an overview of core aspects of acclimatization to altitude and prevention of altitude-related health problems and to exemplarily address practice-oriented problem destinations. PMID- 23732452 TI - [Mass gatherings - health risks and preventive strategies]. AB - Experience from mass gatherings - usually attended by at least 25'000 persons - shows that approximately one in a thousand participants will consult with an on site medical emergency service. Communicable diseases usually play a minor role. Historically outbreaks of meningococcal disease were recorded after the hajj, but this has been well controlled in the past few years subsequent to vaccinations and other measures required by the Kingdom of Saudi Arabia health authorities. Major stress of the regional public health system is associated with accidents and non-communicable diseases, the majority being trivial. Host and environmental risk factors can result in a dramatic increase in the rate of consultations: Age and pre-existing illness play a decisive role particularly in pilgrims, be that in Mecca or Lourdes. Emotional factors may influence behavior; aggressions can develop. Alcohol and drugs, also the duration of an event may play a decisive role. Extreme climatic conditions, both heat and cold, also exhaustion result in a dramatic increase of emergency consultations. Infrastructure must be adapted for the crowd size, particularly stampede associated disasters can be avoided. The World Health Organization and other interested expert groups have in the past few years formulated interdisciplinary programs for prevention. PMID- 23732453 TI - [En route in Switzerland - tick-borne and hantavirus infections]. AB - Tick-borne infections are endemic in Switzerland with borreliosis being the most frequent one, followed by the vaccine-preventable tick-borne encephalitis and more rarely by anaplasmosis, rickettsioses and babesiosis. Short characteristics of these infections are presented. The main preventive measures for stays in endemic regions include not leaving forest tracks and wearing closely fitted clothes and shoes, impregnated with an insecticide. Following at-risk activities, clothes as well as the body should be searched for ticks and they have to be removed using a tick removing tool. The body area of the tick bite has to be observed and a physician visit is strongly urged in case of rising fever and/or of erythema migrans. Hantavirus infections: Nephropathia epidemica is a zoonosis caused by the Puumala type of hantavirus and transmission occurs by inhaling aerolized excretions of the bank vole. There is no known human to human transmission. The incidence of this infection varies in a cyclic fashion and typical clinical symptoms include sudden onset of fever, headache, abdominal and back pain and transient renal impairment with initial oliguria and later polyuria. At-risk activities include camping and cleaning of rodent infestations. In these cases, face masks should be worn and the excretions be moistened before cleaning is started. In Germany, 2 - 3 years-cycles of outbreaks were observed between 2005 and 2012 with regional clusters approaching Switzerland. Therefore, disease awareness of physicians and infection surveillance are essential. PMID- 23732454 TI - [Adventure travel]. AB - Extreme travelling experiences appear to be a quite popular kick offered by tourist operators and sought by some travellers. But some travellers expose themselves to increased risk also during normal holidays, either voluntarily by booking hikes or tours leading them to adventurous locations or to unexpectedly encountering dangerous situations. In planned adventures, precise information in advance, good physical condition, careful planning, and profound medical preparation may contribute to a less hazardous adventure. Advising medical persons may need an expert consultation for specific topics in order to optimise the preparation. Based on three specific environmental situations (jungle, desert, and cave) the specific conditions, dangers and some medical aspects are outlined. PMID- 23732455 TI - [Travel destinations South America]. AB - The number of tourists visiting South America comprises only a small fraction of the worldwide stream of international travellers (approx. 980 Mio. in 2011). Nevertheless, their number has markedly increased in the last years (2000: 15.3 Mio.; 2005: 18.3 Mio.; 2010: 23.6 Mio.; 2011: 26.1 Mio.) and in 2011, South America was ranked top in the list of worldwide travel destinations with the highest increase in annual international tourist arrivals (10.4 %)[1]. This article aims at providing a practice-oriented overview on vaccinations, malaria prophylaxis, and other relevant health risks to be considered when counselling travellers visiting South America. PMID- 23732456 TI - [Travel destination Asia]. AB - Asia is one the most favourite travel destinations of Swiss travellers. Pre travel counselling of travellers going to Asia is therefore also very common for general practitioners. This article aims to give an overview of possible health problems and their prevention while travelling to Asia. PMID- 23732457 TI - Novel platinum-acetylide metallocycles constructed via a stepwise fragment coupling approach and their aggregation behaviour. AB - Through a stepwise fragment coupling approach, a family of novel platinum acetylide metallocycles with well-defined shape and size were successfully constructed. Their aggregation behavior was investigated. PMID- 23732458 TI - Cardiovascular disease: The price of a QALY--cost-effectiveness of statins in CKD. PMID- 23732459 TI - Dialysis: Heparin-free haemodialysis--use and outcomes. PMID- 23732460 TI - Dialysis: Small solute uraemic toxin generation and adequacy of dialysis. PMID- 23732461 TI - Differential vulnerability of adult neurogenesis by adult and prenatal inflammation: role of TGF-beta1. AB - Peripheral inflammation, both during the prenatal period and in adulthood, impairs adult neurogenesis. We hypothesized that, similar to other programming effects of prenatal treatments, only prenatal inflammation causes long-term consequences in adult neurogenesis and its neurogenic niche. To test this, pregnant Wistar rats were subcutaneously injected with lipopolysaccharide (LPS; 0.5 mg/kg) or saline solution every other day from gestational/embryonic day (GD) 14-20. In addition adult animals were injected with a single intraperitoneal saline or LPS injection (1 mg/kg) and the effects on neurogenesis were assessed 7 days later. Alternatively, to evaluate long-term consequences of adult LPS injections, LPS (1 mg/kg) was administered peripherally to adult rats four times every other day, and the effects on neurogenesis were assessed 60 days later. Prenatal and adult LPS treatments reduced adult neurogenesis and provoked specific microglial (but not astroglial) activation in the dentate gyrus (DG). However, only prenatal inflammation-mediated effects were long-lasting (at least 60 days). Moreover, these effects were specific to the DG since the Subventricular Zone (SVZ) and the Rostral Migratory Stream (RMS) were not affected. In addition, these stimuli caused differential effects on the molecular components of the neurogenic niche; only prenatal LPS treatment reduced the local levels of TGF-beta1 mRNA in the DG. Finally, TGF-beta1 exerted its pro-neurogenic effects via the Smad 2/3 pathway in a neural stem cell culture. Taken together, these data add evidence to the duration, regional specificity and dramatic consequences of prenatal immune programming on CNS physiology, compared with the limited response observed in the adult brain. PMID- 23732463 TI - A new luminol chemiluminescence sensor for glucose based on pH-dependent graphene oxide. AB - In this study, graphene oxide (GO) was found to catalyze the luminol-O2 reaction, which yielded a novel chemiluminescence (CL). Remarkably, the CL emission could be tuned by modulating the pH of the GO dispersion. Transmission electron microscopy, CL spectra, electron spin resonance spectra studies were carried out to investigate the CL mechanism. The results indicate that the CL emission was attributed to the intrinsic catalytic effect of GO acting as the radical generation proliferators and electron transfer accelerators. Based on the GO catalyzed luminol-O2 system, we successfully developed a new CL sensor to detect glucose. Under the optimized conditions, glucose could be assayed in the range of 0.05 mM to 5 mM with a detection limit of 0.044 mM. For the detection of clinical serum samples, it is well consistent with the data determined by commercially available method in hospital, indicating that the new CL method provides a possible application for the detection of glucose in clinical diagnostics. PMID- 23732462 TI - Ewing's sarcoma of the larynx. Effective treatment with organ preservation. AB - Extraskeletal Ewing's sarcoma arising in the head and neck region is an extremely rare malignant neoplasm. We describe the unusual case of a tumor originating in the larynx of a 68-year-old male with hoarseness and occasional aphonia. We report successful treatment with sequential chemo- and radiotherapy. Complete regression and larynx preservation with voice function recovery was achieved. To our knowledge, this is the first report of this type of tumor in the larynx with cartilage invasion that documents the effectiveness of radiotherapy as an alternative to surgical management. At present, after 30 months of follow-up, the patient is free of tumor relapse and in very good condition. PMID- 23732464 TI - Improving quality of care in peptic ulcer bleeding: nationwide cohort study of 13,498 consecutive patients in the Danish Clinical Register of Emergency Surgery. AB - OBJECTIVES: The treatment of peptic ulcer bleeding (PUB) is complex, and mortality remains high. We present results from a nationwide initiative to monitor and improve the quality of care (QOC) in PUB. METHODS: All Danish hospitals treating PUB patients between 2004 and 2011 prospectively registered demographic, clinical, and prognostic data. QOC was evaluated using eight process and outcome indicators, including time to initial endoscopy, hemostasis obtainment, proportion undergoing surgery, rebleeding risks, and 30-day mortality. RESULTS: A total of 13,498 PUB patients (median age 74 years) were included, of which one-quarter were in-hospital bleeders. Preadmission use of anticoagulants, multiple coexisting diseases, and the American Society of Anesthesiologists scores increased between 2004 and 2011. Considerable improvements were observed for most QOC indicators over time. Endoscopic treatment was successful with primary hemostasis achieved in more patients (94% in 2010-2011 vs. 89% in 2004-2006, relative risk (RR) 1.06 (95% confidence intervals 1.04-1.08)), endoscopy delay for hemodynamically unstable patients decreased during this period (43% vs. 34% had endoscopy within 6 h, RR 1.33 (1.10 1.61)), and fewer patients underwent open surgery (4% vs. 6%, RR 0.72 (0.59 0.87)). After controlling for time changes in prognostic factors, rebleeding rates improved (13% vs. 18%, adjusted RR 0.77 (0.66-0.91)). Crude 30-day mortality was unchanged (11% vs. 11%), whereas adjusted mortality decreased nonsignificantly over time (adjusted RR 0.89 (0.78-1.00)). CONCLUSIONS: QOC in PUB has improved substantially in Denmark, but the 30-day mortality remains high. Future initiatives to improve outcomes may include earlier endoscopy, having fully trained endoscopists on call, and increased focus on managing coexisting disease. PMID- 23732465 TI - Randomized study of two endo-knives for endoscopic submucosal dissection of esophageal cancer. AB - OBJECTIVES: Settings for endoscopic submucosal dissection (ESD) of esophageal cancer have not been standardized, and no studies have directly compared ESD devices in humans. METHODS: We conducted a randomized study to compare the performances of two different endo-knives, the Flush knife and Mucosectom, for esophageal ESD in 48 lesions. All procedures were initiated by two endoscopists, who were assisted by senior endoscopists with verbal advice. In the Flush-knife group, mucosal incision with a 2-mm Flush knife was followed by submucosal dissection using a 1-mm Flush knife. In the Mucosectom group, mucosal incision with a 2-mm Flush knife was followed by submucosal dissection with a Mucosectom. The primary outcome variable was the procedure time required for submucosal dissection. The secondary outcome variables were total procedure time, self completion rates, and adverse events. RESULTS: Total procedure time in the Mucosectom group was significantly shorter than in the Flush-knife group (57+/-21 vs. 83+/-27 min, respectively; P<0.001). The submucosal-dissection time in the Mucosectom group was significantly shorter than in the Flush-knife group (40+/-18 vs. 61+/-23 min, respectively; P<0.001). The self-completion rate in the Mucosectom group was slightly higher than in the Flush-knife group, but the difference was not significant (91.7% vs. 75%, respectively; P=0.25). One perforation and one postoperative bleeding occurred in the Flush-knife group, both of which were treated successfully by endoscopic treatment. CONCLUSIONS: The Mucosectom reduced the procedure and submucosal-dissection times of esophageal ESD, without increasing adverse events. PMID- 23732466 TI - CYP3A4-catalyzed simvastatin metabolism as a non-invasive marker of small intestinal health in celiac disease. AB - OBJECTIVES: Histological examination of duodenal biopsies is the gold standard for assessing intestinal damage in celiac disease (CD). A noninvasive marker of disease status is necessary, because obtaining duodenal biopsies is invasive and not suitable for routine monitoring of CD patients. As the small intestine is a major site of cytochrome P450 3A4 (CYP3A4) activity and also the location of the celiac lesion, we investigated whether patients with active CD display abnormal pharmacokinetics of an orally administered CYP3A4 substrate, simvastatin (SV), which could potentially be used for noninvasive assessment of their small intestinal health. METHODS: Preclinical experiments were performed in CYP3A4 humanized mice to examine the feasibility of the test. Subsequently, a clinical trial was undertaken with 11 healthy volunteers, 18 newly diagnosed patients with CD, and 25 celiac patients who had followed a gluten-free diet (GFD) for more than 1 year. The maximum concentration (Cmax) of orally administered SV plus its major non-CYP3A4-derived metabolite SV acid (SV equivalent (SVeq)) was measured, and compared with clinical, histological, and serological parameters. RESULTS: In CYP3A4-humanized mice, a marked decrease in SV metabolism was observed in response to enteropathy. In the clinical setting, untreated celiac patients displayed a significantly higher SVeq Cmax (46+/-24 nM) compared with treated patients (21+/-16 nM, P<0.001) or healthy subjects (19+/-11 nM, P<0.005). SVeq Cmax correctly predicted the diagnosis in 16/18 untreated celiac patients, and also the recovery status of all follow-up patients that exhibited normal or near normal biopsies (Marsh 0-2). All patients with abnormal SVeq Cmax showed a reduction in the value after 1 year of following a GFD. CONCLUSIONS: SVeq Cmax is a promising noninvasive marker for assessment of small intestinal health. Further studies are warranted to establish its clinical utility for assessing gut status of patients with CD. PMID- 23732467 TI - Mortality risk according to different clinical characteristics of first episode of liver decompensation in cirrhotic patients: a nationwide, prospective, 3-year follow-up study in Italy. AB - OBJECTIVES: The occurrence of decompensation marks a crucial turning point in the course of cirrhosis. The purpose of this study was to assess the risk of mortality according to the clinical characteristics of first decompensation, considering also the impact of acute-on-chronic liver failure (AoCLF). METHODS: We conducted a prospective nationwide inception cohort study in Italy. Decompensation was defined by the presence of ascites, either overt or detected by ultrasonography (UD), gastroesophageal variceal bleeding (GEVB), and hepatic encephalopathy (HE). AoCLF was defined according to the Asian Pacific Association for the Study of the Liver criteria. Multivariable Cox proportional hazards regression was used to analyze the risk of failure (death or orthotopic liver transplantation (OLT)). RESULTS: A total of 490 consecutive cirrhotic patients (314 males, mean age 60.9+/-12.6 years) fulfilled the study criteria. AoCLF was identified in 59 patients (12.0%). Among the remaining 431 patients, ascites were found in 330 patients (76.6%): in 257 (77.8%) as overt ascites and in 73 (22.2%) as UD ascites. GEVB was observed in 77 patients (17.9%) and HE in 30 patients (7.0%). After a median follow-up of 33 months, 24 patients underwent OLT and 125 died. The cumulative incidence of failure (death or OLT) after 1, 2, and 3 years was, respectively, 28, 53, and 62% in patients with AoCLF; 10, 18, and 25% in patients with UD ascites; 17, 31, and 41% in patients with overt ascites; and 8, 12, and 24% in patients with GEVB (P<0.0001). CONCLUSIONS: AoCLF is responsible for a relevant proportion of first decompensation in cirrhotic patients and is associated with the poorest outcome. Patients with UD ascites do not have a negligible mortality rate and require clinical monitoring similar to that of patients with overt ascites. PMID- 23732468 TI - Associated lesions in posterior wall acetabular fractures: not a valid predictor of failure. AB - BACKGROUND: The general outcome of posterior wall acetabular fractures is still the source of discussion. Posterior wall fractures are recognized throughout the literature as being difficult to treat. The aim of the present study was to analyze in our own patients the relevance of the classical prognostic criteria for the outcome of isolated posterior wall fractures and those with associated lesions. MATERIALS AND METHODS: A prospective cohort of 33 consecutive patients treated operatively between 1996 and 2006 in a single level 1 trauma center for a posterior wall fracture of the acetabulum was analyzed retrospectively. Included were posterior wall acetabular fractures or associated posterior wall fractures, such as the combinations of posterior column with posterior wall, transverse with posterior wall, or T-shaped fracture with posterior wall fracture. Outcome measurement of the postoperative survival of the hip joints until the primary outcome reoperation (total hip replacement or fusion) and secondary outcome diagnosis of symptomatic osteoarthritis were performed. RESULTS: Twenty-six of the 33 patients with posterior wall fractures also had a dislocated joint. Twelve had isolated and 21 associated fractures. Six patients were reoperated with a THA (four patients within 2 years and one after 10 years), and one arthrodesis was done to treat a hematogenous septic arthritis in a degenerative hip joint. Secondary arthritis was observed in 10 patients. CONCLUSIONS: No difference was found between the outcome in cases of isolated posterior wall acetabular fracture and the outcome in those with associated lesions. The classical prognostic criteria were not found to be relevant to the outcome for our group. PMID- 23732469 TI - Cellular mechanisms controlling caspase activation and function. AB - Caspases are the primary drivers of apoptotic cell death, cleaving cellular proteins that are critical for dismantling the dying cell. Initially translated as inactive zymogenic precursors, caspases are activated in response to a variety of cell death stimuli. In addition to factors required for their direct activation (e.g., dimerizing adaptor proteins in the case of initiator caspases that lie at the apex of apoptotic signaling cascades), caspases are regulated by a variety of cellular factors in a myriad of physiological and pathological settings. For example, caspases may be modified posttranslationally (e.g., by phosphorylation or ubiquitylation) or through interaction of modulatory factors with either the zymogenic or active form of a caspase, altering its activation and/or activity. These regulatory events may inhibit or enhance enzymatic activity or may affect activity toward particular cellular substrates. Finally, there is emerging literature to suggest that caspases can participate in a variety of cellular processes unrelated to apoptotic cell death. In these settings, it is particularly important that caspases are maintained under stringent control to avoid inadvertent cell death. It is likely that continued examination of these processes will reveal new mechanisms of caspase regulation with implications well beyond control of apoptotic cell death. PMID- 23732471 TI - Mechanisms of mitochondrial fission and fusion. AB - Mitochondria continually change shape through the combined actions of fission, fusion, and movement along cytoskeletal tracks. The lengths of mitochondria and the degree to which they form closed networks are determined by the balance between fission and fusion rates. These rates are influenced by metabolic and pathogenic conditions inside mitochondria and by their cellular environment. Fission and fusion are important for growth, for mitochondrial redistribution, and for maintenance of a healthy mitochondrial network. In addition, mitochondrial fission and fusion play prominent roles in disease-related processes such as apoptosis and mitophagy. Three members of the Dynamin family are key components of the fission and fusion machineries. Their functions are controlled by different sets of adaptor proteins on the surface of mitochondria and by a range of regulatory processes. Here, we review what is known about these proteins and the processes that regulate their actions. PMID- 23732472 TI - Mitochondrial trafficking in neurons. AB - Neurons, perhaps more than any other cell type, depend on mitochondrial trafficking for their survival. Recent studies have elucidated a motor/adaptor complex on the mitochondrial surface that is shared between neurons and other animal cells. In addition to kinesin and dynein, this complex contains the proteins Miro (also called RhoT1/2) and milton (also called TRAK1/2) and is responsible for much, although not necessarily all, mitochondrial movement. Elucidation of the complex has permitted inroads for understanding how this movement is regulated by a variety of intracellular signals, although many mysteries remain. Regulating mitochondrial movement can match energy demand to energy supply throughout the extraordinary architecture of these cells and can control the clearance and replenishing of mitochondria in the periphery. Because the extended axons of neurons contain uniformly polarized microtubules, they have been useful for studying mitochondrial motility in conjunction with biochemical assays in many cell types. PMID- 23732470 TI - Receptor tyrosine kinases in Drosophila development. AB - Tyrosine phosphorylation plays a significant role in a wide range of cellular processes. The Drosophila genome encodes more than 20 receptor tyrosine kinases and extensive studies in the past 20 years have illustrated their diverse roles and complex signaling mechanisms. Although some receptor tyrosine kinases have highly specific functions, others strikingly are used in rather ubiquitous manners. Receptor tyrosine kinases regulate a broad expanse of processes, ranging from cell survival and proliferation to differentiation and patterning. Remarkably, different receptor tyrosine kinases share many of the same effectors and their hierarchical organization is retained in disparate biological contexts. In this comprehensive review, we summarize what is known regarding each receptor tyrosine kinase during Drosophila development. Astonishingly, very little is known for approximately half of all Drosophila receptor tyrosine kinases. PMID- 23732474 TI - Replicative DNA polymerases. AB - In 1959, Arthur Kornberg was awarded the Nobel Prize for his work on the principles by which DNA is duplicated by DNA polymerases. Since then, it has been confirmed in all branches of life that replicative DNA polymerases require a single-stranded template to build a complementary strand, but they cannot start a new DNA strand de novo. Thus, they also depend on a primase, which generally assembles a short RNA primer to provide a 3'-OH that can be extended by the replicative DNA polymerase. The general principles that (1) a helicase unwinds the double-stranded DNA, (2) single-stranded DNA-binding proteins stabilize the single-stranded DNA, (3) a primase builds a short RNA primer, and (4) a clamp loader loads a clamp to (5) facilitate the loading and processivity of the replicative polymerase, are well conserved among all species. Replication of the genome is remarkably robust and is performed with high fidelity even in extreme environments. Work over the last decade or so has confirmed (6) that a common two metal ion-promoted mechanism exists for the nucleotidyltransferase reaction that builds DNA strands, and (7) that the replicative DNA polymerases always act as a key component of larger multiprotein assemblies, termed replisomes. Furthermore (8), the integrity of replisomes is maintained by multiple protein-protein and protein-DNA interactions, many of which are inherently weak. This enables large conformational changes to occur without dissociation of replisome components, and also means that in general replisomes cannot be isolated intact. PMID- 23732473 TI - DNA repair at telomeres: keeping the ends intact. AB - The molecular era of telomere biology began with the discovery that telomeres usually consist of G-rich simple repeats and end with 3' single-stranded tails. Enormous progress has been made in identifying the mechanisms that maintain and replenish telomeric DNA and the proteins that protect them from degradation, fusions, and checkpoint activation. Although telomeres in different organisms (or even in the same organism under different conditions) are maintained by different mechanisms, the disparate processes have the common goals of repairing defects caused by semiconservative replication through G-rich DNA, countering the shortening caused by incomplete replication, and postreplication regeneration of G tails. In addition, standard DNA repair mechanisms must be suppressed or modified at telomeres to prevent their being recognized and processed as DNA double-strand breaks. Here, we discuss the players and processes that maintain and regenerate telomere structure. PMID- 23732476 TI - Retrograde traffic from the Golgi to the endoplasmic reticulum. AB - Proteins to be secreted are transported from the endoplasmic reticulum (ER) to the Golgi apparatus. The transport of these proteins requires the localization and activity of proteins that create ER exit sites, coat proteins to collect cargo and to reshape the membrane into a transport container, and address labels- SNARE proteins--to target the vesicles specifically to the Golgi apparatus. In addition some proteins may need export chaperones or export receptors to enable their exit into transport vesicles. ER export factors, SNAREs, and misfolded Golgi-resident proteins must all be retrieved from the Golgi to the ER again. This retrieval is also part of the organellar homeostasis pathway essential to maintaining the identity of the ER and of the Golgi apparatus. In this review, I will discuss the different processes in retrograde transport from the Golgi to the ER and highlight the mechanistic insights we have obtained in the last couple of years. PMID- 23732475 TI - Lipid transport between the endoplasmic reticulum and mitochondria. AB - Mitochondria are partially autonomous organelles that depend on the import of certain proteins and lipids to maintain cell survival and membrane formation. Although phosphatidylglycerol, cardiolipin, and phosphatidylethanolamine are synthesized by mitochondrial enzymes, phosphatidylcholine, phosphatidylinositol, phosphatidylserine, and sterols need to be imported from other organelles. The origin of most lipids imported into mitochondria is the endoplasmic reticulum, which requires interaction of these two subcellular compartments. Recently, protein complexes that are involved in membrane contact between endoplasmic reticulum and mitochondria were identified, but their role in lipid transport is still unclear. In the present review, we describe components involved in lipid translocation between the endoplasmic reticulum and mitochondria and discuss functional as well as regulatory aspects that are important for lipid homeostasis. PMID- 23732478 TI - Scout-view assisted interior micro-CT. AB - Micro computed tomography (micro-CT) is a widely-used imaging technique. A challenge of micro-CT is to quantitatively reconstruct a sample larger than the field-of-view (FOV) of the detector. This scenario is characterized by truncated projections and associated image artifacts. However, for such truncated scans, a low resolution scout scan with an increased FOV is frequently acquired so as to position the sample properly. This study shows that the otherwise discarded scout scans can provide sufficient additional information to uniquely and stably reconstruct the interior region of interest. Two interior reconstruction methods are designed to utilize the multi-resolution data without significant computational overhead. While most previous studies used numerically truncated global projections as interior data, this study uses truly hybrid scans where global and interior scans were carried out at different resolutions. Additionally, owing to the lack of standard interior micro-CT phantoms, we designed and fabricated novel interior micro-CT phantoms for this study to provide means of validation for our algorithms. Finally, two characteristic samples from separate studies were scanned to show the effect of our reconstructions. The presented methods show significant improvements over existing reconstruction algorithms. PMID- 23732479 TI - Estimation of biological variation and reference change value of glycated hemoglobin (HbA(1c)) when two analytical methods are used. AB - OBJECTIVES: Available data on biological variation of HbA1c revealed marked heterogeneity. We therefore investigated and estimated the components of biological variation for HbA1c in a group of healthy individuals by applying a recommended and strictly designed study protocol using two different assay methods. DESIGN AND METHODS: Each month, samples were derived on the same day, for three months. Four EDTA whole blood samples were collected from each individual (20 women, 9 men; 20-45 years of age) and stored at -80 degrees C until analysis. HbA1c values were measured by both high performance liquid chromatography (HPLC) (Shimadzu, Prominence, Japan) and boronate affinity chromatography methods (Trinity Biotech, Premier Hb9210, Ireland). All samples were assayed in duplicate in a single batch for each assay method. Estimations were calculated according to the formulas described by Fraser and Harris. RESULTS: The within subject (CV(I))-between subject (CV(G)) biological variations were 1.17% and 5.58%, respectively for HPLC. The calculated CV(I) and CV(G) were 2.15% and 4.03%, respectively for boronate affinity chromatography. Reference change value (RCV) for HPLC and boronate affinity chromatography was 5.4% and 10.4% respectively and individuality index of HbA(1c) was 0.35 and 0.93 respectively. CONCLUSIONS: This study for the first time described the components of biological variation for HbA1c in healthy individuals by two different assay methods. Obtained findings showed that the difference between CV(A) values of the methods might considerably affect RCV. These data regarding biological variation of HbA(1c) could be useful for a better evaluation of HbA(1c) test results in clinical interpretation. PMID- 23732477 TI - Molecular mechanisms of fibroblast growth factor signaling in physiology and pathology. AB - Fibroblast growth factors (FGFs) signal in a paracrine or endocrine fashion to mediate a myriad of biological activities, ranging from issuing developmental cues, maintaining tissue homeostasis, and regulating metabolic processes. FGFs carry out their diverse functions by binding and dimerizing FGF receptors (FGFRs) in a heparan sulfate (HS) cofactor- or Klotho coreceptor-assisted manner. The accumulated wealth of structural and biophysical data in the past decade has transformed our understanding of the mechanism of FGF signaling in human health and development, and has provided novel concepts in receptor tyrosine kinase (RTK) signaling. Among these contributions are the elucidation of HS-assisted receptor dimerization, delineation of the molecular determinants of ligand receptor specificity, tyrosine kinase regulation, receptor cis-autoinhibition, and tyrosine trans-autophosphorylation. These structural studies have also revealed how disease-associated mutations highjack the physiological mechanisms of FGFR regulation to contribute to human diseases. In this paper, we will discuss the structurally and biophysically derived mechanisms of FGF signaling, and how the insights gained may guide the development of therapies for treatment of a diverse array of human diseases. PMID- 23732480 TI - Topologies of amyloidogenic proteins in Congo red-positive sliced sections of formalin-fixed paraffin embedded tissues by MALDI-MS imaging coupled with on tissue tryptic digestion. AB - OBJECTIVES: Matrix-assisted laser desorption time-of flight ionization (MALDI) imaging MS (IMS) with MSMS analysis using on-tissue tryptic digests is a powerful tool for identification of disease-related proteins in formalin-fixed paraffin embedded (FFPE) tissue sections. We applied this novel IMS technique, not only to identify tryptic peptides of deposited amyloidogenic proteins but also to clarify topologies of these proteins in amyloidosis tissue sections. METHODS: Sequence determinations of tryptic peptides derived from amyloidogenic proteins were performed using MALDI-MSMS analysis directly from Congo red positive regions in tissue sections with/without procedure for retrieval of epitopes before on-tissue digestion. RESULTS: Tryptic peptides, m/z=1073.5 and 1924.3 were identified with the sequences, from 48th to 56th and 1st to 19th positions of Ig lambda V-III region, respectively. Other peptides, m/z=1365.5 and 1523.5 were with the sequences, from 22nd to 34th and 36th to 48th positions of TTR, respectively. Heat-map images of all four tryptic peptides were overlapped with Congo red positive regions. Immunohistochemistry of FFPE tissue sections was confirmed to only react with anti-lambda chain antibody in a case of AL-type amyloidosis or anti-TTR antibody in two cases of TTR-type amyloidosis. CONCLUSION: IMS with MSMS analysis using on-tissue tryptic digestion enables us not only to identify amyloidogenic molecule in a sliced tissue section but also to play a complementary role with the conventional pathological examination. PMID- 23732481 TI - Anticancer activity of a synthetic peptide derived from harmoniasin, an antibacterial peptide from the ladybug Harmonia axyridis. AB - Harmoniasin is a defensin-like antimicrobial peptide identified from the ladybug Harmonia axyridis. Among the synthetic homodimer peptide analogues derived from harmoniasin, HaA4 has been found to have antibacterial activity without hemolytic activity. In this study, we investigated whether HaA4 has anticancer activity against human leukemia cell lines such as U937 and Jurkat cells. HaA4 manifested cytotoxicity and decreased the cell viability of U937 and Jurkat cells in MTS assay and LDH release assay. We found that HaA4 induced apoptotic and necrotic cell death of the leukemia cells using flow cytometric analysis, acridine orange/ethidium bromide staining and nucleosomal fragmentation of genomic DNA. Activation of caspase-7 and -9 and fragmentation of poly (ADP-ribose) polymerase was detected in the HaA4-treated leukemia cells, suggesting induction of a caspase-dependent apoptosis pathway by HaA4. Caspase-dependent apoptosis was further confirmed by reversal of the HaA4-induced viability reduction by treatment of Z-VAD-FMK, a pan-caspase inhibitor. In conclusion, HaA4 caused necrosis and caspase-dependent apoptosis in both U937 and Jurkat leukemia cells, which suggests potential utility of HaA4 as a cancer therapeutic agent. PMID- 23732483 TI - Effect of safeners on damage of human erythrocytes treated with chloroacetamide herbicides. AB - Chloroacetamides are used as pre-emergent substances for growth control of annual grasses and weeds. Since they can be harmful for crop plants, protective compounds (safeners) are used along with herbicides. So far, their effects on human blood cells have not been evaluated, and this study is the very first one devoted to this subject. We examined the harmful effects of chloroacetamides, their metabolites and safeners, used alone or in combination with herbicides, on human erythrocytes measuring the extent of hemolysis, lipid peroxidation and catalase activity. Higher impact of herbicides than their metabolites on all of the investigated parameters was found. Safeners alone did not produce any damage to erythrocytes and did not elicit any changes in oxidative stress parameters. Combination of safener with herbicide did not attenuate hemolysis of erythrocytes compared to the herbicide alone. Safeners reduced lipid peroxidation induced by herbicides, which suggest the role of safeners as antioxidants. PMID- 23732482 TI - Benzo(a)pyrene modulates fluoranthene-induced cellular responses in HT-29 colon cells in a dual exposure system. AB - Our environment is contaminated with a diverse array of chemicals; one of which is polycyclic aromatic hydrocarbons (PAHs). While some PAHs are potent by nature, others undergo interactions such as additivity, synergism, antagonism or potentiation to manifest their toxicity. Therefore, the objective of this study was to investigate whether exposure to benzo(a)pyrene (BaP), a PAH compound influences the cytotoxicity and metabolism of fluoranthene (FLA; another PAH compound) using HT-29 cells. Cells cultured in Dulbecco's Modified Eagle Medium were treated with 1, 5, 10, 25MUM BaP and FLA (0.01% dimethylsulfoxide as vehicle) individually and in combination over the course of 0-96h. At the end of exposure, cells were stained with propidium iodide and the changes in cell cycle were analyzed using FACS analysis. Apoptosis was determined by caspase-3 assay. Post-incubation, samples were extracted and analyzed for FLA metabolites by reverse-phase HPLC with fluorescence detection. Cells exposed to BaP+FLA showed a marginal decrease in growth as compared to FLA alone and vehicle controls. Also, a decline in the percentage of cells in the S and G2 phases compared to G1 phase of cell cycle was noted when cells were treated with BaP and FLA together, compared to individual FLA treatment. The rate of FLA metabolism was more when cells were exposed to FLA in combination with BaP, compared to FLA alone. The enhanced biotransformation of FLA as a result of concomitant exposure to BaP may have implications for colon cancer risks arising from human dietary exposure to PAH mixtures through consumption of barbecued meat. PMID- 23732484 TI - Immune response to acetaldehyde-human serum albumin adduct among healthy subjects related to alcohol intake. AB - Acetaldehyde (AA) is the main metabolic product in ethanol metabolism, although it can also derive from sources of airborne pollution. As a typical aldehyde, AA is able to react with a variety of molecular targets, including DNA and protein. This property justifies the hypothesis of a immune reaction against this kind of adduct, to be studied by a seroprevalence screening approach. In this study, the correlation between drinking habits and the amount of circulating AA-human serum albumin adduct (AA-HSA) was evaluated in a group of healthy subjects, non alcohol addicted. Daily ethanol intake (grams) was inferred for each subject using the information collected through a questionnaire, and AA-HSA antibodies (AA-HSA ab) analyses were performed using the Displacement Assay on whole blood samples. The findings showed a correlation between ethanol intake and immune response to molecular adduct. These results underscore the evaluation of AA-HSA ab amount as a suitable molecular marker for alcohol intake that can be applied in future investigations on a large scale for prevention screening. PMID- 23732485 TI - [Predictors of one year mortality among immunocompetent adults hospitalized for community-acquired pneumonia]. AB - BACKGROUND: Mortality increases in adults, especially in older adults, after recovery from an episode of community-acquired pneumonia (CAP). AIM: To analyze survival and predictors of death at one year follow up of a cohort of adult patients hospitalized with CAP. MATERIAL AND METHODS: Immunocompetent patients admitted to a clinical hospital for an episode of CAP were included in the study and were assessed according to a standardized protocol. One year mortality after admission was assessed using death records of the National Identification Service. Clinical and laboratory variables measured at hospital admission associated with risk of death at one year follow up were subjected to univariate and multivariate analysis by a logistic regression model. RESULTS: We evaluated 659 patients aged 68 +/- 19 years, 52% were male, 77% had underlying conditions (especially cardiovascular, neurological and respiratory diseases). Mean hospital length of stay was 9 days, 7.1% died during hospital stay and 15.8% did so during the year of follow-up. A causal agent was identified in one third of cases. The main pathogens isolated were Streptococcus pneumoniae (12.9%), Haemophilus influenzae (4.1%), respiratory viruses (6.5%) and Gram-negative bacilli (6.5%). In multivariate analysis, the clinical variables associated with increased risk of dying during the year of follow-up were older age, chronic neurological disease, malignancies, lack of fever at admission and prolonged hospital length of stay. CONCLUSIONS: Age, specific co-morbidities such as chronic neurological disease and cancer, absence of fever at hospital admission and prolonged hospital length of stay were associated with increased risk of dying during the year after admission among adult patients hospitalized with community-acquired pneumonia. PMID- 23732486 TI - [Vascular endothelial growth factor in malignant and non malignant prostatic tissue: Association with tumor recurrence at one year after prostatectomy]. AB - BACKGROUND: Prostate cancer (PC) is the second cause of death by cancer in men in Chile. Its behavior is so variable that it is necessary to search reliable prognostic markers. Vascular Endothelial Growth Factor (VEGF) is one of the most powerful pro-angiogenic factors. There is no agreement on its validity as a diagnostic or prognostic factor. AIM: To search for VEFG in prostatic tissue. MATERIAL AND METHODS: This study was performed in prostatectomy tissue coming from 41 patients with PC and 39 patients with benign prostatic hyperplasia (BPH). Specimens were studied using immunohistochemical staining for VEGF. The percentage of stained glandular cells per patient was calculated and associated with pathological diagnosis in cancer patients. RESULTS: PC biopsies had a mean of 82% of VEGF (+) stained cells, while BPH had only 1.6% (p < 0.01). No relationship was found between the percentage of staining and recurrence at one year of follow-up in the case of PC. CONCLUSIONS: These results would rule out VEGF as a prognostic factor in this series of patients. PMID- 23732487 TI - [Youth sexuality: behaviors, attitudes and differences by sex and personality variables in Chilean university students]. AB - BACKGROUND: Sexual behavior usually begins in adolescence, and is mediated by biological, personality and socio-cultural variables which can affect the expression of preventive and risky sexual performance, as well as sex and age differences. AIM: To determine sex differences in the age of sexual initiation, the use of protective methods and mate selectivity in young men and women, as well as preventive practices according to age, and the prevalence of partner aggression. SUBJECTS AND METHODS: Participants were 484 university students from public and private institutions, aged 22 +/- 3 years (59% women) assessed using a diversity of self-report measures of personality traits, romantic relationship quality, sexual role, attachment type, socio-sexual openness, and self-esteem; they also answered questions regarding sexual behavior, and violence. RESULTS: Differences in age of sexual initiation, risky sexual behavior, and socio-sexual openness were observed between men and women. Aggression prevalence in romantic relationships also varied according to sex and age. Similarities and differences in patterns of behavior and personality variables were observed in relationship quality, sexual role, kindness, and responsibility in males and females. CONCLUSIONS: The findings present consistencies with the international evidence and differences that may be due to context specificities, providing also an empirical referent to consider in health planning. PMID- 23732488 TI - [Willingness to pay for human papillomavirus vaccine in Metropolitan Santiago, Chile]. AB - BACKGROUND: Human papillomavirus (HPV) infection is a risk factor for cervical cancer and can be prevented with the HPV vaccine. AIM: To explore the willingness of parents to pay for HPV vaccine for their offspring. MATERIAL AND METHODS: A survey about the willingness to pay for HPV vaccine was answered by 386 individuals of the highest socioeconomic level who had a daughter aged between 12 and 18 years. The survey included information about the risks of HPV infection. RESULTS: Parents would pay a mean of US$ 758 for the vaccine. Twenty five percent of parents were not willing to pay for it. If the cost of the vaccine would be reduced by 50%, only 4% of parents would not pay for it. The willingness to pay is associated with the price of the vaccine, the income level of respondents and the size of the family. CONCLUSIONS: Most respondents would pay for HPV vaccine for their daughters, despite the relatively high cost. PMID- 23732489 TI - [Association of family support and knowledge about the disease with glycemic control in diabetic patients]. AB - BACKGROUND: Family interventions may improve glycemic control among diabetic patients AIM: To evaluate the association of glycemic control with family support and level of knowledge in patients with type 2 diabetes. MATERIAL AND METHODS: Patients with type 2 diabetes completed a demographic survey. Glycosylated hemoglobin (HbA1c) was determined and glycemic control was defined as a value < 6,5%. Two validated instruments were applied to evaluate family support, stratifying it in three categories (low, medium and high) and the level of knowledge about diabetes. RESULTS: We studied 81 patients aged 32 to 65 years (53 females). Thirty six percent had an adequate glycemic control. Participants with a medium family support had three times greater risk of having an uncontrolled blood glucose than subjects with high family support. No significant association was found between the level of knowledge and glycemic control. CONCLUSIONS: Family support but not knowledge about the disease is associated with a better glycemic control of patients with type 2 diabetes. PMID- 23732490 TI - [Sociodemographic/clinical characteristics and outcomes of patients admitted to the National Burn Center of Chile]. AB - BACKGROUND: Approximately 150 subjects per year suffer severe burns in Chile. AIM: To analyze sociodemographic/clinical features and outcomes of severely burned patients. MATERIAL AND METHODS: Retrospective cohort study of 936 patients aged 47 +/- 20 years (66% males), admitted to the National Burn Center of Chile between 2006 and 2010. Sociodemographic/clinical and burn variables and outcomes were studied. RESULTS: Mean total percentage of body surface area burned was 27 + 20%. A quarter of the patients had social features that could jeopardize rehabilitation. Fire was the burning agent in 73%, which along with electricity presented greater lethality (p < 0.01). Inhalation injury was diagnosed in 22% of the patients. Twenty eight percent of patients had impaired consciousness at the moment of the accident, leading to larger burns, higher incidence of inhalation injury and greater lethality. Lethality for severe, critical and exceptional survival groups was 8.4,37.7 and 70.4%, respectively. CONCLUSIONS: Severely burned patients in Chile are mainly males at working age. Fire is the main agent and 28% had impaired consciousness, which was associated with an increase in the severity of burns. Knowledge of the characteristics and outcomes of the patients is important to implement prevention and treatment strategies adjusted to the national reality. PMID- 23732492 TI - [Analysis of medication prescription in an Argentinian geriatric hospital]. AB - BACKGROUND: Although polypharmacy may be justified in elderly patients with multiple diseases, it may be dangerous, especially when it includes potentially inappropriate medications (PIM). AIM: To identify inappropriate medication and factors associated with the most relevant prescriptions among older people. MATERIAL AND METHODS: Cross-sectional observational analysis of drugs prescribed during the first trimester of 2010 to 179 older adults aged 77 +/- 8 years (98 women), living in a geriatric reference hospital in Argentina. The use of potentially inappropriate medications (PIM) in elderly patients was analyzed using Beers Criteria updated to 2012. RESULTS: The mean number of drugs prescribed per individual was 6.1 +/- 2.7. The most commonly used drugs were anti ulcer agents (58.1%), agents acting on the renin-angiotensin system (54.2%), antithrombotic medications (50.8%) and benzodiazepines (50.8 %). The use of antacids and anti-ulcer agents, psychotropic drugs and PIM was significantly higher among patients using six or more drugs daily, compared to the less medicated group (odds ratio (OR) = 6.8, 95% confidence intervals (CI) 3.5-13.2; OR=15.0, 95%CI 5.9-38.4; OR=5.0; 95%IC 2.6-9.8, respectively). Thirty one percent of participants using non-steroidal anti-inflammatory drugs, were not receiving medications for gastric protection. One to four drugs included in the Beers list were prescribed to 66% of participants. CONCLUSIONS: Despite the high prevalence of use of antacids and anti-ulcer agents, these drugs were not prescribed to a significant proportion of patients using non-steroidal anti-inflammatory drugs. Strategies to optimize pharmacotherapy in the elderly population are urgently required. PMID- 23732491 TI - [Characteristics of employment and wellbeing among physicians working in Santiago, Chile]. AB - BACKGROUND: Profound changes have been observed in medical practice during the last thirty years. This may be understood as a result of the influence of economic variables in health services management, among other probable causes. At the same time, doctors' work has been diversified, and a tendency to work in several paid jobs simultaneously has been observed. AIM: To describe the characteristics of employment in a representative sample of Chilean physicians. MATERIAL AND METHODS: A probabilistic sample of 414 physicians residing in Metropolitan Santiago answered a survey about their number and type of jobs and completed the BIS UMED questionnaire that measures the subjective wellbeing of physicians. RESULTS: Forty percent of surveyed physicians had three or more jobs (36.3% of men and 47.5% of women). There was a significant inverse association between the number of jobs, general wellbeing and facing medicine from a new perspective. CONCLUSIONS: The number of jobs is inversely related to the general wellbeing of physicians. PMID- 23732493 TI - [Real daily costs of patients admitted to public intensive care units]. AB - BACKGROUND: Patient care costs in intensive care units are high and should be considered in medical decision making. AIM: To calculate the real disease related costs for patients admitted to intensive care units of public hospitals. MATERIAL AND METHODS: Using an activity associated costs analysis, the expenses of 716 patients with a mean age of 56 years, mean APACHE score of 20 (56% males), admitted to intensive care units of two regional public hospitals, were calculated. Patients were classified according to their underlying disease. RESULTS: The costs per day of hospital stay, in Chilean pesos, were $ 426,265 for sepsis, $ 423,300 for cardiovascular diseases, $ 418,329 for kidney diseases, $ 404,873 for trauma, $ 398,913 for respiratory diseases, $ 379,455 for digestive diseases and $ 371,801 for neurologic disease. Human resources and medications determined up to 85 and 12% of costs, respectively. Patients with sepsis and trauma use 32 and 19% of intensive care unit resources, respectively. Twenty seven percent of resources are invested in patients that eventually died. CONCLUSIONS: A real cost benefit analysis should be performed to optimize resource allocation in intensive care units. PMID- 23732494 TI - [Mental health problems among students of a regional Chilean university]. AB - BACKGROUND: The increase in university population in Chile has also increased the number of students presenting mental health disorders. AIM: To determine the frequency of mental health problems and its association with other relevant variables among students of a regional university in Chile. MATERIAL AND METHODS: A sample of 484 students aged 18 to 28 years (45% males) were assessed once using a battery of tests designed to detect mental health problems. The instruments used were Derogates SCL-90-R, Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI-II), Depression, Anxiety and Stress Scales (DASS-21) and a social demographic questionnaire. RESULTS: Fifteen percent of the sample presented high levels of mental health symptoms, determined according to the cut-off points of Beck inventories. This symptomatic group, which also showed high levels of stress, was composed mostly of freshmen and women. There was a significant association between symptoms and socio-demographic variables such as living in rural areas, ethnicity and socioeconomic status, a higher need for psychological and psychiatric care and a lower number of extracurricular activities. CONCLUSIONS: The knowledge of mental health problems among university students will allow to generate strategies for mental health prevention, promotion and treatment. PMID- 23732495 TI - Internal medicine, art and science in the third millennium. AB - Internal medicine, art and science in the third millennium is a statement that Medicine is not only science. It acts on the sick individual to reestablish a natural state as a curative art. Medical art, commissioned by an individual or a society, is service. It requires vocation to obtain satisfaction. However due to the incidence of value changes, market globalization, technological and industrial development, the patient/physician relationship is becoming a user/provider relationship. Physician-related factors such as a higher health care demand, resource shortage and a progressive specialization have also influenced this change of paradigm. This is causing dissatisfaction, loss of self esteem and a lower ethical commitment among professionals. We need to recover a professional repertoire of ideas in the context of a global ethics. Responsibility and co-responsibility are ethical principles addressed to technological civilizations and their collateral effects on people and environment that lead to a "responsible globalization". We also need a scientific futurology to define risks and avoid errors. In this era of progressive specialization, Internal Medicine, with its holistic vision of mankind, may play a fundamental role in the field of bioethics. PMID- 23732496 TI - The broken branch: Darwin's evolutionary tree and the progress of medicine, the evolution of specialism and generalism. AB - The landscape of medical practice and health care has been transformed by specialization over the past Century. There has been an extraordinary acceleration in the proliferation of specialty practice, coincident with rapid growth in technological devices and their clinical applications during the past fifty years. Medicine and medical care are evolving rapidly, a process that has similarities to biologic evolution. Medical educators, policy makers, and practitioners might find a Darwinian overview of medicine and health care of interest. PMID- 23732497 TI - [Effects of statins in cancer]. AB - This review explores the evidence supporting a potential benefit of statins in cancer. In particular, the lipophilic forms (i.e. lovastatin, simvastatin, or similar) would have a therapeutic but not a preventive role. The pleiotropic effects that statins possess mainly explain this phenomenon, influencing the natural history of disease and the response to currently available therapies. By inhibiting the mevalonate pathway, statins would have a systemic effect, similar to that observed in atherosclerosis, reducing the inflammatory stimuli present in the tumor micro-environment and inhibiting the activation of intracellular signaling cascades critical for proliferation, migration/invasion and metastasis of the cancer cell. Despite all this evidence, randomized trials are needed to confirm the benefit of statins on cancer, before promoting their widespread use as a therapeutic or preventive strategy for this condition. PMID- 23732498 TI - [Hypertension in women]. AB - The present review examines the types of hypertension that women may suffer throughout life, their physiopathological characteristics and management. In early life, the currently used low-dose oral contraceptives seldom cause hypertension. Pregnancy provokes preeclampsia, its main medical complication, secondary to inadequate transformation of the spiral arteries and the subsequent multisystem endothelial damage caused by deportation of placental factors and microparticles. Hypertension in preeclampsia is an epiphenomenon which needs to be controlled at levels that reduce maternal risk without impairing placental perfusion. The hemodynamic changes of pregnancy may unmask a hypertensive phenotype, may exacerbate a chronic hypertension, or may complicate hypertension secondary to lupus, renovascular lesions, and pheochromocytoma. On the other hand a primary aldosteronism may benefit from the effect of progesterone and present as a postpartum hypertension. A hypertensive pregnancy, especially preeclampsia, represents a risk for cardiac, vascular and renal disease in later life. Menopause may mimic a pheochromocytoma, and is associated to endothelial dysfunction and salt-sensitivity. Among women, non-pharmacological treatment should be forcefully advocated, except for sodium restriction during pregnancy. The blockade of the renin-angiotensin system should be avoided in women at risk of pregnancy; betablockers could be used with precautions during pregnancy; diuretics, ACE inhibitors and angiotensin receptor antagonists should not be used during breast feeding. Collateral effects of antihypertensives, such as hyponatremia, cough and edema are more common in women. Thus, hypertension in women should be managed according to the different life stages. PMID- 23732499 TI - [Sick leaves caused by psychiatric diseases in Spain during 2011]. AB - BACKGROUND: Psychiatric and mood disorders may hamper the efficiency of workers and cause absenteeism. MATERIAL AND METHODS: Revision of sick leaves related to schizophrenia, bipolar diseases, anxiety, depression and adaptive disorders that were granted in Spain in the period January- December 2011. The mean number of days off work for each disease and the costs per each labor day lost were calculated. RESULTS: The total number of labor days lost for schizophrenia, bipolar diseases and mood disorders were 72,831; 899,107 and 3,666,055 days, respectively. The mean duration of sick leaves for the same diagnoses were 84; 100 and 64 days/year respectively. The total indirect costs of sick leaves for psychiatric diseases during 2011 were ? 100 million approximately, corresponding to 4% of costs for all diseases. CONCLUSIONS: The high costs of absenteeism derived from psychiatric diseases should prompt measures to promote a better adaptation to work environments of people suffering these ailments. PMID- 23732500 TI - [Rapid aspirin desensitization in patients with a history of aspirin hypersensitivity requiring coronary angioplasty. Report of four cases]. AB - Aspirin use is necessary after a coronary angioplasty. It should not be used in patients with a history of hypersensitivity. However, rapid desensitization protocols have been reported to allow its use in such patients. One of these protocols consists in the administration of progressive doses of aspirin, from 1 to 100 mg in a period of 5.5 hours, in a controlled environment. We report four male patients aged 45,49, 59 and 73 years with a history of aspirin hypersensitivity, who were subjected to a coronary angioplasty. In all, the rapid aspirin desensitization protocol was successfully applied, allowing the use of the drug after the intervention without problems. PMID- 23732501 TI - [Spindle and epithelioid hemangio-endothelioma of the lymph node. Report of one case]. AB - Primary vascular tumors of lymph nodes are extremely rare with the exception of AlDS-related Kaposi's sarcoma. The diagnosis of epithelioid hemangio-endothelioma (EH) is difficult to make without ancillary studies, since it is devoid of morphological features indicating its vascular nature and it may be overlooked when it appears as a primary tumor of lymph nodes. Spindle and epithelioid hemangio-endothelioma (SEH) is considered to be a variant of EH, which has been reported to occur exclusively in lymph nodes and the spleen. We report a 70-year old male with chronic lymphocytic leukemia (CLL) and left cervical lymphadenopathy. An excisional biopsy was performed, and microscopically the lymph node showed effacement of nodal architecture by a tumor composed of spindle cells disposed in intersecting fascicles, and characterized by abundant eosinophilic cytoplasm, elongated nuclei and conspicuous nucleoli. A second population of cells had an epithelioid appearance with intracyto-plasmic vacuoles containing red blood cells. lmmunohistochemically, the tumor cells were positive for CD31 and CD34. The final diagnosis was SEH of the lymph node. PMID- 23732502 TI - [Endovascular treatment of aorto-esophageal fistula due to esophageal cancer. Report of one case]. AB - Esophageal squamous cell carcinoma can spread locally to neighboring organs in the mediastinum. When it invades the aorta, the patient may develop an aorto esophageal fistula (AEF), complication that carries a high mortality rate. We report a 62-year-old male with stage IV esophageal carcinoma who, after chemo radiation treatment, developed an AEF. He was successfully treated with the use of an aortic endograft. The patient died 13 months later due to progression of his cancer, without evidence of sepsis or new bleeding episodes. PMID- 23732503 TI - [Orphan pediatric diseases: regarding the world rare diseases day]. PMID- 23732504 TI - [Folate and breast cancer risk]. PMID- 23732505 TI - [Folate and breast cancer risk: authors' reply]. PMID- 23732506 TI - Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. AB - Microglia, the resident immune cells of the central nervous system (CNS), play an important role in CNS homeostasis during development, adulthood and ageing. Their phenotype and function have been widely studied, but most studies have focused on their local interactions in the CNS. Microglia are derived from a particular developmental niche, are long-lived, locally replaced and form a significant part of the communication route between the peripheral immune system and the CNS; all these components of microglia biology contribute to maintaining homeostasis. Microglia function is tightly regulated by the CNS microenvironment, and increasing evidence suggests that disturbances, such as neurodegeneration and ageing, can have profound consequences for microglial phenotype and function. We describe the possible biological mechanisms underlying the altered threshold for microglial activation, also known as 'microglial priming', seen in CNS disease and ageing and consider how priming may contribute to turning immune-to-brain communication from a homeostatic pathway into a maladaptive response that contributes to symptoms and progression of diseases of the CNS. PMID- 23732508 TI - Validity of arterialised-venous P CO2, pH and bicarbonate in obesity hypoventilation syndrome. AB - This prospective study investigated the validity of arterialised-venous blood gases (AVBG) for estimating arterial carbon dioxide P CO2, pH and bicarbonate (HCO3(-)) in people with obesity hypoventilation syndrome (OHS). AVBGs were obtained from an upper limb vein, after heating the skin at 42-46 degrees C. Arterial blood gas (ABG) and AVBG samples were taken simultaneously and compared using Bland Altman analysis. Between-group differences were assessed with independent t-tests or Mann-Whitney U tests. Forty-two viable paired samples were analysed, including 27 paired samples from 15 OHS participants, and 15 paired samples from 16 controls. AVBG-ABG agreement was not different between groups, or between dorsal hand, forearm and antecubital AVBG sampling sites, and was clinically acceptable for P Co2: mean difference (MD) 0.4 mmHg (0.9%), limits of agreement (LOA) -2.7-3.6 mmHg (+/- 6.6%); pH: MD -0.008 (-0.1%), LOA -0.023-0.008 (+/- 0.2%); and HCO3(-): MD -0.3 mmol L(-1) (-1.0%), LOA -1.8-1.2 mmol L(-1) (+/- 5.3%). AVBG provides valid measures of [Formula: see text] , pH, and HCO3(-) in OHS. PMID- 23732509 TI - The motility of the chicken embryo: energetic cost and effects of hypoxia. AB - We estimated the energetic cost of embryonic motility by relating the changes in embryo's motion to the changes in oxygen consumption (VO2). Measurements were conducted on chicken embryos between day 10 and 18 of incubation. Embryonic gross body movement was quantified over ten continuous 3-min periods from the pressure oscillations inside the egg, measured through an implanted catheter, and was correlated to the synchronous changes in VO2, measured by an open-flow methodology. Over the 30 min recording, movements could vary around the mean by up to four folds. The corresponding changes in VO2 were minuscule (0.116 MUl O2/mmHg) or, for all age groups combined, only 2.3% of the mean VO2, ranging from ~ 8% (day 10) to ~ 0.5% (day 16). At E18, hypercapnia and cold respectively increased and decreased motility. Differently, the effects of hypoxia on motility were variable among embryos. It is concluded that, in chicken embryos over the age period investigated, the cost of motility represents an almost negligible fraction of the total energy budget. Because of its low cost, motility can be maintained in hypoxia; conversely, reduction of motility in hypoxia does not provide an important energy saving. PMID- 23732507 TI - Molecular mechanisms regulating NETosis in infection and disease. AB - Neutrophils are the foot soldiers of the immune system. They home in to the site of infection and kill pathogens by phagocytosis, degranulation, and the release of web-like structures called neutrophil extracellular traps (NETs) that trap and kill a variety of microbes. NETs have been shown to play a multitude of additional roles in immunity but have also been implicated in inflammatory and autoimmune disease. Here, we discuss the role of NETs in these various contexts with a particular emphasis on the molecular mechanisms that regulate NET release and clearance. We highlight the comprehensive concepts and explore the important open questions in the field. PMID- 23732510 TI - Respiratory modulation of lingual muscle activity across sleep-wake states in rats. AB - In obstructive sleep apnea (OSA) patients, inspiratory activation (IA) of lingual muscles protects the upper airway from collapse. We aimed to determine when rats' lingual muscles exhibit IA. In 5 Sprague-Dawley and 3 Wistar rats, we monitored cortical EEG and lingual, diaphragmatic and nuchal electromyograms (EMGs), and identified segments of records when lingual EMG exhibited IA. Individual segments lasted 2.4-269 s (median: 14.5 s), most (89%) occurred during slow-wave sleep (SWS), and they collectively occupied 0.3-6.1% of the total recording time. IA usually started to increase with a delay after SWS onset and ended with an arousal, or declined prior to rapid eye movement sleep. IA of lingual EMG was not accompanied by increased diaphragmatic activity or respiratory rate changes, but occurred when cortical EEG power was particularly low in a low beta-1 frequency range (12.5-16.4 Hz). A deep SWS-related activation of upper airway muscles may be an endogenous phenomenon designed to protect the upper airway against collapse. PMID- 23732511 TI - Cerebrospinal fluid of newly diagnosed amyotrophic lateral sclerosis patients exhibits abnormal levels of selenium species including elevated selenite. AB - Exposure to selenium, and particularly to its inorganic forms, has been hypothesized as a risk factor for amyotrophic lateral sclerosis (ALS), a fast progressing motor neuron disease with poorly understood etiology. However, no information is known about levels of inorganic and some organic selenium species in the central nervous system of ALS patients, and recent observations suggest that peripheral biomarkers of exposure are unable to predict these levels for several Se species including the inorganic forms. Using a hospital-referred case control series and advanced selenium speciation methods, we compared the chemical species of selenium in cerebrospinal fluid from 38 ALS patients to those of 38 reference neurological patients matched on age and gender. We found that higher concentrations of inorganic selenium in the form of selenite and of human serum albumin-bound selenium were associated with increased ALS risk (relative risks 3.9 (95% confidence interval 1.2-11.0) and 1.7 (1.0-2.9) for 0.1MUg/L increase). Conversely, lower concentrations of selenoprotein P-bound selenium were associated with increased risk (relative risk 0.2 for 1MUg/L increase, 95% confidence interval 0.04-0.8). The associations were stronger among cases age 50 years or older, who are postulated to have lower rates of genetic disease origin. These results suggest that excess selenite and human serum albumin bound-selenium and low levels of selenoprotein P-bound selenium in the central nervous system, which may be related, may play a role in ALS etiology. PMID- 23732513 TI - Letter to the editor concerning the paper: Boltjes A, Op den Brouw ML, Biesta PJ, et al. Assessment of the effect of ribavirin on myeloid and plasmacytoid dendritic cells during interferon-based therapy of chronic hepatitis B patients [Molecular Immunology 53(1/2) (2013) 72-78]. PMID- 23732512 TI - Effect modification by transferrin C2 polymorphism on lead exposure, hemoglobin levels, and IQ. AB - BACKGROUND: Iron deficiency and lead exposure remain significant public health issues in many parts of the world and are both independently associated with neurocognitive deficits. Polymorphisms in iron transport pathways have been shown to modify the absorption and toxicity of lead. OBJECTIVE: We hypothesized that the transferrin (TF) C2 polymorphism modifies the effects of lead and hemoglobin on intelligence. METHODS: Children aged 3-7 years (N=708) were enrolled from 12 primary schools in Chennai, India. The Binet-Kamath Scale of Intelligence were administered to ascertain intelligence quotient (IQ). Venous blood was analyzed for lead and hemoglobin levels. Genotyping for the TF C2 polymorphism (rs1049296) was carried out using a MassARRAY iPLEXTM platform. Stratified analyses and interaction models, using generalized estimating equations, were examined to explore interactions between lead, hemoglobin, and TF C2 categories. RESULTS: A one-unit increase in log blood lead and 1g/dl higher hemoglobin was associated with -77 (95% CI: -136, -18) and 17 (95% CI 14, 21) IQ points, respectively, among children carrying the C2 variant. In comparison, among children who had the homozygous wildtype allele, the same increment of lead and hemoglobin were associated with -21(95% CI: -65, 24) and 28 (95% CI: 15, 40) IQ points, respectively. There was a significant interaction between lead (p=0.04) and hemoglobin (p=0.07) with the C2 variant. CONCLUSION: Children who carry the TF C2 variant may be more susceptible to the neurotoxic effects of lead exposure and less protected by higher levels of hemoglobin. PMID- 23732514 TI - Silence is golden: effect of encouragement in motivating the weak link in an online exercise video game. AB - BACKGROUND: Despite the physical and mental health benefits, few adults meet US Department of Health and Human Services physical activity guidelines for exercise frequency, intensity, and duration. One strategy that may increase physical activity duration is exercising with an Internet partner (ie, someone who is virtually present, as in video chat). Internet partners help people overcome many barriers associated with face-to-face exercise groups (eg, time, coordinating schedules, social physique anxiety). Past research examining individual performance in groups suggests that an increase in effort occurs when performing a task conjunctively, ie, when a participant is (1) less capable than fellow group members, and (2) participants efforts are particularly indispensable for group success (ie, where the group's potential productivity is equal to the productivity of its least capable member). This boost in effort is more commonly known as the Kohler effect, named after the German psychologist who first observed the effect. While encouragement between group members is common practice in face-to-face group exercise, the effect of encouragement between partners exercising conjunctively across the Internet is unknown. OBJECTIVE: To examine the impact of exercising alone, compared to exercising conjunctively with an Internet partner, both with and without encouragement, on exercise persistence (primary outcomes) and secondary psychosocial outcomes (self-efficacy, enjoyment, exercise intention). METHODS: Participants were recruited online and face-to-face from the campus of Michigan State University. With the assistance of the experimenter, participants (n=115) played an exercise video game in a laboratory, performing a series of five abdominal plank exercises where they were asked to hold the plank for as long as possible (Time 1). They were then randomized to a condition (Individual, Partner-without-encouragement, or Partner-with encouragement), where they performed the exercises again (Time 2). The impact of condition on the primary outcome measures and secondary outcome measures were evaluated using a 2 (Gender) x 3 (Condition) ANOVA on change scores (Time 2-Time 1). RESULTS: Those who exercised in online teams (n=80) exercised significantly longer (time=78.8s, P<.001) than those who worked individually (n=35). However, exercise duration was shorter when one's more capable partner gave verbal encouragement (n=55) than when s/he did not (n=25) (a mean difference of 31.14s). These increases in effort were not accompanied by altered task self-efficacy, enjoyment of the task, or intention to exercise in the future. CONCLUSIONS: Exercising conjunctively with an Internet partner can boost one's duration of exercise. However, encouragement from the stronger to the weaker member can mitigate these gains, especially if one perceives such comments being directed at someone other than themselves. To boost exercise duration, Internet-based physical activity interventions involving group interaction should make relative abilities of participants known and communication clear. PMID- 23732515 TI - Is mild-moderate drinking in pregnancy harmless? New experimental evidence to the opposite. AB - During the last decade a growing number of studies have failed to detect adverse neurodevelopmental effects of mild--to moderate maternal drinking in the exposed child, supporting a climate that "some drinking in pregnancy is OK". A recent experimental study in sheep, mimicking conditions of moderate drinking in the third trimester of pregnancy, provides powerful evidence that there are serious lifelong risks to fetal exposure to alcohol. These should serve as an alarm call to those who legitimize mild-moderate maternal drinking based on incomplete data. PMID- 23732516 TI - Mixed valence eta6-arene cobalt(I) and cobalt(II) compound. AB - The first carbonyl free mixed valence cobalt(I)/cobalt(II) compound [2{L2Co(I)(eta(6)-C7H8)}](2+) [Co(II)2Cl6](2-) (1) [L = PhC(N(t)Bu)2SiCl] was obtained by the reaction of four equivalents of anhydrous CoCl2 with five equivalents of N-heterocyclic chlorosilylene L. In contrast, the reaction of L with CoBr2 yielded [L2CoBr2] (2). Compound 1 was formed by the cleavage of Co-Cl bonds, the reduction of Co(II) to Co(I) and by the coordination of a toluene molecule. The chlorosilylene (L) functions as a reducing agent as well as a neutral sigma-donor ligand. The toluene molecule coordinates to the Co(I) atom in an eta(6)-fashion. PMID- 23732517 TI - Aldose reductase inhibition enhances TRAIL-induced human colon cancer cell apoptosis through AKT/FOXO3a-dependent upregulation of death receptors. AB - One of the major problems associated with the chemotherapy of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) that selectively kills tumor cells is decreased drug resistance. This warranted the development of safe novel pharmacological agents that could sensitize the tumor cells to TRAIL. Herein, we examined the role of aldose reductase (AR) in sensitizing cancer cells to TRAIL and potentiating TRAIL-induced apoptosis of human colon cancer cells. We demonstrate that AR inhibition potentiates TRAIL-induced cytotoxicity in cancer cells by upregulation of both death receptor (DR)-5 and DR4. Knockdown of DR5 and DR4 significantly (>85%) reduced the sensitizing effect of the AR inhibitor fidarestat on TRAIL-induced apoptosis. Further, AR inhibition also downregulates cell survival proteins (Bcl-xL, Bcl-2, survivin, XIAP, and FLIP) and upregulates the expression of proapoptotic proteins such as Bax and alters mitochondrial membrane potential, leading to cytochrome c release, caspases-3 activation, and PARP cleavage. We found that AR inhibition regulates AKT/PI3K-dependent activation of forkhead transcription factor FOXO3a. Knockdown of FOXO3a significantly (>80%) abolished AR inhibition-induced upregulation of DR5 and DR4 and apoptosis in colon cancer cells. Overall, our results show that fidarestat potentiates TRAIL-induced apoptosis through downregulation of cell survival proteins and upregulation of death receptors via activation of the AKT/FOXO3a pathway. PMID- 23732518 TI - Role of oxidants on calcium and sodium movement in healthy and diseased cardiac myocytes. AB - In this review article we give an overview of current knowledge with respect to redox-sensitive alterations in Na(+) and Ca(2+) handling in the heart. In particular, we focus on redox-activated protein kinases including cAMP-dependent protein kinase A (PKA), protein kinase C (PKC), and Ca/calmodulin-dependent protein kinase II (CaMKII), as well as on redox-regulated downstream targets such as Na(+) and Ca(2+) transporters and channels. We highlight the pathological and physiological relevance of reactive oxygen species and some of its sources (such as NADPH oxidases, NOXes) for excitation-contraction coupling (ECC). A short outlook with respect to the clinical relevance of redox-dependent Na(+) and Ca(2+) imbalance will be given. PMID- 23732519 TI - Signaling through the vascular endothelial growth factor receptor VEGFR-2 protects hippocampal neurons from mitochondrial dysfunction and oxidative stress. AB - Vascular endothelial growth factor VEGF (VEGF-A or VEGF165) is a potent angiogenic factor that also signals neuroprotection through activation of its cognate receptor VEGFR-2. In this capacity, VEGF signaling can rescue neurons from the damage induced by stressful stimuli many of which elicit oxidative stress. However, the regulatory role that VEGFR-2 plays in providing neuroprotection remains elusive. Therefore, we investigated the effects of VEGFR 2 inhibition on primary cultures of mature hippocampal neurons undergoing nutritional stress. We found that neurons cultured under nutritional stress had increased expression of VEGF and its receptors, VEGFR-1, VEGFR-2, and NP-1, as well as enhanced levels of VEGFR-2 phosphorylation. These neurons also showed increased activation of the prosurvival pathways for MEK/ERK1/2 and PI3K/Akt, enhanced phosphorylation (inactivation) of the proapoptotic BAD, and higher levels of the antiapoptotic protein Bcl-xL, all of which were augmented by treatments with exogenous VEGF and blocked by VEGFR-2 inhibition. The blockade of VEGFR-2 function also elicited a cytotoxicity that was accompanied by caspase-3 activation, induction of hemeoxygenase-1 (HO-1), oxidative stress, and a collapse in the mitochondrial membrane potential (DeltaPsi(m)). Knockdown of VEGFR-2 by siRNA generated a similar pattern of redox change and mitochondrial impairment. Pretreatments with VEGF, VEGF-B, or the antioxidant N-acetylcysteine (NAC) rescued SU1498 or siRNA-treated neurons from the mitochondrial dysfunction and oxidative stress induced by VEGFR-2 inhibition in a timely fashion. These findings suggested that VEGF or VEGF-B can provide neuroprotection by signaling through an alternate VEGF receptor. Together, our findings suggest that VEGF signaling through VEGFR-2 plays a critical regulatory role in protecting stressed hippocampal neurons from the damaging effects of an oxidative insult. These findings also implicate VEGFR-1 or NP-1 as compensatory receptors that mediate neuroprotection when VEGFR-2 function is blocked. PMID- 23732520 TI - A diterpenoid derivate compound targets selenocysteine of thioredoxin reductases and induces Bax/Bak-independent apoptosis. AB - We have previously shown that the natural diterpenoid derivative S3 induced Bim upregulation and apoptosis in a Bax/Bak-independent manner. However, the exact molecular target(s) of S3 and the mechanism controlling Bim upregulation are still not clear. Here, we identify that S3 targets the selenoproteins TrxR1 and TrxR2 at the selenocysteine residue of the reactive center of the enzymes and inhibits their antioxidant activities. Consequently, cellular ROS is elevated, leading to the activation of FOXO3a, which contributes to Bim upregulation in Bax/Bak-deficient cells. Moreover, S3 retards tumor growth in subcutaneous xenograft tumors by inhibiting TrxR activity in vivo. Our studies delineate the signaling pathway controlling Bim upregulation, which results in Bax/Bak independent apoptosis and provide evidence that the compounds can act as anticancer agents based on mammalian TrxRs inhibition. PMID- 23732521 TI - Nonstoichiometric rutile TiO2 photoelectrodes for improved photoelectrochemical water splitting. AB - A new type of nonstoichiometric rutile titanium dioxide (TiO2) film with around 15 at% oxygen vacancies homogeneously distributed throughout the bulk was prepared. The resultant films, when used as a photoelectrode, showed a photoelectrochemical water splitting activity 1.7 times that of stoichiometric TiO2 at a bias of 0.9 V vs. Ag/AgCl. This is believed to result from the synergistic effect of the improved bulk transport and surface transfer of charge carriers compared to the stoichiometric rutile TiO2. PMID- 23732523 TI - "TET-on" pluripotency. AB - Recent studies have uncovered a specific role of TET proteins in reprogramming somatic cells to induced pluripotent stem cells, a process where O-linked beta-N acetylglucosamine transferase may play a crucial role. PMID- 23732522 TI - Restrictions to HIV-1 replication in resting CD4+ T lymphocytes. AB - CD4(+) T lymphocytes represent the main target cell population of human immunodeficiency virus (HIV). In an activated state, CD4(+) T cells residing in lymphoid organs are a major reservoir of ongoing HIV-1 replication in infected individuals. In contrast, resting CD4(+) T cells are highly resistant to productive HIV-1 infection, yet are massively depleted during disease progression and represent a substantial latent reservoir for the virus in vivo. Barriers preventing replication of HIV-1 in resting CD4(+) T cells include a rigid layer of cortical actin and, early after HIV-1 entry, a block that limits reverse transcription of incoming viral RNA genomes. Defining the molecular bases of these restrictions has remained one of the central open questions in HIV research. Recent advances unraveled mechanisms by which HIV-1 bypasses the entry block and established the host cell restriction factor SAMHD1, a deoxynucleoside triphosphate triphosphohydrolase, as a central determinant of the cellular restriction to HIV-1 reverse transcription in resting CD4(+) T cells. This review summarizes our current molecular and pathophysiological understanding of the multi-faceted interactions of HIV-1 with resting CD4(+) T lymphocytes. PMID- 23732524 TI - Differentiation therapy for IDH1/2 mutant malignancies. AB - Recently discovered recurrent somatic mutations in the key metabolic enzymes IDH1 and IDH2 produce the aberrant oncometabolite 2-HG and contribute to malignant transformation of hematopoietic and glial cells. Two recent reports in Science describe the first IDH1 and IDH2 mutant-specific small-molecule inhibitors, which induce cell differentiation of myeloid leukemias and malignant gliomas. PMID- 23732525 TI - [Ultrasound-guided thoracic paravertebral block for acute thoracic trauma: continuous analgesia after high speed injury]. AB - Paravertebral blocks have experienced a renaissance because ultrasound-guidance is becoming common practice. The method is often presented as an alternative to thoracic epidural anaesthesia, mainly in the field of elective thoracic surgery. It is also propagated as an opioid-saving analgesic procedure in breast tumor surgery. In this case report it was successfully used as a continuous intervention for acute pain therapy of a severe injury of the left thorax. A transverse probe position in the fifth intercostal space was combined with an in plane needle technique from lateral to medial. An ultrasound-enhanced needle positioning was used due to the steep angle of puncture. The absolute limit for medial needle advancement is the acoustic shadow of the transverse process. A catheter was placed 2 cm beyond the needle tip and its correct position was verified by hydrolocation. The excellent and continuous analgesia enabled non invasive patient ventilation to be achieved directly after extubation and was continued for 6 days. PMID- 23732527 TI - Multiple sclerosis: defect in peripheral B-cell tolerance identified in MS. PMID- 23732526 TI - [Peripheral regional anesthesia in patients under general anesthesia: risk assessment with respect to parasthesia, injection pain and nerve damage]. AB - Nerve injury after peripheral regional anesthesia is rare and is not usually permanent. Some authors believe that inducing peripheral nerve blocks in patients during general anesthesia or analgosedation adds an additional risk factor for neuronal damage. This is based on published case reports showing that there is a positive correlation between paresthesia experienced during regional anesthesia and subsequent nerve injury. Therefore, many sources recommend that regional nerve blocks should only be performed in awake or lightly sedated patients, at least in adults. However, there is no scientific basis for this recommendation. Furthermore, there is no proof that regional anesthesia performed in patients under general anesthesia or deep sedation bears a greater risk than in awake or lightly sedated patients. Currently anesthesiologists are free to follow personal preferences in this matter as there is no good evidence favoring one approach over the other. The risk of systemic toxicity of local anesthetic agents is not higher in patients who receive regional anesthesia under general anesthesia or deep sedation. Finally, in children and uncooperative adults the administration of peripheral nerve blocks under general anesthesia or deep sedation is widely accepted. PMID- 23732528 TI - Intracerebral haemorrhage: understanding racial differences in intracerebral haemorrhage. PMID- 23732529 TI - Modulation of IL-2Ralpha with daclizumab for treatment of multiple sclerosis. AB - Multiple sclerosis (MS) is a debilitating neurological disorder involving autoimmune destruction of myelin. Although the pathogenic mechanisms underlying MS are not fully understood, T cells are thought to have a key role in orchestrating the aberrant CNS-directed adaptive immune response in the early and relapsing-remitting phase of disease. New therapeutic interventions with improved efficacy over existing drugs and good tolerability are needed. A promising therapy under investigation is daclizumab--a humanized monoclonal antibody directed against the IL-2 receptor alpha chain (CD25). Clinical trials have shown that daclizumab strongly inhibits disease activity and slows disease progression in MS. Novel and intriguing mechanisms of action of daclizumab have been identified that might explain its clinical efficacy--namely, expansion and enhancement of the immune regulatory function of CD56bright natural killer cells, reduction of early T-cell activation through blockade of IL-2 cross-presentation by dendritic cells, and reduction of lymphoid tissue inducer cells--thereby enhancing endogenous mechanisms of immune tolerance. This Review discusses the efficacy and safety of daclizumab in patients with MS and provides a detailed insight into the multifunctional mechanisms of action of this drug. PMID- 23732530 TI - Uhthoff's phenomena in MS--clinical features and pathophysiology. AB - In the late 19(th) century, Wilhelm Uhthoff reported on a series of patients with acute optic neuritis who manifested similar recurrent, stereotyped visual symptoms that were of paroxysmal onset, short in duration, and reversible. These 'Uhthoff's phenomena', which are a feature of multiple sclerosis (MS) and other demyelinating diseases, can be triggered by factors including the perimenstrual period, exercise, infection, fever, exposure to high ambient temperatures, and psychological stress. Here, we characterize the clinical, pathophysiological and neurotherapeutic challenges associated with Uhthoff's phenomena, and discuss the differentiation of these events from other paroxysmal, acute or subacute changes in functional capabilities and neurological symptoms in MS. For instance, whereas MS exacerbations are contingent on immune dysregulation, Uhthoff's phenomena are predicated on ion channel modifications, in conjunction with thermoregulatory derangements that transiently alter the conduction properties of demyelinated axons. An understanding of these pathophysiological underpinnings of Uhthoff's phenomena is germane to their recognition and timely treatment. PMID- 23732534 TI - Ternary system of dihydroartemisinin with hydroxypropyl-beta-cyclodextrin and lecithin: simultaneous enhancement of drug solubility and stability in aqueous solutions. AB - The purpose of this study was to simultaneously improve the solubility and stability of dihydroartemisinin (DHA) in aqueous solutions by a ternary cyclodextrin system comprised of DHA, hydroxypropyl-beta-cyclodextrin (HP-beta CD) and a third auxiliary substance. Solubility and phase solubility studies were carried out to evaluate the solubilizing efficiency of HP-beta-CD in association with various auxiliary substances. Then, the solid binary (DHA-HP-beta-CD or DHA lecithin) and ternary systems were prepared and characterized by Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC) and power X ray diffraction (PXRD). The effect of the ternary system on the solubility, dissolution and stability of DHA in aqueous solutions was also investigated. As a result, the soybean lecithin was found to be the most promising third component in terms of solubility enhancement. For the solid characterization, the disappearance of the drug crystallinity indicated the formation of new solid phases, implicating the formation of the ternary system. The dissolution rate of the solid ternary system was much faster than that of the drug alone and binary systems. Importantly, compared with binary systems, the ternary system showed a significant improvement in the stability of DHA in Hank's balanced salt solutions (pH 7.4). The solubility and stability of DHA in aqueous solutions were simultaneously enhanced by the ternary system, which might be attributed to the possible formation of a ternary complex. For the ternary interactions, results of molecular docking studies further indicated that the lecithin covered the top of the wide rim of HP-beta-CD and surrounded around the peroxide bridging of DHA, providing the possibility for the ternary complex formation. In summary, the ternary system prepared in our study, with simultaneous enhancement of DHA solubility and stability in aqueous solutions, might have an important pharmaceutical potential in the development of a better oral formulation of DHA. PMID- 23732531 TI - Dementia in the oldest old. AB - People over the age of 90 years--the oldest old--are the fastest growing sector of the population. A substantial proportion of these individuals are affected by dementia, with major implications for the individual as well as society. Research on dementia in the oldest old is important for service planning, and the absence of dementia at this exceptional old age may serve as a model of successful ageing. This Review summarizes population-based epidemiological studies of dementia and its underlying neuropathology in nonagenarians and centenarians. The available data, although somewhat limited, show an age-specific and sex-specific profile of dementia status in very late life, resulting from a variety of neuropathologies that often co-occur. Extensive overlap in neuropathology between cognitively normal and cognitively impaired individuals is evident despite challenges to gathering data particular to this population. A complex picture is emerging of multiple pathogenetic mechanisms underlying dementia, and of the potential risk and protective factors for dementia that interact with genetics and lifestyle in normal and exceptional cognitive ageing. PMID- 23732535 TI - Repeatability of the timing of eye-hand coordinated movements across different cognitive tasks. AB - Quantification of eye-hand coordinated behaviour is a relatively new tool to study neurodegeneration in humans. Its sensitivity depends on the assessment of different behavioural strategies, multiple task testing and repeating tasks within one session. However, large numbers of repetition trials pose a significant burden on subjects. To introduce this method in large-scale population studies, it is necessary to determine whether reducing the number of task repetitions, which will lower subject burden, still leads to acceptable measurement accuracy. The objective of this study was to investigate the validity and reliability of eye-hand coordination outcome parameters in eight healthy volunteers using a test-retest approach. Subjects were assessed during a shortened test procedure consisting of eight repetitions of three behavioural tasks: a reflex-based tapping task, a planning-based tapping task and a memory based tapping task. Eye-hand coordination was quantified in terms of timing (eye and hand latencies), kinematics and accuracy. Eye and hand latencies were found within a normal range (between 150 and 450ms). A paired samples t-test revealed no differences in timing parameters between the first and second measurements. It was concluded that eight trial repetitions are sufficient for quantifying eye hand coordination in terms of timing, kinematics and accuracy. This approach demonstrates the testing of multiple visuomotor behaviours within a reasonable time span of a few minutes per task. PMID- 23732536 TI - Supported monodisperse Pt nanoparticles from [Pt3(CO)3(MU2-CO)3]5(2-) clusters for investigating support-Pt interface effect in catalysis. AB - Here we present a surfactant-free strategy to prepare supported monodisperse Pt nanoparticles from molecular [Pt3(CO)3(MU2-CO)3]5(2-) clusters. The strategy allows facile deposition of same-sized Pt nanoparticles on various oxide supports to unambiguously study the interface effect between noble metal and metal oxide in catalysis. In this study, Fe2O3 is demonstrated to be a superior support over TiO2, CeO2 and SiO2 to prepare highly active supported Pt nanoparticles for CO oxidation, which indicates that the interfaces between Pt and iron oxide are the active sites for O2 activation and CO oxidation. PMID- 23732539 TI - Inheritance of poor writing habits. To improve scientific writing we must break the chain of transmission of complex writing style from senior to junior scientists. PMID- 23732538 TI - Nonrigid point registration for 2D curves and 3D surfaces and its various applications. AB - A nonrigid B-spline-based point-matching (BPM) method is proposed to match dense surface points. The method solves both the point correspondence and nonrigid transformation without features extraction. The registration method integrates a motion model, which combines a global transformation and a B-spline-based local deformation, into a robust point-matching framework. The point correspondence and deformable transformation are estimated simultaneously by fuzzy correspondence and by a deterministic annealing technique. Prior information about global translation, rotation and scaling is incorporated into the optimization. A local B-spline motion model decreases the degrees of freedom for optimization and thus enables the registration of a larger number of feature points. The performance of the BPM method has been demonstrated and validated using synthesized 2D and 3D data, mouse MRI and micro-CT images. The proposed BPM method can be used to register feature point sets, 2D curves, 3D surfaces and various image data. PMID- 23732540 TI - The right to care and the expectations of society--controversial stem cell therapy in Italy. PMID- 23732541 TI - Arabidopsis ARGONAUTE7 selects miR390 through multiple checkpoints during RISC assembly. AB - Plant ARGONAUTE7 (AGO7) assembles RNA-induced silencing complex (RISC) specifically with miR390 and regulates the auxin-signalling pathway via production of TAS3 trans-acting siRNAs (tasiRNAs). However, how AGO7 discerns miR390 among other miRNAs remains unclear. Here, we show that the 5' adenosine of miR390 and the central region of miR390/miR390* duplex are critical for the specific interaction with AGO7. Furthermore, despite the existence of mismatches in the seed and central regions of the duplex, cleavage of the miR390* strand is required for maturation of AGO7-RISC. These findings suggest that AGO7 uses multiple checkpoints to select miR390, thereby circumventing promiscuous tasiRNA production. PMID- 23732542 TI - Reduced SNAP-25 alters short-term plasticity at developing glutamatergic synapses. AB - SNAP-25 is a key component of the synaptic-vesicle fusion machinery, involved in several psychiatric diseases including schizophrenia and ADHD. SNAP-25 protein expression is lower in different brain areas of schizophrenic patients and in ADHD mouse models. How the reduced expression of SNAP-25 alters the properties of synaptic transmission, leading to a pathological phenotype, is unknown. We show that, unexpectedly, halved SNAP-25 levels at 13-14 DIV not only fail to impair synaptic transmission but instead enhance evoked glutamatergic neurotransmission. This effect is possibly dependent on presynaptic voltage-gated calcium channel activity and is not accompanied by changes in spontaneous quantal events or in the pool of readily releasable synaptic vesicles. Notably, synapses of 13-14 DIV neurons with reduced SNAP-25 expression show paired-pulse depression as opposed to paired-pulse facilitation occurring in their wild-type counterparts. This phenotype disappears with synapse maturation. As alterations in short-term plasticity represent a new mechanism contributing to cognitive impairments in intellectual disabilities, our data provide mechanistic clues for neuronal circuit alterations in psychiatric diseases characterized by reduced expression of SNAP-25. PMID- 23732543 TI - A dual role of SNAP-25 as carrier and guardian of synaptic transmission. PMID- 23732544 TI - The relationship between body mass index and quality of life in community-living older adults living in the United States. AB - BACKGROUND: Carrying excess weight is associated with various chronic conditions especially in older adults, and can have a negative influence on the quality of life of this population. OBJECTIVE: The objective of this study was to estimate the independent (i.e. adjusted for demographic, socioeconomic and health status differences) impact of Body Mass Index (BMI) on health-related quality of life. DESIGN: A mail survey was sent to 60,000 older adults living in 10 states. METHODS: The survey assessed quality of life using the average physical component scores (PCS) and mental component scores (MCS) obtained from the Veterans Rand 12 item (VR-12) health status tool embedded in the survey. Ordinary least squares (OLS) regression techniques were used to estimate the independent impact of each BMI category on quality of life, compared to the impact of other chronic conditions. RESULTS: A total of 22,827 (38%) eligible sample members responded to the survey. Of those, 2.2% were underweight, 38.5% had a normal BMI, 37.0% were overweight, 18.5% were obese and 1.9% were morbidly obese. Following OLS regression techniques, respondents' PCS values were statistically significantly lower for the underweight, overweight, obese and morbidly obese BMI categories, compared to the normal BMI group. Compared with all other chronic conditions, being morbidly obese (-6.0 points) had the largest negative impact on the PCS. Underweight was the only BMI category with a statistically significantly lower MCS value. CONCLUSIONS: The greatest negative impacts of the various BMI categories on quality of life were on physical rather than mental aspects, especially for those in the underweight, obese and morbidly obese categories, more so than many other chronic conditions. PMID- 23732545 TI - Meeting the nutritional needs of elderly residents in aged-care: are we doing enough? AB - OBJECTIVES: [corrected] Institutionalized elderly are at high risk of malnutrition, including those residing in low-level aged-care and able to self feed. We used comprehensive dietary intake assessments to determine the nutritional adequacy of food served to residents and if food waste contributed to insufficient nutrient intakes. DESIGN: Cross sectional. SETTING: 18 low-level aged care facilities. PARTICIPANTS: 199 residents (mean age 86.7 yrs, 76% females). MEASUREMENTS: Dietary data using 3-6 day weighed food records. Foods were categorized into main food groups (grains, fruit, vegetables, meats, dairy and 'extra') and quantified based on recommended serving sizes. Chi squared test was used to determine sex differences in proportion of residents below recommended intake levels. RESULTS: Residents were provided with sufficient serves of fruit (>2) and meats (>1), but not dairy (<3), vegetables (<5) and grain foods (women only, <4), and excess serves of 'extra' foods (>2). Mean dietary intakes did not meet recommendations for calcium, zinc, magnesium, potassium, folate and dietary fibre with many residents not meeting energy and protein requirements. Sodium intake was up to 3 times higher than recommended, and sugars consumed in excess. Food waste was 0-15% and resulted in men not consuming recommended serves of grain foods. 'Extra' foods contributed substantially to energy intake but provided few of the required nutrients. CONCLUSION: Substituting some 'extra' foods for serves of dairy, vegetables and wholegrain foods would improve the nutritional quality of foods, without altering food volume, so is feasible to improve nutritional status in elderly aged-care residents. PMID- 23732546 TI - Consuming two additional serves of dairy food a day significantly improves energy and nutrient intakes in ambulatory aged care residents: a feasibility study. AB - OBJECTIVES: [corrected] Low-level aged-care residents are at risk of malnutrition. Oral supplements and fortified foods used to treat malnutrition in the elderly require special preparation and administration by staff. Therefore we aimed to determine if increasing dairy food intake in residents by two serves per day would improve energy and nutrient intakes and prevent malnutrition in residents. DESIGN: Prospective intervention study. SETTING: 2 intervention and 2 control low-level aged-care facilities in Melbourne, Australia. PARTICIPANTS: 130 residents (n = 68 intervention, 78% female, mean age 86.5 years). INTERVENTION: This feasibility study was a 4-week intervention where menus were modified to include at least two additional serves of dairy food/day. Control facilities consumed from their regular menus. MEASUREMENTS: Mean macro- and micro-nutrient intakes before and after intervention and over the same time period in controls were recorded using observed intake (food served minus waste) and changes over time determined using paired t-tests. Comparison in proportion of residents meeting nutritional requirements was determined using Chi-square distribution test. RESULTS: Following intervention, daily increases in mean energy intake (900kJ, P<0.001), protein intake (+25g, P<0.0001), proportion of energy from protein (+4%, P<0.0001) and proportion of estimated energy requirements (EER) (+18%, P<0.0001) were observed, while proportion of energy from fat decreased ( 3%, P<0.0001). In controls mean energy intake remained below the EER, and protein intake remained unchanged. Increases in mean daily micronutrient intakes were observed for numerous nutrients including calcium (+679mg, P<0.0001), vitamin D (+1.4MUg, P<0.0001), phosphorus (+550mg, P<0.0001), and zinc (+2.8mg, P<0.0001), which remained unchanged in control residents. Calcium and zinc intakes achieved recommended intake levels on the higher dairy diet, but were below recommended levels in controls. Mean sodium intakes remained unchanged. During intervention a greater proportion of residents achieved the EER for energy and the RDI for protein and calcium compared to controls. CONCLUSION: Two additional serves of dairy food can significantly improve nutrient intake in aged-care residents and its ease of provision makes it a viable option to potentially prevent malnutrition. PMID- 23732547 TI - Efficacy of specific bioelectrical impedance vector analysis (BIVA) for assessing body composition in the elderly. AB - OBJECTIVES: This study aimed to ascertain the efficacy of bioelectrical impedance vector analysis (BIVA) in assessing body composition in the elderly by comparing findings with the results of dual-energy X-ray absorptiometry (DXA), and to test an analytical variant of the method (specific BIVA). DESIGN: Cross-sectional study. PARTICIPANTS: The sample comprised 207 free-living elderly individuals (75 men and 132 women) aged 65 to 93 years. MEASUREMENTS: Anthropometric and bioelectrical measurements were taken according to standard criteria. BIVA was applied using the 'classic' procedure and correcting bioelectrical values for body geometry to obtain an estimate of the whole-body impedivity. DXA was used as a reference body composition assessment method. BIVA (classic and specific values) and DXA findings were compared using Student's t and Hotelling's T2 tests, and Pearson's correlation coefficient. RESULTS: In both sexes, BIVA distinguished between individuals with different amounts of fat and fat-free mass (lean mass including bone mineral content), according to DXA, but not between those with different proportions of fat mass (FM%). Specific bioelectrical values detected changes in body composition. CONCLUSION: BIVA should be used with caution for evaluating body composition in the elderly. Specific bioelectrical values proved effective, showing promise as a methodological variant of BIVA, suitable for identifying age-related changes in body fatness. PMID- 23732548 TI - Late-life metabolic syndrome prevents cognitive decline among older men aged 75 years and over: one-year prospective cohort study. AB - BACKGROUND: Although metabolic syndrome (MetS) has been reported to be associated with cognitive decline and dementia, little was known about late-life MetS and cognitive decline among older old population. The main purpose of this study was to evaluate the role of MetS and cognitive decline among men aged 75 and over in Taiwan. METHODS: This is a prospective cohort study which recruited men aged 75 years and older with intact cognitive function living in the Banciao Veterans Home, a retirement community for veterans in northern Taiwan. All participants received complete history taking, physical examinations, global cognitive tests and laboratory tests. Cognitive status was re-evaluated one year after enrollment to evaluate the role of MetS to cognitive decline in this study population. RESULTS: Overall, 338 people participated in the study and 62 of them were excluded due to low baseline MMSE score, and the remaining 276 people (mean age: 82.4+/-4.2 years) were enrolled for study. The prevalence of MetS and annual cognitive decline were 22.5% and 15.6%, respectively. During the follow-up period, 9 (3.3%) participants died, 229(83.0%) complete the study. Subjects with cognitive decline were older and had lower serum levels of serum total cholesterol. Multivariate logistic regression showed that older age (OR:1.13, 95% C.I.: 1.01-1.25, P=0.026) and central obesity (OR: 4.19, 95% CI: 1.26-13.91, P=0.019) were independent risk factors for cognitive decline; and MetS defined by Adult Treatment Panel III was a protective factor (OR: 0.20, 95% CI: 0.04-0.94, P=0.041). The protective effect of MetS remained the same when MetS was defined by the criteria of International Diabetes Federation. CONCLUSIONS: Age and central obesity were significant risk factors of cognitive decline, but late-life MetS, however defined, had protective effect on cognitive function. Further investigation is needed to clarify the possible mechanism of MetS and cognitive function in older adults. PMID- 23732549 TI - Homocysteine levels and cognitive function scores measured with MMSE and BCAT of middle-aged and elderly subjects in Tianjin City. AB - OBJECTIVE: China is proceeding into the aging society. There are near 6 million elderly suffering senile dementia,while cognitive impairment is an important clinical feature in dementia. The factors involved in cognitive dysfunction in the middle-aged and the elderly persons were investigated. DESIGN: Cross sectional study. SETTING: Community dwellers and nursing home residents in Tianjin, China. SUBJECTS: Total of 662 subjects(284 men and 378 women) aged 55 93. METHODS: A designed questionnaire was used to collect their demographic data, information of disease and medication, and life style. Mini-mental state examination (MMSE) and Basic Cognitive Aptitude Tests (BCAT) software were applied to evaluate their cognitive function. Serum total homocysteine (tHcy) level was quantified by enzyme conversion method. A multiple linear stepwise regression analysis was applied to find the influencing factors of cognitive function. RESULTS: The average serum tHcy concentrations was 15.95+/-7.29 MUmol/L, while the prevalence of hyperhomocysteinemia (HHE) was 45.4%. The average serum tHcy level and prevalence of HHE were higher in men than those in women after ruling out the age differences. The mean MMSE and BCAT scores were 26.74+/-2.71 and 50.26+/-18.84 respectively. The BCAT score was negatively correlated with age and positively correlated with education. Multiple linear stepwise regression equations showed that the P value was less than 0.001, the BCAT regression equation showed that the R2=0.453. Serum tHcy concentration was negatively correlated with total scores of BCAT, digit copy, Chinese character comparison, mental arithmetic, Chinese character rotation and recall answer of mental arithmetic test. Total scores of BCAT were negatively correlated with education, inhabitancy, serum tHcy concentration and age. In addition, Chinese character rotation was correlated with tea consumption. Remembrance and recognition of dual words and nonsense figures was correlated with income level. CONCLUSIONS: Hyperhomocysteinemia is associated with cognitive impairment in the middle-aged and the elderly persons in Tianjin. The BCAT scores could well represent the detailed cognitive function in elderly and negatively correlate with age, but positively correlated with education level. Serum tHcy concentration was negatively correlated with total BCAT scores. PMID- 23732550 TI - A phase IIA randomized, placebo-controlled clinical trial to study the efficacy and safety of the selective androgen receptor modulator (SARM), MK-0773 in female participants with sarcopenia. AB - BACKGROUND: Sarcopenia, the age-related loss of muscle mass [defined as appendicular LBM/Height2 (aLBM/ht2) below peak value by>1SD], strength and function, is a major contributing factor to frailty in the elderly. MK-0773 is a selective androgen receptor modulator designed to improve muscle function while minimizing effects on other tissues. OBJECTIVES: The primary objective of this study was to demonstrate an improvement in muscle strength and lean body mass (LBM) in sarcopenic frail elderly women treated with MK-0773 relative to placebo. DESIGN: This was a randomized, double-blind, parallel-arm, placebo-controlled, multicenter, 6-month study. Participants were randomized in a 1:1 ratio to receive either MK-0773 50mg b.i.d. or placebo; all participants received Vitamin D and protein supplementation. SETTING: General community. PARTICIPANTS: 170 Women aged >=65 with sarcopenia and moderate physical dysfunction. MEASUREMENTS: Dual energy X-ray absorptiometry, muscle strength and power, physical performance measures. RESULTS: Participants receiving MK-0773 showed a statistically significant increase in LBM from baseline at Month 6 vs. placebo (p<0.001). Participants receiving both MK-0773 and placebo showed a statistically significant increase in strength from baseline to Month 6, but the mean difference between the two groups was not significant (p=0.269). Both groups showed significant improvement from baseline at Month 6 in physical performance measures, but there were no statistically significant differences between participants receiving MK-0773 and placebo. A greater number of participants experienced elevated transaminases in the MK-0773 group vs. placebo, which resolved after discontinuation of study therapy. MK-0773 was generally well tolerated with no evidence of androgenization. CONCLUSIONS: The MK-0773-induced increase in LBM did not translate to improvement in strength or function vs. placebo. The improvement of strength and physical function in the placebo group could be at least partly attributed to protein and vitamin D supplementation. PMID- 23732551 TI - Virgin olive oil supplementation and long-term cognition: the PREDIMED-NAVARRA randomized, trial. AB - OBJECTIVE: To assess the effect on cognition of a controlled intervention testing Mediterranean diets (MedDiet). DESIGN: Randomized trial after 6.5 years of nutritional intervention. SETTING: Eight primary care centers affiliated to the University of Navarra. PARTICIPANTS: A random subsample of 285 participants (95 randomly allocated to each of 3 groups) of the PREDIMED-NAVARRA trial. All of them were at high vascular risk (44.8% men, 74.1+/-5.7 years at cognitive evaluation). INTERVENTIONS: Nutritional intervention comparing two MedDiets (supplemented with extra-virgin olive oil [EVOO] or mixed nuts) versus a low-fat control diet. Participants received intensive education to increase adherence to the intended intervention. Participants allocated to the MedDiet groups received EVOO (1 l/week) or 30 g/day of mixed nuts. Dietary habits were evaluated using a validated 137-item food frequency questionnaire (FFQ). Additionally, adherence to MedDiet was appraised using a 14-item questionnaire both at baseline and yearly thereafter. MEASUREMENTS: Cognitive performance as a main outcome and cognitive status (normal, mild cognitive impairment [MCI] or dementia) as a secondary outcome were evaluated by two neurologists blinded to group assignment after 6.5 years of nutritional intervention. RESULTS: Better post-trial cognitive performance versus control in all cognitive domains and significantly better performance across fluency and memory tasks were observed for participants allocated to the MedDiet+EVOO group. After adjustment for sex, age, education, apolipoprotein E genotype, family history of cognitive impairment/dementia, smoking, physical activity, body mass index, hypertension, dyslipidaemia, diabetes, alcohol and total energy intake, this group also showed lower MCI (OR=0.34 95% CI: 0.12-0.97) compared with control group. Participants assigned to MedDiet+Nuts group did not differ from controls. CONCLUSION: A long-term intervention with an EVOO-rich MedDiet resulted in a better cognitive function in comparison with a control diet. However, non-significant differences were found for most cognitive domains. Participants allocated to an EVOO-rich MedDiet had less MCI than controls. PMID- 23732552 TI - A Jerte valley cherry product provides beneficial effects on sleep quality. Influence on aging. AB - OBJECTIVE: In the present work, we evaluated the effect of the intake of a Jerte Valley cherry-based product (JVCP), compared to a placebo product, on sleep quality, urinary 6-sulfatoxymelatonin (aMT6-s) levels and the serum concentration of interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha) and interleukin-8 (IL-8). DESIGN: This was a blind, placebo-controlled, randomized, crossover study. SETTING: University of Extremadura (Spain). PARTICIPANTS: Ten young (20-30 years old), ten middle-aged (35-55 years old), and ten elderly (65 85 years old) participants. INTERVENTION: A placebo (Kool-Aid(r)) or JVCP (patent no. ES 2342141 B1) were consumed twice a day, as lunch and dinner desserts. MEASUREMENTS: Actigraphic monitoring was used to record and display the temporal patterns of the individuals' activity and rest. Urinary aMT6-s and serum cytokines (IL-1beta, TNF-alpha and IL-8) were also determined. RESULTS: The consumption of the JVCP improved the nocturnal rest, measured by sleep efficiency, number of awakenings, total nocturnal activity, sleep latency, assumed sleep, actual sleep time and immobility. Moreover, it was detected an increase in both the levels of aMT6-s found in first-void morning urine and the concentrations of serum pro-somnogenic cytokines obtained from samples collected at the acrophase of the melatonin rhythm (1.00 am) in all experimental age groups after the JVCP consumption. Generally, better results were obtained with advancing age. CONCLUSION: The ingestion of the JVCP may contribute to establish a high-quality sleep and be used as a potential nutraceutical tool to prevent sleep disorders with the advance of age. PMID- 23732553 TI - Celiac disease is not increased in women with hip fractures and low vitamin D levels. AB - OBJECTIVE: Celiac disease is associated with decreased bone density; however, the risk of fractures in celiac disease patients is unclear. We compared the prevalence of celiac disease between a group of women with hip fractures and a group of women undergoing elective joint replacement surgery and the association between celiac disease and vitamin D levels. METHODS: Two hundred eight community dwelling and postmenopausal women were recruited from Boston, MA (n=81) and Baltimore, MD (n=127). We measured tissue transglutaminase IgA by ELISA to diagnose celiac disease and 25-hydroxyvitamin D (25(OH)D) levels by radioimmunoassay in both women with hip fractures (n=157) and a control group (n=51) of total hip replacement subjects from Boston. Subjects were excluded if they took any medications or had medical conditions that might affect bone. RESULTS: Median serum 25(OH)D levels were significantly lower (p< 0.0001) in the hip fracture cohorts compared to the elective joint replacement cohort (14.1 ng/ml vs. 21.3 ng/ml, respectively). There were no differences in the percentage of subjects with a positive tissue transglutaminase in the women with hip fractures versus the control group (1.91% vs. 1.96%, respectively). CONCLUSION: Vitamin D levels are markedly reduced in women with hip fractures, however hip fracture patients did not show a higher percentage of positive tissue transglutaminase levels compared with controls. These data suggest that routine testing for celiac disease among hip fracture patients may not be necessary in the absence of clinical signs and symptoms, although data from larger studies among hip fracture subjects are needed. PMID- 23732554 TI - Dietary patterns and relationship to obesity-related health outcomes and mortality in adults 75 years of age or greater. AB - BACKGROUND: The prevalence of obesity-related adverse health outcomes is increasing among older adults. Because it is thought that nutrition plays an important role in successful aging, there has been considerable interest in the association between dietary patterns of older adults and obesity-related health outcomes. OBJECTIVE: This study examined the association between dietary patterns and mortality and prevalence of obesity-related health outcomes, namely cardiovascular disease (CVD), type 2 diabetes mellitus, hypertension, and metabolic syndrome (MetSyn), over a 5-year follow-up period in adults aged 75 years or greater. DESIGN: A longitudinal observational study with cross-sectional dietary assessment. SETTING: Rural Central Pennsylvania. PARTICIPANTS: Community dwelling older adults (N = 449; 76.5 years old; 57% female). MEASUREMENTS: Multiple, unannounced, 24-hour dietary recalls were used to collect dietary intake. Cluster analysis was used to derive dietary patterns. Prevalence of CVD, diabetes mellitus, hypertension, and MetSyn was extracted from outpatient electronic medical records. Logistic regression was used to examine the associations between dietary patterns and health outcomes and mortality. RESULTS: 'Sweets and Dairy', 'Health-Conscious' and 'Western' dietary patterns were identified. Compared to the 'Health-Conscious' pattern, those in the 'Sweets and Dairy' pattern had increased odds of hypertension over the follow-up period; adjusted odds ratio (95% CI) was 2.18 (1.11-4.30). No significant associations were found for CVD, diabetes mellitus, MetSyn or mortality with dietary patterns. CONCLUSIONS: These findings support the potential value of healthy dietary patterns in the management of hypertension in older adults. We did not observe any other strong associations between dietary patterns and health outcomes or mortality in persons >= 75 years of age; thus failing to support the use of overly restrictive diet prescriptions for older persons, especially where food intake may be inadequate. PMID- 23732555 TI - Unexplained pain complaints and depression in older people in primary care. AB - OBJECTIVE: Chronic pain and depression are frequent conditions in primary care patients. Depression is frequently overlooked in the presence of pain of uncertain origin. The aim is to measure the prevalence and clinical correlates of unrecognized comorbid mood disorders and chronic pain of uncertain origin in older primary care patients, and to elucidate the differences with younger adults with the same conditions. DESIGN: Cross-sectional study. SETTING: Primary care centres in Spain. PARTICIPANTS: Patients (n= 2720) with persistent pain of uncertain origin. MEASUREMENTS: Pain characteristics, sites and intensity (Visual Analogical Scales), depression (PRIME-MD interview), clinical characteristics and health services use. RESULTS: We observed a similarly high (80.5%) prevalence of undiagnosed mood disorders (especially major depressive disorders) among older and younger adult patients with comorbid chronic pain complaints of uncertain origin. Older patients suffered pain that was more intense, longer lasting and located in a higher number of different areas, when compared to younger patients. Pain intensity was a factor associated with suffering from mood disorders among patients above 65 years, whilst the number of pain sites was a more important factor among younger patients. CONCLUSIONS: Depression is highly associated with pain of uncertain origin in older patients with differences in pain characteristics when compared to younger patients. The robust comorbid relationship between both conditions should alert clinicians to specifically look for depression in the presence of poorly explained painful symptoms. PMID- 23732557 TI - Modeling the presence probability of invasive plant species with nonlocal dispersal. AB - Mathematical models for the spread of invading plant organisms typically utilize population growth and dispersal dynamics to predict the time-evolution of a population distribution. In this paper, we revisit a particular class of deterministic contact models obtained from a stochastic birth process for invasive organisms. These models were introduced by Mollison (J R Stat Soc 39(3):283, 1977). We derive the deterministic integro-differential equation of a more general contact model and show that the quantity of interest may be interpreted not as population size, but rather as the probability of species occurrence. We proceed to show how landscape heterogeneity can be included in the model by utilizing the concept of statistical habitat suitability models which condense diverse ecological data into a single statistic. As ecologists often deal with species presence data rather than population size, we argue that a model for probability of occurrence allows for a realistic determination of initial conditions from data. Finally, we present numerical results of our deterministic model and compare them to simulations of the underlying stochastic process. PMID- 23732556 TI - Elevated homocysteine levels are associated with low muscle strength and functional limitations in older persons. AB - OBJECTIVE: The current study aimed to examine homocysteine in relation to different aspects of physical functioning. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional and longitudinal data (3-years follow-up) from the Longitudinal Aging Study Amsterdam (LASA) were used. The study was performed in persons aged >= 65 years (N= 1301 after imputation). MEASUREMENTS: Different measures of physical functioning, including muscle mass, grip strength, functional limitations, and falling were regarded as outcomes. Gender and serum creatinine level were investigated as effect modifiers. RESULTS: Results were stratified by gender. In men, higher homocysteine levels were associated with lower grip strength (Quartile 4: regression coefficient (B)= -3.07 (-4.91; -1.22)), and more functional limitations at baseline (Quartile 4: B= 1.15 (0.16-2.14)). In women, higher homocysteine levels were associated with more functional limitations after 3 years (Quartile 4: B= 1.19 (0.25; 2.13)). Higher homocysteine levels were not associated with low muscle mass or falling. CONCLUSIONS: These data suggest an inverse association of homocysteine levels with functional limitations in older men and women, and with muscle strength in older men. PMID- 23732558 TI - Transmission dynamics for vector-borne diseases in a patchy environment. AB - In this paper, a mathematical model is derived to describe the transmission and spread of vector-borne diseases over a patchy environment. The model incorporates into the classic Ross-MacDonald model two factors: disease latencies in both hosts and vectors, and dispersal of hosts between patches. The basic reproduction number R(0) is identified by the theory of the next generation operator for structured disease models. The dynamics of the model is investigated in terms of R(0). It is shown that the disease free equilibrium is asymptotically stable if R(0) > 1, and it is unstable if R(0) > 1; in the latter case, the disease is endemic in the sense that the variables for the infected compartments are uniformly persistent. For the case of two patches, more explicit formulas for R(0) are derived by which, impacts of the dispersal rates on disease dynamics are also explored. Some numerical computations for R(0) in terms of dispersal rates are performed which show visually that the impacts could be very complicated: in certain range of the parameters, R(0) is increasing with respect to a dispersal rate while in some other range, it can be decreasing with respect to the same dispersal rate. The results can be useful to health organizations at various levels for setting guidelines or making policies for travels, as far as malaria epidemics is concerned. PMID- 23732559 TI - Foreword: inverse problems in biology. PMID- 23732560 TI - Convergent synthesis of MUC1 glycopeptides via serine ligation. AB - Syntheses of MUC1 glycopeptides (40-mer and 80-mer) are described. The convergent synthesis was achieved by native serine ligation using side-chain unprotected glycopeptide segments. PMID- 23732561 TI - Thermoregulatory deficits in adult Long Evans rat exposed perinatally to the antithyroidal drug, propylthiouracil. AB - Developmental exposure to endocrine disrupting drugs and environmental toxicants has been shown to alter a variety of physiological processes in mature offspring. Body (core) temperature (T(c)) is a tightly regulated homeostatic system but is susceptible to disruptors of the hypothalamic pituitary thyroid (HPT) axis. We hypothesized that thermoregulation would be disrupted in adult offspring exposed perinatally to an HPT disruptor. Propylythiouracil (PTU) was used as a prototypical compound because of its well known antithyroidal properties. PTU was added to the drinking water of pregnant rats in concentrations of 0, 1, 2, 3, and 10 ppm from gestational day (GD) 6 through postnatal day (PND) 21. Adult male offspring were implanted with radiotransmitters to monitor Tc and motor activity (MA) and were observed undisturbed at an ambient temperature of 22 degrees C for 12 consecutive days. Data were averaged into a single 24 hour period to minimize impact of ultradian changes in T(c) and MA. All treatment groups showed a distinct circadian temperature rhythm. Rats exposed to 10 ppm PTU exhibited a marked deviation in their regulated T(c) with a reduction of approximately 0.4 degrees C below that of controls throughout the daytime period and a smaller reduction at night. Rats exposed to 1 or 2 ppm also had smaller but significant reductions in T(c). MA was unaffected by PTU. Overall, developmental exposure to moderate doses of an antithyroidal drug led to an apparent permanent reduction in T(c) of adult offspring that was independent of changes in MA. PMID- 23732562 TI - Prediction of drug target groups based on chemical-chemical similarities and chemical-chemical/protein connections. AB - Drug-target interaction is a key research topic in drug discovery since correct identification of target proteins of drug candidates can help screen out those with unacceptable toxicities, thereby saving expense. In this study, we developed a novel computational approach to predict drug target groups that may reduce the number of candidate target proteins associated with a query drug. A benchmark dataset, consisting of 3028 drugs assigned within nine categories, was constructed by collecting data from KEGG. The nine categories are (1) G protein coupled receptors, (2) cytokine receptors, (3) nuclear receptors, (4) ion channels, (5) transporters, (6) enzymes, (7) protein kinases, (8) cellular antigens and (9) pathogens. The proposed method combines the data gleaned from chemical-chemical similarities, chemical-chemical connections and chemical protein connections to allocate drugs to each of the nine target groups. A jackknife test applied to the training dataset that was constructed from the benchmark dataset, provided an overall correct prediction rate of 87.45%, as compared to 87.79% for the test dataset that was constructed by randomly selecting 10% of samples from the benchmark dataset. These prediction rates are much higher than the 11.11% achieved by random guesswork. These promising results suggest that the proposed method can become a useful tool in identifying drug target groups. This article is part of a Special Issue entitled: Computational Proteomics, Systems Biology & Clinical Implications. Guest Editor: Yudong Cai. PMID- 23732563 TI - RAPID: fast and accurate sequence-based prediction of intrinsic disorder content on proteomic scale. AB - Recent research in the protein intrinsic disorder was stimulated by the availability of accurate computational predictors. However, most of these methods are relatively slow, especially considering proteome-scale applications, and were shown to produce relatively large errors when estimating disorder at the protein- (in contrast to residue-) level, which is defined by the fraction/content of disordered residues. To this end, we propose a novel support vector Regression based Accurate Predictor of Intrinsic Disorder (RAPID). Key advantages of RAPID are speed (prediction of an average-size eukaryotic proteome takes <1h on a modern desktop computer); sophisticated design (multiple, complementary information sources that are aggregated over an input chain are combined using feature selection); and high-quality and robust predictive performance. Empirical tests on two diverse benchmark datasets reveal that RAPID's predictive performance compares favorably to a comprehensive set of state-of-the-art disorder and disorder content predictors. Drawing on high speed and good predictive quality, RAPID was used to perform large-scale characterization of disorder in 200+ fully sequenced eukaryotic proteomes. Our analysis reveals interesting relations of disorder with structural coverage and chain length, and unusual distribution of fully disordered chains. We also performed a comprehensive (using 56000+ annotated chains, which doubles the scope of previous studies) investigation of cellular functions and localizations that are enriched in the disorder in the human proteome. RAPID, which allows for batch (proteome wide) predictions, is available as a web server at http://biomine.ece.ualberta.ca/RAPID/. PMID- 23732564 TI - Intravenous valproate inhibits ongoing and evoked activity of dura-sensitive thalamic neurons in rats. AB - Valproate is widely used for migraine treatments, although precise mechanisms of its anticephalgic action are poorly understood. Migraine attacks are thought to occur due to trigemino-vascular system activation, which in turn, stimulates nociceptive transmission in trigemino-thalamo-cortical pathway. The ventroposteromedial (VPM) nucleus of the thalamus is considered to play a prominent role in neurobiology of headaches by serving as the highest subcortical relay for conveying nociceptive information from intra- and extra-cranial structures to the cortex. While it has been demonstrated that valproate can modulate trigemino-vascular nociceptive neurotransmission in the VPM, its effects have been investigated using only intrathalamic ejection of the compound in pentobarbitone sodium anesthetized rats. The objective of our study was to evaluate the effects of intravenously administered valproate on both ongoing firing of the VPM neurons and their activity induced by electrical stimulation of the dura mater. The experiments were performed on rats under nonbarbiturate anesthesia. To define the dose-dependent properties and longevity of the studied effects of valproate, two distinguished dosing regiments were used: bolus (single infusion at a dose of 300 mg/kg) and cumulative (thrice-repeated administration of 100mg/kg performed 30 min apart). Intravenous administration of valproate produced the dose-dependent suppression of both the ongoing activity of the thalamic VPM neurons and their responses to electrical stimulation of the dura mater. This effect was fast-developing (within 5 min) and short-lasting (no longer than 30 min). These data suggest that intravenous administration of valproate could produce a reduction of the thalamo-cortical nociceptive transmission associated with trigemino-vascular activation. PMID- 23732566 TI - Osteoarthritis: Mohawk is downregulated in ACLs from knees with OA. PMID- 23732571 TI - A possible strategy to produce pigs resistant to porcine reproductive and respiratory syndrome virus. AB - The purpose of this study was to enhance the production of transgenic cloned embryos with porcine reproductive and respiratory syndrome virus (PRRSV) shRNA expression cassettes. To construct transgenic vector with expression targeting against PRRSV, PRRSV shRNA expression cassettes were inserted into pEGFP-N1 and the ability of resulting recombinant plasmid pEGFP-G1 inhibiting virus replication was examined in Marc-145 cells. Results showed that PRRSV replication could be significantly inhibited by pEGFP-G1 in Marc-145 cells compared with the control. The pEGFP-G1 plasmid was used to deliver a transgene expressing EGFP and the PRRSV shRNA into porcine fetal fibroblasts (PFF). Fluorescent-positive cells were used as nuclear donors for somatic cell nuclear transfer (SCNT) to produce shRNA-EGFP transgenic cloned embryos. The effects of trichostatin A (TSA) on production of transgenic cloned embryos were investigated. Reconstructed embryos were designed into 4 groups: Donor cells of Group A were treated with 50nM TSA for 24h before SCNT. Reconstructed embryos of Group B were treated with 50nM TSA for 24h after activation. Both donor cells and reconstructed embryos in Group C were treated with TSA and Group D were the control without TSA treatment. The results showed no difference (p>0.05) in cleavage rates among the 4 groups; however, blastocyst developmental rates of Group B and C (30.9% and 42.0%, respectively) were higher than for Group A and D (21.2% and 22.1%, respectively) with Group C highest among groups (p<0.05). Interestingly, EGFP expression intensity of transgenic cloned blastocysts of Group A was the highest. Our results provide promising evidence toward a new approach for production of transgenic cloned pigs with resistance to PRRSV and possibly a wide variety of other porcine diseases. PMID- 23732569 TI - Gene-function studies in systemic lupus erythematosus. AB - The aetiology of systemic lupus erythematosus (SLE) is complex and is known to involve both genetic and environmental factors. In a small number of patients, single-gene defects can lead to the development of SLE. Such genes include those encoding early components of the complement cascade and the 3'-5' DNA exonuclease TREX1. In addition, genome-wide association studies have identified single nucleotide polymorphisms that confer some susceptibility to SLE. In this Review, we discuss selected examples of genes whose products have distinctly altered function in SLE and contribute to the pathogenic process. Specifically, we focus on the genes encoding integrin alphaM (ITGAM), IgG Fc receptors, sialic acid O acetyl esterase (SIAE), the catalytic subunit of protein phosphatase PP2A (PPP2CA) and signalling lymphocytic activation molecule (SLAM) family members. Moreover, we highlight the changes in epigenetic signatures that occur in SLE. Such epigenetic modifications, which are abundantly present and might alter gene expression in the presence or absence of susceptibility variants, should be carefully considered when deconstructing the contribution of individual genes to the complex pathogenesis of SLE. PMID- 23732572 TI - Crowdsourcing participatory evaluation of medical pictograms using Amazon Mechanical Turk. AB - BACKGROUND: Consumer and patient participation proved to be an effective approach for medical pictogram design, but it can be costly and time-consuming. We proposed and evaluated an inexpensive approach that crowdsourced the pictogram evaluation task to Amazon Mechanical Turk (MTurk) workers, who are usually referred to as the "turkers". OBJECTIVE: To answer two research questions: (1) Is the turkers' collective effort effective for identifying design problems in medical pictograms? and (2) Do the turkers' demographic characteristics affect their performance in medical pictogram comprehension? METHODS: We designed a Web based survey (open-ended tests) to ask 100 US turkers to type in their guesses of the meaning of 20 US pharmacopeial pictograms. Two judges independently coded the turkers' guesses into four categories: correct, partially correct, wrong, and completely wrong. The comprehensibility of a pictogram was measured by the percentage of correct guesses, with each partially correct guess counted as 0.5 correct. We then conducted a content analysis on the turkers' interpretations to identify misunderstandings and assess whether the misunderstandings were common. We also conducted a statistical analysis to examine the relationship between turkers' demographic characteristics and their pictogram comprehension performance. RESULTS: The survey was completed within 3 days of our posting the task to the MTurk, and the collected data are publicly available in the multimedia appendix for download. The comprehensibility for the 20 tested pictograms ranged from 45% to 98%, with an average of 72.5%. The comprehensibility scores of 10 pictograms were strongly correlated to the scores of the same pictograms reported in another study that used oral response-based open-ended testing with local people. The turkers' misinterpretations shared common errors that exposed design problems in the pictograms. Participant performance was positively correlated with their educational level. CONCLUSIONS: The results confirmed that crowdsourcing can be used as an effective and inexpensive approach for participatory evaluation of medical pictograms. Through Web-based open-ended testing, the crowd can effectively identify problems in pictogram designs. The results also confirmed that education has a significant effect on the comprehension of medical pictograms. Since low-literate people are underrepresented in the turker population, further investigation is needed to examine to what extent turkers' misunderstandings overlap with those elicited from low-literate people. PMID- 23732573 TI - Solely targeting "alactatemia" in septic shock resuscitation?: Let's be cautious- it's not so simple. PMID- 23732574 TI - Fatigue is the best pillow: sleepiness vs fatigue in sarcoidosis. PMID- 23732575 TI - Cell therapy for lung disease: a step forward. PMID- 23732576 TI - Lung cancer: is it node number or location?: Pardon me, but what is the question? PMID- 23732577 TI - Occupational lung disease: from case reports to prevention. PMID- 23732579 TI - Point: can Doppler echocardiography estimates of pulmonary artery systolic pressures be relied upon to accurately make the diagnosis of pulmonary hypertension? Yes. PMID- 23732580 TI - Counterpoint: can Doppler echocardiography estimates of pulmonary artery systolic pressures be relied upon to accurately make the diagnosis of pulmonary hypertension? No. PMID- 23732581 TI - Rebuttal from Dr Rudski. PMID- 23732582 TI - Rebuttal from Dr Rich. PMID- 23732583 TI - Quality improvement and pay for performance: barriers to and strategies for success. AB - Linking health-care quality improvement to payment appears straightforward. Improve the care that one provides to one's patients, and one is rewarded financially. Should one fail to improve care, then one is financially penalized. However, this strategy assumes that health-care workers and administrators possess the necessary tools and knowledge to improve care and that the metrics being measured have been rigorously tested. Although health-care workers and hospitals are publically committed to reducing inappropriate care, improving patient safety, achieving better health outcomes, and holding down costs, many are unsure how to do this effectively. We present the case that it is not usually the people who create the problems in our health system; rather, it is the processes of the care-delivery system that require change. Incentivizing performance improvement using simple metrics is unlikely to work before using compensation strategies to incentivize behavior change in clinical systems. But prior to even doing this, leaders and physicians must first create accurate performance measures and understand improvement science. PMID- 23732584 TI - Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with pulmonary vasculopathy. OBJECTIVE: The purpose of this study was to determine whether sildenafil improves 6-min walk distance (6MWD) in subjects with IPF and right ventricular dysfunction. METHODS: The IPFnet, a network of IPF research centers in the United States, conducted a randomized trial examining the effect of sildenafil on 6MWD in patients with advanced IPF, defined by carbon monoxide diffusing capacity < 35% predicted. A substudy examined 119 of 180 randomized subjects where echocardiograms were available for independent review by two cardiologists. Right ventricular (RV) hypertrophy (RVH), right ventricular systolic dysfunction (RVSD), and right ventricular systolic pressure (RVSP) were assessed. Multivariable linear regression models estimated the relationship between RV abnormality, sildenafil treatment, and changes in 6MWD, St. George's Respiratory Questionnaire (SGRQ), the EuroQol instrument, and SF-36 Health Survey (SF-36) from enrollment to 12 weeks. RESULTS: The prevalence of RVH and RVSD were 12.8% and 18.6%, respectively. RVSP was measurable in 71 of 119 (60%) subjects; mean RVSP was 42.5 mm Hg. In the subgroup of subjects with RVSD, subjects treated with sildenafil experienced less decrement in 6MWD (99.3 m; P = .01) and greater improvement in SGRQ (13.4 points; P = .005) and EuroQol visual analog scores (17.9 points; P = .04) than subjects receiving placebo. In the subgroup with RVH, sildenafil was not associated with change in 6MWD (P = .13), but was associated with greater relative improvement in SGRQ (14.8 points; P = .02) vs subjects receiving placebo. Sildenafil treatment in those with RVSD and RVH was not associated with change in SF-36. CONCLUSIONS: Sildenafil treatment in IPF with RVSD results in better preservation of exercise capacity as compared with placebo. Sildenafil also improves quality of life in subjects with RVH and RVSD. PMID- 23732585 TI - Efferocytosis and lung disease. AB - In healthy individuals, billions of cells die by apoptosis each day. Clearance of these apoptotic cells, termed "efferocytosis," must be efficient to prevent secondary necrosis and the release of proinflammatory cell contents that disrupt tissue homeostasis and potentially foster autoimmunity. During inflammation, most apoptotic cells are cleared by macrophages; the efferocytic process actively induces a macrophage phenotype that favors tissue repair and suppression of inflammation. Several chronic lung diseases, particularly airways diseases such as chronic obstructive lung disease, asthma, and cystic fibrosis, are characterized by an increased lung burden of uningested apoptotic cells. Alveolar macrophages from individuals with these chronic airways diseases have decreased efferocytosis relative to alveolar macrophages from healthy subjects. These two findings have led to the hypothesis that impaired apoptotic cell clearance may contribute causally to sustained lung inflammation and that therapies to enhance efferocytosis might be beneficial. This review of the English-language scientific literature (2006 to mid-2012) explains how such existing therapies as corticosteroids, statins, and macrolides may act in part by augmenting apoptotic cell clearance. However, efferocytosis can also impede host defenses against lung infection. Thus, determining whether novel therapies to augment efferocytosis should be developed and in whom they should be used lies at the heart of efforts to differentiate specific phenotypes within complex chronic lung diseases to provide appropriately personalized therapies. PMID- 23732587 TI - Respiratory medicine in China: progress, challenges, and opportunities. AB - The past century witnessed a rapid development of respiratory medicine in China. The major burden of respiratory disease has shifted from infectious diseases to chronic noninfectious diseases. Great achievements have been made in improving the national standard of clinical management of various respiratory diseases and in smoking control. The specialty of respiratory medicine is expanding into pulmonary and critical care medicine. Nevertheless, respiratory diseases remain a major public health problem, with new challenges such as air pollution and nosocomial infections. This review describes the history, accomplishments, new challenges, and opportunities in respiratory medicine in China. PMID- 23732586 TI - Risk stratification of hospitalized patients on the wards. AB - Patients who suffer adverse events on the wards, such as cardiac arrest and death, often have vital sign abnormalities hours before the event. Early warning scores have been developed with the aim of identifying clinical deterioration early and have been recommended by the National Institute for Health and Clinical Excellence. In this review, we discuss recently developed and validated risk scores for use on the general inpatient wards. In addition, we compare newly developed systems with more established risk scores such as the Modified Early Warning Score and the criteria used in the Medical Early Response Intervention and Therapy (MERIT) trial in our database of > 59,000 ward admissions. In general we found the single-parameter systems, such as the MERIT criteria, to have the lowest predictive accuracy for adverse events, whereas the aggregate weighted scoring systems had the highest. The Cardiac Arrest Risk Triage (CART) score was best for predicting cardiac arrest, ICU transfer, and a composite outcome (area under the receiver operating characteristic curve [AUC], 0.83, 0.77, and 0.78, respectively), whereas the Standardized Early Warning Score, VitalPAC Early Warning Score, and CART score were similar for predicting mortality (AUC, 0.88). Selection of a risk score for a hospital or health-care system should be guided by available variables, calculation method, and system resources. Once implemented, ensuring high levels of adherence and tying them to specific levels of interventions, such as activation of a rapid response team, are necessary to allow for the greatest potential to improve patient outcomes. PMID- 23732588 TI - What does the law say to Good Samaritans?: A review of Good Samaritan statutes in 50 states and on US airlines. AB - Physicians may encounter medical emergencies outside a hospital or clinical setting, such as on an airplane or at a sporting event. Physicians, particularly critical care physicians, should feel a call of duty to assist in a medical emergency and may do so without complete knowledge of existing laws for protection. The intent of this article is to encourage physicians to have a detailed awareness of Good Samaritan laws in the United States. The authors reviewed and summarized the Aviation Medical Assistance Act (AMAA) as well as the Good Samaritan laws and external defibrillator laws in 50 states and the District of Columbia. Physicians have an ethical duty to provide appropriate emergency care outside hospital or clinical settings and, therefore, should be aware of applicable protective laws. On airplanes, the AMAA provides protection to those physicians acting in Good Samaritan roles on airlines registered in the United States. On the ground, physicians should understand that statutes exist in all jurisdictions to protect Good Samaritans from liability in medical emergencies and in the use of defibrillators. Although there are common elements, each state has its own unique statutory language protecting physicians licensed in that state. All states except Kentucky have statutory language providing immunity to physicians licensed in any other state as well. Some states have interesting statutes relative to other aspects of medical emergency care. A physician entrusted to practice medicine by society and law should be willing to provide appropriate medical care wherever needed. PMID- 23732589 TI - Stereotactic body radiation therapy for lung cancer. AB - Lung cancer remains the leading cause of death worldwide. Because many patients with non-small cell lung cancer are elderly and have multiple comorbid conditions, many with potentially curable disease are unfit to undergo definitive surgical resection. Stereotactic body radiation therapy (SBRT) is increasingly being used to treat patients with medically inoperable stage I non-small cell lung cancer. SBRT combines reproducible and accurate anatomic targeting with the delivery of a very high dose per fraction of radiation to a target. Planning and delivery of SBRT is a coordinated effort between the radiation oncology team and consulting services. Clinical outcomes, toxicity profiles, treatment delivery, and indications for SBRT are reviewed. Services currently billed during planning and treatment of SBRT are detailed. This article introduces to consulting specialists and subspecialists a new Current Procedural Terminology code that has been proposed to more accurately reflect work performed during SBRT by these consulting providers. This code is described, and its implications for patient care are discussed. PMID- 23732590 TI - Evaluation and management of pill aspiration: case discussion and review of the literature. AB - Pill aspiration represents a unique type of foreign body aspiration requiring a distinct diagnostic and therapeutic approach. In many cases, the "foreign body" itself may no longer be present, whereas the airway manifestations may persist for months to years. Limited data exist to guide management decisions. We report two cases of severe airway injury secondary to pill aspiration and provide a review of the literature. Endobronchial surveillance may be important to identify impending airway obstruction via secretions, edema, granulation tissue, or fibrotic stricture. In many cases, the airway sequelae of pill aspiration can be effectively managed with bronchoscopy. PMID- 23732591 TI - Histoplasmomas of uncommon size. AB - Histoplasma capsulatum infection demonstrates a broad spectrum of acute and chronic clinical manifestations. Unlike the acute reaction to proliferating organisms, the chronic complications are often the result of excessive or prolonged host response with a paucity of organisms. Lung nodules (histoplasmomas) may be noted decades after initial infection and present a challenging clinical problem, as they can be difficult to distinguish from malignancy or tuberculomas. Typically, histoplasmomas are small (<1 cm), asymptomatic, and may be stable in size or slowly enlarge over time. Here we report three patients with unusually large, or giant, histoplasmomas (>3 cm) and describe their extreme phenotype. Importantly, two of the patients presented with subacute symptomatic disease, a presentation that is very atypical for histoplasmoma. The term "buckshot" calcification has been used to describe dozens of small (2-4 mm) calcified nodules, so it may be appropriate to label masses that exceed 3 cm as "cannonball" histoplasmoma. PMID- 23732593 TI - Patient-reported outcome measures for sleep disorders and related problems: clinical and research applications. AB - Patients with sleep disorders are most concerned with the impact of these diseases on their quality of life. Patient-reported outcome (PRO) measurement tools, which assess aspects of a patient's health status that come directly from the patient, are well suited to evaluate quality of life related to sleep disorders. Although PRO data are subjective, they can be quantified, evaluated for reliability and reproducibility, and used to answer questions of clinical and research importance. This article reviews various PRO measure tools used for sleep disorders in clinical and research settings. These instruments may play a role in screening, diagnosis, and monitoring of various sleep disorders. PMID- 23732592 TI - Monitoring tissue perfusion, oxygenation, and metabolism in critically ill patients. AB - Alterations in oxygen transport and use are integral to the development of multiple organ failure; therefore, the ultimate goal of resuscitation is to restore effective tissue oxygenation and cellular metabolism. Hemodynamic monitoring is the cornerstone of management to promptly identify and appropriately manage (impending) organ dysfunction. Prospective randomized trials have confirmed outcome benefit when preemptive or early treatment is directed toward maintaining or restoring adequate tissue perfusion. However, treatment end points remain controversial, in large part because of current difficulties in determining what constitutes "optimal." Information gained from global whole-body monitoring may not detect regional organ perfusion abnormalities until they are well advanced. Conversely, the ideal "canary" organ that is readily accessible for monitoring, yet offers an early and sensitive indicator of tissue "unwellness," remains to be firmly identified. This review describes techniques available for real-time monitoring of tissue perfusion and metabolism and highlights novel developments that may complement or even supersede current tools. PMID- 23732594 TI - A 64-year-old man with refractory hypoxemia in cardiogenic shock. PMID- 23732595 TI - A 62-year-old man with hypotension, hyperkalemia, and hyponatremia. PMID- 23732596 TI - A 40-year-old woman with multiple lung nodules. PMID- 23732601 TI - Heterogeneity of response to constant positive pressure in patients with heart failure and coexisting central and obstructive sleep apnea: why? PMID- 23732602 TI - Response. PMID- 23732603 TI - Response. PMID- 23732604 TI - Ethics of the malpractice system. PMID- 23732605 TI - Dilemma in pulmonary metastasectomy: video-assisted thoracoscopic surgery or thoracotomy? PMID- 23732606 TI - Steroids and arteriovenous thrombosis: the role of underlying disease. PMID- 23732607 TI - Response. PMID- 23732608 TI - Lung point: not for everyone. PMID- 23732609 TI - Response. PMID- 23732610 TI - Basis of estimating pleural effusion size on CT scan: reasonable grouping of volume percentage. PMID- 23732611 TI - Response. PMID- 23732612 TI - The use of average body weight in dosing unfractionated heparin. PMID- 23732613 TI - An 87-year-old woman with diabetes, hypertension, and liver cirrhosis in respiratory distress. PMID- 23732614 TI - [Incomplete cranial burst fracture in the thoracolumbar junction. Results 6 years after thoracoscopic monosegmental spondylodesis]. AB - INTRODUCTION: Ventral thoracoscopic spondylodesis of the thoracolumbar spine is an elegant treatment strategy. MATERIAL AND METHODS: In the years 2002 and 2003 a total of 16 patients with incomplete cranial burst fractures were treated by ventral thoracoscopic monosegmental spondylodesis and were included in this study prospectively. The data acquisition was done preoperatively, postoperatively and after 3, 6, 12 and 18 months. After 6 years a follow-up examination was performed in 13 of these patients (5 men and 8 women, average age 36.3 years, follow-up rate 81%) and 8 patients were treated ventrally only whereas 5 patients were treated dorsoventrally. RESULTS: The operative reduction of the kyphotic malalignment was superior in the dorsoventrally treated patients. The persistent gain of monosegmental correction after 6 years seemed to be higher in the patient group treated dorsoventrally. The average physical component summary (PSC) scores were comparable to a control group of the same age and revision surgery was performed in two patients both related to the iliac crest bone graft. CONCLUSIONS: The ventral and dorsoventral therapy strategies showed good and very good functional outcomes, respectively. The dorsoventral treatment concept secured a persistent gain of monosegmental correction which seemed to be superior compared to a ventral only therapy strategy. PMID- 23732615 TI - [Traumatic elbow dislocations in bouldering]. AB - Bouldering is a new trend sport which has become popular in recent years. From April 2011 to June 2012 a total of 5 patients with elbow dislocations from bouldering were admitted to our level 1 trauma center. The injuries varied from simple elbow dislocations to complex fracture dislocations. Elbow dislocations occurred during falling backwards when patients tried to protect themselves by retroversion of both arms. In all cases the falling height was less than 4 meters. The bouldering injury pattern, the diagnostic and therapeutic management as well as the rehabilitation program are described in detail in this article. To the best of our knowledge this is the first report on the special danger of bouldering for complex elbow injuries. PMID- 23732616 TI - Group 2 innate lymphoid cells show up in the skin. PMID- 23732617 TI - Nitric oxide inhibits CXCL12 expression in neuroinflammation. AB - Chemokine CXCL12 (C-X-C motif chemokine ligand 12) restricts immune cell invasion of the central nervous system (CNS) and limits neuroinflammation in experimental autoimmune encephalomyelitis (EAE), an animal model of inflammatory and demyelinating disease of the CNS, multiple sclerosis (MS). Nitric oxide (NO), by contrast, predominantly contributes to CNS tissue destruction in MS and EAE. Thus, the influence of NO on CXCL12 in the inflamed CNS was investigated. Excess expression of inducible NO synthase was inversely correlated to CXCL12 gene expression in spinal cord homogenates of rats immunized to develop EAE. NO inhibited gene expression of CXCL12 in astrocytes and endothelial cells in vitro. The inhibition was paralleled with reduction of p38 mitogen-activated protein kinase (MAPK) phosphorylation and it was mimicked with inhibitors of p38 MAPK activation in astrocytes. In vivo suppression of nitric generation recovered CXCL12 expression in the CNS and attenuated EAE in Dark Agouti rats. On the contrary, in vivo NO donation decreased CXCL12 expression in the CNS of EAE resistant Albino Oxford (AO) rats. However, the effect was not paralleled with induction of EAE in AO rats. It is suggested that NO acting through suppression of p38 MAPK inhibits CXCL12 expression in neuroinflammation. These results imply that downregulation of NO release and protection of CXCL12 expression within the CNS might present the potential approaches in MS therapy. PMID- 23732618 TI - Synthesis, antibacterial and antifungal evaluation of novel 1,4-dihydropyridine derivatives. AB - 3,5-Diacetyl-1,4-dihydro-2,4,6-trimethylpyridine (I) has been condensed with aromatic aldehydes to give the corresponding cinnamoyl derivatives IIa-e. the behavior of IIc, d towards thiourea, hydroxylamine hydrochloride, hydrazine hydrate and other bifunctional reagents has been investigated. The newly synthesized compounds were screened for their antimicrobial activity against Gram positive bacteria, Gram-negative bacteria and as antifungal reagent. Among all the tested compounds, it was found that compounds IIIa and VIIa, b revealed better activity against the Gram-positive rather than the Gram-negative bacteria. PMID- 23732619 TI - Vibrational spectroscopy investigation using ab initio and DFT vibrational analysis of 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepine-4-oxide. AB - The FT-IR and FT-Raman spectrum of 7-chloro-2-methylamino-5-phenyl-3H-1, 4 benzodiazepine-4-oxide (7CMP4BO) has been recorded in the region 4000-400 and 4000-100 cm(-1) respectively. The optimized geometry, Thermodynamic properties, NBO, Molecular Electrostatic Potentials, PES, frequency and intensity of the vibrational bands of 7CMP4BO were obtained by the ab initio HF and density functional theory (DFT), B3LYP/6-31G (d,p) basis set. The molecule orbital contributions were studied by using the total (TDOS), partial (PDOS), and overlap population (OPDOS) density of states. The harmonic vibrational frequencies were calculated and the scaled values have been compared with experimental FT-IR and FT-Raman spectra. A detailed interpretation of the vibrational spectra of this compound has been made on the basis of the calculated potential energy distribution (PED). The linear polarizability (alpha) and the first order hyperpolarizability (beta) values of the investigated molecule have been computed using DFT quantum mechanical calculations. The observed and the calculated frequencies are found to be in good agreement. The experimental spectra also coincide satisfactorily with those of theoretically calculated values. PMID- 23732620 TI - Photocatalytic degradation of methylene blue with Fe doped ZnS nanoparticles. AB - Fe doped ZnS nanoparticles (Zn1-xFexS; where x=0.00, 0.03, 0.05 and 0.10) were synthesized by a chemical precipitation method. The synthesized products were characterized by X-ray diffraction, scanning electron microscope, transmission electron microscope, UV-Vis and photoluminescence spectrometer. The X-ray diffraction and transmission electron microscope studies show that the size of crystallites is in the range of 2-5 nm. Photocatalytic activities of ZnS and 3, 5 and 10 mol% Fe doped ZnS were evaluated by decolorization of methylene blue in aqueous solution under ultraviolet and visible light irradiation. It was found that the Fe doped ZnS bleaches methylene blue much faster than the undoped ZnS upon its exposure to the visible light as compared to ultraviolet light. The optimal Fe/Zn ratio was observed to be 3 mol% for photocatalytic applications. PMID- 23732623 TI - Dehydrogenative desulfurization of thiourea derivatives to give carbodiimides, using hydrosilane and an iron complex. AB - Dehydrogenative desulfurization of thiourea derivatives (RNHC(S)NHR') has been achieved, to give carbodiimides (RN=C=NR'), in the reaction with hydrosilane and (eta(5)-C5H5)Fe(CO)2Me. The obtained carbodiimide reacted with (eta(5) C5H5)Fe(CO)(SiR3) formed in the reaction to give an N-silylated eta(2)-amidino iron complex, which was isolated and then characterized by X-ray analysis. PMID- 23732621 TI - Octreotide prescribing patterns in the palliation of symptomatic inoperable malignant bowel obstruction patients at a single US academic hospital. AB - BACKGROUND: Medical management is the cornerstone of malignant bowel obstruction (MBO) therapy and may include antisecretory agents such as octreotide. Currently, no data exist regarding octreotide prescribing patterns in US academic hospitals in the palliation of inoperable MBO. The aim of this study is to collect octreotide prescribing data to shape future prospective studies. METHODS: This retrospective chart review evaluated inpatient inoperable MBO admissions at a single academic US hospital between 2008 and 2011. The prescribing primary service (medical vs. surgical), inpatient day initiated, average octreotide daily dose, cumulative octreotide dose, days receiving octreotide, length of stay (LOS), subject age, cancer stage, lines of chemotherapy, cancer type, and overall survival were analyzed utilizing a Wilcoxon rank sum test, Spearman rank correlation test, Kaplan-Meier curves, log rank test, and multiple linear regression analysis when appropriate. RESULTS: A total of 767 patients received octreotide. A cancer diagnosis was documented in 134 patients and 37 of these (24 females and 13 males; mean age, 56.7 years) had a confirmed inoperable MBO. Statistical significance was not achieved for variables analyzed. However, octreotide prescribing trends were observed for several variables: the mean LOS was equivalent on both services (16.8 vs. 17 days), mean octreotide dose was higher on the medical service (201.2 MUg vs. 119 MUg surgical), cumulative octreotide dose was higher on the medical service (3,558 vs. 1,884 mcg), mean day of octreotide initiation was roughly equivalent (7.9 days medical vs. 8.8 days surgical), subjects on the medical service had a decreased overall survival, and earlier octreotide initiation (defined as <7 days) was associated with a decreased overall survival. LIMITATION: The data were collected retrospectively, with a limited population distribution at a specific time. CONCLUSIONS: These data possibly suggest that the MBO patients on the medical vs. surgical services are distinct patient populations. MBO patients on the medical service trended to receive higher cumulative doses and have a decreased overall survival compared with surgical patients. Consequently, future studies should possibly consider these distinct study groups. PMID- 23732624 TI - Changes in the affect of infants before and after episodes of crying. AB - This study examined the affect of infants just before the onset of crying and just after crying stopped. Two infants (between 7 and 14 months old) were observed longitudinally. In total, 102 crying episodes were analyzed. The infants displayed negative affect almost always just before starting to cry and soon after crying terminated. However, there were exceptions. Positive affect was observed. These were crying behaviors that the mother identified as "fake crying" or "emergence of fake crying". These data indicate that, although normally infant affect just before and right after crying is negative, infants also can exhibit positive affect when they show fake crying. Infants who are capable of fake crying might communicate successfully with their caregivers. PMID- 23732625 TI - Infants' scanning of dynamic faces during the first year. AB - This research investigated infants' scanning of a talking, socially engaging face. Three- to four-month-olds looked equally at the mouth and eyes whereas 9 month-olds attended more to the eyes than mouth. These findings shed light on information infants' seek from dynamic face stimuli. PMID- 23732628 TI - Convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of metformin. AB - A convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of antidiabetic agent, metformin, is reported in this study. These acyclic prodrugs were synthesized directly from selected disulfides with basic metformin and silver nitrate by a one-pot reaction under microwave irradiation. The prepared prodrugs had significantly increased lipophilicity, which resulted in excellent permeability of the octylthio prodrug of metformin across a Caco-2 cell monolayer. According to our preliminary in vivo studies, the octylthio prodrug was also absorbed mostly intact after oral administration in rats. In conclusion, this study shows that these types of more lipophilic sulfenamide prodrugs can be promising candidates to improve permeability and passive absorption of highly water-soluble metformin. PMID- 23732626 TI - Leveraging metabolomics to assess the next generation of temozolomide-based therapeutic approaches for glioblastomas. AB - Glioblastoma multiforme (GBM) is the most common adult primary tumor of the central nervous system. The current standard of care for glioblastoma patients involves a combination of surgery, radiotherapy and chemotherapy with the alkylating agent temozolomide. Several mechanisms underlying the inherent and acquired temozolomide resistance have been identified and contribute to treatment failure. Early identification of temozolomide-resistant GBM patients and improvement of the therapeutic strategies available to treat this malignancy are of uttermost importance. This review initially looks at the molecular pathways underlying GBM formation and development with a particular emphasis placed on recent therapeutic advances made in the field. Our focus will next be directed toward the molecular mechanisms modulating temozolomide resistance in GBM patients and the strategies envisioned to circumvent this resistance. Finally, we highlight the diagnostic and prognostic value of metabolomics in cancers and assess its potential usefulness in improving the current standard of care for GBM patients. PMID- 23732629 TI - Contribution of syndecans to lipoplex-mediated gene delivery. AB - The long awaited breakthrough of gene therapy significantly depends on the in vivo efficiency of targeted intracellular delivery. Hidden details of cellular uptake present a great hurdle for non-viral gene delivery with liposomes. Growing scientific evidence supports the involvement of polyanionic cell surface carbohydrates in cellular internalization of cationic liposomes. Syndecans, a highly conserved family of transmembrane heparan sulfate proteoglycans serve attachment sites for great variety of cationic ligands including growth factors, cytokines and even parasites. In the present study we quantitatively measured the contribution of various syndecan isoforms to liposome-mediated gene transfer. The obtained data show the superiority of syndecan-4, the ubiquitously expressed isoform of the syndecan family, in cellular uptake of liposomes. Applied mutational analysis demonstrated that gene delivery could be abolished by mutating the glycosaminoglycan attachment site of syndecans, highlighting the importance of polyanionic heparan sulfate side chains in the attachment of cationic liposomes. Blocking sulfation of syndecans also diminished gene delivery, a finding that confirms the essential role of polyanionic charges in binding cationic liposomes. Mutating other parts of the syndecan extracellular domain, including the cell-binding domain, had clearly smaller effect on liposome internalization. Mutational analyses also revealed that superiority of syndecan-4 in liposome-mediated gene delivery is significantly influenced by its cytoplasmic domain that orchestrates signaling pathways leading to macropinocytosis. In summary our study present a mechanistic insight into syndecan-mediated macropinocytic uptake of lipoplexes and highlights syndecan-4 as a superior target for cationic liposomes. PMID- 23732627 TI - Biomarker profiling for lupus nephritis. AB - Lupus nephritis (LN) is one of the most severe manifestations of systemic lupus erythematosus (SLE), which is associated with significant morbidity and mortality of SLE patients. The pathogenesis of LN involves multiple factors, including genetic predisposition, epigenetic regulation and environmental interaction. Over the last decade, omics-based techniques have been extensively utilized for biomarker screening and a wide variety of variations which are associated with SLE and LN have been identified at the levels of genomics, transcriptomics and proteomics. These studies and discoveries have expanded our understanding of the molecular basis of the disease and are important for identification of potential therapeutic targets for disease prediction and early treatment. In this review, we summarize some of the recent studies targeted at the identification of LN associated biomarkers using genomics and proteomic approaches. PMID- 23732631 TI - Surgery: Good outcomes with low-energy direct current prostate ablation. PMID- 23732630 TI - Room temperature and solvent-free iridium-catalyzed selective alkylation of anilines with alcohols. AB - A bidentate iridium NHC-phosphine complex has been developed and applied to the N monoalkylation of aromatic amines with a wide range of primary alcohols and to the N-heterocyclization of amino alcohols. This reaction resulted in high isolated product yields, even at room temperature and under solvent-free conditions. PMID- 23732632 TI - [Thyroid-like follicular carcinoma of the kidney: a separate tumor entity?]. AB - Thyroid-like follicular carcinoma of the kidney is postulated as a potentially new entity of renal tumor based on nine previously published case reports. This tumor entity is not yet integrated into the classification of tumors of the World Health Organization (WHO). In this article a new case of thyroid-like follicular carcinoma of kidney is described which was incidentally detected at autopsy. The 58-year-old patient died of complications of acute myeloid leukemia after chemotherapy and also had prostatic adenocarcinoma. The renal tumor in the left kidney had a diameter of 3 cm and showed a grey-brown cut surface. Histologically, the tumor presented with a typical thyroid-like microfollicular and macrofollicular structure filled with eosinophilic, colloid-like material with calcification. Immunohistologically the renal tumor was CD 10 positive and negative for thyroid transcription factor 1 (TTF1) and thyroglobulin. A synopsis of the published case reports indicates that thyroid-like follicular carcinoma of the kidney has a low risk of metastasis. More experience with further cases of thyroid-like follicular renal carcinoma is necessary before a recommendation of a separate tumor entity in the next WHO classification is justified. PMID- 23732634 TI - Chitosan and a fungal elicitor inhibit tracheary element differentiation and promote accumulation of stress lignin-like substance in Zinnia elegans xylogenic culture. AB - We investigated the effect of elicitors on xylem differentiation and lignification using a Zinnia elegans xylogenic culture system. Water-soluble chitosan and a fungal elicitor derived from Botrytis cinerea were used as elicitors. Elicitor addition at the start of culturing inhibited tracheary element (TE) differentiation in a concentration-dependent manner, and 30 MUg mL( 1) of chitosan or 16.7 MUg mL(-1) of the fungal elicitor strikingly inhibited TE differentiation and lignification. Addition of chitosan (at 50 MUg mL(-1)) or the fungal elicitor (at 16.7 MUg mL(-1)) during the culturing period also inhibited TE differentiation without inhibiting cell division, except for immature TEs undergoing secondary wall thickening. Elicitor addition after immature TE appearance also caused the accumulation of an extracellular lignin-like substance. It appears that elicitor addition at the start of culturing inhibits the process by which dedifferentiated cells differentiate into xylem cell precursors. Elicitor addition during culturing also appears to inhibit the transition from xylem cell precursors to immature TEs, and induces xylem cell precursors or xylem parenchyma cells to produce an extracellular stress lignin like substance. PMID- 23732636 TI - Spirometry in children. AB - Respiratory disorders are responsible for considerable morbidity and mortality in children. Spirometry is a useful investigation for diagnosing and monitoring a variety of paediatric respiratory diseases, but it is underused by primary care physicians and paediatricians treating children with respiratory disease. We now have a better understanding of respiratory physiology in children, and newer computerised spirometry equipment is available with updated regional reference values for the paediatric age group. This review evaluates the current literature for indications, test procedures, quality assessment, and interpretation of spirometry results in children. Spirometry may be useful for asthma, cystic fibrosis, congenital or acquired airway malformations and many other respiratory diseases in children. The technique for performing spirometry in children is crucial and is discussed in detail. Most children, including preschool children, can perform acceptable spirometry. Steps for interpreting spirometry results include identification of common errors during the test by applying acceptability and repeatability criteria and then comparing test parameters with reference standards. Spirometry results depict only the pattern of ventilation, which may be normal, obstructive, restrictive, or mixed. The diagnosis should be based on both clinical features and spirometry results. There is a need to encourage primary care physicians and paediatricians treating respiratory diseases in children to use spirometry after adequate training. PMID- 23732635 TI - Resistance of plants to gravitational force. AB - Developing resistance to gravitational force is a critical response for terrestrial plants to survive under 1 * g conditions. We have termed this reaction "gravity resistance" and have analyzed its nature and mechanisms using hypergravity conditions produced by centrifugation and microgravity conditions in space. Our results indicate that plants develop a short and thick body and increase cell wall rigidity to resist gravitational force. The modification of body shape is brought about by the rapid reorientation of cortical microtubules that is caused by the action of microtubule-associated proteins in response to the magnitude of the gravitational force. The modification of cell wall rigidity is regulated by changes in cell wall metabolism that are caused by alterations in the levels of cell wall enzymes and in the pH of apoplastic fluid (cell wall fluid). Mechanoreceptors on the plasma membrane may be involved in the perception of the gravitational force. In this review, we discuss methods for altering gravitational conditions and describe the nature and mechanisms of gravity resistance in plants. PMID- 23732637 TI - Managing patients with stable respiratory disease planning air travel: a primary care summary of the British Thoracic Society recommendations. AB - Air travel poses medical challenges to passengers with respiratory disease, principally because of exposure to a hypobaric environment. In 2002 the British Thoracic Society published recommendations for adults and children with respiratory disease planning air travel, with a web update in 2004. New full recommendations and a summary were published in 2011, containing key recommendations for the assessment of high-risk patients and identification of those likely to require in-flight supplemental oxygen. This paper highlights the aspects of particular relevance to primary care practitioners with the following key points: (1) At cabin altitudes of 8000 feet (the usual upper limit of in flight cabin pressure, equivalent to 0.75 atmospheres) the partial pressure of oxygen falls to the equivalent of breathing 15.1% oxygen at sea level. Arterial oxygen tension falls in all passengers; in patients with respiratory disease, altitude may worsen preexisting hypoxaemia. (2) Altitude exposure also influences the volume of any air in cavities, where pressure x volume remain constant (Boyle's law), so that a pneumothorax or closed lung bulla will expand and may cause respiratory distress. Similarly, barotrauma may affect the middle ear or sinuses if these cavities fail to equilibrate. (3) Patients with respiratory disease require clinical assessment and advice before air travel to: (a) optimise usual care; (b) consider contraindications to travel and possible need for in flight oxygen; (c) consider the need for secondary care referral for further assessment; (d) discuss the risk of venous thromboembolism; and (e) discuss forward planning for the journey. PMID- 23732638 TI - The BREATHE study: Breathing REtraining for Asthma--Trial of Home Exercises. a protocol summary of a randomised controlled trial. PMID- 23732639 TI - Models for estimating projections for the prevalence and disease burden of chronic obstructive pulmonary disease (COPD): systematic review protocol. PMID- 23732640 TI - Eccentric contractions increase the phosphorylation of tuberous sclerosis complex 2 (TSC2) and alter the targeting of TSC2 and the mechanistic target of rapamycin to the lysosome. AB - The goal of this study was to determine whether the mechanical activation of mechanistic target of rapamycin (mTOR) signalling is associated with changes in phosphorylation of tuberous sclerosis complex-2 (TSC2) and targeting of mTOR and TSC2 to the lysosome. As a source of mechanical stimulation, mouse skeletal muscles were subjected to eccentric contractions (ECs). The results demonstrated that ECs induced hyper-phosphorylation of TSC2 and at least part of this increase occurred on residue(s) that fall within RxRxxS/T consensus motif(s). Furthermore, in control muscles, we found that both mTOR and TSC2 are highly enriched at the lysosome. Intriguingly, ECs enhanced the lysosomal association of mTOR and almost completely abolished the lysosomal association of TSC2. Based on these results, we developed a new model that could potentially explain how mechanical stimuli activate mTOR signalling. Furthermore, this is the first study to reveal that the activation of mTOR is associated with the translocation of TSC2 away from the lysosome. Since a large number of signalling pathways rely on TSC2 to control mTOR signalling, our results have potentially revealed a fundamental mechanism via which not only mechanical, but also various other types of stimuli, control mTOR signalling. PMID- 23732641 TI - Translational physiology: from molecules to public health. AB - The term 'translational research' was coined 20 years ago and has become a guiding influence in biomedical research. It refers to a process by which the findings of basic research are extended to the clinical research setting (bench to bedside) and then to clinical practice and eventually health policy (bedside to community). It is a dynamic, multidisciplinary research approach. The concept of translational physiology applies the translational research model to the physiological sciences. It differs from the traditional areas of integrative and clinical physiology by its broad investigative scope of basic research to community health. Translational physiology offers exciting opportunities, but presently is under-developed and -utilized. A key challenge will be to expand physiological research by extending investigations to communities of patients and healthy (or at risk) individuals. This will allow bidirectional physiological investigation throughout the translational continuum: basic research observations can be studied up to the population level, and mechanisms can be assessed by 'reverse translation' in clinical research settings and preclinical models based on initial observations made in populations. Examples of translational physiology questions, experimental approaches, roadblocks and strategies for promotion are discussed. Translational physiology provides a novel framework for physiology programs and an investigational platform for physiologists to study function from molecular events to public health. It holds promise for enhancing the completeness and societal impact of our work, while further solidifying the critical role of physiology in the biomedical research enterprise. PMID- 23732642 TI - The du(2J) mouse model of ataxia and absence epilepsy has deficient cannabinoid CB1 receptor-mediated signalling. AB - Cerebellar ataxias are a group of progressive, debilitating diseases often associated with abnormal Purkinje cell (PC) firing and/or degeneration. Many animal models of cerebellar ataxia display abnormalities in Ca2+ channel function. The 'ducky' du(2J) mouse model of ataxia and absence epilepsy represents a clean knock-out of the auxiliary Ca2+ channel subunit alpha2delta-2, and has been associated with deficient Ca2+ channel function in the cerebellar cortex. Here, we investigate effects of du(2J) mutation on PC layer (PCL) and granule cell layer (GCL) neuronal spiking activity and, also, inhibitory neurotransmission at interneurone-Purkinje cell (IN-PC) synapses. Increased neuronal firing irregularity was seen in the PCL and, to a less marked extent, in the GCL in du(2J)/du(2J), but not +/du(2J), mice; these data suggest that the ataxic phenotype is associated with lack of precision of PC firing, that may also impinge on GC activity and requires expression of two du(2J) alleles to manifest fully. The du(2J) mutation had no clear effect on spontaneous inhibitory postsynaptic current (sIPSC) frequency at IN-PC synapses, but was associated with increased sIPSC amplitudes. du(2J) mutation ablated cannabinoid CB1 receptor (CB1R)-mediated modulation of spontaneous neuronal spike firing and CB1R-mediated presynaptic inhibition of synaptic transmission at IN-PC synapses in both +/du(2J) and du(2J)/du(2J) mutants, effects that occurred in the absence of changes in CB1R expression. These results demonstrate that the du(2J) ataxia model is associated with deficient CB1R signalling in the cerebellar cortex, putatively linked with compromised Ca2+ channel activity and the ataxic phenotype. PMID- 23732643 TI - Ageing is associated with diminished muscle re-growth and myogenic precursor cell expansion early after immobility-induced atrophy in human skeletal muscle. AB - Recovery of skeletal muscle mass from immobilisation-induced atrophy is faster in young than older individuals, yet the cellular mechanisms remain unknown. We examined the cellular and molecular regulation of muscle recovery in young and older human subjects subsequent to 2 weeks of immobility-induced muscle atrophy. Retraining consisted of 4 weeks of supervised resistive exercise in 9 older (OM: mean age) 67.3, range 61-74 yrs) and 11 young (YM: mean age 24.4, range 21-30 yrs) males. Measures of myofibre area (MFA), Pax7-positive satellite cells (SCs) associated with type I and type II muscle fibres, as well as gene expression analysis of key growth and transcription factors associated with local skeletal muscle milieu, were performed after 2 weeks immobility (Imm) and following 3 days (+3d) and 4 weeks (+4wks) of retraining. OM demonstrated no detectable gains in MFA (vastus lateralis muscle) and no increases in number of Pax7-positive SCs following 4wks retraining, whereas YM increased their MFA (P < 0.05), number of Pax7-positive cells, and had more Pax7-positive cells per type II fibre than OM at +3d and +4wks (P < 0.05). No age-related differences were observed in mRNA expression of IGF-1Ea, MGF, MyoD1 and HGF with retraining, whereas myostatin expression levels were more down-regulated in YM compared to OM at +3d (P < 0.05). In conclusion, the diminished muscle re-growth after immobilisation in elderly humans was associated with a lesser response in satellite cell proliferation in combination with an age-specific regulation of myostatin. In contrast, expression of local growth factors did not seem to explain the age related difference in muscle mass recovery. PMID- 23732644 TI - Cl- homeodynamics in gap junction-coupled astrocytic networks on activation of GABAergic synapses. AB - The electrophysiological properties and functional role of GABAergic signal transmission from neurons to the gap junction-coupled astrocytic network are still unclear. GABA-induced astrocytic Cl- flux has been hypothesized to affect the driving force for GABAergic transmission by modulating [Cl-]o. Thus, revealing the properties of GABA-mediated astrocytic responses will deepen our understanding of GABAergic signal transmission. Here, we analysed the Cl- dynamics of neurons and astrocytes in CA1 hippocampal GABAergic tripartite synapses, using Cl- imaging during GABA application, and whole cell recordings from interneuron-astrocyte pairs in the stratum lacunosum-moleculare. Astrocytic [Cl-]i was adjusted to physiological conditions (40 mm). Although GABA application evoked bidirectional Cl- flux via GABAA receptors and mouse GABA transporter 4 (mGAT4) in CA1 astrocytes, a train of interneuron firing induced only GABAA receptor-mediated inward currents in an adjacent astrocyte. A GAT1 inhibitor increased the interneuron firing-induced currents and induced bicuculline-insensitive, mGAT4 inhibitor-sensitive currents, suggesting that synaptic spillover of GABA predominantly induced the astrocytic Cl- efflux because GABAA receptors are localized near the synaptic clefts. This GABA-induced Cl- efflux was accompanied by Cl- siphoning via the gap junctions of the astrocytic network because gap junction inhibitors significantly reduced the interneuron firing-induced currents. Thus, Cl- efflux from astrocytes is homeostatically maintained within astrocytic networks. A gap junction inhibitor enhanced the activity-dependent depolarizing shifts of reversal potential of neuronal IPSCs evoked by repetitive stimulation to GABAergic synapses. These results suggest that Cl- conductance within the astrocytic network may contribute to maintaining GABAergic synaptic transmission by regulating [Cl-]o. PMID- 23732645 TI - Increased apical Na+ permeability in cystic fibrosis is supported by a quantitative model of epithelial ion transport. AB - Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes an anion channel. In the human lung CFTR loss causes abnormal ion transport across airway epithelial cells. As a result CF individuals produce thick mucus, suffer persistent bacterial infections and have a much reduced life expectancy. Trans-epithelial potential difference (Vt) measurements are routinely carried out on nasal epithelia of CF patients in the clinic. CF epithelia exhibit a hyperpolarised basal Vt and a larger Vt change in response to amiloride (a blocker of the epithelial Na(+) channel, ENaC). Are these altered bioelectric properties solely a result of electrical coupling between the ENaC and CFTR currents, or are they due to an increased ENaC permeability associated with CFTR loss? To examine these issues we have developed a quantitative mathematical model of human nasal epithelial ion transport. We find that while the loss of CFTR permeability hyperpolarises Vt and also increases amiloride-sensitive Vt, these effects are too small to account for the magnitude of change observed in CF epithelia. Instead, a parallel increase in ENaC permeability is required to adequately fit observed experimental data. Our study provides quantitative predictions for the complex relationships between ionic permeabilities and nasal Vt, giving insights into the physiology of CF disease that have important implications for CF therapy. PMID- 23732647 TI - Restricted diffusion of calretinin in cerebellar granule cell dendrites implies Ca2+-dependent interactions via its EF-hand 5 domain. AB - Ca2+-binding proteins (CaBPs) are important regulators of neuronal Ca2+ signalling, acting either as buffers that shape Ca2+ transients and Ca2+ diffusion and/or as Ca2+ sensors. The diffusional mobility represents a crucial functional parameter of CaBPs, describing their range-of-action and possible interactions with binding partners. Calretinin (CR) is a CaBP widely expressed in the nervous system with strong expression in cerebellar granule cells. It is involved in regulating excitability and synaptic transmission of granule cells, and its absence leads to impaired motor control. We quantified the diffusional mobility of dye-labelled CR in mouse granule cells using two-photon fluorescence recovery after photobleaching. We found that movement of macromolecules in granule cell dendrites was not well described by free Brownian diffusion and that CR diffused unexpectedly slow compared to fluorescein dextrans of comparable size. During bursts of action potentials, which were associated with dendritic Ca2+ transients, the mobility of CR was further reduced. Diffusion was significantly accelerated by a peptide embracing EF-hand 5 of CR. Our results suggest long-lasting, Ca2+-dependent interactions of CR with large and/or immobile binding partners. These interactions render CR a poorly mobile Ca2+ buffer and point towards a Ca2+ sensor function of CR. PMID- 23732646 TI - Atrial selectivity of antiarrhythmic drugs. AB - New antiarrhythmic drugs for treatment of atrial fibrillation should ideally be atrial selective in order to avoid pro-arrhythmic effects in the ventricles. Currently recognized atrial selective targets include atrial Nav1.5 channels, Kv1.5 channels and constitutively active Kir3.1/3.4 channels, each of which confers atrial selectivity by different mechanisms. Na(+) channel blockers with potential- and frequency-dependent action preferentially suppress atrial fibrillation because of the high excitation rate and less negative atrial resting potential, which promote drug binding in atria. Kv1.5 channels are truly atrial selective because they do not conduct repolarizing current IKur in ventricles. Constitutively active IK,ACh is predominantly observed in remodelled atria from patients in permanent atrial fibrillation (AF). A lot of effort has been invested to detect compounds which will selectively block Kir3.1/Kir3.4 in their remodelled constitutively active form. Novel drugs which have been and are being developed aim at atrial-selective targets. Vernakalant and ranolazine which mainly block atrial Na(+) channels are clinically effective. Newly designed selective IKur blockers and IK,ACh blockers are effective in animal models; however, clinical benefit in converting AF into sinus rhythm (SR) or reducing AF burden remains to be demonstrated. In conclusion, atrial-selective antiarrhythmic agents have a lot of potential, but a long way to go. PMID- 23732648 TI - Oxidative stress disrupts purinergic neuromuscular transmission in the inflamed colon. AB - Colitis, induced by trinitrobenzene sulfonic acid (TNBS) in guinea pig, leads to decreased purinergic neuromuscular transmission resulting in a reduction in inhibitory junction potentials (IJPs) in colonic circular muscle. We explored possible mechanisms responsible for this inflammation-induced neurotransmitter plasticity. Previous studies have suggested that the deficit in inflamed tissue involves decreased ATP release. We therefore hypothesized that decreased purinergic transmission results from inflammation-induced free radical damage to mitochondria, leading to decreased purine synthesis and release. Stimulus-induced release of purines was measured using high-performance liquid chromatography, and quantities of all purines measured were significantly reduced in the inflamed colons as compared to controls. To test whether decreased mitochondrial function affects the IJP, colonic muscularis preparations were treated with the mitochondrial ATP synthase inhibitors oligomycin or dicyclohexylcarbodiimide, which resulted in a significant reduction of IJP amplitude. Induction of oxidative stress in vitro, by addition of H2O2 to the preparation, also significantly reduced IJP amplitude. Purinergic neuromuscular transmission was significantly restored in TNBS-inflamed guinea pigs, and in dextran sodium sulfate-inflamed mice, treated with a free radical scavenger. Furthermore, propulsive motility in the distal colons of guinea pigs with TNBS colitis was improved by in vivo treatment with the free radical scavenger. We conclude that oxidative stress contributes to the reduction in purinergic neuromuscular transmission measured in animal models of colitis, and that these changes can be prevented by treatment with a free radical scavenger, resulting in improved motility. PMID- 23732650 TI - A new selective vascular endothelial growth factor receptor 2 inhibitor ablates disease in a mouse model of psoriasis. AB - Psoriasis is a common chronic inflammatory skin disease and its underlying pathogenesis is still not fully understood. Therapeutic interventions are currently limited and restricted to the treatment of symptoms rather than targeting the mechanisms underlying the disease. Vascular remodeling is a hallmark of psoriasis; however, anti-vascular strategies to treat psoriasis have received little attention to date, particularly systemic treatment with a small molecule compound. The aim of this study was to investigate the anti-inflammatory effect of a newly identified vascular endothelial growth factor (VEGF) receptor 2 inhibitor, SKLB1002, and its possible mechanism of action in a transgenic mouse model of psoriasis. Fifteen 8-12-week-old K14-VEGF transgenic mice received consecutive intraperitoneal (i.p.) injections of SKLB1002, vehicle or saline for 4 weeks. After 4 weeks of treatment, the disease symptoms were assessed and histological analyses were performed on ear sections by hematoxylin and eosin (HE) and immunohistochemistry staining. Systemic treatment with SKLB1002 reduced symptoms of ear inflammation in K14/VEGF transgenic mice, the pathological score was significantly decreased, and acanthosis, focal parakeratosis, hyperkeratosis and hemangiectasis were improved. Furthermore, systemic treatment with SKLB1002 significantly reduced vascular abnormalities, permeability and T-cell infiltration. These results demonstrated that targeted inhibition of VEGFR2 by a small molecule inhibitor is an effective method, which may be a new therapeutic option for psoriasis therapy. PMID- 23732649 TI - Pro-arrhythmogenic effects of atrial fibrillation-induced electrical remodelling: insights from the three-dimensional virtual human atria. AB - Chronic atrial fibrillation (AF) is associated with structural and electrical remodelling in the atria, which are associated with a high recurrence of AF. Through biophysically detailed computer modelling, this study investigated mechanisms by which AF-induced electrical remodelling promotes and perpetuates AF. A family of Courtemanche-Ramirez-Nattel variant models of human atrial cell action potentials (APs), taking into account of intrinsic atrial electrophysiological properties, was modified to incorporate various experimental data sets on AF-induced changes of major ionic channel currents (ICaL, IKur, Ito, IK1, IKs, INaCa) and on intracellular Ca(2+) handling. The single cell models for control and AF-remodelled conditions were incorporated into multicellular three dimensional (3D) atrial tissue models. Effects of the AF-induced electrical remodelling were quantified as the changes of AP profile, AP duration (APD) and its dispersion across the atria, and the vulnerability of atrial tissue to the initiation of re-entry. The dynamic behaviour of re-entrant excitation waves in the 3D models was characterised. In our simulations, AF-induced electrical remodelling abbreviated atrial APD non-uniformly across the atria; this resulted in relatively short APDs co-existing with marked regional differences in the APD at junctions of the crista terminalis/pectinate muscle, pulmonary veins/left atrium. As a result, the measured tissue vulnerability to re-entry initiation at these tissue junctions was increased. The AF-induced electrical remodelling also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. Under the AF-remodelled condition, re-entrant scroll waves in the 3D model degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, realistic 3D atrial tissue models indicate that AF induced electrical remodelling produces regionally heterogeneous and shortened APD; these respectively facilitate initiation and maintenance of re-entrant excitation waves. PMID- 23732651 TI - Dual energy imaging using a clinical on-board imaging system. AB - Dual energy (DE) imaging consists of obtaining kilovoltage (kV) x-ray images at two different diagnostic energies and performing a weighted subtraction of these images. A third image is then produced that highlights soft tissue. DE imaging has been used by radiologists to aid in the detection of lung malignancies. However, it has not been used clinically in radiotherapy. The goal of this study is to assess the feasibility of performing DE imaging using a commercial on-board imaging system. Both a simple and an anthropomorphic phantom were constructed for this analysis. Planar kV images of the phantoms were obtained using varied imaging energies and mAs. Software was written to perform DE subtraction using empirically determined weighting factors. Tumor detectability was assessed quantitatively using the signal-difference-to-noise ratio (SDNR). Overall DE subtraction suppressed high density objects in both phantoms. The optimal imaging technique, providing the largest SDNR with a dose less than our reference technique was 140 kVp, 1.0 mAs and 60 kVp, 3.2 mAs. Based on this analysis, DE subtraction imaging is feasible using a commercial on-board imaging system and may improve the visualization of tumors in lung cancer patients undergoing image guided radiotherapy. PMID- 23732652 TI - Individual differences in the immobility behavior in juvenile and adult rats are associated with monoaminergic neurotransmission and with the expression of corticotropin-releasing factor receptor 1 in the nucleus accumbens. AB - The study of individual differences provides an important methodological approach to analyze the neurobehavioral spectrum of a given cohort in order to understand brain function and disease. Based on immobility time in the forced swimming test (FST) juvenile and adult rats were classified as subgroups with low and high immobility. Afterwards, we compared behavior, neurochemical parameters, and gene expression profiles in some brain areas of rats with low and high immobility only. No differences in the open field test (OFT) were observed between subgroups. Regarding neurochemistry, juvenile animals with low immobility showed higher accumbal dopamine turnover and lower hippocampal norepinephrine concentrations, whereas adult rats only differed for accumbal dopamine, although in an opposite direction from that observed in juveniles. Moreover, the expression of accumbal corticotrophin-releasing factor receptor 1 (CRFR1) was significantly different in animals with low and high immobility at both ages, with animals less immobile showing higher levels of CRFR1 mRNA levels. Taken together, our findings suggest that differences in monoaminergic neurotransmission and CRFR1 expression are associated with the coping strategy adopted by the animal and with the tendency to develop depression-related behaviors. Concerning monoaminergic neurotransmission such association is modulated by age, and such modulation could be related to the differential behavioral results observed between juvenile and adult rats. PMID- 23732653 TI - alphaCaMKII autophosphorylation controls the establishment of alcohol-induced conditioned place preference in mice. AB - The autophosphorylation of alpha Ca2+ /calmodulin dependent protein kinase II (alphaCaMKII) is important for memory formation and is becoming increasingly implicated in the development of drug addiction. Previous work suggests that alphaCaMKII acts via the monoaminergic systems to facilitate the establishment of alcohol drinking behaviour. The present study aims to investigate whether alphaCaMKII autophosphorylation deficient alphaCaMKII(T286A) mice show a difference in the rewarding properties of alcohol (2 g/kg, i.p.), as measured by conditioned place preference (CPP). We found that alcohol-induced CPP could be established at an accelerated rate in alphaCaMKII(T286A) compared to wild type (WT) mice. Hyperactivity/hyper-arousal induced by the test environment was normalised by alcohol in the alphaCaMKII(T286A), but not WT mice. This effect could be conditioned to the test environment and may suggest enhanced negative reinforcing action of alcohol in alphaCaMKII autophosphorylation deficient mice. PMID- 23732654 TI - Greener neighborhoods, slimmer people? Evidence from 246,920 Australians. AB - Although there is growing consensus that population-level improvements in cardiovascular health depend upon environments that promote healthy lifestyles, evidence to support large-scale investments in neighborhood greenery to tackle obesity is inconsistent and has not focused on adults in middle-to-old age who experience the greatest burden of chronic health problems. Multilevel linear and multinomial logit regression models were fitted to investigate association between body mass index and an objective measure of green space in a sample of 246,920 Australian adults aged 45 years and older (The 45 and Up Study). Proximity to green space was constructed using catchment areas of 1 km radius around each participant. Women with over 80% proximity to green space had relative risk ratios of 0.90 (95% confidence interval: 0.83, 0.97) for overweight and 0.83 (0.74, 0.94) for obese. No similarly protective association was found for men. These results were consistent after controlling for moderate-to-vigorous physical activity (MVPA) and sitting time, each of which was favorably associated with green space proximity in men and women. Large-scale investments to enhance green spaces may promote MVPA and reduce sedentary behavior in middle-to-older aged adults, but the impact on obesity may not benefit everyone to the same extent. PMID- 23732655 TI - Dietary glycemic index and glycemic load in relation to changes in body composition measures during adolescence: Northern Ireland Young Hearts Study. AB - BACKGROUND: Epidemiologic evidence on the influence of dietary glycemic index (GI) and glycemic load (GL) on the development of obesity is limited. OBJECTIVE: This prospective study examined the associations between dietary GI and GL and changes in body composition measures during adolescence. DESIGN: In a representative sample of Northern Irish adolescents aged 12 years at baseline and 15 years at follow-up (n=426), dietary intake was assessed by a diet history interview. Body composition measures included body mass index (BMI; kg m(-2)), BMI z-score, sum of four skinfold thicknesses, percentage body fat, fat mass index (FMI; kg m(-2)) and fat-free mass index (kg m(-2)). RESULTS: After adjustment for potential confounding factors, baseline GI was associated with increased change in FMI. Mean (95% confidence interval) values of changes in FMI according to tertiles of baseline GI were 0.41 (0.25, 0.57), 0.42 (0.26, 0.58) and 0.67 (0.51, 0.83) kg m(-2), respectively (P for trend=0.03). There was no significant association of baseline GI with changes in other body composition measures (P for trend>=0.054). Conversely, baseline GL showed no association with changes in any of the measures (P for trend>=0.41). Furthermore, changes in GI or GL were not associated with changes in any of the measures (P for trend>=0.16). CONCLUSION: Dietary GI at age 12 years was independently associated with increased change in FMI between ages 12 and 15 years in a representative sample from Northern Ireland, whereas dietary GL showed no association with changes in any of the body composition measures examined. PMID- 23732656 TI - Clinical and laboratory characteristics of 1179 Czech adolescents evaluated for antibodies to human adenovirus 36. AB - BACKGROUND: Human adenovirus 36 (Adv36) is associated with obesity in children. Most prior studies have been small and the association of Adv36 status with markers of metabolic risks has been inconsistent. OBJECTIVES: To determine the prevalence of Adv36 antibodies in different weight categories of adolescents and to evaluate the association of Adv36 infection with anthropometric parameters and cardiometabolic health risks. SUBJECTS AND METHODS: In 1179 Czech adolescents (85 underweight, 506 normal weight, 160 overweight and 428 obese), the following variables were evaluated: anthropometric (body weight, height, body mass index, circumferences, fat mass), blood pressure, biochemical and hormonal (lipid profile, glucose, insulin, liver enzymes, adiponectin) and Adv36 antibodies (enzyme-linked immunosorbent assay). RESULTS: Of the total cohort, 26.5% were positive for Adv36 antibodies (underweight: 22.3%; normal weight: 21.5%; overweight: 40.0% and obese: 28.0%). The odds ratio for Adv36 antibody positivity evaluated vs normal weight was 2.61 for overweight (95% confidence interval (CI): 1.77-3.86, P<0.001) and 1.46 for obesity (95% CI: 1.07-1.99, P=0.016). A significantly higher prevalence of Adv36 infection was observed in female subjects (32.5%) in comparison to male subjects (19.7%; P<0.001). Adv36 positivity of the whole cohort was significantly related to body weight (P=0.042), body mass index (P=0.015), hip circumference (P=0.004), body height z score (P=0.029), and total body fat (P=0.000) and trunk fat (P=0.000). Adv36 antibody-positive girls demonstrated significantly higher body height (167.8 vs 165.0 cm, P=0.01) and waist circumference (77.0 vs 72.0 cm, P=0.01). Infected adolescents exhibited significantly higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), but lower levels of blood glucose. Liver enzymes were significantly increased only in Adv36-positive boys. CONCLUSION: These results demonstrated an association of Adv36 antibodies with obesity and an even greater association with overweight. Adv36 positivity was related to increased fat mass, levels of TC and LDL-C, but to decreased level of blood glucose. No relation to adiponectin levels was revealed. PMID- 23732657 TI - Perceived 'healthiness' of foods can influence consumers' estimations of energy density and appropriate portion size. AB - OBJECTIVE: To compare portion size (PS) estimates, perceived energy density (ED) and anticipated consumption guilt (ACG) for healthier vs standard foods. METHODS: Three pairs of isoenergy dense (kJ per 100 g) foods-healthier vs standard cereals, drinks and coleslaws-were selected. For each food, subjects served an appropriate PS for themselves and estimated its ED. Subjects also rated their ACG about eating the food on a scale of 1 (not at all guilty) to 5 (very guilty). RESULTS: Subjects (n=186) estimated larger portions of the healthier coleslaw than that of the standard version, and perceived all healthier foods to be lower in ED than their standard alternatives, despite being isoenergy dense. Higher ACG was associated with the standard foods. Portion estimates were generally larger than recommendations and the ED of the foods was underestimated. CONCLUSIONS: The larger portions selected for the 'reduced fat' food in association with lower perceived ED and ACG suggests that such nutrition claims could be promoting inappropriate PS selection and consumption behaviour. Consumer education on appropriate portions is warranted to correct such misconceptions. PMID- 23732658 TI - Genomic stability of adipogenic human adenovirus 36. AB - Human adenovirus Ad36 increases adiposity in several animal models, including rodents and non-human primates. Importantly, Ad36 is associated with human obesity, which has prompted research to understand its epidemiology and to develop a vaccine to prevent a subgroup of obesity. For this purpose, understanding the genomic stability of Ad36 in vivo and in vitro infections is critical. Here, we examined whether in vitro cell passaging over a 14-year period introduced any genetic variation in Ad36. We sequenced the whole genome of Ad36 which was plaque purified in 1998 from the original strain obtained from American Type Culture Collection, and passaged approximately 12 times over the past 14 years (Ad36-2012). This DNA sequence was compared with a previously published sequence of Ad36 likely obtained from the same source (Ad36-1988). Compared with Ad36-1988, only two nucleotides were altered in Ad36-2012: a T insertion at nucleotide 1862, which may induce early termination of the E1B viral protein, and a T?C transition at nucleotide 26 136. Virus with the T insertion (designated Ad36-2012-T6) was mixed with wild-type virus lacking the T insertion (designated Ad36-2012-T5) in the viral stock. The transition at nucleotide 26 136 does not change the encoded amino acid (aspartic acid) in the pVIII viral protein. The rate of genetic variation in Ad36 is ~2.37 * 10(-6) mutations/nucleotide/passage. Of particular importance, there were no mutations in the E4orf1 gene, the critical gene for producing obesity. This very-low-variation rate should reduce concerns about genetic variability when developing Ad36 vaccines or developing assays for detecting Ad36 infection in populations. PMID- 23732659 TI - CAFOs and environmental justice: the case of North Carolina. PMID- 23732660 TI - Hyaluronan production enhances shedding of plasma membrane-derived microvesicles. AB - Many cell types secrete plasma membrane-bound microvesicles, suggested to play an important role in tissue morphogenesis, wound healing, and cancer spreading. However, the mechanisms of their formation have remained largely unknown. It was found that the tips of long microvilli induced in cells by overexpression of hyaluronan synthase 3 (HAS3) were detach into the culture medium as microvesicles. Moreover, several cell types with naturally active hyaluronan synthesis released high numbers of plasma membrane-derived vesicles, and inhibition of hyaluronan synthesis reduced their formation. The vesicles contained HAS, and were covered with a thick hyaluronan coat, a part of which was retained even after purification with high-speed centrifugation. HAS3 overexpressing MDCK cells cultured in a 3-D matrix as epithelial cysts released large amounts of HAS- and hyaluronan-positive vesicles from their basal surfaces into the extracellular matrix. As far as we know, hyaluronan synthesis is one of the first molecular mechanisms shown to stimulate the production of microvesicles. The microvesicles have a potential to deliver the hyaluronan synthase machinery and membrane and cytoplasmic materials to other cells, influencing tissue regeneration, inflammation and tumor progression. PMID- 23732661 TI - [Techniques for assaying the activity of transcription factor NF-kappaB]. AB - NF-kappaB is a stimulatory transcription factor that is ubiquitous in almost all kinds of cells. When cells are under various stimuli, NF-kappaB is activated and regulates large numbers of target genes, and thus controls important cellular processes, ranging from cell growth and differentiation to apoptosis and cancer. Therefore, NF-kappaB is a forefront hotspot transcription factor that is intensively studied in virtually all fields of biomedical sciences, and becomes a promising target for disease therapy and drug screening. The activity detection is the first and inevitable step for the studies of NF-kappaB activation and function.Therefore, the techniques for detection of NF-kappaB activity have always been paid more attention and continuously developed. Especially in recent year, along with the development of each disciplines, various new techniques have been developed, including ELISA-like assays based on dsDNA-coupled plate, filter binding assays, FRET assays, fluorescence reporting and nucleic acids amplification assays based on exonuclease and endonuclease, MS and flow cytometry assays based on immunomicrobeads, and other biophysical and electrochemical assays. Some of these techniques have already played important roles in NF-kappaB studies. This paper reviewed new techniques developed in recent years by classification, in order to provide an overview of NF-kappaB activity assays, which may be helpful for researchers to select appropriate techniques used in their studies. Moreover, the learning and understanding of these techniques may inspire researchers to improve currently existing techniques and develop novel methods for the studies of NF-kappaB. PMID- 23732662 TI - [The mechanisms of palindrome-stimulated mutation and related human diseases]. AB - In prokaryotic and eukaryotic genomes, the palindrome regions are highly variable and instable. The reason for this instability is that palindrome can form a hairpin or cruciform structure, which can result in deletions or chromosomal translocations by certain mechanisms, such as slipped mispairing, single-strand annealing and non-homologous end joining. In human genomes, palindromes commonly exist in the essential elements which can regulate the expressions of different genes, and the mutations stimulated by palindromes are also closely associated with the occurrences and progressions of certain human diseases such as male infertility and thalassemia. Based on recent studies, we briefly summarize the types of mutations caused by palindromes and their possible mechanisms, as well as the related human diseases. This review would provide some information for the following researches about the roles and functions of palindromes in gene expression, regulation, mutation and related human diseases. PMID- 23732663 TI - [G protein-coupled receptor 3: a key factor in the regulation of the nervous system and follicle development]. AB - G protein-coupled receptors (GPCRs), the largest cell surface receptor superfamily, are involved in many physiological and pathological processes. G protein-coupled receptor 3 (Gpr3) is a newly discovered sphingosine 1-phosphate receptor, which directly or indirectly takes part in regulating the processes of nervous system and follicle development in the vertebrates. As a potential therapeutic drug target for a variety of neurological diseases and premature ovarian failure, its physiological function and biological mechanisms deserve further studies. In this paper, we reviewed the functions of Gpr3 in the processes of nervous system development and ovarian follicular development in the vertebrates. PMID- 23732664 TI - [Advance on research of gene expression during spermiogenesis at transcription level]. AB - After meiosis, round spermatid develops into mature sperm through metamorphosis. During this stage, most cytoplasm in the germ cell is gradually lost. The histones associated with chromatin are replaced by transition proteins and eventually transformed into protamines. Thus, the spermatid chromatin is stringently packaged and highly concentrated. It was thought that the transcription activity of spermatid is lost and RNAs are absent in spermatid. Nevertheless, many types of transcripts are detected in recent years, including the transcripts needed during chromatin repackaged and some small RNAs, etc. Because histones in the nuclear are not replaced entirely, and there are some active sites on the chromatin, we conjectured that spermatid has some transcription activity, and this activity is regulated by hormone and epigenetic modification. These RNAs may be the residues in the spermatogenesis, or timely expressed during spermiogenesis. A deep study on gene transcription in spermiogenesis will help understand the genetic characteristics and provide the theoretic basis for reproductive control using male gamete. This article reviewed recent advances in spermiogenesis at gene transcription level and proposed the future research directions. PMID- 23732665 TI - [Function of comparative gene identification-58 (CGI-58) on lipid metabolism in animals]. AB - There are some proteins on the surfaces of lipid droplets (LDs) in the cells which could regulate the lipogenesis and lipolysis, and play an important role in lipid metabolism of the whole body. Comparative gene identification-58 (CGI-58), distributing predominantly on the surface of LDs, which is a member of the alpha/beta-hydrolase folding family and an activator of adipose triglyceride lipase (ATGL) and acyl-CoA-dependent lysophosphatidic acid acyltransfer (LPAAT). CGI-58 promotes lipolysis by combining with perilipin which is a member of the PAT family and ATGL. At the same time, the function of CGI-58 to activate ATGL is influenced by protein-protein interaction with the members of the perilipin family. This paper reviews the CGI-58 function in lipid metabolism of animals considering the hot topics. PMID- 23732666 TI - [Evolutionary process unveiled by the maximum genetic diversity hypothesis]. AB - As two major popular theories to explain evolutionary facts, the neutral theory and Neo-Darwinism, despite their proven virtues in certain areas, still fail to offer comprehensive explanations to such fundamental evolutionary phenomena as the genetic equidistance result, abundant overlap sites, increase in complexity over time, incomplete understanding of genetic diversity, and inconsistencies with fossil and archaeological records. Maximum genetic diversity hypothesis (MGD), however, constructs a more complete evolutionary genetics theory that incorporates all of the proven virtues of existing theories and adds to them the novel concept of a maximum or optimum limit on genetic distance or diversity. It has yet to meet a contradiction and explained for the first time the half-century old Genetic Equidistance phenomenon as well as most other major evolutionary facts. It provides practical and quantitative ways of studying complexity. Molecular interpretation using MGD-based methods reveal novel insights on the origins of humans and other primates that are consistent with fossil evidence and common sense, and reestablished the important role of China in the evolution of humans. MGD theory has also uncovered an important genetic mechanism in the construction of complex traits and the pathogenesis of complex diseases. We here made a series of sequence comparisons among yeasts, fishes and primates to illustrate the concept of limit on genetic distance. The idea of limit or optimum is in line with the yin-yang paradigm in the traditional Chinese view of the universal creative law in nature. PMID- 23732667 TI - [Sterol regulatory element binding protein 1 and its target gene networks]. AB - Sterol regulatory element binding protein 1 (SREBP-1) is one of the important nuclear transcription factors. SREBP-1 can maintain lipids dynamic equilibrium by regulating the expression of enzymes required for synthesis of endogenous cholesterol, fatty acids, triglycerides and phospholipids. Anomalies of SREBP-1 and its target genes can cause a series of metabolic diseases such as insulin resistance, type II diabetes, heart dysfunction, vascular complications and hepatic steatosis. In these years, the development of high-throughput technologies has greatly expanded our knowledge about SREBP-1 target genes and the pattern of transcriptional regulation. Here we reviewed recent research progress of SREBP-1, with a focus on the protein structure, activation process, DNA binding sites and target genes. Most importantly, we showed the transcriptional regulatory networks based on omics datasets, which will contribute to a better understanding of the role of SREBP-1 in lipid metabolism and provide new clues for the treatment of lipid metabolism disorders. PMID- 23732668 TI - [Association of single nucleotide polymorphisms(SNPs) in Pygo2 coding gene with idiopathic oligospermia and azoospermia]. AB - Male infertility is often associated with a decreased sperm count. Pygo2 gene is expressed in the elongating spermatid when chromatin remodeling occurs, thus it is possible that impairment of Pygo2 function could lead to spermatogenic arrest, reduction of sperm count and subsequent infertility. The aim of this study was to detect mutations in Pygo2 that lead to idiopathic oligospermia and azoospermia in human. DNA was isolated from venous blood from 77 fertile and 195 idiopathic oligospermic or azoospermic men. PCR-sequencing analysis was performed for the 3 coding regions of Pygo2. Non-synonymous single nucleotide polymorphisms (SNPs) were detected and analyzed using SIFT, Polyphen-2 and Mutation Taster software to determine possible changes in protein structure that could affect phenotype. Of the 195 patients analyzed, sufficient gene sequencing was accomplished for 178 men (30 mild or moderate oligospermic, 57 severe oligospermic and 91 azoospermic men). Three previously reported non-synonymous SNPs were identified in azoospermic and severe oligospermic patients and not in mild and moderate oligozoopermic or normozoospermic men. SNP rs61758740 (M141I) causes the replacement of a hydrophobic amino acid with another hydrophobic amino acid, rs61758741 (K261E) causes the replacement of a basic amino acid with an acidic amino acid and rs141722381 (N261I) causes the replacement of a hydrophilic amino acid with another hydrophobic amino acid. The data predicted by three different software programs showed that SNP rs141722381 results in the damage of tertiary protein structure and thus could be involved in relevant diseases. The study demonstrates that SNPs in the coding region of Pygo2 gene may be one of the causative factors in idiopathic oligospermia and azoospermia, resulting in male infertility. PMID- 23732669 TI - [Establishment of the detection method for two causative genes of cattle arachnomelia syndrome]. AB - Arachnomelia syndrome (AS) is a recessive inherited disease in cattle. Although the arachnomelia phenotypes are virtually identical in Brown Swiss and Simmental cattle, the causative mutation are different, which are a 1 bp insertion c.363 364insG in the sulfite oxidase (SUOX) gene and a 2 bp deletion c.1224_1225delCA in the molybdenum cofactor syn-thesis step 1 (MOCS1) gene, respectively. In the current study, combining fluorescence PCR with capillary electrophoresis technology, an automatic fluorescence method was established, which could detect the two causative loci rapidly and cor-rectly with a single reaction. Samples from 51 Simmental bulls, 80 cows mated artificially using semen of Simmental bulls and their resulted 106 progeny, together with 55 Xinjiang Brown were collected and used for validation of the newly de-signed methods. Our results have laid a foundation for screening AS disease causing mutations in Chinese cattle. PMID- 23732670 TI - [Sequences analysis of jlFABP2 and the correlation between polymorphisms and body weight gain in Cyprinus carpio var. jian]. AB - Two replicate intestine fatty acid binding protein genes (jlFABP2a and jlFABP2b) were cloned from Cyprinus carpio var. jian using PCR. Both ORFs were 399 bp in length sharing 92.2% similarity with each other, and 88.0% and 90.5% with their counterpart in zebrafish, respectively. The gene structure of jlFABP2s was same as other FABPs, which contained four exons and three introns. Sequences and lengths of introns between 2a and 2b. were obviously different Phylogenetic tree displayed that two jlFABP2s corresponded to one zebrafish FABP2 which matches the fact that the chromosome number of common carp was twice of zebrafish. Real time PCR showed that jlFABP2 genes mainly expressed in intestine and the expression level was very significantly higher than other tissues such as brain, liver, muscle, kidney, and gonad (P<0.01). The expression level of jlFABP2a was significantly (male, P<0.05) or very significantly (females, P<0.01) higher than 2b in intestine; and 2b was expressed slightly higher than 2a in other tissues. It seemed that 2a expressed specifically in intestine, while 2b expressed ubiquitously. Twelve and four SNP loci were found at jlFABP2a and 2b introns through comparison sequences from 8 individuals, respectively. Genotypes of I1 A15G, I1-A99G, I2-C487T, and I3-A27T on jlFABP2a were detected using PCR-RFLP in selection population of C. carpio var. jian. The SNP genotypes and individual weight gain correlation indicated that four SNPs were significantly (P<0.05 or P<0.01) associated with adult weight gain. Diplotype analysis displayed that individuals with genotype AGGGCCXX or AGGGXXAT grew faster than other individuals by 15%. The individuals with these two genotypes only occupied 9% in total selection populations, indicating the presence of large selection space. The 4 SNPs detected in this experiment can be used in C. carpio var. Jian growth selection breeding plan. PMID- 23732671 TI - [Expression of Myogenin and MCK genes regulated by PI3K/AKT pathway]. AB - Many intracellular signaling pathways regulate skeletal muscle differentiation. Among them, PI3K/AKT pathway plays an important role. But the mechanisms of chromatin regulation remain unclear. In this study, the murine C2C12 myoblast cell line was used to investigate the expression of Myogenin and MCK genes during the skeletal muscle differentiation. Western blotting analysis showed that the expression of Myogenin and MCK protein was increased significantly after PI3K/AKT activator treatment for 24 h during the C2C12 cell differentiation and the expression of H3K27me3 demethylase UTX was also increased. Chromatin immunoprecipitation (ChIP) and quantitative PCR (Q-PCR) analysis showed that the enrichment of H3K27me3 on the promoter regions of Myogenin and MCK genes and the enhancer region of MCK gene were decreased. It was opposite to the PI3K/AKT inhibitor treatment. We concluded that the PI3K/AKT pathway maybe regulate skeletal muscle differentiation by regulating the expression of UTX gene to change the enrichment of H3K27me3 on the target genes. PMID- 23732672 TI - [Phylogeny and functional divergence of omega-6 and omega-3 fatty acid desaturase families]. AB - The deduced amino acid sequences characteristics, phylogeny, and functional diverge of omega-6 and omega-3 fatty acid desaturase families were analyzed by using Bioinformatics methods. The results showed that all the deduced amino acid sequences shared three highly conserved histidine rich motifs (Hisbox). All the plastidial omega-6 and omega-3 fatty acid desaturases possessed putative N terminal signal peptide with different amino acids. A relatively conserved hydrophobic region composed of 10 amino-acid residues was found in the middle of signal peptides, which is presumed to be the functional region of the signal peptide of these enzymes. Most of the plant microsomal omega-6 and omega-3 fatty acid desaturases (FAD2 and FAD3) contained a KKXX-like motif of endoplasmic reticulum (ER) retention signal at the C-terminus. However, no such motif was detected in safflower CtFAD2-3, CtFAD2-4, CtFAD2-5, CtFAD2-6, and CtFAD2-7, while an aromatic aa enriched signal (YKNK) was found at their C-terminus which has been reported to be both necessary and sufficient for maintaining localization of the enzymes in the ER. All the amino acid sequences were divided into four categories through phylogenetic analysis. It was suggested that omega-3 fatty acid desaturase originates in a prokaryotic lineage from omega-6 fatty acid desaturase. Both plastidial and microsomal omega-3 fatty acid desaturases could be divided into dicotyledonous and monocotyledonous subgroups, which inferred that functional differentiation of plastidial and microsomal omega-3 fatty acid desaturases had been formed before the divergence of dicotyledonous and monocotyledonous plants. Seed type and housekeeping type FAD2 diverged after the formation of dicotyledonous plants. Except for plant FAD3/plant FAD2, posterior probability values over 0.80 amino acid sites were identified among the functional differentiation subsets, which were mainly distributed at the front and back end of Hisbox I, and the front end of Hisbox II. This indicated that the variations of these amino acid sites played an important role in the size and conformation of protein functional domains and subfamily functional divergence. PMID- 23732673 TI - [Molecular mechanism of AtGA3OX1 and AtGA3OX2 genes affecting secondary wall thickening in stems in Arabidopsis]. AB - Bioactive gibberellins (GAs) are a type of important plant growth regulators, which play the key roles in multiple processes, such as seed germination, leaf expansion, flowering, fruit bearing, and stem development. Its biosynthesis is regulated by a variety of enzymes including gibberellin 3-oxidase that is a key rate-limiting enzyme. In Arabidopsis, gibberellin 3-oxidase consists of four members, of which AtGA3OX1 and AtGA3OX2 are highly expressed in stems, suggesting the potential roles in the stem development played by the two genes. To date, there are few studies on AtGA3OX1 and AtGA3OX2 regulating secondary wall thickening in stems. In this study, we used the atga3ox1atga3ox2 double mutant as the materials to study the effects of AtGA3OX1 and AtGA3OX2 genes on secondary wall thickening in stems. The results indicated that simulations repression of AtGA3OX1 and AtGA3OX2 genes resulted in significantly reduction of secondary wall thickening of fiber cells, but not that of vessel cells. Three main components (cellulose, hemicelluloses, and lignin) were also dramatically suppressed in the double mutants. qRT-PCR analysis demonstrated that the expressions of secondary wall biosynthetic genes and the associated transcription factors were obviously affected in AtGA3OX1 and AtGA3OX2 double mutant. Therefore, we presume that Arabidopsis AtGA3OX1 and AtGA3OX2 genes might activate the expression of these transcription factors, thus regulate secondary wall thickening in stems. Together, our results provide a theoretical basis for enhancing the lodging resistance of food crops and improving the biomass of energy plants by genetically engineering Arabidopsis AtGA3OX homologs. PMID- 23732674 TI - [Proteome analysis of potato drought resistance variety in Ninglang 182 leaves under drough stress]. AB - It is utmost important to cultivate potato variety with drought resistance to reduce arid loss by research progress on potato drought resistance molecular mechanism. A comparative study with differences in protein group analysis of potato drought resistance variety in Ninglang 182 leaves was carried out by using two-dimensional gel electrophoresis during drought and normal processing conditions.There were 12 differentially expressed protein spots identified by Electro-phoresis and MALDI-TOF-TOF/MS analysis. The function classification of these proteins results that the potato varieties to drought tolerance could be improved through the protection of photosynthesis and mitochondria, regulation of the signal transduction induced under environmental stress and regulation of plant tissue N and C transport system, these proteins expression were increased under drought.The results showed that these proteins are the drought resistance associated proteins of potato variety in Ninglang 182.This study provided a theoretical basis of the molecular mechanism of improving drought tolerance in order to expound the potato drought resistance variety through multiple paths and the level regulation. PMID- 23732675 TI - [Discussion on some problems in "Chinese terms in Genetics (second edition)"]. AB - The terms in "General" and "Classical genetics" of "Chinese terms in Genetics (second edition)" are discussed. The deficiencies of the definition and comment of these terms on the content, grammar and language are pointed out, and the amendments are proposed. PMID- 23732676 TI - [Revisiting Darwin's theory of heredity-Pangenesis]. AB - Pangenesis, an early theory of heredity, has been regarded as Darwin's error for a long time. The main reason is that it explains the inheritance of acquired characteristics and graft hybridization, which were largely thought to be wrong. In addition, Galton's blood transfusion experiments obtained negative results, and no evidence was found to support Darwin's hypothetical gemmules-molecular carriers of hereditary characteristics, which are supposed to be thrown off by cells and are able to circulate throughout the body. Now, there are growing evidence for the inheritance of acquired characteristics and graft hybridization. The discovery of circulating nucleic acids indicates that there are indeed inherited molecules which can move between cells of the organism, providing evidence for the chemical existence of Darwin's gemmules. This paper briefly introduces Darwin's Pangenesis, the main reasons that it was ignored, the new evidence in support of it and our own rethinking about it. A new understanding of Pangenesis brings a broader perspective on genetics, evolution, and medicine. PMID- 23732678 TI - An aqueous rechargeable lithium battery of high energy density based on coated Li metal and LiCoO2. AB - Using a coated Li metal as an anode and LiCoO2 as a cathode, an aqueous rechargeable battery is built up, whose average discharge voltage is 3.70 V. This high voltage stability is due to the "cross-over" effect of Li(+) ions, which is different from the traditional ways of increasing overpotentials. The total energy density can be 465 W h kg(-1). PMID- 23732677 TI - Association between caffeine intake and age at onset in Huntington's disease. AB - Habitual consumption of caffeine, a non-selective adenosine receptor (AR) antagonist, has been suggested to be beneficial in Parkinson's and Alzheimer's diseases. Experimental evidence support that ARs play a role in Huntington's disease (HD) raising the hypothesis that caffeine may be a life-style modifier in HD. To determine a possible relationship between caffeine consumption and age at onset (AAO) in HD, we retrospectively assessed caffeine consumption in 80 HD patients using a dietary survey and determined relationship with AAO. Following adjustment for gender, smoking status and CAG repeat length, caffeine consumption greater than 190mg/day was significantly associated with an earlier AAO. These data support an association between habitual caffeine intake and AAO in HD patients, but further studies are warranted to understand the link between these variables. PMID- 23732679 TI - A simple scoring method using cardiometabolic risk measurements in pregnancy to determine 10-year risk of type 2 diabetes in women with gestational diabetes. AB - OBJECTIVE: To examine if clustering of cardiometabolic risk factors in pregnancy predicts type 2 diabetes and cardiovascular disease (CVD) risk at 10 years in women with gestational diabetes mellitus (GDM). STUDY DESIGN AND SUBJECTS: A prospective case-control study in 150 GDM and 72 overweight women with normal glucose tolerance (NGT) measured cardiometabolic risk factors (body mass index (BMI), systolic blood pressure (SBP), fasting glucose, insulin, and triglycerides and high-density lipoprotein (HDL) cholesterol) at 28 weeks gestation and 6 months and 10 years after pregnancy. Cluster analysis of cardiometabolic risk factors in pregnancy was used to stratify GDM as 'high' and 'low risk' for diabetes and CVD risk at 10 years. The data in pregnancy were used to determine a simple method for assessing risk of future diabetes. RESULTS: BMI in the 150 GDM at study entry was similar to NGT, but 35% of GDM fell into a 'high-risk cluster' with elevated BMI, SBP, glucose, insulin and triglycerides and lower HDL levels. At 10 years, type 2 diabetes was sixfold higher in 'high-risk' GDM (odds ratio (OR)=6.75, confidence interval (CI)=2.0, 22.7, P=0.002) compared with 'low-risk' GDM and was not reported in NGT. The 'high-risk' cluster predicted type 2 diabetes better than BMI>30 (OR=2.13, CI=0.71, 6.4, P=0.179) or fasting glucose >5.5 mmol l(-1), (OR=4.56, CI=1.50, 13.85, P=0.007). We determined that GDM with any four of the cardiometabolic risk factors (BMI>30 kg m(-2), fasting glucose>5.0 mmol l(-1), insulin>7.8 mU l(-1), triglycerides >2.4 mmol l(-1), HDL<1.6 mmol l(-1) or SBP>105 mm Hg) in pregnancy would be in a 'high-risk' cluster. CONCLUSIONS: A metabolic syndrome-like cluster in pregnant GDM identifies risk for type 2 diabetes providing an opportunity to focus on rigorous lifestyle interventions after delivery to reduce the burden of disease attributed to this condition. PMID- 23732680 TI - Synthesis of a hetero-dinuclear metal complex in a porphyrin/phthalocyanine four fold rotaxane. AB - We report synthesis of a hetero-dinuclear metal complex in a four-fold rotaxane, in which a Cu(2+)-porphyrin and a Zn(2+)-phthalocyanine are cofacially stacked. Interaction between the two metal complexes in the rotaxane was investigated by a UV-Vis absorption spectral study. PMID- 23732681 TI - Oxidative in vitro folding of a cysteine deficient variant of the G protein coupled neuropeptide Y receptor type 2 improves stability at high concentration. AB - In vitro folding of G protein-coupled receptors into a detergent environment represents a promising strategy for obtaining sufficient amounts of functional receptor molecules for structural studies. Typically, these preparations exhibit a poor long-term stability especially at the required high protein concentration. Here, we report a protocol for the stabilization of the Escherichia coli expressed and subsequently folded neuropeptide Y receptor type 2. We identified the free cysteines in the receptor as one major reason for intermolecular protein aggregation. Therefore, six out of the eight cysteine residues were mutated to alanine or serine without any significant loss of functionality of the receptor as demonstrated in cell culture models. Furthermore, the disulfide bond between the remaining two cysteines was irreversibly formed by applying oxidative in vitro folding. Applying this strategy, the stability of the functionally folded Y2 receptor could be increased to 20 days at a concentration of 15 MUm in a micelle environment consisting of 1,2-diheptanoyl-sn-glycero-3-phosphocholine and n-dodecyl-beta-D-maltoside. PMID- 23732682 TI - Technical and clinical evaluation of the VITROS(r) Immunodiagnostic Products 25 OH Vitamin D Total Assay--comparison with marketed automated immunoassays and a liquid chromatography-tandem mass spectrometry method. AB - BACKGROUND: The study was conducted to evaluate the technical and clinical performance of the VITROS(r) Immunodiagnostic Products 25-OH Vitamin D Total Assay, and compare it with the performance of five marketed automated assays and a liquid chromatography/mass spectrometry reference method (LC-MS/MS). METHODS: Three hundred patient serum samples were used to compare the correlation of the VITROS(r) 25-OH Vitamin D Total Assay with both the other immunoassays and the LC MS/MS method, using Passing-Bablok regression and Bland-Altman analyses. Concordance of the diagnosis of vitamin D status was calculated to test the agreement between the different assays. In addition, samples containing vitamin D2 were used to test the assay's ability to detect the D2 form of the vitamin. RESULTS AND CONCLUSIONS: These results from the VITROS(r) 25-OH Vitamin D Total Assay generally correlated well with those from most of the marketed immunoassays. Cross-reactivity of the D2 form was calculated as being close to 100%. Additionally, we found substantial variability in performance amongst the various assays, which suggests the need for optimisation and recalibration of commercial methods. PMID- 23732683 TI - Effect of stimulus rise-time on the ocular vestibular-evoked myogenic potential to bone-conducted vibration. AB - OBJECTIVES: The negative potential at 10 msec (called n10) of the ocular vestibular-evoked myogenic potential (oVEMP) recorded beneath the eyes in response to bone-conducted vibration (BCV) delivered to the skull at the midline in the hairline (Fz) is a new indicator of otolithic, and in particular utricular, function. Our aim is to find the optimum combination of frequency and rise-time for BCV stimulation, to improve the sensitivity of oVEMP testing in the clinic. DESIGN: We tested 10 healthy subjects with 6 msec tone bursts of BCV at three stimulus frequencies, 250, 500, and 750 Hz, at rise-times ranging between 0 and 2 msec. The BCV was delivered at Fz. RESULTS: The n10 response was significantly larger at the shorter rise-times, being largest at zero rise-time. In addition, we examined the effect of stimulus frequency in these same subjects by delivering 6 msec tone bursts at zero rise-time at a range of frequencies from 50 to 1200 Hz. The main effect of rise-time was significant with shorter rise times leading to larger n10 responses and the Rise-Time * Frequency interaction was significant so that at low frequencies (100 Hz) shorter rise-times had a modest effect on n10 whereas at high frequencies (750 Hz) shorter rise-times increased n10 amplitude substantially. The main effect of frequency was also significant: The n10 response tended to be larger at lower frequency, being largest between 250 and 500 Hz. CONCLUSIONS: In summary, in this sample of healthy subjects, the most effective stimulus for eliciting oVEMP n10 to BCV at Fz was found to be a tone burst with a rise-time of 0 msec at low stimulus frequency (250 or 500 Hz). PMID- 23732684 TI - Comparative studies on ectopic bone formation in porous hydroxyapatite scaffolds with complementary pore structures. AB - Vascularized bone grafts were constructed by implanting hydroxyapatite (HA) scaffolds with complementary macro-pore structures into the dorsal muscle of dogs. The relationship between pore structures and ectopic bone formation properties was investigated. Two types of scaffolds with complementary porous structures were fabricated by spherulite-accumulating and porogen-preparing methods, and were named spherulite HA-positive and porogen HA-negative, respectively. After implantation for 1 month, histological observation showed that all the scaffolds were encapsulated by normal muscle tissue and multiple vascular net with cells, indicating excellent biocompatibility and pore interconnectivity of the scaffolds. In the spherulite HA-positive scaffolds, a number of osteoclasts and osteoblasts coupled with new bone tissues were found after 3 and 6 months' implantations, which was better than those in the porogen HA-negative scaffolds. Similarly, the improvement of mechanical properties and the reconstruction of materials in the spherulite HA-positive scaffolds were superior to those in the porogen HA-negative scaffolds. The different ectopic bone formation induced by different macro-pore structures after intramuscular implantation demonstrated the significant effect of macro-pore structures of scaffolds on osteoinduction and vascularization. PMID- 23732685 TI - Time-of-flight angiography: a viable alternative to contrast-enhanced MR angiography and fat-suppressed T1w images for the diagnosis of cervical artery dissection? AB - OBJECTIVES: To compare the use of an unenhanced high-resolution time-of-flight MR angiography sequence (Hr-TOF MRA) with fat-suppressed axial/coronal T1-weighted images and contrast-enhanced angiography (standard MRI) for the diagnosis of cervical artery dissection (cDISS). METHODS: Twenty consecutive patients (9 women, 11 men, aged 24-66 years) with proven cDISS on standard MRI underwent Hr TOF MRA at 3.0 T using dedicated surface coils. Sensitivity (SE), specificity (SP), positive and negative predictive values (PPV, NPV), Cohen's kappa (k) and accuracy of Hr-TOF MRA were calculated using the standard protocol as the gold standard. Image quality and diagnostic confidence were assessed on a four-point scale. RESULTS: Image quality was rated better for standard MRI (P = 0.02), whereas diagnostic confidence did not differ significantly (P = 0.27). There was good agreement between Hr-TOF images and the standard protocol for the presence/absence of cDISS, with k = 0.95 for reader 1 and k = 0.89 for reader 2 (P < 0.001). This resulted in SE, SP, PPV, NPV and accuracy of 97 %, 98 %, 97 %, 98 % and 97 % for reader 1 and 93 %, 96 %, 93 %, 96 % and 95 % for reader 2. CONCLUSIONS: Hr-TOF MRA can be used to diagnose cDISS with excellent agreement compared with the standard protocol. This might be useful in patients with renal insufficiency or if contrast-enhanced MR angiography is of insufficient image quality. KEY POINTS: * New magnetic resonance angiography sequences are increasingly used for vertebral artery assessment. * A high-resolution time-of flight sequence allows the diagnosis of cervical artery dissection. * This technique allows the diagnosis without intravenous contrast medium. * It could help in renal insufficiency or when contrast-enhanced MRA fails. PMID- 23732686 TI - Haemodynamic alterations in cerebral blood vessels after carotid artery revascularisation: quantitative analysis using 2D phase-contrast MRI. AB - OBJECTIVES: This study was conducted to evaluate the effect of revascularisation, whether revascularisation improves total cerebral blood flow volume (FVTCBF), and how cerebral veins would respond to altered FVTCBF. METHODS: The 39 carotid artery stenoses in 37 patients who underwent revascularisation including 32 stentings and 7 endarterectomies were included in this prospective study. From the two-dimensional phase-contrast (2D-PC) MRI acquired before and after revascularisation, the flow volumes (FVs) of the arteries and veins were compared using paired t-test. The relationships between these parameters were correlated using Pearson's correlation coefficient. RESULTS: The mean FV in the treated carotid artery (proportion of treated artery among total FV) increased from 162.06 ml/min (25.80 %) to 267.71 ml/min (37.21 %; P < 0.001). Revascularisation increased the FVTCBF of patients from 638.66 ml/min to 716.72 ml/min (P < 0.001). The FV of the internal jugular veins, superior sagittal and straight sinuses (FVSS + SSS), and transverse sinuses increased after revascularisation (P < 0.05). Positive relationships were shown between the FVTCBF and the FVSS + SSS (r = 0.584-0.741, P < 0.001). CONCLUSIONS: Revascularisation improves the FVTCBF by increasing the FV in the treated carotid artery. The venous drainages are closely linked to FVTCBF. 2D-PC-MRI is a feasible method for evaluating comprehensively the haemodynamic improvement after revascularisation. KEY POINTS: * Revascularisation may be beneficial in ischaemic strokes due to carotid artery stenosis. * Revascularisation of the affected artery increases total cerebral blood flow volume ( FV TCBF). * Cerebral venous drainage, closely linked to FV TCBF, is also improved. * Two-dimensional phase-contrast MRI can comprehensively assess these haemodynamic improvements after carotid revascularisation. PMID- 23732687 TI - Dynamic contrast-enhanced MRI in endometrial carcinoma identifies patients at increased risk of recurrence. AB - OBJECTIVES: To study the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for assessment of tumour microvasculature in endometrial carcinoma patients, and to explore correlations with histological subtype, clinical course and microstructural characteristics based on apparent diffusion coefficient (ADC) values. METHODS: Diffusion-weighted imaging (DWI) and three-dimensional DCE-MRI (1.5 T) with high temporal resolution (2.49 s) were acquired preoperatively in 55 patients. Quantitative modelling allowed the calculation of four independent parameters describing microvasculature: blood flow (Fb), extraction fraction (E), capillary transit time (Tc) and transfer constant from the extravascular extracellular space [EES] to blood (Kep); and four derived parameters: blood volume (Vb), volume of EES (Ve), capillary permeability surface area product (PS) and transfer from blood to EES (Ktrans). RESULTS: Endometrial carcinoma tissue exhibited reduced Fb, E, Vb, Ve, PS and Ktrans compared with normal myometrium. Non-endometrioid carcinomas (n = 12) had lower Fb, and E than endometrioid carcinomas (n = 43; P < 0.05). Tumour Ve positively correlated with tumour ADC value (r = 0.29, P = 0.03). Reduced survival was observed in patients with low tumour Fb and high tumour Tc (P < 0.05). CONCLUSIONS: We demonstrate the feasibility of DCE-MRI in reflecting histological subtype and clinical course in primary endometrial carcinomas. DCE MRI may potentially provide future biomarkers for preoperative risk stratification in endometrial carcinomas. KEY POINTS: * Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) offers new information about endometrial carcinoma. * Pelvic DCE-MRI with subsequent quantitative modelling seems feasible in endometrial carcinoma patients. * Low tumour perfusion is a feature of a more aggressive tumour subtype. * DCE-MRI provides potential biomarkers for preoperative risk stratification in endometrial carcinoma patients. PMID- 23732688 TI - Detection of invasive components in cases of breast ductal carcinoma in situ on biopsy by using apparent diffusion coefficient MR parameters. AB - OBJECTIVES: To evaluate whether apparent diffusion coefficient (ADC) parameters could identify invasive components in cases with ductal carcinoma in situ (DCIS) diagnosed by biopsy. METHODS: This retrospective study was approved by the institutional review board and the requirement to obtain informed consent was waived. Sixty-nine consecutive women with 70 lesions diagnosed with DCIS by biopsy underwent breast magnetic resonance (MR) imaging. Multiple regions of interest were placed (as many as possible) within the lesion on ADC maps. The minimum ADC values and the ADC difference values obtained as the difference between minimum and maximum ADCs were evaluated. RESULTS: Surgical specimens revealed 51 lesions with pure DCIS and the remaining 19 lesions with DCIS with invasive components (DCIS-IC). The minimum ADC value for DCIS-IC (0.99 +/- 0.04 * 10(-3) mm(2)/s) was significantly lower than that of pure DCIS (1.15 +/- 0.03 * 10(-3) mm(2)/s) (P = 0.0037). The ADC difference value for DCIS-IC (0.38 +/- 0.05 * 10(-3) mm(2)/s) was significantly higher than that of pure DCIS (0.17 +/- 0.03 * 10(-3) mm(2)/s). ROC curve analysis for differentiating DCIS-IC from pure DCIS revealed that the area under the curve was 0.71 for minimum ADC value and 0.77 for ADC difference value. CONCLUSIONS: The minimum ADC values and ADC difference values could suggest the presence of invasive components. KEY POINTS: * Identification of invasive components in DCIS before treatment is clinically important. * Diffusion-weighted MR imaging can help lesion assessment in breast cancer. * The minimum ADC value may suggest the presence of an invasive component in DCIS. * The ADC difference value also suggests the presence of an invasive component in DCIS. * Preoperative evaluation of diffusion-weighted MR imaging may help surgical planning for DCIS. PMID- 23732689 TI - Contrast-enhanced free-breathing 3D T1-weighted gradient-echo sequence for hepatobiliary MRI in patients with breath-holding difficulties. AB - OBJECTIVE: Evaluate the image quality and diagnostic performance of a free breathing 3D-gradient-echo sequence with radial acquisition (rGRE) compared with a Cartesian breath-hold 3D-GRE (cGRE) sequence on hepatobiliary phase MRI in patients with breath-holding difficulties. METHODS: Twenty-eight consecutive patients (15 males; mean age 61 +/- 11.9 years) were analysed in this retrospective IRB-approved study. Breath-holding difficulties during gadoxetate disodium-enhanced liver MRI manifested as breathing artefacts during dynamic phase imaging. MRI included axial and coronal cGRE and a radially sampled rGRE sequence during the hepatobiliary phase. Two radiologists independently evaluated cGRE and rGRE images for image quality, liver lesion detection and conspicuity, and bile duct conspicuity on a four-point scale. RESULTS: Liver edge sharpness was significantly higher on rGRE images (P < 0.001). Overall image quality was slightly but significantly higher for rGRE than for cGRE (P < 0.001 and P = 0.039). Bile duct conspicuity scores of rGRE and cGRE were not significantly different. Sensitivity for detection of the 26 liver lesions was similar for rGRE and cGRE (81-77 % and 73-77 %, P = 0.5 and 1.0). Lesion conspicuity scores were significantly higher for rGRE for one reader (P = 0.012). CONCLUSION: In patients with breath-holding difficulties, overall image quality and liver lesion conspicuity on hepatobiliary phase MRI can be improved using the rGRE sequence. KEY POINTS: * Patients with diminished breath-holding capacities present a major challenge in abdominal MRI. * A free-breathing sequence for hepatobiliary-phase MRI can improve image quality. * Further advances are needed to reduce acquisition time of the free-breathing gradient-echo sequence. PMID- 23732690 TI - An optimised patient-specific approach to administration of contrast agent for CT pulmonary angiography. AB - OBJECTIVES: To investigate pulmonary vasculature opacification during CTPA using an optimised patient-specific protocol for administering contrast agent. METHODS: CTPA was performed on 200 patients with suspected PE. Patients were assigned to two protocol groups: protocol A, fixed 80 ml contrast agent; protocol B used a patient-specific approach. The mean cross-sectional opacification profile of 8 central and 11 peripheral pulmonary arteries and veins was measured and the arteriovenous contrast ratio (AVCR) calculated. Protocols were compared using Mann-Whitney U non-parametric statistics. Jack-knife alternative free-response receiver-operating characteristic (JAFROC) analyses assessed diagnostic efficacy. Interobserver variations were investigated using kappa methods. RESULTS: A number of pulmonary arteries demonstrated increases in opacification (P < 0.03) for protocol B compared to A, whilst opacification in the heart and veins was reduced in protocol B (P = 0.05). Increased AVCR in protocol B compared with A was observed at all anatomic locations (P < 0.0002). Increased JAFROC (P < 0.0002) and kappa variation were observed with protocol B (kappa = 0.78) compared to A (kappa = 0.25). Mean contrast volume was reduced in protocol B (33 +/- 9 ml) compared to A (80 +/- 1 ml). CONCLUSIONS: Significant improvements in visualisation of the pulmonary vasculature can be achieved with a low volume of contrast agent using injection timing based on a patient-specific contrast formula. KEY POINTS: * Optimal opacification of the pulmonary arteries is essential for CT pulmonary angiography. * Matching timing with vessel dynamics significantly improves vessel opacification. * This leads to increased arterial opacification and reduced venous opacification. * This can also lead to a reduced volume of contrast agent. PMID- 23732691 TI - Ultrasound-guided pulsed radiofrequency treatment of the intercostal nerve: three cases. PMID- 23732692 TI - Examining the health effects of fructose. PMID- 23732693 TI - A comprehensive analysis of the effects of the main component enzymes of cellulase derived from Trichoderma reesei on biomass saccharification. AB - The aim of this study was a comprehensive analysis of the effects of the component enzymes of cellulase derived from Trichoderma reesei strain PC-3-7 on biomass saccharification. We used cellulases with deleted CBH I, CBH II, or EG I, which contain all other component enzymes, for saccharification of differently pretreated biomasses of rice straw, Erianthus, eucalyptus, and Japanese cedar. We found that CBH I was the most effective in saccharification of all pretreated cellulosic biomasses, although the effect was weaker in saccharification of sulfuric acid- and hydrothermally pretreated rice straw than of others; CBH II was more effective for rice straw than for eucalyptus, and was the most effective at the early stages of biomass degradation; EG I had little effect on pretreated biomasses, in particular, it had no effect on steam-exploded Japanese cedar. Thus, the effects of the main component enzymes depend on the biomass source and pretreatment. These findings will likely help to improve cellulase for industrial use. PMID- 23732694 TI - Highly glucose tolerant beta-glucosidase from Aspergillus unguis: NII 08123 for enhanced hydrolysis of biomass. AB - Aspergillus unguis NII-08123, a filamentous fungus isolated from soil, was found to produce beta-glucosidase (BGL) activity with high glucose tolerance. Cultivation of the fungus in different carbon sources resulted in the secretion of different isoforms of the enzyme. A low molecular weight isoform, which retained ~60 % activity in the presence of 1.5 M glucose, was purified to homogeneity and the purified enzyme exhibited a temperature and pH optima of 60 degrees C and 6, respectively. The K(m) and V(max) of the enzyme were 4.85 mM and 2.95 U/mg, respectively, for 4-nitrophenyl beta-D-glucopyranoside. The glucose inhibition constant of the enzyme was 0.8 M, indicating high glucose tolerance, and this is the second-highest glucose tolerance ever reported from the Aspergillus nidulans group. The glucose-tolerant BGL from A. unguis, when supplemented to cellulase preparation from Penicillium, could improve biomass hydrolysis efficiency by 20 % in 12 h compared to the enzyme without additional beta glucosidase supplementation. The beta glucosidase from A. unguis is proposed as a highly potent "blend-in" for biomass saccharifying enzyme preparations. PMID- 23732695 TI - Rapid enrichment of (homo)acetogenic consortia from animal feces using a high mass-transfer gas-lift reactor fed with syngas. AB - A gas-lift reactor having a high mass transfer coefficient (k(L)a = 80.28 h(-1)) for a relatively insoluble gas (carbon monoxide; CO) was used to enrich (homo)acetogens from animal feces. Samples of fecal matter from cow, rabbit, chicken, and goat were used as sources of inoculum for the enrichment of CO and H(2) utilizing microbial consortia. To confirm the successful enrichment, the Hungate roll tube technique was employed to count and then isolate putative CO utilizers. The results of this work showed that CO and H(2) utilizing consortia were established for each inoculum source after 8 days. The number of colony forming units in cow, rabbit, chicken, and goat fecal samples were 3.83 * 10(9), 1.03 * 10(9), 8.3 * 10(8), and 3.25 * 10(8) cells/ml, respectively. Forty-two colonies from the animal fecal samples were screened for the ability to utilize CO/H(2). Ten of these 42 colonies were capable of utilizing CO/H(2). Five isolates from cow feces (samples 5, 6, 8, 16, and 22) were highly similar to previously unknown (homo)acetogen, while cow-7 has shown 99 % similarity with Acetobacterium sp. as acetogens. On the other hand, four isolates from chicken feces (samples 3, 8, 10, and 11) have also shown high CO/H(2) utilizing activity. Hence, it is expected that this research could be used as the basis for the rapid enrichment of (homo)acetogenic consortia from various environmental sources. PMID- 23732697 TI - GPU-based Monte Carlo radiotherapy dose calculation using phase-space sources. AB - A novel phase-space source implementation has been designed for graphics processing unit (GPU)-based Monte Carlo dose calculation engines. Short of full simulation of the linac head, using a phase-space source is the most accurate method to model a clinical radiation beam in dose calculations. However, in GPU based Monte Carlo dose calculations where the computation efficiency is very high, the time required to read and process a large phase-space file becomes comparable to the particle transport time. Moreover, due to the parallelized nature of GPU hardware, it is essential to simultaneously transport particles of the same type and similar energies but separated spatially to yield a high efficiency. We present three methods for phase-space implementation that have been integrated into the most recent version of the GPU-based Monte Carlo radiotherapy dose calculation package gDPM v3.0. The first method is to sequentially read particles from a patient-dependent phase-space and sort them on the-fly based on particle type and energy. The second method supplements this with a simple secondary collimator model and fluence map implementation so that patient-independent phase-space sources can be used. Finally, as the third method (called the phase-space-let, or PSL, method) we introduce a novel source implementation utilizing pre-processed patient-independent phase-spaces that are sorted by particle type, energy and position. Position bins located outside a rectangular region of interest enclosing the treatment field are ignored, substantially decreasing simulation time with little effect on the final dose distribution. The three methods were validated in absolute dose against BEAMnrc/DOSXYZnrc and compared using gamma-index tests (2%/2 mm above the 10% isodose). It was found that the PSL method has the optimal balance between accuracy and efficiency and thus is used as the default method in gDPM v3.0. Using the PSL method, open fields of 4 * 4, 10 * 10 and 30 * 30 cm(2) in water resulted in gamma passing rates of 99.96%, 99.92% and 98.66%, respectively. Relative output factors agreed within 1%. An intensity modulated radiation therapy patient plan using the PSL method resulted in a passing rate of 97%, and was calculated in 50 s (per GPU) compared to 8.4 h (per CPU) for BEAMnrc/DOSXYZnrc. PMID- 23732698 TI - Could Acinetobacter pittii act as an NDM-1 reservoir for Enterobacteriaceae? PMID- 23732699 TI - Prevalence and risk factors associated with resistance-associated mutations to etravirine in a cohort of perinatally HIV-infected children. AB - BACKGROUND: Etravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with reduced cross-resistance to first-generation NNRTIs. Because many perinatally HIV-infected patients have been treated with first-generation NNRTIs, they may have acquired resistance-associated mutations to etravirine (RAMe). METHODS: We determined for the interval 1998-2009 the prevalence and factors associated with the presence of RAMe. RESULTS: Twenty three of 66 (34.8%) children had RAMe; the most common were 181C (19.6%), 190A (7.5%), 98G (6%), 106I (4.5%), 179D (4.5%), 100I (3%), 181I (1.5%), 138A (1.5%) and 179T (1.5%). Eleven children with RAMe (17%) had a mutation score between 2.5 and 3.5 and 1 (1.5%) a score >=4, indicating an intermediate and reduced response to etravirine. For each 1% increase in CD4% there is a 7% decrease in the odds of RAMe (OR 0.93; 95% CI 0.88-0.97; P < 0.01). History of nevirapine use (OR 8.95; 95% CI 2.31-34.73; P < 0.01) and Hispanic ethnicity (OR 4.76; 95% CI 1.03-21.87; P = 0.04) are significantly associated with risk of RAMe. CONCLUSIONS: RAMe are present and common among antiretroviral-experienced perinatally HIV-infected children without previous exposure to etravirine. This could limit the efficacy of etravirine-based regimens. In addition, our results underscore the importance of taking previous history of nevirapine into account for combined antiretroviral therapy regimens that contain etravirine. PMID- 23732700 TI - MicroRNA-143 inhibits cell migration and invasion by targeting matrix metalloproteinase 13 in prostate cancer. AB - MicroRN-143 (miR-143) has been previously reported to be downregulated in specific types of cancer, including colorectal, bladder, oral squamous cell, pituitary, cervical, nasopharyngeal, lymphoma and prostate cancer. In the present study, the effects of miR-143 on prostate cancer cell migration and invasion were examined. Following transfection with miR-143, miR-143 expression, cell migration and invasion assays, luciferase assay and western blot analysis were conducted in prostate cancer cell lines. The results indicated that miR-143 inhibits cell migration and invasion in DU145 and PC-3 cells. In addition, to the best of our knowledge, miR-143 was reported for the first time to directly target matrix metalloproteinase 13 (MMP-13) in prostate cancer. The results of the present study demonstrated that miR-143 suppresses cell migration and invasion by targeting MMP-13 in prostate cancer cell lines. These results indicated that miR 143 may be suitable for the development of novel molecular markers and therapeutic approaches to inhibit metastasis in prostate cancer. PMID- 23732701 TI - Protein kinase CK2-dependent phosphorylation of the human Regulators of Calcineurin reveals a novel mechanism regulating the calcineurin-NFATc signaling pathway. AB - Cyclosporine A and FK506 produce immunosuppression by blocking calcineurin phosphatase activity and consequently activation of cytosolic Nuclear Factor of Activated T-cell (NFATc) transcription factor. Due to the chronic toxicity associated with their administration, the development of more specific immunosuppressants is currently an important unmet medical need. In this context, an immunosuppressant peptide derived from the CIC motif of the human Regulators of Calcineurin (RCAN) proteins has been shown to inhibit NFATc signaling without affecting general phosphatase activity of calcineurin. Here we show that protein kinase CK2 phosphorylates a conserved serine residue within the CIC motif of vertebrate RCANs, which increases its affinity for calcineurin and consequently its inhibition of NFATc-dependent gene expression in activated T-cells. Molecular modeling studies have led us to identify a positively charged interaction site on the surface of calcineurin where the phosphorylated serine residue of the CIC motif would normally locate. Finally, we have also identified RCAN3 as a new phosphoprotein with multiple phosphorylation sites. Therefore, our findings reveal for the first time a novel molecular mechanism underlying the regulation of calcineurin-NFATc signaling by means of phosphorylation of the CIC motif of RCAN proteins. The knowledge of how RCAN proteins modulate the calcineurin-NFATc pathway paves the way for the development of potent novel selective immunosuppressant drugs. PMID- 23732702 TI - Assessment of the requirement for aquaporins in the thylakoid membrane of plant chloroplasts to sustain photosynthetic water oxidation. AB - Oxygenic photosynthetic organisms use sunlight energy to oxidize water to molecular oxygen. This process is mediated by the photosystem II complex at the lumenal side of the thylakoid membrane. Most research efforts have been dedicated to understanding the mechanism behind the unique water oxidation reactions, whereas the delivery pathways for water molecules into the thylakoid lumen have not yet been studied. The most common mechanisms for water transport are simple diffusion and diffusion facilitated by specialized channel proteins named aquaporins. Calculations using published data for plant chloroplasts indicate that aquaporins are not necessary to sustain water supply into the thylakoid lumen at steady state photosynthetic rates. Yet, arguments for their presence in the plant thylakoid membrane and beneficial action are presented. PMID- 23732703 TI - AtCSP1 regulates germination timing promoted by low temperature. AB - An Arabidopsis gene trap line (GT606), which disrupted the AtCSP1 gene, exhibited an early germination phenotype that was affected by stratification treatment. Comparative analysis of GUS expression in seeds at the early germination stage, with or without stratification, demonstrated that AtCSP1 expression was affected by cold temperature. Evaluation of germination assays with varying concentrations of ABA or NaCl revealed a reduced sensitivity of the atcsp1 mutant to both ABA and NaCl. Taken together, these data support the hypothesis that AtCSP1 affects early stages of seed germination subsequent to stratification treatment of seeds. PMID- 23732704 TI - Spinal sigma-1 receptors activate NADPH oxidase 2 leading to the induction of pain hypersensitivity in mice and mechanical allodynia in neuropathic rats. AB - We have recently demonstrated that spinal sigma-1 receptors (Sig-1Rs) mediate pain hypersensitivity in mice and neuropathic pain in rats. In this study, we examine the role of NADPH oxidase 2 (Nox2)-induced reactive oxygen species (ROS) on Sig-1R-induced pain hypersensitivity and the induction of chronic neuropathic pain. Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. Mechanical allodynia and thermal hyperalgesia were evaluated in mice and CCI-rats. Western blotting and dihydroethidium (DHE) staining were performed to assess the changes in Nox2 activation and ROS production in spinal cord, respectively. Direct activation of spinal Sig-1Rs with the Sig-1R agonist, PRE084 induced mechanical allodynia and thermal hyperalgesia, which were dose-dependently attenuated by pretreatment with the ROS scavenger, NAC or the Nox inhibitor, apocynin. PRE084 also induced an increase in Nox2 activation and ROS production, which were attenuated by pretreatment with the Sig 1R antagonist, BD1047 or apocynin. CCI-induced nerve injury produced an increase in Nox2 activation and ROS production in the spinal cord, all of which were attenuated by intrathecal administration with BD1047 during the induction phase of neuropathic pain. Furthermore, administration with BD1047 or apocynin reversed CCI-induced mechanical allodynia during the induction phase, but not the maintenance phase. These findings demonstrate that spinal Sig-1Rs modulate Nox2 activation and ROS production in the spinal cord, and ultimately contribute to the Sig-1R-induced pain hypersensitivity and the peripheral nerve injury-induced induction of chronic neuropathic pain. PMID- 23732705 TI - Racial differences in depression in the United States: how do subgroup analyses inform a paradox? AB - PURPOSE: Non-Hispanic Blacks in the US have lower rates of major depression than non-Hispanic Whites, in national household samples. This has been termed a "paradox," as Blacks suffer greater exposure to social stressors, a risk factor for depression. Subgroup analyses can inform hypotheses to explain this paradox. For example, it has been suggested that selection bias in household samples undercounts depression in Blacks; if selection is driving the paradox, Black White differences should be most pronounced among young men with low education. METHODS: We examined Black-White differences in lifetime major depression in subgroups defined simultaneously by sex, age, and education using data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) and the Collaborative Psychiatric Epidemiology Surveys (CPES). RESULTS: In NESARC and CPES, Blacks had lower odds than Whites of lifetime major depression in 21 and 23 subgroups, respectively, of 24. All statistically significant differences were in subgroups favoring Blacks, and lower odds in Blacks were more pronounced among those with more education. CONCLUSIONS: These results suggest that hypotheses to explain the paradox must posit global mechanisms that pertain to all subgroups defined by sex, age, and education. Results do not lend support for the selection bias hypothesis. PMID- 23732706 TI - The development of socioeconomic inequalities in anxiety and depression symptoms over the lifecourse. AB - PURPOSE: Socioeconomic inequalities in anxiety and depression widen with increasing age. This may be due to differences in the incidence or persistence of symptoms. This paper investigates the widening of inequalities in anxiety and depression over the lifecourse. METHODS: Data were from the West of Scotland Twenty-07 Study, constituting three cohorts aged approximately 16, 36 and 56 years at baseline and re-visited at 5-yearly intervals for 20 years. Symptoms were measured using the Hospital Anxiety and Depression Scale. Adjusting for age and sex, multilevel models with pairs of interviews (n = 6,878) nested within individuals (n = 3,165) were used for each cohort to estimate associations between current symptoms and education or household social class for both those with and without earlier symptoms, approximating socioeconomic differences in incidence and persistence. RESULTS: Inequalities in current symptom levels were present for both those with and without earlier symptoms. In the youngest cohort, those with less education were more likely to experience persistent depression and to progress from anxiety to depression. At older ages there were educational and social class differences in both the persistence and incidence of symptoms, though there was more evidence of differential persistence than incidence in the middle cohort and more evidence of differential incidence than persistence in the oldest cohort. CONCLUSIONS: Differential persistence and symptom progression indicate that intervening to prevent or treat symptoms earlier in life is likely to reduce socioeconomic inequalities later, but attention also needs to be given to late adulthood where differential incidence emerges more strongly than differential persistence. PMID- 23732707 TI - The effect of spirituality and religious attendance on the relationship between psychological distress and negative life events. AB - PURPOSE: The aim of this study was to assess the effect of religious attendance and spirituality on the relationship between negative life events and psychological distress. METHODS: This was a cross-sectional study of 1,071 community dwelling adults from East Baltimore, Maryland who participated in the fourth (2004-2005) wave of the Baltimore Epidemiologic Catchment Area study. The 20-item General Health Questionnaire (GHQ-20) was used to measure psychological distress. Multiple regression models were used to assess the association between negative life events and distress as well as to measure the effect of religious attendance and spirituality on the association between psychological distress and negative events while adjusting for demographic variables, past distress and social support from friends and relatives. RESULTS: In pooled analysis, negative events were significant predictors of distress, b = 1.00, beta = 0.072, p < 0.05. Religious attendance and spirituality did not affect or modify the association between negative events and distress. However, religious attendance was inversely associated with distress with higher frequency of attendance associated with lower distress after controlling for demographic and social support factors, b = 2.10, beta = -.110, p < 0.01 for attending 1-3 times a month; b = -2.39, beta = 0.156, p < 0.01 for attending weekly; and b = -3.13, beta = -0.160, p < 0.001 for attending more than once per week. In stratified analysis, negative events were associated with distress for those who were low on spirituality, b = 1.23, beta = 0.092, p < .05, but not for those who were high on spirituality; the association between religious attendance and decreased distress was true only for those scoring high in spirituality. Social support accounted for some of the inverse association between religious and distress. CONCLUSION: Religious attendance and spirituality may play a role in how people experience and deal with difficult life situations. PMID- 23732708 TI - Molecular genetic analysis of VRK1 in mammary epithelial cells: depletion slows proliferation in vitro and tumor growth and metastasis in vivo. AB - The vaccinia-related kinases (VRKs) comprise a branch of the casein kinase family. VRK1, a ser/thr kinase with a nuclear localization, is the most well studied paralog and has been described as a proproliferative protein. In lower eukaryotes, a loss of VRK1 activity is associated with severe mitotic and meiotic defects. Mice that are hypomorphic for VRK1 expression are infertile, and depletion of VRK1 in tissue culture cells can impair cell proliferation and alter several signaling pathways. VRK1 has been implicated as part of a 'gene expression signature' whose overexpression correlates with poor clinical outcome in breast cancer patients. We present here our investigation of the role of VRK1 in the growth of normal (MCF10) and malignant (MDA-MB-231) human mammary epithelial cells, and demonstrate that shRNA-mediated depletion of VRK1 slows their proliferation significantly. Conversely, stable overexpression of a FLAG tagged VRK1 transgene imparts a survival advantage to highly malignant MDA-MB-231 cells under conditions of nutrient and growth factor deprivation. Moreover, in a murine orthotopic xenograft model of breast cancer, we demonstrate that tumors depleted of VRK1 show a 50% reduction in size from 4-13 weeks postengraftment. The incidence and burden of distal metastases in the lungs and brain was also significantly reduced in mice engrafted with VRK1-depleted cells. These studies demonstrate that VRK1 depletion or overexpression has an impact on the proliferation and survival of cell lines derived from normal or malignant mammary tissue, and moreover show that depletion of VRK1 in MDA-MB-231 cells reduces their oncogenic and metastatic properties in vivo. PMID- 23732709 TI - Acid ceramidase induces sphingosine kinase 1/S1P receptor 2-mediated activation of oncogenic Akt signaling. AB - Acid ceramidase (AC) is overexpressed in most prostate tumors and confers oncogenic phenotypes to prostate cancer cells. AC modulates the cellular balance between ceramide, sphingosine and sphingosine 1-phosphate (S1P). These bioactive sphingolipids have diverse, powerful and often oppositional impacts on cell signaling, including the activation status of the oncogenic kinase Akt. Our studies show that AC expression correlates with phosphorylation of Akt in human prostate tumors, and elevation of phosphorylated Akt in tumor versus patient matched benign tissue is contingent upon AC elevation. Investigation of the mechanism for AC-induced Akt activation revealed that AC activates Akt through sphingosine kinase 1 (SphK1)-derived generation of S1P. This signaling pathway proceeds through S1P receptor 2 (S1PR2)-dependent stimulation of PI3K. Functionally, AC-overexpressing cells are insensitive to cytotoxic chemotherapy, however, these cells are more susceptible to targeted inhibition of Akt. AC overexpressing cells proliferate more rapidly than control cells and form more colonies in soft agar; however, these effects are profoundly sensitive to Akt inhibition, demonstrating increased dependence on Akt signaling for the oncogenic phenotypes of AC-overexpressing cells. These observations may have clinical implications for targeted therapy as PI3K and Akt inhibitors emerge from clinical trials. PMID- 23732710 TI - The Pak4 protein kinase is required for oncogenic transformation of MDA-MB-231 breast cancer cells. AB - The Pak4 protein kinase, normally expressed at low level in the mammary gland, is commonly overexpressed in breast cancer. Overexpression of Pak4 transforms mouse mammary epithelial cells in vitro and renders these cells tumorigenic in athymic mice in vivo. Here we show that Pak4 is also required for oncogenic transformation of the human breast cancer cell line MDA-MB-231. These high Pak4 expressing human breast cancer cells form highly disorganized three-dimensional (3D) structures in vitro and readily give rise to orthotopic xenograft tumors in nude mice. We have found that when Pak4 levels are reduced, MDA-MB-231 cells exhibit decreased proliferation and migration in vitro, as well as gross restoration of normal 3D mammary acinar organization, the latter in association with a strong induction of apoptosis. Similarly, Pak4 knockdown suppresses MDA-MB 231 breast xenograft tumor formation in nude mice in vivo. These results indicate that Pak4 has a key role in the oncogenic transformation of breast cells. PMID- 23732711 TI - Sunscreen and prevention of skin aging: a randomized trial. AB - BACKGROUND: Sunscreen use and dietary antioxidants are advocated as preventives of skin aging, but supporting evidence is lacking. OBJECTIVE: To determine whether regular use of sunscreen compared with discretionary use or beta-carotene supplements compared with placebo retard skin aging, measured by degree of photoaging. DESIGN: Randomized, controlled, community-based intervention. (Australian New Zealand Clinical Trials Registry: ACTRN12610000086066). SETTING: Nambour, Australia (latitude 26 degrees S). PATIENTS: 903 adults younger than 55 years out of 1621 adults randomly selected from a community register. INTERVENTION: Random assignment into 4 groups: daily use of broad-spectrum sunscreen and 30 mg of beta-carotene, daily use of sunscreen and placebo, discretionary use of sunscreen and 30 mg of beta-carotene, and discretionary use of sunscreen and placebo. MEASUREMENTS: Change in microtopography between 1992 and 1996 in the sunscreen and beta-carotene groups compared with controls, graded by assessors blinded to treatment allocation. RESULTS: The daily sunscreen group showed no detectable increase in skin aging after 4.5 years. Skin aging from baseline to the end of the trial was 24% less in the daily sunscreen group than in the discretionary sunscreen group (relative odds, 0.76 [95% CI, 0.59 to 0.98]). beta-Carotene supplementation had no overall effect on skin aging, although contrasting associations were seen in subgroups with different severity of aging at baseline. LIMITATION: Some outcome data were missing, and power to detect moderate treatment effects was modest. CONCLUSION: Regular sunscreen use retards skin aging in healthy, middle-aged men and women. No overall effect of beta-carotene on skin aging was identified, and further study is required to definitively exclude potential benefit or potential harm. PRIMARY FUNDING SOURCE: National Health and Medical Research Council of Australia. PMID- 23732712 TI - Meeting meaningful use criteria and managing patient populations: a national survey of practicing physicians. AB - BACKGROUND: Meaningful use, as defined by the Centers for Medicare & Medicaid Services, will require the aggregation of patient data to enable population assessment. Little is known about the proportion of physicians who are able to meet meaningful use criteria or their use of electronic health records (EHRs) to manage patient populations. OBJECTIVE: To evaluate physicians' reports of EHR adoption and ease of use and their ability to use EHRs for patient panel management. DESIGN: National mailed survey of practicing physicians (response rate of 60%). SETTING: Late 2011 and early 2012. PARTICIPANTS: 1820 primary care physicians and specialists in office-based practices. MEASUREMENTS: Proportion of physicians who have a basic EHR and meet meaningful use criteria and ease of use of computerized systems designed for patient population management tasks. RESULTS: A total of 43.5% of physicians reported having a basic EHR, and 9.8% met meaningful use criteria. Computerized systems for managing patient populations were not widespread; fewer than one half of respondents reported the presence of computerized systems for any of the patient population management tasks included in the survey. Physicians with such functionalities reported that these systems varied in ease of use. Physicians with an EHR that met meaningful use criteria were significantly more likely than those not meeting the standard to rate panel management tasks as easy. LIMITATION: Ease-of-use measures are subjective. CONCLUSION: Few physicians could meet meaningful use criteria in early 2012 and using computerized systems for the panel management tasks was difficult. Results support the growing evidence that using the basic data input capabilities of an EHR does not translate into the greater opportunity that these technologies promise. PRIMARY FUNDING SOURCE: Commonwealth Fund and Robert Wood Johnson Foundation. PMID- 23732713 TI - Aspirin versus low-molecular-weight heparin for extended venous thromboembolism prophylaxis after total hip arthroplasty: a randomized trial. AB - BACKGROUND: The role of aspirin in thromboprophylaxis after total hip arthroplasty (THA) is controversial. OBJECTIVE: To compare extended prophylaxis with aspirin and dalteparin for prevention of symptomatic venous thromboembolism (VTE) after THA. DESIGN: Multicenter randomized, controlled trial with a noninferiority design based on a minimal clinically important difference of 2.0%. Randomization was electronically generated; patients were assigned to a treatment group through a Web-based program. Patients, physicians, study coordinators, health care team members, outcome adjudicators, and data analysts were blinded to interventions. (Current Controlled Trials: ISRCTN11902170). SETTING: 12 tertiary care orthopedic referral centers in Canada. PATIENTS: 778 patients who had elective unilateral THA between 2007 and 2010. INTERVENTION: After an initial 10 days of dalteparin prophylaxis after elective THA, patients were randomly assigned to 28 days of dalteparin (n = 400) or aspirin (n = 386). MEASUREMENTS: Symptomatic VTE confirmed by objective testing (primary efficacy outcome) and bleeding. RESULTS: Five of 398 patients (1.3%) randomly assigned to dalteparin and 1 of 380 (0.3%) randomly assigned to aspirin had VTE (absolute difference, 1.0 percentage point [95% CI, -0.5 to 2.5 percentage points]). Aspirin was noninferior (P < 0.001) but not superior (P = 0.22) to dalteparin. Clinically significant bleeding occurred in 5 patients (1.3%) receiving dalteparin and 2 (0.5%) receiving aspirin. The absolute between-group difference in a composite of all VTE and clinically significant bleeding events was 1.7 percentage points (CI, -0.3 to 3.8 percentage points; P = 0.091) in favor of aspirin. LIMITATION: The study was halted prematurely because of difficulty with patient recruitment. CONCLUSION: Extended prophylaxis for 28 days with aspirin was noninferior to and as safe as dalteparin for the prevention of VTE after THA in patients who initially received dalteparin for 10 days. Given its low cost and greater convenience, aspirin may be considered a reasonable alternative for extended thromboprophylaxis after THA. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research. PMID- 23732714 TI - Blood tests to diagnose fibrosis or cirrhosis in patients with chronic hepatitis C virus infection: a systematic review. AB - BACKGROUND: Many blood tests have been proposed as alternatives to liver biopsy for identifying fibrosis or cirrhosis. PURPOSE: To evaluate the diagnostic accuracy of blood tests to identify fibrosis or cirrhosis in patients with hepatitis C virus (HCV) infection. DATA SOURCES: MEDLINE (1947 to January 2013), the Cochrane Library, and reference lists. STUDY SELECTION: Studies that compared the diagnostic accuracy of blood tests with that of liver biopsy. DATA EXTRACTION: Investigators abstracted and checked study details and quality by using predefined criteria. DATA SYNTHESIS: 172 studies evaluated diagnostic accuracy. For identifying clinically significant fibrosis, the platelet count, age-platelet index, aspartate aminotransferase-platelet ratio index (APRI), FibroIndex, FibroTest, and Forns index had median positive likelihood ratios of 5 to 10 at commonly used cutoffs and areas under the receiver-operating characteristic curve (AUROCs) of 0.70 or greater (range, 0.71 to 0.86). For identifying cirrhosis, the platelet count, age-platelet index, APRI, and Hepascore had median positive likelihood ratios of 5 to 10 and AUROCs of 0.80 or greater (range, 0.80 to 0.91). The Goteborg University Cirrhosis Index and the Lok index had slightly lower positive likelihood ratios (4.8 and 4.4, respectively). In direct comparisons, the APRI was associated with a slightly lower AUROC than the FibroTest for identifying fibrosis and a substantially higher AUROC than the aspartate aminotransferase-alanine aminotransferase ratio for identifying fibrosis or cirrhosis. LIMITATION: Only English-language articles were included, and most studies had methodological limitations, including failure to describe blinded interpretation of liver biopsy specimens and inadequate description of enrollment methods. CONCLUSION: Many blood tests are moderately useful for identifying clinically significant fibrosis or cirrhosis in HCV infected patients. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 23732715 TI - Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. AB - DESCRIPTION: The Kidney Disease: Improving Global Outcomes (KDIGO) organization developed clinical practice guidelines in 2012 to provide guidance on the evaluation, management, and treatment of chronic kidney disease (CKD) in adults and children who are not receiving renal replacement therapy. METHODS: The KDIGO CKD Guideline Development Work Group defined the scope of the guideline, gathered evidence, determined topics for systematic review, and graded the quality of evidence that had been summarized by an evidence review team. Searches of the English-language literature were conducted through November 2012. Final modification of the guidelines was informed by the KDIGO Board of Directors and a public review process involving registered stakeholders. RECOMMENDATIONS: The full guideline included 110 recommendations. This synopsis focuses on 10 key recommendations pertinent to definition, classification, monitoring, and management of CKD in adults. PMID- 23732717 TI - Demanding utility from health information technology. PMID- 23732716 TI - Influence of study features and methods on overdiagnosis estimates in breast and prostate cancer screening. AB - Knowledge of the likelihood that a screening-detected case of cancer has been overdiagnosed is vitally important to make treatment decisions and develop screening policy. An overdiagnosed case is an excess case detected by screening. Estimates of the frequency of overdiagnosis in breast and prostate cancer screening vary greatly across studies. This article identifies features of overdiagnosis studies that influence results and shows their effect by using published research. First, different ways to define and measure overdiagnosis are considered. Second, contextual features and how they affect overdiagnosis estimates are examined. Third, the effect of estimation approach is discussed. Many studies use excess incidence under screening as a proxy for overdiagnosis. Others use statistical models to make inferences about lead time or natural history and then derive the corresponding fraction of cases that are overdiagnosed. This article concludes with questions that readers of overdiagnosis studies can use to evaluate the validity and relevance of published estimates and recommends that authors of studies quantifying overdiagnosis provide information about these features. PMID- 23732718 TI - Married to medicine. PMID- 23732720 TI - Cognitive impairment associated with atrial fibrillation. PMID- 23732721 TI - Cognitive impairment associated with atrial fibrillation--in response. PMID- 23732722 TI - On being a doctor: leaving is not the answer. PMID- 23732723 TI - Is it time for physicians to focus on the public health threat of gun violence? PMID- 23732724 TI - Is it time for physicians to focus on the public health threat of gun violence? PMID- 23732725 TI - Is it time for physicians to focus on the public health threat of gun violence? PMID- 23732726 TI - Is it time for physicians to focus on the public health threat of gun violence? PMID- 23732727 TI - Is it time for physicians to focus on the public health threat of gun violence? PMID- 23732729 TI - Summaries for patients. Sunscreen and prevention of skin aging. PMID- 23732730 TI - In the clinic. Care of the adult cancer survivor. PMID- 23732731 TI - Unsafe harbor? Elevated blood lead levels in refugee children. PMID- 23732732 TI - Commentary: Mediterranean diet and cognitive function: are we approaching clarity in this area? PMID- 23732733 TI - Commentary: Mediterranean diet and cognitive outcomes: epidemiological evidence suggestive, randomized trials needed. PMID- 23732734 TI - Inactivated influenza vaccines for prevention of community-acquired pneumonia: the limits of using nonspecific outcomes in vaccine effectiveness studies. AB - BACKGROUND: One to 4 million cases of community-acquired pneumonia (CAP) occur annually in the United States, resulting in 600,000 hospitalizations and 45,000 deaths. Influenza infection facilitates secondary bacterial infections, and influenza vaccination may prevent CAP directly by preventing influenza pneumonia or indirectly by preventing secondary bacterial CAP. METHODS: We investigated how influenza vaccination could affect incidence of CAP using deterministic probability and stochastic simulation models. The models included likely influential factors, including vaccine effectiveness (VE) against influenza, rates of influenza in the unvaccinated, vaccination coverage, and the relative risk (RR) of pneumonia, given influenza infection. To estimate effectiveness of influenza vaccine against CAP, we assumed mean VE against influenza of 55% and vaccine coverage of 38%. RESULTS: Given our baseline parameters, influenza vaccine had a mean effectiveness against CAP of 7% (95% confidence interval = 0 25%). Effectiveness of influenza vaccine against CAP increased as its effectiveness against influenza increased, as RR of pneumonia after influenza infection increased, and as rates of influenza among unvaccinated persons increased. CONCLUSIONS: No matter how effective vaccine may be in preventing influenza infection, it is only modestly effective at preventing CAP. Because of the large annual burden of CAP, a vaccine that is only moderately effective in preventing influenza infection has the potential to prevent a substantial number of CAP cases. This modeling approach may be useful for planning influenza vaccine probe studies and evaluating the effectiveness of other interventions targeted against infections that manifest in nonspecific outcomes. PMID- 23732735 TI - Commentary: Country doctor versus epidemiologist: how uncertainty analysis can help see what is in plain view. PMID- 23732736 TI - Rejoinder: Understanding uncertainties in a change versus change study. PMID- 23732737 TI - Commentary: The causal and nosological status of loss in major depression. PMID- 23732738 TI - Lifestyle profile among statin users. PMID- 23732739 TI - Environmental lead--a public health challenge in South Africa. PMID- 23732740 TI - Case fatality: rate, ratio, or risk? PMID- 23732741 TI - Second-hand smoke and dementia. PMID- 23732742 TI - Confounding of incidence density ratio in case-control studies. PMID- 23732743 TI - Confounding of incidence density ratio in case-control studies. PMID- 23732744 TI - Confounding of incidence density ratio in case-control studies. PMID- 23732745 TI - "Threshold findings" in an ecological study. PMID- 23732746 TI - "Threshold findings" in an ecological study. PMID- 23732747 TI - Time scale in follow-up studies: considering disease prognosis. PMID- 23732748 TI - Highly reactive (<1 min) ratiometric "naked eye" detection of hypochlorite with real application in tap water. AB - The de-diaminomaleonitrile reaction in a simple carbazole diaminomaleonitrile hybrid (CDH) was promoted by OCl(-) which disrupted the ICT mechanism by breaking the donor and acceptor linkage. This system utilized an irreversible OCl(-) promoted oxidation reaction and it responded instantaneously at room temperature. The chemosensor also showed excellent performance in tap water and the "dip stick" method. PMID- 23732749 TI - AlCl3-mediated hydroarylation-heteroarylation in a single pot: a direct access to densely functionalized olefins of pharmacological interest. AB - An unprecedented AlCl3-mediated method has been developed involving aromatic C-H bond addition to an alkyne and heteroarylation of an arene in a single pot leading to densely functionalized novel olefins, e.g. 2-(2,2-diarylvinyl)-3 arylquinoxalines, as potential inhibitors of sirtuins. PMID- 23732750 TI - Association of serum B-cell activating factor level and proportion of memory and transitional B cells with clinical response after rituximab treatment of bullous pemphigoid patients. PMID- 23732751 TI - Molecular profiling to diagnose a case of atypical dermatomyositis. PMID- 23732753 TI - Evaluation of a new chemiluminescence immunoassay for laboratory diagnosis of syphilis. AB - The purpose of this study was to evaluate diagnostic performances of automated chemiluminescence immunoassay (CLIA) in comparison with Treponema pallidum hemagglutination test (TPHA). The specificity of CLIA was 98.9% and 99.6% for TPHA, whereas the sensitivity was 98% and 96%, respectively. Considering the suitability for automation, CLIA may represent a suitable alternative. PMID- 23732752 TI - IL-17 and TNF synergistically modulate cytokine expression while suppressing melanogenesis: potential relevance to psoriasis. AB - Inflammation-associated pigmentation changes are extremely common, but the etiology underlying this clinical observation remains elusive. Particularly, it is unclear how the myriad of cytokines known to be involved in inflammatory skin processes affect epidermal melanocytes. We sought to determine how IL-17 and tumor necrosis factor (TNF) influence normal human melanocytes, as these two cytokines have been implicated in various skin diseases. IL-17 and TNF jointly stimulated broad inductions of cytokines, including melanoma mitogens CXCL1 and IL-8. Moreover, IL-17 and TNF synergistically inhibited pigmentation-related signaling and melanin production, and induced keratinocyte production of beta defensin 3, an antagonist for melanocortin 1 receptor. When analyzing psoriasis lesions that are known to overexpress IL-17 and TNF, we observed an increase in melanocyte number and a simultaneous decrease in pigmentation signaling. Furthermore, therapeutic neutralization of TNF and IL-17 with mAbs resulted in a rapid recovery of pigment gene expression in psoriasis lesions. These results demonstrate that IL-17 and TNF can affect both the growth and pigment production of melanocytes, which may contribute to the pigmentation changes associated with psoriasis. These findings may allow the development of novel therapeutics for pigmentary disorders and bring new insights into the immune milieu surrounding melanocytes and related neoplasms. PMID- 23732754 TI - Interleukin 17F level and interferon beta response in patients with multiple sclerosis. AB - IMPORTANCE: High serum levels of interleukin 17F (IL-17F) at baseline have been associated with suboptimal response to interferon beta in patients with relapsing remitting multiple sclerosis. OBJECTIVE: To further investigate the role of IL 17F in predicting treatment response to interferon beta-1b in patients with relapsing-remitting multiple sclerosis using the Singulex Erenna IL-17F immunoassay. DESIGN, SETTING, AND PATIENTS: Serum samples were analyzed from 239 randomly selected patients treated with interferon beta-1b, 250 MUg, for at least 2 years in the Betaferon Efficacy Yielding Outcomes of a New Dose Study. EXPOSURE: Treatment with interferon beta-1b, 250 MUg, for at least 2 years. MAIN OUTCOME MEASURES: Levels of IL-17F at baseline and month 6 as well as the difference between the IL-17F levels at month 6 and baseline were compared between the following: (1) patients with less disease activity vs more disease activity; (2) patients with no disease activity vs some disease activity; and (3) responders vs nonresponders. RESULTS: Levels of IL-17F measured at baseline and month 6 did not correlate with lack of response to treatment after 2 years using clinical and magnetic resonance imaging criteria. Relapses and new lesions on magnetic resonance imaging were not associated with pretreatment serum IL-17F levels. When patients with neutralizing antibodies were excluded, the results did not change. All patients with levels of IL-17F greater than 200 pg/mL were associated with poor response with some clinical or radiological activity. CONCLUSIONS AND RELEVANCE: An increase of IL-17F before and early after treatment with interferon beta-1b was not associated with poor response. These data do not support the value of IL-17F as a treatment response indicator for therapy of patients with multiple sclerosis with interferon beta, although high levels of IL 17F greater than 200 pg/mL may predict nonresponsiveness. PMID- 23732756 TI - Was Mirizzi really the first person to recognize Mirizzi syndrome? PMID- 23732755 TI - Depression, psychological distress, and quality of life in patients with cardioverter defibrillator with or without cardiac resynchronization therapy. AB - Congestive heart failure is frequent and leads to reduced exercise capacity, reduced quality of life (QoL), and depression in many patients. Cardiac resynchronization therapy (CRT) and implantable cardioverter defibrillators (ICD) offer therapeutic options and may have an impact on QoL and depression. This study was performed to evaluate physical and mental health in patients undergoing ICD or combined CRT/ICD-implantation (CRT-D). Echocardiography, spiroergometry, and psychometric questionnaires [Beck Depression Inventory, General World Health Organization Five Well-being Index (WHO-5), Brief Symptom Inventory and 36-item Short Form (SF-36)] were obtained in 39 patients (ICD: 17, CRT-D: 22) at baseline and 6-month follow-up (FU) after device implantation. CRT-D patients had a higher NYHA class and broader left bundle branch block than ICD patients at baseline. At FU, ejection fraction (EF), peak oxygen uptake, and NYHA class improved significantly in CRT-D patients but remained unchanged in ICD patients. Patients with CRT-D implantation showed higher levels of depressive symptoms, psychological distress, and impairment in QoL at baseline and FU compared to ICD patients. These impairments remained mostly unchanged in all patients after 6 months. Overall, these findings imply that there is a need for careful assessment and treatment of psychological distress and depression in ICD and CRT-D patients in the course of device implantation as psychological burden seems to persist irrespective of physical improvement. PMID- 23732758 TI - [Management of epilepsy in patients with brain tumors]. PMID- 23732757 TI - Elevated serum bilirubin in assessing the likelihood of perforation in acute appendicitis: a diagnostic meta-analysis. AB - Hyperbilirubinemia associates with perforated acute appendicitis, but the precise test characteristics have not been determined by sufficiently powered studies. A systematic literature search of reports on hyperbilirubinemia in acute appendicitis was performed. After review and quality assessment of eight studies encompassing a total of 4974 patients the sensitivity, specificity and other measures of accuracy of hyperbilirubinemia as a predictor of perforation in acute appendicitis were pooled using a random-effects model. Summary estimates for hyperbilirubinemia (cutoff 1 mg/dl) as a predictor of perforation in acute appendicitis were as follows: sensitivity, 0.49 (95% confidence interval [CI], 0.45-0.52); specificity, 0.82 (95% CI, 0.80-0.83); positive likelihood ratio, 2.51 (95% CI, 1.58-4.00); negative likelihood ratio, 0.58 (95% CI, 0.44-0.76); diagnostic odds ratio was 4.42 (95% CI, 2.21-8.83). In summary receiving operating characteristic (SROC) analysis, the area under curve was 0.73. The presence of hyperbilirubinemia does not alone distinguish a perforation in acute appendicitis. Serum bilirubin level is of some value as a predictor of appendiceal perforation. Patients with hyperbilirubinemia combined with symptoms and signs consistent with severe acute appendicitis should be considered for early appendectomy. PMID- 23732759 TI - [Functional vascular anatomy of the spine and spinal cord]. PMID- 23732760 TI - [Cluster-like headache cause by cavernous sinus dural arteriovenous fistula, cured by transvenous embolization: a case report]. AB - We report a unique case of cavernous sinus(CS)-dural arteriovenous fistula(dAVF)with cluster headache-like ophthalmalgia without chemosis and exophthalmos, that was successfully treated by transvenous embolization. A 25 year-old man presented with severe right cluster headache-like ophthalmalgia and could not get complete relief of symptoms by medical treatment. MRI showed a hyper-intensity signal in the right cavernous sinus and cerebral angiography revealed Barrow type D cavernous sinus dural arteriovenous fistula, which is thought to be the cause of ophthalmalgia. Percutaneous transvenous embolization of the anterior part of the right CS and superior ophthalmic vein was performed and complete obliteration of dAVF was obtained followed by complete cure of cluster headache-like ophthalmalgia. We can detect neither the recurrence of dAVF on MRI nor any clinical symptom after 23 months of the treatment. This is the first clinical presentation of cluster headache-like ophthalmalgia caused by CS dAVF and it emphasizes the unique and important potential relationship between them. PMID- 23732761 TI - [Radiation-induced intracranial osteosarcoma after radiation for acute lymphocytic leukemia associated with Li-Fraumeni syndrome]. AB - A 28-year-old man presented with osteosarcoma of the occipital bone 16 years after 24 Gy of craniospinal irradiation for acute lymphocytic leukemia. The tumor had both intra- and extra-cranial components. However, the affected skull appeared to be normal on imaging because of permeative infiltration by the tumor. Subtotal resection was achieved and the tumor was verified histologically as an osteosarcoma. The residual tumor soon showed remarkable enlargement and disseminated to the spinal cord. Both of the enlarged and disseminated tumor masses were treated by surgical intervention and chemotherapy. However, the patient deteriorated due to the tumor regrowth and died 11 months after the initial diagnosis. This patient had previously developed a leukemia, a colon cancer, a rectal cancer and a hepatocellular carcinoma. His brother also died of leukemia. The patient had a heterozygous TP53 germ-line mutation of codon 248 in the exon 7. In conclusion, we consider the present tumor to be a rare example of radiation-induced skull osteosarcoma in a member of the cancer-prone family with TP53 germ-line mutation which is associated with Li-Fraumeni syndrome. PMID- 23732762 TI - [Rupture of an internal carotid-posterior communicating artery aneurysm formerly presented with transient pupil-sparing oculomotor nerve palsy in an extremely elderly patient]. AB - We recently encountered experienced a rare case of transient pupil-sparing oculomotor nerve palsy(PSONP)caused by an aneurysm at the junction of the internal carotid-and posterior communicating arteries(IC/PC AN)in an 87-year-old, non-diabetic woman. She initially presented with diplopia 4 years previously, and was diagnosed, based on incomplete right oculomotor paresis without pupil involvement(PSONP), as external ophthalmoplegia. MR-angiography revealed a long protrusion of the IC/PC AN with posterior-inferior projection, for which she chose to receive conservative management. Thirty nine months later, she presented with another transient PSONP. CT angiography(CTA)showed that the aneurysm was enlarged in the posterior-inferior direction. Two days after this last CTA imaging, the aneurysm ruptured with upward enlargement of the bleb. Despite complete external ophthalmoplegia and ptosis, her pupil involvement was still minimal and transient. By reviewing reported cases and our own case, we found that a narrow and long aneurysm body and posterior-inferior projection are characteristic for the IC/PC AN that causes PSONP, implying a possible mechanism for PSONP by upward compression of the oculomotor nerve. Though rare in its incidence, IC/PC AN could present with PSONP prior to their rupture. Therefore, immediate imaging evaluation in patients presenting with PSONP is essential to prevent devastating rupture events. PMID- 23732763 TI - [Endovascular treatment for cervical carotid artery aneurysm: a case report]. AB - We report here a case of cervical carotid artery aneurysm. This 37-year-old male suffered from acute neck swelling when he was taking lunch after physical work. Ultrasonography demonstrated a cervical pseudoaneurysm and a jet flow, which was blowing into the dome from the carotid artery. Angiogram revealed an aneurysm with a diameter of 3 cm at the bifurcation of the common carotid artery. Coil embolization using double-catheter technique was performed and complete occlusion of the aneurysm was obtained without any complications. The patient returned to his normal life. Cervical carotid artery aneurysms are rare and they induce pain by swelling in the neck, hoarseness, swallowing disturbance, hemorrhage, and cerebral ischemia due to embolism. In case of a cervical carotid artery aneurysm, safe and effective treatments are required and endovascular treatment should be considered. Although stent-assisted coil embolization or covered-stent placement were reported as an effective treatment for cervical aneurysms, coil embolization without using a stent was performed in this particular patient who is a young, blue-collar worker because the avoidance of long-term anti-platelet therapy was desirable. Preoperative evaluation is important to select adequate treatment. PMID- 23732764 TI - [Systematic review of complications for proper informed consent (8): carotid endarterectomy]. PMID- 23732765 TI - [Required knowledge for neuroendovascular surgeon (10): revascularization of intracranial large vessel occlusions in acute ischemic stroke]. PMID- 23732766 TI - Asymmetrical gait in adolescents with idiopathic scoliosis. AB - PURPOSE: This study investigated side-to-side gait asymmetry in subjects with adolescent idiopathic scoliosis. METHODS: There were 20 adolescents with idiopathic scoliosis and 20 age-matched control subjects, who participated in the study. To minimize confounding effects, we recruited patients with similar spinal curvature for the scoliosis group, and all participants are right hand dominant. The participants were instructed to ambulate on a 10 m walkway while barefoot. There were two force plates in the middle of the walkway. The ground reaction force (GRF) and angular displacements of six segments (foot, shank, thigh, pelvis, trunk, and head) were measured during one gait cycle based on the right and left lower extremities. To remove the positional information in the kinematic data, the derivative of angular displacement in each segment was calculated. To evaluate the side-to-side gait symmetry, we calculated the cross-correlation of each bilateral gait parameter. RESULTS: In the kinematics, the scoliosis group demonstrated asymmetrical gait in the frontal and transverse planes compared to the control group. In the GRF data, the scoliosis group demonstrated asymmetrical gait in the medial-lateral (M/L) direction compared to the control group. CONCLUSIONS: These results indicated that the scoliosis group produced an asymmetrical rotation pattern of the segments bilaterally in the frontal and transverse planes, resulting in asymmetrical GRF patterns in the M/L direction. This asymmetrical gait may be produced by changes in global postural control during gait and not simply by changes in control of only one or two specific segments. PMID- 23732767 TI - Selection of anti-cancer-associated gene single-chain variable fragments derived from gastric cancer patients using ribosome display. AB - The aim of this study was to construct a human single-chain variable fragment (scFv) gene library for gastric cancer, from which human anti-cancer-associated gene (CAGE) scFvs are selected. Human lymphocytes were isolated from the peripheral blood of 10 gastric cancer patients and whole human heavy and light chain genes were cloned by reverse transcription-polymerase chain reaction (RT PCR). VH and VL were rearranged randomly by splicing by overlap extension PCR. The ribosome complexes were enriched against the recombinant CAGE protein conjugated to magnetic beads. scFv antibodies were evaluated by western blot analysis, and affinity constants in a solution of antigen-antibody complexes were determined by enzyme-linked immunosorbent assay. An scFv library was constructed using the peripheral blood lymphocytes. The expressed scFv proteins from the ternary ribosome complexes were analyzed by western blot analysis and the affinity [equilibrium dissociation constant (KD)] of scFv for CAGE was determined to be 7.6x10-8 M. The ribosome display technique is efficient for selecting a fully human antibody fragment from a patient-derived gene pool. PMID- 23732768 TI - Plant selection for nest building by western lowland gorillas in Cameroon. AB - We examined 834 nests built by western lowland gorillas in Cameroon between July 2008 and July 2011 to identify the plant species used in their construction. Preference for each plant species for nesting was assessed using a 'preference index' calculated by combining information on the occurrence of each species in the forest and in the nests. Forty-six plant species representing about 15 % of the total number of species in the forest and 26 % of species used for nest building were frequently used by gorillas. Preference levels significantly varied among these species. Nests were mostly built with herbs of the families Marantaceae and Zingiberaceae and woody species such as Manniophyton fulvum (liana) and Alchornea floribunda (shrub). As observed in other gorilla populations, suitability for nest building and availability of gorilla food in stems were the likely determinants of plant selection. The total number of species used per nest ranged from 1 to 11, with an average of 4.9. This is high compared to other sites, emphasizing variability in the availability of nest building materials and habitat differences across the range of the western gorilla. Seasonal changes in the use of different habitat types for nesting did not appear to influence plant use for nest building as there was little variation in plant selection across seasons or the composition of nests. Our findings suggest that gorillas non-randomly select plant species to build nests, and use a particular set of species combined at varying proportions, with no clear seasonal or spatial patterns. PMID- 23732769 TI - Three-dimensional image-based high-dose-rate interstitial brachytherapy for mobile tongue cancer. AB - To investigate the influence of a 3D image-based treatment-planning method for high-dose-rate interstitial brachytherapy (HDR-ISBT) for mobile tongue cancer, we analyzed dose-volume histogram results for the clinical target volume (CTV) and the mandible. Between October 2010 and November 2011, one and four patients having T2 and T3 tumors, respectively, were treated with HDR-ISBT. Multiplane implantation using 9-15 treatment applicators was performed. Lugol's iodine staining, metal markers, ultrasonography, and magnetic resonance imaging were used to identify the contours of the gross tumor volume (defined as the CTV). The results of the image-based treatment plan were compared with those of the conventional simulated plan on the basis of a reference point 5 mm from the applicator position. The mean D90(CTV) and V100(CTV) were 112% of the prescribed dose (PD) and 98.1%PD, respectively, for the image-based plan, and 113%PD and 97.2%PD, respectively, for the conventional plan. The median CTVref/Vref was 0.23 for the image-based plan and 0.16 for the conventional plan (P = 0.01). The mean D0.1 cm(3) (mandible), D1 cm(3) (mandible), and D2 cm(3) (mandible) were 80.1%PD, 62.5%PD, and 55.7%PD, respectively, for the image-based plan, and 109.1%PD (P = 0.02), 82.4%PD (P = 0.005), and 74%PD (P = 0.004), respectively, for the conventional plan). Image-based treatment planning may achieve high-conformity radiotherapy for the CTV and decrease irradiated doses to the mandible. PMID- 23732770 TI - Interfractional change of high-risk CTV D90 during image-guided brachytherapy for uterine cervical cancer. AB - The purpose of this study was to evaluate interfractional changes of the minimum dose delivered to 90% of the high-risk clinical target volume (HR-CTV D90) and D2cc of the bladder and rectum during brachytherapy for uterine cervical cancer patients. A total of 52 patients received external beam radiotherapy and high dose-rate intracavitary brachytherapy (ICBT). For each of four ICBT applications, a pelvic CT scan was performed and the HR-CTV was delineated. Retrospectively, these patients were divided into two groups: (i) the standard dose group with 6 Gy to point A in each ICBT, and (ii) the adaptive dose group with a modified dose to point A to cover the HR-CTV with the 6-Gy isodose line as much as possible. The HR-CTV D90 was assessed in every session, and analyzed as interfractional changes. In the standard dose group, the interfractional changes of the HR-CTV D90 showed a linear increase from the first to the third of the four ICBT (average 6.1, 6.6, 7.0 and 7.1 Gy, respectively). In contrast, those of the adaptive dose group remained almost constant (average 7.2, 7.2, 7.3 and 7.4 Gy, respectively). Especially, in the case of a large HR-CTV volume (>=35 cm(3)) at first ICBT, the total HR-CTV D90 of the adaptive dose group with brachytherapy was significantly higher than that of the standard dose group. There were no significant differences in total D2cc in bladder and rectum between the two groups. Image-guided adaptive brachytherapy based on interfractional tumor volume change improves the dose to the HR-CTV while keeping rectal and bladder doses within acceptable levels. PMID- 23732771 TI - Discussions on target theory: past and present. PMID- 23732772 TI - A synthetic biology approach to the development of transcriptional regulatory models and custom enhancer design. AB - Synthetic biology offers novel opportunities for elucidating transcriptional regulatory mechanisms and enhancer logic. Complex cis-regulatory sequences--like the ones driving expression of the Drosophila even-skipped gene--have proven difficult to design from existing knowledge, presumably due to the large number of protein-protein interactions needed to drive the correct expression patterns of genes in multicellular organisms. This work discusses two novel computational methods for the custom design of enhancers that employ a sophisticated, empirically validated transcriptional model, optimization algorithms, and synthetic biology. These synthetic elements have both utilitarian and academic value, including improving existing regulatory models as well as evolutionary questions. The first method involves the use of simulated annealing to explore the sequence space for synthetic enhancers whose expression output fit a given search criterion. The second method uses a novel optimization algorithm to find functionally accessible pathways between two enhancer sequences. These paths describe a set of mutations wherein the predicted expression pattern does not significantly vary at any point along the path. Both methods rely on a predictive mathematical framework that maps the enhancer sequence space to functional output. PMID- 23732774 TI - Equal efficacy of endoscopic and surgical cystogastrostomy for pancreatic pseudocyst drainage in a randomized trial. AB - BACKGROUND & AIMS: Although surgery is the standard technique for drainage of pancreatic pseudocysts, use of endoscopic methods is increasing. We performed a single-center, open-label, randomized trial to compare endoscopic and surgical cystogastrostomy for pancreatic pseudocyst drainage. METHODS: Patients with pancreatic pseudocysts underwent endoscopic (n = 20) or surgical cystogastrostomy (n = 20). The primary end point was pseudocyst recurrence after a 24-month follow up period. Secondary end points were treatment success or failure, complications, re-interventions, length of hospital stay, physical and mental health scores, and total costs. RESULTS: At the end of the follow-up period, none of the patients who received endoscopic therapy had a pseudocyst recurrence, compared with 1 patient treated surgically. There were no differences in treatment successes, complications, or re-interventions between the groups. However, the length of hospital stay was shorter for patients who underwent endoscopic cystogastrostomy (median, 2 days, vs 6 days in the surgery group; P < .001). Although there were no differences in physical component scores and mental health component scores (MCS) between groups at baseline on the Medical Outcomes Study 36-Item Short-Form General Survey questionnaire, longitudinal analysis showed significantly better physical component scores (P = .019) and mental health component scores (P = .025) for the endoscopy treatment group. The total mean cost was lower for patients managed by endoscopy than surgery ($7011 vs $15,052; P = .003). CONCLUSIONS: In a randomized trial comparing endoscopic and surgical cystogastrostomy for pancreatic pseudocyst drainage, none of the patients in the endoscopy group had pseudocyst recurrence during the follow-up period, therefore there is no evidence that surgical cystogastrostomy is superior. However, endoscopic treatment was associated with shorter hospital stays, better physical and mental health of patients, and lower cost. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00826501. PMID- 23732773 TI - Card9 mediates intestinal epithelial cell restitution, T-helper 17 responses, and control of bacterial infection in mice. AB - BACKGROUND & AIMS: Caspase recruitment domain 9 (CARD9) is an adaptor protein that integrates signals downstream of pattern recognition receptors. CARD9 has been associated with autoinflammatory disorders, and loss-of-function mutations have been associated with chronic mucocutaneous candidiasis, but the role of CARD9 in intestinal inflammation is unknown. We characterized the role of Card9 in mucosal immune responses to intestinal epithelial injury and infection. METHODS: We induced intestinal inflammation in Card9-null mice by administration of dextran sulfate sodium (DSS) or Citrobacter rodentium. We analyzed body weight, assessed inflammation by histology, and measured levels of cytokines and chemokines using quantitative reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Cell populations were compared between wild type and Card9-null mice by flow cytometry analysis. RESULTS: Colon tissues and mesenteric lymph nodes of Card9-null mice had reduced levels of interleukin (IL) 6, interferon-gamma, and T-helper (Th)17 cytokines after administration of DSS, compared with wild-type mice. IL-17A and IL-22 expression were reduced in the recovery phase after DSS administration, coincident with decreased expression of antimicrobial peptides and the chemokine (C-C motif) ligand 20 (Ccl20). Although Card9-null mice had more intestinal fungi based on 18S analysis, their Th17 responses remained defective even when an antifungal agent was administered throughout DSS exposure. Moreover, Card9-null mice had impaired immune responses to C rodentium, characterized by decreased levels of colonic IL-6, IL-17A, IL-22, and regenerating islet-derived 3 gamma (RegIIIgamma), as well as fewer IL-22 producing innate lymphoid cells (ILCs) in colon lamina propria. CONCLUSIONS: The adaptor protein CARD9 coordinates Th17- and innate lymphoid cell-mediated intestinal immune responses after epithelial injury in mice. PMID- 23732775 TI - Pancreatic lipase-related protein 2 digests fats in human milk and formula in concert with gastric lipase and carboxyl ester lipase. AB - BACKGROUND: Dietary fats must be digested into fatty acids and monoacylglycerols prior to absorption. In adults, colipase-dependent pancreatic triglyceride lipase (PTL) contributes significantly to fat digestion. In newborn rodents and humans, the pancreas expresses low levels of PTL. In rodents, a homologue of PTL, pancreatic lipase-related protein 2 (PLRP2), and carboxyl ester lipase (CEL) compensate for the lack of PTL. In human newborns, the role of PLRP2 in dietary fat digestion is unclear. To clarify the potential of human PLRP2 to influence dietary fat digestion in newborns, we determined PLRP2 activity against human milk and infant formula. METHODS: The activity of purified recombinant PLRP2, gastric lipase (GL), and CEL against fats in human milk and formula was measured with each lipase alone and in combination with a standard pH-stat assay. RESULTS: Colipase added to human milk stimulated fat digestion. PLRP2 and CEL had activity against human milk and formula. Predigestion with GL increased PLRP2 activity against both substrates. Together, CEL and PLRP2 activity was additive with formula and synergistic with human milk. CONCLUSION: PLRP2 can digest fats in human milk and formula. PLRP2 acts in concert with CEL and GL to digest fats in human milk in vitro. PMID- 23732776 TI - Acute inflammation in young children inhibits C-type natriuretic peptide. AB - BACKGROUND: C-type natriuretic peptide (CNP) is a paracrine growth factor critical in endochondral bone growth. Amino-terminal CNP (NTproCNP), measurable in plasma, correlates with growth-plate activity and can be used as a biomarker of growth velocity in children. Because severe inflammation in adults increases CNP, we studied CNP peptides and inflammatory markers in children with acute illness. METHODS: Forty-two children aged 2 mo to 5 y with acute illness warranting admission to an acute assessment unit were studied. Fifteen age matched healthy children attending an outpatient clinic served as controls. Venous CNP concentrations were measured at admission, along with markers of acute inflammation (body temperature, C-reactive protein (CRP), and white blood cell count) in children with acute illness. RESULTS: NTproCNP and CNP SD scores (SDSs) in the acutely ill group were significantly suppressed (P < 0.001) as compared with those of healthy children or healthy population norms. NTproCNP SDS was significantly inversely related to body temperature (r = -0.42, P < 0.01) and CRP (r = -0.56, P < 0.001). CONCLUSION: Acute inflammation in young children potently reduces CNP production, which needs to be considered when screening for growth disorders. Our data raise the possibility that the adverse effects of inflammatory cytokines on skeletal growth may be mediated in part by reduced CNP. PMID- 23732777 TI - Methylation of the HACE1 gene is frequently detected in hepatocellular carcinoma. AB - BACKGROUND/AIMS: Recently, it has been reported that HACE1, the E3 ubiquitin ligase, is epigenetically inactivated in human Wilms' tumors and HACE 1 expression was also down-regulated in colorectal and gastric carcinomas. METHODOLOGY: In this study, methylation status of the HACE1 gene was examined in primary carcinomas and the corresponding normal tissues derived from 27 patients with HCC using quantitative methylation-specific PCR (qMSP). RESULTS: Methylation of the HACE1 gene was detected in 18 out of the 27 (67%) HCCs, suggesting that the methylation of HACE1 was frequently observed in HCC. The clinicopathological data were then correlated with these results. In the value of serum AFP (alpha fetoprotein), a significant difference was observed (p=0.0025). CONCLUSIONS: All stages of HCCs presented HACE1 methylation, indicating that the HACE1 gene has been methylated from the early stages of HCCs. PMID- 23732778 TI - Association between HLA-G 14-bp insertion/deletion polymorphism and hepatocellular carcinoma in Korean patients with chronic hepatitis B viral infection. AB - BACKGROUND/AIMS: The aim of this study was to determine whether the major HLA-G gene was associated with hepatocellular carcinoma (HCC). Abnormal HLA-G expression is present in various diseases, such as renal cell carcinoma, asthma and classical Hodgkin's lymphoma. METHODOLOGY: To investigate the possible association with susceptibility to HCC, 181 chronic hepatitis patients and 180 HCC patients were enrolled in this study. The HLA-G 14-bp insertion/deletion polymorphism is located in the 3' untranslated region of the HLA-G gene and was analyzed using polymerase chain reaction. For analysis of genetic data, SNPStats and SPSS 18.0 were used. Logistic regression models were performed to determine the odds ratio, 95% confidence interval, and p value. RESULTS: Allele and genotype frequencies of the HLA-G 14-bp insertion/deletion polymorphism in the hepatitis group had a similar pattern, as compared to those in the HCC group. Furthermore, no differences were observed between patients with and without liver cirrhosis. CONCLUSIONS: These results suggest that the HLA-G 14-bp insertion/deletion polymorphism may not be associated with HCC susceptibility and liver cirrhosis development in the Korean population. PMID- 23732779 TI - Inhibition of hepatitis B virus production in vitro by proteasome inhibitor MG132. AB - BACKGROUND/AIMS: To investigate the suppressive effects of proteasome inhibitor MG132 on hepatitis B virus production. METHODOLOGY: HepG2 2.2.15 hepatoblastoma cells, which constitutively produce HBV particles, were used in the present study. MTT assay was used to evaluate the cytotoxicity of MG132. A Proteasome-Glo chymotrypsin-like cell-based assay was used to access the proteasome activity. Quantitative PCR were performed to analyze HBV-DNA. Secreted HBV antigens in the culture medium were measured by ELISA. Western blot and immunofluorescent staining of HBV antigen were also performed. RESULTS: After 6 days of MG132 treatment, proteasome activity was greatly decreased to 64.3 +/- 7.8% and 36.4 +/ 7.7% of untreated cells by 0.1MUM and 0.3MUM of MG132, respectively. The levels of HBsAg and HBeAg, and the copy number of extracellular HBV-DNA, were decreased to nearly half of the control group by 0.1MUM MG132. The HBV replicative intermediates were also suppressed by MG132. Western blot and immunofluorescent staining clearly showed the lower levels of the expression of HBV proteins induced by MG132. CONCLUSIONS: MG132 could effectively inhibit the HBV replication in vitro. Ubiquitin-proteasome pathway plays an important role in HBV life cycle and could be a promising therapeutic target for anti-HBV drugs. PMID- 23732780 TI - Influence of etiology on host immunity in liver cirrhosis patients with advanced hepatocellular carcinoma receiving intra-arterial chemotherapy. AB - BACKGROUND/AIMS: We have shown that continuous intra-arterial combination chemotherapy (IACC) might be more effective for advanced HCC (aHCC) in patients with HCV-related (C-LC) or alcoholic (A-LC) liver cirrhosis (LC) patients than in patients with HBV-related LC (B-LC). This study retrospectively assesses the difference of etiology on host immunity in LC patients with aHCC treated by IACC. METHODOLOGY: Forty-seven adult LC patients with aHCC were treated by IACC between 2005 and 2008, with inoperable tumors according to CT findings. IACC (LV at 12 mg/hr, CDDP at 10 mg/hr, and 5-FU at 250 mg/22 hr) was delivered via the proper hepatic artery every 5 days for 4 weeks using a catheter connected to a subcutaneously implanted drug delivery system. The control group comprised 13 healthy volunteers. RESULTS: Twelve of the 47 patients with aHCC had B-LC, 27 had C-LC, and 8 had A-LC. In the B-LC group, 1 out of 12 patients had a Japan Integrated Staging (JIS) score of 2, 4 had a JIS score of 3, 7 had a JIS score of 4, and no patients had a JIS score of 5, while the respective numbers were 6, 9, 10 and 2 in the C-LC group, and 1, 1, 5 and 1 in the A-LC group. The response rates were 37.0%, 37.5% and 8.3% in the C-LC, A-LC and B-LC group, respectively. In the C-LC group, the percentage of Th1 cells before and after chemotherapy was significantly higher than in the control group. In the B-LC group, the percentage of Th2 cells after chemotherapy was significantly higher than that in the control group. However, there were no significant differences of Th1 and Th2 cells between the A-LC group and the control group. CONCLUSIONS: These results indicate that IACC was more effective for aHCC in A-LC patients with normal Th1/Th2 balance and in C-LC patients without Th2 dominance than in B-LC patients who showed Th2 dominance after chemotherapy. PMID- 23732781 TI - Infection control for prevention of pancreatic fistula after pancreaticoduodenectomy. AB - BACKGROUND/AIMS: Effectiveness of infection control for prevention of pancreatic fistula (PF) after pancreaticoduodenectomy (PD) is not clear. We analyzed the impact of infection on the development of PF and examined the effect of enhanced infection control to prevent PF. METHODOLOGY: Amylase level (D-amylase) and bacterial culture (D-culture) of drainage fluid were evaluated on POD 1, 3, 5 and 7, in 90 consecutive patients with soft pancreas who underwent PD. The study period was divided into two periods. The relationship between D-amylase and D culture was examined, and the clinicopathological factors predicting PF were analyzed in the first period. Then, anti-infection measures were introduced in the second period, and the effect of enhanced infection control was examined. RESULTS: Twenty-nine out of 58 patients (50.0%) developed PF in the first period. D-amylase were higher in patients with D-culture infection than in those without it (p<0.05). D-amylase above 10,000IU/L on POD1 and D-culture infection on POD3 were independent predictive factors for PF by multivariate analysis (p<0.01). After introduction of enhanced infection control in the second period, four out of 32 patients (12.5%) developed PF. The rates of PF and D-culture infection were significantly reduced (p<0.05). CONCLUSIONS: Infection of drainage fluid is related to an increased level of amylase, resulting in PF. Enhanced infection control can effectively prevent PF after PD in soft pancreas. PMID- 23732782 TI - Ten cancer associated genes identified in peripheral blood mononuclear cells from patients with pancreatic adenocarcinoma. AB - BACKGROUND/AIMS: Identification of biomarkers for pancreatic cancer may help diagnosis and treatment of patients. METHODOLOGY: This pilot study evaluated potential markers for pancreatic adenocarcinoma (PAC) in peripheral blood mononuclear cells (PBMC). RNA samples were isolated from PBMCs and hybridized to oligonucleotide arrays. RESULTS: Twenty five-fold leave-two-out analysis identified 10 cancer-associated genes (CAGs). The PAC patients could be identified by the expression profiles of their PBMC with a specificity of 96% and a sensitivity of 80%. CONCLUSIONS: Ten CAGs were potential new markers in PBMC for patients with PAC. PMID- 23732783 TI - Blending our talents. PMID- 23732784 TI - Further validation of the visual analogue scale for irritable bowel syndrome after use in clinical practice. AB - The Visual Analogue Scale for Irritable Bowel Syndrome (VAS-IBS), a self-rating questionnaire, was designed to measure symptoms and the effect of treatment in patients suffering from irritable bowel syndrome. The aim of this descriptive correlational study was to conduct further psychometric validation after the VAS IBS had been used in clinical practice, translate it into English, and compare the results with controls. Forty-nine patients with irritable bowel syndrome (median age = 38 years old [range, 18-69 years]) were compared with 90 healthy persons (median age = 44 years old [range, 21-77 years]) who served as controls. The patients with irritable bowel syndrome completed 3 questionnaires: the VAS IBS, the Gastrointestinal Symptom Rating Scale, and the Perception of Change of Symptoms. Controls completed only the VAS-IBS. Results showed that the VAS-IBS is a valid questionnaire that measures the degree of change of symptoms and discriminates between patients who have irritable bowel syndrome from those who do not. It is important to compare the VAS-IBS among different cultural populations so we suggest that the English version of the VAS-IBS should now be used in English-speaking countries and be further tested for validity and reliability with English-speaking patients. PMID- 23732785 TI - Physical attributes of endoscopy nurses related to musculoskeletal problems. AB - The purpose of this research study was to determine whether specific attributes of endoscopy nurses such as age, body mass, or height contribute to neck, shoulder, or back problems. Study participants included endoscopy nurses who physically assist with endoscopic procedures (hands-on assist). Participants with preexisting neck, shoulder, or back injury prior to employment in endoscopy were excluded. Study participants completed the Standardized Nordic Questionnaire. Results suggested that age or height of less than 68 inches were not contributing factors to neck, shoulder, or back problems. Nurses with a body mass index (BMI) of 25 or more had significantly more upper back problems in the past 12 months. Nurses with BMI of 25 or more and/or those who were taller than 68 inches had a significantly higher incidence of upper and lower back problems that prevented work in the previous 12 months and occurred within the previous 7 days. Nurses with a BMI of 25 or more and/or who are 68 inches or taller should be aware of their higher risk for upper and lower back problems, and adjustments need to be made to their work practice and environment. PMID- 23732786 TI - The nurse endoscopist: moving ahead with time. AB - The field of nursing has rapidly evolved over the last few decades. In the United Kingdom, nurse endoscopists are widely accepted and play an important role in the structure of gastroenterology services. Capsule endoscopy is a relatively new technique to image the small bowel and requires a skill set based on observation, recognition, and interpretation of significant findings from computer images. The reading of the capsule video, however, is time consuming. This article discusses the evolving role of nurses within the field of gastrointestinal endoscopy with specific reference to small bowel endoscopy. We also discuss the potential challenges of the role of the nurse endoscopist and insights into what the future may hold. PMID- 23732787 TI - Photoeducation and photoprotection among liver transplant candidates: a cross sectional study. AB - The incidence of skin cancer after liver transplant ranges from 3% to 16%, considerably higher than that observed in the general population. Skin cancer causes 25% of deaths in patients who have survived more than 3 years after liver transplant. The objective of this study was to identify differences regarding the level of sun exposure, knowledge of potential risk factors, and photoprotection measures among liver transplant candidates and recipients. We carried out a prospective cross-sectional study with 100 patients enrolled at a liver transplant program in a Brazilian center. The patients were interviewed and received oral information regarding skin care and sun exposure. Results reveal that measures of photoprotection and photoeducation are more prevalent among recipients than among candidates. High degrees of solar exposure were observed more frequently among candidates, although recipients showed better knowledge about the risks of sun exposure. Educational actions concerning skin cancer prevention should be part of the guidelines given by the multidisciplinary team to the liver transplant patients, in particular, by the nursing team. PMID- 23732788 TI - A randomized double-blind trial of anesthesia provided for colonoscopy by university-degreed anesthesia nurses in Greece: safety and efficacy. AB - There are numerous studies in the literature of anesthesia administered during colonoscopy including various methods, drugs, and monitoring systems; however, none of them has studied whether a university-degreed nurse anesthesia provider (known as a certified registered nurse anesthetist in the United States) is skillful enough to provide safe anesthesia in patients undergoing endoscopic procedures. The aim of our study was to determine whether anesthesia provided by a university-degreed nurse anesthesia provider during an endoscopic procedure is comparable in terms of safety and efficacy with routine sedation practice. This randomized, double-blind study included 100 adult patients who underwent colonoscopy conducted in the Evgenidion University Hospital during a single year. Subjects were divided into 2 groups: the first group received the usual scheme of intravenous sedation with midazolam and fentanyl administered by a member of the endoscopic team that was blind to Bispectral Index (BIS) values recordings (Group 0). The second group received intravenous bolus injection of propofol bolus by a university-degreed anesthesia registered nurse based on the BIS values (Group 1). The average of the mean BIS values of Group 0 was 85.07 (SD = 8.01) and for Group 1 was 76.1 (SD = 10.88; p = .04). The parameters of "patient memory during procedure" and the satisfaction scores (as self-assessed by the patients as well as 2 gastroenterologists) were also significantly different between the patients of the 2 groups (p = .000). Comparison between the 2 groups showed that the sedation offered by a university-degreed nurse anesthesia provider was absolutely safe and effective, offering particular comfort to the patient during the intervention and contributing significantly to its successful results. PMID- 23732789 TI - Inpatient care of hepatitis C patients candidate for triple therapy. PMID- 23732790 TI - Prestimulus EEG amplitude determinants of ERP responses in a habituation paradigm. AB - Evidence for the nature and extent of the prestimulus EEG contributions to ERP determination has been mounting, and we have recently mapped these within an equiprobable auditory Go/NoGo task. Here we examined if the pattern of relationships in the Go/NoGo would generalise to an auditory habituation paradigm. Count and No-task conditions were assessed, and we predicted broadly corresponding effects between Go and Count, and NoGo and No-task conditions. Single-trial data were obtained at the midline sites (Fz, Cz, Pz). Prestimulus EEG in each of the traditional bands was quantified using a sliding FFT window, and five ERP components were manually identified. The corresponding EEG and ERP data were then correlated across subjects, sites, and trials, separately for each ERP component measure (amplitude, latency), task condition (Count, No-task), and EEG band (delta, theta, alpha, beta). Despite the substantial paradigm and methodological differences, 10 of the 17 expected prestimulus EEG-ERP directional relationships (i.e., direct or inverse effects) were confirmed across the traditional bands and ERP components, and only one was in the opposite direction. Importantly, 18 additional relationships reached significance here; these occurred across the EEG bands, and ERP components. Together these findings confirm the significant contributions of prestimulus EEG to subsequent ERP responses. These appear to be at least partially independent of the paradigm and EEG methodology employed, suggesting that there is merit in mapping these contributions further. Our findings also indicate the improved sensitivity of the statistical approach used here in detecting such EEG-ERP relationships. PMID- 23732792 TI - How hollow structures form from crystalline iron-iron oxide core-shell nanoparticles in the electron beam. AB - Here, we report the effect of oleylamine (OLA) stabilizing molecules on the stability of iron-iron oxide core-shell nanoparticles in the electron beam. The presence of excess OLA (>50 wt%) induces the structural transformation in the highly crystalline, core-shell structures to form hollow iron oxide nanoparticles after 120 s of electron beam exposure. PMID- 23732791 TI - Microfluidic interrogation and mathematical modeling of multi-regime calcium signaling dynamics. AB - Through microfluidic interrogation we analyzed real-time calcium responses of HEK293 cells stimulated with short pulses of the M3 muscarinic receptor ligand carbachol in two different concentration regimes. Lower ligand concentrations elicit oscillatory calcium signals while higher concentrations trigger a rapid rise that eventually settles down at a steady-state slightly above pre-stimulus levels, referred to as an acute signal. Cells were periodically pulsed with carbachol at these two concentration regimes using a custom-made microfluidic platform, and the resulting calcium signals were measured with a single fluorescent readout. Pulsed stimulations at these two concentration regimes resulted in multiple types of response patterns that each delivered complementary information about the M3 muscarinic receptor signaling pathway. These multiple types of calcium response patterns enabled development of a comprehensive mathematical model of multi-regime calcium signaling. The resulting model suggests that dephosphorylation of deactivated receptors is rate limiting for recovery of calcium signals in the acute regime (high ligand concentration), while calcium replenishment and IP3 production determine signal recovery in the oscillatory regime (low ligand concentration). This study not only provides mechanistic insight into multi-regime signaling of the M3 muscarinic receptor pathway, but also provides a general strategy for analyzing multi-regime pathways using only one fluorescent readout. PMID- 23732793 TI - The use of MRI-guided laser-induced thermal ablation for epilepsy. AB - PURPOSE: Epilepsy surgery is constantly researching for new options for patients with refractory epilepsy. MRI-guided laser-induced thermal ablation for epilepsy is an exciting new minimally invasive technology with an emerging use for lesionectomy of a variety of epileptogenic focuses (hypothalamic hamartomas, cortical dysplasias, cortical malformations, tubers) or as a disconnection tool allowing a new option of treatment without the hassles of an open surgery. METHODS: MRI-guided laser interstitial thermal therapy (MRgLITT) is a procedure for destroying tissue-using heat. To deliver this energy in a minimally invasive fashion, a small diameter fiber optic applicator is inserted into the lesion through a keyhole stereotactic procedure. The thermal energy induces damage to intracellular DNA and DNA-binding structures, ultimately leading to cell death. The ablation procedure is supervised by real-time MRI thermal mapping and confirmed by immediate post-ablation T1 or FLAIR MRI images. RESULTS: The present report includes an overview of the development and practice of an MR-guided laser ablation therapy known as MRI-guided laser interstitial thermal therapy (MRgLITT). The role of modern image-guided trajectory planning in MRgLITT will also be discussed, with particular emphasis on the treatment of refractory epilepsy using this novel, minimally invasive technique. CONCLUSION: MRI-guided laser-induced thermal ablation for epilepsy is an exciting new minimally invasive technology that finds potential new applications every day in the neurosurgical field. It certainly brings a new perspective on the way we practice epilepsy surgery even though long-term results should be properly collected and analyzed. PMID- 23732794 TI - Preparation, characterization and antimicrobial efficiency of Ag/PDDA-diatomite nanocomposite. AB - Nanocomposites consisting of diatomaceous earth particles and silver nanoparticles (silver NPs) with high antimicrobial activity were prepared and characterized. For the purpose of nanocomposite preparation, silver NPs with an average size of 28nm prepared by modified Tollens process were used. Nanocomposites were prepared using poly(diallyldimethylammonium) chloride (PDDA) as an interlayer substance between diatomite and silver NPs which enables to change diatomite original negative surface charge to positive one. Due to strong electrostatic interactions between negatively charged silver NPs and positively charged PDDA-modified diatomite, Ag/PDDA-diatomite nanocomposites with a high content of silver (as high as 46.6mgAg/1g of diatomite) were prepared. Because of minimal release of silver NPs from prepared nanocomposites to aqueous media (<0.3mg Ag/1g of nanocomposite), the developed nanocomposites are regarded as a potential useful antimicrobial material with a long-term efficiency showing no risk to human health or environment. All the prepared nanocomposites exhibit a high bactericidal activity against Gram-negative and Gram-positive bacteria and fungicidal activity against yeasts at very low concentrations as low as 0.11g/L, corresponding to silver concentration of 5mg/L. Hence, the prepared nanocomposites constitute a promising candidate suitable for the microbial water treatment in environmental applications. PMID- 23732795 TI - Human vascular endothelial cell morphology and functional cytokine secretion influenced by different size of HA micro-pattern on titanium substrate. AB - Both coverage and morphology of endothelial cells (ECs) on blood contact biomaterials were involved in the antithrombotic and anti-proliferative process. However, most researches have been focused on the ECs amount on the materials surface, but not the morphology. As of now, little is known about the relationship between the ECs morphology and the cytokine secretion, especially those anticoagulant factors on cardiovascular implants. In this study, three sizes of parallel micro-stripes of high molecular weight hyaluronic acid (HMW-HA) were fabricated on the NaOH-treated titanium (TiOH) surface. These micro-patterns of ridges/grooves were used to regulate the distribution, morphology and cytokine secretion of the ECs. The roughness of bare Ti and TiOH was detected by AFM, and the micro-pattern sizes were imaged by SEM. The chemical bonding of HMW-HA to the TiOH surface was demonstrated by FTIR, and the element distribution was examined by EDX. The morphology index of the ECs was analyzed to evaluate the orientation, elongation and spreading of the ECs on the micro-patterned surfaces and the control, while the cell number and cytokine secretion of the ECs were measured by related kits. The characterization of the ECs demonstrated that the bigger L/B index improved NO, PGI2, Fn release and TM, TFPI, E-Selectin expression as well as reducing vWF secretion. The platelet adhesion test and the whole blood clotting time test proved the increasing anticoagulation property of ECs with their elongation increasing. These results suggest that ECs morphology-related function can be regulated by different sizes of micro-patterns. PMID- 23732796 TI - Exploiting the nano-sized features of microfibrillated cellulose (MFC) for the development of controlled-release packaging. AB - Microfibrillated cellulose (MFC) was used in this study to prepare films containing an active molecule, lysozyme, which is a natural antimicrobial agent. The main goal of this research was to assess the potential for exploiting the nano-sized dimension of cellulose fibrils to slow the release of the antimicrobial molecule, thus avoiding a too-quick release into the surrounding medium, which is a major disadvantage of most release systems. For this purpose, the release kinetics of lysozyme over a 10-day period in two different media (pure water and water/ethanol 10wt.%) were obtained, and the experimental data was fitted with a solution of Fick's second law to quantify the apparent diffusion coefficient (D). The results indicate that the MFC retained lysozyme, presumably due to electrostatic, hydrogen, and ion-dipole interactions, with the largest release of lysozyme-approximately 14%-occurring from the initial amount loaded on the films. As expected, ethanol as a co-solvent slightly decreased the diffusion of lysozyme from the MFC polymer network. The addition of two potential modulating release agents-glycerol and sodium chloride-was also evaluated. Findings from this work suggest that MFC-based films can be considered a suitable candidate for use in controlled-release packaging systems. PMID- 23732797 TI - Protein adsorption and covalent bonding to silicon nitride surfaces modified with organo-silanes: comparison using AFM, angle-resolved XPS and multivariate ToF SIMS analysis. AB - Organo-silanes provide a suitable interface between the silicon-based transducers of various biosensing devices and the sensing proteins, immobilized through physical adsorption, as for (3-aminopropyl)triethoxysilane (APTES), or covalent binding, e.g. via protein amine groups to (3-glycidoxypropyl)trimethoxysilane (GOPS) modified surface. Immobilization of rabbit gamma globulins (RgG) to silicon nitride surfaces, modified either with APTES or GOPS, was examined as a function of incubation time using atomic force microscopy (AFM), angle-resolved X ray photoelectron spectroscopy (ARXPS) and time of flight secondary ion mass spectrometry (ToF-SIMS). Multivariate technique of principal component analysis was applied to ToF-SIMS spectra in order to enhance sensitivity of immobilized RgG detection. Principal component regression shows a linear relationship with surface density determined rigorously from ARXPS following an organic bilayer approach, allowing for protein coverage quantification by ToF-SIMS. Taking it overall the surface immobilized amount of RgG is higher and develops faster on the surfaces silanized with APTES rather than with GOPS. Similar, although less distinct, difference is observed between the two surface types concerning the temporal evolution of average AFM height. The average height of protein overlayer correlates well with ARXPS and ToF-SIMS data expressed in terms of protein surface density. However, determined linear regression coefficients are distinctively higher for the surfaces modified with epoxy- rather than amino silane, suggesting different surface density and conformation of the proteins immobilized through to covalent binding and physical adsorption. PMID- 23732798 TI - Surface functionalization of titanium substrates with cecropin B to improve their cytocompatibility and reduce inflammation responses. AB - Bacteria-related inflammation is a common postoperative complication in orthopedic implantation. In this study, cecropin B (CecB), a cationic peptide, was immobilized onto the surfaces of titanium substrates to improve their cytocompatibility and reduce inflammation responses. Polydopamine film was coated onto the surfaces of titanium substrates as an intermediate layer for the further immobilization of the CecB, which was confirmed by scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and water contact angle measurement, respectively. Osteoblasts grown onto the CecB immobilized titanium substrates displayed significantly higher (p<0.01) cell viability than that of native titanium substrates (controls). Gram-positive bacteria - Bacillus subtilis, Staphylococcus aureus and Gram-negative bacteria - Escherichia coli, Pseudomonas aeruginosa were employed for antibacterial characterization. Media-borne assay and anti-biofilm formation showed that CecB immobilized titanium substrates inhibited the adhesion and growth of bacteria. Macrophages cultured onto CecB-immobilized titanium substrates demonstrated statistically lower (p<0.01) levels of tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) than those of the control groups. The results indicated that the immobilization of CecB onto titanium substrates was responsible for improved cytocompatibility and reduced inflammation responses. The approach presented here has great potential in the development of antibacterial titanium based implants in clinical applications. PMID- 23732799 TI - Hydroxypropyl methyl cellulose grafted with polyacrylamide: application in controlled release of 5-amino salicylic acid. AB - In the present study, hydroxypropyl methyl cellulose grafted with polyacrylamide (HPMC-g-PAM) hydrogel was evaluated in vitro as a potential carrier for controlled release of 5-amino salicylic acid (5-ASA). The graft copolymer was developed by grafting PAM chains onto HPMC backbone using potassium persulphate as initiator. The swelling behaviour of hydrogel based tablet was investigated as a function of pH and time in various buffer solutions similar to that of gastric and intestinal fluids. The % equilibrium swelling was found to be higher in case of simulated intestinal fluid (pH=7.4) and lower in simulated gastric fluid (pH=1.2), making an ideal matrix as required for colon specific drug delivery. The drug release study was performed at various pH values akin to the condition of GI tract. The release kinetics of 5-ASA showed non-Fickian diffusion behaviour. This indicates that the release is controlled by a combination of polymer relaxation or erosion of the matrix and diffusion of the drug from the swollen matrix. PMID- 23732800 TI - Electrochemical detection of toxic ractopamine and salbutamol in pig meat and human urine samples by using poly taurine/zirconia nanoparticles modified electrodes. AB - Detection of ractopamine and salbutamol has been developed by employing the facile synthesis of poly taurine/zirconia nanoparticles (ZrO2) modified film glassy carbon electrode. The poly taurine/ZrO2 nanoparticles were directly utilized for the detection of ractopamine and salbutamol using linear sweep voltammetry (LSV). The modified electrode successfully shows the oxidation peak for ractopamine adsorption at 0.65V and salbutamol at 0.71V, which is purely based on the detection of adsorption signals of ractopamine and salbutamol, at the electrode surface. Furthermore, the electrochemical measurements and surface morphology were studied using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and scanning electron microscopy (SEM) analysis. The modified electrode successfully detects the oxidation signals of ractopamine in the linear range of 1-28MUM and salbutamol in the linear range of 5-220MUM in laboratory samples. The proposed film also successfully detects the ractopamine signal (1 26MUM) in pig meat samples and salbutamol signal (1-114MUM) in human urine samples. It also exhibits two well-separated anodic oxidation peaks for uric acid and salbutamol in salbutamol-spiked human urine samples. PMID- 23732801 TI - Electrophoretic interactions between nitrocellulose membranes and proteins: Biointerface analysis and protein adhesion properties. AB - Protein adsorption onto membrane surfaces is important in fields related to separation science and biomedical research. This study explored the molecular interactions between protein, bovine serum albumin (BSA), and nitrocellulose films (NC) using electrokinetic phenomena and the effects of these interactions on the streaming potential measurements for different membrane pore morphologies and pH conditions. The data were used to calculate the streaming ratios of membranes-to-proteins and to compare these values to the electrostatic or hydrophobic attachment of the protein molecules onto the NC membranes. The results showed that different pH and membrane pore morphologies contributes to different protein adsorption mechanisms. The protein adsorption was significantly reduced under conditions where the membrane and protein have like-charges due to electrostatic repulsion. At the isoelectric point (IEP) of the protein, the repulsion between the BSA and the NC membrane was at the lowest; thus, the BSA could be easily attached onto the membrane/solution interface. In this case, the protein was considered to be in a compact layer without intermolecular protein repulsions. PMID- 23732802 TI - Transdermal delivery of betahistine hydrochloride using microemulsions: physical characterization, biophysical assessment, confocal imaging and permeation studies. AB - Transdermal delivery of betahistine hydrochloride encapsulated in various ethyl oleate, Capryol 90((r)), Transcutol((r)) and water microemulsion formulations was studied. Two different kinds of phase diagrams were constructed for the investigated microemulsion system. Pseudoplastic flow that is preferable for skin delivery was recorded for the investigated microemulsions. A balanced and bicontinuous microemulsion formulation was suggested and showed the highest permeation flux (0.50+/-0.030mgcm(-2)h(-1)). The effect of the investigated microemulsions on the skin electrical resistance was used to explain the high permeation fluxes obtained. Confocal laser scanning microscopy was used to confirm the permeation enhancement and to reveal the penetration pathways. The results obtained suggest that the proposed microemulsion system highlighted in the current work can serve as a promising alternative delivery means for betahistine hydrochloride. PMID- 23732804 TI - Cibacron Blue F3GA modified disposable pencil graphite electrode for the investigation of affinity binding to bovine serum albumin. AB - In this work, Cibacron Blue F3GA (CB) modified pencil graphite electrodes (PGEs) were prepared and their affinities to bovine serum albumin were investigated. Preparation of the PGEs was performed using cyclic voltammetry (CV) and passive adsorption techniques. Improved electrochemical results were obtained with the PGEs prepared by CV technique compared to the PGEs prepared by passive adsorption technique. In order to obtain more sensitive results number of scans used in CV technique and the effect of concentration of CB were studied. Scanning electron microscopy (SEM), atomic force microscopy (AFM) and electrochemical impedance spectroscopy (EIS) were used for the characterization of modified electrodes. The modified PGEs were then used for the electrochemical monitoring of affinity interaction between CB and bovine serum albumin. The effect of BSA concentration and interfering species (tryptophan, glucose and immunoglobulin G) on the response of the electrode were examined. The aim of this study was to prepare an easy, fast, stable and cheap modified electrode for the investigation of the well known affinity of CB to serum albumin. The electrochemistry can provide alternative routes for dye-protein interaction instead of using classical time consuming methods. PMID- 23732803 TI - Gradients in surface nanotopography used to study platelet adhesion and activation. AB - Gradients in surface nanotopography were prepared by adsorbing gold nanoparticles on smooth gold substrates using diffusion technique. Following a sintering procedure the particle binding chemistry was removed, and integration of the particles into the underlying gold substrate was achieved, leaving a nanostructured surface with uniform surface chemistry. After pre-adsorption of human fibrinogen, the effect of surface nanotopography on platelets was studied. The use of a gradient in nanotopography allowed for platelet adhesion and activation to be studied as a function of nanoparticle coverage on one single substrate. A peak in platelet adhesion was found at 23% nanoparticle surface coverage. The highest number of activated platelets was found on the smooth control part of the surface, and did not coincide with the number of adhered platelets. Activation correlated inversely with particle coverage, hence the lowest fraction of activated platelets was found at high particle coverage. Hydrophobization of the gradient surface lowered the total number of adhering cells, but not the ratio of activated cells. Little or no effect was seen on gradients with 36nm particles, suggesting the existence of a lower limit for sensing of surface nano-roughness in platelets. These results demonstrate that parameters such as ratio between size and inter-particle distance can be more relevant for cell response than wettability on nanostructured surfaces. The minor effect of hydrophobicity, the generally reduced activation on nanostructured surfaces and the presence of a cut-off in activation of human platelets as a function of nanoparticle size could have implications for the design of future blood-contacting biomaterials. PMID- 23732805 TI - Inhibition of bacterial motility and spreading via release of cranberry derived materials from silicone substrates. AB - The motility of bacteria plays a key role in their colonization of surfaces during infection. Derivatives of cranberry fruit have been shown to interfere with bacterial motility. Herein, we report on the incorporation of cranberry derived materials (CDMs) into silicone substrates with the aim of impairing bacterial pathogen motility and spreading on the substrate surface. The release of CDMs from the silicone substrates when soaking in an aqueous medium was quantified for a period of 24h. Next, we showed that CDMs released from two silicone substrates remain bioactive as they downregulate the expression of the flagellin gene of two key uropathogens - Escherichia coli CFT073 and Proteus mirabilis HI4320. Furthermore, we demonstrate that CDM-modified silicone inhibits the swarming motility of P. mirabilis, an aggressive swarmer. The bioactive, CDM modified substrates can find broad applications in the medical device and food industries where the impairment of bacterial colonization of surfaces is of paramount importance. PMID- 23732806 TI - Novel gel-niosomes formulations as multicomponent systems for transdermal drug delivery. AB - The percutaneous permeation profiles of sulfadiazine sodium salt, propranolol hydrochloride and tyrosol from novel liquid crystal-niosomes formulations as multicomponent systems, were investigated. The new carriers were prepared from mixture of water/surfactant, AOT or Pluronic L64 as anionic and nonionic surfactants, respectively, in order to obtain lamellar LLC phases. The same surfactants were used to prepare also the vesicular systems (niosomes) that were added to the corresponding gel. The obtained multicomponent drug carrier was characterized by deuterium nuclear magnetic resonance spectroscopy, in order to understand if the introduction of the drug or drug-loaded niosomal suspension, as third component in the formulations, could influence the microstructure of the system and then the drug delivery across the skin. Simple AOT and L64-based niosomal formulations and LLCs phases were then prepared and used as control. Different drugs percutaneous availability was achieved, and the results revealed that the obtained gel-niosomes carriers were affected by the chemical structure of the drugs and by their affinity for the components. As a consequence these systems could be proposed as novel transdermal drug delivery systems, since they were found able to control the percutaneous permeation of small drugs across the skin. PMID- 23732807 TI - Adhesion of Escherichia coli to nano-Fe/Al oxides and its effect on the surface chemical properties of Fe/Al oxides. AB - We investigated the adhesion of Escherichia coli to alpha-Fe2O3 and gamma-Al2O3 and the effects of adhesion on the surface properties of the oxides in batch experiments, where we conducted potentiometric titration, zeta potential measurements, and FTIR spectroscopy. The adhesion isotherms fitted a Langmuir equation well. gamma-Al2O3 had a higher adhesion capacity than alpha-Fe2O3 because of the higher positive charge on gamma-Al2O3. The adhesion of E. coli to Fe/Al oxides decreased with increasing pH. Adhesion increased with increasing NaCl concentration, reaching its maximum at 0.05M for alpha-Fe2O3 and at 0.1M for gamma-Al2O3, after which it decreased with further increases in NaCl concentration. Therefore, the electrostatic force plays an important role in the adhesion of E. coli to Fe/Al oxides. The zeta potential-pH curves of the binary system fell between that for bacteria and those for Fe/Al oxides. Thus, overlapping of the diffuse layers of the electric double layers on the negatively charged E. coli and positively-charged Fe/Al oxides reduced the effective surface charge density of the minerals and bacteria. E. coli adhesion decreased the point of zero salt effect and the isoelectric point of the Fe/Al oxides. The FTIR spectra indicated that non-electrostatic force also contributed to the interaction between E. coli and Fe/Al oxides, in addition to the electrostatic force between them. PMID- 23732808 TI - Study on interaction of bile salts with curcumin and curcumin embedded in dipalmitoyl-sn-glycero-3-phosphocholine liposome. AB - Curcumin, often used as a food spice, is a natural polyphenol that has various medicinal benefits such as anti-cancer, anti-amyloid, anti-oxidant, and anti inflammatory properties, among others. The interaction between bile salts having physiological significance and curcumin suggests the aggregation of bile salts dramatically alters the absorption and fluorescence parameters of curcumin. The fluorescence emission maximum as well as the intensity can easily detect critical micellar concentration of sodium cholate and sodium deoxycholate respectively to be 16 and 6mM at room temperature. The mechanism of interaction of curcumin with bile salts has been presented at low, intermediate and high bile salt concentrations and depends on temperature. In the presence of bile salts the DPPH scavenging activity was preserved, though less than in the presence of curcumin alone. The effect of submicellar concentration, 5-50MUM, of bile salt with 1,2 dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes in solid gel and liquid crystalline phases has been investigated using curcumin as an embedded probe in the membrane. The curcumin based fluorescence probing method indicates even at very low concentration, ~5MUM, incorporation of monomeric bile salt molecules disorders the membrane properties. Expulsion of curcumin from the membrane in the presence of bile salt is ruled out, suggesting wetting of membrane. Alteration of membrane fluidity by bile salts is found to have an opposing effect in the liquid crystalline phase compared to in the solid gel phase, and is sensitive to the nature of bile salt. The permeability in the liquid crystalline phase decreases in the presence of bile salt. The phase transition temperature of the membrane is influenced by bile salt. PMID- 23732809 TI - Adsorption of Cu(II), Zn(II), Cd(II) and Pb(II) by dead Avena fatua biomass and the effect of these metals on their growth. AB - The biosorption of copper(II), zinc(II), cadmium(II) and lead(II) from aqueous solutions by dead Avena fatua biomass and the effect of these metals on the growth of this wild oat were investigated. Pseudo-first- and second-order and intra-particle diffusion models were applied to describe the kinetic data and to evaluate the rate constants. The adsorption kinetics of all the metals follows a pseudo-second-order model. The adsorption capacity was determined, and the Freundlich and Langmuir models were applied. The experimental data obtained for all the metals are best described by the Langmuir model. A. fatua was characterized using scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), and zeta potential. The results obtained evidence the presence of Zn(II), Cu(II), Cd(II) or Pb(II) on the surface of the weed. The growth of A. fatua was affected by the presence of all metals. The decrease in the growth rate with increasing metal concentration was more noticeable for zinc. PMID- 23732810 TI - Ellagic acid encapsulated chitosan nanoparticles for drug delivery system in human oral cancer cell line (KB). AB - Ellagic acid (EA), a naturally occurring polyphenolic compound is well documented for its anticancer property in numerous pre-clinical models. The properties like poor water solubility and limited oral bio-availability of ellagic acid has hampered its clinical applications. The present study, reports the preparation of ellagic acid encapsulated chitosan nanoparticles (EA@CS-NP) by ionic gelation method as an effective drug delivery for oral cancer treatment. The synthesized ellagic acid nanoparticle is spherical shaped with an average particle size of 176nm. The drug-encapsulation and loading-efficiency of the nanoparticles were 94+/-1.03% and 33+/-2.15% respectively. The in vitro drug release profile in the PBS medium shows sustained release of EA from EA@CS-NP. Further, this study evaluates the therapeutic efficacy of EA@CS-NP in human oral cancer cell line (KB) using MTT and DNA fragmentation analysis. EA@CS-NP exhibit significant cytotoxicity in KB cells in a dose-dependent manner with a very low IC50 value compared to the free EA. The results of the present study strengthen our hypothesis and hope that this novel formulation could possibly overcome the current limitations of ellagic acid and can open a new avenue for oral cancer therapy. PMID- 23732811 TI - Interaction between a cationic porphyrin and ctDNA investigated by SPR, CV and UV vis spectroscopy. AB - The interaction between ctDNA and a cationic porphyrin was studied in this work. The binding process was monitored by surface plasmon resonance (SPR) spectroscopy in detail. The association, dissociation rate constants and the binding constants calculated by global analysis were 2.4*10(2)+/-26.4M(-1)s(-1), 0.011+/ 0.0000056s(-1) and 2.18*10(4)M(-1), respectively. And the results were confirmed by cyclic voltammetry and UV-vis absorption spectroscopy. The binding constants obtained from cyclic voltammetry and UV-vis absorption spectroscopy were 8.28*10(4)M(-1) and 6.73*10(4)M(-1) at 298K, respectively. The covalent immobilization methodology of ctDNA onto gold surface modified with three different compounds was also investigated by SPR. These compounds all contain sulfydryl but with different terminated functional groups. The results indicated that the 11-MUA (HS(CH2)10COOH)-modified gold film is more suitable for studying the DNA-drug interaction. PMID- 23732812 TI - Metals in lip products: a cause for concern? PMID- 23732813 TI - Expression of CXCL1 in human endothelial cells induces angiogenesis through the CXCR2 receptor and the ERK1/2 and EGF pathways. AB - Endothelial cell growth and proliferation are critical for angiogenesis; thus, greater insight into the regulation of pathological angiogenesis is greatly needed. Previous studies have reported on chemokine (C-X-C motif) ligand 1 (CXCL1) expression in epithelial cells and that secretion of CXCL1 from these epithelial cells induces angiogenesis. However, limited reports have demonstrated CXCL1 expression in endothelial cells. In this report, we present data that expand on the role of CXCL1 in human endothelial cells inducing angiogenesis. Specifically, CXCL1 is expressed and secreted from human endothelial cells. Interference of CXCL1 function using neutralizing antibodies resulted in a reduction in endothelial cell migration and viability/proliferation, the latter associated with a decrease in levels of cyclin D and cdk4. In vitro studies revealed that CXCL1 influenced neoangiogenesis through the regulation of epidermal growth factor and ERK1/2. In a xenograft angiogenesis model, interference of CXCL1 function resulted in inhibition of angiogenesis. A better understanding of the role of CXCL1 in the interactions between the endothelial and epithelial components will provide insight into how human tissues use CXCL1 to survive and thrive in a hostile environment. PMID- 23732815 TI - MiR-203 regulates the proliferation, apoptosis and cell cycle progression of pancreatic cancer cells by targeting Survivin. AB - MicroRNAs have emerged as crucial regulators of tumorigenesis. However, the mechanism by which miR-203 is involved in the pathogenesis of pancreatic cancer (PC) remains elusive. In the present study, PC cell lines were used as an experimental model to investigate the expression and functional role of miR-203 in PC. miR-203 mimic virus, miRNA negative control virus and Survivin shRNA virus were transfected into the PC cell line, CFPAC-1. mRNA and protein levels of Survivin were detected using qPCR and western blot analysis. Proliferation, apoptosis and cell cycle profiles were detected by an MTT assay and flow cytometry. Female BALB/cA-nu nude mice were used to validate the role of miR-203 in vivo. The protein levels of Survivin were found to negatively correlate with miR-203 levels in four PC cell lines. A luciferase assay revealed that Survivin was a direct target of miR-203. Transfection with miR-203 mimic inhibited CFPAC-1 cell proliferation and induced apoptosis and G1 phase cell cycle arrest, similar to knockdown of Survivin. In the in vivo nude mouse model, the downregulation of Survivin by knockdown of Survivin or transfection with miR-203 mimic inhibited tumor growth. Results of the current study indicate that miR-203 regulates the proliferation, apoptosis and cell cycle progression of PC cells by targeting Survivin. PMID- 23732814 TI - Heme oxygenase-1 expression protects the heart from acute injury caused by inducible Cre recombinase. AB - The protective effect of heme oxygenase-1 (HO-1) expression in cardiovascular disease has been previously demonstrated using transgenic animal models in which HO-1 is constitutively overexpressed in the heart. However, the temporal requirements for protection by HO-1 induction relative to injury have not been investigated, but are essential to employ HO-1 as a therapeutic strategy in human cardiovascular disease states. Therefore, we generated mice with cardiac specific, tamoxifen (TAM)-inducible overexpression of a human HO-1 (hHO-1) transgene (myosin heavy chain (MHC)-HO-1 mice) by breeding mice with cardiac specific expression of a TAM-inducible Cre recombinase (MHC-Cre mice), with mice containing an hHO-1 transgene preceded by a floxed-stop signal. MHC-HO-1 mice overexpress HO-1 mRNA and the enzymatically active protein following TAM administration (40 mg/kg body weight on 2 consecutive days). In MHC-Cre controls, TAM administration leads to severe, acute cardiac toxicity, cardiomyocyte necrosis, and 80% mortality by day 3. This cardiac toxicity is accompanied by a significant increase in inflammatory cells in the heart that are predominantly neutrophils. In MHC-HO-1 mice, HO-1 overexpression ameliorates the depression of cardiac function and high mortality rate observed in MHC-Cre mice following TAM administration and attenuates cardiomyocyte necrosis and neutrophil infiltration. These results highlight that HO-1 induction is sufficient to prevent the depression of cardiac function observed in mice with TAM-inducible Cre recombinase expression by protecting the heart from necrosis and neutrophil infiltration. These findings are important because MHC-Cre mice are widely used in cardiovascular research despite the limitations imposed by Cre-induced cardiac toxicity, and also because inflammation is an important pathological component of many human cardiovascular diseases. PMID- 23732816 TI - The impact of ethnicity on glucose homeostasis after gestational diabetes mellitus. AB - The objective of this study was to examine measures of insulin resistance and beta cell function in relation to ethnicity and the development of diabetes after gestational diabetes mellitus (GDM). Glucose homeostasis was assessed during a 75 g oral glucose tolerance test 1-2 years after delivery in 456 women with previous GDM (362 European, 94 non-European; including 41 Arab and 43 Asian women) and 133 control women. Insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR). The insulinogenic index (I/G30) and the disposition index [(I/G30)/HOMA-IR] were used to quantify insulin secretion. Women developing diabetes after GDM were characterized by increased HOMA-IR [p = 0.010, adjusted for body mass index (BMI)], whereas the disposition index was decreased in all women with previous GDM irrespective of glucose tolerance, most pronounced in the presence of diabetes (BMI-adjusted p = 1 * 10(-5)). Non European origin was associated with increased HOMA-IR (p = 0.001 vs. European), strengthened by adjustment for BMI in Asian women (p = 0.046 vs. p = 0.016), but eradicated among Arab women (p = 0.004 vs. p = 0.65). Non-European women exhibited an increased frequency of diabetes after GDM (17 % vs. European 4 %, p = 2 * 10(-5)). In addition to BMI, non-European and Asian origin was associated with the development of diabetes after GDM in a multivariate logistic regression analysis, whereas Arab origin was not. Our results highlight the importance of preventive measures to ensure a healthy lifestyle in women with GDM, particularly in high-risk ethnic groups. PMID- 23732817 TI - Altered insula response to sweet taste processing after recovery from anorexia and bulimia nervosa. AB - OBJECTIVE: Recent studies suggest that altered function of higher-order appetitive neural circuitry may contribute to restricted eating in anorexia nervosa and overeating in bulimia nervosa. This study used sweet tastes to interrogate gustatory neurocircuitry involving the anterior insula and related regions that modulate sensory-interoceptive-reward signals in response to palatable foods. METHOD: Participants who had recovered from anorexia nervosa and bulimia nervosa were studied to avoid confounding effects of altered nutritional state. Functional MRI measured brain response to repeated tastes of sucrose and sucralose to disentangle neural processing of caloric and noncaloric sweet tastes. Whole-brain functional analysis was constrained to anatomical regions of interest. RESULTS: Relative to matched comparison women (N=14), women recovered from anorexia nervosa (N=14) had significantly diminished and women recovered from bulimia nervosa (N=14) had significantly elevated hemodynamic response to tastes of sucrose in the right anterior insula. Anterior insula response to sucrose compared with sucralose was exaggerated in the recovered group (lower in women recovered from anorexia nervosa and higher in women recovered from bulimia nervosa). CONCLUSIONS: The anterior insula integrates sensory reward aspects of taste in the service of nutritional homeostasis. One possibility is that restricted eating and weight loss occur in anorexia nervosa because of a failure to accurately recognize hunger signals, whereas overeating in bulimia nervosa could represent an exaggerated perception of hunger signals. This response may reflect the altered calibration of signals related to sweet taste and the caloric content of food and may offer a pathway to novel and more effective treatments. PMID- 23732818 TI - Intrapsychic and interpersonal guilt: a critical review of the recent literature. AB - Various authors hold that some emotions (i.e., moral emotions) have the function of orienting people toward ethical actions. In addition to embarrassment, shame and pride, the moral emotion of guilt is believed to affect humans' behavior when they carry out transgressions that violate social and cultural standards. Over the past century, many studies (including controversial ones) have been conducted on guilt. In this study, we analyzed and summarized mainly the most recent literature on this emotion. On one side, the destructiveness of guilt is emphasized. It inflicts punishment and pain on individuals for their errors and can lead to psychopathology (e.g., depression). On the other side, it is described as a "friendly" emotion that motivates behavior adapted to social and cultural rules. How can this asymmetry be explained? Different existing views on guilt are presented and discussed, together with recent proposals, supported by research data. Finally, we discussed some systematic models that try to incorporate these different views in a single framework that could facilitate future researches. PMID- 23732819 TI - Hybrid electron microscopy-FRET imaging localizes the dynamical C-terminus of Tfg2 in RNA polymerase II-TFIIF with nanometer precision. AB - TFIIF-a general transcription factor comprising two conserved subunits can associate with RNA polymerase II (RNAPII) tightly to regulate the synthesis of messenger RNA in eukaryotes. Herein, a hybrid method that combines electron microscopy (EM) and Forster resonance energy transfer (FRET) is described and used to localize the C-terminus of the second TFIIF subunit (Tfg2) in the architecture of RNAPII-TFIIF. In the first stage, a poly-histidine tag appended to the Tfg2 C-terminus was labeled with nickel-NTA nanogold and a seven-step single particle EM protocol was devised to obtain the region accessible by the nanogold in 3D, suggesting the Tfg2 C-terminus is proximal to the clamp of RNAPII. Next, the C-termini of the Rpb2 and the Rpb4 subunits of RNAPII, adjacent to the clamp, were selected for placing FRET satellites to enable the nano positioning (NP) analysis, by which the localization precision was improved such that the Tfg2 C-terminus was found to dwell on the clamp ridge but could move to the clamp top during transcription. Because the tag receptive to the EM or FRET probes can be readily introduced to any protein subunit, this hybrid approach is generally applicable to complement cryo-EM study of many protein complexes to nanometer precision. PMID- 23732820 TI - Epigenetic regulation of transcription by RNA polymerase III. AB - Chromatin participates actively in all DNA transactions and all phenomena directly under the influence of chromatin are explained by epigenetic mechanisms. The genes transcribed by RNA polymerase (pol) III are generally found in regions free of nucleosomes, the structural units of chromatin. Yet, histone modifications and positions of nucleosomes in the gene flanking regions have been reported to show direct correlation with activity status of these genes. Gene specific as well as genome-wide studies have also revealed association of several epigenetic components with pol III-transcribed genes. This review presents a summary of the research in past many years, which have gathered enough evidence to conclude that pol III-transcribed genes are important components of an epigenome. PMID- 23732821 TI - Do hormonal changes that appear at the onset of puberty determine the strategies used by female rats when solving a navigation task? AB - The present set of experiments evaluated the possibility that the hormonal changes that appear at the onset of puberty might influence the strategies used by female rats to solve a spatial navigation task. In each experiment, rats were trained in a triangular shaped pool to find a hidden platform which maintained a constant relationship with two sources of information, one individual landmark and one corner of the pool with a distinctive geometry. Then, three test trials were conducted without the platform in counterbalanced order. In one, both the geometry and the landmark were simultaneously presented, although in different spatial positions, in order to measure the rats' preferences. In the remaining test trials what the rats had learned about the two sources of information was measured by presenting them individually. Experiment 1, with 60-day old rats, revealed a clear sex difference, thus replicating a previous finding (Rodriguez et al., 2010): females spent more time in an area of the pool that corresponded to the landmark, whereas males spent more time in the distinctive corner of the pool even though the remaining tests revealed that both sexes had learned about the two sources of information. In Experiment 2, 30-day old female rats, unlike adults, preferred to solve the task using the geometry information rather than the landmark (although juvenile males behaved in exactly the same way as adults). Experiment 3 directly compared the performance of 90- and 30-day old females and found that while the adult females preferred to solve the task using the landmark, the reverse was true in juvenile females. Experiment 4 compared ovariectomized and sham operated females and found that while sham operated females preferred to solve the task using the landmark, the reverse was true in ovariectomized females. Finally, Experiment 5 directly compared adult males and females, juvenile males and females, and ovariectomized females and found that adult males, juvenile males and females, and ovariectomized females did not differ among them in their preferred cue, but they all differed from adult females. PMID- 23732822 TI - Inflammation and microbial translocation in treatment-controlled HIV patients. PMID- 23732823 TI - Heparin-induced thrombocytopenia: general considerations. PMID- 23732824 TI - Caries prevalence and determinants among 12-year-olds in North-West Russia and Northern Norway. AB - OBJECTIVES: To assess oral health and oral health associated factors in 12-year olds and to establish determinants explaining variation in oral health among children representing two areas in the Barents region - Arkhangelsk in North-West Russia and Tromso in Northern Norway. METHODS: The samples consisted of Russian (N=590) and Norwegian (N=264) 12-year-olds and their parents selected according to stratified one-stage cluster design. The study included clinical examination (children) and self-reports (children and parents). The child's oral health was recorded under field conditions. Statistical analyses were conducted on pooled samples of subjects. RESULTS: The mean DMFT/S-scores were 3.0/4.4 for the Russian and 1.2/1.5 for the Norwegian children (p<0.001). In multiple logistic regressions, country of origin (OR=3.8) and filling obtained during last dental visit (OR=5.0) were showing the strongest association with child's dental caries (chi(2)=87; p<0.001). Among parent's variables showing the strongest association with child's dental caries were country of origin (OR=2.4) and oral health problems during the past two years (OR=1.8) (chi(2)=60; p<0.001). CONCLUSIONS: Dental caries prevalence was higher among the Russian than the Norwegian children. The overall regression models were significant for both the child and parental variables. The results indicate different impact on child's oral health from children and parental determinants. PMID- 23732825 TI - Dynamical changes of occlusion and articulation during treatment of mandibular angle fractures. AB - Outcomes of mandibular fractures were stated as frequent reason of temporomandibular joint dysfunctions. The objective of this study was to evaluate dynamical changes of occlusion and articulation during treatment of mandibular angle fractures. 12 subjects with mandibular angle fractures underwent analysis of occlusion and articulation in all stages of healing. Findings of investigations were presented in Posselt's and intercondylar axis diagrams, occlusiograms and relative force vs. time graphs. Comparison of results in first day, 1, 3 and 6 months after trauma showed that despite typical process of fragments healing and good fixation but with insufficiently balanced occlusion and posttraumatic discoordination of muscle activity first signs of TMJ articular discs dysfunction were found. Our results confirm the concept that early rehabilitation of mandibular function and occlusion are essential to prevent developing functional disorders of TMJ. PMID- 23732826 TI - The influence of the design of removable dentures on patient's voice quality. AB - The main condition for speech intelligibility is the specific anatomical characteristics of the human speech apparatus and harmonious work of all organs in the human vocal apparatus. The voice quality is characterized by speech intelligibility (relationship between the voice pitch, volume, timbre and speech speed). Improper functional quality (related to retention,support, stability), inappropriate design of the prosthetic base and disposition of artificial teeth are the basic reasons for dyslalia - impairment of utterance with abnormality of external speech organs. In the case of dyslalia a patient may suffer from a defective utterance of separate phonemes. When designing removable dental prostheses, it is important to evaluate the disposition of the artifical teeth (taking into account phonetic pronunciation), make a phonetically beneficial construction of the base of the dentures and restore the lost alveolar bone with the basis of removable prostheses. The aim of this study was to review literature on voice quality and the way it can be affected after the insertion of removable dental prostheses and to research the literature describing the ways how voice quality can be improved. The literature reviewed in the paper was retrieved from Science Direct, PubMed, MD Consult, Cochrane Libary databases and dates back to the period from 1990 to 2012. PMID- 23732827 TI - Children's dental fear in relation to dental health and parental dental fear. AB - OBJECTIVE: The aim was to (1) assess the proportion of children with dental fear, to (2) compare results obtained by a single fear question to those obtained by using a set of 11 fear questions, to (3) study associations between children's dental fear and their dental health, and to (4) compare children's dental fears to those of their parents. MATERIALS AND METHODS: A cross-sectional sample of 344 8-10-year-old schoolchildren from South Estonian primary schools participated. Children's fears were measured with the modified Dental Subscale of the Children's Fear Survey Schedule (CFSS-DS). The scale includes 11 fear items amongst which five represent less invasive (noninvasive items), another five invasive aspects of dental treatment (invasive items), and one question represents general dental fear of the child. In addition, two questions were included to assess parental dental fear. The dental health of children was examined using the International Caries Detection and Assessment System (ICDAS) criteria. RESULTS: The proportion of children with general dental fear was 6.1%. The mean score of noninvasive fears was higher among the youngest than among the oldest age group (p<0.02). Children whose dmft/DMFT-scores were >0 had higher fear scores than those whose dmft/DMFT-scores were =0 (p<0.01). A total of 16.8% and 15.7% of mothers and fathers afraid of dentistry in general. There were strong correlations between children's dental fears and maternal (p<0.01), and paternal (p<0.01) dental fear. CONCLUSIONS: Children's fears were strongly associated with untreated caries and experience of dental treatment, and with parental fears. PMID- 23732828 TI - 5-aminolevulinic acid based photodynamic therapy for basal cell carcinoma: a 10 years follow-up study. AB - OBJECTIVE: This article presents long-term follow-up after use of topical photodynamic therapy (PDT) for basal cell carcinoma. PDT is treatment option for different tumors, involving use of specific agent which is activated by visible light and results in tissue destruction. MATERIALS AND METHODS: Overall 20 patients with 29 tumors were treated at the Latvian Oncology Center. Two illumination techniques were used: superficial for smaller lesions and multifiber contact for nodular tumors. Clinical outcome was evaluated at 1, 7, 44 months and 10 years after procedure. RESULTS: By 10 year follow up, there were 2 tumor recurrences and in one case there was tumor residual tissue after first PDT treatment. Overall after ten years follow-up complete response was 80% of cases. CONCLUSION: Data in this study supports hypothesis that PDT could be used for the treatment of non-invasive (superficial and nodular) basal cell carcinoma. Results in this study correspond with similar long-term follow-up studies. PMID- 23732829 TI - Air enema reduction of intussusception: a registrar-led, protocol-driven service is safe and effective. AB - PURPOSE: In the UK, air enema reduction of intussusception is predominantly performed by consultant radiologists. At our institution, it is usually performed by a team involving radiology and surgical registrars. The purpose of this study was to assess who performs air enemas in the UK and the efficacy and safety of our registrar-led service. METHODS: A telephone survey of paediatric surgical centres in the UK was performed asking who performs air enema in these institutions. Following this, a retrospective review of all air enemas at our institution between January 2005 and 2011 was performed. Cases were identified from radiology databases and reviewed for grade of radiologist, perforation and outcome. RESULTS: At all 25 centres, consultant radiologists performed air enemas. At our institution 145 enemas were performed in 6 years. 141 were analysed (54 girls, 87 boys). Median age was 9 months (range 3-107 months). 82 % were performed by the registrar-only team. Over 6 years the registrar-led reduction rate was 77.5 % and in the last 3 years 84 %. The perforation rate was 0.9 %. CONCLUSION: A paediatric surgical registrar-led service for air enema reduction can be safe and effective ensuring a team approach is adopted, equipment is efficient and a strict protocol is applied. PMID- 23732830 TI - Development of blood-yolk-polymyxin B-trimethoprim agar for the enumeration of Bacillus cereus in various foods. AB - Blood-yolk-polymyxin B-trimethoprim agar (BYPTA) was developed by the addition of egg yolk, laked horse blood, sodium pyruvate, polymyxin B, and trimethoprim, and compared with mannitol-yolk-polymyxin B agar (MYPA) for the isolation and enumeration of Bacillus cereus (B. cereus) in pure culture and various food samples. In pure culture, there was no statistical difference (p>0.05) between the recoverability and sensitivity of MYPA and BYPTA, whereas BYPTA exhibited higher specificity (p<0.05). To evaluate BYPTA agar with food samples, B. cereus was experimentally spiked into six types of foods, triangle kimbab, sandwich, misugaru, Saengsik, red pepper powder, and soybean paste. No statistical difference was observed in recoverability (p>0.05) between MYPA and BYPTA in all tested foods, whereas BYPTA exhibited higher selectivity than MYPA, especially in foods with high background microflora, such as Saengsik, red pepper powder, and soybean paste. The newly developed selective medium BYPTA could be a useful enumeration tool to assess the level of B. cereus in foods, particularly with high background microflora. PMID- 23732831 TI - Multilocus sequence analysis of Aspergillus Sect. Nigri in dried vine fruits of worldwide origin. AB - Dried vine fruits may be heavily colonized by Aspergillus species. The molecular biodiversity of an Aspergillus population (234 strains) isolated from dried vine fruit samples of worldwide origin were analyzed by investigating four housekeeping gene loci (calmodulin, beta-tubulin, elongation factor 1-alpha, RPB2). Aspergillus Sect. Nigri was dominant and the strains were identified as A. tubingensis (138), A. awamori (38), A. carbonarius (27), A. uvarum (16) and A. niger (11). Four Aspergillus flavus strains were also identified from Chilean raisins. Two clusters closely related to the A. tubingensis species with a significant bootstrap (60% and 99%) were identified as distinct populations. Among the four loci, RPB2 showed the highest genetic variability. This is the first complete study on the worldwide distribution of black Aspergilli occurring on dried vine fruits identified by a molecular approach. PMID- 23732832 TI - Optimization of photobioreactor growth conditions for a cyanobacterium expressing mosquitocidal Bacillus thuringiensis Cry proteins. AB - An Anabaena strain (PCC 7120#11) that was genetically engineered to express Bacillus thuringiensis subsp. israelensis cry genes has shown good larvicidal activity against Anopheles arabiensis, a major vector of malaria in Africa. Response surface methodology was used to evaluate the relationship between key growth factors and the volumetric productivity of PCC 7120#11 in an indoor, flat plate photobioreactor. The interaction of input CO2 concentration and airflow rate had a statistically significant effect on the volumetric productivity of PCC 7120#11, as did the interaction of airflow rate and photosynthetic photon flux density. Model-based numerical optimization indicated that the optimal factor level combination for maximizing PCC 7120#11 volumetric productivity was a photosynthetic photon flux density of 154 MUmol m-2 s-1 and air enriched with 3.18% (v/v) CO2 supplied at a flow rate of 1.02 vessel volumes per minute. At the levels evaluated in the study, none of the growth factors had a significant effect on the median lethal concentration of PCC 7120#11 against An. arabiensis larvae. This finding is important because loss of mosquitocidal activity under growth conditions that maximize volumetric productivity would impact on the feasibility of using PCC 7120#11 in malaria vector control programs. The study showed the usefulness of response surface methodology for determination of the optimal growth conditions for a cyanobacterium that is genetically engineered to have larvicidal activity against malaria vectors. PMID- 23732833 TI - Stirred batch crystallization of a therapeutic antibody fragment. AB - Technical-scale crystallization of therapeutic proteins may not only allow for a significant cost-reduction in downstream processing, but also enable new applications, e.g., the use of crystal suspensions for subcutaneous drug delivery. In this work, the crystallization of the antigen-binding fragment FabC225 was studied. First, vapor diffusion crystallization conditions from the literature were transferred to 10MUL-scale microbatch experiments. A phase diagram was developed in order to identify the crystallization window. The conditions obtained from the microbatch experiments were subsequently transferred to parallelized 5mL-scale stirred-tank crystallizers. This scalable and reproducible agitated crystallization system allowed for an optimization of the crystallization process based on quantitative measurements. The optimized crystallization process resulted in an excellent yield of 99% in less than 2h by increasing the concentration of the crystallization agent ammonium sulfate during the process. The successful scalability of the Fab fragment crystallization process to 100mL-scale crystallizers based on geometric similarity was demonstrated. A favorable crystal size distribution was obtained. Furthermore, a wash step was introduced in order to remove unfavorable low-molecular substances from the crystals. PMID- 23732834 TI - Evaluation of cre recombinase delivery in mammalian cells using baculovirus infection. AB - In vivo conditional knock-out of a protein is a method of choice to decipher its biological function. It can be achieved by encoding the cre-recombinase on a recombinant virus to exert spatio-temporal control of its expression and enzymatic activity and, subsequently, of the target gene deletion. Recombinant baculoviruses have been successfully used to express a wide range of proteins in insect cells. More recently, their potential to infect mammalian cells has been addressed but, so far, their ability to yield a conditional knock-out as a result of efficient in vivo cre-recombinase gene delivery has not been examined. Cre recombinase fused to the green fluorescent protein was cloned under the control of the CAG promoter in a recombinant Autographa californica baculovirus expressing the vesicular stomatitis virus envelope G protein for increased mammalian cell infection. Gene delivery was evaluated in vitro in mammalian cells, neuroblastoma and mouse primary neuronal cultures as well as in vivo in the mouse brain. Infection with adeno-associated viruses encoding the cre recombinase fused to the green fluorescent protein was performed as a positive control. Our results indicate that baculovirus infection leads to functional cre recombinase expression in non-neuronal and neuroblastoma cell lines but not in mouse primary neuronal cultures or brain. PMID- 23732835 TI - One-pot synthesis of sterically congested large aromatic hydrocarbons via 1,4 diphenyl-2,3-triphenylyne. AB - Large polyarenes with unusually complex structures can be obtained in a straightforward manner from commercially available starting materials, by means of aryne chemistry. This approach involves a sequence of tandem reactions that can be performed in one pot to give sterically congested chiral aromatic hydrocarbons that adopt highly twisted conformations. PMID- 23732836 TI - TOFA suppresses ovarian cancer cell growth in vitro and in vivo. AB - A characteristic feature of cancer cells is the activation of de novo fatty acid synthesis. Acetyl-CoA carboxylase (ACC) is a key enzyme in fatty acid synthesis, accelerating the reaction that carboxylates cytosolic acetyl-CoA to form malonyl CoA. ACC is highly expressed in several types of human cancer and is important in breast and prostate cancer cell growth. The aim of the present study was to investigate the effects of 5-tetradecyloxy-2-furoic acid (TOFA), an allosteric inhibitor of ACC, on the proliferation and cell cycle progression of the ovarian cancer cell lines COC1 and COC1/DDP. TOFA was found to be cytotoxic to COC1 and COC1/DDP cells with a 50% inhibitory concentration (IC50) of ~26.1 and 11.6 ug/ml, respectively. TOFA inhibited the proliferation of the cancer cells examined in a time- and dose-dependent manner, arrested the cells in the G0/G1 cell cycle phase and induced apoptosis. The expression of the cell cycle regulating proteins cyclin D1 and cyclin-dependent kinase (CDK) 4, as well as the expression of the apoptosis-related proteins caspase-3 and Bcl-2, were detected by western blot analysis. Cyclin D1, CDK4 and Bcl-2 protein expression was inhibited by TOFA, while caspase-3 was cleaved and activated. To the best of our knowledge, the present study demonstrated for the first time that TOFA inhibits COC1/DDP cell growth in ovarian tumor mouse xenografts. By inhibiting ACC, TOFA may be a promising small molecule agent for ovarian cancer therapy. PMID- 23732837 TI - Methamphetamine and core temperature in the rat: ambient temperature, dose, and the effect of a D2 receptor blocker. AB - RATIONALE: Methamphetamine (METH) induces hyperthermia in warm and hypothermia in cool environments. Our first goal was to further study the role of ambient temperature in METH's effect on core temperature in rats. Previously, these effects were primarily demonstrated in high doses; we extended this investigation to the low-dose range (1 mg/kg METH). Our second goal was to identify the role of the D2 receptor in METH's effects in cool ambient temperatures. METHOD: Rats received METH (saline, 1, 5, and 10 mg/kg), raclopride (saline, 0.3, 0.6, and 1.2 mg/kg), or a combination (all doses of raclopride combined with 10 mg/kg METH). Treatments occurred in ambient temperatures of 18, 24, or 30 degrees C. RESULTS AND CONCLUSIONS: Consistent with prior research, 5 and 10 mg/kg METH caused hyperthermia or hypothermia in a dose- and ambient temperature-dependent manner (60 min after METH). In contrast, 1 mg/kg produced similar levels of hyperthermia at all ambient temperatures. These findings suggest that a threshold METH dose exists; below this dose, METH still changes core temperature, but CNS control over temperature regulation is left intact. In our experiments regarding D2 blockade, raclopride decreased METH-induced core temperature at 30 and 24 degrees C (60 min after METH), consistent with previous findings. We extended these findings by demonstrating that in a cool ambient temperature (18 degrees C), raclopride pretreatment also lowered the core temperature response to METH. Although the D2 receptor is known to mediate hypothermia, the combination of METH and D2 blockade suggests a complex mediation of the core temperature response, perhaps involving neurotransmitter interactions. PMID- 23732838 TI - Determining the heritability of ethanol-induced locomotor sensitization in mice using short-term behavioral selection. AB - RATIONALE: Sensitization to the locomotor stimulant effects of alcohol (ethanol) is thought to be a heritable risk factor for the development of alcoholism that reflects progressive increases in the positive motivational effects of this substance. However, very little is known about the degree to which genes influence this complex behavioral phenomenon. OBJECTIVES: The primary goal of this work was to determine the heritability of ethanol-induced locomotor sensitization in mice using short-term behavioral selection. METHODS: Genetically heterogeneous C57BL/6J (B6) * DBA/2J (D2) F2 mice were generated from B6D2F1 progenitors, phenotyped for the expression of locomotor sensitization, and bred for high (HLS) and low (LLS) expression of this behavior. Selective breeding was conducted in two independently generated replicate sets to increase the confidence of our heritability estimates and for future correlated trait analyses. RESULTS: Large and significant differences in locomotor sensitization between HLS and LLS lines were evident by the fourth generation. Twenty-two percent of the observed line difference(s) were attributable to genes (h2 = .22). Interestingly, locomotor activity in the absence of ethanol was genetically correlated with ethanol sensitization; high activity was associated with high sensitization. CONCLUSIONS: That changes in ethanol sensitivity following repeated exposures are genetically regulated highlights the relevance of studies aimed at determining how genes regulate susceptibility to ethanol-induced behavioral and neural adaptations. As alcohol use and abuse disorders develop following many repeated alcohol exposures, these data emphasize the need for future studies determining the genetic basis by which changes in response to alcohol occur. PMID- 23732840 TI - Volcanic ash and the respiratory immune system: possible mechanisms behind reported infections. PMID- 23732839 TI - Antidepressant effects of AMPA and ketamine combination: role of hippocampal BDNF, synapsin, and mTOR. AB - RATIONALE: A number of preclinical and clinical studies suggest that ketamine, a glutamate N-methyl-D-aspartate receptor antagonist, has a rapid and lasting antidepressant effect when administered either acutely or chronically. It has been postulated that this effect is due to stimulation of alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid (AMPA) receptors. OBJECTIVE: In this study, we tested whether AMPA alone has an antidepressant effect and if the combination of AMPA and ketamine provides added benefit in Wistar-Kyoto rats, a putative animal model of depression. RESULTS: Chronic AMPA treatment resulted in a dose-dependent antidepressant effect in both the forced swim test and sucrose preference test. Moreover, chronic administration (10-11 days) of combinations of AMPA and ketamine, at doses that were ineffective on their own, resulted in a significant antidepressant effect. The behavioral effects were associated with increases in hippocampal brain-derived neurotrophic factor, synapsin, and mammalian target of rapamycin. CONCLUSION: These findings are the first to provide evidence for an antidepressant effect of AMPA and suggest the usefulness of AMPA-ketamine combination in treatment of depression. Furthermore, these effects appear to be associated with increases in markers of hippocampal neurogenesis and synaptogenesis, suggesting a mechanism of their action. PMID- 23732841 TI - Neural mechanisms of frustration in chronically irritable children. AB - OBJECTIVE: Irritability is common in children and adolescents and is the cardinal symptom of disruptive mood dysregulation disorder, a new DSM-5 disorder, yet its neural correlates remain largely unexplored. The authors conducted a functional MRI study to examine neural responses to frustration in children with severe mood dysregulation. METHOD: The authors compared emotional responses, behavior, and neural activity between 19 severely irritable children (operationalized using criteria for severe mood dysregulation) and 23 healthy comparison children during a cued-attention task completed under nonfrustrating and frustrating conditions. RESULTS: Children in both the severe mood dysregulation and the healthy comparison groups reported increased frustration and exhibited decreased ability to shift spatial attention during the frustration condition relative to the nonfrustration condition. However, these effects of frustration were more marked in the severe mood dysregulation group than in the comparison group. During the frustration condition, participants in the severe mood dysregulation group exhibited deactivation of the left amygdala, the left and right striatum, the parietal cortex, and the posterior cingulate on negative feedback trials, relative to the comparison group (i.e., between-group effect) and to the severe mood dysregulation group's responses on positive feedback trials (i.e., within group effect). In contrast, neural response to positive feedback during the frustration condition did not differ between groups. CONCLUSIONS: In response to negative feedback received in the context of frustration, children with severe, chronic irritability showed abnormally reduced activation in regions implicated in emotion, attention, and reward processing. Frustration appears to reduce attention flexibility, particularly in severely irritable children, which may contribute to emotion regulation deficits in this population. Further research is needed to relate these findings to irritability specifically, rather than to other clinical features of severe mood dysregulation. PMID- 23732842 TI - Is catheter rupture rare after totally implantable access port implantation via the right internal jugular vein? Report of a case. AB - Catheter rupture after totally implantable access port (TIAP) implantation via the right internal jugular vein is thought to be very rare. We report a case of catheter rupture found 682 days after TIAP surgery in a 52-year-old woman with recurrent right breast cancer. It is possible that chronic stress at the flexure of the catheter induced by neck movements caused the catheter to rupture. Therefore, when inserting a TIAP via the right internal jugular vein, the site of venous puncture should be decided on carefully. Although a fracture of this type is rarely reported in the literature, the incidence of catheter injury of a TIAP inserted via the internal jugular vein at our institute is 1.8 %. This highlights the need to educate and caution medical staff and patients about preventing catheter fracture being caused by external factors. PMID- 23732843 TI - Development and validation of highly selective and robust method for simultaneous estimation of pioglitazone, hydroxypioglitazone and metformin in human plasma by LC-MS/MS: application to a pharmacokinetic study. AB - A simple, selective and robust reverse phase high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (ESI-MS/MS) method for simultaneous quantitation of pioglitazone (PIO), pioglitazone metabolite M-IV - hydroxypioglitazone (OH-PIO) and metformin (MET) in human plasma using deuterated internal standards (IS) is developed and fully validated as per industrial practices. After acetonitrile-induced protein precipitation of the plasma samples; PIO, OH-PIO, MET and IS were chromatographed on reverse phase column and analyzed in the multiple reaction monitoring in positive ion mode. The ion transitions were monitored at m/z 357.2->134.2 for PIO, 373.0->150.1 for OH PIO, 130.2->71.0 for MET, 361.1->134.2 for PIO-IS and 136.1->77.1 for MET-IS. The total chromatographic run time was 4.0min. A linear response function (r>0.998) was established for the range of concentrations 15-2500ng/mL, 10-1500ng/mL and 25 3000ng/mL for PIO, OH-PIO and MET respectively in human plasma. The intra and inter-day precision and accuracy values have met the set acceptance criteria. The method is simple, selective, robust economic and has been applied successfully to more than 2000 plasma samples as part of pharmacokinetic study in humans. PMID- 23732844 TI - Long-term outcomes after nonlesional extratemporal lobe epilepsy surgery. AB - IMPORTANCE: A focal lesion detected by use of magnetic resonance imaging (MRI) is a favorable prognostic finding for epilepsy surgery. Patients with normal MRI findings and extratemporal lobe epilepsy have less favorable outcomes. Most studies investigating the outcomes of patients with normal MRI findings who underwent (nonlesional) extratemporal epilepsy surgery are confined to a highly select group of patients with limited follow-up. OBJECTIVE: To evaluate noninvasive diagnostic test results and their association with excellent surgical outcomes (defined using Engel classes I-IIA of surgical outcomes) in a group of patients with medically resistant nonlesional extratemporal epilepsy. DESIGN: A retrospective study. SETTING: Mayo Clinic, Rochester, Minnesota. PARTICIPANTS: From 1997 through 2002, we identified 85 patients with medically resistant extratemporal lobe epilepsy who had normal MRI findings. Based on a standardized presurgical evaluation and review at a multidisciplinary epilepsy surgery conference, some of these patients were selected for intracranial electroencephalographic (EEG) monitoring and epilepsy surgery. EXPOSURE: Nonlesional extratemporal lobe epilepsy surgery. MAIN OUTCOMES AND MEASURES: The results of noninvasive diagnostic tests and the clinical variables potentially associated with excellent surgical outcome were examined in patients with a minimum follow-up of 1 year (mean follow-up, 9 years). RESULTS: Based on the noninvasive diagnostic test results, a clear hypothesis for seizure origin was possible for 47 of the 85 patients (55%), and 31 of these 47 patients (66%) proceeded to intracranial EEG monitoring. For 24 of these 31 patients undergoing long-term intracranial EEG (77%), a seizure focus was identified and surgically resected. Of these 24 patients, 9 (38%) had an excellent outcome after resective epilepsy surgery. All patients with an excellent surgical outcome had at least 10 years of follow-up. Univariate analysis showed that localized interictal epileptiform discharges on scalp EEGs were associated with an excellent surgical outcome. CONCLUSIONS AND RELEVANCE: Scalp EEG was the most useful test for identifying patients with normal MRI findings and extratemporal lobe epilepsy who were likely to have excellent outcomes after epilepsy surgery. Extending outcome analysis beyond the resective surgery group to the entire group of patients who were evaluated further highlights the challenge that these patients pose. Although 9 of 24 patients undergoing resective surgery (38%) had excellent outcomes, only 9 of 31 patients undergoing intracranial EEG (29%) and only 9 of 85 patient with nonlesional extratemporal lobe epilepsy (11%) had long-term excellent outcomes. PMID- 23732845 TI - Identification and primary immune characteristics of an amphioxus akirin homolog. AB - Akirin is a recently described nuclear protein that is thought to be required for the NF-kappaB signaling pathway in insects and vertebrates. Here, functional investigations of akirin are described in the basal chordate amphioxus Branchiostoma belcheri tsingtauense in an attempt to link this gene between insect and vertebrate lineages. Phylogenetic analysis indicated that amphioxus akirin represented a true ortholog of the two characterized vertebrate akirin paralogs. Amphioxus akirin, coding 219 amino acids with two nuclear localization signal (NLS) sequences and one 14-3-3 binding motif, was widely expressed in various tissues and up-regulated in response to Escherichia coli (Gram-negative bacterium) and Staphylococcus aureus (Gram-positive bacterium) challenges. Furthermore, amphioxus akirin was strictly localized to the nucleus of HEK293T cells in a confocal analysis. Our work identified and characterized for the first time an amphioxus akirin homolog and will promote a better understanding of the evolution and transcriptional network of the akirin gene family. PMID- 23732846 TI - Molecular cloning and expression analysis of polymeric immunoglobulin receptor in flounder (Paralichthys olivaceus). AB - The polymeric immunoglobulin receptor (pIgR) is one of the most important mucosal effectors mediating the transcytosis of polymeric immunoglobulins (pIgs) to protect the organisms. In this paper, a full-length cDNA of pIgR was firstly cloned from flounder (Paralichthys olivaceus) using rapid amplification of cDNA ends approaches, and it was of 1384 bp, containing an open reading frame (ORF) of 1005 bp encoding a polypeptide of 335 amino acids with the predicted molecular mass of 37.6 kDa. The flounder pIgR exhibited a unique structure containing only two immunoglobulin-like domains (ILD) corresponding to mammalian pIgR ILD1 and ILD5. The mRNA transcripts of pIgR were detected in all the tested tissues of flounder by semi-quantitative RT-PCR, and the pIgR was expressed at the highest level in liver and higher levels in intestine, gill, skin, spleen and head kidney than in stomach and muscle. The ORF was successfully expressed in Escherichia coli BL21 (DE3) and the recombinant protein displayed binding capability to the purified mucus IgM and serum IgM of flounder by ELISA. The polyclonal antibody against flounder recombinant pIgR was developed by immunization of Balb/C mice, which specifically reacted to the recombinant pIgR in Western blot. Moreover, a secretory component-like molecule was detected in the skin mucus but not in the serum of flounder, which molecular mass (about 37 kDa) was near the theoretical mass obtained from the sequence of flounder pIgR. All these results indicated that flounder pIgR probably involved in the pIgs transport and provided insights into the roles of fish pIgR in the mucosal immunity. PMID- 23732847 TI - Chicken-type lysozyme in channel catfish: expression analysis, lysozyme activity, and efficacy as immunostimulant against Aeromonas hydrophila infection. AB - To understand whether chicken-type lysozyme (Lys-c) in channel catfish was induced by infection of Aeromonas hydrophila, the transcriptional levels of Lys-c in skin, gut, liver, spleen, posterior kidney, and blood cells in healthy channel catfish was compared to that in channel catfish infected with A. hydrophila by bath immersion. Quantitative PCR revealed that the transcription levels of Lys-c in infected catfish were significantly (P < 0.05) induced in all five tissues tested as well as in blood cells. Recombinant CC-Lys-c produced in Escherichia coli expression system (R-CC-Lys-c) exhibited significant (P < 0.05) lytic activity to Gram-positive Micrococcus lysodeikticus and Gram-negative A. hydrophila. When pcDNA3.2-vectored recombinant channel catfish lysozyme-c (pcDNA Lys-c) was transfected in channel catfish gill cells G1B, the over-expression of pcDNA-Lys-c offered significant (P < 0.05) protection to G1B against A. hydrophila infection. When channel catfish were intraperitoneally injected with QCDCR adjuvant formulated pcDNA-Lys-c and challenged with a highly virulent A. hydrophila strain AL-09-71 at 1-, 2-, 14-, and 28-days post treatment, pcDNA-Lys c offered 75%, 100%, 60%, and 77% protection to channel catfish, respectively. Macrophages of fish treated with pcDNA-Lys-c produced significantly (P < 0.05) higher amounts of reactive oxygen species and nitric oxide than that of fish treated with pcDNA vector alone. Taken together, our results suggest that pcDNA Lys-c could be used as a novel immunostimulant to protect channel catfish against A. hydrophila infection. PMID- 23732848 TI - Edwardsiella tarda mutant disrupted in type III secretion system and chorismic acid synthesis and cured of a plasmid as a live attenuated vaccine in turbot. AB - Edwardsiella tarda is an intractable Gram-negative pathogen in many fish species to cause edwardsiellosis. Its infection leads to extensive losses in a diverse array of commercially important fish. The type III secretion system (T3SS) has been considered as one of the major virulence factors and plays important roles in its intracellular lifestyle. In this study, an E. tarda EIB202 mutant WED with deletions in the T3SS genes for EseB, EseC, EseD and EscA, along with the aroC gene for the biosynthesis of chorismic acid, as well as the curing of endogenous plasmid pEIB202 was constructed by allelic exchange strategy. Compared to the wild-type EIB202 which was highly virulent towards turbot (Scophthamus maximus) via intraperitoneal (i.p.), intramuscular (i.m.) injection or immersion and caused systemic infection in turbot as well as the unexpected red mouth symptom when immersion challenged, WED was highly attenuated when inoculated into turbot via i.m., i.p. and immersion routes, and exhibited significantly impaired capacity to survive in fish tissues. WED showed 5700-fold higher 50% lethal dose (LD50) than that of the wild type when i.m. or i.p. challenged. Inoculation with WED by i.p. or immersion injection routes elicited significant protection against the challenge of the wild-type E. tarda after 5 weeks of vaccination. The vaccinated fish produced low while significant level of specific antibody and showed increased expression of immune-related factors including IL-1beta, IFN gamma, MHC II, MHC-I and CD8, indicating that WED possesses significant immunoprotective potential. Furthermore, our data indicated that a single dose of i.p. and immersion vaccination with WED could produce significant protection as long as 12 and 6 months, respectively. These results demonstrated the feasibility of WED as a live attenuated vaccine in turbot against edwardsiellosis by immersion or i.p. injection routes. PMID- 23732849 TI - Purification, characterization and functional analysis of a novel beta-1, 3 glucan binding protein from green tiger shrimp Penaeus semisulcatus. AB - A beta-1, 3-Glucan binding protein (beta-GBP) was isolated from green tiger shrimp Penaeus semisulcatus and purified using laminarin precipitation and affinity chromatography on laminarin-Sepharose 6B column respectively. P. semisulcatus beta-GBP exhibits a single band with a molecular weight of 112 kDa on SDS-PAGE and pI of 5.9 in isoelectric focusing (IEF). Negative staining of P. semisulcatus beta-GBP showed large aggregates with crystalline surface when viewed by Electron Microscopy. Circular dichroism spectra of P. semisulcatus beta GBP showed broad negative minimum wavelength extending from 200 to 250 nm can be attributed to the presence of beta-sheets in its secondary structure. P. semisulcatus beta-GBP comprises the specific binding affinity with the polysaccharide beta-1, 3-glucans (laminarin), this recognition and binding leads to the activation of prophenoloxidase cascade. Interestingly, P. semisulcatus beta-GBP also involved in the agglutination of baker's yeast, bacteria, erythrocytes (RBCs) and enhances the PO activity. Herein, we have investigated the importance of beta-GBP in innate immune response of P. semisulcatus and they implicate the evolutionary link with similar proteins found in other invertebrates. PMID- 23732850 TI - Sensorimotor semantics on the spot: brain activity dissociates between conceptual categories within 150 ms. AB - Although semantic processing has traditionally been associated with brain responses maximal at 350-400 ms, recent studies reported that words of different semantic types elicit topographically distinct brain responses substantially earlier, at 100-200 ms. These earlier responses have, however, been achieved using insufficiently precise source localisation techniques, therefore casting doubt on reported differences in brain generators. Here, we used high-density MEG EEG recordings in combination with individual MRI images and state-of-the-art source reconstruction techniques to compare localised early activations elicited by words from different semantic categories in different cortical areas. Reliable neurophysiological word-category dissociations emerged bilaterally at ~ 150 ms, at which point action-related words most strongly activated frontocentral motor areas and visual object-words occipitotemporal cortex. These data now show that different cortical areas are activated rapidly by words with different meanings and that aspects of their category-specific semantics is reflected by dissociating neurophysiological sources in motor and visual brain systems. PMID- 23732851 TI - New pulmonary therapies directed at targets other than CFTR. AB - Our current understanding of the pathogenesis of cystic fibrosis (CF) lung disease stresses the importance of the physical and chemical properties of the airway surface liquid (ASL). In particular, the loss of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel function in CF reduces the volume and fluidity of the ASL, thus impairing mucociliary clearance and innate antimicrobial mechanisms. Besides direct approaches to restoring mutant CFTR function, alternative therapeutic strategies may also be considered to correct the basic defect of impaired salt and water transport. Such alternative strategies are focused on the restoration of mucociliary transport by (1) reducing sodium and fluid absorption by inhibiting the ENaC channel; (2) activating alternative chloride channels; and (3) increasing airway surface hydration with osmotic agents. Therapeutic approaches directed at targets other than CFTR are attractive because they are potentially useful to all patients irrespective of their genotype. Clinical trials are underway to test the efficacy of these approaches. PMID- 23732852 TI - Genome dynamics in Legionella: the basis of versatility and adaptation to intracellular replication. AB - Legionella pneumophila is a bacterial pathogen present in aquatic environments that can cause a severe pneumonia called Legionnaires' disease. Soon after its recognition, it was shown that Legionella replicates inside amoeba, suggesting that bacteria replicating in environmental protozoa are able to exploit conserved signaling pathways in human phagocytic cells. Comparative, evolutionary, and functional genomics suggests that the Legionella-amoeba interaction has shaped this pathogen more than previously thought. A complex evolutionary scenario involving mobile genetic elements, type IV secretion systems, and horizontal gene transfer among Legionella, amoeba, and other organisms seems to take place. This long-lasting coevolution led to the development of very sophisticated virulence strategies and a high level of temporal and spatial fine-tuning of bacteria host cell interactions. We will discuss current knowledge of the evolution of virulence of Legionella from a genomics perspective and propose our vision of the emergence of this human pathogen from the environment. PMID- 23732853 TI - Management of the thalassemias. AB - During the last 30 years, in addition to the considerable progress made in control and prevention of thalassemias(3), there have also been major advances in their symptomatic management, at least in wealthier countries where appropriate facilities are available. Remarkable improvements in survival in the severe forms of thalassemia have followed the more judicious use of blood transfusion and, in particular, the ability to manage the iron accumulation resulting from transfusion with its severe and ultimately lethal effects on endocrine and cardiac function. PMID- 23732854 TI - Mesolimbic dopamine and habenulo-interpeduncular pathways in nicotine withdrawal. AB - The majority of people who attempt to quit smoking without some assistance relapse within the first couple of weeks, indicating the increased vulnerability during the early withdrawal period. The habenula, which projects via the fasciculus retroflexus to the interpeduncular nucleus, plays an important role in the withdrawal syndrome. Particularly the alpha2, alpha5, and beta4 subunits of the nicotinic acetylcholine receptor have critical roles in mediating the somatic manifestations of withdrawal. Furthermore, withdrawal from nicotine induces a hypodopaminergic state, but there is a relative increase in the sensitivity to phasic dopamine release that is caused by nicotine. Therefore, acute nicotine re exposure causes a phasic DA response that more potently reinforces relapse to smoking during the withdrawal period. PMID- 23732855 TI - The "stop" and "go" of nicotine dependence: role of GABA and glutamate. AB - Nicotine plays an important role in the initiation and maintenance of tobacco smoking. Importantly, chronic nicotine exposure alters the function of brain reward systems, resulting in the development of a nicotine-dependent state. This nicotine-dependent state is associated with aversive affective and somatic signs upon abstinence from smoking, often leading to relapse in abstinent smokers. This article reviews the role of the major excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively, in both the reinforcing effects of nicotine and development of nicotine dependence. Evidence suggests that blockade of glutamatergic neurotransmission attenuates both nicotine intake and nicotine seeking. In contrast, both nicotine intake and nicotine seeking are attenuated when GABA neurotransmission is facilitated. In conclusion, medications that either attenuate/negatively modulate glutamatergic neurotransmission or facilitate/positively modulate GABA neurotransmission may be useful for promoting smoking cessation in humans. PMID- 23732856 TI - Pathogenesis of meningococcemia. AB - Neisseria meningitidis is responsible for two major diseases: cerebrospinal meningitis and/or septicemia. The latter can lead to a purpura fulminans, an often-fatal condition owing to the associated septic shock. These two clinical aspects of the meningococcal infection are consequences of a tight interaction of meningococci with host endothelial cells. This interaction, mediated by the type IV pili, is responsible for the formation of microcolonies on the apical surface of the cells. This interaction is followed by the activation of signaling pathways in the host cells leading to the formation of a microbiological synapse. A low level of bacteremia is likely to favor the colonization of brain vessels, leading to bacterial meningitis, whereas the colonization of a large number of vessels by a high number of bacteria is responsible for one of the most severe forms of septic shock observed. PMID- 23732857 TI - Why is organ transplantation clinically important? AB - Solid organ transplantations save lives in patients affected by terminal organ failures and improve quality of life. Organ transplantations have gradually ameliorated in the last two decades and usually provide excellent results in children and young adults, and are increasingly challenged by the growing proportion of elderly transplant patients with comorbidities. Renal transplantation increases patient survival over dialysis, and lifesaving transplants are indispensible to treat patients with liver, heart, or lung irreversible diseases. Solid organ transplant programs activity has been steadily growing but is still far from global needs, with great differences among countries. Solid organ transplantations are essential for developed and mature health care systems. PMID- 23732859 TI - Failure-to-rescue after colorectal cancer surgery and the association with three structural hospital factors. AB - BACKGROUND: This study was designed to evaluate the association between structural hospital characteristics and failure-to-rescue (FTR) after colorectal cancer surgery. A growing body of evidence suggests a large hospital variation concerning mortality rates in patients with a severe complication (FTR) in colorectal cancer surgery. Which structural hospital factors are associated with better FTR rates remains largely unclear. METHODS: All patients undergoing colorectal cancer surgery from 2009 through 2011 in 92 Dutch hospitals were analysed. Univariate and multivariate logistic regression models, including casemix, hospital volume, teaching status, and different levels of intensive care unit (ICU) facilities, were used to analyse risk-adjusted FTR rates. RESULTS: A total of 25,591 patients from 92 hospitals were included. The FTR rate ranged between 0 and 39 %. In univariate analysis, high hospital volume (>200 vs. <=200 patients/year), teaching status (academic vs. teaching vs. nonteaching hospitals) and high level of ICU facilities (highest level 3 vs. lowest level 1) were associated with lower FTR rates. Only the higher levels of ICU facilities (2 or 3 compared with level 1) were independently associated with lower failure-to-rescue rates (odds ratio 0.72; 95 % confidence interval 0.65-0.88) in multivariate analysis. DISCUSSION: Hospital type and annual hospital volume were not independently associated with FTR rates in colorectal cancer surgery. Instead, the lowest level of ICU facilities was independently associated with higher rates. This suggests that a more advanced ICU may be an important factor that contributes to better failure-to-rescue rates, although individual hospitals perform well with lower ICU levels. PMID- 23732860 TI - A novel probe density controllable electrochemiluminescence biosensor for ultra sensitive detection of Hg2+ based on DNA hybridization optimization with gold nanoparticles array patterned self-assembly platform. AB - Biosensor based on DNA hybridization holds great potential to get higher sensitivity as the optimal DNA hybridization efficiency can be achieved by controlling the distribution and orientation of probe strands on the transducer surface. In this work, an innovative strategy is reported to tap the sensitivity potential of current electrochemiluminescence (ECL) biosensing system by dispersedly anchoring the DNA beacons on the gold nanoparticles (GNPs) array which was electrodeposited on the glassy carbon electrode surface, rather than simply sprawling the coil-like strands onto planar gold surface. The strategy was developed by designing a "signal-on" ECL biosensing switch fabricated on the GNPs nanopatterned electrode surface for enhanced ultra-sensitivity detection of Hg(2+). A 57-mer hairpin-DNA labeled with ferrocene as ECL quencher and a 13-mer DNA labeled with Ru(bpy)3(2+) as reporter were hybridized to construct the signal generator in off-state. A 31-mer thymine (T)-rich capture-DNA was introduced to form T-T mismatches with the loop sequence of the hairpin-DNA in the presence of Hg(2+) and induce the stem-loop open, meanwhile the ECL "signal-on" was triggered. The peak sensitivity with the lowest detection limit of 0.1 nM was achieved with the optimal GNPs number density while exorbitant GNPs deposition resulted in sensitivity deterioration for the biosensor. We expect the present strategy could lead the renovation of the existing probe-immobilized ECL genosensor design to get an even higher sensitivity in ultralow level of target detection such as the identification of genetic diseases and disorders in basic research and clinical application. PMID- 23732858 TI - Regulatory cells and transplantation tolerance. AB - Transplantation tolerance is a continuing therapeutic goal, and it is now clear that a subpopulation of T cells with regulatory activity (Treg) that express the transcription factor foxp3 are crucial to this aspiration. Although reprogramming of the immune system to donor-specific transplantation tolerance can be readily achieved in adult mouse models, it has yet to be successfully translated in human clinical practice. This requires that we understand the fundamental mechanisms by which donor antigen-specific Treg are induced and function to maintain tolerance, so that we can target therapies to enhance rather than impede these regulatory processes. Our current understanding is that Treg act via numerous molecular mechanisms, and critical underlying components such as mTOR inhibition, are only now emerging. PMID- 23732861 TI - Filtration of dermal fibroblast-conditioned culture media is required for the reliable quantitation of cleaved carboxy-terminal peptide of collagen type I (CICP) by ELISA. AB - Cleavage of the collagen type I carboxy-terminal peptide (CICP) from the procollagen molecule is an essential step in collagen biosynthesis. The commercial CICP ELISA (Quidel Corporation, USA), developed for quantifying CICP in serum in clinical monitoring, is often also applied to cellular studies as a measure of collagen synthesis. However, unlike in serum samples, which contain only cleaved CICP, cell-conditioned culture media also contains "uncleaved CICP", namely procollagen, and there is no specific guidance on how to interpret the ELISA data obtained with such samples. Here we attempted to reliably quantify cleaved CICP in human dermal fibroblast-conditioned cell culture media using the CICP ELISA. CICP concentration was determined in the parent and filtered samples of culture media of dermal fibroblasts (CCD-25SK). Gel-separated samples were also subjected to protein staining or analyzed by Western blot using the anti CICP antibodies supplied in the ELISA kit. The derived concentrations of CICP in the filtered aliquots and the parent unfiltered samples increased over time. The increase in CICP in the unfiltered samples was not proportional to the increase seen in the filtered aliquot. CICP ELISA antibodies recognized both the cleaved CICP trimer and procollagen molecule. The data presented show that (a) the commercial CICP ELISA recognizes both procollagen and cleaved CICP in cell conditioned culture media and thus attention should be paid in interpreting data from cell culture studies using this ELISA and (b) the filtration method described herein can be used to exclusively and reliably monitor cleaved CICP. PMID- 23732862 TI - Peripheral T-cell apoptosis is not differentially affected by antiretroviral regimens in HIV-infected patients. AB - BACKGROUND: HIV-induced CD4(+) and CD8(+) T-cell apoptosis decreases upon start of combination antiretroviral therapy (cART). Although in vitro evidence suggests an anti-apoptotic effect of protease inhibitors (PIs) as opposed to non nucleoside reverse transcriptase inhibitors (NNRTIs), in vivo studies are inconclusive about effects of differential cART regimens on T-cell apoptosis. METHODS: Peripheral T-cell apoptosis was evaluated in a cross-sectional study including 20 patients on PI- and 19 on NNRTI-based combination antiretroviral therapy (cART), all with backbone therapy of tenofovir and emtricitabine and undetectable viral loads 6 months before inclusion. Spontaneous T-cell apoptosis was measured in freshly isolated peripheral blood mononuclear cells (<4 h after venipuncture) using annexin V, propidium iodide and staining for caspase activity and levels of the anti-apoptotic protein Bcl-2. RESULTS: The groups were comparable in general- and HIV-specific characteristics. In addition, T-cell activation was similar in both groups. We observed no difference in T-cell apoptosis as measured by annexin V, propidium iodide or caspase staining between PI- and NNRTI-treated patients. Interestingly, the level of anti-apoptotic protein Bcl-2 was higher in PI-treated than in NNRTI-treated patients. CONCLUSIONS: In this cross-sectional study on HIV-infected patients, direct ex vivo spontaneous T-cell apoptosis rates are not differentially affected by NNRTI- or PI-based cART. PMID- 23732863 TI - Extending the distance range accessed with continuous wave EPR with Gd3+ spin probes at high magnetic fields. AB - Interspin distances between 0.8 nm and 2.0 nm can be measured through the dipolar broadening of the continuous wave (cw) EPR spectrum of nitroxide spin labels at X band (9.4 GHz, 0.35 T). We introduce Gd(3+) as a promising alternative spin label for distance measurements by cw EPR above 7 Tesla, where the |-1/2> to |1/2> transition narrows below 1 mT and becomes extremely sensitive to dipolar broadening. To estimate the distance limits of cw EPR with Gd(3+), we have measured spectra of frozen solutions of GdCl3 at 8.6 T (240 GHz) and 10 K at concentrations ranging from 50 mM to 0.1 mM, covering a range of average interspin distances. These experiments show substantial dipolar broadening at distances where line broadening cannot be observed with nitroxides at X-band. This data, and its agreement with calculated dipolar-broadened lineshapes, show Gd(3+) to be sensitive to distances as long as ~3.8 nm. Further, the linewidth of a bis-Gd(3+) complex with a flexible ~1.6 nm bridge is strongly broadened as compared to the mono-Gd(3+) complex, demonstrating the potential for application to pairwise distances. Gd-DOTA-based chelates that can be functionalized to protein surfaces display linewidths narrower than aqueous GdCl3, implying they should be even more sensitive to dipolar broadening. Therefore, we suggest that the combination of tailored Gd(3+) labels and high magnetic fields can extend the longest interspin distances measurable by cw EPR from 2.0 nm to 3.8 nm. cw EPR data at 260 K demonstrate that the line broadening remains clear out to similar average interspin distances, offering Gd(3+) probes as promising distance rulers at temperatures higher than possible with conventional pulsed EPR distance measurements. PMID- 23732864 TI - First in-human magnetic resonance visualization of surgical mesh implants for inguinal hernia treatment. AB - OBJECTIVES: Until today, there have been no conventional imaging methods available to visualize surgical mesh implants and related complications. In a new approach, we incorporated iron particles into polymer-based implants and visualized them by magnetic resonance imaging (MRI).After clinical approval of such implants, the purposes of this study were to evaluate the MRI conspicuity of such iron-loaded mesh implants in patients treated for inguinal hernias and to assess the immediate postsurgical mesh configuration. MATERIALS AND METHODS: Approved by the ethics committee, in this prospective cohort study, 13 patients (3 patients with bilateral hernia treatment) were surgically treated for inguinal hernia receiving iron-loaded mesh implants between March and October 2012. The implants were applied via laparoscopic technique (transabdominal preperitoneal technique; n = 8, 3 patients with bilateral hernia treatment) or via open surgical procedure (Lichtenstein surgery; n = 5). Magnetic resonance imaging was performed 1 day after the surgery at a 1.5-T scanner (Achieva; Philips, Best, The Netherlands) with a 16-channel receiver coil using 3 different gradient echo sequences (first gradient echo sequence, second gradient echo sequence, and third gradient echo sequence [GRE1-3]) and 1 T2-weighted turbo spin-echo sequence (T2wTSE). Three radiologists independently evaluated mesh conspicuity and diagnostic value with respect to different structures using a semiquantitative scoring system (1, insufficient; 2, sufficient; 3, good; 4, optimal). Mesh deformation and coverage of the hernia were visually assessed and rated using a 5 point semiquantitative scoring system. Statistical analysis was performed using mixed models and linear contrast. RESULTS: All 16 implants were successfully visualized by MRI. On gradient echo sequences, the mesh is clearly delineated as a thick hypointense line. On T2wTSE, the mesh was depicted as a faint hypointense line, which was difficult to identify. The first gradient echo sequence was rated best for visual conspicuity (mean [SD], 3.8 [0.4]). T2-weighted turbo spin-echo sequence was preferred for evaluation of the surrounding anatomy (mean [SD], 3.7 [0.3]). For the combined assessment of both mesh and anatomy, GRE3 was rated best (mean [SD], 2.9 [0.7]). Local air slightly reduced mesh delineation (lowest mean [SD] rating, 2.9 [0.7] for GRE3). Overall, in both implantation techniques, the meshes exhibited mild to moderate deformations (mean [SD], 3.3 [0.4], 3.1 [0.3], and 2.8 [0.3] on average with open technique, 2.7 [0.3], 2.7 [0.2], and 2.3 [0.3] with laparoscopic technique). Coverage of the hernia was achieved in 15 of the 16 implants. CONCLUSIONS: Combining iron-loaded implants and MRI, we achieved mesh visualization for the first time in patients. For MRI protocol, we propose a combination of different gradient echo sequences and T2-weighted turbo spin-echo sequences: first gradient echo sequence for mesh configuration, T2wTSE for anatomy assessment, and GRE3 for evaluation of hernia coverage and mesh localization. Using our approach, MRI could become a noninvasive alternative to open surgical exploration if mesh-related complications were suspected. PMID- 23732865 TI - Berberine induces selective apoptosis through the AMPK-mediated mitochondrial/caspase pathway in hepatocellular carcinoma. AB - Advanced hepatocellular carcinoma (HCC) is insensitive to traditional chemotherapeutic approaches, which causes difficulty in the development of novel agents for the treatment of HCC. Berberine is the main component of Coptidis Rhizoma, a plant alkaloid with a long history of use in Chinese medicine, and has become a potential candidate for the treatment of HCC due to its high antitumor activity and low toxicity. In this study, we investigated the mechanism via which berberine exerts its inhibitory effects on HCC. The data demonstrated that berberine selectively decreased cell viability in a time- and dose-dependent manner in the HepG2, SMMC-7721 and Bel-7402 HCC cell lines compared with normal hepatocytes (HL-7702 cells), as determined by a sulforhodamine B assay. Flow cytometric analysis revealed that berberine increased the number of late apoptotic cells. Pretreatment with berberine in HepG2 cells resulted in a significant increase in phosphorylated AMP-activated protein kinase (AMPK), as well as a marked elevation in phosphorylated Akt levels. In addition, the activation of AMPK was accompanied by apoptotic effects that occurred in a caspase-dependent manner through the mitochondrial pathway, and was coupled with the release of cytochrome c from the mitochondria and the activation of caspase-9 and -3. Furthermore, the ratio of Bax/Bcl-2 was increased in a dose-dependent manner. Our study supports the theory that berberine selectively inhibits the growth of human hepatocellular cancer cells by inducing AMPK-mediated caspase dependent mitochondrial pathway cell apoptosis, and rarely causes cytotoxicity in normal cells. Therefore, berberine is a promising novel agent for the treatment of HCC. PMID- 23732866 TI - Evaluation of diverse peptidyl motifs for cellular delivery of semiconductor quantum dots. AB - Cell-penetrating peptides (CPPs) have rapidly become a mainstay technology for facilitating the delivery of a wide variety of nanomaterials to cells and tissues. Currently, the library of CPPs to choose from is still limited, with the HIV TAT-derived motif still being the most used. Among the many materials routinely delivered by CPPs, nanoparticles are of particular interest for a plethora of labeling, imaging, sensing, diagnostic, and therapeutic applications. The development of nanoparticle-based technologies for many of these uses will require access to a much larger number of functional peptide motifs that can both facilitate cellular delivery of different types of nanoparticles to cells and be used interchangeably in the presence of other peptides and proteins on the same surface. Here, we evaluate the utility of four peptidyl motifs for their ability to facilitate delivery of luminescent semiconductor quantum dots (QDs) in a model cell culture system. We find that an LAH4 motif, derived from a membrane inserting antimicrobial peptide, and a chimeric sequence that combines a sweet arrow peptide with a portion originating from the superoxide dismutase enzyme provide effective cellular delivery of QDs. Interestingly, a derivative of the latter sequence lacking just a methyl group was found to be quite inefficient, suggesting that even small changes can have significant functional outcomes. Delivery was effected using 1 h incubation with cells, and fluorescent counterstaining strongly suggests an endosomal uptake process that requires a critical minimum number or ratio of peptides to be displayed on the QD surface. Concomitant cytoviability testing showed that the QD-peptide conjugates are minimally cytotoxic in the model COS-1 cell line tested. Potential applications of these peptides in the context of cellular delivery of nanoparticles and a variety of other (bio)molecules are discussed. PMID- 23732867 TI - Separation of poly(acrylic acid) salts according to topology using capillary electrophoresis in the critical conditions. AB - Branching was detected in polyacrylates synthesised through radical polymerization via solution-state NMR, while inconsistencies have been reported for the determination of the molar mass of hydrophilic polyacrylates using aqueous-phase and organic-phase size-exclusion chromatography. In this work, poly(sodium acrylate)s, PNaAs, of various topologies were separated for the first time using free-solution capillary electrophoresis (CE). Free-solution CE does not separate the PNaAs by their molar mass, similarly to separations by liquid chromatography in the critical conditions, rather by different topologies (linear, star branched, and hyperbranched). The electrophoretic mobility of PNaAs increases as the degree of branching decreases. Separation is shown to be not only by the topology but also by the end groups as expected for a separation in the critical conditions: replacing a relatively bulky nitroxide end group with hydrogen atom yielded a higher electrophoretic mobility. This novel method, capillary electrophoresis in the critical conditions enabled, for the first time, the separation of hydrophilic polyacrylates according to their topology (branching) and their chain ends. This will allow meaningful and accurate characterization of their branched topologies as well as molar masses and progress in for advanced applications such as drug delivery or flocculation. PMID- 23732868 TI - Two-dimensional high-performance liquid chromatographic determination of day night variation of D-alanine in mammals and factors controlling the circadian changes. AB - D-Alanine (D-Ala) is one of the naturally occurring D-amino acids in mammals, and its amount is known to have characteristic circadian changes. It is a candidate for a novel physiologically active substance and/or a biomarker, and the regulation mechanisms of the intrinsic amounts of D-Ala are expected to be clarified. In the present study, the effects of the possible factors controlling the D-Ala amounts, e.g., diet, D-amino acid oxidase (DAO) and intestinal bacteria, on the day-night changes in the intrinsic D-Ala amounts have been investigated using a highly sensitive and selective two-dimensional high performance liquid chromatographic system combining a reversed-phase column and an enantioselective column. The circadian rhythm was not changed under fasting conditions. In the mice lacking D-amino acid oxidase activity (ddY/DAO(-) mice), clear day-night changes were still observed, suggesting that the factors controlling the D-Ala rhythm were not their food and DAO activity. On the other hand, in the germ-free mice, quite low amounts of D-Ala were detected compared with those in the control mice, indicating that the main origin of D-Ala in the mice is intestinal bacteria. Because the D-Ala amounts in the digesta containing intestinal bacteria did not show the day-night changes, the controlling factor of the circadian changes of the D-Ala amount was suggested to be the intestinal absorption. PMID- 23732869 TI - Optimization in multidimensional gas chromatography applying quantitative analysis via a stable isotope dilution assay. AB - Trace level analyses in complex matrices benefit from heart-cut multidimensional gas chromatographic (MDGC) separations and quantification via a stable isotope dilution assay. Minimization of the potential transfer of co-eluting matrix compounds from the first dimension ((1)D) separation into the second dimension separation requests narrow cut-windows. Knowledge about the nature of the isotope effect in the separation of labeled and unlabeled compounds allows choosing conditions resulting in at best a co-elution situation in the (1)D separation. Since the isotope effect strongly depends on the interactions of the analytes with the stationary phase, an appropriate separation column polarity is mandatory for an isotopic co-elution. With 3-alkyl-2-methoxypyrazines and an ionic liquid stationary phase as an example, optimization of the MDGC method is demonstrated and critical aspects of narrow cut-window definition are discussed. PMID- 23732870 TI - Improved spectrophotometric human interferon-gamma bioassay. AB - Interferon gamma (IFNgamma) is a cytokine involved in many anti-viral and immunoregulatory processes. One of the major mechanisms through which IFNgamma exerts these effects is by inducing expression of indoleamine 2,3 dioxygenase-1 (IDO1), an enzyme that catalyses the first, rate-limiting step of the kynurenine pathway. In this pathway, tryptophan can be catabolised to many products, including picolinic acid and nicotinamide adenine dinucleotide. However, in endothelial cells, the pathway ends at the production of kynurenine. This is due to little or no expression of enzymes that metabolise kynurenine. Production of kynurenine has been used as an indicator of human IDO1 activity, and hence as an hIDO1 bioassay. Due to IFNgamma's ability to induce IDO1 expression, kynurenine production can also be a measure of human IFNgamma (hIFNgamma) bioactivity. Previously, the levels of hIFNgamma have been commonly determined by anti-viral assays, high performance liquid chromatography and ELISA. Apart from their technical complexity, these assays are costly and only the anti-viral assay measures bioactive IFNgamma. Here, we report the development of an improved IFNgamma spectrophotometric bioassay using a human brain endothelial cell line (HBEC 5i). The method is sensitive, easy to perform and cost efficient. PMID- 23732871 TI - Methamphetamine-induced disruption of frontostriatal reward learning signals: relation to psychotic symptoms. AB - OBJECTIVE: Frontostriatal circuitry is critical to learning processes, and its disruption may underlie maladaptive decision making and the generation of psychotic symptoms in schizophrenia. However, there is a paucity of evidence directly examining the role of modulatory neurotransmitters on frontostriatal function in humans. In order to probe the effects of modulation on frontostriatal circuitry during learning and to test whether disruptions in learning processes may be related to the pathogenesis of psychosis, the authors explored the brain representations of reward prediction error and incentive value, two key reinforcement learning parameters, before and after methamphetamine challenge. METHOD: Healthy volunteers (N=18) underwent functional MRI (fMRI) scanning while performing a reward learning task on three occasions: after placebo, after methamphetamine infusion (0.3 mg/kg body weight), and after pretreatment with 400 mg of amisulpride and then methamphetamine infusion. Brain fMRI representations of learning signals, calculated using a reinforcement Q-learning algorithm, were compared across drug conditions. RESULTS: In the placebo condition, reward prediction error was coded in the ventral striatum bilaterally and incentive value in the ventromedial prefrontal cortex bilaterally. Reward prediction error and incentive value signals were disrupted by methamphetamine in the left nucleus accumbens and left ventromedial prefrontal cortex, respectively. Psychotic symptoms were significantly correlated with incentive value disruption in the ventromedial prefrontal and posterior cingulate cortex. Amisulpride pretreatment did not significantly alter methamphetamine-induced effects. CONCLUSIONS: The results demonstrate that methamphetamine impairs brain representations of computational parameters that underpin learning. They also demonstrate a significant link between psychosis and abnormal monoamine-regulated learning signals in the prefrontal and cingulate cortices. PMID- 23732872 TI - Association of VKORC1-1639G>A polymorphism with susceptibility to ossification of the posterior longitudinal ligament of the spine: a Korean study. AB - BACKGROUND: Abnormalities of bone metabolism may be involved in the pathogenesis of ossification of the posterior longitudinal ligament (OPLL) of the spine. Besides its hemostatic effect, vitamin K epoxide reductase complex subunit 1 (VKORC1) plays a pivotal role in bone mineralization. The aim of this study is to investigate whether single nucleotide polymorphisms (SNPs) of the VKORC1 gene are associated with the occurrence of OPLL in a Korean population. METHOD: A total of 98 patients with OPLL and 200 controls were genotyped for the VKORC1-1639G>A SNP (rs9923231) by polymerase chain reaction and restriction fragment length polymorphism analysis. All the patients (n = 98) in this study underwent surgery (60, posterior-only approach; 36, anterior-only approach; 2, combined anterior and posterior approach) during their admission. We analyzed this association separately according to the gender and OPLL subgroup: OPLL continuous group (continuous type plus mixed type) and OPLL segmental group (segmental and localized type). RESULTS: We found that the genotype VKORC1-1639G>A frequency was significantly associated with the occurrence of the OPLL in the female group (adjusted odds ratio = 5.22, 95 % confidence interval: 1.675 to 16.269, p = 0.004). However, there was no overall association between the OPLL susceptibility and VKORC1-1639G>A polymorphism. A subgroup analysis did not show any significant correlation between VKORC1-1639G>A polymorphism and subgroup of OPLL either. CONCLUSION: Our results suggest that the VKORC1-1639G>A SNP may increase susceptibility to OPLL in women. However, there was only a statistical association in the female group despite a number of stratified analyses. Therefore, the findings should be interpreted with caution, and further genetic study is needed to improve our understanding of the role of VKORC1 polymorphisms in determining the risk of OPLL occurrence. PMID- 23732873 TI - Indocyanine green videoangiography (ICGV) in parasagittal meningiomas surgery. Considerations on veins management and brain function preservation. PMID- 23732874 TI - Deproteinized bovine bone functionalized with the slow delivery of BMP-2 for the repair of critical-sized bone defects in sheep. AB - As an alternative to an autologous bone graft, deproteinized bovine bone (DBB) is widely used in the clinical dentistry. Although DBB provides an osteoconductive scaffold, it is not capable of enhancing bone regeneration because it is not osteoinductive. In order to render DBB osteoinductive, bone morphogenetic protein 2 (BMP-2) has previously been incorporated into a three dimensional reservoir (a biomimetic calcium phosphate coating) on DBB, which effectively promoted the osteogenic response by the slow delivery of BMP-2. The aim of this study was to investigate the therapeutic effectiveness of such coating on the DBB granules in repairing a large cylindrical bone defect (8 mm diameter, 13 mm depth) in sheep. Eight groups were randomly assigned to the bone defects: (i) no graft material; (ii) autologous bone; (iii) DBB only; (iv) DBB mixed with autologous bone; (v) DBB bearing adsorbed BMP-2; (vi) DBB bearing a coating but no BMP-2; (vii) DBB bearing a coating with adsorbed BMP-2; and (viii) DBB bearing a coating incorporated depot of BMP-2. 4 and 8 weeks after implantation, samples were withdrawn for a histological and a histomorphometric analysis. Histological results confirmed the excellent biocompatibility and osteoconductivity of all the grafts tested. At 4 weeks, DBB mixed with autologous bone or functionalized with coating-incorporated BMP-2 showed more newly-formed bone than the other groups with DBB. At 8 weeks, the volume of newly-formed bone around DBB that bore a coating-incorporated depot of BMP-2 was greatest among the groups with DBB, and was comparable to the autologous bone group. The use of autologous bone and BMP-2 resulted in more bone marrow formation. Multinucleated giant cells were observed in the resorption process around DBB, whereas histomorphometric analysis revealed no significant degradation of DBB. In conclusion, it was shown that incorporating BMP-2 into the calcium phosphate coating of DBB induced strong bone formation around DBB for repairing a critical-sized bone defect. PMID- 23732875 TI - Elevated CSF cytokines in the Jarisch-Herxheimer reaction of general paresis. AB - IMPORTANCE: The Jarisch-Herxheimer reaction (JHR) is a well-recognized transient worsening of signs and symptoms occurring soon after the first dose of an appropriate antibiotic for several spirochetal infections. The pathogenesis of this reaction is poorly understood. In this case study of cerebrospinal fluid (CSF) cytokines, we aimed to improve understanding of the pathogenesis of JHR in patients with neurosyphilis who develop transient neurologic signs. OBSERVATIONS: Four hours after receiving penicillin for general paresis, a 55-year-old man developed a severe JHR characterized by fever, tachycardia, hypertension, obtundation, seizures, and a neutrophilia lasting 18 hours. Cerebrospinal fluid obtained at the peak of the JHR demonstrated a switch from a mild lymphophilia to a moderate neutrophilia. He had markedly elevated CSF interleukin (IL) 8 and likely elevated IL-1beta, IL-10, and IL-15 levels, which returned to normal in follow-up CSF examination results. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first report of elevated CSF cytokines in a patient with a JHR, which possibly contributed to the neurologic signs of JHR. Further studies on the innate inflammatory response during episodes of acute infection and inflammation are needed to develop targeted therapies to modulate this system, which could, in turn, improve future outcomes and modify the JHR. PMID- 23732876 TI - Adaptive mutations in the H5N1 polymerase complex. AB - Adaptation of the viral polymerase to host factors plays an important role in interspecies transmission of H5N1 viruses. Several adaptive mutations have been identified that, in general, determine not only host range, but also pathogenicity and transmissibility of the virus. The available evidence indicates that most of these mutations are found in the PB2 subunit of the polymerase. Particularly prominent mutations are located in the C-terminal domain of PB2 involving the amino acid exchanges E627K and D701N. Both mutations, that are also responsible for the adaptation of other avian viruses to mammalian hosts, have been described in human H5N1 isolates. In animal models, it could be demonstrated that they enhance pathogenicity in mice and induce contact transmission in guinea pigs. Mutation E627K has also been identified as a determinant of air-borne H5N1 transmission in ferrets. We are only beginning to understand the underlying mechanisms at the molecular level. Thus, mutation D701N promotes importin-alpha mediated nuclear transport in mammalian cells. Mutation E627K also enhances the replication rate in an importin-alpha dependent fashion in mammalian cells, yet without affecting nuclear entry of PB2. Numerous other adaptive mutations, some of which compensate for the lack of PB2 E627K, have been observed in PB2 as well as in the polymerase subunit PB1, the nucleoprotein NP, and the nuclear export protein NEP (NS2). PMID- 23732877 TI - 708 Common and 2010 rare DISC1 locus variants identified in 1542 subjects: analysis for association with psychiatric disorder and cognitive traits. AB - A balanced t(1;11) translocation that transects the Disrupted in schizophrenia 1 (DISC1) gene shows genome-wide significant linkage for schizophrenia and recurrent major depressive disorder (rMDD) in a single large Scottish family, but genome-wide and exome sequencing-based association studies have not supported a role for DISC1 in psychiatric illness. To explore DISC1 in more detail, we sequenced 528 kb of the DISC1 locus in 653 cases and 889 controls. We report 2718 validated single-nucleotide polymorphisms (SNPs) of which 2010 have a minor allele frequency of <1%. Only 38% of these variants are reported in the 1000 Genomes Project European subset. This suggests that many DISC1 SNPs remain undiscovered and are essentially private. Rare coding variants identified exclusively in patients were found in likely functional protein domains. Significant region-wide association was observed between rs16856199 and rMDD (P=0.026, unadjusted P=6.3 * 10(-5), OR=3.48). This was not replicated in additional recurrent major depression samples (replication P=0.11). Combined analysis of both the original and replication set supported the original association (P=0.0058, OR=1.46). Evidence for segregation of this variant with disease in families was limited to those of rMDD individuals referred from primary care. Burden analysis for coding and non-coding variants gave nominal associations with diagnosis and measures of mood and cognition. Together, these observations are likely to generalise to other candidate genes for major mental illness and may thus provide guidelines for the design of future studies. PMID- 23732878 TI - Childhood cognitive ability accounts for associations between cognitive ability and brain cortical thickness in old age. AB - Associations between brain cortical tissue volume and cognitive function in old age are frequently interpreted as suggesting that preservation of cortical tissue is the foundation of successful cognitive aging. However, this association could also, in part, reflect a lifelong association between cognitive ability and cortical tissue. We analyzed data on 588 subjects from the Lothian Birth Cohort 1936 who had intelligence quotient (IQ) scores from the same cognitive test available at both 11 and 70 years of age as well as high-resolution brain magnetic resonance imaging data obtained at approximately 73 years of age. Cortical thickness was estimated at 81 924 sampling points across the cortex for each subject using an automated pipeline. Multiple regression was used to assess associations between cortical thickness and the IQ measures at 11 and 70 years. Childhood IQ accounted for more than two-third of the association between IQ at 70 years and cortical thickness measured at age 73 years. This warns against ascribing a causal interpretation to the association between cognitive ability and cortical tissue in old age based on assumptions about, and exclusive reference to, the aging process and any associated disease. Without early-life measures of cognitive ability, it would have been tempting to conclude that preservation of cortical thickness in old age is a foundation for successful cognitive aging when, instead, it is a lifelong association. This being said, results should not be construed as meaning that all studies on aging require direct measures of childhood IQ, but as suggesting that proxy measures of prior cognitive function can be useful to take into consideration. PMID- 23732879 TI - Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle derived induced pluripotent stem cells of schizophrenia patients. AB - One of the prevailing hypotheses suggests schizophrenia as a neurodevelopmental disorder, involving dysfunction of dopaminergic and glutamatergic systems. Accumulating evidence suggests mitochondria as an additional pathological factor in schizophrenia. An attractive model to study processes related to neurodevelopment in schizophrenia is reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) and differentiating them into different neuronal lineages. iPSCs from three schizophrenia patients and from two controls were reprogrammed from hair follicle keratinocytes, because of their accessibility and common ectodermal origin with neurons. iPSCs were differentiated into Pax6(+)/Nestin(+) neural precursors and then further differentiated into beta3 Tubulin(+)/tyrosine hydroxylase(+)/DAT(+) dopaminergic neurons. In addition, iPSCs were differentiated through embryonic bodies into beta3-Tubulin(+)/Tbox brain1(+) glutamatergic neurons. Schizophrenia-derived dopaminergic cells showed severely impaired ability to differentiate, whereas glutamatergic cells were unable to maturate. Mitochondrial respiration and its sensitivity to dopamine induced inhibition were impaired in schizophrenia-derived keratinocytes and iPSCs. Moreover, we observed dissipation of mitochondrial membrane potential (Deltapsim) and perturbations in mitochondrial network structure and connectivity in dopaminergic along the differentiation process and in glutamatergic cells. Our data unravel perturbations in neural differentiation and mitochondrial function, which may be interconnected, and of relevance to dysfunctional neurodevelopmental processes in schizophrenia. PMID- 23732880 TI - Getting the drift: methyl bromide application and adverse birth outcomes in an agricultural area. PMID- 23732881 TI - Tinnitus and musical hallucinosis: the same but more. AB - While tinnitus can be interpreted as a simple or elementary form of auditory phantom perception, musical hallucinosis is a more complex auditory phantom phenomenon not only limited to sound perception, but also containing semantic and musical content. It most often occurs in association with hearing loss. To elucidate the relation between simple and complex auditory phantom percepts a source localized electroencephalography (EEG) study is performed. The analyses showed in both simple and complex auditory phantoms an increase in theta-gamma activity and coupling within the auditory cortex that could be associated with the thalamocortical dysrhythmia model. Furthermore increased beta activity within the dorsal anterior cingulate cortex and anterior insula is demonstrated, that might be related to auditory awareness, salience and its attribution to an external sound source. The difference between simple and complex auditory phantoms relies on differential alpha band activity within the auditory cortex and on beta activity in the dorsal anterior cingulate cortex and (para)hippocampal area. This could be related to memory based load dependency, while suppression within the primary visual cortex might be due the presence of a continuous auditory cortex activation inducing an inhibitory signal to the visual system. Complex auditory phantoms further activate the right inferior frontal area (right sided Broca homolog) and right superior temporal pole that might be associated with the musical content. In summary, this study showed for the first time that simple and complex auditory phantoms might share a common neural substrate but differ as complex auditory phantoms are associated with activation in brain areas related to music and language processing. PMID- 23732882 TI - Auditory-motor synchronization facilitates attention allocation. AB - Temporal predictability of auditory events induces larger P300 amplitudes and shorter P300 latencies compared to stimulus presentation with variable onset asynchronies. This suggests that periodic stimuli lead to neuronal entrainment resulting in a more efficient allocation of attentional resources. Simultaneous synchronized motor activity should facilitate the precise temporal encoding of acoustic sequences. Therefore the current event-related potential study investigated whether embodied stimulus encoding enhances the reported effects of stimulus periodicity. We found that simultaneous pedaling on an ergometer compared to a physically passive situation amplified the predictability effect on the P300 component. Furthermore, the temporal variability of cycling behavior correlated positively with both P300 latency and P300 amplitude. These findings indicate that auditory-motor synchronization enhances the attentional processing of periodical auditory stimuli. PMID- 23732883 TI - EEG-fMRI integration for the study of human brain function. AB - Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have proved to be extremely valuable tools for the non-invasive study of human brain function. Moreover, due to a notable degree of complementarity between the two modalities, the combination of EEG and fMRI data has been actively sought in the last two decades. Although initially focused on epilepsy, EEG-fMRI applications were rapidly extended to the study of healthy brain function, yielding new insights into its underlying mechanisms and pathways. Nevertheless, EEG and fMRI have markedly different spatial and temporal resolutions, and probe neuronal activity through distinct biophysical processes, many aspects of which are still poorly understood. The remarkable conceptual and methodological challenges associated with EEG-fMRI integration have motivated the development of a wide range of analysis approaches over the years, each relying on more or less restrictive assumptions, and aiming to shed further light on the mechanisms of brain function along with those of the EEG-fMRI coupling itself. Here, we present a review of the most relevant EEG-fMRI integration approaches yet proposed for the study of brain function, supported by a general overview of our current understanding of the biophysical mechanisms coupling the signals obtained from the two modalities. PMID- 23732884 TI - Beta coherence within human ventromedial prefrontal cortex precedes affective value choices. AB - Ventromedial prefrontal cortex (vmPFC) forms a core region of larger brain circuits that assign value to sensory inputs and interfaces motivational and cognitive dominated brain processes. This network function of the vmPFC could be realized by synchronizing local activity at time scales that are shared by connected brain areas, but it is unknown whether vmPFC circuitry engages in functionally specific synchronization. Here, we recorded in human subcallosal vmPFC while subjects engaged in an emotion tracking task that required the assignment of positive or negative affective value to ambiguous (happy-sad) facial expressions. We found that vmPFC engages in low beta-band (15-20 Hz) coherent activation just before subjects subjectively judged ambiguous facial expressions as conveying negative valence ('sad') information, but not before positive valence ('happy') judgments. The predictive beta coherence emerged particularly for conflicting rather than pure emotional facial cues and dissipated slowly after the choice was made. These results suggest that 15-20 Hz coherent activity within vmPFC marks a functional signature of a valuation process that informs categorical affective choices. We hypothesize that coherent beta band activation signifies functional interactions to anatomical vmPFC projection targets, raising the possibility that dysfunctional biases in affective valuation and an enhanced decision conflict in clinical depression could be indexed by alterations of beta coherent network activation. PMID- 23732885 TI - Adaptation of cerebral oxygen metabolism and blood flow and modulation of neurovascular coupling with prolonged stimulation in human visual cortex. AB - Prolonged visual stimulation results in neurophysiologic and hemodynamic adaptation. However, the hemodynamic adaptation appears to be small compared to neural adaptation. It is not clear how the cerebral metabolic rate of oxygen (CMRO2) is affected by adaptation. We measured cerebral blood flow (CBF) and CMRO2 change in responses to peripheral stimulation either continuously, or intermittently (on/off cycles). A linear system's response to the continuous input should be equal to the sum of the original response to the intermittent input and a version of that response shifted by half a cycle. The CMRO2 response showed a large non-linearity consistent with adaptation, the CBF response adapted to a lesser degree, and the blood oxygenation level dependent (BOLD) response was nearly linear. The metabolic response was coupled with a larger flow in the continuous condition than in the intermittent condition. Our results suggest that contrast adaptation improves energy economy of visual processing. However BOLD modulations may not accurately represent the underlying metabolic nonlinearity due to modulation of the coupling of blood flow and oxygen metabolism changes. PMID- 23732887 TI - Dynamic changes in parietal activation during encoding: implications for human learning and memory. AB - The ventral posterior parietal cortex (vPPC) monitors successful memory retrieval, yet its role during learning remains unclear. Indeed, increased vPPC activation during stimulus encoding is often negatively correlated with subsequent memory performance, suggesting that this region is suppressed during learning. Alternatively, the vPPC may engage in learning-related processes immediately after stimulus encoding thus facilitating retrieval at a later time. To investigate this possibility, we assessed vPPC activity during item presentation and immediately following its offset when a cue to remember was presented. We observed a dynamic change in vPPC response such that activity was negatively correlated with subsequent memory during stimulus presentation but positively correlated immediately following the stimulus during the cue phase. Furthermore, regional differences in this effect suggest a degree of functional heterogeneity within the vPPC. These findings demonstrate that the vPPC is engaged during learning and acts to facilitate post-encoding memory processes that establish long-term cortical representations. PMID- 23732886 TI - Statistical analysis of high density diffuse optical tomography. AB - High density diffuse optical tomography (HD-DOT) is a noninvasive neuroimaging modality with moderate spatial resolution and localization accuracy. Due to portability and wear-ability advantages, HD-DOT has the potential to be used in populations that are not amenable to functional magnetic resonance imaging (fMRI), such as hospitalized patients and young children. However, whereas the use of event-related stimuli designs, general linear model (GLM) analysis, and imaging statistics are standardized and routine with fMRI, such tools are not yet common practice in HD-DOT. In this paper we adapt and optimize fundamental elements of fMRI analysis for application to HD-DOT. We show the use of event related protocols and GLM de-convolution analysis in un-mixing multi-stimuli event-related HD-DOT data. Statistical parametric mapping (SPM) in the framework of a general linear model is developed considering the temporal and spatial characteristics of HD-DOT data. The statistical analysis utilizes a random field noise model that incorporates estimates of the local temporal and spatial correlations of the GLM residuals. The multiple-comparison problem is addressed using a cluster analysis based on non-stationary Gaussian random field theory. These analysis tools provide access to a wide range of experimental designs necessary for the study of the complex brain functions. In addition, they provide a foundation for understanding and interpreting HD-DOT results with quantitative estimates for the statistical significance of detected activation foci. PMID- 23732888 TI - De novo sequence analysis of cytochrome P450 1-3 genes expressed in ostrich liver with highest expression of CYP2G19. AB - The cytochrome P450 (CYP) 1-3 families are involved in xenobiotic metabolism, and are expressed primarily in the liver. Ostriches (Struthio camelus) are members of Palaeognathae with the earliest divergence from other bird lineages. An understanding of genes coding for ostrich xenobiotic metabolizing enzyme contributes to knowledge regarding the xenobiotic metabolisms of other Palaeognathae birds. We investigated CYP1-3 genes expressed in female ostrich liver using a next-generation sequencer. We detected 10 CYP genes: CYP1A5, CYP2C23, CYP2C45, CYP2D49, CYP2G19, CYP2W2, CYP2AC1, CYP2AC2, CYP2AF1, and CYP3A37. We compared the gene expression levels of CYP1A5, CYP2C23, CYP2C45, CYP2D49, CYP2G19, CYP2AF1, and CYP3A37 in ostrich liver and determined that CYP2G19 exhibited the highest expression level. The mRNA expression level of CYP2G19 was approximately 2-10 times higher than those of other CYP genes. The other CYP genes displayed similar expression levels. Our results suggest that CYP2G19, which has not been a focus of previous bird studies, has an important role in ostrich xenobiotic metabolism. PMID- 23732890 TI - Improving vaccine uptake: an overview. AB - A task group was formed with the aim to improve the quality of the service offered by ensuring that all children waiting for an appointment for vaccination would be offered one at the earliest opportunity. Children aged between 12 mo-5 y that were not completely immunized for their age were identified and included in a pilot catch-up session. Following evaluation of the pilot session, four further immunization sessions were delivered. A total of 398 children attended the four sessions, representing an improved attendance rate of 39%. Most parents brought their children between 11 am-3 pm and 728 vaccines were administered: 339 MMR; 255 Pre-school boosters; 53 Hib/MenC and 81 PCV. Uptake of MMR vaccine in the PCT at age 24 mo increased by 9% by Q3 2008. For children aged five years, uptake of the first dose of MMR vaccine increased from 91.9% to 94% for the first dose and from 82.3 to 82.5% for the second dose by Q3 2008. This project demonstrates that new ways of delivering immunization sessions can be successfully implemented which can enhance access through the use of alternative venues and subsequently lead to increased vaccine uptake. PMID- 23732891 TI - Accessing hard to reach groups, travelers and looked after children. PMID- 23732892 TI - Pneumococcal vaccination of older adults: conjugate or polysaccharide? AB - Invasive pneumococcal disease continues to be important problem for older adults. Pneumococcal polysaccharide vaccine (PPV23) has a clinical effectiveness of 43 81%, and following primary vaccination and revaccination, antibody responses last 5-10 y. Hyporesponsiveness to a second dose of vaccine has not been shown to be a significant problem. The use of pneumococcal conjugate vaccines (initially PCV7; more recently PCV13) has led to a dramatic fall in the incidence of conjugate vaccine-type invasive pneumococcal disease in children. Because PCVs are immunogenic in older adults, the question has arisen as to whether to also use PCVs in this age group. However, PCV vaccination of children has also reduced the incidence of conjugate vaccine-serotype disease in older adults, and so wherever PCVs are used in children, there is no epidemiological reason to vaccinate older adults with PCV. The cost-effectiveness of PPV for older adults has changed wherever PCVs have been used for children, and this needs to be periodically re evaluated. PMID- 23732893 TI - Should childhood MMR vaccination be compulsory? Rights, duties and the public interest. AB - When children and young people lack the capacity to make decisions about their care and treatment, decisions have to be made on their behalf based on an assessment of their welfare or interests. In law, parents, or others with the relevant parental responsibility, are ordinarily regarded as the appropriate decision-makers. One way of framing this is to say that parents have certain decision-making rights with respect to their children. Such rights, however, are not generally regarded as absolute, rather they can be seen as secondary to and limited by the duties that parents have with regard to their children, duties to promote their welfare. It is against these parental duties that children could, at least in theory if not in practice, claim a right to certain kinds of protection. The legal rights of parents here, as opposed to the rights of the children, can be thought of as rights that secure for parents the freedom from interference necessary to fulfill the underlying duty. PMID- 23732895 TI - The evidence for use of pneumococcal conjugate over polysaccharide in children. AB - Pneumococcal glycoconjugate vaccines are now used in infant immunization schedules, globally. Pneumococcal polysaccharide vaccines are still, however, advised from the second year of life to provide broader serotype coverage. The use of these polysaccharide vaccines has been under review, especially for children. PMID- 23732894 TI - Meningococcal group B vaccines. AB - Meningococcal disease remains a devastating and feared infection with a significant morbidity and mortality profile. The successful impact of meningococcal capsular group C glyconconjugate vaccines introduced into the UK infant immunization schedule in 1999, has resulted in >80% of disease now being attributable to meningococcal capsular group B (MenB). MenB glyconconjugate vaccines are not immunogenic and hence, vaccine design has focused on sub capsular antigens. Recently, a four component vaccine to combat MenB disease (4CMenB) has progressed through clinical development and was approved by the European Medicines Agency at the end of 2012. This vaccine has proven safe and immunogenic and has been predicted to provide protection against ~73% of the MenB disease from England and Wales. Recommendation/implementation of the vaccine into the UK infant schedule is currently being evaluated. 4CMenB has the potential to provide protection against a significant proportion of MenB disease in the UK which is currently unpreventable. PMID- 23732896 TI - The epidemiological characteristics of measles and difficulties of measles elimination in Hang Zhou, China. AB - OBJECTIVE: Following the national proclaim of Measles Elimination 2012, plenty of activities for controlling the incidence had practiced in Hangzhou. However, the incidence did not decrease to low degree and remained perform as gap to the elimination target. The present study aimed to describe the epidemiological characteristics of measles, and proposed reasonable method to the target in Hangzhou. METHOD: Cases were collected by the National Notifiable Diseases Surveillance System (NNDSS) from 2004 to 2011. The descriptive epidemiology was employed to analyze characteristics of measles. RESULTS: A total of 4712 confirmed cases were enrolled by the NNDSS with 7.87 per 100,000 people of incidence rate on average from 2004 to 2011. Individuals lived urban districts had higher risk of measles than counties. Infants aged<1 year observed the highest incidence rate with 239.35/100,000, and the age-specific incidence rate declined along with aged-group but reversed at adults. 52.20% of cases were floating cases and the measles vaccination was significantly different from the local cases (chi(2)=51.65, p< 0.001). February to June was the epidemic period for measles incidence with 81.88% of cases reported in cluster. CONCLUSION: The descriptive characteristics of measles suggested that factors included infant and adult individual, floating population, and living urban area might be relate to the elimination target. More efforts were need to ensure susceptible population had accepted qualified measles vaccination. PMID- 23732897 TI - Report from the field: Overview of the Sixth Annual Vaccine Renaissance Conference. AB - The Sixth Annual Vaccine Renaissance Conference, hosted by the Institute for Immunology and Informatics (iCubed) at the University of Rhode Island (URI), took place on October 15-17, 2012. This conference provides a forum for the review of current progress in the discovery and development of vaccines, and creates an environment for the exchange of ideas. Dr. Joel McCleary opened the conference with a warning about the importance of preparing for well-defined biowarfare threats, including tularemia and Staphylococcal enterotoxin B. Following the keynote address, sessions explored biodefense and preparation for pandemic and biowarfare threats; vaccines for emerging and re-emerging neglected tropical diseases; animal vaccines and human health; and vaccine vectors and the human microbiome. In this issue of Human Vaccines and Immunotherapeutics, seven Vaccine Renaissance Conference speakers will showcase their work; here, we describe a few of the conference highlights. PMID- 23732898 TI - Attitude of Italian physicians toward pertussis diagnosis. AB - Resurgence of pertussis has been observed in several countries whereas Italy continues to be a low incidence country. We hypothesize that the low reported incidence of pertussis in Italy could be biased by the attitude of physicians to suspect and diagnose pertussis in different age groups. We investigated the attitude of Italian physicians toward pertussis diagnosis through clinical scenarios. A cross-sectional study was conducted in June 2012 sending online questionnaires to pediatricians and general practitioners (GPs) involved in ambulatory primary care. The questionnaire included five clinical scenarios of patients of different ages (45 d, 5 y, 11 y, 24 y, 58 y) with prolonged cough of at least 2 weeks. Respondents were asked to choose a diagnosis among a list of 14. We observed a decreasing trend of suspected pertussis diagnosis with increasing age of the patient (from 46% at 45 d to 0 at 58 y). In Italy pertussis is seldom suspected in the differential diagnosis of cough particularly in adults. This may cause a significant under-notification of pertussis, with a higher impact in older age groups. Educational programs should be reinforced to consider the differential diagnosis of pertussis in individuals with atypical presentation and in older age groups. PMID- 23732899 TI - Divergent contributions of regulatory T cells to the pathogenesis of chronic hepatitis C. AB - Hepatitis C virus, a small single-stranded RNA virus, is a major cause of chronic liver disease. Resolution of primary hepatitis C virus infections depends upon the vigorous responses of CD4(+) and CD8(+) T cells to multiple viral epitopes. Although such broad CD4(+) and CD8(+) T-cell responses are readily detected early during the course of infection regardless of clinical outcome, they are not maintained in individuals who develop chronic disease. Purportedly, a variety of factors contribute to the diminished T-cell responses observed in chronic, virus infected patients including the induction of and biological suppression by CD4(+)FoxP3(+) regulatory T cells. Indeed, a wealth of evidence suggests that regulatory T cells play diverse roles in the pathogenesis of chronic hepatitis C, impairing the effector T-cell response and viral clearance early during the course of infection and suppressing liver injury as the disease progresses. The factors that affect the generation and biological response of regulatory T cells in chronic, hepatitis C virus-infected patients is discussed. PMID- 23732901 TI - HPV vaccination coverage among women aged 18-20 years in Germany three years after recommendation of HPV vaccination for adolescent girls: results from a cross-sectional survey. AB - OBJECTIVE: Routine immunization of adolescent girls aged 12-17 y against human papillomavirus (HPV) was recommended in Germany in March 2007. We aimed to assess HPV-vaccine uptake and knowledge about post-vaccination cervical cancer screening and condom use in women aged 18-20 years, three years after adoption of HPV vaccination into the routine vaccination schedule. RESULTS: Overall 2,001 females participated in our study. Of these, 49% reported receipt of a complete three dose course of HPV-vaccines; 11% received 1 or 2 doses. Living in East Germany, high educational status, and interest in health-related issues were independently associated with HPV-vaccination. Misconceptions among survey-participants were rare: Only 8% believed that HPV-vaccination would obviate the need for cervical screening and 1% that condom use would be dispensible after vaccination. METHODS: In 2010, a nationwide cross-sectional telephone-survey was performed among randomly-selected women aged 18-20 years living in Germany. Telephone interviews were conducted by a large professional market research institute as part of a daily omnibus survey. CONCLUSION: HPV-vaccination coverage is low in Germany. The results indicate that there is an urgent need for the implementation of a coordinated adolescent vaccination program to facilitate access to vaccination, including balanced information tailored to this age group. Otherwise, the HPV vaccination effort will fall short of reaching its maximum public health benefit. PMID- 23732900 TI - Influenza vaccines in low and middle income countries: a systematic review of economic evaluations. AB - OBJECTIVES: Economic evaluations on influenza vaccination from low resource settings are scarce and have not been evaluated using a systematic approach. Our objective was to conduct a systematic review on the value for money of influenza vaccination in low- and middle-income countries. METHODS: PubMed and EMBASE were searched for economic evaluations published in any language between 1960 and 2011. Main outcome measures were costs per influenza outcome averted, costs per quality-adjusted life years gained or disability-adjusted life years averted, costs per benefit in monetary units or cost-benefit ratios. RESULTS: Nine economic evaluations on seasonal influenza vaccine met the inclusion criteria. These were model- or randomized-controlled-trial (RCT)-based economic evaluations from middle-income countries. Influenza vaccination provided value for money for elderly, infants, adults and children with high-risk conditions. Vaccination was cost-effective and cost-saving for chronic obstructive pulmonary disease patients and in elderly above 65 y from model-based evaluations, but conclusions from RCTs on elderly varied. CONCLUSION: Economic evaluations from middle income regions differed in population studied, outcomes and definitions used. Most findings are in line with evidence from high-income countries highlighting that influenza vaccine is likely to provide value for money. However, serious methodological limitations do not allow drawing conclusions on cost-effectiveness of influenza vaccination in middle income countries. Evidence on cost-effectiveness from low income countries is lacking altogether, and more information is needed from full economic evaluations that are conducted in a standardized manner. PMID- 23732902 TI - Addressing heterogeneous parental concerns about vaccination with a multiple source model: a parent and educator perspective. AB - Previous models of vaccine education have not addressed differences in levels and motives of vaccine concerns in parents. These differences may require changes in education approaches based on type of parental concern. Addressing vaccine concerns will require a multi-modal approach involving more than just a pediatrician or primary health care provider, as well as more than one educational approach. PMID- 23732903 TI - Efficacy and safety of pentavalent rotavirus vaccine in Japan: a randomized, double-blind, placebo-controlled, multicenter trial. AB - Rotavirus is the most common cause of severe gastroenteritis in children under 5 y of age. Estimates of disease burden in Japan suggest that between 26,500 and 78,000 children in this age group need hospitalization each year, resulting in a direct medical cost of 10 to 24 billion Yen. Since being introduced in routine infant immunization schedules in the United States in 2006, the oral live pentavalent rotavirus vaccine RV5 (RotaTeqTM) has contributed to dramatic reductions in the incidence of rotavirus gastroenteritis (RVGE) and in health care resource utilization. This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of a 3-dose regimen of RV5 in healthy infants, age 6 to 12 weeks, at 32 sites across Japan. The results indicate that RV5 was significantly efficacious in preventing any severity [74.5% (95% confidence interval [CI]: 39.9%, 90.6%; p<0.001)], moderate-to-severe [80.2% (95% CI: 47.4%, 94.1%)], and severe [100% (95% CI: 55.4%, 100%)] RVGE caused by viruses with serotypes contained in the vaccine. The observed cases of RVGE included rotavirus types G1 (n=19), G3 (n=9), G9 (n=5) and one unspecified G serotype with P1A[8]. No G2 or G4 RVGE cases were observed, and this study was not powered to evaluate efficacy against individual serotypes. RV5 was generally safe and well tolerated in Japanese infants. These results are comparable to those observed in clinical studies conducted in other developed countries. Introduction of the vaccine in Japan may reduce disease burden and associated health care costs. PMID- 23732904 TI - Long-term anti-HBs antibody persistence following infant vaccination against hepatitis B and evaluation of anamnestic response: a 20-year follow-up study in Thailand. AB - Hepatitis B vaccine has been available worldwide since the mid-1980s. This vaccine was evaluated in a clinical trial in Thailand, conducted on subjects born to hepatitis B surface antigen positive and hepatitis B e-antigen positive mothers and vaccinated according to a 4-dose schedule at 0, 1, 2 and 12 mo of age and a single dose of hepatitis B immunoglobulin concomitantly at birth. All enrolled subjects seroconverted and were followed for 20 y to assess the persistence of antibody to the hepatitis B surface antigen (anti-HBs) (NCT00240539). At year 20, 64% of subjects had anti-HBs antibody concentrations>=10 milli-international units per milli liter (mIU/ml) and 92% of subjects had detectable levels (>=3.3 mIU/ml) of anti-HBs antibodies. At year 20, subjects with anti-HBs antibody titer<100 mIU/ml were offered an additional dose of hepatitis B virus (HBV) vaccine to assess immune memory (NCT00657657). Anamnestic response to the challenge dose was observed in 96.6% of subjects with an 82-fold (13.2 to 1082.4 mIU/ml) increase in anti-HBs antibody geometric mean concentrations. This study confirms the long-term immunogenicity of the 4-dose regimen of the HBV vaccine eliciting long-term persistence of antibodies and immune memory against hepatitis B for up to at least 20 y after vaccination. PMID- 23732905 TI - Immunotherapeutic efficiency of a tetravalent Abeta1-15 vaccine in APP/PS1 transgenic mice as mouse model for Alzheimer's disease. AB - Immunization with synthetic, preaggregated beta-amyloid (Abeta) was the first treatment approach able to dramatically reduce brain Abeta pathology in Alzheimer's disease (AD) animal models. For the development of a safe vaccine, we investigated whether 4Abeta1-15 (four tandem repeats of GPGPG-linked Abeta1-15 sequences) had therapeutic effects in the APP/PS1 transgenic mice model of AD. We described the production of anti-Abeta antibodies in APP/PS1 mice immunized with 4Abeta1-15 mixed with MF59 adjuvant. The anti-Abeta antibody concentrations were increased which bound to AD plaques, markedly reduced Abeta pathology in transgenic AD mice and levels of intracerebral Abeta (soluble and insoluble), whereas increased serum Abeta levels. Immunization via 4Abeta1-15 (mainly of the IgG1 Class) may induce a non-inflammatory Th2 reaction. Immunohistochemistry analysis of MHC Class II and CD45 revealed that microglial cells were in a less activated state. Of note, 4Abeta1-15-immunized mice showed improved acquisition of memory compared with controls in a reference-memory Morris water-maze behavior test. The data identify the novel immunogen 4Abeta1-15 as a promising new tool for AD immunotherapy. PMID- 23732907 TI - The potential of 1018 ISS adjuvant in hepatitis B vaccines: HEPLISAVTM review. AB - Hepatitis B (HBV) virus infects the liver, and upon chronic infection, can cause liver cirrhosis and hepatocellular carcinoma. Despite universal vaccination programs against the virus, HBV still affects over 2 billion people worldwide, with over 240 million developing a chronic infection. While current alum adjuvanted vaccines have shown efficacy in promoting seroprotection in healthy adults, 5-10% of immune-competent populations fail to achieve long-lasting seroprotection from these formulations. Furthermore, a large proportion of immunocompromised patients fail to achieve seroprotective antibody titers after receiving these vaccines. A novel vaccine candidate, HEPLISAVTM, uses immunostimulatory sequences (ISS), in its formulation that helps induce a robust humoral and cell mediated immunity against HBV. In Phase III clinical trials, HEPLISAVTM has been shown to elicit seroprotective antibody titers with fewer immunizations. Similar safety profiles are demonstrated when compared with current HBV vaccines. For these reasons, HEPLISAVTM is an attractive vaccine to combat this global disease. PMID- 23732908 TI - Anal human papillomavirus infection among HIV-infected and uninfected men who have sex with men in Beijing, China. AB - BACKGROUND: In light of China's unique ethnic and sociocultural context, and a marked rise in HIV prevalence among MSM, it is important to determine prevalence, genotypes and predictors of anal human papillomavirus (HPV) among HIV-infected and uninfected men who have sex with men (MSM) in Beijing, China. METHODS: In 2010-2011, we recruited MSM (age range 18-61; median 28 years) through peer volunteers, and collected demographic/behavioral information via interviewer administrated questionnaires. Trained health workers collected anal swabs for HPV genotyping by PCR and blood samples for HIV/syphilis serologies. RESULTS: We obtained anal specimens from 212 HIV-infected and 459 HIV-uninfected participants. Among HIV-infected MSM, 82.1% were HPV-infected vs. 57.5% in HIV uninfected (p<0.01). HIV-infected men had the greatest likelihood of multiple types: 17.9% uninfected; 36.3% with one type; 36.8% with 2-3; 9.0% with >=4. Oncogenic HPV prevalence was higher among HIV- infected (61.3%) than uninfected participants (39.7%; p<0.01). HIV-uninfected MSM reporting always using condoms during insertive anal intercourse (past 6 months) were less likely to be HPV infected (OR=0.49, 95%CI: 0.31-0.77). Among HIV-uninfected MSM, HPV infection was associated with unprotected receptive anal intercourse (past 6 months; OR=1.92, 95%CI: 1.19-3.11) and being forced to have sex (previous year; OR=3.32, 95%CI: 1.10-10.0). Multivariable logistic analysis among HIV infected MSM suggested that unprotected oral intercourse (past 6 months) was associated with HPV (adjusted OR=2.12, 95%CI: 1.00-4.48). Syphilis occurred in 55.8% of HIV-infected/HPV infected, 50.0% of HIV-infected/HPV-uninfected, 19.6% of HIV-uninfected/HPV infected, and 13.0% of HIV-uninfected/HPV-uninfected MSM. CONCLUSIONS: HPV anal infections were more common among HIV-infected than uninfected MSM in China, including oncogenic and multiple types. Unprotected oral and receptive anal sex were was independently associated with HPV infection. Promotion of safer sex and HPV vaccination is strongly recommended among MSM. PMID- 23732909 TI - EGLN3 inhibition of NF-kappaB is mediated by prolyl hydroxylase-independent inhibition of IkappaB kinase gamma ubiquitination. AB - NF-kappaB transcription factors are crucial regulators of inflammation, immunity, stress responses, and cell differentiation. Many studies have demonstrated that ubiquitination of IkappaB kinase gamma (IKKgamma), a regulatory subunit of IKK, is instrumental in the activation of IKK and NF-kappaB. We and others previously identified EGLN3, a member of a family of prolyl hydroxylases, as a negative regulator of the NF-kappaB pathway. Here we report that EGLN3, but not EGLN1 or 2, interacts with and inhibits K63-linked ubiquitination of IKKgamma. The effect appears to be related to inhibition of IKKgamma ubiquitination mediated by cIAP1 rather than to stimulation of IKKgamma deubiquitination by the deubiquitinases A20 and CYLD (cylindromatosis). EGLN3 does not affect the protein levels of cIAP1 or its E2 ubiquitin-conjugating enzymes UbcH5 and Ubc13. EGLN3 hydroxylase activity is not responsible for its effect on IKKgamma ubiquitination and NF kappaB signaling. Instead, interaction with IKKgamma is required for the ability of EGLN3 to inhibit IKKgamma ubiquitination and IKK-NF-kappaB signaling. EGLN3 competes with cIAP1 for IKKgamma binding, leading to inhibition of cIAP1-IKKgamma interaction, IKKgamma ubiquitination, and IKK-NF-kappaB signaling. This study provides novel insights into EGLN3 function and sheds new light on the regulation of IKKgamma ubiquitination and NF-kappaB. PMID- 23732910 TI - Direct protein interactions are responsible for Ikaros-GATA and Ikaros-Cdk9 cooperativeness in hematopoietic cells. AB - Ikaros (Ik) is a critical regulator of hematopoietic gene expression. Here, we established that the Ik interactions with GATA transcription factors and cyclin dependent kinase 9 (Cdk9), a component of the positive transcription elongation factor b (P-TEFb), are required for transcriptional activation of Ik target genes. A detailed dissection of Ik-GATA and Ik-Cdk9 protein interactions indicated that the C-terminal zinc finger domain of Ik interacts directly with the C-terminal zinc fingers of GATA1, GATA2, and GATA3, whereas the N-terminal zinc finger domain of Ik is required for interaction with the kinase and T-loop domains of Cdk9. The relevance of these interactions was demonstrated in vivo in COS-7 and primary hematopoietic cells, in which Ik facilitated Cdk9 and GATA protein recruitment to gene promoters and transcriptional activation. Moreover, the oncogenic isoform Ik6 did not efficiently interact with Cdk9 or GATA proteins in vivo and perturbed Cdk9/P-TEFb recruitment to Ik target genes, thereby affecting transcription elongation. Finally, characterization of a novel nuclear Ik isoform revealed that Ik exon 6 is dispensable for interactions with Mi2 and GATA proteins but is essential for the Cdk9 interaction. Thus, Ik is central to the Ik-GATA-Cdk9 regulatory network, which is broadly utilized for gene regulation in hematopoietic cells. PMID- 23732911 TI - A stress-activated, p38 mitogen-activated protein kinase-ATF/CREB pathway regulates posttranscriptional, sequence-dependent decay of target RNAs. AB - Broadly conserved, mitogen-activated/stress-activated protein kinases (MAPK/SAPK) of the p38 family regulate multiple cellular processes. They transduce signals via dimeric, basic leucine zipper (bZIP) transcription factors of the ATF/CREB family (such as Atf2, Fos, and Jun) to regulate the transcription of target genes. We report additional mechanisms for gene regulation by such pathways exerted through RNA stability controls. The Spc1 (Sty1/Phh1) kinase-regulated Atf1-Pcr1 (Mts1-Mts2) heterodimer of the fission yeast Schizosaccharomyces pombe controls the stress-induced, posttranscriptional stability and decay of sets of target RNAs. Whole transcriptome RNA sequencing data revealed that decay is associated nonrandomly with transcripts that contain an M26 sequence motif. Moreover, the ablation of an M26 sequence motif in a target mRNA is sufficient to block its stress-induced loss. Conversely, engineered M26 motifs can render a stable mRNA into one that is targeted for decay. This stress-activated RNA decay (SARD) provides a mechanism for reducing the expression of target genes without shutting off transcription itself. Thus, a single p38-ATF/CREB signal transduction pathway can coordinately induce (promote transcription and RNA stability) and repress (promote RNA decay) transcript levels for distinct sets of genes, as is required for developmental decisions in response to stress and other stimuli. PMID- 23732912 TI - Single quantum dot tracking reveals that an individual multivalent HIV-1 Tat protein transduction domain can activate machinery for lateral transport and endocytosis. AB - The mechanisms underlying the cellular entry of the HIV-1 Tat protein transduction domain (TatP) and the molecular information necessary to improve the transduction efficiency of TatP remain unclear due to the technical limitations for direct visualization of TatP's behavior in cells. Using confocal microscopy, total internal reflection fluorescence microscopy, and four-dimensional microscopy, we developed a single-molecule tracking assay for TatP labeled with quantum dots (QDs) to examine the kinetics of TatP initially and immediately before, at the beginning of, and immediately after entry into living cells. We report that even when the number of multivalent TatP (mTatP)-QDs bound to a cell was low, each single mTatP-QD first locally induced the cell's lateral transport machinery to move the mTatP-QD toward the center of the cell body upon cross linking of heparan sulfate proteoglycans. The centripetal and lateral movements were linked to the integrity and flow of actomyosin and microtubules. Individual mTatP underwent lipid raft-mediated temporal confinement, followed by complete immobilization, which ultimately led to endocytotic internalization. However, bivalent TatP did not sufficiently promote either cell surface movement or internalization. Together, these findings provide clues regarding the mechanisms of TatP cell entry and indicate that increasing the valence of TatP on nanoparticles allows them to behave as cargo delivery nanomachines. PMID- 23732914 TI - PD-1 increases PTEN phosphatase activity while decreasing PTEN protein stability by inhibiting casein kinase 2. AB - Programmed death 1 (PD-1) is a potent inhibitor of T cell responses. PD-1 abrogates activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, but the mechanism remains unclear. We determined that during T cell receptor (TCR)/CD3- and CD28-mediated stimulation, PTEN is phosphorylated by casein kinase 2 (CK2) in the Ser380-Thr382-Thr383 cluster within the C-terminal regulatory domain, which stabilizes PTEN, resulting in increased protein abundance but suppressed PTEN phosphatase activity. PD-1 inhibited the stabilizing phosphorylation of the Ser380-Thr382-Thr383 cluster within the C-terminal domain of PTEN, thereby resulting in ubiquitin-dependent degradation and diminished abundance of PTEN protein but increased PTEN phosphatase activity. These effects on PTEN were secondary to PD-1-mediated inhibition of CK2 and were recapitulated by pharmacologic inhibition of CK2 during TCR/CD3- and CD28-mediated stimulation without PD-1. Furthermore, PD-1-mediated diminished abundance of PTEN was reversed by inhibition of ubiquitin-dependent proteasomal degradation. Our results identify CK2 as a new target of PD-1 and reveal an unexpected mechanism by which PD-1 decreases PTEN protein expression while increasing PTEN activity, thereby inhibiting the PI3K/Akt signaling axis. PMID- 23732913 TI - ADAM17 controls endochondral ossification by regulating terminal differentiation of chondrocytes. AB - Endochondral ossification is a highly regulated process that relies on properly orchestrated cell-cell interactions in the developing growth plate. This study is focused on understanding the role of a crucial regulator of cell-cell interactions, the membrane-anchored metalloproteinase ADAM17, in endochondral ossification. ADAM17 releases growth factors, cytokines, and other membrane proteins from cells and is essential for epidermal growth factor receptor (EGFR) signaling and for processing tumor necrosis factor alpha. Here, we report that mice lacking ADAM17 in chondrocytes (A17DeltaCh) have a significantly expanded zone of hypertrophic chondrocytes in the growth plate and retarded growth of long bones. This abnormality is caused by an accumulation of the most terminally differentiated type of chondrocytes that produces a calcified matrix. Inactivation of ADAM17 in osteoclasts or endothelial cells does not affect the zone of hypertrophic chondrocytes, suggesting that the main role of ADAM17 in the growth plate is in chondrocytes. This notion is further supported by in vitro experiments showing enhanced hypertrophic differentiation of primary chondrocytes lacking Adam17. The enlarged zone of hypertrophic chondrocytes in A17DeltaCh mice resembles that described in mice with mutant EGFR signaling or lack of its ligand transforming growth factor alpha (TGFalpha), suggesting that ADAM17 regulates terminal differentiation of chondrocytes during endochondral ossification by activating the TGFalpha/EGFR signaling axis. PMID- 23732915 TI - Direct regularized estimation of retinal vascular oxygen tension based on an experimental model. AB - Phosphorescence lifetime imaging is commonly used to generate oxygen tension maps of retinal blood vessels by classical least squares (LS) estimation method. A spatial regularization method was later proposed and provided improved results. However, both methods obtain oxygen tension values from the estimates of intermediate variables, and do not yield an optimum estimate of oxygen tension values, due to their nonlinear dependence on the ratio of intermediate variables. In this paper, we provide an improved solution by devising a regularized direct least squares (RDLS) method that exploits available knowledge in studies that provide models of oxygen tension in retinal arteries and veins, unlike the earlier regularized LS approach where knowledge about intermediate variables is limited. The performance of the proposed RDLS method is evaluated by investigating and comparing the bias, variance, oxygen tension maps, 1-D profiles of arterial oxygen tension, and mean absolute error with those of earlier methods, and its superior performance both quantitatively and qualitatively is demonstrated. PMID- 23732916 TI - Alternative fuel production by catalytic hydroliquefaction of solid municipal wastes, primary sludges and microalgae. AB - An alternative fuel production was investigated through catalytic hydroliquefaction of three different carbonaceous sources: solid municipal wastes (MW), primary sludges (PS), and microalgae (MA). The reaction was carried out under hydrogen pressure, at different temperatures (330, 380 and 450 degrees C), with a Raney nickel catalyst and two different hydrogen donor solvents: a "fossil solvent" (tetralin) and a "green solvent" (2-methyl-hydro-furan). The feeds analyses (TDA-TGA, ICP-AES, lipids quantification) showed that MW and PS had similar characteristics and physico-chemical properties, but different from those of MA. The hydroliquefaction of these feeds allowed to obtain high oil yields, with a significant energetic value, similar to that of a bio-petroleum. 2-methyl hydro-furan was more efficient than tetralin for the treatment of the strongly bio-degraded biomasses MW and PS, while better results were obtained with tetralin in the case of MA. PMID- 23732918 TI - Screening and hydrogen-producing characters of a highly efficient H2-producing mutant of Rhodovulum sulfidophilum P5. AB - In this study, transposon mutagenesis technology was utilized to enhance the hydrogen production capability of a wild marine photosynthetic bacterium Rhodovulum sulfidophilum P5. A mutant strain TH-253 that exhibited high hydrogen yield and weaker light absorption ability was screened. Under strong light conditions, the mutant produced more hydrogen than that of the WT. Under optimum light intensity (120 MUmol photons/m(2)s), the mutant achieved its highest hydrogen yield (1,436 +/- 44 mL H2/L, about 3.21 +/- 0.10 mol H2/mol acetate), which was 40.37% higher that of the WT. In continuous operation mode, the hydrogen yield (3.59 +/- 0.11 mol H2/mol acetate) and average hydrogen production rate (16.91 +/- 0.46 mL H2/Lh) of the mutant were 43.40% and 45.07% higher than those of the WT, respectively. The mutant strain TH-253 may be used as an appropriate starting strain for future photosynthesis-based large scale hydrogen production. PMID- 23732917 TI - Biological treatment and modeling aspect of BTEX abatement process in a biofilter. AB - In the present work, a laboratory scale corn-cob based biofilter inoculated with Bacillus sphaericus (MTCC 8103) was used for degradation of BTEX for a period of 86 days. The overall performance of a biofilter evaluated in terms of its elimination capacity by using 3-D mesh technique. Maximum removal efficiency was found more than 96.43% for all four compounds in each phase of experiments. A maximum elimination capacity (EC) of 60.89 gm(-3)h(-1) of the biofilter was obtained at inlet BTEX load of 63.14 gm(-3)h(-1). The follow-up of carbon dioxide concentration profile through the biofilter revealed that the mass ratio of carbon dioxide produced to the BTEX removed was approximately 2.2, which confirms complete degradation of BTEX. Moreover, BTEX concentration profile along the biofilter depth bed also determined by convection-diffusion reactor (CDR) model. PMID- 23732919 TI - Hydrogen peroxide presoaking of bamboo prior to AFEX pretreatment and impact on enzymatic conversion to fermentable sugars. AB - Bamboo is a fast growing plant found worldwide that has high potential as an energy crop. This project evaluated the effectiveness of AFEX pretreatment for converting moso bamboo (Phyllostachys heterocycla var. pubescens) to fermentable sugars, both with and without pre-soaking in hydrogen peroxide. Pretreatment conditions including temperature, water loading, residence time, ammonia loading, and hydrogen peroxide loadings were varied to maximize hydrolysis yields. The optimal conditions for AFEX were 150 degrees C, 0.8 or 2.0 (w/w) water loading, 10-30 min residence time, and 2.0-5.0 (w/w) ammonia loading. The optimal conditions for H-AFEX were same AFEX conditions with 0.7-1.9 (w/w) 30% (wt) hydrogen peroxide solutions loading. Using 15 FPU/g glucan cellulase and under optimal conditions, AFEX pretreatment achieved a theoretical sugars yield of 64.8 72.7% and addition of hydrogen peroxide presoaking increased the yield to 83.4 92.1%. It is about 5-fold and 7-fold increase in sugars yield for AFEX-treated and H-AFEX-treated bamboo respectively. PMID- 23732920 TI - Effects of heavy metal wastewater on the anoxic/aerobic-membrane bioreactor bioprocess and membrane fouling. AB - Heavy metals have significant negative effects on anoxic/aerobic-membrane bioreactors (A/O-MBR). The changes in the performance of A/O-MBR fed with municipal wastewater containing 0.25-2.56 mg/L (low concentrations) and 3.7 32.3mg/L (high concentrations) of zinc, copper, lead, and cadmium were studied in this paper. The nitrification rate decreased to 27% and 46%, whereas the denitrification rate decreased to 20% and 34% under treatment with low/high concentrations of heavy metals, which indicate that heavy metals more significantly affect nitrification than denitrification. Heavy metals also resulted in the increase of carbohydrate of extracellular polymer substances and a smaller particle size distribution. Scanning electron microscope images, energy dispersive X-ray spectroscopy and atomic absorption spectrometry analysis of fouled membranes showed solid inorganic scale deposits on the membrane. All these results suggest that heavy metals affect membrane fouling in two ways: (a) modification of sludge characteristics; and (b) contribution to inorganic fouling. PMID- 23732921 TI - Anaerobic digestion of activated sludge after pressure-assisted ozonation. AB - This study was undertaken to examine the benefits of pressure-assisted ozonation (PAO) in enhancing solids reduction and biogas production in anaerobic digestion. The results showed significant improvements in both. With unacclimated inoculum at varied food-to-inoculum (F/I) ratios of 0.5-2, solids and COD reductions were improved by PAO, as well as by increased F/I ratios even without PAO, which would warrant further optimization of the F/I ratio for an unacclimated inoculum. With acclimated inocula at F/I ratio of 0.8, volatile suspended solids reduction and biogas production were improved by up to 60% and 800%, respectively, when the AS had been subjected to 20 cycles of PAO. In extended operation in plants where acclimated anaerobes are encountered, PAO pretreatment offers improved digestion of AS in terms of solids and COD removals and biogas production. PMID- 23732922 TI - Fermentation of alfalfa wet-fractionation liquids to volatile fatty acids by Streptococcus bovis and Megasphaera elsdenii. AB - "Green juice", obtained by squeezing fresh alfalfa leaves inoculated with lactic acid bacteria, was fermented at room temperature for 7-21 d to obtain 12-47 g lactic acid L(-1). Inoculation of green juice with Streptococcus bovis and incubation at 39 degrees C reduced fermentation time to 8-12h. The resulting "brown juice" from either fermentation had a pH of ~4.5 and a protein precipitate. Upon adjustment to pH 5.2-6.8 and inoculation with Megasphaera elsdenii, brown juice was fermented within 48 h to up to 18 g of mixed volatile fatty acids (VFA) L(-1). Single-stage fermentation of green juice by both species in coculture typically resulted in overgrowth of S. bovis and acid inhibition of M. elsdenii, inhibiting VFA production. Because the juice fermentations are conducted without sterilization or supplemental nutrients, they can potentially contribute to an integrated process featuring protein recovery and fermentation of fractionated solids to VFA and other products. PMID- 23732923 TI - Effect of dynamic oxygen concentrations on the growth of Neochloris oleoabundans at sub-saturating light conditions. AB - In tubular photobioreactors micro-algae continuously experience dynamically changing oxygen and light conditions when circulating from the solar receiver to the dark degasser. These changes in oxygen concentration and light were simulated in a CSTR using sub-saturating light intensity. Elongation of the residence time in the solar receiver from 30 to 300 min was also investigated. Specific growth rates measured at constant low oxygen concentration PO2=0.21 bar were; 1.14 +/- 0.06 day(-1) using continuous light 0.80 +/- 0.16 day(-1) with 30 min light and 1.09 +/- 0.05 day(-1) with 300 min light. The effect of dynamically changing oxygen concentrations from PO2=0.21 to 0.63 bar followed by degassing resulted in similar specific growth rates. The exposure of the algae cells to dark periods in the degasser has a bigger negative impact than the temporary exposure to accumulating oxygen concentrations in the solar receiver. This shows that considerable energy savings for degassing are possible. PMID- 23732924 TI - Power generation by packed-bed air-cathode microbial fuel cells. AB - Catalysts and catalyst binders are significant portions of the cost of microbial fuel cell (MFC) cathodes. Many materials have been tested as aqueous cathodes, but air-cathodes are needed to avoid energy demands for water aeration. Packed bed air-cathodes were constructed without expensive binders or diffusion layers using four inexpensive carbon-based materials. Cathodes made from activated carbon produced the largest maximum power density of 676 +/- 93 mW/m(2), followed by semi-coke (376 +/- 47 mW/m(2)), graphite (122 +/- 14 mW/m(2)) and carbon felt (60 +/- 43 mW/m(2)). Increasing the mass of activated carbon and semi-coke from 5 to >= 15 g significantly reduced power generation because of a reduction in oxygen transfer due to a thicker water layer in the cathode (~3 or ~6 cm). These results indicate that a thin packed layer of activated carbon or semi-coke can be used to make inexpensive air-cathodes for MFCs. PMID- 23732925 TI - Cathepsin B inhibition attenuates cardiac dysfunction and remodeling following myocardial infarction by inhibiting the NLRP3 pathway. AB - Recently, cathepsin B has been demonstrated to be involved in myocardial infarction (MI). This study aimed to elucidate the effects of a specific cathepsin B inhibitor, CA-074Me, on cardiac dysfunction, remodeling and fibrosis following MI in a rat model. Furthermore, the potential mechanisms of action of this inhibitor were investigated. In the present study, Sprague-Dawley rats were anesthetized and subjected to a sham operation or left anterior descending coronary artery ligation, followed by intraperitoneal injection of CA-074Me (10 mg/kg/day) or an equal volume of vehicle for 4 weeks. Activation of the cathepsin B and NLRP3 pathway was detected. Cardiac function was assessed by echocardiography, while hypertrophy and fibrosis were determined by Masson's trichrome, immunofluorescence and morphometry. The results demonstrated that cathepsin B-NLRP3 activation was inhibited by CA-074Me treatment. Following such treatment for 4 weeks, the rats demonstrated smaller decreases in cardiac function, and a decrease in cardiomyocyte hypertrophy and the level of fibrosis. Cathepsin B inhibition significantly attenuated cardiac dysfunction, and reduced cardiomyocyte size and cardiac fibrosis in the experimental MI model, by inhibiting NLRP3 activation. This suggested that targeting the cathepsin B-NLRP3 pathway may represent a novel therapeutic strategy to prevent heart failure and remodeling following MI. PMID- 23732926 TI - Structure and Li+ dynamics of Sb-doped Li7La3Zr2O12 fast lithium ion conductors. AB - Antimony-doped lithium stuffed garnets Li(7-x)La3Zr(2-x)Sb(x)O12 (x = 0.2-1.0) prepared using a conventional solid state reaction method are characterized using Powder X-ray Diffraction (PXRD), Scanning Electron Microscopy (SEM), Energy Dispersive Analysis by X-ray (EDAX), AC Impedance spectroscopy, Magic Angle Spinning Nuclear Magnetic Resonance (MAS NMR) and Raman spectroscopic techniques. PXRD confirms the formation of a garnet-like structure with cubic symmetry for the entire selected compositional range. Among the investigated compounds, the compound with an Sb content corresponding to x = 0.4, i.e. Li6.6La3Zr1.6Sb0.4O12 exhibits the maximum total (bulk + grain boundary) ionic conductivity of 7.7 * 10(-4) S cm(-1) at 30 degrees C. The shape of the imaginary part of the modulus spectra suggests that the relaxation processes are non-Debye in nature. The full width at half maximum (FWHM) for the master modulus curve of Li6.6La3Zr1.6Sb0.4O12 is found to be the smallest among the investigated lithium garnets. The full width at half maximum (FWHM) of the (7)Li MAS NMR spectrum for the composition Li6.6La3Zr1.6Sb0.4O12 is the smallest among the investigated compounds. Raman data collected for the compounds in this series indicates an increase of Li(+) occupancy in the tetrahedrally coordinated site with an associated decrease of Li(+) occupancy in the octahedrally coordinated site during an increase of x in Li(7-x)La3Zr(2-x)Sb(x)O12. The present investigation reveals that the optimal Li(+) concentration required to achieve the maximum room temperature Li(+) conductivity in Li(7-x)La3Zr(2-x)Sb(x)O12 lithium stuffed garnet is around x = 0.4. PMID- 23732927 TI - How phosphorylated can it get? Cardiac myosin binding protein C phosphorylation in heart failure. PMID- 23732928 TI - Genome sequence analysis of the Vibrio parahaemolyticus lytic bacteriophage VPMS1. AB - VPMS1 is a Vibrio parahaemolyticus lytic phage isolated from a marine clam. The 42.3-kb genome was predicted to encode 53 proteins. Comparison of the VPMS1 DNA genome with known phage genomes revealed no similarity; hence, it represents a new VP phage, organized into three differently oriented modules. The module for packaging covers 12 % of the genome, the module for structure covers 31 %, and the module for replication and regulation covers 48 %. The G + C content was 44.67 %. The coding region corresponds to 91 % of the genome, and 9 % apparently does not encode any protein. Thirty genes, constituting 57 % of the genome, had significant similarity to some reported proteins in the protein database; 23 genes, constituting 43 % of the genome, showed no significant homology to any reported protein, and these could be new proteins whose hypothetical functions can be deduced from their position in the genome. PMID- 23732929 TI - Genomic organization of a novel partitivirus from the phytopathogenic fungus Ustilaginoidea virens. AB - From the plant pathogen Ustilaginoidea virens, four double-stranded RNA (dsRNA) segments designated Uv-dsRNA1, -2, -3, and -4 were isolated, cloned, and sequenced. Uv-dsRNA1 (1775 bp) and -2 (1588 bp) potentially encode an RNA dependent RNA polymerase (RdRp) and a viral coat protein (CP), respectively. Since the RdRp and CP sequences encoded by Uv-dsRNA1 and -2, respectively, are most closely related to, but clearly distinct from, those of viruses of the genus Partitivirus, they appear to be the two genome segments of a new partitivirus, for which the name Ustilaginoidea virens partitivirus 1 is proposed. In contrast, Uv-dsRNA3 (1352 bp) did not share significant sequence similarity with GenBank sequences, and the ORF of Uv-dsRNA4 (1119 bp) was only 32 % identical to a functionally unknown protein (GaRVMS2s3gp1) encoded by Gremmeniella abietina RNA virus MS2. PMID- 23732931 TI - Multimorbidity and mental health: can psychiatry rise to the challenge? AB - Multimorbidity--the co-occurrence of two or more long-term conditions in an individual - is highly relevant to psychiatry. Changes to training and a more integrated model of psychiatric and physical healthcare are needed in the future if we are to improve the long-term health of our patients. PMID- 23732930 TI - A cilevirus infects ornamental hibiscus in Hawaii. AB - The complete nucleotide sequence of a virus infecting ornamental hibiscus (Hibiscus sp.) in Hawaii with symptoms of green ringspots on senescing leaves was determined from double-stranded RNA isolated from symptomatic tissue. Excluding polyadenylated regions at the 3' termini, the bipartite RNA genome was 8748 and 5019 nt in length for RNA1 and RNA2, respectively. The genome organization was typical of a cilevirus: RNA1 encoded a large replication-associated protein with methyltransferase, protease, helicase and RNA-dependent RNA polymerase domains as well as a 29-kDa protein of unknown function. RNA2 possessed five open reading frames that potentially encoded proteins with molecular masses of 15, 7, 62, 32, and 24 kDa. The 32-kDa protein is homologous to 3A movement proteins of RNA viruses; the other proteins are of unknown function. A proteome comparison revealed that this virus was 92 % identical to citrus leprosis virus cytoplasmic type 2 (CiLV-C2), a recently characterized cilevirus infecting citrus with leprosis-like symptoms in Colombia. The high sequence similarity suggests that the virus described in this study could be a strain of CiLV-C2, but since the new genus Cilevirus does not have species demarcation criteria established at present, the classification of this virus infecting hibiscus is open to interpretation. This study represents the first documented case of a cilevirus established in the United States and provides insight into the diversity within the genus Cilevirus. PMID- 23732932 TI - A golden age of discovery. AB - Original ideas are needed in developing new interventions for psychosis, and computer-assisted therapy for auditory hallucinations is one such novel approach. As with any early-phase development, it will require further refinement and evaluation. There are now a range of ongoing studies into different intervention strategies and these promise to enhance the therapeutic potency of clinical psychiatrists and mental health teams. If the relative lack of research funding, focus and support from academic sources on this area were to change, even more could be delivered. PMID- 23732933 TI - Antidepressant drugs and sexual dysfunction. AB - Depressive symptoms and depressive illness are associated with impairments in sexual function and satisfaction but the findings of randomised placebo controlled trials demonstrate that antidepressant drugs can be associated with the development or worsening of sexual dysfunction. Sexual difficulties during antidepressant treatment often resolve as depression lifts but may persist over long periods, and can reduce self-esteem and affect mood and relationships adversely. Sexual dysfunction during antidepressant treatment is typically associated with many possible causes, but the risk of dysfunction varies with differing antidepressants, and should be considered when selecting an antidepressant. PMID- 23732934 TI - Role of dietary supplementation in attention-deficit hyperactivity disorder. AB - Dietary constituents have been increasingly researched as both potential aetiological factors and interventions for attention-deficit hyperactivity disorder (ADHD) symptoms. Although the involvement of dietary factors in ADHD is biologically plausible, the literature to date does not indicate causality and there are no grounds yet for the routine recommendation of dietary manipulation in ADHD. PMID- 23732935 TI - The full spectrum of ethical issues in dementia care: systematic qualitative review. AB - BACKGROUND: Integrating ethical issues in dementia-specific training material, clinical guidelines and national strategy plans requires an unbiased awareness of all the relevant ethical issues. AIMS: To determine systematically and transparently the full spectrum of ethical issues in clinical dementia care. METHOD: We conducted a systematic review in Medline (restricted to English and German literature published between 2000 and 2011) and Google books (with no restrictions). We applied qualitative text analysis and normative analysis to categorise the spectrum of ethical issues in clinical dementia care. RESULTS: The literature review retrieved 92 references that together mentioned a spectrum of 56 ethical issues in clinical dementia care. The spectrum was structured into seven major categories that consist of first- and second-order categories for ethical issues. CONCLUSIONS: The systematically derived spectrum of ethical issues in clinical dementia care presented in this paper can be used as training material for healthcare professionals, students and the public for raising awareness and understanding of the complexity of ethical issues in dementia care. It can also be used to identify ethical issues that should be addressed in dementia-specific training programmes, national strategy plans and clinical practice guidelines. Further research should evaluate whether this new genre of systematic reviews can be applied to the identification of ethical issues in other cognitive and somatic diseases. Also, the practical challenges in addressing ethical issues in training material, guidelines and policies need to be evaluated. PMID- 23732936 TI - The 'rest of medicine' and psychiatry: why paradigms would differ. PMID- 23732937 TI - Low Apgar scores in neonates with prenatal antidepressant exposure. PMID- 23732938 TI - Are the conclusions supported by the evidence? PMID- 23732939 TI - Results for behavioural activation are overstated. PMID- 23732940 TI - Effect of 9/11 on suicide: appropriateness of a time series model. PMID- 23732941 TI - Little evidence for the usefulness of violence risk assessment. PMID- 23732942 TI - Anatomical and functional brain abnormalities in drug-naive first-episode schizophrenia. AB - OBJECTIVE: The authors sought to explore whether anatomical and functional brain deficits are present in similar or different brain regions early in the course of schizophrenia, before antipsychotic treatment, and whether these deficits are more severe or otherwise different in patients with prominent negative symptoms. METHOD: A total of 100 drug-naive first-episode schizophrenia patients and 100 matched healthy comparison subjects underwent structural and resting-state functional MRI scanning. Gray matter volume and amplitude of low-frequency fluctuations during resting-state functional studies were measured. RESULTS: Group comparisons of gray matter volume showed significant differences mainly in thalamo-cortical networks, while alterations in the amplitude of low-frequency fluctuations were observed in fronto-parietal and default mode networks. Thus, different brain regions had alterations in gray matter volume and resting state physiology. These changes did not correlate with the duration of untreated illness, nor with acute clinical symptom severity. Patients with prominent negative symptoms had greater regional alterations in brain anatomy, particularly in the left dorsolateral prefrontal cortex, while the pattern of functional alterations was unrelated to severity of negative symptoms. CONCLUSIONS: Anatomical and resting-state functional deficits were observed in different brain regions, indicating that anatomical and functional brain abnormalities are significantly dissociated in the early course of schizophrenia. The lack of association of these abnormalities with illness duration and episode severity suggests that these anatomical and functional changes may be early-evolving features of the illness that are relatively stable early in the course of illness. The different structural deficits of regional gray matter observed in patients with prominent negative symptoms may provide unique insight into the early regional neuropathology of this symptom dimension in schizophrenia. PMID- 23732943 TI - Recent approaches for the synthesis of modified cryptophycins. AB - Cryptophycins are a family of antimitotic depsipeptides with very high cytotoxicity even against multi-drug resistant (MDR) cancer cells. The first representative was isolated from cyanobacteria Nostoc sp. in 1990. Their bioactivity is based on their interaction with the protein tubulin. Cryptophycins were found to induce apoptosis due to inhibition of the microtubule dynamics. Consequently, cryptophycin analogues are considered as potential antitumour agents. Retrosynthetically, cryptophycins can be subdivided into four building blocks, namely units A-D, to be assembled in the total synthesis. Since the discovery of this compound class, numerous synthetic analogues have been designed for structure-activity relationship (SAR) studies. This review gives a critical overview on cryptophycins, while the main focus lies on the synthetic challenges of recently published cryptophycins, together with emerging concepts on cryptophycin bioconjugation and prodrug design. PMID- 23732944 TI - Lipid-based intravesical drug delivery systems with controlled release of trospium chloride for the urinary bladder. AB - The overactive bladder (OAB) is a common disease with an overactivity of the detrusor muscle in the bladder wall. Besides peroral administration of anticholinergic drugs and bladder irrigations, there is a need for a sustained release formulation in the urinary bladder. In order to realise a local long-term treatment of the overactive urinary bladder, lipidic drug delivery systems were prepared. Requirements for an intravesical application are a long-term controlled release of trospium chloride, a high drug loading and small sized drug carriers to permit an insertion through the urethra into the urinary bladder. The drug delivery systems were manufactured by using compression (mini-tablets), solid lipid extrusion (extrudates) and a melting and casting technique (mini-moulds) with different amounts of trospium chloride and glyceryl tristearate as matrix former. Drug release depended on the drug loading and the preparation method. Mini-tablets and lipidic extrudates showed a drug release over five days, whereas that from mini-moulds was negligibly small. The appearance of polymorphic transformations during processing and storage was investigated by using differential scanning calorimetry and X-ray diffraction. In contrast to mini tablets and mini-moulds, lipidic extrudates showed no polymorphic transformations. In summary, lipids are suitable matrix formers for a highly water-soluble drug, like trospium chloride. Despite a drug loading of up to 30%, it was feasible to achieve a drug release ranging from several days up to weeks. In addition, small dosage forms with a size of only a few millimetres were realised. Therefore, an insertion and excretion through the urethra is possible and the requirements for an intravesical application are fulfilled. PMID- 23732945 TI - Neurologists: the last bedside physician-scientists. PMID- 23732946 TI - Running interference? Exercise and PCB-induced changes in the gut microbiome. PMID- 23732947 TI - Three-dimensional volume containing multiple two-dimensional information patterns. AB - We have developed an algorithm for recording multiple gradated two-dimensional projection patterns in a single three-dimensional object. When a single pattern is observed, information from the other patterns can be treated as background noise. The proposed algorithm has two important features: the number of patterns that can be recorded is theoretically infinite and no meaningful information can be seen outside of the projection directions. We confirmed the effectiveness of the proposed algorithm by performing numerical simulations of two laser crystals: an octagonal prism that contained four patterns in four projection directions and a dodecahedron that contained six patterns in six directions. We also fabricated and demonstrated an actual prototype laser crystal from a glass cube engraved by a laser beam. This algorithm has applications in various fields, including media art, digital signage, and encryption technology. PMID- 23732948 TI - A 7T fMRI study of cerebellar activation in sequential finger movement tasks. AB - We investigated whether higher activation of the cerebellar cortex in unpredictable compared to predictable sequential finger movements reflects higher demands in motor response selection or also increases in demands on motor sequencing. Furthermore, we asked the question whether the cerebellar nuclei show a similar or reversed response profile as the cerebellar cortex. Ultra-high-field 7T functional magnetic resonance imaging was performed in nineteen right-handed, healthy young participants. Tasks involved finger tapping of a constant sequence, a random sequence, and with one finger at a time (no sequence). Conditions involved the same number of movements of fingers II-V. The three tasks were accompanied by the activation of the known hand areas within the cerebellar cortex and dentate nuclei. Activation of the cerebellar cortex and the dorsorostral dentate was significantly increased in the random-sequence condition compared to both the constant-sequence and the no-sequence conditions, with no significant difference between the constant-sequence and the no-sequence conditions. Error rate and movement frequency was not significantly different between conditions. Thus, differences between conditions cannot be explained by differences in motor execution. Because no difference was observed between the no sequence and the constant-sequence conditions, increased cerebellar activation in the random-sequence condition likely reflects increased demands in motor response selection. Co-activation of cerebellar cortex and nuclei may be a consequence of excitatory afferent collaterals to the nuclei, "rebound-firing" of dentate neurons, and/or inhibitory synaptic input from Purkinje cells. PMID- 23732949 TI - Micro-movements of varying difficulties: wrist and arm movements. AB - An experiment was designed to determine the degree to which reducing movement amplitude (16 degrees , 8 degrees , to 4 degrees ) while keeping the relative accuracy requirements (IDs 1.5, 3, 4.5, and 6) and visual feedback display constant by increasing the display gain proportional to the decrease in amplitude (1*, 2*, 4*) influences reciprocal aiming movements of the wrist and arm. Research on smaller amplitude movements is limited and inconclusive, but these types of movement conditions are becoming increasingly more important as microsurgery and micro-mechanical applications increase. Participants were asked to flex/extend their limb/lever in the horizontal plane at the wrist (arm stabilized) or elbow joint (wrist stabilized) in an attempt to move back and forth between two targets as quickly and accurately as possible. The targets and current position of the limb were projected on the screen in front of the participant. Target width was manipulated with amplitude constant (16 degrees , 8 degrees or 4 degrees ). Results indicated that the linear relationship between MT and ID, typically observed for Fitts' tasks, was observed. There were moderate decreases in MT as amplitude was decreased but only for high ID movements. ID 6 movements at 4 degrees amplitude, for example, were produced more quickly than at amplitude 16 degrees without sacrificing end-point accuracy. The decrease in movement time was, however, related to increased dwell time and very low peak velocities. PMID- 23732951 TI - Magnetic transitions and spin-glass reentrance in two-dimensional [MnII(TCNE)(NCMe)2]X (X = PF6,AsF6,SbF6) molecular magnets. AB - The structural, spectroscopic and magnetic properties of the two-dimensional (2D) molecule-based magnets of [Mn(II)(TCNE)(NCMe)2]X (X = PF6, AsF6, SbF6; TCNE = tetracyanoethylene, NCMe = acetonitrile) composition are reported. It is shown that the alteration of the interlayer distance by increasing the anion size has little effect on the critical magnetic ordering temperature, Tc, suggesting that it depends predominantly on the intra-plane magnetic exchange. The observed field induced irreversibility in static magnetization, a slow decay of isothermal remanence below Tc, and the dynamic susceptibility data are in accord with a re entrant spin-glass nature of the ground state of all materials. In contrast to the isostructural Fe-based magnets, in which strong magnetocrystalline anisotropy facilitates the finite temperature magnetic ordering with the magnetization easy axis perpendicular to the MU4-TCNE(*-) plane, in the studied Mn-based magnets the easy axis is canted away from the normal direction, due to a small magnetocrystalline anisotropy. The two magnetic transitions observed on cooling are assigned to the ferrimagnetic long-range ordering of the normal magnetization component followed by the re-entrant spin-glass type transition resulting from a random freezing of the in-plane magnetization component. PMID- 23732950 TI - Visually induced postural reactivity is velocity-dependent at low temporal frequencies and frequency-dependent at high temporal frequencies. AB - Visual stimulation alone is sufficient to produce visually induced postural reactivity (VIPR). While some studies have shown that VIPR increases with the velocity of a moving visual stimulus, others have shown that it decreases with the temporal frequency of an oscillating visual stimulus. These results seem contradictory given that these two variables co-vary in the same direction. The purpose of this study is to determine whether the VIPR can be different depending on the frequency range being considered. Twelve subjects were placed standing up in a virtual reality environment that simulated a black and white checkerboard at floor level. This checkerboard oscillated at seven frequencies (0.03-2.0 Hz) and three amplitudes (2, 4, and 8 degrees ), corresponding to nine velocities (0.125 32 degrees /s). The virtual floor oscillated from left to right (mediolateral) or from front to back (anteroposterior). We calculated the subjects' mean velocity (Omega) based on data from electromagnetic sensors positioned on the head and lower back. Our experiment shows that for temporal frequencies below 0.12 Hz, VIPR is visually dependent and increases with stimulus velocity. When stimulus velocity becomes too high, the body becomes incapable of following, and the VIPR saturates between 0.12 and 0.25 Hz. In this frequency range, maximal postural oscillation seems to depend on biomechanical constraints imposed by the positioning of the feet. For frequencies above 0.5 Hz, the body can no longer maintain the same oscillation state. This saturation may be linked to proprioceptive feedback mechanisms in the postural system. PMID- 23732952 TI - Eucapnic voluntary hyperventilation in diagnosing exercise-induced laryngeal obstructions. AB - Exercise-induced laryngeal obstructions (EILOs) cause exercise-related respiratory symptoms (ERRS) and are important differential diagnoses to exercise induced asthma. The diagnostic method for EILOs includes provocation to induce the obstruction followed by a verification of the obstruction and the degree thereof. The objective of the present study was to examine if a eucapnic voluntary hyperventilation (EVH) test could induce laryngeal obstructions laryngoscopically identical in subtypes and development as seen during an exercise test. EVH and exercise testing with continuous laryngoscopy were performed during a screening of two national athletic teams (n = 67). The laryngoscopic recordings were examined for usability, abnormalities and maximal supraglottic and glottic obstruction using two currently available methods (Eilomea and CLE-score). The participants were asked questions on ERRS, and whether the symptoms experienced during each provocation matched those experienced during regular training. A total of 39 completed both tests. There were no significant differences in subtypes and development thereof, the experience of symptoms, and specificity and sensitivity between the methods. Significantly more recordings obtained during the exercise test were usable for evaluation primarily due to resilient mucus on the tip of the fiber-laryngoscope in the EVH test. Only recordings of six athletes from both provocation methods were usable for evaluation using the Eilomea method (high-quality demand). Amongst these, a linear correlation was found for the glottic obstruction. EVH tests can induce EILOs. However, the present test protocol needs adjustments to secure better visualisation of the larynx during provocation. PMID- 23732953 TI - Object-based attentional effects in response to eye-gaze and arrow cues. AB - Recent studies have demonstrated that central cues, such as eyes and arrows, reflexively trigger attentional shifts. However, it is not clear whether the attention induced by these two cues can be attached to objects within the visual scene. In the current study, subjects' attention was directed to one of two objects (square outlines) via the observation of uninformative directional arrows or eye gaze. Then, the objects rotated 90 degrees clockwise or counter-clockwise to a new location and the target stimulus was presented within one of these two objects. Results showed that independent of the cue type participants responded faster to targets in the cued object than to those in the uncued object. This suggests that in dynamic displays, both gaze and arrow cues are able to trigger reflexive shifts of attention to objects moving within the visual scene. PMID- 23732954 TI - Substituted cathinone products: a new trend in "bath salts" and other designer stimulant drug use. AB - There is a growing concern about the availability of a new generation of "designer drug" stimulants that are marketed as "bath salts" and other household products. The products are not true bath salts and contain substituted cathinone stimulant substances, such as methylenedioxypyrovalerone (MDPV) and mephedrone. Calls to the American Association of Poison Control Centers regarding "bath salts" consumption began in 2010 and have continued since that time. Few reports of systematic epidemiologic surveillance or definitive clinical effects of toxicity specifically associated with "bath salts" consumption have been reported in the medical literature. The current narrative review describes the growing trend of designer substituted cathinone use, pharmacology, clinical effects, and recent regulatory changes. It is hoped that a greater understanding of the clinical effects and use patterns will help inform policy and practice. PMID- 23732955 TI - Intranasal substituted cathinone "bath salts" psychosis potentially exacerbated by diphenhydramine. AB - In this report, we describe a case of intranasal "bath salts"-associated psychosis. Symptoms developed during a 3-week binge and were potentially exacerbated by oral diphenhydramine taken for insomnia. The clinical case conference includes expert discussion from 3 disciplines: emergency medicine toxicology, behavioral pharmacology, and addiction medicine. It is hoped that the discussion will provide insight into the clinical aspects and challenges of addressing acute substituted cathinone toxicity, including acute psychosis, a major adverse effect of bath salts consumption. PMID- 23732957 TI - A randomized trial of a behavioral intervention for high risk substance-using MSM. AB - Substance-using men who have sex with men (MSM) are among the groups at highest risk for HIV infection in the United States. We report the results of a randomized trial testing the efficacy of a small group sexual and substance use risk reduction intervention based on empowerment theory compared to an enhanced efficacious control condition among 515 high risk not-in-treatment MSM substance users. Effect sizes for sexual risk and substance use outcomes were moderate to large: HIV transmission risk frequency, d = 0.71 in the control versus 0.66 in the experimental group; number of anal sex partners, d = 1.04 versus 0.98; substance dependence symptoms, d = 0.49 versus 0.53; significant differences were not observed between conditions. Black MSM reduced their risks at a greater rate than White or Latino men. The findings point to a critically important research agenda to reduce HIV transmission among MSM substance users. PMID- 23732958 TI - Syphilis and HIV co-infection in patients who attend an AIDS outpatient clinic in Vitoria, Brazil. AB - Our goal was to determine the prevalence of, and risk factors associated with, syphilis in HIV-infected patients who attend an AIDS outpatient clinic in Vitoria, Brazil. We conducted a cross-sectional study-including interviews for demographic, behavioral, and clinical characteristics-and blood collection (venipuncture and fingerstick) for VDRL and treponemal tests (rapid test) in a total of 438 patients. The mean age was 43.0 years (SD = 11), and mean years of school was 8.1 (SD = 4.2). The prevalence of syphilis was 5.3 % (95 % CI 3.3 7.3). The treponemal test was positive in 18.9 % of participants. In multivariate analysis, prevalent syphilis infection was independently associated with male gender (AOR 4.6, 95 % CI 1.1-20.0), a history of male-male sex (AOR 1.8, 95 % CI 1.6-4.1), current use of antiretroviral therapy (AOR 5.5, 95 % CI 1.7-16.7), and history of treated syphilis infection (AOR 5.5, 95 % CI 2.0-15.8). Syphilis prevalence was high in patients living with HIV/AIDS who attend an AIDS clinic; therefore, routine sexually transmitted infections counseling and screening should be included in their care. PMID- 23732960 TI - The long-term effect of schizophrenia on the brain: dementia praecox? PMID- 23732959 TI - Adenine-induced chronic kidney and cardiovascular damage in rats. AB - BACKGROUND: The incidence of human chronic kidney failure with associated cardiovascular disease is increasing. Kidney damage can be induced in rats by chronic dietary adenine intake. We have used this intervention to investigate the development of concurrent kidney and cardiovascular injury. METHODS: Dose-ranging studies were undertaken on male Wistar rats by feeding with adenine (0.075%, 0.25%, 0.5% or 0.75%) for up to 16weeks. 0.075% adenine produced minimal changes while 0.5% or 0.75% adenine produced marked kidney damage; 0.25% adenine was chosen for further studies since it produced moderate kidney and cardiovascular damage. In rats fed 0.25% adenine, renal function (blood urea nitrogen (BUN), plasma creatinine, and their clearances; plasma uric acid; proteinuria); renal structure (collagen, apoptosis, inflammation, glomerulopathy); and protein expression of markers for oxidative stress (HO-1), fibrosis (TGF-beta, alpha-SMA) and inflammation (TNF-alpha, NF-kappaB p52, NF-kappaB p50, PLA2 and ED1) were measured, along with cardiovascular parameters (blood pressure, left ventricular stiffness, vascular responses). Allopurinol (25mg/kg/day, final 8weeks only) was administered to determine the role of uric acid. RESULTS: 0.25% adenine diet induced characteristics of human chronic kidney disease at 16weeks including increased BUN (0.25% adenine 56.5+/-5.4*; control 6.2+/-0.6mmol/L; *=p<0.05) and plasma creatinine (0.25% adenine 268+/-23*; control 41.9+/-2.8MUg/L), decreased BUN and creatinine clearances; proteinuria; increased chronic inflammation as macrophage and myofibroblast infiltration, increased collagen deposition, tubular atrophy, apoptosis, and TNF-alpha and TGF-beta expression; glomerulopathy as increased podocyte desmin expression; increased HO-1 expression; and increased plasma uric acid. Cardiovascular changes included increased ventricular fibrosis, systolic blood pressure and left ventricular stiffness, and impaired vascular responses. Allopurinol decreased plasma uric acid concentrations and reversed the adenine-induced kidney and cardiovascular changes. CONCLUSION: Administration of 0.25% adenine to rats induced chronic kidney and cardiovascular disease. Increased uric acid production is the most likely cause since allopurinol attenuated this damage. PMID- 23732961 TI - Neuroanatomical correlates of childhood sexual abuse: identifying biological substrates for environmental effects on clinical phenotypes. PMID- 23732962 TI - Workplace depression: personalize, partner, or pay the price. PMID- 23732963 TI - Understanding transitions in illicit drug use and drug use disorders. PMID- 23732964 TI - Neurocognitive disorders in DSM-5. PMID- 23732965 TI - Psychiatric clearance for patients started on interferon-alpha-based therapies. PMID- 23732966 TI - Images in psychiatry. Oppression, depression, and work in the murals of Diego Rivera. PMID- 23732967 TI - Decreased cortical representation of genital somatosensory field after childhood sexual abuse. AB - OBJECTIVE: Sexual dysfunction is a common clinical symptom in women who were victims of childhood sexual abuse. The precise mechanism that mediates this association remains poorly understood. The authors evaluated the relationship between the experience of childhood abuse and neuroplastic thinning of cortical fields, depending on the nature of the abusive experience. METHOD: The authors used MRI-based cortical thickness analysis in 51 medically healthy adult women to test whether different forms of childhood abuse were associated with cortical thinning in areas critical to the perception and processing of specific behavior implicated in the type of abuse. RESULTS: Exposure to childhood sexual abuse was specifically associated with pronounced cortical thinning in the genital representation field of the primary somatosensory cortex. In contrast, emotional abuse was associated with cortical thinning in regions relevant to self-awareness and self-evaluation. CONCLUSIONS: Neural plasticity during development appears to result in cortical adaptation that may shield a child from the sensory processing of the specific abusive experience by altering cortical representation fields in a regionally highly specific manner. Such plastic reorganization may be protective for the child living under abusive conditions, but it may underlie the development of behavioral problems, such as sexual dysfunction, later in life. PMID- 23732968 TI - Maintenance cognitive-behavioral therapy and manualized psychoeducation in the treatment of recurrent depression: a multicenter prospective randomized controlled trial. AB - OBJECTIVE: This multicenter study compared the relapse and recurrence outcomes of two active treatments, maintenance cognitive-behavioral therapy (CBT) and manualized psychoeducation, both in addition to treatment as usual, in patients in remission from depression. METHOD: This was a multicenter prospective randomized observer-blinded study with two parallel groups. The authors assessed 180 patients with three or more previous major depressive episodes who met remission criteria over a 2-month baseline period and who were randomly assigned to 16 sessions of either maintenance CBT or manualized psychoeducation over 8 months and then followed up for 12 months. The main outcome measure was time to first relapse or recurrence of a major depression, based on DSM-IV criteria, as assessed by blinded observers with the Longitudinal Interval Follow-Up Evaluation. RESULTS: Cox regression analysis showed that time to relapse or recurrence of major depression did not differ significantly between treatment conditions, but a significant interaction was observed between treatment condition and number of previous episodes (<5 or >=5). Within the subsample of patients with five or more previous episodes, maintenance CBT was significantly superior to manualized psychoeducation, whereas for patients with fewer than five previous episodes, no significant treatment differences were observed in time to relapse or recurrence. CONCLUSIONS: The results indicate that maintenance CBT has significant effects on the prevention of relapse or recurrence only in patients with a high risk of depression recurrence. For patients with a moderate risk of recurrence, nonspecific effects and structured patient education may be equally effective. PMID- 23732969 TI - "A rose is a rose is a rose"? PMID- 23732970 TI - Sustained weight loss after treatment with a glucagon-like peptide-1 receptor agonist in an obese patient with schizophrenia and type 2 diabetes. PMID- 23732971 TI - Monthly injectable naltrexone for pathological gambling. PMID- 23732972 TI - Genome-wide association study of cognitive decline in schizophrenia. PMID- 23732981 TI - De novo methyltransferase, OsDRM2, interacts with the ATP-dependent RNA helicase, OseIF4A, in rice. AB - Domains rearranged methyltransferases (DRMs) are the de novo methyltransferases that regulate cytosine methylation in plants in a manner similar to the animal de novo methyltransferases, DNMT3a and DNMT3b. These enzymes catalyze the establishment of new methylation patterns and are guided to target sites by small RNAs through the process of RNA-directed DNA methylation (RdDM). In the current accepted view for RdDM, intricate interactions among transcription factors/chromatin modifying proteins and the large subunits of plant-specific polymerases, Pol IV and Pol V, regulate the 24-nt small interfering RNA guided de novo methylation of cytosines. The RNA-induced silencing complex assembled on Pol V-transcribed non-coding RNA finally facilitates the recruitment of DRM2 by unknown mechanism/protein interactions to chromatin sites. In an attempt to determine the cellular proteins that specifically interact with DRM2, a yeast two hybrid screen was performed using young rice panicles. We report that rice DRM2 interacts with the ATP-dependent RNA helicase, eIF4A. Direct interaction between the two proteins is demonstrated in vivo by bimolecular fluorescence complementation method and in vitro by histidine-pull-down assays. Deletion analysis reveals that interaction between OsDRM2 and OseIF4A is specifically mediated through ubiquitin-associated domain of OsDRM2 while, both domains 1 and 2 of OseIF4A are critical for mediating strong interaction with OsDRM2 in vivo. Interaction between Arabidopsis eIF4AI and eIF4AII with OsDRM2 and nuclear localization of these complexes suggests possible conservation of functional interaction between de novo methyltransferases and the translation initiation factor, eIF4A, in RdDM across plant species. PMID- 23732983 TI - Plant protein interactions studied using AFM force spectroscopy: nanomechanical and adhesion properties. AB - The present work was focused on the nanomechanical and adhesion properties of the napin (2S albumin) and cruciferin (12S globulin) rapeseed (Brassica napus L.) proteins, respectively, a low and high molecular weight seed protein. Using chemically modified AFM tips, force spectroscopy experiments demonstrated notable differences in the tip-protein interaction strength with regard to the nature of the protein and pH of the aqueous environment. The results clearly underline the role of residence time and electrostatic interactions in the protein-protein adhesion force. Although the nanomechanical experiments concerned more than a single molecule, unfolding length and force characteristics of the rapeseed proteins have been statistically found to be sensitive to the structural properties of the protein. This study provides insight into the characterization of rapeseed proteins and then a better knowledge of their interaction and assembling at the nanoscale range. PMID- 23732982 TI - Interaction of T4 UvsW helicase and single-stranded DNA binding protein gp32 through its carboxy-terminal acidic tail. AB - Bacteriophage T4 UvsW helicase contains both unwinding and annealing activities and displays some functional similarities to bacterial RecG and RecQ helicases. UvsW is involved in several DNA repair pathways, playing important roles in recombination-dependent DNA repair and the reorganization of stalled replication forks. The T4 single-stranded DNA (ssDNA) binding protein gp32 is a central player in nearly all DNA replication and repair processes and is thought to facilitate their coordination by recruiting and regulating the various proteins involved. Here, we show that the activities of the UvsW protein are modulated by gp32. UvsW-catalyzed unwinding of recombination intermediates such as D-loops and static X-DNA (Holliday junction mimic) to ssDNA products is enhanced by the gp32 protein. The enhancement requires the presence of the protein interaction domain of gp32 (the acidic carboxy-terminus), suggesting that a specific interaction between UvsW and gp32 is required. In the absence of this interaction, the ssDNA annealing and ATP-dependent translocation activities of UvsW are severely inhibited when gp32 coats the ssDNA lattice. However, when UvsW and gp32 do interact, UvsW is able to efficiently displace the gp32 protein from the ssDNA. This ability of UvsW to remove gp32 from ssDNA may explain its ability to enhance the strand invasion activity of the T4 recombinase (UvsX) and suggests a possible new role for UvsW in gp32-mediated DNA transactions. PMID- 23732984 TI - Potassium ion channels in retinal ganglion cells (review). AB - Retinal ganglion cells (RGCs) consolidate visual processing and constitute the last step prior to the transmission of signals to higher brain centers. RGC death is a major cause of visual impairment in optic neuropathies, including glaucoma, age-related macular degeneration, diabetic retinopathy, uveoretinitis and vitreoretinopathy. Discharge patterns of RGCs are primarily determined by the presence of ion channels. As the most diverse group of ion channels, potassium (K+) channels play key roles in modulating the electrical properties of RGCs. Biochemical, molecular and pharmacological studies have identified a number of K+ channels in RGCs, including inwardly rectifying K+ (Kir), ATP-sensitive K+ (KATP), tandem-pore domain K+ (TASK), voltage-gated K+ (Kv), ether-a-go-go (Eag) and Ca2+-activated K+ (KCa) channels. Kir channels are important in the maintenance of the resting membrane potential and controlling RGC excitability. KATP channels are involved in RGC survival and neuroprotection. TASK channels are hypothesized to contribute to the regulation of resting membrane potentials and firing patterns of RGCs. Kv channels are important regulators of cellular excitability, functioning to modulate the amplitude, duration and frequency of action potentials and subthreshold depolarizations, and are also important in RGC development and protection. Eag channels may contribute to dendritic repolarization during excitatory postsynaptic potentials and to the attenuation of the back propagation of action potentials. KCa channels have been observed to contribute to repetitive firing in RGCs. Considering these important roles of K+ channels in RGCs, the study of K+ channels may be beneficial in elucidating the pathophysiology of RGCs and exploring novel RGC protection strategies. PMID- 23732985 TI - Ultrasound-targeted microbubble destruction-mediated gene delivery into canine livers. AB - Ultrasound (US) was applied to a targeted canine liver lobe simultaneously with injection of plasmid DNA (pDNA)/microbubble (MB) complexes into a portal vein (PV) segmental branch and occlusion of the inferior vena cava (IVC) to facilitate DNA uptake. By using a 1.1 MHz, 13 mm diameter transducer, a fivefold increase in luciferase activity was obtained at 3.3 MPa peak negative pressure (PNP) in the treated lobe. For more effective treatment of large tissue volumes in canines, a planar unfocused transducer with a large effective beam diameter (52 mm) was specifically constructed. Its apodized dual element configuration greatly reduced the near-field transaxial pressure variations, resulting in a remarkably uniform field of US exposure for the treated tissues. Together with a 15 kW capacity US amplifier, a 692-fold increase of gene expression was achieved at 2.7 MPa. Transaminase and histology analysis indicated minimal tissue damage. These experiments represent an important developmental step toward US-mediated gene delivery in large animals and clinics. PMID- 23732986 TI - Reading frame correction by targeted genome editing restores dystrophin expression in cells from Duchenne muscular dystrophy patients. AB - Genome editing with engineered nucleases has recently emerged as an approach to correct genetic mutations by enhancing homologous recombination with a DNA repair template. However, many genetic diseases, such as Duchenne muscular dystrophy (DMD), can be treated simply by correcting a disrupted reading frame. We show that genome editing with transcription activator-like effector nucleases (TALENs), without a repair template, can efficiently correct the reading frame and restore the expression of a functional dystrophin protein that is mutated in DMD. TALENs were engineered to mediate highly efficient gene editing at exon 51 of the dystrophin gene. This led to restoration of dystrophin protein expression in cells from Duchenne patients, including skeletal myoblasts and dermal fibroblasts that were reprogrammed to the myogenic lineage by MyoD. Finally, exome sequencing of cells with targeted modifications of the dystrophin locus showed no TALEN-mediated off-target changes to the protein-coding regions of the genome, as predicted by in silico target site analysis. This strategy integrates the rapid and robust assembly of active TALENs with an efficient gene-editing method for the correction of genetic diseases caused by mutations in non essential coding regions that cause frameshifts or premature stop codons. PMID- 23732987 TI - Viral delivery of antioxidant genes as a therapeutic strategy in experimental models of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with no effective treatment to date. Despite its multi-factorial aetiology, oxidative stress is hypothesized to be one of the key pathogenic mechanisms. It is thus proposed that manipulation of the expression of antioxidant genes that are downregulated in the presence of mutant SOD1 may serve as a therapeutic strategy for motor neuronal protection. Lentiviral vectors expressing either PRDX3 or NRF2 genes were tested in the motor neuronal-like NSC34 cell line, and in the ALS tissue culture model, NSC34 cells expressing the human SOD1(G93A) mutation. The NSC34 SOD1(G93A) cells overexpressing either PRDX3 or NRF2 showed a significant decrease in endogenous oxidation stress levels by 40 and 50% respectively compared with controls, whereas cell survival was increased by 30% in both cases. The neuroprotective potential of those two genes was further investigated in vivo in the SOD1(G93A) ALS mouse model, by administering intramuscular injections of adenoassociated virus serotype 6 (AAV6) expressing either of the target genes at a presymptomatic stage. Despite the absence of a significant effect in survival, disease onset or progression, which can be explained by the inefficient viral delivery, the promising in vitro data suggest that a more widespread CNS delivery is needed. PMID- 23732988 TI - Antitumor effects of chimeric receptor engineered human T cells directed to tumor stroma. AB - Cancer-associated fibroblasts (CAFs), the principle component of the tumor associated stroma, form a highly protumorigenic and immunosuppressive microenvironment that mediates therapeutic resistance. Co-targeting CAFs in addition to cancer cells may therefore augment the antitumor response. Fibroblast activation protein-alpha (FAP), a type 2 dipeptidyl peptidase, is expressed on CAFs in a majority of solid tumors making it an attractive immunotherapeutic target. To target FAP-positive CAFs in the tumor-associated stroma, we genetically modified T cells to express a FAP-specific chimeric antigen receptor (CAR). The resulting FAP-specific T cells recognized and killed FAP-positive target cells as determined by proinflammatory cytokine release and target cell lysis. In an established A549 lung cancer model, adoptive transfer of FAP specific T cells significantly reduced FAP-positive stromal cells, with a concomitant decrease in tumor growth. Combining these FAP-specific T cells with T cells that targeted the EphA2 antigen on the A549 cancer cells themselves significantly enhanced overall antitumor activity and conferred a survival advantage compared to either alone. Our study underscores the value of co targeting both CAFs and cancer cells to increase the benefits of T-cell immunotherapy for solid tumors. PMID- 23732989 TI - Recovery from experimental parkinsonism by semaphorin-guided axonal growth of grafted dopamine neurons. AB - Cell therapy in animal models of Parkinson's disease (PD) is effective after intrastriatal grafting of dopamine (DA) neurons, whereas intranigral transplantation of dopaminergic cells does not cause consistent behavioral recovery. One strategy to promote axonal growth of dopaminergic neurons from the substantia nigra (SN) to the striatum is degradation of inhibitory components such as chondroitin sulphate proteoglycans (CSPG). An alternative is the guidance of DA axons by chemotropic agents. Semaphorins 3A and 3C enhance axonal growth of embryonic stem (ES) cell-derived dopaminergic neurons in vitro, while Semaphorin 3C also attracts them. We asked whether intranigral transplantation of DA neurons, combined with either degradation of CSPG or with grafts of Semaphorin 3 expressing cells, towards the striatum, is effective in establishing a new nigrostriatal dopaminergic pathway in rats with unilateral depletion of DA neurons. We found depolarization-induced DA release in dorsal striatum, DA axonal projections from SN to striatum, and concomitant behavioral improvement in Semaphorin 3-treated animals. These effects were absent in animals that received intranigral transplants combined with Chondroitinase ABC treatment, although partial degradation of CSPG was observed. These results are evidence that Semaphorin 3-directed long-distance axonal growth of dopaminergic neurons, resulting in behavioral improvement, is possible in adult diseased brains. PMID- 23732990 TI - Intrapleural administration of AAV9 improves neural and cardiorespiratory function in Pompe disease. AB - Pompe disease is a neuromuscular disease resulting from deficiency in acid alpha glucosidase (GAA), results in cardiac, skeletal muscle, and central nervous system (CNS) pathology. Enzyme replacement therapy (ERT) has been shown to partially correct cardiac and skeletal muscle dysfunction. However, ERT does not cross the blood-brain barrier and progressive CNS pathology ensues. We tested the hypothesis that intrapleural administration of recombinant adeno-associated virus (rAAV9)-GAA driven by a cytomegalovirus (CMV) or desmin (DES) promoter would improve cardiac and respiratory function in Gaa(-/-) mice through a direct effect and retrograde transport to motoneurons. Cardiac magnetic resonance imaging revealed significant improvement in ejection fraction in rAAV9-GAA-treated animals. Inspiratory phrenic and diaphragm activity was examined at baseline and during hypercapnic respiratory challenge. Mice treated with AAV9 had greater relative inspiratory burst amplitude during baseline conditions when compared with Gaa(-/-). In addition, efferent phrenic burst amplitude was significantly correlated with diaphragm activity in both AAV9-DES and AAV9-CMV groups but not in Gaa(-/-). This is the first study to indicate improvements in cardiac, skeletal muscle, and respiratory neural output following rAAV administration in Pompe disease. These results further implicate a role for the CNS in Pompe disease pathology and the critical need to target the neurologic aspects in developing therapeutic strategies. PMID- 23732991 TI - Suppression of antiviral innate immunity by sunitinib enhances oncolytic virotherapy. AB - The use of lytic viruses to preferentially infect and eliminate cancer cells while sparing normal cells is a promising experimental therapeutic approach for treating cancer. However, the efficacy of oncolytic virotherapy is often limited by two innate immunity pathways, the protein kinase PKR and the 2'-5' oligoadenylate (OAS)/RNase L systems, which are widely present in many but not all tumor cell types. Previously, we reported that the anticancer drug, sunitinib, an inhibitor of VEGF-R and PDGF-R, has off-target effects against both PKR and RNase L. Here we show that combining sunitinib treatments with infection by an oncolytic virus, vesicular stomatitis virus (VSV), led to the elimination of prostate, breast, and kidney malignant tumors in mice. In contrast, either virus or sunitinib alone slowed tumor progression but did not eliminate tumors. In prostate tumors excised from treated mice, sunitinib decreased levels of the phosphorylated form of translation initiation factor, eIF2-alpha, a substrate of PKR, by 10-fold while increasing median viral titers by 23-fold. The sunitinib/VSV regimen caused complete and sustained tumor regression in both immunodeficient and immunocompetent animals. Results indicate that transient inhibition of innate immunity with sunitinib enhances oncolytic virotherapy allowing the recovery of tumor-bearing animals. PMID- 23732992 TI - Stem cell-based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study. AB - Distal tibial fractures tend towards delayed- or nonunion. The purpose of this study was to evaluate the safety and efficacy of early minimally invasive intervention (MII) in the treatment of these fractures. A total 24 consecutive patients who underwent operative treatment for distal tibial fractures were randomized into a control and an intervention group. MII entailed aspirating iliac crest bone marrow and peripheral blood, yielding mesenchymal stem cells (MSCs) and platelet-rich plasma (PRP) respectively, that were mixed with demineralized bone matrix (DBM) and injected under fluoroscopic control into the fracture site. No complications occurred in either group. The median time to union was 1.5 months in the MII group and 3 months in the control group. MII was found to be a safe and efficient procedure. PMID- 23732994 TI - Tuning the formation and functionalities of ultrafine CoFe2O4 nanocrystals via interfacial coherent strain. AB - Complex oxide nanocrystals with a spinel structure show their remarkable optical, electronic, mechanical, thermal, and magnetic properties. In this study, we present a simple yet versatile strategy to grow self-assembled epitaxial CoFe2O4 nanocrystals with well-controlled size (less than 10 nm) and single orientation. CoFe2O4 nanocrystals were fabricated via phase separation in a BiFeO3-CoF2O4 ultrathin film by pulsed laser deposition. The coherent strain at the BiFeO3 CoF2O4 interface suppressed the growth of the nanocrystals regardless of substrate temperatures. This strain also resulted in the ferromagnetic anisotropy and interesting conducting behaviors of ultrafine CFO nanocrystals. PMID- 23732993 TI - Systemic delivery of SapC-DOPS has antiangiogenic and antitumor effects against glioblastoma. AB - Saposin C-dioleoylphosphatidylserine (SapC-DOPS) nanovesicles are a nanotherapeutic which effectively target and destroy cancer cells. Here, we explore the systemic use of SapC-DOPS in several models of brain cancer, including glioblastoma multiforme (GBM), and the molecular mechanism behind its tumor-selective targeting specificity. Using two validated spontaneous brain tumor models, we demonstrate the ability of SapC-DOPS to selectively and effectively cross the blood-brain tumor barrier (BBTB) to target brain tumors in vivo and reveal the targeting to be contingent on the exposure of the anionic phospholipid phosphatidylserine (PtdSer). Increased cell surface expression of PtdSer levels was found to correlate with SapC-DOPS-induced killing efficacy, and tumor targeting in vivo was inhibited by blocking PtdSer exposed on cells. Apart from cancer cell killing, SapC-DOPS also exerted a strong antiangiogenic activity in vitro and in vivo. Interestingly, unlike traditional chemotherapy, hypoxic cells were sensitized to SapC-DOPS-mediated killing. This study emphasizes the importance of PtdSer exposure for SapC-DOPS targeting and supports the further development of SapC-DOPS as a novel antitumor and antiangiogenic agent for brain tumors. PMID- 23732995 TI - Clinical utility of biomarkers of endothelial activation and coagulation for prognosis in HIV infection: a systematic review. AB - INTRODUCTION: HIV infection is associated with vascular dysfunction and adverse cardiovascular outcomes. Our objective was to review the evidence regarding the clinical utility of endothelial activation and coagulation biomarkers for the prognosis of HIV-infected patients. METHODS: We searched PubMed and Embase for publications using the keywords "HIV" or "HIV infection" and "endothelium" or "coagulation". We reviewed reference lists and hand-searched for additional relevant articles. All clinical studies that enrolled non-pregnant, HIV-infected adults, measured biomarkers reflecting endothelial activation or coagulation, and prospectively evaluated their associations with vascular dysfunction or clinical outcomes were included. RESULTS: Seventeen studies were identified that fulfilled the inclusion criteria, of which 11 investigated endothelial activation biomarkers and 12 investigated coagulation biomarkers. Biomarkers and outcomes varied widely across studies. Overall, published studies support an association between P-selectin and venous thromboembolism in HIV-infected patients, an association between tissue-type plasminogen activator and death, and associations between D-dimer and several clinical outcomes, including venous thromboembolism, cardiovascular disease, and all-cause mortality. CONCLUSIONS: Several studies have demonstrated associations between biomarkers of endothelial activation and coagulation and clinically important outcomes in HIV-1 infection. Additional large-scale prospective investigations to determine the utility of endothelial activation and coagulation biomarkers for risk stratification and prediction of adverse outcomes are clearly warranted. PMID- 23732996 TI - New triarylpyrazoles as broad-spectrum anticancer agents: design, synthesis, and biological evaluation. AB - A new series of diarylureas and diarylamides possessing 1,3,4-triarylpyrazole scaffold was designed and synthesized. Their in vitro antiproliferative activities against NCI-60 cell line panel were tested. Most of the compounds showed strong and broad-spectrum antiproliferative activities. Compound 18 exerted sub-micromolar IC50 values over all the subpanels of nine different cancer types. Its IC50 value over MDA-MB-435 melanoma cell line was 27 nM. Compounds 10-13, 22, and 23 possessing urea spacer exerted lethal effect over the NCI-60 panel with mean %inhibitions more than 100% in single-dose testing. Compounds 13 and 23 with urea linker and 3',5'-bis(trifluoromethyl)phenyl terminal ring showed the highest mean %inhibition over the NCI-60 panel in single dose testing, and showed high potencies and broad-spectrum anticancer activities in five-dose testing. PMID- 23732998 TI - Impacts of arginine nutrition on embryonic and fetal development in mammals. AB - Embryonic loss and intrauterine growth restriction (IUGR) are significant problems in humans and other animals. Results from studies involving pigs and sheep have indicated that limited uterine capacity and placental insufficiency are major factors contributing to suboptimal reproduction in mammals. Our discovery of the unusual abundance of the arginine family of amino acids in porcine and ovine allantoic fluids during early gestation led to the novel hypothesis that arginine plays an important role in conceptus (embryo and extra embryonic membranes) development. Arginine is metabolized to ornithine, proline, and nitric oxide, with each having important physiological functions. Nitric oxide is a vasodilator and angiogenic factor, whereas ornithine and proline are substrates for uterine and placental synthesis of polyamines that are key regulators of gene expression, protein synthesis, and angiogenesis. Additionally, arginine activates the mechanistic (mammalian) target of rapamycin cell signaling pathway to stimulate protein synthesis in the placenta, uterus, and fetus. Thus, dietary supplementation with 0.83 % L-arginine to gilts consuming 2 kg of a typical gestation diet between either days 14 and 28 or between days 30 and 114 of pregnancy increases the number of live-born piglets and litter birth weight. Similar results have been reported for gestating rats and ewes. In sheep, arginine also stimulates development of fetal brown adipose tissue. Furthermore, oral administration of arginine to women with IUGR has been reported to enhance fetal growth. Collectively, enhancement of uterine as well as placental growth and function through dietary arginine supplementation provides an effective solution to improving embryonic and fetal survival and growth. PMID- 23732997 TI - Autoantibody profiling in multiple sclerosis using arrays of human protein fragments. AB - Profiling the autoantibody repertoire with large antigen collections is emerging as a powerful tool for the identification of biomarkers for autoimmune diseases. Here, a systematic and undirected approach was taken to screen for profiles of IgG in human plasma from 90 individuals with multiple sclerosis related diagnoses. Reactivity pattern of 11,520 protein fragments (representing ~38% of all human protein encoding genes) were generated on planar protein microarrays built within the Human Protein Atlas. For more than 2,000 antigens IgG reactivity was observed, among which 64% were found only in single individuals. We used reactivity distributions among multiple sclerosis subgroups to select 384 antigens, which were then re-evaluated on planar microarrays, corroborated with suspension bead arrays in a larger cohort (n = 376) and confirmed for specificity in inhibition assays. Among the heterogeneous pattern within and across multiple sclerosis subtypes, differences in recognition frequencies were found for 51 antigens, which were enriched for proteins of transcriptional regulation. In conclusion, using protein fragments and complementary high-throughput protein array platforms facilitated an alternative route to discovery and verification of potentially disease-associated autoimmunity signatures, that are now proposed as additional antigens for large-scale validation studies across multiple sclerosis biobanks. PMID- 23732999 TI - Intravital analysis of vascular permeability in mice using two-photon microscopy. AB - Blood vessel endothelium forms a semi-permeable barrier and its permeability controls the traffics of plasma contents. Here we report an intravital evaluation system for vascular permeability in mice using two-photon microscopy. We used various sizes of fluorescein-conjugated dextran as a tracer and its efflux was quantified by measuring the changes of fluorescent intensity both on the blood vessel area and the interstitial space. Using this system, we demonstrated that skin blood vessels limited the passage of dextran larger than 70 kDa under homeostatic conditions. We evaluated the kinetics of vascular permeability in histamine- or IgE-induced type I allergic models and a hapten-induced type IV allergic model. In such inflammatory conditions, the hyperpermeability was selectively induced in the postcapillary venules and dextran as large as 2000-kDa leaked from the bloods. Taken together, our study provides a convenient method to characterize the skin blood vessels as a traffic barrier in physiological conditions. PMID- 23733000 TI - Predictors of hematoma volume in deep and lobar supratentorial intracerebral hemorrhage. AB - IMPORTANCE: Hematoma volume is the strongest predictor of outcome in intracerebral hemorrhage (ICH). Despite known differences in the underlying biology between deep and lobar ICHs, limited data are available on location specificity of factors reported to affect hematoma volume. OBJECTIVE: To evaluate whether determinants of ICH volume differ by topography, we sought to estimate location-specific effects for potential predictors of this radiological outcome. DESIGN: Prospective cohort study. SETTING: Academic medical center. PARTICIPANTS: A total of 744 supratentorial primary ICH patients (388 deep and 356 lobar) aged older than 18 years admitted between January 1, 2000, and December 31, 2010. MAIN OUTCOMES AND MEASURES: Intracerebral hemorrhage volume measured from the computed tomography scan obtained on presentation to the emergency department. Linear regression analysis, stratified by ICH location, was implemented to identify determinants of log-transformed ICH volume. RESULTS: Median ICH volume was larger in lobar hemorrhages (39 mL; interquartile range, 16-75 mL) than in deep hemorrhages (13 mL; interquartile range, 5-40 mL; P < .001). In multivariable linear regression, independent predictors of deep ICH volume were intensity of anticoagulation (beta = 0.32; standard error [SE] = 0.08; P < .001; test for trend across 4 categories of the international normalized ratio), history of coronary artery disease (beta = 0.33; SE = 0.17; P = .05), male sex (beta = 0.28; SE = 0.14; P = .05), and age (beta = -0.02; SE = 0.01; P = .001). Independent predictors of lobar ICH volume were intensity of anticoagulation (beta = 0.14; SE = 0.06; P = .02) and antiplatelet treatment (beta = 0.27; SE = 0.13; P = .03). CONCLUSIONS AND RELEVANCE: Predictors of hematoma volume only partially overlap between deep and lobar ICHs. These findings suggest that the mechanisms that determine the extent of bleeding differ for deep and lobar ICHs. Further studies are needed to characterize the specific biological pathways that underlie the observed associations. PMID- 23733001 TI - Impact of t(11;14)(q13;q32) on the outcome of autologous hematopoietic cell transplantation in multiple myeloma. AB - The t(11;14)(q13;q32) translocation is seen in 15%-20% patients with multiple myeloma (MM). It generally is not associated with worse outcomes. We studied the impact of t(11;14)(q13;q32) on outcome in patients with MM who received high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto HCT). Eligible patients underwent high-dose chemotherapy followed by auto-HCT at the M.D. Anderson Cancer Center between February 2000 and August 2010, and had conventional cytogenetic (CC) or fluorescence in situ hybridization (FISH) results available before auto-HCT (n = 993). The cohort was divided into 3 groups of patients: (1) normal (diploid by CC and negative by FISH; n = 869); (2) t(11;14)(q13;q32) by CC or FISH (n = 27); and (3) high-risk (HR) abnormalities by CC or FISH (n = 97). Of the 27 patients with t(11;14)(q13;q32), 18 had isolated t(11;14)(q13;q32) and 9 had concurrent HR abnormalities. The primary objective was to compare outcomes in patients with t(11;14)(q13;q32) and patients with diploid or HR markers detected by CC or FISH studies. The median duration of follow-up in surviving patients was 37 months. The 3-year progression-free survival (PFS) was 47% for the normal group, 27% for the t(11;14)(q13;q32) group, and 13% for the HR group (P < .00001). The 3-year OS was 83% for the normal group, 63% for the t(11;14)(q13;q32) group, and 34% for the HR group (P < .00001). On multivariate analysis, t(11;14)(q13;q32) and HR abnormalities by CC or FISH and relapsed disease at auto-HCT were associated with shorter PFS, whereas t(11;14)(q13;q32) and HR abnormalities by CC or FISH, beta2 microglobulin of >3.5, and relapsed disease at the time of auto-HCT were associated with shorter OS. In conclusion, patients with t(11;14)(q13;q32) had worse outcomes than patients with normal CC or FISH studies, but better outcomes than patients with HR markers detected by CC or FISH studies. PMID- 23733002 TI - Tenacibaculum caenipelagi sp. nov., a member of the family Flavobacteriaceae isolated from tidal flat sediment. AB - A Gram-stain-negative, non-spore-forming, aerobic, non-flagellated, gliding and rod-shaped bacterial strain, designated HJ-26M(T), was isolated from a tidal flat sediment in the Korean peninsula. It grew optimally at 25-30 degrees C, at pH 7.0-8.0 and in the presence of 2 % (w/v) NaCl. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences revealed that the strain fell within the clade comprising Tenacibaculum species, clustering coherently with the type strains of Tenacibaculum lutimaris and Tenacibaculum aestuarii. Strain HJ-26M(T) exhibited the highest 16S rRNA gene sequence similarity values of 98.4 and 98.2 % to T. lutimaris TF-26(T) and T. aestuarii SMK-4(T), respectively, and of 94.9 97.4 % to the type strains of the other Tenacibaculum species. Strain HJ-26M(T) contained MK-6 as the predominant menaquinone and iso-C15:0 and iso-C17:0 3-OH as the major fatty acids. The DNA G+C content of strain HJ-26M(T) was 34.5 mol% and its mean DNA-DNA relatedness values with the type strains of T. lutimaris and T. aestuarii were 19 and 23 %, respectively. Differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain HJ-26M(T) is separate from other Tenacibaculum species. On the basis of the data presented, strain HJ-26M(T) is considered to represent a novel species of the genus Tenacibaculum, for which the name Tenacibaculum caenipelagi sp. nov. is proposed. The type strain is HJ-26M(T) (= KCTC 32323(T) = CECT 8283(T)). PMID- 23733003 TI - Algibacter miyuki sp. nov., a member of the family Flavobacteriaceae isolated from leachate of a brown algae reservoir. AB - A Gram-negative, aerobic, non-flagellated, non-gliding and rod-shaped bacterial strain, designated WS-MY6(T), was isolated from a brown algae reservoir in South Korea. Strain WS-MY6(T) grew optimally at 25 degrees C, at pH 7.0-8.0 and in the presence of 2 % (w/v) NaCl. Neighbour-joining, maximum-likelihood and maximum parsimony phylogenetic trees based on 16S rRNA gene sequences showed that strain WS-MY6(T) clustered with the type strains of Algibacter lectus and 'Algibacter undariae', showing 16S rRNA gene sequence similarity values of 98.1 and 98.4 %, respectively. It exhibited sequence similarities of 95.4-96.7 % to the type strains of the other Algibacter species, Pontirhabdus pectinovorans and Marinivirga aestuarii, whose reclassification into the genus Algibacter has been recently proposed. Strain WS-MY6(T) contained MK-6 as the predominant menaquinone and iso-C15:1 G, anteiso-C15:0 and iso-C17:0 3-OH as the major fatty acids. It contained phosphatidylethanolamine and two unidentified lipids as the major polar lipids. The DNA G + C content of strain WS-MY6(T) was 35.3 mol% and its DNA-DNA relatedness values with A. lectus KCTC 12103(T) and 'A. undariae' WS-MY9(T) was 21 and 13 %, respectively. The phylogenetic and genetic distinctiveness and differential phenotypic properties revealed that strain WS-MY6(T) is separate from existing Algibacter species. On the basis of the data presented, strain WS MY6(T) is considered to represent a novel species of the genus Algibacter, for which the name Algibacter miyuki sp. nov. is proposed. The type strain is WS MY6(T) (=KCTC 32382(T) =CECT 8300(T)). PMID- 23733004 TI - The efficiency of targeted intervention in limiting the spread of HIV and Hepatitis C Virus among injecting drug users. AB - BACKGROUND: Interventions aimed at minimizing the spread of blood borne infections among Injecting Drug Users (IDU) are impeded by limitations in resources. To enhance their efficiency, it may be beneficial to target specific behavioural subpopulations, distinguished by syringe sharing tendencies. METHODS: We used mathematical modelling to explore the effects of two types of intervention: removal of individuals from the injecting population and risk decrease at group-level (e.g. distribution of syringes). We computed the direct effects of intervention on the probability of obtaining and spreading infection as a function of baseline risk behaviour. Population level effects of (targeted) intervention were explored using a differential equations model, which incorporated two levels of risk. RESULTS: Within most scenarios of risk distribution considered, HIV could be substantially reduced or eliminated by targeting high risk IDU only. Conversely, higher incidence reductions for HCV were reached in many scenarios when targeting low risk IDU. The potential for preventing infections by removal of uninfected IDU increases with baseline risk, but so does the probability that an IDU is already infected before being reached by intervention. Decreasing risk is likely to only delay rather than prevent infection for IDU borrowing many syringes, especially for a very infectious disease such as HCV. CONCLUSIONS: The efficiency of intervention on injecting drug users may be much enhanced by targeting specific risk subgroups. However, the optimal targeting policy depends strongly on the infection under consideration. PMID- 23733005 TI - Statistical inference for extinction rates based on last sightings. AB - Rates of extinction can be estimated from sighting records and are assumed to be implicitly constant by many data analysis methods. However, historical sightings are scarce. Frequently, the only information available for inferring extinction is the date of the last sighting. In this study, we developed a probabilistic model and a corresponding statistical inference procedure based on last sightings. We applied this procedure to data on recent marine extirpations and extinctions, seeking to test the null hypothesis of a constant extinction rate. We found that over the past 500 years extirpations in the ocean have been increasing but at an uncertain rate, whereas a constant rate of global marine extinctions is statistically plausible. The small sample sizes of marine extinction records generate such high uncertainty that different combinations of model inputs can yield different outputs that fit the observed data equally well. Thus, current marine extinction trends may be idiosyncratic. PMID- 23733006 TI - X-ray absorption fine structure study of cobalt ion distribution in ferromagnetic Zn(1-x)Co(x)O films. AB - We examined the distribution of Co ions in ferromagnetic n-type Zn(1-x)Co(x)O semiconducting films with Co concentrations of 0.0-0.07 using x-ray absorption fine structure (XAFS) measurements at the Co and Zn K edges. Extended XAFS (EXAFS) revealed that Co ions mainly occupied the zinc sites in the films. X-ray absorption near edge structure (XANES) spectra demonstrated that the pre-edge peak of the Co K edge was substantially affected by the second neighboring Co ions in the zinc sites due to their environmental potential distortion. From the pre-edge peak and EXAFS analysis using ab initio calculations, we found that Co ions uniformly occupied the zinc sites of the Zn0.93Co0.07O film, whereas the Co ions of the Zn0.97Co0.03O and Zn0.95Co0.05O films were substituted at the zinc sites with a non-uniform distribution. The ferromagnetic properties of the Zn0.93Co0.07O film may be induced by direct interaction between the magnetic dipoles of the Co ions with a mean distance of 4.3 A, or by the Co conduction electron mediation. PMID- 23733007 TI - On the low-dose-radiation exposure in the Techa River Cohort and mortality from circulatory diseases. PMID- 23733008 TI - Reply to "On the low-dose radiation exposure in the Techa River Cohort and mortality from circulatory diseases" by Jargin (2013). PMID- 23733009 TI - Observation and theory of X-ray mirages. AB - The advent of X-ray lasers allowed the realization of compact coherent soft X-ray sources, thus opening the way to a wide range of applications. Here we report the observation of unexpected concentric rings in the far-field beam profile at the output of a two-stage plasma-based X-ray laser, which can be considered as the first manifestation of a mirage phenomenon in X-rays. We have developed a method of solving the Maxwell-Bloch equations for this problem, and find that the experimentally observed phenomenon is due to the emergence of X-ray mirages in the plasma amplifier, appearing as phase-matched coherent virtual point sources. The obtained results bring a new insight into the physical nature of amplification of X-ray radiation in laser-induced plasma amplifiers and open additional opportunities for X-ray plasma diagnostics and extreme ultraviolet lithography. PMID- 23733010 TI - Pharmaceutical and genetic determinants for interindividual differences of tacrolimus bioavailability in renal transplant recipients. AB - PURPOSE: The pharmacokinetics of orally administered immediate-release, twice daily (BID) and modified-release, once-daily (QD) formulations of tacrolimus have high interindividual variability. We investigated factors affecting interindividual variability of tacrolimus bioavailability in renal transplant patients. METHODS: Ninety-seven Japanese renal transplant patients (47 patients on tacrolimus BID and 50 patients on tacrolimus QD) were enrolled in this study. The tacrolimus absolute bioavailability was calculated using the area under the concentration-time curve from 0 to 24 h (AUC0-24) after continuous intravenous infusion and oral formulations of tacrolimus in the same recipient. RESULTS: The median (quartile 1-quartile 3) tacrolimus relative bioavailability for recipients with the CYP3A5*1 or CYP3A5*3/*3 alleles was significantly lower for the tacrolimus QD group [9.1 % (6.3-10.7 %) and 15.4 % (11.5-18.7 %), respectively] than for the tacrolimus BID group [12.6 % (9.9-14.2 %) and 19.3 % (16.5-24.8 %), respectively] (P = 0.004 and 0.028, respectively). Consequently, tacrolimus absolute bioavailability was lowest for recipients with the CYP3A5*1 allele taking tacrolimus QD. The CYP3A5 polymorphism had no impact on the dose-adjusted AUC0-24 of tacrolimus in patients on continuous intravenous infusion (P = 0.906). CONCLUSION: The larger interindividual variability of tacrolimus bioavailability for oral formulations appears to be due to the effects of the CYP3A5 polymorphism and the tacrolimus oral formulation. These factors should therefore be taken into account when determining individualized tacrolimus dosing. PMID- 23733011 TI - Subacute toxicity of copper and glyphosate and their interaction to earthworm (Eisenia fetida). AB - Glyphosate (GPS) and copper (Cu) are common pollutants in soils, and commonly co exist. Due to the chemical structure of GPS, it can form complexes of heavy metals and interface their bioavailability in soil environment. In order to explore the interactions between GPS and Cu, subacute toxicity tests of Cu and GPS on soil invertebrate earthworms (Eisenia fetida) were conducted. The relative weight loss and whole-worm metal burdens increased significantly with the increasing exposure concentration of Cu, while the toxicity of GPS was insignificant. The joint toxicity data showed that the relative weight loss and the uptake of Cu, as well as the superoxide dismutase, catalase and malondialdehyde activities, were significantly alleviated in the present of GPS, which indicated that GPS could reduce the toxicity and bioavailability of Cu in the soil because of its strong chelating effects. PMID- 23733012 TI - Micro x-ray absorption spectroscopic analysis of arsenic localization and biotransformation in Chironomus riparius Meigen (Diptera: Chironomidae) and Culex tarsalis Coquillett (Culicidae). AB - The distribution and speciation of arsenic (As) were analyzed in individuals of various life stages of a midge, Chironomus riparius, and the mosquito Culex tarsalis exposed to 1000 MUg/l arsenate. X-ray absorption spectroscopy (XAS) revealed that C. riparius larvae accumulate As in their midgut, with inorganic arsenate [As(V)] being the predominant form, followed by arsenite [As(III)] and an As-thiol. Reduced concentrations of As in pupal and adult stages of C. riparius indicate excretion of As between the larval and pupal stages. In adults, As was limited to the thorax, and the predominant form was an As-thiol. In Cx. tarsalis, As was not found in high enough concentrations to determine As speciation, but the element was distributed throughout the larva. In adults, As was concentrated in the thorax and eyes of adults. These results have implications for understanding the biotransformation of As and its movement from aquatic to terrestrial environments. PMID- 23733013 TI - Microbial effects on the release and attenuation of arsenic in the shallow subsurface of a natural geochemical anomaly. AB - Critical factors leading to arsenic release and attenuation from the shallow subsurface were studied with multidisciplinary approach in the natural gold arsenic geochemical anomaly at Mokrsko (Czech Republic). The results show that microbial reduction promotes arsenic release from Fe(III) (hydr)oxides and Fe(III) arsenates, thereby enhancing dissolved arsenic in the shallow groundwater at average concentration of 7.76 mg/L. In the organic-rich aggregates and wood particles, however, microbial sulfate reduction triggers the formation of realgar deposits, leading to accumulation of As in the distinct organic-rich patches of the shallow subsurface. We conclude that precipitation of realgar in the shallow subsurface of soil/sediment depends on specific and non-trivial combination of water and rock chemistry, microbial community composition and spatial organisation of the subsurface zone, where speciation in saturated environments varied on a centimeter scale from reduced (decomposed wood, H2S and realgar present) to oxidized (goethite and arsenate minerals are present). PMID- 23733014 TI - Multi-walled carbon nanotube-based carbon/carbon composites with three dimensional network structures. AB - Multi-walled carbon nanotube (MWCNT)-based carbon/carbon composites were fabricated by the chemical vapor infiltration of pyrolytic carbon into pre compressed MWCNT blocks. The pyrolytic carbon was deposited on the surface of the MWCNTs and filled the gaps between the MWCNTs, which improved the connection between the MWCNTs and formed a three-dimensional network structure. The mechanical and electrical properties were improved significantly. The values of the maximum compressed deformation, maximum breaking strength, Young's modulus and energy absorption are measured as 10.9%, 148.6 MPa, 1588.6 MPa and 13.8 kJ kg(-1), respectively. The conductivity reached about 204.4 S cm(-1), more than 10 times larger than that of pre-compressed MWCNT blocks. After annealing at 1800 degrees C in vacuum, the graphitization improved remarkably. The pyrolytic carbon deposited on the surface of the MWCNTs was rearranged along the walls, and resulted in an increase of the number of walls of the MWCNTs. PMID- 23733016 TI - Highly soluble energy relay dyes for dye-sensitized solar cells. AB - High solubility is a requirement for energy relay dyes (ERDs) to absorb a large portion of incident light and significantly improve the efficiency of dye sensitized solar cells (DSSCs). Two benzonitrile-soluble ERDs, BL302 and BL315, were synthesized, characterized, and resulted in a 65% increase in the efficiency of TT1-sensitized DSSCs. The high solubility (180 mM) of these ERDs allows for absorption of over 95% of incident light at their peak wavelength. The overall power conversion efficiency of DSSCs with BL302 and BL315 was found to be limited by their energy transfer efficiency of approximately 70%. Losses due to large pore size, dynamic collisional quenching of the ERD, energy transfer to desorbed sensitizing dyes and static quenching by complex formation were investigated and it was found that a majority of the losses are caused by the formation of statically quenched ERDs in solution. PMID- 23733015 TI - Identification of target genes of PAX3-FOXO1 in alveolar rhabdomyosarcoma. AB - Rhabdomyosarcoma (RMS) is a soft tissue sarcoma categorized into two major subtypes: alveolar RMS (ARMS) and embryonal RMS (ERMS). Most ARMS express the PAX3-FOXO1 (P3F) fusion oncoprotein generated by the 2;13 chromosomal translocation. In the present study, the downstream target genes of P3F were identified by analyzing two independent sets of gene expression profiles: primary RMS tumors and RD ERMS cells transduced with inducible P3F constructs. We found 34 potential target genes (27 upregulated and 7 downregulated) that were significantly and differentially expressed between P3F-positive and P3F-negative categories, both in primary RMS tumors and in the inducible P3F cell culture system. Gene ontology analysis of microarray data of the inducible P3F cell culture system employed indicated apoptosis, cell death, development, and signal transduction as overrepresented significant functional categories found in both upregulated and downregulated genes. Therefore, among the 34 potential target genes, the expression of cell death-related [Gremlin1, cysteine knot superfamily 1, BMP antagonist 1 (GREM1) and death-associated protein kinase 1 (DAPK1)] and development-related [myogenic differentiation 1 (MYOD1) and hairy/enhancer-of split related with YRPW motif 1 (HEY1)] genes were further investigated. The differential expression of GREM1, DAPK1, MYOD1 and HEY1 was confirmed in independent tumors and inducible cell culture systems. The expression of GREM1, DAPK1 and MYOD1 were significantly upregulated; HEY1 was significantly downregulated in independent P3F-positive ARMS tumors and transcriptionally active P3F cells, compared to those in ERMS tumors and transcriptionally inactive P3F cells. This study identified target genes of P3F and suggested that four downstream targets (GREM1, DAPK1, MYOD1 and HEY1) can contribute to the biological activities of P3F involved in growth suppression or cell death and myogenic differentiation. PMID- 23733017 TI - Effect of a mirror-like illusion on activation in the precuneus assessed with functional near-infrared spectroscopy. AB - Mirror therapy is a therapy to treat patients with pain syndromes or hemiparesis after stroke. However, the underlying neurophysiologic mechanisms are not clearly understood. In order to determine the effect of a mirror-like illusion (MIR) on brain activity using functional near-infrared spectroscopy, 20 healthy right handed subjects were examined. A MIR was induced by a digital horizontal inversion of the subjects' filmed hand. Optodes were placed on the primary motor cortex (M1) and the occipito-parietal cortex (precuneus, PC). Regions of interest (ROI) were defined a priori based on previous results of similar studies and confirmed by the analysis of effect sizes. Analysis of variance of the ROI signal revealed a dissociated pattern: at the PC, the MIR caused a significant inversion of a hemispheric lateralization opposite to the perceived hand, independent of the moving hand. In contrast, activity in M1 showed lateralization opposite to the moving hand, but revealed no mirror effect. These findings extend our understanding on interhemispheric rivalry and indicate that a MIR is integrated into visuomotor coordination similar to normal view, irrespective of the hand that is actually performing the task. PMID- 23733018 TI - Deep-penetration photoacoustic array imaging of calcifications. AB - Calcifications are one of the most important indicators for early breast cancer detection. We explore the feasibility of deep-penetration photoacoustic (PA) imaging of calcifications based on a medical ultrasound array imaging platform. Intralipid and chicken breast phantoms embedded with different-sized hydroxyapatite (HA) particles, which are the major components of calcifications, were imaged to verify the equipment's capability and penetration depth for the visualization of calcifications. An optimal near-infrared excitation wavelength was selected to maximize PA signals of HAs, resulting in a better HA signal-to blood ratio. We demonstrated that PA imaging is capable of visualizing 0.5-mm HA particles at a depth of 3 cm in chicken breast phantoms. The noise-equivalent penetration depth of the system for visualizing 0.5-mm HA particles in the human breast was estimated to be about 2.9 to 3.5 cm, which is clinically relevant as calcifications are usually found at a depth of 0.6 to 3.0 cm. Moreover, the feasibility of differentiating HA from blood by the PA spectroscopic technique was presented and the mechanism of the HA signal generation was discussed. The results show that PA imaging is a promising technique for real-time visualization of breast calcifications. PMID- 23733019 TI - Accuracy of retinal oximetry: a Monte Carlo investigation. AB - Retinal hemoglobin oxygen saturation (sO2) level is believed to be associated with the pathophysiology of several leading blinding diseases. Methods to properly measure retinal sO2 have been investigated for decades; however, the accuracy of retinal oximetry is still considered to be limited. The Monte Carlo simulation of photon transport in retina to examine how the accuracy of retinal oximetry is affected by local parameters is discussed. Fundus photography was simulated in a multilayer retinal model, in which a single vessel segment with 0.7 sO2 was embedded, at six optical wavelengths. Then, 200 million photons were traced in each simulation to ensure statistically stable results. The optical reflectance and energy deposit were recorded to measure sO2 using both the reflection method (existing retinal oximetry) and a new absorption method, photoacoustic ophthalmoscopy (PAOM). By varying the vessel diameter and melanin concentration in the retinal pigment epithelium, the relative error of sO2 measurement in the reflection method increased with increasing vessel diameter and melanin concentration; in comparison, the sO2 measurement was insensitive to these two parameters in PAOM. The results suggest that PAOM potentially can be a more accurate tool in quantifying retinal sO2. PMID- 23733020 TI - Dual/differential coherent anti-Stokes Raman scattering module for multiphoton microscopes with a femtosecond Ti:sapphire oscillator. AB - In the last decade, coherent anti-Stokes Raman scattering (CARS) microscopy has emerged as a powerful multiphoton imaging technique offering label-free chemical sensitivity and high three-dimensional resolution. However, its widespread application in the life sciences has been hampered by the use of costly pulsed lasers, the existence of a nonresonant background requiring involved technical solutions for its efficient suppression, and the limited acquisition speed of multiplex techniques addressing several vibrational resonances, if improved chemical specificity is needed. We have recently reported a differential CARS technique (D-CARS), which simultaneously measures two vibrational frequencies, enhancing the chemical selectivity and sensitivity without introducing costly hardware, while maintaining fast acquisition. In this study, we demonstrate a compact, fully automated, cost-effective module, which integrates on hardware and software level with a commercial multiphoton microscope based on a single 100 fs Ti:Sapphire oscillator and enables D-CARS microscopy in a user-friendly format for applications in the life sciences. PMID- 23733021 TI - En face parametric imaging of tissue birefringence using polarization-sensitive optical coherence tomography. AB - A technique for generating en face parametric images of tissue birefringence from scans acquired using a fiber-based polarization-sensitive optical coherence tomography (PS-OCT) system utilizing only a single-incident polarization state is presented. The value of birefringence is calculated for each A-scan in the PS-OCT volume using a quadrature demodulation and phase unwrapping algorithm. The algorithm additionally uses weighted spatial averaging and weighted least squares regression to account for the variation in phase accuracies due to varying OCT signal-to-noise-ratio. The utility of this technique is demonstrated using a model of thermally induced damage in porcine tendon and validated against histology. The resulting en face images of tissue birefringence are more useful than conventional PS-OCT B-scans in assessing the severity of tissue damage and in localizing the spatial extent of damage. PMID- 23733022 TI - Optimizing the performance of dual-axis confocal microscopes via Monte-Carlo scattering simulations and diffraction theory. AB - Dual-axis confocal (DAC) microscopy has been found to exhibit superior rejection of out-of-focus and multiply scattered background light compared to conventional single-axis confocal microscopy. DAC microscopes rely on the use of separated illumination and collection beam paths that focus and intersect at a single focal volume (voxel) within tissue. While it is generally recognized that the resolution and contrast of a DAC microscope depends on both the crossing angle of the DAC beams, 2theta, and the focusing numerical aperture of the individual beams, alpha, a detailed study to investigate these dependencies has not been performed. Contrast and resolution are considered as two main criteria to assess the performance of a point-scanned DAC microscope (DAC-PS) and a line-scanned DAC microscope (DAC-LS) as a function of theta and alpha. The contrast and resolution of these designs are evaluated by Monte-Carlo scattering simulations and diffraction theory calculations, respectively. These results can be used for guiding the optimal designs of DAC-PS and DAC-LS microscopes. PMID- 23733023 TI - Video-rate imaging of microcirculation with single-exposure oblique back illumination microscopy. AB - Oblique back-illumination microscopy (OBM) is a new technique for simultaneous, independent measurements of phase gradients and absorption in thick scattering tissues based on widefield imaging. To date, OBM has been used with sequential camera exposures, which reduces temporal resolution, and can produce motion artifacts in dynamic samples. Here, a variation of OBM that allows single exposure operation with wavelength multiplexing and image splitting with a Wollaston prism is introduced. Asymmetric anamorphic distortion induced by the prism is characterized and corrected in real time using a graphics-processing unit. To demonstrate the capacity of single-exposure OBM to perform artifact-free imaging of blood flow, video-rate movies of microcirculation in ovo in the chorioallantoic membrane of the developing chick are presented. Imaging is performed with a high-resolution rigid Hopkins lens suitable for endoscopy. PMID- 23733024 TI - Efficient discrete cosine transform model-based algorithm for photoacoustic image reconstruction. AB - The model-based algorithm is an effective reconstruction method for photoacoustic imaging (PAI). Compared with the analytical reconstruction algorithms, the model based algorithm is able to provide a more accurate and high-resolution reconstructed image. However, the relatively heavy computational complexity and huge memory storage requirement often impose restrictions on its applications. We incorporate the discrete cosine transform (DCT) in PAI reconstruction and establish a new photoacoustic model. With this new model, an efficient algorithm is proposed for PAI reconstruction. Relatively significant DCT coefficients of the measured signals are used to reconstruct the image. As a result, the calculation can be saved. The theoretical computation complexity of the proposed algorithm is figured out and it is proved that the proposed method is efficient in calculation. The proposed algorithm is also verified through the numerical simulations and in vitro experiments. Compared with former developed model-based methods, the proposed algorithm is able to provide an equivalent reconstruction with the cost of much less time. From the theoretical analysis and the experiment results, it would be concluded that the model-based PAI reconstruction can be accelerated by using the proposed algorithm, so that the practical applicability of PAI may be enhanced. PMID- 23733025 TI - Temperature-controlled optical stimulation of the rat prostate cavernous nerves. AB - Optical nerve stimulation (ONS) may be useful as a diagnostic tool for intraoperative identification and preservation of the prostate cavernous nerves (CN), responsible for erectile function, during prostate cancer surgery. Successful ONS requires elevating the nerve temperature to within a narrow range (~42 to 47 degrees C) for nerve activation without thermal damage to the nerve. This preliminary study explores a prototype temperature-controlled optical nerve stimulation (TC-ONS) system for maintaining a constant (+/-1 degrees C) nerve temperature during short-term ONS of the rat prostate CNs. A 150-mW, 1455-nm diode laser was operated in continuous-wave mode, with and without temperature control, during stimulation of the rat CNs for 15 to 30 s through a fiber optic probe with a 1-mm-diameter spot. A microcontroller opened and closed an in-line mechanical shutter in response to an infrared sensor, with a predetermined temperature set point. With TC-ONS, higher laser power settings were used to rapidly and safely elevate the CNs to a temperature necessary for a fast intracavernous pressure response, while also preventing excessive temperatures that would otherwise cause thermal damage to the nerve. With further development, TC-ONS may provide a rapid, stable, and safe method for intraoperative identification and preservation of the prostate CNs. PMID- 23733026 TI - Fluorescence spectroscopy as a highly potential single-entity tool to identify chromophores and fluorophores: study on neoplastic human brain lesions. AB - Fluorescence and diffuse reflectance spectroscopy are powerful tools to differentiate normal and malignant tissue based on the emissions from endogenous fluorophores and diffuse reflection of absorbers such as hemoglobin. However, separate analytical methods are used for the identification of fluorophores and hemoglobin. The estimation of fluorophores and hemoglobin simultaneously using a single technique of autofluorescence spectroscopy is reported, and its diagnostic potential on clinical tissue samples is potentially exploited. Surgically removed brain tissues from patients that are later identified pathologically as astrocytoma, glioma, meningioma, and schwannoma are studied. The emissions from prominent fluorophores collagen, flavin adenine dinucleotide, phospholipids, and porphyrin are analyzed at 320 and 410 nm excitations. The hemoglobin concentration is also calculated from the ratio of fluorescence emissions at 500 and 570 nm. A better classification of normal and tumor tissues is yielded for 410 nm excitation compared to 320 nm when diagnostic algorithm based on linear discriminant analysis is used. The potential of fluorescence spectroscopy as a single entity to evaluate the prominent fluorophores as well as the hemoglobin concentration within normal and tumor brain tissues is emphasized. PMID- 23733028 TI - Generation of human epidermis-derived mesenchymal stem cell-like pluripotent cells (hEMSCPCs). AB - We isolated human epidermis-derived mesenchymal stem cell-like pluripotent cells (hEMSCPCs) and demonstrate efficient harvesting, maintenance in vitro for at least 30 passages, reprogramming into multiple phenotypes in vivo, and integration into adult host tissues after injection into the mouse blastocyst to create chimeras. Cell phenotype was examined by karyotyping, immunostaining, immunofluorescence, and flow cytometry. A nested PCR protocol using primers specific for human SRY genes was designed to detect hEMSCPC-derived cells in female chimeric mice. FISH was used to validate the results of nested PCR. Results indicated that hEMSCPCs were derived from epidermis but were distinct from epidermal cells; they resembled mesenchymal stem cells (MSCs) morphologically and expressed the main markers of MSCs. About half of all female offspring of mice implanted with embryos injected with hEMSCPCs at the blastocyst stage harbored the human Y chromosome and tissue-specific human protein, thereby demonstrating the transdifferentiation of hEMSCPCs. PMID- 23733029 TI - Ventral encoding of functional affordances: a neural pathway for identifying errors in action. AB - Functional tool usage is a critical aspect of our daily lives. Not only must we know which tools to use for a specific action goal, we must also know how to manipulate those tools in meaningful way to achieve the goal of the action. The purpose of this study was to identify the regions of the brain critical to supporting the process of understanding errors in tool manipulation. Using fMRI, neural activations were recorded while subjects were presented with images demonstrating typical action scenes (screwdriver used on a screw), but with the tool being manipulated either correctly (screwdriver held by handle) or incorrectly (screwdriver held by bit rather than handle). Activations in fMRI for identifying correct over incorrect tool manipulation were seen along the canonical parietofrontal action network, while activations for identifying incorrect over correct tool manipulation were primarily seen at superior temporal areas and insula. We expand our hypotheses about ventral brain networks identifying contextual error to further suggest mechanisms for understanding functional tool actions, which collectively we regard as functional affordances. This proposes a fundamental role for ventral brain areas in functional action understanding. PMID- 23733030 TI - Pharmacogenetics in major depression: a comprehensive meta-analysis. AB - A number of candidate gene studies focused on major depression (MD) and antidepressant (AD) efficacy have been carried out, but results mainly remain inconclusive. We performed a comprehensive meta-analysis of published candidate gene studies focused on AD efficacy in MD to evaluate the cumulative evidence. A random-effect model was applied to study the polymorphisms with genotypic counts available from at least three independent studies. On the base of previous evidence, the analysis was stratified by ethnicity (Caucasian, Asian, and other/mixed), and AD class (SSRIs and mixed/other ADs). Genotypic data were available for 16 polymorphisms in 11 genes. After the exclusion of 5-HTTLPR in SLC6A4 included in another recent meta-analysis, 15 polymorphisms in 11 genes were included in the present meta-analysis (BDNF rs6265, SLC6A4 STin2, HTR1A rs6295, HTR2A rs6311, rs6313 and rs7997012, HTR6 rs1805054, TPH1 rs1800532, SLC6A2 rs5569, COMT rs4680, GNB3 rs5443, FKBP5 rs1360780 and rs3800373, and ABCB1 rs1045642 and rs2032582). Our results suggested that BDNF rs6265 (Val66Met) heterozygous genotype was associated with better SSRIs response compared to the homozygous genotypes, particularly in Asians (OR=1.53, 95%CI 1.12-2.07, p=0.007). SLC6A4 STin2, HTR2A rs6311 and rs7997012, GNB3 rs5443, FKBP5 rs1360780 and rs3800373, and ABCB1 rs2032582 showed associations with AD efficacy, but these results were highly dependent on one or two single studies. In conclusion, our findings suggested the BDNF Val66Met as the best single candidate involved in AD response, with a selective effect on SSRI treatment. Our overall results supported no major effect of any single gene variant on AD efficacy. PMID- 23733031 TI - Flaxseed in pediatric hyperlipidemia: a placebo-controlled, blinded, randomized clinical trial of dietary flaxseed supplementation for children and adolescents with hypercholesterolemia. AB - IMPORTANCE: Nonpharmacological management of hypercholesterolemia in children is challenging with few available options. OBJECTIVES To determine the safety and efficacy of dietary flaxseed supplementation in the management of hypercholesterolemia in children. DESIGN Four-week placebo-controlled, blinded, randomized clinical trial. SETTING: Specialized dyslipidemia clinic at a tertiary pediatric care center. PARTICIPANTS Thirty-two participants aged 8 to 18 years with low-density lipoprotein cholesterol from 135 mg/dL (3.5 mmol/L) to less than 193 mg/dL (5.0 mmol/L). INTERVENTION: The intervention group ate 2 muffins and 1 slice of bread daily containing ground flaxseed (30 g flaxseed total). The control group ate muffins and bread substituted with whole-wheat flour. MAIN OUTCOME AND MEASURE Attributable change in fasting lipid profile. RESULTS Dietary flaxseed supplementation resulted in an attributable decrease of -7.35 mg/dL ( 0.19 mmol/L) in high-density lipoprotein cholesterol (95% CI, -3.09 to -11.60 mg/dL[-0.08 to -0.30 mmol/L]; relative: -15%, 95% CI, -24% to -6%; P = .001), an increase of 29.23 mg/dL (+0.33 mmol/L) in triglycerides (95% CI, 4.43 to 53.14 mg/dL [+0.05 to +0.60 mmol/L]; relative: +26%, 95% CI, +4% to +48%; P = .02), and an increase of +4.88 g/d in dietary polyunsaturated fat intake (95% CI, +0.22 to +9.53; relative: +76%, 95% CI, +3% to +148%; P = .04). Flaxseed had no attributable effects on total cholesterol (-8.51 mg/dL [-0.22 mmol/L]; 95% CI, 21.66 to 4.25 mg/dL [-0.56 to +0.11 mmol/L]; relative: -4%, 95% CI, -10% to +2%; P = .20), low-density lipoprotein cholesterol (-6.96 mg/dL [-0.18 mmol/L]; 95% CI, -16.63 to 2.71 mg/dL [-0.43 to +0.07 mmol/L]; relative: -5%, 95% CI, -12% to +2%; P = .15), body mass index z score (+0.002; 95% CI, -0.147 to +0.150; relative: +0%, 95% CI, -12% to +12%; P = .30), or total caloric intake (+117 kcal; 95% CI, -243 to +479; relative: +8%, 95% CI, -17% to +33%; P = .52). An attributable change in total and low-density lipoprotein cholesterol failed to exclude a potential benefit of flaxseed supplementation based on a prespecified minimum clinically important reduction of 10%. No concerns were noted regarding safety. CONCLUSIONS AND RELEVANCE: The use of dietary flaxseed supplementation, while safe, was associated with adverse changes in the lipid profile of children with hypercholesterolemia, although a potential benefit of low-density lipoprotein cholesterol lowering could not be excluded. The use of flaxseed supplementation in children with hypercholesterolemia might not be a viable option for lipid management in this population. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01007344. PMID- 23733032 TI - Antioxidant activity potential of gamma irradiated carrageenan. AB - The antioxidant capacity of irradiated kappa-, iota-, lambda-carrageenans were investigated using the hydroxyl radical scavenging assay, reducing power assay and DPPH radical scavenging capacity assay. The degree of oxidative inhibition increased with increasing concentration and dose. The type of carrageenan had also an influence on its antioxidant activity which followed the order of lambda10) and the expression levels of miRNA-218 were confirmed by RT-PCR. The group with lymph node metastasis and the elder group (age>64) showed lower expression of miRNA-218 (P=0.003 and 0.002), compared to patients without lymph nodes metastasis and patients in the younger group (age<=64), respectively. The expression of miRNA-218 showed a decreasing trend from normal acinar/ductal epithelium, intraductal papillary mucinous neoplasm (IPMN), pancreatic cancer to metastatic lymph nodes by ISH. Among 8 predicted target genes of miRNA-218, rodent bone (ROBO-1) was confirmed to be upregulated in both mRNA and protein levels in pancreatic cancer. In conclusion, we established a screening strategy based on microarray results and found miRNA-218 to be a notable gene related to lymphatic metastasis of pancreatic cancer. Downregulation of miRNA-218 and upregulation of ROBO-1 were first demonstrated in pancreatic cancer. The miRNA 218 and ROBO-1 signaling axis may contribute to the lymphatic metastasis of pancreatic cancer. PMID- 23733162 TI - Risk of cervical precancer and cancer in women with cervical intraepithelial neoplasia grade 1 on endocervical curettage. AB - OBJECTIVE: This study aimed to characterize the 24-month risk of cervical intraepithelial neoplasia grade 2 or worse (CIN 2+) and grade 3 or worse (CIN 3+) in women with low-risk cytological finding and CIN 1 on endocervical curettage (ECC). MATERIALS AND METHODS: Cervical screening tests and cervical biopsy results from Kaiser Permanente Northern California were reviewed for years 2004 to 2008. Women with index cytological result of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion who underwent excisional procedure within 24 months of CIN 1 diagnosis were grouped by ECC status. A third cohort comprised women with ECC-CIN 1 followed up without excisional procedure. The 24-month cumulative incidence of CIN 2+ and CIN 3+ was calculated for each cohort. RESULTS: Excisional procedures were performed in 224 women; 54 had ECC-CIN 1 with ectocervical biopsy CIN 1 or less, and 170 had ectocervical CIN 1 with negative ECC finding. The 24-month risk of CIN 2+ was lower in the ECC-CIN 1 cohort compared with the ECC-negative (ectocervical CIN 1) cohort (24.1 vs 44.7%, p = .018) and nonsignificantly lower for CIN 3+ (7.4% vs 14.1%, p = .23). Among 203 women with ECC-CIN 1 followed up without excisional procedure but with follow-up ECC at a median of 21.7 months from index ECC, CIN 2 was found in 21 (10.3%, 95% CI = 6.7%-15.6%), and CIN 3 was found in 3 (1.5%, 95% CI = 0.4%-4.6%). CONCLUSIONS: A diagnosis of CIN 1 on ECC preceded by atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion does not increase the risk of CIN 2+ compared with women with ectocervical CIN 1 and negative ECC. The risk of CIN 2+ in women followed up without excisional procedure is sufficiently low that it is reasonable to offer conservative management similar to that for ectocervical CIN 1. PMID- 23733163 TI - Human papillomavirus infection and the association with abnormal Pap findings in Yukon, Canada. AB - OBJECTIVE: Certain types of the human papillomavirus (HPV) are highly associated with cervical cancer or dysplasia, but its prevalence is largely unknown in northern Canada where there is significant aboriginal representation and unique barriers to accessing care. This study determined the prevalence of HPV infection and its association with cervical cancer precursor lesions in Yukon, Canada. MATERIALS AND METHODS: This was a cross-sectional study of 1,542 women attending routine Pap smear screening in 14 communities in Yukon, from February 2009 to June 2010. Type-specific HPV infection was detected by an in-house Luminex assay. Cervical Pap cytology was evaluated by pathologists blinded to HPV test results. RESULTS: The overall HPV prevalence rate in Yukon women was higher than those reported in some Canadian provinces and other countries. Human papillomavirus infection prevalence rates were 24.5% for any type, 18.4% for high-risk types, 6.2% for HPV types 16 or 18, 6.7% for HPV alpha-7 species, and 10.6% for HPV alpha-9 species. Human papillomavirus infection was strongly associated with single marital status or having 2 or more sexual partners in the past year. Human papillomavirus infection (overall, high-risk types, HPV-16/18, alpha-7, or alpha 9 species) was strongly associated with Pap cytological abnormalities (adjusted odds ratios ranged from 8.4 to 44.2). CONCLUSIONS: As in other areas of northern Canada, HPV prevalence for high-risk types and alpha-7 species is high among women in the Yukon. Sexual behavioral factors strongly influence HPV prevalence rates. The findings may have implications for HPV vaccination and health promotion programs in northern regions. PMID- 23733164 TI - Squamous cell carcinoma of the vulva: a comparison between women 35 years or younger and 90 years or older. AB - OBJECTIVE: This study aimed to compare clinical features, diagnosis, management, and outcomes between women 35 years or younger and 90 years or older with vulvar squamous cell carcinoma referred to Queensland Centre for Gynaecological Cancer between 1983 and 2010. MATERIALS AND METHODS: Fifty-seven case records, including pathology reports for these 2 groups were reviewed and analyzed using the computer software SPSS 11.0. RESULTS: Of the cases, 34 were 35 years or younger (mean = 31.6 years), and 23 90 years or older (mean = 92.6 years). International Federation of Gynecology and Obstetrics classification showed grade 1 for 74% in the younger group and 55% for the older group. Patient status showed 22 alive (65%) in the younger group and 4 alive (17%) in the older group. Three younger patients (9%) were dead of disease and 8 (35%) in the older group. Three patients (9%) died of another disease in the younger group and 10 patients (43%) in the older group. Initial treatment was surgical in 30 younger cases (88%) and 18 older cases (78%). CONCLUSIONS: We demonstrated a trend toward younger women presenting with vulvar squamous cell carcinoma and a history of human papillomavirus and vulvar intraepithelial neoplasia. Immune deficiency diseases occurred in 23% of the younger group, but none occurred in the older group, where Alzheimer disease, heart disease, and renal failure (57%) were present. Poorly differentiated tumors and an International Federation of Gynecology and Obstetrics classification of 2 or more resulted in a worse outcome than did better differentiated lesions, irrespective of additional medical conditions. PMID- 23733165 TI - Trichloroacetic acid application versus spray monopolar diathermy for treating benign cervical lesions: a randomized controlled clinical trial. AB - OBJECTIVE: This study aimed to compare efficacy, tolerability, and safety of trichloroacetic acid (TCA) painting versus monopolar spray coagulation of the cervix for treating persistent benign cervical lesions. MATERIALS AND METHODS: A prospective randomized controlled trial was done in a tertiary care referral facility and university hospital. A total of 246 cases with objective evidence of benign cervical lesions were divided into 2 groups according to the line of management. Group A was composed of 126 cases subjected to spray monopolar coagulation, whereas group B was composed of 120 cases subjected to TCA application. Cervical smearing and colposcopy with or without cervical biopsy were performed to exclude underlying malignant lesions. Trichloroacetic acid painting or spray monopolar coagulation of the benign cervical lesion(s) was also performed. Follow-up was performed to assess relief of symptoms and cervical morphology for 1 month. Main outcome measures include success of management tool, relief of symptoms, and normal cervical morphology after 1 month of therapy. RESULTS: A statistically significant cure rate of cervical lesions after treatment in both groups without significant difference between both groups was reported. Failure rate was reported more in group B than group A mainly owing to hypertrophied ectopy and cervical polyp. Patient in group A reported low satisfaction (26.9%) and poor tolerability rate (44.5%) as compared with patients in group B, who reported high satisfaction (77.5%) and good tolerability rate (77.5%), this difference was statistically significant. CONCLUSIONS: Both topical application of 70% TCA and monopolar spray coagulation offer considerable efficacy, acceptable success rates, and minimal complications. Spray coagulation is significantly superior in terms of less persistent or incompletely healed lesions. Nevertheless, topical application of 70% TCA has the advantages of simplicity, higher patient tolerability, and safety, which can be widely used by gynecologists who have limited experience with surgical procedures. It is highly recommended if the cervical lesion is ectopy or nonspecific cervicitis but not hypertrophic lesion such as hypertrophic ectopy or polyp. PMID- 23733166 TI - ALARA in Existing Exposure Situations: 14th European ALARA Network Workshop, 4-6 September 2012, Dublin. PMID- 23733167 TI - Vitamin D deficiency and the risk of preeclampsia and eclampsia in Bangladesh. AB - Maternal vitamin D deficiency has been proposed as a risk factor for preeclampsia, but no significant studies have been conducted to evaluate its relationship with eclampsia. Our goal in this study was to assess the prevalence and potential risk of vitamin D deficiency for both preeclampsia and eclampsia in Bangladesh. Using a case-control design, we measured serum 25(OH)D levels in pregnant women receiving care at the Dhaka Medical College Hospital with preeclampsia (n=33), eclampsia (n=79), and normal pregnancy (controls, n=76). Odds of developing preeclampsia and eclampsia with vitamin D deficiency were calculated using logistic regression analysis. The prevalence of vitamin D insufficiency was very high with more than 3 quarters (78%) of all subjects having a serum 25(OH)D level<30 ng/ml. The mean serum 25(OH)D level was 24.86 ng/ml in controls, 23.96 ng/ml in pre-eclamptic women, and 21.56 ng/ml in eclampsia patients. Comparing to those who had a serum 25(OH)D level of >=30 ng/ml, the odds ratio (95% CI) of developing preeclampsia and eclampsia in mothers with vitamin D insufficiency were 3.9 (95% CI=1.18-12.87) and 5.14 (95% CI=1.98-13.37), respectively (adjusting for age, BMI and duration of pregnancy). The odds of developing preeclampsia and eclampsia may increase by up to 5-fold in women with vitamin D insufficiency. Since preeclampsia and eclampsia can lead to serious complications for both mother and the offspring, vitamin D may be supplemented during pregnancy in high risk populations to decrease these adverse consequences. PMID- 23733168 TI - Synthesis of 4H-1,4-oxazines as transthyretin amyloid fibril inhibitors. AB - 4H-1,4-oxazines were designed as transthyretin (TTR) amyloid fibril inhibitors based on an analysis of the interactions between known small molecule inhibitors and TTR by molecular docking. A series of 2,4,6-triaryl-4H-1,4-oxazines was synthesized by the cyclization of N,N-bis(phenacyl)anilines with POCl3 in pyridine. Inhibition of TTR amyloid fibril was evaluated by a fibril formation assay. The results indicate that 4H-1,4-oxazines significantly inhibit TTR amyloid fibril at a concentration of 7.2 MUM. PMID- 23733169 TI - Ultrafast charge and discharge biscrolled yarn supercapacitors for textiles and microdevices. AB - Flexible, wearable, implantable and easily reconfigurable supercapacitors delivering high energy and power densities are needed for electronic devices. Here we demonstrate weavable, sewable, knottable and braidable yarns that function as high performance electrodes of redox supercapacitors. A novel technology, gradient biscrolling, provides fast-ion-transport yarn in which hundreds of layers of conducting-polymer-infiltrated carbon nanotube sheet are scrolled into ~20 MUm diameter yarn. Plying the biscrolled yarn with a metal wire current collector increases power generation capabilities. The volumetric capacitance is high (up to ~179 F cm(-3)) and the discharge current of the plied yarn supercapacitor linearly increases with voltage scan rate up to ~80 V s(-1) and ~20 V s(-1) for liquid and solid electrolytes, respectively. The exceptionally high energy and power densities for the complete supercapacitor, and high cycle life that little depends on winding or sewing (92%, 99% after 10,000 cycles, respectively) are important for the applications in electronic textiles. PMID- 23733170 TI - Dysbiosis signature of fecal microbiota in colorectal cancer patients. AB - The human gut microbiota is a complex system that is essential to the health of the host. Increasing evidence suggests that the gut microbiota may play an important role in the pathogenesis of colorectal cancer (CRC). In this study, we used pyrosequencing of the 16S rRNA gene V3 region to characterize the fecal microbiota of 19 patients with CRC and 20 healthy control subjects. The results revealed striking differences in fecal microbial population patterns between these two groups. Partial least-squares discriminant analysis showed that 17 phylotypes closely related to Bacteroides were enriched in the gut microbiota of CRC patients, whereas nine operational taxonomic units, represented by the butyrate-producing genera Faecalibacterium and Roseburia, were significantly less abundant. A positive correlation was observed between the abundance of Bacteroides species and CRC disease status (R = 0.462, P = 0.046 < 0.5). In addition, 16 genera were significantly more abundant in CRC samples than in controls, including potentially pathogenic Fusobacterium and Campylobacter species at genus level. The dysbiosis of fecal microbiota, characterized by the enrichment of potential pathogens and the decrease in butyrate-producing members, may therefore represent a specific microbial signature of CRC. A greater understanding of the dynamics of the fecal microbiota may assist in the development of novel fecal microbiome-related diagnostic tools for CRC. PMID- 23733171 TI - Whole-cell MALDI-TOF mass spectrometry and multilocus sequence analysis in the discrimination of Pseudomonas stutzeri populations: three novel genomovars. AB - Pseudomonas stutzeri is a widely distributed species with very high genetic diversity and metabolic capacities, occupying many diverse ecological niches. A collection of 229 P. stutzeri strains isolated from different habitats and geographical locations has been previously characterised phylogenetically by rpoD gene sequencing analysis and in the present study 172 of them phenotypically by whole-cell MALDI-TOF mass spectrometry. Fifty-five strains were further analysed by multilocus sequencing analysis to determine the phylogenetic population structure. Both methods showed coherence in strain grouping; 226 strains were allocated in the 18 genomovars known presently. The remaining three strains are proposed as references for three novel genomovars in the species. The correlation and usefulness of sequence-based phylogenetic analysis and whole-cell MALDI-TOF mass spectrometry, which are essential for autoecological studies in microbial ecology, is discussed for the differentiation of P. stutzeri populations. PMID- 23733172 TI - Is there any association between cerebral vasoconstriction/vasodilatation and microdialysis Lactate to Pyruvate ratio increase? AB - BACKGROUND: Although abnormally high Lactate/Pyruvate ratio (LPR) could indicate cerebral ischemia for brain injury patients, there is a debate on what is primary factor responsible for LPR increase. METHODS: A data analysis experiment is taken to test whether any association between cerebral vasodilatation/vasoconstriction and LPR increase exists. We studied 4,316 microdialysis data samples collected in an average interval of 1.3 h from 30 severe traumatic brain injury (TBI) patients. The LPR increase episodes were automatically identified using a moving time-window of 5 samples. A novel pulse morphological template matching (PMTM) algorithm was applied to the intracranial pressure (ICP) data of the corresponding patients to assess the occurrence of cerebral vasodilatation and vasoconstriction during the identified LPR increase episodes. Several analyses were performed to evaluate the association between cerebral vasoconstriction/vasodilatation and LPR increase. RESULTS: Results revealed that although more than half of the LPR increase episodes are not associated with any detected cerebral vasoconstriction/vasodilatation, when a vaso-change happens in association of LPR increase, it is more likely that this vaso-change is in the form of vasoconstriction rather than vasodilatation. Also for few subjects with dominant number of vasoconstriction episodes, a causality relationship between vasoconstriction and LPR increase were observed (vasoconstriction precedes LPR increase). CONCLUSIONS: Using continuous intracranial pressure monitoring and our pulse morphological template matching (PMTM) algorithm could be potentially helpful in teasing out whether culprit cerebral vascular changes precede metabolic crisis for traumatic brain injury patients and hence guiding the management of this condition. PMID- 23733173 TI - Successful management of severe neuroinvasive eastern equine encephalitis. AB - BACKGROUND: Eastern Equine Encephalitis (EEE) virus is an arbovirus that mostly causes asymptomatic infection in humans; however, some people can develop a neuroinvasive infection associated with a high mortality. METHODS: We present a case of a patient with severe neuroinvasive EEE. RESULTS: A 21-year-old man initially presented with headache, fever, and vomiting and was found to have a neutrophilic pleocytosis in his cerebrospinal fluid. He eventually was diagnosed with EEE, treated with high-dose methylprednisolone and intravenous immunoglobulin. His course in the NeuroIntensive Care Unit was complicated by cerebral edema and intracranial hypertension, requiring osmotherapy, pentobarbital and placement of an external ventricular device, and subclinical seizures, necessitating multiple anti-epileptic drugs CONCLUSIONS: A multifaceted approach including aggressive management of cerebral edema and ICP as well as treatment with immunomodulating agents and cessation of seizures may prevent brain herniation, secondary neurologic injury and death in patients with EEE. Effective management and treatment in our patient contributed to a dramatic recovery and ultimate good outcome. PMID- 23733175 TI - A fast cholinergic modulation of the primary acoustic startle circuit in rats. AB - Cochlear root neurons (CRNs) are the first brainstem neurons which initiate and participate in the full expression of the acoustic startle reflex. Although it has been suggested that a cholinergic pathway from the ventral nucleus of the trapezoid body (VNTB) conveys auditory prepulses to the CRNs, the neuronal origin of the VNTB-CRNs projection and the role it may play in the cochlear root nucleus remain uncertain. To determine the VNTB neuronal type which projects to CRNs, we performed tract-tracing experiments combined with mechanical lesions, and morphometric analyses. Our results indicate that a subpopulation of non olivocochlear neurons projects directly and bilaterally to CRNs via the trapezoid body. We also performed a gene expression analysis of muscarinic and nicotinic receptors which indicates that CRNs contain a cholinergic receptor profile sufficient to mediate the modulation of CRN responses. Consequently, we investigated the effects of auditory prepulses on the neuronal activity of CRNs using extracellular recordings in vivo. Our results show that CRN responses are strongly inhibited by auditory prepulses. Unlike other neurons of the cochlear nucleus, the CRNs exhibited inhibition that depended on parameters of the auditory prepulse such as intensity and interstimulus interval, showing their strongest inhibition at short interstimulus intervals. In sum, our study supports the idea that CRNs are involved in the auditory prepulse inhibition of the acoustic startle reflex, and confirms the existence of multiple cholinergic pathways that modulate the primary acoustic startle circuit. PMID- 23733176 TI - A role for anterior thalamic nuclei in contextual fear memory. AB - Understanding the neural processes that govern the attribution of a predictive value to environmental stimuli is a major issue in behavioural neuroscience. The main strategy to explore this question has been the use of Pavlovian fear conditioning paradigms. While a majority of studies have focussed on the specific role of the hippocampus and amygdala in contextual versus cued fear, very few studies examined the potential role of subcortical limbic areas. Among those, the anterior thalamic nuclei (ATN) connect to both the hippocampus and the amygdala and also to the cingulate region which is known to support fear-related activity. Here, we show that rats sustaining ATN lesions exhibit a specific impairment following context but not tone conditioning. ATN lesions slowed down acquisition without preventing normal freezing behaviour when rats were reexposed to the conditioning context 24 h later. However, ATN rats exhibited poor retrieval of contextual but not cued fear when assessed 3 weeks after conditioning. In addition, extinction was faster in ATN rats and spontaneous recovery of contextual fear was impaired by the lesions. These deficits indicate that contextual fear memories established in the absence of the ATN are not robust. Collectively, these findings support an involvement of the ATN in the circuits underlying contextual fear memory. PMID- 23733177 TI - Exploring the potential environmental functions of viable but non-culturable bacteria. AB - A conventional plate count is the most commonly employed method to estimate the number of living bacteria in environmental samples. In fact, judging the level of viable culture by plate count is limited, because it is often several orders of magnitude less than the number of living bacteria actually present. Most of the bacteria are in "viable but non-culturable" (VBNC) state, whose cells are intact and alive and can resuscitate when surrounding conditions are more favorable. The most exciting recent development in resuscitating VBNC bacteria is a bacterial cytokine, namely, the resuscitation-promoting factor (Rpf), secreted by Micrococcus luteus, which promotes the resuscitation and growth of high G+C Gram positive organisms, including some species of the genus Mycobacterium. However, most of studies deal with VBNC bacteria only from the point of view of medicine and epidemiology. It is therefore of great significance to research whether these VBNC state bacteria also possess some useful environmental capabilities, such as degradation, flocculation, etc. Further studies are needed to elucidate the possible environmental role of the VBNC bacteria, rather than only considering their role as potential pathogens from the point view of epidemiology and public health. We have studied the resuscitation of these VBNC bacteria in polluted environments by adding culture supernatant containing Rpf from M. luteus, and it was found that, as a huge microbial resource, VBNC bacteria could provide important answers to dealing with existing problems of environmental pollution. This mini-review will provide new insight for considering the potentially environmental functions of VBNC bacteria. PMID- 23733178 TI - The impact of radiographic retropharyngeal adenopathy in oropharyngeal cancer. AB - BACKGROUND: We performed this study to define the incidence of radiographic retropharyngeal lymph node (RPLN) involvement in oropharyngeal cancer (OPC) and its impact on clinical outcomes, neither of which has been well established to date. METHODS: Our departmental database was queried for patients irradiated for OPC between 2001 and 2007. Analyzable patients were those with imaging data available for review to determine radiographic RPLN status. Demographic, clinical, and outcome data were retrieved and analyzed. RESULTS: The cohort consisted of 981 patients. The median follow-up was 69 months. The base of the tongue (47%) and the tonsil (46%) were the most common primary sites. The majority of patients had stage T1 to T2 primary tumors (64%), and 94% had stage 3 to 4B disease. Intensity-modulated radiation therapy was used in 77% of patients, and systemic therapy was administered in 58% of patients. The incidence of radiographic RPLN involvement was 10% and was highest for the pharyngeal wall (23%) and lowest for the base of the tongue (6%). RPLN adenopathy correlated with several patient and tumor factors. RPLN involvement was associated with poorer 5 year outcomes on univariate analysis (P<.001 for all) for local control (79% vs 92%), nodal control (80% vs 93%), recurrence-free survival (51% vs 81%), distant metastases-free survival (66% vs 89%), and overall survival (52% vs 82%) and maintained significance on multivariate analysis for local control (P = .023), recurrence-free survival (P = .001), distant metastases-free survival (P = .003), and overall survival (P = .001). CONCLUSIONS: In this cohort of nearly 1000 patients investigating [corrected] radiographic RPLN adenopathy in OPC, RPLN involvement was observed in 10% of patients and portends [corrected] a negative influence on disease recurrence, distant relapse, and survival. In this cohort of nearly 1000 patients investigating radiographic RPLN adenopathy in OPC, RPLN involvement was observed in 10% of patients and portends a negative influence on disease recurrence, distant relapse, and survival. PMID- 23733179 TI - Reducing racial/ethnic disparities in childhood obesity: the role of early life risk factors. AB - IMPORTANCE Many early life risk factors for childhood obesity are more prevalent among blacks and Hispanics than among whites and may explain the higher prevalence of obesity among racial/ethnic minority children. OBJECTIVE To examine the extent to which racial/ethnic disparities in adiposity and overweight are explained by differences in risk factors during pregnancy (gestational diabetes and depression), infancy (rapid infant weight gain, feeding other than exclusive breastfeeding, and early introduction of solid foods), and early childhood (sleeping <12 h/d, presence of a television set in the room where the child sleeps, and any intake of sugar-sweetened beverages or fast food). DESIGN Prospective prebirth cohort study. SETTING Multisite group practice in Massachusetts. PARTICIPANTS Participants included 1116 mother-child pairs (63% white, 17% black, and 4% Hispanic) EXPOSURE Mother's report of child's race/ethnicity. MAIN OUTCOMES AND MEASURES Age- and sex-specific body mass index (BMI) z score, total fat mass index from dual-energy x-ray absorptiometry, and overweight or obesity, defined as a BMI in the 85th percentile or higher at age 7 years. RESULTS Black (0.48 U [95% CI, 0.31 to 0.64]) and Hispanic (0.43 [0.12 to 0.74]) children had higher BMI z scores, as well as higher total fat mass index and overweight/obesity prevalence, than white children. After adjustment for socioeconomic confounders and parental BMI, differences in BMI z score were attenuated for black and Hispanic children (0.22 U [0.05 to 0.40] and 0.22 U [ 0.08 to 0.52], respectively). Adjustment for pregnancy risk factors did not substantially change these estimates. However, after further adjustment for infancy and childhood risk factors, we observed only minimal differences in BMI z scores between whites, blacks (0.07 U [-0.11 to 0.26]), and Hispanics (0.04 U [ 0.27 to 0.35]). We observed similar attenuation of racial/ethnic differences in adiposity and prevalence of overweight or obesity. CONCLUSIONS AND RELEVANCE Racial/ethnic disparities in childhood adiposity and obesity are determined by factors operating in infancy and early childhood. Efforts to reduce obesity disparities should focus on preventing early life risk factors. PMID- 23733180 TI - Selective induction of apoptosis in various cancer cells irrespective of drug sensitivity through a copper chelate, copper N-(2 hydroxy acetophenone) glycinate: crucial involvement of glutathione. AB - Drug induced toxicity and drug resistance are the major impediments to successful application of cancer chemotherapy. Therefore, selective targeting of the key biochemical events of the malignant cells may have a great therapeutic potential in specifically kill the cancer cells. We have evaluated in vitro the cytotoxic efficacy of a previously reported copper complex viz. copper N-(2-hydroxy acetophenone) glycinate (CuNG) on different drug sensitive and resistant cancer cell lines by MTT, annexin V positivity and caspase 3 activation assays. We have also investigated the underlying signalling events in CuNG mediated apoptosis of cancer cells by Western blotting technique. We have found that CuNG preferentially induces apoptosis to malignant cells irrespective of drug sensitivity and spares the normal cells. Our studies disclose that CuNG causes cellular redox imbalance in cancer cells through depletion of intracellular GSH level. CuNG mediated depletion of intracellular GSH level induces mitochondrial superoxide generation, which detaches cyto C from mitochondrial membrane through lipid peroxidation. The detached cyto C then release into the extra mitochondrial milieu in Bax mediated pathway where CuNG facilitates the binding of Bax through dissociation of hexokinase II from mitochondrial membrane. The present study opens the possibility of developing effective chemotherapeutic drugs by synthesizing numerous chemical compounds capable of targeting cellular redox environment and thus specifically kills cancer cells of broad spectrum. PMID- 23733181 TI - The crystal structure of six-transmembrane epithelial antigen of the prostate 4 (Steap4), a ferri/cuprireductase, suggests a novel interdomain flavin-binding site. AB - Steap4 is a cell surface metalloreductase linked to obesity-associated insulin resistance. Initial characterization of its cell surface metalloreductase activity has been reported, but thorough biochemical characterization of this activity is lacking. Here, we report detailed kinetic analysis of the Steap4 cell surface metalloreductase activities. Steap4 shows physiologically relevant Km values for both Fe(3+) and Cu(2+) and retains activity at acidic pH, suggesting it may also function within intracellular organelles to reduce these metals. Flavin-dependent NADPH oxidase activity that was much greater than the equivalent Steap3 construct was observed for the isolated N-terminal oxidoreductase domain. The crystal structure of the Steap4 oxidoreductase domain was determined, providing a structural explanation for these differing activities. Structure function work also suggested Steap4 utilizes an interdomain flavin-binding site to shuttle electrons between the oxidoreductase and transmembrane domains, and it showed that the disordered N-terminal residues do not contribute to enzymatic activity. PMID- 23733182 TI - A novel type of peptidoglycan-binding domain highly specific for amidated D-Asp cross-bridge, identified in Lactobacillus casei bacteriophage endolysins. AB - Peptidoglycan hydrolases (PGHs) are responsible for bacterial cell lysis. Most PGHs have a modular structure comprising a catalytic domain and a cell wall binding domain (CWBD). PGHs of bacteriophage origin, called endolysins, are involved in bacterial lysis at the end of the infection cycle. We have characterized two endolysins, Lc-Lys and Lc-Lys-2, identified in prophages present in the genome of Lactobacillus casei BL23. These two enzymes have different catalytic domains but similar putative C-terminal CWBDs. By analyzing purified peptidoglycan (PG) degradation products, we showed that Lc-Lys is an N acetylmuramoyl-L-alanine amidase, whereas Lc-Lys-2 is a gamma-D-glutamyl-L-lysyl endopeptidase. Remarkably, both lysins were able to lyse only Gram-positive bacterial strains that possess PG with D-Ala(4)->D-Asx-L-Lys(3) in their cross bridge, such as Lactococcus casei, Lactococcus lactis, and Enterococcus faecium. By testing a panel of L. lactis cell wall mutants, we observed that Lc-Lys and Lc Lys-2 were not able to lyse mutants with a modified PG cross-bridge, constituting D-Ala(4)->L-Ala-(L-Ala/L-Ser)-L-Lys(3); moreover, they do not lyse the L. lactis mutant containing only the nonamidated D-Asp cross-bridge, i.e. D-Ala(4)->D-Asp-L Lys(3). In contrast, Lc-Lys could lyse the ampicillin-resistant E. faecium mutant with 3->3 L-Lys(3)-D-Asn-L-Lys(3) bridges replacing the wild-type 4->3 D-Ala(4)-D Asn-L-Lys(3) bridges. We showed that the C-terminal CWBD of Lc-Lys binds PG containing mainly D-Asn but not PG with only the nonamidated D-Asp-containing cross-bridge, indicating that the CWBD confers to Lc-Lys its narrow specificity. In conclusion, the CWBD characterized in this study is a novel type of PG-binding domain targeting specifically the D-Asn interpeptide bridge of PG. PMID- 23733183 TI - The phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2)-dependent Tup1 conversion (PIPTC) regulates metabolic reprogramming from glycolysis to gluconeogenesis. AB - Glucose/carbon metabolism is a fundamental cellular process in living cells. In response to varying environments, eukaryotic cells reprogram their glucose/carbon metabolism between aerobic or anaerobic glycolysis, oxidative phosphorylation, and/or gluconeogenesis. The distinct type of glucose/carbon metabolism that a cell carries out has significant effects on the cell's proliferation and differentiation. However, it is poorly understood how the reprogramming of glucose/carbon metabolism is regulated. Here, we report a novel endosomal PI(3,5)P2 lipid-dependent regulatory mechanism that is required for metabolic reprogramming from glycolysis to gluconeogenesis in Saccharomyces cerevisiae. Certain gluconeogenesis genes, such as FBP1 (encoding fructose-1,6-bisphosphatase 1) and ICL1 (encoding isocitrate lyase 1) are under control of the Mig1 repressor and Cyc8-Tup1 corepressor complex. We previously identified the PI(3,5)P2 dependent Tup1 conversion (PIPTC), a mechanism to convert Cyc8-Tup1 corepressor to Cti6-Cyc8-Tup1 coactivator. We demonstrate that the PIPTC plays a critical role for transcriptional activation of FBP1 and ICL1. Furthermore, without the PIPTC, the Cat8 and Sip4 transcriptional activators cannot be efficiently recruited to the promoters of FBP1 and ICL1, suggesting a key role for the PIPTC in remodulating the chromatin architecture at the promoters. Our findings expand our understanding of the regulatory mechanisms for metabolic reprogramming in eukaryotes to include key regulation steps outside the nucleus. Given that Tup1 and the metabolic enzymes that control PI(3,5)P2 are highly conserved among eukaryotes, our findings may provide important insights toward understanding glucose/carbon metabolic reprogramming in other eukaryotes, including humans. PMID- 23733184 TI - Structure-function studies of the staphylococcal methicillin resistance antirepressor MecR2. AB - Methicillin resistance in Staphylococcus aureus is elicited by the MecI-MecR1 MecA axis encoded by the mec locus. Recently, MecR2 was also identified as a regulator of mec through binding of the methicillin repressor, MecI. Here we show that plasmid-encoded full-length MecR2 restores resistance in a sensitive S. aureus mecR2 deletion mutant of the resistant strain N315. The crystal structure of MecR2 reveals an N-terminal DNA-binding domain, an intermediate scaffold domain, and a C-terminal dimerization domain that contributes to oligomerization. The protein shows structural similarity to ROK (repressors, open reading frames, and kinases) family proteins, which bind DNA and/or sugar molecules. We found that functional cell-based assays of three point mutants affecting residues participating in sugar binding in ROK proteins had no effect on the resistance phenotype. By contrast, MecR2 bound short double-stranded DNA oligonucleotides nonspecifically, and a deletion mutant affecting the N-terminal DNA-binding domain showed a certain effect on activity, thus contributing to resistance less than the wild-type protein. Similarly, a deletion mutant, in which a flexible segment of intermediate scaffold domain had been replaced by four glycines, significantly reduced MecR2 function, thus indicating that this domain may likewise be required for activity. Taken together, these results provide the structural basis for the activity of a methicillin antirepressor, MecR2, which would sequester MecI away from its cognate promoter region and facilitate its degradation. PMID- 23733185 TI - 4-Hydroxynonenal induces G2/M phase cell cycle arrest by activation of the ataxia telangiectasia mutated and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) signaling pathway. AB - 4-Hydroxynonenal (HNE) has been widely implicated in the mechanisms of oxidant induced toxicity, but the detrimental effects of HNE associated with DNA damage or cell cycle arrest have not been thoroughly studied. Here we demonstrate for the first time that HNE caused G2/M cell cycle arrest of hepatocellular carcinoma HepG2 (p53 wild type) and Hep3B (p53 null) cells that was accompanied with decreased expression of CDK1 and cyclin B1 and activation of p21 in a p53 independent manner. HNE treatment suppressed the Cdc25C level, which led to inactivation of CDK1. HNE-induced phosphorylation of Cdc25C at Ser-216 resulted in its translocation from nucleus to cytoplasm, thereby facilitating its degradation via the ubiquitin-mediated proteasomal pathway. This phosphorylation of Cdc25C was regulated by activation of the ataxia telangiectasia and Rad3 related protein (ATR)/checkpoint kinase 1 (Chk1) pathway. The role of HNE in the DNA double strand break was strongly suggested by a remarkable increase in comet tail formation and H2A.X phosphorylation in HNE-treated cells in vitro. This was supported by increased in vivo phosphorylation of H2A.X in mGsta4 null mice that have impaired HNE metabolism and increased HNE levels in tissues. HNE-mediated ATR/Chk1 signaling was inhibited by ATR kinase inhibitor (caffeine). Additionally, most of the signaling effects of HNE on cell cycle arrest were attenuated in hGSTA4 transfected cells, thereby indicating the involvement of HNE in these events. A novel role of GSTA4-4 in the maintenance of genomic integrity is also suggested. PMID- 23733186 TI - Protein signatures that promote operator selectivity among paralog MerR monovalent metal ion regulators. AB - Two paralog transcriptional regulators of the MerR family, CueR and GolS, are responsible for monovalent metal ion sensing and resistance in Salmonella enterica. Although similar in sequence and also in their target binding sites, these proteins differ in signal detection and in the set of target genes they control. Recently, we demonstrated that selective promoter recognition depends on the presence of specific bases located at positions 3' and 3 within the operators they interact with. Here, we identify the amino acid residues within the N terminal DNA-binding domain of these sensor proteins that are directly involved in operator discrimination. We demonstrate that a methionine residue at position 16 of GolS, absolutely conserved among GolS-like proteins but absent in all CueR like xenologs, is the key to selectively recognize operators that harbor the distinctive GolS-operator signature, whereas the residue at position 19 finely tunes the regulator/operator interaction. Furthermore, swapping these residues switches the set of genes recognized by these transcription factors. These results indicate that co-evolution of a regulator and its cognate operators within the bacterial cell provides the conditions to avoid cross-recognition and guarantees the proper response to metal injury. PMID- 23733188 TI - Estrogen receptor alpha L543A,L544A mutation changes antagonists to agonists, correlating with the ligand binding domain dimerization associated with DNA binding activity. AB - A ligand-dependent nuclear transcription factor, ERalpha has two transactivating functional domains (AF), AF-1 and AF-2. AF-1 is localized in the N-terminal region, and AF-2 is distributed in the C-terminal ligand-binding domain (LBD) of the ERalpha protein. Helix 12 (H12) in the LBD is a component of the AF-2, and the configuration of H12 is ligand-inducible to an active or inactive form. We demonstrated previously that the ERalpha mutant (AF2ER) possessing L543A,L544A mutations in H12 disrupts AF-2 function and reverses antagonists such as fulvestrant/ICI182780 (ICI) or 4-hydoxytamoxifen (OHT) into agonists in the AF2ER knock-in mouse. Our previous in vitro studies suggested that the mode of AF2ER activation is similar to the partial agonist activity of OHT for WT-ERalpha. However, it is still unclear how antagonists activate ERalpha. To understand the molecular mechanism of antagonist reversal activity, we analyzed the correlation between the ICI-dependent estrogen-responsive element-mediated transcription activity of AF2ER and AF2ER-LBD dimerization activity. We report here that ICI dependent AF2ER activation correlated with the activity of AF2ER-LBD homodimerization. Prevention of dimerization impaired the ICI-dependent ERE binding and transcription activity of AF2ER. The dislocation of H12 caused ICI dependent LBD homodimerization involving the F-domain, the adjoining region of H12. Furthermore, F-domain truncation also strongly depressed the dimerization of WT-ERalpha-LBD with antagonists but not with E2. AF2ER activation levels with ICI, OHT, and raloxifene were parallel with the degree of AF2ER-LBD homodimerization, supporting a mechanism that antagonist-dependent LBD homodimerization involving the F-domain results in antagonist reversal activity of H12-mutated ERalpha. PMID- 23733187 TI - A novel family of soluble minimal scaffolds provides structural insight into the catalytic domains of integral membrane metallopeptidases. AB - In the search for structural models of integral-membrane metallopeptidases (MPs), we discovered three related proteins from thermophilic prokaryotes, which we grouped into a novel family called "minigluzincins." We determined the crystal structures of the zymogens of two of these (Pyrococcus abyssi proabylysin and Methanocaldococcus jannaschii projannalysin), which are soluble and, with ~100 residues, constitute the shortest structurally characterized MPs to date. Despite relevant sequence and structural similarity, the structures revealed two unique mechanisms of latency maintenance through the C-terminal segments previously unseen in MPs as follows: intramolecular, through an extended tail, in proabylysin, and crosswise intermolecular, through a helix swap, in projannalysin. In addition, structural and sequence comparisons revealed large similarity with MPs of the gluzincin tribe such as thermolysin, leukotriene A4 hydrolase relatives, and cowrins. Noteworthy, gluzincins mostly contain a glutamate as third characteristic zinc ligand, whereas minigluzincins have a histidine. Sequence and structural similarity further allowed us to ascertain that minigluzincins are very similar to the catalytic domains of integral membrane MPs of the MEROPS database families M48 and M56, such as FACE1, HtpX, Oma1, and BlaR1/MecR1, which are provided with trans-membrane helices flanking or inserted into a minigluzincin-like catalytic domain. In a time where structural biochemistry of integral-membrane proteins in general still faces formidable challenges, the minigluzincin soluble minimal scaffold may contribute to our understanding of the working mechanisms of these membrane MPs and to the design of novel inhibitors through structure-aided rational drug design approaches. PMID- 23733189 TI - Signal transducer and activator of transcription 3 (STAT3) degradation by proteasome controls a developmental switch in neurotrophin dependence. AB - Neonatal brains develop through a program that eliminates about half of the neurons. During this period, neurons depend on neurotrophins for their survival. Recently, we reported that, at the conclusion of the naturally occurring death period, neurons become neurotrophin-independent and, further, that this developmental switch is achieved by the emergence of a second survival pathway mediated by signal transducer and activator of transcription 3 (STAT3). Here I show that calcineurin plays a key role in controlling the developmental switch in mouse hippocampal neurons. Calcineurin promotes the degradation of STAT3 via the ubiquitin-proteasome pathway. Inhibition of calcineurin acutely increases total levels of STAT3 as well as its activated forms, resulting in decreased levels of the tumor suppressor p53 and its proapoptotic target, Bax. In vivo and in vitro, calcineurin regulates levels of STAT3 and neurotrophin dependence. TMF/ARA 160 (TATA element modulatory factor/androgen receptor co-activator 160), the key mediator of STAT3 ubiquitination, is required for calcineurin-dependent STAT3 degradation. Thus, these results show that the ubiquitin-proteasome pathway controls the critical developmental switch of neurotrophin dependence in the newborn hippocampus. PMID- 23733190 TI - Nitric oxide and KLF4 protein epigenetically modify class II transactivator to repress major histocompatibility complex II expression during Mycobacterium bovis bacillus Calmette-Guerin infection. AB - Pathogenic mycobacteria employ several immune evasion strategies such as inhibition of class II transactivator (CIITA) and MHC-II expression, to survive and persist in host macrophages. However, precise roles for specific signaling components executing down-regulation of CIITA/MHC-II have not been adequately addressed. Here, we demonstrate that Mycobacterium bovis bacillus Calmette-Guerin (BCG)-mediated TLR2 signaling-induced iNOS/NO expression is obligatory for the suppression of IFN-gamma-induced CIITA/MHC-II functions. Significantly, NOTCH/PKC/MAPK-triggered signaling cross-talk was found critical for iNOS/NO production. NO responsive recruitment of a bifunctional transcription factor, KLF4, to the promoter of CIITA during M. bovis BCG infection of macrophages was essential to orchestrate the epigenetic modifications mediated by histone methyltransferase EZH2 or miR-150 and thus calibrate CIITA/MHC-II expression. NO dependent KLF4 regulated the processing and presentation of ovalbumin by infected macrophages to reactive T cells. Altogether, our study delineates a novel role for iNOS/NO/KLF4 in dictating the mycobacterial capacity to inhibit CIITA/MHC-II mediated antigen presentation by infected macrophages and thereby elude immune surveillance. PMID- 23733191 TI - Non-destructive and selective imaging of the functionally active, pro-invasive membrane type-1 matrix metalloproteinase (MT1-MMP) enzyme in cancer cells. AB - Proteolytic activity of cell surface-associated MT1-matrix metalloproteinase (MMP) (MMP-14) is directly related to cell migration, invasion, and metastasis. MT1-MMP is regulated as a proteinase by activation and conversion of the latent proenzyme into the active enzyme, and also via inhibition by tissue inhibitors of MMPs (TIMPs) and self-proteolysis. MT1-MMP is also regulated as a membrane protein through its internalization and recycling. Routine immunohistochemistry, flow cytometry, reverse transcription-PCR, and immunoblotting methodologies do not allow quantitative imaging and assessment of the cell-surface levels of the active, TIMP-free MT1-MMP enzyme. Here, we developed a fluorescent reporter prototype that targets the cellular active MT1-MMP enzyme alone. The reporter (MP 3653) represents a liposome tagged with a fluorochrome and functionalized with a PEG chain spacer linked to an inhibitory hydroxamate warhead. Our studies using the MP-3653 reporter and its inactive derivative demonstrated that MP-3653 can be efficiently used not only to visualize the trafficking of MT1-MMP through the cell compartment, but also to quantify the femtomolar range amounts of the cell surface-associated active MT1-MMP enzyme in multiple cancer cell types, including breast carcinoma, fibrosarcoma, and melanoma. Thus, the levels of the naturally expressed, fully functional, active cellular MT1-MMP enzyme are roughly equal to 1 * 10(5) molecules/cell, whereas these levels are in a 1 * 10(6) range in the cells with the enforced MT1-MMP expression. We suggest that the reporter we developed will contribute to the laboratory studies of MT1-MMP and then, ultimately, to the design of novel, more efficient prognostic approaches and personalized cancer therapies. PMID- 23733192 TI - Human P-glycoprotein contains a greasy ball-and-socket joint at the second transmission interface. AB - The P-glycoprotein drug pump protects us from toxins. Drug-binding sites in the transmembrane (TM) domains (TMDs) are connected to the nucleotide-binding domains (NBDs) by intracellular helices (IHs). TMD-NBD cross-talk is a key step in the transport mechanism because drug binding stimulates ATP hydrolysis followed by drug efflux. Here, we tested whether the IHs are critical for maturation and TMD NBD coupling by characterizing the effects of mutations to the IH1 and IH2 interfaces. Although IH1 mutations had little effect, most mutations at the IH2 NBD2 interface inhibited maturation or activity. For example, the F1086A mutation at the IH2-NBD2 interface abolished drug-stimulated ATPase activity. The mutant F1086A, however, retained the ability to bind ATP and drug substrates. The mutant was defective in mediating ATP-dependent conformational changes in the TMDs because binding of ATP no longer promoted cross-linking between cysteines located at the extracellular ends of TM segments 6 and 12. Replacement of Phe-1086 (in NBD2) with hydrophobic but not charged residues yielded active mutants. The activity of the F1086A mutant could be restored when the nearby residue Ala-266 (in IH2) was replaced with aromatic residues. These results suggest that Ala 266/Phe-1086 lies in a hydrophobic IH2-NBD2 "ball-and-socket" joint. PMID- 23733194 TI - Ocular manipulation reduces both ipsilateral and contralateral electroretinograms. AB - PURPOSE: To determine the electroretinogram (ERG) changes in eyes manipulated in the course of local ablative therapy (transpupil thermotherapy (TTT), cryotherapy or both) or scleral depression and in un-manipulated fellow, healthy eyes. METHODS: This prospective observational report summarizes 73 ERG studies in 42 patients with retinoblastoma; a study consisted of ERGs of one or both eyes (if present) followed by ocular manipulation (scleral depression, cryotherapy, transpupillary thermotherapy, pressure applied to orbital implant in an anophthalmic socket, or a 5- or 10-min delay without mechanical manipulation) followed by a repeat of the ERGs. Each patient was studied with only a single manipulation modality on any given date: 23 patients were studied only once, and 19 patients were included in more than one study occasion. RESULTS: Following local ablative treatment of patients with unilateral retinoblastoma, the photopic response decreased significantly in both the treated eye and the untouched fellow, healthy eye. Following scleral depression of the diseased eye, the photopic response immediately decreased in the diseased eye by a mean of 16 MUV (21 %, p = .006) and, in the fellow, healthy eye by 40 MUV (23 %, p = .0005). Following scleral depression of the fellow, healthy eye, the photopic response immediately decreased by a mean of 11 MUV (4 %, p = .37) in the fellow, healthy eye, and by 16 MUV (28 %, p = .01) in the diseased eye. CONCLUSIONS: Following physical ocular manipulation, the amplitude of the photopic response decreased in the manipulated, but also the untouched healthy, fellow eyes. These findings may account for some of the variation in clinical ERG recordings, particularly that observed following ocular manipulation by TTT, laser or even scleral depression. PMID- 23733193 TI - Rab family proteins regulate the endosomal trafficking and function of RGS4. AB - RGS4, a heterotrimeric G-protein inhibitor, localizes to plasma membrane (PM) and endosomal compartments. Here, we examined Rab-mediated control of RGS4 internalization and recycling. Wild type and constitutively active Rab5 decreased RGS4 PM levels while increasing its endosomal targeting. Rab5, however, did not appreciably affect the PM localization or function of the M1 muscarinic receptor (M1R)/Gq signaling cascade. RGS4-containing endosomes co-localized with subsets of Rab5-, transferrin receptor-, and Lamp1/Lysotracker-marked compartments suggesting RGS4 traffics through PM recycling or acidified endosome pathways. Rab7 activity promoted TGN association, whereas Rab7(dominant negative) trapped RGS4 in late endosomes. Furthermore, RGS4 was found to co-localize with an endosomal pool marked by Rab11, the protein that mediates recycling/sorting of proteins to the PM. The Cys-12 residue in RGS4 appeared important for its Rab11 mediated trafficking to the PM. Rab11(dominant negative) decreased RGS4 PM levels and increased the number of RGS4-containing endosomes. Inhibition of Rab11 activity decreased RGS4 function as an inhibitor of M1R activity without affecting localization and function of the M1R/Gq signaling complex. Thus, both Rab5 activation and Rab11 inhibition decreased RGS4 function in a manner that is independent from their effects on the localization and function of the M1R/Gq signaling complex. This is the first study to implicate Rab GTPases in the intracellular trafficking of an RGS protein. Thus, Rab GTPases may be novel molecular targets for the selective regulation of M1R-mediated signaling via their specific effects on RGS4 trafficking and function. PMID- 23733195 TI - Psychophysically determined full-field stimulus thresholds (FST) in retinitis pigmentosa: relationships with electroretinography and visual field outcomes. AB - PURPOSE: The purpose of this study is to describe the relationships between full field stimulus threshold (FST), electroretinography (ERG), and visual field (VF) outcomes in retinitis pigmentosa (RP). METHODS: Data from 47 patients with RP (n = 94 eyes) were evaluated. Patients were submitted to comprehensive ophthalmological examination including measurement of best-corrected visual acuity (BCVA), 30-2 threshold static VF, and microperimetry. Full-field ERG (ISCEV standard) was recorded, and achromatic FST was measured using a Diagnosys Espion system with the ColorDomeTM LED full-field stimulator (Diagnosys LLC, Lowell, MA, USA). RESULTS: BCVA mean +/- SD was 0.31 +/- 0.03 logMAR, and FST mean +/- SD was -18.45 +/- 9.53 dB. No significant correlation was found between BCVA and FST. In contrast, statistically significant correlations were found between FST and static 30-2 VF mean deviation (r = -0.389; P < 0.01), microperimetry mean threshold (r = -0.607; P < 0.01). Dark and light-adapted ERGs were detectable in 28 and 48 eyes, respectively. Nevertheless, considering only the eyes with recordable ERG responses, moderate correlations were found between combined dark-adapted a-wave amplitude (r = -0.560; P < 0.01), b-wave amplitude (r = -0.643; P < 0.001), 30-Hz flicker response (r = -0.501; P < 0.01), and FST, and high correlation with FST for cone b-wave amplitude (r = -0.715; P < 0.01). CONCLUSIONS: FST could be successfully determined in RP patients with a wide range of vision loss. FST results showed stronger correlations with full-field ERG amplitude than with sensitivity measured with visual field tests. FST is as an alternative to VF or ERG for assessment of retinal function in patients unable to do visual fields or with non-detectable ERGs. PMID- 23733196 TI - Autologous pancreatic islet transplantation in human bone marrow. AB - The liver is the current site of choice for pancreatic islet transplantation, even though it is far from being ideal. We recently have shown in mice that the bone marrow (BM) may be a valid alternative to the liver, and here we report a pilot study to test feasibility and safety of BM as a site for islet transplantation in humans. Four patients who developed diabetes after total pancreatectomy were candidates for the autologous transplantation of pancreatic islet. Because the patients had contraindications for intraportal infusion, islets were infused in the BM. In all recipients, islets engrafted successfully as shown by measurable posttransplantation C-peptide levels and histopathological evidence of insulin-producing cells or molecular markers of endocrine tissue in BM biopsy samples analyzed during follow-up. Thus far, we have recorded no adverse events related to the infusion procedure or the presence of islets in the BM. Islet function was sustained for the maximum follow-up of 944 days. The encouraging results of this pilot study provide new perspectives in identifying alternative sites for islet infusion in patients with type 1 diabetes. Moreover, this is the first unequivocal example of successful engraftment of endocrine tissue in the BM in humans. PMID- 23733197 TI - Weight cycling increases T-cell accumulation in adipose tissue and impairs systemic glucose tolerance. AB - Obesity is one of the leading causes of morbidity in the U.S. Accumulation of proinflammatory immune cells in adipose tissue (AT) contributes to the development of obesity-associated disorders. Weight loss is the ideal method to counteract the negative consequences of obesity; however, losses are rarely maintained, leading to bouts of weight cycling. Fluctuations in weight have been associated with worsened metabolic and cardiovascular outcomes; yet, the mechanisms explaining this potential correlation are not known. For determination of whether weight cycling modulates AT immune cell populations, inflammation, and insulin resistance, mice were subjected to a diet-switch protocol designed to induce weight cycling. Weight-cycled mice displayed decreased systemic glucose tolerance and impaired AT insulin sensitivity when compared with mice that gained weight but did not cycle. AT macrophage number and polarization were not modulated by weight cycling. However, weight cycling did increase the number of CD4(+) and CD8(+) T cells in AT. Expression of multiple T helper 1-associated cytokines was also elevated subsequent to weight cycling. Additionally, CD8(+) effector memory T cells were present in AT of both obese and weight-cycled mice. These studies indicate that an exaggerated adaptive immune response in AT may contribute to metabolic dysfunction during weight cycling. PMID- 23733199 TI - NH2-terminal pro-brain natriuretic peptide and risk of diabetes. AB - Brain natriuretic peptide (BNP) has an established role in cardiovascular disease (CVD). However, recent animal studies suggest direct metabolic effects of BNP. To determine the association of BNP with the risk of diabetes, we conducted a prospective analysis of participants from the Atherosclerosis Risk in Communities (ARIC) study. We included 7,822 men and women without history of diabetes, CVD, or reduced kidney function at baseline. At baseline, NH2-terminal (NT)-proBNP, a cleavage product of BNP, was inversely associated with adiposity, fasting glucose, insulin, and cholesterol but positively associated with blood pressure and C-reactive protein levels. During a median follow-up of 12 years, 1,740 participants reported a new diagnosis of diabetes or medication use for diabetes. Baseline quartiles of NT-proBNP were inversely associated with diabetes risk, even after multivariable adjustment including fasting glucose. The adjusted HRs for diabetes were 1.0 (reference), 0.84 (95% CI 0.74-0.96), 0.79 (95% CI 0.68 0.90), and 0.75 (95% CI 0.64-0.87) for the 1st, 2nd, 3rd, and 4th quartiles of baseline NT-proBNP, respectively (P for trend <0.001). This inverse association was robust across sex, race, and obesity subgroups. Our results extend animal studies and support a direct and important metabolic role of BNP in humans. PMID- 23733198 TI - ADAMTS13 predicts renal and cardiovascular events in type 2 diabetic patients and response to therapy. AB - In patients with diabetes, impaired ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13) proteolysis of highly thrombogenic von Willebrand factor (VWF) multimers may accelerate renal and cardiovascular complications. Restoring physiological VWF handling might contribute to ACE inhibitors' (ACEi) reno- and cardioprotective effects. To assess how Pro618Ala ADAMTS13 variants and related proteolytic activity interact with ACEi therapy in predicting renal and cardiovascular complications, we genotyped 1,163 normoalbuminuric type 2 diabetic patients from BErgamo NEphrologic DIabetes Complications Trial (BENEDICT). Interaction between Pro618Ala and ACEi was significant in predicting both renal and combined renal and cardiovascular events. The risk for renal or combined events versus reference Ala carriers on ACEi progressively increased from Pro/Pro homozygotes on ACEi (hazard ratio 2.80 [95% CI 0.849-9.216] and 1.58 [0.737-3.379], respectively) to Pro/Pro homozygotes on non-ACEi (4.77 [1.484-15.357] and 1.99 [0.944-4.187]) to Ala carriers on non ACEi (8.50 [2.416-29.962] and 4.00 [1.739-9.207]). In a substudy, serum ADAMTS13 activity was significantly lower in Ala carriers than in Pro/Pro homozygotes and in case subjects with renal, cardiovascular, or combined events than in diabetic control subjects without events. ADAMTS13 activity significantly and negatively correlated with all outcomes. In patients with diabetes, ADAMTS13 618Ala variant associated with less proteolytic activity, higher risk of chronic complications, and better response to ACEi therapy. Screening for Pro618Ala polymorphism may help identify patients with diabetes at highest risk who may benefit the most from early reno- and cardioprotective therapy. PMID- 23733200 TI - Effects of a single bout of interval hypoxia on cardiorespiratory control in patients with type 1 diabetes. AB - Hypoxemia is common in diabetes, and reflex responses to hypoxia are blunted. These abnormalities could lead to cardiovascular/renal complications. Interval hypoxia (IH) (5-6 short periods of hypoxia each day over 1-3 weeks) was successfully used to improve the adaptation to hypoxia in patients with chronic obstructive pulmonary disease. We tested whether IH over 1 day could initiate a long-lasting response potentially leading to better adaptation to hypoxia. In 15 patients with type 1 diabetes, we measured hypoxic and hypercapnic ventilatory responses (HCVRs), ventilatory recruitment threshold (VRT-CO2), baroreflex sensitivity (BRS), blood pressure, and blood lactate before and after 0, 3, and 6 h of a 1-h single bout of IH. All measurements were repeated on a placebo day (single-blind protocol, randomized sequence). After IH (immediately and after 3 h), hypoxic and HCVR increased, whereas the VRT-CO2 dropped. No such changes were observed on the placebo day. Systolic and diastolic blood pressure increased, whereas blood lactate decreased after IH. Despite exposure to hypoxia, BRS remained unchanged. Repeated exposures to hypoxia over 1 day induced an initial adaptation to hypoxia, with improvement in respiratory reflexes. Prolonging the exposure to IH (>2 weeks) in type 1 diabetic patients will be a matter for further studies. PMID- 23733201 TI - Mitochondrial substrate availability and its role in lipid-induced insulin resistance and proinflammatory signaling in skeletal muscle. AB - The relationship between glucose and lipid metabolism has been of significant interest in understanding the pathogenesis of obesity-induced insulin resistance. To gain insight into this metabolic paradigm, we explored the potential interplay between cellular glucose flux and lipid-induced metabolic dysfunction within skeletal muscle. Here, we show that palmitate (PA)-induced insulin resistance and proinflammation in muscle cells, which is associated with reduced mitochondrial integrity and oxidative capacity, can be attenuated under conditions of glucose withdrawal or glycolytic inhibition using 2-deoxyglucose (2DG). Importantly, these glucopenic-driven improvements coincide with the preservation of mitochondrial function and are dependent on PA oxidation, which becomes markedly enhanced in the absence of glucose. Intriguingly, despite its ability to upregulate mitochondrial PA oxidation, glucose withdrawal did not attenuate PA induced increases in total intramyocellular diacylglycerol and ceramide. Furthermore, consistent with our findings in cultured muscle cells, we also report enhanced insulin sensitivity and reduced proinflammatory tone in soleus muscle from obese Zucker rats fed a 2DG-supplemented diet. Notably, this improved metabolic status after 2DG dietary intervention is associated with markedly reduced plasma free fatty acids. Collectively, our data highlight the key role that mitochondrial substrate availability plays in lipid-induced metabolic dysregulation both in vitro and in vivo. PMID- 23733202 TI - XRCC1 codon 280 polymorphism and susceptibility to lung cancer: a meta-analysis of the literatures. AB - The X-ray repair cross-complementation group 1 (XRCC1) protein plays an important role in base excision repair, and the genetic polymorphisms in the XRCC1 gene influence its function. XRCC1 codon 280 polymorphism is an Arg-His change in the XRCC1 gene. Many studies were published to investigate the association between XRCC1 codon 280 polymorphism and risk of lung cancer, but the results were inconsistent. We performed a meta-analysis of 16 studies with a total of 18,660 subjects (8,736 cases and 9,924 controls). The pooled odds ratios (OR) and corresponding 95 % confidence intervals (95 % CI) for the gene-disease association were calculated. Overall, there was a significant association between XRCC1 codon 280 polymorphism and increased risk of lung cancer (HisHis vs. ArgArg: OR = 1.53, 95 % CI 1.08-2.16, P = 0.016; HisHis vs. ArgArg/ArgHis: OR = 1.55, 95 % CI 1.10-2.19, P = 0.012). However, subgroup analysis by race failed to confirm the obvious association in Europeans and Asians. Therefore, there is a significant association between XRCC1 codon 280 polymorphism and increased risk of lung cancer. More studies with a large sample are needed to further evaluate the possible race-specific effect in the association above. PMID- 23733203 TI - SB365, Pulsatilla saponin D suppresses proliferation and induces apoptosis of pancreatic cancer cells. AB - Pulsatilla koreana has been used as a traditional medicine for the treatment of various diseases. The purpose of this study was to determine whether SB365, Pulsatilla saponin D isolated from the root of Pulsatilla koreana inhibits the progression of pancreatic cancer. We found that SB365 strongly suppressed the growth and proliferation of 5 human pancreatic cancer cell lines (MIAPaCa-2, BXPC 3, PANC-1, AsPC-1 and HPAC). The apoptotic effect of SB365 was demonstrated by increased levels of cleaved caspase-3 and decreased Bcl-2 expression via mitochondrial membrane potential, as well as elevated numbers of terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL)-positive apoptotic cells. SB365 was also found to exert an anti-angiogenic effect by decreasing the expression of HIF-1alpha and VEGF, major factors of angiogenesis, which was confirmed by the suppression of tumor sphere formation of pancreatic cancer cells. An in vivo mouse xenograft study showed that SB365 significantly inhibited tumor growth through the induction of apoptosis and inhibition of angiogenesis with strong anticancer activity. Therefore, SB365 is a good candidate as a natural product for use in the treatment of pancreatic cancer. PMID- 23733204 TI - Influences of textured substrates on the heart rate of developing zebrafish embryos. AB - Identification of the effects of different textured substrates on zebrafish (Danio rerio) embryos provides insights into the influence of external stimuli on normal cardiovascular functions in the developmental stages of the embryos. This knowledge can be used in numerous genetic studies using zebrafish as an animal model as well as in bioanalytical assays using digital microfluidics. In this study, zebrafish embryos were systematically positioned and in vivo imaged on four types of silicon substrates. These substrates exhibited surface textures and surface wettability that were well modulated by wet chemical etching. The heart rate of the developing embryos significantly increased by 9.1% upon exposure to textured Si substrates with nanostructured surfaces compared with bare Si substrates. Modulation of surface wettability in the tested substrates also responded to the increase in the heart rate of the embryo; however, the effect of surface wettability on heart rate was slight compared with the effect of texture. In-depth experimental and statistical investigations of heart rate under the effects of substrate textures imply a pathway through which the inner mass of the embryo reacts to external stimuli. These findings contribute to zebrafish-related studies and suggest other factors to consider in the design of nanostructure based microfluidics and other biomedical devices. PMID- 23733205 TI - Combined exposure to cyanobacteria and carbaryl results in antagonistic effects on the reproduction of Daphnia pulex. AB - In aquatic ecosystems, Daphnia are exposed to a wide variety of natural and chemical stressors that can cause interactive effects resulting in an increased impact on aquatic ecosystems. The authors therefore investigated the interactive effects of harmful cyanobacteria (cyanoHABs) with carbaryl in Daphnia pulex, because cyanobacteria have become an important concern for aquatic ecosystems. Daphnia were exposed for 21 d to 4 selected cyanobacteria (Aphanizomenon sp., Cylindrospermopsis raciborskii, Microcystis aeruginosa, and Oscillatoria sp), carbaryl, and all binary combinations of carbaryl and each individual cyanobacterium. Results were analyzed with both the independent action and the concentration addition model. The estimated median effect concentration (EC50) for carbaryl was comparable between the experiments, ranging from 2.28 ug/L to 5.94 ug/L. The EC50 for cyanobacteria ranged from 13.45% of the total diet ratio for Microcystis to 66.69% of the diet ratio for Oscillatoria. In combination with carbaryl, the response of Daphnia to 3 of the 4 cyanobacteria demonstrated antagonistic deviation patterns (p < 0.05). Exposure to combinations of carbaryl and Cylindrospermopsis did not result in statistically significant deviations from both reference models. The results may have important implications for pesticide risk assessment, underlining the impact of interactive effects on aquatic organisms. Based on these results, the authors suggest that both the independent action and the concentration addition model can serve as a protective approach in risk assessment of carbaryl in the presence of cyanobacterial blooms. PMID- 23733206 TI - Transoral sonographic diagnosis of submandibular duct calculi. AB - We present a case of submandibular duct calculi diagnosed using transoral sonography. Sonography is the first-line imaging modality of salivary gland calculi. However, it is performed via a transcutaneous approach, which is limited in identifying small salivary duct calculi. Using an intraoral transducer, transoral sonography can visualize the submandibular duct and detect the presence of small calculi, thus overcoming the limitations of transcutaneous sonography. PMID- 23733207 TI - Efficient bioconjugation of 5-fluoro-5-deoxy-ribose (FDR) to RGD peptides for positron emission tomography (PET) imaging of alpha(v)beta(3) integrin receptor. AB - The utility of 5-fluoro-5-deoxyribose (FDR) as an efficient bioconjugation agent for radiolabelling of the RGD peptides c(RGDfK) and c(RGDfC) is demonstrated. The bioconjugation is significantly superior to that achieved with 2-fluoro-2 deoxyglucose (FDG) and benefits from the location of the fluorine at C-5, and that ribose is a 5-membered ring sugar rather than a 6-membered ring. Both features favour ring opening to the aldehydic form of the sugar to promote smooth oxime ligation with aminooxy ether functionalised peptides. [(18)F]FDR was prepared in this study by synthesis from fluoride-18 using an automated synthesis protocol adapting that used routinely for [(18)F]FDG. c(RGDfK) was functionalised with an aminooxyacetyl group (Aoa) via its lysine terminus, while c(RGDfC) was functionalised with an aminooxyhexylmaleimide (Ahm) through a cysteine-maleimide conjugation. Bioconjugation of [(18)F]FDR to c(RGDfC)-Ahm proved to be more efficient than c(RGDfK)-Aoa (92% versus 65%). The unlabelled ((19)F) bioconjugates c(RGDfK)-Aoa-FDR and c(RGDfC)-Ahm-FDR were prepared and their in vitro affinity to purified integrin alphavbeta3 was determined. c(RGDfK)-Aoa-FDR showed the greater affinity. Purified "hot" bioconjugates c(RGDfK)-Aoa-[(18)F]FDR and c(RGDfC)-Ahm-[(18)F]FDR were assayed by incubation with MCF7, LNCaP and PC3 cell lines. In both cases the conjugated RGD peptides showed selectivity for PC3 cells, which express alphavbeta3 integrin, with the c(RGDfK)-Aoa-[(18)F]FDR demonstrating better binding, consistent with its higher in vitro affinity. The study demonstrates that [(18)F]FDR is an efficient bioconjugation ligand for RGD bioactive peptides. PMID- 23733208 TI - Glomus tumor as a cause of coccydynia. AB - Glomus coccygeum is a network of glomus bodies located around pericoccygeal soft tissue. The question of whether it accounts for coccydynia has been debated. We report on a patient whose preoperative symptoms suggested the impression of glomus tumor of the coccyx; pain was relieved after removal of the lesion without coccygectomy. A 57-year-old woman was referred to us with a history of a pain in the coccygeal area lasting longer than 3 years. The patient complained of sharp pain whenever pressure was applied to the coccyx. Pain was aggravated by exposure to cold. MRI revealed a coccygeal lesion measuring 2 cm with a well-circumscribed margin. The lesion was excised without removal of any portion of the coccyx. The pathology report confirmed a glomus tumor, which was an identical finding to the conventional one of the subungual region. Ten months after surgery, she had no pain on the coccygeal region and no difficulty with sitting on a chair and in performing activities of daily living. Findings reported here suggest that although most glomus bodies are normal anatomical variants, development of a glomus tumor could occur in the coccygeal region and could be a cause of coccydynia. PMID- 23733210 TI - Cancer's true breakthroughs. AB - A new regulatory pathway established last year allows drugs with dramatic early clinical promise to be expedited to the market quicker than ever before. To date, most of these 'breakthrough' designations have gone to cancer agents, raising the prospect of faster access to the latest lifesaving therapies for the estimated 4,500 people newly diagnosed with cancer each day in the US. Elie Dolgin looks at what sets these breakthrough medicines apart. PMID- 23733209 TI - Ethics of the electrified mind: defining issues and perspectives on the principled use of brain stimulation in medical research and clinical care. AB - In recent years, non-pharmacologic approaches to modifying human neural activity have gained increasing attention. One of these approaches is brain stimulation, which involves either the direct application of electrical current to structures in the nervous system or the indirect application of current by means of electromagnetic induction. Interventions that manipulate the brain have generally been regarded as having both the potential to alleviate devastating brain-related conditions and the capacity to create unforeseen and unwanted consequences. Hence, although brain stimulation techniques offer considerable benefits to society, they also raise a number of ethical concerns. In this paper we will address various dilemmas related to brain stimulation in the context of clinical practice and biomedical research. We will survey current work involving deep brain stimulation, transcranial magnetic stimulation and transcranial direct current stimulation. We will reflect upon relevant similarities and differences between them, and consider some potentially problematic issues that may arise within the framework of established principles of medical ethics: nonmaleficence and beneficence, autonomy, and justice. PMID- 23733212 TI - Biomimetic ion nanochannels as a highly selective sequential sensor for zinc ions followed by phosphate anions. AB - A novel biomimetic ion-responsive multi-nanochannel system is constructed by covalently immobilizing a metal-chelating ligand, 2,2'-dipicolylamine (DPA), in polyporous nanochannels prepared in a polymeric membrane. The DPA-modified multi nanochannels show specific recognition of zinc ions over other common metal ions, and the zinc-ion-chelated nanochannels can be used as secondary sensors for HPO4(2-) anions. The immobilized DPA molecules act as specific-receptor binding sites for zinc ions, which leads to the highly selective zinc-ion response through monitoring of ionic current signatures. The chelated zinc ions can be used as secondary recognition elements for the capture of HPO4(2-) anions, thereby fabricating a sensing nanodevice for HPO4(2-) anions. The success of the DPA immobilization and ion-responsive events is confirmed by measurement of the X ray photoelectron spectroscopy (XPS), contact angle (CA), and current-voltage (I V) characteristics of the systems. The proposed nanochannel sensing devices display remarkable specificity, high sensitivity, and wide dynamic range. In addition, control experiments performed in complex matrices suggest that this sensing system has great potential applications in chemical sensing, biotechnology, and many other fields. PMID- 23733213 TI - Endobiliary stent: marker for patient alignment in image-guided radiotherapy in pancreatic and periampullary cancers. AB - PURPOSE: The aim of this study was to analyse the possibility of using stent in pretreatment megavoltage computed tomography (MVCT) images with respect to that on planning kilovoltage computed tomography as tumour surrogate during matching for daily registration in cases of pancreatic and periampullary cancer treated on a TomoTherapy Hi-Art system. METHODS: Planning CT and pretreatment MVCT of the first and then after every three fractions were transferred to a FocalSim workstation for ten patients. Planning CT of each patient was independently fused with each of the seven MVCT images of that patient. The stent was contoured on all of the eight images for each patient. The difference between the three co ordinates of centre of mass (CM) of the stent on the planning CT and seven MVCT images was found. The difference between CM of the liver and stents on the planning CT as well as on the MVCT for all seven fractions was also calculated. The mean of these differences across all patients was calculated and analysed. RESULTS: The mean difference in planning and MVCT CMs for stents in the X, Y and Z directions was 0.13 cm (+/-0.4), 0.16 cm (+/-2.2) and 0.35 cm (+/-0.7), respectively. Average difference between CM of the liver and stent on the planning CT in the X, Y and Z directions was found to be 1.832 cm (+/-1.64), 5.34 cm (+/-1.33) and 0.54 cm (+/-0.26), respectively. Average difference between CM of the liver and CM of stent on the MVCT for that day in the X, Y and Z directions was found to be 1.93 cm (+/-1.5), 4.6 cm (+/-1.03) and 0.654 cm (+/ 0.35), respectively. CONCLUSIONS: Endobiliary stents are stable tumour localisation surrogates and can be used to correct for interfraction target motion. PMID- 23733215 TI - Femtisecond single-mole infrared spectroscopy of molecular clusters. AB - The sensitivity limitations of Fourier transform infrared (FTIR) spectroscopy for the detection of molecular clusters formed in rarefied gas expansions can be overcome by synchronizing intense gas pulses at a low duty cycle with rapid interferometer scans. This turns the broadband FTIR approach into a universal cluster spectroscopy tool applicable from the far (200 cm(-1)) to the near (8000 cm(-1)) IR. It nicely complements more selective and more restricted laser-based techniques and it provides a gas-phase variant of the matrix-isolation method, the main drawback being substance consumption. A survey over the capabilities, limitations and perspectives of this high-throughput nozzle approach to cluster FTIR spectroscopy is given. PMID- 23733214 TI - Characterizing the interaction between enantiomers of eight psychoactive drugs and highly sulfated-beta-cyclodextrin by counter-current capillary electrophoresis. AB - The estimation of apparent binding constants and limit mobilities of the complexes of the enantiomers that characterize the interaction of enantiomers with chiral selectors, in this case highly sulfated beta-cyclodextrin, was approached using a simple and economic electrophoretic modality, the complete filling technique (CFT) in counter-current mode. The enantiomers of eight psychoactive drugs, four antihistamines (dimethindene, promethazine, orphenadrine and terfenadine) and four antidepressants (bupropion, fluoxetine, nomifensine and viloxazine) were separated for the first time for this cyclodextrin (CD). Estimations of thermodynamic and electrophoretic enantioselectivies were also performed. Results indicate that, in general, thermodynamic enantioselectivity is the main component explaining the high resolution found, but also one case suggests that electrophoretic enantioselectivity itself is enough to obtain a satisfactory resolution. CFT results advantageous compared with conventional capillary electrophoresis (CE) and partial filling technique (PFT) for the study of the interaction between drugs and chiral selectors. It combines the use of a simple fitting model (as in CE), when the enantiomers do not exit the chiral selector plug during the separation (i.e. mobility of electroosmotic flow larger than mobility of CD), and drastic reduction of the consumption (and cost; ~99.7%) of the CD reagent (as in PFT) compared with the conventional CE. PMID- 23733219 TI - Playing the odds. PMID- 23733221 TI - Picture of the month. Allergic contact dermatitis to nickel-containing dental work. PMID- 23733223 TI - Clostridium difficile: a cause of diarrhea in children. PMID- 23733224 TI - [Burnout: a German phenomenon?]. AB - OBJECTIVE: To examine whether the term "burnout" is particularly popular in Germany. METHODS: Results from four representative population surveys on public beliefs and attitudes about mental disorders, which have been conducted in Germany, Austria, France, and Italy between 2009 and 2012, are compared. In all surveys, respondents had been presented with a case-vignette depicting someone suffering from a moderate depressive episode. Following that, they were asked how they would call the condition described in the case-vignette. RESULTS: While in Germany and Austria over 10 % of respondents labeled the depressive symptoms as "burnout", in France only 2 % and in Italy not a single respondent used this "diagnosis". In Germany, another 9.5 % employed the German equivalent to the English term "burned out" or expressions like "exhausted" or "overworked" whereas in the other countries hardly anybody used those words. CONCLUSION: Obviously the term "burnout" enjoys greater popularity in Germany and Austria than in France and Italy. Apart from linguistic and stigma-related aspects, this may be explained by differences in the perception of current work conditions in the various countries. PMID- 23733225 TI - [The collective modes of ordering of the voice-hearing experience]. AB - OBJECTIVE: The article examines how voice-hearing as an (in)direct experience can become a subject of ethnographic observation. METHODS: An ethnographic participant observation was conducted over a five-month period of time in two "Trialogue" self-help groups organized by the "Netzwerk Stimmenhoren", an NGO based in Berlin, Germany. Additionally, feedback interviews were held within the groups. RESULTS: Four different collective modes of ordering of voice-hearing are captured: Within the groups the phenomenon was at times (1) normalized in the mode of normalization, structured in the mode of voice-hearing (2) as a passion, (3) as a turn of fate or (4) as a disability. CONCLUSIONS: Psychiatric-social anthropological cooperative research projects may help to achieve and support a change of perspectives for actors working in the psychiatry, actors in psychiatric self-help organizations and individuals who hear voices. Due to the applied methods results may not only be of interest within field of scientific discourse and furthermore create a different insight into the field. PMID- 23733226 TI - [Effectiveness of Dialectical Behavior Therapy (DBT) in an outpatient clinic for borderline personality disorders - impact of medication use and treatment costs]. AB - OBJECTIVE: Investigation of the clinical effectiveness of dialectical behavioral therapy in a day clinic setting (DBT-DC) for borderline personality disorders (BPD), and impact of medication and daily costs. METHODS: In a prospective, naturalistic, open and uncontrolled design BPD patients were enclosed in a 12 week DBT-DC. This DBT-program was certified by the German network of DBT. We collected data from the Symptom Checklist (SCL-90), the Beck Depression Inventory (BDI) and the Borderline Symptom List 95 (BSL-95) in the first and at the end of the 11th week. The concomitant medication and its changes were described. RESULTS: 31 cases were included (9 drop-outs: 29 %). The average age was 33.3 years (18 - 52, SD = 10.6). 21 females and one male completed the program. There was no relationship between changes of BDI, SCL-90 and BSL-95 scores (p < 0.001) and medication (and its alteration). The BDI scores improved by 50.8 % (p < 0.001), the SCL-90 by 42.9 % (p < 0.01) and the BSL-95 by 48.4 % (p < 0.001). The power was 0.99 (alpha = 0.05), the effect size was 1.41. In our setting the daily costs showed a reduction of about 6500 ? per case compared to an inpatient DBT. Medications played no significant role for improvement. CONCLUSIONS: For the first time a partial remission for BPD patients after 12 weeks has been shown to be achieved in a DBT-DC setting. DBT-DC reduces the primary costs of BPD compared to a specific inpatient therapy. PMID- 23733227 TI - Avidity of onconeural antibodies is of clinical relevance. AB - Onconeural antibodies are important in the detection of paraneoplastic neurological syndromes (PNS). The avidity of Hu, Yo, and CRMP5 antibodies from 100 patients was determined by immunoprecipitation (IP), and 13 of the Yo positive sera were also tested by surface plasmon resonance (SPR). There was a significant association between the results from IP and SPR. Yo antibodies had higher avidity than Hu and CRMP5 antibodies, and both high- and low-avidity antibodies were associated with tumors and PNS. High-avidity Yo antibodies were mainly associated with ovarian cancer, whereas high-avidity Hu and CRMP5 antibodies were mainly associated with small-cell lung cancer. Low-avidity CRMP5 and Yo antibodies were less often detected by a commercial line blot than high avidity antibodies. The failure to detect low-avidity onconeural antibodies may result in under diagnosis of PNS. PMID- 23733228 TI - 2-Aminothiophene-3-carboxylic acid ester derivatives as novel highly selective cytostatic agents. AB - Cytostatic agents often do not discriminate in their cytostatic potential between different tumor cell types in vitro. In this study, several 2-aminothiophene-3 carboxylic acid ester derivatives were discovered that show an unusual cytostatic selectivity for several T-cell (but not B-cell) lymphoma, prostate cancer, kidney carcinoma and hepatoma cell lines. Their 50 % cytostatic concentrations were generally in the higher nanomolar range and were approximately 20- to 50-fold lower for these tumor cell types than for any other tumor cell line or non tumorigenic cells. The tumor-selective compounds caused a more preferential suppression of protein synthesis than DNA or RNA synthesis and the prototype compound 3 resulted in an accumulation of prostate cancer cells in the G1 phase of their cell cycle. Compound 3 was also shown to induce apoptosis in prostate cancer cells. The 2-aminothiophene-3-carboxylic acid ester derivatives represent novel candidate cytostatic agents to be further explored for their tumor selective potential. PMID- 23733229 TI - MR signal amplification for imaging of the mutant EGF receptor in orthotopic human glioma model. AB - PURPOSE: To investigate the potential of targeted MR signal amplification strategy for imaging of EGF receptor variant III (EGFRvIII) overexpression associated with the infiltrating margin of aggressive orthotopic brain tumors. PROCEDURES: F(ab')2 fragments of humanized anti-EGFRvIII monoclonal antibody (EMD72000) were linked to deglycosylated horseradish peroxidase (HRP) and glucose oxidase (GOX). Detection of the F(ab')2 conjugate pair colocalization in vivo was enabled by a subsequent IV injection of a low molecular weight paramagnetic substrate of HRP, diTyr-GdDTPA. RESULTS: The delivery of the targeted fragments to the tumor was validated using SPECT/CT imaging of radiolabeled anti-EGFRvIII F(ab')2 conjugates. Further, by using 3 T MRI, we observed time-dependent differences in tumor signal intensity and signal retention at the endpoint depending on whether or not the animals were pre-injected with the anti-EGFRvIII F(ab')2 conjugates. CONCLUSIONS: Imaging of EGFRvIII expression in vivo was enabled by consecutive administration of targeted F(ab')2 conjugates and a paramagnetic substrate resulting in a tumor-specific receptor detection with high specificity and resolution. PMID- 23733230 TI - Effect of bone marrow mesenchymal stem cells from blastic phase chronic myelogenous leukemia on the growth and apoptosis of leukemia cells. AB - Chronic myelogenous leukemia (CML) has a typical progressive course with transition from a chronic phase to a terminal blast crisis phase. However, the mechanisms that lead to disease progression remain unclear. Bone marrow mesenchymal stem cells (BMMSCs) play important roles in maintaining the bone marrow microenvironment. In the present study, the biological characteristics of BMMSCs were determined including proliferation, apoptosis and secretion of cytokines during blastic phase CML (CML-Bp). The effect of BMMSCs in CML-Bp on K562 human CML cells and the CML-Bp original generation leukemia cells were also explored. Our results showed that CML-Bp BMMSCs protect tumor cells and increase their anti-apoptotic ability through regulating the expression of apoptosis related proteins and activating the Wnt pathway. PMID- 23733231 TI - Determinants of patient satisfaction with care in a Spanish oncology day hospital and its relationship with quality of life. AB - OBJECTIVE: This study evaluates satisfaction with care (SC) in cancer patients treated at a Spanish day hospital to identify SC determinants and assess the relationship between SC and quality of life. METHODS: One hundred seventy-six patients with different tumour sites and disease stages completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the Cancer Outpatient Satisfaction with Care questionnaire for chemotherapy (OUT-PATSAT35 CT), the Oberst patients' perception of care quality and satisfaction scales, and an item on intention to recommend the hospital. Frequencies in the SC instruments, Spearman correlations between each scale of the OUT-PATSAT35 CT and overall satisfaction and between the subscales of OUT PATSAT35 CT and of QLQ-C30 were calculated, and the determinants of patients' SC were calculated through multivariate regression models. RESULTS: Satisfaction with care was high: mean scores were >70 in all OUT-PATSAT35 CT areas except doctor availability and environment. These scores were in line with the other SC instruments. Correlation with overall satisfaction was high and statistically significant (p < 0.01) for all subscales, especially for the nurses domain, which also had higher SC scores. Correlations between the EORTC QLQ-C30 and the OUT PATSAT35 CT were low (<= 0.35). Younger patients and those with breast cancer showed significantly lower satisfaction in most subscales. Unmarried patients and patients that had undergone surgery reported lower satisfaction only in specific subscales. CONCLUSIONS: Satisfaction with care among cancer patients treated at the day hospital is high. Nurses play a key and successful role. Age and tumour location revealed stronger relationships with SC. Correlations between SC and quality of life indicate that these concepts are complementary. PMID- 23733232 TI - The efficacy and safety of alphacypermethrin as a pour-on treatment for water buffalo (Bubalus bubalis) infested with Haematopinus tuberculatus (Phthiraptera: Haematopinidae). AB - The sucking louse Haematopinus tuberculatus (Burmeister 1839) is an ectoparasite of buffaloes, cattle, camels, and American bison. Alphacypermethrin (ACYP) is a pyrethroid insecticide commonly used to control arthropods of veterinary and public health interest. Therapeutics, such as antiparasitic compounds, is often administered to buffaloes based on dosage and intervals recommended for cattle because very few drugs have buffalo-specific label indications. A trial was conducted on 20 louse-infested buffaloes at a farm to assess the efficacy and safety of ACYP pour-on, at the manufacturer's recommended dose for cattle, on buffaloes naturally infested by H. tuberculatus. Ten animals were assigned to ACYP-treated group (ACYP-group) and ten to untreated control group (C-group). On day 0, all ACYP-group buffaloes received alphacypermethrin pour-on. Louse counts were performed on days -1, 7, 14, 21, 28, 35, 42, 49, and 56 at eight predilection sites on the skin of each buffalo. ACYP was completely effective (100%) at day 7, highly effective (99.8%) at day 14, and completely effective (100%) from day 21 until the end of the study (day 56 post-treatment). During the trial, ACYP was well tolerated by all animals as there were no observed clinically adverse reactions. The results of this trial suggest that ACYP is an effective, safe, and user-friendly compound suitable for treatment of buffaloes with natural louse infestations. PMID- 23733233 TI - Beyond heme detoxification: a role for hemozoin in iron transport in S. japonicum. AB - Hemozoin (Hz) is considered a disposal product during the digestion of red blood cells by some blood-feeding parasites, such as Plasmodium, Schistosome, and Rhodnius. The only function of Hz that has been reported is to detoxify the free heme (Fe((III))-protoporphyrin-IX) in worms. Here we report a new role for Hz in iron transport in Schistosoma japonicum. Using transmission electron microscopy (TEM), we observed that S. japonicum hemozoin (sjHz) granules were a group of electron-dense, globe-, and comma-shaped granules. At the anterior end of female worm gut, these dark brown granules were found to be mixed with biconcave disc shaped erythrocytes, in the middle portion of the gut these granules attached to destroyed erythrocytes and in the posterior portion of the gut no intact erythrocytes were observed except free sjHz granules. By energy dispersive spectroscopy (EDS) and Prussian blue iron staining, we found that these iron containing sjHz granules are degraded near the microvilli adjacent to vitelline glands, resulting in the accumulation of a large amount of iron in the vitelline cells and eggs of developed S. japonicum. The accumulation of iron in vitelline glands was synchronized with the increase of sjHz granules in the gut. When S. japonicum just contained a little amount of sjHz granules in gut, hardly any accumulation of iron was detected in vitelline glands. However, when the lumen of gut filled full with sjHz granules, large amounts of iron was detected in vitelline glands. Solexa sequencing revealed that expression of iron store protein, ferritin-1 (CAX77379.1), is just significantly up-regulated in worms that contained a large amount of sjHz in gut. In contrast to the idea that sjHz granules are simply by-product of heme detoxification, we found that formation and degradation of sjHz granules in vivo likely serve for the iron transport. Our findings provide new insights into the biological significance of Hz formation. PMID- 23733234 TI - Comparative infectivity of three larval nematode species in three different salmonids. AB - Host specificity of parasites may depend both on ecological and physiological factors. Basic descriptions of the susceptibility/resistance of fish to specific nematodes are needed in order to reveal mechanisms in the host-parasite relation. Rainbow trout (Oncorhynchus mykiss), brown trout (Salmo trutta), and Atlantic salmon (Salmo salar) were orally infected with larval stages of three different anisakid nematodes-Hysterothylacium aduncum, Contracaecum osculatum, and Anisakis simplex-and parasite survival and location was subsequently recorded for up to 14 days post infection (dpi). H. aduncum was most prevalent and numerous in brown trout 2 dpi, but a large proportion of the worms were recovered dead. No tissue penetration was observed. Rainbow trout exhibited the highest susceptibility to C. osculatum larvae at 2, 7, and 14 dpi. Mean intensities and mean abundances were lower in brown trout and salmon at all time points. The pyloric cecum was penetrated in rainbow trout on two occasions. A. simplex larvae established more successfully in salmon compared to rainbow trout; brown trout exhibited the highest natural resistance. Mean intensity and mean abundance was highest in rainbow trout at 2 and 7 dpi, but not after 14 days. A range of tissues, including muscle and liver, were found penetrated by larvae, but the pyloric ceca were the preferred microhabitat for Anisakis in both rainbow trout and salmon. It can be concluded that closely related salmonids differ in susceptibility towards different anisakid larvae and these parasites select different microhabitats in the hosts. The physiological basis for this specificity is discussed. PMID- 23733235 TI - Autosomal recessive hereditary spastic paraplegia-clinical and genetic characteristics of a well-defined cohort. AB - We describe the clinical and genetic features of a well-characterized cohort of patients with autosomal recessive hereditary spastic paraplegia (ARHSP) in the province of Ontario. Patients with documented corticospinal tract abnormalities were screened by whole gene sequencing and multiplex ligation probe amplification for mutations in nine genes known to cause ARHSP. Of a cohort of 39 patients, a genetic diagnosis was established in 17 (44 %) and heterozygous mutations were detected in 8 (21 %). Mutations were most frequent in SPG7 (12 patients), followed by SPG11 (10 patients), PNPLA6 (SPG39, 2 patients), and ZFYVE26 (SPG15, 2 patients). Although there are associations between some clinical manifestations of ARHSP and specific genes, many patients are tested at an early stage of the disease when phenotype/genotype correlations are not obvious. Accurate molecular characterization of well-phenotyped cohorts of patients will be essential to establishing the natural history of these rare degenerative disorders to enable future clinical trials. PMID- 23733236 TI - A comparison of Diamond Forrester and coronary calcium scores as gatekeepers for investigations of stable chest pain. AB - To determine if calcium scores (CS) could act as a more effective gatekeeper than Diamond Forrester (DF) in the assessment of patients with suspected coronary artery disease (CAD). A sub-study of the Cardiac CT for the Assessment of Chest Pain and Plaque (CAPP) study, a randomised control trial evaluating the cost effectiveness of cardiac CT in symptomatic patients with stable chest pain. Stable pain was defined as troponin negative pain without symptoms of unstable angina. 250 patients undergoing cardiac CT had both DF scores and CS calculated, with the accuracy of both evaluated against CT coronary angiogram. Criteria given in UK national guidelines were compared. Of the 250 patients, 4 withdrew. 140 (57 %) patients were male. The mean DF was 47.8 and mean CS 172.5. Of the 144 patients with non-anginal pain 19.4 % had significant disease (>50 % stenosis). In general the DF over estimated the presence of CAD whereas the CS reclassified patients to lower risk groups, with 91 in the high risk DF category compared to 26 in the CS. Both receiver operating curve and McNemar Bowker test analysis suggested the DF was less accurate in the prediction of CAD compared to CS [Formula: see text] Projected downstream investigations were also calculated, with the cost per number of significant stenoses identified cheaper with the CS criteria. Patients with suspected stable CAD are more accurately risk stratified by CS compared to the traditional DF. CS was more successful in the prediction of significant stenosis and appears to be more effective at targeting clinical resources to those patients that are in need of them. PMID- 23733237 TI - Head-to-head comparison of 1 week versus 6 months CMR-derived infarct size for prediction of late events after STEMI. AB - Infarct size (IS) at 1 week after ST-elevation myocardial infarction (MI) diminishes during the first months. The incremental prognostic value of IS regression and of scar size (SS) at 6 months is unknown. We compared cardiovascular magnetic resonance (CMR)-derived IS at 1 week and SS at 6 months after MI for predicting late major adverse cardiac events (MACE). 250 patients underwent CMR at 1 week and 6 months after MI. IS and SS were determined as the extent of transmural late enhancement (in >50 % of wall thickness, ETLE). During 163 weeks, 23 late MACE (cardiac death, MI or readmission for heart failure after the 6 months CMR) occurred. Patients with MACE had a larger IS at 1 week (6 [4-9] vs. 3 [1-5], p < .0001) and a larger SS at 6 months (5 [2-6] vs. 3 [1-5], p = .005) than those without MACE. Late MACE rates in IS >median were higher at 1 week (14 vs. 4 %, p = .007) and in SS >median at 6 months (12 vs. 5 %, p = .053). The C-statistic for predicting late MACE of CMR at 1 week and 6 months was comparable (.720 vs. .746, p = .1). Only ETLE at 1 week (HR 1.31 95 % CI [1.14 1.52], p < .0001, per segment) independently predicted late MACE. CMR-derived SS at 6 months does not offer prognostic value beyond IS at 1 week after MI. The strongest predictor of late MACE is ETLE at 1 week. PMID- 23733238 TI - Prognosis of normal stress-only gated-SPECT myocardial perfusion imaging: a single center study. AB - It has been advocated that using the stress followed by rest protocol, if the stress images were normal there is no need of rest images, reducing radiation exposure and costs. Our purpose was to assess the prognosis of a group of patients with normal stress-only gated-SPECT myocardial perfusion imaging. This was retrospective study that includes 790 patients with normal myocardial stress only perfusion gated SPECT images. Images were considered as normal if a homogeneous myocardial distribution of the tracer was associated with a normal ejection fraction. The mean follow-up was of 42.8 +/- 13.3 months. The considered events were death of all causes, myocardial infarction and myocardial revascularization. During this period there were 85 events (10.8 %), including 57 deaths of all causes (67.1 %), 9 myocardial infarctions (10.6 %), 19 revascularizations (2.4 %). In the first year of follow-up there were 32 events (4.0 %) and excluding non cardiac deaths there were 8 events (1.0 %). Using Cox survival analysis, diabetes (HR = 2.2; CI = 1.4-3.4; p <= 0.0005), the history of coronary artery disease (CAD) (HR = 2.1; CI = 1.3-3.2; p <= 0.001), age (HR = 1.0; CI = 1.0-1.0; p <= 0.05) and type of stress protocol were related with events (exercise test vs. adenosine) (Exercise test: HR = 0.5; CI = 0.3-0.8; p <= 0.01). In a multivariate analysis the independent predictors were diabetes, CAD and the type of stress protocol. Based on these results, normal stress-only images are associated with an excellent prognosis even in patients at higher risk, diabetics and patients with known CAD. PMID- 23733239 TI - Heterogeneity of myocardial iron distribution in response to chelation therapy in patients with transfusion-dependent anemias. AB - The purpose of this study is to examine the effect of different iron chelation regimens on the distribution of myocardial iron in patients with transfusion dependent anemias. Institutional review board approval was obtained. Patients treated with iron chelation therapy who had undergone baseline and 1-year follow up cardiac T2* MR studies in a four-year period were identified retrospectively. One hundred and eight patients (44 % male, mean age 31.6 +/- 9.7 years) were included. The interventricular septum on three short-axis slices (basal, mid and apical) was divided into anterior and inferior regions of interest for T2* analysis. Cardiac iron concentration (CIC) was calculated from T2* values. Statistical analysis included analysis of variance and paired t-test, using Bonferroni adjustment in all pairwise comparisons. At baseline, T2* measurements varied significantly across all six regions (p < 0.001): lowest in the mid anteroseptum (mean 22.3 +/- 10.1 ms) and highest in the apical inferoseptum (mean 26.2 +/- 12.8 ms). At follow-up, T2* and CIC values improved significantly in all segments [mean change of 3.78 ms (95 % CI (2.93, 4.62), p < 0.001) and 0.23 mg/g (95 % CI (0.16, 0.29), p < 0.001), respectively]. Change in T2* values varied significantly between segments (p < 0.001) with greatest improvement in the apical inferoseptum [4.26 ms, 95 % CI (2.42, 6.11)] and least improvement in the basal anteroseptum [2.95 ms, 95 % CI (1.37, 4.54)]. The largest improvement in T2* values was noted in patients treated with deferiprone [4.96 ms, 95 % CI (2.34, 7.58)]. There was a statistically significant difference in improvement in CIC values between chelation regimens (p = 0.016). This is the first study to report heterogeneity in response to iron chelating drugs with variable segmental changes in T2* values. PMID- 23733240 TI - The applicability of a seminal professional development theory to creative arts therapies students. AB - The purpose of this mixed-methods study was to test the extent to which a seminal theory of the professional development of counsellors and therapists is applicable to the particular experiences of creative arts therapies graduate students who learn how to use the arts in psychotherapy. Nevertheless, readers may consider the results of the present study transferable to other healthcare disciplines. Questionnaires for each developmental phase were used for data collection, and analysis included data quantification, assessment of inter-rater agreement and theory derivation procedure. Results indicate that creative arts therapies students were concerned about translating theory into practice, learning how experienced therapists concretely function in practice, and reducing cognitive dissonance upon realization that their pre-training lay conceptions of helping were no longer valid. Stress and anxiety drove students to adopt easily mastered techniques that were implemented creatively in practicum. The results confirm that students who were older and had undergraduate human-service education and/or considerable life experience were less concerned about their suitability to the profession, were more acquainted with a professional working style and searched for their individual way of becoming therapists. Finally, recommendations for future research are suggested, and implications for practice are offered. PMID- 23733241 TI - Primary orbital eosinophilic angiocentric fibrosis with intranasal extension. AB - BACKGROUND: Eosinophilic angiocentric fibrosis is a chronic, idiopathic disorder that usually involves the upper respiratory tract and features progressive submucosal perivascular fibrosis of unknown etiology. To our knowledge, only 5 cases of eosinophilic angiocentric fibrosis with primary orbital involvement have been reported. METHODS AND RESULTS: We report the case of a 46-year-old man with right proptosis and lateral globe displacement caused by a primary eosinophilic angiocentric fibrosis extending from the orbit into the anterior ethmoid. The nasal extension of the lesion helped in establishing the correct diagnosis. CONCLUSION: Physicians involved in the treatment of orbital pathologies should be familiar with this entity, because it may manifest as an intraorbital mass growing primarily or secondly into the orbit. The clinical manifestations of eosinophilic angiocentric fibrosis with orbital involvement often mimic other more common ophthalmological diseases. Biopsies are necessary for diagnosis and treatment planning, although cures are usually of palliative effect. PMID- 23733243 TI - [Rectal cancer surgery in Germany - a 10-year-analysis based on the data of the "Institute of Quality Assurance in Operative Medicine" at the Otto-von-Guericke University Magdeburg]. AB - BACKGROUND: The treatment of rectal cancer has undergone pronounced changes during the last two decades. There has been a significant improvement in local tumour control due to consequent use of neo-adjuvant therapy and total mesorectal excision in cases of distal rectal cancer. The presented analysis examines the realisation of the multimodal therapy for rectal cancer under the conditions of routine patient-centred care over a period of ten years. METHOD: The data acquired in the prospective multicentre observational study "Quality Assurance - Rectal Cancer" from the years 2000 to 2010 were analysed. N = 33,724 patients were documented. The resection rate was 95.2 %. The rate of curative resection was 84.2 %. RESULTS: No change was detected in perioperative total morbidity and lethality during the course of the study. The percentage of patients with neo adjuvant treatment and curative resection rose from 5.6 % (2000) to 40.5 % (2012). The rate of performed TME in distal rectal cancer rose from 75.2 % (2000) to 95.3 % (2012). For patients who underwent curative resection in the years 2000/2001 the 5-year local recurrence rate was 11.7 %, while it was found to be 4.6 % for patients who were thus treated in the years 2005/2006 (p < 0.001). There was no improvement of total survival. CONCLUSION: While an increase in the use of neo-adjuvant treatment for rectal cancer and the establishment of TME in routine patient-centred care have led to a significant improvement in local tumour control with a constant total morbidity and lethality, there is no detectable influence on the patients' total survival. PMID- 23733242 TI - Diazido mixed-amine platinum(IV) anticancer complexes activatable by visible light form novel DNA adducts. AB - Platinum diam(m)ine complexes, such as cisplatin, are successful anticancer drugs, but suffer from problems of resistance and side-effects. Photoactivatable Pt(IV) prodrugs offer the potential of targeted drug release and new mechanisms of action. We report the synthesis, X-ray crystallographic and spectroscopic properties of photoactivatable diazido complexes trans,trans,trans [Pt(N3)2(OH)2(MA)(Py)] (1; MA=methylamine, Py=pyridine) and trans,trans,trans [Pt(N3)2(OH)2(MA)(Tz)] (2; Tz=thiazole), and interpret their photophysical properties by TD-DFT modelling. The orientation of the azido groups is highly dependent on H bonding and crystal packing, as shown by polymorphs 1p and 1q. Complexes 1 and 2 are stable in the dark towards hydrolysis and glutathione reduction, but undergo rapid photoreduction with UVA or blue light with minimal amine photodissociation. They are over an order of magnitude more potent towards HaCaT keratinocytes, A2780 ovarian, and OE19 oesophageal carcinoma cells than cisplatin and show particular potency towards cisplatin-resistant human ovarian cancer cells (A2780cis). Analysis of binding to calf-thymus (CT), plasmids, oligonucleotide DNA and individual nucleotides reveals that photoactivated 1 and 2 form both mono- and bifunctional DNA lesions, with preference for G and C, similar to transplatin, but with significantly larger unwinding angles and a higher percentage of interstrand cross-links, with evidence for DNA strand cross linking further supported by a comet assay. DNA lesions of 1 and 2 on a 50 bp duplex were not recognised by HMGB1 protein, in contrast to cisplatin-type lesions. The photo-induced platination reactions of DNA by 1 and 2 show similarities with the products of the dark reactions of the Pt(II) compounds trans-[PtCl2(MA)(Py)] (5) and trans-[PtCl2(MA)(Tz)] (6). Following photoactivation, complex 2 reacted most rapidly with CT DNA, followed by 1, whereas the dark reactions of 5 and 6 with DNA were comparatively slow. Complexes 1 and 2 can therefore give rapid potent photocytotoxicity and novel DNA lesions in cancer cells, with no activity in the absence of irradiation. PMID- 23733244 TI - Self-aligned active quantum nanostructures in photonic crystals via selective wet chemical etching. AB - We propose a method of forming quantum-size emitters within a pre-defined photonic crystal in a self-aligned fashion through controlled removal of quantum well layers via selective wet-chemical etching. To demonstrate the effectiveness of our method, we take the example of a two-dimensional photonic crystal slab containing multiple quantum wells at its center. We successfully fabricate vertically stacked quantum nanostructures (or quantum dots) well aligned with respect to the photonic crystal backbone. Micro-photoluminescence measurements performed at 78 K reveal that the radiative transition energy blue-shifts when the lateral dimension reaches less than 100 nm, which is compared with a simple model based on the 'particle-in-a-box' picture. The proposed method may find a broad range of applications in photonics and quantum optics, where the coupling between an emitter and an optical mode needs to be maximized. PMID- 23733245 TI - Genetic variants in telomerase-related genes are associated with an older age at diagnosis in glioma patients: evidence for distinct pathways of gliomagenesis. AB - BACKGROUND: Genome-wide association studies have implicated single nucleotide polymorphisms (SNPs) in 7 genes as glioma risk factors, including 2 (TERT, RTEL1) involved in telomerase structure/function. We examined associations of these 7 established glioma risk loci with age at diagnosis among patients with glioma. METHODS: SNP genotype data were available for 2286 Caucasian glioma patients from the University of California, San Francisco (n = 1434) and the Mayo Clinic (n = 852). Regression analyses were performed to test for associations between "number of risk alleles" and "age at diagnosis," adjusted for sex and study site and stratified by tumor grade/histology where appropriate. RESULTS: Four SNPs were significantly associated with age at diagnosis. Carrying a greater number of risk alleles at rs55705857 (CCDC26) and at rs498872 (PHLDB1) was associated with younger age at diagnosis (P = 1.4 * 10(-22) and P = 9.5 * 10(-7), respectively). These SNPs are stronger risk factors for oligodendroglial tumors, which tend to occur in younger patients, and their association with age at diagnosis varied across tumor subtypes. In contrast, carrying more risk alleles at rs2736100 (TERT) and at rs6010620 (RTEL1) was associated with older age at diagnosis (P = 6.2 * 10(-4) and P = 2.5 * 10(-4), respectively). These SNPs are risk factors for all glioma grades/histologies, and their association with age at diagnosis was consistent across tumor subgroups. CONCLUSIONS: Carrying a greater number of risk alleles might be expected to decrease age at diagnosis. However, glioma susceptibility conferred by variation in telomerase-related genes did not follow this pattern. This supports the hypothesis that telomerase-related mechanisms of telomere maintenance are more associated with gliomas that develop later in life than those utilizing telomerase-independent mechanisms (ie, alternative lengthening of telomeres). PMID- 23733247 TI - A laboratory and in situ postexposure feeding assay with a freshwater snail. AB - Contaminant-driven feeding inhibition has direct and immediate consequences at higher levels of biological organization, by depressing the population consumption and thus hampering ecosystem functioning (e.g., grazing, organic matter decomposition). The present study aimed at developing a short-term laboratory and in situ assay based on the postexposure feeding of the freshwater snail Theodoxus fluviatilis. A method to precisely quantify feeding rates was first developed, consisting of a 3-h feeding period, in darkness, on 150 defrosted nauplii of the brine shrimp Artemia franciscana. Postexposure feeding after a 48-h exposure to cadmium was approximately as sensitive as survival, with the median effective concentration (EC50) and median lethal concentration (LC50) being 85 ug/L and 102 ug/L, respectively, and the 20% effective concentration (EC20) and 20% lethal concentration (LC20) being 41 ug/L and 77 ug/L, respectively. Together, both effects at the LC20 reduced population consumption by 56%. In situ experiments at reference sites covering broad ranges of current velocity, hardness, conductivity, sediment organic matter content, and sediment particle size distribution revealed the influence of these abiotic conditions on postexposure feeding, in the absence of contamination, to be negligible. The effectiveness of the in situ assay was evaluated at 5 sites contaminated with acid mine drainage. Surviving organisms at the single partially lethal site (37% mortality) presented a 54% feeding inhibition relative to the reference, whereas the population consumption would be inhibited by 71%, confirming the integration of survival and feeding to be pertinent for estimating contaminant effects at higher levels of biological organization. PMID- 23733248 TI - Fabrication of complex three-dimensional polymer brush nanostructures through light-mediated living radical polymerization. PMID- 23733246 TI - MicroRNA-128 coordinately targets Polycomb Repressor Complexes in glioma stem cells. AB - BACKGROUND: The Polycomb Repressor Complex (PRC) is an epigenetic regulator of transcription whose action is mediated by 2 protein complexes, PRC1 and PRC2. PRC is oncogenic in glioblastoma, where it is involved in cancer stem cell maintenance and radioresistance. METHODS: We used a set of glioblastoma patient samples, glioma stem cells, and neural stem cells from a mouse model of glioblastoma. We characterized gene/protein expression and cellular phenotypes by quantitative PCR/Western blotting and clonogenic, cell-cycle, and DNA damage assays. We performed overexpression/knockdown studies by lentiviral infection and microRNA/small interfering RNA oligonucleotide transfection. RESULTS: We show that microRNA-128 (miR-128) directly targets mRNA of SUZ12, a key component of PRC2, in addition to BMI1, a component of PRC1 that we previously showed as a target as well. This blocks the partially redundant functions of PRC1/PRC2, thereby significantly reducing PRC activity and its associated histone modifications. MiR-128 and SUZ12/BMI1 show opposite expression in human glioblastomas versus normal brain and in glioma stemlike versus neural stem cells. Furthermore, miR-128 renders glioma stemlike cells less radioresistant by preventing the radiation-induced expression of both PRC components. Finally, miR 128 expression is significantly reduced in neural stem cells from the brain of young, presymptomatic mice in our mouse model of glioblastoma. This suggests that loss of miR-128 expression in brain is an early event in gliomagenesis. Moreover, knockdown of miR-128 expression in nonmalignant mouse and human neural stem cells led to elevated expression of PRC components and increased clonogenicity. CONCLUSIONS: MiR-128 is an important suppressor of PRC activity, and its absence is an early event in gliomagenesis. PMID- 23733249 TI - Mechanisms of proteasome inhibitor-induced cytotoxicity in malignant glioma. AB - The 26S proteasome constitutes an essential degradation apparatus involved in the consistent recycling of misfolded and damaged proteins inside cells. The aberrant activation of the proteasome has been widely observed in various types of cancers and implicated in the development and progression of carcinogenesis. In the era of targeted therapies, the clinical use of proteasome inhibitors necessitates a better understanding of the molecular mechanisms of cell death responsible for their cytotoxic action, which are reviewed here in the context of sensitization of malignant gliomas, a tumor type particularly refractory to conventional treatments. PMID- 23733250 TI - Use of aquaculture ponds and other habitats by autumn migrating shorebirds along the lower Mississippi river. AB - Populations of many shorebird species are declining; habitat loss and degradation are among the leading causes for these declines. Shorebirds use a variety of habitats along interior migratory routes including managed moist soil units, natural wetlands, sandbars, and agricultural lands such as harvested rice fields. Less well known is shorebird use of freshwater aquaculture facilities, such as commercial cat- and crayfish ponds. We compared shorebird habitat use at drained aquaculture ponds, moist soil units, agricultural areas, sandbars and other natural habitat, and a sewage treatment facility in the in the lower Mississippi River Alluvial Valley (LMAV) during autumn 2009. Six species: Least Sandpiper (Calidris minutilla), Killdeer (Charadrius vociferous), Semipalmated Sandpiper (Calidris pusilla), Pectoral Sandpiper (C. melanotos), Black-necked Stilt (Himantopus himantopus), and Lesser Yellowlegs (Tringa flavipes), accounted for 92 % of the 31,165 individuals observed. Sewage settling lagoons (83.4, 95 % confidence interval [CI] 25.3-141.5 birds/ha), drained aquaculture ponds (33.5, 95 % CI 22.4-44.6 birds/ha), and managed moist soil units on public lands (15.7, CI 11.2-20.3 birds/ha) had the highest estimated densities of shorebirds. The estimated 1,100 ha of drained aquaculture ponds available during autumn 2009 provided over half of the estimated requirement of 2,000 ha by the LMAV Joint Venture working group. However, because of the decline in the aquaculture industry, autumn shorebird habitats in the LMAV may be limited in the near future. Recognition of the current aquaculture habitat trends will be important to the future management activities of federal and state agencies. Should these aquaculture habitat trends continue, there may be a need for wildlife biologists to investigate other habitats that can be managed to offset the current and expected loss of aquaculture acreages. This study illustrates the potential for freshwater aquaculture to provide habitat for a taxa at risk. With the rapid growth of aquaculture worldwide, the practices of this industry deserve attention to identify benefits as well as risks to wildlife. PMID- 23733251 TI - Environmental effects of storage preservation practices: controlled flushing of fine sediment from a small hydropower reservoir. AB - Sediment flushing may be effective in mitigating loss of reservoir storage due to siltation, but flushing must be controlled to limit the impact on the downstream environment. A reliable prediction of the environmental effects of sediment flushing is hindered by the limited scientific information currently available. Consequently, there may be some controversy as regards to management decisions, planning the work, and monitoring strategies. This paper summarizes the main results of a monitoring campaign on the stream below a small alpine hydropower reservoir subjected to annual flushing between 2006 and 2009. The removed sediment was essentially silt, and the suspended solid concentration (SSC) of the discharged water was controlled to alleviate downstream impact. Control was achieved through hydraulic regulation and mechanical digging, alternating daytime sediment evacuation, and nocturnal clear water release. The four operations lasted about two weeks each and had an average SSC of about 4 g L(-1). Maximum values of SSC were generally kept below 10 g L(-1). Downstream impact was quantified through sampling of fish fauna (brown trout) and macroinvertebrate in the final reach of the effluent stream. The benthic community was severely impaired by the flushing operations, but recovered to pre-flushing values in a few months. As expected, the impact on brown trout was heavier on juveniles. While data biasing due to fish removal and re-stocking cannot be ruled out, the fish community seems to have reached a state of equilibrium characterized by a lower density than was measured before the flushing operations. PMID- 23733252 TI - Mammographic surveillance in women aged 35-39 at enhanced familial risk of breast cancer (FH02). AB - Although there have been encouraging recent studies showing a potential benefit from annual mammography in women aged 40-49 years of age with an elevated breast cancer risk due to family history there is little evidence of efficacy in women aged <40 years of age. A prospective study (FH02) has been developed to assess the efficacy of mammography screening in women aged 35-39 years of age with a lifetime breast cancer risk of >= 17 % who are not receiving MRI screening. Retrospective analyses from five centres with robust recall systems identified 47 breast cancers (n = 12 in situ) with an interval cancer rate of 15/47 (32%). Invasive tumour size, lymph node status and current vital status were all significantly better than in two control groups of unscreened women (including those with a family history) recruited to the POSH study. Further evaluation of the prospective arm of FH02 is required to assess the potential added value of digital mammography and the cancer incidence rates in moderate and high risk women in order to inform cost effectiveness analyses. PMID- 23733253 TI - Alternative splicing of the chromodomain protein Morf4l1 pre-mRNA has implications on cell differentiation in the developing chicken retina. AB - The proliferation, cell cycle exit and differentiation of progenitor cells are controlled by several different factors. The chromodomain protein mortality factor 4-like 1 (Morf4l1) has been ascribed a role in both proliferation and differentiation. Little attention has been given to the existence of alternative splice variants of the Morf4l1 mRNA, which encode two Morf41l isoforms: a short isoform (S-Morf4l1) with an intact chromodomain and a long isoform (L-Morf4l1) with an insertion in or in the vicinity of the chromodomain. The aim of this study was to investigate if this alternative splicing has a function during development. We analysed the temporal and spatial distribution of the two mRNAs and over-expressed both isoforms in the developing retina. The results showed that the S-Morf4l1 mRNA is developmentally regulated. Over-expression of S Morf4l1 using a retrovirus vector produced a clear phenotype with an increase of early-born neurons: retinal ganglion cells, horizontal cells and cone photoreceptor cells. Over-expression of L-Morf4l1 did not produce any distinguishable phenotype. The over-expression of S-Morf4l1 but not L-Morf4l1 also increased apoptosis in the infected regions. Our results suggest that the two Morf4l1 isoforms have different functions during retinogenesis and that Morf4l1 functions are fine-tuned by developmentally regulated alternative splicing. The data also suggest that Morf4l1 contributes to the regulation of cell genesis in the retina. PMID- 23733254 TI - Remote ischemic postconditioning promotes the survival of retinal ganglion cells after optic nerve injury. AB - Ischemic conditioning, the application of a mild ischemic stimulus to an ischemia sensitive structure like the heart or brain either before (preconditioning) or after (postconditioning) its exposure to a lethal ischemic insult, is known to switch on endogenous protective mechanisms. However, most studies of its neuroprotective effect in the central nervous system (CNS) have focused on ischemic damage or related conditions like hypoxia, while its potential in treating other neural diseases remains uncertain. In particular, the recent discovery of remote ischemic postconditioning whereby mild ischemia applied to a region remote from the target after the main ischemic insult also confers protection offers an attractive paradigm to study its potential in other types of neural injury. Retinal ganglion cells damaged by optic nerve transection undergo extensive cell death. However, application of a series of mild ischemic/reperfusion cycles to the hind limb (limb remote ischemic postconditioning) at 10 min or 6 h after optic nerve cut was found to promote ganglion cell survival at 7 days post-injury, with the 10 min postconditioning still exerting protection at 14 days post-injury. Concomitant with the increased ganglion cell survival, 51 % more ganglion cells expressed the small heat shock protein HSP27, when remote ischemic postconditioning was performed at 10 min post injury, as compared to the sham conditioning group. Our results highlight the potential of using remote ischemic postconditioning as a noninvasive neuroprotective strategy in different CNS disorders like spinal cord and traumatic brain injury. PMID- 23733255 TI - Increased prevalence of obstructive lung disease in patients with obstructive sleep apnea. AB - STUDY PURPOSES: This study aims to determine whether there is an increased prevalence of obstructive lung diseases (OLDs) in patients with obstructive sleep apnea (OSA). We also determined whether among the OLD patients there is a difference in the prevalences of specific chronic disease co-morbidities between patients with and without OSA. METHODS: The prevalences of COPD, asthma, and COPD combined with asthma (ICD-9 coding) were compared between 1,497 adult OSA patients and 1,489 control patients, who were matched for age, gender, geographic location, and primary care physician. The prevalences of specific co-morbidities were measured in the OLD groups between patients with OSA and the matched control group. RESULTS: COPD, asthma, and COPD combined with asthma were found to be more prevalent among OSA patients compared to the matched controls. Prevalences among patients with and without OSA, respectively, were COPD-7.6 and 3.7 % (P<0.0001), asthma-10.4 and 5.1 % (P<0.0001), COPD plus asthma-3.3 and 0.9 % (P<0.0001). The Charlson Comorbidity Index was greater for OSA patients (2.3 +/- 0.2) than for controls (1.9 +/- 1.8; P<0.0001). These trends held for all severity ranges of OSA. Patients with OSA and COPD were characterized by more severe hypoxia at night compared with the OSA patients without OLD. CONCLUSION: OSA was associated with an increased prevalence of OLDs. PMID- 23733257 TI - "Phasic jaw motor episodes in healthy subjects with or without clinical signs and symptoms of sleep bruxism: a pilot study". A critical commentary. PMID- 23733256 TI - Endothelial function is well preserved in obese patients with mild obstructive sleep apnea. AB - PURPOSE: Endothelial dysfunction is one of the early markers of cardiovascular complications in obstructive sleep apnea (OSA). The aim of our study was to evaluate whether overweight patients with mild OSA displayed endothelial dysfunction, and to assess the effect of 1-year lifestyle intervention with an early very low calorie diet in endothelial function. METHODS: At baseline, the study population consisted of 83 overweight patients with mild OSA and 46 weight matched non-OSA subjects. OSA patients were further randomized into a 1-year supervised lifestyle intervention group or control group which received routine lifestyle counselling. Endothelial function measured by brachial artery flow mediated dilatation (FMD), apnea-hypopnea index (AHI), body mass index (BMI), and metabolic parameters were assessed at baseline and 12 months. RESULTS: No correlations between endothelial function and mild OSA were detected. However, patients with impaired endothelial function had lower mean saturation and impaired endothelial function correlated significantly with glucose intolerance and dyslipidemia. After the lifestyle intervention and successful weight reduction, AHI, BMI, serum triglycerides and insulin improved significantly; however, no improvement in FMD was detected. CONCLUSIONS: Mild OSA was not observed to be associated with endothelial dysfunction. Although in mild OSA endothelial function is still preserved, lifestyle intervention with weight reduction did achieve an improvement in other obesity-related risk factors for cardiovascular diseases, thus highlighting the importance of early intervention. PMID- 23733258 TI - Phase I/II clinical study on safety and antivascular effects of paclitaxel encapsulated in cationic liposomes for targeted therapy in advanced head and neck cancer. AB - BACKGROUND: The purpose of this phase I/II clinical trial was to test safety and effectiveness of 2 doses of vascular targeting cationic liposomes encapsulating paclitaxel (EndoTAG-1 [ET]) in human head and neck squamous cell carcinoma (HNSCC). METHODS: Patients with nonresectable therapy-refractory HNSCC were recruited for both ET treatment groups (3 or 4 patients per group). In cutaneous metastases, laser Doppler blood flow measurements were conducted during infusions. RESULTS: Only adverse events of grade 1 or 2 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 3.0) - in particular fatigue, chills, and hypertension - occurred. Follow up tumor volume measurements revealed stable disease in 4 of 5 cases. Reproducible dose-dependent blood flow reductions in skin metastases during ET infusions provide evidence of biological effectiveness. CONCLUSION: Infusions of ET seem to be safe and further phase II and III studies are warranted to prove efficacy in the treatment of HNSCC. PMID- 23733260 TI - Diastereoselective hydrogen-transfer reactions: an experimental and DFT study. AB - Radical reductions of halogenated precursors bearing a heterocycle exo (alpha) to the carbon-centered radical proceed with enhanced anti-selectivity, a phenomenon that we termed "exocyclic effect". New experimental data and DFT calculations at the BHandHLYP/TZVP level demonstrate that the origin of the exocyclic effect is linked to the strain energy required for a radical intermediate to reach its reactive conformation at the transition state (DeltaE(?)(strain)). Furthermore, radical reductions of constrained THP systems indicate that high 2,3-anti inductions are reached only when the radical chain occupies an equatorial orientation. Hydride deliveries to different acyclic substrates and calculations also suggest that the higher anti-selectivities obtained with borinate intermediates are not related to the formation of a complex mimicking an exocycle. From a broader standpoint, this study reveals important conformational factors for reactions taking place at a center vicinal to a heterocycle or an alpha-alkoxy group. PMID- 23733259 TI - Effects of metal ion adduction on the gas-phase conformations of protein ions. AB - Changes in protein ion conformation as a result of nonspecific adduction of metal ions to the protein during electrospray ionization (ESI) from aqueous solutions were investigated using traveling wave ion mobility spectrometry (TWIMS). For all proteins examined, protein cations (and in most cases anions) with nonspecific metal ion adducts are more compact than the fully protonated (or deprotonated) ions with the same charge state. Compaction of protein cations upon nonspecific metal ion binding is most significant for intermediate charge state ions, and there is a greater reduction in collisional cross section with increasing number of metal ion adducts and increasing ion valency, consistent with an electrostatic interaction between the ions and the protein. Protein cations with the greatest number of adducted metal ions are no more compact than the lowest protonated ions formed from aqueous solutions. These results show that smaller collisional cross sections for metal-attached protein ions are not a good indicator of a specific metal-protein interaction in solution because nonspecific metal ion adduction also results in smaller gaseous protein cation cross sections. In contrast, the collisional cross section of alpha-lactalbumin, which specifically binds one Ca(2+), is larger for the holo-form compared with the apo-form, in agreement with solution-phase measurements. Because compaction of protein cations occurs when metal ion adduction is nonspecific, elongation of a protein cation may be a more reliable indicator that a specific metal ion-protein interaction occurs in solution. PMID- 23733262 TI - A sensitive LC-MS/MS method for the quantification of febuxostat in human plasma and its pharmacokinetic application. AB - An improved, simple and highly sensitive LC-MS/MS method has been developed and validated for quantification of febuxostat with 100 MUL human plasma using febuxostat-d7 as an internal standard (IS) according to regulatory guidelines. The analyte and IS were extracted from human plasma via liquid-liquid extraction using diethyl ether. The chromatographic separation was achieved on a Zorbax C18 column using a mixture of acetonitrile and 5 mm ammonium formate (60:40, v/v) as the mobile phase at a flow rate of 0.5 mL/min. The total run time was 5.0 min and the elution of febuxostat and IS occurred at 1.0 and 1.5 min, respectively. A linear response function was established for the range of concentrations 1-6000 ng/mL (r > 0.99). The precursor to product ion transitions monitored for febuxostat and IS were m/z 317.1 -> 261.1 and 324.2 -> 262.1, respectively. The intra- and inter-day precisions (%RSD) were within 1.29-9.19 and 2.85-7.69%, respectively. The proposed method was successfully applied to pharmacokinetic studies in humans. PMID- 23733263 TI - Realistic quantum design of silicon quantum dot intermediate band solar cells. AB - A highly periodical Si nanodisk superlattice has been fabricated by our top-down process. Based on the realistic structure, a 3D simulation program using the finite element method is developed to calculate energy band structure, optical and electrical properties, as well as the intermediate band solar cell operation. Both the experiments and simulations reveal that miniband formation enhances the optical and electrical collections. Consequently, detailed electronic structure and conversion efficiency are examined to guide the optimal design of minibands. A theoretically predicted maximal efficiency of the explored Si nanodisk superlattice is 50.3%, which is promising, compared with well-known complicated Si tandem solar cells. PMID- 23733261 TI - Proteomic analysis revealed the altered tear protein profile in a rabbit model of Sjogren's syndrome-associated dry eye. AB - Sjogren's syndrome (SS) is an autoimmune disease that results in pathological dryness of mouth and eye. The diagnosis of SS depends on both clinical evaluation and specific antibodies. The goal of this study was to use quantitative proteomics to investigate changes in tear proteins in a rabbit model of SS associated dry eye, induced autoimmune dacryoadenitis (IAD). Proteomic analysis was performed by iTRAQ and nano LC-MS/MS on tears collected from the ocular surface, and specific proteins were verified by high resolution MRM. It was found that in the tears of IAD rabbits at 2 and 4 weeks after induction, S100 A6, S100 A9, and serum albumin were upregulated, whereas serotransferrin (TF), prolactin inducible protein (PIP), polymeric immunoglobulin receptor (pIgR), and Ig gamma chain C region were downregulated. High resolution MRM with mTRAQ labeling verified the changes in S100 A6, TF, PIP, and pIgR. Our results indicated significant changes of tear proteins in IAD rabbits, suggesting these proteins could potentially be used as biomarkers for the diagnosis and prognosis of dry eye. Several of these proteins were also found in the tears of non-SS dry eye patients indicating a common basis of ocular surface pathology, however, pIgR appears to be unique to SS. PMID- 23733264 TI - Endoscopic third ventriculostomy: preoperative considerations and intraoperative strategy based on 300 procedures. AB - PURPOSE: Although successful endoscopic third ventriculostomy (ETV) has been reported for many indications, peculiarities of the surgical technique in each separate indication require particular respect. METHODS: A detailed account of the authors' surgical technique, their presurgical considerations, and their intraoperative strategies to perform ETV is presented. Surgery of representative obstructive hydrocephalus cases in posterior fossa lesions (cerebellar infarction, posterior fossa tumor), in distortion of the ventricular system (intracranial hemorrhage, basilar artery aneurysm) and in membranous obstruction (aqueductal stenosis, posterior fossa malformation), is illustrated in detail. RESULTS: In posterior fossa lesions, careful evaluation of the prepontine space and localization of the basilar artery is mandatory. Recognition of mammillary bodies and infundibular recess is of particular importance since the third ventricle floor is rather thick and nontranslucent. In distortion of the ventricular system, careful analysis of the preoperative imaging allows the selection of the optimal approach. Sometimes, blood clot removal and vigorous irrigation is required. Frequently, the landmarks are difficult to identify. These are cases for experienced endoscopic neurosurgeons. In aqueductal stenosis and posterior fossa malformation, perforation of the often thin and translucent ventricular floor is easy because of clear anatomical landmarks. Those are ideal candidates for ETV. For experienced neuroendoscopists, the authors advocate inspection of the fourth ventricle with a flexible scope to ensure cerebrospinal fluid (CSF) circulation obstruction. CONCLUSIONS: ETV is a frequent and well established endoscopic technique. Based on the underlying pathology, the technique has to be modified to obtain good results with minimal complications. PMID- 23733265 TI - Histological organization of the central nervous system and distribution of a gonadotropin-releasing hormone-like peptide in the blue crab, Portunus pelagicus. AB - We present a detailed histological description of the central nervous system (CNS: brain, subesophageal ganglion, thoracic ganglia, abdominal ganglia) of the blue crab, Portunus pelagicus. Because the presence of gonadotropin-releasing hormone (GnRH) in crustaceans has been disputed, we examine the presence and localization of a GnRH-like peptide in the CNS of the blue crab by using antibodies against lamprey GnRH (lGnRH)-III, octopus GnRH (octGnRH) and tunicate GnRH (tGnRH)-I. These antibodies showed no cross-reactivity with red-pigment concentrating hormone, adipokinetic hormone, or corazonin. In the brain, strong lGnRH-III immunoreactivity (-ir) was detected in small (7-17 MUm diameter) neurons of clusters 8, 9 and 10, in medium-sized (21-36 MUm diameter) neurons of clusters 6, 7 and 11 and in the anterior and posterior median protocerebral neuropils, olfactory neuropil, median and lateral antenna I neuropils, tegumentary neuropil and antenna II neuropil. In the subesophageal ganglion, lGnRH-III-ir was detected in medium-sized neurons and in the subesophageal neuropil. In the thoracic and abdominal ganglia, lGnRH-III-ir was detected in medium-sized and small neurons and in the neuropils. OctGnRH-ir was observed in neurons of the same clusters with moderate staining, particularly in the deutocerebrum, whereas tGnRH-I-ir was only detected in medium-sized neurons of cluster 11 in the brain. Thus, anti-lGnRH-III shows greater immunoreactivity in the crab CNS than anti-octGnRH and anti-tGnRH-I. Moreover, our functional bioassay demonstrates that only lGnRH-III has significant stimulatory effects on ovarian growth and maturation. We therefore conclude that, although the true identity of the crab GnRH eludes us, crabs possess a putative GnRH hormone similar to lGnRH-III. The identification and characterization of this molecule is part of our ongoing research. PMID- 23733266 TI - Expression of miR-206 during the initiation of mammary gland development. AB - MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translational repression or RNA degradation. The aberrant expression of miRNAs might be involved in human diseases, including cancer. The expression of miR-206 in estrogen receptor alpha (ER-alpha)-positive human breast cancer tissues is well known. However, the expression and regulation of miR-206 in the developing mammary gland has not yet been studied. To understand the effects of miR-206 on mammary gland development, we have profiled gene expression in scramble-transfected and miR-206 overexpressing developing mammary buds. The genes that are potentially regulated by miR-206 in the mammary epithelium and/or mesenchyme, such as Tachykinin1 and Gata3, are known to be breast cancer markers. The expression of Wnt, which is involved in gland positioning, and of the transcription factors Tbx3 and Lef1, which are essential for mammary gland development, changes after miR-206 overexpression. Using a mammary bud in vitro culture system, we have demonstrated that miR-206 acts downstream of ER-alpha during mammary gland growth. Thus, miR 206 might be a novel candidate for morphogenesis during the initiation of mammary gland formation and the regulation of genes related to mammary gland development and breast cancer. PMID- 23733267 TI - Phototoxicity of TiO2 nanoparticles to zebrafish (Danio rerio) is dependent on life stage. AB - Zebrafish embryos have been used increasingly to evaluate nanomaterial toxicity. The present study compared phototoxicity of TiO2 nanoparticles with zebrafish at 4 life stages (embryos, yolk-sac larvae, free-swimming larvae, and juvenile) under simulated sunlight using the 96-h standard toxicity assay. Yolk-sac larvae were found to be the most sensitive to TiO2 phototoxicity, suggesting that the widely used zebrafish embryo test may not fully or accurately predict hazard and risk of these nanoparticles to small fish. PMID- 23733270 TI - Desloratadine-montelukast combination improves quality of life and decreases nasal obstruction in patients with perennial allergic rhinitis. AB - BACKGROUND: The effects of desloratadine-montelukast combination on quality of life (QoL) and nasal airflow of patients with perennial allergic rhinitis (PAR) has not been reported. The objective of this work was investigate the efficacy of desloratadine-montelukast combination on nasal obstruction and health-related quality of life (HRQL) of patients with PAR. METHODS: The patients with PAR (n = 40) were assessed using acoustic rhinometry (AcR) and Rhinoconjunctivitis QoL Questionnaire (RQLQ) before therapy. Desloratadine-montelukast fixed-dose combination treatment was applied to every patient once daily. The AcR and RQLQ score were reevaluated at the first and third months; and statistical comparison of pretreatment and posttreatment results was performed. RESULTS: Nasal symptoms and signs such as itching, sneezing, discharge, congestion, and edema, and color change of turbinates have been decreased after treatment. In AcR, minimum cross sectional area (MCA) measurements and volume results were increased after the treatment. Correlation was found between the volume results and nasal discharge and/or congestion in right nasal passages. In left nasal passages, statistical relation was observed between the MCA and itching and/or change of turbinate color (p < 0.05). A significant decrease in the overall RQLQ score was determined at the first and third months of therapy. The difference between scores at baseline and end of the first and third months for all domains was statically significant (p < 0.001). The treatment difference in change from the first month to the end of the third month was statistically significant (p < 0.05). CONCLUSION: Desloratadine-montelukast combination therapy causes subjective and objective decrease in nasal obstruction, reduces the other symptoms of PAR and improves the disease-specific QoL. PMID- 23733271 TI - Calpains are required for invasive and metastatic potentials of human HCC cells. AB - Calpains are a conserved family of calcium-dependent cysteine proteinases involved in various cellular functions. Two ubiquitous isoforms, u- and m calpain, are key members of the calpain family that play essential roles in regulating cell migration and invasion. However, it remains unclear whether they are involved in the progression of hepatocellular carcinoma (HCC). Here, we investigated the functions of u- and m-calpain in the invasive and metastatic processes of human hepatoma cells. Our results indicated that the expression levels of calpains were elevated in HCC cells compared with those in normal hepatic cells. Our results indicated that small interfering RNA (siRNA)-mediated silencing of u- and m-calpain expressions significantly suppressed the adhesive, migrative and invasive potentials of human hepatoma cells. The matrix metalloproteinases (MMPs) are key regulators of malignant tumour invasion and metastasis. siRNA-mediated down-regulation of u- and m-calpain expressions also significantly attenuated MMP-2 and MMP-9 secretion. Thus u- and m-calpain may play important roles in the invasion and metastasis of human hepatoma cells, and calpains may be drug targets for preventing HCC metastasis. PMID- 23733272 TI - In situ catalytic generation of allylcopper species for asymmetric allylation: toward 1H-isochromene skeletons. PMID- 23733273 TI - Effectiveness of an integrated adventure-based training and health education program in promoting regular physical activity among childhood cancer survivors. AB - BACKGROUND: There is growing concern about declining levels of physical activity in childhood cancer survivors. This study aimed to examine the effectiveness of an integrated adventure-based training and health education program in promoting changes in exercise behavior and enhancing the physical activity levels, self efficacy, and quality of life of Hong Kong Chinese childhood cancer survivors. METHODS: A randomized controlled trial, two-group pretest and repeated post-test, between-subjects design was conducted to 71 childhood cancer survivors (9- to 16 year-olds). Participants in the experimental group joined a 4-day integrated adventure-based training and health education program. Control group participants received the same amount of time and attention as the experimental group but not in such a way as to have any specific effect on the outcome measures. Participants' exercise behavior changes, levels of physical activity, self efficacy, and quality of life were assessed at the time of recruitment, 3, 6, and 9 months after starting the intervention. RESULTS: Participants in the experimental group reported statistically significant differences in physical activity stages of change (p < 0.001), higher levels of physical activity (p < 0.001) and self-efficacy (p = 0.04) than those in the control group. Besides, there were statistically significant mean differences (p < 0.001) in physical activity levels (-2.6), self-efficacy (-2.0), and quality of life (-4.3) of participants in the experimental group from baseline to 9 months after starting the intervention. CONCLUSIONS: The integrated adventure-based training and health education program was found to be PMID- 23733274 TI - Comparison of different measures of diffusing capacity for carbon monoxide (DLCO) in systemic sclerosis. AB - In systemic sclerosis (SSc), impaired diffusing capacity for carbon monoxide (DLCO) can indicate interstitial lung disease (ILD), pulmonary hypertension (PH), and/or other disease manifestations, including anemia. We undertook this study to compare the various measures of DLCO in the setting of a complex disease like SSc. We analyzed the pulmonary function tests of a cohort of SSc subjects, as a whole and among subjects with isolated PH and ILD separately. Associations were assessed using Spearman correlation coefficients, Student's t tests, and F tests by one-way ANOVA. P values <0.05 were considered statistically significant. This study included 225 subjects (mean age, 57 years; 88 % women; mean disease duration, 9.6 years; 32 % with diffuse disease, 44 % with ILD, and 17 % with PH). Mean percent predicted DLCO values were 75 % for DLCOsb and 83 % for DLCOrb. Adjustment for alveolar volume (VA) resulted in near normalization of both DLCOsb/VAsb (91 %) and DLCOrb/VArb (91 %). Subjects with ILD had significantly lower DLCOsb but not DLCOsb/VAsb, whereas those with PH had significantly lower DLCOsb and DLCOsb/VAsb. Among the various measures of DLCO, DLCOsb had the strongest and most consistent associations with clinical outcomes of interest. Adjusting for alveolar volume dampened the associations except with PH, with which DLCOsb/VAsb was more strongly associated than DLCOsb. Low DLCOsb is the most sensitive measure to detect abnormalities in gas exchange in SSc but reflects both parenchymal lung disease and pulmonary vascular disease. Low DLCOsb/VAsb is more specific for pulmonary vascular disease and should be the preferred measure of gas exchange in SSc. PMID- 23733275 TI - Transcatheter intervention for non-variceal gastrointestinal bleeding: what have we learned in 45 years? PMID- 23733276 TI - Expression variability of absorption, distribution, metabolism, excretion-related microRNAs in human liver: influence of nongenetic factors and association with gene expression. AB - Genes that are important for the detoxification of drugs and other xenobiotics show a high degree of interindividual variation attributable to regulation by diverse genetic, nongenetic, and epigenetic mechanisms including microRNAs (miRNAs). We selected a set of 56 miRNAs predicted to target the 3'-untranslated region of absorption, distribution, metabolism, excretion (ADME) genes to assess their hepatic expression levels and interindividual variability in a well documented human liver tissue cohort (n = 92), together with the well-known hepatic miRNAs miR-122, miR-21, miR-27b, and miR-148a. Quantification by stem loop real-time reverse-transcription polymerase chain reaction confirmed high expression for these microRNAs and revealed particularly strong variability of expression (>1000-fold) for miR-539, miR-200c, miR-31, miR-15a, and miR-22. Association analysis revealed a high degree of correlation among various miRNAs, suggesting coregulation. Statistical analysis considering liver donor meta-data including correction for multiple testing revealed strongly elevated levels of miR-21, miR-34a, miR-130b, and miR-132 in cholestatic liver and of miR-21 and miR 130b during inflammation, as indicated by elevated C-reactive protein levels in serum. Although none of the miRNAs was strongly associated with sex, several miRNAs, including miR-34a and miR-200a/b, were positively correlated with age. Association analysis with ADME gene expression profiles and with cytochrome P450 gene expression phenotypes (mRNA, protein, enzymatic activity) revealed numerous significant correlations. Negatively affected protein and/or activity levels were observed for CYP1A1 (e.g., miR-132, miR-142-3p, miR-21), CYP2A6 (miR-142-3p, miR 21), CYP2C19 (e.g., miR-130b, miR-185, miR-34a), and CYP2E1 (miR-10a, let-7g, miR 200c). These data should be useful to further elucidate regulatory functions of miRNAs in liver pathophysiology and regulation of ADME gene expression. PMID- 23733277 TI - Nanoparticle formulation of a poorly soluble cannabinoid receptor 1 antagonist improves absorption by rat and human intestine. AB - The inclusion of nanoparticles dispersed in a hydrophilic matrix is one of the formulation strategies to improve the bioavailability of orally administered Biopharmaceutics Classification System (BCS) class II and IV drugs by increasing their dissolution rate in the intestine. To confirm that the increased dissolution rate results in increased bioavailability, in vitro and in vivo animal experiments are performed, however, translation to the human situation is hazardous. In this study, we used a range of in vitro and ex vivo methods, including methods applying human tissue, to predict the in vivo oral bioavailability of a model BCS class II CB-1 antagonist, formulated as a nanoparticle solid dispersion. The enhanced dissolution rate from the nanoparticle formulation resulted in an increased metabolite formation in both rat and human precision-cut intestinal slices, suggesting increased uptake and intracellular drug concentration in the enterocytes. In Ussing chamber experiments with human tissue, both the metabolite formation and apical efflux of the metabolite were increased for the nanoparticulate solid dispersion compared with a physical mixture, in line with the results in intestinal slices. The pharmacokinetics of the different formulations was studied in rats in vivo. The nanoparticle formulation indeed improved the absorption of the cannabinoid receptor 1 (CB-1) antagonist and the delivery into the brain compared with the physical mixture. In conclusion, the combined approach provides a valuable set of tools to investigate the effects of formulation on the absorption of poorly soluble compounds in human intestine and may provide relevant information on the oral bioavailability in humans early in the development process. PMID- 23733278 TI - Comparison of autologous in situ blood coagulum versus sutures for conjunctival autografting after pterygium excision. AB - Our aim was to compare the efficacy and safety of autologous in-situ blood coagulum versus sutures for attaching conjunctival limbal autografts (CAG) among patients undergoing primary pterygium excision over a period of 1 year. Thirty two eyes of 32 patients with primary pterygium were randomly divided in into two groups: group I (16 eyes) underwent CAG with 10-0 monofilament nylon sutures and group II (16 eyes) underwent CAG with patient's own in-situ blood coagulum acting as bioadhesive or fixative followed by bandaging for 48 h. Patients were followed up postoperatively on the 2nd day, 1 week, 2 weeks, 4 weeks, and 12 months. All the surgeries were done by the same surgeon. Graft success, recurrence rate, operating time, patient comfort, graft retraction or any other complication were studied. The duration of surgery was significantly less (P < 0.001) in group II (mean duration 15 +/- 2 min) than group I (mean duration 67 +/- 2 min). Postoperative symptoms were fewer for group II than group I. Rate of recurrence was equal in both groups (one patient in each group, 6.25 %). But complications regarding graft failure and graft retraction were more common in group II (two patients, 12.5 %) than group I (one patient, 6.25 %); however, the difference was not statistically significant (Z = 0.61). Thus, autologous in-situ blood coagulum is a useful method for graft fixation in pterygium surgery with shorter operating time and less postoperative discomfort. PMID- 23733279 TI - The influence of pterygium morphology on fibrin glue conjunctival autografting pterygium surgery. AB - To evaluate the influence of pterygium morphology on the efficacy and safety of fibrin glue in pterygium surgery with conjunctival autografting. A prospective case series. During a period of 15 months, 45 patients (51 eyes) were recruited from the General Hospital for pterygium surgery. Seven eyes (13.73 %) were operated on for a recurrent pterygium. Autologous conjunctiva was harvested from the superior bulbar conjunctiva and fixed with fibrin glue. The pterygia were preoperatively divided into atrophic/grade 1 (n = 18; 35.29 %), intermediate/grade 2 (n = 22; 43.14 %) or fleshy/grade 3 (n = 11; 21.57 %) according to clinical morphology. Patients were evaluated for intraoperative and postoperative complications and recurrence rates. The success rate was defined by no pterygium recurrences. Patients with 2-year follow-ups were included in this study. Fifty-one patients (21 females/30 males) with a mean age of 60-65 years (range 24-87 years) took part in the study. All patients completed the study. No intraoperative complications were noted. Postsurgical complications included graft edema (n = 4; 7.8 %), graft hyperemia (n = 2; 3.8 %), and graft dislocation (n = 3; 5.9 %); these complications were transient. One graft unfastened completely (2 %) and five pterygium recurrences occurred (n = 5; 9.8 %). The overall success rate was 90 % after 2 years. In grade I group there were no recurrences, in grade 2 group there were two recurrences, and in grade 3 group there were three recurrences. There were significantly more recurrences in grade 3 group than in grade 2 group. There were more recurrences in both groups than in group 1 (60 vs 40 vs 0 % of all recurrences, p <= 0.05). The use of fibrin glue is a safe, easy and effective technique for attaching the conjunctival autograft in pterygium surgery. The morphology of pterygium influences recurrence rates, without significance for intraoperative and postoperative complications. PMID- 23733280 TI - Primary acute angle closure: long-term clinical outcomes over a 10-year period in the Chinese population. AB - To investigate long-term clinical outcomes after acute angle closure in the Chinese population. A 10-year retrospective review of primary acute angle closure in Hong Kong Chinese to document patient demographics, treatment, and pre- and post-acute angle closure intraocular pressure (IOP) and visual acuity (VA). The year of attack was correlated with the timing of laser, last VA and IOP, and the number of anti-glaucoma eye drops. In 210 eyes (200 patients), 10 % had a simultaneous bilateral acute angle closure. VA improvement was noted in 68.6 % of eyes whilst 11.4 % were blinded. At 3.7 +/- 2.4 years of follow-up, 49.5 % had IOP <21 mmHg with medication or surgery, 41.9 % needed anti-glaucoma eye drops, and 13.8 % had undergone trabeculectomy. The older the year of attack, the poorer the VA (r = 0.2, p = 0.03) and the longer the laser wait time (r = 0.3, p < 0.0001). VA outcome and laser promptness in acute angle closure has improved over the years. At 4 years after the attack, 50 % had normal IOP, 69 % had improved VA but 11 % were blinded. PMID- 23733281 TI - Spatializing health research: what we know and where we are heading. AB - Beyond individual-level factors, researchers have adopted a spatial perspective to explore potentially modifiable environmental determinants of health. A spatial perspective can be integrated into health research by incorporating spatial data into studies or analysing georeferenced data. Given the rapid changes in data collection methods and the complex dynamics between individuals and environment, we argue that geographical information system (GIS) functions have shortcomings with respect to analytical capability and are limited when it comes to visualizing the temporal component in spatio-temporal data. In addition, we maintain that relatively little effort has been made to handle spatial heterogeneity. To that end, health researchers should be persuaded to better justify the theoretical meaning underlying the spatial matrix in analysis, while spatial data collectors, GIS specialists, spatial analysis methodologists and the different breeds of users should be encouraged to work together making health research move forward through addressing these issues. PMID- 23733282 TI - Spatial scale effects in environmental risk-factor modelling for diseases. AB - Studies attempting to identify environmental risk factors for diseases can be seen to extract candidate variables from remotely sensed datasets, using a single buffer-zone surrounding locations from where disease status are recorded. A retrospective case-control study using canine leptospirosis data was conducted to verify the effects of changing buffer-zones (spatial extents) on the risk factors derived. The case-control study included 94 case dogs predominantly selected based on positive polymerase chain reaction (PCR) test for leptospires in urine, and 185 control dogs based on negative PCR. Land cover features from National Land Cover Dataset (NLCD) and Kansas Gap Analysis Program (KS GAP) around geocoded addresses of cases/controls were extracted using multiple buffers at every 500 m up to 5,000 m, and multivariable logistic models were used to estimate the risk of different land cover variables to dogs. The types and statistical significance of risk factors identified changed with an increase in spatial extent in both datasets. Leptospirosis status in dogs was significantly associated with developed high-intensity areas in models that used variables extracted from spatial extents of 500-2000 m, developed medium-intensity areas beyond 2,000 m and up to 3,000 m, and evergreen forests beyond 3,500 m and up to 5,000 m in individual models in the NLCD. Significant associations were seen in urban areas in models that used variables extracted from spatial extents of 500 2,500 m and forest/woodland areas beyond 2,500 m and up to 5,000 m in individual models in Kansas gap analysis programme datasets. The use of ad hoc spatial extents can be misleading or wrong, and the determination of an appropriate spatial extent is critical when extracting environmental variables for studies. Potential work-arounds for this problem are discussed. PMID- 23733283 TI - A scoping review of spatial cluster analysis techniques for point-event data. AB - Spatial cluster analysis is a uniquely interdisciplinary endeavour, and so it is important to communicate and disseminate ideas, innovations, best practices and challenges across practitioners, applied epidemiology researchers and spatial statisticians. In this research we conducted a scoping review to systematically search peer-reviewed journal databases for research that has employed spatial cluster analysis methods on individual-level, address location, or x and y coordinate derived data. To illustrate the thematic issues raised by our results, methods were tested using a dataset where known clusters existed. Point pattern methods, spatial clustering and cluster detection tests, and a locally weighted spatial regression model were most commonly used for individual-level, address location data (n = 29). The spatial scan statistic was the most popular method for address location data (n = 19). Six themes were identified relating to the application of spatial cluster analysis methods and subsequent analyses, which we recommend researchers to consider; exploratory analysis, visualization, spatial resolution, aetiology, scale and spatial weights. It is our intention that researchers seeking direction for using spatial cluster analysis methods, consider the caveats and strengths of each approach, but also explore the numerous other methods available for this type of analysis. Applied spatial epidemiology researchers and practitioners should give special consideration to applying multiple tests to a dataset. Future research should focus on developing frameworks for selecting appropriate methods and the corresponding spatial weighting schemes. PMID- 23733284 TI - Disparity in the spatial distribution of clinics within a metropolitan city. AB - A methodology for evaluating and understanding how healthcare agencies are distributed within a city is provided. The study undertaken analysed the disparity in the spatial distribution of clinics within the metropolitan city of Daejeon, South Korea. Address and specialty of clinics in use were collected from five public health centres in 2010. Buffer analysis, hot-spot analysis, and generalized linear models were applied to the data collected. Multivariate analysis was also conducted on data collected in 2008 from the annual records of five ward offices (mid-level city administration units) taking the lowest administrative level of the city (the dong) into account. Buffer analysis showed that numerous clinics were located near major roads, while the hot-spot analysis identified three areas with concentrations of clinics and one area with hardly any clinics. The results of the generalized linear models showed variations depending on the specialty of the clinics suggesting that their distribution differed depending on specialty. There are no current regulations in force governing clinic location. Policy makers should consider improving the clinic distribution taking their speciality into account. PMID- 23733285 TI - Does altitude moderate the impact of lithium on suicide? A spatial analysis of Austria. AB - Suicide, the tenth leading cause of death worldwide, is a complex phenomenon. Models aiming to explain the interaction of ambient variables such as socioeconomic factors, lithium content of drinking water and altitude are poorly developed. While controlling for several risk factors, this research bridges two different, but complementary research lines by investigating statistically the relationship on suicide mortality between lithium levels in drinking water in response to altitude above sea level. Besides regression models with main effects, a multiplicative interaction model between lithium and altitude has been developed providing estimates at the district-level for Austria where spatial autocorrelation was accounted for through spatial filtering. The correlation results showed a negative association between lithium levels and altitude. The regression confirmed a negative association of lithium levels and suicide mortality. Altitude was found to be positively associated with suicide mortality. On the other hand, lithium effects on suicide mortality were found to be moderated by altitude. In lower altitude regions the effect turned out to be negatively related to suicide mortality, while lithium had a positive association in high-altitude regions. These results provide evidence for the fact that the relationship between lithium, altitude and suicide rates is more complex than hitherto assumed. Further research on the effects of ambient variables such as low levels of lithium on suicide is needed and particularly the lithium-altitude interaction is worth further investigation to understand possible underlying neurochemical processes. PMID- 23733286 TI - Bayesian spatio-temporal modelling of tobacco-related cancer mortality in Switzerland. AB - Tobacco smoking is a main cause of disease in Switzerland; lung cancer being the most common cancer mortality in men and the second most common in women. Although disease-specific mortality is decreasing in men, it is steadily increasing in women. The four language regions in this country might play a role in this context as they are influenced in different ways by the cultural and social behaviour of neighbouring countries. Bayesian hierarchical spatio-temporal, negative binomial models were fitted on subgroup-specific death rates indirectly standardized by national references to explore age- and gender-specific spatio temporal patterns of mortality due to lung cancer and other tobacco-related cancers in Switzerland for the time period 1969-2002. Differences influenced by linguistic region and life in rural or urban areas were also accounted for. Male lung cancer mortality was found to be rather homogeneous in space, whereas women were confirmed to be more affected in urban regions. Compared to the German speaking part, female mortality was higher in the French-speaking part of the country, a result contradicting other reports of similar comparisons between France and Germany. The spatio-temporal patterns of mortality were similar for lung cancer and other tobacco-related cancers. The estimated mortality maps can support the planning in health care services and evaluation of a national tobacco control programme. Better understanding of spatial and temporal variation of cancer of the lung and other tobacco-related cancers may help in allocating resources for more effective screening, diagnosis and therapy. The methodology can be applied to similar studies in other settings. PMID- 23733288 TI - Increased cancer mortality in Taiwanese inter-island migrants. AB - Higher mortality due to various forms of cancer was observed in emigrants, who had moved from the isolated and impoverished Taiwanese island of Matsu to the more affluent main island. A total of 13,691 ethnic Matsunese aged 30 years and above were enrolled in a study comparing cumulative and standardised mortality rates between emigrants to the main island of Taiwan and those who stayed behind. Poisson regression modelling was used to analyse the effects of migration. For all causes of mortality, the adjusted relative risk was 1.24 with a confidence interval (CI) at the 95% level of 1.08-1.42 for emigrants compared to Matsunese non-emigrants. Deaths from cancer and diabetes in emigrants showed similar results, i.e. an adjusted relative risk of 1.25 (95% CI, 1.00-1.57) and 1.93 (95% CI, 1.20-3.11), respectively. Higher cumulative incidence rates for all cancers and the three leading cancer forms (hepatocellular carcinoma, gastric cancer and lung cancer) in emigrants were also observed. However, no significant difference in the survival time of most of the cancer forms was noted between the two groups. The finding that moving to a more affluent area paradoxically leads to incidence of cancer and higher mortality might be explained by adoption of various forms of unhealthy behaviour, psycho-social factors and the general risks related to life in urbanized environments. PMID- 23733287 TI - Dying in their prime: determinants and space-time risk of adult mortality in rural South Africa. AB - A longitudinal dataset was used to investigate adult mortality in rural South Africa in order to determine location, trends, high impact determinants and policy implications. Adult (15-59 years) mortality data for the period 1993-2010 were extracted from the health and demographic surveillance system in the rural sub-district of Agincourt. A Bayesian geostatistical frailty survival model was used to quantify significant associations between adult mortality and various multilevel (individual, household and community) variables. It was found that adult mortality significantly increased over time with a reduction observed late in the study period. Non-communicable disease mortality appeared to increase and decrease in parallel with communicable mortality, whilst deaths due to external causes remained constant. Male gender, unemployment, circular (labour) migrant status, age and gender of household heads, partner and/or other household death, low education and low household socio-economic status were identified as significant and highly attributable determinants of adult mortality. Health facility remoteness was a risk for adult mortality and households falling outside a critical buffering zone were identified. Spatial foci of higher adult mortality risk were observed, indicating a strong non-random pattern. Communicable diseases differed from non-communicable diseases with respect to spatial distribution of mortality. Areas with significant excess mortality risk (hot spots) were found to be part of a complex interaction of highly attributable factors that continues to drive differential space-time risk patterns of communicable (HIV/AIDS and tuberculosis) mortality in Agincourt. The impact of HIV mortality and its subsequent lowering due to the introduction of antiretroviral therapy was found to be clearly evident in this rural population. PMID- 23733289 TI - Identifying inequitable exposure to toxic air pollution in racialized and low income neighbourhoods to support pollution prevention. AB - Numerous environmental justice studies have confirmed a relationship between population characteristics such as low-income or minority status and the location of environmental health hazards. However, studies of the health risks from exposure to harmful substances often do not consider their toxicological characteristics. We used two different methods, the unit-hazard and the distance based approach, to evaluate demographic and socio-economic characteristics of the population residing near industrial facilities in the City of Toronto, Canada. In addition to the mass of air emissions obtained from the national pollutant release inventory (NPRI), we also considered their toxicity using toxic equivalency potential (TEP) scores. Results from the unit-hazard approach indicate no significant difference in the proportion of low-income individuals living in host versus non-host census tracts (t(107) = 0.3, P = 0.735). However, using the distance-based approach, the proportion of low-income individuals was significantly higher (+5.1%, t(522) = 6.0, P <0.001) in host tracts, while the indicator for "racialized" communities ("visible minority") was 16.1% greater (t(521) = 7.2, P <0.001) within 2 km of a NPRI facility. When the most toxic facilities by non-carcinogenic TEP score were selected, the rate of visible minorities living near the most toxic NPRI facilities was significantly higher (+12.9%, t(352) = 3.5, P = 0.001) than near all other NPRI facilities. TEP scores were also used to identify areas in Toronto that face a double burden of poverty and air toxics exposure in order to prioritise pollution prevention. PMID- 23733290 TI - Spatial analyses of typhoid fever in Jiangsu province, People's Republic of China. AB - An analysis of the geographical distribution of typhoid incidence rates, based on various statistical approaches such as trend surface, spatial autocorrelation, spatial correlation and spatial regression, was carried out at the county level in Jiangsu province, People's Republic of China. Temperature, moisture content, proximity to water bodies and the normalized difference vegetation index in the autumn were the four underlying factors found to contribute the most to the development of the epidemic. Typhoid infection was most severe in the south eastern region of Jiangsu and a significant hotspot with high positive autocorrelation was detected in Taicang county in the south-east of the province. To improve the typhoid situation, intervention efforts should be concentrated in the south-eastern region of the province, targeting the hotspot and include reduction of lake pollution. PMID- 23733291 TI - Socio-ecology of the marsh rice rat (Oryzomys palustris) and the spatio-temporal distribution of Bayou virus in coastal Texas. AB - Along the southeastern coast of the United States of America (USA), the marsh rice rat (Oryzomys palustris) is the primary host for the hantavirus, genotype Bayou. According to the socio-ecological model for a territorial, polygamous species, females should be distributed across space and time by habitat resources and predation risks, whereas males should space themselves according to the degree of female aggregation and reproductive synchrony. To investigate how females affect the male-male transmission paradigm of Bayou virus, rodents were captured, marked, released in two macrohabitat types and followed across a 30 month period. Microhabitat cover variables were quantified around the individual trap stations. A geodatabase was created from habitat and rodent capture data and analysed in a geographical information system. The ratio of breeding to non breeding females was ~1:1, with breeding females overly dispersed and non breeding females randomly dispersed. Spatial analyses revealed both macro- and microhabitat preferences in females. Compared to seronegatives, higher proportions of seropositive adult males were found consistently within closer proximities to breeding females but not to non-breeding females, indicating that male locations were not driven simply by habitat selection. Activities to acquire dispersed receptive females could be an important driver of Bayou virus transmission among male hosts. Herein, we describe an interdisciplinary effort providing a novel approach to elucidate the complexity of hantavirus trafficking and maintenance in rodent populations of a coastal marsh ecosystem. PMID- 23733292 TI - Identification of environmental parameters and risk mapping of visceral leishmaniasis in Ethiopia by using geographical information systems and a statistical approach. AB - Visceral leishmaniasis (VL), a vector-borne disease strongly influenced by environmental factors, has (re)-emerged in Ethiopia during the last two decades and is currently of increasing public health concern. Based on VL incidence in each locality (kebele) documented from federal or regional health bureaus and/or hospital records in the country, geographical information systems (GIS), coupled with binary and multivariate logistic regression methods, were employed to develop a risk map for Ethiopia with respect to VL based on soil type, altitude, rainfall, slope and temperature. The risk model was subsequently validated in selected sites. This environmental VL risk model provided an overall prediction accuracy of 86% with mean land surface temperature and soil type found to be the best predictors of VL. The total population at risk was estimated at 3.2 million according to the national population census in 2007. The approach presented here should facilitate the identification of priority areas for intervention and the monitoring of trends as well as providing input for further epidemiological and applied research with regard to this disease in Ethiopia. PMID- 23733293 TI - Population dynamics and spatial structure of human-biting mosquitoes, inside and outside of houses, in the Chockwe irrigation scheme, southern Mozambique. AB - Focal control of malaria vectors, a potentially cost-effective alternative to conventional control, requires a spatio-temporal understanding of the mosquitoes. Trapping of African malaria vectors has generally been limited to inside houses making distribution estimates dependent on the location of dwellings. The development of tent-traps to sample outdoor biting mosquitoes has enabled more independent estimates. Here we describe both temporal and spatial variation in mosquito movements in an irrigation project village in southern Mozambique. Six hundred and ninety-three tent-trap collections (525 of which were paired with light-trap collections), 552 exit collections and 391 collections of mosquitoes resting inside houses were undertaken from March 2005 to April 2006. Fifteen species of mosquito were collected (five exclusively as larvae). Mansonia africana was the most common finding, numbers being greatest away from the village. Only Anopheles funestus, An. tenebrosus and Culex quinquefasciatus were collected in greater numbers in light-traps compared to tent-traps. Among the common mosquitoes, correlations in numbers of mosquito collected in paired tent and in light-traps were significant for all but An. tenebrosus. Inverse distance weighting was used to produce raster density maps of the most common mosquitoes. All species, with minor variations, in both hot and cool seasons, were collected in greatest numbers close to the edges of the village where water suitable for larval development was available. All exophilic anophelines species tested negative for sporozoites. It is suggested that focal control of larvae, applied by the villagers themselves, could be a suitable alternative to conventional control in this and similar villages. PMID- 23733294 TI - Soil-transmitted helminthiasis in Latin America and the Caribbean: modelling the determinants, prevalence, population at risk and costs of control at sub-national level. AB - We present an example of a tool for quantifying the burden, the population in need of intervention and resources need to contribute for the control of soil transmitted helminth (STH) infection at multiple administrative levels for the region of Latin America and the Caribbean (LAC). The tool relies on published STH prevalence data along with data on the distribution of several STH transmission determinants for 12,273 sub-national administrative units in 22 LAC countries taken from national censuses. Data on these determinants was aggregated into a single risk index based on a conceptual framework and the statistical significance of the association between this index and the STH prevalence indicators was tested using simple linear regression. The coefficient and constant from the output of this regression was then put into a regression formula that was applied to the risk index values for all of the administrative units in order to model the estimated prevalence of each STH species. We then combine these estimates with population data, treatment thresholds and unit cost data to calculate total control costs. The model predicts an annual cost for the procurement of preventive chemotherapy of around US$ 1.7 million and a total cost of US$ 47 million for implementing a comprehensive STH control programme targeting an estimated 78.7 million school-aged children according to the WHO guidelines throughout the entirety of the countries included in the study. Considerable savings to this cost could potentially be made by embedding STH control interventions within existing health programmes and systems. A study of this scope is prone to many limitations which restrict the interpretation of the results and the uses to which its findings may be put. We discuss several of these limitations. PMID- 23733295 TI - Role of malnutrition and parasite infections in the spatial variation in children's anaemia risk in northern Angola. AB - Anaemia is known to have an impact on child development and mortality and is a severe public health problem in most countries in sub-Saharan Africa. We investigated the consistency between ecological and individual-level approaches to anaemia mapping by building spatial anaemia models for children aged <=15 years using different modelling approaches. We aimed to (i) quantify the role of malnutrition, malaria, Schistosoma haematobium and soil-transmitted helminths (STHs) in anaemia endemicity; and (ii) develop a high resolution predictive risk map of anaemia for the municipality of Dande in northern Angola. We used parasitological survey data for children aged <=15 years to build Bayesian geostatistical models of malaria (PfPR<=15), S. haematobium, Ascaris lumbricoides and Trichuris trichiura and predict small-scale spatial variations in these infections. Malnutrition, PfPR<=15, and S. haematobium infections were significantly associated with anaemia risk. An estimated 12.5%, 15.6% and 9.8% of anaemia cases could be averted by treating malnutrition, malaria and S. haematobium, respectively. Spatial clusters of high risk of anaemia (>86%) were identified. Using an individual-level approach to anaemia mapping at a small spatial scale, we found that anaemia in children aged <=15 years is highly heterogeneous and that malnutrition and parasitic infections are important contributors to the spatial variation in anaemia risk. The results presented in this study can help inform the integration of the current provincial malaria control programme with ancillary micronutrient supplementation and control of neglected tropical diseases such as urogenital schistosomiasis and STH infections. PMID- 23733296 TI - Mapping and prediction of schistosomiasis in Nigeria using compiled survey data and Bayesian geospatial modelling. AB - Schistosomiasis prevalence data for Nigeria were extracted from peer-reviewed journals and reports, geo-referenced and collated in a nationwide geographical information system database for the generation of point prevalence maps. This exercise revealed that the disease is endemic in 35 of the country's 36 states, including the federal capital territory of Abuja, and found in 462 unique locations out of 833 different survey locations. Schistosoma haematobium, the predominant species in Nigeria, was found in 368 locations (79.8%) covering 31 states, S. mansoni in 78 (16.7%) locations in 22 states and S. intercalatum in 17 (3.7%) locations in two states. S. haematobium and S. mansoni were found to be co endemic in 22 states, while co-occurrence of all three species was only seen in one state (Rivers). The average prevalence for each species at each survey location varied between 0.5% and 100% for S. haematobium, 0.2% to 87% for S. mansoni and 1% to 10% for S. intercalatum. The estimated prevalence of S. haematobium, based on Bayesian geospatial predictive modelling with a set of bioclimatic variables, ranged from 0.2% to 75% with a mean prevalence of 23% for the country as a whole (95% confidence interval (CI): 22.8-23.1%). The model suggests that the mean temperature, annual precipitation and soil acidity significantly influence the spatial distribution. Prevalence estimates, adjusted for school-aged children in 2010, showed that the prevalence is <10% in most states with a few reaching as high as 50%. It was estimated that 11.3 million children require praziquantel annually (95% CI: 10.3-12.2 million). PMID- 23733297 TI - Assessing bias associated with geocoding of historical residence in epidemiology research. AB - The use of geocoded historical residence as proxy for retrospective assessment of exposure in early life is increasing in epidemiological studies of chronic health outcomes. Dealing with historical residence poses challenges, primarily due to higher uncertainties associated with data collection and processing. A possible source of bias is connected with the exclusion of subjects, who cannot, for various reasons, be geocoded. We evaluated the potential bias that may arise due to incomplete geocoding, using birth residence data collected as part of a population-based case-control study of breast cancer in western New York state. We found that geocoded and non-geocoded populations did not differ in the distribution of most risk factors compared, and that the geocoding status did not modify the spatial patterns of the study populations. However, the results emphasize the need for epidemiological studies to consider the potential biases that may be introduced by geocoding of historical residence when investigating retrospectively chronic disease and early-life exposure. PMID- 23733298 TI - Feasibility study to objectively assess activity and location of Hispanic preschoolers: a short communication. AB - Both physical and social environmental factors influence young children's physical activity, yet little is known about where Hispanic children are more likely to be active. We assessed the feasibility of simultaneously measuring, then processing objective measures of location and physical activity among Hispanic preschool children. Preschool-aged Hispanic children (n = 15) simultaneously wore QStarz BT100X global positioning system (GPS) data loggers and Actigraph GT3X accelerometers for a 24- to 36-hour period, during which time their parents completed a location and travel diary. Data were aggregated to the minute and processed using the personal activity location measurement system (PALMS). Children successfully wore the GPS data loggers and accelerometers simultaneously, 12 of which yielded data that met quality standards. The average percent correspondence between GPS- and diary-based estimates of types of location was high and Kappa statistics were moderate to excellent, ranging from 0.49-0.99. The between-method (GPS monitor, parent-reported diary) correlations of estimated participant-aggregated minutes spent on vehicle-based trips were strong. The simultaneous use of GPS and accelerometers to assess Hispanic preschool children's location and physical activity is feasible. This methodology has the potential to provide more precise findings to inform environmental interventions and policy changes to promote physical activity among Hispanic preschool children. PMID- 23733299 TI - Spatial dynamic patterns of hand-foot-mouth disease in the People's Republic of China. AB - Hand-foot-mouth disease (HFMD) is the most common and widespread infectious disease in the People's Republic of China. Although there has been a substantial increase of HFMD in many parts of the country in recent years, its spatial dynamics and determinants remain unclear. When we collected and analysed weekly data on HFMD cases from 1,456 counties and the corresponding meteorological factors from 1 May 2008 to 27 March 2009, it was found that HFMD was spatially dispersed across the country in the summer and winter, while clustered in the spring and autumn. The spatial variation of HFMD was found to be affected by a combination of climate variables, while its spatio-temporal transmission was largely driven by temperature variations with a 7-week lag implying that (i) the dispersal of the disease can be anticipated based on the variation of the temperature and other climate variables; and (ii) the spatial dynamics of HFMD can be robustly predicted 7 weeks ahead of time using temperature data only. The findings reported allow prompt preparation and implementation of appropriate public health interventions to control and prevent disease outbreaks. PMID- 23733300 TI - Socio-environmental variables and transmission risk of lymphatic filariasis in central and northern Mozambique. AB - Lymphatic filariasis (LF) is endemic in Mozambique, where it is caused by Wuchereria bancrofti with Culex quinquefasciatus as the main vector. It affects approximately 10% of the population (2 million) with about 16 million at risk. Prevalence rates in 40 out of 65 districts that together comprise the four endemic provinces Niassa, Cabo Delgado, Nampula and Zambezia were analysed with the aim of elucidating the socio-environmental variables influencing the transmission. The levels of prevalence were divided into six ranks and certain climatic, environmental and social factors were considered independent variables. A climadiagram was created and the LF risk and the water budget-based index were calculated for each district. Factors influencing the risk of the overall transmission and that of the provincial levels were established by discriminant analysis. The results show that LF transmission increased with mean maximum temperature and decreased with altitude. The almost constant annual temperature (especially in the tropical area), altitude, general economic conditions and predominant crop production (rice) were found to be responsible for the abundance and presence of the vector. However, despite the presence of the vector in the hinterland, presence and survival of the parasite were not found to be favoured there. The transmission risk was found to be highest in Zambezia, and consequently also the prevalence, while the situation in Niassa was the opposite. The conclusion is that temperature, altitude and the development/poverty index (particularly in the urban areas) have to be considered as transmission risk factors for LF in Mozambique. The extent of rice culturing probably also plays a role with respect to this infection. PMID- 23733301 TI - Geospatial (s)tools: integration of advanced epidemiological sampling and novel diagnostics. AB - Large-scale control and progressive elimination of a wide variety of parasitic diseases is moving to the fore. Indeed, there is good pace and broad political commitment. Yet, there are some worrying signs ahead, particularly the anticipated declines in funding and coverage of key interventions, and the paucity of novel tools and strategies. Further and intensified research and development is thus urgently required. We discuss advances in epidemiological sampling, diagnostic tools and geospatial methodologies. We emphasise the need for integrating sound epidemiological designs (e.g. cluster-randomised sampling) with innovative diagnostic tools and strategies (e.g. Mini-FLOTAC for detection of parasitic elements and pooling of biological samples) and high-resolution geospatial tools. Recognising these challenges, standardisation of quality procedures, and innovating, validating and applying new tools and strategies will foster and sustain long-term control and eventual elimination of human and veterinary public health issues. PMID- 23733302 TI - Taming the beast: rabies control in the cradle of mankind. AB - Between 2006 and 2012, a rabies control programme has been conducted in the area of Lake Turkana in northern Kenya. Spatial data obtained for this project were analysed with the aim of assessing the importance of dog home ranges with the view of possible overlapping between dog populations from adjacent localities. In contrast to our expectation of the maximum home ranges of dogs in the harsh semi desert environment, the results provided by geographical information system (GIS) analysis showed that in 14 out of 16 localities considered for the study, the dog populations were fully isolated from each other. The data obtained should be helpful for designing rabies control strategies. PMID- 23733303 TI - Silicon nanowire array/Cu2O crystalline core-shell nanosystem for solar-driven photocatalytic water splitting. AB - P-type Cu2O nanocrystals were deposited on n-type silicon nanowire arrays (Si NWs) to form core-shell heterojunction arrays structure via a simple electroless deposition technique. Scanning electron microscopy, transmission electron microscope and x-ray diffraction were utilized to characterize the morphology and structure of the core-shell nanosystem. The reflectivity of the obtained core shell structure measured by UV/vis spectrometry showed a comparatively low reflectivity in the visible-light region, which implied good optical absorption performance. The water splitting performance of the obtained Si NWs, planar Si/Cu2O structure and Si NW/Cu2O core-shell nanosystem were studied. Owing to the large specific surface area, heterojunctions formed between Cu2O nanocrystallites and Si NWs and the light trapping effect of the NW array structure, the photocatalytic performance of the Si NW/Cu2O core-shell nanosystem increased markedly compared with that of pure silicon NWs and a planar Si/Cu2O structure, which means excellent hydrogen production capacity under irradiation with simulated sunlight. In addition, the photocatalytic performance of the core-shell nanosystem was improved obviously after platinum nanoparticles were electrodeposited on it. PMID- 23733304 TI - Cervical metastases from squamous cell carcinoma of hard palate and maxillary alveolus: a retrospective study of 10 years. AB - BACKGROUND: The purpose of this study was to investigate the incidence of cervical metastasis in squamous cell carcinoma (SCC) of hard palate and maxillary alveolus and to define its impact factors. METHODS: We conducted a retrospective study of patients surgically treated for SCC of hard palate and maxillary alveolus from 2002 to 2011. In situ hybridization was performed to detect high risk human papillomavirus (HPV) infection. RESULTS: The incidences of cervical metastasis and occult metastasis were 17.2% (11/64) and 9.8% (5/51), respectively. The pT classification and vascular invasion were correlated with cervical metastasis. Occult metastatic risk was significantly higher among patients with pT4. Presence of positive nodes impaired prognosis significantly. CONCLUSION: SCC of hard palate and maxillary alveolus has nonnegligible incidences of both overall and occult metastasis, which were highly associated with pT classification. We recommend routine, synchronous elective neck dissection for T4 lesions, whereas observation is an alternative for T1 to T3 lesions. PMID- 23733305 TI - Detection and quantification of chlordecone in contaminated soils from the French West Indies by GC-MS using the 13C10-chlordecone stable isotope as a tracer. AB - Chlordecone is an organochlorine insecticide that has been widely used to control banana weevil in the French West Indies. As a result of this intense use, up to 20,000 ha are contaminated by this insecticide in the French West Indies, and this causes environmental damage and health problems. A scenario of exposure was drawn by French authorities, based on land usage records. Many efforts have been made to monitor the occurrence of chlordecone and its main metabolites using different analytical methods, including GC, GC/MS, LC/MS, and NIRS. Although these different methods allow for the detection and quantification of chlordecone from soils, none of them estimate the bottleneck caused by extraction of this organochlorine from soils with high adsorption ability. In this study, we used (13)C10-chlordecone as a tracer to estimate chlordecone extraction yield and to quantify chlordecone in soil extracts based on the (13)C/(12)C isotope dilution. We report the optimization of (13)C10-chlordecone extraction from an Andosol. The method was found to be linear from 0.118 to 43 mg kg(-1) in the Andosol, with an instrumental detection limit estimated at 8.84 MUg kg(-1). This method showed that chlordecone ranged from 35.4 down to 0.18 mg kg(-1) in Andosol, Nitisol, Ferralsol, and Fluvisol soil types. Traces of the metabolite beta monohydrochlordecone were detected in the Andosol, Nitisol, and Ferralsol soil samples. This last result indicates that this method could be useful to monitor the fate of chlordecone in soils of the French West Indies. PMID- 23733306 TI - Arsenic, copper, and zinc contamination in soil and wheat during coal mining, with assessment of health risks for the inhabitants of Huaibei, China. AB - Field studies were conducted to investigate arsenic (As), copper (Cu), and zinc (Zn) contamination in agricultural soils and wheat crops at two areas in Huaibei, China. Area A is in the proximity of Shuoli coal mine. In area B, three coal mines and a coal cleaning plant were distributed. The potential health risk of As, Cu, and Zn exposure to the local inhabitants through consumption of wheat grains was also estimated. The results showed that significantly higher (p<0.05) concentrations of As, Cu, and Zn were found in soils collected from area B than in those from area A. Arsenic concentrations in wheat sampled from area A were negatively correlated with the distance from the coal mine (p<0.001). Concentrations of Cu and Zn in wheat seedlings and grains collected from area B were significantly higher (p<0.05) than in those collected from area A, with the exception of Zn in wheat seedlings. Concentrations of Cu and Zn in most wheat grain samples were above the permissible limits of Cu and Zn in edible plants set by the Food and Agriculture Organization/World Health Organization. The hazard index of aggregate risk through consumption of wheat grains was 2.3-2.4 for rural inhabitants and 1.4-1.5 for urban inhabitants. The average intake of inorganic As for rural inhabitants in Huaibei was above 10 MUg day(-1). These findings indicated that the inhabitants around the coal mine are experiencing a significant potential health risk due to the consumption of locally grown wheat. PMID- 23733307 TI - Neurovirulence of Cryptococcus neoformans determined by time course of capsule accumulation and total volume of capsule in the brain. AB - Cryptococcal meningitis remains a significant opportunistic infection in HIV infected individuals worldwide, despite availability of antiretroviral therapies in developed nations. Current therapy with amphotericin B is difficult to administer and only partially effective. Mechanisms of cryptococcal neuropathogenesis are still not clearly defined. In the present study, we used a C57Bl/6 mouse model with intravenous inoculation of three isogenic strains of Cryptococcus neoformans: H99, Cap59, and Pkr1-33. These strains differ in their capsule production and are normocapsular, hypocapsular, and hypercapsular, respectively. We studied the role of capsule in the morbidity and mortality of our host animal. Surprisingly, we found that the hypercapsular strain was least virulent while the strains that produced less capsule were more virulent and had higher concentrations of organism in the brain. These results suggest that neurovirulence is related to total capsule volume and rate of capsule accumulation in the brain, rather than the amount of capsule produced per organism. Therapies which decrease central nervous system dissemination and inhibit replication rates in the brain may be more effective than therapies which target capsule production. PMID- 23733308 TI - A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes. AB - Immune reconstitution has improved outcomes for progressive multifocal leukoencephalopathy (PML), a potentially lethal brain disease caused by JC virus (JCV). However, an antiviral treatment to control JCV is needed when immune reconstitution is delayed or not possible. On the basis of in vitro efficacy, this study evaluated the effect of mefloquine on PML and factors that may predict PML outcomes. This 38-week, open-label, randomized, parallel-group, proof-of concept study compared patients with PML who received standard of care (SOC) with those who received SOC plus mefloquine (250 mg for 3 days, then 250 mg weekly). Patients randomized to SOC could add mefloquine treatment at week 4. The primary endpoint was change from baseline to weeks 4 and 8 in JCV DNA copy number (load) in cerebrospinal fluid (CSF). Exploratory analyses evaluated factors that might correlate with clinical outcome. The majority of enrolled patients were HIV positive. Preplanned interim data analyses suggested that the study was unlikely to successfully demonstrate a significant difference between groups; therefore, the study was terminated prematurely. There was no significant difference between groups in CSF JCV DNA loads or clinical/MRI findings. Decrease in CSF JCV DNA load from baseline to week 4 was associated with a better clinical outcome at 16 weeks, as measured by Karnofsky scores. This study found no evidence of anti-JCV activity by mefloquine. An early decrease of CSF JCV DNA load appears to be associated with a better clinical outcome. PMID- 23733309 TI - Hilary Koprowski, MD. December 5, 1916-April 11, 2013. PMID- 23733310 TI - An investigation into the use of music as potential auditory enrichment for moloch gibbons (Hylobates moloch). AB - The use of music as enrichment has rarely been explored in zoos, despite evidence that music has a positive effect on a range of laboratory housed animals. In this study of moloch gibbons, Hylobates moloch, at Howletts Wild Animal Park (Kent, England), instrumental classical music was played to eight individuals in two family groups. Music was played 7 hr a day during three of six study weeks for each group, alternating with control weeks in which no music was played. In focal watches, data were recorded on a measure of activity, brachiation, and on two rates of affiliative behavior, giving and receiving grooming. In addition, to assess potential impacts on emotional state, data were recorded on self scratching and self-grooming, two widely used indices of anxiety or stress. Analyses were carried out for each individual separately, as previous studies of primates indicate animals may differ in their response to enrichment. Results revealed little evidence for effects of music on gibbons' behavior. During the music compared to control weeks, the adult male from one group showed higher rates of self-scratching and higher durations of both self-grooming and grooming others. The adult female from the same group was groomed more during the music weeks than control weeks. For the six other animals, no significant differences in behaviors were seen between music and control conditions. Our findings suggest music may not be an effective enrichment for captive gibbons, and further highlight the importance of considering individual differences when assessing the effects of potential enrichment. PMID- 23733312 TI - Region-specific myoelectric manifestations of fatigue in human rectus femoris muscle. AB - INTRODUCTION: Anatomical properties between proximal and other regions within the human rectus femoris (RF) muscle are nonuniform. We aimed to clarify the possible region-specific myoelectric manifestations of fatigue within the RF muscle by using an advanced surface electromyography (SEMG) technique. METHODS: Nine healthy men performed sustained contractions at 50% of maximal voluntary contraction until exhaustion during isometric knee extension and hip flexion. During these contractions, multi-channel SEMG was recorded from the RF by using 46 electrode pairs which cover most of the superficial area of the muscle. RESULTS: Fatigue-induced SEMG, i.e., an increase in root mean square and a decrease in median frequency, was not uniform within the muscle during both tasks and was greater in proximal regions. CONCLUSIONS: Our findings suggest that myoelectric manifestations of fatigue within the human RF muscle are localized, and proximal regions are more fatigable than other regions within this muscle. PMID- 23733311 TI - C-kit(+) cells isolated from developing kidneys are a novel population of stem cells with regenerative potential. AB - The presence of tissue specific precursor cells is an emerging concept in organ formation and tissue homeostasis. Several progenitors are described in the kidneys. However, their identity as a true stem cell remains elusive. Here, we identify a neonatal kidney-derived c-kit(+) cell population that fulfills all of the criteria as a stem cell. These cells were found in the thick ascending limb of Henle's loop and exhibited clonogenicity, self-renewal, and multipotentiality with differentiation capacity into mesoderm and ectoderm progeny. Additionally, c kit(+) cells formed spheres in nonadherent conditions when plated at clonal density and expressed markers of stem cells, progenitors, and differentiated cells. Ex vivo expanded c-kit(+) cells integrated into several compartments of the kidney, including tubules, vessels, and glomeruli, and contributed to functional and morphological improvement of the kidney following acute ischemia reperfusion injury in rats. Together, these findings document a novel neonatal rat kidney c-kit(+) stem cell population that can be isolated, expanded, cloned, differentiated, and used for kidney repair following acute kidney injury. These cells have important biological and therapeutic implications. PMID- 23733313 TI - PTPN12 inhibits oral squamous epithelial carcinoma cell proliferation and invasion and can be used as a prognostic marker. AB - Protein tyrosine phosphatase nonreceptor type 12 (PTPN12) has been recognized as a tumor suppressor gene that may inhibit tumor growth. However, PTPN12 expression in oral squamous carcinoma (OSCC) has not been studied. We showed reduced expression of PTPN12 in OSCC tissues. Decreased PTPN12 expression was significantly associated with clinical stage of the disease (P < 0.01). Moreover, reduction in PTPN12 correlated with the overactivation of STAT3. PTPRD negatively related to STAT3 phosphorylation (R = -0.535). Low expression of PTPN12 and high level of phosphorylation of STAT3 correlated with poor prognosis. Overexpression of PTPN12 inhibited proliferation and migration in OSCC cells. PTPN12 was associated with STAT3 and induced STAT3 dephosphorylation. Moreover, our results suggested that PTPN12 might function through binding and dephosphorylation of STAT3. Therefore, PTPN12 is a potential marker for prognosis of OSCC. PMID- 23733315 TI - Discovery of neuritogenic compound classes inspired by natural products. PMID- 23733314 TI - Regulation of inflammation-associated olfactory neuronal death and regeneration by the type II tumor necrosis factor receptor. AB - BACKGROUND: Olfactory loss is a debilitating symptom of chronic rhinosinusitis. To study the impact of inflammation on the olfactory system, the inducible olfactory inflammation (IOI) transgenic mouse was created in which inflammation can be turned on and off within the olfactory epithelium. In this study, the type II tumor necrosis factor (TNF) receptor (TNFR2) was knocked out, and the effect on the olfactory loss phenotype was assessed. METHODS: IOI mice were bred to TNFR2 knockout mice to yield progeny IOI mice lacking the TNFR2 receptor (TNFR2( /-) ). TNF-alpha expression was induced within the olfactory epithelium for 6 weeks to generate chronic inflammation. Olfactory function was assayed by electro olfactogram (EOG), and olfactory tissue was processed for histology and immunohistochemical staining. RESULTS: Compared to IOI mice with wild-type TNFR2, IOI mice lacking the TNFR2 demonstrated similar levels of inflammatory infiltration and enlargement of the subepithelial layer. However, IOI-TNFR2(-/-) mice differed markedly in that the neuronal layer was largely preserved and active progenitor cell proliferation was present. Odorant responses were maintained in the IOI-TNFR2(-/-) mice, in contrast to IOI mice. CONCLUSION: TNFR2 is the minor receptor for TNF-alpha, but appears to play an important role in mediating TNF-induced disruption of the olfactory system. This finding suggests that neuronal death and inhibition of proliferation in CRS may be mediated by TNFR2 on olfactory neurons and progenitor cells. Further studies are needed to elucidate the subcellular pathways involved and develop novel therapies for treating olfactory loss in the setting of CRS. PMID- 23733316 TI - Dimensional control of block copolymer nanofibers with a pi-conjugated core: crystallization-driven solution self-assembly of amphiphilic poly(3 hexylthiophene)-b-poly(2-vinylpyridine). AB - With the aim of accessing colloidally stable, fiberlike, pi-conjugated nanostructures of controlled length, we have studied the solution self-assembly of two asymmetric crystalline-coil, regioregular poly(3-hexylthiophene)-b-poly(2 vinylpyridine) (P3HT-b-P2VP) diblock copolymers, P3HT23-b-P2VP115 (block ratio=1:5) and P3HT44-b-P2VP115 (block ratio=ca. 1:3). The self-assembly studies were performed under a variety of solvent conditions that were selective for the P2VP block. The block copolymers were prepared by using Cu-catalyzed azide-alkyne cycloaddition reactions of azide-terminated P2VP and alkyne end-functionalized P3HT homopolymers. When the block copolymers were self-assembled in a solution of a 50% (v/v) mixture of THF (a good solvent for both blocks) and an alcohol (a selective solvent for the P2VP block) by means of the slow evaporation of the common solvent; fiberlike micelles with a P3HT core and a P2VP corona were observed by transmission electron microscopy (TEM). The average lengths of the micelles were found to increase as the length of the hydrocarbon chain increased in the P2VP-selective alcoholic solvent (MeOH3 MUm) fiberlike micelles were prepared by the dialysis of solutions of the block copolymers in THF against iPrOH. Furthermore the widths of the fibers were dependent on the degree of polymerization of the chain-extended P3HT blocks. The crystallinity and pi-conjugated nature of the P3HT core in the fiberlike micelles was confirmed by a combination of UV/Vis spectroscopy, photoluminescence (PL) measurements, and wide-angle X-ray scattering (WAXS). Intense sonication (iPrOH, 1 h, 0 degrees C) of the fiberlike micelles formed by P3HT23-b-P2VP115 resulted in small (ca. 25 nm long) stublike fragments that were subsequently used as initiators in seeded growth experiments. Addition of P3HT23-b-P2VP115 unimers to the seeds allowed the preparation of fiberlike micelles with narrow length distributions (L(w)/L(n) < 1.11) and lengths from about 100-300 nm, that were dependent on the unimer-to-seed micelle ratio. PMID- 23733317 TI - A tool to evaluate correspondence between extraction ion chromatographic peaks and peptide-spectrum matches in shotgun proteomics experiments. AB - Chromatographed peptide signals form the basis of further data processing that eventually results in functional information derived from data-dependent bottom up proteomics assays. We seek to rank LC/MS parent ions by the quality of their extracted ion chromatograms. Ranked extracted ion chromatograms act as an intuitive physical/chemical preselection filter to improve the quality of MS/MS fragment scans submitted for database search. We identify more than 4900 proteins when considering detector shifts of less than 7 ppm. High quality parent ions for which the database search yields no hits become candidates for subsequent unrestricted analysis for PTMs. Following this rational approach, we prioritize identification of more than 5000 spectrum matches from modified peptides and confirmed the presence of acetylaldehyde-modified His/Lys. We present a logical workflow that scores data-dependent selected ion chromatograms and leverage information about semianalytical LC/LC dimension prior to MS. Our method can be successfully used to identify unexpected modifications in peptides with excellent chromatography characteristics, independent of fragmentation pattern and activation methods. We illustrate analysis of ion chromatograms detected in two different modes by RF linear ion trap and electrostatic field orbitrap. PMID- 23733318 TI - Seroprevalence of avian influenza H9N2 among poultry workers in Shandong Province, China. AB - H9N2 avian influenza virus has been circulating widely in birds, with occasional infection among humans. Poultry workers are considered to be at high risk of infection with avian influenza due to their frequent exposure to chickens, but the frequency of H9N2 avian influenza virus infections among them is still indistinct. This study was carried out in order to identify the seroprevalence of H9N2 avian influenza virus among poultry workers in Shandong, China. During the period from December 2011 to February 2012, a total of 482 subjects took part in this study, including 382 poultry workers and 100 healthy residents without occupational poultry exposure. Serum samples were collected and tested for the presence of antibodies against H9N2 avian influenza virus by hemagglutination inhibition (HI) and microneutralization (MN) assays. Nine subjects (9/382 = 2.3%) were positive for antibodies against H9N2 avian influenza virus among poultry workers by either HI or MN assays using >=40 cut-off, while none of the 100 healthy residents were seropositive. In conclusion, our study identified H9N2 avian influenza infections among poultry workers in Shandong, China, and continuous surveillance of H9N2 avian influenza virus infection in humans should be carried out to evaluate the threat to public health. PMID- 23733320 TI - Self-assembled silver nanoparticles for plasmon-enhanced solar cell back reflectors: correlation between structural and optical properties. AB - The spectra of localized surface plasmon resonances (LSPRs) in self-assembled silver nanoparticles (NPs), prepared by solid-state dewetting of thin films, are discussed in terms of their structural properties. We summarize the dependences of size and shape of NPs on the fabrication conditions with a proposed structural phase diagram. It was found that the surface coverage distribution and the mean surface coverage (SC) size were the most appropriate statistical parameters to describe the correlation between the morphology and the optical properties of the nanostructures. The results are interpreted with theoretical predictions based on Mie theory. The broadband scattering efficiency of LSPRs in the nanostructures is discussed towards application as plasmon-enhanced back reflectors in thin-film solar cells. PMID- 23733319 TI - Antibiotic resistance, population structure and spread of Staphylococcus aureus in nursing homes in the Euregion Meuse-Rhine. AB - To determine the spread of Staphylococcus aureus within and between nursing home (NH) residents in the Euregion Meuse-Rhine, a cross-border region of the Netherlands and Germany, we investigated the prevalence of antibiotic resistance, genetic background and population structure of both methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) isolates. A total of 245 S. aureus isolates were collected from NH residents. Susceptibility testing was performed with microbroth dilution. The genetic background was determined using spa typing, SCCmec typing, pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Differences in the prevalence of resistance between the German and Dutch MSSA isolates were observed for the macrolides (15 % vs. 2 %, p = 0.003), clindamycin (15 % vs. 0 %, p = 0.003) and ciprofloxacin (34 % vs. 25 %). The macrolide and ciprofloxacin resistance varied between the NHs, while trimethoprim-sulfamethoxazole resistance was low in all residents. The MRSA prevalence was 3.5 % and <1 % among the German and Dutch NH residents, respectively (p = 0.005). The German MRSAs, isolated in 7 out of 10 NHs, belonged to ST22-MRSA-IV or ST225-MRSA-II. spa clonal complexes (spa-CCs) 015 and 002 were prevalent among the German MSSA isolates and spa-CCs 024 and 1716 were prevalent among the Dutch MSSA isolates. The antibiotic resistance of MSSA and the MRSA prevalence were significantly higher among the German NH residents. The spread of two MRSA clones was observed within and between the German NHs, but not between the Dutch and German NHs. Differences in the prevalence of resistance and the prevalence of MRSA between NHs on both sides of the border warrant the continuation of surveillance at a local level. PMID- 23733321 TI - Characterizing the relationship between in-hospital measures and workers' compensation outcomes among severely injured construction workers using a data linkage strategy. AB - BACKGROUND: To characterize the relationship between acute measures of severity and three important workers' compensation outcomes associated with a worker's ability to return to work and the cost of a work-related injury. METHODS: Probabilistic data linkage of workers' compensation claims made by injured construction workers from 2000 to 2005 with two Illinois medical record registries. Multivariable robust regression models were built to assess the relationship between three in-hospital measures and three outcomes captured in the Workers' Compensation data. RESULTS: In the final multivariable models, a categorical increase in injury severity was associated with an extra $7,830 (95% CI: $4,729-$10,930) of monetary compensation awarded, though not with temporary total disability (TTD) or permanent partial disability (PPD). Our models also predicted that every extra day spent in the hospital results in an increase of 0.51 (95% CI: 0.23-0.80) weeks of TTD and an extra $1,248 (95% CI: $810-$1,686) in monetary compensation. Discharge to an intermediate care facility following the initial hospitalization was associated with an increase of 8.15 (95% CI: 4.03 12.28) weeks of TTD and an increase of $23,440 (95% CI: $17,033-$29,847) in monetary compensation. CONCLUSIONS: We were able to link data from the initial hospitalization for an injured worker with the final workers' compensation claims decision or settlement. The in-hospital measures of injury severity were associated with total monetary compensation as captured in the workers' compensation process. PMID- 23733322 TI - Proposing a two-level stochastic model for epileptic seizure genesis. AB - By assuming the brain as a multi-stable system, different scenarios have been introduced for transition from normal to epileptic state. But, the path through which this transition occurs is under debate. In this paper a stochastic model for seizure genesis is presented that is consistent with all scenarios: a two level spontaneous seizure generation model is proposed in which, in its first level the behavior of physiological parameters is modeled with a stochastic process. The focus is on some physiological parameters that are essential in simulating different activities of ElectroEncephaloGram (EEG), i.e., excitatory and inhibitory synaptic gains of neuronal populations. There are many depth-EEG models in which excitatory and inhibitory synaptic gains are the adjustable parameters. Using one of these models at the second level, our proposed seizure generator is complete. The suggested stochastic model of first level is a hidden Markov process whose transition matrices are obtained through analyzing the real parameter sequences of a seizure onset area. These real parameter sequences are estimated from real depth-EEG signals via applying a parameter identification algorithm. In this paper both short-term and long-term validations of the proposed model are done. The long-term synthetic depth-EEG signals simulated by this model can be taken as a suitable tool for comparing different seizure prediction algorithms. PMID- 23733323 TI - Acetazolamide for high intracranial pressure cerebrospinal fluid leaks. AB - BACKGROUND: Acetazolamide has become a standard treatment for cerebrospinal fluid (CSF) leaks associated with intracranial hypertension. The purpose of the current study was to evaluate the effectiveness of acetazolamide at decreasing elevated CSF pressure in this patient population. METHODS: Prospective evaluation and data collection of high intracranial pressure CSF leaks was performed. Subjects underwent CSF diversion and postoperative assessment of pressure changes via a standard protocol. Lumbar drains or ventriculostomies were clamped on postoperative day 2 for 4 hours prior to assessment with a manometer. Acetazolamide (500 mg) was administered orally immediately following the recording and CSF pressure was measured after 4 hours. Data regarding demographics, etiology of CSF leak, body mass index (BMI), location and size of defect, and clinical follow-up were also collected. RESULTS: Thirty-six patients (average age 50 years) with 42 CSF leaks (39 spontaneous, 3 traumatic) and an average BMI of 36.1 were evaluated. Success rate of primary repair was 94.4%, but all patients were effectively sealed with subsequent endoscopic reconstruction (average 80 weeks follow-up). Intracranial pressure (cm H2 O) via lumbar puncture or ventriculostomy (n = 2) after clamping was 32.0 +/- 7.4. Administration of acetazolamide significantly decreased intracranial pressure to 21.9 +/- 7.5 in the 4-6 hour time frame studied (p < 0.0001). CONCLUSION: This study provides some of the first direct evidence of decreased intracranial pressure associated with the oral administration of acetazolamide. In combination with the excellent endoscopic repair outcomes noted in a high risk population, this evidence supports the routine use of acetazolamide in patients with high intracranial pressure CSF leaks. PMID- 23733324 TI - Delinquency best treatments: how to divert youths from violence while saving lives and detention costs. AB - Youth development and violence prevention are two sides of the same public policy. The focus of much theoretical and empirical effort is identifying delinquency risks and intervening. Given the great costs of homicide and the historically high nationwide prison population, new policies must address increasing violence and rising expenses. Treatments of prenatal care, home visitation, bullying prevention, alcohol-substance abuse education, alternative thinking promotion, mentoring, life skills training, rewards for graduation and employment, functional family and multi-systemic therapy, and multi-dimensional foster care are effective, because they ameliorate age-specific risks for delinquency. At present, these interventions only yield a 10-40% diversion from crime however. Returns on investment (ROIs) vary from $1 to $98. Targeting empirical treatments to those determined to be most at risk, based on statistical models or actuarial testing, and using electronic surveillance for non-violent prisoners significantly diverted youth from violence, improving ROI, while simultaneously saving costs. PMID- 23733326 TI - Effects of short-term resistance training and subsequent detraining on the electromechanical delay. AB - INTRODUCTION: The purpose of this study was to examine and compare the effects of 3 days of dynamic constant external resistance (DCER) and isokinetic (ISOK) training and subsequent detraining on the electromechanical delay (EMD). METHODS: Thirty-one men [age 22.2 +/- 4.2 years, body mass 77.9 +/- 12.9 kg, height 173.9 +/- 5.4 cm (mean +/- SD)] were randomly assigned to a DCER training group, ISOK training group, or control (CONT) group. RESULTS: No significant changes were found for EMD from pre- to posttraining assessments 1, 2, and 3 [4.5 +/- 0.2 ms, 4.7 +/- 0.2 ms, 4.5 +/- 0.1 ms, 4.5 +/- 0.2 ms, respectively (mean +/- SE)] (P > 0.05). CONCLUSIONS: It can be hypothesized that increases in strength observed after a short-term resistance training program may not be attributed to stiffness changes in the series-elastic component. PMID- 23733325 TI - Assessment of functional outcomes in patients with head and neck cancer according to the International Classification of Functioning, Disability and Health Core Sets from the perspective of the multi-professional team: results of 4 Delphi surveys. AB - BACKGROUND: The International Classification of Functioning, Disability and Health Core Set for Head and Neck Cancer (ICF-HNC) covers the typical spectrum of problems in functioning in head and neck cancer. This study is part of a multistep process to develop practical guidelines in Germany. The purpose of this study was to identify instruments for the assessment of functioning using the ICF HNC as reference. METHODS: Four Delphi surveys with physicians, physiotherapists, psychologists, and social workers were performed to identify which aspects of the ICF-HNC are being treated and which assessment tools are recommended for the assessment of functioning. RESULTS: Ninety-seven percent categories of the ICF HNC were treated by healthcare professionals participating in the current study. Altogether, 33 assessment tools were recommended for therapy monitoring, food intake, pain, further organic problems/laboratory tests, and psychosocial areas. CONCLUSION: Although the ICF-HNC is being currently implemented by the head and neck cancer experts, several areas are not covered regularly. Additionally, validated tools were rarely recommended. PMID- 23733327 TI - A novel solid-phase extraction-spectrofluorimetric method for the direct determination of atenolol in human urine. AB - A novel, simple, sensitive and selective solid-phase extraction (SPE) spectrofluorimetric method has been developed for the determination of atenolol (ATE) in human urine. Because an extraction procedure is required to isolate ATE or eliminate the interfering molecules present in complex human urine for the direct spectrofluorimetric determination, a pH-sensitive poly(acrylic acid ethylene glycol dimethacrylate) [poly(AA-EGDMA)] hydrogel was developed and used as a SPE adsorbent. Some factors affecting the ATE extraction efficiency, such as washing solvent type and volume, and the volume of elution solvent were optimized. Eluates from SPE cartridges were analyzed using a spectrofluorimeter (lambda(ex) = 277 nm and lambda(em) = 300 nm). The calibration graph was linear over the concentration range 0.15-4.0 ug/mL. Limit of detection (LOD) and limit of quantification (LOQ) values were found to be 0.03 and 0.10 ug/mL, respectively. Relatively high intraday [2.06%, mean relative standard deviation (RSD)] and interday (2.6%, mean RSD) precisions were achieved. High mean recovery (95.4%) and low RSD values (3.8%) were obtained for spiked ATE in human urine. The spectrofluorimetric method presented here can be easily applied to assay trace amounts of ATE in pharmaceuticals and biological samples. PMID- 23733328 TI - Cognitive behavioural therapy for anxiety disorders in children and adolescents. AB - BACKGROUND: A previous Cochrane review (James 2005) showed that cognitive behavioural therapy (CBT) was effective in treating childhood anxiety disorders; however, questions remain regarding (1) the relative efficacy of CBT versus non CBT active treatments; (2) the relative efficacy of CBT versus medication and the combination of CBT and medication versus placebo; and (3) the long-term effects of CBT. OBJECTIVES: To examine (1) whether CBT is an effective treatment for childhood and adolescent anxiety disorders in comparison with (a) wait-list controls; (b) active non-CBT treatments (i.e. psychological placebo, bibliotherapy and treatment as usual (TAU)); and (c) medication and the combination of medication and CBT versus placebo; and (2) the long-term effects of CBT. SEARCH METHODS: Searches for this review included the Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Depression, Anxiety and Neurosis Group Register, which consists of relevant randomised controlled trials from the bibliographic databases-The Cochrane Library (1970 to July 2012), EMBASE, (1970 to July 2012) MEDLINE (1970 to July 2012) and PsycINFO (1970 to July 2012). SELECTION CRITERIA: All randomised controlled trials (RCTs) of CBT versus waiting list, active control conditions, TAU or medication were reviewed. All participants must have met the criteria of the Diagnostic and Statistical Manual (DSM) or the International Classification of Diseases (ICD) for an anxiety diagnosis, excluding simple phobia, obsessive-compulsive disorder, post-traumatic stress disorder and elective mutism. DATA COLLECTION AND ANALYSIS: The methodological quality of included trials was assessed by three reviewers independently. For the dichotomous outcome of remission of anxiety diagnosis, the odds ratio (OR) with 95% confidence interval (CI) based on the random-effects model, with pooling of data via the inverse variance method of weighting, was used. Significance was set at P < 0.05. Continuous data on each child's anxiety symptoms were pooled using the standardised mean difference (SMD). MAIN RESULTS: Forty-one studies consisting of 1806 participants were included in the analyses. The studies involved children and adolescents with anxiety of mild to moderate severity in university and community clinics and school settings. For the primary outcome of remission of any anxiety diagnosis for CBT versus waiting list controls, intention-to-treat (ITT) analyses with 26 studies and 1350 participants showed an OR of 0.13 (95% CI 0.09 to 0.19, Z = 10.26, P < 0.0001), but with evidence of moderate heterogeneity (P = 0.04, I2 = 33%). The number needed to treat (NNT) was 6.0 (95% CI 7.5 to 4.6). No difference in outcome was noted between individual, group and family/parental formats. ITT analyses revealed that CBT was no more effective than non-CBT active control treatments (six studies, 426 participants) or TAU in reducing anxiety diagnoses (two studies, 88 participants). The few controlled follow-up studies (n = 4) indicate that treatment gains in the remission of anxiety diagnosis are not statistically significant. AUTHORS' CONCLUSIONS: Cognitive behavioural therapy is an effective treatment for childhood and adolescent anxiety disorders; however, the evidence suggesting that CBT is more effective than active controls or TAU or medication at follow-up, is limited and inconclusive. PMID- 23733329 TI - Natural killer cell-activating receptor NKG2D mediates innate immune targeting of allogeneic neural progenitor cell grafts. AB - Cell replacement therapy holds promise for a number of untreatable neurological or psychiatric diseases but the immunogenicity of cellular grafts remains controversial. Emerging stem cell and reprogramming technologies can be used to generate autologous grafts that minimize immunological concerns but autologous grafts may carry an underlying genetic vulnerability that reduces graft efficacy or survival. Healthy allogeneic grafts are an attractive and commercially scalable alternative if immunological variables can be controlled. Stem cells and immature neural progenitor cells (NPC) do not express major histocompatibility complex (MHC) antigens and can evade adaptive immune surveillance. Nevertheless, in an experimental murine model, allogeneic NPCs do not survive and differentiate as well as syngeneic grafts, even when traditional immunosuppressive treatments are used. In this study, we show that natural killer (NK) cells recognize the lack of self-MHC antigens on NPCs and pose a barrier to NPC transplantation. NK cells readily target both syngeneic and allogeneic NPC, and killing is modulated primarily by NK-inhibiting "self" class I MHC and NK-activating NKG2D-ligand expression. The absence of NKG2D signaling in NK cells significantly improves NPC derived neuron survival and differentiation. These data illustrate the importance of innate immune mechanisms in graft outcome and the potential value of identifying and targeting NK cell-activating ligands that may be expressed by stem cell derived grafts. PMID- 23733330 TI - Complex span and n-back measures of working memory: a meta-analysis. AB - Working memory is a construct of primary relevance to many areas of psychology. Two types of tasks have been used to measure working memory, primarily in different research areas: Complex span tasks are commonly used in behavioral studies in the cognitive and individual-differences literature, whereas n-back tasks have been used more frequently in cognitive neuroscience studies investigating the neural underpinnings of working memory. Despite both categories of tasks being labeled as "working memory" measures, previous empirical studies have provided mixed evidence regarding the shared amount of overlapping processes between complex span and n-back tasks. The present meta-analysis showed that the complex span and n-back tasks are weakly correlated, although significant heterogeneity across studies was observed. A follow-up analysis of unpublished data indicated that the sample composition affects the relationship between the complex span and n-back tasks, following the law of diminishing returns. Finally, a separate meta-analysis indicated that the simple span and n-back tasks are correlated to the same extent as are the complex span and n-back tasks. The present findings indicate that the complex span and n-back tasks cannot be used interchangeably as working memory measures in research applications. PMID- 23733331 TI - Small bowel tuberculosis by multidetector CT enteroclysis. AB - PURPOSE: To prospectively evaluate the role of multidetector computed tomography (CT) enteroclysis in evaluation and diagnostic characterization of suspected small bowel tuberculosis. MATERIALS AND METHODS: The study group included 21 human subjects suspected of having small bowel tuberculosis. A nasoenteric tube was positioned into the duodenojejunal junction under fluoroscopic guidance and water was infused by hand injection. After intravenous administration of 120 mL of iodinated contrast material, multidetector CT enteroclysis images were obtained with 40 * 0.625 mm collimation and findings were analyzed by three readers working in consensus. Findings were compared with the results of endoscopy, histopathological analysis, and clinical follow up. RESULTS: Multidetector CT enteroclysis was well tolerated in 20 patients; one of the patients complained of vomiting during intubation. Using multidetector CT enteroclysis diagnosis of abdominal tuberculosis was made in sixteen patients, out of which small bowel involvement was seen in 13 patients. Multidetector CT enteroclysis demonstrated Crohn's disease in one patients and normal in four patients. The sensitivity and specificity in diagnosing abdominal tuberculosis by CT enteroclysis came out to be 93.75 and 100 % respectively. CONCLUSIONS: Multidetector CT enteroclysis is well tolerable and accurate modality for evaluation and diagnostic characterization of small bowel tuberculosis. PMID- 23733332 TI - A novel T-type overhangs improve the enzyme-free cloning of PCR products. AB - PCR product cloning is the foundational technology for almost all fields in the life sciences. Numerous innovative methods have been designed during the past few decades. Enzyme-free cloning is the only one that avoids post-amplification enzymatic treatments, making the technique reliable and cost effective. However, the complementary staggered overhangs used in enzyme-free cloning tend to result in self-ligation of the vector under some circumstances. Here, we describe a "T type" enzyme-free cloning method: instead of designing the complementary staggered overhangs used in conventional enzyme-free cloning, we create "T-type" overhangs that reduce the possibility of self-ligation and are more convenient for multi-vector cloning. In this study, we systematically optimize "T-type" enzyme-free cloning, compare its cloning background with that in conventional enzyme-free cloning, and demonstrate a promising application of this technique in multi-vector cloning. Our method simplifies post-amplification procedures and greatly reduces cost, offering a competitive option for PCR product cloning. PMID- 23733333 TI - A combined experimental and theoretical study on the gas-phase synthesis of toluene under single collision conditions. PMID- 23733334 TI - Ultrathin SnO2 scaffolds for TiO2-based heterojunction photoanodes in dye sensitized solar cells: oriented charge transport and improved light scattering. AB - In this paper, band-structure matching strategy of a TiO2-based heterojunction within which electrons can be collected from TiO2 nanoparticles and transported rapidly in the bulk structure is reported. On the basis of the band-structure analysis of different TiO2-based heterostructures, focus was directed to the SnO2 nanosheet because of its appropriate band position and high electrical conductivity. Through a systematic investigation of the incorporation of ultrathin SnO2 nanosheet scaffolds for TiO2-based photoanodes in dye-sensitized solar cells (DSCs), we propose an anisotropy "constrained random walk" model to describe the controlled electron transit process. In this system, electrons are transferred orientedly overall, as well as randomly locally, leading to a significant reduction in the charge diffusion route compared to the conventional isotropic "random walk" model. In brief, the 2D ultrathin nanosheets provide rapid transit pathways and improved light-scattering centers, which can ensure a sufficient amount of dye loading and slow recombination. An overall light-to electricity conversion efficiency as high as 8.25% is achieved by embedding the appropriate amount of SnO2 scaffold in a TiO2-based photoanode. PMID- 23733335 TI - Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment. AB - Acute myeloid leukemia (AML) is the most common acute leukemia in adults and the second most common frequent leukemia of childhood. Patients may present with lymphopenia or pancytopenia at diagnosis. We investigated the mechanisms by which AML causes pancytopenia and suppresses patients' immune response. This study identified for the first time that AML blasts alter the immune microenvironment through enhanced arginine metabolism. Arginase II is expressed and released from AML blasts and is present at high concentrations in the plasma of patients with AML, resulting in suppression of T-cell proliferation. We extended these results by demonstrating an arginase-dependent ability of AML blasts to polarize surrounding monocytes into a suppressive M2-like phenotype in vitro and in engrafted nonobese diabetic-severe combined immunodeficiency mice. In addition, AML blasts can suppress the proliferation and differentiation of murine granulocyte-monocyte progenitors and human CD34(+) progenitors. Finally, the study showed that the immunosuppressive activity of AML blasts can be modulated through small-molecule inhibitors of arginase and inducible nitric oxide synthase, suggesting a novel therapeutic target in AML. The results strongly support the hypothesis that AML creates an immunosuppressive microenvironment that contributes to the pancytopenia observed at diagnosis. PMID- 23733336 TI - Quiescent complement in nonhuman primates during E coli Shiga toxin-induced hemolytic uremic syndrome and thrombotic microangiopathy. AB - Enterohemorrhagic Escherichia coli (EHEC) produce ribosome-inactivating Shiga toxins (Stx1, Stx2) responsible for development of hemolytic uremic syndrome (HUS) and acute kidney injury (AKI). Some patients show complement activation during EHEC infection, raising the possibility of therapeutic targeting of complement for relief. Our juvenile nonhuman primate (Papio baboons) models of endotoxin-free Stx challenge exhibit full spectrum HUS, including thrombocytopenia, hemolytic anemia, and AKI with glomerular thrombotic microangiopathy. There were no significant increases in soluble terminal complement complex (C5b-9) levels after challenge with lethal Stx1 (n = 6) or Stx2 (n = 5) in plasma samples from T0 to euthanasia at 49.5 to 128 hours post challenge. d-dimer and cell injury markers (HMGB1, histones) confirmed coagulopathy and cell injury. Thus, complement activation is not required for the development of thrombotic microangiopathy and HUS induced by EHEC Shiga toxins in these preclinical models, and benefits or risks of complement inhibition should be studied further for this infection. PMID- 23733337 TI - Notch-HES1 signaling axis controls hemato-endothelial fate decisions of human embryonic and induced pluripotent stem cells. AB - Notch signaling regulates several cellular processes including cell fate decisions and proliferation in both invertebrates and mice. However, comparatively less is known about the role of Notch during early human development. Here, we examined the function of Notch signaling during hematopoietic lineage specification from human pluripotent stem cells of both embryonic and adult fibroblast origin. Using immobilized Notch ligands and small interfering RNA to Notch receptors we have demonstrated that Notch1, but not Notch2, activation induced hairy and enhancer of split 1 (HES1) expression and generation of committed hematopoietic progenitors. Using gain- and loss-of function approaches, this was shown to be attributed to Notch-signaling regulation through HES1, which dictated cell fate decisions from bipotent precursors either to the endothelial or hematopoietic lineages at the clonal level. Our study reveals a previously unappreciated role for the Notch pathway during early human hematopoiesis, whereby Notch signaling via HES1 represents a toggle switch of hematopoietic vs endothelial fate specification. PMID- 23733338 TI - Bacillus anthracis peptidoglycan activates human platelets through FcgammaRII and complement. AB - Platelet activation frequently accompanies sepsis and contributes to the sepsis associated vascular leakage and coagulation dysfunction. Our previous work has implicated peptidoglycan (PGN) as an agent causing systemic inflammation in gram positive sepsis. We used flow cytometry and fluorescent microscopy to define the effects of PGN on the activation of human platelets. PGN induced platelet aggregation, expression of the activated form of integrin alphaIIbbeta3, and exposure of phosphatidylserine (PS). These changes were dependent on immunoglobulin G and were attenuated by the Fcgamma receptor IIa-blocking antibody IV.3, suggesting they are mediated by PGN-anti-PGN immune complexes signaling through Fcgamma receptor IIa. PS exposure was not blocked by IV.3 but was sensitive to inhibitors of complement activation. PGN was a potent activator of the complement cascade in human plasma and caused deposition of C5b-9 on the platelet surface. Platelets with exposed PS had greatly accelerated prothrombinase activity. We conclude that PGN derived from gram-positive bacteria is a potent platelet agonist when complexed with anti-PGN antibody and could contribute to the coagulation dysfunction accompanying gram-positive infections. PMID- 23733339 TI - Exome sequencing identifies putative drivers of progression of transient myeloproliferative disorder to AMKL in infants with Down syndrome. AB - Some neonates with Down syndrome (DS) are diagnosed with self-regressing transient myeloproliferative disorder (TMD), and 20% to 30% of those progress to acute megakaryoblastic leukemia (AMKL). We performed exome sequencing in 7 TMD/AMKL cases and copy-number analysis in these and 10 additional cases. All TMD/AMKL samples contained GATA1 mutations. No exome-sequenced TMD/AMKL sample had other recurrently mutated genes. However, 2 of 5 TMD cases, and all AMKL cases, showed mutations/deletions other than GATA1, in genes proven as transformation drivers in non-DS leukemia (EZH2, APC, FLT3, JAK1, PARK2-PACRG, EXT1, DLEC1, and SMC3). One patient at the TMD stage revealed 2 clonal expansions with different GATA1 mutations, of which 1 clone had an additional driver mutation. Interestingly, it was the other clone that gave rise to AMKL after accumulating mutations in 7 other genes. Data suggest that GATA1 mutations alone are sufficient for clonal expansions, and additional driver mutations at the TMD stage do not necessarily predict AMKL progression. Later in infancy, leukemic progression requires "third-hit driver" mutations/somatic copy-number alterations found in non-DS leukemias. Putative driver mutations affecting WNT (wingless related integration site), JAK-STAT (Janus kinase/signal transducer and activator of transcription), or MAPK/PI3K (mitogen-activated kinase/phosphatidylinositol-3 kinase) pathways were found in all cases, aberrant activation of which converges on overexpression of MYC. PMID- 23733340 TI - A case of paroxysmal nocturnal hemoglobinuria caused by a germline mutation and a somatic mutation in PIGT. AB - To ascertain the genetic basis of a paroxysmal nocturnal hemoglobinuria (PNH) case without somatic mutations in PIGA, we performed deep next-generation sequencing on all exons of known genes of the glycosylphosphatidylinositol (GPI) anchor synthesis pathway. We identified a heterozygous germline splice site mutation in PIGT and a somatic 8-MB deletion in granulocytes affecting the other copy of PIGT. PIGA is essential for GPI anchor synthesis, whereas PIGT is essential for attachment of the preassembled GPI anchor to proteins. Although a single mutation event in the X-chromosomal gene PIGA is known to cause GPI anchored protein deficiency, 2 such hits are required in the autosomal gene PIGT. Our data indicate that PNH can occur even in the presence of fully assembled GPI if its transfer to proteins is defective in hematopoietic stem cells. PMID- 23733342 TI - Erythrocytosis: the HIF pathway in control. AB - Organisms living under aerobic conditions need oxygen for the metabolic conversion of nutrition into energy. With the appearance of increasingly complex animals, a specialized transport system (erythrocytes) arose during evolution to provide oxygen to virtually every single cell in the body. Moreover, in case of low environmental partial pressure of oxygen, the number of erythrocytes automatically increases to preserve sustained oxygen delivery. This process relies predominantly on the cytokine erythropoietin (Epo) and its transcription factor hypoxia inducible factor (HIF), whereas the von Hippel-Lindau (VHL) ubiquitin ligase as well as the oxygen-sensitive prolyl hydroxylases (PHDs) represent essential regulators of this oxygen-sensing system. Deregulation of particular members of this pathway (eg, PHD2, HIF2alpha, VHL) lead to disorders in blood homeostasis as a result of insufficient (anemia) or excessive (erythrocytosis) red blood cell production. PMID- 23733341 TI - A vasculo-protective circuit centered on lipoxin A4 and aspirin-triggered 15-epi lipoxin A4 operative in murine microcirculation. AB - Endogenous protective pathways mitigate the overshooting of inflammation after sterile or infectious injury. Here we report that formyl peptide receptor 2 (Fpr2/3) null mice display a major phenotype with exacerbated vascular inflammation observed postischemia reperfusion (IR) injury of the mesenteric artery, characterized by marked neutrophil adhesion and extravasation as visualized by intravital microscopy. Analysis of endogenous agonists for Fpr2/3 revealed that lipoxin A4 (LXA4) was generated by platelet/neutrophil aggregates during ischemia: this cellular response was attenuated in Fpr2/3(-/-) mice; hence, LXA4 levels were lower after 30 minutes' ischemia, and associated with augmented vascular inflammation in the reperfusion (45-180 minutes) phase. Exogenous delivery of LXA4 attenuated IR-mediated inflammation in Fpr2/3(+/+) but not Fpr2/3(-/-) mice; conversely, an Fpr2/3 antagonist skewed the vascular phenotype of Fpr2/3(+/+) mice to that of Fpr2/3(-/-) animals. Such LXA4-based circuit could be activated by aspirin (30-100 mg/kg), which triggered formation of 15-epi-LXA4 in wild-type mice, yet it was effective in Fpr2/3(-/-) mice. In summary, we propose that during ischemia, neutrophil Fpr2/3 controls platelet/neutrophil aggregates with the rapid generation of circulating LXA4, which in turn modulates downstream vascular inflammatory responses evident during the reperfusion phase. PMID- 23733343 TI - The Hippo pathway polarizes the actin cytoskeleton during collective migration of Drosophila border cells. AB - Collective migration of Drosophila border cells depends on a dynamic actin cytoskeleton that is highly polarized such that it concentrates around the outer rim of the migrating cluster of cells. How the actin cytoskeleton becomes polarized in these cells to enable collective movement remains unknown. Here we show that the Hippo signaling pathway links determinants of cell polarity to polarization of the actin cytoskeleton in border cells. Upstream Hippo pathway components localize to contacts between border cells inside the cluster and signal through the Hippo and Warts kinases to polarize actin and promote border cell migration. Phosphorylation of the transcriptional coactivator Yorkie (Yki)/YAP by Warts does not mediate the function of this pathway in promoting border cell migration, but rather provides negative feedback to limit the speed of migration. Instead, Warts phosphorylates and inhibits the actin regulator Ena to activate F-actin Capping protein activity on inner membranes and thereby restricts F-actin polymerization mainly to the outer rim of the migrating cluster. PMID- 23733344 TI - Injury-induced BMP signaling negatively regulates Drosophila midgut homeostasis. AB - Although much is known about injury-induced signals that increase rates of Drosophila melanogaster midgut intestinal stem cell (ISC) proliferation, it is largely unknown how ISC activity returns to quiescence after injury. In this paper, we show that the bone morphogenetic protein (BMP) signaling pathway has dual functions during midgut homeostasis. Constitutive BMP signaling pathway activation in the middle midgut mediated regional specification by promoting copper cell differentiation. In the anterior and posterior midgut, injury-induced BMP signaling acted autonomously in ISCs to limit proliferation and stem cell number after injury. Loss of BMP signaling pathway members in the midgut epithelium or loss of the BMP signaling ligand decapentaplegic from visceral muscle resulted in phenotypes similar to those described for juvenile polyposis syndrome, a human intestinal tumor caused by mutations in BMP signaling pathway components. Our data establish a new link between injury and hyperplasia and may provide insight into how BMP signaling mutations drive formation of human intestinal cancers. PMID- 23733347 TI - An emerging functional natural silk biomaterial from the only domesticated non mulberry silkworm Samia ricini. AB - Mulberry silk fibroin is a widely used biomaterial and recent work on non mulberry silk fibroin also suggests it may have similar uses. We expect silk fibroin from the only domesticated non-mulberry eri silkworm, Samia ricini, to possess useful properties as a biomaterial. Eri silk gland fibroin is a heterodimeric protein of approximately 450 kDa. Cytocompatibility evaluation with fibroblasts and osteoblast-like cells shows good cell attachment, viability and proliferation. The matrices, which have high thermal stability and good swellability, are also haemocompatible. Eri silk production is cost effective as no agronomic practices are required for their host plant cultivation. This fibroin provide new opportunities as an alternative natural functional biomaterial in various biomedical applications. PMID- 23733346 TI - A novel pathway spatiotemporally activates Rac1 and redox signaling in response to fluid shear stress. AB - Hemodynamic forces regulate embryonic organ development, hematopoiesis, vascular remodeling, and atherogenesis. The mechanosensory stimulus of blood flow initiates a complex network of intracellular pathways, including activation of Rac1 GTPase, establishment of endothelial cell (EC) polarity, and redox signaling. The activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase can be modulated by the GTP/GDP state of Rac1; however, the molecular mechanisms of Rac1 activation by flow are poorly understood. Here, we identify a novel polarity complex that directs localized Rac1 activation required for downstream reactive oxygen species (ROS) production. Vav2 is required for Rac1 GTP loading, whereas, surprisingly, Tiam1 functions as an adaptor in a VE cadherin-p67phox-Par3 polarity complex that directs localized activation of Rac1. Furthermore, loss of Tiam1 led to the disruption of redox signaling both in vitro and in vivo. Our results describe a novel molecular cascade that regulates redox signaling by the coordinated regulation of Rac1 and by linking components of the polarity complex to the NADPH oxidase. PMID- 23733345 TI - Long-range heterochromatin association is mediated by silencing and double-strand DNA break repair proteins. AB - The eukaryotic genome is highly organized in the nucleus, and this organization affects various nuclear processes. However, the molecular details of higher-order organization of chromatin remain obscure. In the present study, we show that the Saccharomyces cerevisiae silenced loci HML and HMR cluster in three-dimensional space throughout the cell cycle and independently of the telomeres. Long-range HML-HMR interactions require the homologous recombination (HR) repair pathway and phosphorylated H2A (gamma-H2A). gamma-H2A is constitutively present at silenced loci in unperturbed cells, its localization requires heterochromatin, and it is restricted to the silenced domain by the transfer DNA boundary element. SMC proteins and Scc2 localize to the silenced domain, and Scc2 binding requires the presence of gamma-H2A. These findings illustrate a novel pathway for heterochromatin organization and suggest a role for HR repair proteins in genomic organization. PMID- 23733348 TI - Effectiveness of theory-based invitations to improve attendance at cardiac rehabilitation: a randomized controlled trial. AB - BACKGROUND: Despite well-established evidence of benefit from cardiac rehabilitation, typically fewer than 35% of eligible patients attend. OBJECTIVE: The purpose of this study was to evaluate whether theory-based invitations increase attendance at cardiac rehabilitation. METHOD: The study was a randomized controlled trial (RCT) with two by two factorial design. A total of 375 participants with acute myocardial infarction or coronary revascularization was recruited from medical and surgical cardiac wards at Aberdeen Royal Infirmary (ARI). They were randomly assigned to receive either the standard invitation letter or a letter with wording based on the 'theory of planned behavior (TPB)' and the 'common sense model of illness perception', and either a supportive leaflet with motivational messages or not. The primary outcome was one or more attendances at cardiac rehabilitation. RESULTS: The theory-based letter increased attendance at cardiac rehabilitation compared to the standard letter (84% versus 74%, odds ratio (OR) 2.93, 95% confidence interval (CI) 1.54-5.56), independent of age, gender, working status, hypertension, identity and TPB constructs. The number needed to treat (NNT) was 9 (95% CI 7-12). The motivational leaflet had no significant effect on attendance at rehabilitation (OR 1.02, 95% CI 0.57-1.83). CONCLUSIONS: The use of theory-based wording in invitation letters is a simple method to improve attendance at cardiac rehabilitation. Our letter, reproduced in this paper, could provide a template for practitioners and researchers. PMID- 23733349 TI - 'I am still a bit unsure how much of a heart attack it really was!' Patients presenting with non ST elevation myocardial infarction lack understanding about their illness and have less motivation for secondary prevention. AB - BACKGROUND: There are considerable differences in the type of treatments offered to patients presenting with acute myocardial infarction (AMI), in terms of the speed and urgency with which they are admitted, treated and discharged from hospital. The impact of these different treatment experiences on patients' illness perception and motivation for behavioural changes is unknown. AIM: The aim of this study was to explore and compare patients' illness perception and motivation for behavioural change following myocardial infarction (MI) treated by different methods. METHODS: Semi-structured, domiciliary interviews (n=15) based on the common sense model of self regulation, were conducted with three groups of MI patients within four weeks of diagnosis: (a) primary percutaneous coronary intervention (PPCI) (n=5); (b) thrombolysis (n=5); (c) non ST elevation MI (NSTEMI) (n=5). Framework analysis was used to identify and compare themes between groups. RESULTS: Patients presenting with a ST-elevation MI (STEMI) receiving either PPCI or thrombolysis had similar perceptions of their illness as a serious, life-threatening event and were determined to make lifestyle changes. In contrast, patients with a NSTEMI experienced uncertainty about symptoms and diagnosis, causing misconceptions about the severity of their condition and less determination for lifestyle changes. CONCLUSION: Patients with NSTEMI in this study expressed very different perceptions of their illness compared to those experiencing STEMI. Patients' clinical presentation and treatment experience during an AMI can impact on their illness perception, motivation for behavioural change and uptake of cardiac rehabilitation. Nurses should consider the patients' illness experience and perception when planning secondary prevention interventions. PMID- 23733350 TI - Cognitive function and self-care management in older patients with heart failure. AB - AIMS: People with heart failure have difficulty with self-care management. We do not know if patients with heart failure have difficulty with self-care management due to underlying, mild cognitive impairment (MCI). The purpose of this study was to determine whether MCI, as identified on a simple screening tool, is significantly associated with self-care management in a sample of community dwelling older patients with heart failure. METHODS AND RESULTS: Using a cross sectional design, heart failure patients (n=100, mean age 72 SD 10 years) attending an outpatient heart failure clinic completed the Montreal Cognitive Assessment tool (MoCA), Self-Care in Heart Failure Index (SCHFI) and Geriatric Depression Scale. The presence of MCI, as defined by a MoCA score <26, was present in 73% patients; 21% had an adequate self-care management SCHFI score; and 12% reported symptoms of depression. Participants with a MoCA score <26 vs. >= 26 scored significantly lower on the self-care management subscale of the SCHFI (48.1 SD 24 vs. 59.3 SD 22 respectively, p=0.035). Using backward regression, the final model was fitted to self-care management while controlling for age and sex and was significant, with (F= 7.04 df (3, 96), and p<0.001), accounting for 18% of the total variance in self-care management (R (2) = 18.03%). The MoCA score was the only variable which remained in the model significantly with p= 0.001. CONCLUSION: Findings from this study highlight the difficulty older heart failure patients have with self-care management and the need to include formal screening for MCI when exploring variables contributing to self-care management in heart failure patients. PMID- 23733351 TI - Pretreatment circulating monocyte count associated with poor prognosis in patients with oral cavity cancer. AB - BACKGROUND: The purpose of this study was to investigate whether the pretreatment total and differential leukocyte counts can predict the prognosis of patients with oral cavity cancer. METHODS: In a retrospective analysis of patients treated between 2004 and 2011, medical records of 202 patients with oral cavity cancer were evaluated. RESULTS: Patients with oral cavity cancer, the peripheral total white blood cell (WBC) count, monocyte, and neutrophil counts and neutrophil lymphocyte ratio increased with the advancement of clinical stage. In contrast, the lymphocyte count decreased. Further, total WBC, monocyte, and neutrophil counts were increased in those with pathologic stage T4 and poor tumor differentiation, and the monocyte count was also increased in those with lymph node metastasis. Moreover, the pretreatment circulating monocyte count was an independent prognostic factor for cancer-specific survival. CONCLUSION: A higher pretreatment circulating monocyte count can be considered as a useful prognostic marker in patients with oral cavity cancer. PMID- 23733352 TI - High incidence of regional and in-transit lymph node metastasis in patients with alveolar rhabdomyosarcoma. AB - BACKGROUND: Rhabdomyosarcoma has different extension patterns, including a higher propensity for lymph nodes metastasis, compared with other types of soft tissue sarcoma. The aims of this study were to investigate the patterns of regional and distant metastasis in patients with rhabdomyosarcomas, particularly lymphatic route metastasis, and clarify the clinical factors that affect the pattern of metastasis. METHODS: Forty-four patients with rhabdomyosarcomas were enrolled in this study. The mean age of the patients was 26 (range 1-69) years, and 18 were males. The histological subtypes included alveolar (17 patients), embryonal (10 patients), pleomorphic (7 patients), and unknown (10 patients). Based on location, the sarcomas were divided into three groups: extremity (17 cases), favorable prognosis (10 cases), and unfavorable prognosis (15 cases). There were three cases (7 %) of local relapse, ten cases of regional lymph node relapse, and three cases of in-transit metastasis (total 30 %). Twenty-one patients (48 %) developed distant metastases. Initial sites of metastases were bone (9 patients, 20 %), lung (5 patients), and bone marrow dissemination (5 patients). Clinico pathological variables affecting relapse patterns were analyzed. RESULTS: Of the three cases of local relapse, two were alveolar type and one was unknown. The three cases of in-transit metastasis were all alveolar type. Patients with alveolar type had a significantly high propensity for lymph node metastasis (P = 0.027). Excluding the pleomorphic type, alveolar type was still a significant factor for lymph node metastasis (P = 0.017). CONCLUSION: Physicians should be aware of in-transit spread, particularly in patients with alveolar-type rhabdomyosarcoma. Novel treatment modalities are required to detect and treat in transit metastasis. PMID- 23733353 TI - Possible peripheral mechanism for taste disorder in rats administered S-1. AB - BACKGROUND: Taste disorders are frequently observed in cancer patients undergoing chemotherapy and are serious adverse events which impair the quality of life (QoL) of the cancer patient. Nevertheless, taste disorder mechanisms in cancer patients undergoing chemotherapy have not yet been fully elucidated. The aim of this study was to reveal taste disorder-related peripheral mechanisms using the two-bottle preference test (TBPT) and histological examination of tongues by hematoxylin-eosin staining and immunohistochemistry with protein-gene product 9.5. METHODS: In the TBPT, one bottle was filled with the 0.01 mM quinine hydrochloride (quinine), as a bitter compound, and the other was filled with water. Doses of 50 and 100 mg kg(-1) day(-1) S-1 (tegafur/gimeracil/oteracil potassium) are lethal to Wistar rats. Therefore, doses ranging from 2-20 mg kg( 1) day(-1) were administered to the rats for 3 weeks. The S-1 dose of 2 mg kg(-1) day(-1) corresponds to the clinical dose administered to cancer patients. The part of the tongue containing the circumvallate papillae was excised the following TBPT. RESULTS: The rate of increase in terms of the average preference rate for the quinine vs. all intake (quinine plus water) was significant from the initial S-1 period to the final one, compared with that in control rats, suggesting the possibility of a worsening sensation for the bitter taste. In S-1 rats, the area of taste nerve fibers were significantly decreased and the rate of degeneration of intra-tongue ganglionic nerve cells was significantly increased. These changes were significantly correlated with the rate of increase in average preference rate of the quinine. CONCLUSION: Neuropathy of the gustatory nerve at the periphery may be involved in taste disorders induced by an anticancer drug. PMID- 23733354 TI - Recruiting and retaining indigenous farmworker participants. AB - There is limited information on the specific practices used to successfully recruit and retain indigenous and Latino farmworkers in research studies. This article describes the strategies used in a community-based participatory research project with indigenous agricultural workers. Participants were recruited through consulting with indigenous relatives and friends, identifying and meeting with indigenous leaders from hometown associations in countries of origin, and asking current participants to recruit fellow farmworkers. Adjustments were initiated to the second year protocol to enhance recruitment and retention. The difference in attrition rates between years one and two was statistically significant, a difference partially attributed to modifications to recruitment and retention protocol. Findings confirmed that active recruitment techniques and word-of-mouth recruitment were more effective than passive methods. Trust among academic, organization, and community partners, and shared language and culture between those doing the recruitment and the participants, contributed to sustained farmworker participation. PMID- 23733355 TI - Timing of motor milestones achievement and development of overweight in childhood: a study within the Danish National Birth Cohort. AB - BACKGROUND: Overweight may hinder achievement of gross motor milestones and delayed achievement of milestones may increase the risk of later overweight for reasons involving physical activity and the building of lean body mass. OBJECTIVE: To investigate whether increased birth weight and body mass index (BMI) at 5 months is associated with the achievement of the ability to sit up and walk and whether delayed achievement of these milestones is associated with overweight at age 7 years. METHODS: We used data from the Danish National Birth Cohort on 25,148 children born between 1998 and 2003. Follow-up took place from 2003 to 2010. Mean age at follow-up was 7.04 years. We used logistic and linear regression analyses. RESULTS: Birth weight and BMI at 5 months were marginally associated with earlier achievement of the ability to sit up and walk (regression coefficients between -0.027 months; [CI -0.042; -0.013] and -0.092 months [CI 0.118; -0.066]). Age in months of sitting and walking were not associated with overweight at age 7 years (ORs between 0.97 [CI 0.95-1.00] and 1.00 [CI 0.96 1.04]). Later achievement of sitting and walking predicted lower BMI at age 7 years (ln-BMI -z-scores between -0.023 [CI -0.029; -0.017] and -0.005 [CI -0.015; 0.005)). CONCLUSIONS: All observed associations were of negligible magnitude and we conclude that birth weight or BMI at age 5 months and motor milestones appear largely independent of each other and that timing of achievement of motor milestones seems not to be associated with later overweight or increased BMI. PMID- 23733357 TI - Neuropeptide Y modulates fracture healing through Y1 receptor signaling. AB - Neuropeptide Y acting via it's Y1 receptor represents a powerful pathway in the control of bone mass. The global or osteoblast-specific Y1 receptor deletion induces pronounced bone anabolic effects in mice. However, the contribution of Y1 receptor deletion in bone repair/healing remained to be clarified. Therefore, in this study we characterized the role of Y1 receptor deletion in fracture healing. Closed tibial fractures were generated in germline (Y1 (-/-) ) and osteoblastic specific Y1 receptor knockout mice. The progression of tibial repair monitored from 1- until 6-weeks post-fracture demonstrated that in Y1 (-/-) mice there is a delay in fracture repair, as seen by a decrease in bone callus volume and callus strength. Moreover, the histological features included elevated avascular and cartilage area and consequently delayed cartilage removal, and hence impaired union. Interestingly, this delay in bone repair was not related directly to Y1 receptors expressed by mature osteoblasts. These findings suggest that the global absence of the Y1 receptor delays fracture healing, through impairing the early phases of fracture repair to achieve bony union. The data acquired on the role of Y1 receptor signaling disruption in bone regeneration is critical for the design of future therapeutic strategies. PMID- 23733356 TI - The ortholog of the human proto-oncogene ROS1 is required for epithelial development in C. elegans. AB - The orphan receptor ROS1 is a human proto-oncogene, mutations of which are found in an increasing number of cancers. Little is known about the role of ROS1, however in vertebrates it has been implicated in promoting differentiation programs in specialized epithelial tissues. In this study we show that the C. elegans ortholog of ROS1, the receptor tyrosine kinase ROL-3, has an essential role in orchestrating the morphogenesis and development of specialized epidermal tissues, highlighting a potentially conserved function in coordinating crosstalk between developing epithelial cells. We also provide evidence of a direct relationship between ROL-3, the mucin SRAP-1, and BCC-1, the homolog of mRNA regulating protein Bicaudal-C. This study answers a longstanding question as to the developmental function of ROL-3, identifies three new genes that are expressed and function in the developing epithelium of C. elegans, and introduces the nematode as a potentially powerful model system for investigating the increasingly important, yet poorly understood, human oncogene ROS1. PMID- 23733358 TI - Ethambutol toxicity exacerbating the phenotype of CMT2A2. AB - INTRODUCTION: CMT2A2 is associated with mutations in the mitofusin 2 gene, which encodes a protein involved in mitochondrial fusion. Ethambutol is an antimycobacterial agent associated with toxic optic neuropathies. Ethambutol induced optic neuropathy occurs in patients with mutations in a related fusion gene, OPA1, which is responsible for autosomal dominant optic atrophy. METHODS: We describe a patient with CMT2A2 (MFN2 mutation: T669G, F223L) who developed accelerated weakness, vocal cord paralysis, and optic atrophy after receiving ethambutol. RESULTS: Deterioration began within months of initiating ethambutol therapy. After discontinuation of ethambutol, neurologic deterioration stabilized with subsequent improvement in visual fields. CONCLUSIONS: CMT2A2 is part of a group of genetic disorders which share an association with the process of mitochondrial fusion. This case shows that patients with CMT2A2, and possibly other mitochondrial fusion defects, may be uniquely susceptible to ethambutol induced neurotoxicity. This has implications regarding the underlying pathophysiology of mitochondrial fusion defects. PMID- 23733359 TI - Developing a comprehensive and comparative questionnaire for measuring personality in chimpanzees using a simultaneous top-down/bottom-up design. AB - One effective method for measuring personality in primates is to use personality trait ratings to distill the experience of people familiar with the individual animals. Previous rating instruments were created using either top-down or bottom up approaches. Top-down approaches, which essentially adapt instruments originally designed for use with another species, can unfortunately lead to the inclusion of traits irrelevant to chimpanzees or fail to include all relevant aspects of chimpanzee personality. Conversely, because bottom-up approaches derive traits specifically for chimpanzees, their unique items may impede comparisons with findings in other studies and other species. To address the limitations of each approach, we developed a new personality rating scale using a combined top-down/bottom-up design. Seventeen raters rated 99 chimpanzees on the new 41-item scale, with all but one item being rated reliably. Principal components analysis, using both varimax and direct oblimin rotations, identified six broad factors. Strong evidence was found for five of the factors (Reactivity/Undependability, Dominance, Openness, Extraversion, and Agreeableness). A sixth factor (Methodical) was offered provisionally until more data are collected. We validated the factors against behavioral data collected independently on the chimpanzees. The five factors demonstrated good evidence for convergent and predictive validity, thereby underscoring the robustness of the factors. Our combined top-down/bottom-up approach provides the most extensive data to date to support the universal existence of these five personality factors in chimpanzees. This framework, which facilitates cross-species comparisons, can also play a vital role in understanding the evolution of personality and can assist with husbandry and welfare efforts. PMID- 23733360 TI - A tale of two sisters. PMID- 23733361 TI - Degradation products from naturally aged paper leaves of a 16th-century-printed book: a spectrochemical study. AB - In this work, we present a wide-range spectrochemical analysis of the degradation products from naturally aged paper. The samples obtained from wash waters used during the de-acidification treatment of leaves from a 16th-century-printed book were analysed through NMR, IR, Raman UV/Vis, EPR and X-ray fluorescence (XRF) spectroscopy and HPLC-MS and inductively coupled plasma (ICP) analysis. By these methods we also studied some of the previous samples treated by acidification (sample AP) and catalytic hydrogenation (sample HP). Crossing all the data, we obtained precise indications about the main functional groups occurring on the degraded, water-soluble cellulose oligomers. These results point out that the chromophores responsible for browning are conjugated carbonyl and carboxyl compounds. As a whole, we show that the analysis of wash waters, used in the usual conservation treatments of paper de-acidification, gives much valuable information about both the conservation state of the book and the degradation reactions occurring on the leaves, due to the huge amount of cellulose by products contained in the samples. We propose therefore this procedure as a new very convenient general method to obtain precious and normally unavailable information on the cellulose degradation by-products from naturally aged paper. PMID- 23733362 TI - What patients and surgeons should know about the consequences of appendectomy for acute appendicitis after long-term follow-up: factors influencing the incidence of chronic abdominal complaints. AB - INTRODUCTION: Abscess formation and perforation are complications of acute appendicitis that lead to localized or generalized peritonitis. The long-term implications of complicated appendectomy remain largely unknown. MATERIALS AND METHODS: In the present study, it was investigated whether patients with complicated appendicitis experienced more abdominal complaints after long-term follow-up when compared to uncomplicated cases. In addition, the influence of operation technique (open versus laparoscopic) was studied. A retrospective analysis of 1,481 appendectomies for acute appendicitis was performed in two centers from January 2000 until January 2006. Demographic data, operative reports, intraoperatively adhesions and complications, abdominal pain, and satisfaction were monitored. In total, 1,433 patients were invited to fill out a questionnaire with a median follow-up of 7.1 years. Questionnaires of 526 (37 %) patients were suitable for analysis. RESULTS: Perforation, abdominal abscesses, or adhesions at initial operation did not result in more abdominal complaints when compared to appendectomy for uncomplicated acute appendicitis. Additionally, no significant differences in abdominal complaints were seen between laparoscopic and open techniques. CONCLUSION: In conclusion, the results of our study show that after follow-up of 7 years, the incidence of abdominal complaints was not influenced by operative technique or whether acute appendicitis was complicated or not. This finding does not support a causative role for adhesions with regard to chronic abdominal complaints. Our data enables surgeons to inform their patients about the long-term results of appendectomy, whether it was complicated or not. PMID- 23733363 TI - Influence of age on clinical outcome of acute diverticulitis. AB - BACKGROUND: The controversy about the treatment of acute colonic diverticulitis in young patients continues. The discussion is focused on whether younger age is a risk factor for recurrence or a complicated course, thereby subject to different treatment choices. AIM: In this study, we investigated whether an episode of acute diverticulitis at a younger age (<=50 years) has a higher recurrence rate or a more severe outcome. MATERIAL AND METHODS: A retrospective cohort study was conducted in four teaching hospitals using hospital registry codes for diverticulitis. All patients diagnosed with acute diverticulitis between January 2004 and January 2012, confirmed by imaging, were included. RESULTS: A total of 1,441 consecutive patients were identified as having primary acute diverticulitis of the sigmoid colon. Four hundred and sixty-three patients (32.1%) were <=50 years (group 1) and 978 patients (67.9%) were older than 50 years (group 2). Twenty patients (4.3%) needed emergency surgery, due to perforated diverticulitis, within 72 h at first presentation in group 1 compared to 77 patients (7.8%) in group 2 (p = 0.029). Surgery within 30 days was needed for 29 of 463 patient (6.2%) in group 1 and 104 of 978 patients (10.6%) in group 2 (p = 0.02). Recurrence rate after a median follow-up of 22 months was comparable among groups (25.6% (111 patients) in group 1 versus 23.8% (208 patients) in group 2; p = 0.278). Also, cumulative recurrence was comparable among groups. CONCLUSION: Younger age is neither associated with a more severe presentation of diverticulitis nor with a higher incidence in recurrence. PMID- 23733364 TI - Corticosteroids for acute bacterial meningitis. AB - BACKGROUND: In experimental studies, the outcome of bacterial meningitis has been related to the severity of inflammation in the subarachnoid space. Corticosteroids reduce this inflammatory response. OBJECTIVES: To examine the effect of adjuvant corticosteroid therapy versus placebo on mortality, hearing loss and neurological sequelae in people of all ages with acute bacterial meningitis. SEARCH METHODS: We searched CENTRAL 2012, Issue 12, MEDLINE (1966 to January week 2, 2013), EMBASE (1974 to January 2013), Web of Science (2010 to January 2013), CINAHL (2010 to January 2013) and LILACS (2010 to January 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) of corticosteroids for acute bacterial meningitis. DATA COLLECTION AND ANALYSIS: We scored RCTs for methodological quality. We collected outcomes and adverse effects. We performed subgroup analyses for children and adults, causative organisms, low-income versus high-income countries, time of steroid administration and study quality. MAIN RESULTS: Twenty-five studies involving 4121 participants were included. Corticosteroids were associated with a non-significant reduction in mortality (17.8% versus 19.9%; risk ratio (RR) 0.90, 95% confidence interval (CI) 0.80 to 1.01, P = 0.07). A similar non-significant reduction in mortality was observed in adults receiving corticosteroids (RR 0.74, 95% CI 0.53 to 1.05, P = 0.09). Corticosteroids were associated with lower rates of severe hearing loss (RR 0.67, 95% CI 0.51 to 0.88), any hearing loss (RR 0.74, 95% CI 0.63 to 0.87) and neurological sequelae (RR 0.83, 95% CI 0.69 to 1.00).Subgroup analyses for causative organisms showed that corticosteroids reduced mortality in Streptococcus pneumoniae (S. pneumoniae) meningitis (RR 0.84, 95% CI 0.72 to 0.98), but not in Haemophilus influenzae (H. influenzae) orNeisseria meningitidis (N. meningitidis) meningitis. Corticosteroids reduced severe hearing loss in children with H. influenzae meningitis (RR 0.34, 95% CI 0.20 to 0.59) but not in children with meningitis due to non-Haemophilus species.In high-income countries, corticosteroids reduced severe hearing loss (RR 0.51, 95% CI 0.35 to 0.73), any hearing loss (RR 0.58, 95% CI 0.45 to 0.73) and short-term neurological sequelae (RR 0.64, 95% CI 0.48 to 0.85). There was no beneficial effect of corticosteroid therapy in low-income countries.Subgroup analysis for study quality showed no effect of corticosteroids on severe hearing loss in high-quality studies.Corticosteroid treatment was associated with an increase in recurrent fever (RR 1.27, 95% CI 1.09 to 1.47), but not with other adverse events. AUTHORS' CONCLUSIONS: Corticosteroids significantly reduced hearing loss and neurological sequelae, but did not reduce overall mortality. Data support the use of corticosteroids in patients with bacterial meningitis in high-income countries. We found no beneficial effect in low-income countries. PMID- 23733365 TI - Antibiotics for community-acquired pneumonia in children. AB - BACKGROUND: Pneumonia caused by bacterial pathogens is the leading cause of mortality in children in low-income countries. Early administration of antibiotics improves outcomes. OBJECTIVES: To identify effective antibiotic drug therapies for community-acquired pneumonia (CAP) of varying severity in children by comparing various antibiotics. SEARCH METHODS: We searched CENTRAL 2012, Issue 10; MEDLINE (1966 to October week 4, 2012); EMBASE (1990 to November 2012); CINAHL (2009 to November 2012); Web of Science (2009 to November 2012) and LILACS (2009 to November 2012). SELECTION CRITERIA: Randomised controlled trials (RCTs) in children of either sex, comparing at least two antibiotics for CAP within hospital or ambulatory (outpatient) settings. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from the full articles of selected studies. MAIN RESULTS: We included 29 trials, which enrolled 14,188 children, comparing multiple antibiotics. None compared antibiotics with placebo.Assessment of quality of study revealed that 5 out of 29 studies were double-blind and allocation concealment was adequate. Another 12 studies were unblinded but had adequate allocation concealment, classifying them as good quality studies. There was more than one study comparing co-trimoxazole with amoxycillin, oral amoxycillin with injectable penicillin/ampicillin and chloramphenicol with ampicillin/penicillin and studies were of good quality, suggesting the evidence for these comparisons was of high quality compared to other comparisons.In ambulatory settings, for treatment of World Health Organization (WHO) defined non severe CAP, amoxycillin compared with co-trimoxazole had similar failure rates (odds ratio (OR) 1.18, 95% confidence interval (CI) 0.91 to 1.51) and cure rates (OR 1.03, 95% CI 0.56 to 1.89). Three studies involved 3952 children.In children with severe pneumonia without hypoxaemia, oral antibiotics (amoxycillin/co trimoxazole) compared with injectable penicillin had similar failure rates (OR 0.84, 95% CI 0.56 to 1.24), hospitalisation rates (OR 1.13, 95% CI 0.38 to 3.34) and relapse rates (OR 1.28, 95% CI 0.34 to 4.82). Six studies involved 4331 children below 18 years of age.In very severe CAP, death rates were higher in children receiving chloramphenicol compared to those receiving penicillin/ampicillin plus gentamicin (OR 1.25, 95% CI 0.76 to 2.07). One study involved 1116 children. AUTHORS' CONCLUSIONS: For treatment of patients with CAP in ambulatory settings, amoxycillin is an alternative to co-trimoxazole. With limited data on other antibiotics, co-amoxyclavulanic acid and cefpodoxime may be alternative second-line drugs. Children with severe pneumonia without hypoxaemia can be treated with oral amoxycillin in an ambulatory setting. For children hospitalised with severe and very severe CAP, penicillin/ampicillin plus gentamycin is superior to chloramphenicol. The other alternative drugs for such patients are co-amoxyclavulanic acid and cefuroxime. Until more studies are available, these can be used as second-line therapies.There is a need for more studies with radiographically confirmed pneumonia in larger patient populations and similar methodologies to compare newer antibiotics. Recommendations in this review are applicable to countries with high case fatalities due to pneumonia in children without underlying morbidities and where point of care tests for identification of aetiological agents for pneumonia are not available. PMID- 23733366 TI - A mathematical model of avian influenza with half-saturated incidence. AB - The widespread impact of avian influenza viruses not only poses risks to birds, but also to humans. The viruses spread from birds to humans and from human to human In addition, mutation in the primary strain will increase the infectiousness of avian influenza. We developed a mathematical model of avian influenza for both bird and human populations. The effect of half-saturated incidence on transmission dynamics of the disease is investigated. The half saturation constants determine the levels at which birds and humans contract avian influenza. To prevent the spread of avian influenza, the associated half saturation constants must be increased, especially the half-saturation constant H m for humans with mutant strain. The quantity H m plays an essential role in determining the basic reproduction number of this model. Furthermore, by decreasing the rate beta m at which human-to-human mutant influenza is contracted, an outbreak can be controlled more effectively. To combat the outbreak, we propose both pharmaceutical (vaccination) and non-pharmaceutical (personal protection and isolation) control methods to reduce the transmission of avian influenza. Vaccination and personal protection will decrease beta m, while isolation will increase H m. Numerical simulations demonstrate that all proposed control strategies will lead to disease eradication; however, if we only employ vaccination, it will require slightly longer to eradicate the disease than only applying non-pharmaceutical or a combination of pharmaceutical and non pharmaceutical control methods. In conclusion, it is important to adopt a combination of control methods to fight an avian influenza outbreak. PMID- 23733367 TI - Triphenylene-based tris(N-heterocyclic carbene) ligand: unexpected catalytic benefits. PMID- 23733369 TI - A general model-based design of experiments approach to achieve practical identifiability of pharmacokinetic and pharmacodynamic models. AB - The use of pharmacokinetic (PK) and pharmacodynamic (PD) models is a common and widespread practice in the preliminary stages of drug development. However, PK-PD models may be affected by structural identifiability issues intrinsically related to their mathematical formulation. A preliminary structural identifiability analysis is usually carried out to check if the set of model parameters can be uniquely determined from experimental observations under the ideal assumptions of noise-free data and no model uncertainty. However, even for structurally identifiable models, real-life experimental conditions and model uncertainty may strongly affect the practical possibility to estimate the model parameters in a statistically sound way. A systematic procedure coupling the numerical assessment of structural identifiability with advanced model-based design of experiments formulations is presented in this paper. The objective is to propose a general approach to design experiments in an optimal way, detecting a proper set of experimental settings that ensure the practical identifiability of PK-PD models. Two simulated case studies based on in vitro bacterial growth and killing models are presented to demonstrate the applicability and generality of the methodology to tackle model identifiability issues effectively, through the design of feasible and highly informative experiments. PMID- 23733370 TI - Lack of pattern of birth in patients with bulimia nervosa. AB - OBJECTIVE: An excess of bulimia nervosa (BN) births during the fall has been recently reported, but this finding has not been yet adequately replicated. The purpose of our study was to evaluate the presence of a seasonal birth pattern in a representative clinical sample of women with BN. METHOD: We registered the month of birth of 216 female patients who fulfilled all the criteria for BN according to DSM-IV on admission to a specialized eating disorders service in Spain. RESULTS: Our analyses showed no significant variation in the season of birth of our BN sample when compared to a general population. DISCUSSION: Our data do not support the hypothesis of a season of birth bias in BN. PMID- 23733368 TI - MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways. AB - Activation of inflammatory pathways in the endothelium contributes to vascular diseases, including sepsis and atherosclerosis. We demonstrate that miR-146a and miR-146b are induced in endothelial cells upon exposure to pro-inflammatory cytokines. Despite the rapid transcriptional induction of the miR-146a/b loci, which is in part mediated by EGR-3, miR-146a/b induction is delayed and sustained compared to the expression of leukocyte adhesion molecules, and in fact coincides with the down-regulation of inflammatory gene expression. We demonstrate that miR 146 negatively regulates inflammation. Over-expression of miR-146a blunts endothelial activation, while knock-down of miR-146a/b in vitro or deletion of miR-146a in mice has the opposite effect. MiR-146 represses the pro-inflammatory NF-kappaB pathway as well as the MAP kinase pathway and downstream EGR transcription factors. Finally, we demonstrate that HuR, an RNA binding protein that promotes endothelial activation by suppressing expression of endothelial nitric oxide synthase (eNOS), is a novel miR-146 target. Thus, we uncover an important negative feedback regulatory loop that controls pro-inflammatory signalling in endothelial cells that may impact vascular inflammatory diseases. PMID- 23733371 TI - Neurodegenerative and inflammatory biomarkers in cerebrospinal fluid in patients with Cushing's syndrome in remission. AB - OBJECTIVE: Patients with Cushing's syndrome (CS) in long-term remission have impaired cognitive function. Cerebrospinal fluid (CSF) biomarkers are important diagnostic tools in the work-up of patients with cognitive impairment. The aim of this study was to analyze neurodegenerative and inflammatory biomarkers in the CSF of patients with CS in remission. DESIGN: A cross-sectional, single-center study. PATIENTS: Twelve women previously treated for CS and six healthy subjects. MEASUREMENTS: Neurodegenerative CSF markers: total tau, hyperphosphorylated tau, amyloid beta peptides, soluble amyloid precursor protein alpha and beta, neurofilament light proteins, glial fibrillary acidic protein, and monocyte chemoattractant protein 1; and inflammatory CSF markers: interferon gamma, interleukin (IL) 1B, IL2, IL4, IL5, IL8, IL10, IL12p70, IL13, and tumor necrosis factor alpha. RESULTS: The mean age (mean+/-S.D.) was similar in patients with CS in remission (44.9+/-14 years) and healthy subjects (42.3+/-15.7 years; P=0.726). No differences were observed in the concentrations of any neurodegenerative biomarkers between the patients and healthy subjects. Nor were the concentrations of inflammatory biomarkers different between the groups. CONCLUSIONS: The pattern of neurodegenerative and inflammatory biomarkers in the CSF of patients with CS in remission does not differ from that of the healthy subjects. The underlying mechanisms of the cognitive deficits in patients with CS in remission are different from those observed in patients with neurodegenerative disorders and remain to be explained. PMID- 23733372 TI - Hyperglycemia associated with pasireotide: results from a mechanistic study in healthy volunteers. AB - CONTEXT: Pasireotide (SOM230) is a somatostatin analog with affinity for somatostatin receptor subtypes sst1-3 and sst5. Clinical trials have demonstrated the efficacy of pasireotide in treating Cushing's disease and acromegaly but have also shown adverse effects on glucose metabolism. OBJECTIVE: The aim of the study was to evaluate the mechanism of pasireotide-associated hyperglycemia. DESIGN: We conducted a randomized, single-center, open-label study. SUBJECTS AND INTERVENTION: Forty-five healthy male volunteers were randomized to pasireotide 600 (n = 19), 900 (n = 19), or 1200 MUg (n = 7) sc twice a day for 7 days. Randomization to 1200 MUg was discontinued because of increased severity of gastrointestinal adverse events in this arm. An oral glucose tolerance test (OGTT), a hyperglycemic clamp test, and a hyperinsulinemic-euglycemic clamp test were performed on 3 consecutive days at baseline and treatment end. MAIN OUTCOME MEASURE: The effect of pasireotide on insulin secretion and hepatic/peripheral insulin sensitivity was measured. The secondary objective was to evaluate the effects of pasireotide on oral glucose absorption. RESULTS: Pasireotide treatment resulted in significant decreases in insulin AUC0-180 min during both the hyperglycemic clamp test (-77.5%; P < .001 in both dose groups) and the OGTT ( 61.9%; P < .001 in both dose groups). Suppression of glucagon levels was less pronounced. No significant changes in hepatic or peripheral insulin sensitivity were found during the hyperinsulinemic-euglycemic clamp test. Additionally, significant increases in glucose AUC0-180 min (+67.4%) and decreases in AUC0-180 min glucagon-like peptide-1 (-46.7%) and glucose-dependent insulinotropic polypeptide levels (-69.8%) were observed during the OGTT. No dose dependency or unexpected adverse events were observed. CONCLUSIONS: Pasireotide-associated hyperglycemia is related to decreases in insulin secretion and incretin hormone responses, without changes in hepatic/peripheral insulin sensitivity. PMID- 23733373 TI - Back attack. PMID- 23733374 TI - Economic analyses of the Be Fit Be Well program: a weight loss program for community health centers. AB - BACKGROUND: The U.S. Preventive Services Task Force has released new guidelines on obesity, urging primary care physicians to provide obese patients with intensive, multi-component behavioral interventions. However, there are few studies of weight loss in real world nonacademic primary care, and even fewer in largely racial/ethnic minority, low-income samples. OBJECTIVE: To evaluate the recruitment, intervention and replications costs of a 2-year, moderate intensity weight loss and blood pressure control intervention. DESIGN: A comprehensive cost analysis was conducted, associated with a weight loss and hypertension management program delivered in three community health centers as part of a pragmatic randomized trial. PARTICIPANTS: Three hundred and sixty-five high risk, low income, inner city, minority (71 % were Black/African American and 13 % were Hispanic) patients who were both hypertensive and obese. MAIN MEASURES: Measures included total recruitment costs and intervention costs, cost per participant, and incremental costs per unit reduction in weight and blood pressure. KEY RESULTS: Recruitment and intervention costs were estimated $2,359 per participant for the 2-year program. Compared to the control intervention, the cost per additional kilogram lost was $2,204 /kg, and for blood pressure, $621 /mmHg. Sensitivity analyses suggest that if the program was offered to a larger sample and minor modifications were made, the cost per participant could be reduced to the levels of many commercially available products. CONCLUSIONS: The costs associated with the Be Fit Be Well program were found to be significantly more expensive than many commercially available products, and much higher than the amount that the Centers for Medicare and Medicaid reimburse physicians for obesity counseling. However, given the serious and costly health consequences associated with obesity in high risk, multimorbid and socioeconomically disadvantaged patients, the resources needed to provide interventions like those described here may still prove to be cost-effective with respect to producing long-term behavior change. PMID- 23733375 TI - Overcoming roadblocks: current and emerging reimbursement strategies for integrated mental health services in primary care. AB - The Chronic Care Model (CCM) has been shown to improve medical and psychiatric outcomes for persons with mental disorders in primary care settings, and has been proposed as a model to integrate mental health care in the patient-centered medical home under healthcare reform. However, the CCM has not been widely implemented in primary care settings, primarily because of a lack of a comprehensive reimbursement strategy to compensate providers for day-to-day provision of its core components, including care management and provider decision support. Drawing upon the existing literature and regulatory guidelines, we provide a critical analysis of challenges and opportunities in reimbursing CCM components under the current fee-for-service system, and describe an emerging financial model involving bundled payments to support core CCM components to integrate mental health treatment into primary care settings. Ultimately, for the CCM to be used and sustained over time to integrate physical and mental health care, effective reimbursement models will need to be negotiated across payers and providers. Such payments should provide sufficient support for primary care providers to implement practice redesigns around core CCM components, including care management, measurement-based care, and mental health specialist consultation. PMID- 23733376 TI - Inhibitory effects of hypoxia on metabolic switch and osteogenic differentiation of human mesenchymal stem cells. AB - We previously demonstrated that metabolic switch and mitochondrial activation are required for osteogenic differentiation of human mesenchymal stem cells (hMSCs). However, stem cells in niches or transplanted into injured tissues constantly encounter hypoxic stress that hinders aerobic metabolism. Therefore, we investigated the effects of oxygen tension (1% vs. 21%) on metabolism and osteogenic differentiation of hMSCs. We found that hypoxia impaired osteogenic differentiation as indicated by attenuation of alkaline phosphatase activity and expression of osteogenic markers core binding factor a-1 and osteopontin. In addition, differentiation-induced mitochondrial activation was compromised as shown by the decrease in the expression of respiratory enzymes and oxygen consumption rate. On the contrary, anaerobic metabolism was augmented as revealed by the upregulation of glycolytic enzymes and increase of lactate production, rendering the cells to rely more on anaerobic glycolysis for energy supply. Moreover, administration of 2-deoxyglucose (a glycolytic inhibitor) but not antimycin A (a respiratory inhibitor) significantly decreased intracellular ATP levels of hMSCs differentiating under hypoxia. Treatment with cobalt chloride, a hypoxia-inducible factor-1alpha (HIF-1alpha) stabilizer, recapitulated the inhibitory effects of hypoxia, suggesting that HIF-1alpha is involved in the compromise of hMSCs differentiation. These results suggest that hypoxia inhibits metabolic switch and mitochondrial function and therefore suppresses osteogenic differentiation of hMSCs. PMID- 23733377 TI - An electron-precise, tetrahedral MU3 boride complex. PMID- 23733378 TI - Detection of intracellular bacterial communities in a child with Escherichia coli recurrent urinary tract infections. AB - The formation of intracellular bacterial communities (IBC) has been proposed as a new pathogenic model for urinary tract infections. Scarce reports describe this phenomenon in humans. We describe the presence of IBC in uroepithelial cells of a child with recurrent urinary infections. Urine specimen was collected from a child with Escherichia coli UTI and analyzed by light and confocal laser scanning microscopy (CLSM). The capability of this strain to produce intracellular infection in bladder tissue was confirmed in mice models. Escherichia coli phylogenetic group, presence of virulence factors genes, and its multiple locus sequence type were determined. CLSM showed large collections of morphologically coccoid and rod bacteria in eukaryotic cells cytoplasm, even seemingly protruding from the cells. Escherichia coli EC7U, ST3626, harbored type 1, P, and S/F1C fimbriae and K1 capsule genes. In this report, we confirm the presence of IBC in children with UTI, as it has been described before in women. PMID- 23733380 TI - Primary-tertiary diamine/Bronsted acid catalyzed C-C coupling between para vinylanilines and aldehydes. PMID- 23733379 TI - Factors associated with discontinuation of bupropion and counseling among African American light smokers in a randomized clinical trial. AB - BACKGROUND: African Americans are at risk of inadequate adherence to smoking cessation treatment, yet little is known about what leads to treatment discontinuation. PURPOSE: The purpose of this study was to examine the factors associated with discontinuation of treatment in African American light smokers (<=10 cigarettes per day). METHODS: Bupropion plasma levels and counseling attendance were measured among 540 African American light smokers in a placebo controlled randomized trial of bupropion. RESULTS: By week 3, 28.0 % of subjects in the bupropion arm had discontinued bupropion, and only moderate associations were found between the plasma levels and self-reported bupropion use (r s = 0.38). By week 16, 36.9 % of all subjects had discontinued counseling. Males had greater odds of discontinuing medication (OR = 2.02, 95% CI = 1.10-3.71, p = 0.02), and older adults had lower odds of discontinuing counseling (OR = 0.96, 95% CI = 0.94-0.97, p < 0.0001). CONCLUSIONS: Bupropion and smoking cessation counseling are underutilized even when provided within the context of a randomized trial. Future research is needed to examine strategies for improving treatment utilization among African American smokers. PMID- 23733381 TI - Antibiotics for the common cold and acute purulent rhinitis. AB - BACKGROUND: It has long been believed that antibiotics have no role in the treatment of common colds yet they are often prescribed in the belief that they may prevent secondary bacterial infections. OBJECTIVES: To determine the efficacy of antibiotics compared with placebo for reducing general and specific nasopharyngeal symptoms of acute upper respiratory tract infections (URTIs) (common colds).To determine if antibiotics have any influence on the outcomes for acute purulent rhinitis and acute clear rhinitis lasting less than 10 days before the intervention.To determine whether there are significant adverse outcomes associated with antibiotic therapy for participants with a clinical diagnosis of acute URTI or acute purulent rhinitis. SEARCH METHODS: For this 2013 update we searched CENTRAL 2013, Issue 1, MEDLINE (March 2005 to February week 2, 2013), EMBASE (January 2010 to February 2013), CINAHL (2005 to February 2013), LILACS (2005 to February 2013) and Biosis Previews (2005 to February 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any antibiotic therapy against placebo in people with symptoms of acute upper respiratory tract infection for less than seven days, or acute purulent rhinitis less than 10 days in duration. DATA COLLECTION AND ANALYSIS: Both review authors independently assessed trial quality and extracted data. MAIN RESULTS: This updated review included 11 studies. Six studies contributed to one or more analyses related to the common cold, with up to 1047 participants. Five studies contributed to one or more analyses relating to purulent rhinitis, with up to 791 participants. One study contributed only to data on adverse events and one met the inclusion criteria but reported only summary statistics without providing any numerical data that could be included in the meta-analyses. Interpretation of the combined data is limited because some studies included only children, or only adults, or only males; a wide range of antibiotics were used and outcomes were measured in different ways. There was a moderate risk of bias because of unreported methods details or because an unknown number of participants were likely to have chest or sinus infections.Participants receiving antibiotics for the common cold did no better in terms of lack of cure or persistence of symptoms than those on placebo (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.59 to 1.51, (random effects)), based on a pooled analysis of six trials with a total of 1047 participants. The RR of adverse effects in the antibiotic group was 1.8, 95% CI 1.01 to 3.21, (random-effects). Adult participants had a significantly greater risk of adverse effects with antibiotics than with placebo (RR 2.62, 95% CI 1.32 to 5.18) (random-effects) while there was no greater risk in children (RR 0.91, 95% CI 0.51 to 1.63).The pooled RR for persisting acute purulent rhinitis with antibiotics compared to placebo was 0.73 (95% CI 0.47 to 1.13) (random-effects), based on four studies with 723 participants. There was an increase in adverse effects in the studies of antibiotics for acute purulent rhinitis (RR 1.46, 95% CI 1.10 to 1.94). AUTHORS' CONCLUSIONS: There is no evidence of benefit from antibiotics for the common cold or for persisting acute purulent rhinitis in children or adults. There is evidence that antibiotics cause significant adverse effects in adults when given for the common cold and in all ages when given for acute purulent rhinitis. Routine use of antibiotics for these conditions is not recommended. PMID- 23733382 TI - Heated, humidified air for the common cold. AB - BACKGROUND: Heated, humidified air has long been used by sufferers of the common cold. The theoretical basis is that steam may help congested mucus drain better and heat may destroy the cold virus as it does in vitro. OBJECTIVES: To assess the effects of inhaling heated water vapour (steam) in the treatment of the common cold by comparing symptoms, viral shedding and nasal resistance. SEARCH METHODS: In this updated review we searched CENTRAL 2013, Issue 2, MEDLINE (1966 to February week 4, 2013), EMBASE (1990 to March 2013) and Current Contents (1994 to March 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) using heated water vapour in participants with the common cold or participants with experimentally induced common cold. DATA COLLECTION AND ANALYSIS: The two review authors independently reviewed all retrieved articles and excluded any articles, editorials and abstracts with inadequate outcome descriptions. The studies we included were subjected to a methodological assessment. MAIN RESULTS: We included six trials (394 trial participants). Three trials in which patient data could be pooled found benefits of steam for symptom relief for the common cold (odds ratio (OR) 0.31; 95% confidence interval (CI) 0.16 to 0.60). However, results on symptom indices were equivocal. No studies demonstrated an exacerbation of clinical symptom scores. One study conducted in the USA demonstrated worsened nasal resistance, while an earlier Israeli study showed improvement. One study examined viral shedding and antibody titres in nasal washings; there was no change in either between treatment and placebo groups. Minor side effects (including discomfort or irritation of the nose) were reported in some studies. AUTHORS' CONCLUSIONS: Steam inhalation has not shown any consistent benefits in the treatment of the common cold, hence is not recommended in the routine treatment of common cold symptoms until more double-blind, randomised trials with a standardised treatment modality are conducted. PMID- 23733383 TI - Glucocorticoids for acute viral bronchiolitis in infants and young children. AB - BACKGROUND: Previous systematic reviews have not shown clear benefit of glucocorticoids for acute viral bronchiolitis, but their use remains considerable. Recent large trials add substantially to current evidence and suggest novel glucocorticoid-including treatment approaches. OBJECTIVES: To review the efficacy and safety of systemic and inhaled glucocorticoids in children with acute viral bronchiolitis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2012, Issue 12), MEDLINE (1950 to January week 2, 2013), EMBASE (1980 to January 2013), LILACS (1982 to January 2013), Scopus(r) (1823 to January 2013) and IRAN MedEx (1998 to November 2009). SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing short-term systemic or inhaled glucocorticoids versus placebo or another intervention in children under 24 months with acute bronchiolitis (first episode with wheezing). Our primary outcomes were: admissions by days 1 and 7 for outpatient studies; and length of stay (LOS) for inpatient studies. Secondary outcomes included clinical severity parameters, healthcare use, pulmonary function, symptoms, quality of life and harms. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data on study and participant characteristics, interventions and outcomes. We assessed risk of bias and graded strength of evidence. We meta-analysed inpatient and outpatient results separately using random-effects models. We pre-specified subgroup analyses, including the combined use of bronchodilators used in a protocol. MAIN RESULTS: We included 17 trials (2596 participants); three had low overall risk of bias. Baseline severity, glucocorticoid schemes, comparators and outcomes were heterogeneous. Glucocorticoids did not significantly reduce outpatient admissions by days 1 and 7 when compared to placebo (pooled risk ratios (RRs) 0.92; 95% confidence interval (CI) 0.78 to 1.08 and 0.86; 95% CI 0.7 to 1.06, respectively). There was no benefit in LOS for inpatients (mean difference -0.18 days; 95% CI -0.39 to 0.04). Unadjusted results from a large factorial low risk of bias RCT found combined high-dose systemic dexamethasone and inhaled epinephrine reduced admissions by day 7 (baseline risk of admission 26%; RR 0.65; 95% CI 0.44 to 0.95; number needed to treat 11; 95% CI 7 to 76), with no differences in short-term adverse effects. No other comparisons showed relevant differences in primary outcomes. AUTHORS' CONCLUSIONS: Current evidence does not support a clinically relevant effect of systemic or inhaled glucocorticoids on admissions or length of hospitalisation. Combined dexamethasone and epinephrine may reduce outpatient admissions, but results are exploratory and safety data limited. Future research should further assess the efficacy, harms and applicability of combined therapy. PMID- 23733384 TI - Non-steroidal anti-inflammatory drugs for the common cold. AB - BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used for the treatment of pain and fever associated with the common cold. However, there is no systematic review to assess the effects of NSAIDs in treating the common cold. OBJECTIVES: To determine the effects of NSAIDs versus placebo (and other treatments) on signs and symptoms of the common cold, and to determine any adverse effects of NSAIDs in people with the common cold. SEARCH METHODS: We searched CENTRAL (The Cochrane Library 2013, Issue 1), MEDLINE (January 1966 to April week 4, 2013), EMBASE (January 1980 to April 2013), CINAHL (January 1982 to April 2013) and ProQuest Digital Dissertations (January 1938 to April 2013). SELECTION CRITERIA: Randomised controlled trials (RCTs) of NSAIDS in adults or children with the common cold. DATA COLLECTION AND ANALYSIS: Four review authors extracted data. We subdivided trials into placebo-controlled RCTs and head-to head comparisons of NSAIDs. We extracted and summarised data on global efficacies of analgesic effects (such as reduction of headache and myalgia), non-analgesic effects (such as reduction of nasal symptoms, cough, sputum and sneezing) and side effects. We expressed dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI) and continuous data as mean differences (MD) or standardised mean differences (SMD). We pooled data using the fixed- and random effects models. MAIN RESULTS: We included nine RCTs with 1069 participants, describing 37 comparisons: six were NSAIDs versus placebo and three were NSAIDs versus NSAIDs. The overall risk of bias in the included studies was mixed. In a pooled analysis, NSAIDs did not significantly reduce the total symptom score (SMD -0.40, 95% CI -1.03 to 0.24, three studies, random-effects model), or duration of colds (MD -0.23, 95% CI -1.75 to 1.29, two studies, random-effects model). For respiratory symptoms, cough did not improve (SMD -0.05, 95% CI -0.66 to 0.56, two studies, random-effects model) but the sneezing score significantly improved (SMD -0.44, 95% CI -0.75 to -0.12, two studies, random-effects model). For outcomes related to the analgesic effects of NSAIDs (headache, ear pain, and muscle and joint pain) the treatment produced significant benefits. The risk of adverse effects was not high with NSAIDs (RR 2.94, 95% CI 0.51 to 17.03, two studies, random-effects model) and it is difficult to conclude that such drugs are not different from placebo. AUTHORS' CONCLUSIONS: NSAIDs are somewhat effective in relieving discomfort caused by a cold but there is no clear evidence of their effect in easing respiratory symptoms. The balance of benefit and harms needs to be considered when using NSAIDs for colds. PMID- 23733385 TI - Singular and plural pronominal reference in Spanish. AB - In two self-paced, sentence-by-sentence reading experiments, we examined the difference in the processing of Spanish discourses containing overt and null pronouns. In both experiments, antecedents appeared in a single phrase (John met Mary) or in a conjoined phrase (John and Mary met). In Experiment 1, we compared reading times of sentences containing singular overt and null pronouns referring to the first or to the second mentioned antecedent. Overt pronouns caused a processing delay relative to null pronouns when they referred to the first antecedent in single but not in conjoined phrases. In Experiment 2, we compared reading times of sentences containing overt and null pronouns referring to singular or plural entities. Plural null pronouns were read faster than their singular counterparts in conjoined conditions. Plural overt pronouns were read more slowly than their null counterparts both in single and conjoined conditions. We explain our findings in a framework based on the notion of balance between processing cost and discourse function in line with the Informational Load Hypothesis. PMID- 23733386 TI - Socioeconomic status and parent-child relationships predict metacognitive questions to preschoolers. AB - The importance of metacognitive language exposure to early educational achievement is widely recognized in the development literature. However, few studies have explored parents' metacognitive language, while accounting for family SES and stress within the parent-child relationship. This is a preliminary descriptive study to explore metacognitive language to preschoolers during a collaborative task, and explored family SES (parent education and occupation) and stress within the parent-child relationship as predictors. Using partial correlations controlling for child age and language ability, parent education, occupation, and stress associated with parent-child dysfunctional interaction were found to significantly correlate with parents' metacognitive questions. A hierarchical regression (controlling for child age and language ability) indicated that only parent education levels uniquely predicted questions overall. PMID- 23733387 TI - Prolonged ventilatory failure and flaccid quadriparesis after ingestion of poison hemlock. AB - INTRODUCTION: A 28-year-old man presented with acute flaccid paralysis and respiratory failure that persisted for 2 weeks after suicidal ingestion of unknown substances. METHODS: Extensive clinical, nerve, laboratory, and neuroimaging testing excluded alternative causes of this neuromuscular syndrome. Prompted by clues provided by family members, liquid chromatography time-of flight mass spectrometry was used to investigate for the presence of poison hemlock. RESULTS: Testing of the residue in a jar used for the ingestion of a poisonous concoction confirmed the presence of the nicotinic alkaloid coniine. Analysis of patient serum suggested the presence of conhydrine. Concentrations of amitriptyline and diazepam were also found to be supratherapeutic, but only through the first few days of hospitalization. CONCLUSIONS: Herein we describe a case of reversible coma, flaccid quadriparesis, and neuromuscular respiratory failure caused by intentional ingestion of poison hemlock. PMID- 23733388 TI - Inhibition of Leishmania infantum trypanothione reductase by azole-based compounds: a comparative analysis with its physiological substrate by X-ray crystallography. AB - Herein we report a study aimed at discovering a new class of compounds that are able to inhibit Leishmania donovani cell growth. Evaluation of an in-house library of compounds in a whole-cell screening assay highlighted 4-((1-(4 ethylphenyl)-2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-3 yl)methyl)thiomorpholine (compound 1) as the most active. Enzymatic assays on Leishmania infantum trypanothione reductase (LiTR, belonging to the Leishmania donovani complex) shed light on both the interaction with, and the nature of inhibition by, compound 1. A molecular modeling approach based on docking studies and on the estimation of the binding free energy aided our rationalization of the biological data. Moreover, X-ray crystal structure determination of LiTR in complex with compound 1 confirmed all our results: compound 1 binds to the T(SH)2 binding site, lined by hydrophobic residues such as Trp21 and Met113, as well as residues Glu18 and Tyr110. Analysis of the structure of LiTR in complex with trypanothione shows that Glu18 and Tyr110 are also involved in substrate binding, according to a competitive inhibition mechanism. PMID- 23733389 TI - The effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin, a novel sodium glucose co-transporter 2 (SGLT2) inhibitor. AB - BACKGROUND: Ipragliflozin (ASP1941), a potent selective sodium glucose co transporter 2 inhibitor, is in development for the treatment of type 2 diabetes mellitus. Ipragliflozin is primarily eliminated via conjugation by the liver as five pharmacologically inactive metabolites (M1, M2, M3, M4 and M6). This study evaluated the effect of moderate hepatic impairment on the pharmacokinetics of ipragliflozin and its metabolites. METHODS: In an open-label, single-dose, parallel-group study, 16 subjects (eight with moderate hepatic impairment [Child Pugh score 7-9] and eight healthy, matched controls) received a single oral dose of 100-mg ipragliflozin. Plasma concentrations of ipragliflozin and its metabolites were determined. Adverse events (AEs) and other clinical laboratory parameters were monitored. RESULTS: All subjects completed the study. Least squares geometric mean ratios (GMRs) (90 % confidence interval [CI]) for maximum plasma concentration (C max) and area under the plasma concentration-time curve from time zero to infinity (AUCinfinity) of ipragliflozin were 127 % (93-173 %) and 125 % (94-166 %), respectively, in moderate hepatic impairment versus controls. No changes in elimination half-life and protein binding of ipragliflozin were observed in moderate hepatic impairment subjects. Least squares GMRs for C max and AUCinfinity of M2, the major metabolite, were respectively 95 % (68-133 %) and 100 % (77-130 %) in moderate hepatic impairment versus controls. No deaths, other serious AEs or AEs leading to discontinuation occurred. CONCLUSIONS: Moderate hepatic impairment had no clinically relevant effects on the single-dose pharmacokinetics of ipragliflozin and its major metabolite, M2. A single oral dose of ipragliflozin, 100 mg, was well tolerated in both healthy subjects and those with moderate hepatic impairment. PMID- 23733390 TI - Sleeve gastrectomy in the elderly: a safe and effective procedure with minimal morbidity and mortality. AB - BACKGROUND: Previously, we demonstrated the safety and efficacy of laparoscopic gastric bypass surgery in patients over 65 years of age. The aim of this study is to demonstrate the safety and efficacy of this procedure as a final step for treatment of morbid obesity in the same population. METHODS: A retrospective review of a prospectively collected database was performed. Between 2004 and 2010, a total of 35 patients age 60 and greater were analyzed from a total of 512 sleeve gastrectomy patients. Demographics, preoperative body mass index, complications, and excess weight loss were recorded and compared to bougie size and follow-up in months. Mean age was 66.3 years (range, 60-79 years), mean body mass index was 46.3 kg/m(2) (range, 33.7-77.6 kg/m(2)), and mean excess weight loss was 148.49 lb (range, 72-252 lb). RESULTS: One patient (2.8 %) had an incidental colotomy as a result of trocar insertion, one patient (2.0 %) bled, and one patient (2.8 %) had small-bowel enterotomy. Overall, morbidity was 8.4 % with no mortality. Mean percent excess weight loss results for bougie size 52 were 28, 34, 26, 18, and 27 % at 3, 6, 12, 24 and 48 months, respectively; for bougie size 46 were 31, 57, 64, 62, and 82 % at 3, 6, 12, 24 and 48 months, respectively; and bougie size 38 were 37, 50, 55, and 56 % at 3, 6, 12 and 24 months, respectively. CONCLUSIONS: Laparoscopic sleeve gastrectomy is an effective procedure for morbidly obese patients age 60 and greater that can be performed safely. PMID- 23733391 TI - PDGF signaling is required for primitive endoderm cell survival in the inner cell mass of the mouse blastocyst. AB - At the end of the preimplantation period, the inner cell mass (ICM) of the mouse blastocyst is composed of two distinct cell lineages, the pluripotent epiblast (EPI) and the primitive endoderm (PrE). The current model for their formation involves initial co-expression of lineage-specific markers followed by mutual exclusive expression resulting in a salt-and-pepper distribution of lineage precursors within the ICM. Subsequent to lineage commitment, cell rearrangements and selective apoptosis are thought to be key processes driving and refining the emergence of two spatially distinct compartments. Here, we have addressed a role for Platelet Derived Growth Factor (PDGF) signaling in the regulation of programmed cell death during early mouse embryonic development. By combining genetic and pharmacological approaches, we demonstrate that embryos lacking PDGF activity exhibited caspase-dependent selective apoptosis of PrE cells. Modulating PDGF activity did not affect lineage commitment or cell sorting, suggesting that PDGF is involved in the fine-tuning of patterning information. Our results also indicate that PDGF and fibroblast growth factor (FGF) tyrosine kinase receptors exert distinct and non-overlapping functions in PrE formation. Taken together, these data uncover an early role of PDGF signaling in PrE cell survival at the time when PrE and EPI cells are segregated. PMID- 23733393 TI - Effect of glucose concentration on peripheral nerve and its response to anoxia. AB - INTRODUCTION: Glucose has a significant effect on nerve function. METHODS: The effects of glucose on the nerve action potential (NAP) were investigated for concentrations between 0 and 55.5 mmol/L in an in vitro system using rat sciatic nerve. The effects of glucose were investigated in nerves exposed to oxygenated perfusate and those subjected to anoxia. Multiple aspects of the NAP were analyzed. RESULTS: Hypoglycemia produces immediate reductions in NAP amplitude and velocity, whereas hyperglycemia has the opposite effect in the short term. Over a 12-hour experiment, the amplitude of the NAP remained stable for glucose concentrations in the range 2.8-5.6 mmol/L, but, when the glucose concentration was <2.8 mmol/L or >27.8 mmol/L, the amplitude of the NAP declined. The deleterious effects of hyperglycemia (>=27.8 mmol/L) or hypoglycemia (<4.2 mmol/L) were more pronounced in nerves exposed to intermittent anoxia. CONCLUSIONS: This findings confirm the importance of glucose concentration for nerve function especially during anoxia. PMID- 23733394 TI - Guanidine hydrochloride denaturation of dopamine-induced alpha-synuclein oligomers: a small-angle X-ray scattering study. AB - Alpha-synuclein (alpha-syn) forms the amyloid-containing Lewy bodies found in the brain in Parkinson's disease. The neurotransmitter dopamine (DA) reacts with alpha-syn to form SDS-resistant soluble, non-amyloid, and melanin-containing oligomers. Their toxicity is debated, as is the nature of their structure and their relation to amyloid-forming conformers of alpha-syn. The small-angle X-ray scattering technique in combination with modeling by the ensemble optimization method showed that the un-reacted native protein populated three broad classes of conformer, while reaction with DA gave a restricted ensemble range suggesting that the rigid melanin molecule played an important part in their structure. We found that 6 M guanidine hydrochloride did not dissociate alpha-syn DA-reacted dimers and trimers, suggesting covalent linkages. The pathological significance of covalent association is that if they are non-toxic, the oligomers would act as a sink for toxic excess DA and alpha-syn; if toxic, their stability could enhance their toxicity. We argue it is essential, therefore, to resolve the question of whether they are toxic or not. PMID- 23733395 TI - Assembly of {Mn2(salen)2}2+ dimers by cyclic V4O12(4-) clusters: a 3D compound with open-framework structure exhibiting slow magnetization relaxation. PMID- 23733397 TI - Bias in randomised factorial trials. AB - Factorial trials are an efficient method of assessing multiple treatments in a single trial, saving both time and resources. However, they rely on the assumption of no interaction between treatment arms. Ignoring the possibility of an interaction in the analysis can lead to bias and potentially misleading conclusions. Therefore, it is often recommended that the size of the interaction be assessed during analysis. This approach can be formalised as a two-stage analysis; if the interaction test is not significant, a factorial analysis (where all patients receiving treatment A are compared with all not receiving A, and similarly for treatment B) is performed. If the interaction is significant, the analysis reverts to that of a four-arm trial (where each treatment combination is regarded as a separate treatment arm). We show that estimated treatment effects from the two-stage analysis can be biased, even in the absence of a true interaction. This occurs because the interaction estimate is highly correlated with treatment effect estimates from a four-arm analysis. Simulations show that bias can be severe (over 100% in some cases), leading to inflated type I error rates. Therefore, the two-stage analysis should not be used in factorial trials. A preferable approach may be to design multi-arm trials (i.e. four separate treatment groups) instead. This approach leads to straightforward interpretation of results, is unbiased regardless of the presence of an interaction, and allows investigators to ensure adequate power by basing sample size requirements on a four-arm analysis. PMID- 23733396 TI - Concise review: role of DEK in stem/progenitor cell biology. AB - Understanding the factors that regulate hematopoiesis opens up the possibility of modifying these factors and their actions for clinical benefit. DEK, a non histone nuclear phosphoprotein initially identified as a putative proto-oncogene, has recently been linked to regulate hematopoiesis. DEK has myelosuppressive activity in vitro on proliferation of human and mouse hematopoietic progenitor cells and enhancing activity on engraftment of long-term marrow repopulating mouse stem cells, has been linked in coordinate regulation with the transcription factor C/EBPalpha, for differentiation of myeloid cells, and apparently targets a long-term repopulating hematopoietic stem cell for leukemic transformation. This review covers the uniqueness of DEK, what is known about how it now functions as a nuclear protein and also as a secreted molecule that can act in paracrine fashion, and how it may be regulated in part by dipeptidylpeptidase 4, an enzyme known to truncate and modify a number of proteins involved in activities on hematopoietic cells. Examples are provided of possible future areas of investigation needed to better understand how DEK may be regulated and function as a regulator of hematopoiesis, information possibly translatable to other normal and diseased immature cell systems. PMID- 23733398 TI - Postnatal development of Homer1a in the rat hippocampus. AB - Homer1a (H1a) is an immediate early gene involved in multiple forms of synaptic plasticity. It exhibits a postnatal increase in the rat forebrain (Brakeman et al. (1997) Nature 386:284-288) and reduces the density and size of dendritic spines in hippocampal neurons (Sala et al. (2003) J Neurosci 23:6327-6337). We evaluated hippocampal H1a expression at different postnatal ages (P3, P5, P7, P9, P15, P19, P23, P35, and adult) using Fluorescence In Situ Hybridization (FISH) and qRT-PCR. Maximal electroconvulsive shock (MECS) was used to induce maximal expression relative to home cage (HC) controls. Large scale images and confocal z stacks from dorsal subiculum (DS), CA1, CA3, and dentate gyrus (DG) were analyzed by both manual and automated methods. In DS, CA1, and CA3 a significant proportion of cells (40%) expressed small but detectable levels of H1a from P3; however, MECS did not up-regulate H1a during the first postnatal week. MECS induced H1a positive cells during the second postnatal week and induction reached adult levels at P9. H1a-Intra Nuclear Foci (INF) size and intensity varied with age, increasing at P19-23 in CA1 and CA3 and from P9 to P23 in DS. In DG, H1a expression exhibited a lamination pattern and an H1a-INF size and intensity gradient across the granule cell layer, consistent with the outside-in maturation of DG granule cells. The developmental progression of H1a corresponds to the synaptic refinement period supporting the conclusion that H1a could play an important role in this process. PMID- 23733399 TI - Re: Overweight patients achieve ideal body weight following curative gastrectomy resulting in better long-term prognosis. PMID- 23733400 TI - Reply to "Overweight patients achieve ideal body weight following curative gastrectomy resulting in better long-term prognosis. Letter". PMID- 23733401 TI - Preoperative OSA screening: still an open question. PMID- 23733402 TI - Fundamental interactions in RNA: Questions answered and remaining. AB - Interpreting the tsunami of sequence information for RNA would be facilitated by an understanding of all the physical principles determining RNA structure. In principle, a complete understanding would make it computationally possible to find RNA sequences that fold for function and to predict their three-dimensional structure. It would, thus, also facilitate discovery of new principles relating structure to function. This review covers some of the progress in understanding RNA over roughly the preceding 40 years and suggests progress still to be made. PMID- 23733404 TI - Synthesis of C8-N9 annulated purines by iron-catalyzed C-H amination. PMID- 23733403 TI - The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer's disease taking cholinesterase inhibitors. AB - INTRODUCTION: Immediate-release memantine (10 mg, twice daily) is approved in the USA for moderate-to-severe Alzheimer's disease (AD). This study evaluated the efficacy, safety, and tolerability of a higher-dose, once-daily, extended-release formulation in patients with moderate-to-severe AD concurrently taking cholinesterase inhibitors. METHODS: In this 24-week, double-blind, multinational study (NCT00322153), outpatients with AD (Mini-Mental State Examination scores of 3-14) were randomized to receive once-daily, 28-mg, extended-release memantine or placebo. Co-primary efficacy parameters were the baseline-to-endpoint score change on the Severe Impairment Battery (SIB) and the endpoint score on the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC Plus). The secondary efficacy parameter was the baseline-to-endpoint score change on the 19-item Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL19); additional parameters included the baseline-to-endpoint score changes on the Neuropsychiatric Inventory (NPI) and verbal fluency test. Data were analyzed using a two-way analysis of covariance model, except for CIBIC-Plus (Cochran-Mantel-Haenszel test). Safety and tolerability were assessed through adverse events and physical and laboratory examinations. RESULTS: A total of 677 patients were randomized to receive extended-release memantine (n = 342) or placebo (n = 335); completion rates were 79.8 and 81.2 %, respectively. At endpoint (week 24, last observation carried forward), memantine-treated patients significantly outperformed placebo-treated patients on the SIB (least squares mean difference [95 % CI] 2.6 [1.0, 4.2]; p = 0.001), CIBIC-Plus (p = 0.008), NPI (p = 0.005), and verbal fluency test (p = 0.004); the effect did not achieve significance on ADCS-ADL19 (p = 0.177). Adverse events with a frequency of >=5.0 % that were more prevalent in the memantine group were headache (5.6 vs. 5.1 %) and diarrhea (5.0 vs. 3.9 %). CONCLUSION: Extended-release memantine was efficacious, safe, and well tolerated in this population. PMID- 23733405 TI - Identification of veno-occlusive regions in a right liver graft after reconstruction of vein segments 5 and 8: application of indocyanine green fluorescence imaging. PMID- 23733407 TI - Ischiopagus and diprosopus in India: two pairs of conjoined twins perceived as incarnations of Hindu deities. AB - This article briefly reviews two specific types of conjoined twins, ischiopagus and diprosopus, and discusses recent cases of such twins born in India. Some members of the Hindu community worshiped these conjoined twins as incarnations of Hindu deities. In discussing this phenomenon, the authors aim to elucidate certain features of the faith tradition of Hinduism itself. The reception of these conjoined twins as incarnations of Hindu deities can be understood by examining two salient features of Hindu polytheism: the pictorial depiction of Hindu deities with multiple appendages and the concept of an incarnation, or avatar, of a Hindu deity. PMID- 23733406 TI - Knockdown of aberrantly upregulated aryl hydrocarbon receptor reduces tumor growth and metastasis of MDA-MB-231 human breast cancer cell line. AB - The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that belongs to the basic-helix-loop-helix (bHLH)-Per-ARNT-Sim (PAS) superfamily of transcription factors, mediates toxic response induced by environmental chemicals such as polycyclic aromatic hydrocarbons (PAH). AhR is expressed at high levels in several human breast carcinoma cell lines in direct correlation with the degree of their malignancy. Recent studies suggest a possible role for AhR in cancer independent of PAH. Therefore, we established stable AhR knockdown cells of the human breast cancer cell line MDA-MB-231 and analyzed their tumorigenic properties in in vitro and in vivo model systems. In addition we analyzed their response to radiation and chemotherapeutic treatment. AhR knockdown attenuated these cells tumorigenic properties in vitro including proliferation, anchorage independent growth, migration and apoptosis and reduced orthotopic xenograft tumor growth and lung metastasis in vivo. Notably, we observed that AhR knockdown enhanced radiation-induced apoptosis as well as significantly decreased cell clonogenic survival. Furthermore, AhR knockdown in MDA-MB-231 cells sensitized them to paclitaxel treatment, evident by a decrease in the required cytotoxic dose. Subsequent analysis revealed AhR knockdown significantly reduced phosphorylation of AKT, which impacts cell proliferation and survival. Apoptosis focused gene expression analyses revealed an altered expression of genes regulating apoptosis in MDA-MB-231 cells. Collectively, our data identify AhR as a potential novel therapeutic target in the treatment of metastatic breast cancer. PMID- 23733408 TI - Charity donations in name of UK doctor killed in Syria rise beyond expectations. PMID- 23733409 TI - Pregnant woman in El Salvador whose life was in danger has been allowed a caesarean section. PMID- 23733410 TI - European clinical trials database gathers pace. PMID- 23733411 TI - Current financial pressures are worst ever, say NHS chiefs. PMID- 23733412 TI - Poor catch-up growth in late adolescent boys with eating disorders, weight loss and stunting of growth. AB - OBJECTIVE: The study aims to investigate the catch-up growth of boys presenting with an eating disorder (ED) and a stunting of growth. METHOD: Weight gain and growth of 46 boys with ED were followed up for 1-3 years. RESULTS: A total of 13 boys who had not started their pubertal growth spurt at presentation started catch-up growth immediately following nutritional rehabilitation and weight gain. After 3 years, they had returned to their premorbid growth curve. Thirty-three boys who had started their pubertal growth spurt prior to presentation never caught up in height but continued to catch down despite weight gain. After 3 years, they had lost 0.64 +/- 0.55 height standard deviation scores corresponding to approximately 4.5 cm of potential height. CONCLUSIONS: In prepubertal boys with EDs, catch-up growth is possible. Pubertal boys are at a disadvantage in that catch-up growth may not occur despite weight gain. PMID- 23733413 TI - Photobleaching lifetimes of cyanine fluorophores used for single-molecule Forster resonance energy transfer in the presence of various photoprotection systems. AB - Lengthening smFRET lifetimes: We investigated various photoprotection system combinations to find the combination that optimally extended the photobleach lifetime of a Cy3/Cy5 smFRET pair attached to a DNA hairpin in a single-molecule environment. We found that the glucose/glucose oxygen-scavenging solution in combination with redox-based photostabilization solutions yielded the longest average photobleaching lifetimes. PMID- 23733414 TI - SEM evaluation of the interface between filling and root-end filling materials. AB - The aim of this ex vivo study was to evaluate, by scanning electron microscopy (SEM), the presence of gaps at the interface between filling material and three root-end filling materials. Thirty human upper molars disto-buccal roots were instrumented and filled with gutta-percha and eugenol-based sealer. The apicoectomy was performed 2 mm from the apex and retrograde cavities were prepared with ultrasonic points (3 mm in deep). The samples were divided into three experimental groups (n = 10): Group I-white mineral trioxide aggregate (MTA); Group II-Super EBA; and Group III-Portland cement. The root-end filling materials were inserted into the retocavities using a MTA carrier. After 48 h, the roots were transversally sectioned in order to obtain the apical 5 mm. Next, each specimen was prepared longitudinally with crescent granulation of abrasives water-wet sandpapers in order to expose the filling and root-end filling materials. Then, the specimens were subjected to slow dehydration with silica gel, mounted onto specific stubs and coated with paladium coverage for SEM analysis of the interface between filling and root-end filling materials. The percentage of gaps at the interfacial area was calculated by using Image Tool 3.0 software. Super EBA presented the higher percentage of gaps (1.5 +/- 0.67%), whereas MTA presented the lowest values (0.33 +/- 0.20%; p = 0.0004). Despite the statistical differences observed between Super EBA and MTA, all the root-end filling materials presented great adaptation to the filling material, presenting small amount of gaps. PMID- 23733415 TI - Different input and output properties characterize parvalbumin-positive basket and Axo-axonic cells in the hippocampal CA3 subfield. AB - In the hippocampus, parvalbumin-expressing basket (BC) and axo-axonic cells (AAC) show different discharge patterns during distinct network states, but the cellular mechanisms underlying these differences are not well understood. Using whole-cell patch-clamp techniques, we investigated the single-cell properties and excitatory synaptic features of anatomically identified BCs and AACs in the CA3 region of mouse hippocampal slices. The results showed that BCs had lower threshold for action potential (AP) generation and lower input resistance, narrower AP and afterhyperpolarization than AACs. In addition, BCs fired with higher frequencies and with more modest accommodation compared with AACs. The kinetic properties of excitatory postsynaptic currents (EPSC), the rectification of AMPA receptor-mediated currents, the fraction of the NMDA receptor-mediated component in EPSCs, and the EPSC magnitude necessary to evoke an AP were similar in both cell types. However, smaller excitatory postsynaptic potential and lower intensity fiber stimulation in stratum oriens was necessary to drive firing in BCs. Moreover, the rate of spontaneous EPSCs in BCs was higher than in AACs. Neurolucida analysis revealed that the dendrites of BCs in strata radiatum and oriens were longer and more extensively ramified. Since the density of the excitatory synapses was estimated to be comparable in both cell types, we conclude that the more elaborated dendritic arbor of BCs ensures that they receive a larger number of proximal excitatory inputs. Thus, CA3 pyramidal cells more profoundly innervate BCs than AACs, which could explain, at least in part, their distinct spiking behavior under different hippocampal network activities. PMID- 23733416 TI - A simple fabrication of interconnected CuO nanotube electrodes for high performance lithium-ion batteries. AB - Staying connected: Robust and interconnected CuO nanotube anodes were fabricated by a thermal oxidation process of spin-coated CuO nanowire networks. The CuO electrodes strongly adhered to the stainless steel foils and exhibited a high specific capacity (ca. 635 mAh g(-1)), a stable cycling (capacity retention of >99 % after 50 cycles), and excellent rate capabilities (315 mAh g(-1) at 20 C rate). PMID- 23733417 TI - Structural and thermodynamic folding characterization of triosephosphate isomerases from Trichomonas vaginalis reveals the role of destabilizing mutations following gene duplication. AB - We report the structures and thermodynamic analysis of the unfolding of two triosephosphate isomerases (TvTIM1 and TvTIM2) from Trichomonas vaginalis. Both isoforms differ by the character of four amino acids: E/Q 18, I/V 24, I/V 45, and P/A 239. Despite the high sequence and structural similarities between both isoforms, they display substantial differences in their stabilities. TvTIM1 (E18, I24, I45, and P239) is more stable and less dissociable than TvTIM2 (Q18, V24, V45, and A239). We postulate that the identities of residues 24 and 45 are responsible for the differences in monomer stability and dimer dissociability, respectively. The structural difference between both amino acids is one methyl group. In TvTIMs, residue 24 is involved in packing alpha-helix 1 against alpha helix 2 of each monomer and residue 45 is located at the center of the dimer interface forming a "ball and socket" interplay with a hydrophobic cavity. The mutation of valine at position 45 for an alanine in TvTIM2 produces a protein that migrates as a monomer by gel filtration. A comparison with known TIM structures indicates that this kind of interplay is a conserved feature that stabilizes dimeric TIM structures. In addition, TvTIMs are located in the cytoplasm and in the membrane. As TvTIM2 is an easily dissociable dimer, the dual localization of TvTIMs may be related to the acquisition of a moonlighting activity of monomeric TvTIM2. To our knowledge, this is the simplest example of how a single amino acid substitution can provide alternative function to a TIM barrel protein. PMID- 23733418 TI - Vertical bone augmentation procedures: basics and techniques in dental implantology. AB - An appropriate bony situation is essential for dental implant placement and bony support of soft tissues (pink esthetic). Loss of teeth often results in complex horizontal and vertical alveolar ridge defects. They demand advanced bone augmentation techniques for reconstruction. We present the different techniques and materials used in complex bone augmentation. Clinical cases show the application of the methods in the clinical setting. We present current techniques and materials used in complex bone augmentations. Clinical cases show the application of the methods in the clinical setting. Applied techniques include stabilized-guided bone regeneration (GBR), autologous local block augmentation, modified techniques such as Gellrich shell technique including piezosurgery, pelvic bone blocks, complex materials such as graft-derived bone blocks and their unique handling problems. Successful basic principles are reduction of cortical bone healing due to long remodeling time and possible late loss; extended application of materials with interconnecting porous system and particulate material resulting in fast healing analogous to cancellous bone; mechanical stabilization of the augmentation to allow bony healing in vertical defect situations. GBR and autologous bone blocks with minimal cortical thickness and a high volume of particulated material are most favorable techniques. PMID- 23733420 TI - SAR study and conformational analysis of a series of novel peptide G protein coupled receptor kinase 2 inhibitors. AB - G protein-coupled receptor kinase 2 (GRK2) plays a central role in the cellular transduction network. In particular, during chronic heart failure GRK2 is upregulated and believed to contribute to disease progression. Thereby, its inhibition offers a potential therapeutic solution to several pathological conditions. In the present study, we performed a SAR study and a NMR conformational analysis of peptides derived from HJ loop of GRK2 and able to selectively inhibit GRK2. From Ala-scan and D-Ala point replacement, we found that Arg residues don't affect the inhibitory properties, while a D-amino acid at position 5 is key to the activity. Conformational analysis identified two beta turns that involve N-terminal residues, followed by a short extended region. These information can help the design of peptides and peptido-mimetics with enhanced GRK2 inhibition properties. PMID- 23733419 TI - Identifying the odds ratio estimated by a two-stage instrumental variable analysis with a logistic regression model. AB - An adjustment for an uncorrelated covariate in a logistic regression changes the true value of an odds ratio for a unit increase in a risk factor. Even when there is no variation due to covariates, the odds ratio for a unit increase in a risk factor also depends on the distribution of the risk factor. We can use an instrumental variable to consistently estimate a causal effect in the presence of arbitrary confounding. With a logistic outcome model, we show that the simple ratio or two-stage instrumental variable estimate is consistent for the odds ratio of an increase in the population distribution of the risk factor equal to the change due to a unit increase in the instrument divided by the average change in the risk factor due to the increase in the instrument. This odds ratio is conditional within the strata of the instrumental variable, but marginal across all other covariates, and is averaged across the population distribution of the risk factor. Where the proportion of variance in the risk factor explained by the instrument is small, this is similar to the odds ratio from a RCT without adjustment for any covariates, where the intervention corresponds to the effect of a change in the population distribution of the risk factor. This implies that the ratio or two-stage instrumental variable method is not biased, as has been suggested, but estimates a different quantity to the conditional odds ratio from an adjusted multiple regression, a quantity that has arguably more relevance to an epidemiologist or a policy maker, especially in the context of Mendelian randomization. PMID- 23733421 TI - Effect of siRNA-mediated knockdown of eIF3c gene on survival of colon cancer cells. AB - Eukaryotic initiation factor subunit c (eIF3c) has been identified as an oncogene that is over-expressed in tumor cells and, therefore, is a potential therapeutic target for gene-based cancer treatment. This study was focused on investigating the effect of small interfering RNA (siRNA)-mediated eIF3c gene knockdown on colon cancer cell survival. The eIF3c gene was observed to be highly expressed in colon cancer cell models. The expression levels of the gene in eIF3c siRNA infected and control siRNA infected cells were compared via real-time polymerase chain reaction (PCR) and western blotting analysis. Cell proliferation levels were analyzed employing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays. Furthermore, the effects of eIF3c gene knockdown on the cell cycle and apoptosis were analyzed using flow cytometry. The results showed that suppression of eIF3c expression significantly (P<0.001) reduced cell proliferation and colony formation of RKO colon cancer cells. The cell cycle was arrested by decreasing the number of cells entering S phase. Further, apoptosis was induced as a result of eIF3c knockdown. Collectively, eIF3c deletion effectively reduced the survival of colon cancer cells and could be used as a therapeutic tool for colon cancer therapy. PMID- 23733422 TI - Down-regulation of eIF5A-2 prevents epithelial-mesenchymal transition in non small-cell lung cancer cells. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) is believed to be the critical process in malignant tumor invasion and metastases, and has a great influence on improving the survival rate in non-small-cell lung cancer (NSCLC) patients. Recent studies suggested that eukaryotic initiation factor 5A-2 (eIF5A 2) might serve as an adverse prognostic marker of survival. We detected eIF5A-2 in NSCLC A549 cells, and found that the invasive capability correlates with the eIF5A-2 expression. METHODS: Transforming growth factor (TGF)-beta1 was used to induce EMT in A549 cells. Western blotting, immunofluorescence, wound healing assay, and transwell-matrigel invasion chambers were used to identify phenotype changes. Western blotting was also used to observe changes of the expression of eIF5A-2. We down-regulated the eIF5A-2 expression using an eIF5A-2 siRNA and identified the phenotype changes by western blotting and immunofluorescence. We tested the change of migration and invasion capabilities of A549 cells by the wound healing assay and transwell-matrigel invasion chambers. RESULTS: After stimulating with TGF-beta1, almost all A549 cells changed to the mesenchymal phenotype and acquired more migration and invasion capabilities. These cells also had higher eIF5A-2 protein expression. Down-regulation of eIF5A-2 expression with eIF5A-2 siRNA transfection could change the cells from mesenchymal to epithelial phenotype and decrease tumor cell migration and invasive capabilities significantly. CONCLUSIONS: The expression of eIF5A-2 was up-regulated following EMT phenotype changes in A549 cells, which correlated with enhanced tumor invasion and metastatic capabilities. Furthermore, in the A549 cell line, the process of EMT phenotype change could be reversed by eIF5A-2 siRNA, with a consequent weakening of both invasive and metastatic capabilities. PMID- 23733423 TI - Systematic review of laparoscopy-assisted versus open gastrectomy for advanced gastric cancer. AB - OBJECTIVE: The study compared laparoscopy-assisted gastrectomy (LAG) with open gastrectomy (OG) in the management of advanced gastric cancer (AGC). METHODS: Literature search was performed in the Medline, Embase, and Cochrane Library databases to identify control studies that compared LAG and OG for AGC. A meta analysis was conducted to examine the surgical safety and oncologic adequacy, using the random-effect model. RESULTS: Seven eligible studies including 815 patients were analyzed. LAG was associated with less blood loss, less use of analgesics, shorter time of flatus and periods of hospital stay, but longer time of operation. The incidence of most complications was similar between the two groups. However, LAG was associated with a lower rate of pulmonary infection (odds ratio (OR) 0.19; 95% confidence interval (CI) 0.05 to 0.68; P<0.05). No significant differences were noted in terms of the number of harvested lymph nodes (weighted mean difference (WMD) 1.165; 95% CI -2.000 to 4.311; P>0.05), overall mortality (OR 0.65; 95% CI 0.39 to 1.10; P>0.05), cancer-related mortality (OR 0.64; 95% CI 0.32 to 1.25; P>0.05), or recurrence (OR 0.62; 95% CI 0.33 to 1.16; P>0.05). CONCLUSIONS: LAG could be performed safely for AGC with adequate lymphadenectomy and has several short-term advantages compared with conventional OG. No differences were found in long-term outcomes. However, these results should be validated in large randomized controlled studies (RCTs) with sufficient follow-up. PMID- 23733424 TI - Novel mutation c.980_983delATTA compound with c.986C>A mutation of the FRMD7 gene in a Chinese family with X-linked idiopathic congenital nystagmus. AB - OBJECTIVE: To screen mutations in FERM domain-containing protein 7 (FRMD7) gene in two Chinese families with X-linked idiopathic congenital nystagmus (XLICN). METHODS: Common ophthalmic data and peripheral blood of two Chinese XLICN families (families A and B) were collected after informed consent. Genomic DNA was prepared from the peripheral blood of members of the two families and from 100 normal controls. Mutations in the FRMD7 gene were determined by directly sequencing polymerase chain reaction (PCR) products. RESULTS: We identified a novel mutation c.980_983delATTA compound with c.986C>A mutation in the 11th exon of FRMD7 in family B, and a previously reported splicing mutation c.781C>G (p.R261G) [corrected] in family A. The mutations were detected in patients and female carriers, while they were absent in other relatives or in the 100 normal controls. CONCLUSIONS: Our results expand the spectrum of FRMD7 mutations in association with XLICN, and further confirm that the mutations of FRMD7 are the underlying molecular mechanism for XLICN. PMID- 23733426 TI - Epidemiological and clinical characteristics of 266 cases of intracerebral hemorrhage in Hangzhou, China. AB - Ethnicity and socioeconomic factors can influence disease susceptibility, clinical presentation, and outcome. We investigated the clinical characteristics (age, sex, seasonal variation, lesion site, symptoms, complications, prognosis, and sequelae) and risk factors for intracerebral hemorrhage (ICH) in 266 cases treated at our hospital in Hangzhou City, China, from January 2011 to December 2011. Risk of ICH increased dramatically with age; only 4.3% of cases were <30 years old, while 44.4% were >60 years of age. Men outnumbered women by 2:1 (67.3% vs. 32.7%). Single hemorrhage was most often located in the cerebral lobes (37.2% of cases), basal ganglia (34.2%), thalamus (8.3%), cerebellum (6.8%), ventricle (1.5%), and brainstem (1.1%), while 10.9% of cases exhibited hemorrhages at multiple sites. Hypertension was also a major risk factor for ICH, as 47% of all patients were hypertensive and the percentage increased with age. In hypertensive patients, the most common hemorrhage site was the basal ganglia and ICH was often associated with thrombopenia. In patients with leukemia (all forms), most hemorrhages were lobar. Warfarin- and encephalic operation-associated ICHs were all lobar. Headache was the major symptom of occipital, temporal, and frontal lobe hemorrhage. Dizziness, nausea, and vomiting were the major symptoms of cerebellum hemorrhage. Limb dysfunction was the major symptom of thalamic and basal ganglia hemorrhage. Disturbed level of consciousness was the major symptom in multisite, ventricular, parietal lobe, and brainstem hemorrhage. Hyperspasmia occurred most often in lobar hemorrhage and blurred vision in occipital lobe hemorrhage. Hospital mortality was 24.4% (n=65) with a mean delay from presentation to death of (10.5+/-18.5) d. The majority of fatalities were cerebral hernia cases (58.5%) and these patients also had the shortest time to death [(2.9+/-3.5) d]. Mortality was 100% in brainstem ICH and hemorrhagic conversion of cerebral infarct. Thrombopenia-associated ICH also had a high mortality rate (81.0%), while patients with cerebrovascular malformations and cerebral aneurysms demonstrated a much better prognosis (46.2% recovery). PMID- 23733425 TI - Reducing the oxidative stress mediates the cardioprotection of bicyclol against ischemia-reperfusion injury in rats. AB - OBJECTIVE: To investigate the beneficial effect of bicyclol on rat hearts subjected to ischemia-reperfusion (IR) injuries and its possible mechanism. METHODS: Male Sprague-Dawley rats were intragastrically administered with bicyclol (25, 50 or 100 mg/(kg?d)) for 3 d. Myocardial IR was produced by occlusion of the coronary artery for 1 h and reperfusion for 3 h. Left ventricular hemodynamics was continuously monitored. At the end of reperfusion, myocardial infarct was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and serum lactate dehydrogenase (LDH) level and myocardial superoxide dismutase (SOD) activity were determined by spectrophotometry. Isolated ventricular myocytes from adult rats were exposed to 60 min anoxia and 30 min reoxygenation to simulate IR injuries. After reperfusion, cell viability was determined with trypan blue; reactive oxygen species (ROS) and mitochondrial membrane potential of the cardiomyocytes were measured with the fluorescent probe. The mitochondrial permeability transition pore (mPTP) opening induced by Ca(2+) (200 MUmol/L) was measured with the absorbance at 520 nm in the isolated myocardial mitochondria. RESULTS: Low dose of bicyclol (25 mg/(kg?d)) had no significant improving effect on all cardiac parameters, whereas pretreatment with high bicyclol markedly reduced the myocardial infarct and improved the left ventricular contractility in the myocardium exposed to IR (P<0.05). Medium dose of bicyclol (50 mg/(kg?d)) markedly improved the myocardial contractility, left ventricular myocyte viability, and SOD activity, as well decreased infarct size, serum LDH level, ROS production, and mitochondrial membrane potential in rat myocardium exposed to IR. The reduction of ventricular myocyte viability in IR group was inhibited by pretreatment with 50 and 100 mg/(kg?d) bicyclol (P<0.05 vs. IR), but not by 25 mg/(kg?d) bicyclol. The opening of mPTP evoked by Ca(2+) was significantly inhibited by medium bicyclol. CONCLUSIONS: Bicyclol exerts cardioprotection against IR injury, at least, via reducing oxidative stress and its subsequent mPTP opening. PMID- 23733427 TI - beta-Receptor blocker influences return of spontaneous circulation and chemical examination in rats during cardiopulmonary resuscitation. AB - OBJECTIVE: We investigated the influence of beta-receptor blocker metoprolol on return of spontaneous circulation (ROSC) during cardiopulmonary resuscitation (CPR) in rats with induced myocardial infarction (MI). METHODS: Male Sprague Dawley rats were randomly divided into three groups: the sham-operated group, the MI group without metoprolol, which was fed the vehicle, and the MI+metoprolol group receiving intragastric metoprolol. Each group was further divided randomly into three subgroups, depending on the dosage of epinephrine administered during subsequent CPR applied after the induction of asphyxial cardiac arrest. RESULTS: The ROSC rate was significantly decreased in the low dose subgroup of MI group, unchanged in the medium dose subgroup of MI group, and significantly decreased in the high dose subgroup of MI group, compared with the same dose subgroup of sham operated group. MI+metoprolol group had a lower ROSC rate than MI group in the medium dose subgroup, and a higher ROSC rate than MI group in the high dose subgroup. There was no difference in blood K(+) values of successful rats between MI group and MI+metoprolol group. The rats with successful CPR had lower blood K(+) values than rats with unsuccessful CPR in each of the three treatment groups. CONCLUSIONS: Metoprolol administered to MI rats over a long period significantly improved ROSC rates under an appropriate dose of epinephrine during CPR. An increasing high blood K(+) value would attenuate the rate of a successful CPR. PMID- 23733428 TI - Activation of Akt and cardioprotection against reperfusion injury are maximal with only five minutes of sevoflurane postconditioning in isolated rat hearts. AB - It had been proved that administration of sevoflurane for the first two minutes of reperfusion effectively protects the heart against reperfusion injury in rats in vivo. Our aim was to investigate the duration of effective sevoflurane administration and its underlying mechanism in isolated rat hearts exposed to global ischemia/reperfusion (I/R) injury. Adult male Sprague-Dawley rats were randomly divided into six groups (n=12): a sham-operation group, an I/R group, and four sevoflurane postconditioning groups (S2, S5, S10, and S15). In the S2, S5, S10, and S15 groups, the duration times of sevoflurane administration were 2, 5, 10, and 15 min after the onset of reperfusion, respectively. The isolated rat hearts were mounted on the Langendorff system, and after a period of equilibrium were subjected to 40 min global ischemia and 120 min reperfusion. Left ventricular (LV) hemodynamic parameters were monitored throughout each experiment and the data at 30 min of equilibrium and 30, 60, 90, and 120 min of reperfusion were analyzed. Myocardial infarct size at the end of reperfusion (n=7 in each group) and the expression of myocardial phosphorylated Akt (p-Akt) after 15-min reperfusion were determined in a duplicate set of six groups of rat hearts (n=5 in each group). Compared with the I/R group, the S5, S10, and S15 groups had significantly improved left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), and the maximal rate of rise or fall of the LV pressure (+/-dP/dtmax), and decreased myocardial infarct size (P<0.05), but not the S2 group. After 15 min of reperfusion, the expression of p-Akt was markedly up-regulated in the S5, S10, and S15 groups compared with that in the I/R group (P<0.05), but not in the S2 group. Sevoflurane postconditioning for 5 min was sufficient to activate Akt and exert maximal cardioprotection against I/R injury in isolated rat hearts. PMID- 23733429 TI - Effects of zinc-substituted nano-hydroxyapatite coatings on bone integration with implant surfaces. AB - OBJECTIVE: The purpose of this study was to investigate the effects of a zinc substituted nano-hydroxyapatite (Zn-HA) coating, applied by an electrochemical process, on implant osseointegraton in a rabbit model. METHODS: A Zn-HA coating or an HA coating was deposited using an electrochemical process. Surface morphology was examined using field-emission scanning electron microscopy. The crystal structure and chemical composition of the coatings were examined using an X-ray diffractometer (XRD) and Fourier transform infrared spectroscopy (FTIR). A total of 78 implants were inserted into femurs and tibias of rabbits. After two, four, and eight weeks, femurs and tibias were retrieved and prepared for histomorphometric evaluation and removal torque (RTQ) tests. RESULTS: Rod-like HA crystals appeared on both implant surfaces. The dimensions of the Zn-HA crystals seemed to be smaller than those of HA. XRD patterns showed that the peaks of both coatings matched well with standard HA patterns. FTIR spectra showed that both coatings consisted of HA crystals. The Zn-HA coating significantly improved the bone area within all threads after four and eight weeks (P<0.05), the bone to implant contact (BIC) at four weeks (P<0.05), and RTQ values after four and eight weeks (P<0.05). CONCLUSIONS: The study showed that an electrochemically deposited Zn-HA coating has potential for improving bone integration with an implant surface. PMID- 23733430 TI - Effect of proximal contact strength on the three-dimensional displacements of implant-supported cantilever fixed partial dentures under axial loading. AB - OBJECTIVE: This study investigated the effect of proximal contact strength on the three-dimensional displacements of cantilever fixed partial denture (CFPD) under vertically concentrated loading with digital laser speckle (DLS) technique. METHODS: Fresh mandible of beagle dog was used to establish the implant-supported CFPD for specimen. DLS technique was employed for measuring the three-dimensional displacement of the prosthesis under vertically concentrated loading ranging from 200 to 3000 g. The effect of the contact tightness on the displacement of CFPD was investigated by means of changing the contact tightness. RESULTS: When an axial concentrated loading was exerted on the pontic of the implant-supported CFPD, the displacement of the CFPD was the greatest. The displacement of the prosthesis decreased with the increase of contact strength. When the contact strength was 0, 0.95, and 3.25 N, the displacement of the buccolingual direction was smaller than that of the mesiodistal direction but greater than that of the occlusogingival direction. When the force on the contact area was 6.50 N, the mesiodistal displacement of the prosthesis was the biggest while the buccolingual displacement was the smallest. CONCLUSIONS: The implant-supported CFPD is an effective therapy for fully or partially edentulous patients. The restoration of the contact area and the selection of the appropriate contact strength can reduce the displacement of the CFPD, and get a better stress distribution. The most appropriate force value is 3.25 N in this study. PMID- 23733431 TI - Allelic frequency distributions of 21 non-combined DNA index system STR loci in a Russian ethnic minority group from Inner Mongolia, China. AB - We studied the allelic frequency distributions and statistical forensic parameters of 21 new short tandem repeat (STR) loci and the amelogenin locus, which are not included in the combined DNA index system (CODIS), in a Russian ethnic minority group from the Inner Mongolia Autonomous Region, China. A total of 114 bloodstain samples from unrelated individuals were extracted and co amplified with four fluorescence-labeled primers in a multiplex polymerase chain reaction (PCR) system. Using capillary electrophoresis, the PCR products of the 21 STR loci were separated and genotyped. A total of 161 alleles were observed in the Russian ethnic minority group, and corresponding allelic frequencies ranged from 0.0044 to 0.5965. The 21 non-CODIS STR loci of the Russian ethnic minority group were characterized by high genetic diversity and therefore may be useful for elucidating the population's genetic background, for individual identification, and for paternity testing in forensic practice. PMID- 23733432 TI - A survey of five first-level hospital ethics committees in Urumqi, China. AB - This paper presents the results from a survey of first-level hospitals in Urumqi, China. The survey had two parts: the first part was aimed at understanding the operation of the ethics committees of first-level hospitals, including the process for electing members and the variety of members' backgrounds. Information was also gathered about the establishment of criteria, operational rules and regulations, and standard operational procedures. The aim of the second part was to investigate the level of understanding among technicians and doctors about the function of the ethics committees. This paper identifies and analyzes some deficiencies found in the operation of hospital ethics committees, offers some constructive suggestions for improvement, and promotes the role of the Xinjiang Uygur autonomous region hospital ethics committees. PMID- 23733433 TI - Acute pancreatitis associated left-sided portal hypertension with severe gastrointestinal bleeding treated by transcatheter splenic artery embolization: a case report and literature review. AB - Left-sided portal hypertension (LSPH) followed by acute pancreatitis is a rare condition with most patients being asymptomatic. In cases where gastrointestinal (GI) bleeding is present, however, the condition is more complicated and the mortality is very high because of the difficulty in diagnosing and selecting optimal treatment. A successfully treated case with severe GI bleeding by transcatheter splenic artery embolization is reported in this article. The patient exhibited severe uncontrollable GI bleeding and was confirmed as gastric varices secondary to LSPH by enhanced computed tomography (CT) scan and CT angiography. After embolization, the bleeding stopped and stabilized for the entire follow-up period without any severe complications. In conclusion, embolization of the splenic artery is a simple, safe, and effective method of controlling gastric variceal bleeding caused by LSPH in acute pancreatitis. PMID- 23733434 TI - Cancer incidence among population utilizing geothermal hot water: a census-based cohort study. AB - The aim of the study was to assess whether utilization of geothermal hot-water is associated with risk of cancer. The cohort from census was followed from 1981 to 2010 in nation-wide death and cancer registries. The moving apart of American Eurasian tectonic plates, observed in Iceland, results in high volcanic activity. The definition of the study populations was based on geological information. The target population was inhabitants of communities located on bedrock younger than 3.3 million years, utilizing hot-water supply generated from geothermal wells since 1972. The two reference populations were inhabitants of communities without this hot-water supply located on areas with less volcanic/geothermal activity, and bedrock older than 3.3 million years. Hazard ratio (HR), and 95% confidence intervals (CI) were adjusted for age, gender, education, housing, reproductive factors and smoking. HR in the geothermal hot-water supply areas for all cancer was 1.15 (95% CI 1.05-1.25) as compared with nongeothermal areas. The HR for breast cancer was 1.40 (1.12-1.75), prostate cancer 1.61 (1.29-2.00), kidney cancer 1.64 (1.11-2.41), lymphatic and haematopoietic tissue cancers 1.45 (1.08 1.95), and for basal cell carcinoma (BCC) of the skin 1.46 (1.16-1.82). Positive exposure-response relations were observed between the risk of these cancers and the degree of volcanic/geothermal activity in the reference areas. Increased incidence of all cancers, breast, prostate, kidney cancer and BCC of the skin was found among the population utilizing geothermal hot-water for decades. More precise information on exposure is needed in future studies. PMID- 23733435 TI - Positive daily family interactions eliminate gender differences in internalizing symptoms among adolescents. AB - By the age of 18, girls are more than twice as likely as boys to experience internalizing symptoms. Focusing upon the family, a significant factor for adolescent mental health, we examined how positive and negative daily family interactions relate to gender differences in internalizing symptoms. 681 12th grade students (54 % female) completed diary checklists each night for 2 weeks in which they indicated whether they got along with their family (positive family interactions) and argued with their family (negative family interactions). Results indicate that negative daily family interactions explain, in part, why females experience heightened internalizing symptoms. Yet, even in the face of negative family interactions, positive daily family interactions have salutatory effects, reducing females' emotional distress and eliminating gender differences in internalizing symptoms at high levels of positive interactions. These findings underscore the importance of positive family interactions for adolescent girls' mental health. PMID- 23733436 TI - Safety and efficacy of shilajit (mumie, moomiyo). AB - Shilajit (mumie; moomiyo, mummiyo) has been used for a wide variety of illnesses and conditions for many years. However, relatively few well-controlled human studies have been conducted on the effects of shiliajit, although a growing number of studies have been published in recent years involving animal and in vitro systems. The safety of shilajit is well documented based on animal and human studies. Various research studies indicate that shilajit exhibits antioxidant, anti-inflammatory, adaptogenic, immunomodulatory, and anti dyslipidemic properties. Animal and human studies indicate that shilajit enhances spermatogenesis. Furthermore, animal and human data support its use as a 'revitalizer', enhancing physical performance and relieving fatigue with enhanced production of ATP. Key constituents in shilajit responsible for these effects appear to be dibenzo-alpha-pyrones and fulvic acid and their derivatives. Various mechanistic studies provide support for the above observed effects. Additional well-controlled human and animal studies involving the use of standardized products are needed. PMID- 23733437 TI - Incidental post-surgical pseudoaneurysm of the left ventricle: an unexpected finding. PMID- 23733438 TI - Aorta-right atrial tunnel. PMID- 23733439 TI - Hamartoma of mature cardiac myocytes: a cardiac tumour with preserved contractility. PMID- 23733440 TI - Coronary aneurysm mimicking a five chamber heart. PMID- 23733441 TI - Secundum atrial septal defect resulting in hypoxaemia. PMID- 23733442 TI - Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging. AB - Valvular regurgitation represents an important cause of cardiovascular morbidity and mortality. Echocardiography has become the primary non-invasive imaging method for the evaluation of valvular regurgitation. The echocardiographic assessment of valvular regurgitation should integrate the quantification of the regurgitation, assessment of the valve anatomy and function, as well as the consequences of valvular disease on cardiac chambers. In clinical practice, the management of patients with valvular regurgitation thus largely integrates the results of echocardiography. It is crucial to provide standards that aim at establishing a baseline list of measurements to be performed when assessing regurgitation. PMID- 23733443 TI - Improvement of major depression is associated with increased erythrocyte DHA. AB - The aim of this study was to determine if changes in omega-3 polyunsaturated fatty acid status following tuna oil supplementation correlated with changes in scores of depression. A total of 95 volunteers receiving treatment for major depression were randomised to consume 8 * 1 g capsules per day of HiDHA (2 g DHA, 0.6 g EPA and 10 mg Vitamin E) or olive oil (placebo) for 16 weeks, whilst undergoing weekly counseling sessions by trained clinical psychologists using a standard empirically validated psychotherapy. Depression status was assessed using the 17 item Hamilton rating scale for depression and the Beck Depression Inventory by a psychodiagnostician who was blind to the treatment. Blood was taken at baseline and 16 weeks (n = 48) for measurement of erythrocyte fatty acids. With HiDHA supplementation, erythrocyte DHA content rose from 4.1 +/- 0.2 to 7.9 +/- 0.4 % (mean +/- SEM, p < 0.001) of total fatty acids but did not change (4.0 +/- 0.2 to 4.1 +/- 0.2 %) in the olive oil group. The mean changes in scores of depression did not differ significantly between the two groups (-12.2 +/- 2.1 for tuna oil and -14.4 +/- 2.3 for olive oil). However, analysis of covariance showed that in the fish oil group there was a significant correlation (r = -0.51) between the change in erythrocyte DHA and the change in scores of depression (p < 0.05). Further study of the relationship between DHA and depression is warranted. PMID- 23733444 TI - Patterning human neuronal networks on photolithographically engineered silicon dioxide substrates functionalized with glial analogues. AB - Interfacing neurons with silicon semiconductors is a challenge being tackled through various bioengineering approaches. Such constructs inform our understanding of neuronal coding and learning and ultimately guide us toward creating intelligent neuroprostheses. A fundamental prerequisite is to dictate the spatial organization of neuronal cells. We sought to pattern neurons using photolithographically defined arrays of polymer parylene-C, activated with fetal calf serum. We used a purified human neuronal cell line [Lund human mesencephalic (LUHMES)] to establish whether neurons remain viable when isolated on-chip or whether they require a supporting cell substrate. When cultured in isolation, LUHMES neurons failed to pattern and did not show any morphological signs of differentiation. We therefore sought a cell type with which to prepattern parylene regions, hypothesizing that this cellular template would enable secondary neuronal adhesion and network formation. From a range of cell lines tested, human embryonal kidney (HEK) 293 cells patterned with highest accuracy. LUHMES neurons adhered to pre-established HEK 293 cell clusters and this coculture environment promoted morphological differentiation of neurons. Neurites extended between islands of adherent cell somata, creating an orthogonally arranged neuronal network. HEK 293 cells appear to fulfill a role analogous to glia, dictating cell adhesion, and generating an environment conducive to neuronal survival. We next replaced HEK 293 cells with slower growing glioma derived precursors. These primary human cells patterned accurately on parylene and provided a similarly effective scaffold for neuronal adhesion. These findings advance the use of this microfabrication-compatible platform for neuronal patterning. PMID- 23733445 TI - Chemistry and biology of the potent endotoxin from a Burkholderia dolosa clinical isolate from a cystic fibrosis patient. AB - This is the first report of the chemical and biological properties of the lipooligosaccharide (LOS) endotoxin isolated from Burkholderia dolosa IST4208, an isolate recovered from a cystic fibrosis (CF) patient in a Portuguese CF center. B. dolosa is a member of the Burkholderia cepacia complex, a group of closely related species that are highly problematic and opportunistic pathogens in CF. B. dolosa infection leads to accelerated loss of lung function and decreased survival. The structural determination of its endotoxin was achieved using a combination of chemistry and spectroscopy, and has revealed a novel endotoxin structure. The purified LOS was tested for its immunostimulatory activity on human HEK 293 cells expressing TLR-4, MD-2, and CD-14. In these assays, the LOS showed strong proinflammatory activity. PMID- 23733446 TI - Discordant lymphocyte-depleted classical Hodgkin's and peripheral T-cell lymphoma arising in a patient 11 years after diagnosis of multicentric Castleman's disease. AB - Castleman's disease (CD) is thought to be related with an initially benign viral disease with cytokine-driven propagation and malignant transformation. This paper reports the first case of a simultaneous discordant lymphoma consisting of lymphocyte-depleted classical Hodgkin's lymphoma (LDCHL) and peripheral T-cell lymphoma (PTCL) arising in a patient with multicentric CD (MCD). PTCL occurred 4 years after the diagnosis of MCD, and LDCHL was developed 6 years after the treatment of PTCL, sequentially. The following year, the patient presented with a relapse of a simultaneous discordant lymphoma. On excisional cervical LN biopsy, immunohistochemical stain pattern was identical with previously diagnosed LDCHL, which expressed CD30, CD15, PAX5, and Epstein-Barr virus (EBV)-encoded RNA. PTCL was positive for CD3, CD4, CD5, CD10, and CD56, and showed identical TCRB and TCRG gene rearrangements to those detected initially. MCD was thought to be the major contributing factor leading to initial PTCL, while EBV-positive LDCHL is thought to have promoted the development of PTCL, as a persistently abnormal immune microenvironment may induce the recurrence of PTCL. MCD runs a more aggressive course and can progress to Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), or combined HL/NHL. Due to its malignant potential, prompt recognition and therapy is critical for these situations, which may be life threatening. PMID- 23733447 TI - HIV-associated neurocognitive disorders: perspective on management strategies. AB - Potent combination antiretroviral therapy (ART) has resulted in dramatic improvements in AIDS-associated morbidity and mortality. Although combination ART has resulted in a significant reduction in HIV-associated dementia, the most severe of the HIV-associated neurocognitive disorders (HAND), the overall prevalence of HAND among this population is estimated at 40%. It has been recognized that the central nervous system (CNS) serves as a reservoir for HIV, and neuronal damage begins at the time of acute infection and persists due to chronic infection of microglial and perivascular macrophages. Although combination ART has resulted in virologic control in the plasma compartment, virologic breakthrough can potentially ensue within the CNS compartment due to limited ART drug exposure. The purpose of this review is to discuss the definition, clinical spectrum, and risk factors associated with HAND, review the pathogenesis of HAND, and address the pharmacologic challenges associated with ART drug exposure in the CNS compartment. PMID- 23733450 TI - Aging and KIBRA/WWC1 genotype affect spatial memory processes in a virtual navigation task. AB - Spatial navigation relies on multiple mnemonic mechanisms and previous work in younger adults has described two separate types of spatial memory. One type uses directional as well as boundary-related information for spatial memory and mainly implicates the hippocampal formation. The other type has been linked to directional and landmark-related information and primarily involves the striatum. Using a virtual reality navigation paradigm, we studied the impacts of aging and a single nucleotide polymorphism (SNP rs17070145) of the KIBRA gene (official name: WWC1) on these memory forms. Our data showed that older adult's spatial learning was preferentially related to processing of landmark information, whereas processing of boundary information played a more prominent role in younger adults. Moreover, among older adults T-allele carriers of the examined KIBRA polymorphism showed better spatial learning compared to C homozygotes. Together these findings provide the first evidence for an effect of the KIBRA rs17070145 polymorphism on spatial memory in humans and age differences in the reliance on landmark and boundary-related spatial information. PMID- 23733451 TI - Unusual cutaneous lesions indicating fat embolism syndrome in homozygous sickle cell disease. PMID- 23733452 TI - Using the Cre-lox system to randomize target gene expression states and generate diverse phenotypes. AB - Modifying the expression of multiple genes enables both deeper understanding of their function and the engineering of complex multigenic cellular phenotypes. However, deletion or overexpression of multiple genes is typically laborious and involves multiple sequential genetic modifications. Here we describe a strategy to randomize the expression state of multiple genes in Saccharomyces cerevisiae using Cre-loxP recombination. By inserting promoters flanked by inverted loxP sites in front of a gene of interest we can randomly alter its expression by turning it OFF or ON, or between four distinct expression states. We show at least 6 genes can be randomized independently and argue that using orthogonal loxP sites should increase this number to at least 15. Finally, we show how combining this strategy with mating allows easy introduction of native regulation as an additional expression state and use this to probe the role of four different enzymes involved in base excision repair in tolerance to methyl methane sulfonate (MMS), a genotoxic DNA alkylating agent. The set of vectors developed here can be used to randomize the expression of both heterologous genes and endogenous genes, and could immediately prove useful for metabolic engineering in yeast. Because Cre-loxP recombination works in many organisms, this strategy should be readily extendable. PMID- 23733453 TI - Psychotropic drug treatment in anorexia nervosa. Search for differences in efficacy/tolerability between adolescent and mixed-age population. AB - BACKGROUND: During the last 10 years, the use of psychotropic medications in youth with psychiatric disorders, including eating disorders, has significantly increased, but their role in the treatment of adolescent anorexia nervosa is still controversial. OBJECTIVE: This paper aims to review the literature on the use of antidepressants and antipsychotics in adolescents with anorexia nervosa, comparing the efficacy and tolerability in this population with those reported in trials with patients not selected by age. METHOD: A systematic review of the available literature published so far. RESULTS: Only few studies met the selection criteria. No strong evidence of beneficial effects was found in using antidepressants and antipsychotics neither in adults nor in adolescents. Side effects were more frequently reported in studies including adolescent population. Among psychotropic drugs, the majority of studies focused on olanzapine, which seems to have, in some studies, only positive effects on body mass index, eating disorder symptoms and functional impairment in both age groups. PMID- 23733454 TI - First outbreak of KPC-3-producing Klebsiella pneumoniae (ST258) clinical isolates in a Mexican Medical Center. PMID- 23733455 TI - A novel genetic region flanks the plasmid-carried blaNDM-1 isolated from a patient in Rhode Island in 2012. PMID- 23733456 TI - Evaluation of a nisin-eluting nanofiber scaffold to treat Staphylococcus aureus induced skin infections in mice. AB - Staphylococcus aureus is a virulent pathogen and a major causative agent of superficial and invasive skin and soft tissue infections (SSSTIs). Antibiotic resistance in S. aureus, among other bacterial pathogens, has rapidly increased, and this is placing an enormous burden on the health care sector and has serious implications for infected individuals, especially immunocompromised patients. Alternative treatments thus need to be explored to continue to successfully treat infections caused by S. aureus, including antibiotic-resistant strains of S. aureus. In this study, an antimicrobial nanofiber wound dressing was generated by electrospinning nisin (Nisaplin) into poly(ethylene oxide) and poly(d,l-lactide) (50:50) blend nanofibers. Active nisin diffused from the nanofiber wound dressings for at least 4 days in vitro, as shown by consecutive transfers onto plates seeded with strains of methicillin-resistant S. aureus (MRSA). The nisin containing nanofiber wound dressings significantly reduced S. aureus Xen 36 bioluminescence in vivo and viable cell numbers in a murine excisional skin infection model. The bacterial burden of wounds treated with nisin-containing nanofiber wound dressings was 4.3 * 10(2) CFU/wound, whereas wounds treated with control nanofiber wound dressings had 2.2 * 10(7) CFU/wound on the last day of the trial (day 7). Furthermore, the wound dressings stimulated wound closure of excisional wounds, and no adverse effects were observed by histological analysis. Nisin-containing nanofiber wound dressings have the potential to treat S. aureus skin infections and to potentially accelerate wound healing of excisional wounds. PMID- 23733457 TI - Characterization of a new blaOXA-48-carrying plasmid in Enterobacteriaceae. AB - In this work, we characterized a new, 160-kb, blaOXA-48-harboring IncL/M-type plasmid isolated from a Klebsiella pneumoniae strain from France. Moreover, we report the transfer of a 60-kb OXA-48-encoding plasmid from Klebsiella pneumoniae to other Enterobacteriaceae in two patients. PMID- 23733458 TI - Virulence of vancomycin-resistant Enterococcus faecium according to linezolid resistance and clinical outbreak status. AB - Assessing clinical virulence differences between vancomycin-resistant Enterococcus faecium (VREF) strains resistant to linezolid (LRVRE) and linezolid susceptible VRE (LSVRE) strains is difficult due to confounding patient variables. Galleria mellonella is a validated host interaction model allowing straightforward organism virulence assessment. The objective of this study was to assess the virulence of VREF in G. mellonella according to linezolid resistance and clinical outbreak status. A genetically related pair of VREF strains with and without genotypically confirmed linezolid resistance was selected for analysis. Additionally, six strains of LSVRE and two strains of LRVRE were selected according to epidemiologic outbreak status. Mortality of G. mellonella was assessed daily over a 5-day period and analyzed using Kaplan-Meier survival curves and log rank tests. Linezolid resistance did not have a significant effect on G. mellonella mortality in the genetically related pair (P = 0.93). There was no significant difference in mortality over time between strains (non-outbreak [i.e., no patient transmissions were recorded] [n = 2] versus outbreak [i.e., transmission occurred between 3 or more patients in a period of 30 days] [n = 6], P = 0.84; extensive transmission [i.e., the isolate was transmitted between at least 80 patients] [n = 2] versus limited transmission [i.e., the isolate was transmitted between fewer than 10 patients] [n = 4], P = 0.78). These results suggest that patients infected with LRVRE or outbreak strains of VREF are at no greater risk of poor outcomes mediated by organism virulence than those infected with LSVRE or non-outbreak strains. PMID- 23733459 TI - Lethal hydroxyl radical accumulation by a lactococcal bacteriocin, lacticin Q. AB - The antimicrobial mechanism of a lactococcal bacteriocin, lacticin Q, can be described by the toroidal pore model without any receptor. However, lacticin Q showed different degrees of activity (selective antimicrobial activity) against Gram-positive bacteria even among related species. The ability of lacticin Q to induce pore formation in liposomes composed of lipids from different indicator strains indicated that its selective antimicrobial activity could not be attributed only to membrane lipid composition. We investigated the accumulation of deleterious hydroxyl radicals after exposure to lacticin Q as a contributing factor to cell death in the indicator strains. When lacticin Q of the same concentration as the MIC or minimum bactericidal concentration was added to the indicator cultures, high levels of hydroxyl radical accumulation were detected. Treatment with hydroxyl radical scavengers, thiourea and 2,2'-bipyridyl, decreased the levels of hydroxyl radical accumulation and recovered cell viability. These results suggest that, with or without pore formation, the final antimicrobial mechanism of lacticin Q is the accumulation of hydroxyl radicals, which varies by strain, resulting in the selective antimicrobial activity of lacticin Q. PMID- 23733460 TI - A quinazoline-2,4-diamino analog suppresses Vibrio cholerae flagellar motility by interacting with motor protein PomB and induces envelope stress. AB - Vibrio cholerae strains of serogroups O1 and O139, the causative agents of the diarrheal illness cholera, express a single polar flagellum powered by sodium motive force and require motility to colonize and spread along the small intestine. In a previous study, we described a high-throughput assay for screening for small molecules that selectively inhibit bacterial motility and identified a family of quinazoline-2,4-diamino analogs (Q24DAs) that (i) paralyzed the sodium-driven polar flagellum of Vibrios and (ii) diminished cholera toxin secreted by El Tor biotype V. cholerae. In this study, we provide evidence that a Q24DA paralyzes the polar flagellum by interacting with the motor protein PomB. Inhibition of motility with the Q24DA enhanced the transcription of the cholera toxin genes in both biotypes. We also show that the Q24DA interacts with outer membrane protein OmpU and other porins to induce envelope stress and expression of the extracellular RNA polymerase sigma factor sigma(E). We suggest that Q24DA-induced envelope stress could affect the correct folding, assembly, and secretion of pentameric cholera toxin in El Tor biotype V. cholerae independently of its effect on motility. PMID- 23733461 TI - Antibiotic trapping by plasmid-encoded CMY-2 beta-lactamase combined with reduced outer membrane permeability as a mechanism of carbapenem resistance in Escherichia coli. AB - A liver transplant patient was admitted with cholangitis, for which meropenem therapy was started. Initial cultures showed a carbapenem-susceptible (CS) Escherichia coli strain, but during admission, a carbapenem-resistant (CR) E. coli strain was isolated. Analysis of the outer membrane protein profiles showed that both CS and CR E. coli lacked the porins OmpF and OmpC. Furthermore, PCR and sequence analysis revealed that both CS and CR E. coli possessed bla(CTX-M-15) and bla(OXA-1). The CR E. coli strain additionally harbored bla(CMY-2) and demonstrated a >15-fold increase in beta-lactamase activity against nitrocefin, but no hydrolysis of meropenem was detected. However, nitrocefin hydrolysis appeared strongly inhibited by meropenem. Furthermore, the CMY-2 enzyme demonstrated lower electrophoretic mobility after its incubation either in vitro or in vivo with meropenem, indicative of its covalent modification with meropenem. The presence of the acyl-enzyme complex was confirmed by mass spectrometry. By transformation of the CMY-2-encoding plasmid into various E. coli strains, it was established that both porin deficiency and high-level expression of the enzyme were needed to confer meropenem resistance. In conclusion, carbapenem resistance emerged by a combination of elevated beta lactamase production and lack of porin expression. Due to the reduced outer membrane permeability, only small amounts of meropenem can enter the periplasm, where they are trapped but not degraded by the large amount of the beta lactamase. This study, therefore, provides evidence that the mechanism of "trapping" by CMY-2 beta-lactamase plays a role in carbapenem resistance. PMID- 23733462 TI - Escherichia coli resistance to nonbiocidal antibiofilm polysaccharides is rare and mediated by multiple mutations leading to surface physicochemical modifications. AB - Antivirulence strategies targeting bacterial behavior, such as adhesion and biofilm formation, are expected to exert low selective pressure and have been proposed as alternatives to biocidal antibiotic treatments to avoid the rapid occurrence of bacterial resistance. Here, we tested this hypothesis using group 2 capsule polysaccharide (G2cps), a polysaccharidic molecule previously shown to impair bacterium-surface interactions, and we investigated the nature of bacterial resistance to a nonbiocidal antibiofilm strategy. We screened an Escherichia coli mutant library for an increased ability to form biofilm in the presence of G2cps, and we identified several mutants displaying partial but not total resistance to this antibiofilm polysaccharide. Our genetic analysis showed that partial resistance to G2cps results from multiple unrelated mutations leading to modifications in surface physicochemical properties that counteract the changes in ionic charge and Lewis base properties induced by G2cps. Moreover, some of the identified mutants harboring improved biofilm formation in the presence of G2cps were also partially resistant to other antibiofilm molecules. This study therefore shows that alterations of bacterial surface properties mediate only partial resistance to G2cps. It also experimentally validates the potential value of nonbiocidal antibiofilm strategies, since full resistance to antibiofilm compounds is rare and potentially unlikely to arise in clinical settings. PMID- 23733463 TI - Efficacy of humanized carbapenem exposures against New Delhi metallo-beta lactamase (NDM-1)-producing enterobacteriaceae in a murine infection model. AB - Enterobacteriaceae producing the novel carbapenemase New Delhi metallo-beta lactamase (NDM-1) are emerging worldwide. While these organisms often display high levels of in vitro resistance to multiple antibiotics, in vivo efficacy data are lacking. Here, the activities of humanized ertapenem and doripenem exposures were characterized against a wild-type K. pneumoniae and its derived isogenic strains harboring either an NDM-1 or KPC-2 plasmid in immunocompetent mice. In addition, four clinical isolates expressing NDM-1 were evaluated. Human-simulated regimens of ertapenem at 1 g every 24 h and high-dose, prolonged infusion of doripenem at 2 g every 8 h as a 4-h infusion were evaluated over 24 h, and efficacy was determined by the change in bacterial density compared to that in 24 h growth controls. CFU reductions in bacterial density of greater than 1 log unit were observed against the wild-type strain as well as the derived isogenic NDM-1 strain, while no reduction was observed against the derived KPC-2 strain. Postexposure MICs confirmed the in vitro maintenance of the ertapenem resistance marker in both the NDM-1 and KPC-2 strains. Similar to the case for the isogenically derived NDM-1 strain, bacterial density was reduced at 24 h against all four clinical NDM-1 isolates showing variable levels of MICs for carbapenems, with near-maximal activity of both agents occurring when the doripenem MIC was <= 8 MUg/ml. While carbapenem monotherapy does not appear to be an option against KPC-based infections, these data suggest that carbapenem monotherapy may be a viable option for treating NDM-1-producing Enterobacteriaceae under certain conditions, and this warrants further in vivo exploration. PMID- 23733464 TI - Cell wall perturbation sensitizes fungi to the antimalarial drug chloroquine. AB - Chloroquine (CQ) has been a mainstay of antimalarial drug treatment for several decades. Additional therapeutic actions of CQ have been described, including some reports of fungal inhibition. Here we investigated the action of CQ in fungi, including the yeast model Saccharomyces cerevisiae. A genomewide yeast deletion strain collection was screened against CQ, revealing that bck1Delta and slt2Delta mutants of the cell wall integrity pathway are CQ hypersensitive. This phenotype was rescued with sorbitol, consistent with cell wall involvement. The cell wall targeting agent caffeine caused hypersensitivity to CQ, as did cell wall perturbation by sonication. The phenotypes were not caused by CQ-induced changes to cell wall components. Instead, CQ accumulated to higher levels in cells with perturbed cell walls: CQ uptake was 2- to 3-fold greater in bck1Delta and slt2Delta mutants than in wild-type yeast. CQ toxicity was synergistic with that of the major cell wall-targeting antifungal drug, caspofungin. The MIC of caspofungin against the yeast pathogen Candida albicans was decreased 2-fold by 250 MUM CQ and up to 8-fold at higher CQ concentrations. Similar effects were seen in Candida glabrata and Aspergillus fumigatus. The results show that the cell wall is critical for CQ resistance in fungi and suggest that combination treatments with cell wall-targeting drugs could have potential for antifungal treatment. PMID- 23733466 TI - Electronic estimations of renal function are inaccurate in solid-organ transplant recipients and can result in significant underdosing of prophylactic valganciclovir. AB - In a prospective study of solid-organ transplant recipients (n = 22; 15 hepatic and 7 renal) receiving valganciclovir for cytomegalovirus (CMV) prophylaxis, electronic estimation of glomerular filtration rate (eGFR) underestimated the true GFR (24-h urine creatinine clearance) by >20% in 14/22 (63.6%). Its use was associated with inappropriate underdosing of valganciclovir, while the Cockroft Gault equation was accurate in 21/22 patients (95.4%). Subtherapeutic ganciclovir levels (<= 0.6 mg/liter) were common, occurring in 10/22 patients (45.4%); 7 had severely deficient levels (<0.3 mg/liter). PMID- 23733465 TI - Role of the LytSR two-component regulatory system in adaptation to cationic antimicrobial peptides in Staphylococcus aureus. AB - Many host defense cationic antimicrobial peptides (HDPs) perturb the staphylococcal cell membrane (CM) and alter transmembrane potential (DeltaPsi) as key parts of their lethal mechanism. Thus, a sense-response system for detecting and mediating adaptive responses to such stresses could impact organism survival; the Staphylococcus aureus LytSR two-component regulatory system (TCRS) may serve as such a DeltaPsi sensor. One well-known target of this system is the lrgAB operon, which, along with the related cidABC operon, has been shown to be a regulator in the control of programmed cell death and lysis. We used an isogenic set of S. aureus strains: (i) UAMS-1, (ii) its isogenic DeltalytS and DeltalrgAB mutants, and (iii) plasmid-complemented DeltalytSR and DeltalrgAB mutants. The DeltalytS strain displayed significantly increased in vitro susceptibilities to all HDPs tested (neutrophil-derived human neutrophil peptide 1 [hNP-1], platelet derived thrombin-induced platelet microbicidal proteins [tPMPs], and the tPMP mimetic peptide RP-1), as well as to calcium-daptomycin (DAP), a cationic antimicrobial peptide (CAP). In contrast, the DeltalrgAB strain exhibited no significant changes in susceptibilities to these cationic peptides, indicating that although lytSR positively regulates transcription of lrgAB, increased HDP/CAP susceptibilities in the DeltalytS mutant were lrgAB independent. Further, parental UAMS-1 (but not the DeltalytS mutant) became more resistant to hNP-1 and DAP following pretreatment with carbonyl cyanide m-chlorophenylhydrazone (CCCP) (a CM-depolarizing agent). Of note, lytSR-dependent survival against CAP/HDP killing was not associated with changes in either surface positive charge, expression of mprF and dlt, or CM fluidity. The DeltalytS strain (but not the DeltalrgAB mutant) displayed a significant reduction in target tissue survival in an endocarditis model during DAP treatment. Collectively, these results suggest that the lytSR TCRS plays an important role in adaptive responses of S. aureus to CM-perturbing HDPs/CAPs, likely by functioning as a sense-response system for detecting subtle changes in DeltaPsi. PMID- 23733467 TI - Efficacy and safety of metronidazole for pulmonary multidrug-resistant tuberculosis. AB - Pulmonary lesions from active tuberculosis patients are thought to contain persistent, nonreplicating bacilli that arise from hypoxic stress. Metronidazole, approved for anaerobic infections, has antituberculosis activity against anoxic bacilli in vitro and in some animal models and may target persistent, nonreplicating bacilli. In this double-blind, placebo-controlled trial, pulmonary multidrug-resistant tuberculosis subjects were randomly assigned to receive metronidazole (500 mg thrice daily) or placebo for 8 weeks in addition to an individualized background regimen. Outcomes were measured radiologically (change on high-resolution computed tomography [HRCT]), microbiologically (time to sputum smear and culture conversion), and clinically (status 6 months after stopping therapy). Enrollment was stopped early due to excessive peripheral neuropathies in the metronidazole arm. Among 35 randomized subjects, 31 (15 metronidazole, 16 placebo) were included in the modified intent-to-treat analysis. There were no significant differences by arm in improvement of HRCT lesions from baseline to 2 or 6 months. More subjects in the metronidazole arm converted their sputum smear (P = 0.04) and liquid culture (P = 0.04) to negative at 1 month, but these differences were lost by 2 months. Overall, 81% showed clinical success 6 months after stopping therapy, with no differences by arm. However, 8/16 (50%) of subjects in the metronidazole group and 2/17 (12%) of those in the placebo group developed peripheral neuropathy. Subjects who received metronidazole were 4.3 fold (95% confidence interval [CI], 1.1 to 17.1) more likely to develop peripheral neuropathies than subjects who received placebo. Metronidazole may have increased early sputum smear and culture conversion but was too neurotoxic to use over the longer term. Newer nitroimidazoles with both aerobic and anaerobic activity, now in clinical trials, may increase the sterilizing potency of future treatment regimens. PMID- 23733468 TI - Azithromycin attenuates lung inflammation in a mouse model of ventilator associated pneumonia by multidrug-resistant Acinetobacter baumannii. AB - Acinetobacter baumannii is one of the main pathogens that cause ventilator associated pneumonia (VAP) and is associated with a high rate of mortality. Little is known about the efficacy of macrolides against A. baumannii. In order to confirm the efficacy of azithromycin (AZM) against VAP caused by multidrug resistant A. baumannii (MDRAB), we used a mouse model that mimics VAP by placement of a plastic tube in the bronchus. AZM (10 and 100 mg/kg of body weight) was administered subcutaneously every 24 h beginning at 3 h after inoculation. Phosphate-buffered saline was administered as the control. Survival was evaluated over 7 days. At 48 h postinfection, mice were sacrificed and the numbers of viable bacteria in lungs and bronchoalveolar lavage fluid were compared. Histopathological analysis of lung specimens was also performed. The treatment groups displayed significantly longer survival than the control group (P < 0.05). AZM did not have an antimicrobial effect. Histopathological examination of lung specimens indicated that the progression of lung inflammation was prevented in the AZM-treated groups. Furthermore, total cell and neutrophil counts, as well as cytokine levels, in bronchoalveolar lavage fluid were significantly decreased (P < 0.05) in the AZM-treated groups. AZM may have a role for the treatment of VAP with MDRAB because of its anti-inflammatory effects. PMID- 23733469 TI - Molecular characterization of an rsmD-like rRNA methyltransferase from the Wolbachia endosymbiont of Brugia malayi and antifilarial activity of specific inhibitors of the enzyme. AB - The endosymbiotic organism Wolbachia is an attractive antifilarial drug target. Here we report on the cloning and expression of an rsmD-like rRNA methyltransferase from the Wolbachia endosymbiont of Brugia malayi, its molecular properties, and assays for specific inhibitors. The gene was found to be expressed in all the major life stages of B. malayi. The purified enzyme expressed in Escherichia coli was found to be in monomer form in its native state. The activities of the specific inhibitors (heteroaryl compounds) against the enzyme were tested with B. malayi adult and microfilariae for 7 days in vitro at various concentrations, and NSC-659390 proved to be the most potent compound (50% inhibitory concentration [IC50], 0.32 MUM), followed by NSC-658343 (IC50, 4.13 MUM) and NSC-657589 (IC50, 7.5 MUM). On intraperitoneal administration at 5 mg/kg of body weight for 7 days to adult jirds into which B. malayi had been transplanted intraperitoneally, all the compounds killed a significant proportion of the implanted worms. A very similar result was observed in infected mastomys when inhibitors were administered. Docking studies of enzyme and inhibitors and an in vitro tryptophan quenching experiment were also performed to understand the binding mode and affinity. The specific inhibitors of the enzyme showed a higher affinity for the catalytic site of the enzyme than the nonspecific inhibitors and were found to be potent enough to kill the worm (both adults and microfilariae) in vitro as well as in vivo in a matter of days at micromolar concentrations. The findings suggest that these compounds be evaluated against other pathogens possessing a methyltransferase with a DPPY motif and warrant the design and synthesis of more such inhibitors. PMID- 23733470 TI - Candida albicans mucin Msb2 is a broad-range protectant against antimicrobial peptides. AB - The human fungal pathogen Candida albicans releases a large glycofragment of the Msb2 surface protein (Msb2*) into the growth environment, which protects against the action of human antimicrobial peptides (AMPs) LL-37 and histatin-5. Quantitation of Msb2*/LL-37 interactions by microscale thermophoresis revealed high-affinity binding (dissociation constant [KD] = 73 nM), which was lost or greatly diminished by lack of O-glycosylation or by Msb2* denaturation. Msb2* also interacted with human alpha- and beta-defensins and protected C. albicans against these AMPs. In addition, the lipopeptide antibiotic daptomycin was bound and inactivated by Msb2*, which prevented the killing of bacterial pathogens Staphylococcus aureus, Enterococcus faecalis, and Corynebacterium pseudodiphtheriticum. In coculturings or mixed biofilms of S. aureus with C. albicans wild-type but not msb2 mutant strains, the protective effects of Msb2* on the bactericidal action of daptomycin were demonstrated. These results suggest that tight binding of shed Msb2* to AMPs that occurs during bacterial coinfections with C. albicans compromises antibacterial therapy by inactivating a relevant reserve antibiotic. PMID- 23733471 TI - Pharmacokinetics of caspofungin in critically ill patients on continuous renal replacement therapy. AB - Caspofungin pharmacokinetics was assessed in 27 critically ill patients, including 7 on continuous venovenous hemofiltration (CVVH), 8 on continuous venovenous hemodialysis (CVVHD), and 13 not requiring continuous renal replacement therapy (CRRT). Caspofungin exposure during CRRT was very similar to that of the control group and comparable to that in healthy volunteers. Caspofungin clearance by CRRT was very low. Therefore, the standard dosage of caspofungin is probably adequate for critically ill patients undergoing CVVH or CVVHD. PMID- 23733472 TI - First report of the multiresistance gene cfr in Streptococcus suis. AB - The multiresistance gene cfr was identified for the first time in streptococci, namely, in porcine Streptococcus suis isolate S10. The cfr gene was detected on the ~100-kb plasmid pStrcfr, where it was bracketed by two copies of the novel insertion sequence ISEnfa5, located in the same orientation. The detection of a cfr- and ISEnfa5-containing amplicon by inverse PCR suggests that ISEnfa5 may play a role in the dissemination of cfr. PMID- 23733473 TI - Potent rifamycin-sparing regimen cures guinea pig tuberculosis as rapidly as the standard regimen. AB - Strategies involving new drug combinations, as well as new uses of existing drugs, are urgently needed to reduce the time required to cure patients with drug sensitive or multidrug-resistant (MDR) tuberculosis (TB). We compared the sterilizing activity of the standard first-line antitubercular regimen, rifampin isoniazid-pyrazinamide (RHZ), with that of the novel regimen PA-824-moxifloxacin pyrazinamide (PaMZ), which is currently being studied in clinical trials (NCT01498419), in the guinea pig model of chronic TB infection, in which animals develop necrotic granulomas histologically resembling their human counterparts. Guinea pigs were aerosol infected with ~2 log10 bacilli of wild-type Mycobacterium tuberculosis H37Rv, and antibiotic treatment was initiated 6 weeks after infection. Separate groups of animals received RHZ, PaMZ, or single or two drug components of the latter regimen administered at human-equivalent doses 5 days/week for a total of 8 weeks. Relapse rates were assessed 3 months after discontinuation of treatment to determine the sterilizing activity of each combination regimen. PaMZ given at human-equivalent doses was safe and well tolerated for the entire treatment period and rendered guinea pig lungs culture negative more rapidly than RHZ did. After 1 month of treatment, 80% and 50% of animals in the RHZ and PaMZ groups, respectively, had lung culture-positive relapse. Both combination regimens prevented microbiological relapse when administered for a total of 2 months. Our data support the use of PaMZ as a novel isoniazid- and rifamycin-sparing regimen suitable for treatment of both drug sensitive TB and MDR-TB. PMID- 23733474 TI - Multiple genetic pathways involving amino acid position 143 of HIV-1 integrase are preferentially associated with specific secondary amino acid substitutions and confer resistance to raltegravir and cross-resistance to elvitegravir. AB - Y143C,R substitutions in HIV-1 integrase define one of three primary raltegravir (RAL) resistance pathways. Here we describe clinical isolates with alternative substitutions at position 143 (Y143A, Y143G, Y143H, and Y143S [Y143A,G,H,S]) that emerge less frequently, and we compare the genotypic and phenotypic profiles of these viruses to Y143C,R viruses to reconcile the preferential selection of Y143C,R variants during RAL treatment. Integrase amino acid sequences and RAL susceptibility were characterized in 117 patient isolates submitted for drug resistance testing and contained Y143 amino acid changes. The influence of specific Y143 substitutions on RAL susceptibility and their preferential association with particular secondary substitutions were further defined by evaluating the composition of patient virus populations along with a large panel of site-directed mutants. Our observations demonstrate that the RAL resistance profiles of Y143A,G,H,S viruses and their association with specific secondary substitutions are similar to the well-established Y143C profile but distinct from the Y143R profile. Y143R viruses differ from Y143A,C,G,H,S viruses in that Y143R confers a greater reduction in RAL susceptibility as a single substitution, consistent with a lower resistance barrier. Among Y143A,C,G,H,S viruses, the higher prevalence of Y143C viruses is the result of a lower genetic barrier than that of the Y143A,G,S viruses and a lower resistance barrier than that of the Y143H viruses. In addition, Y143A,C,G,H,S viruses require multiple secondary substitutions to develop large reductions in RAL susceptibility. Patient-derived viruses containing Y143 substitutions exhibit cross-resistance to elvitegravir. PMID- 23733475 TI - Analysis of the small RNA transcriptional response in multidrug-resistant Staphylococcus aureus after antimicrobial exposure. AB - The critical role of noncoding small RNAs (sRNAs) in the bacterial response to changing conditions is increasingly recognized. However, a specific role for sRNAs during antibiotic exposure has not been investigated in Staphylococcus aureus. Here, we used Illumina RNA-Seq to examine the sRNA response of multiresistant sequence type 239 (ST239) S. aureus after exposure to four antibiotics (vancomycin, linezolid, ceftobiprole, and tigecycline) representing the major classes of antimicrobials used to treat methicillin-resistant S. aureus (MRSA) infections. We identified 409 potential sRNAs and then compared global sRNA and mRNA expression profiles at 2 and 6 h, without antibiotic exposure and after exposure to each antibiotic, for a vancomycin-susceptible strain (JKD6009) and a vancomycin-intermediate strain (JKD6008). Exploration of this data set by multivariate analysis using a novel implementation of nonnegative matrix factorization (NMF) revealed very different responses for mRNA and sRNA. Where mRNA responses clustered with strain or growth phase conditions, the sRNA responses were predominantly linked to antibiotic exposure, including sRNA responses that were specific for particular antibiotics. A remarkable feature of the antimicrobial response was the prominence of antisense sRNAs to genes encoding proteins involved in protein synthesis and ribosomal function. This study has defined a large sRNA repertoire in epidemic ST239 MRSA and shown for the first time that a subset of sRNAs are part of a coordinated transcriptional response to specific antimicrobial exposures in S. aureus. These data provide a framework for interrogating the role of staphylococcal sRNAs in antimicrobial resistance and exploring new avenues for sRNA-based antimicrobial therapies. PMID- 23733476 TI - Bacterial and clinical characteristics of health care- and community-acquired bloodstream infections due to Pseudomonas aeruginosa. AB - Health care-associated infections, including Pseudomonas aeruginosa bloodstream infection, have been linked to delays in appropriate antibiotic therapy and an increased mortality rate. The objective of this study was to evaluate intrinsic virulence, bacterial resistance, and clinical outcomes of health care-associated bloodstream infections (HCABSIs) in comparison with those of community-acquired bloodstream infections (CABSIs) caused by P. aeruginosa. We conducted a retrospective multicenter study of consecutive P. aeruginosa bacteremia patients at two university-affiliated hospitals. Demographic, clinical, and treatment data were collected. Microbiologic analyses included in vitro susceptibility profiles and type III secretory (TTS) phenotypes. Sixty CABSI and 90 HCABSI episodes were analyzed. Patients with HCABSIs had more organ dysfunction at the time of bacteremia (P = 0.05) and were more likely to have been exposed to antimicrobial therapy (P < 0.001) than those with CABSIs. Ninety-two percent of the carbapenem resistant P. aeruginosa infections were characterized as HCABSIs. The 30-day mortality rate for CABSIs was 26% versus 36% for HCABSIs (P = 0.38). The sequential organ failure assessment score at the time of bacteremia (hazard ratio [HR], 1.2; 95% confidence interval [CI], 1.1 to 1.3) and the TTS phenotype (HR 2.1; 95% CI, 1.1 to 3.9) were found to be independent predictors of the 30-day mortality rate. No mortality rate difference was observed between CABSIs and HCABSIs caused by P. aeruginosa. Severity of illness and expression of TTS proteins were the strongest predictors of the 30-day mortality rate due to P. aeruginosa bacteremia. Future P. aeruginosa bacteremia trials designed to neutralize TTS proteins are warranted. PMID- 23733477 TI - Prevalence and genetic characterization of second-line drug-resistant and extensively drug-resistant Mycobacterium tuberculosis in Rural China. AB - This study aimed to investigate the prevalence of resistance to second-line antituberculosis (anti-TB) drugs and its association with resistance-related mutations in Mycobacterium tuberculosis isolated in China. In the present study, we collected 380 isolates from a population-based study in China and tested the drug susceptibility to first- and selected second-line drugs. These results were compared with polymorphisms in the DNA sequences of genes associated with drug resistance and MIC values of the studied second-line drugs. Of 43 multidrug resistant M. tuberculosis isolates, 13 showed resistance to fluoroquinolones or injectable second-line drugs (preextensively drug-resistant TB [pre-XDR-TB]), and 4 were resistant to both and thus defined as extensively drug-resistant TB (XDR TB). Age and previous TB therapy, including use of second-line drugs, were two independent factors associated with increased resistance to both first- and second-line drugs. Molecular analysis identified the most frequent mutations in the resistance-associated genes: D94G in gyrA (29.1%) and A1401G in rrs (30.8%). Meanwhile, all 4 XDR-TB isolates had a mutation in gyrA, and 3 of them carried the A1401G mutation in rrs. Mutations in gyrA and rrs were associated with high level resistance to fluoroquinolones and the second-line injectable drugs. In addition to the identification of resistance-associated mutations and development of a rapid molecular test to diagnose the second-line drug resistance, it should be a priority to strictly regulate the administration of second-line drugs to maintain their efficacy to treat multidrug-resistant TB. PMID- 23733479 TI - Understanding the knowledge and practice of medicine: papers from the fourth Philosophy of Medicine Roundtable. PMID- 23733478 TI - Is LMNB1 a susceptibility gene for neural tube defects in humans? AB - BACKGROUND: Lamins are intermediate filament proteins that form a major component of the nuclear lamina, a protein complex at the surface of the inner nuclear membrane. Numerous clinically diverse conditions, termed laminopathies, have been found to result from mutation of LMNA. In contrast, coding or loss of function mutations of LMNB1, encoding lamin B1, have not been identified in human disease. In mice, polymorphism in Lmnb1 has been shown to modify risk of neural tube defects (NTDs), malformations of the central nervous system that result from incomplete closure of the neural folds. METHODS: Mutation analysis by DNA sequencing was performed on all exons of LMNB1 in 239 samples from patients with NTDs from the United Kingdom, Sweden, and United States. Possible functional effects of missense variants were analyzed by bioinformatics prediction and fluorescence in photobleaching. RESULTS: In NTD patients, we identified two unique missense variants that were predicted to disrupt protein structure/function and represent putative contributory mutations. Fluorescence loss in photobleaching analysis showed that the A436T variant compromised stability of lamin B1 interaction within the lamina. CONCLUSION: The genetic basis of human NTDs appears highly heterogenous with possible involvement of multiple predisposing genes. We hypothesize that rare variants of LMNB1 may contribute to susceptibility to NTDs. PMID- 23733480 TI - The molecular rationale of Src inhibition in colorectal carcinomas. AB - Src has been one of the most studied proto-oncogenes. The cellular Src (c-Src) holds a critical role in several human malignancies and has emerged as a key factor that promotes tumor progression during the multistep process of colorectal cancer (CRC) pathogenesis. The robust activation of Src in CRC of aggressive phenotype and poor prognosis seems to be a subsequent event of a strong link between its deregulated activity and the tumor's cell adhesion properties, invasiveness and metastatic potential. The rarely detected genetic defects drive interest in signaling networks that control Src kinase activity and integrate the association of Src with receptor tyrosine kinases (RTKs), such as the epidermal growth factor receptor (EGFR). Therefore, a dynamic crosstalk is being formed with oncogenic capacity and therapeutic applications, because Src inhibition seems to sensitize previously unresponsive cancer cells to chemotherapy and anti EGFR inhibitors. The present review explores the molecular basis behind Src inhibition in colorectal carcinomas. Furthermore, preclinical studies and clinical trials of Src inhibitors and combination regimens are discussed, providing new insights for further investigation and new therapeutic strategies. PMID- 23733481 TI - European drug agency's attempts to improve transparency stalled by legal action from two US drug companies. PMID- 23733482 TI - Dignitas accepts the first case of suicide for dementia from the UK. PMID- 23733483 TI - Identification of receptor-interacting regions of vitellogenin within evolutionarily conserved beta-sheet structures by using a peptide array. AB - Vitellogenesis, a key process in oviparous animals, is characterized by enhanced synthesis of the lipoprotein vitellogenin, which serves as the major yolk-protein precursor. In most oviparous animals, and specifically in crustaceans, vitellogenin is mainly synthesized in the hepatopancreas, secreted to the hemolymph, and taken up into the ovary by receptor-mediated endocytosis. In the present study, localization of the vitellogenin receptor and its interaction with vitellogenin were investigated in the freshwater prawn Macrobrachium rosenbergii. The receptor was immuno-histochemically localized to the cell periphery and around yolk vesicles. A receptor blot assay revealed that the vitellogenin receptor interacts with most known vitellogenin subunits, the most prominent being the 79 kDa subunit. The receptor was, moreover, able to interact with trypsin-digested vitellogenin peptides. By combining a novel peptide-array approach with tandem mass spectrometry, eleven vitellogenin-derived peptides that interacted with the receptor were identified. A 3D model of vitellogenin indicated that four of the identified peptides are N-terminally localized. One of the peptides is homologous to the receptor-recognized site of vertebrate vitellogenin, and assumes a conserved beta-sheet structure. These findings suggest that this specific beta-sheet region in the vitellogenin N-terminal lipoprotein domain is the receptor-interacting site, with the rest of the protein serving to enhance affinity for the receptor. The conservation of the receptor recognition site in invertebrate and vertebrate vitellogenin might have vast implications for oviparous species reproduction, development, immunity, and pest management. PMID- 23733484 TI - One-dimensional patterning of cells in silicone wells via compression-induced fracture. AB - We have adapted our existing compression-induced fracture technology to cell culture studies by generating linear patterns on a complex cell culture well structure rather than on simple solid constructs. We present a simple method to create one-dimensional (1D), submicron, and linear patterns of extracellular matrix on a multilayer silicone material. We identified critical design parameters necessary to optimize compression-induced fracture patterning on the wells, and applied stresses using compression Hoffman clamps. Finite-element analyses show that the incorporation of the well improves stress homogeneity (stress variation = 25%), and, thus, crack uniformity over the patterned region. Notably, a shallow well with a thick base (vs. deeper wells with thinner bases) reduces out-of-plane deflections by greater than a sixth in the cell culture region, improving clarity for optical imaging. The comparison of cellular and nuclear shape indices of a neuroblast line cultured on patterned 1D lines and unpatterned 2D surfaces reveals significant differences in cellular morphology, which could impact many cellular functions. Because 1D cell cultures recapitulate many important phenotypical traits of 3D cell cultures, our culture system offers a simple means to further study the relationship between 1D and 3D cell culture environments, without demanding expensive engineering techniques and expertise. PMID- 23733485 TI - Effect of readout direction in the edge profile on the modulation transfer function of computed radiographic systems by use of the edge method. AB - We investigated the effect of the readout direction of the edge profile obtained by the edge method on the presampled modulation transfer function (MTF) in various computed radiographic (CR) systems. There were no differences in the MTFs derived from two edge profiles in the sub-scanning direction of four CR systems used in this study. On the other hand, the MTFs measured at a readout direction from the low (edge) to the high (direct exposure) exposure region were higher than those measured at a readout direction from the high to the low exposure region in the laser-beam scanning direction for three of the four CR systems. Although this phenomenon depends on the CR system, it is important to understand and indicate both MTFs at the two edge profiles in the laser-beam scanning direction for accurate assessment of the resolution property. PMID- 23733486 TI - Very low levels of surface CD45 reflect CLL cell fragility, are inversely correlated with trisomy 12 and are associated with increased treatment-free survival. AB - It has recently been suggested that the percentage of smudge cells on blood smears from patients with chronic lymphocytic leukemia (CLL) could predict overall survival. However, smudge cells are a cytological artifact influenced by multiple physical factors not related to CLL. To identify simple parameters reflecting CLL cell fragility, we studied CD45 expression in a series of 66 patients with Binet stage A CLL. Decreased CD45 expression was specific for CLL cells when compared to 44 patients with a leukemic phase of B-cell non Hodgkin lymphoma and 42 control B-cells. CD45 expression was markedly decreased for all patients with CLL with high percentages of smudge cells. CLL cells with the lowest CD45 expression were the most sensitive to osmotic shock. Very low levels of CD45 expression were significantly associated with lack of CD38 expression, absence of trisomy 12, and with increased treatment free survival time. Altogether, these results demonstrate that low levels of CD45 expression are specific to CLL cells and reflect cell fragility, suggesting that this is an important intrinsic biological feature that determines disease course. PMID- 23733487 TI - The role of oxygen intermediates in the retention time of diacetyl adaptation in the nematode Caenorhabditis elegans. AB - Continuous presentation of the odorant diacetyl to the nematode Caenorhabditis elegans causes a decrease in the level of chemotactic response to diacetyl. This decline in response is caused by diacetyl adaptation. When wild-type nematodes were maintained at 15 degrees C after pre-exposure to diacetyl, diacetyl adaptation did not continue up to 2 hr. Adaptation continued up to 6 hr in nematodes bred at 20 degrees C, and it continued beyond 12 hr in nematodes bred at 25 degrees C. These results indicate that the retention time of diacetyl adaptation is dependent on the environmental breeding temperature and suggest that moderate oxygen signals are required for maintaining the attenuated response to diacetyl because of the correlation between breeding temperature and production of oxygen intermediates. When isp-1 and clk-1 mutants, which show reduced rates of oxygen intermediate production, were maintained at 20 and 25 degrees C after pre-exposure to diacetyl, the mutants showed a shorter retention time of diacetyl adaptation compared with that of wild-type nematodes. When gas-1 and mev-1 mutants, which have a hypersensitive response to oxidative stress, were maintained at 15 and 20 degrees C, they showed a longer retention time of adaptation, that is, adaptation continued beyond 2 and 12 hr, respectively. When wild-type nematodes were maintained on plates that included 0.05% alpha-lipoic acid, which suppresses production of oxygen intermediates, the retention time of adaptation did not continue up to 6 hr in nematodes bred at 20 degrees C and up to 12 hr in nematodes bred at 25 degrees C. These results support the possibility that oxygen intermediates contribute to retention time for diacetyl adaptation in the nematode C. elegans. PMID- 23733488 TI - Effect of Crocus sativus L. (saffron) on coagulation and anticoagulation systems in healthy volunteers. AB - Saffron showed some effects on blood coagulation and platelet aggregation in in vitro and in vivo studies. In a clinical trial with a limited number volunteers, saffron tablets influenced on bleeding time. In this study, the effect of saffron on plasma level of fibrinogen, factor VII (as coagulant agent), C and S protein (as anti-coagulant agent), PT and PTT in a larger sample size was evaluated. The study was a double-blind, placebo-controlled study consisting of 1 week treatment with 200 mg and 400 mg saffron tablets. Sixty healthy volunteers (age range 20-50 years) were selected for the study. The volunteers were divided into three groups of 20 each. Group 1 received placebo; Groups 2 and 3 received 200 mg and 400 mg saffron tablets, respectively, for 7 days (1 tablet per day). Before and after 7 days treatment and also 1 month after that, blood samples were taken. The plasma levels of fibrinogen, factor VII, C and S protein, PT and PTT were evaluated. Statistical analysis showed no difference between groups for any of evaluated factors. This study rejected any effect of saffron with dose of 200 and 400 mg for 1 week on coagulant and anticoagulant system. PMID- 23733489 TI - Memory reconsolidation allows the consolidation of a concomitant weak learning through a synaptic tagging and capture mechanism. AB - Motivated by the synaptic tagging and capture (STC) hypothesis, it was recently shown that a weak learning, only able to produce short-term memory (STM), can succeed in establishing long-term memory (LTM) with a concomitant, stronger experience. This is consistent with the capture, by the first-tagged event, of the so-called plasticity-related proteins (PRPs) provided by the second one. Here, we describe how a concomitant session of reactivation/reconsolidation of a stronger, contextual fear conditioning (CFC) memory, allowed LTM to result from a weak spatial object recognition (wSOR) training. Consistent with an STC process, the effect was observed only during a critical time window and was dependent on the CFC reconsolidation-related protein synthesis. Retrieval by itself (without reconsolidation) did not have the same promoting effect. We also found that the inactivation of the NMDA receptor by AP5 prevented wSOR training to receive this support of CFC reconsolidation (supposedly through the production of PRPs), which may be the equivalent of blocking the setting of a learning tag in the dorsal CA1 region for that task. Furthermore, either a Water Maze reconsolidation, or a CFC extinction session, allowed the formation of wSOR-LTM. These results suggest for the first time that a reconsolidation session can promote the consolidation of a concomitant weak learning through a probable STC mechanism. These findings allow new insights concerning the influence of reconsolidation in the acquisition of memories of otherwise unrelated events during daily life situations. PMID- 23733490 TI - Continuous development of schemes for parallel computing of the electrostatics in biological systems: implementation in DelPhi. AB - Due to the enormous importance of electrostatics in molecular biology, calculating the electrostatic potential and corresponding energies has become a standard computational approach for the study of biomolecules and nano-objects immersed in water and salt phase or other media. However, the electrostatics of large macromolecules and macromolecular complexes, including nano-objects, may not be obtainable via explicit methods and even the standard continuum electrostatics methods may not be applicable due to high computational time and memory requirements. Here, we report further development of the parallelization scheme reported in our previous work (Li, et al., J. Comput. Chem. 2012, 33, 1960) to include parallelization of the molecular surface and energy calculations components of the algorithm. The parallelization scheme utilizes different approaches such as space domain parallelization, algorithmic parallelization, multithreading, and task scheduling, depending on the quantity being calculated. This allows for efficient use of the computing resources of the corresponding computer cluster. The parallelization scheme is implemented in the popular software DelPhi and results in speedup of several folds. As a demonstration of the efficiency and capability of this methodology, the electrostatic potential, and electric field distributions are calculated for the bovine mitochondrial supercomplex illustrating their complex topology, which cannot be obtained by modeling the supercomplex components alone. PMID- 23733491 TI - Tandem Ru-alkylidene-catalysed cross metathesis/hydrogenation: synthesis of lipophilic amino acids. AB - Highly efficient synthesis of lipidic amino acids can be achieved via Ru alkylidene-catalysed cross metathesis of long chain alkenes with commercially available allylglycine. The resultant unsaturated analogues can be then optionally hydrogenated under mild reaction conditions by using the spent metathesis catalyst. PMID- 23733492 TI - Embryonic development of endoderm in chicken (Gallus gallus domesticus). AB - The poultry industry is a sector of agribusiness which represents an important role in the country's agricultural exports. Therefore, the study about embryogenesis of the domestic chicken (Gallus gallus domesticus) has a great economic importance. The aim of this study was to evaluate embryonic development of the endoderm in chicken (Gallus gallus domesticus). Forty fertilized eggs of domestic chickens, starting from the 1st day of gestation and so on until the 19 days of the incubation were collected from the Granja Sao Jose (Amparo, SP, Brazil). Embryos and fetus were fixed in 10% formaldehyde solution, identified, weighed, measured, and subjected to light and scanning electron microscopy. The endoderm originates the internal lining epithelium of the digestive, immune, respiratory systems, and the organs can be visualized from the second day (48 h) when the liver is formed. The formation of the digestive system was complete in the 12th day. Respiratory system organs begin at the fourth day as a disorganized tissue and undifferentiated. Their complete differentiation was observed at the 10 days of incubation, however, until the 19 days the syrinx was not observed. The formation of immune system at 10th day was observed with observation of the spleen, thymus, and cloacal bursa. The study of the organogenesis of the chicken based on germ layers is very complex and underexplored, and the study of chicken embryology is very important due the economic importance and growth of the use of this animal model studies such as genetic studies. PMID- 23733493 TI - Cytochrome P450 2A6 deletion polymorphism and risk of lung cancer: a meta analysis. AB - Previous studies concerning the association between cytochrome P450 2A6 (CYP2A6) deletion polymorphism and lung cancer risk provided controversial results. To clarify the precise association, a meta-analysis was performed. The electronic databases PubMed, Chinese Biomedical Database and Chinese National Knowledge Infrastructure Database were searched for case-control studies last updated on June 3, 2012 that investigated CYP2A6 deletion polymorphism and lung cancer risk. The odds ratio (OR) and its respective 95 % confidence interval (95 % CI) were used to measure the strength of association by means of a genetic model free approach. A total of 8 studies including 2,607 cases and 2,595 controls met the inclusion criteria and were subjected to the final analysis. The most appropriate co-dominant model was adopted. Overall, we found that CYP2A6 *1/*1 genotype was associated with an increased risk of lung cancer relative to *4/*4 genotype (OR = 2.65, 95 % CI: 1.84-3.81, P < 0.001). Significant association was also detected among Asians. Publication bias was absent in this meta-analysis. Therefore, our data suggested that the presence of the CYP2A6 *1/*1 might be associated with an increased lung cancer risk, especially for Asians. Further studies well-designed among different ethnicity populations are required. PMID- 23733496 TI - Structures of KOD and 9 degrees N DNA polymerases complexed with primer template duplex. AB - Replicate it: Structures of KOD and 9 degrees N DNA polymerases, two enzymes that are widely used to replicate DNA with highly modified nucleotides, were solved at high resolution in complex with primer/template duplex. The data elucidate substrate interaction of the two enzymes and pave the way for further optimisation of the enzymes and substrates. PMID- 23733495 TI - Living alone and cardiovascular health status in residents of a rural village of coastal Ecuador (The Atahualpa Project). AB - OBJECTIVES: Knowledge of region-specific factors affecting the cardiovascular health (CVH) is mandatory to reduce the growing burden of stroke and ischemic heart disease in rural areas of Latin American. We conducted a population-based case-control study to assess the CVH status of Atahualpa residents-a rural village representative of Coastal Ecuador-according to their living arrangements. METHODS: All Atahualpa residents aged >=40 years and free of stroke or ischemic heart disease that lived alone were identified during a door-to-door census, and their CVH status was compared to that of a sample of residents that lived with relatives. Four controls individually matched for age, gender, education, job and alcohol intake, and randomly selected from different households, were selected for each case-person. RESULTS: A total of 185 persons (37 who lived alone and 148 matched controls) were included. A poor CVH status was found in 89.2 % case patients and 72.3 % controls (p = 0.03). We found significantly worse levels of physical activity (p < 0.0001) and non-significant trends for worse healthy diet and glucose levels among case-persons than controls. CONCLUSIONS: This study suggests that social isolation is associated with a worse CVH in rural coastal Ecuador. An ongoing community-based intervention may prove effective to improve CVH status in these social isolated persons. PMID- 23733497 TI - Familial aggregation of childhood and adult cancer in the Utah genealogy. AB - A small proportion of childhood cancer is attributable to known hereditary syndromes, but whether there is any familial component to the remainder remains uncertain. We explored familial aggregation of cancer in a population-based case control study using genealogical record linkage and designed to overcome limitations of previous studies. Subjects were selected from the Utah Population Database. We compared risk of cancer in adult first-degree relatives of children who were diagnosed with cancer with the risk in relatives of children who had not had a cancer diagnosed. We identified 1,894 childhood cancer cases and 3,788 controls; 7,467 relatives of cases and 14,498 relatives of controls were included in the analysis. Relatives of children with cancer had a higher risk of cancer in adulthood than relatives of children without cancer [odds ratio (OR) 1.31, 95% confidence interval (CI) 1.11-1.56]; this was restricted to mothers and siblings and was not evident in fathers. Familial aggregation appeared stronger among relatives of cases diagnosed before 5 years of age (OR 1.48, 95% CI 1.13-1.95) than among relatives of cases who were older when diagnosed (OR 1.22, 95% CI 0.98 1.51). These findings provide evidence of a generalized excess of cancer in the mothers and siblings of children with cancer. The tendency for risk to be higher in the relatives of children who were younger at cancer diagnosis should be investigated in other large data sets. The excesses of thyroid cancer in parents of children with cancer and of any cancer in relatives of children with leukemia merit further investigation. PMID- 23733498 TI - Valproate prescriptions for nonepilepsy disorders in reproductive-age women. AB - BACKGROUND: Scientific evidence has consistently shown taking valproate during pregnancy increases risks of congenital malformations and cognitive impairment. As such, elimination of its use would be an important step in birth defects prevention. There are guidelines discouraging its use among women with epilepsy, but none exists for women without epilepsy, nor is the prevalence of valproate for nonepilepsy indications known. METHODS: Using de-identified data from the National Hospital and Ambulatory Medical Care Surveys (1996-2007), we examined individual prescriptions for reproductive-age adolescent girls and adult women ages 15 to 44 years in the United States, and estimated the number of antiepileptic drug and valproate prescriptions in the aggregate. We classified our study population using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes, as women with epilepsy and women without epilepsy. The prevalence of antiepileptic drug and valproate prescriptions among women without epilepsy was estimated as prescriptions per 1000 patient visits for every 3-year time interval and the overall study period. RESULTS: We found 83% of valproate prescriptions were issued to women without epilepsy and 74% of these were for psychiatric diagnoses. The prevalence of antiepileptic drug prescriptions among women without epilepsy tripled during the study period (10.3 [1996-1998] vs. 34.9 [2005-2007] per 1000 patient visits), whereas valproate prescriptions remained relatively stable (3.1 [1996-1998] vs. 3.7 [2005-2007] per 1000 patient visits). CONCLUSION: Most women of reproductive age who receive a valproate prescription do not have epilepsy. Valproate prescriptions did not decline, despite increasing knowledge of its teratogenicity. Reducing valproate use among women of reproductive age, especially among those who use the drug for psychiatric indications, would prevent birth defects and cognitive deficits. PMID- 23733499 TI - The effectiveness of therapeutic class IV (10 W) laser treatment for epicondylitis. AB - BACKGROUND AND OBJECTIVE: Photobiomodulation has been shown to modulate cellular protein production and stimulate tendon healing in a dose-dependent manner. Previous studies have used class IIIb lasers with power outputs of less than 0.5 W. Here we evaluate a dual wavelength (980/810 nm) class IV laser with a power output of 10 W for the purpose of determining the efficacy of class IV laser therapy in alleviating the pain and dysfunction associated with chronic epicondylitis. METHODS: Sixteen subjects volunteered for laser therapy, or an identically appearing sham instrument in a randomized, placebo-controlled, double blinded clinical trial. Subjects underwent clinical examination (pain, function, strength, and ultrasonic imaging) to confirm chronic tendinopathy of the extensor carpi radialis brevis tendon, followed by eight treatments of 6.6 +/- 1.3 J/cm(2) (laser), or sham over 18 days. Safety precautions to protect against retinal exposure to the laser were followed. The exam protocol was repeated at 0, 3, 6 and 12 months post-treatment. RESULTS: No initial differences were seen between the two groups. In the laser treated group handgrip strength improved by 17 +/- 3%, 52 +/- 7%, and 66 +/- 6% at 3, 6, and 12 months respectively; function improved by 44 +/- 1%, 71 +/- 3%, and 82 +/- 2%, and pain with resistance to extension of the middle finger was reduced by 50 +/- 6%, 93 +/- 4%, and 100 +/- 1% at 3, 6 and 12 months, respectively. In contrast, no changes were seen until 12 months following sham treatment (12 months: strength improved by 13 +/- 2%, function improved by 52 +/- 3%, pain with resistance to extension of the middle finger reduced by 76 +/- 2%). No adverse effects were reported at any time. CONCLUSIONS: These findings suggest that laser therapy using the 10 W class IV instrument is efficacious for the long-term relief of the symptoms associated with chronic epicondylitis. The potential for a rapidly administered, safe and effective treatment warrants further investigation. PMID- 23733500 TI - Inflammatory response and bone healing capacity of two porous calcium phosphate ceramics in critical size cortical bone defects. AB - In the present study, two open porous calcium phosphate ceramics, beta-tricalcium phosphate (beta-TCP), and hydroxyapatite (HA) were compared in a critical-sized femoral defect in rats. Previous comparisons of these two ceramics showed significantly greater osteoinductive potential of beta-TCP upon intramuscular implantation and a better performance in a spinal fusion model in dogs. Results of the current study also showed significantly more bone formation in defects grafted with beta-TCP compared to HA; however, both the ceramics were not capable of increasing bone formation to such extend that it bridges the defect. Furthermore, a more pronounced degradation of beta-TCP was observed as compared to HA. Progression of inflammation and initiation of new bone formation were assessed for both materials at multiple time points by histological and fluorochrome-based analyses. Until 12 days postimplantation, a strong inflammatory response in absence of new bone formation was observed in both ceramics, without obvious differences between the two materials. Four weeks postimplantation, signs of new bone formation were found in both beta-TCP and HA. At 6 weeks, inflammation had subsided in both ceramics while bone deposition continued. In conclusion, the two ceramics differed in the amount of bone formed after 8 weeks of implantation, whereas no differences were found in the duration of the inflammatory phase after implantation or initiation of new bone formation. PMID- 23733501 TI - New developments in arterial spin labeling pulse sequences. AB - Since it was introduced over 20 years ago, arterial spin labeling and related methods have steadily evolved over the years, and the field has seen not only improvements in technical specifications, such as signal-to-noise ratio and accuracy, but also the introduction of methods that allow for the collection of new information, such as maps of vascular territories and measurement of venous oxygenation. Some of these recent advances are reviewed here. PMID- 23733502 TI - Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine binding site of N-methyl-D-aspartate receptor. AB - Sunifiram is a novel pyrrolidone nootropic drug structurally related to piracetam, which was developed for neurodegenerative disorder like Alzheimer's disease. Sunifiram is known to enhance cognitive function in some behavioral experiments such as Morris water maze task. To address question whether sunifiram affects N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic function in the hippocampal CA1 region, we assessed the effects of sunifiram on NMDAR-dependent long-term potentiation (LTP) by electrophysiology and on phosphorylation of synaptic proteins by immunoblotting analysis. In mouse hippocampal slices, sunifiram at 10-100 nM significantly enhanced LTP in a bell-shaped dose-response relationship which peaked at 10 nM. The enhancement of LTP by sunifiram treatment was inhibited by 7-chloro-kynurenic acid (7-ClKN), an antagonist for glycine binding site of NMDAR, but not by ifenprodil, an inhibitor for polyamine site of NMDAR. The enhancement of LTP by sunifilam was associated with an increase in phosphorylation of alpha-amino-3-hydroxy-5-methylisozazole-4-propionate receptor (AMPAR) through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and an increase in phosphorylation of NMDAR through activation of protein kinase Calpha (PKCalpha). Sunifiram treatments at 1-1000 nM increased the slope of field excitatory postsynaptic potentials (fEPSPs) in a dose-dependent manner. The enhancement was associated with an increase in phosphorylation of AMPAR receptor through activation of CaMKII. Interestingly, under the basal condition, sunifiram treatments increased PKCalpha (Ser-657) and Src family (Tyr 416) activities with the same bell-shaped dose-response curve as that of LTP peaking at 10 nM. The increase in phosphorylation of PKCalpha (Ser-657) and Src (Tyr-416) induced by sunifiram was inhibited by 7-ClKN treatment. The LTP enhancement by sunifiram was significantly inhibited by PP2, a Src family inhibitor. Finally, when pretreated with a high concentration of glycine (300 MUM), sunifiram treatments failed to potentiate LTP in the CA1 region. Taken together, sunifiram stimulates the glycine-binding site of NMDAR with concomitant PKCalpha activation through Src kinase. Enhancement of PKCalpha activity triggers to potentiate hippocampal LTP through CaMKII activation. PMID- 23733503 TI - Does learning in clinical context in anatomical sciences improve examination results, learning motivation, or learning orientation? AB - The preclinical compulsory elective course "Ready for the Operating Room (OR)!?" [in German]: "Fit fur den OP (FOP)"] was implemented for students in their second year, who were simultaneously enrolled in the gross anatomy course. The objective of the study was to determine whether the direct practical application of anatomical knowledge within the surgical context of the course led to any improvement in learning motivation, learning orientation, and ultimately examination results in the gross anatomy course, as compared with a control group. Within the scope of five teaching sessions, the students learned surgical hand disinfection, suturing techniques, and the identification of commonly used surgical instruments. In addition, the students attended five surgical demonstrations performed by surgical colleagues on cadavers. Successful learning of these basic skills was then assessed based on an Objectively Structured Practical Examination. Learning motivation and learning orientation in both subgroups was determined using the SELLMO-ST motivation test and the Approaches and Study Skills Inventory test. While a significant increase in work avoidance was identified in the control group, this was not the case for FOP participants. Similarly, an increase in the "deep approach" to learning, as well as a decrease in the "surface approach," was able to be documented among the FOP participants following completion of the course. The results suggest that students enrolled in the gross anatomy course, who were simultaneously provided with the opportunity to learn in clinical context, were more likely to be successful at maintaining learning motivation and learning orientation required for the learning process, than students who attended the gross anatomy course alone. PMID- 23733504 TI - Superselective renal artery embolization in the treatment of renal hemorrhage. AB - BACKGROUND: Renal hemorrhage is a potentially life-threatening event that may follow trauma, operation, biopsy, and sudden spontaneous rupture of renal tumors or aneurysms. Superselective renal artery embolization (SRAE) is a well established method for such cases. OBJECTIVES: To assess the effectiveness of SRAE in the treatment of renal hemorrhage at our institute. MATERIALS AND METHODS: We respectively reviewed the medical records of patients who underwent SRAE for renal hemorrhage from January 2005 to June 2012. Data on patients' characteristics, indications, requirement of pre-embolization blood transfusion, angiographic finding, location of bleeding site, embolization agents, post embolization transfusion requirement, complications and the outcome were recorded. RESULTS: A total of 46 patients, aged 26-73 years, underwent SRAE because of hemorrhage after percutaneous nephrolithotomy (n = 25), partial nephrectomy (n = 6), renal biopsy (n = 2), trauma (n = 2), rupture of angiomyolipoma (n = 4), renal aneurysm (n = 1), and renal ateriovenous malformations (n = 6). A total of 41 patients (80.8 %) underwent successful embolization. Treatment failed in 5 patients with hemorrhage caused by percutaneous nephrolithotomy. Of these, four patients underwent a secondly superselective embolization and had a successful outcome. The remaining one was managed by conservative therapy with repeated blood transfusions. No patient required nephrectomy to save the life of the patient. No serious procedure related complications occurred. CONCLUSIONS: SRAE is an effective and minimal invasive method for the control of renal hemorrhage. Our experience strongly recommended the first-line use of SRAE for severe renal hemorrhage. PMID- 23733505 TI - Dominant role of oncogene dosage and absence of tumor suppressor activity in Nras driven hematopoietic transformation. AB - Biochemical properties of Ras oncoproteins and their transforming ability strongly support a dominant mechanism of action in tumorigenesis. However, genetic studies unexpectedly suggested that wild-type (WT) Ras exerts tumor suppressor activity. Expressing oncogenic Nras(G12D) in the hematopoietic compartment of mice induces an aggressive myeloproliferative neoplasm that is exacerbated in homozygous mutant animals. Here, we show that increased Nras(G12D) gene dosage, but not inactivation of WT Nras, underlies the aggressive in vivo behavior of Nras(G12D/G12D) hematopoietic cells. Modulating Nras(G12D) dosage had discrete effects on myeloid progenitor growth, signal transduction, and sensitivity to MAP-ERK kinase (MEK) inhibition. Furthermore, enforced WT N-Ras expression neither suppressed the growth of Nras-mutant cells nor inhibited myeloid transformation by exogenous Nras(G12D). Importantly, NRAS expression increased in human cancer cell lines with NRAS mutations. These data have therapeutic implications and support reconsidering the proposed tumor suppressor activity of WT Ras in other cancers. SIGNIFICANCE: Understanding the mechanisms of Ras -induced transformation and adaptive cellular responses is fundamental. The observation that oncogenic Nras lacks tumor suppressor activity, whereas increased dosage strongly modulates cell growth and alters sensitivity to MEK inhibition, suggests new therapeutic opportunities in cancer. PMID- 23733507 TI - Measure of microscopy mineral image clarity constructed using the sequentially combined toggle and top-hat based contrast operator. AB - Correctly and effectively quantifying the clarity of microscopy mineral image is important and useful to produce clear image for mineral analysis. To well quantify the clarity of mineral image, an effective measure constructed using the sequentially combined toggle and top-hat based contrast operator is proposed in this article. First, the sequentially combined toggle and top-hat based contrast operator is used to extract the effective features which represent the clarity of mineral image. Second, the multiscale clarity features corresponding to each scale are extracted. Finally, after combining the multiscale clarity features in one feature image, the mean value of the feature image is constructed as the measure of mineral image clarity. Because the sequentially combined toggle and top-hat based contrast operator could effectively extract the clarity features, the clarity features are directly used as the measure of image clarity. Therefore, the proposed measure is effective and reasonable. The experimental results on different types of microscopy mineral images verified the effective performance of the proposed measure. PMID- 23733506 TI - Time-course of neuroendocrine changes and its correlation with hypertension induced by ethanol consumption. AB - Ethanol (ETOH) consumption has been associated with endocrine and autonomic changes, including the development of hypertension. However, the sequence of pathophysiological events underlying the emergence of this effect is poorly understood. AIMS: This study aimed to establish a time-course correlation between neuroendocrine and cardiovascular changes contributing to the development of hypertension following ETOH consumption. METHODS: Male adult Wistar rats were subjected to the intake of increasing ETOH concentrations in their drinking water (first week: 5%, second week: 10%, third and fourth weeks: 20% v/v). RESULTS: ETOH consumption decreased plasma and urinary volumes, as well as body weight and fluid intake. Furthermore, plasma osmolality, plasma sodium and urinary osmolality were elevated in the ETOH-treated rats. ETOH intake also induced a progressive increase in the mean arterial pressure (MAP), without affecting heart rate. Initially, this increase in MAP was correlated with increased plasma concentrations of adrenaline and noradrenaline. After the second week of ETOH treatment, plasma catecholamines returned to basal levels, and incremental increases were observed in plasma concentrations of vasopressin (AVP) and angiotensin II (ANG II). Conversely, plasma oxytocin, atrial natriuretic peptide, prolactin and the hypothalamus-pituitary-adrenal axis components were not significantly altered by ETOH. CONCLUSIONS: Taken together, these results suggest that increased sympathetic activity may contribute to the early increase in MAP observed in ETOH-treated rats. However, the maintenance of this effect may be predominantly regulated by the long-term increase in the secretion of other circulating factors, such as AVP and ANG II, the secretion of both hormones being stimulated by the ETOH-induced dehydration. PMID- 23733508 TI - No strong temporal relationship between obesity and multisite pain--results from a population-based 20-year follow-up study. AB - BACKGROUND: Multisite pain and obesity are cross-sectionally related and are common conditions that may influence each other through socio-demographic, lifestyle and/or health-related factors. The aim of the present study was to examine the cross-sectional and prospective associations between overweight/obesity and multisite pain in a general population. METHODS: In a 20 year population-based prospective cohort study, persons aged 20-62 years in 1990 participated in postal surveys in 1990, 1994, 2004 and 2010 (n = 855). Multisite pain was defined as reporting >= 2 number of pain sites (NPS) on the Standardized Nordic Questionnaire. Overweight was defined as body mass index (BMI) 25-30 kg/m(2) and obesity as BMI >= 30 kg/m(2). To exploit all measurement times, generalized estimating equation analyses adjusting for age, sex, educational and occupational status, smoking, sleep quality, mental distress and physical activity were employed. RESULTS: The mean age was 41 years at baseline and 57% were women. Overweight/obesity and NPS were significantly associated cross sectionally. Being overweight/obese was associated with reporting future NPS >= 2 [overweight: odds ratio (OR), 1.40, 95% confidence interval (CI), 1.12-1.75, obese: OR, 1.54, 95% CI, 1.04-2.28]. Having NPS >= 2 was not associated with becoming overweight, but increased the OR for future obesity (OR 1.27, 95% CI, 1.02, 1.59). Smoking was a confounder in this relationship. CONCLUSIONS: Being overweight or obese was associated with future multisite pain, although the magnitude of the association was small and the dose-response relationship observed in cross-sectional analyses disappeared in prospective analyses. There was less evidence that having multisite pain was a predictor of future overweight/obesity. PMID- 23733509 TI - Identification of submicroscopic genetic changes and precise breakpoint mapping in myelofibrosis using high resolution mate-pair sequencing. AB - We used high resolution mate-pair sequencing (HRMPS) in 15 patients with primary myelofibrosis (PMF): eight with normal karyotype and seven with PMF characteristic cytogenetic abnormalities, including der(6)t(1;6)(q21-23;p21.3) (n = 4), der(7)t(1;7)(q10;p10) (n = 2), del(20)(q11.2q13.3) (n = 3), and complex karyotype (n = 1). We describe seven novel deletions/translocations in five patients (including two with normal karyotype) whose breakpoints were PCR validated and involved MACROD2, CACNA2D4, TET2, SGMS2, LRBA, SH3D19, INTS3, FOP (CHTOP), SCLT1, and PHF17. Deletions with breakpoints involving MACROD2 (lysine deacetylase; 20p12.1) were recurrent and found in two of the 15 study patients. A novel fusion transcript was found in one of the study patients (INTS3-CHTOP), and also in an additional non-study patient with PMF. In two patients with der(6)t(1;6)(q21-23;p21.3), we were able to map the precise translocation breakpoints, which involved KCNN3 and GUSBP2 in one case and HYDIN2 in another. This study demonstrates the utility of HRMPS in uncovering submicroscopic deletions/translocations/fusions, and precise mapping of breakpoints in those with overt cytogenetic abnormalities. The overall results confirm the genetic heterogeneity of PMF, given the low frequency of recurrent specific abnormalities, identified by this screening strategy. Currently, we are pursuing the pathogenetic relevance of some of the aforementioned findings. PMID- 23733510 TI - A rotaxane turing machine for peptides. AB - A ringing belt: An artificial molecular machine was invented to build up a programmable peptidic sequence. By molecular movements, the rotaxane-based machine progressively introduces amino acids to form a short peptide chain. The journey towards an artificial ribosome is still quite long, but a conceivable future can be envisaged. PMID- 23733512 TI - Effect of fibrous septa in radiofrequency heating of cutaneous and subcutaneous tissues: computational study. AB - BACKGROUND AND OBJECTIVES: Radiofrequency (RF) energy exposure is a popular non invasive method for generating heat within cutaneous and subcutaneous tissues. Subcutaneous fat consists of fine collagen fibrous septa meshed with clusters of adipocytes having distinct structural, electrical and thermal properties that affect the distribution and deposition of RF energy. The objectives of this work are to (i) determine the electric and thermal effects of the fibrous septa in the RF heating; (ii) investigate the RF heating of individual fat lobules enclosed by fibrous septa; and, (iii) discuss the clinical implications. METHODS AND RESULTS: We used the finite element method to model the two-dimensional, time-dependent, electro-thermal response of a three-layer tissue (skin, subcutaneous fat, and muscle). We considered two different configurations of subcutaneous fat tissue: a homogenous layer of fat only and a honeycomb-like layer of fat with septa. Architecture of the fibrous septa was anatomically accurate, constructed from sagittal images from human micro-MRI. For a large electrode applied to the skin surface, results show that the absorbed electric power density is greater in some septa than in the surrounding fat lobules, favoring the flux of electric current density. Fibers aligned parallel to the electric field have higher electric flux and, consequently, absorb more power. Heat transfer from the septa occurs over time during and after RF energy delivery. There is a greater temperature rise in fat with fibrous septa. CONCLUSIONS: The presence of septa affects the local distribution of the static electric field, facilitates the flux of electric current and enhances the bulk electric power absorption of the subcutaneous fat layer. Fibrous septa aligned with the local electric field have higher absorbed power density than septa oriented perpendicular to the electric field. Individual fat lobules gain heat instantly by local power absorption and, eventually, by diffusion from the surrounding septa. PMID- 23733511 TI - Transplant-related mortality following allogeneic hematopoeitic stem cell transplantation for pediatric acute lymphoblastic leukemia: 25-year retrospective review. AB - BACKGROUND: Over the last 25 years, donor source, conditioning, graft-versus-host disease prevention and supportive care for children undergoing hematopoeitic stem cell transplantation (HSCT) have changed dramatically. HSCT indications for acute lymphoblastic leukemia (ALL) now include high-risk patients in first and subsequent remission. There is a large burden of infectious and pre-HSCT morbidities, due to myelosuppressive therapy required for remission induction. We hypothesized that, despite these trends, overall survival (OS) had increased. PROCEDURE: A retrospective audit of allogeneic pediatric HSCT for ALL was performed in our institution over 25 years. Outcomes for 136 HSCTs were analyzed in three consecutive 8-year periods (Period 1: 1/1/1984-31/8/1992, Period 2: 1/9/1992-30/4/2001, Period 3: 1/5/2001-31/12/2009). RESULTS: Despite a significant increase in unrelated donor HSCT, event-free and OS over 25 years improved significantly. (EFS 31.6-64.8%, P = 0.0027; OS 41.8-78.9%, P < 0.0001) Concurrently, TRM dropped from 33% to 5% (P = 0.0004) whilst relapse rate was static (P = 0.07). TRM reduced significantly for matched sibling and unrelated cord blood transplantation (UCT) in Period 3 compared with earlier periods (P = 0.036, P = 0.0098, respectively). Factors leading to improved survival in patients undergoing UCT include better matching, higher total nucleated cell doses, and significantly faster neutrophil engraftment. Length of initial HSCT admission was similar over time. CONCLUSION: EFS and OS have increased significantly despite heightened HSCT complexity. This survival gain was due to TRM reduction. Contemporary patients have benefited from refined donor selection and improved supportive care. Overall rates of leukemic relapse post-HSCT are unchanged, and remain the focus for improvement. PMID- 23733513 TI - A simple quantitative approach for the determination of long and medium chain lipids in bio-relevant matrices by high performance liquid chromatography with refractive index detection. AB - There is increasing attention in the literature towards understanding the behaviour of lipid-based drug formulations under digestion conditions using in vitro and in vivo methods. This necessitates a convenient method for quantitation of lipids and lipid digestion products. In this study, a simple and accessible method for the separation and quantitative determination of typical formulation and digested lipids using high performance liquid chromatography coupled to refractive index detection (HPLC-RI) is described. Long and medium chain lipids were separated and quantified in a biological matrix (gastrointestinal content) without derivatisation using HPLC-RI on C18 and C8 columns, respectively. The intra- and inter-assay accuracy was between 92% and 106%, and the assays were precise to within a coefficient of variation of less than 10% over the range of 0.1-2 mg/mL for both long and medium chain lipids. This method is also shown to be suitable for quantifying the lipolysis products collected from the gastrointestinal tract in the course of in vivo lipid digestion studies. PMID- 23733514 TI - Physicomechanical characterization and optimization of EDTA-mPEG and Avicel(r) EDTA-mPEG in situ melt dispersion mini-pellets. AB - The purpose of this study was to develop a physicomechanically customizable oral metal chelatory in situ hot melt dispersion mini-pellet entity which could be utilized within a binary drug delivery system. Avicel((r)) RC/CL type R-591 was included within the in situ hot melt dispersion mini-pellet formulations to determine the physicomechanical effect this compound would have on the mini pellet formulations. The physicomechanical properties of the hot melt in situ mini-pellet formulations were mathematically fitting to regression curves. Physicomechanical adjustment of the in situ hot melt dispersion mini-pellet formulations could be mathematically predicted with the derived regression curve equations. The addition of Avicel((r)) RC/CL type R-591 increased the physicomechanical properties such as matrix hardness and increased total disintegration of the in situ hot melt dispersion mini-pellet formulations. The utilization of a physicomechanically customizable oral metal chelatory in situ hot melt dispersion mini-pellet entity within a binary drug delivery system would to achieve a synergistically enhance the activity of a drug-carrying entity or a permeation enhancing entity within a single drug delivery unit. The experimental results indicated that weights of the pellets that achieved optimal hardness ranged between 35 and 45 mg. The melt-dispersion formulations disintegrated within shorter time periods and maintained higher ethylenediaminetetraacetic acid (EDTA) concentrations whereas melt-dispersion formulations which included Avicel((r)) had superior physicomechanical properties. Disintegration times ranged between 1,000 s for melt-dispersions containing EDTA and methyloxy polyethylene glycol 2000 (mPEG) only, to >6,000 s for melt-dispersions comprising EDTA, mPEG, and Avicel((r)). PMID- 23733515 TI - Acceleration of peripheral nerve regeneration using nerve conduits in combination with induced pluripotent stem cell technology and a basic fibroblast growth factor drug delivery system. AB - Various modifications including addition of Schwann cells or incorporation of growth factors with bioabsorbable nerve conduits have been explored as options for peripheral nerve repair. However, no reports of nerve conduits containing both supportive cells and growth factors have been published as a regenerative therapy for peripheral nerves. In the present study, sciatic nerve gaps in mice were reconstructed in the following groups: nerve conduit alone (control group), nerve conduit coated with induced pluripotent stem cell (iPSc)-derived neurospheres (iPSc group), nerve conduit coated with iPSc-derived neurospheres and basic fibroblast growth factor (bFGF)-incorporated gelatin microspheres (iPSc + bFGF group), and autograft. The fastest functional recovery and the greatest axon regeneration occurred in the autograft group, followed in order by the iPSc + bFGF group, iPSc group, and control group until 12 weeks after reconstruction. Thus, peripheral nerve regeneration using nerve conduits and functional recovery in mice was accelerated by a combination of iPSc-derived neurospheres and a bFGF drug delivery system. The combination of all three fundamental methodologies, iPSc technology for supportive cells, bioabsorbable nerve conduits for scaffolds, and a bFGF drug delivery system for growth factors, was essential for peripheral nerve regenerative therapy. PMID- 23733516 TI - Cyst of the filum terminale: two cases detected on prenatal ultrasound. PMID- 23733518 TI - MiRNA-199a-3p: A potential circulating diagnostic biomarker for early gastric cancer. AB - BACKGROUND: Tumor-associated miRNAs have been detected in serum or plasma. We investigated whether plasma miRNA-199a-3p could be a potential circulating biomarker for early gastric cancer (EGC). METHODS: By using real-time qRT-PCR, the expression of miRNA-199a-3p were compared between these pre-operative plasmas from 30 EGC patients and 70 healthy controls, and between these pre-operative and post-operative plasmas. Further validation was on an independent set of plasmas from 50 EGC patients. RESULTS: The expression of miRNA-199a-3p (47.5 +/- 6.5) in plasma in EGC patients was significantly higher than that from healthy controls (13.9 +/- 2.7, P < 0.001) and gastric precancerous diseases (GPD) patients (19.2 +/- 2.5, P = 0.004), respectively. Furthermore, the expression levels of miRNA 199a-3p (11.8 +/- 2.9, P = 0.012) in the post-operative plasmas were significantly reduced when compared to the pre-operative plasmas. With respect of clinicopathological characteristics, the expression of miRNA-199a-3p in plasma was not associated with the depth of tumor invasion. Moreover, the AUC of the expression of miRNA-199a-3p in plasma for EGC diagnosis was 0.818, which was significantly higher than that of combined tumor markers (0.556). The sensitivity, specificity and accuracy of miRNA-199a-3p expression in plasma for EGC diagnosis were 76%, 74%, and 75%, respectively. CONCLUSIONS: Plasma miRNA 199a-3p could be a novel potential diagnostic biomarkers for EGC. PMID- 23733517 TI - Iron deficiency with or without anemia impairs prepulse inhibition of the startle reflex. AB - Iron deficiency (ID) during early life causes long-lasting detrimental cognitive sequelae, many of which are linked to alterations in hippocampus function, dopamine synthesis, and the modulation of dopaminergic circuitry by the hippocampus. These same features have been implicated in the origins of schizophrenia, a neuropsychiatric disorder with significant cognitive impairments. Deficits in sensorimotor gating represent a reliable endophenotype of schizophrenia that can be measured by prepulse inhibition (PPI) of the acoustic startle reflex. Using two rodent model systems, we investigated the influence of early-life ID on PPI in adulthood. To isolate the role of hippocampal iron in PPI, our mouse model utilized a timed (embryonic day 18.5), hippocampus-specific knockout of Slc11a2, a gene coding an important regulator of cellular iron uptake, the divalent metal transport type 1 protein (DMT-1). Our second model used a classic rat dietary-based global ID during gestation, a condition that closely mimics human gestational ID anemia (IDA). Both models exhibited impaired PPI in adulthood. Furthermore, our DMT-1 knockout model displayed reduced long-term potentiation (LTP) and elevated paired-pulse facilitation (PPF), electrophysiological results consistent with previous findings in the IDA rat model. These results, in combination with previous findings demonstrating impaired hippocampus functioning and altered dopaminergic and glutamatergic neurotransmission, suggest that iron availability within the hippocampus is critical for the neurodevelopmental processes underlying sensorimotor gating. Ultimately, evidence of reduced PPI in both of our models may offer insights into the roles of fetal ID and the hippocampus in the pathophysiology of schizophrenia. PMID- 23733519 TI - Distribution of six effector protein virulence genes among Salmonella enterica enterica serovars isolated from children and their correlation with biofilm formation and antimicrobial resistance. AB - PURPOSE: Salmonella enterica enterica encodes a variety of virulence factors. Among them, the type III secretion system (TTSS) encoded in the Salmonella pathogenicity islands (SPIs) is required for induction of proinflammatory responses, invasion of intestinal epithelial cells, induction of cell death in macrophages, and elicitation of diarrhea. The presence of the effector protein genes sopB, sopD, sopE, sopE2, avrA, and sptP of the SPIs was analyzed in 194 S. enterica enterica strains belonging to 19 serovars. METHODS: S. enterica enterica strains were collected from children with gastroenteritis, either hospitalized or attending the outpatient clinic, aged 1-14 years. Nineteen different serotypes were included in the study. Serotyping, biofilm formation determination, and antimicrobial resistance of the planktonic as well as the biofilm forms of the strains have been reported previously. RESULTS: At least one virulence gene was present in all Salmonella isolates. Biofilm formation was statistically independent of any of the six genes. Strains lacking sopE and sopE2 were more resistant to all the antimicrobials. CONCLUSIONS: The association of the virulence genes with the antimicrobial resistance of Salmonella in general has been previously reported and is a matter of further investigation. For the clinical expression of pathogenicity in humans, the contribution of these genes is questionable, as some strains bearing only a single gene (either sptP or avrA) were still capable of causing gastroenteritis. PMID- 23733520 TI - The neural interaction between the arterial baroreflex and muscle metaboreflex is preserved in older men. AB - Sympathetic baroreflex sensitivity is increased during selective activation of the skeletal muscle metaboreflex with postexercise ischaemia (PEI) in young adults. However, to date, there are no data demonstrating this neural interaction between the arterial baroreflex and the muscle metaboreflex in healthy older adults. Therefore, the goal of the present study was to examine the influence of healthy ageing on the metabolic component of the exercise pressor reflex and its interaction with the arterial baroreflex in the control of sympathetic outflow. Postexercise ischaemia following static hand grip performed at 30% maximal voluntary contraction was used to isolate muscle metaboreflex activation in young [n = 10; 24 +/- 1 years old; resting blood pressure (BP) 116 +/- 3/64 +/- 3 mmHg] and older men (n = 9; 59 +/- 2 years old; resting BP 120 +/- 2/77 +/- 2 mmHg). Arterial BP (Finometer) and muscle sympathetic nerve activity (MSNA) were measured continuously. Weighted linear regression analysis between MSNA and diastolic BP was used to estimate arterial baroreflex MSNA gain. There were no age-related differences in the increase in mean BP (young, Delta14 +/- 3 mmHg versus older, Delta15 +/- 2 mmHg; P > 0.05) or MSNA burst frequency (young, Delta11 +/- 2 bursts min(-1) versus older, Delta9 +/- 1 bursts min(-1); P > 0.05) during PEI. Likewise, the gain of arterial baroreflex control of total MSNA increased to a similar extent in both groups during PEI (young, -4.2 +/- 0.9 baseline versus -6.3 +/- 1.1 PEI a.u. beat(-1) mmHg(-1); and older, -3.7 +/- 1.1 baseline versus -6.7 +/- 1.4 PEI a.u. beat(-1) mmHg(-1); P < 0.05 for both). Collectively, these findings indicate that the neural interaction between the arterial baroreflex and the skeletal muscle metaboreflex in the regulation of MSNA is preserved in healthy ageing. PMID- 23733521 TI - Cardiovascular responses to ATP microinjected into the paraventricular nucleus are mediated by nitric oxide and NMDA glutamate receptors in awake rats. AB - We hypothesize that a local ATP-NO-NMDA glutamate receptor interaction in the paraventricular nucleus (PVN) modulates the baseline mean arterial pressure and heart rate in unanaesthetized rats. The microinjection of alpha,beta-methylene ATP [methyl ATP; 0.06, 0.12 and 1.2 nmol (100 nl)(-1)] into the PVN caused pressor and tachycardiac responses. Cardiovascular responses evoked by methyl ATP [0.12 nmol (100 nl)(-1)] in the PVN were blocked by pretreatment with the ganglion blocker pentolinium (5 mg kg(-1) i.v.). Also, responses to the injection of methyl ATP [0.12 nmol (100 nl)(-1)] into the PVN were reduced by pretreatment with the selective P2 purinergic receptor antagonist pyridoxalphosphate-6 azophenyl-2',4'-disulfonic acid [0.5 nmol (100 nl)(-1)], the neuronal NO synthase inhibitor N(omega)-propyl-l-arginine [0.04 nmol (100 nl)(-1)] or the selective NMDA glutamate receptor antagonist LY235959 [2 nmol (100 nl)(-1)]. In addition, an injection of the NO donor sodium nitroprusside [27 nmol (100 nl)(-1)] into the PVN caused similar cardiovascular responses to those observed after methyl ATP, which were blocked by local pretreatment with LY235959. Therefore, the present results suggest that cardiovascular responses evoked by methyl ATP in the PVN involve a local production of NO, which promotes local glutamate release and activation of NMDA receptors that are probably located in pre-autonomic parvocellular neurons, leading to sympathetic nervous system stimulation. PMID- 23733522 TI - Exercise-induced heart mitochondrial cholesterol depletion influences the inhibition of mitochondrial swelling. AB - The significance of the reduction of the cholesterol pool in heart mitochondria after exercise is still unknown. Recently, published data have suggested that cholesterol may influence the components of mitochondrial contact site and affect mitochondrial swelling. Therefore, the aim of this study was to determine whether the decreased cholesterol content in heart mitochondria caused by prolonged swimming may provoke changes in their bioenergetics and result in an increased resistance to calcium chloride-induced mitochondrial swelling. Male Wistar rats were divided into a sedentary control group and an exercise group. The rats exercised for 3 h, burdened with an additional 3% of their body weight. Their hearts were removed immediately after completing the exercise. The left ventricle was divided and used for experiments. Mitochondrial cholesterol content, membrane fluidity and mitochondrial bioenergetics were measured in the control and exercised rat heart mitochondria. To assess whether mitochondrial modifications are linked to disruption of lipid microdomains, methyl-beta-cyclodextrin, a well known lipid microdomain-disrupting agent and cholesterol chelator, was applied to the mitochondria of the control group. Cholesterol depletion, increased membrane fluidity and increased resistance to calcium chloride-induced swelling were observed in postexercise heart crude mitochondrial fraction. Similar results were achieved in control mitochondria treated with 2% methyl-beta-cyclodextrin. All of the mitochondrial bioenergetics parameters were similar between the groups. Therefore, the disruption of raft-like microdomains appears to be an adaptive change in the rat heart following exercise. PMID- 23733523 TI - A matter of detail: assessing the true potential of microalgal biofuels. PMID- 23733524 TI - Participation in asynchronous online discussion forums does improve student learning of gross anatomy. AB - Asynchronous online discussion forums are common in blended learning models and are popular with students. A previous report has suggested that participation in these forums may assist student learning in a gross anatomy subject but it was unclear as to whether more academically able students post more often or whether participation led to improved learning outcomes. This study used a path model to analyze the contribution of forum participation, previous academic ability, and student campus of enrolment to final marks in a multicampus gross anatomy course for physiotherapy students. The course has a substantial online learning management system (LMS) that incorporates asynchronous forums as a learning tool, particularly to answer learning objectives. Students were encouraged to post new threads and answer queries in threads started by others. The forums were moderated weekly by staff. Discussion forums were the most used feature of the LMS site with 31,920 hits. Forty-eight percent of the students posted at least once with 186 threads initiated by students and a total of 608 posts. The total number of posts made a significant direct contribution to final mark (P = 0.008) as did previous academic ability (P = 0.002). Although campus did not contribute to final mark, there was a trend for students at the campus where the course coordinator was situated to post more often than those at the other campus (P = 0.073). These results indicate that asynchronous online discussion forums can be an effective tool for improving student learning outcomes as evidenced by final marks in gross anatomy teaching. PMID- 23733525 TI - Imaging of the parafoveal capillary network in diabetes. AB - The retinal vasculature is an extremely complex system that is adapted to support the metabolic demands of the retinal structures, but on the other hand maintain the optimal optical qualities of this tissue. Through histological studies and clinical studies using fluorescein angiography we have learned a lot about the retinal vasculature in its physiological state and in different diseases, but both of these study methods have serious limitations that limit their extensive application in healthy subjects or in patients with early disease. In this current review we will present early observations about the retinal vasculature from several novel noninvasive imaging modalities like adaptive optics SLO, retinal functional imager, adaptive optics OCT and Doppler OCT. Some of these instruments allow a more detailed in vivo examination of the retinal vasculature than fluorescein angiography without its potentially serious side effects, thus better allowing us to further study retinal vascular homeostasis in healthy subjects and to identify preclinical changes in early disease stages. PMID- 23733526 TI - Solution-processable graphene quantum dots. AB - This minireview describes recent progress in solution-processable graphene quantum dots (SGQDs). Advances in the preparation, modification, properties, and applications of SGQDs are highlighted in detail. As one of emerging nanostructured materials, possible ongoing research related to the precise control of the lateral size, edge structure and surface functionality; the manipulation and characterization; the relationship between the properties and structure; and interfaces with biological systems of SGQDs have been speculated upon. PMID- 23733527 TI - Intracranial blood flow velocities in patients with sickle cell disease and beta thalassemia intermedia. PMID- 23733528 TI - A medication diary-book for pediatric patients with acute lymphoblastic leukemia in Indonesia. AB - BACKGROUND: Event-free survival of pediatric patients with acute lymphoblastic leukemia (ALL) in Yogyakarta, Indonesia was low (20%). The aim of the study was to evaluate the effectiveness of using a medication diary-book on the treatment outcome of childhood ALL. PROCEDURE: A randomized study was conducted with 109 pediatric patients with ALL in a pediatric oncology center in Yogyakarta, Indonesia. Both intervention and control groups received a structured parental education program and donated chemotherapy. The intervention group received a medication diary-book to remind parents and families to take oral chemotherapy and present for scheduled appointments or admissions. Event-free survival estimate (EFS) at 3 years was assessed. RESULTS: Among pediatric patients with ALL with highly educated mothers (senior high school or higher), the EFS-estimate at 3 years of the intervention group was significantly higher than the EFS estimate at 3 years of the control group (62% vs. 29%, P = 0.04). Among pediatric patients with ALL with low-educated mothers, no significant difference was found in the EFS-estimates at 3 years between the intervention and control group (26% vs. 18%, P = 0.86). CONCLUSIONS: We conclude that a medication diary-book might be useful to improve the survival of pediatric patients with ALL in resource limited settings, particularly in patients with highly educated mothers. PMID- 23733530 TI - Invasive congeners are unlikely to hybridize with native Hawaiian Bidens (Asteraceae). AB - PREMISE OF THE STUDY: Invasive plant species threaten native plants in multiple ways, one of which is genetic assimilation through hybridization. However, information regarding hybridization between related alien and native plant species is generally lacking. In Hawaii, the invasive Central American species Bidens pilosa and Bidens alba have colonized natural areas and often grow alongside the native Hawaiian Bidens species, a clade representing an adaptive radiation of 27 endemic taxa, many of which are threatened or endangered. * METHODS: To assess the risk of hybridization between introduced and native Hawaiian Bidens (which will readily hybridize with one another), we undertook crosses in cultivation between the invasive species and nine native Bidens taxa. * KEY RESULTS: The majority of the crosses formed no viable seed. Although seed did mature in several of the crosses, morphological screening of the resulting seedlings indicated that they were the result of self-pollination. * CONCLUSIONS: This result suggests that B. alba and B. pilosa are incapable of hybridizing with these Hawaiian Bidens taxa. Further, we found that B. alba in Hawaii was self compatible, despite self-incompatibility throughout its native range, and that the tetraploid species B. alba and the hexaploid species B. pilosa were cross compatible, although pollen fertility was low. PMID- 23733529 TI - Duloxetine use in chronic painful conditions--individual patient data responder analysis. AB - BACKGROUND: Duloxetine has been studied in four distinct chronic pain conditions osteoarthritis (OA), fibromyalgia, chronic low back pain (CLBP) and diabetic peripheral neuropathic pain (DPNP). These trials have involved large numbers of patients with at least moderate pain, and have used similar methods for recording pain intensity, over about 12 weeks. METHODS: Data from the trials were pooled according to painful condition, and reanalysed at the level of the individual patient and using increasing levels of pain intensity reduction (<15%, 15-29%, 30 49%, >= 50%), with different imputation methods on withdrawal. RESULTS: The proportion of patients recording at least 50% pain intensity reduction plateaued after 2-6 weeks in fibromyalgia, and 8-12 weeks in other conditions. The duloxetine-specific benefit [number needed to treat (NNT) for at least 50% pain intensity reduction] was fairly constant after about 2 weeks for DPNP and fibromyalgia and after about 4 or 5 weeks for OA and CLBP. In all conditions, responses were bimodal, with patients generally experiencing either very good or very poor pain relief. Last-observation-carried-forward imputation produced numerically and occasionally statistically better (lower) NNTs than use of baseline-observation-carried-forward (true response). CONCLUSIONS: Baseline observation-carried-forward (true response), which combines the success of high levels of pain relief with the failure to experience pain relief on withdrawal of the drug is conservative and probably reflective of clinical practice experience. The distribution of effect was not normal; few patients had the average response and averages are not an appropriate descriptor for these data. PMID- 23733531 TI - First-trimester assessment of nasal bone using retronasal triangle view: a prospective study. AB - OBJECTIVE: To examine the feasibility and accuracy of fetal nasal bone (NB) assessment in the retronasal triangle (RNT) view for aneuploidy screening in the first trimester of pregnancy. METHODS: Consecutive women with singleton pregnancies undergoing sonographic screening at 11-13 weeks' gestation were prospectively evaluated. In all cases, assessment of the NB by using the RNT view was attempted and classified as present (if one or both of the NBs were clearly seen) or absent/hypoplastic (if the NB was not visualized or if it was small and less echogenic than the surrounding bones). The detection rate of fetal karyotypic abnormalities by the assessment of the NB in the RNT view was calculated. RESULTS: In total, 1977 women were scanned. The RNT was successfully examined in 1970 fetuses (99.6%). Fetal outcome was available in 1767 (89.7%) of evaluated cases, and of these, 39 (2.2%) cases of aneuploidy were documented (trisomy 21, n=17; trisomy 18, n=8; trisomy 13, n=5; Turner syndrome, n=5; and triploidy, n=4). The prevalence of absent/hypoplastic NB was 12/1728 (0.7%) in chromosomally normal fetuses and 12/17 (70.6%) in trisomy 21 fetuses. Sensitivity, specificity and positive and negative predictive values of absent/hypoplastic NB for trisomy 21 were 70.6%, 99.3%, 50.0% and 99.7%, respectively. The positive and negative likelihood ratios of NB assessment were 101 (95% CI, 53-193) and 0.3 (95% CI, 0.14-0.62), respectively. CONCLUSIONS: The RNT view is a useful technique for assessing the NB during the first trimester of pregnancy. With this new approach, performance of absent/hypoplastic NB as a marker of aneuploidy, mainly trisomy 21, appears to be similar to that previously reported by using the mid-sagittal plane. PMID- 23733532 TI - Achiral-to-chiral transition in benzil solidification: analogies with racemic conglomerates systems showing deracemization. AB - Experimental results show that benzil (1,2-diphenyl-1,2-ethanedione), an achiral compound that crystallizes as a racemic conglomerate, yields by solidification polycrystalline scalemic mixtures of high enantiomeric excesses. These results are related to those previously reported in this type of compounds on deracemizations of racemic mixtures of crystal enantiomorphs obtained by wet grinding. However, the present results strongly suggest that these experiments cannot be explained without taking into account chiral recognition interactions at the level of precritical clusters. The conditions that would define a general thermodynamic scenario for such deracemizations are discussed. PMID- 23733533 TI - Heterogeneity of spine density in pyramidal neurons of isocortex of mongoose, Herpestes edwardsii (E. Geoffroy Saint-Hilaire 1818). AB - The characteristics of pyramidal neurons within six layers of Indian gray mongoose (Herpestes edwardsii) isocortex have been investigated using Golgi and Cresyl-Violet methods. Pyramidal neurons and the cytoarchitecture of isocortex of mongoose were photographed with the help of computer aided Nikon eclipse 80i microscope whereas the lucida drawings were made by simple light microscope equipped with camera lucida. The cortical neurons exhibit marked regional differences in phenotype. The differences occur in morphology and distribution of spines within the cortical neurons not only among different species but also within an animal's brain. The present investigation aims at studying the features of pyramidal neurons and to find out the differences if any in distribution of spines in different layers (II-VI) as well as regions (Frontal, Temporal, Parietal, and Occipital) of isocortex of mongoose, which will provide information regarding importance of different layer and region. This piece of work embarks the findings that spine density shows inter-regional as well as interlaminar variations within isocortex of mongoose indicating that pyramidal cells present in varied layer and region are not equally functional and there do exists differences in activity among layers and regions. Among regions, the Temporal region possessing highest spine density contributes more toward functioning of mongoose isocortex and might play significant role in predatory nature of mongoose because this region in mammals is associated with auditory, visual perception, and object recognition. PMID- 23733534 TI - The use of a polycaprolactone-tricalcium phosphate scaffold for bone regeneration of tooth socket facial wall defects and simultaneous immediate dental implant placement in Macaca fascicularis. AB - Bone regeneration and aesthetic outcomes may be compromised when immediate implants are placed at extraction sites with dehiscence defects. The aim of this study was to compare, in a monkey model, peri-implant bone regeneration and implant stability after immediate implant placement into tooth sockets with facial wall defects in two treatment groups. In eight control monkeys, the bony defect was reconstructed with autogenous particulate bone, whereas in 10 test monkeys a polycaprolactone-tricalcium phosphate (PCL-TCP) scaffold was used. The monkeys were sacrificed after 6 months and the specimens were analyzed by histology and histomorphometry. Better maintenance of facial bone contour was noted in the test group; however, bone regeneration was seen only at areas adjacent to a bony wall of the defect. The mean bone-to-implant contact was 27.6 +/- 19.1% (control group) versus 6.8 +/- 7.9% (test group). The mean bone area percentage was 11.8 +/- 10.1% (control group) versus 6.8 +/- 6.9% (test group). Implant survival was 100% at 6 months for both the groups. It was concluded that although the use of a PCL-TCP scaffold showed better maintenance of the alveolar contour as compared to autogenous particulate bone at 6 months, there was minimal bone regeneration within the defect. PMID- 23733535 TI - Is systematic identification of all four parathyroid glands necessary during total thyroidectomy?: a prospective study. AB - OBJECTIVES/HYPOTHESIS: Routine identification of all four parathyroid glands has been advocated as a means of reducing rates of postoperative hypocalcemia and inadvertent parathyroidectomy. The object of the present study was to investigate whether identification of more parathyroid glands during thyroidectomy performed by capsular dissection technique had any impact on incidence of postoperative hypocalcemia and unintentional parathyroid resection. STUDY DESIGN: Prospective cohort study of consecutive patients undergoing total thyroidectomy by capsular dissection technique over a 3-year period. Exclusion criteria included performance of concomitant central neck dissection, hyperparathyroidism, revision surgery, and invasive cancer. METHODS: The number of parathyroid glands identified intraoperatively was recorded. No effort was made to find glands that were not obviously apparent during the course of dissection. Patients were not placed on routine calcium supplementation. RESULTS: The final study population consisted of 126 patients. The mean number of parathyroid glands identified was 2.3. The incidence of biochemical (any postoperative calcium <2 mmol/L) and clinical hypocalcemia was 22.2% and 10.3%, respectively. Patients in group A (0-2 parathyroids identified) had a significantly lower incidence of clinical hypocalcemia than patients in group B (3-4 parathyroids identified) (3.2% vs. 17.1%, P = .02). The differences in biochemical hypocalcemia were not significant (16.1% vs. 28.1%, P = .13). The incidence of inadvertent parathyroidectomy was 9.5%. There was no difference between the groups in incidence of inadvertent parathyroidectomy (9.7% vs. 9.4%, P = 1.0). CONCLUSIONS: Routine identification of all four parathyroid glands is not necessary in thyroidectomy performed using capsular dissection technique. PMID- 23733536 TI - Whole body MRI and fluorescent microscopy for detection of stem cells labeled with superparamagnetic iron oxide (SPIO) nanoparticles and DiI following intramuscular and systemic delivery. AB - Methods to monitor transplanted stem cells in vivo are of great importance for potential therapeutic applications. Of particular interest are methods allowing noninvasive detection of stem cells throughout the body. Magnetic resonance imaging (MRI) is a tool that would allow detection of cells in nearly any tissue in the body and is already commonly used in the clinic. MRI tracking of stem cells is therefore feasible and likely to be easily adapted to patients receiving donor cells. Patients with Duchenne muscular dystrophy are good candidates for stem cell therapy, given the naturally regenerative nature of skeletal muscle, which repairs damage by employing endogenous stem cells from the muscle interstitium to regenerate muscle fibers throughout adulthood. We describe methods for labeling stem cells with superparamagnetic iron oxide nanoparticles (SPIO) to enhance MRI contrast, injecting them locally into skeletal and cardiac muscle, or systemically in mouse models for Duchenne muscular dystrophy, and tracking them in muscle tissue of live mice following injection. We focus on the use of whole body MRI to detect stem cells, as this is necessary for conditions such as muscular dystrophy, in which affected tissues are present throughout the body and systemic delivery of stem cells may be necessary. Emphasis is placed on the development of an MRI coil that is field of view (FOV) adjustable and can be used for both whole body imaging to determine stem cell localization as well as subsequent focusing on smaller, local regions where stem cells are present to obtain high-resolution images. We discuss the coil design and its significance for stem cell tracking. We also describe methods for labeling stem cells with a fluorescent dye and for tracking them in postmortem tissue specimens with fluorescent microscopy to correlate, compare, and contrast with results of whole body MRI in preclinical studies. PMID- 23733537 TI - Noninvasive multimodal imaging of stem cell transplants in the brain using bioluminescence imaging and magnetic resonance imaging. AB - Transplantation of stem cells represents a promising approach for the therapy of different brain diseases, including stroke, Parkinson's, and Huntington's disease. Tracking of stem cells with noninvasive imaging technologies provides insight into location, migration, and proliferation of the cells-key features for a possible clinical translation. This chapter describes a multimodal and noninvasive approach employing magnetic resonance imaging (MRI) and bioluminescence imaging (BLI), both of which offer the opportunity for repetitive measurements on the same individual, revealing the full temporal profile of cell dynamics. The combination of these modalities allows the simultaneous investigation of different aspects of the graft fate. We will present the detailed protocol for noninvasive multimodal tracking of labeled and transplanted neural stem cells, specifically optimized for brain applications, which allows repetitive assessment of localization as well as identification of cell viability and cell quantity after transplantation. PMID- 23733538 TI - Bioluminescence imaging of human embryonic stem cell-derived endothelial cells for treatment of myocardial infarction. AB - Myocardial infarction is a leading cause of mortality and morbidity worldwide, and current treatments fail to address the underlying scarring and cell loss, which is a major cause of heart failure after infarction. The novel strategy, therapeutic angiogenesis and/or vasculogenesis with endothelial progenitor cells transplantation holds great promise to increase blood flow in ischemic areas, thus rebuild the injured heart and reverse the heart failure. Given the potential of self-renewal and differentiation into virtually all cell types, human embryonic stem cells (hESCs) may provide an alternate source of therapeutic cells by allowing the derivation of large numbers of endothelial cells for therapeutic angiogenesis and/or vasculogenesis of ischemic heart diseases. Moreover, to fully understand the fate of implanted hESCs or hESC derivatives, investigators need to monitor the motility of cells in living animals over time. In this chapter, we describe the application of bioluminescence reporter gene imaging to track the transplanted hESC-derived endothelial cells for treatment of myocardial infarction. The technology of inducing endothelial cells from hESCs will also be discussed. PMID- 23733539 TI - Quantitative evaluation of stem cell grafting in the central nervous system of mice by in vivo bioluminescence imaging and postmortem multicolor histological analysis. AB - Stem cell transplantation in the central nervous system (CNS) is currently under intensive investigation as a novel therapeutic approach for a variety of brain disorders and/or injuries. However, one of the main hurdles at the moment is the lack of standardized procedures to evaluate cell graft survival and behavior following transplantation into CNS tissue, thereby leading to the publication of confusing and/or conflicting research results. In this chapter, we therefore provide validated in vivo bioluminescence and postmortem histological procedures to quantitatively determine: (a) the survival of grafted stem cells, and (b) the microglial and astroglial cell responses following cell grafting. PMID- 23733540 TI - Potential survival benefit with lumpectomy for patients with early-stage breast cancer. PMID- 23733541 TI - Detection of myo-inositol tris pyrophosphate (ITPP) in equine following an administration of ITPP. AB - Myo-Inositol tris pyrophosphate (ITPP) is a powerful allosteric modulator of haemoglobin that increases oxygen-releasing capacity of red blood cells. It is capable of crossing the red blood cell membrane unlike its open polyphosphate analog myo-inositol hexakisphosphate (IHP). Systemic administration of ITPP enhanced the exercise capacity in mice. There have been rumours of its abuse in the horse racing industry to enhance the performance of racing horses. In this paper, the detection of ITPP in equine plasma and urine after an administration of ITPP is reported. A Standardbred mare was administered 200 mg of ITPP intravenously. Urine and plasma samples were collected up to 120 h post administration and analyzed for ITPP by liquid chromatography-tandem mass spectrometry. ITPP was detected in post administration plasma samples up to 6 hours. The peak concentration was detected at 5 min post administration. In urine, ITPP was detected up to 24 h post administration. The peak concentration was detected at 1.5 h post administration. PMID- 23733542 TI - Biological imaging of atherosclerosis: moving beyond anatomy. AB - Biological or molecular imaging is now providing exciting new strategies to study atherosclerosis in both animals and humans. These technologies hold the promise to provide disease-specific, molecular information within the context of a systemic or organ-specific disease beyond traditional anatomical-based imaging. By integration of biological, chemical, and anatomical imaging knowledge into diagnostic strategies, a more comprehensive and predictive picture of atherosclerosis is likely to emerge. As such, biological imaging is well positioned to study different stages of atherosclerosis and its treatment, including the sequence of atheroma initiation, progression, and plaque rupture. In this review, we describe the evolving concepts in atherosclerosis imaging with a focus on coronary artery disease, and we provide an overview of recent exciting translational developments in biological imaging. The illuminated examples and discussions will highlight how biological imaging is providing new clinical approaches to identify high-risk plaques, and to streamline the development process of new atherosclerosis therapies. PMID- 23733543 TI - Method for percutaneously introducing, and removing, anatomical stenosis of predetermined severity in vivo: the "stenotic stent". AB - Current in vivo models of arterial lesions often lead to unpredictable results in terms of lesion anatomy and hemodynamical significance. This study aimed to evaluate the impact of coronary stenosis using a novel in vivo adjustable stenosis model capable of mimicking advanced human coronary lesions. We developed a series of balloon expandable covered coronary stents with a central restriction, mimicking different intermediate to severe stenosis, and implanted them percutaneously in coronary arteries of eight healthy hybrid Landrace pigs. Optical coherence tomography (OCT) pullbacks and fractional flow reserve (FFR) were acquired along the artery after implantation of the stenotic stents for precise evaluation of anatomy and functional impact. Diameter and area stenosis after deployment of the stenosis implant were, on average, respectively, 54.1 +/- 5.9 and 78.4 +/- 5.8 % and average FFR value was 0.83 (SD 0.13). There was a low correlation between FFR and MLA evaluated by OCT (r = 0.02, p = 0.94), improved with percentage area stenosis (r = -0.55, p = 0.12), or OCT volumetric evaluation of the stenosis taking into account not only the MLA but also the length of the lesion (r = -0.78, p = 0.01). This study presents a method and proof of concept for percutaneously introducing, and removing, anatomical stenosis of predetermined severity in vivo. Such in vivo model may be used to create and evaluate the impact of focal stenoses on physiological parameters such as FFR. PMID- 23733544 TI - Biomarkers and heart disease: what is translational success? PMID- 23733545 TI - Diffusion tensor tractography of the uncinate fasciculus: pitfalls in quantitative analysis due to traumatic volume changes. AB - PURPOSE: To demonstrate the sensitivity of quantitative diffusion tensor tractography to traumatic injury of the uncinate fasciculus (UF), and to evaluate the effect of volume changes on the accuracy of quantitative analysis. MATERIALS AND METHODS: Diffusion tensor imaging (DTI) was performed at 3 T for 110 patients with traumatic brain injury (TBI) and 60 control subjects. Volume, mean diffusivity (MD), and mean fractional anisotropy (FA) of the UF were measured by means of tractography. The influence of FA threshold on mean FA values was determined and the values were further related to the tract volume. RESULTS: In patients with TBI, 16% of the volumes and 29% of the FA values were decreased and 25% of the MD values were increased (>2 SD from the mean of controls). Small tracts (6% of trajectories) often had normal mean FA, but low volume-related FA values. Large UFs often had decreased mean FA values, but normal volume-related central values (3% of trajectories). CONCLUSION: Posttraumatic FA and MD changes and volume reductions are common in the tractography of UF. Trauma-induced volume changes can cause misleading whole-tract mean FA values. Therefore, additional volume-based analysis of the central part is beneficial for clinical assessment. PMID- 23733547 TI - Structure and stability of (NG)nCN3Be3(+) clusters and comparison with (NG)BeY(0/+). AB - The noble gas binding ability of CN3Be3(+) clusters was assessed both by ab intio and density functional studies. The global minimum structure of the CN3Be3(+) cluster binds with four noble-gas (NG) atoms, in which the Be atoms are acting as active centers. The electron transfer from the noble gas to the Be atom plays a key role in binding. The dissociation energy of the Be-NG bond gradually increases from He to Rn, maintaining the periodic trend. The HOMO-LUMO gap, an indicator for stability, gives additional insight into these NG-bound clusters. The temperature at which the NG-binding process is thermodynamically feasible was identified. In addition, we investigated the stability of two new neutral NG compounds, (NG)BeSe and (NG)BeTe, and found them to be suitable candidates to be detected experimentally such as (NG)BeO and (NG)BeS. The dissociation energies of the Be-NG bond in monocationic analogues of (NG)BeY (Y=O, S, Se, Te) were found to be larger than in the corresponding neutral counter-parts. Finally, the higher the positive charge on the Be atoms, the higher the dissociation energy for the Be-NG bond becomes. PMID- 23733546 TI - Angiotensin-converting enzyme inhibition and angiotensin AT1 receptor blockade downregulate angiotensin-converting enzyme expression and attenuate renal injury in streptozotocin-induced diabetic rats. AB - Angiotensin-converting enzyme (ACE) is upregulated in the diabetic kidney and contributes to renal injury. This study investigates the possible beneficial effects of the ACE inhibitor (ACEI), enalapril and the AT1 receptor blocker (ARB), valsartan, on renal ACE expression, renal structure, and function in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were allocated into four groups: control, STZ-diabetic rats, and STZ-diabetic rats treated with either enalapril (10 mg/kg/day) or valsartan (50 mg/kg/day) for 8 weeks. Enalapril and valsartan reduced renal ACE mRNA and protein expression, Na(+) /K(+) -ATPase activity, oxidative stress, and serum transforming growth factor beta1 levels compared to the diabetic group. Both treatments normalized renal nitrate/nitrite levels and ameliorated the observed histopathological changes. In conclusion, ACE downregulation by ACEI and ARB indicates that angiotensin II upregulates ACE through AT1 receptor. Prevention of diabetes-induced changes in ACE expression and Na(+) /K(+) -ATPase activity could be a new explanation of the renoprotective effects of ACEIs and ARBs. PMID- 23733548 TI - Ejaculatory duct obstruction: current diagnosis and treatment. AB - Ejaculatory duct obstruction is an infrequent cause of obstructive azoospermia, occurring in up to 5 % of such patients. However, it is potentially correctable and warrants consideration in the differential diagnosis of the patient presenting for infertility evaluation. This review provides an overview of ejaculatory duct obstruction: its various etiologies, presentation, and associated clinical assessment. It includes a description of diagnostic imaging and interventional studies available to the practicing urologist and concludes with a discussion of current endoscopic management. PMID- 23733550 TI - When is a global health program global? PMID- 23733549 TI - Racial and ethnic differences in hospice enrollment among children with cancer. AB - BACKGROUND: Hospice is an important provider of end of life care. Adult minorities are less likely to enroll on hospice; little is known regarding the prevalence of pediatric hospice use or the characteristics of its users. Our primary objective was to determine whether race/ethnicity was associated with hospice enrollment in children with cancer. We hypothesized that minority (Latino) race/ethnicity is negatively associated with hospice enrollment in children with cancer. PROCEDURE: In this single-center retrospective cohort study, inclusion criteria were patients who died of cancer or stem cell transplant between January 1, 2006 and December 31, 2010. The primary outcome variable was hospice enrollment and primary predictor was race/ethnicity. RESULTS: Of the 202 patients initially identified, 114 met inclusion criteria, of whom 95 were enrolled on hospice. Patient race/ethnicity was significantly associated with hospice enrollment (P = 0.02), the association remained significant (P = 0.024) after controlling for payor status (P = 0.995), patient diagnosis (P = 0.007), or religion (P = 0.921). Latinos enrolled on hospice significantly more often than patients of other races. Despite initial enrollment on hospice however, 34% of Latinos and 50% of non-Latinos had withdrawn from hospice at the time of death (P = 0.10). Race/ethnicity was not significantly associated with dying on hospice. CONCLUSIONS: These results indicate that race/ethnicity and diagnosis are likely to play a role in hospice enrollment during childhood. A striking number of patients of all race/ethnicities left hospice prior to death. More studies describing the impact of culture on end of life decision-making and the hospice experience in childhood are warranted. PMID- 23733551 TI - Creation of the AAN Global Health Section, part II: vision and goals. PMID- 23733552 TI - Genetic risk factors for intracranial aneurysms: a meta-analysis in more than 116,000 individuals. AB - OBJECTIVE: There is an urgent need to identify risk factors for sporadic intracranial aneurysm (IA) development and rupture. A genetic component has long been recognized, but firm conclusions have been elusive given the generally small sample sizes and lack of replication. Genome-wide association studies have overcome some limitations, but the number of robust genetic risk factors for IA remains uncertain. METHODS: We conducted a comprehensive systematic review and meta-analysis of all genetic association studies (including genome-wide association studies) of sporadic IA, conducted according to Strengthening the Reporting of Genetic Association Studies and Human Genome Epidemiology Network guidelines. We tested the robustness of associations using random-effects and sensitivity analyses. RESULTS: Sixty-one studies including 32,887 IA cases and 83,683 controls were included. We identified 19 single nucleotide polymorphisms associated with IA. The strongest associations, robust to sensitivity analyses for statistical heterogeneity and ethnicity, were found for the following single nucleotide polymorphisms: on chromosome 9 within the cyclin-dependent kinase inhibitor 2B antisense inhibitor gene (rs10757278: odds ratio [OR] 1.29; 95% confidence interval [CI] 1.21-1.38; and rs1333040: OR 1.24; 95% CI 1.20-1.29), on chromosome 8 near the SOX17 transcription regulator gene (rs9298506: OR 1.21; 95% CI 1.15-1.27; and rs10958409: OR 1.19; 95% CI 1.13-1.26), and on chromosome 4 near the endothelin receptor A gene (rs6841581: OR 1.22; 95% CI 1.14-1.31). CONCLUSIONS: Our comprehensive meta-analysis confirms a substantial genetic contribution to sporadic IA, implicating multiple pathophysiologic pathways, mainly relating to vascular endothelial maintenance. However, the limited data for IA compared with other complex diseases necessitates large-scale replication studies in a full spectrum of populations, with investigation of how genetic variants relate to phenotype (e.g., IA size, location, and rupture status). PMID- 23733553 TI - Arteriovenous fistula after ventriculostomy in aneurysmal subarachnoid hemorrhage. PMID- 23733554 TI - Development of an online tool to determine appropriateness for an epilepsy surgery evaluation. PMID- 23733555 TI - Burden of uncontrolled epilepsy in patients requiring an emergency room visit or hospitalization. PMID- 23733556 TI - Opinion & special articles: the lost resident: why resident physicians still need mentoring. AB - Mentoring is deeply rooted in medical practice. More than just a role model, a mentor is invested in the development of the mentee, providing personal and professional support, guidance, and the means for advancement. Mentoring is vital at all levels of medical training and plays an important role in the development of academicians. Increasing clinical demands, the competitive research environment, numerous administrative pressures, and the relative undervaluing of mentoring for faculty promotion have created challenges to resident mentoring. A greater emphasis on promoting mentoring opportunities for residents is needed at many levels. PMID- 23733557 TI - Teaching neuroimages: swollen T1 nerve root in neurogenic thoracic outlet syndrome. PMID- 23733558 TI - Teaching neuroimages: hydroxychloroquine-induced vacuolar myopathy. PMID- 23733559 TI - Comparison of the prevalence of convulsions associated with the use of cefepime and meropenem. AB - BACKGROUND: The US Food and Drug Administration reported seizures associated with the use of cefepime (primarily in patients with renal impairment who did not receive appropriate dose adjustments of cefepime). OBJECTIVE: The maximum dose of cefepime in the USA (6 g per day) is higher than that in Japan (4 g per day). We investigated the prevalence of convulsions associated with the use of cefepime by comparing it with that of meropenem. METHODS: A retrospective study was undertaken in 183 patients treated with cefepime and 745 patients treated with meropenem over 2 years at Ehime University Hospital. Cefepime or meropenem associated convulsions were defined according to the following criteria: (1) administration or dose escalation of diazepam, phenytoin, phenobarbital and thiamylal given via the intravenous route (2) convulsions recorded in medical records during administration of cefepime or meropenem. RESULTS: The prevalence of convulsions was significantly greater in the cefepime treated group than in the meropenem-treated group. Among the patients who had cefepime-associated convulsions, none had renal failure. Cefepime-associated convulsions occurred only in patients with brain disorders. CONCLUSION: Cefepime-associated convulsions should be recognized as potential complications even in patients with normal renal function. Brain disorders may increase the risk of cefepime associated convulsions. PMID- 23733560 TI - Sugarcane cell wall structure and lignin distribution investigated by confocal and electron microscopy. AB - Lignocellulosic plant cell wall is considered a potential source for second generation biofuels. The plant cell wall is a highly complex structure mainly composed of cellulose, hemicelluloses, and lignin that form a network of crosslinked fibers. The structural organization of the sugarcane cell wall has not been previously analyzed in detail, and this analysis is a prerequisite for further studies on the recalcitrance and deconstruction of its biomass. In this work, cellulose and lignin localization were investigated by confocal laser scanning microscopy. In addition, the internode sugarcane cell wall structural organization was analyzed by electron microscopy. Internode stem anatomy showed a typical monocot structure consisting of epidermis, hypoderm, and vascular bundles scattered throughout ground parenchyma tissue and surrounded by sclerenchyma fibers. Confocal images of safranin labeled sugarcane showed that lignin distribution was predominant in the vessel elements, cell wall corners (CC), and middle lamella (ML), while cellulose-rich cell walls were randomly distributed in the ML and organized in the other cell wall layers. KMnO4 cytochemistry revealed that lignin was predominantly distributed in secondary cell walls, ML and CC. Cell wall sublayers (S1, S2, and S3) were identified and measured by transmission electron microscopy. Our results provide insights that may help further understanding of sugarcane cell wall organization, which is crucial for the research and technology of plant-based biofuel production. PMID- 23733561 TI - Heparin functionalized polyaspartamide/polyester scaffold for potential blood vessel regeneration. AB - An interesting issue in tissue engineering is the development of a biodegradable vascular graft able to substitute a blood vessel and to allow its complete regeneration. Here, we report a new scaffold potentially useful as a synthetic vascular graft, produced through the electrospinning of alpha,beta-poly(N-2 hydroxyethyl) (2-aminoethylcarbamate)-D,L-aspartamide-graft-polylactic acid (PHEA EDA-g-PLA) in the presence of polycaprolactone (PCL). The scaffold degradation profile has been evaluated as well as the possibility to bind heparin to electrospun fibers, being it a known anticoagulant molecule able to bind growth factors. In vitro cell compatibility has been investigated using human vascular endothelial cells (ECV 304) and the ability of heparinized PHEA-EDA-g-PLA/PCL scaffold to retain basic fibroblast growth factor has been evaluated in comparison with not heparinized sample. PMID- 23733563 TI - Hospital-acquired conditions in head and neck cancer surgery. AB - OBJECTIVES/HYPOTHESIS: The Centers for Medicare and Medicaid Services has identified 10 hospital-acquired conditions (HACs) for which they will not reimburse care. We sought to determine the incidence of HACs in head and neck cancer (HNCA) surgery and the association with in-hospital mortality, complications, length of hospitalization, and costs. STUDY DESIGN: Retrospective cross-sectional study. METHODS: Discharge data from the Nationwide Inpatient Sample for 123,662 patients who underwent an ablative procedure for a malignant oral cavity, laryngeal, hypopharyngeal, or oropharyngeal neoplasm during 2001 2008 were analyzed using cross-tabulations and multivariate regression modeling. RESULTS: HACs occurred in <1% of cases, with vascular catheter-associated infection comprising >70% of all HACs. The occurrence of HACs was significantly associated with urgent or emergent admission (odds ratio [OR]=2.0, P=.004), major surgical procedures (OR=2.3, P<.001), flap reconstruction (OR=3.5, P<.001), and advanced comorbidity (OR=2.0, P<.001). There was no association between HACs and hospital size, location, ownership, volume status, or safety-net burden. HACs were significantly associated with in-hospital mortality (OR=3.8, P=.001), surgical complications (OR=4.9, P<.001), and medical complications (OR=5.6, P<.001). After controlling for all other variables, HACs were associated with significantly increased length of hospitalization and hospital-related costs, with vascular catheter-associated infection and foreign object after surgery associated with the greatest increase in length of stay and costs. CONCLUSIONS: HACs are uncommon events in HNCA surgical patients. Because prediction of HACs is poor and the potential for human error crosses demographic, geographic, and structural boundaries, universal innovative measures to reduce the occurrence of HACs are needed. PMID- 23733562 TI - Low-risk lifestyle, coronary calcium, cardiovascular events, and mortality: results from MESA. AB - Unhealthy lifestyle habits are a major contributor to coronary artery disease. The purpose of the present study was to investigate the associations of smoking, weight maintenance, physical activity, and diet with coronary calcium, cardiovascular events, and mortality. US participants who were 44-84 years of age (n = 6,229) were followed in the Multi-Ethnic Study of Atherosclerosis from 2000 to 2010. A lifestyle score ranging from 0 to 4 was created using diet, exercise, body mass index, and smoking status. Coronary calcium was measured at baseline and a mean of 3.1 (standard deviation, 1.3) years later to assess calcium progression. Participants who experienced coronary events or died were followed for a median of 7.6 (standard deviation, 1.5) years. Participants with lifestyle scores of 1, 2, 3, and 4 were found to have mean adjusted annual calcium progressions that were 3.5 (95% confidence interval (CI): 0.0, 7.0), 4.2 (95% CI: 0.6, 7.9), 6.8 (95% CI: 2.0, 11.5), and 11.1 (95% CI: 2.2, 20.1) points per year slower, respectively, relative to the reference group (P = 0.003). Unadjusted hazard ratios for death by lifestyle score were as follows: for a score of 1, the hazard ratio was 0.79 (95% CI: 0.61, 1.03); for a score of 2, the hazard ratio was 0.61 (95% CI: 0.46, 0.81); for a score of 3, the hazard ratio was 0.49 (95% CI: 0.32, 0.75); and for a score of 4, the hazard ratio was 0.19 (95% CI: 0.05, 0.75) (P < 0.001 by log-rank test). In conclusion, a combination of regular exercise, healthy diet, smoking avoidance, and weight maintenance was associated with lower coronary calcium incidence, slower calcium progression, and lower all cause mortality over 7.6 years. PMID- 23733564 TI - An antibody-free strategy for screening putative HDM2 inhibitors using crude bacterial lysates expressing GST-HDM2 recombinant protein. AB - Targeting the interaction of p53 with its natural inhibitor MDM2 by the use of small synthetic molecules has emerged as a promising pharmacological approach to restore p53 oncosuppressor function in cancers retaining wild-type p53. The first critical step in the experimental validation of newly synthesized small molecules developed to inhibit MDM2-p53 interaction is represented by the evaluation of their efficacy in preventing the formation of the MDM2-p53 complex. This can be achieved using the in vitro reconstructed recombinant MDM2-p53 complex in cell free assays. A number of possible approaches have been proposed, which are however not suitable for screening large chemical libraries, due to the high costs of reagents and instrumentations, or the need of large amounts of highly pure recombinant proteins. Here we describe a rapid and cheap method for high throughput screening of putative inhibitors of MDM2-p53 complex formation--based on the use of GST-recombinant proteins--that does not require antibodies and recombinant protein purification steps from bacterial cell lysates. PMID- 23733565 TI - Navigation to the graveyard-induction of various pathways of necrosis and their classification by flow cytometry. AB - Apoptosis and necrosis reflect the program of cell death employed by a dying cell and the final stage of death, respectively. Whereas apoptosis is defined as a physiological, highly organized cell death process, necrosis is commonly considered to be accidental and uncontrolled. Physiological and weak pathological death stimuli preferentially induce apoptosis, while harsh non-physiological insults often immediately instigate (primary) necrosis. If an apoptosing cell transits into a phase of plasma membrane disintegration, this stage of death is referred to as secondary or post-apoptotic necrosis.Here, we present several conditions that stimulate primary and/or secondary necrosis and show that necrosis displays considerably different time courses. For subclassification of necrotic phenotypes we employed a flow cytometric single-tube 4-color staining technique including annexin A5-FITC, propidium iodide, DiIC1(5), and Hoechst 33342. PMID- 23733566 TI - Time-lapse imaging of necrosis. AB - The processes of dying are as tightly regulated as those of growth and proliferation. Recent work into the molecular pathways that regulate and execute cell death have uncovered a plethora of signalling cascades that lead to distinct modes of cell death, including "apoptosis," "necrosis," "autophagic cell death," and "mitotic catastrophe." Given that cells can readily switch from one form of death to another, it is vital to carefully monitor the form of death under investigation. Particularly, end-point techniques are intrinsically unsuitable for assessing apoptosis versus necrosis, as they cannot reconstruct the sequence of events that have led to cell death. Since apoptotic cells frequently undergo secondary necrosis under in vitro culture conditions, novel methods relying on high-throughput time-lapse fluorescence video microscopy have been developed. Here we describe the use of this technique to reliably distinguish necrosis from apoptosis and secondary necrosis. PMID- 23733567 TI - Activity assays for receptor-interacting protein kinase 1:a key regulator of necroptosis. AB - Necroptosis is a novel form of regulated non-apoptotic cell death, which displays morphological features of necrosis. The kinase activity of receptor-interacting protein kinase 1 (RIP1) is a critical component in signaling for necroptosis. The development of assays to evaluate RIP1 kinase activity is important in the further development of existing and novel inhibitors of necroptosis. Here, we describe RIP1 protein expression and purification from mammalian and insect cells as well as two in vitro kinase assays to detect RIP1 kinase activity and inhibition. PMID- 23733568 TI - Fluorescent biosensors for the detection of HMGB1 release. AB - During necrosis and following some instances of apoptosis (in particular in the absence of a proficient phagocytic system), the nonhistone chromatin component high-mobility group box 1 (HMGB1) is released in the extracellular space. In vivo, extracellular HMGB1 can bind Toll-like receptor 4 on the surface of dendritic cells, de facto operating as a danger-associated molecular pattern and alarming the organism to the presence of stressful conditions. Recent results indicate that the release of HMGB1 is one of the key features for cell death to be perceived as immunogenic, i.e., to be capable of triggering a cognate immune response in vivo. Thus, only anticancer agents that-among other features-allow for the release of HMGB1 as they induce cell death are expected to stimulate anticancer immune responses. To investigate the immunogenic potential of conventional anticancer agents and novel cell death inducers on a high-throughput scale, we engineered human osteosarcoma U2OS cells to express HMGB1 fused at the N-terminus of the green fluorescent protein (GFP). Coupled to fluorescence microscopy workstations for automated image acquisition and analysis, this HMGB1 GFP-based biosensor is amenable for the identification of potential inducers of immunogenic cell death among large chemical libraries. PMID- 23733569 TI - Methods for the study of entosis. AB - Entosis is a recently described nonapoptotic cell death mechanism that is initiated by the engulfment of live epithelial cells, leading to the formation of "cell-in-cell" structures. Entotic cell engulfment is induced by matrix detachment, and is driven by imbalances in actomyosin contraction between neighboring cells. Here we describe methods to quantify the formation of cell-in cell structures by entosis, for cells cultured in suspension or in soft agar, by fluorescence imaging and time-lapse microscopy. PMID- 23733570 TI - Analysis of pyroptosis in bacterial infection. AB - Eukaryotic cells undergo death by several different mechanisms: apoptosis, a cell death that prevents inflammatory response; necrosis, when the cell membrane lyses and all the intracellular content is spilled outside; and pyroptosis, a cell death that is accompanied by the release of inflammatory cytokines by the dying cells. Pyroptosis is designed to attract a nonspecific innate response to the site of infection or tumor. In this chapter, we describe the methods used to study pyroptosis in a mammalian cell. The model organism used is Mycobacterium tuberculosis, which suppresses pyroptosis by macrophages, and possibly in dendritic cells. PMID- 23733571 TI - Analysis of cell death by electron microscopy. AB - Cell death is said to occur mostly by two alternative, opposite modes: apoptosis, which involves a highly genetically regulated and elaborate network of biochemical events and cascades, and necrosis, considered a passive cell death without underlying regulatory mechanisms. Here, we describe the different morphological features of cells undergoing apoptotic and necrotic cell death, through the analysis of transmission (TEM) and scanning (SEM) electron microscopy. TEM allows detailed studies of ultrastructural changes, within the cell, such as the nuclear alteration, the cytoplasmic reorganization, and the loss of membrane integrity. The cell-surface changes, including membrane blebbing and loss of features, such as microvilli, can be assessed by SEM. PMID- 23733572 TI - Histological analysis of neurodegeneration in the mouse brain. AB - Neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by chronic and progressive neuronal loss. Being able to detect and quantify neurodegeneration is the first step to identify mechanisms underlying neuronal cell death and to develop novel therapeutic strategies. In this chapter, we describe a practical method for detecting and quantifying neurodegeneration in adult and aging mouse brains based on protocols developed in our laboratory over the last decade. We include protocols on sample preparation, immunohistochemical analysis, and stereological methods for counting neurons using examples of AD and PD mouse models. We also describe how to use Fluoro-Jade staining and terminal deoxynucleotidyl transferase dUTP nick end labeling to detect degenerating neurons and apoptotic cells, respectively, and how to use specific proteins as early markers of neurodegeneration. PMID- 23733573 TI - Quantitation of acute necrosis after experimental myocardial infarction. AB - Myocardial infarction (MI) is death and necrosis of myocardial tissue secondary to ischemia. MI is associated with adverse cardiac remodeling, progressive heart chamber dilation, ventricular wall thinning, and loss of cardiac function. Myocardial necrosis can be experimentally induced in rodents to simulate human MI by surgical occlusion of coronary arteries. When induced in knockout or transgenic mice, this model is useful for the identification of molecular modulators of cell death, cardiac remodeling, and preclinical therapeutic potential. Herein we outline in tandem, methods for microsurgical ligation of the left anterior descending artery followed by quantitation of myocardial necrosis. Necrosis is quantified after staining the heart with triphenyltetrazolium chloride. PMID- 23733574 TI - Immunohistological tools to discriminate apoptotic and necrotic cell death in the skin. AB - Perturbances in skin homeostasis are responsible for the development of skin inflammatory diseases such as psoriasis or atopic dermatitis. While the role of apoptosis has been extensively studied in the skin, the role of the newly described programmed necrosis also termed necroptosis in human skin remains poorly understood. We have recently described a mouse model of skin inflammation dependent on necroptotic cell death. Here we describe an immunohistological protocol allowing for the discrimination of apoptotic from necroptotic cell death in a single staining procedure on tissue sections. PMID- 23733575 TI - Identification and characterization of programmed cell death markers in bacterial models. AB - In eukaryotic organisms facing terminal stress, activation of genetically encoded cell death pathways underlies fundamental changes in core cellular processes and functional modification of critical biomolecules. These physiological alterations manifest themselves as phenotypic hallmarks during programmed cell death, and are markers of the particular mode of death initiated. A growing volume of work has illustrated that prokaryotes too are capable of exhibiting hallmarks of programmed cell death, albeit without the multiple, tight regulatory layers which control these events in higher order organisms.This chapter describes how methods and materials which have been used to assay for hallmarks of programmed cell death in eukaryotic models are transferrable to prokaryotic models. In particular, we describe the applicability of these methods to the study of post antibiotic effects on bacteria, notably the biochemical changes induced by the interaction of drug molecules and targets, including oxidative stress, that accompany and ensure cell death. Specifically we discuss techniques for detecting DNA fragmentation, chromosomal condensation, phosphatidylserine exposure, membrane depolarization, and caspase substrate peptide binding, thereby providing a launchpoint for the study of the evolution of these physiological events in bacteria. PMID- 23733576 TI - Quantification of genetically controlled cell death in budding yeast. AB - Yeast are the foremost genetic model system. With relative ease, entire chemical libraries can be screened for effects on essentially every gene in the yeast genome. Until recently, researchers focused only on whether yeast were killed by the conditions applied, irrespective of the mechanisms by which they died. In contrast, considerable effort has been devoted to understanding the mechanisms of mammalian cell death. However, most of the methodologies for detecting programmed apoptotic and necrotic death of mammalian cells have not been applicable to yeast. Therefore, we developed a cell death assay for baker's yeast Saccharomyces cerevisiae to identify genes involved in the mechanisms of yeast cell death. Small volumes of yeast suspensions are subjected to a precisely controlled heat ramp, allowing sufficient time for yeast cell factors to suppress or facilitate death, which can be quantified by high-throughput automated analyses. This assay produces remarkably reliable results that typically reflect results with other death stimuli. Here we describe the protocol and its caveats, which can be easily overcome. PMID- 23733577 TI - Necrosis in C. elegans. AB - To use Caenorhabditis elegans to study the mechanisms for initiation and execution of necrosis, the experimentalist should be familiar with the established models of necrosis in C. elegans and the genetic and molecular tools available. We present a summary of two contrasting models for studying necrosis in C. elegans and outline the methods for scoring necrosis in each. These methods are useful for the study of necrosis under other conditions in C. elegans and for comparative studies both between established and new necrosis models. We also present a list of the genetic and drug tools available for perturbing pathways known to be important for initiation or execution of necrosis and describe their use in C. elegans. Specifically, we outline methods to inhibit autophagy, to perturb calcium homeostasis, and to disrupt lysosomal function in the C. elegans system. PMID- 23733578 TI - Monitoring the clearance of apoptotic and necrotic cells in the nematode Caenorhabditis elegans. AB - The nematode Caenorhabditis elegans is an excellent model organism for studying the mechanisms -controlling cell death, including apoptosis, a cell suicide event, and necrosis, pathological cell deaths caused by environmental insults or genetic alterations. C. elegans has also been established as a model for understanding how dying cells are cleared from animal bodies. In particular, the transparent nature of worm bodies and eggshells make C. elegans particularly amenable for live-cell microscopy. Here we describe methods for identifying apoptotic and necrotic cells in living C. elegans embryos, larvae, and adults and for monitoring their clearance during development. We further discuss specific methods to distinguish engulfed from unengulfed apoptotic cells, and methods to monitor cellular and molecular events occurring during phagosome maturation. These methods are based on Differential Interference Contrast (DIC) microscopy or fluorescence microscopy using GFP-based reporters. PMID- 23733579 TI - Modeling calcium-overload mediated necrosis in Drosophila. AB - Necrotic cell death (necrosis) occurs in many acute-onset diseases. However, our poor understanding of its mechanism has greatly limited medical interventions. Here we describe two methods to establish necrosis models in Drosophila. Our strategy is to overload calcium by expression of leaky cation channels. PMID- 23733580 TI - Use of necrotic markers in the Drosophila ovary. AB - Necrosis is a form of cell death characterized by cytoplasmic and organelle swelling, compromised -membrane integrity, intracellular acidification, and increased levels of reactive oxygen species (ROS) and cytosolic Ca(2+). In the Drosophila ovary, two distinct forms of cell death occur naturally. In response to starvation, caspase-dependent cell death occurs during mid-oogenesis. Additionally, the nurse cells, which support the developing oocyte, undergo developmental programmed cell death during late oogenesis after they dump their contents into the oocyte. Evidence suggests that necrosis may be playing an important role during developmental programmed cell death of the nurse cells during late oogenesis. Here, we describe several methods to detect events associated with necrosis in the Drosophila ovary. Propidium iodide is used to detect cells with compromised membrane integrity, and H2DCFDA is used as an indicator of ROS levels in a cell. In addition, LysoTracker detects intracellular acidification and X-rhod-1 detects cytosolic Ca(2+). We also describe transgenic methods to detect Ca(2+) levels and expression patterns. These methods performed in the Drosophila ovary, as well as other tissues, may lead to a further understanding of the mechanisms of necrosis as a form of programmed cell death. PMID- 23733581 TI - Detection and measurement of necrosis in plants. AB - Necrosis plays a fundamental role in plant physiology and pathology. When plants or plant cell cultures are subjected to abiotic stress they initiate rapid cell death with necrotic morphology. Likewise, when plants are attacked by pathogens, they develop necrotic lesions, the reaction known as hypersensitive response. Great advances in the understanding of signaling pathways that lead to necrosis during plant-pathogen interaction have been made in the last two decades using Arabidopsis thaliana as a model plant. Further understanding of these signaling pathways, as well as those regulating the execution phase of necrotic cell death per se would require a robust set of readout assays to detect and measure necrosis in various plant model systems. Here we provide description of such assays, beginning from electron microscopy, as the "gold standard" to diagnose necrosis. This is followed by two groups of biochemical and cytochemical assays used by our group to detect and quantify mitochondrial dysfunction and the loss of protoplast integrity during necrosis in Arabidopsis plants and cell suspension cultures of both Arabidopsis and Norway spruce. PMID- 23733582 TI - Impact of fasting on human brain acid-base homeostasis using natural abundance (13) C and (31) P MRS. AB - PURPOSE: To use (13) C magnetic resonance spectroscopy (MRS) and (31) P MRS to develop a direct assay for regional [HCO3-] in the human brain and to define brain pH and physiological response of [HCO3-] to fasting. MATERIALS AND METHODS: Seven healthy subjects underwent MRS examinations on a 1.5T MRI scanner. Subjects were well fed with repeated examinations performed after 4 and 12 hours of fasting. Proton noise decoupling (13) C MRS were acquired using pulse and acquired acquisition while (31) P MRS were acquired using a 2D chemical shift imaging method with relaxation time (TR) of 2 seconds. RESULTS: Fasting brain bicarbonate concentrations (6.7 +/- 2.5 mM for 12-hour fasting, P = 0.002 and 8.3 +/- 2.1 mM for 4-hour fasting, P = 0.015) are significantly reduced compared to fed state (11.6 +/- 1.3 mM). However, no significant difference in brain pH was observed, confirming the critical role of pCO2 in intracerebral pH homeostasis. CONCLUSION: We demonstrated that the intracellular HCO3- in human brain is readily modified by diet but appears to have no measurable effect on cerebral pH. Natural abundance (13) C can provide useful information relevant to human brain pH homeostasis by providing information for HCO3-. PMID- 23733583 TI - Correlation of muscle function and bone strain in the hindlimb of the river cooter turtle (Pseudemys concinna). AB - During terrestrial locomotion, limb muscles must generate mechanical work and stabilize joints against the ground reaction force. These demands can require high force production that imposes substantial loads on limb bones. To better understand how muscle contractile function influences patterns of bone loading in terrestrial locomotion, and refine force platform equilibrium models used to estimate limb bone safety factors, we correlated in vivo recordings of femoral strain with muscle activation and strain in a major propulsive hindlimb muscle, flexor tibialis internus (FTI), of a species with a published model of hindlimb force production (river cooter turtles, Pseudemys concinna). Electromyography (EMG) recordings indicate FTI activity prior to footfall that continues through approximately 50% of the stance phase. Large EMG bursts occur just after footfall when the muscle has reached its maximum length and is beginning to actively shorten, concurrent with increasing compressive strain on the anterior femur. The FTI muscle shortens through 35% of stance, with mean fascicle shortening strains reaching 14.0 +/- 5.4% resting length (L0 ). At the time of peak compressive strains on the femur, the muscle fascicles remain active, but fascicles typically lengthen until mid-stance as the knee extends. Influenced by the activity of the dorsal knee extensor femorotibialis, the FTI muscle continues to passively lengthen simultaneously with knee extension and a shift to tensile axial strain on the anterior femur at approximately 40% of stance. The near coincidence in timing of peak compressive bone strain and peak muscle shortening (5.4 +/- 4.1% stance) indicates a close correlation between the action of the hip extensor/knee flexor, FTI, and femoral loading in the cooter hindlimb. In the context of equilibrium models of limb bone loading, these results may help explain differences in safety factor estimates observed between previous force platform and in vivo strain analyses in cooters. PMID- 23733584 TI - Isolated ventricular septal defects in the era of advanced fetal echocardiography: risk of chromosomal anomalies and spontaneous closure rate from diagnosis to age of 1 year. AB - OBJECTIVES: To evaluate, in a cohort of 248 fetuses seen at a tertiary referral center, the frequency of isolated ventricular septal defects (VSD) among all congenital heart defects (CHD), the association with chromosomal and postnatal anomalies and the rate of spontaneous closure. METHODS: This was a 6-year study on 10,800 women referred for fetal echocardiography, with 995 confirmed cases of CHD. The prevalence and characteristics of VSDs were analyzed, including follow up until 1 year of age. Multivariate binary logistic regression analysis was performed to test the independent contribution of the ratio of the diameter of the VSD to that of the aorta (VSD/aorta ratio) (< 0.5 or >= 0.5) and location of VSD (perimembranous or muscular) in the prediction of spontaneous closure before the age of 1 year. RESULTS: Two hundred and forty-eight VSDs (24.9% of all CHDs) were diagnosed, of which 216 (87.1%) were muscular and 32 (12.9%) perimembranous. Median gestational age at diagnosis was 30.4 (range, 17-41) weeks and mean size 2.6 +/- 0.77 mm. Clinically relevant chromosomal anomalies were found in one (3.1%) perimembranous VSD compared with none in 216 muscular defects (P = 0.12). Postnatal malformations were diagnosed in eight of the 211 cases (3.8%) evaluated at 12 months postpartum. Spontaneous closure occurred prenatally in 13 fetuses (5.2%) and postnatally in 151 of the 198 infants (76.3%) who had an open VSD at birth. Closure was predicted by the VSD/aorta ratio (odds ratio (OR) 0.445 (95% CI, 0.216-0.914); P < 0.03) and location (OR 0.385 (95% CI, 0.160-0.926); P < 0.03). CONCLUSIONS: In our fetal cardiology unit, isolated muscular VSD is today the most prevalent CHD. In contrast to the findings of postnatal studies, muscular VSDs were more common than perimembranous VSDs. Perimembranous VSDs were associated with a higher risk of chromosomal anomalies than were muscular VSDs, which had a similar risk to those of normal pregnancies. Spontaneous closure of the VSD was frequent and occurred in most cases postnatally. PMID- 23733585 TI - Attenuated effects of Neu2000 on hypoxia-induced synaptic activities in a rat hippocampus. AB - Neu2000 (NEU; 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino) benzoic acid), a recently developed derivative of acetylsalicylic acid and sulfasalazine, potently protects against neuronal cell death following ischemic brain injury by antagonizing NMDA receptor-mediated neuronal toxicity and oxidative stress. However, it has yet to be determined whether NEU can attenuate hypoxia-induced impairment of neuronal electrical activity. In this study, we carried out extracellular recordings of hippocampal slices in order to investigate the effects of NEU on the electrical activity of neurons exposed to a hypoxic insult (oxygen and glucose deprivation). NEU prominently suppressed hypoxia-induced impairment of neuronal activity in a concentration-dependent manner. NEU, at a low dose (1 MUM), competently depressed the hypoxia-induced convulsive activity in a manner similar to trolox. Furthermore, high concentrations of NEU (50 MUM) markedly abolished all hypoxia-mediated impairment of neuronal activity and accelerated the slow recovery of neuronal activity more efficiently than ifenprodil and APV. These results suggest that NEU attenuates hypoxia-induced impairment of neuronal activity more potently than the antioxidant, trolox, and the NMDA receptor antagonists, ifenprodil and APV. We propose that NEU is a striking pharmacological candidate for neuroprotection against hypoxia because of its defensive action on hypoxia-mediated impairment of electrical neurotransmission as well as its neuroprotective action against neuronal cell death induced by exposure to pathological hypoxic conditions. PMID- 23733586 TI - Small reduction in quality of life seen with bevacizumab maintenance in patients with ovarian cancer. PMID- 23733587 TI - Prior experience in micro-surgery may improve the surgeon's performance in robotic surgical training. AB - SUMMARY BACKGROUND DATA: Robotic surgery has witnessed a huge expansion. Robotic simulators have proved to be of major interest in training. Some authors have suggested that prior experience in micro-surgery could improve robotic surgery training. OBJECTIVE: To test micro-surgery as a new approach in training, we proposed a prospective study comparing the surgical performance of micro-surgeons with that of general surgeons on a robotic simulator. METHODS: 49 surgeons were enrolled; 11 in the micro-surgery group (MSG); 38 n the control group (CG). Performance was evaluated based on five dV-Trainer(r) exercises. RESULTS: MSG achieved better results for all exercises including exercises requiring visual evaluation of force feed-back, economy of motion, instrument force and position. CONCLUSIONS: These results show that experience in micro-surgery could significantly improve surgeons' abilities and their performance in robotic training. So, as micro-surgery practice is relatively cheap, it could be easily included in basic robotic surgery training. PMID- 23733588 TI - Benefits and challenges of international clinical education from a US-based physiotherapist faculty perspective. AB - INTRODUCTION: The influence of internationalization on physiotherapist education in at least North American-based programmes has become more apparent. Faculty and students have been involved in various international activities. One category of activities includes international clinical education (ICE), where students earn clinical education credit for their learning activities at international sites. Although this educational strategy appears to be increasingly used in at least the United States and Canada, the related literature is limited in scope. The purpose of this portion of the present study was to investigate the benefits and challenges of ICE for US-based students, US-based physiotherapy programmes and international partners from the perspective of US-based faculty sending students for clinical education internationally. METHODS: Content analysis was used for this qualitative study. Fifteen US-based faculty members who had experience in sending physiotherapist students for ICE were recruited. The primary researcher conducted semi-structured phone interviews, averaging approximately 60 minutes in length. The primary and secondary researchers completed data analysis using NVivo 8 software (QSR International Inc., Cambridge, MA). RESULTS: Benefits of ICE to the students included exposure to alternate health systems, broadening of student perspectives and clinical competence. Challenges consisted of funding and possible language barrier. Increased visibility, expanded global perspective and faculty collaborations were benefits to the programme. Ensuring a quality learning experience was the greatest programme challenge. Benefits to the international site included education and faculty collaborations/exchanges; challenges were language, student clinical preparation and unfamiliarity with the student evaluation tool. Because the sample was limited to 15 US-based faculty members, the results may not be relevant to all programmes inside or outside of the United States. Additionally, the study lacked perspectives from the students or international sites. IMPLICATION FOR PHYSIOTHERAPY PRACTICE: The present study is an early step in the important examination of the impact of this emerging educational trend on physiotherapy education and practice. PMID- 23733589 TI - Performance of scientific cameras with different sensor types in measuring dynamic processes in fluorescence microscopy. AB - The plethora of available scientific cameras of different types challenges the biologically oriented experimenter when picking the appropriate camera for his experiment. In this study, we chose to investigate camera performances in a typical nonsingle molecule situation in life sciences, that is, quantitative measurements of fluorescence intensity changes from video data with typically skewed intensity distributions. Here, intensity profile dynamics of pH-sensors upon triggered changes of pH-environments in living cells served as a model system. The following camera types were tested: sCMOS, CCD (scientific and nonscientific) and EM-CCD (back- and front-illuminated). We found that although the EM-CCD cameras achieved the best absolute spatial SNR (signal-to-noise ratio) values, the sCMOS was at least of equal performance when the spatial SNR was related to the effective dynamic range, and it was superior in terms of temporal SNR. In the measurements of triggered intensity changes, the sCMOS camera had the advantage that it used the smallest fraction of its dynamic range when depicting intensity changes, and thus featured the best SNR at full usage of its dynamic range. PMID- 23733590 TI - Constitutional varus does not affect joint line orientation in the coronal plane. AB - BACKGROUND: In a previous study, we described the distribution of coronal alignment in a normal asymptomatic population and recognized the occurrence of constitutional varus in one of four individuals. It is important to further investigate the influence of this condition on the joint line orientation and how the latter is affected by the onset and progression of arthritis. QUESTIONS/PURPOSES: The purposes of this study are (1) to describe the distribution of joint line orientation in the coronal plane in the normal population; (2) to compare joint line orientation between patients with constitutional varus and neutral mechanical alignment; and (3) to compare joint line orientation between a cohort of patients with prearthritic constitutional varus and a cohort of patients with established symptomatic varus arthritis. METHODS: Full-leg standing hip-to-ankle digital radiographs were performed in 248 young healthy individuals and 532 patients with knee arthritis. Hip-knee-ankle (HKA) angle and tibial joint line angle (TJLA) were measured in the coronal plane. Patients were subdivided into varus (HKA <= -3 degrees ), neutral, and valgus (HKA >= 3 degrees ). RESULTS: The mean TJLA in healthy subjects was 0.3 degrees (SD 2.0 degrees ). TJLA was parallel to the floor in healthy subgroups with neutral alignment (TJLA 0.3 degrees , SD 1.9) and constitutional varus (TJLA 0.2 degrees , SD 2.2 degrees ). In patients with symptomatic arthritis and varus alignment, the TJLA opened medially (mean -1.9 degrees , SD 3.5 degrees ). CONCLUSIONS: Constitutional varus does not affect joint line orientation. Advanced medial arthritis causes divergence of the joint line from parallel to the floor. These findings influence decision-making for osteotomy and alignment in total knee arthroplasty. PMID- 23733592 TI - CORR Insights (r): Is premorbid glenoid anatomy altered in patients with glenohumeral osteoarthritis? PMID- 23733593 TI - Pharmacokinetics of GHB and detection window in serum and urine after single uptake of a low dose of GBL - an experiment with two volunteers. AB - During the last few years gamma-hydroxybutyric acid (GHB) and gamma-butyrolactone (GBL) have attracted much interest as recreational drugs and knock-out drops in drug-facilitated sexual assaults. This experiment aims at getting an insight into the pharmacokinetics of GHB after intake of GBL. Therefore Two volunteers took a single dose of 1.5 ml GBL, which had been spiked to a soft drink. Assuming that GBL was completely metabolized to GHB, the corresponding amount of GHB was 2.1 g. Blood and urine samples were collected 5 h and 24 h after ingestion, respectively. Additionally, hair samples (head hair and beard hair) were taken within four to five weeks after intake of GBL. Samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) after protein precipitation with acetonitrile. The following observations were made: spiked to a soft drink, GBL, which tastes very bitter, formed a liquid layer at the bottom of the glass, only disappearing when stirring. Both volunteers reported weak central effects after approximately 15 min, which disappeared completely half an hour later. Maximum concentrations of GHB in serum were measured after 20 min (95 ug/ml and 106 ug/ml). Already after 4-5 h the GHB concentrations in serum decreased below 1 ug/ml. In urine maximum GHB concentrations (140 ug/ml and 120 ug/ml) were measured after 1-2 h, and decreased to less than 1 ug/ml within 8-10 h. The ratio of GHB in serum versus blood was 1.2 and 1.6. PMID- 23733594 TI - Testicular sex cord stromal tumors: analysis of patients from the MAKEI study. AB - BACKGROUND: In children and adolescents, testicular sex cord stromal tumors (TSCSTs) are rare. There is only limited information available regarding their clinical presentation, biology, and prognosis. METHODS: Between 1993 and 2009, 42 patients were prospectively reported to the cooperative MAHO and MAKEI studies on childhood germ cell tumors. Based on standardized documentation, data on epidemiology, clinical presentation, diagnostic features, histopathological differentiation, therapy, and follow-up were evaluated. RESULTS: During the study period, a gradual increase of the documentation of these rare tumors was observed. Palpable, indolent testicular swelling was the most common clinical finding. In three patients, retention of the testis was observed. Two patients showed sexual precocity, and one patient showed a 45X/46XY mosaic. Juvenile granulosa cell tumors (n = 16) and Sertoli cell tumor (n = 15) were the leading histopathological subtypes. The first were commonly diagnosed during the first weeks of life (median age: 6(0-162) days, the latter during infancy (median 7(0 14) months, P < 0.05). Other histological diagnoses included Leydig cell and Large Cell Calcifying Sertoli cell tumors (both n = 3) and not-otherwise specified TSCSTs (n = 5), which were diagnosed during childhood and adolescence. All tumors were limited to the testis; there were no metastases. Treatment was surgical, only. After a median follow-up of 3.8 years, no relapse was observed. CONCLUSIONS: Diagnosis and therapy of testicular tumors should be planned in accordance with the recommendations of the respective childhood germ cell tumor protocols. High inguinal orchiectomy is safe and constitutes definitive therapy. Diagnostic work-up and follow-up should also consider potentially associated tumor predisposition syndromes. PMID- 23733595 TI - Rapid on-site cytologic examination of 1500 breast lesions using the modified Shorr's stain. AB - BACKGROUND: Rapid on-site evaluation (ROSE) cytology enables sample quality assessment in the procedure room and facilitates the process of examination. While its use for mammary lesions in one-stop breast clinics has been reported, its usefulness as a cytologic diagnostic tool has not been fully explored. METHODS: A total of 1500 examinations of core-needle biopsy imprint/fine-needle aspiration cytology were performed for outpatients with breast lesions. The slides were immediately processed with modified Shorr's stain, which can be completed within a few minutes yet produces specimens of similar staining quality as the Papanicolaou (Pap) stain. The adequacy of sampling was evaluated on site, and a cytologic diagnosis was also made. ROSE cytologic findings were classified into five grades: class 1, inadequate; class 2, benign; class 3, indeterminate; class 4, suspicious for malignancy; class 5, malignant. If enough epithelial cells could not be obtained despite repeated examinations, the sample was scored as ineligible. These scores were utilized for patient management. Final cytologic diagnoses were made with conventional Pap stains. RESULTS: Reproducibility of scores between both staining methods was excellent (weighted kappa statistic = 0.985). When compared class by class, concordance of cytologic diagnoses was particularly high in class 2 and 5 Shorr scores, in which the agreement with Pap diagnoses was 92.8 and 93.6 %, respectively. CONCLUSIONS: Our modified Shorr's staining protocol was useful to reduce the time for the diagnosis and treatment planning of breast lesions suspected of being breast cancer. It is beneficial for both the patients and clinicians. PMID- 23733596 TI - L-cysteine and hydrogen sulfide increase PIP3 and AMPK/PPARgamma expression and decrease ROS and vascular inflammation markers in high glucose treated human U937 monocytes. AB - Diabetic patients have lower blood levels of L-cysteine (LC) and hydrogen sulfide (H2 S) and a higher incidence of vascular inflammation. This study examined whether impaired LC or H2S levels affect vascular inflammation markers in diabetes. Human U937 monocytic cells were treated with high-glucose (HG, 25 mM, 20 h) in the presence or absence of LC (100, 500, or 1,000 uM, an endogenous precursor of H2 S) or Na2S (5 or 25 uM, an exogenous source of H2S). Both LC and Na2 S supplementation decreased intracellular ROS production and increased cellular PIP3 (phosphatidylinositol-3,4,5-trisphosphate) in HG-exposed cells. The effect of LC on PIP3 was prevented by propargylglycine, an inhibitor of cystathionine-gamma-lyase (CSE) that catalyzes H2S formation from LC. Signal silencing studies with CSE siRNA also showed the inhibition of H2S formation and PIP3 upregulation in LC-supplemented CSE knockdown cells exposed to HG. This demonstrates that H2S plays a role in mediating the effect of LC on increased PIP3. Using the PI3K specific inhibitor LY294002, this study demonstrated that PI3K activation mediates the effect of LC and Na2S on PIP3 upregulation. Results showed that supplementation with LC and Na2S reduced NF-kappaB phosphorylation and the secretion of TNF-alpha, MCP-1, IL-8, IL-1beta, and IP-10. Treatment with LC (500 uM), Na2S (25 uM), and PIP3 (5 nM) increased the AMPK phosphorylation and PPARgamma expression in cells exposed to HG. This study reports for the first time a novel molecular mechanism by which Na2S or LC supplementation can lower oxidative stress and various markers of vascular inflammation in diabetes. PMID- 23733597 TI - Gas-driven ultrafast reversible switching of super-hydrophobic adhesion on palladium-coated silicon nanowires. AB - A gas-driven ultrafast adhesion switching of water droplets on palladium-coated Si nanowire arrays is demonstrated. By regulating the gas-ambient between the atmosphere and H2 , the super-hydrophobic adhesion is repeatedly switched between water-repellent and water-adhesive. The capability of modulating the super hydrophobic adhesion on a super-hydrophobic surface with a non-contact mode could be applicable to novel functional lab-on-a-chip platforms. PMID- 23733598 TI - Clinical significance of first-trimester chorionic bumps: a matched case-control study. AB - OBJECTIVE: To determine the clinical significance of a chorionic bump diagnosed by ultrasound in women attending an early pregnancy unit in a teaching hospital. METHODS: This was a retrospective case-control study over an 8-year period (2003 2010). Cases of chorionic bump were identified by searching our early pregnancy database and were matched to controls in a ratio of 1:3. The primary outcome measure was miscarriage vs ongoing pregnancy. Secondary outcomes were gestational age at delivery and the presence or absence of fetal abnormality. RESULTS: A total of 37 798 pregnancies were examined over the study period and 57 pregnancies with a chorionic bump were identified, giving an estimated prevalence of 1.5 per 1000 pregnancies (0.15%; 95% CI, 0.01-0.73%). Of the 52 women with follow-up data, 20 (38.5%; 95% CI, 26.4-52.1%) miscarried vs 31/151 (20.5%; 95% CI, 14.8-27.7%) in the control group (P = 0.01). There were four second-trimester miscarriages in the study group and none in the controls (P < 0.01). Out of 52 pregnancies in the study group there were 32 live births (62%; 95% CI, 47.9 73.6%) vs 118/151 (78%; 95% CI, 70.9-84.0%) in the control group (P = 0.02). There were no differences in preterm delivery rates or fetal anomalies. No significant relationship was found between size of the bump or location in relation to the umbilical cord insertion and risk of miscarriage. CONCLUSIONS: Women presenting to early pregnancy units with a chorionic bump discovered at first-trimester ultrasound examination had approximately double the risk of miscarriage compared with matched controls, the difference being due to a greater number of miscarriages during the second trimester of pregnancy. PMID- 23733599 TI - The effect of obesity on antibiotic treatment failure: a historical cohort study. AB - PURPOSE: Obesity, a major health issue, is also an important risk factor for infections. Evidence demonstrates that excess weight affects the disposition of antibiotics but little work has been done to explore if this results in antibiotic treatment failure (ATF). ATF has serious adverse health outcomes and may increase treatment resistance. Given that obese patients often have other health issues, it is important to determine if excess weight independently increases the likelihood of ATF. METHODS: Consenting patients (N = 18 014), randomly sampled from Sante Quebec Health surveys (1992, 1998), were linked with administrative health databases. Patients were within the normal, overweight, and obese weight categories aged 20-79 years old, receiving at least one course of antibiotic therapy from the survey date until December 2005. ATF was defined as any additional antibiotic prescriptions or hospitalizations for infections within the 30 days after initial therapy. Logistic regression was used to assess the impact of excess weight on ATF after adjusting for patient characteristics, comorbidities, history of antibiotic use, antibiotic resistance, and flu season. RESULTS: Of the final sample size (N = 6 179), 39.0% were overweight and 21.4% were obese. The most frequently prescribed antibiotics were amoxicillin (16.0%), ciprofloxacin (9.2%), phenoxymethylpenicillin (8.8%), trimethroprim/sulfamethoxazole (8.6%), and clarithromycin (8.5%). ATF occurred in 828 (13.4%) of the 6 179 study patients. Obesity was a significant predictor of ATF (adjusted OR 1.26; 95% CI 1.03-1.52). CONCLUSION: Obesity is a significant risk factor for ATF, and this association may be due to the current "one size fits all" dosing strategy, which warrants further investigation. PMID- 23733600 TI - Expression of the genes coding for plastidic acetyl-CoA carboxylase subunits is regulated by a location-sensitive transcription factor binding site. AB - Plastidic acetyl-CoA carboxylase (ACCase) regulates the rate of fatty acid synthesis. This enzyme is composed of biotin carboxyl carrier protein (BCCP), biotin carboxylase (BC), and carboxyltransferase (CT), which consists of alpha and beta subunits. Among these components, CTbeta is encoded by the plastidic genome. In Arabidopsis, BC and CTalpha are each encoded by a single gene, and there are two genes for BCCP, BCCP1 and BCCP2. Promoter analysis revealed that the 5'-UTR containing the AW box is necessary for the expression of these genes in seeds and seedlings. The results indicated that there are other transcription factors besides WRI1 that bind to the AW box and regulate these genes in organs other than seeds. Although the AW boxes at 748 and 532 bp upstream from the transcription start sites (TSSs) of the BC and CTalpha genes, respectively, were not functional in seeds, the latter was functional in seedlings. In addition, when these AW boxes were moved to approximately 200 bp upstream from the TSS, they became active in seeds but not in seedlings. These results suggest that the distance from the TSS affects the function of the AW box, and the AW box alone is not sufficient for expression in seedlings. A comparison of the protein levels of BC, BCCP1, BCCP2 and CTbeta between a wri1 mutant, a WRI1-overexpressing line and control plants showed that protein levels of BCCP2 and BC but not BCCP1 and CTbeta are affected by WRI1. The results suggest that ACCase subunits are differentially regulated by WRI1. PMID- 23733602 TI - Socio-emotional Problems in Children with CDG. AB - BACKGROUND: Congenital disorders of glycosylation (CDG) form a group of inherited metabolic diseases. Although the clinical presentation shows extreme variability, the nervous system is frequently affected. Several parents of our patients diagnosed with CDG reported behavioral problems, including mood swings, depressive behavior, and anxiety. This raised the question whether patients with CDG have an increased risk for socio-emotional problems. METHODS: We evaluated 18 children with confirmed CDG. The Child Behavior Checklist (CBCL) was used to screen for socio-emotional problems. To determine the disease progression and severity in CDG, the Nijmegen Paediatric CDG Rating Scale (NPCRS) was used. RESULTS were compared to "norm scores" and to children with mitochondrial disorders and children with other chronic metabolic disorders with multisystem involvement. RESULTS: RESULTS showed a high prevalence of socio-emotional problems in children with CDG. Mean total scores, scores on withdrawn/depressed behavior, social problems, and somatic complaints were significantly increased. More than two thirds of our CDG patients have abnormal scores on CBCL. The mean score on social problems was significantly higher compared to our two control groups of patients with other chronic metabolic disorders. CONCLUSIONS: Patients with CDG have an increased risk of developing socio-emotional problems. A standard screening for psychological problems is recommended for the early detection of psychological problems in CDG patients. PMID- 23733601 TI - Study of nsLTPs in Lotus japonicus genome reveal a specific epidermal cell member (LjLTP10) regulated by drought stress in aerial organs with a putative role in cutin formation. AB - The cuticle is the first defense against pathogens and the second way water is lost in plants. Hydrophobic layers covering aerial plant organs from primary stages of development form cuticle, including major classes of aliphatic wax components and cutin. Extensive research has been conducted to understand cuticle formation mechanisms in plants. However, many questions remain unresolved in the transport of lipid components to form cuticle. Database studies of the Lotus japonicus genome have revealed the presence of 24 sequences classified as putative non-specific lipid transfer proteins (nsLTPs), which were classified in seven groups; four groups were selected because of their expression in aerial organs. LjLTP8 forms a cluster with DIR1 in Arabidopsis thaliana while LjLTP6, LjLTP9, and LjLTP10 were grouped as type I LTPs. In silico studies showed a high level of structural conservation, and substrate affinity studies revealed palmitoyl-CoA as the most likely ligand for these LTPs, although the Lyso Myristoyl Phosphatidyl Choline, Lyso-myristoyl phosphatidyl glycerol, and Lyso stearyl phosphatidyl choline ligands also showed a high affinity with the proteins. The LjLTP6 and LjLTP10 genes were expressed in both the stems and the leaves under normal conditions and were highly induced during drought stress. LjLTP10 was the most induced gene in shoots during drought. The gene was only expressed in the epidermal cells of stems, primordial leaves, and young leaflets. LjLTP10 was positively regulated by MeJA but repressed by abscisic acid (ABA), ethylene, and H2O2, while LjLTP6 was weakly induced by MeJA, repressed by H2O2, and not affected by ABA and ethylene. We suggest that LjLTP10 is involved in plant development of stem and leaf cuticle, but also in acclimation to tolerate drought stress in L. japonicus. PMID- 23733603 TI - Metabolic profiling of total homocysteine and related compounds in hyperhomocysteinemia: utility and limitations in diagnosing the cause of puzzling thrombophilia in a family. AB - We describe a family illustrating the diagnostic difficulties occurring when pyridoxine-responsive cystathionine beta-synthase (CBS) deficiency presents with thrombotic disease without associated ocular, skeletal, or CNS abnormalities, a situation increasingly recognized. This family had several thromboembolic episodes in two generations with apparently inconstant elevations of plasma total homocysteine (tHcy). When taking (sometimes even low amounts) of pyridoxine, the affected family members had low-normal tHcy and normal values for cystathionine, methionine, and cysteine. Withdrawal of vitamin therapy was necessary before lower cystathionine, elevated methionine, and decreased cysteine became apparent, a pattern suggestive of CBS deficiency, leading to the finding that the affected members were each compound heterozygotes for CBS p.G307S and p.P49L. To assist more accurate diagnosis of adults presenting with thrombophilia found to have elevated tHcy, the patterns of methionine-related metabolites in CBS-deficient patients are compared in this article to those in patients with homocysteine remethylation defects, including inborn errors of folate or cobalamin metabolism, and untreated severe cobalamin or folate deficiency. Usually serum cystathionine is low in subjects with CBS deficiency and elevated in those with remethylation defects. S-Adenosylmethionine and S-adenosylhomocysteine are often markedly elevated in CBS deficiency when tHcy is above 100 umol/L. We conclude that there are likely other undiagnosed, highly B6-responsive adult patients with CBS deficiency, and that additional testing of cystathionine, total cysteine, methionine, and S-adenosylmethionine will be helpful in diagnosing them correctly and distinguishing CBS deficiency from remethylation defects. PMID- 23733604 TI - Surface hydride on titanium by cathodic polarization promotes human gingival fibroblast growth. AB - Connective tissue seal to dental abutment is crucial for peri-implant health. Several efforts have been made previously to optimize abutment surfaces, but no consensus has been reached regarding the optimal surface architecture and/or composition for soft tissue seal. Here, we report on experiments using cathodic polarization in organic acids to optimize titanium (Ti) surfaces for use as abutments. The three main factors affecting surface topography and chemistry were electrolyte composition, current density, and polarization time. Under identical conditions, oxalic acid created rougher surfaces than tartaric acid and acetic acid, and acetic acid produced more surface hydride. Surface hydride amount was suggested to first increase and then decrease with current density from 1 mA/cm(2) to 15 mA/cm(2) . The complexity of the surface topography and hydride production both increased with polarization time. Proliferation rate of human gingival fibroblasts (HGFs) was positively correlated with surface hydride content, suggesting the positive effect of surface hydride on connective tissue growth around dental abutment. Changes in surface topography and hydrophilicity did not significantly influence HGF growth. PMID- 23733605 TI - Supporting people with intellectual and developmental disabilities to participate in their communities through support staff pilot intervention. AB - BACKGROUND: Increasingly, people with intellectual and developmental disabilities (I/DD) are supported to participate in least-restricted settings in the community. However, little is known about desired community participation choice and control of people with I/DD, nor effective strategies to support full participation. Furthermore, service providers of this population in community and residential settings have unique roles in influencing choice and control in community participation. RESEARCH AIM: The purpose of this project is to empower adults with I/DD in community participation by collaborating with agency staff and administrators to strategize change in service provision and programming. METHODS: This article describes the development, imple-mentation and mixed methods evaluation of a pilot staff intervention. RESULTS: Findings indicate staff who participated in pilot intervention report increased confidence in supporting adults with I/DD to participate in their communities. CONCLUSIONS: Intervention development has implications for staff, administrators and agencies in planning and executing opportunities to support choice and control for community participation for adults with I/DD. PMID- 23733606 TI - Anatomical landmarks for point-matching registration in image-guided neurosurgery. AB - BACKGROUND: Accurate patient to image registration is the core for successful image-guided neurosurgery. While skin adhesive markers (SMs) are widely used in point-matching registration, a proper implementation of anatomical landmarks (ALs) may overcome the inconvenience brought by the use of SMs. METHODS: Using nine ALs, a set of three configurations of different combinations of them is proposed. These configurations are defined according to the required positioning of the patient's head during surgery and the resulting distribution of the expected target registration error (TRE). These configurations were first evaluated by simulation experiment using the data of 20 patients from two hospitals, and then testing the applicability of them in eight real clinical surgeries of neuronavigation. RESULTS: The results of the simulation experiment showed that, by incorporating a fiducial registration error (FRE) of 3.5 mm measured in the clinical setting, the expected TRE in the whole skull was less than 2.5 mm, and the expected TRE in the whole brain was less than 1.75 mm when using all the nine ALs. A small TRE could also be achieved in the corresponding surgical field by using the other three configurations with less ALs. In the clinical experiment, the FLE ranges in the image and the patient space were 1.4 3.6 mm and 1.6-5.5 mm, respectively. The measured TRE and FRE were 3.1 +/- 0.75 mm and 3.5 +/- 0.17 mm, respectively. CONCLUSIONS: The AL configurations proposed in this investigation provide sufficient registration accuracy and can help to avoid the disadvantages of SMs if used clinically. PMID- 23733608 TI - Female smokers have increasing risk of lung cancer mortality. PMID- 23733609 TI - Missing links: New survey shows need for improvements in cancer diagnosis. PMID- 23733610 TI - MRT letter: Micro- to nanoscale sample collection for high throughput microscopy. AB - In high throughput microscopy, it is often assumed that the objects under investigation are fixed spatially. In addition, it is also presumed that the objects are sufficiently populated, otherwise there will be need to search through vast tracks of field of views before any recording can be done. The ability to collect objects at one location in the hydrated state is thus desirable and this is a challenge when the density of target objects in a sample is very low. In this work, we report that the generation of a squeezing flow from a circular coverslip compressing on suspensions is able to collect particulate (microbeads, fluorescent nanobeads and live algal cells) and non-particulate (EGFP) objects at the rim region of the coverslip. With a coverslip of 13 mm diameter, volumes between 2 uL and 4 uL were found to completely fill the coverslip without breaching the rims. Sample compression speeds between 100 um/s and 1000 um/s did not have any effect on object collection outcomes. In effect, the simple placement of coverslips on top the drop of sample by hand without a motorized translator was found to produce similar collection outcomes. Quantitative measurements confirmed that all the objects investigated were displaced and relocated at the rim regions to a very high degree. PMID- 23733611 TI - Physiotherapy in degenerative cerebellar ataxias: utilisation, patient satisfaction, and professional expertise. AB - Physiotherapy plays an important role in the management of patients with degenerative cerebellar ataxias. However, our insight in the quantity and quality of physiotherapy prescription in this group of patients is incomplete. The purposes of this study were to investigate the utilization of physiotherapy and patient satisfaction in patients with degenerative ataxias in The Netherlands and to examine the level of expertise and needs of physiotherapists treating ataxia patients. Questionnaires were sent to members of the Dutch association for patients with degenerative cerebellar ataxias (n = 532). In addition, 181 questionnaires were sent to the physiotherapists who had recently treated the patients who responded. Eventually, 317 questionnaires from patients (60 %) and 114 questionnaires from physiotherapists (63 %) could be used for further analysis. Sixty-four percent of the patients were currently treated by a physiotherapist. Their median treatment duration was 5 years. Nineteen percent of the patients had never been referred, often despite the presence of limitations in daily activities. On the other hand, some participants without reported limitations had received physiotherapy. In general, participants were satisfied with their physiotherapist. The most reported treatment goals were improvement or maintenance of balance, general physical condition, and mobility. Physiotherapists reported lack of ataxia-specific expertise and expressed the need for education and evidence-based guidelines. Referral to and use of physiotherapy in patients with degenerative cerebellar ataxia in The Netherlands are currently inconsistent and not in agreement with the little scientific evidence available. Referral rates are high, but referrals and actual necessity are discrepant; treatment duration is long; and ataxia-specific expertise among physiotherapists is insufficient. Evidence-based recommendations and specific training of physiotherapists are needed. PMID- 23733612 TI - A multicolor photoinitiator for cationic polymerization and interpenetrated polymer network synthesis: 2,7-di-tert-butyldimethyldihydropyrene. AB - For polymer synthesis upon visible light, actual photoinitiator operates in a restricted part of the spectrum. As a consequence, several photoinitiators are necessary to harvest all of the emitted visible photons. Herein, 2,7-di-tert butyldimethyldihydropyrene is used for the first time as a multicolor photoinitiator for the cationic polymerization of epoxides. Upon addition of diphenyliodonium hexafluorophosphate and optionally N-vinylcarbazole, the originality of this approach is to allow efficient monomer conversions under various excitation light sources in the 360-650 nm wavelength range: halogen lamps, and light-emitting and laser diodes. The synthesis of an interpenetrated polymer network from an epoxide/acrylate blend using a red light at 635 nm is also feasible. The formed polymer material exhibits a photochromic character. PMID- 23733613 TI - What is predictive of preterm delivery in the first trimester: isthmus or cervical length? AB - OBJECTIVE: This study aims to evaluate the utility of first trimester cervical ultrasonography in predicting preterm delivery by separate analysis of measurements of cervical and isthmus length. METHODS: This is a cohort study based on data collected prospectively on singletons between 1 July 2011 and 1 February 2013. Mean cervical, isthmus and cervico-isthmic complex length were measured for deliveries before and after 37 weeks. RESULTS: A total of 1494 pregnancies were analysed, including 51 cases of spontaneous preterm delivery (3.4%). The cervico-isthmic complex in the first trimester was significantly shorter in patients who delivered before term (43.8 mm vs 47.5 mm, p = 0.04). This difference is related to differences in length at the isthmus (10.7 mm vs 14.1 mm, p = 0.005) rather than at the cervix proper (34.5 mm vs 35.0 mm, p = 0.56). CONCLUSIONS: Measurement of the cervico-isthmic complex enables detection of a number of patients who will go on to deliver before term. Further studies are necessary to confirm that isthmic length and not cervical length is predictive of preterm delivery. PMID- 23733615 TI - Chronic parvovirus infection in a pediatric cardiac transplant recipient: a case report. PMID- 23733616 TI - CO2-concentrating mechanism in cyanobacterial photosynthesis: organization, physiological role, and evolutionary origin. AB - The cellular and molecular organization of the CO2-concentrating mechanism (CCM) of cyanobacteria is reviewed. The primary processes of uptake, translocation, and accumulation of inorganic carbon (Ci) near the active site of carbon assimilation by the enzyme ribulose-1,5-bisphosphate carboxylase in the C3 cycle in cyanobacteria are described as one of the specialized forms of CO2 concentration which occurs in some photoautotrophic cells. The existence of this form of CO2 concentration expands our understanding of photosynthetic Ci assimilation. The means of supplying Ci to the C3 cycle in cyanobacteria is not by simple diffusion into the cell, but it is the result of coordinated functions of high-affinity systems for the uptake of CO2 and bicarbonate, as well as intracellular CO2/HCO3 (-) interconversions by carbonic anhydrases. These biochemical events are under genetic control, and they serve to maintain cellular homeostasis and adaptation to CO2 limitation. Here we describe the organization of the CCM in cyanobacteria with a special focus on the CCM of relict halo- and alkaliphilic cyanobacteria of soda lakes. We also assess the role of the CCM at the levels of the organism, the biosphere, and evolution. PMID- 23733617 TI - Brown spider phospholipase-D containing a conservative mutation (D233E) in the catalytic site: identification and functional characterization. AB - Brown spider (Loxosceles genus) bites have been reported worldwide. The venom contains a complex composition of several toxins, including phospholipases-D. Native or recombinant phospholipase-D toxins induce cutaneous and systemic loxoscelism, particularly necrotic lesions, inflammatory response, renal failure, and hematological disturbances. Herein, we describe the cloning, heterologous expression and purification of a novel phospholipase-D toxin, LiRecDT7 in reference to six other previously described in phospholipase-D toxin family. The complete cDNA sequence of this novel brown spider phospholipase-D isoform was obtained and the calculated molecular mass of the predicted mature protein is 34.4 kDa. Similarity analyses revealed that LiRecDT7 is homologous to the other dermonecrotic toxin family members particularly to LiRecDT6, sharing 71% sequence identity. LiRecDT7 possesses the conserved amino acid residues involved in catalysis except for a conservative mutation (D233E) in the catalytic site. Purified LiRecDT7 was detected as a soluble 36 kDa protein using anti-whole venom and anti-LiRecDT1 sera, indicating immunological cross-reactivity and evidencing sequence-epitopes identities similar to those of other phospholipase-D family members. Also, LiRecDT7 exhibits sphingomyelinase activity in a concentration dependent-manner and induces experimental skin lesions with swelling, erythema and dermonecrosis. In addition, LiRecDT7 induced a massive inflammatory response in rabbit skin dermis, which is a hallmark of brown spider venom phospholipase-D toxins. Moreover, LiRecDT7 induced in vitro hemolysis in human erythrocytes and increased blood vessel permeability. These features suggest that this novel member of the brown spider venom phospholipase-D family, which naturally contains a mutation (D233E) in the catalytic site, could be useful for future structural and functional studies concerning loxoscelism and lipid biochemistry. HIGHLIGHTS: 1- Novel brown spider phospholipase-D recombinant toxin contains a conservative mutation (D233E) on the catalytic site. 2-LiRecDT7 shares high identity level with isoforms of Loxosceles genus. 3-LiRecDT7 is a recombinant protein immunodetected by specific antibodies to native and recombinant phospholipase-D toxins. 4-LiRecDT7 shows sphingomyelinase-D activity in a concentration-dependent manner, but less intense than other isoforms. 5-LiRecDT7 induces dermonecrosis and inflammatory response in rabbit skin. 6-LiRecDT7 increases vascular permeability in mice. 7-LiRecDT7 triggers direct complement-independent hemolysis in erythrocytes. PMID- 23733618 TI - A prospective, phase 1/2 study of everolimus and temozolomide in patients with advanced pancreatic neuroendocrine tumor. AB - BACKGROUND: Both everolimus and temozolomide are associated with single-agent activity in patients with pancreatic neuroendocrine tumor (NET). A phase 1/2 study was performed to evaluate the safety and efficacy of temozolomide in combination with everolimus in patients who have advanced pancreatic NET. METHODS: Patients were treated with temozolomide at a dose of 150 mg/m(2) per day on days 1 through 7 and days 15 through 21 in combination with everolimus daily in each 28-day cycle. In cohort 1, temozolomide was administered together with everolimus at 5 mg daily. Following demonstration of safety in this cohort, subsequent patients in cohort 2 were treated with temozolomide plus everolimus at 10 mg daily. The duration of temozolomide treatment was limited to 6 months. Patients were followed for toxicity, radiologic and biochemical response, and survival. RESULTS: A total of 43 patients were enrolled, including 7 in cohort 1 and 36 in cohort 2. Treatment was associated with known toxicities of each drug; no synergistic toxicities were observed. Among 40 evaluable patients, 16 (40%) experienced a partial response. The median progression-free survival duration was 15.4 months. Median overall survival was not reached. CONCLUSIONS: Temozolomide and everolimus can be safely administered together in patients with advanced pancreatic NET, and the combination is associated with encouraging antitumor activity. Future studies evaluating the efficacy of combination therapy compared to treatment with either agent alone are warranted. PMID- 23733620 TI - Characterization of purine catabolic pathway genes in coelacanths. AB - Coelacanths are a critically valuable species to explore the gene changes that took place in the transition from aquatic to terrestrial life. One interesting and biologically relevant feature of the genus Latimeria is ureotelism. However not all urea is excreted from the body; in fact high concentrations are retained in plasma and seem to be involved in osmoregulation. The purine catabolic pathway, which leads to urea production in Latimeria, has progressively lost some steps, reflecting an enzyme loss during diversification of terrestrial species. We report the results of analyses of the liver and testis transcriptomes of the Indonesian coelacanth Latimeria menadoensis and of the genome of Latimeria chalumnae, which has recently been fully sequenced in the framework of the coelacanth genome project. We describe five genes, uricase, 5-hydroxyisourate hydrolase, parahox neighbor B, allantoinase, and allantoicase, each coding for one of the five enzymes involved in urate degradation to urea, and report the identification of a putative second form of 5-hydroxyisourate hydrolase that is characteristic of the genus Latimeria. The present data also highlight the activity of the complete purine pathway in the coelacanth liver and suggest its involvement in the maintenance of high plasma urea concentrations. PMID- 23733619 TI - Neurocognitive and behavioral outcomes in Latino childhood cancer survivors. AB - BACKGROUND: Children with brain tumors and leukemia are at risk for neurocognitive and behavioral late effects due to central nervous system-directed therapies. Few studies have examined these outcomes in ethnic minority samples, despite speculation that socio-demographic factors may increase vulnerability for adverse neurobehavioral outcomes. We evaluated the neurocognitive and behavioral outcomes and their impact on the health-related quality of life in survivors of childhood cancer drawn from Latino families in the Los Angeles region. PROCEDURE: Using culturally-relevant recruitment strategies, 73 predominantly Spanish speaking parents of pediatric brain tumor or leukemia survivors completed standardized questionnaires, including the Conners parent-report and the Bidimensional Acculturation Scales. Clinical and socio-demographic factors influencing the development of neurocognitive and behavioral dysfunction were examined. RESULTS: Approximately 50% of the children placed at or above the "elevated" level for difficulties with attention, school-based learning, and peer relations. Younger age at diagnosis significantly predicted dysfunction in inattention, learning problems, and hyperactivity/impulsivity. Children whose parents were less adherent to the non-Hispanic white culture were more likely to have problems with peer relations and executive functioning. HRQL was significantly lower in survivors with neurocognitive and behavioral dysfunction relative to those with normal range scores on the Conners scale. CONCLUSIONS: In addition to the child's age at diagnosis, acculturation appears to predict select neurocognitive and behavioral outcomes in this socio-demographically homogeneous sample of Latino families. Further research is needed to understand the interaction of ethnic and cultural factors with therapeutic exposures in determining the adverse neurobehavioral outcomes, so as to optimally design interventions. PMID- 23733621 TI - Effects of 85 dB noise exposure on macro and trace element levels in plasma and brain areas of rats. AB - In this study, our hypothesis was that workplace noise can alter brain element levels like immobilization and light-dark cycle shift, and we aimed to investigate the effects of workplace noise on element levels of brain areas as well as changes in blood of chronically noise-exposed rats. Twenty-four rats were randomly divided into three groups. The first group was the control. The second group (noise exposed) was subjected to daily 8 h 85 dB workplace noise for 15 days, and the third group (noise exposed plus normal condition) was also subjected to the same noise exposure and then returned to normal condition for 15 days. In noise-exposed group, Na, K, Ca, Mg , Fe, Cu, and Zn levels in plasma significantly increased when compared with controls (p = 0.03 for Na; p = 0.005 for K and Mg; p = 0.002 for Ca and Fe; p = 0.01 for Cu and Zn). In this group, Fe level of temporal lobe significantly increased (p = 0.021) while Mg level significantly increased in frontal (p = 0.021) and temporal (p = 0.001) lobes when compared with controls. In the noise-exposed plus normal condition group, plasma Na, K, Fe, Cu, and Zn levels were greatly similar to controls. But, plasma Ca and Mg levels significantly decreased when compared with controls (p = 0.002 and p = 0.007) and noise-exposed group (p = 0.002 and p = 0.001). Fe level of temporal lobe significantly increased when compared with controls (p = 0.001) and noise exposed group (p = 0.001). These alterations may be attributed to impaired intake of water and micronutrients or their excretions, emerging by acoustic stress. PMID- 23733622 TI - Cancer cachexia raises the plasma concentration of oxymorphone through the reduction of CYP3A but not CYP2D6 in oxycodone-treated patients. AB - This study evaluated the plasma concentrations of oxycodone and its demethylates and opioid-induced adverse effects based on cachexia stage in cancer patients receiving oxycodone. Seventy patients receiving oxycodone for cancer pain were enrolled. Cachexia was evaluated using the Glasgow Prognostic Score (GPS). Predose plasma concentrations of oxycodone, oxymorphone, and noroxycodone were determined at the titration dose. Opioid-induced adverse effects were monitored for 2 weeks after the titration. Plasma concentrations of oxycodone and oxymorphone but not noroxycodone in patients with a GPS of 2 were significantly higher than that with a GPS of 0. The metabolic ratios of noroxycodone but not oxymorphone to oxycodone in patients with a GPS of 1 and 2 were significantly lower than in those with a GPS of 0. A higher GPS was associated with a higher incidence of somnolence, while the GPS did not affect the incidence of vomiting. Plasma concentrations of oxycodone and oxymorphone were not associated with the incidence of adverse effects. In conclusion, cancer cachexia raised the plasma exposures of oxycodone and oxymorphone through the reduction of CYP3A but not CYP2D6. Although the cachexia elevated the incidence of somnolence, alterations in their pharmacokinetics were not associated with the incidence. PMID- 23733623 TI - Use of selective serotonin reuptake inhibitors in pregnancy and cardiac malformations: a propensity-score matched cohort in CPRD. AB - PURPOSE: Research on the association of maternal selective serotonin reuptake inhibitor (SSRI) use and cardiac malformations in the offspring has yielded conflicting findings. We therefore sought to further investigate the association using data from a large population-based cohort in the UK. METHODS: The study population consisted of 149 464 pregnancies ending in a live birth between January/1996 and November/2010 from the Clinical Practice Research Datalink's Mother Baby Link. We created propensity-score matched cohorts of first-trimester SSRI users who did not use other antidepressants in the same gestational period ('SSRI users', n=3046) and non-antidepressant users (no use from the 3 months before pregnancy through the second trimester of pregnancy, 'non-users'; n=8991). Weighted logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of cardiac malformations overall and septal defects diagnosed in the first year of life, or in the first 6 years of life. RESULTS: Sixteen infants with cardiac malformations were identified among SSRI users; 10 of them were septal defects. Among non-users, there were 48 infants with cardiac malformations, 26 of whom had septal defects. The OR (95% CI) for cardiac malformations was 1.00 (0.50; 2.00), and for septal defects was 1.15 (0.46; 2.87). Results were similar for cardiac malformations diagnosed in the first 6 years of life, and in several sensitivity analyses that were also implemented. CONCLUSIONS: The results of this study are most compatible with no association between maternal use of SSRIs in early pregnancy and cardiac malformations or septal defects in the offspring. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. PMID- 23733624 TI - Iron-catalyzed oxidative radical cross-coupling/cyclization between phenols and olefins. PMID- 23733625 TI - Digital diagnosis. AB - The emerging practice of telemedicine allows physicians to consult with patients over the telephone and through live Internet chats, a webcam, or other electronic means. However, it has its limits. Telemedicine may increase patients' access to care, but face-to-face examinations are still vital. PMID- 23733626 TI - ACOs, Texas-style. PMID- 23733627 TI - Payback possible. PMID- 23733628 TI - Investing in prevention. PMID- 23733629 TI - Bad air day. PMID- 23733630 TI - Magic number. PMID- 23733631 TI - SEM studies on immature stages of the drone flies (diptera, syrphidae): Eristalis similis (Fallen, 1817) and Eristalis tenax (Linnaeus, 1758). AB - Adult drone flies (Syrphidae: Eristalis spp.) resemble male honeybees in appearance. Their immature stages are commonly known as rat-tailed maggots due to the presence of a very long anal segment and a telescopic breathing tube. The larvae are associated with decaying organic material in liquid or semi-liquid media, as in the case of other saprophagous eristalines. Biological and morphological data were obtained from both laboratory cultures and sampling in the field. Drone flies are important pollinators for wild flowers and crops. In fact, mass rearing protocols of Eristalis species are being developed to be used as efficient alternative pollinators. However, deeper knowledge of larval morphology and biology is required to improve artificial rearing. The production quality control of artificial rearing must manage the consistency and reliability of the production output avoiding, for example contamination with similar species. This article presents the first description of the larva and puparium of E. similis, including a comparative morphological study of preimaginal stages of the anthropophilic and ubiquitous European hoverfly species E. tenax. Scanning electron microscopy has been used for the first time to describe larvae and puparia of both species. Moreover, the preimaginal morphology of E. similis has been compared with all known descriptions of the genus Eristalis. The main diagnostic characters of the preimaginal stages of E. similis are the morphology of the anterior spiracles (shape of clear area and arrangement of facets) and pupal spiracles (length, shape, and arrangement of tubercles). PMID- 23733632 TI - Port site metastases after robot-assisted surgery: a systematic review. AB - BACKGROUND: Robotic surgery is a new technique and the aim of this study was to review the available literature on robotic port-site metastasis in oncological patients. METHODS: The results of this study were retrieved after performing a systematic electronic search in PubMed, Scopus and Cochrane databases. RESULTS: In total 204 patients were included in the study, of which five had robotic port site metastasis. Their age ranged from 35-77 years. The types of cancers causing port-site metastasis were one squamous cell cervical carcinoma, two cervical adenocarcinomas, one gallbladder carcinoma and one transitional cell bladder carcinoma. The port-site metastasis occurred from 3 weeks up to 18 months postoperatively with the tumor measuring from 1.1 to 10.5 cm. CONCLUSIONS: Port site metastasis is an extremely rare complication of robotic surgery. No safe conclusion can be drawn, but the aim of this study was to raise doctors' suspicion levels to such a rare new entity. PMID- 23733633 TI - Clinical and electromyographic results of proximal and distal realignment procedures in young patients with recurrent patellar dislocations. AB - BACKGROUND: Until now, no study has been published about the electromyographic changes in the extensor apparatus after the Green procedure for proximal realignment in young patients with recurrent patellar dislocations. This electromyographic study was performed to analyze imbalances between the vastus medialis and vastus lateralis muscles after different patellar realignment procedures. HYPOTHESIS: Surgical proximal realignment leads to electromyographic changes in the extensor apparatus of the knee and to imbalances between the vastus medialis and vastus lateralis muscles. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 28 knees of 25 patients, with a mean age of 15 years, were treated operatively for recurrent patellar dislocations. The mean follow-up was 6.3 years. Depending on the type of surgical intervention, the patients were assigned to 3 different groups: the patients of group 1 underwent only the Green vastus medialis obliquus (VMO) advancement, group 2 was treated with a combination of the Green proximal and the Roux-Goldthwait distal realignment, and group 3 was treated with a combination of the Green proximal realignment and an additional tubercle transfer. All patients underwent clinical, radiological, and electromyographic examinations. The muscle activities of a healthy control group without patellar dislocations were used for comparison. RESULTS: A combination of the Green procedure and tubercle transfer led to significantly better clinical results and a lower number of redislocations (P < .05) compared with patients who underwent only the Green proximal realignment. While ascending or descending stairs, the ratio between the electromyographic activities of the vastus medialis and vastus lateralis muscles in groups 1 and 2 was significantly smaller compared with the control group (P < .02). Only the electromyograms of group 3 revealed a balanced extensor apparatus during loading with comparable activities of the vastus medialis and vastus lateralis muscles and no significant difference to the control group (P = .37). CONCLUSION: Our electromyographic investigations showed the importance of the vastus medialis in the pathogenesis of malalignment of the extensor mechanism. The Green VMO advancement without tibial tubercle transfer is not able to balance the activities of the vastus medialis and vastus lateralis muscles and cannot be recommended for further use. PMID- 23733634 TI - Performance outcomes after repair of complete achilles tendon ruptures in national basketball association players. AB - BACKGROUND: A complete rupture of the Achilles tendon is a devastating injury. Variables affecting return to competition and performance changes for National Basketball Association (NBA) players are not readily evident. HYPOTHESIS: Players in the NBA who ruptured their Achilles tendons and who underwent surgical repair would have more experience in the league, and the performance of those who were able to return to competition would be decreased when compared with their performance before injury and with their control-matched peers. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data for 18 basketball players with Achilles tendon repair over a 23-year period (1988-2011) were obtained from injury reports, press releases, and player profiles. Variables included age, body mass index (BMI), player position, and number of years playing in the league. Individual season statistics were obtained, and the NBA player efficiency rating (PER) was calculated for 2 seasons before and after injury. Controls were matched by playing position, number of seasons played, and performance statistics. Univariate and multivariate analyses were performed to assess the effect of each factor. RESULTS: At the time of injury, the average age was 29.7 years, average BMI was 25.6, and average playing experience was 7.6 years. Seven players never returned to play an NBA game, whereas 11 players returned to play 1 season, with 8 of those players returning for >=2 seasons. Players who returned missed an average of 55.9 games. The PER was reduced by 4.57 (P = .003) in the first season and by 4.38 (P = .010) in the second season. When compared with controls, players demonstrated a significant decline in the PER the first season (P = .038) and second season (P = .081) after their return. CONCLUSION: The NBA players who returned to play after repair of complete Achilles tendon ruptures showed a significant decrease in playing time and performance. Thirty-nine percent of players never returned to play. PMID- 23733635 TI - Psychological responses matter in returning to preinjury level of sport after anterior cruciate ligament reconstruction surgery. AB - BACKGROUND: Up to two-thirds of athletes may not return to their preinjury level of sport by 12 months after anterior cruciate ligament (ACL) reconstruction surgery, despite being physically recovered. This has led to questions about what other factors may influence return to sport. PURPOSE: To determine whether psychological factors predicted return to preinjury level of sport by 12 months after ACL reconstruction surgery. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: Recreational and competitive-level athletes seen at a private orthopaedic clinic with an ACL injury were consecutively recruited. The primary outcome was return to the preinjury level of sports participation. The psychological factors evaluated were psychological readiness to return to sport, fear of reinjury, mood, emotions, sport locus of control, and recovery expectations. Participants were followed up preoperatively and at 4 and 12 months postoperatively. RESULTS: In total, 187 athletes participated. At 12 months, 56 athletes (31%) had returned to their preinjury level of sports participation. Significant independent contributions to returning to the preinjury level by 12 months after surgery were made by psychological readiness to return to sport, fear of reinjury, sport locus of control, and the athlete's estimate of the number of months it would take to return to sport, as measured preoperatively (chi(2) 2 = 18.3, P < .001, classification accuracy = 70%) and at 4 months postoperatively (chi(2) 4 = 38.7, P < .001, classification accuracy = 86%). CONCLUSION: Psychological responses before surgery and in early recovery were associated with returning to preinjury level of sport at 12 months, suggesting that attention to psychological recovery in addition to physical recovery after ACL injury and reconstruction surgery may be warranted. Clinical screening for maladaptive psychological responses in athletes before and soon after surgery may help clinicians identify athletes at risk of not returning to their preinjury level of sport by 12 months. PMID- 23733636 TI - Dopamine and renal function and blood pressure regulation. AB - Dopamine is an important regulator of systemic blood pressure via multiple mechanisms. It affects fluid and electrolyte balance by its actions on renal hemodynamics and epithelial ion and water transport and by regulation of hormones and humoral agents. The kidney synthesizes dopamine from circulating or filtered L-DOPA independently from innervation. The major determinants of the renal tubular synthesis/release of dopamine are probably sodium intake and intracellular sodium. Dopamine exerts its actions via two families of cell surface receptors, D1-like receptors comprising D1R and D5R, and D2-like receptors comprising D2R, D3R, and D4R, and by interactions with other G protein coupled receptors. D1-like receptors are linked to vasodilation, while the effect of D2-like receptors on the vasculature is variable and probably dependent upon the state of nerve activity. Dopamine secreted into the tubular lumen acts mainly via D1-like receptors in an autocrine/paracrine manner to regulate ion transport in the proximal and distal nephron. These effects are mediated mainly by tubular mechanisms and augmented by hemodynamic mechanisms. The natriuretic effect of D1 like receptors is caused by inhibition of ion transport in the apical and basolateral membranes. D2-like receptors participate in the inhibition of ion transport during conditions of euvolemia and moderate volume expansion. Dopamine also controls ion transport and blood pressure by regulating the production of reactive oxygen species and the inflammatory response. Essential hypertension is associated with abnormalities in dopamine production, receptor number, and/or posttranslational modification. PMID- 23733637 TI - Mechanisms of exercise-induced mitochondrial biogenesis in skeletal muscle: implications for health and disease. AB - Mitochondria have paradoxical functions within cells. Essential providers of energy for cellular survival, they are also harbingers of cell death (apoptosis). Mitochondria exhibit remarkable dynamics, undergoing fission, fusion, and reticular expansion. Both nuclear and mitochondrial DNA (mtDNA) encode vital sets of proteins which, when incorporated into the inner mitochondrial membrane, provide electron transport capacity for ATP production, and when mutated lead to a broad spectrum of diseases. Acute exercise can activate a set of signaling cascades in skeletal muscle, leading to the activation of the gene expression pathway, from transcription, to post-translational modifications. Research has begun to unravel the important signals and their protein targets that trigger the onset of mitochondrial adaptations to exercise. Exercise training leads to an accumulation of nuclear- and mtDNA-encoded proteins that assemble into functional complexes devoted to mitochondrial respiration, reactive oxygen species (ROS) production, the import of proteins and metabolites, or apoptosis. This process of biogenesis has important consequences for metabolic health, the oxidative capacity of muscle, and whole body fitness. In contrast, the chronic muscle disuse that accompanies aging or muscle wasting diseases provokes a decline in mitochondrial content and function, which elicits excessive ROS formation and apoptotic signaling. Research continues to seek the molecular underpinnings of how regular exercise can be used to attenuate these decrements in organelle function, maintain skeletal muscle health, and improve quality of life. PMID- 23733638 TI - Airway gas flow. AB - Local characteristics of airflow and its global distribution in the lung are determined by interaction between resistance to flow through the airways and the compliance of the tissue, with tissue compliance dominating flow distribution in the healthy lung. Current understanding is that conceptualizing the airways of the lung as a system of smooth adjoined cylinders through which air traverses laminarly is insufficient for understanding flow and energy dissipation and is particularly poor for predicting physiologically realistic transport of particles by the airflow. With rapid advances in medical imaging, computer technologies, and computational techniques, computational fluid dynamics is now becoming a viable tool for providing detailed information on the mechanics of airflow in the human respiratory tract. Studies using such techniques have shown that the upper airway (specifically its development of a turbulent laryngeal jet in the trachea), airway geometry, branching and rotation angle, and the pattern of joining of successive bifurcations are important in determining airflow structures. It is now possible to compute airflow in physical domains that are anatomically accurate and subject specific, enabling comparisons among intersubjects, that among subjects of different ages, and that among different species. PMID- 23733639 TI - Endocytosis of environmental and engineered micro- and nanosized particles. AB - There are many studies with cells to find out how particles interact with them. In contrast to micronsized particles, which are actively taken up by phagocytosis or macropinocytosis, nanosized particles may be taken up by cells through different endocytic pathways or by another, yet to be defined mechanism. There is increasing evidence that it is the nanosized particles, which are a particular risk because of their high content of organic chemicals and their pro-oxidative potential due to the high surface-to-volume ratio of the particles as compared to the bulk material. It is the goal of this article to create an understanding for the interaction of particles with biological systems, with particular consideration of the interaction of nanoparticles (NPs) with lung cells. One is attempting to understand, how NPs interact with cellular membranes, as it is hardly known, how they are taken up by cells, how they are trafficking in cells, and how they interact with subcellular compartments, such as with mitochondria or with the nucleus. Cells tend to defend themselves against any foreign material, which is taken up. In general, they try to eliminate particulate intruders and this is what they usually manage with micronsized particles. However, with NPs it is different. NPs may not be eliminated easily, and, hence may stimulate the cells to react in an unfavorable way. What we can learn is that NPs behave differently than microparticles. PMID- 23733641 TI - Oscillation mechanics of the respiratory system. AB - The mechanical impedance of the respiratory system defines the pressure profile required to drive a unit of oscillatory flow into the lungs. Impedance is a function of oscillation frequency, and is measured using the forced oscillation technique. Digital signal processing methods, most notably the Fourier transform, are used to calculate impedance from measured oscillatory pressures and flows. Impedance is a complex function of frequency, having both real and imaginary parts that vary with frequency in ways that can be used empirically to distinguish normal lung function from a variety of different pathologies. The most useful diagnostic information is gained when anatomically based mathematical models are fit to measurements of impedance. The simplest such model consists of a single flow-resistive conduit connecting to a single elastic compartment. Models of greater complexity may have two or more compartments, and provide more accurate fits to impedance measurements over a variety of different frequency ranges. The model that currently enjoys the widest application in studies of animal models of lung disease consists of a single airway serving an alveolar compartment comprising tissue with a constant-phase impedance. This model has been shown to fit very accurately to a wide range of impedance data, yet contains only four free parameters, and as such is highly parsimonious. The measurement of impedance in human patients is also now rapidly gaining acceptance, and promises to provide a more comprehensible assessment of lung function than parameters derived from conventional spirometry. PMID- 23733642 TI - Mechanics of the respiratory muscles. AB - This article examines the mechanics of the muscles that drive expansion or contraction of the chest wall during breathing. The diaphragm is the main inspiratory muscle. When its muscle fibers are activated in isolation, they shorten, the dome of the diaphragm descends, pleural pressure (P(pl)) falls, and abdominal pressure (P(ab)) rises. As a result, the ventral abdominal wall expands, but a large fraction of the rib cage contracts. Expansion of the rib cage during inspiration is produced by the external intercostals in the dorsal portion of the rostral interspaces, the intercartilaginous portion of the internal intercostals (the so-called parasternal intercostals), and, in humans, the scalenes. By elevating the ribs and causing an additional fall in P(pl), these muscles not only help the diaphragm expand the chest wall and the lung, but they also increase the load on the diaphragm and reduce the shortening of the diaphragmatic muscle fibers. The capacity of the diaphragm to generate pressure is therefore enhanced. In contrast, during expiratory efforts, activation of the abdominal muscles produces a rise in P(ab) that leads to a cranial displacement of the diaphragm into the pleural cavity and a rise in P(pl). Concomitant activation of the internal interosseous intercostals in the caudal interspaces and the triangularis sterni during such efforts contracts the rib cage and helps the abdominal muscles deflate the lung. PMID- 23733643 TI - Transport of gases between the environment and alveoli--theoretical foundations. AB - The transport of oxygen and carbon dioxide in the gas phase from the ambient environment to and from the alveolar gas/blood interface is accomplished through the tracheobronchial tree, and involves mechanisms of bulk or convective transport and diffusive net transport. The geometry of the airway tree and the fluid dynamics of these two transport processes combine in such a way that promotes a classical fractionation of ventilation into dead space and alveolar ventilation, respectively. This simple picture continues to capture much of the essence of gas phase transport. On the other hand, a more detailed look at the interaction of convection and diffusion leads to significant new issues, many of which remain open questions. These are associated with parallel and serial inhomogeneities especially within the distal acinar units, velocity profiles in distal airways and terminal spaces subject to moving boundary conditions, and the serial transport of respiratory gases within the complex acinar architecture. This article focuses specifically on the theoretical foundations of gas transport, addressing two broad areas. The first deals with the reasons why the classical picture of alveolar and dead space ventilation is so successful; the second examines the underlying assumptions within current approximations to convective and diffusive transport, and how they interact to effect net gas exchange. PMID- 23733645 TI - Exercise and muscular dystrophy: implications and analysis of effects on musculoskeletal and cardiovascular systems. AB - The muscular dystrophies are a heterogeneous collection of progressive, inherited diseases of muscle weakness and degeneration. Although these diseases can vary widely in their etiology and presentation, nearly all muscular dystrophies cause exercise intolerance to some degree. Here, we focus on Duchenne muscular dystrophy (DMD), the most common form of muscular dystrophy, as a paradigm for the effects of muscle disease on exercise capacity. First described in the mid 1800s, DMD is a rapidly progressive and lethal muscular dystrophy caused by mutations in the dystrophin gene. Dystrophin is a membrane-associated cytoskeletal protein, the loss of which causes numerous cellular defects including mechanical instability of the sarcolemma, increased influx of extracellular calcium, and cell signaling defects. Here, we discuss the physiological basis for exercise intolerance in DMD, focusing on the molecular and cellular defects caused by loss of dystrophin and how these manifest as organ level dysfunction and reduced exercise capacity. The main focus of this article is the defects present in dystrophin-deficient striated muscle. However, discussion regarding the effects of dystrophin loss on other tissues, including vascular smooth muscle is also included. Collectively, the goal of this article is to summarize the current state of knowledge regarding the mechanistic basis for exercise intolerance in DMD, which may serve as an archetype for other muscular dystrophies and diseases of muscle wasting. PMID- 23733646 TI - Oxidants and redox signaling in acute lung injury. AB - Acute lung injury (ALI) and its more severe form of clinical manifestation, the acute respiratory distress syndrome is associated with significant dysfunction in air exchange due to inflammation of the lung parenchyma. Several factors contribute to the inflammatory process, including hypoxia (inadequate oxygen), hyperoxia (higher than normal partial pressure of oxygen), inflammatory mediators (such as cytokines), infections (viral and bacterial), and environmental conditions (such as cigarette smoke or noxious gases). However, studies over the past several decades suggest that oxidants formed in the various cells of the lung including endothelial, alveolar, and epithelial cells as well as lung macrophages and neutrophils in response to the factors mentioned above mediate the pathogenesis of ALI. Oxidants modify cellular proteins, lipids, carbohydrates, and DNA to cause their aberrant function. For example, oxidation of lipids changes membrane permeability. Interestingly, recent studies also suggest that spatially and temporally regulated production of oxidants plays an important role antimicrobial defense and immunomodulatory function (such as transcription factor activation). To counteract the oxidants an arsenal of antioxidants exists in the lung to maintain the redox status, but when overwhelmed tissue injury and exacerbation of inflammation occurs. We present below the current understanding of the pathogenesis of oxidant-mediated ALI. PMID- 23733647 TI - Molecular mechanisms of muscle plasticity with exercise. AB - The skeletal muscle phenotype is subject to considerable malleability depending on use. Low-intensity endurance type exercise leads to qualitative changes of muscle tissue characterized mainly by an increase in structures supporting oxygen delivery and consumption. High-load strength-type exercise leads to growth of muscle fibers dominated by an increase in contractile proteins. In low-intensity exercise, stress-induced signaling leads to transcriptional upregulation of a multitude of genes with Ca(2+) signaling and the energy status of the muscle cells sensed through AMPK being major input determinants. Several parallel signaling pathways converge on the transcriptional co-activator PGC-1alpha, perceived as being the coordinator of much of the transcriptional and posttranscriptional processes. High-load training is dominated by a translational upregulation controlled by mTOR mainly influenced by an insulin/growth factor dependent signaling cascade as well as mechanical and nutritional cues. Exercise induced muscle growth is further supported by DNA recruitment through activation and incorporation of satellite cells. Crucial nodes of strength and endurance exercise signaling networks are shared making these training modes interdependent. Robustness of exercise-related signaling is the consequence of signaling being multiple parallel with feed-back and feed-forward control over single and multiple signaling levels. We currently have a good descriptive understanding of the molecular mechanisms controlling muscle phenotypic plasticity. We lack understanding of the precise interactions among partners of signaling networks and accordingly models to predict signaling outcome of entire networks. A major current challenge is to verify and apply available knowledge gained in model systems to predict human phenotypic plasticity. PMID- 23733648 TI - Lung transplantation and lung volume reduction surgery. AB - Since the publication of the last edition of the Handbook of Physiology, lung transplantation has become widely available, via specialized centers, for a variety of end-stage lung diseases. Lung volume reduction surgery, a procedure for emphysema first conceptualized in the 1950s, electrified the pulmonary medicine community when it was rediscovered in the 1990s. In parallel with their technical and clinical refinement, extensive investigation has explored the unique physiology of these procedures. In the case of lung transplantation, relevant issues include the discrepant mechanical function of the donor lungs and recipient thorax, the effects of surgical denervation, acute and chronic rejection, respiratory, chest wall, and limb muscle function, and response to exercise. For lung volume reduction surgery, there have been new insights into the counterintuitive observation that lung function in severe emphysema can be improved by resecting the most diseased portions of the lungs. For both procedures, insights from physiology have fed back to clinicians to refine patient selection and to scientists to design clinical trials. This section will first provide an overview of the clinical aspects of these procedures, including patient selection, surgical techniques, complications, and outcomes. It then reviews the extensive data on lung and muscle function following transplantation and its complications. Finally, it reviews the insights from the last 15 years on the mechanisms whereby removal of lung from an emphysema patient can improve the function of the lung left behind. PMID- 23733644 TI - Lung parenchymal mechanics. AB - The lung parenchyma comprises a large number of thin-walled alveoli, forming an enormous surface area, which serves to maintain proper gas exchange. The alveoli are held open by the transpulmonary pressure, or prestress, which is balanced by tissues forces and alveolar surface film forces. Gas exchange efficiency is thus inextricably linked to three fundamental features of the lung: parenchymal architecture, prestress, and the mechanical properties of the parenchyma. The prestress is a key determinant of lung deformability that influences many phenomena including local ventilation, regional blood flow, tissue stiffness, smooth muscle contractility, and alveolar stability. The main pathway for stress transmission is through the extracellular matrix. Thus, the mechanical properties of the matrix play a key role both in lung function and biology. These mechanical properties in turn are determined by the constituents of the tissue, including elastin, collagen, and proteoglycans. In addition, the macroscopic mechanical properties are also influenced by the surface tension and, to some extent, the contractile state of the adherent cells. This chapter focuses on the biomechanical properties of the main constituents of the parenchyma in the presence of prestress and how these properties define normal function or change in disease. An integrated view of lung mechanics is presented and the utility of parenchymal mechanics at the bedside as well as its possible future role in lung physiology and medicine are discussed. PMID- 23733650 TI - Physiological and pathological angiogenesis in the adult pulmonary circulation. AB - Angiogenesis occurs during growth and physiological adaptation in many systemic organs, for example, exercise-induced skeletal and cardiac muscle hypertrophy, ovulation, and tissue repair. Disordered angiogenesis contributes to chronic inflammatory disease processes and to tumor growth and metastasis. Although it was previously thought that the adult pulmonary circulation was incapable of supporting new vessel growth, over that past 10 years new data have shown that angiogenesis within this circulation occurs both during physiological adaptive processes and as part of the pathogenic mechanisms of lung diseases. Here we review the expression of vascular growth factors in the adult lung, their essential role in pulmonary vascular homeostasis and the changes in their expression that occur in response to physiological challenges and in disease. We consider the evidence for adaptive neovascularization in the pulmonary circulation in response to alveolar hypoxia and during lung growth following pneumonectomy in the adult lung. In addition, we review the role of disordered angiogenesis in specific lung diseases including idiopathic pulmonary fibrosis, acute adult distress syndrome and both primary and metastatic tumors of the lung. Finally, we examine recent experimental data showing that therapeutic enhancement of pulmonary angiogenesis has the potential to treat lung diseases characterized by vessel loss. PMID- 23733651 TI - History of respiratory gas exchange. AB - As early as the 6th century B.C. the Greeks speculated on a substance pneuma that meant breath or soul, and they argued that this was essential for life. An important figure in the 2nd century A.D. was Galen whose school developed an elaborate cardiopulmonary system that influenced scientific thinking for 1400 years. A key concept was that blood was mixed with pneuma from the lung in the left ventricle thus forming vital spirit. It was also believed that blood flowed from the right to the left ventricle of the heart through pores in the interventricular septum but this view was challenged first by the Arab physician Ibn al-Nafis in the 13th century and later by Michael Servetus in the 16th century. The 17th century saw an enormous burgeoning of knowledge about the respiratory gases. First Torricelli explained the origin of atmospheric pressure, and then a group of physiologists in Oxford clarified the properties of inspired gas that were necessary for life. This culminated in the work of Lavoisier who first clearly elucidated the nature of the respiratory gases, oxygen, carbon dioxide and nitrogen. At that time it was thought that oxygen was consumed in the lung itself, and the fact that the actual metabolism took place in peripheral tissues proved to be a very elusive concept. It was not until the late 19th century that the issue was finally settled by Pfluger. In the early 20th century there was a colorful controversy about whether oxygen was secreted by the lung. During and shortly after World War II, momentous strides were made on the understanding of pulmonary gas exchange, particularly the role of ventilation perfusion inequality. A critical development in the 1960s was the introduction of blood gas electrodes, and these have transformed the management of patients with severe lung disease. PMID- 23733652 TI - Comparative physiology of the pulmonary circulation. AB - Two selective pressures have shaped the evolution of the pulmonary circulation. First, as animals evolved from heterothermic ectotherms to homeothermic endoderms with their corresponding increase in the ability to sustain high oxygen consumptions, the blood-gas barrier had to become successively thinner, and also provide an increasingly large area for diffusive gas exchange. Second, the barrier had to find a way to maintain its mechanical integrity in the face of extreme thinness, and this was assisted by the increasing separation of the pulmonary from the systemic circulation. A remarkable feature throughout the evolution of air-breathing vertebrates has been the tight conservation of the tripartite structure of the blood-gas barrier with its three layers: capillary endothelium, extracellular matrix, and alveolar epithelium. The strength of the barrier can be ascribed to the very thin layer of type IV collagen in the extracellular matrix. In the phylogenic progression from amphibia and reptiles to mammals and birds, the blood-gas barrier became successively thinner. Also, the area increased greatly reflecting the greater oxygen demands of the organism. The gradual separation of the pulmonary from the systemic circulation continued from amphibia through reptiles to mammals and birds. Only in the last two classes are the circulations completely separate with the result that the pulmonary capillary pressures can be maintained low enough to avoid stress failure of the blood-gas barrier. Remarkably, the barrier is generally much thinner in birds than mammals, and it is also much more uniform in thickness. These advantages for gas exchange can be explained by the support of avian pulmonary capillaries by the surrounding air capillaries. This arrangement was made possible by the adoption of the flow through system of ventilation in birds as opposed to the reciprocating pattern in mammals. PMID- 23733653 TI - Causes of and compensations for hypoxemia and hypercapnia. AB - By far the commonest cause of impaired gas exchange in patients with lung disease is ventilation-perfusion inequality. This is a complicated topic and much can be learned from computer models. Ventilation-perfusion inequality always causes hypoxemia, that is, an abnormally low PO2 in arterial blood. However, it is also the commonest cause of an increased arterial PCO2, or hypercapnia, in patients with chronic obstructive pulmonary disease (COPD). There is often confusion in this area with some people attributing the CO2 retention to "hypoventilation" when in fact these patients are usually moving much more air into their lungs than normal subjects. A patient with COPD can often return the arterial PCO2 to normal by increasing the ventilation. However, this does not return the arterial PO2 to normal because of the different shapes of the oxygen and carbon dioxide dissociation curves. Increasing pulmonary blood flow in the presence of ventilation-perfusion inequality usually raises the arterial PO2 but much less than increasing ventilation. Raising the inspired oxygen concentration is typically very effective in increasing the arterial PO2. Ventilation-perfusion inequality interferes with the transfer of all gases by the lung including the anesthetic gases. The gas exchange behavior of a lung depends greatly on the pattern of ventilation-perfusion inequality. It is theoretically possible to find a distribution that improves the transfer of some gases but this requires bizarre conditions that can never occur in practice. PMID- 23733649 TI - Pulmonary vascular stiffness: measurement, modeling, and implications in normal and hypertensive pulmonary circulations. AB - This article introduces the concept of pulmonary vascular stiffness, discusses its increasingly recognized importance as a diagnostic marker in the evaluation of pulmonary vascular disease, and describes methods to measure and model it clinically, experimentally, and computationally. It begins with a description of systems-level methods to evaluate pulmonary vascular compliance and recent clinical efforts in applying such techniques to better predict patient outcomes in pulmonary arterial hypertension. It then progresses from the systems-level to the local level, discusses proposed methods by which upstream pulmonary vessels increase in stiffness, introduces concepts around vascular mechanics, and concludes by describing recent work incorporating advanced numerical methods to more thoroughly evaluate changes in local mechanical properties of pulmonary arteries. PMID- 23733640 TI - Pathophysiology of the diabetic kidney. AB - Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the molecular mechanism involved and of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. Here we review the pathophysiological changes that occur in the kidney in response to hyperglycemia, including the cellular responses to high glucose and the responses in vascular, glomerular, podocyte, and tubular function. The molecular basis, characteristics, and consequences of the unique growth phenotypes observed in the diabetic kidney, including glomerular structures and tubular segments, are outlined. We delineate mechanisms of early diabetic glomerular hyperfiltration including primary vascular events as well as the primary role of tubular growth, hyperreabsorption, and tubuloglomerular communication as part of a "tubulocentric" concept of early diabetic kidney function. The latter also explains the "salt paradox" of the early diabetic kidney, that is, a unique and inverse relationship between glomerular filtration rate and dietary salt intake. The mechanisms and consequences of the intrarenal activation of the renin-angiotensin system and of diabetes-induced tubular glycogen accumulation are discussed. Moreover, we aim to link the changes that occur early in the diabetic kidney including the growth phenotype, oxidative stress, hypoxia, and formation of advanced glycation end products to mechanisms involved in progressive kidney disease. PMID- 23733656 TI - Evolution of sex differences in lifespan and aging: causes and constraints. AB - Why do the two sexes have different lifespans and rates of aging? Two hypotheses based on asymmetric inheritance of sex chromosomes ("unguarded X") or mitochondrial genomes ("mother's curse") explain sex differences in lifespan as sex-specific maladaptation leading to increased mortality in the shorter-lived sex. While asymmetric inheritance hypotheses equate long life with high fitness, considerable empirical evidence suggests that sexes resolve the fundamental tradeoff between reproduction and survival differently resulting in sex-specific optima for lifespan. However, selection for sex-specific values in life-history traits is constrained by intersexual genetic correlations resulting in intra locus sexual conflict over optimal lifespan. The available data suggest that the evolution of sexual dimorphism only partially resolves these conflicts. Sexual conflict over optimal trait values, which has been demonstrated in model organisms and in humans, is likely to play a key role in shaping the evolution of lifespan, as well as in maintaining genetic variation for sex-specific diseases. PMID- 23733657 TI - Lobe-related concentration- and Ca(2+)-dependent interactions of calmodulin with C- and N-terminal tails of the CaV1.2 channel. AB - This study examined the bindings of calmodulin (CaM) and its mutants with the C- and N-terminal tails of the voltage-gated Ca(2+) channel CaV1.2 at different CaM and Ca(2+) concentrations ([Ca(2+)]) by using the pull-down assay method to obtain basic information on the binding mode, including its concentration- and Ca(2+)-dependencies. Our data show that more than one CaM molecule could bind to the CaV1.2 C-terminal tail at high [Ca(2+)]. Additionally, the C-lobe of CaM is highly critical in sensing the change of [Ca(2+)] in its binding to the C terminal tail of CaV1.2, and the binding between CaM and the N-terminal tail of CaV1.2 requires high [Ca(2+)]. Our data provide new details on the interactions between CaM and the CaV1.2 channel. PMID- 23733654 TI - Endothelial and smooth muscle cell ion channels in pulmonary vasoconstriction and vascular remodeling. AB - The pulmonary circulation is a low resistance and low pressure system. Sustained pulmonary vasoconstriction and excessive vascular remodeling often occur under pathophysiological conditions such as in patients with pulmonary hypertension. Pulmonary vasoconstriction is a consequence of smooth muscle contraction. Many factors released from the endothelium contribute to regulating pulmonary vascular tone, while the extracellular matrix in the adventitia is the major determinant of vascular wall compliance. Pulmonary vascular remodeling is characterized by adventitial and medial hypertrophy due to fibroblast and smooth muscle cell proliferation, neointimal proliferation, intimal, and plexiform lesions that obliterate the lumen, muscularization of precapillary arterioles, and in situ thrombosis. A rise in cytosolic free Ca(2+) concentration ([Ca(2+)]cyt) in pulmonary artery smooth muscle cells (PASMC) is a major trigger for pulmonary vasoconstriction, while increased release of mitogenic factors, upregulation (or downregulation) of ion channels and transporters, and abnormalities in intracellular signaling cascades are key to the remodeling of the pulmonary vasculature. Changes in the expression, function, and regulation of ion channels in PASMC and pulmonary arterial endothelial cells play an important role in the regulation of vascular tone and development of vascular remodeling. This article will focus on describing the ion channels and transporters that are involved in the regulation of pulmonary vascular function and structure and illustrating the potential pathogenic role of ion channels and transporters in the development of pulmonary vascular disease. PMID- 23733658 TI - Seventeen years' experience of peritoneal dialysis in Iran: first official report of the Iranian peritoneal dialysis registry. AB - BACKGROUND: To facilitate planning, national renal registries provide reliable and up-to-date information on numbers of patients with end-stage renal disease (ESRD), developing trends, treatment modalities, and outcomes. To that end, the present publication represents the first official report from Iranian Peritoneal Dialysis Registry. METHODS: The prevalence, demographics, and clinical characteristics of patients on peritoneal dialysis (PD) were collected from all PD centers throughout the country. RESULTS: By the end of 2009, the prevalence of ESRD was 507 per million population in Iran. The most common renal replacement modality was hemodialysis (51.2%), followed by kidney transplantation (44.7%), and then PD (4.1%). The mean age of PD patients was 46 years, and the most common causes of ESRD were diabetes (33.5%), hypertension (24.4%), and glomerulonephritis (8.2%). Overall patient mortality was 25%, with cardiac events (46%), cerebral stroke (10%), and infection (8%) being the main causes of death. The 1-, 3-, and 5-year survivals were 89%, 64%, and 49% respectively. The most common cause of dropout was peritonitis (17.6%). Staphylococcus (coagulase negative and S. aureus) was the most prevalent causative organism in peritonitis episodes; however, in more than 50% of episodes, a sterile culture was reported. Mean baseline serum hemoglobin and albumin were 10.7 g/dL and 3.6 g/dL respectively. CONCLUSIONS: Our registry results, representing the second largest report of PD in the Middle East, is almost comparable to available regional data. We hope that, in future, we can improve our shortcomings and lessen the gap with developed countries. PMID- 23733659 TI - Clinical characteristics and outcomes of peritoneal dialysis-related peritonitis with different trends of change in effluent white cell count: a longitudinal study. AB - BACKGROUND: Effluent white cell count (WCC) is among the important prognostic factors for peritonitis outcome, but its trend has never been studied. We aimed to explore the clinical characteristics and outcomes of peritonitis episodes having different trends in effluent WCC change in the first 5 days. METHODS: For each peritonitis episode, we examined the patient's demographic and biochemical data, serial effluent WCC, and organisms cultured. Peritonitis-associated death and transfer to hemodialysis were defined as treatment failure. RESULTS: Based on the trend of effluent WCC in the first 5 days, we divided 190 peritonitis episodes into group A (WCC persistently declined), group B (WCC declined after a transient increase), group C (WCC increased after a transient decline), and group D (WCC persistently increased). In group A, peritonitis was caused mostly by gram positive organisms, and effluent WCC declined the most quickly, leading to a good prognosis. Although the elevation of effluent WCC was prolonged in group B, and the infections were, compared with those in group A, more often caused by gram negative organisms, outcomes were not worse. In group C, the effluent WCC was more likely to be higher than 100/MUL on day 5, and the infection was, compared with those in groups A and B, less likely to be caused by gram-positive organisms. Accordingly, membership in group C independently predicted the worst outcome of peritonitis even adjusted for age, sex, and causative organism. CONCLUSIONS: Different trends of change in effluent WCC during the early stage of peritonitis represent different clinical patterns and outcomes. Further investigation for optimizing outcomes is required. PMID- 23733660 TI - Localized encapsulating peritoneal sclerosis constricting the terminal ileum--an unusual appearance requiring surgical intervention. AB - BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis (PD). It is characterized by encapsulation of the bowel, causing symptoms of intestinal obstruction. Exclusive involvement of parts of the bowel may occur and may be more common than previously thought. Our main objective was to investigate and report on patients with localized EPS. METHODS: Between July 2002 and December 2011, 9 of 17 EPS patients were referred to our department of surgery for a diagnostic laparotomy. Three of the 9 cases showed localized encapsulation of the small bowel and were selected for the purpose of this study. RESULTS: All 3 patients presented with an acute inflammatory state and symptoms of bowel obstruction. In 2 patients, EPS became clinically overt after kidney transplantation; the third patient was diagnosed while on hemodialysis. All shared a history of PD ranging from 31 to 101 months. In none of the patients was radiologic examination conclusive, although 2 showed peritoneal thickening and ascites. Each patient underwent laparotomy, confirming EPS. In all cases, a thickened peritoneal membrane became apparent, predominantly covering the ileocecal region of the intestine. In addition, a constrictive membrane at the level of the terminal ileum was noted. In 2 cases, the patients underwent enterolysis and dissection of the constricting fibrotic peritoneal membrane (peritonectomy) without bowel resection. The 3rd patient was managed with parenteral nutrition and tamoxifen. The postoperative course in 1 patient was complicated by infected ascites that resolved with antibiotic treatment. Eventually, all patients were doing well, with adequate oral intake and without the need for repeat surgery. CONCLUSIONS: Localized EPS may be more common than previously thought. It has a predilection for the level of the terminal ileum. We believe that an elective diagnostic laparotomy should be considered early, because this procedure offers both diagnostic opportunities and therapeutic options. Localized EPS cases may benefit most from enterolysis and peritonectomy. PMID- 23733662 TI - Reply to association between exercise and primary incidence of prostate cancer: does race matter? PMID- 23733655 TI - Genomics and genetics in the biology of adaptation to exercise. AB - This article is devoted to the role of genetic variation and gene-exercise interactions in the biology of adaptation to exercise. There is evidence from genetic epidemiology research that DNA sequence differences contribute to human variation in physical activity level, cardiorespiratory fitness in the untrained state, cardiovascular and metabolic response to acute exercise, and responsiveness to regular exercise. Methodological and technological advances have made it possible to undertake the molecular dissection of the genetic component of complex, multifactorial traits, such as those of interest to exercise biology, in terms of tissue expression profile, genes, and allelic variants. The evidence from animal models and human studies is considered. Data on candidate genes, genome-wide linkage results, genome-wide association findings, expression arrays, and combinations of these approaches are reviewed. Combining transcriptomic and genomic technologies has been shown to be more powerful as evidenced by the development of a recent molecular predictor of the ability to increase VO2max with exercise training. For exercise as a behavior and physiological fitness as a state to be major players in public health policies will require that the role of human individuality and the influence of DNA sequence differences be understood. Likewise, progress in the use of exercise in therapeutic medicine will depend to a large extent on our ability to identify the favorable responders for given physiological properties to a given exercise regimen. PMID- 23733663 TI - Quality of life in head and neck cancer patients after tumor therapy and subsequent rehabilitation: an exploratory study. AB - PURPOSE: The aim of the study was to evaluate patient-reported quality of life effects of post-treatment intraoral and extraoral rehabilitation in head and neck cancer by repeated measures. METHODS: Fifty-nine patients were involved. Basic socio-demographic, oncological and epidemiological data were gathered, and the type of rehabilitation was recorded. For the assessment of quality of life changes, two widely used brief questionnaires, the University of Washington Quality of Life Questionnaire and the Head and Neck module of the European Organization of Research and Treatment for Cancer Quality of Life Questionnaire, were used. The questionnaires were administered to patients two times: the first time after tumor therapy, but before rehabilitation (upon arriving for rehabilitation) and the second time 6 months after the application of any particular method of rehabilitation. Quality of life data were gathered prospectively, while socio-demographic data were gathered from patient files. RESULTS: Quality of life after rehabilitation was significantly enhanced as compared to the post-treatment status, in all domains of both questionnaires (p < 0.05 and p < 0.01, Mann-Whitney U). CONCLUSIONS: The results support the hypothesis that post-treatment maxillofacial rehabilitation in head and neck cancer does not only restore lost physical capabilities, but also brings about profound changes in patients' quality of life in general. PMID- 23733664 TI - Winner and runners-up of the 2012 best paper award. PMID- 23733665 TI - Assessing sediment toxicity: past, present, and future. PMID- 23733666 TI - Predicting modes of toxic action from chemical structure. PMID- 23733667 TI - Children with hemoglobin E/beta-thalassemia have a high risk of being vitamin D deficient even if they get abundant sun exposure: a study from Thailand. AB - BACKGROUND: Vitamin D is a key component in calcium homeostasis, bone mineralization and immune function, and people with a vitamin D deficiency may therefore be at higher risk of osteoporosis, osteopenia, delayed growth and fractures. Vitamin D deficiency is a known clinical complication of patients with beta-thalassemia major; however, as yet there are limited data on the vitamin D status of patients with Hb E/beta-thalassemia. Hb E/beta-thalassemia is characterized by a wide clinical heterogeneity ranging from non-transfusion dependency to transfusion dependency. Because patients with Hb E/beta-thalassemia are so clinically diverse, the prevalence of vitamin D deficiency might differ among Hb E/beta-thalassemia patients. PROCEDURE: We investigated the vitamin D status of 109 children with Hb E/beta-thalassemia who attended the Pediatric Hematology Clinic at the Siriraj Hospital in Bangkok, Thailand, from April 2009 to March 2010. RESULTS: Forty-nine of the children were classified as transfusion dependent (TD) and the remainder (n = 60) as non-transfusion-dependent (NTD). Only 10.1% of the children in our study had normal vitamin D levels, despite Thailand's geographic position 15 degrees N and 100 degrees E and climate, which provides abundant sunlight exposure and therefore efficient vitamin D synthesis. In addition, NTD children were significantly more likely to be vitamin D deficient than TD children (P = 0.01). CONCLUSIONS: Our results highlight the importance of monitoring serum vitamin D levels in children with Hb E/beta thalassemia regardless of their clinical severity or the amount of sunlight they are exposed to. PMID- 23733668 TI - Effect of intravenous infusion of dexmedetomidine combined with inhalation of isoflurane on arterial oxygenation and intrapulmonary shunt during single-lung ventilation. AB - To investigate the changes in arterial oxygenation and intrapulmonary shunt during one-lung ventilation (OLV) with intravenous infusion of dexmedetomidine combined with isoflurane inhalation. ASA I-II 60 patients aged 18-70 year, undergoing OLV during elective thoracic surgery were randomly allocated to two groups: (1) isoflurane + saline (group NISO, n = 30) and (2) isoflurane + dexmedetomidine (group DISO, n = 30). After induction, anesthesia was maintained with intravenous infusion of remifentanil 0.1-0.2 MUg kg(-1) min(-1) and inhalation isoflurane (1.0-2.0%). In addition, anesthesia was maintained with intravenous infusion of dexmedetomidine 0.7 MUg kg(-1) h(-1) in DISO group and saline 0.25 ml kg(-1) h(-1) in NISO group. Bispectral Index values were maintained within 40-60 by changing the concentration of isoflurane in all groups. Arterial blood gas samples and central venous blood gas samples were taken as follows: during two-lung ventilation before OLV and during the first 40 min of OLV. 45 Patients completed the study, with 23 patients in DISO group and 22 patients in NISO group. The two groups were comparable in terms of demographic variables, hemodynamic, PaO2, Qs/QT, end expiration isoflurane and BIS levels during the operation. Compared with patients in the group NISO, there were significant increases with PaO2, significant decrease with Qs/QT, significant decrease with end expiration isoflurane, and significant decrease with HR in the group DISO during the first 40 min of OLV (P < 0.05). Dexmedetomidine infusions decrease the requirement for isoflurane, decrease intrapulmonary shunt, and moderate the change in PaO2 and may be useful in managing OLV. PMID- 23733670 TI - Determination of concentration of methotrexate enantiomers in intracellular and extracellular fluids of HepG2 cells by liquid chromatography-tandem mass spectrometry. AB - A rapid and sensitive liquid chromatography-tandem mass spectrometry assay (LC MS/MS) with electrospray ionization was developed and validated for the quantitative determination of the concentration of methotrexate (MTX) enantiomers in intracellular and extracellular fluids of HepG2 cells. The analytes were extracted from homogenates using organic solvent to precipitate proteins. The extracted samples were analyzed by LC-MS/MS, operating in multiple reactions monitoring (MRM) mode. The condition of HPLC included the following: Gemini column (3 MUm, 3.0 * 75 mm) with chromatographic column was used, and the mobile phase consisting of gradient elution utilized 0.1% formic acid as solvent A and acetonitrile as solvent B at a flow rate of 0.4 mL min(-1). The gradient was as follows: 0-7.0 min 10-90% B, 7.0-10 min 90% B followed by 3 min. The column temperature was maintained at 40 degrees C. The condition of MS included using electrospray ionization source; MRM mode with the transitions of m/z 455.2 -> m/z 308.1 was used to quantify MTX enantiomers. The linear calibration curve was obtained in the concentration range of 10.0 to 10,000 ng mL(-1) for MTX enantiomers in intracellular and extracellular fluids. The inter- and intraday precision was less than 15%. The mean recovery of (+)-MTX and (-)-MTX in the extracellular fluid of HepG2 cells were 95.30 and 96.53%, respectively, and the mean recovery of (+)-MTX and (-)-MTX in the intracellular fluid of HepG2 cells were 93.53 and 94.12%, respectively. This method was successfully used to detect the concentration of MTX enantiomers in the intracellular and extracellular fluids of HepG2 cells and that the concentration of (+)-MTX in intracellular fluid was twice higher than the concentration of (-)-MTX in intracellular fluid. The inhibitory effect of (+)-MTX and (-)-MTX was (+)-MTX > (-)-MTX. It is a simple, precise method that can effectively explain the difference in pharamocological effect of MTX enantiomers in vitro. PMID- 23733669 TI - Mapping the structural topology of IRS family cascades through computational biology. AB - Structural topologies of proteins play significant roles in analyzing their biological functions. Converting the amino acid data in a protein sequence into structural information to outline the function of a protein is a major challenge in post-genome research which can add an extra room in understanding the protein sequence-structure-function relationships. In this study, we performed a comprehensive bioinformatics analysis of structural topology of the IRS family members such as IRS-1, IRS-2, IRS-3, IRS-4, IRS-5 and IRS-6. Based on this assessment, we found that IRS-2 encloses the highest number of alpha helices, beta sheets and beta turns in the secondary structure topology compared to IRS-1 and IRS-6. IRS family members are rich in serine or leucine residues. Among the IRS family members, the highest percentage of serine and leucine was observed in IRS-1 (15%) and IRS-5 (10%), respectively. Notably, the highest number of disulphide bonds was observed in IRS-1 (10) which is responsible for structural stability of the protein. Hydrogen bond pattern in alpha helices and beta sheet was recorded in IRS-1, IRS-2 and IRS-6. By conservation analysis, the longest protein IRS-3 was found to be highly conserved among the IRS family members. The cluster of sequence logo present in the N terminus of these cascades was noted, and highly conserved residues in N-terminal region help in the formation of the two highly conserved domains such as PH domain and PTB domain. Results generated from this analysis will be more beneficial to researchers in understanding more about insulin signalling mechanism(s) as well as insulin resistance pathway. We discuss here that bioinformatics tools utilized in this study can play a vital role in addressing the complexity of structural topology to understand structure function relationships in insulin signalling cascades. PMID- 23733671 TI - Profiling deleterious non-synonymous SNPs of smoker's gene CYP1A1. AB - CYP1A1 gene belongs to the cytochrome P450 family and is known better as smokers' gene due to its hyperactivation as a consequence of long term smoking. The expression of CYP1A1 induces polycyclic aromatic hydrocarbon production in the lungs, which when over expressed, is known to cause smoking related diseases, such as cardiovascular pathologies, cancer, and diabetes. Single nucleotide polymorphisms (SNPs) are the simplest form of genetic variations that occur at a higher frequency, and are denoted as synonymous and non-synonymous SNPs on the basis of their effects on the amino acids. This study adopts a systematic in silico approach to predict the deleterious SNPs that are associated with disease conditions. It is inferred that four SNPs are highly deleterious, among which the SNP with rs17861094 is commonly predicted to be harmful by all tools. Hydrophobic (isoleucine) to hydrophilic (serine) amino acid variation was observed in the candidate gene. Hence, this investigation aims to characterize a candidate gene from 159 SNPs of CYP1A1. PMID- 23733672 TI - Surfactin-induced apoptosis through ROS-ERS-Ca2+-ERK pathways in HepG2 cells. AB - Although surfactin is able to inhibit cancer cell proliferation and to induce cancer cell apoptosis, the molecular mechanism responsible for this process remain elusive. In this study, the signaling network underlying the apoptosis of human hepatoma (HepG2) cells induced by surfactin was investigated. It is found that the reaction oxygen species (ROS) production and intracellular calcium ([Ca(2+)]i) accumulation are both induced HepG2 cells apoptosis. The [Ca(2+)]i exaltation was partly depended on the Ca(2+) release from inositol 1,4,5 trisphosphate (IP3) and ryanodine (Ry) receptors channels, which both triggered endoplasmic reticulum stress (ERS). The results showed that surfactin induced the ROS production and ROS production led to ERS. The occurrence of ERS increased the [Ca(2+)]i level and the processes associated with blocking extracellular signal regulated kinase (ERK) pathway. According to a comprehensive review of all the evidence, it is concluded that surfactin induces apoptosis of HepG2 cells through a ROS-ERS-Ca(2+) mediated ERK pathway. PMID- 23733673 TI - Study on the effect of kidney transplantation on the health of the patients' offspring: a report on 252 Chinese children. AB - Even though the incidence of pregnancies in the female recipients is lower and also chronic renal disease in male patients is associated with impaired spermatogenesis, the health of the children born to these patients was not studied. In this report, we discuss information on the growth and development of offspring of 248 male and female kidney recipient patients. Physical and routine clinical measurements of the 252 offspring (129 male and 123 female) born to these transplantation patients were made along with the intelligence tests. In some of these children chest X-ray and immune indices were assessed. Among the recipients, 219 males fathered 223 children with an average birth weight of 3,255 +/- 374 g and 29 female recipients gave birth to 29 children with an average birth weight of 2,923 +/- 551. While most of these children were normal, we noticed a case of soft double toe, a case of short tongue tie, five cases of marginal mental retardation, three cases of proteinuria, six cases of microscopic hematuria, 15 cases of low hemoglobin, and 21 cases with recurrent respiratory tract infections. We conclude that kidney transplantation has no significant impact on the growth, development, health, and intelligence of the offspring born to recipients. PMID- 23733674 TI - Efficacy of nimotuzumab combined with docetaxel-cisplatin-fluorouracil regimen in treatment of advanced oral carcinoma. AB - The present study aimed to evaluate efficacy and adverse effects of Nimotuzumab combined with docetaxel-cisplatin-fluorouracil regimen in the treatment of advanced oral carcinoma. Nine patients with advanced oral carcinoma were treated with Nimotuzumab combined with docetaxel-cisplatin-fluorouracil regimen (test group). The treatment was given as follows: Nimotuzumab 200 mg, given as intravenous infusion once a week for 6 weeks; docetaxel and cisplatin, 75 mg/m(2) each, on day 1 only; 5-fluorouracil, 750 mg/m(2) infused continually for 8 h, used from day 1 to 5; the total cycle was for 21 days. Another eight patients comprised control group (docetaxel-cisplatin-fluorouracil regimen alone). Study patients from both groups were evaluated for objective response. The response rate was significantly (p = 0.044) higher in test group (88.9 vs. 37.5 % in control group). The disease control rate also tended to be higher in test group (100 vs. 62.5 % in control group; p = 0.083). The major adverse effects were bone marrow suppression, nausea, vomiting, and alopecia. The incidence of adverse effects was similar between both study groups. In conclusion, Nimotuzumab combined with docetaxel-cisplatin-fluorouracil regimen is effective and safe in the treatment of advanced oral carcinoma. PMID- 23733676 TI - Assessing the effect of a guideline change on drug use prevalence by including the birth cohort dimension: the case of benzodiazepines. AB - PURPOSE: The aim of this study was to investigate whether including the birth cohort dimension in time series analysis leads to a more accurate estimation of the (long-term) effect of a guideline change on the trend of benzodiazepine use. METHODS: We calculated age-specific (20-84 years) and sex-specific prevalence of benzodiazepine use per 1000 population per quarter year (1998 to 2008) using a prescription database set in the Netherlands. We studied the prevalence over time by age group and within birth cohorts through interrupted time series analyses to estimate the effect of the guideline change in 2001. RESULTS: From 1998 to 2008, the overall age-standardized prevalence of benzodiazepine use per 1000 population declined from ~54 for men and ~107 for women to ~45 for men and ~85 for women. The relative change increased significantly after 2001 for both sexes and for the majority of age groups. Within birth cohorts, the prevalence increased with age until the year 2001 and leveled thereafter. The age-period approach overall had worse model fit indicators than the within-cohort approach and predicted larger long-term effects than the within-cohort approach. The age-period projection estimated 36% decline in benzodiazepine use relative to 2008, whereas the birth cohort projection estimated 8% decline. CONCLUSION: Explicitly following birth cohort trajectories led to models with better fit; the conventional approach estimated a stronger long-term guideline effect. This has important implications for professional practice. PMID- 23733675 TI - Ginseng panaxoside Rb1 reduces body weight in diet-induced obese mice. AB - Crude extracts from ginseng demonstrated anti-obesity properties. Ginsenoside Rb1 is the main component of ginseng, however, there are only few studies examining its effects in obesity. In the present study, we evaluated its potential anti obesity effects in the murine model of diet-induced obesity. Seventy male C57BL/6 mice were randomly divided to consume for 12 weeks either chow diet (N = 8) or high-fat (HF) diet (N = 62). The latter mice were then divided into four groups: diet-induced obesity group (DIO; N = 10), obesity-resistant group (OR; N = 10), HF group (N = 5), and the group whose diet was changed from HF to normal diet (DC; N = 5). Intraperitoneal injections of Rb-1 were administered daily to mice in the DIO and OR groups for 3 weeks. Body weight and energy intake were monitored, and fasting blood glucose, lipids, neuropeptide Y, Y2 receptor, and peptide YY were quantified. Compared with HF group, weight gain and food intake of DIO mice with Rb-1 injection was significantly decreased (p < 0.05). Further, levels of blood glucose and some lipids were also decreased in DIO-Rb1 group compared with HF group. Furthermore, Rb1 was also found to modulate serum levels of PYY and NPY, and mRNA expression of NPY, Y2 receptor and PYY in tissue samples of DIO mice. Taken together, ginsenoside Rb1 may be useful in the treatment of obesity via modifying the serum content and mRNA expression of NPY, Y2 receptor and PYY. PMID- 23733677 TI - Simplifying proton NMR spectra by instant homonuclear broadband decoupling. PMID- 23733678 TI - Assembly of Pt nanowires into cubelike superstructures supported on aligned carbon nanotubes as highly stable electrocatalysts. PMID- 23733681 TI - A novel remote center of motion mechanism for the force-reflective master robot of haptic tele-surgery systems. AB - BACKGROUND: An effective master robot for haptic tele-surgery applications needs to provide a solution for the inversed movements of the surgical tool, in addition to sufficient workspace and manipulability, with minimal moving inertia. METHOD: A novel 4 + 1-DOF mechanism was proposed, based on a triple parallelogram linkage, which provided a Remote Center of Motion (RCM) at the back of the user's hand. The kinematics of the robot was analyzed and a prototype was fabricated and evaluated by experimental tests. RESULTS: With a RCM at the back of the user's hand the actuators far from the end effector, the robot could produce the sensation of hand-inside surgery with minimal moving inertia. The target workspace was achieved with an acceptable manipulability. The trajectory tracking experiments revealed small errors, due to backlash at the joints. CONCLUSIONS: The proposed mechanism meets the basic requirements of an effective master robot for haptic tele-surgery applications. PMID- 23733682 TI - Identification of bio-active metabolites of gentiopicroside by UPLC/Q-TOF MS and NMR. AB - Gentiopicroside (GPS), the main bioactive component in Gentiana scabra Bge., has attracted our attention owing to its high bioactivity, especially the treatment of hepatobiliary disorders. The aglycone form of GPS, a typical secoiridoid glycoside, is considered to be more readily absorbed than its parent drug. This study aimed to identify and characterize the metabolites after GPS incubated with beta-glucosidase in buffer solution at 37 degrees C. Samples of biotransformed solution were collected and analyzed by ultraperformance liquid chromatography (UPLC)/quadrupole-time-of-flight mass spectrometry (Q-TOF MS). A total of four metabolites were detected: two were isolated and elucidated by preparative-HPLC and NMR techniques, and one of those four is reported for the first time. The mass spectral fragmentation pattern and accurate masses of metabolites were established on the basis of UPLC/Q-TOF MS analysis. Structure elucidation of metabolites was achieved by comparing their fragmentation pattern with that of the parent drug. A fairly possible metabolic pathway of GPS by beta-glucosidase was proposed. The hepatoprotective activities of metabolites M1 and M2 were investigated and the results showed that their hepatoprotective activities were higher than that of parent drug. Our results provided a meaningful basis for discovering lead compounds from biotransformation related to G. scabra Bge. in traditional Chinese medicine. PMID- 23733683 TI - Awareness and interest in biospecimen donation for cancer research: views from gatekeepers and prospective participants in the Latino community. AB - Latinos are one of the fastest-growing population groups in the USA, and are underrepresented in scientific research and even more so in genetic research. The disproportionately lower number of certain subpopulations participating in biomedical research has a significant impact on the representativeness of scientific outcomes. We established a collaboration with scientists at a designated National Cancer Institute comprehensive cancer center to test the feasibility of community-based approaches for engaging Latinos in biospecimen donation for cancer genomic research. A methods triangulation approach was applied to gain a deeper understanding from the community, that included key informant interviews with Latino community leaders (N = 6), four focus groups (N = 22) with members of the Latino community, and the use of an audience response system within the focus groups to capture quantitative data. Overall, the majority of participants had never participated in biospecimen donation; however, despite being unaware of the biobank, they expressed willingness to participate as a way to help advance research. Themes included: Confusion on what biospecimen donation process entails; Barriers to and incentives for participation; Strategies and locations for reaching the Latino community. Clear communication of the "public good" as it relates to biospecimen donation by healthy/non-patient participants is a less clearly conceptualized message; yet, the significance of delivering this message is important to gaining participation and increasing the diversity of samples available for cancer genomic studies from a broader community context. PMID- 23733684 TI - Exercise physiology of normal development, sex differences, and aging. AB - The scientific study of human development has evolved from studies of children to studies of the full lifespan. Many physiological changes occur throughout the lifespan and unique changes occur during normal development compared to healthy aging. An enlarging body of data supports the idea that there exist critical periods of development during which physiological perturbations to the internal milieu (e.g., disease or physical activity) can alter the overall programming of developmental processes. Although different physiological functions decline with age with widely varying rates, the aging changes accumulated throughout the physiological systems reduce the capacity to cope with the stress and maintain homeostasis. The understanding of this process of development and aging is complicated by important physiologic sex differences with regard to nearly all physiological systems. Regular physical activity can favorably modulate this developmental and aging process and can have important health benefits. However, a physically inactive lifestyle can markedly impair normal development and lead to numerous diseases. Life-long physical activity is essential for preserving or delaying the onset of functional disability and chronic cardiovascular and metabolic diseases. PMID- 23733685 TI - Metabolism, temperature, and ventilation. AB - In mammals and birds, all oxygen used (VO2) must pass through the lungs; hence, some degree of coupling between VO2 and pulmonary ventilation (VE) is highly predictable. Nevertheless, VE is also involved with CO2 elimination, a task that is often in conflict with the convection of O2. In hot or cold conditions, the relationship between VE and VO2 includes the participation of the respiratory apparatus to the control of body temperature and water balance. Some compromise among these tasks is achieved through changes in breathing pattern, uncoupling changes in alveolar ventilation from VE. This article examines primarily the relationship between VE and VO2 under thermal stimuli. In the process, it considers how the relationship is influenced by hypoxia, hypercapnia or changes in metabolic level. The shuffling of tasks in emergency situations illustrates that the constraints on VE-VO2 for the protection of blood gases have ample room for flexibility. However, when other priorities do not interfere with the primary goal of gas exchange, VE follows metabolic rate quite closely. The fact that arterial CO2 remains stable when metabolism is changed by the most diverse circumstances (moderate exercise, cold, cold and exercise combined, variations in body size, caloric intake, age, time of the day, hormones, drugs, etc.) makes it unlikely that VE and metabolism are controlled in parallel by the condition responsible for the metabolic change. Rather, some observations support the view that the gaseous component of metabolic rate, probably CO2, may provide the link between the metabolic level and VE. PMID- 23733686 TI - Regulation of NhaA by protons. AB - H(+), a most common ion, is involved in very many biological processes. However, most proteins have distinct ranges of pH for function; when the H(+) concentration in the cells is too high or too low, protons turn into very potent stressors to all cells. Therefore, all living cells are strictly dependent on homeostasis mechanisms that regulate their intracellular pH. Na(+)/H(+) antiporters play primary role in pH homeostatic mechanisms both in prokaryotes and eukaryotes. Regulation by pH is a property common to these antiporters. They are equipped with a pH sensor to perceive the pH signal and a pH transducer to transduce the signal into a change in activity. Determining the crystal structure of NhaA, the Na(+)/H(+) antiporter of Escherichia coli have provided the basis for understanding in a realistic rational way the unique regulation of an antiporter by pH and the mechanism of the antiport activity. The physical separation between the pH sensor/transducer and the active site revealed by the structure entailed long-range pH-induced conformational changes for NhaA pH activation. As yet, it is not possible to decide whether the amino acid participating in the pH sensor and the pH transducer overlap or are separated. The pH sensor/transducer is not a single amino acid but rather a cluster of electrostatically interacting residues. Thus, integrating structural, computational, and experimental approaches are essential to reveal how the pH signal is perceived and transduced to activate the pH regulated protein. PMID- 23733687 TI - Cyclooxygenase metabolites in the kidney. AB - In the mammalian kidney, prostaglandins (PGs) are important mediators of physiologic processes, including modulation of vascular tone and salt and water. PGs arise from enzymatic metabolism of free arachidonic acid (AA), which is cleaved from membrane phospholipids by phospholipase A2 activity. The cyclooxygenase (COX) enzyme system is a major pathway for metabolism of AA in the kidney. COX are the enzymes responsible for the initial conversion of AA to PGG2 and subsequently to PGH2, which serves as the precursor for subsequent metabolism by PG and thromboxane synthases. In addition to high levels of expression of the "constitutive" rate-limiting enzyme responsible for prostanoid production, COX-1, the "inducible" isoform of cyclooxygenase, COX-2, is also constitutively expressed in the kidney and is highly regulated in response to alterations in intravascular volume. PGs and thromboxane A2 exert their biological functions predominantly through activation of specific 7-transmembrane G-protein-coupled receptors. COX metabolites have been shown to exert important physiologic functions in maintenance of renal blood flow, mediation of renin release and regulation of sodium excretion. In addition to physiologic regulation of prostanoid production in the kidney, increases in prostanoid production are also seen in a variety of inflammatory renal injuries, and COX metabolites may serve as mediators of inflammatory injury in renal disease. PMID- 23733688 TI - Erythropoietin. AB - The hormone erythropoietin (Epo) is the main humoral regulator of erythropoiesis. It binds to specific receptors belonging to the cytokine receptor superfamily. Epo stimulates proliferation and differentiation of erythroid precursor cells, but may also bind to and exert some additional effects in nonhemopoietic tissues. It is mainly produced in the kidneys and to minor extents also in the liver and in the brain. The plasma concentration of erthyropoietin is inversely related to the oxygen content of the blood. The secretion of Epo into the circulation and hence its plasma concentrations are mainly determined by the transcription rate of the Epo gene, which itself is essentially under control of the cellular oxygen concentration. Sinks of the oxygen concentrations increase the activity of the hypoxia-inducible transcription factor (HIF), which in turn triggers Epo gene transcription. Disorders of kidney function lead to inappropriate Epo production, what may result in anemia or polycythemia. PMID- 23733689 TI - Renal transport of organic anions and cations. AB - Organic anions and cations (OAs and OCs, respectively) comprise an extraordinarily diverse array of compounds of physiological, pharmacological, and toxicological importance. The kidney, primarily the renal proximal tubule, plays a critical role in regulating the plasma concentrations of these organic electrolytes and in clearing the body of potentially toxic xenobiotics agents, a process that involves active, transepithelial secretion. This transepithelial transport involves separate entry and exit steps at the basolateral and luminal aspects of renal tubular cells. Basolateral and luminal OA and OC transport reflects the concerted activity of a suite of separate proteins arranged in parallel in each pole of proximal tubule cells. The cloning of multiple members of several distinct transport families, the subsequent characterization of their activity, and their subcellular localization within distinct regions of the kidney, now allows the development of models describing the molecular basis of the renal secretion of OAs and OCs. New information on naturally occurring genetic variation of many of these processes provides insight into the basis of observed variability of drug efficacy and unwanted drug-drug interactions in human populations. The present review examines recent work on these issues. PMID- 23733690 TI - Airway gas exchange and exhaled biomarkers. AB - During inspiration and expiration, gases traverse the conducting airways as they are transported between the environment and the alveolar region of the lungs. The term "conducting" airways is used broadly as the airway tree is thought largely to provide a conduit for the respiratory gases, oxygen and carbon dioxide. However, despite a significantly smaller surface area, and thicker barrier separating the gas phase from the blood when compared to the alveolar region, the airway tree can participate in gas exchange under special conditions such as high water solubility, high chemical reactivity, or production of the gas within the airway wall tissue. While these conditions do not apply to the respiratory gases, other gases demonstrate substantial exchange of the airways and are of particular importance to the inflammatory response of the lungs, the medical-legal field, occupational health, metabolic disorders, or protection of the delicate alveolar membrane. Given the significant structural differences between the airways and the alveolar region, the physical determinants that control airway gas exchange are unique and require different models (both experimental and mathematical) to explore. Our improved physiological understanding of airway gas exchange combined with improved analytical methods to detect trace compounds in the exhaled breath provides future opportunities to develop new exhaled biomarkers that are characteristic of pulmonary and systemic conditions. PMID- 23733691 TI - Expiratory flow limitation. AB - Expiratory flow limitation occurs when flow ceases to increase with increasing expiratory effort. The equal pressure point concept has been largely successful in providing intuitive understanding of the phenomenon, wherein maximal flows are determined by lung recoil and resistance upstream of the site where bronchial transmural pressure is zero (the EPP). Subsequent work on the fluid dynamical foundations led to the wave-speed theory of flow limitation, where flow is limited at a site when the local gas velocity is equal to speed of propagation of pressure waves. Each is a local theory; full predictions require knowledge of both density-dependent Bernoulli pressure drops and viscosity-dependent pressure losses due to dissipation. The former is dominant at mid to high lung volumes, whereas the latter is more important at low lung volumes as the flow-limiting site moves peripherally. The observation of relative effort independence of the maximal flow versus volume curves is important clinically insofar as such maneuvers, when carefully performed, offer a unique window into the mechanics of the lung itself, with little confounding effects. In particular, the important contributions of lung recoil and airways resistance can often be assessed, with implications and applications to diagnosis and management of pulmonary disease. PMID- 23733692 TI - Integrated physiological mechanisms of exercise performance, adaptation, and maladaptation to heat stress. AB - This article emphasizes significant recent advances regarding heat stress and its impact on exercise performance, adaptations, fluid electrolyte imbalances, and pathophysiology. During exercise-heat stress, the physiological burden of supporting high skin blood flow and high sweating rates can impose considerable cardiovascular strain and initiate a cascade of pathophysiological events leading to heat stroke. We examine the association between heat stress, particularly high skin temperature, on diminishing cardiovascular/aerobic reserves as well as increasing relative intensity and perceptual cues that degrade aerobic exercise performance. We discuss novel systemic (heat acclimation) and cellular (acquired thermal tolerance) adaptations that improve performance in hot and temperate environments and protect organs from heat stroke as well as other dissimilar stresses. We delineate how heat stroke evolves from gut underperfusion/ischemia causing endotoxin release or the release of mitochondrial DNA fragments in response to cell necrosis, to mediate a systemic inflammatory syndrome inducing coagulopathies, immune dysfunction, cytokine modulation, and multiorgan damage and failure. We discuss how an inflammatory response that induces simultaneous fever and/or prior exposure to a pathogen (e.g., viral infection) that deactivates molecular protective mechanisms interacts synergistically with the hyperthermia of exercise to perhaps explain heat stroke cases reported in low risk populations performing routine activities. Importantly, we question the "traditional" notion that high core temperature is the critical mediator of exercise performance degradation and heat stroke. Published 2011. This article is a U.S. Government work and is in the public domain in the USA. PMID- 23733693 TI - Inflammatory mechanisms in the pathogenesis of pulmonary arterial hypertension. AB - Inflammation is a prominent feature of human and experimental pulmonary hypertension (PH) as suggested by infiltration of various inflammatory cells and increased expression of certain cytokines in remodeled pulmonary vessels. Macrophages, T and B lymphocytes, and dendritic cells are found in the vascular lesions of idiopathic pulmonary arterial hypertension (PAH) as well as in PAH associated with connective tissue diseases or infectious etiologies such as HIV. In addition, PAH is often characterized by the presence of circulating chemokines and cytokines, increased expression of growth (such as VEGF and PDGF) and transcriptional (e.g., nuclear factor of activated T cells or NFAT) factors, and viral protein components (e.g., HIV-1 Nef), which directly contribute to further recruitment of inflammatory cells and the pulmonary vascular remodeling process. These inflammatory pathways may thus serve as potential specific therapeutic targets. This article provides an overview of inflammatory pathways involving chemokines and cytokines as well as growth factors, highlighting their potential role in pulmonary vascular remodeling and the possibility of future targeted therapy. PMID- 23733694 TI - Exercise and osteoarthritis: cause and effects. AB - Osteoarthritis (OA) is a common chronic joint condition predominantly affecting the knee, hip, and hand joints. Exercise plays a role in the development and treatment of OA but most of the literature in this area relates to knee OA. While studies indicate that exercise and physical activity have a generally positive effect on healthy cartilage metrics, depending upon the type of the activity and its intensity, the risk of OA development does appear to be moderately increased with sporting participation. In particular, joint injury associated with sports participation may be largely responsible for this increased risk of OA with sport. Various repetitive occupational tasks are also linked to greater likelihood of OA development. There are a number of physical impairments associated with OA including pain, muscle weakness and altered muscle function, reduced proprioception and postural control, joint instability, restricted range of motion, and lower aerobic fitness. These can result directly from the OA pathological process and/or indirectly as a result of factors such as pain, effusion, and reduced activity levels. These impairments and their underlying physiology are often targeted by exercise interventions and evidence generally shows that many of these can be modified by specific exercise. There is currently little clinical trial evidence to show that exercise can alter mechanical load and structural disease progression in those with established OA, although a number of impairments, that are amenable to change with exercise, appears to be associated with increased mechanical load and/or disease progression in longitudinal studies. PMID- 23733696 TI - Mechanisms of muscle injury, repair, and regeneration. AB - Skeletal muscle continuously adapts to changes in its mechanical environment through modifications in gene expression and protein stability that affect its physiological function and mass. However, mechanical stresses commonly exceed the parameters that induce adaptations, producing instead acute injury. Furthermore, the relatively superficial location of many muscles in the body leaves them further vulnerable to acute injuries by exposure to extreme temperatures, contusions, lacerations or toxins. In this article, the molecular, cellular, and mechanical factors that underlie muscle injury and the capacity of muscle to repair and regenerate are presented. Evidence shows that muscle injuries that are caused by eccentric contractions result from direct mechanical damage to myofibrils. However, muscle pathology following other acute injuries is largely attributable to damage to the muscle cell membrane. Many feaures in the injury repair-regeneration cascade relate to the unregulated influx of calcium through membrane lesions, including: (i) activation of proteases and hydrolases that contribute muscle damage, (ii) activation of enzymes that drive the production of mitogens and motogens for muscle and immune cells involved in injury and repair, and (iii) enabling protein-protein interactions that promote membrane repair. Evidence is also presented to show that the myogenic program that is activated by acute muscle injury and the inflammatory process that follows are highly coordinated, with myeloid cells playing a central role in modulating repair and regeneration. The early-invading, proinflammatory M1 macrophages remove debris caused by injury and express Th1 cytokines that play key roles in regulating the proliferation, migration, and differentiation of satellite cells. The subsequent invasion by anti-inflammatory, M2 macrophages promotes tissue repair and attenuates inflammation. Although this system provides an effective mechanism for muscle repair and regeneration following acute injury, it is dysregulated in chronic injuries. In this article, the process of muscle injury, repair and regeneration that occurs in muscular dystrophy is used as an example of chronic muscle injury, to highlight similarities and differences between the injury and repair processes that occur in acutely and chronically injured muscle. PMID- 23733697 TI - Insights into biomedicine from animal adaptations. AB - Evolution represents a natural experimental process for testing animal design features. Driven by environmental pressures, animals have evolved adaptations which can give valuable insights into human biomedical conditions. The giraffe by virtue of its extremely long neck has a mean arterial pressure much higher than other mammals. However, the giraffe does not develop vascular damage or heart failure despite its high mean arterial pressure. The giraffe's cardiovascular physiology challenges a number of current concepts concerning the genesis of hypertensive vascular damage in the human. All animals senesce, and, in general, the manifestations of this senescence are similar to the aging features observed in humans. The characteristics of aging in natural animals strongly suggest that the so-called chronic degenerative diseases of humans are not really diseases but actually manifestations of the aging phenotype. Glucose regulation in birds and the naked mole rat has features which mimic the characteristics of the diabetic state, yet these animals do not develop the complications occurring in humans with diabetes. Disruptions in the functioning of the circadian molecular clock are thought to underlie certain neuropsychiatric disorders. The honeybee and the zebrafish have emerged as natural animal models for studying the regulation of molecular clocks and the mechanisms underlying plasticity of circadian rhythms. These examples underscore the valuable insights that natural animals can furnish with respect to biomedical disorders. Yet, this information data base remains a largely untapped resource. PMID- 23733695 TI - Mechanics of the lung in the 20th century. AB - Major advances in respiratory mechanics occurred primarily in the latter half of the 20th century, and this is when much of our current understanding was secured. The earliest and ancient investigations involving respiratory physiology and mechanics were frequently done in conjunction with other scientific activities and often lacked the ability to make quantitative measurements. This situation changed rapidly in the 20th century, and this relatively recent history of lung mechanics has been greatly influenced by critical technological advances and applications, which have made quantitative experimental testing of ideas possible. From the spirometer of Hutchinson, to the pneumotachograph of Fleisch, to the measurement of esophageal pressure, to the use of the Wilhelmy balance by Clements, and to the unassuming strain gauges for measuring pressure and rapid paper and electronic chart recorders, these enabling devices have generated numerous quantitative experimental studies with greatly increased physiologic understanding and validation of mechanistic theories of lung function in health and disease. PMID- 23733698 TI - Na+/H+ exchangers. AB - Tightly coupled exchange of Na(+) for H(+) occurs across the surface membrane of virtually all living cells. For years, the underlying molecular entity was unknown and the full physiological significance of the exchange process was not appreciated, but much knowledge has been gained in the last two decades. We now realize that, unlike most of the other transporters that specialize in supporting one specific function, Na(+)/H(+) exchangers (NHE) participate in a remarkable assortment of physiological processes, ranging from pH homeostasis and epithelial salt transport, to systemic and cellular volume regulation. In parallel, we have learned a great deal about the biochemistry and molecular biology of Na(+)/H(+) exchange. Indeed, it has now become apparent that exchange is mediated not by one, but by a diverse family of related yet distinct carriers (antiporters) sometimes present in different cell types and located in various intracellular compartments. Each one of these has unique structural features that dictate its functional role and mode of regulation. The biological relevance of Na(+)/H(+) exchange is emphasized by its evolutionary conservation; analogous exchangers are present from bacteria to man. Because of its wide distribution and versatile function, Na(+)/H(+) exchange has attracted an enormous amount of interest and therefore generated a vast literature. The vastness and complexity of the field has been compounded by the multiplicity of NHE isoforms. For reasons of space and in the spirit of this series, this overview is restricted to the family of mammalian NHEs. PMID- 23733699 TI - Neuronal control of breathing: sex and stress hormones. AB - There is a growing public awareness that hormones can have a significant impact on most biological systems, including the control of breathing. This review will focus on the actions of two broad classes of hormones on the neuronal control of breathing: sex hormones and stress hormones. The majority of these hormones are steroids; a striking feature is that both groups are derived from cholesterol. Stress hormones also include many peptides which are produced primarily within the paraventricular nucleus of the hypothalamus (PVN) and secreted into the brain or into the circulatory system. In this article we will first review and discuss the role of sex hormones in respiratory control throughout life, emphasizing how natural fluctuations in hormones are reflected in ventilatory metrics and how disruption of their endogenous cycle can predispose to respiratory disease. These effects may be mediated directly by sex hormone receptors or indirectly by neurotransmitter systems. Next, we will discuss the origins of hypothalamic stress hormones and their relationship with the respiratory control system. This relationship is 2-fold: (i) via direct anatomical connections to brainstem respiratory control centers, and (ii) via steroid hormones released from the adrenal gland in response to signals from the pituitary gland. Finally, the impact of stress on the development of neural circuits involved in breathing is evaluated in animal models, and the consequences of early stress on respiratory health and disease is discussed. PMID- 23733700 TI - Gastric H+,K+-ATPase. AB - The gastric H(+),K(+)-ATPase is responsible for gastric acid secretion. This ATPase is composed of two subunits, the catalytic alpha subunit and the structural beta subunit. The alpha subunit with molecular mass of about 100 kDa has 10 transmembrane domains and is strongly associated with the beta subunit with a single transmembrane segment and a peptide mass of 35 kDa. Its three dimensional structure is based on homology modeling and site-directed mutagenesis resulting in a proton extrusion and K(+) reabsorption model. There are three conserved H3O(+)-binding sites in the middle of the membrane domain and H3O(+) secretion depends on a conformational change involving Lys(791) insertion into the second H3O(+) site enclosed by E795, E820, and D824 that allows export of protons at a concentration of 160 mM. K(+) countertransport involves binding to this site after the release of protons with retrograde displacement of Lys(791) and then K(+) transfer to E343 and exit to the cytoplasm. This ATPase is the major therapeutic target in treatment of acid-related diseases and there are several known luminal inhibitors allowing analysis of the luminal vestibule. One class contains the acid-activated covalent, thiophilic proton pump inhibitors, the most effective of current acid-suppressive drugs. Their binding sites and trypsinolysis allowed identification of all ten transmembrane segments of the ATPase. In addition, various K(+)-competitive inhibitors of the ATPase are being developed, with the advantage of complete and rapid inhibition of acid secretion independent of pump activity and allowing further refinement of the structure of the luminal vestibule of the E2 form of this ATPase. PMID- 23733701 TI - Ca2+-activated Cl- channels. AB - Ca(2+)-activated Cl(-) channels (CaCCs) are plasma membrane proteins involved in various important physiological processes. In epithelial cells, CaCC activity mediates the secretion of Cl(-) and of other anions, such as bicarbonate and thiocyanate. In smooth muscle and excitable cells of the nervous system, CaCCs have an excitatory role coupling intracellular Ca(2+) elevation to membrane depolarization. Recent studies indicate that TMEM16A (transmembrane protein 16 A or anoctamin 1) and TMEM16B (transmembrane protein 16 B or anoctamin 2) are CaCC forming proteins. Induced expression of TMEM16A and B in null cells by transfection causes the appearance of Ca(2+)-activated Cl(-) currents similar to those described in native tissues. Furthermore, silencing of TMEM16A by RNAi causes disappearance of CaCC activity in cells from airway epithelium, biliary ducts, salivary glands, and blood vessel smooth muscle. Mice devoid of TMEM16A expression have impaired Ca(2+)-dependent Cl(-) secretion in the epithelial cells of the airways, intestine, and salivary glands. These animals also show a loss of gastrointestinal motility, a finding consistent with an important function of TMEM16A in the electrical activity of gut pacemaker cells, that is, the interstitial cells of Cajal. Identification of TMEM16 proteins will help to elucidate the molecular basis of Cl(-) transport. PMID- 23733702 TI - Membrane proteins structure and dynamics by nuclear magnetic resonance. AB - Membrane proteins represent a challenging class of biological systems to study. They are extremely difficult to crystallize and in most cases they retain their structure and functions only in membrane environments. Therefore, commonly used diffraction methods fail to give detailed molecular structure and other approaches have to be utilized to obtain biologically relevant information. Nuclear magnetic resonance (NMR) spectroscopy, however, can provide powerful structural and dynamical constraints on these complicated systems. Solution- and solid-state NMR are powerful methods for investigating membrane proteins studies. In this work, we briefly review both solution and solid-state NMR techniques for membrane protein studies and illustrate the applications of these methods to elucidate proteins structure, conformation, topology, dynamics, and function. Recent advances in electronics, biological sample preparation, and spectral processing provided opportunities for complex biological systems, such as membrane proteins inside lipid vesicles, to be studied faster and with outstanding quality. New analysis methods therefore have emerged, that benefit from the combination of sample preparation and corresponding specific high-end NMR techniques, which give access to more structural and dynamic information. PMID- 23733703 TI - Clinical and molecular genetic features of hereditary pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a rare disorder that may be hereditary (HPAH), idiopathic (IPAH), or associated with either drug-toxin exposures or other medical conditions. Familial cases have long been recognised and are usually due to mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2), or, much less commonly, two other members of the transforming growth factor-beta superfamily, activin-like kinase-type 1 (ALK1), and endoglin (ENG), which are associated with hereditary hemorrhagic telangiectasia. In addition, approximately 20% of patients with IPAH carry mutations in BMPR2. Clinical testing for BMPR2 mutations is available and may be offered to HPAH and IPAH patients but should be preceded by genetic counselling, since lifetime penetrance is only 10% to 20%, and there are currently no known effective preventative measures. Identification of a familial mutation can be valuable in reproductive planning and identifying family members who are not mutation carriers and thus will not require lifelong surveillance. With advances in genomic technology and with international collaborative efforts, genome-wide association studies will be conducted to identify additional genes for HPAH, genetic modifiers for BMPR2 penetrance, and genetic susceptibility to IPAH. In addition, collaborative studies of BMPR2 mutation carriers should enable identification of environmental modifiers, biomarkers for disease development and progression, and surrogate markers for efficacy end points in clinical drug development, thereby providing an invaluable resource for trials of PAH prevention. PMID- 23733705 TI - Evaluation of pregnancy outcome records in the German Pharmacoepidemiological Research Database (GePaRD). AB - PURPOSE: Routine health care data are a valuable source for the assessment of risks of drugs during pregnancy. Therefore, the aim of the current analysis was the evaluation of pregnancy outcome records in German health insurance data. METHODS: We used the German Pharmacoepidemiologic Research Database including data of more than 15 million insurants (about 18% of the German population). Among 10-49 year-old women, we identified six categories of pregnancy outcomes: term births, preterm births, stillbirths, induced abortions, spontaneous abortions and ectopic pregnancies. In order to assess the validity of these records, we have set our results in relation to representative data for the corresponding outcomes in Germany. We also investigated whether pregnancy markers (diagnoses, procedures or medical services which indicate an existing pregnancy) can be used to identify pregnancies. RESULTS: In total, we identified 94 261 pregnancy outcomes in 2005. The percentage of births outside hospital (1.2%) and of preterm births (11.6%), the rate of stillbirths (3 per 1000 live births) and the rate of ectopic pregnancies (20 per 1000 live births) agreed well with representative data for Germany. Compared to epidemiological data, the occurrence of spontaneous abortions was underestimated (5.4% of all pregnancies). There were 4.1 induced abortions per 100 live births, compared to 18.1 in national data. Positive predictive values and sensitivities of markers varied across marker categories and for different pregnancy outcomes. CONCLUSIONS: Completeness of pregnancy outcomes recorded in the database varied by pregnancy outcome. This should be taken into account in studies of drug safety in pregnancy. PMID- 23733704 TI - Mesenchymal stem cells, nanofiber scaffolds and ocular surface reconstruction. AB - Ocular surface defects represent one of the most common causes of impaired vision or even blindness. For treatment, keratoplasty represents the first choice. However, if corneal defects are more extensive and associated with a limbal stem cell (LSC) deficiency, corneal transplantation is not a sufficient therapeutic procedure and only viable approach to treatment is the transplantation of LSCs. When the LSC deficiency is a bilateral disorder, autologous LSCs are not available. The use of allogeneic LSCs requires strong immunosuppression, which leads to side-effects, and the treatment is not always effective. The alternative and perspective approach to the treatment of severe ocular surface injuries and LSC deficiency is offered by the transplantation of autologous mesenchymal stem cells (MSCs). These cells can be obtained from the bone marrow or adipose tissue of the particular patient, grow well in vitro and can be transferred, using an appropriate scaffold, onto the damaged ocular surface. Here they exert beneficial effects by possible direct differentiation into corneal epithelial cells, by immunomodulatory effects and by the production of numerous trophic and growth factors. Recent experiments utilizing the therapeutic properties of MSCs in animal models with a mechanically or chemically injured ocular surface have yielded promising results and demonstrated significant corneal regeneration, improved corneal transparency and a rapid healing process associated with the restoration of vision. The use of autologous MSCs thus represents a promising therapeutic approach and offers hope for patients with severe ocular surface injuries and LSC deficiency. PMID- 23733706 TI - Risk factors associated with nephrocalcinosis in preterm infants. AB - PURPOSE: The objective was to identify the risk factors associated with nephrocalcinosis (NC) in preterm infants. METHODS: NC was diagnosed by renal sonography at 4 or 8 weeks of life, and 10 infants who had findings of type 3 or 4 NC were classified as the NC group. Various clinical and laboratory factors were compared between NC and control groups. RESULTS: Serum sodium (Na) on day 1, serum creatinine and fractional excretion of calcium (FeCa) at 1 and 2 weeks, and serum calcium (Ca), fractional excretion of sodium (FeNa), and urine Na on 2 weeks of life were significantly different between the two groups: the NC group showed significantly higher serum creatinine, FeNa, and FeCa than the control group, suggesting a greater decrease in renal function in the NC group. Differences of the laboratory findings disappeared after 4 weeks of life. The strongest risk factor was birth weight. CONCLUSION: A transient decrease in renal function during the first 2 weeks of life was associated with development of NC in preterm very low-birth-weight infants, and the risk of NC increased as birth weight decreased. PMID- 23733707 TI - Fine structure of the ommatidia of the short-faced scorpionfly Panorpodes kuandianensis (Mecoptera: Panorpodidae). AB - The fine structure of the ommatidia in males of the short-faced scorpionfly Panorpodes kuandianensis was investigated using scanning and transmission electron microscopy. The result shows that the compound eyes of male P. kuandianensis are of the apposition type, consisting of over 1700 ommatidia. Each ommatidium is composed of a laminated cornea, a eucone crystalline cone, eight retinula cells, a pair of primary pigment cells, and a group of 16 secondary pigment cells. Along the optical axis of the ommatidium, seven elongated retinula cells contribute their rhabdomeres to a centrally fused rhabdom, which is in tight contact with the proximal end of the crystalline cone, but smaller than the cone end in diameter. The eighth retinula cell is located above the basal lamina and only contributes its rhabdomere to the proximal part of the rhabdom. The microvilli of the rhabdom show an orthogonally-arranged orientation. The ommatidia of Panorpodidae are more similar to those of Panorpidae than Bittacidae in structure, adding weight to the view that the sister group of Panorpodidae is Panorpidae rather than Bittacidae. PMID- 23733708 TI - Tumor location-dependent skip lateral cervical lymph node metastasis in papillary thyroid cancer. AB - BACKGROUND: Lateral cervical lymph node metastasis without central lymph node (CLN) metastasis is not infrequent in papillary thyroid cancer (PTC). This study was designed to investigate the frequency and pattern of skip metastasis in PTC. METHODS: We reviewed 131 patients who underwent total thyroidectomy with CLN dissection and selective lymph node dissection. Tumor location was classified in 3 areas (upper, middle, and lower third) based on preoperative ultrasonographic findings. RESULTS: All skip metastases occurred in patients whose tumors had been on the upper part of the thyroid (p < .001). Among 9 patients with skip metastasis, level III lymph nodes (66.7%) were the lymph nodes that were most frequently involved in skip metastasis. CONCLUSION: Primary tumors in the upper portion of the thyroid are closely linked to skip metastasis. Careful preoperative evaluation of lateral cervical lymph nodes is suggested when a tumor is in the upper portion. PMID- 23733709 TI - NHC-capped cyclodextrins (ICyDs): insulated metal complexes, commutable multicoordination sphere, and cavity-dependent catalysis. PMID- 23733710 TI - 10-fold liraglutide overdose over 7 months resulted only in minor side-effects. PMID- 23733711 TI - Functional DNA nanostructures for photonic and biomedical applications. AB - DNA nanostructures, especially DNA origami, receive close interest because of the programmable control over their shape and size, precise spatial addressability, easy and high-yield preparation, mechanical flexibility, and biocompatibility. They have been used to organize a variety of nanoscale elements for specific functions, resulting in unprecedented improvements in the field of nanophotonics and nanomedical research. In this review, the discussion focuses on the employment of DNA nanostructures for the precise organization of noble metal nanoparticles to build interesting plasmonic nanoarchitectures, for the fabrication of visualized sensors and for targeted drug delivery. The effects offered by DNA nanostructures are highlighted in the areas of nanoantennas, collective plasmonic behaviors, single-molecule analysis, and cancer-cell targeting or killing. Finally, the challenges in the field of DNA nanotechnology for realistic application are discussed and insights for future directions are provided. PMID- 23733712 TI - Association between exercise and primary incidence of prostate cancer: does race matter? PMID- 23733713 TI - Mechanistic investigations on the photoisomerization reactions of 1,2-dihydro-1,2 azaborine. AB - The mechanisms of the photochemical isomerization reactions were investigated theoretically by using a model system of 1,2-dihydro-1,2-azaborine with the CAS(6,6)/6-311G(d,p) and MP2-CAS-(6,6)/6-311++G(3df,3pd)//CAS(6,6)/6-311G(d,p) methods. Three reaction pathways, which lead to three kinds of photoisomers, have been examined. The structures of the conical intersections, which play a decisive role in such photorearrangements, were obtained. The thermal (or dark) reactions of the reactant species have also been examined by using the same level of theory to assist in providing a qualitative explanation of the reaction pathways. The model investigations suggest that the preferred reaction route for 1,2-dihydro 1,2-azaborine, which leads to the Dewar 1,2-dihydro-1,2-azaborine photoproduct, is as follows: reactant->Franck-Condon region->conical intersection >photoproduct. The results obtained allow a number of predictions to be made. PMID- 23733714 TI - Acute psychosis associated with recreational use of benzofuran 6-(2 aminopropyl)benzofuran (6-APB) and cannabis. AB - INTRODUCTION: There is evidence from around Europe of the availability and use of 6-(2-aminopropyl)benzofuran (6-APB) as a recreational drug. However, there is currently limited information on the acute toxicity of this compound. We describe here a case of acute toxicity associated with recreational use of legal high (6 APB) and cannabis, in which the comprehensive toxicological analysis confirmed the presence of a significant amount of 6-APB together with metabolites of both tetrahydrocannabinol and the synthetic cannabinoid receptor agonist (JWH-122). CASE REPORT: A 21-year-old gentleman with no previous medical and psychiatric history was brought to the emergency department (ED) after he had developed agitation and paranoid behaviour following the use of 6-APB purchased over the Internet. There was no obvious medical cause for his acute psychosis. He required diazepam to control his agitation and was subsequently transferred to a psychiatric hospital for ongoing management of his psychosis. Toxicological screening of a urine sample collected after presentation to the ED detected 6 APB, with an estimated urinary concentration of 2,000 ng/ml; other drugs were also detected, but at lower concentrations including metabolites of the synthetic cannabinoid receptor agonist JWH-122 and tetrahydrocannabinol. CONCLUSION: This is the first case of analytically confirmed acute toxicity associated with the detection of 6-APB which will provide some information on acute toxicity of this drug to help clinicians with the management of such patients and legislative authorities in their consideration for the need of its control. PMID- 23733715 TI - Numerical analysis of non-Newtonian blood flow and wall shear stress in realistic single, double and triple aorto-coronary bypasses. AB - Considering the fact that hemodynamics plays an important role in the patency and overall performance of implanted bypass grafts, this work presents a numerical investigation of pulsatile non-Newtonian blood flow in three different patient specific aorto-coronary bypasses. The three bypass models are distinguished from each other by the number of distal side-to-side and end-to-side anastomoses and denoted as single, double and triple bypasses. The mathematical model in the form of time-dependent nonlinear system of incompressible Navier-Stokes equations is coupled with the Carreau-Yasuda model describing the shear-thinning property of human blood and numerically solved using the principle of the SIMPLE algorithm and cell-centred finite volume method formulated for hybrid unstructured tetrahedral grids. The numerical results computed for non-Newtonian and Newtonian blood flow in the three aorto-coronary bypasses are compared and analysed with emphasis placed on the distribution of cycle-averaged wall shear stress and oscillatory shear index. As shown in this study, the non-Newtonian blood flow in all of the considered bypass models does not significantly differ from the Newtonian one. Our observations further suggest that, especially in the case of sequential grafts, the resulting flow field and shear stimulation are strongly influenced by the diameter of the vessels involved in the bypassing. PMID- 23733716 TI - A new automatic contact point detection algorithm for AFM force curves. AB - A new method for estimating the contact point in AFM force curves, based on a local regression algorithm, is presented. The main advantage of this method is that can be easily implemented as a computer algorithm and used for a fully automatic detection of the contact points in the approach force curves on living cells. The estimated contact points have been compared to those obtained by other published methods, which were applied either for materials with an elastic response to indentation forces or for experiments at high loading rates. We have found that the differences in the values of the contact points estimated with three different methods were not statistically significant and thus the algorithm is reliable. Also, we test the convenience of the algorithm for batch-processing by computing the contact points of a force curve map of 625 (25*25) curves. PMID- 23733717 TI - Management of orocutaneous fistulas using a vacuum-assisted closure system. AB - BACKGROUND: The vacuum-assisted closure (VAC) system has been used to manage complicated wounds. The purpose of this study was to describe a novel technique in using the VAC system for orocutaneous fistulas. METHODS: A retrospective study was performed on 10 patients treated at the National Cancer Centre, Singapore, who developed postoperative orocutaneous fistulas. Hydrogum dental paste was used as a sealant together with the VAC system to close the fistulas. We used either the RENASYS or VAC ATS system with 50 mm Hg to 125 mm Hg continuous suction. RESULTS: The 10 patients developed 11 fistulas. The median age of this cohort was 67 years (range, 33-80 years). Nine patients had successful closure of their fistulas with VAC therapy whereas 1 patient had unsuccessful VAC therapy and required flap reconstruction. The median time to fistula closure was 19 days (range, 6-36 days). The median time to radiotherapy after surgery was 46 days (range, 26-62 days). CONCLUSION: VAC therapy is an effective treatment option for orocutaneous fistulas. PMID- 23733718 TI - Selective biodegradation of naphthenic acids and a probable link between mixture profiles and aquatic toxicity. AB - The toxicity of oil sands process-affected waters (OSPW) from the Athabasca Oil Sands (AOS) in northern Alberta, Canada, is related to a relatively persistent group of dissolved organic acids known as naphthenic acids (NAs). Naphthenic acids are a complex mixture of carboxylic acids, with a general formula C(n)H(2n+Z)O2, where n indicates the carbon number and Z specifies the number of rings in the molecule. The present study is the first to evaluate the potential for the selective biodegradation of NAs and the associated reduction in aquatic toxicity of 2 OSPWs, maintained under 2 different hydraulic retention times and increased nutrient availability (nitrate and phosphate), using flow-through laboratory wetland microcosms over a 52-wk test period. High-performance liquid chromatography/quadrupole time of flight-mass spectrometry analysis was used to track the changes in NA mixture profiles, or "fingerprints," in each treatment over time. Based on first-order degradation kinetics, more rapid degradation was observed for NAs that had lower carbon numbers and fewer degrees of cyclization (NA congeners with carbon numbers 11-16 and Z series -2 to -4; half-lives between 19 and 28 wk). Within the NA mixture fingerprints, the 2 most persistent groups of homologues were also identified (NAs with carbon numbers 17-20 and Z series -6 to -12; half-lives between 37 and 52 wk). The persistence of this group of NAs may aid in explaining the residual chronic toxicological response as measured by the Microtox bioassay (effective concentration for 20%), after the degradation of the more labile fractions of NA mixtures in OSPW. PMID- 23733719 TI - Theoretical considerations on the electroreduction of CO to C2 species on Cu(100) electrodes. PMID- 23733720 TI - A tailored, supportive care intervention using systematic assessment designed for people with inoperable lung cancer: a randomised controlled trial. AB - OBJECTIVE: People with inoperable lung cancer experience higher levels of distress, more unmet needs and symptoms than other cancer patients. There is an urgent need to test innovative approaches to improve psychosocial and symptom outcomes in this group. This study tested the hypothesis that a tailored, multidisciplinary supportive care programme based on systematic needs assessment would reduce perceived unmet needs and distress and improve quality of life. METHODS: A randomised controlled trial design was used. The tailored intervention comprised two sessions at treatment commencement and completion. Sessions included a self-completed needs assessment, active listening, self-care education and communication of unmet psychosocial and symptom needs to the multidisciplinary team for management and referral. Outcomes were assessed with the Needs Assessment for Advanced Lung Cancer Patients, Hospital Anxiety and Depression Scale, Distress Thermometer and European Organization of Research and Treatment of Cancer Quality of Life Q-C30 V2.0. RESULTS: One hundred and eight patients with a diagnosis of inoperable lung or pleural cancer (including mesothelioma) were recruited from a specialist facility before the trial closed prematurely (original target 200). None of the primary contrasts of interest were significant (all p > 0.10), although change score analysis indicated a relative benefit from the intervention for unmet symptom needs at 8 and 12 weeks post assessment (effect size = 0.55 and 0.40, respectively). CONCLUSION: Although a novel approach, the hypothesis that the intervention would benefit perceived unmet needs, psychological morbidity, distress and health-related quality of life was not supported overall. PMID- 23733722 TI - ...and good bye! PMID- 23733723 TI - Hand hygiene - an underestimated issue in endoscopy? PMID- 23733724 TI - Predictive endoscopy: form follows function. PMID- 23733725 TI - Improving hand hygiene adherence in an endoscopy unit. AB - BACKGROUND AND STUDY AIMS: Although hand hygiene is the most important measure in preventing infection transmission in healthcare settings, adherence to recommendations among healthcare workers is low. We implemented and assessed the impact of a World Health Organization-recommended educational intervention to improve hand hygiene adherence at the endoscopy unit of a Brazilian tertiary hospital. PATIENTS AND METHODS: Hand hygiene adherence and techniques used by healthcare workers of the endoscopy unit in the course of their duties were observed unobtrusively by four nurses from the infection control unit. Data were collected at every opportunity for hand hygiene. Evaluations were carried out before and 1 and 10 months after an educational intervention. The intervention consisted of task-orientated training sessions, with live demonstrations of the multitude of opportunities for hand hygiene and the appropriate techniques. In addition to assessing hand hygiene practices, we also evaluated staff knowledge through standardized questionnaires administered before and after the education intervention. Adherence was defined as hand hygiene/disinfection at an opportunity for hand hygiene. RESULTS: Adherence improved from 21.4 % before the intervention to 63.3 % 1 month and 73.5 % 10 months after the educational intervention. Correct answers to the questionnaire were 82.1 % on pre intervention test and 85.7 % on post-intervention test. CONCLUSION: Hand hygiene rates were low before the education intervention and improved significantly after it. Against expectations, adherence to hand hygiene practices had increased further at 10 months after the intervention, reinforcing the intervention's positive impact. PMID- 23733726 TI - Duration of acetowhitening as a novel objective tool for diagnosing high risk neoplasia in Barrett's esophagus: a prospective cohort trial. AB - BACKGROUND AND STUDY AIMS: Acetic acid reacts with Barrett's mucosa to produce acetowhitening which disappears with time. The clinical significance of this is unknown. We aimed to quantify the acetowhitening time, developing an objective tool for diagnosis of neoplasia in Barrett's esophagus. PATIENTS AND METHODS: Prospective cohort study in a tertiary referral center, enrolling patients undergoing surveillance of Barrett's metaplasia or referred with suspected neoplasia. Acetic acid 2.5 % was applied to the mucosa via a spray catheter. Acetowhitening was observed and time to disappearance recorded. Targeted biopsies of any neoplasia and quadrantic 2-cm biopsies of residual Barrett's area were then taken. Histological findings were investigated in relation to duration of acetowhitening. RESULTS: 132 patients were examined. A receiver operating characteristic (ROC) curve was produced for identifying high risk neoplasia according to acetowhitening duration. The area under the curve (AUC) was 0.93 (0.89 - 0.97). Using a threshold of 142 seconds yielded a sensitivity for neoplasia of 98 % (95 % confidence interval [95 %CI] 89 % - 100 %) and specificity of 84 % (74 % - 91 %). The ROC curve for mucosal neoplasia (high grade dysplasia or intramucosal carcinoma) versus deep invasive cancer showed an AUC of 0.786 (0.61 - 0.96); a cutoff of 20 seconds yielded a sensitivity and specificity for invasive cancer of 67 % (35 % - 90 %) and 85 % (69 % - 95 %), respectively. CONCLUSION: The time to disappearance of acetowhitening can serve as a simple but very sensitive tool for the diagnosis of high risk neoplasia in Barrett's esophagus. It can be used to distinguish mucosal neoplasia from deep invasive cancer. PMID- 23733727 TI - Endoscopic closure of esophageal intrathoracic leaks: stent versus endoscopic vacuum-assisted closure, a retrospective analysis. AB - BACKGROUND AND STUDY AIM: Placement of covered self-expanding metal or plastic stents (SEMS or SEPS) is an established method for managing intrathoracic leaks. Recently, endoscopic vacuum-assisted closure (EVAC) has been described as a new effective treatment option. Our aim was to compare stent placement with EVAC for nonsurgical closure of intrathoracic anastomotic leaks. PATIENTS AND METHODS: In a retrospective analysis we were able to identify 39 patients who were treated with SEMS or SEPS and 32 patients who were treated with EVAC for intrathoracic leakage. In addition to successful fistula closure, we analyzed hospital mortality, number of endoscopic interventions, incidence of stenoses, and duration of hospitalization. RESULTS: In a multivariate analysis, successful wound closure was independently associated with EVAC therapy (hazard ratio 2.997, 95 % confidence interval [95 %CI] 1.568 - 5.729; P = 0.001). The overall closure rate was significantly higher in the EVAC group (84.4 %) compared with the SEMS/SEPS group (53.8 %). No difference was found for hospitalization and hospital mortality. We found significantly more strictures in the stent group (28.2 % vs. 9.4 % with EVAC, P < 0,05). CONCLUSIONS: EVAC is an effective endoscopic treatment option for intrathoracic leaks and showed higher effectiveness than stent placement in our cohort. PMID- 23733728 TI - Validation of a live animal model for training in endoscopic hemostasis of upper gastrointestinal bleeding ulcers. AB - BACKGROUND AND STUDY AIMS: The management of upper gastrointestinal bleeding requires training of the endoscopist. We aimed to validate a live animal model of bleeding ulcers for training in endoscopic hemostasis. MATERIALS AND METHODS: Bleeding ulcers were created by repeated grasp-and-snare gastric mucosectomies in pigs rendered "bleeders" by preadministration of clopidogrel, aspirin, and unfractionated heparin. The feasibility and reproducibility of the model (proportion of bleeding ulcers, number of ulcers per animal, and time needed to produce a bleeding ulcer) were prospectively evaluated in six animals. Ten endoscopic experts assessed the similarity of this pig model to human bleeding ulcers (four-point Likert scale). The training capabilities of the model for hemostatic techniques (needle injection, bipolar electrocoagulation, and hemoclipping) were evaluated in 46 fellows (four-point Likert scale). RESULTS: A total of 53 gastric ulcers were created in 6 animals (8.8 +/- 1.5 ulcers/animal). Successful active ulcer bleeding (Forrest Ib) was achieved in 96.2 % of cases. Bleeding was moderate to abundant in 79 % of cases. Ulcerations consistently reached the submucosal layer. The mean (+/- SD) time taken to create a bleeding ulcer was 3.8 +/- 0.6 minutes. Endoscopic experts assessed the realism of the ulcers and bleeding at 3.2 +/- 0.7 and 3.6 +/- 0.7 respectively on a four-point Likert scale. The training significantly improved the endoscopic skills of the 46 fellows (P < 0.0001) in all hemostatic techniques. CONCLUSIONS: The live porcine model of bleeding ulcers was demonstrated to be realistic, reproducible, feasible, time efficient, and easy to perform. It was favorably assessed as an excellent model for training in endoscopic treatment of bleeding ulcers. PMID- 23733729 TI - Animal models for endoscopic training: do we really need them? AB - Gastrointestinal endoscopy currently includes many therapeutic methods that are technically challenging and frequently associated with a significant risk of complications. Several issues such as the limited number of clinical cases and practice in emergency situations, and technical difficulty may limit the opportunity for training, and increased exposure in more relaxed situations would be desirable. Moreover, providing the patient with the best possible standard of care is a must. Animal models are the most easily available simulators. Training in these models has been recommended for several complex techniques, among which hemostasis, endoscopic ultrasound, endoscopic retrograde cholangiopancreatography, and endoscopic submucosal dissection are reviewed here. Ex vivo models are much easier to set up and, from an ethical standpoint, they should be used for the initial step in training whenever possible before moving on to in vivo models. Although simulation with animal models has been the subject of a good number of studies, very few of them have evaluated the impact on clinical outcomes, and clearly more studies are needed. Nevertheless, available evidence does suggest that practicing on animal models has an influence on the learning curve and facilitates the acquisition of skills in the complex endoscopic techniques reviewed. PMID- 23733731 TI - Self-expanding metal stents for treatment of anastomotic complications after colorectal resection. AB - Self-expanding metal stents (SEMS) can be used to treat patients with symptomatic anastomotic complications after colorectal resection. In the present case series, 16 patients with symptomatic anastomotic stricture after colorectal resection were treated with endoscopic placement of SEMS. Seven patients had a "simple" anastomotic stricture and nine patients had a fistula associated with the stricture. The anastomotic fistula healed without evidence of residual stricture or major fecal incontinence in seven of the nine patients. Overall the anastomotic stricture was resolved in 10 of the 16 patients. SEMS placement represents a valid adjunctive to treatment in patients with symptomatic anastomotic complications after colorectal resection for cancer. PMID- 23733732 TI - Radiofrequency ablation and endoscopic mucosal resection in Barrett's esophagus with early neoplasia. Can we avoid complications? PMID- 23733733 TI - Reply to Conio et al. PMID- 23733735 TI - Simultaneous determination of nine anticoagulant rodenticides in soil and water by LC-ESI-MS. AB - A new and sensitive analytical method is presented to determine nine anticoagulant rodenticide (chlorophacinone, bromadiolone, pindone, diphacinone, warfarin, coumatetralyl, brodifacoum, floucomafen, and difenacoum) residues in water and soil samples by LC-ESI-MS. Rodenticides were extracted from soil using a methanol and ammonium formate 30 mM mixture, while ethyl acetate was employed in the water samples. A Gemini 5 MUm C18 column was employed, and a mobile phase comprising a mixture of ammonium formate 30 mM and di-n-butylamine 30 mM in water (pH 3.5), ammonium formate 30 mM and di-n-butylamine 20 mM in water (pH 4.4), ammonium formate 30 mM in water (pH 6.5), and methanol in a gradient elution mode was selected. The method was fully validated and it was found to be selective and precise in terms of linearity and accuracy. Extraction recoveries ranged from 90 to 104% for the compounds studied, while the detection and quantification limits were between 0.09 and 2.2 MUg/kg in soil or 0.08 and 1.7 MUg/L in water. The method was applied to simultaneously measure these compounds in water and soil samples. PMID- 23733736 TI - Axis-oriented, continuous anatase titania films with exposed reactive {100} facets. AB - Homogeneous TiO2 single crystals with high exposure of {100} reactive facets were constructed as a seed monolayer on transparent conductive substrates with the desired orientation of reactive facets. A secondary growth process was subsequently carried out on the monolayer seed film to form an axis-oriented continuous reactive film. Performing secondary growth with different precursors led to optimized conditions for high-performance photoelectrochemical activity of anatase TiO2 films. Experimental techniques such as UV/Vis absorption spectroscopy, X-ray diffraction, high-resolution SEM, and photoelectrochemistry were used to characterize the structural, optical, and photoelectrochemical properties of the as-synthesized films. As a photoanode in a photoelectrochemical cell, the axis-oriented reactive film shows a maximum photocurrent density of 0.3 mA cm(-2), as opposed to 0.075 mA cm(-2) for non-axis-oriented (randomly oriented) TiO2 film. PMID- 23733737 TI - Hydrocolonic sonography: a complete colorectal evaluation technique with preliminary results. AB - BACKGROUND: Hydrocolonic ultrasound (HUS) is a low-cost imaging modality as compared with standard colonoscopy. However, HUS is not popular in the clinical setting due to its somewhat complicated technique of examination and inability to visualize the rectum. We developed a technique to overcome these limitations. METHODS: Ten patients with cancer-suggestive symptoms and 70 asymptomatic patients were included in this study. All patients underwent HUS, with the technique described herein, before colonoscopy on the same day. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated. RESULTS: There were 30 men and 50 women with a mean age of 60.9 +/- 7.3 (SD) years. Thirteen polyps with a size >=0.6 cm (four lesions size 0.6 to 0.9 cm and nine lesions size >=1 cm) were detected by colonoscopy. The detection rate of lesions by HUS was 25% for polyps size 0.6-0.9 cm and 89% for lesions size >=1 cm in size. Three lesions were missed in the sigmoid colon, one in the transverse colon, and one in the rectum. CONCLUSIONS: HUS is a low-cost and noninvasive procedure for colorectal study. This technique has the potential to be used for the detection of colorectal cancer and polyps. PMID- 23733738 TI - Accurate determination of patient-specific boundary conditions in computational vascular hemodynamics using 3D cine phase-contrast MRI. AB - In the patient-specific vascular CFD, determination of the inlet and outlet boundary conditions (BCs) is an important issue for a valid diagnosis. The 3D cine phase-contrast MRI (4D Flow) velocimetry is promising for this issue; yet, its measured velocities contain relatively large error and are not admissible as the BCs without any correction. This paper proposes a novel correction method for determining the BCs accurately using the 4D Flow velocimetry. First, we reveal that the error of the velocity measured by the 4D Flow at each measurement voxel is large but is distributed symmetrically. Secondly, our method pays attention to the incompressibility of the blood and the fact that the volume flow rate (VFR) in each vessel is constant on any cross sections. We reveal that the average of the cross-sectional VFRs integrated from many measurement voxel in each vessel is accurate despite the large error. Finally, we propose the novel correction method, which applies a smoothing to the measured velocities on each inlet or outlet boundary with a low-pass filter and then corrects them with the VFR. The results of the several phantom studies are presented to validate the accuracy of our method. A demonstrative analysis for an actual aneurysm is also presented to show the feasibility and effectiveness of our method. PMID- 23733739 TI - Treatment of paranoid personality disorder with cognitive analytic therapy: a mixed methods single case experimental design. AB - Paranoid personality disorder (PPD) presents as chronic and widespread interpersonal distrust, whereby the actions of others are interpreted as malevolent and malicious. This research details the assessment, formulation and treatment of a case of PPD within a 24-session contract of cognitive analytic therapy (CAT). The outcome methodology was an A/B with extended follow-up single case experimental design (SCED). The SCED was supplemented with qualitative patient interviewing via the Change Interview regarding their experience of CAT, whether change had taken place and detailing of any identified change mechanisms. Quantitative results show that five out of the six daily rated paranoia target complaint measures were extinguished during the treatment phase. Qualitatively, the patient attributed change to the therapy conducted. The results suggest that CAT was an effective intervention in this case of PPD and are discussed in terms of identified methodological shortcomings, treatment implications and the potential for generating a convincing evidence base for the psychotherapy of PPD. KEY PRACTITIONER MESSAGE: Narrative reformulation using a CAT model offers a key opportunity for the patient to achieve a new understanding of their paranoia. Psychotherapy for PPD requires a cognitive component, within a boundaried and relational therapy, that is able to reflect on paranoid enactments and ruptures within the therapeutic relationship.There is a large role for clinician researchers in developing a PPD outcome evidence base. PMID- 23733740 TI - Endoscope-assisted frenotomy approach to median upper neck masses: clinical outcomes and safety (from a phase II clinical trial). AB - BACKGROUND: An endoscope-assisted frenotomy approach (EFA) to resection of the median upper neck mass has been introduced to clinical practice. However, its technical feasibility, indications, and safety have not been fully studied. Here, we report the results of a prospective phase II clinical trial to evaluate the clinical outcomes. METHODS: Twenty patients were enrolled in this trial. The masses were divided into 3 subtypes. We implemented EFA to remove the masses after receiving informed patient consent. We evaluated the clinical outcomes and complications related to this procedure for more than a 2-year period. RESULTS: EFA successfully removed the masses in all cases without any injuries to adjacent nerves or ducts. During the more than 2-year follow-up period, recurrence or revision surgeries were not required. CONCLUSION: EFA can be a very effective and safe approach for median upper neck masses, and can also lead to excellent cosmetic and functional results. PMID- 23733741 TI - Red flags for persistent or worsening anxiety and depression after an acute cardiac event: a 6-month longitudinal study in regional and rural Australia. AB - BACKGROUND: While early symptoms of anxiety and depression resolve for many patients soon after an acute cardiac event, the persistence or worsening of symptoms indicates increased mortality risk. It is therefore important to identify the predictors, or red flags, of persistent or worsening anxiety and depression symptoms. Most previous research has focussed on metropolitan patients, hence the need for studies of regional and rural dwellers. METHOD: In this study, 160 cardiac patients consecutively admitted to two hospitals in regional Victoria, Australia, were interviewed in hospital and 2 and 6 months after discharge. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Growth mixture modelling was used to identify the trajectories of anxiety and depression over the 6 months after the acute event, and post-hoc tests identified predictors of persistent or worsening symptoms. RESULTS: For both anxiety and depression, three common symptom trajectories were identified. Inhospital anxiety symptoms tended to persist over time, whereas inhospital depression symptoms resolved for some patients and worsened for others. A mental health history, younger age, smoking, financial stress, poor self-rated health, and social isolation were red flags for persistent anxiety and worsening depression. Additionally, diabetes, and other comorbidities were red flags for persistent anxiety. CONCLUSIONS: The results highlight several potential red flags for increased risk of persistent anxiety or worsening depressive symptoms after a cardiac event, including demographic, psychosocial, and behavioural indicators. These red flags could assist with identification of at-risk patients on admission to or discharge from hospital, thereby enabling targeting of interventions. PMID- 23733742 TI - Implications of changing definitions of myocardial infarction on number of events and all-cause mortality: the WHO 1979, ESC/ACC 2000, AHA 2003, and Universal 2007 definitions revisited. AB - PURPOSE: To analyse the impact of four different definitions of acute myocardial infarction (AMI) on number of events and all-cause mortality after AMI. METHODS: We retrospectively examined number of AMI events and mortality according to four different definitions of AMI, among 1494 patients admitted to Haukeland University Hospital in Norway from March 2002 to February 2003. Eligible for analysis were 815 patients with a discharge diagnosis of an AMI, and 679 patients without any AMI discharge diagnosis but with elevated cardiac troponin I level during admission. RESULTS: Applying the WHO 1979 definition resulted in 566 definite AMIs among the 1494 patients and was used as reference. According to the other definitions, there were 455 (-20%) definite AMIs by the original troponin 'rise and fall' version of the ESC/ACC 2000 definition, 729 (+29%) by the troponin 'rise or fall' interpretation of the ESC/ACC 2000 definition, 761 (+34%) by the AHA 2003 definition, and 743 (+31%) by the Universal 2007 definition (all p < 0.001). The 28-day, 1-year, 5-year, and 8-year mortality for definite AMI applying the WHO 1979 definition was 12, 19, 32, and 40%, whereas applying the Universal 2007 definition resulted in a mortality of 14, 21, 35, and 43%, respectively. CONCLUSIONS: The change of definitions of AMI during the last decades has had a significant impact on the number of AMI events and a moderate impact on the AMI mortality among hospitalized patients. PMID- 23733743 TI - Evaluation of a newly designed shirt-based ECG and breathing sensor for home based training as part of cardiac rehabilitation for coronary artery disease. AB - BACKGROUND: Participation in phase-III cardiac rehabilitation (CR) remains low but adherence could potentially be improved with supervised home-based CR. New technological approaches are needed to provide sufficient supervision with respect to safety and performance of individual exercise programmes. DESIGN: The newly designed closed-loop tool, HeartCycle's guided exercise (GEX) system, will support professionals and patients during exercise-based CR. Patients wear a dedicated shirt with incorporated wireless sensors, and ECG, heart rate (HR), breathing frequency (BF), and activity are monitored during exercise. This information is streamed live to a mobile device (PDA) that processes these parameters. METHODS: A phase-I study was performed to evaluate feasibility, function, and reliability of this GEX device and compare it to conventional cardiac exercise testing (CPX, spiroergometry) in 50 patients (seven women, mean +/- SD age 69 +/- 9 years, body mass index 26 +/- 3 kg/m(2), ejection fraction 58 +/- 10%). ECG, HR, and BF were monitored using standard equipment and the GEX device simultaneously. Furthermore, HR recorded on the PDA was compared with CPX measurements. RESULTS: The fit of the shirt and the sensor was good. No technical problems were encountered. All occurring arrhythmia were reliably detected. There was an acceptable comparability between HR on the GEX device vs. CPX, a good comparability between HR on the PDA vs. CPX, and a moderate comparability between BF on the GEX device vs. CPX CONCLUSIONS: Comparability between CPX and the GEX device was acceptable for HR measurement and moderate for BF; arrhythmias were reliably detected. HR processing and display on the PDA was even better comparable. The whole system seems suitable for monitoring home-based CR. Further studies are now needed to implement training prescription to facilitate individual exercise. PMID- 23733744 TI - Incidence of subclinical atherosclerosis as assessed with electron beam CT in adults <=45 years old. PMID- 23733745 TI - Fast ultrasound-assisted extraction combined with LC-MS/MS of perfluorinated compounds in manure. AB - A fast analytical method for the determination of perfluorinated compounds in poultry manure by LC-MS/MS was developed. The extraction was carried out by ultrasound-assisted extraction of 1 g of sample, during 2 * 15 min using low volume (5.5 mL) of a mixture of methanol and acetonitrile. An efficient extraction of perfluoroalkyl carboxylates, perfluoroalkyl sulfonates, and perfluoroalkyl sulfonamides from poultry manure was obtained with recoveries higher than 81%. The cleanup of extracts was carried out by dispersive SPE. The validation of the proposed method showed the suitability of this procedure to determine perfluorinated compounds in poultry manure with detection limits in the range of 0.44-2.12 ng/g, depending on the target compound. In comparison with previously published methods, the miniaturization of the sample preparation method with ultrasound-assisted extraction together with the use of a core-shell column permit a lower consumption of organic solvents and a fast analysis of perfluorinated compounds. Manure samples obtained from Spanish commercial farms were analyzed and low perfluorinated compounds levels were found, which may be originated by dietary or environmental exposure. The highest concentrations measured corresponded to the perfluoroalkyl sulfonates, which varied from 8.2 to 35.9 ng/g. PMID- 23733746 TI - Photocatalytic hydrogen evolution with a self-assembling reductant-sensitizer catalyst system. AB - A noble-metal-free system for photochemical hydrogen production is described, based on ascorbic acid as sacrificial donor, aluminium pyridyl porphyrin as photosensitizer, and cobaloxime as catalyst. Although the aluminium porphyrin platform has docking sites for both the sacrificial donor and the catalyst, the resulting associated species are essentially inactive because of fast unimolecular reversible electron-transfer quenching. Rather, the photochemically active species is the fraction of sensitizer present, in the aqueous/organic solvent used for hydrogen evolution, as free species. As shown by nanosecond laser flash photolysis experiments, its long-lived triplet state reacts bimolecularly with the ascorbate donor, and the reduced sensitizer thus formed, subsequently reacts with the cobaloxime catalyst, thereby triggering the hydrogen evolution process. The performance is good, particularly in terms of turnover frequencies (TOF=10.8 or 3.6 min(-1), relative to the sensitizer or the catalyst, respectively) and the quantum yield (Phi=4.6%, that is, 9.2% of maximum possible value). At high sacrificial donor concentration, the maximum turnover number (TON=352 or 117, relative to the sensitizer or the catalyst, respectively) is eventually limited by hydrogenation of both sensitizer (chlorin formation) and catalyst. PMID- 23733747 TI - Optical rhinometry in nonallergic irritant rhinitis: a capsaicin challenge study. AB - BACKGROUND: Patients with nonallergic irritant rhinitis (NAIR) have symptoms of nasal congestion, nasal irritation, rhinorrhea, and sneezing in response to nasal irritants. We currently have no reliable objective means to quantify these patients' subjective symptoms. In this study, we used the transient receptor potential vanilloid receptor (TRPV1) receptor agonist, capsaicin, as an intranasal challenge while comparing the changes in blood flow with optical rhinometry between subjects with NAIR and healthy controls (HCs). METHODS: Six HCs and 6 NAIR subjects were challenged intranasally with saline solution followed by increasing concentrations of capsaicin (0.005 mM, 0.05 mM, and 0.5 mM) at 15-minute intervals. We recorded maximum optical density (OD) and numeric analog scores (NAS) for nasal congestion, nasal irritation, rhinorrhea, and sneezing for each subject after each challenge. Correlations between NAS and maximum OD were calculated. RESULTS: Maximum OD increased with increasing concentrations of intranasal capsaicin in NAIR subjects. There were significant differences in maximum OD obtained for 0.05 mM and 0.5 mM capsaicin between NAIR subjects and HCs. Significant differences were found in the NAS for nasal irritation at 0.005 mM, 0.05 mM, and 0.5 mM, and nasal congestion at 0.5 mM. Correlation between maximum OD and mean NAS was most significant for 0.05 mM capsaicin. CONCLUSION: Optical rhinometry with intranasal capsaicin challenge could prove a viable option in the diagnosis of NAIR. Further studies will investigate its use to monitor a patient's response to pharmacologic therapy and provide further information about the underlying mechanisms of NAIR. PMID- 23733748 TI - Cancer- and endotoxin-induced cachexia require intact glucocorticoid signaling in skeletal muscle. AB - Cachexia is a wasting condition defined by skeletal muscle atrophy in the setting of systemic inflammation. To explore the site at which inflammatory mediators act to produce atrophy in vivo, we utilized mice with a conditional deletion of the inflammatory adaptor protein myeloid differentiation factor 88 (MyD88). Although whole-body MyD88-knockout (wbMyD88KO) mice resist skeletal muscle atrophy in response to LPS, muscle-specific deletion of MyD88 is not protective. Furthermore, selective reexpression of MyD88 in the muscle of wbMyD88KO mice via electroporation fails to restore atrophy gene induction by LPS. To evaluate the role of glucocorticoids as the inflammation-induced mediator of atrophy in vivo, we generated mice with targeted deletion of the glucocorticoid receptor in muscle (mGRKO mice). Muscle-specific deletion of the glucocorticoid receptor affords a 71% protection against LPS-induced atrophy compared to control animals. Furthermore, mGRKO mice exhibit 77% less skeletal muscle atrophy than control animals in response to tumor growth. These data demonstrate that glucocorticoids are a major determinant of inflammation-induced atrophy in vivo and play a critical role in the pathogenesis of endotoxemic and cancer cachexia. PMID- 23733749 TI - Sensitization of gram-negative bacteria by targeting the membrane potential. AB - Toward generating new tools for fighting multidrug-resistant (MDR) bacteria, we assessed the ability of a membrane-active peptide to sensitize gram-negative bacteria to various antibiotics. The mechanism for affecting inner and/or outer membrane functions was assessed by complementary biophysical methods (SPR, DSC, ITC). The implication of efflux pumps was examined using Acr-AB mutants, as tested with representative antibiotics, host defense peptides, and synthetic mimics. The ability to affect disease course systemically was compared for a single therapy and combination therapy, using the mouse thigh-infection model. The data show that potent antibiotic action can be provoked in vitro and in vivo, by a treatment combining two antibacterial compounds whose individual inefficiency against gram-negative bacteria stems from their efflux. Thus, at subminimal inhibitory concentrations, the lipopeptide-like sequence, N(alpha)(omega7)dodecenoyl-lysyl-[lysyl-aminododecanoyl-lysyl]-amide (designated C12(omega7)K-beta12), has, nonetheless, rapidly achieved a transient membrane depolarization, which deprived bacteria of the proton-motive force required for active efflux. Consequently, bacteria became significantly sensitive to intracellular targeting antibiotics. Collectively, these findings suggest a potentially useful approach for expanding the antibiotics sensitivity spectrum of MDR gram-negative bacteria to include efflux substrates. PMID- 23733750 TI - Patient-derived tumor xenografts: transforming clinical samples into mouse models. AB - Tumor graft models (also known as patient-derived xenografts or PDX) are based on the transfer of primary tumors directly from the patient into an immunodeficient mouse. Because PDX mice are derived from human tumors, they offer a tool for developing anticancer therapies and personalized medicine for patients with cancer. In addition, these models can be used to study metastasis and tumor genetic evolution. This review examines the development, challenges, and broad use of these attractive preclinical models. PMID- 23733751 TI - Loss of p120-catenin induces metastatic progression of breast cancer by inducing anoikis resistance and augmenting growth factor receptor signaling. AB - Metastatic breast cancer remains the chief cause of cancer-related death among women in the Western world. Although loss of cell-cell adhesion is key to breast cancer progression, little is known about the underlying mechanisms that drive tumor invasion and metastasis. Here, we show that somatic loss of p120-catenin (p120) in a conditional mouse model of noninvasive mammary carcinoma results in formation of stromal-dense tumors that resemble human metaplastic breast cancer and metastasize to lungs and lymph nodes. Loss of p120 in anchorage-dependent breast cancer cell lines strongly promoted anoikis resistance through hypersensitization of growth factor receptor (GFR) signaling. Interestingly, p120 deletion also induced secretion of inflammatory cytokines, a feature that likely underlies the formation of the prometastatic microenvironment in p120-negative mammary carcinomas. Our results establish a preclinical platform to develop tailored intervention regimens that target GFR signals to treat p120-negative metastatic breast cancers. PMID- 23733752 TI - PLZF confers effector functions to donor T cells that preserve graft-versus-tumor effects while attenuating GVHD. AB - Efforts to limit GVHD mediated by alloreactive donor T cells after allogeneic bone marrow transplantation are limited by a concomitant decrease in graft-versus tumor (GVT) activity and increased possibilities of tumor relapse. Using a novel approach, we adoptively transferred conventional T cells expressing the transcription factor promyelocytic leukemia zinc finger (PLZF), which confers effector properties resembling invariant natural killer T cells, such as copious production of cytokines under suboptimal stimulation. PLZF expression in T-cell allografts attenuates expansion of alloreactive T cells, leading to lower GVHD. Intact alloreactivity-driven antitumor cytokine responses result in preserved GVT effects, leading to improved survival. Our findings suggest that therapy with PLZF-overexpressing T cells would result in overall improved outcomes due to less GVHD and intact GVT effects. PMID- 23733754 TI - Role of expression profiling in carcinoma of unknown primary remains unknown. PMID- 23733753 TI - Feasibility of long-term patient self-reporting of toxicities from home via the Internet during routine chemotherapy. AB - PURPOSE: Patient-reported outcomes are increasingly used in routine outpatient cancer care to guide clinical decisions and enhance communication. Prior evidence suggests good patient compliance with reporting at scheduled clinic visits, but there is limited evidence about compliance with long-term longitudinal reporting between visits. PATIENTS AND METHODS: Patients receiving chemotherapy for lung, gynecologic, genitourinary, or breast cancer at a tertiary cancer center, with access to a home computer and prior e-mail experience, were asked to self-report seven symptomatic toxicities via the Web between visits. E-mail reminders were sent to participants weekly; patient-reported high-grade toxicities triggered e mail alerts to nurses; printed reports were provided to oncologists at visits. A priori threshold criteria were set to determine if this data collection approach merited further development based on monthly (>= 75% participants reporting at least once per month on average) and weekly compliance rates (60% at least once per week). RESULTS: Between September 2006 and November 2010, 286 patients were enrolled (64% were women; 88% were white; median age, 58 years). Mean follow-up was 34 weeks (range, 2 to 214). On average, monthly compliance was 83%, and weekly compliance was 62%, without attrition until the month before death. Greater compliance was associated with older age and higher education but not with performance status. Compliance was greatest during the initial 12 weeks. Symptomatic illness and technical problems were rarely barriers to compliance. CONCLUSION: Monthly compliance with home Web reporting was high, but weekly compliance was lower, warranting strategies to enhance compliance in routine care settings. PMID- 23733755 TI - Pregnancy during or after breast cancer diagnosis: what do we know and what do we need to know? PMID- 23733756 TI - Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. AB - PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is common and leads to suboptimal treatment. Acetyl-L-carnitine (ALC) is a natural compound involved in neuronal protection. Studies have suggested ALC may be effective for the prevention and treatment of CIPN. PATIENTS AND METHODS: A 24-week randomized double-blind trial comparing ALC (3,000 mg per day) with placebo in women undergoing adjuvant taxane-based chemotherapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the Functional Assessment of Cancer Therapy (FACT) -Taxane scale at 12 weeks. Secondary objectives included changes in 24 week end points, functional status (FACT-Trial Outcome Index [TOI]), fatigue (Functional Assessment of Chronic Illness Therapy [FACIT] -Fatigue), and NTX grade. RESULTS: A total of 409 patients were evaluable (208 received ALC; 201, placebo). In a multivariate linear regression, week-12 scores were 0.9 points lower (more CIPN) with ALC than placebo (95% CI, -2.2 to 0.4; P = .17), whereas week-24 scores were 1.8 points lower with ALC (95% CI, -3.2 to -0.4; P = .01). Patients receiving ALC were more likely to have a > 5-point decrease in FACT-NTX scores (38% v 28%; P = .05), and FACT-TOI scores were 3.5 points lower with ALC (P = .03). Grade 3 to 4 neurotoxicity was more frequent in the ALC arm (eight v one). No differences between arms were observed for FACIT-Fatigue or other toxicities. Serum carnitine level increased with ALC but remained stable with placebo. CONCLUSION: There was no evidence that ALC affected CIPN at 12 weeks; however, ALC significantly increased CIPN by 24 weeks. This is the first study to our knowledge showing that a nutritional supplement increased CIPN. Patients should be discouraged from using supplements without proven efficacy. PMID- 23733757 TI - Population-based molecular screening for Lynch syndrome: implications for personalized medicine. AB - PURPOSE: Molecular screening techniques are available to identify hereditary Lynch syndrome in people with newly diagnosed colorectal cancer (CRC). We aimed to determine whether decisions of patients or clinicians reduced detection of Lynch syndrome. PATIENTS AND METHODS: A prospective cohort of 245 consecutive individuals with mismatch repair-deficient CRC recruited from a population-based molecular screening program of all incident patient cases of CRC in a health care region of 1.2 million inhabitants. All incident CRCs were analyzed for mismatch repair protein loss, supported by BRAF mutation and microsatellite instability testing. Advice regarding referral for germline testing was provided to treating surgeons. RESULTS: The mean age of patients was 72.5 +/- standard deviation of 12 years; 64% were women; 65% had BRAF-mutant cancers. Consent for germline testing was received from 194 patients (79%): 120 with low and 74 with high likelihood of Lynch syndrome based on tumor molecular profile. Of patients who consented, 143 provided samples for germline analysis, with 12 of 143 showing a mutation (8.4%; 95% CI, 4.4% to 14.2%). Among the 102 patients who chose not to provide a sample or did not consent, an estimated 5.3 of 102 had germline mutations (5.2%; 95% CI, 2.0% to 17.5%). CONCLUSION: A universal screening strategy for Lynch syndrome is potentially effective because the overall estimate of germline mutations was 17.3 of 245 patient cases (7.1%; 95% CI, 2.8% to 18.2%). However, the true value of screening is likely to be greatly limited by the decisions and circumstances of patients in taking up germline testing. PMID- 23733758 TI - Dramatic response induced by vemurafenib in a BRAF V600E-mutated lung adenocarcinoma. PMID- 23733759 TI - Fatal necrosis of the hand. PMID- 23733760 TI - Methotrexate-induced lymphoproliferative disease: Epstein-Barr virus-associated lymphomatoid granulomatosis. PMID- 23733762 TI - Does quality of life supplant survival in patients with brain metastasis? PMID- 23733761 TI - Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. AB - PURPOSE: Epidermal growth factor receptor is overexpressed in metastatic triple negative breast cancers (mTNBCs), an aggressive subtype of breast cancer. Our randomized phase II study investigated cisplatin with or without cetuximab in this setting. PATIENTS AND METHODS: Patients who had received no more than one previous chemotherapy regimen were randomly assigned on a 2:1 schedule to receive no more than six cycles of cisplatin plus cetuximab or cisplatin alone. Patients receiving cisplatin alone could switch to cisplatin plus cetuximab or cetuximab alone on disease progression. The primary end point was overall response rate (ORR). Secondary end points studied included progression-free survival (PFS), overall survival (OS), and safety profiles. Analyses included a significance level of alpha = .10 with no adjustments for multiplicity. RESULTS: The full analysis set comprised 115 patients receiving cisplatin plus cetuximab and 58 receiving cisplatin alone; 31 patients whose disease progressed on cisplatin alone switched to cetuximab-containing therapy. The ORR was 20% (95% CI, 13 to 29) with cisplatin plus cetuximab and 10% (95% CI, 4 to 21) with cisplatin alone (odds ratio, 2.13; 95% CI, 0.81 to 5.59; P = .11). Cisplatin plus cetuximab resulted in longer PFS compared with cisplatin alone (median, 3.7 v 1.5 months; hazard ratio [HR], 0.67; 95% CI, 0.47 to 0.97; P = .032). Corresponding median OS was 12.9 versus 9.4 months (HR, 0.82; 95% CI, 0.56 to 1.20; P = .31). Common grade 3/4 adverse events included acne-like rash, neutropenia, and fatigue. CONCLUSION: While the primary study end point was not met, adding cetuximab to cisplatin doubled the ORR and appeared to prolong PFS and OS, warranting further investigation in mTNBC. PMID- 23733763 TI - Rapid response to vemurafenib in a heavily pretreated patient with hairy cell leukemia and a BRAF mutation. PMID- 23733764 TI - Recurrent aleukemic leukemia cutis in a patient with pre-B-cell acute lymphoblastic leukemia. PMID- 23733765 TI - Impact of age on the efficacy of newer adjuvant therapies in patients with stage II/III colon cancer: findings from the ACCENT database. AB - PURPOSE: Prior studies have suggested that patients with stage II/III colon cancer receive similar benefit from intravenous (IV) fluoropyrimidine adjuvant therapy regardless of age. Combination regimens and oral fluorouracil (FU) therapy are now standard. We examined the impact of age on colon cancer recurrence and mortality after adjuvant therapy with these newer options. PATIENTS AND METHODS: We analyzed 11,953 patients age < 70 and 2,575 age >= 70 years from seven adjuvant therapy trials comparing IV FU with oral fluoropyrimidines (capecitabine, uracil, or tegafur) or combinations of fluoropyrimidines with oxaliplatin or irinotecan in stage II/III colon cancer. End points were disease-free survival (DFS), overall survival (OS), and time to recurrence (TTR). RESULTS: In three studies comparing oxaliplatin-based chemotherapy with IV FU, statistically significant interactions were not observed between treatment arm and age (P interaction = .09 for DFS, .05 for OS, and .36 for TTR), although the stratified point estimates suggested limited benefit from the addition of oxaliplatin in elderly patients (DFS hazard ratio [HR], 0.94; 95% CI, 0.78 to 1.13; OS HR, 1.04; 95% CI, 0.85 to 1.27). No significant interactions by age were detected with oral fluoropyrimidine therapy compared with IV FU; noninferiority was supported in both age populations. CONCLUSION: Patients age >= 70 years seemed to experience reduced benefit from adding oxaliplatin to fluoropyrimidines in the adjuvant setting, although statistically, there was not a significant effect modification by age, whereas oral fluoropyrimidines retained their efficacy. PMID- 23733766 TI - Radiofrequency ablation with or without transcatheter arterial chemoembolization. PMID- 23733767 TI - Randomized open-label phase II study of decitabine in patients with low- or intermediate-risk myelodysplastic syndromes. AB - PURPOSE: This open-label, randomized phase II trial assessed efficacy and tolerability of two low-dose regimens of subcutaneous (SC) decitabine in patients with low- or intermediate-1-risk myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Patients received decitabine 20 mg/m(2) SC per day for 3 consecutive days on days 1, 2, and 3 every 28 days (schedule A) or 20 mg/m(2) SC per day once every 7 days on days 1, 8, and 15 every 28 days (schedule B) for up to 1 year. Primary efficacy end point was overall improvement rate (OIR: complete remission [CR], partial remission [PR], marrow CR [mCR], or hematologic improvement [HI]). Secondary end points were HI, transfusion independence, cytogenetic response, overall survival (OS), and time to acute myeloid leukemia or death. RESULTS: Efficacy and safety populations were identical: schedule A, n = 43; schedule B, n = 22. Median time from MDS diagnosis to treatment was 3.6 months; 89% had de novo MDS. The trial was terminated early on achievement of protocol-defined OIR superiority of schedule A over schedule B; OIR was 23% for schedule A (seven CRs, three HIs) and 23% for schedule B (one mCR, one PR, three HIs). No differences were observed in secondary end points. Median OS was not reached; approximately 70% of patients were alive at 500 days. Patients in schedule A (67%) and schedule B (59%) were RBC/platelet independent on study. The most frequent drug-related adverse events overall were neutropenia (28% v 36%), anemia (23% v 18%), and thrombocytopenia (16% v 32%). CONCLUSION: In this phase II study, low-dose decitabine showed promising results in patients with low- or intermediate-1-risk MDS. PMID- 23733768 TI - Underuse of hospice care by Medicaid-insured patients with stage IV lung cancer in New York and California. AB - PURPOSE: Medicare patients with advanced cancer have low rates of hospice use. We sought to evaluate hospice use among patients in Medicaid, which insures younger and indigent patients, relative to those in Medicare. PATIENTS AND METHODS: Using linked patient-level data from California (CA) and New York (NY) state cancer registries, state Medicaid programs, NY Medicare, and CA Surveillance, Epidemiology, and End Results-Medicare data, we identified 4,797 CA Medicaid patients and 4,001 NY Medicaid patients ages 21 to 64 years, as well as 27,416 CA Medicare patients and 16,496 NY Medicare patients ages >= 65 years who were diagnosed with stage IV lung cancer between 2002 and 2006. We evaluated hospice use, timing of enrollment, and location of death (inpatient hospice; long-term care facility or skilled nursing facility; acute care facility; home with hospice; or home without hospice). We used multiple logistic regressions to evaluate clinical and sociodemographic factors associated with hospice use. RESULTS: Although 53% (CA) and 44% (NY) of Medicare patients ages >= 65 years used hospice, fewer than one third of Medicaid-insured patients ages 21 to 64 years enrolled in hospice after a diagnosis of stage IV lung cancer (CA, 32%; NY, 24%). A minority of Medicaid patient deaths (CA, 19%; NY, 14%) occurred at home with hospice. Most Medicaid patient deaths were either in acute-care facilities (CA, 28%; NY, 36%) or at home without hospice (CA, 39%; NY, 41%). Patient race/ethnicity was not associated with hospice use among Medicaid patients. CONCLUSION: Given low rates of hospice use among Medicaid enrollees and considerable evidence of suffering at the end of life, opportunities to improve palliative care delivery should be prioritized. PMID- 23733770 TI - Biased view of the role of site-specific therapy in carcinoma of unknown primary. PMID- 23733769 TI - Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors. AB - PURPOSE: The incidence of pediatric adrenocortical tumors (ACTs) is remarkably high in southern Brazil, where more than 90% of patients carry the germline TP53 mutation R337H. We assessed the impact of early detection of this mutation and of surveillance of carriers. PATIENTS AND METHODS: Free newborn screening was offered at all hospitals in the state of Parana. Parents of positive newborns were tested, and relatives in the carrier line were offered screening. Positive newborns and their relatives age < 15 years were offered surveillance (periodic clinical, laboratory, and ultrasound evaluations). ACTs detected by imaging were surgically resected. RESULTS: Of 180,000 newborns offered screening, 171,649 were screened, and 461 (0.27%) were carriers. As of April 2012, ACTs had been diagnosed in 11 of these carriers but in only two neonatally screened noncarriers (P < .001); six patient cases were identified among 228 carrier relatives age < 15 years (total, 19 ACTs). Surveillance participants included 347 (49.6%) of 699 carriers. Tumors were smaller in surveillance participants (P < .001) and more advanced in nonparticipants (four with stage III disease; two deaths). Neonatally screened carriers also had neuroblastoma (n = 1), glioblastoma multiforme (n = 1), choroid plexus carcinoma (n = 2), and Burkitt lymphoma (n = 1). Cancer histories and pedigrees were obtained for 353 families that included 1,704 identified carriers. ACTs were the most frequent cancer among carrier children (n = 48). CONCLUSION: These findings establish the prevalence of the TP53 R337H mutation in Parana state and the penetrance of ACTs among carriers. Importantly, screening and surveillance of heterozygous carriers are effective in detecting ACTs when readily curable. PMID- 23733772 TI - Lymphocytic vasculitis of the uterus in a patient with melanoma receiving ipilimumab. PMID- 23733773 TI - Vanishing bile duct syndrome arising in a patient with T-cell-rich large B-cell lymphoma. PMID- 23733774 TI - Posterior reversible encephalopathy syndrome: more than meets the eye. PMID- 23733775 TI - Progression-free survival benefit or health-related quality-of-life advantage: which one to choose? PMID- 23733771 TI - Type I and II endometrial cancers: have they different risk factors? AB - PURPOSE: Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. PATIENTS AND METHODS: Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. RESULTS: Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m(2) increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (P heterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar. CONCLUSION: The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed. PMID- 23733776 TI - Clinical benefit and potential pitfalls in combining thermal ablation and radiation therapy to treat liver metastases. PMID- 23733777 TI - Neoadjuvant versus induction chemotherapy: more than semantics. PMID- 23733778 TI - Somatostatin analogs for malignant bowel obstruction resulting from peritoneal carcinomatosis. PMID- 23733779 TI - Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study. AB - PURPOSE: Adding taxanes to anthracycline-based adjuvant therapy improves survival outcomes of patients with node-positive breast cancer (BC). Currently, however, most patients with BC are node negative at diagnosis. The only pure node-negative study (Spanish Breast Cancer Research Group 9805) reported so far showed a docetaxel benefit but significant toxicity. Here we tested the efficacy and safety of weekly paclitaxel (wP) in node-negative patients, which is yet to be established. PATIENTS AND METHODS: Patients with BC having T1-T3/N0 tumors and at least one high-risk factor for recurrence (according to St. Gallen 1998 criteria) were eligible. After primary surgery, 1,925 patients were randomly assigned to receive fluorouracil, doxorubicin, and cyclophosphamide (FAC) * 6 or FAC * 4 followed by wP * 8 (FAC-wP). The primary end point was disease-free survival (DFS) after a median follow-up of 5 years. Secondary end points included toxicity and overall survival. RESULTS: After a median follow-up of 63.3 months, 93% and 90.3% of patients receiving FAC-wP or FAC regimens, respectively, remained disease free (hazard ratio [HR], 0.73; 95% CI, 0.54 to 0.99; log-rank P = .04). Thirty-one patients receiving FAC-wP versus 40 patients receiving FAC died (one and seven from cardiovascular diseases, respectively; HR, 0.79; 95% CI, 0.49 to 1.26; log-rank P = .31). The most relevant grade 3 and 4 adverse events in the FAC-wP versus the FAC arm were febrile neutropenia (2.7% v 3.6%), fatigue (7.9% v 3.4%), and sensory neuropathy (5.5% v 0%). CONCLUSION: For patients with high risk node-negative BC, the adjuvant FAC-wP regimen was associated with a small but significant improvement in DFS compared with FAC therapy, in addition to manageable toxicity, especially regarding long-term cardiac effects. PMID- 23733780 TI - Non-Hodgkin lymphoma mimicking pancreatic adenocarcinoma and peritoneal carcinomatosis. PMID- 23733781 TI - Minimal residual disease assessed by multiparameter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study. AB - PURPOSE: To investigate the prognostic value of minimal residual disease (MRD) assessment in patients with multiple myeloma treated in the MRC (Medical Research Council) Myeloma IX trial. PATIENTS AND METHODS: Multiparameter flow cytometry (MFC) was used to assess MRD after induction therapy (n = 378) and at day 100 after autologous stem-cell transplantation (ASCT; n = 397) in intensive-pathway patients and at the end of induction therapy in non-intensive-pathway patients (n = 245). RESULTS: In intensive-pathway patients, absence of MRD at day 100 after ASCT was highly predictive of a favorable outcome (PFS, P < .001; OS, P = .0183). This outcome advantage was demonstrable in patients with favorable and adverse cytogenetics (PFS, P = .014 and P < .001, respectively) and in patients achieving immunofixation-negative complete response (CR; PFS, P = .0068). The effect of maintenance thalidomide was assessed, with the shortest PFS demonstrable in those MRD-positive patients who did not receive maintenance and longest in those who were MRD negative and did receive thalidomide (P < .001). Further analysis demonstrated that 28% of MRD-positive patients who received maintenance thalidomide became MRD negative. MRD assessment after induction therapy in the non-intensive-pathway patients did not seem to be predictive of outcome (PFS, P = .1). CONCLUSION: MRD assessment by MFC was predictive of overall outcome in patients with myeloma undergoing ASCT. This predictive value was seen in patients achieving conventional CR as well as patients with favorable and adverse cytogenetics. The effects of maintenance strategies can also be evaluated, and our data suggest that maintenance thalidomide can eradicate MRD in some patients. PMID- 23733782 TI - Minimal residual disease in multiple myeloma. PMID- 23733783 TI - Population-based universal screening for Lynch syndrome: ready, set... How? PMID- 23733784 TI - Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia. AB - Severe aplastic anemia (AA) is a bone marrow (BM) failure (BMF) disease frequently caused by aberrant immune destruction of blood progenitors. Although a Th1-mediated pathology is well described for AA, molecular mechanisms driving disease progression remain ill defined. The NOTCH signaling pathway mediates Th1 cell differentiation in the presence of polarizing cytokines, an action requiring enzymatic processing of NOTCH receptors by gamma-secretase. Using a mouse model of AA, we demonstrate that expression of both intracellular NOTCH1(IC) and T-BET, a key transcription factor regulating Th1 cell differentiation, was increased in spleen and BM-infiltrating T cells during active disease. Conditionally deleting Notch1 or administering gamma-secretase inhibitors (GSIs) in vivo attenuated disease and rescued mice from lethal BMF. In peripheral T cells from patients with untreated AA, NOTCH1(IC) was significantly elevated and bound to the TBX21 promoter, showing NOTCH1 directly regulates the gene encoding T-BET. Treating patient cells with GSIs in vitro lowered NOTCH1(IC) levels, decreased NOTCH1 detectable at the TBX21 promoter, and decreased T-BET expression, indicating that NOTCH1 signaling is responsive to GSIs during active disease. Collectively, these results identify NOTCH signaling as a primary driver of Th1-mediated pathogenesis in AA and may represent a novel target for therapeutic intervention. PMID- 23733785 TI - The length of the shortest telomere as the major determinant of the onset of replicative senescence. AB - The absence of telomerase in many eukaryotes leads to the gradual shortening of telomeres, causing replicative senescence. In humans, this proliferation barrier constitutes a tumor suppressor mechanism and may be involved in cellular aging. Yet the heterogeneity of the senescence phenotype has hindered the understanding of its onset. Here we investigated the regulation of telomere length and its control of senescence heterogeneity. Because the length of the shortest telomeres can potentially regulate cell fate, we focus on their dynamics in Saccharomyces cerevisiae. We developed a stochastic model of telomere dynamics built on the protein-counting model, where an increasing number of protein-bound telomeric repeats shift telomeres into a nonextendable state by telomerase. Using numerical simulations, we found that the length of the shortest telomere is well separated from the length of the others, suggesting a prominent role in triggering senescence. We evaluated this possibility using classical genetic analyses of tetrads, combined with a quantitative and sensitive assay for senescence. In contrast to mitosis of telomerase-negative cells, which produces two cells with identical senescence onset, meiosis is able to segregate a determinant of senescence onset among the telomerase-negative spores. The frequency of such segregation is in accordance with this determinant being the length of the shortest telomere. Taken together, our results substantiate the length of the shortest telomere as being the key genetic marker determining senescence onset in S. cerevisiae. PMID- 23733786 TI - Expansion of the pseudo-autosomal region and ongoing recombination suppression in the Silene latifolia sex chromosomes. AB - There are two very interesting aspects to the evolution of sex chromosomes: what happens after recombination between these chromosome pairs stops and why suppressed recombination evolves. The former question has been intensively studied in a diversity of organisms, but the latter has been studied largely theoretically. To obtain empirical data, we used codominant genic markers in genetic mapping of the dioecious plant Silene latifolia, together with comparative mapping of S. latifolia sex-linked genes in S. vulgaris (a related hermaphrodite species without sex chromosomes). We mapped 29 S. latifolia fully sex-linked genes (including 21 newly discovered from transcriptome sequencing), plus 6 genes in a recombining pseudo-autosomal region (PAR) whose genetic map length is ~25 cM in both male and female meiosis, suggesting that the PAR may contain many genes. Our comparative mapping shows that most fully sex-linked genes in S. latifolia are located on a single S. vulgaris linkage group and were probably inherited from a single autosome of an ancestor. However, unexpectedly, our maps suggest that the S. latifolia PAR region expanded through translocation events. Some genes in these regions still recombine in S. latifolia, but some genes from both addition events are now fully sex-linked. Recombination suppression is therefore still ongoing in S. latifolia, and multiple recombination suppression events have occurred in a timescale of few million years, much shorter than the timescale of formation of the most recent evolutionary strata of mammal and bird sex chromosomes. PMID- 23733787 TI - Testing for the footprint of sexually antagonistic polymorphisms in the pseudoautosomal region of a plant sex chromosome pair. AB - The existence of sexually antagonistic (SA) polymorphism is widely considered the most likely explanation for the evolution of suppressed recombination of sex chromosome pairs. This explanation is largely untested empirically, and no such polymorphisms have been identified, other than in fish, where no evidence directly implicates these genes in events causing loss of recombination. We tested for the presence of loci with SA polymorphism in the plant Silene latifolia, which is dioecious (with separate male and female individuals) and has a pair of highly heteromorphic sex chromosomes, with XY males. Suppressed recombination between much of the Y and X sex chromosomes evolved in several steps, and the results in Bergero et al. (2013) show that it is still ongoing in the recombining or pseudoautosomal, regions (PARs) of these chromosomes. We used molecular evolutionary approaches to test for the footprints of SA polymorphisms, based on sequence diversity levels in S. latifolia PAR genes identified by genetic mapping. Nucleotide diversity is high for at least four of six PAR genes identified, and our data suggest the existence of polymorphisms maintained by balancing selection in this genome region, since molecular evolutionary (HKA) tests exclude an elevated mutation rate, and other tests also suggest balancing selection. The presence of sexually antagonistic alleles at a locus or loci in the PAR is suggested by the very different X and Y chromosome allele frequencies for at least one PAR gene. PMID- 23733788 TI - Rates and genomic consequences of spontaneous mutational events in Drosophila melanogaster. AB - Because spontaneous mutation is the source of all genetic diversity, measuring mutation rates can reveal how natural selection drives patterns of variation within and between species. We sequenced eight genomes produced by a mutation accumulation experiment in Drosophila melanogaster. Our analysis reveals that point mutation and small indel rates vary significantly between the two different genetic backgrounds examined. We also find evidence that ~2% of mutational events affect multiple closely spaced nucleotides. Unlike previous similar experiments, we were able to estimate genome-wide rates of large deletions and tandem duplications. These results suggest that, at least in inbred lines like those examined here, mutational pressures may result in net growth rather than contraction of the Drosophila genome. By comparing our mutation rate estimates to polymorphism data, we are able to estimate the fraction of new mutations that are eliminated by purifying selection. These results suggest that ~99% of duplications and deletions are deleterious--making them 10 times more likely to be removed by selection than nonsynonymous mutations. Our results illuminate not only the rates of new small- and large-scale mutations, but also the selective forces that they encounter once they arise. PMID- 23733790 TI - Trisomy 18 and complex congenital heart disease: seeking the threshold benefit. AB - A prenatal diagnosis of ductal-dependent, complex congenital heart disease was made in a fetus with trisomy 18. The parents requested that the genetic diagnosis be excluded from all medical and surgical decision-making and that all life prolonging therapies be made available to their infant. There was conflict among the medical team about what threshold of neonatal benefit could outweigh maternal and neonatal treatment burdens. A prenatal ethics consultation was requested. PMID- 23733789 TI - Unexpected role for dosage compensation in the control of dauer arrest, insulin like signaling, and FoxO transcription factor activity in Caenorhabditis elegans. AB - During embryogenesis, an essential process known as dosage compensation is initiated to equalize gene expression from sex chromosomes. Although much is known about how dosage compensation is established, the consequences of modulating the stability of dosage compensation postembryonically are not known. Here we define a role for the Caenorhabditis elegans dosage compensation complex (DCC) in the regulation of DAF-2 insulin-like signaling. In a screen for dauer regulatory genes that control the activity of the FoxO transcription factor DAF 16, we isolated three mutant alleles of dpy-21, which encodes a conserved DCC component. Knockdown of multiple DCC components in hermaphrodite and male animals indicates that the dauer suppression phenotype of dpy-21 mutants is due to a defect in dosage compensation per se. In dpy-21 mutants, expression of several X linked genes that promote dauer bypass is elevated, including four genes encoding components of the DAF-2 insulin-like pathway that antagonize DAF-16/FoxO activity. Accordingly, dpy-21 mutation reduced the expression of DAF-16/FoxO target genes by promoting the exclusion of DAF-16/FoxO from nuclei. Thus, dosage compensation enhances dauer arrest by repressing X-linked genes that promote reproductive development through the inhibition of DAF-16/FoxO nuclear translocation. This work is the first to establish a specific postembryonic function for dosage compensation in any organism. The influence of dosage compensation on dauer arrest, a larval developmental fate governed by the integration of multiple environmental inputs and signaling outputs, suggests that the dosage compensation machinery may respond to external cues by modulating signaling pathways through chromosome-wide regulation of gene expression. PMID- 23733793 TI - Using otoacoustic emissions to screen young children for hearing loss in primary care settings. AB - OBJECTIVES: Otoacoustic emissions (OAE) technology, used widely in newborn hearing screening programs and validated by professional organizations as a reliable and objective tool, is beginning to be recognized as superior to subjective methods when screening young children in a variety of settings. This study examines the efficacy of integrating OAE hearing screening into services routinely provided in health care settings. METHODS: Three federally funded clinics serving low-income and uninsured people in a metropolitan area participated in the 10-month study. Subjects included 846 children (842 in the target population <5 years of age and 4 older siblings) who were screened during routine visits to their primary care providers using a distortion product OAE instrument. A multistep screening and diagnostic protocol, incorporating middle ear evaluation and treatment, was followed when children did not pass the initial screening. Audiological evaluation was sought for children not passing a subsequent OAE screening. RESULTS: Of the 846 children screened, 814 (96%) ultimately passed the screening or audiological assessment and 29 (3%) exited the study. Three children (1 was <5 years of age and 2 were >5) were identified with permanent hearing loss. CONCLUSIONS: The rate of identification of permanent hearing loss in this study is similar to findings from a study of OAE screening in early childhood educational settings. OAE screening holds the potential for being an effective method for helping to identify young children with permanent hearing loss in primary care settings. PMID- 23733792 TI - Adult prescription drug use and pediatric medication exposures and poisonings. AB - BACKGROUND AND OBJECTIVES: Nontherapeutic medication ingestions continue to be a major pediatric health problem, with recent increases in ingestions despite a number of public health interventions. It is unknown how changes in adult prescription drug use relate to pediatric medication poisonings. The objective of the study was to measure the association between changing adult prescription drug patterns and pediatric medication exposures and poisonings and identify high-risk classes of medications and pediatric age groups. METHODS: We measured monthly pediatric exposures and poisonings using the National Poison Data System and prescriptions written for adults using the National Ambulatory Medical Care Surveys for 2000 through 2009. Associations between adult prescriptions for oral hypoglycemics, antihyperlipidemics, beta-blockers, and opioids and exposures and poisonings among children 0 to 5, 6 to 12, and 13 to 19 years were analyzed by using multiple time-series analysis. Emergency department visits, serious injuries, and hospitalizations stemming from these associations were described. RESULTS: Adult medication prescriptions were statistically significantly associated with exposures and poisonings in children of all ages, with the strongest association observed for opioids. Across medications, the greatest risk was among children 0 to 5 years old, followed by 13- to 19-year-olds. Rates of emergency department visits were highest for events related to hypoglycemics (60.1%) and beta-blockers (59.7%), whereas serious injuries and hospitalizations occurred most frequently with opioids (26.8% and 35.2%, respectively) and hypoglycemics (19.5% and 49.4%, respectively). CONCLUSIONS: Increasing adult drug prescriptions are strongly associated with rising pediatric exposures and poisonings, particularly for opioids and among children 0 to 5 years old. These associations have sizable impacts, including high rates of serious injury and health care use. PMID- 23733794 TI - Discharge timing, outpatient follow-up, and home care of late-preterm and early term infants. AB - OBJECTIVE: To compare the timing of hospital discharge, time to outpatient follow up, and home care practices (breastfeeding initiation and continuation, tobacco smoke exposure, supine sleep position) for late-preterm (LPT; 34 0/7-36 6/7 weeks) and early-term (ET; 37 0/7-38/6/7 weeks) infants with term infants. METHODS: We analyzed 2000-2008 data from the Centers for Disease Control and Prevention's Pregnancy Risk Assessment Monitoring System. chi(2) Analyses were used to measure differences in maternal and infant characteristics, hospital discharge, outpatient care, and home care among LPT, ET, and term infants. We calculated adjusted risk ratios for the risk of adverse care outcomes among LPT and ET infants compared with term infants. RESULTS: In the adjusted analysis, LPT infants were less likely to be discharged early compared with term infants, whereas there was no difference for ET infants (risk ratio [RR; 95% confidence interval (CI)]: 0.65 [0.54-0.79]; 0.95 [0.88-1.02]). [corrected]. LPT and ET infants were more likely to have timely outpatient follow-up (1.07 [1.06-1.08]; 1.02 [1.02-1.03]), more likely to experience maternal tobacco smoke exposure (1.09 [1.05-1.14]; 1.08 [1.06-1.11]), less likely to be initially breastfed (0.95 [0.94-0.97]; 0.98 [0.97-0.98]), less likely to be breastfed for >=10 weeks (0.88 [0.86-0.90]; 0.94 [0.93-0.96]), and less likely to be placed in a supine sleep position (0.95 [0.93-0.97]; 0.97 [0.96-0.98]). CONCLUSIONS: Given that LPT and ET infants bear an increased risk of morbidity and mortality, greater efforts are needed to ensure safe and healthy posthospitalization and home care practices for these vulnerable infants. PMID- 23733795 TI - Religious exemptions for immunization and risk of pertussis in New York State, 2000-2011. AB - OBJECTIVE: The objective of this study was to describe rates of religious vaccination exemptions over time and the association with pertussis in New York State (NYS). METHODS: Religious vaccination exemptions reported via school surveys of the NYS Department of Health from 2000 through 2011 were reviewed by county, and the changes were assessed against incidence rates of pertussis among children reported to the NYS Department of Health Communicable Disease Electronic Surveillance System. RESULTS: The overall annual state mean prevalence (+/- SD) of religious exemptions for >=1 vaccines in 2000-2011 was 0.4% +/- 0.08% and increased significantly from 0.23% in 2000 to 0.45% in 2011 (P = .001). The prevalence of religious exemptions varied greatly among counties and increased by >100% in 34 counties during the study period. Counties with mean exemption prevalence rates of >=1% reported a higher incidence of pertussis, 33 per 100 000 than counties with lower exemption rates, 20 per 100 000, P < .001. In addition, the risk of pertussis among vaccinated children living in counties with high exemption rate increased with increase of exemption rate among exempted children (P = .008). CONCLUSIONS: The prevalence of religious exemptions varies among NYS counties and increased during the past decade. Counties with higher exemption rates had higher rates of reported pertussis among exempted and vaccinated children when compared with the low-exemption counties. More studies are needed to characterize differences in the process of obtaining exemptions among NYS schools, and education is needed regarding the risks to the community of individuals opting out from recommended vaccinations. PMID- 23733796 TI - Plastic bags for prevention of hypothermia in preterm and low birth weight infants. AB - BACKGROUND AND OBJECTIVES: Hypothermia contributes to neonatal mortality and morbidity, especially in preterm and low birth weight infants in developing countries. Plastic bags covering the trunk and extremities of very low birth weight infants reduces hypothermia. This technique has not been studied in larger infants or in many resource-limited settings. The objective was to determine if placing preterm and low birth weight infants inside a plastic bag at birth maintains normothermia. METHODS: Infants at 26 to 36 weeks' gestational age and/or with a birth weight of 1000 to 2500 g born at the University Teaching Hospital in Lusaka, Zambia, were randomized by using a 1:1 allocation and parallel design to standard thermoregulation (blanket or radiant warmer) care or to standard thermoregulation care plus placement inside a plastic bag at birth. The primary outcome measure was axillary temperature in the World Health Organization-defined normal range (36.5-37.5 degrees C) at 1 hour after birth. RESULTS: A total of 104 infants were randomized. At 1 hour after birth, infants randomized to plastic bag (n = 49) were more likely to have a temperature in the normal range as compared with infants in the standard thermoregulation care group (n = 55; 59.2% vs 32.7%; relative risk 1.81; 95% confidence interval 1.16-2.81; P = .007). The temperature at 1 hour after birth in the infants randomized to plastic bag was 36.5 +/- 0.5 degrees C compared with 36.1 +/- 0.6 degrees C in standard care infants (P < .001). Hyperthermia (>38.0 degrees C) did not occur in any infant. CONCLUSIONS: Placement of preterm/low birth weight infants inside a plastic bag at birth compared with standard thermoregulation care reduced hypothermia without resulting in hyperthermia, and is a low-cost, low-technology tool for resource-limited settings. PMID- 23733797 TI - Misdiagnosed food allergy resulting in severe malnutrition in an infant. AB - As food allergies become increasingly prevalent and testing methods to identify "food allergy" increase in number, the importance of careful diagnosis has become even more critical. Misdiagnosis of food allergy and inappropriate use of unproven testing modalities may lead to a harmful food-elimination diet. This case is an example of an infant who was placed on an overly restrictive elimination diet at the recommendation of her health care providers, resulting in kwashiorkor and acquired acrodermatitis enteropathica. PMID- 23733798 TI - Short-course prophylactic zinc supplementation for diarrhea morbidity in infants of 6 to 11 months. AB - BACKGROUND: Zinc supplementation during diarrhea substantially reduces the incidence and severity of diarrhea. However, the effect of short-course zinc prophylaxis has been observed only in children >12 months of age. Because the incidence of diarrhea is comparatively high in children aged 6 to 11 months, we assessed the prophylactic effect of zinc on incidence and duration of diarrhea in this age group. METHODS: In this randomized, double-blind, placebo-controlled trial, we enrolled infants aged 6 to 11 months from an urban resettlement colony in Delhi, India, between January 1, 2011, and January 15, 2012. We randomly assigned 272 infants to receive either 20 mg of zinc or a placebo suspension orally every day for 2 weeks. The primary outcome was the incidence of diarrhea per child-year. All analyses were done by intention-to-treat. RESULTS: A total of 134 infants in the zinc and 124 in the placebo groups were assessed for the incidence of diarrhea. There was a 39% reduction (crude incident rate ratio [IRR] 0.61, 95% confidence interval [CI] 0.53-0.71) in episodes of diarrhea, 39% (adjusted IRR 0.61, 95% CI 0.54-0.69) in the total number of days that a child suffered from diarrhea, and reduction of 36% in duration per episode of diarrhea (IRR 0.64, 95% CI 0.56-0.74) during the 5 months of follow-up. CONCLUSIONS: Short course prophylactic zinc supplementation for 2 weeks may reduce diarrhea morbidity in infants of 6 to 11 months for up to 5 months, in populations with high prevalence of wasting and stunting. PMID- 23733791 TI - Ten-year review of major birth defects in VLBW infants. AB - OBJECTIVE: Birth defects (BDs) are an important cause of infant mortality and disproportionately occur among low birth weight infants. We determined the prevalence of BDs in a cohort of very low birth weight (VLBW) infants cared for at the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) centers over a 10-year period and examined the relationship between anomalies, neonatal outcomes, and surgical care. METHODS: Infant and maternal data were collected prospectively for infants weighing 401 to 1500 g at NRN sites between January 1, 1998, and December 31, 2007. Poisson regression models were used to compare risk of outcomes for infants with versus without BDs while adjusting for gestational age and other characteristics. RESULTS: A BD was present in 1776 (4.8%) of the 37 262 infants in our VLBW cohort. Yearly prevalence of BDs increased from 4.0% of infants born in 1998 to 5.6% in 2007, P < .001. Mean gestational age overall was 28 weeks, and mean birth weight was 1007 g. Infants with BDs were more mature but more likely to be small for gestational age compared with infants without BDs. Chromosomal and cardiovascular anomalies were most frequent with each occurring in 20% of affected infants. Mortality was higher among infants with BDs (49% vs 18%; adjusted relative risk: 3.66 [95% confidence interval: 3.41-3.92]; P < .001) and varied by diagnosis. Among those surviving >3 days, more infants with BDs underwent major surgery (48% vs 13%, P < .001). CONCLUSIONS: Prevalence of BDs increased during the 10 years studied. BDs remain an important cause of neonatal morbidity and mortality among VLBW infants. PMID- 23733799 TI - Successful implementation of a neonatal pain and sedation protocol at 2 NICUs. AB - OBJECTIVE: To evaluate the implementation of a neonatal pain and sedation protocol at 2 ICUs. METHODS: The intervention started with the evaluation of local practice, problems, and staff satisfaction. We then developed and implemented the Vienna Protocol for Neonatal Pain and Sedation. The protocol included well-defined strategies for both nonpharmacologic and pharmacologic interventions based on regular assessment of a translated version of the Neonatal Pain Agitation and Sedation Scale and titration of analgesic and sedative therapy according to aim scores. Health care staff was trained in the assessment by using a video-based tutorial and bedside teaching. In addition, we performed reevaluation, retraining, and random quality checks. Frequency and quality of assessments, pharmacologic therapy, duration of mechanical ventilation, and outcome were compared between baseline (12 months before implementation) and 12 months after implementation. RESULTS: Cumulative median (interquartile range) opiate dose (baseline dose of 1.4 [0.5-5.9] mg/kg versus intervention group dose of 2.7 [0.4-57] mg/kg morphine equivalents; P = .002), pharmacologic interventions per episode of continuous sedation/analgesia (4 [2-10] vs 6 [2-13]; P = .005), and overall staff satisfaction (physicians: 31% vs 89%; P < .001; nurses: 17% vs 55%; P < .001) increased after implementation. Time on mechanical ventilation, length of stay at the ICU, and adverse outcomes were similar before and after implementation. CONCLUSIONS: Implementation of a neonatal pain and sedation protocol at 2 ICUs resulted in an increase in opiate prescription, pharmacologic interventions, and staff satisfaction without affecting time on mechanical ventilation, length of intensive care stay, and adverse outcomes. PMID- 23733800 TI - Invasive pneumococcal disease in infants younger than 90 days before and after introduction of PCV7. AB - BACKGROUND: Introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) changed the epidemiology of invasive pneumococcal disease (IPD). We evaluated the changes that occurred after PCV7 introduction among Utah infants aged 1 to 90 days, too young to be fully immunized. METHODS: We identified children <18 years with culture-confirmed IPD from 1997-2010. We analyzed demographic, clinical, and serotype data for infants aged 1-90 days. The pre- and post-vaccine introduction periods spanned 1997-2000 and 2001-2010, respectively. RESULTS: Of 513 children with IPD, 36 were 1 to 90 days and accounted for 7% of IPD cases in both the pre- and post-vaccine introduction period. The pre-vaccine IPD incidence rate was 5.0 per 100 000 live births, and was unchanged in the post-vaccine introduction period. IPD caused by PCV7 serotypes decreased by 74% (from 2.2 to 0.58 per 100 000), whereas non-vaccine serotype IPD increased by 57% (from 2.8 to 4.4 per 100 000). Sixteen infants (44%) required intensive care, and 3 (8%) died. Bacteremia without focus (56%) and meningitis (44%) were the predominant syndromes in the pre- and post-vaccine introduction periods, respectively. In the post-vaccine introduction period, serotype 7F was the most common serotype among infants and was responsible for 50% of meningitis. CONCLUSIONS: The incidence of IPD in Utah infants aged 1 to 90 days caused by PCV7 serotypes decreased after PCV7 introduction, but overall incidence was unchanged. In the post-vaccine introduction period, serotype 7F predominated in this age group and was associated with meningitis. PMID- 23733801 TI - Trends in bronchiolitis hospitalizations in the United States, 2000-2009. AB - OBJECTIVE: To examine temporal trend in the national incidence of bronchiolitis hospitalizations, use of mechanical ventilation, and hospital charges between 2000 and 2009. METHODS: We performed a serial, cross-sectional analysis of a nationally representative sample of children hospitalized with bronchiolitis. The Kids Inpatient Database was used to identify children <2 years of age with bronchiolitis by International Classification of Diseases, Ninth Revision, Clinical Modification code 466.1. Primary outcome measures were incidence of bronchiolitis hospitalizations, mechanical ventilation (noninvasive or invasive) use, and hospital charges. Temporal trends were evaluated accounting for sampling weights. RESULTS: The 4 separated years (2000, 2003, 2006, and 2009) of national discharge data included 544 828 weighted discharges with bronchiolitis. Between 2000 and 2009, the incidence of bronchiolitis hospitalization decreased from 17.9 to 14.9 per 1000 person-years among all US children aged <2 years (17% decrease; P(trend) < .001). By contrast, there was an increase in children with high-risk medical conditions (5.9%-7.9%; 34% increase; P(trend) < .001) and use of mechanical ventilation (1.9%-2.3%; 21% increase; P(trend) = .008). Nationwide hospital charges increased from $1.34 billion to $1.73 billion (30% increase; P(trend) < .001); this increase was driven by a rise in the geometric mean of hospital charges per case from $6380 to $8530 (34% increase; P(trend) < .001). CONCLUSIONS: Between 2000 and 2009, we found a significant decline in bronchiolitis hospitalizations among US children. By contrast, use of mechanical ventilation and hospital charges for bronchiolitis significantly increased over this same period. PMID- 23733802 TI - Possible prevention of tuberous sclerosis complex lesions. AB - Tuberous sclerosis complex (TSC) is a genetic disorder characterized by mammalian target of rapamycin (mTOR) activation and growth of benign tumors. Some TSC lesions, such as cardiac rhabdomyomas and cortical tubers in the brain, occur in fetuses, and some, such as renal angiomyolipomas (AMLs) and skin angiofibromas, develop over years. Recently, the mTOR inhibitor everolimus was shown to be effective in the treatment of subependymal giant cell astrocytomas (a brain tumor) and renal AMLs (kidney tumors) in TSC patients. We present monozygotic twin sisters affected with TSC. Since age 4 years, 1 of the sisters has been treated with everolimus; the other sister received no mTOR inhibitor treatment. After 24-month follow-up, everolimus treatment resulted in a significant brain tumor volume decrease in the treated twin. This child presents no facial angiofibroma, and no renal AMLs. The brain tumor in the nontreated sister is stable in size, but in the meantime, she has developed significant facial angiofibroma and renal AMLs. This observation indicates that early mTOR inhibition in TSC patients may prevent the development of TSC lesions and alter the natural history of the disease. PMID- 23733803 TI - Sick-visit immunizations and delayed well-baby visits. AB - OBJECTIVE: Giving recommended immunizations during sick visits for minor and acute illness such as acute otitis media has long been an American Academy of Pediatrics/Advisory Committee on Immunization Practice recommendation. An addition to the American Academy of Pediatrics policy in 2010 advised considering whether giving immunizations at the sick visit would discourage making up missed well-baby visits. This study quantifies the potential tradeoff between sick-visit immunizations and well-baby visits. METHODS: This study was a retrospective cohort analysis with a case-control component of sick visits for acute otitis media that supplanted normal well-baby visits at age 2, 4, or 6 months. Infants were stratified for sick-visit immunization, no sick-visit immunization but quick makeup well-baby visits, or no sick-visit immunizations or quick makeup visits. Immunization rates and well-baby visit rates were assessed through 24 months of age. RESULTS: For 1060 study cases, no significant difference was detected in immunization rates or well-baby visits through 24 months of age between those with or without sick-visit immunizations. Thirty-nine percent of infants without a sick-visit shot failed to return for a quick makeup well-baby visit; this delayed group was significantly less likely to be up-to-date for immunizations (relative risk: 0.66) and had fewer well-baby visits (mean: 3.8) from 2 through 24 months of age compared with those with sick-visit shots (mean: 4.7). CONCLUSIONS: The substantial risk that infants will not return for a timely makeup well-baby visit after a sick visit should be included in any consideration of whether to delay immunizations. PMID- 23733804 TI - Outcomes of infants born at 22 and 23 weeks' gestation. AB - OBJECTIVE: To provide instructive information on death and neurodevelopmental outcomes of infants born at 22 and 23 weeks' gestational age. METHODS: The study cohort consisted of 1057 infants born at 22 to 25 weeks in the Neonatal Research Network, Japan. Neurodevelopmental impairment (NDI) at 36 to 42 months' chronological age was defined as any of the following: cerebral palsy, hearing impairment, visual impairment, and a developmental quotient <70. A systematic review was performed by using databases of publications of cohort studies with neonatal and neurodevelopmental outcomes at 22 and 23 weeks. RESULTS: Numbers and incidences (%) of infants with death or NDI were 60 (80%) at 22 weeks and 156 (64%) at 23 weeks. In logistic regression analysis, gestational ages of 22 weeks (odds ratio [OR]: 5.40; 95% confidence interval [CI]: 2.48-11.76) and 23 weeks (OR: 2.14; 95% CI: 1.38-3.32) were associated with increased risk of death or NDI compared with 24 weeks, but a gestational age of 25 weeks (OR: 0.65; 95% CI: 0.45 0.95) was associated with decreased risk of death or NDI. In the systematic review, the medians (range) of the incidence of death or NDI in 8 cohorts were 99% (90%-100%) at 22 weeks and 98% (67%-100%) at 23 weeks. CONCLUSIONS: Infants born at 22 and 23 weeks' gestation were at higher risk of death or NDI than infants at born at 24 weeks. However, outcomes were improved compared with those in previous studies. There is a need for additional discussions on interventions for infants born at 22 or 23 weeks' gestation. PMID- 23733805 TI - Euestrogenemia and healthy mitochondria. PMID- 23733806 TI - Reply to Turner and Kerber. PMID- 23733807 TI - Effect of different post mortem temperatures on carcass quality of suckling lamb. AB - The effect of post mortem treatment on microbiological lamb carcass quality was studied. Suckling lambs carcasses were assigned to three different post mortem treatments: conventional (2 for 24 h), ultra-rapid (-20 for 3.5 h then 2 until 24 h post mortem) and slow (12 for 7 h then 2 until 24 h post mortem). Carcass pH and temperature were measured at 0, 3.5, 7 and 24 h post slaughter. Lamb carcasses were sampled for total aerobic viable and Enterobacteriaceae counts just after dressing and 24 h post mortem. A significant effect (p < 0.05) of post mortem treatment on carcasses temperature and pH was found corresponding the faster pH fall to slowly chilled muscles. However, no differences were found at 24 h post mortem among treatments in both parameters. Regarding microbiological results, carcasses of ultra-rapid treatment had the lowest total aerobic viable and Enterobacteriaceae counts and those belonging to conventional treatment had the highest total aerobic viable counts. From 0 to 24 h post mortem, an increase of total aerobic viable was observed in conventional and slow treatments whilst Enterobacteriaceae counts remained constant in all cases. From a microbiological point of view, the ultra-rapid treatment was the only one allowed to maintain the hygienic carcasses quality. However, according to pH and temperature results the carcasses subjected to this treatment may be susceptible to cold shortening. PMID- 23733808 TI - Influence of hot water dip on fruit quality, phenolic compounds and antioxidant capacity of Satsuma mandarin during storage. AB - The influence of hot water dips (50, 52 and 54 for 3 min) on fruit quality, phenolic compounds and antioxidant capacity of Satsuma mandarin during 60 days' storage at 10 was investigated. Hot water dips did not affect fruit quality attributes as well as ascorbic acid content, and 50 treatment significantly reduced fruit weight loss. Significant increases of flavonoids were found in all hot water treated fruit from after treatments till 15 days of storage, whereas phenolic acids were not greatly affected. Hot water dipping at 50 significantly increased total phenolics and antioxidant capacity of Satsuma mandarin immediately after treatment and maintained similar levels with control during storage, while 52 and 54 treatments showed relatively lower levels. The results suggested that hot water dipping at 50 for 3 min can be a promising way to retain functional quality of storing Satsuma mandarin. PMID- 23733809 TI - Assessment of by-products from fresh-cut products for reuse as bioactive compounds. AB - The fresh-cut industry is constantly growing and generating wastes. The major challenge for this industry consists in an environmentally sustainable production through re-utilization of by-products, for instance, in extraction of bioactive compounds. In this paper, the nutritional and functional compounds of apple, potato, cucumber, melon and watermelon by-products were investigated. The amount of by-product produced was of 10.10 to 30.80% of initial fresh weight depending on the product. By-products were characterized by low protein (<20 g/kg fresh weight) and fatty acid content (<5 g/kg fresh weight) and high levels of minerals. Carbohydrates content ranged from 43.7 to 235 g/kg fresh weight, while total dietary fibre was between 20 and 150 g/kg fresh weight The content of antioxidants (53.6 to 3453.2 mg/kg fresh weight) and total polyphenols (124.5 to 4250.2 mg/kg fresh weight) depended strongly on the type of by-product. In most cases, the nutritional and bioactive content was higher in the peel than in whole product. Apple peel was rich in carbohydrates, total dietary fibre, antioxidants and total polyphenols. Potato peel was high in iron. Melon was rich in magnesium. Watermelon peel was characterized by the level of potassium, and cucumber peel was rich in manganese, zinc, phosphorous, calcium and sodium. All these data demonstrate than natural by-product from fresh-cut industry could potentially be utilized as ingredients to design new functional foods with a future market. PMID- 23733810 TI - Mashed potatoes enriched with soy protein isolate and inulin: chemical, rheological and structural basis. AB - Soy protein isolate is typical vegetable protein with health-enhancing activities. Inulin, a prebiotic no digestible carbohydrate, has functional properties. A mashed potato serving of 200 g with added soy protein isolate and/or inulin concentrations of 15-60 g/kg provides from 3 to 12 g of soy protein isolate and/or inulin, respectively. Currently, no information is available about the possible texture-modifying effect of this non-ionizable polar carbohydrate in different soy-based food systems. In this study, the effect of the addition of soy protein isolate and inulin blends at different soy protein isolate: inulin ratios on the degree of inulin polymerization and the rheological and structural properties of fresh mashed and frozen/thawed mashed potatoes were evaluated. The inulin chemical structure remained intact throughout the various treatments, and soy protein isolate did not affect inulin composition being a protein compatible with this fructan. Small-strain rheology showed that both ingredients behaved like soft fillers. In the frozen/thawed mashed potatoes samples, addition of 30 : 30 and 15 : 60 blend ratios significantly increased elasticity (G' value) compared with 0 : 0 control, consequently reducing the freeze/thaw stability conferred by the cryoprotectants. Inulin crystallites caused a significant strengthening effect on soy protein isolate gel. Micrographs revealed that soy protein isolate supports the inulin structure by building up a second fine stranded network. Thereby, possibility of using soy protein isolate and inulin in combination with mashed potatoes to provide a highly nutritious and healthy product is promising. PMID- 23733811 TI - Sensory characteristics of antioxidant extracts from Uruguayan native plants: influence of deodorization by steam distillation. AB - Polyphenolic-rich antioxidant extracts from native plants have potential applications as ingredients in functional foods; however, their intense characteristic flavour is a major limitation to their application. In this context, the aim of the present work was to evaluate the influence of steam distillation on the sensory and physicochemical characteristics of extracts of five native Uruguayan plants (Acca sellowiana, Achyrocline satureioides, Aloysia gratisima, Baccharis trimera and Mikania guaco). Aqueous extracts from the five native plants were obtained. Steam distillation was used to produce two types of deodorized extracts: extracts from deodorized leaves and extracts deodorized after the extraction. The extracts were characterized in terms of their total polyphenolic content and antioxidant activity (using 2,2-diphenyl-1-picryl hydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid methods). A trained assessor panel evaluated characteristic odour, characteristic flavour, bitterness and astringency of the extracts. The total polyphenolic content of the extracts ranged from 112.4 to 974.4 mg/100 mL, whereas their antioxidant capacity ranged from 9.6 to 1008.7 mg vitamin C equivalents/100 mL, depending on the type of extract and the method being considered. Steam distillation was effective in reducing the characteristic odour and flavour of the extracts, without causing large changes in their polyphenolic content and antioxidant activity. In general, in terms of sensory characteristics, steam distillation performed on the extracts gave better results than when performed on the leaves; whereas the opposite trend was found for polyphenolic content and antioxidant activity. Results suggested that steam distillation could be a promising low-cost procedure for the production of antioxidant extracts for food products. PMID- 23733812 TI - Statistical approach to study the interactive effects of process parameters for enhanced xylitol production by Candida tropicalis and its potential for the synthesis of xylitol monoesters. AB - Previous results showed that an indigenously isolated yeast strain of Candida tropicalis was found to produce 12.11 g/L of xylitol under unoptimized conditions in presence of 50 g/L of xylose. In the present study, optimizing the process using one-variable at-a-time resulted in the production of 59.07 g/L of xylitol in 96 h in presence of 100 g/L xylose. Further optimization using response surface methodology led to the production of 65.45 g/L in medium containing 100 g/L xylose, 0.5% yeast extract, 0.03% MgSO(4).7H(2)O and 0.2% KH(2)PO(4), pH-4.5, 30 degrees C, 200 r/min for 96 h with 4% inoculum level. Addition of 1% methanol in response surface methodology optimized-medium led to the production of 67.12 g/L. Scaling up in 10 L fermentor resulted in productivity of 0.80 g/Lh with yield of 0.68 g/g. Efficient synthesis of xylitol esters was achieved with butyric acid (50.32%) and caproic acid (38.36%) in 4 h using Pseudomonas aeruginosa lipase in t-butanol: tetrahydrofuran (1:1 v/v). PMID- 23733813 TI - Effect of flaxseed flour incorporation on the physical properties and consumer acceptability of cereal bars. AB - Extensive research has revealed numerous nutritional and health benefits of flaxseed due primarily to its nutrients content. The objective of this study was to evaluate the effect of flaxseed flour addition on the physical and sensory characteristics of cereal bars. Four formulations of the flaxseed cereal bars were prepared by partially replacing oats with flaxseed flour added at levels of 0 (control), 6%, 12% and 18%. There were no significant differences (p > 0.05) in water activity, moisture and firmness values between the flaxseed bars and control. Flaxseed addition significantly (p < 0.05) decreased lightness and increased redness of the bars. There were no significant differences (p > 0.05) between the 12% flax cereal bars and the control with respect to sensory attributes and overall acceptability. The overall acceptability for both 12% flax bars and the control was in between 'like moderately' and 'like slightly' on the 9-point hedonic scale. The overall acceptability was most highly correlated with flavor acceptability for both control (r = 0.80) and 12% flax (r = 0.82) cereal bars. Flaxseed bars provided 12% dietary fiber of the daily recommended value. These results indicated that flaxseed flour incorporation up to 12% substantially enhanced the nutritional qualities of the cereal bars without affecting their sensory and quality properties. PMID- 23733814 TI - Characterization of mutual relations between Geotrichum candidum and Lactobacillus rhamnosus GG in milk: a quantitative approach. AB - The growth interactions between Geotrichum candidum and Lactobacillus rhamnosus GG were studied in milk. The effect of temperature on the growth rate of the fungus was modelled using the cardinal temperature model with inflection. The secondary modelling was applied also on the other data set containing the growth rates of G. candidum in co-culture with a commercial starter culture. The low temperature in combination with L. rhamnosus GG in co-culture showed the most negative effect on the growth rate of G. candidum. On the other hand, neither L. rhamnosus GG nor the starter culture had significant effect on the optimum and maximum temperature parameters calculated for growth of G. candidum. Their values ranged from 28.9 degrees C to 31.3 degrees C and 35.3 degrees C to 37.3 degrees C, respectively. The quantitative data presented in the study showed a non-specific effect of lactic acid bacteria on the growth rate of G. candidum observed mainly around the optimal temperature. PMID- 23733815 TI - Pectin extraction from quince (Cydonia oblonga) pomace applying alternative methods: effect of process variables and preliminary optimization. AB - The objectives of this study were to introduce alternative methods in the process of pectin extraction from quince pomace, to determine the effect of selected process variables (factors) on the obtained pectin, and to perform a preliminary optimization of the process. A fractional factorial experimental design was applied, where the factors considered were six: quince pomace pretreatment (washing vs blanching), drying method (hot air vs LPSSD), acid extraction conditions (pH, temperature, and time), and pectin extract concentration method (vacuum evaporation vs ultrafiltration). The effects of these factors and their interactions on pectin yield (Y: 0.2-34.2 mg/g), GalA content (44.5-76.2%), and DM (47.5-90.9%), were determined. For these three responses, extraction pH was the main effect, but it was involved in two and three factors interactions. Regarding alternative methods, LPSSD was required for maximum Y and GalA, and ultrafiltration for maximum GalA and DM. Response models were used to predict optimum process conditions (quince blanching, pomace drying by LPSSD, acid extraction at pH 2.20, 80 , 3 h, and concentration under vacuum) to simultaneously maximize Y (25.2 mg/g), GalA (66.3%), and DM (66.4%). PMID- 23733816 TI - Study of the effect of post-packaging pasteurization and argon modified atmosphere packaging on the sensory quality and growth of endogenous microflora of a sliced cooked meat product. AB - The objective of this work was to study the effect of post-packaging pasteurization on the sensory quality and growth of natural microorganisms during refrigerated storage (6 degrees C) of a cooked meat product considering two packaging atmospheres based on mixture of typical gases (CO(2)/N(2) (22/78%) and novel gases (CO(2)/Ar (17/83%)). Growth of lactic acid bacteria was significantly different between samples with and without post-packaging pasteurization, showing a growth rate >0.44 and equal to 0.28 log cfu/day, respectively. For samples with post-packaging pasteurization, atmosphere CO(2)/Ar resulted in a lower growth of lactic acid bacteria and a better sensory quality. Overall, samples without post packaging pasteurization did not show a significant reduction of sensory quality during storage time (121 days) while samples with post-packaging pasteurization showed deterioration in their sensory quality. Further investigation is needed to obtain more definitive conclusions about the effect of post-packaging pasteurization and argon-based packaging atmospheres on cooked meat products. PMID- 23733817 TI - Effect of gamma irradiation and storage time on microbial growth and physicochemical characteristics of pumpkin (Cucurbita Moschata Duchesne ex Poiret) puree. AB - The effect of gamma irradiation (0-2 kGy) and storage time (0-28 days) on microbial growth and physicochemical characteristics of a packed pumpkin puree was studied. For that purpose, a factorial design was applied. The puree contained potassium sorbate, glucose and vanillin was stored at 25 degrees C . Gamma irradiation diminished and storage time increased microbial growth. A synergistic effect between both variables on microbial growth was observed. Storage time decreased pH and color of purees. Sorbate content decreased with storage time and gamma irradiation. Mathematical models of microbial growth generated by the factorial design allowed estimating that a puree absorbing 1.63 kGy would have a shelf-life of 4 days. In order to improve this time, some changes in the applied hurdles were assayed. These included a thermal treatment before irradiation, a reduction of irradiation dose to 0.75 kGy and a decrease in storage temperature at 20 degrees C . As a result, the shelf-life of purees increased to 28 days. PMID- 23733818 TI - Free radical scavenging activity of peptide fractions from defatted soybean meal hydrolysates evaluated by electron spin resonance. AB - Defatted soybean meal, a by-product of soybean oil extraction, was pretreated by ultrasonic and hydrolyzed with neutrase. The DSMH pretreated at 400 W of ultrasonic power, identified to possess the strongest antioxidant activity, was fractionated according to molecular weight into three fractions of DSMH-I (>10 kDa), DSMH-II (5-10 kDa), and DSMH-III (<5 kDa) using ultrafiltration. The fraction, DSMH-III (<5 kDa), exhibited the highest antioxidative activity and was further purified using ion-exchange chromatography. The DSMH-III was separated into five fractions (A, B, C, D, and E). Fraction C with molecular weight of 2434 Da exhibited the strongest free radical scavenging, which was evidenced by the electron spin resonance of 1,1-diphenyl-2-pycryl hydrazyl and hydroxyl radicals. Fraction C was subjected to reverse-phase high performance liquid chromatography and the sequences of the highest activity peptide were determined by liquid chromatography tandem mass spectrometry. The strongest antioxidant activity peptide had the amino acid sequence of Glu-Glu-Gln-Glu-Trp-Pro-Arg-Lys-Glu-Glu Lys. In conclusion, ultrasonic treatment and ultrafiltration could enhanced antioxidant activity of DSMH. PMID- 23733819 TI - Effect of ultrafine grinding on physicochemical and antioxidant properties of dietary fiber from wine grape pomace. AB - Wine grape pomace dietary fiber powders were prepared by superfine grinding, whose effects were investigated on the composition, functional and antioxidant properties of the wine grape pomace dietary fiber products. The results showed that superfine grinding could effectively pulverize the fiber particles to submicron scale. As particle size decrease, the functional properties (water holding capacity, water-retention capacity, swelling capacity, oil-binding capacity, and nitrite ion absorption capacity) of wine grape pomace dietary fiber were significantly (p < 0.05) decreased and a redistribution of fiber components from insoluble to soluble fractions was observed. The antioxidant activities of wine grape pomace and dietary fiber before and after grinding were in terms of DPPH radical scavenging activity, ABTS diammonium salt radical scavenging activity, ferric reducing antioxidant power, and total phenolic content. Compared with dietary fiber before and after grinding, micronized insoluble dietary fiber showed increased ABTS radical scavenging activity, ferric reducing antioxidant power, and total phenolic content yet decreased DPPH radical scavenging activity. Positive correlations were detected between ABTS radical scavenging activity, ferric reducing antioxidant power, and total phenolic content. PMID- 23733820 TI - Modelling drying kinetics of thyme (Thymus vulgaris L.): theoretical and empirical models, and neural networks. AB - The drying kinetics of thyme was analyzed by considering different conditions: air temperature of between 40 degrees C and 70 degrees C , and air velocity of 1 m/s. A theoretical diffusion model and eight different empirical models were fitted to the experimental data. From the theoretical model application, the effective diffusivity per unit area of the thyme was estimated (between 3.68 * 10(-5) and 2.12 * 10 (-4) s(-1)). The temperature dependence of the effective diffusivity was described by the Arrhenius relationship with activation energy of 49.42 kJ/mol. Eight different empirical models were fitted to the experimental data. Additionally, the dependence of the parameters of each model on the drying temperature was determined, obtaining equations that allow estimating the evolution of the moisture content at any temperature in the established range. Furthermore, artificial neural networks were developed and compared with the theoretical and empirical models using the percentage of the relative errors and the explained variance. The artificial neural networks were found to be more accurate predictors of moisture evolution with VAR >= 99.3% and ER <= 8.7%. PMID- 23733821 TI - Effect of seasonal changes on the gelling properties of farmed sea bass (Dicentrarchus labrax). AB - The effect of seasonal changes (summer versus winter) upon the quality of heat induced gel products from farmed sea bass (Dicentrarchus labrax) was studied. Moreover, the effect of microbial transglutaminase addition (0.5%, w/w) on the quality was assessed. Fat content of gel products attained from sea bass grown during summer was higher (12.0% versus 7.6%). Textural properties of the gels from the summer fish were higher. Protein of gels from winter fish was less soluble in SDS + DTT (sodium dodecyl sulphate, SDS; dithiothreitol, DTT). Contrary to some literature, higher fat level may have played a protective role during processing. Accordingly, season via fat content variation had a strong effect on the gelling ability of heat-induced gels prepared from sea bass. PMID- 23733822 TI - Effectiveness of almond gum trees exudate as a novel edible coating for improving postharvest quality of tomato (Solanum lycopersicum L.) fruits. AB - The use of coatings is a technique used to increase postharvest life of the fruit. Almond gum exudate was used, in comparison with gum arabic, at concentrations of 10% as a novel edible coating, to preserve the quality parameters of tomato (Solanumlycopersicum). Fruits were harvested at the mature green stage of ripening. Results showed that the coatings delayed significantly (p < 0.05) the changes in color, weight loss, firmness, titratable acidity, ascorbic acid content, soluble solids concentration, and decay percentage compared to uncoated control fruits. Sensory evaluation proved the efficacy of 10% almond gum and gum arabic coatings to maintain the overall quality of tomato fruits during storage period (20 days). In addition, the difference between gum arabic and almond gum coatings was not significant (p > 0.05) except for pulp color. Therefore, we can suggest the use of almond gum exudate as a novel edible coating extends the shelf-life of tomato fruits on postharvest. PMID- 23733823 TI - Study of process variables in supercritical carbon dioxide extraction of soybeans. AB - Soybean flakes were extracted using supercritical carbon dioxide at 48.3 MPa and 80 degrees C, which is a higher temperature than previously reported. Several operational parameters were explored to determine their effect on extractions. Flakes, as typically used in this industry, provided the best extraction performance. Particle size distributions were created through grinding. Reducing average particle diameters smaller than 0.069 mm had no appreciable effect on increasing extraction efficiencies. Exploration of flow rate indicated that a residence time of less than 60 s for the supercritical carbon dioxide would be sufficient for complete extractions. A solvent mass to load mass ratio of 10:1 was found to be sufficient for extraction of oils from soybean flakes. Increasing moisture in the soybeans led to decreasing extraction efficiency of oils. Finally, soybean hulls had no effect on extraction efficiency. Thus, the de hulling procedure can be removed from the extraction process without decreasing extraction efficiency. PMID- 23733825 TI - Methods to obtain protein concentrates from jumbo squid (Dosidicus gigas) and evaluation of their functionality. AB - Jumbo squid is an important fishery resource in Mexico, and its muscle is lean and white and it has a very low price in the market. It is abundant, but with little or nothing added value, therefore is necessary to search alternatives of processing. Due to muscle characteristics, the aim of this study was to obtain protein concentrates using different methods. They were obtained by means of acidic (acid protein concentrates) and alkaline (alkaline protein concentrates) dissolution. Moreover, a protein concentrate was obtained by direct isoelectric precipitation and by the traditional method (neutral protein concentrates). The yield with better results was alkaline protein concentrates (63.58 +/- 1.8%). The gel hardness was significantly different (p < 0.05), especially for the alkaline protein concentrates. The acid protein concentrates, isoelectric precipitation and alkaline protein concentrates were better with regard to the neutral protein concentrates, concerning the emulsifying and foaming properties. The protein concentrates by means of alkaline dissolution gave a better gelling property, but all the processes had the potential to obtain protein with emulsifying and foaming properties. PMID- 23733824 TI - Effect of amaranth flour (Amaranthus mantegazzianus) on the technological and sensory quality of bread wheat pasta. AB - The technological and sensory quality of pasta made from bread wheat flour substituted with wholemeal amaranth flour (Amaranthus mantegazzianus) at four levels, 15, 30, 40 and 50% w/w was investigated. The quality of the resulted pasta was compared to that of control pasta made from bread wheat flour. The flours were analyzed for chemical composition and pasting properties. Cooking behavior, color, raw and cooked pasta texture, scanning electron microscopy and sensory evaluation were determined on samples. The pasta obtained from amaranth flour showed some detriment of the technological and sensory quality. So, a maximum substitution level of 30% w/w was defined. This is an equilibrium point between an acceptable pasta quality and the improved nutritional and functional properties from the incorporation of amaranth flour. PMID- 23733826 TI - Physicochemical and microbial quality of stored green slender pepper treated with different washing solutions and packaging films. AB - The effects of different washing solutions and packaging films on textural, biochemical and microbial quality of green slender peppers (Capsicum annuum L.) were evaluated. Fresh pepper samples were packaged either in 35 um polypropylene or polyethylene bag without washing or after washing in tap water (TW), 100-ppm chlorine solution, 0.5% calcinated calcium solution followed by 25% ethanol rinsing (CC+E) and 1% citric acid solution followed by 50% ethanol spray (CA+E) and then stored at 10 for 4 weeks. Significant differences were found in gas composition between the two packaging films. Changes in skin puncture force, hue angle, soluble solid content, titratable acidity and pH were statistically insignificant. Chlorophyll a, chlorophyll b and total chlorophyll content declined significantly (P < 0.05) in all treatments during storage. Significant reduction (P < 0.05) in aerobic plate count was found in all washing treatments compared to unwashed sample except in TW. Yeast and mold count of chlorine and CC+E-treated samples were lower than other treatments. Samples of these two treatments also received marketable limit of visual quality scores until 4 weeks of storage in polypropylene film. Results suggest that CC+E could be a potential sanitizer and alternative to chlorine washing and polypropylene film would provide a little better advantage than polyethylene for green slender pepper. PMID- 23733827 TI - Influence of fruit maturity in the susceptibility of Navelina oranges to develop postharvest non-chilling peel pitting. AB - Peel pitting is a disorder occurring mostly during postharvest storage at non chilling temperatures in different varieties of citrus fruit and consists in collapse of flavedo and albedo tissues that may affect oil glands. It has been demonstrated that during postharvest, sharp variations in water potential of cells from flavedo and albedo are sufficient to provoke fractures in cell walls from external albedo resulting in tissue collapse. However, morphology and composition of cells and cell walls in flavedo and albedo varies during fruit maturation and this may affect water flow through the different fruit peel layers and susceptibility of fruit to develop peel pitting. In this paper, we have studied the influence of the stage of maturation in the susceptibility of Navelina orange to develop peel pitting. Except in mature-green fruit, peel pitting increased with maturation after transferring fruit from 45% to 95% relative humidity and was also more severe as more dehydrated was the tissue before transference. Also, differences in water potential of fruit maintained at 45 or 95% relative humidity increased as fruit matured, suggesting that tissue reduces the ability of water adjustment during maturation. In this sense, only mature-green fruit flavedo was able to recover water potential when transferred from 45 to 95% relative humidity. Ethylene production upon transfer from low to high relative humidity increased only in mature tissue and was rapid and transient, and before initial symptoms of peel pitting. Flavedo and albedo water potential (psiw) was substantially reduced during fruit maturation. As lower was the psiw of freshly harvested fruit, minor variations were observed by changes in the storage relative humidity and higher the induced damage. Therefore, the increasing susceptibility of Navelina fruits to develop peel pitting with fruit maturation may be related to a reduced ability to regulate peel evapotranspiration and osmotic adjustment during postharvest storage. PMID- 23733828 TI - Understanding psychopathology in migrants: a mixed categorical-dimensional approach. AB - BACKGROUND: Literature on mental disorders in migrants is constantly increasing. Only a few studies describe psychopathological dimensions in migrants over their nosographic diagnoses; however, there is a growing literature about the greater utility of a categorical-dimensional approach, rather than a solely categorical approach, in the understanding of mental disorders. The aim of this paper is to describe the phenomenology of mental disorders in migrants referred to the Transcultural Psychiatric Team of Bologna (BoTPT), by analysing the psychopathological dimensions that underlie their clinical diagnoses. METHODS: We recruited all migrants who attended the BoTPT between May 1999 and July 2009. The psychopathological assessment was conducted with the Association for Methodology and Documentation in Psychiatry (AMDP) and clinical diagnoses were formulated according to ICD-10. We proceeded through a two-step analysis: (1) comparing the prevalence rates of psychopathological symptoms across diagnoses; then (2) conducting a factor analysis to assess how those symptoms configure psychopathological dimensions and how these dimensions underlie clinical diagnoses. RESULTS: As expected, we found significant associations between diagnoses and the prevalence of their core psychopathological symptoms. Factor analysis revealed a strong polymorphism of the psychopathological presentation of mental disorders and unexpectedly showed that in each diagnostic cluster, the first extracted factor was not composed of core symptoms. CONCLUSIONS: A mixed categorical-dimensional approach seems to improve the description of the psychopathology among migrants, as it adds relevant information regarding psychopathological dimensions useful to the understanding of the peculiar clinical expressivity of our patients. PMID- 23733829 TI - Open sesame. PMID- 23733830 TI - The effects of meniscus injury on the development of knee osteoarthritis: data from the osteoarthritis initiative. AB - BACKGROUND: Osteoarthritis (OA) is a leading cause of pain and disability, and the knee is one of the most commonly affected joints. Many have speculated that injury to the meniscus may play a key role in the development of knee OA; however, the exact relationship of meniscus injury and knee OA is unknown. PURPOSE: To examine the rate of meniscus injuries in patients with and without incident radiographic knee OA and to explore how the type, size, and location of the meniscus injury affects the development of OA. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A secondary case-control analysis was conducted of the Knee Osteoarthritis Initiative (OAI) database, which is a prospective, longitudinal, multicenter cohort study of knee health in patients at risk for knee OA. Eligible patients included those without radiographic OA at baseline in 1 knee. Thirty-two patients who developed radiographic OA in a previously unaffected knee after 2 years of follow-up were matched to 64 age-, sex-, and body mass index-matched patients who did not develop OA. The study analyzed the relationship between the development of OA and the presence of a meniscus tear or degenerative signal, meniscus extrusion, tear type, and size of injury on the baseline magnetic resonance imaging scans. Conditional logistic regression was used to identify significant predictors of OA. RESULTS: The rate of medial meniscus lesions (tear or degeneration) was not significantly higher in those who developed incident OA (85%) compared with the control patients (68%; P = .07). However, medial meniscus extrusion (odds ratio [OR], 3.03; 95% confidence interval [CI], 1.4-6.5), complex tears (OR, 5.0; 95% CI, 1.0-25), and tears with large radial involvement (OR, 5.92; 95% CI, 1.7-7.5) were more common at baseline in cases compared with controls. CONCLUSION: Knees with meniscus tears with greater radial involvement and extrusion are at greater risk for later development of radiographic OA. PMID- 23733831 TI - Sports activity after surgical treatment of intra-articular tibial plateau fractures in skiers. AB - BACKGROUND: Tibial plateau fractures occur frequently while participating in winter sports, but there is no information on whether skiers can resume sports and recreational activities after internal fixation of these fractures. HYPOTHESIS: Skiers can resume low-impact sports activity after internal fixation of tibial plateau fractures. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 103 patients were surveyed by postal questionnaires to determine their sports activities at a mean of 7.8 +/- 1.8 years after internal fixation of intra-articular tibial plateau fractures. The survey also included the Lysholm score, the Tegner activity scale, and a visual analog scale (VAS) for pain. RESULTS: At the time of the survey, 88% of the patients were engaged in sports activities (rate of return to sports, 88%), and 53% continued to participate in downhill skiing. The median number of different activities declined from 5 (range, 1-17) preoperatively to 4 (range, 0-11) postoperatively (P < .01). Sports frequency and duration per week did not change: 3 (range, 1-7) preoperatively versus 3 (range, 0-7) postoperatively (P = .275) and 4 hours (range, 1-16 hours) preoperatively versus 3.5 hours (range, 0-15 hours) postoperatively (P = .217), respectively. Median values of all outcome scores declined: Lysholm score, 100 (range, 85-100) preoperatively versus 94.5 (range, 37-100) postoperatively (P < .01); VAS, 0 (range, 0-7) preoperatively versus 1 (range, 0-8) postoperatively (P < .01). Median Tegner activity scale scores declined in all age groups except for patients aged 51 to 60 years. The ability to participate in sports at the time of follow-up compared with the ability before the accident was rated as "similar" by 57 patients (62.0%) and as "worse" by 35 patients (38.0%). The more severe fracture types, B3 and C3 according to the AO classification system, were associated with poorer outcomes related to return to sports and functional scores. CONCLUSION: A large percentage of skiers with surgically treated intra-articular tibial plateau fractures cannot continue to participate in downhill skiing; however, the majority could resume an active lifestyle for several years after the trauma. Fracture type seems to be an important factor influencing physical activity and general functional outcome. PMID- 23733832 TI - The Positive Illusory Bias in Children and Adolescents With ADHD: Further Evidence. AB - OBJECTIVE: This study aimed to examine the accuracy of self-reports of children and adolescents with ADHD in evaluating activity limitations. METHOD: Self reports of children/adolescents with ADHD (n = 89) were compared with those of nonreferred children (n = 94), relative to parent reports about children's competence. Competence was measured with a 34-item rating scale. Behavioral disorders were documented with the Child Behavior Checklist. RESULTS: Children/adolescents with ADHD were much more likely than controls to overestimate their competence in certain daily activities relative to parent reports, demonstrating a positive illusory bias. Positive illusory bias was found to be pronounced in activities, which were expected to be affected by symptoms of ADHD. Overestimations of competencies were more likely to be accompanied with externalizing problems. CONCLUSION: Results support the presence of the positive illusory bias also in the domain of everyday life activities. Improvement of self evaluation of competencies should become a focus of treatment. PMID- 23733833 TI - Recovery-oriented practices of psychiatric-mental health nursing staff in an acute hospital setting. AB - BACKGROUND: There is a national initiative to integrate recovery-oriented practices into the delivery of mental health services. Few empirical studies have been conducted to measure these practices in psychiatric-mental health (PMH) nursing, particularly in short-term acute hospital settings. OBJECTIVE: This study examined the reliability of the Recovery Self Assessment-Registered Nurse Version (RSA-RN) and explored recovery practices of PMH nurses and nursing staff in an acute treatment setting. DESIGN: A descriptive one-group design with convenience sampling was employed. One hundred and five participants completed the RSA-RN and the demographic data form. RESULTS: The RSA-RN full-scale instrument demonstrated excellent internal consistency, and the five subscales demonstrated acceptable internal consistency. Significant, favorable relationships were found between RSA-RN scores and nursing staff who (a) had formal education in mental health recovery, (b) considered themselves knowledgeable about recovery, and (c) considered their place of work to be "recovery-oriented." CONCLUSION: The RSA-RN is a useful tool in measuring recovery-oriented practice. Formal education should be considered as an intervention to increase recovery-oriented practices in PMH nursing. PMID- 23733837 TI - Stent fabric fatigue of grafts supported by Z-stents versus ringed stents: an in vitro buckling test. AB - Stent-grafts externally fitted with a Z-shaped stents were compared to devices fitted with ringed stents in an in vitro oscillating fatigue machine at 200 cycles per minute and a pressure of 360 mmHg for scheduled durations of up to 1 week. The devices fitted with Z-stents showed a considerably lower endurance limit to buckling compared to the controls. The contact between the apexes of adjacent Z-stents resulted in significant damage to the textile scaffolds and polyester fibers due to the sharp angle of the Z-stents. The ringed stents did not cause any fraying in the textile scaffolds. PMID- 23733834 TI - T cell regulation of natural killer cells. AB - In light of their role in the immune response against tumors and viruses, natural killer (NK) cells represent a promising target for immunotherapy. Before this target is reached, the various mechanisms that control NK cell activity must first be identified and understood. In the past decades, studies have identified two critical processes that prevent spontaneous NK cell-mediated autoimmune activation while maximizing the efficiency of these cells during an immune response. First is the education process, whereby NK cells adapt to their environment by sensing ligands for inhibitory and activating receptors. Second is the priming phase of NK cell activation, which arms NK cells with appropriate cytotoxic molecules during inflammation. New studies now indicate that NK cell proliferation, accumulation, and activation are also under the control of regulatory T cells that restrict availability of IL-2 released by activated CD4(+) T cells. Together with other recent studies, these data highlight the importance of the adaptive immune system in the regulation of NK cell activity. PMID- 23733838 TI - Structure and blood compatibility of highly oriented PLA/MWNTs composites produced by solid hot drawing. AB - Highly oriented poly(lactic acid) (PLA)/multi-walled carbon nanotubes (MWNTs) composites were fabricated through solid hot drawing technology in an effort to improve the mechanical properties and blood biocompatibility of PLA as blood contacting medical devices. It was found that proper MWNTs content and drawing orientation can improve the tensile strength and modulus of PLA dramatically. With the increase in draw ratio, the cold crystallization peak became smaller, and the glass transition and the melting peak of PLA moved to high temperature, while the crystallinity increased, and the grain size decreased, indicating the stress-induced crystallization of PLA during drawing. MWNTs showed a nucleation effect on PLA, leading to the rise in the melting temperature, increase in crystallinity and reduction of spherulite size for the composites. Moreover, the intensity of (002) diffraction of MWNTs increased with draw ratio, indicating that MWNTs were preferentially aligned and oriented during drawing. Microstructure observation demonstrated that PLA matrix had an ordered fibrillar bundle structure, and MWNTs in the composite tended to align parallel to the drawing direction. In addition, the dispersion of MWNTs in PLA was also improved by orientation. Introduction of MWNTs and drawing orientation could significantly enhance the blood compatibility of PLA by prolonging kinetic clotting time, reducing hemolysis ratio and platelet activation. PMID- 23733839 TI - Thromboelastometric maximum clot firmness in platelet-free plasma is influenced by the assay used. AB - BACKGROUND: Viscoelastic tests such as functional fibrinogen polymerization assays (FFPAs) in thrombelastography (TEG((r))) or thromboelastometry (ROTEM((r))) measure the elasticity of extrinsically activated clotting under conditions of platelet inhibition. There are no reports on whether components of the FFPAs have any effects on fibrin polymerization, aside from the effects of platelet inhibition. METHODS: Using various platelet-free plasma (PFP) preparations, we compared the extrinsically activated EXTEM thromboelastometric assay with 3 FFPAs: FIBTEM, FIBTEM PLUS, and the Functional Fibrinogen Test((r)) (FFTEG). These FFPAs activate coagulation extrinsically but additionally inhibit platelet function. We used calibration plasma (Instrumentation Laboratory and Siemens), pooled fresh-frozen plasma (Octaplas) and freshly prepared PFP from a healthy volunteer. EXTEM and all FFPAs were run in parallel on a ROTEM device. RESULTS: Median (interquartile range) maximum clot firmness (MCF) values for all plasma preparations were: 20.5 mm (17.25-22.0 mm) in EXTEM, 23.0 mm (18.5-24.0 mm) in FIBTEM, 23.0 mm (18.25-24.75 mm) in FIBTEM PLUS, and 18.0 mm (16.0-19.0 mm) in FFTEG. Compared with EXTEM, FIBTEM and FIBTEM PLUS (P < 0.01) showed increased MCF values whereas FFTEG (P < 0.001) showed decreased MCF values. Further experiments in PFP showed that the platelet inhibitors used in the FFPAs (cytochalasin D or the glycoprotein-IIb/IIIa inhibitor abciximab) were not causing these alterations in MCF. However, reducing the activating tissue factor concentration (by diluting the extrinsic assay) decreased the MCF. CONCLUSIONS: We speculate that FIBTEM and FIBTEM PLUS may contain stabilizing agents that enhance fibrin polymerization whereas FFTEG might contain less tissue factor than the ROTEM assays. PMID- 23733840 TI - Special article: airway management in reconstructive surgery for noma (cancrum oris). AB - Noma (cancrum oris) is a disease of poverty and malnutrition, which predominantly affects children younger than 10 years in developing countries. Although the majority of sufferers die of sepsis at the time of the initial infection, or of subsequent starvation due to severe trismus and an inability to eat, a small minority of patients survive and require reconstructive surgery for severe facial scarring and deformity. These patients present significant problems to the anesthesiologist with regard to airway management. We present a series of 26 patients undergoing primary and subsequent reconstructive surgery, with particular focus on airway management. We show that airway management, while challenging, can be performed safely and successfully by using individualized airway plans but may require advanced techniques and equipment. Traditional tests focusing on the anterior/superior airway are helpful in assessing patients with facial deformity due to noma. PMID- 23733841 TI - Mechanism of autoinduction of methadone N-demethylation in human hepatocytes. AB - BACKGROUND: There is considerable interindividual and intraindividual variability in methadone metabolism and clearance. Methadone dosing is particularly challenging during initiation of therapy, because of time-dependent increases in hepatic clearance (autoinduction). Although methadone N-demethylation is catalyzed in vitro by cytochrome P4502B6 (CYP2B6) and CYP3A4, and clearance in vivo depends on CYP2B6, mechanism(s) of autoinduction are incompletely understood. In this investigation, we determined mechanism(s) of methadone autoinduction using human hepatocytes. METHODS: Fresh human hepatocytes were exposed to 0.1 to 10 uM methadone for 72 hours. Cells were washed and methadone N demethylation assessed. CYP2B6, CYP3A4, and CYP3A5 messenger RNA (mRNA), protein expression (by gel-free high-performance liquid chromatography mass spectrometry) and catalytic activity (bupropion hydroxylation and alfentanil dealkylation for CYP2B6 and CYP3A4/5, respectively) were measured. Mechanisms of CYP induction were characterized using pregnane X receptor and constitutive androstane receptor reporter gene assays. RESULTS: Methadone (10 uM) increased methadone N demethylation 2-fold, CYP2B6 and CYP3A4 mRNA 3-fold, and protein expression 2 fold. CYP3A5 mRNA was unchanged. CYP2B6 and CYP3A4/5 activities increased 2-fold. Induction by methadone enantiomers (R-methadone versus S-methadone) did not differ. Induction was relatively weak compared with maximum induction by phenobarbital and rifampin. Lower methadone concentrations had smaller effects. Methadone was an agonist for the pregnane X receptor but not the constitutive androstane receptor. CONCLUSIONS: Methadone caused concentration-dependent autoinduction of methadone N-demethylation in human hepatocytes, related to induction of CYP2B6 and CYP3A4 mRNA expression, protein expression, and catalytic activity. Induction was related to pregnane X receptor but not constitutive androstane receptor activation. These in vitro findings provide mechanistic insights into clinical autoinduction of methadone metabolism and clearance. PMID- 23733843 TI - Value of a scheduled duration quantified in terms of equivalent numbers of historical cases. AB - BACKGROUND: Probabilistic estimates of case duration are important for several decisions on and soon before the day of surgery, including filling or preventing a hole in the operating room schedule, and comparing the durations of cases between operating rooms with and without use of specialized equipment to prevent resource conflicts. Bayesian methods use a weighted combination of the surgeon's estimated operating room time and historical data as a prediction for the median duration of the next case of the same combination. Process variability around that prediction (i.e., the coefficient of variation) is estimated using data from similar procedures. A Bayesian method relies on a parameter, tau, that specifies the equivalence between the scheduled estimate and the information contained in the median of a certain number of historical data. METHODS: Times from operating room entrance to exit ("case duration") were obtained for multiple procedures and surgeons at 3 U.S. academic hospitals. A new method for estimating the parameter tau was developed. RESULTS: (1) The method is reliable and has content, convergent, concurrent, and construct validity. (2) The magnitudes of the Somer's D correlations between scheduled and actual durations are small when stratified by procedure (0.05-0.14), but substantial when pooled among all cases and procedures (0.58-0.78). This pattern of correlations matches that when medians (or means) of historical durations are used. Thus, scheduled durations and historical data are essentially interchangeable for estimating the median duration of a future case. (3) Most cases (79%-88%) either have so few historical durations (0-2) that the Bayesian estimate is influenced principally by the scheduled duration, or so many historical durations (>10) that the Bayesian estimate is influenced principally by the historical durations. Thus, the balance between the scheduled duration versus historical data has little influence on results for most cases. (4) Mean absolute predictive errors are insensitive to a wide range of values (e.g., 1-10) for the parameter. The implication is that tau does not routinely need to be calculated for a given hospital, but can be set to any reasonable value (e.g., 5). CONCLUSIONS: Understanding performance of Bayesian methods for case duration is important because variability in durations has a large influence on appropriate management decisions the working day before and on the day of surgery. Both scheduled durations and historical data need to be used for these decisions. What matters is not the choice of tau but quantifying the variability using the Bayesian method and using it in managerial decisions. PMID- 23733842 TI - Special article: evaluation of a novel noninvasive respiration monitor providing continuous measurement of minute ventilation in ambulatory subjects in a variety of clinical scenarios. AB - BACKGROUND: Currently there is no technology that noninvasively measures the adequacy of ventilation in nonintubated patients. A novel, noninvasive Respiratory Volume Monitor (RVM) has been developed to continuously measure and display minute ventilation (MV), tidal volume (TV), and respiratory rate (RR) in a variety of clinical settings. We demonstrate the RVM's accuracy and precision as compared with a standard spirometer under a variety of clinically relevant breathing patterns in nonintubated subjects. METHODS: Thirty-one voluntary subjects completed the primary study. MV, TV, and RR measurements were collected from the RVM and spirometer simultaneously for each participant on day 1 and day 2 and analyzed to determine accuracy, precision, and bias for normal, fast, slow, irregular, and closed-glottis breathing. RESULTS: Data demonstrated that RVM and spirometer measurements of MV and TV are equivalent in a wide range of ambulatory subjects with an average error <10% (95% confidence interval for accuracy <16%, precision <12%, and bias <11%). Repeated measures analysis of variance found no significant difference between spirometry and RVM individual measurements of MV, TV, and RR (P > 0.7), whereas a paired-difference equivalent test demonstrated, with 99% power, that both MV and TV measurements from the 2 devices are equivalent within +/-15%. CONCLUSIONS: This study demonstrates RVM's clinically relevant accuracy and precision in measuring MV, TV, and RR over a 24-hour period and during various breathing patterns. PMID- 23733844 TI - Research, education, and nonclinical service productivity of new junior anesthesia faculty during a 2-year faculty development program. AB - BACKGROUND: As a specialty, anesthesiology has relatively low research productivity. Prior studies indicate that junior faculty development programs favorably affect academic performance. We therefore initiated a junior faculty development program and hypothesized that most (>50%) new junior faculty would take <50 nonclinical days to achieve a primary program goal (e.g., investigation or publication), and <5 nonclinical days to achieve a secondary program goal (e.g., teaching or nonclinical service). METHODS: Twenty new junior faculty participated in the 2-year program which had a goal-oriented structure and was supported by nonclinical time, formally assigned mentors, and a didactic curriculum. Goal productivity equaled the number of program goals accomplished divided by the amount of nonclinical time received. Primary goal productivity was expressed as primary goals accomplished per 50 nonclinical days. Secondary goal productivity was expressed as secondary goals accomplished per 5 nonclinical days. RESULTS: Median primary goal productivity was 0.45 primary goals per 50 nonclinical days (25th-75th interquartile range = 0.00-0.73). Contrary to our hypothesis, most new junior faculty needed >50 nonclinical days to achieve a primary goal (17/20, P = 0.0026). Median secondary goal productivity was 0.57 secondary goals per 5 nonclinical days (25th-75th interquartile range = 0.38 0.77). Contrary to our hypothesis, most new junior faculty needed >5 nonclinical days to accomplish a secondary goal (18/20, P = 0.0004). It was not clear that the faculty development program increased program goal productivity. CONCLUSIONS: Even with structured developmental support, most new junior anesthesia faculty needed >50 nonclinical days to achieve a primary (traditional academic) goal and >5 nonclinical days to achieve a secondary goal. Currently, most new anesthesia faculty are not productive in traditional academic activities (research). They are more productive in activities related to clinical care, education, and patient care systems management. PMID- 23733845 TI - A high-content screening assay for small-molecule modulators of oncogene-induced senescence. AB - Cellular senescence is a state of stable cell growth arrest. Activation of oncogenes such as RAS in mammalian cells typically triggers cellular senescence. Oncogene-induced senescence (OIS) is an important tumor suppression mechanism, and suppression of OIS contributes to cell transformation. Oncogenes trigger senescence through a multitude of incompletely understood downstream signaling events that frequently involve protein kinases. To identify target proteins required for RAS-induced senescence, we developed a small-molecule screen in primary human fibroblasts undergoing senescence induced by oncogenic RAS (H Ras(G12V)). Using a high-content imaging system to monitor two hallmarks of senescence, senescence-associated beta-galactosidase activity expression and inhibition of proliferation, we screened a library of known small-molecule kinase inhibitors for those that suppressed OIS. Identified compounds were subsequently validated and confirmed using a third marker of senescence, senescence-associated heterochromatin foci. In summary, we have established a novel high-content screening platform that may be useful for elucidating signaling pathways mediating OIS by targeting critical pathway components. PMID- 23733846 TI - Establishing a high-throughput and automated cancer cell proliferation panel for oncology lead optimization. AB - Tumor cell proliferation assays are widely used for oncology drug discovery, including target validation, lead compound identification, and optimization, as well as determination of compound off-target activities. Taking advantage of robotic systems to maintain cell culture and perform cell proliferation assays would greatly increase productivity and efficiency. Here we describe the establishment of automated systems for high-throughput cell proliferation assays in a panel of 13 human tumor cell lines. These cell lines were selected from various types of human tumors containing a broad range of well-characterized mutations in multiple cellular signaling pathways. Standard procedures for cell culture and assay performance were developed and optimized in each cell line. Moreover, in-house developed software (i.e., Toolset, Curvemaster, and Biobars) was applied to analyze the data and generate data reports. Using tool compounds, we have shown that results obtained through this panel exhibit high reproducibility over a long period. Furthermore, we have demonstrated that this panel can be used to identify sensitive and insensitive cell lines for specific cancer targets, to drive cellular structure-activity relationships, and to profile compound off-target activities. All those efforts are important for cancer drug discovery lead optimization. PMID- 23733847 TI - The modest beginnings of one genome project. AB - One of the top things on a geneticist's wish list has to be a set of mutants for every gene in their particular organism. Such a set was produced for the yeast, Saccharomyces cerevisiae near the end of the 20th century by a consortium of yeast geneticists. However, the functional genomic analysis of one chromosome, its smallest, had already begun more than 25 years earlier as a project that was designed to define most or all of that chromosome's essential genes by temperature-sensitive lethal mutations. When far fewer than expected genes were uncovered, the relatively new field of molecular cloning enabled us and indeed, the entire community of yeast researchers to approach this problem more definitively. These studies ultimately led to cloning, genomic sequencing, and the production and phenotypic analysis of the entire set of knockout mutations for this model organism as well as a better concept of what defines an essential function, a wish fulfilled that enables this model eukaryote to continue at the forefront of research in modern biology. PMID- 23733848 TI - Identity by descent: variation in meiosis, across genomes, and in populations. AB - Gene identity by descent (IBD) is a fundamental concept that underlies genetically mediated similarities among relatives. Gene IBD is traced through ancestral meioses and is defined relative to founders of a pedigree, or to some time point or mutational origin in the coalescent of a set of extant genes in a population. The random process underlying changes in the patterns of IBD across the genome is recombination, so the natural context for defining IBD is the ancestral recombination graph (ARG), which specifies the complete ancestry of a collection of chromosomes. The ARG determines both the sequence of coalescent ancestries across the chromosome and the extant segments of DNA descending unbroken by recombination from their most recent common ancestor (MRCA). DNA segments IBD from a recent common ancestor have high probability of being of the same allelic type. Non-IBD DNA is modeled as of independent allelic type, but the population frame of reference for defining allelic independence can vary. Whether of IBD, allelic similarity, or phenotypic covariance, comparisons may be made to other genomic regions of the same gametes, or to the same genomic regions in other sets of gametes or diploid individuals. In this review, I present IBD as the framework connecting evolutionary and coalescent theory with the analysis of genetic data observed on individuals. I focus on the high variance of the processes that determine IBD, its changes across the genome, and its impact on observable data. PMID- 23733849 TI - Meiotic and mitotic recombination in meiosis. AB - Meiotic crossovers facilitate the segregation of homologous chromosomes and increase genetic diversity. The formation of meiotic crossovers was previously posited to occur via two pathways, with the relative use of each pathway varying between organisms; however, this paradigm could not explain all crossovers, and many of the key proteins involved were unidentified. Recent studies that identify some of these proteins reinforce and expand the model of two meiotic crossover pathways. The results provide novel insights into the evolutionary origins of the pathways, suggesting that one is similar to a mitotic DNA repair pathway and the other evolved to incorporate special features unique to meiosis. PMID- 23733850 TI - Studying recombination with high-throughput sequencing: an educational primer for use with "fine-scale heterogeneity in crossover rate in the garnet-scalloped region of the Drosophila melanogaster X chromosome". AB - An article by Singh and colleagues in this issue of GENETICS quantifies variation in recombination rate across a small region of the Drosophila melanogaster genome, providing an opportunity for instructors of genetics to introduce or reinforce important concepts such as recombination and recombination rate variation, genome sequencing, and sequence features of the genome. Additional background information, a detailed explanation of the methods used in this study, and discussion questions are provided. PMID- 23733854 TI - The relationship between schizophrenia and frontotemporal dementia. AB - Schizophrenia is a relatively common disorder diagnosed by the presentation of psychotic symptoms in the absence of identifiable neurologic or other organic cause. Frontotemporal dementia (FTD) is a relatively rare progressive neurodegenerative disorder that can present with a multitude of cognitive and behavioral symptoms including psychosis. At times, this phenotypic overlap can mean that schizophrenia and FTD are 2 possibilities in the differential diagnosis of a psychotic presentation. In this article, we systematically review the literature on the relationship between schizophrenia and FTD including case reports that highlight the potential for diagnostic confusion, clinical studies examining the relationship between the disorders, and the molecular evidence of shared pathophysiologic mechanisms. Although a relationship between the disorders is not definitively supported by the current literature, we identify the characteristics of a psychotic presentation that should alert the clinician to the possibility of FTD and describe the areas where further research is needed to clarify the pathophysiologic relationship. PMID- 23733853 TI - Next-generation sequencing of paired tyrosine kinase inhibitor-sensitive and resistant EGFR mutant lung cancer cell lines identifies spectrum of DNA changes associated with drug resistance. AB - Somatic mutations in kinase genes are associated with sensitivity of solid tumors to kinase inhibitors, but patients with metastatic cancer eventually develop disease progression. In EGFR mutant lung cancer, modeling of acquired resistance (AR) with drug-sensitive cell lines has identified clinically relevant EGFR tyrosine kinase inhibitor (TKI) resistance mechanisms such as the second-site mutation, EGFR T790M, amplification of the gene encoding an alternative kinase, MET, and epithelial-mesenchymal transition (EMT). The full spectrum of DNA changes associated with AR remains unknown. We used next-generation sequencing to characterize mutational changes associated with four populations of EGFR mutant drug-sensitive and five matched drug-resistant cell lines. Comparing resistant cells with parental counterparts, 18-91 coding SNVs/indels were predicted to be acquired and 1-27 were lost; few SNVs/indels were shared across resistant lines. Comparison of two related parental lines revealed no unique coding SNVs/indels, suggesting that changes in the resistant lines were due to drug selection. Surprisingly, we observed more CNV changes across all resistant lines, and the line with EMT displayed significantly higher levels of CNV changes than the other lines with AR. These results demonstrate a framework for studying the evolution of AR and provide the first genome-wide spectrum of mutations associated with the development of cellular drug resistance in an oncogene-addicted cancer. Collectively, the data suggest that CNV changes may play a larger role than previously appreciated in the acquisition of drug resistance and highlight that resistance may be heterogeneous in the context of different tumor cell backgrounds. PMID- 23733855 TI - Association between functional impairment, depression, and extrapyramidal signs in neuroleptic-free patients with Alzheimer disease. AB - BACKGROUND: Extrapyramidal signs (EPSs) are commonly observed in patients with Alzheimer disease (AD). We report here the base rate of EPS in a large cohort of patients with AD who were not receiving neuroleptic drugs, and the associations of EPS with functional outcomes and depressive symptoms. METHODS: In a consortium involving 56 clinics, we recruited 2614 patients with AD. We estimated basic activities of daily living (ADL) and instrumental ADL by the Barthel index and the Seoul-Instrumental Activities of Daily Living (S-IADL) scales, respectively. Depressive symptoms were assessed using the 15-item Geriatric Depression Scale (GDS-15). The EPS group was defined by the presence of at least 1 EPS based on a focused neurologic examination. RESULTS: The prevalence of EPS-positive patients was 12%. These had lower Korean version of the Mini-Mental State Examination (K MMSE) scores than the EPS-negative cases (P < .001). After controlling for demographic, medical, radiological, genetic, and cognitive (K-MMSE) factors, the proportion of patients with impaired ADL was significantly higher in the EPS group than in the non-EPS group (P < .001, odds ratio = 1.90, 95% confidence interval, 1.45-2.48, and logistic regression). The S-IADL scores were significantly higher in the EPS group than this in the non-EPS group (P < .001, regression coefficient = 3.19, and median regression). The GDS-15 scores were higher in the EPS group (P = .04, regression coefficient = 0.89, and median regression). CONCLUSION: The presence of EPS in patients with AD who were not receiving neuroleptic drugs was associated with more impaired basic and instrumental ADL functioning and with greater depression symptoms. PMID- 23733851 TI - Autophagic processes in yeast: mechanism, machinery and regulation. AB - Autophagy refers to a group of processes that involve degradation of cytoplasmic components including cytosol, macromolecular complexes, and organelles, within the vacuole or the lysosome of higher eukaryotes. The various types of autophagy have attracted increasing attention for at least two reasons. First, autophagy provides a compelling example of dynamic rearrangements of subcellular membranes involving issues of protein trafficking and organelle identity, and thus it is fascinating for researchers interested in questions pertinent to basic cell biology. Second, autophagy plays a central role in normal development and cell homeostasis, and, as a result, autophagic dysfunctions are associated with a range of illnesses including cancer, diabetes, myopathies, some types of neurodegeneration, and liver and heart diseases. That said, this review focuses on autophagy in yeast. Many aspects of autophagy are conserved from yeast to human; in particular, this applies to the gene products mediating these pathways as well as some of the signaling cascades regulating it, so that the information we relate is relevant to higher eukaryotes. Indeed, as with many cellular pathways, the initial molecular insights were made possible due to genetic studies in Saccharomyces cerevisiae and other fungi. PMID- 23733856 TI - Functional status and mortality in older women with gynecological cancer. AB - BACKGROUND: Screening tools for the identification of vulnerable older patients with cancer are needed. Aim of this study is to measure the prognostic value of multiple screening tools for the assessment of mortality risk in oncogeriatrics. METHODS: The prognostic value of the following assessment tools was tested in 200 older women with gynecological cancer (mean age = 73.5 years) for 1-year mortality: Short Physical Performance Battery, usual gait speed, handgrip strength, Eastern Cooperative Oncology Group Performance Status scale, Karnofsky Performance Status scale, Vulnerable Elders Scale-13, activities of daily living, and instrumental activities of daily living. Cox proportional hazard models were performed to estimate the associations of the performance measures with mortality. Areas under receiver operating characteristic curves were also estimated. RESULTS: Twenty-three participants (11.5%) died during the follow-up. The Short Physical Performance Battery, usual gait speed, and instrumental activities of daily living were the only parameters significantly associated with mortality, even after adjustment for confounders. No statistically significant results were reported for other functional measures. Similar results were obtained when testing the predictive values of the performance measures at the receiver operating characteristic analyses. CONCLUSIONS: The Short Physical Performance Battery and especially the usual gait speed may represent promising tools for measuring the mortality risk of older cancer patients, thus potentially supporting clinical decisions. Further studies are needed to confirm and extend the present findings. PMID- 23733857 TI - "You are such a disappointment!": negative emotions and parents' perceptions of adult children's lack of success. AB - OBJECTIVES: Parents' perceptions of their adult children's successes (or lack thereof) may be associated in different ways with discrete negative emotions (e.g., guilt, anger, disappointment, and worry). Furthermore, mothers and fathers may vary in their reactions to children's success in different domains. METHOD: Participants included 158 mothers and fathers from the same families (N = 316) and their adult child. Mothers and fathers evaluated their adult children's successes in (a) career and (b) relationship domains. Mothers and fathers also reported on several negative emotions in the parent-child tie: guilt, anger, disappointment, and worry. RESULTS: For fathers, perceptions of children's poorer career success were associated with disappointment, anger, and guilt. Mothers' perceptions of children's lack of career success were associated with disappointment and worry. Mothers' perceptions of children's poorer success in relationships were associated with each of the negative emotions, with the exception of anger. DISCUSSION: Parents experience emotions associated with unmet goals and future concerns in relationships with less successful children. Mothers may respond emotionally to career and relationship success, whereas fathers may respond emotionally primarily to their child's career success. Findings underscore the importance of considering the context of parents' negative emotional experiences in ties to adult children. PMID- 23733858 TI - Selectivity of attrition in longitudinal studies of cognitive functioning. AB - OBJECTIVES: Identify characteristics distinguishing people who do and do not continue to participate in a longitudinal study and determine whether the longitudinal changes for people who continue are representative of the changes that would have occurred had longitudinal data been available from all of the initial participants. METHOD: Moderately large samples of returning (N = 2,082) and nonreturning (N = 1,698) participants across a wide age range (i.e., 18-97 years of age) performed a battery of cognitive tests and completed personality and mood questionnaires. Differences between the groups were examined with multiple regression analyses with age, returner status, and their interaction as predictors. RESULTS: Compared with participants who did not return, returning participants at the initial occasion had higher levels of each cognitive ability and of certain personality characteristics (e.g., agreeableness and openness), but many of the differences were only apparent among adults older than 50 years of age. Importantly, there was no evidence that the longitudinal change for nonreturning participants would have been different from that among the participants who did return. DISCUSSION: The phenomenon of selective attrition is more complex than often assumed, and it may not necessarily limit the generalizability of longitudinal comparisons. PMID- 23733867 TI - The Duke Center for the Study of Aging: one of our earliest roots. AB - The Duke University Center for the Study of Aging and Human Development (Duke CFA) was established by a multidisciplinary group of visionary scientists in 1955. It is the oldest continually operating center or institute dedicated to aging in the United States. This article outlines the origins of the Duke CFA and summarizes the major research initiatives conducted in its early years. The primary focus is on these landmark studies and their legacies. Those studies made important initial contributions to the knowledge base, introduced measurement tools and research designs that became standards in the field, and served as the impetus for later and current research. The hallmarks of these studies are their multidisciplinary foundations and their focus on the health and well-being of older adults. The Duke CFA's current research clearly builds upon the goals, insights, and empirical results of previous research initiatives. Although aging research is and has been the bedrock of the Duke CFA, developing services responsive to the needs of older adults and multidisciplinary training have also been hallmarks of the Duke CFA. Duke's Geriatric Evaluation and Treatment Clinic was established in 1974 and remains a national model for geriatric assessment. Our postdoctoral research training program has graduated more than 200 scholars and our Geriatric Fellowship program has graduated 113 geriatricians. Many of our graduates have exemplary careers in aging, contributing to important research advances, providing care to thousands of older adults, serving as leaders in the field, and training new generations of gerontologists and geriatricians. PMID- 23733868 TI - Role of high endothelial venule-expressed heparan sulfate in chemokine presentation and lymphocyte homing. AB - Lymphocyte homing to peripheral lymph nodes (PLNs) is mediated by multistep interactions between lymphocytes and high endothelial venules (HEVs). Heparan sulfate (HS) has been implicated in the presentation of chemokines on the surface of HEVs during this process. However, it remains unclear whether this cell surface presentation is a prerequisite for lymphocyte homing. In this study, we generated conditional knockout (cKO) mice lacking Ext1, which encodes a glycosyltransferase essential for HS synthesis, by crossing Ext1(flox/flox) mice with GlcNAc6ST-2-Cre transgenic mice expressing Cre recombinase in HEVs. Immunohistochemical studies indicated that HS expression was specifically eliminated in PLN HEVs but retained in other blood vessels in the cKO mice. The accumulation of a major secondary lymphoid tissue chemokine, CCL21, on HEVs was also abrogated without affecting CCL21 mRNA levels, indicating that HS presents CCL21 on HEVs in vivo. Notably, a short-term lymphocyte homing assay indicated that lymphocyte homing to PLNs was diminished in the cKO mice by 30-40%. Consistent with this result, contact hypersensitivity responses were also diminished in the cKO mice. The residual lymphocyte homing to PLNs in the cKO mice was dependent on pertussis toxin-sensitive Gi protein signaling, in which lysophosphatidic acid-mediated signaling was partly involved. These results suggest that chemokine presentation by HS on the surface of HEVs facilitates but is not absolutely required for lymphocyte homing. PMID- 23733869 TI - Structural evaluation of a mimicry-recognizing paratope: plasticity in antigen antibody interactions manifests in molecular mimicry. AB - Molecular mimicry manifests antagonistically with respect to the specificity of immune recognition. However, it often occurs because different Ags share surface topologies in terms of shape or chemical nature. It also occurs when a flexible paratope accommodates dissimilar Ags by adjusting structural features according to the antigenic epitopes or differential positioning in the Ag combining site. Toward deciphering the structural basis of molecular mimicry, mAb 2D10 was isolated from a maturing immune response elicited against methyl alpha-d mannopyranoside and also bound equivalently to a dodecapeptide. The physicochemical evidence of this carbohydrate-peptide mimicry in the case of mAb 2D10 had been established earlier. These studies had strongly suggested direct involvement of a flexible paratope in the observed mimicry. Surprisingly, comparison of the Ag-free structure of single-chain variable fragment 2D10 with those bound to sugar and peptide Ags revealed a conformationally invariant state of the Ab while binding to chemically and structurally disparate Ags. This equivalent binding of the two dissimilar Ags was through mutually independent interactions, demonstrating functional equivalence in the absence of structural correlation. Thus, existence of a multispecific, mature Ab in the secondary immune response was evident, as was the plasticity in the interactions while accommodating topologically diverse Ags. Although our data highlight the structural basis of receptor multispecificity, they also illustrate mechanisms adopted by the immune system to neutralize the escape mutants generated during pathogenic insult. PMID- 23733870 TI - Dormant Mycobacterium tuberculosis fails to block phagosome maturation and shows unexpected capacity to stimulate specific human T lymphocytes. AB - Dormancy is defined as a stable but reversible nonreplicating state of Mycobacterium tuberculosis. It is currently thought that dormant M. tuberculosis (D-Mtb) is responsible for latent tuberculosis (TB) infection. Recently, D-Mtb was also shown in sputa of patients with active TB, but the capacity of D-Mtb to stimulate specific immune responses was not investigated. We observed that purified protein derivative-specific human CD4(+) T lymphocytes recognize mycobacterial Ags more efficiently when macrophages are infected with D-Mtb instead of replicating M. tuberculosis (R-Mtb). The different Ag recognition occurs even when the two forms of mycobacteria equally infect and stimulate macrophages, which secrete the same cytokine pattern and express MHC class I and II molecules at the same levels. However, D-Mtb but not R-Mtb colocalizes with mature phagolysosome marker LAMP-1 and with vacuolar proton ATPase in macrophages. D-Mtb, unlike R-Mtb, is unable to interfere with phagosome pH and does not inhibit the proteolytic efficiency of macrophages. We show that D-Mtb downmodulates the gene Rv3875 encoding for ESAT-6, which is required by R-Mtb to block phagosome maturation together with Rv3310 gene product SapM, previously shown to be downregulated in D-Mtb. Thus, our results indicate that D-Mtb cannot escape MHC class II Ag-processing pathway because it lacks the expression of genes required to block the phagosome maturation. Data suggest that switching to dormancy not only represents a mechanism of survival in latent TB infection, but also a M. tuberculosis strategy to modulate the immune response in different stages of TB. PMID- 23733871 TI - Scavenger receptor A modulates the immune response to pulmonary Cryptococcus neoformans infection. AB - Scavenger receptors represent an important class of pattern recognition receptors shown to mediate both beneficial and detrimental roles in host defense against microbial pathogens. The role of the major macrophage scavenger receptor, scavenger receptor A (SRA), in the immune response against the pathogenic fungus, Cryptococcus neoformans, is unknown. To evaluate the role of SRA in anticryptococcal host defenses, SRA(+/+) mice and SRA(-/-) mice were infected intratracheally with C. neoformans. Results show that infection of SRA(-/-) mice resulted in a reduction in the pulmonary fungal burden at the efferent phase (3 wk) compared with SRA(+/+) mice. Improved fungal clearance in SRA(-/-) mice was associated with decreased accumulation of eosinophils and greater accumulation of CD4(+) T cells and CD11b(+) dendritic cells. Additional parameters were consistent with enhanced anticryptococcal immunity in the infected SRA(-/-) mice: 1) increased expression of the costimulatory molecules CD80 and CD86 by lung APCs, 2) decreased expression of Th2 cytokines (IL-4 and IL-13) and IL-10 in lung leukocytes and in cryptococcal Ag-pulsed splenocytes, 3) diminished IgE production in sera, and 4) increased hallmarks of classical pulmonary macrophage activation. These effects were preceded by increased expression of early pro-Th1 genes in pulmonary lymph nodes at the afferent phase (1 wk). Collectively, our data show that SRA can be exploited by C. neoformans to interfere with the early events of the afferent responses that support Th1 immune polarization. This results in amplification of Th2 arm of the immune response and subsequently impaired adaptive control of C. neoformans in the infected lungs. PMID- 23733872 TI - Regulatory CD8+ T cells associated with erosion of immune surveillance in persistent virus infection suppress in vitro and have a reversible proliferative defect. AB - CD4(+) T cell help is critical for CD8(+) T cell memory and immune surveillance against persistent virus infections. Our recent data have showed the lack of CD4(+) T cells leads to the generation of an IL-10-producing CD8(+) T cell population during persistent murine gamma-herpesvirus-68 (MHV-68) infection. IL 10 from these cells is partly responsible for erosion in immune surveillance, leading to spontaneous virus reactivation in lungs. In this study, we further characterized the generation, phenotype, and function of these IL-10-producing CD8(+) T cells by comparing with a newly identified IL-10-producing CD8(+) T cell population present during the acute stage of the infection. The IL-10-producing CD8(+) populations in acute and chronic stages differed in their requirement for CD4(+) T cell help, the dependence on IL-2/CD25 and CD40-CD40L pathways, and the ability to proliferate in vitro in response to anti-CD3 stimulation. IL-10 producing CD8(+) T cells in the chronic stage showed a distinct immunophenotypic profile, sharing partial overlap with the markers of previously reported regulatory CD8(+) T cells, and suppressed the proliferation of naive CD8(+) T cells. Notably, they retained the ability to produce effector cytokines and cytotoxic activity. In addition, the proliferative defect of the cells could be restored by addition of exogenous IL-2 or blockade of IL-10. These data suggest that the IL-10-producing CD8(+) T cells arising in chronic MHV-68 infection in the absence of CD4(+) T cell help belong to a subset of CD8(+) regulatory T cells. PMID- 23733873 TI - Both NK cell-intrinsic and -extrinsic STAT1 signaling are required for NK cell response against vaccinia virus. AB - NK cells play an important role in innate immune control of the infection with vaccinia virus (VV). However, it remains incompletely defined how the activation of NK cells in response to VV is regulated. In this study, we showed that STAT1 was critical for NK cell activation upon VV infection and the subsequent clearance of VV infection in vivo. We further demonstrated that STAT1 signaling in both NK and accessory cells such as dendritic cells was required for efficient NK cell activation upon VV infection. Mechanistically, STAT1 signaling in dendritic cells promoted the expression of NKG2D ligands, which is required for NK cell activation via the NKG2D pathway. Taken together, our data suggest that STAT1 mediates anti-VV effect by promoting NK cell activation through both NK intrinsic and extrinsic mechanisms and may provide insights into the design of effective NK cell-based therapies for viral infections. PMID- 23733874 TI - Autologous Tax-specific CTL therapy in a primary adult T cell leukemia/lymphoma cell-bearing NOD/Shi-scid, IL-2Rgammanull mouse model. AB - We expanded human T-lymphotropic virus type 1 Tax-specific CTL in vitro from PBMC of three individual adult T cell leukemia/lymphoma (ATL) patients and assessed their therapeutic potential in an in vivo model using NOG mice bearing primary ATL cells from the respective three patients (ATL/NOG). In these mice established with cells from a chronic-type patient, treatment by i.p. injection of autologous Tax-CTL resulted in greater infiltration of CD8-positive T cells into each ATL lesion. This was associated with a significant decrease of ATL cell infiltration into blood, spleen, and liver. Tax-CTL treatment also significantly decreased human soluble IL-2R concentrations in the sera. In another group of ATL/NOG mice, Tax-CTL treatment led to a significant prolongation of survival time. These findings show that Tax-CTL can infiltrate the tumor site, recognize, and kill autologous ATL cells in mice in vivo. In ATL/NOG mice with cells from an acute type patient, whose postchemotherapeutic remission continued for >18 mo, antitumor efficacy of adoptive Tax-CTL therapy was also observed. However, in ATL/NOG mice from a different acute-type patient, whose ATL relapsed after 6 mo of remission, no efficacy was observed. Thus, although the therapeutic effects were different for different ATL patients, to the best of our knowledge, this is the first report that adoptive therapy with Ag-specific CTL expanded from a cancer patient confers antitumor effects, leading to significant survival benefit for autologous primary cancer cell-bearing mice in vivo. The present study contributes to research on adoptive CTL therapy, which should be applicable to several types of cancer. PMID- 23733875 TI - Cyclooxygenase-2 deficiency in macrophages leads to defective p110gamma PI3K signaling and impairs cell adhesion and migration. AB - Cyclooxygenase (Cox)-2 dependent PGs modulate several functions in many pathophysiological processes, including migration of immune cells. In this study, we addressed the role of Cox-2 in macrophage migration by using in vivo and in vitro models. Upon thioglycolate challenge, CD11b(+) F4/80(+) macrophages showed a diminished ability to migrate to the peritoneal cavity in cox-2(-/-) mice. In vivo migration of cox-2(-/-) macrophages from the peritoneal cavity to lymph nodes, as well as cell adhesion to the mesothelium, was reduced in response to LPS. In vitro migration of cox-2(-/-) macrophages toward MCP-1, RANTES, MIP 1alpha, or MIP-1beta, as well as cell adhesion to ICAM-1 or fibronectin, was impaired. Defects in cell migration were not due to changes in chemokine receptor expression. Remarkably, cox-2(-/-) macrophages showed a deficiency in focal adhesion formation, with reduced phosphorylation of paxillin (Tyr(188)). Interestingly, expression of the p110gamma catalytic subunit of PI3K was severely reduced in the absence of Cox-2, leading to defective Akt phosphorylation, as well as cdc42 and Rac-1 activation. Our results indicate that the paxillin/p110gamma-PI3K/Cdc42/Rac1 axis is defective in cox-2(-/-) macrophages, which results in impaired cell adhesion and migration. PMID- 23733876 TI - The IL-33/ST2 pathway controls coxsackievirus B5-induced experimental pancreatitis. AB - Coxsackievirus B (CVB) is a common cause of acute and chronic infectious myocarditis and pancreatitis. Th1 cells producing IFN-gamma and TNF-alpha are important for CVB clearance, but they are also associated with the pathogenesis of inflammatory lesions, suggesting that the modulation of Th1 and Th2 balance is likely important in controlling CVB-induced pancreatitis. We investigated the role of IL-33, which is an important recently discovered cytokine for induction of Th2-associated responses, in experimental CVB5 infection. We found that mice deficient in IL-33R, T1/ST2, significantly developed more severe pancreatitis, had greater weight loss, and contained higher viral load compared with wild-type (WT) mice when infected with CVB5. Conversely, WT mice treated with rIL-33 developed significantly lower viral titers, and pancreatitis was attenuated. Mechanistic studies demonstrated that IL-33 enhances the degranulation and production of IFN-gamma and TNF-alpha by CD8(+) T and NK cells, which is associated with viral clearance. Furthermore, IL-33 triggers the production of IL 4 from mast cells, which results in enhanced differentiation of M2 macrophages and regulatory T cells, leading to the attenuation of inflammatory pancreatitis. Adoptively transferred mast cells or M2 macrophages reversed the heightened pancreatitis in the T1/ST2(-/-) mice. In contrast, inhibition of regulatory T cells exacerbated the disease in WT mice. Together, our findings reveal an unrecognized IL-33/ST2 functional pathway and a key mechanism for CVB5-induced pancreatitis. These data further suggest a novel approach in treating virus induced pancreatitis, which is a major medical condition with unmet clinical needs. PMID- 23733877 TI - Fetal-maternal alignment of regulatory T cells correlates with IL-10 and Bcl-2 upregulation in pregnancy. AB - Transplacental immune regulation refers to the concept that during pregnancy, significant cross-talk occurs between the maternal and fetal immune system with potential long-term effects for both the mother and child. In this study, we made the surprising observation that there is a strong correlation of peripheral blood regulatory T (Treg) cells between the mother and the fetus. In contrast, there is no significant Treg cell correlation between paternal fetal dyads (pairs), suggesting that the specific context of pregnancy, rather than the genetic parental similarity to the fetus, is responsible for this correlation. Gene microarray analysis of Treg cells identified a typical IL-10-dependent signature in maternal and fetal Treg cells. In addition, a direct correlation of serum IL 10 protein levels between maternal fetal dyads was observed. Furthermore, we show that maternal serum IL-10 levels correlate with serum estradiol and estriol, implicating hormonal involvement in this alignment. Interestingly, we show that Treg cells possess higher expression of IL-10 receptor alpha and that Treg cell IL-10 receptor alpha expression directly correlates with their Bcl-2 expression. Indeed, in vitro data in both humans and mice demonstrate that IL-10 upregulates Bcl-2 specifically in Treg cells but not non-Treg cells. Our results provide evidence for transplacental regulation of cellular immunity and suggest that IL 10 may influence Treg cell homeostasis through its effect on Treg cell Bcl-2 expression. These novel findings have important implications on immune tolerance in pregnancy and beyond in areas of autoimmunity, allergy, and transplantation. PMID- 23733878 TI - Optimal germinal center B cell activation and T-dependent antibody responses require expression of the mouse complement receptor Cr1. AB - Follicular dendritic cells (FDCs) and complement receptor (Cr)1 and complement receptor (Cr)2 are important for the generation of humoral immunity. Cr1/2 expression on B cells and FDCs was shown to provide a secondary signal for B cell activation, to facilitate transport of Ag in immune follicles, and to enhance retention of immune complexes by FDCs. We show in this study that murine B cells predominantly express the Cr2 product from the Cr2 gene, whereas FDCs almost exclusively express the Cr1 isoform generated from the Cr2 gene. To define the specific role of Cr1, we created an animal that maintains normal cell-restricted expression of Cr2 but does not express Cr1. Cr1-deficient (Cr1KO) mice develop normal B1 and B2 immature and mature B cell subsets and have normal levels of naive serum Abs but altered levels of natural Abs. Immunization of the Cr1KO animal demonstrates deficient Ab responses to T-dependent, but not T-independent, Ags. Germinal centers from the immunized Cr1KO animal possess a deficiency in activated B cells, similar to that seen for animals lacking both Cr1 and Cr2 or C3. Finally, animals lacking only Cr1 respond similarly to wild-type animals to infections with Streptococcus pneumoniae, a pathogen to which animals lacking C3 or both Cr1 and Cr2 are particularly sensitive. Altogether, these data suggest that the production of Cr1, primarily by FDCs, is critical in the generation of appropriately activated B cells of the germinal center and the generation of mature Ab responses. PMID- 23733879 TI - The disease-ameliorating function of autoregulatory CD8 T cells is mediated by targeting of encephalitogenic CD4 T cells in experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS, and CD8 T cells are the predominant T cell population in MS lesions. Given that transfer of CNS-specific CD8 T cells results in an attenuated clinical demyelinating disease in C57BL/6 mice with immunization-induced experimental autoimmune encephalomyelitis (EAE), we investigated the cellular targets and mechanisms of autoreactive regulatory CD8 T cells. In this study we report that myelin oligodendrocyte glycoprotein peptide (MOG35-55)-induced CD8 T cells could also attenuate adoptively transferred, CD4 T cell-mediated EAE. Whereas CD8(-/-) mice exhibited more severe EAE associated with increased autoreactivity and inflammatory cytokine production by myelin-specific CD4 T cells, this was reversed by adoptive transfer of MOG-specific CD8 T cells. These autoregulatory CD8 T cells required in vivo MHC class Ia (K(b)D(b)) presentation. Interestingly, MOG-specific CD8 T cells could also suppress adoptively induced disease using wild-type MOG35-55-specific CD4 T cells transferred into K(b)D(b-/-) recipient mice, suggesting direct targeting of encephalitogenic CD4 T cells. In vivo trafficking analysis revealed that autoregulatory CD8 T cells are dependent on neuroinflammation for CNS infiltration, and their suppression/cytotoxicity of MOG specific CD4 T cells is observed both in the periphery and in the CNS. These studies provide important insights into the mechanism of disease suppression mediated by autoreactive CD8 T cells in EAE. PMID- 23733880 TI - Cutting edge: inhaled antigen upregulates retinaldehyde dehydrogenase in lung CD103+ but not plasmacytoid dendritic cells to induce Foxp3 de novo in CD4+ T cells and promote airway tolerance. AB - Dendritic cell (DC)-T cell interactions that underlie inducible/adaptive regulatory T cell generation and airway tolerance are not well understood. In this study, we show that mice lacking CD11c(hi) lung DCs, but containing plasmacytoid DCs (pDCs), fail tolerization with inhaled Ag and cannot support Foxp3 induction in vivo in naive CD4(+) T cells. CD103(+) DCs from tolerized mice efficiently induced Foxp3 in cocultured naive CD4(+) T cells but pDCs and lung macrophages failed to do so. CD103(+) DCs, but not pDCs or lung macrophages, upregulated the expression of retinaldehyde dehydrogenase 2 (aldh1a2), which is key for the production of retinoic acid, a cofactor for TGF-beta for Foxp3 induction. Batf3(-/-) mice, selectively lacking CD103(+) DCs, failed tolerization by inhaled Ag. Collectively, our data show that pulmonary tolerance is dependent on CD103(+) DCs, correlating with their ability to upregulate aldh1a2, which can promote Foxp3 expression in T cells. PMID- 23733881 TI - Critical role of dendritic cell-derived IL-27 in antitumor immunity through regulating the recruitment and activation of NK and NKT cells. AB - Critical roles of IL-27 in autoimmune diseases and infections have been reported; however, the contribution of endogenous IL-27 to tumor progression remains elusive. In this study, by using IL-27p28 conditional knockout mice, we demonstrate that IL-27 is critical in protective immune response against methyl cholanthrene-induced fibrosarcoma and transplanted B16 melanoma, and dendritic cells (DCs) are the primary source. DC-derived IL-27 is required for shaping tumor microenvironment by inducing CXCL-10 expression in myeloid-derived suppressor cells and regulating IL-12 production from DCs, which lead to the recruitment and activation of NK and NKT cells resulting in immunological control of tumors. Indeed, reconstitution of IL-27 or CXCL-10 in tumor site significantly inhibits tumor growth and restores the number and activation of NK and NKT cells. In summary, our study identifies a previous unknown critical role of DC-derived IL-27 in NK and NKT cell-dependent antitumor immunity through shaping tumor microenvironment, and sheds light on developing novel therapeutic approaches based on IL-27. PMID- 23733882 TI - FoxO1 controls effector-to-memory transition and maintenance of functional CD8 T cell memory. AB - During a T cell response, naive CD8 T cells differentiate into effector cells. Subsequently, a subset of effector cells termed memory precursor effector cells further differentiates into functionally mature memory CD8 T cells. The transcriptional network underlying this carefully scripted process is not well understood. In this study, we report that the transcription factor FoxO1 plays an integral role in facilitating effector-to-memory transition and functional maturation of memory CD4 and CD8 T cells. We find that FoxO1 is not required for differentiation of effector cells, but in the absence of FoxO1, memory CD8 T cells displayed features of senescence and progressive attrition in polyfunctionality, which in turn led to impaired recall responses and poor protective immunity. These data suggest that FoxO1 is essential for maintenance of functional CD8 T cell memory and protective immunity. Under competing conditions in bone marrow chimeric mice, FoxO1 deficiency did not perturb clonal expansion or effector differentiation. Instead, FoxO1-deficient memory precursor effector cells failed to survive and form memory CD8 T cells. Mechanistically, FoxO1 deficiency perturbed the memory CD8 T cell transcriptome, characterized by pronounced alterations in the expression of genes that encode transcription factors (including Tcf7), effector molecules, cell cycle regulators, and proteins that regulate fatty acid, purine, and pyramidine metabolism and mitochondrial functions. We propose that FoxO1 is a key regulator that reprograms and steers the differentiation of effector cells to functionally competent memory cells. These findings have provided fundamental insights into the mechanisms that regulate the quality of CD8 T cell memory to intracellular pathogens. PMID- 23733883 TI - Naturally occurring ERAP1 haplotypes encode functionally distinct alleles with fine substrate specificity. AB - Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims peptides for MHC class I presentation, influencing the degree and specificity of CD8(+) T cell responses. Single-nucleotide polymorphisms within the exons encoding ERAP1 are associated with autoimmune diseases and cervical carcinoma, but it is not known whether they act independently or as disease-associated haplotypes. We sequenced ERAP1 from 20 individuals and show that single-nucleotide polymorphisms occur as distinct haplotypes in the human population and that these haplotypes encode functionally distinct ERAP1 alleles. Using a wide range of substrates, we are able to demonstrate that for any given substrate distinct ERAP1 alleles can be "normal," "hypofunctional," or "hyperfunctional" and that each allele has a trend bias toward one of these three activities. Thus, the repertoire of peptides presented at the cell surface for recognition by CTL is likely to depend on the precise combination of both MHC class I and ERAP1 alleles expressed within an individual, and has important implications for predisposition to disease. PMID- 23733884 TI - Commonly used "nutrition" indicators do not predict outcome in the critically ill: a systematic review. AB - BACKGROUND: In everyday practice, clinicians use a variety of anthropometric, biochemical, and clinical indicators to monitor nutrition therapy, but these have limitations in the critically ill. This systematic review of randomized controlled trials aimed to assess whether commonly used anthropometric, biochemical, and clinical nutrition indicators are predictive of patient outcomes in the critically ill. MATERIALS AND METHODS: A computerized bibliographic search was performed using MEDLINE, EMBASE, and CINAHL from 1950 to December 2012, as well as a citation review of relevant articles. Randomized clinical trials of any nutrition interventions in critically ill patients were included if they reported any nutrition indicator after baseline and any clinically meaningful outcome variables. Information about study quality, setting, and findings was extracted using standardized protocols. Because of the heterogeneity of study characteristics, only a narrative synthesis was undertaken. RESULTS: Of 223 studies obtained with the search strategy, 2 independent reviewers identified selected 51 studies meeting the eligibility criteria. These reported indicators such as serum albumin, serum prealbumin (transthyretin), retinol-binding protein, transferrin, and lymphocytes. Thirty studies did not report a significant difference in clinical outcomes. Of the remainder, the number of studies supporting a statistical relationship between outcome and particular nutrition indicators was equal to, or outnumbered by, the studies not supporting such a relationship. CONCLUSION: None of the commonly used nutrition monitoring parameters demonstrated consistent associations with outcome in randomized controlled trials. Development of nutrition indicators other than laboratory tests that are more closely linked to the patient's clinical progress should be a priority. PMID- 23733885 TI - Deficiency of liver Comparative Gene Identification-58 causes steatohepatitis and fibrosis in mice. AB - Triglyceride (TG) accumulation in hepatocytes (hepatic steatosis) preludes the development of advanced nonalcoholic fatty liver diseases (NAFLDs) such as steatohepatitis, fibrosis, and cirrhosis. Mutations in human Comparative Gene Identification-58 (CGI-58) cause cytosolic TG-rich lipid droplets to accumulate in almost all cell types including hepatocytes. However, it is unclear if CGI-58 mutation causes hepatic steatosis locally or via altering lipid metabolism in other tissues. To directly address this question, we created liver-specific CGI 58 knockout (LivKO) mice. LivKO mice on standard chow diet displayed microvesicular and macrovesicular panlobular steatosis, and progressed to advanced NAFLD stages over time, including lobular inflammation and centrilobular fibrosis. Compared with CGI-58 floxed control littermates, LivKO mice showed 8 fold and 52-fold increases in hepatic TG content, which was associated with 40% and 58% decreases in hepatic TG hydrolase activity at 16 and 42 weeks, respectively. Hepatic cholesterol also increased significantly in LivKO mice. At 42 weeks, LivKO mice showed increased hepatic oxidative stress, plasma aminotransferases, and hepatic mRNAs for genes involved in fibrosis and inflammation, such as alpha-smooth muscle actin, collagen type 1 alpha1, tumor necrosis factor alpha, and interleukin-1beta. In conclusion, CGI-58 deficiency in the liver directly causes not only hepatic steatosis but also steatohepatitis and fibrosis. PMID- 23733886 TI - The LXR-IDOL axis defines a clathrin-, caveolae-, and dynamin-independent endocytic route for LDLR internalization and lysosomal degradation. AB - Low density lipoprotein (LDL) cholesterol is taken up into cells via clathrin mediated endocytosis of the LDL receptor (LDLR). Following dissociation of the LDLR-LDL complex, LDL is directed to lysosomes whereas the LDLR recycles to the plasma membrane. Activation of the sterol-sensing nuclear receptors liver X receptors (LXRs) enhances degradation of the LDLR. This depends on the LXR target gene inducible degrader of the LDLR (IDOL), an E3-ubiquitin ligase that promotes ubiquitylation and lysosomal degradation of the LDLR. How ubiquitylation of the LDLR by IDOL controls its endocytic trafficking is currently unknown. Using genetic- and pharmacological-based approaches coupled to functional assessment of LDL uptake, we show that the LXR-IDOL axis targets a LDLR pool present in lipid rafts. IDOL-dependent internalization of the LDLR is independent of clathrin, caveolin, macroautophagy, and dynamin. Rather, it depends on the endocytic protein epsin. Consistent with LDLR ubiquitylation acting as a sorting signal, degradation of the receptor can be blocked by perturbing the endosomal sorting complex required for transport (ESCRT) or by USP8, a deubiquitylase implicated in sorting ubiquitylated cargo to multivesicular bodies. In summary, we provide evidence for the existence of an LXR-IDOL-mediated internalization pathway for the LDLR that is distinct from that used for lipoprotein uptake. PMID- 23733887 TI - Genome-wide association study and pathway-level analysis of tocochromanol levels in maize grain. AB - Tocopherols and tocotrienols, collectively known as tocochromanols, are the major lipid-soluble antioxidants in maize (Zea mays L.) grain. Given that individual tocochromanols differ in their degree of vitamin E activity, variation for tocochromanol composition and content in grain from among diverse maize inbred lines has important nutritional and health implications for enhancing the vitamin E and antioxidant contents of maize-derived foods through plant breeding. Toward this end, we conducted a genome-wide association study of six tocochromanol compounds and 14 of their sums, ratios, and proportions with a 281 maize inbred association panel that was genotyped for 591,822 SNP markers. In addition to providing further insight into the association between ZmVTE4 (gamma-tocopherol methyltransferase) haplotypes and alpha-tocopherol content, we also detected a novel association between ZmVTE1 (tocopherol cyclase) and tocotrienol composition. In a pathway-level analysis, we assessed the genetic contribution of 60 a priori candidate genes encoding the core tocochromanol pathway (VTE genes) and reactions for pathways supplying the isoprenoid tail and aromatic head group of tocochromanols. This analysis identified two additional genes, ZmHGGT1 (homogentisate geranylgeranyltransferase) and one prephenate dehydratase parolog (of four in the genome) that also modestly contribute to tocotrienol variation in the panel. Collectively, our results provide the most favorable ZmVTE4 haplotype and suggest three new gene targets for increasing vitamin E and antioxidant levels through marker-assisted selection. PMID- 23733888 TI - Targeting of Painting of fourth to roX1 and roX2 proximal sites suggests evolutionary links between dosage compensation and the regulation of the fourth chromosome in Drosophila melanogaster. AB - In Drosophila melanogaster, two chromosome-specific targeting and regulatory systems have been described. The male-specific lethal (MSL) complex supports dosage compensation by stimulating gene expression from the male X-chromosome, and the protein Painting of fourth (POF) specifically targets and stimulates expression from the heterochromatic 4(th) chromosome. The targeting sites of both systems are well characterized, but the principles underlying the targeting mechanisms have remained elusive. Here we present an original observation, namely that POF specifically targets two loci on the X-chromosome, PoX1 and PoX2 (POF-on X). PoX1 and PoX2 are located close to the roX1 and roX2 genes, which encode noncoding RNAs important for the correct targeting and spreading of the MSL complex. We also found that the targeting of POF to PoX1 and PoX2 is largely dependent on roX expression and identified a high-affinity target region that ectopically recruits POF. The results presented support a model linking the MSL complex to POF and dosage compensation to regulation of heterochromatin. PMID- 23733889 TI - The genetic architecture of methotrexate toxicity is similar in Drosophila melanogaster and humans. AB - The severity of the toxic side effects of chemotherapy varies among patients, and much of this variation is likely genetically based. Here, we use the model system Drosophila melanogaster to genetically dissect the toxicity of methotrexate (MTX), a drug used primarily to treat childhood acute lymphoblastic leukemia and rheumatoid arthritis. We use the Drosophila Synthetic Population Resource, a panel of recombinant inbred lines derived from a multiparent advanced intercross, and quantify MTX toxicity as a reduction in female fecundity. We identify three quantitative trait loci (QTL) affecting MTX toxicity; two colocalize with the fly orthologs of human genes believed to mediate MTX toxicity and one is a novel MTX toxicity gene with a human ortholog. A fourth suggestive QTL spans a centromere. Local single-marker association scans of candidate gene exons fail to implicate amino acid variants as the causative single-nucleotide polymorphisms, and we therefore hypothesize the causative variation is regulatory. In addition, the effects at our mapped QTL do not conform to a simple biallelic pattern, suggesting multiple causative factors underlie the QTL mapping results. Consistent with this observation, no single single-nucleotide polymorphism located in or near a candidate gene can explain the QTL mapping signal. Overall, our results validate D. melanogaster as a model for uncovering the genetic basis of chemotoxicity and suggest the genetic basis of MTX toxicity is due to a handful of genes each harboring multiple segregating regulatory factors. PMID- 23733890 TI - Increased glyoxalase-1 levels in Fkbp5 knockout mice caused by glyoxalase-1 gene duplication. AB - Fkbp5 is genetically linked to stress-related diseases. Fkbp5 knockout mice are available and widely used to explore the role of Fkbp5 in health and disease. We found that these mice carry a gene duplication of glyoxylase-1, which explains why glyoxylase-1 levels are increased in the Fkbp5 knockout mice. PMID- 23733892 TI - Upper airway anatomical changes after velopharyngeal surgery in obstructive sleep apnea patients with small tonsils. AB - OBJECTIVE: To evaluate the relationships between anatomical changes and treatment outcomes after velopharyngeal surgery in obstructive sleep apnea (OSA) patients with small tonsils (grade 0-2 on the Brodsky scale). STUDY DESIGN: Case series with planned data collection. SETTING: University medical center. SUBJECTS AND METHODS: Thirty-six OSA patients with small tonsils underwent velopharyngeal surgery including revised uvulopalatopharyngoplasty with uvula preservation and transpalatal advancement pharyngoplasty. Pre- and postoperative upper airway 3 dimensional computed tomography and polysomnography findings were obtained for comparison and analysis. RESULTS: The overall apnea hypopnea index (AHI) decreased from 56.8 (interquartile range, 37.5-70.1) preoperatively to 16.1 (10.8 33.5) postoperatively (P < .001). The change in minimal cross-sectional area of the velopharynx (VmCSA) was independently associated with the change in AHI (P = .001, R (2) = 0.271). Preoperative VmCSA was the only preoperative anatomical variable that was an independent predictor of change in VmCSA (P = .009, R (2) = 0.184). Postoperative VmCSA was independently associated with postoperative AHI (P < .001, R (2) = 0.341). CONCLUSION: In patients with small tonsils, an adequate increase in VmCSA is associated with a successful outcome after surgery. Patients with a relatively small preoperative VmCSA are more likely to have favorable anatomical changes after surgery. PMID- 23733891 TI - Genetic selection for constitutively trimerized human HSF1 mutants identifies a role for coiled-coil motifs in DNA binding. AB - Human heat shock transcription factor 1 (HSF1) promotes the expression of stress responsive genes and is a critical factor for the cellular protective response to proteotoxic and other stresses. In response to stress, HSF1 undergoes a transition from a repressed cytoplasmic monomer to a homotrimer, accumulates in the nucleus, binds DNA, and activates target gene transcription. Although these steps occur as sequential and highly regulated events, our understanding of the full details of the HSF1 activation pathway remains incomplete. Here we describe a genetic screen in humanized yeast that identifies constitutively trimerized HSF1 mutants. Surprisingly, constitutively trimerized HSF1 mutants do not bind to DNA in vivo in the absence of stress and only become DNA binding competent upon stress exposure, suggesting that an additional level of regulation beyond trimerization and nuclear localization may be required for HSF1 DNA binding. Furthermore, we identified a constitutively trimerized and nuclear-localized HSF1 mutant, HSF1 L189P, located in LZ3 of the HSF1 trimerization domain, which in response to proteotoxic stress is strongly compromised for DNA binding at the Hsp70 and Hsp25 promoters but readily binds to the interleukin-6 promoter, suggesting that HSF1 DNA binding is in part regulated in a locus-dependent manner, perhaps via promoter-specific differences in chromatin architecture. Furthermore, these results implicate the LZ3 region of the HSF1 trimerization domain in a function beyond its canonical role in HSF1 trimerization. PMID- 23733893 TI - Clinical practice guideline: improving voice outcomes after thyroid surgery. AB - OBJECTIVE: Thyroidectomy may be performed for clinical indications that include malignancy, benign nodules or cysts, suspicious findings on fine needle aspiration biopsy, dysphagia from cervical esophageal compression, or dyspnea from airway compression. About 1 in 10 patients experience temporary laryngeal nerve injury after surgery, with longer lasting voice problems in up to 1 in 25. Reduced quality of life after thyroid surgery is multifactorial and may include the need for lifelong medication, thyroid suppression, radioactive scanning/treatment, temporary and permanent hypoparathyroidism, temporary or permanent dysphonia postoperatively, and dysphagia. This clinical practice guideline provides evidence-based recommendations for management of the patient's voice when undergoing thyroid surgery during the preoperative, intraoperative, and postoperative period. PURPOSE: The purpose of this guideline is to optimize voice outcomes for adult patients aged 18 years or older after thyroid surgery. The target audience is any clinician involved in managing such patients, which includes but may not be limited to otolaryngologists, general surgeons, endocrinologists, internists, speech-language pathologists, family physicians and other primary care providers, anesthesiologists, nurses, and others who manage patients with thyroid/voice issues. The guideline applies to any setting in which clinicians may interact with patients before, during, or after thyroid surgery. Children under age 18 years are specifically excluded from the target population; however, the panel understands that many of the findings may be applicable to this population. Also excluded are patients undergoing concurrent laryngectomy. Although this guideline is limited to thyroidectomy, some of the recommendations may extrapolate to parathyroidectomy as well. RESULTS: The guideline development group made a strong recommendation that the surgeon should identify the recurrent laryngeal nerve(s) during thyroid surgery. The group made recommendations that the clinician or surgeon should (1) document assessment of the patient's voice once a decision has been made to proceed with thyroid surgery; (2) examine vocal fold mobility, or refer the patient to a clinician who can examine vocal fold mobility, if the patient's voice is impaired and a decision has been made to proceed with thyroid surgery; (3) examine vocal fold mobility, or refer the patient to a clinician who can examine vocal fold mobility, once a decision has been made to proceed with thyroid surgery if the patient's voice is normal and the patient has (a) thyroid cancer with suspected extrathyroidal extension, or (b) prior neck surgery that increases the risk of laryngeal nerve injury (carotid endarterectomy, anterior approach to the cervical spine, cervical esophagectomy, and prior thyroid or parathyroid surgery), or (c) both; (4) educate the patient about the potential impact of thyroid surgery on voice once a decision has been made to proceed with thyroid surgery; (5) inform the anesthesiologist of the results of abnormal preoperative laryngeal assessment in patients who have had laryngoscopy prior to thyroid surgery; (6) take steps to preserve the external branch of the surperior laryngeal nerve(s) when performing thyroid surgery; (7) document whether there has been a change in voice between 2 weeks and 2 months following thyroid surgery; (8) examine vocal fold mobility or refer the patient for examination of vocal fold mobility in patients with a change in voice following thyroid surgery; (9) refer a patient to an otolaryngologist when abnormal vocal fold mobility is identified after thyroid surgery; (10) counsel patients with voice change or abnormal vocal fold mobility after thyroid surgery on options for voice rehabilitation. The group made an option that the surgeon or his or her designee may monitor laryngeal electromyography during thyroid surgery. The group made no recommendation regarding the impact of a single intraoperative dose of intravenous corticosteroid on voice outcomes in patients undergoing thyroid surgery. PMID- 23733894 TI - Estrogen receptor alpha (ESR1) over-expression mediated apoptosis in Hep3B cells by binding with SP1 proteins. AB - Previous studies have reported that estrogen receptors (ERs) are expressed in normal human liver, chronic hepatitis, and benign hepatic tumor tissues. However, decreased expression of ERs can be observed in hepatocellular carcinoma (HCC) and the role of ERs in HCC is not fully understood. Thus, the present study aimed to investigate the molecular mechanism induced by the overexpression of ERalpha (ERalpha (ESR1)) in Hep3B cells. We first detected the induction of apoptosis in ER-negative Hep3B cells using DNA fragmentation assay and flow cytometry. We found that ERalpha and ERalpha plus 17beta-estradiol treatment increased apoptosis in Hep3B cells. Additionally, western blotting showed increased expression of active caspase 3 and tumor necrosis factor alpha (TNFalpha (TNF)) in ERalpha-transfected cells. To further understand the importance of SP1-binding sites in the TNFalpha promoter, ERalpha-negative Hep3B cells were co-transfected with ERalpha and a wild-type TNFalpha plasmid or TNFalpha with deleted SP1 regions. Deletion of both distant and primal SP1 sites abolished the activity of ERalpha, and similar results were observed by blocking the expression of SP1 protein using mithramycin (MA). This result indicates that SP1 protein is essential for ERalpha-activated TNFalpha promoter activity. Co immunoprecipitation assay further confirmed the binding interaction between ERalpha and SP1 in a ligand-dependent manner. In general, we demonstrate that the overexpression of ERalpha mediates apoptosis in ERalpha-negative Hep3B cells by the binding of ERalpha to SP1 protein. Additionally, this ERalpha-SP1 complex binds to the proximal and distal sites of the TNFalpha gene promoter and further induces the expression of active caspase 3 in a ligand-dependent manner. PMID- 23733895 TI - Why is type 1 diabetes increasing? AB - A series of studies have reported a constant global rise in the incidence of type 1 diabetes. Epidemiological and immunological studies have demonstrated that environmental factors may influence the pathogenesis, leading to a cell-mediated pancreatic beta-cell destruction associated with humoral immunity. The search for the triggering factor(s) has been going on for the past century, and yet they are still unknown. This review provides an overview of some of the most well-known theories found in the literature: hygiene, viral, vitamin D deficiency, breast milk and cow's milk hypotheses. Although the hygiene hypothesis appears to be the most promising, positive evidence from animal, human and epidemiological studies precludes us from completely discarding any of the other hypotheses. Moreover, due to contrasting evidence in the literature, a single factor is unlikely to cause an increase in the incidence of diabetes all over the world, which suggests that a multifactorial process might be involved. Although the immunological mechanisms are still unclear, there seems to be some overlap between the various hypotheses. It is thought that the emphasis should be shifted from a single to a multifactorial process and that perhaps the 'balance shift' model should be considered as a possible explanation for the rise in the incidence of type 1 diabetes. PMID- 23733896 TI - Guidelines or a plea for help? PMID- 23733897 TI - Sleep-disordered breathing and resistant hypertension (February 2013). PMID- 23733898 TI - Should healthy people take calcium and vitamin D to prevent fractures? What the US Preventive Services Task Force and others say. PMID- 23733899 TI - Medication-assisted treatment of opiate dependence is gaining favor. AB - People addicted to opiates are more likely to avoid returning to these drugs if they participate in a program that includes taking maintenance doses of methadone or buprenorphine than with an abstinence program. Although medical opinion has long been divided on the issue of abstinence vs medication-assisted treatment, the latter seems to be gaining respect as an evidence-based approach. PMID- 23733900 TI - Managing severe acute pancreatitis. AB - Severe acute pancreatitis causes high rates of illness and death. Simple scoring predictors can help identify patients at risk so that treatment, primarily supportive, can begin promptly after presentation. Medical therapy is the mainstay, with supportive therapy consisting of controlled volume resuscitation and enteral feeding. Minimally invasive drainage and debridement play a role in managing infective pancreatic necrosis but in general should not be used until at least 4 weeks after the acute illness. PMID- 23733901 TI - Stiff, numb hands. PMID- 23733902 TI - A 74-year-old man with abdominal pain. PMID- 23733903 TI - Q: Which patients may benefit from coronary artery calcification scoring? PMID- 23733904 TI - Does coronary artery calcification scoring still have a role in practice? PMID- 23733905 TI - Evaluation and management of premature ventricular complexes. AB - Premature ventricular complexes (PVCs) are a common cause of palpitations. Related symptoms include difficulty breathing, chest pain, fatigue, and dizziness. PVCs are also commonly detected incidentally on electrocardiography, outpatient ambulatory monitoring, and inpatient telemetry. Treatment goals include palliating symptoms, restoring cardiac function if affected, and preventing progression to tachycardia-related cardiomyopathy if the PVC burden is high, even in patients without symptoms. Responses to caffeine reduction, cessation of stimulants, and stress reduction are inconsistent. Aerobic exercise is rarely effective and can sometimes exacerbate PVCs. PMID- 23733906 TI - Changes in political astuteness following nurse legislative day. AB - Political astuteness, including awareness, knowledge, and involvement, is necessary if nurses are to engage in policy advocacy-a vital aspect of the nursing profession. However, little is known about the effects of learning activities, such as legislative days, on political astuteness. The purpose of this research was to determine if political astuteness changed after participants attended a state nurse legislative day. Pre and post data were collected from participants in two studies (N = 80 and N = 34) using the Political Astuteness Inventory (PAI). Political astuteness scores were significantly higher after participants attended legislative day as compared to before. Age and educational rank were positively correlated with political astuteness. Experiential activities such as attending nurse legislative days that offer opportunities to learn policy advocacy skills can enhance knowledge of and participation in the policy process. PMID- 23733907 TI - Primary hrHPV DNA testing in cervical cancer screening: how to manage screen positive women? A POBASCAM trial substudy. AB - BACKGROUND: High-risk human papillomavirus (hrHPV) testing has higher sensitivity but lower specificity than cytology for cervical (pre)-cancerous lesions. Therefore, triage of hrHPV-positive women is needed in cervical cancer screening. METHODS: A cohort of 1,100 hrHPV-positive women, from a population-based screening trial (POBASCAM: n = 44,938; 29-61 years), was used to evaluate 10 triage strategies, involving testing at baseline and six months with combinations of cytology, HPV16/18 genotyping, and/or repeat hrHPV testing. Clinical endpoint was cervical intraepithelial neoplasia grade 3 or worse (CIN3(+)) detected within four years; results were adjusted for women not attending repeat testing. A triage strategy was considered acceptable, when the probability of no CIN3(+) after negative triage (negative predictive value, NPV) was at least 98%, and the CIN3(+) risk after positive triage (positive predictive value, PPV) was at least 20%. RESULTS: Triage at baseline with cytology only yielded an NPV of 94.3% [95% confidence interval (CI), 92.0-96.0] and a PPV of 39.7% (95% CI, 34.0-45.6). An increase in NPV, against a modest decrease in PPV, was obtained by triaging women with negative baseline cytology by repeat cytology (NPV 98.5% and PPV 34.0%) or by baseline HPV16/18 genotyping (NPV 98.8% and PPV 28.5%). The inclusion of both HPV16/18 genotyping at baseline and repeat cytology testing provided a high NPV (99.6%) and a moderately high PPV (25.6%). CONCLUSIONS: Triaging hrHPV-positive women by cytology at baseline and after 6 to 12 months, possibly in combination with baseline HPV16/18 genotyping, seems acceptable for cervical cancer screening. IMPACT: Implementable triage strategies are provided for primary hrHPV screening in an organized setting. PMID- 23733908 TI - How next-generation sequencing could change cancer care. PMID- 23733910 TI - Cardiotoxicity debated for anthracyclines and trastuzumab in breast cancer. PMID- 23733912 TI - Stability-indicating chromatographic methods for the determination of sertindole. AB - In this work, two chromatographic methods have been developed and validated for the determination of sertindole (an antipsychotic agent) in the presence of its oxidative degradation product. Sertindole was subjected to stress stability studies, including acid, alkali, oxidative, photolytic and thermal degradation. The chromatographic methods included the use of thin-layer chromatography (TLC densitometry) and high-performance liquid chromatography (HPLC). The TLC method employed aluminum TLC plates precoated with silica gel G.F254 as the stationary phase and methanol-ethyl acetate-33% ammonia (1:9:0.1, by volume) as the mobile phase, and the chromatograms were scanned at 227 nm. The developed HPLC method used a reversed-phase C18 column with isocratic elution. The mobile phase was composed of phosphate buffer pH 3.0-acetonitrile-triethylamine (45:55:0.03, by volume) and run at a flow rate of 1.0 mL/min. Quantitation was achieved with ultraviolet detection at 256 nm. The linearity ranges were found to be 2-14 ug/band and 5-200 ug/mL for TLC and HPLC, respectively. The developed methods were validated according to the International Conference on Harmonization guidelines and were applied for bulk powder and dosage forms. PMID- 23733911 TI - Dopamine replacement modulates oscillatory coupling between premotor and motor cortical areas in Parkinson's disease. AB - Efficient neural communication between premotor and motor cortical areas is critical for manual motor control. Here, we used high-density electroencephalography to study cortical connectivity in patients with Parkinson's disease (PD) and age-matched healthy controls while they performed repetitive movements of the right index finger at maximal repetition rate. Multiple source beamformer analysis and dynamic causal modeling were used to assess oscillatory coupling between the lateral premotor cortex (lPM), supplementary motor area (SMA), and primary motor cortex (M1) in the contralateral hemisphere. Elderly healthy controls showed task-related modulation in connections from lPM to SMA and M1, mainly within the gamma-band (>30 Hz). Nonmedicated PD patients also showed task-related gamma-gamma coupling from lPM to M1, but gamma coupling from lPM to SMA was absent. Levodopa reinstated physiological gamma-gamma coupling from lPM to SMA and significantly strengthened coupling in the feedback connection from M1 to lPM expressed as beta-beta as well as theta-beta coupling. Enhancement in cross-frequency theta-beta coupling from M1 to lPM was correlated with levodopa-induced improvement in motor function. The results show that PD is associated with an altered neural communication between premotor and motor cortical areas, which can be modulated by dopamine replacement. PMID- 23733913 TI - Subepicardial action potential characteristics are a function of depth and activation sequence in isolated rabbit hearts. AB - BACKGROUND: Electric excitability in the ventricular wall is influenced by cellular electrophysiology and passive electric properties of the myocardium. Action potential (AP) rise time, an indicator of myocardial excitability, is influenced by conduction pattern and distance from the epicardial surface. This study examined AP rise times and conduction velocity as the depolarizing wavefront approaches the epicardial surface. METHODS AND RESULTS: Two-photon excitation of di-4-aminonaphthenyl-pyridinum-propylsulfonate was used to measure electric activity at discrete epicardial layers of isolated Langendorff-perfused rabbit hearts to a depth of 500 MUm. Endo-to-epicardial wavefronts were studied during right atrial or ventricular endocardial pacing. Similar measurements were made with epi-to-endocardial, transverse, and longitudinal pacing protocols. Results were compared with data from a bidomain model of 3-dimensional (3D) electric propagation within ventricular myocardium. During right atrial and endocardial pacing, AP rise time (10%-90% of upstroke) decreased by ~50% between 500 and 50 MUm from the epicardial surface, whereas conduction velocity increased and AP duration was only slightly shorter (~4%). These differences were not observed with other conduction patterns. The depth-dependent changes in rise time were larger at higher pacing rates. Modeling data qualitatively reproduced the behavior seen experimentally and demonstrated a parallel reduction in peak I(Na) and electrotonic load as the wavefront approaches the epicardial surface. CONCLUSIONS: Decreased electrotonic load at the epicardial surface results in more rapid AP upstrokes and higher conduction velocities compared with the bulk myocardium. Combined effects of tissue depth and pacing rate on AP rise time reduce conduction safety and myocardial excitability within the ventricular wall. PMID- 23733914 TI - Comparative effectiveness research: enhancing nursing science. PMID- 23733915 TI - Failing heart of patients with type 2 diabetes mellitus can adapt to extreme short-term increases in circulating lipids and does not display features of acute myocardial lipotoxicity. AB - BACKGROUND: Circulating lipid levels and myocardial lipid content (MyLC) is increased in type 2 diabetes mellitus. This may cause a state of lipotoxicity that compromises left ventricular function and aggravate heart failure. We investigated the relationship among circulating lipid levels, MyLC, and cardiac function together with the acute cardiac effects of high as opposed to low circulating free fatty acid (FFA) and triglyceride levels in patients with type 2 diabetes mellitus and heart failure. METHODS AND RESULTS: Eighteen patients underwent 8-hour intralipid/heparin-infusion (high FFA) and hyperinsulinemic euglycemic clamping (low FFA) in a randomized crossover-designed study. We applied magnetic resonance proton spectroscopy to measure MyLC. Cardiac function was assessed by advanced echocardiography, cardiopulmonary exercise, and MRI. MyLC correlated positively with circulating triglyceride (r=0.47; r(2)=0.22; P=0.003) and FFA (r=0.45; r(2)=0.20; P=0.001) levels and inversely with left ventricular ejection fraction (r=-0.54; r(2)=0.29; P=0.004). Circulating FFA concentrations differed between study arms (0.05 +/- 0.04 mmol/L [low FFA] versus 1.04 +/- 0.27 mmol/L [high FFA]; P<0.001) and MyLC increased from 0.78 +/- 0.59% (low FFA) to 1.16 +/- 0.73% (high FFA; P<0.01). Resting left ventricular ejection fraction and global strain did not differ between high and low FFA, whereas resting systolic mitral plane velocity (S'max) was highest during high FFA (3.6+/ 0.8 cm/s [low FFA] versus 3.8+/-0.7 cm/s [high FFA]; P=0.02). Peak exercise capacity and oxygen consumption did not differ between the study arms, and neither did postexercise measurements of left ventricular ejection fraction, global strain, and S'max. CONCLUSIONS: Our findings indicate that the failing heart of patients with type 2 diabetes mellitus can adapt to short-term extreme changes in circulating substrates and does not display features of acute myocardial lipotoxicity. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01192373. PMID- 23733916 TI - Evaluation of the role of endomyocardial biopsy in 851 patients with unexplained heart failure from 2000-2009. AB - BACKGROUND: Endomyocardial biopsy (EMB) is often considered when the pathogenesis of heart failure cannot be determined by noninvasive testing. Uncertainty remains about the diagnostic and clinical use of EMB in various clinical scenarios. METHODS AND RESULTS: We examined the characteristics of a cohort of patients with unexplained heart failure who underwent EMB at a tertiary care medical center. We categorized each patient into a clinical scenario as outlined by the 2007 AHA/ACC/ESC guidelines and determined the number of times EMB provided a diagnosis or altered the clinical course. A total of 851 patients underwent EMB from 2000-2009. Overall, 25.5% of EMBs provided a diagnosis and 22.7% of EMBs changed clinical course. Heart failure associated with unexplained restrictive cardiomyopathy was the most common clinical scenario, comprising 33.6% (286/851) of EMBs, and 84 (29.4%) of these EMBs were diagnostic. EMB for unexplained heart failure of <2 weeks duration had a diagnostic yield at 35% (39/109). There were 4 uncommon scenarios where EMB had a high diagnostic and clinical yield. There were 16 complications for an overall rate of 1.9%. CONCLUSIONS: We confirm that EMB is useful in acute onset unexplained cardiomyopathy. We demonstrate a role for EMB in suspected infiltrative disease and in the management of rare clinical scenarios, such as suspected hypersensitivity myocarditis, anthracycline cardiomyopathy, cardiac tumors, and arrhythmogenic right ventricular dysplasia/cardiomyopathy. Our results suggest low use of EMB in chronic heart failure that responds to usual care. PMID- 23733917 TI - Mechanistic features associated with improvement in mitral regurgitation after cardiac resynchronization therapy and their relation to long-term patient outcome. AB - BACKGROUND: Mechanisms of mitral regurgitation (MR) reduction with cardiac resynchronization therapy (CRT) are complex, and their association with long-term outcome is unclear. We sought to elucidate mechanistic features of reduction in MR with CRT, which impact long-term patient survival. METHODS AND RESULTS: A prospective longitudinal study of 277 patients with heart failure with QRS width >= 120 ms and ejection fraction <= 35% for CRT was performed. Quantitative echocardiography, including dyssynchrony analysis, was performed at baseline. MR was quantified by color Doppler before and 6 months after CRT. Predefined end points of death, transplant, or left ventricular assist device were tracked during 4 years. There were 114 (48%) patients with CRT with significant MR (>= moderate) at baseline; of whom 48 (42%) patients had MR improvement, and 24 (19%) patients had MR worsening after CRT. The 66 events (47 deaths, 10 transplantations, and 9 left ventricular assist devices) were strongly associated with significant MR after CRT (hazard ratio, 3.58; 95% confidence interval, 2.18 5.87; P<0.0001). Three echocardiographic features were independently associated with amelioration of significant MR after CRT by multivariable analysis: anteroseptal to posterior wall radial strain dyssynchrony >200 ms, lack of severe left ventricular dilatation (end-systolic dimension index <29 mm/m(2)), and lack of echocardiographic scar at papillary muscle insertion sites (all P<0.05) and, when combined, were additively associated with long-term survival (P=0.0001). CONCLUSIONS: Significant MR after CRT was strongly associated with less favorable long-term survival. Echocardiographic mechanistic features were identified that were associated with improvement in MR after CRT and favorable long-term survival. PMID- 23733918 TI - Estimating the cost of a smoking employee. AB - OBJECTIVE: We attempted to estimate the excess annual costs that a US private employer may attribute to employing an individual who smokes tobacco as compared to a non-smoking employee. DESIGN: Reviewing and synthesising previous literature estimating certain discrete costs associated with smoking employees, we developed a cost estimation approach that approximates the total of such costs for U.S. employers. We examined absenteeism, presenteesim, smoking breaks, healthcare costs and pension benefits for smokers. RESULTS: Our best estimate of the annual excess cost to employ a smoker is $5816. This estimate should be taken as a general indicator of the extent of excess costs, not as a predictive point value. CONCLUSIONS: Employees who smoke impose significant excess costs on private employers. The results of this study may help inform employer decisions about tobacco-related policies. PMID- 23733920 TI - Embryonic catalase protects against ethanol-initiated DNA oxidation and teratogenesis in acatalasemic and transgenic human catalase-expressing mice. AB - Reactive oxygen species (ROS) are implicated in fetal alcohol spectrum disorders (FASD) caused by alcohol (ethanol, EtOH). Although catalase detoxifies hydrogen peroxide, embryonic catalase activity is only about 5% of maternal levels. To determine the roles of ROS and embryonic catalase in FASD, pregnant mice with enhanced (expressing human catalase, hCat) or deficient (acatalasemic, aCat) catalase activity, or their respective wild-type (WT) controls, were treated ip on gestational day 9 with 4 or 6g/kg EtOH or its saline vehicle, and embryos and fetuses were, respectively, evaluated for oxidatively damaged DNA and structural anomalies. Untreated hCat and aCat dams had, respectively, more and less offspring than their WT controls. hCat progenies were protected from all EtOH fetal anomalies at the low dose (p < .01) and from reduced head diameter and resorptions at the high dose (p < .001). Conversely, aCat progenies were more sensitive to dose-dependent EtOH fetal anomalies (p < .001) and exhibited a 50% increase in maternal lethality (p < .05) at the high dose. Maternal pretreatment of aCat mice with polyethylene glycol-conjugated catalase (PEG-Cat) reduced EtOH fetal anomalies (p < .001). EtOH-initiated embryonic DNA oxidation was reduced in hCat and WT mice pretreated with PEG-Cat and enhanced in aCat mice. Plasma concentrations of EtOH in catalase-altered mice were similar to controls, precluding a pharmacokinetic basis for altered EtOH teratogenesis. Endogenous embryonic catalase, despite its low level, is an important embryoprotective enzyme for EtOH teratogenesis and a likely determinant of individual risk. PMID- 23733921 TI - The fate of beta-hexabromocyclododecane in female C57BL/6 mice. AB - 1,2,5,6,9,10-Hexabromocyclododecane (HBCD) is a high production volume cycloaliphatic used as an additive flame retardant primarily in polystyrene foam building materials. HBCD mixtures contain three major stereoisomers, alpha (alpha), beta (beta), and gamma (gamma), at a typical ratio of 1.2:0.6:8.2. The toxicokinetic properties of the alpha and gamma isomers differ. For instance, alpha-HBCD has greater bioavailability and potential for accumulation in mice than gamma-HBCD. The present study reports comparative kinetics data for beta HBCD needed to support toxicological evaluations of HBCD mixtures. Results indicated that a single oral dose of 3mg/kg of [(14)C]-labeled beta-HBCD was absorbed rapidly (>= 85% total dose) in the female C57BL/6 mouse. The C max for beta-HBCD-derived radioactivity in tissues, except adipose, was observed 3h following gavage. Approximately 90% of the administered dose was excreted in urine and feces within 24h, primarily as beta-HBCD-derived metabolites. A portion of the dose (circa 9%) was excreted in feces as gamma-HBCD. Oral administration of 30 or 100mg/kg of beta-HBCD resulted initially in slower rates of [(14)C] elimination; however, cumulative excretion data were similar across the dosing range 4 days postdosing. Residual concentrations of [(14)C] in tissues were highest in adipose and liver. beta-HBCD-derived radioactivity accumulated in most tissues following four consecutive daily oral doses of 3mg/kg. The extent of metabolism and excretion of beta-HBCD in female C57BL/6 mice was similar to that for gamma-HBCD. The potential for accumulation of beta-HBCD-derived material in most tissues appeared to be less than for alpha-HBCD. PMID- 23733922 TI - Bilateral stereotactic anterior capsulotomy for obsessive-compulsive disorder: long-term follow-up. AB - BACKGROUND AND PURPOSE: Psychosurgery, such as anterior capsulotomy, is a therapeutic option for treatment-resistant obsessive-compulsive disorder (OCD). In this paper, we present a prospective, long-term follow-up study aimed at evaluating both the efficacy and the safety of anterior capsulotomy for the treatment of severe, refractory OCD. METHODS: Twenty-four patients were surgically treated in our centre between 1997 and 2009, 19 of whom were included in this study. Patients were assessed at 3, 6, 12, and 24 months and last follow up (mean of 7 years) was carried out by phone. OCD symptom severity was evaluated using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). A patient with an improvement rate of over 35% in the Y-BOCS score was considered a responder, while a patient with a 25% improvement was considered a partial responder. RESULTS: With a mean improvement of 31% in the Y-BOCS score at long-term follow up, 36.8% of the patients responded fully to the procedure and 10.5% were considered partial responders, for an overall response rate of 47.3% of patients. At the end of the study, 3/19 patients had recovered (Y-BOCS score <8) and 3/19 were in remission (Y-BOCS score <16). No cases of mortality were reported and the overall adverse event rate was 57.9%. Only 2 patients had permanent surgical complications. CONCLUSIONS: Anterior capsulotomy is an effective and safe technique for the treatment of severe refractory OCD in patients who have no other alternative to improve their symptoms. PMID- 23733923 TI - Mediterranean food for thought? PMID- 23733924 TI - Addendum to the editorial "Joint guidance on peptide receptor radionuclide therapy in neuroendocrine tumors". PMID- 23733925 TI - 99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen for molecular imaging of prostate cancer. AB - Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer, and small-molecule radiopharmaceuticals targeting PSMA rapidly detect the location and extent of disease. Here we evaluated preclinically 4 novel (99m)Tc labeled small-molecule inhibitors of PSMA with the potential for clinical translation for molecular imaging of prostate cancer in humans. METHODS: Four PSMA inhibitors derived from the glutamate-urea-glutamate or glutamate-urea lysine pharmacophores conjugated to CIM or TIM chelators were radiolabeled with (99m)Tc and evaluated in vitro and in vivo. RESULTS: High-affinity, saturable binding to PSMA on LNCaP cells was observed with Kd values of 0.64 +/- 0.46 nM for (99m)Tc-MIP-1427, 1.07 +/- 0.89 nM for (99m)Tc-MIP-1404, 1.75 +/- 0.32 nM for (99m)Tc-MIP-1428, and 4.35 +/- 0.35 nM for (99m)Tc-MIP-1405. (99m)Tc-labeled PSMA inhibitors did not bind human prostate cancer PC3 cells, which lack PSMA, demonstrating specificity, and binding was abolished with 2 (phosphonomethyl)pentanedioic acid (PMPA), a structurally unrelated PSMA inhibitor. (99m)Tc-labeled PSMA inhibitors were shown to internalize at 37 degrees C. Uptake in LNCaP xenografts ranged from 9.3% to 12.4% injected dose per gram at 1 h after injection and from 7.2% to 11.0% at 4 h, with tumor-to-blood ratios ranging from 29:1 to 550:1 and tumor-to-skeletal muscle ratios ranging from 31:1 to 157:1 at 4 h. (99m)Tc-MIP-1404 exhibited the best combination of high tumor uptake and rapid clearance from kidney and nontarget tissues. (99m)Tc MIP-1404 specifically bound to PSMA in vivo as demonstrated by the absence of uptake in PC3 xenografts and by competition with PMPA. SPECT/CT imaging corroborated the tissue distribution results, demonstrating uptake only in PSMA expressing kidney and tumor tissue and clearance through the urinary bladder. CONCLUSION: These (99m)Tc-labeled radiopharmaceuticals targeting PSMA may provide a SPECT molecular imaging option to assist in the initial diagnosis of prostate cancer and the management of patient care by monitoring disease progression. PMID- 23733926 TI - Revised microcalcification hypothesis for fibrous cap rupture in human coronary arteries. AB - Using 2.1-um high-resolution microcomputed tomography, we have examined the spatial distribution, clustering, and shape of nearly 35,000 microcalcifications (uCalcs) >= 5 um in the fibrous caps of 22 nonruptured human atherosclerotic plaques. The vast majority of these uCalcs were <15 um and invisible at the previously used 6.7-um resolution. A greatly simplified 3D finite element analysis has made it possible to quickly analyze which of these thousands of minute inclusions are potentially dangerous. We show that the enhancement of the local tissue stress caused by particle clustering increases rapidly for gap between particle pairs (h)/particle diameter (D) < 0.4 if particles are oriented along the tensile axis of the cap. Of the thousands of uCalcs observed, there were 193 particle pairs with h/D <= 2 (tissue stress factor > 2), but only 3 of these pairs had h/D <= 0.4, where the local tissue stress could increase a factor > 5. Using nondecalcified histology, we also show that nearly all caps have uCalcs between 0.5 and 5 um and that the uCalcs >= 5 um observed in high resolution microcomputed tomography are agglomerations of smaller calcified matrix vesicles. uCalcs < 5 um are predicted to be not harmful, because the tiny voids associated with these very small particles will not explosively grow under tensile forces because of their large surface energy. These observations strongly support the hypothesis that nearly all fibrous caps have uCalcs, but only a small subset has the potential for rupture. PMID- 23733927 TI - Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis. AB - Methacrylated hyaluronic acid (HA) hydrogels provide a backbone polymer with which mesenchymal stem cells (MSCs) can interact through several cell surface receptors that are expressed by MSCs, including CD44 and CD168. Previous studies showed that this 3D hydrogel environment supports the chondrogenesis of MSCs, and here we demonstrate through functional blockade that these specific cell-material interactions play a role in this process. Beyond matrix interactions, cadherin molecules, a family of transmembrane glycoproteins, play a critical role in tissue development during embryogenesis, and N-cadherin is a key factor in mediating cell-cell interactions during mesenchymal condensation and chondrogenesis. In this study, we functionalized HA hydrogels with N-cadherin mimetic peptides and evaluated their role in regulating chondrogenesis and cartilage matrix deposition by encapsulated MSCs. Our results show that conjugation of cadherin peptides onto HA hydrogels promotes both early chondrogenesis of MSCs and cartilage-specific matrix production with culture, compared with unmodified controls or those with inclusion of a scrambled peptide domain. This enhanced chondrogenesis was abolished via treatment with N-cadherin specific antibodies, confirming the contribution of these N-cadherin peptides to chondrogenesis. Subcutaneous implantation of MSC-seeded constructs also showed superior neocartilage formation in implants functionalized with N-cadherin mimetic peptides compared with controls. This study demonstrates the inherent biologic activity of HA-based hydrogels, as well as the promise of biofunctionalizing HA hydrogels to emulate the complexity of the natural cell microenvironment during embryogenesis, particularly in stem cell-based cartilage regeneration. PMID- 23733928 TI - Negative expansions of interatomic distances in metallic melts. AB - When a material is heated, generally, it dilates. Here, we find a general trend that the average distance between a center atom and atoms in the first nearest neighbor shell contracts for several metallic melts upon heating. Using synchrotron X-ray diffraction technique and molecular dynamics simulations, we elucidate that this anomaly is caused by the redistribution of polyhedral clusters affected by temperature. In metallic melts, the high-coordinated polyhedra are inclined to evolve into low-coordinated ones with increasing temperature. As the coordination number decreases, the average atomic distance between a center atom and atoms in the first shell of polyhedral clusters is reduced. This phenomenon is a ubiquitous feature for metallic melts consisting of various-sized polyhedra. This finding sheds light on the understanding of atomic structures and thermal behavior of disordered materials and will trigger more experimental and theoretical studies of liquids, amorphous alloys, glasses, and casting temperature effect on solidification process of crystalline materials. PMID- 23733929 TI - Insights into capacity-constrained optimal transport. AB - A variant of the classical optimal transportation problem is the following: among all joint measures with fixed marginals and that are dominated by a given density, find the optimal one. Existence and uniqueness of solutions to this variant were established by Korman and McCann. In the present article, we expose an unexpected symmetry leading to explicit examples in two and more dimensions. These are inspired in part by simulations in one dimension that display singularities and topology and in part by two further developments: the identification of all extreme points in the feasible set and an approach to uniqueness based on constructing feasible perturbations. PMID- 23733930 TI - Gene flow from North Africa contributes to differential human genetic diversity in southern Europe. AB - Human genetic diversity in southern Europe is higher than in other regions of the continent. This difference has been attributed to postglacial expansions, the demic diffusion of agriculture from the Near East, and gene flow from Africa. Using SNP data from 2,099 individuals in 43 populations, we show that estimates of recent shared ancestry between Europe and Africa are substantially increased when gene flow from North Africans, rather than Sub-Saharan Africans, is considered. The gradient of North African ancestry accounts for previous observations of low levels of sharing with Sub-Saharan Africa and is independent of recent gene flow from the Near East. The source of genetic diversity in southern Europe has important biomedical implications; we find that most disease risk alleles from genome-wide association studies follow expected patterns of divergence between Europe and North Africa, with the principal exception of multiple sclerosis. PMID- 23733931 TI - Emergence of the advancing neuromechanical phase in a resistive force dominated medium. AB - Undulatory locomotion, a gait in which thrust is produced in the opposite direction of a traveling wave of body bending, is a common mode of propulsion used by animals in fluids, on land, and even within sand. As such, it has been an excellent system for discovery of neuromechanical principles of movement. In nearly all animals studied, the wave of muscle activation progresses faster than the wave of body bending, leading to an advancing phase of activation relative to the curvature toward the tail. This is referred to as "neuromechanical phase lags" (NPL). Several multiparameter neuromechanical models have reproduced this phenomenon, but due to model complexity, the origin of the NPL has proved difficult to identify. Here, we use perhaps the simplest model of undulatory swimming to predict the NPL accurately during sand-swimming by the sandfish lizard, with no fitting parameters. The sinusoidal wave used in sandfish locomotion, the friction-dominated and noninertial granular resistive force environment, and the simplicity of the model allow detailed analysis, and reveal the fundamental mechanism responsible for the phenomenon: the combination of synchronized torques from distant points on the body and local traveling torques. This general mechanism should help explain the NPL in organisms in other environments; we therefore propose that sand-swimming could be an excellent system with which to generate and test other neuromechanical models of movement quantitatively. Such a system can also provide guidance for the design and control of robotic undulatory locomotors in complex environments. PMID- 23733932 TI - Regulatory interplay of Cockayne syndrome B ATPase and stress-response gene ATF3 following genotoxic stress. AB - Cockayne syndrome type B ATPase (CSB) belongs to the SwItch/Sucrose nonfermentable family. Its mutations are linked to Cockayne syndrome phenotypes and classically are thought to be caused by defects in transcription-coupled repair, a subtype of DNA repair. Here we show that after UV-C irradiation, immediate early genes such as activating transcription factor 3 (ATF3) are overexpressed. Although the ATF3 target genes, including dihydrofolate reductase (DHFR), were unable to recover RNA synthesis in CSB-deficient cells, transcription was restored rapidly in normal cells. There the synthesis of DHFR mRNA restarts on the arrival of RNA polymerase II and CSB and the subsequent release of ATF3 from its cAMP response element/ATF target site. In CSB-deficient cells ATF3 remains bound to the promoter, thereby preventing the arrival of polymerase II and the restart of transcription. Silencing of ATF3, as well as stable introduction of wild-type CSB, restores RNA synthesis in UV-irradiated CSB cells, suggesting that, in addition to its role in DNA repair, CSB activity likely is involved in the reversal of inhibitory properties on a gene-promoter region. We present strong experimental data supporting our view that the transcriptional defects observed in UV-irradiated CSB cells are largely the result of a permanent transcriptional repression of a certain set of genes in addition to some defect in DNA repair. PMID- 23733933 TI - Arabidopsis MU-adaptin subunit AP1M of adaptor protein complex 1 mediates late secretory and vacuolar traffic and is required for growth. AB - Adaptor protein (AP) complexes are the predominant coat proteins of membrane vesicles in post-Golgi trafficking of mammalian cells. Each AP complex contains a specific medium subunit, MU-adaptin, that selects cargo proteins bearing sequence specific sorting motifs. Much less is known about the AP complexes and their MU subunits in plants. Because of uncertain homology, the MU-adaptins of Arabidopsis have been designated muA through muD [Happel et al. (2004) Plant J 37(5):678 693]. Furthermore, only muD has been assigned to a specific AP complex, AP-3, involved in Golgi-vacuolar trafficking [Niihama et al. (2009) Plant Cell Physiol 50(12):2057-2068, Zwiewka et al. (2011) Cell Res 21(12):1711-1722, and Wolfenstetter et al. (2012) Plant Cell 24(1):215-232]. In contrast, the MU subunit of neither the post-Golgi trafficking AP-1 complex nor the endocytic AP-2 complex has been identified. Here, we report the functional analysis of redundant AP-1 MU-adaptins AP1M1 (also known as muB1) and AP1M2 (also known as muB2). Coimmunoprecipitation revealed that both AP1M2 and its less strongly expressed isoform AP1M1 are complexed with the large subunit gamma-adaptin of AP-1. In addition, AP1M2 was localized at or near the trans-Golgi network. Knockout mutations of AP1M2 impaired pollen function and arrested plant growth whereas the ap1m1 ap1m2 double mutant was nearly pollen-lethal. At the cellular level, the absence of AP1M2 entailed inhibition of multiple trafficking pathways from the trans-Golgi network to the vacuole and to the plasma membrane in interphase and to the plane of cell division in cytokinesis. Thus, AP-1 is crucial in post-Golgi trafficking in plant cells and required for cell division and plant growth. PMID- 23733934 TI - Evaluation of radiation doses and associated risk from the Fukushima nuclear accident to marine biota and human consumers of seafood. AB - Radioactive isotopes originating from the damaged Fukushima nuclear reactor in Japan following the earthquake and tsunami in March 2011 were found in resident marine animals and in migratory Pacific bluefin tuna (PBFT). Publication of this information resulted in a worldwide response that caused public anxiety and concern, although PBFT captured off California in August 2011 contained activity concentrations below those from naturally occurring radionuclides. To link the radioactivity to possible health impairments, we calculated doses, attributable to the Fukushima-derived and the naturally occurring radionuclides, to both the marine biota and human fish consumers. We showed that doses in all cases were dominated by the naturally occurring alpha-emitter (210)Po and that Fukushima derived doses were three to four orders of magnitude below (210)Po-derived doses. Doses to marine biota were about two orders of magnitude below the lowest benchmark protection level proposed for ecosystems (10 uGy?h(-1)). The additional dose from Fukushima radionuclides to humans consuming tainted PBFT in the United States was calculated to be 0.9 and 4.7 uSv for average consumers and subsistence fishermen, respectively. Such doses are comparable to, or less than, the dose all humans routinely obtain from naturally occurring radionuclides in many food items, medical treatments, air travel, or other background sources. Although uncertainties remain regarding the assessment of cancer risk at low doses of ionizing radiation to humans, the dose received from PBFT consumption by subsistence fishermen can be estimated to result in two additional fatal cancer cases per 10,000,000 similarly exposed people. PMID- 23733935 TI - Evidence for reactive reduced phosphorus species in the early Archean ocean. AB - It has been hypothesized that before the emergence of modern DNA-RNA-protein life, biology evolved from an "RNA world." However, synthesizing RNA and other organophosphates under plausible early Earth conditions has proved difficult, with the incorporation of phosphorus (P) causing a particular problem because phosphate, where most environmental P resides, is relatively insoluble and unreactive. Recently, it has been proposed that during the Hadean-Archean heavy bombardment by extraterrestrial impactors, meteorites would have provided reactive P in the form of the iron-nickel phosphide mineral schreibersite. This reacts in water, releasing soluble and reactive reduced P species, such as phosphite, that could then be readily incorporated into prebiotic molecules. Here, we report the occurrence of phosphite in early Archean marine carbonates at levels indicating that this was an abundant dissolved species in the ocean before 3.5 Ga. Additionally, we show that schreibersite readily reacts with an aqueous solution of glycerol to generate phosphite and the membrane biomolecule glycerol phosphate under mild thermal conditions, with this synthesis using a mineral source of P. Phosphite derived from schreibersite was, hence, a plausible reagent in the prebiotic synthesis of phosphorylated biomolecules and was also present on the early Earth in quantities large enough to have affected the redox state of P in the ocean. Phosphorylated biomolecules like RNA may, thus, have first formed from the reaction of reduced P species with the prebiotic organic milieu on the early Earth. PMID- 23733936 TI - Laser-induced plasma cloud interaction and ice multiplication under cirrus cloud conditions. AB - Potential impacts of lightning-induced plasma on cloud ice formation and precipitation have been a subject of debate for decades. Here, we report on the interaction of laser-generated plasma channels with water and ice clouds observed in a large cloud simulation chamber. Under the conditions of a typical storm cloud, in which ice and supercooled water coexist, no direct influence of the plasma channels on ice formation or precipitation processes could be detected. Under conditions typical for thin cirrus ice clouds, however, the plasma channels induced a surprisingly strong effect of ice multiplication. Within a few minutes, the laser action led to a strong enhancement of the total ice particle number density in the chamber by up to a factor of 100, even though only a 10(-9) fraction of the chamber volume was exposed to the plasma channels. The newly formed ice particles quickly reduced the water vapor pressure to ice saturation, thereby increasing the cloud optical thickness by up to three orders of magnitude. A model relying on the complete vaporization of ice particles in the laser filament and the condensation of the resulting water vapor on plasma ions reproduces our experimental findings. This surprising effect might open new perspectives for remote sensing of water vapor and ice in the upper troposphere. PMID- 23733937 TI - Beginning of viniculture in France. AB - Chemical analyses of ancient organic compounds absorbed into the pottery fabrics of imported Etruscan amphoras (ca. 500-475 B.C.) and into a limestone pressing platform (ca. 425-400 B.C.) at the ancient coastal port site of Lattara in southern France provide the earliest biomolecular archaeological evidence for grape wine and viniculture from this country, which is crucial to the later history of wine in Europe and the rest of the world. The data support the hypothesis that export of wine by ship from Etruria in central Italy to southern Mediterranean France fueled an ever-growing market and interest in wine there, which, in turn, as evidenced by the winepress, led to transplantation of the Eurasian grapevine and the beginning of a Celtic industry in France. Herbal and pine resin additives to the Etruscan wine point to the medicinal role of wine in antiquity, as well as a means of preserving it during marine transport. PMID- 23733938 TI - Rhythmic alternating patterns of brain activity distinguish rapid eye movement sleep from other states of consciousness. AB - Rapid eye movement (REM) sleep constitutes a distinct "third state" of consciousness, during which levels of brain activity are commensurate with wakefulness, but conscious awareness is radically transformed. To characterize the temporal and spatial features of this paradoxical state, we examined functional interactions between brain regions using fMRI resting-state connectivity methods. Supporting the view that the functional integrity of the default mode network (DMN) reflects "level of consciousness," we observed functional uncoupling of the DMN during deep sleep and recoupling during REM sleep (similar to wakefulness). However, unlike either deep sleep or wakefulness, REM was characterized by a more widespread, temporally dynamic interaction between two major brain systems: unimodal sensorimotor areas and the higher-order association cortices (including the DMN), which normally regulate their activity. During REM, these two systems become anticorrelated and fluctuate rhythmically, in reciprocally alternating multisecond epochs with a frequency ranging from 0.1 to 0.01 Hz. This unique spatiotemporal pattern suggests a model for REM sleep that may be consistent with its role in dream formation and memory consolidation. PMID- 23733939 TI - The DMAP interaction domain of UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1 phosphotransferase is a substrate recognition module. AB - UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase (GlcNAc-1 phosphotransferase) is an alpha2beta2gamma2 heterohexamer that mediates the initial step in the formation of the mannose 6-phosphate recognition signal on lysosomal acid hydrolases. We previously reported that the specificity of the reaction is determined by the ability of the alpha/beta subunits to recognize a conformation-dependent protein determinant present on the acid hydrolases. We now present evidence that the DNA methyltransferase-associated protein (DMAP) interaction domain of the alpha subunit functions in this recognition process. First, GST-DMAP pulled down several acid hydrolases, but not nonlysosomal glycoproteins. Second, recombinant GlcNAc-1-phosphotransferase containing a missense mutation in the DMAP interaction domain (Lys732Asn) identified in a patient with mucolipidosis II exhibited full activity toward the simple sugar alpha-methyl d-mannoside but impaired phosphorylation of acid hydrolases. Finally, unlike the WT enzyme, expression of the K732N mutant in a zebrafish model of mucolipidosis II failed to correct the phenotypic abnormalities. These results indicate that the DMAP interaction domain of the alpha subunit functions in the selective recognition of acid hydrolase substrates and provides an explanation for the impaired phosphorylation of acid hydrolases in a patient with mucolipidosis II. PMID- 23733940 TI - Global human appropriation of net primary production doubled in the 20th century. AB - Global increases in population, consumption, and gross domestic product raise concerns about the sustainability of the current and future use of natural resources. The human appropriation of net primary production (HANPP) provides a useful measure of human intervention into the biosphere. The productive capacity of land is appropriated by harvesting or burning biomass and by converting natural ecosystems to managed lands with lower productivity. This work analyzes trends in HANPP from 1910 to 2005 and finds that although human population has grown fourfold and economic output 17-fold, global HANPP has only doubled. Despite this increase in efficiency, HANPP has still risen from 6.9 Gt of carbon per y in 1910 to 14.8 GtC/y in 2005, i.e., from 13% to 25% of the net primary production of potential vegetation. Biomass harvested per capita and year has slightly declined despite growth in consumption because of a decline in reliance on bioenergy and higher conversion efficiencies of primary biomass to products. The rise in efficiency is overwhelmingly due to increased crop yields, albeit frequently associated with substantial ecological costs, such as fossil energy inputs, soil degradation, and biodiversity loss. If humans can maintain the past trend lines in efficiency gains, we estimate that HANPP might only grow to 27-29% by 2050, but providing large amounts of bioenergy could increase global HANPP to 44%. This result calls for caution in refocusing the energy economy on land-based resources and for strategies that foster the continuation of increases in land use efficiency without excessively increasing ecological costs of intensification. PMID- 23733941 TI - Structure and function of an insect alpha-carboxylesterase (alphaEsterase7) associated with insecticide resistance. AB - Insect carboxylesterases from the alphaEsterase gene cluster, such as alphaE7 (also known as E3) from the Australian sheep blowfly Lucilia cuprina (LcalphaE7), play an important physiological role in lipid metabolism and are implicated in the detoxification of organophosphate (OP) insecticides. Despite the importance of OPs to agriculture and the spread of insect-borne diseases, the molecular basis for the ability of alpha-carboxylesterases to confer OP resistance to insects is poorly understood. In this work, we used laboratory evolution to increase the thermal stability of LcalphaE7, allowing its overexpression in Escherichia coli and structure determination. The crystal structure reveals a canonical alpha/beta-hydrolase fold that is very similar to the primary target of OPs (acetylcholinesterase) and a unique N-terminal alpha-helix that serves as a membrane anchor. Soaking of LcalphaE7 crystals in OPs led to the capture of a crystallographic snapshot of LcalphaE7 in its phosphorylated state, which allowed comparison with acetylcholinesterase and rationalization of its ability to protect insects against the effects of OPs. Finally, inspection of the active site of LcalphaE7 reveals an asymmetric and hydrophobic substrate binding cavity that is well-suited to fatty acid methyl esters, which are hydrolyzed by the enzyme with specificity constants (~10(6) M(-1) s(-1)) indicative of a natural substrate. PMID- 23733942 TI - Genome-wide RNAi screen reveals a role for the ESCRT complex in rotavirus cell entry. AB - Rotavirus (RV) is the major cause of childhood gastroenteritis worldwide. This study presents a functional genome-scale analysis of cellular proteins and pathways relevant for RV infection using RNAi. Among the 522 proteins selected in the screen for their ability to affect viral infectivity, an enriched group that participates in endocytic processes was identified. Within these proteins, subunits of the vacuolar ATPase, small GTPases, actinin 4, and, of special interest, components of the endosomal sorting complex required for transport (ESCRT) machinery were found. Here we provide evidence for a role of the ESCRT complex in the entry of simian and human RV strains in both monkey and human epithelial cells. In addition, the ESCRT-associated ATPase VPS4A and phospholipid lysobisphosphatidic acid, both crucial for the formation of intralumenal vesicles in multivesicular bodies, were also found to be required for cell entry. Interestingly, it seems that regardless of the molecules that rhesus RV and human RV strains use for cell-surface attachment and the distinct endocytic pathway used, all these viruses converge in early endosomes and use multivesicular bodies for cell entry. Furthermore, the small GTPases RHOA and CDC42, which regulate different types of clathrin-independent endocytosis, as well as early endosomal antigen 1 (EEA1), were found to be involved in this process. This work reports the direct involvement of the ESCRT machinery in the life cycle of a nonenveloped virus and highlights the complex mechanism that these viruses use to enter cells. It also illustrates the efficiency of high-throughput RNAi screenings as genetic tools for comprehensively studying the interaction between viruses and their host cells. PMID- 23733944 TI - Influence of sulfate reduction rates on the Phanerozoic sulfur isotope record. AB - Phanerozoic levels of atmospheric oxygen relate to the burial histories of organic carbon and pyrite sulfur. The sulfur cycle remains poorly constrained, however, leading to concomitant uncertainties in O2 budgets. Here we present experiments linking the magnitude of fractionations of the multiple sulfur isotopes to the rate of microbial sulfate reduction. The data demonstrate that such fractionations are controlled by the availability of electron donor (organic matter), rather than by the concentration of electron acceptor (sulfate), an environmental constraint that varies among sedimentary burial environments. By coupling these results with a sediment biogeochemical model of pyrite burial, we find a strong relationship between observed sulfur isotope fractionations over the last 200 Ma and the areal extent of shallow seafloor environments. We interpret this as a global dependency of the rate of microbial sulfate reduction on the availability of organic-rich sea-floor settings. However, fractionation during the early/mid-Paleozoic fails to correlate with shelf area. We suggest that this decoupling reflects a shallower paleoredox boundary, primarily confined to the water column in the early Phanerozoic. The transition between these two states begins during the Carboniferous and concludes approximately around the Triassic-Jurassic boundary, indicating a prolonged response to a Carboniferous rise in O2. Together, these results lay the foundation for decoupling changes in sulfate reduction rates from the global average record of pyrite burial, highlighting how the local nature of sedimentary processes affects global records. This distinction greatly refines our understanding of the S cycle and its relationship to the history of atmospheric oxygen. PMID- 23733943 TI - Abnormal accumulation and recycling of glycoproteins visualized in Niemann-Pick type C cells using the chemical reporter strategy. AB - Niemann-Pick type C (NPC) disease is characterized by impaired cholesterol efflux from late endosomes and lysosomes and secondary accumulation of lipids. Although impaired trafficking of individual glycoproteins and glycolipids has been noted in NPC cells and other storage disorders, there is currently no effective way to monitor their localization and movement en masse. Using a chemical reporter strategy in combination with pharmacologic treatments, we demonstrate a disease specific and previously unrecognized accumulation of a diverse set of glycoconjugates in NPC1-null and NPC2-deficient fibroblasts within endocytic compartments. These labeled vesicles do not colocalize with the cholesterol-laden compartments of NPC cells. Experiments using the endocytic uptake marker dextran show that the endosomal accumulation of sialylated molecules can be largely attributed to impaired recycling as opposed to altered fusion of vesicles. Treatment of either NPC1-null or NPC2-deficient cells with cyclodextrin was effective in reducing cholesterol storage as well as the endocytic accumulation of sialoglycoproteins, demonstrating a direct link between cholesterol storage and abnormal recycling. Our data further demonstrate that this accumulation is largely glycoproteins, given that inhibitors of O-glycan initiation or N-glycan processing led to a significant reduction in staining intensity. Taken together, our results provide a unique perspective on the trafficking defects in NPC cells, and highlight the utility of this methodology in analyzing cells with altered recycling and turnover of glycoproteins. PMID- 23733945 TI - Anoxic photochemical oxidation of siderite generates molecular hydrogen and iron oxides. AB - Photochemical reactions of minerals are underappreciated processes that can make or break chemical bonds. We report the photooxidation of siderite (FeCO3) by UV radiation to produce hydrogen gas and iron oxides via a two-photon reaction. The calculated quantum yield for the reaction suggests photooxidation of siderite would have been a significant source of molecular hydrogen for the first half of Earth's history. Further, experimental results indicate this abiotic, photochemical process may have led to the formation of iron oxides under anoxic conditions. The reaction would have continued through the Archean to at least the early phases of the Great Oxidation Event, and provided a mechanism for oxidizing the atmosphere through the loss of hydrogen to space, while simultaneously providing a key reductant for microbial metabolism. We propose that the photochemistry of Earth-abundant minerals with wide band gaps would have potentially played a critical role in shaping the biogeochemical evolution of early Earth. PMID- 23733946 TI - Iron traps terrestrially derived dissolved organic matter at redox interfaces. AB - Reactive iron and organic carbon are intimately associated in soils and sediments. However, to date, the organic compounds involved are uncharacterized on the molecular level. At redox interfaces in peatlands, where the biogeochemical cycles of iron and dissolved organic matter (DOM) are coupled, this issue can readily be studied. We found that precipitation of iron hydroxides at the oxic surface layer of two rewetted fens removed a large fraction of DOM via coagulation. On aeration of anoxic fen pore waters, >90% of dissolved iron and 27 +/- 7% (mean +/- SD) of dissolved organic carbon were rapidly (within 24 h) removed. Using ultra-high-resolution MS, we show that vascular plant-derived aromatic and pyrogenic compounds were preferentially retained, whereas the majority of carboxyl-rich aliphatic acids remained in solution. We propose that redox interfaces, which are ubiquitous in marine and terrestrial settings, are selective yet intermediate barriers that limit the flux of land-derived DOM to oceanic waters. PMID- 23733947 TI - Small molecule inhibitors of trans-translation have broad-spectrum antibiotic activity. AB - The trans-translation pathway for protein tagging and ribosome release plays a critical role for viability and virulence in a wide range of pathogens but is not found in animals. To explore the use of trans-translation as a target for antibiotic development, a high-throughput screen and secondary screening assays were used to identify small molecule inhibitors of the pathway. Compounds that inhibited protein tagging and proteolysis of tagged proteins were recovered from the screen. One of the most active compounds, KKL-35, inhibited the trans translation tagging reaction with an IC50 = 0.9 uM. KKL-35 and other compounds identified in the screen exhibited broad-spectrum antibiotic activity, validating trans-translation as a target for drug development. This unique target could play a key role in combating strains of pathogenic bacteria that are resistant to existing antibiotics. PMID- 23733948 TI - Functional significance of evolving protein sequence in dihydrofolate reductase from bacteria to humans. AB - With the rapidly growing wealth of genomic data, experimental inquiries on the functional significance of important divergence sites in protein evolution are becoming more accessible. Here we trace the evolution of dihydrofolate reductase (DHFR) and identify multiple key divergence sites among 233 species between humans and bacteria. We connect these sites, experimentally and computationally, to changes in the enzyme's binding properties and catalytic efficiency. One of the identified evolutionarily important sites is the N23PP modification (~mid Devonian, 415-385 Mya), which alters the conformational states of the active site loop in Escherichia coli dihydrofolate reductase and negatively impacts catalysis. This enzyme activity was restored with the inclusion of an evolutionarily significant lid domain (G51PEKN in E. coli enzyme; ~2.4 Gya). Guided by this evolutionary genomic analysis, we generated a human-like E. coli dihydrofolate reductase variant through three simple mutations despite only 26% sequence identity between native human and E. coli DHFRs. Molecular dynamics simulations indicate that the overall conformational motions of the protein within a common scaffold are retained throughout evolution, although subtle changes to the equilibrium conformational sampling altered the free energy barrier of the enzymatic reaction in some cases. The data presented here provide a glimpse into the evolutionary trajectory of functional DHFR through its protein sequence space that lead to the diverged binding and catalytic properties of the E. coli and human enzymes. PMID- 23733949 TI - Structure of the archaeal head-tailed virus HSTV-1 completes the HK97 fold story. AB - It has been proposed that viruses can be divided into a small number of structure based viral lineages. One of these lineages is exemplified by bacterial virus Hong Kong 97 (HK97), which represents the head-tailed dsDNA bacteriophages. Seemingly similar viruses also infect archaea. Here we demonstrate using genomic analysis, electron cryomicroscopy, and image reconstruction that the major coat protein fold of newly isolated archaeal Haloarcula sinaiiensis tailed virus 1 has the canonical coat protein fold of HK97. Although it has been anticipated previously, this is physical evidence that bacterial and archaeal head-tailed viruses share a common architectural principle. The HK97-like fold has previously been recognized also in herpesviruses, and this study expands the HK97-like lineage to viruses from all three domains of life. This is only the second established lineage to include archaeal, bacterial, and eukaryotic viruses. Thus, our findings support the hypothesis that the last common universal ancestor of cellular organisms was infected by a number of different viruses. PMID- 23733950 TI - Neisseria gonorrhoeae-derived heptose elicits an innate immune response and drives HIV-1 expression. AB - Clinical and epidemiological synergy exists between the globally important sexually transmitted infections, gonorrhea and HIV. Neisseria gonorrhoeae, which causes gonorrhea, is particularly adept at driving HIV-1 expression, but the molecular determinants of this relationship remain undefined. N. gonorrhoeae liberates a soluble factor that potently induces expression from the HIV-1 LTR in coinfected cluster of differentiation 4-positive (CD4(+)) T lymphocytes, but this factor is not a previously described innate effector. A genome-wide mutagenesis approach was undertaken to reveal which component(s) of N. gonorrhoeae induce HIV 1 expression in CD4(+) T lymphocytes. A mutation in the ADP-heptose biosynthesis gene, hldA, rendered the bacteria unable to induce HIV-1 expression. The hldA mutant has a truncated lipooligosaccharide structure, contains lipid A in its outer membrane, and remains bioactive in a TLR4 reporter-based assay but did not induce HIV-1 expression. Mass spectrometry analysis of extensively fractionated N. gonorrhoeae-derived supernatants revealed that the LTR-inducing fraction contained a compound having a mass consistent with heptose-monophosphate (HMP). Heptose is a carbohydrate common in microbes but is absent from the mammalian glycome. Although ADP-heptose biosynthesis is common among Gram-negative bacteria, and heptose is a core component of most lipopolysaccharides, N. gonorrhoeae is peculiar in that it effectively liberates HMP during growth. This N. gonorrhoeae-derived HMP activates CD4(+) T cells to invoke an NF-kappaB dependent transcriptional response that drives HIV-1 expression and viral production. Our study thereby shows that heptose is a microbial-specific product that is sensed as an innate immune agonist and unveils the molecular link between N. gonorrhoeae and HIV-1. PMID- 23733951 TI - Structural characterization of a unique marine animal family 7 cellobiohydrolase suggests a mechanism of cellulase salt tolerance. AB - Nature uses a diversity of glycoside hydrolase (GH) enzymes to convert polysaccharides to sugars. As lignocellulosic biomass deconstruction for biofuel production remains costly, natural GH diversity offers a starting point for developing industrial enzymes, and fungal GH family 7 (GH7) cellobiohydrolases, in particular, provide significant hydrolytic potential in industrial mixtures. Recently, GH7 enzymes have been found in other kingdoms of life besides fungi, including in animals and protists. Here, we describe the in vivo spatial expression distribution, properties, and structure of a unique endogenous GH7 cellulase from an animal, the marine wood borer Limnoria quadripunctata (LqCel7B). RT-quantitative PCR and Western blot studies show that LqCel7B is expressed in the hepatopancreas and secreted into the gut for wood degradation. We produced recombinant LqCel7B, with which we demonstrate that LqCel7B is a cellobiohydrolase and obtained four high-resolution crystal structures. Based on a crystallographic and computational comparison of LqCel7B to the well characterized Hypocrea jecorina GH7 cellobiohydrolase, LqCel7B exhibits an extended substrate-binding motif at the tunnel entrance, which may aid in substrate acquisition and processivity. Interestingly, LqCel7B exhibits striking surface charges relative to fungal GH7 enzymes, which likely results from evolution in marine environments. We demonstrate that LqCel7B stability and activity remain unchanged, or increase at high salt concentration, and that the L. quadripunctata GH mixture generally contains cellulolytic enzymes with highly acidic surface charge compared with enzymes derived from terrestrial microbes. Overall, this study suggests that marine cellulases offer significant potential for utilization in high-solids industrial biomass conversion processes. PMID- 23733952 TI - Fusing enacted and expected mimicry generates a winning strategy that promotes the evolution of cooperation. AB - Although cooperation and trust are essential features for the development of prosperous populations, they also put cooperating individuals at risk for exploitation and abuse. Empirical and theoretical evidence suggests that the solution to the problem resides in the practice of mimicry and imitation, the expectation of opponent's mimicry and the reliance on similarity indices. Here we fuse the principles of enacted and expected mimicry and condition their application on two similarity indices to produce a model of mimicry and relative similarity. Testing the model in computer simulations of behavioral niches, populated with agents that enact various strategies and learning algorithms, shows how mimicry and relative similarity outperforms all the opponent strategies it was tested against, pushes noncooperative opponents toward extinction, and promotes the development of cooperative populations. The proposed model sheds light on the evolution of cooperation and provides a blueprint for intentional induction of cooperation within and among populations. It is suggested that reducing conflict intensities among human populations necessitates (i) instigation of social initiatives that increase the perception of similarity among opponents and (ii) efficient lowering of the similarity threshold of the interaction, the minimal level of similarity that makes cooperation advisable. PMID- 23733953 TI - MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells. AB - The MYC genes are the most frequently activated oncogenes in human tumors and are hence attractive therapeutic targets. MYCN amplification leads to poor clinical outcome in childhood neuroblastoma, yet strategies to modulate the function of MYCN do not exist. Here we show that 10058-F4, a characterized c-MYC/Max inhibitor, also targets the MYCN/Max interaction, leading to cell cycle arrest, apoptosis, and neuronal differentiation in MYCN-amplified neuroblastoma cells and to increased survival of MYCN transgenic mice. We also report the discovery that inhibition of MYC is accompanied by accumulation of intracellular lipid droplets in tumor cells as a direct consequence of mitochondrial dysfunction. This study expands on the current knowledge of how MYC proteins control the metabolic reprogramming of cancer cells, especially highlighting lipid metabolism and the respiratory chain as important pathways involved in neuroblastoma pathogenesis. Together our data support direct MYC inhibition as a promising strategy for the treatment of MYC-driven tumors. PMID- 23733954 TI - Unphosphorylated STAT5A stabilizes heterochromatin and suppresses tumor growth. AB - Tumor suppressors known to date impede cancer growth by arresting the cell cycle or promoting apoptosis. Here we show that unphosphorylated human STAT5A functions as a tumor suppressor capable of repressing multiple oncogenes via heterochromatin formation. Unphosphorylated STAT5A binds to heterochromatin protein 1alpha (HP1alpha) and stabilizes heterochromatin. Expressing unphosphorylated STAT5A or HP1alpha inhibits colon cancer growth in mouse xenograft models. Transcriptome profiling shows that expressing an unphosphorylatable STAT5A has similar effects to overexpressing HP1alpha in global gene expression. Notably, the majority of the genes commonly repressed by unphosphorylated STAT5A and HP1alpha have been implicated in cancer development. Finally, down-regulation, somatic mutations, and deletions of STAT5 genes are found in certain human cancers. These results suggest that unphosphorylated STAT5A may epigenetically suppress tumor growth by promoting heterochromatin formation. PMID- 23733955 TI - Marital satisfaction and break-ups differ across on-line and off-line meeting venues. AB - Marital discord is costly to children, families, and communities. The advent of the Internet, social networking, and on-line dating has affected how people meet future spouses, but little is known about the prevalence or outcomes of these marriages or the demographics of those involved. We addressed these questions in a nationally representative sample of 19,131 respondents who married between 2005 and 2012. Results indicate that more than one-third of marriages in America now begin on-line. In addition, marriages that began on-line, when compared with those that began through traditional off-line venues, were slightly less likely to result in a marital break-up (separation or divorce) and were associated with slightly higher marital satisfaction among those respondents who remained married. Demographic differences were identified between respondents who met their spouse through on-line vs. traditional off-line venues, but the findings for marital break-up and marital satisfaction remained significant after statistically controlling for these differences. These data suggest that the Internet may be altering the dynamics and outcomes of marriage itself. PMID- 23733956 TI - High-resolution structures of the IgM Fc domains reveal principles of its hexamer formation. AB - IgM is the first antibody produced during the humoral immune response. Despite its fundamental role in the immune system, IgM is structurally only poorly described. In this work we used X-ray crystallography and NMR spectroscopy to determine the atomic structures of the constant IgM Fc domains (Cu2, Cu3, and Cu4) and to address their roles in IgM oligomerization. Although the isolated domains share the typical Ig fold, they differ substantially in dimerization properties and quaternary contacts. Unexpectedly, the Cu4 domain and its C terminal tail piece are responsible and sufficient for the specific polymerization of Cu4 dimers into covalently linked hexamers of dimers. Based on small angle X-ray scattering data, we present a model of the ring-shaped Cu4 structure, which reveals the principles of IgM oligomerization. PMID- 23733957 TI - Kinetics of gene derepression by ERK signaling. AB - ERK controls gene expression in development, but mechanisms that link ERK activation to changes in transcription are not well understood. We used high resolution analysis of signaling dynamics to study transcriptional interpretation of ERK signaling during Drosophila embryogenesis, at a stage when ERK induces transcription of intermediate neuroblasts defective (ind), a gene essential for patterning of the nerve cord. ERK induces ind by antagonizing its repression by Capicua (Cic), a transcription factor that acts as a sensor of receptor tyrosine kinases in animal development and human diseases. A recent study established that active ERK reduces the nuclear levels of Cic, but it remained unclear whether this is required for the induction of Cic target genes. We provide evidence that Cic binding sites within the regulatory DNA of ind control the spatial extent and the timing of ind expression. At the same time, we demonstrate that ERK induces ind before Cic levels in the nucleus are reduced. Based on this, we propose that ERK-dependent relief of gene repression by Cic is a two-step process, in which fast reduction of repressor activity is followed by slower changes in nuclear localization and overall protein levels. This may be a common feature of systems in which ERK induces genes by relief of transcriptional repression. PMID- 23733958 TI - Peripheral elevation of TNF-alpha leads to early synaptic abnormalities in the mouse somatosensory cortex in experimental autoimmune encephalomyelitis. AB - Sensory abnormalities such as numbness and paresthesias are often the earliest symptoms in neuroinflammatory diseases including multiple sclerosis. The increased production of various cytokines occurs in the early stages of neuroinflammation and could have detrimental effects on the central nervous system, thereby contributing to sensory and cognitive deficits. However, it remains unknown whether and when elevation of cytokines causes changes in brain structure and function under inflammatory conditions. To address this question, we used a mouse model for experimental autoimmune encephalomyelitis (EAE) to examine the effect of inflammation and cytokine elevation on synaptic connections in the primary somatosensory cortex. Using in vivo two-photon microscopy, we found that the elimination and formation rates of dendritic spines and axonal boutons increased within 7 d of EAE induction--several days before the onset of paralysis--and continued to rise during the course of the disease. This synaptic instability occurred before T-cell infiltration and microglial activation in the central nervous system and was in conjunction with peripheral, but not central, production of TNF-alpha. Peripheral administration of a soluble TNF inhibitor prevented abnormal turnover of dendritic spines and axonal boutons in presymptomatic EAE mice. These findings indicate that peripheral production of TNF-alpha is a key mediator of synaptic instability in the primary somatosensory cortex and may contribute to sensory and cognitive deficits seen in autoimmune diseases. PMID- 23733959 TI - Decreased RyR2 refractoriness determines myocardial synchronization of aberrant Ca2+ release in a genetic model of arrhythmia. AB - Dysregulated intracellular Ca(2+) signaling is implicated in a variety of cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia. Spontaneous diastolic Ca(2+) release (DCR) can induce arrhythmogenic plasma membrane depolarizations, although the mechanism responsible for DCR synchronization among adjacent myocytes required for ectopic activity remains unclear. We investigated the synchronization mechanism(s) of DCR underlying untimely action potentials and diastolic contractions (DCs) in a catecholaminergic polymorphic ventricular tachycardia mouse model with a mutation in cardiac calsequestrin. We used a combination of different approaches including single ryanodine receptor channel recording, optical imaging (Ca(2+) and membrane potential), and contractile force measurements in ventricular myocytes and intact cardiac muscles. We demonstrate that DCR occurs in a temporally and spatially uniform manner in both myocytes and intact myocardial tissue isolated from cardiac calsequestrin mutation mice. Such synchronized DCR events give rise to triggered electrical activity that results in synchronous DCs in the myocardium. Importantly, we establish that synchronization of DCR is a result of a combination of abbreviated ryanodine receptor channel refractoriness and the preceding synchronous stimulated Ca(2+) release/reuptake dynamics. Our study reveals how aberrant DCR events can become synchronized in the intact myocardium, leading to triggered activity and the resultant DCs in the settings of a cardiac rhythm disorder. PMID- 23733960 TI - Wolbachia uses a host microRNA to regulate transcripts of a methyltransferase, contributing to dengue virus inhibition in Aedes aegypti. AB - The endosymbiont Wolbachia is common among insects and known for the reproductive manipulations it exerts on hosts as well as inhibition of virus replication in their hosts. Recently, we showed that Wolbachia uses host microRNAs to manipulate host gene expression for its efficient maintenance in the dengue mosquito vector, Aedes aegypti. Cytosine methylation is mediated by a group of proteins called DNA (cytosine-5) methyltransferases, which are structurally and functionally conserved from prokaryotes to eukaryotes. The biological functions of cytosine methylation include host defense, genome stability, gene regulation, developmental promotion of organs, and lifespan regulation. Ae. aegypti has only one DNA methyltransferase gene (AaDnmt2) belonging to the cytosine methyltransferase family 2, which is the most deeply conserved and widely distributed gene among metazoans. Here, we show that in mosquitoes the introduced endosymbiont, Wolbachia, significantly suppresses expression of AaDnmt2, but dengue virus induces expression of AaDnmt2. Interestingly, we found that aae-miR 2940 microRNA, which is exclusively expressed in Wolbachia-infected mosquitoes, down-regulates the expression of AaDnmt2. Reversely, overexpression of AaDnmt2 in mosquito cells led to inhibition of Wolbachia replication, but significantly promoted replication of dengue virus, suggesting a causal link between this Wolbachia manipulation and the blocking of dengue replication in Wolbachia infected mosquitoes. In addition, our findings provide an explanation for hypomethylation of the genome in Wolbachia-infected Ae. aegypti. PMID- 23733961 TI - Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase. AB - Glucokinase (GK) is a monomeric allosteric enzyme and plays a pivotal role in blood glucose homeostasis. GK is regulated by GK regulatory protein (GKRP), and indirectly by allosteric effectors of GKRP. Despite the critical roles of GK and GKRP, the molecular basis for the allosteric regulation mechanism of GK by GKRP remains unclear. We determined the crystal structure of Xenopus GK and GKRP complex in the presence of fructose-6-phosphate at 2.9 A. GKRP binds to a super open conformation of GK mainly through hydrophobic interaction, inhibiting the GK activity by locking a small domain of GK. We demonstrate the molecular mechanism for the modulation of GK activity by allosteric effectors of GKRP. Importantly, GKRP releases GK in a sigmoidal manner in response to glucose concentration by restricting a structural rearrangement of the GK small domain via a single ion pair. We find that GKRP acts as an allosteric switch for GK in blood glucose control by the liver. PMID- 23733962 TI - Essential, dose-dependent role for the transcription factor Gata3 in the development of IL-5+ and IL-13+ type 2 innate lymphoid cells. AB - Group 2 innate lymphoid cells (ILC2s; also called nuocytes, innate helper cells, or natural helper cells) provide protective immunity during helminth infection and play an important role in influenza-induced and allergic airway hyperreactivity. Whereas the transcription factor GATA binding protein 3 (Gata3) is important for the production of IL-5 and -13 by ILC2s in response to IL-33 or 25 stimulation, it is not known whether Gata3 is required for ILC2 development from hematopoietic stem cells. Here, we show that chimeric mice generated with Gata3-deficient fetal liver hematopoietic stem cells fail to develop systemically dispersed ILC2s. In these chimeric mice, in vivo administration of IL-33 or -25 fails to expand ILC2 numbers or to induce characteristic ILC2-dependent IL-5 or 13 production. Moreover, cell-intrinsic Gata3 expression is required for ILC2 development in vitro and in vivo. Using mutant and transgenic mice in which Gata3 gene copy number is altered, we show that ILC2 generation from common lymphoid progenitors, as well as ILC2 homeostasis and cytokine production, is regulated by Gata3 expression levels in a dose-dependent fashion. Collectively, these results identify Gata3 as a critical early regulator of ILC2 development, thereby extending the paradigm of Gata3-dependent control of type 2 immunity to include both innate and adaptive lymphocytes. PMID- 23733963 TI - Several scales of biodiversity affect ecosystem multifunctionality. AB - Society values landscapes that reliably provide many ecosystem functions. As the study of ecosystem functioning expands to include more locations, time spans, and functions, the functional importance of individual species is becoming more apparent. However, the functional importance of individual species does not necessarily translate to the functional importance of biodiversity measured in whole communities of interacting species. Furthermore, ecological diversity at scales larger than neighborhood species richness could also influence the provision of multiple functions over extended time scales. We created experimental landscapes based on whole communities from the world's longest running biodiversity-functioning field experiment to investigate how local species richness (alpha diversity), distinctness among communities (beta diversity), and larger scale species richness (gamma diversity) affected eight ecosystem functions over 10 y. Using both threshold-based and unique multifunctionality metrics, we found that alpha diversity had strong positive effects on most individual functions and multifunctionality, and that positive effects of beta and gamma diversity emerged only when multiple functions were considered simultaneously. Higher beta diversity also reduced the variability in multifunctionality. Thus, in addition to conserving important species, maintaining ecosystem multifunctionality will require diverse landscape mosaics of diverse communities. PMID- 23733965 TI - Diet of Australopithecus afarensis from the Pliocene Hadar Formation, Ethiopia. AB - The enhanced dietary flexibility of early hominins to include consumption of C4/crassulacean acid metabolism (CAM) foods (i.e., foods derived from grasses, sedges, and succulents common in tropical savannas and deserts) likely represents a significant ecological and behavioral distinction from both extant great apes and the last common ancestor that we shared with great apes. Here, we use stable carbon isotopic data from 20 samples of Australopithecus afarensis from Hadar and Dikika, Ethiopia (>3.4-2.9 Ma) to show that this species consumed a diet with significant C4/CAM foods, differing from its putative ancestor Au. anamensis. Furthermore, there is no temporal trend in the amount of C4/CAM food consumption over the age of the samples analyzed, and the amount of C4/CAM food intake was highly variable, even within a single narrow stratigraphic interval. As such, Au. afarensis was a key participant in the C4/CAM dietary expansion by early australopiths of the middle Pliocene. The middle Pliocene expansion of the eastern African australopith diet to include savanna-based foods represents a shift to use of plant food resources that were already abundant in hominin environments for at least 1 million y and sets the stage for dietary differentiation and niche specialization by subsequent hominin taxa. PMID- 23733966 TI - Stable isotope-based diet reconstructions of Turkana Basin hominins. AB - Hominin fossil evidence in the Turkana Basin in Kenya from ca. 4.1 to 1.4 Ma samples two archaic early hominin genera and records some of the early evolutionary history of Paranthropus and Homo. Stable carbon isotopes in fossil tooth enamel are used to estimate the fraction of diet derived from C3 or C4 resources in these hominin taxa. The earliest hominin species in the Turkana Basin, Australopithecus anamensis, derived nearly all of its diet from C3 resources. Subsequently, by ca. 3.3 Ma, the later Kenyanthropus platyops had a very wide dietary range--from virtually a purely C3 resource-based diet to one dominated by C4 resources. By ca. 2 Ma, hominins in the Turkana Basin had split into two distinct groups: specimens attributable to the genus Homo provide evidence for a diet with a ca. 65/35 ratio of C3- to C4-based resources, whereas P. boisei had a higher fraction of C4-based diet (ca. 25/75 ratio). Homo sp. increased the fraction of C4-based resources in the diet through ca. 1.5 Ma, whereas P. boisei maintained its high dependency on C4-derived resources. PMID- 23733968 TI - Evolution and emergence of therapeutic monoclonal antibodies: what cardiologists need to know. PMID- 23733967 TI - Diet of Theropithecus from 4 to 1 Ma in Kenya. AB - Theropithecus was a common large-bodied primate that co-occurred with hominins in many Plio-Pleistocene deposits in East and South Africa. Stable isotope analyses of tooth enamel from T. brumpti (4.0-2.5 Ma) and T. oswaldi (2.0-1.0 Ma) in Kenya show that the earliest Theropithecus at 4 Ma had a diet dominated by C4 resources. Progressively, this genus increased the proportion of C4-derived resources in its diet and by 1.0 Ma, had a diet that was nearly 100% C4-derived. It is likely that this diet was comprised of grasses or sedges; stable isotopes cannot, by themselves, give an indication of the relative importance of leaves, seeds, or underground storage organs to the diet of this primate. Theropithecus throughout the 4- to 1-Ma time range has a diet that is more C4-based than contemporaneous hominins of the genera Australopithecus, Kenyanthropus, and Homo; however, Theropithecus and Paranthropus have similar proportions of C4-based resources in their respective diets. PMID- 23733969 TI - Retained epicardial pacing wires: "a baby in the heart". PMID- 23733970 TI - Active cardiac sarcoidosis: first clinical experience of simultaneous positron emission tomography--magnetic resonance imaging for the diagnosis of cardiac disease. PMID- 23733971 TI - Cardiology patient page. Managing your angina symptoms with nitroglycerin: what about exercise? PMID- 23733973 TI - Letter by Wang et al regarding article, "Childhood air pollutant exposure and carotid artery intima-media thickness in young adults". PMID- 23733974 TI - Health Affairs: fast forward into health policy future. PMID- 23733975 TI - With just months to go, New York State's Health Benefit Exchange gears up for open enrollment. PMID- 23733976 TI - For states that opt out of Medicaid expansion: 3.6 million fewer insured and $8.4 billion less in federal payments. AB - The US Supreme Court's ruling on the Affordable Care Act in 2012 allowed states to opt out of the health reform law's Medicaid expansion. Since that ruling, fourteen governors have announced that their states will not expand their Medicaid programs. We used the RAND COMPARE microsimulation to analyze how opting out of Medicaid expansion would affect coverage and spending, and whether alternative policy options-such as partial expansion of Medicaid-could cover as many people at lower costs to states. With fourteen states opting out, we estimate that 3.6 million fewer people would be insured, federal transfer payments to those states could fall by $8.4 billion, and state spending on uncompensated care could increase by $1 billion in 2016, compared to what would be expected if all states participated in the expansion. These effects were only partially mitigated by alternative options we considered. We conclude that in terms of coverage, cost, and federal payments, states would do best to expand Medicaid. PMID- 23733977 TI - Wisconsin experience indicates that expanding public insurance to low-income childless adults has health care impacts. AB - As states consider expanding Medicaid to low-income childless adults under the Affordable Care Act, their decisions will depend, in part, on how such coverage may affect the use of medical care. In 2009 Wisconsin created a new public insurance program for low-income uninsured childless adults. We analyzed administrative claims data spanning 2008 and 2009 using a case-crossover study design on a population of 9,619 Wisconsin residents with very low incomes who were automatically enrolled in this program in January 2009. In the twelve months following enrollment in public insurance, outpatient visits for the study population increased 29 percent, and emergency department visits increased 46 percent. Inpatient hospitalizations declined 59 percent, and preventable hospitalizations fell 48 percent. These results demonstrate that public insurance coverage expansions to childless adults have the potential to improve health and reduce costs by increasing access to outpatient care and reducing hospitalizations. PMID- 23733979 TI - Recession led to a decline in out-of-pocket spending for children with special health care needs. AB - The 2007-09 recession led to an overall slowing in health care spending growth, but it is unclear whether the slowed spending growth had different impacts on adults and children. Although most children are healthy, forgoing routine health care could have long-term adverse implications for public health. Furthermore, children with special health care needs are at risk of adverse outcomes if they do not receive adequate care. Focusing on privately insured families with children, we investigated how out-of-pocket spending trends changed before and during the recession. Medical Expenditure Panel Survey data from the period 2001 09 revealed that the recession did not affect out-of-pocket spending for most children, but it led to a decline in spending for children with special needs, who had much higher out-of-pocket spending at baseline. Adults had significantly lower out-of-pocket spending during the recession, which suggests that parents may reduce their own medical care in difficult economic times to meet their children's health care needs. PMID- 23733978 TI - Black patients more likely than whites to undergo surgery at low-quality hospitals in segregated regions. AB - Research has shown that black patients more frequently undergo surgery at low quality hospitals than do white patients. We assessed the extent to which living in racially segregated areas and living in geographic proximity to low-quality hospitals contribute to this disparity. Using national Medicare data for all patients who underwent one of three high-risk surgical procedures in 2005-08, we found that black patients actually tended to live closer to higher-quality hospitals than white patients did but were 25-58 percent more likely than whites to receive surgery at low-quality hospitals. Racial segregation was also a factor, with black patients in the most segregrated areas 41-96 percent more likely than white patients to undergo surgery at low-quality hospitals. To address these disparities, care navigators and public reporting of comparative quality could steer patients and their referring physicians to higher-quality hospitals, while quality improvement efforts could focus on improving outcomes for high-risk surgery at hospitals that disproportionately serve black patients. Unfortunately, existing policies such as pay-for-performance, bundled payments, and nonpayment for adverse events may divert resources and exacerbate these disparities. PMID- 23733980 TI - AIDS Drug Assistance Programs: managers confront uncertainty and need to adapt as the Affordable Care Act kicks in. AB - With the Affordable Care Act set to expand insurance coverage to millions more Americans next year, existing discretionary health programs that receive federal support might find themselves competing for funds as the health reform law is fully implemented. To assess the implications the Affordable Care Act might have for discretionary health programs, we focused on state AIDS Drug Assistance Programs, which provide free medications to low-income HIV patients. We conducted semistructured interviews with program managers from twenty-two states. Many of the managers predicted that their programs will change focus to provide "wrap around services," such as helping newly insured clients finance out-of-pocket expenses, including copayments, deductibles, and premiums. Although program managers acknowledged that they must adapt to a changing environment, many said that they were overwhelmed by the complexity of the Affordable Care Act, and some expressed fear that state AIDS Drug Assistance Programs would be eliminated entirely. To remain viable, such programs must identify and justify the need for services in the context of the Affordable Care Act and receive sufficient political support and funding. PMID- 23733981 TI - Welfare programs that target workforce participation may negatively affect mortality. AB - During the 1990s reforms to the US welfare system introduced new time limits on people's eligibility to receive public assistance. These limits were developed to encourage welfare recipients to seek employment. Little is known about how such social policy programs may have affected participants' health. We explored whether the Florida Family Transition Program randomized trial, a welfare reform experiment, led to long-term changes in mortality among participants. The Florida program included a 24-36-month time limit for welfare participation, intensive job training, and placement assistance. We linked 3,224 participants from the experiment to 17-18 years of prospective mortality follow-up data and found that participants in the program experienced a 16 percent higher mortality rate than recipients of traditional welfare. If our results are generalizable to national welfare reform efforts, they raise questions about whether the cost savings associated with welfare reform justify the additional loss of life. PMID- 23733982 TI - Innovations at Miami practice show promise for treating high-risk Medicare patients. AB - Patients with five or more chronic conditions drive most Medicare costs. Our organization, ChenMed, developed a scalable primary care-led delivery model that focuses on this population while getting reimbursed through full-risk capitation by Medicare Advantage plans. ChenMed is a primary care-led group practice based in Florida that serves low-to-moderate-income elderly patients, largely through the Medicare Advantage program. Our model includes a number of innovations: a one stop-shop approach for delivering multispecialty services in the community, smaller physician panel sizes of 350-450 patients that allow for intensive health coaching and preventive care, on-site physician pharmacy dispensing, a collaborative physician culture with peer review, and customized information technology. These innovations have improved patient medication adherence, increased the time doctors and patients spend together, and led to high rates of patient satisfaction. Additionally, our Medicare patients have substantially lower rates of hospital use than their peers in the Miami Medicare market. Creating chronic disease centers focused on seniors with multiple chronic conditions is a promising delivery system innovation with major potential to improve the cost and quality of care. PMID- 23733983 TI - Limits of readmission rates in measuring hospital quality suggest the need for added metrics. AB - Recent national policies use risk-standardized readmission rates to measure hospital performance on the theory that readmissions reflect dimensions of the quality of patient care that are influenced by hospitals. In this article our objective was to assess readmission rates as a hospital quality measure. First we compared quartile rankings of hospitals based on readmission rates in 2009 and 2011 to see whether hospitals maintained their relative performance or whether shifts occurred that suggested either changes in quality or random variation. Next we examined the relationship between readmission rates and several commonly used hospital quality indicators, including risk-standardized mortality rates, volume, teaching status, and process-measure performance. We found that quartile rankings fluctuated and that readmission rates for lower-performing hospitals in 2009 tended to improve by 2011, while readmission rates for higher-performing hospitals tended to worsen. Regression to the mean (a form of statistical noise) accounted for a portion of the changes in hospital performance. We also found that readmission rates were higher in teaching hospitals and were weakly correlated with the other indicators of hospital quality. Policy makers should consider augmenting the use of readmission rates with other measures of hospital performance during care transitions and should build on current efforts that take a communitywide approach to the readmissions issue. PMID- 23733984 TI - The Aligning Forces for Quality experience: lessons on getting consumers involved in health care improvements. AB - Aligning Forces for Quality is the Robert Wood Johnson Foundation's signature effort to improve the overall quality of health care in targeted communities, reduce racial and ethnic disparities in care, and provide models for national reform. Activities in each of the sixteen Aligning Forces for Quality alliance communities are guided by a multistakeholder alliance of consumers, providers, and payers. To achieve goals established at the national and local levels, the alliances integrate local consumers into governance and decision making, program design and implementation, and information dissemination efforts. This article describes how the Aligning Forces for Quality investments have evolved since the initiative's launch in 2006 and offers some early lessons learned. Individual alliances have engaged consumers in numerous capacities, from serving on dedicated consumer advisory boards to representing the consumer's perspective in the design of public reports of providers' quality. The alliances' ongoing and mindful inclusion of consumers provides insights into eliciting and applying their perspectives in the pursuit of improved health care quality, value, and transparency. PMID- 23733985 TI - Fair pricing law prompts most California hospitals to adopt policies to protect uninsured patients from high charges. AB - Millions of uninsured Americans rely on hospital emergency departments (EDs) for medical care. Throughout the United States, uninsured patients treated in or admitted to the hospital through the ED receive hospital bills based on what hospitals call "billed charges." These charges are much higher than those paid by insured patients. In 2006 California approved "fair pricing" legislation to protect uninsured patients from having to pay full billed charges. We found that by 2011 most California hospitals had responded to the law by adopting financial assistance policies to make care more affordable for the state's 6.8 million uninsured people. Ninety-seven percent of California hospitals reported that they offered free care to uninsured patients with incomes at or below 100 percent of the federal poverty level. California's approach offers a promising policy option to other states seeking to protect the uninsured from receiving bills based on full billed charges. PMID- 23733986 TI - Medicare covers the majority of FDA-approved devices and Part B drugs, but restrictions and discrepancies remain. AB - The Food and Drug Administration (FDA) and Medicare use different standards to determine, first, whether a new drug or medical device can be marketed to the public and, second, if the federal health insurance program will pay for use of the drug or device. This discrepancy creates hurdles and uncertainty for drug and device manufacturers. We analyzed discrepancies between FDA approval and Medicare national coverage determinations for sixty-nine devices and Part B drugs approved during 1999-2011. We found that Medicare covered FDA-approved drugs or devices 80 percent of the time. However, Medicare often added conditions beyond FDA approval, particularly for devices and most often restricting coverage to patients with the most severe disease. In some instances, Medicare was less restrictive than the FDA. Our findings highlight the importance for drug and device makers of anticipating Medicare's needs when conducting clinical studies to support their products. Our findings also provide important insights for the FDA's and Medicare's pilot parallel review program. PMID- 23733987 TI - Decline in placebo-controlled trial results suggests new directions for comparative effectiveness research. AB - The Affordable Care Act offers strong support for comparative effectiveness research, which entails comparisons among active treatments, to provide the foundation for evidence-based practice. Traditionally, a key form of research into the effectiveness of therapeutic treatments has been placebo-controlled trials, in which a specified treatment is compared to placebo. These trials feature high-contrast comparisons between treatments. Historical trends in placebo-controlled trials have been evaluated to help guide the comparative effectiveness research agenda. We investigated placebo-controlled trials reported in four leading medical journals between 1966 and 2010. We found that there was a significant decline in average effect size or average difference in efficacy (the ability to produce a desired effect) between the active treatment and placebo. On average, recently studied treatments offered only small benefits in efficacy over placebo. A decline in effect sizes in conventional placebo-controlled trials supports an increased emphasis on other avenues of research, including comparative studies on the safety, tolerability, and cost of treatments with established efficacy. PMID- 23733988 TI - Consumer-directed health plans reduce the long-term use of outpatient physician visits and prescription drugs. AB - Consumer-directed health plans (CDHPs) are designed to make employees more cost- and health-conscious by exposing them more directly to the costs of their care, which should lower demand for care and, in turn, control premium growth. These features have made consumer-directed plans increasingly attractive to employers. We explored effects of consumer-directed health plans on health care and preventive care use, using data from two large employers-one that adopted a CDHP in 2007 and another with no CDHP. Our study had mixed results relative to expectations. After four years under the CDHP, there were 0.26 fewer physician office visits per enrollee per year and 0.85 fewer prescriptions filled, but there were 0.018 more emergency department visits. Also, the likelihood of receiving recommended cancer screenings was lower under the CDHP after one year and, even after recovering somewhat, still lower than baseline at the study's conclusion. If CDHPs succeed in getting people to make more cost-sensitive decisions, plan sponsors will have to design plans to incentivize primary care and prevention and educate members about what the plan covers. PMID- 23733989 TI - Survey shows consumers open to a greater role for physician assistants and nurse practitioners. AB - Impending physician shortages in the United States will necessitate greater reliance on physician assistants and nurse practitioners, particularly in primary care. But how willing are Americans to accept that change? This study examines provider preferences from patients' perspective, using data from the Association of American Medical Colleges' Consumer Survey. We found that about half of the respondents preferred to have a physician as their primary care provider. However, when presented with scenarios wherein they could see a physician assistant or a nurse practitioner sooner than a physician, most elected to see one of the other health care professionals instead of waiting. Although our findings provide evidence that US consumers are open to the idea of receiving care from physician assistants and nurse practitioners, it is important to consider barriers to more widespread use, such as scope-of-practice regulations. Policy makers should incorporate such evidence into solutions for the physician shortage. PMID- 23733990 TI - Awakening advocacy: how students helped save a safety-net hospital in Georgia. PMID- 23733992 TI - Midwives and cesarean sections. PMID- 23733993 TI - Cesarean sections: the authors reply. PMID- 23733994 TI - Broken mental health services. PMID- 23733995 TI - Mental health care: the author replies. PMID- 23733996 TI - Wellness programs and cost reductions. PMID- 23733997 TI - Wellness programs: the author replies. PMID- 23733998 TI - Technologies for patient engagement. PMID- 23733999 TI - Do-it-yourself health care. PMID- 23734000 TI - Malpractice claims in Taiwan. PMID- 23734001 TI - Timing of myocardial trpm7 deletion during cardiogenesis variably disrupts adult ventricular function, conduction, and repolarization. AB - BACKGROUND: Transient receptor potential (TRP) channels are a superfamily of broadly expressed ion channels with diverse physiological roles. TRPC1, TRPC3, and TRPC6 are believed to contribute to cardiac hypertrophy in mouse models. Human mutations in TRPM4 have been linked to progressive familial heart block. TRPM7 is a divalent-permeant channel and kinase of unknown function, recently implicated in the pathogenesis of atrial fibrillation; however, its function in ventricular myocardium remains unexplored. METHODS AND RESULTS: We generated multiple cardiac-targeted knockout mice to test the hypothesis that TRPM7 is required for normal ventricular function. Early cardiac Trpm7 deletion (before embryonic day 9; TnT/Isl1-Cre) results in congestive heart failure and death by embryonic day 11.5 as a result of hypoproliferation of the compact myocardium. Remarkably, Trpm7 deletion late in cardiogenesis (about embryonic day 13; alphaMHC-Cre) produces viable mice with normal adult ventricular size, function, and myocardial transcriptional profile. Trpm7 deletion at an intermediate time point results in 50% of mice developing cardiomyopathy associated with heart block, impaired repolarization, and ventricular arrhythmias. Microarray analysis reveals elevations in transcripts of hypertrophy/remodeling genes and reductions in genes important for suppressing hypertrophy (Hdac9) and for ventricular repolarization (Kcnd2) and conduction (Hcn4). These transcriptional changes are accompanied by action potential prolongation and reductions in transient outward current (Ito; Kcnd2). Similarly, the pacemaker current (If; Hcn4) is suppressed in atrioventricular nodal cells, accounting for the observed heart block. CONCLUSIONS: Trpm7 is dispensable in adult ventricular myocardium under basal conditions but is critical for myocardial proliferation during early cardiogenesis. Loss of Trpm7 at an intermediate developmental time point alters the myocardial transcriptional profile in adulthood, impairing ventricular function, conduction, and repolarization. PMID- 23734003 TI - Hypertension after preeclampsia is preceded by changes in cardiac structure and function. AB - Preeclampsia is associated with a 4-fold higher risk for developing remote chronic hypertension. Preeclampsia is accompanied by left ventricular hypertrophy and decreased diastolic function, which may or may not resolve postpartum. We tested the hypothesis that increased measures of cardiac geometry and decreased cardiac function persisting for >= 6 months postpartum in normotensive women with a history of preeclampsia precede the development of later chronic hypertension. Formerly preeclamptic women (n=652) underwent echocardiography at 9 months (range, 6-19) postpartum. We excluded women with preexisting hypertension (n=42), hypertension at the postpartum screening (n=133), and those that did not return any checklist (n=128). Eventually, 349 women were included. Remote health was evaluated by a biennially checklist. We used Cox regression for analysis. Twenty seven (8%) normotensive women had developed chronic hypertension during a medium follow-up period of 6 years. At screening they differed from their counterparts who remained normotensive by hazard ratio for left ventricular mass index (1.11; 95% confidence interval [CI], 1.03-1.18), diastolic blood pressure (1.13; 95% CI, 1.06-1.20), systolic blood pressure (1.07; 95% CI, 1.02-1.11), mean arterial pressure (1.11; 95% CI, 1.05-1.18), heart rate (1.05; 95% CI, 1.01-1.10), and E/A ratio (0.22; 95% CI, 0.06-0.85). Backward stepwise analysis showed independent hazard ratio for left ventricular mass index and diastolic blood pressure 1.08 (95% CI, 1.01-1.16) and 1.13 (95% CI, 1.06-1.21), respectively. In conclusion, the development of later chronic hypertension in initially normotensive formerly preeclamptic women is preceded by increased left ventricular mass index and diastolic blood pressure at postpartum screening. PMID- 23734002 TI - Targeted deletion of murine CEACAM 1 activates PI3K-Akt signaling and contributes to the expression of (Pro)renin receptor via CREB family and NF-kappaB transcription factors. AB - The carcinoembryonic antigen-related cell adhesion molecule 1 regulates insulin sensitivity by promoting hepatic insulin clearance. Mice bearing a null mutation of Ceacam1 gene (Cc1(-/-)) develop impaired insulin clearance followed by hyperinsulinemia and insulin resistance, in addition to visceral obesity and increased plasma fatty acids. Because insulin resistance is associated with increased blood pressure, we investigated whether they develop higher blood pressure with activated renal renin-angiotensin system and whether this is mediated, in part, by the upregulation of renal (pro)renin receptor (PRR) expression. Compared with age-matched wild-type littermates, Cc1(-/-) mice exhibited increased blood pressure with increased activation of renal renin angiotensin systems and renal PRR expression. Cytoplasmic and nuclear immunostaining of phospho-PI3K p85alpha and phospho-Akt was enhanced in the kidney of Cc1(-/-) mice. In murine renal inner medullary collecting duct epithelial cells with lentiviral-mediated small hairpin RNA knockdown of carcinoembryonic antigen-related cell adhesion molecule 1, PRR expression was upregulated and phosphorylation of PI3K (Tyr508), Akt (Ser473), NF-kappaB p65 (Ser276), cAMP response element-binding protein/activated transcription factor (ATF)-1 (Ser133), and ATF-2 (Thr71) was enhanced. Inhibiting PI3K with LY294002 or Akt with Akt inhibitor VIII attenuated PRR expression. In conclusion, global null deletion of Ceacam1 caused an increase in blood pressure with increased renin-angiotensin system activation together with upregulation of PRR via PI3K Akt activation of cAMP response element-binding protein 1, ATF-1, ATF-2, and NF kappaB p65 transcription factors. PMID- 23734004 TI - Sexual dimorphism in the transition from masked to sustained hypertension in healthy youths. AB - The risk and factors related to the development of hypertension among healthy youths with elevated ambulatory and normal conventional blood pressure, masked hypertension, have not been established. We performed a long-term follow-up study assessing how hypertension develops over time in healthy, masked hypertensive youths. The potential sex dimorphism in the incidence and timing of the development of hypertension has been analyzed. In a long-term follow-up study (median follow-up, 36 months), we enrolled 272 healthy conventional normotensive youths (aged 6-18 years; 55.8% girls) of whom 39 had masked hypertension at baseline. Development of sustained hypertension (hypertension in both conventional and ambulatory measurement) was recorded. The daytime systolic blood pressure increased from baseline to last available follow-up in boys (3.5 mm Hg; P<0.001) but not in girls (0.7 mm Hg; P=0.23), leading to a significant between sex difference (P=0.0022). The incidence of sustained hypertension was 7.0/100 subjects/y (n=12) in masked hypertensives and 0.6/100 subjects/y (n=4) in normotensives. Masked hypertensive boys more frequently proceeded to sustained hypertension as compared with masked hypertensive girls (50.0% versus 17.4%; P=0.041). Masked hypertension at baseline (hazard ratio, 15.6; 95% confidence interval, 4.91-49.7; P<0.0001) and male sex (hazard ratio, 3.25; 95% confidence interval, 1.12-9.39; P=0.0295) were independent factors associated with the incidence of sustained hypertension during the follow-up. In youth, masked hypertension is a precursor of sustained hypertension. The risk of developing sustained hypertension is higher in boys than it is for girls. The fact that masked hypertension is not prognostically innocent increases the importance of the diagnosis at an early age. PMID- 23734006 TI - Euglycemic clamp insulin sensitivity and longitudinal systolic blood pressure: role of sex. AB - Insulin resistance may be an independent risk factor for the development of hypertension, but change in blood pressure (BP) over time has not been adequately studied in healthy individuals fully characterized for insulin sensitivity. In the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study, we measured insulin sensitivity (M/I) using the euglycemic clamp technique in 1073 healthy European adults (587 women, 486 men) aged 30 to 60 years followed up 3 years later. Systolic BP (SBP) at baseline was higher in insulin-resistant women (ie, those in the low sex-specific M/I tertile) compared with those in the intermediate (P<0.001) or high tertiles (P=0.06; mean +/- SD: 117 +/- 13, 111 +/- 12, 114 +/- 12 mm Hg, respectively). It did not differ across M/I tertiles in men. After adjustment for age, body mass index, baseline SBP, and other covariates, low insulin sensitivity (M/I) predicted a longitudinal rise in SBP in women but not in men; M/I was not associated with change in diastolic BP. SBP rose over time in both sexes and within all M/I tertiles (P<0.05), except in women with high insulin sensitivity. Therefore, in women (but not in men), low insulin sensitivity was associated with higher SBP at 3 years, and high insulin sensitivity was associated with a lower rise in SBP over time. PMID- 23734005 TI - An update on immune system activation in the pathogenesis of hypertension. PMID- 23734007 TI - One or two, does it matter as long as the arterial wall is coxygenated? PMID- 23734008 TI - Endothelial dysfunction in small arteries of essential hypertensive patients: role of cyclooxygenase-2 in oxidative stress generation. AB - Essential hypertensive patients show a reduced nitric oxide availability secondary to oxidative stress generation in peripheral microcirculation. Cyclooxygenase (COX) contributes to reduce nitric oxide availability. We assessed the possible vascular sources of oxidative stress, including COX-1, COX-2, and nicotinamide adenine dinucleotide phosphate oxidase, as determinants of endothelial dysfunction in small arteries isolated from essential hypertensive patients or normotensive controls. Small arteries were dissected after subcutaneous fat biopsies and evaluated on a pressurized micromyograph. Endothelium-dependent vasodilation was assessed by acetylcholine, repeated under NG-nitro-l-arginine methyl ester, SC-560 (COX-1 inhibitor), DuP-697 (COX-2 inhibitor), ascorbic acid, or the nicotinamide adenine dinucleotide phosphate oxidase inhibitors apocynin or diphenylene iodonium. Vascular oxidative stress generation (fluorescent dihydroethidium), COX-1 and COX-2 expression (Western blot), and localization (immunohistochemistry) were also assessed. In controls, response to acetylcholine was blunted by NG-nitro-l-arginine methyl ester (P<0.001) and unmodified by SC-560, DuP-697, or ascorbic acid. In hypertensive patients, relaxation to acetylcholine was blunted, resistant to NG-nitro-l arginine methyl ester or SC-560, and enhanced (P<0.01) by DuP-697, apocynin, or diphenylene iodonium (P<0.05). Furthermore, in hypertensive patients, response to acetylcholine was normalized by ascorbic acid or apocynin+DuP-697. Intravascular oxidative stress generation was enhanced in hypertensive patients, decreased (P<0.01) by DuP-697, partly attenuated by apocynin or diphenylene iodonium, and prevented by ascorbic acid. Enhanced COX-2 expression and localization in the vascular media of hypertensive patients were also detected. In small resistance arteries of essential hypertensive patients, COX-2 is overexpressed and reduces nitric oxide availability. COX-2 represents a major source of oxidative stress generation, whereas nicotinamide adenine dinucleotide phosphate oxidase plays a minor, but significant, role in promoting superoxide generation. PMID- 23734014 TI - Purification and culture of astrocytes. AB - For years, studies of neural-glial interactions have relied on the use of astrocytes derived from the extended culture of immature precursor cells isolated from the neonatal rodent brain. Although the astrocytes cultured under these selective cell survival conditions have been important tools for understanding astrocyte behavior, they do not necessarily reflect the behavior and function of mature astrocytes. We have developed methods for acute, prospective isolation and culture of mature astrocytes from rodent brains in a serum-free, defined medium. These immunopanning-based methods facilitate the study of astrocyte biology and function. PMID- 23734009 TI - Human beta-defensin 2 is a novel opener of Ca2+-activated potassium channels and induces vasodilation and hypotension in monkeys. AB - Human beta-defensin 2 (HBD2) is a cysteine-rich cationic antimicrobial peptide known for its important role in innate immune system. Intensive studies have demonstrated its antimicrobial and chemotactic activities in vitro. In this study, ELISA analysis showed that HBD2 was significantly downregulated in sera of patients with hypertension. It relaxed vessel smooth muscle by acting on the major regulatory pathways, contributing to vessel smooth muscle contraction. Electrophysiology analysis indicated that HBD2 acted as an opener of large conductance Ca(2+)-activated potassium (BKCa)-mSlo+hbeta1 channels and increased BKCa currents. Mutation analysis revealed that HBD2 activated BKCa-mSlo+hbeta1 channels via interacting with Leu41 and Gln43 of beta1-loop. In vivo experiments suggested that HBD2 at 4 * to 6 * of physiological concentration exerted hypotensive effect in monkeys significantly, whereas the selective blocker of BKCa channels, Paxilline, inhibited the effect. HBD2 is the first peptide opener of BKCa-mSlo+hbeta1 channels. It may be a novel regulator of blood pressure and provides a new therapeutic target for the treatment of hypertension. The HBD2 blockade of the BKCa channels may represent a new type of cross-talk between immune and cardiovascular systems. PMID- 23734015 TI - Optimizing the sampling scheme for a stereological study: how many individuals, sections, and probes should be used. AB - Stereology provides meaningful quantitative descriptions of the geometry of three dimensional (3D) structures from measurements that are made on two-dimensional (2D) images. A pilot stereological study will provide information that can be used to rationalize how many individuals, sections, and probes should be used to ensure that one is sampling enough, but not too much, to achieve the goal of a study. This general approach is exemplified in the thought experiment described here, which involves a comparison of the means of estimates of the total number of neurons N in two groups, using the simplest of statistical tests, the Student's t-test. It is also applicable to studies involving other estimates of total quantities such as volume, surface, and length obtained from a parallel series of sections. PMID- 23734016 TI - Cycling assay for determining intracellular cyclic adp-ribose levels. AB - Cyclic ADP-ribose (cADPR) is a Ca(2+)-mobilizing second messenger involved in the regulation of various physiological processes. The ability to detect changes in endogenous cADPR is a fundamental step in the identification of its role in signal transduction triggered by hormones and other stimuli. Because the intracellular concentration of cADPR can be very low, depending on the expression level of the ADP-ribosyl cyclase activity (forming cADPR and nicotinamide from NAD) in the cell type of interest, very sensitive and selective methods are required. The method presented here exploits the ability of the ADP-ribosyl cyclase to catalyze the reverse reaction (i.e., to synthesize NAD stoichiometrically starting from cADPR) in the presence of an excess of nicotinamide. The generation of NAD can be coupled to a cycling assay using the enzymes alcohol dehydrogenase and diaphorase. The former reduces NAD to NADH in the presence of ethanol and the latter oxidizes NADH to NAD in the presence of resazurin and flavin mononucleotide. The formation of the fluorescent reduced resazurin (resofurin) can be detected with a plate reader. Thus, this cycling assay for cADPR determination can be considered a high-throughput method, potentially screening cADPR concentration simultaneously in many samples. PMID- 23734017 TI - Measuring CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) activity by reverse-phase HPLC. AB - Cyclic ADP-ribose (cADPR) is a Ca(2+)-mobilizing second messenger active in many cell types, tissues, and organisms. The mammalian NAD-glycohydrolase CD38 catalyzes formation of cADPR by removing nicotinamide and forming a new intramolecular bond between N1 of adenine and C1 of the "northern" ribose. In contrast to the ADP-ribosyl cyclase (ADPRC) from Aplysia californica, which almost exclusively catalyzes the formation of cADPR, CD38 mainly produces adenosine diphosphoribose (ADPR), while cADPR is found as a side product. Interestingly, CD38 also catalyzes the breakdown of cADPR to ADPR. These enzyme activities can be determined by incubating the substrates NAD or cADPR with either crude membranes, purified proteins, or intact cells expressing CD38; the latter is possible because the catalytic site of CD38 is on the cell surface. Analysis of substrate and products is performed by reverse-phase (RP) HPLC. Before HPLC analysis, cells and proteins must be removed from samples by centrifugation and/or ultrafiltration to stop further metabolism and to prevent HPLC columns from clogging. PMID- 23734018 TI - Measuring Ca2+ release evoked by cyclic adp-ribose. AB - As a ubiquitous second messenger, the Ca(2+) mobilizing activity of cyclic ADP ribose (cADPR) has been observed in many different cell types. The measurement of Ca(2+) release evoked by cADPR comprises several practical challenges. At physiological pH, cADPR has a net negative charge and it therefore cannot cross the cell membrane in cells that lack a suitable cADPR-transporting system. Thus, either the plasma membrane must be permeabilized or microinjection must be used to deliver cADPR to the cytosol. In this article, two methods for cADPR delivery (using permeabilized cells or microinjection) are explained step-by-step. Because most of our work has been performed using the Jurkat T-lymphoma cell line, the methods are tailored for this specific cell type. For other cell types, the procedures may need to be adapted. PMID- 23734019 TI - Purification of astrocytes from transgenic rodents by fluorescence-activated cell sorting. AB - The purification of astrocytes by fluorescence-activated cell sorting (FACS) requires that an astrocyte-specific promoter drive the expression of the green fluorescent protein (GFP). Our laboratory uses FACS to acutely isolate astrocytes from young and old tissue as well as to isolate GFP-negative neurons at the end of the FACS sorting to conduct comparative unbiased, large-scale gene expression studies. Because of the relatively harsh nature of FACS sorting, few astrocytes or neurons survive long enough after the sort to be cultured. PMID- 23734020 TI - Measuring leukocyte-endothelial interactions in mice. AB - Intravital imaging techniques are powerful tools in the study of tumor pathophysiology. These techniques can be used to measure vascular parameters (e.g., angiogenesis, hemodynamics, and leukocyte-endothelial interactions) in tumors and normal vascular networks in mice. This protocol describes the use of single-photon microscopy and multiphoton laser-scanning microscopy to follow the migration of Rhodamine-6G, a fluorescently labeled tracer, following injection into the tail vein of a mouse. The Rhodamine-6G enters the circulatory system and labels leukocytes. It is possible to monitor changes in the interactions between leukocytes and the endothelium by determining the numbers of rolling and adhering leukocytes as well as the total flux of these cells. PMID- 23734021 TI - Preparation of Drosophila embryos for quantitative imaging of gene expression. AB - Quantitative measurements derived using sophisticated microscopy techniques are essential for understanding the basic principles that control the behavior of biological systems. We have developed a five-step data pipeline to extract quantitative data on segmentation gene expression from confocal images of gene expression patterns in Drosophila. This protocol describes the preparation of Drosophila embryos for imaging by confocal microscopy. Embryos are collected at the appropriate developmental stage and fixed. They are then stained with both primary antibodies and secondary antibodies conjugated with fluorophores to reveal the segmentation gene expression patterns. PMID- 23734022 TI - Quantitative imaging of gene expression in Drosophila embryos. AB - Quantitative measurements derived using sophisticated microscopy techniques are essential for understanding the basic principles that control the behavior of biological systems. Here we describe a data pipeline developed to extract quantitative data on segmentation gene expression from confocal images of gene expression patterns in Drosophila. The pipeline consists of image segmentation, background removal, temporal characterization of an embryo, data registration, and data averaging. This pipeline has been successfully applied to obtain quantitative gene expression data at cellular resolution in space and at 6.5-min resolution in time. It has also enabled the construction of a spatiotemporal atlas of segmentation gene expression. We describe the software used to construct a workflow for extracting quantitative data on segmentation gene expression and the BREReA package, which implements the methods for background removal and registration of segmentation gene expression patterns. PMID- 23734023 TI - Imaging green fluorescent protein-labeled neurons using light and electron microscopy. AB - The ability to observe axons and dendrites with transmission electron microscopy (EM) after they have been previously imaged live with laser-scanning microscopy is a useful technique to study their synaptic connectivity. This protocol provides a detailed method by which neurons that were imaged in a live brain or slice culture can be reimaged using EM. First, brain tissue expressing green fluorescent protein (GFP) is chemically fixed. Then, an immunocytochemistry process is used to render the fluorescent protein electron dense so that it can first be located using light microscopy and then serial thin-sectioned for EM so that the ultrastructure of specific parts of neurites can be analyzed in three dimensions. Patterns of blood vessels observed in the live brain are used to locate the previously imaged neurons. The method described here allows for a complete three-dimensional (3D) reconstruction to be made of the imaged structures from serial electron micrographs. PMID- 23734024 TI - How to build a two-photon microscope with a confocal scan head. AB - This article provides practical guidelines for the conversion of a standard confocal microscope into a two-photon microscope. This conversion enables the investigator to have access to two-photon microscopy without the large budget necessary to purchase a commercial instrument. Two-photon fluorescence microscopy allows deep-tissue imaging in highly scattering preparations and long-term imaging of live tissue without the photodamage that is caused by out-of-focus light. It is, therefore, an essential tool for imaging cells under physiologically relevant conditions such as acute or cultured brain slices or in vivo. PMID- 23734025 TI - Stochastic optical reconstruction microscopy (STORM): a method for superresolution fluorescence imaging. AB - The relatively low spatial resolution of the optical microscope presents significant limitations for the observation of biological ultrastructure. Subcellular structures and molecular complexes essential for biological function exist on length scales from nanometers to micrometers. When observed with light, however, structural features smaller than ~0.2 um are blurred and are difficult or impossible to resolve. In this article, we describe stochastic optical reconstruction microscopy (STORM), a method for superresolution imaging based on the high accuracy localization of individual fluorophores. It uses optically switchable fluorophores: molecules that can be switched between a nonfluorescent and a fluorescent state by exposure to light. The article discusses photoswitchable fluorescent molecules, STORM microscope design and the imaging procedure, data analysis, imaging of cultured cells, multicolor STORM, and three dimensional (3D) STORM. This approach is generally applicable to biological imaging and requires relatively simple experimental apparatus; its spatial resolution is theoretically unlimited, and a resolution improvement of an order of magnitude over conventional optical microscopy has been experimentally demonstrated. PMID- 23734026 TI - Transfection of genetically encoded photoswitchable probes for STORM imaging. AB - Conventional fluorescence microscopy is limited by its spatial resolution, leaving many biological structures too small to be studied in detail. Stochastic optical reconstruction microscopy (STORM) is a method for superresolution fluorescence imaging based on the high accuracy localization of individual fluorophores. It uses optically switchable fluorophores: molecules that can be switched between a nonfluorescent and a fluorescent state by exposure to light. This protocol describes the transfection of genetically encoded photoswitchable probes for STORM imaging. It includes a discussion of how to choose a photoswitchable fluorescent protein; standard molecular biology techniques should be used to generate a plasmid containing the sequence of the photoswitchable protein linked to the gene of interest. Once the plasmid has been generated and has been verified, it can be introduced into cells via any standard means of gene delivery, such as lipofection or electroporation. Optimal conditions will vary considerably for different cell lines and plasmids. Here, we present an example protocol for the transfection of BS-C-1 cells with an mEos2-vimentin plasmid using the lipid-based reagent FuGENE6. PMID- 23734027 TI - Preparation of photoswitchable labeled antibodies for STORM imaging. AB - Stochastic optical reconstruction microscopy (STORM) is a method for superresolution fluorescence imaging based on the high accuracy localization of individual fluorophores. It uses optically switchable fluorophores: molecules that can be switched between a nonfluorescent and a fluorescent state by exposure to light. Many synthetic fluorescent dye molecules show photoswitchable fluorescence emission. In particular, photoswitchable cyanine fluorophores such as Cy5, Alexa 647, and Cy7, may be paired with a second fluorophore, which serves as an activator, determining the wavelength of light that re-activates the fluorescence of the photoswitchable molecule. This protocol describes the preparation of antibodies labeled with one such pairing scheme of synthetic fluorophores, Alexa 405 and Alexa 647. It may easily be adapted for labeling with other fluorophores or for labeling other substrate molecules. PMID- 23734028 TI - Preparation of Nuclear Extracts from HeLa cells. AB - HeLa cells are the archetypal tissue culture cell line for the preparation of mammalian cell-free systems. These cells, derived from a cervical carcinoma, have been maintained in culture since the late 1940s. They grow with a doubling time of ~24 h and can be cultured in medium containing fetal bovine serum (optimal serum for growth) or medium containing horse serum (in which they grow more slowly, but this serum is considerably less expensive). Nuclear extracts prepared from these cells have been used to determine the mechanisms of splicing and polyadenylation, and such extracts have been characterized extensively. HeLa cells are usually the cell type of choice for initiating cell-free analysis of nearly any aspect of mammalian gene expression. In some instances (e.g., analysis of tissue-specific alternative splicing), it is necessary to use nuclei from a different cell type. We have found that the protocol described here can be used successfully to prepare active nuclear extracts from a wide variety of tissue culture cells, including Drosophila S2 cells. PMID- 23734029 TI - Analysis of pre-mRNA splicing using HeLa cell nuclear extracts. AB - This protocol is used to determine the splicing behavior of pre-mRNAs in cell extracts that are capable of carrying out splicing (e.g., nuclear extracts from HeLa cells). (32)P-labeled RNA is incubated under splicing conditions for various times, and the resulting products are analyzed on denaturing polyacrylamide gels. PMID- 23734030 TI - Bicuspid aortic valve disease. PMID- 23734031 TI - US approves "new class" of diabetes drug, under review in Canada. PMID- 23734032 TI - New research leads to end of blood ban. PMID- 23734033 TI - Risks and benefits of intensive blood pressure lowering in patients with type 2 diabetes. PMID- 23734035 TI - UK doctors must show fitness to practise every five years. PMID- 23734037 TI - Segregated bike lanes are safest for cyclists. PMID- 23734036 TI - Risk of acute kidney injury associated with the use of fluoroquinolones. AB - BACKGROUND: Case reports indicate that the use of fluoroquinolones may lead to acute kidney injury. We studied the association between the use of oral fluoroquinolones and acute kidney injury, and we examined interaction with renin angiotensin-system blockers. METHODS: We formed a nested cohort of men aged 40-85 enrolled in the United States IMS LifeLink Health Plan Claims Database between 2001 and 2011. We defined cases as men admitted to hospital for acute kidney injury, and controls were admitted to hospital with a different presenting diagnosis. Using risk-set sampling, we matched 10 controls to each case based on hospital admission, calendar time (within 6 wk), cohort entrance (within 6 wk) and age (within 5 yr). We used conditional logistic regression to assess the rate ratio (RR) for acute kidney injury with current, recent and past use of fluoroquinolones, adjusted by potential confounding variables. We repeated this analysis with amoxicillin and azithromycin as controls. We used a case-time control design for our secondary analysis. RESULTS: We identified 1292 cases and 12 651 matched controls. Current fluoroquinolone use had a 2.18-fold (95% confidence interval [CI] 1.74-2.73) higher adjusted RR of acute kidney injury compared with no use. There was no association between acute kidney injury and recent (adjusted RR 0.87, 95% CI 0.66-1.16) or past (RR 0.86, 95% CI 0.66-1.12) use. The absolute increase in acute kidney injury was 6.5 events per 10 000 person-years. We observed 1 additional case per 1529 patients given fluoroquinolones or per 3287 prescriptions dispensed. The dual use of fluoroquinolones and renin-angiotensin-system blockers had an RR of 4.46 (95% CI 2.84-6.99) for acute kidney injury. Our case-time-control analysis confirmed an increased risk of acute kidney injury with fluoroquinolone use (RR 2.16, 95% CI 1.52-3.18). The use of amoxicillin or azithromycin was not associated with acute kidney injury. INTERPRETATION: We found a small, but significant, increased risk of acute kidney injury among men with the use of oral fluoroquinolones, as well as a significant interaction between the concomitant use of fluoroquinolones and renin-angiotensin-system blockers. PMID- 23734038 TI - Fears of humanitarian crisis in western Myanmar's camps for internally displaced persons. PMID- 23734039 TI - Canada needs more-aggressive problem-gambling policies, say researchers. PMID- 23734040 TI - Quebec sticks with CR mammography machines. PMID- 23734045 TI - Analysis of the vascular responses in a murine model of polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of there productive age, but the exact pathophysiological mechanisms involved remain unclear. Cardiovascular disease risk is increased in PCOS patients and endothelial damage has been observed. We recently developed a mouse model of PCOS with reproductive and metabolic characteristics resembling those observed in women with PCOS. In this model we studied vascular function with particular emphasis on markers of vascular endothelial function. Animals were treated for 90 days with dihydrotestosterone (DHT; 27.5 mg/day) or placebo using subcutaneous continuous-release pellets. Aortas were isolated for isometric force recordings in organ baths to investigate endothelial and vascular smooth muscle characteristics. Lungs were used to analyze endothelial nitric oxide synthase (eNOS) expression and phosphorylation. Asymmetric dimethylarginine (ADMA) levels were investigated in serum to assess endothelial damage. Expression of androgen receptor (Ar) mRNA was studied in aortas. DHT treatment (compared with placebo) induced i) a significant decrease in acetylcholine-induced aortic relaxations, with no change in calcitonin gene related peptide- or sodium nitroprusside induced relaxations, as well as 5-hydroxytryptamine-induced contractions; ii) no change in eNOS expression/phosphorylation in lungs or in plasma ADMA levels; and iii) a twofold increase in aortic AR expression. Our results suggest that, in DHT exposed mice, hyperandrogenemia specifically decreases endothelium dependent vasorelaxation without deterioration of smooth muscle function. This study may initiate further investigations to elucidate underlying mechanism for the phenotype that is present in these animals, as well as in PCOS patients. PMID- 23734046 TI - Surface science investigations of the role of CO2 in astrophysical ices. AB - We have recorded reflection-absorption infrared spectroscopy (RAIRS) and temperature-programmed desorption (TPD) data for a range of CO2-bearing model astrophysical ices adsorbed on a graphitic dust grain analogue surface. Data have been recorded for pure CO2, for CO2 adsorbed on top of amorphous solid water, for mixed CO2:H2O ices and for CO2 adsorbed on top of a mixed CH3OH:H2O ice. For the TPD data, kinetic parameters for desorption have been determined, and the trapping behaviour of the CO2 in the H2O (CH3OH) ice has been determined. Data of these types are important as they can be used to model desorption in a range of astrophysical environments. RAIR spectra have also shown the interaction of the CO2 with H2O and CH3OH and can be used to compare with astronomical observations, allowing the accurate assignment of spectra. PMID- 23734047 TI - Stardust silicate nucleation kick-started by SiO+TiO2. AB - Dust particles are quintessential for the chemical evolution of the Universe. Dust nucleates in stellar outflows of dying stars and subsequently travels through the interstellar medium, continuously evolving via energetic processing, collisions and condensation. Finally, dust particles are incorporated in the next generation star or its surrounding planetary system. In oxygen-rich stellar outflows, silicates are observed in the condensation zone (1200-1000 K), but, in spite of several decades of experimental and theoretical study, the stardust nucleation process remains poorly understood. We have previously shown that under these conditions ternary Mg-Si-O clusters may start forming at high enough rates from SiO, Mg and H2O through heteromolecular association processes. In this reaction scheme, none of the possible initial association reactions was thermodynamically favourable owing to the large entropy loss at these temperatures. Here, we follow a previous idea that the incorporation of TiO2 could help to initiate stardust nucleation. In contrast to these studies, we find that there is no need for TiO2 cluster seeds-instead, one molecule of TiO2 is sufficient to kick-start the subsequent nucleation of a silicate dust particle. PMID- 23734048 TI - Modelling the formation of atmospheric dust in brown dwarfs and planetary atmospheres. AB - Atmospheric dust from volcanoes, sand storms and biogenic products provides condensation seeds for water cloud formation on the Earth. Extrasolar planetary objects such as brown dwarfs and extrasolar giant planets have no comparable sources of condensation seeds. Hence, understanding cloud formation and further its implications for the climate requires a modelling effort that includes the treatment of seed formation (nucleation), growth and evaporation, in addition to rain-out, mixing and gas-phase depletion. This paper discusses nucleation in the ultra-cool atmospheres of brown dwarfs and extrasolar giant planets whose chemical gas-phase composition differs largely from the terrestrial atmosphere. A kinetic model for atmospheric dust formation is described, which, in recent work, has become part of a cloud-formation model. For the first time, diffusive replenishment of the upper atmosphere is introduced as a source term into our model equations. This paper further aims to show how experimental and computational chemistry work links into our dust-formation model, which is driven by applications in extraterrestrial environments. PMID- 23734049 TI - A first-principles characterization of water adsorption on forsterite grains. AB - Numerical simulations examining chemical interactions of water molecules with forsterite grains have demonstrated the efficacy of nebular gas adsorption as a viable mechanism for water delivery to the terrestrial planets. Nevertheless, a comprehensive picture detailing the water-adsorption mechanisms on forsterite is not yet available. Towards this end, using accurate first-principles density functional theory, we examine the adsorption mechanisms of water on the (001), (100), (010) and (110) surfaces of forsterite. While dissociative adsorption is found to be the most energetically favourable process, two stable associative adsorption configurations are also identified. In dual-site adsorption, the water molecule interacts strongly with surface magnesium and oxygen atoms, whereas single-site adsorption occurs only through the interaction with a surface Mg atom. This results in dual-site adsorption being more stable than single-site adsorption. PMID- 23734050 TI - Accretion disc origin of the Earth's water. AB - Earth's water is conventionally believed to be delivered by comets or wet asteroids after the Earth formed. However, their elemental and isotopic properties are inconsistent with those of the Earth. It was thus proposed that water was introduced by adsorption onto grains in the accretion disc prior to planetary growth, with bonding energies so high as to be stable under high temperature conditions. Here, we show both by laboratory experiments and numerical simulations that water adsorbs dissociatively on the olivine {100} surface at the temperature (approx. 500-1500 K) and water pressure (approx. 10-8 bar) expected for the accretion disc, leaving an OH adlayer that is stable at least up to 900 K. This may result in the formation of many Earth oceans, provided that a viable mechanism to produce water from hydroxyl exists. This adsorption process must occur in all disc environments around young stars. The inevitable conclusion is that water should be prevalent on terrestrial planets in the habitable zone around other stars. PMID- 23734052 TI - Modelling interstellar physics and chemistry: implications for surface and solid state processes. AB - We discuss several types of regions in the interstellar medium of the Milky Way and other galaxies in which the chemistry appears to be influenced or dominated by surface and solid-state processes occurring on or in interstellar dust grains. For some of these processes, for example, the formation of H2 molecules, detailed experimental and theoretical approaches have provided excellent fundamental data for incorporation into astrochemical models. In other cases, there is an astrochemical requirement for much more laboratory and computational study, and we highlight these needs in our description. Nevertheless, in spite of the limitations of the data, it is possible to infer from astrochemical modelling that surface and solid-state processes play a crucial role in astronomical chemistry from early epochs of the Universe up to the present day. PMID- 23734051 TI - Laboratory studies of electron and ion irradiation of solid acetonitrile (CH3CN). AB - The structure and bonding of solid acetonitrile (CH3CN) films on amorphous silica are studied, and chemical and physical processes under irradiation with 200 keV protons and 250-400 eV electrons are quantified using transmission infrared spectroscopy, reflection-absorption infrared spectroscopy and temperature programmed desorption, with the assistance of basic computational chemistry and nuclear materials calculations. The thermal desorption profiles are found to depend strongly on the balance between CH3CN-surface and CH3CN-CH3CN interactions, passing from a sub-monolayer regime (binding energy: 35-50 kJ mol 1) to a multilayer regime (binding energy: 38.2+/-1.0 kJ mol-1) via a fractional order desorption regime characteristic of islanding as the coverage increases. Calculations using the SRIM code reveal that the effects of the ion irradiation are dominated by electronic stopping of incident protons, and the subsequent generation of secondary electrons. Therefore, ion irradiation and electron irradiation experiments can be quantitatively compared. During ion irradiation of thicker CH3CN films, a cross section for secondary electron-promoted chemical destruction of CH3CN of 4 (+/-1) * 10-18 cm2 was measured, while electron promoted desorption was not detected. A significantly higher cross section for electron-promoted desorption of 0.82-3.2 * 10-15 cm2 was measured during electron irradiation of thinner CH3CN films, while no chemical products were detected. The differences between the experimental results can be rationalized by recognizing that chemical reaction is a bulk effect in the CH3CN film, whereas desorption is a surface sensitive process. In thicker films, electron-promoted desorption is expected to occur a rate that is independent of the film thickness; i.e. show zeroth-order kinetics with respect to the surface concentration. PMID- 23734053 TI - Catalytic conversion of acetylene to polycyclic aromatic hydrocarbons over particles of pyroxene and alumina. AB - Polycyclic aromatic hydrocarbons (PAHs) are known to be present in many astrophysical objects and environments, but our understanding of their formation mechanism(s) is far from satisfactory. In this paper, we describe an investigation of the catalytic conversion reaction of acetylene gas to PAHs over pyroxene and alumina. Crystalline silicates such as pyroxenes (with general formula [Mg, Fe]SiO3) and alumina (Al2O3) are observed astrophysically through their infrared spectra and are likely to promote grain surface chemical reactions. In the experiments reported here, gas-phase PAHs were produced by the catalytic reaction of acetylene over crystalline silicates and alumina using a pulsed jet expansion technique and the gaseous products detected using time-of flight mass spectrometry. In a separate experiment, the catalytic formation of PAHs from acetylene was further confirmed with acetylene gas at atmospheric pressure flowing continuously through a fixed-bed reactor. The gas effluent and carbonaceous compounds deposited on the catalysts were dissolved separately in dichloromethane and analysed using gas chromatography-mass spectrometry. Among the samples studied, alumina showed higher activity than the pyroxene-type grains for the acetylene reaction. It is proposed that formation of the PAHs relies on the Mg2+ ions in the pyroxenes and Al3+ ions in alumina, where these ions act as Lewis acid sites. X-ray diffraction, Fourier transform infrared and high resolution transmission electron microscopy techniques were used to characterize the structure and physical properties of the pyroxene and alumina samples. PMID- 23734054 TI - The interaction of hydrogen with the {010} surfaces of Mg and Fe olivine as models for interstellar dust grains: a density functional theory study. AB - There is no consensus as yet to account for the significant presence of water on the terrestrial planets, but suggested sources include direct hydrogen adsorption from the parent molecular cloud after the planets' formation, and delivery of hydrous material via comets or asteroids external to the zone of the terrestrial planets. Alternatively, a more recent idea is that water may have directly adsorbed onto the interstellar dust grains involved in planetary formation. In this work, we use electronic structure calculations based on the density functional theory to investigate and compare the bulk and {010} surface structures of the magnesium and iron end-members of the silicate mineral olivine, namely forsterite and fayalite, respectively. We also report our results on the adsorption of atomic hydrogen at the mineral surfaces, where our calculations show that there is no activation barrier to the adsorption of atomic hydrogen at these surfaces. Furthermore, different surface sites activate the atom to form either adsorbed hydride or proton species in the form of hydroxy groups on the same surface, which indicates that these mineral surfaces may have acted as catalytic sites in the immobilization and reaction of hydrogen atoms to form dihydrogen gas or water molecules. PMID- 23734055 TI - On the nucleation of dust in oxygen-rich stellar outflows. AB - Understanding the nature of dust condensation in the outflow from oxygen-rich asymptotic giant branch stars is a continuing problem. A kinetic model has been developed to describe the formation of gas-phase precursors from Ca, Mg, Fe, SiO and TiO in an outflow cooling from 1500 to 1000 K. Electronic structure calculations are used to identify efficient reaction pathways that lead to the formation of metal titanates and silicates. The molecular properties of the stationary points on the relevant potential energy surfaces are then used in a multi-well master equation solver to calculate pertinent rate coefficients. The outflow model couples an explicit treatment of gas-phase chemistry to a volume conserving particle growth model. CaTiO3 is shown to be the overwhelming contributor to the formation of condensation nuclei (CN), with less than 0.01 per cent provided by CaSiO3, (TiO2)2 and FeTiO3. Magnesium species make a negligible contribution. Defining CN as particles with radii greater than 2 nm, the model shows that for stellar mass loss rates above 3*10-5 M? yr-1, more than 10-13 CN per H nucleus will be produced when the outflow temperature is still well above 1000 K. This is sufficient to explain the observed number density of grains in circumstellar dust shells. PMID- 23734056 TI - Interstellar medium. Preface. PMID- 23734057 TI - 'In vivo' average glandular dose evaluation: one-to-one comparison between digital breast tomosynthesis and full-field digital mammography. AB - We analysed 300 patients X rayed with digital breast tomosynthesis (DBT), full field digital mammography (FFDM) and 'COMBO' (single view both in FFDM and DBT in a single breast compression)-Hologic Selenia Dimension-W/Rh-Ag-Al: three different anode-filter combinations-automatic exposure control modalities. Examination parameter data collection (EPDC) and 'in vivo' dosimetry using metal oxide semiconductor field effect transistor (MOSFET) were utilised to determine and compare entrance skin air kerma (ESAK) and average glandular dose (AGD) from a radioprotection viewpoint in the DBT and COMBO modalities. MOSFET has been tested to be introduced in clinical routine. EPDC of DBT underlines increase in ESAK and AGD compared with FFDM (p < 0.05). The mean percentage increase was 34 % (+17 %) in ESAK and 46 % (+16 %) in AGD. In the COMBO modality, the mean percentage increase in ESAK was 162 % (+41 %) and in AGD was 202 % (+61 %). Differences between MOSFET measurement and calculated values were <8 % for breasts thicker than 30 mm; otherwise, the errors are >15 %. DBT increases ESAK and AGD, due to the 3D acquisition modality. MOSFET may be considered in DBT as a routine check. PMID- 23734058 TI - Image quality and age-specific dose estimation in head and chest CT examinations with organ-based tube-current modulation. AB - The purpose of this study was to investigate the effects of an organ-based tube current modulation (OBTCM) system on image quality and age-specific dose in head and chest CT examinations. Image noise, contrast-to-noise ratio (CNR) and image entropy were assessed using statistical and entropy analyses. Radiation doses for newborn, 6-y-old child and adult phantoms were measured with in-phantom dosimetry systems. The quality of CT images obtained with OBTCM was not different from that obtained without OBTCM. In head CT scans, the eye lens dose decreased by 20-33 % using OBTCM. In chest CT scans, breast dose decreased by 5-32 % using OBTCM. Posterior skin dose, however, increased by 11-20 % using OBTCM in head and chest CT scans. The reduction of effective dose using OBTCM was negligibly small. Detailed image quality and dose information provided in this study can be effectively used for OBTCM application. PMID- 23734059 TI - Methylation patterns in whole blood correlate with symptoms in schizophrenia patients. AB - DNA methylation, one of the main epigenetic mechanisms to regulate gene expression, appears to be involved in the development of schizophrenia (SZ). In this study, we investigated 7562 DNA methylation markers in blood from 98 SZ patients and 108 healthy controls. A linear regression model including age, gender, race, alcohol, nicotine and cannabis use status, and diagnosis was implemented to identify C-phosphate-G (CpG) sites significantly associated with diagnosis. These CpG sites were further validated using an independent data set. Sixteen CpG sites were identified with hyper- or hypomethylation in patients. A further verification of expression of the corresponding genes identified 7 genes whose expression levels were also significantly altered in patients. While such altered methylation patterns showed no correlation with disorganized symptoms and negative symptoms in patients, 11 CpG sites significantly correlated with reality distortion symptoms. The direction of the correlations indicates that methylation changes possibly play a protective mechanism to lessen delusion and hallucination symptoms in patients. Pathway analyses showed that the most significant biological function of the differentially methylated CpGs is inflammatory response with CD224, LAX1, TXK, PRF1, CD7, MPG, and MPO genes directly involved in activations of T cells, B cells, and natural killer cells or in cytotoxic reaction. Our results suggest that such methylation changes may modulate aspects of the immune response and hence protect against the neurobiological substrate of reality distortion symptoms in SZ patients. PMID- 23734060 TI - Concise review: tissue-engineered skin and nerve regeneration in burn treatment. AB - Burns not only destroy the barrier function of the skin but also alter the perceptions of pain, temperature, and touch. Different strategies have been developed over the years to cover deep and extensive burns with the ultimate goal of regenerating the barrier function of the epidermis while recovering an acceptable aesthetic aspect. However, patients often complain about a loss of skin sensation and even cutaneous chronic pain. Cutaneous nerve regeneration can occur from the nerve endings of the wound bed, but it is often compromised by scar formation or anarchic wound healing. Restoration of pain, temperature, and touch perceptions should now be a major challenge to solve in order to improve patients' quality of life. In addition, the cutaneous nerve network has been recently highlighted to play an important role in epidermal homeostasis and may be essential at least in the early phase of wound healing through the induction of neurogenic inflammation. Although the nerve regeneration process was studied largely in the context of nerve transections, very few studies have been aimed at developing strategies to improve it in the context of cutaneous wound healing. In this concise review, we provide a description of the characteristics of and current treatments for extensive burns, including tissue-engineered skin approaches to improve cutaneous nerve regeneration, and describe prospective uses for autologous skin-derived adult stem cells to enhance recovery of the skin's sense of touch. PMID- 23734061 TI - Transient proteolytic modification of mesenchymal stromal cells increases lung clearance rate and targeting to injured tissue. AB - Systemic infusion of therapeutic cells would be the most practical and least invasive method of administration in many cellular therapies. One of the main obstacles especially in intravenous delivery of cells is a massive cell retention in the lungs, which impairs homing to the target tissue and may decrease the therapeutic outcome. In this study we showed that an alternative cell detachment of mesenchymal stromal/stem cells (MSCs) with pronase instead of trypsin significantly accelerated the lung clearance of the cells and, importantly, increased their targeting to an area of injury. Cell detachment with pronase transiently altered the MSC surface protein profile without compromising cell viability, multipotent cell characteristics, or immunomodulative and angiogenic potential. The transient modification of the cell surface protein profile was sufficient to produce effective changes in cell rolling behavior in vitro and, importantly, in the in vivo biodistribution of the cells in mouse, rat, and porcine models. In conclusion, pronase detachment could be used as a method to improve the MSC lung clearance and targeting in vivo. This may have a major impact on the bioavailability of MSCs in future therapeutic regimes. PMID- 23734063 TI - Why were they in such a hurry to see her die? PMID- 23734062 TI - Engineering a blood-retinal barrier with human embryonic stem cell-derived retinal pigment epithelium: transcriptome and functional analysis. AB - Retinal degenerations are a major cause of impaired vision in the elderly. Degenerations originate in either photoreceptors or the retinal pigment epithelium (RPE). RPE forms the outer blood-retinal barrier and functions intimately with photoreceptors. Animal models and cultures of RPE are commonly used to screen potential pharmaceuticals or explore RPE replacement therapy, but human RPE differs from that of other species. Human RPE forms a barrier using tight junctions composed of a unique set of claudins, proteins that determine the permeability and selectivity of tight junctions. Human adult RPE fails to replicate these properties in vitro. To develop a culture model for drug development and tissue-engineering human retina, RPE were derived from human embryonic stem cells (hESCs). Barrier properties of RPE derived from the H1 and H9 hESC lines were compared with a well-regarded model of RPE function, human fetal RPE isolated from 16-week-gestation fetuses (hfRPE). A serum-free medium (SFM-1) that enhanced the redifferentiation of hfRPE in culture also furthered the maturation of hESC-derived RPE. In SFM-1, the composition, selectivity, and permeability of tight junctions were similar to those of hfRPE. Comparison of the transcriptomes by RNA sequencing and quantitative reverse transcription polymerase chain reaction revealed a high correlation between the hESCs and hfRPE, but there were notable differences in the expression of adhesion junction and membrane transport genes. These data indicated that hESC-derived RPE is highly differentiated but may be less mature than RPE isolated from 16-week fetuses. The study identified a panel of genes to monitor the maturation of RPE. PMID- 23734064 TI - Longitudinal measurement invariance of psychosocial measures in physical activity research: An application to adolescent data. AB - The current study served as a practical and substantive guide to establishing longitudinal measurement invariance of psychosocial measures commonly used in adolescent physical activity (PA) research. Psychosocial data on an initial sample of 878 adolescents (ages 11 - 15) recruited through primary care providers were provided at baseline, 6, 12, and 24 months. The target measures included family support, peer support, decisional balance (pros, cons), self-efficacy, and behavioral strategies. Five of the six psychosocial measures exhibited strict longitudinal measurement invariance, with the 6th measure (self-efficacy) exhibiting strong longitudinal measurement invariance. These findings support the equivalence of these measures across time, and provide the foundation to substantively interpret group differences and associations involving these measures and PA. PMID- 23734065 TI - Perceptions of smokers influence nonsmoker attitudes and preferences for interactions. AB - In two studies, we examined nonsmokers' perceptions of smokers and consequences of the perceptions. In Study 1, smokers answered questions about their sense of self, dependence on smoking, and motivation to quit. Nonsmokers answered questions about their perceptions of these characteristics. Differences between smokers' self-descriptions and nonsmokers' perceptions were observed. Study 2 asked nonsmokers to judge two types of smokers for which the descriptions were based on Study 1 findings. Results showed that nonsmokers held a more negative attitude about and were less willing to engage in different close relationships with the smoker who was described in terms of nonsmokers' perceptions rather than smokers' reports. Attitude mediated the relationship between type of smoker and willingness to date a smoker. PMID- 23734066 TI - Parallel multiscale simulations of a brain aneurysm. AB - Cardiovascular pathologies, such as a brain aneurysm, are affected by the global blood circulation as well as by the local microrheology. Hence, developing computational models for such cases requires the coupling of disparate spatial and temporal scales often governed by diverse mathematical descriptions, e.g., by partial differential equations (continuum) and ordinary differential equations for discrete particles (atomistic). However, interfacing atomistic-based with continuum-based domain discretizations is a challenging problem that requires both mathematical and computational advances. We present here a hybrid methodology that enabled us to perform the first multi-scale simulations of platelet depositions on the wall of a brain aneurysm. The large scale flow features in the intracranial network are accurately resolved by using the high order spectral element Navier-Stokes solver epsilonkappaalphar . The blood rheology inside the aneurysm is modeled using a coarse-grained stochastic molecular dynamics approach (the dissipative particle dynamics method) implemented in the parallel code LAMMPS. The continuum and atomistic domains overlap with interface conditions provided by effective forces computed adaptively to ensure continuity of states across the interface boundary. A two way interaction is allowed with the time-evolving boundary of the (deposited) platelet clusters tracked by an immersed boundary method. The corresponding heterogeneous solvers ( epsilonkappaalphar and LAMMPS) are linked together by a computational multilevel message passing interface that facilitates modularity and high parallel efficiency. Results of multiscale simulations of clot formation inside the aneurysm in a patient-specific arterial tree are presented. We also discuss the computational challenges involved and present scalability results of our coupled solver on up to 300K computer processors. Validation of such coupled atomistic-continuum models is a main open issue that has to be addressed in future work. PMID- 23734067 TI - Atomic structure and composition of the yttria-stabilized zirconia (111) surface. AB - Anomalous and nonanomalous surface X-ray diffraction is used to investigate the atomic structure and composition of the yttria-stabilized zirconia (YSZ)(111) surface. By simulation it is shown that the method is sensitive to Y surface segregation, but that the data must contain high enough Fourier components in order to distinguish between different models describing Y/Zr disorder. Data were collected at room temperature after two different annealing procedures. First by applying oxidative conditions at 10- 5 mbar O2 and 700 K to the as-received samples, where we find that about 30% of the surface is covered by oxide islands, which are depleted in Y as compared with the bulk. After annealing in ultrahigh vacuum at 1270 K the island morphology of the surface remains unchanged but the islands and the first near surface layer get significantly enriched in Y. Furthermore, the observation of Zr and oxygen vacancies implies the formation of a porous surface region. Our findings have important implications for the use of YSZ as solid oxide fuel cell electrode material where yttrium atoms and zirconium vacancies can act as reactive centers, as well as for the use of YSZ as substrate material for thin film and nanoparticle growth where defects control the nucleation process. PMID- 23734068 TI - Meta-Analysis of Rare Binary Adverse Event Data. AB - We examine the use of fixed-effects and random-effects moment-based meta-analytic methods for analysis of binary adverse event data. Special attention is paid to the case of rare adverse events which are commonly encountered in routine practice. We study estimation of model parameters and between-study heterogeneity. In addition, we examine traditional approaches to hypothesis testing of the average treatment effect and detection of the heterogeneity of treatment effect across studies. We derive three new methods, simple (unweighted) average treatment effect estimator, a new heterogeneity estimator, and a parametric bootstrapping test for heterogeneity. We then study the statistical properties of both the traditional and new methods via simulation. We find that in general, moment-based estimators of combined treatment effects and heterogeneity are biased and the degree of bias is proportional to the rarity of the event under study. The new methods eliminate much, but not all of this bias. The various estimators and hypothesis testing methods are then compared and contrasted using an example dataset on treatment of stable coronary artery disease. PMID- 23734069 TI - Dispositional factors affecting motivation during learning in adult basic and secondary education programs. AB - Research indicates that about a quarter of adult students separate from formal adult basic and secondary education (ABE/ASE) programs before completing one educational level. This retrospective study explores individual dispositional factors that affect motivation during learning, particularly students' goals, goal-directed thinking and action based on hope theory and attendance behaviors, and self-perceptions of competency based on affective domain attributions about external and internal obstacles to learning and employment, and demographic factors. Among 274 ABE/ASE students, those learners who made an education gain in 1 year significantly differed from those who did not in only a few dispositional or demographic variables; and by educational level they significantly differed in a wide variety of dispositional and demographic variables. These findings suggest researchable questions and programmatic considerations that may lead to future innovations that improve learner persistence. PMID- 23734070 TI - Ageing, productivity and wages in Austria. AB - Current demographic developments in industrialized countries and their consequences for workforce ageing challenge the sustainability of intergenerational transfers and economic growth. A shrinking share of the young workforce will have to support a growing share of elderly, non-working people. Therefore, the productivity of the workforce is central to a sustainable economic future. Using a new matched employer-employee panel dataset for Austrian firms for the period 2002-2005, we study the relationship between the age structure of employees, labour productivity and wages. These data allow us to account, simultaneously, for both socio-demographic characteristics of employees and firm heterogeneity, in order to explain labour productivity and earnings. Our results indicate that firm productivity is not negatively related to the share of older employees it employs. We also find no evidence for overpayment of older employees. Our results do not show any association between wages and the share of older employees. Furthermore, we find a negative relationship between the share of young employees and labour productivity as well as wages, which is more prevalent in the industry and construction sector. PMID- 23734071 TI - Functional robust support vector machines for sparse and irregular longitudinal data. AB - Functional and longitudinal data are becoming more and more common in practice. This paper focuses on sparse and irregular longitudinal data with a multicategory response. The predictor consists of sparse and irregular observations, potentially contaminated with measurement errors, on the predictor trajectory. To deal with this type of complicated predictors, we borrow the strength of large margin classifiers in statistical learning for classification of sparse and irregular longitudinal data. In particular, we propose functional robust truncated-hinge-loss support vector machines to perform multicategory classification with the aid of functional principal component analysis. PMID- 23734072 TI - Training Addiction Counselors to Implement an Evidence-Based Intervention: Strategies for Increasing Organizational and Provider Acceptance. AB - One barrier to widespread public access to empirically supported treatments (ESTs) is the limited availability and high cost of professionals trained to deliver them. Our earlier work from two clinical trials demonstrated that front line addiction counselors could be trained to deliver a manualized, group-based cognitive behavioral therapy (GCBT) for depression, a prototypic example of an EST, with a high level of adherence and competence. This follow-up article provides specific recommendations for the selection and initial training of counselors, and for the structure and process of their ongoing clinical supervision. Unique challenges in working with counselors unaccustomed to traditional clinical supervision are highlighted. The recommendations are based on comprehensive feedback derived from clinician notes taken throughout the clinical trials, a focus group with counselors conducted one year following implementation, and interviews with key organization executives and administrators. PMID- 23734073 TI - A novel GUCY2D mutation in a Chinese family with dominant cone dystrophy. AB - PURPOSE: To describe the clinical and genetic findings in a Chinese family with autosomal dominant cone dystrophy (adCOD). METHODS: One family was examined clinically, and genomic DNA was extracted from venous blood of all participants. Genotyping and haplotyping analysis was performed on the known genetic loci for adCOD and autosomal dominant cone-rod dystrophies (adCORD) with a panel of polymorphic markers in this family. All coding exons of the AIPL1, PTTPNM3, and GUCY2D gene were directly sequenced. Allele-specific PCR was used to validate a substitution in all available family members and 100 normal controls. Bioinformatics analysis was done using the Garnier-Osguthorpe-Robson method to predict the effect of the variants detected on the secondary structure of the GUCY2D protein. RESULTS: Clinical examination and pedigree analysis revealed a three-generation family with four members diagnosed with adCOD. Through genotyping, the disease-causing genes were mapped to chromosomes 17p13.1-2 (AIPL1, PITPNM3, and GUCY2D gene). A novel A->G transition at position 2545 (p.T849A) of the cDNA sequence was identified in the GUCY2D gene. No mutation was detected in the AIPL1 and PITPNM3 genes. This missense mutation co-segregated with the disease phenotype of the family but was not found in the 100 normal controls. CONCLUSIONS: A novel missense mutation of the GUCY2D gene was identified in this study. Our results further confirm that the dimerization zone of RetGC-1 is the mutational hot region for COD and CORD. PMID- 23734074 TI - Retinal O-linked N-acetylglucosamine protein modifications: implications for postnatal retinal vascularization and the pathogenesis of diabetic retinopathy. AB - PURPOSE: Hyperglycemia activates several metabolic pathways, including the hexosamine biosynthetic pathway. Uridine diphosphate N-acetylglucosamine (GlcNAc) is the product of the hexosamine biosynthetic pathway and the substrate for O linked GlcNAc (O-GlcNAc) modification. This modification affects a wide range of proteins by altering their activity, cellular localization, and/or protein interactions. However, the role O-GlcNAcylation may play in normal postnatal retinal vascular development and in the ocular complications of diabetes, including diabetic retinopathy, requires further investigation. METHODS: The total levels of O-GlcNAc-modified proteins were evaluated by western blot analysis of lysates prepared from retinas obtained at different days during postnatal retinal vascularization and oxygen-induced ischemic retinopathy. Similar experiments were performed with retinal lysate prepared from diabetic Ins2(Akita/+) mice with different durations of diabetes and retinal vascular cells cultured under various glucose conditions. The localization of O-GlcNAc modified proteins in the retinal vasculature was confirmed by immunofluorescence staining. The impact of altered O-GlcNAcylation on the migration of retinal vascular cells was determined using scratch wound and transwell migration assays. RESULTS: We detected an increase in protein O-GlcNAcylation during mouse postnatal retinal vascularization and aging, in part through the regulation of the enzymes that control this modification. The study of the diabetic Ins2(Akita/+) mouse retina showed an increase in the O-GlcNAc modification of retinal proteins. We also observed an increase in retinal O-GlcNAcylated protein levels during the neovascularization phase of oxygen-induced ischemic retinopathy. Our fluorescence microscopy data confirmed that the alterations in retinal O-GlcNAcylation are similarly represented in the retinal vasculature and in retinal pericytes and endothelial cells. Particularly, the migration of retinal pericytes, but not retinal endothelial cells, was attenuated by increased O-GlcNAc modification. CONCLUSIONS: The O-GlcNAc modification pattern changes during postnatal retinal vascular development and neovascularization, and its dysregulation under hyperglycemia and/or ischemia may contribute to the pathogenesis of the diabetic retinopathy and retinal neovascularization. PMID- 23734076 TI - Insulin-like growth factor 1 is not associated with high myopia in a large Japanese cohort. AB - PURPOSE: To investigate whether genetic variations in the insulin-like growth factor 1 (IGF-1) gene are associated with high myopia in Japanese. METHODS: A total of 1,339 unrelated Japanese patients with high myopia (axial length >=26 mm in both eyes) and two independent control groups were evaluated (334 cataract patients without high myopia and 1,194 healthy Japanese individuals). The mean axial length (mm+/-SD) in the case group was 29.18+/-1.85 mm, and the mean spherical equivalent (D+/-SD) of the phakic eyes was -12.69+/-4.54 D. We genotyped five tagging single nucleotide polymorphisms (SNPs) in IGF-1: rs6214, rs978458, rs5742632, rs12423791, and rs2162679. Chi-square tests for trend, multivariable logistic regression, and haplotype regression analysis were conducted. RESULTS: We found no significant association between the IGF-1 SNPs and high or extreme myopia (axial length >=28 mm in both eyes, 837 subjects) in the additive model, even when compared with the cataract and general population controls, with or without adjustments for age and sex. The evaluation using dominant and recessive models also did not reveal any significant associations. The haplotype analysis with a variable-sized sliding-window strategy also showed a lack of association of IGF-1 SNPs with high or extreme myopia. CONCLUSIONS: The results of the present study using a Japanese subset do not support the proposal that the IGF-1 gene determines susceptibility to high or extreme myopia in Caucasians and Chinese. Further studies are needed to confirm our reports in other populations and to identify the underlying genetic determinants of these ocular pathological conditions. PMID- 23734075 TI - Prolonged light exposure induces widespread phase shifting in the circadian clock and visual pigment gene expression of the Arvicanthis ansorgei retina. AB - PURPOSE: Prolonged periods of constant lighting are known to perturb circadian clock function at the molecular, physiological, and behavioral levels. However, the effects of ambient lighting regimes on clock gene expression and clock outputs in retinal photoreceptors--rods, cones and intrinsically photosensitive retinal ganglion cells--are only poorly understood. METHODS: Cone-rich diurnal rodents (Muridae: Arvicanthis ansorgei) were maintained under and entrained to a 12 h:12 h light-dark cycle (LD; light: ~300 lux). Three groups were then examined: control (continued maintenance on LD); animals exposed to a 36 h dark period before sampling over an additional 24 h period of darkness (DD); and animals exposed to a 36 h light period before sampling over an additional 24 h period of light (~300 lux, LL). Animals were killed every 3 or 4 h over 24 h, their retinas dissected, and RNA extracted. Oligonucleotide primers were designed for the Arvicanthis clock genes Per1, Per2, Cry1, Cry2, and Bmal1, and for transcripts specific for rods (rhodopsin), cones (short- and mid-wavelength sensitive cone opsin, cone arrestin, arylalkylamine N-acetyltransferase) and intrinsically photosensitive retinal ganglion cells (melanopsin). Gene expression was analyzed by real-time PCR. RESULTS: In LD, expression of all genes except cone arrestin was rhythmic and coordinated, with acrophases of most genes at or shortly following the time of lights on (defined as zeitgeber time 0). Arylalkylamine N-acetyltransferase showed maximal expression at zeitgeber time 20. In DD conditions the respective profiles showed similar phase profiles, but were mostly attenuated in amplitude, or in the case of melanopsin, did not retain rhythmic expression. In LL, however, the expression profiles of all clock genes and most putative output genes were greatly altered, with either abolition of daily variation (mid-wavelength cone opsin) or peak expression shifted by 4-10 h. CONCLUSIONS: These data are the first to provide detailed measures of retinal clock gene and putative clock output gene expression in a diurnal mammal, and show the highly disruptive effects of inappropriate (nocturnal) lighting on circadian and photoreceptor gene regulation. PMID- 23734077 TI - Longitudinal fluorescent observation of retinal degeneration and regeneration in zebrafish using fundus lens imaging. AB - PURPOSE: Longitudinal observation of retinal degeneration and regeneration in animal models is time-consuming and expensive. To address this challenge, we used a custom fundus lens and zebrafish transgenic lines with cell-specific fluorescent reporters to document the state of individual retinal neurons in vivo. METHODS: We empirically tested several versions of a custom fundus lens and assessed its capabilities under a stereomicroscope to image retinal neurons in transgenic zebrafish lines expressing fluorescent reporters. Vascular branch points provided spatial references enabling determination of whether changes induced by ablating photoreceptors were repaired over the course of several days. RESULTS: Individual ultraviolet- and blue-sensitive cone photoreceptors were readily visualized in vivo, and green fluorescent protein-labeled blood vessels were used as landmarks to facilitate orientation. Sequential imaging of the same retinal areas over several weeks permitted documentation of photoreceptor reappearance in individual animals. Photoreceptor regeneration in these regions was evidenced by the reappearance of individual fluorescent cells. CONCLUSIONS: This technique permits real-time in vivo serial examination of individual fish, permitting temporal analysis of changes to the retinal mosaic. The key benefits this technique offers include that the same retinal locations can be recovered and viewed at multiple time points, that in vivo observations are comparable to those made ex vivo, and that fewer animals need to be euthanized over the course of an experiment. Our results promise the ability to detect individual cells, including reappearing cone photoreceptors, and to monitor disease progression during screening of therapies in an adult animal model of late onset disease. PMID- 23734078 TI - Differential expression of the Slc4 bicarbonate transporter family in murine corneal endothelium and cell culture. AB - PURPOSE: To characterize the relative expression levels of all the solute carrier 4 (Slc4) transporter family members (Slc4a1-Slc4a11) in murine corneal endothelium using real-time quantitative (qPCR), to identify further important members besides Slc4a11 and Slc4a4, and to explore how close to the baseline levels the gene expressions remain after cells have been subjected to expansion and culture. METHODS: Descemet's membrane-endothelial layers of 8-10-week-old C57BL6 mice were stripped from corneas and used for both primary cell culture and direct RNA extraction. Total RNA (from uncultured cells as well as cultured cells at passages 2 and 7) was reverse transcribed, and the cDNA was used for real time qPCR using specific primers for all the Slc4 family members. The geNorm method was applied to determine the most stable housekeeping genes and normalization factor, which was calculated from multiple housekeeping genes for more accurate and robust quantification. RESULTS: qPCR analyses revealed that all Slc4 bicarbonate transporter family members were expressed in mouse corneal endothelium. Slc4a11 showed the highest expression, which was approximately three times higher than that of Slc4a4 (3.4+/-0.3; p=0.004). All Slc4 genes were also expressed in cultured cells, and interestingly, the expression of Slc4a11 in cultured cells was significantly reduced by approximately 20-fold (0.05+/-0.001; p=0.000001) in early passage and by approximately sevenfold (0.14+/-0.002; p=0.000002) in late passage cells. CONCLUSIONS: Given the known involvement of SLC4A4 and SLC4A11 in corneal dystrophies, we speculate that the other two highly expressed genes in the uncultured corneal endothelium, SLC4A2 and SLC4A7, are worthy of being considered as potential candidate genes for corneal endothelial diseases. Moreover, as cell culture can affect expression levels of Slc4 genes, caution and careful design of experiments are necessary when undertaking studies of Slc4-mediated ion transport in cultured cells. PMID- 23734080 TI - Technical brief: a comparison of two methods of euthanasia on retinal dopamine levels. AB - PURPOSE: Mice are commonly used in biomedical research, and euthanasia is an important part of mouse husbandry. Approved, humane methods of euthanasia are designed to minimize the potential for pain or discomfort, but may also influence the measurement of experimental variables. METHODS: We compared the effects of two approved methods of mouse euthanasia on the levels of retinal dopamine. We examined the level of retinal dopamine, a commonly studied neuromodulator, following euthanasia by carbon dioxide (CO2)-induced asphyxiation or by cervical dislocation. RESULTS: We found that the level of retinal dopamine in mice euthanized through CO2 overdose substantially differed from that in mice euthanized through cervical dislocation. CONCLUSIONS: The use of CO2 as a method of euthanasia could result in an experimental artifact that could compromise results when studying labile biologic processes. PMID- 23734079 TI - An angiotensin-converting enzyme inhibitor modulates stromal-derived factor-1 through CD26/dipeptidyl peptidase IV to inhibit laser-induced choroidal neovascularization. AB - PURPOSE: Stromal-derived factor (SDF)-1 is a chemokine that recruits bone marrow derived endothelial precursor cells (EPCs) for choroidal neovascularization (CNV) development. Angiotensin-converting enzyme (ACE) inhibitors mediate the compensatory effects of ACE and CD26/dipeptidyl peptidase IV (DPP IV), which results in the degradation and inactivation of SDF-1 in vivo. ACE inhibitors, such as imidapril, exhibit potential antiangiogenic effects on laser-induced CNV in mice. The role that this imidapril-mediated effect plays in modulating SDF-1 signals has not been defined. The present study assessed the effect of the CD26/SDF-1 signaling pathway on the inhibitory effect of imidapril in CNV development. METHODS: CNV was induced in C57BL/6J mice by focally rupturing Bruch's membrane using a 532-nm diode laser. The animals were pretreated with PBS, imidapril, diprotin-A (a DPP IV antagonist), or imidapril plus diprotin-A for 5 days before photocoagulation. Treatments were continued daily for 14 days following the laser induction. The normal control group did not undergo laser rupture or receive treatment. CD26 activity was measured using a substrate conversion assay and flow cytometry. SDF-1 levels in both the blood and the bone marrow were measured using an enzyme-linked immunosorbent assay, and the number of circulating endothelial progenitor cells (EPCs) and leukocytes was quantified. Functional analyses of circulating SDF-1 were performed using actin polymerization blood biomarker assays, and the CNV-related responses were evaluated using fluorescein angiography and isolectin-B4-labeled flatmounts. RESULTS: Imidapril directly amplified CD26 activity and had a minor effect on the number of CD26+ cells in the bone marrow. However, decreased CD26 activity in the plasma was secondary to a decrease in the number of circulating CD26+ cells and blood leukocytes. Furthermore, imidapril increased SDF-1 concentrations in the peripheral circulation via CD26-induced degradation of SDF-1 in the bone marrow, an effect that coincided with elevated numbers of circulating EPCs. CD26-mediated SDF-1 inactivation was demonstrated by a decrease in SDF-1-induced actin polymerization in the whole blood of imidapril-treated mice. Imidapril markedly decreased angiographic leakage and CNV size. CD26 inhibition completely blocked the CD26/SDF-1 signaling pathway in vivo and reduced the antiangiogenic effect of imidapril. CONCLUSIONS: These results strongly suggest that the antiangiogenic effects of imidapril on laser-induced CNV partially involve the modulation of the CD26/SDF-1 signaling pathway. PMID- 23734081 TI - Age-dependent alteration of intraocular soluble heparan sulfate levels and its implications for proliferative diabetic retinopathy. AB - PURPOSE: To assess the relationship between intraocular soluble heparan sulfate (HS) concentration and age in subjects with and without diabetic retinopathy. METHODS: Vitreous from subjects with idiopathic maculopathies (n=17), i.e., macula hole or epiretinal membrane, or nonproliferative diabetic retinopathy (non PDR; n=5) and aqueous humor from subjects with PDR (n=16), non-PDR (n=7), or cataracts (n=15) was collected. The levels of HS and vascular endothelial growth factor (VEGF) were measured using enzyme-linked immunosorbent assay. Concentrations of sulfated glycosaminoglycan were determined through dimethylmethylene blue-based assay. The effect of the vitreal HS level on the binding of exogenous VEGF to surface-bound heparin was determined in vitro. RESULTS: The level of HS in vitreous samples from subjects with idiopathic maculopathies increased concomitantly with age (p=0.020, R2=0.327). Meanwhile, HS levels in aqueous humor were lower in PDR subjects than in non-PDR (p=0.003) and cataract subjects (p=0.007). However, the PDR subjects were significantly younger than the non-PDR subjects (p<0.001) or cataract subjects (p<0.001). When the three groups were controlled for age, the levels of HS glycosaminoglycans were no longer different between the three (p=0.247). The increasing level of HS or sulfated glycosaminoglycan in the vitreous was associated with its increased inhibitory effect on interaction between VEGF and surface heparin in vitro (p=0.014, R2=0.377). CONCLUSIONS: The HS level of the intraocular fluid increased with age. The possible link between low HS in intraocular fluid and increased localization of VEGF at the retinal surface may provide one explanation for the higher susceptibility of younger subjects with diabetes mellitus to developing PDR. PMID- 23734082 TI - Genetic association study of mitochondrial polymorphisms in neovascular age related macular degeneration. AB - PURPOSE: Age-related macular degeneration (AMD) is a multifactorial disease involving genetic and environmental factors. Most of the genetic factors identified so far involve the nuclear genome. Recently, two studies in North America and Australia reported an association between advanced AMD and the mitochondrial T2 haplogroup. Our purpose was to assess this association in a large French population. METHODS: This case control study included 1,224 patients with neovascular AMD and 559 controls with normal fundus. Mitochondrial DNA polymorphisms at and around nucleotides 4917, 11,812, and 14,233 were determined using PCR amplification and direct sequencing of mitochondrial DNA. RESULTS: No association was found between the mitochondrial T2 haplogroup and neovascular AMD in the French population: 94/1,152 patients with neovascular AMD had the T2 haplogroup (8.2%) versus 34/482 controls (7.1%; odds ratio=0.9 [0.5-1.5], p=0.66). CONCLUSIONS: An association between AMD and the T2 haplogroup, previously described in North American and Australian populations, was not confirmed in a large French population. PMID- 23734083 TI - Mutational screening of Indian families with hereditary congenital cataract. AB - PURPOSE: To screen for pathogenic mutations in ten candidate genes in Indian families diagnosed with autosomal recessive and autosomal dominant cataracts. METHODS: Families with two or more affected individuals with bilateral familial congenital/developmental cataract were ophthalmically evaluated, and blood samples were obtained. Genomic DNA extracted from the blood leukocytes was screened with PCR amplification of the exons and the flanking intronic regions of various genes selected for analysis. The amplified products were subjected to single strand conformation polymorphism (SSCP) analysis. The variants in SSCP analysis were subjected to bidirectional sequencing by automated methods. RESULTS: We identified four novel sequence changes that cosegregated with the disease phenotype in each family and were absent in at least 50 ethnically matched unrelated normal controls. These changes include a homozygous missense change of c.649G>A (Val196Met) in GJA8/connexin 50 (Cx50) in a family with autosomal recessive cataract, two heterozygous missense changes, c.658C>T (Pro199Ser) in GJA8/Cx50 and c.589C>T (Pro197Ser) in GJA3/connexin 46 (Cx46) in two separate families with autosomal dominant cataract, and a silent change ( c.84G>A/p.Val28Val, predicted to result in the creation of a new potential branch point) in GJA8 one family with an autosomal dominant inheritance of cataract. Of the four novel mutations identified, three mutations, Val196Met (GJA8), Pro199Ser (GJA8), and Pro197Ser (GJA3), are predicted to be in the second extracellular domain of the respective connexin proteins. CONCLUSIONS: Our report extends the mutation spectrum of connexin genes GJA8 and GJA3 and confirms that connexin genes are among the most frequently mutated genes in hereditary cataracts. Our results suggest that connexin gene (GJA8 and GJA3) mutations occur in approximately 10% (4/40 families) of families with congenital hereditary cataracts in a population from southern India. PMID- 23734085 TI - Assessment of ultraviolet B-blocking effects of weekly disposable contact lenses on corneal surface in a mouse model. AB - PURPOSE: Weekly disposable soft contact lenses have been widely used recently, but their shield effects against ultraviolet (UV) irradiation remain to be evaluated. This study investigated the bioprotective effects of several weekly soft contact lenses against UVB irradiation on the corneal surface in a mouse model. METHODS: Fifty ICR mice were randomly divided into five groups: (1) blank control, (2) exposed to UVB without contact lens protection, (3) exposed to UVB and protected with Vifilcon A contact lenses, (4) exposed to UVB and protected with Etafilcon A contact lenses, and (5) exposed to UVB and protected with HEMA+MA contact lenses. The exposure to UVB irradiation was performed at 0.72 J/cm2)/day after anesthesia for a 7-day period, followed by cornea surface assessment for smoothness, opacity, and grading of lissamine green staining. Tissue sections were prepared for hematoxylin and eosin staining and immunohistochemical detection by using antibodies against myeloperoxidase, cytokeratin-5, P63, Ki-67, nuclear factor-kappa B (p65), cyclooxygenase-2, Fas L, and Fas. RESULTS: The results showed impaired corneal surface with myeloperoxidase+ polymorphonuclear leukocyte infiltration into the stroma after UVB exposure, in contrast to the intact status of the blank controls. The corneas with Etafilcon A and HEMA+MA contact lenses maintained more cells positive for cytokeratin-5, P63, and Ki-67 compared to those with Vifilcon A or without contact lens protection. Furthermore, less proinflammatory factors, including nuclear factor-kappa (p65), cyclooxygenase-2, Fas L, and Fas, were induced in the corneas protected by Etafilcon A and HEMA+MA. CONCLUSIONS: This study demonstrated various protective effects of weekly disposable contact lenses against UVB irradiation. The mouse model used in the present study may be used extensively for in vivo assessment of UV shield efficacy. PMID- 23734084 TI - Explant cultures of Rpe65-/- mouse retina: a model to investigate cone opsin trafficking. AB - PURPOSE: In the absence of 11-cis retinal (e.g., Rpe65-/-), the chromophore for all pigments, cone opsins are mislocalized in vivo. Using the systemic application of 11-cis retinal, appropriate protein localization can be promoted. Here, we asked whether explant cultures of Rpe65-/- mouse retina are amenable to screening retinoids for their ability to promote opsin trafficking. METHODS: Retina-retinal pigment epithelium (RPE) cultures were prepared from 7-day-old Rpe65-/- Rho-/- or wild-type pups and cultured for 11 days. Explants were treated with retinoids throughout this period. Ultraviolet (UV)-opsin trafficking was analyzed by immunohistochemistry and quantitative image analysis, while its messenger RNA expression was examined by quantitative real-time PCR, and the interaction of retinoids with UV-opsin was probed in transducing-activation assays. RESULTS: In wild-type explant cultures, UV-opsin was restricted to the outer segments, whereas in those derived from Rpe65-/- Rho-/- mice, opsin trafficking was impaired. In Rpe65-/- Rho-/- explants, administration of 11-cis retinal, 11-cis retinol or retinoic acid (RA) reversed the opsin trafficking phenotype. RA analogs designed to act by binding to the retinoic acid receptor or the retinoid X-receptor, however, had no effect. RA was shown to interact with the UV-cone opsin, demonstrated by its ability to effect ligand-dependent activation of transducin by UV-cone opsin. All compounds tested increased cone opsin messenger RNA expression. CONCLUSIONS: Cone-opsin trafficking defects were replicated in Rpe65-/- Rho-/- retina-RPE cultures, and were reversed by 11-cis retinal treatment. Comparing the effects of different retinoids on their ability to promote UV-opsin trafficking to outer segments confirmed the critical role of agents that bind in the retinoid binding pocket. Retinoids that act as transcription factors, however, were ineffective. Thus, organ cultures may be a powerful low-throughput screening tool to identify novel compounds to promote cone survival. PMID- 23734086 TI - Mutation analysis of paired box 6 gene in inherited aniridia in northern China. AB - PURPOSE: Aniridia is phenotypically and genetically heterogeneous. This study is to summarize the phenotypes and identify the underlying genetic cause of the paired box 6 (PAX6) gene responsible for aniridia in two three-generation Chinese families in northern China. METHODS: A detailed family history and clinical data were collected from patients during an ophthalmologic examination. All exons and flanking intronic sequences of the PAX6 gene were amplified with PCR and screened for mutation with direct DNA sequencing. Haplotyping was used to confirm the mutation sequence. Real-time PCR was used to determine the PAX6 messenger ribonucleic acid(mRNA) level in patients with aniridia and in unaffected family members. RESULTS: The probands and other patients in the two families were affected with aniridia accompanied with or without congenital cataract. A heterozygous PAX6 mutation in exon 5 (c.112delC, p.Arg38GlyfsX16) was identified in FAMILY-1, which was predicted to generate a frameshift and created a premature termination codon. A heterozygous PAX6 mutation in exon 7 (c.362C>T, p.Ser121Leu) was identified in FAMILY-2. Each mutation cosegregated with the affected individuals in the family and did not exist in unaffected family members and 200 unrelated normal controls. The PAX6 messenger ribonucleic acid level was about 50% lower in patients with aniridia than in unaffected family members in FAMILY 1. CONCLUSIONS: The deletion mutation (c.112delC) in the PAX6 gene was first identified in a Chinese family with aniridia, congenital progressive cataract, developmental delay, or the absence of ulna. The mutation (c.362C>T, p.Ser121Leu) in the PAX6 gene was first identified in a patient with aniridia with congenital ptosis. We summarized the variable phenotypes among the patients, which expanded the phenotypic spectrum of aniridia in a different ethnic background. PMID- 23734087 TI - Photoreceptor-like cells from reprogramming cultured mammalian RPE cells. AB - PURPOSE: Previous studies showed that chick retinal pigment epithelium (RPE) cells can be reprogrammed by a specific gene to take on the path of photoreceptor differentiation. In this study, we tested whether this reprogramming scheme could be applied to mammalian RPE cells. METHODS: Human RPE cell lines ARPE-19, a spontaneously transformed line of RPE cells derived from a 19-year-old person, and hTERT-RPE1, a telomerase-immortalized RPE cell line derived from a 1-year-old person, were commercially obtained and cultured as recommended. Primary RPE cell cultures were established using RPE isolated from 3- to 6-month-old pig and postnatal day 5 mouse. Cultured cells were transduced with a virus expressing neuroD, neurogenin1 (ngn1), or ngn3, basic helix-loop-helix (bHLH) genes previously identified as capable of inducing RPE-to-photoreceptor reprogramming in the chick system. Alternatively, cells in the culture were transfected chemically or physically through electroporation with vector DNA expressing one of the three genes. The cultures were then analyzed for RPE-to-photoreceptor reprogramming with in situ hybridization and/or immunostaining for photoreceptor gene expression. RESULTS: Both hTERT-RPE1 and ARPE-19 cultures gave rise to cells bearing markers of photoreceptors after transduction or transfection with vehicles expressing neuroD or ngn1. The new cells expressed genes encoding photoreceptor proteins, including interphotoreceptor retinoid-binding protein IRBP), recoverin, retinal cone arrestin 3, transducin alpha-subunit, Cone-rod homeobox protein (Crx), and red opsin. They displayed morphologies resembling differentiating photoreceptor cells. In primary porcine and mouse RPE cell cultures, transduction with lenti virus (Lvx-IRES-ZsGreen1) expressing ngn1 or ngn3 resulted in the emergence of ZsGreen1+ cells that exhibited morphologies reminiscent of differentiating photoreceptor cells. Immunochemistry showed that some ZsGreen1+ cells were positive for neural marker microtubule-associated protein 2 (Map2) and photoreceptor hallmark proteins red opsin and rhodopsin. CONCLUSIONS: The results suggest that cells in human RPE cell lines and in primary cultures of porcine and mouse RPE respond to gene-induced reprogramming by giving rise to photoreceptor-like cells. The responsiveness of primary RPE cells, especially those from porcine cells, enhances the biologic feasibility of exploring RPE-to-photoreceptor reprogramming for in situ mammalian photoreceptor replacement without cell transplantation. PMID- 23734088 TI - Saffron administration prevents selenite-induced cataractogenesis. AB - PURPOSE: The present study sought to investigate whether Crocus sativus stigmas (saffron) extract prevents selenium-induced cataractogenesis in vivo, and to study its possible protective mechanism. METHODS: Wistar rat pups were randomized into three groups. Group I (control) received subcutaneous injection of normal saline on postnatal day 10. Groups II (selenite-treated) and III (selenite+saffron-treated) received subcutaneous injection of sodium selenite (20 umol/kg body weight) on postnatal day 10. Group III also received intraperitoneal injections of saffron extract (60 mg/kg body weight) on postnatal days 9 and 12. On postpartum day 21, rats were sacrificed and the lenses were isolated and examined for cataract formation. Activities of superoxide dismutase, glutathione peroxidase, catalase, and glutathione levels, as markers of antioxidant defense, were measured in the isolated lenses. Levels of the indicator of lipid peroxidation, malondialdehyde, and protein oxidation (sulfhydryl content) in the lens were also determined. The effect of the different treatments on lens protein profile was evaluated through an estimation of the soluble to insoluble protein ratio and sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis of the water-soluble fraction (WSF) of lens proteins. RESULTS: Saffron demonstrated significant protection against selenite-induced cataractogenesis in vivo. The mean activities of superoxide dismutase, glutathione peroxidase, catalase, and glutathione levels were significantly increased in group III compared to the selenite-treated group. Saffron significantly prevented selenite-induced lipid peroxidation, protein oxidation, and proteolysis and insolubilization of the lens WSF. CONCLUSIONS: Saffron extract prevented selenite-induced cataract formation in Wistar rats, possibly through the reinforcement of antioxidant status, reduction of the intensity of lipid peroxidation, protection of the sulfhydryl groups, and inhibition of proteolysis of the lens WSF. These findings highlight the anticataractogenic potential of saffron by virtue of its antioxidant property. PMID- 23734089 TI - Suprachoroidal delivery in a rabbit ex vivo eye model: influence of drug properties, regional differences in delivery, and comparison with intravitreal and intracameral routes. AB - PURPOSE: First, to determine the influence of drug lipophilicity (using eight beta-blockers) and molecular weight (using 4 kDa and 40 kDa fluoroscein isothiocyanate [FITC]-dextrans) on suprachoroidal delivery to the posterior segment of the eye by using a rabbit ex vivo eye model. Second, to determine whether drug distribution differs between the dosed and undosed side of the eye following suprachoroidal delivery. Third, to compare the suprachoroidal delivery of sodium fluorescein (NaF) with the intracameral and intravitreal routes by using noninvasive fluorophotometry. METHODS: Using a small hypodermic 26G needle (3/8") with a short bevel (250 um), location of the suprachoroidal injection in an ex vivo New Zealand white rabbit eye model was confirmed with India ink. Ocular tissue distribution of NaF (25 ul of 1.5 ug/ml) at 37 degrees C was monitored noninvasively using the Fluorotron Master(TM) at 0, 1, and 3 h following suprachoroidal, intravitreal, or intracameral injections in ex vivo rabbit eyes. For assessing the influence of lipophilicity and molecular size, 25 ul of a mixture of eight beta-blockers (250 ug/ml each) or FITC-dextran (4 kDa and 40 kDa, 30 mg/ml) was injected into the suprachoroidal space of excised rabbit eyes and incubated at 37 degrees C. Eyes were incubated for 1 and 3 h, and frozen at the end of incubation. Ocular tissues were isolated in frozen condition. Beta-blocker and FITC-dextran levels in excised ocular tissue were measured by liquid chromatography-tandem mass spectrometry and spectrofluorometry, respectively. RESULTS: Histological sections of India ink injected albino rabbit eye showed the localization of dye as a black line in the suprachoroidal space. Suprachoroidal injection of NaF showed signal localization to the choroid and retina at 1 and 3 h post injection when compared with intravitreal and intracameral injections. Drug delivery to the vitreous after suprachoroidal injection decreased with an increase in solute lipophilicity and molecular weight. With an increase in drug lipophilicity, drug levels in the choroid-retinal pigment epithelium (RPE) and retina generally increased with some exceptions. Beta-blockers and FITC-dextrans were localized more to the dosed side when compared to the opposite side of the sclera, choroid-RPE, retina, and vitreous. These differences were greater for FITC-dextrans as compared to the beta-blockers. CONCLUSIONS: The suprachoroidal route of injection allows localized delivery to the choroid-RPE and retina for small as well as large molecules. Suprachoroidal drug delivery to the vitreous declines with an increase in drug lipophilicity and molecular weight. Drug delivery differs between the dosed and opposite sides following suprachoroidal injection, at least up to 3 h. PMID- 23734090 TI - On the origin of rhythmic contractile activity of the esophagus in early achalasia, a clinical case study. AB - A patient with early achalasia presented spontaneous strong rhythmic non propulsive contractions at ~7/min, independent of swallows. Our aim was to evaluate characteristics of the rhythmic contractions, provide data on the structure of pacemaker cells in the esophagus and discuss a potential role for interstitial cells of Cajal (ICC) in the origin of rhythmicity. We hypothesize that intramuscular ICC (ICC-IM) are the primary pacemaker cells. The frequency but not the amplitude of the rhythmic contractions was inhibited by the phosphodiesterase inhibitor drotaverine consistent with cAMP inhibiting pacemaker currents in ICC-IM. The frequency increased by wet swallows but not dry swallows, consistent with stretch causing increase in slow wave frequency in ICC-IM. New studies on archival material showed that ICC-IM were present throughout the human esophageal musculature and were not diminished in early achalasia. Although ICC IM exhibited a low density, they were connected to PDGFRalpha-positive fibroblast like cells with whom they formed a dense gap junction coupled network. Nitrergic innervation of ICC was strongly diminished in early achalasia because of the loss of nitrergic nerves. It therefore appears possibly that ICC-IM function as pacemaker cells in the esophagus and that the network of ICC and PDGFRalpha positive cells allows for coupling and propagation of the pacemaker activity. Loss of nitrergic innervation to ICC in achalasia may render them more excitable such that its pacemaker activity is more easily expressed. Loss of propagation in achalasia may be due to loss of contraction-induced aboral nitrergic inhibition. PMID- 23734092 TI - Learning from silver linings. PMID- 23734091 TI - The immune consequences of preterm birth. AB - Preterm birth occurs in 11% of live births globally and accounts for 35% of all newborn deaths. Preterm newborns have immature immune systems, with reduced innate and adaptive immunity; their immune systems may be further compromised by various factors associated with preterm birth. The immune systems of preterm infants have a smaller pool of monocytes and neutrophils, impaired ability of these cells to kill pathogens, and lower production of cytokines which limits T cell activation and reduces the ability to fight bacteria and detect viruses in cells, compared to term infants. Intrauterine inflammation is a major contributor to preterm birth, and causes premature immune activation and cytokine production. This can induce immune tolerance leading to reduced newborn immune function. Intrauterine inflammation is associated with an increased risk of early-onset sepsis and likely has long-term adverse immune consequences. Requisite medical interventions further impact on immune development and function. Antenatal corticosteroid treatment to prevent newborn respiratory disease is routine but may be immunosuppressive, and has been associated with febrile responses, reductions in lymphocyte proliferation and cytokine production, and increased risk of infection. Invasive medical procedures result in an increased risk of late-onset sepsis. Respiratory support can cause chronic inflammatory lung disease associated with increased risk of long-term morbidity. Colonization of the infant by microorganisms at birth is a significant contributor to the establishment of the microbiome. Caesarean section affects infant colonization, potentially contributing to lifelong immune function and well-being. Several factors associated with preterm birth alter immune function. A better understanding of perinatal modification of the preterm immune system will allow for the refinement of care to minimize lifelong adverse immune consequences. PMID- 23734094 TI - Epigenetic regulation of the oxytocin receptor gene: implications for behavioral neuroscience. AB - Genetic approaches have improved our understanding of the neurobiological basis of social behavior and cognition. For instance, common polymorphisms of genes involved in oxytocin signaling have been associated with sociobehavioral phenotypes in healthy samples as well as in subjects with mental disorders. More recently, attention has been drawn to epigenetic mechanisms, which regulate genetic function and expression without changes to the underlying DNA sequence. We provide an overview of the functional importance of oxytocin receptor gene (OXTR) promoter methylation and summarize studies that have investigated the role of OXTR methylation in behavioral phenotypes. There is first evidence that OXTR methylation is associated with autism, high callous-unemotional traits, and differential activation of brain regions involved in social perception. Furthermore, psychosocial stress exposure might dynamically regulate OXTR. Given evidence that epigenetic states of genes can be modified by experiences, especially those occurring in sensitive periods early in development, we conclude with a discussion on the effects of traumatic experience on the developing oxytocin system. Epigenetic modification of genes involved in oxytocin signaling might be involved in the mechanisms mediating the long-term influence of early adverse experiences on socio-behavioral outcomes. PMID- 23734093 TI - RNA-binding proteins and translational regulation in axons and growth cones. AB - RNA localization and regulation play an important role in the developing and adult nervous system. In navigating axons, extrinsic cues can elicit rapid local protein synthesis that mediates directional or morphological responses. The mRNA repertoire in axons is large and dynamically changing, yet studies suggest that only a subset of these mRNAs are translated after cue stimulation, suggesting the need for a high level of translational regulation. Here, we review the role of RNA-binding proteins (RBPs) as local regulators of translation in developing axons. We focus on their role in growth, guidance, and synapse formation, and discuss the mechanisms by which they regulate translation in axons. PMID- 23734095 TI - Ion channels in the central regulation of energy and glucose homeostasis. AB - Ion channels are critical regulators of neuronal excitability and synaptic function in the brain. Recent evidence suggests that ion channels expressed by neurons within the brain are responsible for regulating energy and glucose homeostasis. In addition, the central effects of neurotransmitters and hormones are at least in part achieved by modifications of ion channel activity. This review focuses on ion channels and their neuronal functions followed by a discussion of the identified roles for specific ion channels in the central pathways regulating food intake, energy expenditure, and glucose balance. PMID- 23734096 TI - Transgenic mouse lines for non-invasive ratiometric monitoring of intracellular chloride. AB - Chloride is the most abundant physiological anion and participates in a variety of cellular processes including trans-epithelial transport, cell volume regulation, and regulation of electrical excitability. The development of tools to monitor intracellular chloride concentration ([Cli]) is therefore important for the evaluation of cellular function in normal and pathological conditions. Recently, several Cl-sensitive genetically encoded probes have been described which allow for non-invasive monitoring of [Cli]. Here we describe two mouse lines expressing a CFP-YFP-based Cl probe called Cl-Sensor. First, we generated transgenic mice expressing Cl-Sensor under the control of the mouse Thy1 mini promoter. Cl-Sensor exhibited good expression from postnatal day two (P2) in neurons of the hippocampus and cortex, and its level increased strongly during development. Using simultaneous whole-cell monitoring of ionic currents and Cl dependent fluorescence, we determined that the apparent EC 50 for Cli was 46 mM, indicating that this line is appropriate for measuring neuronal [Cli] in postnatal mice. We also describe a transgenic mouse reporter line for Cre dependent conditional expression of Cl-Sensor, which was targeted to the Rosa26 locus and by incorporating a strong exogenous promoter induced robust expression upon Cre-mediated recombination. We demonstrate high levels of tissue-specific expression in two different Cre-driver lines targeting cells of the myeloid lineage and peripheral sensory neurons. Using these mice the apparent EC 50 for Cli was estimated to be 61 and 54 mM in macrophages and DRG, respectively. Our data suggest that these mouse lines will be useful models for ratiometric monitoring of Cli in specific cell types in vivo. PMID- 23734097 TI - Genetic control of adult neurogenesis: interplay of differentiation, proliferation and survival modulates new neurons function, and memory circuits. AB - Within the hippocampal circuitry, the basic function of the dentate gyrus is to transform the memory input coming from the enthorinal cortex into sparse and categorized outputs to CA3, in this way separating related memory information. New neurons generated in the dentate gyrus during adulthood appear to facilitate this process, allowing a better separation between closely spaced memories (pattern separation). The evidence underlying this model has been gathered essentially by ablating the newly adult-generated neurons. This approach, however, does not allow monitoring of the integration of new neurons into memory circuits and is likely to set in motion compensatory circuits, possibly leading to an underestimation of the role of new neurons. Here we review the background of the basic function of the hippocampus and of the known properties of new adult generated neurons. In this context, we analyze the cognitive performance in mouse models generated by us and others, with modified expression of the genes Btg2 (PC3/Tis21), Btg1, Pten, BMP4, etc., where new neurons underwent a change in their differentiation rate or a partial decrease of their proliferation or survival rate rather than ablation. The effects of these modifications are equal or greater than full ablation, suggesting that the architecture of circuits, as it unfolds from the interaction between existing and new neurons, can have a greater functional impact than the sheer number of new neurons. We propose a model which attempts to measure and correlate the set of cellular changes in the process of neurogenesis with the memory function. PMID- 23734098 TI - Rho GTPase-dependent plasticity of dendritic spines in the adult brain. AB - Brain activity is associated with structural changes in the neural connections. However, in vivo imaging of the outer cortical layers has shown that dendritic spines, on which most excitatory synapses insist, are predominantly stable in adulthood. Changes in dendritic spines are governed by small GTPases of the Rho family through modulation of the actin cytoskeleton. Yet, while there are abundant data about this functional effect of Rho GTPases in vitro, there is limited evidence that Rho GTPase signaling in the brain is associated with changes in neuronal morphology. In the present work, both chronic in vivo two photon imaging and Golgi staining reveal that the activation of Rho GTPases in the adult mouse brain is associated with little change of dendritic spines in the apical dendrites of primary visual cortex pyramidal neurons. On the contrary, considerable increase in spine density is observed (i) in the basal dendrites of the same neurons (ii) in both basal and apical dendrites of the hippocampal CA1 pyramidal cells. While confirming that Rho GTPase-dependent increase in spine density can be substantial, the study indicates region and dendrite selectivity with relative stability of superficial cortical circuits. PMID- 23734101 TI - Motoneuron double discharges: only one or two different entities? PMID- 23734099 TI - The brain's best friend: microglial neurotoxicity revisited. AB - One long standing aspect of microglia biology was never questioned; their involvement in brain disease. Based on morphological changes (retracted processes and amoeboid shape) that inevitably occur in these cells in case of damage in the central nervous system, microglia in the diseased brain were called "activated." Because "activated" microglia were always found in direct neighborhood to dead or dying neuron, and since it is known now for more than 20 years that cultured microglia release numerous factors that are able to kill neurons, microglia "activation" was often seen as a neurotoxic process. From an evolutionary point of view, however, it is difficult to understand why an important, mostly post mitotic and highly vulnerable organ like the brain would host numerous potential killers. This review is aimed to critically reconsider the term microglia neurotoxicity and to discuss experimental problems around microglia biology, that often have led to the conclusion that microglia are neurotoxic cells. PMID- 23734100 TI - The effects of maternal depression and maternal selective serotonin reuptake inhibitor exposure on offspring. AB - It has been estimated that 20% of pregnant women suffer from depression and it is well-documented that maternal depression can have long-lasting effects on the child. Currently, common treatment for maternal depression has been the selective serotonin reuptake inhibitor medications (SSRIs) which are used by 2-3% of pregnant women in the Nordic countries and by up to 10% of pregnant women in the United States. Antidepressants cross the placenta and are transferred to the fetus, thus, the question arises as to whether children of women taking antidepressants are at risk for altered neurodevelopmental outcomes and, if so, whether the risks are due to SSRI medication exposure or to the underlying maternal depression. This review considers the effects of maternal depression and SSRI exposure on offspring development in both clinical and preclinical populations. As it is impossible in humans to study the effects of SSRIs without taking into account the possible underlying effects of maternal depression (healthy pregnant women do not take SSRIs), animal models are of great value. For example, rodents can be used to determine the effects of maternal depression and/or perinatal SSRI exposure on offspring outcomes. Unraveling the joint (or separate) effects of maternal depression and SSRI exposure will provide more insights into the risks or benefits of SSRI exposure during gestation and will help women make informed decisions about using SSRIs during pregnancy. PMID- 23734102 TI - High frequency burst firing of granule cells ensures transmission at the parallel fiber to purkinje cell synapse at the cost of temporal coding. AB - Cerebellar granule cells (GrCs) convey information from mossy fibers (MFs) to Purkinje cells (PCs) via their parallel fibers (PFs). MF to GrC signaling allows transmission of frequencies up to 1 kHz and GrCs themselves can also fire bursts of action potentials with instantaneous frequencies up to 1 kHz. So far, in the scientific literature no evidence has been shown that these high-frequency bursts also exist in awake, behaving animals. More so, it remains to be shown whether such high-frequency bursts can transmit temporally coded information from MFs to PCs and/or whether these patterns of activity contribute to the spatiotemporal filtering properties of the GrC layer. Here, we show that, upon sensory stimulation in both un-anesthetized rabbits and mice, GrCs can show bursts that consist of tens of spikes at instantaneous frequencies over 800 Hz. In vitro recordings from individual GrC-PC pairs following high-frequency stimulation revealed an overall low initial release probability of ~0.17. Nevertheless, high frequency burst activity induced a short-lived facilitation to ensure signaling within the first few spikes, which was rapidly followed by a reduction in transmitter release. The facilitation rate among individual GrC-PC pairs was heterogeneously distributed and could be classified as either "reluctant" or "responsive" according to their release characteristics. Despite the variety of efficacy at individual connections, grouped activity in GrCs resulted in a linear relationship between PC response and PF burst duration at frequencies up to 300 Hz allowing rate coding to persist at the network level. Together, these findings support the hypothesis that the cerebellar granular layer acts as a spatiotemporal filter between MF input and PC output (D'Angelo and De Zeeuw, 2009). PMID- 23734103 TI - Aversive cues fail to activate fos expression in the asymmetric olfactory habenula pathway of zebrafish. AB - The dorsal habenular nuclei of the zebrafish epithalamus have become a valuable model for studying the development of left-right (L-R) asymmetry and its function in the vertebrate brain. The bilaterally paired dorsal habenulae exhibit striking differences in size, neuroanatomical organization, and molecular properties. They also display differences in their efferent connections with the interpeduncular nucleus (IPN) and in their afferent input, with a subset of mitral cells distributed on both sides of the olfactory bulb innervating only the right habenula. Previous studies have implicated the dorsal habenulae in modulating fear/anxiety responses in juvenile and adult zebrafish. It has been suggested that the asymmetric olfactory-habenula pathway (OB-Ha), revealed by selective labeling from an lhx2a:YFP transgene, mediates fear behaviors elicited by alarm pheromone. Here we show that expression of the fam84b gene demarcates a unique region of the right habenula that is the site of innervation by lhx2a:YFP-labeled olfactory axons. Upon ablation of the parapineal, which normally promotes left habenular identity; the fam84b domain is present in both dorsal habenulae and lhx2a:YFP-labeled olfactory bulb neurons form synapses on the left and the right side. To explore the relevance of the asymmetric olfactory projection and how it might influence habenular function, we tested activation of this pathway using odorants known to evoke behaviors. We find that alarm substance or other aversive odors, and attractive cues, activate fos expression in subsets of cells in the olfactory bulb but not in the lhx2a:YFP expressing population. Moreover, neither alarm pheromone nor chondroitin sulfate elicited fos activation in the dorsal habenulae. The results indicate that L-R asymmetry of the epithalamus sets the directionality of olfactory innervation, however, the lhx2a:YFP OB-Ha pathway does not appear to mediate fear responses to aversive odorants. PMID- 23734104 TI - Ultrastructural examination of the corticocollicular pathway in the guinea pig: a study using electron microscopy, neural tracers, and GABA immunocytochemistry. AB - Projections from auditory cortex (AC) can alter the responses of cells in the inferior colliculus (IC) to sounds. Most IC cells show excitation and inhibition after stimulation of the AC. AC axons release glutamate and excite their targets, so inhibition is presumed to result from cortical activation of GABAergic IC cells that inhibit other IC cells via local projections. However, it is not known whether cortical axons contact GABAergic IC cells directly. We labeled corticocollicular axons by injecting fluorescent dextrans into the AC in guinea pigs. We visualized the tracer with diaminobenzidine and processed the tissue for electron microscopy. We identified presumptive GABAergic profiles with post embedding anti-GABA immunogold histochemistry on ultrathin sections. We identified dextran-labeled cortical boutons in the IC and identified their postsynaptic targets according to morphology (e.g., spine, dendrite) and GABA reactivity. Cortical synapses were observed in all IC subdivisions, but were comparatively rare in the central nucleus. Cortical boutons contain round vesicles and few mitochondria. They form asymmetric synapses with spines (most frequently), dendritic shafts and, least often, with cell bodies. Excitatory boutons in the IC can be classified as large, medium or small; most cortical boutons belong to the small excitatory class, while a minority (~14%) belong to the medium excitatory class. Approximately 4% of the cortical targets were GABA positive; these included dendritic shafts, spines, and cell bodies. We conclude that the majority of cortical boutons contact non-GABAergic (i.e., excitatory) IC cells and a small proportion (4%) contact GABAergic cells. Given that most IC cells show inhibition (as well as excitation) after cortical stimulation, it is likely that the majority of cortically-driven inhibition in the IC results from cortical activation of a relatively small number of IC GABAergic cells that have extensive local axons. PMID- 23734105 TI - Modulation of firing and synaptic transmission of serotonergic neurons by intrinsic G protein-coupled receptors and ion channels. AB - Serotonergic neurons project to virtually all regions of the central nervous system and are consequently involved in many critical physiological functions such as mood, sexual behavior, feeding, sleep/wake cycle, memory, cognition, blood pressure regulation, breathing, and reproductive success. Therefore, serotonin release and serotonergic neuronal activity have to be precisely controlled and modulated by interacting brain circuits to adapt to specific emotional and environmental states. We will review the current knowledge about G protein-coupled receptors and ion channels involved in the regulation of serotonergic system, how their regulation is modulating the intrinsic activity of serotonergic neurons and its transmitter release and will discuss the latest methods for controlling the modulation of serotonin release and intracellular signaling in serotonergic neurons in vitro and in vivo. PMID- 23734109 TI - Memories of the future: new insights into the adaptive value of episodic memory. PMID- 23734108 TI - Environmental enrichment protects against functional deficits caused by traumatic brain injury. AB - Environmental enrichment (EE) increases cortical weight, neuronal density, dendritic branching, and angiogenesis, all of which may be critical for functional recovery following insult. Our study was designed to determine possible benefits of pre-exposure to EE in preventing functional deficits following traumatic brain injury (TBI) to the prefrontal cortex. To examine the benefit of EE, adult male rats were placed in an enriched environment for 15 days. Enrichment was provided through social interaction, exercise, olfactory stimulation, and new objects/toys to explore. Following enrichment, experimental and age-matched controls were subjected to a moderate medial prefrontal cortex injury via controlled cortical impact (CCI). After 1 week recovery, animals were behaviorally tested to assess memory, anxiety, and sensory neglect. Lesion induced deficits in spatial memory [Morris water maze (MWM)] were significantly attenuated in EE pre-exposed rats 18-21 days following injury. In addition, TBI induced sensory neglect was significantly reduced in EE rats relative to non enriched animals. No differences in anxiety-like behavior on the elevated plus maze (EPM) were detected. The behavioral data suggest that EE is neuroprotective when applied prior to TBI, resulting in improved recovery following injury. PMID- 23734107 TI - Don't be Too Strict with Yourself! Rigid Negative Self-Representation in Healthy Subjects Mimics the Neurocognitive Profile of Depression for Autobiographical Memory. AB - Autobiographical memory (AM) comprises representation of both specific (episodic) and generic (semantic) personal information. Depression is characterized by a shift from episodic to semantic AM retrieval. According to theoretical models, this process ("overgeneralization"), would be linked to reduced executive resources. Moreover, "overgeneral" memories, accompanied by a negativity bias in depression, lead to a pervasive negative self-representation. As executive functions and AM specificity are also closely intricate among "non-clinical" populations, "overgeneral" memories could result in depressive emotional responses. Consequently, our hypothesis was that the neurocognitive profile of healthy subjects showing a rigid negative self-image would mimic that of patients. Executive functions and self-image were measured and brain activity was recorded, by means of fMRI, during episodic AMs retrieval in young healthy subjects. The results show an inverse correlation, that is, a more rigid and negative self-image produces lower performances in both executive and specific memories. Moreover, higher negative self-image is associated with decreased activity in the left ventro-lateral prefrontal and in the anterior cingulate cortex, repeatedly shown to exhibit altered functioning in depression. Activity in these regions, on the contrary, positively correlates with executive and memory performances, in line with their role in executive functions and AM retrieval. These findings suggest that rigid negative self-image could represent a marker or a vulnerability trait of depression by being linked to reduced executive function efficiency and episodic AM decline. These results are encouraging for psychotherapeutic approaches aimed at cognitive flexibility in depression and other psychiatric disorders. PMID- 23734106 TI - Episodic memories and their relevance for psychoactive drug use and addiction. AB - The majority of adult people in western societies regularly consume psychoactive drugs. While this consumption is integrated in everyday life activities and controlled in most consumers, it may escalate and result in drug addiction. Non addicted drug use requires the systematic establishment of highly organized behaviors, such as drug-seeking and -taking. While a significant role for classical and instrumental learning processes is well established in drug use and abuse, declarative drug memories have largely been neglected in research. Episodic memories are an important part of the declarative memories. Here a role of episodic drug memories in the establishment of non-addicted drug use and its transition to addiction is suggested. In relation to psychoactive drug consumption, episodic drug memories are formed when a person prepares for consumption, when the drug is consumed and, most important, when acute effects, withdrawal, craving, and relapse are experienced. Episodic drug memories are one trial memories with emotional components that can be much stronger than "normal" episodic memories. Their establishment coincides with drug-induced neuronal activation and plasticity. These memories may be highly extinction resistant and influence psychoactive drug consumption, in particular during initial establishment and at the transition to "drug instrumentalization." In that, understanding how addictive drugs interact with episodic memory circuits in the brain may provide crucial information for how drug use and addiction are established. PMID- 23734110 TI - Reward-based behaviors and emotional processing in human with narcolepsy cataplexy. AB - Major advances in the past decade have led a better understanding of the pathophysiology of narcolepsy with cataplexy (NC) caused by the early loss of hypothalamic hypocretin neurons. Although a role for hypocretin in the regulation of sleep/wakefulness state is widely recognized, other functions, not necessarily related to arousal, have been identified. Hence, the hypocretin system enhances signaling in the mesolimbic pathways regulating reward processing, emotion and mood regulation, and addiction. Although studies on hypocretin-deficient mice have shown that hypocretin plays an essential role in reward-seeking, depression like behavior and addiction, results in human narcolepsy remained subject to debate. Most of studies revealed that hypocretin-deficient narcolepsy patients either drug-free or medicated with psychostimulant had preferences toward risky choices in a decision-making task under ambiguity together with higher frequency of depressive symptoms and binge eating disorder compared to controls. However, human studies mostly reported the lack of association with pathological impulsivity and gambling, and substance and alcohol abuse in the context of narcolepsy-cataplexy. Prospective larger studies are required to confirm these findings in drug-free and medicated patients with narcolepsy. Inclusion of patients with other central hypersomnias without hypocretin deficiency will provide answer to the major question of the role of the hypocretin system in reward-based behaviors and emotional processing in humans. PMID- 23734112 TI - The role of empathy in choosing rewards from another's perspective. AB - As social animals, we regularly act in the interest of others by making decisions on their behalf. These decisions can take the form of choices between smaller short-term rewards and larger long-term rewards, and can be effectively indexed by temporal discounting (TD). In a TD paradigm, a reward loses subjective value with increasing delay presumably because it becomes more difficult to simulate how much the recipient (e.g., future self) will value it. If this is the case, then the value of delayed rewards should be discounted even more steeply when we are choosing for someone whose feelings we do not readily simulate, such as socially distant strangers. Second, the ability to simulate shows individual differences and is indexed by trait empathy. We hypothesized that individuals high in trait empathy will more readily simulate, and hence discount less steeply for distant others, compared to those who are low on trait empathy. To test these predictions, we asked 63 participants from the general population to perform a TD task from the perspectives of close and distant others, as well as their own. People were found to discount less steeply for themselves, and the steepness of TD increased with increasing distance from self. Additionally, individuals who scored high in trait empathy were found to discount less steeply for distant others compared to those who scored low. These findings confirm the role of empathy in determining how we choose rewards for others. PMID- 23734111 TI - Hippocampal signatures of episodic memory: evidence from single-unit recording studies. AB - What hippocampal neural firing patterns signal memory and, more importantly, how is this memory code used by associated structures to translate a memory into a decision or action? Candidate hippocampal activity patterns will be discussed including (1) trajectory-specific firing of place cells with place fields on an overlapping segment of two (or more) distinct trajectories (2) prospective firing of hippocampal neurons that signal an upcoming event or action, and (3) place cell remapping to changes in environment and task. To date, there has not been compelling evidence for any of these activity patterns being the neural substrate of episodic memory. New findings suggest that learning and memory processes are emergent properties of interregional interactions and not localized within any one discrete brain region. Therefore, the next step in understanding how remapping and trajectory coding participate in memory coding may be to investigate how these activity patterns relate to activity in anatomically connected structures such as the prefrontal cortex. PMID- 23734113 TI - Exploring sarcasm detection in amyotrophic lateral sclerosis using ecologically valid measures. AB - Amyotrophic lateral sclerosis (ALS) is a rapidly progressive condition involving degeneration of both upper and lower motor neurons. Recent research suggests that a proportion of persons with ALS show a profile similar to that of frontotemporal dementia (FTD), with this group of ALS patients exhibiting social cognitive deficits. Although social cognitive deficits have been partially explored in ALS, research has yet to investigate such changes using ecologically valid measures. Therefore, this study aimed to further characterize the scope of social cognitive and emotion recognition deficits in non-demented ALS patients using an ecologically valid measure of social cognition. A sample of 35 ALS patients and 30 age-and-education matched controls were assessed using the Addenbrooke's Cognitive Examination, the Brixton Spatial Anticipation Test, and The Awareness of Social Inference Test, where participants were required to discriminate between various emotions and decipher socially challenging scenarios enacted in video vignettes. Participants with ALS showed significant difficulties in recognizing both sarcastic and paradoxical sarcastic statements, but not sincere statements, when compared to controls. After controlling for executive difficulties, ALS patients still displayed significant difficulties on tasks that assessed their comprehension of both sarcastic and paradoxical sarcastic statements. The inability to read social cues and make social inferences has the potential to place significant strain on familial/interpersonal relationships in ALS. The findings of this study highlight the importance of employing a broader range of neuropsychological assessment tools to aid in early detection of frontal lobe impairment in non-demented ALS patients. PMID- 23734114 TI - The influence of APOE and TOMM40 polymorphisms on hippocampal volume and episodic memory in old age. AB - Mitochondrial dysfunction is implicated in neurodegenerative disorders, such as Alzheimer's disease (AD). Translocase of outer mitochondrial membrane 40 (TOMM40) may be influential in this regard by influencing mitochondrial neurotoxicity. Little is known about the influence of the TOMM40 gene on hippocampal (HC) volume and episodic memory (EM), particularly in healthy older adults. Thus, we sought to discern the influence of TOMM40 single nucleotide polymorphisms (SNPs), which have previously been associated with medial temporal lobe integrity (rs11556505 and rs2075650), on HC volume and EM. The study sample consisted of individuals from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) who were free of dementia and known neurological disorders, and 60-87 years of age (n = 424). EM was measured by using a 16-item word list with a 2-min free recall period and delineation of the HC was performed manually. The influence of Apolipoprotein E (APOE) and TOMM40 was assessed by 2 * 2 ANOVAs and partial correlations. There was no effect of APOE and TOMM40 on EM performance and HC volume. However, partial correlations revealed that HC volume was positively associated with free recall performance (r = 0.21, p < 0.01, r (2) = 0.04). When further stratified for TOMM40, the observed association between HC volume and free recall in APOE epsilon4 carriers was present in combination with TOMM40 rs11556505 any T (r = 0.28, p < 0.01, R (2) = 0.08) and rs2075650 any G (r = 0.28, p < 0.01, R (2) = 0.08) "risk" alleles. This pattern might reflect higher reliance on HC volume for adequate EM performance among APOE epsilon4 carriers with additional TOMM40 "risk" alleles suggesting that the TOMM40 gene cannot merely be considered a marker of APOE genotype. Nevertheless, neither APOE nor TOMM40 influenced HC volume or EM in this population-based sample of cognitively intact individuals over the age of 60. PMID- 23734115 TI - Paying attention to orthography: a visual evoked potential study. AB - In adult readers, letters, and words are rapidly identified within visual networks to allow for efficient reading abilities. Neuroimaging studies of orthography have mostly used words and letter strings that recruit many hierarchical levels in reading. Understanding how single letters are processed could provide further insight into orthographic processing. The present study investigated orthographic processing using single letters and pseudoletters when adults were encouraged to pay attention to or away from orthographic features. We measured evoked potentials (EPs) to single letters and pseudoletters from adults while they performed an orthographic-discrimination task (letters vs. pseudoletters), a color-discrimination task (red vs. blue), and a target detection task (respond to #1 and #2). Larger and later peaking N1 responses (~170 ms) and larger P2 responses (~250 ms) occurred to pseudoletters as compared to letters. This reflected greater visual processing for pseudoletters. Dipole analyses localized this effect to bilateral fusiform and inferior temporal cortices. Moreover, this letter-pseudoletter difference was not modulated by task and thus indicates that directing attention to or away from orthographic features did not affect early visual processing of single letters or pseudoletters within extrastriate regions. Paying attention to orthography or color as compared to disregarding the stimuli (target-detection task) elicited selection negativities at about 175 ms, which were followed by a classical N2-P3 complex. This indicated that the tasks sufficiently drew participant's attention to and away from the stimuli. Together these findings revealed that visual processing of single letters and pseudoletters, in adults, appeared to be sensory-contingent and independent of paying attention to stimulus features (e.g., orthography or color). PMID- 23734116 TI - Still feeling it: the time course of emotional recovery from an attentional perspective. AB - Emotional reactivity and the time taken to recover, particularly from negative, stressful, events, are inextricably linked, and both are crucial for maintaining well-being. It is unclear, however, to what extent emotional reactivity during stimulus onset predicts the time course of recovery after stimulus offset. To address this question, 25 participants viewed arousing (negative and positive) and neutral pictures from the International Affective Picture System (IAPS) followed by task-relevant face targets, which were to be gender categorized. Faces were presented early (400-1500 ms) or late (2400-3500 ms) after picture offset to capture the time course of recovery from emotional stimuli. Measures of reaction time (RT), as well as face-locked N170 and P3 components were taken as indicators of the impact of lingering emotion on attentional facilitation or interference. Electrophysiological effects revealed negative and positive images to facilitate face-target processing on the P3 component, regardless of temporal interval. At the individual level, increased reactivity to: (1) negative pictures, quantified as the IAPS picture-locked Late Positive Potential (LPP), predicted larger attentional interference on the face-locked P3 component to faces presented in the late time window after picture offset. (2) Positive pictures, denoted by the LPP, predicted larger facilitation on the face-locked P3 component to faces presented in the earlier time window after picture offset. These results suggest that subsequent processing is still impacted up to 3500 ms after the offset of negative pictures and 1500 ms after the offset of positive pictures for individuals reacting more strongly to these pictures, respectively. Such findings emphasize the importance of individual differences in reactivity when predicting the temporality of emotional recovery. The current experimental model provides a novel basis for future research aiming to identify profiles of adaptive and maladaptive recovery. PMID- 23734117 TI - Effects of individual glucose levels on the neuronal correlates of emotions. AB - This study aimed to directly assess the effect of changes in blood glucose levels on the psychological processing of emotionally charged material. We used functional magnetic resonance imaging (fMRI) to evaluate the effect of blood glucose levels on three categories of visually presented emotional stimuli. Seventeen healthy young subjects participated in this study (eight females; nine males; body weight, 69.3 +/- 14.9 kg; BMI, 22 +/- 2.7; age, 24 +/- 3 years), consisting of two functional MRI sessions: (1) after an overnight fast under resting conditions (before glucose administration); (2) after reaching the hyperglycemic state (after glucose administration). During each session, subjects were presented with visual stimuli featuring funny, neutral, and sad content. Single-subject ratings of the stimuli were used to verify the selection of stimuli for each category and were covariates for the fMRI analysis. Analysis of the interaction effect of the two sessions (eu- and hyperglycemia), and the emotional categories accounting for the single-subject glucose differences, revealed a single activation cluster in the hypothalamus. Analysis of the activation profile of the left amygdala corresponded to the three emotional conditions, and this profile was obtained for both sessions regardless of glucose level. Our results indicate that, in a hyperglycemic state, the hypothalamus can no longer respond to emotions. This study offers novel insight for the understanding of disease-related behavior associated with dysregulation of glucose and glucose availability, potentially offering improved diagnostic and novel therapeutic strategies in the future. PMID- 23734118 TI - Through the looking glass: self-reassuring meta-cognitive capacity and its relationship with the thematic content of voices. AB - AIMS: To examine the self-critical thoughts and self-reassuring meta-cognitive capacity of those who hear voices and explore whether they are associated with the theme of voice content and appraisals of voice power and voice expressed emotion. METHOD: A cross-sectional design was used, combining semi-structured interviews and self-report measures. Data on symptomatology, self-critical thoughts and self-reassuring meta-cognitive capacity, thematic voice content, and appraisals of voice power and expressed emotion were collected from 74 voice hearers in Birmingham, UK. RESULTS: Common themes of voice content reflected issues of shame, control, and affiliation. Controlling content was the most prevalent theme, however, no significant predictor of this theme was found; shaming thematic voice content linked with reduced capacity to self-reassure following self-critical thoughts. Voice-hearers with the greatest level of self critical thoughts appraised their voices as powerful and high in voice expressed emotion. CONCLUSIONS: Findings suggest that voice-hearers self-critical thoughts are reflected in the type of relationship they have with their voice. However, access to self-reassuring meta-cognitive capacity may serve as a protective factor for those who hear voices, resulting in more benign voice content. These findings highlight the importance of this specific meta-cognitive capacity and will inform future therapeutic interventions for the management of voices in this vulnerable group. PMID- 23734119 TI - Time course based artifact identification for independent components of resting state FMRI. AB - In functional magnetic resonance imaging (fMRI) coherent oscillations of the blood oxygen level-dependent (BOLD) signal can be detected. These arise when brain regions respond to external stimuli or are activated by tasks. The same networks have been characterized during wakeful rest when functional connectivity of the human brain is organized in generic resting-state networks (RSN). Alterations of RSN emerge as neurobiological markers of pathological conditions such as altered mental state. In single-subject fMRI data the coherent components can be identified by blind source separation of the pre-processed BOLD data using spatial independent component analysis (ICA) and related approaches. The resulting maps may represent physiological RSNs or may be due to various artifacts. In this methodological study, we propose a conceptually simple and fully automatic time course based filtering procedure to detect obvious artifacts in the ICA output for resting-state fMRI. The filter is trained on six and tested on 29 healthy subjects, yielding mean filter accuracy, sensitivity and specificity of 0.80, 0.82, and 0.75 in out-of-sample tests. To estimate the impact of clearly artifactual single-subject components on group resting-state studies we analyze unfiltered and filtered output with a second level ICA procedure. Although the automated filter does not reach performance values of visual analysis by human raters, we propose that resting-state compatible analysis of ICA time courses could be very useful to complement the existing map or task/event oriented artifact classification algorithms. PMID- 23734120 TI - Cortical oxygen consumption in mental arithmetic as a function of task difficulty: a near-infrared spectroscopy approach. AB - The present study investigated changes in cortical oxygenation during mental arithmetic using near-infrared spectroscopy (NIRS). Twenty-nine male volunteers were examined using a 52-channel continuous wave system for analyzing activity in prefrontal areas. With the help of a probabilistic mapping method, three regions of interest (ROIs) on each hemisphere were defined: The inferior frontal gyri (IFG), the middle frontal gyri (MFG), and the superior frontal gyri (SFG). Oxygenation as an indicator of functional brain activation was compared over the three ROI and two levels of arithmetic task difficulty (simple and complex additions). In contrast to most previous studies using fMRI or NIRS, in the present study arithmetic tasks were presented verbally in analogue to many daily life situations. With respect to task difficulty, more complex addition tasks led to higher oxygenation in all defined ROI except in the left IFG compared to simple addition tasks. When compared to the channel positions covering different gyri of the temporal lobe, the observed sensitivity to task complexity was found to be restricted to the specified ROIs. As to the comparison of ROIs, the highest oxygenation was found in the IFG, while MFG and SFG showed significantly less activation compared to IFG. The present cognitive-neuroscience approach demonstrated that NIRS is a suitable and highly feasible research tool for investigating and quantifying neural effects of increasing arithmetic task difficulty. PMID- 23734121 TI - Interpersonal motor resonance in autism spectrum disorder: evidence against a global "mirror system" deficit. AB - The mirror neuron hypothesis of autism is highly controversial, in part because there are conflicting reports as to whether putative indices of mirror system activity are actually deficient in autism spectrum disorder (ASD). Recent evidence suggests that a typical putative mirror system response may be seen in people with an ASD when there is a degree of social relevance to the visual stimuli used to elicit that response. Individuals with ASD (n = 32) and matched neurotypical controls (n = 32) completed a transcranial magnetic stimulation (TMS) experiment in which the left primary motor cortex (M1) was stimulated during the observation of static hands, individual (i.e., one person) hand actions, and interactive (i.e., two person) hand actions. Motor-evoked potentials (MEP) were recorded from the contralateral first dorsal interosseous, and used to generate an index of interpersonal motor resonance (IMR; a putative measure of mirror system activity) during action observation. There was no difference between ASD and NT groups in the level of IMR during the observation of these actions. These findings provide evidence against a global mirror system deficit in ASD, and this evidence appears to extend beyond stimuli that have social relevance. Attentional and visual processing influences may be important for understanding the apparent role of IMR in the pathophysiology of ASD. PMID- 23734122 TI - Recollection, familiarity, and content-sensitivity in lateral parietal cortex: a high-resolution fMRI study. AB - Numerous studies have identified brain regions where activity is consistently correlated with the retrieval (recollection) of qualitative episodic information. This 'core recollection network' can be contrasted with regions where activity differs according to the contents of retrieval. The present study used high resolution fMRI to investigate whether these putatively-distinct retrieval processes engage common versus dissociable regions. Subjects studied words with two encoding tasks and then performed a memory test in which they distinguished between recollection and different levels of recognition confidence. The fMRI data from study and test revealed several overlapping regions where activity differed according to encoding task, suggesting that content was selectively reinstated during retrieval. The majority of recollection-related regions, though, did not exhibit reinstatement effects, providing support for a core recollection network. Importantly, lateral parietal cortex demonstrated a clear dissociation, whereby recollection effects were localized to angular gyrus and confidence effects were restricted to intraparietal sulcus. Moreover, the latter region exhibited a non-monotonic pattern, consistent with a neural signal reflecting item familiarity rather than a generic form of memory strength. Together, the findings show that episodic retrieval relies on both content sensitive and core recollective processes, and these can be differentiated from familiarity-based recognition memory. PMID- 23734123 TI - Indicators of implicit and explicit social anxiety influence threat-related interpretive bias as a function of working memory capacity. AB - Interpretive biases play a crucial role in anxiety disorders. The aim of the current study was to examine factors that determine the relative strength of threat-related interpretive biases that are characteristic of individuals high in social anxiety. Different (dual process) models argue that both implicit and explicit processes determine information processing biases and behavior, and that their impact is moderated by the availability of executive resources such as working memory capacity (WMC). Based on these models, we expected indicators of implicit social anxiety to predict threat-related interpretive bias in individuals low, but not high in WMC. Indicators of explicit social anxiety should predict threat-related interpretive bias in individuals high, but not low in WMC. As expected, WMC moderated the impact of implicit social anxiety on threat-related interpretive bias, although the simple slope for individuals low in WMC was not statistically significant. The hypotheses regarding explicit social anxiety (with fear of negative evaluation used as an indicator) were fully supported. The clinical implications of these findings are discussed. PMID- 23734125 TI - The neural decoding toolbox. AB - Population decoding is a powerful way to analyze neural data, however, currently only a small percentage of systems neuroscience researchers use this method. In order to increase the use of population decoding, we have created the Neural Decoding Toolbox (NDT) which is a Matlab package that makes it easy to apply population decoding analyses to neural activity. The design of the toolbox revolves around four abstract object classes which enables users to interchange particular modules in order to try different analyses while keeping the rest of the processing stream intact. The toolbox is capable of analyzing data from many different types of recording modalities, and we give examples of how it can be used to decode basic visual information from neural spiking activity and how it can be used to examine how invariant the activity of a neural population is to stimulus transformations. Overall this toolbox will make it much easier for neuroscientists to apply population decoding analyses to their data, which should help increase the pace of discovery in neuroscience. PMID- 23734124 TI - Distinct Thalamo-Cortical Controls for Shoulder, Elbow, and Wrist during Locomotion. AB - Recent data from this laboratory on differential controls for the shoulder, elbow, and wrist exerted by the thalamo-cortical network during locomotion is presented, based on experiments involving chronically instrumented cats walking on a flat surface and along a horizontal ladder. The activity of the following three groups of neurons is characterized: (1) neurons of the motor cortex that project to the pyramidal tract (PTNs), (2) neurons of the ventrolateral thalamus (VL), many identified as projecting to the motor cortex (thalamo-cortical neurons, TCs), and (3) neurons of the reticular nucleus of thalamus (RE), which inhibit TCs. Neurons were grouped according to their receptive field into shoulder-, elbow-, and wrist/paw-related categories. During simple locomotion, shoulder-related PTNs were most active in the late stance and early swing, and on the ladder, often increased activity and stride-related modulation while reducing discharge duration. Elbow-related PTNs were most active during late swing/early stance and typically remained similar on the ladder. Wrist-related PTNs were most active during swing, and on the ladder often decreased activity and increased modulation while reducing discharge duration. In the VL, shoulder-related neurons were more active during the transition from swing-to-stance. Elbow-related cells tended to be more active during the transition from stance-to-swing and on the ladder often decreased their activity and increased modulation. Wrist-related neurons were more active throughout the stance phase. In the RE, shoulder-related cells had low discharge rates and depths of modulation and long periods of activity distributed evenly across the cycle. In sharp contrast, wrist/paw related cells discharged synchronously during the end of stance and swing with short periods of high activity, high modulation, and frequent sleep-type bursting. We conclude that thalamo-cortical network processes information related to different segments of the forelimb differently and exerts distinct controls over the shoulder, elbow, and wrist during locomotion. PMID- 23734126 TI - An evaluation of a working memory training scheme in older adults. AB - Working memory is a cognitive process that is particularly vulnerable to decline with age. The current study sought to evaluate the efficacy of a working memory training scheme in improving memory in a group of older adults. A 5-week online training scheme was designed to provide training in the main components of Baddeley's (2000) working memory model, namely auditory and visuospatial short term and working memory. A group of older adults aged between 64 and 79 were randomly assigned to a trainee (n = 19) or control (n = 17) group, with trainees engaging in the adaptive training scheme and controls engaging in a non-adaptive version of the program. Before and after training and at 3- and 6-month follow-up sessions, trainees and controls were asked to complete measures of short-term and working memory, long-term episodic memory, subjective ratings of memory, and attention and achievement of goals set at the beginning of training. The results provided evidence of an expansion of auditory short-term memory span, which was maintained 6 months later, and transfer to long-term episodic memory but no evidence of improvement in working memory capacity per se. A serendipitous and intriguing finding of a relationship between time spent training, psychological stress, and training gains provided further insight into individual differences in training gains in older adults. PMID- 23734127 TI - Editorial on research topic: aldo-keto reductases and role in human disease. PMID- 23734128 TI - Burden of Friedreich's Ataxia to the Patients and Healthcare Systems in the United States and Canada. AB - OBJECTIVE: The study intended to substantiate healthcare resource utilization, costs, and funding patterns of US and Canadian Friedreich's Ataxia (FRDA) populations, to assess compliance with treatment guidance and to identify areas where novel healthcare measures or improved access to existing care may improve patients' functional and social capabilities and reduce the financial impact on the healthcare systems. METHODS: Healthcare resource utilization and costs were collected in a cross-sectional study in the US (N = 197) and Canada (N = 43) and analyzed across severity of disease categories. Descriptive statistics, correlation analysis, and hypothesis testing were applied. RESULTS: In the US, healthcare costs of FRDA patients were higher than those of "adults with two and more chronic conditions." Significantly higher costs were incurred in advanced stages of the disease, with paid homecare being the main driver. This pattern was also observed in Canada. Compliance with the recommended annual neurological and cardiological follow-up was high, but was low for the recommended regular speech therapy. In the US public and private funding ratios were similar for the FRDA and the general populations. In Canada the private funding ratio for FRDA was higher than average. CONCLUSION: The variety of healthcare measures addressing the broad range of symptoms of FRDA, and the increasing use of paid home care as disease progresses made total US healthcare costs of FRDA exceed the costs of US adults with two and more chronic conditions. Therefore, measures delaying disease progression will allow patients to maintain their independence longer and may reduce costs to the healthcare system. Novel measures to address dysarthria and to ensure access to them should be further investigated. The higher than average private funding ratio in Canada was due to the relatively high cost of the pharmacological treatment of FRDA. PMID- 23734129 TI - Interfering amino terminal peptides and functional implications for heteromeric gap junction formation. AB - Connexin43 (Cx43) is widely expressed in many different tissues of the human body. In cells of some organs, Cx43 is co-expressed with other connexins (Cx), including Cx46 and Cx50 in lens, Cx40 in atrium, Purkinje fibers, and the blood vessel wall, Cx45 in heart, and Cx37 in the ovary. Interactions with the co expressed connexins may have profound functional implications. The abilities of Cx37, Cx45, Cx46, and Cx50 to function in heteromeric gap junction combinations with Cx43 are well documented. Different studies disagree regarding the ability of Cx43 and Cx40 to produce functional heteromeric gap junctions with each other. We review previous studies regarding the heteromeric interactions of Cx43. The possibility of negative functional interactions between the cytoplasmic pore forming amino-terminal (NT) domains of these connexins was assessed using pentameric connexin sequence-specific NT domain [interfering NT (iNT)] peptides applied to cells expressing homomeric Cx40, Cx37, Cx45, Cx46, and Cx50 gap junctions. A Cx43 iNT peptide corresponding to amino acids 9-13 (Ac-KLLDK-NH2) specifically inhibited the electrical coupling of Cx40 gap junctions in a transjunctional voltage (V j)-dependent manner without affecting the function of homologous Cx37, Cx46, Cx50, and Cx45 gap junctions. A Cx40 iNT (Ac-EFLEE-OH) peptide counteracted the V j-dependent block of Cx40 gap junctions, whereas a similarly charged Cx50 iNT (Ac-EEVNE-OH) peptide did not, suggesting that these NT domain interactions are not solely based on electrostatics. These data are consistent with functional Cx43 heteromeric gap junction formation with Cx37, Cx45, Cx46, and Cx50 and suggest that Cx40 uniquely experiences functional suppressive interactions with a Cx43 NT domain sequence. These findings present unique functional implications about the heteromeric interactions between Cx43 and Cx40 that may influence cardiac conduction in atrial myocardium and the specialized conduction system. PMID- 23734131 TI - Should we train alcohol-dependent patients to avoid alcohol? PMID- 23734130 TI - How to assess performance in cycling: the multivariate nature of influencing factors and related indicators. AB - Finding an optimum for the cycling performance is not a trivial matter, since the literature shows the presence of many controversial aspects. In order to quantify different levels of performance, several indexes have been defined and used in many studies, reflecting variations in physiological and biomechanical factors. In particular, indexes such as Gross Efficiency (GE), Net Efficiency (NE) and Delta Efficiency (DE) have been referred to changes in metabolic efficiency (EffMet), while the Indexes of Effectiveness (IE), defined over the complete crank revolution or over part of it, have been referred to variations in mechanical effectiveness (EffMech). All these indicators quantify the variations of different factors [i.e., muscle fibers type distribution, pedaling cadence, setup of the bicycle frame, muscular fatigue (MFat), environmental variables, ergogenic aids, psychological traits (PsychTr)], which, moreover, show high mutual correlation. In the attempt of assessing cycling performance, most studies in the literature keep all these factors separated. This may bring to misleading results, leaving unanswered the question of how to improve cycling performance. This work provides an overview on the studies involving indexes and factors usually related to performance monitoring and assessment in cycling. In particular, in order to clarify all those aspects, the mutual interactions among these factors are highlighted, in view of a global performance assessment. Moreover, a proposal is presented advocating for a model-based approach that considers all factors mentioned in the survey, including the mutual interaction effects, for the definition of an objective function E representing the overall effectiveness of a training program in terms of both EffMet and EffMech. PMID- 23734132 TI - Aging and audio-visual and multi-cue integration in motion. AB - The perception of naturalistic events relies on the ability to integrate information from multiple sensory systems, an ability that may change with healthy aging. When two objects move toward and then past one another, their trajectories are perceptually ambiguous: the objects may seem to stream past one another or bounce off one another. Previous research showed that auditory or visual events that occur at the time of disks' coincidence could bias the percept toward bouncing or streaming. We exploited this malleable percept to assay age related changes in the integration of multiple inter- and intra-modal cues. The disks' relative luminances were manipulated to produce stimuli strongly favoring either bouncing or streaming, or to produce ambiguous motion (equal luminances). A sharp sound coincident with the disks' overlap increased both groups' perception of bouncing, but did so significantly less for older subjects. An occluder's impact on motion perception varied with its duration: a long duration occluder promoted streaming in both groups; a brief occluder promoted bouncing in younger subjects, but not older ones. Control experiments demonstrated that the observed differences between younger and older subjects resulted from neither age related changes in retinal illuminance nor age-related changes in hearing, pointing to weakened inter- and intra-modal integration with aging. These changes could contribute to previously demonstrated age-related perceptual and memory deficits. PMID- 23734133 TI - The many faces of precision (Replies to commentaries on "Whatever next? Neural prediction, situated agents, and the future of cognitive science"). AB - An appreciation of the many roles of "precision-weighting" (upping the gain on select populations of prediction error units) opens the door to better accounts of planning and "offline simulation," makes suggestive contact with large bodies of work on embodied and situated cognition, and offers new perspectives on the "active brain". Combined with the complex affordances of language and culture, and operating against the essential backdrop of a variety of more biologically basic ploys and stratagems, the result is a maximally context-sensitive, restless, constantly self-reconfiguring architecture. PMID- 23734134 TI - Action-sentence compatibility: the role of action effects and timing. AB - Research on embodied approaches to language comprehension suggests that we understand linguistic descriptions of actions by mentally simulating these actions. Evidence is provided by the action-sentence compatibility effect (ACE) which shows that sensibility judgments for sentences are faster when the direction of the described action matches the response direction. In two experiments, we investigated whether the ACE relies on actions or on intended action effects. Participants gave sensibility judgments of auditorily presented sentences by producing an action effect on a screen at a location near the body or far from the body. These action effects were achieved by pressing a response button that was located in either the same spatial direction as the action effect, or in the opposite direction. We used a go/no-go task in which the direction of the to-be-produced action effect was either cued at the onset of each sentence (Experiment 1) or at different points in time before and after sentence onset (Experiment 2). Overall, results showed a relationship between the direction of the described action and the direction of the action effect. Furthermore, Experiment 2 indicated that depending on the timing between cue presentation and sentence onset, participants responded either faster when the direction of the described action matched the direction of the action effect (positive ACE), or slower (negative ACE). These results provide evidence that the comprehension of action sentences involves the activation of representations of action effects. Concurrently activated representations in sentence comprehension and action planning can lead to both priming and interference, which is discussed in the context of the theory of event coding. PMID- 23734136 TI - Measuring belief in conspiracy theories: the generic conspiracist beliefs scale. AB - The psychology of conspiracy theory beliefs is not yet well understood, although research indicates that there are stable individual differences in conspiracist ideation - individuals' general tendency to engage with conspiracy theories. Researchers have created several short self-report measures of conspiracist ideation. These measures largely consist of items referring to an assortment of prominent conspiracy theories regarding specific real-world events. However, these instruments have not been psychometrically validated, and this assessment approach suffers from practical and theoretical limitations. Therefore, we present the Generic Conspiracist Beliefs (GCB) scale: a novel measure of individual differences in generic conspiracist ideation. The scale was developed and validated across four studies. In Study 1, exploratory factor analysis of a novel 75-item measure of non-event-based conspiracist beliefs identified five conspiracist facets. The 15-item GCB scale was developed to sample from each of these themes. Studies 2, 3, and 4 examined the structure and validity of the GCB, demonstrating internal reliability, content, criterion-related, convergent and discriminant validity, and good test-retest reliability. In sum, this research indicates that the GCB is a psychometrically sound and practically useful measure of conspiracist ideation, and the findings add to our theoretical understanding of conspiracist ideation as a monological belief system unpinned by a relatively small number of generic assumptions about the typicality of conspiratorial activity in the world. PMID- 23734135 TI - Enhancement and suppression in the visual field under perceptual load. AB - The perceptual load theory of attention proposes that the degree to which visual distractors are processed is a function of the attentional demands of a task greater demands increase filtering of irrelevant distractors. The spatial configuration of such filtering is unknown. Here, we used steady-state visual evoked potentials (SSVEPs) in conjunction with time-domain event-related potentials (ERPs) to investigate the distribution of load-induced distractor suppression and task-relevant enhancement in the visual field. Electroencephalogram (EEG) was recorded while subjects performed a foveal go/no go task that varied in perceptual load. Load-dependent distractor suppression was assessed by presenting a contrast reversing ring at one of three eccentricities (2, 6, or 11 degrees ) during performance of the go/no-go task. Rings contrast reversed at 8.3 Hz, allowing load-dependent changes in distractor processing to be tracked in the frequency-domain. ERPs were calculated to the onset of stimuli in the load task to examine load-dependent modulation of task-relevant processing. Results showed that the amplitude of the distractor SSVEP (8.3 Hz) was attenuated under high perceptual load (relative to low load) at the most proximal (2 degrees ) eccentricity but not at more eccentric locations (6 or 11 degrees ). Task-relevant ERPs revealed a significant increase in N1 amplitude under high load. These results are consistent with a center-surround configuration of load-induced enhancement and suppression in the visual field. PMID- 23734137 TI - Accent imitation positively affects language attitudes. AB - People in conversation tend to accommodate the way they speak. It has been assumed that this tendency to imitate each other's speech patterns serves to increase liking between partners in a conversation. Previous experiments examined the effect of perceived social attractiveness on the tendency to imitate someone else's speech and found that vocal imitation increased when perceived attractiveness was higher. The present experiment extends this research by examining the inverse relationship and examines how overt vocal imitation affects attitudes. Participants listened to sentences spoken by two speakers of a regional accent (Glaswegian) of English. They vocally repeated (speaking in their own accent without imitating) the sentences spoken by a Glaswegian speaker, and subsequently imitated sentences spoken by a second Glaswegian speaker (order counterbalanced across participants). After each repeating or imitation session, participants completed a questionnaire probing the speakers' perceived power, competence, and social attractiveness. Imitating had a positive effect on the perceived social attractiveness of the speaker compared to repeating. These results are interpreted in light of Communication Accommodation Theory. PMID- 23734138 TI - Distraction and mind-wandering under load. AB - Attention research over the last several decades has provided rich insights into the determinants of distraction, including distractor characteristics, task features, and individual differences. Load Theory represented a particularly important breakthrough, highlighting the critical role of the level and nature of task-load in determining both the efficiency of distractor rejection and the stage of processing at which this occurs. However, until recently studies of distraction were restricted to those measuring rather specific forms of distraction by external stimuli which I argue that, although intended to be irrelevant, were in fact task-relevant. In daily life, attention may be distracted by a wide range of stimuli, which may often be entirely unrelated to any task being performed, and may include not only external stimuli but also internally generated stimuli such as task-unrelated thoughts. This review outlines recent research examining these more general, entirely task-irrelevant, forms of distraction within the framework of Load Theory. I discuss the relation between different forms of distraction, and the universality of load effects across different distractor types and individuals. PMID- 23734139 TI - Beyond perceptual load and dilution: a review of the role of working memory in selective attention. AB - The perceptual load and dilution models differ fundamentally in terms of the proposed mechanism underlying variation in distractibility during different perceptual conditions. However, both models predict that distracting information can be processed beyond perceptual processing under certain conditions, a prediction that is well-supported by the literature. Load theory proposes that in such cases, where perceptual task aspects do not allow for sufficient attentional selectivity, the maintenance of task-relevant processing depends on cognitive control mechanisms, including working memory. The key prediction is that working memory plays a role in keeping clear processing priorities in the face of potential distraction, and the evidence reviewed and evaluated in a meta-analysis here supports this claim, by showing that the processing of distracting information tends to be enhanced when load on a concurrent task of working memory is high. Low working memory capacity is similarly associated with greater distractor processing in selective attention, again suggesting that the unavailability of working memory during selective attention leads to an increase in distractibility. Together, these findings suggest that selective attention against distractors that are processed beyond perception depends on the availability of working memory. Possible mechanisms for the effects of working memory on selective attention are discussed. PMID- 23734141 TI - Invisible emotional expressions influence social judgments and pupillary responses of both depressed and non-depressed individuals. AB - We used filtered low spatial frequency images of facial emotional expressions (angry, fearful, happy, sad, or neutral faces) that were blended with a high frequency image of the same face but with a neutral facial expression, so as to obtain a "hybrid" face image that "masked" the subjective perception of its emotional expression. Participants were categorized in three groups of participants: healthy control participants (N = 49), recovered previously depressed (N = 79), and currently depressed individuals (N = 36), All participants were asked to rate how friendly the person in the picture looked. Simultaneously we recorded, by use of an infrared eye-tracker, their pupillary responses. We expected that depressed individuals (either currently or previously depressed) would show a negative bias and therefore rate the negative emotional faces, albeit the emotions being invisible, as more negative (i.e., less friendly) than the healthy controls would. Similarly, we expected that depressed individuals would overreact to the negative emotions and that this would result in greater dilations of the pupil's diameter than those shown by controls for the same emotions. Although we observed the expected pattern of effects of the hidden emotions on both ratings and pupillary changes, both responses did not differ significantly among the three groups of participants. The implications of this finding are discussed. PMID- 23734140 TI - Do the flash-lag effect and representational momentum involve similar extrapolations? AB - In the flash-lag effect (FLE) and in representational momentum (RM), the represented position of a moving target is displaced in the direction of motion. Effects of numerous variables on the FLE and on RM are briefly considered. In many cases, variables appear to have the same effect on the FLE and on RM, and this is consistent with a hypothesis that displacements in the FLE and in RM result from overlapping or similar mechanisms. In other cases, variables initially appear to have different effects on the FLE and on RM, but accounts reconciling those apparent differences with a hypothesis of overlapping or similar mechanisms are suggested. Given that RM is simpler and accounts for a wider range of findings (i.e., RM involves a single stimulus rather than the relationship between two stimuli, RM accounts for displacement in absolute position of a single stimulus and for differences in relative position of two stimuli), it is suggested that (at least some cases of) the FLE might be a special case of RM in which the position of the target is assessed relative to the position of another stimulus (i.e., the flashed object) rather than relative to the actual position of the target. PMID- 23734142 TI - Number without language: comparative psychology and the evolution of numerical cognition. PMID- 23734143 TI - Potential use and challenges of functional connectivity mapping in intractable epilepsy. AB - This review focuses on the use of resting-state functional magnetic resonance imaging data to assess functional connectivity in the human brain and its application in intractable epilepsy. This approach has the potential to predict outcomes for a given surgical procedure based on the pre-surgical functional organization of the brain. Functional connectivity can also identify cortical regions that are organized differently in epilepsy patients either as a direct function of the disease or through indirect compensatory responses. Functional connectivity mapping may help identify epileptogenic tissue, whether this is a single focal location or a network of seizure-generating tissues. This review covers the basics of connectivity analysis and discusses particular issues associated with analyzing such data. These issues include how to define nodes, as well as differences between connectivity analyses of individual nodes, groups of nodes, and whole-brain assessment at the voxel level. The need for arbitrary thresholds in some connectivity analyses is discussed and a solution to this problem is reviewed. Overall, functional connectivity analysis is becoming an important tool for assessing functional brain organization in epilepsy. PMID- 23734145 TI - The marine phosphorus cycle. PMID- 23734146 TI - Chronological Change of Resistance to beta-Lactams in Salmonella enterica serovar Infantis Isolated from Broilers in Japan. AB - Epidemiologic surveillance study was conducted in southern Japan to determine the antimicrobial resistance phenotypes and characterize the beta-lactamase genes and the plasmids harboring these genes in Salmonella enterica serovar Infantis (S. Infantis) isolates from broilers. Between January, 2007 and December, 2008, a total of 1,472 fecal samples were collected and examined at the Laboratory of Veterinary Public Health, Kagoshima University, Japan. In 93 (6.3%) isolates recovered, 33 (35.5%) isolates showed resistance to cefotaxime, an extended spectrum cephalosporin (ESC), conferred by TEM-20, TEM-52 and CTX-M-25 extended spectrum beta-lactamases (ESBLs). In addition to ESC-resistance, eight (8.6%) isolates exhibited resistance to cefoxitin mediated by CMY-2 AmpC beta-lactamase. Plasmid analysis and polymerase chain reaction replicon typing revealed the bla TEM-20 and bla CMY-2 genes were associated with IncP plasmids, bla TEM-52 was linked with a non-typable plasmid and bla CTX-M-25 was carried by an IncA/C plasmid. Non-beta-lactam resistance to streptomycin, sulfamethoxazole, and oxytetracycline encoded by the aadA1, sul1, and tet(A) genes, respectively, was found in 86 (92.5%) isolates. Resistance to kanamycin and ofloxacin was exhibited in 12 (12.9%) and 11 (11.8%) isolates, respectively, the former was mediated by aphA1-Iab. These data indicate that S. Infantis isolates producing ESBLs and AmpC beta-lactamase have spread among broiler farms in Japan. These data demonstrated that the incidence of ESC-resistant S. Infantis carrying bla TEM-52 remarkably increased and S. Infantis strains harboring bla CMY-2, bla TEM-20, or bla CTX-M 25 genes emerged from broilers in Japan for the first time in 2007 and 2008. PMID- 23734144 TI - Alternative Splicing of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor PAC1: Mechanisms of Fine Tuning of Brain Activity. AB - Alternative splicing of the precursor mRNA encoding for the neuropeptide receptor PAC1/ADCYAP1R1 generates multiple protein products that exhibit pleiotropic activities. Recent studies in mammals and zebrafish have implicated some of these splice isoforms in control of both cellular and body homeostasis. Here, we review the regulation of PAC1 splice variants and their underlying signal transduction and physiological processes in the nervous system. PMID- 23734147 TI - Beta-lactamase induction and cell wall metabolism in Gram-negative bacteria. AB - Production of beta-lactamases, the enzymes that degrade beta-lactam antibiotics, is the most widespread and threatening mechanism of antibiotic resistance. In the past, extensive research has focused on the structure, function, and ecology of beta-lactamases while limited efforts were placed on the regulatory mechanisms of beta-lactamases. Recently, increasing evidence demonstrate a direct link between beta-lactamase induction and cell wall metabolism in Gram-negative bacteria. Specifically, expression of beta-lactamase could be induced by the liberated murein fragments, such as muropeptides. This article summarizes current knowledge on cell wall metabolism, beta-lactam antibiotics, and beta-lactamases. In particular, we comprehensively reviewed recent studies on the beta-lactamase induction by muropeptides via two major molecular mechanisms (the AmpG-AmpR-AmpC pathway and BlrAB-like two-component regulatory system) in Gram-negative bacteria. The signaling pathways for beta-lactamase induction offer a broad array of promising targets for the discovery of new antibacterial drugs used for combination therapies. Therefore, to develop effective mitigation strategies against the widespread beta-lactam resistance, examination of the molecular basis of beta-lactamase induction by cell wall fragment is highly warranted. PMID- 23734148 TI - Away from darkness: a review on the effects of solar radiation on heterotrophic bacterioplankton activity. AB - Heterotrophic bacterioplankton are main consumers of dissolved organic matter (OM) in aquatic ecosystems, including the sunlit upper layers of the ocean and freshwater bodies. Their well-known sensitivity to ultraviolet radiation (UVR), together with some recently discovered mechanisms bacteria have evolved to benefit from photosynthetically available radiation (PAR), suggest that natural sunlight plays a relevant, yet difficult to predict role in modulating bacterial biogeochemical functions in aquatic ecosystems. Three decades of experimental work assessing the effects of sunlight on natural bacterial heterotrophic activity reveal responses ranging from high stimulation to total inhibition. In this review, we compile the existing studies on the topic and discuss the potential causes underlying these contrasting results, with special emphasis on the largely overlooked influences of the community composition and the previous light exposure conditions, as well as the different temporal and spatial scales at which exposure to solar radiation fluctuates. These intricate sunlight bacteria interactions have implications for our understanding of carbon fluxes in aquatic systems, yet further research is necessary before we can accurately evaluate or predict the consequences of increasing surface UVR levels associated with global change. PMID- 23734149 TI - The defective RNAs of Closteroviridae. AB - The family Closteroviridae consists of two genera, Closterovirus and Ampelovirus with monopartite genomes transmitted respectively by aphids and mealybugs and the Crinivirus with bipartite genomes transmitted by whiteflies. The Closteroviridae consists of more than 30 virus species, which differ considerably in their phytopathological significance. Some, like beet yellows virus and citrus tristeza virus (CTV) were associated for many decades with their respective hosts, sugar beets and citrus. Others, like the grapevine leafroll-associated ampeloviruses 1, and 3 were also associated with their grapevine hosts for long periods; however, difficulties in virus isolation hampered their molecular characterization. The majority of the recently identified Closteroviridae were probably associated with their vegetative propagated host plants for long periods and only detected through the considerable advances in dsRNA isolation and sequencing of PCR amplified replicons. Molecular characterization of CTV and several other Closteroviridae revealed that, in addition to genomic and subgenomic RNAs, infected plants contain several different subviral defective RNAs (dRNAs). The roles and biological functions of dRNAs associated with Closteroviridae remain terra incognita. PMID- 23734151 TI - Biogeochemical implications of the ubiquitous colonization of marine habitats and redox gradients by Marinobacter species. AB - The Marinobacter genus comprises widespread marine bacteria, found in localities as diverse as the deep ocean, coastal seawater and sediment, hydrothermal settings, oceanic basalt, sea-ice, sand, solar salterns, and oil fields. Terrestrial sources include saline soil and wine-barrel-decalcification wastewater. The genus was designated in 1992 for the Gram-negative, hydrocarbon degrading bacterium Marinobacter hydrocarbonoclasticus. Since then, a further 31 type strains have been designated. Nonetheless, the metabolic range of many Marinobacter species remains largely unexplored. Most species have been classified as aerobic heterotrophs, and assessed for limited anaerobic pathways (fermentation or nitrate reduction), whereas studies of low-temperature hydrothermal sediments, basalt at oceanic spreading centers, and phytoplankton have identified species that possess a respiratory repertoire with significant biogeochemical implications. Notable physiological traits include nitrate dependent Fe(II)-oxidation, arsenic and fumarate redox cycling, and Mn(II) oxidation. There is also evidence for Fe(III) reduction, and metal(loid) detoxification. Considering the ubiquity and metabolic capabilities of the genus, Marinobacter species may perform an important and underestimated role in the biogeochemical cycling of organics and metals in varied marine habitats, and spanning aerobic-to-anoxic redox gradients. PMID- 23734152 TI - Changing views of the evolution of immunity. PMID- 23734154 TI - Underwater photosynthesis of submerged plants - recent advances and methods. AB - We describe the general background and the recent advances in research on underwater photosynthesis of leaf segments, whole communities, and plant dominated aquatic ecosystems and present contemporary methods tailor made to quantify photosynthesis and carbon fixation under water. The majority of studies of aquatic photosynthesis have been carried out with detached leaves or thalli and this selectiveness influences the perception of the regulation of aquatic photosynthesis. We thus recommend assessing the influence of inorganic carbon and temperature on natural aquatic communities of variable density in addition to studying detached leaves in the scenarios of rising CO2 and temperature. Moreover, a growing number of researchers are interested in tolerance of terrestrial plants during flooding as torrential rains sometimes result in overland floods that inundate terrestrial plants. We propose to undertake studies to elucidate the importance of leaf acclimation of terrestrial plants to facilitate gas exchange and light utilization under water as these acclimations influence underwater photosynthesis as well as internal aeration of plant tissues during submergence. PMID- 23734153 TI - Acetylation of woody lignocellulose: significance and regulation. AB - Non-cellulosic cell wall polysaccharides constitute approximately one quarter of usable biomass for human exploitation. In contrast to cellulose, these components are usually substituted by O-acetyl groups, which affect their properties and interactions with other polymers, thus affecting their solubility and extractability. However, details of these interactions are still largely obscure. Moreover, polysaccharide hydrolysis to constituent monosaccharides is hampered by the presence of O-acetyl groups, necessitating either enzymatic (esterase) or chemical de-acetylation, increasing the costs and chemical consumption. Reduction of polysaccharide acetyl content in planta is a way to modify lignocellulose toward improved saccharification. In this review we: (1) summarize literature on lignocellulose acetylation in different tree species, (2) present data and current hypotheses concerning the role of O-acetylation in determining woody lignocellulose properties, (3) describe plant proteins involved in lignocellulose O-acetylation, (4) give examples of microbial enzymes capable to de-acetylate lignocellulose, and (5) discuss prospects for exploiting these enzymes in planta to modify xylan acetylation. PMID- 23734150 TI - Genetic mechanisms of antimicrobial resistance identified in Salmonella enterica, Escherichia coli, and Enteroccocus spp. isolated from U.S. food animals. AB - The prevalence of antimicrobial resistance (AR) in bacteria isolated from U.S. food animals has increased over the last several decades as have concerns of AR foodborne zoonotic human infections. Resistance mechanisms identified in U.S. animal isolates of Salmonella enterica included resistance to aminoglycosides (e.g., alleles of aacC, aadA, aadB, ant, aphA, and StrAB), beta-lactams (e.g., bla CMY-2, TEM-1, PSE-1), chloramphenicol (e.g., floR, cmlA, cat1, cat2), folate pathway inhibitors (e.g., alleles of sul and dfr), and tetracycline [e.g., alleles of tet(A), (B), (C), (D), (G), and tetR]. In the U.S., multi-drug resistance (MDR) mechanisms in Salmonella animal isolates were associated with integrons, or mobile genetic elements (MGEs) such as IncA/C plasmids which can be transferred among bacteria. It is thought that AR Salmonella originates in food animals and is transmitted through food to humans. However, some AR Salmonella isolated from humans in the U.S. have different AR elements than those isolated from food animals, suggesting a different etiology for some AR human infections. The AR mechanisms identified in isolates from outside the U.S. are also predominantly different. For example the extended spectrum beta-lactamases (ESBLs) are found in human and animal isolates globally; however, in the U.S., ESBLs thus far have only been found in human and not food animal isolates. Commensal bacteria in animals including Escherichia coli and Enterococcus spp. may be reservoirs for AR mechanisms. Many of the AR genes and MGEs found in E. coli isolated from U.S. animals are similar to those found in Salmonella. Enterococcus spp. isolated from animals frequently carry MGEs with AR genes, including resistances to aminoglycosides (e.g., alleles of aac, ant, and aph), macrolides [e.g., erm(A), erm(B), and msrC], and tetracyclines [e.g., tet(K), (L), (M), (O), (S)]. Continuing investigations are required to help understand and mitigate the impact of AR bacteria on human and animal health. PMID- 23734155 TI - Strategies for vitamin B6 biofortification of plants: a dual role as a micronutrient and a stress protectant. AB - Vitamin B6 has an essential role in cells as a cofactor for several metabolic enzymes. It has also been shown to function as a potent antioxidant molecule. The recent elucidation of the vitamin B6 biosynthesis pathways in plants provides opportunities for characterizing their importance during developmental processes and exposure to stress. Humans and animals must acquire vitamin B6 with their diet, with plants being a major source, because they cannot biosynthesize it de novo. However, the abundance of the vitamin in the edible portions of the most commonly consumed plants is not sufficient to meet daily requirements. Genetic engineering has proven successful in increasing the vitamin B6 content in the model plant Arabidopsis. The added benefits associated with the enhanced vitamin B6 content, such as higher biomass and resistance to abiotic stress, suggest that increasing this essential micronutrient could be a valuable option to improve the nutritional quality and stress tolerance of crop plants. This review summarizes current achievements in vitamin B6 biofortification and considers strategies for increasing vitamin B6 levels in crop plants for human health and nutrition. PMID- 23734156 TI - Fourier transform infrared difference spectroscopy for studying the molecular mechanism of photosynthetic water oxidation. AB - The photosystem II reaction center mediates the light-induced transfer of electrons from water to plastoquinone, with concomitant production of O2. Water oxidation chemistry occurs in the oxygen-evolving complex (OEC), which consists of an inorganic Mn4CaO5 cluster and its surrounding protein matrix. Light-induced Fourier transform infrared (FTIR) difference spectroscopy has been successfully used to study the molecular mechanism of photosynthetic water oxidation. This powerful technique has enabled the characterization of the dynamic structural changes in active water molecules, the Mn4CaO5 cluster, and its surrounding protein matrix during the catalytic cycle. This mini-review presents an overview of recent important progress in FTIR studies of the OEC and implications for revealing the molecular mechanism of photosynthetic water oxidation. PMID- 23734157 TI - Hop-on hop-off: importin-alpha-guided tours to the nucleus in innate immune signaling. AB - Nuclear translocation of immune regulatory proteins and signal transducers is an essential process in animal and plant defense signaling against pathogenic microbes. Import of proteins containing a nuclear localization signal (NLS) into the nucleus is mediated by nuclear transport receptors termed importins, typically dimers of a cargo-binding alpha-subunit and a beta-subunit that mediates translocation through the nuclear pore complex. Here, we review recent reports of importin-alpha cargo specificity and mutant phenotypes in plant- and animal-microbe interactions. Using homology modeling of the NLS-binding cleft of nine predicted Arabidopsis alpha-importins and analyses of their gene expression patterns, we discuss functional redundancy and specialization within this transport receptor family. In addition, we consider how pathogen effector proteins that promote infection by manipulating host cell nuclear processes might compete with endogenous cargo proteins for nuclear uptake. PMID- 23734158 TI - Fermentation metabolism and its evolution in algae. AB - Fermentation or anoxic metabolism allows unicellular organisms to colonize environments that become anoxic. Free-living unicellular algae capable of a photoautotrophic lifestyle can also use a range of metabolic circuitry associated with different branches of fermentation metabolism. While algae that perform mixed-acid fermentation are widespread, the use of anaerobic respiration is more typical of eukaryotic heterotrophs. The occurrence of a core set of fermentation pathways among the algae provides insights into the evolutionary origins of these pathways, which were likely derived from a common ancestral eukaryote. Based on genomic, transcriptomic, and biochemical studies, anaerobic energy metabolism has been examined in more detail in Chlamydomonas reinhardtii (Chlamydomonas) than in any other photosynthetic protist. This green alga is metabolically flexible and can sustain energy generation and maintain cellular redox balance under a variety of different environmental conditions. Fermentation metabolism in Chlamydomonas appears to be highly controlled, and the flexible use of the different branches of fermentation metabolism has been demonstrated in studies of various metabolic mutants. Additionally, when Chlamydomonas ferments polysaccharides, it has the ability to eliminate part of the reductant (to sustain glycolysis) through the production of H2, a molecule that can be developed as a source of renewable energy. To date, little is known about the specific role(s) of the different branches of fermentation metabolism, how photosynthetic eukaryotes sense changes in environmental O2 levels, and the mechanisms involved in controlling these responses, at both the transcriptional and post-transcriptional levels. In this review, we focus on fermentation metabolism in Chlamydomonas and other protists, with only a brief discussion of plant fermentation when relevant, since it is thoroughly discussed in other articles in this volume. PMID- 23734159 TI - The barley grain thioredoxin system - an update. AB - Thioredoxin (Trx) reduces disulfide bonds and play numerous important functions in plants. In cereal seeds, cytosolic h-type Trx facilitates the release of energy reserves during the germination process and is recycled by NADPH-dependent Trx reductase. This review presents a summary of the research conducted during the last 10 years to elucidate the structure and function of the barley seed Trx system at the molecular level combined with proteomic approaches to identify target proteins. PMID- 23734160 TI - Strategies to increase vitamin C in plants: from plant defense perspective to food biofortification. AB - Vitamin C participates in several physiological processes, among others, immune stimulation, synthesis of collagen, hormones, neurotransmitters, and iron absorption. Severe deficiency leads to scurvy, whereas a limited vitamin C intake causes general symptoms, such as increased susceptibility to infections, fatigue, insomnia, and weight loss. Surprisingly vitamin C deficiencies are spread in both developing and developed countries, with the latter actually trying to overcome this lack through dietary supplements and food fortification. Therefore new strategies aimed to increase vitamin C in food plants would be of interest to improve human health. Interestingly, plants are not only living bioreactors for vitamin C production in optimal growing conditions, but also they can increase their vitamin C content as consequence of stress conditions. An overview of the different approaches aimed at increasing vitamin C level in plant food is given. They include genotype selection by "classical" breeding, bio-engineering and changes of the agronomic conditions, on the basis of the emerging concepts that plant can enhance vitamin C synthesis as part of defense responses. PMID- 23734161 TI - Genomic risk models improve prediction of longitudinal lipid levels in children and young adults. AB - In clinical medicine, lipids are commonly measured biomarkers used to assess an individual's risk for cardiovascular disease, heart attack, and stroke. Accurately predicting longitudinal lipid levels based on genomic information can inform therapeutic practices and decrease cardiovascular risk by identifying high risk patients prior to onset. Using genotyped and imputed genetic data from 523 unrelated Caucasian Americans from the Bogalusa Heart Study, surveyed on 4,026 occasions from 4 to 48 years of age, we generated various lipid genomic risk models based on previously reported markers. We observed a significant improvement in prediction over non-genetic risk models in high density lipoprotein cholesterol (increase in the squared correlation between observed and predicted values, DeltaR (2) = 0.032), low density lipoprotein cholesterol (DeltaR (2) = 0.053), total cholesterol (DeltaR (2) = 0.043), and triglycerides (DeltaR (2) = 0.031). Many of our approaches are based on an n-fold cross validation procedure that are, by design, adaptable to a clinical environment. PMID- 23734164 TI - Beware of risk for increased false positive rates in genome-wide association studies for phenotypic variability. PMID- 23734163 TI - Role of Extrachromosomal Histone H2B on Recognition of DNA Viruses and Cell Damage. AB - Histones are essential components of chromatin structure, and histone modification plays an important role in various cellular functions including transcription, gene silencing, and immunity. Histones also play distinct roles in extrachromosomal settings. Extrachromosomal histone H2B acts as a cytosolic sensor to detect double-stranded DNA (dsDNA) fragments derived from infectious agents or damaged cells to activate innate and acquired immune responses in various cell types. It also physically interacts with interferon (IFN)-beta promoter stimulator 1 (IPS-1), an essential adaptor molecule that activates innate immunity, through COOH-terminal importin 9-related adaptor organizing histone H2B and IPS-1 (CIAO), resulting in a distinct signaling complex that induces dsDNA-induced type I IFN production. Such a molecular platform acts as a cellular sensor to recognize aberrant dsDNA in cases of viral infection and cell damage. This mechanism may also play roles in autoimmunity, transplantation rejection, gene-mediated vaccines, and other therapeutic applications. PMID- 23734165 TI - Catechol-O-methyltransferase: characteristics, polymorphisms and role in breast cancer. AB - Catechol estrogens are carcinogenic, probably because of their estrogenicity and potential for further oxidative metabolism to reactive quinones. Estrogenic quinones cause oxidative DNA damage as well as form mutagenic depurinating adenine and guanine adducts. O-Methylation by catechol-O-methyltransferase (COMT) blocks their estrogenicity and prevents their oxidation to quinones. A single gene encodes both membrane bound (MB) and soluble (S) forms of COMT. The COMT gene contains 34 single nucleotide polymorphisms (SNPs). The valine108 (S COMT)/158 (MB-COMT) SNP encodes a low activity form of COMT and has been widely studied as a putative risk factor for breast cancer, with inconsistent results. Investigations of two other SNPs in the promoter of MB-COMT that may affect its expression have also provided mixed results. Future studies on the role of COMT in breast cancer should incorporate measurement of biomarkers that reflect COMT activity and its protective effects. PMID- 23734166 TI - A Neural Mechanism for Reward Discounting: Insights from Modeling Hippocampal Striatal Interactions. AB - Decision-making often requires taking into consideration immediate gains as well as delayed rewards. Studies of behavior have established that anticipated rewards are discounted according to a decreasing hyperbolic function. Although mathematical explanations for reward delay discounting have been offered, little has been proposed in terms of neural network mechanisms underlying discounting. There has been much recent interest in the potential role of the hippocampus. Here we demonstrate that a previously-established neural network model of hippocampal region CA3 contains a mechanism that could explain discounting in downstream reward-prediction systems (e.g., basal ganglia). As part of its normal function, the model forms codes for stimuli that are similar to future, predicted stimuli. This similarity provides a means for reward predictions associated with future stimuli to influence current decision-making. Simulations show that this "predictive similarity" decreases as the stimuli are separated in time, at a rate that is consistent with hyperbolic discounting. PMID- 23734168 TI - Acute effects of ambient ozone on mortality in Europe and North America: results from the APHENA study. AB - The "Air Pollution and Health: A Combined European and North American Approach" (APHENA) project is a collaborative analysis of multi-city time-series data on the association between air pollution and adverse health outcomes. The main objective of APHENA was to examine the coherence of findings of time-series studies relating short-term fluctuations in air pollution levels to mortality and morbidity in 125 cities in Europe, the US, and Canada. Multi-city time-series analysis was conducted using a two-stage approach. We used Poisson regression models controlling for overdispersion with either penalized or natural splines to adjust for seasonality. Hierarchical models were used to obtain an overall estimate of excess mortality associated with ozone and to assess potential effect modification. Potential effect modifiers were city-level characteristics related to exposure to other ambient air pollutants, weather, socioeconomic status, and the vulnerability of the population. Regionally pooled risk estimates from Europe and the US were similar; those from Canada were substantially higher. The pooled estimated excess relative risk associated with a 10 ug/m3 increase in 1 h daily maximum O3 was 0.26 % (95 % CI, 0.15 %, 0.37 %). Across regions, there was little consistent indication of effect modification by age or other effect modifiers considered in the analysis. The findings from APHENA on the effects of O3 on mortality in the general population were comparable with previously reported results and relatively robust to the method of data analysis. Overall, there was no indication of strong effect modification by age or ecologic variables considered in the analysis. PMID- 23734167 TI - A Systematic Review of Quality of Life Measures in Pregnant and Postpartum Mothers. AB - Quality of life has emerged as an essential health component that broadens the traditionally narrow concerns focused on only morbidity and life expectancy. Although a growing number of tools to measure quality of life are in circulation, there is a lack of guidelines as well as rigorous assessment for their use with pregnant and postpartum populations. It is also unclear whether these instruments could validly be employed to measure patient-reported outcomes in comparative effectiveness research of maternal care interventions. This paper reviews articles cited in CINAHL, COCHRANE, EMBASE, PSYCINFO, and PUBMED that addressed quality of life in pregnant and postpartum populations. Instruments used to measure quality of life in selected articles were assessed for their adherence to international guidelines for health outcomes instrument development and validation. The authors identified 129 articles that addressed quality of life in pregnant and/or postpartum women. Out of these, only 64 quality (generic and specific) scales were judged relevant to be included in this study. Analysis of measurement scales used in the pregnant and/or postpartum populations revealed important validity, reliability and psychometric inadequacies that negate their use in comparative effectiveness analysis in pregnant and post-partum populations. Valid, reliable, and responsive instruments to measure patient reported outcomes in pregnant and postpartum populations are lacking. To demonstrate the effectiveness of various treatment and prevention programs, future research to develop and validate a robust and responsive quality of life measurement scale in pregnant and postpartum populations is needed. PMID- 23734169 TI - Microfluidic-driven viral infection on cell cultures: Theoretical and experimental study. AB - Advanced cell culture systems creating a controlled and predictable microenvironment together with computational modeling may be useful tools to optimize the efficiency of cell infections. In this paper, we will present a phenomenological study of a virus-host infection system, and the development of a multilayered microfluidic platform used to accurately tune the virus delivery from a diffusive-limited regime to a convective-dominated regime. Mathematical models predicted the convective-diffusive regimes developed within the system itself and determined the dominating mass transport phenomena. Adenoviral vectors carrying the enhanced green fluorescent protein (EGFP) transgene were used at different multiplicities of infection (MOI) to infect multiple cell types, both in standard static and in perfused conditions. Our results validate the mathematical models and demonstrate how the infection processes through perfusion via microfluidic platform led to an enhancement of adenoviral infection efficiency even at low MOIs. This was particularly evident at the longer time points, since the establishment of steady-state condition guaranteed a constant viral concentration close to cells, thus strengthening the efficiency of infection. Finally, we introduced the concept of effective MOI, a more appropriate variable for microfluidic infections that considers the number of adenoviruses in solution per cell at a certain time. PMID- 23734170 TI - Do reproductive factors influence T, N, and M classes of ductal and lobular breast cancers? A nation-wide follow-up study. AB - BACKGROUNDS: The clinical tumor-node-metastasis (T, N and M) classes of breast cancers provide important prognostic information. However, the possible association of TNM classes with reproductive factors has remained largely unexplored. Because every woman has a reproductive history, implications to outcome prediction are potentially significant. METHODS: During the study period from 2002 through 2008, 5,614 pre- and 27,310 postmenopausal patients were identified in the Swedish Family-Cancer Database. Ordinal logistic regression analysis was used to estimate odds ratios (ORs) for TNM classes of breast cancers by histology. The reproductive variables were parity, age at first and last childbirth and time interval between first and last childbirth. RESULTS: Among postmenopausal patients, the ORs for high-T class (T2-T4) (tumor size >=2 cm) and metastasis were decreased by parity. A late age at first and last childbirth associated with high-T class and the effects were higher for lobular (OR for late age at first childbirth = 2.85) than ductal carcinoma. Overall, long time interval between first and last childbirth was related to high-T class and metastasis. However, a short time interval between first and last childbirth in patients with late age at first or last childbirth increased the risk of metastasis. Late age at last childbirth was associated with increased occurrence of lobular carcinoma in situ. Among premenopausal ductal carcinoma patients, nulliparity and early age at first childbirth were associated with high-T class. CONCLUSIONS: Increasing parity was protective against high-T class and metastasis; late ages at first and last childbirth were risk factors for high-T class in postmenopausal breast cancers. The current decline in parity and delayed age at first childbirth in many countries may negatively influence prognosis of breast cancer. PMID- 23734172 TI - Semen levels of spermatid-specific thioredoxin-3 correlate with pregnancy rates in ART couples. AB - Spermatid specific thioredoxin-3 (SPTRX3 or TXNDC8) is a testis/male germ line specific member of thioredoxin family that accumulates in the superfluous cytoplasm of defective human spermatozoa. We hypothesized that semen levels of SPTRX3 are reflective of treatment outcome in assisted reproductive therapy (ART) couples treated by in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). Relationship between SPTRX3 and treatment outcome was investigated in 239 couples undergoing ART at an infertility clinic. Sperm content of SPTRX3 was evaluated by flow cytometry and epifluorescence microscopy, and correlated with clinical semen analysis parameters, and data on embryo development and pregnancy establishment. High SPTRX3 levels (>15% SPTRX3-positive spermatozoa) were found in 51% of male infertility patients (n = 72), in 20% of men from couples with unexplained, idiopathic infertility (n = 61) and in 14% of men from couples previously diagnosed with female-only infertility (n = 85). Couples with high SPTRX3 produced fewer two-pronuclear zygotes and had a reduced pregnancy rate (19.2% pregnant with >15% SPTRX3-positive spermatozoa vs. 41.2% pregnant with <5% SPTRX3-positive sperm; one-sided p<0.05). The average pregnancy rate of all 239 couples was 25.1%. Live birth rate was 19.2% and lowest average SPTRX3 levels were found in couples that delivered twins. Men with >15% of SPTRX3 positive spermatozoa, a cutoff value established by ROC analysis, had their chance of fathering children by IVF or ICSI reduced by nearly two-thirds. The percentage of SPTRX3-positive spermatozoa had predictive value for pregnancy after ART. Gradient purification and sperm swim-up failed to remove all SPTRX3 positive spermatozoa from semen prepared for ART. In summary, the elevated semen content of SPTRX3 in men from ART couples coincided with reduced incidence of pregnancy by IVF or ICSI, identifying SPTRX3 as a candidate biomarker reflective of ART outcome. PMID- 23734174 TI - Occupation and environmental heat-associated deaths in Maricopa county, Arizona: a case-control study. AB - BACKGROUND: Prior research shows that work in agriculture and construction/extraction occupations increases the risk of environmental heat associated death. PURPOSE: To assess the risk of environmental heat-associated death by occupation. METHODS: This was a case-control study. Cases were heat caused and heat-related deaths occurring from May-October during the period 2002 2009 in Maricopa County, Arizona. Controls were selected at random from non-heat associated deaths during the same period in Maricopa County. Information on occupation, age, sex, and race-ethnicity was obtained from death certificates. Logistic regression analysis was used to estimate odds ratios for heat-associated death. RESULTS: There were 444 cases of heat-associated deaths in adults (18+ years) and 925 adult controls. Of heat-associated deaths, 332 (75%) occurred in men; a construction/extraction or agriculture occupation was described on the death certificate in 115 (35%) of these men. In men, the age-adjusted odds ratios for heat-associated death were 2.32 (95% confidence interval 1.55, 3.48) in association with construction/extraction and 3.50 (95% confidence interval 1.94, 6.32) in association with agriculture occupations. The odds ratio for heat associated death was 10.17 (95% confidence interval 5.38, 19.23) in men with unknown occupation. In women, the age-adjusted odds ratio for heat-associated death was 6.32 (95% confidence interval 1.48, 27.08) in association with unknown occupation. Men age 65 years and older in agriculture occupations were at especially high risk of heat-associated death. CONCLUSION: The occurrence of environmental heat-associated death in men in agriculture and construction/extraction occupations in a setting with predictable periods of high summer temperatures presents opportunities for prevention. PMID- 23734173 TI - Multiplex PCR system for rapid detection of pathogens in patients with presumed sepsis - a systemic review and meta-analysis. AB - BACKGROUND: Blood culture is viewed as the golden standard for the diagnosis of sepsis but suffers from low sensitivity and long turnaround time. LightCycler SeptiFast (LC-SF) is a real-time multiplex polymerase chain reaction test able to detect 25 common pathogens responsible for bloodstream infections within hours. We aim to assess the accuracy of LC-SF by systematically reviewing the published studies. METHOD: Related literature on Medline, Embase, and Cochrane databases was searched up to October 2012 for studies utilizing LC-SF to diagnose suspected sepsis and that provided sufficient data to construct two-by-two tables. RESULTS: A total of 34 studies enrolling 6012 patients of suspected sepsis were included. The overall sensitivity and specificity for LC-SF to detect bacteremia or fungemia was 0.75 (95% CI: 0.65-0.83) and 0.92 (95%CI:0.90-0.95), respectively. LC-SF had a high positive likelihood ratio (10.10) and a moderate negative likelihood ratio (0.27). Specifically, LC-SF had a sensitivity of 0.80 (95%CI: 0.70-0.88) and a specificity of 0.95(95%CI: 0.93-0.97) for the bacteremia outcome, and a sensitivity of 0.61 (95%CI: 0.48-0.72) and a specificity of 0.99 (95%CI: 0.99-0.99) for the fungemia outcome. High heterogeneity was found in the bacteremia outcome subgroup but not in the fungemia outcome subgroup. CONCLUSION: LC-SF is of high rule-in value for early detection of septic patients. In a population with low pretest probability, LC-SF test can still provide valuable information for ruling out bacteremia or fungemia. PMID- 23734175 TI - Chimpanzees and bonobos exhibit emotional responses to decision outcomes. AB - The interface between cognition, emotion, and motivation is thought to be of central importance in understanding complex cognitive functions such as decision making and executive control in humans. Although nonhuman apes have complex repertoires of emotional expression, little is known about the role of affective processes in ape decision-making. To illuminate the evolutionary origins of human like patterns of choice, we investigated decision-making in humans' closest phylogenetic relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). In two studies, we examined these species' temporal and risk preferences, and assessed whether apes show emotional and motivational responses in decision making contexts. We find that (1) chimpanzees are more patient and more risk prone than are bonobos, (2) both species exhibit affective and motivational responses following the outcomes of their decisions, and (3) some emotional and motivational responses map onto species-level and individual-differences in decision-making. These results indicate that apes do exhibit emotional responses to decision-making, like humans. We explore the hypothesis that affective and motivational biases may underlie the psychological mechanisms supporting value based preferences in these species. PMID- 23734176 TI - Database citation in full text biomedical articles. AB - Molecular biology and literature databases represent essential infrastructure for life science research. Effective integration of these data resources requires that there are structured cross-references at the level of individual articles and biological records. Here, we describe the current patterns of how database entries are cited in research articles, based on analysis of the full text Open Access articles available from Europe PMC. Focusing on citation of entries in the European Nucleotide Archive (ENA), UniProt and Protein Data Bank, Europe (PDBe), we demonstrate that text mining doubles the number of structured annotations of database record citations supplied in journal articles by publishers. Many thousands of new literature-database relationships are found by text mining, since these relationships are also not present in the set of articles cited by database records. We recommend that structured annotation of database records in articles is extended to other databases, such as ArrayExpress and Pfam, entries from which are also cited widely in the literature. The very high precision and high-throughput of this text-mining pipeline makes this activity possible both accurately and at low cost, which will allow the development of new integrated data services. PMID- 23734171 TI - In-depth tanscriptomic analysis on giant freshwater prawns. AB - Gene discovery in the Malaysian giant freshwater prawn (Macrobrachium rosenbergii) has been limited to small scale data collection, despite great interest in various research fields related to the commercial significance of this species. Next generation sequencing technologies that have been developed recently and enabled whole transcriptome sequencing (RNA-seq), have allowed generation of large scale functional genomics data sets in a shorter time than was previously possible. Using this technology, transcriptome sequencing of three tissue types: hepatopancreas, gill and muscle, has been undertaken to generate functional genomics data for M. rosenbergii at a massive scale. De novo assembly of 75-bp paired end Ilumina reads has generated 102,230 unigenes. Sequence homology search and in silico prediction have identified known and novel protein coding candidate genes (~24%), non-coding RNA, and repetitive elements in the transcriptome. Potential markers consisting of simple sequence repeats associated with known protein coding genes have been successfully identified. Using KEGG pathway enrichment, differentially expressed genes in different tissues were systematically represented. The functions of gill and hepatopancreas in the context of neuroactive regulation, metabolism, reproduction, environmental stress and disease responses are described and support relevant experimental studies conducted previously in M. rosenbergii and other crustaceans. This large scale gene discovery represents the most extensive transcriptome data for freshwater prawn. Comparison with model organisms has paved the path to address the possible conserved biological entities shared between vertebrates and crustaceans. The functional genomics resources generated from this study provide the basis for constructing hypotheses for future molecular research in the freshwater shrimp. PMID- 23734177 TI - An unusual basal Therizinosaur dinosaur with an ornithischian dental arrangement from northeastern China. AB - Therizinosauria are an unusual group of theropod dinosaurs, found mostly in the Cretaceous deposits in Mongolia, China and western USA. The basal forms of this group are represented by incomplete or disarticulated material. Here, we report a nearly complete, articulated skeleton of a new basal therizinosaur from the Early Cretaceous Yixian Formation of Jianchang County, western part of Liaoning Province, which sheds light on our understanding of anatomy of basal therizinosaurs. This new dinosaur shows some typical therizinosaur features, such as neural spines of the anterior caudal vertebrae that possess anterior and posterior alae, a rectangular buttress on the ventrolateral side of the proximal end of metacarpal I, and appressed metatarsal shafts. Our phylogenetic analysis suggests that it is a basal therizinosaur (sister taxon to Therizinosauroidea) because it bears many basal therizinosaur characters in the dentition, pelvis and hind limbs. The new therizinosaur described here has unique tooth and jaw characters such as the offsetting of the tooth row by a shelf and dentary teeth with labially concave and lingually convex dentary teeth, similar to ornithopods and ceratopsians. PMID- 23734178 TI - Characterization of a tumor-associated activating mutation of the p110beta PI 3 kinase. AB - The PI3-kinase pathway is commonly activated in tumors, most often by loss of PTEN lipid phosphatase activity or the amplification or mutation of p110alpha. Oncogenic mutants have commonly been found in p110alpha, but rarely in any of the other catalytic subunits of class I PI3-kinases. We here characterize a p110beta helical domain mutation, E633K, first identified in a Her2-positive breast cancer. The mutation increases basal p110beta activity, but does not affect activation of p85/p110beta dimers by phosphopeptides or Gbetagamma. Expression of the mutant causes increases in Akt and S6K1 activation, transformation, chemotaxis, proliferation and survival in low serum. E633 is conserved among class I PI3 Ks, and its mutation in p110beta is also activating. Interestingly, the E633K mutant occurs near a region that interacts with membranes in activated PI 3-kinases, and its mutation abrogates the requirement for an intact Ras binding domain in p110beta-mediated transformation. We propose that the E633K mutant activates p110beta by enhancing its basal association with membranes. This study presents the first analysis of an activating oncogenic mutation of p110beta. PMID- 23734179 TI - Regional similarities in seasonal mortality across the United States: an examination of 28 metropolitan statistical areas. AB - Human mortality exhibits a strong seasonal pattern with deaths in winter far exceeding those in the summer. While the pattern itself is clear, there have been very few studies examining whether the magnitude or timing of seasonal mortality varies considerably across space. Thus, the goal of this study is to conduct a comprehensive geographic analysis of seasonal mortality across the United States and to uncover systematic regional differences in such mortality. Unique seasonal mortality curves were created for 28 metropolitan statistical areas across the United States, and the amplitude and timing of mortality peaks were determined. The findings here indicate that the seasonality of mortality exhibits strong spatial variation with the largest seasonal mortality amplitudes found in the southwestern United States and the smallest in the North, along with South Florida. In addition, there were strong intra-regional similarities that exist among the examined cities, implying that environmental factors are more important than social factors in determining seasonal mortality response. This work begins to fill a large gap within the scientific literature concerning the geographic variation and underlying causes of seasonal mortality across the United States. PMID- 23734180 TI - Edible crabs "go west": migrations and incubation cycle of Cancer pagurus revealed by electronic tags. AB - Crustaceans are key components of marine ecosystems which, like other exploited marine taxa, show seasonable patterns of distribution and activity, with consequences for their availability to capture by targeted fisheries. Despite concerns over the sustainability of crab fisheries worldwide, difficulties in observing crabs' behaviour over their annual cycles, and the timings and durations of reproduction, remain poorly understood. From the release of 128 mature female edible crabs tagged with electronic data storage tags (DSTs), we demonstrate predominantly westward migration in the English Channel. Eastern Channel crabs migrated further than western Channel crabs, while crabs released outside the Channel showed little or no migration. Individual migrations were punctuated by a 7-month hiatus, when crabs remained stationary, coincident with the main period of crab spawning and egg incubation. Incubation commenced earlier in the west, from late October onwards, and brooding locations, determined using tidal geolocation, occurred throughout the species range. With an overall return rate of 34%, our results demonstrate that previous reluctance to tag crabs with relatively high-cost DSTs for fear of loss following moulting is unfounded, and that DSTs can generate precise information with regards life-history metrics that would be unachievable using other conventional means. PMID- 23734181 TI - The eicosapentaenoic acid metabolite 15-deoxy-delta(12,14)-prostaglandin J3 increases adiponectin secretion by adipocytes partly via a PPARgamma-dependent mechanism. AB - The intake of omega-3 polyunsaturated fatty acids (PUFAs), which are abundant in marine fish meat and oil, has been shown to exert many beneficial effects. The mechanisms behind those effects are numerous, including interference with the arachidonic acid cascade that produces pro-inflammatory eicosanoids, formation of novel bioactive lipid mediators, and change in the pattern of secreted adipocytokines. In our study, we show that eicosapentaenoic acid (EPA) increases secreted adiponectin from 3T3-L1 adipocytes and in plasma of mice as early as 4 days after initiation of an EPA-rich diet. Using 3T3-L1 adipocytes, we report for the first time that 15-deoxy-delta(12,14)-PGJ3 (15d-PGJ3), a product of EPA, also increases the secretion of adiponectin. We demonstrate that the increased adiponectin secretion induced by 15d-PGJ3 is partially peroxisome proliferator activated receptor-gamma (PPAR-gamma)-mediated. Finally, we show that 3T3-L1 adipocytes can synthesize 15d-PGJ3 from EPA. 15d-PGJ3 was also detected in adipose tissue from EPA-fed mice. Thus, these studies provide a novel mechanism(s) for the therapeutic benefits of omega-3 polyunsaturated fatty acids dietary supplementation. PMID- 23734182 TI - Body adiposity index and cardiovascular health risk factors in Caucasians: a comparison with the body mass index and others. AB - BACKGROUND: Several studies have shown a relation between the adipose tissue accumulation and a higher risk for developing metabolic and cardiovascular diseases. Thus, body fat content and, mainly, the fat distribution or adiposity could be considered as important indicators of health risk. In spite of presenting several limitations, BMI is the most widely used and accepted index for classifying overweight and obesity. The aim of the study was to evaluate the correlations between Body Adiposity Index (BAI), BMI and other adiposity indexes such as WC, WHR and WHtR with cardiovascular and metabolic risk factors. Furthermore, the behavior of BAI and BMI regarding the ability to discriminate overweight or obese individuals was also analyzed. RESEARCH METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study was conducted in Spanish Caucasian adult workers. Participants in the study (29.214 men and 21.040 women, aged 20-68 years) were systematically selected during their work health periodic examinations. BAI, BMI, WHR, WHtR, body weight, hip and waist circumference (WC) as well as systolic and diastolic blood pressure were measured. Serum levels of high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG) and glucose were also determined. Results of the study indicated that BAI was less correlated with cardiovascular risk factors and metabolic risk factors than other adiposity indexes (BMI, WC and WHtR). The best correlations were found for WHtR. In addition, the BAI presented lower discriminatory capacity than BMI for diagnosing metabolic syndrome (MS) using both IDF and ATP III criteria. A different behavior of the BAI in men and women when considering the ability to discriminate overweight or obese individuals was also observed. CONCLUSIONS: The adiposity indexes that include the waist circumference (WHtR and WC) may be better candidates than BAI and BMI to evaluate metabolic and cardiovascular risk in both clinical practice and research. PMID- 23734183 TI - Molecular epidemiology and phylodynamics of the human respiratory syncytial virus fusion protein in northern Taiwan. AB - BACKGROUND AND AIMS: The glycoprotein (G protein) and fusion protein (F protein) of respiratory syncytial virus (RSV) both show genetic variability, but few studies have examined the F protein gene. This study aimed to characterize the molecular epidemiology and phylodynamics of the F protein gene in clinical RSV strains isolated in northern Taiwan from 2000-2011. METHODS: RSV isolates from children presenting with acute respiratory symptoms between July 2000 and June 2011 were typed based on F protein gene sequences. Phylogeny construction and evaluation were performed using the neighbor-joining (NJ) and maximum likelihood (ML) methods. Phylodynamic patterns in RSV F protein genes were analyzed using the Bayesian Markov Chain Monte Carlo framework. Selection pressure on the F protein gene was detected using the Datamonkey website interface. RESULTS: From a total of 325 clinical RSV strains studied, phylogenetic analysis showed that 83 subgroup A strains (RSV-A) could be further divided into three clusters, whereas 58 subgroup B strains (RSV-B) had no significant clustering. Three amino acids were observed to differ between RSV-A and -B (positions 111, 113, and 114) in CTL HLA-B*57- and HLA-A*01-restricted epitopes. One positive selection site was observed in RSV-B, while none was observed in RSV-A. The evolution rate of the virus had very little change before 2000, then slowed down between 2000 and 2005, and evolved significantly faster after 2005. The dominant subtypes of RSV-A in each epidemic were replaced by different subtypes in the subsequent epidemic. CONCLUSIONS: Before 2004, RSV-A infections were involved in several small epidemics and only very limited numbers of strains evolved and re-emerged in subsequent years. After 2005, the circulating RSV-A strains were different from those of the previous years and continued evolving through 2010. Phylodynamic pattern showed the evolutionary divergence of RSV increased significantly in the recent 5 years in northern Taiwan. PMID- 23734185 TI - Thermal limit for metazoan life in question: in vivo heat tolerance of the Pompeii worm. AB - The thermal limit for metazoan life, expected to be around 50 degrees C, has been debated since the discovery of the Pompeii worm Alvinella pompejana, which colonizes black smoker chimney walls at deep-sea vents. While indirect evidence predicts body temperatures lower than 50 degrees C, repeated in situ temperature measurements depict an animal thriving at temperatures of 60 degrees C and more. This controversy was to remain as long as this species escaped in vivo investigations, due to irremediable mortalities upon non-isobaric sampling. Here we report from the first heat-exposure experiments with live A. pompejana, following isobaric sampling and subsequent transfer in a laboratory pressurized aquarium. A prolonged (2 hours) exposure in the 50-55 degrees C range was lethal, inducing severe tissue damages, cell mortalities and triggering a heat stress response, therefore showing that Alvinella's upper thermal limit clearly is below 55 degrees C. A comparison with hsp70 stress gene expressions of individuals analysed directly after sampling in situ confirms that Alvinella pompejana does not experience long-term exposures to temperature above 50 degrees C in its natural environment. The thermal optimum is nevertheless beyond 42 degrees C, which confirms that the Pompeii worm ranks among the most thermotolerant metazoans. PMID- 23734184 TI - Genetic analyses reveal a role for vitamin D insufficiency in HCV-associated hepatocellular carcinoma development. AB - BACKGROUND: Vitamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. We therefore aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). METHODOLOGY/PRINCIPAL FINDINGS: Associations between CYP2R1, GC, and DHCR7 genotypes that are determinants of reduced 25 hydroxyvitamin D (25[OH]D3) serum levels and the risk of HCV-related HCC development were investigated for 1279 chronic hepatitis C patients with HCC and 4325 without HCC, respectively. The well-known associations between CYP2R1 (rs1993116, rs10741657), GC (rs2282679), and DHCR7 (rs7944926, rs12785878) genotypes and 25(OH)D3 serum levels were also apparent in patients with chronic hepatitis C. The same genotypes of these single nucleotide polymorphisms (SNPs) that are associated with reduced 25(OH)D3 serum levels were found to be associated with HCV-related HCC (P = 0.07 [OR = 1.13, 95% CI = 0.99-1.28] for CYP2R1, P = 0.007 [OR = 1.56, 95% CI = 1.12-2.15] for GC, P = 0.003 [OR = 1.42, 95% CI = 1.13-1.78] for DHCR7; ORs for risk genotypes). In contrast, no association between these genetic variations and liver fibrosis progression rate (P>0.2 for each SNP) or outcome of standard therapy with pegylated interferon alpha and ribavirin (P>0.2 for each SNP) was observed, suggesting a specific influence of the genetic determinants of 25(OH)D3 serum levels on hepatocarcinogenesis. CONCLUSIONS/SIGNIFICANCE: Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV related hepatocarcinogenesis. PMID- 23734186 TI - Functional interaction of cockroach allergens and mannose receptor (CD206) in human circulating fibrocytes. AB - BACKGROUND: The innate pattern recognition C-type-lectin receptors (CLRs), including mannose receptor (MRC1; CD206), have been suggested to functionally interact with allergens and are critical in controlling immune response. Fibrocytes have been considered to play a role in allergic asthma. Here we sought to investigate the functional interaction of cockroach allergens with CD206 in fibrocytes. METHODS: Profiling of N-linked glycans from natural purified cockroach allergen Bla g 2 was accomplished by MALDI-MS. The binding activity of cockroach allergens to CD206 was determined by solid-phase binding assays. Levels of CD206 expression on human fibrocytes and CD206 mediated signaling and cytokine production in Bla g 2 treated fibrocytes were determined. RESULTS: Profiling of N linked glycans from Bla g 2 revealed a predominance of small, mannose-terminated glycans with and without fucose. Significant binding of Bla g 2 to CD206 was observed, which was inhibited by yeast mannan (a known CD206 ligand), free mannose, and a blocking antibody (anti-hMR). Flow cytometric analyses of human fibrocytes (CD45(+) and collagen-1(+)) showed selective expression of CD206 on fibrocytes. Functionally, a concentration-dependent uptake of FITC labeled Bla g 2 by fibrocytes was observed, but was significantly inhibited by anti-hMR. Bla g 2 can stimulate up-regulation of inflammatory cytokines including TNF-alpha and IL-6 and activation of nuclear factor kappa B (NF-kB/p65), p38 mitogen-activated protein kinase (p38), ERK, and JNK in cultured fibrocytes. This increased secretion of TNF-alpha and IL-6 and activation of NF-kB, ERK, and JNK was significantly inhibited by the addition of either mannan or mannose. Furthermore, Bla g 2 induced increase in TNF-alpha and IL-6 production was also inhibited by the use of NF-kB, ERK, and JNK inhibitors. CONCLUSION: These results provide evidence supporting the existence of a functional cockroach allergen-CD206 axis in human fibrocytes, suggesting a role for CD206 in regulating allergen induced allergic responses in asthma. PMID- 23734187 TI - Prenatal exposure to urban air nanoparticles in mice causes altered neuronal differentiation and depression-like responses. AB - Emerging evidence suggests that excessive exposure to traffic-derived air pollution during pregnancy may increase the vulnerability to neurodevelopmental alterations that underlie a broad array of neuropsychiatric disorders. We present a mouse model for prenatal exposure to urban freeway nanoparticulate matter (nPM). In prior studies, we developed a model for adult rodent exposure to re aerosolized urban nPM which caused inflammatory brain responses with altered neuronal glutamatergic functions. nPMs are collected continuously for one month from a local freeway and stored as an aqueous suspension, prior to re aerosolization for exposure of mice under controlled dose and duration. This paradigm was used for a pilot study of prenatal nPM impact on neonatal neurons and adult behaviors. Adult C57BL/6J female mice were exposed to re-aerosolized nPM (350 ug/m(3)) or control filtered ambient air for 10 weeks (3*5 hour exposures per week), encompassing gestation and oocyte maturation prior to mating. Prenatal nPM did not alter litter size, pup weight, or postnatal growth. Neonatal cerebral cortex neurons at 24 hours in vitro showed impaired differentiation, with 50% reduction of stage 3 neurons with long neurites and correspondingly more undifferentiated neurons at Stages 0 and 1. Neuron number after 24 hours of culture was not altered by prenatal nPM exposure. Addition of exogenous nPM (2 ug/ml) to the cultures impaired pyramidal neuron Stage 3 differentiation by 60%. Adult males showed increased depression-like responses in the tail-suspension test, but not anxiety-related behaviors. These pilot data suggest that prenatal exposure to nPM can alter neuronal differentiation with gender-specific behavioral sequelae that may be relevant to human prenatal exposure to urban vehicular aerosols. PMID- 23734188 TI - Spatial probability dynamically modulates visual target detection in chickens. AB - The natural world contains a rich and ever-changing landscape of sensory information. To survive, an organism must be able to flexibly and rapidly locate the most relevant sources of information at any time. Humans and non-human primates exploit regularities in the spatial distribution of relevant stimuli (targets) to improve detection at locations of high target probability. Is the ability to flexibly modify behavior based on visual experience unique to primates? Chickens (Gallus domesticus) were trained on a multiple alternative Go/NoGo task to detect a small, briefly-flashed dot (target) in each of the quadrants of the visual field. When targets were presented with equal probability (25%) in each quadrant, chickens exhibited a distinct advantage for detecting targets at lower, relative to upper, hemifield locations. Increasing the probability of presentation in the upper hemifield locations (to 80%) dramatically improved detection performance at these locations to be on par with lower hemifield performance. Finally, detection performance in the upper hemifield changed on a rapid timescale, improving with successive target detections, and declining with successive detections at the diagonally opposite location in the lower hemifield. These data indicate the action of a process that in chickens, as in primates, flexibly and dynamically modulates detection performance based on the spatial probabilities of sensory stimuli as well as on recent performance history. PMID- 23734189 TI - Dietary uptake of Wedelia chinensis extract attenuates dextran sulfate sodium induced colitis in mice. AB - SCOPE: Traditional medicinal herbs are increasingly used as alternative therapies in patients with inflammatory diseases. Here we evaluated the effect of Wedelia chinensis, a medicinal herb commonly used in Asia, on the prevention of dextran sulfate sodium (DSS)-induced acute colitis in mice. General safety and the effect of different extraction methods on the bioactivity of W. chinensis were also explored. METHODS AND RESULTS: C57BL/6 mice were administrated hot water extract of fresh W. chinensis (WCHF) orally for one week followed by drinking water containing 2% DSS for nine days. WCHF significantly attenuated the symptoms of colitis including diarrhea, rectal bleeding and loss of body weight; it also reduced the shortening of colon length and histopathological damage caused by colonic inflammation. Among four W. chinensis extracts prepared using different extraction techniques, WCHF showed the highest anti-colitis efficacy. Analyses of specific T-cell regulatory cytokines (TNF-alpha, IL-4, IFN-gamma, IL-17, TGF beta, IL-12) revealed that WCHF treatment can suppress the Th1 and Th17, but not Th2, responses in colon tissues and dendritic cells of DSS-induced colitis mice. A 28-day subacute toxicity study showed that daily oral administration of WCHF (100, 500, 1000 mg/kg body weight) was not toxic to mice. CONCLUSION: Together, our findings suggest that specific extracts of W. chinensis have nutritional potential for future development into nutraceuticals or dietary supplements for treatment of inflammatory bowel disease. PMID- 23734190 TI - B cells promote tumor progression via STAT3 regulated-angiogenesis. AB - The role of B cells in cancer and the underlying mechanisms remain to be further explored. Here, we show that tumor-associated B cells with activated STAT3 contribute to tumor development by promoting tumor angiogenesis. B cells with or without Stat3 have opposite effects on tumor growth and tumor angiogenesis in both B16 melanoma and Lewis Lung Cancer mouse models. Ex vivo angiogenesis assays show that B cell-mediated tumor angiogenesis is mainly dependent on the induction of pro-angiogenic gene expression, which requires Stat3 signaling in B cells. Furthermore, B cells with activated STAT3 are mainly found in or near tumor vasculature and correlate significantly with overall STAT3 activity in human tumors. Moreover, the density of B cells in human tumor tissues correlates significantly with expression levels of several STAT3-downstream pro-angiogenic genes, as well as the degree of tumor angiogenesis. Together, these findings define a novel role of B cells in promoting tumor progression through angiogenesis and identify STAT3 in B cells as potential therapeutic target for anti-angiogenesis therapy. PMID- 23734191 TI - Investigating the link between molecular subtypes of glioblastoma, epithelial mesenchymal transition, and CD133 cell surface protein. AB - In this manuscript, we use genetic data to provide a three-faceted analysis on the links between molecular subclasses of glioblastoma, epithelial-to-mesenchymal transition (EMT) and CD133 cell surface protein. The contribution of this paper is three-fold: First, we use a newly identified signature for epithelial-to mesenchymal transition in human mammary epithelial cells, and demonstrate that genes in this signature have significant overlap with genes differentially expressed in all known GBM subtypes. However, the overlap between genes up regulated in the mesenchymal subtype of GBM and in the EMT signature was more significant than other GBM subtypes. Second, we provide evidence that there is a negative correlation between the genetic signature of EMT and that of CD133 cell surface protein, a putative marker for neural stem cells. Third, we study the correlation between GBM molecular subtypes and the genetic signature of CD133 cell surface protein. We demonstrate that the mesenchymal and neural subtypes of GBM have the strongest correlations with the CD133 genetic signature. While the mesenchymal subtype of GBM displays similarity with the signatures of both EMT and CD133, it also exhibits some differences with each of these signatures that are partly due to the fact that the signatures of EMT and CD133 are inversely related to each other. Taken together these data shed light on the role of the mesenchymal transition and neural stem cells, and their mutual interaction, in molecular subtypes of glioblastoma multiforme. PMID- 23734192 TI - ATP dependent rotational motion of group II chaperonin observed by X-ray single molecule tracking. AB - Group II chaperonins play important roles in protein homeostasis in the eukaryotic cytosol and in Archaea. These proteins assist in the folding of nascent polypeptides and also refold unfolded proteins in an ATP-dependent manner. Chaperonin-mediated protein folding is dependent on the closure and opening of a built-in lid, which is controlled by the ATP hydrolysis cycle. Recent structural studies suggest that the ring structure of the chaperonin twists to seal off the central cavity. In this study, we demonstrate ATP dependent dynamics of a group II chaperonin at the single-molecule level with highly accurate rotational axes views by diffracted X-ray tracking (DXT). A UV light-triggered DXT study with caged-ATP and stopped-flow fluorometry revealed that the lid partially closed within 1 s of ATP binding, the closed ring subsequently twisted counterclockwise within 2-6 s, as viewed from the top to bottom of the chaperonin, and the twisted ring reverted to the original open state with a clockwise motion. Our analyses clearly demonstrate that the biphasic lid-closure process occurs with unsynchronized closure and a synchronized counterclockwise twisting motion. PMID- 23734193 TI - Comparative transcriptome profiling reveals different expression patterns in Xanthomonas oryzae pv. oryzae strains with putative virulence-relevant genes. AB - Xanthomonas oryzae pv. oryzae (Xoo) is the causal agent of rice bacterial blight, which is a major rice disease in tropical Asian countries. An attempt has been made to investigate gene expression patterns of three Xoo strains on the minimal medium XOM2, PXO99 (P6) and PXO86 (P2) from the Philippines, and GD1358 (C5) from China, which exhibited different virulence in 30 rice varieties, with putative virulence factors using deep sequencing. In total, 4,781 transcripts were identified in this study, and 1,151 and 3,076 genes were differentially expressed when P6 was compared with P2 and with C5, respectively. Our results indicated that Xoo strains from different regions exhibited distinctly different expression patterns of putative virulence-relevant genes. Interestingly, 40 and 44 genes involved in chemotaxis and motility exhibited higher transcript alterations in C5 compared with P6 and P2, respectively. Most other genes associated with virulence, including exopolysaccharide (EPS) synthesis, Hrp genes and type III effectors, including Xanthomonas outer protein (Xop) effectors and transcription activator-like (TAL) effectors, were down-regulated in C5 compared with P6 and P2. The data were confirmed by real-time quantitative RT-PCR, tests of bacterial motility, and enzyme activity analysis of EPS and xylanase. These results highlight the complexity of Xoo and offer new avenues for improving our understanding of Xoo-rice interactions and the evolution of Xoo virulence. PMID- 23734194 TI - Early nutrition and weight gain in preterm newborns and the risk of retinopathy of prematurity. AB - OBJECTIVE: To identify nutritional and weight gain limitations associated with retinopathy of prematurity (ROP) severity among very preterm newborns. PATIENTS AND METHODS: 1180 infants <28 weeks GA at birth with ROP examination results were grouped and analyzed by quartile of weekly total calorie, carbohydrate, protein, and lipid intake, as well as growth velocity between postnatal days 7 and 28 (adjusted for GA and birth weight Z-score). ROP was categorized by development of no, mild (=-1). RESULTS: 53 809 children were eligible for this re analysis and contributed a total of 55 359 person-years, during which 1315 deaths were observed. All degrees of underweight, stunting and wasting were associated with significantly higher mortality. The strength of association increased monotonically as Z scores decreased. Pooled mortality HR was 1.52 (95% Confidence Interval 1.28, 1.81) for mild underweight; 2.63 (2.20, 3.14) for moderate underweight; and 9.40 (8.02, 11.03) for severe underweight. Wasting was a stronger determinant of mortality than stunting or underweight. Mortality HR for severe wasting was 11.63 (9.84, 13.76) compared with 5.48 (4.62, 6.50) for severe stunting. Using older NCHS standards resulted in larger HRs compared with WHO standards. In cause-specific analyses, all degrees of anthropometric deficits increased the hazards of dying from respiratory tract infections and diarrheal diseases. The study had insufficient power to precisely estimate effects of undernutrition on malaria mortality. CONCLUSIONS: All degrees of anthropometric deficits are associated with increased risk of under-five mortality using the 2006 WHO Standards. Even mild deficits substantially increase mortality, especially from infectious diseases. PMID- 23734211 TI - Phylogenomic analyses of nuclear genes reveal the evolutionary relationships within the BEP clade and the evidence of positive selection in Poaceae. AB - BEP clade of the grass family (Poaceae) is composed of three subfamilies, i.e. Bambusoideae, Ehrhartoideae, and Pooideae. Controversies on the phylogenetic relationships among three subfamilies still persist in spite of great efforts. However, previous evidence was mainly provided from plastid genes with only a few nuclear genes utilized. Given different evolutionary histories recorded by plastid and nuclear genes, it is indispensable to uncover their relationships based on nuclear genes. Here, eleven species with whole-sequenced genome and six species with transcriptomic data were included in this study. A total of 121 one to-one orthologous groups (OGs) were identified and phylogenetic trees were reconstructed by different tree-building methods. Genes which might have undergone positive selection and played important roles in adaptive evolution were also investigated from 314 and 173 one-to-one OGs in two bamboo species and 14 grass species, respectively. Our results support the ((B, P) E) topology with high supporting values. Besides, our findings also indicate that 24 and nine orthologs with statistically significant evidence of positive selection are mainly involved in abiotic and biotic stress response, reproduction and development, plant metabolism and enzyme etc. from two bamboo species and 14 grass species, respectively. In summary, this study demonstrates the power of phylogenomic approach to shed lights on the evolutionary relationships within the BEP clade, and offers valuable insights into adaptive evolution of the grass family. PMID- 23734212 TI - Clostridium perfringens beta-toxin induces necrostatin-inhibitable, calpain dependent necrosis in primary porcine endothelial cells. AB - Clostridium perfringens beta-toxin (CPB) is a beta-barrel pore-forming toxin and an essential virulence factor of C. perfringens type C strains, which cause fatal hemorrhagic enteritis in animals and humans. We have previously shown that CPB is bound to endothelial cells within the intestine of affected pigs and humans, and that CPB is highly toxic to primary porcine endothelial cells (pEC) in vitro. The objective of the present study was to investigate the type of cell death induced by CPB in these cells, and to study potential host cell mechanisms involved in this process. CPB rapidly induced lactate dehydrogenase (LDH) release, propidium iodide uptake, ATP depletion, potassium efflux, a marked rise in intracellular calcium [Ca(2+)]i, release of high-mobility group protein B1 (HMGB1), and caused ultrastructural changes characteristic of necrotic cell death. Despite a certain level of caspase-3 activation, no appreciable DNA fragmentation was detected. CPB induced LDH release and propidium iodide uptake were inhibited by necrostatin-1 and the two dissimilar calpain inhibitors PD150606 and calpeptin. Likewise, inhibition of potassium efflux, chelation of intracellular calcium and treatment of pEC with cyclosporin A also significantly inhibited CPB-induced LDH release. Our results demonstrate that rCPB primarily induces necrotic cell death in pEC, and that necrotic cell death is not merely a passive event caused by toxin induced membrane disruption, but is propagated by host cell-dependent biochemical pathways activated by the rise in intracellular calcium and inhibitable by necrostatin-1, consistent with the emerging concept of programmed necrosis ("necroptosis"). PMID- 23734213 TI - Functional domains of androgen receptor coactivator p44/Mep50/WDR77and its interaction with Smad1. AB - p44/MEP50/WDR77 has been identified as a coactivator of androgen receptor (AR), with distinct growth suppression and promotion function in gender specific endocrine organs and their malignancies. We dissected the functional domains of p44 for protein interaction with transcription factors, transcriptional activation, as well as the functional domains in p44 related to its growth inhibition in prostate cancer. Using a yeast two-hybrid screen, we identified a novel transcription complex AR-p44-Smad1, confirmed for physical interaction by co-immunoprecipitaion and functional interaction with luciferase assays in human prostate cancer cells. Yeast two-hybrid assay revealed that the N-terminal region of p44, instead of the traditional WD40 domain at the C-terminus, mediates the interaction among p44, N-terminus of AR and full length Smad1. Although both N and C terminal domains of p44 are necessary for maximum AR transcriptional activation, the N terminal fragment of p44 alone maintains the basic effect on AR transcriptional activation. Cell proliferation assays with N- and C- terminal deletion mutations indicated that the central portion of p44 is required for nuclear p44 mediated prostate cancer growth inhibition. PMID- 23734209 TI - Transcriptome and proteome data reveal candidate genes for pollinator attraction in sexually deceptive orchids. AB - BACKGROUND: Sexually deceptive orchids of the genus Ophrys mimic the mating signals of their pollinator females to attract males as pollinators. This mode of pollination is highly specific and leads to strong reproductive isolation between species. This study aims to identify candidate genes responsible for pollinator attraction and reproductive isolation between three closely related species, O. exaltata, O. sphegodes and O. garganica. Floral traits such as odour, colour and morphology are necessary for successful pollinator attraction. In particular, different odour hydrocarbon profiles have been linked to differences in specific pollinator attraction among these species. Therefore, the identification of genes involved in these traits is important for understanding the molecular basis of pollinator attraction by sexually deceptive orchids. RESULTS: We have created floral reference transcriptomes and proteomes for these three Ophrys species using a combination of next-generation sequencing (454 and Solexa), Sanger sequencing, and shotgun proteomics (tandem mass spectrometry). In total, 121 917 unique transcripts and 3531 proteins were identified. This represents the first orchid proteome and transcriptome from the orchid subfamily Orchidoideae. Proteome data revealed proteins corresponding to 2644 transcripts and 887 proteins not observed in the transcriptome. Candidate genes for hydrocarbon and anthocyanin biosynthesis were represented by 156 and 61 unique transcripts in 20 and 7 genes classes, respectively. Moreover, transcription factors putatively involved in the regulation of flower odour, colour and morphology were annotated, including Myb, MADS and TCP factors. CONCLUSION: Our comprehensive data set generated by combining transcriptome and proteome technologies allowed identification of candidate genes for pollinator attraction and reproductive isolation among sexually deceptive orchids. This includes genes for hydrocarbon and anthocyanin biosynthesis and regulation, and the development of floral morphology. These data will serve as an invaluable resource for research in orchid floral biology, enabling studies into the molecular mechanisms of pollinator attraction and speciation. PMID- 23734215 TI - The digital evolution of occupy wall street. AB - We examine the temporal evolution of digital communication activity relating to the American anti-capitalist movement Occupy Wall Street. Using a high-volume sample from the microblogging site Twitter, we investigate changes in Occupy participant engagement, interests, and social connectivity over a fifteen month period starting three months prior to the movement's first protest action. The results of this analysis indicate that, on Twitter, the Occupy movement tended to elicit participation from a set of highly interconnected users with pre-existing interests in domestic politics and foreign social movements. These users, while highly vocal in the months immediately following the birth of the movement, appear to have lost interest in Occupy related communication over the remainder of the study period. PMID- 23734214 TI - L-type calcium channels play a critical role in maintaining lens transparency by regulating phosphorylation of aquaporin-0 and myosin light chain and expression of connexins. AB - Homeostasis of intracellular calcium is crucial for lens cytoarchitecture and transparency, however, the identity of specific channel proteins regulating calcium influx within the lens is not completely understood. Here we examined the expression and distribution profiles of L-type calcium channels (LTCCs) and explored their role in morphological integrity and transparency of the mouse lens, using cDNA microarray, RT-PCR, immunoblot, pharmacological inhibitors and immunofluorescence analyses. The results revealed that Ca (V) 1.2 and 1.3 channels are expressed and distributed in both the epithelium and cortical fiber cells in mouse lens. Inhibition of LTCCs with felodipine or nifedipine induces progressive cortical cataract formation with time, in association with decreased lens weight in ex-vivo mouse lenses. Histological analyses of felodipine treated lenses revealed extensive disorganization and swelling of cortical fiber cells resembling the phenotype reported for altered aquaporin-0 activity without detectable cytotoxic effects. Analysis of both soluble and membrane rich fractions from felodipine treated lenses by SDS-PAGE in conjunction with mass spectrometry and immunoblot analyses revealed decreases in beta-B1-crystallin, Hsp-90, spectrin and filensin. Significantly, loss of transparency in the felodipine treated lenses was preceded by an increase in aquaporin-0 serine-235 phosphorylation and levels of connexin-50, together with decreases in myosin light chain phosphorylation and the levels of 14-3-3epsilon, a phosphoprotein binding regulatory protein. Felodipine treatment led to a significant increase in gene expression of connexin-50 and 46 in the mouse lens. Additionally, felodipine inhibition of LTCCs in primary cultures of mouse lens epithelial cells resulted in decreased intracellular calcium, and decreased actin stress fibers and myosin light chain phosphorylation, without detectable cytotoxic response. Taken together, these observations reveal a crucial role for LTCCs in regulation of expression, activity and stability of aquaporin-0, connexins, cytoskeletal proteins, and the mechanical properties of lens, all of which have a vital role in maintaining lens function and cytoarchitecture. PMID- 23734216 TI - Drosophila host model reveals new enterococcus faecalis quorum-sensing associated virulence factors. AB - Enterococcus faecalis V583 is a vancomycin-resistant clinical isolate which belongs to the hospital-adapted clade, CC2. This strain harbours several factors that have been associated with virulence, including the fsr quorum-sensing regulatory system that is known to control the expression of GelE and SprE proteases. To discriminate between genes directly regulated by Fsr, and those indirectly regulated as the result of protease expression or activity, we compared gene expression in isogenic mutants of V583 variously defective in either Fsr quorum sensing or protease expression. Quorum sensing was artificially induced by addition of the quorum signal, GBAP, exogenously in a controlled manner. The Fsr regulon was found to be restricted to five genes, gelE, sprE, ef1097, ef1351 and ef1352. Twelve additional genes were found to be dependent on the presence of GBAP-induced proteases. Induction of GelE and SprE by GBAP via Fsr resulted in accumulation of mRNA encoding lrgAB, and this induction was found to be lytRS dependent. Drosophila infection was used to discern varying levels of toxicity stemming from mutations in the fsr quorum regulatory system and the genes that it regulates, highlighting the contribution of LrgAB and bacteriocin EF1097 to infection toxicity. A contribution of SprE to infection toxicity was also detected. This work brought to light new players in E. faecalis success as a pathogen and paves the way for future studies on host tolerance mechanisms to infections caused by this important nosocomial pathogen. PMID- 23734217 TI - MicroRNA-449a is downregulated in non-small cell lung cancer and inhibits migration and invasion by targeting c-Met. AB - MicroRNA-449a is expressed at a low level in several tumors and cancer cell lines, and induces G1 arrest, apoptosis, and senescence. To identify the function of miR-449a in non-small cell lung cancer (NSCLC), we discussed the potential relevance of miR-449a to clinicopathological characteristics and prognosis in NSCLC. We also investigated the impact of miR-449a on migration and invasion in NSCLC cells. The expression of miR-449a in NSCLC tissues and cell lines was detected using RT-qPCR. In vitro, gain-of-function, loss-of-function experiments, and fluorescence assays were performed to identify the potential target of miR 449a and the function of miR-449a in NSCLC cells. MiR-449a was downregulated in both NSCLC tissues and cell lines. Moreover, a low expression level of miR-449a appeared to be correlated with lymph node metastasis and poor survival. In vitro, miR-449 regulated cell migration and invasion in NSCLC cells as a potential tumor suppressor, at least in part by targeting c-Met. Furthermore, reciprocal expression of miR-449a and c-Met was shown in NSCLC tissue samples. This study indicates that miR-449a might be associated with NSCLC progression, and suggests a crucial role for miR-449a in NSCLC. PMID- 23734218 TI - The association between progression of atherosclerosis and the methylated amino acids asymmetric dimethylarginine and trimethyllysine. AB - OBJECTIVE: We previously showed that treatment with folic acid (FA)/B12 was associated with more rapid progression of coronary artery disease (CAD). High doses of FA may induce methylation by increasing the availability of S-adenosyl methionine (SAM). Asymmetric dimethylarginine (ADMA) and trimethyllysine (TML) are both produced through proteolytic release following post-translational SAM dependent methylation of precursor amino acid. ADMA has previously been associated with CAD. We investigated if plasma levels of ADMA and TML were associated with progression of CAD as measured by quantitative coronary angiography (QCA). METHODS: 183 patients from the Western Norway B Vitamin Intervention Trial (WENBIT) undergoing percutaneous coronary intervention (PCI) were randomized to daily treatment with 0.8 mg FA/0.4 mg B12 with and without 40 mg B6, B6 alone or placebo. Coronary angiograms and plasma samples of ADMA and TML were obtained at both baseline and follow-up (median 10.5 months). The primary end-point was progression of CAD as measured by diameter stenosis (DS) evaluated by linear quantile mixed models. RESULTS: A total of 309 coronary lesions not treated with PCI were identified. At follow-up median (95% CI) DS increased by 18.35 (5.22-31.49) percentage points per umol/L ADMA increase (p value 0.006) and 2.47 (0.37-4.58) percentage points per umol/L TML increase (p value 0.021) in multivariate modeling. Treatment with FA/B12 (+/-B6) was not associated with ADMA or TML levels. CONCLUSION: In patients with established CAD, baseline ADMA and TML was associated with angiographic progression of CAD. However, neither ADMA nor TML levels were altered by treatment with FA/B12 (+/ B6). TRIAL REGISTRATION: Controlled-Trials.com NCT00354081. PMID- 23734219 TI - Draft genome sequence, and a sequence-defined genetic linkage map of the legume crop species Lupinus angustifolius L. AB - Lupin (Lupinus angustifolius L.) is the most recently domesticated crop in major agricultural cultivation. Its seeds are high in protein and dietary fibre, but low in oil and starch. Medical and dietetic studies have shown that consuming lupin-enriched food has significant health benefits. We report the draft assembly from a whole genome shotgun sequencing dataset for this legume species with 26.9x coverage of the genome, which is predicted to contain 57,807 genes. Analysis of the annotated genes with metabolic pathways provided a partial understanding of some key features of lupin, such as the amino acid profile of storage proteins in seeds. Furthermore, we applied the NGS-based RAD-sequencing technology to obtain 8,244 sequence-defined markers for anchoring the genomic sequences. A total of 4,214 scaffolds from the genome sequence assembly were aligned into the genetic map. The combination of the draft assembly and a sequence-defined genetic map made it possible to locate and study functional genes of agronomic interest. The identification of co-segregating SNP markers, scaffold sequences and gene annotation facilitated the identification of a candidate R gene associated with resistance to the major lupin disease anthracnose. We demonstrated that the combination of medium-depth genome sequencing and a high-density genetic linkage map by application of NGS technology is a cost-effective approach to generating genome sequence data and a large number of molecular markers to study the genomics, genetics and functional genes of lupin, and to apply them to molecular plant breeding. This strategy does not require prior genome knowledge, which potentiates its application to a wide range of non-model species. PMID- 23734220 TI - Seeing and hearing a word: combining eye and ear is more efficient than combining the parts of a word. AB - To understand why human sensitivity for complex objects is so low, we study how word identification combines eye and ear or parts of a word (features, letters, syllables). Our observers identify printed and spoken words presented concurrently or separately. When researchers measure threshold (energy of the faintest visible or audible signal) they may report either sensitivity (one over the human threshold) or efficiency (ratio of the best possible threshold to the human threshold). When the best possible algorithm identifies an object (like a word) in noise, its threshold is independent of how many parts the object has. But, with human observers, efficiency depends on the task. In some tasks, human observers combine parts efficiently, needing hardly more energy to identify an object with more parts. In other tasks, they combine inefficiently, needing energy nearly proportional to the number of parts, over a 60?1 range. Whether presented to eye or ear, efficiency for detecting a short sinusoid (tone or grating) with few features is a substantial 20%, while efficiency for identifying a word with many features is merely 1%. Why? We show that the low human sensitivity for words is a cost of combining their many parts. We report a dichotomy between inefficient combining of adjacent features and efficient combining across senses. Joining our results with a survey of the cue-combination literature reveals that cues combine efficiently only if they are perceived as aspects of the same object. Observers give different names to adjacent letters in a word, and combine them inefficiently. Observers give the same name to a word's image and sound, and combine them efficiently. The brain's machinery optimally combines only cues that are perceived as originating from the same object. Presumably such cues each find their own way through the brain to arrive at the same object representation. PMID- 23734221 TI - High myeloperoxidase positive cell infiltration in colorectal cancer is an independent favorable prognostic factor. AB - BACKGROUND: Colorectal cancer (CRC) infiltration by adaptive immune system cells correlates with favorable prognosis. The role of the innate immune system is still debated. Here we addressed the prognostic impact of CRC infiltration by neutrophil granulocytes (NG). METHODS: A TMA including healthy mucosa and clinically annotated CRC specimens (n = 1491) was stained with MPO and CD15 specific antibodies. MPO+ and CD15+ positive immune cells were counted by three independent observers. Phenotypic profiles of CRC infiltrating MPO+ and CD15+ cells were validated by flow cytometry on cell suspensions derived from enzymatically digested surgical specimens. Survival analysis was performed by splitting randomized data in training and validation subsets. RESULTS: MPO+ and CD15+ cell infiltration were significantly correlated (p<0.0001; r = 0.76). However, only high density of MPO+ cell infiltration was associated with significantly improved survival in training (P = 0.038) and validation (P = 0.002) sets. In multivariate analysis including T and N stage, vascular invasion, tumor border configuration and microsatellite instability status, MPO+ cell infiltration proved an independent prognostic marker overall (P = 0.004; HR = 0.65; CI:+/-0.15) and in both training (P = 0.048) and validation (P = 0.036) sets. Flow-cytometry analysis of CRC cell suspensions derived from clinical specimens showed that while MPO+ cells were largely CD15+/CD66b+, sizeable percentages of CD15+ and CD66b+ cells were MPO-. CONCLUSIONS: High density MPO+ cell infiltration is a novel independent favorable prognostic factor in CRC. PMID- 23734223 TI - Ranking landscape development scenarios affecting natterjack toad (Bufo calamita) population dynamics in Central Poland. AB - When data are limited it is difficult for conservation managers to assess alternative management scenarios and make decisions. The natterjack toad (Bufo calamita) is declining at the edges of its distribution range in Europe and little is known about its current distribution and abundance in Poland. Although different landscape management plans for central Poland exist, it is unclear to what extent they impact this species. Based on these plans, we investigated how four alternative landscape development scenarios would affect the total carrying capacity and population dynamics of the natterjack toad. To facilitate decision making, we first ranked the scenarios according to their total carrying capacity. We used the software RAMAS GIS to determine the size and location of habitat patches in the landscape. The estimated carrying capacities were very similar for each scenario, and clear ranking was not possible. Only the reforestation scenario showed a marked loss in carrying capacity. We therefore simulated metapopulation dynamics with RAMAS taking into account dynamical processes such as reproduction and dispersal and ranked the scenarios according to the resulting species abundance. In this case, we could clearly rank the development scenarios. We identified road mortality of adults as a key process governing the dynamics and separating the different scenarios. The renaturalisation scenario clearly ranked highest due to its decreased road mortality. Taken together our results suggest that road infrastructure development might be much more important for natterjack toad conservation than changes in the amount of habitat in the semi natural river valley. We gained these insights by considering both the resulting metapopulation structure and dynamics in the form of a PVA. We conclude that the consideration of dynamic processes in amphibian conservation management may be indispensable for ranking management scenarios. PMID- 23734222 TI - Increase of IL-12 following reconstruction for total en bloc spondylectomy using frozen autografts treated with liquid nitrogen. AB - BACKGROUND: Total en bloc spondylectomy (TES) is a surgery designed to achieve complete resection of a malignant spinal tumor such as spinal metastasis. Although this procedure decreases the rate of local recurrence, it is questionable whether local control prolongs patient's survival. We developed a "second-generation TES" that brings about TES enhancing antitumor immunity to prolong patient's survival. Our purpose is to present a second-generation TES applied tumor-induced cryoimmunology and assess the immunity-enhancing effect after implementing this surgery. METHODS: We performed a retrospective review of prospectively collected data in second-generation TES as carried out in 56 cases. In second-generation TES, instead of harvesting autograft from the ilium or fibula, the resected lamina and vertebral body from TES are frozen using liquid nitrogen and used as grafted bone for spinal reconstruction. In recent 26 of the 56 cases, in addition to the TES procedure, a small amount of the tumor tissue from the resected tumor-bearing vertebra was also placed into liquid nitrogen. This small amount of tumor tissue was then implanted subcutaneously on one side of the axilla. In 52 of 56 cases, measurement of interleukin 12 (IL-12) was performed before surgery and at both 1 and 3 months after surgery. RESULTS: IL-12 increased after TES surgery in 38 of 52 cases (73.1%). The mean IL-12 relative concentrations at both 1 and 3 months after surgery, as compared to before surgery, were significantly higher (121+/-89 and 149+/-111%: P<0.05 and P<0.01). CONCLUSIONS: Our results show that second-generation TES may provide not only a local radical cure but also a systemic immunological enhancement. Further prolonged survival in patients with a malignant spinal tumor is promising by second-generation TES. PMID- 23734224 TI - Insights into the folding and unfolding processes of wild-type and mutated SH3 domain by molecular dynamics and replica exchange molecular dynamics simulations. AB - Src-homology regions 3 (SH3) domain is essential for the down-regulation of tyrosine kinase activity. Mutation A39V/N53P/V55L of SH3 is found to be relative to the urgent misfolding diseases. To gain insight, the human and gallus SH3 domains (PDB ID: 1NYG and 2LP5), including 58 amino acids in each protein, were selected for MD simulations (Amber11, ff99SB force field) and cluster analysis to investigate the influence of mutations on the spatial structure of the SH3 domain. It is found that the large conformational change of mutations mainly exists in three areas in the vicinity of protein core: RT loop, N-src loop, distal beta-hairpin to 310 helix. The C-terminus of the mutated gallus SH3 is disordered after simulation, which represents the intermediate state of aggregation. The disappeared strong Hbond net in the mutated human and gallus systems will make these mutated proteins looser than the wild-type proteins. Additionally, by performing the REMD simulations on the gallus SH3 domain, the mutated domain is found to have an obvious effect on the unfolding process. These studies will be helpful for further aggregation mechanisms investigations on SH3 family. PMID- 23734225 TI - Electrostatic mis-interactions cause overexpression toxicity of proteins in E. coli. AB - A majority of E. coli proteins when overexpressed inhibit its growth, but the reasons behind overexpression toxicity of proteins remain unknown. Understanding the mechanism of overexpression toxicity is important from evolutionary, biotechnological and possibly clinical perspectives. Here we study sequence and functional features of cytosolic proteins of E. coli associated with overexpression toxicity to understand its mechanism. We find that number of positively charged residues is significantly higher in proteins showing overexpression toxicity. Very long proteins also show high overexpression toxicity. Among the functional classes, transcription factors and regulatory proteins are enriched in toxic proteins, while catalytic proteins are depleted. Overexpression toxicity could be predicted with reasonable accuracy using these few properties. The importance of charged residues in overexpression toxicity indicates that nonspecific electrostatic interactions resulting from protein overexpression cause toxicity of these proteins and suggests ways to improve the expression level of native and foreign proteins in E. coli for basic research and biotechnology. These results might also be applicable to other bacterial species. PMID- 23734226 TI - Eliciting renal failure in mosquitoes with a small-molecule inhibitor of inward rectifying potassium channels. AB - Mosquito-borne diseases such as malaria and dengue fever take a large toll on global health. The primary chemical agents used for controlling mosquitoes are insecticides that target the nervous system. However, the emergence of resistance in mosquito populations is reducing the efficacy of available insecticides. The development of new insecticides is therefore urgent. Here we show that VU573, a small-molecule inhibitor of mammalian inward-rectifying potassium (Kir) channels, inhibits a Kir channel cloned from the renal (Malpighian) tubules of Aedes aegypti (AeKir1). Injection of VU573 into the hemolymph of adult female mosquitoes (Ae. aegypti) disrupts the production and excretion of urine in a manner consistent with channel block of AeKir1 and renders the mosquitoes incapacitated (flightless or dead) within 24 hours. Moreover, the toxicity of VU573 in mosquitoes (Ae. aegypti) is exacerbated when hemolymph potassium levels are elevated, suggesting that Kir channels are essential for maintenance of whole animal potassium homeostasis. Our study demonstrates that renal failure is a promising mechanism of action for killing mosquitoes, and motivates the discovery of selective small-molecule inhibitors of mosquito Kir channels for use as insecticides. PMID- 23734227 TI - Extracting physician group intelligence from electronic health records to support evidence based medicine. AB - Evidence-based medicine employs expert opinion and clinical data to inform clinical decision making. The objective of this study is to determine whether it is possible to complement these sources of evidence with information about physician "group intelligence" that exists in electronic health records. Specifically, we measured laboratory test "repeat intervals", defined as the amount of time it takes for a physician to repeat a test that was previously ordered for the same patient. Our assumption is that while the result of a test is a direct measure of one marker of a patient's health, the physician's decision to order the test is based on multiple factors including past experience, available treatment options, and information about the patient that might not be coded in the electronic health record. By examining repeat intervals in aggregate over large numbers of patients, we show that it is possible to 1) determine what laboratory test results physicians consider "normal", 2) identify subpopulations of patients that deviate from the norm, and 3) identify situations where laboratory tests are over-ordered. We used laboratory tests as just one example of how physician group intelligence can be used to support evidence based medicine in a way that is automated and continually updated. PMID- 23734228 TI - Predicting cognitive state from eye movements. AB - In human vision, acuity and color sensitivity are greatest at the center of fixation and fall off rapidly as visual eccentricity increases. Humans exploit the high resolution of central vision by actively moving their eyes three to four times each second. Here we demonstrate that it is possible to classify the task that a person is engaged in from their eye movements using multivariate pattern classification. The results have important theoretical implications for computational and neural models of eye movement control. They also have important practical implications for using passively recorded eye movements to infer the cognitive state of a viewer, information that can be used as input for intelligent human-computer interfaces and related applications. PMID- 23734229 TI - Conservation of the patchily distributed and declining purple-crowned fairy-wren (Malurus coronatus coronatus) across a vast landscape: the need for a collaborative landscape-scale approach. AB - Conservation of species that are patchily distributed must consider processes that influence both the occurrence of individuals within patches, and the persistence of populations across multiple habitat patches within the landscape. Here we present a rare regional assessment of the population size and distribution of a patchily distributed, threatened species, the purple-crowned fairy-wren (Malurus coronatus coronatus), across a vast landscape. We used data from aerial vegetation mapping of waterways, with on-ground bird surveys to predict the occurrence of suitable habitat for M. c. coronatus across 14 catchments in the Kimberley region of Western Australia. Suitable habitat was extremely limited (305 km of riparian vegetation) and fragmented (342 patches) along the 2700 km of waterway surveyed within catchments where the species occurs. Populations were predicted to be large on the Fitzroy, Durack and Drysdale catchments, and small on the Isdell and northern Pentecost catchments, and a total population of 2834 to 4878 individuals could be supported. The sub populations spanned numerous patches of habitat across multiple properties of varying tenure. Therefore, a landscape-scale approach to conservation management, across multiple tenures, is critical to safe-guard connectivity within populations. The greatest benefit may be achieved by a combination of broad-scale actions to reduce the impact of ubiquitous threatening processes, and fine-scale targeted effort in areas where populations are most vulnerable. Controlling access of stock to waterways and management of fire are most important to conserve suitable habitat. Such a landscape-scale approach to conservation may be of benefit to other patchily distributed species. PMID- 23734230 TI - Brain responses to words in 2-year-olds with autism predict developmental outcomes at age 6. AB - Autism Spectrum Disorder (ASD) is a developmental disability that affects social behavior and language acquisition. ASD exhibits great variability in outcomes, with some individuals remaining nonverbal and others exhibiting average or above average function. Cognitive ability contributes to heterogeneity in autism and serves as a modest predictor of later function. We show that a brain measure (event-related potentials, ERPs) of word processing in children with ASD, assessed at the age of 2 years (N = 24), is a broad and robust predictor of receptive language, cognitive ability, and adaptive behavior at ages 4 and 6 years, regardless of the form of intensive clinical treatment during the intervening years. The predictive strength of this brain measure increases over time, and exceeds the predictive strength of a measure of cognitive ability, used here for comparison. These findings have theoretical implications and may eventually lead to neural measures that allow early prediction of developmental outcomes as well as more individually tailored clinical interventions, with the potential for greater effectiveness in treating children with ASD. PMID- 23734231 TI - Decomposing the gap in childhood undernutrition between poor and non-poor in urban India, 2005-06. AB - BACKGROUND: Despite the growing evidence from other developing countries, intra urban inequality in childhood undernutrition is poorly researched in India. Additionally, the factors contributing to the poor/non-poor gap in childhood undernutrition have not been explored. This study aims to quantify the contribution of factors that explain the poor/non-poor gap in underweight, stunting, and wasting among children aged less than five years in urban India. METHODS: We used cross-sectional data from the third round of the National Family Health Survey conducted during 2005-06. Descriptive statistics were used to understand the gap in childhood undernutrition between the urban poor and non poor, and across the selected covariates. Blinder-Oaxaca decomposition technique was used to explain the factors contributing to the average gap in undernutrition between poor and non-poor children in urban India. RESULT: Considerable proportions of urban children were found to be underweight (33%), stunted (40%), and wasted (17%) in 2005-06. The undernutrition gap between the poor and non-poor was stark in urban India. For all the three indicators, the main contributing factors were underutilization of health care services, poor body mass index of the mothers, and lower level of parental education among those living in poverty. CONCLUSIONS: The findings indicate that children belonging to poor households are undernourished due to limited use of health care services, poor health of mothers, and poor educational status of their parents. Based on the findings the study suggests that improving the public services such as basic health care and the education level of the mothers among urban poor can ameliorate the negative impact of poverty on childhood undernutrition. PMID- 23734232 TI - Hierarchical organization of multi-site phosphorylation at the CXCR4 C terminus. AB - The chemokine receptor CXCR4 regulates cell migration during ontogenesis and disease states including cancer and inflammation. Upon stimulation by the endogenous ligand CXCL12, CXCR4 becomes phosphorylated at multiple sites in its C terminal domain. Mutations in the CXCR4 gene affecting C-terminal phosphorylation sites are a hallmark of WHIM syndrome, a genetic disorder characterized by a gain of-CXCR4-function. To better understand how multi-site phosphorylation of CXCR4 is organized and how perturbed phosphorylation might affect CXCR4 function, we developed novel phosphosite-specific CXCR4 antibodies and studied the differential regulation and interaction of three C-terminal phosphorylation sites in human embryonic kidney cells (HEK293). CXCL12 promoted a robust phosphorylation at S346/347 which preceded phosphorylation at S324/325 and S338/339. After CXCL12 washout, the phosphosites S338/339 and S324/325 were rapidly dephosphorylated whereas phosphorylation at S346/347 was long-lasting. CXCL12-induced phosphorylation at S346/347 was staurosporine-insensitive and mediated by GRK2/3. WHIM syndrome-associated CXCR4 truncation mutants lacking the S346/347 phosphosite and the recently identified E343K WHIM mutant displayed strongly impaired phosphorylation at S324/325 and S338/339 as well as reduced CXCL12-induced receptor internalization. Relevance of the S346-S348 site was confirmed by a S346-348A mutant showing strongly impaired CXCL12-promoted phosphorylation at S324/325 and S338/339, defective internalization, gain of calcium mobilization, and reduced desensitization. Thus, the triple serine motif S346-S348 contains a major initial CXCR4 phosphorylation site and is required for efficient subsequent multi-site phosphorylation and receptor regulation. Hierarchical organization of CXCR4 phosphorylation explains why small deletions at the extreme CXCR4 C terminus typically associated with WHIM syndrome severely alter CXCR4 function. PMID- 23734233 TI - A novel carboxyl-terminal heptapeptide initiates the regulated secretion of LH from unique sub-domains of the ER. AB - The coordinated secretion of LH and FSH are critical for reproductive functions. After translocation into the endoplasmic reticulum (ER), their biosynthetic routes diverge at a determinative step prior to sorting in the regulated (LH) and constitutive (FSH) secretion pathways. Recently, we identified a C-terminal heptapeptide sequence, present only in the LHbeta subunit, as a critical signal for entry of the LH dimer into the regulated pathway. We showed that an LHbeta mutant lacking the heptapeptide (LHbetaDeltaT) assembled more efficiently with the alpha subunit than wild-type LHbeta subunit, and this LHDeltaT dimer was secreted constitutively. Thus, an association exists between the presence of the C-terminal heptapeptide and sorting of the LH heterodimer to the regulated pathway. To study how this delayed LHbeta subunit assembly is related to the trafficking of LH, we exploited the single subunit transfection model in rat somatotrope-derived GH3 cells with the use of immunofluorescence confocal microscopy. The LHbeta subunit showed a distinct immunofluorescent localization as compared to the FSHbeta subunit and LHbeta mutants. The wild-type LHbeta subunit exhibited a perinuclear staining corresponding to the ER/nuclear envelope region. In contrast, the wild-type FSHbeta subunit and the mutants LHbetaDeltaT and LHbetaL119A displayed no detectable perinuclear staining; only peripheral ER puncta were observed. Also, no perinuclear fluorescence was detected in cells expressing the LH heterodimer. We propose that the C-terminal heptapeptide is responsible for delayed heterodimer assembly within an ER sub-domain of the nuclear envelope, as an early partitioning event necessary for the entrance of LH into the regulated secretory pathway, whereas FSHbeta does not traverse the nuclear envelope region. These data suggest that, at least for LH, the molecular decision to enter the regulated secretory pathway is a pre-Golgi event controlled by the novel C-terminal heptapeptide. PMID- 23734234 TI - Species-specific traits plus stabilizing processes best explain coexistence in biodiverse fire-prone plant communities. AB - Coexistence in fire-prone Mediterranean-type shrublands has been explored in the past using both neutral and niche-based models. However, distinct differences between plant functional types (PFTs), such as fire-killed vs resprouting responses to fire, and the relative similarity of species within a PFT, suggest that coexistence models might benefit from combining both neutral and niche-based (stabilizing) approaches. We developed a multispecies metacommunity model where species are grouped into two PFTs (fire-killed vs resprouting) to investigate the roles of neutral and stabilizing processes on species richness and rank-abundance distributions. Our results show that species richness can be maintained in two ways: i) strictly neutral species within each PFT, or ii) species within PFTs differing in key demographic properties, provided that additional stabilizing processes, such as negative density regulation, also operate. However, only simulations including stabilizing processes resulted in structurally realistic rank-abundance distributions over plausible time scales. This result underscores the importance of including both key species traits and stabilizing (niche) processes in explaining species coexistence and community structure. PMID- 23734235 TI - Sleep promotes consolidation of emotional memory in healthy children but not in children with attention-deficit hyperactivity disorder. AB - Fronto-limbic brain activity during sleep is believed to support the consolidation of emotional memories in healthy adults. Attention deficit hyperactivity disorder (ADHD) is accompanied by emotional deficits coincidently caused by dysfunctional interplay of fronto-limbic circuits. This study aimed to examine the role of sleep in the consolidation of emotional memory in ADHD in the context of healthy development. 16 children with ADHD, 16 healthy children, and 20 healthy adults participated in this study. Participants completed an emotional picture recognition paradigm in sleep and wake control conditions. Each condition had an immediate (baseline) and delayed (target) retrieval session. The emotional memory bias was baseline-corrected, and groups were compared in terms of sleep dependent memory consolidation (sleep vs. wake). We observed an increased sleep dependent emotional memory bias in healthy children compared to children with ADHD and healthy adults. Frontal oscillatory EEG activity (slow oscillations, theta) during sleep correlated negatively with emotional memory performance in children with ADHD. When combining data of healthy children and adults, correlation coefficients were positive and differed from those in children with ADHD. Since children displayed a higher frontal EEG activity than adults these data indicate a decline in sleep-related consolidation of emotional memory in healthy development. In addition, it is suggested that deficits in sleep-related selection between emotional and non-emotional memories in ADHD exacerbate emotional problems during daytime as they are often reported in ADHD. PMID- 23734236 TI - Environment exploration and colonization behavior of the pea aphid associated with the expression of the foraging gene. AB - Aphids respond to specific environmental cues by producing alternative morphs, a phenomenon called polyphenism, but also by modulating their individual behavior even within the same morph. This complex plasticity allows a rapid adaptation of individuals to fluctuating environmental conditions, but the underlying genetic and molecular mechanisms remain largely unknown. The foraging gene is known to be associated with behavior in various species and has been shown to mediate the behavioral shift induced by environmental changes in some insects. In this study, we investigated the function of this gene in the clonal forms of the pea aphid Acyrthosiphon pisum by identifying and cloning cDNA variants, as well as analyzing their expression levels in developmental morphs and behavioral variants. Our results indicate that the expression of foraging changes at key steps of the aphid development. This gene is also highly expressed in sedentary wingless adult morphs reared under crowded conditions, probably just before they start walking and foraging. The cGMP-dependent protein kinase (PKG) enzyme activity measured in the behavioral variants correlates with the level of foraging expression. Altogether, our results suggest that foraging could act to promote the shift from a sedentary to an exploratory behavior, being thus involved in the behavioral plasticity of the pea aphid. PMID- 23734237 TI - Changes in the hydrocarbon proportions of colony odor and their consequences on nestmate recognition in social wasps. AB - In social insects, colonies have exclusive memberships and residents promptly detect and reject non-nestmates. Blends of epicuticular hydrocarbons communicate colony affiliation, but the question remains how social insects use the complex information in the blends to discriminate between nestmates and non-nestmates. To test this we altered colony odor by simulating interspecific nest usurpation. We split Polistes dominulus paper-wasp nests into two halves and assigned a half to the original foundress and the other half to a P. nimphus usurper for 4 days. We then removed foundresses and usurpers from nests and investigated whether emerging P. dominulus workers recognized their never-before-encountered mothers, usurpers and non-nestmates of the two species. Behavioral and chemical analyses of wasps and nests indicated that 1) foundresses marked their nests with their cuticular hydrocarbons; 2) usurpers overmarked foundress marks and 3) emerging workers learned colony odor from nests as the odor of the female that was last on nest. However, notwithstanding colony odor was usurper-biased in usurped nests, workers from these nests recognized their mothers, suggesting that there were pre imaginal and/or genetically encoded components in colony-odor learning. Surprisingly, workers from usurped nests also erroneously tolerated P. nimphus non-nestmates, suggesting they could not tell odor differences between their P. nimphus usurpers and P. nimphus non-nestmates. Usurpers changed the odors of their nests quantitatively, because the two species had cuticular hydrocarbon profiles that differed only quantitatively. Possibly, P. dominulus workers were unable to detect differences between nestmate and non-nestmate P. nimphus because the concentration of some peaks in these wasps was beyond the range of workers' discriminatory abilities (as stated by Weber's law). Indeed, workers displayed the least discrimination abilities in the usurped nests where the relative odor changes due to usurpation were the largest, suggesting that hydrocarbon variations beyond species-specific ranges can alter discrimination abilities. PMID- 23734238 TI - Communicative versus strategic rationality: Habermas theory of communicative action and the social brain. AB - In the philosophical theory of communicative action, rationality refers to interpersonal communication rather than to a knowing subject. Thus, a social view of rationality is suggested. The theory differentiates between two kinds of rationality, the emancipative communicative and the strategic or instrumental reasoning. Using experimental designs in an fMRI setting, recent studies explored similar questions of reasoning in the social world and linked them with a neural network including prefrontal and parietal brain regions. Here, we employed an fMRI approach to highlight brain areas associated with strategic and communicative reasoning according to the theory of communicative action. Participants were asked to assess different social scenarios with respect to communicative or strategic rationality. We found a network of brain areas including temporal pole, precuneus, and STS more activated when participants performed communicative reasoning compared with strategic thinking and a control condition. These brain regions have been previously linked to moral sensitivity. In contrast, strategic rationality compared with communicative reasoning and control was associated with less activation in areas known to be related to moral sensitivity, emotional processing, and language control. The results suggest that strategic reasoning is associated with reduced social and emotional cognitions and may use different language related networks. Thus, the results demonstrate experimental support for the assumptions of the theory of communicative action. PMID- 23734239 TI - Rapid 16S rRNA next-generation sequencing of polymicrobial clinical samples for diagnosis of complex bacterial infections. AB - Classifying individual bacterial species comprising complex, polymicrobial patient specimens remains a challenge for culture-based and molecular microbiology techniques in common clinical use. We therefore adapted practices from metagenomics research to rapidly catalog the bacterial composition of clinical specimens directly from patients, without need for prior culture. We have combined a semiconductor deep sequencing protocol that produces reads spanning 16S ribosomal RNA gene variable regions 1 and 2 (~360 bp) with a de noising pipeline that significantly improves the fraction of error-free sequences. The resulting sequences can be used to perform accurate genus- or species-level taxonomic assignment. We explore the microbial composition of challenging, heterogeneous clinical specimens by deep sequencing, culture-based strain typing, and Sanger sequencing of bulk PCR product. We report that deep sequencing can catalog bacterial species in mixed specimens from which usable data cannot be obtained by conventional clinical methods. Deep sequencing a collection of sputum samples from cystic fibrosis (CF) patients reveals well described CF pathogens in specimens where they were not detected by standard clinical culture methods, especially for low-prevalence or fastidious bacteria. We also found that sputa submitted for CF diagnostic workup can be divided into a limited number of groups based on the phylogenetic composition of the airway microbiota, suggesting that metagenomic profiling may prove useful as a clinical diagnostic strategy in the future. The described method is sufficiently rapid (theoretically compatible with same-day turnaround times) and inexpensive for routine clinical use. PMID- 23734240 TI - Association between non-high-density-lipoprotein-cholesterol levels and the prevalence of asymptomatic intracranial arterial stenosis. AB - OBJECTIVE: The aim of this study was to assess the association between non-high density-lipoprotein-cholesterol (non-HDL-C) and the prevalence of asymptomatic intracranial arterial stenosis (ICAS). METHODS AND RESULTS: The Asymptomatic Polyvascular Abnormalities Community (APAC) study is a prospective cohort study based on the Kailuan district (China) population. A total of 5351 eligible subjects, aged >=40, and without history of stroke or myocardial infarction, were enrolled in this study. Transcranial Doppler Ultrasonography (TCD) was performed on all enrolled subjects for the evaluation of ICAS presence. Out of 5351 patients, 698 subjects showed evidence of ICAS (prevalence of 13.04%). Multivariate analysis showed that non-HDL-C is an independent indicator for the presence of ICAS (OR = 1.15, 95%CI: 1.08 - 1.23), but with a gender difference (P for interaction<0.01): in men, non-HDL-C is an independent indicator for ICAS (multivariate-adjusted OR = 1.28, 95%CI: 1.18-1.39), but not in women (multivariate-adjusted OR = 1.03, 95%CI: 0.93-1.14). Subjects were divided into five subgroups based non-HDL-C levels and these levels correlated linearly with the prevalence of ICAS (P for trend <0.01). Compared with the first quintile, multivariate-adjusted OR (95%CI) of the second, third, fourth and fifth quintiles were: 1.05 (0.71-1.56), 1.33 (0.91-1.95), 1.83 (1.27-2.63), 2.48 (1.72-3.57), respectively. CONCLUSION: Non-HDL-C is an independent predictor of ICAS prevalence in men but not in women, suggesting that non-HDL-C levels could be used as a surveillance factor in the primary prevention of ischemic stroke, especially in men. PMID- 23734241 TI - Impact of low blood lead concentrations on IQ and school performance in Chinese children. AB - OBJECTIVES: Examine the relationships between blood lead concentrations and children's intelligence quotient (IQ) and school performance. PARTICIPANTS AND METHODS: Participants were 1341 children (738 boys and 603 girls) from Jintan, China. Blood lead concentrations were measured when children were 3-5 years old. IQ was assessed using the Chinese version and norms of the Wechsler Preschool and Primary Scale of Intelligence - Revised when children were 6 years old. School performance was assessed by standardized city tests on 3 major subjects (Chinese, Math, and English [as a foreign language]) when children were age 8-10 years. RESULTS: Mean blood lead concentration was 6.43 ug/dL (SD = 2.64). For blood lead concentrations, 7.8% of children (n = 105) had >=10.0 ug/dL, 13.8% (n = 185) had 8.0 to <10.0 ug/dL, and 78.4% (n = 1051) had <8.0 ug/dL. Compared to children with blood lead concentrations <8 ug/dL, those with blood lead concentrations >=8 ug/dL scored 2-3 points lower in IQ and 5-6 points lower in school tests. There were no significant differences in IQ or school tests between children with blood lead concentrations groups 8-10 and >=10 ug/dL. After adjustment for child and family characteristics and IQ, blood lead concentrations >=10 ug/dL vs <8 ug/dL at ages 3-5 years was associated with reduced scores on school tests at age 8-10 years (Chinese, beta = -3.54, 95%CI = -6.46, -0.63; Math, beta = -4.63, 95%CI = 7.86, -1.40; English, beta = -4.66, 95%CI = -8.09, -1.23). IQ partially mediated the relationship between elevated blood lead concentrations and later school performance. CONCLUSIONS: Findings support that blood lead concentrations in early childhood, even <10 ug/dL, have a long-term negative impact on cognitive development. The association between blood lead concentrations 8-10 ug/dL and cognitive development needs further study in Chinese children and children from other developing countries. PMID- 23734242 TI - High efficiency In Vivo genome engineering with a simplified 15-RVD GoldyTALEN design. AB - Transcription activator-like effector nucleases (TALENs) enable genome engineering in cell culture and many organisms. Recently, the GoldyTALEN scaffold was shown to readily introduce mutations in zebrafish (Danio rerio) and livestock through non-homologous end joining (NHEJ) and homology-directed repair (HDR). To deploy the GoldyTALEN system for high-throughput mutagenesis in model organisms, a simple design with high efficacy is desirable. We tested the in vivo efficacy of a simplified 15-RVD GoldyTALEN design (spacer between 13-20 bp and T nucleotide preceding each TALEN binding site) in zebrafish. All 14 tested TALEN pairs (100%) introduced small insertions and deletions at somatic efficacy ranging from 24 to 86%, and mutations were inheritable at high frequencies (18 100%). By co-injecting two GoldyTALEN pairs, inheritable deletions of a large genomic fragment up to 18 kb were successfully introduced at two different loci. In conclusion, these high efficiency 15-RVD GoldyTALENs are useful for high throughput mutagenesis in diverse application including hypothesis testing from basic science to precision medicine. PMID- 23734243 TI - The importance of the secure base effect for domestic dogs - evidence from a manipulative problem-solving task. AB - BACKGROUND: It has been suggested that dogs display a secure base effect similar to that found in human children (i.e., using the owner as a secure base for interacting with the environment). In children, this effect influences their daily lives and importantly also their performance in cognitive testing. Here, we investigate the importance of the secure base effect for dogs in a problem solving task. METHODOLOGY/PRINCIPAL FINDINGS: Using a manipulative task, we tested dogs in three conditions, in which we varied the owner's presence and behavior (Experiment 1: "Absent owner", "Silent owner", "Encouraging owner") and in one additional condition, in which the owner was replaced by an unfamiliar human (Experiment 2: "Replaced owner"). We found that the dogs' duration of manipulating the apparatus was longer when their owner was present than absent, irrespective of the owner's behavior. The presence of an unfamiliar human however did not increase their manipulation. Furthermore, the reduced manipulation during the absence of the owner was not correlated with the dog's degree of separation distress scored in a preceding attachment experiment. CONCLUSIONS/SIGNIFICANCE: Our study is the first to provide evidence for an owner-specific secure base effect in dogs that extends from attachment tests to other areas of dogs' lives and also manifests itself in cognitive testing - thereby confirming the remarkable similarity between the secure base effect in dogs and in human children. These results also have important implications for behavioral testing in dogs, because the presence or absence of the owner during a test situation might substantially influence dogs' motivation and therefore the outcome of the test. PMID- 23734244 TI - Testing adaptive hypotheses of convergence with functional landscapes: a case study of bone-cracking hypercarnivores. AB - Morphological convergence is a well documented phenomenon in mammals, and adaptive explanations are commonly employed to infer similar functions for convergent characteristics. I present a study that adopts aspects of theoretical morphology and engineering optimization to test hypotheses about adaptive convergent evolution. Bone-cracking ecomorphologies in Carnivora were used as a case study. Previous research has shown that skull deepening and widening are major evolutionary patterns in convergent bone-cracking canids and hyaenids. A simple two-dimensional design space, with skull width-to-length and depth-to length ratios as variables, was used to examine optimized shapes for two functional properties: mechanical advantage (MA) and strain energy (SE). Functionality of theoretical skull shapes was studied using finite element analysis (FEA) and visualized as functional landscapes. The distribution of actual skull shapes in the landscape showed a convergent trend of plesiomorphically low-MA and moderate-SE skulls evolving towards higher-MA and moderate-SE skulls; this is corroborated by FEA of 13 actual specimens. Nevertheless, regions exist in the landscape where high-MA and lower-SE shapes are not represented by existing species; their vacancy is observed even at higher taxonomic levels. Results highlight the interaction of biomechanical and non biomechanical factors in constraining general skull dimensions to localized functional optima through evolution. PMID- 23734245 TI - Biodiversity sampling using a global acoustic approach: contrasting sites with microendemics in New Caledonia. AB - New Caledonia is a Pacific island with a unique biodiversity showing an extreme microendemism. Many species distributions observed on this island are extremely restricted, localized to mountains or rivers making biodiversity evaluation and conservation a difficult task. A rapid biodiversity assessment method based on acoustics was recently proposed. This method could help to document the unique spatial structure observed in New Caledonia. Here, this method was applied in an attempt to reveal differences among three mountain sites (Mandjelia, Koghis and Aoupinie) with similar ecological features and species richness level, but with high beta diversity according to different microendemic assemblages. In each site, several local acoustic communities were sampled with audio recorders. An automatic acoustic sampling was run on these three sites for a period of 82 successive days. Acoustic properties of animal communities were analysed without any species identification. A frequency spectral complexity index (NP) was used as an estimate of the level of acoustic activity and a frequency spectral dissimilarity index (Df ) assessed acoustic differences between pairs of recordings. As expected, the index NP did not reveal significant differences in the acoustic activity level between the three sites. However, the acoustic variability estimated by the index Df , could first be explained by changes in the acoustic communities along the 24-hour cycle and second by acoustic dissimilarities between the three sites. The results support the hypothesis that global acoustic analyses can detect acoustic differences between sites with similar species richness and similar ecological context, but with different species assemblages. This study also demonstrates that global acoustic methods applied at broad spatial and temporal scales could help to assess local biodiversity in the challenging context of microendemism. The method could be deployed over large areas, and could help to compare different sites and determine conservation priorities. PMID- 23734246 TI - Using magnetic resonance imaging to evaluate dendritic cell-based vaccination. AB - Cancer immunotherapy with antigen-loaded dendritic cell-based vaccines can induce clinical responses in some patients, but further optimization is required to unlock the full potential of this strategy in the clinic. Optimization is dependent on being able to monitor the cellular events that take place once the dendritic cells have been injected in vivo, and to establish whether antigen specific immune responses to the tumour have been induced. Here we describe the use of magnetic resonance imaging (MRI) as a simple, non-invasive approach to evaluate vaccine success. By loading the dendritic cells with highly magnetic iron nanoparticles it is possible to assess whether the injected cells drain to the lymph nodes. It is also possible to establish whether an antigen-specific response is initiated by assessing migration of successive rounds of antigen loaded dendritic cells; in the face of a successfully primed cytotoxic response, the bulk of antigen-loaded cells are eradicated on-route to the node, whereas cells without antigen can reach the node unchecked. It is also possible to verify the induction of a vaccine-induced response by simply monitoring increases in draining lymph node size as a consequence of vaccine-induced lymphocyte trapping, which is an antigen-specific response that becomes more pronounced with repeated vaccination. Overall, these MRI techniques can provide useful early feedback on vaccination strategies, and could also be used in decision making to select responders from non-responders early in therapy. PMID- 23734247 TI - To clone or not to clone? Induced pluripotent stem cells can be generated in bulk culture. AB - Induced pluripotent stem cells (iPSCs) are usually clonally derived. The selection of fully reprogrammed cells generally involves picking of individual colonies with morphology similar to embryonic stem cells (ESCs). Given that fully reprogrammed cells are highly proliferative and escape from cellular senescence, it is conceivable that they outgrow non-pluripotent and partially reprogrammed cells during culture expansion without the need of clonal selection. In this study, we have reprogrammed human dermal fibroblasts (HDFs) with episomal plasmid vectors. Colony frequency was higher and size was larger when using murine embryonic fibroblasts (MEFs) as stromal support instead of HDFs or human mesenchymal stromal cells (MSCs). We have then compared iPSCs which were either clonally derived by manual selection of a single colony, or derived from bulk cultures of all initial colonies. After few passages their morphology, expression of pluripotency markers, and gene expression profiles did not reveal any significant differences. Furthermore, clonally-derived and bulk-cultured iPSCs revealed similar in vitro differentiation potential towards the three germ layers. Therefore, manual selection of individual colonies does not appear to be necessary for the generation of iPSCs - this is of relevance for standardization and automation of cell culture procedures. PMID- 23734248 TI - Quantitative analysis of forest fragmentation in the atlantic forest reveals more threatened bird species than the current red list. AB - Habitat loss and attendant fragmentation threaten the existence of many species. Conserving these species requires a straightforward and objective method that quantifies how these factors affect their survival. Therefore, we compared a variety of metrics that assess habitat fragmentation in bird ranges, using the geographical ranges of 127 forest endemic passerine birds inhabiting the Atlantic Forest of Brazil. A common, non-biological metric - cumulative area of size ranked fragments within a species range - was misleading, as the least threatened species had the most habitat fragmentation. Instead, we recommend a modified version of metapopulation capacity. The metric links detailed spatial information on fragment sizes and spatial configuration to the birds' abilities to occupy and disperse across large areas (100,000+ km(2)). In the Atlantic Forest, metapopulation capacities were largely bimodal, in that most species' ranges had either low capacity (high risk of extinction) or high capacity (very small risk of extinction). This pattern persisted within taxonomically and ecologically homogenous groups, indicating that it is driven by fragmentation patterns and not differences in species ecology. Worryingly, we found IUCN considers some 28 of 58 species in the low metapopulation capacity cluster to not be threatened. We propose that assessing the effect of fragmentation will separate species more clearly into distinct risk categories than does a simple assessment of remaining habitat. PMID- 23734249 TI - Protection reduces loss of natural land-cover at sites of conservation importance across Africa. AB - There is an emerging consensus that protected areas are key in reducing adverse land-cover change, but their efficacy remains difficult to quantify. Many previous assessments of protected area effectiveness have compared changes between sets of protected and unprotected sites that differ systematically in other potentially confounding respects (e.g. altitude, accessibility), have considered only forest loss or changes at single sites, or have analysed changes derived from land-cover data of low spatial resolution. We assessed the effectiveness of protection in reducing land-cover change in Important Bird Areas (IBAs) across Africa using a dedicated visual interpretation of higher resolution satellite imagery. We compared rates of change in natural land-cover over a c. 20 year period from around 1990 at a large number of points across 45 protected IBAs to those from 48 unprotected IBAs. A matching algorithm was used to select sample points to control for potentially confounding differences between protected and unprotected IBAs. The rate of loss of natural land-cover at sample points within protected IBAs was just 42% of that at matched points in unprotected IBAs. Conversion was especially marked in forests, but protection reduced rates of forest loss by a similar relative amount. Rates of conversion increased from the centre to the edges of both protected and unprotected IBAs, but rates of loss in 20-km buffer zones surrounding protected IBAs and unprotected IBAs were similar, with no evidence of displacement of conversion from within protected areas to their immediate surrounds (leakage). PMID- 23734250 TI - Low- and high-volume of intensive endurance training significantly improves maximal oxygen uptake after 10-weeks of training in healthy men. AB - Regular exercise training improves maximal oxygen uptake (VO2max), but the optimal intensity and volume necessary to obtain maximal benefit remains to be defined. A growing body of evidence suggests that exercise training with low volume but high-intensity may be a time-efficient means to achieve health benefits. In the present study, we measured changes in VO2max and traditional cardiovascular risk factors after a 10 wk. training protocol that involved three weekly high-intensity interval sessions. One group followed a protocol which consisted of 4*4 min at 90% of maximal heart rate (HRmax) interspersed with 3 min active recovery at 70% HRmax (4-AIT), the other group performed a single bout protocol that consisted of 1*4 min at 90% HRmax (1-AIT). Twenty-six inactive but otherwise healthy overweight men (BMI: 25-30, age: 35-45 y) were randomized to either 1-AIT (n = 11) or 4-AIT (n = 13). After training, VO2max increased by 10% (~5.0 mL?kg(-1)?min(-1)) and 13% (~6.5 mL?kg(-1)?min(-1)) after 1-AIT and 4-AIT, respectively (group difference, p = 0.08). Oxygen cost during running at a sub maximal workload was reduced by 14% and 13% after 1-AIT and 4-AIT, respectively. Systolic blood pressure decreased by 7.1 and 2.6 mmHg after 1-AIT and 4-AIT respectively, while diastolic pressure decreased by 7.7 and 6.1 mmHg (group difference, p = 0.84). Both groups had a similar ~5% decrease in fasting glucose. Body fat, total cholesterol, LDL-cholesterol, and ox-LDL cholesterol only were significantly reduced after 4-AIT. Our data suggest that a single bout of AIT performed three times per week may be a time-efficient strategy to improve VO2max and reduce blood pressure and fasting glucose in previously inactive but otherwise healthy middle-aged individuals. The 1-AIT type of exercise training may be readily implemented as part of activities of daily living and could easily be translated into programs designed to improve public health. TRIAL REGISTRATION: ClinicalTrials.govNCT00839579. PMID- 23734251 TI - Silencing abnormal wing disc gene of the Asian citrus psyllid, Diaphorina citri disrupts adult wing development and increases nymph mortality. AB - Huanglongbing (HLB) causes considerable economic losses to citrus industries worldwide. Its management depends on controlling of the Asian citrus Psyllid (ACP), the vector of the bacterium, Candidatus Liberibacter asiaticus (CLas), the causal agent of HLB. Silencing genes by RNA interference (RNAi) is a promising tool to explore gene functions as well as control pests. In the current study, abnormal wing disc (awd) gene associated with wing development in insects is used to interfere with the flight of psyllids. Our study showed that transcription of awd is development-dependent and the highest level was found in the last instar (5(th)) of the nymphal stage. Micro-application (topical application) of dsRNA to 5(th) instar of nymphs caused significant nymphal mortality and adult wing malformation. These adverse effects in ACP were positively correlated with the amounts of dsRNA used. A qRT-PCR analysis confirmed the dsRNA-mediated transcriptional down-regulation of the awd gene. Significant down-regulation was required to induce a wing-malformed phenotype. No effect was found when dsRNA-gfp was used, indicating the specific effect of dsRNA-awd. Our findings suggest a role for awd in ACP wing development and metamorphosis. awd could serve as a potential target for insect management either via direct application of dsRNA or by producing transgenic plants expressing dsRNA-awd. These strategies will help to mitigate HLB by controlling ACP. PMID- 23734252 TI - Obstructive sleep apnea is a predictor of abnormal glucose metabolism in chronically sleep deprived obese adults. AB - CONTEXT: Sleep abnormalities, including obstructive sleep apnea (OSA), have been associated with insulin resistance. OBJECTIVE: To determine the relationship between sleep, including OSA, and glucose parameters in a prospectively assembled cohort of chronically sleep-deprived obese subjects. DESIGN: Cross-sectional evaluation of a prospective cohort study. SETTING: Tertiary Referral Research Clinical Center. MAIN OUTCOME MEASURES: Sleep duration and quality assessed by actigraphy, sleep diaries and questionnaires, OSA determined by a portable device; glucose metabolism assessed by oral glucose tolerance test (oGTT), and HbA1c concentrations in 96 obese individuals reporting sleeping less than 6.5 h on a regular basis. RESULTS: Sixty % of subjects had an abnormal respiratory disturbance index (RDI>=5) and 44% of these subjects had abnormal oGTT results. Severity of OSA as assessed by RDI score was associated with fasting glucose (R = 0.325, p = 0.001) and fasting insulin levels (rho = 0.217, p = 0.033). Subjects with moderate to severe OSA (RDI>15) had higher glucose concentrations at 120 min than those without OSA (RDI<5) (p = 0.017). Subjects with OSA also had significantly higher concentrations of plasma ACTH (p = 0.009). Several pro inflammatory cytokines were higher in subjects with OSA (p<0.050). CRP levels were elevated in this sample, suggesting increased cardiovascular risk. CONCLUSIONS: OSA is associated with impaired glucose metabolism in obese, sleep deprived individuals. Since sleep apnea is common and frequently undiagnosed, health care providers should be aware of its occurrence and associated risks. TRIAL REGISTRATION: This study was conducted under the NIDDK protocol 06-DK-0036 and is listed in ClinicalTrials.gov NCT00261898. PMID- 23734253 TI - Diagnostic value of sTREM-1 in bronchoalveolar lavage fluid in ICU patients with bacterial lung infections: a bivariate meta-analysis. AB - BACKGROUND: The serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is a useful biomarker in differentiating bacterial infections from others. However, the diagnostic value of sTREM-1 in bronchoalveolar lavage fluid (BALF) in lung infections has not been well established. We performed a meta analysis to assess the accuracy of sTREM-1 in BALF for diagnosis of bacterial lung infections in intensive care unit (ICU) patients. METHODS: We searched PUBMED, EMBASE and Web of Knowledge (from January 1966 to October 2012) databases for relevant studies that reported diagnostic accuracy data of BALF sTREM-1 in the diagnosis of bacterial lung infections in ICU patients. Pooled sensitivity, specificity, and positive and negative likelihood ratios were calculated by a bivariate regression analysis. Measures of accuracy and Q point value (Q*) were calculated using summary receiver operating characteristic (SROC) curve. The potential between-studies heterogeneity was explored by subgroup analysis. RESULTS: Nine studies were included in the present meta-analysis. Overall, the prevalence was 50.6%; the sensitivity was 0.87 (95% confidence interval (CI), 0.72-0.95); the specificity was 0.79 (95% CI, 0.56-0.92); the positive likelihood ratio (PLR) was 4.18 (95% CI, 1.78-9.86); the negative likelihood ratio (NLR) was 0.16 (95% CI, 0.07-0.36), and the diagnostic odds ratio (DOR) was 25.60 (95% CI, 7.28-89.93). The area under the SROC curve was 0.91 (95% CI, 0.88-0.93), with a Q* of 0.83. Subgroup analysis showed that the assay method and cutoff value influenced the diagnostic accuracy of sTREM-1. CONCLUSIONS: BALF sTREM-1 is a useful biomarker of bacterial lung infections in ICU patients. Further studies are needed to confirm the optimized cutoff value. PMID- 23734254 TI - Detection of osteogenic differentiation by differential mineralized matrix production in mesenchymal stromal cells by Raman spectroscopy. AB - Mesenchymal stromal cells (MSCs) hold great potential in skeletal tissue engineering and regenerative medicine. However, conventional methods that are used in molecular biology to evaluate osteogenic differentiation of MSCs require a relatively large amount of cells. Cell lysis and cell fixation are also required and all these steps are time-consuming. Therefore, it is imperative to develop a facile technique which can provide real-time information with high sensitivity and selectivity to detect the osteogenic maturation of MSCs. In this study, we use Raman spectroscopy as a biosensor to monitor the production of mineralized matrices during osteogenic induction of MSCs. In summary, Raman spectroscopy is an excellent biosensor to detect the extent of maturation level during MSCs-osteoblast differentiation with a non-disruptive, real-time and label free manner. We expect that this study will promote further investigation of stem cell research and clinical applications. PMID- 23734255 TI - Uniparental markers in Italy reveal a sex-biased genetic structure and different historical strata. AB - Located in the center of the Mediterranean landscape and with an extensive coastal line, the territory of what is today Italy has played an important role in the history of human settlements and movements of Southern Europe and the Mediterranean Basin. Populated since Paleolithic times, the complexity of human movements during the Neolithic, the Metal Ages and the most recent history of the two last millennia (involving the overlapping of different cultural and demic strata) has shaped the pattern of the modern Italian genetic structure. With the aim of disentangling this pattern and understanding which processes more importantly shaped the distribution of diversity, we have analyzed the uniparentally-inherited markers in ~900 individuals from an extensive sampling across the Italian peninsula, Sardinia and Sicily. Spatial PCAs and DAPCs revealed a sex-biased pattern indicating different demographic histories for males and females. Besides the genetic outlier position of Sardinians, a North West-South East Y-chromosome structure is found in continental Italy. Such structure is in agreement with recent archeological syntheses indicating two independent and parallel processes of Neolithisation. In addition, date estimates pinpoint the importance of the cultural and demographic events during the late Neolithic and Metal Ages. On the other hand, mitochondrial diversity is distributed more homogeneously in agreement with older population events that might be related to the presence of an Italian Refugium during the last glacial period in Europe. PMID- 23734256 TI - Reporting quality of social and psychological intervention trials: a systematic review of reporting guidelines and trial publications. AB - BACKGROUND: Previous reviews show that reporting guidelines have improved the quality of trial reports in medicine, yet existing guidelines may not be fully suited for social and psychological intervention trials. OBJECTIVE/DESIGN: We conducted a two-part study that reviewed (1) reporting guidelines for and (2) the reporting quality of social and psychological intervention trials. DATA SOURCES: (1) To identify reporting guidelines, we systematically searched multiple electronic databases and reporting guideline registries. (2) To identify trials, we hand-searched 40 journals with the 10 highest impact factors in clinical psychology, criminology, education, and social work. ELIGIBILITY: (1) Reporting guidelines consisted of articles introducing a checklist of reporting standards relevant to social and psychological intervention trials. (2) Trials reported randomised experiments of complex interventions with psychological, social, or health outcomes. RESULTS: (1) We identified 19 reporting guidelines that yielded 147 reporting standards relevant to social and psychological interventions. Social and behavioural science guidelines included 89 standards not found in CONSORT guidelines. However, CONSORT guidelines used more recommended techniques for development and dissemination compared to other guidelines. (2) Our review of trials (n = 239) revealed that many standards were poorly reported, such as identification as a randomised trial in titles (20% reported the information) and abstracts (55%); information about blinding (15%), sequence generation (23%), and allocation concealment (17%); and details about actual delivery of experimental (43%) and control interventions (34%), participant uptake (25%), and service environment (28%). Only 11 of 40 journals referenced reporting guidelines in "Instructions to Authors." CONCLUSION: Existing reporting guidelines have important limitations in content, development, and/or dissemination. Important details are routinely missing from trial publications; most leading journals in social and behavioural sciences do not ask authors to follow reporting standards. Findings demonstrate a need to develop a CONSORT extension with updated standards for social and psychological intervention trials. PMID- 23734258 TI - An occult hepatitis B-derived hepatoma cell line carrying persistent nuclear viral DNA and permissive for exogenous hepatitis B virus infection. AB - Occult hepatitis B virus (HBV) infection is defined as persistence of HBV DNA in liver tissues, with or without detectability of HBV DNA in the serum, in individuals with negative serum HBV surface antigen (HBsAg). Despite accumulating evidence suggesting its important clinical roles, the molecular and virological basis of occult hepatitis B remains unclear. In an attempt to establish new hepatoma cell lines, we achieved a new cell line derived from a hepatoma patient with chronic hepatitis C virus (HCV) and occult HBV infection. Characterization of this cell line revealed previously unrecognized properties. Two novel human hepatoma cell lines were established. Hep-Y1 was derived from a male hepatoma patient negative for HCV and HBV infection. Hep-Y2 was derived from a female hepatoma patient suffering from chronic HCV and occult HBV infection. Morphological, cytogenetic and functional studies were performed. Permissiveness to HBV infection was assessed. Both cell lines showed typical hepatocyte-like morphology under phase-contrast and electron microscopy and expressed alpha fetoprotein, albumin, transferrin, and aldolase B. Cytogenetic analysis revealed extensive chromosomal anomalies. An extrachromosomal form of HBV DNA persisted in the nuclear fraction of Hep-Y2 cells, while no HBsAg was detected in the medium. After treated with 2% dimethyl sulfoxide, both cell lines were permissive for exogenous HBV infection with transient elevation of the replication intermediates in the cytosol with detectable viral antigens by immunoflurescence analysis. In conclusions, we established two new hepatoma cell lines including one from occult HBV infection (Hep-Y2). Both cell lines were permissive for HBV infection. Additionally, Hep-Y2 cells carried persistent extrachromosomal HBV DNA in the nuclei. This cell line could serve as a useful tool to establish the molecular and virological basis of occult HBV infection. PMID- 23734257 TI - Functional diversity and structural disorder in the human ubiquitination pathway. AB - The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. PMID- 23734259 TI - Regulation of SIRT1 in vascular smooth muscle cells from streptozotocin-diabetic rats. AB - Sirtuins enzymes are a conserved family of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases and ADP-ribosyltransferases that mediate responses to oxidative stress, fasting and dietary restriction in mammals. Vascular smooth muscle cells (VSMCs) are involved in many mechanisms that regulate vascular biology in vivo but the role of SIRT1 has not been explored in much detail. Therefore, we investigated the regulation of SIRT1 in cultured VSMCs under various stress conditions including diabetes. Sprague-Dawley rats were made diabetic by injecting a single dose of streptozotocin (65 mg/Kg), and aortic VSMCs were isolated after 4 weeks. Immunocytochemistry showed that SIRT1 was localized predominantly in the nucleus, with lower staining in VSMCs from STZ diabetic as compared with normoglycemic rats. Previous diabetes induction in vivo and high glucose concentrations in vitro significantly downregulated SIRT1 amounts as detected in Western blot assays, whereas TNF-alpha (30 ng/ml) stimulation failed to induce significant changes. Because estrogen signaling affects several pathways of oxidative stress control, we also investigated SIRT1 modulation by 17beta-estradiol. Treatment with the hormone (10 nM) or a selective estrogen receptor-alpha agonist decreased SIRT1 levels in VSMCs from normoglycemic but not in those from STZ-diabetic animals. 17beta-estradiol treatment also enhanced activation of AMP-dependent kinase, which partners with SIRT1 in a signaling axis. SIRT1 downregulation by 17beta-estradiol could be observed as well in human peripheral blood mononuclear cells, a cell type in which SIRT1 downregulation is associated with insulin resistance and subclinical atherosclerosis. These data suggest that SIRT1 protein levels are regulated by diverse cellular stressors to a variable extent in VSMCs from diabetic and normoglycemic rats, warranting further investigation on SIRT1 as a modulator of VSMC activity in settings of vascular inflammation. PMID- 23734260 TI - Women versus men with chronic atrial fibrillation: insights from the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY). AB - BACKGROUND: Gender-based clinical differences are increasingly being identified as having significant influence on the outcomes of patients with cardiovascular disease (CVD), including atrial fibrillation (AF). OBJECTIVE: To perform detailed clinical phenotyping on a cohort of hospitalised patients with chronic forms of AF to understand if gender-based differences exist in the clinical presentation, thrombo-embolic risk and therapeutic management of high risk patients hospitalised with chronic AF. METHODS: We are undertaking the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY) - a multi-centre, randomised controlled trial of an AF-specific management intervention versus usual care. Extensive baseline profiling of recruited patients was undertaken to identify gender-specific differences for risk delineation. RESULTS: We screened 2,438 patients with AF and recruited 335 into SAFETY. Of these, 48.1% were women who were, on average, 5 years older than their male counterparts. Women and men displayed divergent antecedent profiles, with women having a higher thrombo embolic risk but being prescribed similar treatment regimens. More women than men presented to hospital with co-morbid thyroid dysfunction, depression, renal impairment and obesity. In contrast, more men presented with coronary artery disease (CAD) and/or chronic obstructive pulmonary disease (COPD). Even when data was age-adjusted, women were more likely to live alone (odds ratio [OR] 2.33; 95% confidence interval [CI] 1.47 to 3.69), have non-tertiary education (OR 2.69; 95% CI 1.61 to 4.48) and be symptomatic (OR 1.93; 95% CI 1.06 to 3.52). CONCLUSION: Health care providers should be cognisant of gender-specific differences in an attempt to individualise and, hence, optimise the management of patients with chronic AF and reduce potential morbidity and mortality. PMID- 23734261 TI - Rapid identification of novel immunodominant proteins and characterization of a specific linear epitope of Campylobacter jejuni. AB - Campylobacter jejuni remains one of the major gut pathogens of our time. Its zoonotic nature and wide-spread distribution in industrialized countries calls for a quick and reliable diagnostic tool. Antibody-based detection presents a suitable means to identify pathogenic bacteria. However, the knowledge about immunodominant targets is limited. Thus, an approach is presented, which allows for the rapid screening of numerous cDNA derived expression clones to identify novel antigens. The deeper understanding of immunodominant proteins assists in the design of diagnostic tools and furthers the insight into the bacterium's pathogenicity as well as revealing potential candidates for vaccination. We have successfully screened 1536 clones of an expression library to identify 22 proteins that have not been described as immunodominant before. After subcloning the corresponding 22 genes and expression of full-length proteins, we investigated the immunodominant character by microarrays and ELISA. Subsequently, seven proteins were selected for epitope mapping. For cj0669 and cj0920c linear epitopes were identified. For cj0669, specificity assays revealed a specific linear epitope site. Consequently, an eleven amino acid residue sequence TLIKELKRLGI was analyzed via alanine scan, which revealed the glycine residue to be significant for binding of the antibody. The innovative approach presented herein of generating cDNAs of prokaryotes in combination with a microarray platform rendering time-consuming purification steps obsolete has helped to illuminate novel immunodominant proteins of C.jejuni. The findings of a specific linear epitope pave the way for a plethora of future research and the potential use in diagnostic applications such as serological screenings. Moreover, the current approach is easily adaptable to other highly relevant bacteria making it a formidable tool for the future discovery of antigens and potential biomarkers. Consequently, it is desirable to simplify the identification of structural epitopes, as this would extend the spectrum of novel epitopes to be detected. PMID- 23734262 TI - Aesthetic and incentive salience of cute infant faces: studies of observer sex, oral contraception and menstrual cycle. AB - Infant cuteness can influence adult-infant interaction and has been shown to activate reward centres in the brain. In a previous study, we found men and women to be differentially sensitive to small differences in infant facial cuteness, with reproductive hormone status as the potential underlying cause. It is unclear, however, whether reproductive hormone status impacts on the aesthetic and incentive salience of infant faces. To address this question, we conducted two interlinked studies. We used static images of the same smiling and neutral looking infant faces in both a rating task, in which participants had to rate the cuteness of infant faces (aesthetic salience - 'liking'), and a key-press task, in which participants could prolong or shorten viewing time of infant faces by rapid alternating key-presses (incentive salience - 'wanting'). In a first study, we compared the performance of men, women who are taking oral contraceptives, and regularly cycling women. In this study, we found a significant correlation between cuteness ratings within and between groups, which implies that participants had the same concept of cuteness. Cuteness ratings and effort to look at faces was linked regardless of sex and reproductive hormone status, in that cute faces were looked at for longer than less cute faces. A happy facial expression contributed only marginally to the incentive salience of the face. To explore the potential impact of reproductive hormone status in more detail, we followed a subset of regularly cycling women during the menstrual, follicular and luteal phases of their cycle. The aesthetic and incentive salience of infant faces did not change across the menstrual cycle. Our findings suggest that reproductive hormone status does not modulate the aesthetic and incentive value of infant faces. PMID- 23734263 TI - Genetic structure in the coral, Montastraea cavernosa: assessing genetic differentiation among and within Mesophotic reefs. AB - Mesophotic coral reefs (30-150 m) have recently received increased attention as a potential source of larvae (e.g., the refugia hypothesis) to repopulate a select subset of the shallow water (<30 m) coral fauna. To test the refugia hypothesis we used highly polymorphic Amplified Fragment Length Polymorphism (AFLP) markers as a means to assess small-scale genetic heterogeneity between geographic locations and across depth clines in the Caribbean coral, Montastraea cavernosa. Zooxanthellae-free DNA extracts of coral samples (N = 105) were analyzed from four depths, shallow (3-10 m), medium (15-25 m), deep (30-50 m) and very deep (60 90 m) from Little Cayman Island (LCI), Lee Stocking Island (LSI), Bahamas and San Salvador (SS), Bahamas which range in distance from 170 to 1,600 km apart. Using AMOVA analysis there were significant differences in PhiST values in pair wise comparisons between LCI and LSI. Among depths at LCI, there was significant genetic differentiation between shallow and medium versus deep and very deep depths in contrast there were no significant differences in PhiST values among depths at LSI. The assignment program AFLPOP, however, correctly assigned 95.7% of the LCI and LSI samples to the depths from which they were collected, differentiating among populations as little as 10 to 20 m in depth from one another. Discriminant function analysis of the data showed significant differentiation among samples when categorized by collection site as well as collection depth. FST outlier analyses identified 2 loci under positive selection and 3 under balancing selection at LCI. At LSI 2 loci were identified, both showing balancing selection. This data shows that adult populations of M. cavernosa separated by depths of tens of meters exhibits significant genetic structure, indicative of low population connectivity among and within sites and are not supplying successful recruits to adjacent coral reefs less than 30 m in depth. PMID- 23734264 TI - Complete sequence and analysis of plastid genomes of two economically important red algae: Pyropia haitanensis and Pyropia yezoensis. AB - BACKGROUND: Pyropia haitanensis and P. yezoensis are two economically important marine crops that are also considered to be research models to study the physiological ecology of intertidal seaweed communities, evolutionary biology of plastids, and the origins of sexual reproduction. This plastid genome information will facilitate study of breeding, population genetics and phylogenetics. PRINCIPAL FINDINGS: We have fully sequenced using next-generation sequencing the circular plastid genomes of P. hatanensis (195,597 bp) and P. yezoensis (191,975 bp), the largest of all the plastid genomes of the red lineage sequenced to date. Organization and gene contents of the two plastids were similar, with 211-213 protein-coding genes (including 29-31 unknown-function ORFs), 37 tRNA genes, and 6 ribosomal RNA genes, suggesting a largest coding capacity in the red lineage. In each genome, 14 protein genes overlapped and no interrupted genes were found, indicating a high degree of genomic condensation. Pyropia maintain an ancient gene content and conserved gene clusters in their plastid genomes, containing nearly complete repertoires of the plastid genes known in photosynthetic eukaryotes. Similarity analysis based on the whole plastid genome sequences showed the distance between P. haitanensis and P. yezoensis (0.146) was much smaller than that of Porphyra purpurea and P. haitanensis (0.250), and P. yezoensis (0.251); this supports re-grouping the two species in a resurrected genus Pyropia while maintaining P. purpurea in genus Porphyra. Phylogenetic analysis supports a sister relationship between Bangiophyceae and Florideophyceae, though precise phylogenetic relationships between multicellular red alage and chromists were not fully resolved. CONCLUSIONS: These results indicate that Pyropia have compact plastid genomes. Large coding capacity and long intergenic regions contribute to the size of the largest plastid genomes reported for the red lineage. Possessing the largest coding capacity and ancient gene content yet found reveal that Pyropia are more primitive multicellular red algae. PMID- 23734265 TI - TLR4 ligand/H2O2 enhances TGF-beta1 signaling to induce metastatic potential of non-invasive breast cancer cells by activating non-Smad pathways. AB - TGF-beta1 has the potential to activate multiple signaling pathways required for inducing metastatic potential of tumor cells. However, TGF-beta1 was inefficient in inducing metastatic potential of many non-invasive human tumor cells. Here we report that the enhancement of TGF-beta1 signaling is required for inducing metastatic potential of non-invasive breast cancer cells. TGF-beta1 alone could not efficiently induce the sustained activation of Smad and non-Smad pathways in non-invasive breast cancer cells. TLR4 ligand (LPS) and H2O2 cooperated with TGF beta1 to enhance the sustained activation of non-Smad pathways, including p38MAPK, ERK, JNK, PI3K, and NF-kappaB. The activation of MAPK and PI3K pathways resulted in a positive feed-back effect on TGF-beta1 signaling by down-regulating Nm23-H1 expression and up-regulating the expression of TbetaRI and TbetaRII, favoring further activation of multiple signaling pathways. Moreover, the enhanced TGF-beta1 signaling induced higher expression of SNAI2, which also promoted TbetaRII expression. Therefore, the sustained activation levels of both Smad and non-Smad pathways were gradually increased after prolonged stimulation with TGF-beta1/H2O2/LPS. Consistent with the activation pattern of signaling pathways, the invasive capacity and anoikis-resistance of non-invasive breast cancer cells were gradually increased after prolonged stimulation with TGF beta1/H2O2/LPS. The metastatic potential induced by TGF-beta1/H2O2/LPS was sufficient for tumor cells to extravasate and form metastatic foci in an experimental metastasis model in nude mice. The findings in this study suggested that the enhanced signaling is required for inducing higher metastatic capacity of tumor cells, and that targeting one of stimuli or signaling pathways might be potential approach in comprehensive strategy for tumor therapy. PMID- 23734266 TI - Determinants of tuberculosis treatment default in Morocco: results from a national cohort study. AB - INTRODUCTION: Studies have shown an association between smoking and tuberculosis (TB) infection, disease and TB-related mortality. We thus documented the impact of smoking and others factors on TB treatment default. METHODS: A cohort of 1039 new TB cases matched on smoking status was followed between 2004 and 2009 in eight Moroccan regions. Treatment default was defined according to international criteria. Univariate analyses were used to assess associations of treatment default with smoking status and demographic characteristics. Multivariate logistic regression was used to adjust for potential confounding. RESULTS: Patients' mean age was 35.0 +/-13.2 years. The rate of treatment default was 30.2%. Default was significantly higher among men, smokers, persons living in urban areas and non-religious Muslims. After adjusting for confounding variables, factors that remained significantly associated with treatment default were: being male (OR = 3.2; 95% CI: 1.2-8.7), being a non-religious Muslim (OR = 2.0; 95% CI: 1.4-2.9) and living in an urban area OR = 3.0; 95% CI: 1.8-4.9). CONCLUSION: The high rate found for default suggests important program's inadequacies and an urgent need for change. Therefore continued research of predictors of default and strategies to reinforce adherence is recommended. PMID- 23734267 TI - Off pump coronary artery bypass surgery in a Nigerian teaching hospital. AB - Coronary artery bypass grafting has not been previously reported in the Nigeria medical literature. We report the case performed in our institution of a 56 year old Nigerian female who underwent off pump coronary artery bypass surgery (OPCAB) for an ostial lesion of the left anterior descending coronary artery. The left internal mammary artery was successfully anastomosed to the left anterior descending coronary artery. The patient was discharged home after 2 weeks, following correction of problems with glycemic control. PMID- 23734268 TI - [A confusional syndrome revealing a Fahr syndrome with hyperparathyroidism]. PMID- 23734269 TI - [Laminar cortical necrosis complicating a scorpion sting]. PMID- 23734270 TI - [Survey of toxicological aspects of herbal medicine used by a herbalist in Fes, Morocco]. PMID- 23734271 TI - Prevalence of tuberculosis in HIV in Ethiopia in early HAART era: retrospective analysis. PMID- 23734272 TI - [A rare and distinct tumor of breast cancer: carcinosarcoma, about eight cases and review of the literature]. PMID- 23734273 TI - [An intoxication can hide another one more serious. Example of a fatal poisoning with ethylene glycol intoxication masked by a pyrethroid insecticide]. PMID- 23734274 TI - Organizational HIV monitoring and evaluation capacity rapid needs assessment: the case of Kenya. AB - INTRODUCTION: Due to the commitment by the Government of Kenya (GoK) and international donors to address HIV/AIDS, Kenya has some of Africa's most developed health infrastructure for tackling the crisis. Despite this commitment, significant gaps exist in the national HIV/AIDS monitoring and evaluation (M&E) system. To identify these gaps and opportunities for improvement, the U.S. Centers for Disease Control and Prevention funded the Strengthening HIV Strategic Information in Kenya project, which conducted an organizational HIV M&E capacity rapid needs assessment (RNA). METHODS: The project included an in-depth desk review of national documents, policies, tools, and international best practices. National, regional, and district officials from government agencies, development partners, and implementing partners participated in key informant interviews and focus group discussions. Given the large number of regions and districts, purposive sampling was used to select 16 facilities in 8 districts across 2 regions based on the general quality of the reported HIV data and the number of partners supporting the regions. RESULTS: RNA findings revealed tremendous improvements at the national level and in the various subsystems that contribute to the overall HIV strategic information. There also were significant gaps, including in a lack of M&E guidelines, parallel reporting systems, feedback given to subnational levels, and data use and general data management and use capacity at subnational levels. CONCLUSION: An urgent need exists for the development of national M&E guidelines and a comprehensive training curriculum. To ensure success further, capacity building for subnational levels should be conducted and feedback channels to subnational staff should be established and maintained. PMID- 23734275 TI - [Portal vein thrombosis in a type 1 autoimmune hepatitis]. PMID- 23734276 TI - Clinical case of botryomycome fulminant at the center of diagnostic and treatment of tuberculosis of Baleng (West - Cameroon). AB - Botryomycome also called pyogenic granuloma, is an inflammatory tumor of the skin and mucous membranes often caused by superinfection of minor traumatism. Its uniqueness lies in its granulomatous organization in which each granulation contains bacteria and the predominance of many newly formed blood vessels, with the lights on variables ratings and a turgid endothelium responsible for the ulcero-hemorragic appearance. This delicate condition poses a real problem of treatment which included: an appropriate antibiotherapy, surgical removal or electrocoagulation which, until today is more difficult in countries with limited income. An octogenarian came to our hospital with a large mass on the left foot. This mass had the appearance of a malignant tumor. However, the anatomopathologic diagnosis showed that it was a pyogenic granuloma. The importance of the mass, its location on the sole of the foot, imposed the functional impairment of this member. Electrocoagulation is not available in our hospital and the surgical excision proposed was refused by the patient. The patient was treated with the antibiotics Ceftriaxone and Gentalline at indicated doses for 15 days. After the failure of that antibiotherapy treatment, as a last resort, the patient was treated for a month with another combination of antibiotics (free of cost) made of dapsone and rifampicin. This new combination gave very good results. This example shows dapsone and rifampicin can be use as a new weapon for the management of pyogenic granuloma in countries with limited incomes. PMID- 23734277 TI - What do Libyan doctors perceive as the benefits, ethical issues and influences of their interactions with pharmaceutical company representatives? AB - INTRODUCTION: Evidence suggests that 80-90% of doctors in most countries across the world are frequently visited by pharmaceutical company representatives (PCRs). The objective of study to examine perceptions of Libyan doctors between August and October 2010, regarding the benefits, ethical issues and influences of their interactions with (PCRs). METHODS: An anonymous questionnaire was circulated to 1,000 Libyan doctors in selected public and private practice settings in Tripoli, Benghazi and Sebha. RESULTS: The major benefits of PCR visits reported in the 608 evaluable responses were; receiving new information about products (94.4%). The majority of doctors (75%) were not against the provision of gifts but were more comfortable if it was "cheap" (51%) and had educational value (51%). Doctors who received more printed materials, simple gifts or drug samples were less likely to disapprove of accepting gifts (p5]. Effective marketing can positively influence an individual's attitude towards a product and because there is an association between attitude, intention and behaviour [6], persuasive communication can generate a positive attitude and increase the potential for influence [7]. PCRs can accomplish behaviour change because they directly communicate with prescribers. During a visit they attempt to raise awareness of their products, provide product information and encourage a favourable attitude towards their company and product [8]. They employ verbal persuasion techniques and also provide other incentives such as gifts, free drug samples and sponsored educational events [2]. The provision of promotional gifts can be seen as a friendship building technique to reinforce the communication nexus between PCRs and doctors but it can also potentially erode professional barriers [9]. Contact between a PCR and a medical practitioner is therefore viewed by drug companies as a vital part of their marketing strategy and frequent visits, together with written promotional materials, gifts and other incentives, can help alter behaviour even if the initial attitudes towards a product were weak or unclear [10]. PMID- 23734278 TI - Antinocieptive and anti-inflammatory effects of Toddalia asiatica (L) Lam. (Rutaceae) root extract in Swiss albino mice. AB - INTRODUCTION: Toddalia asiatica is a commonly used medicinal plant in East Africa for the management of pain and inflammatory conditions. The present study investigated the antinociceptive and the anti-inflammatory effects of T. asiatica in Swiss albino mice. METHODS: The antinociceptive and the anti-inflammatory effects of T. asiatica were investigated using formalin-induced pain test and the carrageenin-induced oedema paw. The extract solvent (vehicle), aspirin and indomethacin were employed as negative and positive controls respectively. Eight mice were used in each experiment. RESULTS: In the early phase of the formalin test, the 100mg/kg dose showed no significant antinociceptive activity while the 200mg/kg showed significant (p < 0.01) antinociceptive activity. The 100 mg/kg dose showed highly significant antinociceptive activity (p < 0.001) in the late phase of the formalin test while the 200mg/kg dose showed no significant antinociceptive activity. A reduction in carragenin induced acute inflammation paw oedema was significant (p < 0.01) following administration of 100mg/kg dose but not with the 200mg/kg dose. CONCLUSION: The present study therefore lends support to the anecdotal evidence for use of T. asiatica in the management of painful and inflammatory conditions. PMID- 23734279 TI - Pregnancy outcome at advanced maternal age in a group of African women in two teaching Hospitals in Yaounde, Cameroon. AB - INTRODUCTION: Women older than 40 years have been termed "advanced maternal age" and considered to be at risk of adverse pregnancy outcome. This study aimed to examine the obstetrical outcomes among primiparous and multiparous African advanced maternal age women. METHODS: We conducted a retrospective cohort study study at two teaching hospitals at Yaounde, Cameroon. From the hospital records, obstetrical characteristics of 585 consecutive women aged 40 or above who delivered from January 2007 to December 2011 were compared with those of 1816 younger mothers aged 20 to 29 years as control cases. Associations between maternal age and selected obstetrical variables were assessed with the contigency X (2) test or two-tailed Fisher exact test. RESULTS: Primiparous and multiparous advanced maternal age were more likely to undergo cesarean delivery than were their younger counterparts (38.5% vs 13.5%, RR=2.85, p<0.05 and 16.1% vs 9.1%, RR=1.76, p<0.05). Older primiparous women had similar perinatal outcomes than their younger counterparts. Older multiparous women had increased incidence of preeclampsia/eclampsia (2.4% vs 0.6%, RR=4, p<0.01); antepartum hemorrhage (1.8% vs 0.8%, RR=2.25, p<0.01); fetal distress (3.5% vs 1.3%, RR=2.69, p<0.01); fetal death (3.5% vs 1.6%, RR= 2.18, p<0.05); postpartum hemorrhage (2.4% vs 1.2%; RR=2, p<0.05); preterm delivery (12% vs 9.2%, RR=1.30, p<0.05); low birth weight (11% vs 7.7%, RR=1.42, p<0.05); admission to special care neonatalogy unit(14.1% vs 10.2%, RR=1.38, p<0.05); low Apgar scores at 1min and 5min; and perinatal mortality (3.5% vs 1.6, RR=2.18, p<0.05). CONCLUSION: Advanced maternal age women are at higher risk to cesarean delivery. Increased risk of antepartum and intra partum complications among multiparous advanced maternal age women were associated to adverse perinatal outcome. Our results are in concordance with the view that increased risk of adverse perinatal outcome with advanced maternal age is indirectly related to age through the increased risk of obstetrical complications associated with age. PMID- 23734280 TI - [Sweat gland eccrine porocarcinoma of the face: a rare annexal tumor]. PMID- 23734281 TI - A safe world for kids. PMID- 23734282 TI - Sports Specialization vs Diversification. PMID- 23734283 TI - Ramification of indexing of medical journals. PMID- 23734285 TI - The safety and efficacy of dexmedetomidine for postoperative sedation in the cardiac surgery intensive care unit. AB - INTRODUCTION: The alpha2-adrenoceptor agonist dexmedetomidine is an effective postoperative sedative without clear advantages over midazolam or propofol. We hypothesized that routine use of dexmedetomidine allows early extubation in cardiac surgery patients. Secondary outcomes included the use of narcotic and non narcotic analgesics during the first 48 hours, early postoperative functional status, and the incidence of bradycardia or hypotension. METHODS: We retrospectively analyzed patients admitted to a cardiothoracic intensive care unit after cardiac surgery. Patient charts and the Society of Thoracic Surgery National database were reviewed. Patients who received no sedation were compared to those who received dexmedetomidine. RESULTS: Ninety-nine patients (52 receiving no sedation and 47 receiving dexmedetomidine) were included in this study. The median time to extubation was 3.9 (2.8-5.4) hours in the control group versus 4.7 (3.45-6.52) hours in the dexmedetomidine (P=.16). The incidence of bradycardia, hypotension, the ability to ambulate, and Glascow Coma Scores = 15 on postoperative day 0 did not differ significantly. Acetaminophen was used more frequently in the first 48 hours postoperatively in dexmedetomidine patients (P=.02) and a trend toward higher opioid (P=.09) and ketorolac use (P=.30) over the first 48 hours was noted. CONCLUSIONS: The use of dexmedetomidine did not allow earlier extubation or less use of analgesics when compared to no sedation. Bradycardia and hypotension were not a problem with the use of dexmedetomidine. PMID- 23734284 TI - Major themes for 2012 in cardiovascular anesthesia and intensive care. AB - There was major progress through 2012 in cardiovascular anesthesia and intensive care. Although recent meta-analysis has supported prophylactic steroid therapy in adult cardiac surgery, a large Dutch multicenter trial found no outcome advantage with dexamethasone. A second large randomized trial is currently testing the outcome effects of methyprednisolone in this setting. Due to calibration drift, the logistic EuroSCORE has recently been recalibrated. Despite this model revision, EuroSCORE II still overestimates mortality after transcatheter aortic valve implantation. It is likely that a specific perioperative risk model will be developed for this unique patient population. Recent global consensus has prioritized 12 non-surgical interventions that merit further study for reducing mortality after surgery. There is currently a paradigm shift in the conduct of adult aortic arch repair. Recent advances have facilitated aortic arch reconstruction with routine antegrade cerebral perfusion at mild-to-moderate hypothermia. Further integration of hybrid endovascular techniques may allow future aortic arch repair without hypothermia or circulatory arrest. These advances will likely further improve patient outcomes. PMID- 23734286 TI - Current conduct of deep hypothermic circulatory arrest in China. AB - INTRODUCTION: Deep hypothermic circulatory arrest for adult aortic arch repair is still associated with significant mortality and morbidity. Furthermore, there is still significant variation in the conduct of this complex perioperative technique. This variation in deep hypothermic circulatory arrest practice has not been adequately characterized and may offer multiple opportunities for outcome enhancement. The hypothesis of this study was that the current practice of adult deep hypothermic circulatory arrest in China has significant variations that might offer therapeutic opportunities for reduction of procedural risk. METHODS: An adult deep hypothermic circulatory arrest questionnaire was developed and then administered at a thoracic aortic session at the International Cardiothoracic and Vascular Anesthesia Congress convened in Beijing during 2010. The data was abstracted and analyzed. RESULTS: The majority of the 56 respondents were anesthesiologists based in China at low-volume deep hypothermic circulatory arrest centers. The typical aortic arch repair had a prolonged deep hypothermic circulatory arrest time at profound hypothermia. The target temperature for deep hypothermic circulatory arrest was frequently measured distal to the brain. The most common perfusion adjunct was antegrade cerebral perfusion, typically monitored with radial arterial pressure and cerebral venous oximetry. The preferred neuroprotective agents were steroids and propofol. CONCLUSIONS: The identified opportunities for outcome improvement in this delineated deep hypothermic circulatory arrest model include nasal/tympanic temperature measurement and routine cerebral perfusion, preferably with unilateral antegrade cerebral perfusion monitored with radial artery pressure and cerebral oximetry. Development and dissemination of an evidence-based consensus would enhance these practice-improvement opportunities. PMID- 23734287 TI - Prophylactic intraaortic balloon counterpulsation in high-risk cardiac surgery: a survey of opinion and current practice. AB - INTRODUCTION: Patients undergoing cardiac surgery increasingly have greater comorbidities and subsequently are at higher risk of adverse postoperative outcomes. Despite some evidence suggests that prophylactic intraaortic balloon counterpulsation reduces mortality in selected high-risk patients, its use remains low. The aim of this study was to investigate reported management strategies of high-risk patients and attitudes towards further research in this area. METHODS: A 22-question survey was developed and distributed electronically to all practicing cardiothoracic fellows through the email list of the Australian and New Zealand Society of Cardiac and Thoracic Surgeons. RESULTS: The response rate was 28% (n=31). Reported use of prophylactic intraaortic balloon counterpulsation varied depending on the specified preoperative indication. Prophylactic intraaortic balloon counterpulsation was used occasionally or never by the majority of respondents for their patients with characteristics similar to those of previous trials. The most frequent reason given for not using prophylactic intraaortic balloon counterpulsation was lack of data (42.9%), with a willingness to consider participation in an randomised controlled trial of prophylactic intraaortic balloon counterpulsation by a large majority of respondents (79.3%). CONCLUSIONS: The majority of surgeons who responded to this survey do not routinely use prophylactic intraaortic balloon counterpulsation for high-risk patients. Further prospective data is warranted to ascertain whether potential barriers to a randomised control trial of prophylactic intraaortic balloon counterpulsation, such as adequate patient numbers and clear selection criteria, can be overcome. PMID- 23734288 TI - Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin-controlled network meta-analyses. AB - INTRODUCTION: Novel oral anticoagulants have been tested against warfarin for atrial fibrillation, yet no direct comparison is available. We thus aimed to perform pair-wise (direct) and warfarin-adjusted network (i.e. indirect) meta analyses of novel oral anticoagulants for atrial fibrillation. METHODS: Databases were searched for randomized warfarin-controlled trials of novel anticoagulants for non-valvular atrial fibrillation. The primary end-point was long-term stroke/systemic embolism. Odds ratios (95% intervals) were computed with RevMan and WinBUGS. RESULTS: Seven trials (52701 patients) were included, focusing on apixaban, dabigatran, edoxaban and rivaroxaban. Pair-wise meta-analysis showed that after a weighted average of 23 months these novel anticoagulants lead to significant reductions in the risk of stroke/systemic embolism (odds ratio=0.81 [0.71-0.92], I2=23%) and all cause death (odds ratio=0.88 [0.82-0.95], I2=0%) in comparison to warfarin. Network meta-analysis showed that apixaban and dabigatran proved similarly superior to warfarin in preventing stroke/systemic embolism (odds ratio=0.78 [0.62-0.96] for apixaban vs warfarin; odds ratio=0.66 [0.52 0.84] for high-dose dabigatran vs warfarin; odds ratio for apixaban vs high-dose dabigatran=1.17 [0.85-1.63]), but apixaban was associated with fewer major bleedings (odds ratio=0.73 [0.57-0.93]) and drug discontinuations (odds ratio=0.64 [0.52-0.78]) than dabigatran. Rivaroxaban did not reduce stroke/systemic embolism (odds ratio=0.87 [0.71-1.07]) or major bleedings in comparison to warfarin (odds ratio=0.87 [0.71-1.07]) and was associated with more major bleedings in comparison to apixaban (odds ratio=1.52 [1.19-1.92]). Data for edoxaban were inconclusive. CONCLUSIONS: Novel oral anticoagulants appear as a very promising treatment option for atrial fibrillation. PMID- 23734290 TI - From Osler to the cone technique. PMID- 23734289 TI - The FENO-HSR study: details of statistical analyses. PMID- 23734293 TI - Dynamic transposable element accumulation in the nascent sex chromosomes of papaya. AB - From their inception, Y chromosomes in plants and animals are subjected to the powerful effects of Muller's ratchet, a process spurred by suppression of recombination that results in a rapid accumulation of mutations and repetitive elements. These mutations eventually lead to gene loss and degeneration of the Y chromosome. Y chromosomes in mammals are ancient, whereas most sex chromosomes in plants and many in insects and fish evolved recently. Sex type in papaya is controlled by a pair of nascent sex chromosomes that evolved around 7 million years ago. The papaya X and Yh were recently sequenced, providing valuable insight into the early stages of sex chromosome evolution. Here we discuss the fruits of this work with a focus on the repeat accumulation, gene trafficking and promiscuous DNA sequences found in the slowly degenerating Yh chromosome of papaya. PMID- 23734294 TI - Extensive genomic variation within clonal bacterial groups resulted from homologous recombination. AB - Due to divergence, genetic variation is generally believed to be high among distantly related strains, low among closely related ones and little or none within the same classified clonal groups. Several recent genome-wide studies, however, revealed that significant genetic variation resides in a considerable number of genes among strains with identical MLST (Multilocus sequence typing) types and much of the variation was introduced by homologous recombination. Recognizing and understanding genomic variation within clonal bacterial groups could shed new light on the evolutionary path of infectious agents and the emergence of particularly pathogenic or virulent variants. This commentary presents our recent contributions to this line of work. PMID- 23734295 TI - IS-mediated loss of virulence by Aeromonas salmonicida: A tangible piece of an evolutionary puzzle. AB - Insertion sequences (IS) are abundant in the bacterial fish pathogen Aeromonas salmonicida genome. IS are involved in rearrangement events that lead to the loss of virulence. In previous work, we studied a plasmid rearrangement that causes the deletion of the type three secretion system in A. salmonicida, resulting in a loss of virulence. We showed that the rearrangement is caused by the recombination of two IS (ISAS11) on an unstable plasmid (pAsa5). However, many rearrangements cannot be explained by our experimental approach and are thought to be the result of more complex or incomplete rearrangement events, as suggested by other plasmid loss profiles observed in various A. salmonicida strains. In this commentary, we examine the genetic instability of A. salmonicida indicating that its genome is rapidly evolving. PMID- 23734296 TI - From passengers to drivers: Impact of bacterial transposable elements on evolvability. AB - Microbes have several mechanisms that promote evolutionary adaptation in stressful environments. The corresponding molecular pathways promote diversity through modulating rates of recombination, mutation or influence the activity of transposable genetic elements. Recent experimental studies suggest an evolutionary conflict between these mechanisms. Specifically, presence of mismatch repair mutator alleles in a bacterial population dramatically reduced fixation of bacterial insertion sequence elements. When rare, these elements had only a limited impact on adaptive evolution compared with other mutation generating pathways. IS elements may initially spread like molecular parasites, but once present in many copies in a given genome, they might become generators of novelty during bacterial evolution. PMID- 23734297 TI - Transposable element invasions. AB - Transposable elements have an ongoing, largely parasitic interaction with their hosts. We are interested in the timescale of this interaction. In a recent publication, we have examined the sequence divergence between class II DNA transposons from mammalian genomes. We asked whether these sequences undergo a continuing process of turnover, keeping a family as an integrated whole, as members of the family are continually created and lost. Alternatively, we envisaged that elements might have been involved in a burst of amplification, soon after they first occupied a mammalian genome, and the shared ancestry of present-day elements harks back to this initial amplification, a process that we termed a "life cycle." We resolved between these processes by estimating the time to common ancestry predicted from the genetic diversity of sequences found in a transposon family, and also estimating, from the mammalian orders that currently possess copies of the family, the time when the family first entered the mammalian genome. These times are approximately the same, supporting the "life cycle" model. This casts light on how far we can infer genetic changes in the past through the study of DNA sequences from the present. PMID- 23734298 TI - Cell-host, LINE and environment: Three players in search of a balance. AB - Long interspersed nuclear elements -1 (LINEs, L1s) are retroelements occupying almost 17% of the human genome. L1 retrotransposition can cause deleterious effects on the host-cell and it is generally inhibited by suppressive mechanisms, but it can occur in some specific cells during early development as well as in some tumor cells and in the presence of several environmental factors. In a recent publication we reported that extremely low frequency pulsed magnetic field can affect L1 retrotransposition in neuroblastoma cells. In this commentary we discuss the interaction between environment and L1 activity in the light of the new emerging paradigm of host-LINE relationship. PMID- 23734299 TI - Revisiting bacterial phylogeny: Natural and experimental evidence for horizontal gene transfer of 16S rRNA. AB - Current methods used for phylogenetic classification of prokaryotes largely rely on the sequences of 16S rRNA genes that are ubiquitously present in the cell. Theoretical basis of this methodology is based on the assumption that 16S rRNA genes are only vertically inherited and are thus indigenous to each species. However, microbial genomic analysis has revealed the existence of prokaryotic species containing two types of rRNA (rrn) operons of seemingly different origins. It has also been reported that some bacteria contain 16S rRNA that are mosaics of sequences from multiple species. This suggests that horizontal gene transfer (HGT) occurred for 16S rRNA genes. In addition, a recent HGT experiment mimicking the natural HGT process has shown that a wide range of foreign 16S rRNA genes can be transferred into Escherichia coli, including those from different phylogenetic classes (with a minimum sequence identity of 80.9% to the Escherichia coli 16S rRNA gene). Thus, in contrast to the complexity hypothesis that states informational genes are rarely horizontally transferred between species, 16S rRNA is occasionally amenable to HGT. Results of the current method for rapid identification and classification of prokaryotes based on the 16S rRNA gene should thus be carefully analyzed and interpreted. PMID- 23734301 TI - In this issue of Mobile Genetic Elements. PMID- 23734300 TI - Ordering the bestiary of genetic elements transmissible by conjugation. AB - Phylogenetic reconstruction of three highly conserved proteins involved in bacterial conjugation (relaxase, coupling protein and a type IV secretion system ATPase) allowed the classification of transmissible elements in relaxase MOB families and mating pair formation MPF groups. These evolutionary studies point to the existence of a limited number of module combinations in transmissible elements, preferentially associated with specific genetic or environmental backgrounds. A practical protocol based on the MOB classification was implemented to detect and assort transmissible plasmids and integrative elements from gamma Proteobacteria. It was called "Degenerate Primer MOB Typing" or DPMT. It resulted in a powerful technique that discovers not only backbones related to previously classified elements (typically by PCR-based replicon typing or PBRT), but also distant new members sharing a common evolutionary ancestor. The DPMT method, conjointly with PBRT, promises to be useful to gain information on plasmid backbones and helpful to investigate the dissemination routes of transmissible elements in microbial ecosystems. PMID- 23734302 TI - High-density lipoproteins delivering interleukin-15. AB - Circulating lipoproteins may offer interesting properties as therapeutic carriers for cytokines and hormones, in terms of both stability and bio-distribution. The fusion of apolipoprotein A-I with interleukin-15 (IL-15) targets the latter to high-density lipoproteins (HDLs). The bioactivity of this chimera can be further enhanced by creating triple fusions with IL-15 receptor alpha domain involved in IL-15 trans-presentation. PMID- 23734303 TI - Immunotherapy with artificial adjuvant vector cells: Harnessing both arms of the immune response. AB - Both innate and adaptive immunity underpin cancer immunosurveillance. To stimulate both these arms of the immune system, we used allogeneic cells loaded with natural killer T (NKT) cell ligands and expressing tumor-associated antigens, resulting in NKT cell activation, dendritic-cell maturation and ultimately in the elicitation of adaptive T-cell responses. This approach holds great promise for the development of novel anticancer immunotherapies. PMID- 23734304 TI - Personalized medicine for cancer therapy: Lessons learned from tumor-associated antigens. AB - Antibody signatures may become sophisticated screening tools for early diagnosis and the development of personalized anticancer treatments. We used biopanning to enrich the immune response of head and neck squamous cell carcinoma (HNSCC) patients. This method revealed a HNSCC-specific antibody signature and allowed for the discovery of a novel oncogene, L23. PMID- 23734305 TI - Distribution, function and predictive value of tumor-infiltrating gammadelta T lymphocytes. AB - Although gammadelta T cells are known to exert both tumor-preventing and tumor promoting activity, there is still little information on the functional characteristics and clinical significance of gammadelta T cells isolated from the tumor site. In a recent study, we have investigated the distribution of different gammadelta T-cell populations in melanoma and their impact on disease outcome. PMID- 23734306 TI - Co-stimulatory tumor necrosis factor ligands as adjuvants for the development of subunit-based anticancer vaccines. AB - Tumor-associated antigen (TAA) subunit-based vaccines constitute promising tools for the anticancer immunotherapy. Given the weak antigenic nature of most TAAs, however, the efficacy of TAA-based vaccines requires adjuvants exerting potent immunostimulatory functions. Co-stimulatory members of the tumor necrosis factor ligand (TNFL) family may be used in this sense due to their pleiotropic and robust effects on cells of innate, adaptive and regulatory immune responses. PMID- 23734307 TI - Ectopic CD137 expression facilitates the escape of Hodgkin and Reed-Sternberg cells from immunosurveillance. AB - CD137 is ectopically expressed on Hodgkin and Reed-Sternberg (HRS) cells, causing the removal of the immunostimulatory CD137 ligand from HRS cells as well as from surrounding antigen presenting cells. This inhibits T-cell co-stimulation and supports the immune evasion of Hodgkin's lymphoma. PMID- 23734308 TI - Targeting cathepsin G in myeloid leukemia. AB - Cathepsin G (CG) is a serine protease normally found within the azurophil granules of neutrophils. CG is expressed during the early stages of normal myeloid differentiation and-aberrantly-by myeloid leukemia cells. We have recently identified CG-derived HLA-A*0201-binding peptides that constitute promising targets for the immunotherapy of myeloid leukemia. PMID- 23734309 TI - Mimotope vaccine efficacy gets a "boost" from native tumor antigens. AB - Tumor-associated antigen (TAA)-targeting mimotope peptides exert more prominent immunostimulatory functions than unmodified TAAs, with the caveat that some T cell clones exhibit a relatively low affinity for TAAs. Combining mimotope-based vaccines with native TAAs in a prime-boost setting significantly improves antitumor immunity. PMID- 23734310 TI - Immunomodulation of the tumor microenvironment by Toll-like receptor-3 (TLR3) ligands. AB - In hepatocellular carcinoma (HCC) patients, the intratumoral expression of Toll like receptor-3 (TLR3) correlates with prolonged survival. We demonstrated that TLR3 ligands can operate through three independent mechanisms: by directly killing TLR3-expressing cancer cells, by inducing T- and natural killer (NK)-cell infiltration and by activating TLR3-expressing NK cells. PMID- 23734312 TI - Delineating the "galectin signature" of the tumor microenvironment. AB - Galectins, a family of glycan-binding proteins, can control tumor progression by promoting transformation, angiogenesis and immune escape. We identified a dynamically regulated 'galectin signature', which delineates the progression of prostate cancer, highlighting galectin-1 as an attractive target for anti angiogenic therapy in advanced stages of the disease. PMID- 23734311 TI - Collaboration of chimeric antigen receptor (CAR)-expressing T cells and host T cells for optimal elimination of established ovarian tumors. AB - Conditioning strategies that deplete host lymphocytes have been shown to enhance clinical responses to some adoptive T-cell therapies. However, host T cells are capable of eliminating tumor cells upon the relief of immunosuppression, indicating that lymphodepletion prior to T-cell transfer may reduce optimal tumor protection elicited by cell treatments that are capable of shaping host immunity. In this study, we show that adoptively transferred T cells bearing a chimeric antigen receptor (CAR) harness endogenous T cells for optimal tumor elimination and the development of a tumor-specific memory T cell response. Mice bearing ID8 ovarian cancer cells were treated with T cells transduced with a NKG2D-based CAR. CAR-expressing T cells increased the number of host CD4+ and CD8+ T cells at the tumor site in a CXCR3-dependent manner and increased the number of antigen specific host CD4+ T cells in the tumor and draining lymph nodes. In addition, the administration of CAR-expressing T cells increased antigen presentation to CD4+ T cells, and this increase was dependent on interferon gamma and granulocyte macrophage colony-stimulating factor produced by the former. Host CD4+ T cells were sufficient for optimal tumor protection mediated by NKG2D CAR-expressing T cells, but they were not necessary if CD4+ T cells were adoptively co transferred. However, host CD4+ T cells were essential for the development of an antigen-specific memory T-cell response to tumor cells. Moreover, optimal tumor elimination as orchestrated by NKG2D CAR-expressing T cells was dependent on host CD8+ T cells. These results demonstrate that adoptively transferred T cells recruit and activate endogenous T-cell immunity to enhance the elimination of tumor cells and the development of tumor-specific memory responses. PMID- 23734313 TI - The RIG-I/MAVS signaling pathway in cancer cell-selective apoptosis. AB - A replication-incompetent hemagglutinating virus of Japan (HVJ) envelope (HVJ-E) induces apoptosis selectively in cancer cells. Fragments of the viral RNA genome transported by HVJ-E are recognized by retinoic acid-inducible gene I (RIG-I) and mitochondrial antiviral signaling (MAVS). Specific pro-apoptotic factor are selectively upregulated in cancer cells downstream of the RIG-I/MAVS pathway. PMID- 23734314 TI - Interferon alpha may be back on track to treat acute myeloid leukemia. AB - Our own experience and a thorough literature review suggest that interferon alpha (IFNalpha) should be reconsidered for the treatment of acute myeloid leukemia patients. Most likely, the success of such treatment depends on the achievement of high serum levels of IFNalpha for several months, which can be obtained by using pegylated IFNalpha. PMID- 23734315 TI - Toll-like receptor 5 and the emerging role of bacteria in carcinogenesis. AB - Toll-like receptor 5 (TLR5) is an pattern recognition receptor expressed by several cells of the immune system that recognizes bacterial flagellin. We studied the influence of TLR5 in oral tongue squamous carcinoma and found that its expression levels predict patient survival and recurrence. Considering the role of microbiome in oral cancer, TLR5 may represent an important link between bacteria and oral oncogenesis. PMID- 23734316 TI - Lessons learned from a highly-active CD22-specific chimeric antigen receptor. AB - CD22 is an attractive target for the development of immunotherapeutic approaches for the therapy of B-cell malignancies. In particular, an m971 antibody-derived, second generation chimeric antigen receptor (CAR) that targets CD22 holds significant therapeutic promise. The key aspect for the development of such a highly-active CAR was its ability to target a membrane-proximal epitope of CD22. PMID- 23734317 TI - NK cells from malignant pleural effusions are potent antitumor effectors: A clue for adoptive immunotherapy? AB - Natural killer (NK) cells exert potent antitumor activity. However, NK cells infiltrating solid tumors are severely impaired in their function. Remarkably, NK cells isolated from malignant pleural effusions kill very efficiently tumor cells upon exposure to interleukin-2, offering an important clue for the development of novel approaches for tumor immunotherapy. PMID- 23734318 TI - A novel bispecific antibody recruits T cells to eradicate tumors in the "immunologically privileged" central nervous system. AB - Bispecific T-cell engagers (BiTEs) may break multiple barriers that currently limit the use of immunotherapy in glioblastoma patients. We have recently described a novel BiTE specific for a mutated form of the epidermal growth factor receptor, EGFRvIII, that exerts potent antineoplastic effects against established invasive tumors of the brain. PMID- 23734319 TI - Uncovering a novel mechanism whereby NK cells interfere with glioblastoma virotherapy. AB - Despite initial promising results, the success of clinical trials testing oncolytic viruses in glioblastoma patients has been limited. Innate immunity appears to be one among several barriers against successful viral oncolysis. Recent findings suggest a mechanism by which natural killer cells limit the efficacy of oncolytic viruses via natural cytotoxicity receptors. PMID- 23734320 TI - Glycan-mediated modification of the immune response. AB - Aberrantly glycosylated tumor antigens represent promising targets for the development of anti-cancer vaccines, yet how glycans influence immune responses is poorly understood. Recent studies have demonstrated that GalNAc-glycosylation enhances antigen uptake by dendritic cells as well as CD4+ T-cell and humoral responses, but prevents CD8+ T-cell activation. Here, we briefly discuss the relevance of glycans as candidate targets for anti-cancer vaccines. PMID- 23734321 TI - The CCL5/CCR5 axis promotes metastasis in basal breast cancer. AB - Recently, we have shown that the CCL5/CCR5 axis is active in patients affected by an aggressive basal subtype of breast cancer. Using preclinical models, we have demonstrated that CCR5 promotes breast cancer invasiveness and metastatic potential, while CCR5 inhibition abrogates them. Thus, CCR5 antagonists may constitute an alternative therapeutic approach for patients affected by metastatic basal breast cancer. PMID- 23734322 TI - Re-orienting the immune system: Durable tumor regression and successful re induction therapy using anti-PD1 antibodies. AB - The blockade of immune regulatory checkpoints is emerging as a powerful anticancer strategy. We recently reported long-term results from the first-in human clinical trial of anti-PD1 antibody-based immunotherapy, demonstrating durable tumor control off-therapy in subjects affected by colorectal and kidney cancer, as well as successful re-induction therapy in a melanoma patient. PMID- 23734323 TI - Inhibition of tumor angiogenesis by globotriaosylceramide immunotargeting. AB - Current antiangiogenic immunotherapeutic strategies mainly focus on the blockade of circulating cytokines or receptors that are overexpressed by endothelial cells. We proposed globotriaosylceramide (Gb3) as a viable alternative target for antiangiogenic therapies. In this setting, we developed an anti-Gb3 antibody and validated its therapeutic efficacy in metastatic tumor models. PMID- 23734324 TI - Dacarbazine mediate antimelanoma effects via NK cells. AB - Melanoma is a highly chemoresistant and metastatic tumor that, in the absence of BRAF mutations, is generally treated with the alkylating agent dacarbazine (DTIC). We discovered that DTIC upregulates the expression of NKG2D ligands on tumor cells, leading to the activation of natural killer (NK) and CD8+ T cells. These observations underscore the immunogenic properties of DTIC and provide a rationale to combine DTIC with immunotherapeutic agents. PMID- 23734325 TI - Exploiting invariant NKT cells to promote T-cell responses to cancer vaccines. AB - Invariant natural killer T (iNKT) cells have the capacity to amplify adaptive immune responses by licensing antigen-presenting cells. A simple vaccine consisting of whole tumor cells pulsed with an iNKT-cell agonist efficiently delivers antigens plus adjuvants to endogenous dendritic cells and has potential for clinical applications. PMID- 23734326 TI - Enhanced immunity in slowly aging mutant mice with high mitochondrial oxidative stress. AB - The mitochondria of slowly aging Mclk1+/- mutant mice produce high levels of reactive oxygen species (ROS). These animals display enhanced immune reactivity in response to lipopolysaccharide, Salmonella, and tumor-cell grafts, experience limited damage from these treatments and are partially protected from infection and tumorigenesis. We propose that the activation of the immune system by mitochondrial ROS reduces the rate of aging. PMID- 23734327 TI - The immunological identity of tumor: Self implications. AB - By means of well-characterized autoimmunity models, we comparatively probed the "selfness" of malignant cells and their normal counterparts. We found that tumors activate self-tolerance mechanisms much more efficiently than normal tissues, reflecting a status of immunoprivileged "self." Our findings indicate that potent autoimmune responses can eradicate established malignancies, yet the collateral destruction of healthy tissues may prove difficult to circumvent. PMID- 23734329 TI - Toward the next generation of NK cell-based adoptive cancer immunotherapy. AB - The adoptive transfer of interleukin (IL)-2-expanded natural killer (NK) cells has provided unsatisfactory clinical benefits to patients affected by solid tumors. Our study demonstrates that the activation of NK cells with IL-12/IL 15/IL-18 prior to transfer into tumor-bearing mice is critical for obtaining high recovery rates, effector functions in vivo and tumor regression. PMID- 23734330 TI - Functional characterization of a STAT3-dependent dendritic cell-derived CD14+ cell population arising upon IL-10-driven maturation. AB - Interleukin (IL)-10 is a major cancer-related immunosuppressive factor, exhibiting a unique ability to hamper the maturation of dendritic cells (DCs). We have previously reported that IL-10 induces the conversion of activated, migratory CD1a+ DCs found in the human skin to CD14+CD141+ macrophage-like cells. Here, as a model of tumor-conditioned DC maturation, we functionally assessed CD14- and CD14+ DCs that matured in vitro upon exposure to IL-10. IL-10-induced CD14+ DCs were phenotypically characterized by a low maturation state as well as by high levels of BDCA3 and DC-SIGN, and as such they closely resembled CD14+ cells infiltrating melanoma metastases. Compared with DC matured under standard conditions, CD14+ DCs were found to express high levels of B7-H1 on the cell surface, to secrete low levels of IL-12p70, to preferentially induce TH2 cells, to have a lower allogeneic TH cell and tumor antigen-specific CD8+ T-cell priming capacity and to induce proliferative T-cell anergy. In contrast to their CD14+ counterparts, CD14- monocyte-derived DCs retained allogeneic TH priming capacity but induced a functionally anergic state as they completely abolished the release of effector cytokines. Transcriptional and cytokine release profiling studies indicated a more profound angiogenic and pro-invasive signature of CD14+ DCs as compared with DCs matured in standard conditions or CD14- DCs matured in the presence of IL-10. Importantly, signal transducer and activator of transcription 3 (STAT3) depletion by RNA interference prevented the development of the IL-10 associated CD14+ phenotype, allowing for normal DC maturation and providing a potential means of therapeutic intervention. PMID- 23734328 TI - Trial watch: DNA vaccines for cancer therapy. AB - The foundation of modern vaccinology dates back to the 1790s, when the English physician Edward Jenner uncovered the tremendous medical potential of prophylactic vaccination. Jenner's work ignited a wave of nationwide vaccination campaigns abating the incidence of multiple life-threatening infectious diseases and culminating with the eradication of natural smallpox virus, which was definitively certified by the WHO in 1980. The possibility of using vaccines against cancer was first proposed at the end of the 19th century by Paul Ehrlich and William Coley. However, it was not until the 1990s that such a hypothesis began to be intensively investigated, following the realization that the immune system is not completely unresponsive to tumors and that neoplastic cells express immunogenic tumor-associated antigens (TAAs). Nowadays, anticancer vaccines are rapidly moving from the bench to the bedside, and a few prophylactic and therapeutic preparations have already been approved by FDA for use in humans. In this setting, one interesting approach is constituted by DNA vaccines, i.e., TAA encoding circularized DNA constructs, often of bacterial origin, that are delivered to patients as such or by means of specific vectors, including (but not limited to) liposomal preparations, nanoparticles, bacteria and viruses. The administration of DNA vaccines is most often performed via the intramuscular or subcutaneous route and is expected to cause (1) the endogenous synthesis of the TAA by myocytes and/or resident antigen-presenting cells; (2) the presentation of TAA-derived peptides on the cell surface, in association with MHC class I molecules; and (3) the activation of potentially therapeutic tumor-specific immune responses. In this Trial Watch, we will summarize the results of recent clinical trials that have evaluated/are evaluating DNA vaccines as therapeutic interventions against cancer. PMID- 23734331 TI - TIM3+FOXP3+ regulatory T cells are tissue-specific promoters of T-cell dysfunction in cancer. AB - T-cell immunoglobulin mucin 3 (TIM3) is an inhibitory molecule that has emerged as a key regulator of dysfunctional or exhausted CD8+ T cells arising in chronic diseases such as cancer. In addition to exhausted CD8+ T cells, highly suppressive regulatory T cells (Tregs) represent a significant barrier against the induction of antitumor immunity. We have found that the majority of intratumoral FOXP3+ Tregs express TIM3. TIM3+ Tregs co-express PD-1, are highly suppressive and comprise a specialized subset of tissue Tregs that are rarely observed in the peripheral tissues or blood of tumor-bearing mice. The co blockade of the TIM3 and PD-1 signaling pathways in vivo results in the downregulation of molecules associated with TIM3+ Treg suppressor functions. This suggests that the potent clinical efficacy of co-blocking TIM3 and PD-1 signal transduction cascades likely stems from the reversal of T-cell exhaustion combined with the inhibition of regulatory T-cell function in tumor tissues. Interestingly, we find that TIM3+ Tregs accumulate in the tumor tissue prior to the appearance of exhausted CD8+ T cells, and that the depletion of Tregs at this stage interferes with the development of the exhausted phenotype by CD8+ T cells. Collectively, our data indicate that TIM3 marks highly suppressive tissue resident Tregs that play an important role in shaping the antitumor immune response in situ, increasing the value of TIM3-targeting therapeutic strategies against cancer. PMID- 23734332 TI - Priming of PRAME- and WT1-specific CD8+ T cells in healthy donors but not in AML patients in complete remission: Implications for immunotherapy. AB - Active immunotherapy may prevent the relapse of acute myeloid leukemia (AML) by inducing leukemia-specific T cells. Here, we investigated whether Wilms' tumor 1 (WT1) and preferentially expressed antigen in melanoma (PRAME)-specific T cells could be induced upon the priming of healthy donor- and AML patient-derived T cells with HLA-A2-matched, peptide-loaded allogeneic dendritic cells. AML reactive, tetramer (Tm)-binding and interferon-producing, cytotoxic T lymphocytes specific for PRAME could readily be isolated from healthy individuals and maintained in culture. In this setting, priming efficacy was significantly higher for PRAME than for WT1. The priming of T cells from patient-derived material proved to be near-to-impossible: No leukemia-associated antigen (LAA)-specific T cell could be primed in 4 patients that had recently achieved a complete response (CR), and in only 1 out of 3 patients exhibiting a sustained CR we did observe WT1-specific T cells, though with a low frequency. These findings suggest that the functionality and/or repertoire of T cells differ in healthy subjects and AML patients in CR, and may have repercussions for the implementation of active vaccination approaches against AML. PMID- 23734333 TI - Role of dendritic cells in the regulation of antitumor immunity. AB - The majority of rodent and human tumors express antigens that can be recognized by T lymphocytes and are infiltrated by immune cells. Although tumor infiltration by T lymphocytes has been associated with a favorable prognosis, the role of dendritic cells (DCs), which may present tumor-associated antigens in an immunogenic or tolerogenic context, remains elusive. Here, we discuss recent observations suggesting that the function of DCs in the tumor microenvironment may impact the spontaneous resistance of neoplasms to chemotherapy as well as treatment outcome. PMID- 23734334 TI - The immune checkpoint regulator PD-L1 is a specific target for naturally occurring CD4+ T cells. AB - Programmed cell death 1 ligand 1 (PD-L1) is an important regulator of T-cell responses and may consequently limit anticancer immunity. We have recently identified PD-L1-specific, cytotoxic CD8+ T cells. In the present study, we develop these findings and report that CD4+ helper T cells spontaneously recognize PD-L1. We examined the locality of a previously identified HLA-A*0201 restricted PD-L1-epitope for the presence of possible CD4+ T-cell epitopes. Thus, we identified naturally occurring PD-L1-specific CD4+ T cells among the peripheral blood lymphocytes of cancer patients and - to lesser extents - healthy donors, by means of ELISPOT assays. PD-L1-specific CD4+ T cells appeared to be TH17 cells exhibiting an effector T-cell cytokine profile. Hence, PD-L1-specific CD4+ T cells released interferon gamma (IFNgamma), tumor necrosis factor alpha (TNFalpha) and interleukin-17 (IL-17) in response to a long PD-L1-derived peptide. Furthermore, we demonstrate that the specific recognition of PD-L1 by CD4+ T cells is MHC class II-restricted. Natural T-cell responses against PD-L1 are noteworthy as they may play a prominent role in the regulation of the immune system. Thus, cytokine release from PD-L1-specific CD4+ T cells may surmount the overall immunosuppressive actions of this immune checkpoint regulator. Moreover, PD-L1-specific T cells might be useful for anticancer immunotherapy, as they may counteract common mechanisms of immune escape mediated by the PD-L1/PD-1 pathway. PMID- 23734335 TI - Hepatic metastases of colorectal cancer are rather homogeneous but differ from primary lesions in terms of immune cell infiltration. AB - The immune system plays an important role in shaping the clinical course of colorectal cancer (CRC). However, it is still unclear how the immune infiltrates of primary CRC lesions and distant metastases by immune effector cells are related to each other. To address this issue, we quantified CD3+, CD8+ and granzyme B+ lymphocytes in primary CRC samples and corresponding liver metastases. This analysis showed that the prognostic predictions that can be drawn from the infiltration of immune cells in primary CRCs and their metastases are heterogeneous. To investigate whether such heterogeneity would also be observed within CRC hepatic metastases, the density of the immune infiltrate and cytokine production were assessed in opposite sides of the same metastatic lesion. In addition, tumor-infiltrating lymphocytes were assessed in sequential sections of the same metastatic lesion, with a spacing of 30 MUm. In summary, consistent cell counts and cytokine levels were detected within the same lesion. The study of a case of synchronous metastases, however, suggested that different metastatic lesions within the same patient may be heterogeneous, perhaps indicating a major impact for local causes on tumor infiltration by immune cells. In summary, our study demonstrates a consistent degree of heterogeneity between primary tumors and hepatic metastases but an excellent intra-lesional homogeneity. These findings may be of key importance for patient stratification and the development of personalized strategies against CRC. PMID- 23734336 TI - Myeloid derived suppressor cells: Targets for therapy. AB - The goal of achieving measurable response with cancer immunotherapy requires counteracting the immunosuppressive characteristics of tumors. One of the mechanisms that tumors utilize to escape immunosurveillance is the activation of myeloid derived suppressor cells (MDSCs). Upon activation by tumor-derived signals, MDSCs inhibit the ability of the host to mount an anti-tumor immune response via their capacity to suppress both the innate and adaptive immune systems. Despite their relatively recent discovery and characterization, anti MDSC agents have been identified, which may improve immunotherapy efficacy. PMID- 23734337 TI - Human perforin mutations and susceptibility to multiple primary cancers. AB - Loss-of-function mutations in the gene coding for perforin (PRF1) markedly reduce the ability of cytotoxic T lymphocytes and natural killer cells to kill target cells, causing immunosuppression and impairing immune regulation. In humans, nearly half of the cases of type 2 familial hemophagocytic lymphohistiocytosis are due to bi-allelic PRF1 mutations. The partial inactivation of PRF1 due to mutations that promote protein misfolding or the common hypomorphic allele coding for the A91V substitution have been associated with lymphoid malignancies in childhood and adolescence. To investigate whether PRF1 mutations also predispose adults to cancer, we genotyped 566 individuals diagnosed with melanoma (101), lymphoma (65), colorectal carcinoma (30) or ovarian cancer (370). The frequency of PRF1 genotypes was similar in all disease groups and 424 matched controls, indicating that the PRF1 status is not associated with an increased susceptibility to these malignancies. However, four out of 15 additional individuals diagnosed with melanoma and B-cell lymphoma during their lifetime expressed either PRF1A91V or the rare pathogenic PRF1R28C variant (p = 0.04), and developed melanoma relatively early in life. Both PRF1A91V- and PRF1R28C expressing lymphocytes exhibited severely impaired but measurable cytotoxic function. Our results suggest that defects in human PRF1 predispose individuals to develop both melanoma and lymphoma. However, these findings require validation in larger patient cohorts. PMID- 23734338 TI - Cancer immunotherapy turns viral. PMID- 23734340 TI - Some poleward movement of British native vascular plants is occurring, but the fingerprint of climate change is not evident. AB - Recent upperward migration of plants and animals along altitudinal gradients and poleward movement of animal range boundaries have been confirmed by many studies. This phenomenon is considered to be part of the fingerprint of recent climate change on the biosphere. Here I examine whether poleward movement is occurring in the vascular plants of Great Britain. The ranges of plants were determined from detection/non-detection data in two periods, 1978 to 1994 and 1995 to 2011. From these, the centre of mass of the population was calculated and the magnitude and direction of range shifts were determined from movements of the centre of mass. A small, but significant, northward movement could be detected in plants with expanding ranges, but not among declining species. Species from warmer ranges were not more likely to be moving northward, nor was dispersal syndrome a predictor of migration success. It is concluded that simply looking at northward movement of species is not an effective way to identify the effect of climate change on plant migration and that other anthropogenic changes obscure the effect of climate. PMID- 23734339 TI - Determinants of neonatal mortality in rural India, 2007-2008. AB - Background. Despite the growing share of neonatal mortality in under-5 mortality in the recent decades in India, most studies have focused on infant and child mortality putting neonatal mortality on the back seat. The development of focused and evidence-based health interventions to reduce neonatal mortality warrants an examination of factors affecting it. Therefore, this study attempt to examine individual, household, and community level factors affecting neonatal mortality in rural India. Data and methods. We analysed information on 171,529 singleton live births using the data from the most recent round of the District Level Household Survey conducted in 2007-08. Principal component analysis was used to create an asset index. Two-level logistic regression was performed to analyse the factors associated with neonatal deaths in rural India. Results. The odds of neonatal death were lower for neonates born to mothers with secondary level education (O R = 0.60, p = 0.01) compared to those born to illiterate mothers. A progressive reduction in the odds occurred as the level of fathers' education increased. The odds of neonatal death were lower for infants born to unemployed mothers (O R = 0.89, p = 0.00) compared to those who worked as agricultural worker/farmer/laborer. The odds decreased if neonates belonged to Scheduled Tribes (O R = 0.72, p = 0.00) or 'Others' caste group (O R = 0.87, p = 0.04) and to the households with access to improved sanitation (O R = 0.87, p = 0.02), pucca house (O R = 0.87, p = 0.03) and electricity (O R = 0.84, p = 0.00). The odds were higher for male infants (O R = 1.21, p = 0.00) and whose mother experienced delivery complications (O R = 1.20, p = 0.00). Infants whose mothers received two tetanus toxoid injections (O R = 0.65, p = 0.00) were less likely to die in the neonatal period. Children of higher birth order were less likely to die compared to first birth order. Conclusion. Ensuring the consumption of an adequate quantity of Tetanus Toxoid (TT) injections by pregnant mothers, targeting vulnerable groups like young, first time and Scheduled Caste mothers, and improving overall household environment by increasing access to improved toilets, electricity, and pucca houses could also contribute to further reductions in neonatal mortality in rural India. Any public health interventions aimed at reducing neonatal death in rural India should consider these factors. PMID- 23734341 TI - Benthic communities at two remote Pacific coral reefs: effects of reef habitat, depth, and wave energy gradients on spatial patterns. AB - Kingman Reef and Palmyra Atoll in the central Pacific are among the most remote coral reefs on the planet. Here we describe spatial patterns in their benthic communities across reef habitats and depths, and consider these in the context of oceanographic gradients. Benthic communities at both locations were dominated by calcifying organisms (54-86% cover), namely hard corals (20-74%) and crustose coralline algae (CCA) (10-36%). While turf algae were relatively common at both locations (8-22%), larger fleshy macroalgae were virtually absent at Kingman (<1%) and rare at Palmyra (0.7-9.3%). Hard coral cover was higher, but with low diversity, in more sheltered habitats such as Palmyra's backreef and Kingman's patch reefs. Almost exclusive dominance by slow-growing Porites on Kingman's patch reefs provides indirect evidence of competitive exclusion, probably late in a successional sequence. In contrast, the more exposed forereef habitats at both Kingman and Palmyra had higher coral diversity and were characterized by fast growing corals (e.g., Acropora and Pocillopora), indicative of more dynamic environments. In general at both locations, soft coral cover increased with depth, likely reflecting increasingly efficient heterotrophic abilities. CCA and fleshy macroalgae cover decreased with depth, likely due to reduced light. Cover of other calcified macroalgae, predominantly Halimeda, increased with depth. This likely reflects the ability of many calcifying macroalgae to efficiently harvest light at deeper depths, in combination with an increased nutrient supply from upwelling promoting growth. At Palmyra, patterns of hard coral cover with depth were inconsistent, but cover peaked at mid-depths at Kingman. On Kingman's forereef, benthic community composition was strongly related to wave energy, with hard coral cover decreasing and becoming more spatially clustered with increased wave energy, likely as a result of physical damage leading to patches of coral in localized shelter. In contrast, the cover of turf algae at Kingman was positively related to wave energy, reflecting their ability to rapidly colonize newly available space. No significant patterns with wave energy were observed on Palmyra's forereef, suggesting that a more detailed model is required to study biophysical coupling there. Kingman, Palmyra, and other remote oceanic reefs provide interesting case studies to explore biophysical influences on benthic ecology and dynamics. PMID- 23734342 TI - A response to the opioid overdose epidemic: naloxone nasal spray. AB - Opioid overdose morbidity and mortality is recognized to have epidemic proportions. Medical and public health agencies are adopting opioid harm reduction strategies to reduce the morbidity and mortality associated with overdose. One strategy developed by emergency medical services and public health agencies is to deliver the opioid antidote naloxone injection intranasally to reverse the effects of opioids. Paramedics have used this route to quickly administer naloxone in a needle-free system and avoiding needle-stick injuries and contracting a blood-born pathogen disease such as hepatitis or human immunodeficiency virus. Public health officials advocate broader lay person access since civilians are likely witnesses or first responders to an opioid overdose in a time-acute setting. The barrier to greater use of naloxone is that a suitable and optimized needlefree drug delivery system is unavailable. The scientific basis for design and study of an intranasal naloxone product is described. Lessons from nasal delivery of opioid analgesics are applied to the consideration of naloxone nasal spray. PMID- 23734344 TI - Radiotherapy effects on anti-tumor immunity: implications for cancer treatment. PMID- 23734343 TI - Differential Roles of PML Isoforms. AB - The tumor suppressor promyelocytic leukemia (PML) protein is fused to the retinoic acid receptor alpha in patients suffering from acute promyelocytic leukemia (APL). Treatment of APL patients with arsenic trioxide (As2O3) reverses the disease phenotype by a process involving the degradation of the fusion protein via its PML moiety. Several PML isoforms are generated from a single PML gene by alternative splicing. They share the same N-terminal region containing the RBCC/tripartite motif but differ in their C-terminal sequences. Recent studies of all the PML isoforms reveal the specific functions of each. Here, we review the nomenclature and structural organization of the PML isoforms in order to clarify the various designations and classifications found in different databases. The functions of the PML isoforms and their differential roles in antiviral defense also are reviewed. Finally, the key players involved in the degradation of the PML isoforms in response to As2O3 or other inducers are discussed. PMID- 23734345 TI - Current Challenges for HER2 Testing in Diagnostic Pathology: State of the Art and Controversial Issues. AB - HER2 overexpression and anti-HER2 agents represent probably the best story of success of individualized therapy in breast cancer. Due to the important therapeutic implications, the issue under the spotlight has been, since ever, the correct identification of true HER2 positivity on tissue specimens. Eligibility to anti-HER2 agents is strictly dependent on the demonstration of HER2 overexpression (by immunohistochemistry) or of HER2 gene amplification by in situ techniques (fluorescence in situ hybridization, FISH), however there are controversial issues involving cases with "equivocal" HER2 status based on conventional techniques (about 20% of specimens). In terms of HER2 expression a major debate is the presence of full-length and truncated forms of the protein and controversial clinical data have been reported on the therapeutic implications of these HER2 fragments. In terms of HER2 gene assessment, the occurrence of amplification of the chromosome 17 centromeric region (CEP17) has been proven responsible for misleading HER2 FISH results, precluding anti-HER2 based therapy to some patients. Finally HER2 activating mutations have been recently described as a biological mechanisms alternative to HER2 gene amplification. In this review we will focus on the controversies that pathologists and oncologists routinely face in the attempt to design the most tailored treatment for breast cancer patients. We will focus on the HER2 gene and on the protein, both at technical and interpretational levels. PMID- 23734347 TI - Blood biomarker measurement as disease target: the case for generic treatment of high natriuretic peptide levels without a diagnosis of heart failure. PMID- 23734348 TI - Aberrant clinical coding: an underappreciated entity for NHS Trusts, clinicians and coders. PMID- 23734346 TI - Genomic instability and colon carcinogenesis: from the perspective of genes. AB - Colon cancer is the second most lethal cancer; approximately 600,000 people die of it annually in the world. Colon carcinogenesis generally follows a slow and stepwise process of accumulation of mutations under the influence of environmental and epigenetic factors. To adopt a personalized (tailored) cancer therapy approach and to improve current strategies for prevention, diagnosis, prognosis, and therapy overall, advanced understanding of molecular events associated with colon carcinogenesis is necessary. A contemporary approach that combines genetics, epigenomics, and signaling pathways has revealed many genetic/genomic alterations associated with colon cancer progression and their relationships to a genomic instability phenotype prevalent in colon cancer. In this review, we describe the relationship between gene mutations associated with colon carcinogenesis and a genomic instability phenotype, and we discuss possible clinical applications of genomic instability studies. Colon carcinogenesis is associated with frequent mutations in several pathways that include phosphatidylinositol 3-kinase, adenomatous polyposis coli, p53 (TP53), F-box and WD repeat domain containing 7, transforming growth factor-beta, chromosome cohesion, and K-RAS. These genes frequently mutated in pathways affecting colon cancer were designated colon cancer (CAN) genes. Aberrations in major colon CAN genes have a causal relationship to genomic instability. Conversely, genomic instability itself plays a role in colon carcinogenesis in experimental settings, as demonstrated in transgenic mouse models with high genomic instability. Thus, there is a feedback-type relationship between CAN gene mutations and genomic instability. These genetic/genomic studies have led to emerging efforts to apply the knowledge to colon cancer prognosis and to targeted therapy. PMID- 23734349 TI - Hospital-acquired Clostridium difficile infection among patients with type 2 diabetes mellitus in acute medical wards. AB - BACKGROUND: Clostridum difficile (C. difficile) infection is increasingly seen among hospitalised patients with type 2 diabetes mellitus but its rate and associated risk factors are not known. We aimed to determine the rate and characteristics of hospital-acquired C. difficile infection in subjects with type 2 diabetes mellitus admitted into acute medical wards. METHODS: Our prospective cross-sectional study involved 159 patients with established type 2 diabetes mellitus admitted into acute medical wards who developed a hospital-acquired C. difficile infection. Stools were tested for C. difficile toxins using a toxin A/B kit and a toxin A kit. Clinical features, laboratory findings, types of antibiotics, and use of a proton pump inhibitor were examined for their association with the infection. RESULTS: Thirteen subjects were positive for toxin A and one for toxin B. Using univariable analysis, we found that patients with type 2 diabetes mellitus and hospital acquired C. difficile infection were younger (mean 53.8 years, p=0.02), had diarrhoea and abdominal pain (p=0.001) but no fever. Sepsis (p=0.02) and use of a proton pump inhibitor (p=0.01) were more commonly implicated as the cause of the infection. Of the various types of antibiotics prescribed, carbapenem (28.6% vs 4.1%, p=0.01) and metronidazole (42.9% vs 19.3%, p=0.04) were significantly associated with hospital acquired C. difficile infection. CONCLUSIONS: Patients with type 2 diabetes mellitus admitted into acute medical wards and who developed hospital-acquired C. difficile infection have distinct characteristics. PMID- 23734350 TI - Improving the use of sputum cultures in lower respiratory tract infection. AB - BACKGROUND: The clinical value of sputum culture in suspected lower respiratory tract infection (LRTI) remains contentious. The quality of samples submitted significantly impacts their clinical usefulness. METHODS: Using pre-defined criteria we prospectively analysed the appropriateness of sputum samples submitted from consecutive patients with suspected LRTI attending two acute hospital units over ten weeks. We then provided an education package for staff on when and how to collect appropriate sputum samples, and repeated the evaluation. RESULTS: Our intervention reduced sample numbers from 347 to 133, simultaneously increasing the proportion of appropriately sent samples from 40.5 to 60.2% (p=0.001) and reducing cost. Appropriate sampling was associated with a higher yield of pathogens (relative risk 1.51, 95% confidence intervals 1.03-2.21, p=0.03). The rate at which sputum samples appeared to alter clinicians' management remained low and constant at 18% pre- and post-intervention. CONCLUSION: A simple educational intervention can significantly increase appropriateness of sputum sampling, reducing workload and cost. PMID- 23734351 TI - The differential diagnosis of suspected stroke: a systematic review. AB - BACKGROUND: We aimed to determine the proportion of patients who had suffered a stroke and compare this to those patients with suspected stroke, and the range of differential diagnosis for suspected stroke. METHODS: We searched for prospective studies of suspected stroke in electronic databases and our personal files. We undertook a meta-analysis of these studies, aimed at determining the proportions of patients with confirmed stroke in different settings. RESULTS: We identified 29 studies involving 8,839 patients: 13 studies were from emergency departments, five from stroke units or transient ischaemic attack (TIA) clinics, three from primary care, three from ambulance services and five were unspecified. About three-quarters (74% [95% confidence interval (CI): 66 to 83%]) of patients had a diagnosis of stroke, though there was significant heterogeneity in this estimate. The five most frequent non-stroke diagnoses were seizure, syncope, sepsis, migraine and brain tumours. CONCLUSION: Patients who had not had a stroke accounted for a significant proportion of people referred to stroke services. Expertise in the differential diagnoses of stroke is needed in order to manage the patients at the point of referral. PMID- 23734352 TI - An unusual but reversible cause of ventricular fibrillation. AB - A 61-year-old woman was admitted with general malaise, chest pain and breathlessness. During her inpatient stay she sustained a ventricular fibrillation (VF) arrest which was successfully terminated with direct current cardioversion. Cardiac investigations revealed poor left ventricular systolic function but unequivocally normal coronary arteries. During the course of her admission a macular rash developed and following investigations including a renal biopsy, a new diagnosis of systemic lupus erythematosus (SLE) and related myocarditis was reached. First presentation of lupus with myocarditis and VF is uncommon, however reaching the correct diagnosis is important as due to the reversible nature of the condition and improvement in left ventricular systolic function with medical therapy, an implantable cardioverter defibrillator (ICD) might not be appropriate. Our case report demonstrates the importance of screening for reversible conditions when considering ICD therapy for secondary prevention of malignant arrhythmias. PMID- 23734353 TI - Reversible acute kidney injury requiring haemodialysis five days after starting dronedarone in a stable 71-year-old man at risk of cardiovascular polypharmacy. AB - We present a case of severe acute kidney injury (AKI) occurring shortly after the initiation of dronedarone therapy, which we suspect was the result of an adverse drug reaction. The mechanism of AKI cannot be definitively determined. The most probable mechanism however involves dehydration secondary to diarrhoea, and medications causing hypotension, both precipitating AKI, further exacerbated by reduced excretion of medications reducing tissue perfusion. This case adds to the growing number of reports submitted to pharmacovigilance authorities regarding the association between dronedarone and AKI. It serves as a reminder of the risks of cardiovascular polypharmacy likely to be prevalent in patients considered for dronedarone (which causes diarrhoea as a common side-effect). PMID- 23734354 TI - IgG4-related disease: a novel, important but easily missed condition. AB - Immunoglobulin G4-related disease (IgG4-RD) is a multisystem, fibroinflammatory condition unrecognised in medical science until the last decade. It is characterised by progressive scarring and dysfunction of affected organs and tissues including the pancreas, hepatobiliary tree, kidneys, salivary glands, retroperitoneum and lungs. The diagnosis is made with the presence of numerous IgG4 positive plasma cells within a histologically-distinct chronic inflammatory process; most patients also have elevated serum IgG4. Though early cases were all identified in Japan, subsequent reports clearly demonstrate that IgG4-RD exists worldwide. There are no data confirming the prevalence of IgG4-RD in the West but it is thought to be very rare. Limited awareness of the condition and its heterogeneous presentation frequently results in misdiagnosis. Prompt and correct diagnosis is critical, as a rapid reversal of even advanced disease is often seen with corticosteroid therapy. We present three cases that illustrate some of the typical features of this condition. PMID- 23734355 TI - Familial risk of early and late onset cancer. PMID- 23734356 TI - Autonomy, patients' preferences, and leaving decisions to doctors. PMID- 23734357 TI - Is there still a role for mediastinoscopy as the first mediastinal staging procedure in lung cancer? AB - Lung cancer staging has evolved with the advent of endobronchial and endoscopic ultrasound (EBUS and EUS) as an alternative to mediastinoscopy and other surgical staging techniques. This has led to the debate now as to what the first-line staging investigation should be. Mr Waller makes the case that although EBUS and EUS are welcomed staging techniques, mediastinoscopy still has an important role as the first-line staging investigation in specific scenarios (when there is potentially surgically resectable mediastinal disease). Dr Skwarski argues that EBUS and EUS should be used in conjunction with CT-PET and considered as a complete alternative to mediastinoscopy. PMID- 23734358 TI - Cystic fibrosis. AB - There are now more adult than paediatric cystic fibrosis (CF) patients and their life expectancy continues to improve. This means that CF patients will be more commonly encountered in a variety of hospital settings including fertility services, gastrointestinal (GI) clinics, diabetes clinics, surgical wards, and acute admissions. Cystic fibrosis units welcome early contact when patients are admitted to other units and it is important to have a structured approach to their assessment and management. PMID- 23734359 TI - Novel oral anticoagulants for the prevention of thromboembolism in patients with atrial fibrillation. AB - The most significant complication of atrial fibrillation (AF) is thromboembolic stroke. Furthermore, the consequences of AF-related stroke tend to be more severe than those of other aetiologies. The need for safe, effective and convenient anticoagulation is clear. Warfarin is the current mainstay of treatment but its prescription and use remains sub-optimal, despite clear evidence and guidance to support its use. Many patients taking warfarin spend a significant amount of time subtherapeutically anticoagulated and the requirement for regular monitoring of warfarin's anticoagulant activity is both inconvenient and costly. Novel oral anticoagulants promise more predictable and convenient anticoagulation. They have potential superiority over warfarin for preventing thromboembolic stroke and appear to be associated with fewer haemorrhagic effects. Understanding the important background to the novel agents presents an opportunity to tailor anticoagulant treatment to the individual. This should allow a greater proportion of the eligible population access to effective anticoagulation. Furthermore, it should reduce their exposure to the risk of both thromboembolic and haemorrhagic stroke and their potentially devastating consequences. PMID- 23734360 TI - Computer-based diagnosis of illness in historical persons. AB - Retrospective diagnosis of illness in historical figures is a popular but somewhat unreliable pastime due to the lack of detailed information and reliable reports about clinical features and disease progression. Modern computer-based diagnostic programmes have been used to supplement historical documents and accounts, offering new and more objective approaches to the retrospective investigations of the medical conditions of historical persons. In the case of King George III, modern technology has been used to strengthen the findings of previous reports rejecting the popular diagnosis of variegate porphyria in the King, his grandson Augustus d'Este and his antecedent King James VI and I. Alternative diagnoses based on these programmes are indicated. The Operational Criteria in Studies of Psychotic Illness (OPCRIT) programme and the Young mania scale have been applied to the features described for George III and suggest a diagnosis of bipolar disorder. The neuro-diagnostic programme SimulConsult was applied to Augustus d'Este and suggests a diagnosis of neuromyelitis optica rather than acute porphyria with secondarily multiple sclerosis, as proposed by others. James VI and I's complex medical history and the clinical features of his behavioural traits were also subjected to SimulConsult analysis; acute porphyria was rejected and the unexpected diagnosis of attenuated (mild) Lesch-Nyhan disease offered. A brief review of these approaches along with full reference listings to the methodology including validation are provided. Textual analysis of the written and verbal outputs of historical figures indicate possible future developments in the diagnosis of medical disorders in historical figures. PMID- 23734361 TI - The extraordinary undergraduate career of Oliver St John Gogarty: has the modern medical student anything to learn from him? AB - Oliver St John Gogarty (1878-1957) was a celebrated Irish doctor and poet. A 'Renaissance' figure, he was renowned as a surgeon, poet, memoirist, senator, athlete and wit. His years as a medical student, although not crowned by academic success, were remarkable for many other achievements. A study of Gogarty's University career provides a number of lessons in the art of being a medical student. Although it is more than a century since Gogarty qualified as a doctor, this paper suggests that these lessons are still relevant today. PMID- 23734363 TI - Curriculum integration will help newly qualified doctors provide better supportive and end-of-life care. PMID- 23734364 TI - The RCPE response to Mid Staffordshire. PMID- 23734365 TI - The role of scurvy in Scott's return from the South Pole. AB - Scurvy, caused by lack of vitamin C, was a major problem for polar explorers. It may have contributed to the general ill-health of the members of Scott's polar party in 1912 but their deaths are more likely to have been caused by a combination of frostbite, malnutrition and hypothermia. Some have argued that Oates's war wound in particular suffered dehiscence caused by a lack of vitamin C, but there is little evidence to support this. At the time, many doctors in Britain overlooked the results of the experiments by Axel Holst and Theodor Frolich which showed the effects of nutritional deficiencies and continued to accept the view, championed by Sir Almroth Wright, that polar scurvy was due to ptomaine poisoning from tainted pemmican. Because of this, any advice given to Scott during his preparations would probably not have helped him minimise the effect of scurvy on the members of his party. PMID- 23734366 TI - Global Vaccine Action Plan. Decade of vaccine collaboration. PMID- 23734367 TI - Reply: To PMID 22936030. PMID- 23734368 TI - Circumferential wires as a supplement to intramedullary nailing in unstable trochanteric hip fractures---reply. PMID- 23734369 TI - Reply to M. Gallen et al and R.S. Midgley et al. PMID- 23734370 TI - Reply to S. Buti and S. Culine. PMID- 23734371 TI - Reply to A. Grothey et al and R.S. Midgley et al. PMID- 23734372 TI - Trans-atlantic debate: the role of completion imaging following carotid artery endarterectomy. PMID- 23734373 TI - Trans-atlantic debate: the role of completion imaging following carotid artery endarterectomy. PMID- 23734374 TI - Reply to I Hawkins and J Sabate. PMID- 23734375 TI - [Protein rich diet promotes weight loss and kidney health]. PMID- 23734376 TI - [Reply: Diogenes study does not show weight loss]. PMID- 23734377 TI - [There is no effect of drotrecogin alfa in severe sepsis]. PMID- 23734378 TI - [Is it so good to be the most unitary health care system in the world?]. PMID- 23734379 TI - [Cooperation with the industry is a hallmark--not a disgrace]. PMID- 23734380 TI - [The most unitary health care system for critically ill--in the world?]. PMID- 23734381 TI - Reply to: time to ROLL with it? PMID- 23734382 TI - [Rigid oesophagoscopy in the hands of the right specialty]. PMID- 23734383 TI - [Reply: we need national guidelines]. PMID- 23734385 TI - [Drug substitution is dangerous and creates inequality. Many immigrants have problems when drugs are substituted]. PMID- 23734386 TI - [Misleading by the Danish Cancer Society about mammography screening]. PMID- 23734387 TI - Revising the Declaration of Helsinki. PMID- 23734389 TI - [Drugs are still used for executions]. PMID- 23734390 TI - [Challenges in psychiatry]. PMID- 23734391 TI - Global drug policy fuels hepatitis C epidemic, report warns. PMID- 23734392 TI - Rights abuses linked to Irish surgical college in Bahrain. PMID- 23734393 TI - [Antibiotics in severe malnutrition in children]. PMID- 23734394 TI - The lure of the epigenome. PMID- 23734395 TI - 2011 Annual Meeting of the American Society for Bone and Mineral Research San Diego, CA September 16-20, 2011. Abstracts. PMID- 23734397 TI - An opportunity for nephrologists to step up. PMID- 23734396 TI - Commentary on in-home monitoring support for dementia caregivers: feasibility study. PMID- 23734398 TI - Developing a gung fu work and lifestyle. PMID- 23734399 TI - Incentives for nondiscriminatory wellness programs in group health plans. Final rule. AB - This document contains final regulations, consistent with the Affordable Care Act, regarding nondiscriminatory wellness programs in group health coverage. Specifically, these final regulations increase the maximum permissible reward under a health-contingent wellness program offered in connection with a group health plan (and any related health insurance coverage) from 20 percent to 30 percent of the cost of coverage. The final regulations further increase the maximum permissible reward to 50 percent for wellness programs designed to prevent or reduce tobacco use. These regulations also include other clarifications regarding the reasonable design of health-contingent wellness programs and the reasonable alternatives they must offer in order to avoid prohibited discrimination. PMID- 23734400 TI - Patient Protection and Affordable Care Act; establishment of exchanges and qualified health plans; Small Business Health Options Program. Final rule. AB - This final rule implements provisions of the Patient Protection and Affordable Care Act and the Health Care and Education Reconciliation Act of 2010 (collectively referred to as the Affordable Care Act) related to the Small Business Health Options Program (SHOP). Specifically, this final rule amends existing regulations regarding triggering events and special enrollment periods for qualified employees and their dependents and implements a transitional policy regarding employees' choice of qualified health plans (QHPs) in the SHOP. PMID- 23734401 TI - Human exposure to radiofrequency electromagnetic fields. Final rule. AB - This document resolves several issues regarding compliance with the Federal Communications Commission's (FCC's) regulations for conducting environmental reviews under the National Environmental Policy Act (NEPA) as they relate to the guidelines for human exposure to RF electromagnetic fields. More specifically, the Commission clarifies evaluation procedures and references to determine compliance with its limits, including specific absorption rate (SAR) as a primary metric for compliance, consideration of the pinna (outer ear) as an extremity, and measurement of medical implant exposure. The Commission also elaborates on mitigation procedures to ensure compliances with its limits, including labeling and other requirements for occupational exposure classification, clarification of compliance responsibility at multiple transmitter sites, and labeling of fixed consumer transmitters. PMID- 23734402 TI - Integrating cultural competence: animal health, food safety ultimately benefit as AVMA incorporates cultural competence in CE. PMID- 23734403 TI - Submerged by Sandy: some practitioners still bailing out of dire situations. PMID- 23734404 TI - A pioneer in research: work of Theobald Smith, MD, advanced veterinary medicine. PMID- 23734406 TI - Slaughter facilities won't be able to hold downed calves. PMID- 23734405 TI - Letting the numbers tell the story: AAVMC places new focus on collecting, disseminating data. PMID- 23734407 TI - Worms' adaptation a critical problem: anthelmintic resistance a problem in ruminants, horses. PMID- 23734408 TI - Veterinary education and global food policy. PMID- 23734409 TI - The author responds. PMID- 23734411 TI - Patients need our protection. PMID- 23734410 TI - Dural ossification (ossifying pachymeningitis). PMID- 23734412 TI - Report appraises the contribution of volunteers. PMID- 23734413 TI - Healthcare regulator switches focus to analyse best and worst providers. PMID- 23734414 TI - Guarding against collective failures. PMID- 23734415 TI - Developing a clinical management tool to evaluate quality. AB - Peer review is used increasingly in the NHS as a form of evaluation between professionals, services and organisations, and as a way of offering participants a snapshot assessment of particular health services or at points in a clinical pathway. The model outlined in this article has been developed as an aide-memoire to clinical commissioning groups, provider organisations and clinical staff for the process of gathering evidence of good assurance and governance arrangements. PMID- 23734416 TI - The value of active followership. AB - Followership is an emerging concept based on human factors science. It describes a set of skills and behaviours that help improve team performance. An effective leader creates vision, sets direction and enables a culture in which others can thrive and work together to deliver the goals. Like leadership, good followership is increasingly being recognised as an important component for high performance. Good followership is based on good communication and 'upward influencing' (Willson 2012). This article discusses the concept arid provides scenarios to illustrate examples of good and poor followership, and how they affect care. PMID- 23734417 TI - A 'roll-on, roll-off' preceptorship pathway for new registrants. AB - The need to support high numbers of new registrants simultaneously at the Royal United Hospital, Bath, led to the development of a preceptorship pathway. The 'roll-on, roll-off' structure allows newly registered nurses and allied health professionals to start preceptorship as soon as they take up their roles. Essential competencies are negotiated with managers and achieved through subject focused teaching sessions, workplace preceptorship, reflection, peer support and the use of distance-learning materials that link to the NHS knowledge and skills framework and appraisal requirements. Evaluation suggests that the pathway provides a high standard of learning and support, but development will continue, particularly in relation to monitoring and recording new practitioners' involvement in clinical incidents and their completion rates. PMID- 23734418 TI - Nurse practitioner roles in Australian healthcare settings. AB - There is evidence of support for nurse practitioner (NP) roles in national and international literature. However, despite this, and numerous Australian government feasibility and evaluation studies, barriers to implementing NP roles in mainstream health care and developing them to their full potential remain. A study was undertaken to explore nurse practitioners', managers' and nurse policymakers' perceptions of the roles in general, and this article reports on the findings from the initial survey phase. The article also discusses barriers to full integration and development of NPs. PMID- 23734419 TI - Bitten by the travel bug. PMID- 23734420 TI - Doctor boost. Immigration bill could raise healthcare workforce. PMID- 23734421 TI - Preparedness under assault. AB - Boston's response to last week's bombings put to the test the city's extensive training for emergencies and abundance of trauma centers. Not every city's hospitals may be well-prepared. While the Joint Commission requires hospitals to conduct drills with local emergency response agencies, hospitals can in some cases do "tabletop" drills instead of real exercises. "Some communities don't have funds to do that. So to facilitate that, we allow this to be a tabletop," says George Mills, left, of the Joint Commission. PMID- 23734422 TI - Conspiracy theory. Jailed CEO was for-profit booster in poor locale. PMID- 23734423 TI - Updated protocol. Guide clarifies self-disclosure for violations. PMID- 23734424 TI - Stiff resistance. Docs fight encroachment in turf war with nurses. PMID- 23734425 TI - Expansion attention. Ark. approves plan, likely to face federal scrutiny. PMID- 23734426 TI - Dual-eligible dilemma. States test managed care, but critics question if approach is cost-effective. PMID- 23734427 TI - Looking ahead. Noseworthy paves way for growth. Interviewed by Jessica Zigmond. PMID- 23734428 TI - Mass casualty preparedness. PMID- 23734429 TI - Prescription for change. PMID- 23734430 TI - How to fix the SGR. Evaluation and management services at issue. PMID- 23734431 TI - Top business graduate schools for physician-executives. Data collected January March 2013 for the 2012-13 school year. PMID- 23734432 TI - Long latency fluctuation of the finger movement evoked by cerebellar TMS during visually guided manual tracking task. AB - The purpose of this study was to investigate whether right index finger movement during visually guided manual tracking task is fluctuated by transcranial magnetic stimulation (TMS) specifically over the cerebellum and is differently fluctuated by TMS over different sites of the cerebellum. TMS was delivered over the left, middle, or right cerebellum, or Pz. Index finger movement and electromyographic response in the first dorsal interosseous were recorded. Fluctuation of the finger movement appeared approximately 100 ms after cerebellar TMS with a probability of approximately 20%. The probability was significantly higher than that after TMS over the Pz or that after sham TMS. The probability was not significantly different among different TMS sites over the cerebellum. The long latency fluctuation of the finger movement during visually guided manual tracking task is evoked by TMS specifically over the cerebellum, but is not preferentially evoked by a specific site of the cerebellum. Cerebellar TMS induced long latency motor response may be useful to investigate the neural pathways activated by TMS over the cerebellum. PMID- 23734433 TI - Effects of ergoreflex on respiration and other efferent effects in adult male patients with chronic obstructive pulmonary disease. AB - In COPD, overactivation of ergoreceptors may be a link between peripheral changes, sympathetic over activation and increased hemodynamic and ventilatory responses to exercise. The current study was undertaken to test the hypothesis that, ergoreflex in COPD patients is hyperactive and contributes to breathlessness and exercise limitation. The aim of study was to (1) demonstrate its hyperactivity in COPD (2). To record other efferent effects. Twenty stable COPD male patients aged 50 +/- 2.5 years and twenty healthy male subjects aged 48 +/- 3.5 years were studied under experimental and control groups. The ergoreflex contribution to cardio respiratory parameters was assessed by post-handgrip regional circulatory occlusion method (PH-RCO) and computed as the difference in heart rate and respiratory rate response between PH-RCO and control run without PH-RCO. Results were analyzed for significance between two groups by repeated measures ANOVA. COPD patients showed over activation of ergoreflex as compared to control subjects in terms of heart rate during sustained hand grip (SHG) exercise (117 +/- 1.22 versus 89 +/- 0.89) beats/min, recovery heart rate (p < 0.001), and respiratory rate during SHG (24 +/- 0.54 versus 19 +/- 03.24) breaths/min and recovery respiratory rate (p < 0.001). Degree of overactivation of ergoreflex was significant in COPD patients (p < 0.001). In COPD, overactivity of ergoreflex is associated with abnormal cardio respiratory reflex control. COPD patients showed overactivation of sympathetic nervous system as evidenced by heart rate changes during exercise and delayed recovery. PMID- 23734434 TI - Heart rate variability responses to standing are attenuated in drug naive depressed patients. AB - Depression has been linked to altered cardiac autonomic regulation. Previous studies have been inconsistent in terms of measurement of heart rate variability (HRV), selection of depressed patients with cardiac disorders and not controlling for co-morbid conditions such as substance use and anxiety disorders. The objective of this study is to compare the effect of posture on spectral measures of HRV in drug naive healthy patients with major depression with age and gender matched healthy controls. Spectral measures of HRV in supine position and with active standing were obtained (using Task force recommendations). Repeated measure ANOVA revealed an attenuated response in HRV parameters (HF normalized units & LH/HF ratio) to active standing in depressed subjects compared to healthy controls. We conclude that there is an impaired parasympathetic modulation in response to physiological maneuver (orthostatic challenge) in drug naive subjects with major depression (co-morbid medical or psychiatric conditions) compared to healthy controls. PMID- 23734435 TI - Comparison of cardiac autonomic activity between malnourished and healthy children. AB - Severe malnutrition can significantly compromise autonomic nervous system. However, less is known about the cardiac autonomic activity in mild and moderate grades of malnutrition in children. Therefore, the objective of this study was to assess the effect of mild/moderate malnutrition on heart rate variability (HRV), a non invasive tool to estimate the cardiac autonomic activity. A cross sectional, community based study was conducted in which 35 malnourished children (mean age: 6.06 +/- 2.04 yrs), on the basis of anthropometric parameters, were enrolled in the study group by random samplings, who were the children of urban slum dwellers and 35 age and sex matched healthy children, were taken as controls. Grading of malnutrition was done according to Indian Academy of Pediatrics (IAP) classification. Anthropometry, basal heart rate (BHR), blood pressure were determined. Time domain and frequency domain indices of HRV were assessed using RMS Polyrite D (version 2.4). Weight, height, mid arm circumference (MAC) and body mass index (BMI) were found to be statistically lower in the study group. There was a strong negative correlation between MAC and LF component (P < 0.01). BHR was found to be increased in the malnourished group (P = 0.027). Low frequency (LFnu) & LF-HF ratio were found to be increased (P = 0.000 & P = 0.001 respectively) while high frequency (HFnu) component was decreased (P = 0.000) in malnourished group. Our results suggested that impaired cardiac autonomic nerve function characterized by sympathetic over activity may occur in malnourished children. This study also enables us to compare, in future works, HRV in pediatric subjects with different grades of malnutrition. PMID- 23734436 TI - Association of sleep duration with blood glucose level of Gujarati Indian adolescents. AB - Recently studies conducted in various parts of the world indicate short sleep duration as a novel risk factor for development of type 2 diabetes. However, ethnic differences exist in the etiopathogenesis of diseases, the current study was undertaken to study the effect of sleep duration on the blood glucose level of Gujarati Indian adolescents. A randomized, non-experimental, cross-sectional study was done on the voluntary participants n = 332 Gujarati adolescent boys and girls of age group 13-20 years studying at the schools and colleges in the Anand district. The participants were assessed for their sleep duration, body composition and blood glucose level. The sleep duration was reported by the subjects as the number of hours they slept on most of the nights in a week over the last one-year. The observations of the study were then analyzed after grouping them into: 1) Adequate sleep duration at night, ASDN (> or = 7 hrs) and 2) Inadequate sleep duration at night, ISDN (< 7 hrs) groups. One-way ANOVA and post hoc Tuky-Krammer test were used for finding significant differences (P < 0.05) between groups. No significant difference was found in all parameters of body composition and fasting blood glucose level between the ASDN group and ISDN group in both boys and girls. However, gender difference exists in the body composition and blood glucose level. The current study indicates that inadequate sleep duration at night (< 7 hrs) does not affect the blood glucose level of the Gujarati Indian adolescents of age group 13-20 years. PMID- 23734437 TI - Oxidative status in workers engaged in recycling of plastic: occupational hazard. AB - Recycling plastic industry is on rise. Plastic waste in environment is a pollutant so recycling of it can save environment and is economical too. However its recycling is associated with harmful effects on workers engaged in it. The present study was designed to elucidate the role of free radicals and cytochrome c in pathogenesis of polypropylene associated diseases. Thirty workers from plastic recycling factory occupationally exposed to polypropylene between the age of 18-40 years and working for atleast 8 hours a day for more than a year but less than 10 years were selected for the study. A trend in increase of FRAP and decrease of MDA was observed but they could not reach the level of significance. The level of serum cytochrome c, which is an indirect marker of oxidative stress, was also detectable in only two subjects. Since the number of subjects in the study was less, the result needs to be confirmed on larger number. More over cause of pulmonary dysfunction and carcinomas in these workers needs to be investigated. PMID- 23734438 TI - Role of exercise and nutrition on cardiopulmonary fitness and pulmonary functions on residential and non-residential school children. AB - Physical fitness is the prime criterion for survival and to lead a healthy life. Our aim is to find out effect of exercise and nutrition on physical fitness on growing children with scientific records. The present study was designed on healthy school children of a Residential-Sainik (100) and Non-Residential (100) school children (12-16 yrs) of Bijapur. To evaluate cardiopulmonary fitness parameters included are VO2Max (ml/kg/min) and Physical Fitness Index (PFI %). Harvard Step Test determined VO2 Max and PFI. Also recorded pulmonary function parameters like Forced Expiratory Volume in 1 sec (FEV1 in %) by recording spirometry. Peak Expiratory Flow Rate (PEFR in L/Min) by Peak flow meter and Maximal Expiratory Pressure (MEP in mmHg) by modified Black's apparatus. We found statistically significant higher values (p = 0.000) of VO2Max, PFI, FEV1, PEFR and MEP in residential school children compared to nonresidential school children higher. So, our study shows that regular exercise and nutritious food increase the cardiopulmonary fitness values and pulmonary functions in Residential school children. PMID- 23734439 TI - Effect of yoga on different aspects of mental health. AB - State anxiety, somatization of stress, quality of life, self-rated quality of sleep, and discomfort due to over-breathing which occurs when stressed were studied. Out of a total of 140 participants, seventy participants self-selected to be in a yoga group for stress relief (group mean age +/- SD, 33.0 +/- 6.5 years; 37 males). Seventy age and gender matched participants were in a control group. State anxiety, somatization of stress, quality of life, discomfort and self-rated quality of sleep were assessed using the State-Trait Anxiety Inventory, Symptom Checklist-90-R, SF-12, Nijmegen Discomfort Evaluation Scale and a Sleep Rating Questionnaire respectively. Assessments were made at the beginning and end of the week. Repeated measures ANOVAs with Bonferroni adjusted post-hoc analyses showed a significant decrease in state anxiety (P < 0.001), somatization of stress (P < 0.01), improved health-related quality of life (P < 0.01), self-rated quality of sleep (P < 0.01), and decrease in discomfort due to over-breathing (P < 0.001). No changes (except decreased discomfort due to over breathing; P < 0.01) occurred in the control group. This study suggests that a brief yoga program may be beneficial in decreasing anxiety, somatization of stress and discomfort, improving health-related quality of life and self-rated sleep quality. PMID- 23734440 TI - Clinical validation of aneroid sphygmomanometer. AB - Recent concerns about the mercury toxicity and its ill effects on the environment and health has led to widespread use of aneroid manometers. Present study was conducted to analyse whether this change would lead to any systematic shift in measured blood pressure or consistency of blood pressure measurement in clinical setting. The clinical accuracy of the Welch Allyn aneroid sphygmomanometer model 7670-04 was studied against the mercury sphygmomanometer on 83 volunteers from Dehradun. Two blood pressure reading of each study subject was recorded with pretested instruments (aneroid and mercury sphygmomanometer). Data analysis showed the difference of means between the reading of two devices against mean of the observer reading for both systolic (-3.62 +/- 4.88) and diastolic (-2.36 +/- 3.77) blood pressure were not statistically different. The corresponding values of the SBP and DBP from both the instruments showed significant correlation. Regression analysis of mercury versus aneroid showed regression line (Y = 9.52 + 0.95X for SBP, Y = 0.36 + 0.96X for DBP) significantly different from line of equality (P < 0.001). The study has demonstrated that the aneroid device (model: 7670-04) achieved grade B performance according to the British Hypertensive Society criteria. PMID- 23734441 TI - Effect of gender on antisperm antibodies in infertile couples in central India. AB - The presence of antisperm antibodies in serum may impair sperm function leading to immunological infertility. The aim of study was to determine the presence of antisperm antibodies in the circulating blood of infertile couples. This cross sectional study included 109 couples suffering from infertility for more than one year duration. Serum antisperm antibodies were determined by Varelisa Sperm Antibodies Enzyme Immunoassay kit. The percentage incidence of antisperm antibodies in infertile men was 30.27% was statistically not significant from the 33.03% incidence in infertile women (P Value > 0.05). In the nineteen (15.59%) couples both the husband as well as wife was positive for sperm antibodies. The presence of antisperm antibodies may impair fertilizing ability therefore its assessment should be consideredas an essential part of infertility management. PMID- 23734442 TI - Effect of thyroxine on fibrinolytic system in rat. AB - Thyroid hormones have many effects on the cardiovascular system. Thyroid dysfunction accelerates atherosclerosis not only through conventional risk factors (dyslipidemia) but they also show a very close relationship with hemodynamic parameters. Thyroxine is determinant of the several components of fibrinolytic system even though the exact relationship is far from clear. Present study was carried out to determine the effect of thyroxine on fibrinolytic parameters such as plasminogen activators (PA) in rat heart, levels of PA and plasminogen activator inhibitor (PAI), glucose in plasma and serum lipid profile. Rats were injected with 50 ug eltroxine/100 gm(-1) body weight intraperitoneally for one week. Compared with controls, thyroxine treatment increased PA activity significantly in rat heart. No changes were seen in PA, PAI and glucose in plasma of two groups of rats. A significant decrease in total cholesterol and LDL cholesterol levels was seen in serum of treated group resulting in the decrease of LDL/HDL and Total cholesterol/HDL-cholesterol ratios. These results suggest that thyroxine treatment may have considerable clinical significance. It raised PA activity in heart as well as reduced cholesterol content in blood. It is possible that thyroxine treatment may confer a beneficial effect on cardiovascular risk. PMID- 23734443 TI - Immediate cardiovascular effects of pranava pranayama in hypertensive patients. AB - Slow, deep, pranayama-based breathing training has been shown to be effective in reducing blood pressure (BP). The present study was undertaken to determine immediate effects of performing pranava pranayama on cardiovascular parameters in hypertensive patients. 29 hypertensive patients who were on medical treatment and also attending yoga sessions were recruited for the present study. Supine heart rate (HR) and BP were recorded before and after performance of pranava pranayama for five minutes. Post intervention statistical analysis revealed a significant (P < 0.05) reduction in systolic pressure (SP) and a more significant (P < 0.01) reduction in HR, pulse pressure and double product (Do P). The reduction in rate pressure product (RPP) was highly significant (P < 0.001). Pranava pranayama is effective in reducing HR and SP in hypertensive patients within five minutes of the practice. This may be due to a normalization of autonomic cardiovascular rhythms as a result of increased vagal modulation and/or decreased sympathetic activity and improved baroreflex sensitivity along with an augmentation of endogenous nitric oxide production. Our findings have potential therapeutic applications in day-to-day as well as clinical situations where blood pressure needs to be brought down at the earliest. The significant fall in RPP and Do P signifies a reduction in oxygen consumption and work done by the heart. It is concluded that pranava pranayama, a simple and cost effective technique can be used in the management of hypertensive patients in addition to the regular medical management. Further studies are required to enable a deeper understanding of the mechanisms involved and its usefulness in the long- term management of hypertension. PMID- 23734444 TI - Validity of heart rate based nomogram fors estimation of maximum oxygen uptake in Indian population. AB - Maximal oxygen uptake (VO2max) during a graded maximal exercise test is the objective method to assess cardiorespiratory fitness. Maximal oxygen uptake testing is limited to only a few laboratories as it requires trained personnel and strenuous effort by the subject. At the population level, submaximal tests have been developed to derive VO2max indirectly based on heart rate based nomograms or it can be calculated using anthropometric measures. These heart rate based predicted standards have been developed for western population and are used routinely to predict VO2max in Indian population. In the present study VO2max was directly measured by maximal exercise test using a bicycle ergometer and was compared with VO2max derived by recovery heart rate in Queen's College step test (QCST) (PVO2max I) and with VO2max derived from Wasserman equation based on anthropometric parameters and age (PVO2max II) in a well defined age group of healthy male adults from New Delhi. The values of directly measured VO2max showed no significant correlation either with the estimated VO2max with QCST or with VO2max predicted by Wasserman equation. Bland and Altman method of approach for limit of agreement between VO2max and PVO2max I or PVO2max II revealed that the limits of agreement between directly measured VO2max and PVO2max I or PVO2max II was large indicating inapplicability of prediction equations of western population in the population under study. Thus it is evident that there is an urgent need to develop nomogram for Indian population, may be even for different ethnic sub-population in the country. PMID- 23734445 TI - Prevalence and progression of refractive errors among medical students. PMID- 23734446 TI - Setting APPI vision 2020: animal experiments in physiology and pharmacology. PMID- 23734447 TI - Isozymic variations in specific and nonspecific esterase and its thermostability in silkworm, Bombyx mori L. AB - Esterase isozymic variations were documented in the haemolymph of developed multivoltine and bivoltine silkworm breeds during unfavorable seed crop seasons of May - September using a- and a- napthylacetate separately to identify specific and nonspecific esterase having thermotolerant potentiality. Variations existed in the isozyme pattern with three bands (Est-2, 3 and 4) in pure Nistari race and other developed multivoltine and bivoltine breeds. Est-2 and Est-3 were non specific esterases as they were observed when both a- and a-napthylacetate was used as substrates separately. Est-4 band was observed only with a-napthylacetate as substrate and was therefore confirmed to be specific a-esterase band in the haemolymph of silkworm, Bombyx mori L. Zymograms showed that the non-specific esterase band (Est-3) with R1 of 0.43 and specific a-esterase band (Est-4) with R(f) of 0.32 predominately withstood a temperature of 70 +/- 2 degrees C for a duration of 10 min and were confirmed as thermostable esterases in haemolymph of silkworm, Bombyx mori L. This also categorized the presence of thermostable esterases in developed multivoltine and bivoltine breeds of silkworm, even though the qualitative activity was more in the former than the latter. The qualitative presence of thermostable esterases and their activity could be adopted as an indicative biochemical marker in relation to thermotolerance in silkworm. PMID- 23734448 TI - Studies on strains of Trichoderma spp. from high altitude of Garhwal Himalayan region. AB - Two species of Trichoderma i.e. T. harzianum and T. viride have been isolated from the soil samples collected from the higher altitude (2000-3500 m) of Garhwal Himalayan region in India. The two species were grown in Petri plates on TSM agar media and it was also observed that the optimum temperature and pH for Trichoderma growth was 30 degrees C and 5.5 respectively. When incubated on TSM agar medium at 4 degrees C, the fungus grew normally with heavy induced sporulation within three weeks of incubation. Induction of sporulation on exposure to low temperature appeared to be strategies for survival of these species in extreme cold environment temperature 4 to 5 degrees C. Antifungal activities of the two species of Trichoderma were demonstrated with phytopathogenic fungi in dual cultures. The antifungal metabolites produced by Trichoderma spp., diffusible as well as volatile, caused abnormalities in pathogenic fungi. Plant growth promotion of Trichoderma spp. was also shown through plant analysis in greenhouse. PMID- 23734449 TI - Effect of textile waste water on tomato plant, Lycopersicon esculentum. AB - In this study Sanganer town, Jaipur was selected as study area. The plants of Lycopersicon esculentum var. K 21(Tomato) treated with 20 and 30% textile wastewater were analyzed for metal accumulation, growth and biochemical parameters at per, peak and post flowering stages. Findings of the study revealed that chlorophyll content was most severely affected with the increase in metal concentration. Total chlorophyll content showed a reduction of 72.44% while carbohydrate, protein and nitrogen content showed a reduction of 46.83, 71.65 and 71.65% respectively. With the increase in waste water treatment the root and shoot length, root and shoot dry weight and total dry weight were reduced to 50.55, 52.06, 69.93, 72.42, 72.10% respectively. After crop harvesting, the fruit samples of the plants treated with highest concentration of textile waste water contained 2.570 mg g(-1)d.wt. of Zn, 0.800 mg g(-1) d.wt. Cu, 1.520 mg g(-1) d.wt. Cr and 2.010 mg g(-1) d.wt. Pb. PMID- 23734450 TI - Analysis of vegetation in an Imperata grassland of Barak valley, Assam. AB - Imperata grassland at Dorgakona, Barak valley, North Eastern India was analyzed for species composition and diversity pattern in relation to traditional management practices. 19 families were in the burnt and unburnt plots of the study site with Poaceae as the most dominant one. 29 species occurred in the burnt plot and 28 in the unburnt plot. Most of the species were common in both the plots. The pattern of frequency diagrams indicated that the vegetation was homogeneous. Imperata cylindrica, a rhizomatous grass was the dominant species based on density (318.75 and 304.18 nos. m(-2)), basal cover (158.22 and 148.34 cm2 m(-2)) and Importance value index (IVI) (132.64 and 138.74) for the burnt and unburnt plots respectively. Borreria pusilla was the co-dominant species constituting Imperata-Borreria assemblage of the studied grassland. It was observed that B. pusilla (162.25 nos. m(-2) and 50.37 nos. m(-2), I. cylindrica (318.75 nos. m(-2) and 304.18 nos. m(-2)) and Setaria glauca (24.70 nos. m(-2) and 16.46 nos. m(-2) were benefited from burning as shown by the values sequentially placed for burnt and unburnt plots. Certain grasses like Chrysopogon aciculatus and Sacciolepis indica were restricted to burnt plot while Oxalis corniculata showed its presence to unburnt plot. Grasses dominated the grassland as revealed by their contribution to the mean percentage cover of 72% in burnt plot and 76% in umburnt plot. The dominance-diversity curves in the study site approaches a log normal series distribution suggesting that the resources are shared by the constituent species. Seasonal pattern in diversity index suggested definite influence of climatic seasonality on species diversity; rainy season was conducive for maximum diversity (1.40 and 1.38 in the burnt and unburnt plots, respectively). Dominance increased with concentration of fewer species (0.0021 in burnt plot and 0.0055 in unbumt plot) in summer and behaves inversely to index of diversity. This study showed that the traditional management practices benefits the farmers as it promote grassland regeneration with I. cylindrica as the dominant grass. PMID- 23734451 TI - Copper induced oxidative stress in tea (Camellia sinensis) leaves. AB - Tea [Camellia sinensis L. (O.) Kuntze] is an economically important plantation crop of India but is prone to attack by several fungal pathogens. Copper based fungicides are being used for decades to control fungal diseases in tea which may lead to accumulation of copper in the soil. The biochemical responses to increasing concentrations of copper (50 to 700 microM) were investigated in the leaves of two cultivars of tea commonly grown in the Darjeeling hills. Exposure to excess Cu resulted in increased lipid peroxidation (level of TBARS increased from 3.5 micromol g(-1) f.wt. in control to 12 micromol g(-1) f.wt. in TS-520 plants exposed to 700 mM of Cu), reduced chlorophyll content (from 83.7 microg g( 1) f.wt. in control to 22.5 microg g(-1) f.wt. in TS-520 plants exposed to 700 mM of Cu), higher levels of phenolic compounds(total phenol content increased from 4.54 mg g(-1) f.wt. in control to 5.79 mg g(-1) f.wt. in TS-520 plants exposed to 400 mM of Cu) and an increase in peroxidase enzyme levels. Two new peroxidase isozymes (POD1 and POD2) were detected in plants exposed to Cu. In addition, biochemical responses in two tested cultivars, TS-462 and TS-520 differed significantly. TS-520 was found to be more sensitive to increasing concentrations of Cu. Superoxide dismutase activity increased progressively from 2.55 U mg(-1) protein in control to 5.59 U mg(-1) protein in TS-462 but declined from 4.75 U mg(-1) protein in control to 3.33 U mg(-1) protein in TS-520 when exposed to Cu concentrations higher than 400 microM. Asharp increase in the activity of ascorbate peroxidase (from 0.53 units in control to 2.37 units in plants exposed to 400 mM of Cu) was noticed at the 10th day of exposure in the more tolerant cultivar. On the other hand, catalase levels increased only marginally (from 8.4 to 10.1 units in TS 520 and 8.7 to 10.9 units in TS 462) in both the cultivars. From this study, it appears that Cu exposure led to the production of reactive oxygen species in the leaves resulting in significant lipid peroxidation. Tea plants try to mitigate this oxidative damage through accumulation of phenolic compounds and induction of antioxidant enzymes. PMID- 23734452 TI - Effects of tert-butyl hydroperoxide on Ca(2+) ATPase activity in isolated rat hepatocytes and its reversal by antioxidants. AB - Calcium ions play an importantrole in various physiological processes such as nerve impulse transmission, muscle contraction, hormone action, blood clotting. They ions act as an intracellular second messenger, relaying information within cells to regulate their activity. To understand the mechanism of hepatotoxicity of t-BHP, studies were carried out using freshly isolated rat hepatocytes. The effect of t-BHP on Ca(2+) accumulation and Ca(2+) uptake by rat hepatocytes was monitored using 45Ca(2+). It caused decrease in 15% accumulation of 45Ca(2+) in comparison to the control group. t-BHP also significantly decreased the Ca(2+) ATPase activity in isolated hepatocytes .This decrease in Ca(2+) ATPase activity by t-BHP was reversed 40% by naturally occurring antioxidant glutathione (GSH) and 20% by the synthetic antioxidant butylated hydroxy toluene (BHT). These results indicate that the hepatotoxic action of t-BHP involves oxidative stress as evident by the protection accorded by various antioxidants employed in the study as well as impairment of intracellular calcium homeostasis which can lead to liver cell injury. PMID- 23734453 TI - Biology and conservation of the genus Scylla in India subcontinent. AB - Mud crabs usually inhabit brackish water bodies of South-East Asia including India. The biological significance of the species is its survibility in wide range of hydro-biological fluctuating environments including salinity. The life cycle of the species includes two important larval stages at which they are vulnerable to various predators. Pathophysiological status of the species is a challenge for its aquaculture. Inspite of a huge economical and high food values, informations on biochemical, molecular, physiological, ecological and taxonomical aspects of mud crabs (Scylla sp.) in comparison to other important aquaculture candidates are very limited. The present review is an attempt to string together various informations available on mud crabs (S. serrata) so that it will provide a platform to have all the basic informations regarding the species for interested workers. It is believed that understanding the pathology, ecophysiology, genetics and reproduction of the species in its natural environment will not only help in its conservation but also will help in its enhanced production. PMID- 23734454 TI - Evaluations of allelopathic effect of Echinochloa colona weed on rice (Oryza sativa L. 'Vandana'). AB - Echinochloa colona (L.) Link is a very problematic weed in up land and medium land rice causing significant reduction in yield. In the present investigation, laboratory and field experiments were conducted to evaluate the nature of interaction E. colona on germination and growth of the up land rice cultivar 'Vandana'. The effects of decomposing and decomposed aqueous leachates (1-10% w/v) obtained from the dried biomass of 20, 30, 40 and 60 days old Ecolona plants were studied on rice using petridish bioassay technique with three different types of culture media like filter paper, soil, and soil + activated charcoal. The decomposing leachates of E. colona showed strong toxic effect on root and shoot growth of rice, the highest being noted with 10% leachates of 60 days old plant residue. It inhibited root and shoot growth by 100% and 43.9% respectively as compared to control. The corresponding decomposed leachates inhibited rice germination by 90% and root and shoot growth by 70 and 25% respectively. These toxic effects of leachates showed in filter paper medium were significantly reduced in soil and soil plus activated charcoal media proving their allelopathic nature. In a field experiment, E. colona and rice were grown in proportions of 1:1, 1: 2 and 1:4, the total plant density being maintained at 100 pants m(-2). The height and dry matter of rice were adversely affected with increasing in E. colona population. From another similar field trial, data on dry matter of 20, 30, 40, and 60 days old plants were taken and their plant relative yield (PRY) and relative yield total (RYT) values were calculated. The PRY and RYT values were found to be less than unit (< 1) throughout the growth period studied which suggested the presence of severe antagonistic interspecific interaction between rice and E. colona due to allelopathy. PMID- 23734455 TI - Phytoremediation of crude oil contaminated soil using nut grass, Cyperus rotundus. AB - The aim of this study was to evaluate the efficacy of Cyperus rotundus (nut grass), that could be effective in phytoremediation of crude oil contaminated soil. A net house experiment was conducted with different concentrations (2.05, 4.08, 6.1, 8.15 and 10.2%) of crude oil-contaminated soil for 180 days. Plant growth, biomass, total oil and grease (TOG) degradation and microbial numbers were analyzed at different intervals i.e. 60,120 and 180 days in different percentages of crude oil contaminated soil. In presence of crude oil, plant biomass and heights reduced up to 26 and 21.9% respectively. Concerning TOG content in soil, C. rotundus could decrease up to 50.01, 46.1, 42.6, 38.8 and 32.6% in treatment I, II, III, IV and V respectively in vegetated pots during 180 days. In case of unvegetated pots, the reductions of TOG were 4.4, 5.6, 6.6, 7.6 and 9.6% in treatment A, B, C, D and E respectively. However, there was significant degradation (P = 0.05) of TOG in vegetated pots in comparison to unvegetated pots thereby proving the efficacy of this plant species for use in phytoremediation. PMID- 23734456 TI - Morphometric and molecular characterization of fungus Pestalotiopsis using nuclear ribosomal DNA analysis. AB - Taxonomy of the fungus Pestalotiopsis based on morphological characters has been equivocal. Molecular characterization often Pestalotiopsis species was done based on nuclear ribosomal DNA internal transcribed spacer (ITS) amplifications. Results of the analyses showed that species of genus Pestalotiopsis are monophyletic. We report ITS length variations, single nucleotide polymorphisms (SNPs) and insertions/ deletions (INDELS) among ten species of Pestalotiopsis that did not cause any phylogenetic error at either genus or species designation levels. New gene sequences have been assigned (Gen Accession numbers from HM 190146 to HM 190155) by the National Centre for Biotechnology Information, USA. PMID- 23734457 TI - Comparative study on foraminifera of east and west coast of India. AB - The oceanographic conditions of west and east coasts of India provide variations in ecological conditions. Hence, the present study was undertaken to assess the geographic distribution and diversity of foraminifera (Protista) of west and east Coasts of India to gain insights in to ecological conditions that effect their distribution. The intertidal sediment samples, collected for a period of two years from October 2004 to September 2006 were analysed for foraminiferal diversity and sediment characteristics by standard methods. Relatively high densities (west coast--156 to 19,400 g(-1), east coast--37-214 g(-1)) and diversities were observed at all the sites of the West (74 species) compared to the east coast (57 species). Thirty three species were common to both the coasts. Forty one and 24 species were found to be unique to west and east coast, respectively. Foraminifera of west and east coasts form distinct clusters as revealed by Bray-Curtis cluster analysis, indicating distinctly different foraminiferal assemblages. The geographical and oceanographic conditions thus seem to influence a differential diversity of forams. PMID- 23734458 TI - Studies on radionuclides 228Ra, 238U, 228Th and 40K in selected seaweeds of coastal Tamil Nadu, India. AB - Studies on natural and anthropogenic radioactivity assume greater importance in the context of human health and development. Hence two species of seaweeds viz: Gracilaria edulis and Ulva lactuca, from three high background radiation areas (Arockiapuram, Kadiapattinam and Kurumpanai) on the southwest coast of Tamil Nadu, and Mandapam as low background radiation area of the southeast coast of Tamil Nadu were studied for variations in activity concentration of 228Ra, 40K, 238U and 228Th. Among these radionuclides, 40K recorded significant inter-species variation while 238 U and 228Th showed significant association. The overall mean concentration of radionuclides was found high in G. edulis (5.31,57.49,36.05,356.55 Bq kg(-1) for 228Ra, 40K, 238U, 228Th respectively), while the mean concentrations for U. lactuca were 4.88, 42.35, 34.40,347.70 Bqkg( 1) for 228Ra, 40K, 238U, 228Th respectively. The mean concentration of radionuclides was uniformly found low during northeast monsoon season in both the seaweed species. PMID- 23734459 TI - Assessment of soft bottom polychaete diversity in Thondi, Palk Bay, India. AB - Polychaete assemblages are relatively poorly known in comparison to other components from Indian waters. In the present study, the spatial and seasonal distributions of polychaetes were investigated in the Thondi coastal area. Polychaete assemblage structure seems to be influenced by environmental parameters, such as temperature, salinity, pH, dissolved oxygen and total organic carbon. A total of 34 polychaete species were found, of which 26 species were in station I while 22 species in station II. There was a pronounced variation in diversity of polychaetes between the studied sites. Among the families maximum percentage of species constituted by Glyceridae (12%) and minimum Owenidae (4%) at station I and in station II, the Eunicidae (14%) was maximum and Pisinidae as (4%) minimum. The population density varied from 1456 to 2456 no m(-2) in station I; 2120 to 4424 in station II and diversity index varied from 1.96 to 2.48 in station I; 2.01 to 2.53 in station II. Species richness varied from 1.21 to 1.65 in station I; 1.36 to 1.69 in station II and evenness index varied from 0.9 to 0.97 in station I; 0.91 to 0.98 in station II. BIO-ENV analysis showed that salinity, TOC and temperature as the key variables in influencing the faunal distribution. PMID- 23734460 TI - Accumulation of metals in selected macrophytes grown in mixture of drain water and tannery effluent and their phytoremediation potential. AB - Phytoremediation is an emerging, ecofriendly and economically feasible technique for the restoration of heavy metals contaminated environment. In the present investigation, five native macrophytes growing naturally in a drain receiving tannery effluent viz Bacopa monnieri, Eichhornia crassipes, Hydrilla verticillata, Ipomoea aquatica and Marsilea minuta were evaluated for their heavy metal (Cr, Cu, Ni and Pb) accumulation potential in field conditions at Unnao, U.P., India. The results showed that metal accumulation by these macrophytes differed among species and tissue parts. The concentration of Cr, Cu, Ni and Pb in the root tissues were estimated in the range 3.38-45.59,1.01-16.85,1.81-4.43 and 1.02-4.24 microg g(-1) d.wt., whereas the corresponding shoot values were 8.79-48.81, 1.01-8.67, 0.84-2.89 and 1.02-2.84 for Cr, Cu, Ni and Pb respectively. Among the studied plants the translocation factor (TF) ranged between 1.07-2.60, 0.75-3.83, 1.44-2.57 and 0.49-3.76 for Cr, Cu, Ni and Pb, respectively. The highest metal TF was found in M. minuta (2.60, 3.83 and 2.57) for Cr, Cu and Ni respectively, whereas Pb was best translocated (3.76) by B. monnieri. Roots and shoots of the studied macrophytes showed a value of greater than 1 for metal enrichment coefficient. Findings suggest that E. crassipes can be used for phytoremediation of Cu and Ni whereas M. minuta and H. verticillata can be applied for the removal of Cr and Pb respectively from the contaminated water bodies. PMID- 23734461 TI - Growth rate studies of marine ornamental fish Pomacentrus caeruleus in artificial conditions. AB - Aquaculture industry depends on development and testing of protocols for rearing and breeding of new aquaculture species as these techniques vary with species. In the present study attempts have been made to study the effect of temperature and salinity on the rate of growth of the marine ornamental fish, Pomacentrus caeruleus under artificial conditions. Results reveal the length and weight of the fish to increase gradually at an average rate of 0.10 cm and 0.23 g with decreasing salinity (25 ppt to 5 ppt) at 25 degrees C and 6.54 condition factor (K). Statistical output indicates a significant positive relationship between K at 25 degrees C and K at 30 degrees C (R = 0.557, P < 0.05). Correlation indicated growth rate to be higher between 25 degrees C and 30 degrees C. This is in contrast to the hypothesis which states the weight of the fish to be different at different temperatures, F (2,54) = 5.713, P < 0.05. Tukey's test results indicate a significant difference in the weight of the fishes acclimatized at different temperatures. Mortality rate was highest in 20 degrees C followed by 30 degrees C while least in 25 degrees C. The incidence of diseases was highest in 20 degrees C and the acclimatization period highest in 30 degrees C. In conclusion it appears that Pomacentrus caeruleus exhibits allometric growth at lower salinities and at a controlled temperature of 25 degrees C. PMID- 23734462 TI - Effects of saline tolerant Azospirillum species on the growth parameters of mangrove seedlings. AB - Five species of Azospirillum isolated from Manakkudi mangrove ecosystem were subjected for their efficiency to find out their growth parameters potential for the successful establishment of mangrove seedlings. Of the isolated five Azospirillum species, Azospirillum lipoferum (60%) was found to be the dominant one. But the level of maximum indole acetic acid (IAA) production (19.8 mg.ml( 1)) and nitrogen fixation (5.9 C2H2hr1) was identified with A. brasilense. Further, A. brasilense showed significant (p < 0.05) level of increased growth parameters [maximum root length (29.55%), average root length (7.39%), total Chl (55.36%), carrotenoids (28.57%), Chl b (37.50%), carbohydrates (90.91%) and total amino acids (78.95%)] in Avicennia officinals when compared with control group. Further, A. brasilense also showed significant (p < 0.05) level of increased growth parameters [average number of primary roots (40%), average biomass (44.44%), average shoot biomass (55.56%), total Chl (20%), Chl b (77.78%) and carotenoid (1.54%)] in C. decandra seedlings when compared with control group. Similarly, the average number of primary roots (23.08%), average root biomass (15.52%), average shoot biomass (15.30%), carbohydrate (20%) and total amino acids (44.44%) were found significant (p < 0.05) in A. irakense inoculated R. apiculata seedlings. In conclusion, Azospirillum brasilense was found better for the growth of Avicennia officinalis and Ceriops decandra seedlings, but Azospirillum irakense was found better for Rhizophora apiculata seedlings. PMID- 23734463 TI - Environmental friendly alkaline sulfite anthra quinone-methonal (ASAM) pulping with Rumex crispus plant extract of woody materials. AB - ASAM with Rumex crispus extract organosolv pulping was developed by using 1,5 dihydroxy-3-methoxy-7-methyl-anthraquinone from Rumex crispus root, instead of anthraquinone. ASAM was also produced as a control pulping. Both pulps were made by handsheets from fast growing P. deltoides clone (Samsun p. clone), Robinia pseudoacacia L. and Pinus pinaster grown in Turkey for wood fibrous raw materials. The mechanical consisting tensile, bursting and tear values and optical values of ASAM handsheets yellowness, brightness and whiteness were compared to ASAM with Rumex crispus L. extracted. It is concluded that ASAM with Rumex crispus extract pulping suits well in the manufacturing of special papers. PMID- 23734464 TI - Variations in phytoplankton carbon biomass, community assemblages and species succession along Lake Burullus, Northern Egypt. AB - Phytoplankton assemblages and species succession along Lake Burullus (Southern Mediterranean) is expressed as carbon biomass (mg cm3) using a standard spreadsheet based on the species cell volume cell(-1) carbon relationship. High Chl a levels were measured (maximum 85-126 mg m(-3)) reflecting a dense phytoplankton population (up to 8.3 x 10(3) cell ml(-1) and 5.5 x 10(3) mg cm( 3)) throughout the lake body with maximum concentrations at the western sector of the lake (S1). Adiverse phytoplankton community was determined. Cell count data revealed the dominance of a mixed phytoplankton taxa, however biomass data indicates over-dominance of Bacillariophyceae (up to 98%). Good correlation (r = 0.73, p < 0.05) was found between Chl a and carbon biomass with various cell carbon/Chl a ratio according to variations in community structure. Bacillariophyceae were the most dominant, particularly at the middle (S2) and the western parts (S1) during periods of high nutrient (silicate) and good weather conditions (during spring/summer months). Chlorophyceae were abundant with Scenedesmus sp. mostly dominant, particularly at P-rich sites. Dinoflagellates peaked only during calm and high light summer months (May-July) being at a maximum level at S1. Euglenophyceae were less contributed to total phytoplankton abundance and peaked only; as a transition stage; at S1 during Jannuary and March (winter months). Cyanophyceae were numerous along with maximum peak at S2 affected by the southern drains. Excessive nutrient enrichment into the lake alters the existent structure of phytoplankton community. The water quality index indicated a poor water quality status of the lake.This may led to increase the possibility of toxic algal blooms to invade the lake ecosystem and, in turn, affect the lake fish yield. PMID- 23734465 TI - Application of nano-TiO2/LDPE composite film on photocatalytic oxidation degradation of dichloromethane. AB - This study focused on the photocatalytic destruction of dichloromethane (DCM) in indoor air using the nano-TiO2/LDPE composite film as an economical photocatalyst. The nano-TiO2 was dispersed in a polyethylene matrix to form composite film. The photocatalytic activity of the nano-TiO2/LDPE composite films was evaluated through the degradation of dichloromethane(DCM) under UV-C irradiance at specific wavelength of 254 nm. The percentage of nano-TiO2 contents varied from 0, 5, and 10% (wt cat./wt LDPE composite film). The results derived from the kinetic model revealed that the photocatalytic rates of 5 and 10 wt.% nano-TiO2/ LDPE composite films follow the first order reaction while the rate of the film without TiO2 followed the zero order reaction. At low concentration of DCM, the rate of photocatalytic degradation of the DCM was slower than that at high DCM concentration. The 10 wt.% of TiO2 content of the nano-TiO2/LDPE composite film yielded the highest degradation efficiency of 78%, followed by the removal efficiency of 55% for the 5 wt.% of TiO2 content of the nano-TiO2/LDPE composite film. In contrast with the composite film containing nano-TiO2, the LDPE film without adding nano-TiO2 expressed the degradation efficiency of 28%. PMID- 23734466 TI - Analysis and assessment of trace elements pollution in sediments of Lake Uluabat, Turkey. AB - During the period 2008-2009, eight sampling stations were carried out on Lake Uluabat to assess trace element distribution in the lake sediments and to identify major sources of the sediment pollution. Ten elements, including Iron (Fe), Manganese (Mn), Zinc (Zn), Chromium (Cr), Nickel (Ni), Copper (Cu), Lead (Pb), Cadmium (Cd), Arsenic (As), Boron (B) were determined in the sampled lake sediments. The lowest and highest variation intervals (5.0377-27664.197 mg kg( 1)) were found for Cd and Fe, respectively. Concentrations of Cr (131.627 mg kg( 1)), Ni (220.032 mg kg(-1)) and Cd (5.0377 mg kg(-1)) in sediment samples were higher than in the other regions. Moreover, suspended solids, conductivity, pH, temperature and the organic matter % were found to affect the concentrations of sediment. On the basis of the findings of the study, it was concluded that higher concentrations of trace elements in dry seasons increased with the increase in suspended matter, pH, percentage organic content, and conductivity. PMID- 23734467 TI - Studies on technology for seaweed forest construction and transplanted Ecklonia cava growth for an artificial seaweed reef. AB - We installed seaweed reef for restoration of barron ground coast. We hollowed out a U-shaped groove in a cross-shaped artificial seaweed reef and covered it with a zinc sheet (U-bar) to transplant Ecklonia cava growing on Dellenia wood by hand, installing the U-bar on the artificial seaweed reef, fixing it with concrete. Thus seaweed can be attached easily, with pre-installed stainless bolts and nuts. The length of Ecklonia cava leaf transplanted to the cross-shaped reef was 7.2 cm in February 2005 reached its maximum size, 35.9 cm (n = 30) by July. Thereafter, it decreased to 18.9 cm in October due to shedding. The leaf weight after the experiment was 24.8 from the initial 0.4 cm (n = 30). Regression analysis showed Y = 0.7875X-4.6488 (R2 = 0.7225) for blade length and Y = 0.0025X2.6733 (R2 = 0.8711) for leaf weight. The high values of the R2 values for the two measurements were highly reliable, with the reliability of the linear regression function higher than that of the functions of 2 variables. The artificial seaweed forest constructed in the barren ground was highly comparable with natural seaweed forest in terms of growth, indicating that the artificial seaweed construction can be done in an easy, efficient and economically viable way. This further indicates that the technology developed by the present study can be extensively used for the project for artificial seaweed forest construction. PMID- 23734468 TI - Diversity and gradients in cedar forests on Taurus mountain range (Turkey). AB - Cedrus libani forests have been under anthropogenic pressure for thousands of years. The unattainable topography of the Taurus mountain range (Southern Anatolia) has prevented cedar in this region from being extirpated, in contrast to its other distribution areas in Syria and Lebanon. Numerical analyses of releves confirmed the individuality of associations, as well as the division of C. libani forests into two ecological and floristically different groups/alliances (Abieti-Cedrion and Lonicero-Cedrion). Abieti-Cedrion is distributed in the middle and eastern Taurus whereas Lonicero-Cedrion appears in the Western Taurus. The main gradients of C. libani forests were detected. It was noticed that the distribution and floristic composition of C. libani forests is strongly affected by the geographical factors. Topographical factors are also influential on their distribution. C. libani forests are fundemantal components of the Mediterranean phytogeographical region and floral elements, but under more continental conditions, where the influence of the Mediterranean climate decreased, the proportion of Iran-Turanian and Euro-Siberian floral elements increase, especially towards the east and north, as well at higher altitudes and on steeper sites. PMID- 23734469 TI - Relevance of service learning to nursing education. PMID- 23734470 TI - Increasing awareness in African American BSN students of the health risks of obesity. AB - This paper reports on the perceived effectiveness of a program to increase awareness of the health risks of obesity among African-American students. Thirty (n = 30) senior level Bachelor of Science in Nursing students attending a Historically Black College and University (HBCU) took a knowledge test, then participated in an hour-long educational session on obesity. Following the session, the students completed a 10-item post-test to evaluate the effectiveness of the program in increasing awareness of obesity as a risk for heart disease and diabetes. The findings suggested a need to further educate African-American students on the consequences of obesity as well as recommendations to advance the science of personal and family risk awareness in nursing students. PMID- 23734471 TI - A measure of acculturation for Afro-Caribbean youth. AB - The purpose of this study was to develop and test a measure of acculturation for Afro-Caribbean teens who might be at high risk for Sexually Transmitted Disease including Human Immunodeficiency Virus (HIV) and Acquired Immune Deficiency Syndrome (AIDS). Adaptation needs become challenging as many Caribbean immigrants to the United States who are undocumented or without financial fortitude, often live in substandard urban communities with highest rates of HIV and STDs. After obtaining permission to revise the instruments and participants' consents, two existing measures of acculturation were used in this instrument development. Eight Afro-Caribbean adolescents served as judges to revise the instruments for appropriateness to Afro-Caribbean culture; they developed a composite of the two instruments. Afro-Caribbean community experts and a researcher with instrument development expertise further checked for readability and content validity. The new instrument with good content validity and high reliability was tested among 42 Afro-Caribbean youth. The results are discussed. PMID- 23734472 TI - Mentoring as the key to minority success in nursing education. AB - Though the number of minorities is steadily increasing in the United States, the number of minority nurses is not growing in equal proportion. Minority nursing students are often faced with barriers that prevent their success in rigorous nursing programs. MENTOR is a program that can be implemented into any nursing curriculum using a semester format. The purpose of the program is to provide ethnically diverse students with the support and resources they need to successfully graduate. The tools needed to implement a program such as MENTOR into a nursing curriculum is provided. PMID- 23734473 TI - Young Adult African American family members' perceptions, knowledge, attitudes, and utilization toward advance directives. AB - Advance directives (ADs) give patients autonomy in making decisions regarding end of-life preferences prior to becoming incapacitated or otherwise unable to communicate. Limited family-related research currently exists on young, adult African American families and their knowledge, attitudes, and perceptions toward the utilization of ADs. A mixed-method design of quantitative data, using the Advance Directives-Knowledge, Attitudes, and Utilization Questionnaire (AD-KAUQ); and qualitative data, using a focused group session, was conducted in a southeastern city in the United States. The study surveyed 112 young, adult African American family members, ages 21-40 years, to explore their perceptions, knowledge, and attitudes toward utilizing ADs, as well as to determine whether there was a relationship between gender, education level, marital status, and occupation in making this decision. The study findings did not support evidence of significant relationships between the variables with the exception for the relationship between gender and the feeling of being treated differently for having a living will in place. This finding suggested that there was a need for members of young, adult African American families to obtain knowledge of ADs. PMID- 23734474 TI - Who do we think we are? Analysing the content and form of identity work in the English National Health Service. AB - PURPOSE: The language used by National Health Service (NHS) "commissioning" managers when discussing their roles and responsibilities can be seen as a manifestation of "identity work", defined as a process of identifying. This paper aims to offer a novel approach to analysing "identity work" by triangulation of multiple analytical methods, combining analysis of the content of text with analysis of its form. DESIGN/METHODOLOGY/APPROACH: Fairclough's discourse analytic methodology is used as a framework. Following Fairclough, the authors use analytical methods associated with Halliday's systemic functional linguistics. FINDINGS: While analysis of the content of interviews provides some information about NHS Commissioners' perceptions of their roles and responsibilities, analysis of the form of discourse that they use provides a more detailed and nuanced view. Overall, the authors found that commissioning managers have a higher level of certainty about what commissioning is not rather than what commissioning is; GP managers have a high level of certainty of their identity as a GP rather than as a manager; and both GP managers and non-GP managers oscillate between multiple identities depending on the different situations they are in. ORIGINALITY/VALUE: This paper offers a novel approach to triangulation, based not on the usual comparison of multiple data sources, but rather based on the application of multiple analytical methods to a single source of data. This paper also shows the latent uncertainty about the nature of commissioning enterprise in the English NHS. PMID- 23734475 TI - Schools' absorptive capacity to innovate in health promotion. AB - PURPOSE: A comprehensive "health promoting schools" (HPS) approach is advocated by the World Health Organization to foster the health of students. To date, few studies have evaluated schools' capacity to implement it in an optimal way. The purpose of this paper is to present a conceptual framework that identifies core features likely to facilitate the incorporation of innovation, such as HPS, into school functioning. DESIGN/METHODOLOGY/APPROACH: The framework was built by combining dimensions derived from two major strands of literature, i.e. management and HPS. It has taken root in Zahra and George's model of organisation absorptive capacity (AC) for new knowledge but has been adapted to better explore AC in a school context. The contrasting cases of two secondary schools that adopted a HPS approach in Quebec, Canada, for at least three years were used to illustrate the value of the framework. FINDINGS: The framework proposed is a multidimensional model that considers components such as modulators, antecedents, integration mechanisms and strategic levers as potential determinants of AC, i.e. acquisition, assimilation, transformation and exploitation. The conceptual framework helped to qualify and compare AC regarding HPS in the two cases and holds promise to appreciate mechanisms having the greatest influence on it. ORIGINALITY/VALUE: The framework can serve as a conceptual guide to facilitate the absorption of innovation in schools and to design future empirical research to better understand the underlying process by which schools strengthen their capacities to become settings conducive to the health of youth. PMID- 23734476 TI - Process antecedents of challenging, under-cover and readily-adopted innovations. AB - PURPOSE: The purpose of the study is to test the utility of a taxonomy of innovation based on perceived characteristics in the context of healthcare by exploring the extent to which discrete innovation types could be distinguished from each other in terms of process antecedents. DESIGN/METHODOLOGY/APPROACH: A qualitative approach was adopted to explore the process antecedents of nine exemplar cases of "challenging", "under-cover" and "readily-adopted" healthcare innovations. Data were collected by semi-structured interview and from secondary sources, and content analysed according to a theoretically informed framework of innovation process. Cluster analysis was applied to determine whether innovation types could be distinguished on the basis of process characteristics. FINDINGS: The findings provide moderate support for the proposition that innovations differentiated on the basis of the way they are perceived by potential users exhibit different process characteristics. Innovations exhibiting characteristics previously believed negatively to impact adoption may be successfully adopted but by a different configuration of processes than by innovations exhibiting a different set of characteristics. RESEARCH LIMITATIONS/IMPLICATIONS: The findings must be treated with caution because the sample consists of self-selected cases of successful innovation and is limited by sample size. Nevertheless, the study sheds new light on important process differences in healthcare innovation. PRACTICAL IMPLICATIONS: The paper offers a heuristic device to aid clinicians and managers to better understand the relatively novel task of promoting and managing innovation in healthcare. The paper advances the argument that there is under exploited opportunity for cross-disciplinary organisational learning for innovation management in the NHS. If efficiency and quality improvement targets are to be met through a strategy of encouraging innovation, it may be advantageous for clinicians and managers to reflect on what this study found mostly to be absent from the processes of the innovations studied, notably management commitment in the form of norms, resource allocation and top management support. ORIGINALITY/VALUE: This paper is based on original empirical work. It extends previous adoption related studies by applying a configurational approach to innovation attributes to offer new insights on healthcare innovation and highlight the importance of attention to process. PMID- 23734477 TI - Healthcare performance turned into decision support. AB - PURPOSE: The purpose of this study is to first create an overview of relevant factors directly influencing employee absence in the healthcare sector. The overview is used to further investigate the factors identified using employee satisfaction survey scores exclusively. The result of the overall objective is a management framework that allows managers to gain insight into the current status of risk factors with high influence on employee absence levels. DESIGN/METHODOLOGY/APPROACH: The research consists of a quantitative literature study supported by formal and semi-formal interviews conducted at the case organisations. Employee satisfaction surveys were applied to analyse the development over time of selected factors correlated with concurrent employee absence rates. Checking for causal results, comparisons with the included published literature findings were also carried out. FINDINGS: Four major clustered factors, three of which constitute the term "social capital", showed a high degree of connection with employee absence rates. The factors are general satisfaction, fairness, reliance and co-operation. Integrating the four elements in a management framework will provide valuable and holistic information about the determinants with regard to current levels of employee absence. The framework will be a valuable support for leaders with the authority to alter the determinants of employee absence. RESEARCH LIMITATIONS/IMPLICATIONS: Since a great part of the empirical material is supplied from the healthcare sector, the results obtained could be restricted to this sector. Inclusion of data from Arbejdsmarkedets Tillaegspension (ATP) showed no deviation from the results in the healthcare sector. PRACTICAL IMPLICATIONS: The product of the study is a decision support tool for leaders to cope with levels of employee absence. The framework is holistic and can prove to be a valuable tool to take a bearing of where to focus future initiatives. ORIGINALITY/VALUE: Gathering former observational studies in a complete overview embracing many relevant factors that influence sickness absence has not yet been attempted. Hospital management is provided with valuable information when given insight into the factors that control employee absence behaviour. Having this insight will enable the managers to promote a healthy working environment, thus lowering employee absence rates to a minimum. PMID- 23734478 TI - An evaluation of staff engagement programmes in four National Health Service Acute Trusts. AB - PURPOSE: The purpose of this paper is to report the findings from an evaluation project conducted to investigate the impact of two staff engagement programmes introduced to four National Health Service (NHS) hospital Trusts in England. It seeks to examine this development in the context of current policy initiatives aimed at increasing the level of staff involvement in decision-making, and the related literature. DESIGN/METHODOLOGY/APPROACH: A mixed-methods approach incorporating document analysis, interviews, a survey and appreciative inquiry, informed by the principles of impact evaluation design, was used. FINDINGS: The main finding to emerge was that leadership was crucial if widespread staff engagement was to be achieved. Indeed, in some of the trusts the staff engagement programmes were seen as mechanisms for developing leadership capability. The programmes had greater impact when they were "championed" by the Chief Executive. Effective communication throughout the organisations was reported to be a prerequisite for staff engagement. Problems were identified at the level of middle management where the lack of confidence in engaging with staff was a barrier to implementation. PRACTICAL IMPLICATIONS: The nature of the particular organisational context is crucial to the success of efforts to increase levels of staff engagement. The measures that were found to work in the trusts would need to be adapted and applied to best meet the needs of other organisations. ORIGINALITY/VALUE: Many health care organisations in England will need to harness the efforts of their workforce if they are to meet the significant challenges of dealing with financial restraint and increasing patient demand. This paper provides some insights on how this can be done. PMID- 23734479 TI - Structuring agency: examining healthcare management in the USA and Australia using organizational theory. AB - PURPOSE: Since the 1970s, the healthcare industry has undergone significant changes. Using neo-institutional and resource dependency theories, the purpose of this paper is to explore how managers perceive constraint and enact agency amidst these historic challenges--perhaps most significantly, declining funding and increasing regulation. DESIGN/METHODOLOGY/APPROACH: The data come from ten interviews with healthcare managers, spanning for-profit, non-profit, and government legal forms and hospital and nursing home sub-industries in both Queensland, Australia and North Carolina, USA. The authors look for patterns across the interviews. FINDINGS: The paper shows that governments and umbrella "parent" organizations force managers to adhere to institutional expectations in exchange for resource investment. Managers navigate these environmental obstacles using a shared business-minded approach and competitive differentiation. Yet various interest groups--including front-line workers, physicians, and patients- challenge this paradigm, as they demand a focus on quality of care. Managers' efforts are likewise curbed by the very resource and institutional pressures they resist. ORIGINALITY/VALUE: The authors understand changes in the healthcare industry as resulting from an increasingly powerful managerial logic, at odds with traditional professional and societal values. Interest groups are best positioned to challenge this logic. PMID- 23734480 TI - Thinking about the emotional labour of nursing--supporting nurses to care. AB - PURPOSE: The aim of this article is to report some of the work undertaken by a nursing "think tank", focussed on examining the causes of poor nursing care in hospitals, and potential solutions. DESIGN/METHODOLOGY/APPROACH: A "think tank" was convened which incorporated widespread discussion with national, regional and local stakeholders, a critical literature review, and a focus group of senior nurses. FINDINGS: It was found that there are no widespread systems of staff support that help nurses working in hospitals to cope with the emotional component of their work. This is one element that contributes to nurses providing poor care. A number of approaches to staff support have been developed that warrant further study. PRACTICAL IMPLICATIONS: If episodes of poor care are to be prevented it is necessary for hospital boards to recognise the importance of supporting nurses in managing the emotional labour of caring. The introduction of routine systems of staff support should be considered. ORIGINALITY/VALUE: In addition to highlighting and condemning poor care, it is important to seek solutions. This article offers a new perspective on an enduring problem and identifies approaches that can be part of the solution. PMID- 23734481 TI - Illusions of team working in health care. AB - PURPOSE: The ubiquity and value of teams in healthcare are well acknowledged. However, in practice, healthcare teams vary dramatically in their structures and effectiveness in ways that can damage team processes and patient outcomes. The aim of this paper is to highlight these characteristics and to extrapolate several important aspects of teamwork that have a powerful impact on team effectiveness across healthcare contexts. DESIGN/METHODOLOGY/APPROACH: The paper draws upon the literature from health services management and organisational behaviour to provide an overview of the current science of healthcare teams. FINDINGS: Underpinned by the input-process-output framework of team effectiveness, team composition, team task, and organisational support are viewed as critical inputs that influence key team processes including team objectives, leadership and reflexivity, which in turn impact staff and patient outcomes. Team training interventions and care pathways can facilitate more effective interdisciplinary teamwork. ORIGINALITY/VALUE: The paper argues that the prevalence of the term "team" in healthcare makes the synthesis and advancement of the scientific understanding of healthcare teams a challenge. Future research therefore needs to better define the fundamental characteristics of teams in studies in order to ensure that findings based on real teams, rather than pseudo like groups, are accumulated. PMID- 23734482 TI - Regional variation in forest harvest regimes in the northeastern United States. AB - Logging is a larger cause of adult tree mortality in northeastern U.S. forests than all other causes of mortality combined. We used Forest Inventory and Analysis (FIA) data to develop statistical models to quantify three different aspects of aggregate regional forest harvest regimes: (1) the annual probability that a plot is logged, as a function of total aboveground tree biomass, (2) the fraction of adult tree basal area removed if a plot was logged, and (3) the probability that an individual tree within a plot was removed, as a function of the fraction of basal area removed at the plot level, the species of tree, and its size. Results confirm that relatively frequent partial harvesting dominates the logging regimes, but with significant variation among different parts of the region and different forest types. The harvest regimes have similarities with natural disturbance regimes in imposing spatially and temporally dynamic mortality that varies predictably as a function of stand structure as well as tree species and size. PMID- 23734483 TI - The behavior of multiple independent managers and ecological traits interact to determine prevalence of weeds. AB - Management of damaging invasive plants is often undertaken by multiple decision makers, each managing only a small part of the invader's population. As weeds can move between properties and re-infest eradicated sites from unmanaged sources, the dynamics of multiple decision makers plays a significant role in weed prevalence and invasion risk at the landscape scale. We used a spatially explicit agent-based simulation to determine how individual agent behavior, in concert with weed population ecology, determined weed prevalence. We compared two invasive grass species that differ in ecology, control methods, and costs: Nassella trichotoma (serrated tussock) and Eragrostis curvula (African love grass). The way decision makers reacted to the benefit of management had a large effect on the extent of a weed. If benefits of weed control outweighed the costs, and either net benefit was very large or all agents were very sensitive to net benefits, then agents tended to act synchronously, reducing the pool of infested agents available to spread the weed. As N. trichotoma was more damaging than E. curvula and had more effective control methods, agents chose to manage it more often, which resulted in lower prevalence of N. trichotoma. A relatively low number of agents who were intrinsically less motivated to control weeds led to increased prevalence of both species. This was particularly apparent when long distance dispersal meant each infested agent increased the invasion risk for a large portion of the landscape. In this case, a small proportion of land mangers reluctant to control, regardless of costs and benefits, could lead to the whole landscape being infested, even when local control stopped new infestations. Social pressure was important, but only if it was independent of weed prevalence, suggesting that early access to information, and incentives to act on that information, may be crucial in stopping a weed from infesting large areas. The response of our model to both behavioral and ecological parameters was highly nonlinear. This implies that the outcomes of weed management programs that deal with multiple land mangers could be highly variable in both space and through time. PMID- 23734484 TI - Impact of labile and recalcitrant carbon treatments on available nitrogen and plant communities in a semiarid ecosystem. AB - In a 10-year study, we assessed the influence of five carbon (C) treatments on the labile C and nitrogen (N) pools of historically N-enriched plots on the Shortgrass Steppe Long Term Ecological Research site located in northeastern Colorado. For eight years, we applied sawdust, sugar, industrial lignin, sawdust + sugar, and lignin + sugar to plots that had received N and water additions in the early 1970s. Previous work showed that past water and N additions altered plant species composition and enhanced rates of nutrient cycling; these effects were still apparent 25 years later. We hypothesized that labile C amendments would stimulate microbial activity and suppress rates of N mineralization, whereas complex forms of carbon (sawdust and lignin) could enhance humification and lead to longer-term reductions in N availability. Results indicated that, of the five carbon treatments, sugar, sawdust, and sawdust + sugar suppressed N availability, with sawdust + sugar being the most effective treatment to reduce N availability. The year after treatments stopped, N availability remained less in the sawdust + sugar treatment plots than in the high-N control plots. Three years after treatments ended, reductions in N availability were smaller (40-60%). Our results suggest that highly labile forms of carbon generate strong short-term N sinks, but these effects dissipate within one year of application, and that more recalcitrant forms reduce N longer. Sawdust + sugar was the most effective treatment to decrease exotic species canopy cover and increase native species density over the long term. Labile carbon had neither short- nor long-term effects on exotic species. Even though the organic amendments did not contribute to recovery of the dominant native species Bouteloua gracilis, they were effective in increasing another native species, Carex eleocharis. These results indicate that organic amendments may be a useful tool for restoring some native species in the shortgrass steppe, though not all. PMID- 23734485 TI - Historical fire regimes, reconstructed from land-survey data, led to complexity and fluctuation in sagebrush landscapes. AB - Sagebrush landscapes provide habitat for Sage-Grouse and other sagebrush obligates, yet historical fire regimes and the structure of historical sagebrush landscapes are poorly known, hampering ecological restoration and management. To remedy this, General Land Office Survey (GLO) survey notes were used to reconstruct over two million hectares of historical vegetation for four sagebrush dominated (Artemisia spp.) study areas in the western United States. Reconstructed vegetation was analyzed for fire indicators used to identify historical fires and reconstruct historical fire regimes. Historical fire-size distributions were inverse-J shaped, and one fire > 100 000 ha was identified. Historical fire rotations were estimated at 171-342 years for Wyoming big sagebrush (A. tridentata ssp. wyomingensis) and 137-217 years for mountain big sagebrush (A. tridentata ssp. vaseyana). Historical fire and patch sizes were significantly larger in Wyoming big sagebrush than mountain big sagebrush, and historical fire rotations were significantly longer in Wyoming big sagebrush than mountain big sagebrush. Historical fire rotations in Wyoming were longer than those in other study areas. Fine-scale mosaics of burned and unburned area and larger unburned inclusions within fire perimeters were less common than in modern fires. Historical sagebrush landscapes were dominated by large, contiguous areas of sagebrush, though large grass-dominated areas and finer-scale mosaics of grass and sagebrush were also present in smaller amounts. Variation in sagebrush density was a common source of patchiness, and areas classified as "dense" made up 24.5% of total sagebrush area, compared to 16.3% for "scattered" sagebrush. Results suggest significant differences in historical and modern fire regimes. Modern fire rotations in Wyoming big sagebrush are shorter than historical fire rotations. Results also suggest that historical sagebrush landscapes would have fluctuated, because of infrequent episodes of large fires and long periods of recovery and maturity. Due to fragmentation of sagebrush landscapes, the large, contiguous expanses of sagebrush that dominated historically are most at risk and in need of conservation, including both dense and scattered sagebrush. Fire suppression in Wyoming big sagebrush may also be advisable, as modern fire rotations are shorter than their historical counterparts. PMID- 23734486 TI - Human and biophysical influences on fire occurrence in the United States. AB - National-scale analyses of fire occurrence are needed to prioritize fire policy and management activities across the United States. However, the drivers of national-scale patterns of fire occurrence are not well understood, and how the relative importance of human or biophysical factors varies across the country is unclear. Our research goal was to model the drivers of fire occurrence within ecoregions across the conterminous United States. We used generalized linear models to compare the relative influence of human, vegetation, climate, and topographic variables on fire occurrence in the United States, as measured by MODIS active fire detections collected between 2000 and 2006. We constructed models for all fires and for large fires only and generated predictive maps to quantify fire occurrence probabilities. Areas with high fire occurrence probabilities were widespread in the Southeast, and localized in the Mountain West, particularly in southern California, Arizona, and New Mexico. Probabilities for large-fire occurrence were generally lower, but hot spots existed in the western and south-central United States The probability of fire occurrence is a critical component of fire risk assessments, in addition to vegetation type, fire behavior, and the values at risk. Many of the hot spots we identified have extensive development in the wildland--urban interface and are near large metropolitan areas. Our results demonstrated that human variables were important predictors of both all fires and large fires and frequently exhibited nonlinear relationships. However, vegetation, climate, and topography were also significant variables in most ecoregions. If recent housing growth trends and fire occurrence patterns continue, these areas will continue to challenge policies and management efforts seeking to balance the risks generated by wildfires with the ecological benefits of fire. PMID- 23734487 TI - Pharmaceuticals suppress algal growth and microbial respiration and alter bacterial communities in stream biofilms. AB - Pharmaceutical and personal care products are ubiquitous in surface waters but their effects on aquatic biofilms and associated ecosystem properties are not well understood. We measured in situ responses of stream biofilms to six common pharmaceutical compounds (caffeine, cimetidine, ciprofloxacin, diphenhydramine, metformin, ranitidine, and a mixture of each) by deploying pharmaceutical diffusing substrates in streams in Indiana, Maryland, and New York. Results were consistent across seasons and geographic locations. On average, algal biomass was suppressed by 22%, 4%, 22%, and 18% relative to controls by caffeine, ciprofloxacin, diphenhydramine, and the mixed treatment, respectively. Biofilm respiration was significantly suppressed by caffeine (53%), cimetidine (51%), ciprofloxacin (91%), diphenhydramine (63%), and the mixed treatment (40%). In autumn in New York, photosynthesis was also significantly suppressed by diphenhydramine (99%) and the mixed treatment (88%). Pyrosequencing of 16S rRNA genes was used to examine the effects of caffeine and diphenhydramine on biofilm bacterial community composition at the three sites. Relative to the controls, diphenhydramine exposure significantly altered bacterial community composition and resulted in significant relative increases in Pseudomonas sp. and decreases in Flavobacterium sp. in all three streams. These ubiquitous pharmaceuticals, alone or in combination, influenced stream biofilms, which could have consequences for higher trophic levels and important ecosystem processes. PMID- 23734488 TI - Genetic and ecological assessment of population rehabilitation: walleye in Lake Superior. AB - Sustainable management of exploited species is an ongoing challenge, particularly where populations have collapsed or been depleted by overharvest and habitat alteration. The walleye (Sander vitreus) population in Lake Superior's Black Bay historically supported more than 90% of the commercial walleye harvest from the entire lake, but collapsed in 1968 and has still not recovered despite long-term closure of the fishery. In an effort to rehabilitate this population, hatchery origin walleye from exogenous sources were released into Black Bay between 2003 and 2005. We used individual-based analysis of genetic data collected between 2007 and 2010 to examine the contributions of different wild sources and hatchery stocking events to the contemporary walleye population in Black Bay. We found that 75% of the walleye in Black Bay originated from above- and below-barrier native populations in the Black Sturgeon River. The hatchery stocking events differed considerably in their effectiveness: the 2003 release of fry had no measurable contribution, whereas the 2004 and 2005 releases of fingerlings contributed 71% and 45% of the fish in their respective age classes. Hatchery and wild fish were similar in size, but hatchery fish rarely utilized the river habitat where Black Bay walleye historically spawned, and there was little genetic evidence of interbreeding or natural recruitment of stocked fish. Overall, our results suggest that restoring habitat connectivity to facilitate wild recruitment has greater potential than further exogenous stocking to contribute to the recovery of walleye in this system. PMID- 23734489 TI - Cessation of a salmon decline with control of parasites. AB - The resilience of coastal social-ecological systems may depend on adaptive responses to aquaculture disease outbreaks that can threaten wild and farm fish. A nine-year study of parasitic sea lice (Lepeophtheirus salmonis) and pink salmon (Oncorhynchus gorbuscha) from Pacific Canada indicates that adaptive changes in parasite management on salmon farms have yielded positive conservation outcomes. After four years of sea lice epizootics and wild salmon population decline, parasiticide application on salmon farms was adapted to the timing of wild salmon migrations. Winter treatment of farm fish with parasiticides, prior to the out migration of wild juvenile salmon, has reduced epizootics of wild salmon without significantly increasing the annual number of treatments. Levels of parasites on wild juvenile salmon significantly influence the growth rate of affected salmon populations, suggesting that these changes in management have had positive outcomes for wild salmon populations. These adaptive changes have not occurred through formal adaptive management, but rather, through multi-stakeholder processes arising from a contentious scientific and public debate. Despite the apparent success of parasite control on salmon farms in the study region, there remain concerns about the long-term sustainability of this approach because of the unknown ecological effects of parasticides and the potential for parasite resistance to chemical treatments. PMID- 23734490 TI - Recovery from disturbance requires resynchronization of ecosystem nutrient cycles. AB - Nitrogen (N) and phosphorus (P) are tightly cycled in most terrestrial ecosystems, with plant uptake more than 10 times higher than the rate of supply from deposition and weathering. This near-total dependence on recycled nutrients and the stoichiometric constraints on resource use by plants and microbes mean that the two cycles have to be synchronized such that the ratio of N:P in plant uptake, litterfall, and net mineralization are nearly the same. Disturbance can disrupt this synchronization if there is a disproportionate loss of one nutrient relative to the other. We model the resynchronization of N and P cycles following harvest of a northern hardwood forest. In our simulations, nutrient loss in the harvest is small relative to postharvest losses. The low N:P ratio of harvest residue results in a preferential release of P and retention of N. The P release is in excess of plant requirements and P is lost from the active ecosystem cycle through secondary mineral formation and leaching early in succession. Because external P inputs are small, the resynchronization of the N and P cycles later in succession is achieved by a commensurate loss of N. Through succession, the ecosystem undergoes alternating periods of N limitation, then P limitation, and eventually co-limitation as the two cycles resynchronize. However, our simulations indicate that the overall rate and extent of recovery is limited by P unless a mechanism exists either to prevent the P loss early in succession (e.g., P sequestration not stoichiometrically constrained by N) or to increase the P supply to the ecosystem later in succession (e.g., biologically enhanced weathering). Our model provides a heuristic perspective from which to assess the resynchronization among tightly cycled nutrients and the effect of that resynchronization on recovery of ecosystems from disturbance. PMID- 23734491 TI - Inferential consequences of modeling rather than measuring snow accumulation in studies of animal ecology. AB - It is increasingly common for studies of animal ecology to use model-based predictions of environmental variables as explanatory or predictor variables, even though model prediction uncertainty is typically unknown. To demonstrate the potential for misleading inferences when model predictions with error are used in place of direct measurements, we compared snow water equivalent (SWE) and snow depth as predicted by the Snow Data Assimilation System (SNODAS) to field measurements of SWE and snow depth. We examined locations on elk (Cervus canadensis) winter ranges in western Wyoming, because modeled data such as SNODAS output are often used for inferences on elk ecology. Overall, SNODAS predictions tended to overestimate field measurements, prediction uncertainty was high, and the difference between SNODAS predictions and field measurements was greater in snow shadows for both snow variables compared to non-snow shadow areas. We used a simple simulation of snow effects on the probability of an elk being killed by a predator to show that, if SNODAS prediction uncertainty was ignored, we might have mistakenly concluded that SWE was not an important factor in where elk were killed in predatory attacks during the winter. In this simulation, we were interested in the effects of snow at finer scales (< 1 km2) than the resolution of SNODAS. If bias were to decrease when SNODAS predictions are averaged over coarser scales, SNODAS would be applicable to population-level ecology studies. In our study, however, averaging predictions over moderate to broad spatial scales (9-2200 km2) did not reduce the differences between SNODAS predictions and field measurements. This study highlights the need to carefully evaluate two issues when using model output as an explanatory variable in subsequent analysis: (1) the model's resolution relative to the scale of the ecological question of interest and (2) the implications of prediction uncertainty on inferences when using model predictions as explanatory or predictor variables. PMID- 23734492 TI - Mapping behavioral landscapes for animal movement: a finite mixture modeling approach. AB - Because of its role in many ecological processes, movement of animals in response to landscape features is an important subject in ecology and conservation biology. In this paper, we develop models of animal movement in relation to objects or fields in a landscape. We took a finite mixture modeling approach in which the component densities are conceptually related to different choices for movement in response to a landscape feature, and the mixing proportions are related to the probability of selecting each response as a function of one or more covariates. We combined particle swarm optimization and an expectation maximization (EM) algorithm to obtain maximum-likelihood estimates of the model parameters. We used this approach to analyze data for movement of three bobcats in relation to urban areas in southern California, USA. A behavioral interpretation of the models revealed similarities and differences in bobcat movement response to urbanization. All three bobcats avoided urbanization by moving either parallel to urban boundaries or toward less urban areas as the proportion of urban land cover in the surrounding area increased. However, one bobcat, a male with a dispersal-like large-scale movement pattern, avoided urbanization at lower densities and responded strictly by moving parallel to the urban edge. The other two bobcats, which were both residents and occupied similar geographic areas, avoided urban areas using a combination of movements parallel to the urban edge and movement toward areas of less urbanization. However, the resident female appeared to exhibit greater repulsion at lower levels of urbanization than the resident male, consistent with empirical observations of bobcats in southern California. Using the parameterized finite mixture models, we mapped behavioral states to geographic space, creating a representation of a behavioral landscape. This approach can provide guidance for conservation planning based on analysis of animal movement data using statistical models, thereby linking connectivity evaluations to empirical data. PMID- 23734493 TI - Incredible evolution or incredulous application? PMID- 23734494 TI - Assembling the pieces of Lake Victoria's many food webs: reply to Kolding. PMID- 23734495 TI - Can land use intensity be reliably quantified by using a single self-thinning relationship? PMID- 23734496 TI - Can land use intensity be reliably quantified by using a single self-thinning relationship? Reply to Schall and Ammer. PMID- 23734497 TI - How transparency will change the revenue cycle. An interview with Bob Kocher. PMID- 23734498 TI - Business intelligence: the imperative investment. PMID- 23734499 TI - Using middleware to merge revenue cycles. PMID- 23734500 TI - [United theory of aging]. AB - In attempts to develop a means of life prolongation the humankind has created more than three hundred theories of the aging; each of them offers the original cause of aging. However, none of them has given practical result by now. The majority of the theories have now only historical interest. There are several different theories that are mainly under consideration currently. They are based on reliable, proven evidence: the free radical theory, the protein error theory, the replicative senescence theory, the theory of reparation weakening, the immunological theory, several versions of neuroendocrinal theories, and programmed aging theory. The theory presented here is based on conception that the life as the phenomenon represents many of the interconnected physical and chemical processes propelled by energy of the mitochondrial bioenergetical machine. Gradual degradation of all vital processes is caused by the programmed decrease in level of bioenergetics. This theory unites all existing theories of aging constructed on authentic facts: it is shown, that such fundamental phenomena accompanying aging process as the increase in level of reactive oxygen species (ROS), the decrease in the general level of protein synthesis, the limitation of cellular dividing (Haiflick limit), decrease in efficiency of reparation mechanisms are caused by bioenergetics attenuation. Each of these phenomena in turn generates a number of harmful secondary processes. Any of the theories bases on one of these destructive phenomena or their combination. Hence, each of them describes one of sides of process of the aging initially caused by programmed decrease of level of bioenergetics. This united theory gives the chance to understand the nature of aging clock and explains a phenomenon of increase in longevity at the condition of food restriction. Failures of attempts to develop means from aging are explained by that the manipulations with the separate secondary phenomena of attenuation of bioenergetics, now in use, are not capable to advance longevity beyond the bounds of its natural duration. There is only one way to achieve an unlimited healthy life--to find a way of bioenergetics management. PMID- 23734501 TI - [Gerontological aspects of age-dependent mortality from malignant neoplasms of the population in the Russian Federation]. AB - The demographic analysis of population-age mortality from malignant neoplasms of the population of RF in the years 1980-2008 enables to see the real presentation of the positive impact of medicine and the negative impact of the environment, but also to reveal fundamental biological processes that determine the health and life expectancy of Russian men and women. The authors allocate the leading role in the origin and development of malignant tumors for the aging process. PMID- 23734502 TI - [Morbidity and mortality rate from tumors and other causes in female rats under different light regime]. AB - The influence of different light regimes (constant light--LL; constant darkness- DD; standard light regime--LD, 12 hours light/12 hours darkness; natural lightening of the North-West of Russia--NL) on the dynamics of life's morbidity rate, spontaneous tumorigenesis and frequency of some kinds of non-tumor pathology revealed at the post-mortem examination of female rats was studied. It was found out that the maintenance of animals at LL and NL conditions led to the increase of the number of infectious diseases, substantially faster development of spontaneous tumors (2,9 and 3,3 diseases per one rat, respectively) and the increase of non-tumor diseases in comparison with the animals kept at LD (standard light) regime (1,72 diseases per one rat). Light deprivation (DD) led to substantial reduction of development of new growth, of non-tumor and infectious diseases (1,06 diseases per one rat) in comparison with the similar parameters in standard light regime. PMID- 23734503 TI - [Age-related changes in the number of CD45+ cells in human dermis]. AB - The aim of this work was the study of age-related changes in the number of CD45+ cells in human dermis. The results showed that the number of CD45+ cells in dermis increased gradually with age. At the same time, a total number of fibroblasts in dermis decreased with age. The number of PCNA+ fibroblasts in dermis showing their proliferative activity was observed to be decreased with the progression of age. The results of the correlation analysis show that the age related increase of CD45+ cells number is statistically associated with the decrease in the total number of fibroblasts and with the quantity of PCNA+ fibroblasts in dermis through age. Therefore, accumulation of CD45+ cells in human dermis with age may be regarded as a mechanism which brings about inflammatory reaction and emergence of signs of aging. It is also possible that the increased number of bone marrow derived cells has an impact on the age related decline in the number of fibroblasts in dermis with age. PMID- 23734504 TI - [Participation of morphofunctional zones in aging processes]. AB - There are morphofunctional zones in organism tissues, where proliferation and differentiation processes occur. Daughter cells are differentiated in the electric field excited by 12 mother and daughter cell pairs, turned out at cambial cell division. With aging, the cambial cell number is reduced to 7, close to thresholds level (6 cells), at which the differentiation of daughter cells is absent. The depression of cambial cell number with aging is connected with the work of another morphofunctional zone--the hypothalamus, which is the major center of vegetative regulation and initially has very high RhoA activity, which has been established in embryogenesis. Estrogens, influencing over the hypothalamus and activating Src kinase in its nuclei, reduce the level of RhoA activity, including SCN, responsible for many biorhythms of an organism. As a result, the hyperestrogenemia and therefore a connective tissue at first occur. Then there happens a hypoestrogenemia that leads to sharp falling of proliferative activity of cells, causing the depression of cambial cell number and possibility of a malignant tumor development. Along with this, there are the deep lesions of hormone regulation, leading to some lethal diseases. Thus, the RhoA increasing in hypothalamus and especially in SCN circadian rhythm can counteract the Src kinase intensifying and prevent the processes connected with this. PMID- 23734505 TI - [Paravasal connective tissue of the in-wall blood vessels of the heart during aging]. AB - The structural organization of the paravasal connective tissue of the in-wall myocardial blood vessels in the stages of postnatal ontogenesis was studied. The study was carried out on preparations of the heart 80 corpses of men in three age groups (the first period of adulthood (n = 20) and elderly (n = 30) and old (n = 30) ages.) The peculiarities of the structure as well as qualitative and quantitative transformation of fibrous component of the paravasal connective tissue in each age period were revealed. PMID- 23734506 TI - [Age dependence of metabolic syndrome association with obesity types among women]. AB - The study included 335 women aged 21 to 74 years. Results showed that age appears to be associated with progressive accumulation of fat tissue and magnitude of the waist-to-hip circumference ratio, which are mostly expressed in the second period of middle age. Ratio of gynoid and android species frequency among women with overweight and obesity in the first and second period of middle age groups and elderly age was 2.7:1; 1.3:1 and 0.2:1, respectively. Occurrence of metabolic syndrome in this age groups of women with gynoid species was 16.3; 18.9 and 30.0%; but with android species 62.5; 47.9 and 83.0%, respectively. Our results allow to state that women with gynoid species have the lowest risk of metabolic syndrome even in elderly age. PMID- 23734507 TI - [The blood system and bone marrow during aging. The new method of hemogram assessment: blood analysis along with synthesis]. AB - This article represents the particularities of people's blood and bone marrow referent parameters during aging. On the basis of 56 blood parameters of apparently healthy people a mathematical model of blood's morphofunctional state during physical aging was created. The following integral changes have been discovered: in age group of 35-59 years the integral indicator amounts to 0.05 +/ 0.0008, it approaches the benchmark in elderly age (0.02 +/- 0.0001) and becomes negative with people of gerontic age (-0.06 +/- 0.0003). On the basis of 14 selected blood parameters a calculation of referent integral indicators of blood state for healthy people of various age groups was performed, which serve as standards in clinical practice. Out of 70 peripheral blood cells' indicators the integral indicators for patients suffering from community-acquired pneumonia were calculated. The organism reacts to pneumonia most appropriately at the age of 22 34 years (integral indicator amounts to -0.0386). In patients of 35-59 years the integral indicator descends closer to zero mark (-0.0236), pointing to minor reaction to inflammation. Patients over 60 years of age show the biggest divergence of integral indicator from the benchmark (-0.0613), which points to an inadequate reaction of the organism to inflammation in this age. Based on discriminant analysis of 80 indicators (clinical blood analysis, cytograms, cardiac beat count, breath count, C-reactive protein) the most informatory indicators used to create the algorithm for determination of pneumonia severity were chosen. PMID- 23734508 TI - [The role of IL-6 in the development of morphological changes in renal tissue in elderly patients with type 2 diabetes complicated by diabetic nephropathy]. AB - Studies in recent years suggest a role for inflammation, proinflammatory cytokines in particular, the development of microvascular complications of diabetes, including nephropathy. We investigated the expression of IL-6 in the biopsy tissue kidneys (in glomeruli and interstitium) in 24 elderly patients with type 2 diabetes complicated by diabetic nephropathy. The significant influence of intrarenal expression of IL-6 on the development of morphological (glomerular and tubulointerstitial) changes in renal tissue in patients with diabetic nephropathy is shown. PMID- 23734509 TI - [Bioelectric activity of the brain in patients of elderly and senile age with a cerebrovascular pathology]. AB - According to this work, bioelectric activity of a brain of 345 patients with a cerebrovascular pathology was studied; among them 139 patients with ischemic strokes (IS) in carotid pools, 206 sick with chronic ischemia of a brain (CIB), 91 patients with discircular encephalopathy of the 1st stage (DE-1), 115 patients with DE of the 2nd stage (DE-2). All observation has been subdivided into two categories: the basic, including 4 basic groups of supervision, and control. Criteria of division of the basic category observation into groups were the region of residing and a nationality. At EEG analysis of patients with IS dominating slow-wave activity is registered in all cases. At patients with CIB changes of bioelectric activity of the expressed degree had a diffusive character. PMID- 23734510 TI - [Age-related features of microviscosity of erythrocyte membranes in experimental cardiosclerosis]. AB - The age-related changes in the coefficient of microviscosity and polarity in the area of lipid-lipid and protein-lipid contacts of erythrocyte membranes in 4 months old (group I, n = 20) and 12 months old (group II, n = 20) rats by the method of lateral diffusion of the pyrene probe were investigated. Each age group consisted of 10 intact animals and animals after postinfarction cardiac remodeling (PICS). An increase of microviscosity and polarity of the annular and total lipids of erythrocyte membranes in 12-month animals was found. When modeling PICS in 4-month animals is pronounced increase the polarity and microviscosity of erythrocyte membranes in the annular and total lipids. The 12 month animals after PICS demonstrate a decrease of microviscosity in a lipid bilayer, and its increase in the area of annular lipids for consistently high polarity lipids. PMID- 23734511 TI - [Effect of physical activity on age involution of functional abilities of humans]. AB - A survey of 433 healthy, mature- and middle-aged men with different modes of habitual daily physical activity was made. Depending on the modes of motor activity all the surveyed were divided into 4 groups, each of which has been ranked by the ten-year age interval. The assessment of functional status using automated hardware-software complex "AMSAT-Covert" to determine the level of maximum oxygen consumption, lipid peroxidation and activity of the antioxidant defense system was performed. Results of the study enabled the authors to formulate a provision under which to extend the period of active, creative longevity and increased life expectancy we need to review the approaches to the regulation of physical activity by rationally constructed motor mode as part of a comprehensive system of health protection. Exercises, not increasing the requirements to the functionality involved and not causing physiological changes should be included in the recommended motor mode, which are incomparably less than officially accepted in modern practice fitness training. PMID- 23734512 TI - [Epidemiological characteristic of non-psychotic mental disorders in elderly persons in Arkhangelsk region]. AB - The epidemiological characteristic of non-psychotic mental disorders (NMD) in elderly persons in the Arkhangelsk region in 1999-2010 has been studied. The results of the study show that the NMD prevalence among the elderly persons in the Arkhangelsk region was 07-1.1%; in the morbidity dynamics, there has been registered an increase in the number of the NMD cases among the elderly persons with the increase peak in 2007 and the tendency of development beginning from 2009. In NMD structure the organic nonpsychotic disorders and neurotic and somatoform disorders predominated. Since 2010, a tendency of a decrease in the share of organic non-psychotic disorders (up to 58.5%), an increase in the share of neurotic and somatoform disorders (up to 32.2%) and personality disorders (up to 4.2%) are observed. An analysis of specificity of psychotherapy delivery has been done, a necessity of registration of the NMD prevalence and structure, the comorbide pathology, the age and social-economic characteristics of the elderly persons has been grounded. PMID- 23734513 TI - [Characteristics of antihypertensive therapy in patients of older age groups]. AB - The review presents the data on the characteristics of drug therapy in elderly and senile patients with arterial hypertension in terms of real-life clinical practice. The age and gender differences of these problems are discussed. The pharmacy epidemiologic analysis of antihypertensive therapy shows that nowadays treatment corresponds not fully to modern national and international recommendations about diagnostics and treatment of arterial hypertension. In the treatment of the associate states patients with arterial hypertension do not receive enough beta adrenoblockers, desagreganthy and gypocholesterinemics therapy. The doctors rarely prescribe thiazide diuretics, calcium antagonists, angiotensin II receptors antagonists and the combined forms of medicines. The positive factor is a small fraction of the short-acting preparations, the "old" drugs with poor safety profile used for the treatment of hypertension. PMID- 23734514 TI - [Quality of life in patients of different age groups with ischemic heart disease: effect of multifocal atherosclerosis]. AB - The aim of the research was to study the quality of life for the patients of different age groups with coronary artery disease and to evaluate the factors affecting its decline. The present study included 709 patients aged 31 to 79 years examined before elective coronary artery bypass graft surgery. All patients underwent coronary angiography, echocardiography, ultrasonography of the aorta, brachiocephalic, and peripheral arteries. With age, significantly increased incidence of multifocal atherosclerosis (p = 0.01 for the trend). To study the quality of life (QL) a non-specific questionnaire SF-36 was used, according to which the reduction of QL equally in all the groups (p > 0.05) was detected. Multivariate analysis showed that the level of QL was influenced by diabetes, myocardial infarction and the presence of multifocal atherosclerosis (p < 0.05). Thus, in order to improve the QL in aged patients with multifocal atherosclerosis is reasonable to conduct of reconstructive operations at different arterial basins. PMID- 23734515 TI - [Age-related brain energy activity in patients after traumatic cranio-cerebral injury and brain infarction]. AB - Stroke and traumatic brain injury (TBI) are disabling diseases, which determine the medical and social relevance of the rehabilitation. Age is one of the important risk factor and course factors of stroke. The aim of this research was to study features of the restoration of cognitive function and brain activity in patients undergoing ischemic stroke and TBI. 72 persons were examined (43 males, 29 females; mean age 37.51 +/- 42.97 years). Brain DC potentials were recorded in all patients before and after rehabilitation treatment. Age factor plays an important role in the process of cerebral recovering after brain injury. In patients before 40 years but not after 40 years the rehabilitation was connected with increasing of right hemisphere activity. In patients older 40 years the restoration of cerebral functions was connected with activity of left brain hemisphere. PMID- 23734517 TI - [Association of erectile dysfunction with hypogonadism and metabolic syndrome among men of various age groups]. AB - The integrated study included 184 men aged from 22 to 60 years who were formed into two groups, of the first and second period of middle age. The direct relation of both erectile dysfunction frequency and expressiveness from age was developed. The same dependence was found for hypogonadism clinical features, metabolic syndrome and its components, but inverse relation was detected between age and testosterone content in blood. The presence of erectile dysfunction was associated with testosterone level reduction, hypogonadism clinical features frequency, metabolic syndrome and most its components increase without the age. It was shown that first and second period of middle age men with erectile dysfunction did not display the difference in blood testosterone content, metabolic syndrome and its components frequency. Hence, the main risk factors of erectile dysfunction development form qualitatively already in young men; they accumulate quantitatively with age producing the androgenous disorders evolution. PMID- 23734516 TI - [Tetrapeptide stimulates functional activity of the pancreatic cells in aging]. AB - In this study the molecular mechanisms of pancreoprotective action of researched tetrapeptide H-Lys-Glu-Asp-Trp-NH2 in aging pancreatic cells of a human were investigated. It is established that the studied tetrapeptide increases the expression of matrix metalloproteinase MMP2, MMP9, serotonin, glycoprotein CD79alpha, antiapoptotic protein Mcl1, proliferation markers PCNA and Ki67 and decreases the expression of proapoptotic protein p53 in aged pancreatic cell cultures. Thus, the capability to activate the expression of signaling molecules- markers of functional activity of pancreatic cells lies behind the clinical effect of studied tetrapeptide observing in elderly patients with type 2 diabetes mellitus. PMID- 23734518 TI - [Optimization of respiratory support of elderly patients with pneumonia in the early stages of respiratory failure]. AB - The article provides an assessment of the effectiveness of noninvasive ventilation (NIV) in elderly patients with pneumonia in the early stages of acute respiratory failure (ARF). A total of 83 elderly patients with pneumonia were examined. By the method of randomization, patients were divided into 2 groups. The first group consisted of patients treated by the method of NIV, the second one of patients receiving standard oxygen therapy. The results of the study show that the use of NIV in the treatment of pneumonia, complicated by the ARF in elderly patients resulted in a significant improvement of arterial blood gas as well as hemodynamic and respiratory systems, in comparison with those of patients receiving oxygen therapy. PMID- 23734519 TI - [Peptide bioregulators: the new class of geroprotectors. Communication 1. Results of experimental studies]. AB - This review summarizes the results of long-term researches of the authors who studied the mechanisms of aging and the effectiveness of peptide bioregulators in preventing age-related diseases in laboratory animals. The data is provided on the evaluation of peptides effects which were produced using the most modern techniques in scientific institutions in Russia and abroad. The main attention is paid to the ability of peptide bioregulators to increase the life span and inhibit the carcinogenesis in animals. PMID- 23734520 TI - [Assessment of accelerated aging among automobile drivers using model of the biological age based on physical work capacity]. AB - The studies of biological age, aging rate, physical work capacity in professional drivers were conducted. The examination revealed peculiarities of system organization of functions, which determine the physical work capacity levels. Dynamics of the aging process of professional driver's organism in relation with calendar age and driving experience were shown using the biological age on physical work capacity model. The results point at the premature decrease of the physical work capacity in professional drivers. The premature contraction of the range of cardio-vascular system adaptive reactions on submaximum physical load in the drivers as compared with control group was revealed. It was proved that premature age-related changes of physiologic indices in drivers are just "risk indicators", while long driving experience is a real risk factor, accelerating the ageing process. The "risk group" with manifestations of accelerating ageing was observed in 40-49-year old drivers with 15-19 years of professional experience. The expediency of using the following methods for the age rate estimation according to biologic age indices and necessity of prophylactic measures for premature and accelerated ageing prevention among working population was demonstrated. PMID- 23734521 TI - [The peptide correction of neurotic disorders among professional truck-drivers]. AB - This study was designed to estimate the neurobehavioral status and to compare the prevalence of psychoadaptive disorders among lorry-drivers (experimental group) and metal craftsmen (control group) in connection with their age, length of service, occupational hazards, work schedule and sociodemographic characteristics. 150 male lorry-drivers (mean age 43.3 +/- 0.9) and 150 male metal craftsmen (mean age 42.8 +/- 0.9) were examined using a clinical questionnaire to identify, estimate and compare neurotic states. The study comprised 3 groups: 1st--subjects with stable psychic adaptation, 2nd--subjects with unstable psychic adaptation, a risk group, 3rd--subjects with stable psychic disadaptation, i.e. with some borderline mental disorders (BMD). Significant differences in the prevalence of psychic adaptation and disadaptation among groups under study were found. The predominance of the 2nd and 3rd groups among lorry-drivers in comparison with control group was found. The results showed that social and demographic characteristics had no significant influence neither in experimental nor in control groups (p > 0.1). Variability of psychoemotional imbalance levels among lorry-drivers was found to be due to a combination of the following factors: occupational exposure and their work schedule, while in control group--to the age of metal craftsmen. Comparative analysis of neurobehavioral disorders revealed the predominance of the asthenic symptoms, anxious and depressive manifestations, hysterical reactions among lorry-drivers, and the vegetative disorders only in control group. The results thus obtained support the hypothesis of occupational hazards and long driving experience being the risk factors for the development of BMD. The application of bioregulating peptides was found to restore the organism adaptive potential, improved psychoemotional indices, intensified resistance to work stress and reduced occupational risk of borderline mental disorders (p < 0.001-0.05). The best effect was obtained in case of combined application of several cytogens (pinealon and vezugen), which were optimally selected regarding the effect of each adverse occupational factor on a target organ or system. The employed parameters of psychoemotional state were rather informative for assessing the peptidergic properties of cytogens in occupational medicine and geriatrics. PMID- 23734522 TI - [Age-dependent occupational stress in doctors of various specialties]. AB - A comparative assessment of the extent and structure of the various forms of professional burnout among doctors-organizers as well as therapeutists and surgeons depending on age was given. It is shown that the professional burnout in doctors-organizers conjugates with a high level of emotional tension manifested in avoidance of over-saturated emotional and professional communication outside professional activities, increased irritability and temper, reluctance to exercise empathy towards colleagues and compassion for patients. The comparison of three age groups of physicians to each other in terms of the level and features of the burnout was adduced; the results demonstrate the significant differences between the age periods of 30 and 40 years and over 41 years old. Physicians in the age group of 30-40 years old are inclined to depersonalization at a relatively low level of reduction of professional achievement. It was found that age specificity of formation of the syndrome of professional burnout among surgeons was caused by the increased tendency to development of professional burnout syndrome of young and middle-aged surgeons at low levels of professional burnout among older people. PMID- 23734523 TI - [Psychophysiological characteristics of professional burnout syndrome in doctors of various specialties and different age groups]. AB - Based on clinical psychopathology, psycho-physiological and medical tests the risk factors of professional burnout among medical professionals of all ages were revealed and the assessment of their impact on the formation of adverse functional status of physicians under research was conducted. The role of psycho physiological factors (neuro-psychological stability, coping strategies, psychological defense mechanisms, psychosemantic self-relation space, asthenic, obsessive-phobic, hypothymic, anancastic symptoms, the dynamic characteristics of the inhibitory processes, and emotional lability) in the formation of professional burnout among medical specialists of young, middle and elderly age was defined. Neurophysiological markers of professional burnout among medical specialists of young, middle and old age, which are characterized by lower levels of reserve capacity of the cerebral cortex of alpha-rhythm, the prevalence and strength of excitation and balance of beta-rhythm were examined. It was shown that clinical examination of medical specialists of different age groups with symptoms of professional burnout should include the clinical-psychopathological and psychophysiological examinations to determine the psychopathological and personal features, psychological and emotional states of the border areas, which help to identify reactive neurotic disorders and conduct its targeted correction. PMID- 23734524 TI - [Early diagnostics of bladder cancer recurrence with fluorescence in situ hybridization method in the first 24 months after a transurethral resection of a bladder in old and elderly persons]. AB - This article presents the results of experience of application of a technique fluorescent in situ hybridization (FISH) in early diagnostics of relapses of a superficial bladder cancer in 103 middle-aged, old and senile persons who had transurethral resection of the bladder. PMID- 23734525 TI - See you at the AEC!: CU P2P @ AEC #77! PMID- 23734526 TI - Complaints associated with animal feeding facilities as reported to Ohio local health departments, 2006-2008. AB - Confined animal feeding facilities of all sizes have long been targeted as a source of human health and quality of life concerns. In order to describe and quantify these concerns in Ohio, a retrospective survey of local health departments was conducted focusing on reported complaints associated with animal feeding facilities. During 2006-2008, the most common complaints pertaining to any type of animal feeding facility were air quality and odor outside the home, followed by manure storage and application issues. The study described here showed that larger permitted livestock feeding facilities were not a major source of health and nuisance complaints associated with animal feeding facilities as reported to Ohio local health departments. Local health departments received few health complaints associated with any animal feeding facility. None were validated or confirmed by a physician in 2008. PMID- 23734527 TI - A community-based participatory research partnership to reduce vehicle idling near public schools. AB - The authors implemented and assessed the effectiveness of a public health initiative aimed at reducing traffic-related air pollution exposure of the school community at four Cincinnati public schools. A partnership was fostered with academic environmental health researchers and community members. Anti-idling campaign materials were developed and education and training were provided to school bus drivers, students, parents, and school staff. Pledge drives and pre- and posteducation assessments were documented to measure the effectiveness of the program. After completing the educational component of the public health initiative, bus drivers (n = 397), community members (n = 53), and staff (n = 214) demonstrated significantly increased knowledge about the health effects of idling (p < .05). More than 30% of parents signed the pledge to reduce idling after the public health intervention. A community-driven public health initiative can be effective in both 1) enhancing community awareness about the benefits of reducing idling vehicles and 2) increasing active participation in idling reduction. The partnership initially developed has continued to develop toward a sustainable and growing process. PMID- 23734528 TI - Lead-based paint awareness, work practices, and compliance during residential construction and renovation. AB - The U.S. Environmental Protection Agency recently implemented the Renovation, Repair and Painting (RRP) rule that applies to pre-1978 residences because of the potential presence of lead-based paint. Enforcement of this rule may be difficult and therefore it is crucial to understand the awareness and beliefs of contractors and the general public because these will likely be major determinants of exposures resulting from residential renovation work. The study described in this article utilized two mailed surveys: one directed to the general public and the other directed to contractors. The surveys were conducted in New Jersey and Virginia. Field observations were also recorded for work sites in New Jersey. Results indicated a high awareness among the general public about the hazards of lead, a low level of screening by children's doctors for lead exposure, frequent use of work practices that generate lots of dust, poor hygiene among contractors, and the potential for low compliance of contractors with the RRP rule. In particular, contractors who do not believe lead is a serious health hazard are expected to have the lowest compliance with the RRP rule. These findings serve as targets for effective public health interventions through education and outreach. PMID- 23734529 TI - An outbreak of Cryptosporidium at a recreational water park in Niagara Region, Canada. AB - Cryptosporidium is a parasitic protozoan found in water sources and spread through the fecal-oral route. Cryptosporidiosis is characterized by gastroenteritis and is increasingly associated with recreational water sources. On December 3, 2010, Niagara Region Public Health was informed of a laboratory confirmed case of Cryptosporidium. Over the subsequent two weeks, a total of three additional laboratory-confirmed cases were reported. All cases had visited the same water park in Niagara Region, Canada, over November 14-16, 2010. A total of 12 cases associated with the outbreak ranged in age from 1 to 66 years. This article describes the outbreak, environmental investigation, and control measures. The environmental investigation revealed that the ultraviolet disinfection system was offline on November 14, 2010, which may have allowed for the transmission of Cryptosporidium to bathers. Further research into the detection of Cryptosporidium outbreaks and regulations and guidelines for water park operators may help to decrease future outbreaks. PMID- 23734530 TI - Across the country: what's happening in environmental health. PMID- 23734532 TI - Healthy and safe swimming: pool chemical-associated health events. PMID- 23734531 TI - Community exposures to chemicals through vapor intrusion: a review of past agency for toxic substances and Disease Registry public health evaluations. PMID- 23734533 TI - Four unexpected macro trends for 2013 and beyond: the last two. PMID- 23734534 TI - Medical marijuana: a crossroads between land use planning and environmental health. PMID- 23734535 TI - An exciting NEHA grant initiative and history is bunk! PMID- 23734536 TI - Strategy for effective percutaneous drainage of pancreatic collections: results on 121 patients. AB - There is a lack of technical guidelines for image-guided percutaneous drainage (IGPD) of pancreatic fluid collections (PFCs). To fill that void, we present a strategy and guidelines for systematic IGPD for effective PFCs evacuation. METHODS: Institutional Review Board (IRB)-approved study of 121 pancreatitis patients with symptomatic PFCs that underwent IGPD. IGPD strategy aimed at evacuation of the PFCs compartments using vigorous catheter drainage and manipulations. PFCs resolution and patients' outcome were measured. RESULTS: Pancreatitis pathogenesis and etiology included: necrotizing, 79 patients (alcoholic, 40; biliary, 20; hyperlipidemia, 8; other, 11); traumatic, 32 patients; and chronic ductal, 10 patients (pseudocysts). An ipsilateral retroperitoneal access was used for pararenal spaces PFCs (61, 50% patients), a transabdominal IGPD approach for anterior PFCs (49 patients, 41%), an intercostal/subcostal access for left subphrenic PFCs (22 patients, 18%), and a transgastric drainage route for retrogastric PFCs (9 patients, 7%). Table 1 lists the site of the pancreatic fluid collections and number and size of the catheter(s) used for IGPD of the PFCs in the 121 patients. Fifty-seven (47%) patients had positive cultures PFCs. Of these, 24 (20%) had polymicrobial infections, and 18 (15%) had fungal infections. There were 20 (11%) patients with multi-compartment drainage. PFCs resolution occurred in 102 (84%) patients. PFCs recurrence was treated by surgery (four patients) or IGPD (one patient). Pancreatic fistulas closed, except in one patient. Nine patients (7%) experienced multiorgan failure/death; 5 (4%) were lost to follow-up. PMID- 23734537 TI - Hitting the target: Lyme or STARI? AB - Erythema migrans (EM) is a characteristic rash most commonly associated with Lyme disease (LD) in the northeastern and north central United States. EM rash found in the southeastern United States is usually classified as Southern Tick Associated Rash Illness (STARI). Here we describe an EM rash in a 3-year-old female from central Louisiana, whose laboratory and clinical findings were suspicious for LD. This case report highlights the importance of distinguishing STARI from LD, as LD left untreated can lead to long-term complications. PMID- 23734538 TI - Psoas impingement causing labrum tear: a series from three tertiary hip arthroscopy centers. AB - BACKGROUND: The term hip impingement is usually associated with psoas impingement after arthroplasty or femoroacetabular impingement (FAI). A recently, less commonly described mechanism of impingement and labrum pathology is the psoas tendon applying pressure to the acetabular labrum more medial to the typical FAI labrum lesion. Much is still unkown about the anatomy, pathology, and treatment of this entity. PURPOSE: This paper describes the successful arthroscopic treatment of a series of patients with a recently recognized cause of hip pain in the young athletic population without significant bony pathology or coxa saltans. Awareness of this entity is important to allow appropriate treatment of the labrum and psoas tendon. METHODS: Seven hundred hip arthroscopies by three surgeons at different centers were retrospectively reviewed. Athletes with labrum tears from the two to three o'clock position were evaluated for inclusion in the study. Patients with osteoarthritis, crossover sign, coxa profunda, CAM lesion, acute trauma, or coxa saltans were excluded. All authors were the primary surgeons and are fellowship-trained hip arthroscopists working in tertiary hip arthroscopy centers. Pre- and postoperative Harris Hip scores were obtained. Patients underwent diagnostic and therapeutic hip arthroscopy. The psoas tendon was released in all patients at the level of the capsule via a transcapsular approach. Labrum repairs were performed when deemed beneficial by the operative surgeon. RESULTS: Twenty-two patients (26 hips, 4 bilateral) were identified with a labrum tear apparently caused by psoas impingement and had no other significant hip abnormalities. All but one were female. Average age was 19 (12-25 years). Labral repair was performed in all but two patients. Average anchors used were 1.2 per hip. Pre- and postoperative Harris hip scores were obtained with a minimum follow-up of six months for 16 patients. Average Harris hip score improved from 70 preop to 94 postop. There were no significant complications identified. CONCLUSION: We describe a recently recognized entity encountered in the treatment of athletes with hip pain consisting of labrum pathology associated with the psoas tendon rather than bony abnormality. Arthroscopic treatment, including a psoas tendon release and a more medial labrum repair, can provide relief with no significant complications in the short term. CLINICAL RELEVANCE: Understanding the unique pathoanatomy of this entity may allow the surgeon to provide more thorough informed consent, prepare for a more medial labrum repair than usual, and provide appropriate referral when necessary. PMID- 23734539 TI - Stapler-assisted closure in total laryngectomy. AB - The total laryngectomy is a surgical procedure that requires technically sound reconstruction in order to preserve a patient's swallowing function. Traditionally, a handsewn technique has been utilized to accomplish this endeavor. Recent applications of surgical stapling devices have been noted in an attempt to circumvent the need for handsewn reconstruction. This paper documents the application of a surgical stapling device in reconstructing a total laryngectomy defect. A brief review of the literature is provided to compare the differences between handsewn techniques and stapling techniques. PMID- 23734540 TI - ECG of the month: Found down. Marked sinus bradycardia. PMID- 23734541 TI - Bilateral patellar hypoplasia: beyond the skeletal anomalies. PMID- 23734542 TI - "There's no research to be done around here". PMID- 23734543 TI - Oral and maxillofacial pathology. Case of the month. Histoplasmosis. PMID- 23734544 TI - Soft palate length and upper airway relationship in OSA and non-OSA subjects. AB - BACKGROUND: The narrowest area of the airway between the posterior nasal opening and the epiglottis is usually located in the retro palatal area. Many consider this the most likely site of airway obstruction during an obstructive sleep apnea (OSA) event. The aim of this study was to investigate the differences in soft palate and airway length between OSA and non-OSA patients. METHODS: In this study, we analyzed the ratio of the soft palate and the upper airway length in 45 consecutive patients. Twenty-five had an Apnea-Hypoapnea Index of more than 5 events per hour and were classified in the OSA group (male, 19; female, 6). These patients were compared with 20 normal controls (male, 12; female, 8). Controls who complained of snoring did have sleep studies (n = 5). The other fifteen controls were clinically asymptomatic and did not have sleep studies. Medical computed tomography scans were taken to determine the length of the upper airway and the soft palate length measured in the midsagittal image. RESULTS: Soft palate length was significantly larger in OSA patients compared to controls (p = 0.009), and in men compared to women (p = 0.002). However, there were no differences in airway length. The soft palate length, as a percent of oropharyngeal airway length, was significantly larger in OSA patients compared to controls (p = < 0.0001) and in men compared to women (p = 0.02). Soft palate length increases significantly with age by 0.3 mm per year in males (after adjustment for body mass index (BMI) and OSA). Soft palate length as a percent of airway length is larger in OSA patients and increases significantly with BMI in males only after adjusting for age. CONCLUSION: In this study, OSA patients had a longer soft palate in proportion to their oropharyngeal airway compared to controls as well as men compared to women. This proportion could be used for identifying patients at risk for OSA in combination with age. PMID- 23734545 TI - Bisphenol-A exposure from dental sealants is minimal and does not cause increased morbidity or mortality (UT CAT# 2313). PMID- 23734546 TI - Time for the cure. PMID- 23734547 TI - 2012 financial report Texas Dental Association. PMID- 23734548 TI - Evolution of chairside CAD/CAM dentistry. PMID- 23734549 TI - Value for your profession. Four productive ways to retire used equipment. PMID- 23734550 TI - Military service through the eyes of this nurse. PMID- 23734551 TI - Military women's urinary patterns, practices, and complications in deployment settings. AB - Military women's urination patterns and practices can be affected when deployed to austere environments. Current measures utilized for urination difficulties predispose women to dehydration, urinary symptoms, and/or urinary tract infections. This article explores the current issues related to this topic. PMID- 23734552 TI - The ability of military health systems applications to coordinate combat casualty care. AB - On February 23, 2007, Former Secretary of Defense Robert Gates said, "Our nation is truly blessed that so many talented and patriotic young people have stepped forward to serve. They deserve the very best facilities and care to recuperate from their injuries and ample assistance to navigate the next step in their lives, and that is what we intend to give them. Apart from the war itself, this department and I have no higher priority" (p. e1). Veterans and active duty Armed Forces personnel operate in a complex continuum that often requires being in harm's way to perform their duties. In doing so, their injuries encountered can be complex. Caring for those with more common injuries, such as injuries to the extremities (30% to 39.6%), is difficult; caring for those with less common injuries, such as genitourinary (0.5% to 8%), takes on an added level of complexity (Fisher, 2009). A complete picture of the injury can only be gained by visualizing their entire record of care. Traditionally, members of the health care team have not been able to link the episodes of care together seamlessly, preventing the ability to see the entire picture. The electronic health record enables better continuity of care and enhances quality (Menachemi, 2008). The availability of a system to document health care provided in austere environments and connect these data with care provided in tertiary military medical care centers using records available throughout the Veterans Health Administration (VHA) will enhance the care provided. Members of the Department of Defense, the VHA, and private sector organizations are collaborating to provide world-class seamless health care. Although the end goal of a completely integrated record has not been reached, the advent of several recent initiatives has placed military health care firmly on the track to reach those goals. PMID- 23734553 TI - 'We did the best we could'--the United States Army nurses of Ie Shima. AB - During World War II, Army Nurses of the 156th Army Evacuation Hospital delivered care while under attack, demonstrated incredible bravery, endured extreme hardships, and unknowingly defined advanced nursing practice as we know it today. First Lieutenant Edythe (Goldstein) Pallin, BS, RN, was a 23-year old registered nurse who served in the Pacific and was stationed near the front lines on the remote island of Ie Shima in the Ryukyu Island Chain near Okinawa. This article, as told to Edythe's daughter, draws heavily on her memories and her military photo album stored in the attic of her home for over 50 years. Edythe only acknowledges her military experience by saying, "We did the best we could." Yes, these nurses not only did the best they could, they also changed nursing from a subservient position to an independent practice long before nurses even understood their professional possibilities. Edythe passed away October 26, 2012. PMID- 23734554 TI - Urologic cancer risks for veterans exposed to Agent Orange. AB - Agent Orange, an herbicide widely used during the Vietnam War, has been linked to various health risks, including urologic malignancy. Exposed veterans are at risk for prostate cancer and may be entitled to compensation if diagnosed with prostate cancer. Current research studies are aimed at mitigating prostate dysplasia and prostate cancer PMID- 23734555 TI - Army nurse. PMID- 23734556 TI - Veterans' stories: what they may have to tell us--a personal reflection. AB - It has been said that we learn much from war. Not only how to conduct it and to be successful, but we learn how the body works and how to assist in regaining function. Without our veterans, much of today's medical knowledge would not be nearly as complete. We have learned how to care for and celebrate our veterans when they return from the war. Vietnam veterans can share what it is like to come home to a country that is not only entirely different, but even antagonistic, to the veteran as a person. This article will consider the types of homecoming experiences veterans have encountered while also introducing examples of the medical knowledge that has been gained from the struggles of those who have fought, and often died, for our country. PMID- 23734557 TI - Life as a military spouse. AB - Military spouses live a capricious life. They often move away from everything familiar to support their active duty spouse. Honor, courage, and commitment are values military spouses need to assist them in being strong and resilient. Effective coping skills aid in the various roles these spouses assume, which may cause personal sacrifices to be made in support of the service member. PMID- 23734558 TI - Controlling the band gap energy of cluster-assembled materials. AB - Cluster-assembled materials combine the nanoscale size and composition-dependent properties of clusters, which have highly tunable magnetic and electronic properties useful for a great variety of potential technologies. To understand the emergent properties as clusters are assembled into hierarchical materials, we have synthesized 23 cluster-assembled materials composed of As7(3-)-based motifs and different countercations and measured their band gap energies. We found that the band gap energy varies from 1.09 to 2.21 eV. In addition, we have carried out first principles electronic structure studies to identify the physical mechanisms that enable control of the band gap edges of the cluster assemblies. The choice of counterion has a profound effect on the band gap energy in ionic cluster assemblies. The top of the valence band is localized on the arsenic cluster, while the conduction band edge is located on the alkali metal counterions. Changing the counterion changes the position of the conduction band edge, enabling control of the band gap energy. We can also vary the architecture of the ionic solid by incorporating cryptates as counterions, which provide charge but are separated from the clusters by bulky ligands. Higher dimensionality typically decreases the band gap energy through band broadening; however band gap energies increased upon moving from zero-dimensional (0D) to two-dimensional (2D) assemblies. This is because internal electric fields generated by the counterion preferentially stabilize the adjacent lone pair orbitals that mark the top of the valence band. Thus, the choice of the counterion can control the position of the conduction band edge of ionic cluster assemblies. In addition, the dimensionality of the solid via internal electric fields can control the valence band edge. Through covalently linking arsenic clusters into composite building blocks, we have also been able to tune the band gap energy. We used a theoretical description based on cluster orbital theory to provide microscopic understanding of the electronic character of the composite building blocks and the observed variations in the band gap energy. Also, we have shown how dimeric linkers can be used to control the band gap energy. Lastly, we also investigated the effects of charge transfer complexes of M(CO)3 on the band gap energy. PMID- 23734560 TI - One-pot synthesis of hypervalent iodine reagents for electrophilic trifluoromethylation. AB - Simplified syntheses suited for large scale preparations of the two hypervalent iodine reagents 1 and 2 for electrophilic trifluoromethylation are reported. In both cases, the stoichiometric oxidants sodium metaperiodate and tert-butyl hypochlorite have been replaced by trichloroisocyanuric acid. Reagent 1 is accessible in a one-pot procedure from 2-iodobenzoic acid in 72% yield. Reagent 2 was prepared via fluoroiodane 11 in a considerably shorter reaction time and with no need of an accurate temperature control. PMID- 23734559 TI - Bivalent ligands that target MU opioid (MOP) and cannabinoid1 (CB1) receptors are potent analgesics devoid of tolerance. AB - Given that MU opioid (MOP) and canabinoid (CB1) receptors are colocalized in various regions of the central nervous system and have been reported to associate as heteromer (MOP-CB1) in cultured cells, the possibility of functional, endogenous MOP-CB1 in nociception and other pharmacologic effects has been raised. As a first step in investigating this possibility, we have synthesized a series of bivalent ligands 1-5 that contain both MU agonist and CB1 antagonist pharmacophores for use as tools to study the functional interaction between MOP and CB1 receptors in vivo. Immunofluorescent studies on HEK293 cells coexpressing both receptors suggested 5 (20-atom spacer) to be the only member of the series that bridges the protomers of the heteromer. Antinociceptive testing in mice revealed 5 to be the most potent member of the series. As neither a mixture of monovalent ligands 9 + 10 nor bivalents 2-5 produced tolerance in mice, MOR-CB1 apparently is not an important target for reducing tolerance. PMID- 23734561 TI - The effect of one-step vs. two-step impression techniques on long-term accuracy and dimensional stability when the finish line is within the gingival sulcular area. AB - PURPOSE: To evaluate the effect of two putty-wash impression techniques on the long-term accuracy and dimensional stability of poly(vinyl siloxane) (PVS) in the gingival sulcus area. MATERIALS AND METHODS: Impressions were taken from a master cast to simulate molar crown preparation. A space around the abutment served as the gingival sulcus. Fifteen impressions using the one- and two-step impression techniques were taken using Express Regular, Express Fast, and President impression materials with custom trays. Using a Toolmaker's microscope, the long (LD) and short distances (SD) of the abutment and the planar distance between two parallel lines (PL) at the circumference of the cast were taken at 0.5, 2, 24, 48, 72, 96, 120, and 144 hours after mixing. ANOVA was performed, with the discrepancy between the distances of the impressions and the master cast as the dependent variable. RESULTS: The differences when different materials and impression techniques were used were significant (p < 0.001) for LD, SD, and PL, as was the interaction between the material, time, and technique (p < 0.001). SD discrepancies were higher than those of LD for all materials and times. The two step impression technique was more accurate, with smaller discrepancies than the one-step impression technique. For all materials, the PL discrepancy was deemed acceptable (less than 0.5%) for all tested times. President had higher discrepancies than the other materials. CONCLUSIONS: When using the two-step putty-wash impression technique, pouring of the impressions may be postponed up to 30 hours; however, when using the one-step impression technique, pouring should be performed within 2 hours. PMID- 23734562 TI - Automated Patent Categorization and Guided Patent Search using IPC as Inspired by MeSH and PubMed. AB - Document search on PubMed, the pre-eminent database for biomedical literature, relies on the annotation of its documents with relevant terms from the Medical Subject Headings ontology (MeSH) for improving recall through query expansion. Patent documents are another important information source, though they are considerably less accessible. One option to expand patent search beyond pure keywords is the inclusion of classification information: Since every patent is assigned at least one class code, it should be possible for these assignments to be automatically used in a similar way as the MeSH annotations in PubMed. In order to develop a system for this task, it is necessary to have a good understanding of the properties of both classification systems. This report describes our comparative analysis of MeSH and the main patent classification system, the International Patent Classification (IPC). We investigate the hierarchical structures as well as the properties of the terms/classes respectively, and we compare the assignment of IPC codes to patents with the annotation of PubMed documents with MeSH terms.Our analysis shows a strong structural similarity of the hierarchies, but significant differences of terms and annotations. The low number of IPC class assignments and the lack of occurrences of class labels in patent texts imply that current patent search is severely limited. To overcome these limits, we evaluate a method for the automated assignment of additional classes to patent documents, and we propose a system for guided patent search based on the use of class co-occurrence information and external resources. PMID- 23734563 TI - Double aortic arch presenting in an adult with dysphagia. AB - Double aortic arch is a congenital anomaly that rarely presents in adults. We describe the case of a 69-year-old male who presented with a double aortic arch, right arch dominant, left arch patent, experiencing progressive dysphagia since childhood. PMID- 23734564 TI - Correction to "quantifying functional group interactions that determine urea effects on nucleic Acid helix formation". PMID- 23734565 TI - Responses of aquatic insects to Cu and Zn in stream microcosms: understanding differences between single species tests and field responses. AB - Field surveys of metal-contaminated streams suggest that some aquatic insects, particularly mayflies (Ephemeroptera) and stoneflies (Plecoptera), are highly sensitive to metals. However, results of single species toxicity tests indicate these organisms are quite tolerant, with LC50 values often several orders of magnitude greater than those obtained using standard test organisms (e.g., cladocerans and fathead minnows). Reconciling these differences is a critical research need, particularly since water quality criteria for metals are based primarily on results of single species toxicity tests. In this research we provide evidence based on community-level microcosm experiments to support the hypothesis that some aquatic insects are highly sensitive to metals. We present results of three experiments that quantified effects of Cu and Zn, alone and in combination, on stream insect communities. EC50 values, defined as the metal concentration that reduced abundance of aquatic insects by 50%, were several orders of magnitude lower than previously published values obtained from single species tests. We hypothesize that the short duration of laboratory toxicity tests and the failure to evaluate effects of metals on sensitive early life stages are the primary factors responsible for unrealistically high LC50 values in the literature. We also observed that Cu alone was significantly more toxic to aquatic insects than the combination of Cu and Zn, despite the fact that exposure concentrations represented theoretically similar toxicity levels. Our results suggest that water quality criteria for Zn were protective of most aquatic insects, whereas Cu was highly toxic to some species at concentrations near water quality criteria. Because of the functional significance of aquatic insects in stream ecosystems and their well-established importance as indicators of water quality, reconciling differences between field and laboratory responses and understanding the mechanisms responsible for variation in sensitivity among metals and metal mixtures is of critical importance. PMID- 23734566 TI - Making sense of joint commissioning: three discourses of prevention, empowerment and efficiency. AB - BACKGROUND: In recent years joint commissioning has assumed an important place in the policy and practice of English health and social care. Yet, despite much being claimed for this way of working there is a lack of evidence to demonstrate the outcomes of joint commissioning. This paper examines the types of impacts that have been claimed for joint commissioning within the literature. METHOD: The paper reviews the extant literature concerning joint commissioning employing an interpretive schema to examine the different meanings afforded to this concept. The paper reviews over 100 documents that discuss joint commissioning, adopting an interpretive approach which sought to identify a series of discourses, each of which view the processes and outcomes of joint commissioning differently. RESULTS: This paper finds that although much has been written about joint commissioning there is little evidence to link it to changes in outcomes. Much of the evidence base focuses on the processes of joint commissioning and few studies have systematically studied the outcomes of this way of working. Further, there does not appear to be one single definition of joint commissioning and it is used in a variety of different ways across health and social care. The paper identifies three dominant discourses of joint commissioning - prevention, empowerment and efficiency. Each of these offers a different way of seeing joint commissioning and suggests that it should achieve different aims. CONCLUSIONS: There is a lack of clarity not only in terms of what joint commissioning has been demonstrated to achieve but even in terms of what it should achieve. Joint commissioning is far from a clear concept with a number of different potential meanings. Although this ambiguity can be helpful in some ways in the sense that it can bring together disparate groups, for example, if joint commissioning is to be delivered at a local level then more specificity may be required in terms of what they are being asked to deliver. PMID- 23734567 TI - Evaluating genome architecture of a complex region via generalized bipartite matching. AB - With the remarkable development in inexpensive sequencing technologies and supporting computational tools, we have the promise of medicine being personalized by knowledge of the individual genome. Current technologies provide high throughput, but short reads. Reconstruction of the donor genome is based either on de novo assembly of the (short) reads, or on mapping donor reads to a standard reference. While such techniques demonstrate high success rates for inferring 'simple' genomic segments, they are confounded by segments with complex duplication patterns, including regions of direct medical relevance, like the HLA and the KIR regions.In this work, we address this problem with a method for assessing the quality of a predicted genome sequence for complex regions of the genome. This method combines two natural types of evidence: sequence similarity of the mapped reads to the predicted donor genome, and distribution of reads across the predicted genome. We define a new scoring function for read-to-genome matchings, which penalizes for sequence dissimilarities and deviations from expected read location distribution, and present an efficient algorithm for finding matchings that minimize the penalty. The algorithm is based on a formal problem, first defined in this paper, called Coverage Sensitive many-to-many min cost bipartite Matching (CSM). This new problem variant generalizes the standard (one-to-one) weighted bipartite matching problem, and can be solved using network flows. The resulting Java-based tool, called SAGE (Scoring function for Assembled GEnomes), is freely available upon request. We demonstrate over simulated data that SAGE can be used to infer correct haplotypes of the highly repetitive KIR region on the Human chromosome 19. PMID- 23734569 TI - Adsorption of sodium dodecyl sulfate on functionalized graphene measured by conductometric titration. AB - We report on the adsorption of sodium dodecyl sulfate (SDS) onto functionalized graphene sheets (FGSs) in an aqueous system, measured at broad SDS and FGS concentration ranges by conductometric surfactant titration. At dilute SDS concentrations (<12 MUM in bulk solution), there is evidence of a counterion exchange between hydronium ions (from the dissociation of acidic chemical functionalities on FGS) and sodium ions coadsorbing with dodecyl sulfate monomers onto FGSs. We find that, for FGS with a carbon-to-oxygen ratio of ~18, monolayer adsorption of SDS on FGS reaches full surface coverage by ~12 MUM SDS. Additionally, the critical surface aggregation concentration (csac) for surface micelle formation on FGS is measured to be ~1.5 mM SDS. The transition from monolayer adsorption to surface micelle formation appears to occur at a similar SDS concentration on FGSs as on graphite, suggesting there is little difference in the surfactant adsorption behavior on both materials. We estimate that the FGS surface area available for SDS adsorption is ~600 m(2)/g, which is significantly less than expected for FGSs in suspension and indicates the presence of regions on FGS on which SDS adsorption does not occur. PMID- 23734568 TI - A selective antagonist of histamine H4 receptors prevents antigen-induced airway inflammation and bronchoconstriction in guinea pigs: involvement of lipocortin-1. AB - BACKGROUND AND PURPOSE: Among the pathogenic mechanisms of asthma, a role for oxidative/nitrosative stress has been well documented. Recent evidence suggests that histamine H4 receptors play a modulatory role in allergic inflammation. Here we report the effects of compound JNJ 7777120 (JNJ), a selective H4 receptor antagonist, on antigen-induced airway inflammation, paying special attention to its effects on lipocortin-1 (LC-1/annexin-A1), a 37 kDA anti-inflammatory protein that plays a key role in the production of inflammatory mediators. EXPERIMENTAL APPROACH: Ovalbumin (OA)-sensitized guinea pigs placed in a respiratory chamber were challenged with antigen. JNJ (5, 7.5 and 10 mg.kg-1) was given i.p. for 4 days before antigen challenge. Respiratory parameters were recorded. Bronchoalveolar lavage (BAL) fluid was collected and lung specimens taken for further analyses 1 h after antigen challenge. In BAL fluid, levels of LC-1, PGD2 , LTB4 and TNF-alpha were measured. In lung tissue samples, myeloperoxidase, caspase-3 and Mn-superoxide dismutase activities and 8-hydroxy-2-deoxyguanosine levels were measured. KEY RESULTS: OA challenge decreased LC-1 levels in BAL fluid, induced cough, dyspnoea and bronchoconstriction and increased PGD2 , LTB4 and TNF-alpha levels in lung tissue. Treatment with JNJ dose-dependently increased levels of LC-1, reduced respiratory abnormalities and lowered levels of PGD2 , LTB4 and TNF-alpha in BAL fluid. CONCLUSIONS AND IMPLICATIONS: Antigen induced asthma-like reactions in guinea pigs decreased levels of LC-1 and increased TNF-alpha and eicosanoid production. JNJ pretreatment reduced allergic asthmatic responses and airway inflammation, an effect associated with LC-1 up regulation. PMID- 23734570 TI - An integrative literature review on preparing nursing students through simulation to recognize and respond to the deteriorating patient. AB - AIMS: To synthesize studies that explored simulation as preparation of nursing students for recognition and response to the deteriorating patient. BACKGROUND: New graduate nurses are expected to have the skills to recognize and respond to rapidly deteriorating patient conditions. To this end, education programmes have turned increasingly to simulation to assist students to gain the necessary skills. DESIGN: Integrative review. DATA SOURCES: CINAHL, Informit, ProQuest, Ovid MEDLINE, SAGE Journals and Web of Knowledge electronic databases, keywords and inclusion/exclusion criteria were searched. Eighteen studies published between 2004-2012 were found. REVIEW METHODS: Studies were appraised using recognized evaluation tools. Thematic analysis was undertaken and emergent themes were extracted with similar and divergent perspectives sought. RESULTS: Six themes were identified namely, 'transferability of simulation skills to clinical practice', 'exposure to broader range of experiences', 'confidence levels in relation to simulation training', 'competence/performance', 'clinical judgment' and 'student perceptions of preparedness for practice following simulation'. CONCLUSION: Simulation exposes students to a broader range of experiences whilst in a safe environment with transference of skills to clinical practice occurring. Confidence, clinical judgement, knowledge and competence, all vital in the care of a deteriorating patient, were enhanced. However, evidence of simulation used specifically to prepare nursing students to recognize and respond to the deteriorating patient appeared limited. This educational field appears rich for interprofessional collaboration and further research. PMID- 23734571 TI - Sex ratio at birth is associated with first-trimester maternal thyrotropin in women receiving levothyroxine. AB - BACKGROUND: The sex ratio at birth (male out of total alive newborns) is historically established at 0.515 and is influenced by numerous factors. It is not known, however, whether it is influenced by maternal thyroid conditions. Our aim was to analyze its association with maternal thyroid autoimmunity and first trimester thyrotropin (TSH). METHODS: We performed a retrospective cohort study at a tertiary care center. We studied 167 women who had received pregestational treatment with levothyroxine for hypothyroidism or differentiated thyroid carcinoma and gave birth to live infants. Women with secondary/tertiary hypothyroidism, pregestational diabetes mellitus, or multiple pregnancies were excluded. Autoimmunity was defined as present/absent, and mean first-trimester TSH was tested both as a quantitative variable and using six predefined categories. The outcome measure was sex ratio at birth. RESULTS: The sex ratio at birth was 0.485, not significantly different from expected. Maternal characteristics were similar in mothers of female and male newborns with the exception of mean first-trimester TSH, which was higher in pregnancies of female fetuses (3.27 vs. 2.52 mUI/L, p<0.025). Newborn sex differed across predefined TSH categories (p<0.021, with a sex ratio of 0.200 [95% confidence interval 0.00 0.402] for TSH >=10 mUI/L). A multiple logistic regression analysis to predict newborn male sex confirmed maternal mean first-trimester TSH as the single predictor (odds ratio 0.900 [95% confidence interval 0.823-0.984], p<0.020). CONCLUSIONS: In women under pregestational treatment with levothyroxine, mean maternal first-trimester TSH is negatively associated with sex ratio at birth. This association has not been previously described. PMID- 23734572 TI - Rupatadine improves quality of life in mastocytosis: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Mastocytosis is frequently associated with mast cell-mediated symptoms which require relieving medication. While second generation antihistamines (sgAHs) are the first line therapeutic strategy to treat mast cell mediator-related symptoms, controlled clinical trials on how they improve quality of life have not been performed. METHODS: This randomized, double-blind, placebo controlled, cross-over trial assessed rupatadine 20 mg daily in the treatment of mastocytosis symptoms in 30 adult patients. Symptoms were assessed by a visual analogue scale (VAS) and symptom specific quality of life questionnaire (ItchyQoL). RESULTS: The mean ItchyQoL total score and VAS symptom score were significantly improved in the rupatadine treatment phase compared with placebo. There were also significant reductions from placebo in the severity of itch, wheal and flare, flushing, tachycardia and headache but not gastrointestinal symptoms. CONCLUSIONS: In this first comprehensive trial of a sgAH in mastocytosis, rupatadine 20 mg daily for 4 weeks significantly controlled symptoms and improved patients' quality of life. PMID- 23734573 TI - Intraocular sarcoma associated with a rupture lens in a rabbit (Oryctolagus cuniculus). AB - This case report describes the clinical manifestations and ocular pathology of an intraocular sarcoma in a spayed female 7-year-old rabbit that developed clinical signs consistent with phacoclastic uveitis at 6 months of age, which was left untreated for most of the next 6 years. Ophthalmologic examination confirmed pupillary occlusion, aqueous flare, fibrin, and lens debris within the anterior chamber of the right eye. The right eye was blind and phthisical. The tentative clinical diagnosis was chronic phacoclastic uveitis, and a routine transconjunctival enucleation of the right eye was completed. The globe was formalin-fixed and submitted for histologic examination. Light microscopic examination revealed a ruptured cataractous lens, uveitis, retinal detachment, and an intraocular sarcoma centered around the lens. Immunohistochemical (IHC) staining was positive for smooth muscle actin and vimentin and negative for Desmin and cytokeratin intermediate filaments. PMID- 23734574 TI - Trends in resource utilization associated with the inpatient treatment of neonatal congenital heart disease. AB - INTRODUCTION: While neonates account for a significant proportion of health care expenditures related to inpatient care for congenital heart disease, key drivers of resource utilization among this population are poorly defined. METHODS: Data from 2005 through 2011 were extracted from the Pediatric Health Information System for patients assigned a discharge All Patient Refined Diagnosis Related Group of 630 (neonates with birthweight >2499 g undergoing a major cardiovascular procedure). Mortality risk adjustment for patients undergoing operative interventions was performed with the Risk Adjusment in Congenital Heart Surgery (RACHS-1) score. RESULTS: A total of 13 156 cases were included in the analysis. Despite only a 3% increase in case mix index and no significant change in operative acuity over the study period (RACHS classifications of 3 or greater 67% in 2005 vs. 66% in 2011, P = .64), there were inflation-adjusted increases in both total estimated cost per case of (50% to $151 760 in 2011, P < .001), and mean charge per case (33% to $433 875 in 2011, P < .001). Pharmacy charges increased by 16% (P < .001), with agents including chlorothiazide and albumin accounting for the highest patient charges over the study period. Imaging charges increased by 42% (P < .001), with an average of 5.7 echocardiograms and $6517 in associated charges per case by 2011. While the proportion of patients receiving nitric oxide remained consistent, mean duration of administration increased by 25% to 6.6 days by 2011, accounting for average charges of $52 141 per patient exposed. CONCLUSIONS: Among neonates with serious congenital heart disease, increases in both institutional costs and charges to the patient are associated with relatively consistent utilization practices in recent years. Multiinstitutional collaboration may prove useful in aligning evidence-based reductions in practice variation with limitations in resource utilization without compromising the quality of care. PMID- 23734575 TI - Investigating mathematical models of immuno-interactions with early-stage cancer under an agent-based modelling perspective. AB - Many advances in research regarding immuno-interactions with cancer were developed with the help of ordinary differential equation (ODE) models. These models, however, are not effectively capable of representing problems involving individual localisation, memory and emerging properties, which are common characteristics of cells and molecules of the immune system. Agent-based modelling and simulation is an alternative paradigm to ODE models that overcomes these limitations. In this paper we investigate the potential contribution of agent-based modelling and simulation when compared to ODE modelling and simulation. We seek answers to the following questions: Is it possible to obtain an equivalent agent-based model from the ODE formulation? Do the outcomes differ? Are there any benefits of using one method compared to the other? To answer these questions, we have considered three case studies using established mathematical models of immune interactions with early-stage cancer. These case studies were re conceptualised under an agent-based perspective and the simulation results were then compared with those from the ODE models. Our results show that it is possible to obtain equivalent agent-based models (i.e. implementing the same mechanisms); the simulation output of both types of models however might differ depending on the attributes of the system to be modelled. In some cases, additional insight from using agent-based modelling was obtained. Overall, we can confirm that agent-based modelling is a useful addition to the tool set of immunologists, as it has extra features that allow for simulations with characteristics that are closer to the biological phenomena. PMID- 23734576 TI - Multiplex PCR assay for the detection of common dermatophyte nail infections. AB - Onychomycosis is one of the most prevalent dermatophytic diseases. Mycological methods used in the conventional diagnosis may not be optimal. Multiplex (MX) PCR was reported as a reliable alternative. Dermatophyte gene sequence records were used to design a MX PCR for detection and identification of dermatophytes in nail specimens. A MX PCR method based on the amplification of the chitin synthase 1 and internal transcribed spacer genes was developed. The study included 93 strains of dermatophytes and non-dermatophytic fungi, six dermatophytic reference strains and 201 nail specimens from patients with dermatophytic onyxis. DNA extraction directly from nail samples was carried out by using the QIAamp DNA extraction kit (Quiagen). A set of primers was designed and their specificity was assessed. MX PCR detected the causal agent in specimens from which Trichophyton rubrum and T. interdigitale grew in culture and also identified a dermatophyte species in an additional 32 specimens that were negative in microscopy and culture. None of the investigated non-dermatophytic strains was positive. Sensitivity of MX PCR was higher as compared to mycological examination (97% vs. 81.1%). MX PCR for direct detection of dermatophytes from nail samples yielded mixed flora in 32.8% of samples. MX PCR proved sensitive and adequate for the diagnosis of dermatophytic onychomycosis. It is much adapted to cases where culture is negative or contaminated by overgrowing moulds, which makes the identification of the causal agent problematic. PMID- 23734577 TI - Radiation exposure in the follow-up of patients with urolithiasis comparing digital tomosynthesis, non-contrast CT, standard KUB, and IVU. AB - OBJECTIVE: To compare the effective doses (EDs) associated with imaging modalities for follow-up of patients with urolithiasis, including stone protocol non-contrast computed tomography (NCCT), kidney, ureter, and bladder radiograph (KUB), intravenous urogram (IVU), and digital tomosynthesis (DT). METHODS: A validated Monte-Carlo simulation-based software PCXMC 2.0 (STUK) designed for estimation of patient dose from medical X-ray exposures was used to determine the ED for KUB, IVU (KUB scout plus three tomographic images), and DT (two scouts and one tomographic sweep). Simulations were performed using a two-dimensional stationary field onto the corresponding body area of the built-in digital phantom, with actual kVp, mAs, and geometrical parameters of the protocols. The ED for NCCT was determined using an anthropomorphic male phantom that was placed prone on a 64-slice GE Healthcare volume computed tomography (VCT) scanner. High sensitivity metal oxide semiconductor field effect transistors dosimeters were placed at 20 organ locations and used to measure organ radiation doses. RESULTS: The ED for a stone protocol NCCT was 3.04+/-0.34 mSv. The ED for a KUB was 0.63 and 1.1 mSv for the additional tomographic film. The total ED for IVU was 3.93 mSv. The ED for DT performed with two scouts and one sweep (14.2 degrees ) was 0.83 mSv. CONCLUSIONS: Among the different imaging modalities for follow-up of patients with urolithiasis, DT was associated with the least radiation exposure (0.83 mSv). This ED corresponds to a fifth of NCCT or IVU studies. Further studies are needed to demonstrate the sensitivity and specificity of DT for the follow-up of nephrolithiasis patients. PMID- 23734578 TI - Prevalence and sociodemographic associations of common mental disorders in a nationally representative sample of the general population of Greece. AB - BACKGROUND: No study in Greece has assessed so far the full range of common mental disorders using a representative sample of the population from both mainland and insular regions of the country. The aim of the present paper was to present the results of the first such study. METHODS: The study was carried out between 2009-2010 in a nationally representative sample of 4894 individuals living in private households in Greece. Common mental disorders in the past week were assessed with the revised Clinical Interview Schedule (CIS-R). We also assessed alcohol use disorders (using AUDIT), smoking and cannabis use. RESULTS: 14% of the population (Male: 11%, Female: 17%) was found to have clinically significant psychiatric morbidity according to the scores on the CIS-R. The prevalence (past seven days) of specific common mental disorders was as follows: Generalized Anxiety Disorder: 4.10% (95% CI: 3.54, 4.65); Depression: 2.90% (2.43, 3.37); Panic Disorder: 1.88% (1.50, 2.26); Obsessive-Compulsive Disorder: 1.69% (1.33, 2.05); All Phobias: 2.79% (2.33, 3.26); Mixed anxiety-depression: 2.67% (2.22, 3.12). Harmful alcohol use was reported by 12.69% of the population (11.75, 13.62). Regular smoking was reported by 39.60% of the population (38.22, 40.97) while cannabis use (at least once during the past month) by 2.06% (1.66, 2.46). Clinically significant psychiatric morbidity was positively associated with the following variables: female gender, divorced or widowed family status, low educational status and unemployment. Use of all substances was more common in men compared to women. Common mental disorders were often comorbid, undertreated, and associated with a lower quality of life. CONCLUSIONS: The findings of the present study can help in the better planning and development of mental health services in Greece, especially in a time of mental health budget restrictions. PMID- 23734579 TI - Novel GHB-derived natural products from European mistletoe (Viscum album). AB - CONTEXT: The European white-berry mistletoe [Viscum album L. (Loranthaceae)] is among the oldest known medicinal plants. At present the most important application of mistletoe extracts is in the treatment of cancer. However, natural products specific to mistletoe have rarely been encountered in the current literature. OBJECTIVE: To discover novel natural products specific to European mistletoe. MATERIALS AND METHODS: European mistletoe was extracted with methanol, purified to partition against diethyl ether and further purified with XAD-7 column chromatography. Pure compounds were separated by Sephadex column chromatography and preparative HPLC. The structures of the novel compounds were established using a combination of several 2D NMR spectroscopic techniques and mass spectrometry. RESULTS: A new type of natural product derived from the methyl ester of gamma-hydroxybutyric acid (GHB) coupled to hydroxybenzoic acids, namely 3-(3'-carbomethoxypropyl) gallic acid and 3-(3'-carbomethoxypropyl)-7->3" protocatechoyl galloate were characterized from European white-berry mistletoe. Condensation of the 3-hydroxyl of gallic acid with the 4-hydroxyl of GHB significantly reduced the radical scavenging properties of the former compound. DISCUSSION AND CONCLUSION: The characterized compounds define a novel group of natural products that may be of particular interest because it appears that the two new compounds are not closely related to any known natural product. PMID- 23734581 TI - Generalized fabrication of monolayer nonclose-packed colloidal crystals with tunable lattice spacing. AB - Here, we report a simple colloidal transfer technology that enables scalable fabrication of monolayer nonclose-packed silica colloidal crystals on a large variety of substrates. Two-dimensional colloidal crystals with an unusual nonclose-packed structure are first assembled on silicon wafers by a spin-coating technique. A poly(vinyl alcohol) (PVA) film cast upon the spin-coated colloidal crystal is used to transfer the nonclose-packed particle arrays onto various substrates. The lattice spacing of the transferred monolayer colloidal crystal can easily be adjusted by thermally treating the PVA-silica spheres composite film for varied durations. We also have demonstrated the templating fabrication of periodic arrays of gold nanodots using a transferred monolayer nonclose-packed colloidal crystal as a structural template. The resultant plasmonic array exhibits high surface-enhanced Raman scattering enhancement factor (~3.8 * 10(7)) for adsorbed benzenethiol molecules. PMID- 23734580 TI - Multiscale perspectives of virus entry via endocytosis. AB - Most viruses take advantage of endocytic pathways to gain entry into host cells and initiate infections. Understanding of virus entry via endocytosis is critically important for the design of antiviral strategies. Virus entry via endocytosis is a complex process involving hundreds of cellular proteins. The entire process is dictated by events occurring at multiple time and length scales. In this review, we discuss and evaluate the available means to investigate virus endocytic entry, from both experimental and theoretical/numerical modeling fronts, and highlight the importance of multiscale features. The complexity of the process requires investigations at a systems biology level, which involves the combination of different experimental approaches, the collaboration of experimentalists and theorists across different disciplines, and the development of novel multiscale models. PMID- 23734582 TI - Role of intraoperative regional oxygen saturation using near infrared spectroscopy in the prediction of low output syndrome after pediatric heart surgery. AB - BACKGROUND: We report on the applicability of intraoperative regional oxygen saturation (rSO2) desaturation score by near-infrared spectroscopy in the early detection of postoperative low output state (LOS) in infants with congenital heart disease who underwent cardiac surgery. MATERIALS AND METHODS: Between July and October 2011 the intra- and immediate postoperative courses of 22 patients undergoing elective cardiac surgery for congenital heart disease were analyzed. The intraoperative cerebral and somatic rSO2 were measured and a rSO2 desaturation score calculated (by multiplying the rSO2 below 50% of the threshold by seconds). The aim of the study was to evaluate the applicability of intraoperative rSO2 de-saturation score in the early detection of postoperative LOS. RESULTS: Thirteen of 22 patients (62%) had an intraoperative cerebral rSO2 desaturation score >3000% per second. Patients with a rSO2 de-saturation score >3000% per second had a significantly lower intraoperative central venous saturation (SvO2, p = 0.002), cardiac index (CI, p = 0.004), oxygen availability indexed (DO2I, p = 0.0004), and a significantly higher extraction of oxygen (ERO2, p = 0.0005) when compared to patients with a rSO2 desaturation score <3000% per second. Nine patients had postoperative LOS; all of them had an intraoperative rSO2 de-saturation score >3000% per second (9/13 patients, 69%; p = 0.001) requiring prompt treatment with major inotropic support, surface hypothermia, and extracorporeal membrane oxygenation (ECMO) support (n = 4). Twenty-one patients survived. One patient died from ventricular failure and inability to wean from ECMO support. CONCLUSION: The intraoperative use of NIRS provided an early warning sign of hemodynamic or metabolic compromise, enabling early and rapid intervention to prevent or reduce the severity of potentially life-threatening complications. PMID- 23734583 TI - Bacterial immune interaction in experimental colitis. AB - OBJECTIVES: This study aimed to analyze the effects of 5-aminosalicylic acid (5 ASA) on intestinal microbiota and immune regulation in inflammatory bowel disease (IBD) and to investigate the correlation between intestinal microbiota and immune factors. METHODS: Colitis in mice was induced by oxazolone. The community composition of luminal and mucosal microbiota was analyzed by a terminal restriction fragment length polymorphism. The expression of occludin, toll-like receptor (TLR)-2, TLR-4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) p65 proteins were measured by immunohistochemistry and Western blot. Linear correlation between intestinal microbial community and the severity of the colitis or intestinal microbial community and expressions of immune factors were determined. RESULTS: Protective bacteria decreased while aggressive bacteria increased in the colitis group. The richness and diversity of both luminal and mucosal microbiota decreased in the colitis group the decrease was enhanced in the 5-ASA-treated group. The diversity of mucosal microbiota significantly correlated with the extent of the colitis. Expressions of occludin, TLR-2, TLR-4, tumor necrosis factor-alpha and NF-kappaB p65 were significantly correlated with the diversity of mucosal microbiota. CONCLUSIONS: Mucosal microbiota are important in the pathogenesis of IBD. 5-ASA increases protective bacteria but decreases aggressive bacteria, thus inducing the new intestinal microbial homeostasis. PMID- 23734584 TI - Spotted fever group rickettsioses documented in Morocco. PMID- 23734585 TI - Risk factors associated with physical restraints in residential aged care facilities: a community-based epidemiological survey in Taiwan. AB - AIM: To identify the rate and risk factors of physical restraint in residential aged care facilities in Taiwan. BACKGROUND: In Taiwan, physical restraint is commonly used in aged care facilities to prevent accidents. Many are unaware of the associated risks. Restrained residents cannot move freely, increasing the risk of atrophy and leading to reduced physical functioning. DESIGN: A community based epidemiological survey. METHODS: Data were collected from June-December 2007 across 178 residential aged care facilities with 5,173 residential beds in the target city of Taiwan. Twenty facilities were sampled using probability proportional to size by beds and accreditation ranking. In all, 256 primary caregivers (78 nurses and 178 care aides) and 847 residents completed the study questionnaires and tests. A multilevel analysis approach was used to identify individual- and facility-level risk factors for physical restraint and assess the variation in physical restraint at the individual- and facility-level. RESULTS: Of 847 residents, 62% (527) were restrained during the study period. The main reasons for restraint use were fall prevention and prevention of tube removal. Resident level risk factors for physical restraint included lower Barthel Index scores (more dependent) and an agreement allowing the use of physical restraint to avoid injury signed by a family member or social worker. A facility-level risk factor for physical restraint was younger primary caregivers. CONCLUSION: To reduce the incidence of physical restraint in residential aged care facilities in Taiwan, educational programmes should target primary caregivers and families in facilities. PMID- 23734586 TI - Clinical evaluation of a novel commercial multiplex-based PCR diagnostic test for differential diagnosis of dermatomycoses. AB - Dermatomycoses are very common worldwide with increasing prevalence. An accurate and rapid detection of fungi is most important for the choice of antimycotics and the success of treatment. The aim of this study was to evaluate a new commercial multiplex-based PCR which allows the detection and differentiation of the most relevant human pathogen fungi causing dermatomycoses in Europe. The accuracy and reproducibility of this application were verified in a clinical performance assessment in comparison to direct microscopy and culture using DNA isolates from 253 clinical samples. Sensitivity, specificity, positive predictive value and negative predictive value of 87.3%, 94.3%, 87.3% and 94.3%, respectively, were calculated for dermatophytes when confirmed by direct microscopy, culture or both. The corresponding values for Candida spp. were 62.7%, 93.5%, 77.8%, and 87.4%, respectively. Furthermore, in comparison to culture, the multiplex PCR was able to detect additional 38 Trichophytum rubrum and 12 Trichophytum interdigitale infections. These results were confirmed by independent PCR analysis. From DNA isolation to diagnosis the multiparameter diagnostic kit gives rise to a 1-day workflow, enables fast clarification of disease aetiology and, thus, contributes to specific therapy selection. The latter is particularly important in light of growing resistance to antimycotics. PMID- 23734588 TI - Phaeochromocytoma and hepatocellular carcinoma with nuclear glycogenation of the hepatocytes in a predatory carp, Chanodichthys erythropterus (Basilewsky). PMID- 23734589 TI - Organic molecules as tools to control the growth, surface structure, and redox activity of colloidal quantum dots. AB - In order to achieve efficient and reliable technology that can harness solar energy, the behavior of electrons and energy at interfaces between different types or phases of materials must be understood. Conversion of light to chemical or electrical potential in condensed phase systems requires gradients in free energy that allow the movement of energy or charge carriers and facilitate redox reactions and dissociation of photoexcited states (excitons) into free charge carriers. Such free energy gradients are present at interfaces between solid and liquid phases or between inorganic and organic materials. Nanostructured materials have a higher density of these interfaces than bulk materials. Nanostructured materials, however, have a structural and chemical complexity that does not exist in bulk materials, which presents a difficult challenge: to lower or eliminate energy barriers to electron and energy flux that inevitably result from forcing different materials to meet in a spatial region of atomic dimensions. Chemical functionalization of nanostructured materials is perhaps the most versatile and powerful strategy for controlling the potential energy landscape of their interfaces and for minimizing losses in energy conversion efficiency due to interfacial structural and electronic defects. Colloidal quantum dots are semiconductor nanocrystals synthesized with wet-chemical methods and coated in organic molecules. Chemists can use these model systems to study the effects of chemical functionalization of nanoscale organic/inorganic interfaces on the optical and electronic properties of a nanostructured material, and the behavior of electrons and energy at interfaces. The optical and electronic properties of colloidal quantum dots have an intense sensitivity to their surface chemistry, and their organic adlayers make them dispersible in solvent. This allows researchers to use high signal-to-noise solution-phase spectroscopy to study processes at interfaces. In this Account, I describe the varied roles of organic molecules in controlling the structure and properties of colloidal quantum dots. Molecules serve as surfactant that determines the mechanism and rate of nucleation and growth and the final size and surface structure of a quantum dot. Anionic surfactant in the reaction mixture allows precise control over the size of the quantum dot core but also drives cation enrichment and structural disordering of the quantum dot surface. Molecules serve as chemisorbed ligands that dictate the energetic distribution of surface states. These states can then serve as thermodynamic traps for excitonic charge carriers or couple to delocalized states of the quantum dot core to change the confinement energy of excitonic carriers. Ligands, therefore, in some cases, dramatically shift the ground state absorption and photoluminescence spectra of quantum dots. Molecules also act as protective layers that determine the probability of redox processes between quantum dots and other molecules. How much the ligand shell insulates the quantum dot from electron exchange with a molecular redox partner depends less on the length or degree of conjugation of the native ligand and more on the density and packing structure of the adlayer and the size and adsorption mode of the molecular redox partner. Control of quantum dot properties in these examples demonstrates that nanoscale interfaces, while complex, can be rationally designed to enhance or specify the functionality of a nanostructured system. PMID- 23734587 TI - The evolving small-molecule fluorescent-conjugate toolbox for Class A GPCRs. AB - The past decade has witnessed fluorescently tagged drug molecules gaining significant attraction in their use as pharmacological tools with which to visualize and interrogate receptor targets at the single-cell level. Additionally, one can generate detailed pharmacological information, such as affinity measurements, down to almost single-molecule detection limits. The now accepted utilization of fluorescence-based readouts in high-throughput/high content screening provides further evidence that fluorescent molecules offer a safer and more adaptable substitute to radioligands in molecular pharmacology and drug discovery. One such drug-target family that has received considerable attention are the GPCRs; this review therefore summarizes the most recent developments in the area of fluorescent ligand design for this important drug target. We assess recently reported fluorescent conjugates by adopting a receptor family-based approach, highlighting some of the strengths and weaknesses of the individual molecules and their subsequent use. This review adds further strength to the arguments that fluorescent ligand design and synthesis requires careful planning and execution; providing examples illustrating that selection of the correct fluorescent dye, linker length/composition and geographic attachment point to the drug scaffold can all influence the ultimate selectivity and potency of the final conjugate when compared with its unlabelled precursor. When optimized appropriately, the resultant fluorescent conjugates have been successfully employed in an array of assay formats, including flow cytometry, fluorescence microscopy, FRET and scanning confocal microscopy. It is clear that fluorescently labelled GPCR ligands remain a developing and dynamic research arena. PMID- 23734590 TI - Aminolysis of phenyl N-phenylcarbamate via an isocyanate intermediate: theory and experiment. AB - A comprehensive examination of the mechanism of the uncatalyzed and base catalyzed aminolysis of phenyl N-phenylcarbamate by theoretical quantum mechanical methods at M06-2X/6-311+G(2d,2p) and B3LYP-D3/6-31G(d,p) levels, combined with an IR spectroscopic study of the reaction, was carried out. Three alternative reaction channels were theoretically characterized: concerted, stepwise via a tetrahedral intermediate, and stepwise involving an isocyanate intermediate. In contrast to dominating views, the theoretical results revealed that the reaction pathway through the isocyanate intermediate (E1cB) is energetically favored. These conclusions were supported by an IR spectroscopic investigation of the interactions of phenyl N-phenylcarbamate with several amines possessing varying basicities and nucleophilicities: n-butylamine, diethylamine, triethylamine, N-methylpyrrolidine, and trimethylamine. The reactivity of substituted phenyl N-phenylcarbamates in the aminolysis reaction was rationalized using theoretical and experimental reactivity indexes: electrostatic potential at nuclei (EPN), Hirshfeld and NBO atomic charges, and Hammett constants. The obtained quantitative relationships between these property descriptors and experimental kinetic constants reported in the literature emphasize the usefulness of theoretical parameters (EPN, atomic charges) in characterizing chemical reactivity. PMID- 23734592 TI - Outcomes of permanent peritoneal ports for the management of recurrent malignant ascites. AB - BACKGROUND AND OBJECTIVE: Ascites complicates many advanced malignancies, resulting in abdominal pain, discomfort, anorexia, nausea, and dyspnea. Percutaneous drainage relieves symptoms in the vast majority of patients. The aim of this study was to determine the course and outcomes in a consecutive series of patients with recurrent ascites managed with permanent peritoneal ports. METHODS: A prospective longitudinal descriptive study from 2006 to 2011, involving patients treated at the Sydney Cancer Center (New South Wales, Australia). RESULTS AND CONCLUSIONS: A total of 155 drainages were performed in 24 patients; 26% of drainages (n=40) in the patient's home and the remainder in the ambulatory care clinic. Grade 3 or higher adverse events occured in less than 25% of all draining procedures. An improvement in symptoms was demonstrated in almost half of all individual drainage procedures. Our findings suggest that peritoneal ports are efficacious, safe, and are associated with symptomatic relief in most patients. PMID- 23734591 TI - Mutations in DNA-binding loop of NFAT5 transcription factor produce unique outcomes on protein-DNA binding and dynamics. AB - The nuclear factor of activated T cells 5 (NFAT5 or TonEBP) is a Rel family transcriptional activator and is activated by hypertonic conditions. Several studies point to a possible connection between nuclear translocation and DNA binding; however, the mechanism of NFAT5 nuclear translocation and the effect of DNA binding on retaining NFAT5 in the nucleus are largely unknown. Recent experiments showed that different mutations introduced in the DNA-binding loop and dimerization interface were important for DNA binding and some of them decreased the nuclear-cytoplasm ratio of NFAT5. To understand the mechanisms of these mutations, we model their effect on protein dynamics and DNA binding. We show that the NFAT5 complex without DNA is much more flexible than the complex with DNA. Moreover, DNA binding considerably stabilizes the overall dimeric complex and the NFAT5 dimer is only marginally stable in the absence of DNA. Two sets of NFAT5 mutations from the same DNA-binding loop are found to have different mechanisms of specific and nonspecific binding to DNA. The R217A/E223A/R226A (R293A/E299A/R302A using isoform c numbering) mutant is characterized by significantly compromised binding to DNA and higher complex flexibility. On the contrary, the T222D (T298D in isoform c) mutation, a potential phosphomimetic mutation, makes the overall complex more rigid and does not significantly affect the DNA binding. Therefore, the reduced nuclear cytoplasm ratio of NFAT5 can be attributed to reduced binding to DNA for the triple mutant, while the T222D mutant suggests an additional mechanism at work. PMID- 23734593 TI - Kinetics and mechanism of direct reaction between CO2 and Ca(OH)2 in micro fluidized bed. AB - Even at present it is still difficult to characterize the reaction between CO2 and Ca(OH)2 at high temperature and atmospheric pressure using traditional instruments such as thermogravimetric analyzer and differential scanning calorimeter. This study was devoted to characterizing such a reaction in a newly developed micro fluidized bed reaction analyzer (MFBRA) under isothermal conditions in the temperature range of 773-1023 K. The results indicated that the MFBRA has not only a good adaptability for characterizing the above-mentioned reaction but enables as well a new insight into the mechanism of the reaction. An obvious time delay was identified for the release of the formed steam (H2O) in comparison with the onset of its CO2 absorption, which might be attributed to the formation of an unstable intermediate product Ca(HCO3)2 in the reaction process between CO2 and Ca(OH)2. The activation energy for forming Ca(HCO3)2 was found to be about 40 kJ/mol, which is much lower than that of the reaction between CO2 and CaO. PMID- 23734594 TI - Photoinduced charge transfer and acetone sensitivity of single-walled carbon nanotube-titanium dioxide hybrids. AB - The unique physical and chemical properties of single-walled carbon nanotubes (SWNTs) make them ideal building blocks for the construction of hybrid nanostructures. In addition to increasing the material complexity and functionality, SWNTs can probe the interfacial processes in the hybrid system. In this work, SWNT-TiO2 core/shell hybrid nanostructures were found to exhibit unique electrical behavior in response to UV illumination and acetone vapors. By experimental and theoretical studies of UV and acetone sensitivities of different SWNT-TiO2 hybrid systems, we established a fundamental understanding on the interfacial charge transfer between photoexcited TiO2 and SWNTs as well as the mechanism of acetone sensing. We further demonstrated a practical application of photoinduced acetone sensitivity by fabricating a microsized room temperature acetone sensor that showed fast, linear, and reversible detection of acetone vapors with concentrations in few parts per million range. PMID- 23734595 TI - Subtype B was the dominant strain among HIV type 1 infections except for the population of men who have sex with men in Harbin City, China. AB - We sought to identify the prevalent subtypes and study the genetic variation of HIV-1 circulating in HIV infections in Harbin City, China. Forty-seven samples from the env V3-V4 region were successfully sequenced and analyzed, which involved thirty-one men who have sex with men (MSM), eight heterosexuals, seven former plasma donors (FPD)/blood transfusion recipients (BT), and one injection drug user (IDU). In all, 46.8% of CRF01_AE, 40.4% of subtype B, and 12.8% of CRF07_BC were identified. CRF01_AE (64.5%) was the dominant strain in MSM, and subtype B (81.2%) was the chief strain in other infected subjects except for the MSM population. Among all the genotypes, the B subtype possesses greater diversity of the tetramer on the tip of V3 loop than CRF07_BC and CRF01_AE, in which the peculiar GWGR was commonly found. Because nationwide there is a trend toward the increasing presence of CRF01_AE, a consecutive surveillance campaign was necessary among all HIV vulnerable populations in this locality. PMID- 23734596 TI - Enzymatic hydrolysis of N-benzoyl-L-tyrosine p-nitroanilide by alpha-chymotrypsin in DMSO-water/AOT/n-heptane reverse micelles. A unique interfacial effect on the enzymatic activity. AB - The reverse micelle (RM) media are very good as nanoreactors because they can create a unique microenvironment for carrying out a variety of chemical and biochemical reactions. The aim of the present work is to determine the influence of different water-dimethyl sulfoxide (DMSO) mixtures encapsulated in 1,4-bis-2 ethylhexylsulfosuccinate (AOT)/n-heptane RMs on the enzymatic hydrolysis of N benzoyl-L-tyrosine p-nitroanilide (Bz-Try-pNA) by alpha-chymotrypsin (alpha-CT). The reaction was first studied in homogeneous media at different DMSO-water mixture compositions and in DMSO-water/AOT/n-heptane RMs. The hydrolysis rates of Bz-Try-pNA catalyzed by alpha-CT were determined by UV-vis spectroscopy. The reaction follows the Michaelis-Menten mechanism and the kinetic parameters: kcat, KM, and kcat/KM were evaluated under different conditions. In this homogeneous media, DMSO plays an important role in the solubilization process of the peptide which is almost insoluble in water, but it has a tremendous impact on the inactivation of alpha-CT. It is shown that the enzyme dissolved in a 20% molar ratio of the DMSO-water mixture does not present enzymatic activity. Dynamic light scattering has been used to assess the formation of DMSO-water/AOT/heptane RMs at different DMSO compositions. The results also show that there is preferential solvation of the AOT RM interface by water molecules. To test the use of these RMs as nanoreactors, the kinetic parameters for the enzymatic reaction in these systems have been evaluated. The parameters were determined at fixed W(S) {W(S) = ([water] + [DMSO])/[AOT] = 20} at different DMSO-water compositions. The results show that the Michaelis-Menten mechanism is valid for alpha-CT in all the RM systems studied and that the reaction takes place at the RM interface. Surprisingly, it was observed that the enzyme encapsulated by the RMs show catalytic effects with similar kcat/KM values at any DMSO composition investigated, which evidence that DMSO molecules are localized far from the RM interface. PMID- 23734597 TI - Ocular comparative anatomy of the family Rodentia. AB - There is little information regarding ocular anatomy and histology in many of the rodent species. Histological analyses for morphologic features were performed in 31 globes from 18 rodent species submitted to and archived at the Comparative Ocular Pathology Laboratory of Wisconsin. The following measurements were taken: thickness of the cornea, corneal epithelium, corneal stroma, Descemet's membrane, and retina. H&E sections were evaluated for the following anatomical features: presence of pigmented epithelial cells in the peripheral cornea, presence and location of Schlemm's canal, presence of iridal sphincter and dilator and ciliary body muscles, presence of pars plicata and plana, presence of retinal vessels, presence of lamina cribrosa, and presence of tapetum lucidum. The springhaas was the only rodent in our collection that presented a well-developed tapetum lucidum fibrosum. The presence of retinal vessels was variable: vessels were observed in all of the members of the mouse-related clade, except the springhaas and the beaver, in all of the squirrel-related clade members, and in none of the Ctenohystrica. In the flying squirrels, blood vessels extended to the outer limiting membrane in the photoreceptor layer. Beavers, chinchillas, capybara, and guinea pigs lacked vessels within the retina; however, they had vessels within the optic nerve head. Ground squirrels have an optic nerve head, which is linear in the horizontal plane and an asymmetric retina. The tree-dwelling squirrels have a rounded but still elongated optic nerve, and the flying squirrel has a round optic nerve head like all the other rodents. PMID- 23734598 TI - Tb(3+)-tRNA for LRET studies of protein synthesis. AB - When suitably labeled bulk tRNAs are transfected into cells they give rise to FRET (fluorescence resonance energy transfer) signals via binding to ribosomes that provide a measure of total protein synthesis. Application of this approach to monitoring rates of specific protein synthesis requires achieving a very high signal-to-noise ratio. Such high ratios may be attainable using LRET (luminescence resonance energy transfer) in place of FRET. Lanthanide complexes containing an antenna chromophore are excellent LRET donors. Here we describe the synthesis of a Phe-tRNA(Phe) labeled with a Tb(3+) complex, denoted Tb(3+)-Phe tRNA(Phe) that, notwithstanding the bulkiness of the Tb(3+) complex, is active in protein synthesis. PMID- 23734599 TI - A task-based approach for Gene Ontology evaluation. AB - BACKGROUND: The Gene Ontology and its associated annotations are critical tools for interpreting lists of genes. Here, we introduce a method for evaluating the Gene Ontology annotations and structure based on the impact they have on gene set enrichment analysis, along with an example implementation. This task-based approach yields quantitative assessments grounded in experimental data and anchored tightly to the primary use of the annotations. RESULTS: Applied to specific areas of biological interest, our framework allowed us to understand the progress of annotation and structural ontology changes from 2004 to 2012. Our framework was also able to determine that the quality of annotations and structure in the area under test have been improving in their ability to recall underlying biological traits. Furthermore, we were able to distinguish between the impact of changes to the annotation sets and ontology structure. CONCLUSION: Our framework and implementation lay the groundwork for a powerful tool in evaluating the usefulness of the Gene Ontology. We demonstrate both the flexibility and the power of this approach in evaluating the current and past state of the Gene Ontology as well as its applicability in developing new methods for creating gene annotations. PMID- 23734600 TI - Familial nonmedullary thyroid carcinoma. AB - BACKGROUND: Nonmedullary thyroid cancers (NMTC) originate from the follicular cells of the thyroid gland and account for over 90% of all thyroid cancers. About 3-10% of the NMTCs are of familial origin, and familial NMTC (FNMTC) is defined as two or more affected first-degree relatives with NMTC in the absence of other known familial syndromes. SUMMARY: The genes involved in the pathogenesis of FNMTC are yet to be elucidated, although some recent studies identified several predisposition loci with a high degree of genetic heterogeneity. To date, several studies have evaluated the aggressive tumor characteristics associated with FNMTC with conflicting results. Several studies demonstrated that patients with FNMTC have increased rates of multifocal disease, extrathyroidal invasion, and involved lymph nodes compared with sporadic disease. It has been hypothesized that this increased aggressiveness translates into higher recurrence rates and decreased survival of patients with FNMTC. CONCLUSION: This review highlights clinical aspects and management dilemmas as well as controversial issues in FNMTC. Management recommendations are deduced. PMID- 23734601 TI - High incidence of prostate cancer metastasis in Afro-Brazilian men with low educational levels: a retrospective observational study. AB - BACKGROUND: This study investigated factors related to ethnicity and educational level, their correlation with tumor stage at the time of diagnosis, and their influence on treatment outcomes in patients with prostate cancer. METHODS: In this retrospective observational study, we analyzed the medical records of 1,349 male patients treated for prostatic adenocarcinoma. We collected information about sociodemographic variables, including educational level and self-reported skin color. We also classified the disease according whether it was to more likely to present with metastasis and measured the tumor response to treatment. RESULTS: Less-educated (<8 years of education) individuals were 4.8 times more likely to develop metastasis than those with more education (>11 years of education; p < 0.001). Similarly, patients with a self-reported black skin color had a 300% increased risk of metastasis at diagnosis (p = 0.001). Distant metastasis was independently correlated with worse outcomes, such that individuals with distant metastasis were 10 times more likely to die than were those without distant metastasis. CONCLUSIONS: Patients with self-reported black skin color and <8 years of education were more likely to display advanced disease at the time of diagnosis compared with their counterparts. Only the presence of metastasis was independently associated with mortality or progressive disease. PMID- 23734602 TI - On the computational modeling of the innate immune system. AB - In recent years, there has been an increasing interest in the mathematical and computational modeling of the human immune system (HIS). Computational models of HIS dynamics may contribute to a better understanding of the relationship between complex phenomena and immune response; in addition, computational models will support the development of new drugs and therapies for different diseases. However, modeling the HIS is an extremely difficult task that demands a huge amount of work to be performed by multidisciplinary teams. In this study, our objective is to model the spatio-temporal dynamics of representative cells and molecules of the HIS during an immune response after the injection of lipopolysaccharide (LPS) into a section of tissue. LPS constitutes the cellular wall of Gram-negative bacteria, and it is a highly immunogenic molecule, which means that it has a remarkable capacity to elicit strong immune responses. We present a descriptive, mechanistic and deterministic model that is based on partial differential equations (PDE). Therefore, this model enables the understanding of how the different complex phenomena interact with structures and elements during an immune response. In addition, the model's parameters reflect physiological features of the system, which makes the model appropriate for general use. PMID- 23734604 TI - Co-operation and conflict under hard and soft contracting regimes: case studies from England and Wales. AB - BACKGROUND: This paper examines NHS secondary care contracting in England and Wales in a period which saw increasing policy divergence between the two systems. At face value, England was making greater use of market levers and utilising harder-edged service contracts incorporating financial penalties and incentives, while Wales was retreating from the 1990 s internal market and emphasising cooperation and flexibility in the contracting process. But there were also cross border spill-overs involving common contracting technologies and management cultures that meant that differences in on-the-ground contracting practices might be smaller than headline policy differences suggested. METHODS: The nature of real-world contracting behaviour was investigated by undertaking two qualitative case studies in England and two in Wales, each based on a local purchaser/provider network. The case studies involved ethnographic observations and interviews with staff in primary care trusts (PCTs) or local health boards (LHBs), NHS or Foundation trusts, and the overseeing Strategic Health Authority or NHS Wales regional office, as well as scrutiny of relevant documents. RESULTS: Wider policy differences between the two NHS systems were reflected in differing contracting frameworks, involving regional commissioning in Wales and commissioning by either a PCT, or co-operating pair of PCTs in our English case studies, and also in different oversight arrangements by higher tiers of the service. However, long-term relationships and trust between purchasers and providers had an important role in both systems when the financial viability of organisations was at risk. In England, the study found examples where both PCTs and trusts relaxed contractual requirements to assist partners faced with deficits. In Wales, news of plans to end the purchaser/provider split meant a return to less precisely-specified block contracts and a renewed concern to build cooperation between LHB and trust staff. CONCLUSIONS: The interdependency of local purchasers and providers fostered long-term relationships and co-operation that shaped contracting behaviour, just as much as the design of contracts and the presence or absence of contractual penalties and incentives. Although conflict and tensions between contracting partners sometimes surfaced in both the English and Welsh case studies, cooperative behaviour became crucial in times of trouble. PMID- 23734605 TI - CLASS: constrained transcript assembly of RNA-seq reads. AB - BACKGROUND: RNA-seq has revolutionized our ability to survey the cellular transcriptome in great detail. However, while several approaches have been developed, the problem of assembling the short reads into full-length transcripts remains challenging. RESULTS: We developed a novel algorithm and software tool, CLASS (Constraint-based Local Assembly and Selection of Splice variants), for accurately assembling splice variants using local read coverage patterns of RNA seq reads, contiguity constraints from read pairs and spliced reads, and optionally information about gene structure extracted from cDNA sequence databases. The algorithmic underpinnings of CLASS are: i) a linear program to infer exons, ii) a compact splice graph representation of a gene and its splice variants, and iii) a transcript selection scheme that takes into account contiguity constraints and, where available, knowledge about gene structure. CONCLUSION: In comparisons against leading transcript assembly programs, CLASS is more accurate on both simulated and real reads and produces results that are easier to interpret when applied to large scale real data, and therefore is a promising analysis tool for next generation sequencing data. AVAILABILITY: CLASS is available from http://sourceforge.net/projects/splicebox. PMID- 23734606 TI - CABG mortality is not influenced by prior PCI in low risk patients. AB - BACKGROUND AND AIMS: An increasing number of patients referred for coronary artery bypass grafting (CABG) have had prior percutaneous coronary intervention (PCI). We sought to determine whether a relationship exists between increased postoperative mortality and morbidity following CABG procedure in patients with prior PCI. METHODS: Over an 18-month period, 950 patients having first-time isolated CABG were divided into two groups based on absence (Group A, 819 patients--86.21%) or presence of a prior PCI (Group B, 131 patients--13.79%). RESULTS: In the prior PCI population, 74 patients (56.4%) had only one stent, and only 6.8% had multiple admissions for PCI. The overall incidence of three vessel disease in the entire patient population was only 65% and the average ejection fraction was 52%. Multivariate analysis demonstrated age (OR 1.080; 95% CI: 1.020 to 1.145; p = 0.009), left ventricular ejection fraction (OR 0.939; 95% CI: 0.901 to 0.978; p = 0.002), and emergency surgery (OR 0.138; 95% CI: 0.0.045 to 0.424; p = 0.001) as risk factors for 30-day mortality, while age (OR 1.059; 95% CI: 1.016 to 1.104; p = 0.007) and emergency surgery (OR 0.205; 95% CI: 0.078 to 0.537; p = 0.001) predicted major adverse cardiac events (MACE). Prior PCI did not influence mortality or MACE at 30 days. CONCLUSION: In this study involving low risk patients, a PCI prior to CABG did not increase morbidity or mortality. PMID- 23734607 TI - Antinociceptive activity and pathway of the pallanalgesin isolated from venom of Agkistrodon halys (Pallas). AB - CONTEXT: Venom of Agkstrodon halys (Pallas) is a traditional Chinese medicine for the control of severe pain, but its analgesic mechanism is not clear. OBJECTIVE: To isolate the analgesic fraction from the venom, evaluate the profile of its action on pain using preclinical nociceptive tests and determine the involvement of neurotransmitters in its action. MATERIALS AND METHODS: Venom was separated with SPXL resin, and further purified by Superdex 75 and Superdex 30 resin. Its biochemical characteristics were analyzed including molecular weight (MW), isoelectric point (pI) and amino acid sequence. Animal pain models were applied including the hot plate test, acetic acid-induced writhing test, formalin test, Randall-Selitto pressure test, antagonistic test, spinalized rats test and intracerebral injection test. The endogenous neuropeptides leucine-enkephalin, beta-endorphin and P substance were determined by HPLC in the tissues of brain and spinal cord. RESULTS: An analgesic protein named pallanalgesin (MW 16.6 kDa, pI 8.8) was obtained from the venom of A. halys. It had significant antinociceptive activity in different animal pain models of thermal, chemical and mechanical stimulation. It effects both central and peripheral nerve systems, and it is related to opiate receptors and monoamines rather than acetylcholine receptors. Pallanalgesin could modulate the levels of neuropeptides in the brain and spinal cord, which contributes to the recovery of nerve injury and pain control. CONCLUSION: As a novel analgesic, pallanalgesin has been found to explain the function of the venom of A. halys on severe pain control in traditional uses, and can be used as a new analgesic in the future. PMID- 23734609 TI - VAMMPIRE: a matched molecular pairs database for structure-based drug design and optimization. AB - Structure-based optimization to improve the affinity of a lead compound is an established approach in drug discovery. Knowledge-based databases holding molecular replacements can be supportive in the optimization process. We introduce a strategy to relate the substitution effect within matched molecular pairs (MMPs) to the atom environment within the cocrystallized protein-ligand complex. Virtually Aligned Matched Molecular Pairs Including Receptor Environment (VAMMPIRE) database and the supplementary web interface ( http://vammpire.pharmchem.uni-frankfurt.de ) provide valuable information for structure-based lead optimization. PMID- 23734608 TI - Multiplex PCR followed by restriction length polymorphism analysis for the subtyping of bovine herpesvirus 5 isolates. AB - BACKGROUND: Several types and subtypes of bovine herpesviruses 1 and 5 (BoHV-1 and BoHV-5) have been associated to different clinical conditions of cattle, making type/subtype differentiation essential to understand the pathogenesis and epidemiology of BoHV infections. BoHV-5 subtyping is currently carried out by BstEII restriction enzyme analysis (REA) of the complete virus genome. This method allowed the description of three subtypes, one of which is the most widespread while the remaining two have so far only been found in South America. The present work describes a multiplex PCR followed by REA for BoHV-5 subtyping. RESULTS: The method consists in the simultaneous amplification of glycoprotein B and UL54 gene fragments of 534 and 669 base pairs (bp), respectively, BstEII digestion of amplicons, separation of products in 1% agarose gels, and analysis of fragment length polymorphims. The multiplex PCR detected up to 227 BoHV-5 genome copies and 9.2 * 105 BoHV-5 genome copies when DNA was extracted from purified virus or infected tissue homogenates, respectively. The applicability of multiplex PCR-REA was demonstrated on 3 BoHV-5 reference strains. In addition, subtyping of two new isolates and seventeen previously reported ones (17 BHV-5a and 2 BHV-5b) by this method gave coincident results with those obtained with the classic BstEII REA assay. CONCLUSIONS: Multiplex PCR-REA provides a new tool for the fast and simple diagnosis and subtyping of BoHV-5. PMID- 23734610 TI - Clinical and microbial impact of screening kidney allograft preservative solution for bacterial contamination with high-sensitivity methods. AB - The clinical and bacteriological consequences of routinely performing highly sensitive bacterial screening of kidney transplant preservation solution (PS) are not known. To evaluate the clinical and microbiological impacts of this strategy, we retrospectively analyzed 200 consecutive kidney allograft recipients from March 2009 to February 2011 for whom PS samples were routinely screened. PS were inoculated into aerobic and anaerobic blood culture bottles, as well as blood agar plates. A rectal swab for extended-spectrum beta-lactamase-producing Enterobacteriaceae (EBSL-PE) faecal carriage was also routinely obtained from each patient at admission and every 7 days until hospital discharge. In addition, a standard culture of drain fluid was collected on the day after kidney transplantation. Complete samples and cultures of PS were performed in 165 cases (82.5%), and 62 (37.6%) had positive blood culture results. The most frequent microbial agent isolated was coagulase-negative staphylococci (51.8%). Of these 62 positive samples, only seven (11.3%) were confirmed to contain the same organism by the standard culture method. Drain fluid and PS culture positivity with the same microorganism occurred in only two patients. Of the 62 patients with positive PS cultures, 26 (41.9%) received pre-emptive antibiotic therapy initiated within 48 h post-transplant. During the hospitalization period, patients with a positive PS culture, regardless of whether they received pre emptive antibiotic therapy, did not exhibit any invasive infections (urinary, blood, peritoneal or wound) related to the microorganisms isolated in the PS. Patients with positive PS cultures who were treated with antibiotic therapy acquired significantly more colonizing ESBL-PE than patients who did not receive antibiotics (53.8% vs. 16.6%; P = 0.01); these patients also developed more clinical infections related to the ESBL-PE (23.1% vs. 5.2%; P < 0.01). The use of antibiotics for patients with positive PS cultures was an independent risk factor for ESBL-PE acquisition in both univariate and multivariate analyses. In conclusion, the use of more sensitive culture methods increases the rate of bacterial contamination of PS and is associated with an increased prescription of antibiotics and increased ESBL-PE carriage and related infections. Therefore, the systematic use of PS blood bottle cultures in kidney transplantation may have no benefit and might increase the rate of ESBL-PE emergence. PMID- 23734611 TI - Development of asymmetric deacylative allylation. AB - Herein we present the development of asymmetric deacylative allylation of ketone enolates. The reaction directly couples readily available ketone pronucleophiles with allylic alcohols using facile retro-Claisen cleavage to form reactive intermediates in situ. The simplicity and robustness of the reaction conditions is demonstrated by the preparation of >6 g of an allylated tetralone from commercially available materials. Furthermore, use of nonracemic PHOX ligands allows intermolecular formation of quaternary stereocenters directly from allylic alcohols. PMID- 23734612 TI - Pd-catalyzed asymmetric allylic alkylation of pyrazol-5-ones with allylic alcohols: the role of the chiral phosphoric acid in C-O bond cleavage and stereocontrol. AB - The combination of a palladium complex with a chiral phosphoramidite ligand and a chiral phosphoric acid enables the first highly efficient asymmetric allylic alkylation of pyrazol-5-ones with allylic alcohols, affording multiply functionalized heterocyclic products in high yields with excellent enantioselectivities that would be of great potential in the synthesis of pharmaceutically interesting molecules. PMID- 23734613 TI - Computerized memory training leads to sustained improvement in visuospatial short term memory skills in children with Down syndrome. AB - This study evaluated the impact of a computerized visuospatial memory training intervention on the memory and behavioral skills of children with Down syndrome. Teaching assistants were trained to support the delivery of a computerized intervention program to individual children over a 10-16 week period in school. Twenty-one children aged 7-12 years with Down syndrome were randomly allocated to either an intervention or waiting list control group. Following training, performance on trained and non-trained visuospatial short-term memory tasks was significantly enhanced for children in the intervention group. This improvement was sustained four months later. These results suggest that computerized visuospatial memory training in a school setting is both feasible and effective for children with Down syndrome. PMID- 23734614 TI - Cognitive flexibility among individuals with Down syndrome: assessing the influence of verbal and nonverbal abilities. AB - The influences of verbal mental age (VMA) and performance mental age (PMA) on cognitive flexibility were examined among a group of participants with Down syndrome (DS), in order to disentangle the relative contributions of each. The impaired cognitive flexibility typically observed among individuals with DS in combination with uneven VMA and PMA development suggests an opportunity to further understand the developmental relationship between VMA, PMA, and cognitive flexibility. We examined the performance of 22 participants with DS on the Flexible Item Selection Task (FIST), used for measuring cognitive flexibility among preschoolers. Partial correlations revealed that only VMA was related to the FIST after controlling for PMA, highlighting the role of verbal abilities in the development of cognitive flexibility. PMID- 23734615 TI - Diurnal cortisol profile in Williams syndrome in novel and familiar settings. AB - Williams syndrome (WS) is a neurodevelopmental genetic disorder associated with high rates of anxiety and social issues. We examined diurnal cortisol, a biomarker of the stress response, in adults with WS in novel and familiar settings, and compared these profiles to typically developing (TD) adults. WS and TD participants had similar profiles in a familiar setting, while participants with WS had elevated cortisol late in the day in the novel setting when social demands were higher. The cortisol awakening response in WS was associated with parent-reported levels of somatic complaints and social difficulties. Results suggest that adults with WS have a typical diurnal cortisol profile that may be sensitive to social and activity transitions throughout the day. PMID- 23734616 TI - The effects of symptom recognition and diagnostic labels on public beliefs, emotional reactions, and stigma [corrected] associated with intellectual disability. AB - Labels are firmly rejected by the disability rights movement, yet the complex effects of labeling on lay beliefs are poorly understood. This study examined the effects of labeling on the general public's reactions to people with intellectual disabilities. A sample of 1,233 adult members of the UK general population were randomly presented with either a diagnostically labeled or unlabeled case vignette, and their emotional reactions, causal beliefs, and social distance were assessed. Providing a label reduced social distance, increased biomedical attributions, and had a small positive direct effect on emotional reactions. Making a diagnosis of mild intellectual disability known may prevent misattribution to more stigmatizing causes and thus reduce social distance. Some undesirable effects were observed though on causal beliefs and associated emotional reactions. PMID- 23734617 TI - Effecting healthy lifestyle changes in overweight and obese young adults with intellectual disability. AB - We evaluated a 12-week recreation center-based healthy lifestyle intervention for 30 obese home-dwelling young adults (YA) with intellectual disabilities. Three cohorts participated: YA only, YA and parents, and parents only. The YA cohorts received a nutrition/exercise intervention; parents focused on modeling healthy lifestyle behaviors. Outcomes included YA blood, nutrition, anthropometric, and fitness measures at pre, post, and 3-month follow-up. Compared with wait-list controls, the YA-only cohort improved immediately postintervention in blood pressure (BP), weight, and balance (p < .05). At 3-month follow-up, no intervention was consistently superior; overall reductions in weight, BP, hip circumference, and exercise barriers were obtained (p < .05). Linear and curvilinear changes from baseline to 3 months after the intervention varied by outcome and participant. Participants with Down syndrome lost less weight. PMID- 23734619 TI - Stabilization of activation induced cytidine deaminase by bortezomib does not confer increased drug target mutation frequency. PMID- 23734620 TI - Cranial irradiation in adults diagnosed with acute myelogenous leukemia presenting with hyperleukocytosis and neurologic dysfunction. AB - This study describes our institution's experience using whole brain radiation therapy (WBRT) to treat patients with acute myelogenous leukemia (AML) presenting with hyperleukocytosis. After approval by the institutional review board, we identified patients with AML and hyperleukocytosis using hospital records. The primary endpoints in the study included alleviation of neurological symptoms (or prevention if prophylactic RT was used), overall survival, development of intracranial hemorrhage (ICH) and >= grade 3 toxicities using the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Eighteen patients received WBRT for the treatment of AML hyperleukocytosis. Thirteen patients received treatment in order to control neurological symptoms. Clinical assessment showed that 12 of 13 patients (92%) achieved resolution of neurological symptoms either concurrent with RT or immediately after RT. The mean overall survival for all of the patients who received WBRT was 14.2 months (95% confidence interval, 5.4-23.0). No patient who received RT experienced >= grade 3 toxicity. Two (6%) patients developed ICH following therapy. Our institution's experience demonstrates that WBRT may be utilized as part of multimodality therapy in order to alleviate or prevent neurological symptoms in patients with AML presenting with leukostasis. PMID- 23734621 TI - Swarming behavior of gradient-responsive colloids with chemical signaling. AB - The article describes swarm dynamics of a system composed of colloidal particles that release chemical signals to navigate their peers toward the location of a static point target in two dimensions. The time evolution of the system is calculated by employing a combination of Brownian dynamics method for the particle motion and the diffusion problem for spatial transport of chemical signals, coupled via diffusiophoresis. A parametric study is performed with respect to crucial model parameters that control the diffusivity of the particles and the chemical signals. This includes the initial concentration of chemical signals carried by the particles, the chemical signal release rate, the diffusion coefficient of the chemical signals, the diffusiophoretic mobility of the particles, and the topological complexity of the surrounding environment. Three measures are used to evaluate the performance of the system: the target arrival time, the target localization success rate, and the target residence time. Since the particle motion is determined by the local concentration gradients of the chemical signals, parameter values that result in steep and durable concentration gradients lead to the best performance in navigating a swarm of colloidal particles toward the target. However, the results show that a trade-off principle exists, as it is not always possible to improve all the performance criteria simultaneously. For a topologically complex environment, the particles often become trapped in areas where the chemical signals accumulate, leading to a significant decrease in the localization success rate. PMID- 23734622 TI - Biotea: RDFizing PubMed Central in support for the paper as an interface to the Web of Data. AB - BACKGROUND: The World Wide Web has become a dissemination platform for scientific and non-scientific publications. However, most of the information remains locked up in discrete documents that are not always interconnected or machine-readable. The connectivity tissue provided by RDF technology has not yet been widely used to support the generation of self-describing, machine-readable documents. RESULTS: In this paper, we present our approach to the generation of self describing machine-readable scholarly documents. We understand the scientific document as an entry point and interface to the Web of Data. We have semantically processed the full-text, open-access subset of PubMed Central. Our RDF model and resulting dataset make extensive use of existing ontologies and semantic enrichment services. We expose our model, services, prototype, and datasets at http://biotea.idiginfo.org/ CONCLUSIONS: The semantic processing of biomedical literature presented in this paper embeds documents within the Web of Data and facilitates the execution of concept-based queries against the entire digital library. Our approach delivers a flexible and adaptable set of tools for metadata enrichment and semantic processing of biomedical documents. Our model delivers a semantically rich and highly interconnected dataset with self-describing content so that software can make effective use of it. PMID- 23734623 TI - Climate change adaptation through urban heat management in Atlanta, Georgia. AB - This study explores the potential effectiveness of metropolitan land cover change as a climate change adaptation strategy for managing rising temperatures in a large and rapidly warming metropolitan region of the United States. Through the integration of a mesoscale meteorological model with estimated land cover data for the Atlanta, Georgia region in 2010, this study quantifies the influence of extensive land cover change at the periphery of a large metropolitan region on temperature within the city center. The first study to directly model a metropolitan scale heat transfer mechanism, we find both enhanced tree canopy and impervious cover in the suburban zones of the Atlanta region to produce statistically significant cooling and warming effects in the urban core. Based on these findings, we conclude that urban heat island management both within and beyond the central developed core of large cities may provide an effective climate change adaptation strategy for large metropolitan regions. PMID- 23734624 TI - Short outpatient pulmonary rehabilitation programme reduces readmission following a hospitalization for an exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: The benefits of pulmonary rehabilitation (PR) are now firmly established. However, less is known about the provision and efficacy of PR immediately after an acute exacerbation of chronic obstructive pulmonary disease (COPD). The study aimed to explore the effectiveness of a short outpatient PR programme and the impact upon readmission rates. METHODS: One hundred sixty (87 males) patients, mean (SD) age 70.35 (8.59) years, forced expiratory volume in 1 s 0.99 (0.44) litres were assessed for a 7-week PR programme following a hospital admission for an acute exacerbation of COPD. Patients were assessed and commenced PR within 4 weeks of discharge from hospital. Outcome measures included: Incremental Shuttle Walking Test (ISWT), Endurance Shuttle Walk Test (ESWT), Chronic Respiratory Questionnaire Self-Reported (CRQ-SR). Patients were assessed at baseline and at 7 weeks (after the 4-week supervised and 3-week unsupervised components). Readmission data were collected retrospectively for the 12 months pre and post admission (n = 155). RESULTS: Statistically significant improvements were found in the ISWT, ESWT and CRQ-SR at discharge (P < 0.05). The number of admission was significantly less in the 12-month post-pulmonary rehabilitation compared to the previous 12 months. CONCLUSIONS: A short course of PR showed improvements in exercise capacity and health status in patients who have had an acute exacerbation of COPD. The number of readmissions was also significantly lower in the year following PR. PMID- 23734625 TI - Obesity: a systematic review on parental involvement in long-term European childhood weight control interventions with a nutritional focus. AB - In Europe, about 20% of children are overweight. Focus on parental responsibility is an effective method in weight control interventions in children. In this systematic review we describe the intensity of parental involvement and behaviour change aimed at parents in long-term European childhood weight control interventions. We include European Union studies targeting parents in order to improve children's weight status in multi-component (parental, behaviour change and nutrition) health promotion or lifestyle interventions. The included studies have at least one objectively measured anthropometric outcome in the weight status of the child. Parental involvement was described and categorized based on the intensity of parental involvement and coded using a validated behaviour change taxonomy specific to childhood obesity. Twenty-four studies were analysed. In effective long-term treatment studies, medium and high intensity parental involvement were identified most frequently; whereas in prevention studies low intensity parental involvement was identified most frequently. Parenting skills, generic and specific to lifestyle behaviour, scored frequently in effective weight control interventions. To list parental skills in generic and specific to lifestyle, descriptions of the included studies were summarized. We conclude that intensity of parental involvement and behaviour change techniques are important issues in the effectiveness of long-term childhood weight control interventions. PMID- 23734626 TI - Evaluation of four point-of-care glucose meters in alpacas. AB - PURPOSE: Hospitalized alpacas are often hyperglycemic requiring frequent blood glucose testing. OBJECTIVES: To compare the performance of 4 brands of glucometers with a laboratory-based analyzer (LCA) over a range of glucose concentrations in alpacas. ANIMALS: Four healthy male alpacas. METHODS: A 2 treatment cross-over study was utilized. The alpacas were given 0.4 U/kg of regular insulin intravenously and then 500 mg/kg of dextrose intravenously with a 1 week washout period between treatments. Blood samples were collected from 10 minutes before until 6 hours after drug administration. Glucose concentrations were measured in whole blood and plasma samples on 4 glucometers, and serum glucose was measured on an LCA. RESULTS: Glucometer performance varied depending on whether glucose concentrations were measured in plasma or whole blood. Based on error grid analysis, the Precision Xtra and One Touch Ultra 2 glucometers were clinically acceptable for testing whole blood samples, whereas the Accu-Chek Aviva and Nova StatStrip Xpress glucometers were clinically acceptable for testing plasma samples in comparison with serum glucose concentrations determined by the LCA. All glucometers had systematic and proportional biases that varied based on sample type. CONCLUSIONS AND CLINICAL IMPORTANCE: Human-based glucometers in alpacas should be used cautiously, particularly at higher blood glucose concentrations. The blood sample type (plasma or whole blood) can alter meter performance when compared with serum glucose concentrations and potentially lead to errors in clinical decisions. PMID- 23734627 TI - A novel min-cost flow method for estimating transcript expression with RNA-Seq. AB - BACKGROUND: Through transcription and alternative splicing, a gene can be transcribed into different RNA sequences (isoforms), depending on the individual, on the tissue the cell is in, or in response to some stimuli. Recent RNA-Seq technology allows for new high-throughput ways for isoform identification and quantification based on short reads, and various methods have been put forward for this non-trivial problem. RESULTS: In this paper we propose a novel radically different method based on minimum-cost network flows. This has a two-fold advantage: on the one hand, it translates the problem as an established one in the field of network flows, which can be solved in polynomial time, with different existing solvers; on the other hand, it is general enough to encompass many of the previous proposals under the least sum of squares model. Our method works as follows: in order to find the transcripts which best explain, under a given fitness model, a splicing graph resulting from an RNA-Seq experiment, we find a min-cost flow in an offset flow network, under an equivalent cost model. Under very weak assumptions on the fitness model, the optimal flow can be computed in polynomial time. Parsimoniously splitting the flow back into few path transcripts can be done with any of the heuristics and approximations available from the theory of network flows. In the present implementation, we choose the simple strategy of repeatedly removing the heaviest path. CONCLUSIONS: We proposed a new very general method based on network flows for a multiassembly problem arising from isoform identification and quantification with RNA-Seq. Experimental results on prediction accuracy show that our method is very competitive with popular tools such as Cufflinks and IsoLasso. Our tool, called Traph (Transcrips in gRAPHs), is available at: http://www.cs.helsinki.fi/gsa/traph/. PMID- 23734628 TI - A pilot study of a school-based prevention and early intervention program to reduce oppositional defiant disorder/conduct disorder. AB - Oppositional defiant disorder (ODD) or conduct disorder (CD) occurs when children's disruptive and antisocial behaviours start to interfere with their academic, emotional and/or social development. Recently, there has been a considerable investment to implement national school-based early intervention programs to help prevent the onset of ODD/CD. AIM: This paper describes the delivery of the Royal Children's Hospital, Child and Adolescent Mental Health Service and Schools Early Action Program: a whole school, multi-level, multidisciplinary approach to address emerging ODD/CD and pre- versus post delivery assessment in 40 schools over a 4-year period (2007-2010). METHODS: All children from preparatory to grade 3 (ages 4-10 years) were screened for conduct problems (n = 8546) using the Strengths and Difficulties Questionnaire. Universal, targeted and indicated interventions were delivered in school settings. In total, 304 children participated in the targeted group program where the Child Behaviour Checklist was used as a pre- and post-intervention measure. Cohen's d effect sizes and a reliability change index were calculated to determine clinical significance. RESULTS: Significant reductions in both parent- and teacher-reported internalizing and externalizing symptoms were noted. Parent, teacher and child feedback were very positive. CONCLUSIONS: A future randomized controlled trial of the program would address potential placebo and selection bias effects. PMID- 23734629 TI - How oligoclonal are germinal centers? A new method for estimating clonal diversity from immunohistological sections. AB - BACKGROUND: The germinal center (GC) reaction leads to antibody affinity maturation and generation of memory B cells, but its underlying mechanisms are poorly understood. To assemble this puzzle, several key pieces of information are needed, one in particular being the number of participating B cell clones. Since this clonal diversity cannot be observed directly, earlier studies resorted to interpreting two types of available experimental data: Immunohistology of GCs containing two phenotypically distinct B-cell populations, and antibody gene sequences of small B-cell samples from GCs. Based on a simple model, investigators concluded that a typical GC was seeded by 2-8 B cells, endorsing the current notion that GCs are oligoclonal from the onset. RESULTS: A re evaluation of these data showed that the used simple model is not statistically consistent with the original data. From an analysis of the experimental system, we propose a new model for estimating GC clonal diversity, including the initially neglected sampling and measurement errors, and making more general assumptions. Consistency analysis with the new model yielded an estimation of sampling and measurement errors in the experimental data of 10-11% for one B-cell population and 62-64% for the other population, and an average number of 19-23 seeder B cells. An independent analysis of antibody gene sequences of small B cell samples from GCs, using an adapted Yule estimator of diversity, yielded a minimum estimation of 20-30 GC founder B cells, confirming the previous results. CONCLUSIONS: Our new experimental-based model provides a highly improved method to estimate the clonal diversity of GCs from immunohistochemistry data of chimeric animals. Calculations based on this model, and validated by an independent approach, indicate that GCs most likely contain broadly varying numbers of different B cell clones, averaging 5- to 10-fold more clones than previously estimated. These findings, in line with recent results showing that GC sizes and life times are also subject to high variability, dramatically change the picture of GC dynamics. PMID- 23734630 TI - Brain metastases from thyroid carcinoma: a retrospective study of 21 patients. AB - BACKGROUND: Brain metastases (BM) from differentiated thyroid carcinoma (DTC) are uncommon, and many questions about their management remain unsolved. The objective of this retrospective study was to analyze the characteristics, treatments, and outcomes of patients with BM from DTC. METHODS: Among the 1523 patients with a DTC prospectively recorded in institutional databases between 1989 and 2012, 21 patients (1.4%) with BM were retrospectively retrieved. Patient characteristics, histological findings on initial thyroidectomy specimen, treatments, and time to death were reviewed. Overall survival (OS) was calculated using the Kaplan-Meier method. Survival curves for various subgroups of patients according to baseline characteristics and treatment received were compared. RESULTS: The mean age at initial and BM diagnosis was, respectively, 52.7 and 63.2 years. World Health Organization performance status (PS) at BM diagnosis was good (<2) for 12 patients and poor (>=2) for 9. The initial carcinoma was papillary for 12 patients, follicular for 5, and poorly differentiated for 4. Eighteen patients had other previous and/or synchronous distant metastases: lung (11), bone (10), and others (2 peritoneum, 1 liver, 1 adrenal gland, and 1 uterine cervix). The average interval between the first metastasis and the BM was 3 years (range 0-35.6 years). The mean number and the mean size of BM were, respectively, 2.8 (range 1-10) and 22.5 mm (range 3-44 mm). Surgery was performed for 10 patients and radiotherapy (RT) for 18, with 2 stereotactic radiosurgery (SRS), 2 conformal RT limited to the metastasis, and 15 whole-brain RT. The median OS after BM was 7.1 months. OS at 1 and 2 years were 41.6% and 35.6%. PS and realization of surgery or SRS had an impact on survival, with OS of 27 months when PS <2 versus 3 months when PS >=2 (p=0.0009), and OS of 11.9 months after surgery or SRS versus 3.6 months in their absence (p=0.04). CONCLUSIONS: BM from thyroid cancer may have an indolent evolution with survival of one to two years or longer for specific groups of patients. Therefore, aggressive treatment options such as neurosurgery and RT should be strongly considered in patients with good PS. PMID- 23734631 TI - How managed a market? Modes of commissioning in England and Germany. AB - BACKGROUND: In quasi-markets governance over healthcare providers is mediated by commissioners. Different commissioners apply different combinations of six methods of control ('media of power') for exercising governance: managerial performance, negotiation, discursive control, incentives, competition and juridical control. This paper compares how English and German healthcare commissioners do so. METHODS: Systematic comparison of observational national level case studies in terms of six media of power, using data from multiple sources. RESULTS: The comparison exposes and contrasts two basic generic modes of commissioning: 1. Surrogate planning (English NHS), in which a negotiated order involving micro-commissioning, provider competition, financial incentives and penalties are the dominant media of commissioner power over providers. 2. Case mix commissioning (Germany), in which managerial performance, an 'episode based' negotiated order and juridical controls appear the dominant media of commissioner power. CONCLUSIONS: Governments do not necessarily maximise commissioners' power over providers by implementing as many media of power as possible because these media interact, some complementing and others inhibiting each other. In particular, patient choice of provider inhibits commissioners' use of provider competition as a means of control. PMID- 23734632 TI - The Gutenberg Health Study: measuring psychosocial factors at work and predicting health and work-related outcomes with the ERI and the COPSOQ questionnaire. AB - BACKGROUND: Several instruments have been developed to assess psychosocial workload. We compared two of these instruments, the Effort-Reward Imbalance (ERI) model and the Copenhagen Psychosocial Questionnaire (COPSOQ) with regard to congruent validity and internal validity. METHODS: This analysis is based on a population-based sample of the baseline examination of 2,783 employees from the Gutenberg Health Study (GHS). About half of the participants completed the ERI questionnaire (n = 1,342), the other half completed the COPSOQ (n = 1,441). First, the two samples were compared and descriptive analyses were carried out calculating mean values for both instruments in general, then separately for age, gender and main occupational groups. Second, we analyzed the relationship between ERI and COPSOQ scales on the workplace situation and on the workplace outcomes: job satisfaction, general health, burnout, satisfaction with life, by applying stepwise logistic regression analysis. RESULTS AND DISCUSSION: For the majority of occupations, high effort as reflected by the ERI corresponded with high demands as reflected by the COPSOQ. Comparably, high reward (according to ERI) yielded a good agreement with high "influence and development" (according to COPSOQ). However, we could also find differences between ERI and COPSOQ concerning the intensity of psychosocial workload in some occupations (e.g., physicians/pharmacists or warehouse managers/warehousemen/transport workers). These differences point to differing theoretical concepts of ERI and COPSOQ. When the ability of ERI and COPSOQ was examined to determine the associations with health and work outcomes, burnout could be better predicted by the COPSOQ; this might be due to the fact that COPSOQ comprises the constructs "work-privacy conflict" and "emotional demand", which are closely related to burnout. However, methodological differences between these instruments limit their direct comparability. CONCLUSIONS: The ERI and COPSOQ instrument yielded similar results for most occupational groups. The slightly stronger association between psychosocial workload as assessed by COPSOQ and burnout might be explained by its broader approach. The ability of the ERI and COPSOQ instrument to reflect relevant risk factors for clinically manifest disorders (e.g., coronary heart disease) will be derived from subsequent prospective analyses of the GHS with the follow-up data. PMID- 23734633 TI - Monitoring behaviour in a time-based prospective memory task: the involvement of executive functions and time perception. AB - This study investigated time-based prospective memory (PM) performance in 76 younger and 76 older adults with a time-monitoring task in which participants were required to press a designated key every 5 minutes while watching a movie. Participants were assigned to two conditions, free and fixed monitoring. In free monitoring participants could check a clock when they wanted, but in fixed monitoring they were restricted a maximum of six times every 5 minutes. We also investigated the involvement of time perception, inhibition, and updating in time based PM performance. We hypothesised that participants with inefficiencies in those three cognitive functions would have less strategic monitoring behaviour and would also be less accurate at the target time. In the free-monitoring condition older adults checked the clock more frequently than younger participants, but presented with a similar pattern of monitoring behaviour and increased their frequency of clock checking closer to the target time. In the fixed-monitoring condition younger participants checked the clock more frequently than older adults and showed a strategic pattern of monitoring. Older adults did not show strategic use of clock checking and their monitoring function remained unchanged. Differences in PM accuracy and monitoring behaviour are discussed according to different involvement of cognitive abilities. PMID- 23734635 TI - Drug use and treatment success among gang and non-gang members in El Salvador: a prospective cohort study. AB - BACKGROUND: This article focuses on examining drug abuse treatment (DAT) in El Salvador highlighting gang vs. non-gang membership differences in drug use and treatment outcomes. METHODS: Cross-sectional and prospective cohort designs were employed to examine the study aims. The 19 centers that met the study's inclusion criteria of one year or less in planned treatment offered varying treatment services: individual, group, family, and vocational therapy, dual diagnosis treatment, psychological testing, 12-step program, and outreach and re-entry aftercare. Most directors describe their treatment approach as "spiritual." Data were collected from 625 patients, directors, and staff from the 19 centers at baseline, of which 34 patients were former gang members. Seventy-two percent (72%) of the former patients (448) were re-interviewed six-months after leaving treatment and 48% were randomly tested for drug use. RESULTS: Eighty-nine percent (89%) of the DAT patients at baseline were classified as heavy alcohol users and 40% were using illegal drugs, i.e., crack, marijuana, cocaine, tranquilizers, opiates, and amphetamines. There were large decreases after treatment in heavy alcohol and illegal drug use, crime, and gang related risk activities. Gang members reported illegal drug use, crime, and gang related risk activity more than non-gang members, yet only 5% of the study participants were gang members; further, positive change in treatment outcomes among gang members were the same or larger as compared to non-gang members. CONCLUSIONS: Alcohol use is the drug of choice among DAT patients in El Salvador with gang member patients having used illegal drugs more than non-gang members. The study shows that DAT centers successfully reduced the use of illegal drugs and alcohol among gang and non-gang members. Although our study could not include a control group, we believe that the DAT treatment centers in El Salvador contributed to producing this treatment success among former patients. These efforts should be continued and complemented by funding support from the Salvadoran government for DAT centers that obtain certification. In addition, tailored/alternative treatment modalities are needed for gang members in treatment for heavy drinking. PMID- 23734636 TI - Linearly distributed syringoma: a case report. PMID- 23734634 TI - The sigma2 receptor: a novel protein for the imaging and treatment of cancer. AB - The sigma2 receptor is an important target for the development of molecular probes in oncology because of its 10-fold higher density in proliferating tumor cells compared with that in quiescent tumor cells and because of the observation that sigma2 receptor agonists are able to kill tumor cells via apoptotic and nonapoptotic mechanisms. Although recent evidence indicates that the sigma2 receptor binding site is localized within the progesterone receptor membrane component 1 (PGRMC1), most information regarding this protein has been obtained using either radiolabeled or fluorescent receptor-based probes and from biochemical analysis of the effect of sigma2 selective ligands on cells grown in culture. This article reviews the development of sigma2 receptor ligands and presents an overview of how they have been used in vitro and in vivo to increase our understanding of the role of the sigma2 receptor in cancer and proliferation. PMID- 23734637 TI - The role of histamine in neurogenic inflammation. AB - The term 'neurogenic inflammation' has been adopted to describe the local release of inflammatory mediators, such as substance P and calcitonin gene-related peptide, from neurons. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established. The aim of this review is to summarize the most recent findings on the role of histamine in neurogenic inflammation, with particular regard to nociceptive pain, as well as neurogenic inflammation in the skin, airways and bladder. PMID- 23734638 TI - Synovial deposition of wild-type transthyretin-derived amyloid in knee joint osteoarthritis patients. AB - OBJECTIVE: To investigate histological features of deposited amyloid in the synovial tissue and its clinical significance in knee joint osteoarthritis (OA) patients. METHODS: We prospectively enrolled 232 consecutive patients who underwent arthroplasty or total replacement of the knee joint for treatment of OA. Congo red staining and immunohistochemistry were performed in the synovial tissue obtained at surgery. When transthyretin (TTR)-derived amyloid was positive, we analyzed all 4 exons of the TTR gene using the direct DNA sequencing method in order to detect mutations. RESULTS: We analyzed 322 specimens in this study. Twenty-six specimens (8.1%) obtained from 21 patients (5 men and 16 women; mean, 79.0 +/- 4.6 years) showed deposition of amyloid, which was positively stained with the anti-TTR antibody. Eighteen patients showed inhomogeneous accumulations of amyloid in the loose connective tissue under the synovial epithelia sometimes with nodule formation, while in the remaining three, small vessels in the adipose tissue were involved. Medical records of these patients revealed nothing remarkable in the clinical course, laboratory data or macroscopic intraarticular findings at surgery. No mutations were detectable in the TTR gene analysis. CONCLUSION: Wild-type TTR-derived amyloid may affect the synovial tissue as a result of long-term mechanical stress or as a part of senile systemic amyloidosis in approximately 8% of knee joint OA patients. No obvious clinical significance was found in synovial deposition of amyloid. PMID- 23734639 TI - Pd/C-catalyzed synthesis of oxamates by oxidative cross double carbonylation of amines and alcohols under co-catalyst, base, dehydrating agent, and ligand-free conditions. AB - This work reports a mild, efficient, and ligand-free Pd/C-catalyzed protocol for the oxidative cross double carbonylation of amines and alcohols. Notably, the reaction does not requires any base, co-catalyst, dehydrating agent, or ligand. Pd/C solves the problem of catalyst recovery, and the catalyst was recycled up to six times. PMID- 23734640 TI - First-principles calculation of dielectric response in molecule-based materials. AB - The dielectric properties of materials are of fundamental significance to many chemical processes and the functioning of numerous solid-state device technologies. While experimental methods for measuring bulk dielectric constants are well-established, far less is known, either experimentally or theoretically, about the origin of dielectric response at the molecular/multimolecular scale. In this contribution we report the implementation of an accurate first-principles approach to calculating the dielectric response of molecular systems. We assess the accuracy of the method by reproducing the experimental dielectric constants of several bulk pi-electron materials and demonstrating the ability of the method to capture dielectric properties as a function of frequency and molecular orientation in representative arrays of substituted aromatic derivatives. The role of molecular alignment and packing density on dielectric response is also examined, showing that the local dielectric behavior of molecular assemblies can diverge significantly from that of the bulk material. PMID- 23734641 TI - Why are women more vulnerable to chronic obstructive pulmonary disease? PMID- 23734642 TI - The association between body shape and nontuberculous mycobacterial lung disease. PMID- 23734644 TI - Lung protective ventilation: a summary of the current evidence from the 2012 American Association for Respiratory Care International Congress. AB - Over 150 invited experts presented to almost 6000 participants at the most recent American Association for Respiratory Care International Congress. These participants represented a broad international audience with a range of expertise that included respiratory therapists, physicians, nurses and others. While the program incorporated an extensive curriculum, the theme of lung protective ventilation was highlighted throughout the Congress. Experts reviewed the current evidence regarding the risk for ventilator-induced lung injury in mechanically ventilated patients without pre-existing lung disease and in those with acute lung injury. In addition, several experts reviewed the cutting edge approach of extracorporeal membrane oxygenation as a lung protective approach. PMID- 23734645 TI - Recent advances in alpha-1-antitrypsin deficiency-related lung disease. AB - alpha-1-antitrypsin deficiency (A1ATD) is an under-recognized hereditary disorder associated with the premature onset of chronic obstructive pulmonary disease. There is considerable heterogeneity in the phenotypic expression of lung disease in A1ATD and the pathophysiology is complex, involving the interaction of multiple pathways. Other genetic factors that may contribute to emphysema risk in A1AT-deficient individuals are beginning to be identified. Methods of monitoring disease progression have evolved, including the use of computed tomography densitometry and biomarkers of disease activity. Progress in the development of novel treatment strategies continues, including the hope for a potential cure through the use of gene therapies. In this article, the authors review the recent advances in this field and outline potential future directions of research in A1ATD. PMID- 23734648 TI - The use of ambulatory strategies for the diagnosis and treatment of obstructive sleep apnea in adults. AB - Obstructive sleep apnea (OSA) is a highly prevalent disorder associated with complications such as arterial hypertension, coronary heart disease, cerebrovascular disease and traffic accidents. Patients with untreated OSA consume more financial and healthcare resources and have higher mortality than those treated properly. The resources allocated for OSA are insufficient in some countries for such a prevalent disorder. This has given rise to a significant public health problem and a search for alternative strategies based on the ambulatory management. In the diagnostic process, portable monitors have been evaluated. Continuous positive airway pressure is the most effective treatment in OSA, but other forms of treatments have also been used (weight loss, oral appliances, surgery and so on). Ambulatory monitoring of the therapeutic modalities has been evaluated to enhance the care process and reduce costs compared with the conventional approach, without sacrificing efficiency. This review aims to highlight the most important advances in this field, analyzing the results of the main works to date, in order to assess the current situation and future research needs. PMID- 23734646 TI - Novel end points for clinical trials in young children with cystic fibrosis. AB - Cystic fibrosis (CF) lung disease commences early in the disease progression and is the most common cause of mortality. While new CF disease-modifying agents are currently undergoing clinical trial evaluation, the implementation of such trials in young children is limited by the lack of age-appropriate clinical trial end points. Advances in infant and preschool lung function testing, imaging of the chest and the development of biochemical biomarkers have led to increased possibility of quantifying mild lung disease in young children with CF and objectively monitoring disease progression over the course of an intervention. Despite this, further standardization and development of these techniques is required to provide robust objective measures for clinical trials in this age group. PMID- 23734647 TI - The role of the bacterial microbiome in lung disease. AB - Novel culture-independent techniques have recently demonstrated that the lower respiratory tract, historically considered sterile in health, contains diverse communities of microbes: the lung microbiome. Increasing evidence supports the concept that a distinct microbiota of the lower respiratory tract is present both in health and in various respiratory diseases, although the biological and clinical significance of these findings remains undetermined. In this article, the authors review and synthesize published reports of the lung microbiota of healthy and diseased subjects, discuss trends of microbial diversity and constitution across disease states, and look to the extrapulmonary microbiome for hypotheses and future directions for study. PMID- 23734649 TI - Recent advances in understanding inflammation and remodeling in the airways in chronic obstructive pulmonary disease. AB - The authors have reviewed the current literature on airway inflammation and remodeling in smoking-related chronic obstructive pulmonary disease (COPD). Detailed data on airway remodeling in COPD are especially sparse and how these changes lead to decline in lung function is not well understood. Small airway fibrosis and obliteration are likely to be the main contributors to physiological airway dysfunction and occur earlier than any subsequent development of emphysema. One potential mechanism contributing to small airway fibrosis/obliteration and change in extracellular matrix is epithelial mesenchymal transition. When associated with angiogenesis (so-called epithelial mesenchymal transition type 3) it may well also be the link with the development of cancer, which is closely associated with COPD, predominantly in large airways. The authors have focused on our recent publications in these areas. Further investigations teasing out these mechanisms will help improve our understanding of key airway disease processes in COPD, which may have major therapeutic implications. PMID- 23734650 TI - Bronchiolitis: adopting a unifying definition and a comprehensive etiological classification. AB - Bronchiolitis is an inflammatory and potentially fibrosing condition affecting mainly the intralobular conducting and transitional small airways. Secondary bronchiolitis participates in disease process of the airways and/or the surrounding lobular structures in the setting of several already defined clinical entities, mostly of known etiology, and occurs commonly. Primary or idiopathic bronchiolitis dominates and characterizes distinct clinical entities, all of unknown etiology, and occurs rarely. Secondary bronchiolitis regards infections, hypersensitivity disorders, the whole spectrum of smoking-related disorders, toxic fumes and gas inhalation, chronic aspiration, particle inhalation, drug induced bronchiolar toxicities, sarcoidosis and neoplasms. Idiopathic or primary bronchiolitis defines clinicopathologic entities sufficiently different to be designated as separate disease entities and include cryptogenic constrictive bronchiolitis, diffuse panbronchiolitis, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, neuroendocrine hyperplasia in infants, bronchiolitis obliterans syndrome in lung and allogeneic hematopoietic cell transplantation, connective tissue disorders, inflammatory bowel disease and bronchiolitis obliterans organizing pneumonia. Most of the above are pathological descriptions used as clinical diagnosis. Acute bronchiolitis, though potentially life threatening, usually regresses. Any etiology chronic bronchiolitis contributes to morbidity and/or mortality if it persists and/or progresses to diffuse airway narrowing and distortion or complete obliteration. Bronchiolitis in specific settings leads to bronchiolectasis, resulting in bronchiectasis. PMID- 23734651 TI - The misuse of asthma drugs. AB - There are three major problems with asthma care in the USA and misuse of asthma drug therapy contributes to each. Asthma patients suffer from symptoms regularly partly because healthcare providers do not understand the Expert Panel Report III (EPR3) recommendations on assessing asthma symptoms to determine drug treatment and, consequently, undertreat the disease. Asthma patients experience exacerbations often in part because the EPR3 provides limited guidance on using exacerbation risk to guide asthma treatment, again leading to undertreatment. The EPR3 recommends inhaled corticosteroids as the preferred therapy for mild persistent asthma but American healthcare providers disregard this recommendation based on different perceptions about the risks and benefits of inhaled corticosteroids and choose drug treatments with higher healthcare costs. PMID- 23734653 TI - Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone is beneficial but toxic in very elderly patients with diffuse large B-cell lymphoma: a population-based cohort study on treatment, toxicity and outcome. AB - To assess treatment strategies, toxicity and outcome in very elderly patients (aged >= 75 years) diagnosed with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, an observational population-based cohort study was performed. From 103 patients with a median age of 81 years, data of clinical characteristics, treatment, toxicity and outcome were evaluated. Advanced stage DLBCL was documented in 74 patients. In 80 patients chemotherapy was initiated; 70 patients received rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). In this group, 39 patients completed all cycles and 30 patients achieved a complete remission. Severe chemotherapy-related toxicity occurred in 69%. Two-year overall survival was 70% for elderly patients who completed chemotherapy, 28% for those treated with incomplete or suboptimal chemotherapy and 21% for those receiving palliative radiotherapy or supportive care. In conclusion, the ability to complete R-CHOP was associated with better overall survival compared to other treatment strategies at the expense of severe treatment-related toxicity. PMID- 23734654 TI - Treatment of primary mediastinal B-cell lymphoma with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone is associated with a high rate of primary refractory disease. AB - The optimal therapy for primary mediastinal B-cell lymphoma is a subject of ongoing debate, with no accepted standard of care. We performed a retrospective analysis of 63 patients in the modern era treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), with or without radiation. Median age was 37 years (range 20-82). Eighty percent had limited stage disease and 71% were bulky. By age-adjusted International Prognostic Index (IPI), 15% were low-risk, 52% low-intermediate, 27% high intermediate and 6% high-risk. Some 77% of responding patients received consolidative radiotherapy. Overall and complete response rates were 79% and 71%. Primary induction failure occurred in 13 (21%) patients. Five-year PFS and OS were 68% and 79%, respectively. Adverse prognostic features included increased IPI, advanced stage, advanced age and multiple extranodal sites. These data demonstrate an unacceptably high rate of primary refractory disease on R-CHOP, particularly among patients with high-risk features. Novel treatment approaches are needed that reduce primary refractory disease and reliance on mediastinal radiation in young people. PMID- 23734655 TI - Inhibition of autophagy augments the anticancer activity of alpha-mangostin in chronic myeloid leukemia cells. AB - Natural products possessing anticancer activity have been extensively studied because of their low toxicity and potential effect. alpha-Mangostin, a component of Garcinia mangostana Linn, is a xanthone derivative shown to have antioxidant and antitumor properties. This study was carried out to investigate how to improve the anticancer effects of alpha-mangostin in chronic myeloid leukemia (CML) cell lines bearing wild-type BCR-ABL or BCR-ABL-T315I mutation. We showed that alpha-mangostin inhibited cell proliferation of K562, KBM5 and KBM5-T315I cells in both a time- and dose-dependent manner. Significantly, alpha-mangostin increased the number of apoptotic cells and induced DNA fragmentation compared to control cells. Moreover, alpha-mangostin selectively inhibited proliferation in primary CML cells, while showing limited lethality in normal hematopoietic progenitors. Additionally, alpha-mangostin induced not only apoptosis but also autophagy in CML cells. alpha-Mangostin dramatically increased the expression levels of LC-3II, an autophagosome marker in mammals, and the accumulation of autophagic vacuoles (AVs). Inhibition of autophagy by chloroquine enhanced alpha mangostin-mediated cytotoxicity through increasing apoptosis. Taken together, our data suggest that targeting the autophagy pathway is a promising therapeutic strategy to enhance alpha-mangostin-induced apoptosis. Our study provides an approach for future studies to explore this combination for the treatment of CML. PMID- 23734656 TI - Mouse LSTRA leukemia as a model of human natural killer T cell and highly aggressive lymphoid malignancies. PMID- 23734657 TI - Inherited susceptibility to chronic lymphocytic leukemia: the good candidates. PMID- 23734658 TI - The use of 90yttrium-ibritumomab tiuxetan in patients on dialysis: what do we know regarding its pharmacokinetics? PMID- 23734659 TI - Effective and reversible DNA condensation induced by a simple cyclic/rigid polyamine containing carbonyl moiety. AB - The transfection of DNA in gene therapy largely depends on the possibility of obtaining its condensation. The details of nanoparticle formation are essential for functioning, as mediated by the diverse elements containing molecular structure, ionic strength in mediums, and condensing motivator. Here, we report two kinds of DNA condensing agents based on simple cyclic/rigid polyamine molecules, having evaluated their structural effect on nanoparticle formation. The reversible condensation-dissociation process was achieved by ion-switching, attributing to a possible condensing mechanism-competitive building of external hydrogen bonds. Using poly[(dA-dT)2] and poly[(dG-dC)2] as substrates, respectively, circular dichroism (CD) signals clearly presented dissimilar interactions between polyamines and both rich sequences, implying potential preference for G-C sequence. The presence of divalent ion Zn(2+) as an efficient motivator accelerated the achievement of DNA condensation, and an accessible schematic model was depicted to explain the promotion in detail. In addition, by comparison with the behaviors of linear polyamines, differences between condensation and aggregation were explicitly elucidated in aspects of morphology and surface charges, as well as induced condition. The present work may have the potential to reveal the precise mechanism of DNA nanoparticle formation and, in particular, be applied to gene delivery as an efficient nonviral vector. PMID- 23734660 TI - Query enhancement through the practical application of ontology: the IEDB and OBI. AB - Ontologies categorize entities, express relationships between them, and provide standardized definitions. Thus, they can be used to present and enforce the specific relationships between database components. The Immune Epitope Database (IEDB, http://www.iedb.org) utilizes the Ontology for Biomedical Investigations (OBI) and several additional ontologies to represent immune epitope mapping experiments. Here, we describe our experiences utilizing this representation in order to provide enhanced database search functionality. We applied a simple approach to incorporate the benefits of the information captured in a formal ontology directly into the user web interface, resulting in an improved user experience with minimal changes to the database itself. The integration is easy to maintain, provides standardized terms and definitions, and allows for subsumption queries. In addition to these immediate benefits, our long-term goal is to enable true semantic integration of data and knowledge in the biomedical domain. We describe our progress towards that goal and what we perceive as the main obstacles. PMID- 23734662 TI - Effects of school-based interventions for direct delivery of physical activity on fitness and cardiometabolic markers in children and adolescents: a systematic review of randomized controlled trials. AB - To evaluate the effectiveness of school-based physical activity interventions on fitness, adiposity and cardiometabolic outcomes among schoolchildren. Medline, Embase, EBSCOhost CINAHL and ERIC databases were searched up to October 2012. INCLUSION CRITERIA: intervention delivered at school with controls having no intervention or usual physical education classes; participants aged 5-18 years; outcomes spanning some or all of the above. We assessed levels of evidence for identified trials based on methodological quality and sample size. Dose of the interventions (a total summary measure of intensity, frequency and duration) were considered. Eighteen randomized controlled trials (RCTs, total participants = 6,207) were included, of which six were large, higher quality trials with high dose of the intervention. The intervention was consistent in increasing fitness with large, higher quality studies and high dose of intervention providing strong evidence. Dose of school-based physical activity is an important determinant of trial efficiency. Some large, higher quality RCTs provided strong evidence for interventions to decrease skin-fold thickness, increase fitness and high-density lipoprotein cholesterol. Evidence for body mass index, body fat and waist circumference, blood pressure and triglycerides, low-density lipoprotein cholesterol and total cholesterol remain inconclusive and require additional higher quality studies with high dose of interventions to provide conclusive evidence. PMID- 23734661 TI - Remarkable stabilization of plasminogen activator inhibitor 1 in a "molecular sandwich" complex. AB - Plasminogen activator inhibitor 1 (PAI-1) levels are elevated in a number of life threatening conditions and often correlate with unfavorable outcomes. Spontaneous inactivation due to active to latent transition limits PAI-1 activity in vivo. While endogenous vitronectin (Vn) stabilizes PAI-1 by 1.5-2.0-fold, further stabilization occurs in a "molecular sandwich" complex (MSC) in which a ligand that restricts the exposed reactive center loop is bound to PAI-1/Vn. The effects of S195A two-chain urokinase (tcuPA) and Vn on inactivation of wild-type (wt) glycosylated (Gl-PAI-1), nonglycosylated (rPAI-1), and nonglycosylated Q123K PAI 1 (lacks Vn binding) forms were studied. S195A tcuPA decreased the rate constant (kL) for spontaneous inactivation at 37 degrees C for rPAI-1, Q123K, and Gl-PAI 1 by 6.7-, 3.4-, and 7.8-fold, respectively, and both S195A tcuPA and Vn by 66.7 , 5.5-, and 103.3-fold, respectively. Analysis of the temperature dependences of kL revealed a synergistic increase in the Gibbs free activation energy for spontaneous inactivation of wt Gl-PAI-1 and rPAI-1 in MSC from 99.8 and 96.1 to 111.3 and 107.0 kJ/mol, respectively, due to an increase in the activation enthalpy and a decrease in the activation entropy. Anti-PAI-1 monoclonal antibodies (mAbs) competing with proteinase also stabilize PAI-1/Vn. The rate of inhibition of target proteinases by MSCs, with a stoichiometry close to unity, was limited by the dissociation (k = 10(-4) to 10(-3) s(-1)) of S195A tcuPA or mAb. The stabilization of PAI-1 in MSCs in vivo may potentiate uncontrolled thrombosis or extravascular fibrin deposition, suggesting a new paradigm for using PAI-1 inhibitors and novel potential targets for therapy. PMID- 23734663 TI - Gene set enrichment analysis of RNA-Seq data: integrating differential expression and splicing. AB - BACKGROUND: RNA-Seq has become a key technology in transcriptome studies because it can quantify overall expression levels and the degree of alternative splicing for each gene simultaneously. To interpret high-throughout transcriptome profiling data, functional enrichment analysis is critical. However, existing functional analysis methods can only account for differential expression, leaving differential splicing out altogether. RESULTS: In this work, we present a novel approach to derive biological insight by integrating differential expression and splicing from RNA-Seq data with functional gene set analysis. This approach designated SeqGSEA, uses count data modelling with negative binomial distributions to first score differential expression and splicing in each gene, respectively, followed by two strategies to combine the two scores for integrated gene set enrichment analysis. Method comparison results and biological insight analysis on an artificial data set and three real RNA-Seq data sets indicate that our approach outperforms alternative analysis pipelines and can detect biological meaningful gene sets with high confidence, and that it has the ability to determine if transcription or splicing is their predominant regulatory mechanism. CONCLUSIONS: By integrating differential expression and splicing, the proposed method SeqGSEA is particularly useful for efficiently translating RNA-Seq data to biological discoveries. PMID- 23734664 TI - Bioconcentration of perfluorinated alkyl acids: how important is specific binding? AB - Perfluorinated alkyl acids (PFAAs) are important global pollutants with unique pharmacokinetics. Evidence is accumulating that their behavior within organisms is affected by interaction with a number of proteins. In mammals, serum albumin, fatty acid binding proteins (FABPs) and organic anion transporters (OATs) have been identified as important to the tissue distribution, species-specific accumulation, and species- and gender-specific elimination rates of perfluoroalkyl carboxylates and perfluoroalkane sulfonates. Similar pharmacokinetics has been identified in fish. Yet, no mechanistic model exists for the bioaccumulation of PFAAs in fish that explicitly considers protein interactions. In this work, we present the first mechanistic protein-binding bioconcentration model for PFAAs in fish. Our model considers PFAA uptake via passive diffusion at the gills, association with serum albumin in the circulatory and extracellular spaces, association with FABP in the liver, and renal elimination and reabsorption facilitated by OAT proteins. The model is evaluated using measured bioconcentration and tissue distribution data collected in two previous studies of rainbow trout (Oncorhynchus mykiss) and common carp (Cyprinus carpio). Comparing our model with previous attempts to describe PFAA bioconcentration using a nonspecific (partitioning-type) approach shows that inclusion of protein interactions is key to accurately predicting tissue-specific PFAA distribution and bioconcentration. PMID- 23734665 TI - Clinical characteristics and outcome in dogs with splenic marginal zone lymphoma. AB - BACKGROUND: Splenic marginal zone lymphoma (MZL) is a form of indolent B-cell lymphoma that is not well characterized in dogs. HYPOTHESIS/OBJECTIVES: The purpose of this study was to describe clinical characteristics and outcome in dogs with splenic MZL confirmed by histopathology, immunophenotyping, and molecular clonality assessment. We hypothesized that affected dogs would have prolonged survival time with splenectomy alone. ANIMALS: Thirty-four dogs were included. Twenty-nine dogs were diagnosed after splenectomy, and 5 dogs were diagnosed at necropsy. METHODS: Pathology records were searched for dogs with histologically confirmed splenic MZL. Clinical and outcome data were retrospectively collected by medical record review, and prognostic factors were evaluated. Histopathology was reviewed by a board-certified pathologist, and tissue sections were subjected to immunophenotyping and molecular clonality assessment by PCR. RESULTS: Immunohistochemistry confirmed a B-cell phenotype for all dogs. Molecular clonality assessment was performed in 33 of 34 dogs, of which 24 had clonal rearrangement of immunoglobulin (Ig) loci, 3 had pseudoclonal rearrangement, and 6 had polyclonal rearrangement. The overall median survival time (MST) for the 29 dogs that underwent splenectomy was 383 days. The MST for 14 of 29 asymptomatic dogs that underwent splenectomy for MZL was 1,153 days as compared to 309 days for 15/29 dogs with clinical signs referable to splenic MZL (P = .018). Lymph node involvement, hemoabdomen, anemia, chemotherapy, and concurrent malignancy did not affect survival outcome. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs diagnosed with splenic MZL can have prolonged survival with splenectomy alone, without the use of adjuvant chemotherapy. Asymptomatic dogs may have a better survival outcome. PMID- 23734666 TI - In silico investigation into dendritic cell regulation of CD8Treg mediated killing of Th1 cells in murine experimental autoimmune encephalomyelitis. AB - BACKGROUND: Experimental autoimmune encephalomyelitis has been used extensively as an animal model of T cell mediated autoimmunity. A down-regulatory pathway through which encephalitogenic CD4Th1 cells are killed by CD8 regulatory T cells (Treg) has recently been proposed. With the CD8Treg cells being primed by dendritic cells, regulation of recovery may be occuring around these antigen presenting cells. CD4Treg cells provide critical help within this process, by licensing dendritic cells to prime CD8Treg cells, however the spatial and temporal aspects of this help in the CTL response is currently unclear. RESULTS: We have previously developed a simulator of experimental autoimmune encephalomyelitis (ARTIMMUS). We use ARTIMMUS to perform novel in silico experimentation regarding the priming of CD8Treg cells by dendritic cells, and the resulting CD8Treg mediated killing of encephalitogenic CD4Th1 cells. Simulations using dendritic cells that present antigenic peptides in a mutually exclusive manner (either MBP or TCR-derived, but not both) suggest that there is no significant reliance on dendritic cells that can prime both encephalitogenic CD4Th1 and Treg cells. Further, in silico experimentation suggests that dynamics of CD8Treg priming are significantly influenced through their spatial competition with CD4Treg cells and through the timing of Qa-1 expression by dendritic cells. CONCLUSION: There is no requirement for the encephalitogenic CD4Th1 cells and cytotoxic CD8Treg cells to be primed by the same dendritic cells. We conjecture that no significant portion of CD4Th1 regulation by Qa-1 restricted CD8Treg cells occurs around individual dendritic cells, and as such, that CD8Treg mediated killing of CD4Th1 cells occurring around dendritic cells is not critical for recovery from the murine autoimmune disease. Furthermore, the timing of the CD4Treg licensing of dendritic cells and the spatial competition between CD4Treg and CD8Treg cells around the dendritic cell is critical for the size of the cytotoxic T lymphocyte response, because dendritic cells have a limited lifespan. If treatments can be found to either speed up the licensing process, or increase the spatial competitiveness of CD8Treg cells, the magnitude of the cytotoxic T lymphocyte response can be increased. PMID- 23734667 TI - Relationship between airway pathophysiology and airway inflammation in older asthmatics. AB - BACKGROUND AND OBJECTIVE: Asthma-related morbidity is greater in older compared with younger asthmatics. Airway closure is also greater in older asthmatics, an observation that may be explained by differences in airway inflammation. We hypothesized that in older adult patients with asthma, neutrophil airway inflammation increases airway closure during bronchoconstriction, while eosinophil airway inflammation increases airway hyperresponsiveness (AHR). METHODS: Asthmatic subjects (n = 26), aged >=55 years (68% female), were studied, and AHR to 4.5% saline challenge was measured by the response-dose ratio (%fall in forced expiratory volume in 1 s (FEV1 )/mg saline). Airway closure was assessed during bronchoconstriction percent change in forced vital capacity (FVC)/percent change in FEV1 (i.e. Closing Index). Airway inflammation was assessed by induced sputum and exhaled nitric oxide (eNO). RESULTS: Mean patient age was 67 years (confidence interval: 63-71) with a mean FEV1 of 78 % predicted (confidence interval: 70-85%). AHR correlated with sputum eosinophils (r = 0.68, P = 0.005) and eNO (r = 0.71, P < 0.001), but not with neutrophils or neutrophil mediators. The Closing Index correlated with total sputum neutrophils (r = 0.66, P = 0.005), neutrophil elastase, matrix metalloproteinase-9 and interleukin-8 (all P < 0.05). Further, FEV1 /FVC and residual volume/total lung capacity at rest correlated with neutrophil elastase (r = -0.46 and 0.66 respectively, P < 0.05) but not with eosinophils or eNO. CONCLUSIONS: In older patients with asthma, airway inflammatory cells are linked to abnormal airway physiology. Eosinophilic airway inflammation is associated with AHR while neutrophilic inflammation may be an important determinant of airflow limitation at rest and airway closure during bronchoconstriction. The clinical implications of these findings remain to be determined. PMID- 23734668 TI - A case report of cognitive behavioural therapy for social anxiety in an ultra high risk patient. AB - AIM: Psychological treatments such as cognitive behavioural therapy (CBT) may have efficacy in young people at ultra-high risk (UHR) for psychosis. Case reports can illuminate the obstacles and challenges, and potential trajectory of symptom changes, observed with this treatment. METHODS: This is a detailed case report of a young adult at UHR for psychosis who received manualized CBT for accompanying social anxiety. RESULTS: Cognitive deficits and suspiciousness created initial challenges for successful implementation of CBT. Engagement in treatment occurred with slowing of pace and simplification of material, and modelling of social interaction. Treatment of social anxiety was accompanied by decreases in suspiciousness, conceptual disorganization, and social anhedonia, and increase in range of affect. CONCLUSIONS: Adaptation of manualized CBT to accommodate cognitive deficits and suspiciousness in UHR patients may improve engagement. CBT focused on social anxiety can lead to improvement across symptom domains in UHR patients. PMID- 23734669 TI - How Conversational Therapy influences language recovery in chronic non-fluent aphasia. AB - The study aimed to determine the efficacy of a Conversational Therapy approach in the treatment of chronic patients with moderately severe non-fluent aphasia. Eight patients completed a six week intensive language training. Every two weeks, each patient received rehabilitation using a different videoclip depicting everyday life. To elicit verbal communication, patients were required to observe each videoclip and to converse about it with the help of an experienced clinician. To measure any significant improvement in speech production all patients were tested before and after treatment. A significant increase in their ability to produce correct informative words (C-Units), verbs, nouns, adjectives, adverbs, as well as closed-class words (pronouns, articles and conjunctions) and well-formed sentences was found after therapy. Such improvement persisted at one week and one month after the end of the treatment. These results suggest that conversational therapy, applied through intensive language training, has a significant efficacy in the recovery of verbal communication in chronic non fluent aphasic individuals. This approach should be considered for patients with moderately severe non-fluent aphasia, as it enhances not only the ability to use informative language but also its correct use in daily living. PMID- 23734670 TI - Assessment of total cardiovascular risk using WHO/ISH risk prediction charts in three low and middle income countries in Asia. AB - BACKGROUND: Recent research has used cardiovascular risk scores intended to estimate "total cardiovascular disease (CVD) risk" in individuals to assess the distribution of risk within populations. The research suggested that the adoption of the total risk approach, in comparison to treatment decisions being based on the level of a single risk factor, could lead to reductions in expenditure on preventive cardiovascular drug treatment in low- and middle-income countries. So that the patient benefit associated with savings is highlighted. METHODS: This study used data from national STEPS surveys (STEPwise Approach to Surveillance) conducted between 2005 and 2010 in Cambodia, Malaysia and Mongolia of men and women aged 40-64 years. The study compared the differences and implications of various approaches to risk estimation at a population level using the World Health Organization/International Society of Hypertension (WHO/ISH) risk score charts. To aid interpretation and adjustment of scores and inform treatment in individuals, the charts are accompanied by practice notes about risk factors not included in the risk score calculations. Total risk was calculated amongst the populations using the charts alone and also adjusted according to these notes. Prevalence of traditional single risk factors was also calculated. RESULTS: The prevalence of WHO/ISH "high CVD risk" (>=20% chance of developing a cardiovascular event over 10 years) of 6%, 2.3% and 1.3% in Mongolia, Malaysia and Cambodia, respectively, is in line with recent research when charts alone are used. However, these proportions rise to 33.3%, 20.8% and 10.4%, respectively when individuals with blood pressure > = 160/100 mm/Hg and/or hypertension medication are attributed to "high risk". Of those at "moderate risk" (10- < 20% chance of developing a cardio vascular event over 10 years), 100%, 94.3% and 30.1%, respectively are affected by at least one risk-increasing factor. Of all individuals, 44.6%, 29.0% and 15.0% are affected by hypertension as a single risk factor (systolic >= 140 mmHg or diastolic >= 90 mmHg or medication). CONCLUSIONS: Used on a population level, cardiovascular risk scores may offer useful insights that can assist health service delivery planning. An approach based on overall risk without adjustment of specific risk factors however, may underestimate treatment needs.At the individual level, the total risk approach offers important clinical benefits. However, countries need to develop appropriate clinical guidelines and operational guidance for detection and management of CVD risk using total CVD-risk approach at different levels of health system. Operational research is needed to assess implementation issues. PMID- 23734671 TI - Determination of the apoptotic index in osteosarcoma tissue and its relationship with patients prognosis. AB - BACKGROUND: Nowadays it remains a controversial issue whether a correlation exists between the apoptosis rate of tumor tissue and the prognosis of the patients. We aimed to explore the prognostic significance of apoptosis index of human osteosarcoma tissue. METHODS: The technique of terminal DNA breakpoints in situ 3 - hydroxy end labeling (TUNEL) was used to detect and analysis apoptosis index in 56 osteosarcoma specimens. The relationships between apoptosis index of tumor tissue and long term survival of patients as well as pathologic classification, tumor clinical stages, tumor size and level of serum alkaline phosphatase were analyzed. RESULTS: Our studies showed the cases with high apoptosis index had significantly longer survival time. Apoptosis index in osteosarcoma tissue was correlated with tumor size and level of serum alkaline phosphatase but not with pathologic classifications and clinical stages of tumor. CONCLUSION: Our results demonstrated that apoptosis index of osteosarcoma tissue combined with serum alkaline phosphatase could used as valid indicators to predicate the malignant level and prognosis of osteosarcoma cases, which would contribute to enhance efficacy of clinical treatments for osteosarcoma. PMID- 23734672 TI - Fading vision: knowledge translation in the implementation of a public health policy intervention. AB - BACKGROUND: In response to several high profile public health crises, public health renewal is underway in Canada. In the province of British Columbia, the Ministry of Health initiated a collaborative evidence-informed process involving a steering committee of representatives from the six health authorities. A Core Functions (CF) Framework was developed, identifying 21 core public health programs. For each core program, an evidence review was conducted and a model core program paper developed. These documents were distributed to health authorities to guide development of their own renewed public health services. The CF implementation was conceptualized as an embedded knowledge translation process. A CF coordinator in each health authority was to facilitate a gap analysis and development of a performance improvement plan for each core program, and post these publically on the health authority website. METHODS: Interviews (n = 19) and focus groups (n = 8) were conducted with a total of 56 managers and front line staff from five health authorities working in the Healthy Living and Sexually Transmitted Infection Prevention core programs. All interviews and focus groups were digitally recorded, transcribed and verified by the project coordinator. Five members of the research team used NVivo 9 to manage data and conducted a thematic analysis. RESULTS: Four main themes emerged concerning implementation of the CF Framework generally, and the two programs specifically. The themes were: 'you've told me what, now tell me how'; 'the double bind'; 'but we already do that'; and the 'selling game.' Findings demonstrate the original vision of the CF process was lost in the implementation process and many participants were unaware of the CF framework or process. CONCLUSIONS: Results are discussed with respect to a well-known framework on the adoption, assimilation, and implementation of innovations in health services organizations. Despite attempts of the Ministry of Health and the Steering Committee to develop and implement a collaborative, evidence-informed policy intervention, there were several barriers to the realization of the vision for core public health functions implementation, at least in the early stages. In neglecting the implementation process, it seems unlikely that the expected benefits of the public health renewal process will be realized. PMID- 23734674 TI - CDX2 expression in columnar variant of papillary thyroid carcinoma. PMID- 23734673 TI - Chemistry, pharmacology, and behavioral studies identify chiral cyclopropanes as selective alpha4beta2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile. Part II. AB - A 3-pyridyl ether scaffold bearing a cyclopropane-containing side chain was recently identified in our efforts to create novel antidepressants that act as partial agonists at alpha4beta2-nicotinic acetylcholine receptors. In this study, a systematic structure-activity relationship investigation was carried out on both the azetidine moiety present in compound 3 and its right-hand side chain, thereby discovering a variety of novel nicotinic ligands that retain bioactivity and feature improved chemical stability. The most promising compounds, 24, 26, and 30, demonstrated comparable or enhanced pharmacological profiles compared to the parent compound 4, and the N-methylpyrrolidine analogue 26 also exhibited robust antidepressant-like efficacy in the mouse forced swim test. The favorable ADMET profile and chemical stability of 26 further indicate this compound to be a promising lead as a drug candidate warranting further advancement down the drug discovery pipeline. PMID- 23734675 TI - Representation of probabilistic scientific knowledge. AB - The theory of probability is widely used in biomedical research for data analysis and modelling. In previous work the probabilities of the research hypotheses have been recorded as experimental metadata. The ontology HELO is designed to support probabilistic reasoning, and provides semantic descriptors for reporting on research that involves operations with probabilities. HELO explicitly links research statements such as hypotheses, models, laws, conclusions, etc. to the associated probabilities of these statements being true. HELO enables the explicit semantic representation and accurate recording of probabilities in hypotheses, as well as the inference methods used to generate and update those hypotheses. We demonstrate the utility of HELO on three worked examples: changes in the probability of the hypothesis that sirtuins regulate human life span; changes in the probability of hypotheses about gene functions in the S. cerevisiae aromatic amino acid pathway; and the use of active learning in drug design (quantitative structure activity relation learning), where a strategy for the selection of compounds with the highest probability of improving on the best known compound was used. HELO is open source and available at https://github.com/larisa-soldatova/HELO. PMID- 23734676 TI - Simple and sustainable iron-catalyzed aerobic C-H functionalization of N,N dialkylanilines. AB - Iron(III) chloride catalyzes the aerobic oxidation of tertiary anilines, including tetrahydroisoquinolines, to form reactive iminium ion intermediates that undergo Mannich reactions with silyloxyfurans, nitroalkanes, and other nucleophiles to give the corresponding butenolides, nitro compounds, and alpha substituted tetrahydroisoquinolines, respectively, in good to excellent yields. PMID- 23734677 TI - Synthesis of functionalized pseudopeptides through five-component sequential Ugi/nucleophilic reaction of N-substituted 2-alkynamides with hydrazides. AB - Five-component sequential Ugi/nucleophilic addition reaction of aromatic aldehydes, primary amines, propiolic acid, isocyanides, and hydrazides has been developed in order to access polyfunctional pseudopeptides. The reaction may proceed through formation of N-substituted 2-alkynamides as intermediates. This process is found to be mild and operationally simple with broad substrate scope. PMID- 23734678 TI - De novo inference of stratification and local admixture in sequencing studies. AB - Analysis of population structures and genome local ancestry has become increasingly important in population and disease genetics. With the advance of next generation sequencing technologies, complete genetic variants in individuals' genomes are quickly generated, providing unprecedented opportunities for learning population evolution histories and identifying local genetic signatures at the SNP resolution. The successes of those studies critically rely on accurate and powerful computational tools that can fully utilize the sequencing information. Although many algorithms have been developed for population structure inference and admixture mapping, many of them only work for independent SNPs in genotype or haplotype format, and require a large panel of reference individuals. In this paper, we propose a novel probabilistic method for detecting population structure and local admixture. The method takes input of sequencing data, genotype data and haplotype data. The method characterizes the dependence of genetic variants via haplotype segmentation, such that all variants detected in a sequencing study can be fully utilized for inference. The method further utilizes a infinite-state Bayesian Markov model to perform de novo stratification and admixture inference. Using simulated datasets from HapMapII and 1000Genomes, we show that our method performs superior than several existing algorithms, particularly when limited or no reference individuals are available. Our method is applicable to not only human studies but also studies of other species of interests, for which little reference information is available.Software Availability: http://stat.psu.edu/~yuzhang/software/dbm.tar. PMID- 23734679 TI - Drug resistance: the problem that keeps on giving. PMID- 23734680 TI - miRNA: the new frontier in cancer medicine. PMID- 23734682 TI - Small-molecule inhibitors of p21 as novel therapeutics for chemotherapy-resistant kidney cancer. PMID- 23734684 TI - Manipulation of autophagy in cancer cells: an innovative strategy to fight drug resistance. AB - Autophagy is a catabolic process activated by stress conditions and nutrient deprivation, to which it reacts by promoting the degradation of damaged organelles and misfolded/aggregated proteins, as well as generating new energetic pools. Paradoxically, in cancer cells, which signal the dangerous microenvironment occurring during clinical therapies, autophagy could promote their proliferation and sustain drug resistance. Special attention is given to autophagy manipulation in order to counteract drug resistance of cancer cells. This article describes the basic properties of autophagy and focuses on the strategies of manipulating it. PMID- 23734683 TI - RGS17: an emerging therapeutic target for lung and prostate cancers. AB - Ligands for G-protein-coupled receptors (GPCRs) represent approximately 50% of currently marketed drugs. RGS proteins modulate heterotrimeric G proteins and, thus, GPCR signaling, by accelerating the intrinsic GTPase activity of the Galpha subunit. Given the prevalence of GPCR targeted therapeutics and the role RGS proteins play in G protein signaling, some RGS proteins are emerging as targets in their own right. One such RGS protein is RGS17. Increased RGS17 expression in some prostate and lung cancers has been demonstrated to support cancer progression, while reduced expression of RGS17 can lead to development of chemotherapeutic resistance in ovarian cancer. High-throughput screening is a powerful tool for lead compound identification, and utilization of high throughput technologies has led to the discovery of several RGS inhibitors, thus far. As screening technologies advance, the identification of novel lead compounds the subsequent development of targeted therapeutics appears promising. PMID- 23734685 TI - Development of new estrogen receptor-targeting therapeutic agents for tamoxifen resistant breast cancer. AB - Despite our deepening understanding of the mechanisms of resistance and intensive efforts to develop therapeutic solutions to combat resistance, de novo and acquired tamoxifen resistance remains a clinical challenge, and few effective regimens exist to treat tamoxifen-resistant breast cancer. The complexity of tamoxifen resistance calls for diverse therapeutic approaches. This review presents several therapeutic strategies and lead compounds targeting the estrogen receptor signaling pathways for treatment of tamoxifen-resistant breast cancer, with a critical assessment of challenges and potentials regarding clinical outcome. Medicinal chemistry holds the key to effective, personalized combination therapy for tamoxifen-resistant breast cancer by making available a diverse arsenal of small-molecule drugs that specifically target signaling pathways modulating hormone resistance. These combination therapy candidates should have the desired specificity, selectivity and low toxicity to resensitize tumor response to tamoxifen and/or inhibit the growth and proliferation of resistant breast cancer cells. PMID- 23734686 TI - ABCG2: recent discovery of potent and highly selective inhibitors. AB - ABCG2 impacts oral availability, tissue distribution and excretion of its substrates, including anticancer and anti-infectious drugs. Highly expressed at physiological barriers, its secretion level significantly controls drug distribution. Furthermore, its increased content into many types of cancer may lead to cell chemoresistance. Owing to the clinical relevance of ABCG2 in the multidrug resistance phenomenon, ABCG2 constitutes an appealing therapeutic target to increase drug distribution. Development of ABCG2 inhibitors can be used in combination with anticancer drugs to block the drug secretion from cancer cells. Very recently, an alternative use of ABCG2 inhibitors in enhancing the bioavailability of ABCG2 substrates has emerged. Hence, it is important to investigate ABCG2 inhibitors with high selectivity, high potency and safety. New inhibitors discovered during the last 5 years will be presented and discussed. PMID- 23734687 TI - Targeting GRP78 and antiestrogen resistance in breast cancer. AB - Breast cancer is the most prevalent cancer in women, with over 200,000 new cases diagnosed each year. Over 70% of breast cancers express the estrogen receptor alpha, and drugs targeting these receptors such as tamoxifen or Faslodex((r)) often fail to cure these patients. Many estrogen receptor-positive tumors lose drug sensitivity, making endocrine resistance a major clinical problem. Recently, investigation into the molecular mechanisms of endocrine resistance has highlighted a causative role of the unfolded protein response in antiestrogen resistance. In particular, the master regulator of the unfolded protein response, GRP78, was observed to be elevated in endocrine-resistant breast cancer and directly affected antiestrogen therapy responsiveness. GRP78 was found to impact many different cellular processes that may affect breast cancer survival. Recently, various compounds have been reported to affect GRP78 activity and it may be advantageous to combine these drugs with antiestrogens to overcome endocrine therapy resistance. PMID- 23734688 TI - Contributions of co-chaperones and post-translational modifications towards Hsp90 drug sensitivity. AB - Hsp90 is a molecular chaperone and important driver of stabilization and activation of several oncogenic proteins that are involved in the malignant transformation of tumor cells. Therefore, it is not surprising that Hsp90 has been reported to be a promising target for the treatment of several neoplasias, such as non-small-cell lung cancer and HER2-positive breast cancer. Hsp90 chaperone function depends on its ability to bind and hydrolyze ATP and Hsp90 inhibitors have been shown to compete with nucleotides for binding to Hsp90. Multiple factors, such as co-chaperones and post-translational modification, are involved in regulating Hsp90 ATPase activity. Here, the impact of post translational modifications and co-chaperones on the efficacy of Hsp90 inhibitors are reviewed. PMID- 23734690 TI - Soluble form of urokinase-type plasminogen activator receptor as a diagnostic and prognostic marker in hematological patients with neutropenic fever. PMID- 23734691 TI - Synthesis of [N(CH3)4]2O3SOSO2(s) and [N(CH3)4]2[(O2SO)2SO2].SO2(s) containing (SO4)(SO2)x(2-) x = 1, 2, members of a new class of sulfur oxydianions. AB - One mole equivalent of SO2 reversibly reacts with [N(CH3)4]2SO4(s) to give [N(CH3)4]2S2O6(s) (1) containing the [O3SOSO2](2-), shown by Raman and IR to be an isomer of the [O3SSO3](2-) dianion. The experimental and calculated (B3PW91/6 311+G(3df)) vibrational spectra are in excellent agreement, and the IR spectrum is similar to that of the isoelectronic O3ClOClO2. Crystals of [N(CH3)4]2(O2SO)2SO2.SO2 (2) were isolated from solutions of [N(CH3)4]2SO4 in liquid SO2. The X-ray structure showed that 2 contained the [(O2SO)2SO2](2-) dianion. The characterized N(CH3)4(+) salts 1 and 2 are the first two members of the (SO4)(SO2)x(2-) class of sulfur oxydianions analogous to the well-known small cation salts of the SO4(SO3)x(2-) polysulfates. PMID- 23734693 TI - Detailed EPR study of spin crossover dendrimeric iron(III) complex. AB - The unusual magnetic behavior of the first dendritic Fe(3+) complex with general formula [Fe(L)2](+)Cl(-).H2O based on a branched Schiff base has been investigated by electron paramagnetic resonance (EPR) and Mossbauer spectroscopy. EPR displays that complex consists of the three types of magnetically active iron centers: one S = 1/2 low-spin (LS) and two S = 5/2 high-spin (HS) centers with strong low-symmetry and weak distorted octahedral crystal fields. Analysis of the magnetic behavior reflected by I versus T (where I is the EPR lines integrated intensity of the spectrum) demonstrates that the dendritic Fe(3+) complex has sufficiently different behavior in three temperature intervals. The first (4.2-50 K) interval corresponds to the antiferromagnetic exchange interactions between LS LS, LS-HS, and HS-HS centers. The appearance of a presumable magnetoelectric effect is registered in the second (50-200 K) temperature interval, whereas a spin transition process between LS and HS centers occurs in the third (200-330 K) one. The coexistence of the magnetic ordering, presumable magnetoelectric effect, and spin crossover in one and the same material has been detected for the first time. The Mossbauer spectroscopy data completely confirm the EPR results. PMID- 23734692 TI - Benefit of doxycycline treatment on articular disability caused by dialysis related amyloidosis. AB - Abstract Doxycycline inhibits amyloid formation in vitro and its therapeutic efficacy is under evaluation in clinical trials for different protein conformational diseases, including prion diseases, Alzheimer's disease and transthyretin amyloidosis. In patients on chronic hemodialysis, a persistently high concentration of beta2-microglobulin causes a form of amyloidosis (dialysis related amyloidosis, DRA) localized in bones and ligaments. Since doxycycline inhibits beta2-microglobulin fibrillogenesis in vitro and accumulates in bones, DRA represents an ideal form of amyloidosis where doxycycline may reach a therapeutic concentration at the site of amyloid deposition. Three patients on long-term dialysis with severe articular impairment and uncontrollable pain due to DRA were treated with 100 mg of doxycycline daily. Pharmacokinetics and safety of treatment were conducted. Plasmatic levels of the drug reached a plateau after one week (1.1-2.3 ug/ml). Treatment was well tolerated in two patients for a year, while one was suspended after 5 months due to mild esophagitis. Treatment was associated with a significant reduction in articular pain and with a significant and measurable improvement in passive and active movements in all cases, despite the persistence of unchanged amyloid deposits measured by magnetic resonance imaging. PMID- 23734694 TI - Case of azacitidine-induced maculopapular erythematous eruption. PMID- 23734696 TI - Well-designed employer-sponsored wellness programs can lead to a healthier workforce. PMID- 23734695 TI - Voluntary HIV testing and risky sexual behaviours among health care workers: a survey in rural and urban Burkina Faso. AB - BACKGROUND: Voluntary counselling and testing (VCT) together with a safe sexual behaviour is an important preventive strategy in the control of HIV. Although Health care workers (HCWs) are critical in the response to HIV, little is known about VCT and high risk behaviours (HRB) among this group in West Africa. This study aims to assess the prevalence of VCT and HRB among HCWs in Burkina Faso. METHODS: We collected data through a questionnaire in urban areas (Ouagadougou and Bobo-Dioulasso) and rural areas (Poni and Yatenga) among HCWs from 97 health care facilities. Urine samples were collected, screened for HIV using a Calypte((r)) test kit and confirmed by Western Blot. Multiple logistic regression analysis was performed to identify factors associated with the use of VCT services and with high-risk sex behaviour. RESULTS: About 92.5% of eligible HCWs participated (1570 out of 1697). Overall, 38.2% of them (34.6% of women and 42.6% of men) had ever used VCT services. About 40% of HCWs reported that fear of knowing the test result was the main reason for not doing the HIV test. Male HCWs (p = 0.001), laboratory workers (p < 0.001), those having two years or more experience (p = 0.03), and those who had multiple partners (p = 0.001) were more likely to have tested for HIV. One fifth of HCWs reported multiple partners. Of these, thirteen percent did not use condoms. HCWs who had multiple partners were significantly more likely to be men, single, living in rural areas, and under the age of 29 years. CONCLUSION: VCT was still very low among HCWs in Burkina Faso, while HRB was high.These findings suggest that 'HCW-friendly' VCT centres should be implemented, securing confidentiality among colleagues. In addition, refreshment courses on HIV risk reduction, counselling and testing are certainly required during the professional career of HCWs. PMID- 23734697 TI - Activation of KCa3.1 by SKA-31 induces arteriolar dilatation and lowers blood pressure in normo- and hypertensive connexin40-deficient mice. AB - BACKGROUND AND PURPOSE: The calcium-activated potassium channel KCa3.1 is expressed in the vascular endothelium where its activation causes endothelial hyperpolarization and initiates endothelium-derived hyperpolarization (EDH) dependent dilatation. Here, we investigated whether pharmacological activation of KCa3.1 dilates skeletal muscle arterioles and whether myoendothelial gap junctions formed by connexin40 (Cx40) are required for EDH-type dilatations and pressure depressor responses in vivo. EXPERIMENTAL APPROACH: We performed intravital microscopy in the cremaster muscle microcirculation and blood pressure telemetry in Cx40-deficient mice. KEY RESULTS: In wild-type mice, the KCa3.1 activator SKA-31 induced pronounced concentration-dependent arteriolar EDH-type dilatations, amounting to ~40% of maximal dilatation, and enhanced the effects of ACh. These responses were absent in mice devoid of KCa3.1 channels. In contrast, SKA-31-induced dilatations were not attenuated in mice with endothelial cells deficient in Cx40 (Cx40(fl/fl):Tie2-Cre). In isolated endothelial cell clusters, SKA-31 induced hyperpolarizations of similar magnitudes (by ~38 mV) in Cx40(fl/fl):Tie2-Cre, ubiquitous Cx40-deficient mice (Cx40(-/-)) and controls (Cx40(fl/fl)), which were reversed by the specific KCa3.1-blocker TRAM-34. In normotensive wild-type and Cx40(fl/fl):Tie2-Cre as well as in hypertensive Cx40( /-) animals, i.p. injections of SKA-31 (30 and 100 mg.kg(-1)) decreased arterial pressure by ~32 mmHg in all genotypes. The depressor response to 100 mg.kg(-1) SKA-31 was associated with a decrease in heart rate. CONCLUSIONS AND IMPLICATIONS: We conclude that endothelial hyperpolarization evoked by pharmacological activation of KCa3.1 channels induces EDH-type arteriolar dilatations that are independent of endothelial Cx40 and Cx40-containing myoendothelial gap junctions. As SKA-31 reduced blood pressure in hypertensive Cx40-deficient mice, KCa3.1 activators may be useful drugs for severe treatment resistant hypertension. PMID- 23734698 TI - Evolutionary diversification of secondary mechanoreceptor cells in tunicata. AB - BACKGROUND: Hair cells are vertebrate secondary sensory cells located in the ear and in the lateral line organ. Until recently, these cells were considered to be mechanoreceptors exclusively found in vertebrates that evolved within this group. Evidence of secondary mechanoreceptors in some tunicates, the proposed sister group of vertebrates, has recently led to the hypothesis that vertebrate and tunicate secondary sensory cells share a common origin. Secondary sensory cells were described in detail in two tunicate groups, ascidians and thaliaceans, in which they constitute an oral sensory structure called the coronal organ. Among thaliaceans, the organ is absent in salps and it has been hypothesised that this condition is due to a different feeding system adopted by this group of animals. No information is available as to whether a comparable structure exists in the third group of tunicates, the appendicularians, although different sensory structures are known to be present in these animals. RESULTS: We studied the detailed morphology of appendicularian oral mechanoreceptors. Using light and electron microscopy we could demonstrate that the mechanosensory organ called the circumoral ring is composed of secondary sensory cells. We described the ultrastructure of the circumoral organ in two appendicularian species, Oikopleura dioica and Oikopleura albicans, and thus taxonomically completed the data collection of tunicate secondary sensory cells. To understand the evolution of secondary sensory cells in tunicates, we performed a cladistic analysis using morphological data. We constructed a matrix consisting of 19 characters derived from detailed ultrastructural studies in 16 tunicate species and used a cephalochordate and three vertebrate species as outgroups. CONCLUSIONS: Our study clearly shows that the circumoral ring is the appendicularian homologue of the coronal organ of other tunicate taxa. The cladistic analysis enabled us to reconstruct the features of the putative ancestral hair cell in tunicates, represented by a simple monociliated cell. This cell successively differentiated into the current variety of oral mechanoreceptors in the various tunicate lineages. Finally, we demonstrated that the inferred evolutionary changes coincide with major transitions in the feeding strategies in each respective lineage. PMID- 23734699 TI - Clinical findings and survival in cats naturally infected with feline immunodeficiency virus. AB - BACKGROUND: The clinical course and outcome of natural feline immunodeficiency virus (FIV) infection are variable and incompletely understood. Assigning clinical relevance to FIV infection in individual cats represents a considerable clinical challenge. OBJECTIVE: To compare signalment, hematologic and biochemical data, major clinical problem, and survival among client-owned, FIV-infected, and uninfected domestic cats. ANIMALS: Client-owned, domestic cats tested for FIV (n = 520). METHODS: Retrospective, case control study. Logistic regression analyses were conducted to identify risk factors for FIV infection and to compare hematologic and biochemical data between cases and controls, after adjusting for potential confounders. Survival times were compared using Kaplan-Meier curves. RESULTS: The prevalence of FIV infection was 14.6%. Mixed breed, male sex, and older age were risk factors for FIV infection. Hematologic abnormalities, biochemical abnormalities or both were common in both FIV-infected and uninfected cats. Lymphoid malignancies were slightly more common in FIV-infected than uninfected cats. Survival of FIV-infected cats was not significantly different from that of uninfected cats. CONCLUSIONS AND CLINICAL IMPORTANCE: Multiple hematologic and biochemical abnormalities are common in old, sick cats regardless of their FIV status. Their presence should not be assumed to indicate clinical progression of FIV infection. A negative effect of FIV on survival was not apparent in this study. PMID- 23734701 TI - Bioactive limonoid and triterpenoid constituents of Turraea pubescens. AB - Eleven new limonoids, turrapubins A-K (1-11), and three new triterpenoids (12 14), along with 14 known compounds, were isolated from the twigs of Turraea pubescens. The structures of 1-14 were elucidated on the basis of NMR and MS analysis. Compounds 12, 16, 18, and 19 exhibited inhibitory activities against lipopolysaccharide-induced nitric oxide production in RAW264.7 cells. In addition, compounds 2, 11, 18, and 26 exhibited inhibitory activities against brine shrimp larvae (Artemia salina) at 100 ppm with the corrected mortality ranging from 81.7% to 100%. PMID- 23734700 TI - The acceptance of e-health solutions among patients with chronic respiratory conditions. AB - OBJECTIVE: The main objective of this study was to assess the acceptance of the use of e-health applications by patients suffering from bronchial asthma and other chronic respiratory conditions. SUBJECTS AND METHODS: The questionnaire, consisting of 73 items, was distributed among 200 patients remaining under the care of a tertiary-care pulmonology center in Krakow, Poland (return rate, 82.5%; n=165). RESULTS: The mean age (standard deviation) of respondents was 50.8 (14.9) years. Of the respondents, 48.5% (n=80) suffered from bronchial asthma, 29.1% (n=48) from chronic obstructive pulmonary disease, and 32.1% (n=53) from other respiratory diseases. The Internet was used by 58.2% (n=96) of respondents. The most frequent types of health-related information searched for online included diseases (59.4%) and treatments (medication, 54.2%; treatment options, 58.3%), as well as information about physicians and healthcare institutions (32.3% and 31.3%, respectively). The differences between acceptance scores for specific e health applications were significant (analysis of variance, Friedman chi squared=166.315, p<0.001). The respondents revealed the highest acceptance of e health solutions allowing them to book appointments with physicians, access laboratory test results, view educational resources, and renew prescriptions. The acceptance of the most popular e-health applications depended on the duration of disease, respondent's age and education, and his or her use of computers and the Internet. CONCLUSIONS: Patients suffering from chronic respiratory conditions demonstrate higher levels of acceptance of e-health applications such as appointment booking, prescription renewal, and access to information (laboratory test results, educational resources) than of solutions directly related to medical care (communication with healthcare providers, disease monitoring). PMID- 23734702 TI - Cloning, expression, and immunocharacterization of surface protein containing an altered thrombospondin repeat domain (SPATR) from Plasmodium knowlesi. AB - BACKGROUND: Plasmodium knowlesi is the fifth species identified to cause malaria in humans and is often misdiagnosed as Plasmodium malariae due to morphological similarities. The development of an inexpensive, serological detection method utilizing antibodies specific to P. knowlesi would be a valuable tool for diagnosis. However, the identification of specific antigens for these parasites remains a major challenge for generating such assays. In this study, surface protein containing an altered thrombospondin repeat domain (SPATR) was selected as a potentially specific antigen from P. knowlesi. Its multistage expression by sporozoites, asexual erythrocytic forms and gametocytes, along with its possible role in liver cell invasion, suggests that SPATR could be used as a biomarker for diagnosis of P. knowlesi. METHODS: The spatr gene from P. knowlesi was codon optimized and cloned (pkhspatr). Recombinant pkHSPATR protein was expressed, purified, and evaluated for its sensitivity and specificity in immunoblot and ELISA-based assays for detecting P. knowlesi infection. RESULTS: The recombinant pkHSPATR protein allows sensitive detection of human P. knowlesi infection in serum samples by immunoblot and ELISA. CONCLUSIONS: With further research, recombinant pkHSPATR protein could be exploited as a marker for detection of P. knowlesi infection in humans. Therefore, this finding should contribute to the development of immunodiagnostic assays for the species-specific detection of malaria. PMID- 23734703 TI - A multi-level system quality improvement intervention to reduce racial disparities in hypertension care and control: study protocol. AB - BACKGROUND: Racial disparities in blood pressure control have been well documented in the United States. Research suggests that many factors contribute to this disparity, including barriers to care at patient, clinician, healthcare system, and community levels. To date, few interventions aimed at reducing hypertension disparities have addressed factors at all of these levels. This paper describes the design of Project ReD CHiP (Reducing Disparities and Controlling Hypertension in Primary Care), a multi-level system quality improvement project. By intervening on multiple levels, this project aims to reduce disparities in blood pressure control and improve guideline concordant hypertension care. METHODS: Using a pragmatic trial design, we are implementing three complementary multi-level interventions designed to improve blood pressure measurement, provide patient care management services and offer expanded provider education resources in six primary care clinics in Baltimore, Maryland. We are staggering the introduction of the interventions and will use Statistical Process Control (SPC) charting to determine if there are changes in outcomes at each clinic after implementation of each intervention. The main hypothesis is that each intervention will have an additive effect on improvements in guideline concordant care and reductions in hypertension disparities, but the combination of all three interventions will result in the greatest impact, followed by blood pressure measurement with care management support, blood pressure measurement with provider education, and blood pressure measurement only. This study also examines how organizational functioning and cultural competence affect the success of the interventions. DISCUSSION: As a quality improvement project, Project ReD CHiP employs a novel study design that specifically targets multi level factors known to contribute to hypertension disparities. To facilitate its implementation and improve its sustainability, we have incorporated stakeholder input and tailored components of the interventions to meet the specific needs of the involved clinics and communities. Results from this study will provide knowledge about how integrated multi-level interventions can improve hypertension care and reduce disparities. TRIAL REGISTRATION: ClinicalTrials.gov NCT01566864. PMID- 23734704 TI - Determinants in the rpsT mRNAs recognized by the 5'-sensor domain of RNase E. AB - RNase E plays a central role in processing virtually all classes of cellular RNA in many bacterial species. A characteristic feature of RNase E and its paralogue RNase G, as well as several other unrelated ribonucleases, is their preference for 5'-monophosphorylated substrates. The basis for this property has been explored in vitro. At limiting substrate, cleavage of the rpsT mRNA by RNase E (residues 1-529) is inefficient, requiring excess enzyme. The rpsT mRNA is cleaved sequentially in a 5' to 3' direction, with the initial cleavage(s) at positions 116/117 or 190/191 being largely driven by direct entry, independent of the 5'-terminus or the 5'-sensor domain of RNase E. Generation of the 147 nt 3' limit product requires sequential cleavages that generate 5'-monophosphorylated termini on intermediates, and the 5'-sensor domain of RNase E. These requirements can be bypassed with limiting enzyme by deleting a stem-loop structure adjacent to the site of the major, most distal cleavage. Alternatively, this specific cleavage can be activated substantially by a 5'-phosphorylated oligonucleotide annealed 5' to the cleavage site. This finding suggests that monophosphorylated small RNAs may destabilize their mRNA targets by recruiting the 5-sensor domain of RNase E 'in trans'. PMID- 23734706 TI - Health problems in survivors of childhood cancer: the need for international collaboration in long-term follow-up care. PMID- 23734705 TI - Light-activated, in situ forming gel for sustained suprachoroidal delivery of bevacizumab. AB - A light-activated polycaprolactone dimethacrylate (PCM) and hydroxyethyl methacrylate (HEMA) based gel network was developed to sustain the release of stable, active bevacizumab (an anti-VEGF antibody used to treat choroidal neovascularization) and used to assess sustained ex vivo delivery in rabbit eyes and in vivo delivery in rat eyes following in situ gel formation in the suprachoroidal space. PCM was synthesized from polycaprolactone diol (PCD) and evaluated using NMR spectroscopy. PCM was used to cross-link HEMA in the presence of 365 nm UV light and 2,2-dimethoxy-2-phenylacetophenone (DMPA) as a photoinitiator. Bevacizumab was entrapped in the gel using three different cross linking durations of 3, 7, and 10 min. In vitro release of bevacizumab in PBS pH 7.4 at 37 degrees C during a 4 month study was quantified using a VEGF-binding based ELISA. The stability of released bevacizumab was monitored by size exclusion chromatography (SEC) and circular dichroism. Alexa Fluor 488 dye conjugated bevacizumab mixed with polymers was injected suprachoroidally in rabbit eyes to study the effect of different cross-linking durations on the spread of the dye conjugated bevacizumab. In vivo delivery was assessed in Sprague-Dawley (SD) rats by injecting Alexa Fluor 488 dye conjugated bevacizumab mixed with polymers followed by cross-linking for 10 min. Spread in the rabbit eyes and in vivo delivery in rat eyes was monitored noninvasively using a fundus camera and Fluorotron Master. The formation of PCM was confirmed by the disappearance of hydroxyl peak in NMR spectra. A cross-linking duration of 10 min resulted in a burst release of 21% of bevacizumab. Other cross-linking durations had >=62% burst release. Bevacizumab release from 10 min cross-linked gel was sustained for ~4 months. Release samples contained >=96.1% of bevacizumab in the monomeric form as observed in SEC chromatograms. Circular dichroism confirmed that secondary beta-sheet structure of bevacizumab was maintained after release from the gel. As the cross-linking duration was increased to 10 min, the gel/antibody was better confined at the injection site in excised rabbit eye suprachoroidal space. Delivery of Alexa Fluor 488 dye conjugated bevacizumab was sustained for at least 60 days in the suprachoroidal space of SD rats. PCM and HEMA gel sustained bevacizumab release for 4 months and maintained the stability and VEGF-binding activity of bevacizumab. Therefore, light-activated PCM and HEMA gel is suitable for in situ gel formation and sustained protein delivery in the suprachoroidal space. PMID- 23734708 TI - NCBO Technology: Powering semantically aware applications. AB - As new biomedical technologies are developed, the amount of publically available biomedical data continues to increase. To help manage these vast and disparate data sources, researchers have turned to the Semantic Web. Specifically, ontologies are used in data annotation, natural language processing, information retrieval, clinical decision support, and data integration tasks. The development of software applications to perform these tasks requires the integration of Web services to incorporate the wide variety of ontologies used in the health care and life sciences. The National Center for Biomedical Ontology, a National Center for Biomedical Computing created under the NIH Roadmap, developed BioPortal, which provides access to one of the largest repositories of biomedical ontologies. The NCBO Web services provide programmtic access to these ontologies and can be grouped into four categories; Ontology, Mapping, Annotation, and Data Access. The Ontology Web services provide access to ontologies, their metadata, ontology versions, downloads, navigation of the class hierarchy (parents, children, siblings) and details of each term. The Mapping Web services provide access to the millions of ontology mappings published in BioPortal. The NCBO Annotator Web service "tags" text automatically with terms from ontologies in BioPortal, and the NCBO Resource Index Web services provides access to an ontology-based index of public, online data resources. The NCBO Widgets package the Ontology Web services for use directly in Web sites. The functionality of the NCBO Web services and widgets are incorporated into semantically aware applications for ontology development and visualization, data annotation, and data integration. This overview will describe these classes of applications, discuss a few examples of each type, and which NCBO Web services are used by these applications. PMID- 23734707 TI - The human DeltaNp53 isoform triggers metabolic and gene expression changes that activate mTOR and alter mitochondrial function. AB - A naturally occurring p53 isoform that lacks 39 residues at the N-terminus (denoted DeltaNp53), when expressed with wild-type p53 (WTp53), forms mixed DeltaNp53:WTp53 tetramers and causes accelerated aging in mice. Cellular alterations specific to DeltaNp53:WTp53 have been difficult to assess because DeltaNp53 and WTp53 coexpression results in tetramer heterogeneity, including formation of contaminating WTp53 tetramers. Based on the p53 tetramer structure, we expressed DeltaNp53 and WTp53 as a single transcript that maintained tetramer architecture, ensuring a 2:2 DeltaNp53:WTp53 stoichiometry. As expected, DeltaNp53:WTp53 tetramers were stable and transcriptionally active in vitro and in cells, largely mimicking the function of WTp53 tetramers. Microarray analyses, however, revealed about 80 genes whose expression was altered twofold or more in DeltaNp53:WTp53 cells. Moreover, global metabolomic profiling quantitated hundreds of biochemicals across different experiments (WTp53, DeltaNp53:WTp53, plus controls). When evaluated collectively, these data suggested altered mTOR signaling and mitochondrial function-each canonical regulators of longevity-in cells expressing DeltaNp53:WTp53 vs. WTp53. Increased levels of free amino acids, increased expression of IRS-1, and decreased expression of INPP5D/SHIP-1 suggested activated mTOR signaling in DeltaNp53:WTp53 cells; this was confirmed upon comparative analyses of several mTOR pathway intermediates. We also observed changes in mitochondrial function in DeltaNp53:WTp53 cells, which correlated with increased MARS2 expression and increased levels of carnitine, acetyl CoA, ATP, and Krebs cycle intermediates. Finally, increased levels of succinate and 2 hydroxyglutarate indicate potential epigenetic means to propagate DeltaNp53:WTp53 induced gene expression changes to cell progeny. This may be especially important for aging, as biological effects manifest over time. PMID- 23734709 TI - Insights into the mechanism by which interferon-gamma basic amino acid clusters mediate protein binding to heparan sulfate. AB - The extensive functional repertoire of heparin and heparan sulfate, which relies on their ability to interact with a large number of proteins, has recently emerged. To understand the forces that drive such interactions the binding of heparin to interferon-gamma (IFNgamma), used as a model system, was investigated. NMR-based titration experiments demonstrated the involvement of two adjacent cationic domains (D1: KTGKRKR and D2: RGRR), both of which are present within the carboxy-terminal sequence of the cytokine. Kinetic analysis showed that these two domains contribute differently to the interaction: D1 is required to form a complex and constitutes the actual binding site, whereas D2, although unable to associate with heparin by itself, increased the association rate of the binding. These data are consistent with the view that D2, through nonspecific electrostatic forces, places the two molecules in favorable orientations for productive binding within the encounter complex. This mechanism was supported by electrostatic potential analysis and thermodynamic investigations. They showed that D1 association to heparin is driven by both favorable enthalpic and entropic contributions, as expected for a binding sequence, but that D2 gives rise to entropic penalty, which opposes binding in a thermodynamic sense. The binding mechanism described herein, by which the D2 domain kinetically drives the interaction, has important functional consequences and gives a structural framework to better understand how specific are the interactions between proteins and heparin. PMID- 23734710 TI - metaBEETL: high-throughput analysis of heterogeneous microbial populations from shotgun DNA sequences. AB - Environmental shotgun sequencing (ESS) has potential to give greater insight into microbial communities than targeted sequencing of 16S regions, but requires much higher sequence coverage. The advent of next-generation sequencing has made it feasible for the Human Microbiome Project and other initiatives to generate ESS data on a large scale, but computationally efficient methods for analysing such data sets are needed.Here we present metaBEETL, a fast taxonomic classifier for environmental shotgun sequences. It uses a Burrows-Wheeler Transform (BWT) index of the sequencing reads and an indexed database of microbial reference sequences. Unlike other BWT-based tools, our method has no upper limit on the number or the total size of the reference sequences in its database. By capturing sequence relationships between strains, our reference index also allows us to classify reads which are not unique to an individual strain but are nevertheless specific to some higher phylogenetic order.Tested on datasets with known taxonomic composition, metaBEETL gave results that are competitive with existing similarity based tools: due to normalization steps which other classifiers lack, the taxonomic profile computed by metaBEETL closely matched the true environmental profile. At the same time, its moderate running time and low memory footprint allow metaBEETL to scale well to large data sets.Code to construct the BWT indexed database and for the taxonomic classification is part of the BEETL library, available as a github repository at git@github.com:BEETL/BEETL.git. PMID- 23734711 TI - Serological survey of veterinarians to assess the zoonotic potential of three emerging swine diseases in Mexico. AB - We conducted an immunological assay of blood samples taken from 85 swine specialist veterinarians attending the Congress of the Mexican Association of Swine Specialist Veterinarians in Mexico in 2011. Serum samples were assayed for Porcine rubulavirus (PorPV), Encephalomyocarditis virus (EMCV) and Leptospira spp. antibodies. Using a hemagglutination inhibition test, we registered 2.3% and 27% seropositivity for PorPV and EMCV, respectively. Using viral neutralization tests, we registered 5.8% and 47% seropositivity for PorPV and EMCV, respectively. For Leptospira spp., we registered a seropositivity of 38.8%. The variables (sex, age, years of exposure, number of visited farms, biosecurity level and region) showed no significant effect (P > 0.05) on the seropositivity for EMCV, PorPV and Leptospira spp. except for number of visited farms on HI seropositivity for EMCV (P < 0.05; odds ratio: 1.38). The data obtained provide information on the epidemiology of emerging diseases with zoonotic potential in occupational risk groups. PMID- 23734712 TI - Vibrational origin of the thermal stability in the highly distorted alpha-quartz type material GeO2: an experimental and theoretical study. AB - We report an experimental and theoretical vibrational study of the high performance piezoelectric GeO2 material. Polarized and variable-temperature Raman spectroscopic measurements on high-quality, water-free, flux-grown alpha-quartz GeO2 single crystals combined with state-of-the-art first-principles calculations allow the controversies on the mode symmetry assignment to be solved, the nature of the vibrations to be described in detail, and the origin of the high thermal stability of this material to be explained. The low-degree of dynamic disorder at high-temperature, which makes alpha-GeO2 one of the most promising piezoelectric materials for extreme temperature applications, is found to originate from the absence of a libration mode of the GeO4 tetrahedra. PMID- 23734713 TI - Hyaline fibromatosis syndrome resulting from a new homozygous missense mutation, p.Gly116Val, in ANTXR2. PMID- 23734714 TI - Immunodetection of fungal and oomycete pathogens: established and emerging threats to human health, animal welfare and global food security. AB - Filamentous fungi (moulds), yeast-like fungi, and oomycetes cause life threatening infections of humans and animals and are a major constraint to global food security, constituting a significant economic burden to both agriculture and medicine. As well as causing localized or systemic infections, certain species are potent producers of allergens and toxins that exacerbate respiratory diseases or cause cancer and organ damage. We review the pathogenic and toxigenic organisms that are etiologic agents of both animal and plant diseases or that have recently emerged as serious pathogens of immunocompromised individuals. The use of hybridoma and phage display technologies and their success in generating monoclonal antibodies for the detection and control of fungal and oomycete pathogens are explored. Monoclonal antibodies hold enormous potential for the development of rapid and specific tests for the diagnosis of human mycoses, however, unlike plant pathology, their use in medical mycology remains to be fully exploited. PMID- 23734715 TI - Well-defined and sequence-specific noncovalent binding forces of DNA. AB - The specific binding between the two DNA strands in a double helix is one of the most fundamental and influential molecular interactions in biochemistry. Using force-induced remnant magnetization spectroscopy (FIRMS), we obtained well defined binding forces of DNA oligomers, with a narrow force distribution of 1.8 pN. The narrow force distribution allows for directly resolving two DNA duplexes with a single base-pair difference in the same sample. Therefore, binding force can serve as a discriminating parameter for probing different DNA interactions. Furthermore, we observed that the binding forces depend on the position of the mismatching base pair. Our results show that FIRMS is capable of high-precision mechanical measurements of biochemical processes involving multiple DNA interactions and has the potential for characterizing the binding strength of materials based on DNA origami. PMID- 23734716 TI - Chemical method for retrieval of cells encapsulated in alginate-polyethersulfone microcapsules. AB - We present a method for retrieval of cells encapsulated in alginate polyethersulfone (AP) microcapsules. AP microcapsules consist of alginate hydrogel core and a semi-permeable polymer membrane. Proposed method is based on chemical destruction of microcapsule structure that is, polymer membranes are removed by dissolution in 1-methyl-2-pyrrolidone subsequently the cells immobilized in the cores are released by liquefaction of alginate gel. The viability of Saccharomyces cerevisiae cells retrieved by this technique exceeds 98%, while the concentration of recovered cells reaches 98%-102% of cell concentration in suspension used for microencapsulation, which proves that proposed method allows to effectively and quantitatively retrieve encapsulated cells without compromising their viability. PMID- 23734717 TI - Late-life rapamycin treatment reverses age-related heart dysfunction. AB - Rapamycin has been shown to extend lifespan in numerous model organisms including mice, with the most dramatic longevity effects reported in females. However, little is known about the functional ramifications of this longevity-enhancing paradigm in mammalian tissues. We treated 24-month-old female C57BL/6J mice with rapamycin for 3 months and determined health outcomes via a variety of noninvasive measures of cardiovascular, skeletal, and metabolic health for individual mice. We determined that while rapamycin has mild transient metabolic effects, there are significant benefits to late-life cardiovascular function with a reversal or attenuation of age-related changes in the heart. RNA-seq analysis of cardiac tissue after treatment indicated inflammatory, metabolic, and antihypertrophic expression changes in cardiac tissue as potential mechanisms mediating the functional improvement. Rapamycin treatment also resulted in beneficial behavioral, skeletal, and motor changes in these mice compared with those fed a control diet. From these findings, we propose that late-life rapamycin therapy not only extends the lifespan of mammals, but also confers functional benefits to a number of tissues and mechanistically implicates an improvement in contractile function and antihypertrophic signaling in the aged heart with a reduction in age-related inflammation. PMID- 23734718 TI - Gestational age assessment in malaria pregnancy cohorts: a prospective ultrasound demonstration project in Malawi. AB - BACKGROUND: Malaria during pregnancy is associated with an increased risk for low birth weight (<2500 grams). Distinguishing infants that are born premature (< 37 weeks) from those that are growth-restricted (less than the 10th percentile at birth) requires accurate assessment of gestational age. Where ultrasound is accessible, sonographic confirmation of gestational age is more accurate than menstrual dating. The goal was to pilot the feasibility and utility of adding ultrasound to an observational pregnancy malaria cohort. METHODS: In July 2009, research staff (three mid-level clinical providers, one nurse) from The Blantyre Malaria Project underwent an intensive one-week ultrasound training to perform foetal biometry. Following an additional four months of practice and remote image review, subjects from an ongoing cohort were recruited for ultrasound to determine gestational age. Gestational age at delivery established by ultrasound was compared with postnatal gestational age assessment (Ballard examination). RESULTS: One hundred and seventy-eight women were enrolled. The majority of images were of good quality (94.3%, 509/540) although a learning curve was apparent with 17.5% (24/135) images of unacceptable quality in the first 25% of scans. Ultrasound was used to date 13% of the pregnancies when menstrual dates were unknown and changed the estimated gestational age for an additional 25%. There was poor agreement between the gestational age at delivery as established by the ultrasound protocol compared to that determined by the Ballard examination (bias 0.8 weeks, limits of agreement -3.5 weeks to 5.1 weeks). The distribution of gestational ages by Ballard suggested a clustering of gestational age around the mean with 87% of the values falling between 39 and 41 weeks. The distribution of gestational age by ultrasound confirmed menstrual dates was more typical. Using ultrasound confirmed dates as the gold standard, 78.5% of preterm infants were misclassified as term and 26.8% of small-for gestational age infants misclassified as appropriately grown by Ballard. CONCLUSION: Ultrasound should be strongly considered in prospective malaria studies with obstetric endpoints to confirm gestational age and avoid misclassification of infants as premature or growth-restricted. The use of ultrasound does require a significant investment of time to maintain quality image acquisition. PMID- 23734719 TI - The EAL domain containing protein STM2215 (rtn) is needed during Salmonella infection and has cyclic di-GMP phosphodiesterase activity. AB - Salmonella Typhimurium gene STM2215 (rtn) is conserved among many enterobacteriaceae. Mutants lacking STM2215 poorly colonized the liver and spleen in intraperitoneal infection of mice and poorly colonized the intestine and deeper tissues in oral infection. These phenotypes were complemented by a wild type copy of STM2215 provided in trans. STM2215 deletion mutants grew normally in J774A.1 murine macrophages but were unable to invade Caco-2 colonic epithelial cells. Consistent with this finding, mutants in STM2215 produced lower levels of effectors of the TTSS-1. STM2215 is a predicted c-di-GMP phosphodiesterase, but lacks identifiable sensor domains. Biochemical analysis of STM2215 determined that it is located in the inner membrane and has c-di-GMP phosphodiesterase activity in vitro dependent on an intact EAL motif. Unlike some previously identified members of this family, STM2215 did not affect motility, was expressed on plates, and in liquid media at late exponential and early stationary phase during growth. Defined mutations in STM2215 revealed that neither the predicted periplasmic domain nor the anchoring of the protein to the inner membrane is necessary for the activity of this protein during infection. However, the EAL domain of STM2215 is required during infection, suggesting that its phosphodiesterase activity is necessary during infection. PMID- 23734720 TI - Association between absolute tumor burden and serum bone-specific alkaline phosphatase in canine appendicular osteosarcoma. AB - BACKGROUND: In dogs with appendicular osteosarcoma (OSA), increased pretreatment serum bone-specific alkaline phosphatase (BALP) activity is a negative prognostic factor, associated with shorter disease-free intervals and survival times, but a biologic basis for observed differential serum BALP activities in canine OSA patients remains incompletely defined. OBJECTIVE: Serum BALP activity will correlate with absolute tumor burden in dogs with OSA. ANIMALS: This study included 96 client-owned dogs with appendicular OSA. METHODS: In canine OSA cell lines, the expression and membranous release of BALP was evaluated in vitro. The correlation between serum BALP activity and radiographic primary tumor size was evaluated in OSA-bearing dogs. In dogs developing visceral OSA metastases, serial changes in serum BALP activities were evaluated in relation to progression of macroscopic metastases, and visceral metastatic OSA cells were evaluated for BALP expression. RESULTS: In vitro, BALP expression was not associated with either tumorigenic or metastatic phenotype, rather the quantity of membranous BALP released was proportional with cell density. In dogs devoid of macroscopic metastases, there was a positive correlation between serum BALP activity and absolute primary tumor size. In dogs with progressive OSA metastases, serum BALP activity increased and coincided with the development of macroscopic metastases. OSA cells derived from visceral metastatic lesions retained BALP expression. CONCLUSIONS AND CLINICAL IMPORTANCE: Tumor burden is a determinant of serum BALP activity in dogs with appendicular OSA. The association between increased pretreatment BALP activity and negative clinical prognosis may simply be attributed to greater initial tumor burden, and consequently more advanced tumor stage. PMID- 23734721 TI - Sesquiterpenes and alkaloids from the roots of Alangium chinense. AB - Four new sesquiterpenes (1-4), four new alkaloids (5a, 6a, 6b, and 7), and nine known compounds (5b and 8-15) were isolated from an ethanolic extract of roots of Alangium chinense. The structure of 1 was confirmed by X-ray crystallography. The configurations of 5 and 6 were assigned by chiral HPLC analysis and CD spectra. Compounds 3, 4, 8-13, and 15 exhibited antiviral activity against Coxsackie virus B3 with IC50 values of 1.4-15.4 MUM. Compounds 2-4, 7, and 9-13 showed antioxidant activities against Fe(2+)-cysteine-induced rat liver microsomal lipid peroxidation, with IC50 values of 3.8-45.7 MUM. Compound 5b displayed neuritis inhibitory activity against microglial inflammation factor, with an IC50 value of 6.7 MUM. None of the compounds exhibited detectable cytotoxic activity toward any of five tumor cell lines (A549, Be-17402, BGC-823, HCT-8, and A2780) in the MTT assay. PMID- 23734722 TI - Emergence and Distribution of Foot-and-Mouth Disease Virus Serotype A and O in Bangladesh. AB - Foot-and-mouth disease (FMD) is endemic in Bangladesh and is predominantly due to FMDV serotype O. In 2012, FMD outbreaks were identified in five different districts of Bangladesh. Of 56 symptomatic cattle epithelial tissue samples, diagnostic PCR assay based on 5'-URT detected 38 FMDV infections. Viral genotyping targeting VP1-encoding region confirmed emergence of two distinct serotypes, A and O with an abundance of serotype A in Chittagong and Gazipur districts and serotype O in Pabna and Faridpur. Only single lineage of both A and O was retrieved from samples of five different regions. Sequencing and phylogenetic analysis of VP1 sequences revealed that serotype O sequences were closely related to the Ind 2001 sublineage of Middle East-South Asia (ME-SA) topotype that was previously circulating in Bangladesh, and serotype A sequences belonging to the genotype VII that was dominant in India during the last decade. The results suggest that extensive cross-border animal movement from neighbouring countries is the most likely source of FMDV serotypes in Bangladesh. PMID- 23734723 TI - Rare earth metal-mediated group-transfer polymerization: from defined polymer microstructures to high-precision nano-scaled objects. AB - Poly(2-isopropenyl-2-oxazoline) (PIPOx) and poly(2-vinylpyridine) (P2VP) have been efficiently synthesized using bis(cyclopentadienyl)methylytterbium (Cp2YbMe) as catalyst. The polymerizations of 2-isopropenyl-2-oxazoline (IPOx) and 2 vinylpyridine (2VP) follow a living group-transfer polymerization (GTP) mechanism, allowing a precise molecular-weight control of both polymers with very narrow molecular-weight distribution. The GTP of IPOx and 2VP occurs via N coordination at the rare earth metal center, which has rarely been reported previously. The relative coordination strength of different monomers at the ytterbium center is determined by copolymerization investigations to be in the order of DEVP > MMA > IPOx > 2VP. In combination with living cationic ring opening polymerization, PIPOx is converted to molecular brushes with defined backbone and poly(2-oxazoline) side chains using the grafting-from method. PMID- 23734724 TI - Joint genotype inference with germline and somatic mutations. AB - The joint sequencing of related genomes has become an important means to discover rare variants. Normal-tumor genome pairs are routinely sequenced together to find somatic mutations and their associations with different cancers. Parental and sibling genomes reveal de novo germline mutations and inheritance patterns related to Mendelian diseases.Acute lymphoblastic leukemia (ALL) is the most common paediatric cancer and the leading cause of cancer-related death among children. With the aim of uncovering the full spectrum of germline and somatic genetic alterations in childhood ALL genomes, we conducted whole-exome re sequencing on a unique cohort of over 120 exomes of childhood ALL quartets, each comprising a patient's tumor and matched-normal material, and DNA from both parents. We developed a general probabilistic model for such quartet sequencing reads mapped to the reference human genome. The model is used to infer joint genotypes at homologous loci across a normal-tumor genome pair and two parental genomes.We describe the algorithms and data structures for genotype inference, model parameter training. We implemented the methods in an open-source software package (QUADGT) that uses the standard file formats of the 1000 Genomes Project. Our method's utility is illustrated on quartets from the ALL cohort. PMID- 23734725 TI - Synergistic combination of small molecule inhibitor and RNA interference against antiapoptotic Bcl-2 protein in head and neck cancer cells. AB - B-cell lymphoma 2 (Bcl-2) is an antiapoptotic protein that is overexpressed in head and neck squamous cell carcinomas, which has been implicated in development of radio- and chemoresistance. Small molecule inhibitors such as AT-101 (a BH3 mimetic drug) have been developed to inhibit the antiapoptotic activity of Bcl-2 proteins, which proved effective in restoring radio- and chemo-sensitivity in head and neck cancer cells. However, high doses of AT-101 are associated with gastrointestinal, hepatic, and fertility side effects, which prompted the search for other Bcl-2 inhibitors. Short interfering RNA (siRNA) proved to inhibit antiapoptotic Bcl-2 protein expression and trigger cancer cell death. However, transforming siRNA molecules into a viable therapy remains a challenge due to the lack of efficient and biocompatible carriers. We report the development of degradable star-shaped polymers that proved to condense anti-Bcl-2 siRNA into "smart" pH-sensitive and membrane-destabilizing particles that shuttle their cargo past the endosomal membrane and into the cytoplasm of head and neck cancer cells. Results show that "smart" anti-Bcl-2 particles reduced the mRNA and protein levels of antiapoptotic Bcl-2 protein in UM-SCC-17B cancer cells by 50 60% and 65-75%, respectively. Results also show that combining "smart" anti-Bcl-2 particles with the IC25 of AT-101 (inhibitory concentration responsible for killing 25% of the cells) synergistically inhibits cancer cell proliferation and increases cell apoptosis, which reduce the survival of UM-SCC-17B cancer cells compared to treatment with AT-101 alone. Results indicate the therapeutic benefit of combining siRNA-mediated knockdown of antiapoptotic Bcl-2 protein expression with low doses of AT-101 for inhibiting the growth of head and neck cancer cells. PMID- 23734726 TI - Traffic medicine-related research: a scientometric analysis. AB - OBJECTIVE: Traffic crashes and related injuries are important causes of morbidity and mortality and impose insofar an important burden on public health. However, research in this area is often under-funded. The aim of this study was to analyse quantity, evolution and geographic distribution of traffic medicine-related research. This multi-sectorial field covers both transport and health care sectors. DESIGN: A scientometric approach in combination with visualizing density equalizing mapping was used to analyse published data related to the field of traffic medicine between 1900 and 2008 within the "Web of Science" (WoS) database. RESULTS: In total, 5,193 traffic medicine-associated items were produced between 1900 and 2008. The United States was found to have the highest research activity with a production of n = 2,330 published items, followed by Germany (n = 298) and Canada (n = 219). Cooperation analyses resulted in a peak of published multilateral cooperations in the year of 2003. The country with the highest multilateral activity was the USA. The average number of cited references per publication varied heavily over the last 20 years with a maximum of 27.67 in 1995 and a minimum of 15.08 in 1998. Also, a further in-depth analysis was performed with a focus solely on public health aspects which revealed similar trends. CONCLUSIONS: Summarizing the present data it can be stated traffic medicine-related research productivity grows annually. Also, an active networking between countries is present. The data of the present study may be used by scientific organisations in order to gain detailed information about research activities in this field which is extremely important for public health. PMID- 23734727 TI - Cell based therapy in Parkinsonism. AB - Parkinson's disease (PD) is a synucleinopathy-induced chronic progressive neurodegenerative disorder, worldwide affecting about 5 million humans. As of yet, actual therapies are symptomatic, and neuroprotective strategies are an unmet need. Due to their capability to transdifferentiate, to immune modulate and to increase neuroplasticity by producing neurotrophic factors, adult stem cells (ASC) might fill this gap. Preclinical research in 6-hydroxydopamine (6-OHDA) and/or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned animals established persistent improvements of motor behavior after ASC-treatment. Histological/histochemical measurements in these animals evidenced an intracerebral applied ASC-induced increase of Tyrosine Hydroxylase-positive (TH+) cells with increased striatal dopamine levels, suggesting cell rescue. Likewise, clinical experience with subventricular applied ASCs in PD patients, although limited, is encouraging, evidencing neurorescue especially during the early phase of the disease. In multiple system atrophy (MSA) or progressive supranuclear palsy (PSP) patients, though, only marginal reduced progression of natural progression could be established after subventricular or intravasal ASC implantations. PMID- 23734728 TI - Differential sensitivity of polyhydroxyalkanoate producing bacteria to fermentation inhibitors and comparison of polyhydroxybutyrate production from Burkholderia cepacia and Pseudomonas pseudoflava. AB - BACKGROUND: The aim of this study is determine the relative sensitivity of a panel of seven polyhydroxyalkanoate producing bacteria to a panel of seven lignocellulosic-derived fermentation inhibitors representing aliphatic acids, furans and phenolics. A further aim was to measure the polyhydroxybutyrate production of select organisms on lignocellulosic-derived monosaccharides arabinose, xylose, glucose and mannose. FINDINGS: We examined the sensitivity of seven polyhydroxyalkanoate producing bacteria: Azohydromonas lata, Bacillus megaterium, Bacillus cereus, Burkholderia cepacia, Pseudomonas olevorans, Pseudomonas pseudoflava and Ralstonia eutropha, against seven fermentation inhibitors produced by the saccharification of lignocellulose: acetic acid, levulinic acid, coumaric acid, ferulic acid, syringaldehyde, furfural, and hyroxymethyfurfural. There was significant variation in the sensitivity of these microbes to representative phenolics ranging from 0.25-1.5 g/L coumaric and ferulic acid and between 0.5-6.0 g/L syringaldehyde. Inhibition ranged from 0.37 4 g/L and 0.75-6 g/L with acetic acid and levulinic acid, respectively. B. cepacia and P. pseudoflava were selected for further analysis of polyhydroxyalkanoate production. CONCLUSIONS: We find significant differences in sensitivity to the fermentation inhibitors tested and find these variations to be over a relevant concentration range given the concentrations of inhibitors typically found in lignocellulosic hydrolysates. Of the seven bacteria tested, B. cepacia demonstrated the greatest inhibitor tolerance. Similarly, of two organisms examined for polyhydroxybutyrate production, B. cepacia was notably more efficient when fermenting pentose substrates. PMID- 23734730 TI - High-performance UV photodetection of unique ZnO nanowires from zinc carbonate hydroxide nanobelts. AB - Zinc carbonate hydroxide nanobelts are prepared by the hydrolysis of zinc acetate aqueous solution in the presence of urea at 90 degrees C. The zinc carbonate hydroxide nanobelts can be facilely self-assembled in a circular flexible freestanding film with a diameter of 8.4 cm and thickness of ~48 MUm. The calcination of the zinc carbonate hydroxide nanobelts at 300 degrees C under normal atmospheric condition results in the formation of ZnO nanowires. The zinc carbonate hydroxide nanobelts and resultant ZnO nanowires are characterized by XRD, SEM, TEM, TG-DSC, PL, and impedance measurement. The characterization results indicate that the ZnO nanowires exhibit unique nanostructure characterized by long chains of closely attached ZnO nanocrystals with ZnO/ZnO nanocrystal junctions. The unique ZnO nanowire-based UV photodetector exhibit much higher photoresponse currents (at the milliampere level) and on/off current ratio (~1000) than ZnO nanocrystal-based UV photodetector. Under the UV irradiance of 120 mW cm(-2) and low applied voltage of 0.5 V, the peak photoresponse current and on/off current ratio of the ZnO nanowire photodetector are 56 and 36 times higher than those of the ZnO nanocrystal UV photodetector, respectively. The reason for the superior photodetection performance of the ZnO nanowires over the ZnO nanocrystals is discussed. PMID- 23734729 TI - Evolution by selection, recombination, and gene duplication in MHC class I genes of two Rhacophoridae species. AB - BACKGROUND: Comparison of major histocompatibility complex (MHC) genes across vertebrate species can reveal molecular mechanisms underlying the evolution of adaptive immunity-related proteins. As the first terrestrial tetrapods, amphibians deserve special attention because of their exposure to probably increased spectrum of microorganisms compared with ancestral aquatic fishes. Knowledge regarding the evolutionary patterns and mechanisms associated with amphibian MHC genes remains limited. The goal of the present study was to isolate MHC class I genes from two Rhacophoridae species (Rhacophorus omeimontis and Polypedates megacephalus) and examine their evolution. RESULTS: We identified 27 MHC class I alleles spanning the region from exon 2 to 4 in 38 tree frogs. The available evidence suggests that these 27 sequences all belong to classical MHC class I (MHC Ia) genes. Although several anuran species only display one MHC class Ia locus, at least two or three loci were observed in P. megacephalus and R. omeimontis, indicating that the number of MHC class Ia loci varies among anuran species. Recombination events, which mainly involve the entire exons, played an important role in shaping the genetic diversity of the 27 MHC class Ia alleles. In addition, signals of positive selection were found in Rhacophoridae MHC class Ia genes. Amino acid sites strongly suggested by program to be under positive selection basically accorded with the putative antigen binding sites deduced from crystal structure of human HLA. Phylogenetic relationships among MHC class I alleles revealed the presence of trans-species polymorphisms. CONCLUSIONS: In the two Rhacophoridae species (1) there are two or three MHC class Ia loci; (2) recombination mainly occurs between the entire exons of MHC class Ia genes; (3) balancing selection, gene duplication and recombination all contribute to the diversity of MHC class Ia genes. These findings broaden our knowledge on the evolution of amphibian MHC systems. PMID- 23734731 TI - Mitochondrial genome of Psenopsis anomala (Pacific rudderfish) and structure schema comparison of control region in Stromateoidei. AB - In this study, the complete mitochondrial genome of Psenopsis anomala (Perciformes, Centrolophidae) was first determined. The mitochondrial DNA was 16,509 base pairs in length. The overall base composition of P. anomala is A 28.4%, C 27.5%, G 16.6% and T 27.5%, with a slight A + T bias of 55.9%. It consists of 22 tRNA genes, 2 ribosomal RNA genes, 13 protein-coding genes and 2 main non-coding regions (the origin of the light strand replication and the putative control region), in which the genes structure and order are similar to most other vertebrates. These mitogenome sequence data would play an important role in population genetics and phylogenetic analysis of the Centrolophidae. PMID- 23734732 TI - Multimetastability in a spin-crossover compound leading to different high-spin-to low-spin relaxation dynamics. AB - The relaxation kinetics of both the thermally trapped and photoinduced high-spin (HS) states of the spin-crossover compound [Fe(H4L)2](ClO4)2.H2O.2(CH3)2CO (1) were measured and found to differ significantly. Calorimetry measurements then demonstrated that relaxation of the thermally trapped phase was concurrent with two separate processes, not previously detected as such. Determination of the photogenerated HS structure revealed a new metastable HS state of the system, much closer structurally to the low-spin phase than the thermally trapped one. This difference is proposed as the root of the disparate kinetic behavior, which is proposed to require two processes in the case of the structurally more complex thermally trapped state. Therefore, light irradiation is shown as a mechanism to decouple effectively the structural and magnetic phase transitions that occur in 1 during the course of its spin crossover. PMID- 23734733 TI - Using Monte Carlo simulation to compute liquid-vapor saturation properties of ionic liquids. AB - We discuss Monte Carlo (MC) simulation methods for calculating liquid-vapor saturation properties of ionic liquids. We first describe how various simulation tools, including reservoir grand canonical MC, growth-expanded ensemble MC, distance-biasing, and aggregation-volume-biasing, are used to address challenges commonly encountered in simulating realistic models of ionic liquids. We then indicate how these techniques are combined with histogram-based schemes for determining saturation properties. Both direct methods, which enable one to locate saturation points at a given temperature, and temperature expanded ensemble methods, which provide a means to trace saturation lines to low temperature, are discussed. We study the liquid-vapor phase behavior of the restricted primitive model (RPM) and a realistic model for 1,3 dimethylimidazolium tetrafluoroborate ([C1mim][BF4]). Results are presented to show the dependence of saturation properties of the RPM and [C1mim][BF4] on the size of the simulation box and the boundary condition used for the Ewald summation. For [C1mim][BF4] we also demonstrate the ability of our strategy to sample ion clusters that form in the vapor phase. Finally, we provide the liquid vapor saturation properties of these models over a wide range of temperature. Overall, we observe that the choice of system size and boundary condition have a non-negligible effect on the calculated properties, especially at high temperature. Also, we find that the combination of grand canonical MC simulation and isothermal-isobaric temperature expanded ensemble MC simulation provides a computationally efficient means to calculate liquid-vapor saturation properties of ionic liquids. PMID- 23734734 TI - Germline stem cell arrest inhibits the collapse of somatic proteostasis early in Caenorhabditis elegans adulthood. AB - All cells rely on highly conserved protein folding and clearance pathways to detect and resolve protein damage and to maintain protein homeostasis (proteostasis). Because age is associated with an imbalance in proteostasis, there is a need to understand how protein folding is regulated in a multicellular organism that undergoes aging. We have observed that the ability of Caenorhabditis elegans to maintain proteostasis declines sharply following the onset of oocyte biomass production, suggesting that a restricted protein folding capacity may be linked to the onset of reproduction. To test this hypothesis, we monitored the effects of different sterile mutations on the maintenance of proteostasis in the soma of C. elegans. We found that germline stem cell (GSC) arrest rescued protein quality control, resulting in maintenance of robust proteostasis in different somatic tissues of adult animals. We further demonstrated that GSC-dependent modulation of proteostasis requires several different signaling pathways, including hsf-1 and daf-16/kri-1/tcer-1, daf-12, daf-9, daf-36, nhr-80, and pha-4 that differentially modulate somatic quality control functions, such that each signaling pathway affects different aspects of proteostasis and cannot functionally complement the other pathways. We propose that the effect of GSCs on the collapse of proteostasis at the transition to adulthood is due to a switch mechanism that links GSC status with maintenance of somatic proteostasis via regulation of the expression and function of different quality control machineries and cellular stress responses that progressively lead to a decline in the maintenance of proteostasis in adulthood, thereby linking reproduction to the maintenance of the soma. PMID- 23734735 TI - International differences in cost and consumption of ready-to-consume food and drink products: United Kingdom and Brazil, 2008-2009. AB - This paper tests the hypothesis that one important factor determining household availability of ready-to-consume products is their cost relative to the rest of the diet. National food expenditure surveys in the UK (2008) and Brazil (2008-09) were used. Purchased food quantities were converted into dietary energy (calories) and classified into three groups: (1) foods that are unprocessed or minimally processed; (2) processed culinary ingredients; and (3) ready-to-consume products, either processed or ultra-processed. The contribution of these groups to diets in each country was calculated as a percentage of total energy. Relative cost of ready-to-consume products in each country was calculated by dividing their cost by the cost of the rest of the diet (foods plus culinary ingredients). Linear regression analysis was used to test the association between the UK to Brazil ratios of the caloric share of different ready-to-consume products, and of the relative cost of these products. The caloric share of ready-to-consume products in the UK (63.4%) was well over double that of Brazil (27.7%), whereas their cost relative to the rest of the diet was 43% lower. The lower the relative cost of ready-to-consume products in the UK (compared with Brazil), the higher their relative consumption (R(2)=0.38, p<0.01). PMID- 23734736 TI - The majority of newly generated cells in the adult mouse substantia nigra express low levels of Doublecortin, but their proliferation is unaffected by 6-OHDA induced nigral lesion or Minocycline-mediated inhibition of neuroinflammation. AB - Parkinson's disease is characterized by a selective loss of dopaminergic neurons in the substantia nigra (SN). However, whether regenerative endogenous neurogenesis is taking place in the mammalian SN of parkinsonian and non parkinsonian brains remains of debate. Here, we tested whether proliferating cells in the SN and their neurogenic potential would be affected by anti inflammatory treatment under physiological conditions and in the 6-hydroxy dopamine (6-OHDA) Parkinson's disease mouse model. We report that the majority of newly generated nigral cells are positive for Doublecortin (Dcx), which is an often used marker for neural progenitor cells. Yet, Dcx expression levels in these cells were much lower than in neural progenitor cells of the subventricular zone and the dentate gyrus neural progenitor cells. Furthermore, these newly generated nigral cells are negative for neuronal lineage markers such as TuJ1 and NeuN. Therefore, their neuronal commitment is questionable. Instead, we found evidence for oligodendrogenesis and astrogliosis in the SN. Finally, neither short-term nor long-term inhibition of neuroinflammation by Minocycline- or 6 OHDA-induced lesion affected the numbers of newly generated cells in our disease paradigm. Our findings of adult generated Dcx(+) cells in the SN add important data for understanding the cellular composition and consequently the regenerative capacity of the SN. PMID- 23734737 TI - Involvement of lipoprotein PpiA of Streptococcus gordonii in evasion of phagocytosis by macrophages. AB - Streptococcus gordonii is a commensal gram-positive bacterium that resides in the human oral cavity, and is one of the most common causes of infective endocarditis (IE). Bacterial surface molecules play an important role in establishing IE, and several S. gordonii proteins have been implicated in binding to host cells during the establishment of IE. In this study, we identified a putative lipoprotein, peptidyl-prolyl cis/trans isomerase (PpiA), and clarified its role in evasion of phagocytosis by macrophages. Attenuation of the gene encoding prolipoprotein diacylglyceryl transferase (Lgt) altered the localization of PpiA from the cell surface to the culture supernatant, indicating that PpiA is lipid-anchored in the cell membrane by Lgt. Both human and murine macrophages showed higher phagocytic activity towards ppiA and lgt mutants than the wild-type, indicating that the presence of PpiA suppresses phagocytosis of S. gordonii. Human macrophages treated with dextran sulfate had significantly impaired phagocytosis of S. gordonii, suggesting that class A scavenger receptors in human macrophages are involved in the phagocytosis of S. gordonii. These results provide evidence that S. gordonii lipoprotein PpiA plays an important role in inhibiting phagocytic engulfment and in evasion of the host immune response. PMID- 23734738 TI - Case of giant sclerosing epithelioid fibrosarcoma with ossification. PMID- 23734739 TI - Cloning and characterization of bifunctional enzyme farnesyl diphosphate/geranylgeranyl diphosphate synthase from Plasmodium falciparum. AB - BACKGROUND: Isoprenoids are the most diverse and abundant group of natural products. In Plasmodium falciparum, isoprenoid synthesis proceeds through the methyl erythritol diphosphate pathway and the products are further metabolized by farnesyl diphosphate synthase (FPPS), turning this enzyme into a key branch point of the isoprenoid synthesis. Changes in FPPS activity could alter the flux of isoprenoid compounds downstream of FPPS and, hence, play a central role in the regulation of a number of essential functions in Plasmodium parasites. METHODS: The isolation and cloning of gene PF3D7_18400 was done by amplification from cDNA from mixed stage parasites of P. falciparum. After sequencing, the fragment was subcloned in pGEX2T for recombinant protein expression. To verify if the PF3D7_1128400 gene encodes a functional rPfFPPS protein, its catalytic activity was assessed using the substrate [4-14C] isopentenyl diphosphate and three different allylic substrates: dimethylallyl diphosphate, geranyl diphosphate or farnesyl diphosphate. The reaction products were identified by thin layer chromatography and reverse phase high-performance liquid chromatography. To confirm the product spectrum formed of rPfFPPS, isoprenic compounds were also identified by mass spectrometry. Apparent kinetic constants KM and Vmax for each substrate were determined by Michaelis-Menten; also, inhibition assays were performed using risedronate. RESULTS: The expressed protein of P. falciparum FPPS (rPfFPPS) catalyzes the synthesis of farnesyl diphosphate, as well as geranylgeranyl diphosphate, being therefore a bifunctional FPPS/geranylgeranyl diphosphate synthase (GGPPS) enzyme. The apparent KM values for the substrates dimethylallyl diphosphate, geranyl diphosphate and farnesyl diphosphate were, respectively, 68 +/- 5 MUM, 7.8 +/- 1.3 MUM and 2.06 +/- 0.4 MUM. The protein is expressed constitutively in all intra-erythrocytic stages of P. falciparum, demonstrated by using transgenic parasites with a haemagglutinin-tagged version of FPPS. Also, the present data demonstrate that the recombinant protein is inhibited by risedronate. CONCLUSIONS: The rPfFPPS is a bifunctional FPPS/GGPPS enzyme and the structure of products FOH and GGOH were confirmed mass spectrometry. Plasmodial FPPS represents a potential target for the rational design of chemotherapeutic agents to treat malaria. PMID- 23734742 TI - CD169-positive macrophages in regional lymph nodes are associated with a favorable prognosis in patients with colorectal carcinoma. AB - CD169 (sialoadhesin) is a sialic acid receptor that is expressed on specific macrophages such as lymph node sinus macrophages. Animal studies have suggested that CD169(+) macrophages have a pro-inflammatory property, however, the role of these cells in human diseases has not been clarified. In our in vitro experiments with human macrophages, pro-inflammatory cytokines, such as type 1 interferon, induced strong expression of CD169, suggesting that CD169 might be a specific marker of inflammatory macrophages. To examine the role of CD169 in antitumor immunity, we examined the expression of CD169 in regional lymph nodes (RLNs) and its association with overall survival in colorectal carcinoma (CRC). In a clinicopathological analysis on 83 CRC patients, paraffin-embedded specimens were evaluated for CD169 expression of RLN macrophages by immunohistochemistry. We found, for the first time, a high density of CD169(+) macrophages was significantly associated with longer overall survival; multivariate analysis showed that the ratio of CD169(+) cells to CD68(+) cells was an independent prognostic factor. The majority of CD169(+) macrophages were in direct contact with CD8(+) T cells expressing CD43, a major ligand of CD169. We also found that the density of CD169(+) macrophages had a positive correlation with the number of CD8(+) cytotoxic T cells infiltrating tumor tissues. These data suggest that CD169(+) macrophages in RLNs promote CD8(+) T-cell-mediated antitumor immunity and are associated with a better prognosis for CRC patients. CD169(+) macrophages in RLNs could be a useful marker for assessing clinical prognosis and monitoring antitumor immunity in patients with CRC. PMID- 23734743 TI - Discovering and mapping chromatin states using a tree hidden Markov model. AB - New biological techniques and technological advances in high-throughput sequencing are paving the way for systematic, comprehensive annotation of many genomes, allowing differences between cell types or between disease/normal tissues to be determined with unprecedented breadth. Epigenetic modifications have been shown to exhibit rich diversity between cell types, correlate tightly with cell-type specific gene expression, and changes in epigenetic modifications have been implicated in several diseases. Previous attempts to understand chromatin state have focused on identifying combinations of epigenetic modification, but in cases of multiple cell types, have not considered the lineage of the cells in question.We present a Bayesian network that uses epigenetic modifications to simultaneously model 1) chromatin mark combinations that give rise to different chromatin states and 2) propensities for transitions between chromatin states through differentiation or disease progression. We apply our model to a recent dataset of histone modifications, covering nine human cell types with nine epigenetic modifications measured for each. Since exact inference in this model is intractable for all the scale of the datasets, we develop several variational approximations and explore their accuracy. Our method exhibits several desirable features including improved accuracy of inferring chromatin states, improved handling of missing data, and linear scaling with dataset size. The source code for our model is available at http:// http://github.com/uci-cbcl/tree-hmm. PMID- 23734744 TI - Anti-inflammatory and antinociceptive activity of epiisopiloturine, an imidazole alkaloid isolated from Pilocarpus microphyllus. AB - The aim of this study was to investigate the antinociceptive and anti inflammatory activities of epiisopiloturine (1), an imidazole alkaloid found in the leaves of Pilocarpus microphyllus. The anti-inflammatory activity of 1 was evaluated using several agents that induce paw edema and peritonitis in Swiss mice. Paw tissue and peritoneal fluid samples were obtained to determine myeloperoxidase (MPO) activity or tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta levels. The antinociceptive activity was evaluated by acetic acid-induced writhing, the hot plate test, and pain induction using formalin. Compared to vehicle treatment, pretreatment with 1 (0.1, 0.3, and 1 mg/kg, ip) of mice significantly reduced carrageenan-induced paw edema (p < 0.05). Furthermore, compound 1 at a dose of 1 mg/kg effectively inhibited edema induced by dextran sulfate, serotonin, and bradykinin, but had no effect on histamine-induced edema. The administration of 1 (1 mg/kg) following carrageenan induced peritonitis reduced total and differential peritoneal leukocyte counts and also carrageenan-induced paw MPO activity and TNF-alpha and IL-1beta levels in the peritoneal cavity. Pretreatment with 1 also reduced acetic acid-induced writhing and inhibited the first and second phases of the formalin test, but did not alter response latency in the hot plate test. Pretreatment with naloxone reversed the antinociceptive effect of 1. PMID- 23734745 TI - How can erythropoeitin-stimulating agent use be reduced in chronic dialysis patients?: The "forgotten adjunct therapy": the link between ESA use and control of hyperparathyroidism in chronic kidney disease. PMID- 23734746 TI - The efficacy of Ezetimibe added to ongoing Fibrate-Statin therapy on postprandial lipid profile in the patients with type 2 Diabetes mellitus. AB - BACKGROUND: Postprandial hypertriglyceridemia in diabetes mellitus can be followed by endothelial dysfunction, impaired vascular compliance and increased cardiovascular complications. So focus on better control of postprandial hypertriglyceridemia is as important as controlling fasting triglyceride level in type 2 DM. OBJECTIVE: We evaluated the effect of ezetimibe adding to fibrate or statin on postprandial hypertriglyceridemia. METHODS: In a randomized controlled clinical trial, 47 subjects with type 2 diabetes and hypertiglyceridemia were enrolled and divided in three treatment groups including Gemfibrozil 1200mg/d + placebo(group A), Ezetimibe10mg/d + Gemfibrozile 1200mg/d(group B) or Ezetimibe10mg/d + Atorvastatin10mg/d (group C) for a 6- week period. Oral fat loading test were performed in the initiation and also at the end of the study and lipid profile and APOB were measured. RESULTS: Fasting and postprandial serum triglyceride (TG) decreased significantly with all the three treatment groups with no difference between them in the percent of TG reduction. Although serum total cholesterol decreased significantly in all the three groups of treatment its reduction was more prominent in group C(-38.1% +/- 11.2%in group C vs. -16.5% +/- 19.6% and -7.2% +/- 10.7% in groups B & A respectively, p < 0.0001 ). Fasting serum HDL increased significantly only by Gemfibrozil (23.4% +/- 28.4% vs. 6.4% +/- 18.9% and 1.8% +/- 17.7%, p < 0.05 ). Fasting serum APOB was reduced only in ezetimibe containing groups (B &C). CONCLUSION: Adding ezetimibe to gemfibrozil has no additional effect on reducing postprandial TG but ezetimibe can potentiate the effect of low-dose atorvastatin on lowering TG and LDL-c. PMID- 23734747 TI - Expulsion of ions from hydrophobic hydration shells. AB - Raman spectroscopy is combined with multivariate curve resolution to quantify interactions between ions and molecular hydrophobic groups in water. The molecular solutes in this study all have similar structures, with a trimethyl hydrophobic domain and a polar or charged headgroup. Our results imply that aqueous sodium and fluoride ions are strongly expelled from the first hydration shells of the hydrophobic (methyl) groups, while iodide ions are found to enter the hydrophobic hydration shell, to an extent that depends on the methyl group partial charge. However, our quantitative estimates of the corresponding ion binding equilibrium constants indicate that the iodide concentration in the first hydrophobic hydration shell is generally lower than that in the surrounding bulk water, and so an iodide ion cannot be viewed as having a true affinity for the molecular hydrophobic interface, but rather is less strongly expelled from such an interface than fluoride. PMID- 23734748 TI - Association of genes of protease-antiprotease balance pathway to lung function and emphysema subtypes. AB - BACKGROUND: The imbalance between proteases and antiproteases has been proposed to participate to the pathogenesis of chronic obstructive pulmonary disease (COPD) and emphysema. Gene level variation in different metalloproteinases, metalloproteinase inhibitors, and cytokines affecting them may contribute to this imbalance and destruction of the lung parenchyma. We investigated whether polymorphisms in selected protease-antiprotease balance pathway genes predispose to different emphysema subtypes (centrilobular, paraseptal, panlobular, and bullae) and airflow limitation among Finnish construction workers. METHODS: Eleven single nucleotide polymorphisms (SNPs) from seven genes (GC: rs7041 and rs4588; MMP1: rs1799750; MMP9: rs3918242; MMP12: rs652438; TIMP2: rs2277698; TNF: rs1799724 and rs1800629; TGFB1: rs1800469, rs1800470, and rs2241718) were analyzed from 951 clinically and radiologically characterized construction workers. The genotype and haplotype data was compared to different emphysematous signs confirmed with high resolution computed tomography (HRCT), forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and maximal expiratory flow at 50% of FVC (MEF50) by using linear and logistic regression analyses, adjusted for potential confounders. RESULTS: The TIMP2 rs2277698 SNP was associated with overall (p = 0.022) and paraseptal (p = 0.010) emphysema, as well as with FEV1/FVC ratio (p = 0.035) and MEF50 (p = 0.008). The TGFB1 rs2241718 and MMP9 rs3918242 SNPs were associated with centrilobular emphysema (p = 0.022 and p = 0.008), and the TNF rs1800629 SNP with paraseptal emphysema (p = 0.017). In stratified analysis, individuals with at least one TIMP2 rs2277698 or TNF rs1800629 variant allele were found to be at around two-fold risk for pathological paraseptal changes (OR 1.94, 95% CI 1.14-3.30; OR 2.10, 95% CI 1.24 3.56). On the contrary, the risk for pathological centrilobular changes was halved for individuals with at least one MMP9 rs3918242 (OR 0.51, 95% CI 0.30 0.86) or TGFB1 rs2241718 (OR 0.53, 95% CI 0.30-0.90) variant allele, or TGFB1 rs1800469-rs1800470 AT-haplotype (OR 0.55, 95% CI 0.33-0.93). MEF50, in turn, was significantly reduced among individuals with at least one TIMP2 rs2277698 variant allele (p = 0.011). CONCLUSION: Our findings strengthen the hypothesis of the importance of protease-antiprotease balance in pathogenesis of emphysema and shed light on the aetiology of different emphysema subtypes by associating MMP9 and TGFB1 to centrilobular emphysema, and TIMP2 and TNF to paraseptal emphysema and/or airflow obstruction. PMID- 23734749 TI - Identification of stress-responsive genes in Ammopiptanthus mongolicus using ESTs generated from cold- and drought-stressed seedlings. AB - BACKGROUND: Ammopiptanthus mongolicus is the only evergreen broadleaf shrub in the northwest desert of China, which can survive long-term aridity and extremely cold environments. In order to understand the genetic mechanisms underlying stress tolerance and adaptation to unfavorable environments of woody plants, an EST approach was used to investigate expression patterns of A. mongolicus in response to abiotic stresses. RESULTS: ESTs were generated from a cDNA library constructed from A. mongolicus seedlings subjected to cold and drought stresses. Analysis of 5,637 cDNA sequences led to the identification of 5,282 ESTs and 1,594 unigenes, which were denoted as the AmCDUnigene set. Of these, 70% of unigenes were annotated and classified into 12 functional categories according to Gene Ontology, and 30% of unigenes encoded unknown function proteins, suggesting some of them were novel or A. mongolicus specific genes. Using comparative analysis with the reported genes from other plants, 528 (33%) unigenes were identified as stress-responsive genes. The functional classification of the 528 genes showed that a majority of them are associated with scavenging reactive oxygen species, stress response, cellular transport, signal transduction and transcription. To further identify candidate abiotic stress-tolerance genes, the 528 stress-responsive genes were compared with reported abiotic stress genes in the Comparative Stress Genes Catalog of GCP. This comparative analysis identified 120 abiotic stress-responsive genes, and their expression in A. mongolicus seedlings under cold or drought stress were characterized by qRT-PCR. Significantly, 82 genes responded to cold and/or drought stress. These cold- and/or drought-inducible genes confirmed that the ROS network, signal transduction and osmolyte accumulation undergo transcriptional reorganization when exposed to cold or drought stress treatments. Additionally, among the 1,594 unigenes sequences, 155 simple sequence repeats (SSRs) were identified. CONCLUSION: This study represents a comprehensive analysis of cold and/or drought stress-responsive transcriptiome of A. mongolicus. The newly characterized genes and gene-derived markers from the AmCDUnigene set are valuable resources for a better understanding of the mechanisms that govern stress tolerance in A. mongolicus and other related species. Certain up-regulated genes characterizing these processes are potential targets for breeding for cold and/or drought tolerance of woody plants. PMID- 23734750 TI - Modelling the glycocalyx-endothelium-erythrocyte interaction in the microcirculation: a computational study. AB - A novel, coarse-grained, single-framework 'Eulerian' model for blood flow in the microvascular circulation is presented and used to estimate the variations in flow properties that accrue from all of the following: (i) wall position variation, associated with the endothelial cells' (ECs) shape, (ii) glycocalyx layer (GL) effects and (iii) the particulate nature of blood. We stress that our new model is fully coupled and uses only a single Eulerian computational framework to recover complex effects, dispensing altogether with the need for, e.g. re-meshing and advected sets of Lagrangian points. Physically, blood is modelled as a two-component, incompressible fluid - the plasma and corpuscular elements dispersed in it. The latter are modelled as deformable liquid droplets of increased viscosity. Interfacial membrane effects are present to mimic key blood properties and to avoid droplets' coalescence. The model is encapsulated within a multi-component lattice Boltzmann method that uses a sub-lattice 'wavy wall' closure to represent the ECs. Between this boundary and the flow domain, the model incorporates a coarse-grained representation of the endothelial GL, which is known to cover microvessel walls. The endothelial glycocalyx is modelled as a medium of variable and adaptive porosity, with approaching droplets being subject to a repulsive elastic force. Numerical simulations are presented to show the combined and simultaneous influence on fundamental flow properties of the EC wall undulation, the glycocalyx compression and repulsion and the particulate nature of blood. Several characteristic hemodynamical features of microvessel flow are successfully reproduced, including the deformability of particulates and the Fahraeus-Lindqvist effect. Moreover, the importance of modelling the GL is manifest in the magnitude of and the temporal variations in the flow rate and wall shear stresses. PMID- 23734751 TI - Dynamics of self-assembly of model viral capsids in the presence of a fluctuating membrane. AB - A coarse-grained computational model is used to investigate the effect of a fluctuating fluid membrane on the dynamics of patchy-particle assembly into virus capsid-like cores. Results from simulations for a broad range of parameters are presented, showing the effect of varying interaction strength, membrane stiffness, and membrane viscosity. Furthermore, the effect of hydrodynamic interactions is investigated. Attraction to a membrane may promote assembly, including for subunit interaction strengths for which it does not occur in the bulk, and may also decrease single-core assembly time. The membrane budding rate is strongly increased by hydrodynamic interactions. The membrane deformation rate is important in determining the finite-time yield. Higher rates may decrease the entropic penalty for assembly and help guide subunits toward each other but may also block partial cores from being completed. For increasing subunit interaction strength, three regimes with different effects of the membrane are identified. PMID- 23734752 TI - The influence of pain sensitivity on the treatment outcome of transforaminal epidural steroid injection in patients with lumbar spinal stenosis. AB - The aim of this study was to investigate the effect of individual pain sensitivity on the results of transforaminal epidural steroid injection (TFESI) for the patients with lumbar spinal stenosis (LSS). Seventy-seven patients with LSS were included in this study. Prospectively planned evaluations were performed twice consecutively before and 2 months after TFESI. These included a detailed medical history, a physical examination, and completion of a series of questionnaires, including pain sensitivity questionnaire (PSQ), Oswestry disability index (ODI), and visual analog scale (VAS) for back and leg pain. The correlations were analyzed among variables between total PSQ/PSQ-moderate/PSQ minor and pain and disability level measured by VAS for back/leg pain and ODI both before and 2 months after TFESI. Two months after TFESI, there were significant decreases in VAS for back/leg pain and ODI compared with those before injection. Before injection, VAS for back pain and leg pain was highly associated with the PSQ scores including total PSQ and PSQ subscores after adjustment for age, BMI, and grade of canal stenosis. However, any subscores of PSQ and total PSQ scores were not correlated with either VAS for back pain/leg pain or ODI 2 months after TFESI with adjustment made to age, BMI, gender, and grade of canal stenosis. This study highlights that individual pain sensitivity does not influence the outcomes of TFESI treatment in patients with LSS, even though pain sensitivity has a significant negative correlation with symptom severity of LSS. PMID- 23734753 TI - Associations between health-related physical fitness and obesity in Taiwanese youth. AB - This study examined associations between four health-related physical fitness measures and obesity in Taiwanese youth aged 10-18 years. Data from 13,500 school aged youth were randomly selected from the "School Physical Fitness Database" of Taiwan by sex and age. Variables examined were height, body mass and performance on modified sit-and-reach (flexibility), bent-leg sit-up (abdominal muscular strength/endurance), standing long jump (lower body explosive strength) and distance run/walk (cardiorespiratory endurance). Adjusted logistic regression analyses were performed. Increased odds of being obese with decreased fitness levels were observed for lower body explosive strength and cardiorespiratory endurance in both sexes. The highest odds of being obese was found in the least fit quintile of cardiorespiratory endurance compared with the most fit quintile both in boys (Odds ratio, OR = 10.44; 95% confidence interval (CI), 7.94-13.73) and girls (OR = 5.40; 95% CI, 3.90-7.47). These findings suggest that in addition to cardiorespiratory fitness, lower body explosive strength is also associated with childhood and adolescent obesity. PMID- 23734754 TI - Severe rhabdomyolysis associated with concurrent use of simvastatin and sirolimus after cisplatin-based chemotherapy in a kidney transplant recipient. AB - OBJECTIVES: Cardiovascular disease is the most common cause of sickness and death for long-term kidney transplant recipients, and dyslipidemia is an important risk factor for developing cardiovascular disease. Lipid-lowering strategies, with the use of statins, have been shown to reduce the cardiovascular risks related to dyslipidemia, but concomitant use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and immunosuppressive agents may increase the risk of rhabdomyolysis owing to a drug-drug interaction. We report a case of simvastatin induced rhabdomyolysis and acute kidney injury triggered by addition of sirolimus and cisplatin-based chemotherapy to a kidney transplant recipient who had previously tolerated chronic statin therapy. PMID- 23734755 TI - Radiation resistance of sequencing chips for in situ life detection. AB - Life beyond Earth may be based on RNA or DNA if such life is related to life on Earth through shared ancestry due to meteoritic exchange, such as may be the case for Mars, or if delivery of similar building blocks to habitable environments has biased the evolution of life toward utilizing nucleic acids. In this case, in situ sequencing is a powerful approach to identify and characterize such life without the limitations or expense of returning samples to Earth, and can monitor forward contamination. A new semiconductor sequencing technology based on sensing hydrogen ions released during nucleotide incorporation can enable massively parallel sequencing in a small, robust, optics-free CMOS chip format. We demonstrate that these sequencing chips survive several analogues of space radiation at doses consistent with a 2-year Mars mission, including protons with solar particle event-distributed energy levels and 1 GeV oxygen and iron ions. We find no measurable impact of irradiation at 1 and 5 Gy doses on sequencing quality nor on low-level hardware characteristics. Further testing is required to study the impacts of soft errors as well as to characterize performance under neutron and gamma irradiation and at higher doses, which would be expected during operation in environments with significant trapped energetic particles such as during a mission to Europa. Our results support future efforts to use in situ sequencing to test theories of panspermia and/or whether life has a common chemical basis. PMID- 23734756 TI - Impact of Al passivation and cosputter on the structural property of beta-FeSi2 for Al-doped beta-FeSi2/n-Si(100) based solar cells application. AB - The aluminum (Al) doped polycrystalline p-type beta-phase iron disilicide (p-beta FeSi2) is grown by thermal diffusion of Al from Al-passivated n-type Si(100) surface into FeSi2 during crystallization of amorphous FeSi2 to form a p-type beta-FeSi2/n-Si(100) heterostructure solar cell. The structural and photovoltaic properties of p-type beta-FeSi2/n-type c-Si structures is then investigated in detail by using X-ray diffraction, Raman spectroscopy, transmission electron microscopy analysis, and electrical characterization. The results are compared with Al-doped p-beta-FeSi2 prepared by using cosputtering of Al and FeSi2 layers on Al-passivated n-Si(100) substrates. A significant improvement in the maximum open-circuit voltage (Voc) from 120 to 320 mV is achieved upon the introduction of Al doping through cosputtering of Al and amorphous FeSi2 layer. The improvement in Voc is attributed to better structural quality of Al-doped FeSi2 film through Al doping and to the formation of high quality crystalline interface between Al-doped beta-FeSi2 and n-type c-Si. The effects of Al-out diffusion on the performance of heterostructure solar cells have been investigated and discussed in detail. PMID- 23734758 TI - Consumer-perceived risks and choices about pharmaceuticals in the environment: a cross-sectional study. AB - BACKGROUND: There is increasing concern that pollution from pharmaceuticals used in human medicine and agriculture can be a threat to the environment. Little is known, however, if people are aware that pharmaceuticals may have a detrimental influence on the environment. The present study examines people's risk perception and choices in regard to environmental risks of pharmaceuticals used in human medicine and for agricultural purposes. METHODS: A representative sample of the U.S. population (N = 640) was surveyed. Respondents completed a hypothetical choice task that involved tradeoffs between human and environmental health. In addition, it was examined how much people would support an environment policy related to drug regulation. RESULTS: For agricultural pharmaceuticals, respondents reported a high level of satisfaction for a policy requiring farms to limit their use of antibiotics. In the domain of pharmaceuticals used in human medicine, we found that people were willing to consider environmental consequences when choosing a drug, but only when choices were made about treatment options for a rather harmless disease. In contrast, when decisions were made about treatment options for a severe disease, the drug's effectiveness was the most important criterion. CONCLUSIONS: It can be concluded that the environmental impact of a drug will be hardly considered in decisions about pharmaceuticals for severe diseases like cancer, and this may be due to the fact that these decisions are predominantly affective in nature. However, for less severe health risks, people are willing to balance health and environmental considerations. PMID- 23734757 TI - Human Wharton's jelly-derived mesenchymal stromal cells reduce renal fibrosis through induction of native and foreign hepatocyte growth factor synthesis in injured tubular epithelial cells. AB - INTRODUCTION: Based on some well-documented reports, we attempted to clarify the antifibrotic mechanisms of human Wharton's-jelly-derived mesenchymal stromal cells (WJ-MSCs) from the perspective of induction of hepatocyte growth factor (HGF) expression in tubular epithelial cells (TECs). METHODS: A rat model of acute kidney injury (AKI) was established through unilateral renal ischemia for 1 hour. Two days later, a single intravenous cell or vehicle injection, or contralateral nephrectomy, was performed. Rats were sacrificed at 1 day, 1 week, 4 weeks, or 6 weeks after the intervention. Renal fibrosis was evaluated by Masson trichrome staining and Sircol collagen assay. The upregulation of alpha smooth muscle actin (alpha-SMA) versus E-cadherin expression was adopted as an indicator of tubular epithelial-mesenchymal transition (EMT). Gene and protein expression of HGF or transforming growth factor-beta1 (TGF-beta1) was determined by real-time polymerase chain reaction (RT-PCR) and Western blot, respectively. HGF expression in TECs was detected with immunostaining. In vitro, rat TECs subjected to hypoxia injury were incubated with or without conditioned medium (CM) from WJ-MSCs for 1, 3, 24, or 48 hours. Rat or human HGF synthesis in TECs was assessed with immunostaining, RT-PCR, or ELISA. RESULTS: Cell delivery or nephrectomy led to abrogation of renal scarring. At the incipient period of AKI, through induction of HGF expression, either of them remarkably promoted the upregulation of HGF versus TGF-beta1 expression in damaged kidney. Rat TECs were not only the principal cells expressing HGF but also exhibited human HGF expression after cell infusion. During fibrogenesis, the downregulation of HGF versus TGF-beta1 expression was greatly prevented by WJ-MSCs or kidney removal, thereby resulting in tubular EMT delay. In vitro, after 24 or 48 hours of incubation, CM not only robustly induced the upregulation of rat HGF gene expression in TECs but substantially amplified the release of rat HGF. Under the induction of CM, human HGF mRNA and protein were detected in rat TECs. CONCLUSIONS: WJ-MSCs contribute to tubular EMT delay and the alleviation of renal fibrosis. Induction of native and foreign HGF synthesis in damaged TECs at the initial stage of AKI leads to recovery of the disturbed balance of HGF/TGF-beta1 during scar formation, being one of the vital mechanisms. PMID- 23734761 TI - Synthesis of electron-rich uranium(IV) complexes supported by tridentate Schiff base ligands and their multi-electron redox chemistry. AB - The synthesis, structure, and reactivity of a new complex of U(IV) with the tridentate Schiff base ligand Menaphtquinolen are reported. The reduction of the bis-ligand complexes [UX2((Me)naphtquinolen)2] (X = Cl, (1-Cl) ; I (1-I)) with potassium metal affords the U(IV) complex of the new tetranionic hexadentate ligand MU-bis-(Me)naphtquinolen formed through the intramolecular reductive coupling of the imino groups of each (Me)naphtquinolen unit. The solid state structure of the [U(MU-bis-(Me)naphtquinolen)]2 dimer 2 isolated from toluene confirms the presence of a U(IV) complex of the reduced ligand. Reactivity studies with molecular oxygen and 9,10-phenanthrenequinone show that complex 2 can act as a multielectron reducing agent releasing two electrons through the cleavage of the C-C bond to restore the original imino function of the ligand. In the resulting U(IV) and U(VI) complexes [U(9,10 phenanthrenediol)((Me)naphtquinolen)2], 3, and [UO2((Me)naphtquinolen)2], 4, the restored tridentate Schiff base allows for the coordination of the reduced substrate to the metal. Electrochemical studies of complex 2 show the presence of irreversible ligand centered reduction processes and of a reversible U(IV)/U(III) couple. PMID- 23734759 TI - Metabolic syndrome, adiponectin, and cardiovascular risk in Spain (the Segovia study): impact of consensus societies criteria. AB - BACKGROUND: We aimed to investigate the prevalence of metabolic syndrome in rural and urban areas in the province of Segovia, Spain, and its relationship to lifestyle habits, cardiovascular risk, and serum adiponectin concentrations. METHODS: The study had a cross-sectional design and included 888 individual residents in the province of Segovia, Autonomous Community of Castilla-Leon. RESULTS: The age/sex standardized prevalence of the metabolic syndrome was by: (1) American Heart Association/National Heart Lung and Blood Institute criteria (AHA/NHLBI), 17%; (2) International Diabetes Federation (IDF), 24.3%; and (3) Consensus Societies/Joint Interim Statement (CS), 27.8%. A high correlation was found between the different criteria. No formal education [odds ratio (OR) 6.9 (2.4-20.2)] and primary education [6.7 (2.8-15.9)] were independently associated with metabolic syndrome. An inverse association with metabolic syndrome was found for subjects doing a high level of exercise during work [0.4 (0.2-0.7)] as well as those who were mild drinkers [alcohol intake of less than 15 grams/daily, 0.4 (0.3-0.8)]. Among subjects with low estimated cardiovascular risk, adiponectin levels are higher in those who do not meet criteria of metabolic syndrome. A total of 29.7% of subjects meeting CS criteria had >20% 10-year predicted risk of cardiovascular disease (CVD) by the Framingham risk score criteria [4.5 (2.4 8.5)]. CONCLUSIONS: Our results show: (1) A higher estimated prevalence of metabolic syndrome according to IDF and CS criteria. (2) Low educational level was independently associated with metabolic syndrome. A high level of physical activity and a daily alcohol intake of less than 15 grams/day were inversely associated with metabolic syndrome. (3) Metabolic syndrome increases the predicted CVD risk. (4) Adiponectin levels are not inversely related to insulin resistance in subjects with high cardiovascular risk and metabolic syndrome. PMID- 23734760 TI - Genetic variation in the patatin-like phospholipase domain-containing protein-3 (PNPLA-3) gene in Asian Indians with nonalcoholic fatty liver disease. AB - BACKGROUND: The association of the rs738409 polymorphism of patatin-like phospholipase-3 (PNPLA3) with nonalcoholic fatty liver disease (NAFLD) has been suggested in other populations, but not in Asian Indians. We investigated the association of the rs738409 polymorphism of PNPLA3 with clinical, anthropometric, and biochemical profiles in Asian Indians with NAFLD. METHODS: In this case control study, 162 cases and 173 controls were recruited. Abdominal ultrasound, clinical, anthropometry, and biochemical profiles were determined. Fasting insulin levels and values for homeostasis model assessment of insulin resistance (HOMA-IR) were determined. Polymerase chain reaction and restriction fragment length polymorphism of the PNPLA3 gene were performed. The associations of this polymorphism with clinical, anthropometric, and biochemical profiles were investigated. RESULTS: A higher frequency of C/G and G/G genotypes of the rs738409 polymorphism was obtained in cases as compared to controls (P=0.04), and as a consequence the frequency of the minor allele G was significantly higher in cases (P=0.003). In this study, the G allele was associated with significantly higher fasting insulin (P=0.002), HOMA-IR (P=0.05), alanine transaminase (P=0.003), and aspartate transaminase (P=0.04) values only in cases, but not in the controls. The values of serum triglycerides and total cholesterol were slightly higher in cases with G/C+G/G genotypes but statistically not significant (P>0.05). Using a multivariate logistic regression model after adjusting for age, sex, body mass index, and fasting insulin, subjects with the G/G genotype showed higher risk of NAFLD [odds ratio (OR), 1.98, 95% confidence interval (CI) 1.43 2.73, P=0.04). The relationships of the rs738409 polymorphism with the metabolic parameters were not significant after adjustment for multiple comparisons. CONCLUSION: Asian Indians in north India carrying the allele rs738490 of PNPLA3 is predispose to develop NAFLD. PMID- 23734762 TI - Prioritization of candidate disease genes by topological similarity between disease and protein diffusion profiles. AB - BACKGROUND: Identification of gene-phenotype relationships is a fundamental challenge in human health clinic. Based on the observation that genes causing the same or similar phenotypes tend to correlate with each other in the protein protein interaction network, a lot of network-based approaches were proposed based on different underlying models. A recent comparative study showed that diffusion-based methods achieve the state-of-the-art predictive performance. RESULTS: In this paper, a new diffusion-based method was proposed to prioritize candidate disease genes. Diffusion profile of a disease was defined as the stationary distribution of candidate genes given a random walk with restart where similarities between phenotypes are incorporated. Then, candidate disease genes are prioritized by comparing their diffusion profiles with that of the disease. Finally, the effectiveness of our method was demonstrated through the leave-one out cross-validation against control genes from artificial linkage intervals and randomly chosen genes. Comparative study showed that our method achieves improved performance compared to some classical diffusion-based methods. To further illustrate our method, we used our algorithm to predict new causing genes of 16 multifactorial diseases including Prostate cancer and Alzheimer's disease, and the top predictions were in good consistent with literature reports. CONCLUSIONS: Our study indicates that integration of multiple information sources, especially the phenotype similarity profile data, and introduction of global similarity measure between disease and gene diffusion profiles are helpful for prioritizing candidate disease genes. AVAILABILITY: Programs and data are available upon request. PMID- 23734763 TI - Columnar metaplasia in a surgical mouse model of gastro-esophageal reflux disease is not derived from bone marrow-derived cell. AB - The incidence of esophageal adenocarcinoma has increased in the last 25 years. Columnar metaplasia in Barrett's mucosa is assumed to be a precancerous lesion for esophageal adenocarcinoma. However, the induction process of Barrett's mucosa is still unknown. To analyze the induction of esophageal columnar metaplasia, we established a mouse gastro-esophageal reflux disease (GERD) model with associated development of columnar metaplasia in the esophagus. C57BL/6 mice received side to-side anastomosis of the esophagogastric junction with the jejunum, and mice were killed 10, 20, and 40 weeks after operation. To analyze the contribution of bone marrow-derived cells to columnar metaplasia in this surgical GERD model, some mice were transplanted with GFP-marked bone marrow after the operation. Seventy-three percent of the mice (16/22) showed thickened mucosa in esophagus and 41% of mice (9/22) developed columnar metaplasia 40 weeks after the operation with a mortality rate of 4%. Bone marrow-derived cells were not detected in columnar metaplastic epithelia. However, scattered epithelial cells in the thickened squamous epithelia in regions of esophagitis did show bone marrow derivation. The results demonstrate that reflux induced by esophago-jejunostomy in mice leads to the development of columnar metaplasia in the esophagus. However, bone marrow-derived cells do not contribute directly to columnar metaplasia in this mouse model. PMID- 23734764 TI - Copper-catalyzed oxidative Heck reactions between alkyltrifluoroborates and vinyl arenes. AB - We report herein that potassium alkyltrifluoroborates can be utilized in oxidative Heck-type reactions with vinyl arenes. The reaction is catalyzed by a Cu(OTf)2/1,10-phenanthroline with MnO2 as the stoichiometric oxidant. In addition to the alkyl Heck, amination, esterification, and dimerization reactions of alkyltrifluoroborates are demonstrated under analogous reaction conditions. Evidence for an alkyl radical intermediate is presented. PMID- 23734765 TI - Areolar sebaceous hyperplasia associated with oral and genital Fordyce spots. PMID- 23734766 TI - Bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone antagonize methamphetamine-induced efflux of dopamine according to their potencies as dopamine uptake inhibitors: implications for the treatment of methamphetamine dependence. AB - BACKGROUND: Methamphetamine-abuse is a worldwide health problem for which no effective therapy is available. Inhibition of methamphetamine-induced transporter mediated dopamine (DA) release could be a useful approach to treat methamphetamine-addiction. We assessed the potencies of bupropion, methylphenidate, and 3,4-methylenedioxypyrovalerone (MDPV) to block DA uptake or to inhibit methamphetamine-induced DA release in HEK-293 cells expressing the human DA transporter. FINDINGS: Bupropion, methylphenidate, and MDPV inhibited methamphetamine-induced DA release with relative potencies corresponding to their potencies to block DA uptake (potency ranks: MDPV > methylphenidate > bupropion). CONCLUSIONS: Bupropion and methylphenidate antagonize the effects of methamphetamine in vitro and may be potential candidates for the treatment of stimulant addiction. However, drugs that very potently antagonize the effect of methamphetamine are likely to also exhibit considerable abuse liability (MDPV > methylphenidate > bupropion). PMID- 23734767 TI - De novo production of metabolites by fungal co-culture of Trichophyton rubrum and Bionectria ochroleuca. AB - The co-cultivation of fungi has recently been described as a promising strategy to induce the production of novel metabolites through possible gene activation. A large screening of fungal co-cultures in solid media has identified an unusual long-distance growth inhibition between Trichophyton rubrum and Bionectria ochroleuca. To study metabolite induction in this particular fungal interaction, differential LC-MS-based metabolomics was performed on pure strain cultures and on their co-cultures. The comparison of the resulting fingerprints highlighted five de novo induced compounds, which were purified using software-oriented semipreparative HPLC-MS. One metabolite was successfully identified as 4" hydroxysulfoxy-2,2"-dimethylthielavin P (a substituted trimer of 3,5 dimethylorsellinic acid). The nonsulfated form, as well as three other related compounds, were found in the pure strain culture of B. ochroleuca. PMID- 23734768 TI - Idiopathic pulmonary fibrosis in 2011: key updates on guidelines and therapeutics. PMID- 23734769 TI - Assessment and clinical course of hypocalcemia in critical illness. AB - INTRODUCTION: Hypocalcemia is common in critically ill patients. However, its clinical course during the early days of admission and the role of calcium supplementation remain uncertain, and the assessment of calcium status is inconsistent. We aimed to establish the course of hypocalcemia during the early days of critical illness in relation to mortality and to assess the impact of calcium supplementation on calcium normalization and mortality. METHODS: Data were collected on 1,038 admissions to the critical care units of a tertiary care hospital. One gram of calcium gluconate was administered intravenously once daily to patients with adjusted calcium (AdjCa)<2.2 mmol/L. Demographic and outcome data were compared in normocalcemic (ionized calcium, iCa, 1.1-1.3 mmol/L) and mildly and severely hypocalcemic patients (iCa 0.9-1.1 mmol/L and <0.9 mmol/L, respectively). The change in iCa concentrations was monitored during the first four days of admission and comparisons between groups were made using Repeated Measures ANOVA. Comparisons of normalization and outcome were made between hypocalcemic patients who did and did not receive calcium replacement according to the local protocol. The suitability of AdjCa to predict low iCa was determined by analyzing sensitivity, specificity and receiver operating characteristic (ROC) curves. Multivariate logistic regression was performed to determine associations of other electrolyte derangements with hypocalcemia. RESULTS: 55.2% of patients were hypocalcemic on admission; 6.2% severely so. Severely hypocalcemic patients required critical care for longer (P=0.001) compared to normocalcemic or mildly hypocalcemic patients, but there was no difference in mortality between groups (P=0.48). iCa levels normalized within four days in most, with no difference in normalization between those who died and survived (P=0.35). Severely hypocalcemic patients who failed to normalize their iCa by day 4 had double the mortality (38% vs. 19%, P=0.15). Neither iCa normalization nor survival were superior in hypocalcemic patients receiving supplementation on admission. AdjCa<2.2 mmol/L had a sensitivity of 78.2% and specificity of 63.3% for predicting iCa<1.1 mmol/L. Low magnesium, sodium and albumin were independently associated with hypocalcemia on admission. CONCLUSIONS: Hypocalcemia usually normalizes within the first four days after admission to ICU and failure to normalize in severely hypocalcemic patients may be associated with increased mortality. Calcium replacement appears not to improve normalization or mortality. AdjCa is not a good surrogate of iCa in an ICU setting. PMID- 23734770 TI - Symptomatic venous thromboembolism and mortality in orthopaedic surgery - an observational study of 45 968 consecutive procedures. AB - BACKGROUND: Little information exists on the presentation of symptomatic venous thromboembolism (VTE) in orthopaedic surgery when a defined protocol for thromboprophylaxis is used. The objective with this study was to establish the VTE rate and mortality rate in orthopaedic surgery. METHODS: We performed a prospective, single centre observational cohort study of 45 968 consecutive procedures in 36 388 patients over a 10 year period. Follow-up was successful in 99.3%. The primary study outcome was the incidence of symptomatic deep vein thrombosis (DVT), symptomatic pulmonary embolism (PE) and mortality at 6 weeks, specified for different surgical procedures. The secondary outcome was to describe the DVT distribution in proximal and distal veins and the proportion of VTEs diagnosed after hospital discharge. For validation purposes, a retrospective review of VTEs diagnosed 7-12 weeks postoperatively was also performed. RESULTS: In total, 514 VTEs were diagnosed (1.1%; 95% CI: 1.10-1.14), the majority (84%) after hospital discharge (432 out of 514).With thromboprophylaxis, high incidence of VTE was found after internal fixation (IF) of pelvic fracture (12%; 95% CI: 5 26), knee replacement surgery (3.7%; 95% CI: 2.8-5.0), after internal fixation (IF) of proximal tibia fracture (3.8%; 95% CI: 2.3-6.3) and after IF of ankle fracture (3.6%; 95% CI: 2.9-4.4). Without thromboprophylaxis, high incidence of VTE was found after Achilles tendon repair (7.2%; 95% CI: 5.5-9.4). In total 1094 patients deceased (2.4%; 95% confidence interval (CI): 2.33- 2.44) within 6 weeks of surgery. Highest mortality was seen after lower limb amputation (16.3%, CI: 13.8-19.1) and after hip hemiarthroplasty due to hip fracture (9.6%, CI; 7.6 12.1). CONCLUSION: The overall incidence of VTE is low after orthopaedic surgery but our study highlights surgical procedures after which the risk for VTE remains high and improved thromboprophylaxis is needed. PMID- 23734771 TI - Enantioselective palladium-catalyzed diamination of alkenes using N fluorobenzenesulfonimide. AB - An enantioselective Pd-catalyzed vicinal diamination of unactivated alkenes using N-fluorobenzenesulfonimide as both an oxidant and a source of nitrogen is reported. The use of Ph-pybox and Ph-quinox ligands afforded differentially protected vicinal diamines in good yields with high enantioselectivities. Mechanistic experiments revealed that the high enantioselectivity arises from selective formation of only one of four possible diastereomeric aminopalladation products of the chiral Pd complex. The aminopalladation complex was characterized by X-ray crystallography. PMID- 23734772 TI - Role of the eIF4E binding protein 4E-BP1 in regulation of the sensitivity of human pancreatic cancer cells to TRAIL and celastrol-induced apoptosis. AB - BACKGROUND INFORMATION: Tumour cells can be induced to undergo apoptosis after treatment with the tumour necrosis factor alpha-related death-inducing ligand (TRAIL). Although human pancreatic cancer cells show varying degrees of response they can be sensitised to the pro-apoptotic effects of TRAIL in the presence of celastrol, a natural compound extracted from the plant Tripterygium wilfordii Hook F. One important aspect of the cellular response to TRAIL is the control of protein synthesis, a key regulator of which is the eukaryotic initiation factor 4E-binding protein, 4E-BP1. RESULTS: We examined the effects of celastrol and TRAIL in several pancreatic cancer cell lines. In cells that are normally resistant to TRAIL, synergistic effects of TRAIL plus celastrol on commitment to apoptosis and inhibition of protein synthesis were observed. These were associated with a strong up-regulation and dephosphorylation of 4E-BP1. The enhancement of 4E-BP1 expression, which correlated with a threefold increase in the level of the 4E-BP1 transcript, was blocked by inhibitors of reactive oxygen species and the JNK protein kinase. When the expression of 4E-BP1 was reduced by an inducible micro-RNA, TRAIL-mediated apoptosis was inhibited. CONCLUSION: These results suggest that 4E-BP1 plays a critical role in the mechanism by which TRAIL and celastrol together cause apoptotic cell death in human pancreatic tumour cells. PMID- 23734774 TI - Phosphonate- and carboxylate-based self-assembled monolayers for organic devices: a theoretical study of surface binding on aluminum oxide with experimental support. AB - We report a computational study on the chemical bonding of phosphonates and carboxylates to aluminum oxide surfaces and how the binding properties are related to the amount of water in the experimental environment. Two different surface structures were used in the calculations in order to model representative adsorption sites for the phosphonates and carboxylates and to account for the amorphous nature of the hydroxylated AlOx films in experiment. For the phosphonates, we find that the thermodynamically preferred binding mode changes between mono-, bi-, and tridentate depending on the surface structure and the amount of residual water. For the carboxylates, on the other hand, monodentate adsorption is always lower in energy at all experimental conditions. Phosphonates are more strongly bound to aluminum oxide than carboxylates, so that carboxylates can be replaced easily by phosphonates. The theoretical findings are consistent with those obtained in adsorption, desorption, and exchange reactions of n-alkyl phosphonic and carboxylic acids on AlOx surfaces. The results provide an atomistic understanding of the adsorption and help to optimize experimental conditions for self-assembly of organic films on aluminum oxide surfaces. PMID- 23734773 TI - "Let's get the best quality research we can": public awareness and acceptance of consent to use existing data in health research: a systematic review and qualitative study. AB - BACKGROUND: Opt-in consent is usually required for research, but is known to introduce selection bias. This is a particular problem for large scale epidemiological studies using only pre-collected health data. Most previous studies have shown that members of the public value opt-in consent and can perceive research without consent as an invasion of privacy. Past research has suggested that people are generally unaware of research processes and existing safeguards, and that education may increase the acceptability of research without prior informed consent, but this recommendation has not been formally evaluated. Our objectives were to determine the range of public opinion about the use of existing medical data for research and to explore views about consent to a secondary review of medical records for research. We also investigated the effect of the provision of detailed information about the potential effect of selection bias on public acceptability of the use of data for research. METHODS: We carried out a systematic review of existing literature on public attitudes to secondary use of existing health records identified by searching PubMed (1966-present), Embase (1974-present) and reference lists of identified studies to provide a general overview, followed by a qualitative focus group study with 19 older men recruited from rural and suburban primary care practices in the UK to explore key issues in detail. RESULTS: The systematic review identified twenty-seven relevant papers and the findings suggested that males and older people were more likely to consent to a review of their medical data. Many studies noted participants' lack of knowledge about research processes and existing safeguards and this was reflected in the focus groups. Focus group participants became more accepting of the use of pre-collected medical data without consent after being given information about selection bias and research processes. All participants were keen to contribute to NHS-related research but some were concerned about data sharing for commercial gain and the potential misuse of information. CONCLUSIONS: Increasing public education about research and specific targeted information provision could promote trust in research processes and safeguards, which in turn could increase the acceptability of research without specific consent where the need for consent would lead to biased findings and impede research necessary to improve public health. PMID- 23734775 TI - How can erythropoeitin-stimulating agent use be reduced in chronic dialysis patients?: Can reduction of inflammation improve ESA dose response? PMID- 23734776 TI - Association of IFIH1 rs1990760 polymorphism with susceptibility to autoimmune diseases: a meta-analysis. AB - Published data on the association between the IFIH1 rs1990760 polymorphism and multiple autoimmune diseases are controversial and inconclusive. To more precisely estimate the association between the IFIH1 rs1990760 polymorphism and susceptibility to autoimmune diseases, a meta-analysis was conducted. Studies examining the association of the IFIH1 rs1990760 polymorphism with autoimmune diseases were exhaustively searched using PubMed, Web of Science and a review of the references. A total of 19 studies with 26 comparisons including 8 type 1 diabetes (T1D), 5 systemic lupus erythematosus (SLE), 5 Graves' disease (GD), 2 multiple sclerosis (MS), 2 rheumatoid arthritis (RA), 2 Hashimoto's thyroiditis (HT), 2 autoimmune Addison's disease (AAD) were available for this meta-analysis. Meta-analysis was performed for genotype T/T + T/C (dominant model), genotype T/T (recessive model) and T-allele in fixed or random-effects models. The overall odds ratios (ORs) and 95% confidence intervals (CIs) for T-allele were T1D (OR = 1.184, 95% CI = 1.142-1.229), SLE (OR = 1.143, 95% CI = 1.073-1.217), MS (OR = 1.181, 95% CI = 1.062-1.313) and RA (OR = 1.115, 95% CI = 1.004-1.239), respectively. For T1D and SLE, significant association was observed in the population of European ancestry, but not in the Asian population. This meta analysis demonstrates that the IFIH1 rs1990760 T-allele confers susceptibility to T1D, SLE, MS and RA and suggests that the IFIH1 rs1990760 polymorphism might have no effect on GD and AAD. Our result provides further evidence for the notion of common gene underlying multiple autoimmune diseases. PMID- 23734778 TI - Ylide hydrolysis in tandem reactions: a highly Z/E-selective access to 3 alkylidene dihydrobenzofurans and related analogues. AB - An efficient synthetic approach to benzoheterocycles has been developed based on the hydrolysis of key ylide intermediates in a tandem reaction, upon which a variety of 3-alkylidene dihydrobenzofurans and related benzoheterocyclic products can be obtained in high yields with excellent Z/E selectivity. PMID- 23734777 TI - Lack of strong effect modification by NFE2L2/CYP3A5/ABO of the risk of venous thrombosis associated with oral hormone therapy. PMID- 23734779 TI - In planta effector competition assays detect Hyaloperonospora arabidopsidis effectors that contribute to virulence and localize to different plant subcellular compartments. AB - The genome of the pathogenic oomycete Hyaloperonospora arabidopsidis is predicted to encode at least 134 high-confidence effectors (HaRxL) carrying the RxLR motif implicated in their translocation into plant cells. However, only four avirulence genes (ATR1, ATR13, ATR5, and ATR39) have been isolated. This indicates that identification of HaRxL effectors based on avirulence is low throughput. We aimed at rapidly identifying H. arabidopsidis effectors that contribute to virulence by developing methods to detect and quantify multiple candidates in bacterial mixed infections using either Illumina sequencing or capillary electrophoresis. In these assays, referred to here as in planta effector competition assays, we estimate the contribution to virulence of individual effectors by calculating the abundance of each HaRxL in the bacterial population recovered from leaves 3 days after inoculation relative to abundance in the initial mixed inoculum. We identified HaRxL that enhance Pseudomonas syringae pv. tomato DC3000 growth in some but not all Arabidopsis accessions. Further analysis showed that HaRxLL464, HaRxL75, HaRxL22, HaRxLL441, and HaRxL89 suppress pathogen-associated molecular pattern-triggered immunity (PTI) and localize to different subcellular compartments in Nicotiana benthamiana, providing evidence for a multilayered suppression of PTI by pathogenic oomycetes and molecular probes for the dissection of PTI. PMID- 23734781 TI - Observational analysis of the offensive sequences that ended in a shot by the winning team of the 2010 UEFA Futsal Championship. AB - This article analyses the offensive phase of the national team than won the 2010 UEFA Championship. More specifically, the observational sampling includes all plays in which the Spanish national futsal team managed to "shoot" in the competition in question. This data was obtained by adapting an observational and recording tool typically used for football to the technical specifications of futsal; the SOF-CODER (Jonsson et al., 2006). Two types of analysis have been performed. One statistical analysis using the SPSS programme, version 15.0, the most relevant results from which refer to the significant differences found on linking: the zone from which the shot is made and the type of shot (chi2 = 55.821, P = 0.006); and the contact surface used and the type of shot (chi2 = 30.293, P = 0.017). And another, using the Theme programme, version 5.0, through which regular behaviour structures (temporal patterns) have been detected within the plays that include shooting. The temporal patterns obtained--in addition to elaborating on the relationship between the area from which the shot is made, the contact surface used and the type of shot--enable a tactical interpretation of the technical actions that support the development of the offensive phase of futsal. PMID- 23734780 TI - Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) are adult, multipotent, stem cells with immunomodulatory properties. The mechanisms involved in the capacity of MSCs to inhibit the proliferation of proinflammatory T lymphocytes, which appear responsible for causing autoimmune disease, have yet to be fully elucidated. One of the underlying mechanisms studied recently is the ability of MSCs to generate T regulatory (Treg) cells in vitro and in vivo from activated peripheral blood mononuclear cells (PBMC), T-CD4+ and also T-CD8(+) cells. In the present work we investigated the capacity of MSCs to generate Treg cells using T-CD4(+) cells induced to differentiate toward the proinflammatory Th1 and Th17 lineages. METHODS: MSCs were obtained from mouse bone marrow and characterized according to their surface antigen expression and their multilineage differentiation potential. CD4(+) T cells isolated from mouse spleens were induced to differentiate into Th1 or Th17 cells and co-cultured with MSCs added at day 0, 2 or 4 of the differentiation processes. After six days, CD25, Foxp3, IL-17 and IFN gamma expression was assessed by flow cytometry and helios and neuropilin 1 mRNA levels were assessed by RT-qPCR. For the functional assays, the 'conditioned' subpopulation generated in the presence of MSCs was cultured with concanavalin A activated CD4(+) T cells labeled with carboxyfluorescein succinimidyl ester. Finally, we used the encephalomyelitis autoimmune diseases (EAE) mouse model, in which mice were injected with MSCs at day 18 and 30 after immunization. At day 50, the mice were euthanized and draining lymph nodes were extracted for Th1, Th17 and Treg detection by flow cytometry. RESULTS: MSCs were able to suppress the proliferation, activation and differentiation of CD4(+) T cells induced to differentiate into Th1 and Th17 cells. This substantial suppressive effect was associated with an increase of the percentage of functional induced CD4(+)CD25(+)Foxp3(+) regulatory T cells and IL-10 secretion. However, using mature Th1 or Th17 cells our results demonstrated that while MSCs suppress the proliferation and phenotype of mature Th1 and Th17 cells they did not generate Treg cells. Finally, we showed that the beneficial effect observed following MSC injection in an EAE mouse model was associated with the suppression of Th17 cells and an increase in the percentage of CD4(+)CD25(+)Foxp3(+) T lymphocytes when administrated at early stages of the disease. CONCLUSIONS: This study demonstrated that MSCs contribute to the generation of an immunosuppressive environment via the inhibition of proinflammatory T cells and the induction of T cells with a regulatory phenotype. Together, these results might have important clinical implications for inflammatory and autoimmune diseases. PMID- 23734782 TI - Social network analysis of wild chimpanzees provides insights for predicting infectious disease risk. AB - 1. Heterogeneity in host association patterns can alter pathogen transmission and strategies for control. Great apes are highly social and endangered animals that have experienced substantial population declines from directly transmitted pathogens; as such, network approaches to quantify contact heterogeneity could be crucially important for predicting infection probability and outbreak size following pathogen introduction, especially owing to challenges in collecting real-time infection data for endangered wildlife. 2. We present here the first study using network analysis to quantify contact heterogeneity in wild apes, with applications for predicting community-wide infectious disease risk. Specifically, within a wild chimpanzee community, we ask how associations between individuals vary over time, and we identify traits of highly connected individuals that might contribute disproportionately to pathogen spread. 3. We used field observations of behavioural encounters in a habituated wild chimpanzee community in Kibale National Park, Uganda to construct monthly party level (i.e. subgroup) and close contact (i.e. <= 5 m) association networks over a 9-month period. 4. Network analysis revealed that networks were highly dynamic over time. In particular, oestrous events significantly increased pairwise party associations, suggesting that community-wide disease outbreaks should be more likely to occur when many females are in oestrus. 5. Bayesian models and permutation tests identified traits of chimpanzees that were highly connected within the network. Individuals with large families (i.e. mothers and their juveniles) that range in the core of the community territory and to a lesser extent high-ranking males were central to association networks, and thus represent the most important individuals to target for disease intervention strategies. 6. Overall, we show striking temporal variation in network structure and traits that predict association patterns in a wild chimpanzee community. These empirically-derived networks can inform dynamic models of pathogen transmission and have practical applications for infectious disease management of endangered wildlife species. PMID- 23734784 TI - Efficacy of base-modification on target binding of small molecule DNA aptamers. AB - Nucleic acid aptamers are receptors of single-stranded oligonucleotides that specifically bind to their targets. Significant interest is currently focused on development of small molecule aptamers owing to their applications in biosensing, diagnostics, and therapeutics involving low molecular weight biomarkers and drugs. Despite great potential for their diverse applications, relatively few aptamers that bind to small molecules have been reported, and methodologies to enhance and broaden their functions by expanding chemical repertories have barely been examined. Here we describe construction of a modified DNA library that includes (E)-5-(2-(N-(2-(N(6)-adeninyl)ethyl))carbamylvinyl)-uracil bases and discovery of high-affinity camptothecin-binding DNA aptamers using a systematic evolution of ligands by the exponential enrichment method. Our results are the first to demonstrate the superior efficacy of base modification on affinity enhancement and the usefulness of unnatural nucleic acid libraries for development of small molecule aptamers. PMID- 23734783 TI - Bellerophon: a hybrid method for detecting interchromosomal rearrangements at base pair resolution using next-generation sequencing data. AB - BACKGROUND: Somatically-acquired translocations may serve as important markers for assessing the cause and nature of diseases like cancer. Algorithms to locate translocations may use next-generation sequencing (NGS) platform data. However, paired-end strategies do not accurately predict precise translocation breakpoints, and "split-read" methods may lose sensitivity if a translocation boundary is not captured by many sequenced reads. To address these challenges, we have developed "Bellerophon", a method that uses discordant read pairs to identify potential translocations, and subsequently uses "soft-clipped" reads to predict the location of the precise breakpoints. Furthermore, for each chimeric breakpoint, our method attempts to classify it as a participant in an unbalanced translocation, balanced translocation, or interchromosomal insertion. RESULTS: We compared Bellerophon to four previously published algorithms for detecting structural variation (SV). Using two simulated datasets and two prostate cancer datasets, Bellerophon had overall better performance than the other methods. Furthermore, our method accurately predicted the presence of the interchromosomal insertions placed in our simulated dataset, which is an ability that the other SV prediction programs lack. CONCLUSIONS: The combined use of paired reads and soft clipped reads allows Bellerophon to detect interchromosomal breakpoints with high sensitivity, while also mitigating losses in specificity. This trend is seen across all datasets examined. Because it does not perform assembly on soft clipped subreads, Bellerophon may be limited in experiments where sequence read lengths are short. AVAILABILITY: The program can be downloaded from http://cbc.case.edu/Bellerophon. PMID- 23734785 TI - Towards real-time simulation of cardiac electrophysiology in a human heart at high resolution. AB - We have developed the capability to rapidly simulate cardiac electrophysiological phenomena in a human heart discretised at a resolution comparable with the length of a cardiac myocyte. Previous scientific investigation has generally invoked simplified geometries or coarse-resolution hearts, with simulation duration limited to 10s of heartbeats. Using state-of-the-art high-performance computing techniques coupled with one of the most powerful computers available (the 20 PFlop/s IBM BlueGene/Q at Lawrence Livermore National Laboratory), high resolution simulation of the human heart can now be carried out over 1200 times faster compared with published results in the field. We demonstrate the utility of this capability by simulating, for the first time, the formation of transmural re-entrant waves in a 3D human heart. Such wave patterns are thought to underlie Torsades de Pointes, an arrhythmia that indicates a high risk of sudden cardiac death. Our new simulation capability has the potential to impact a multitude of applications in medicine, pharmaceuticals and implantable devices. PMID- 23734786 TI - Assignment of serotype to Salmonella enterica isolates obtained from poultry and their environment in southern Brazil. AB - To assess diversity of Salmonella enterica serotypes present in poultry and their environment from southern Brazil, the Kauffmann-White-Le Minor (KWL) scheme was used to serotype a total of 155 isolates. Isolates were then re-examined with nested PCR and sequencing of the dkgB-linked intergenic sequence ribotyping (ISR) region that assesses single nucleotide polymorphisms occurring around a 5S ribosomal gene. Serotypes identified were Heidelberg (40.6%), Enteritidis (34.2%), Hadar (8.4%), Typhimurium (3.9%), Gallinarum (3.2%), Agona (1.3%), Cerro (1.3%), Livingstone (1.3%), Infantis (0.6%), Isangi (0.6%), Mbandaka (0.6%), Montevideo (0.6%) and Senftenberg (0.6%). Three unique ISRs were detected from four strains. Day old chicks yielded only S. Enteritidis, whereas S. Heidelberg was most often associated with poultry carcasses. Overall agreement between KWL and ISR was 85.2%, with disagreement possibly due to the ability of ISR to detect mixtures of serotypes in culture. Overall, ISR provided more information than did KWL about the ecology of Salm. enterica on-farm. The O-antigen group D Salm. enterica serovars such as Pullorum, Gallinarum and Enteritidis appear susceptible to overgrowth by other serotypes. SIGNIFICANCE AND IMPACT OF THE STUDY: Single nucleotide polymorphisms found in a group of poultry-associated Salmonella isolates from southern Brazil provided evidence of mixtures of serovar group D serotypes on-farm and in single samples from birds. This finding suggests that co infection and interserotype competition of Salmonella enterica in poultry could impact the incidence of disease in animals or humans. In addition, unique serotypes were identified on-farm that escaped characterization by antibody typing. Application of cost-efficient and highly discriminatory genomic methods for assigning serotype may alter concepts about the epidemiology of Salm. enterica on-farm and in foods. PMID- 23734787 TI - BaAu2P4: layered zintl polyphosphide with infinite infinity(1)(P-) chains. AB - Barium gold polyphosphide BaAu2P4 was synthesized from elements and structurally characterized by single crystal X-ray diffraction. BaAu2P4 crystallizes in a new structure type, in the orthorhombic space group Fddd (No. 70) with a = 6.517(1) A, b = 8.867(2) A, c = 21.844(5) A. The crystal structure of BaAu2P4 consists of Au-P layers separated by layers of Ba atoms. Each Au-P layer is composed of infinite infinity(1)(P-) chains of unique topology linked together by almost linearly coordinated Au atoms. According to Zintl-Klemm formalism, this compound is charge balanced assuming closed shell d10 configuration for Au: Ba2+(Au+)2(P )4. Magnetic and solid state NMR measurements together with quantum-chemical calculations reveal diamagnetic and semiconducting behavior for the investigated polyphosphide, which is as expected for the charged balanced Zintl phase. Electron localization function and crystal orbital Hamilton population analyses reveal strong P-P and Au-P bonding and almost nonbonding Au-Au interactions in BaAu2P4. PMID- 23734789 TI - Graphene oxide induces toll-like receptor 4 (TLR4)-dependent necrosis in macrophages. AB - Graphene and graphene-based nanomaterials display novel and beneficial chemical, electrical, mechanical, and optical characteristics, which endow these nanomaterials with promising applications in a wide spectrum of areas such as electronics and biomedicine. However, its toxicity on health remains unknown and is of great concern. In the present study, we demonstrated that graphene oxide (GO) induced necrotic cell death to macrophages. This toxicity is mediated by activation of toll-like receptor 4 (TLR4) signaling and subsequently in part via autocrine TNF-alpha production. Inhibition of TLR4 signaling with a selective inhibitor prevented cell death nearly completely. Furthermore, TLR4-deficient bone marrow-derived macrophages were resistant to GO-triggered necrosis. Similarly, GO did not induce necrosis of HEK293T/TLR4-null cells. Macrophagic cell death upon GO treatment was partially attributed to RIP1-RIP3 complex mediated programmed necrosis downstream of TNF-alpha induction. Additionally, upon uptake into macrophages, GO accumulated primarily in cytoplasm causing dramatic morphologic alterations and a significant reduction of the macrophagic ability in phagocytosis. However, macrophagic uptake of GO may not be required for induction of necrosis. GO exposure also caused a large increase of intracellular reactive oxygen species (ROS), which contributed to the cause of cell death. The combined data reveal that interaction of GO with TLR4 is the predominant molecular mechanism underlying GO-induced macrophagic necrosis; also, cytoskeletal damage and oxidative stress contribute to decreased viability and function of macrophages upon GO treatment. PMID- 23734788 TI - Esophagogastric Junction pressure morphology: comparison between a station pull through and real-time 3D-HRM representation. AB - BACKGROUND: Esophagogastric junction (EGJ) competence is the fundamental defense against reflux making it of great clinical significance. However, characterizing EGJ competence with conventional manometric methodologies has been confounded by its anatomic and physiological complexity. Recent technological advances in miniaturization and electronics have led to the development of a novel device that may overcome these challenges. METHODS: Nine volunteer subjects were studied with a novel 3D-HRM device providing 7.5 mm axial and 45 degrees radial pressure resolution within the EGJ. Real-time measurements were made at rest and compared to simulations of a conventional pull-through made with the same device. Moreover, 3D-HRM recordings were analyzed to differentiate contributing pressure signals within the EGJ attributable to lower esophageal sphincter (LES), diaphragm, and vasculature. KEY RESULTS: 3D-HRM recordings suggested that sphincter length assessed by a pull-through method greatly exaggerated the estimate of LES length by failing to discriminate among circumferential contractile pressure and asymmetric extrinsic pressure signals attributable to diaphragmatic and vascular structures. Real-time 3D EGJ recordings found that the dominant constituents of EGJ pressure at rest were attributable to the diaphragm. CONCLUSIONS & INFERENCES: 3D-HRM permits real-time recording of EGJ pressure morphology facilitating analysis of the EGJ constituents responsible for its function as a reflux barrier making it a promising tool in the study of GERD pathophysiology. The enhanced axial and radial recording resolution of the device should facilitate further studies to explore perturbations in the physiological constituents of EGJ pressure in health and disease. PMID- 23734790 TI - Double Reformatsky reaction: divergent synthesis of delta-hydroxy-beta ketoesters. AB - The double Reformatsky reaction, tandem addition of two molecules of zinc alkanoate to a carbonyl compound, and its synthetic application to a series of delta-hydroxy-beta-ketoesters has been developed. The key to accelerate the double Reformatsky reaction is considered to be a complex-induced proximity effect of the in situ generated zinc alkoxide coordinated with the pyridyl group of the substrate or bidentate amines. A noteworthy feature of the reaction system is its high tolerance of functional groups due to the moderate nucleophilicity of organozinc reagents and the mild reaction conditions. Moreover, spectroscopic and crystallographic analyses of the zinc complex of the double Reformatsky product support the proposed mechanism of reaction site discrimination for ketones, aldehydes, nitriles, carboxylic acid anhydrides, and esters. PMID- 23734791 TI - Swedish version of the multi dimensional health assessment questionnaire -- translation and psychometric evaluation. AB - BACKGROUND: Health assessment measurements for patients with Rheumatoid arthritis (RA) have to be meaningful, valid and relevant. A commonly used questionnaire for patients with RA is the Stanford Health Assessment Questionnaire Disability Index (HAQ), which has been available in Swedish since 1988. The HAQ has been revised and improved several times and the latest version is the Multi Dimensional Health Assessment Questionnaire (MDHAQ). The aim of this study was to translate the MDHAQ to Swedish conditions and to test the validity and reliability of this version for persons with RA. METHODS: Translation and adaption of the MDHAQ were performed according to guidelines by Guillemin et al. The translated version was tested for face validity and test-retest in a group of 30 patients with RA. Content validity, criterion validity and internal consistency were tested in a larger study group of 83 patients with RA. Reliability was tested with test retest and Cronbach's alpha for internal consistency. Two aspects of validity were explored: content and criterion validity. Content validity was tested with a content validity index.Criterion validity was tested with concurrent validity by exploring the correlation between the MDHAQ-S and the AIMS2-SF. Floor and ceiling effects were explored. RESULTS: Test-retest with intra-class correlation coefficient (ICC) gave a coefficient of 0.85 for physical function and 0.79 for psychological properties. Reliability test with Cronbach's alpha gave an alpha of 0.65 for the psychological dimension and an alpha of 0.88 for the physical dimension of the MDHAQ-S.The average sum of the content validity index for each item was of the MDHAQ-S was 0.94. The MDHAQ-S had mainly a moderate correlation with the AIMS2-SF, except for the social dimension of the AIMS2-SF, which had a very low correlation with the MDHAQ-S. CONCLUSIONS: The MDHAQ-S was considered to be reliable and valid, but further research is needed concerning sensitivity to change. PMID- 23734792 TI - Solitary angiokeratoma on palms and soles: a clinicopathological analysis of 21 cases. AB - Angiokeratoma includes a group of unrelated diseases characterized by hyperkeratosis and dilation of vessels in the superficial dermis. In this study, 21 cases of solitary lesions located on palms and soles and histopathologically diagnosed as angiokeratoma were analyzed retrospectively. All lesions presented as red to violet macules or plaques. Histopathologically, all of them showed hyperkeratosis and vascular dilation in the papillary to deep dermis. The elongated vessels were of different sizes and shape, lined by a single layer of endothelial cells. In 13 lesions, the endothelial cells protruded into the lumen, forming a hobnail appearance. Immunohistochemical study showed the endothelial cells were positive for CD31 and CD34, negative for D2-40, and focally positive for Wilms tumor 1 (WT-1) in most cases. Our cases represented a rare type of angiokeratoma located on the palms and soles, in which the focal positivity of WT 1 was different from previously reported vascular proliferations. PMID- 23734793 TI - Survival of stroke patients after introduction of the 'Dutch Transmural Protocol TIA/CVA'. AB - BACKGROUND: Earlier research showed that healthcare in stroke could be better organized, aiming for improved survival and less comorbidity. Therefore, in 2004 the Dutch College of General Practitioners (NHG) and the Dutch Association of Neurology (NVN) introduced the 'Dutch Transmural Protocol TIA/CVA' (the LTA) to improve survival, minimize the risk of stroke recurrence, and increase quality of life after stroke. This study examines whether survival improved after implementation of the new protocol, and whether there was an increase in contacts with the general practitioner (GP)/nurse practitioner, registration of comorbidity and prescription of medication. METHODS: From the primary care database of the Registration Network Groningen (RNG) two cohorts were composed: one cohort compiled before and one after introduction of the LTA. Cohort 1 (n = 131, first stroke 2001-2002) was compared with cohort 2 (n = 132, first stroke 2005-2006) with regard to survival and the secondary outcomes. RESULTS: Comparison of the two cohorts showed no significant improvement in survival. In cohort 2, the number of contacts with the GP was significantly lower and with the nurse practitioner significantly higher, compared with cohort 1. All risk factors for stroke were more prevalent in cohort 2, but were only significant for hypercholesterolemia. In both cohorts more medication was prescribed after stroke, whereas ACE inhibitors were prescribed more frequently only in cohort 2. CONCLUSION: No major changes in survival and secondary outcomes were apparent after introduction of the LTA. Although, there was a small improvement in secondary prevention, this study shows that optimal treatment after introduction of the LTA has not yet been achieved. PMID- 23734794 TI - The role of biomarkers in the prevention of globally important diseases. PMID- 23734795 TI - Point-of-care testing and the control of infectious diseases. AB - Point-of-care tests (POCTs) play an important role in bridging the gap between centralized laboratory diagnostics and peripheral healthcare service providers. Particularly in infectious diseases such as HIV/AIDS and TB where early detection is imperative to improve disease outcome, uptake of an accurate test that is simple, rapid and robust can significantly alter the epidemiology and control of the disease. However, a good POCT can only serve its full potential when adopted in a comprehensive programmatic context linking patients to on-site case management. Immunochromatographic lateral flow devices for detection of antibody or antigen currently dominate available POCTs, and development of such devices has relied on the discovery and optimization of definitive biomarkers suitable for such platforms. In the future, however, there will be an increasing need to develop cost-effective POCTs that address biomarkers that are well established in laboratory settings but are not currently amenable to point-of-care, such as molecular tests for drug resistance in TB and viral load in HIV and viral hepatitis. PMID- 23734796 TI - Biomarkers of tuberculosis: a research roadmap. AB - Tuberculosis (TB) continues to represent a major public health problem worldwide. Prompt and accurate diagnosis and effective treatment are fundamental to reducing morbidity and mortality and curtailing spread of infection. Furthermore, tackling the large reservoir of latent infection is the cornerstone to TB control in many high income low TB incidence countries. However, our existing toolkit for prevention, diagnosis and treatment remains outdated and inadequate. Here, we discuss the key targets for biomarker research and discovery in TB and recent developments in the field. We focus on host biomarkers, in particular: correlates of vaccine efficacy and sterilizing immunity; biomarkers of latent TB infection, including diagnosis, risk of progression to active TB and response to treatment; and markers of active TB, including diagnosis, response to treatment and risk of relapse. Recent scientific and technological advances have contributed to significant recent progression in biomarker discovery. Although there are clear remaining paucities, continued efforts within scientific, translational and clinical studies are likely to yield a number of clinically useful biomarkers of TB in the foreseeable future. PMID- 23734797 TI - The mechanistic, diagnostic and prognostic utility of biomarkers in severe malaria. AB - Malaria remains an important global cause of severe illness and mortality. This literature review summarizes available data on how biomarkers might be applied to diagnose, prognosticate and provide mechanistic insights in patients with severe malaria. Of the large number of candidate biomarkers, only PfHRP2 has consistently demonstrated clinical utility and, when incorporated into rapid antigen detection tests, has shown diagnostic sensitivity above 95%, which is at least as good as light microscopy. As a quantitative test, PfHRP2 also shows some promise in differentiating severe malarial from non-malarial disease in areas where asymptomatic carriage of malaria parasites is common, and possibly as a tool to estimate sequestered parasite burden and subsequent mortality. Biomarkers such as pLDH and panmalarial antigen have lower sensitivity for non-falciparum malaria in rapid antigen detection tests. There is an urgent need to discover and validate better biomarkers for incorporation into rapid antigen detection tests in countries where Plasmodium vivax is a common cause of severe disease. A large number of host-derived acute-phase reactants, markers of endothelial dysfunction and immune mediators have been proposed as biomarkers. Although they have provided mechanistic insights into the immunopathology of severe malaria, their roles as clinical tools remain uncertain. PMID- 23734798 TI - Are we closer to finding biomarkers for identifying acute drug-induced liver injury? PMID- 23734799 TI - miRNAs as biomarkers for brain metastasis of breast cancer. PMID- 23734800 TI - MPO is a potential biomarker of acute graft-versus-host disease. PMID- 23734802 TI - A gripping problem: cardiac biomarkers in patients with intermittent claudication. PMID- 23734803 TI - Conference scene: ISOBM 2013 in Israel: part 1: biomarkers - where we are now? AB - The 40th annual Congress of the International Society of Oncology and Biomarkers took place in Jerusalem, Israel. The subtitle of this year's conference was: 'Innovations in oncological treatments and tumor markers'. Many issues on the potential use of markers were discussed, such as the potential use of markers for therapy response prediction in personalized medicine and for the proposal of algorithms for clinical practice use. A series of lectures was presented related to the discovery and preclinical and clinical validation of new biomarkers. The presentations were also split into keynote lectures, oral presentation in sessions and poster presentations. The conference was attended by approximately 186 participants and was attended by some of today's leading laboratory researchers in the field of oncology research. When comparing this conference with other meetings from previous years, it was evident that the biomarkers that are gaining in significance are DNA changes in association with the cancer process and epigenetic changes, which is seen to be methodically moving the field of immunoassays into molecular biology methods. PMID- 23734804 TI - Conference scene: ISOBM 2013 in Israel: part 2: biomarkers - a challenging issue for futher investigation. AB - This is the second article dedicated to The Annual 40th Congress of the International Society of Oncology and Biomarkers, which took place in Jerusalem, Israel. This second part of this article will be dedicated to the special presentations from individual sessions. Sessions were organised according to the cancer type or etiopathogenesis, while some sessions were dedicated to the relationship between diagnostics and therapy choice. PMID- 23734805 TI - Plasma NGAL similarly predicts acute kidney injury in sepsis and nonsepsis. AB - AIM: Plasma NGAL is released in sepsis irrespective of acute kidney injury (AKI). The current study investigated the effect of sepsis on the diagnostic value of NGAL for AKI. MATERIALS & METHODS: In 700 intensive care unit admissions, NGAL was measured at four time points (<24 h) following admission. RESULTS: In total, 663 admissions were included in the final analysis, of which 80 patients had sepsis (12%). AKI occurred in 22% of the patients without and 66% with sepsis. NGAL levels were higher in non-AKI patients with sepsis compared with non-AKI patients without sepsis at all time points (p = 0.03 or lower). In patients with AKI a similar difference was observed (p < 0.001). The area under the curve for AKI was unaffected by the presence of sepsis (0.76 in sepsis vs 0.78 in nonsepsis; p = 0.72); however, the optimal test cutoff values were higher in the former. CONCLUSION: Sepsis enhances the production of plasma NGAL in critically ill adult patients irrespective of the presence of AKI. However, the diagnostic test accuracy for AKI is unaffected by sepsis, although optimal cutoff values are elevated. PMID- 23734806 TI - Relationship of adipokines (adiponectin, resistin and RBP4) with metabolic syndrome components in pubertal obese children. AB - AIM: To investigate the relationship between serum adiponectin, resistin and RBP4 levels and the components of metabolic syndrome. PATIENTS & METHODS: Serum adiponectin, resistin and RBP4 levels were detected and analyzed in 148 8-18-year old Turkish obese pubertal children with/without metabolic syndrome. RESULTS: Adiponectin and resistin concentrations were significantly inversely correlated with BMI standard deviation score, homeostatic model assessment insulin resistance, waist circumference, triglyceride levels and diastolic and systolic blood pressure, and were directly correlated with high-density lipoprotein cholesterol. RBP4 concentrations were directly correlated with homeostatic model assessment insulin resistance, waist circumference, triglyceride levels and diastolic and systolic blood pressure, and inversely correlated with high-density lipoprotein cholesterol. CONCLUSION: Adiponectin, RBP4 and, in particular, resistin levels may be used as suitable predictive biomarkers of metabolic syndrome. PMID- 23734808 TI - Clinical use of biomarkers for toxicant-induced acute kidney injury. AB - Toxicant-induced acute kidney injury (ToxAKI) causes substantial morbidity and retards drug development. ToxAKI is relatively underexplored compared with ischemia-reperfusion injury in clinical biomarker studies. We highlight the rationale for novel AKI biomarkers in management of ToxAKI, and review the contemporary evidence supporting their clinical use. Directly-acting nephrotoxins, such as cisplatin, aminoglycosides, vancomycin and radiocontrast, remain widely used and highlight how novel biomarkers can either improve the detection of changes in glomerular filtration rate or directly signal cellular injury and structural damage. Serum cystatin C has already improved clinical risk prediction and drug dosing although its clinical use for early diagnosis awaits validation. The use of novel functional and structural biomarkers to stage ToxAKI and aid prognosis requires robust validation and better understanding of the relationship between biomarkers, morbidity and mortality. Biomarkers that illustrate the probable mechanisms and phase of ToxAKI may guide mechanism specific diagnosis and therapy. PMID- 23734807 TI - Length of psychiatric hospitalization is correlated with CYP2D6 functional status in inpatients with major depressive disorder. AB - AIM: This study aimed to determine the effect of the CYP2D6 genotype on the length of hospitalization stay for patients treated for major depressive disorder. METHODS: A total of 149 inpatients with a diagnosis of major depressive disorder at the Institute of Living, Hartford Hospital (CT, USA), were genotyped to detect altered alleles in the CYP2D6 gene. Prospectively defined drug metabolism indices (metabolic reserve, metabolic alteration and allele alteration) were determined quantitatively and assessed for their relationship to length of hospitalization stay. RESULTS: Hospital stay was significantly longer in deficient CYP2D6 metabolizers (metabolic reserve <2) compared with functional or suprafunctional metabolizers (metabolic reserve >=2; 7.8 vs 5.7 days, respectively; p = 0.002). CONCLUSION: CYP2D6 enzymatic functional status significantly affected length of hospital stay, perhaps due to reduced efficacy or increased side effects of the medications metabolized by the CYP2D6 isoenzyme. Functional scoring of CYP2D6 alleles may have a substantial impact on the quality of care, patient satisfaction and the economics of psychiatric treatment. PMID- 23734809 TI - Assessing the functional properties of high-density lipoproteins: an emerging concept in cardiovascular research. AB - Although plasma concentrations of high-density lipoprotein (HDL) cholesterol correlate inversely with the incidence of atherosclerotic cardiovascular disease, results from recent epidemiological, genetic and pharmacological intervention studies resulted in a shift of concept. Rather than HDL cholesterol mass levels, the functionality of HDL particles is increasingly regarded as potentially clinically important. This review provides an overview of four key functional properties of HDL, namely cholesterol efflux and reverse cholesterol transport; antioxidative activities; anti-inflammatory activities; and the ability of HDL to increase vascular nitric oxide production resulting in vasorelaxation. Currently available assays are put into context with different HDL isolation procedures yielding compositional heterogeneity of the particle. Gathered knowledge on the impact of different disease states on HDL function is discussed together with potential underlying causative factors modulating HDL functionalities. In addition, a perspective is provided regarding how a better understanding of the determinants of (dys)functional HDL might impact clinical practice and the future design of rational and specific therapeutic approaches targeting atherosclerotic cardiovascular disease. PMID- 23734810 TI - Impact of expression of the uPA system in sarcomas. AB - The uPA system mainly comprises the urokinase-type plasminogen activator uPA, the cell-surface receptor uPA receptor and the inhibitor PAI-1. Its clinical and prognostic impact especially in breast cancer is well investigated. In this short report, we summarize the published data describing expression of uPA, PAI-1 and uPA receptor and their relevance to clinical and survival data in sarcomas underlining their impact as tumor biomarkers in this tumor type as well. PMID- 23734811 TI - High peripheral levels of h-FABP are associated with poor prognosis in end-stage heart failure patients with mechanical circulatory support. AB - AIM: To associate the time-course of h-FABP and N-terminal pro B-type natriuretic peptide (NT-proBNP)after left ventricular assist device (LVAD) implantation to outcome in end-stage heart failure patients. MATERIALS & METHODS: Patients (n = 14, NYHA class III/IV; left ventricular ejection fraction <25% were enrolled; ten survived up to 1 month after LVAD (survivors) and four died of multiorgan failure within 2 weeks (nonsurvivors). Blood samples were obtained at admission; at 4, 24 and 72 h; and at 1 and 4 weeks after LVAD. RESULTS: h-FABP significantly increases after surgery, decreasing since 72 h in all patients. At 72 h all survivor patients present h-FABP lower than the median value. N-terminal pro B type natriuretic peptide is not associated with patient outcome at any time. CONCLUSION: High h-FABP levels, indicating the presence of more severe myocardial damage, are associated with a poor prognosis in patients with LVAD, suggesting that an early cardiac injury marker could improve the prediction of clinical outcome. PMID- 23734813 TI - Deciphering the metal-C60 interface in optoelectronic devices: evidence for C60 reduction by vapor deposited Al. AB - The formation of interfacial midgap states due to the reduction of buckminsterfullerene (C60) to amorphous carbon upon subsequent vapor deposition of Al is confirmed using Raman spectroscopy and X-ray, ultraviolet, and inverse photoemission spectroscopies. We demonstrate that vapor deposition of Al results in n-type doping of C60 due to an electron transfer from Al to the LUMO of C60, resulting in the formation of midgap states near the C60 Fermi level. Raman spectroscopy in ultrahigh vacuum clearly identifies the presence of the C60 anion radical (C60(*-)) as well as amorphous carbon created by further degradation of C60(*-). In contrast, the interface formed by vapor deposition of Ag shows only a slight Ag/C60 interfacial charge displacement with no evidence for complete metal to-C60 electron transfer to form the anion radical or its further degradation products. These results confirm previous speculations of metal-induced chemical damage of C60 films after Al deposition, which is widely suspected of decreasing charge collection efficiency in OPVs, and provide key insight into charge collection at metal/organic interfaces in such devices. PMID- 23734814 TI - Total synthesis of the cytotoxic enehydrazide natural products hydrazidomycins A and B by a carbazate addition/Peterson olefination approach. AB - The first total syntheses of two natural antitumor enehydrazide compounds (hydrazidomycins A and B) and a related positional isomer of hydrazidomycin B (elaiomycin B) have been accomplished in a rapid and stereocontrolled fashion using a Peterson elimination approach. A regioselective silyl epoxide ring opening reaction with Boc-carbazate followed by base-mediated Peterson siloxide elimination stereospecifically installed the key Z-enehydrazide functionality. The use of Boc-carbazate allowed for the differential functionalization of the hydrazide nitrogens. PMID- 23734815 TI - Fludarabine treatment favors the retention of miR-485-3p by prostate cancer cells: implications for survival. AB - BACKGROUND: Circulating microRNAs (miRNAs) have been found in many body fluids and represent reliable markers of several physio-pathological disorders, including cancer. In some cases, circulating miRNAs have been evaluated as markers of the efficacy of anticancer treatment but it is not yet clear if miRNAs are actively released by tumor cells or derive from dead tumor cells. RESULTS: We showed that a set of prostate cancer secretory miRNAs (PCS-miRNAs) were spontaneously released in the growth medium by DU-145 prostate cancer cells and that the release was greater after treatment with the cytotoxic drug fludarabine. We also found that the miRNAs were associated with exosomes, implying an active mechanism of miRNA release. It should be noted that in fludarabine treated cells the release of miR-485-3p, as well as its association with exosomes, was reduced suggesting that miR-485-3p was retained by surviving cells. Monitoring the intracellular level of miR-485-3p in these cells, we found that miR-485-3p was stably up regulated for several days after treatment. As a possible mechanism we suggest that fludarabine selected cells that harbor high levels of miR-485-3p, which in turn regulates the transcriptional repressor nuclear factor-Y triggering the transcription of topoisomerase IIalpha, multidrug resistance gene 1 and cyclin B2 pro-survival genes. CONCLUSIONS: Cytotoxic treatment of DU-145 cells enhanced the release of PCS-miRNAs with the exception of miR-485-3p which was retained by surviving cells. We speculate that the retention of miR-485-3p was a side effect of fludarabine treatment in that the high intracellular level of miR 485-3p plays a role in the sensitivity to fludarabine. PMID- 23734816 TI - Successful endovascular salvage of a pancreatic graft after a venous thrombosis: case report and literature review. AB - Simultaneous kidney and pancreatic transplant is the criterion standard for treatment of end-stage renal failure because of diabetic nephropathy. Venous thrombosis occurs in approximately 5% of pancreatic transplants, and it is notoriously difficult to treat, forming the most common nonimmunologic cause of graft loss. We report a case of early detection of pancreatic graft venous thrombosis by measuring urinary amylase, resulting in the successful endovascular salvage of the pancreatic graft. PMID- 23734817 TI - Arsenic speciation in the blood of arsenite-treated F344 rats. AB - Arsenic speciation in blood can improve understanding of the metabolism and toxicity of arsenic. In this study, arsenic species in the plasma and red blood cells (RBCs) of arsenite-treated female F344 rats were characterized using anion exchange and size exclusion chromatography separation with inductively coupled plasma mass spectrometry (ICPMS) and electrospray ionization tandem mass spectrometry (ESI MS/MS) detection. Arsenite (iAs(III)), arsenate (iAs(V)), monomethylarsonic acid (MMA(V)), dimethylarsinic acid (DMA(V)), trimethylarsine oxide (TMAO(V)), monomethylmonothioarsonic acid (MMMTA(V)), and dimethylmonothioarsinic acid (DMMTA(V)) were detected in the plasma, with DMA(V) being the predominant metabolite. Upon oxidative pretreatment with 5% hydrogen peroxide (H2O2), plasma proteins released bound arsenic in the form of DMA(V) as the major species and MMA(V) as the minor species. The ratio of protein-bound arsenic to total arsenic decreased with increasing dosage of iAs(III) administered to the rats, suggesting a possible saturation of the binding capacity of the plasma proteins. The proportion of the protein-bound arsenic in the plasma varied among rats. In the H2O2-treated lysates of red blood cells of rats, DMA(V) was consistently found as the predominant arsenic species, probably reflecting the preferential binding of dimethylarsinous acid (DMA(III)) to rat hemoglobin. iAs(V), MMA(V), and trimethylarsine oxide (TMAO(V)) were also detected in the hydrogen peroxide-treated lysates of red blood cells. Importantly, DMMTA(V) and MMMTA(V) have not been reported in rat blood, and the present finding of DMMTA(V) and MMMTA(V) in the rat plasma is toxicologically relevant because these pentavalent thioarsenicals are more toxic than their counterparts DMA(V) and MMA(V). Identifying novel thiolated arsenicals and determining protein-bound arsenicals in the blood provide useful insights into the metabolism and toxicity of arsenic in animals. PMID- 23734818 TI - An investigation of prospective memory functions in people with traumatic brain injury using Virtual Week. AB - Prospective memory (PM) refers to memory for future intentions and is critically linked to independent living. Previous laboratory research has shown that people who have sustained a traumatic brain injury (TBI) have difficulties with PM, but few of these have used measures of PM that closely represent the types of PM activities that occur in everyday life. One measure that incorporates more ecologically valid tasks, and which also allows systematic investigation of different PM task parameters (regular, irregular, and event and time based), is Virtual Week. Consequently, in the present study, Virtual Week was administered to participants with TBI (n = 18) and demographically matched controls (n = 18). Consistent with considerable prior literature, the results indicated that people with TBI had significant difficulties executing PM tasks, with these deficits more pronounced for time-based than for event-based tasks. These data point to there being a relatively global PM deficit in people with TBI. Of particular interest was the finding that the magnitude of TBI impairment was consistent across regular and irregular tasks. Because the key distinction between these tasks is that they place low and high demands on retrospective memory, respectively, these data suggest that failures of retrospective memory are not the major cause of TBI-related impairment in PM. The implications of these results for the assessment and rehabilitation of PM impairment in people with TBI are discussed. PMID- 23734819 TI - In vitro degradation of oxalate by recombinant Lactobacillus plantarum expressing heterologous oxalate decarboxylase. AB - AIM: The aim of the present study is to constitutively express heterologous oxalate decarboxylase (OxdC) in Lactobacillus plantarum and to examine its ability to degrade oxalate in vitro for their future therapy against enteric hyperoxaluria. METHOD AND RESULTS: In this study, we generated a recombinant strain of Lb. plantarum to constitutively overexpress B. subtilis oxalate decarboxylase (oxdC) using a host lactate dehydrogenase promoter (PldhL ). The recombinant Lb. plantarum was able to degrade more than 90% oxalate compared to 15% by the wild type. In addition, the recombinant strain also had higher tolerance up to 500 mmol l(-1) oxalate. CONCLUSION: We developed a recombinant Lb. plantarum NC8 that constitutively expressed heterologous oxalate decarboxylase and degraded oxalate efficiently under in vitro conditions. SIGNIFICANCE AND IMPACT OF STUDY: The long-term aim is to develop an efficient strain for future therapy against oxalosis. PMID- 23734820 TI - The revised ATS/ERS/JRS/ALAT diagnostic criteria for idiopathic pulmonary fibrosis (IPF)--practical implications. AB - Idiopathic pulmonary fibrosis (IPF), the most prevalent idiopathic interstitial pneumonia, is associated with a poor prognosis. An accurate diagnosis of IPF is essential for optimal management. The recent ATS/ERS/JRS/ALAT recommendations on the diagnosis and management of IPF were developed from a systematic review of the published literature. High-resolution computed tomography (HRCT) scanning has a central role in the IPF diagnostic pathway with formal designation of criteria for an HRCT pattern of UIP. In the correct clinical context, a UIP pattern on HRCT is indicative of a definite diagnosis of IPF without the need for a surgical lung biopsy. However, although the 2011 ATS/ERS/JRS/ALAT statement is a major advance, the application of guideline recommendations by clinicians has identified limitations that need to be addressed in future statements. Key problems include: 1) the lack of management recommendations for the highly prevalent clinical scenarios of probable and possible IPF; 2) the ongoing confusion about the diagnostic role of bronchoalveolar lavage (reflecting ambiguity in the current recommendation); 3) HRCT misdiagnosis by less experienced radiologists, increasingly recognised as a major problem; and 4) the lack of integration of clinical data, including the treated course of disease, in the designation of the diagnostic likelihood of IPF. PMID- 23734821 TI - Sweating under pressure: skin conductance level reactivity moderates the association between peer victimization and externalizing behavior. AB - BACKGROUND: This study examined whether the association between peer victimization and externalizing behavior may be illuminated by individual differences in skin conductance level reactivity (SCLR) in the context of peer stress. METHODS: Participants included 123 fifth and sixth graders (Mean age = 12.03 years, 50% females; 42% ethnic minorities). SCLR was assessed in the context of an ecologically relevant, lab-based peer-evaluative stress experience in preadolescence. RESULTS: As hypothesized, self-reported peer victimization was linked with parent- and teacher-reported externalizing behavior, and SCLR consistently moderated these associations. Peer victimization was associated with parent- and teacher-reported externalizing behavior among preadolescents who exhibited lower SCLR, but not among preadolescents who exhibited higher SCLR. CONCLUSIONS: Results suggest that promoting engagement with peer stress experiences and enhancing inhibitory control are potential intervention targets that may reduce externalizing behavior in the context of peer victimization (or reduce peer victimization among preadolescents who exhibit externalizing behavior). PMID- 23734822 TI - De Bruijn Superwalk with Multiplicities Problem is NP-hard. AB - De Bruijn Superwalk with Multiplicities Problem is the problem of finding a walk in the de Bruijn graph containing several walks as subwalks and passing through each edge the exactly predefined number of times (equal to the multiplicity of this edge). This problem has been stated in the talk by Paul Medvedev and Michael Brudno on the first RECOMB Satellite Conference on Open Problems in Algorithmic Biology in August 2012. In this paper we show that this problem is NP-hard. Combined with results of previous works it means that all known models for genome assembly are NP-hard. PMID- 23734824 TI - Clinical case: Differential diagnosis of idiopathic pulmonary fibrosis. AB - BACKGROUND: The diagnosis of idiopathic pulmonary fibrosis can be quite challenging, even after careful clinical evaluation, imaging and pathological tests. This case report intends to demonstrate and discuss these difficulties, especially those concerning the differential diagnosis with chronic hypersensitivity pneumonitis. CASE PRESENTATION: A 58-year-old white male presented with shortness of breath, dry cough, fatigue and weight loss for two months. He was a former smoker and had regular exposure to a parakeet and poultry. Physical examination revealed bilateral basal crackles and chest imaging showed subpleural cystic lesions and traction bronchiectasis with a right side and upper level predominance. Auto-antibodies and IgG immunoglobulins to parakeet and fungal proteins were negative. Lung function tests displayed moderate restriction, low diffusion capacity and resting hypoxaemia. Bronchoalveolar lavage showed increased lymphocytes (28%) and neutrophils (12%) and surgical lung biopsy was compatible with a pattern of usual interstitial pneumonia. According to the possibility of either idiopathic pulmonary fibrosis or chronic hypersensitivity pneumonitis, treatment included prednisolone, azathioprine, acetylcysteine and avoidance of contact with the parakeet, but there was an unfavorable response and the patient was subsequently referred for lung transplant. CONCLUSION: Chronic hypersensitivity pneumonitis and idiopathic pulmonary fibrosis can present with the same clinical and radiological manifestations In this case, despite careful evaluation, no definite diagnosis could be achieved. PMID- 23734825 TI - Adaptation of a commonly used, chemically defined medium for human embryonic stem cells to stable isotope labeling with amino acids in cell culture. AB - Metabolic labeling with stable isotopes is a prominent technique for comparative quantitative proteomics, and stable isotope labeling with amino acids in cell culture (SILAC) is the most commonly used approach. SILAC is, however, traditionally limited to simple tissue culture regimens and only rarely employed in the context of complex culturing conditions as those required for human embryonic stem cells (hESCs). Classic hESC culture is based on the use of mouse embryonic fibroblasts (MEFs) as a feeder layer, and as a result, possible xenogeneic contamination, contribution of unlabeled amino acids by the feeders, interlaboratory variability of MEF preparation, and the overall complexity of the culture system are all of concern in conjunction with SILAC. We demonstrate a feeder-free SILAC culture system based on a customized version of a commonly used, chemically defined hESC medium developed by Ludwig et al. and commercially available as mTeSR1 [mTeSR1 is a trade mark of WiCell (Madison, WI) licensed to STEMCELL Technologies (Vancouver, Canada)]. This medium, together with adjustments to the culturing protocol, facilitates reproducible labeling that is easily scalable to the protein amounts required by proteomic work flows. It greatly enhances the usability of quantitative proteomics as a tool for the study of mechanisms underlying hESCs differentiation and self-renewal. Associated data have been deposited to the ProteomeXchange with the identifier PXD000151. PMID- 23734823 TI - Transmission ecosystems of Echinococcus multilocularis in China and Central Asia. AB - From continental to regional scales, the zoonosis alveolar echinococcosis (AE) (caused by Echinococcus multilocularis) forms discrete patches of endemicity within which transmission hotspots of much larger prevalence may occur. Since the late 80s, a number of hotspots have been identified in continental Asia, mostly in China, wherein the ecology of intermediate host communities has been described. This is the case in south Gansu, at the eastern border of the Tibetan plateau, in south Ningxia, in the western Tian Shan of Xinjiang, and in the Alay valley of south Kyrgyzstan. Here we present a comparative natural history and characteristics of transmission ecosystems or ecoscapes. On this basis, regional types of transmission and their ecological characteristics have been proposed in a general framework. Combining climatic, land cover and intermediate host species distribution data, we identified and mapped 4 spatially distinct types of transmission ecosystems typified by the presence of one of the following small mammal 'flagship' species: Ellobius tancrei, Ochotona curzoniae, Lasiopodomys brandtii or Eospalax fontanierii. Each transmission ecosystem had its own characteristics which can serve as a reference for further in-depth research in the transmission ecology of E. multilocularis. This approach may be used at fine spatial scales to characterize other poorly known transmission systems of the large Eurasian endemic zone, and help in consideration of surveillance systems and interventions. PMID- 23734826 TI - The relationship between exercise capacity and masked hypertension in sedentary patients with diabetes mellitus. AB - AIM: Although exaggerated blood pressure responses (EBPR) to exercise have been related to future hypertension and masked hypertension (MHT), the relationship between exercise capacity and MHT remains unclear. A sedentary life style has been related to increased cardiovascular mortality, diabetes mellitus (DM), and hypertension. In this study, we aimed to examine the relationship between exercise capacity and MHT in sedentary patients with DM. METHODS: This study included 85 sedentary and normotensive patients with DM. Each patient's daily physical activity level was assessed according to the INTERHEART study. All patients underwent an exercise treadmill test, and exercise duration and capacity were recorded. Blood pressure (BP) was recorded during all exercise stages and BP values >= 200/110 mmHg were accepted as EBPR. MHT was diagnosed in patients having an office BP <140/90 mmHg and a daytime ambulatory BP >135/85 mmHg. Patients were divided into two groups according to their ambulatory BP monitoring (MHT and normotensive group). RESULTS: The prevalence of MHT was 28.2%. Exercise duration and capacity were lower in the MHT group than in the normotensive group (p<0.05) and were negatively correlated with age, HbA1c, mean daytime BP, and mean 24 hour BP. Peak exercise systolic BP and the frequency of EBPR were both increased in the MHT group (25.0% and 8.1%, respectively, p=0.03). According to a multivariate regression, exercise capacity (OR: 0.61, CI95%: 0.39-0.95, p=0.03), EBPR (OR: 9.45, CI95%: 1.72-16.90, p=0.01), and the duration of DM (OR: 0.84, CI95%: 0.71-0.96, p=0.03) were predictors of MHT. CONCLUSION: Exercise capacity, EBPR, and the duration of DM were predictors of MHT in sedentary subjects with DM. PMID- 23734828 TI - DNA origami nanopores for controlling DNA translocation. AB - We combine DNA origami structures with glass nanocapillaries to reversibly form hybrid DNA origami nanopores. Trapping of the DNA origami onto the nanocapillary is proven by imaging fluorescently labeled DNA origami structures and simultaneous ionic current measurements of the trapping events. We then show two applications highlighting the versatility of these DNA origami nanopores. First, by tuning the pore size we can control the folding of dsDNA molecules ("physical control"). Second, we show that the specific introduction of binding sites in the DNA origami nanopore allows selective detection of ssDNA as a function of the DNA sequence ("chemical control"). PMID- 23734827 TI - Generation of a tumor- and tissue-specific episomal non-viral vector system. AB - BACKGROUND: A key issue for safe and reproducible gene therapy approaches is the autologous and tissue-specific expression of transgenes. Tissue-specific expression in vivo is either achieved by transfer vectors that deliver the gene of interest into a distinct cell type or by use of tissue-specific expression cassettes. Here we present the generation of non-viral, episomally replicating vectors that are able to replicate in a tissue specific manner thus allowing tissue specific transgene expression in combination with episomal replication. The episomal replication of the prototype vector pEPI-1 and its derivatives depends exclusively on a transcription unit starting from a constitutively active promoter extending into the scaffold/matrix attachment region (S/MAR). RESULTS: Here, we exchanged the constitutive promoter in the pEPI derivative pEPito by the tumor specific alpha fetoprotein (AFP) or the muscle specific smooth muscle 22 (SM22) promoter leading to specific transgene expression in AFP positive human hepatocellular carcinoma (HUH7) and in a SM22 positive cell line, respectively. The incorporation of the hCMV enhancer element into the expression cassette further boosted the expression levels with both promoters. Tissue specific replication could be exemplary proven for the smooth muscle protein 22 (SM22) promoter in vitro. With the AFP promoter-driven pEPito vector hepatocellular carcinoma-specific expression could be achieved in vivo after systemic vector application together with polyethylenimine as transfection enhancer. CONCLUSIONS: In this study we present an episomal plasmid system designed for tissue specific transgene expression and replication. The human AFP-promoter in combination with the hCMV enhancer element was demonstrated to be a valuable tissue-specific promoter for targeting hepatocellular carcinomas with non-viral gene delivery system, and tissue specific replication could be shown in vitro with the muscle specific SM22 promoter. In combination with appropriate delivery systems, the tissue specific pEPito vector system will allow higher tissue-specificity with less undesired side effects and is suitable for long term transgene expression in vivo within gene therapeutical approaches. PMID- 23734830 TI - Warm-up strategies of professional soccer players: practitioners' perspectives. AB - Recent research has challenged the typical pre-match and half-time (HT) interval warm-up (WU) routines currently used by professional soccer players. This study surveyed 2010/11 season WU strategies and their underpinning scientific reasoning and situational factors via an internet-based questionnaire, which was distributed to English Premier League and Championship practitioners, of which 43% responded. The pre-match WU duration was 30.8 (8.2) min, ranging between 15 45 min, and 89% of practitioners administered a WU of >= 25 min. Respondents also reported a 12.4 (3.8) min period between the end of the WU and match kick-off. Eighty-nine per cent recognised the physiological benefits of re-WUs during this "down-time" period, with 63% instructing players to engage in such activity. During HT, 58% instructed players to re-WU either on the pitch or within stadia facilities, but "unwillingness of the coach/manager" (42%) and a "lack of time" (63%) were major constraints. Practitioners reported that 2.6 (1.6) min might be available for HT re-WUs. Factors such as match regulations, league policy, and stadia facilities were not generally considered as major barriers to the delivery of WUand re-WU strategies. We suggest that researchers consider the time-demands and barriers faced by practitioners whendeveloping experimental designs to examine WU regimens. PMID- 23734829 TI - Influence of efavirenz pharmacokinetics and pharmacogenetics on neuropsychological disorders in Ugandan HIV-positive patients with or without tuberculosis: a prospective cohort study. AB - BACKGROUND: HIV infection, anti-tuberculosis and efavirenz therapy are associated with neuropsychological effects. We evaluated the influence of rifampicin cotreatment, efavirenz pharmacokinetics and pharmacogenetics on neuropsychiatric disorders in Ugandan HIV patients with or without tuberculosis coinfection. METHODS: 197 treatment naive Ugandan HIV patients, of whom 138 were TB co infected, enrolled prospectively and received efavirenz based HAART. TB-HIV confected patients received concomitant rifampicin based anti-TB therapy. Genotypes for CYP2B6 (*6, *11), CYP3A5 (*3, *6, *7), ABCB1 (c.3435C>T and c.4036 A/G rs3842), CYP2A6 (*9, *17) and NR1I3 rs3003596 T/C were determined. Efavirenz plasma concentrations were serially quantified at 3rd day, 1st, 2nd, 4th, 6th, 8th and 12th weeks during therapy. Efavirenz neuropsychiatric symptoms were evaluated in terms of sleep disorders, hallucinations and cognitive effects at baseline, at two and twelve weeks of efavirenz treatment using a modified Mini Mental State Examination (MMSE) score. RESULTS: During the first twelve weeks of ART, 73.6% of the patients experienced at least one efavirenz related neuropsychiatric symptom. Commonest symptoms experienced were sleep disorders 60.5% (n=124) and hallucination 30.7% (n=63). Neuropsychiatric symptoms during HAART were significantly predicted by efavirenz plasma concentrations consistently. Rifampicin cotreatment reduced plasma efavirenz concentrations significantly only during the first week but not afterwards. There was no significant difference in the incidence of neuropsychiatric symptoms between patients receiving efavirenz with or without rifampicin cotreatment. CYP2B6*6 and ABCB1 c.4036 A/G genotype significantly predicted efavirenz concentrations. The tendency of CYP2B6*6 genotype association with higher incidence of having vivid dream (p=0.05), insomnia (p=0.19) and tactile hallucination (p=0.09) was observed mainly at week-2. CONCLUSIONS: Efavirenz related neuropsychiatric symptoms are common among Ugandan HIV patients receiving ART and is mainly predicted by higher efavirenz plasma concentrations and CYP2B6 genotype but not by rifampicin based anti-TB co-treatment. PMID- 23734831 TI - Conversion of twice-daily tacrolimus to once-daily tacrolimus formulation in stable pediatric kidney transplant recipients: pharmacokinetics and efficacy. AB - The pharmacokinetics, efficacy and safety of once-daily tacrolimus formulation (Tac-OD) were assessed in 34 stable pediatric kidney transplant recipients. Enrolled patients received their dose of twice-daily tacrolimus formulation (Tac BID) on study Days 0 through 7. On the morning of study Day 8, the total daily doses for patients were converted to Tac-OD on a 1:1 basis and maintained on a once-daily morning dosing regimen. Tacrolimus pharmacokinetic profiles were obtained on study Days 7, 14 and 28 (after dose adjustment). Although the mean C0 concentrations (4.10 +/- 1.16-3.53 +/- 1.10 ng/mL, p = 0.004), and AUC0-24 (151.8 +/- 41.6-129.8 +/- 39.3 ng h/mL, p < 0.001) were decreased significantly after a 1:1 based conversion, there was high interindividual variability. The dose of Tac OD was decreased in 26.5% and increased in 44.1% of patients. The resultant tacrolimus dose and pharmacokinetic profiles on study Day 28 were comparable to those on Day 7. There were no serious adverse events. In conclusion, Tac-BID can be safely converted to Tac-OD in stable pediatric kidney transplant patients with the heightened therapeutic drug monitoring. Effects of drug conversion on the cardiovascular risk factors, neurological side effects and adherence should be further evaluated. PMID- 23734832 TI - Case of phaeohyphomycosis producing sporotrichoid lesions. AB - A 90-year-old Japanese woman, taking prednisolone (5-10 mg/day) for polyarthritis, presented to our hospital with multiple subcutaneous lesions on her left arm in 2009. Her history included excision of a phaeomycotic cyst on the left middle finger in 2007. There were three subcutaneous nodules approximately 15 mm in diameter around her left wrist and a large soft cystic lesion measuring 80 mm * 60 mm on her left elbow. A granuloma with neutrophilic infiltration was detected in the deep dermis of a biopsy specimen. Chains composed of round brown cells and short pseudomycelia were found in the granuloma. Fungal cultures from the samples confirmed Exophiala sp. to be the causative agent. Treatment with terbinafine and local hyperthermia seemed effective as all the lesions tended to subside. However, the patient died due to pneumonia approximately 1 month after commencement of therapy. PMID- 23734833 TI - Abstracts of the 24th Congress of the International Association of Pediatric Dentistry. Seoul, Korea. June 12-15, 2013. PMID- 23734834 TI - Palladium-catalyzed intermolecular aminoacetoxylation of alkenes and the influence of PhI(OAc)2 on aminopalladation stereoselectivity. AB - A modified protocol has been identified for Pd-catalyzed intermolecular aminoacetoxylation of terminal and internal alkenes that enables the alkene to be used as the limiting reagent. The results prompt a reassessment of the stereochemical course of these reactions. X-ray crystallographic characterization of two of the products, together with isotopic labeling studies, show that the amidopalladation step switches from a cis-selective process under aerobic conditions to a trans-selective process in the presence of diacetoxyiodobenzene. PMID- 23734835 TI - A multiaddressable photochromic bisthienylethene with sequence-dependent responses: construction of an INHIBIT logic gate and a keypad lock. AB - A photochromic bisthienylethene derivative (BIT) containing two imidazole units has been synthesized and fully characterized. When triggered by chemical ions (Ag(+)), protons, and light, BIT can behave as an absorbance switch, leading to a multiaddressable system. BIT exhibits sequence-dependent responses via efficient interaction of the specific imidazole unit with protons and Ag(+). Furthermore, an INHIBIT logic gate and a keypad lock with three inputs are constructed with the unimolecular platform by employing an absorption mode at different wavelengths as outputs on the basis of an appropriate combination of chemical and photonic stimuli. PMID- 23734836 TI - Volvalerenol A, a new triterpenoid with a 12-membered ring from Valeriana hardwickii. AB - Volvalerenol A (1), an unprecedented type of triterpenoid with a 7/12/7 tricyclic ring system, was obtained from the ethanol extracts of the roots of Valeriana hardwickii. The structure and relative configurations were established by comprehensive analysis of MS and NMR spectroscopic data. The possible biogenetic pathway of 1 was also deduced. PMID- 23734837 TI - IL-1beta suppresses TGF-beta-mediated myofibroblast differentiation in cardiac fibroblasts. AB - Cardiac fibrosis is a maladaptive response of the injured myocardium and is mediated through a complex interplay between molecular triggers and cellular responses. Interleukin (IL)-1beta is a key inflammatory inducer in cardiac disease and promotes cell invasion and cardiomyocyte injury, but little is known of its impact on fibrosis. A major cornerstone of fibrosis is the differentiation of cardiac fibroblasts (CFs) into myofibroblasts (myoFbs), which is highly promoted by Transforming Growth Factor (TGF)-beta. Therefore, we asked how IL 1beta functionally modulated CF-to-myoFb differentiation. Using a differentiation model of ventricular fibroblasts, we found that IL-1beta instigated substantial anti-fibrogenic effects. In specific, IL-1beta reduced proliferation, matrix activity, cell motility and alpha-smooth muscle actin expression, which are all hallmarks of myoFb differentiation. These findings suggest that IL-1beta, besides from its acknowledged adverse role in the inflammatory response, can also exert beneficial effects in cardiac fibrosis by actively suppressing differentiation of CFs into fibrogenic myoFbs. PMID- 23734838 TI - Epiregulin induces human SK-N-BE cell differentiation through ERK1/2 signaling pathway. AB - Epidermal growth factor (EGF) and other EGF-related growth factors, such as transforming growth factor-alpha, are able to stimulate neuroblastoma (NB) cell proliferation. Epiregulin (Epi) is a growth factor belonging to the EGF family known to be more potent than EGF in mediating mitogenic signals. In this study, we tested the ability of Epi to stimulate a human NB cell line (SK-N-BE) proliferation. Surprisingly, Epi (50-1000 ng/ml) induced a reduction in SK-N-BE proliferation along with a morphological differentiation, associated with an increase in MMP-9 expression. Moreover, Epi-induced differentiation was inhibited by ERK1/2 phosphorilation inhibition. In conclusion, Epi could represent a novel and useful tool to oppose NB cell proliferation. PMID- 23734839 TI - Total cholesterol and lipoprotein composition are associated with dry eye disease in Korean women. AB - BACKGROUND: This study aimed to determine the relationship between dyslipidemia and dry eye disease (DED) in a Korean population. METHODS: This population-based study enrolled 5,627 adults (aged >19 years) who were participating in the first year of the fifth annual Korea National Health and Nutrition Examination Survey from 2010 to 2011. Clinically diagnosed DED and its symptoms were surveyed, and biochemical blood analysis data were collected. Dyslipidemia was defined as any of the following: hypercholesterolemia (total cholesterol > 200 mg/dL), hypertriglyceridemia (triglyceride > 150 mg/dL), low levels of high-density lipoprotein (<40 mg/dL), or high levels of low-density lipoprotein (>100 mg/dL). RESULTS: After adjusting for demographics (age and body mass index), lifestyle (smoking, drinking, exercise, and residential district), and medical factors (diabetes, hypertension, previous ophthalmic surgery, menopause, and rheumatologic disease), elevated serum cholesterol level was found to be associated with increased likelihood of DED (odds ratio, 1.77; 95% confidence interval, 1.127-2.78) in women. CONCLUSIONS: DED in a Korean population was found to be associated with high serum cholesterol levelsThe results of this study highlight the significance of eye examinations and independent lipid profile monitoring in patients with dyslipidemia because of its possible correlation with DED progression. PMID- 23734840 TI - Randomised clinical trial: evaluation of the efficacy of mesalazine (mesalamine) suppositories in patients with ulcerative colitis and active rectal inflammation - a placebo-controlled study. AB - BACKGROUND: Mesalazine suppositories are recommended and widely used as the standard therapy in induction and maintenance of remission for proctitis. AIM: To evaluate the efficacy of mesalazine suppositories in patients with ulcerative colitis (UC) and rectal inflammation; and in patient groups categorised by the extent of lesions. METHODS: This study was a phase III multicentre, randomised, double-blind, placebo-controlled, parallel-group study. Mild-to-moderate UC patients with rectal inflammation were randomly assigned either a 1 g mesalazine or placebo suppository. The suppository was administered in the rectum once daily for 4 weeks. The primary efficacy end point was the rate of endoscopic remission (mucosal score of 0 or 1) after 4 weeks. RESULTS: The endoscopic remission rates after 4 weeks in the mesalazine and placebo suppository groups were 81.5% and 29.7%, respectively, and the superiority of mesalazine to placebo was confirmed (P < 0.0001, chi-squared test). For proctitis, the endoscopic remission rates after 4 weeks were 83.8% and 36.1% in the mesalazine and placebo suppository groups, respectively, and the corresponding rates for all other types of UC were 78.6% and 21.4%, respectively. The superiority of mesalazine to placebo was confirmed in both subgroups (P < 0.0001, Fisher's exact test). The percentage of patients without bleeding was significantly higher in the mesalazine group than the placebo group from Day 3 of treatment (P = 0.0001, Fisher's exact test). CONCLUSIONS: The effectiveness of mesalazine suppositories in all types of UC patients with rectal inflammation was confirmed for the first time in a double blind, placebo-controlled, parallel-group study (JapicCTI- 111421). PMID- 23734841 TI - Highlights of HRCT imaging in IPF. AB - High-resolution computed tomography (HRCT) imaging has a central role in the diagnosis of interstitial lung diseases, particularly in the evaluation of patients with suspected idiopathic pulmonary fibrosis (IPF). In approximately half of cases, HRCT scans are sufficient to allow a confident IPF diagnosis. Advances in HRCT scanning and interpretation have facilitated improved accuracy for use in diagnosing IPF, eliminating the need for a surgical biopsy in many patients. HRCT may also have a role to play in predicting the prognosis of the disease;. The role of routine follow-up with HRCT to monitor patients with IPF remains unclear due to lack of sufficient evidence, although, sometimes follow-up HRCT might be necessary to rule out progressive disease in patients with undetermined diagnosis. Advances in the field of HRCT imaging are discussed, along with insights into the clinical utility of this procedure in the diagnosis and management of IPF. PMID- 23734843 TI - Human leukocyte antigen-DR mismatch is associated with increased in-hospital mortality after a heart transplant. AB - OBJECTIVES: Although previous studies have investigated the effect of human leukocyte antigen matching on long-term outcomes after heart transplants, its role in the prognosis after a heart transplant remains unclear, particularly with respect to short-term survival. MATERIALS AND METHODS: We evaluated the human leukocyte antigen mismatch on in-hospital mortality of 158 consecutive patients who had undergone a heart transplant between 2000 and 2008. Human leukocyte antigens-A, -B, and -DR were determined by means of serologic and molecular techniques. Univariate analysis and a multiple logistic regression models evaluated the effect of human leukocyte antigen variants on mortality, independent of clinical variables. RESULTS: In-hospital mortality was 11.4%. Higher prevalence of acute kidney injury (50.0% vs 12.9%), higher levels of troponins 48 hours after transplant (15.6 +/- 12.0 ng/mL vs 9.7 +/- 9.4 ng/mL), prolonged ischemia (188.2 +/- 32.5 min vs 162.6 +/- 40.7 min), higher frequency of reoperation (61.1% vs 17.9%), and higher human leukocyte antigen-DR mismatch (1.61 +/- 0.5 vs 1.30 +/- 0.6) were found in patients who died. By logistic regression analysis, humanleukocyte antigen-DR mismatch is associated with in hospital mortality (OR=5.159, 95% CI=1.348-19.754), independent of the effect of covariates such as recipient age, mismatch sex, mismatch human leukocyte antigen A, human leukocyte antigen-B, acute kidney injury, reoperation, ischemia duration, and levels of troponins. CONCLUSIONS: Human leukocyte antigen-DR mismatch is associated with in-hospital mortality in heart transplant. PMID- 23734844 TI - Heart rate variability arterial hypertension in young heart-transplanted recipients: association progression of cardiac allograft vasculopathy? AB - Hypertension and reduced HRV are frequent in heart-transplanted recipients. We studied 26 young recipients to investigate the relationship between BP and HRV during simultaneous 24-h monitoring. Presence of CAV was considered. All HRV measures were significantly lower than normal values. Significant correlations were found between mean daytime systolic BP and the rMSSD (p = 0.04), and mean daytime DBP and SDANN for all 5-min segments (p = 0.03) and between rMSSD and mean nighttime DBP (p = 0.03). Four patients were hypertensive during daytime, seven had a reduced nocturnal fall and two had a nocturnal rise in BP. Eight patients showed severe CAV grade (grade IV) on the Stanford scale, 13 moderate (grade III) and five mild (grade I-II). After a follow-up time of 30 months, four of the 13 patients (30%) with CAV grade III showed an increase to grade IV and all showed abnormalities of both HRV and ABPM patterns. The relationship between HRV abnormalities and arterial hypertension and CAV should be further explored. PMID- 23734842 TI - Generation of guanine-thymine cross-links in human cells by one-electron oxidation mechanisms. AB - The one-electron oxidation of cellular DNA in cultured human HeLa cells initiated by intense nanosecond 266 nm laser pulse irradiation produces cross-links between guanine and thymine bases (G*-T*), characterized by a covalent bond between C8 guanine (G*) and N3 thymine (T*) atoms. The DNA lesions were quantified by isotope dilution LC-MS/MS methods in the multiple reaction-monitoring mode using isotopically labeled [(15)N, (13)C]-nucleotides as internal standards. Among several known pyrimidine and 8-oxo-7,8-dihydroguanine lesions, the G*-T* cross linked lesions were detected at levels of ~0.21 and 1.19 d(G*-T*) lesions per 10(6) DNA bases at laser intensities of 50 and 280 mJ/cm(2)/pulse, respectively. PMID- 23734845 TI - Application of design-based stereology for estimation of absolute volume and surface area of the articular and calcified cartilage compartments of undecalcified human femoral heads. AB - Design-based stereological methods using systematic uniform random sampling, the Cavalieri estimator and vertical sections are used to investigate undecalcified human femoral heads. Ten entire human femoral heads, obtained from normal women and normal men, were systematically sampled and thin undecalcified vertical sections were obtained. Absolute volumes and surface areas of the entire femoral head, the articular cartilage and the calcified cartilage compartments were estimated. In addition, the average thickness of the articular cartilage and the calcified cartilage were calculated. The stereological procedures applied to the human femoral heads resulted in average coefficient of errors, which were 0.03 0.06 for the volume estimates and 0.03-0.04 for the surface area estimates. We conclude that design-based stereology using the Cavalieri estimator and vertical sections can successfully be used in large undecalcified tissue specimens, like the human femoral head, to estimate the absolute volume and surface area of macroscopic as well as of microscopic tissue compartments. The application of well-known design-based stereological methods carries potential advantage for investigating the pathology in inflammatory and degenerative joint diseases. PMID- 23734846 TI - A random-permutations-based approach to fast read alignment. AB - BACKGROUND: Read alignment is a computational bottleneck in some sequencing projects. Most of the existing software packages for read alignment are based on two algorithmic approaches: prefix-trees and hash-tables. We propose a new approach to read alignment using random permutations of strings. RESULTS: We present a prototype implementation and experiments performed with simulated and real reads of human DNA. Our experiments indicate that this permutations-based prototype is several times faster than comparable programs for fast read alignment and that it aligns more reads correctly. CONCLUSIONS: This approach may lead to improved speed, sensitivity, and accuracy in read alignment. The algorithm can also be used for specialized alignment applications and it can be extended to other related problems, such as assembly.More information: http://alignment.commons.yale.edu. PMID- 23734847 TI - Cyclic acyloxonium ions as diagnostic aids in the characterization of chloropropanol esters under electron impact (EI), electrospray ionization (ESI), and atmospheric pressure chemical ionization (APCI) conditions. AB - During mass spectrometric analysis of various lipids and lipid derivatives such as the chlorinated counterparts of triacylglycerols, the detailed structure of the characteristic and common ions formed under electron impact (EI), electrospray ionization (ESI), and atmospheric pressure chemical ionization (APCI) conditions by the loss of a single fatty acid remains ambiguous. These ions are designated in the literature as "diacylglyceride ions" and are frequently depicted with a molecular formula without showing any structural features and sometimes represented as cyclic acyloxonium ions. Characterization of these ions is of considerable importance due to their utility in structural identification of lipid derivatives. This study provides complementary evidence on the cyclic nature of "diacylglyceride ions" through the use of the simplest 3 monochloropropanediol diester as a model and the use of isotope labeling technique. Tandem MS/MS studies have indicated that the ion at m/z 135.6 generated from 1,2-bis(acetoyl)-3-chloropropane through the loss of an acetyl group was identical to the ion at m/z 135.6 generated from 4-chloromethyl-2,2 dimethyl-1,3-dioxolane, the latter being generated from a cyclic precursor through the loss of a methyl radical, keeping the dioxolane ring structure intact, thus confirming the cyclic nature of these ions. The corresponding cyclic oxonium ions generated from longer chain chloropropanol diesters, such as the ion at m/z 331.2 originating from 3-monochloropropanediol (3-MCPD) diesters containing palmitic acid(s), could serve as chemical markers for the presence chloropropanol esters. PMID- 23734848 TI - Mechanism of the reaction of OH with alkynes in the presence of oxygen. AB - Previous work has shown that the branching ratio of the reaction of OH/C2H2/O2 to glyoxal and formic acid is dependent on oxygen fraction, and a significant component of the product yield under atmospheric conditions is formed from reaction of chemically activated OH-C2H2 adduct. In this article, isotopic substitution is used to determine the mechanism of the OH/C2H2/O2 reaction resolving previous contradictory observations in the literature. Using laser flash photolysis and probing OH concentrations via laser induced fluorescence, a rate coefficient of kHO-C2H2+O2 = (6.17 +/- 0.68) * 10(-12) cm(3) molecule(-1) s( 1) is determined at 298 K from the analysis of biexponential OH decays in the presence of C2H2 and low concentrations of O2. The studies have been extended to propyne and but-2-yne. The reactions of OH with propyne and but-2-yne have been studied as a function of pressure in the absence of oxygen. The reaction of OH with propyne is in the fall off region from 2-25 Torr of nitrogen at room temperature. A pressure independent value of (4.21 +/- 0.47) * 10(-12) cm(3) molecule(-1) s(-1) was obtained from averaging the eight independent measurements at 25 and 75 Torr. The reaction of OH with but-2-yne at 298 K is pressure independent (5-25 Torr N2) with a value of (1.87 +/- 0.19) * 10(-11) cm(3) molecule(-1) s(-1). Analysis of biexpontial OH decays in alkyne/low O2 conditions gives the following rate coefficients at 298 K: kHO-C3H4+O2 = (8.00 +/- 0.82) * 10(-12) cm(3) molecule(-1) s(-1) and kHO-C4H6+O2 = (6.45 +/- 0.68) * 10(-12) cm(3) molecule(-1) s(-1). The branching ratio of bicarbonyl to organic acid in the presence of excess oxygen also shows an oxygen fraction dependence for propyne and but-2-yne, qualitatively similar to that for acetylene. For an oxygen fraction of 0.2 at 298 K, pressure independent yields of methylglyoxal (0.70 +/- 0.03) and biacetyl (0.74 +/- 0.03) were determined for the propyne and but-2-yne systems, respectively. The yield of acid increases with temperature from 212-500 K. Master equation calculations show that, under atmospheric conditions, the acetyl cofragment of organic acid production will dissociate, consistent with experimental observations. PMID- 23734849 TI - Modification of the liver fatty acids by Hibiscus sabdariffa Linnaeus (Malvaceae) infusion, its possible effect on vascular reactivity in a metabolic syndrome model. AB - We investigated the effects of Hibiscus sabdariffa Linnaeus (HSL)-fed infusion on the fatty acid (FA) profile in liver of metabolic syndrome (MS) rats and its possible effect on vascular reactivity. Body mass, intra-abdominal fat, triglycerides, insulin, blood pressure, saturated, monounsaturated FA, NEFAs, Delta(9)-, Delta(6)-desaturases and vasoconstriction were increased, while vasorelaxation, polyunsaturated FA, endothelial nitric oxide and [Formula: see text]/[Formula: see text] ratio decreased in MS versus Control, but HSL infusion modified it and increased Delta(5)-desaturase. The results suggest that the alteration in FA liver metabolism in the MS contributes to impaired vascular reactivity, but treatment with of HSL infusion can improve this condition. PMID- 23734850 TI - "Oxidative addition" of halogens to uranium(IV) bis(amidophenolate) complexes. AB - A series of U(IV) complexes, ((R)ap)2U(THF)2 [R = tert-butyl (t-Bu) (1), adamantyl (Ad) (2), diisopropylphenyl (dipp) (3)], supported by the redox-active 4,6-di-tert-butyl-2-(R)amidophenolate ligand, have been synthesized by salt metathesis of 2 equiv of the alkali metal salt of the ligand, M2[(R)ap] [M = K (1 and 2), Na (3)], with UCl4. Exposure of these uranium complexes to 1 equiv of PhICl2 results in oxidative addition to uranium, forming the bis-(4,6-di-tert butyl-2-(R)iminosemiquinone) ([(R)isq](1-)) uranium(IV) dichloride dimer, [((R)isq)2UCl]2(MU(2)-Cl)2 [R = t-Bu (4), Ad (5), dipp (6)]. The addition of iodine to 1 forms ((tBu)isq)2UI2(THF) (7), while the reactivity of I2 with 2 and 3 results in decomposition. Complexes 1-7 have been characterized by (1)H NMR and electronic absorption spectroscopies. X-ray crystallography was employed to elucidate structural parameters of 2, 3, 5, and 7. PMID- 23734851 TI - Clinical case: Combined pulmonary fibrosis and emphysema with pulmonary hypertension--clinical management. AB - BACKGROUND: Combined idiopathic pulmonary fibrosis (IPF) with pulmonary emphysema (CPFE) is a syndrome with a characteristic presentation of upper lobe emphysema and lower lobe fibrosis. While CPFE is a strong determinant of secondary precapillary pulmonary hypertension (PH), there is limited evidence regarding the management of patients with CPFE and PH. CASE PRESENTATION: A 63 year-old male presented in 2006 with dyspnoea on exertion having quit smoking in 2003. Clinical examination, together with high resolution computed tomography, bronchoalveolar lavage, and echocardiographic assessments, suggested a diagnosis of CPFE without PH. In 2007, the patient received intravenous cyclophosphamide, N-acetylcysteine, and short-term anticoagulation treatment. Due to remission of acute exacerbations, the patient received triple combination therapy (prednisone, N acetylcysteine and azathioprine). Upon progressive clinical worsening, long-term supplemental oxygen therapy was initiated in 2009. Repeated right heart catheterisation in 2011 confirmed PH and worsening pulmonary haemodynamics, and off-label ambrisentan therapy was initiated. Dyspnoea remained at follow-up, although significant haemodynamic improvement was observed. CONCLUSION: CFPE is a distinct but under-recognized and common syndrome with a characteristic presentation. Further studies are needed to ascertain the etiology, morbidity, and mortality of CPEF with or without PH, and to evaluate novel management options. PMID- 23734852 TI - A case report of syndrome of inappropriate antidiuretic hormone secretion with Castleman's disease and lymphoma. AB - BACKGROUND: Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia in hospitalized patients and is often described in patients with small-cell carcinoma of the lung. In this report, we described both Castleman's disease and lymphoma coexisting in one patient with SIADH. CASE PRESENTATION: A 70-year-old Chinese woman with a history of diabetes mellitus and insulin therapy had severe hyponatremia and gastrointestinal symptoms. Through a series of examinations, common causes such as pulmonary carcinoma were excluded. An abdominal mass was detected by computed tomography. Although the peripheral lymph node biopsy showed the pathological result as Castleman's disease, the pathology of the abdominal lymph node revealed diffuse large B-cell lymphoma. After chemotherapy, the hyponatremia was treated during a period of follow-up. CONCLUSION: This patient presented with the rare clinical condition of inappropriate antidiuretic hormone secretion alongside Castleman's disease and lymphoma. Asymptomatic hyponatremia may persist for some time suggesting that clinical physicians should pay attention to the mild cases of hyponatremia. We also hypothesized that Castleman's disease is a condition of pre-lymphoma with both having the ability to cause SIADH. The possibility of lymphoma as well as Castleman's disease triggering the development of SIADH should also be taken into consideration for conducting recurrent biopsies. PMID- 23734853 TI - The ghost of parasites past: eggs of the blood fluke Cardicola chaetodontis (Aporocotylidae) trapped in the heart and gills of butterflyfishes (Perciformes: Chaetodontidae) of the Great Barrier Reef. AB - We explored the distribution of Cardicola chaetodontis in chaetodontid fishes from the Great Barrier Reef. We found just four infections of adult worms in 238 individuals of 26 chaetodontid species. By contrast, eggs were present in hearts of 75 fishes (31.5%) and 19 of 26 chaetodontid species (all Chaetodon species). In 10 cases eggs contained moving miracidia; all the others were dead and degenerating. Eggs were sought in the gills of 51 individual fish. There were 17 cases of eggs being present in gills while present in the heart, but also 13 cases where eggs were absent from gills but present in the heart, suggesting that eggs remain longer in heart tissue than in gills. ITS2 rDNA sequences from two adult worms and eggs extracted from gills of five fishes (all different species) were identical to previously reported sequences of C. chaetodontis except for a single base-pair difference in two samples. We conclude that aporocotylid eggs trapped in fish heart tissues may inform understanding of the distributions and host ranges of aporocotylids, especially where adult prevalence is low. The low host-specificity of C. chaetodontis contrasts with higher specificity of trematodes of chaetodontids that have trophic transmission. PMID- 23734854 TI - Effect of hairpieces on perceived quality of life in female pattern hair loss patients: questionnaire based study. PMID- 23734855 TI - Efficient charge injection in p-type polymer field-effect transistors with low cost molybdenum electrodes through V2O5 interlayer. AB - Here we report high-performance polymer OFETs with a low-cost Mo source/drain electrode by efficient charge injection through the formation of a thermally deposited V2O5 thin film interlayer. A thermally deposited V2O5 interlayer is formed between a regioregular poly(3-hexylthiophene) (rr-P3HT) or a p-type polymer semiconductor containing dodecyl-substituted thienylenevinylene (TV) and dodecylthiophene (PC12TV12T) and the Mo source/drain electrode. The P3HT or PC12TV12T OFETs with the bare Mo electrode exhibited lower charge carrier mobility than those with Au owing to a large barrier height for hole injection (0.5-1.0 eV). By forming the V2O5 layer, the P3HT or PC12TV12T OFETs with V2O5 on the Mo electrode exhibited charge carrier mobility comparable to that of a pristine Au electrode. Best P3HT or PC12TV12T OFETs with 5 nm thick V2O5 on Mo electrode show the charge carrier mobility of 0.12 and 0.38 cm(2)/(V s), respectively. Ultraviolet photoelectron spectroscopy results exhibited the work function of the Mo electrode progressively changed from 4.3 to 4.9 eV with an increase in V2O5 thickness from 0 to 5 nm, respectively. Interestingly, the V2O5 deposited Mo exhibits comparable Rc to Au, which mainly results from the decreased barrier height for hole carrier injection from the low-cost metal electrode to the frontier molecular orbital of the p-type polymer semiconductor after the incorporation of the transition metal oxide hole injection layer, such as V2O5. This enables the development of large-area, low-cost electronics with the Mo electrodes and V2O5 interlayer. PMID- 23734856 TI - Copper-catalyzed nondecarboxylative cross coupling of alkenyltrifluoroborate salts with carboxylic acids or carboxylates: synthesis of enol esters. AB - A mild copper-catalyzed Chan-Lam-Evans type cross-coupling reaction for the regioselective and stereospecific preparation of (E)- or (Z)-enol esters is described. The method couples carboxylate salts or carboxylic acids with potassium alkenyltrifluoroborate salts in the presence of catalytic CuBr and DMAP with 4 A molecular sieves under O2 at 60 degrees C. Overall, this method demonstrates carboxylic acids as suitable reaction partners for nondecarboxylative copper-catalyzed cross-couplings to form C-O bonds in an Ullmann-like reaction. PMID- 23734857 TI - Carbon nanotubes instruct physiological growth and functionally mature syncytia: nongenetic engineering of cardiac myocytes. AB - Myocardial tissue engineering currently represents one of the most realistic strategies for cardiac repair. We have recently discovered the ability of carbon nanotube scaffolds to promote cell division and maturation in cardiomyocytes. Here, we test the hypothesis that carbon nanotube scaffolds promote cardiomyocyte growth and maturation by altering the gene expression program, implementing the cell electrophysiological properties and improving networking and maturation of functional syncytia. In our study, we combine microscopy, biological and electrophysiological methodologies, and calcium imaging, to verify whether neonatal rat ventricular myocytes cultured on substrates of multiwall carbon nanotubes acquire a physiologically more mature phenotype compared to control (gelatin). We show that the carbon nanotube substrate stimulates the induction of a gene expression profile characteristic of terminal differentiation and physiological growth, with a 2-fold increase of alpha-myosin heavy chain (P < 0.001) and upregulation of sarcoplasmic reticulum Ca(2+) ATPase 2a. In contrast, markers of pathological hypertrophy remain unchanged (beta-myosin heavy chain, skeletal alpha-actin, atrial natriuretic peptide). These modifications are paralleled by an increase of connexin-43 gene expression, gap junctions and functional syncytia. Moreover, carbon nanotubes appear to exert a protective effect against the pathologic stimulus of phenylephrine. Finally, cardiomyocytes on carbon nanotubes demonstrate a more mature electrophysiological phenotype of syncytia and intracellular calcium signaling. Thus, carbon nanotubes interacting with cardiomyocytes have the ability to promote physiological growth and functional maturation. These properties are unique in the current vexing field of tissue engineering, and offer unprecedented perspectives in the development of innovative therapies for cardiac repair. PMID- 23734859 TI - Chironomid midge sensitization in sewage workers: case study. AB - Non-biting chironomid midges (Diptera: Chironomidae) may cause sensitization and allergic reactions in humans and have recently been identified as a potential health problem in Swedish municipal sewage treatment plants. To investigate, on a pilot scale, the allergenic potential of chironomids in sewage workers, all workers (n = 8) at a sewage treatment plant and local controls (n = 16) completed a symptom questionnaire, underwent measurement of the fraction of nitric oxide in exhaled air, spirometry, and provided serum samples for the determination of atopy status and the prevalence of specific immunoglobulin E (IgE) antibodies against Chironomus thummi (Chi t) using a commercial fluorescence enzyme immunoassay (FEIA). Three sewage workers (38%) but no controls (0%) were FEIA positive for C. thummi-specific IgE antibodies (P < 0.05). No other health related findings were significantly different between the groups. The study suggested that occupational exposure to Chironomids may cause sensitization with circulating IgE-antibodies in sewage workers. PMID- 23734858 TI - Comparison of behavioral treatment conditions in buprenorphine maintenance. AB - BACKGROUND AND AIMS: The Controlled Substances Act requires physicians in the United States to provide or refer to behavioral treatment when treating opioid dependent individuals with buprenorphine; however, no research has examined the combination of buprenorphine with different types of behavioral treatments. This randomized controlled trial compared the effectiveness of four behavioral treatment conditions provided with buprenorphine and medical management (MM) for the treatment of opioid dependence. DESIGN: After a 2-week buprenorphine induction/stabilization phase, participants were randomized to one of four behavioral treatment conditions provided for 16 weeks: cognitive behavioral therapy (CBT = 53); contingency management (CM = 49); both CBT and CM (CBT + CM = 49); and no additional behavioral treatment (NT = 51). SETTING: Study activities occurred at an out-patient clinical research center in Los Angeles, California, USA. PARTICIPANTS: Included were 202 male and female opioid-dependent participants. MEASUREMENTS: Primary outcome was opioid use, measured as a proportion of opioid-negative urine results over the number of tests possible. Secondary outcomes include retention, withdrawal symptoms, craving, other drug use and adverse events. FINDINGS: No group differences in opioid use were found for the behavioral treatment phase (chi2 = 1.25, P = 0.75), for a second medication-only treatment phase, or at weeks 40 and 52 follow-ups. Analyses revealed no differences across groups for any secondary outcome. CONCLUSION: There remains no clear evidence that cognitive behavioural therapy and contingency management reduce opiate use when added to buprenorphine and medical management in opiate users seeking treatment. PMID- 23734860 TI - Predictors of consistent condom use based on the Information-Motivation-Behavior Skill (IMB) model among senior high school students in three coastal cities in China. AB - BACKGROUND: High prevalence of risky sexual behaviors and lack of information, skills and preventive support mean that, adolescents face high risks of HIV/AIDS. This study applied the information-motivation-behavioral skills (IMB) model to examine the predictors of consistent condom use among senior high school students from three coastal cities in China and clarify the relationships between the model constructs. METHODS: A cross-sectional study was conducted to assess HIV/AIDS related information, motivation, behavioral skills and preventive behaviors among senior high school students in three coastal cities in China. Structural equation modelling (SEM) was used to assess the IMB model. RESULTS: Of the 12313 participants, 4.5% (95% CI: 4.2-5.0) reported having had premarital sex and among them 25.0% (95% CI: 21.2-29.1) reported having used a condom in their sexual debut. Only about one-ninth of participants reported consistent condom use. The final IMB model provided acceptable fit to the data (CFI = 0.981, RMSEA = 0.014). Consistent condom use was significantly predicted by motivation (beta = 0.175, P < 0.01) and behavioral skills (beta = 0.778, P < 0.01). Information indirectly predicted consistent condom use, and was mediated by behavioral skills (beta = 0.269, P < 0.05). CONCLUSIONS: The results highlight the importance of conducting HIV/AIDS preventive health promotion among senior high school students in China. The IMB model could predict consistent condom use and suggests that future interventions should focus on improving motivation and behavioral skills. PMID- 23734861 TI - Eradication of breast cancer with bone metastasis by autologous formalin-fixed tumor vaccine (AFTV) combined with palliative radiation therapy and adjuvant chemotherapy: a case report. AB - Skeletal metastasis of breast carcinoma is refractory to intensive chemo radiation therapy and therefore is assumed impossible to cure. Here, we report an advanced case of breast cancer with vertebra-Th7 metastasis that showed complete response to combined treatments with formalin-fixed autologous tumor vaccine (AFTV), palliative radiation therapy with 36 Gy, and adjuvant chemotherapy with standardized CEF (cyclophosphamide, epirubicin, and 5FU), zoledronic acid, and aromatase inhibitors following mastectomy for the breast tumor. The patient has been disease-free for more than 4 years after the mammary surgery and remains well with no evidence of metastasis or local recurrence. Thus, a combination of AFTV, palliative radiation therapy, and adjuvant chemotherapy may be an effective treatment for this devastating disease. PMID- 23734862 TI - Polycyclic aromatic hydrocarbon reaction rates with peroxy-acid treatment: prediction of reactivity using local ionization potential. AB - Property-Encoded Surface Translator (PEST) descriptors were found to be correlated with the degradation rates of polycyclic aromatic hydrocarbons (PAHs) by the peroxy-acid process. Reaction rate constants (k) in hr(-1) for nine PAHs (acenaphthene, anthracene, benzo[a]pyrene, benzo[k]fluoranthene, fluoranthene, fluorene, naphthalene, phenanthrene, and pyrene) were determined by a peroxy-acid treatment method that utilized acetic acid, hydrogen peroxide, and a sulphuric acid catalyst to degrade the polyaromatic structures. Molecular properties of the selected nine PAHs were derived from structures optimized at B3LYP/6-31G(d) and HF/6-31G(d) levels of theory. Properties of adiabatic and vertical ionization potential (IP), highest occupied molecular orbitals (HOMO), HOMO/lowest unoccupied molecular orbital (LUMO) gap energies and HOMO/singly occupied molecular orbital (SOMO) gap energies were not correlated with rates of peroxy acid reaction. PEST descriptors were calculated from B3LYP/6-31G(d) optimized structures and found to have significant levels of correlation with k. PIP Min described the minimum local IP on the surface of the molecule and was found to be related to k. PEST technology appears to be an accurate method in predicting reactivity and could prove to be a valuable asset in building treatment models and in remediation design for PAHs and other organic contaminants in the environment. PMID- 23734863 TI - Spinocerebellar ataxia-13 Kv3.3 potassium channels: arginine-to-histidine mutations affect both functional and protein expression on the cell surface. AB - The voltage-gated potassium channel Kv3.3 is the causative gene of SCA13 (spinocerebellar ataxia type 13), an autosomal dominant neurological disorder. The four dominant mutations identified to date cause Kv3.3 channels to be non functional or have altered gating properties in Xenopus oocytes. In the present paper, we report that SCA13 mutations affect functional as well as protein expression of Kv3.3 channels in a mammalian cell line. The reduced protein level of SCA13 mutants is caused by a shorter protein half-life, and blocking the ubiquitin-proteasome pathway increases the total protein of SCA13 mutants more than wild-type. SCA13 mutated amino acids are highly conserved, and the side chains of these residues play a critical role in the stable expression of Kv3.3 proteins. In addition, we show that mutant Kv3.3 protein levels could be partially rescued by treatment with the chemical chaperone TMAO (trimethylamine N oxide) and to a lesser extent with co-expression of Kv3.1b. Thus our results suggest that amino acid side chains of SCA13 positions affect the protein half life and/or function of Kv3.3, and the adverse effect on protein expression cannot be fully rescued. PMID- 23734864 TI - Enhanced dispersibility and bioactivity of curcumin by encapsulation in casein nanocapsules. AB - In this work, a novel encapsulation method was studied by spray-drying a warm aqueous ethanol solution with codissolved sodium caseinate (NaCas) and lipophilic food components, using curcumin as a model compound. The encapsulation caused the loss of crystallinity of curcumin. After hydration of spray-dried powder and centrifugation, 137 MUg/mL curcumin was dispersed in the transparent dispersion, which was 4 decades higher than its water solubility. Dynamic light scattering and atomic force microscopy results showed that curcumin-loaded casein nanoparticles were bigger than those of NaCas processed at encapsulation conditions but were smaller than those of the native NaCas. The increased nanoparticle dimension, together with fluorescence and FTIR spectroscopy results, suggested that curcumin was entrapped in the nanoparticle core through hydrophobic interactions. The curcumin encapsulated in casein nanoparticles had higher biological activity, as assessed by antioxidant and cell proliferation assays, than pristine curcumin, likely due to the improved dispersibility. This simple approach may be applied to encapsulate various lipophilic bioactive compounds. PMID- 23734865 TI - Correlative light and electron microscopy for the analysis of cell division. AB - Correlative light and electron microscopy (CLEM) has recently gained increasing attention, because it enables the acquisition of dynamic as well as ultrastructural information about subcellular processes. It is the power of combining the two imaging modalities that gives additional information as compared to using the imaging techniques separately. Here, we briefly summarize two CLEM approaches for the analysis of cells in mitosis and cytokinesis. PMID- 23734866 TI - Assembling contigs in draft genomes using reversals and block-interchanges. AB - The techniques of next generation sequencing allow an increasing number of draft genomes to be produced rapidly in a decreasing cost. However, these draft genomes usually are just partially sequenced as collections of unassembled contigs, which cannot be used directly by currently existing algorithms for studying their genome rearrangements and phylogeny reconstruction. In this work, we study the one-sided block (or contig) ordering problem with weighted reversal and block interchange distance. Given a partially assembled genome pi and a completely assembled genome sigma, the problem is to find an optimal ordering to assemble (i.e., order and orient) the contigs of pi such that the rearrangement distance measured by reversals and block-interchanges (also called generalized transpositions) with the weight ratio 1:2 between the assembled contigs of pi and sigma is minimized. In addition to genome rearrangements and phylogeny reconstruction, the one-sided block ordering problem particularly has a useful application in genome resequencing, because its algorithms can be used to assemble the contigs of a draft genome pi based on a reference genome sigma. By using permutation groups, we design an efficient algorithm to solve this one sided block ordering problem in Odeltan time, where n is the number of genes or markers and delta is the number of used reversals and block-interchanges. We also show that the assembly of the partially assembled genome can be done in On time and its weighted rearrangement distance from the completely assembled genome can be calculated in advance in On time. Finally, we have implemented our algorithm into a program and used some simulated datasets to compare its accuracy performance to a currently existing similar tool, called SIS that was implemented by a heuristic algorithm that considers only reversals, on assembling the contigs in draft genomes based on their reference genomes. Our experimental results have shown that the accuracy performance of our program is better than that of SIS, when the number of reversals and transpositions involved in the rearrangement events between the complete genomes of pi and sigma is increased. In particular, if there are more transpositions involved in the rearrangement events, then the gap of accuracy performance between our program and SIS is increasing. PMID- 23734867 TI - Clinical trials of investigational agents for IPF: a review of a Cochrane report. AB - The magnitude of treatment effect can be assessed by a number of methods. One reliable method of collectively analysing data from randomised clinical trials is that used in Cochrane reviews. These systematic reviews identify and analyse the available evidence using the reliable method of meta-analysis. These often combine data from studies to provide robust evaluations of overall treatment effects. In 2003, a review of data from studies of corticosteroid use in IPF patients found no evidence of a treatment effect. Similarly, very little evidence was found to support the use of immunomodulatory agents. A recent update of these Cochrane reviews failed to identify any new evidence supporting the use of corticosteroids in IPF. However, a review of non-steroid agents for the treatment of IPF identified data from 15 RCTs that was suitable for analysis. Two trials of interferon gamma-1b were pooled and analysed, but no treatment effect was observed in terms of survival. Meta-analysis of three Phase III studies of pirfenidone treatment in IPF patients suggested that progression-free survival was significantly increased by 30%, demonstrating a reduction in the decline of lung function in IPF patients. In addition, there are numerous ongoing trials investigating potential therapeutic agents which provides hope for IPF patients and their doctors. PMID- 23734868 TI - How to approach endocrine assessment in severe obesity? AB - The increasing numbers of severely obese patients (body mass index BMI >40 kg/m(2) ) represent a significant management challenge. These patients are at risk of obesity-related complications that may be driven by changes in endocrine function. Their care may potentially be complex at times, and therefore, an appropriate assessment strategy will be relevant to timely diagnosis and management. In this article, we discuss an approach to the endocrine assessment of the severely obese patient. We consider the clinical question in three categories that may also represent different complexities in terms of subsequent management: (i) obesity as a consequence of structural lesions at the hypothalamic-pituitary region; (ii) obesity as a consequence of inherited and genetic syndromes; and (iii) functional neuroendocrine hormone abnormalities relating to obesity. The first two categories are associated with hypothalamic dysfunction, of which hypothalamic obesity is a consequence. Additionally, the implications and difficulties associated with imaging severely obese patients are discussed from an endocrinological perspective and we provide practical guidance on which to base practice. PMID- 23734869 TI - Successful management on a case of dermatomyositis with hydropneumothorax, tracheoesophageal fistula and esophago-thoracic cavity fistula. PMID- 23734870 TI - The mediatory role of maladaptive schema modes between parental care and non suicidal self-injury. AB - Non-suicidal self-injury (NSSI) is being increasingly recognised as a behaviour of significant clinical importance. Yet, there remains uncertainty regarding the underlying mechanisms of NSSI. This study aimed to explore the relationship between maladaptive schema modes, parental bonding, and NSSI. Seventy psychiatric outpatients with a history of NSSI completed the Deliberate Self-Harm Inventory, Schema Mode Inventory, and Parental Bonding Inventory. Results revealed that maladaptive schema modes were significantly associated with low parental care and with an earlier age of onset, longer duration, and higher number of methods of NSSI. Maladaptive schema modes also significantly mediated the relationship between parental care and age of onset of NSSI and between parental care and duration of NSSI. Two maladaptive schema modes (namely, Punitive Parent and Angry Child) were also found to be significant mediators in this relationship. The clinical implications of this research are discussed. PMID- 23734871 TI - Effects of a computerized feedback intervention on safety performance by junior doctors: results from a randomized mixed method study. AB - BACKGROUND: The behaviour of doctors and their responses to warnings can inform the effective design of Clinical Decision Support Systems. We used data from a University hospital electronic prescribing and laboratory reporting system with hierarchical warnings and alerts to explore junior doctors' behaviour. The objective of this trial was to establish whether a Junior Doctor Dashboard providing feedback on prescription warning information and laboratory alerting acceptance rates was effective in changing junior doctors' behaviour. METHODS: A mixed methods approach was employed which included a parallel group randomised controlled trial, and individual and focus group interviews. Junior doctors below the specialty trainee level 3 grade were recruited and randomised to two groups. Every doctor (N = 42) in the intervention group was e-mailed a link to a personal dashboard every week for 4 months. Nineteen participated in interviews. The 44 control doctors did not receive any automated feedback. The outcome measures were the difference in responses to prescribing warnings (of two severities) and laboratory alerting (of two severities) between the months before and the months during the intervention, analysed as the difference in performance between the intervention and the control groups. RESULTS: No significant differences were observed in the rates of generating prescription warnings, or in the acceptance of laboratory alarms. However, responses to laboratory alerts differed between the pre-intervention and intervention periods. For the doctors of Foundation Year 1 grade, this improvement was significantly (p = 0.002) greater in the group with access to the dashboard (53.6% ignored pre-intervention compared to 29.2% post intervention) than in the control group (47.9% ignored pre-intervention compared to 47.0% post intervention). Qualitative interview data indicated that while junior doctors were positive about the electronic prescribing functions, they were discriminating in the way they responded to other alerts and warnings given that from their perspective these were not always immediately clinically relevant or within the scope of their responsibility. CONCLUSIONS: We have only been able to provide weak evidence that a clinical dashboard providing individualized feedback data has the potential to improve safety behaviour and only in one of several domains. The construction of metrics used in clinical dashboards must take account of actual work processes. TRIAL REGISTRATION ISRCTN: ISRCTN72253051. PMID- 23734872 TI - A closer look at the bromine-lithium exchange with tert-butyllithium in an aryl sulfonamide synthesis. AB - A practical protocol for the one-pot synthesis of various aryl sulfonamides, notably of pyridine-core-substituted 7-azaindolyl sulfonamides, is described. A key step is the well-known bromine-lithium exchange reaction of an aryl bromide with tert-butyllithium (t-BuLi). Differing from the common practice to use 2 or more equiv of organolithium, the exact amount of t-BuLi needed for a sufficient exchange reaction is determined for each aryl bromide in a GC-MS-assisted experiment. PMID- 23734873 TI - Investigation on new CuInS2/carbon composite counter electrodes for CdS/CdSe cosensitized solar cells. AB - The search for semiconductor-sensitized solar cell (SSC) counter electrode alternatives has been a continuous effort and long ongoing work, while the studies in counter electrode kinetic performance and stability are important to improve the overall efficiency. Here, a ternary chalcopyrite compound CuInS2 is first employed as counter electrode (CE) material for CdS/CdSe cosensitized solar cells. Besides, in order to increase the electron transfer activity at the counter electrode/electrolyte interface and stability, an appropriate amount of active carbon/carbon black mixture is introduced to afford CuInS2/carbon composite electrodes. Electron transfer processes in CuInS2-based electrodes are investigated in detail with the aid of electrochemical impedance spectroscopy and I-E measurement. Up to 4.32% of the light-to-electricity conversion efficiency has been achieved for the CdS/CdSe SSCs with the CuInS2/carbon composite electrode. Besides, a preliminary long-term stability test reveals that the new CuInS2/carbon composite counter electrode exhibits good stability after being kept in the dark at room temperature and without current flow for 1000 h. PMID- 23734874 TI - Multilocus microsatellite signature and identification of specific molecular markers for Leishmania aethiopica. AB - BACKGROUND: Leishmaniasis is a clinically and epidemiologically diverse zoonotic disease caused by obligatory, intracellular protozoan parasites of the genus Leishmania. Cutaneous leishmaniasis is the most widely distributed form of the disease characterized by skin lesions. Leishmania aethiopica is considered the predominant etiological agent in Ethiopia. The current study was aimed at developing multilocus microsatellite markers for L. aethiopica isolated from human cutaneous leishmaniasis patients in Ethiopia. RESULTS: L. aethiopica parasites for the study were obtained from Ethiopia and laboratory analysis was conducted at The Ohio State University. DNA was extracted from cultured parasites and an internal transcribed spacer located at the ribosomal region of L. aethiopica genomic DNA was PCR amplified for species identification. Microsatellite markers were identified using multilocus microsatellite typing. We generated an enriched genomic library, and using Primer3 software, designed PCR primers to amplify sequences flanking the detected microsatellites. Subsequent screening of the amplified markers for length variations was performed by gel electrophoresis.Using a variety of molecular methods, 22 different microsatellite markers were identified and tested for typing L. aethiopica strains using a number of clinical isolates. Of the 22 markers tested, 5 were polymorphic and showed distinctive multilocus genotypes, classifying them into four clusters. One marker was found to be specific for L. aethiopica, discriminating it from other species of Leishmania. CONCLUSION: Multilocus microsatellite typing using the markers developed in this study could be useful for epidemiological and population genetic studies of strains of L. aethiopica in order to investigate the structure and dynamics of the corresponding natural foci. It could also help to answer specific clinical questions, such as the occurrence of local and diffuse lesions, strain correlates of parasite persistence after subclinical infection and lesion comparisons from patients suffering from L. aethiopica infections. PMID- 23734875 TI - A prospective study of endothelial activation biomarkers, including plasma angiopoietin-1 and angiopoietin-2, in Kenyan women initiating antiretroviral therapy. AB - BACKGROUND: HIV-1-related inflammation is associated with increased levels of biomarkers of vascular adhesion and endothelial activation, and may increase production of the inflammatory protein angiopoietin-2 (ANG-2), an adverse prognostic biomarker in severe systemic infection. We hypothesized that antiretroviral therapy (ART) initiation would decrease endothelial activation, reducing plasma levels of ANG-2. METHODS: Antiretroviral-naive Kenyan women with advanced HIV infection were followed prospectively. Endothelial activation biomarkers including soluble intercellular adhesion molecule-1 (ICAM-1), vascular adhesion molecule-1 (VCAM-1), and E-selectin, and plasma ANG-2 and angiopoietin-1 (ANG-1) were tested in stored plasma samples from 0, 6, and 12 months after ART initiation. We used Wilcoxon matched-pairs signed rank tests to compare endothelial activation biomarkers across time-points, generalized estimating equations to analyze associations with change in log10-transformed biomarkers after ART initiation, and Cox proportional-hazards regression to analyze associations with mortality. RESULTS: The 102 HIV-1-seropositive women studied had advanced infection (median CD4 count, 124 cells/MUL). Soluble ICAM-1 and plasma ANG-2 levels decreased at both time-points after ART initiation, with concomitant increases in the beneficial protein ANG-1. Higher ANG-2 levels after ART initiation were associated with higher plasma HIV-1 RNA, oral contraceptive pill use, pregnancy, severe malnutrition, and tuberculosis. Baseline ANG-2 levels were higher among five women who died after ART initiation than among women who did not (median 2.85 ng/mL [inter-quartile range (IQR) 2.47-5.74 ng/mL] versus median 1.32 ng/mL [IQR 0.35-2.18 ng/mL], p = 0.01). Both soluble ICAM-1 and plasma ANG-2 levels predicted mortality after ART initiation. CONCLUSIONS: Biomarkers of endothelial activation decreased after ART initiation in women with advanced HIV-1 infection. Changes in plasma ANG-2 were associated with HIV-1 RNA levels over 12 months of follow-up. Soluble ICAM-1 and plasma ANG-2 levels represent potential biomarkers for adverse outcomes in advanced HIV-1 infection. PMID- 23734877 TI - Genetic risk of suicidal behavior in bipolar spectrum disorder: analysis of 737 pedigrees. AB - OBJECTIVES: Suicide is a significant cause of mortality in patients with major affective disorders (MAD), and suicidal behavior and MAD co-aggregate in families. However, the transmission of suicidal behavior is partially independent from that of MAD. We analyzed the lifetime prevalence of completed and attempted suicides in a large sample of families with bipolar disorder (BD), its relation to family history of MAD and BD, and the contribution of clinical and treatment factors to the risk of suicidal behavior. METHODS: We studied 737 families of probands with MAD with 4919 first-degree relatives (818 affected, 3948 unaffected, and 153 subjects with no information available). Lifetime psychiatric diagnoses and suicidal behavior in first-degree relatives were assessed using semi-structured interviews, family history methods, and reviews of clinical records. Cox proportional hazard and logistic regression models were used to investigate the role of clinical covariates in the risk of suicidal behavior, and in the prevalence of MAD and BD. RESULTS: The estimated lifetime prevalence of suicidal behavior (attempted and completed suicides) in 737 probands was 38.4 +/- 3.0%. Lithium treatment decreased suicide risk in probands (p = 0.007). In first degree relatives, a family history of suicidal behavior contributed significantly to the joint risk of MAD and suicidal behavior (p = 0.0006). CONCLUSIONS: The liability to suicidal behavior is influenced by genetic factors (particularly family history of suicidal behavior and MAD). Even in the presence of high genetic risk for suicidal behavior, lithium treatment decreases suicide rates significantly. PMID- 23734876 TI - Determination of antiprotozoal drug mechanisms by metabolomics approaches. AB - The discovery, development and optimal utilization of pharmaceuticals can be greatly enhanced by knowledge of their modes of action. However, many drugs currently on the market act by unknown mechanisms. Untargeted metabolomics offers the potential to discover modes of action for drugs that perturb cellular metabolism. Development of high resolution LC-MS methods and improved data analysis software now allows rapid detection of drug-induced changes to cellular metabolism in an untargeted manner. Several studies have demonstrated the ability of untargeted metabolomics to provide unbiased target discovery for antimicrobial drugs, in particular for antiprotozoal agents. Furthermore, the utilization of targeted metabolomics techniques has enabled validation of existing hypotheses regarding antiprotozoal drug mechanisms. Metabolomics approaches are likely to assist with optimization of new drug candidates by identification of drug targets, and by allowing detailed characterization of modes of action and resistance of existing and novel antiprotozoal drugs. PMID- 23734878 TI - Deviant smooth pursuit in preschool children exposed prenatally to methadone or buprenorphine and tobacco affects integrative visuomotor capabilities. AB - BACKGROUND AND AIMS: Although an increasing number of children are born to mothers in opioid maintenance therapy (OMT), little is known about the long-term effects of these opioids. Previous studies suggest an association between prenatal OMT exposure and difficulties in eye movement control. Also, the effects of tobacco smoking on eye movements have been reported. The present study examined the influence of eye movements, i.e. smooth pursuit, on visuomotor capabilities in children of smoking mothers in OMT. DESIGN: The study comprised a 2 (OMT versus contrast group) * 2 (slow versus fast smooth pursuit) between subject factorial design. SETTING: The cognitive developmental research unit at the University of Oslo, Norway. PARTICIPANTS: Participants were 26 4-year-old children of tobacco-smoking women in OMT and 23 non-exposed 4-year-old children, with non-smoking mothers, matched by gender and age. MEASUREMENT: Eye movements and smooth pursuit were recorded using a Tobii 1750 eyetracker. Visuomotor functions were examined by Bender test. FINDINGS: The OMT group tracked slowly moving objects with smooth pursuit in a similar manner to their non-exposed peers. When fast smooth pursuit was measured, the OMT group of children tracked the object more slowly than the contrast group, P = 0.02, etap(2) = 0.11. A regression analysis showed that fast smooth pursuit predicted children's performance on a visuomotor task, R(2) = 0.37. CONCLUSION: Impaired eye-tracking skills in 4-year-old children exposed to methadone or buprenorphine and tobacco prenatally could inhibit the development of some cognitive functions in later life. PMID- 23734879 TI - Interaction of a hydrated electron with anthracenethiosemicarbazone: a pulse radiolysis study. AB - The thiosemicarbazide derivative of anthracene, ATSC, has been synthesized and characterized by elemental analysis, IR, UV-visible, (1)H NMR, fluorescence, and mass spectroscopy experiments. The interaction of hydrated electron (e(-)aq) with ATSC proceeds via radical anion formation followed by intramolecular transfer that cleaves the thiosemicarbazide side chain on the anthracene moiety. HPLC and ESI-MS experiments suggested that the anthrylmethyl radical combines with different ATSC fragments during the reaction. ATSC, its one-electron reduction products, and dimers were analyzed combining experiments with density functional theory. PMID- 23734880 TI - Smart pH-sensitive and temporal-controlled polymeric micelles for effective combination therapy of doxorubicin and disulfiram. AB - The combination of a chemotherapeutic drug with a multidrug resistance (MDR) modulator has emerged as a promising strategy for treating MDR cancer. To ensure two drugs could be simultaneously delivered to tumor region at the optimum ratio, and the MDR modulator could be released earlier and faster than the chemotherapeutic drug to inactivate P-glycoprotein (P-gp) and subsequently inhibit the pumping out of the chemotherapeutic drug, a smart pH-sensitive polymeric micelles system with high drug loading and precise drug ratio was designed and prepared by conjugating doxorubicin (DOX) to poly(styrene-co-maleic anhydride) (SMA) derivative with adipic dihydrazide (ADH) through a acid cleavable hydrazone bond, and then encapsulating disulfiram (DSF), a P-gp inhibitor as well as an apoptosis inducer, into the micelles formed by the self assembly of SMA-ADH-DOX (SAD) conjugate. The pH-sensitive polymeric micelles system enabled a temporal release of two drugs: encapsulated DSF was released fast to inhibit the activity of P-gp and restore cell apoptotic signaling pathways, while conjugated DOX was released in a sustained and pH-dependent manner and highly accumulated in drug resistant cells to exert therapeutic effect, due to the inactivation of P-gp by DSF. The smart co-delivery system was very effective in enhancing the cytotoxicity by increasing the intracellular accumulation of DOX and promoting the apoptotic response, and showed the most effective inhibitory effect on the growth of drug-resistant breast cancer xenografts as compared to other combinations of both drugs. In a word, this smart co-delivery system has significant promise for the clinical therapy of MDR cancer. PMID- 23734881 TI - Alteration of the content of primary and secondary metabolites in strawberry fruit by Colletotrichum nymphaeae infection. AB - The effects of infection with Colletotrichum nymphaeae , the causative agent of strawberry black spot, were studied on two strawberry cultivars: susceptible 'Elsanta' and tolerant 'Honeoye' cultivars. Four treatments were established: (1) artificial inoculation; (2) spray application of pyraclostrobin + boscalid (Signum); (3) foliar spraying with calcium (Stopit); and (4) control (spraying with water). Primary metabolites (sugars and organic acids) and secondary metabolites (phenolic compounds) were determined in strawberry fruit with the use of HPLC-MS(n). Infected fruit accumulated large amounts of total sugars and low levels of organic acids. The sugar/acid ratio was higher in the infected and in Ca-treated strawberries. The contents of ellagic acid derivatives, flavonols, oligomeric procyanidins, flavan-3-ols, and total phenolics were highest in inoculated strawberry fruit. Results indicated that fungicide and calcium sprayings did not alter polyphenolic levels in plant tissue. PMID- 23734882 TI - Proteomic analyses of different human tumour-derived chaperone-rich cell lysate (CRCL) anti-cancer vaccines reveal antigen content and strong similarities amongst the vaccines along with a basis for CRCL's unique structure: CRCL vaccine proteome leads to unique structure. AB - PURPOSE: The aim of this paper was to compare protein content of chaperone-rich cell lysate (CRCL) anti-cancer vaccines prepared from human tumours of different histological origins to evaluate the uniformity of their protein content. MATERIALS AND METHODS: Clinical grade CRCL was prepared under Good Manufacturing Practice (GMP) conditions from surgically resected human tumours (colorectal cancer, glioblastoma, non-small cell lung cancer, ovarian cancer). Protein samples were separated by SDS-PAGE and slices cut from gels for protease digestion followed by mass spectrometry analysis. Proteins were identified, and the content assessed by gene ontogeny/networking programmatic computation. CRCL preparations were also analysed by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). RESULTS: We identified between 200 and 550 proteins in the various CRCL preparations. Gene ontogeny analysis indicated that the vaccines showed clear relationships, despite different tumour origins. A total of 95 proteins were common to all the CRCLs. Networking analyses implicated heat shock proteins in antigen processing pathways, and showed connections to the cytoskeletal network. We found that CRCL vaccines showed a particulate structure by NTA, and TEM revealed an extended fence-like structural network in CRCL, with regions that were microns in size. CONCLUSIONS: We conclude that it is feasible to prepare and characterise CRCL from a variety of different tissue sources; a substantial portion of the protein content is identical among the different CRCLs, while the overall compositions also suggest high overlaps in functional categories. The protein content indicates the presence of antigens and implies a potential structure, which we believe may play a role in CRCL's ability to stimulate innate antigen presenting cell activation. PMID- 23734883 TI - Interferon-gamma ELISPOT detecting reactivity of T cells to TSH receptor peptides in Graves' disease. AB - OBJECTIVE: While thyrotrophin receptor (TSHR) is recognized as the main autoantigen in Graves' disease (GD), the actual antigen specificity of T cells that infiltrate the thyroid and the orbit is unknown. Identifying T cell responses to TSHR peptides has been difficult in the past due to the low frequency of autoreactive T cells and to the diversity of the putative epitopes identified by proliferation assays. METHODS: We used the interferon-gamma ELISPOT assay to identify T cell reactivity to TSHR peptides in patients with GD. Peripheral blood T cells were exposed in vitro to four pools of 10 overlapping TSHR peptides. RESULTS: T cells from 11 of 31 (35%) patients with GD and 1 of 22 (4%) healthy controls reacted to at least one peptide pool (P = 0.009). Mean time since diagnosis was 3.2 years in responder patients and 5.6 years in nonresponders (P = 0.07). In two patients, T cell reactivity was observed shortly after radioiodine treatment and not thereafter. CONCLUSIONS: Our findings demonstrate that the ELISPOT assay is effective to test T cell reactivity in patients with GD and that patients with GD have significantly more interferon gamma responses towards TSHR peptides than controls. The data suggest that screening for T cell responses in patients with GD might be more efficient in recent-onset disease or after radioiodine treatment. PMID- 23734886 TI - Editorial: Update guidelines dermatologic oncology. PMID- 23734888 TI - Brief S1 guidelines--Cutaneous angiosarcoma and Kaposi sarcoma. PMID- 23734889 TI - Brief S2k guidelines--Basal cell carcinoma of the skin. PMID- 23734891 TI - Brief S2k guidelines--Dermatofibrosarcoma protuberans. PMID- 23734893 TI - Brief S2k guidelines--Cutaneous lymphomas. PMID- 23734895 TI - Brief S2k guidelines--Merkel cell carcinoma. PMID- 23734897 TI - Brief S2k guidelines--Cutaneous squamous cell carcinoma. PMID- 23734901 TI - Intramolecular carbocupration of N-aryl-ynamides: a modular indole synthesis. AB - A modular indole synthesis based on an intramolecular 5-endo-dig carbocupration starting from readily available N-aryl-ynamides is reported. A variety of ynamides are converted to indoles in moderate to good yields and with varying substitution pattern on the indole ring. This further extends the synthetic utility of ynamides in organic synthesis and provides additional insights on the use of intramolecular carbometalation reactions. PMID- 23734900 TI - Incidence, risk factors, and outcomes of Fusobacterium species bacteremia. AB - BACKGROUND: Fusobacterium species (spp.) bacteremia is uncommon and has been associated with a variety of clinical presentations. We conducted a retrospective, population based study to determine the relative proportion of species in this genus causing bacteremia and the risk factors for infection and adverse clinical outcomes. METHODS: All cases of Fusobacterium spp. bacteremia detected at a regional microbiology laboratory serving outpatient and acute care for a population of approximately 1.3 million people over 11 years were identified from a computerized database. Clinical data on these cases was extracted from an administrative database and analyzed to determine underlying risk factors for and outcomes of infection. RESULTS: There were 72 incident cases of Fusobacterium spp. bacteremia over the study period (0.55 cases/100,000 population per annum). F. nucleatum was the most frequent species (61%), followed by F. necrophorum (25%). F. necrophorum bacteremia occurred in a younger population without underlying comorbidities and was not associated with mortality. F. nucleatum bacteremia was found in an older population and was associated with underlying malignancy or receiving dialysis. Death occurred in approximately 10% of F. nucleatum cases but causality was not established in this study. CONCLUSIONS: Fusobacterium spp. bacteremia in our community is uncommon and occurs in approximately 5.5 cases per million population per annum. F. necrophorum occurred in an otherwise young healthy population and was not associated with any mortality. F. nucleatum was found primarily in older patients with chronic medical conditions and was associated with a mortality of approximately 10%. Bacteremias from other Fusobacterium spp. were rare. PMID- 23734899 TI - Locally-advanced primary neuroendocrine carcinoma of the breast: case report and review of the literature. AB - BACKGROUND: Primary neuroendocrine carcinoma of the breast is a heterogeneous group of rare tumors with positive immunoreactivity to neuroendocrine markers in at least 50% of cells. Diagnosis also requires that other primary sites be ruled out and that the same tumor show histological evidence of a breast in situ component. Primary neuroendocrine carcinoma of the breast rarely presents as locally advanced disease and less frequently with such widespread metastatic disease as described herein. The review accompanying this case report is the first to provide an overview of all the cases of primary neuroendocrine carcinoma of the breast published in the literature and encompasses detailed information regarding epidemiology, histogenesis, clinical and histologic diagnosis criteria, classification, surgical and adjuvant treatment, as well as prognosis. We also provide recommendations for common clinical and histologic pitfalls associated with this tumor. CASE PRESENTATION: We describe a case of a 51-year-old Hispanic woman initially diagnosed with locally-advanced invasive ductal carcinoma that did not respond to neoadjuvant treatment. After undergoing modified radical mastectomy the final surgical pathology showed evidence of alveolar-type primary neuroendocrine carcinoma of the breast. The patient was treated with cisplatin/etoposide followed by paclitaxel/carboplatinum. Thirteen months after surgery the patient is alive, but developed pulmonary, bone, and hepatic metastasis. CONCLUSION: The breast in situ component of primary neuroendocrine carcinoma of the breast may prevail on a core biopsy samples increasing the probability of underdiagnosing this tumor preoperatively. Being aware of the existence of this disease allows for timely diagnosis and management. Optimal treatment requires simultaneous consideration of both the neuroendocrine and breast in situ tumor features. PMID- 23734902 TI - Reconstruction of regulatory networks through temporal enrichment profiling and its application to H1N1 influenza viral infection. AB - BACKGROUND: H1N1 influenza viruses were responsible for the 1918 pandemic that caused millions of deaths worldwide and the 2009 pandemic that caused approximately twenty thousand deaths. The cellular response to such virus infections involves extensive genetic reprogramming resulting in an antiviral state that is critical to infection control. Identifying the underlying transcriptional network driving these changes, and how this program is altered by virally-encoded immune antagonists, is a fundamental challenge in systems immunology. RESULTS: Genome-wide gene expression patterns were measured in human monocyte-derived dendritic cells (DCs) infected in vitro with seasonal H1N1 influenza A/New Caledonia/20/1999. To provide a mechanistic explanation for the timing of gene expression changes over the first 12 hours post-infection, we developed a statistically rigorous enrichment approach integrating genome-wide expression kinetics and time-dependent promoter analysis. Our approach, TIme Dependent Activity Linker (TIDAL), generates a regulatory network that connects transcription factors associated with each temporal phase of the response into a coherent linked cascade. TIDAL infers 12 transcription factors and 32 regulatory connections that drive the antiviral response to influenza. To demonstrate the generality of this approach, TIDAL was also used to generate a network for the DC response to measles infection. The software implementation of TIDAL is freely available at http://tsb.mssm.edu/primeportal/?q=tidal_prog. CONCLUSIONS: We apply TIDAL to reconstruct the transcriptional programs activated in monocyte-derived human dendritic cells in response to influenza and measles infections. The application of this time-centric network reconstruction method in each case produces a single transcriptional cascade that recapitulates the known biology of the response with high precision and recall, in addition to identifying potentially novel antiviral factors. The ability to reconstruct antiviral networks with TIDAL enables comparative analysis of antiviral responses, such as the differences between pandemic and seasonal influenza infections. PMID- 23734903 TI - The implementation of NICE guidance on venous thromboembolism risk assessment and prophylaxis: a before-after observational study to assess the impact on patient safety across four hospitals in England. AB - BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity and mortality in hospitalised patients. VTE prevention has been identified as a major health need internationally to improve patient safety. A National Institute for Health and Clinical Excellence (NICE) guideline was issued in February 2010. Its key priorities were to assess patients for risk of VTE on admission to hospital, assess patients for bleeding risk and evaluate the risks and benefits of prescribing VTE prophylaxis. The aim of this study was to evaluate the implementation of NICE guidance and its impact on patient safety. METHODS: A before-after observational design was used to investigate changes in VTE risk assessment documentation and inappropriate prescribing of prophylaxis between the year prior to (2009) and the year following (2010) the implementation of NICE guidance, using data from a 3-week period during each year. A total of 408 patients were sampled in each year across four hospitals in the NHS South region. RESULTS: Implementation strategies such as audit, education and training were used. The percentage of patients for whom a VTE risk assessment was documented increased from 51.5% (210/408) in 2009 to 79.2% (323/408) in 2010; difference 27.7% (95% CI: 21.4% to 33.9%; p < 0.001). There was little evidence of change in the percentage who were prescribed prophylaxis amongst patients without a risk assessment (71.7% (142/198) in 2009 and 68.2% (58/85) in 2010; difference -3.5% (95% CI: -15.2% to 8.2%; p =0.56) nor the percentage who were prescribed low molecular weight heparin amongst patients with a contraindication (14% (4/28) in 2009 and 15% (6/41) in 2010; RD = 0.3% (95% CI: -16.5% to 17.2%; p =0.97). CONCLUSIONS: The documentation of risk assessment improved following the implementation of NICE guidance; it is questionable, however, whether this led to improved patient safety with respect to prescribing appropriate prophylaxis. PMID- 23734904 TI - A case series of CAEBV of children and young adults treated with reduced intensity conditioning and allogeneic bone marrow transplantation: a single center study. AB - BACKGROUND: Epstein-Barr virus (EBV)-infected T or NK cells cause chronic active EBV infection (CAEBV). Allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment for CAEBV patients. However, chemotherapy prior to HSCT and optimal conditioning regimen for allogeneic HSCT are still controversial. PATIENTS AND METHODS: We retrospectively analyzed five patients with CAEBV treated with reduced-intensity conditioning (RIC) consisted of fludarabine, cyclophosphamide, and low-dose total-body irradiation followed by allogeneic bone marrow transplantation in a single institute. Only one of five patients received chemotherapy prior to transplantation. We analyzed EBV-infected cells in a patient whose EBV load increased after HSCT by T-cell repertoire assay, separation of T-cell subpopulations, in situ hybridization and microsatellite analysis. RESULTS: All five patients achieved engraftment, complete chimera, and eradication of EBV load. All patients have been alive without any serious regimen related toxicity for more than 16 months following HSCT. However, one patient transplanted from HLA-matched sibling donor developed clonal proliferation of CD4+ Vbeta3+ T cells caused by monoclonal EBV infection on day 99 after transplantation. Further analysis revealed that the CD4+ Vbeta3+ T cells selectively harbored EBV genome, and these infected cells were derived from donor T cells. CONCLUSIONS: Allogeneic HSCT with RIC is a safe and effective treatment for better overall survival and less regimen-related toxicity in patients with CAEBV. Our first pediatric case reported in the literature suggests that we should consider the possibility of persistent EBV infection in donor T cells as well as the relapse in recipient cells if EBV load increases after allogeneic HSCT. PMID- 23734905 TI - Modeling the structure of the attitudes and belief scale 2 using CFA and bifactor approaches: Toward the development of an abbreviated version. AB - The Attitudes and Belief Scale-2 (ABS-2: DiGiuseppe, Leaf, Exner, & Robin, 1988. The development of a measure of rational/irrational thinking. Paper presented at the World Congress of Behavior Therapy, Edinburg, Scotland.) is a 72-item self report measure of evaluative rational and irrational beliefs widely used in Rational Emotive Behavior Therapy research contexts. However, little psychometric evidence exists regarding the measure's underlying factor structure. Furthermore, given the length of the ABS-2 there is a need for an abbreviated version that can be administered when there are time demands on the researcher, such as in clinical settings. This study sought to examine a series of theoretical models hypothesized to represent the latent structure of the ABS-2 within an alternative models framework using traditional confirmatory factor analysis as well as utilizing a bifactor modeling approach. Furthermore, this study also sought to develop a psychometrically sound abbreviated version of the ABS-2. Three hundred and thirteen (N = 313) active emergency service personnel completed the ABS-2. Results indicated that for each model, the application of bifactor modeling procedures improved model fit statistics, and a novel eight-factor intercorrelated solution was identified as the best fitting model of the ABS-2. However, the observed fit indices failed to satisfy commonly accepted standards. A 24-item abbreviated version was thus constructed and an intercorrelated eight factor solution yielded satisfactory model fit statistics. Current results support the use of a bifactor modeling approach to determining the factor structure of the ABS-2. Furthermore, results provide empirical support for the psychometric properties of the newly developed abbreviated version. PMID- 23734906 TI - Real-world comparative outcomes of US type 2 diabetes patients initiating analog basal insulin therapy. AB - OBJECTIVE: To evaluate outcomes in insulin-naive patients with type 2 diabetes mellitus (T2DM) who initiated insulin glargine or insulin detemir. METHODS: Retrospective data were analyzed from the US General Electric Centricity electronic medical records (EMR) database from patients (>=18 years old) with T2DM initiating insulin glargine or detemir between January 1, 2006, and December 31, 2010. Included patients had EMR data for >=6 months prior to (baseline) and >=12 months after (follow-up) the index date (date of first insulin prescription), and at least one OAD and/or GLP-1 receptor agonist prescription order during baseline, but no previous insulin prescription. Patients were matched on baseline characteristics 5:1, insulin glargine to detemir, to ameliorate selection bias. Outcomes assessed were persistence with insulin therapy, glycemic control, hypoglycemia, body weight, and body mass index over follow-up. RESULTS: Insulin glargine and detemir groups were similar in terms of gender (51.0% and 51.5% female, P = 0.7356), age (57.8 and 57.4 years, P = 0.3368), A1C (9.4% and 9.4%, P = 0.6642), and body weight (101.9 kg and 102.4 kg, P = 0.4920) at baseline. During follow-up, patients initiating insulin glargine were more persistent (80.1% vs 67.8%, P < 0.0001) and had a greater change in A1C (-1.11% vs -0.96%, P = 0.0479). Percentage change in weight (0.91% and 0.65%, P = 0.2734) and hypoglycemia prevalence (3.6% vs 4.1%, P = 0.4338) were similar between groups. CONCLUSIONS: Results from this real-world EMR analysis suggest that among T2DM patients, initiating insulin treatment with insulin glargine may be associated with better treatment persistence and glycemic control, with similar prevalence of hypoglycemia and weight change, compared with initiating with insulin detemir. This study is limited by the retrospective nature of the data collection using EMRs and inability to confirm accuracy and completeness of data by secondary chart review. PMID- 23734907 TI - Cutaneous pseudolymphomas after leech therapy. PMID- 23734908 TI - The role of pirfenidone in the treatment of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a progressive disease, with a median survival time of 2-5 years. The search for effective treatment has involved numerous clinical trials of investigational agents without significant success. However, in 2011, pirfenidone was the first drug to be approved for the treatment of IPF in Europe. Four key clinical trials supported the efficacy and tolerability of pirfenidone. In the two recently published Phase III CAPACITY trials evaluating pirfenidone (studies 004 and 006), patients with mild-to moderate IPF were treated with pirfenidone or placebo. Study 004 and pooled analysis of primary endpoint data from both studies showed that pirfenidone significantly reduced decline in percent-predicted forced vital capacity (FVC) compared with placebo (p<0.005). Evidence of beneficial effects of pirfenidone treatment was also observed with regard to several secondary endpoints. Pirfenidone was generally well tolerated, with the most common side effects being gastrointestinal and photosensitivity. Data from the RECAP extension phase of the CAPACITY studies, where patients were treated with pirfenidone for up to three years, further support the manageable tolerability profile of pirfenidone. The efficacy data, coupled with long-term safety data, provide further evidence of a clinically-meaningful treatment effect with pirfenidone in patients with IPF. PMID- 23734909 TI - Cell cycle regulation of purine synthesis by phosphoribosyl pyrophosphate and inorganic phosphate. AB - Cells must increase synthesis of purine nucleotides/deoxynucleotides before or during S-phase. We found that rates of purine synthesis via the de novo and salvage pathways increased 5.0- and 3.3-fold respectively, as cells progressed from mid-G1-phase to early S-phase. The increased purine synthesis could be attributed to a 3.2-fold increase in intracellular PRPP (5-phosphoribosyl-alpha-1 pyrophosphate), a rate-limiting substrate for de novo and salvage purine synthesis. PRPP can be produced by the oxidative and non-oxidative pentose phosphate pathways, and we found a 3.1-fold increase in flow through the non oxidative pathway, with no change in oxidative pathway activity. Non-oxidative pentose phosphate pathway enzymes showed no change in activity, but PRPP synthetase is regulated by phosphate, and we found that phosphate uptake and total intracellular phosphate concentration increased significantly between mid G1-phase and early S-phase. Over the same time period, PRPP synthetase activity increased 2.5-fold when assayed in the absence of added phosphate, making enzyme activity dependent on cellular phosphate at the time of extraction. We conclude that purine synthesis increases as cells progress from G1- to S-phase, and that the increase is from heightened PRPP synthetase activity due to increased intracellular phosphate. PMID- 23734910 TI - Thermoresponsive cellulosic hydrogels with cell-releasing behavior. AB - Here we report the preparation and characterization of thermoresponsive cellulosic hydrogels with cell-releasing behavior. Hydroxypropyl cellulose (HPC) was modified with methacrylic anhydride (MA). The resultant macromonomer, HPC-MA, retains the characteristic thermoresponsive phase behavior of HPC, with an onset temperature of 36 degrees C and a lower critical solution temperature (LCST) of 37-38 degrees C, as determined by turbidity measurement. Homogenous HPC-MA hydrogels were prepared by UV-cross-linking the aqueous solutions of the macromonomer at room temperature, and characterized by water contact angle and swelling ratio measurements, and dynamic mechanical analysis. These hydrogels exhibit temperature-dependent surface hydrophilicity and hydrophobicity, equilibrium water content as well as mechanical properties. Cell-releasing characteristics were demonstrated using African green monkey kidney cell line (COS-7 cells) and murine-derived embryonic stem cell line (Oct4b2). By reducing temperature to 4 degrees C, the cultivated cells spontaneously detached from the hydrogels without the need of trypsin treatment. These unique properties make our HPC-MA hydrogels potential substrates for cell sheet engineering. PMID- 23734911 TI - Identification of elderly drivers whose crash involvement risks are alleviated by passenger presence. AB - It is essential to find measures to compensate for the decline in elderly drivers' driving ability in order to meet their mobility needs and ensure their safety when driving. Although it has been well documented that elderly drivers' risks of crash involvement are alleviated by the presence of passengers, few studies have investigated whether the protective effect of passengers is influenced by driver characteristics including the degree of cognitive impairment. This study aimed to identify subgroups of elderly drivers whose crash involvement risks are more effectively alleviated by passenger presence. After dividing elderly drivers into three levels of cognitive impairment, as measured by the Short-Memory Questionnaire, and two gender groups, the present study found that only male drivers in the middle cognitive level benefited from passenger presence. The effectiveness of passenger presence may be more successfully achieved by proper selection of the appropriate range of cognitive decline and gender. PMID- 23734912 TI - Molecular dynamics simulation and characterization of graphene-cellulose nanocomposites. AB - The mechanical properties of graphene-cellulose (GC) nanocomposites are investigated using molecular dynamic (MD) simulations in this work. The influences of graphene concentrations, aspect ratios, and agglomeration on elastic constants and interfacial properties are reported. A polymer consistent force field (pcff) was used in the analysis. The GC nanocomposites system underwent NVT (constant number of atoms, volume, and temperature) and NPT (constant number of atoms, pressure, and temperature) ensemble with an applied uniform strain during the MD simulations. The stress-strain responses were evaluated for both randomly dispersed and stacked GC unit cell in order to study the effects of graphene concentrations, aspect ratio, and agglomeration on Young's modulus. The results indicate that Young's modulus of neat cellulose may be enhanced by incorporating graphene in the GC nanocomposites. It is observed that dispersed graphene shows a comparatively higher Young's modulus than the same with agglomerated graphene. The cohesive and pullout forces versus displacement data are reported under normal and shear modes. It is seen that both cohesive and pullout forces are enhanced for GC specimens with higher graphene aspect ratios due to enlarged surface/interfacial area. The MD simulation results show reasonable agreement with available experimental data. PMID- 23734913 TI - Childhood conduct disorder trajectories, prior risk factors and cannabis use at age 16: birth cohort study. AB - AIMS: To investigate the prevalence of cannabis use and problem use in boys and girls at age 16 years, and to investigate the role of adversity in early life and of conduct disorder between the ages of 4 and 13 years as risk factors for these outcomes. DESIGN: Birth cohort study. SETTING: England. PARTICIPANTS: A total of 4159 (2393 girls) participants in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort providing information on cannabis use at age 16. MEASUREMENTS: Cannabis use and problem cannabis use at age 16 were assessed by postal questionnaire. Material adversity, maternal substance use, maternal mental health and child conduct disorder were all assessed by maternal report. FINDINGS: Cannabis use was more common among girls than boys (21.4% versus 18.3%, P = 0.005). Problem cannabis use was more common in boys than girls (3.6% versus 2.8%, P = 0.007). Early-onset persistent conduct problems were associated strongly with problem cannabis use [odds ratio (OR) = 6.46, 95% confidence interval (CI) = 4.06-10.28]. Residence in subsidized housing (OR = 3.10, 95% CI = 1.95, 4.92); maternal cannabis use (OR 8.84, 95% CI 5.64-13.9) and any maternal smoking in the postnatal period (OR = 2.69, 95% CI = 1.90-3.81) all predicted problem cannabis use. Attributable risks for adolescent problem cannabis use associated with the above factors were 25, 13, 17 and 24%, respectively. CONCLUSIONS: Maternal smoking and cannabis use, early material disadvantage and early-onset persistent conduct problems are important risk factors for adolescent problem cannabis use. This may have implications for prevention. PMID- 23734915 TI - Fast and robust method to determine phenoyl and acetyl esters of polysaccharides by quantitative 1H NMR. AB - The acetyl (AcE), feruloyl (FE), and p-coumaroyl (pCE) ester contents of different cereal and grass polysaccharides were determined by a quantitative 1H NMR-based method. The repeatability and the robustness of the method were demonstrated by analyzing different plant polysaccharide preparations. Good sensitivity and selectivity for AcE, FE, and pCE were observed. Moreover, an optimized and easy sample preparation allowed for simultaneous quantification of AcE, FE, and pCE. The method is suitable for high-throughput analysis, and it is a good alternative for currently used analytical procedures. A comparison of the method presented to a conventional HPLC-based method showed that the results obtained are in good agreement, whereas the combination of the optimized sample preparation and analysis by the 1H NMR-based methodology results in significantly reduced analysis time. PMID- 23734914 TI - Examination of the predictive value of structural magnetic resonance scans in bipolar disorder: a pattern classification approach. AB - BACKGROUND: Bipolar disorder (BD) is one of the leading causes of disability worldwide. Patients are further disadvantaged by delays in accurate diagnosis ranging between 5 and 10 years. We applied Gaussian process classifiers (GPCs) to structural magnetic resonance imaging (sMRI) data to evaluate the feasibility of using pattern recognition techniques for the diagnostic classification of patients with BD. METHOD: GPCs were applied to gray (GM) and white matter (WM) sMRI data derived from two independent samples of patients with BD (cohort 1: n = 26; cohort 2: n = 14). Within each cohort patients were matched on age, sex and IQ to an equal number of healthy controls. RESULTS: The diagnostic accuracy of the GPC for GM was 73% in cohort 1 and 72% in cohort 2; the sensitivity and specificity of the GM classification were respectively 69% and 77% in cohort 1 and 64% and 99% in cohort 2. The diagnostic accuracy of the GPC for WM was 69% in cohort 1 and 78% in cohort 2; the sensitivity and specificity of the WM classification were both 69% in cohort 1 and 71% and 86% respectively in cohort 2. In both samples, GM and WM clusters discriminating between patients and controls were localized within cortical and subcortical structures implicated in BD. CONCLUSIONS: Our results demonstrate the predictive value of neuroanatomical data in discriminating patients with BD from healthy individuals. The overlap between discriminative networks and regions implicated in the pathophysiology of BD supports the biological plausibility of the classifiers. PMID- 23734916 TI - Trends in the use of implantable cardioverter defibrillators in Australia: a 10 year nationwide study from 2000-2009. AB - BACKGROUND: Implantable cardioverter defibrillators (ICD) have been demonstrated to reduce mortality in survivors of life-threatening arrhythmias (secondary prevention) and in patients at increased risk of sudden cardiac death (primary prevention). Other nations have reported significant increases in ICD use in recent years. AIM: To investigate Australian nationwide trends of ICD procedures over a 10-year period (2000-2009). METHODS: A retrospective analysis of the Australian Institute of Health and Welfare's National Hospital Morbidity Database was performed to determine the annual number of ICD implantation and replacement procedures between 2000 and 2009. Rates were calculated using Australian Bureau of Statistics data on the annual estimated population. Time trends in the yearly procedure number and rate were analysed using negative binomial regression models with comparisons made by age and sex. RESULTS: The number of new ICD implantations increased from 708 to 3198 procedures between 2000 and 2009. Replacement procedures increased from 290 to 1378. The implantation rate (per million) increased from 37.0 to 145.6 and the replacement rate from 15.1 to 62.7. When rates were adjusted for age and sex, the implantation rate increased annually by 15.8% and the replacement rate by 16.6% (P < 0.0001). Procedures occurred most commonly in men (implantations: 80.1%; replacements: 78.0%) between ages 70-79. CONCLUSIONS: ICD procedures increased significantly in Australia between 2000-2009. Despite these increases, other studies have suggested ICD devices are currently under-utilised. During the study period, males accounted for the majority of ICD procedures. While there are numerous reasons for this, it is not known if device under-use is more common in females. PMID- 23734918 TI - The invited presenter: outrageousness and outrage. AB - I describe aspects of a multimodal presentation sponsored by a professional organization of group psychotherapists, entailing lecture and discussion, a small demonstration or fishbowl group, and a large group experience. As the invited presenter, I was being counted on to attract attendees, to stimulate and maintain their interest, and to draw enthusiasm to the host organization and its future conferences. This required, in short order, promoting cohesion, establishing norms, and creating a safe enough culture to embrace challenge, to take risks, to learn, and to seek help. Events occurring in both the larger and smaller groups were to be utilized for the benefit of the individuals and the groups themselves, to make the experience interesting and sufficiently compelling, to teach the basic principles promised by the conference's theme, and to demonstrate technique. Dysfunction or negative consequences were to be avoided. My mode of leadership was perceived by some as positive if not outrageous, but for others it just provoked outrage. Perhaps such reactions are to be expected whenever a leader challenges a group to experience and think in new ways. I tried to utilize the ensuring controversy to illustrate the conference's topic: loving, hating, and curiosity-group processes of resistance, rebellion, and refusal. PMID- 23734917 TI - Evaluation of magnetic nanoparticle samples made from biocompatible ferucarbotran by time-correlation magnetic particle imaging reconstruction method. AB - BACKGROUND: Molecular imaging using magnetic nanoparticles (MNPs)-magnetic particle imaging (MPI)-has attracted interest for the early diagnosis of cancer and cardiovascular disease. However, because a steep local magnetic field distribution is required to obtain a defined image, sophisticated hardware is required. Therefore, it is desirable to realize excellent image quality even with low-performance hardware. In this study, the spatial resolution of MPI was evaluated using an image reconstruction method based on the correlation information of the magnetization signal in a time domain and by applying MNP samples made from biocompatible ferucarbotran that have adjusted particle diameters. METHODS: The magnetization characteristics and particle diameters of four types of MNP samples made from ferucarbotran were evaluated. A numerical analysis based on our proposed method that calculates the image intensity from correlation information between the magnetization signal generated from MNPs and the system function was attempted, and the obtained image quality was compared with that using the prototype in terms of image resolution and image artifacts. RESULTS: MNP samples obtained by adjusting ferucarbotran showed superior properties to conventional ferucarbotran samples, and numerical analysis showed that the same image quality could be obtained using a gradient magnetic field generator with 0.6 times the performance. However, because image blurring was included theoretically by the proposed method, an algorithm will be required to improve performance. CONCLUSIONS: MNP samples obtained by adjusting ferucarbotran showed magnetizing properties superior to conventional ferucarbotran samples, and by using such samples, comparable image quality (spatial resolution) could be obtained with a lower gradient magnetic field intensity. PMID- 23734919 TI - The compulsion to repeat relationships with abusive partners and how group therapy can help. AB - The mystery of why some people are compelled to repeatedly engage in relationships with people who are cruel to them is frequently pondered in literature and psychology. The present paper posits that the etiology of this pathological relationship pattern derives from a parental relationship that was both highly exciting and highly frustrating. Spontaneous recapitulations of the passionate masochistic relationship in the therapy group allow the patient, the therapist and the group to appreciate the exact nature of the "bad" partner's appeal for the patient and its link to parental antecedents. In addition, the author suggests, group therapy can provide attachment experiences that are stimulating and rewarding enough to override the patient's attraction to the toxic partner(s) and build an enhanced capacity for intimacy. The cases of two patients are presented who spent three and a half years in the same long term psychodynamic group, and who, through the processes described above, successfully resolved their masochistic relationship patterns. PMID- 23734920 TI - Development of group climate in short- and long-term psychodynamic group psychotherapy. AB - This study examined the development of group climate using the Engaged, Conflict, and Avoiding subscales of the Group Climate Questionnaire-Short Version (GCQ-S) in a sample of 145 patients attending either short- (20 sessions) or long-term (80 sessions) psychodynamic group psychotherapy. Linear mixed models were used to compare changes in group climate over time. Engaged developed along similar lines in the two psychotherapy formats. During the first 18 sessions, conflict and avoidance decreased toward the termination of the short-term groups, in contrast to an increase in this still-early stage of the long-term groups. When compared according to the stages of therapy (early, middle, late), a low-high-low pattern for conflict and avoidance emerged in both psychotherapy formats, with a stronger decrease toward termination in long-term groups. This finding can be seen as reflecting an accelerated progress of development within the short-term groups, and a delayed but strengthened process in the long-term groups. Review of empirical studies indicated that most theories of group development have a relatively narrow range of validity, but the parallel pattern of group climate found in this study across early, middle, and late stages for short- and long term groups suggests that the perspective of developmental stages is still important to both group process theory and clinical practice. PMID- 23734921 TI - Group climate as predictor of short- and long-term outcome in group therapy for social phobia. AB - A longitudinal study of 80 participants in cognitive and interpersonal group therapy for social phobia was conducted. The aim was to investigate the relationship between group climate and patients' short-term and long-term outcome. Group climate data was collected every other week during treatment, whereas social phobia symptoms were assessed at admission, discharge, and one year follow-up. Abbreviated symptom assessments were performed weekly. Regression analyses and mixed models were used in the analyses. Engagement predicted symptom reduction during treatment, from pretreatment to follow-up, and from posttreatment to follow-up. During treatment, avoidance predicted higher symptomatic distress. The results imply that group engagement should be emphasized for patients with social phobia. Avoidance, on the other hand, should be addressed as a process that interferes with treatment progress. PMID- 23734922 TI - Group climate research: where do we go from here? AB - We review the articles by Bakali, Wilberg, Klungsoyr, and Lorentzen (this issue) and Bonsaksen, Borge, and Hoffart (this issue) that examine different aspects of group Climate using the Group Climate Questionnaire. Both articles build on the previous group climate literature and both provide important new insights into the relationship between individual group members' perceptions of group climate and their treatment outcome (Bonsaksen et al., 2013) and the development of group climate across time. Our comments focus on how these two areas of research can be extended. Specifically, we recommend that group development researchers use new statistical techniques that describe patterns in how group climate changes across time. In addition, we encourage researchers examining the relationship between group climate and outcome to use the Actor Partner Interdependence Model to include other groups members' perceptions of group climate as a predictor of an individual group member's treatment outcome. PMID- 23734924 TI - Editor's note. PMID- 23734923 TI - Beware of storming: research implications for interpreting group climate questionnaire scores over time. PMID- 23734925 TI - Group therapy for intimate partner violence (IPV). PMID- 23734931 TI - Does implementation of a hospitalist program in a Canadian community hospital improve measures of quality of care and utilization? an observational comparative analysis of hospitalists vs. traditional care providers. AB - BACKGROUND: Despite the growth of hospitalist programs in Canada, little is known about their effectiveness for improving quality of care and use of scarce healthcare resources. The objective of this study is to compare measures of cost and quality of care (in-hospital mortality, 30-day same-facility readmission, and length of stay) of hospitalists vs. traditional physician providers in a large Canadian community hospital setting. METHODS: We performed a retrospective analysis of data from the Canadian Institute for Health Information (CIHI) Discharge Abstract Database, using multivariate logistic and linear regression analyses comparing performance of four provider groups of traditional family physicians (FPs), traditional internal medicine subspecialists (other-IM), family physician-trained hospitalists (FP-Hospitalist), and general internal medicine trained hospitalists (GIM-Hospitalist). RESULTS: Compared to traditional FPs, FP Hospitalists and GIM-Hospitalists demonstrate lower mortality [OR 0.881, (CI 0.779 - 0.996); and OR 0.355, (CI 0.288 - 0.436)] and readmission rates [OR 0.766, (CI 0.678 - 0.867); and OR 0.800, (CI 0.675 - 0.948)]. Compared to traditional FPs, GIM-Hospitalists appear to improve length of stay [OR-2.975, (CI -3.302 - -2.647)] while FP-Hospitalists perform similarly [OR 0.096, (CI -0.136 - 0.329)]. Compared to other-IM, GIM-Hospitalists have similar performance on all measures while FP-Hospitalists show a mixed impact. CONCLUSIONS: Compared to traditional family physicians, hospitalists appear to improve measures of quality and resource utilization. Specifically, hospitalists demonstrate lower in hospital mortality and 30-day readmission rates while improving (or at least showing similar) length of stay. Compared to traditional subspecialists, hospitalists demonstrate similar performance despite looking after sicker and more complex medical patients. PMID- 23734932 TI - Genome-wide comparative analysis revealed significant transcriptome changes in mice after Toxoplasma gondii infection. AB - BACKGROUND: Toxoplasma gondii is an intracellular parasite that can modulate host responses and presumably host behavior. Host responses as well as pathogenesis vary depending on the parasite strains that are responsible for infection. In immune competent individuals, T. gondii preferentially infects tissues of the central nervous systems (CNS), which might be an additional factor in certain psychiatric disorders. While in immune-compromised individuals and pregnant women, the parasite can cause life-threatening infections. With the availability of the genome-wide investigation platform, the global responses in gene expression of the host after T. gondii infection can be systematically investigated. METHODS: Total RNA of brain tissues and peripheral lymphocytes of BALB/C mice infected with RH and ME 49 strain T. gondii as well as that of healthy mice were purified and converted to cRNA with incorporated Cy5-CTP (experimental samples), or Cy3-CTP (control samples). The labeled cRNA probes were hybridized to the Whole Mouse Genome Microarray. The impact of parasite infection on gene expression in both brain tissues and peripheral lymphocytes were analyzed. Differentially expressed genes were revalidated with real-time quantitative reverse transcriptase-polymerase chain reaction (Q-PCR). RESULTS: Data indicated that the genes associated with immunity were up-regulated after infection by the two parasite strains, but significant up-regulation was observed in both brain tissues and peripheral lymphocytes of mice infected with ME49 strain compared to that infected by RH strain. The pathways related to pathogenesis of the nervous system were more significantly up-regulated in mice infected with RH strain. CONCLUSIONS: Genetically distinct T. gondii strains showed clear differences in modulation of host pathophysiological and immunological responses in both brain tissue and peripheral lymphocytes. It was likely that some of the host responses to T. gondii infection were universal, but the immune response and CNS reaction were in a strain-specific manner. PMID- 23734933 TI - Dermatological side-effects of telaprevir-based triple therapy for chronic hepatitis C in phase III trials in Japan. AB - Telaprevir-based triple therapy is highly effective for chronic hepatitis C. However, concern has been expressed over the high frequency and severity of its dermatological side-effects compared with those associated with peginterferon (PEG-IFN) and ribavirin (RBV) therapy. Thus, here, we evaluated the dermatological adverse reactions of telaprevir-based triple therapy in Japanese multicenter phase III clinical trials in an attempt to characterize the dermatological side-effects and establish appropriate management plans. In these trials, 126 treatment-naive patients and 141 treatment-failure patients were administrated telaprevir, PEG-IFN-alpha-2b and RBV for 12 weeks followed by PEG IFN-alpha-2b and RBV for another 12 weeks (T12/PR24 group), and 63 treatment naive patients were administrated PEG-IFN-alpha-2b and RBV for 48 weeks (PR48 group). Dermatological adverse reactions developed in over 80% patients in both groups, and most of them were grade 1 or 2. In the T12/PR24 group, there were more grade 2 or grade 3 events, and the time to onset was earlier than that in the PR48 group. Most reactions could be managed with topical corticosteroids and oral antihistamines, and the rates of discontinuation due to dermatological reactions were not high even in the T12/PR24 group. In the T12/PR24 group, however, two cases of Stevens-Johnson syndrome and one case of drug rash with eosinophilia and systemic symptoms, which corresponds to drug-induced hypersensitivity syndrome in Japan, were reported. For appropriate treatments of individual dermatological adverse reactions, the judgment of discontinuation of antiviral drugs and treatment based on the severity are extremely important in this triple therapy. PMID- 23734934 TI - Guianolides A and B, new carbon skeletal limonoids from the seeds of Carapa guianensis. AB - Two novel limonoids, named guianolides A (1) and B (2), were isolated from the seeds of Carapa guianensis AUBLET (Meliaceae). Their structures were established by spectroscopic analyses and X-ray crystallography. Guianolides A (1) and B (2) featured an unprecedented carbon skeleton via the formation of a C-11-C-21 bond. PMID- 23734935 TI - Social support provided to caregivers of children with cerebral palsy. AB - OBJECTIVE: To describe the perception of caregivers of children with cerebral palsy (CP) concerning social support received and to verify how the characteristics of the children (i.e. type of CP and severity of motor impairment) and those of their caregivers (i.e. age, level of education, occupation, income and number of children) are significantly related to this perception. METHOD: A total of 50 children with CP aged between 3 and 12 years and their respective caregivers participated in this study. Children were grouped in terms of type of CP and according to the severity of motor impairment through the Gross Motor Function Classification System (GMFCS). The Social Support Questionnaire (SSQ) was used to evaluate the perception of caregivers concerning the social support they receive (number of people offering support - SSQ-N index, and level of satisfaction concerning such support - SSQ-S index). RESULTS: The caregivers reported receiving support from a mean of 1.67 people. Core and extended family members (i.e. husband, mother, siblings) and friends are the most common providers of support. In regard to level of satisfaction, caregivers considered the support they received to be positive, obtaining a mean of 5.52 out of a total of six points. Children's and caregivers' characteristics were not significantly related to the SSQ-N and SSQ-S indexes. CONCLUSION: Family members are the caregivers' primary source of social support and caregivers reported being satisfied with the support they received. PMID- 23734936 TI - Recommendations on treatment for IPF. AB - Patient management in Idiopathic Pulmonary Fibrosis (IPF) is largely based on societal guidelines and recommendations. A recent update by the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS) and Latin American Thoracic Association (ALAT) provided updated guidance on the diagnosis and management of IPF, along with recommendations on pharmacologic and non-pharmacologic approaches to patient management. The treatment guidance is based on GRADE criteria, which rates the quality of evidence according to previously published methodology. Here we discuss how to interpret the recent guideline updates and the implications of this guidance for clinical practice. In addition we discuss the assessment and recommendations for a number of pharmacological agents that have been the focus of clinical trials over the past years. Although no single pharmacological agent was recommended by the guidelines committee, we discuss how since then, more recent data have resulted in the approval of pirfenidone in Europe, and preliminary negative findings regarding the safety of a triple therapy regimen consisting of prednisone, azathioprine and N-acetylcysteine have raised the question of whether it is no longer a treatment option. As clinicians, we must interpret the available guidance and recommendations as we consider each individual patient and as we discuss the available clinical data and the patient's own preferences in our approach to the management of this disease. PMID- 23734937 TI - Meditating metal coenhanced fluorescence and SERS around gold nanoaggregates in nanosphere as bifunctional biosensor for multiple DNA targets. AB - Gold nanoparticles (Au NPs) are very attractive candidate nanoparticles in biological assay because of their high chemical stabilities, high homogeneities, good biocompatibilities, and low toxicities. However, molecular beacon assays via encapsulating the combined fluorescence or surface-enhanced Raman scattering (SERS) signals of reporters and Au NPs in nanobarcodes particles usually suffer from fluorescence quenching or weak Raman enhancement when Au NPs are employed (especially with size smaller than 15 nm). Herein, we present a new design of simultaneously realizing metal-enhanced fluorescence and coenhanced surface enhanced Raman scattering by facilely embedding Ag nanoparticle into the shell of two kinds of Au nanoaggregate (5 and 10 nm), meanwhile, fluorophore is located between the silver core and gold nanoparticle layers and the distance among them is adjusted by SiO2 spacer (Ag@first SiO2 spacer@FiTC+SiO2@second SiO2 spacer@Au nanoaggregate). In this architecture, Ag nanoparticle not only is utilized as an efficient fluorescence enhancer to overcome the common fluorescence quenching around Au nanoaggregates but also behaves like a mirror. Thus, incident light that passes through the SERS-active Au nanoaggregate and the intervening dielectric layer of SiO2 could be reflected multiply from the surface of Ag nanoparticle and coupled with the light at the nanogap between the Au nanoaggregates to further amplify Raman intensity. This results in enhancement factors for fluorescence and SERS ~1.6-fold and more than 300-fold higher than the control samples without silver core under identical experimental conditions, respectively. Moreover, fluorophore and SERS reporters are assembled onto different layers of the concentric hybrid microsphere, resulting in a feasible fabrication protocol when a large number of agents need to be involved into the dual-mode nanobarcodes. A proof-of-concept chip-based DNA sandwich hybridization assay using genetically modified organisms as a model system has been investigated based on the concentric hybrid microsphere. The high specificity and sensitivity of the assays suggest that the new architecture has a potential for various bioanalytical applications and provides opportunities for other similar metal nanoparticles to realize coenhancement effect. PMID- 23734938 TI - Natural killer expansion, human leukocyte antigens-E expression and CD14(+) CD56(+) monocytes in a myelodysplastic syndrome patient. AB - Myelodysplastic syndromes (MDS) are clonal disorders characterized by ineffective hematopoiesis and possible evolution to acute leukemia. Occurrence of stem cell defects and of immune-mediated mechanisms was evidenced as relevant for pathophysiology of MDS. Here, we described one case of MDS patient carrying CD14(+) CD56(+) monocytes in bone marrow (BM), in the presence of a defective human leukocyte antigen (HLA)-E expression on peripheral blood (PB) cells and of natural killer (NK) cell expansion in PB and BM. The defective HLA-E expression and the NK expansion are proposed to be relevant for the pathogenesis of myelodysplasia in those patients showing CD14(+) CD56(+) monocytes in BM. PMID- 23734939 TI - Forecasting supply and demand in nursing professions: impacts of occupational flexibility and employment structure in Germany. AB - BACKGROUND: In light of Germany's ageing society, demand for nursing professionals is expected to increase in the coming years. This will pose a challenge for policy makers to increase the supply of nursing professionals. METHODOLOGY: To portray the different possible developments in the supply of nursing professionals, we projected the supply of formally trained nurses and the potential supply of persons who are able to work in a nursing profession. This potential supply of nursing professionals was calculated on the basis of empirical information on occupational mobility provided by the German Microcensus 2005 (Labour Force Survey). We also calculated how the supply of full-time equivalents (FTEs) will develop if current employment structures develop in the direction of employment behaviour in nursing professions in eastern and western Germany. We then compared these different supply scenarios with two demand projections ('status quo' and 'compression of morbidity' scenarios) from Germany's Federal Statistical Office. RESULTS: Our results show that, even as early as 2005, meeting demand for FTEs in nursing professions was not arithmetically possible when only persons with formal qualification in a nursing profession were taken into account on the supply side. When additional semi skilled nursing professionals are included in the calculation, a shortage of labour in nursing professions can be expected in 2018 when the employment structure for all nursing professionals remains the same as the employment structure seen in Germany in 2005 (demand: 'status quo scenario'). Furthermore, given an employment structure as in eastern Germany, where more nursing professionals work on a full-time basis with longer working hours, a theoretical shortage of nursing professionals could be delayed until 2024. CONCLUSIONS: Our analysis of occupational flexibility in the nursing field indicates that additional potential supply could be generated by especially training more young people for a nursing profession as they tend to stay in their initial occupation. Furthermore, the number of FTEs in nursing professions could be increased by promoting more full-time contracts in Western Germany. Additionally, employment contracts for just a small number of weekly working hours (marginal employment) cannot be considered an adequate instrument for keeping formally trained nursing professionals employed in the nursing field. PMID- 23734940 TI - Long-term clinical outcomes in patients with refractory uveitis associated with Behcet disease treated with infliximab. AB - PURPOSE: To assess long-term efficacy and safety of infliximab for refractory Behcet disease (BD) uveitis and to evaluate the effect of withdrawal of infliximab after achieving long-term remission. METHODS: Retrospective study of 19 patients. RESULTS: Mean follow-up was 44.1 +/- 36.5 months and mean number of infliximab infusions was 21.6 +/- 14.6. At end of follow-up, there was significant improvement of visual acuity and reduction of central macular thickness. All patients achieved remission, 14 of whom were able to discontinue corticosteroids. Ten patients developed autoantibodies and 1 patient developed infusion reactions. Eight eyes underwent intraocular surgery without exacerbation of quiescent uveitis. After achieving complete remission, 5 patients discontinued infliximab and maintained remission during a mean of 24.6 +/- 5.5 months. CONCLUSIONS: Infliximab is effective and safe for long-term treatment for refractory BD uveitis. Repeated infusions are required to maintain long-term remission, which may be sustained despite withdrawal of infliximab. Induction of autoantibodies is common. PMID- 23734941 TI - Metacognitive awareness of cognitive problems in schizophrenia: exploring the role of symptoms and self-esteem. AB - BACKGROUND: People with a diagnosis of schizophrenia have limited metacognitive awareness of their symptoms. This is also evident for cognitive difficulties when neuropsychological assessments and self-reports are compared. Unlike for delusions and hallucinations, little attention has been given to factors that may influence the mismatch between objective and subjectively reported cognitive problems. Symptom severity, and also self-esteem and social functioning, can have an impact on cognitive problem perception and help to explain the gap between objective and subjective cognitive assessments in psychosis. METHOD: One-hundred participants with a diagnosis of schizophrenia were recruited and assessed with a comprehensive neuropsychological battery, a measure of awareness of cognitive problems and measures of psychotic symptoms, social and behavioural functioning and self-esteem. Regression was used to investigate the influence of symptoms, social functioning and self-esteem, and patients with different levels of cognitive problem awareness were contrasted. RESULTS: Simple correlation analysis replicated the lack of association between objective cognitive measures and metacognitive awareness of cognitive problems. However, the results of the regression analyses highlight that self-esteem and negative symptoms predict metacognitive awareness. When significant predictors were controlled, individuals with better awareness had more impaired working memory but higher IQ. CONCLUSIONS: Poor self-esteem and high negative symptoms are negatively associated with metacognitive awareness in people with schizophrenia. Interventions that aim to improve cognition should consider that cognitive problem reporting in people with schizophrenia correlates poorly with objective measures and is biased not only by symptoms but also by self-esteem. Future studies should explore the causal pathways using longitudinal designs. PMID- 23734942 TI - Traits in transition: the structure of parent-reported personality traits from early childhood to early adulthood. AB - The present research was conducted to map the hierarchical structure of youths' personality traits, to identify the foundational level of this structure, and to test whether the meanings of some youth personality dimensions shift with age. We addressed these issues by analyzing personality parent reports describing a cross sectional sample of 16,000 children, adolescents, and young adults (ages 3 to 20). These parent reports were made using a broadband measure of youths' personal characteristics, the common-language California Child Q-Set. Analyses of the full sample and comparisons of 16 age groups supported three main conclusions. First, the hierarchical structure of youths' personality traits both resembles and differs from the adult personality hierarchy in important ways. Second, a set of six dimensions--Extraversion, Agreeableness, Conscientiousness, Neuroticism, Openness to Experience, and Activity--may constitute the foundational level of the youth personality hierarchy from middle childhood through adolescence. This "Little Six" structure represents a union of the most prominent personality and temperament dimensions. Third, the meanings of some youth personality dimensions (e.g., Activity, Conscientiousness) shift systematically with age. These findings advance our understanding of when and how personality structure develops during the first two decades of life. PMID- 23734943 TI - Managing psychiatric comorbidity within versus outside of methadone treatment settings: a randomized and controlled evaluation. AB - BACKGROUND AND AIMS: Integrating psychiatric services within substance abuse treatment settings is a promising service delivery model, but has not been evaluated using random assignment to psychiatric treatment setting and controlled delivery of psychiatric care. This study evaluates the efficacy of on-site and integrated psychiatric service delivery in an opioid-agonist treatment program on psychiatric and substance use outcomes. DESIGN: Participants at the Addiction Treatment Services (ATS) were assigned randomly to receive on-site and integrated substance abuse and psychiatric care (on-site: n = 160) versus off-site and non integrated substance abuse and psychiatric care (off-site: n = 156), and observed for 1 year. On-site participants received all psychiatric care within the substance abuse program by the same group of treatment providers. The same type and schedule of psychiatric services were available to off-site participants at a community psychiatry program. SETTING: All participants received routine methadone maintenance at the ATS program in Baltimore, Maryland, USA. PARTICIPANTS: Participants were opioid-dependent men and women with at least one comorbid psychiatric disorder, as assessed by the Structured Clinical Interview for DSM-IV and confirmed by expert clinical reappraisal. MEASUREMENTS: Outcomes included psychiatric service utilization and retention, Hopkins Symptom Checklist Global Severity Index (GSI) change scores and urinalysis test results. FINDINGS: On-site participants were more likely to initiate psychiatric care 96.9 to 79.5%; P < 0.001), remain in treatment longer (195.9 versus 101.9 days; P < 0.001), attend more psychiatrist appointments (12.9 versus 2.7; P < 0.001) and have greater reductions in GSI scores (4.2 versus 1.7; P = 0.003) than off-site participants; no differences were observed for drug use. CONCLUSIONS: On-site and integrated psychiatric and substance misuse services in a methadone treatment setting might improve psychiatric outcomes compared with off-site and non integrated substance misuse and psychiatric care. However, this might not translate into improved substance misuse outcomes. PMID- 23734944 TI - Impact of opening a new emergency department on healthcare service and patient outcomes: analyses based on linking ambulance, emergency and hospital databases. AB - BACKGROUND: Emergency department (ED) crowding caused by access block is an increasing public health issue and has been associated with impaired healthcare delivery, negative patient outcomes and increased staff workload. AIM: To investigate the impact of opening a new ED on patient and healthcare service outcomes. METHODS: A 24-month time series analysis was employed using deterministically linked data from the ambulance service and three ED and hospital admission databases in Queensland, Australia. RESULTS: Total volume of ED presentations increased 18%, while local population growth increased by 3%. Healthcare service and patient outcomes at the two pre-existing hospitals did not improve. These outcomes included ambulance offload time: (Hospital A PRE: 10 min, POST: 10 min, P < 0.001; Hospital B PRE: 10 min, POST: 15 min, P < 0.001); ED length of stay: (Hospital A PRE: 242 min, POST: 246 min, P < 0.001; Hospital B PRE: 182 min, POST: 210 min, P < 0.001); and access block: (Hospital A PRE: 41%, POST: 46%, P < 0.001; Hospital B PRE: 23%, POST: 40%, P < 0.001). Time series modelling indicated that the effect was worst at the hospital furthest away from the new ED. CONCLUSIONS: An additional ED within the region saw an increase in the total volume of presentations at a rate far greater than local population growth, suggesting it either provided an unmet need or a shifting of activity from one sector to another. Future studies should examine patient decision making regarding reasons for presenting to a new or pre-existing ED. There is an inherent need to take a 'whole of health service area' approach to solve crowding issues. PMID- 23734945 TI - Roles of EXTL2, a member of the EXT family of tumour suppressors, in liver injury and regeneration processes. AB - The gene products of two members of the EXT (exostosin) gene family, EXT1 and EXT2, function together as a polymerase in the biosynthesis of heparan sulfate. EXTL2 (EXT-like 2), one of the three EXTL genes in the human genome that are homologous to EXT1 and EXT2, encodes an N-acetylhexosaminyltransferase. We have demonstrated that EXTL2 terminates chain elongation of GAGs (glycosaminoglycans), and thereby regulates GAG biosynthesis. The abnormal GAG biosynthesis caused by loss of EXTL2 had no effect on normal development or normal adult homoeostasis. Therefore we examined the role of EXTL2 in CCl4 (carbon tetrachloride)-induced liver failure, a model of liver disease. On the fifth day after CCl4 administration, the liver/body weight ratio was significantly smaller for EXTL2 knockout mice than for wild-type mice. Consistent with this observation, hepatocyte proliferation following CCl4 treatment was lower in EXTL2-knockout mice than in wild-type mice. EXTL2-knockout mice experienced less HGF (hepatocyte growth factor)-mediated signalling than wild-type mice specifically because GAG synthesis was altered in these mutant mice. In addition, GAG synthesis in hepatic stellate cells was up-regulated during liver repair in EXTL2-knockout mice. Taken together, the results of the present study indicated that EXTL2-mediated regulation of GAG synthesis was important to the tissue regeneration processes that follow liver injury. PMID- 23734946 TI - Comparing neural-network scoring functions and the state of the art: applications to common library screening. AB - We compare established docking programs, AutoDock Vina and Schrodinger's Glide, to the recently published NNScore scoring functions. As expected, the best protocol to use in a virtual-screening project is highly dependent on the target receptor being studied. However, the mean screening performance obtained when candidate ligands are docked with Vina and rescored with NNScore 1.0 is not statistically different than the mean performance obtained when docking and scoring with Glide. We further demonstrate that the Vina and NNScore docking scores both correlate with chemical properties like small-molecule size and polarizability. Compensating for these potential biases leads to improvements in virtual screen performance. Composite NNScore-based scoring functions suited to a specific receptor further improve performance. We are hopeful that the current study will prove useful for those interested in computer-aided drug design. PMID- 23734948 TI - Analytical results on the Beauchemin model of lymphocyte migration. AB - The Beauchemin model is a simple particle-based description of stochastic lymphocyte migration in tissue, which has been successfully applied to studying immunological questions. In addition to being easy to implement, the model is also to a large extent mathematically tractable. This article provides a comprehensive overview of both existing and new analytical results on the Beauchemin model within a common mathematical framework. Specifically, we derive the motility coefficient, the mean square displacement, and the confinement ratio, and discuss four different methods for simulating biased migration of pre defined speed. The results provide new insight into published studies and a reference point for future research based on this simple and popular lymphocyte migration model. PMID- 23734949 TI - The limits of market-based reforms. PMID- 23734951 TI - Mechanism studies on nanoPCR and applications of gold nanoparticles in genetic analysis. AB - Recently, the applications of nanomaterial-assisted polymerase chain reaction (nanoPCR) have received considerable attention. Several potential mechanisms have been proposed, but mainly according to the results of PCR assays under specific conditions and lacking direct and general evidence. The mechanism of nanoPCR has not been elucidated yet. Here, taking gold nanoparticles (AuNPs) as an example, we report the three general effects of AuNPs: (1) AuNPs adsorb polymerase and modulate the amount of active polymerase in PCR, which was directly demonstrated by a simple and straightforward colorimetric assay and the dynamic light scattering measurements. (2) AuNPs adsorb primers and decrease the melting temperatures (Tm) of the duplexes formed with perfectly matched and mismatched primers and increase the Tm difference between them. (3) AuNPs adsorb PCR products and facilitate the dissociation of them in the denaturing step. All these effects were confirmed by addition of a rationally selected surface adsorbent, bovine thrombin, to highly efficiently modulate the surface adsorption of PCR components. These findings suggested that AuNPs should have multiple effects on PCR: (1) to regulate PCR in a case-by-case way via modulating the amount of active polymerase in PCR; (2) to improve PCR specificity in the annealing step via increasing the Tm difference between the perfectly matched and mismatched primers; (3) to improve PCR efficiency via speeding up the dissociation of the PCR products in the denaturing step. Taken together, we proposed the mechanism of nanoPCR is that the surface interaction of PCR components (polymerase, primers, and products) with AuNPs regulates nanoPCR. We further demonstrated that the applications of these findings improve the PCR of the amelogenin genes and Hepatitis B virus gene for genetic analysis. These findings could also provide helpful insight for the applications of other nanomaterials in nanoPCR. PMID- 23734950 TI - Retinoid machinery in distinct neural stem cell populations with different retinoid responsiveness. AB - Retinoic acid (RA) is present at sites of neurogenesis in both the embryonic and adult brain. While it is widely accepted that RA signaling is involved in the regulation of neural stem cell differentiation, little is known about vitamin A utilization and biosynthesis of active retinoids in the neurogenic niches, or about the details of retinoid metabolism in neural stem cells and differentiating progenies. Here we provide data on retinoid responsiveness and RA production of distinct neural stem cell/neural progenitor populations. In addition, we demonstrate differentiation-related changes in the expression of genes encoding proteins of the retinoid machinery, including components responsible for uptake (Stra6) and storage (Lrat) of vitamin A, transport of retinoids (Rbp4, CrbpI, CrabpI-II), synthesis (Rdh10, Raldh1-4), degradation of RA (Cyp26a1-c1) and RA signaling (Raralpha,beta,gamma, Rxralpha,beta,gamma). We show that both early embryonic neuroectodermal (NE-4C) stem cells and late embryonic or adult derived radial glia like progenitors (RGl cells) are capable to produce bioactive retinoids but respond differently to retinoid signals. However, while neuronal differentiation of RGl cells can not be induced by RA, neuron formation by NE-4C cells is initiated by both RA and RA-precursors (retinol or retinyl acetate). The data indicate that endogenous RA production, at least in some neural stem cell populations, may result in autocrine regulation of neuronal differentiation. PMID- 23734953 TI - A fragment based approach toward thia[n]helicenes. AB - The synthesis of [9]- and [11]thiahelicenes, as well as the preparation of lower homologues such as [5]-, [6]-, and [7]thiahelicenes is reported. Efficient palladium catalyzed coupling reactions were employed. Triorganoindium derivatives were selectively mono-cross-coupled with N-methyl-3,4-dibromomaleimide followed by Stille coupling with the readily available building block naphthodithiophene. Oxidative photocyclization of the conjugated precursors using visible light was employed to synthesize a series of thia[n]helicenes. This modular synthetic methodology is independent of the length of the helical backbone. PMID- 23734954 TI - Density functional calculations of the structural and electronic properties of (Y2O3)(n)(0,+/-1) clusters with n = 1-10. AB - We report results of ab initio calculations on yttrium oxide clusters using a plane wave pseudopotential method within density functional theory. (Y2O3)n clusters in the size range n = 1-10 prefer compact and symmetric globular configurations where preference for an octahedron unit of Y6O8 is seen. The evolution of the atomic structures shows similarity with that of the local structure in the bulk cubic (C-Y2O3) phase. The maximum coordinations of Y and O atoms are 6 and 4, respectively. The addition (removal) of an electron to (from) the lowest energy configurations of the neutral clusters induces significant changes for some of the cluster sizes. Sequential addition of a Y2O3 unit to the (Y2O3)n cluster leads to an increase in the binding energy. However, the HOMO LUMO gap, ionization potential, and electron affinity do not show any systematic variation in these clusters with increasing size. The bonding characteristics have been studied using charge density and Bader charge analysis. The charge transfer from Y atoms to oxygens increases with the increase in the cluster size and approaches the value in bulk. The stability of the clusters is dominated by ionic Y-O interactions. However, a small degree of covalency is also seen in Y-O bonding. All the lowest energy configurations of neutral clusters prefer the lowest spin state and the ionic clusters prefer a doublet state. PMID- 23734952 TI - Cardiovascular risk estimation in women with a history of hypertensive pregnancy disorders at term: a longitudinal follow-up study. AB - BACKGROUND: Cardiovascular disease is associated with major morbidity and mortality in women in the Western world. Prediction of an individual cardiovascular disease risk in young women is difficult. It is known that women with hypertensive pregnancy complications have an increased risk for developing cardiovascular disease in later life and pregnancy might be used as a cardiovascular stress test to identify women who are at high risk for cardiovascular disease. In this study we assess the possibility of long term cardiovascular risk prediction in women with a history of hypertensive pregnancy disorders at term. METHODS: In a longitudinal follow-up study, between June 2008 and November 2010, 300 women with a history of hypertensive pregnancy disorders at term (HTP cohort) and 94 women with a history of normotensive pregnancies at term (NTP cohort) were included. From the cardiovascular risk status that was known two years after index pregnancy we calculated individual (extrapolated) 10 and 30-year cardiovascular event risks using four different risk prediction models including the Framingham risk score, the SCORE score and the Reynolds risk score. Continuous data were analyzed using the Student's T test and Mann-Whitney U test and categorical data by the Chi-squared test. A poisson regression analysis was performed to calculate the incidence risk ratios and corresponding 95% confidence intervals for the different cardiovascular risk estimation categories. RESULTS: After a mean follow-up of 2.5 years, HTP women had significantly higher mean (SD) extrapolated 10-year cardiovascular event risks (HTP 7.2% (3.7); NTP 4.4% (1.9) (p<.001, IRR 5.8, 95% CI 1.9 to 19)) and 30-year cardiovascular event risks (HTP 11% (7.6); NTP 7.3% (3.5) (p<.001, IRR 2.7, 95% CI 1.6 to 4.5)) as compared to NTP women calculated by the Framingham risk scores. The SCORE score and the Reynolds risk score showed similar significant results. CONCLUSIONS: Women with a history of gestational hypertension or preeclampsia at term have higher predicted (extrapolated) 10-year and 30-year cardiovascular event risks as compared to women with a history of uncomplicated pregnancies. Further large prospective studies have to evaluate whether hypertensive pregnancy disorders have to be included as an independent variable in cardiovascular risk prediction models for women. PMID- 23734955 TI - Development of psoriasis in a patient with chronic myelogenous leukaemia during nilotinib treatment. AB - The tyrosine kinase inhibitor (TKI) imatinib has been shown to promote psoriasis in some patients with chronic myelogenous leukaemia (CML), but it remained unclear whether second-generation TKIs such as nilotinib and dasatinib had a similar potential. Here, we present a patient in whom psoriatic erythema appeared at 26 months after initiation of nilotinib treatment. Topical ointments of activated vitamin D3 derivative and corticosteroid were applied; whereupon, the erythema gradually improved. During the clinical course, nilotinib administration continued without reduction in its dose. This is the first report of psoriasis that developed during nilotinib treatment. We also discuss the mechanisms of nilotinib-mediated progression of psoriasis. PMID- 23734956 TI - Where do we stand with IPF treatment? AB - Despite receiving 'weak no' recommendations in the updated guidelines on treating patients with Idiopathic Pulmonary Fibrosis (IPF), two key treatment options are pirfenidone and N-acetylcysteine (NAC), and both are used in clinical practice. The efficacy of pirfenidone is supported by a number of Phase III trials as well as a Cochrane meta-analysis. Tolerability data are also provided by clinical trials and a long-term extension phase of these studies. Pirfenidone is approved in Europe for the treatment of patients with mild-to-moderate IPF. NAC-based therapy has no such approval, but is commonly used to treat patients. A Phase III trial suggested some benefit of the NAC, prednisone and azathioprine regimen for IPF patients, but the study had many limitations. A further study to investigate this regimen, compared with a placebo alone arm, was recently stopped due to increased mortality in the triple-therapy arm. Discussion of these data and recent findings highlight the importance of a further update to the existing guidelines, so that IPF specialists can provide the most up-to-date advice and treatment to patients in clinical practice. PMID- 23734957 TI - A highly efficient peptide substrate for EGFR activates the kinase by inducing aggregation. AB - Formation of an asymmetric dimer by the EGFR (epidermal growth factor receptor) kinase domains results in allosteric activation. Since this dimer does not readily form in solution, the EGFR kinase domain phosphorylates most peptide substrates with a relatively low catalytic efficiency. Peptide C is a synthetic peptide substrate of EGFR developed by others that is phosphorylated with a significantly higher catalytic efficiency, and we sought to understand the basis for this. Peptide C was found to increase EGFR kinase activity by promoting formation of the EGFR kinase domain asymmetric dimer. Activation of the kinase domain by Peptide C also enhances phosphorylation of other substrates. Aggregation of the EGFR kinase domain by Peptide C probably underlies activation, and Peptide C precipitates several other proteins. Peptide C was found to form fibrils independent of the presence of EGFR, and these fibrils may facilitate aggregation and activation of the kinase domain. These results establish that a peptide substrate of EGFR may increase catalytic activity by promoting kinase domain dimerization by an aggregation-mediated mechanism. PMID- 23734959 TI - The validity and reliability of the Finnish Family Empowerment Scale (FES): a survey of parents with small children. AB - BACKGROUND: The Family Empowerment Scale (FES) is a widely used instrument which measures the parents' own sense of their empowerment at the level of the family, service system and community. It was originally developed for parents of children with emotional disabilities. AIM: The aims of this study were to evaluate the validity and reliability of the Finnish FES and to examine its responsiveness in measuring the empowerment of parents with small children. METHODS AND PARTICIPANTS: The English FES was translated into Finnish using back translation and modified so as to be generic and convenient for all families. The construct, convergent, discriminant and concurrent validities, reliability and responsiveness of the Finnish FES were examined. Participants (n = 955) were the parents of children aged 0-9 years who had been selected using stratified random sampling. RESULTS: Confirmatory factor analysis proved that the Finnish FES had three subscales based on the original FES. Convergent and discriminant validities confirmed and supported the same construct. The relationship between parents' participation and empowerment was tested for concurrent validity. As in previous FES studies, the participating parents were more empowered, which supported the concurrent validity. The reliability of the Finnish FES proved acceptable for both parents. The Finnish FES could also discriminate the responses of the parents. Participation in the activities organized by the family service system influenced parents' perceptions of empowerment more than did their background characteristics. CONCLUSIONS: The Finnish FES is a valid and reliable instrument and it is suitable for measuring the empowerment of parents. However, it is necessary to consider how the FES would identify in the best way the parents who perhaps need some help. PMID- 23734960 TI - New insights into carbon allocation by trees from the hypothesis that annual wood production is maximized. AB - Allocation of carbon (C) between tree components (leaves, fine roots and woody structures) is an important determinant of terrestrial C sequestration. Yet, because the mechanisms underlying C allocation are poorly understood, it is a weak link in current earth-system models. We obtain new theoretical insights into C allocation from the hypothesis (MaxW) that annual wood production is maximized. MaxW is implemented using a model of tree C and nitrogen (N) balance with a vertically resolved canopy and root system for stands of Norway spruce (Picea abies). MaxW predicts optimal vertical profiles of leaf N and root biomass, optimal canopy leaf area index and rooting depth, and the associated optimal pattern of C allocation. Key insights include a predicted optimal C-N functional balance between leaves at the base of the canopy and the deepest roots, according to which the net C export from basal leaves is just sufficient to grow the basal roots required to meet their N requirement. MaxW links the traits of basal leaves and roots to whole-tree C and N uptake, and unifies two previous optimization hypotheses (maximum gross primary production, maximum N uptake) that have been applied independently to canopies and root systems. PMID- 23734961 TI - Evaluation of corneal parameters with scheimpflug imaging in patients with rheumatoid arthritis. AB - PURPOSE: To evaluate corneal parameters of rheumatoid arthritis (RA) patients by Pentacam-HR. METHODS: Seventy RA patients and 100 control subjects were enrolled. All participants underwent Pentacam (Pentacam-HR, Oculus, Germany) evaluation. Both RA and control groups were divided into two subgroups as dry eye (DE) (Schirmer test with topical anesthesia (STA) <= 5 mm) and without DE (STA > 5 mm). RESULTS: Pachymetric measurements and the mean corneal volume were significantly lower in RA group (p < 0.001). Disease duration was negatively correlated with pachymetric measurements in RA group. Pachymetric measurements and corneal volume of RA patients with DE were significantly lower than all the other subgroups. Control subgroups with or without DE were similar in pachymetric measurements and corneal volume. CONCLUSIONS: The results suggest that RA patients have thinner corneas compared to control subjects that may be affected by disease duration. Furthermore, coexistence of DE and RA seems to aggravate the thinning of cornea as well. PMID- 23734962 TI - An economic analysis of the limits of market based reforms in the English NHS. AB - BACKGROUND: Over the past three decades, a limited range of market like mechanisms have been introduced into the hierarchically structured English National Health Service ('NHS'), which is a nationally tax funded, budget limited healthcare system, with access to care for all, producing structures known as a quasi market. Recently, the Health and Social Care Act 2012 ('HSCA') has been enacted, introducing further market elements. The paper examines the theory and effects of these market mechanisms. METHODS: Using neo-classical economics as a primary theoretical framework, as well as new institutional economics and socio legal theory, the paper first examines the fundamental elements of markets, comparing these with the operation of authority and resource allocation employed in hierarchical structures. Second, the paper examines the application of market concepts to the delivery of healthcare, drawing out the problems which economic and socio-legal theories predict are likely to be encountered. Third, the paper discusses the research evidence concerning the operation of the quasi market in the English NHS. This evidence is provided by research conducted in the UK which uses economic and socio-legal logic to investigate the operation of the economic aspects of the NHS quasi market. Fourth, the paper provides an analysis of the salient elements of the quasi market regime amended by the HSCA 2012. RESULTS: It is not possible to construct a market conforming to classical economic principles in respect of healthcare. Moreover, it is not desirable to do so, as goals which markets cannot deliver (such as fairness of access) are crucial in England. Most of the evidence shows that the quasi market mechanisms used in the English NHS do not appear to be effective either. This finding should be seen in the light of the fact that the operation of these mechanisms has been significantly affected by the national political (i.e. continuingly hierarchical) and budgetary context in which they are operating. CONCLUSION: The organisational structures of a hierarchy are more appropriate for the delivery of healthcare in the English NHS. PMID- 23734963 TI - Retinal vasculitis in two pediatric patients with systemic lupus erythematosus: a case report. AB - We report two pediatric female patients with systemic lupus erythematosus (SLE) who presented with decreased vision. Both patients were found to have retinal vasculitis and occlusive disease. The first patient also presented with vitreous hemorrhage and later non-arteritic ischemic optic neuropathy. She was treated with panretinal photocoagulation and steroid therapy and later in her disease course was treated with rituximab and cyclophosphamide. Her vision remained decreased. The second patient was treated with rituximab and monthly cyclophosphamide infusions early in her disease course, and her vision improved dramatically. The difference in the presentations and outcomes of these two pediatric patients with SLE highlights the spectrum of severity of SLE retinopathy. We suggest that early recognition of disease and early intervention with B-cell depletion therapy in addition to a traditional cytotoxic agent should be considered in pediatric patients with SLE and occlusive retinopathy. PMID- 23734964 TI - Aldose reductase from Schistosoma japonicum: crystallization and structure-based inhibitor screening for discovering antischistosomal lead compounds. AB - BACKGROUND: Schistosomiasis is a neglected tropical disease with high morbidity and mortality in the world. Currently, the treatment of this disease depends almost exclusively on praziquantel (PZQ); however, the emergence of drug resistance to PZQ in schistosomes makes the development of novel drugs an urgent task. Aldose reductase (AR), an important component that may be involved in the schistosome antioxidant defense system, is predicted as a potential drug target. METHODS: The tertiary structure of Schistosoma japonicum AR (SjAR) was obtained through X-ray diffraction method and then its potential inhibitors were identified from the Maybridge HitFinder library by virtual screening based on this structural model. The effects of these identified compounds on cultured adult worms were evaluated by observing mobility, morphological changes and mortality. To verify that SjAR was indeed the target of these identified compounds, their effects on recombinant SjAR (rSjAR) enzymatic activity were assessed. The cytotoxicity analysis was performed with three types of human cell lines using a Cell Counting Kit-8. RESULTS: We firstly resolved the SjAR structure and identified 10 potential inhibitors based on this structural model. Further in vitro experiments showed that one of the compounds, renamed as AR9, exhibited significant inhibition in the activity of cultured worms as well as inhibition of enzymatic activity of rSjAR protein. Cytotoxicity analysis revealed that AR9 had relatively low toxicity towards host cells. CONCLUSIONS: The work presented here bridges the gap between virtual screening and experimental validation, providing an effective and economical strategy for the development of new anti-parasitic drugs. Additionally, this study also found that AR9 may become a new potential lead compound for developing novel antischistosomal drugs against parasite AR. PMID- 23734965 TI - Investigating polypharmacy and drug burden index in hospitalised older people. AB - AIMS: To investigate the changes in polypharmacy and the drug burden index (DBI) occurring during hospitalisation for older people. The secondary aim was to examine the associations of these two measures with the length of hospital stay and admission for falls or delirium. METHODS: A retrospective analysis of patients' medical records was undertaken at a large university teaching hospital (Sydney, Australia) for patients with the age of >= 65 years and admitted under the care of the geriatric medicine or rehabilitation teams. Polypharmacy was defined as the use of more than five regular medications. The DBI measures exposure to drugs with anticholinergic and sedative effects. Logistic regression analysis was conducted to investigate the associations between polypharmacy and DBI with outcome measures. Data are presented using odds ratios with 95% confidence intervals. RESULTS: A total of 329 patients was included in this study. The mean (+/- standard deviation) age of the population was 84.6 +/- 7.0 years, 62% were female and 40% were admitted from residential aged-care facilities. On admission, polypharmacy was observed in 60% of the cohort and DBI exposure for 50%. DBI and polypharmacy exposure decreased during hospitalisation, but only the number of medications taken decreased by a statistically significant margin (P = 0.02). Patients with a high DBI (>= 1) were approximately three times more likely to be admitted for delirium than those with no DBI exposure (odds ratio, 2.95; 95% confidence interval, 1.34-6.51). CONCLUSIONS: In the present study, DBI was associated with an increased risk of hospital admission for delirium only. Polypharmacy was not associated with any of the clinical measures. PMID- 23734966 TI - Tunable touch sensor and combined sensing platform: toward nanoparticle-based electronic skin. AB - In this paper, we present touch (or pressure) flexible sensors based on monolayer capped nanoparticles (MCNPs) that are potentially inexpensive, could allow low voltage operation, and could provide a platform for multifunctional applications. We show that modifying the mechanical and geometrical properties of the flexible substrates, on which the MCNP films are deposited, allows measuring a large span of loads ranging between tens of mg to tens of grams. All flexible sensors exhibited repeatable responses even after a large number of bending cycles. In addition, we show that modified platforms of those touch (or pressure) sensors allow precise detection and monitoring of environmental temperature and humidity. Relying on their superior characteristics, we were able to build an MCNP-based prototype allowing simultaneous detection and monitoring of multiple environmental parameters of touch (or pressure), humidity, and temperature. The excellent temperature (resolution higher than 1 degrees C and average error of ~5%) and relative humidity (resolution higher than 1% RH and average error of ~9%) sensitivities and the possibility to integrate those sensing abilities makes the suggested platform interesting for potentially inexpensive and low-voltage multifunctional electronic-skin applications. PMID- 23734967 TI - Study of the etiopathogenesis and differential diagnosis of oral vascular lesions by immunoexpression of GLUT-1 and HIF-1alpha. AB - BACKGROUND: To investigate whether the immunohistochemical expression of GLUT-1 and HIF-1alpha is related to the diagnosis and pathogenesis of oral vascular lesions. STUDY METHODS: Thirty cases each of pyogenic granuloma (PG) and hemangioma were studied. Antibodies against GLUT-1 and HIF-1alpha were detected by immunoperoxidase staining in 3-MUm histological sections, and the results were analyzed qualitatively and quantitatively, respectively. Positive and negative cells were counted, and the mean number of positive cells was calculated for each case. RESULTS: The initial diagnosis of hemangioma was maintained in only 7 (23%) of the 30 cases studied, which were positive for GLUT-1. The remaining 23 cases were reclassified as vascular malformation (VM) (n = 13) and PG (n = 10) due to the absence of staining. The endothelium of blood vessels was negative for GLUT-1 in all cases initially diagnosed as PG (n = 30). The percentage of HIF-1alpha positive cells was higher in cases of PG, followed by hemangiomas and VMs (P = 0.005). CONCLUSIONS: Histological features are not sufficient to establish the correct diagnosis of oral hemangiomas, and an accurate anamnesis is essential in these cases. In addition, these findings demonstrate that vascular lesions express mediators of angiogenesis, HIF-1alpha, and suggest that his process may play a role in the pathogenesis of vascular. PMID- 23734968 TI - Seroprevalence of Bordetella pertussis in the Mexican population: a cross sectional study. AB - SUMMARY Serum samples collected during the National Health and Nutrition survey (ENSANUT 2006) were obtained from subjects aged 1-95 years (January-October 2010) and analysed to assess the seroprevalence of Bordetella pertussis (BP) in Mexico. Subjects' gender, age, geographical region and socioeconomic status were extracted from the survey and compiled into a subset database. A total of 3344 subjects (median age 29 years, range 1-95 years) were included in the analysis. Overall, BP seroprevalence was 47.4%. BP seroprevalence was significantly higher in males (53.4%, P = 0.0007) and highest in children (59.3%) decreasing with advancing age (P = 0.0008). BP seroprevalence was not significantly different between regions (P = 0.1918) and between subjects of socioeconomic status (P = 0.0808). Women, adolescents and young adults were identified as potential sources of infection to infants. Booster vaccination for adolescents and primary contacts (including mothers) for newborns and infants may provide an important public health intervention to reduce the disease burden. PMID- 23734969 TI - Selected ebselen analogs reduce mechlorethamine toxicity in vitro. AB - Sulfur mustard (SM) is a potent vesicant. The lack of an effective antidote makes SM a continued threat to both military and civilian settings. A surrogate agent, namely mechlorethamine (HN2), was used here to mimic the toxicity of SM, and the main objective of this study was to demonstrate if selected organoselenium analogs could protect cultured A-431 skin cells from HN2 toxicity. Test compounds included ebselen (EB-1) and three related organoselenium analogs (EB-2, EB-3 and EB-4). In the absence of test compound, a reproducible and robust cell death was observed in the cells following incubation with HN2 (25 uM, 24 or 48 h) while cells treated with test compound alone (15, 30 or 60 uM) for similar periods of time were generally not affected. When incubated in the presence of both HN2 and test compound for 24 or 48 h, it was found that EB-1, EB-2, EB-3 and EB-4 could spare the cells from death, with the EB-4 compound being the most effective at reducing HN2 toxicity. Light microscopy confirmed these findings. The organoseleniums were also examined for their effects on reducing lipid peroxidation in the A-431 skin cells. Among the test compounds, EB-4 reduced lipid peroxidation by HN2 to the greatest extent. These studies, taken together, validate that the organoselenium antioxidants tested here may serve a purpose in the discovery of medical countermeasures to vesicants. PMID- 23734970 TI - Peierls stress of dislocations in molecular crystal cyclotrimethylene trinitramine. AB - Dislocation mediated plasticity in the alpha phase of the energetic molecular crystal cyclotrimethylene trinitramine (RDX) was investigated using a combination of atomistic simulations and the Peierls-Nabarro (PN) model. A detailed investigation of core structures and dislocation Peierls stress was conducted using athermal atomistic simulations at atmospheric pressure to determine the active slip systems. Generalized stacking fault energy surfaces calculated using atomistic simulations were used in the PN model to also estimate the critical shear stress for dislocation motion. The primary slip plane is found to be (010) in agreement with experimental observations, with the (010)[100] slip systems having the lowest Peierls stress. In addition, atomistic simulations predict the (021)[01[overline]2], (021)[100], (011)[100], (001)[100], and (001)[010] slip systems to have Peierls stress values small enough to allow plastic activity. However, there are less than five independent slip systems in this material in all situations. The ranking of slip systems based on the Peierls stress values is provided, and implications are discussed in relation to experimental data from nanoindentation and shock-induced plastic deformation. PMID- 23734971 TI - Are the most dedicated nurses more vulnerable to job insecurity? Age-specific analyses on family-related outcomes. AB - AIM: To examine the moderating roles of job dedication and age in the job insecurity-family-related well-being relationship. BACKGROUND: As job insecurity is a rather permanent stressor among nurses nowadays, more research is needed on the buffering factors alleviating its negative effects on well-being. METHODS: A total of 1719 Finnish nurses representing numerous health care organisations participated in this cross-sectional study. Moderated hierarchical regression analysis was used to examine the associations. RESULTS: Nurses' younger age and low job dedication operated as protective factors against the negative effect of high job insecurity on parental satisfaction. The effect of job dedication on family-related well-being was also age-specific: high job dedication protected younger nurses from the negative effect of job insecurity on work-family conflict and parental stress, whereas among older nurses those who reported low job dedication showed better well-being in the presence of high job insecurity. CONCLUSIONS: The most job-dedicated nurses were more vulnerable to job insecurity in relation to parental satisfaction. In addition, high job dedication combined with high age implied more work-family conflict and parental stress in the presence of high job insecurity. IMPLICATIONS FOR NURSING MANAGEMENT: Managers should seek to boost younger nurses' job dedication and to prevent older nurses' over-commitment. PMID- 23734972 TI - Graphene oxide-peptide nanocomplex as a versatile fluorescence probe of protein kinase activity based on phosphorylation protection against carboxypeptidase digestion. AB - The research on complicated kinomics and kinase-target drug discovery requires the development of simple, cost-effective, and multiplex kinase assays. Herein, we propose a novel and versatile biosensing platform for the detection of protein kinase activity based on graphene oxide (GO)-peptide nanocomplex and phosphorylation-induced suppression of carboxypeptidase Y (CPY) cleavage. Kinase catalyzed phosphorylation protects the fluorophore-labeled peptide probe against CPY digestion and induces the formation of a GO/peptide nanocomplex resulting in fluorescence quenching, while the nonphosphopeptide is degraded by CPY to release free fluorophore as well as restore fluorescence. This GO-based nanosensor has been successfully applied to sensitively detect two model kinases, casein kinase (CKII) and cAMP-dependent protein kinase (PKA) with low detection limits of 0.0833 mU/MUL and 0.134 mU/MUL, respectively. The feasibility of this GO-based sensor was further demonstrated by the assessment of kinase inhibition by staurosporine and H-89, in vitro kinase assay in cell lysates, and simultaneous detection of CKII and PKA activity. Moreover, the GO-based fluorescence anisotropy (FA) kinase assay has been also developed using GO as a FA signal amplifier. The proposed sensor is homogeneous, facile, universal, label-free, and applicable for multiplexed kinase assay, presenting a promising method for kinase related biochemical fundamental research and inhibitor screening. PMID- 23734973 TI - Inhaled corticosteroid adherence and emergency department utilization among Medicaid-enrolled children with asthma. AB - OBJECTIVES: Asthma is the most prevalent chronic disease among children enrolled in Medicaid. This study measured real-world adherence and outcomes after an initial prescription for inhaled corticosteroid therapy in a multi-state Medicaid population. METHODS: We conducted a retrospective study among Medicaid-enrolled children aged 5-12 years with asthma in 14 southern states using 2007 Medicaid Analytic eXtract file claims data to assess adherence and outcomes over the 3 months following an initial prescription drug claim for inhaled corticosteroids (ICS-Rx). Adherence was measured by the long-term controller-to-total asthma drug claims ratio. RESULTS: Only one-third of children (33.4%) with an initial ICS-Rx achieved a controller-to-total drug ratio >0.5 over the next 90 days. Children for whom long-term control drugs represented less than half of their total asthma drug claims had a 21% higher risk of emergency department (ED) visit (adjusted odds ratio (AOR) 1.21 [95% CI 1.14, 1.27]), and a 70% higher risk of hospital admission (AOR 1.70 [95% CI 1.45, 1.98]) than those with a controller-to-total asthma drug ratio >0.5. CONCLUSION: Real-world adherence to long-term controller medications is quite low in this racially diverse, low-income segment of the population, despite Medicaid coverage of medications. Adherence to long-term controller therapy had a measurable impact on real-world outcomes. Medicaid programs are a potential surveillance system for both medication adherence and ED utilization. PMID- 23734974 TI - Multi-level model for the investigation of oncoantigen-driven vaccination effect. AB - BACKGROUND: Cancer stem cell theory suggests that cancers are derived by a population of cells named Cancer Stem Cells (CSCs) that are involved in the growth and in the progression of tumors, and lead to a hierarchical structure characterized by differentiated cell population. This cell heterogeneity affects the choice of cancer therapies, since many current cancer treatments have limited or no impact at all on CSC population, while they reveal a positive effect on the differentiated cell populations. RESULTS: In this paper we investigated the effect of vaccination on a cancer hierarchical structure through a multi-level model representing both population and molecular aspects. The population level is modeled by a system of Ordinary Differential Equations (ODEs) describing the cancer population's dynamics. The molecular level is modeled using the Petri Net (PN) formalism to detail part of the proliferation pathway. Moreover, we propose a new methodology which exploits the temporal behavior derived from the molecular level to parameterize the ODE system modeling populations. Using this multi-level model we studied the ErbB2-driven vaccination effect in breast cancer. CONCLUSIONS: We propose a multi-level model that describes the inter-dependencies between population and genetic levels, and that can be efficiently used to estimate the efficacy of drug and vaccine therapies in cancer models, given the availability of molecular data on the cancer driving force. PMID- 23734975 TI - Two novel null HLA-A alleles with identical exon 4 nonsense mutations: HLA A*24:183N and A*02:356N. AB - HLA-A*24:183N, A*02:356N, and A*02:15N share the same stop codon at the same position in exon 4. PMID- 23734976 TI - Outbreak of acute respiratory disease caused by human adenovirus type 7 in a military training camp in Shaanxi, China. AB - Outbreaks of ARD associated with HAdV have been reported in military populations in many countries. Here, we report an ARD outbreak caused by HAdV-7 in a military training camp in Shaanxi Province, China, from February to March of 2012. Epidemic data and samples from the patients were collected, and viral nucleotides from samples and viral isolations were detected and sequenced. IgG and IgA antibodies against HAdV, and the neutralization antibodies against the viral strain isolated in this outbreak, were detected. Epidemiological study showed that all personnel affected were males with an average age of 19.1 years. Two peaks appeared on the epicurve and there was an 8-day interval between peaks. Laboratory results of viral nucleotide detection carried out with clinical specimens were positive for HAdV (83.33%, 15/18). Further study through serum antibody assay, virus isolation and phylogenetic analysis showed that HAdV-7 was the etiological agent responsible for the outbreak. IgA antibody began to appear on the 4th day after the onset and showed 100% positivity on the 8th day. The virus strain in the present outbreak was highly similar to the virus isolated in Hanzhong Shaanxi in 2009. We conclude that HAdV-7 was the pathogen corresponding to the outbreak, and this is the first report of an ARD outbreak caused by HAdV-7 in military persons in China. Vaccine development, as well as enhanced epidemiological and virological surveillance of HAdV infections in China should be emphasized. PMID- 23734977 TI - NOTCH1 mutations influence survival in chronic lymphocytic leukemia patients. AB - BACKGROUND: NOTCH1 PEST domain mutations in chronic lymphocytic leukemia have recently been shown to be of prognostic relevance. Both NOTCH1 and NOTCH2 are constitutively activated in B-cell CLL but not expressed in normal B cells and may be involved in survival and resistance to apoptosis in CLL. We screened for mutations in different parts of both NOTCH1 and NOTCH2 genes and related the changes to survival and other known risk factors. METHODS: In a cohort of 209 CLL patients, we used single strand conformation analysis to determine which of the samples carrying the NOTCH mutations and direct dideoxy sequencing was used to determine the exact nucleotide changes. Kaplan-Meier curves and log rank test were used to determine overall survival for NOTCH1 mutated cases and Cox regression analysis was used to calculate hazardous ratios. RESULTS: In the present study, we found NOTCH1 PEST domain mutations in 6.7% of the cases. A shorter overall survival was found in patients with NOTCH1 mutations compared to wildtype (p = 0.049). Further, we also examined the extracellular and the heterodimerisation domains of the NOTCH1 gene and the PEST domain and heterodimerisation domain of the NOTCH2 gene, but no mutations were found in these regions. NOTCH1 mutations were most commonly observed in patients with unmutated IGHV gene (10/14), and associated with a more aggressive disease course. In addition, NOTCH1 mutations were almost mutually exclusive with TP53 mutations. In the combined group of NOTCH1 (6.7%) or TP53 (6.2%) mutations, a significant difference in overall survival compared to the wildtype NOTCH1 and TP53 was found (p = 0.002). CONCLUSIONS: Both NOTCH1 and TP53 mutations seem to be independent predictive markers for worse outcome in CLL-patients and this study emphasizes the contention that NOTCH1 mutations is a novel risk marker. PMID- 23734978 TI - Photoinduced self-epitaxial crystal growth of a diarylethene derivative with antireflection moth-eye and superhydrophobic lotus effects. AB - We identified the mechanism of the formation of needle-shaped microcrystals on which the contact angle of a water droplet exceeds 170 degrees [Nishikawa, N. et al. Langmuir, 2012, 28, 17817-17824]. The standing needle-shaped crystal of the closed-ring isomer of a diarylethene 3c grew at a much lower temperature than the eutectic temperature by irradiation of UV light on the thin films of the open ring isomer 3o, due to the epitaxial growth of the 013 plane of 3c over the 110 plane of the crystal lattice of 3o in the subphase. Therefore, the new crystal growth mechanism triggered by the photoisomerization does not require special inorganic single-crystal substrates and may be called self-epitaxial crystal growth. The needle-shaped crystals appeared well-ordered and stood inclined at an angle of about 60 degrees to the surface. Consequently, the photo-induced rough surface shows not only the superhydrophobic lotus effect, but also the antireflection moth-eye effect, and these effects were switchable by alternate irradiation with UV and visible light. PMID- 23734979 TI - Synthesis and reactivity of dibenzoselenacycloheptynes. AB - Dibenzoselenacycloheptynes were prepared in three steps from commercially available reagents and trapped in situ with benzyl azide to form the corresponding triazoles. Surprisingly, the dibenzoselenacycloheptynes also abstracted hydrogen atoms from solvents such as THF or toluene, forming dibenzoselenacycloheptene products. These alkenyl compounds arise from a hydrogen transfer reaction from solvent to the unisolable intermediate, and we postulate that the reaction proceeds via a radical mechanism originating from the strained alkynyl bond that has unusually high radical character. PMID- 23734980 TI - Synthesis, characterization, and heterobimetallic cooperation in a titanium chromium catalyst for highly branched polyethylenes. AB - A heterobimetallic catalyst, {Ti--Cr}, consisting of a constrained-geometry titanium olefin polymerization center (CGC(Et)Ti) covalently linked to a chromium bis(thioether)amine ethylene trimerization center (SNSCr) was synthesized and fully characterized. In ethylene homopolymerizations it affords linear low density polyethylene with molecular weights as high as 460 kg.mol(-1) and exclusively n-butyl branches in conversion-insensitive densities of ~18 branches/1000 carbon atoms, which are ~17 and ~3 times (conversion-dependent), respectively, those achieved by tandem mononuclear CGC(Et)Ti and SNSCr catalysts under identical reaction conditions. PMID- 23734981 TI - Development and characterization of glutathione-conjugated albumin nanoparticles for improved brain delivery of hydrophilic fluorescent marker. AB - The glutathione-conjugated bovine serum albumin (BSA) nanoparticles were constructed in the present exploration as a novel biodegradable carrier for brain specific drug delivery with evaluation of its in vitro and in vivo delivery properties. BSA nanocarriers were activated and conjugated to the distal amine functions of the glutathione via carbodiimide chemistry using EDAC as a mediator. These nanoparticles were characterized for particle shape, average size, SPAN value, drug entrapment and in vitro drug release. Further, presence of glutathione on the surface of BSA nanoparticles was confirmed by Ellman's assay, which has suggested that approximately 750 units of glutathione were conjugated per BSA nanoparticle. To evaluate the brain delivery properties of the glutathione-conjugated BSA nanoparticles fluorescein sodium was used as a model hydrophilic compound. Permeability and neuronal uptake properties of developed formulations were evaluated against the MDCK-MDR1 endothelial and neuro-glial cells, respectively. The permeability of glutathione-conjugated BSA nanoparticles across the monolayer of MDCK-MDR1 endothelial tight junction was shown significantly higher than that of unconjugated nanoparticles and fluorescein sodium solution. Similarly, glutathione-conjugated nanoparticles exhibited considerably higher uptake by neuro-glial cells which was inferred by high fluorescence intensity under microscope in comparison to unconjugated nanoparticles and fluorescein sodium solution. Following an intravenous administration, nearly three folds higher fluorescein sodium was carried to the rat brain by glutathione-conjugated nanoparticles as compared to unconjugated nanoparticles. The significant in vitro and in vivo results suggest that glutathione-conjugated BSA nanoparticles is a promising brain drug delivery system with low toxicity. PMID- 23734982 TI - The role of Arabidopsis thaliana NAR1, a cytosolic iron-sulfur cluster assembly component, in gametophytic gene expression and oxidative stress responses in vegetative tissue. AB - Iron-sulfur proteins have iron-sulfur clusters as a prosthetic group and are responsible for various cellular processes, including general transcriptional regulation, photosynthesis and respiration. The cytosolic iron-sulfur assembly (CIA) pathway of yeast has been shown to be responsible for regulation of iron sulfur cluster assembly in both the cytosol and the nucleus. However, little is known about the roles of this pathway in multicellular organisms. In a forward genetic screen, we identified an Arabidopsis thaliana mutant with impaired expression of the endosperm-specific gene Flowering Wageningen (FWA). To characterize this mutant, we carried out detailed phenotypic and genetic analyses during reproductive and vegetative development. The mutation affects NAR1, which encodes a homolog of a yeast CIA pathway component. Comparison of embryo development in nar1-3 and other A. thaliana mutants affected in the CIA pathway showed that the embryos aborted at a similar stage, suggesting that this pathway potentially functions in early seed development. Transcriptome analysis of homozygous viable nar1-4 seedlings showed transcriptional repression of a subset of genes involved in 'iron ion transport' and 'response to nitrate'. nar1-4 also exhibited resistance to the herbicide paraquat. Our results indicate that A. thaliana NAR1 has various functions including transcriptional regulation in gametophytes and abiotic stress responses in vegetative tissues. PMID- 23734983 TI - Minimising time to treatment: targeted strategies to minimise time to thrombolysis for acute ischaemic stroke. AB - Time to thrombolysis is a critical determinant of favourable outcomes in acute ischaemic stroke. It is not infrequent that patient outcomes are compromised due to out-of-hospital and in-hospital time delays. On the other hand, time delays could be minimised through the identification of barriers and the implementation of targeted solutions. This review outlines the different strategies in minimising treatment delays and offers recommendations. Literature search in PubMed, Medline and EBSCO Host was conducted to identify studies that are relevant to reduction of time to treatment from January 1995 to December 2012. Strategies to reduce time to thrombolysis are categorised into pre-hospital strategies, in-hospital strategies and post-treatment decision strategies. Proposed pre-hospital strategies include public education on stroke symptoms awareness, prioritising stroke by emergency medical services, increasing ease of access to medical records, pre-hospital notification, and mobile computed tomography scanning. In-hospital strategies include a streamlined code stroke system, computed tomography scanner co-location with emergency department, 24/7 availability of stroke physicians, point-of-care laboratory testing and access to expert neuroimaging interpretation. Post-decision strategies include increasing availability of intravenous thrombolysis and simplification of informed consent procurement. Time to thrombolysis delays is multifactorial. Effective reduction of time delays for acute ischaemic stroke requires the correct identification of and targeted strategies to overcome time barriers. PMID- 23734984 TI - Angiotensin-converting enzyme inhibition increases glucose-induced insulin secretion in response to acute restraint. AB - There is increasing evidence suggesting involvement of the renin-angiotensin system (RAS) in carbohydrate metabolism and its response to stress. Thus, the aim of the present study was to evaluate the effects of chronic inhibition of the RAS on glucose and insulin levels during acute restraint stress. Male Holtzman rats were treated with 10 mg/kg per day enalapril solution or vehicle for 14 days. After 14 days, rats were divided into three experimental groups: enalapril + restraint (ER), vehicle + restraint (VR) and enalapril + saline (ES). Rats in the restraint groups were subjected to 30 min restraint stress, whereas rats in the ES groups were given saline infusion instead. Blood samples were collected at baseline and after 5, 10, 20 and 30 min restraint stress or saline infusion. After restraint, a hyperglycaemic response was observed in the ER and VR groups that peaked at 20 and 10 min, respectively (P < 0.05 compared with baseline). The area under the glucose curve was markedly increased in the ER and VR groups compared with that in the ES group (P < 0.05 for both). Importantly, restraint induced a marked increase in insulin secretion in the ER group compared with only a mild elevation in the VR group; insulin secretion in both groups peaked at 20 min (P < 0.05 compared with baseline). Analysis of the area under the insulin curve confirmed an increase in insulin secretion in the ER compared with the VR and ES groups (P < 0.05 for both). The results of the present study reinforce that the RAS is involved in modulating responses to stress and suggest that RAS inhibition with enalapril may increase glucose-induced insulin secretion in response to acute restraint. PMID- 23734985 TI - Palladium-catalyzed arylic/allylic aminations: permutable domino sequences for the synthesis of dihydroquinolines from Morita-Baylis-Hillman adducts. AB - An efficient palladium-catalyzed synthesis of 1,2-dihydroquinolines has been developed via the reaction between anilines and Morita-Baylis-Hillman adducts derived from o-bromobenzaldehyde. This new Pd(0)-catalyzed pseudo-domino type I sequence involves a Buchwald-Hartwig arylic amination and an allylic amination. When starting from an o-bromo allylic alcohol, the chronology is arylic amination/allylic arylation. However, the sequence reverses when the reaction is performed on the corresponding o-bromo allylic acetate. PMID- 23734986 TI - Characteristics of prehospital ST-segment elevation myocardial infarctions. AB - INTRODUCTION: Despite attention directed at treatment times of ST-segment elevation myocardial infarctions (STEMIs), little is known about the types of STEMIs presenting to the emergency department (ED). OBJECTIVE: The purpose of this study was to determine the relative frequencies and characteristics of emergency medical services (EMS) STEMIs compared with those in patients who present to the ED by walk-in. This information may be applied in EMS training, system planning, and public education. METHODS: This was a query of a prospectively gathered database of all STEMIs in patients presenting to Summa Akron City Hospital ED in 2009 and 2010. We collected demographic information, chief complaint, mode and time of arrival, and STEMI pattern (anterior, lateral, inferior, or posterior). We excluded transfers and in-hospital STEMIs. We calculated means, percentages, significance, and 95% confidence intervals (CIs) +/- 10%. RESULTS: We analyzed data from 308 patients. Most patients (241/308, 78%, CI 73%-83%) arrived by EMS, were male (203/308, 66%, CI 60%-71%), and were white (286/308, 93%, CI 89%-96%). Patients arriving by EMS were older (average 63 years, range 35-95) than walk-in patients (average 57 years, range 24-92). Two percent (5/241, 2%, CI 1%-5%) of EMS STEMI patients were under 40 years of age, compared with 10% (7/67, 10%, CI 4%-20%) of walk-in patients (p = 0.0017). The most common chief complaint was chest pain (278/308, 90%, CI 86%-93%). Inferior STEMIs were most common (167/308, 54%, CI 49%-60%), followed by anterior (127/308, 41%, CI 48%-60%), lateral (8/308, 3%, CI 1%-5%), and posterior (6/308, 2%, CI 1%-4%). A day-of-the-week analysis showed that no specific day was most common for STEMI presentation. Forty percent (122/308, 40%, CI 34%-45%) of patients presented during open catheterization laboratory hours (Monday through Friday, 0730-1700 hours). There was no significant statistical difference between EMS and walk-in patients with regard to STEMI pattern or patient demographics. CONCLUSIONS: In this study, 95% (294/308) of all STEMIs were inferior or anterior infarctions, and these types of presentations should be stressed in EMS education. Most STEMI patients at this institution arrived by ambulance and during off-hours. Younger patients were more likely to walk in. We need further study, but we may have identified a target population for future interventions. Key words: emergency medical services; allied health personnel; electrocardiography; myocardial infarction; heart catheterization; STEMI. PMID- 23734987 TI - Do infants less than 12 months of age with an apparent life-threatening event need transport to a pediatric critical care center? AB - BACKGROUND: Some emergency medical services (EMS) systems transport infants with an apparent life-threatening event (ALTE) directly to hospitals capable of pediatric critical care (PCC) monitoring. OBJECTIVE: To describe factors identifiable by EMS providers that distinguish ALTE patients who may require PCC monitoring and management. METHODS: This was an observational analysis of ALTE patients who were transported by EMS and presented to four emergency departments (EDs). ED data were prospectively collected. Hospital records or reports from contacted parents were reviewed for interventions that mandated PCC management. We defined a priori the criteria by which PCC monitoring and management were required: if the subject needed 1) airway intervention with bag-valve-mask ventilation or advanced airway (e.g., endotracheal intubation) in the field, ED, or pediatric intensive care unit (PICU); 2) administration of vasopressors; 3) invasive monitoring; 4) surgery during the hospitalization; or 5) subspecialty consultation. Univariate analysis was performed to describe factors associated with requiring PCC management, and a multivariable model, accounting for within hospital correlations, was developed. RESULTS: A total of 513 patients were enrolled. Of these, 51 (9.9%) had an intervention warranting PCC management. Univariate predictors for requiring PCC management included prematurity, past medical history, resuscitation attempt, upper respiratory infection, apnea, previous ALTE, more than one ALTE in 24 hours, and cyanosis. The multivariable model yielded the following independent predictors for requiring PCC management: resuscitation attempt before EMS arrival, cyanosis, and more than one ALTE in 24 hours. This model demonstrated a sensitivity of 96.3%, a specificity of 25.8%, a negative predictive value of 98.3%, and a positive predictive value of 13.5%. CONCLUSION: Only 9.9% of infants presenting in the field with ALTE had an intervention warranting PCC management, suggesting that many ALTE patients may be safely transported to hospitals without PCC capability. This would allow for better resource utilization of specialty care hospitals and still provide an option for secondary transports for those few patients not correctly identified in the field as requiring PCC. History of resuscitation attempt, cyanosis, and more than one ALTE in 24 hours are independent risk factors for requiring PCC management. PMID- 23734988 TI - EMS runs for suspected opioid overdose: implications for surveillance and prevention. AB - BACKGROUND: Opioid (including prescription opiate) abuse and overdose rates in the United States have surged in the past decade. The dearth and limitations of opioid abuse and overdose surveillance systems impede the development of interventions to address this epidemic. Objective. We explored evidence to support the validity of emergency medical services (EMS) data on naloxone administration as a possible proxy for estimating incidence of opioid overdose. METHODS: We reviewed data from Baltimore City Fire Department EMS patient records matched with dispatch records over a 13-month time period (2008-2009) based on 2008 Census data. We calculated incidence rates and patient demographic and temporal patterns of naloxone administration, and examined patient evaluation data associated with naloxone administration. Results were compared with the demographic distributions of the EMS patient and city populations and with prior study findings. RESULTS: Of 116,910 EMS incidents during the study period for patients aged 15 years and older, EMS providers administered naloxone 1,297 times (1.1% of incidents), an average of 100 administrations per month. The overall incidence was 1.87 administrations per 1,000 residents per year. Findings indicated that naloxone administration peaked in the summer months (31% of administrations), on weekends (32%), and in the late afternoon (4:00-5:00 pm [8%]); and there was a trend toward peaking in the first week of the month. The incidence of suspected opioid overdose was highest among male patients, white patients, and those in the 45-54-year age group. Findings on temporal patterns were comparable with findings from prior studies. Demographic patterns of suspected opioid overdose were similar to medical examiner reports of demographic patterns of fatal drug- or alcohol-related overdoses in Baltimore in 2008-2009 (88% of which involved opioids). The findings on patient evaluation data suggest some inconsistencies with previously recommended clinical indications of opioid overdose. CONCLUSIONS: While our findings suggest limitations of EMS naloxone administration data as a proxy indicator of opioid overdose, the results provide partial support for using these data for estimating opioid overdose incidence and suggest ways to improve such data. The study findings have implications for an EMS role in conducting real-time surveillance and treatment and prevention of opioid abuse and overdose. PMID- 23734989 TI - Expanding paramedic scope of practice in the community: a systematic review of the literature. AB - BACKGROUND: Paramedics are an important health human resource and are uniquely mobile in most communities across Canada. In the last dozen years, challenges in the delivery of health care have prompted governments from around the globe to consider expanding the role paramedics play in health systems. Utilizing paramedics for the management of urgent, low-acuity illnesses and injuries has been coined "community paramedicine," but the role, safety, and effectiveness of this concept are poorly understood. OBJECTIVE: We undertook a systematic review of the international literature to describe existing community paramedic programs. METHOD: We used the Cochrane methodology for systematic reviews. An international group of experts developed a search strategy and a health information specialist executed this search in Medline, Embase, and CINAHL starting January 1, 2000. We included all research articles in the English language that reported a research methodology. We excluded commentaries and letters to the editor. Two investigators independently screened citations in a hierarchical manner and abstracted data. RESULTS: Of 3,089 titles, 10 articles were included in the systematic review and one additional paper was author nominated. The nature of the 11 articles was heterogeneous, and only one randomized controlled trial (RCT) was found. This trial showed community paramedicine to be beneficial to patients and health systems. The other articles drew conclusions favoring community paramedicine. CONCLUSION: Community paramedicine research to date is lacking, but programs in the United Kingdom, Australia, and Canada are perceived to be promising, and one RCT shows that paramedics can safely practice with an expanded scope and improve system performance and patient outcomes. Further research is required to fully understand how expanding paramedic roles affect patients, communities, and health systems. PMID- 23734990 TI - A national assessment of the roles and responsibilities of training officers. AB - INTRODUCTION: Since the inception of emergency medical services (EMS), individuals have assumed the role of "training officer" without a clear and concise description of the responsibilities inherent in this position. Furthermore, EMS system leaders rely heavily on these individuals to implement changes within an EMS system and to ensure the competency of practicing out-of hospital professionals. The limited understanding of and research in training officer roles highlight the need for study in this area. OBJECTIVES: Specific objectives of our study were to describe demographic and work-life characteristics of training officers, estimate the number of hours spent on specific training officer tasks in a typical week, and determine methods of training officer appointment and education received after appointment. METHODS: This was a questionnaire-based cross-sectional census analysis of all training officers in the National Registry of Emergency Medical Technicians (NREMT) database. This questionnaire contained items related to demographics, work-life characteristics, and specific roles and responsibilities of training officers. Descriptive statistics, chi-square, and Mann-Whitney U tests were utilized to assess specific differences among training officers. RESULTS: Over 2,500 individuals responded to this questionnaire (2,528/4,956). The majority of the respondents were male (79.0%), held a full-time salaried position (64.9%), and were of nonminority status (93.4%). Individuals reported an overall median number of years worked in EMS of 19.0 (standard deviation [SD] = 8.7, range = 0-45) and a median of 4.0 years of serving as a training officer (SD = 5.1, range = 0-33), and planned to serve as a training officer for a median of 10.0 years (SD = 7.6, range = 0-50). The highest median numbers of hours spent on specific training officer tasks in a typical week were for providing patient care (median = 8.0, SD = 18.1); developing, delivering, and accounting for continuing education (median = 5.0, SD = 9.8); department administration (median = 5.0, SD = 12.8); and performing run reviews (median = 3.0, SD = 6.4). CONCLUSION: The role of the training officer in ensuring the continued competence of the EMS professional has not been delineated in this paper, and future efforts should seek to answer this research question. Key words: emergency medical services; training officers; system administration. PMID- 23734991 TI - Stability of tranexamic acid after 12-week storage at temperatures from -20 degrees c to 50 degrees c. AB - BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic agent that reduces blood loss during surgery, decreases mortality in civilian and military trauma populations, was adopted for prehospital use by the British military, and is now issued to U.S. Special Operations Forces for use on the battlefield. OBJECTIVE: This study tested whether storage of TXA ampoules at four temperatures (-20 degrees C, 4 degrees C, 22 degrees C, or 50 degrees C) for 1, 2, 4, and 12 weeks would result in chemical degradation and the loss of activity to block streptokinase-induced fibrinolysis in human plasma. METHODS: For each temperature and storage duration, normal plasma, plasma plus streptokinase (SK) (50 units/mL), and plasma + SK + TXA (0.2 MUg/mL, n = 4) were tested for D-dimer (DD), for fibrin degradation products (FDP), by thromboelastography (to measure the units/mL of SK needed to get 100% fibrinolysis at 60 minutes [LY60]), and by high-performance liquid chromatography (HPLC). The results were similar for all temperatures and storage durations, and were therefore combined. RESULTS: Streptokinase led to a rise in LY60, DD, and FDP that was significantly (p < 0.05) attenuated with TXA. The results in the three test conditions were LY60: 0.00% +/- 0.00%, 70.52% +/- 4.7%, 0.02% +/- 0.01%; DD: 0.23 +/- 0.1, 205.05 +/- 101.59, 0.31 +/- 0.01 mg/L; and FDP: <10, >40, and <10 MUg/mL, respectively. The HPLC results showed no chemical breakdown of TXA. All TXA glass ampoules at -20 degrees C were cracked by week 1. CONCLUSIONS: Except for the finding that TXA ampoules cracked when frozen, this study indicated that the drug remains effective when stored under conditions likely to be encountered in the prehospital environment and outside the manufacturer's recommended temperature range for at least 12 weeks. PMID- 23734992 TI - Evaluation of ambulance decontamination using gaseous chlorine dioxide. AB - OBJECTIVE: We evaluated gaseous chlorine dioxide (ClO2) decontamination of an ambulance using a variety of bacterial biological agents. METHODS: Spores of attenuated Bacillus anthracis and Bacillus atrophaeus as well as vegetative cells of Acinetobacter baumannii, Mycobacterium smegmatis, and Staphylococcus aureus were exposed to ClO2 gas inside an ambulance. Log reduction in viability was assessed following decontamination using organism plate counts. RESULTS: Ambulance decontamination with ClO2 gas concentrations of 362 to 695 ppm maintained to exposures of 756 ppm-hours with 65% relative humidity (RH) achieved inactivation of all the bacterial agents tested. Decreasing exposure (ppm-hours) and RH (<65%) or restricting air flow reduced inactivation but still achieved greater than 6-log reductions in organism viability. CONCLUSION: Up to 10-log reductions were achieved in an ambulance interior following exposure to ClO2, indicating that gas concentrations needed to mitigate biological agent contamination can be achieved and maintained safely in an ambulance. Future studies are ongoing to evaluate gaseous ClO2 in other environments contaminated with biological agents of health care concern. PMID- 23734993 TI - Effectiveness and safety of in-water resuscitation performed by lifeguards and laypersons: a crossover manikin study. AB - OBJECTIVE: Drowning is associated with a high mortality and morbidity and a common cause of death. In-water resuscitation (IWR) in the case of drowning accidents has been recommended by certain resuscitation guidelines in the last several years. IWR has been discussed controversially in the past, especially with regard to the delay of chest compressions, effectiveness of ventilation, and hazard to the rescuer. The aim of the present study was to assess the effectiveness and safety of IWR. METHODS: In this crossover manikin study, 21 lifeguards and 21 laypersons performed two rescue procedures in an indoor swimming pool over a 50-meter distance: In random order, one rescue procedure was performed with in-water ventilation and one without. Tidal and minute volumes were recorded using a modified Laerdal Resusci Anne (Laerdal Medical, Stavanger, Norway) and total rescue duration, submersions, water aspiration by the victim, and physical effort were assessed. RESULTS: IWR resulted in significant increases in rescue duration (lifeguards: 106 vs. 82 seconds; laypersons: 133 vs. 106 seconds) and submersions (lifeguards: 3 vs. 1; laypersons: 5 vs. 0). Furthermore, water aspiration (lifeguards: 112 vs. 29 mL; laypersons: 160 vs. 56 mL) and physical effort (lifeguards: visual analog scale [VAS] score 7 vs. 5; laypersons: VAS score 8 vs. 6) increased significantly when IWR was performed. Lifeguards achieved significantly better ventilation characteristics and performed both rescue procedures faster and with lower side effects. IWR performed by laypersons was insufficient with regard to both tidal and minute volumes. CONCLUSIONS: In water resuscitation is associated with a delay of the rescue procedure and a relevant aspiration of water by the victim. IWR appears to be possible when performed over a short distance by well-trained professionals. The training of lifeguards must place particular emphasis on a reduction of submersions and aspiration when IWR is performed. IWR by laypersons is exhausting, time consuming, and inefficient and should probably not be recommended. Key words: drowning; near-drowning; hypoxia; ventilation, artificial; respiration, artificial; resuscitation, in-water. PMID- 23734994 TI - Simulating the decentralized processes of the human immune system in a virtual anatomy model. AB - BACKGROUND: Many physiological processes within the human body can be perceived and modeled as large systems of interacting particles or swarming agents. The complex processes of the human immune system prove to be challenging to capture and illustrate without proper reference to the spatial distribution of immune related organs and systems. Our work focuses on physical aspects of immune system processes, which we implement through swarms of agents. This is our first prototype for integrating different immune processes into one comprehensive virtual physiology simulation. RESULTS: Using agent-based methodology and a 3 dimensional modeling and visualization environment (LINDSAY Composer), we present an agent-based simulation of the decentralized processes in the human immune system. The agents in our model - such as immune cells, viruses and cytokines - interact through simulated physics in two different, compartmentalized and decentralized 3-dimensional environments namely, (1) within the tissue and (2) inside a lymph node. While the two environments are separated and perform their computations asynchronously, an abstract form of communication is allowed in order to replicate the exchange, transportation and interaction of immune system agents between these sites. The distribution of simulated processes, that can communicate across multiple, local CPUs or through a network of machines, provides a starting point to build decentralized systems that replicate larger scale processes within the human body, thus creating integrated simulations with other physiological systems, such as the circulatory, endocrine, or nervous system. Ultimately, this system integration across scales is our goal for the LINDSAY Virtual Human project. CONCLUSIONS: Our current immune system simulations extend our previous work on agent-based simulations by introducing advanced visualizations within the context of a virtual human anatomy model. We also demonstrate how to distribute a collection of connected simulations over a network of computers. As a future endeavour, we plan to use parameter tuning techniques on our model to further enhance its biological credibility. We consider these in silico experiments and their associated modeling and optimization techniques as essential components in further enhancing our capabilities of simulating a whole-body, decentralized immune system, to be used both for medical education and research as well as for virtual studies in immunoinformatics. PMID- 23734995 TI - The ORF slr0091 of Synechocystis sp. PCC6803 encodes a high-light induced aldehyde dehydrogenase converting apocarotenals and alkanals. AB - Oxidative cleavage of carotenoids and peroxidation of lipids lead to apocarotenals and aliphatic aldehydes called alkanals, which react with vitally important compounds, promoting cytotoxicity. Although many enzymes have been reported to deactivate alkanals by converting them into fatty acids, little is known about the mechanisms used to detoxify apocarotenals or the enzymes acting on them. Cyanobacteria and other photosynthetic organisms must cope with both classes of aldehydes. Here we report that the Synechocystis enzyme SynAlh1, encoded by the ORF slr0091, is an aldehyde dehydrogenase that mediates oxidation of both apocarotenals and alkanals into the corresponding acids. Using a crude lysate of SynAlh1-expressing Escherichia coli cells, we show that SynAlh1 converts a wide range of apocarotenals and alkanals, with a preference for apocarotenals with defined chain lengths. As suggested by in vitro incubations and using engineered retinal-forming E. coli cells, we found that retinal is not a substrate for SynAlh1, making involvement in Synechocystis retinoid metabolism unlikely. The transcript level of SynAlh1 is induced by high light and cold treatment, indicating a role in the stress response, and the corresponding gene is a constituent of a stress-related operon. The assumptions regarding the function of SynAlh are further supported by the surprisingly high homology to human and plant aldehyde dehydrogenase that have been assigned to aldehyde detoxification. SynAlh1 is the first aldehyde dehydrogenase that has been shown to form both apocarotenoic and fatty acids. This dual function suggests that its eukaryotic homologs may also be involved in apocarotenal metabolism, a function that has not been considered so far. PMID- 23734996 TI - Berberine ameliorates cold and mechanical allodynia in a rat model of diabetic neuropathy. AB - This study evaluated the antiallodynic properties of berberine on cold and mechanical allodynia after streptozotocin (STZ)-induced diabetes using a rat model. Diabetic neuropathy was induced in rats by intraperitoneal injection of STZ. To measure cold and mechanical allodynia, a 4 degrees C plate and von Frey filament were used, respectively. Cold and mechanical allodynia induced by diabetes were significantly decreased by single and repeated intraperitoneal treatment of amitriptyline at 10 mg/kg, and berberine at 10 and 20 mg/kg. The hepatic malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase activities were significantly increased in diabetic rats as compared with those in intact rats; however, in amitriptyline- and berberine-treated rats, they were significantly decreased as compared to the STZ control. The overall effects of berberine 20 mg/kg on cold and mechanical allodynia were quite similar to those of amitriptyline 10 mg/kg, and berberine exhibited similar antioxidant effects as the same dosage of amitriptyline. In conclusion, berberine (10 and 20 mg/kg) was observed to have antiallodynic effects against diabetes, which are presumed to be associated with antioxidative effects. It can be considered that the anti-inflammatory or antidepressant capacity of berberine could contribute to the antiallonynic effects shown in this study. PMID- 23734997 TI - Resolution of liver fibrosis by isoquinoline alkaloid berberine in CCl4 intoxicated mice is mediated by suppression of oxidative stress and upregulation of MMP-2 expression. AB - Liver fibrosis is the result of chronic liver injury, and it represents a widespread medical problem. The aim of this study is to investigate the antifibrotic activity of isoquinoline alkaloid berberine in carbon tetrachloride (CCl4)-induced damage in mice. Hepatic fibrosis was induced by intraperitoneal (i.p.) administration of CCl4 (2 mL/kg, 20% v/v in olive oil) twice a week for 8 weeks. Berberine at the doses of 3 and 9 mg/kg and silymarin at the dose of 50 mg/kg were given i.p. once daily for the next 2 weeks. CCl4 intoxication increased the levels of serum transaminases and induced oxidative stress in the liver. Hepatic fibrosis was evidenced by a massive deposition of collagen, which coincided with increased expression of tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1 and the activation of hepatic stellate cells. The high-dose berberine (9 mg/kg) ameliorated oxidative stress, decreased TNF-alpha and TGF-beta1 expression, increased the levels of matrix metalloproteinase (MMP)-2, and stimulated the elimination of fibrous deposits. Berberine at the dose of 9 mg/kg exhibited stronger therapeutic activity against hepatic fibrosis than silymarin at the dose of 50 mg/kg. In vitro analyses show an important scavenging activity of berberine against oxygen and nitrogen reactive species. The results of this study suggest that berberine could ameliorate liver fibrosis through the suppression of hepatic oxidative stress and fibrogenic potential, concomitantly stimulating the degradation of collagen deposits by MMP-2. PMID- 23734998 TI - Antidiabetic effect of the Chrysobalanus icaco L. aqueous extract in rats. AB - Chrysobalanus icaco L. is a medicinal plant popularly known in Brazil as "Grageru" or "Abageru." It is used in African and American continents as medicinal food in the treatment of several diseases, including diabetes. This study used phytochemical screening to determine the antioxidant and alpha-amylase inhibitor activities of the aqueous extract (AECI) of C. icaco, and evaluated its antidiabetic potential in rodents. Phytochemical screening was performed using colorimetric tests with specific reagents. The in vitro antioxidant activity was evaluated by the scavenging activity of 2,2-diphenyl-1-picril-hydrazyl. The lethality test and behavioral screening was performed using an oral administration of 5 g/kg of AECI. The antidiabetic potential of AECI was evaluated through the oral glucose tolerance test (OGTT) and chronic hypoglycemic test at the doses of 100, 200, and 400 mg/kg (orally). Metformin was used as a reference drug in all tests. Diabetes was induced by injection of alloxan (40 mg/kg; intravenously). Phytochemical screening showed the presence of various compounds, including tannins, flavones, triterpenoids, steroids, saponins, and alkaloids. The in vitro antioxidant test demonstrated that AECI presented potent antioxidant activity. The lethality test and behavioral screening did not show lethality signs. In the OGTT test, AECI administration was not able to inhibit the elevation of glycemia. However, chronically administrated, it was able to cause a significant (P<.05) reduction of glycemia from 335+/-27 up to 197+/-15 mg/dL. These results demonstrate that the AECI presents a potential beneficial effect for diabetes. PMID- 23734999 TI - Protective effect of beta-caryophyllene, a natural bicyclic sesquiterpene, against cerebral ischemic injury. AB - beta-Caryophyllene (trans-4,11,11-trimethyl-8-methylenebicyclo[7,2,0]undec-4 ene), found in various plants, is a natural bicyclic sesquiterpene with a low toxicity. Here, we show that a single intraperitoneal injection of beta caryophyllene (10 mg/kg) significantly reduced the cortical infarct volume by 67% when given immediately before middle cerebral artery occlusion (MCAO). Neurological deficits caused by MCAO were also significantly decreased by beta caryophyllene. beta-Caryophyllene treatment of cortical cells exposed to oxygen glucose deprivation revealed a significant protection in a dose-dependent manner. However, beta-caryophyllene neither suppressed N-methyl-D-aspartate excitotoxicity in cultured cortical cells nor markedly decreased the oxidative stress measured in the cellular or acellular systems. By contrast, treatments with beta-caryophyllene dose-dependently inhibited mRNA expression of inducible nitric oxide synthetase, interleukin (IL)-1beta, IL-6, and cyclooxygenase 2 in C6 microglial cells, and decreased the level of nitric oxide and prostaglandin E2 at a 100 MUM concentration. All of these findings suggest that beta-caryophyllene has a potent neuroprotective activity, and its neuroprotection may be partly related to the modulation of inflammatory mediators. PMID- 23735000 TI - Curcumin downregulates aquaporin-1 expression in cultured rat choroid plexus cells. AB - Aquaporin-1 (AQP1) is a water channel that is highly expressed on the apical side of the choroid plexus epithelium (CP) and thought to be one of the major pathways for the high water permeability of this structure. Blockade of AQP1 in the CP reduce the production of cerebrospinal fluid (CSF). Downregulation of AQP1 might be protective against some neurological disorders correlated with increased intracranial pressure and/or poor drainage of CSF. Curcumin, the major constituent of the rhizome of Curcuma longa, has been shown to inhibit potassium channels, Na+-K+ ATPase, as well as AQP3 in some cells. We therefore speculated that curcumin might be a useful tool to inhibit and/or decrease AQP1, and thus might be useful in the regulation of CSF production in pathophysiological conditions, including traumatic brain injury, hydrocephalus, stroke, systemic hyponatremia, acute cerebral edema, and hypertension. Choroidal epithelial cells of the lateral ventricle of Wistar rats were isolated and grown in in-vitro cultures for 24 h. Curcumin was then added to the medium at different concentrations, and the cell viability tested by the (3,4,5-dimethylthiazol-2-yl) 2-5-diphenyltetrazolium bromide assay. Additional wells of cells were tested for AQP1 protein expression using immunocytochemistry, immunoblotting, and flow cytometry. Our results showed that curcumin treatment decreases AQP1 expression in rat choroid epithelium cells in a dose-dependent manner. We conclude that curcumin may be a useful tool to regulate CSF production in pathophysiological conditions such as hydrocephalus, systemic hyponatremia, hypertension, and other neurological conditions. PMID- 23735001 TI - Antihypertensive effect of celery seed on rat blood pressure in chronic administration. AB - This study investigated the effects of different celery (Apium graveolens) seed extracts on blood pressure (BP) in normotensive and deoxycorticosterone acetate induced hypertensive rats. The hexanic, methanolic, and aqueous-ethanolic extracts were administered intraperitoneally and their effects on BP and heart rate (HR) were evaluated in comparison with spirnolactone as a diuretic and positive control. Also, the amount of n-butylphthalide (NBP), as an antihypertensive constituent, in each extract was determined by HPLC. The results indicated that all extracts decreased BP and increased the HR in hypertensive rats, but had no effect on normotensive rats. The data showed that administration of 300 mg/kg of hexanic, methanolic, and aqueous-ethanolic (20/80, v/v) extracts of the celery seed caused 38, 24, and 23 mmHg reduction in BP and 60, 25, and 27 beats per minute increase in the HR, respectively. Also, the HPLC analysis data revealed that the content of NBP in the hexanic extract was 3.7 and 4 times greater than methanolic and aqueous-ethanolic extracts. It can be concluded that celery seed extracts have antihypertensive properties, which appears to be attributable to the actions of its active hydrophobic constitutes such as NBP and can be considered as an antihypertensive agent in chronic treatment of elevated BP. PMID- 23735003 TI - A child with interstitial granulomatous dermatitis and juvenile idiopathic arthritis. AB - We describe a case of interstitial granulomatous dermatitis (IGD) with juvenile idiopathic arthritis (JIA) in an 11-year-old girl. She complained of erythematous plaques on her thighs and polyarthritis for 1 year. Histopathologic examination revealed the features of IGD. This case indicates that IGD with arthritis can occur in children and should be considered in the differential diagnosis of cutaneous lesions associated with arthritis in children. PMID- 23735002 TI - SAG2A protein from Toxoplasma gondii interacts with both innate and adaptive immune compartments of infected hosts. AB - BACKGROUND: Toxoplasma gondii is an intracellular parasite that causes relevant clinical disease in humans and animals. Several studies have been performed in order to understand the interactions between proteins of the parasite and host cells. SAG2A is a 22 kDa protein that is mainly found in the surface of tachyzoites. In the present work, our aim was to correlate the predicted three dimensional structure of this protein with the immune system of infected hosts. METHODS: To accomplish our goals, we performed in silico analysis of the amino acid sequence of SAG2A, correlating the predictions with in vitro stimulation of antigen presenting cells and serological assays. RESULTS: Structure modeling predicts that SAG2A protein possesses an unfolded C-terminal end, which varies its conformation within distinct strain types of T. gondii. This structure within the protein shelters a known B-cell immunodominant epitope, which presents low identity with its closest phyllogenetically related protein, an orthologue predicted in Neospora caninum. In agreement with the in silico observations, sera of known T. gondii infected mice and goats recognized recombinant SAG2A, whereas no serological cross-reactivity was observed with samples from N. caninum animals. Additionally, the C-terminal end of the protein was able to down modulate pro-inflammatory responses of activated macrophages and dendritic cells. CONCLUSIONS: Altogether, we demonstrate herein that recombinant SAG2A protein from T. gondii is immunologically relevant in the host-parasite interface and may be targeted in therapeutic and diagnostic procedures designed against the infection. PMID- 23735004 TI - Orlistat improves endothelial function in obese adolescents: a randomised trial. AB - AIM: To investigate the effect of orlistat on endothelial function in obese adolescents. METHODS: Single-blind 10-week controlled trial of 67 normolipidaemic obese adolescents randomised into three groups. Group 1 (diet alone), Group 2 (diet and orlistat), Group 3 (diet, orlistat and exercise). Endothelial function measured by flow-mediated dilatation (FMD) of the brachial artery, anthropometric parameters, blood pressure, fasting blood lipids, insulin and glucose levels were recorded at baseline and at 10 weeks. RESULTS: Sixty four subjects completed the study. Groups were comparable at baseline. FMD increased significantly with orlistat (Groups 2 and 3) but not in Group 1. Orlistat treatment resulted in significantly reduced bodyweight, body mass index (BMI), waist circumference, total and low-density lipoprotein (LDL) cholesterol levels. High-density lipoprotein cholesterol levels were unchanged. Triglyceride and insulin levels were significantly reduced in all three groups. The reduction in cholesterols did not correlate with reductions in weight and BMI. A slight reduction of body fat, both with and without orlistat treatment, correlated with reduction in BMI after adjustment for baseline values. Blood pressure was unaltered by orlistat. Calorie intake was reduced with orlistat, and the decrease noted in % fat and increase in % carbohydrate was significant only in those taking orlistat. The addition of exercise (Group 3 compared with Group 2) altered no parameter. CONCLUSIONS: Orlistat improves endothelial function and reduces bodyweight, BMI, fasting total and LDL-cholesterol in obese adolescents when combined with dietary control. Improvement in endothelial function if maintained could reflect long-term cardiovascular benefit. PMID- 23735005 TI - Diagnostic markers of urothelial cancer based on DNA methylation analysis. AB - BACKGROUND: Early detection and risk assessment are crucial for treating urothelial cancer (UC), which is characterized by a high recurrence rate, and necessitates frequent and invasive monitoring. We aimed to establish diagnostic markers for UC based on DNA methylation. METHODS: In this multi-center study, three independent sample sets were prepared. First, DNA methylation levels at CpG loci were measured in the training sets (tumor samples from 91 UC patients, corresponding normal-appearing tissue from these patients, and 12 normal tissues from age-matched bladder cancer-free patients) using the Illumina Golden Gate methylation assay to identify differentially methylated loci. Next, these methylated loci were validated by quantitative DNA methylation by pyrosequencing, using another cohort of tissue samples (Tissue validation set). Lastly, methylation of these markers was analyzed in the independent urine samples (Urine validation set). ROC analysis was performed to evaluate the diagnostic accuracy of these 12 selected markers. RESULTS: Of the 1303 CpG sites, 158 were hyper ethylated and 356 were hypo ethylated in tumor tissues compared to normal tissues. In the panel analysis, 12 loci showed remarkable alterations between tumor and normal samples, with 94.3% sensitivity and 97.8% specificity. Similarly, corresponding normal tissue could be distinguished from normal tissues with 76.0% sensitivity and 100% specificity. Furthermore, the diagnostic accuracy for UC of these markers determined in urine samples was high, with 100% sensitivity and 100% specificity. CONCLUSION: Based on these preliminary findings, diagnostic markers based on differential DNA methylation at specific loci can be useful for non-invasive and reliable detection of UC and epigenetic field defect. PMID- 23735006 TI - Constrained H-Phe-Phe-NH2 analogues with high affinity to the substance P 1-7 binding site and with improved metabolic stability and cell permeability. AB - We recently reported the discovery of H-Phe-Phe-NH2 as a small and high affinity ligand for the substance P 1-7 (SP(1-7), H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH) specific binding site and its intriguing ability to reduce neuropathic pain. With the overall aim to develop stable and orally bioavailable SP(1-7) mimetics, the dipeptide was chosen as a lead compound. Herein the structure-activity relationship (SAR) of a set of modified H-Phe-Phe-NH2 analogues is presented together with their potential active uptake by PEPT1 transporter, intestinal permeability, and metabolic stability. Local constraints via peptide backbone methylation or preparation of cyclized analogues based on pyrrolidine were evaluated and were shown to significantly improve the in vitro pharmacokinetic properties. The SAR was rationalized by deriving a plausible binding pose for the high affinity ligands. Rigidification using a 3-phenylpyrrolidine moiety in the C terminal of H-Phe-Phe-NH2 resulted in high affinity and improved intrinsic clearance and intestinal epithelial permeability. PMID- 23735007 TI - Will people change their vector-control practices in the presence of an imperfect dengue vaccine? AB - Human behaviours, which are influenced by social, cultural, economic and political factors, can increase or decrease the risk of dengue infection, depending on the relationship with the insect vector. Because no vaccine is currently available, the spread of dengue can only be curtailed by controlling vector populations (Aedes aegypti and others) and by protecting individuals. This study tested the hypothesis that dengue-affected populations are likely to relax their vector-control habits if a potentially protective vaccine becomes available. The hypothesis was tested using two approaches: a mathematical model designed to describe dengue transmission and an empirical field test in which the local population of an endemic area was interviewed about their vector-control habits given the presence of a theoretical vaccine. The model demonstrated that depending on the level of vector-control reduction, there is a threshold in vaccine efficacy below which it is better not to introduce the vaccine. The interview showed that people who were informed that a very effective vaccine is available would reduce their vector-control habits significantly compared to a group that was informed that the vaccine is not very effective. PMID- 23735008 TI - Commissioning healthcare for people with long term conditions: the persistence of relational contracting in England's NHS quasi-market. AB - BACKGROUND: Since 1991, there has been a series of reforms of the English National Health Service (NHS) entailing an increasing separation between the commissioners of services and a widening range of public and independent sector providers able to compete for contracts to provide services to NHS patients. We examine the extent to which local commissioners had adopted a market-oriented (transactional) model of commissioning of care for people with long term conditions several years into the latest period of market-oriented reform. The paper also considers the factors that may have inhibited or supported market oriented behaviour, including the presence of conditions conducive to a health care quasi-market. METHODS: We studied the commissioning of services for people with three long term conditions - diabetes, stroke and dementia - in three English primary care trust (PCT) areas over two years (2010-12). We took a broadly ethnographic approach to understanding the day-to-day practice of commissioning. Data were collected through interviews, observation of meetings and from documents. RESULTS: In contrast to a transactional, market-related approach organised around commissioner choice of provider and associated contracting, commissioning was largely relational, based on trust and collaboration with incumbent providers. There was limited sign of commissioners significantly challenging providers, changing providers, or decommissioning services.In none of the service areas were all the conditions for a well functioning quasi-market in health care in place. Choice of provider was generally absent or limited; information on demand and resource requirements was highly imperfect; motivations were complex; and transaction costs uncertain, but likely to be high. It was difficult to divide care into neat units for contracting purposes. As a result, it is scarcely surprising that commissioning practice in relation to all six commissioning developments was dominated by a relational approach. CONCLUSIONS: Our findings challenge the notion of a strict separation of commissioners and providers, and instead demonstrate the adaptive persistence of relational commissioning based on continuity of provision, trust and interdependence between commissioners and providers, at least for services for people with long-term conditions. PMID- 23735009 TI - How do liquid mixtures solubilize insoluble gelators? Self-assembly properties of pyrenyl-linker-glucono gelators in tetrahydrofuran-water mixtures. AB - The self-assembly behavior of a series of glucono-appended 1-pyrenesulfonyl derivatives containing alpha,omega-diaminoalkane spacers (Pn, where n, the number of methylene units separating the amino groups, is 2, 3, 4, 6, 7, and 8) in v:v tetrahydrofuran (THF):water mixtures is examined at room temperature. The Pn at 2 w/v % concentrations do not dissolve in either THF or water at room temperature. However, the Pn can be dissolved in some THF:water mixtures, and they form gels spontaneously in other compositions without dissolving completely. The self assembly of the Pn in the liquid mixtures has been investigated using a variety of techniques. The particle sizes of the Pn in their solutions/sols, critical gelation concentrations, microstructures, thermal and mechanical stabilities of the gels, and molecular packing modes of Pn molecules in their gel networks are found to be very dependent on the composition of the liquid mixtures. Correlations between the self-assembly behavior of the Pn and the polarity of the liquid mixtures, as probed by E(T)(30) and Hansen solubility parameters, yield both qualitative and quantitative insights into why self-assembly of the Pn can or cannot be achieved in different liquid compositions. As revealed by UV-vis and fluorescence spectroscopy studies, pi-pi stacking of the pyrenyl groups occurs as part of the aggregation process. Correlations between the rheological properties of the gels and the Hansen solubility parameters of the Pn and the solvent mixtures indicate that hydrogen-bonding interactions are a major contributor to the mechanical stability. Overall, the results of this study offer a new strategy to investigate the balance between dissolution and aggregation of molecular gelators. To the best of our knowledge, this is the first example of the spontaneous formation of molecular gels without heating by placing gelators in mixtures of liquids in which they are insoluble in the neat components. PMID- 23735010 TI - Effect of concentration on the photophysics of dyes in light-scattering materials. AB - Photoactive materials based on dye molecules incorporated into thin films or bulk solids are useful for applications as photosensitization, photocatalysis, solar cell sensitization and fluorescent labeling, among others. In most cases, high concentrations of dyes are desirable to maximize light absorption. Under these circumstances, the proximity of dye molecules leads to the formation of aggregates and statistical traps, which dissipate the excitation energy and lower the population of excited states. The search for enhancement of light collection, avoiding energy wasting requires accounting the photophysical parameters quantitatively, including the determination of quantum yields, complicated by the presence of light scattering when particulate materials are considered. In this work we summarize recent advances on the photophysics of dyes in light-scattering materials, with particular focus on the effect of dye concentration. We show how experimental reflectance, fluorescence and laser-induced optoacoustic spectroscopy data can be used together with theoretical models for the quantitative evaluation of inner filter effects, fluorescence and triplet formation quantum yields and energy transfer efficiencies. PMID- 23735011 TI - The effect of prenatal exposure of a non-steroidal anti-inflammatory drug on the optic nerve of female rats: a stereological, histological, and electron microscopic study. AB - OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) can have adverse effects for in both mother and fetus following administration during the prenatal period. If given during pregnancy, diclofenac sodium (DS), an NSAID, is given during the pregnancy, may also affect the development of the central nervous system (CNS) or related structures. METHODS: Pregnant rats were separated into pure control (PG), saline (SG) and diclofenac groups (DG). A daily dose of 1 mg/kg of DS and 1 mL/kg saline was injected intraperitoneally to the DG and SG groups, respectively, from the 5th gestation day for a 15 day of period; the PG group received no treatment. After spontaneous delivery, female offspring were obtained from all groups. After the 20th week of postnatal life, the animals (n = 6 for each group) were perfused and the right optic nerves were resected. Sections were subjected to stereological and histological analysis. RESULTS: There were no significant differences (p > 0.05) between PG, SG and DG groups with respect to myelin thickness, axonal cross-sectional area, axon numerical density, total section area of optic nerve and axon number. CONCLUSIONS: Histological and stereological results indicated that treatment with DS or saline produced undesirable effects on female rat optic nerve development and myelinization with respect to morphology. PMID- 23735012 TI - Self-perceived performance and satisfaction with performance of daily activities in persons with multiple sclerosis following interdisciplinary rehabilitation. AB - PURPOSE: To assess self-perceived performance and satisfaction with performance of daily activities in persons with multiple sclerosis (MS) on admission to and at discharge from interdisciplinary rehabilitation. METHOD: A retrospective study with a pre-post design. Twenty-seven women and 16 men with MS (mean age 51 years; median EDSS 6.5) participated in an individualised, goal-oriented, interdisciplinary, rehabilitation programme (average length 4 weeks). The Canadian Occupational Performance Measure (COPM) was used on admission to rehabilitation and at discharge. RESULTS: On admission, the persons prioritised 216 activities that they perceived difficult to perform (mean number 3, range 2 8). Of these, 136 (63%) were in the COPM area of self-care, 52 (24%) in productivity and 28 (13%) in leisure. The lowest mean ratings of performance were found in the subgroups active recreation, community management and socialisation, and for satisfaction in the subgroup socialisation. For about 60% of the 216 prioritised activities, ratings of COPM performance as well as satisfaction were higher at discharge than on admission. For 18 (42%) and 24 (56%) persons, respectively, the mean change scores of performance and of satisfaction were equal to or greater than 2.0 at discharge, indicating a clinically significant change. CONCLUSIONS: Persons with MS can experience problems with all types of daily activities upon admission to rehabilitation, but also perceive improvements in their performance and satisfaction with performance in these activities at discharge from rehabilitation. Using patient-reported outcome measures, such as the COPM, may contribute to a broader understanding of the benefits of interdisciplinary rehabilitation in persons with MS. Implications for Rehabilitation Persons with MS can perceive problems with all types of daily activities which have to be considered during interdisciplinary rehabilitation. Following interdisciplinary rehabilitation, persons with MS can perceive improvements in their performance and satisfaction with performance in all types of daily activities. Patient-reported outcome measures can contribute to a broader understanding of the benefits of interdisciplinary rehabilitation in persons with MS. PMID- 23735013 TI - Use of an online survey to explore positive and negative outcomes of rehabilitation for people with CFS/ME. AB - PURPOSE: First, to explore the experiences of people with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME) of rehabilitation therapies so as to build an understanding of reasons for the discrepancy between the notably mixed experiences regarding effectiveness reported in patient surveys and the RCT evidence about the efficacy of Graded Exercise Therapy (GET). GET is a form of structured and supervised activity management that aims for gradual but progressive increases in physical activity. Second, to review patient experiences of two related rehabilitation approaches, Exercise on Prescription (EoP) and Graded Activity Therapy (GAT). METHOD: An online survey conducted by the charity Action for ME generated qualitative data about 76 patient experiences of rehabilitation undertaken during or after 2008, examined using thematic analysis. RESULTS: Both positive and negative experiences of rehabilitation were reported. Positive themes included supportive communication, the benefits of a routine linked with baseline setting and pacing, the value of goal setting, and increasing confidence associated with exercise. Negative themes included poor communication, feeling pushed to exercise beyond a sustainable level, having no setback plan, and patients feeling blamed for rehabilitation not working. CONCLUSIONS: The negative themes may help explain the negative outcomes from rehabilitation reported by previous patient surveys. The negative themes indicate rehabilitation processes which contradict the NICE (National Institute for Health and Clinical Excellence) Guideline advice regarding GET, indicating that some clinical encounters were not implementing these. These findings suggest areas for improving therapist training, and for developing quality criteria for rehabilitation in CFS/ME. Implications for Rehabilitation The insensitive delivery of rehabilitation support for people with CFS/ME can explain negative outcomes reported in patient surveys. Therapist-patient collaboration, establishing a sustainable baseline and agreeing a setback plan are all examples of higher quality rehabilitation indicated by this research. Greater awareness of the positive and negative experiences of rehabilitation therapies should enable avoidance of the potential pitfalls identified in this research. Positive experiences of rehabilitation therapies include supportive communication with a therapist, treatment which included routines and goals, and value attached to baselines and controlled pacing. By contrast, factors leading to negative experiences include poor communication and support, conflict in beliefs about CFS/ME and rehabilitation, pressure to comply with treatment, worsening of symptoms, baselines experienced as unsustainable, and feeling blamed for rehabilitation not working. PMID- 23735014 TI - Meta-analysis of variables affecting mouse protection efficacy of whole organism Brucella vaccines and vaccine candidates. AB - BACKGROUND: Vaccine protection investigation includes three processes: vaccination, pathogen challenge, and vaccine protection efficacy assessment. Many variables can affect the results of vaccine protection. Brucella, a genus of facultative intracellular bacteria, is the etiologic agent of brucellosis in humans and multiple animal species. Extensive research has been conducted in developing effective live attenuated Brucella vaccines. We hypothesized that some variables play a more important role than others in determining vaccine protective efficacy. Using Brucella vaccines and vaccine candidates as study models, this hypothesis was tested by meta-analysis of Brucella vaccine studies reported in the literature. RESULTS: Nineteen variables related to vaccine induced protection of mice against infection with virulent brucellae were selected based on modeling investigation of the vaccine protection processes. The variable "vaccine protection efficacy" was set as a dependent variable while the other eighteen were set as independent variables. Discrete or continuous values were collected from papers for each variable of each data set. In total, 401 experimental groups were manually annotated from 74 peer-reviewed publications containing mouse protection data for live attenuated Brucella vaccines or vaccine candidates. Our ANOVA analysis indicated that nine variables contributed significantly (P-value < 0.05) to Brucella vaccine protection efficacy: vaccine strain, vaccination host (mouse) strain, vaccination dose, vaccination route, challenge pathogen strain, challenge route, challenge-killing interval, colony forming units (CFUs) in mouse spleen, and CFU reduction compared to control group. The other 10 variables (e.g., mouse age, vaccination-challenge interval, and challenge dose) were not found to be statistically significant (P-value > 0.05). The protection level of RB51 was sacrificed when the values of several variables (e.g., vaccination route, vaccine viability, and challenge pathogen strain) change. It is suggestive that it is difficult to protect against aerosol challenge. Somewhat counter-intuitively, our results indicate that intraperitoneal and subcutaneous vaccinations are much more effective to protect against aerosol Brucella challenge than intranasal vaccination. CONCLUSIONS: Literature meta-analysis identified variables that significantly contribute to Brucella vaccine protection efficacy. The results obtained provide critical information for rational vaccine study design. Literature meta-analysis is generic and can be applied to analyze variables critical for vaccine protection against other infectious diseases. PMID- 23735016 TI - Exercise training upregulates nitric oxide synthases in the kidney of rats with chronic heart failure. AB - There is an interaction between heart and kidney diseases, which is a condition termed cardiorenal syndrome. Exercise training has cardioprotective effects, involving upregulation of endothelial (e) nitric oxide synthase (NOS) in the cardiovascular system. However, the effects of exercise training on NOS in the kidney with heart disease are unknown. The aim of the present study was to investigate whether exercise training upregulates NOS in the kidney, left ventricle and aorta of rats with chronic heart failure (CHF). Male Sprague-Dawley rats underwent left coronary artery ligation (LCAL) to induce CHF and were randomly assigned to sedentary or treadmill exercise groups 4 weeks after LCAL. Three days after exercising for 4 weeks, urine samples were collected for 24 h and blood samples were collected following decapitation. Nitric oxide synthase activity and protein expression were examined. Significant interactions between CHF and exercise training were observed on parameters of cardiac and renal function. Exercise training improved cardiac function, decreased plasma B-type natriuretic peptide levels, decreased urinary albumin excretion and increased creatinine clearance in CHF rats. Nitric oxide synthase activity, eNOS expression and neuronal (n) NOS expression were significantly decreased in the left ventricle and kidney of CHF rats. Exercise training significantly increased NOS activity and eNOS and nNOS expression. Upregulation of NOS in the kidney and left ventricle may contribute, in part, to the renal and cardiac protective effects of exercise training in cardiorenal syndrome in CHF rats. PMID- 23735017 TI - Rationalizing the use of PPIs: an unresolved matter. PMID- 23735015 TI - Distinct roles of KAP1, HP1 and G9a/GLP in silencing of the two-cell-specific retrotransposon MERVL in mouse ES cells. AB - BACKGROUND: In mouse embryonic stem cells (mESCs), transcriptional silencing of numerous class I and II endogenous retroviruses (ERVs), including IAP, ETn and MMERVK10C, is dependent upon the H3K9 methyltransferase (KMTase) SETDB1/ESET and its binding partner KAP1/TRIM28. In contrast, the H3K9 KMTases G9a and GLP and HP1 proteins are dispensable for this process. Intriguingly, MERVL retroelements are actively transcribed exclusively in the two-cell (2C) embryo, but the molecular basis of silencing of these class III ERVs at later developmental stages has not been systematically addressed. RESULTS: Here, we characterized the roles of these chromatin factors in MERVL silencing in mESCs. While MMERVK10C and IAP ERVs are bound by SETDB1 and KAP1 and are induced following their deletion, MERVL ERVs show relatively low levels of SETDB1 and KAP1 binding and are upregulated exclusively following KAP1 depletion, indicating that KAP1 influences MERVL expression independent of SETDB1. In contrast to class I and class II ERVs, MERVL and MERVL LTR-driven genic transcripts are also upregulated following depletion of G9a or GLP, and G9a binds directly to these ERVs. Consistent with a direct role for H3K9me2 in MERVL repression, these elements are highly enriched for G9a-dependent H3K9me2, and catalytically active G9a is required for silencing of MERVL LTR-driven transcripts. MERVL is also derepressed in HP1alpha and HP1beta KO ESCs. However, like KAP1, HP1alpha and HP1beta are only modestly enriched at MERVL relative to IAP LTRs. Intriguingly, as recently shown for KAP1, RYBP, LSD1 and G9a-deficient mESCs, many genes normally expressed in the 2C embryo are also induced in HP1 KO mESCs, revealing that aberrant expression of a subset of 2C-specific genes is a common feature in each of these KO lines. CONCLUSIONS: Our results indicate that G9a and GLP, which are not required for silencing of class I and II ERVs, are recruited to MERVL elements and play a direct role in silencing of these class III ERVs, dependent upon G9a catalytic activity. In contrast, induction of MERVL expression in KAP1, HP1alpha and HP1beta KO ESCs may occur predominantly as a consequence of indirect effects, in association with activation of a subset of 2C-specific genes. PMID- 23735018 TI - Laparoscopic common bile duct exploration and antegrade biliary stenting: leaving behind the Kehr tube. AB - INTRODUCTION: single-stage laparoscopic surgery of cholelithiasis and associated common bile duct stones (CL-CBDS) has shown similar results when compared to laparoscopic cholecystectomy combined with ERCP. Classically, choledochorrhaphy has been protected by a T-tube drain to allow external bypass of bile flow. However, its removal is associated with a significant complication rate. Use of antegrade biliary stents avoids T-tube removal associated morbidity. The aim of this study is to compare the results of choledochorrhaphy plus T-tube drainage versus antegrade biliary stenting in our series of laparoscopic common bile duct explorations (LCBDE). MATERIAL AND METHODS: between 2004 and 2011, 75 patients underwent a LCBDE. Choledochorrhaphy was performed followingKehr tube placements in 47 cases and transpapillary biliary stentingwas conducted in the remaining 28 patients. RESULTS: postoperative hospital stay was shorter in the stent group (5 +/- 10.26 days) than in the Kehr group (12 +/- 10.6 days), with a statistically significant difference. There was a greater trend to grade B complications in the stent group (10.7 vs. 4.3 %) and to grade C complications in the Kehr group (6.4 vs. 3.6 %). Therewere 3 cases of residual common bile duct stones in the Kehr group (6.4 %) and none in the stent group. CONCLUSIONS: antegrade biliary stenting following laparoscopic common bile duct exploration for CL-CBDS is an effective and safe technique that prevents T-tube related morbidity. PMID- 23735019 TI - Inadequate prescription of chronic consumption of proton pump inhibitors in a hospital in Mexico. Cross-sectional study. AB - INTRODUCTION: PPIs have been an enormous therapeutic advance in acid-related diseases. However, it has been detected an abuse in its consumption. The aim of this study was to determine the frequency of inadequate prescription of chronic use of PPIs in outpatients in a speciality hospital. MATERIAL AND METHODS: we performed a cross-sectional descriptive study review. The study population were patients, chronic users of proton pump inhibitors (PPIs), attending outpatient consult in a hospital of government workers. We defined as chronic user of PPIs that patient that takes medication daily for over a year and inappropriate prescription, that one that has not been approved by the clinical guidelines. A simple random sampling was utilized. The following parameters were investigated: diagnosis and prescription of PPIs, time of use, at which level of care PPIs were prescribed (primary care or specialist), self-medication, with or without endoscopy. Forthe statistical analysis, we used Student's t-test and Chi-square, 95 % confidence intervals and significance 0.05 %. RESULTS: we reviewed 153 patients, 40 (26.1 %) men and 113 (73.9 %) women, mean age 58 +/- 11.4 years. The prescription of chronic treatment with PPIs was adequate in 64.7 % of patients and inadequate in 35.3 %. The most common appropriate prescription (31.3 %) of chronic use of PPIs was due to gastroesophageal reflux disease. The most common inadequate prescription was absence of diagnosis (22.2 %), polypharmacy without nonsteroidal anti-inflammatory drugs (16.6 %) and chronic gastritis (16.6 %). History of endoscopy were not statistically significant. CONCLUSIONS: the frequency of inappropriate prescriptions of chronic use of PPIs was high, around 35.3 %, similar to those reported in hospitals in developed countries. PMID- 23735020 TI - Preparation of a three-dimensional extracellular matrix by decellularization of rabbit livers. AB - INTRODUCTION: the availability of transplantable livers is not sufficient to fulfill the current demand for grafts, with the search for therapeutic alternatives having generated different lines of research, one of which is the use of decellularized three-dimensional biological matrices and subsequent cell seeding to obtain a functional organ. OBJECTIVE: to produce a decellularization protocol from rabbit liver to generate a three-dimensional matrix. METHODS: a combination of physical, chemical (Triton X-100 and SDS) and enzymatic agents to decellularize rabbit livers was used. After 68 h of retrograde perfusion, a decellularized translucent matrix was generated. To evaluate if the decellularization protocol was successful, with the extracellular matrix being preserved, we carried out histological (light microscopy and scanning electron microscopy) and biochemical (DNA quantification) studies. RESULTS: the decellularization process was verified by macroscopic observation of the organ using macroscopic staining, which revealed a correct conservation of bile and vascular trees. A microscopic observation corroborated these macroscopic results, with the hematoxylin-eosin staining showing no cells or nuclear material and the presence of a portal triad. Wilde's staining demonstrated the conservationof reticulin fibers in the decellularized matrix. In addition, scanning electron microscopy revealed a preserved Glisson's capsule and a decellularized matrix, with the DNA quantification being less than 10 % in the decellularized liver compared to control. Finally, the time taken to develop the decellularization protocol was less than 96 hours. CONCLUSIONS: the proposed decellularization protocol was correct, and was verified by an absence of cells. The hepatic matrix had preserved vascular and bile ducts with a suitable three-dimensional architecture permitting further cell seeding. PMID- 23735022 TI - Bone mineral density in adult coeliac disease: an updated review. AB - INTRODUCTION AND OBJECTIVES: coeliac disease (CD) affects around 1-2 % of the world population. Most patients are now diagnosed when adults, suffering the consequences of an impaired bone mineralization. This review aims to provide an updated discussion on the relationship between low bone mineral density (BMD), osteopenia and osteoporosis, and CD. METHODS: a PubMed search restricted to the last 15 years was conducted. Sources cited in the results were also reviewed to identify potential sources of information. RESULTS: low BMD affects up to 75 % of celiac patients, and can be found at any age, independently of positive serological markers and presence of digestive symptoms. The prevalence of CD among osteoporotic patients is also significantly increased. Two theories try to explain this origin of low BMD: Micronutrients malabsorption (including calcium and vitamin D) determined by villous atrophy has been related to secondary hyperparathyroidism and incapacity to achieve the potential bone mass peak; chronic inflammation was also related with RANKL secretion, osteoclasts activation and increased bone resorption. As a consequence, celiac patients have a risk for bone fractures that exceed 40 % that of matched non-affected population. Treatment of low BMD in CD comprises gluten-free diet, calcium and vitamin D supplementation, and biphosphonates, although its effects on CD have not been specifically assessed. CONCLUSIONS: up to 75 % of celiac patients and 40 % of that diagnosed in adulthood present a low BMD and a variable increase in the risk of bone fractures. Epidemiological changes in CD make bone density scans more relevant for adult coeliacs. PMID- 23735021 TI - Questionnaries for measuring fatigue and its impact on health perception in inflammatory bowel disease. AB - INTRODUCTION: fatigue impacts perceived health, but its importance in inflammatory bowel disease is not known. OBJECTIVES: to define the applicability of the fatigue measurement questionnaires and analyze it in patients with Crohn's disease and ulcerative colitis. MATERIAL AND METHODS: in a first phase, the psychometric properties of 3 fatigue measurement questionnaires were determined in 99 patients: Daily Fatigue Impact Scale, Fatigue Severity Scale, and Modified Fatigue Impact Scale. In a second phase, fatigue status and its relationship to disease and quality of life was determined in 127 patients and 69 healthy controls. RESULTS: the first part of the study showed the applicability of the questionnaires listed in inflammatory bowel disease, the Daily Fatigue Impact Scale (DFIS) having the best correlation with the quality of life and clinical activity. In the second phase, significantly higher levels of fatigue were observed in active disease than in disease in remission and healthy controls (p < 0,05). The severity of fatigue was significantly correlated with quality of life (r = -0.66 and -0.72 between IBDQ-9 and DFIS and in Crohn's disease and ulcerative colitis, respectively) and with disease activity (r = 0.25 and Crohn's disease and ulcerative colitis, respectively, p < 0.05). CONCLUSIONS: in inflammatory bowel disease, fatigue measurement questionnaires have good properties and show that fatigue is an important manifestation of the disease, which has a significant impact on quality of life of patients. PMID- 23735023 TI - Double endosonography-guided transgastric and transduodenal drainage of infected pancreatic-fluid collections using metallic stents. PMID- 23735024 TI - Gastric plasmablastic lymphoma in HIV-negative patient. PMID- 23735025 TI - Treatment with adalimumab in a patient with regenerative nodular hyperplasia secondary to azathioprine. AB - INTRODUCTION: regenerative nodular hyperplasia (RNH) is a rare liver disease with an etiology that is not well understood. Among the etiological factors are purine analogue drugs such asazathioprine. CASE REPORT: we present a case of a 47-year old patient diagnosed with Crohn's disease in treatment with azathioprine due to corticosteroid dependency who developed RNH with clinical and laboratory signs of portal hypertension one year after starting treatment. After discontinuation of azathioprine, the patient started treatment and, given the poor disease progression, started treatment with adalimumab. This was continued with an excellent response and without deleterious effects on the liver. DISCUSSION: the relevance of this case is twofold: First, this is a rare and early side effect of azathioprine treatment and this is an irreversible disease with potentially serious complications. Second, because treatment was carried out with biological drugs (adalimumab) despite the patient having advance liver disease with portal hypertension without any evidence of it worsening, nor signs of deleterious effects or complications, given that there is scarce or no experience with adalimumab treatment in this type of situation. PMID- 23735026 TI - Collagenous sprue: don't forget connective tissue in chronic diarrhea evaluation. AB - Collagenous sprue is a rare disease of the small bowel characterized by mucosal atrophy and excessive subepithelial collagen deposition. The etiology remains unclear and the diagnosis is based upon patient's clinical picture and anatomopathological findings. Clinically, collagenous sprue is characterized by persistent diarrhoea, severe malabsorption, multiple nutrient deficiencies and progressive weight loss. Differential diagnosis includes celiac disease, which is mandatory to rule out because of their frequent association. Glutenfree diet is the first therapeutic step, but it usually is not effective. However, recent studies show high success rates with immunomodulators, mainly corticosteroids. We report the case of a patient presenting with chronic diarrhea and severe malabsorption who was diagnosed with collagenous sprue, with no response to gluten free diet, but with excellent response to budesonida. PMID- 23735027 TI - [Ogilvie syndrome]. PMID- 23735028 TI - Solid pseudopapillary neoplasm of the pancreas or Frantz's tumour: report of two cases with different locations. PMID- 23735029 TI - Right-sided paraduodenal hernia: rare cause of recurrent abdominal pain. PMID- 23735030 TI - Sigmoid volvulus as a presentation of neuronal intestinal dysplasia type B in an adolescent. PMID- 23735031 TI - A rare case of collision tumor combined with multiple primary squamous carcinomas. PMID- 23735032 TI - Severe rhabdomyolysis and hyponatremia induced by picosulfate and bisacodyl during the preparation of colonoscopy. PMID- 23735033 TI - Intended follow up of women with breast cancer at low risk of recurrence and at least 5 years from diagnosis. AB - BACKGROUND: Although there is evidence that minimal surveillance is compatible with an optimal outcome in women after early stage breast cancer, little is known of the surveillance that these women receive. AIMS: To describe the intended clinical follow up and patterns of use of imaging modalities in low-risk breast cancer survivors who are at least 5 years from diagnosis. METHODS: Participants in the Bupa Health Foundation Health and Wellbeing After Breast Cancer Study with stage 1 invasive breast cancer at diagnosis, who had survived free of recurrence or new primary breast cancer for at least 5 years, provided information for this analysis. RESULTS: The most common choice of physician follow up was with one doctor only (54%). Within this group, the most frequent choice was a general practitioner (GP) (63%) followed by medical oncologist (23%). Thirty-five per cent of women said that they intended to consult two doctors and within this group, the most common combination was a GP and a medical oncologist (45%). This was despite two out of three women reporting being advised that there was no need to consult a medical oncologist. Over 90% of women reported having a mammogram with, or without, breast ultrasound in the previous 12 months. There was a low rate of use of other imaging tests in the absence of clear indications. CONCLUSIONS: Minimising unnecessary medical consultations by women with breast cancer at low risk of recurrence 5 years from diagnosis will require education about the benefits of a minimal surveillance strategy. PMID- 23735034 TI - Infections in pediatric acute promyelocytic leukemia: from the Canadian infections in acute myeloid leukemia research group. AB - BACKGROUND: It is not known whether children with acute promyelocytic leukemia (APL) have an infection risk similar to non- APL acute myeloid leukemia. The objective was to describe infectious risk in children with newly diagnosed APL and to describe factors associated with these infections. METHODS: We conducted a retrospective, population-based cohort study that included children <= 18 years of age with de novo APL treated at 15 Canadian centers. Thirty-three children with APL were included; 78.8% were treated with APL -specific protocols. RESULTS: Bacterial sterile site infection occurred in 12 (36.4%) and fungal sterile site infection occurred in 2 (6.1%) children. Of the 127 chemotherapy courses, 101 (79.5%) were classified as intensive and among these, the proportion in which a sterile site microbiologically documented infection occurred was 14/101 (13.9%). There was one infection-related death. CONCLUSIONS: One third of children with APL experienced at least one sterile site bacterial infection throughout treatment and 14% of intensive chemotherapy courses were associated with a microbiologically documented sterile site infection. Infection rates in pediatric APL may be lower compared to non- APL acute myeloid leukemia although these children may still benefit from aggressive supportive care during intensive chemotherapy. PMID- 23735035 TI - Hydrophosphinylation of unactivated terminal alkenes catalyzed by nickel chloride. AB - The room-temperature hydrophosphinylation of unactivated monosubstituted alkenes using phosphinates (ROP(O)H2) and catalytic NiCl2 in the presence of dppe is described. The method is competitive with prior palladium-catalyzed reactions and uses a much cheaper catalyst and simple conditions. The scope of the reaction is quite broad in terms of unactivated terminal olefins, proceeds at room temperature, often avoids chromatographic purification, and allows one-pot conversion to various organophosphorus compounds. PMID- 23735037 TI - The interpersonal core of personality pathology. AB - The purpose of this article is to demonstrate that personality pathology is, at its core, fundamentally interpersonal. The authors review the proposed DSM-5 Section 3 redefinition of personality pathology involving self and interpersonal dysfunction, which they regard as a substantial improvement over the DSM-IV (and Section 2) definition. They note similarities between the proposed scheme and contemporary interpersonal theory and interpret the Section 3 definition using the underlying assumptions and evidence base of the interpersonal paradigm in clinical psychology. The authors describe how grounding the proposed Section 3 definition in interpersonal theory, and in particular a focus on the "interpersonal situation," adds to its theoretical texture, empirical support, and clinical utility. They provide a clinical example that demonstrates the ability of contemporary interpersonal theory to augment the definition of personality pathology. The authors conclude with directions for further research that could clarify the core of personality pathology, and how interpersonal theory can inform research aimed at enhancing the Section 3 proposal and ultimately justify its migration to Section 2. PMID- 23735038 TI - Combining interpersonal and intrapersonal perspectives on personality pathology: a commentary on Hopwood et al. PMID- 23735039 TI - The search for critical dimensions of personality pathology to inform diagnostic assessment and treatment planning: a commentary on Hopwood et al. PMID- 23735040 TI - An ecumenical approach to conceptualizing and studying the core of personality psychopathology: a commentary on Hopwood et al. PMID- 23735041 TI - Levels of personality functioning and their association with clinical features and interpersonal functioning in patients with personality disorders. AB - Recently, the DSM-5 Personality and Personality Disorders Work Group has proposed a multiple level approach toward the classification and diagnosis of personality disorders (PDs), with the first level entailing a rating of impairments in levels of personality functioning. Although a number of measures that assess levels of personality functioning have been validated, given its prominent status in the DSM-5 proposal and contemporary theories of personality pathology, the Work Group has called for more research in this area (e.g., Bender, Morey, & Skodol, 2011). In response to this call, this study investigates the relationship between two major, well-validated dimensional measures of levels of personality functioning, that is, the Differentiation-Relatedness Scale (DR-S; Diamond, Blatt, Stayner, & Kaslow, 1991), as scored on the Object Relations Inventory (ORI; Blatt, Wein, Chevron, & Quinlan, 1979), and the Inventory of Personality Organization (IPO; Lenzenweger, Clarkin, Kernberg, & Foelsch, 2001), a self-report instrument, and their relationship with different measures of clinical and interpersonal functioning in 70 patients with a PD. First, results showed that higher levels of differentiation and relatedness of descriptions of self and significant others, and of the self in particular, were negatively related to indices of personality functioning as assessed by the IPO. Lower levels of personality functioning, as measured with both the DR-S and the IPO, were positively related to severity of depression, symptomatic distress, self-harm, and interpersonal problems. Finally, results showed that the DR-S and the IPO independently predicted clinical features and interpersonal functioning. Hence, this study lends further support for the concurrent and predictive validity of the DR-S and the IPO in assessing levels of personality functioning. However, more research concerning the validity of these measures in assessing levels of personality functioning is needed. Suggestions for further research are formulated. PMID- 23735043 TI - Effect of primary language on developmental testing in children born extremely preterm. AB - AIM: The aim of this study was to better understand the impact of non-English language spoken in the home on measures of cognition, language and behaviour in toddlers born extremely preterm. METHODS: Eight hundred and fifty children born at <28 weeks of gestational ages were studied. 427 male and 423 female participants from three racial/ethnic groups (White, Black and Hispanic) were evaluated at 18-22 months adjusted for age using the Bayley Scales of Infant Development third edition and the Brief Infant Toddler Social Emotional Assessment (BITSEA). Children whose primary language was Spanish (n = 98) were compared with children whose primary language was English (n = 752), using multivariable regression adjusted for medical and psychosocial factors. RESULTS: Cognitive scores were similar between groups; however, receptive, expressive and composite language scores were lower for children whose primary language was Spanish. These differences remained significant after adjustment for medical and socio-economic factors. Spanish-speaking children scored worse on the BITSEA competence and problem scores using univariate analysis, but not after adjustment for medical and socio-economic factors. CONCLUSION: Our finding that preterm children whose primary language was Spanish had similar cognitive but lower language scores than those whose primary language was English suggests that using English language-based testing tools may introduce bias against non-English speaking children born preterm. PMID- 23735045 TI - Challenges and opportunities for faecal microbiota transplantation therapy. AB - The incidence, morbidity, and mortality associated with Clostridium difficile gastrointestinal infections has increased greatly over recent years, reaching epidemic proportions; a trend due, in part, to the emergence of hypervirulent and antibiotic-resistant strains. The need to identify alternative, non-antibiotic, treatment strategies is therefore urgent. The ability of bacteria in faecal matter transplanted from healthy individuals to displace pathogen populations is well recognized. Further, there is growing evidence that such faecal microbiota transplantation can be of benefit in a wide range of conditions associated with gut dysbiosis. Recent technical advances have greatly increased our ability to understand the processes that underpin the beneficial changes in bacterial community composition, as well as to characterize their extent and duration. However, while much of the research into faecal microbiota transplantation focuses currently on achieving clinical efficacy, the potential for such therapies to contribute to the transmission of infective agents also requires careful consideration. PMID- 23735044 TI - A genetically encoded acrylamide functionality. AB - Nepsilon-Acryloyl-l-lysine, a noncanonical amino acid with an electron deficient olefin, is genetically encoded in Escherichia coli using a pyrrolysyl-tRNA synthetase mutant in coordination with tRNACUAPyl. The acrylamide moiety is stable in cells, whereas it is active enough to perform a diverse set of unique reactions for protein modifications in vitro. These reactions include 1,4 addition, radical polymerization, and 1,3-dipolar cycloaddition. We demonstrate that a protein incorporated with Nepsilon-acryloyl-l-lysine is efficiently modified with thiol-containing nucleophiles at slightly alkali conditions, and the acrylamide moiety also allows rapid radical copolymerization of the same protein into a polyacrylamide hydrogel at physiological pH. At physiological conditions, the acrylamide functionality undergoes a fast 1,3-dipolar cycloaddition reaction with diaryl nitrile imine to show turn-on fluorescence. We have used this observation to demonstrate site-specific fluorescent labeling of proteins incorporated with Nepsilon-acryloyl-l-lysine both in vitro and in living cells. This critical development allows easy access to an array of modified proteins for applications where high specificity and reaction efficiency are needed. PMID- 23735046 TI - Idiopathic pulmonary fibrosis in 2011: key updates on guidelines and therapeutics. Concluding remarks. PMID- 23735047 TI - Diabetes in young people in the Top End of the Northern Territory. AB - AIM: There is an increasing prevalence and burden of diabetes in young people, particularly Indigenous Australians. There have been no previous reports of the prevalence or burden of diabetes in young people in the Top End of the Northern Territory, a region of many risk factors for diabetes. METHODS: This is a retrospective study of cases of diabetes in children and adults aged less than 25 years who were seen at Royal Darwin Hospital as inpatients or outpatients between 2007 and 2011. RESULTS: From a population base of approximately 75 000 young people living north of Tenant Creek, there were 70 young people with type 1 diabetes (12 Aboriginal and/or Torres Strait Islander Australians) and 37 young people with type 2 diabetes (31 Aboriginal or Torres Strait Islander Australians). The median body mass index of those with type 2 diabetes was 28 kg/m(2) , and only 29% had a body mass index >30 kg/m(2) . Overall, glycaemic control was poor. CONCLUSIONS: Rates of diabetes in young people in the Top End appear high. Case ascertainment and data collection were difficult for this study, highlighting the need for better database and systems for diabetes management. PMID- 23735048 TI - Discovery of Dap-3 polymyxin analogues for the treatment of multidrug-resistant Gram-negative nosocomial infections. AB - We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages. PMID- 23735049 TI - Measuring the spatial distribution of dielectric constants in polymers through quasi-single molecule microscopy. AB - The variation in dielectric constant is measured for thin films of poly(methyl methacrylate) (PMMA) and poly(vinylidene fluoride) (PVDF) using confocal fluorescence microscopy. Spatial variation in the local dielectric constant of the polymer films on the ~250 nm length scale is measured using the solvochromatic emission from incorporated nile red (NR) at "quasi-single molecule" (10(-7) M) and true single molecule (SM) concentrations (10(-9) M). Correlation of the NR fluorescence wavelength maximum with dielectric constant is used to transform images of NR's emission maxima to spatial variation in local dielectric constant. We demonstrate that the distributions of dielectric environments measured in the quasi- and true SM approaches are equivalent; however, the enhanced signal rates present in the quasi-SM approach result in this technique being more efficient. In addition, the quasi-SM technique reports directly on the continuous spatial variation in dielectric constant, information that is difficult to obtain in true SM studies. With regards to the polymers of interest, the results presented here demonstrate that a limited distribution of dielectric environments is present in PMMA; however, a broad distribution of environments exists in PVDF consistent with this polymer existing as a distribution of structural phases. PMID- 23735050 TI - Lying low but ready for action: the quiescent muscle satellite cell. AB - The muscle satellite cell is essential for skeletal muscle regeneration. It is located on the muscle fibre, under the basal lamina as a quiescent cell, which becomes activated after injury, when it leaves the fibre, proliferates, and either undergoes myogenesis to form new fibres or reconstitutes the satellite cell pool. In this review, we discuss the cellular environment of the quiescent cell, including the extracellular matrix, which constitutes its niche. Cell adhesion molecules and some signalling pathways reinforce its quiescent state, whereas other signals lead to activation. We discuss how the satellite cell is ready to respond with the appropriate receptors, but protects its quiescence by mechanisms that include immobilization of ligands by extracellular matrix components and synthesis of inhibitors for intracellular signalling pathways and for metalloproteinases that break down the matrix and promote ligand processing and receptor activation. The quiescent satellite cell is also well protected against toxins and oxidative stress. It has a low metabolic rate, as shown by few active mitochondria and anaerobic glycolysis. Different subpopulations of quiescent satellite cells can be distinguished on the basis of cell surface markers and stem cell-like properties. We discuss the latter in the context of the small proportion of satellite cells that express high levels of Pax7, or that are derived from cells that have never activated the Myf5 myogenic determination gene. However, many quiescent satellite cells transcribe Myf5, but do not enter myogenesis because of post-transcriptional regulation, which prevents Myf5 protein accumulation. Post-transcriptional regulation, through microRNA repression of a potential cell cycle activator, further illustrates how these cells are ready for action. PMID- 23735051 TI - The limits of market-based reforms in the NHS: the case of alternative providers in primary care. AB - BACKGROUND: Historically, primary medical care in the UK has been delivered by general practitioners who are independent contractors, operating under a contract, which until 2004 was subject to little performance management. In keeping with the wider political impetus to introduce markets and competition into the NHS, reforms were introduced to allow new providers to bid for contracts to provide primary care services in England. These contracts known as 'Alternative Provider Medical Services', were encouraged by two centrally-driven rounds of procurement (2007/8 and 2008/9). This research investigated the commissioning and operation of such Alternative Providers of Primary Care (APPCs). METHODS: Two qualitative case studies were undertaken in purposively sampled English Primary Care Trusts (PCTs) and their associated APPCs over 14 months (2009-10). We observed 65 hours of meetings, conducted 23 interviews with PCT and practice staff, and gathered relevant associated documentation. RESULTS AND CONCLUSIONS: We found that the procurement and contracting process was costly and time-consuming. Extensive local consultation was undertaken, and there was considerable opposition in some areas. Many APPCs struggled to build up their patient list sizes, whilst over-performing on walk-in contracts. Contracting for APPCs was 'transactional', in marked contrast to the 'relational' contracting usually found in the NHS, with APPCs subject to tight performance management. These complicated and costly processes contrast to those experienced by traditionally owned GP partnerships. However, managers reported that the perception of competition had led existing practices to improve their services. The Coalition Government elected in 2010 is committed to 'Any Qualified Provider' of secondary care, and some commentators argue that this should also be applied to primary care. Our research suggests that, if this is to happen, a debate is needed about the operation of a market in primary care provision, including the trade-offs between transparent processes, fair procurement, performance assurance and cost. PMID- 23735052 TI - Sensitization of ovarian carcinoma cells to Bcl-xL-targeting strategies through indirect modulation of Mcl-1 activity by MR22388, a molecule of the tripentone family. AB - BACKGROUND: Our work has been carried out in the context of the therapeutic failure in ovarian carcinoma, which remains the leading cause of death by gynecologic malignancy. In these tumours, recurrence and subsequent acquired chemoresistance constitute major hurdles to successful therapy. Here we studied the interest of a member of the tripentone chemical family, MR22388, for the treatment of chemoresistant ovarian cancer cells. FINDINGS: MR22388 activity has been assessed in vitro on cisplatin-resistant (SKOV3 and IGROV1-R10) ovarian cancer cell lines by conventional analysis, alone or combined to a BH3-mimetic molecule, ABT-737. MR22388 exerts its activity on cisplatin resistant cells, and we showed that it induces a decrease of the Mcl-1 anti-apoptotic protein expression. Considering our previous work demonstrating that the efficiency of Bcl-xL targeting strategies is conditioned to the concomitant inhibition of Mcl-1 we studied the interest of the association of this MR22388 with ABT-737, and showed that this combination was highly cytotoxic in chemoresistant cells. CONCLUSIONS: This work thus opens new perspectives for the use of this promising molecule for the treatment of highly chemoresistant ovarian cancer cells and for sensitization of emerging Bcl-xL targeting strategies such as the use of BH3 mimetic molecules. PMID- 23735053 TI - Evolving concepts of the renin-angiotensin system. Introduction. PMID- 23735054 TI - Polyelectrolyte-coated gold magnetic nanoparticles for immunoassay development: toward point of care diagnostics for syphilis screening. AB - Immediate response for disease control relies on simple, inexpensive, and sensitive diagnostic tests, highly sought after for timely and accurate test of various diseases, including infectious diseases. Composite Fe3O4/Au nanoparticles have attracted considerable interest in diagnostic applications due to their unique physical and chemical properties. Here, we developed a simple coating procedure for gold magnetic nanoparticles (GMNs) with poly(acrylic acid) (PAA). PAA-coated GMNs (PGMNs) were stable and monodispersed and characterized by Fourier transform-infrared spectroscopy (FT-IR), transmission electron microscopy, UV-visible scanning spectrophotometry, thermogravimetric analysis, and Zetasizer methodologies. For diagnostic application, we established a novel lateral flow immunoassay (LFIA) strip test system where recombinant Treponema pallidum antigens (r-Tp) were conjugated with PGMNs to construct a particle probe for detection of anti-Tp antibodies. Intriguingly, the particle probes specifically identified Tp antibodies with a detection limitation as low as 1 national clinical unit/mL (NCU/mL). An ample pool of 1020 sera samples from three independent hospitals were obtained to assess our PGMNs-based LFIA strips, which exhibited substantially high values of sensitivity and specificity for all clinical tests (higher than 97%) and, therefore, proved to be a suitable approach for syphilis screening at a point-of-care test manner. PMID- 23735055 TI - Development of selective colorimetric probes for hydrogen sulfide based on nucleophilic aromatic substitution. AB - Hydrogen sulfide is an important biological signaling molecule and an important environmental target for detection. A major challenge in developing H2S detection methods is separating the often similar reactivity of thiols and other nucleophiles from H2S. To address this need, the nucleophilic aromatic substitution (SNAr) reaction of H2S with electron-poor aromatic electrophiles was developed as a strategy to separate H2S and thiol reactivity. Treatment of aqueous solutions of nitrobenzofurazan (7-nitro-1,2,3-benzoxadiazole, NBD) thioethers with H2S resulted in thiol extrusion and formation of nitrobenzofurazan thiol (lambdamax = 534 nm). This reactivity allows for unwanted thioether products to be converted to the desired nitrobenzofurazan thiol upon reaction with H2S. The scope of the reaction was investigated using a Hammett linear free energy relationship study, and the determined rho = +0.34 is consistent with the proposed SN2Ar reaction mechanism. The efficacy of the developed probes was demonstrated in buffer and in serum with associated submicromolar detection limits as low as 190 nM (buffer) and 380 nM (serum). Furthermore, the sigmoidal response of nitrobenzofurazan electrophiles with H2S can be fit to accurately quantify H2S. The developed detection strategy offers a manifold for H2S detection that we foresee being applied in various future applications. PMID- 23735057 TI - Context heterogeneity has a sustained impact on attention deployment: behavioral and electrophysiological evidence. AB - In visual search, similar nearby stimuli can be grouped and thus enhance processing of an embedded target. The aim of the present study was to examine the time course of attention deployment after a brief presentation of stimulus arrays of different heterogeneity. Targets in less heterogeneous, grouped contexts yielded higher accuracy and larger N2pc amplitudes than targets in more heterogeneous, random contexts, indicating more efficient selection in the former. Subsequently presented probes yielded shorter reaction times and a larger posterior positivity when presented at the target location. This advantage was more pronounced after grouped compared to random contexts at the shorter compared to the longer interstimulus interval. The results show that less heterogeneous contexts that allow for grouping not only enhance processing of stimuli within that context, but have a sustained effect on visual attention. PMID- 23735056 TI - Association between psychiatric disorders and iron deficiency anemia among children and adolescents: a nationwide population-based study. AB - BACKGROUND: A great deal of evidence has shown that iron is an important component in cognitive, sensorimotor, and social-emotional development and functioning, because the development of central nervous system processes is highly dependent on iron-containing enzymes and proteins. Deficiency of iron in early life may increase the risk of psychiatric morbidity. METHODS: Utilizing the National Health Insurance Database from 1996 to 2008, children and adolescents with a diagnosis of IDA were identified and compared with age and gender-matched controls (1:4) in an investigation of the increased risk of psychiatric disorders. RESULTS: A total of 2957 patients with IDA, with an increased risk of unipolar depressive disorder (OR = 2.34, 95% CI = 1.58 ~ 3.46), bipolar disorder (OR = 5.78, 95% CI = 2.23 ~ 15.05), anxiety disorder (OR = 2.17, 95% CI = 1.49 ~ 3.16), autism spectrum disorder (OR = 3.08, 95% CI = 1.79 ~ 5.28), attention deficit hyperactivity disorder (OR = 1.67, 95% CI = 1.29 ~ 2.17), tic disorder (OR = 1.70, 95% CI = 1.03 ~ 2.78), developmental delay (OR = 2.45, 95% CI = 2.00 ~ 3.00), and mental retardation (OR = 2.70, 95% CI = 2.00 ~ 3.65), were identified. A gender effect was noted, in that only female patients with IDA had an increased OR of bipolar disorder (OR = 5.56, 95% CI = 1.98 ~ 15.70) and tic disorder (OR = 2.95, 95% CI = 1.27 ~ 6.86). CONCLUSION: Iron deficiency increased the risk of psychiatric disorders, including mood disorders, autism spectrum disorder, attention deficit hyperactivity disorder, and developmental disorders. Further study is required to clarify the mechanism in the association between IDA and psychiatric disorder. PMID- 23735058 TI - AllerTOP--a server for in silico prediction of allergens. AB - BACKGROUND: Allergy is a form of hypersensitivity to normally innocuous substances, such as dust, pollen, foods or drugs. Allergens are small antigens that commonly provoke an IgE antibody response. There are two types of bioinformatics-based allergen prediction. The first approach follows FAO/WHO Codex alimentarius guidelines and searches for sequence similarity. The second approach is based on identifying conserved allergenicity-related linear motifs. Both approaches assume that allergenicity is a linearly coded property. In the present study, we applied ACC pre-processing to sets of known allergens, developing alignment-independent models for allergen recognition based on the main chemical properties of amino acid sequences. RESULTS: A set of 684 food, 1,156 inhalant and 555 toxin allergens was collected from several databases. A set of non-allergens from the same species were selected to mirror the allergen set. The amino acids in the protein sequences were described by three z descriptors (z1, z2 and z3) and by auto- and cross-covariance (ACC) transformation were converted into uniform vectors. Each protein was presented as a vector of 45 variables. Five machine learning methods for classification were applied in the study to derive models for allergen prediction. The methods were: discriminant analysis by partial least squares (DA-PLS), logistic regression (LR), decision tree (DT), naive Bayes (NB) and k nearest neighbours (kNN). The best performing model was derived by kNN at k = 3. It was optimized, cross validated and implemented in a server named AllerTOP, freely accessible at http://www.pharmfac.net/allertop. AllerTOP also predicts the most probable route of exposure. In comparison to other servers for allergen prediction, AllerTOP outperforms them with 94% sensitivity. CONCLUSIONS: AllerTOP is the first alignment-free server for in silico prediction of allergens based on the main physicochemical properties of proteins. Significantly, as well allergenicity AllerTOP is able to predict the route of allergen exposure: food, inhalant or toxin. PMID- 23735061 TI - The utilization and perceived usefulness of health care and other support services by people exposed to traumatic events related to the war in the Balkans. AB - OBJECTIVE: To explore which health care and other support services people exposed to traumatic events related to the war use, how helpful they perceive them in the course of their post-war adaptation and whether utilization and perceived usefulness depend on the mental health status of participants. METHODS: A community sample of 3304 adults exposed to at least one war-related traumatic event was randomly selected in different regions in the former Yugoslavia. A specifically designed instrument, the Matrix for the Assessment of Community and Healthcare Services, was used to record service utilization and their perceived usefulness. The mental health status of participants was assessed using the Mini International Neuropsychiatric Interview. RESULTS: Primary health care was the most frequently used type of service (80.5%). Services providing help with leisure activities, social support and social contacts were perceived as most helpful. Participants with current post-traumatic stress disorder used all types of health care services and employment support services significantly more often than participants without mental disorders and participants with other mental disorders. They were more satisfied with primary health care services than participants without mental disorders and less satisfied with financial and material support services as compared to participants with other mental disorders. CONCLUSIONS: The frequency of utilization of different types of services varies greatly in war affected communities. Medical services are widely used and therefore have a central role in the care provision following a war. Services providing help with leisure activities and social support are most appreciated and may be more widely established. PMID- 23735062 TI - Comparison of double disk synergy test, VITEK 2 and Check-MDR CT102 for detection of ESBL producing isolates. AB - OBJECTIVE: This study is to define the statistical significance for detection of ESBL producers by the double disk synergy test and molecular test (Check-MDR CT102), microdilution test (VITEK 2 with AES) and double disk synergy test (DDST), as well as the microdilution test and molecular test. MATERIALS AND METHODS: Phenotypic testing of 55 isolates Enterobacteriaceae (Escherichia coli (14/55), Klebsiella pneumoniae (34/55), Klebsiella oxytoca (3/55) and Proteus mirabilis (4/55) was performed by VITEK 2 Compact/AES. When this test showed positive results for the ESBL phenotype, then DDST with amoxicillin/clavulanate, ceftazidime, cefpodoxime, aztreonam, ceftriaxone and cefoxitin disks was performed along with Check-MDR CT102 which identified CTX-M, TEM and SHV beta lactamases. RESULTS: Applying the McNemar test, we determined that there was a statistically significant difference in the results of detection of ESBLs bacteria using DDST compared to molecular methods (95% CI=41.92 to 54.55; p<0.0001), as well as a DDST and VITEK 2/AES (95% CI=40.13 to 52.73; p<0.0001). We did not find any statistically significant difference in the results of detection of ESBL producers using molecular techniques and VITEK 2/AES (CI=-4,43 to 5,36; p=1). Also we did not find any statistical.. difference between the resistance to cefpodoxime and ceftriaxone (50/50) compared to the results of molecular tests. CONCLUSION: In routine daily testing, good detection of ESBLs bacteria, especially CTX-M can be obtained with phenotypic methods with VITEK 2/AES and by DDST with cefpodoxime, and ceftriaksone disks. PMID- 23735059 TI - Association of MDM2 T309G and p53 Arg72Pro polymorphisms and gastroesophageal reflux disease with survival in esophageal adenocarcinoma. AB - BACKGROUND AND AIM: Although gastroesophageal reflux disease (GERD) is a risk factor for esophageal adenocarcinoma (EAC), some patients develop EAC in the absence of GERD. A putative mechanism of reflux-induced tumorigenesis involves disruptions in the p53 pathway. We assessed the interaction of GERD and p53 pathway polymorphisms on EAC prognosis. METHODS: In a prospective cohort of 358 EAC patients, clinical data (including GERD history and survival) were collected. Germline DNA was genotyped for MDM2 T309G and p53 Arg72Pro. Cox proportional hazards models were used to determine adjusted hazard ratios (AHR) for associations between genotype, GERD, and genotype-GERD interactions with survival. RESULTS: Compared with other genotypes, MDM2 G/G (median overall survival 21 vs 30 months; P < 0.001) and p53 Pro/Pro (12 vs 30 months; P = 0.004) were associated with shorter survival. When analyzed by GERD, MDM2 G/G was associated with shorter survival in patients without GERD (AHR 3.4, 95% CI 2.0 6.0), but not in patients with GERD (AHR 1.1 [0.7-1.8]); the MDM2-GERD interaction was significant (P = 0.003). A similar trend was seen for p53 Pro/Pro (AHRs 2.5 without GERD vs 1.4 with GERD). Combined analysis of at-risk variants (MDM2 G or p53 Pro), revealed each additional at-risk variant was associated with shorter survival in patients without GERD (AHR 1.6) but not with GERD (AHR 1.0). CONCLUSIONS: MDM2 G/G and the combination of MDM2 G and p53 Pro were negative prognostic factors for EAC patients without GERD but not for those with GERD. There may be biological differences between GERD positive and GERD negative EAC. PMID- 23735063 TI - An outbreak of multidrug-resistant Serratia marcescens: the importance of continuous monitoring of nosocomial infections. AB - OBJECTIVE: Serratia marcescens is a well-established as a nosocomial pathogen, resulting in considerable morbidity and mortality in immunocompromised patients. The aim of this study was to investigate an outbreak of Serratia marcescens at the Orthopaedic Clinic of the Clinical Center University of Sarajevo. METHODS: A total of 96 strains from 79 patients were isolated. The isolates were identified by conventional methods. Susceptibility testing was performed by the discdiffusion method following CLSI guidelines. Results were confirmed by VITEC-2 Compact. RESULTS: From January to December 2010, 96 strains from 79 patients were isolated at the Orthopaedic Clinic of the Clinical Center, University of Sarajevo.The strains were isolated from wound swabs, blood cultures and cerebrospinal fluid. The strains were identifed using current phenotypic methods as Serratia marcescens with identical biochemical characteristics and antibiotic susceptibility patterns. All strains were susceptible to imipenem, meropenem, amikacin, ciprofloxacin, levofloxacin and piperacillin/tazobactam. The infection control team was alerted and after investigation they discovered the same phenotype of Serratia marcescens in the anaesthetic vials used in procedures. This outbreak was extremely difficult to terminate, even with cohorting of patients, sterilisation of equipment, reinforcement of handwashing and deep cleaning of facilities. The implementation of new control measures terminated the outbreak in February 2011. CONCLUSION: Continuous monitoring of nosocomial infections is indispensable. Phenotypic characterization of the isolates is useful for studying the relationship of microbial pathogens. The relationship of one clinical isolate to another during an outbreak is important in motivating the search for a common source or mode of transmission. PMID- 23735064 TI - Impact of a recruitment campaign on students' applications to medical school. AB - OBJECTIVE: Medical schools might benefit if they have information about the activities that may help them to increase the number of applicants with superior academic qualifications. METHODS: The study was carried out at the Split University School of Medicine, Croatia. Medical school applicants were surveyed in 2007 and 2009. Promotional activities consisted of presentations on medical education covering six general high-schools in 2008, and a presentation on regional television, aired in 2008 and 2009 shortly before the admission term. RESULTS: The survey response rate was 79% (299/379). The number of applicants in 2009 increased by 37% and the percentage of applicants from general high schools increased by 10%, in relation to 2007. The percentage of students with the best grades in all four years of high school was 42% in the both surveys. Presumed quality was a major influencing factor for choosing Split University Medical School. However, the medical school in the Croatian capital remained the first choice for students. Only a few applicants stated that the medical schools' promotional campaigns influenced their decision about where to study; 9.7% and 1.5%, respectively. CONCLUSION: Presentations in elected general high schools and a television campaign should be further explored as possible activities that regional schools may use to recruit potential applicants. PMID- 23735065 TI - Occipitalization of the atlas: its incidence and clinical implications. AB - OBJECTIVE: The aim of the present study was to investigate the incidence of occipitalization of the atlas among Thai dried skulls, in order to contribute to baseline awareness of this condition. MATERIALS AND METHODS: The skulls of 633 adult Thais from the collection maintained in the Department of Anatomy, Faculty of Medicine, Khon Kaen University, Thailand, were examined for evidence of occipitalization of the atlas. The skulls were well-preserved and did not show any traits of craniofacial deformation. The skulls for which the age and sex were unknown were excluded from the analysis. From the cadaveric records on each individual, we learned that the skulls belonged to 373 men (age of decease between 25 and 90 years), and 260 women (age of decease between 28 and 92 years). RESULTS: Occipitalization of the atlas was detected in 2 skulls (0.32%). The first case was a male skull (54 years of age at decease), where the atlas was partially fused to the occipital bone. The second case was also a male skull (59 years of age at decease) showing complete fusion of the anterior arch of the atlas. CONCLUSION: The incidence of occipitalization of the atlas is low; however, if present this abnormality may cause a wide range of neurological problems. Knowledge of occipitalization of the atlas may be of substantial importance to orthopedists, neurosurgeons, physiotherapists and radiologists dealing with abnormalities of the cervical spine. Mistaken diagnoses have led to delayed treatment and at times adverse results. PMID- 23735066 TI - Musculoskeletal symptoms and job satisfaction among office-workers: a cross sectional study from Iran. AB - OBJECTIVE: Office-work poses a high-risk for musculoskeletal disorders (MSDs), with consequences for workers, employers and society. The aims of this study were to determine the prevalence of musculoskeletal symptoms in a sample of Iranian office workers, to investigate the association between pain severity and job satisfaction and to investigate the association between MSDs and job satisfaction. MATERIALS AND METHODS: Iranian office workers from a university setting (n=91) were randomly selected and included in this cross-sectional study. The Nordic musculoskeletal questionnaire plus visual analogue scale of pain, and the Brayfield-Rothe Job Satisfaction Index were used to study the prevalence of MSDs, pain intensity and job satisfaction, respectively. Descriptive analysis, Pearson's correlation, and multiple regression analysis were performed for statistical assessment. RESULTS: Eighty-nine percent of participants reported musculoskeletal symptoms during the past 12 months, most commonly in the neck (69.2%), low back (58.2%), knees (41.8%), shoulders (35.2%), and upper back (34.1%). There was a significant negative correlation between pain intensity and job satisfaction. Pain intensity, low-back pain in the last week, wrist pain in the past 12 months and shoulder pain were significantly associated with job satisfaction (p<0.05). CONCLUSION: This study provides evidence that musculoskeletal symptoms are common in Iranian office workers, associated with low job satisfaction. These findings indicate the need for more attention to MSDs among office workers and designing effective preventive interventions. PMID- 23735068 TI - Doctoral degree in health professions: professional needs and legal requirement. AB - To respond to ever increasing complexity of health care professions, education of nurses, midwives, physiotherapists, radiology engineers, and medical laboratory workers, has been upgraded to pregraduate, graduate and postgraduate university levels. In Croatia, nursing was defined as a branch of clinical medical science in 1997. Croatia and Bosnia and Herzegovina have introduced first two levels, but there is a strong need for the third one (doctoral degree). It should last three years and contain 180 ECTS points. It includes acquisition of evidence-based advanced health care, and the ability for independent research and critical analysis. Doctoral degrees in health professions are instrumental for academic careers of faculty of health professions. Yet this will not separate them from their patients or make them administrators, as the majority of their work will still be spent alongside patients. PMID- 23735067 TI - Palatal lifting prosthesis and velopharyngeal insufficiency: preliminary report. AB - OBJECTIVES: Our study aimed to highlight the effectiveness of palatal lift prosthesis in patients with velopharyngeal insufficiency with previous operated cleft palate. METHODS: This study was done undertaken January 2008 to December of 2009 in the Phoniatic unit of Alnoor Specialist Hospital, Makkah, Saudi Arabia. Ten patients of >= 8 years to <= 10 years of age, who had previously undergone surgery for cleft palate, with or without cleft lip, with no other systemic illness and normal intelligent quotient level, were selected and managed by palatal lift prosthesis. All the study subjects were subjected to auditory perceptual speech evaluation for assessment of the degree of hypernasality, compensatory articulator mechanisms, glottal and pharyngeal articulation, audible nasal emission, facial grimace and overall intelligibility of speech. Data were analyzed using SPSS version 16. RESULTS: The study included 10 subjects whose mean +/- standard deviation of age was (8.9+/-0.9). On auditory speech perceptual evaluation after prosthesis application, significant improvement was found in glottal articulation 6 (85.7%), p=0.04, facial grimace 6 (85.7%) p=0.04, hyper nasality 10 (10%) p=0.008, and speech intelligibility 9 (90%) p=0.008. CONCLUSION: Young patients with repaired palatal cleft have significant improvement after application of palatal lift prosthesis. PMID- 23735069 TI - A proposal for enhancement of research capacities in Croatian general practice. AB - Research in family medicine contributes to the increase of knowledge, and its practical application improves the work of family physicians. Although research in family medicine in the Republic of Croatia has a long tradition, no sustainable research network exists as yet. Enhancing such a network is essential to efficaciously conduct research that is specific and important for family practice. This article describes the experiences of other countries and offers a proposal for a conceptual model for the development of a permanent research network in family medicine through three key elements: recognition of research as an indicator of quality of care that is specifically funded, introducing a continuing cycle of education for family physicians/researchers in the field of scientific research and building the capacity of academic family medicine and the success of their applications for domestic and international projects and funding sources. CONCLUSION: The application of the conceptual model from Australian primary health care research, adjusted to our circumstances, could further enhance research capacity building in Croatian family medicine. PMID- 23735070 TI - An unusual renal accessory artery originating from the thoracic aorta and its potential clinical implications. AB - We report a case of an unsual anatomical vascular blood supply to the right kidney. In an analysis of kidneys, by dissection of 39 foetuses, additional renal arteries were found in 18 cases (46.15%). In only one case (2.5%) was it noticed that the right kidney was supplied with blood by three renal arteries, one main and two additional arteries. One of the additional arteries, marked as the upper pole artery of aortic origin, separated from the thoracic aorta at the level of T11 (the eleventh thoracic rib), 1.5 cm above the truncus coeliacus. This artery, after passing through the diaphragm, entered the renal hilus at its upper part and served to vasculate that part of the kidney. CONCLUSION: The importance of this study is seen in the fact that anatomic knowledge of variations in the vascularization of the kidneys is of exceptional practical importance. Also, this information may concern transplant surgeons involved in living donor nephrectomies. PMID- 23735071 TI - Brachytherapy dose received by bladder and rectum in patients with inoperable cervical cancer: CT-based 3D view. PMID- 23735072 TI - Solitary extramedullary plasmocytoma of the liver. PMID- 23735073 TI - Local ordering in lead-based relaxor ferroelectrics. AB - Lead-based ferroelectric materials are both well-studied and widely used and have a wide range of applications from ultrasonics to energy harvesting and beyond. However, the use of Pb-containing materials is environmentally undesirable, due to the toxicity of lead. This is particularly highlighted by the disposal of Pb based devices when their lifespan is through. Because of this large drawback, chemists have been searching for Pb-free ferroic materials that can replace PZN (PbZn1/3Nb2/3O3), PMN (PbMg1/3Nb2/3O3), PZT (PbZr1-xTixO3), and all their derivatives. Underlying much of materials chemistry is the idea that function arises from structure, so if we can determine the structure of a material, we can understand how its useful properties arise. This understanding can then lead to the tuning of these properties and the development of new materials. However, the question arises: What is meant by structure? Conventionally, structure is determined by X-ray or neutron diffraction, in which the Bragg peak intensities are measured and a unit cell is determined. In many materials, local ordering, order that persists only for few unit cells or nanometers, is important in determining the physical properties. This is very much the case in the relaxor ferroelectrics, an important class of functional oxides. Indeed, disorder, randomness, and short-range order (SRO) are all invoked to help explain many of the key properties. The local order in Pb-based ferroelectrics has been extensively studied, with the most definitive probe being single-crystal diffuse scattering. In this Account, I outline the current debate on the nature of the local order and explore how this information can inform the search for lead-free materials. Local order, as distinct from the overall average order revealed by conventional techniques, relates more closely to the crystal chemistry of the individual ions and so appears to give a better insight into how the crystal chemistry leads to the ferroelectric properties. PMID- 23735074 TI - Prospective data collection of off-label use of rituximab in Australian public hospitals. AB - BACKGROUND: Rituximab is a chimeric, anti-CD20 monoclonal antibody registered for the treatment of B-cell malignancies and refractory rheumatoid arthritis in Australia. In addition to these approved indications, there has been growing interest in the use of off-label rituximab in the management of a variety of diseases. AIMS: To determine the current usage of off-label rituximab in Australia, we collected nationwide data. METHODS: Information regarding patients receiving rituximab for off-label indications was prospectively collected for a 6 month period from Australian public hospitals. Data recorded included clinical indication, dosing schedule, previous therapy and efficacy assessment. The level of evidence for the use of rituximab was determined for each off-label indication. RESULTS: During the 6-month period, a total of 364 instances of off label rituximab use was recorded in the national database. A total of 63 underlying diagnoses was identified. These were subclassified into haematological disorders (19%), autoimmune connective tissue diseases (12%), vasculitis (12%), neurological disorders (12%), transplant-related uses (12%), haematological malignancies (11%), muscle disorders (8%), renal diseases (6%), dermatological conditions (5%), other conditions (2%) and ocular diseases (1%). Forty percent of these requests were supported only by level 4 evidence of benefit. Data highlighted the non-standardised approaches to drug approval mechanisms, dosing schedules and monitoring for efficacy. CONCLUSIONS: Off-label rituximab is prescribed for a diverse range of clinical conditions. Determining a safe and effective means of regulating this use within an evidence-based framework remains an ongoing challenge. PMID- 23735075 TI - ATP-noncompetitive CDK inhibitors for cancer therapy: an overview. AB - INTRODUCTION: Cyclin-dependent kinases (CDKs) are the key drivers of cell cycle progression and are often deregulated in cancer, therefore, targeting CDKs has long been pursued as a therapeutic strategy to tackle cancer. Unfortunately, however, none of the first-generation CDK inhibitors has yielded the expected efficacy to be successfully translated to the clinic mostly because, by targeting the very conserved kinase ATP-binding site resulted to be poorly specific and quite toxic. AREAS COVERED: Here, the authors review recent approaches aimed at developing more specific CDK inhibitors mostly through the aid of computational drug design studies and report various small molecules and peptides, which resulted in promising CDK ATP-noncompetitive inhibitors. EXPERT OPINION: Despite few successes, these new approaches still need additional considerations to generate effective antitumoral agents. The authors discuss some of the hurdles to overcome for a successful clinical translation. PMID- 23735076 TI - Oxidative stress status in umbilical cord blood from neonates born to mothers with atopic asthma. AB - OBJECTIVE: Our objective was to assess the oxidative stress status and analyse the relationship between an oxidant/antioxidant imbalance and the mediator release properties of cord blood basophils from neonates born to mothers with atopic asthma. METHODS: Cord blood was collected from the neonates of 16 asthmatic mothers and 18 healthy mothers Basophils were purified and stimulated by Dermatophagoides farinae (Df), hyperosmotic mannitol or peptidoglycan (PGN). Immunoblotting detected nuclear factor kappaB (NFkappaB) as a measure of functional receptor response. The linear correlations between IL-4 levels in the supernatants and 3-nitrotyrosine (3-NT), glutathione peroxidase (GSH-Px) in the serum were evaluated. RESULTS: Compared with the healthy group, the levels of 3 NT in maternal blood and cord blood were significantly higher in allergic asthma group, whereas the GSH-Px activity were lower. After stimulation, cord blood basophils from the neonates born to atopic mothers produced more IL-4 involving NF-kappaB pathways. There was a significant relationship between the IL-4 levels produced by basophils and 3-NT (or GSH-Px) in cord blood from allergic asthma group. CONCLUSION: In asthma, mediator release properties of human basophils induced by environmental allergens and irritants are associated with oxidative stress, which may be one of the pathogenesis of allergic diseases. PMID- 23735077 TI - ABCB1-overexpressing MG63/DOX cell xenograft model: maintain the MDR phenotype in vivo. AB - CONTEXT: Multi-drug resistance (MDR) constitutes a major obstacle in the effectiveness of chemotherapy. P-Glycoprotein (P-gp), the product of ABCB1 gene, is a transmembrane transporter that actively pumps cytotoxic drugs out of tumor cells resulting in MDR. OBJECTIVE: We sought to establish an MG63/DOX cell xenografts model that maintained the MDR phenotype and molecular properties in vivo in order to screen for new P-gp inhibitors. MATERIALS AND METHODS: The cytotoxicities of doxorubicin, paclitaxel and cytarabine were evaluated by MTT assays. P-gp activity was measured by rhodamine 123 accumulation using flow cytometry. P-gp expression in MG63/DOX cells and tumor tissues was detected by western blotting and immunohistochemistry. RESULTS: Our results showed that MG63/DOX cells exhibited 70-fold resistance to doxorubicin and more than 150-fold resistance to paclitaxel compared with parent MG63 cells. Furthermore, the ABCB1 inhibitor verapamil (10 MUM) effectively reversed doxorubicin and paclitaxel resistance by 90- and 200-fold, respectively. The intracellular accumulation of rhodamine 123 was significantly increased (8.35-fold) in MG63/DOX cell, as compared to MG63 cells, in the presence of 10 MUM verapamil. MG63/DOX tumor chunk xenografts had a high formation rate (88%). Finally, we found that the ABCB1 gene was overexpressed in different generations of solid tumors. DISCUSSION AND CONCLUSION: These data demonstrated that MG63/DOX tumor chunk subculture in vivo retained their molecular properties. This model could serve as a convenient system for the preclinical investigation of drug combinations and the screening of new agents to reverse ABCB1-mediated MDR. PMID- 23735078 TI - Fatigue behavior of zirconia-ceramic, galvano-ceramic, and porcelain-fused-to metal fixed partial dentures. AB - PURPOSE: This study evaluated the fatigue behavior of three fixed partial dentures (FPDs) before and after artificial fatigue testing. MATERIALS AND METHODS: Sixty, three-unit zirconia-ceramic (ZC), galvano-ceramic (GC), and porcelain-fused-to-metal (PFM) FPDs (N = 20) were fabricated. Ten specimens from each group were exposed to fatigue testing by being thermocycled (5 to 55 degrees C, 10,000 cycles) and loaded (100,000 cycles, 50 N, 0.5 Hz). All specimens were then subjected to occlusal loading in a universal testing machine until fracture. The fractures were characterized using scanning electron microscopy. Data were analyzed using one-way ANOVA followed by Tukey's significant difference post hoc test and the paired t-test. The chi-squared test was used to evaluate the type of fracture (alpha = 0.05). RESULTS: The mean fracture loads of non-fatigued and fatigued specimens for ZC were 2434.9 +/- 154.3 and 2333.1 +/- 183.0 N, respectively; for GC were 1678.1 +/- 211.6 and 1475.8 +/- 227.9 N, respectively; and 1878.5 +/- 176.5 and 1687.8 +/- 162.2 N, respectively, for PFM restorations. Significant differences were observed between fatigued and non-fatigued specimens of both the GC group and PFM group (p < 0.05), but not between fatigued and non fatigued ZC specimens (p > 0.05). Differences between the PFM and GC specimens were not statistically significant for fatigued or non-fatigued specimens (p > 0.05). Fracture types did not differ significantly among groups. CONCLUSIONS: ZC specimens were not significantly affected by fatigue, whereas GC and PFM specimens were affected. All tested restorations have the potential to withstand occlusal forces applied in the posterior region. PMID- 23735079 TI - Impact of an enhanced antibiotic stewardship on reducing methicillin-resistant Staphylococcus aureus in primary and secondary healthcare settings. AB - The objective of this study was to evaluate the impact of restricting high-risk antibiotics on methicillin-resistant Staphylococcus aureus (MRSA) incidence rates in a hospital setting. A secondary objective was to assess the impact of reducing fluoroquinolone use in the primary-care setting on MRSA incidence in the community. This was an interventional, retrospective, ecological investigation in both hospital and community (January 2006 to June 2010). Segmented regression analysis of interrupted time-series was employed to evaluate the intervention. The restriction of high-risk antibiotics was associated with a significant change in hospital MRSA incidence trend (coefficient=-0.00561, P=0.0057). Analysis showed that the intervention relating to reducing fluoroquinolone use in the community was associated with a significant trend change in MRSA incidence in community (coefficient=-0.00004, P=0.0299). The reduction in high-risk antibiotic use and fluoroquinolone use contributed to both a reduction in incidence rates of MRSA in hospital and community (primary-care) settings. PMID- 23735080 TI - Discovering motifs that induce sequencing errors. AB - BACKGROUND: Elevated sequencing error rates are the most predominant obstacle in single-nucleotide polymorphism (SNP) detection, which is a major goal in the bulk of current studies using next-generation sequencing (NGS). Beyond routinely handled generic sources of errors, certain base calling errors relate to specific sequence patterns. Statistically principled ways to associate sequence patterns with base calling errors have not been previously described. Extant approaches either incur decisive losses in power, due to relating errors with individual genomic positions rather than motifs, or do not properly distinguish between motif-induced and sequence-unspecific sources of errors. RESULTS: Here, for the first time, we describe a statistically rigorous framework for the discovery of motifs that induce sequencing errors. We apply our method to several datasets from Illumina GA IIx, HiSeq 2000, and MiSeq sequencers. We confirm previously known error-causing sequence contexts and report new more specific ones. CONCLUSIONS: Checking for error-inducing motifs should be included into SNP calling pipelines to avoid false positives. To facilitate filtering of sets of putative SNPs, we provide tracks of error-prone genomic positions (in BED format). AVAILABILITY: http://discovering-cse.googlecode.com. PMID- 23735081 TI - Ovarian adult granulosa cell tumor and vulval lichenoid inflammation. PMID- 23735082 TI - The practice of commissioning healthcare from a private provider: learning from an in-depth case study. AB - BACKGROUND: The direction of health service policy in England is for more diversification in the design, commissioning and provision of health care services. The case study which is the subject of this paper was selected specifically because of the partnering with a private sector organisation to manage whole system redesign of primary care and to support the commissioning of services for people with long term conditions at risk of unplanned hospital admissions and associated service provision activities. The case study forms part of a larger Department of Health funded project on the practice of commissioning which aims to find the best means of achieving a balance between monitoring and control on the one hand, and flexibility and innovation on the other, and to find out what modes of commissioning are most effective in different circumstances and for different services. METHODS: A single case study method was adopted to explore multiple perspectives of the complexities and uniqueness of a public private partnership referred to as the "Livewell project". 10 single depth interviews were carried out with key informants across the GP practices, the PCT and the private provider involved in the initiative. RESULTS: The main themes arising from single depth interviews with the case study participants include a particular understanding about the concept of commissioning in the context of primary care, ambitions for primary care redesign, the importance of key roles and strong relationships, issues around the adoption and spread of innovation, and the impact of the current changes to commissioning arrangements. The findings identified a close and high trust relationship between GPs (the commissioners) and the private commissioning support and provider firm. The antecedents to the contract for the project being signed indicated the importance of leveraging external contacts and influence (resource dependency theory). CONCLUSIONS: The study has surfaced issues around innovation adoption in the healthcare context. The case identifies 'negotiated order', managerial performance of providers and disciplinary control as three media of power used in combination by commissioners. The case lends support for stewardship and resource dependency governance theories as explanations of the underpinning conditions for effective commissioning in certain circumstances within a quasi marketised healthcare system. PMID- 23735083 TI - A novel ATP8 gene mutation in an infant with tetralogy of Fallot. AB - We report the case of a novel mitochondrial DNA mutation in the MT-ATP8 gene in an infant with tetralogy of Fallot. Next-generation sequencing was applied to sequence whole mitochondrial DNA of the patient. A known Leber's hereditary optic neuropathy-associated mutation (G9804A), a heteroplasmic T7501C mutation (17%), and a novel C8481 T Pro > Leu missense mutation in the MT-ATP8 gene was identified. PMID- 23735085 TI - Nursing students' views of sociocultural factors in clinical learning: a qualitative content analysis. AB - AIM: The aim of this study is description of nursing students' views of sociocultural factors in clinical learning. METHODS: A qualitative content analysis was conducted to describe nursing students' views of sociocultural factors in clinical learning. The participants consisted of 21 nursing students. Semi-structured and interactive interviews were used to collect data. All the interviews were recorded and transcribed, and then, they were analyzed using Qualitative Content Analysis and Max Qualitative Data Analysis 2010. RESULTS: From the transcripts, a remarkable number of primary themes, main themes, and sub themes emerged. The main themes consisted of elements related to "society and culture", "family", "staff", and "classmates". The themes encompassed a spectrum of facilitators of and impediments to clinical learning. CONCLUSION: The findings showed that the administrators of nursing education should coordinate with faculty and staff by adopting interactive and participatory solutions, including the establishment of clinical learning teams and the transformation of hospitals into suitable sociocultural environments for education. PMID- 23735084 TI - Novel Mycobacterium tuberculosis complex isolate from a wild chimpanzee. AB - Tuberculosis (TB) is caused by gram-positive bacteria known as the Mycobacterium tuberculosis complex (MTBC). MTBC include several human-associated lineages and several variants adapted to domestic and, more rarely, wild animal species. We report an M. tuberculosis strain isolated from a wild chimpanzee in Cote d'Ivoire that was shown by comparative genomic and phylogenomic analyses to belong to a new lineage of MTBC, closer to the human-associated lineage 6 (also known as M. africanum West Africa 2) than to the other classical animal-associated MTBC strains. These results show that the general view of the genetic diversity of MTBC is limited and support the possibility that other MTBC variants exist, particularly in wild mammals in Africa. Exploring this diversity is crucial to the understanding of the biology and evolutionary history of this widespread infectious disease. PMID- 23735086 TI - Development and evaluation of a self-care assessment inventory for workers. AB - AIM: To develop and evaluate a self-care assessment inventory for workers (SCAI W). METHODS: A study using a self-care assessment inventory for workers consisting of 27 self-care items, the Japanese version of the Beck Depression Inventory (BDI), and the Japanese version of the University of Wales Institute of Science and Technology Mood Adjective Checklist (JUMACL) was conducted. These questionnaires were distributed to 2297 workers. There were 893 valid responses (39.9%, 584 men and 309 women, mean age 37.2+/-10.2 years). RESULTS: Three primary and eight secondary factors were established for the conceptual structure of self-care and validated by structural equation modeling. "Positive attitude" comprised the secondary factors, "hope" and "sense of fulfillment", and was influenced by another secondary factor, "social support". "Positive attitude" contributed to "attitude toward health". "Attitude toward health" comprised the secondary factors, "care about one's health" and "correction of bad habits". "Attitude toward health" influenced a primary factor, "everyday behavior", comprised of "wakefulness", "eating in moderation", and "lack of self-control". The primary factors "positive attitude" and "everyday behavior" influenced the BDI scores. A multiple regression analysis indicated that JUMACL subscale scores (energetic arousal and tense arousal), demographic data (living alone, sex, and age) and health-related data (exercise, smoking, body mass index, drinking more than three alcoholic drinks/day, and gambling) predicted the scores of the self care assessment inventory for workers. CONCLUSION: This assessment inventory could be a useful measure of workers' self-care because it establishes a relationship between psychological and behavioral concepts that are important for health promotion. PMID- 23735087 TI - Effectiveness of a condom use educational program developed on the basis of the Information-Motivation-Behavioral Skills model. AB - AIM: To assess a condom use educational program developed using the Information Motivation-Behavioral Skills (IMB) model to enable Japanese young people to use condoms. METHODS: The program was implemented in two sessions of approximately 90 min each over a 2 day period. The participants underwent the program in small same-sex groups. The study participants were divided into the intervention group (n=94) and the control group (n=186). Knowledge relating to HIV/sexually transmitted diseases (STDs), attitudes towards contraception and sex, the risk perceptions of pregnancy and HIV/STD infection, anticipated reaction to proposed condom use, self-efficacy of condom use, and sexual behaviors were assessed. Data were obtained at baseline, immediately after the program, and 1 and 3 months after the program or baseline survey. RESULTS: Intervention group participants with experience of sexual intercourse (n=14) had significantly higher scores for knowledge relating to HIV/STDs, self-efficacy of condom use, and relief/confusion associated with condom use than the control group (n=13) at the 1 and 3 month surveys. Intervention group participants with no experience of sexual intercourse (n=14) had significantly higher scores for knowledge relating to HIV/STDs and self-efficacy of condom use, and significantly lower scores for condom avoidance, than the control group (n=116). Condom use behavior was not changed in either group. CONCLUSION: The program used in this study did not promote condom use, but it increased knowledge relating to HIV/STDs and self-efficacy of condom use and reduced resistance to condom use. PMID- 23735088 TI - Experiences of infertility through the lens of Iranian infertile women: a qualitative study. AB - AIM: The purpose of this study was to explore and describe the experiences of Iranian infertile women regarding infertility. METHODS: A qualitative design, based on a content analysis approach, was used to reach this study aim. After employing purposive sampling to choose 10 women who were seeking infertility treatment at a referral center in Tehran, Iran, semi-structured interviews were carried out to gather data. RESULTS: During the data analysis, four main themes emerged including "abuse", "marital instability", "social isolation", and "loss of self- esteem". CONCLUSION: Infertility influences both the psychological and social well-being of women. Improving the knowledge of healthcare professionals especially nurses about the complications of infertility and its related cultural contextual factors are crucial in order to provide high quality care to infertile women. PMID- 23735089 TI - Traditional neonatal care practices in Turkey. AB - AIM: The research was conducted as a descriptive and cross-sectional study in order to identify the traditional neonatal care practices applied by women in the 15-49 year age range. METHODS: The research sample comprised 263 married mothers aged 15-49 years living in the seven health center regions in Sivas city center and agreeing to participate in the study between 7 March 2008 and 30 April 2008. In data collection, a questionnaire form devised by the researchers on the basis of expert opinion was used. The data collected were assessed by computer by means of percentage analysis and chi(2)-tests. RESULTS: The traditional neonatal care practices for treatment of jaundice, rash, thrush, earache, swelling in the baby's chest (milk accumulation), falling of the umbilical cord, umbilical infection, eye crust, nail cut, and temperature were examined. The most frequently conducted traditional practices were identified as rubbing swollen nipples, "making the forties" (bathing the mother and neonate in a special ritual on the 40th day postpartum), salting, using holluk (sand-filled nappy), and swaddling the baby. It was found that the mothers with low levels of education applied traditional practices like swaddling, salting, holluk, and making the forties more frequently (P<0.05). CONCLUSION: According to the study findings, mothers practiced traditional applications at least once during neonatal care. It was observed that the lower the mother's educational level, the more frequent the traditional practices were applied. For this reason, neonatal healthcare services should be delivered by midwives/nurses or other healthcare workers. PMID- 23735090 TI - Development of competence scale for senior clinical nurses. AB - AIM: The aim of this study was to develop a new scale, the Competence Scale for Senior Clinical Nurses (CS-SCN), to assess and evaluate senior clinical nurses in hospitals, and to confirm the validity and reliability of the scale. METHOD: A cross-sectional questionnaire survey was undertaken at a hospital in Japan, using an anonymous self-administered questionnaire administered to clinical nurses (n=374). A useable sample of 218 was achieved, which was used in the analysis. Statistical analysis examined exploratory/confirmatory factor analysis, internal consistency, and construct validity. RESULTS: A five factor solution with 22 items was extracted for nursing competence in senior clinical nurses, which was the interpretable questionnaire. In the confirmatory factor analysis, the indices of fitness supported these results. Cronbach's alpha coefficient was 0.93 for the total score and varied between 0.63 and 0.90 in the five factors. Five factors emerged from an oblique factor analysis, with a cumulative variance of 66.7%: "role accomplishment"; "self-management"; "research"; "practice and coordination"; and "work implementation". The five factors had only a moderate correlation (0.30-0.77, P<0.001) with each other, which indicated construct validity. CONCLUSION: The CS-SCN, a concise scale to measure and evaluate the competence of senior clinical nurses, was developed. Results suggest initial support for the new instrument as a measure of competence of senior clinical nurses, but it must be further refined, tested, and evaluated. Both the validity and reliability of the scale were verified. Future studies using the CS-SCN might lead to improvement in the competence of senior clinical nurses. PMID- 23735091 TI - Smoking cessation and characteristics of success and failure among female high school smokers. AB - AIM: The purpose of this study was to investigate the effects of a smoking cessation program on female high-school students and to analyze the characteristics of students who quit smoking compared to those of students who failed to quit. METHODS: This study used a mixed research design, including a pre and post-experimental design for measuring the effects of the smoking cessation intervention and a qualitative design using a focus group interview to analyze the characteristics of individuals who successfully quit in comparison to those who failed to stop smoking. Data were collected before and after the intervention through a self-report questionnaire, a biochemical index, and a focus group interview. RESULTS: After the intervention, positive changes in stage in the transtheoretical model for smoking-cessation behavior increased significantly (P<0.001), and the number of cigarettes smoked daily (P=0.001), dependency on nicotine, expiratory CO levels, and positive frequency of urine nicotine levels decreased significantly (P<0.001). Based on data from the focus group interview, students who stopped smoking showed different intrapersonal, interpersonal, and environmental characteristics compared to students who failed to stop smoking. CONCLUSION: The results suggest that the smoking-cessation program could be more effective if it were to involve teachers and family members. In addition, a smoking-prohibited community environment could assist in the control of adolescents' smoking behavior. PMID- 23735092 TI - Investigation of actual daily lifestyle leading to continuous self-management after living-donor liver transplantation: more than 5 years living with living donor liver transplantation and emotions of recipients. AB - AIM: This research aimed to investigate the actual daily lifestyle leading to continuous self-management after living-donor liver transplantation (LDLT), by interviewing more than 5 year survivors of transplantation on their lifestyles from various angles, such as meals, rests, and human relationships. METHOD: In this research, survivors of more than 5 years were interviewed about their daily lifestyle, and a qualitative inductive approach to the analysis of continuous self-management was taken. RESULTS: Interviews were conducted with 26 patients: 11 men and 15 women with an average age of 49 years (range, 22-76). Through analysis, 205 labels were extracted, which were aggregated into one core category, 13 categories and 68 subcategories. Differences in the three patterns of lifestyle--"the reflected lifestyle after operation", "unchanged daily lifestyle", and "self-management eases along with recovery"--occurred owing to differences in changes in values through the transplantation experience. The changes in values were affected by realization of the experience and the action, which come from various internal and external influences during the process of recovery. All of the recipients used consulting behavior to complement self management after leaving hospital. CONCLUSION: The daily lifestyle of transplant recipients was clarified by the patterns of lifestyle. Differences in the three lifestyle types occurred owing to differences in changes in values though the transplantation experience. PMID- 23735093 TI - Development of a Decision Tree Analysis model that predicts recovery from acute brain injury. AB - AIM: The present study was conducted to identify significant demographic, illness related, and physiological factors associated with recovery at 1 month after brain injury, and to develop and evaluate a Decision Tree Analysis-based prediction model. METHODS: This study was conducted using a prospective study design. The study subjects were 190 adult patients with brain injury admitted to the neurological intensive care unit of a university hospital located in Incheon, South Korea. Degree of recovery from brain injury was evaluated 1 month after admission using the Glasgow Outcome Scale. RESULTS: A prediction model was developed using Decision Tree Analysis. The most significant predictor of recovery at 1 month after brain injury using the devised model was Glasgow Coma Scale score on admission, and its optimum cut-off value for the differentiation of good and poor recovery was 8.5. The next best predictors were age and blood glucose level on admission, which had cut-off values of 49.5 years and 155 mg/dL, respectively. In addition, hematoma volume, systolic blood pressure, and respiratory rate on admission were also found to predict 1 month recovery significantly, with corresponding cut-off values of 44 cc, 168 mmHg, and 29/min, respectively. CONCLUSION: The developed model includes common and routinely used monitoring parameters as significant predictors, and proposes cut-off values for these predictors. This model appears to be useful for predicting 1 month recovery in various brain injury types. The authors believe that the devised model provides a basis for the evidence-based nursing care of brain injured patients during the acute stage. PMID- 23735094 TI - Ethical issues in practice: a survey of home-visiting nurses in Japan. AB - AIM: The purposes of this study were to identify specific components and frequencies of ethical issues that home-visiting nurses encountered in their practice, relationships between ethical issues and demographic data, and experience of ethics education and workplace environment. METHODS: A self administered questionnaire was distributed to home-visiting nurses in Japan. Usable data (1961) were analyzed. RESULTS: Item and exploratory factor analysis for the frequency of encountering ethical issues revealed: (i) concern about respecting client or relationships with relevant professionals; (ii) differences in treatment or care-taking views among home-visiting nurse and client and family, or relevant professionals; and (iii) discrepancy of intention between family and client or home-visiting nurse. All factors were significantly positively related to the current position, duration of working experience as a home-visiting nurse, and type of nursing education; age was significantly negatively related. Home-visiting nurses noted that programmed continuing education systems and staff-training programs were not sufficiently available. CONCLUSION: The findings of this study indicated the characteristics of ethical issues that home-visiting nurses encountered in their practice and insufficient continuing education system including ethics education. Ethics education programs tailored to home-visiting nurses ethical concerns and traits and continuing education systems are needed. PMID- 23735095 TI - Empirical analysis of content of support in regional intractable disease consultation. AB - AIM: The purpose of this research is to study the content of support provided by nurses who were employed in a regional intractable disease consultation project. METHODS: The content of support was classified using records of 943 consultations with intractable disease patients and their families conducted over a 5 year period in a regional intractable disease consultation project in one prefecture of Japan as the subject of analysis. The number of recording units in respective categories was compared. RESULTS: A total of 1276 recording units were extracted from the data and organized into two major categories, eight minor categories, and 24 subcategories. The major category [Support for problem solving by patients' and their families' own efforts] comprised four minor categories, which have the aims of respect of the independence of the patient and patient's family and support for the solution of problems. The major category [Coordination with support division] comprised four minor categories, as support for problems which are difficult for the patient and their family to solve. CONCLUSION: The distinctive features of regional intractable disease consultations conducted by nurses are support from the combined viewpoints of medical care and everyday life, specialized support based on the features of the patient's disease, and coordination with close support persons. In education for nurses who are to be employed in this field, it is necessary to develop competence in responding to the specialized support needs of intractable diseases and coordination of support persons. PMID- 23735097 TI - Secondary analysis of national survey datasets. AB - AIM: This paper describes the methodological issues associated with secondary analysis of large national survey datasets. METHODS: Issues about survey sampling, data collection, and non-response and missing data in terms of methodological validity and reliability are discussed. RESULTS: Although reanalyzing large national survey datasets is an expedient and cost-efficient way of producing nursing knowledge, successful investigations require a methodological consideration of the intrinsic limitations of secondary survey analysis. CONCLUSIONS: Nursing researchers using existing national survey datasets should understand potential sources of error associated with survey sampling, data collection, and non-response and missing data. Although it is impossible to eliminate all potential errors, researchers using existing national survey datasets must be aware of the possible influence of errors on the results of the analyses. PMID- 23735096 TI - Barriers to diabetes control from Syrian women's perspectives. AB - AIM: Diabetes constitutes a major public health problem and is a leading cause of morbidity and mortality. The purpose of this study was to explore the barriers to diabetes control of middle-aged Syrian women with type 2 diabetes. METHODS: A qualitative approach was adopted using conventional content analysis of semi structured interviews carried out with 12 women with type 2 diabetes in the diabetic center in Lattakia (Syria) between March 2010 and December 2010. The participants were recruited by the purposeful sampling method. RESULTS: Three main themes emerged from the data analysis: (i) a poor patient-healthcare provider relationship; (ii) inadequate education; (iii) and psychosocial problems. The first theme had two subthemes: (i) relationship with doctors; and (ii) relationship with nurses. The second theme was without subthemes. The third theme consisted of six subthemes: (i) work and family responsibilities; (ii) motherhood role; (iii) lack of social support; (iv) anxiety; (v) depression; and (vi) low self-efficacy. CONCLUSION: The findings support that effective relationships can be enhanced through active listening and by opening a free channel for the flow of ideas and information between patients and healthcare providers. Additionally, providers have an important role to play in learning to identify and manage the psychosocial problems that arise in living with diabetes, so that their patients can be supported in overcoming barriers to managing their diabetes more effectively. PMID- 23735098 TI - Occupational therapy for inpatients with chronic schizophrenia: a pilot randomized controlled trial. AB - AIM: People with schizophrenia tend to experience difficulties in social and cognitive function, self-care, residual negative symptoms, high rates of unemployment, and social exclusion. Occupational therapy has contributed to the treatment and rehabilitation of people with severe mental health problems. Therefore, this study investigated the effects of occupational therapy on symptoms of patients with schizophrenia. METHODS: This survey was an experimental study in which positive and negative symptoms of patients with schizophrenia were assessed with a scale for the assessment of positive and negative symptoms (SANS, SAPS, respectively). The study was conducted in Sina Hospital, Shahrekord, Iran. The samples consisted of patients with schizophrenia who were divided randomly into intervention and usual treatment groups (30 patients in each group). The occupational therapy was performed in the intervention group for 18 h/week for 6 months. SANS and SAPS were assessed at the beginning and after 6 months of treatment. RESULTS: The groups were homogeneous in demographic variables, SANS and SAPS scores at baseline. The occupational therapy group showed significant improvement in the total score for the SANS and SAPS at 6 months (P<0.001), but the control group did not show any significant improvement. CONCLUSION: The results of this study indicated that occupational therapy combined with medications can improve the symptoms of schizophrenia. PMID- 23735099 TI - Role of capillary electrophoresis in the fight against doping in sports. AB - At present the role of capillary electrophoresis in the detection of doping agents in athletes is, for the most part, nonexistent. More traditional techniques, namely gas and liquid chromatography with mass spectrometric detection, remain the gold standard of antidoping tests. This Feature will investigate the in-roads that capillary electrophoresis has made, the limitations that the technique suffers from, and where the technique may grow into being a key tool for antidoping analysis. PMID- 23735100 TI - One-pot synthesis of polysubstituted indolizines by an addition/cycloaromatization sequence. AB - Indolizines carrying various substituents in positions 5-8 were obtained from readily available 2-(1H-pyrrol-1-yl)nitriles and alpha,beta-unsaturated ketones or aldehydes in a one-pot procedure. Michael addition of the deprotonated aminonitriles to the acceptors followed by acid-catalyzed electrophilic cyclization produces 5,6-dihydroindolizine-5-carbonitriles. From these stable intermediates, substituted indolizines were obtained via base-induced dehydrocyanation. PMID- 23735101 TI - Red flag imaging techniques in Barrett's esophagus. AB - The key to detection and treatment of early neoplasia in Barrett's esophagus (BE) is thorough and careful inspection of the Barrett's segment. The greatest role for red flag techniques is to help identify neoplastic lesions for targeted biopsy and therapy. High-definition white light endoscopy (HD-WLE) can potentially improve endoscopic imaging of BE compared with standard endoscopy, but little scientific evidence supports this. The addition of autofluorescence imaging to HD-WLE and narrow band imaging increases sensitivity and the false positive rate without significantly improving overall detection of BE-related neoplasia. PMID- 23735102 TI - Optical coherence tomography in Barrett's esophagus. AB - The incidence of Barrett's-related adenocarcinoma of the esophagus continues to increase at an alarming rate. Studies to date show great promise for optical coherence tomography (OCT) in screening, surveillance, and guiding management of Barrett's esophagus. With continued innovation in rapid, accurate scanning systems, such as volumetric laser endomicroscopy or optical frequency domain imaging, advanced OCT seems likely to have an important impact. The next few years are likely to see the initiation of large clinical studies that will define the extent and significance of this impact. PMID- 23735103 TI - Endomicroscopy in Barrett's esophagus. AB - Barrett's esophagus has been a focus of confocal laser endomicroscopy (CLE) research. There are two CLE systems available, one probe-based and the other with a microscope embedded in the tip of an endoscope. Several CLE image classification systems are available. Studies suggest that CLE has good sensitivity, negative predictive value, and accuracy for detecting neoplasia, with good interobserver agreement using the CLE image classification systems. Larger, multicenter studies have been completed evaluating the impact of CLE on treatment of patients with BE. Future developments may include more specific contrast agents and new types of endomicroscopes. PMID- 23735104 TI - Red-flag technologies in gastric neoplasia. AB - Given its morbidity and mortality, the early detection and diagnosis of gastric cancer is an area of intense research focus. This article reviews the emerging use of enhanced endoscopic imaging technologies in the detection and management of gastric cancer. The combined use of white-light endoscopy with enhanced imaging technologies, such as magnification narrow-band imaging, chromoendoscopy, and autofluorescence endoscopy, demonstrates promise in the improved ability to detect and delineate gastric neoplasia. However, widespread clinical use is still limited, mainly because of the restricted availability of the technologies. PMID- 23735105 TI - Endomicroscopy and targeted imaging of gastric neoplasia. AB - Confocal laser endomicroscopy (CLE) allows microscopic imaging of the gastric mucosa in real time during endoscopy. Gastroenterologists are able to evaluate gastric pathologies in real time, which is used to target fewer biopsies to regions of interest by providing multiple "optical" biopsies, and guide endoscopic interventions. CLE provides a powerful tool for translational studies to unravel the pathophysiology of diseases in vivo virtually free of artifacts. Molecular imaging may help to detect suspicious lesions and to predict response to targeted therapy. This review provides an overview of current applications of endomicroscopy of the stomach in clinical and translational science. PMID- 23735106 TI - Advanced EUS imaging for early detection of pancreatic cancer. AB - Endoscopic ultrasound (EUS)-fine needle aspiration remains the gold standard for diagnosing pancreatic malignancy. However, in a subset of patients, limitations remain in regards to image quality and diagnostic yield of biopsies. Several new devices and processors have been developed that allow for enhancement of the EUS image. Initial studies of these modalities do show promise. However, cost, availability, and overall incremental benefit to EUS-fine needle aspiration have yet to be determined. PMID- 23735107 TI - Advanced techniques for endoscopic biliary imaging: cholangioscopy, endoscopic ultrasonography, confocal, and beyond. AB - Cholangioscopy, endosonography, and confocal microscopy represent important technologies that expand biliary imaging beyond a level previously realized by noninvasive modalities (ultrasonography, computed tomography, and magnetic resonance cholangiopancreatography) and endoscopic retrograde cholangiopancreatography. Endoscopic ultrasonography has shown efficacy for the evaluation of indeterminate biliary strictures; however, this modality seems most reliable for distal bile duct abnormalities and in the setting of a moderate to high pretest probability for malignancy. Further refinement of these technologies, validation of their respective diagnostic criteria, and study within the context of comparative, randomized trials are needed and will contribute greatly to expedient patient care. PMID- 23735108 TI - The new view of colon cancer screening: forwards and backwards. AB - Many different techniques for colon cancer screening are available. The fecal immunochemical test is best for fecal-based screening, although the DNA investigation may be more specific when further developed. Computed tomographic colonography is as good as colonoscopy for detecting colon cancer and is almost as good as colonoscopy for detecting advanced adenomas, but has limitations. The flexible sigmoidoscopic examination markedly decreases the incidence of cancer in the visualized segments, but colonoscopy is currently the best procedure for evaluating the large bowel. Techniques for retroflexion or backward view of the colon have been investigated, with all showing increased polyp detection. PMID- 23735109 TI - Colonic polyps: are we ready to resect and discard? AB - Colorectal cancer represents a major cause of mortality in Western countries, and population-based colonoscopy screening is supported by official guidelines. A significant determinant of the cost of colonoscopy screening/surveillance is driven by polypectomy of diminutive (<=5 mm) lesions. When considering the low prevalence of advanced neoplasia within diminutive polyps, the additional cost of pathologic examination is mainly justified by the need to differentiate between precancerous adenomatous versus hyperplastic polyps. The aim of this review is to summarize the data supporting the clinical application of a resect and discard strategy, also addressing the potential pitfalls associated with this approach. PMID- 23735110 TI - Surveillance in inflammatory bowel disease: chromoendoscopy and digital mucosal enhancement. AB - Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer. Performing periodic dysplasia screening and surveillance may diminish this risk. To date, chromoendoscopy is the only technique that has consistently yielded positive results in large, well-designed dysplasia-detection trials. Most major society guidelines endorse chromoendoscopy as an adjunct, accepted, or preferred dysplasia-detection tool. This review outlines the available endoscopic technologies for the detection of dysplasia in IBD, considers the evidence supporting their use, and assesses which modalities are ready for use in clinical practice. PMID- 23735111 TI - Endomicroscopy and endocytoscopy in IBD. AB - Two types of endomicroscopy systems exist. One is integrated into a standard, high-resolution endoscope and one is probe-based, capable of passage through the working channel of a standard endoscope. Endocytoscopy allows visualization of the superficial mucosal layer. Endoscope-integrated and probe-based devices allow magnification of the mucosa up to 1400-fold. Endomicroscopy can differentiate histologic changes of Crohn disease and ulcerative colitis in vivo in real time. Endocytoscopy can discriminate mucosal inflammatory cells, allowing determination of histopathologic activity of ulcerative colitis. Molecular imaging with fluorescence-labeled probes against disease-specific receptors will enable individualized management of inflammatory bowel diseases. PMID- 23735113 TI - Advanced imaging for GI endoscopy. PMID- 23735112 TI - Optical molecular imaging in the gastrointestinal tract. AB - Recent developments in optical molecular imaging allow for real-time identification of morphologic and biochemical changes in tissue associated with gastrointestinal neoplasia. This review summarizes widefield and high-resolution imaging modalities in preclinical and clinical evaluation for the detection of colorectal cancer and esophageal cancer. Widefield techniques discussed include high-definition white light endoscopy, narrow band imaging, autofluoresence imaging, and chromoendoscopy; high-resolution techniques discussed include probe based confocal laser endomicroscopy, high-resolution microendoscopy, and optical coherence tomography. New approaches to enhance image contrast using vital dyes and molecular-specific targeted contrast agents are evaluated. PMID- 23735114 TI - The evolving field of endoscopic imaging. PMID- 23735115 TI - Selective conversion of CO2 to CO with high efficiency using an inexpensive bismuth-based electrocatalyst. AB - The wide-scale implementation of solar and other renewable sources of electricity requires improved means for energy storage. An intriguing strategy in this regard is the reduction of CO2 to CO, which generates an energy-rich commodity chemical that can be coupled to liquid fuel production. In this work, we report an inexpensive bismuth-carbon monoxide evolving catalyst (Bi-CMEC) that can be formed upon cathodic polarization of an inert glassy carbon electrode in acidic solutions containing Bi(3+) ions. This catalyst can be used in conjunction with ionic liquids to effect the electrocatalytic conversion of CO2 to CO with appreciable current density at overpotentials below 0.2 V. Bi-CMEC is selective for production of CO, operating with a Faradaic efficiency of approximately 95%. When taken together, these correspond to a high-energy efficiency for CO production, on par with that which has historically only been observed using expensive silver and gold cathodes. PMID- 23735116 TI - Vitamin D status in cord blood and newborns: ethnic differences. AB - BACKGROUND: A deficiency in vitamin D (25OHD) is common throughout the world in both adults and children, being related to skin pigmentation, sun exposure, dietary intake and obesity. Limited data are available for the neonatal age. The aim of the study is to understand the differences in 25OHD levels with respect to skin colour and ethnicity in newborns. METHODS: We randomly enrolled 62 neonates, born at term and appropriate for gestational age. Thirty two were born from Italian mothers with fair skin (FS) and 30 from non-Caucasian mothers (North African, African, Asian and Latin American): 10 with light olive/light brown (LOB) and 20 with medium brown/black skin (MBB). Vitamin D was measured in the cord blood at birth and in neonatal serum during metabolic screening. RESULTS: 25OHD levels were (mean +/- SD) 21.4 +/- 11 ng/ml in cord blood and 14.9 +/- 7 ng/ml in serum after birth. 25OHD values were higher in cord blood (p < 0.01) and neonatal serum (p < 0.001) in subjects supplemented with Vitamin D. Newborn FS showed higher vitamin D levels in cord blood when compared to LOB and MBB (p < 0.01), and higher levels in neonatal serum when compared to LOB (p < 0.01). In cord blood, 25OHD levels were higher in Italian newborns than in North African (p < 0.004) and African (p < 0.01). In neonatal serum, 25OHD levels were higher in Italian infants only when compared with North African infants (p < 0.03). CONCLUSIONS: The present study shows a high prevalence of vitamin D insufficiency and deficiency in newborns with significant differences observed to be due to ethnicity, skin colour and maternal supplementation during the pregnancy. PMID- 23735117 TI - Shewanella haliotis associated with severe soft tissue infection, Thailand, 2012. PMID- 23735118 TI - Efficacy of "seeking safety" in a Dutch population of traumatized substance-use disorder outpatients: study protocol of a randomized controlled trial. AB - BACKGROUND: Traumatic experiences and, more specifically, posttraumatic stress disorder (PTSD) are highly prevalent among substance use disorder (SUD) patients. This comorbidity is associated with worse treatment outcomes in substance use treatment programs and more crisis interventions. International guidelines advise an integrated approach to the treatment of trauma related problems and SUD. Seeking Safety is an integrated treatment program that was developed in the United States. The aim of the current study is to test the efficacy of this program in the Netherlands in an outpatient SUD population. METHODS/DESIGN: A randomized controlled trial (RCT) will be used to test the efficacy of Seeking Safety compared to Cognitive Behavioral Therapy (CBT) in a population of SUD outpatients. Each treatment will consist of 12 group sessions. The primary outcome measure will be substance use severity. Secondary outcome measures are PTSD and trauma symptoms, coping skills, functioning, and cognitions. Questionnaires will be administered at the start of treatment, at the end of treatment (three months after the start of treatment) and at follow-up (six months after the start of treatment). DISCUSSION: This study protocol presents a RCT in which the efficacy of an integrated treatment for comorbid PTSD and SUD, Seeking Safety, is evaluated in a SUD outpatient population compared to CBT. It is expected that the intervention group will show significantly more improvement in substance use severity compared to the control group at end-of-treatment and at follow-up. Furthermore, a lower drop-out rate is expected for the intervention group. If the intervention proves to be effective, it can be implemented. A cost effectiveness analysis will be conducted to evaluate the two treatments. TRIAL REGISTRATION: The protocol for this study is registered with the Netherlands Trial Register with number NTR3084 and approved by the local medical ethical committee (METC?11270.haa). PMID- 23735119 TI - An in vitro model for spontaneous angiogenesis using rat mesenteric endothelial cells: possible therapeutic perspective for obesity and related disorders. AB - CONTEXT: Abnormal obesity and the related diseases, such as diabetes and cardiovascular disease, are the main causes of mortality, around the world. A key feature of the adipogenesis and obesity is angiogenesis-dependent tissue growth accompanied with extracellular remodeling. In this way, suppression of angiogenesis may be a key point for preventing the adipogenesis. OBJECTIVE: In the present study, to provide a deeper insight to understand obesity and screening for more effective therapeutics, we have developed a three-dimensional in vitro model of microvessel formation under collagen matrix culture using endothelial cells, extracted from a suitable tissue. MATERIALS AND METHODS: In a successful approach for developing an angiogenesis model, the rat mesenteric microvascular endothelial cells (RMMECs) were isolated, coated on dextran beads and then suspended in collagen gel. Additionally, the proliferation as well as migration of endothelial cells were analyzed and compared with human umbilical vein endothelial cells (HUVECs). RESULTS: RMMECs showed remarkable migration ability and had higher growth during the logarithmic growth phase, when compared with HUVECs. Also, no significance differences in morphogenesis were observed between HUVECs and RMMECs. DISCUSSION AND CONCLUSION: The model may be useful in providing insights to develop potential intervention strategies in vivo against obesity-related disorders. Targeting endothelial cells is an interesting and exciting possibility that may be raised in further investigations. PMID- 23735120 TI - Cognitive control adjustments and conflict adaptation in major depressive disorder. AB - Individuals with major depressive disorder (MDD) show alterations in the cognitive control function of conflict processing. We examined the influence of these deficits on behavioral and event-related potential (ERP) indices of conflict adaptation, a cognitive control process wherein previous-trial congruency modulates current-trial performance, in 55 individuals with MDD and 55 matched controls. ERPs were calculated while participants completed a modified flanker task. There were nonsignificant between-groups differences in response time, error rate, and N2 indices of conflict adaptation. Higher depressive symptom scores were associated with smaller mean N2 conflict adaptation scores for individuals with MDD and when collapsed across groups. Results were consistent when comorbidity and medications were analyzed. These findings suggest N2 conflict adaptation is associated with depressive symptoms rather than clinical diagnosis alone. PMID- 23735121 TI - Renal and mesenteric tissue oxygenation in preterm infants treated with oral ibuprofen. AB - BACKGROUND: Hemodynamically significant patent ductus arteriosus (PDA) is a common problem in preterm infants which often causes significant morbidities. Although PDA induces alterations in various tissue perfusion, there is scarce information about the effect of oral ibuprofen on hemodynamics of regional tissues. OBJECTIVE: To investigate, using near-infrared spectroscopy, the effect of oral ibuprofen on renal and mesenteric tissue oxygenation and oxygen extraction in preterm infants with a diagnosis of hemodynamically significant PDA. PATIENTS AND METHODS: Fifteen infants (gestational age <32 weeks) with the diagnosis of hemodynamically significant PDA treated with oral ibuprofen were monitored for near-infrared spectroscopy - determined renal and mesenteric oxygenation. The infants with PDA were matched for gestational age, postnatal age with infants without PDA, who served as control subjects. RESULTS: In infants with PDA, mean arterial blood pressure was significantly lower compared with the control infants [39.3 (range:36-54) versus 51 (range:43-66) mmHg, respectively; p < 0.001)]. There were no significant differences in regional oxygen saturation and fractional oxygen extraction of renal and mesenteric tissues in PDA and control infants (p > 0.05). And ibuprofen treatment did not negatively influence renal and mesenteric oxygenation and extraction in infants with PDA (p > 0.05). CONCLUSION: Renal and mesenteric tissue oxygenation and oxygen extraction were preserved in preterm infants with a diagnosis of hemodynamically significant PDA treated with oral ibuprofen. PMID- 23735122 TI - Software tool for 3D extraction of germinal centers. AB - BACKGROUND: Germinal Centers (GC) are short-lived micro-anatomical structures, within lymphoid organs, where affinity maturation is initiated. Theoretical modeling of the dynamics of the GC reaction including follicular CD4+ T helper and the recently described follicular regulatory CD4+ T cell populations, predicts that the intensity and life span of such reactions is driven by both types of T cells, yet controlled primarily by follicular regulatory CD4+ T cells. In order to calibrate GC models, it is necessary to properly analyze the kinetics of GC sizes. Presently, the estimation of spleen GC volumes relies upon confocal microscopy images from 20-30 slices spanning a depth of ~ 20 - 50 MUm, whose GC areas are analyzed, slice-by-slice, for subsequent 3D reconstruction and quantification. The quantity of data to be analyzed from such images taken for kinetics experiments is usually prohibitively large to extract semi-manually with existing software. As a result, the entire procedure is highly time-consuming, and inaccurate, thereby motivating the need for a new software tool that can automatically identify and calculate the 3D spot volumes from GC multidimensional images. RESULTS: We have developed pyBioImage, an open source cross platform image analysis software application, written in python with C extensions that is specifically tailored to the needs of immunologic research involving 4D imaging of GCs. The software provides 1) support for importing many multi-image formats, 2) basic image processing and analysis, and 3) the ExtractGC module, that allows for automatic analysis and visualization of extracted GC volumes from multidimensional confocal microscopy images. We present concrete examples of different microscopy image data sets of GC that have been used in experimental and theoretical studies of mouse model GC dynamics. CONCLUSIONS: The pyBioImage software framework seeks to be a general purpose image application for immunological research based on 4D imaging. The ExtractGC module uses a novel clustering algorithm for automatically extracting quantitative spatial information of a large number of GCs from a collection of confocal microscopy images. In addition, the software provides 3D visualization of the GCs reconstructed from the image stacks. The application is available for public use at http://sourceforge.net/projects/pybioimage/. PMID- 23735123 TI - Neural plasticity and the Kennard principle: Does it work for the preterm brain? AB - The Kennard principle suggests that the immature brain should be more able to recover from injury than the more developed brain. Curiously, preterm infants continue to have a high rate of debilitating neurodevelopmental handicaps despite a progressive improvement in structural damage to the brain, from acute necrotic injury of the periventricular white matter, with axonal loss in historical cohorts, to diffuse gliosis with trivial axonal damage. In the present review we examine recent evidence that disability after preterm birth is largely mediated by disturbed development of neuronal connections. Potential mechanisms include impaired white matter maturation associated with gliosis, suboptimal neuronal maturation, adverse effects of infection/inflammation on the cell environment, exposure to clinical therapies that modulate brain function (including maternal glucocorticoids), upregulation of physiological apoptosis and loss or misprogramming of progenitor cells in the subventricular zone. These findings suggest that insults during this critical phase alter the trajectory of brain development and that a key focus of basic science and clinical research should be to understand neuronal connectivity, as well as the triggers of cell death. PMID- 23735124 TI - Personalized commissioning, public spaces: the limits of the market in English social care services. AB - BACKGROUND: The article explores the implications of personal budgets within English social care services, which position the individual as market actor. Rooting the research in the broader personalization agenda, the study looks at the limitations of the market in relation to individual purchase of private goods (e.g. home care), in the pooling of funds to purchase group services and in the provision of public goods such as building-based services. METHOD: The article takes a multi-method approach, combining an interpretive focus on the framing of the personal budget-holder by advocates of personalization with national evaluation data, and data from a small survey of day centre workers. RESULTS: The article identifies three framings of the individual budget-holder articulated by advocates of personalization. The first is that personal budget-holders will be empowered market actors, commissioning the services they need. The second is that budget-holders will pool resources with others to purchase group services in order to broaden the range of options available to them. The third is that services which cannot be disaggregated into individual or group budgets - such as day centres - are not valued by service users. The article looks at the evaluation data on these three claims in turn. It identifies four limitations to the capacity of people to purchase care goods on an individual basis: lack of transparency in allocating budgets, complexity in managing a budget, excessive auditing of spending and lack of responsiveness from the provider market. Pooling of budgets to purchase collective services is found to be underdeveloped, and hampered by the complexity which is a broader limitation on personal budgets. Day centres are found to be closing not in response to commissioning decisions by individual budget-holders but because of decommissioning by local authorities, minimising the scope for individuals to express a preference for this type of care. The survey highlights patterns of day centre closure, rising fees for attendance and reduced eligibility, and the underdevelopment of mechanisms to facilitate commissioning of new collective spaces. CONCLUSIONS: The paper concludes that the transition to personal budgets - in the context of the accompanying financial crisis in local authorities - has led to inadequate attention to the potential for an undersupply of collective and public goods. The loss of day centre provision will be felt by personal budget holders but also by self-funders and people in residential accommodation who may no longer be eligible for, or able to afford, to access shared spaces. Local authorities are actively taking on the role of decommissioners without sufficient responsiveness to how and what individuals want them to commission. PMID- 23735125 TI - Positive emotions from social company in women with persisting subclinical psychosis: lessons from daily life. AB - OBJECTIVE: Altered social reward functioning is associated with psychosis irrespective of stage and severity. Examining the role of social reward functioning prospectively in relation to psychotic experiences before these become persistent and potentially disabling can aid in elucidating social mechanisms that induce shifts toward more severe psychotic states, without the confounding effects of clinical disorder. METHOD: In a longitudinal general population sample (N = 566), the experience sampling method (repetitive random sampling of momentary emotions and social context) was used to assess daily life social functioning at baseline. Persistence of subclinical psychotic experiences was based on the Community Assessment of Psychic Experiences assessed three times over 14 months. Analyses examined to what degree i) social context and ii) appreciation thereof differentiated between those who did and did not develop persistent psychotic experiences. RESULTS: Although individuals with persistent psychotic experiences did not differ in overall level of positive effect, the amount of time spent alone or the level of social satisfaction compared to individuals without persistent psychotic experiences, they were more sensitive to the rewarding effects of social company. CONCLUSION: Alterations in social reward experience may form one of the mechanisms that precede the development of the extended psychosis phenotype over time. PMID- 23735126 TI - An optimized algorithm for detecting and annotating regional differential methylation. AB - BACKGROUND: DNA methylation profiling reveals important differentially methylated regions (DMRs) of the genome that are altered during development or that are perturbed by disease. To date, few programs exist for regional analysis of enriched or whole-genome bisulfate conversion sequencing data, even though such data are increasingly common. Here, we describe an open-source, optimized method for determining empirically based DMRs (eDMR) from high-throughput sequence data that is applicable to enriched whole-genome methylation profiling datasets, as well as other globally enriched epigenetic modification data. RESULTS: Here we show that our bimodal distribution model and weighted cost function for optimized regional methylation analysis provides accurate boundaries of regions harboring significant epigenetic modifications. Our algorithm takes the spatial distribution of CpGs into account for the enrichment assay, allowing for optimization of the definition of empirical regions for differential methylation. Combined with the dependent adjustment for regional p-value combination and DMR annotation, we provide a method that may be applied to a variety of datasets for rapid DMR analysis. Our method classifies both the directionality of DMRs and their genome-wide distribution, and we have observed that shows clinical relevance through correct stratification of two Acute Myeloid Leukemia (AML) tumor sub-types. CONCLUSIONS: Our weighted optimization algorithm eDMR for calling DMRs extends an established DMR R pipeline (methylKit) and provides a needed resource in epigenomics. Our method enables an accurate and scalable way of finding DMRs in high-throughput methylation sequencing experiments. eDMR is available for download at http://code.google.com/p/edmr/. PMID- 23735127 TI - Review of direct-acting antiviral agents for the treatment of chronic hepatitis C. AB - INTRODUCTION: Rapid breakthroughs in the treatment of hepatitis C virus (HCV) infection have dramatically altered the treatment landscape for this chronic disease. In 2011, the protease inhibitors (PIs) boceprevir and telaprevir in combination with peginterferon (peg-IFN) and ribavirin (RBV) were the first direct-acting antivirals (DAAs) approved in the United States for treatment of genotype (GT) 1 HCV. Several DAAs currently in late-stage clinical trials, including NS3/NS4A serine PIs, NS5A inhibitors, NS5B polymerase inhibitors (both nucleoside and non-nucleoside) and cyclophilin inhibitors, both with and without peg-IFN and RBV, are promising for the treatment of HCV. DAA regimens offer several advantages including that they specifically target HCV viral replication and thus appear to be less dependent on host characteristics, very high SVR rates accompanied by fewer side effects (SE) and lower pill burdens. A review on the treatment of HCV is important and timely as the development on DAAs is progressing rapidly and the health-care providers need to be aware about this as these regimens are anticipated to become clinically available soon. AREAS COVERED: The literature was searched and reviewed using PubMed as well as data gathered from those presented at the international liver meetings, AASLD and EASL as well as CROI. EXPERT OPINION: With the potential of eliminating IFN and RBV, several DAAs under clinical development appear to be promising using novel approaches with good antiviral effects, shorter duration and lower SE profile. PMID- 23735129 TI - Surgical training and assessment: 2013. PMID- 23735130 TI - Assessment of surgical trainees in the workplace. PMID- 23735131 TI - In-training assessment at the Royal Australasian College of Surgeons. PMID- 23735133 TI - In-training assessments used in the United States surgical residency programmes. AB - INTRODUCTION: Quality and safety concerns have always been the impetus for evaluating surgical competence. This paper provides a focused overview of key historical events that lead to the development and implementation of surgical training standards and competency assessments in the United States. METHODS: Focused review of surgical literature. RESULTS: The following events were found to correlate with the development and implementation of training standards and competency assessments: (i) The Flexner Report issued in 1910; (ii) The American Medical Association's 1928 endorsement of the 'Essentials of Approved Residencies and Fellowships'; and (iii) The formation of several major surgical organizations - American College of Surgeons (1913), American Board of Surgery (1937), Residency Review Committee for Surgery (1950) and Association of Program Directors in Surgery (1966). DISCUSSION: The process by which competence is assessed in the US surgical training programmes is multifactorial and heavily linked to the structure and function of several national organizations in surgery and medicine. PMID- 23735134 TI - An extremely rare case of giant mesocolonic haemangioma. PMID- 23735135 TI - Case report of bowel perforation after metallic 'Buckyball' ingestion. PMID- 23735136 TI - Endovascular repair of popliteal artery pseudoaneurysm with covered stent following total knee joint replacement. PMID- 23735137 TI - A limb threatening complication of intravenous fluid resuscitation. PMID- 23735138 TI - A rare differential diagnosis of a common clinical presentation. PMID- 23735139 TI - Aortocaval fistula: patting the 'purring tiger'. PMID- 23735140 TI - Developmental potential of in vitro or in vivo matured oocytes. AB - This study compared the embryological features of mature and immature oocytes (different stages) collected from stimulated cycles of in vitro fertilization (IVF). Immature oocytes were identified, classified as PI (prophase I - germinal vesicle, GV) or MI (metaphase I), were matured in vitro and fertilized using the intra-cytoplasmic sperm injection (ICSI) technique. Fertilization potential, cleavage, and subsequent transfer/cryopreservation of the embryos derived from these in vitro matured oocytes were compared with those of in vivo matured oocytes (collected at the MII stage). The characteristics of embryos derived from gametes recovered in the MI and MII stages were similar. The fertilization rate of immature oocytes recovered in PI was significantly lower than that of MII oocytes (P = 0.031), and the cleavage rate of the PI group was also lower than that of the MI (P = 0.004) and MII (P < 0.001) groups. In vitro maturation of MI oocytes is a suitable alternative when immature oocytes are recovered, as their characteristics and development are similar to those of in vivo matured oocytes. Optimization of outcomes for PI oocytes will require development of techniques that can distinguish which of these gametes will mature and fertilize. PMID- 23735141 TI - Presidential address upon appointment to the Japanese Society for Dialysis Therapy. PMID- 23735142 TI - Clinical practice guideline for the management of chronic kidney disease-mineral and bone disorder. PMID- 23735143 TI - Occult hepatitis B virus infection in Japanese chronic hemodialysis patients. AB - We investigated the prevalence of occult hepatitis B virus (HBV) infection in Japanese chronic hemodialysis patients. Hemodialysis patients (n = 1041) were screened for occult HBV. The presence of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody, and hepatitis B core antibody (anti-HBc) was determined by various chemiluminescent immunoassays. HBV-DNA was quantified in patients positive for anti-HBc using quantitative real-time polymerase chain reaction. Among the 1041 patients, six (0.6%) were HBsAg-positive and 218 (20.9%) were anti-HBc-positive. All HBsAg-positive patients also tested positive for the presence of HBV DNA. Of 212 HBsAg-negative and anti-HBc-positive patients, three were positive for HBV DNA. Our study showed that the prevalence of occult HBV infection in chronic hemodialysis patients from eastern Japan was 0.3%. PMID- 23735144 TI - Hemodialysis patients born with a low birth weight should have a different time course of kidney diseases than those born with a normal birth weight. AB - Low birth weight (LBW) is thought to be one of the risk factors for the progression of kidney diseases. This study hypothesized that the onset age of kidney disease, the rate of progression of kidney disease, or the age at the time of hemodialysis (HD) induction among HD patients that were born with LBW is different from those without a history of LBW. A questionnaire survey in nine dialysis units in Japan was performed and 427 answer sheets were collected. There were statistically significant differences in the present age, the age of kidney disease onset, and the age of HD induction between LBW group and normal birth weight group (NBW). An analysis limited to participants whose underlying disease was diabetic nephropathy revealed that the duration from the onset of nephropathy to HD induction was much shorter in HD patients with a history of LBW than those with a NBW history. In addition, the Pearson's correlation coefficient between the birth weight and the period from onset of diabetic nephropathy to HD induction was 0.283. Although these results might partly support the primary hypothesis, the necessity to perform other clinical studies is also emphasized. PMID- 23735145 TI - Cause-specific excess mortality among dialysis patients: comparison with the general population in Japan. AB - Despite significant therapeutic advances, mortality of dialysis patients remains unacceptably high. The aim of this study is to compare mortality and its causes in dialysis patients with those in the general Japanese population. We used data for 2008 and 2009 from the Japanese Society for Dialysis Therapy registry and a national Vital Statistics survey. Cardiovascular mortality was defined as death attributed to heart failure, cerebrovascular disorders, myocardial infarction, hyperkalemia/sudden death, and pulmonary thromboembolism. Non-cardiovascular mortality was defined as death attributed to infection, malignancies, cachexia/uremia, chronic hepatitis/cirrhosis, ileus, bleeding, suicide/refusal of treatment, and miscellaneous. We calculated standardized mortality ratios and age adjusted mortality differences between dialysis patients and the general population for all-cause, cardiovascular versus non-cardiovascular, and cause specific mortality. During the 2-year study period, there were 2,284,272 and 51,432 deaths out of 126 million people and 273,237 dialysis patients, respectively. The standardized mortality ratio for all-cause mortality was 4.6 (95% confidence interval, 4.6-4.7) for the dialysis patients compared to the general population. Age-adjusted mortality differences for cardiovascular and non cardiovascular disease were 33.1 and 30.0 per 1000 person-years, respectively. The standardized mortality rate ratios were significant for all cause-specific mortality rates except accidental death. Our study revealed that excess mortality in dialysis patients compared to the general population in Japan is large, and differs according to age and cause of death. Cause-specific mortality studies should be planned to improve life expectancies of dialysis patients. PMID- 23735146 TI - Timing for initiation of continuous renal replacement therapy in patients with septic shock and acute kidney injury. AB - The optimal timing for renal replacement therapy initiation in septic acute kidney injury (AKI) remains controversial. This study investigates the impact of early versus late initiation of continuous renal replacement therapy (CRRT) on organ dysfunction among patients with septic shock and AKI. Patients were dichotomized into "early" (simplified RIFLE Risk) or "late" (simplified RIFLE Injury or Failure) CRRT initiation. Patients with chronic kidney disease stage 5 or those on long-term dialysis were excluded. Organ dysfunction was quantified by Sequential Organ Failure Assessment (SOFA) score. From January 2008 to June 2011, 120 patients fulfilled the inclusion criteria. Thirty-one (26%) underwent "early" while 89 (74%) had "late" CRRT. No significant difference was noted between groups on improvement of total SOFA/non-renal SOFA score or noradrenaline equivalent in the first 24 and 48 h after CRRT initiation. Dialysis requirement and mortality (at 28 days, 3 months and 6 months) did not differ. In conclusion, improvement of non-renal SOFA score 48 h after CRRT correlated with SOFA score on CRRT initiation (P = 0.040) and APACHE IV risk of death (P = 0.000), but not estimated glomerular filtration rate on CRRT initiation (P = 0.377). Improvement of non-renal SOFA score correlated with SOFA score on CRRT initiation and APACHE IV risk of death. However, this retrospective review cannot identify any significant clinical benefit of early CRRT initiation in patients presenting with septic shock and AKI. PMID- 23735147 TI - Distal radial artery pressures predict angiographic result and short-term patency outcome in hemodialysis patients with juxta-anastomotic inflow stenosis of radiocephalic fistula undergoing transradial angioplasty. AB - Distal radial artery pressure (RAP) was observed to be reduced after transradial percutaneous transluminal angioplasty (PTA) on the juxta-anastomotic venous stenosis of radiocephalic arteriovenous fistula (RCAVF). Distal RAPs are easily obtained from a pressure transducer connected with an introducer retrograde inserted into distal radial artery. The clinical role of distal RAP in the setting of transradial PTA remains unknown. This prospective and observational study aimed to explore the relationship between distal RAPs and clinical outcomes. This study recruited hemodialysis patients with RCAVF juxta-anastomotic venous stenosis undergoing transradial PTA. RAP-related variables and procedural data before PTA (pre-PTA) and after PTA (post-PTA) were analyzed. The study endpoint was dysfunction-driven re-PTA during the 1-year follow-up. Overall, 73 PTAs significantly reduced the mean of systolic RAPs from 159.6 +/- 41.4 to 108.4 +/- 41.5 mm Hg; P < 0.0001. Post-PTA systolic RAP was associated with angiographic outcome (P = 0.004) and unassisted patency at 3 months (P = 0.036), but not at 6, 9, or 12 months (P > 0.05). The group with angiographically successful PTAs had a significantly lower mean of post-PTA systolic RAPs compared with that with unsuccessful PTAs (98.4 +/- 35.4 vs. 128.7 +/- 46.1 mm Hg; P = 0.003). The post-PTA systolic RAP may be seen as a predictor for 3-month unassisted patency (AUC = 0.669; P = 0.048). In conclusion, this study provides the RAP profile to help guide transradial PTA on RCAVF juxta-anastomotic venous stenosis and predict 3-month unassisted patency in a hemodynamic manner. PMID- 23735148 TI - Dialyzability and pharmacokinetics of sitafloxacin following multiple oral dosing in infected hemodialysis patients. AB - The pharmacokinetics and dialyzability of oral sitafloxacin, a newly available quinolone, in infected intermittent hemodialysis patients have not been reported previously. Seven infected maintenance hemodialysis patients lacking residual renal function were enrolled. Sitafloxacin (50 mg after hemodialysis on the first day, on the next day and 4 h before scheduled hemodialysis session on the 3rd day) was orally administered. On the 3rd day, blood was taken from arterial and venous sides before and 2 and 4 h after session initiation. Another sampling was performed 1 h after the session and on the 5(th) day of the study. Pharmacokinetic parameters and dialyzability of sitafloxacin were evaluated. All patients exhibited improved symptoms without major problems. Drug concentrations in all arterial samples were above the MIC of targeted bacteria. Dialyzer clearance and elimination fraction were 49.9 +/- 0.9 mL/min per m(2) and 53.3 +/- 2.1%, respectively. Apparent half-life during dialysis session was significantly shorter than that after the session (4.0 +/- 0.4 and 46.5 +/- 3.6 h, during and after the session, respectively). Dialyzer clearance was positively correlated with urea reduction ratio and negatively correlated with serum albumin concentration. About 23% of the drug in the body was removed by dialysis. Rebound of the drug concentration after the dialysis was not seen. Oral dosing of this drug at 50 mg daily in maintenance hemodialysis patients provides a safe drug concentration compatible with that of healthy subjects orally receiving 100 mg daily. Because a significant amount of the drug was removed, administration might be undertaken after the dialysis session. PMID- 23735149 TI - Chronic hemodialysis patients without marked elevation of intact parathyroid hormone are also good candidates for early intervention with cinacalcet. AB - Management of calcium (Ca) and phosphorus (P) metabolism is crucial in chronic hemodialysis (HD) patients. Cinacalcet is usually used for chronic kidney disease mineral and bone disorders (CKD-MBD) patients with elevated intact parathyroid hormone (iPTH) levels. However, a certain number of CKD-MBD patients have normal iPTH levels and are not subjected to cinacalcet therapy. Here, we evaluated the efficacy of a new treatment algorithm of early initiation of cinacalcet therapy in this subgroup of patients, mainly for correcting Ca and P metabolism. Seventy one HD patients, including 44 patients without marked elevation of iPTH (102 < iPTH <= 300 pg/mL), who received cinacalcet therapy, were enrolled in this study. Serum parameters relating to CKD-MBD patient metabolism, doses of phosphate binders, and type of vitamin D sterols were compared between pre- and post cinacalcet administration retrospectively. Sixty-four of 71 patients did not require discontinuation of cinacalcet. In these 64 patients, serum Ca (P = 0.0003), P (P = 0.0153), and iPTH (P < 0.0001) levels were significantly reduced after cinacalcet administration, even in those without marked elevation of iPTH (Ca; P < 0.0001, P; P = 0.0422, and iPTH; P = 0.0018). The proportion of patients who received vitamin D sterols was unchanged (P = 0.5930) but the proportion of patients who received maxacalcitol was significantly reduced after cinacalcet administration (P = 0.0108). The new treatment algorithm of early initiation of cinacalcet is considered to be well tolerated and effective for controlling hypercalcemia, and/or hyperphosphatemia and/or increased iPTH of CKD-MBD patients. PMID- 23735150 TI - Potential role of neutrophil gelatinase-associated lipocalin in identifying critically ill patients with acute kidney injury stage 2-3 who subsequently require renal replacement therapy. AB - Delayed initiation of renal replacement therapy (RRT) in critically ill acute kidney injury (AKI) patients results in high mortality while too early RRT causes unnecessary risks of the treatment. Current traditional indications cannot clearly identify the appropriate time for initiating RRT. This prospective cohort study was conducted to determine the accuracy of using plasma neutrophil gelatinase-associated lipocalin (pNGAL) and urine NGAL (uNGAL) in early identifying of the AKI patients who subsequently required RRT. Forty-seven critically ill patients with AKI stage 2-3 who did not reach the traditional indications for RRT were enrolled in this study. The pNGAL, uNGAL, and other parameters were determined in each patient. The primary end point was RRT initiation according to the traditional indications within 3 days. The mean age of the patients was 63.0 +/- 18.1 years. pNGAL could predict subsequent RRT requirements with area under ROC 0.813 (P < 0.001, 95%CI 0.66-0.90). The cut-off point of 960 ng/mL provided sensitivity and specificity of 72.2 and 89.6%, respectively, and positive and negative predictive values of 81.25% and 83.8%, respectively. The uNGAL provided slightly lower significance of statistical parameters. The combination of pNGAL level of 960 ng/mL and APACHE II score of 20 improved statistical values. In conclusion, pNGAL is an excellent early biomarker for RRT initiation in critically ill patients with AKI stage 2-3. The pNGAL value of 960 ng/mL, alone or in combination with APACHE II score might be used as the early new indicator for early initiation of RRT in AKI stage 2-3 and this might improve patient survival. PMID- 23735151 TI - First human application of a novel adsorptive-type cytapheresis module in patients with active ulcerative colitis: a pilot study. AB - The aim of this study was to evaluate the safety, tolerability, technical performance and clinical efficacy of a novel adsorptive-type cytapheresis module in patients with active ulcerative colitis. Ten patients with ulcerative colitis (clinical activity index 6-10) were recruited. The new adsorber (Nikkiso, Tokyo, Japan) was specifically designed to remove platelets, granulocytes and monocytes from peripheral blood using an extracorporeal circulation. Cytapheresis treatments were performed weekly for five consecutive weeks (each with a 60-min duration). Safety and tolerability were evaluated by investigating vital parameters, routine laboratory tests, adverse event reporting and a questionnaire. Disease activity was evaluated by assessing the clinical activity index as well as the endoscopic index, according to Rachmilewitz. Technical performance and biocompatibility were investigated by repeated measurements of cellular blood count, complement factor C3a and cell surface markers before, during and after the apheresis treatments. The cytapheresis treatments were "well" to "very well" tolerated by the patients. All measured safety parameters remained essentially unchanged. Performance data showed that platelets, monocytes and neutrophil granulocytes were effectively reduced during the cytapheresis treatments. Apheresis treatment was associated with high remission rates (80% at week 10). Clinical remission was accompanied by the reduction of the endoscopic index in four out of the nine eligible patients. Levels of C3a did not significantly increase during cytapheresis treatments. The novel device has been shown to be safe, well tolerated and clinically efficient. It offered a very good biocompatibility and platelet elimination capacity. PMID- 23735152 TI - Regression of tumoral calcinosis after the appropriate control of a deranged mineral and bone metabolism, in conjugation with cinacalcet hydrochloride treatment, in a chronic hemodialysis patient. PMID- 23735153 TI - Catheter related infection due to Mycobacterium abscessus in a patient under peritoneal dialysis. PMID- 23735154 TI - Chylous ascites observed during catheter insertion. PMID- 23735155 TI - Extracorporeal depuration technique as treatment of acute kidney injury related to multiple myeloma. PMID- 23735158 TI - Meta-worry in adolescents: examination of the psychometric properties of the meta worry questionnaire in an adolescent sample. AB - BACKGROUND: Meta-worry is considered a central component of the Metacognitive Model of Generalized Anxiety Disorder. Although initial research provides support for the applicability of this model to adolescent samples, the construct of meta worry has yet to be examined in adolescents. AIMS: The purpose of this study was to examine the psychometric properties of the Meta-Worry Questionnaire (MWQ), a measure designed to assess negative beliefs about worry, in an adolescent sample, and to examine the degree to which meta-worry is associated with pathological worry in adolescents. METHOD: A non-referred sample of 175 adolescents completed a modified version of the MWQ along with the Meta-Cognitions Questionnaire Children (MCQ-C) and the Penn State Worry Questionnaire for Children (PSWQ-C). RESULTS: The MWQ was found to exhibit strong psychometric properties. Most noteworthy, the MWQ was found to be a particularly robust predictor of scores on the PSWQ-C, and incremental validity was also demonstrated. CONCLUSIONS: Overall, the current findings provide support for the reliability and validity of the MWQ in adolescents and support for meta-worry as a predictor of worry symptoms in adolescents. PMID- 23735159 TI - pH-responsive delivery of doxorubicin from citrate-apatite nanocrystals with tailored carbonate content. AB - In this work, the efficiency of bioinspired citrate-functionalized nanocrystalline apatites as nanocarriers for delivery of doxorubicin (DOXO) has been assessed. The nanoparticles were synthesized by thermal decomplexing of metastable calcium/citrate/phosphate solutions both in the absence (Ap) and in the presence (cAp) of carbonate ions. The presence of citrate and carbonate ions in the solution allowed us to tailor the size, shape, carbonate content, and surface chemistry of the nanoparticles. The drug-loading efficiency of the two types of apatite was evaluated by means of the adsorption isotherms, which were found to fit a Langmuir-Freundlich behavior. A model describing the interaction between apatite surface and DOXO is proposed from adsorption isotherms and zeta potential measurements. DOXO is adsorbed as a dimer by means of a positively charged amino group that electrostatically interacts with negatively charged surface groups of nanoparticles. The drug-release profiles were explored at pHs 7.4 and 5.0, mimicking the physiological pH in the blood circulation and the more acidic pH in the endosome-lysosome intracellular compartment, respectively. After 7 days at pH 7.4, cAp-DOXO released around 42% less drug than Ap-DOXO. However, at acidic pH, both nanoassemblies released similar amounts of DOXO. In vitro assays analyzed by confocal microscopy showed that both drug-loaded apatites were internalized within GTL-16 human carcinoma cells and could release DOXO, which accumulated in the nucleus in short times and exerted cytotoxic activity with the same efficiency. cAp are thus expected to be a more promising nanocarrier for experiments in vivo, in situations where intravenous injection of nanoparticles are required to reach the targeted tumor, after circulating in the bloodstream. PMID- 23735160 TI - Endemic norovirus infections in children, Ho Chi Minh City, Vietnam, 2009-2010. AB - We performed a case-control investigation to identify risk factors for norovirus infections among children in Vietnam. Of samples from 1,419 children who had diarrhea and 609 who were asymptomatic, 20.6% and 2.8%, respectively, were norovirus positive. Risk factors included residential crowding and symptomatic contacts, indicating person-to-person transmission of norovirus. PMID- 23735162 TI - Can axillary reverse mapping avoid lymphedema in node positive breast cancer patients? AB - BACKGROUND: Tracing lymphatic drainage of the ipsilateral arm of node positive breast cancer patients, termed "axillary reverse mapping" (ARM), has recently been described in several reports. We analyzed our experience with this new technique in patients scheduled for axillary lymph node dissection (ALND) and evaluated its usefulness for reducing the incidence of lymphedema. METHODS: Blue dye was injected subcutaneously along the intermuscular groove of the upper inner arm; radioisotope was injected subcutaneously in the interdigital webspace of the hand. All blue and radioactive lymph vessels and lymph nodes were recorded. Only unsuspicious "ARM lymph nodes" located in the lateral part of the axillary basin were preserved. All other level I and II axillary lymph nodes were removed. Resected ARM nodes were immediately separated from all other lymph nodes. RESULTS: ARM was performed in 143 patients subsequently undergoing ALND. ARM lymph nodes were successfully identified in 112 cases (78%). In 55 patients at least one ARM lymph node had to be removed. In 14 of these, tumor involvement was confirmed. In 71 patients one or more ARM nodes were preserved. During a median follow-up time of 19 months no axillary recurrence was noted. 35 of 114 evaluated patients developed lymphedema. Preservation of ARM lymph nodes did not significantly decrease the incidence of lymphedema. CONCLUSION: ARM is feasible for patients with node positive breast cancer. However, we found no evidence that it reduces the incidence of lymphedema. PMID- 23735163 TI - Protective arms of the renin-angiotensin-system in neurological disease. AB - In recent years it has been firmly established that apart from the classic renin angiotensin system (RAS) comprising angiotensin (Ang) II, angiotensin converting enzyme (ACE; responsible for AngII generation) and the angiotensin AT1 receptor (AT1 R), there also exist protective arms of the RAS that comprise the angiotensin AT2 receptor (AT2 R), Ang-(1-7), ACE2 (mainly responsible for Ang-(1 7) synthesis) and Mas, the receptor for Ang-(1-7). Stimulation of AT2 R promotes neuronal differentiation, neurite outgrowth and axonal regeneration, which results in an acceleration of repair and improved functional outcome after injury of peripheral nerves or the spinal cord. Stimulation of AT2 R and the receptor Mas has been shown to reduce infarct size and ameliorate neurological deficits in various animal models of stroke. The underlying mechanisms of action are comprised of activation of direct neurotrophic, anti-inflammatory and anti oxidant pathways, as well as the augmentation of cerebral blood flow. Cognitive function is improved by AT2 R stimulation due, at least in part, to increased cerebral blood flow. There is indirect evidence that Ang-(1-7) could also play a role in protection against cognitive decline, but studies confirming this have not yet been published. In view of the data reviewed in this article, it can be assumed that the protective arms of the RAS are putative targets in the treatment of neurological diseases, which involve tissue damage or cognitive impairment. PMID- 23735164 TI - Miniature biofuel cell as a potential power source for glucose-sensing contact lenses. AB - A microscale membrane-less biofuel cell, capable of generating electrical energy from human lachrymal liquid, was developed by utilizing the ascorbate and oxygen naturally present in tears as fuel and oxidant. The biodevice is based on three dimensional nanostructured gold electrodes covered with abiotic (conductive organic complex) and biological (redox enzyme) materials functioning as efficient anodic and cathodic catalysts, respectively. Three-dimensional nanostructured electrodes were fabricated by modifying 100 MUm gold wires with 17 nm gold nanoparticles, which were further modified with tetrathiafulvalene tetracyanoquinodimethane conducting complex to create the anode and with Myrothecium verrucaria bilirubin oxidase to create the biocathode. When operated in human tears, the biodevice exhibited the following characteristics: an open circuit voltage of 0.54 V, a maximal power density of 3.1 MUW cm(-2) at 0.25 V and 0.72 MUW cm(-2) at 0.4 V, with a stable current density output of over 0.55 MUA cm(-2) at 0.4 V for 6 h of continuous operation. These findings support our proposition that an ascorbate/oxygen biofuel cell could be a suitable power source for glucose-sensing contact lenses to be used for continuous health monitoring by diabetes patients. PMID- 23735165 TI - Intellectual function evaluation of first generation immigrant children with sickle cell disease: the role of language and sociodemographic factors. AB - BACKGROUND: Sickle Cell Disease (SCD) is the most common genetic disease worldwide. Neurological events are among the most worrisome clinical complications of SCD and are frequently accompanied by cognitive impairment. Intellectual function in SCD may vary according to genetic and environmental factors. Immigrant children with SCD are increasing at a global level and display specific health care needs. The aim of our multicenter study was to describe the intellectual function of first generation African immigrants with SCD and the influence of sociodemographic factors on its characteristics. METHODS: The Wechsler Intelligence Scales were administered to evaluate broad intellectual functions in children with SCD and in age-matched healthy siblings. Patients' clinical, socio-demographic, Magnetic Resonance Imaging (MRI) and Angiography (MRA) data were correlated to intellectual function scores. RESULTS: 68 children, mean age 8.95 years were evaluated. 72% spoke three languages, 21% two. FSIQ was <75 in 25% of the children. Mean VIQ was lower than PIQ in 75%. Mean verbal subtest scores were lower than performance scores. Female gender, number of languages spoken at home and mother's employment were associated with single subtest performances (p < 0.05). MRA was abnormal in 73.4% and MRI in 35.9%. No significant correlation was established between silent lesions and intellectual function, even if patients with lesions performed worse. Fifteen siblings performed better than patients on cognitive domains, including language (p < 0.05). CONCLUSIONS: Immigrant bilingual children with SCD seem to display a rate of cognitive impairment similar to their monolingual counterparts but a more pronounced and precocious onset of language difficulties. Adjunctive tests need to be considered in this group of patients to better define their specific deficits. PMID- 23735166 TI - Adverse reaction after administration of progesterone. PMID- 23735167 TI - Investigation of underlying primary immunodeficiencies in patients with severe atopic dermatitis. AB - BACKGROUND: Primary immunodeficiency diseases (PIDs) are a group of heterogeneous inherited disorders, characterised by recurrent infections, autoimmunity and malignancy. Some PIDs such as hyper IgE syndrome (HIES) and Wiskott-Aldrich syndrome (WAS) may be initially presented as atopic dermatitis (AD), especially in its severe form, resulting in diagnostic delay and poor prognosis of patients. OBJECTIVE: The aim of this study was to evaluate the frequency of PIDs among patients with severe AD and to determine factors that can help to raise suspicion towards these disorders. METHODS: Seventy-five patients with a well-established diagnosis of severe AD were enrolled in this study. Initial immunological evaluations, including humoral and cellular investigation, were performed in all individuals. Patients underwent further investigations in a case of suspicion of a probable PID. RESULTS: Among all patients with severe AD, five (6.6%) were diagnosed with HIES and one (1.3%) with WAS. Family history of PIDs, family history of death in early infancy, positive history of recurrent infections such as skin and respiratory infections, otitis media and sinusitis were observed significantly higher in patients with a diagnosis of PID. CONCLUSIONS: The presence of an underlying PID could explain the poor prognosis and refraction to the treatment of some patients with severe AD. Several clinical and laboratory findings can help the physicians to focus towards PIDs which are more serious. Delay in diagnosis of PID cases with skin manifestation of AD without proper management may result in lower quality of life and higher morbidity and mortality rates. PMID- 23735168 TI - How are 'urban' and 'rural' defined in publications regarding asthma and related diseases? AB - BACKGROUND: Global variations in the prevalence of asthma and related diseases have suggested that environmental factors are causative, and that factors associated with urbanisation are of particular interest. A range of definitions for 'urban' and 'rural' have been used in articles on asthma and related diseases, making it difficult to assess their importance as aetiological factors. This study sets out to examine such definitions used in the literature. METHODS: Medical and social science databases were searched for articles that made distinctions of 'urban' and/or 'rural' in the context of asthma and related diseases. RESULTS: The search identified 73 articles and categorised four types of definitions. A specific definition of urban or rural was used in 19 (26%) articles. Nine (12%) articles used non-specific and/or administrative definitions. There were 23 (32%) articles that described locations as 'urban' or 'rural' but did not indicate if the description defined 'urban' or 'rural'. Distinctions were made between urban and rural locations without a description or definition in 22 (30%) articles. CONCLUSIONS: There is substantial variation in the definitions of 'urban' and 'rural' in articles regarding asthma and related diseases. It would be advantageous to have clearer and more precise definitions of 'urban' and 'rural' which could facilitate aetiological research and also comparisons between locations, especially in international studies. PMID- 23735169 TI - Classification of excoriation (skin picking) disorder: current status and future directions. PMID- 23735171 TI - The timing of monozygotic twinning: a criticism of the common model. AB - In the dominant model, monozygotic (MZ) twinning is universally accepted as a post-fertilization event resulting from splitting of the embryo along its first 2 weeks of development. The stage at which splitting occurs determines chorionicity and amnionicity. A short history on how the model was built is presented, stressing the role played by some embryologists, in particular George Corner, in its completion and final success. Strikingly, for more than 60 years no deep criticisms have been raised against the model, which, in virtue of its rational and plausible character, enjoys the status of undisputed truth. At close examination, the embryological support of the model shows some important weak points, particularly when dealing with late splitting. In the author's view, the model not only has contributed to 'suspend' our knowledge on the timing of MZ twinning, but seems indefensible and claims to be substituted. That factor could imply relevant consequences for embryology and bioethics. As an alternative to the model, a new theory to explain the timing of MZ twinning is proposed. It is based on two premises. First, MZ twinning would be a fertilization event. In that case, due to an alteration of the zygote-blastomere transition, the first zygotic division, instead of producing two blastomeres, generates twin zygotes. Second, monochorionicity and monoamnionicity would not depend on embryo splitting, but on fusion of membranes. Some support for this theory can be found in recent embryological advances and also in some explanations of old. PMID- 23735170 TI - Perinatally HIV-infected youth presenting with acute stroke: progression/evolution of ischemic disease on neuroimaging. AB - BACKGROUND AND PURPOSE: Although HIV infection is decreasing in infants and children, there is a steady cohort of perinatally HIV-infected (PHIV) children that are growing older. Increased risk of acute stroke has been reported in PHIV children. Our goal was to evaluate evolution/progression of neuroimaging findings in PHIV youth initially presenting with acute stroke. MATERIALS AND METHODS: The medical records of PHIV pediatric patients (n = 179) from 1996 to 2010 were reviewed and patients with clinical documentation of acute stroke referred to the neuroradiology service were eligible for the study. Neuroimaging (brain CT, MRI, and MRA) and charts were evaluated; clinical and neuroimaging findings at the initial acute stroke and at the last presentation to the neuroradiology service were documented and analyzed. RESULTS: Eight PHIV patients with clinical findings of acute stroke referred to the neuroimaging were identified. CT and MRI findings of infarction were found in all (8/8) patients in their first and/or last neuroimaging study; including basal ganglia-thalami (BGT) infarction (7/8), focal cortical infarction (4/8), and internal capsule infarction (4/8). Imaging depicted cortical atrophy (5/8), BGT calcification (3/8), and posterior reversible encephalopathy syndrome, wallerian degeneration, and periventricular white matter hyperintense T2 signal each in one patient. No tumors or infectious masses, cysts or abscesses were identified. Subsequent available neuroimaging revealed progression of the cerebrovascular disease in seven patients, 5/7 in the absence of new clinical signs or symptoms. Segmental occlusion, narrowing or narrowing/dilatation in the circle of Willis was found in 6/6 patients who underwent MR angiography and fusiform aneurysms were detected in three of them, a saccular aneurysm in one patient. CONCLUSION: Asymptomatic progression of cerebrovascular disease was found in PHIV adolescents with prior stroke. These findings may have implications for long-term risk and outcomes for this patient population. There should be a low threshold to evaluate for CNS pathology even with minor symptoms in this population. More studies are necessary to determine if there is a benefit from screening of asymptomatic patients. PMID- 23735172 TI - Misperception of body weight among overweight Danish adults: trends from 1995 to 2008. AB - OBJECTIVE: To examine changes in the prevalence of overweight and weight misperception among overweight Danes from 1995 to 2008, and to identify factors associated with weight misperception. DESIGN: Cross-sectional studies, in which data on self-reported weight, height and self-perception of overweight status were obtained through face-to-face interviews. 'Overweight' includes obesity. Weight misperception was defined as overweight individuals who did not perceive themselves as overweight. The chi 2 test was used to analyse changes over time and multiple logistic regression analysis was applied to identify factors associated with weight misperception. SETTING: The Danish National Survey of Diet and Physical Activity in three periods: 1995, 2000-2004 and 2005-2008. SUBJECTS: A random sample of 9623 Danes aged 15-75 years. RESULTS: The prevalence of overweight increased in men and women from 1995 to 2005-2008 (from 35.1 % to 43.0 %, P < 0.001). Concurrently, there was a reduction in the proportion of overweight men (from 77.5 % to 71.4 %, P = 0.001) and women (from 54.8 % to 51.9 %, P = 0.24) who misperceived their weight. Factors associated with weight misperception were 'never intend to eat healthily' (men), high levels of leisure time physical activity, 'very good/excellent' self-rated health and survey year (higher misperception in 2000-2004 than 2005-2008; P < 0.05). CONCLUSIONS: The increase in overweight from 1995 to 2005-2008 was accompanied by a reduction in the proportion of overweight men misperceiving their weight. This may indicate that more men see overweight as a personally relevant health problem. Our findings also suggest that overweight individuals who are more physically active and have better self-rated health may not consider their excess weight a health problem. PMID- 23735173 TI - Murine typhus in humans, Yucatan, Mexico. PMID- 23735174 TI - Linking inflammation to tumorigenesis in a mouse model of high-fat-diet-enhanced colon cancer. AB - Many observational epidemiologic studies suggest an association between high-fat diet (HFD) and colon cancer risk. However, the lack of controlled experimental studies that examine this relationship and the mechanisms involved weaken the basis for inferring a causal relationship. Inflammation plays a role in colon cancer progression and HFDs have been reported to increase inflammation; however, the inflammatory effects of HFD in colon cancer have yet to be firmly established. We examined the effects of a novel HFD that closely mimics the standard American diet (12% and 40% of total caloric intake from saturated fat and total fat, respectively) on macrophage markers and inflammatory mediators in a mouse model of intestinal tumorigenesis and relate this to polyp characteristics as well as measures of adiposity. Male Apc(Min/+) mice (7 8/group) were fed a Control Diet (Con) or novel high-fat-diet (HFD) from 4 to 12weeks of age. Body weight and body composition were measured weekly and monthly, respectively. Intestinal tissue was analyzed for polyp burden (number and size). Gene expression of macrophage markers and inflammatory mediators were examined in the adipose tissue and polyps. The HFD increased the expression of macrophage markers and inflammatory mediators in the adipose tissue (F4/80, CD11c, TLR-4 and MCP-1) and tumor microenvironment (IL-12, MCP-1, IL-6 and TNF alpha). As expected, the HFD increased body weight, body fat percent, fat mass and blood glucose (P<0.05), and was associated with an increase in the number of large polyps (P<0.05) but not total polyps. In summary, consumption of a HFD, similar in macronutrient composition to the standard American diet, altered the expression of macrophage phenotypic markers and inflammatory mediators in adipose tissue and intestinal polyps and this was associated with increased tumorigenesis. PMID- 23735175 TI - Precipitation of alacranite (As8S9) by a novel As(V)-respiring anaerobe strain MPA-C3. AB - Strain MPA-C3 was isolated by incubating arsenic-bearing sediments under anaerobic, mesophilic conditions in minimal media with acetate as the sole source of energy and carbon, and As(V) as the sole electron acceptor. Following growth and the respiratory reduction of As(V) to As(III), a yellow precipitate formed in active cultures, while no precipitate was observed in autoclaved controls, or in uninoculated media supplemented with As(III). The precipitate was identified by X ray diffraction as alacranite, As8 S9 , a mineral previously only identified in hydrothermal environments. Sequencing of the 16S rRNA gene indicated that strain MPA-C3 is a member of the Deferribacteres family, with relatively low (90%) identity to Denitrovibrio acetiphilus DSM 12809. The arsenate respiratory reductase gene, arrA, was sequenced, showing high homology to the arrA gene of Desulfitobacterium halfniense. In addition to As(V), strain MPA-C3 utilizes NO3( ), Se(VI), Se(IV), fumarate and Fe(III) as electron acceptors, and acetate, pyruvate, fructose and benzoate as sources of carbon and energy. Analysis of a draft genome sequence revealed multiple pathways for respiration and carbon utilization. The results of this work demonstrate that alacranite, a mineral previously thought to be formed only chemically under hydrothermal conditions, is precipitated under mesophilic conditions by the metabolically versatile strain MPA-C3. PMID- 23735176 TI - Effect of food processing on exposure assessment studies with mycotoxins. AB - The goals of the present work were, on the one hand, to assess the effect of baking on the stability of zearalenone (ZEA) and deoxynivalenol (DON), as well as the transfer of DON from pasta to boiling water, and, on the other hand, to quantify the impact of DON depletion, during cooking of pasta, on overall exposure estimates. Therefore, the bread-making process was simulated on a pilot plant scale by using naturally contaminated flour with DON and ZEA. Transfer of DON from pasta to water was evaluated at different boiling times. Pasta was prepared on a pilot-plant scale by using naturally contaminated durum wheat flour; subsequently, it was boiled simulating home cooking. The experiments examined the stability of DON and ZEA during the bread-making process, including fermentation with Saccharomyces cerevisiae and baking at 200 degrees C. Our results showed a high transfer of DON from pasta to boiling water, reaching depletion levels of almost 75%, which correlated with levels found in water. Accordingly, these cooking depletion rates were computed through a stochastic exposure model to weight their impact on the final exposure estimates. Finally, statistically significant differences were found in most of the parameters and populations assessed, but these were not enough to consider the process as protective because the contribution of pasta to the overall DON intake was commonly low. PMID- 23735177 TI - Investigation of the reductive cleavage of BINAP and application to the rapid synthesis of phospholes. AB - A rapid and easy entry into lambda(3)-phospholes and lambda(4)-phosphole oxides derived from BINAP is reported herein featuring a variety of C and Si substituents and functional groups, as well the investigative work on the mechanistic pathway. DFT calculations using B3LYP functionals have been carried out to rationalize the mechanism. The observed experimental (31)P resonance shifts were compared with the calculated shifts of the proposed intermediates after calibration of the shielding tensors. The calculations included the use of polarizable continuum models to take into account solvent effects and were found to be in excellent agreement, providing further evidence for the proposed mechanism. PMID- 23735178 TI - Tacrolimus dose individualization in "de novo" patients after 10 years of experience in liver transplantation: pharmacokinetic considerations and patient pathophysiology. AB - AIM: To determine how changes in tacrolimus (TAC) immunosuppression clinical practice, in the first 15 days post liver transplantation (LT) and across a decade, impact a clinical covariate - pharmacokinetic (PK) model, developed in data from 1998, thus testing its utility in dose individualization across time. Patient cohorts from 1998 (Reference: R-1998) and 2007 (EVALUATION: E-2007) were compared. METHODS: Analysis of monitoring observations (Cmin and Cmin/dose) and the biochemical variables aspartate aminotransferase (AST), hematocrit (HCT), albumin (ALB) and serum creatinine (SCr) was done for 0 - 3 and 4 - 15 days post transplantation (PT). The population PK model developed for R-1998 [1] was re evaluated for the two cohorts. RESULTS: Significant differences in R-1998 vs. E 2007 existed in Cmin and Cmin/dose and in covariates AST (as hepatic function marker) and SCr (as toxicity marker). E-2007 had lower levels of Cmin and Cmin/dose (1/CL), lower AST with faster recovery and lower variability in Cmin/dose for similar dose. AST was a covariate on CL/F in the 0 - 3 day PT period. In 4 - 15 days PT for E-2007, low levels of HCT and ALB as CL/F predictors confirmed a subgroup with higher CL/F (23.8 l/h vs. 19.3 l/h). The R 1998 model's original structure was confirmed. CONCLUSIONS: Ten years of use of TAC shows gain in therapeutic targeting efficiency, due to improvement in LT methods, knowledge of the drug and consideration of PK steady state. The remaining uncertainty with TAC monitoring in LT can be resolved with application of PK principles combined with patients' diosyncrasies in the model developed for TAC dose individualization in R-1998. The applicability of the model as nucleus in Bayes individualization remains intact across a decade. PMID- 23735179 TI - The safety, pharmacokinetics and pharmacodynamics of a combination of fluticasone furoate and vilanterol in healthy Japanese subjects. AB - OBJECTIVE: To evaluate the safety, pharmacokinetics and pharmacodynamics of fluticasone furoate (FF) and vilanterol (VI) administered alone or in combination in three Phase I studies in healthy Japanese male subjects. MATERIALS: FF, VI and FF/VI inhalation powder in a novel dry powder inhaler (nDPI). METHODS: Study A: 48 subjects received the first dose on Day 1, followed by a 4-day washout and once-daily (OD) repeat doses of FF 200, 400 or 800 MUg or placebo from Day 5 to Day 11 (7 days). Study B: 32 subjects received repeat doses of VI (12.5, 25 MUg) OD for 7 days. Study C: 16 subjects received single doses of FF (800 MUg), VI (50 MUg), FF/VI (800/50 MUg) and placebo. RESULTS: Overall, there were no safety concerns and no major differences were found in treatment-related adverse events when FF and VI were administered alone or in combination. Peak plasma concentration of FF and VI following repeat dosing was up to two times higher compared with the single dose. Individual pharmacokinetic parameters of FF and VI differed when co-administered but the differences from monotherapy were not clinically significant. Repeat dosing of FF affected weighted mean (0 - 24 hours) serum cortisol with FF 200, 400 and 800 MUg resulting in respective reductions from placebo of 32%, 38% and 97%, respectively. Mean maximum heart rate (0 - 4 hours) was comparable between placebo, VI 12.5 and 25 MUg over 7 days of dosing; for single dosing of FF/VI 800/50 and VI 50 MUg, heart rate was comparable (70 and 73 bpm, respectively) and this was higher than FF 800 MUg (66 bpm) or placebo (64 bpm), but the difference was not clinically significant. CONCLUSIONS: In healthy Japanese subjects, no safety concerns were found following repeat dosing of FF and VI or single dosing of FF, VI and FF/VI. Systemic exposure to FF and VI increased in a dose-dependent manner. Serum cortisol level was suppressed by 97% after 7 days repeat administration of FF at a dose of 800 MUg. Heart rate with a single dose of VI 50 MUg was higher than that of placebo, though not to a clinically significant extent. PMID- 23735180 TI - Comparative bioavailability and pharmacokinetics of sirolimus tablets in healthy Chinese volunteers. AB - OBJECTIVES: Although sirolimus tablets and oral solutions have been used in clinical practice, no study has been reported on the pharmacokinetics and bioavailability of a single-dose of sirolimus tablets in healthy Chinese volunteers. The purpose of this study was to compare the bioavailability and pharmacokinetic (PK) properties of two different 1-mg sirolimus tablets in healthy Chinese male volunteers and evaluate whether a generic tablet of sirolimus meets the criteria for bioequivalence from the State Food and Drug Administration (SFDA) of China when compared with a reference product. MATERIALS AND METHODS: A total of 24 healthy Chinese volunteers was eligible for this 6 mg single dose, randomized-sequence, open-label, 2-period crossover study. Blood samples were collected before dosing and at 0.25, 0.50, 0.75, 1.0, 1.5, 2, 3, 4, 8, 12, 24, 48, 72, 120, 168, 216, and 264 hours after dosing. Whole blood sirolimus concentration was analyzed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Pharmacokinetic properties of sirolimus were assessed using noncompartmental analysis. RESULTS: The mean (range) Cmax values of the test and the reference were 15.25 (8.48 - 24.40) and 13.43 (7.90 - 22.90) ng/ml; AUC0-t values were 475.65 (293.33 - 1049.86) and 451.96 (221.52 - 809.11) ng/h/ml. The medians (range) tmax values were 2.0 (1.0 - 8.0) and 2.0 (1.0 - 8.0) hours, respectively. The 90% confidence intervals (CIs) for the ratios of Cmax, AUC0-264, and AUC0-infinity were 103.7% to 124.4%, 97.5% to 113.6%, and 98.0% to 114.8%, respectively. CONCLUSION: In this single-dose crossover study the test sirolimus tablets met the criteria for bioequivalence in terms of both rate and extent. Each sirolimus formulation was well tolerated during the study. PMID- 23735181 TI - The effects of a TRPV1 antagonist, SB-705498, in the treatment of seasonal allergic rhinitis. AB - BACKGROUND: Current pharmacotherapy for allergic rhinitis (AR) does not totally ameliorate all symptoms for all patients. Residual symptoms could be due to nasal neuronal hyperresponsiveness caused by stimulation of the ion channel transient receptor potential vanilloid 1 (TRPV1). SB-705498 is a TRPV1 antagonist that has been developed in an intranasal formulation for treatment of AR. METHODS: This randomized, double-blind, 3-way incomplete block crossover study evaluated the effects of 8 days treatment with SB-705498 12 mg alone, SB-705498 12 mg plus fluticasone propionate 200 MUg (FP), FP 200 MUg alone or placebo on allergen induced symptoms in 70 patients with AR. The primary endpoint was total nasal symptom score (TNSS), expressed as mean over 4 hours or maximum TNSS during allergen challenge in the Vienna Challenge Chamber on 8th day of treatment. RESULTS: At the end of treatment, there were no differences in allergen-induced mean TNSS between SB-705498 alone and placebo or between SB-705498 plus FP and FP alone. Treatment with FP and SB-705498 plus FP resulted in a significant decrease in TNSS vs. placebo. Mean (90% CI) treatment differences in TNSS over 0 - 4 hours were: SB-705498 - placebo: -0.2 (-0.9, 0.4); SB-705498 plus FP - FP: 0.7 (0.2, 1.2); FP - placebo: -2.9 (-3.4, -2.5); SB-705498 plus FP - placebo: -2.3 (-2.8, 1.8). SB-705498 had no impact on diary card symptoms, nasal airflow or Rhinoconjunctivitis Quality of Life Questionnaire scores. SB-705498 was well tolerated and pharmacokinetics exposure results supported the dosing regimen. CONCLUSION: SB-705498 12 mg for 8 days did not alleviate the allergen-induced symptoms of AR, or provide additional relief of symptoms when in combination with FP. Despite engagement of the TRPV1 receptor there was no translation to clinical efficacy, suggesting redundancy in symptom pathways. PMID- 23735182 TI - Bending moments of zirconia and titanium implant abutments supporting all-ceramic crowns after aging. AB - OBJECTIVES: To test the fracture load and fracture patterns of zirconia abutments restored with all-ceramic crowns after fatigue loading, exhibiting internal and external implant-abutment connections as compared to restored and internally fixed titanium abutments. MATERIALS AND METHODS: A master abutment was used for the customization of 5 groups of zirconia abutments to a similar shape (test). The groups differed according to their implant-abutment connections: one-piece internal connection (BL; Straumann Bonelevel), two-piece internal connection (RS; Nobel Biocare ReplaceSelect), external connection (B; Branemark MkIII), two-piece internal connection (SP, Straumann StandardPlus) and one-piece internal connection (A; Astra Tech AB OsseoSpeed). Titanium abutments with internal implant-abutment connection (T; Straumann Bonelevel) served as control group. In each group, 12 abutments were fabricated, mounted to the respective implants and restored with glass-ceramic crowns. All samples were embedded in acrylic holders (ISO-Norm 14801). After aging by means of thermocycling in a chewing simulator, static load was applied until failure (ISO-Norm 14801). Fracture load was analyzed by calculating the bending moments. Values of all groups were compared with one-way ANOVA followed by Scheffe post hoc test (P-value<0.05). Failure mode was analyzed descriptively. RESULTS: The mean bending moments were 464.9 +/- 106.6 N cm (BL), 581.8 +/- 172.8 N cm (RS), 556.7 +/- 128.4 N cm (B), 605.4 +/- 54.7 N cm (SP), 216.4 +/- 90.0 N cm (A) and 1042.0 +/- 86.8 N cm (T). No difference of mean bending moments was found between groups BL, RS, B and SP. Test group A exhibited significantly lower mean bending moment than the other test groups. Control group T had significantly higher bending moments than all test groups. Failure due to fracture of the abutment and/or crown occurred in the test groups. In groups BL and A, fractures were located in the internal part of the connection, whereas in groups RS and SP, a partial deformation of the implant components occurred and cracks and fractures of the zirconia abutment were detected. CONCLUSION: The differently connected zirconia abutments exhibited similar bending moments with the exception of one group. Hence, the type of connection only had a minor effect on the stability of restored zirconia abutments. In general, restored titanium abutments exhibited the highest bending moments. PMID- 23735183 TI - Allergy management in primary care across European countries -- actual status. AB - The standard of care for allergies within a primary care (PC) setting has a strong influence on disease prevention and control, quality of life, and patient satisfaction. The level of knowledge of allergic diseases and the accessibility to regular follow-up are essential. EAACI and IPCRG conducted a survey to evaluate the actual status of care for allergic diseases in PC. Access to allergy and asthma specialist treatment was identified as the greatest 'unmet need'. The average waiting time between a referral and being seen in a public health service is usually >6 weeks. Referring the patients to an 'organ' specialist is much easier compared with referral to an allergist. Most PCPs have access to blood tests for total and specific IgE. Skin prick testing is available in only half of the cases, while provocation tests, allergen quantification in homes, and a dietician service are even less available. 20.6% of practices do not have access to allergy tests at all. Other issues raised were low political or general public awareness, lack of understanding by the patients of their allergic disease, the need to invest in PC, and to achieve sufficient competence at the appropriate level of care. PMID- 23735184 TI - Electroplating and magnetostructural characterization of multisegmented Co54Ni46/Co85Ni15 nanowires from single electrochemical bath in anodic alumina templates. AB - Highly hexagonally ordered hard anodic aluminum oxide membranes, which have been modified by a thin cover layer of SiO2 deposited by atomic layer deposition method, were used as templates for the synthesis of electrodeposited magnetic Co Ni nanowire arrays having diameters of around 180 to 200 nm and made of tens of segments with alternating compositions of Co54Ni46 and Co85Ni15. Each Co-Ni single segment has a mean length of around 290 nm for the Co54Ni46 alloy, whereas the length of the Co85Ni15 segments was around 430 nm. The composition and crystalline structure of each Co-Ni nanowire segment were determined by transmission electron microscopy and selected area electron diffraction techniques. The employed single-bath electrochemical nanowire growth method allows for tuning both the composition and crystalline structure of each individual Co-Ni segment. The room temperature magnetic behavior of the multisegmented Co-Ni nanowire arrays is also studied and correlated with their structural and morphological properties. PMID- 23735185 TI - Left main coronary atresia in a child with absent pulmonary valve syndrome: early entrapment of an innocent bystander. AB - Atresia of the left main coronary artery is a rare anomaly that, if left untreated, has an unfavorable outcome. We hereby report left main coronary artery atresia in a child with tetralogy of Fallot with absent pulmonary valve and discuss the possible developmental basis of the association. PMID- 23735186 TI - A mixture model for expression deconvolution from RNA-seq in heterogeneous tissues. AB - BACKGROUND: RNA-seq, a next-generation sequencing based method for transcriptome analysis, is rapidly emerging as the method of choice for comprehensive transcript abundance estimation. The accuracy of RNA-seq can be highly impacted by the purity of samples. A prominent, outstanding problem in RNA-seq is how to estimate transcript abundances in heterogeneous tissues, where a sample is composed of more than one cell type and the inhomogeneity can substantially confound the transcript abundance estimation of each individual cell type. Although experimental methods have been proposed to dissect multiple distinct cell types, computationally "deconvoluting" heterogeneous tissues provides an attractive alternative, since it keeps the tissue sample as well as the subsequent molecular content yield intact. RESULTS: Here we propose a probabilistic model-based approach, Transcript Estimation from Mixed Tissue samples (TEMT), to estimate the transcript abundances of each cell type of interest from RNA-seq data of heterogeneous tissue samples. TEMT incorporates positional and sequence-specific biases, and its online EM algorithm only requires a runtime proportional to the data size and a small constant memory. We test the proposed method on both simulation data and recently released ENCODE data, and show that TEMT significantly outperforms current state-of-the-art methods that do not take tissue heterogeneity into account. Currently, TEMT only resolves the tissue heterogeneity resulting from two cell types, but it can be extended to handle tissue heterogeneity resulting from multi cell types. TEMT is written in python, and is freely available at https://github.com/uci-cbcl/TEMT. CONCLUSIONS: The probabilistic model-based approach proposed here provides a new method for analyzing RNA-seq data from heterogeneous tissue samples. By applying the method to both simulation data and ENCODE data, we show that explicitly accounting for tissue heterogeneity can significantly improve the accuracy of transcript abundance estimation. PMID- 23735187 TI - Dissociations among daytime sleepiness, nighttime sleep, and cognitive status in Parkinson's disease. AB - BACKGROUND: Daytime and nighttime sleep disturbances and cognitive impairment occur frequently in Parkinson's disease (PD), but little is known about the interdependence of these non-motor complications. Thus, we examined the relationships among excessive daytime sleepiness, nighttime sleep quality and cognitive impairment in PD, including severity and specific cognitive deficits. METHODS: Ninety-three PD patients underwent clinical and neuropsychological evaluations including the Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI). Patients were classified as having normal cognition (PD NC), mild cognitive impairment (PD-MCI), or dementia (PDD) using recently proposed Movement Disorder Society PD-MCI and PDD criteria. Relationships between the sleep and cognitive measures and PD cognitive groups were examined. RESULTS: The PD cohort included PD-NC (n = 28), PD-MCI (n = 40), and PDD (n = 25) patients. ESS scores, as a measure of daytime sleepiness, were significantly worse (p = 0.005) in cognitively impaired PD patients, particularly PDD patients. ESS scores correlated significantly with Mini-Mental State Examination scores and also with cognitive domain scores for attention/working memory, executive function, memory, and visuospatial function. In contrast, PSQI scores, as a measure of nighttime sleep quality, neither differed among cognitive groups nor correlated with any cognitive measures. CONCLUSIONS: Daytime sleepiness in PD, but not nighttime sleep problems, is associated with cognitive impairment in PD, especially in the setting of dementia, and attention/working memory, executive function, memory, and visuospatial deficits. The presence of nighttime sleep problems is pervasive across the PD cognitive spectrum, from normal cognition to dementia, and is not independently associated with cognitive impairment or deficits in cognitive domains. PMID- 23735188 TI - Resistance to paclitxel in breast carcinoma cells requires a quality control of mitochondrial antiapoptotic proteins by TRAP1. AB - TRAP1 is a mitochondrial antiapoptotic protein up-regulated in several human malignancies. However, recent evidences suggest that TRAP1 is also localized in the endoplasmic reticulum (ER) where it is involved in ER stress protection and protein quality control of tumor cells. Based on the mechanistic link between ER stress, protection from apoptosis and drug resistance, we questioned whether these novel roles of TRAP1 are relevant for its antiapoptotic function. Here, we show for the first time that: i) TRAP1 expression is increased in about 50% of human breast carcinomas (BC), and ii) the ER stress protecting activity of TRAP1 is conserved in human tumors since TRAP1 is co-upregulated with the ER stress marker, BiP/Grp78. Notably, ER-associated TRAP1 modulates mitochondrial apoptosis by exerting a quality control on 18 kDa Sorcin, a TRAP1 mitochondrial client protein involved in TRAP1 cytoprotective pathway. Furthermore, this TRAP1 function is relevant in favoring resistance to paclitaxel, a microtubule stabilizing/ER stress inducer agent widely used in BC therapy. Indeed, the transfection of a TRAP1 deletion mutant, whose localization is restricted to the ER, in shTRAP1 cells enhances the expression of mitochondrial Sorcin and protects from apoptosis induced by ER stress agents and paclitaxel. Furthermore, BC cells adapted to paclitaxel or ER stress inducers share common resistance mechanisms: both cell models exhibit cross-resistance to single agents and the inhibition of TRAP1 by siRNAs or gamitrinib, a mitochondria-directed HSP90 family inhibitor, in paclitaxel-resistant cells rescues the sensitivity to paclitaxel. These results support the hypothesis that ER-associated TRAP1 is responsible for an extramitochondrial control of apoptosis and, therefore, an interference of ER stress adaptation through TRAP1 inhibition outside of mitochondria may be considered a further compartment-specific molecular approach to rescue drug resistance. PMID- 23735190 TI - Molecular dynamics simulations on gate opening in ZIF-8: identification of factors for ethane and propane separation. AB - Gate opening of zeolitic imidazolate frameworks (ZIFs) is an important microscopic phenomenon in explaining the adsorption, diffusion, and separation processes for large guest molecules. We present a force field, with input from density functional theory (DFT) calculations, for the molecular dynamics simulation on the gate opening in ZIF-8. The computed self-diffusivities for sorbed C1 to C3 hydrocarbons were in good agreement with the experimental values. The observed sharp diffusion separation from C2H6 to C3H8 was elucidated by investigating the conformations of the guest molecules integrated with the flexibility of the host framework. PMID- 23735189 TI - Human melioidosis, Malawi, 2011. AB - A case of human melioidosis caused by a novel sequence type of Burkholderia pseudomallei occurred in a child in Malawi, southern Africa. A literature review showed that human cases reported from the continent have been increasing. PMID- 23735191 TI - Selected papers from the 15th Annual Bio-Ontologies Special Interest Group Meeting. AB - Over the 15 years, the Bio-Ontologies SIG at ISMB has provided a forum for discussion of the latest and most innovative research in the bio-ontologies development, its applications to biomedicine and more generally the organisation, presentation and dissemination of knowledge in biomedicine and the life sciences. The seven papers and the commentary selected for this supplement span a wide range of topics including: web-based querying over multiple ontologies, integration of data, annotating patent records, NCBO Web services, ontology developments for probabilistic reasoning and for physiological processes, and analysis of the progress of annotation and structural GO changes. PMID- 23735193 TI - Formation mechanisms of nano and microcones by laser radiation on surfaces of Si, Ge, and SiGe crystals. AB - In this work we study the mechanisms of laser radiation interaction with elementary semiconductors such as Si and Ge and their solid solution SiGe. As a result of this investigation, the mechanisms of nanocones and microcones formation on a surface of semiconductor were proposed. We have shown the possibility to control the size and the shape of cones both by the laser. The main reason for the formation of nanocones is the mechanical compressive stresses due to the atoms' redistribution caused by the gradient of temperature induced by strongly absorbed laser radiation. According to our investigation, the nanocone formation mechanism in semiconductors is characterized by two stages. The first stage is characterized by formation of a p-n junction for elementary semiconductors or of a Ge/Si heterojunction for SiGe solid solution. The generation and redistribution of intrinsic point defects in elementary semiconductors and Ge atoms concentration on the irradiated surface of SiGe solid solution in temperature gradient field take place at this stage due to the thermogradient effect which is caused by strongly absorbed laser radiation. The second stage is characterized by formation of nanocones due to mechanical plastic deformation of the compressed Ge layer on Si. Moreover, a new 1D-graded band gap structure in elementary semiconductors due to quantum confinement effect was formed. For the formation of microcones Ni/Si structure was used. The mechanism of the formation of microcones is characterized by two stages as well. The first stage is the melting of Ni film after irradiation by laser beam and formation of Ni islands due to surface tension force. The second step is the melting of Ni and subsequent manifestations of Marangoni effect with the growth of microcones. PMID- 23735192 TI - Pharmacokinetics of intravitreally injected bevacizumab in vitrectomized eyes. AB - PURPOSE: To compare the pharmacokinetics (PKs) of intravitreally injected bevacizumab in vitrectomized versus nonvitrectomized control rabbit eyes. METHODS: Twenty-five-gauge pars plana vitrectomy without lensectomy was performed in 17 right rabbit eyes (V) and 18 nonvitrectomized right rabbit eyes served as controls (C). After 1.25 mg/0.05 mL intravitreal bevacizumab (IVB) injections, eyes were enucleated at 1 h, 1, 2, 5, 14, and 30 days after the injection and immediately frozen at -80 degrees C. Bevacizumab concentrations were determined after separation of frozen vitreous and aqueous humor (AH) compartments using indirect enzyme-linked immunosorbent assay. Bevacizumab concentration-time data were analyzed to obtain PK data. RESULTS: Vitreous clearance of IVB consisted of 2 phases, the first fast distribution and second slow elimination phase. Clearance of IVB was accelerated in V eyes only during the first phase and not in the second phase. The vitreous concentration percent ratios between V and C eyes were 94.7% (1 h), 70.5% (1 day), 89.2% (2 days), 94.2% (5 days), 99.2% (14 days), and 79.1% (30 days). Overall vitreous half-lives were 6.99 and 7.06 days for V and C eyes, respectively (1.6-h difference). CONCLUSION: Overall IVB PKs in rabbit eyes after vitrectomy without lensectomy are not substantially different from nonvitrectomized control eyes. PMID- 23735194 TI - Quality of dying of nursing home residents with dementia as judged by relatives. AB - BACKGROUND: Providing good quality care for the growing number of patients with dementia is a major challenge. There is little international comparative research on how people with dementia die in nursing homes. We compared the relative's judgment on quality of care at the end of life and quality of dying of nursing home residents with dementia in Belgium and the Netherlands. METHODS: This was a Belgian cross-sectional retrospective study (2010) combined with a prospective and retrospective study from the Netherlands (January 2007-July 2011). Relatives of deceased residents of 69 Belgian and 34 Dutch nursing homes were asked to complete questionnaires. We included 190 and 337 deceased nursing home residents with dementia in Belgium and the Netherlands, respectively. RESULTS: Of all identified deceased nursing home residents with dementia, respectively 53.2% and 74.8% of their relatives in Belgium and the Netherlands responded. Comfort while dying (CAD-EOLD, range 14-42) was rated better for Dutch nursing home residents than for Belgian nursing homes residents (26.1 vs. 31.1, OR 4.5, CI 1.8-11.2). We found no differences between countries regarding Satisfaction With Care (SWCEOLD, range 10-40, means 32.5 (the Netherlands) and 32.0 (Belgium)) or symptom frequency in the last month of life (SM-EOLD, range 0-45, means 26.4 (the Netherlands) and 27.2 (Belgium)). CONCLUSION: Although nursing home structures differ between Belgium and the Netherlands, the quality of care in the last month of life for residents with dementia is similar according to their relatives. However, Dutch residents experience less discomfort while dying. The results suggest room for improved symptom management in both countries and particularly in the dying phase in Belgium. PMID- 23735195 TI - Flaviviruses in game birds, southern Spain, 2011-2012. PMID- 23735196 TI - Ontology-Based Querying with Bio2RDF's Linked Open Data. AB - BACKGROUND: A key activity for life scientists in this post "-omics" age involves searching for and integrating biological data from a multitude of independent databases. However, our ability to find relevant data is hampered by non-standard web and database interfaces backed by an enormous variety of data formats. This heterogeneity presents an overwhelming barrier to the discovery and reuse of resources which have been developed at great public expense.To address this issue, the open-source Bio2RDF project promotes a simple convention to integrate diverse biological data using Semantic Web technologies. However, querying Bio2RDF remains difficult due to the lack of uniformity in the representation of Bio2RDF datasets. RESULTS: We describe an update to Bio2RDF that includes tighter integration across 19 new and updated RDF datasets. All available open-source scripts were first consolidated to a single GitHub repository and then redeveloped using a common API that generates normalized IRIs using a centralized dataset registry. We then mapped dataset specific types and relations to the Semanticscience Integrated Ontology (SIO) and demonstrate simplified federated queries across multiple Bio2RDF endpoints. CONCLUSIONS: This coordinated release marks an important milestone for the Bio2RDF open source linked data framework. Principally, it improves the quality of linked data in the Bio2RDF network and makes it easier to access or recreate the linked data locally. We hope to continue improving the Bio2RDF network of linked data by identifying priority databases and increasing the vocabulary coverage to additional dataset vocabularies beyond SIO. PMID- 23735197 TI - The effect of mandibular 2-implant overdentures on oral health-related quality of life: an international multicentre study. AB - OBJECTIVES: To determine the difference in oral health-related quality of life (OHRQoL) in patients who received mandibular 2-implant overdentures and conventional dentures in a pragmatic international study. MATERIALS AND METHODS: In this prospective study, data were gathered from 203 edentulous patients (mean age, 68.8; SD: 10.4 years) at eight centres in North America, South America and Europe. The patients were provided with new mandibular conventional dentures or implant overdentures supported by 2 implants and ball attachments and opposed by conventional dentures. At baseline and at 6 months post-treatment, patients rated their oral health-related quality of life using the OHIP-20. RESULTS: A significantly higher proportion of the participants in the implant group in North America reported improvement in both the psychological and the handicap domains, compared to those who received conventional dentures (93% vs. 52%; P < 0.05). In South America, 100% of participants who received implant overdentures reported improvement in physical pain, compared to 66% in the conventional group (P < 0.05). Differences in mean change scores among those who expressed improvement were not significantly different between sites or treatments. CONCLUSION: Mandibular 2-implant overdentures are more likely than conventional dentures to improve OHRQL for edentulous patients. Cultural differences were also observed in the impact of implant overdentures on the different domains of the OHIP-20. PMID- 23735198 TI - BSE-associated prion-amyloid cardiomyopathy in primates. AB - Prion amyloidosis occurred in the heart of 1 of 3 macaques intraperitoneally inoculated with bovine spongiform encephalopathy prions. This macaque had a remarkably long duration of disease and signs of cardiac distress. Variant Creutzfeldt-Jakob disease, caused by transmission of bovine spongiform encephalopathy to humans, may manifest with cardiac symptoms from prion-amyloid cardiomyopathy. PMID- 23735199 TI - Gene prediction in metagenomic fragments based on the SVM algorithm. AB - BACKGROUND: Metagenomic sequencing is becoming a powerful technology for exploring micro-ogranisms from various environments, such as human body, without isolation and cultivation. Accurately identifying genes from metagenomic fragments is one of the most fundamental issues. RESULTS: In this article, we present a novel gene prediction method named MetaGUN for metagenomic fragments based on a machine learning approach of SVM. It implements in a three-stage strategy to predict genes. Firstly, it classifies input fragments into phylogenetic groups by a k-mer based sequence binning method. Then, protein coding sequences are identified for each group independently with SVM classifiers that integrate entropy density profiles (EDP) of codon usage, translation initiation site (TIS) scores and open reading frame (ORF) length as input patterns. Finally, the TISs are adjusted by employing a modified version of MetaTISA. To identify protein-coding sequences, MetaGun builds the universal module and the novel module. The former is based on a set of representative species, while the latter is designed to find potential functionary DNA sequences with conserved domains. CONCLUSIONS: Comparisons on artificial shotgun fragments with multiple current metagenomic gene finders show that MetaGUN predicts better results on both 3' and 5' ends of genes with fragments of various lengths. Especially, it makes the most reliable predictions among these methods. As an application, MetaGUN was used to predict genes for two samples of human gut microbiome. It identifies thousands of additional genes with significant evidences. Further analysis indicates that MetaGUN tends to predict more potential novel genes than other current metagenomic gene finders. PMID- 23735200 TI - The role of radical prostatectomy and lymph node dissection in lymph node positive prostate cancer: a systematic review of the literature. AB - CONTEXT: Because pelvic lymph node (LN)-positive prostate cancer (PCa) is generally considered a regionally metastatic disease, surgery needs to be better defined. OBJECTIVE: To review the impact of radical prostatectomy (RP) and pelvic lymph node dissection (PLND), possibly in conjunction with a multimodal approach using local radiotherapy and/or androgen-deprivation therapy (ADT), in LN positive PCa. EVIDENCE ACQUISITION: A systematic Medline search for studies reporting on treatment regimens and outcomes in patients with LN-positive PCa undergoing RP between 1993 and 2012 was performed. EVIDENCE SYNTHESIS: RP can improve progression-free and overall survival in LN-positive PCa, although there is a lack of high-level evidence. Therefore, the former practice of aborting surgery in the presence of positive nodes might no longer be supported by current evidence, especially in those patients with a limited LN tumor burden. Current data demonstrate that the lymphatic spread takes an ascending pathway from the pelvis to the retroperitoneum, in which the internal and the common iliac nodes represent critical landmarks in the metastatic distribution. Sophisticated imaging technologies are still under investigation to improve the prediction of LN-positive PCa. Nonetheless, extended PLND including the common iliac arteries should be offered to intermediate- and high-risk patients to improve nodal staging with a possible benefit in prostate-specific antigen progression-free survival by removing significant metastatic load. Adjuvant ADT has the potential to improve overall survival after RP; the therapeutic role of a trimodal approach with adjuvant local radiotherapy awaits further elucidation. Age is a critical parameter for survival because cancer-specific mortality exceeds overall mortality in younger patients (<60 yr) with high-risk PCa and should be an impetus to treat as thoroughly as possible. CONCLUSIONS: Increasing evidence suggests that RP and extended PLND improve survival in LN-positive PCa. Our understanding of surgery of the primary tumor in LN-positive PCa needs a conceptual change from a palliative option to the first step in a multimodal approach with a significant improvement of long-term survival and cure in selected patients. PMID- 23735201 TI - Allogeneic stem cell transplantation for children with acquired severe aplastic anaemia: a retrospective study by the Viva-Asia Blood and Marrow Transplantation Group. AB - We retrospectively analysed the outcomes of 127 children with acquired severe aplastic anaemia (SAA) who had received haematopoietic stem cell transplantation (HSCT) between 2000 and 2011 in one of the 10 Asia Pacific institutions. Fifty three were matched sibling donor (MSD) and 74 were alternative donor (AD), including 22 matched unrelated donor, 32 mismatched unrelated donor and 20 mismatched related donor. With a median follow up 45.5 months (13-139) and when compared to the MSD group, AD recipients had more grade II-IV acute graft-versus host disease (aGVHD; 14.3% vs. 32.8%, P = 0.029), but similar grade III-IV aGVHD (10.2% vs. 12.5%, P = 0.774), graft failure (GF) (15.1% vs. 15.5%, P = 0.658) and 5-year overall survival (90.6% vs. 83.7%, P = 0.251). As a source of stem cell, peripheral blood stem cells (PBSC) resulted in less GF (18% vs. 9.1% P = 0.013), similar grade II-IV aGVHD (28.1% vs. 17.4%, P = 0.258), chronic GVHD (25.8% vs. 29.3%, P = 0.822) and similar outcomes (89.7% vs. 82.4%, P =0.665) when compared to bone marrow (BM). In univariate analysis, GF (P < 0.001) and grade II-IV aGVHD (P = 0.009) were predictors of poor survival. In multivariate analysis, only GF was associated with poor survival (P = 0.012). The outcome of AD and PBSC HSCT were comparable to that of MSD and BM HSCT in the Asia Pacific region. PMID- 23735202 TI - Frequent sensitization to Candida albicans and profilins in adult eosinophilic esophagitis. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is often associated with atopic airway and skin diseases. More than 80% of EoE patients are sensitized to aero- and/or food allergens. Immunoglobulin (Ig)E-mediated immune responses to microbes have been reported to be deleterious in connection with atopic diseases. AIM: The aim of this study was to obtain a comprehensive overview about the sensitization spectrum of adult EoE patients. METHODS: IgE in sera of 35 patients with active EoE were analyzed for reactivity to Candida albicans, as well as to a panel of recombinant and purified natural allergen components, using a microarray. RESULTS: IgE sensitization to Candida albicans was found in 43% of EoE patients. More than 80% of EoE patients were sensitized to aeroallergens and 22% to food specific allergen components, whereas 69% of the patients exhibited specific IgE to cross-reactive allergens. Among the latter, profilins were identified as most frequent IgE cross-reactive allergen components. Interestingly, dysphagia, the main symptom of adult EoE patients following rice and/or bread ingestion, was associated with sensitization to cross-reactive allergens such as profilins, pathogenesis-related (PR) 10 and lipid transfer proteins (LTP). Intolerance toward meat rarely correlated with sensitization to animal food allergens. CONCLUSION: Candida albicans and cross-reactive plant allergen components, in particular profilins, were identified as frequent sensitizers in adult EoE patients. Specific elimination therapies are suggested to reveal their actual roles in the pathogenesis of EoE. PMID- 23735203 TI - The effects of omega-3 polyunsaturated fatty acids on cardiac rhythm: a critical reassessment. AB - Although epidemiological studies provide strong evidence for an inverse relationship between omega-3 polyunsaturated fatty acids (n-3 PUFAs) and cardiac mortality, inconsistent and often conflicting results have been obtained from both animal studies and clinical prevention trials. Despite these heterogeneous results, some general conclusions can be drawn from these studies: 1) n-PUFAs have potent effects on ion channels and calcium regulatory proteins that vary depending on the route of administration. Circulating (acute administration) n-3 PUFAs affect ion channels directly while incorporation (long-term supplementation) of these lipids into cell membranes indirectly alter cardiac electrical activity via alteration of membrane properties. 2) n-3 PUFAs reduce baseline HR and increase HRV via alterations in intrinsic pacemaker rate rather than from changes in cardiac autonomic neural regulation. 3) n-3 PUFAs may be only effective if given before electrophysiological or structural remodeling has begun and have no efficacy against atrial fibrillation. 5) Despite initial encouraging results, more recent clinical prevention and animal studies have not only failed to reduce sudden cardiac death but actually increased mortality in angina patients and increased rather than decreased malignant arrhythmias in animal models of regional ischemia. 6) Given the inconsistent benefits reported in clinical and experimental studies and the potential adverse actions on cardiac rhythm noted during myocardial ischemia, n-3 PUFA must be prescribed with caution and generalized recommendations to increase fish intake or to take n-3 PUFA supplements need to be reconsidered. PMID- 23735204 TI - Synthesis and X-ray crystal structure of isomeric pyridine-based leuco-TAM dyes, 2,2-(2-(pyridinyl)propane-1,3-diylidene)bis(5-chloro-1,3,3-trimethyl indoline) derivatives and unusual stability of 4-pyridinyl compound. AB - The solid-state structures and unequivocal stereochemistries of isomeric pyridine based leuco-triarylmethane (LTAM) dyes 2,2'-(2-(pyridin-4 or 3-yl)propane-1,3 diylidene)bis(5-chloro-1,3,3-trimethylindoline) derivatives were established by X ray crystallography. Surprisingly, the EE isomer was formed for the 4-pyridinyl compound, whereas the 3-pyridinyl compound formed ZE isomers. In addition, the latter have a so-called three-bladed propeller conformation, whereas the former possess a Y-shaped conformation. These pyridine-based LTAM compounds stack to form a dimer, adopting either an orthorhombic, with Pcmn space group, or monoclinic crystal system with P21/n space group in the crystal unit cell. PMID- 23735205 TI - Vibrational spectra, NBO analysis, first order hyperpolarizabilities, thermodynamic functions and NMR chemical shielding anisotropy (CSA) parameters of 5-nitro-2-furoic acid by ab initio HF and DFT calculations. AB - In this work, FT-IR and FT-Raman spectra are recorded on the solid phase of 5 nitro-2-furoic acid (abbreviated as NFA) in the regions 4000-400 cm(-1) and 3500 100 cm(-1) respectively. The geometrical parameters, vibrational assignments, HOMO-LUMO energies and NBO calculations are obtained for the monomer and dimer of NFA from HF and DFT (B3LYP) with 6-311++G (d, p) basis set calculations. Second order perturbation energies and electron density (ED) transfer from filled lone pairs of Lewis base to unfilled Lewis acid sites of NFA are discussed on the basis of NBO analysis. Intermolecular hydrogen bonds exist through COOH groups; give the evidence for the formation of dimer entities in the title molecule. The theoretically calculated harmonic frequencies are scaled by common scale factor. The observed and the calculated frequencies are found to be in good agreement. The thermodynamic functions were obtained for the range of temperature 100-1000 K. The polarizability, first hyperpolarizability, anisotropy polarizability invariant has been computed using quantum chemical calculations. The chemical parameters were calculated from the HOMO and LUMO values. The NMR chemical shielding anisotropy (CSA) parameters were also computed for the title molecule. PMID- 23735206 TI - Thermo- and cathodoluminescence properties of lepidolite. AB - Lepidolite, K(Li,Al)3(Si,Al)4O10(F,OH)2, and many of the related phyllosilicate mineral of the mica group have been well studied from the chemical and structural point of view; however, to the best of our knowledge, studies on their luminescence properties have been scarcely reported. This work focuses on the thermoluminescence (TL) and cathodoluminescence (CL) response of a natural lepidolite from Portugal previously characterized by means of environmental scanning electron microscope (ESEM) and X-ray fluorescence (XRF) and atomic absorption spectroscopy (AAS) techniques. The complexity of the thermoluminescence glow curves of non-irradiated and 1 Gy irradiated samples suggests a structure of a continuous trap distribution involving multiorder kinetics. UV-IR CL spectral emission shows seven peaks centered at 330, 397, 441, 489, 563, 700, and 769 nm. Such emission bands could be due to (i) structural defects, i.e., [AlO4] or non-bridging oxygen hole centers and (ii) the presence of point defects associated with Mn(2+) and Fe(3+). PMID- 23735207 TI - Lattice vibrations of AVO4 crystals (A=Lu, Yb, Dy, Tb, Ce). AB - A short range force constant model has been applied using normal coordinates to investigate the Raman and the infrared wavenumbers in rare earth AVO4 compounds (A=Lu, Yb, Dy, Tb, Ce) having space group I41/a and symmetry C4h(6). The calculation of zone center phonons has been made by using four stretching and five bending force constants. The calculated Raman and infrared wavenumbers are in very good agreement with the observed ones. The present calculations interpret reasonably the mode assignment of 779 cm(-1) as Eg mode and 853 cm(-1) as Ag mode in case of LuVO4, which were assigned differently in earlier observation. The potential energy distribution has also been investigated for determining the significance of contribution from each force constant toward the Raman and the infrared wavenumbers. PMID- 23735208 TI - Simultaneous determination of Cinnarizine and Domperidone by area under curve and dual wavelength spectrophotometric methods. AB - Accurate, selective and sensitive spectrophotometric methods have been developed and validated for simultaneous determination of Cinnarizine and Domperidone, a binary mixture with overlapping spectra, without preliminary separation. These methods include area under the curve (AUC) and dual wavelength spectrophotometry. For the AUC method, the area under curve of mixture solutions in the wavelength ranges 241-258 nm and 280-292 nm were selected for determination of Cinnarizine and Domperidone and by applying Cramer's rule, concentration of each drug was obtained. In dual wavelength method, two wavelengths were selected for each drug in a way so that the difference in absorbance is zero for another drug. Domperidone shows equal absorbance at 240.2 nm and 273.2 nm, where the differences in absorbance were measured for the determination of Cinnarizine. Similarly, differences in absorbance at 230.8 nm and 259.2 nm were measured for determination of Domperidone. The proposed methods were applied for determination of Cinnarizine and Domperidone over the concentration ranges of 2-20 and 2-22 MUg mL(-1), respectively. The suggested methods were validated as per USP guidelines and the results revealed that they are reliable, reproducible and precise for routine use with short analysis time. The results obtained by the proposed methods were statistically compared to the reported method, and there was no significant difference between them regarding both accuracy and precision. PMID- 23735209 TI - In situ observation of ninhydrin and phenylhydrazine reaction in solution by FTIR. AB - The current work was performed for hydrazone formation reaction of ninhydrin with phenylhydrazine in chloroform by using "background defining method" in FTIR liquid cell. The method allowed following the consumption and formation of the reagent and product at the same time. Negative absorption bands are based on reagent consumption and positive absorbances are based on product formation. The method was applied for two different mol ratios (1:1, 1:3) of reagent. Both ratios resulted in same product (1,2,3-tris-phenylhydrazonoindan). The results showed that, phenylhydrazine react with all of the carbonyl groups in ninhydrin at both run. PMID- 23735210 TI - Phenylazoindole dyes--part I: the syntheses, characterizations, crystal structures, quantum chemical calculations and antimicrobial properties. AB - In this study, the synthesis of four new phenylazo indole dyes (dye 1-4) were carried out by diazotization of 4-aminoacetophenone and coupling with various 2- and 1,2-disubstituted indole derivatives. The dyes were characterized by UV-vis, FT-IR, (1)H NMR, HRMS and X-ray single crystal diffraction methods. Azo-hydrazone tautomeric bahavior of the dyes in different solvents (DMSO, methanol, acetic acid and chloroform) was investigated by using (1)H NMR and UV-vis results. The experimental results were compared with the corresponding calculated values. The results of experimental data and theoretical calculations showed that the azo tautomer is more stable than hydrazone tautomer. In addition to this, the antimicrobial activity of the dyes was also evaluated. PMID- 23735211 TI - Efficacy of second generation antipsychotics in treating acute mixed episodes in bipolar disorder: a meta-analysis of placebo-controlled trials. AB - BACKGROUND: The literature on the treatment mixed episodes in Bipolar Disorder [BD] is sparse. Second generation antipsychotics [SGA] have documented efficacy in mania, but not mixed episodes. The objective of this meta-analysis was to ascertain the efficacy of SGA, either as mono- and/or adjunctive therapy, in the treatment of acute mixed episodes of BD, compared to placebo. METHODS: A MEDLINE search for English language publications of randomized controlled trials [RCTs] comparing SGA with placebo in the treatment of an acute manic/mixed episode of BD, during the period 1990-2012, was performed using the terms 'atypical antipsychotics', 'SGA', 'mixed episodes', 'dysphoric mania' and each SGA independently. 9 RCTs reporting data on 1289 mixed episode patients treated with aripiprazole, asenapine, olanzapine, paliperidone-ER, risperidone, and ziprasidone, either as monotherapy or as adjunctive therapy, versus placebo, for 3-6 weeks, were included in the meta-analysis. We extracted data on the number of patients, SGA, duration of study and mean change in mania and depression scores from baseline to endpoint. Standardized mean difference between SGA and placebo for the mean baseline-to-endpoint change in mania and depression rating scores was calculated, with a 95% confidence limit. RESULTS: SGA, either alone or in combination with mood stabilizers, had superior efficacy in treating manic symptoms of mixed episodes compared to placebo (-0.41, 95% CI -0.53, -0.30; overall effect p<0.00001). SGA were equally effective for manic symptoms in mixed episodes and pure mania (p=0.99). SGA had superior efficacy in treating depressive symptoms of mixed episodes (-0.30, 95% CI -0.47, -0.13; p<0.001) compared to placebo in two trials reporting this information. LIMITATIONS: Thirteen relevant studies could not be included as data for mixed-episodes were not presented separately. CONCLUSIONS: SGA are effective in treating acute mixed episodes of BD, with predominant manic symptoms. Their efficacy in treating depressed mixed episodes remains unclear. PMID- 23735212 TI - Comorbidity between hypomania and substance use disorders. AB - BACKGROUND: Bipolar disorder is associated with substance use and misuse. However, to date few studies have examined the relationship between hypomania and substance misuse and dependence in the general population. METHODS: Data come from the National Institute of Mental Health Collaborative Psychiatric Epidemiology Surveys (CPES), a set of multi-stage area probability samples of US adults (N=10,404). Multivariable linear and logistic regression was used to assess the relationship between DSM-IV hypomania and nicotine, alcohol, cannabis, cocaine, and prescription drug use. Models were adjusted for age, gender, education, and marital status. Stratified analyses and interaction terms were used to determine whether the relationship between hypomania and substance misuse varied by race/ethnicity. RESULTS: The 12-month prevalence of hypomania was 0.5%. Hypomania was more common among African Americans (0.9%) relative to non-Hispanic Whites (0.5%) or other race/ethnicities (0.7%). Individuals with hypomania were 3.6 (95% CI: 1.5, 8.5) and 2.9 (95% CI: 1.3, 6.8) times more likely to also meet criteria for alcohol abuse/dependence and drug abuse/dependence relative to individuals without. The relationship between hypomania and substance use outcomes did not vary by race/ethnicity. LIMITATIONS: The primary limitation of this study is its cross-sectional design, which precludes any inference about the causal nature of comorbid hypomania-substance use. CONCLUSIONS: Hypomania is associated with increased likelihood of substance use and dependence/abuse across a broad range of substances. These associations were consistent across racial/ethnic groups. Findings indicate that even sub-syndromal conditions, such as hypomania, are significantly related to substance use and misuse in the community. PMID- 23735213 TI - Sex differences in clinical predictors of depression: a prospective study. AB - BACKGROUND: Estimating the likelihood of future major depressive episodes (MDEs) would assist clinicians in decision-making regarding the optimal length of treatment for MDE. Unfortunately, little data are available to guide clinical practice. METHODS: We followed 200 females and 152 males who responded to treatment for a MDE for 2 years to determine risk factors for future MDE. Cox Proportional Hazard Regression modeled time to first relapse into MDE and mixed effect logistic regression modeled monthly depression status. RESULTS: Females were more likely than males to experience a MDE in any month of the study, and marginally more likely to experience a relapse. By 12 months, 60% of females had relapsed compared to 51% of males (median time to relapse 8 vs. 13 months, respectively). Several factors predicted worse outcome for both men and women: reported childhood abuse, earlier age of onset of first MDE, bipolar disorder, unemployment, and more years of education. For females, but not males, suicidal ideation predicted MDE relapse and both suicidal ideation and prior suicide attempts were associated with more time in a MDE. LIMITATIONS: The naturalistic treatment of participants, exclusion of individuals with current comorbid alcohol or substance use disorder, and a follow up period of two years are limitations. CONCLUSIONS: Women are more vulnerable to relapse and spend more time depressed compared to men. Identification of general and sex-specific risk factors for future depression may provide clinicians with useful tools to estimate need for ongoing pharmacotherapy in MDE. PMID- 23735215 TI - Understanding the variegation of fat: novel regulators of adipocyte differentiation and fat tissue biology. AB - The differentiation of uncommitted cells into specialized adipocytes occurs through a cascade of transcriptional events culminating in the induction and activation of the nuclear receptor PPARgamma, the central coordinator of fat cell function. Since the discovery of PPARgamma, two decades ago, our views of how this molecule is activated have been significantly refined. Beyond the cell, we also now know that diverse signals and regulators control PPARgamma function in a fat-depot specific manner. The goal of this article is to review the latest in our understanding of the early and late transcriptional events that regulate adipocyte development and their potential impact on energy storage and expenditure in different fat depots. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. PMID- 23735214 TI - Adipocytes under assault: environmental disruption of adipose physiology. AB - The burgeoning obesity epidemic has placed enormous strains on individual and societal health mandating a careful search for pathogenic factors, including the contributions made by endocrine disrupting chemicals (EDCs). In addition to evidence that some exogenous chemicals have the capacity to modulate classical hormonal signaling axes, there is mounting evidence that several EDCs can also disrupt metabolic pathways and alter energy homeostasis. Adipose tissue appears to be a particularly important target of these metabolic disruptions. A diverse array of compounds has been shown to alter adipocyte differentiation, and several EDCs have been shown to modulate adipocyte physiology, including adipocytic insulin action and adipokine secretion. This rapidly emerging evidence demonstrating that environmental contaminants alter adipocyte function emphasizes the potential role that disruption of adipose physiology by EDCs may play in the global epidemic of metabolic disease. Further work is required to better characterize the molecular targets responsible for mediating the effects of EDCs on adipose tissue. Improved understanding of the precise signaling pathways altered by exposure to environmental contaminants will enhance our understanding of which chemicals pose a threat to metabolic health and how those compounds synergize with lifestyle factors to promote obesity and its associated complications. This knowledge may also improve our capacity to predict which synthetic compounds may alter energy homeostasis before they are released into the environment while also providing critical evidentiary support for efforts to restrict the production and use of chemicals that pose the greatest threat to human metabolic health. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. PMID- 23735218 TI - Use of a bacteriophage cocktail to control Salmonella in food and the food industry. AB - The use of lytic bacteriophages for the biocontrol of food-borne pathogens in food and in the food industry is gaining increasing acceptance. In this study, the effectiveness of a bacteriophage cocktail composed of three different lytic bacteriophages (UAB_Phi 20, UAB_Phi78, and UAB_Phi87) was determined in four different food matrices (pig skin, chicken breasts, fresh eggs, and packaged lettuce) experimentally contaminated with Salmonella enterica serovar Typhimurium and S. enterica serovar Enteritidis. A significant bacterial reduction (>4 and 2 log/cm(2) for S. Typhimurium and S. Enteritidis, respectively; p<=0.005) was obtained in pig skin sprayed with the bacteriophage cocktail and then incubated at 33 degrees C for 6h. Significant decreases in the concentration of S. Typhimurium and S. Enteritidis were also measured in chicken breasts dipped for 5 min in a solution containing the bacteriophage cocktail and then refrigerated at 4 degrees C for 7 days (2.2 and 0.9 log10 cfu/g, respectively; p<=0.0001) as well as in lettuce similarly treated for 60 min at room temperature (3.9 and 2.2 log10 cfu/g, respectively; p<=0.005). However, only a minor reduction of the bacterial concentration (0.9 log10 cfu/cm(2) of S. Enteritidis and S. Typhimurium; p<=0.005) was achieved in fresh eggs sprayed with the bacteriophage cocktail and then incubated at 25 degrees C for 2 h. These results show the potential effectiveness of this bacteriophage cocktail as a biocontrol agent of Salmonella in several food matrices under conditions similar to those used in their production. PMID- 23735216 TI - Deconstructing the roles of glucocorticoids in adipose tissue biology and the development of central obesity. AB - Central obesity is associated with insulin resistance and dyslipidemia. Thus, the mechanisms that control fat distribution and its impact on systemic metabolism have importance for understanding the risk for diabetes and cardiovascular disease. Hypercortisolemia at the systemic (Cushing's syndrome) or local levels (due to adipose-specific overproduction via 11beta-hydroxysteroid dehydrogenase 1) results in the preferential expansion of central, especially visceral fat depots. At the same time, peripheral subcutaneous depots can become depleted. The biochemical and molecular mechanisms underlying the depot-specific actions of glucocorticoids (GCs) on adipose tissue function remain poorly understood. GCs exert pleiotropic effects on adipocyte metabolic, endocrine and immune functions, and dampen adipose tissue inflammation. GCs also regulate multiple steps in the process of adipogenesis. Acting synergistically with insulin, GCs increase the expression of numerous genes involved in fat deposition. Variable effects of GC on lipolysis are reported, and GC can improve or impair insulin action depending on the experimental conditions. Thus, the net effect of GC on fat storage appears to depend on the physiologic context. The preferential effects of GC on visceral adipose tissue have been linked to higher cortisol production and glucocorticoid receptor expression, but the molecular details of the depot-dependent actions of GCs are only beginning to be understood. In addition, increasing evidence underlines the importance of circadian variations in GCs in relationship to the timing of meals for determining their anabolic actions on the adipocyte. In summary, although the molecular mechanisms remain to be fully elucidated, there is increasing evidence that GCs have multiple, depot-dependent effects on adipocyte gene expression and metabolism that promote central fat deposition. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. PMID- 23735217 TI - The role of JAK-STAT signaling in adipose tissue function. AB - Adipocytes play important roles in lipid storage, energy homeostasis and whole body insulin sensitivity. The JAK-STAT (Janus Kinase-Signal Transducer and Activator of Transcription) pathway mediates a variety of physiological processes including development, hematopoiesis, and inflammation. Although the JAK-STAT signaling pathway occurs in all cells, this pathway can mediate cell specific responses. Studies in the last two decades have identified hormones and cytokines that activate the JAK-STAT signaling pathway. These cytokines and hormones have profound effects on adipocytes. The content of this review will introduce the types of adipocytes and immune cells that make up adipose tissue, the impact of obesity on adipose cellular composition and function, and the general constituents of the JAK-STAT pathway and how its activators regulate adipose tissue development and physiology. A summary of the identification of STAT target genes in adipocytes reveals how these transcription factors impact various areas of adipocyte metabolism including insulin action, modulation of lipid stores, and glucose homeostasis. Lastly, we will evaluate exciting new data linking the JAK STAT pathway and brown adipose tissue and consider the future outlook in this area of investigation. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. PMID- 23735219 TI - Weight loss surgery for non-morbidly obese populations with type 2 diabetes: is this an acceptable option for patients? AB - AIM: To explore the views of non-morbidly obese people (BMI 30-40 kg/m2) with type 2 diabetes regarding: (a) the acceptability of bariatric surgery (BS) as a treatment for type 2 diabetes, and (b) willingness to participate in randomised controlled trials comparing BS versus non-surgical intervention. BACKGROUND: Despite weight management being a key therapeutic goal in type 2 diabetes, achieving and sustaining weight loss is problematic. BS is an effective treatment for people with morbid obesity and type 2 diabetes; it is less certain whether non-morbidly obese patients (BMI 30-39.9 kg/m2) with type 2 diabetes benefit from this treatment and whether this approach would be cost-effective. Before evaluating this issue by randomised trials, it is important to understand whether BS and such research are acceptable to this population. METHODS: Non-morbidly obese people with type 2 diabetes were purposively sampled from primary care and invited to participate in semi-structured interviews. Interviews explored participants' thoughts surrounding their diabetes and weight, the acceptability of BS and the willingness to participate in BS research. Data were analysed using Framework Analysis. PMID- 23735220 TI - Absence of Rift Valley fever virus in wild small mammals, Madagascar. PMID- 23735221 TI - New paradigms in the diagnosis and classification of the spondylarthritis. PMID- 23735222 TI - Schnitzler syndrome. PMID- 23735223 TI - Comparison of 2 referral strategies for the diagnosis of axial spondyloarthritis in Spain. The RADAR study. AB - OBJECTIVES: Improving referral of patients with back pain to rheumatologists could accelerate the diagnosis of axial spondyloarthritis. The RADAR study compared two strategies in the referral of patients with chronic back pain (>3 months) with an onset before the age of 45 years from primary care centers to rheumatology departments, in relation to the diagnosis of axial spondyloarthritis. PATIENTS AND METHODS: Each primary care center was assigned a referral strategy for its patients: (a) strategy 1, patients who had one of the 3 following criteria: inflammatory back pain, HLA-B27 positivity or sacroiliitis in imaging; or (b) strategy 2, patients who had 2 of the following 6: inflammatory back pain, HLA-B27 positivity, sacroiliitis in imaging, family history of axial spondyloarthritis, extra-articular manifestations or good response to nonsteroidal antiinflammatory drugs. The rheumatologist established the final diagnosis. RESULTS: Eighty-eight Spanish patients (mean age 36.8 years [SD 8.7], 55.7% females and 44.3% males) were referred for evaluation, 60 patients under strategy 1 and 28 under strategy 2. A definitive diagnosis of axial spondyloarthritis was established in 25.4% with strategy 1 and in 28.6% with strategy 2 (p=NS). Inflammatory back pain was the criterion most commonly used for referral, and the agreement rate between the primary care physician and rheumatologist was 75%. CONCLUSIONS: A simple referral strategy based on one of three3 criteria proved as effective as a strategy based on two of 6 criteria in diagnosing axial spondyloarthritis. Inflammatory back pain was the criterion most commonly used for patient referral. PMID- 23735224 TI - Management of osteoporosis in primary care before and after the result of densitometry: treatments in real practice versus the recommended by guidelines. CANAL study. AB - OBJECTIVES: To analyze the requirements for osteoporosis (OP) treatment of primary care physicians (PCP), before and after knowing the result of a bone densitometry (DXA). MATERIAL AND METHODS: We studied 50 years older women from two Spanish health areas (Canary Islands and Alicante). The FRAX risk factors were collected and we reviewed the requirements for OP treatment before DXA and in the subsequent months (bisphosphonates, strontium, raloxifene/bazedoxifene, estrogens, parathyroid hormone). To evaluate the appropriateness of treatment we used published guidelines. A high risk for hip fracture was considered if FRAX >= 3% or the patient had a history of fragility fracture RESULTS: We included 339 women (mean age: 63 years). Before DXA, 14% of Canarias and 58% of Alicante were receiving treatment. Thirty seven percent of treated patients and 26% of the untreated patients had a high fracture risk before DXA. The average FRAX for a high risk of fracture and hip fracture was 5.6% and 2%, respectively. After DXA, the percentage of treated patients rose from 35 to 39%: increasing from 14 to 28% in the Canary Islands and decreasing from 58 to 51% in Alicante. Overall, treatment was received by 64% of patients with OP, 38% of patients with osteopenia and 15% of those with normal DXA. When the OP treatment guidelines were applied, we found that 7% needed treatment according to the most restrictive guidelines and 43% according to the most flexible guidelines. CONCLUSIONS: There is great variability in treatment for OP prescribed before after DXA between GP. A broad consensus guideline between different specialties is required to optimize clinical practice. PMID- 23735225 TI - The collateral circulation of the heart. AB - The coronary arteries have been regarded as end arteries for decades. However, there are functionally relevant anastomotic vessels, known as collateral arteries, which interconnect epicardial coronary arteries. These vessels provide an alternative source of blood supply to the myocardium in cases of occlusive coronary artery disease. The relevance of these collateral arteries is a matter of ongoing debate, but increasing evidence indicates a relevant protective role in patients with coronary artery disease. The collateral circulation can be assessed by different methods; the gold standard involves intracoronary pressure measurements. While the first clinical trials to therapeutically induce growth of collateral arteries have been unavailing, recent pilot studies using external counterpulsation or growth factors such as granulocyte colony stimulating factor (G-CSF) have shown promising results. PMID- 23735226 TI - RNA: the new revolution in nucleic acid vaccines. AB - Nucleic acid vaccines have the potential to address issues of safety and effectiveness sometimes associated with vaccines based on live attenuated viruses and recombinant viral vectors. In addition, methods to manufacture nucleic acid vaccines are suitable as generic platforms and for rapid response, both of which will be very important for addressing newly emerging pathogens in a timely fashion. Plasmid DNA is the more widely studied form of nucleic acid vaccine and proof of principle in humans has been demonstrated, although no licensed human products have yet emerged. The RNA vaccine approach, based on mRNA and engineered RNA replicons derived from certain RNA viruses, is gaining increased attention and several vaccines are under investigation for infectious diseases, cancer and allergy. Human clinical trials are underway and the prospects for success are bright. PMID- 23735227 TI - Cytokine productive capacity of alveolar macrophages and Kupffer cells after femoral fracture and blunt chest trauma in a murine trauma model. AB - INTRODUCTION: Specific cellular and inflammatory factors that contribute to the severity of pulmonary dysfunction after blunt chest trauma and osteosynthesis of femoral fractures are yet not fully understood. Therefore, we investigated alterations of the cytokine productive capacity of alveolar macrophages (AM) and Kupffer cells (KC) after femoral fracture stabilized with intramedullary pin with or without blunt chest trauma. MATERIALS AND METHODS: In male C57BL/6N mice an intramedullary pin was implanted in an intact femur as the sham procedure. In trauma groups mice either received an isolated femoral fracture with subsequent fracture stabilization with an intramedullary pin (group Fx) or a combined trauma of blunt chest trauma and femur fracture also stabilized by an intramedullary pin (group TTFx). Animals were sacrificed 0h, 6h, 12h, 24h and 3d after trauma induction. Cytokine concentrations were measured in plasma and supernatant of cultivated AM and KC by FACS analysis. Pulmonary and hepatic infiltration of polymorphonuclear leukocytes (PMN) was determined by Ly6G-staining. RESULTS: At 6h, isolated femoral fracture with intramedullary stabilization resulted in a significantly increased productive capacity of KC (IL-6, TNF-alpha, CCL2, CCL3, CCL5 and CCL7) compared to sham animals. Combined trauma additionally resulted in an increased productive capacity of AM (IL-6, TNF-alpha, CCL2, CCL3, CCL4, CCL5 and CCL7) at 6h and the effect was prolonged up to 3d compared to controls. Combined trauma also led to a significant higher amount of plasma CCL2 at 3d and plasma CCL7 at 6h after the insult compared to group Fx. Compared to shams, pulmonary and hepatic infiltrations of PMNs were increased in group Fx and TTFx after 6h, but in the combined trauma model the effect was prolonged up to 3d. CONCLUSION: An intramedullary stabilized femur fracture alone results in a significant activation of the immune response. The combination of femoral fracture and blunt chest trauma however, results in an increased and prolonged activation of the inflammatory response. Transferred to the clinical setting, these results emphasize the critical role of severe chest trauma for treatment strategies of femoral fractures in multiple trauma patients. PMID- 23735228 TI - Alcohol policy changes and trends in adolescent drinking in Finland from 1981 to 2011. AB - AIMS: To test if changes in national alcohol policy have had an impact on alcohol use among 12- to 18-year-old adolescents in Finland over a 30-year period. METHODS: Frequencies of drinking any amounts of alcohol and drinking alcohol until really drunk from bi-annual repeated cross-sectional surveys from 1981 to 2011 were examined against a national alcohol policy review using nationally representative samples of 12-, 14-, 16- and 18-year-old adolescents (n = 99,724) in Finland. RESULTS: Twelve-year-olds' alcohol drinking remained rare throughout the period. Drinking among 18-year-olds generally increased throughout the period. Significant increases until the late 1990s and decreases thereafter were observed in 14- and 16-year-olds' drinking patterns. A sharp increase was predicted between 2003 and 2005 as a result of EU-related processes, but instead decrease was observed among 14-16-year-olds. The tests of hypothesized decrease from 2005 to 2011 due to tightening alcohol policy including several tax raises produced mixed results. CONCLUSION: Alcohol policy changes between 1981 and 2011 seem not to have had noticeable influence on alcohol drinking or drunkenness among the under-aged in Finland. Conspicuous increases seen in population total consumption in association with EU-related developments have not materialized among adolescents. PMID- 23735231 TI - Representing physiological processes and their participants with PhysioMaps. AB - BACKGROUND: As the number and size of biological knowledge resources for physiology grows, researchers need improved tools for searching and integrating knowledge and physiological models. Unfortunately, current resources-databases, simulation models, and knowledge bases, for example-are only occasionally and idiosyncratically explicit about the semantics of the biological entities and processes that they describe. RESULTS: We present a formal approach, based on the semantics of biophysics as represented in the Ontology of Physics for Biology, that divides physiological knowledge into three partitions: structural knowledge, process knowledge and biophysical knowledge. We then computationally integrate these partitions across multiple structural and biophysical domains as computable ontologies by which such knowledge can be archived, reused, and displayed. Our key result is the semi-automatic parsing of biosimulation model code into PhysioMaps that can be displayed and interrogated for qualitative responses to hypothetical perturbations. CONCLUSIONS: Strong, explicit semantics of biophysics can provide a formal, computational basis for integrating physiological knowledge in a manner that supports visualization of the physiological content of biosimulation models across spatial scales and biophysical domains. PMID- 23735230 TI - The structure of the Mycobacterium smegmatis trehalose synthase reveals an unusual active site configuration and acarbose-binding mode. AB - Trehalose synthase (TreS) catalyzes the reversible conversion of maltose into trehalose in mycobacteria as one of three biosynthetic pathways to this nonreducing disaccharide. Given the importance of trehalose to survival of mycobacteria, there has been considerable interest in understanding the enzymes involved in its production; indeed the structures of the key enzymes in the other two pathways have already been determined. Herein, we present the first structure of TreS from Mycobacterium smegmatis, thereby providing insights into the catalytic machinery involved in this intriguing intramolecular reaction. This structure, which is of interest both mechanistically and as a potential pharmaceutical target, reveals a narrow and enclosed active site pocket within which intramolecular substrate rearrangements can occur. We also present the structure of a complex of TreS with acarbose, revealing a hitherto unsuspected oligosaccharide-binding site within the C-terminal domain. This may well provide an anchor point for the association of TreS with glycogen, thereby enhancing its role in glycogen biosynthesis and degradation. PMID- 23735233 TI - Surfactant-mediated complement activation in beagle dogs. PMID- 23735232 TI - Antagonism of histamine H4 receptors exacerbates clinical and pathological signs of experimental autoimmune encephalomyelitis. AB - BACKGROUND AND PURPOSE: The histamine H4 receptor has a primary role in inflammatory functions, making it an attractive target for the treatment of asthma and refractory inflammation. These observations suggested a facilitating action on autoimmune diseases. Here we have assessed the role of H4 receptors in experimental autoimmune encephalomyelitis (EAE) a model of multiple sclerosis (MS). EXPERIMENTAL APPROACH: We induced EAE with myelin oligodendrocyte glycoprotein (MOG35-55 ) in C57BL/6 female mice as a model of MS. The histamine H4 receptor antagonist 5-chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-indole (JNJ7777120) was injected i.p. daily starting at day 10 post-immunization (D10 p.i.). Disease severity was monitored by clinical and histopathological evaluation of inflammatory cells infiltrating into the spinal cord, anti-MOG35-55 antibody production, assay of T-cell proliferation by [(3) H]-thymidine incorporation, mononucleate cell phenotype by flow cytometry, cytokine production by elisa assay and transcription factor quantification of mRNA expression. KEY RESULTS: Treatment with JNJ7777120 exacerbated EAE, increased inflammation and demyelination in the spinal cord of EAE mice and increased IFN-gamma expression in lymph nodes, whereas it suppressed IL-4 and IL-10, and augmented expression of the transcription factors Tbet, FOXP3 and IL-17 mRNA in lymphocytes. JNJ7777120 did not affect proliferation of anti-MOG35-55 T-cells, anti-MOG35-55 antibody production or mononucleate cell phenotype. CONCLUSIONS AND IMPLICATIONS: H4 receptor blockade was detrimental in EAE. Given the interest in the development of H4 receptor antagonists as anti-inflammatory compounds, it is important to understand the role of H4 receptors in immune diseases to anticipate clinical benefits and also predict possible detrimental effects. PMID- 23735234 TI - Author response to commentaries. PMID- 23735235 TI - Rasagiline in Parkinson's disease: a review based on meta-analysis of clinical data. AB - Rasagiline (Azilect((r))) is a selective and irreversible monoamine oxidase B inhibitor, which is well tolerated, safe, improves motor symptoms, and prevents motor complications in Parkinson's disease (PD). Rasagiline is effective in monotherapy and as an adjunct to levodopa-therapy, with beneficial effects on quality-of-life parameters in early and late stages of PD. In this review, we compare the efficacy of rasagiline versus placebo for decreasing PD symptoms. Major databases (Medline, the Cochrane Library) were systematically searched to identify and select clinical randomized control trials of rasagiline. The Unified Parkinson Disease Rating Scale (UPDRS) for rasagiline monotherapy and reduction in off-time for combined treatment were the outcomes assessed. Rasagiline monotherapy, in early stages of the disease, reduces the UPDRS score [-3.06 (95% CI -3.81 to -2.31, p<0.00001) with rasagiline 1mg/day]. In combination with levodopa, 1mg/day of rasagiline reduced off-time [-0.93h (95% CI -1.17 to -0.69, p<0.00001)]. However, although rasagiline reduces the UPDRS score [-0.89 (95% CI from -1.78 to 0, p=0.05)] in trials with a delayed-start design, we found a disagreement between studies and doses, making it difficult to interpret this result. In conclusion, our results confirm the efficacy of rasagiline in PD, but the clinical significance of these data remains to be established. Furthermore, the delayed-start study design did not establish with certainty the neuroprotective effect of rasagiline. It is advisable to carry out comparative trials with other drugs used in Parkinson's disease. PMID- 23735236 TI - Human papillomavirus genital infections among men, China, 2007-2009. AB - To determine prevalence of genital human papillomavirus (HPV) infection among men in rural China, we analyzed genital swab specimens. Among 2,236 male residents of rural Henan Province, HPV infection prevalence was 17.5%. The most common oncogenic and nononcogenic types were HPV-16 and HPV-3, respectively. Infection was associated with younger age and multiple sex partners. PMID- 23735237 TI - Clinical significance of differences between home and clinic systolic blood pressure readings in patients with hypertension. AB - OBJECTIVES: To elucidate the clinical significance of differences between home- and clinic-measured systolic blood pressure (SBP) in patients with treated hypertension, and to assess the correlations between SBPs and arterial stiffness. METHODS: Patients with treated hypertension measured their blood pressure (BP) themselves once, at home, in the morning (<1 h after awakening) using an automated oscillometric sphygmomanometer. Clinic BP was measured once, at an outpatient clinic on the same day, using a similar instrument. Arterial stiffness was measured by cardio-ankle vascular index (CAVI). Differences between home and clinic SBPs, and the correlations between CAVI and home SBP, clinic SBP, and the difference between home and clinic SBPs, were analysed. RESULTS: Seventy-six patients with treated hypertension (mean age, 71 years) were evaluated. There was no statistically significant difference between home and clinic SBP (mean +/- SD 132 +/- 14 and 133 +/- 16 mmHg, respectively). Home SBP showed no correlation with CAVI, whereas clinic SBP showed a weak correlation. The difference between the home and clinic SBP showed a stronger correlation with CAVI, and was statistically significant. CONCLUSIONS: The difference between home- and clinic measured SBP showed a better correlation with arterial stiffness than did either home or clinic SBP alone. PMID- 23735238 TI - Management of the N0 neck in early stage oral squamous cell cancer: a modeling study of the cost-effectiveness. AB - OBJECTIVES: To assess the cost-effectiveness of five strategies for diagnosing and treating cT1-2N0 oral squamous cell cancer. MATERIALS AND METHODS: A Markov decision analytic model was used to evaluate the cost-effectiveness of (1) elective neck dissection (END), (2) watchful waiting (WW), (3) gene expression profiling (GEP) followed by neck dissection (ND) or WW, (4) sentinel lymph node (SLN) procedure followed by ND or WW, and (5) GEP and SLN (for positive GEP) followed by ND or WW. Uncertainty was addressed using one-way and probabilistic sensitivity analyses. RESULTS: Base-case analysis showed that SLN procedure followed by ND or WW was the most effective and most cost effective strategy. Compared with direct END the incremental cost effectiveness ratio was ?3356 per QALY gained. Uncertainty analysis showed that the model was sensitive to changes in assumed occult metastases incidence and utility values. SLN was found to have the highest probability (66%) of being cost-effective of the five strategies, at a willingness to pay of ?80,000 per QALY. CONCLUSIONS: Given the current evidence and costs the SLN procedure followed by ND or WW appears to be the most cost effective strategy for diagnosing and treating oral squamous cell cancer patients. Our model provides the foundation for future diagnostic and therapeutic research in this field and shows that further information on quality of life in this population is highly valuable. PMID- 23735239 TI - Determination and pharmacokinetics of amygdalin in rats by LC-MS-MS. AB - A sensitive and specific liquid chromatography-tandem mass spectrometric (LC-MS MS) method was developed for the determination and pharmacokinetics of amygdalin in rats. Rat plasma pretreated by solid-phase extraction was analyzed by LC-MS-MS with negative electrospray ionization in the multiple reaction monitoring mode. Amygdalin and geniposide [the internal standard (IS)] were separated on a C18 column eluted with a mobile phase of methanol and water (85:15; v/v) at a flow rate of 0.25 mL/min in a run time of 3.0 min. The precursor to product ion transitions were monitored at m/z 457.2 -> 279.1 for amygdalin and m/z 387.1 -> 224.9 for the IS. The calibration curve of amygdalin showed good linearity over a concentration range of 10-2,000 ng/mL. The limit of quantification was 10 ng/mL. Intra-day and inter-day precisions and accuracy (percent relative standard deviation) were both within 10%. The method was fully validated for its selectivity, sensitivity, matrix effect, recovery and stability. This accurate and specific assay produced a useful LC-MS-MS method, which was successfully applied to pharmacokinetic studies after the oral administration of amygdalin to rats. PMID- 23735240 TI - Beneficial effect of TNF-alpha inhibition on diabetic peripheral neuropathy. AB - BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is an important inflammatory factor produced by activated macrophages and monocytes and plays an important role in the pathogenesis of diabetic peripheral neuropathy (DPN). To evaluate the effect of TNF-alpha signaling suppression and the potential of TNF-alpha in the treatment of DPN, a recombinant human TNF-alpha receptor-antibody fusion protein (rhTNFR:Fc) was used. We focused on the pathophysiology of the sciatic nerve and examined the expression of myelin basic protein (MBP) under DPN status with or without TNF-alpha inhibition. METHODS: The DPN rat model was generated by intraperitoneal injection of streptozotocin and by feeding with a high-fat, high sugar diet. The nerve conduction velocity (NCV) in sciatic nerve of rat was monitored over a period of four weeks. The histopathological changes in nerve tissue were examined through traditional tissue histology and ultrastructure transmission electron microscopy (TEM). The expression of MBP was examined through western blot analysis. RESULTS: The DPN induced rats showed significant signs of nerve damage including lower NCV, demyelination of nerve fibers, disorganization of lamellar and axonal structures, and decreased expression of MBP in the nerve tissue. The inhibition of TNF-alpha in the DPN rats resulted in a significant recovery from those symptoms compared to the DPN rats. CONCLUSIONS: Our study demonstrates that TNF-alpha plays a key role in the pathogenesis of DPN and its inhibition by rhTNFR:Fc can prove to be a useful therapeutic strategy for the treatment of and/or prevention from DPN symptoms. PMID- 23735241 TI - Colostrum replacer and bovine leukemia virus seropositivity in calves. PMID- 23735242 TI - Sparse methods in spectroscopy: an introduction, overview, and perspective. AB - Multivariate calibration methods such as partial least-squares build calibration models that are not parsimonious: all variables (either wavelengths or samples) are used to define a calibration model. In high-dimensional or large sample size settings, interpretable analysis aims to reduce model complexity by finding a small subset of variables that significantly influences the model. The term "sparsity", as used here, refers to calibration models having many zero-valued regression coefficients. Only the variables associated with non-zero coefficients influence the model. In this paper, we briefly review the regression problems associated with sparse models and discuss their spectroscopic applications. We also discuss how one can re-appropriate sparse modeling algorithms that perform wavelength selection for purposes of sample selection. In particular, we highlight specific sparse modeling algorithms that are easy to use and understand for the spectroscopist, as opposed to the overly complex "black-box" algorithms that dominate much of the statistical learning literature. We apply these sparse modeling approaches to three spectroscopic data sets. PMID- 23735243 TI - Time-resolved principal component imaging analysis of chlorophyll fluorescence induction for monitoring leaf water stress. AB - Chlorophyll fluorescence induction is widely applied to investigate plant growth conditions by calculating the ratio of its intensity at oxidized and reduced states. We examined the applicability of a time-resolved profile of chlorophyll fluorescence induction with the aid of multivariate analysis to monitor the leaf water stress. Principal component (PC) analysis of time-resolved images of chlorophyll fluorescence induction and their score images were reconstructed. Control leaves (non-stressed leaves) and water-stressed leaves could be classified by normalized PC3 score images. This technique has the potential to monitor the water stress condition of plants by using a simple device. PMID- 23735244 TI - Stress transfer of a Kevlar 49 fiber pullout test studied by micro-Raman spectroscopy. AB - The interfacial stress transfer behavior of a Kevlar 49 aramid fiber-epoxy matrix was studied with fiber pullout tests, the fibers of which were stretched by a homemade microloading device. Raman spectra on the embedded fiber were recorded by micro-Raman spectroscopy, under different strain levels. Then, the fiber axial stress was obtained by the relationship between the stress and Raman shift of the aramid fiber. Experimental results revealed that the fiber axial stress increased significantly with the load. The shear stress concentration occurred at the fiber entry to the epoxy resin. Thus, interfacial friction stages exist in the debonded fiber segment, and the interfacial friction shear stress is constant within one stage. The experimental results are consistent with the theoretical model predictions. PMID- 23735245 TI - Structural study of photodegraded acrylic-coated lime wood using Fourier transform infrared and two-dimensional infrared correlation spectroscopy. AB - The weathering of acrylic films and acrylic-coated lime wood (Tillia cordata Mill.) were examined using Fourier transform infrared (FT-IR) and two-dimensional infrared correlation spectroscopy. The obtained results showed chemical changes induced by exposure to weathering conditions, in both films and coated wood. The observed spectral changes of the acrylic films refer to the absorption band assigned to the C-O stretching, which progressively decreases with increasing exposure time. In the spectra of treated wood samples the main signal indicating the advance of oxidation during the photodegradation exposure is the gradual increase and broadening of the band in the carbonyl region. This is due to the formation of the non-hydrogen bonded aliphatic carboxylic acids and gamma-lactone structures in the acrylic resin and of the nonconjugated ketones, carboxyl groups, and lactones in wood. As a consequence, the increase of the 1734 cm(-1) band is due to the degradation of lignin from wood surface. These observations are also supported by the decreased intensities of the bands at 1598 and 1505 cm( 1), assigned to C=C of aromatic skeletal (lignin). The relative intensity of the characteristic aromatic lignin band at 1505 cm(-1) decreases up to 25% of its original value after weathering, being less than half of the value obtained for uncoated wood. Two-dimensional infrared (2D IR) correlation spectroscopy was used to identify the sequence of the modifications of the different stretching vibrations bands under the weathering conditions, the method allowing the prediction of the order of degradation reactions. The acrylic resin degradation starts with the formation of radicals by abstraction of the tertiary hydrogen atoms of the methyl acrylate units and the alpha-CH3 groups from the ethyl methacrylate units. The subsequent decomposition and oxidation led to the formation of alcohol groups, hydroperoxides, ketones, and/or carboxylic acid groups. The 2D IR correlation spectra of weathered impregnated wood also revealed the elimination of low molecular weight compounds following the degradation of lignin and carbohydrates components from wood. PMID- 23735246 TI - Polystyrene beads as probes of the surface-enhanced Raman scattering response characteristics of silver nanorod arrays. AB - Polystyrene microspheres were used to interrogate the surface-enhanced Raman scattering (SERS) response of silver nanorod (AgNR) array substrates. It has been suggested that enhancement between nanorods is significantly greater than that at the top due to contributing electromagnetic fields from each nanostructure. To test this theory, two different sized fluorescent polystyrene microspheres were used. The SERS intensity of beads small enough to fit within the array was compared with that of larger beads confined to rest on top of the array. Location of the beads within the array was established using optical fluorescence and scanning electron microscopy. The findings presented herein suggest that evaporation of the sample produces a nonuniform distribution of scatterers across the AgNR array and that the enhancement found for beads located on top of the AgNRs was significantly greater than that for beads located within the array. PMID- 23735247 TI - Taxonomic classification of phytoplankton with multivariate optical computing, part I: design and theoretical performance of multivariate optical elements. AB - Phytoplankton are single-celled, photosynthetic algae and cyanobacteria found in all aquatic environments. Differential pigmentation between phytoplankton taxa allows use of fluorescence excitation spectroscopy for discrimination and classification. For this work, we applied multivariate optical computing (MOC) to emulate linear discriminant vectors of phytoplankton fluorescence excitation spectra by using a simple filter-fluorometer arrangement. We grew nutrient replete cultures of three differently pigmented species: the coccolithophore Emiliania huxleyi, the diatom Thalassiosira pseudonana, and the cyanobacterium Synechococcus sp. Linear discriminant analysis (LDA) was used to determine a suitable set of linear discriminant functions for classification of these species over an optimal wavelength range. Multivariate optical elements (MOEs) were then designed to predict the linear discriminant scores for the same calibration spectra. The theoretical performance specifications of these MOEs are described. PMID- 23735248 TI - Taxonomic classification of phytoplankton with multivariate optical computing, part II: design and experimental protocol of a shipboard fluorescence imaging photometer. AB - Differential pigmentation between phytoplankton allows use of fluorescence excitation spectroscopy for the discrimination and classification of different taxa. Here, we describe the design and performance of a fluorescence imaging photometer that exploits taxonomic differences for discrimination and classification. The fluorescence imaging photometer works by illuminating individual phytoplankton cells through an asynchronous spinning filter wheel, which produces bar code-like streaks in a fluorescence image. A filter position is covered with an opaque filter to create a reference dark position in the filter wheel rotation that is used to match each fluorescence streak with the corresponding filter. Fluorescence intensities of the imaged streaks are then analyzed for the purpose of spectral analysis, which allows taxonomic classification of the organism that produced the streaks. The theoretical performance and signal-to-noise ratio (SNR) specifications of these MOEs are described in Part I of this series. This report describes optical layout, flow cell design, magnification, depth of field, constraints on filter wheel and flow velocities, procedures for blank subtraction and flat-field correction, the measurement scheme of the instrument, and measurement of SNR as a measurement of filter wheel frequency. This is followed by an analysis of the sources of variance in measurements made by the photometer on the coccolithophore Emiliania huxleyi. We conclude that the SNR of E. huxleyi measurements is not limited by the sensitivity or noise attributes of the measurement system, but by dynamics in the fluorescence efficiency of the E. huxleyi cells. Even so, the minimum SNR requirements given in Part I for the instrument are met. PMID- 23735249 TI - Taxonomic classification of phytoplankton with multivariate optical computing, part III: demonstration. AB - We describe the automatic analysis of fluorescence tracks of phytoplankton recorded with a fluorescence imaging photometer. The optical components and construction of the photometer were described in Part I and Part II of this series in this issue. An algorithm first isolates tracks corresponding to a single phytoplankter transit in the nominal focal plane of a flow cell. Then, the fluorescence streaks in the track that correspond to individual optical elements on the filter wheel are identified. The fluorescence intensity of each streak is integrated and used to calculate ratios. This approach was tested using 853 fluorescence measurements of the coccolithophore Emiliania huxleyi and the diatom Thalassiosira pseudonana. Average intensity ratios for the two classes closely follow those predicted in Part I of this series, with a distribution of ratios in each class that is consistent with the signal-to-noise ratio calculations in Part II for single cells. No overlap of the two class ratios was observed, yielding perfect classification. PMID- 23735250 TI - Investigation of the interaction of pepsin with ionic liquids by using fluorescence spectroscopy. AB - The molecular mechanism of the interaction between pepsin and two typical ionic liquids (ILs), 1-butyl-3-methylimidazolium chloride ([C4mim]Cl) and 1-octyl-3 methylimidazolium chloride ([C8mim]Cl), was investigated with fluorescence spectroscopy, ultraviolet absorption, and circular dichroism spectroscopy at a pH value of 1.6. The results suggest that ILs could quench the intrinsic fluorescence of pepsin, probably via a dynamic quenching mechanism. The fluorescence quenching constants were determined by employing the classic Stern Volmer equation. The constant values are very small, indicating that only a very weak interaction between ILs and pepsin exists. The Gibbs free-energy change, enthalpy change (DeltaH), and entropy change (DeltaS) during the interaction of pepsin and ILs were estimated. Positive values of DeltaH and DeltaS indicate that the interaction between ILs and pepsin is mainly driven by hydrophobic interaction. Synchronous and three-dimensional fluorescence spectra demonstrate that the addition of ILs (0-0.20 mol L(-1) for each IL) does not bring apparent changes to the microenvironments of tyrosine and tryptophan residues. Activity experiments show that the activity of pepsin is concentration dependent; higher concentrations of ILs (>0.22 mol L(-1) for [C8mim]Cl and >0.30 mol L(-1) for [C4mim]Cl) cause the remarkable reduction of enzyme activity. The presence of ILs also does not improve the thermal stability of pepsin. PMID- 23735251 TI - Toward a reusable surface-enhanced Raman spectroscopy (SERS) substrate by soft landing ion mobility. AB - Soft-landing ion mobility has been applied to the development of a reusable surface-enhanced Raman spectroscopic substrate. Sections of silicon wafers were cleaved and modified with 3-(mercaptopropyl) triethoxysilane. After modification, gold was deposited using a soft-landing ion mobility system at thermal kinetic energies. It was found that 30 min of deposition provided the optimal feature size for surface-enhanced Raman scattering, and thus deposition was completed in a pressure-dependent fashion. After gold deposition, caffeine was deposited from the solution phase and checked for Raman activity. The Raman spectroscopic signature for caffeine increased as an inverse function of pressure pertaining to surface coverage of captured Au particles. After Raman spectroscopic confirmation of caffeine, the 1 Torr surface was ultrasonically cleaned in deionized water and respotted with sodium bicarbonate solution. There was no interference on the sodium bicarbonate solution from residual caffeine on the surface. PMID- 23735252 TI - Use of total internal reflection Raman (TIR) and attenuated total reflection infrared (ATR-IR) spectroscopy to analyze component separation in thin offset ink films after setting on coated paper surfaces. AB - The interactive behavior of ink constituents with porous substrates during and after the offset print process has an important effect on the quality of printed products. To help elucidate the distribution of ink components between the retained ink layer and the substrate, a variety of spectroscopic and microscopic analysis techniques have been developed. This paper describes for the first time the use of total internal reflection (TIR) Raman spectroscopy to analyze the penetration behavior of separated offset ink components (linseed oil, solid color pigment) in coated papers providing chemically intrinsic information rapidly, nondestructively, and with minimal sample preparation. In addition, the already widely applied technique of attenuated total reflection infrared spectroscopy (ATR-IR) was evaluated in parallel and compared. The results of the ATR-IR Raman clearly revealed an improvement in uppermost depth resolution compared with values previously published from other nondestructive techniques, and the method is shown to be capable of providing new knowledge of the setting of thin (0.25-2 MUm) offset ink films, allowing the spreading and the penetration behavior on physically different paper coating surfaces to be studied. PMID- 23735253 TI - Interaction of carbocyanine dyes with DNA: synthesis and spectroscopic studies. AB - Six carbocyanine dyes have been synthesized and their interactions with DNA have been investigated for their prospective use as fluorescent markers in molecular biology. The noncovalent binding of the compounds with DNA was explored by fluorescence spectroscopy, ultraviolet/visible spectrophotometry, and photobleaching. The electron-withdrawing ability of the substituents in N position of free thio- and selenocarbocyanines strongly affected their photostabilities. Changes in the experimental conditions, such as the presence or absence of oxygen, had an impact on the rate of photobleaching. In the presence of DNA, absorbance photofading and fluorescence photobleaching occurred. It appears that the reduction of fluorescence intensity was due to quenching of the dye fluorescence by interaction with DNA. PMID- 23735254 TI - Real-time monitoring of lycopene content in tomato-derived products during processing: implementation of a novel double-slit Raman spectrometer. AB - Lycopene is a very attractive antioxidant associated with cancer prevention in humans. Therefore, it is important to develop new analytical methods that allow for differentiation of food production streams that contain various antioxidant concentrations. The lycopene content in tomato juice, an intermediate between raw tomatoes and the final tomato paste product, was monitored on-line for 46 days at a production plant with a novel, patented double-channel Raman setup. The setup comprises a double-channel mini spectrometer placed in a fixed optical setup, and for each measurement there are two slightly shifted Raman spectra on the x-axis that opens up for additional data processing. The prototype was constructed specifically for 532 nm excitation with no moving parts, and it was designed to optimize each part for the rest of the system. That was the first step toward an integrated optical in-line process analytical solution for industry. As proof of concept, the developed prototype was able to perform a real-time differentiation of the normal and medium to high lycopene content in tomato juice. A correlation factor for double-channel measurements was compared with a correlation factor for background-corrected single-channel measurements by correlating with high performance liquid chromatography reference measurements (1-20 mg of lycopene per 100 g of wet sample). The latter gave a slightly better correlation for the specific application (R(2) = 0.76), acceptable for proof of concept. Real-time information is extremely valuable for the tomato processing plant, mainly because it can be used for improved differentiation of high lycopene content tomato paste to ensure a higher product price. In addition, the developed process analytical technology solution allows for differentiated payment of the tomato farmers based on the lycopene content in their crops. PMID- 23735255 TI - Facile characterization of the immobilization of streptavidin on magnetic submicron particles with a fluorescent probe of streptavidin. AB - To characterize streptavidin immobilization on magnetic submicron particles (MSPs), residual streptavidin after magnetic removal of immobilized streptavidin was quantified with N-biotinyl-N'-(1-naphthyl)-ethylenediamine (BNEDA) based on Forster resonance energy transfer. Residual BNEDA after magnetic removal of bound BNEDA was measured by its own fluorescence. Streptavidin was immobilized at about 12 mg per gram of MSPs and easily retained over 50% of its original activity. These assays facilitated optimized streptavidin immobilization on MSPs. PMID- 23735256 TI - Reduction of artifacts in fluorescence correlation spectroscopy due to sample adsorption on optical glass surfaces. AB - The preparation of glass cell surfaces that are chemically functionalized with poly(ethylene glycol) (PEG) chains to reduce sample adsorption and their use in fluorescence correlation spectroscopy (FCS) is described. Optical glass coverslips were acid etched and reacted with either 750 Mr PEG (PEG-750) or 5000 Mr PEG (PEG-5000) to produce adsorption-resistant optical surfaces. FCS data for Nile red-loaded Triton X-100 micelles (NR-TX-100) and Alexa Fluor 555-labeled proteins, bovine serum albumin (BSA-A555), lipidized BSA (lipid-BSA-A555), and three low molecular weight dyes deposited on PEGylated coverslips were evaluated. Measurement artifacts due to sample adsorption on the PEG-5000 functionalized coverslips were reduced significantly for the majority of test materials. Calculations of translational diffusion coefficients and Stokes radii confirmed the effectiveness of this approach. PEG-5000 functionalized coverslips were demonstrated as more effective in inhibiting adsorption than PEG-750 functionalized coverslips. Neither of the functionalized coverslips inhibited the adsorption of one test compound, rhodamine B, a dye that adsorbs strongly on glass surfaces. The use of longer PEG chains in conjunction with chemical cross linking is proposed for producing a denser, less porous PEG layer for the prevention of strongly glass-adsorbing fluorophores that do not interact with the PEG layer. PMID- 23735257 TI - Correspondence regarding the article "On the nature of the evanescent wave" (Appl. Spectrosc. 2013. 67[2]: 126-130). How "total" is total reflection from powdered samples? PMID- 23735258 TI - Mitochondria-targeted plastoquinone antioxidant SkQ1 prevents amyloid-beta induced impairment of long-term potentiation in rat hippocampal slices. AB - Bath application of 200 nM amyloid-beta1-42 (Abeta) to rat hippocampal slices impairs induction of long-term potentiation (LTP) of the population spike in pyramidal layer of the CA1 field of the hippocampus. Intraperitoneal injection of mitochondria-targeted plastoquinone derivative SkQ1 at very low concentrations (250 nmol/kg body weight) given 24 h before the slice preparation or 1 h treatment of hippocampal slices with 250 nM SkQ1 prevents the deleterious effect of Abeta on LTP. To elucidate which part of the molecule is responsible for this type of neuroprotective activity, the effect of the analog of SkQ1 lacking plastoquinone (C12TPP) was studied. It was found that C12TPP was much less efficient in LTP protection than SkQ1 itself. It means that the plastoquinone part of the SkQ1 molecule is responsible for the LTP rescue. To summarize, in vivo and in vitro injection of SkQ1 compensates for Abeta-induced oxidative damage of long-term synaptic plasticity in the hippocampus, which is considered to be the main reason of memory loss and impairment of other cognitive functions associated with Alzheimer's disease. Therefore, SkQ1 may be considered as a promising candidate for the treatment of early-stage Alzheimer's disease. PMID- 23735259 TI - The cruciform model of striate generation of the early VEP, re-illustrated, not revoked: a reply to Ales et al. (2013). AB - Here we summarize the points raised in our dialog with Ales and colleagues on the cortical generators of the early visual evoked potential (VEP), and offer observations on the results of additional simulations that were run in response to our original comment. For small stimuli placed at locations in the upper and lower visual field for which the human VEP has been well characterized, simulated scalp projections of each of the visual areas V1, V2 and V3 invert in polarity. However, the empirically measured, earliest VEP component, "C1," matches the simulated V1 generators in terms of polarity and topography, but not the simulated V2 and V3 generators. We thus conclude that, 1) consistent with the title of Ales et al. (2010a), polarity inversion on its own is not a sufficient criterion for inferring neuroelectric sources in primary visual cortex; but 2) inconsistent with additional claims made in Ales et al. (2010a), the simulated topographies provide additional evidence for - not against - the tenet that the C1 component is generated in V1. PMID- 23735261 TI - Group-level impacts of within- and between-subject hemodynamic variability in fMRI. AB - Inter-subject fMRI analyses have specific issues regarding the reliability of the results concerning both the detection of brain activation patterns and the estimation of the underlying dynamics. Among these issues lies the variability of the hemodynamic response function (HRF), that is usually accounted for using functional basis sets in the general linear model context. Here, we use the joint detection-estimation approach (JDE) (Makni et al., 2008; Vincent et al., 2010) which combines regional nonparametric HRF inference with spatially adaptive regularization of activation clusters to avoid global smoothing of fMRI images. We show that the JDE-based inference brings a significant improvement in statistical sensitivity for detecting evoked activity in parietal regions. In contrast, the canonical HRF associated with spatially adaptive regularization is more sensitive in other regions, such as motor cortex. This different regional behavior is shown to reflect a larger discrepancy of HRF with the canonical model. By varying parallel imaging acceleration factor, SNR-specific region-based hemodynamic parameters (activation delay and duration) were extracted from the JDE inference. Complementary analyses highlighted their significant departure from the canonical parameters and the strongest between-subject variability that occurs in the parietal region, irrespective of the SNR value. Finally, statistical evidence that the fluctuation of the HRF shape is responsible for the significant change in activation detection performance is demonstrated using paired t-tests between hemodynamic parameters inferred by GLM and JDE. PMID- 23735260 TI - Resting state network estimation in individual subjects. AB - Resting state functional magnetic resonance imaging (fMRI) has been used to study brain networks associated with both normal and pathological cognitive functions. The objective of this work is to reliably compute resting state network (RSN) topography in single participants. We trained a supervised classifier (multi layer perceptron; MLP) to associate blood oxygen level dependent (BOLD) correlation maps corresponding to pre-defined seeds with specific RSN identities. Hard classification of maps obtained from a priori seeds was highly reliable across new participants. Interestingly, continuous estimates of RSN membership retained substantial residual error. This result is consistent with the view that RSNs are hierarchically organized, and therefore not fully separable into spatially independent components. After training on a priori seed-based maps, we propagated voxel-wise correlation maps through the MLP to produce estimates of RSN membership throughout the brain. The MLP generated RSN topography estimates in individuals consistent with previous studies, even in brain regions not represented in the training data. This method could be used in future studies to relate RSN topography to other measures of functional brain organization (e.g., task-evoked responses, stimulation mapping, and deficits associated with lesions) in individuals. The multi-layer perceptron was directly compared to two alternative voxel classification procedures, specifically, dual regression and linear discriminant analysis; the perceptron generated more spatially specific RSN maps than either alternative. PMID- 23735262 TI - Connectomic approaches before the connectome. AB - Connectome is a term with a short history but a long past. Since the origins of neuroscience the concept of a 'map of neural connections' has been a constant inspiring idea for those who believed the brain as the organ of intellect. A myriad of proto-connectome maps have been produced throughout the centuries, each one reflecting the theory and method of investigation that prevailed at the time. Even contemporary definitions of the connectome rest upon the formulation of a neuronal theory that has been proposed over a hundred years ago. So, what is new? In this article we attempt to trace the development of certain anatomical and physiological concepts at the origins of modern definitions of the connectome. We argue that compared to previous attempts current connectomic approaches benefit from a wealth of imaging methods that in part could justify the enthusiasm for finally succeeding in achieving the goal. One of the unique advantages of contemporary approaches is the possibility of using quantitative methods to define measures of connectivity where structure, function and behaviour are integrated and correlated. We also argue that many contemporary maps are inaccurate surrogates of the true anatomy and a comprehensive connectome of the human brain remains a far distant point in the history to come. PMID- 23735263 TI - Re: Body mass index influences prostate cancer risk at biopsy in Japanese men. PMID- 23735264 TI - An advance letter did not increase the response rates in a telephone survey: a randomized trial. AB - OBJECTIVE: To test the impact of an advance letter on response and cooperation rates in a nationwide telephone survey, given previous inconsistent results. STUDY DESIGN AND SETTING: Within the context of a larger telephone survey, 1,000 Australian households were randomly selected to take part in this trial. Half were randomly allocated to receive an advance letter, whereas the remainder did not receive any advance communication. Response and cooperation rates were compared between the two groups. RESULTS: A total of 244 interviews were completed, 134 of which were with households that had been sent an advance letter. Intention-to-treat analysis revealed no significant difference in response between those who had received a letter and those who had not (26.8% vs. 22.0%, respectively). In addition, there was no significant difference between the groups in terms of either cooperation (78.4% vs. 79.7%) or response rate (56.3% vs. 57.9%), and no clear differences emerged in terms of the demographic characteristics of the two groups. CONCLUSION: An advance letter was not seen to be effective in increasing response or cooperation rates in a nationwide telephone survey. Researchers should consider alternative methods of increasing participation in telephone surveys. PMID- 23735265 TI - ACR radiology education days in Haiti. PMID- 23735266 TI - Trying something new. PMID- 23735267 TI - Imaging informatics: lead, follow, or become irrelevant. PMID- 23735268 TI - The $64,000 question. PMID- 23735269 TI - The robot as radiologist. PMID- 23735270 TI - The physician payments sunshine act: what the average radiologist and manager need to know. AB - The Physician Payments Sunshine Act (PPSA) was enacted in 2010 and requires applicable manufacturers of medical devices, drugs, biological material, or medical supplies to report payments or transfers of value that are provided to physicians or teaching hospitals. PPSA has value in creating greater transparency in the financial relationships between industry, physicians, and teaching hospitals, and in potentially reducing problematic conflicts of interest. PPSA requires that this data be published, in searchable form, on a public website. CMS has delayed the reporting under PPSA until after January 1, 2013, and has yet to issue its final rules for PPSA; however, Physician Payments data already exist in a publically searchable database. It is important to realize that names of individuals may appear in the PPSA public database, even if those individuals did not actually receive a transfer of value. As with all broad-stroke legislation, consequences not anticipated or not considered sufficiently important for our government leaders may well present a problem for individuals. It behooves all physicians and healthcare managers to carefully follow the CMS PPSA regulations. In advance of meeting or interacting with any PPSA-applicable manufacturer, obtain a clear and mutual understanding regarding what reportable value, if any, will be prepared for and provided by the applicable manufacturer. In this, as in all situations in which government regulations are at play, "knowledge is strength." PMID- 23735271 TI - Rate of radiation therapy events in a large academic institution. AB - PURPOSE: The goals of this study were to determine the rate of radiation therapy patient events at a large academic institution and to evaluate temporal trends in this rate using statistical process control tools. METHODS: An incident reporting system was used to prospectively collect information on radiation therapy patient events and near misses or good catches, using paper-based reports through December 2010 and an online electronic reporting system from January 2011 onward. Patient events were classified into 3 categories on the basis of their severity. The rate of these events from January 2008 to December 2011 was determined. p charts were used to evaluate trends over time. RESULTS: There were 188 radiation therapy events in the 4-year period, of which 38 were level I or II (more severe) events and 150 were level III (less severe) events. During this 4-year period, a total of 28,488 new patients were treated, and a total of 618,461 radiation fractions were delivered. The rate of radiation therapy events was 0.66% per patient and 0.03% per radiation fraction. There were 358 near misses and good catches in the 4-year period. The p charts indicated that there were no significant changes in the rate of radiation therapy events over time. CONCLUSIONS: The rate of radiation therapy events was very low and remained stable over a 4-year period. In the absence of a national reporting system, single-institution reports can provide valuable information on radiotherapy patient event rates and can augment quality improvement efforts. PMID- 23735272 TI - Why can't these health plans pay my claims right? PMID- 23735273 TI - Sociodemographic factors and clerkship experience influence Ibadan medical students' preference for radiology specialty. PMID- 23735274 TI - Performance quality improvement projects in musculoskeletal radiology. PMID- 23735275 TI - JACR radiation dose optimization in CT: an online resource center for radiologists. PMID- 23735276 TI - John Murray Dennis. PMID- 23735277 TI - Re: "recent measures to improve radiology reporting: perspectives from primary care physicians". PMID- 23735278 TI - Re: "the declining radiology job market: how should radiologists respond?". PMID- 23735280 TI - Real-time probe based quantitative determination of material properties at the nanoscale. AB - Tailoring the properties of a material at the nanoscale holds the promise of achieving hitherto unparalleled specificity of the desired behavior of the material. Key to realizing this potential of tailoring materials at the nanoscale are methods for rapidly estimating physical properties of the material at the nanoscale. In this paper, we report a method for simultaneously determining the topography, stiffness and dissipative properties of materials at the nanoscale in a probe based dynamic mode operation. The method is particularly suited for investigating soft-matter such as polymers and bio-matter. We use perturbation analysis tools for mapping dissipative and stiffness properties of material into parameters of an equivalent linear time-invariant model. Parameters of the equivalent model are adaptively estimated, where, for robust estimation, a multi frequency excitation of the probe is introduced. We demonstrate that the reported method of simultaneously determining multiple material properties can be implemented in real-time on existing probe based instruments. We further demonstrate the effectiveness of the method by investigating properties of a polymer blend in real-time. PMID- 23735279 TI - Targeted human cerebrospinal fluid proteomics for the validation of multiple Alzheimer's disease biomarker candidates. AB - There is significant interest in the development of methods to validate novel biomarkers for Alzheimer's disease (AD) diagnosis. Previously, a proteomic panel of cerebrospinal fluid (CSF) biomarker candidates that differentiated AD and non AD CSF with accuracy higher than 90% was found; information about these CSF proteins can be used to develop multiple reaction monitoring (MRM) based analytical assays, which offer the possibility of quantifying protein expression level changes in samples, as well as, validation among multiple laboratories. Here we report an MRM assay that demonstrates good linearity (average R(2)=0.969) and reproducibility (average coefficient of variance of 6.93%) for the proposed AD CSF biomarkers. MRM quantification results of Abeta1-40, Abeta1-42, retinol binding protein and cystatin C correlated well with those from ELISA (average R(2)=0.974). Analysis shows that 12 out of 16 selected targets exhibit the same trend in protein expression as that in literature. PMID- 23735281 TI - Stereoselective synthesis and anti-proliferative effects on prostate cancer evaluation of 5-substituted-3,4-diphenylfuran-2-ones. AB - Series of 5-substituted-3,4-diphenylfuran-2-ones were stereoselectively prepared. Their potential anti-proliferative effects on prostate cancer and some of their cyclooxygenases (COXs) inhibitory activities were evaluated. Structure-activity relationship (SAR) data, acquired by substituent modification at the para position and ortho-position of the C-3 phenyl ring and 5-substituted modification of the central furanone, showed that 3-(2-chloro-phenyl)-4-(4-methanesulfonyl phenyl)-5-(1-methoxy-ethyl)-5H-furan-2-one (13p) was the most potent compound and could effectively reduce the proliferation of prostate cancer cells (PC3 cell IC50 = 20 MUM; PC3 PCDNA cell IC50 = 5 MUM; PC3 SKP2 cell IC50 = 5 MUM; DU145 cell IC50 = 25 MUM). The cell cycle analysis for 13p in DU145 indicated that 13p may induce G1 phase arrest. PMID- 23735282 TI - Evaluation of thiazole containing biaryl analogs as diacylglycerol acyltransferase 1 (DGAT1) inhibitors. AB - Biphenyl carboxylic acids, exemplified by compound 5, are known potent inhibitors of diacylglycerol acyltransferase, DGAT1, an enzyme involved in the final committed step of triglyceride biosynthesis. We have synthesized and evaluated 2 phenylthiazole, 4-phenylthiazole, and 5-phenylthiazole analogs as DGAT1 inhibitors. The 5-phenylthiazole series exhibited potent DGAT1 inhibition when evaluated using an in vitro enzymatic assay and an in vivo fat tolerance test in mice. Compound 33 (IC50 = 23 nM) exhibiting promising oral pharmacokinetic parameters (AUCinf = 7058 ng h/ml, T1/2 = 0.83 h) coupled with 87 percent reduction of plasma triglycerides in vivo may serve as a lead for developing newer anti-obesity agents. PMID- 23735283 TI - Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients. AB - Neutrophil extracellular traps (NETs) trap and kill pathogens very efficiently but also activate dendritic cells and prime T cells. Previously, we demonstrated that neutrophils are primed and circulating NETs are elevated in relapsing remitting multiple sclerosis (RRMS), a T cell-mediated autoimmune disease. Here, we demonstrate gender specific differences in circulating NETs but not in neutrophil priming in RRMS patients. Although the results from our systematic and in depth characterization of these patients argue against a major role of circulating NETs in this disease, they suggest that NETs may underlie gender specific differences in MS pathogenesis. PMID- 23735284 TI - Block of a subset of sodium channels exacerbates experimental autoimmune encephalomyelitis. AB - Voltage-gated sodium channels (Navs) are involved in several aspects of the pathogenesis of multiple sclerosis (MS). Within acute MS plaques, they are expressed along demyelinated axons. Studies in experimental autoimmune encephalomyelitis (EAE) demonstrated a neuroprotective effect of non-specific Nav blockers. Further, block of specific Navs involved in MS is suggested to have an advantage over non-specific blockers. We investigated the effects of the synthetic Midi peptide in EAE, as it potently and specifically blocks Nav1.2, Nav1.4 and Nav1.6. Administration of this Midi peptide worsens the clinical disease pattern and Nav1.2 and Nav1.6 expression levels were elevated in brain but not in spinal cord of Midi-treated mice, implicating that Navs play a complex role in the pathogenesis of EAE. PMID- 23735285 TI - Treatment of tularemia in pregnant woman, France. AB - A pregnant woman who had oropharyngeal tularemia underwent treatment with azithromycin and lymph node resection and recovered without obstetrical complication or infection in the child. Azithromycin represents a first-line treatment option for tularemia during pregnancy in regions where the infecting strains of Francisella tularensis have no natural resistance to macrolides. PMID- 23735286 TI - In-situ subaqueous capping of mercury-contaminated sediments in a fresh-water aquatic system, Part II-evaluation of sorption materials. AB - The function and longevity of traditional, passive, isolation caps can be augmented through the use of more chemically active capping materials which have higher sorptive capacities, ideally rendering metals non-bioavailable. In the case of Hg, active caps also mitigate the rate and extent of methylation. This research examined low cost, readily available, capping materials for their ability to sequester Hg and MeHg. Furthermore, selected capping materials were evaluated to inhibit the methylation of Hg in an incubation study as well as the capacity of a selected capping material to inhibit translocation of Hg and MeHg with respect to ebullition-facilitated contaminant transport in a column study. Results indicated that bauxite had a better capacity for mercury sorption than the other test materials. However, bauxite as well as soil capping materials did not decrease methylation to a significant extent. Materials with larger surface areas, higher organic matter and acid volatile sulfide (AVS) content displayed a larger partitioning coefficient. In the incubation experiments, the presence of a carbon source (lactate), electron acceptor (sulfate) and the appropriate strains of SRB provided the necessary conditions for Hg methylation to occur. The column study showed effectiveness in sequestering Hg and MeHg and retarding transport to the overlying water column; however, disturbances to the soil capping material resulting from gas ebullition negated its effectiveness. PMID- 23735287 TI - Novel respiratory syncytial virus a genotype, Germany, 2011-2012. PMID- 23735289 TI - The role of the third occipital nerve in surgical treatment of occipital migraine headaches. AB - BACKGROUND: The third occipital nerve is often encountered during the occipital migraine surgery, however its contribution to migraine headaches is unclear. The objective of this study was to determine whether removing the third occipital nerve plays any role in the clinical outcomes of occipital migraine surgery. METHODS: A retrospective comparative review was conducted on all occipital migraine headache (Site IV) patients from 1/2000 to 12/2010. Inclusion criteria were: 1) completion of migraine questionnaire, 2) migraine Site IV decompression, and 3) minimum 6 months of follow-up. Patients were divided into those who had the third occipital nerve removed and those who did not. Outcome variables included overall Migraine Headache Index reduction and Site IV pain elimination. RESULTS: 229 patients met the study inclusion criteria. The third occipital nerve removed group (111 patients) and the third occipital nerve not removed group (118 patients) were comparable in terms of age, gender, number of surgical sites, and statistically well matched regarding preoperative headache characteristics. Comparing the third occipital nerve removed to the third occipital nerve not removed group, Migraine headache index reduction was 63% vs. 64%. Patients experiencing migraine headache elimination (third occipital nerve removed 26% vs. third occipital nerve not removed 29%; p=0.45) and surgery success with at least 50% reduction in migraine headache (third occipital nerve removed 80% vs. third occipital nerve not removed 81%; p=0.82) were also similar. There was also no difference between the two groups in symptomatic neuroma formation. Site IV specific pain elimination was similar between the two groups (third occipital nerve removed 58% vs. third occipital nerve not removed 64%; p=0.54). CONCLUSIONS: Removal of the third occipital nerve did not alter migraine surgery success. PMID- 23735290 TI - Helical rim reconstruction using two bi-pedicled tube flaps. AB - Thermal injury can result in substantial auricular deformity and subsequent psychosocial morbidity. Helical rim repair, in particular, poses formidable challenges to the reconstructive surgeon. Bi-pedicled tube flaps are one option that have the potential to restore much of the helix's natural contours. This case report discusses the unique strengths and weaknesses of the flap, as well as the reasoning that must be implemented when deciding which situations are appropriate for its utilization. Superior outcomes resulting in a high degree of patient and surgeon satisfaction are possible when the techniques of this report are employed appropriately. PMID- 23735291 TI - Femur-fibula-fillet of leg chimeric free flap for sacral-pelvic reconstruction. AB - We describe the first case of a femur free flap in which we utilized the femur to restore pelvic ring continuity following a combined external hemipelvectomy sacrectomy for cancer. We feel that the femur flap can be an important reconstructive tool for load-bearing bony reconstruction of the pelvis and spine when lower extremity amputation is required. We also utilized a fibula flap to stabilize the spine and a fillet of leg flap to provide soft tissue coverage as part of a chimeric femur-fibula-fillet of leg free flap from the same limb, allowing us to reconstruct a large, complex defect with "spare parts" from the discarded lower extremity, thereby totally eliminating any donor site morbidity. PMID- 23735288 TI - Intravenous immunoglobulin and Alzheimer's disease: what now? AB - Intravenous immunoglobulin (IVIG) products are prepared from purified plasma immunoglobulins from large numbers of healthy donors. Pilot studies with the IVIG preparations Octagam and Gammagard in individuals with mild-to-moderate Alzheimer's disease (AD) suggested stabilization of cognitive functioning in these patients, and a phase II trial with Gammagard reported similar findings. However, subsequent reports from Octagam's phase II trial and Gammagard's phase III trial found no evidence for slowing of AD progression. Although these recent disappointing results have reduced enthusiasm for IVIG as a possible treatment for AD, it is premature to draw final conclusions; a phase III AD trial with the IVIG product Flebogamma is still in progress. IVIG was the first attempt to use multiple antibodies to treat AD. This approach should be preferable to administration of single monoclonal antibodies in view of the multiple processes that are thought to contribute to AD neuropathology. Development of "AD-specific" preparations with higher concentrations of selected human antibodies and perhaps modified in other ways (such as increasing their anti-inflammatory effects and/or ability to cross the blood-brain barrier) should be considered. Such preparations, if generated with recombinant technology, could overcome the problems of high cost and limited supplies, which have been major concerns relating to the possible widespread use of IVIG in AD patients. This review summarizes the recent AD IVIG trials and discusses the major issues relating to possible use of IVIG for treating AD, as well as the critical questions which remain. PMID- 23735292 TI - Demographics and management practices of horses and ponies in Great Britain: a cross-sectional study. AB - The objectives of this study were to describe the demographic characteristics and management practices undertaken by owners of horses/ponies within GB and assess seasonal and geographical variations in management practices. A cross-sectional study was conducted, surveying a random sample of veterinary-registered owners in GB, using a self-administered postal questionnaire. A total of 797 useable responses were received. Only 4.0% of animals were stabled 24h/day, this proportion being greater in winter compared to other seasons (p<0.001). Shavings (45.7%) and straw (35.3%) were the most frequently used bedding. Ninety-two percent of animals had access to pasture (median 91 h/week). The majority of animals received forage (82.6%) and concentrate/supplementary feeding (86.1%). Retired/companion animals and ponies received supplementary feed less frequently and most animals were used for pleasure riding (60.6%). Seasonal and regional differences in management practices were identified, of relevance to practitioners and researchers in the investigation and management of disease conditions. PMID- 23735294 TI - Arabidopsis AUGMIN subunit8 is a microtubule plus-end binding protein that promotes microtubule reorientation in hypocotyls. AB - In plant cells, cortical microtubules provide tracks for cellulose-synthesizing enzymes and regulate cell division, growth, and morphogenesis. The role of microtubules in these essential cellular processes depends on the spatial arrangement of the microtubules. Cortical microtubules are reoriented in response to changes in cell growth status and cell shape. Therefore, an understanding of the mechanism that underlies the change in microtubule orientation will provide insight into plant cell growth and morphogenesis. This study demonstrated that AUGMIN subunit8 (AUG8) in Arabidopsis thaliana is a novel microtubule plus-end binding protein that participates in the reorientation of microtubules in hypocotyls when cell elongation slows down. AUG8 bound to the plus ends of microtubules and promoted tubulin polymerization in vitro. In vivo, AUG8 was recruited to the microtubule branch site immediately before nascent microtubules branched out. It specifically associated with the plus ends of growing cortical microtubules and regulated microtubule dynamics, which facilitated microtubule reorientation when microtubules changed their growth trajectory or encountered obstacle microtubules during microtubule reorientation. This study thus reveals a novel mechanism underlying microtubule reorientation that is critical for modulating cell elongation in Arabidopsis. PMID- 23735295 TI - A rapid ribosome profiling method elucidates chloroplast ribosome behavior in vivo. AB - The profiling of ribosome footprints by deep sequencing has revolutionized the analysis of translation by mapping ribosomes with high resolution on a genome wide scale. We present a variation on this approach that offers a rapid and cost effective alternative for the genome-wide profiling of chloroplast ribosomes. Ribosome footprints from leaf tissue are hybridized to oligonucleotide tiling microarrays of the plastid ORFeome and report the abundance and translational status of every chloroplast mRNA. Each assay replaces several time-consuming traditional methods while also providing information that was previously inaccessible. To illustrate the utility of the approach, we show that it detects known defects in chloroplast gene expression in several nuclear mutants of maize (Zea mays) and that it reveals previously unsuspected defects. Furthermore, it provided firm answers to several lingering questions in chloroplast gene expression: (1) the overlapping atpB/atpE open reading frames, whose translation had been proposed to be coupled, are translated independently in vivo; (2) splicing is not a prerequisite for translation initiation on an intron-containing chloroplast RNA; and (3) a feedback control mechanism that links the synthesis of ATP synthase subunits in Chlamydomonas reinhardtii does not exist in maize. An analogous approach is likely to be useful for studies of mitochondrial gene expression. PMID- 23735296 TI - Aspartic proteinases of Candida spp.: role in pathogenicity and antifungal resistance. AB - Fungal infections represent a serious health risk as they are particularly prevalent in immunocompromised individuals. Candida spp. pathogenicity depends on several factors and secreted aspartic proteinases (Sap) are considered one of the most critical factors as they are associated with adhesion, invasion and tissue damage. The production of proteinases is encoded by a family of 10 genes known as SAP, which are distributed differently among the species. The expression of these genes may be influenced by environmental conditions, which generally result in a higher fungal invasive potential. Non-pathogenic Candida spp. usually have fewer SAP genes, which are not necessarily expressed in the genome. Exposure to subinhibitory concentrations of antifungal agents promotes the development of resistant strains with an increased expression of SAP genes. In general, Candida spp. isolates that are resistant to antifungals show a higher secretion of Sap than the susceptible isolates. The relationship between Sap secretion and the susceptibility profile of the isolates is of great interest, although the role of SAPs in the development of resistance to antifungal agents remains still unclear. This review is the first one to address these issues. PMID- 23735298 TI - Notch-RBP-J signaling is required by bone marrow stromal cells for the treatment of acute graft versus host disease. AB - Recent evidence has shown that bone marrow stromal cells (BMSCs) may exhibit immuno-suppression activities through soluble mediators and direct cell-cell contact, but how these processes are modulated has been poorly understood. In this study, we show that the Notch signaling pathway participates in the modulation of BMSCs to elicit their immuno-suppressive roles. In a murine lethal acute graft versus host disease (aGvHD) model, BMSCs deficient for RBP-J, the critical transcription factor mediating signaling from all four mammalian Notch receptors, failed to delay the development of the disease. RBP-J deficient BMSCs were not able to inhibit the proliferation and activation of allogenic T-cells. Moreover, RBP-J deficient BMSCs could not down-regulate the expression of MHC II and co-stimulation molecules CD80 and CD86 on dendritic cells (DCs). The antigen presentation capacity of DCs co-cultured with RBP-J deficient BMSCs was not impaired in contrast to wild type BMSCs. Furthermore, we showed that the productions of IL-6 and PGE2, two critical molecules mediating the immuno suppressive activities of BMSCs, were reduced significantly in RBP-J deficient BMSCs. Both of the two molecules were importantly involved in the regulation of BMSCs by Notch signaling. In conclusion, our data suggests that the immuno suppressive effects of BMSCs in aGvHD are dependent on Notch-RBP-J signaling, which regulates the productions of IL-6 and PGE2. PMID- 23735300 TI - Lack of effect of bovine lactoferrin in respiratory syncytial virus replication and clinical disease severity in the mouse model. AB - BACKGROUND: Lactoferrin (LF) is a glycoprotein present in human milk with known antimicrobial effects. In vitro, LF has demonstrated antiviral activity against respiratory syncytial virus (RSV). We sought to assess the effect of bovine (b)LF in RSV replication, lung inflammation and function, cytokine profiles and clinical disease in an in vivo murine model. METHODS: Female BALB/c mice were inoculated with 10(7)PFU RSV A2 or 10% EMEM. bLF or placebo (DPBS) were administered once or twice daily by oral gavage or intraperitoneal (IP) injection at doses ranging from 2 to 10mg/animal/day, from 48h before until 96h post-RSV inoculation. Bronchoalveolar lavage (BAL), whole lung and serum samples were harvested on day 5 post-inoculation to asses RSV loads, lung inflammation and cytokine concentrations. Weight loss, airway obstruction and disease severity were assessed daily in all groups. RESULTS: On day 5 post-inoculation BAL RSV loads, lung inflammation and serum innate, Th1, Th2 and Th17 cytokine concentrations showed no differences between RSV infected mice treated with bLF and RSV infected but untreated mice independent of bLF dosing and administration route (p>0.05). In addition, all bLF groups showed similar weight loss, degree of airway obstruction, and disease severity scores on days 1-5 post-inoculation which was comparable to infected untreated mice (p>0.05) but higher than uninfected controls. CONCLUSIONS: Administration of oral or IP bLF at different doses did not demonstrate antiviral activity or significant effects on disease severity in the RSV mouse model. Whether these observations could be extrapolated to infants at risk for RSV infection needs to be further explored. PMID- 23735299 TI - Inhibition of multiplication of the prototypic arenavirus LCMV by valproic acid. AB - Valproic acid (VPA), a short chain fatty acid commonly used for treatment of neurological disorders, has been shown to inhibit production of infectious progeny of different enveloped viruses including the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV). In this study we have investigated the mechanisms by which VPA inhibits LCMV multiplication in cultured cells. VPA reduced production of infectious LCMV progeny and virus propagation without exerting a major blockage on either viral RNA or protein synthesis, but rather affecting the cell release and specific infectivity of LCMV progeny from infected cells. Our results would support the repurposing of VPA as a candidate antiviral drug to combat arenavirus infections. PMID- 23735301 TI - Identification of a new dengue virus inhibitor that targets the viral NS4B protein and restricts genomic RNA replication. AB - Dengue virus (DENV) is an important human arthropod-borne virus with a major impact on public health. Nevertheless, a licensed vaccine or specific treatment is still lacking. We therefore screened the NIH Clinical Collection (NCC), a library of drug-like small molecules, for inhibitors of DENV replication using a cell line that contains a stably replicating DENV serotype 2 (DENV2) subgenomic replicon. The most potent DENV inhibitor in the NCC was delta opioid receptor antagonist SDM25N. This compound showed antiviral activity against wild-type DENV2 in both Hela and BHK-21 cells, but not in the C6/36 cell line derived from the mosquito Aedes albopictus. The structurally related compound naltrindole also inhibited DENV replication, albeit less potently. Using a transient subgenomic replicon, we demonstrate that SDM25N restricts genomic RNA replication rather than translation of the viral genome. We identified a single amino acid substitution (F164L) in the NS4B protein that confers resistance to SDM25N. Remarkably, an NS4B amino acid substitution (P104L), which was previously shown to confer resistance to the DENV inhibitor NITD-618, also provided resistance to SDM25N. In conclusion, we have identified a new DENV inhibitor, SDM25N, which restricts genomic RNA replication by - directly or indirectly - targeting the viral NS4B protein. PMID- 23735302 TI - Molecular cloning and tissue distribution of hyaluronan binding protein 2 (HABP2) in red sea bream Pagrus major. AB - Previously we have isolated a novel gelatinolytic serine proteinase, named G1, from the muscle and the plasma of red sea bream. In order to clarify the structure and function of G1, we cloned the full-length cDNA of G1 from the hepatopancreas of red sea bream. G1 cDNA encoded 633 amino acids with a secretory signal sequence at N-terminus, three epidermal growth factor-like domains, a kringle domain, and a trypsin-like serine protease domain. The active site residues of a serine proteinase were conserved in the serine protease domain of G1. The tissue distributions of the mRNA and gelatinolytic activity of G1 were investigated using RT-PCR and gelatin zymography, respectively. Its activity was detected in various tissues while the mRNA of it was strongly expressed in the hepatopancreas. These results suggest that G1 is synthesized in hepatopancreas and carried to the muscle, kidney, heart and ovary via the bloodstream in the red sea bream. The enzyme has a similar domain structure and tissue distribution to those of human hyaluronan binding protein 2 (HABP2) engaged in the extracellular matrix (ECM) turnover. Thus, it is suggested that G1 is identified as HABP2 and is possibly involved in ECM proteolysis of red sea bream. PMID- 23735304 TI - Lateral bending of tapered piezo-semiconductive nanostructures for ultra sensitive mechanical force to voltage conversion. AB - Quasi-1D piezoelectric nanostructures may offer unprecedented sensitivity for transducing minuscule input mechanical forces into high output voltages due to both scaling laws and increased piezoelectric coefficients. However, until now both theoretical and experimental studies have suggested that, for a given mechanical force, lateral bending of piezoelectric nanowires results in lower output electric potentials than vertical compression. Here we demonstrate that this result only applies to nanostructures with a constant cross-section. Moreover, though it is commonly believed that the output electric potential of a strained piezo-semiconductive device can only be reduced by the presence of free charges, we show that the output piezopotential of laterally bent tapered nanostructures, with typical doping levels and very small input forces, can be even increased up to two times by free charges.Our analyses confirm that, though not optimal for piezoelectric energy harvesting, lateral bending of tapered nanostructures with typical doping levels can be ideal for transducing tiny input mechanical forces into high and accessible piezopotentials. Our results provide guidelines for designing high-performance piezo-nano-devices for energy harvesting, mechanical sensing, piezotronics, piezo-phototronics, and piezo controlled chemical reactions, among others. PMID- 23735303 TI - Evaluation of optimized b-value sampling schemas for diffusion kurtosis imaging with an application to stroke patient data. AB - Diffusion kurtosis imaging (DKI) is a new method of magnetic resonance imaging (MRI) that provides non-Gaussian information that is not available in conventional diffusion tensor imaging (DTI). DKI requires data acquisition at multiple b-values for parameter estimation; this process is usually time consuming. Therefore, fewer b-values are preferable to expedite acquisition. In this study, we carefully evaluated various acquisition schemas using different numbers and combinations of b-values. Acquisition schemas that sampled b-values that were distributed to two ends were optimized. Compared to conventional schemas using equally spaced b-values (ESB), optimized schemas require fewer b values to minimize fitting errors in parameter estimation and may thus significantly reduce scanning time. Following a ranked list of optimized schemas resulted from the evaluation, we recommend the 3b schema based on its estimation accuracy and time efficiency, which needs data from only 3 b-values at 0, around 800 and around 2600 s/mm2, respectively. Analyses using voxel-based analysis (VBA) and region-of-interest (ROI) analysis with human DKI datasets support the use of the optimized 3b (0, 1000, 2500 s/mm2) DKI schema in practical clinical applications. PMID- 23735305 TI - The impact of mobility on quality of life among older persons. AB - OBJECTIVE: The purpose of this cross-sectional study was to determine the extent and manner in which mobility is related to quality of life (QOL) in a representative sample of older adults. METHOD: Two models were assessed using structured equation modeling. The first hypothesized that mobility would have a direct effect on QOL along with other variables, including; number of health conditions and satisfaction with functional capacity, life essentials (e.g., transport, access to health services, and conditions of living space) and personal relationships. The second hypothesized that mobility would have its greatest influence on QOL through satisfaction with functional capacity. RESULTS: While both models found that mobility and all three measures of life satisfaction were significantly associated with QOL, goodness of fit indices were higher for the second model. DISCUSSION: The findings from this study suggest that mobility interventions designed to enhance QOL should address satisfaction with functional capacity as well. PMID- 23735306 TI - Identification of well-differentiated gene expressions between Han Chinese and Japanese using genome-wide microarray data analysis. AB - BACKGROUND: Investigating variations in gene expression, which can be quantitatively measured on a genome-wide scale, is essential to understand and interpret phenotypic differences among human populations. Several previous studies have examined and compared variations in gene expression between continental populations. However, differences in gene expression variation between closely related populations have not been studied yet. METHOD: We performed a genome-wide analysis and systematically compared expression profiles of Han Chinese with those of the Japanese population. RESULTS: We identified 768 genes (4.4% of 17 354 expressed genes) which were expressed differentially between the two populations, with 165 showing highly differential expression and enriched in genes involved in the spliceosome pathway, mRNA processing, mRNA metabolic process, RNA processing, RNA splicing and mitochondrial transport. We further identified cis- and trans-variants that regulated these differential gene expressions, and found that cis-variants shared in the two populations were centred within a range of 200 kb around transcription start site. Our analysis indicated that genetic differences in the cis-associated genes between the two populations could explain 7-43% of the identified expression divergence. CONCLUSIONS: In summary, despite considerable heterogeneity, gene expression profiles between Han Chinese and Japanese did show an overall difference, with well-differentiated expressions regulated by genetic variants which have been reported associated with hematological and biochemical traits in Japanese populations. Our results supported that gene expression is regulated by genetic variants and there is a genetic basis for the phenotypic differences between Han Chinese and Japanese populations. PMID- 23735307 TI - Optimum interpulse interval for transcranial electrical train stimulation to elicit motor evoked potentials of maximal amplitude in both upper and lower extremity target muscles. AB - OBJECTIVE: The aim of this study was to determine the optimum interpulse interval (OIPI) for transcranial electrical train stimulation to elicit muscle motor evoked potentials (TES-MEP) with maximal amplitude in upper and lower extremities during intra-operative spinal cord monitoring. METHODS: Intraoperative spinal cord monitoring with TES-MEP was performed in 26 patients who had (corrective) spine surgery. Optimum interpulse interval (OIPI) were determined for the abductor pollicis brevis muscle (APB) representing the upper extremity and the anterior tibialis muscle (TA) representing the lower extremity. The IPI was varied between 0.5 and 4.0ms, where the OIPI was defined as the IPI with the highest muscle MEP amplitude for each muscle group. Differences between upper and lower extremity OIPIs were analyzed. Furthermore, the MEP amplitudes difference between the upper and lower extremity OIPIs and between the OIPI and IPI 2 ms was determined. RESULTS: The mean OIPI(APB) representing the upper extremity was 1.78 +/- 1.09 ms on the left side and 1.82 +/- 0.93 ms on the right side. The lower extremity showed a mean OIPI(TA) of 2.26 +/- 1.16 ms on the left and 2.73 +/- 0.88 ms on the right side. The mean differences between the OIPI(APB) and OIPI(TA) were significant for p=0.019 (Student's T-test). No within patient differences in OIPIs between the left and the right side were found. The mean MEP amplitude reduction, the APB amplitude at OIPI(TA) compared to the APB at OIPI(APB), was 32.5 +/- 27.9%. For the TA a mean amplitude reduction of 33.4 +/- 27.4% was found. The mean amplitude reduction for the OIPI amplitudes compared to the amplitudes at IPI 2 ms was 53.6 +/- 25.5% for the APB and 45.8 +/- 28.3% for the TA. CONCLUSION: Large intra- and interindividual differences were found between the mean OIPIs of the TA and APB muscles (range 1.78-2.73 ms) representing the upper and lower extremity. SIGNIFICANCE: Based on the results of this study, it is advisable to perform a set-up procedure for each individual patient undergoing TES-MEP to determine the optimal parameter settings when using supramaximal intensity of TES. PMID- 23735308 TI - Using a bayesian latent class model to evaluate the utility of investigating persons with negative polymerase chain reaction results for pertussis. AB - Pertussis remains difficult to control. Imperfect sensitivity of diagnostic tests and lack of specific guidance regarding interpretation of negative test results among patients with compatible symptoms may contribute to its spread. In this study, we examined whether additional pertussis cases could be identified if persons with negative pertussis test results were routinely investigated. We conducted interviews among 250 subjects aged <=18 years with pertussis polymerase chain reaction (PCR) results reported from 2 reference laboratories in Wisconsin during July-September 2010 to determine whether their illnesses met the Centers for Disease Control and Prevention's clinical case definition (CCD) for pertussis. PCR validity measures were calculated using the CCD as the standard for pertussis disease. Two Bayesian latent class models were used to adjust the validity measures for pertussis detectable by 1) culture alone and 2) culture and/or more sensitive measures such as serology. Among 190 PCR-negative subjects, 54 (28%) had illnesses meeting the CCD. In adjusted analyses, PCR sensitivity and the negative predictive value were 1) 94% and 99% and 2) 43% and 87% in the 2 types of models, respectively. The models suggested that public health follow-up of reported pertussis patients with PCR-negative results leads to the detection of more true pertussis cases than follow-up of PCR-positive persons alone. The results also suggest a need for a more specific pertussis CCD. PMID- 23735309 TI - Professional fighters brain health study: rationale and methods. AB - Repetitive head trauma is a risk factor for Alzheimer's disease and is the primary cause of chronic traumatic encephalopathy. However, little is known about the natural history of, and risk factors for, chronic traumatic encephalopathy or about means of early detection and intervention. The Professional Fighters Brain Health Study is a longitudinal study of active professional fighters (boxers and mixed martial artists), retired professional fighters, and controls matched for age and level of education. The main objective of the Professional Fighters Brain Health Study is to determine the relationships between measures of head trauma exposure and other potential modifiers and changes in brain imaging and neurological and behavioral function over time. The study is designed to extend over 5 years, and we anticipate enrollment of more than 400 boxers and mixed martial artists. Participants will undergo annual evaluations that include 3 tesla magnetic resonance imaging scanning, computerized cognitive assessments, speech analysis, surveys of mood and impulsivity, and blood sampling for genotyping and exploratory biomarker studies. Statistical models will be developed and validated to predict early and progressive changes in brain structure and function. A composite fight exposure index, developed as a summary measure of cumulative traumatic exposure, shows promise as a predictor of brain volumes and cognitive function. PMID- 23735310 TI - Travel-related Neisseria meningitidis serogroup W135 infection, France. PMID- 23735311 TI - Presence of antibodies against genogroup VI norovirus in humans. AB - BACKGROUND: Noroviruses are important enteric pathogens in humans and animals. Recently, we reported a novel canine norovirus (CaNoV) in dogs with diarrhea belonging to a new genogroup (GVI). No data are available on exposure of humans to this virus. METHODS: Sera from 373 small animal veterinarians and 120 age matched population controls were tested for IgG antibodies to CaNoV by a recombinant virus like particle based enzyme-linked immunosorbent assay. RESULTS: Antibodies to CaNoV were found in 22.3% of the veterinarians and 5.8% of the control group (p < 0.001). Mean corrected OD450 values for CaNoV antibodies were significantly higher in small animal veterinarians compared to the control group. CONCLUSIONS: These findings suggest that CaNoV may infect humans and small animal veterinarians are at an increased risk for exposure to this virus. Additional studies are needed to assess if this virus is able to cause disease in humans. PMID- 23735312 TI - Ciprofloxacin-resistant Salmonella enterica serovar Kentucky in Canada. AB - We report emergence of ciprofloxacin-resistant Salmonella enterica serovar Kentucky in Canada during 2003-2009. All isolates had similar macrorestriction patterns and were multilocus sequence type ST198, which has been observed in Europe and Africa. Ciprofloxacin-resistant S. enterica serovar Kentucky represents 66% of all ciprofloxacin-resistant nontyphoidal Salmonella sp. isolates observed in Canada since 2003. PMID- 23735313 TI - Necrostatin-1 inhibits the degeneration of neural cells induced by aluminum exposure. AB - PURPOSE: There are many in vivo and in vitro studies suggested the involvement of apoptosis in neurodegenerative processes. There is considerable evidence that various complex events may contribute to neural cell death. The present study focuses on the underlined neurodegenerative mechanism and the preventive effect of necrostatin-1 (Nec-1) on neural cell death induced by aluminum (Al). METHODS: Al-exposed primary cultures of newborn mice cortical cells were separately treated with 3-methylamphetamine (3-MA), benzyloxycarbonylvalyl-alanyl-aspartic acid (O-methyl)-fluoro-methylketone (zVAD-fmk), and Nec-1, the cell viability analysis was used to evaluate cell damage from apoptosis, necroptosis and autophagy. Morphology of neural cells treated with 2 mM Al, and 2 mM Al plus 60 MUM Nec-1 were examined by fluorescent microscope, and the cell death rates were quantified by cytometry. For the in vivo experiments, male ICR mice were microinjected with normal saline, 2 mM Al, and 2 mM Al plus Nec-1 at the concentrations of 2 mM, 4 mM and 8 mM into the lateral cerebral ventricles. The Morris water maze task was performed in 20 days after intracerebroventricular injection, Nissl staining was used to demonstrate the loss of Nissl substance and the number of neural cells, and western blot was used to analyze the expressing of cell death and Alzheimer's disease related proteins. RESULTS: The cell viabilities inhibited by Al could be enhanced by 3-MA, zVAD-fmk and Nec-1, of which Nec-1 improved the cell viability most significantly. Furthermore, the cell viability of neural cells treated with Nec-1 increased concentration-dependently, and the expressions of cell death-related proteins were decreased also in a concentration-dependent manner. The in vivo experiments indicated that administration of Nec-1 on Al-treated mice significantly improved learning and memory retention in the Morris water maze task, decreased the neural cells death and inhibited the expression of Alzheimer's disease related proteins in the mice brain. CONCLUSIONS: The present study provides the first direct evidence of a connection between necroptosis and neurodegeneration, which indicates that necroptosis is involved in neurodegenerative cell death. Furthermore, Nec-1 may be useful for the prevention and treatment of neurodegenerative disorders. PMID- 23735314 TI - Modulatory effects of locomotor training on extensor spasticity in individuals with motor-incomplete spinal cord injury. AB - PURPOSE: Sparse data exist about effects of locomotor training on spasticity in individuals with spinal cord injury (SCI). We investigated changes in spastic responses in individuals with motor-incomplete SCI (MISCI) associated with locomotor training and examined properties of a biomechanical measure of clonus severity, plantar flexor reflex threshold angle (PF RTA). METHODS: In 18 individuals with chronic MISCI, we assessed biomechanical and electrophysiologic measures of extensor spasticity and their relationship with walking speed before and after 12 weeks of body-weight supported locomotor training. Measures included PF RTA, plantar flexor (ankle clonus) and quadriceps spasm duration, soleus H reflex, and ankle muscle electromyography. PF RTA validity was assessed by measuring PF RTA and clonus duration in 40 individuals with SCI and 10 non disabled individuals. RESULTS: Locomotor training was associated with decreased PF RTA (p = 0.06), ankle clonus (p = 0.09) and quadriceps spasm (p = 0.05). PF RTA discriminated between non-disabled individuals and individuals with SCI and was moderately correlated with walking speed, soleus H/M ratio, and quadriceps spasm duration. CONCLUSIONS: In persons with spastic paresis due to MISCI, locomotor training was associated with decreased spasticity as measured by decreased plantar flexor excitability, ankle clonus, and quadriceps spasm. PMID- 23735315 TI - Education protects against cognitive changes associated with multiple sclerosis. AB - PURPOSE: Although neuropsychological impairments are common in Multiple Sclerosis (MS), the manifestation of cognitive deficits may vary greatly across MS patients. Here, we explored the influence of cognitive reserve proxy indices (education and occupation) and perceived fatigue on cognitive performance. METHODS: Fifty relapsing-remitting MS patients were evaluated. Cognitive performance was measured using the Paced Auditory Serial Addition Test (PASAT), in which information processing speed can be manipulated by varying the presentation speed of stimuli. RESULTS: MS patients with low education performed worse than healthy controls at faster PASAT speeds. By contrast, no difference was observed between MS patients with high education and matched healthy controls, regardless of PASAT speed. Moreover, we found that neither occupational attainment nor perceived fatigue has an influence on MS patients' cognitive performance. CONCLUSION: These findings provide evidence that higher education could be protective against MS-associated cognitive deficits and that high speed PASAT versions are more suitable for identifying compensatory capacities compared to low speed PASAT versions. PMID- 23735316 TI - Barriers to drug delivery in interventional oncology. AB - Although much attention has been paid to mechanisms of anticancer drug resistance that focus on intracellular processes that protect tumor cells, it has recently become increasingly evident that the unique features of the tumor microenvironment profoundly impact the efficacy of cancer therapies. The properties of this extracellular milieu, including increased interstitial pressure, decreased pH, hypoxia, and abnormal vascularity, result in limited drug efficacy; this finding is true not only for systemic chemotherapy but also for catheter-based therapies, including chemoembolization and radioembolization. The present review summarizes the barriers to drug delivery imposed by the tumor microenvironment and provides methods to overcome these hurdles. PMID- 23735317 TI - Metabolic effects of aloe vera gel complex in obese prediabetes and early non treated diabetic patients: randomized controlled trial. AB - OBJECTIVE: The metabolic effects of an aloe vera gel complex (Aloe QDM complex) on people with prediabetes or early diabetes mellitus (DM) are unknown. The goal of this study was to determine the effects of Aloe QDM complex on body weight, body fat mass (BFM), fasting blood glucose (FBG), fasting serum insulin, and Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR) in obese individuals with prediabetes or early DM who were not on diabetes medications. METHODS: Participants (n = 136) were randomly assigned to an intervention or a control group and evaluated at baseline and at 4 and 8 wk. RESULTS: The study lost six participants in the control group and eight in the intervention group. At 8 wk, body weight (P = 0.02) and BFM (P = 0.03) were significantly lower in the intervention group. At 4 wk, serum insulin level (P = 0.04) and HOMA-IR (P = 0.047) were lower in the intervention group; they also were lower at 8 wk but with borderline significance (P = 0.09; P = 0.08, respectively). At 8 wk, FBG tended to decrease in the intervention group (P = 0.02), but the between-group difference was not significant (P = 0.16). CONCLUSION: In obese individuals with prediabetes or early untreated DM, Aloe QDM complex reduced body weight, BFM, and insulin resistance. PMID- 23735318 TI - [Septic shock due to a community acquired Clostridium difficile infection. A case study and a review of the literature]. AB - The epidemiology of Clostridium difficile infection has changed in the past decade. The incidence rate of community acquired cases has increased in patients with no typical risk factors. We present a patient who was diagnosed with community-acquired Clostridium difficile infection who presented with acute abdominal pain, and subsequently developed acute renal failure and septic shock. We describe the diagnosis, treatment and outcome and brief review of the literature. PMID- 23735319 TI - Comments on the paper "A comprehensive modeling and vibration analysis of AFM microcantilevers subjected to nonlinear tip-sample interaction forces" by Sohrab Eslami and Nader Jalili. AB - This comment on the paper "A comprehensive modeling and vibration analysis of AFM microcantilevers subjected to nonlinear tip-sample interaction forces" by Sohrab Eslami and Jalili (2012) [1] aims to: (1) discuss and elucidate the concept of "virtual resonance" and thus (2) avert a misinterpretation of the experimental results and findings reported in the Tetard et al. Physical Review Letters 106, 180801 (2011) [2]. PMID- 23735320 TI - Validities of three multislice algorithms for quantitative low-energy transmission electron microscopy. AB - Three different types of multislice algorithms, namely the conventional multislice (CMS) algorithm, the propagator-corrected multislice (PCMS) algorithm and the fully-corrected multislice (FCMS) algorithm, have been evaluated in comparison with respect to the accelerating voltages in transmission electron microscopy. Detailed numerical calculations have been performed to test their validities. The results show that the three algorithms are equivalent for accelerating voltage above 100kV. However, below 100 kV, the CMS algorithm will introduce significant errors, not only for higher-order Laue zone (HOLZ) reflections but also for zero-order Laue zone (ZOLZ) reflections. The differences between the PCMS and FCMS algorithms are negligible and mainly appear in HOLZ reflections. Nonetheless, when the accelerating voltage is further lowered to 20 kV or below, the PCMS algorithm will also yield results deviating from the FCMS results. The present study demonstrates that the propagation of the electron wave from one slice to the next slice is actually cross-correlated with the crystal potential in a complex manner, such that when the accelerating voltage is lowered to 10 kV, the accuracy of the algorithms is dependent of the scattering power of the specimen. PMID- 23735321 TI - Differences in somatosensory and motor improvement during temporary functional deafferentation in stroke patients and healthy subjects. AB - Temporary functional deafferentation is of interest to become an additional tool in neurorehabilitative treatments. Temporary functional deafferentation is known to improve sensory and motor outcomes in chronic stroke patients and healthy subjects. The present study soughts to indicate differences in the efficiency of pharmacologically induced temporary functional deafferentation between chronic stroke patients and matched healthy subjects. 46 chronic stroke patients and 20 age- and gender-matched healthy subjects were deafferented on one forearm by an anesthetic cream. Somatosensory performance was assessed using von-Frey Hair testing and Grating orientation task; motor performance was assessed by means of a shape-sorter-drum task. Grating orientation task and shape-sorter-drum task were significantly improved during temporary functional deafferentation in stroke patients but not in healthy subjects. Von-Frey Hair testing revealed no improvement of absolute tactile thresholds during temporary functional deafferentation in both groups. Furthermore, the stroke patients showed deficits at baseline measurement in all assessments except the von-Frey Hair test. Temporary functional deafferentation of a forearm by an anesthetic cream results in improvements of motor performance and somatosensory discrimination in stroke patients but not in healthy subjects. Therefore, it is reasonable to test in a next step whether temporary functional deafferentation might become an additional tool in motor rehabilitation of post stroke patients. PMID- 23735322 TI - Role of 5-HT5A receptors in the consolidation of memory. AB - 5-HT5 receptor occurs in brain areas implicated in learning and memory. Hence, the effects (0.01-3.0 mg/kg) of SB-6995516 (a 5-HT5A receptor antagonist) in the associative learning task of autoshaping were studied. The results showed that post-training injection of SB-699551 decreased conditioned responses (CR) during short-term (STM; 1.5h; at 0.1mg/kg) and long-term memory (LTM; 24 h; at 3.0 mg/kg) relative to the vehicle animals. Moreover, considering that there are no selective 5-HT5A receptor agonists, next, diverse doses of the serotonin precursor l-tryptophan were studied during STM and LTM, showing that l-tryptophan (5-100mg/kg) facilitated performance, particularly at 50mg/kg. In interactions experiments, l-tryptophan (50 mg/kg) attenuated the impairment effect induced by SB-699551 (either 0.3 or 3.0 mg/kg). All together this evidence suggests that the blockade of 5-HT5A receptor appear to be able to impair STM and LTM (24 h), while its stimulation might facilitate it. Of course further investigation is necessary, meanly with selective 5-HT5A compounds are necessary. PMID- 23735323 TI - Necessity of education for oral contraceptive use in Korea: results from the fourth Korean national health and nutrition examination survey 2007-2009. AB - BACKGROUND/AIMS: To compare the prevalence of contraindications to oral contraceptive (OC) use between OC users and nonusers and to identify high-risk groups related to contraindications to OC use among OC users. METHODS: This health-interview survey is part of the Fourth Korean National Health and Nutrition Examination Survey 2007-2009. Of 13,561 women who participated in the survey, 672 were OC users and 3,720 were OC nonusers. The adjusted proportions of contraindications to OC use were measured according to the current OC use status. Factors associated with contraindications to OC use among OC users were identified using multivariate analysis. RESULTS: The prevalence of contraindications to OC use was higher in OC users than in OC nonusers (12.6 vs. 7.8%, p < 0.001). The adjusted proportion of women who were smokers and aged >= 35 years was greater in OC users than in OC nonusers (5.8 vs. 1.9%, p < 0.001). Among OC users, the 40-50 age group, lower education level, and a BMI >= 25 had higher odds of having contraindications. CONCLUSION: Education programs for OC use are urgently required to improve knowledge about correct use of and contraindications to OC use. PMID- 23735324 TI - Oncostatin M promotes mesenchymal stem cell-stimulated tumor growth through a paracrine mechanism involving periostin and TGFBI. AB - Oncostatin M, a member of the interleukin-6 family of cytokines, has been implicated in tumorigenesis of human prostate cancer. In the current study, we demonstrate that oncostatin M promotes human adipose tissue-derived mesenchymal stem cell-stimulated tumor growth in an in vivo xenograft transplantation model of the human prostate cancer cell line PC-3M-luc-C6, a PC3M cell line expressing the luciferase gene. Conditioned medium derived from oncostatin M-treated mesenchymal stem cells stimulated adhesion of PC-3M-luc-C6 cells. We identified TGFBI and periostin, extracellular matrix proteins implicated in tumorigenesis and metastasis, as oncostatin M-induced secreted proteins in mesenchymal stem cells. Treatment with oncostatin M stimulated secretion of periostin and TGFBI from mesenchymal stem cells in a time-dependent manner. Immunodepletion of TGFBI and periostin from conditioned medium derived from oncostatin M-treated mesenchymal stem cells resulted in abrogation of adhesion of PC-3M-luc-C6 cells stimulated by oncostatin M-conditioned medium. In addition, small interfering RNA mediated silencing of TGFBI and periostin resulted in abrogation of cell adhesion stimulated by oncostatin M-conditioned medium. These results suggest that mesenchymal stem cell-derived TGFBI and periostin play a key role in tumorigenesis by stimulating adhesion of prostate cancer cells. PMID- 23735326 TI - Intracellular observation of nanocarriers modified with a mitochondrial targeting signal peptide. AB - This study focused on the intracellular observation of nanocarriers modified with a mitochondrial targeting signal peptide (MTS). The nanocarriers showed an efficient cellular uptake, and the MTS had a positive effect on their mitochondrial targeting. This is the first report of an intracellular observation of nanocarriers modified with MTS. PMID- 23735325 TI - Chondrogenic differentiation of human pluripotent stem cells in chondrocyte co culture. AB - Chondrogenic differentiation of human embryonic (hESCs) or induced pluripotent stem cells (hiPSCs) has been achieved in embryoid bodies (EBs) by adding selected growth factors to the medium. Also chondrocyte-secreted factors have been considered to promote the chondrogenic differentiation. Hence, we studied whether co-culture with primary chondrocytes can induce hESCs or hiPSCs to differentiate into chondrocyte lineage. Co-culture of hESCs or hiPSCs was established in a transwell insert system in feeder-free culture conditions, while hESCs or hiPSCs grown alone in the wells were used as controls. After 3-week co-culture with weekly replenished chondrocytes, the chondrogenically committed cells (hCCCs) were evaluated by morphology, immunocytochemistry, quantitative real-time RT-PCR, and analysis of chondrogenic, osteogenic and adipogenic differentiation markers. The expressions of chondrocyte- and pluripotency-associated genes were frequently measured during the monolayer expansion of hCCCs from passage 1 to 10. Human CCCs displayed morphology similar to chondrocytes, and expressed chondrocyte associated genes, which were declined following passaging, similarly to passaged chondrocytes. They also formed a chondrogenic cell pellet, and differentiated into chondrocytic cells, which secreted abundant extracellular matrix. Human CCCs also proliferated rapidly. However, they did not show osteogenic or adipogenic differentiation capacity. Our results show that co-culture of hESCs or hiPSCs with primary chondrocytes could induce specific chondrogenic differentiation. PMID- 23735327 TI - Novel strategy for production of aggregation-prone proteins and lytic enzymes in Escherichia coli based on an anchored periplasmic expression system. AB - For over 2 decades, Escherichia coli has been successfully used for the production of various recombinant proteins. However, several technical limitations have influenced the extent of recombinant protein expression in the E. coli host because of (i) heterologous protein accumulation often observed in inactive inclusion bodies either in the cytoplasm or periplasm, or (ii) lytic activity of recombinant proteins, which causes cell lysis, that hinder high production yield. We developed a novel strategy for the efficient production of aggregation-prone proteins and lytic enzymes in the E. coli host. For this purpose, we used an anchored periplasmic expression (APEx) system, in which target proteins are produced in the periplasm and tethered on the inner membrane. Protein aggregation and lytic activity can be prevented through anchoring of individual proteins to the inner membrane. Two model proteins (aggregation-prone human leptin and lytic Pseudomonas fluorescens SIK W1 lipase) were examined, and both proteins were successfully produced and anchored to the inner membrane under optimized culture conditions. Upon expression, the inner membrane-anchored proteins were subjected to simple purification procedures; the proteins were confirmed to be of high purity and bioactivity. PMID- 23735328 TI - Characterization of mouse embryoid bodies cultured on microwell chips with different well sizes. AB - Microwell chip culture is a promising technique for the generation of homogenous embryoid bodies (EBs). In this study, we focused on the relationship between microwell size and mouse EB properties. The basic chip design was 195 microwells in a triangular arrangement on a polymethylmethacrylate plate with a surface modified by polyethylene glycol to render it nonadhesive, and 4 similar chips were fabricated with microwell diameters of 400, 600, 800, and 1000 MUm. The cell proliferation rate of EBs in larger microwells was higher than that of EBs in smaller microwells. The decrease in the expression levels of undifferentiated marker genes (Oct3/4 and Nanog) in larger microwells was faster than that in smaller microwells. The expression of hepatic (transthyretin and alpha fetoprotein), cardiac (Nkx2.5 and alpha-myosin heavy chain), and vascular (fetal liver kinase-1; Flk1) markers in larger microwells was higher than that in smaller microwells. The expression levels of differentiation markers except Flk1 in the chip with a diameter of 1000 MUm were similar to those in hanging drop culture. However, Flk1 expression in microwell chip was markedly lower than that in hanging drop culture, suggesting that microwell chip culture promotes differentiation of hepatic and cardiac lineages. Furthermore, glucose consumption and lactate production were higher in smaller microwells, suggesting that the culture proceeds under anaerobic conditions in smaller microwells. These results indicate that the difference in microwell size affects the proliferation and differentiation of embryonic stem cells, and that microwell culture is a promising technique to control EB properties. PMID- 23735329 TI - Detection of Candida albicans by using a designed fluorescence-quenched peptide. AB - Convenient detection of Candida albicans in human bodies is essential to treat patients with candidiasis. In this study, we designed a fluorescence-quenched peptide that emits fluorescence after being cleaved by virulent proteases secreted by C. albicans. The designed peptide will enable easy detection of candidiasis in immunocompromised patients. PMID- 23735331 TI - High severity and fatality of human infections with avian influenza A(H7N9) infection in China. PMID- 23735330 TI - Incidence and timing of cancer in HIV-infected individuals following initiation of combination antiretroviral therapy. AB - BACKGROUND: Cancer is an important cause of morbidity and mortality in individuals infected with human immunodeficiency virus (HIV), but patterns of cancer incidence after combination antiretroviral therapy (ART) initiation remain poorly characterized. METHODS: We evaluated the incidence and timing of cancer diagnoses among patients initiating ART between 1996 and 2011 in a collaboration of 8 US clinical HIV cohorts. Poisson regression was used to estimate incidence rates. Cox regression was used to identify demographic and clinical characteristics associated with cancer incidence after ART initiation. RESULTS: At initiation of first combination ART among 11 485 patients, median year was 2004 (interquartile range [IQR], 2000-2007) and median CD4 count was 202 cells/mm(3) (IQR, 61-338). Incidence rates for Kaposi sarcoma (KS) and lymphomas were highest in the first 6 months after ART initiation (P < .001) and plateaued thereafter, while incidence rates for all other cancers combined increased from 416 to 615 cases per 100 000 person-years from 1 to 10 years after ART initiation (average 7% increase per year; 95% confidence interval, 2%-13%). Lower CD4 count at ART initiation was associated with greater risk of KS, lymphoma, and human papillomavirus-related cancer. Calendar year of ART initiation was not associated with cancer incidence. CONCLUSIONS: KS and lymphoma rates were highest immediately following ART initiation, particularly among patients with low CD4 cell counts, whereas other cancers increased with time on ART, likely reflecting increased cancer risk with aging. Our results underscore recommendations for earlier HIV diagnosis followed by prompt ART initiation along with ongoing aggressive cancer screening and prevention efforts throughout the course of HIV care. PMID- 23735332 TI - A large community outbreak of blastomycosis in Wisconsin with geographic and ethnic clustering. AB - BACKGROUND: Blastomycosis is a potentially life-threatening infection caused by the soil-based dimorphic fungus Blastomyces dermatitidis, which is endemic throughout much of the Midwestern United States. We investigated an increase in reported cases of blastomycosis that occurred during 2009-2010 in Marathon County, Wisconsin. METHODS: Case detection was conducted using the Wisconsin Electronic Disease Surveillance System (WEDSS). WEDSS data were used to compare demographic, clinical, and exposure characteristics between outbreak-related and historical case patients, and to calculate blastomycosis incidence rates. Because initial mapping of outbreak case patients' homes and recreational sites demonstrated unusual neighborhood and household case clustering, we conducted a 1:3 matched case-control study to identify factors associated with being in a geographic cluster. RESULTS: Among the 55 patients with outbreak-related cases, 33 (70%) were hospitalized, 2 (5%) died, 30 (55%) had cluster-related cases, and 20 (45%) were Hmong. The overall incidence increased significantly since 2005 (average 11% increase per year, P < .001), and incidence during 2005-2010 was significantly higher among Asians than non-Asians (2010 incidence: 168 vs 13 per 100 000 population). Thirty of the outbreak cases grouped into 5 residential clusters. Outdoor activities were not risk factors for blastomycosis among cluster case patients or when comparing outbreak cases to historical cases. CONCLUSIONS: This outbreak of blastomycosis, the largest ever reported, was characterized by unique household and neighborhood clustering likely related to multifocal environmental sources. The reasons for the large number of Hmong affected are unclear, but may involve genetic predisposition. PMID- 23735333 TI - Coronary artery calcification and outcomes in diabetic patients with and without chronic kidney disease. AB - BACKGROUND/AIMS: Presence and progression of coronary artery calcification (CAC) indicate severe atherosclerosis and predict cardiovascular events (CVE) in dialysis (ESRD patients) and nondialysis patients (CKD patients). This study aimed at evaluating the prevalence and progression of CAC and CVE in CKD patients with diabetes in whom atherosclerosis of coronary arteries is the leading cause of CVE. METHODS: This was a retrospective study conducted in both out- and in patients with chronic kidney disease, stage 2-5. CAC were assessed by the total calcium (TC) score. CT scans were performed at the entry and at the end of the study. RESULTS: Patients (n = 341) were divided into nondiabetic (n = 281) and diabetic patients (n = 60). CAC prevalence and TC score were higher in diabetics and associated with age, diabetes mellitus and pulse pressure. Diabetics with CKD presented a higher percentage of CAC progression and CVE. CONCLUSION: Prevalence, extent, progression of CAC and CVE are higher in diabetics with concomitant CKD. These findings may promote a more aggressive protocol of screening and care in type 2 diabetics with concomitant CKD. PMID- 23735335 TI - Role of T cell immunity in hepatitis C virus infections. AB - Chronic infections with the hepatitis C virus (HCV) are a major global health issue. Viral replication is restricted to hepatocytes, and occurs for decades at high replication rates. Over the last decade, it became accepted that HCV specific CD4(+) and CD8(+) T cells are crucial for protective immunity to HCV. However, a characteristic feature of persistent HCV infection is the dysfunctional T cell response, and over recent years enormous progress has been made in understanding the mechanisms that dampen the antiviral T cell responses in blood and liver of chronic HCV patients and also impact disease progression. PMID- 23735336 TI - Anger control and cardiovascular outcomes. PMID- 23735334 TI - Evasion of adaptive and innate immune response mechanisms by gamma-herpesviruses. AB - gamma-Herpesviral immune evasion mechanisms are optimized to support the acute, lytic and the longterm, latent phase of infection. During acute infection, specific immune modulatory proteins limit, but also exploit, the antiviral activities of cell intrinsic innate immune responses as well as those of innate and adaptive immune cells. During latent infection, a restricted gene expression program limits immune targeting and cis-acting mechanisms to reduce the antigen presentation as well as antigenicity of latency-associated proteins. Here, we will review recent progress in our understanding of gamma-herpesviral immune evasion strategies. PMID- 23735337 TI - Association between hematocrit in late adolescence and subsequent myocardial infarction in Swedish men. AB - BACKGROUND: Hematocrit is an independent predictor of cardiovascular risk in middle and old age, but whether hematocrit is also a predictor at younger ages is presently not known. In this study, we examined whether hematocrit measured in adolescence was associated with the risk of myocardial infarction later in life. METHODS: During Swedish national conscription tests conducted between 1969 and 1978, the hematocrit was measured in 417,099 young Swedish men. The cohort was followed for subsequent myocardial infarction events through December 2010. Associations between hematocrit and myocardial infarction were accessed using Cox regression models. RESULTS: During a median follow-up period of 36 years, 9322 first-time myocardial infarctions occurred within the study cohort. After adjusting for relevant confounders and potential risk factors for myocardial infarction, men with a hematocrit>=49% had a 1.4-fold increased risk of myocardial infarction compared with men with a hematocrit<=44%. This relationship was dose dependent (p<0.001 for trend) and remained consistent throughout the follow-up period. CONCLUSIONS: In this cohort of young Swedish men, hematocrit was associated with the risk of myocardial infarction later in life after controlling for other coronary risk factors. The study findings indicate that hematocrit may aid future risk assessments in young individuals. PMID- 23735338 TI - Inconsistencies in the development of the ESC Clinical Practice Guidelines for Heart Failure. AB - The publication of the European Society of Cardiology (ESC) guidelines for the management of heart failure, in 2012 represented the latest and arguably the most comprehensive document to date summarising recommended treatment and diagnostic options for the care of heart failure patients. The impact of clinical practice guidelines is now so great that it is important to review the processes that underlie guideline development. The ESC guideline process is compared and contrasted to those of other guideline bodies. The ESC uses its own internal experts inclined to review source clinical trial data rather than published or commissioned meta-analyses and systematic reviews. Uncertainties exist in several areas, such as how are the scope of potential treatments to be reviewed chosen, if there is no call for proposals or external consultation?, Two illustrative discrepancies are highlighted i) the non-surgical MitraClip device for reducing mitral regurgitation is given the verbal equivalent of a Class IIb recommendation on the basis of 107 patients in an uncontrolled registry, whereas no drug is reviewed based on such data, and another device, the subject of 3 prospective randomised controlled trials, was not reviewed at all and ii) for Ivabradine the whole trial population was included in the recommendation, despite a subgroup not benefitting, whereas for CRT the sub-group not thought to benefit was excluded from the recommendation. We propose that more interaction is needed between ESC and stakeholders so each can better understand the processes for producing guidelines to improve some of these aspects. PMID- 23735339 TI - New double balloon delivery catheter for chemical denervation of the renal artery with vincristine. PMID- 23735340 TI - The role of ivabradine in the incidence of perioperative coronary complications in patients undergoing vascular surgery. PMID- 23735341 TI - A comparison of non-HDL and LDL cholesterol goal attainment in the CHILLAS trial. PMID- 23735342 TI - Mortality after clopidogrel in the non-invasive PLATO cohort and TRILOGY ACS trial: another mismatched death paradox. AB - BACKGROUND: Excess mortality especially in the clopidogrel arm of the PLATO trial raise concerns of data integrity, and call for independent verification of vital records in the national death registries. Recently published data focused on outcomes in patients after non-invasive strategies yielded from the PLATO (PLATO NIS) and TRILOGY ACS trials allowing comparison of all cause mortality (ACM) between trials. METHODS: To compare the prorated over follow-up duration rates of ACM in the clopidogrel arms of PLATO-NIS cohort and TRILOGY ACS trial. RESULTS: The background clinical characteristics indicate similar if not higher mortality should be expected in TRILOGY ACS. PLATO trial was almost half the duration with a mean follow-up of 277 days compared to TRILOGY ACS (513 days). Matching prorated over follow-up duration of ACM rates in the clopidogrel arm revealed 0.027/day or 9.86% yearly mortality in PLATO-NIS cohort (195 fatalities among 2615 patients enrolled). The ACM rates in TRILOGY ACS (409/4663) were only 0.017/day or 6.2% annually after clopidogrel, suggesting that the risk to die in the control PLATO-NIS group was 63% higher and barely missed significance (p=0.051) compared to TRILOGY ACS. CONCLUSIONS: Prorated over length of follow-up PLATO-NIS mortality rates after clopidogrel far exceeded those observed in a similar medically managed patients in a TRILOGY ACS trial. The background clinical differences between trials are not responsible for the elevated PLATO NIS mortality numbers. These data further challenge the death paradox reported in the overall PLATO trial and call for the urgent independent verification of vital records. PMID- 23735343 TI - Culotte stenting with bioabsorbable everolimus-eluting stents. PMID- 23735344 TI - Association between hemoglobin level and cardiopulmonary performance in heart failure: insights from the HF-ACTION study. PMID- 23735345 TI - An alternative immunosuppressive regimen to prolong transplant free survival in a patient with giant cell myocarditis. PMID- 23735346 TI - Studying cross-cultural differences in temperament in toddlerhood: United States of America (U.S.) and Italy. AB - Cross-cultural differences between matched samples (N=306) of Italian and U.S. toddlers were evaluated. Italian toddlers received higher scores on cuddliness, impulsivity, low intensity pleasure, perceptual sensitivity and positive anticipation, whereas US toddlers were higher on frustration, high-intensity pleasure, inhibitory control, shyness, and soothability. PMID- 23735347 TI - Clostridium difficile infection associated with pig farms. PMID- 23735348 TI - Analysis on accuracy improvement of rotor-stator rubbing localization based on acoustic emission beamforming method. AB - This paper attempts to introduce an improved acoustic emission (AE) beamforming method to localize rotor-stator rubbing fault in rotating machinery. To investigate the propagation characteristics of acoustic emission signals in casing shell plate of rotating machinery, the plate wave theory is used in a thin plate. A simulation is conducted and its result shows the localization accuracy of beamforming depends on multi-mode, dispersion, velocity and array dimension. In order to reduce the effect of propagation characteristics on the source localization, an AE signal pre-process method is introduced by combining plate wave theory and wavelet packet transform. And the revised localization velocity to reduce effect of array size is presented. The accuracy of rubbing localization based on beamforming and the improved method of present paper are compared by the rubbing test carried on a test table of rotating machinery. The results indicate that the improved method can localize rub fault effectively. PMID- 23735349 TI - Antihistaminic drug olopatadine downmodulates T cell chemotaxis toward CXCL10 by reducing CXCR3 expression, F-actin polymerization and calcium influx in patients with alopecia areata. PMID- 23735350 TI - Is it all downhill after fellowship? Continuing procedural training for practicing physicians. PMID- 23735351 TI - New-generation drug-eluting stent experience in the percutaneous treatment of unprotected left main coronary artery disease: the NEST registry. AB - OBJECTIVES: To explore the 2-year clinical outcomes in patients with unprotected left main coronary artery (ULMCA) disease treated with overall new drug-eluting stent (DES) options. BACKGROUND: Recent available data have shown the feasibility and the safety of new DESs, mainly evaluating the everolimus-eluting stents in the setting of ULMCA disease. METHODS: Patients with ULMCA disease undergoing percutaneous coronary intervention (PCI) with everolimus-, zotarolimus-, and biolimus A9-eluting stents were prospectively evaluated. The study objective was the composite of major adverse cardiac events (MACEs), consisting of all-cause mortality, myocardial infarction (MI), and target vessel revascularization (TVR) at 2-year clinical follow-up. RESULTS: A total of 154 patients were analyzed. The mean EuroSCORE and SYNTAX scores were 4.7 +/- 2.6 and 27.5 +/- 8.3, respectively. Distal location was present in 126 patients (81.8%) and 96 lesions (76.3%) were true Medina bifurcations. The 2-stent technique was used in 73 cases (57.9%). Everolimus-, zotarolimus-, and biolimus A9-eluting stents were implanted in 68 patients (44.2%), 46 patients (29.9%), and 40 patients (25.9%), respectively. At a median clinical follow-up of 551.5 days (interquartile range, 360.8-1045.5 days), MACEs occurred in 29 patients (18.8%). Ten patients (6.5%) died, and 2 deaths (1.3%) were adjudicated as cardiac. No patient had myocardial infarction or definite stent thrombosis (ST). One probable and 1 possible ST were adjudicated. TVR was required in 19 patients (12.3%) and target lesion revascularization was required in only 7 patients (4.5%). CONCLUSIONS: In our experience, despite the presence of complex distal left main lesions, new DESs in ULMCA disease appear to be promising in terms of safety and efficacy at 2-year clinical follow-up. PMID- 23735352 TI - Usefulness of N-acetylcysteine or ascorbic acid versus placebo to prevent contrast-induced acute kidney injury in patients undergoing elective cardiac catheterization: a single-center, prospective, randomized, double-blind, placebo controlled trial. AB - BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is a serious complication of procedures requiring contrast media associated with rising costs, prolonged hospitalization, and increased mortality. The aim of this study was to assess whether prophylactic administration of standard dosages of intravenous N acetylcysteine or ascorbic acid reduce the incidence of CI-AKI in patients with chronic renal insufficiency undergoing elective cardiac catheterization. METHODS: In a single-center, prospective, randomized, double-blind, placebo-controlled trial, the preventive effects of N-acetylcysteine and ascorbic acid were evaluated in 520 patients with chronically impaired renal function (serum creatinine >=1.3 mg/dL) undergoing elective cardiac catheterization. The study drugs (600 mg N-acetylcysteine, 500 mg ascorbic acid, placebo) were administered intravenously twice (at 24 hours and 1 hour before the procedure). Serum creatinine, estimated glomerular filtration rate (eGFR) and serum urea were assessed at baseline and at 24 hours and 72 hours after contrast media exposure. CI-AKI was defined as a postangiographical increase in serum creatinine >=0.5 mg/dL. Results. The incidence of CI-AKI was 27.6% in the N-acetylcysteine group (P=.20 vs placebo group) and in 24.5% in the ascorbic acid group (P=.11 vs placebo group). CI-AKI occurred in 32.1% of the placebo group. CONCLUSIONS: Standard doses of N-acetylcysteine and ascorbic acid did not prevent CI-AKI in patients at high risk undergoing cardiac catheterization with non-ionic, low osmolality contrast agent. PMID- 23735353 TI - Anomalous left circumflex artery from the right coronary cusp: a benign variant? AB - OBJECTIVE: To determine the incidence of angiographically evident coronary artery disease (CAD) of the anomalous left circumflex artery (ALCx). BACKGROUND: Due to the acute angulation of its origin from the aorta and its retroaortic course, some have proposed an increase in CAD in these vessels. METHODS: We performed a retrospective cohort study of all patients (n = 5205) presenting for left heart catheterization at the St Louis Veterans Affairs hospital from 2006-2012. Quantitative coronary angiography (QCA) was performed by two independent operators for all cases identified as having ALCx (n = 18). RESULTS: We identified 18 patients (0.346%) with this anomaly. Sixteen of 18 cases (89%) had atherosclerosis involving the ALCx. QCA performed on the ALCx for all 18 patients resulted in a mean stenosis of 61% (range, 10%-100%). Seven out of 18 patients (39%) had obstructive CAD of the ALCx with the majority (n = 6; 86%) also having concomitant obstructive disease in the left anterior descending (LAD) or right coronary artery (RCA). In the 5 cases where the ALCx underwent intervention, the mean diameter stent was 2.25 mm, with a mean length of 15 mm, indicating that these vessels were small in caliber with focal disease. At a mean follow-up of 18 months for all patients, there was 1 non-cardiac death in the non-intervened group, with the 17 remaining patients (94.7%) free of major adverse cardiovascular events (target lesion revascularization, target vessel revascularization, or death). CONCLUSIONS: This study suggests that indeed this most common anomaly appears to be benign in that its unique origin and/or retroaortic course do not increase the occurrence of atherosclerosis relative to the LAD and RCA. PMID- 23735354 TI - Early experience with the cryoablation balloon procedure for the treatment of atrial fibrillation by an experienced radiofrequency catheter ablation center. AB - BACKGROUND: Radiofrequency (RF) catheter ablation has provided an effective method for treating drug-refractory symptomatic atrial fibrillation. Recently, a cryoablation balloon approach has also received approval. The purpose of this study was to compare RF catheter ablation to cryoablation for the treatment of atrial fibrillation with respect to safety, immediate efficacy, and effects on procedural and fluoroscopy times. In addition, actual procedural costs were compared. METHODS: This study was approved by the Winthrop University Hospital Institutional Review Board to retrospectively examine cryoablation with the Arctic Front Cardiac CryoAblation balloon catheter (Medtronic, Inc) and compare it to RF catheter ablation for the treatment of drug-refractory symptomatic atrial fibrillation. Patient and procedural characteristics as well as immediate success were compared. Immediate failure was defined as incomplete pulmonary vein isolation of all veins. RESULTS: A total of 124 procedures (62 RFs and 62 cryoablations) were performed from December 2010 through July 2012. The cryoablation procedure took longer to perform than RF (171 +/- 61 minutes vs 126 +/- 49 minutes, respectively; P<.0001). There was no difference in fluoroscopy times between the two groups (29 +/- 20 minutes for RF vs 32 +/- 18 minutes for cryoablation; P=.39). The infusion of protamine following procedures was much more common in the cryoablation group (30 patients vs 2 patients in the RF group; P<.0001). The immediate success rate was 93.5% with RF ablation vs 96.7% with cryoablation (P=NS). There was not a significant difference in complications between the two approaches. The cost for each procedure was $24,391.88 +/- 4826.77 for RF and $31,874.02 +/- 8349.70 for cryoablation (P<.0001). CONCLUSION: Cryoablation provides an additional and alternative approach to RF ablation for the treatment of symptomatic drug-refractory atrial fibrillation with comparable immediate success and complications. It is synergistic with RF and permits the ability to tackle the entire gamut of atrial fibrillation (ie, paroxysmal and persistent). This study showed no decrease in procedural or fluoroscopy times with our early experience. One significant limitation with cryoablation is the cost. Cryoablation resulted in over $7000 extra cost to the hospital per procedure. The clinical benefits achieved by this additional cost warrant further investigation. PMID- 23735355 TI - In vivo lipid core plaque modification with percutaneous coronary revascularization: a near-infrared spectroscopy study. AB - BACKGROUND: Coronary revascularization is associated with no-reflow phenomenon and elevation of cardiac biomarkers. This may occur due to plaque modification. We used near-infrared spectroscopy (NIRS) to evaluate lipid core plaque (LCP) modification with coronary revascularization and its correlation with periprocedural myocardial infarction. METHODS: Patients presenting to the cardiac catheterization laboratory who underwent NIRS, NIRS/intravascular ultrasound (IVUS) were reviewed and their lipid core burden index (LCBI) was assessed. Using fuzzy c-means clustering algorithm, the coronary was divided into three zones and the lipid burden was recalculated. Its correlation to postprocedure troponin elevation and outcomes with a mean follow-up of 42 months were studied. RESULTS: A total of 77 coronaries were evaluated. There was an overall decrease in the LCBI after percutaneous revascularization (P<.0001). Using fuzzy c-means clustering algorithm, there was always a decrease in the lipid burden at the site of the percutaneous revascularization (P<.0001). Postprocedure troponin elevation was only noted in patients with an axial shifting of the LCP. There was no difference in long-term outcomes due to the degree of reduction of lipid burden or its axial. CONCLUSIONS: Plaque modification may be performed successfully using interventional methods and can be evaluated with NIRS. Axial plaque shifting is an acute prognostic marker for postprocedure myocardial infarction. PMID- 23735356 TI - Use of the trellis device in the management of deep vein thrombosis: a retrospective single-center experience. AB - OBJECTIVES: The Trellis thrombectomy system (Covidien) is one of the newer devices that incorporates isolated pharmacomechanical thrombectomy and thrombolysis (PMT) for treatment of deep venous thrombosis (DVT). We conducted a retrospective review of patients with upper- and lower-extremity DVT managed with the Trellis thrombectomy system at our center. METHODS: All patients with symptomatic DVT who presented to our center between April 2010 and April 2011 who underwent PMT by the Trellis device were included in this retrospective review. RESULTS: Twenty-eight patients (mean age, 46.4 +/- 21.2 years) presented with symptoms with a mean duration of 1.3 +/- 1.8 months. Eighty-six percent had 100% occlusion on admission, while 14.3% had 70%-90% stenosis. The mean lytic dose used was tPA 20.7 +/- 12 mg. The mean Trellis treatment time was 25.1 +/- 11.5 minutes. Grade 3 lysis was achieved in 23 of 28 patients (85.8%), while grade 2 lysis was achieved in 14.2%. Mean total hospital stay was 2.6 +/- 2.7 days. Postprocedure symptom resolution was 100%, and there was no reocclusion in 78.6% of patients at 1 year. At 12 months, the patency rate (primary or secondary) was 80% as determined by Doppler ultrasound. CONCLUSIONS: In patients with DVT involving the ilio-femoral and the upper-extremity vessels, the use of the Trellis device was associated with a high technical success rate as well as a satisfactory 12-month patency rate. Moreover, this strategy was associated with reduced lytic dose, shorter treatment time and hospital stay, and no bleeding complications. PMID- 23735357 TI - Transradial diagnosis and intervention of supraaortic vessels. AB - BACKGROUND: The transradial approach (TRA) is becoming widespread, mainly for coronary interventions, but it has rarely been used for diagnosis and even less for therapeutic treatment of supraaortic arterial vessel (SAAV) atherosclerotic disease. OBJECTIVES: We report our last year's experience in both diagnostic and therapeutic endovascular procedures for SAAV atherosclerotic disease using the TRA. METHODS: The TRA was used in 20 diagnostic and 18 therapeutic procedures for SAAV atherosclerotic disease performed on 26 males and 12 females with a mean age of 65 +/- 7 years. Indications for diagnostic or therapeutic procedures were: clinical findings; and symptoms related to SAAV disease. Indications for the TRA were: no option of femoral approach (9/38); hostile arch anatomy (3/38); technical failure via femoral approach (4/38); ostial vertebral disease (6/38); or patient preference (16/38). All diagnostic procedures were undertaken using 5 Fr catheters. Treated vessels were: brachiocephalic; subclavian; carotid; vertebral; extracranial segments V1 and V2; and intracranial segment V4 and basilar arteries. Technical success was achieved in 17/18 therapeutic procedures (95%). We switched to the femoral approach in 1 patient with right-sided carotid disease where the distal protection device could not be propagated cranial to the narrowed segment. No vascular or neurological complications were recorded in any of the procedures. Patients were discharged the same day after diagnostic procedure and 1 day after therapeutic procedure. At a mean 7-month follow-up exam, neither neurological symptoms nor clinical restenosis were detected. CONCLUSIONS: Diagnostic and therapeutic procedures involving SAAV can be safely and successfully performed via the TRA by experienced interventional cardiologists. PMID- 23735358 TI - In-stent thrombosis due to neoatherosclerosis: insight from optical coherence tomography. AB - Neoatherosclerosis is one of the multiple mechanisms that cause stent thrombosis, which is one of the rare but severe complications of drug-eluting stent implantation. This case study highlights the use of optical coherence tomography in identifying the precise mechanism of the stent thrombosis, which helped guide the appropriate intervention. PMID- 23735359 TI - Electrophysiological evaluation of atrioventricular conduction disturbances in transcatheter aortic valve implantation with Edwards SAPIEN prosthesis. AB - AIMS: Permanent pacemaker requirement is a known complication after transcatheter aortic valve implantation (TAVI). The aim of the present study was to analyze the effects of Edwards SAPIEN prosthesis implantation on atrioventricular conduction. METHODS: The study included 28 patients who underwent TAVI due to severe aortic valve stenosis. An electrophysiological study was performed in the catheterization room immediately before the initial balloon valvuloplasty and immediately after Edwards SAPIEN prosthesis implantation. RESULTS: His-ventricle interval was significantly prolonged postprocedure (55.9 +/- 11.5 ms) vs preprocedure (47.3 +/- 7.8 ms) (P<.001). The antegrade Wenckebach point was observed to be significantly prolonged postprocedure (354.4 +/- 41.3 ms) vs preprocedure (333.7 +/- 45.4 ms) (P=.001). Despite atrial-His interval prolongation, it was not statistically significant. After the procedure, we observed significant conduction disturbances in 3 patients (10.7%). These conduction problems recovered before discharge. One of the patients (3.6%) with right bundle branch block + left anterior fascicular block required permanent pacemaker implantation. At postprocedure electrocardiogram, QRS duration increased, QRS axis shifted to the left, and both of the values became normal before discharge. The patient's echocardiographic and clinical parameters were improved during follow-up. CONCLUSION: The effect of Edwards SAPIEN on the conduction system was mostly infranodal and temporary. The physical properties of the Edwards SAPIEN prosthesis may explain this observation. This complication may be lessened if the frame height characteristics can be improved. PMID- 23735360 TI - Percutaneous transcatheter valve-in-valve implantation with the balloon expandable valve for the treatment of a dysfunctional tricuspid bioprosthetic valve: a pediatric case report. AB - An inverted Edwards SAPIEN 23 mm valve was implanted in a 14-year-old patient with Ebstein's anomaly who received a Medtronic Mosaic 25 mm valve 8 years earlier and presented with significant progressive symptoms related to severe valvular regurgitation and moderate stenosis. The procedure was performed via the femoral vein using the RetroFlex 3 system and predilatation of the tricuspid valve, under transesophageal echocardiographic guidance. The patient had an immediate drop in right atrial and trans-tricuspid pressures with mild regurgitation, and had stable results on short-term follow-up. PMID- 23735361 TI - The link between vasculogenic erectile dysfunction, coronary artery disease, and peripheral artery disease: role of metabolic factors and endovascular therapy. AB - Erectile dysfunction (ED) is estimated to affect 150 million people worldwide and may indicate diffuse systemic macrovascular disease. Endothelial dysfunction represents the probable pathophysiological link between vasculogenic ED, coronary artery disease (CAD), and peripheral artery disease (PAD), and the artery size hypothesis along with evidence-based research support ED as the incident clinical event. Given that many common risk factors for atherosclerosis, including smoking, diabetes mellitus, hyperlipidemia, and obesity are prevalent and causative in patients with ED, it is likely that metabolic factors play a crucial role in the link between the two disorders. The interplay of these factors provides a unifying physiological, endocrinological, and behavioral model for the association between ED, CAD, and PAD. Current therapy is unlikely to reverse the natural history of ED. Percutaneous revascularization may improve ED symptoms, and thereby quality of life, in a select group of patients. Large prospective studies are needed to define male pelvic arterial anatomy and thus enhance the utilization of internal pudendal angiography and revascularization. In this review, we provide an overview of normal erectile anatomy and physiology, the pathophysiology of ED, currently accepted diagnostic imaging modalities and treatments for ED, and recently investigated endovascular therapies for ED. PMID- 23735362 TI - Reducing air embolism and improving accuracy during pediatric wedge measurements. PMID- 23735363 TI - Full metal atrium. PMID- 23735364 TI - Stent "concertina:" stent design does matter. AB - The development of modern coronary stent platforms has transformed the landscape of interventional cardiology. Contemporary coronary stents are much more deliverable than older-generation stents. However, longitudinal deformation has emerged as a "new" complication in modern coronary stent platforms. Although most reported cases of longitudinal stent deformation involve mechanical or technical mishaps, it appears that it is more frequently associated with a particular stent design: the "offset peak-to-peak" stent design. This review summarizes the latest data around stent performance. Within this context, two clinical cases where longitudinal deformation was observed in the absence of any mechanical mishaps are also presented. Collectively, this evidence suggests that stent design may be a major determinant of stent performance. PMID- 23735365 TI - Migraine headaches following mitral valvuloplasty: Koch's postulates finally satisfied? AB - The relationship between patent foramen ovale and migraine headache is a topic surrounded by much controversy. We present the case of a 45-year-old woman who underwent successful percutaneous mitral balloon valvuloplasty for rheumatic mitral valve stenosis, but had an immediate postprocedural course complicated by refractory migraine headaches. Interestingly, resolution of her headaches coincided with the spontaneous closure of the interatrial communication created during valvuloplasty. This suggests interatrial flow as an important trigger for migraine headaches in this patient. PMID- 23735366 TI - Successful primary PCI in a patient with single coronary artery. AB - Sudden occlusion of the only patent coronary artery is usually a devastating event. We describe the case of a successful percutaneous recanalization of a single coronary artery originating at the right sinus of Valsalva. PMID- 23735367 TI - Ablation of hypertrophic septum using radiofrequency energy: an alternative for gradient reduction in patient with hypertrophic obstructive cardiomyopathy? AB - INTRODUCTION: Alcohol septal ablation and surgical myectomy represent accepted therapeutic options for treatment of symptomatic patients with hypertrophic obstructive cardiomyopathy. Long-term experience with radiofrequency ablation of arrhythmogenic substrates raised a question if this technique might be effective for left ventricular outflow tract (LVOT) gradient reduction. CASE REPORT: We report on a 63-year-old patient with recurrence of symptoms 1 year after alcohol septal ablation (ASA) leading originally to a significant reduction of both symptoms and gradient. Due to a new increase of gradient in the LVOT up to 200 mm Hg with corresponding worsening of symptoms and due to refusal of surgical myectomy by the patient, endocardial radiofrequency ablation of the septal hypertrophy (ERASH) was indicated. Radiofrequency ablation was performed in the LVOT using irrigated-tip ablation catheter; the target site was identified using intracardiac echocardiography and electroanatomical CARTO mapping. ERASH caused an immediate gradient reduction due to hypokinesis of the ablated septum. At 2 month follow-up exam, significant clinical improvement was observed, together with persistent gradient reduction assessed with Doppler echocardiography. Echocardiography and magnetic resonance revealed persistent septal hypokinesis and slight thinning of the ablated region. CONCLUSION: Septal ablation using radiofrequency energy may be a promising alternative or adjunct to the treatment of hypertrophic obstructive cardiomyopathy. Intracardiac echocardiography and electroanatomical CARTO mapping enable exact lesion placement and preservation of atrioventricular conduction. PMID- 23735368 TI - Successful endovascular treatment for simultaneous multiple thromboemboli following myocardial infarction. AB - An 81-year-old female was referred for myocardial infarction with heart failure. She was successfully treated with percutaneous coronary intervention (PCI), and left ventriculogram revealed an apical thrombus 20 mm in diameter. Multiple simultaneous thromboemboli occurred in her right renal artery, supramesenteric artery (SMA), and right popliteal artery on the fifth day after PCI despite anticoagulant therapy. Emergency endovascular therapy (EVT) with an aspiration catheter and ballooning were performed to the popliteal and renal artery, in addition to additional stenting of the SMA because of an intramural hematoma. This one session of emergency EVT was sufficient to save this patient, and no sequelae were observed after this treatment. PMID- 23735369 TI - A rare case of percutaneous coronary intervention in achondroplasia. AB - Achondroplastic individuals are associated with increased cardiac risk when compared to the general population. Coronary interventions in patients with achondroplasia have not been studied previously. We report the case of a 32-year old male smoker with achondroplasia who presented with acute chest pain of 3 hours duration. He was diagnosed with acute inferior and right ventricular myocardial infarction and thrombolyzed with streptokinase. Since the patient continued to have pain and hypotension, he was taken for rescue percutaneous coronary intervention (PCI). Because of short stature and kyphoscoliosis, difficulties were faced in cannulating the coronaries and performing intervention. He had total occlusion of proximal right coronary artery, for which angioplasty with stenting was done. To our knowledge, this is the first case of PCI conducted in an achondroplastic patient. PMID- 23735370 TI - Geometric morphometric assessment of sexually dimorphic characteristics of the distal humerus. AB - A number of recent studies investigated the use of morphological characteristics of the distal humerus to estimate the sex of unknown individuals. Using visual assessment, accuracies ranging from 74% to more than 90% were reported. The aim of this study was to assess these traits with geometric morphometrics, in order to determine if they corroborate the findings described with pure visual assessment. A total sample of 155 female and 175 male humeri of South Africans were used. All humeri were photographed in standardized positions from a posterior and inferior view, and homologous landmarks assigned. Olecranon fossa shape, angle of the medial epicondyle and trochlear symmetry were assessed. Males and females could be separated with accuracies ranging from 78% to 91%. The results of this study confirm the existence of these traits and their usability in assessment of sex from skeletal remains, and the observed anatomical characteristics largely agree with what have been described by visual assessment. PMID- 23735371 TI - Decreased uric acid levels correlate with poor outcomes in acute ischemic stroke patients, but not in cerebral hemorrhage patients. AB - BACKGROUND: The relationship between uric acid and stroke prognosis is ambiguous. Some studies have explored this relationship in acute stroke but have different results. In this study, we explored the relationship between uric acid levels and 1-year outcomes and vascular events of acute ischemic stroke patients and cerebral hemorrhage patients. METHODS: In all, 1452 continued first, acute ischemic stroke patients and 380 continued cerebral hemorrhage patients were admitted to our hospitals. Serum uric acid concentrations were measured in 1351 ischemic stroke patients and 380 cerebral hemorrhage patients at admission. We evaluated the relationship between uric acid levels and outcomes (modified Rankin scale [mRS] > 2, all-cause death, vascular events, stroke recurrent) at 14 days, 90 days, and 1 year after stroke onset. RESULTS: The median uric acid concentration was 303.0 MUmol/L in ischemic stroke patients and 269 MUmol/L in cerebral hemorrhage patients. In univariate analysis, uric acid levels were not correlated with outcomes in cerebral hemorrhage patients. We used multiple logistic regression analysis to show that lower serum uric acid levels independently predicted poor functional outcomes (mRS >2) at 1 year after ischemic stroke onset (odds ratio [OR] = .335, 95% confidence interval [CI]: .164 .684, P = .003). Also, lower serum uric acid levels were independently correlated with vascular events in the first year in ischemic stroke patients. By multiple cox proportional hazards analysis, we obtained data which reveal that serum uric acid levels were not correlated with all-cause death (OR = .992, 95% CI: .683 1.443, P = .969) in ischemic stroke patients. CONCLUSIONS: Serum uric acid may be neuroprotective in acute ischemic stroke patients. PMID- 23735372 TI - C-reactive protein and homocysteine predict long-term mortality in young ischemic stroke patients. AB - BACKGROUND: We investigated the relationship between C-reactive protein (CRP) and homocysteine on follow-up and subsequent mortality in young ischemic stroke patients in a population-based study. METHODS: Young ischemic stroke patients were followed-up on average 6 years after the index stroke. CRP and homocysteine levels were measured and risk factors were recorded, including myocardial infarction, diabetes mellitus, hypertension, smoking, alcoholism, and cancer. Stroke outcome was measured using the modified Rankin Scale score. Subsequent survival was obtained by examining the official population registry. Cox regression analyses were performed. RESULTS: In total, 198 patients were included in this study (82 [41%] women and 116 [59%] men). The mean age on follow-up was 47.8 years. In total, 36 (18.2%) patients died during the subsequent mean follow up of 12.4 years. Cox regression analysis revealed that mortality was associated with CRP (hazard ratio [HR] 1.05; P=.001) and homocysteine levels (HR 1.04; P=.02) in patients without dissection. Kaplan-Meier curves grouped by dichotomized CRP (CRP<=1 v >1 mg/L) showed increasing separation between the survival curves, and likewise for dichotomized homocysteine (<=9 v >9 MUg/L). CONCLUSIONS: There is an independent association between CRP and homocysteine levels obtained several years after ischemic stroke in young adults and subsequent mortality, even when adjusting for traditional risk factors. This association seems to continue for at least 12 years after the measurements. PMID- 23735373 TI - Hospital discharges and mortality registries: 2 complementary databases for the epidemiological surveillance of stroke. AB - BACKGROUND: Stroke is a public health concern and the availability of a stroke registry would provide valuable information. Administrative hospital data and mortality registries have been previously suggested as suitable sources of information. The aim of this study was to evaluate the utility of merging data from a hospital discharge database and the mortality registry (MR) to estimate the incidence of stroke in La Rioja, Spain. METHODS: A cross-sectional study about events of stroke occurred in our region in 2009 was carried out. Patients were selected among those registered in the discharge hospital database and in the MR, using the International Classification of Diseases. The databases were merged to detect duplicated occurrences and to estimate the number of cases identified by each source. Characteristics of the study population were analyzed and crude- and age-adjusted incidence rates were assessed. RESULTS: Using both databases, 1133 stroke events were detected, 153 (13.5%) representing coincident or recurrent cases. A total of 980 incident stroke cases were obtained, 150 provided by the MR (15.3%) and 830 by the hospital discharge database (84.7%). Incidence of stroke was similar in men than in women, the ischemic stroke being the major type. Most of the study population (66%) were older than 74 years. Crude incidence rate was 304.6 per 100,000, and age-adjusted rates were 171.1 per 100,000 (adjusted to the European population) and 107.9 per 100,000 (adjusted to the World population). CONCLUSIONS: Considering both the Minimum Basic Data Set and the MR as data sources appears advisable to build a stroke registry to evaluate the incidence and to perform epidemiological surveillance of stroke. PMID- 23735374 TI - Fibromuscular dysplasia dawdling for 8 years before showing its true face. AB - We present a case of acute left-sided carotid dissection associated with contralateral carotid fibromuscular dysplasia and pseudoaneurysm. She had a history of an incidental finding, 8 years earlier, of a right-sided carotid pseudoaneurysm (interpreted as a sequella of an earlier asymptomatic carotid dissection) in the absence of features of fibromuscular dysplasia. This case shows that fibromuscular dysplasia-related pseudoaneurysm/dissection can be seen in the absence of initial radiological fibromuscular dysplasia only occurring many years later during follow-up. PMID- 23735375 TI - Evaluation of SCCVII tumor cell survival in clamped and non-clamped solid tumors exposed to carbon-ion beams in comparison to X-rays. AB - The aim of this study was to measure the RBE (relative biological effectiveness) and OER (oxygen enhancement ratio) for survival of cells within implanted solid tumors following exposure to 290MeV/nucleon carbon-ion beams or X-rays. Squamous cell carcinoma cells (SCCVII) were transplanted into the right hind legs of syngeneic C3H male mice. Irradiation with either carbon-ion beams with a 6-cm spread-out Bragg peak (SOBP, at 46 and 80keV/MUm) or X-rays was delivered to 5-mm or less diameter tumors. We defined three different oxygen statuses of the irradiated cells. Hypoxic and normoxic conditions in tumors were produced by clamping or not clamping the leg to avoid blood flow. Furthermore, single-cell suspensions were prepared from non-irradiated tumors and directly used to determine the radiation response of aerobic cells. Single-cell suspensions (aerobic condition) were fully air-saturated. Single-cell suspensions were prepared from excised and trypsinized tumors, and were used for in vivo-in vitro colony formation assays to obtain cell survival curves. The RBE values increased with increasing LET in SOBP beams. The maximum RBE values in three different oxygen conditions; hypoxic tumor, normoxic tumor and aerobic cells, were 2.16, 1.76 and 1.66 at an LET of 80keV/MUm, respectively. After X-ray irradiation the OERh/n values (hypoxic tumor/normoxic tumor) were lower than the OERh/a (hypoxic tumor/aerobic cells), and were 1.87+/-0.13 and 2.52+/-0.11, respectively. The OER values of carbon-ion irradiated samples were small in comparison to those of X ray irradiated samples. However, no significant changes of the OER at proximal and distal positions within the SOBP carbon-ion beams were observed. To conclude, we found that the RBE values for cell survival increased with increasing LET and that the OER values changed little with increasing LET within the SOBP carbon-ion beams. PMID- 23735376 TI - Editor's briefing. PMID- 23735377 TI - Unlocking the research potential of the GP electronic care record. PMID- 23735378 TI - Giving patients online access to their records: opportunities, challenges, and scope for service transformation. PMID- 23735379 TI - Capturing general practice quality: a new paradigm? PMID- 23735380 TI - Use of e-mail for consulting with patients in general practice. PMID- 23735381 TI - The challenge of communication in interpreted consultations in diabetes care. PMID- 23735382 TI - Don't shoot the messenger: the problem of whistleblowing in general practice. PMID- 23735383 TI - Sharing control of appointment length with patients in general practice. PMID- 23735384 TI - HIV testing: the danger of keeping secrets. PMID- 23735385 TI - Transforming the delivery of health and social care: the case for fundamental change. PMID- 23735386 TI - GP nomenclature. PMID- 23735387 TI - Euthyphro dilemma. PMID- 23735388 TI - How not to contact the dead. PMID- 23735389 TI - Healthcare datasets: ethical concerns. PMID- 23735390 TI - Foucault. PMID- 23735391 TI - All change on the life support course. PMID- 23735392 TI - Helen Lester: an appreciation. PMID- 23735393 TI - Exception reporting as a quality marker. PMID- 23735394 TI - Computer-generated reminders influence professional practice. PMID- 23735395 TI - The death of my dog: lessons learned from the palliative care of an animal. PMID- 23735396 TI - Coaching for health: holding the curtains so patients can change. PMID- 23735403 TI - Made to measure? PMID- 23735404 TI - Patients' access to their electronic record: proceed with caution. PMID- 23735405 TI - Diagnosis and management of hereditary haemochromatosis. PMID- 23735406 TI - Tips for GP trainees working in haematology. PMID- 23735407 TI - Assessing the predictive value of HIV indicator conditions in general practice: a case-control study using the THIN database. AB - BACKGROUND: UK HIV guidelines identify 37 clinical indicator conditions for adult HIV infection that should prompt an HIV test. However, few data currently exist to show their predictive value in identifying undiagnosed HIV. AIM: To identify symptoms and clinical diagnoses associated with HIV infection and assess their relative importance in identifying HIV cases, using data from The Health Improvement Network (THIN) general practice database. DESIGN AND SETTING: A case control study in primary care. METHOD: Cases (HIV-positive patients) were matched to controls (not known to have HIV). Data from 939 cases and 2576 controls were included (n = 3515). Statistical analysis assessed the incidence of the 37 clinical conditions in cases and controls, and their predictive value in indicating HIV infection, and derived odds ratios (ORs) for each indicator condition. RESULTS: Twelve indicator conditions were significantly associated with HIV infection; 74.2% of HIV cases (n = 697) presented with none of the HIV indicator conditions prior to diagnosis. The conditions most strongly associated with HIV infection were bacterial pneumonia (OR = 47.7; 95% confidence interval [CI] = 5.6 to 404.2) and oral candidiasis (OR = 29.4; 95% CI = 6.9 to 125.5). The signs and symptoms most associated with HIV were weight loss (OR = 13.4; 95% CI = 5.0 to 36.0), pyrexia of unknown origin (OR = 7.2; 95% CI = 2.8 to 18.7), and diarrhoea (one or two consultations). CONCLUSION: This is the first study to quantify the predictive value of clinical diagnoses related to HIV infection in primary care. In identifying the conditions most strongly associated with HIV, this study could aid GPs in offering targeted HIV testing to those at highest risk. PMID- 23735408 TI - Patient self-monitoring of blood pressure and self-titration of medication in primary care: the TASMINH2 trial qualitative study of health professionals' experiences. AB - BACKGROUND: Self-monitoring with self-titration of antihypertensives leads to reduced blood pressure. Patients are keen on self-monitoring but little is known about healthcare professional views. AIM: To explore health professionals' views and experiences of patient self-management, particularly with respect to future implementation into routine care. DESIGN AND SETTING: Qualitative study embedded within a randomised controlled trial of healthcare professionals participating in the TASMINH2 trial of patient self-monitoring with self-titration of antihypertensives from 24 West Midlands general practices. METHOD: Taped and transcribed semi-structured interviews with 13 GPs, two practice nurses and one healthcare assistant. Constant comparative method of analysis. RESULTS: Primary care professionals were positive about self-monitoring, but procedures for ensuring patients measured blood pressure correctly were haphazard. GPs interpreted home readings variably, with many not making adjustment for lower home blood pressure. Interviewees were satisfied with patient training and arrangements for blood pressure monitoring and self-titration of medication during the trial, but less sure about future implementation into routine care. There was evidence of a need for training of both patients and professionals for successful integration of self-management. CONCLUSION: Health professionals wanted more patient involvement in hypertension care but needed a framework to work within. Consideration of how to train patients to measure blood pressure and how home readings become part of their care is required before self-monitoring and self-titration can be implemented widely. As home monitoring becomes more widespread, the development of patient self-management, including self-titration of medication, should follow but this may take time to achieve. PMID- 23735409 TI - Do referral-management schemes reduce hospital outpatient attendances? Time series evaluation of primary care referral management. AB - BACKGROUND: Ninety-one per cent of primary care trusts were using some form of referral management in 2009, although evidence for its effectiveness is limited. AIM: To assess the impact of three referral-management centres (RMCs) and two internal peer-review approaches to referral management on hospital outpatient attendance rates. DESIGN AND SETTING: A retrospective time-series analysis of 376 000 outpatient attendances over 3 years from 85 practices divided into five groups, with 714 000 registered patients in one English primary care trust. METHOD: The age-standardised GP-referred first outpatient monthly attendance rate was calculated for each group from April 2009 to March 2012. This was divided by the equivalent monthly England rate, to derive a rate ratio. Linear regression tested for association between the introduction of referral management and change in the outpatient attendance rate and rate ratio. Annual group budgets for referral management were obtained. RESULTS: Referral management was not associated with a reduction in the outpatient attendance rate in any group. There was a statistically significant increase in attendance rate in one group (a RMC), which had an increase of 1.05 attendances per 1000 persons per month (95% confidence interval = 0.46 to 1.64; attendance rate ratio increase of 0.07) after adjustment for autocorrelation. Mean annual budgets ranged from L0.55 to L6.23 per registered patient in 2011/2012. RMCs were more expensive (mean annual budget L5.18 per registered patient) than internal peer-review approaches (mean annual budget L0.97 per registered patient). CONCLUSION: Referral-management schemes did not reduce outpatient attendance rates. RMCs were more expensive than internal peer review. PMID- 23735411 TI - Cardiovascular risk scores: qualitative study of how primary care practitioners understand and use them. AB - BACKGROUND: The National Institute for Health and Care Excellence guidelines and the Quality Outcomes Framework require practitioners to use cardiovascular risk scores in assessments for the primary prevention of cardiovascular disease. AIM: To explore GPs understanding and use of cardiovascular risk scores. DESIGN AND SETTING: Qualitative study with purposive maximum variation sampling of 20 GPs working in Oxfordshire, UK. Method Thematic analysis of transcriptions of face-to face interviews with participants undertaken by two individuals (one clinical, one non-clinical). RESULTS: GPs use cardiovascular risk scores primarily to guide treatment decisions by estimating the risk of a vascular event if the patient remains untreated. They expressed considerable uncertainty about how and whether to take account of existing drug treatment or other types of prior risk modification. They were also unclear about the choice between the older scores, based on the Framingham study, and newer scores, such as QRISK. There was substantial variation in opinion about whether scores could legitimately be used to illustrate to patients the change in risk as a result of treatment. The overall impression was of considerable confusion. CONCLUSION: The drive to estimate risk more precisely by qualifying guidance and promoting new scores based on partially-treated populations appears to have created unnecessary confusion for little obvious benefit. National guidance needs to be simplified, and, to be fit for purpose, better reflect the ways in which cardiovascular risk scores are currently used in general practice. Patients may be better served by simple advice to use a Framingham score and exercise more clinical judgement, explaining to patients the necessary imprecision of any individual estimate of risk. PMID- 23735410 TI - Development and evaluation of a brief self-completed family history screening tool for common chronic disease prevention in primary care. AB - BACKGROUND: Family history is an important risk factor for many common chronic diseases, but it remains underutilised for diagnostic assessment and disease prevention in routine primary care. AIM: To develop and validate a brief self completed family history questionnaire (FHQ) for systematic primary care assessment for family history of diabetes, ischaemic heart disease, breast cancer, and colorectal cancer. DESIGN AND SETTING: Two-stage diagnostic validation study in 10 general practices in eastern England. Method Participants aged 18-50 years were identified via random sampling from electronic searches of general practice records. Participants completed a FHQ then had a three generational 'gold standard' pedigree taken, to determine disease risk category. In stage 1, the FHQ comprised 12 items; in stage 2 the shorter 6-item FHQ was validated against the same 'gold standard'. RESULTS: There were 1147 participants (stage 1: 618; stage 2: 529). Overall, 32% were at increased risk of one or more marker conditions (diabetes 18.9%, ischaemic heart disease 13.3%, breast cancer 6.2%, colorectal cancer 2.2%). The shorter 6-item FHQ performed very well for all four conditions: pooled data from both stages show diabetes, sensitivity = 98%, specificity = 94%; ischaemic heart disease, sensitivity = 93%, specificity = 81%; breast cancer, sensitivity = 81%, specificity = 83%; colorectal cancer, sensitivity = 96%, specificity = 88%, with an area under the receiver operating characteristic curve of 0.90 for males and 0.89 for females. CONCLUSION: This brief self-completed FHQ shows good diagnostic accuracy for identifying people at higher risk of four common chronic diseases. It could be used in routine primary care to identify patients who would be most likely to benefit from a more detailed pedigree and risk assessment, and consequent management strategies. PMID- 23735412 TI - Implementation of pay for performance in primary care: a qualitative study 8 years after introduction. AB - BACKGROUND: Pay for performance is now a widely adopted quality improvement initiative in health care. One of the largest schemes in primary care internationally is the English Quality and Outcomes Framework (QOF). AIM: To obtain a longer term perspective on the implementation of the QOF. DESIGN AND SETTING: Qualitative study with 47 health professionals in 23 practices across England. Method Semi-structured interviews. RESULTS: Pay for performance is accepted as a routine part of primary care in England, with previous more individualistic and less structured ways of working seen as poor practice. The size of the QOF and the evidence-based nature of the indicators are regarded as key to its success. However, pay for performance may have had a negative impact on some aspects of medical professionalism, such as clinical autonomy, and led a significant minority of GPs to prioritise their own pay rather than patients' best interests. A small minority of GPs tried to increase their clinical autonomy with further unintended consequences. CONCLUSION: Pay for performance indicators are now welcomed by primary healthcare teams and GPs across generations. Almost all interviewees wanted to see a greater emphasis on involving front line practice teams in developing indicators. However, almost all GPs and practice managers described a sense of decreased clinical autonomy and loss of professionalism. Calibrating the appropriate level of clinical autonomy is critical if pay for performance schemes are to have maximal impact on patient care. PMID- 23735414 TI - Patients' access to their electronic record: offer patients access as soon as you can. PMID- 23735413 TI - Pandemic influenza A(H1N1)pdm09: risk of infection in primary healthcare workers. AB - BACKGROUND: Healthcare workers in primary care are at risk of infection during an influenza pandemic. The 2009 influenza pandemic provided an opportunity to assess this risk. AIM: To measure the prevalence of seropositivity to influenza A(H1N1)pdm09 among primary healthcare workers in Canterbury, New Zealand, following the 2009 influenza pandemic, and to examine associations between seropositivity and participants' sociodemographic characteristics, professional roles, work patterns, and seasonal influenza vaccination status. DESIGN AND SETTING: An observational study involving a questionnaire and testing for influenza A(H1N1)pdm09 seropositivity in all primary healthcare workers in Canterbury, New Zealand between December 2009 and February 2010. Method Participants completed a questionnaire that recorded sociodemographic and professional data, symptoms of influenza-like illness, history of seasonal influenza vaccination, and work patterns. Serum samples were collected and haemagglutination inhibition antibody titres to influenza A(H1N1)pdm09 measured. RESULTS: Questionnaires and serum samples were received from 1027 participants, from a workforce of 1476 (response rate 70%). Seropositivity was detected in 224 participants (22%). Receipt of seasonal influenza vaccine (odds ratio [OR] = 2.0, 95% confidence interval [CI] = 1.2 to 3.3), recall of influenza (OR = 1.9, 95% CI = 1.3 to 2.8), and age <=45 years (OR = 1.4, 95% CI = 1.0 to 1.9) were associated with seropositivity. CONCLUSION: A total of 22% of primary care healthcare workers were seropositive. Younger participants, those who recalled having influenza, and those who had been vaccinated against seasonal influenza were more likely to be seropositive. Working in a dedicated influenza centre was not associated with an increased risk of seropositivity. PMID- 23735415 TI - Point-of-care testing for coeliac disease: primary care diagnostic technology update. PMID- 23735416 TI - Quantitative profiling and identification of plasma proteins of spinocerebellar ataxia type 2 patients. AB - BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) is an autosomal-dominant hereditary ataxia characterized by progressive gait and limb ataxia, dysarthria, slow saccades, neuropathy and dementia. The expansion of trinucleotide CAG repeats in the coding region of the ATXN-2 gene leads to expanded polyglutamine stretch in the mutated protein which causes neuronal death. OBJECTIVE: In this study, we investigated the blood plasma of SCA2 patients to find protein biomarkers. METHODS: Thirty-two ataxia patients clinically suspected for SCA2 were evaluated by the International Co-operative Ataxia Rating Scale followed by genetic analysis using PCR. Plasma proteomics of SCA2 patients and age- and gender-matched healthy controls was done using 2D-difference in-gel electrophoresis, LC-MS/MS and Western blot. RESULTS: Genetic analysis confirmed 10 of 32 suspected SCA2 patients. Proteomic data revealed nine differentially expressed proteins in SCA2. These proteins find good association with oxidative stress, calcium-dependent apoptosis, neuropathy, and cognitive impairment in SCA2 patients. Interestingly, the elevated levels of the voltage-dependent calcium channel gamma-3 subunit showed a direct correlation with calcium-generated apoptosis of Purkinje cells. The cognitive deficit, a common symptom in SCA2 patients, seems to correlate with decreased levels of transthyretin and retinol binding protein-4. CONCLUSIONS: Some of these identified proteins in SCA2 can be useful for therapeutic, diagnostic and prognostic purposes. PMID- 23735417 TI - Special section dedicated to The Sixth q-bio Conference: meeting report and preface. PMID- 23735418 TI - Altered vascular structure and wave reflection in hypertensive women with low magnesium levels. AB - Magnesium has been implicated in the pathogenesis of hypertension, but the role of its intracellular levels in cardiovascular diseases is not clear yet. We investigated the relationships of low concentrations of serum magnesium (sMg) and intracellular Mg (iMg) with clinical and vascular parameters. Thiazide-treated hypertensive women were separated into two groups according to lower (<2.0 mg/dL) or normal (>=2.0 mg/dL) sMg concentrations. The same patients were later divided according to lower (<3.75 mg/dL erythrocytes) and normal (>=3.75 mg/dL erythrocytes) iMg concentrations. Carotid ultrasound, radial applanation, and peripheral arterial tonometry were performed in all patients. Low sMg levels were associated with increased Framingham Risk Score (16% +/- 3% vs 11% +/- 1%; P = .024), higher systolic (148 +/- 7 vs 135 +/- 3 mm Hg; P = .049) and diastolic (91 +/- 3 vs 84 +/- 2 mm Hg; P = .042) blood pressure, and carotid intima-media thickness (0.92 +/- 0.09 vs 0.76 +/- 0.02 mm; P = .023). Low concentrations of iMg were related to wave reflection parameters such as increased augmentation pressure (20 +/- 2 vs 15 +/- 1 mm Hg; P = .032) and augmentation index (43% +/- 2% vs 33% +/- 2%; P = .004). In conclusion, in these diuretic-treated hypertensive women, low sMg was associated with higher blood pressure values, and more intense wave reflection were closely linked to iMg depletion, processes that might contribute to hypertension and other cardiovascular risk factors. PMID- 23735419 TI - Independent and interactive effects of blood pressure and cardiac function on brain volume and white matter hyperintensities in heart failure. AB - BACKGROUND: Reduced systemic perfusion and comorbid medical conditions are key contributors to adverse brain changes in heart failure (HF). Hypertension, the most common co-occurring condition in HF, accelerates brain atrophy in aging populations. However, the independent and interactive effects of blood pressure and systemic perfusion on brain structure in HF have yet to be investigated. METHODS: Forty-eight older adults with HF underwent impedance cardiography to assess current systolic blood pressure status and cardiac index to quantify systemic perfusion. All participants underwent brain magnetic resonance imaging to quantify total brain, total and subcortical gray matter volume, and white matter hyperintensities (WMH) volume. RESULTS: Regression analyses adjusting for medical and demographic factors showed decreased cardiac index was associated with smaller subcortical gray matter volume (P < .01), and higher systolic blood pressure predicted reduced total gray matter volume (P = .03). The combination of higher blood pressure and lower cardiac index exacerbated WMH (P = .048). CONCLUSIONS: Higher blood pressure and systemic hypoperfusion are associated with smaller brain volume, and these factors interact to exacerbate WMH in HF. Prospective studies are needed to clarify the effects of blood pressure on the brain in HF, including the role of long-term blood pressure fluctuations. PMID- 23735420 TI - Dietary potassium: a key mediator of the cardiovascular response to dietary sodium chloride. AB - Potassium and sodium share a yin/yang relationship in the regulation of blood pressure (BP). BP is directly associated with the total body sodium and negatively correlated with the total body potassium. Epidemiologic, experimental, and clinical studies have shown that potassium is a significant regulator of BP and further improves cardiovascular outcomes. Hypertensive cardiovascular damage, stroke, and stroke-related death are accelerated by salt intake but might be curbed by increasing dietary potassium intake. The antihypertensive effect of potassium supplementation appears to occur through several mechanisms that include regulation of vascular sensitivity to catecholamines, promotion of natriuresis, limiting plasma renin activity, and improving endothelial function. In the absence of chronic kidney disease, the combined evidence suggests that a diet rich in potassium content serves a vasculoprotective function, particularly in the setting of salt-sensitive hypertension and prehypertension. PMID- 23735421 TI - Novel poxvirus in big brown bats, northwestern United States. AB - A wildlife hospital and rehabilitation center in northwestern United States received several big brown bats with necrosuppurative osteomyelitis in multiple joints. Wing and joint tissues were positive by PCR for poxvirus. Thin-section electron microscopy showed poxvirus particles within A-type inclusions. Phylogenetic comparison supports establishment of a new genus of Poxviridae. PMID- 23735423 TI - Dyslipidemia and fasting glucose impairment among HIV patients three years after the first antiretroviral regimen in a Brazilian AIDS outpatient clinic. AB - OBJECTIVE: To evaluate the cumulative incidence of dyslipidemia and fasting glucose impairment three years after initiating the first antiretroviral (ART) regimen and the association with the type of ART regimen in an AIDS outpatient clinic in Brazil. METHODS: Retrospective cohort of HIV-1 infected patients attending an outpatient HIV clinic in Vitoria, Brazil, between January/2010 and May/2011. Data, including blood pressure, dyslipidemia (high total cholesterol and low HDL-C), fasting glucose, and cardiovascular risk by Framingham Risk Score were abstracted from medical records from clinic visits six months prior and three years after starting ART. We assessed independent associated factors for dyslipidemia using multiple logistic regression. RESULTS: Four hundred and ninety eight patients on ART were studied. Median age was 45 years (interquartile range (IQR): 37-52), and median time since HIV diagnosis was 7.7 years (IQR: 3.8-10.0). The proportion of patients with dyslipidemia was 22.3% (95% CI: 18.6-25.9%) 36 months after ART initiation. Triglycerides levels >150mg/dL (55.2% vs. 25.4%, p=0.021) and high fasting glucose (5.8% vs. 2.3%, p=0.034) were diagnosed more frequently after ART use when compared to baseline values. Multiple logistic regression analysis has shown dyslipidemia to be associated with lopinavir/r use [OR=1.74 (95% CI: 1.12-2.86)]. CONCLUSION: These data show high chance of dyslipidemia after initiation of ART. Long-term follow-up will help identify the impact of ART on cardiovascular risk. PMID- 23735424 TI - Tachycardic responses to stimulation of beta-adrenoceptors in the brain parenchyma in conscious rats. AB - This study aimed to investigate how stimulation of beta-adrenoceptors in the anteroventral third ventricular region (AV3V; a pivotal forebrain area for autonomic functions) and other brain regions affects heart rate (HR) in conscious rats. Topical injections of the beta-adrenergic agonist isoproterenol (Isop) into the AV3V caused dose-related and reversible increases in HR. Only its highest dose utilized significantly affected blood pressure (BP), inducing a decrease. The tachycardia due to AV3V Isop lasted significantly longer than that elicited by hypotension, and was inhibited by AV3V administration of the beta-adrenergic antagonist propranolol or systemic infusion of a ganglion blocker hexamethonium. Plasma noradrenaline indicative of sympathetic nerve activity increased in parallel with rises in HR after the AV3V application of Isop. When Isop was locally injected into various brain regions other than the AV3V, region-related effectiveness in provoking tachycardia was observed that tended to be large in limbic structures and the hypothalamic paraventricular nucleus. No region responded to Isop applications with decreases in HR. These results suggest that beta-adrenoceptors in the AV3V and other brain regions may be able to produce tachycardia by enhancing, at least in part, the efferent sympathetic nerve activity controlling cardiac function. PMID- 23735422 TI - Management options for reducing the release of antibiotics and antibiotic resistance genes to the environment. AB - BACKGROUND: There is growing concern worldwide about the role of polluted soil and water environments in the development and dissemination of antibiotic resistance. OBJECTIVE: Our aim in this study was to identify management options for reducing the spread of antibiotics and antibiotic-resistance determinants via environmental pathways, with the ultimate goal of extending the useful life span of antibiotics. We also examined incentives and disincentives for action. METHODS: We focused on management options with respect to limiting agricultural sources; treatment of domestic, hospital, and industrial wastewater; and aquaculture. DISCUSSION: We identified several options, such as nutrient management, runoff control, and infrastructure upgrades. Where appropriate, a cross-section of examples from various regions of the world is provided. The importance of monitoring and validating effectiveness of management strategies is also highlighted. Finally, we describe a case study in Sweden that illustrates the critical role of communication to engage stakeholders and promote action. CONCLUSIONS: Environmental releases of antibiotics and antibiotic-resistant bacteria can in many cases be reduced at little or no cost. Some management options are synergistic with existing policies and goals. The anticipated benefit is an extended useful life span for current and future antibiotics. Although risk reductions are often difficult to quantify, the severity of accelerating worldwide morbidity and mortality rates associated with antibiotic resistance strongly indicate the need for action. PMID- 23735425 TI - Reliability of the active and passive knee extension test in acute hamstring injuries. AB - BACKGROUND: Hamstring flexibility measurements are of clinical relevance for the prognosis of hamstring injury and for monitoring recovery after such injury. The active knee extension test (AKET) and passive knee extension test (PKET) are proven to be reliable in healthy subjects. Reliability has not been determined in patients with acute hamstring injuries. PURPOSE: The purpose of this study was to determine intertester reliability of the AKET and the PKET in patients with acute hamstring injuries. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: Fifty consecutive athletes with acute hamstring injuries confirmed with magnetic resonance imaging were included in this study. For each subject, 2 testers performed the AKET and the PKET within 5 days after injury. Intraclass correlation coefficient (ICC), standard error of measurement (SEM), and minimal detectable difference (MDD) were determined. RESULTS: In the injured leg, the ICC of the AKET was 0.89 and of the PKET 0.77, the SEM of the AKET was 5.3 degrees and of the PKET 7.6 degrees , and the MDD of the AKET of the 15 degrees and of the PKET 21 degrees . CONCLUSION: Good intertester reliability was found for the AKET and the PKET in injured hamstrings. Thus, both tests can be reliably used to assess flexibility in injured hamstrings, despite pain and discomfort during testing. PMID- 23735426 TI - Quadriceps tendon injuries in national football league players. AB - BACKGROUND: Distal quadriceps tendon tears are uncommon injuries that typically occur in patients older than 40 years of age, and they have a guarded prognosis. Predisposing factors, prodromal findings, mechanisms of injury, treatment guidelines, and recovery expectations are not well described in high-level athletes. HYPOTHESIS: Professional American football players with an isolated tear of the quadriceps tendon treated with timely surgical repair will return to their sport. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Fourteen unilateral distal quadriceps tendon tears were identified in National Football League (NFL) players from 1994 to 2004. Team physicians retrospectively reviewed training room and clinic records, operative notes, and imaging studies for each of these players. Data on each player were analyzed to identify variables predicting return to play. A successful outcome was defined as returning to play in regular-season NFL games. RESULTS: Eccentric contraction of the quadriceps was the most common mechanism of injury, occurring in 10 players. Only 1 player had antecedent ipsilateral extensor mechanism symptoms. Eleven players had a complete rupture of the quadriceps tendon, and 3 had partial tears. There were no associated knee injuries. All ruptures were treated with surgical repair, 1 of which was delayed after failure of nonoperative treatment. Fifty percent of players returned to play in regular-season NFL games. There was a trend toward earlier draft status for those who returned to play compared with those who did not (draft round, 3.1 +/- 2.5 vs. 6.0 +/- 2.9, respectively; P = .073). For those who returned to play, the average number of games after injury was 40.9 (range, 12-92). CONCLUSION: Quadriceps tendon tears are rare in professional American football players, and they usually occur from eccentric load on the extensor mechanism. Prodromal symptoms and predisposing factors are usually absent. Even with timely surgical repair, there is a low rate of return to play in regular season games. There is a trend toward early draft rounds for those who successfully return to play. PMID- 23735427 TI - Financial implications of installing air filtration systems to prevent PRRSV infection in large sow herds. AB - Air filtration systems implemented in large sow herds have been demonstrated to decrease the probability of having a porcine reproductive and respiratory syndrome virus (PRRSV) outbreak. However, implementation of air filtration represents a considerable capital investment, and does not eliminate the risk of new virus introductions. The specific objectives of the study were: 1) to determine productivity differences between a cohort of filtered and non-filtered sow farms; and 2) to employ those productivity differences to model the profitability of filtration system investments in a hypothetical 3000 sow farm. Variables included in the study were production variables (quarterly) from respective herds; air filtration status; number of pig sites within 4.7 km of the farm; occurrence of a PRRSV outbreak in a quarter, and season. For the investment analyses, three Scenarios were compared in a deterministic spreadsheet model of weaned pig cost: (1) control, (2) filtered conventional attic, and (3) filtered tunnel ventilation. Model outputs indicated that a filtered farm produced 5927 more pigs than unfiltered farms. The payback periods for the investments, were estimated to be 5.35 years for Scenario 2 and 7.13 years for Scenario 3 based solely on sow herd productivity. Payback period sensitivity analyses were performed for both biological and financial inputs. The payback period was most influenced by the premium for weaned pig sales price for PRRSV-negative pigs, and the relative proportions of time that filtered vs. unfiltered farms produced PRRSV-negative pigs. A premium of $5 per pig for PRRS-negative weaned pigs reduced the estimated payback periods to 2.1 years for Scenario 2 and 2.8 years for Scenario 3. PMID- 23735428 TI - Molecular characterization of Cryptosporidium isolates from pre-weaned calves in western France in relation to age. AB - Eighteen pre-weaned female calves from a single beef cattle herd in western France were sampled weekly from birth to 21/2 months of age in order to characterize Cryptosporidium oocyst output. 182 fecal samples were screened for the presence of oocysts after concentration using immunofluorescence analysis. DNA was extracted from positive samples and a PCR-RFLP protocol, with the restriction enzyme SspI and MboII, to amplify the partial SSU rRNA gene was performed. For the subtyping of Cryptosporidium parvum, a gp60 PCR was carried out. All animals excreted oocysts at at least one sampling date and 80% of the calves presented a mild diarrhea at at least one occasion, with no mortality. The prevalence of excretion reached 94% when calves were 17-23 days of age. The mean number of oocysts at the peak of excretion (10-16 days) was 5 * 10(5) oocysts per gram of feces. PCR-RFLP analysis was successful for 61 of 84 positive samples: 14 were identified as C. parvum, 15 as Cryptosporidium bovis, and 22 as Cryptosporidium ryanae. Ten mixed infections with all combinations of these species were also identified. Calves excreted the following Cryptosporidium species: C. parvum between 7 and 27 days of age, C. bovis between 11 and 38 days and C. ryanae from 19 to 72 days. The IIaA15G2R1 zoonotic subtype of C. parvum subtype was the only subtype identified. We observed the presence of different Cryptosporidium species depending on the age of the animals. This study showed that C. parvum and C. bovis can infect beef calf neonates at similar levels of oocyst excretion with or without clinical signs and that C. parvum isolates had zoonotic potential. PMID- 23735429 TI - Prolonged incubation period for Cryptococcus gattii infection in cat, Alaska, USA. PMID- 23735430 TI - De novo dup p/del q or dup q/del p rearranged chromosomes: review of 104 cases of a distinct chromosomal mutation. AB - We compiled 104 constitutional de novo or sporadic rearranged chromosomes mimicking recombinants from a parental pericentric inversion in order to comment on their occurrence and parental derivation, meiotic or postzygotic origin, mean parental ages, and underlying pathways. Chromosomes involved were 1-9, 13-18, 20 22, and X (64 autosomes and 40 X chromosomes). In the whole series, mean paternal and maternal ages in cases of paternal (proved or possible; n=29) or maternal (proved or possible; n=36) descent were 31.14 and 28.31 years, respectively. Rearranged X chromosomes appeared to be of paternal descent and to arise through intrachromosomal non-allelic homologous recombination (NAHR), whereas rec-like autosomes were of either maternal or paternal origin and resulted from mechanisms proper of non-recurrent rearrangements. Except for some mosaic cases, most rearranged chromosomes apparently had a meiotic origin. Except for 8 rearranged X chromosomes transmitted maternally, all other cases compiled here were sporadic. Hence, the recurrence risk for sibs of propositi born to euploid parents is virtually zero, regardless of the imbalance's size. In brief, recombinant-like or rea chromosomes are not related to advanced parental age, may (chromosome X) or may not (autosomes) have a parent-of-origin bias, arise in meiosis or postzygotically, and appear to be mediated by NAHR, nonhomologous end joining, and telomere transposition. Because rearranged chromosomes 10, 11, and Y are also on record, albeit just in abstracts or listed in large series, we remark that all chromosomes can undergo this distinct rearrangement, even if it is still to be described for pairs 12 and 19. PMID- 23735431 TI - Does it make sense to measure only the brachial blood pressure? AB - The significant reduction in cardiovascular mortality in the second half of the 20th century, due to an effective battle against high blood pressure, may be considered one of the greatest medical success stories of the past century. However, several epidemiological and clinical studies have recently highlighted that the single acquisition of blood pressure values at brachial level is inadequate to accurately predict the cardiovascular risk of patients with high blood pressure values. Furthermore, some studies suggest the importance of central systolic blood pressure and central pulse pressure (central systolic blood pressure - diastolic blood pressure) as cardiovascular prognostic factors. Central systolic blood pressure and central pulse pressure are able to evaluate the real pressure load imposed on the left ventricle much better than peripheral systolic blood pressure and peripheral pulse pressure. Moreover, the disappearance of the blood pressure amplification phenomenon (i.e. the difference between peripheral and central systolic blood pressure) is a significant predictor of all-cause (including cardiovascular) mortality, independent of age and other standard confounding factors. Thus, the measurement of central arterial pressure provides more precise information on the cardiovascular risk than brachial artery blood pressure measurement. PMID- 23735432 TI - Glucosamine alleviates scopolamine induced spatial learning and memory deficits in rats. AB - INTRODUCTION AND OBJECTIVE: Beneficial effects of glucosamine in spatial learning and memory impairment induced by scopolamine has been evaluated in rats by using Morris water maze. METHODS: Male Wistar rats were randomly divided into control, scopolamine and scopolamine plus glucosamine groups. All injections were given in 5 consecutive days and 30min after each injection, the rats were tested in the Morris water maze test. Escape latency and path length to reach the hidden platform were subjected to analysis of variance [ANOVA]. RESULTS: The rats treated with scopolamine showed increased escape latency and path length to reach the hidden platform compared to control group (P<0.001). Both escape latency and traveled path length to reach the hidden platform in glucosamine treated animals (1 and 2g/kg) were significantly lower (P<0.05 to P<0.001) than in the scopolamine group. CONCLUSION: The results of this study showed that the glucosamine can inhibit scopolamine-induced impairments of spatial learning and memory in rats. Glucosamine might offer a promise in either the prevention or the treatment of neurodegenerative diseases such as Alzheimer's disease. PMID- 23735433 TI - Block-diagonal discriminant analysis and its bias-corrected rules. AB - High-throughput expression profiling allows simultaneous measure of tens of thousands of genes at once. These data have motivated the development of reliable biomarkers for disease subtypes identification and diagnosis. Many methods have been developed in the literature for analyzing these data, such as diagonal discriminant analysis, support vector machines, and k-nearest neighbor methods. The diagonal discriminant methods have been shown to perform well for high dimensional data with small sample sizes. Despite its popularity, the independence assumption is unlikely to be true in practice. Recently, a gene module based linear discriminant analysis strategy has been proposed by utilizing the correlation among genes in discriminant analysis. However, the approach can be underpowered when the samples of the two classes are unbalanced. In this paper, we propose to correct the biases in the discriminant scores of block diagonal discriminant analysis. In simulation studies, our proposed method outperforms other approaches in various settings. We also illustrate our proposed discriminant analysis method for analyzing microarray data studies. PMID- 23735434 TI - Bayesian hierarchical graph-structured model for pathway analysis using gene expression data. AB - In genomic analysis, there is growing interest in network structures that represent biochemistry interactions. Graph structured or constrained inference takes advantage of a known relational structure among variables to introduce smoothness and reduce complexity in modeling, especially for high-dimensional genomic data. There has been a lot of interest in its application in model regularization and selection. However, prior knowledge on the graphical structure among the variables can be limited and partial. Empirical data may suggest variations and modifications to such a graph, which could lead to new and interesting biological findings. In this paper, we propose a Bayesian random graph-constrained model, rGrace, an extension from the Grace model, to combine a priori network information with empirical evidence, for applications such as pathway analysis. Using both simulations and real data examples, we show that the new method, while leading to improved predictive performance, can identify discrepancy between data and a prior known graph structure and suggest modifications and updates. PMID- 23735435 TI - Modeling the DNA copy number aberration patterns in observational high-throughput cancer data. AB - The process of occurrence of genomic aberrations over time in the genetic material of cancer cells reflects the progression of the cancer. Modern technologies like aCGH (array Comparative Genomic Hybridization) and MPS (Massive Parallel Sequencing) provide high-resolution measurements of DNA copy number aberrations, that reveal the full scale of genomic aberrations. A continuous time Markov chain model is proposed to describe the accumulation of aberrations over time. Time however is a latent variable (with the number of aberrations as a proxy). Integrating out time, yields the distribution of the observed DNA copy number data. The model parameters are estimated from high-dimensional DNA copy number data by means of penalized maximum pseudo- and likelihood and method of moments procedures. Having fitted the model, posterior time estimates of the advancement of each sample's cancer are obtained and the most likely locations of a sample's aberrations are predicted. The three estimation methods are compared in a simulation study. The paper closes with an application of the proposed methodology on cancer data. PMID- 23735436 TI - Exploring the issue of failure to fail in a nursing program. AB - A study using a qualitative descriptive design was undertaken to explore the issue of "failure to fail" in a nursing program. Individual in-depth interviews were conducted with nursing university faculty members, preceptors, and faculty advisors (n=13). Content analysis was used to analyze the data. Results indicate that: (a) failing a student is a difficult process; (b) both academic and emotional support are required for students and preceptors and faculty advisors; (c) there are consequences for programs, faculty, and students when a student has failed a placement; (d) at times, personal, professional, and structural reasons exist for failing to fail a student; and (e) the reputation of the professional program can be diminished as a result of failing to fail a student. Recommendations for improving assessment, evaluation, and intervention with a failing student include documentation, communication, and support. These findings have implications for improving the quality of clinical experiences. PMID- 23735437 TI - Resisting, reaching out and re-imagining to independence: LPN's transitioning towards BNs and beyond. AB - Little is known about the process of how nurses transition between vocational training and institutions of higher education. Understanding this process provides educators with the knowledge to support new groups of university students making this transition. Grounded theory (GT) was used to explore and understand this process. Three studies from a 7-year research program were used as data. The analysis led to the generation of a GT illuminating the process of students transitioning from post-LPN to BN. This GT illustrates how students overcome difficulties encountered moving to a more complex nursing role. The students' main concern was a lack of independence. The core variable, which resolves this main concern, and which emerged from the analysis of the data is developing independence. There are three sub-core variables, resisting, reaching out and re-imagining which support this core variable of developing independence. PMID- 23735438 TI - Bridging the gap: clinical practice nursing and the effect of role strain on successful role transition and intent to stay in academia. AB - The shortage of registered nurses is inextricably linked to the shortage of nursing faculty which has resulted in the turning away of over 40,000 qualified students in 2010. One solution to the faculty shortage has been to recruit faculty from clinical practice. This often becomes problematic resulting in intent to leave academia within five years. Possible factors contributing to this action are role ambiguity and role strain. This study, therefore, examined role strain experienced by nursing faculty and the extent to which role strain predicted satisfaction with the role transition and intent to stay in academia. Findings revealed that role strain does exist among nursing faculty. Role ambiguity and self-assessed competency are significant predictors of role strain, and role strain is a significant predictor of satisfaction with the role transition and intent to stay. The study also looked at whether age, education, and experience affected role strain, and they were found to be poor predictors. PMID- 23735439 TI - Analysis and design of sliding mode controller gains for boost power factor corrector. AB - This paper presents a systematic procedure to compute the gains of sliding mode controller based on an optimization scheme. This controller is oriented to drive an AC-DC converter operating in continuous mode with power factor near unity, and in order to improve static and dynamic performances with large variations of reference voltage and load. This study shows the great influence of the controller gains on the global performances of the system. Hence, a methodology for choosing the gains is detailed. The sliding surface used in this study contains two state variables, input current and output voltage; the advantage of this surface is getting reactions against various disturbances-at the power source, the reference of the output, or the value of the load. The controller is experimentally confirmed for steady-state performance and transient response. PMID- 23735440 TI - The impact of prior TURP on radical prostatectomy surgical margins: a multicenter analysis. AB - OBJECTIVE: To analyze positive surgical margins (PSM) after radical prostatectomy (RP) in the overall population and in patients previously treated with transurethral resection of the prostate (TURP). MATERIALS AND METHODS: 2,408 patients treated with RP for clinically localized prostate cancer (PCa) were consecutively enrolled in 135 departments. We correlated PSM rates and all preoperative, surgical and pathological features. We stratified the site of PSM as unique or multifocal. Moreover, we analyzed differences between 75 patients who had undergone previous TURP and the remaining 2,333 patients. RESULTS: In the entire study population, we identified 702 patients with PSM (29%). Using univariate analysis, we reported a significant correlation between overall PSM and prostate-specific antigen (PSA), stage cT, biopsy Gleason score, number of biopsy cores, number of positive cores, percentage of positive cores and nerve sparing approach. PSM proved to be strongly dependent on pT in particular in patients with pT2 PCa. When we compared the data from 75 patients previously treated with TURP and those from 2,333 without previous prostatic surgery, a statistically significant difference in margin localization was found. Moreover, we analyzed the 75 patients mentioned above, stratified in incidental PCa diagnosed at TURP or PCa detected with prostate biopsy for PSA rising during the post-TURP follow-up: no statistical differences were found between the 2 groups regarding margin status, even if PSM were more frequent in incidental PCa with no significance deriving from the stratification for PSM location at the apex or base. CONCLUSION: Men treated with TURP before RP presented an overall incidence of PSM similar to those without previous TURP, but with a higher risk of PSM at the bladder neck and a lower risk of PSM at the prostatic apex. PMID- 23735441 TI - Comprehensive assessment of the genetics and virulence of tick-borne encephalitis virus strains isolated from patients with inapparent and clinical forms of the infection in the Russian Far East. AB - We analyzed the genetics and virulence of 35 strains of TBEV isolated from patients with different forms of the infection living in the southern Far East region of Russia. The results of moleculargenetics studies of the TBEV strains showed that most of the strains that cause inapparent infections form a single cluster (I) with the Oshima 5-10 strain from Japan on the phylogenetic tree. A comparison of the amino acid sequences of the viral polyproteins of the studied strains identified 17 amino acid residues distributed unevenly across the polyprotein that distinctly differed between the clusters of inapparent and virulent strains. We detected additional substitutions in the NS1 and NS5 proteins. These substitutions might influence the pathogenic potential of the strains. Using a model of inbred mice of different ages, we examined the virulence of these strains and showed the different pathogenic potentials of strains belonging to different clusters. PMID- 23735442 TI - Noninvasive assessment of LV contraction patterns using CMR to identify responders to CRT. AB - OBJECTIVES: Type II activation describes the U-shaped electrical activation of the left ventricle (LV) with a line of block in patients with left bundle branch block (LBBB). We sought to determine if a corresponding pattern of contraction could be identified using cardiac magnetic resonance (CMR) cine imaging and whether this predicted response to cardiac resynchronization therapy (CRT). BACKGROUND: U-shaped LV electrical activation in LBBB has been shown to predict favorable response to CRT. It is not known if the degree of electromechanical coupling is such that the same is true for LV contraction patterns. METHODS: A total of 52 patients (48% ischemic) scheduled for CRT implantation prospectively underwent pre-implantation CMR cine analysis using endocardial contour tracking software to generate time-volume curves and contraction propagation maps. These were analyzed to assess the contraction sequence of the LV. The effect of contraction pattern on CRT response in terms of reverse remodeling (RR) and clinical parameters (New York Heart Association functional class, 6-min walk distance and Heart Failure Questionnaire score) was assessed at 6 months. RESULTS: Two types of contraction pattern were identified; homogenous spread from septum to lateral wall (type I, n = 27) and presence of block with a subsequent U shaped contraction pattern (type II, n = 25). Rates of RR in those with a type 2 pattern were significantly greater at 6 months (80% vs. 26%, p < 0.001) as was mean increase in 6-min walk distance (126 +/- 106 m vs. 55 +/- 60 m; p = 0.004). CONCLUSIONS: Cine CMR can identify a U-shaped pattern of contraction which predicts increased echocardiographic and clinical response rates to CRT in patients with LBBB. PMID- 23735443 TI - Survival of patients with superficial esophageal adenocarcinoma after endoscopic treatment vs surgery. AB - BACKGROUND & AIMS: Endoscopic therapy can improve long-term outcomes of patients with superficial esophageal adenocarcinoma (EAC), producing fewer complications than esophagectomy. However, there have been few population-based studies to compare long-term outcomes of patients who received these treatments. We used a large national cancer database to evaluate the outcomes of patients with superficial EAC who underwent endoscopic therapy or surgery. METHODS: We used the Surveillance Epidemiology and End Results database to identify 1618 patients with Tis or T1 N0M0 EAC from 1998-2009. Patients were grouped on the basis of whether they received endoscopic therapy (n = 306) or surgery (n = 1312). Multivariate logistic regression was performed to identify factors associated with endoscopic therapy. We collected survival data through the end of 2009; overall survival and esophageal cancer-specific survival were compared after controlling for relevant covariates. RESULTS: The use of endoscopic therapy increased progressively from 3% in 1998 to 29% in 2009. Factors associated with use of endoscopic therapy included age older than 65 years, diagnosis in 2006-2009 vs 1998-2001, and the absence of submucosal invasion. Overall survival after 5 years was higher in the surgery group than in the endoscopic therapy group (70% vs 58%, respectively). After adjusting for patient and tumor factors, patients treated by endoscopy had similar overall survival times (hazard ratio, 1.21; 95% confidence interval, 0.92 1.58) and esophageal cancer-specific survival times (hazard ratio, 0.74; 95% confidence interval, 0.49-1.11). CONCLUSION: In a population-based analysis, the use of endoscopic therapy for superficial EAC tended to increase from 1998-2009. Long-term survival of patients with EAC did not appear to differ between those who received endoscopic therapy and those treated with surgery. PMID- 23735444 TI - Hepatocellular carcinoma and hepatitis B virus: family matters. PMID- 23735445 TI - Multiple elevated red spots in a woman with nausea, altered stools, and weight loss. PMID- 23735446 TI - Reply: To PMID 23220165. PMID- 23735447 TI - New anticoagulant and antiplatelet agents: a primer for the gastroenterologist. AB - A large number of patients worldwide receive anticoagulant and antiplatelet agents, collectively known as antithrombotic agents. Several new anticoagulants and antiplatelet agents recently were approved for use. Gastroenterologists may be unfamiliar with the mechanism of action, indications for use, and pharmacokinetics of these newer drugs. In patients undergoing elective and urgent endoscopic procedures, clinicians must be familiar with these medications to optimize outcomes. When the decision is made to continue the newer antithrombotic agents for elective procedures, the clinician must understand the risk that these agents may impart on procedural-induced bleeding. Finally, it is important to understand how to manage these agents in the presence of acute gastrointestinal bleeding. In this article the use of newer antithrombotic agents is reviewed. PMID- 23735449 TI - Acute exacerbation among chronic hepatitis C patients: tip of the iceberg that deserves more attention. PMID- 23735448 TI - Diet and upper gastrointestinal cancers: in search of dark matter. PMID- 23735450 TI - The economic burden of traumatic spinal cord injury in Canada. AB - INTRODUCTION: The purpose of this study is to estimate the current lifetime economic burden of traumatic spinal cord injury (tSCI) in Canada from a societal perspective, including both direct and indirect costs, using an incidence-based approach. METHODS: Available resource use and cost information for complete/incomplete tetraplegia and paraplegia was applied to the estimated annual incidence of tSCI, by severity, in Canada. RESULTS: The estimated lifetime economic burden per individual with tSCI ranges from $1.5 million for incomplete paraplegia to $3.0 million for complete tetraplegia. The annual economic burden associated with 1389 new persons with tSCI surviving their initial hospitalization is estimated at $2.67 billion. CONCLUSION: While the number of injuries per year in Canada is relatively small, the annual economic burden is substantial. PMID- 23735451 TI - Quantifying Canadians' use of the Internet as a source of information on behavioural risk factor modifications related to cancer prevention. AB - INTRODUCTION: The purpose of this study was to quantify the frequency and timing of Canadians' Internet searches for information on modifying cancer prevention related behavioural risk factors. METHODS: We used the Google AdWords Keyword tool to estimate the number of Internet searches in Canada from July 2010 to May 2011 for content associated with the keywords "physical activity / exercise," "healthy eating / weight loss" and "quit smoking." RESULTS: For "physical activity / exercise," 663 related keywords resulted in 117 951 699 searches. For "healthy eating / weight loss," 687 related search terms yielded 98 277 954 searches. "Quit smoking" was associated with 759 related keywords with 31 688 973 searches. All search patterns noticeably peaked in January 2011. CONCLUSION: Many Canadians are actively searching for information on the Internet to support health behaviour change associated with cancer prevention, especially during the month of January. To take advantage of this opportunity, key stakeholders in cancer prevention need to identify knowledge translation priorities and work with health agencies to develop evidence-based strategies to support Internet facilitated behaviour change. PMID- 23735452 TI - Emergency department presentations for injuries associated with inflatable amusement structures, Canada, 1990-2009. AB - INTRODUCTION: Inflatable amusement attractions, structures that are air-supported and inflated by a blower, have recently gained popularity. The purpose of this study was to describe the epidemiology of inflatable-related injuries presenting to Canadian emergency departments. METHODS: The Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP) is an injury and poisoning surveillance system presently operating in the emergency departments of all 11 pediatric and 4 general hospitals across Canada. The CHIRPP was searched for cases of injuries associated with commercial inflatable amusement structures. RESULTS: Overall, 674 cases were identified over the 20-year surveillance period, during which time the average annual percent increase was 24.6% (95% CI: 21.6, 27.7). Children aged 2 to 9 years were the most frequently injured (59.3/100,000 CHIRPP cases), and fractures accounted for 34.5% of all injuries. DISCUSSION: A sharp increase in emergency department visits for injuries associated with commercial inflatable amusement structures has been observed in recent years. Injury mechanisms could be mitigated by product design modifications and stricter business operational practices. PMID- 23735453 TI - Evolution of the determinants of chronic liver disease in Quebec. AB - INTRODUCTION: Chronic liver diseases (CLDs) are a worldwide problem. Morbidity and mortality due to CLDs could be avoided or reduced by targeting the main risk factors, including obesity and alcohol use. METHODS: To describe the evolution of the key determinants of CLDs in Quebec, we studied the trends in obesity, alcohol use, viral hepatitis B and C, CLD mortality and hospitalization rates, and the liver cancer incidence rate between January 1, 1981, and December 31, 2009. RESULTS: We observed an increase in the obesity indicators among young men and in alcohol use among adolescent girls and middle-aged women. The overall hepatitis B and C incidence and CLD mortality rates are falling. However, liver cancer and mortality rates, especially among men and the elderly, are on the rise. CONCLUSION: These results highlight the importance of targeted public health interventions and of maintaining or improving access to care for CLDs. PMID- 23735454 TI - Deprivation and food access and balance in Saskatoon, Saskatchewan. AB - INTRODUCTION: We explored food access and balance in Saskatoon, Saskatchewan, Canada in relation to material and social deprivation. METHODS: We mapped the location of all large supermarkets and fast food retailers in Saskatoon. Supermarket accessibility index scores and food balance scores were compared to material and social deprivation indexes to determine significant associations. RESULTS: Our results indicate that the poorest access to supermarkets occurred in areas west of the South Saskatchewan River and also in suburban areas around the perimeter of the city. Areas west of the river are some of the most deprived areas in the city. Saskatoon's mean food balance ratio of 2.3 indicates that access favours fast food. However, we did not find a clear pattern or clear socio economic gradient for most measures. CONCLUSION: This study highlights the importance of contextual studies of food access. This study also highlighted a number of other issues that should be explored in the Saskatoon context such as individual-level food consumption patterns, mobility, temporal dimensions of food access and economic access as well as interventions that could improve food access in the city. PMID- 23735455 TI - Identifying cases of congestive heart failure from administrative data: a validation study using primary care patient records. AB - INTRODUCTION: To determine if using a combination of hospital administrative data and ambulatory care physician billings can accurately identify patients with congestive heart failure (CHF), we tested 9 algorithms for identifying individuals with CHF from administrative data. METHODS: The validation cohort against which the 9 algorithms were tested combined data from a random sample of adult patients from EMRALD, an electronic medical record database of primary care physicians in Ontario, Canada, and data collected in 2004/05 from a random sample of primary care patients for a study of hypertension. Algorithms were evaluated on sensitivity, specificity, positive predictive value, area under the curve on the ROC graph and the combination of likelihood ratio positive and negative. RESULTS: We found that that one hospital record or one physician billing followed by a second record from either source within one year had the best result, with a sensitivity of 84.8% and a specificity of 97.0%. CONCLUSION: Population prevalence of CHF can be accurately measured using combined administrative data from hospitalization and ambulatory care. PMID- 23735456 TI - Pain and health-related quality of life in people with chronic leg ulcers. AB - INTRODUCTION: Venous leg ulceration is associated with pain and poor health related quality of life (HRQL). The purpose of this study was to identify demographic and clinical characteristics associated with pain and decreased HRQL in patients with active venous ulcers. METHODS: Baseline data were combined from two trials that took place between 2001 and 2007 (n = 564). Pain was measured using the Numeric Pain Scale (NPS), and HRQL was measured using the Medical Outcomes Survey 12-item Short Form (SF-12), which generates a Physical (PCS) and Mental Component Summary (MCS). Analyses included logistic and linear regression (for pain and HRQL, respectively). RESULTS: Mean age was 66.5 years; 47% were male. Median NPS score was 2.2 (out of 10) and mean PCS and MCS scores were 38.0 and 50.5, respectively (scores are standardized to a mean of 50 representing average HRQL). Younger age, living with others, and arthritis were associated with pain. Poorer PCS was associated with being female, venous/mixed ulcer etiology, larger ulcers, longer ulcer duration, cardiovascular disease, arthritis and higher pain intensity. Poorer MCS was associated with younger age, longer ulcer duration, comorbidity and higher pain intensity. CONCLUSION: Research is needed to test strategies to reduce pain and possibly improve HRQL in high risk groups. PMID- 23735457 TI - Injuries related to consumer products in Canada--a systematic literature review. AB - OBJECTIVES: To conduct a systematic literature review of injury related to certain consumer products. METHODS: Forty-six empirical research reports along with 32 surveillance reports from the Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP) were examined to determine the approximate number of injuries associated with a given product per year and any trends in frequency. Percentages of injuries that: (1) resulted in hospitalization, (2) appeared to result from the product itself and (3) were associated with risky or inappropriate use and/or non-use of a helmet were also extracted from the reports. RESULTS: Outdoor play and sports equipment appear to be associated with the greatest numbers of injuries. A relatively high proportion of injuries appear to result from inappropriate or risky use of a product and/or inadequate safety precautions. CONCLUSION: This review identified the following areas of concern regarding consumer products and injuries: lack of helmet use by people using in line skates, sleds, snowboards, downhill skis and personal-powered watercraft; operation of all-terrain vehicles (ATVs) and snowmobiles by alcohol-impaired people; operation of snowmobiles at excessive speeds; poor design of playground equipment; and unsafe storage and use of matches. PMID- 23735458 TI - Cross-Canada forum--National Population Health Study of Neurological Conditions in Canada. PMID- 23735459 TI - Status report--enhancing the Canadian Best Practices Portal. PMID- 23735460 TI - Planning practice in support of economically and environmentally sustainable roads in floodplains: the case of the Mekong delta floodplains. AB - Road development in relatively undisturbed floodplain systems, such as the floodplains of the Mekong River, will impact hydraulics and interrupt the natural flow of water. This affects the ecology and environment, and the livelihoods of people who depend on fishing and agriculture. On the other hand, floods can severely damage road infrastructure in years with large floods and can cause high annual maintenance costs. Improving road development practices in floodplains is a complex, multidimensional task involving hydraulic and geotechnical analysis, ecosystem analysis, socio-economic analysis, policy analysis, etc. This paper analyses the planning practice of road development and rehabilitation and how this practice can be improved in support of economically and environmentally sustainable roads in floodplains. It is concluded that although ample technical, planning and environmental assessment guidelines exist, guidelines need updating to address cumulative impacts at floodplain level and factors hampering the implementation in guidelines should be addressed in the guideline design (process). PMID- 23735461 TI - Influence of volatile fatty acid concentration stability on anaerobic degradation of linear alkylbenzene sulfonate. AB - Linear alkylbenzene sulfonate (LAS) is an anionic surfactant used in cleaning products, which is usually found in wastewaters. Despite the greater LAS removal rate related to a lower concentrations of volatile fatty acids (VFA), the influence of different ranges of VFA on LAS degradation is not known. LAS degradation was evaluated in upflow anaerobic sludge blanket (UASB) and expanded granular sludge bed (EGSB) reactors at different ranges of VFA concentrations. The reactors were fed with a synthetic wastewater containing LAS (14 mg/L). A greater LAS removal rate (40-80%) was related to the lower and narrower range of acetic acid concentration (1-22 mg/L) in the EGSB reactor. In the UASB reactor, the acetic acid concentrations presented a wider range (2-45 mg/L), and some low LAS removal rates (around 20-25%) were observed even at low acetic acid concentrations (<10 mg/L). The high recirculation rate in the EGSB reactor improved substrate-biomass contact, which resulted in a narrower range of VFA and greater LAS removal rate. PMID- 23735463 TI - Birth outcome measures and maternal exposure to heavy metals (lead, cadmium and mercury) in Saudi Arabian population. AB - This cross-sectional study was conducted to assess the association between exposure to heavy metals (lead, cadmium and mercury) during pregnancy and birth outcomes in 1578 women aged 16-50 years who delivered in Al-Kharj hospital, Saudi Arabia, in 2005 and 2006. The levels of lead, cadmium and mercury were measured in umbilical cord blood, maternal blood and the placenta. Outcome variables were anthropometric measures taken at birth, along with the risk of being small-for gestational age (SGA). We selected the 10th percentile as the cutoff for dichotomizing measures of birth outcome. Cadmium, despite its partial passage through the placenta had the most prominent effect on several measures of birth outcome. After adjustment for potential confounders, logistic regression models revealed that crown-heel length (p=0.034), the Apgar 5-minute score (p=0.004), birth weight (p=0.015) and SGA (p=0.049) were influenced by cadmium in the umbilical cord blood. Significant decreases in crown-heel length (p=0.007) and placental thickness (p=0.022) were seen with higher levels of cadmium in maternal blood. As placental cadmium increased, cord length increased (p=0.012) and placental thickness decreased (p=0.032). Only lead levels in maternal blood influenced placental thickness (p=0.011). Mercury in both umbilical cord and maternal blood was marginally associated with placental thickness and placental weight, respectively. Conversely, placental mercury levels significantly influenced head circumference (p=0.017), the Apgar 5-minute score (p=0.01) and cord length (p=0.026). The predictions of these models were further assessed with the area under the curve (AUC) of the receiver operating curves (ROCs), which were modest (larger than 0.5 and smaller than 0.7). The independence of gestational age or preterm births on the observed effect of metals on some measures of birth outcome, suggested detrimental effects of exposure on fetal development. The magnitude of the estimated effects might not necessarily be of clinical significance for infants but may have a considerable public-health relevance given the high prevalence of exposure to heavy metals. Further research should be conducted to confirm these findings and to evaluate their long-term risks, if any. PMID- 23735462 TI - Polycyclic aromatic hydrocarbons and their quinones modulate the metabolic profile and induce DNA damage in human alveolar and bronchiolar cells. AB - The release of particulate pollutants into the air through burning of coal, crude oil, diesel, coal tar, etc. raises concerns of potential health hazards to the exposed human population. Polycyclic aromatic hydrocarbons (PAHs) are major toxic constituents of particulate matter (PM), which upon ingestion get metabolized to even more toxic metabolites such as quinones. The PAHs levels were assessed in both respirable particulate matter (RSPM, <10MUM size) and suspended particulate matter (SPM, >10MUM size) of urban ambient air (UAA) and that of major contributors viz. diesel exhaust particles (DEPs) and coal tar combustions emissions (CTCE). Seven US Environmental Protection Agency (USEPA) prioritized PAHs in RSPM and 10 in SPM were detected in UAA. Ten and 15 prioritized PAHs, respectively, were also detected in diesel exhaust particles (DEP) and coal tar combustion emission (CTCE) evidencing their release in the air. These PM associated PAHs for UAA, DEP and CTCE showed significant increase (p<0.05) in mutagenicity and mammalian genotoxicity in the order CTCE>DEP>UAA. Human lung alveolar (A549) and bronchiolar (BEAS-2B) cells when treated with PAH-metabolites viz. 1,4-benzoquinone (1,4-BQ), hydroquinone (HQ), 1,2-naphthoquinone (1,2-NQ), 1,4-naphthoquinone (1,4-NQ) and 9,10-phenanthroquinone (9,10-PQ) showed metabolic modulation in these cell lines with significant depletion of principal cellular metabolites viz. NADP, uracil, asparagines, glutamine, and histidine and accumulation of di-methyl amine and beta-hydroxybutyrate, identified using (1)H NMR spectroscopy. These results suggest that PAH-quinones induce genotoxic effects by modulating the metabolic machinery inside the cells by a combined effect of oxidative stress and energy depletion. Our data for metabolic profiling of human lung cells could also help in understanding the mechanism of toxicity of other xenobiotics. PMID- 23735464 TI - Capillary-based enzyme-linked immunosorbent assay for highly sensitive detection of thrombin-cleaved osteopontin in plasma. AB - In this study, a highly sensitive capillary-based enzyme-linked immunosorbent assay (ELISA) has been developed for the analysis of picomolar levels of thrombin cleaved osteopontin (trOPN), a potential biomarker for ischemic stroke, in human plasma. Using a square capillary coated with 8.5 MUg/ml anti-human trOPN capture antibody for ELISA, the linear range obtained was 2 to 16 pM trOPN antigen. This concentration range was in the detection window of trOPN antigen in plasma samples. Compared with the conventional microplate-based ELISA, the current capillary technique significantly reduced the amounts of reagent from milliliter to microliter, reduced the analysis time from 8 to 3 h, and had a better sensitivity and detection limit performance from approximately 50 pM down to 2 pM of trOPN antigen. These results indicate that this capillary-based immunoassay is a potential tool for biomarker detection and may be useful in clinical trials and medical diagnostic applications. PMID- 23735466 TI - Treatment of neuropathic pain in acute intermittent porphyria with gabapentin. PMID- 23735465 TI - Ulcerative colitis and perfluorooctanoic acid (PFOA) in a highly exposed population of community residents and workers in the mid-Ohio valley. AB - BACKGROUND: Little is known about environmental determinants of autoimmune diseases. OBJECTIVES: We studied autoimmune diseases in relation to level of exposure to perfluorooctanoic acid (PFOA), which was introduced in the late 1940s and is now ubiquitous in the serum of residents of industrialized countries. METHODS: In 2008-2011 we interviewed 32,254 U.S. adults with high serum PFOA serum levels (median, 28 ng/mL) associated with drinking contaminated water near a chemical plant. Disease history was assessed retrospectively from 1952 or birth (if later than 1952) until interview. Self-reported history of autoimmune disease was validated via medical records. Cumulative exposure to PFOA was derived from estimates of annual mean serum PFOA levels during follow-up, which were based on plant emissions, residential and work history, and a fate-transport model. Cox regression models were used to estimate associations between quartiles of cumulative PFOA serum levels and the incidence of autoimmune diseases with >= 50 validated cases, including ulcerative colitis (n = 151), Crohn's disease (n = 96), rheumatoid arthritis (n = 346), insulin-dependent diabetes (presumed to be type 1) (n = 160), lupus (n = 75), and multiple sclerosis (n = 98). RESULTS: The incidence of ulcerative colitis was significantly increased in association with PFOA exposure, with adjusted rate ratios by quartile of exposure of 1.00 (referent), 1.76 (95% CI: 1.04, 2.99), 2.63 (95% CI: 1.56, 4.43), and 2.86 (95% CI: 1.65, 4.96) (ptrend < 0.0001). A prospective analysis of ulcerative colitis diagnosed after the baseline 2005-2006 survey (n = 29 cases) suggested a positive but non-monotonic trend (ptrend = 0.21). DISCUSSION: To our knowledge, this is the first study of associations between this common environmental exposure and autoimmune diseases in humans. We found evidence that PFOA is associated with ulcerative colitis. PMID- 23735467 TI - A conceptual framework for the evolutionary origins of multicellularity. AB - The evolution of multicellular organisms from unicellular counterparts involved a transition in Darwinian individuality from single cells to groups. A particular challenge is to understand the nature of the earliest groups, the causes of their evolution, and the opportunities for emergence of Darwinian properties. Here we outline a conceptual framework based on a logical set of possible pathways for evolution of the simplest self-replicating groups. Central to these pathways is the recognition of a finite number of routes by which genetic information can be transmitted between individual cells and groups. We describe the form and organization of each primordial group state and consider factors affecting persistence and evolution of the nascent multicellular forms. Implications arising from our conceptual framework become apparent when attempting to partition fitness effects at individual and group levels. These are discussed with reference to the evolutionary emergence of individuality and its manifestation in extant multicellular life-including those of marginal Darwinian status. PMID- 23735468 TI - Esmolol administration in patients with VV ECMO: why not? PMID- 23735469 TI - Incorporating oliguria into the diagnostic criteria for acute kidney injury after on-pump cardiac surgery: impact on incidence and outcomes. AB - OBJECTIVES: Consensus definitions represent an important step toward defining the epidemiology of acute kidney injury (AKI). However, the oliguric component of these definitions remains of uncertain impact and utility after cardiac surgery. The authors sought to define the specific impact of oliguric criteria, both alone and in combination with serum creatinine criteria, on the observed incidence of AKI and associated adverse outcomes following adult cardiac surgery. DESIGN: Retrospective observational study over a 1-year period. SETTING: Academic medical institution. PARTICIPANTS: A total of 311 adult patients undergoing elective valve and/or coronary artery bypass graft surgery with cardiopulmonary bypass. INTERVENTIONS: No interventions were performed as part of the study. MEASUREMENTS AND MAIN RESULTS: Hourly urine output and daily serum creatinine were recorded in the 2 days following surgery. AKI was defined by Acute Kidney Injury Network oliguric and serum creatinine criteria. Defined by serum creatinine criteria alone, the incidence of AKI was 17.7% and was associated strongly with in hospital mortality (odds ratio 6.6, 95% confidence interval 1.4-30.5, p = 0.02) and renal replacement therapy (odds ratio 12.7, 95% confidence interval 2.4-67.3, p = 0.003) as well as time to discharge from the intensive care unit and hospital. Defined by oliguric criteria alone through 48 hours following surgery, the incidence of AKI dramatically increased to 55.6% but was not associated with mortality, renal replacement therapy, or time to discharge. CONCLUSIONS: Acute Kidney Injury Network oliguric criteria applied over 48 hours after surgery dramatically increased the measured incidence of AKI after cardiac surgery, but was not associated with adverse outcomes. PMID- 23735470 TI - Plasma PTX3 levels in sickle cell disease patients, during vaso occlusion and acute chest syndrome (data from Saudi population). AB - BACKGROUND: Sickle cell disease (SCD) is a chronic, incurable hereditary disease. The vaso-occlusive crisis (VOC) is the most frequently occurring acute complication in sickle cell patients and accounts for the majority of SCD-related hospital admissions. Another major complication is the potentially fatal acute chest syndrome (ACS). The prototypic long pentraxin-3 (PTX3), an acute phase protein and a key component of innate immunity, is linked to ischemia-induced inflammation, a condition incriminated in SCD complications. AIM: To investigate the expression of PTX3 in stable SCD and VOC patients and to assess its relation to the development and progression of ACS. SUBJECTS AND METHODS: We conducted this study on 160 patients with confirmed SCD (20 stable SCD and 140 in VOC), and 10 healthy age- and sex-matched controls. Patients were diagnosed as SCD by high performance liquid chromatography. PTX3 levels were assessed using enzyme-linked immunosorbant assay. RESULTS: In the stable state, all 20 SCD patients had PTX3 levels (range = 0.9-2.1 ng/ml; median = 1.1) comparable to those of healthy controls (range = 0.8-2.0 ng/ml; median = 1.0) (P > 0.05). During the VOC, plasma PTX3 significantly increased (range = 8.7-37.2 ng/ml; median = 22.3) (P < 0.01). Out of 140 VOC patients, 15 (10.7%) developed ACS and four required mechanical ventilation, of which two died. The median plasma level of PTX3 (22.3 ng/ml) was set as a cut-off value to stratify patients into low- and high-PTX3 expressers. Of the 140 VOC patients, 43 (30.7%) had PTX3 levels >22.3 ng/ml, of these, 13 patients developed ACS (13/43; 30.2%); of the remaining 97 patients who had PTX3 <=22.3 ng/ml, only two patients (2/97; 2.1%) progressed to ACS, with a further increment in PTX3 in all of them. PTX3 levels were correlated with length of hospital stay in VOC patients and markers of lung injury in ACS patients. CONCLUSION: PTX3 levels were higher in SCD patients in VOC, being associated with longer hospital stay. Higher initial PTX3 concentrations were related to the development of ACS with a further increase in PTX3 levels observed upon progression to ACS. Thus, PTX3 could be used as a subjective method to predict occurrence and severity of SCD acute complications. PMID- 23735471 TI - Prostate-sparing radical cystectomy for selected patients with bladder cancer. AB - OBJECTIVES: To review the current literature about prostate-sparing radical cystectomy (PSRC) and its potential for management of a selected population of patients with bladder cancer. MATERIALS AND METHODS: The PubMed, EMBASE and Scopus databases were searched for the key words 'prostate', 'sparing' and 'cystectomy' between 1984 and 2012. Articles in English, French and German were considered relevant for review. Institutional experience with this procedure was also included. RESULTS: PSRC remains a controversial procedure for the treatment of patients harboring bladder carcinoma, mainly due to insufficient knowledge of clear indications and/or contraindications. Experience with PSRC is still limited to very few referral centers and there is a lack of large series with long-term outcomes. The potential for excellent functional outcomes must be carefully balanced against inconsistent oncological results. CONCLUSIONS: PSRC may become an option for carefully selected and extensively informed patients. Suggestions for possible indications and contraindications are presented. PMID- 23735472 TI - Transulnar compared with transradial artery approach as a default strategy for coronary procedures: a randomized trial. The Transulnar or Transradial Instead of Coronary Transfemoral Angiographies Study (the AURA of ARTEMIS Study). AB - BACKGROUND: The ulnar artery is rarely selected for coronary angiography or percutaneous coronary intervention despite the expanding use of the transradial approach. We aimed to establish noninferiority of a default transulnar relative to transradial approach in terms of feasibility and safety. METHODS AND RESULTS: This was a prospective, randomized, multicenter, parallel-group study involving 902 patients at 5 sites eligible to undergo diagnostic coronary angiography and percutaneous coronary intervention. Patients were randomized in a 1:1 ratio to either transradial approach (reference intervention) or transulnar approach (experimental intervention) regardless of the Allen test results. The primary end point was a composite of cross-over to another arterial access, major adverse cardiovascular events, and major vascular events of the arm at 60 days. The study was prematurely terminated after the first interim analysis because of inferiority of the transulnar approach. Although the difference in the primary end point became inconclusive after adjustment for operator clustering (24.30%; 99.99% confidence interval [CI], -7.98% to 56.58%; P=0.03 at alpha=0.0001), need for cross-over in the transulnar group remained inferior to transradial access site with a difference of 26.34% (95% CI, 11.96%-40.69%; P=0.004). CONCLUSIONS: As a result of higher cross-over rates, a first-line transulnar strategy was proven inferior to the transradial approach for coronary procedures. At present, the transulnar route should not be regarded as an acceptable alternative to the transradial access site. PMID- 23735473 TI - Differential effect of ticagrelor versus prasugrel on coronary blood flow velocity in patients with non-ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention: an exploratory study. AB - BACKGROUND: Prasugrel and ticagrelor provide a superior anti-ischemic action than clopidogrel, with some of ticagrelor's benefits possibly attributed to adenosine mediated mechanisms. We aimed to compare the effect of maintenance dose of ticagrelor versus prasugrel on coronary blood flow velocity (CBFV) during increasing doses of intravenously administered adenosine. METHODS AND RESULTS: In a prospective, single-center, single-blind, crossover study, 56 patients with non ST-elevation acute coronary syndrome undergoing percutaneous coronary intervention were randomized to receive either ticagrelor 90 mg BID or prasugrel 10 mg OD with a 15-day treatment period. At the end of each treatment period, CBFV by transthoracic Doppler echocardiography was assessed at baseline and under incremental doses (50 MUg/kg per minute, 80 MUg/kg per minute, 110 MUg/kg per minute, and 140 MUg/kg per minute) of adenosine infusion. Maximal CBFV area under the curve was higher for ticagrelor-treated than for prasugrel-treated patients, with a least squares mean difference of 7.16 (95% confidence interval, 2.61-11.7; P=0.003). Maximal CBFV/baseline CBFV ratio was higher with ticagrelor than prasugrel at 50, 80, and 110 MUg/kg per minute but not at 140 MUg/kg per minute adenosine infusion rate, with mean difference (95% confidence interval) of 0.17 (0.08-0.26; P<0.001), 0.21 (0.02-0.41; P=0.03), 0.24 (0.01-0.47; P=0.04), and 0.14 (-0.12 to 0.4; P=0.3), respectively. CONCLUSIONS: In patients with non-ST elevation acute coronary syndrome undergoing percutaneous coronary intervention, ticagrelor augments CBFV to a greater extent than prasugrel when incremental doses of adenosine are administered. Although exploratory, these results may represent a pleiotropic action of ticagrelor, possibly contributing to its beneficial effects in such patients. PMID- 23735474 TI - Comparison of manual thrombus aspiration with rheolytic thrombectomy in acute myocardial infarction. AB - BACKGROUND: Manual thrombus aspiration (MTA) is completely ineffective in 30% of cases, and the high profiles of the catheters prevent their use in tortuous and calcified vessels. The rheolytic thrombectomy (RT) device has the potential for improved thrombus removal in acute myocardial infarction as compared with MTA. No data exist on the comparison between the 2 techniques. METHODS AND RESULTS: Randomized study, including 80 acute myocardial infarction patients allocated to RT or MTA before infarct artery stenting. Primary end point of this study is residual thrombus burden by optical coherence tomography. Secondary end points are (1) residual thrombolysis in myocardial infarction thrombus grade; (2) postintervention thrombolysis in myocardial infarction flow and myocardial blush; (3) early ST-segment resolution; (4) percentage of malapposed stent struts at 6 months; (5) 6-month restenosis; and (6) 6-month major adverse cardiovascular events. All but 1 patient had residual thrombus after manual aspiration thrombectomy or RT. The number of optical coherence tomography quadrants containing thrombus in MTA arm was higher than in the RT arm, but this difference did not reach significance (median value 65 and 53, respectively; P=0.083). Large residual thrombus was more frequently revealed in the manual aspiration thrombectomy arm (patients with number of quadrants above the median value 60% in the manual aspiration thrombectomy arm and 37% in the RT arm, P=0.039). All markers of reperfusion were better in the RT arm. At 6 months, the percentage of malapposed stent struts in the MTA arm was higher than in the RT arm (2.7+/-4.5% and 0.8+/-1.6%, respectively; P=0.019). CONCLUSIONS: MTA or RT allows only incomplete removal of thrombus in patients with acute myocardial infarction. The primary end point of the study was not met. However, RT as compared with MTA seems to be more effective in thrombus removal and myocardial reperfusion. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01281033. PMID- 23735475 TI - Infective endocarditis after transcatheter pulmonary valve replacement using the Melody valve: combined results of 3 prospective North American and European studies. AB - BACKGROUND: Transcatheter (percutaneous) pulmonary valve (TPV) replacement has emerged as a viable therapy for right ventricular outflow tract conduit dysfunction. Little is known about the incidence, clinical course, and outcome of infective endocarditis (IE) after TPV implant. We reviewed combined data from 3 ongoing prospective multicenter trials to evaluate the experience with IE among patients undergoing TPV replacement using the Melody valve. METHODS AND RESULTS: Any clinical episode reported by investigators as IE with documented positive blood cultures and fever, regardless of TPV involvement, was considered IE. Cases were classified as TPV-related if there was evidence of vegetations on or new dysfunction of the TPV. The 3 trials included 311 patients followed for 687.1 patient-years (median, 2.5 years). Sixteen patients were diagnosed with IE 50 days to 4.7 years after TPV implant (median, 1.3 years), including 6 who met criteria for TPV-related IE: 3 with vegetations, 2 with TPV dysfunction, and 1 with both. The annualized rate of a first episode of IE was 2.4% per patient-year and of TPV-related IE was 0.88% per patient-year. Freedom from TPV-related IE was 97+/-1% 4 years after implant. All patients were treated with intravenous antibiotics, 4 had the valve explanted, and 2 received a second TPV. There was 1 sepsis-related death, 1 patient died of sudden hemoptysis, and 2 patients developed recurrent IE. CONCLUSIONS: Bacterial endocarditis has occurred in all 3 prospective multicenter studies of the Melody valve in North America and Europe. Most cases did not involve the TPV and responded to antibiotics. More data are necessary to understand risk factors in this population. PMID- 23735476 TI - Impact of coronary microvascular function on long-term cardiac mortality in patients with acute ST-segment-elevation myocardial infarction. AB - BACKGROUND: Microvascular function is increasingly being recognized as an important marker of risk in coronary artery disease, and may be accurately assessed by intracoronary Doppler flow velocity measurements. In the setting of ST-segment-elevation myocardial infarction there are limited data regarding the prognostic value of microvascular function in both infarct-related and reference coronary arteries for long-term clinical outcome. We sought to determine the prognostic value of microvascular function, as assessed by Doppler flow velocity measurements, for cardiac mortality after primary percutaneous coronary intervention for acute ST-segment-elevation myocardial infarction. METHODS AND RESULTS: Between April 1997 and August 2000, we included 100 consecutive patients with a first anterior wall ST-segment-elevation myocardial infarction. Immediately after primary percutaneous coronary intervention, intracoronary Doppler flow velocity was measured in the infarct-related artery, to determine coronary flow velocity reserve (CFVR), diastolic deceleration time, and the presence of systolic retrograde flow, as well as in a reference vessel to determine reference vessel CFVR. The primary end point was cardiac mortality at 10-year follow-up. Complete follow-up was obtained in 94 patients (94%). At 10 year follow-up, cardiac mortality amounted to 14%. Cardiac mortality amounted to 5% when reference vessel CFVR was normal (>=2.1), in contrast to 31% when abnormal (<2.1; P=0.001). Reference vessel CFVR <2.1 was associated with a 4.09 increase in long-term cardiac mortality hazard after multivariate adjustment for identified predictors for cardiac mortality (hazard ratio, 4.09; 95% confidence interval, 1.18-14.17; P=0.03) CONCLUSIONS: Microvascular dysfunction, measured by reference vessel CFVR determined after primary percutaneous coronary intervention for acute anterior wall ST-segment-elevation myocardial infarction is associated with a significantly increased long-term cardiac mortality. PMID- 23735477 TI - Etymologia: Shewanella haliotis. PMID- 23735478 TI - Structure elucidation and inhibitory effects on human platelet aggregation of chlorogenic acid from Wrightia tinctoria. AB - BACKGROUND: Interest in natural compounds as sources of potentially new treatment options is growing rapidly. Preliminary screening of many different plant extracts showed that Wrightia tinctoria acts as a potent human platelet aggregation inhibitor. The aim of the present study was to isolate and characterize the active compound responsible for potent inhibition of human platelet aggregation in vitro. METHODS: A 70% ethanolic extract derived from W. tinctoria seeds was fractionated with chloroform followed by ethyl acetate. The ethyl acetate fraction was further fractionated and purified through a series of three successive column chromatographic separations using silica gel, Sephadex LH 20, and C-18 columns. Liquid chromatography coupled to negative electrospray ionization tandem mass spectrometry (LC-MS/MS) and nuclear magnetic resonance (NMR) studies were performed in the structure determination of the active phenolic compound present in the ethyl acetate fraction of W. tinctoria seeds. RESULTS: A phenolic compound has been isolated and identified as chlorogenic acid by LC-MS/MS and NMR studies. Chlorogenic acid showed concentration-dependent inhibitory effect on collagen-induced platelet aggregation in vitro with an IC50 of 0.2363 MUg/MUl. CONCLUSION: The present data suggest that chlorogenic acid can be developed as potential antiplatelet agent in the treatment of cardiovascular diseases in diabetes mellitus. PMID- 23735479 TI - Hericium erinaceus: an edible mushroom with medicinal values. AB - Mushrooms are considered as nutritionally functional foods and source of physiologically beneficial medicines. Hericium erinaceus, also known as Lion's Mane Mushroom or Hedgehog Mushroom, is an edible fungus, which has a long history of usage in traditional Chinese medicine. This mushroom is rich in some physiologically important components, especially beta-glucan polysaccharides, which are responsible for anti-cancer, immuno-modulating, hypolipidemic, antioxidant and neuro-protective activities of this mushroom. H. erinaceus has also been reported to have anti-microbial, anti-hypertensive, anti-diabetic, wound healing properties among other therapeutic potentials. This review article has overviewed the recent advances in the research and study on H. erinaceus and discussed the potential health beneficial activities of this mushroom, with the recognition of bioactive compounds responsible for these medicinal properties. PMID- 23735480 TI - Positive impact of Tai Chi Chuan participation on biopsychosocial quality of life compared to exercise and sedentary controls: a cross-sectional survey. AB - Tai Chi Chuan (TCC) is a traditional Chinese medicine practice and martial art with biopsychosocial aspects. This study aimed to examine the impact of participation in TCC on multiple domains of Quality of Life (QoL) and to assess the involvement of the psychological factors of self-efficacy, Locus of Control (LoC) and Hope in these effects. A total of 68 participants from the general community (13 males and 55 females) aged between 18 and 68 (M=43.55 years) and not currently suffering from a mental or physical illness took part in the study. It was found that TCC participants, as a group, scored significantly better than those in sedentary (book club) and active (gym exercise) control conditions on Psychological and Physical QoL, and that the Physical QoL benefits of TCC continue to accrue with years of practice. The three psychological factors were shown to variously mediate (self-efficacy) and moderate (internal LoC and Hope) this latter relationship. Whilst the results bear limitations (in particular small sample sizes), it is hoped that these findings will encourage further research into TCC, and consideration of TCC as part of the range of treatment options available in community-based mental and physical health management. PMID- 23735481 TI - Protein-bound polysaccharide activates dendritic cells and enhances OVA-specific T cell response as vaccine adjuvant. AB - Protein-bound polysaccharide-K (PSK) is a hot water extract from Trametes versicolor mushroom. It has been used traditionally in Asian countries for its immune stimulating and anti-cancer effects. We have recently found that PSK can activate Toll-like receptor 2 (TLR2). TLR2 is highly expressed on dendritic cells (DC), so the current study was undertaken to evaluate the effect of PSK on DC activation and the potential of using PSK as a vaccine adjuvant. In vitro experiments using mouse bone marrow-derived DC (BMDC) demonstrated that PSK induces DC maturation as shown by dose-dependent increase in the expression of CD80, CD86, MHCII, and CD40. PSK also induces the production of multiple inflammatory cytokines by DC, including IL-12, TNF-alpha, and IL-6, at both mRNA and protein levels. In vivo experiments using PSK as an adjuvant to OVAp323-339 vaccine showed that PSK as adjuvant leads to enlarged draining lymph nodes with higher number of activated DC. PSK also stimulates proliferation of OVA-specific T cells, and induces T cells that produce multiple cytokines, IFN-gamma, IL-2, and TNF-alpha. Altogether, these results demonstrate the ability of PSK to activate DC in vitro and in vivo and the potential of using PSK as a novel vaccine adjuvant. PMID- 23735482 TI - Quercetin disrupts tyrosine-phosphorylated phosphatidylinositol 3-kinase and myeloid differentiation factor-88 association, and inhibits MAPK/AP-1 and IKK/NF kappaB-induced inflammatory mediators production in RAW 264.7 cells. AB - Quercetin is a major bioflavonoid widely present in fruits and vegetables. It exhibits anti-inflammatory, anti-tumor, antioxidant properties and reduces cardiovascular disease risks. However, the molecular mechanism of action against inflammation in RAW 264.7 cells is only partially explored. Quercetin effect on LPS-induced gene and protein expressions of inflammatory mediators and cytokines were determined. Moreover, involvement of heme-oxygenase-1, protein kinases, adaptor proteins and transcription factors in molecular mechanism of quercetin action against inflammation were examined. Quercetin inhibited LPS-induced NO, PGE2, iNOS, COX-2, TNF-alpha, IL-1beta, IL-6 and GM-CSF mRNA and protein expressions while it promoted HO-1 induction in a dose- and time-dependent manner. It also suppressed I-kappaB-phosphorylation, NF-kappaB translocation, AP 1 and NF-kappaB-DNA-binding and reporter gene transcription. Quercetin attenuated p38(MAPK) and JNK1/2 but not ERK1/2 activations and this effect was further confirmed by SB203580 and SP600125-mediated suppressions of HO-1, iNOS, and COX-2 protein expressions. Moreover, quercetin arrested Src, PI3K, PDK1 and Akt activation in a time- and dose-dependent manner, which was comparable to PP2 and LY294002 inhibition of Src, PI3K/Akt and iNOS expressions. Quercetin further arrested Src and Syk tyrosine phosphorylations and their kinase activities followed by inhibition of PI3K tyrosine phosphorylation. Moreover, quercetin disrupted LPS-induced p85 association to TLR4/MyD88 complex and it then limited activation of IRAK1, TRAF6 and TAK1 with a subsequent reduction in p38 and JNK activations, and suppression in IKKalpha/beta-mediated I-kappaB phosphorylation. Quercetin limits LPS-induced inflammation via inhibition of Src- and Syk-mediated PI3K-(p85) tyrosine phosphorylation and subsequent TLR4/MyD88/PI3K complex formation that limits activation of downstream signaling pathways. PMID- 23735483 TI - Impact of non-thermal plasma treatment on MAPK signaling pathways of human immune cell lines. AB - In the field of wound healing research non-thermal plasma (NTP) increasingly draws attention. Next to its intensely studied antibacterial effects, some studies already showed stimulating effects on eukaryotic cells. This promises a unique potential in healing of chronic wounds, where effective therapies are urgently needed. Immune cells do play an important part in the process of wound healing and their reaction to NTP treatment has yet been rarely examined. Here, we studied the impact of NTP treatment using the kinpen on apoptotic and proliferative cell signaling pathways of two human immune cell lines, the CD4(+)T helper cell line Jurkat and the monocyte cell line THP-1. Depending on NTP treatment time the number of apoptotic cells increased in both investigated cell types according to a caspase 3 assay. Western blot analysis pointed out that plasma treatment activated pro-apoptotic signaling proteins like p38 mitogen activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase 1 and 2 (JNK 1/2) in both cell types. Stronger signals were detected in Jurkat cells at comparable plasma treatment times. Intriguingly, exposure of Jurkat and THP-1 cells to plasma also activated the pro-proliferative signaling molecules extracellular signal-regulated kinase 1/2 (ERK 1/2) and MAPK/ERK kinase 1 and 2 (MEK 1/2). In contrast to Jurkat cells, the anti-apoptotic heat shock protein 27 (HSP27) was activated in THP-1 cells after plasma treatment, indicating a possible mechanism how THP-1 cells may reduce programmed cell death. In conclusion, several signaling cascades were activated in the examined immune cell lines after NTP treatment and in THP-1 monocytes a possible defense mechanism against plasma impacts could be revealed. Therefore, plasma might be a treatment option for wound healing. PMID- 23735484 TI - Regulation of alcohol oxidase 1 (AOX1) promoter and peroxisome biogenesis in different fermentation processes in Pichia pastoris. AB - Production of recombinant proteins is affected by process conditions, where transcriptional regulation of Pichia pastoris alcohol oxidase 1 (PpAOX1) promoter has been a key factor to influence expression levels of proteins of interest. Here, we demonstrate that the AOX1 promoter and peroxisome biogenesis are regulated based on different process conditions. Two types of GFP-fusion proteins, Ub-R-GFP (short-lived GFP in the cytosol) and GFP-SKL (peroxisomal targeting GFP), were successfully used to characterize the time-course of the AOX1 promoter and peroxisome biogenesis, respectively. The activity of the AOX1 promoter and peroxisome biogenesis was highly subjected to different fermentation process conditions - methanol-limited condition at normoxy (ML), switched feeding of carbon sources (e.g., glucose and methanol) under carbon-limited condition at normoxy (SML), and oxygen-limited (OL) condition. The AOX1 promoter was most active under the ML, but less active under the OL. Peroxisome biogenesis showed a high dependency on methanol consumption. In addition, the proliferation of peroxisomes was inhibited in a medium containing glucose and stimulated in the methanol phase under a carbon-limited fed-batch culture condition. The specific productivity of a monoclonal antibody (qp) under the AOX1 promoter was higher at 86h of induction in the ML than in the OL (0.026 vs 0.020mgg(-1)h(-1)). However, the oxygen-limited condition was a robust process suitable for longer induction (180h) due to high cell fitness. Our study suggests that the maximal production of a recombinant protein is highly dependent on methanol consumption rate that is affected by the availability of methanol and oxygen molecules. PMID- 23735485 TI - Forecasting respiratory collapse: theory and practice for averting life threatening infant apneas. AB - Apnea of prematurity is a common disorder of respiratory control among preterm infants, with potentially serious adverse consequences on infant development. We review the capability for automatically assessing apnea risk and predicting apnea episodes from multimodal physiological measurements, and for using this knowledge to provide timely therapeutic intervention. We also review other, similar clinical domains of respiratory distress assessment and prediction in the hope of gaining useful insights. We propose an algorithmic framework for constructing discriminative feature vectors from physiological measurements, and for building robust and effective statistical models for apnea assessment and prediction. PMID- 23735487 TI - Isolated percutaneous transluminal angioplasty of the profunda femoris artery for limb ischemia. AB - OBJECTIVE: To compare the outcome of endovascular profunda femoral artery revascularization (ePFR) with ePFR and concurrent endovascular femoropopliteal revascularization (eFPR). METHODS: A retrospective review of the consecutive patients with PFA and femoropopliteal vaso-occulsive disease who underwent ePFR or ePFR + eFPR for severe limb ischemia was performed. RESULTS: A total of 18 ePFRs and 26 ePFR + eFPRs were performed; 17 (94%) ePFRs and 22 (85%) ePFR + eFPRs were technically successful. The 12-month survival free from amputation and reintervention rates following isolated ePFR were 78% and 72%, respectively, and following ePFR + eFPR were 96% and 81%, respectively. There was no significant difference in the survival free from amputation (P = .4) or reintervention (P = .91) rates between the 2 groups. CONCLUSION: These contemporary data suggest isolated ePFRs and ePFR + eFPRs are associated with good and comparable early limb salvage rates. PMID- 23735488 TI - A membrane-integrated advanced scheme for treatment of industrial wastewater: dynamic modeling towards scale up. AB - Modeling and simulation was carried out for an advanced membrane-integrated hybrid treatment process that ensures reuse of water with conversion and recovery of ammoniacal nitrogen as value-added struvite fertilizer from coke wastewater. While toxic cyanide was largely removed in a pre-chemical treatment unit using Fenton's reagents under optimized conditions, more than 95% of NH4(+)-N could be recovered as a valuable by-product called struvite through addition of appropriate doses of magnesium and phosphate salts. Water could be turned reusable through a polishing treatment by nanofiltration membranes in a largely fouling free membrane module following a biodegradation step. Mathematical modeling of such an integrated process was done with Haldane-Andrew approach for the associated microbial degradation of phenol by Pseudomonas putida. Residual NH4(+) was degraded by nitrification and denitrification following the modified Monod kinetics. The model could successfully predict the plant performance as reflected in reasonably low relative error (0.03-0.18) and high Willmott d-index (>0.98). PMID- 23735489 TI - Statistical uncertainty in hazardous terrestrial concentrations estimated with aquatic ecotoxicity data. AB - Since chemicals' ecotoxic effects depend for most soil species on the dissolved concentration in pore water, the equilibrium partitioning (EP) method is generally used to estimate hazardous concentrations (HC50) in the soil from aquatic toxicity tests. The present study analyzes the statistical uncertainty in terrestrial HC50s derived by the EP-method. For 47 organic chemicals, we compared freshwater HC50s derived from standard aquatic ecotoxicity tests with porewater HC50s derived from terrestrial ecotoxicity tests. Statistical uncertainty in the HC50s due to limited species sample size and in organic carbon-water partitioning coefficients due to predictive error was treated with probability distributions propagated by Monte Carlo simulations. Particularly for specifically acting chemicals, it is very important to base the HC50 on a representative sample of species, composed of both target and non-target species. For most chemical groups, porewater HC50 values were approximately a factor of 3 higher than freshwater HC50 values. The ratio of the porewater HC50/freshwater HC50 was typically 3.0 for narcotic chemicals (2.8 for nonpolar and 3.4 for polar narcotics), 0.8 for reactive chemicals, 2.9 for neurotoxic chemicals (4.3 for AChE agents and 0.1 for the cyclodiene type), and 2.5 for herbicides-fungicides. However, the statistical uncertainty associated with this ratio was large (typically 2.3 orders of magnitude). For 81% of the organic chemicals studied, there was no statistical difference between the hazardous concentration of aquatic and terrestrial species. We conclude that possible systematic deviations between the HC50s of aquatic and terrestrial species appear to be less prominent than the overall statistical uncertainty. PMID- 23735486 TI - The physiological determinants of sudden infant death syndrome. AB - It is well-established that environmental and biological risk factors contribute to Sudden Infant Death Syndrome (SIDS). There is also growing consensus that SIDS requires the intersection of multiple risk factors that result in the failure of an infant to overcome cardio-respiratory challenges. Thus, the critical next steps in understanding SIDS are to unravel the physiological determinants that actually cause the sudden death, to synthesize how these determinants are affected by the known risk factors, and to develop novel ideas for SIDS prevention. In this review, we will examine current and emerging perspectives related to cardio-respiratory dysfunctions in SIDS. Specifically, we will review: (1) the role of the preBotzinger complex (preBotC) as a multi-functional network that is critically involved in the failure to adequately respond to hypoxic and hypercapnic challenges; (2) the potential involvement of the preBotC in the gender and age distributions that are characteristic for SIDS; (3) the link between SIDS and prematurity; and (4) the potential relationship between SIDS, auditory function, and central chemosensitivity. Each section underscores the importance of marrying the epidemiological and pathological data to experimental data in order to understand the physiological determinants of this syndrome. We hope that a better understanding will lead to novel ways to reduce the risk to succumb to SIDS. PMID- 23735490 TI - Symmetry-breaking, grouped images and multistability with transient unconsciousness. AB - Multistability in consciousness is characterised by transient switches in which the attributes of space and time are locally absent. An extensive number of studies has attempted to describe and predict the causes and duration of such switches, and many are obviously incomplete models or wrong, but some show promise. Models have, for example, drawn on neural network theory, psychophysics, signal detection theory, Markov matrices, and Shilnikov dynamics. Levels of macro , meso- and micro-dynamics are employed by writers and contrasted. We compare some of those models and find problems in attempting to identify their properties and causality. Discontinuities in the observed local evolution of dynamical time series may be modelled in various ways; they are observed in multistability switches, in saddle-node bifurcations, and in cusp catastrophes. Three models, involving psychophysics, rapid recurrence, and neural networks, are considered as complementing rather than competing for representation. PMID- 23735491 TI - Complexity of everyday life heart rate dynamics and attentional control in healthy students. AB - Effective regulation of emotions requires the ability to voluntarily manage attention, i.e. attentional control (AC), which has been related to heart rate variability and vagal tone in laboratory based research. In this study, we calculated the correlation dimension (CD), the fractal-like properties (scaling exponents ?1 and ?2, and fractal dimension) and the sample entropy of heart rate time series obtained from ECG recordings (4 hours long each) taken from a sample of healthy students (n=47) during everyday activities. AC was assessed through a self-reported questionnaire. As expected, a linear positive correlation was found between AC scores and CD and entropy, but no associations were found between AC and ?1 and fractal dimension. The association between AC and ?2 was negative and marginally significant. No associations were found between AC and linear heart rate variability measures. These results show that nonlinear measures of long, everyday life, heart rate time series may provide useful information about the AC ability of healthy students. PMID- 23735492 TI - Recalling items from a category for 1 hour: an inquiry into power-law behavior and memory foraging. AB - There are two complementary approaches to characterizing performance in a free recall task (retrieving items from a specified category). The historic, or top down approach, considers the overall structure of the produced responses, generally as the parameters of a fitted cumulative recall curve. Alternatively, free recall can be considered as a time series of recalls or inter-recall intervals. Earlier work employing this approach (Rhodes & Turvey, 2007) suggested power law behavior. Long trial durations (1 hour) are employed to more rigorously test for the presence of power law behavior and more generally, the hypothesis that the dynamics of free recall reflect complex, multiplicative processes. The outlined empirical methods are also employed to test predictions about the relative structure of differently sized categories. Consequences for an asymptotic curve based understanding of free recall and foraging metaphors of retrieval are discussed. PMID- 23735494 TI - The minimum entropy principle and task performance. AB - According to the minimum entropy principle, efficient cognitive performance is produced with a neurocognitive strategy that involves a minimum of degrees of freedom. Although high performance is often regarded as consistent performance as well, some variability in performance still remains which allows the person to adapt to changing goal conditions or fatigue. The present study investigated the connection between performance, entropy in performance, and four task-switching strategies. Fifty-one undergraduates performed 7 different computer-based cognitive tasks producing sets of 49 responses under instructional conditions requiring task quotas or no quotas. The temporal patterns of performance were analyzed using orbital decomposition to extract pattern types and lengths, which were then compared with regard to Shannon entropy, topological entropy, and overall performance. Task switching strategies from a previous study were available for the same participants as well. Results indicated that both topological entropy and Shannon entropy were negatively correlated with performance. Some task-switching strategies produced lower entropy in performance than others. Stepwise regression showed that the top three predictors of performance were Shannon entropy and arithmetic and spatial abilities. Additional implications for the prediction of work performance with cognitive ability measurements and the applicability of the minimum entropy principle to multidimensional performance criteria and team work are discussed. PMID- 23735493 TI - Intention to use condom, cusp modeling, and evaluation of an HIV prevention intervention trial. AB - Adolescents are at particularly high risk to acquire HIV infection; increasing the likelihood of condom use is an effective measure to reduce the risk of such infections. Challenges in assessing actual condom use behavior among early adolescents render the precursor measure, intention to use condoms, an appealing alternative. While analyzing data from a randomized controlled trial to evaluate a theory-based intervention program to promote condom use among early adolescents, we observed a modest effect with regard to condom use intention when the linear analytical approach was used. If intention, as a measure of the readiness to perform a behavior, also contains a nonlinear discrete component, it would be more appropriately modeled using a nonlinear approach. In this study, data from a randomized controlled trial (N=1360) were analyzed using the cusp catastrophe method with HIV knowledge and condom skills as the asymmetry variables and condom use self-efficacy as the bifurcation variables. Findings from concurrent and longitudinal modeling analyses indicated a much better fit of the cusp model (R2 = 0.85); AIC and BIC were one-fourth that of than the linear (R2 lt; 0.10) or the logistic model (R2 lt; 0.15). Receipt of the intervention as an asymmetry variable was significantly predicted condom use intention but did not as a bifurcation variable. In conclusion, adolescent intentions to use a condom contain both a continuous process and a discrete process and can better be modeled with cusp catastrophe methods. A much greater program effect is likely from the same prevention intervention if additional measures are taken to foster sudden changes in condom intention. PMID- 23735495 TI - Interpersonal, intrapersonal, extrapersonal? Qualitatively investigating coordinative couplings between rowers in Olympic sculling. AB - Coordinative couplings are commonly classified as interpersonal and intrapersonal. Interpersonal coordination is normally thought of as between organisms but a subset can also be considered where the co-actors movements are coupled to an environmental rhythm. This can be termed extrapersonal coordination. This study explores how coordination is achieved in a situation that demands that at least one actor makes use of extrapersonal sources. In this case multi-seat rowing, where one actor cannot see the other one behind them. A qualitative approach using experiential knowledge from expert rowers (N=9) and coaches (N=4) was used to examine how interpersonal coordination was achieved and maintained in 2 person rowing boats. It was reported that where possible, both rowers coordinated their movements by coupling with an invariant provided by the boat. This invariant is underpinned by perception of water flow past the boat; which is in turn used to determine changes in acceleration - 'rowing with the boat.' Bow seat also identified the rower in front and stroke seat identified the looming of the stern as viable alternative sources for coupling. PMID- 23735496 TI - Accelerated degradation of perS protein provides insight into light-mediated phase shifting. AB - Phase resetting by light is an important feature of circadian rhythms, and the current Drosophila model focuses on light-mediated degradation of the clock protein TIMELESS (TIM). PERIOD (PER) is the binding partner of TIM and a major repressor of the molecular clock, but direct evidence of PER in phase resetting is lacking. Because light sensitivity of the per(S) short period mutant strain is strongly enhanced compared with wild-type strains, we assayed the importance of PER degradation for light-induced phase shifting. The per(S) protein (PERS) is markedly less stable than wild-type PER, in tissue culture and in flies, and PERS as well as PER is stabilized by TIM in both systems. Consistent with this finding, light-induced TIM degradation appears to trigger PER degradation. Moreover, TIM degradation is similar in the clock neurons of both strains, suggesting that it is not strongly affected by PERS and does not dictate the difference in the light response. In contrast, there is a dramatic quantitative difference between PER and PERS degradation in these neurons, indicating that PER degradation dictates the enhanced amplitude of the light-induced phase response. The data indicate that TIM inhibits PER degradation and that PER degradation follows light-mediated TIM degradation within circadian neurons; PER degradation then dictates qualitative as well as quantitative features of light-mediated phase-resetting. PMID- 23735497 TI - Fibroblast PER2 circadian rhythmicity depends on cell density. AB - Like neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in the brain, single fibroblasts can function as independent oscillators. In the SCN, synaptic and paracrine signaling among cells creates a robust, synchronized circadian oscillation, whereas there is no evidence for such integration in fibroblast cultures. However, interactions among single-cell fibroblast oscillators cannot be completely excluded, because fibroblasts were not isolated in previous work. In this study, we tested the autonomy of fibroblasts as single cell circadian oscillators in high- and low-density culture, by single-cell imaging of cells from PER2::LUC circadian reporter mice. We found greatly reduced PER2::LUC rhythmicity in low-density cultures, which could result from lack of either constitutive or rhythmic paracrine signals from neighboring fibroblasts. To discriminate between these 2 possibilities, we mixed PER2::LUC wild-type (WT) cells with nonluminescent, nonrhythmic Bmal1-/- cells, so that density of rhythmic cells was low but overall cell density remained high. In this condition, WT cells showed clear rhythmicity similar to high-density cultures. We also mixed PER2::LUC WT cells with nonluminescent, long period Cry2-/- cells. In this condition, WT cells showed a period no different from cells cultured with rhythmic WT cells or nonrhythmic Bmal1-/- cells. In previous work, we found that low K+ suppresses fibroblast rhythmicity, and we and others have found that either low K+ or low Ca2+ suppresses SCN rhythmicity. Therefore, we attempted to rescue rhythmicity of low-density fibroblasts with high K+ (21 mM), high Ca2+ (3.6 mM), or conditioned medium. Conditioned medium from high-density fibroblast cultures rescued rhythmicity of low-density cultures, whereas high K+ or Ca2+ medium did not consistently rescue rhythmicity. These data suggest that fibroblasts require paracrine signals from adjacent cells for normal expression of rhythmicity, but that these signals do not have to be rhythmic, and that rhythmic signals from other cells do not affect the intrinsic periods of fibroblasts. PMID- 23735498 TI - Exogenous T3 elicits long day-like alterations in testis size and the RFamides Kisspeptin and gonadotropin-inhibitory hormone in short-day Siberian hamsters. AB - Siberian hamsters (Phodopus sungorus) exhibit robust seasonal rhythms of reproduction driven by changes in day length. Day length is encoded endogenously by the duration of nocturnal melatonin (Mel) secretion from the pineal gland. Short duration Mel signals stimulate whereas long duration Mel signals inhibit reproduction. The mechanism by which Mel regulates the reproductive axis has not been fully characterized. In Siberian hamsters, the thyroid hormone triiodothyronine (T3) is thought to be part of the photoperiodic mechanism. The availability of T3 is decreased in hamsters housed in short day lengths, and injections of exogenous T3 stimulate testicular growth in short-day (SD) Siberian hamsters. Thus, T3 acts as a neuroendocrine intermediate between the Mel rhythm and the reproductive axis. The RFamides kisspeptin (Kiss1) and gonadotropin inhibitory hormone (GnIH) also act as a link between the Mel rhythm and the reproductive axis. Expression of both of these neuropeptides is regulated by photoperiod and Mel. Kiss1 stimulates, and GnIH inhibits, the reproductive axis in long-day housed hamsters. It remains unknown whether T3 acts through changes in RFamide expression in the regulation of reproduction or whether these molecules act independently of one another. We tested the hypothesis that exogenous T3 administered to SD hamsters, a treatment that stimulates testicular growth, would also result in alterations in the patterns of Kiss1- and GnIH immunoreactivity. Administration of T3 to SD hamsters resulted in significant testicular growth as well as a long day-like pattern of RFamide peptide expression. Thus, exogenous T3 elicited increased numbers of Kiss1-positive cells in the hypothalamic anteroventral periventricular nucleus, decreased numbers of Kiss1-positive cells in the arcuate nucleus, and a greater number of GnIH positive cells in the dorsomedial hypothalamus compared with SD controls. The results are consistent with the hypothesis that T3 elicits alterations in the reproductive axis through alterations in RFamide peptide expression. PMID- 23735499 TI - Circannual rhythm in body temperature, torpor, and sensitivity to A1 adenosine receptor agonist in arctic ground squirrels. AB - A1 adenosine receptor (A1AR) activation within the central nervous system induces torpor, but in obligate hibernators such as the arctic ground squirrel (AGS; Urocitellus parryii), A1AR stimulation induces torpor only during the hibernation season, suggesting a seasonal increase in sensitivity to A1AR signaling. The purpose of this research was to investigate the relationship between body temperature (Tb) and sensitivity to an adenosine A1 receptor agonist in AGS. We tested the hypothesis that increased sensitivity in A1AR signaling would lead to lower Tb in euthermic animals during the hibernation season when compared with the summer season. We further predicted that if a decrease in euthermic Tb reflects increased sensitivity to A1AR activation, then it should likewise predict spontaneous torpor. We used subcutaneous IPTT-300 transponders to monitor Tb in AGS housed under constant ambient conditions (12:12 L:D, 18 degrees C) for up to 16 months. These animals displayed an obvious rhythm in euthermic Tb that cycled with a period of approximately 8 months. Synchrony in the Tb rhythm within the group was lost after several months of constant L:D conditions; however, individual rhythms in Tb continued to show clear sine wave-like waxing and waning. AGS displayed spontaneous torpor only during troughs in euthermic Tb. To assess sensitivity to A1AR activation, AGS were administered the A1AR agonist N(6)-cyclohexyladenosine (CHA, 0.1 mg/kg, ip), and subcutaneous Tb was monitored. AGS administered CHA during a seasonal minimum in euthermic Tb showed a greater drug-induced decrease in Tb (1.6 +/- 0.3 degrees C) than did AGS administered CHA during a peak in euthermic Tb (0.4 +/- 0.3 degrees C). These results provide evidence for a circannual rhythm in Tb that is associated with increased sensitivity to A1AR signaling and correlates with the onset of torpor. PMID- 23735500 TI - The noncircadian function of the circadian Clock gene in the regulation of male fertility. AB - Mice homozygous for a dominant-negative allele of the Clock gene (Clock (Delta19/Delta19)) have slightly but significantly decreased male fertility. The molecular mechanism for this reduction in fertility is unknown. In the present study, we used a small hairpin RNA (shRNA) strategy to specifically knock down the Clock gene expression in the testes of male mice and determined its effect on male fertility. Clock knockdown led to smaller litter size, a lower in vitro fertility rate, lower blastula formation rate, and lower acrosin activity of the knockdown sperm. Locomotor activity analysis of the Clock knockdown mice revealed that Clock knockdown in testes did not alter their circadian rhythm. Taken together, these results provide the first evidence that Clock gene expression in round spermatids is essential for maintaining male reproductivity and suggest that acrosin may be a novel regulatory target of the Clock gene that would regulate the fertilization and early embryonic development to blastula. These findings may provide new clues for development of novel male contraceptive strategies. PMID- 23735501 TI - Effects of sex pheromones and sexual maturation on locomotor activity in female sea lamprey (Petromyzon marinus). AB - Synchronization of male and female locomotor rhythmicity can play a vital role in ensuring reproductive success. Several physiological and environmental factors alter these locomotor rhythms. As sea lamprey, Petromyzon marinus, progress through their life cycle, their locomotor activity rhythm changes multiple times. The goal of this study was to elucidate the activity patterns of adult female sea lamprey during the sexual maturation process and discern the interactions of these patterns with exposure to male pheromones. During these stages, preovulated and ovulated adult females are exposed to sex pheromone compounds, which are released by spermiated males and attract ovulated females to the nest for spawning. The locomotor behavior of adult females was monitored in a natural stream with a passive integrated tag responder system as they matured, and they were exposed to a sex pheromone treatment (spermiated male washings) or a control (prespermiated male washings). Results showed that, dependent on the hour of day, male sex pheromone compounds reduce total activity (p < 0.05) and cause increases in activity during several daytime hours in preovulated and ovulated females. These results are one of the first examples of how sex pheromones modulate a locomotor rhythm in a vertebrate, and they suggest that the interaction between maturity stage and sex pheromone exposure contributes to the differential locomotor rhythms found in adult female sea lamprey. This phenomenon may contribute to the reproductive synchrony of mature adults, thus increasing reproductive success in this species. PMID- 23735502 TI - Diurnal 24-hour rhythm in ambulatory heart rate variability during the day shift in rotating shift workers. AB - Circadian variation in cardiac autonomic nervous system activity and behavior during the day shifts of shift workers has not hitherto been clarified. This study examined diurnal 24-h variation in heart rate variability (HRV), sleep-wake cycle, physical activity, and food intake during the day shift in rotating shift workers. The subjects were female nurses and caregivers working at a health care facility (14 day workers and 13 rotating shift workers). Each subject was asked to undergo 24-h electrocardiograph and step count recordings. Coarse graining spectral analysis was used for approximately 10-min segments of HRV (600 beats) to derive the total power (TOT: >0.04 Hz), integrated power in the low-frequency (LF: 0.04-0.15 Hz) and high-frequency (HF: >0.15 Hz) ranges, the ratio of HF power to TOT (HF nu), and the ratio of LF power to HF power (LF/HF). Double cosinor analysis was used to obtain 24-h and 12-h period variations in variables of HRV and physical activity. While no difference was found in the acrophases of either period for step counts or in the 12-h period of HRV variables between the groups, the acrophases of the 24-h period for HRV variables were delayed by 1.3 to 5.5 h in rotating shift workers, and their differences in HF power, HF nu, and LF/HF reached a significant level (p < 0.05). On the days of the experiment, retiring time, waking up time, total time in bed, sleep efficiency, and mealtimes and energy intake for each diet did not differ between the groups. These results suggest that there is a possibility of an abnormal phase angle between circadian variation in cardiac autonomic nervous system activity and the sleep-wake cycle during the day shift in shift workers. PMID- 23735503 TI - A new treatment for avulsion fracture of the calcaneus using an Ilizarov external fixator. AB - INTRODUCTION: In the treatment of avulsion fractures of the posterior calcaneal tuberosity, open reduction and internal fixation are prone to several complications. We describe a new treatment using an Ilizarov external fixator, which can minimise the complications and achieve sufficient stability of the displaced fragment. CASE PRESENTATION: A 55-year-old woman sustained an avulsion fracture of the calcaneus. Examination revealed the development of bruising with extremely taut skin over the posterior prominence of the displaced bone. Radiographs demonstrated grossly proximal displacement of the tuberosity fragment. Surgery was exclusively percutaneous using an Ilizarov external fixator. The displaced fragment was adequately reduced and stabilised. Progressive weight bearing in the equinus position was initiated at the third week after surgery and the external fixator was removed at the seventh week. There was no skin necrosis or loss of reduction while the fixator was maintained. Postoperative follow-up for 2 years revealed full recovery. DISCUSSION: Major postoperative complications after conventional open reduction and internal fixation include skin necrosis, skin irritation by metal implants and re displacement of the reduced fragment. Our method of using an external fixator may decrease the incidence of these three complications. Skin incision and the risk of skin necrosis are inevitable during internal fixation. On the other hand, the use of an external fixator reduces or eliminates skin necrosis, as it is applied percutaneously for reduction and stabilisation of the fragment. External fixation is mostly recommended in cases of poor vascularity or bruising. In addition, skin irritation can be avoided upon removal of the external fixator. Re-displacement occurs occasionally as a serious complication in lag screw fixation, particularly in cases with poor purchase of the osteoporotic bone. Tension band wiring and application of an Ilizarov external fixator in avulsion fractures of the calcaneus can neutralise tension on the Achilles tendon during the healing process. Thus, both these methods are believed to provide sufficient mechanical stability to fix the fragment. CONCLUSION: This new method, involving application of an Ilizarov external fixator, is recommended when the avulsion fragment is large enough to accommodate Ilizarov wires, especially in cases of circulatory problems or bruising. PMID- 23735504 TI - The role of TIR-NBS and TIR-X proteins in plant basal defense responses. AB - Toll/interleukin receptor (TIR) domain-containing proteins encoded in the Arabidopsis (Arabidopsis thaliana) genome include the TIR-nucleotide binding site (TN) and TIR-unknown site/domain (TX) families. We investigated the function of these proteins. Transient overexpression of five TX and TN genes in tobacco (Nicotiana benthamiana) induced chlorosis. This induced chlorosis was dependent on ENHANCED DISEASE RESISTANCE1, a dependency conserved in both tobacco and Arabidopsis. Stable overexpression transgenic lines of TX and TN genes in Arabidopsis produced a variety of phenotypes associated with basal innate immune responses; these were correlated with elevated levels of salicylic acid. The TN protein AtTN10 interacted with the chloroplastic protein phosphoglycerate dehydrogenase in a yeast (Saccharomyces cerevisiae) two-hybrid screen; other TX and TN proteins interacted with nucleotide binding-leucine-rich repeat proteins and effector proteins, suggesting that TN proteins might act in guard complexes monitoring pathogen effectors. PMID- 23735505 TI - Comparative transcriptome analysis of three oil palm fruit and seed tissues that differ in oil content and fatty acid composition. AB - Oil palm (Elaeis guineensis) produces two oils of major economic importance, commonly referred to as palm oil and palm kernel oil, extracted from the mesocarp and the endosperm, respectively. While lauric acid predominates in endosperm oil, the major fatty acids (FAs) of mesocarp oil are palmitic and oleic acids. The oil palm embryo also stores oil, which contains a significant proportion of linoleic acid. In addition, the three tissues display high variation for oil content at maturity. To gain insight into the mechanisms that govern such differences in oil content and FA composition, tissue transcriptome and lipid composition were compared during development. The contribution of the cytosolic and plastidial glycolytic routes differed markedly between the mesocarp and seed tissues, but transcriptional patterns of genes involved in the conversion of sucrose to pyruvate were not related to variations for oil content. Accumulation of lauric acid relied on the dramatic up-regulation of a specialized acyl-acyl carrier protein thioesterase paralog and the concerted recruitment of specific isoforms of triacylglycerol assembly enzymes. Three paralogs of the WRINKLED1 (WRI1) transcription factor were identified, of which EgWRI1-1 and EgWRI1-2 were massively transcribed during oil deposition in the mesocarp and the endosperm, respectively. None of the three WRI1 paralogs were detected in the embryo. The transcription level of FA synthesis genes correlated with the amount of WRI1 transcripts and oil content. Changes in triacylglycerol content and FA composition of Nicotiana benthamiana leaves infiltrated with various combinations of WRI1 and FatB paralogs from oil palm validated functions inferred from transcriptome analysis. PMID- 23735506 TI - Arabidopsis enhanced drought tolerance1/HOMEODOMAIN GLABROUS11 confers drought tolerance in transgenic rice without yield penalty. AB - Enhancing drought tolerance without yield decrease has been a great challenge in crop improvement. Here, we report the Arabidopsis (Arabidopsis thaliana) homodomain-leucine zipper transcription factor Enhanced Drought Tolerance/HOMEODOMAIN GLABROUS11 (EDT1/HDG11) was able to confer drought tolerance and increase grain yield in transgenic rice (Oryza sativa) plants. The improved drought tolerance was associated with a more extensive root system, reduced stomatal density, and higher water use efficiency. The transgenic rice plants also had higher levels of abscisic acid, proline, soluble sugar, and reactive oxygen species-scavenging enzyme activities during stress treatments. The increased grain yield of the transgenic rice was contributed by improved seed setting, larger panicle, and more tillers as well as increased photosynthetic capacity. Digital gene expression analysis indicated that AtEDT1/HDG11 had a significant influence on gene expression profile in rice, which was consistent with the observed phenotypes of transgenic rice plants. Our study shows that AtEDT1/HDG11 can improve both stress tolerance and grain yield in rice, demonstrating the efficacy of AtEDT1/HDG11 in crop improvement. PMID- 23735507 TI - A suppressor screen of the chimeric AtCNGC11/12 reveals residues important for intersubunit interactions of cyclic nucleotide-gated ion channels. AB - To investigate the structure-function relationship of plant cyclic nucleotide gated ion channels (CNGCs), we identified a total of 29 mutant alleles of the chimeric AtCNGC11/12 gene that induces multiple defense responses in the Arabidopsis (Arabidopsis thaliana) mutant, constitutive expresser of PR genes22 (cpr22). Based on computational modeling, two new alleles, S100 (AtCNGC11/12:G459R) and S137 (AtCNGC11/12:R381H), were identified as counterparts of human CNGA3 (a human CNGC) mutants. Both mutants lost all cpr22-mediated phenotypes. Transient expression in Nicotiana benthamiana as well as functional complementation in yeast (Saccharomyces cerevisiae) showed that both AtCNGC11/12:G459R and AtCNGC11/12:R381H have alterations in their channel function. Site-directed mutagenesis coupled with fast-protein liquid chromatography using recombinantly expressed C-terminal peptides indicated that both mutations significantly influence subunit stoichiometry to form multimeric channels. This observation was confirmed by bimolecular fluorescence complementation in planta. Taken together, we have identified two residues that are likely important for subunit interaction for plant CNGCs and likely for animal CNGCs as well. PMID- 23735508 TI - The trehalose 6-phosphate/SnRK1 signaling pathway primes growth recovery following relief of sink limitation. AB - Trehalose 6-P (T6P) is a sugar signal in plants that inhibits SNF1-related protein kinase, SnRK1, thereby altering gene expression and promoting growth processes. This provides a model for the regulation of growth by sugar. However, it is not known how this model operates under sink-limited conditions when tissue sugar content is uncoupled from growth. To test the physiological importance of this model, T6P, SnRK1 activities, sugars, gene expression, and growth were measured in Arabidopsis (Arabidopsis thaliana) seedlings after transfer to cold or zero nitrogen compared with sugar feeding under optimal conditions. Maximum in vitro activities of SnRK1 changed little, but T6P accumulated up to 55-fold, correlating with tissue Suc content in all treatments. SnRK1-induced and repressed marker gene expression strongly related to T6P above and below a threshold of 0.3 to 0.5 nmol T6P g(-1) fresh weight close to the dissociation constant (4 um) of the T6P/ SnRK1 complex. This occurred irrespective of the growth response to Suc. This implies that T6P is not a growth signal per se, but through SnRK1, T6P primes gene expression for growth in response to Suc accumulation under sink-limited conditions. To test this hypothesis, plants with genetically decreased T6P content and SnRK1 overexpression were transferred from cold to warm to analyze the role of T6P/SnRK1 in relief of growth restriction. Compared with the wild type, these plants were impaired in immediate growth recovery. It is concluded that the T6P/SnRK1 signaling pathway responds to Suc induced by sink restriction that enables growth recovery following relief of limitations such as low temperature. PMID- 23735509 TI - Growth platform-dependent and -independent phenotypic and metabolic responses of Arabidopsis and its halophytic relative, Eutrema salsugineum, to salt stress. AB - Comparative studies of the stress-tolerant Arabidopsis (Arabidopsis thaliana) halophytic relative, Eutrema salsugineum, have proven a fruitful approach to understanding natural stress tolerance. Here, we performed comparative phenotyping of Arabidopsis and E. salsugineum vegetative development under control and salt-stress conditions, and then compared the metabolic responses of the two species on different growth platforms in a defined leaf developmental stage. Our results reveal both growth platform-dependent and -independent phenotypes and metabolic responses. Leaf emergence was affected in a similar way in both species grown in vitro but the effects observed in Arabidopsis occurred at higher salt concentrations in E. salsugineum. No differences in leaf emergence were observed on soil. A new effect of a salt-mediated reduction in E. salsugineum leaf area was unmasked. On soil, leaf area reduction in E. salsugineum was mainly due to a fall in cell number, whereas both cell number and cell size contributed to the decrease in Arabidopsis leaf area. Common growth platform-independent leaf metabolic signatures such as high raffinose and malate, and low fumarate contents that could reflect core stress tolerance mechanisms, as well as growth platform-dependent metabolic responses were identified. In particular, the in vitro growth platform led to repression of accumulation of many metabolites including sugars, sugar phosphates, and amino acids in E. salsugineum compared with the soil system where these same metabolites accumulated to higher levels in E. salsugineum than in Arabidopsis. The observation that E. salsugineum maintains salt tolerance despite growth platform specific phenotypes and metabolic responses suggests a considerable degree of phenotypic and metabolic adaptive plasticity in this extremophile. PMID- 23735510 TI - Genome-wide detection of condition-sensitive alternative splicing in Arabidopsis roots. AB - Iron (Fe) deficiency is a world-wide nutritional disorder in both plants and humans, resulting from its restricted bioavailability for plants and, subsequently, low Fe concentration in edible plant parts. Plants have evolved sophisticated mechanisms to alleviate Fe deficiency, with the aim of recalibrating metabolic fluxes and maintaining cellular Fe homeostasis. To analyze condition-sensitive changes in precursor mRNA (pre-mRNA) splicing pattern, we mapped the transcriptome of Fe-deficient and Fe-sufficient Arabidopsis (Arabidopsis thaliana) roots using the RNA sequencing technology and a newly developed software toolbox, the Read Analysis & Comparison Kit in Java (RACKJ). In alternatively spliced genes, stress-related Gene Ontology categories were overrepresented, while housekeeping cellular functions were mainly transcriptionally controlled. Fe deficiency increased the complexity of the splicing pattern and triggered the differential alternative splicing of 313 genes, the majority of which had differentially retained introns. Several genes with important functions in Fe acquisition and homeostasis were both differentially expressed and differentially alternatively spliced upon Fe deficiency, indicating a complex regulation of gene activity in Fe-deficient conditions. A comparison with a data set for phosphate-deficient plants suggests that changes in splicing patterns are nutrient specific and not or not chiefly caused by stochastic fluctuations. In sum, our analysis identified extensive posttranscriptional control, biasing the abundance and activity of proteins in a condition-dependent manner. The production of a mixture of functional and nonfunctional transcripts may provide a means to fine-tune the abundance of transcripts with critical importance in cellular Fe homeostasis. It is assumed that differential gene expression and nutrient deficiency-induced changes in pre mRNA splicing represent parallel, but potentially interacting, regulatory mechanisms. PMID- 23735512 TI - Subendocardial viability ratio predicts cardiovascular mortality in chronic kidney disease patients. AB - BACKGROUND: The subendocardial viability ratio (SEVR), calculated by pulse wave analysis, is an index of myocardial oxygen supply and demand. Here we analyze the relation between SEVR and cardiovascular mortality in the chronic kidney disease (CKD) population of a post hoc analysis of a multicenter, prospective, randomized, nonblinded study. METHODS: We studied 212 consecutive asymptomatic outpatients receiving care at 12 nephrology clinics in south Italy. Inclusion criteria were age >18 years, 6 months of follow-up before the enrollment and stage 3-4 CKD. RESULTS: During follow-up, 34 subjects died, 29 of them for cardiovascular causes. SEVR correlated inversely with vascular calcifications (r = -0.37) and myocardial mass (r = -0.45); SEVR changed from 1.33 +/- 0.24 to 1.36 +/- 0.16 (p = NS; baseline and final values, respectively) in living patients, and from 1.16 +/- 0.31 to 0.68 +/- 0.26 in deceased patients (p < 0.001). Kaplan Meier curves show that that a greater reduction of SEVR values during the study (third tertile) significantly predicts cardiovascular mortality (p < 0.0001). CONCLUSIONS: This post hoc analysis shows that a reduction of SEVR values impacts cardiovascular mortality in CKD patients. PMID- 23735511 TI - Mutually exclusive alterations in secondary metabolism are critical for the uptake of insoluble iron compounds by Arabidopsis and Medicago truncatula. AB - The generally low bioavailability of iron in aerobic soil systems forced plants to evolve sophisticated genetic strategies to improve the acquisition of iron from sparingly soluble and immobile iron pools. To distinguish between conserved and species-dependent components of such strategies, we analyzed iron deficiency induced changes in the transcriptome of two model species, Arabidopsis (Arabidopsis thaliana) and Medicago truncatula. Transcriptional profiling by RNA sequencing revealed a massive up-regulation of genes coding for enzymes involved in riboflavin biosynthesis in M. truncatula and phenylpropanoid synthesis in Arabidopsis upon iron deficiency. Coexpression and promoter analysis indicated that the synthesis of flavins and phenylpropanoids is tightly linked to and putatively coregulated with other genes encoding proteins involved in iron uptake. We further provide evidence that the production and secretion of phenolic compounds is critical for the uptake of iron from sources with low bioavailability but dispensable under conditions where iron is readily available. In Arabidopsis, homozygous mutations in the Fe(II)- and 2-oxoglutarate-dependent dioxygenase family gene F6'H1 and defects in the expression of PLEIOTROPIC DRUG RESISTANCE9, encoding a putative efflux transporter for products from the phenylpropanoid pathway, compromised iron uptake from an iron source of low bioavailability. Both mutants were partially rescued when grown alongside wild type Arabidopsis or M. truncatula seedlings, presumably by secreted phenolics and flavins. We concluded that production and secretion of compounds that facilitate the uptake of iron is an essential but poorly understood aspect of the reduction based iron acquisition strategy, which is likely to contribute substantially to the efficiency of iron uptake in natural conditions. PMID- 23735513 TI - A South American origin of the genus Dynastes (Coleoptera: Scarabaeidae: Dynastinae) demonstrated by chromosomal analyses. AB - The karyotypes of 5 species of Dynastes, D. hercules, D. tityus, D. granti, D. satanas, and D. neptunus, and 2 subspecies of D. hercules are compared with those of 6 other selected Dynastinae species. In the 3 former species, there are 18 chromosomes, including neo-sex chromosomes formed by the fusion of an acrocentric autosome with the X and Y chromosomes. In all other species, including D. neptunus and D. satanas, free X and Y chromosomes are observed in 20,Xyp karyotypes. The acrocentric autosome presumably involved in the fusion is present in D. neptunus and D. satanas (pair No. 8). It replaces a submetacentric observed in the other Dynastinae species. Thus, the karyotypes of D. neptunus and D. satanas derive from that of ancestral Dynastinae by an inversion in chromosome 8, and those of D. hercules, D. granti and D. tityus derive from that of D. neptunus by the translocation of this inverted chromosome to sex chromosomes. Because the Dynastes species with the most derived karyotype occur in North and Central America and Lesser Antilles, while D. neptunus and D. satanas are limited to the northern part of the South American Andes, we suggest a South American origin of the genus Dynastes. PMID- 23735514 TI - Selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment for BRAF-mutant metastatic melanoma: a phase 2 double-blind randomised study. AB - BACKGROUND: Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients with BRAF-mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of selumetinib and dacarbazine with dacarbazine alone. METHODS: This double-blind, randomised, placebo-controlled phase 2 study investigated selumetinib plus dacarbazine versus placebo plus dacarbazine as first-line treatment in patients older than 18 years with histologically or cytologically confirmed advanced BRAF-mutant cutaneous or unknown primary melanoma. Patients were randomly assigned by central interactive voice response system (1:1 ratio, block size four) to take either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo; all patients received intravenous dacarbazine (1000 mg/m(2) on day 1 of a 21-day cycle). Patients, investigators, and the study team were masked to the treatment assigned. The primary endpoint was overall survival analysed by intention to treat. This study is registered at ClinicalTrials.gov, NCT00936221. FINDINGS: Between July 20, 2009, and April 8, 2010, 91 patients were randomly assigned to receive dacarbazine in combination with selumetinib (n=45) or placebo (n=46). Overall survival did not differ significantly between groups (median 13.9 months, 80% CI 10.2-15.6, in the selumetinib plus dacarbazine group and 10.5 months, 9.6 14.7, in the placebo plus dacarbazine group; hazard ratio [HR] 0.93, 80% CI 0.67 1.28, one-sided p=0.39). However, progression-free survival was significantly improved in the selumetinib plus dacarbazine group versus the placebo plus dacarbazine group (HR 0.63, 80% CI 0.47-0.84, one-sided p=0.021), with a median of 5.6 months (80% CI 4.9-5.9) versus 3.0 months (2.8-4.6), respectively. The most frequent adverse events included nausea (28 [64%] of 44 patients on selumetinib vs 25 [56%] of 45 on placebo), acneiform dermatitis (23 [52%] vs one [2%]), diarrhoea (21 [48%] vs 13 [29%]), vomiting (21 [48%] vs 15 [33%]), and peripheral oedema (19 [43%] vs three [7%]). The most common grade 3-4 adverse event was neutropenia (six [14%] patients in the selumetinib plus dacarbazine group vs four [9%] in the placebo plus dacarbazine group). INTERPRETATION: Selumetinib plus dacarbazine showed clinical activity in patients with BRAF mutant cutaneous or unknown primary melanoma, reflected by a significant benefit in progression-free survival compared with placebo plus dacarbazine group, although no significant change in overall survival was noted. The tolerability of this combination was generally consistent with monotherapy safety profiles. FUNDING: AstraZeneca. PMID- 23735515 TI - Development of a quality of life scale for vitiligo. AB - BACKGROUND: No vitiligo-specific quality of life scale exists. OBJECTIVE: To develop a reliable and valid quality of life scale for vitiligo patients. METHODS: The content was derived from in-depth interviews with vitiligo patients. The internal consistency, test-retest reliability and validity of the scale, VLQI (Vitiligo Life Quality Index), were evaluated. RESULTS: Internal consistency was high with 30 patients and then with 183 patients (Cronbach's alpha 0.92 and 0.91). Test-retest scores were correlated (r = 0.86, p < 0.001). There was no difference between the test and retest scores (p > 0.05). VLQI was correlated with DLQI (Dermatology Life Quality Index) (r = 0.77, p < 0.001) and with the perceived severity by the patients (r = 0.57, p < 0.001). There was a significant relationship between the VLQI and the extent of the disease (p = 0.015). Factor analysis revealed six subscales. CONCLUSION: The VLQI is a valid and reliable instrument assessing quality of life of vitiligo patients. PMID- 23735517 TI - More is more. PMID- 23735516 TI - Modulating cell-to-cell variability and sensitivity to death ligands by co drugging. AB - TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) holds promise as an anti-cancer therapeutic but efficiently induces apoptosis in only a subset of tumor cell lines. Moreover, even in clonal populations of responsive lines, only a fraction of cells dies in response to TRAIL and individual cells exhibit cell to-cell variability in the timing of cell death. Fractional killing in these cell populations appears to arise not from genetic differences among cells but rather from differences in gene expression states, fluctuations in protein levels and the extent to which TRAIL-induced death or survival pathways become activated. In this study, we ask how cell-to-cell variability manifests in cell types with different sensitivities to TRAIL, as well as how it changes when cells are exposed to combinations of drugs. We show that individual cells that survive treatment with TRAIL can regenerate the sensitivity and death-time distribution of the parental population, demonstrating that fractional killing is a stable property of cell populations. We also show that cell-to-cell variability in the timing and probability of apoptosis in response to treatment can be tuned using combinations of drugs that together increase apoptotic sensitivity compared to treatment with one drug alone. In the case of TRAIL, modulation of cell-to-cell variability by co-drugging appears to involve a reduction in the threshold for mitochondrial outer membrane permeabilization. PMID- 23735518 TI - Design, methods, and population for a study of PFOA health effects among highly exposed mid-Ohio valley community residents and workers. AB - BACKGROUND: A cohort of community residents and workers is the basis for a series of epidemiologic studies of a Mid-Ohio Valley population with substantial perfluorooctanoic acid (PFOA) exposure due to releases from a chemical plant. OBJECTIVES: We describe study design, methods, and study participants for a longitudinal cohort study of associations between PFOA exposure and adult chronic diseases. METHODS: Two cohorts were formed, one recruited from community residents who participated in a previous community-wide survey, and one from plant workers. Study participants were interviewed during 2008-2011 regarding demographics, health-related behaviors, and personal history of chronic diseases. Reported diseases were validated through medical records review and registry matching. Here we describe cohort characteristics, compare survey respondents and nonrespondents, provide data on the number of diseases reported and validated, and describe historical estimates of serum PFOA concentrations over time. RESULTS: The final combined cohort included 32,254 participants (28,541 community; 3,713 worker). Participation rates were high (community, 81.5%; worker, 72.9% of target population). The final population from each cohort was representative of the target population in terms of demographic characteristics and measured serum PFOA concentrations in 2005-2006. The study had a wide exposure range and the number of reported cases of chronic diseases was high, resulting in greater power to detect associations than has been the case for many previous studies. CONCLUSIONS: This is the largest study to date of the health effects of PFOA. The information from this cohort is being used to examine associations between PFOA exposure and multiple adult chronic diseases. PMID- 23735519 TI - Medical complications during inpatient rehabilitation among patients with traumatic disorders of consciousness. AB - OBJECTIVE: To assess the incidence of medical complications in patients with recent traumatic disorders of consciousness (DOCs). DESIGN: Data on adverse events in a placebo controlled trial of amantadine hydrochloride revealed no group difference, which allowed these events to be reanalyzed descriptively as medical complications experienced by the 2 groups collectively. SETTING: Eleven clinical facilities in the United States, Denmark, and Germany with specialty rehabilitation programs for patients with DOCs. PARTICIPANTS: Patients (N=184) with nonpenetrating traumatic brain injury enrolled from acute inpatient rehabilitation programs between 4 and 16 weeks postinjury. INTERVENTIONS: Participants were randomized to receive 200 to 400mg of amantadine hydrochloride or placebo daily for 4 weeks, and followed for an additional 2 weeks. Adverse events were recorded and categorized with respect to their nature, timing, and severity. MAIN OUTCOME MEASURE: Number, type, and severity of medical complications occurring during the 6-week study interval. RESULTS: A total of 468 medical complications were documented among the patients (.40 events per week per patient). More than 80% of patients experienced at least 1 medical complication, and 41 of these were defined as serious adverse events. New medical complications declined over time in rehabilitation and were not dependent on time since injury. Hypertonia, agitation/aggression, urinary tract infection, and sleep disturbance were the most commonly reported problems. Hydrocephalus, pneumonia, gastrointestinal problems, and paroxysmal sympathetic hyperactivity were the most likely to be severe. CONCLUSIONS: Patients with DOCs have a high rate of medical complications early after injury. Many of these complications require brain injury expertise for optimal management. Active medical management appears to contribute to the reduction in new complications. An optimal system of care for DOC patients must provide expert medical management in the early weeks after injury. PMID- 23735520 TI - Can mental imagery functional magnetic resonance imaging predict recovery in patients with disorders of consciousness? AB - OBJECTIVE: To determine the potential prognostic value of using functional magnetic resonance imaging (fMRI) to identify patients with disorders of consciousness, who show potential for recovery. DESIGN: Observational study. SETTING: Unit for acute rehabilitation care. PARTICIPANTS: Patients (N=22) in a vegetative state (VS; n=10) and minimally conscious state (MCS; n=12) during the first 200 days after the initial incident. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Further course on the Coma Recovery Scale-Revised. RESULTS: Participants performed a mental imagery fMRI paradigm. They were asked to alternately imagine playing tennis and navigating through their home. In 14 of the 22 examined patients (VS, n=5; MCS, n=9), a significant activation of the regions of interest (ROIs) of the mental imagery paradigm could be found. All 5 patients with activation of a significant blood oxygen level dependent signal, who were in a VS at the time of the fMRI examination, reached at least an MCS at the end of the observation period. In contrast, 5 participants in a VS who failed to show activation in ROIs, did not (sensitivity 100%, specificity 100%). Six of 9 patients in an MCS with activation in ROIs emerged from an MCS. Of 3 patients in an MCS who did not show activation, 2 patients stayed in an MCS and 1 patient emerged from the MCS (sensitivity 85%, specificity 40%). CONCLUSIONS: The fMRI paradigm mental imagery displays a high concordance with the further clinical course of patients in a VS. All 5 patients in a VS who showed significant activation of ROIs had a favorable further course until the end of the observation period. We therefore propose the term "functional minimally conscious state" for these patients. They may benefit from rehabilitation treatment. In cases where no significant activation was seen, the method has no prognostic value. Prediction of the clinical course of patients in an MCS by fMRI was considerably less accurate than in patients in a VS. PMID- 23735521 TI - Medical comorbidities in disorders of consciousness patients and their association with functional outcomes. AB - OBJECTIVE: To identify, for patients in states of seriously impaired consciousness, comorbid conditions present during inpatient rehabilitation and their association with function at 1 year. DESIGN: Abstracted data from a prospective cross-sectional observational study with data collection occurring January 1996 through December 2007. SETTING: Four inpatient rehabilitation facilities in metropolitan areas. PARTICIPANTS: The study sample of 68 participants is abstracted from a database of 157 patients remaining in states of seriously impaired consciousness for at least 28 days. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: One-year cognitive, motor, and total FIM score. RESULTS: The most common medical complications during inpatient rehabilitation for the study sample are active seizures (46%), spasticity (57%), urinary tract infections (47%), and hydrocephalus with and without shunt (38%). Presence of >=3 medical complications during inpatient rehabilitation, controlling for injury severity, is significantly (P<.05) associated with poorer total FIM and FIM motor scores 1 year after injury. The presence of hydrocephalus with and without shunt (r=-.20, -.21, -.18; P <=.15), active seizures (r=-.31, -.22, -.42), spasticity (r=-.38, -.28, -.40), and urinary tract infections (r=-.25, -.24, -.26) were significantly (P<.10) associated with total FIM, FIM cognitive, and FIM motor scores, respectively. CONCLUSIONS: Reported findings indicate that persons in states of seriously impaired consciousness with higher numbers of medical complications during inpatient rehabilitation are more likely to have lower functional levels 1-year postinjury. The findings indicate that persons with >=3 medical complications during inpatient rehabilitation are at a higher risk for poorer functional outcomes at 1 year. It is, therefore, prudent to evaluate these patients for indications of these complications during inpatient rehabilitation. PMID- 23735522 TI - Safety and usability evaluation of a web-based insulin self-titration system for patients with type 2 diabetes mellitus. AB - OBJECTIVE: The rising incidence of type 2 diabetes mellitus (T2DM) induces severe challenges for the health care system. Our research group developed a web-based system named PANDIT that provides T2DM patients with insulin dosing advice using state of the art clinical decision support technology. The PANDIT interface resembles a glucose diary and provides advice through pop-up messages. Diabetes nurses (DNs) also have access to the system, allowing them to intervene when needed. The objective of this study was to establish whether T2DM patients can safely use PANDIT at home. To this end, we assessed whether patients experience usability problems with a high risk of compromising patient safety when interacting with the system, and whether PANDIT's insulin dosing advice are clinically safe. RESEARCH DESIGN AND METHODS: The study population consisted of patients with T2DM (aged 18-80) who used a once daily basal insulin as well as DNs from a university hospital. The usability evaluation consisted of think-aloud sessions with four patients and three DNs. Video data, audio data and verbal utterances were analyzed for usability problems encountered during PANDIT interactions. Usability problems were rated by a physician and a usability expert according to their potential impact on patient safety. The usability evaluation was followed by an implementation with a duration of four weeks. This implementation took place at the patients' homes with ten patients to evaluate clinical safety of PANDIT advice. PANDIT advice were systematically compared with DN advice. Deviating advice were evaluated with respect to patient safety by a panel of experienced physicians, which specialized in diabetes care. RESULTS: We detected seventeen unique usability problems, none of which was judged to have a high risk of compromising patient safety. Most usability problems concerned the lay-out of the diary, which did not clearly indicate which data entry fields had to be entered in order to obtain an advice. 27 out of 74 (36.5%) PANDIT advice differed from those provided by DNs. However, only one of these (1.4%) was considered unsafe by the panel. CONCLUSION: T2DM patients with no prior experience with the web-based self-management system were capable of consulting the system without encountering significant usability problems. Furthermore, the large majority of PANDIT advice were considered clinically safe according to the expert panel. One advice was considered unsafe. This could however easily be corrected by implementing a small modification to the system's knowledge base. PMID- 23735523 TI - [Mind control with optogenetic mice: exploring the causal relationships between brain activity and the mind]. AB - Every scientific endeavor starts with observation. However, observation alone can only lead to an analysis of correlations. Experimental perturbations are required to understand the causal relationships between the components that constitute the system under study. Our current understanding of the function of the brain, which is a complex multicellular organ, suggests that communication between cells underlies the formation of the mind. This has been mainly deduced from studies of correlations between cell activity and animal behavior. Recently developed tools have enabled the specific control of cell activity. For example, light-sensitive proteins, such as channelrhodopsin-2, that are found in microorganisms can now be genetically expressed in mammalian brain cells, allowing experimenters to optically control cell activity at will. In this review, I introduce the recently established method, Knockin-mediated ENhanced Gene Expression by the improved tetracycline-controlled gene induction (KENGE-tet) method, which has generated a repertoire of transgenic mice that express levels of the highly light-sensitive channelrhodopsin-2 mutant that are sufficient to stimulate multiple cell types. In addition to neurons, manipulations of the activities of nonexcitable glial cells in vivo have also proved possible. A recent report that used the KENGE-tet has shown that the selective optogenetic stimulation of glia can lead to the release of glutamate as a gliotransmitter, synaptic plasticity, and the acceleration of cerebellar-modulated motor learning. These findings have suggested that glia also participate in brain information processing, a function once thought to be solely mediated by neuronal activity. These reports have demonstrated the use of optogenetic tools in exploring the causal relationships between brain activity and the mind. PMID- 23735524 TI - [Mechanisms of neural circuit remodeling in the primary somatosensory cortex in mouse models of chronic pain]. AB - Chronic pain is caused by injury or inflammation of the peripheral tissues and by abnormal activities in the central nervous system including the spinal cord area related to generation and maintenance of chronic pain. In the cerebral cortex, several areas respond to noxious stimulation. Since activities of these cortical areas are enhanced in chronic pain conditions, not only a single cortical area, but also the interaction between multiple cortical areas seems to contribute to chronic pain. The primary somatosensory cortex (S1), which is one of the pain related cortical areas, plays a role in recognition of strength, location, and duration of pain. Since activities of the S1 are enhanced in chronic pain conditions, this area is likely to have an important role in the generation or maintenance of chronic pain. The S1 consists of 6 layers and has both excitatory and inhibitory neurons. The excitatory neurons integrate pain information from the peripheral nerves and send it to other excitatory neurons in the S1 and other cortical areas. On the other hand, the inhibitory neurons modulate activities of the excitatory neurons and contribute to sensory processing. However, how these neuronal structures and functions alter in chronic pain and contribute to chronic pain behavior is unknown. In this review, we highlight recent two-photon microscopy studies that elucidate the mechanisms of neuronal circuit remodeling in the S1 under chronic pain conditions. PMID- 23735525 TI - [Selective ablation of certain neural pathways by gene transfer using viral vectors: analysis of primate basal ganglia functions by using immunotoxin mediated tract targeting]. AB - Using a neuron-specific retrograde gene-transfer vector based on the lentivirus, we established immunotoxin (IT)-mediated tract targeting in the primate brain; this technique allows ablation of a neuronal population constituting a certain pathway. Here, we introduce a recent study on selective removal of the cortico subthalamic "hyperdirect" pathway. Together with the direct and indirect pathways, the hyperdirect pathway plays a crucial role in motor information processing in the basal ganglia. This pathway links the motor-related areas of the frontal lobe directly to the subthalamic nucleus (STN) without relay at the striatum. After electrical stimulation of the motor-related areas, such as the supplementary motor area (SMA), triphasic responses consisting of an early excitation, an inhibition, and a late excitation are usually detected in the internal segment of the globus pallidus (GPi). Several lines of evidence suggest that the early excitation may be derived from the hyperdirect pathway. We injected the lentiviral vector expressing human interleukin-2 receptor alpha subunit into the monkey STN. IT was then injected into the SMA. We recorded GPi neuron responses to SMA stimulation. We found that the early excitation was reduced neither with the inhibition nor with the late excitation. The spontaneous firing rate and pattern of GPi neurons remained unchanged. This indicated that IT mediated tract targeting successfully and selectively eliminated the hyperdirect pathway from the basal ganglia circuitry without affecting the spontaneous activity of STN neurons. This electrophysiological finding was confirmed using anatomical data obtained from retrograde and anterograde neural tracings. The present results show that the cortically driven early excitation in GPi neurons is mediated by the hyperdirect pathway. The IT-mediated tract targeting technique will provide us with novel strategies for elucidating various neural network functions. PMID- 23735526 TI - [Representation and readout of object information in macaque higher visual cortex]. AB - Electrocorticogram (ECoG) is an electrophysiological brain activity recording technique that has been widely revisited in recent years, not only for clinical monitoring, but also for prosthetic applications. However, the extent and limitations of the technique are poorly understood. Higher areas of human and macaque ventral visual cortices are known to have functional domain structures that are selective to certain categories, and population vectors that have been derived from visually evoked single-unit activity (SUA) recording in this region have been shown to form category clusters. How can visually evoked potentials recorded with ECoG from the same region be exploited to extract category information? To answer this question, the development of a simultaneous ECoG and SUA recording device by the modification of a previously reported flexible mesh ECoG probe with a microelectromechanical system has been promising (Toda et al., 2011). Indeed, Toda et al. conducted simultaneous recordings and reported that mesh ECoG signals exhibited comparable or better signal variabilities compared to conventional methods in the rat visual cortex. With this approach, we conducted intensive simultaneous ECoG and SUA recordings from the macaque anterior inferior temporal (IT) cortex. We compared how basic visual category and fine information is decoded from different recording modalities. Our preliminary results indicated that ECoG signals from the IT cortex may be a useful source for reading out certain levels of category information from visual input. PMID- 23735527 TI - [Imaging non-synaptic transmission via glutamate]. AB - Glutamate is the major excitatory neurotransmitter in the mammalian brain. The conventional view is that glutamate mediates synaptically confined point-to-point transmission at excitatory synapses. However, glutamate has also been suggested to escape from the synaptic cleft and mediate volume transmission, which is often referred to as glutamate spillover. This non-synaptic transmission via glutamate has been implicated in the regulation of a variety of important neural and glial functions. Despite the immense potential physiological and pathophysiological importance of glutamate spillover, the spatiotemporal dynamics of extrasynaptic glutamate concentrations have been only inferred indirectly, and their characteristics remain elusive because of a lack of appropriate technology. The recent development of fluorescent glutamate indicators has enabled the quantitative analysis of glutamate spillover. With a hybrid-type fluorescent indicator, we succeeded in imaging glutamate spillover in brain slices and in vivo. Our results showed that glutamate spillover was locally induced by the spatiotemporal cluster of synaptic activities due to the summation of glutamate originating from neighboring synapses. We also showed that glutamate spillover had magnitudes and durations that were sufficient for activating high-affinity glutamate receptors. Moreover, we successfully observed sensory input-induced glutamate spillover in the cerebral cortex in vivo. Thus, the present study clarified the features of non-synaptic transmission via glutamate and, furthermore, made it possible to directly visualize synaptic activity in live animals. PMID- 23735528 TI - [Network analyses in neuroimaging studies]. AB - Neurons are anatomically and physiologically connected to each other, and these connections are involved in various neuronal functions. Multiple important neural networks involved in neurodegenerative diseases can be detected using network analyses in functional neuroimaging. First, the basic methods and theories of voxel-based network analyses, such as principal component analysis, independent component analysis, and seed-based analysis, are described. Disease- and symptom specific brain networks have been identified using glucose metabolism images in patients with Parkinson's disease. These networks enable us to objectively evaluate individual patients and serve as diagnostic tools as well as biomarkers for therapeutic interventions. Many functional MRI studies have shown that "hub" brain regions, such as the posterior cingulate cortex and medial prefrontal cortex, are deactivated by externally driven cognitive tasks; such brain regions form the "default mode network." Recent studies have shown that this default mode network is disrupted from the preclinical phase of Alzheimer's disease and is associated with amyloid deposition in the brain. Some recent studies have shown that the default mode network is also impaired in Parkinson's disease, whereas other studies have shown inconsistent results. These incongruent results could be due to the heterogeneous pharmacological status, differences in mesocortical dopaminergic impairment status, and concomitant amyloid deposition. Future neuroimaging network analysis studies will reveal novel and interesting findings that will uncover the pathomechanisms of neurological and psychiatric disorders. PMID- 23735529 TI - [Neural mechanism of blindsight]. AB - "Blindsight" is a phenomenon whereby hemianopic patients with damage in the primary visual cortex (V1) are able to process visual information in their blind visual field. Two pathways that bypass the V1 may be responsible for this residual vision. The first pathway is the retinotectal pathway in which the superior colliculus in the midbrain receives direct retinal signals and sends them to the extrastriate cortex via the pulvinar. The second pathway is the geniculo-extrastriate pathway in which direct retinal input to the lateral geniculate nucleus is sent straight to the extrastriate cortex. Herein, I summarize evidence supporting the involvement of either pathway. The evidence was obtained from anatomical, neurophysiological, imaging, and behavioral studies carried out on macaque monkeys and humans. I emphasize three points: 1) crosstalk exists between the retinotectal pathway and the geniculo-extrastriate pathway, that is, the projection from the superficial layer of the superior colliculus to the koniocellular layer of the lateral geniculate nucleus; 2) three visual channels (the luminance in the magnocellular pathway, the red-green opponency in the parvocellular pathway, and the blue-yellow opponency in the koniocellular pathway) are not independent, as previously assumed; and 3) a global reorganization in the brain circuit occurs following the lesions of the V1 and subsequent recovery. Finally, I introduce a recent study that employed a saliency computational model to quantitatively evaluate the residual visual channels in blindsight monkeys during free-viewing behavior. Their findings suggest that plastic changes occur in the color-processing pathways. PMID- 23735530 TI - [Recent advances in social neuroscience research using macaques]. AB - The last decade has seen a surge of interest in the study of social brain functions. Research in this field, called social neuroscience, has been mostly carried out on human subjects by using a functional neuroimaging technique. This is largely because of the fact that humans have sophisticated social abilities and are capable of performing various demanding tasks in a scanner. However, given the limited spatiotemporal resolution inherent in the methodology, a systems neuroscience approach using macaque monkeys may provide a useful platform that promotes the understanding of social brain functions at the cellular level, thereby complementing neuroimaging techniques. Recently, it has been demonstrated to be technically feasible to train macaque monkeys to perform socially oriented behavioral tasks and directly examine cellular activity in their brains. In this paper, we review the literature on this new branch of social neuroscience. Emerging evidence now suggests that diverse aspects of social cognition, such as social valuation, gaze following, joint attention, monitoring of other's behavior, and social comparison are implemented by distributed neuronal networks, including the orbital, lateral, and medial sectors of the prefrontal cortex, premotor cortex, posterior parietal cortex, amygdala, and superior temporal sulcus. Continuing efforts in this research direction could uncover the neural basis whereby primates have become such successful social beings in the animal kingdom. PMID- 23735531 TI - [Risk factors for fractures in Parkinson's disease: a questionnaire survey]. AB - This study investigated the risk factors for fractures in patients with Parkinson's disease (PD). A questionnaire specifically designed to examine these risk factors was mailed to 172 PD patients registered in our self-developed PD database. We subsequently received replies from 158 patients, 22(14.8%)of whom had experienced fractures after PD onset. A multiple logistic regression model was used to evaluate the responses, and together with the clinical information stored in our PD database, it was revealed that psychiatric symptoms and falls within 1 year of our investigation were statistically correlated with the occurrence of fractures (adjusted odds ratio: 4.8 and 3.6, respectively). Thus, these results emphasize that psychiatric symptoms are an essential risk factor for fracture in PD patients. PMID- 23735532 TI - [Amyloid beta-related angiitis: brain lesions showing leptomeningeal gadolinium enhancement on MRI and characteristic surgical pathologic features]. AB - Amyloid-beta-related angiitis (ABRA) of the CNS occurs in association with vasculitis of small-and medium-sized leptomeningeal arteries. Here, we describe the clinicopathological features of a 76-year-old man with ABRA. The patient suffered progressive truncal oscillation, aphasia, and recent memory disturbance with a subacute disease onset. His cerebrospinal fluid showed a mild increase in protein levels (101 mg/dL) and pleocytosis (8/mm(3)). High-intensity brain lesion were detected on T(2)-weighted and FLAIR MRI scans, and prominent spread of gadolinium enhancement spreading was observed through the sulci of the left occipital and temporal lobes and left cerebellar hemisphere. A biopsy of the left temporal lesion showed a granulomatous and angiodestructive inflammation with infiltration of many CD4(+) T-lymphocytes and multinucleated giant cells and with fibrinoid necrosis of the arterial walls in the subarachnoid space. Immunolabeling for Abeta(1-40) revealed the abundant deposition of this protein in the affected arteries. On the basic of the diagnosis of ABRA, immunosuppressive therapy was conducted, and it ameliorated the clinical course. PMID- 23735534 TI - Immune responses to infection with H5N1 influenza virus. AB - Influenza A H5N1 viruses remain a substantial threat to global public health. In particular, the expanding genetic diversity of H5N1 viruses and the associated risk for human adaptation underscore the importance of better understanding host immune responses that may protect against disease or infection. Although much emphasis has been placed on investigating early virus-host interactions and the induction of innate immune responses, little is known of the consequent adaptive immune response to H5N1 virus infection. In this review, we describe the H5N1 virus-specific and cross-reactive antibody and T cell responses in humans and animal models. Data from limited studies suggest that although initially robust, there is substantial waning of the serum antibody responses in survivors of H5N1 virus infection. Characterization of monoclonal antibodies generated from memory B cells of survivors of H5N1 virus infection has provided an understanding of the fine specificity of the human antibody response to H5N1 virus infection and identified strategies for immunotherapy. Human T cell responses induced by infection with seasonal influenza viruses are directed to relatively conserved internal proteins and cross-react with the H5N1 subtype. A role for T cell-based heterosubtypic immunity against H5N1 viruses is suggested in animal studies. Further studies on adaptive immune responses to H5N1 virus infection in both humans and animals are needed to inform the design of optimal immunological treatment and prevention modalities. PMID- 23735533 TI - The emergence and diversification of panzootic H5N1 influenza viruses. AB - The Asian highly pathogenic avian influenza H5N1 virus was first detected in the goose population of Guangdong, China in 1996. The viruses in this lineage are unique in their ecological success, demonstrating an extremely broad host range and becoming established in poultry over much of Asia and in Africa. H5N1 viruses have also diverged into multiple clades and subclades that generally do not cross neutralize, which has greatly confounded control measures in poultry and pre pandemic vaccine strain selection. Although H5N1 viruses currently cannot transmit efficiently between mammals they exhibit high mortality in humans and recent experimental studies have shown that it is possible to generate an H5N1 virus that is transmissible in mammals. In addition to causing unprecedented economic losses, the long-term presence of the H5N1 virus in poultry and its frequent introductions to humans continue to pose a significant pandemic threat. Here we provide a summary of the genesis, molecular epidemiology and evolution of this H5N1 lineage, particularly the factors that have contributed to the continued diversification and ecological success of H5N1 viruses, with particular reference to the poultry production systems they have emerged from. PMID- 23735536 TI - A qualitative assessment of challenges to tuberculosis management and prevention in Northern Ethiopia. AB - OBJECTIVE: To elicit Ethiopian health care providers' understanding of challenges to effectively preventing, diagnosing and treating tuberculosis (TB). DESIGN: Qualitative data were collected via in-depth interviews and focus group discussions with 73 providers, including physicians, nurses, pharmacists and laboratory technicians, in five hospitals in the Northern Ethiopian regions of Amhara and Tigray. There was no intervention. RESULTS: Focus groups and interviews shared a number of prominent common themes. Respondents identified numerous challenges associated with active case identification, infection control practices, diagnostics, including the absence of TB culture and drug susceptibility testing capacity, and the lack of infrastructure for diagnosing and treating multidrug-resistant TB. Pharmacists noted a need for improved procurement practices and pediatric dosages for TB medications. Providers shared concerns regarding isoniazid preventive therapy, health workforce challenges and the risk of contracting TB in the workplace. CONCLUSIONS: Health care providers in the Northern Ethiopian regions of Tigray and Amhara identified many challenges to effectively preventing, diagnosing and treating TB. These challenges are complicated by severe resource constraints and challenges in attracting and retaining providers in government hospitals in centers outside Addis Ababa. PMID- 23735537 TI - Ultrafiltration in heart failure with preserved ejection fraction: comparison with systolic heart failure patients. AB - BACKGROUND: Ultrafiltration (UF) is a widely used technology for inpatient management of acute decompensated heart failure in patients with volume overload. However, the safety and efficacy of UF in patients with heart failure and preserved left ventricular ejection fraction (heart failure with preserved ejection fraction [HFPEF]) need further clarification. We hypothesized that UF could be used in this population with outcomes similar to acute decompensated heart failure patients with low left ventricular ejection fraction (HFLEF). METHODS AND RESULTS: Prospective evaluation was performed on 2 patient cohorts admitted to a single institution for acute decompensated heart failure and treated with UF: HFLEF (left ventricular ejection fraction <= 40%; n=87) and HFPEF (left ventricular ejection fraction >40%; n=97). Selected demographic and clinical data were compared, including clinical and serological information, as well as in-hospital and 90-day postdischarge mortality. HFPEF patients were more likely to be women, have higher blood pressures, and less likely to have ischemic heart disease. There were no significant differences in total weight loss (7.7% in HFLEF and 7.0% in HFPEF), electrolyte and renal disturbances, or in-hospital mortality (3.4% in HFLEF and 3.3% in HFPEF) between the 2 groups. Mortality at 90 days tended to be greater in HFLEF (24.1%) than in HFPEF (15.5%). CONCLUSIONS: Therapeutic responses in patients with HFPEF meeting current indication for UF are similar to those with HFLEF. Larger studies are warranted to better characterize acute heart failure management with UF in this population. PMID- 23735538 TI - Chromatin alterations during pollen development in Hordeum vulgare. AB - The dynamics of posttranslational histone modifications in relation to nuclear architecture has been analyzed during pollen development in Hordeum vulgare L. cv. Igri. Notwithstanding the asymmetry of cytokinesis associated with pollen mitosis I, immunolabeling revealed that the vegetative and generative nuclei initially display identical chromatin modification patterns. Yet, differential chromatin modification patterns between vegetative and generative nuclei emerge with the development of conspicuous differences in nuclear morphology as visualized by 4',6-diamidino-2-phenylindole staining. The temporal and spatial distribution of most histone modifications observed is in agreement with reduced gene activity in the generative nucleus and increased expression in the vegetative nucleus as indicated by immunolabeling of active RNA polymerase II. Signals of trimethylation of histone H3 lysine 27 proved to be particularly enriched in euchromatic domains of subtelomeric regions. In the context of nuclear differentiation in bicellular pollen, this modification became restricted to the vegetative nucleus, indicating a role in activating rather than suppressing gene expression. The presence of acetylated histone H3 at lysine 9 in the cytoplasm of the generative cell is indicative of a more complex, still unknown function of this particular modification. PMID- 23735539 TI - Unrecognized paraganglioma of the urinary bladder as a cause for basilar-type migraine. AB - Extra-adrenal paraganglioma with isolated localization in the urinary bladder is a rare neuroendocrine tumor. Although the typical symptoms like headache, nausea, weight loss, flushing, heart palpitation or paroxysmal hypertension during micturition are well established, we present an unusual case of bladder paraganglioma, 'misdiagnosed' with basilar-type migraine due to headache for the past 8 years. As urologists linked the presence of a tumor (by CT) and symptoms connected with micturition, no cystoscopy and no transurethral resection of the bladder was performed prior to detailed diagnostic workup. After diagnosis of an extra-adrenal paraganglioma, the patient was scheduled for open partial cystectomy. In consideration of the fact that bladder paraganglioma is an infrequent genitourinary cancer, this case report clearly points out the importance of an exact anamnesis and clinical examination to minimize the probability of misdiagnosis with possible fatal consequences in any case with clinical suspicion of bladder paraganglioma. PMID- 23735535 TI - Natural history of highly pathogenic avian influenza H5N1. AB - The ecology of highly pathogenic avian influenza (HPAI) H5N1 has significantly changed from sporadic outbreaks in terrestrial poultry to persistent circulation in terrestrial and aquatic poultry and potentially in wild waterfowl. A novel genotype of HPAI H5N1 arose in 1996 in Southern China and through ongoing mutation, reassortment, and natural selection, has diverged into distinct lineages and expanded into multiple reservoir hosts. The evolution of Goose/Guangdong-lineage highly pathogenic H5N1 viruses is ongoing: while stable interactions exist with some reservoir hosts, these viruses are continuing to evolve and adapt to others, and pose an un-calculable risk to sporadic hosts, including humans. PMID- 23735540 TI - Zoonotic Mycobacterium bovis-induced tuberculosis in humans. AB - We aimed to estimate the global occurrence of zoonotic tuberculosis (TB) caused by Mycobacterium bovis or M. caprae infections in humans by performing a multilingual, systematic review and analysis of relevant scientific literature of the last 2 decades. Although information from many parts of the world was not available, data from 61 countries suggested a low global disease incidence. In regions outside Africa included in this study, overall median proportions of zoonotic TB of <=1.4% in connection with overall TB incidence rates <=71/100,000 population/year suggested low incidence rates. For countries of Africa included in the study, we multiplied the observed median proportion of zoonotic TB cases of 2.8% with the continental average overall TB incidence rate of 264/100,000 population/year, which resulted in a crude estimate of 7 zoonotic TB cases/100,000 population/year. These generally low incidence rates notwithstanding, available data indicated substantial consequences of this disease for some population groups and settings. PMID- 23735541 TI - Apoptosis induced by paclitaxel via Bcl-2, Bax and caspases 3 and 9 activation in NB4 human leukaemia cells is not modulated by ERK inhibition. AB - We have studied the role of pivotal bio-molecules involved in signalling of cytotoxic effects induced by paclitaxel (Ptx) on acute promyelocytic human leukaemia NB4 cells. A time-dependent increase in cell death and DNA cleavage was observed after 30MUM Ptx treatment. Cell death induction by Ptx proceeds mainly as programmed cell death as shown by annexin V-FITC, reaching up to 30% of apoptotic cells after 24h. Significant reductions of p53, changes in Bax and Bcl 2 and activation of caspases 3 and 9 were observed as the treatment was applied for long times. Ptx treatments produced NFkB depletion with expression levels abolished at 19h what could be involved in reduction of survival signals. Phosphorylation of intracellular kinases showed that pERK1/2 decreased significantly at 19h of Ptx treatment. When these cells were preincubated for 90min with 20MUM PD98059, 2'-amino-3'-methoxyflavone, an inhibitor of ERK phosphorylation, a slight reduction of cell viability was observed in comparison to that produced by Ptx alone. Pretreatment with PD98059 neither activated caspases nor significantly increased the apoptotic effect of Ptx. Taken together, our data reveal that the inhibition of ERK phosphorylation does not seem to be an essential pathway for bursting an increased induction of apoptosis by Ptx. Decrease of p53 and Bcl-2, fragmentation of DNA, increase of Bax and, finally, activation of caspases 3 and 9 in NB4 leukaemia cells make the apoptotic process induced by Ptx irreversible. Application of Ptx in leukaemia cells shows therefore a promising potential with particular effects on different leukaemia cell types. PMID- 23735542 TI - Retrograde ejaculation associated spontaneous sperm cystolithiasis in four rhesus macaques (Macaca mulatta). AB - Retrograde ejaculation (RE) has been reported in humans and animals but RE with subsequent sperm calculi has rarely been reported. This report documents clinical and pathological findings of spontaneous sperm cystolithiasis in four rhesus macaques. While this condition has been associated with repeated electroejaculation, spontaneous sperm cystolithiasis is highly unusual. The animals presented with either stranguria, dysuria, hematuria, distended abdomen or lethargy. Ultrasound examination revealed several hyperechoic masses within the lumen of the urinary bladder. The animals were euthanized due to poor prognosis or study end points. Postmortem examination revealed multiple angular, amorphous, soft to firm, pale yellow to greenish-brown and variably sized calculi in the lumen of the urinary bladder or prostatic/penile urethra. Histologically, the calculi were composed of numerous sperm embedded in abundant brightly eosinophilic matrix. Based on gross and histologic findings, RE associated sperm cystolithiasis was diagnosed, with ulcerative urethritis as the major primary apparent etiology. To the authors' knowledge, this is the first report of four spontaneous cases of sperm cystolithiasis in rhesus macaques. PMID- 23735543 TI - The transmembrane domain of the T4SS coupling protein TrwB and its role in protein-protein interactions. AB - Bacteria use type IV secretion systems to transfer genetic material and proteins from donor to recipient cells, using proteins encoded by conjugative plasmids. Among those proteins the so-called Type IV Coupling Protein plays a central role in the process. One of the best studied members of this family is TrwB, the conjugative coupling protein of R388 plasmid. Previous studies indicated that the transmembrane domain of TrwB plays a role beyond the mere anchoring of the protein to the membrane. TrwB has also been shown to interact with other conjugative proteins, such as the VirB10-like protein of R388 TrwE. The goal of this study is to elucidate the role of the different domains of TrwB and TrwE in their biological function, and in both self- and TrwB-TrwE interactions. To this aim, a series of TrwB and TrwE deletion mutant proteins were constructed. Conjugation and interaction studies revealed that the transmembrane domain of TrwB, and particularly its second transmembrane helix, is needed for TrwB self interaction and for R388 conjugative transfer and that there are contacts between TrwB and TrwE in the membrane. On the contrary, the lack of the TMD of TrwE does not completely abolish R388 conjugation although the interaction between TrwE TrwB is lost. These results identify protein-protein interactions inside the membrane needed for T4SS function. PMID- 23735544 TI - Transcriptomic and iTRAQ proteomic approaches reveal novel short-term hyperosmotic stress responsive proteins in the gill of the Japanese eel (Anguilla japonica). AB - Osmoregulation is critical for the survival of fishes that migrate between freshwater (FW) and seawater (SW). The eel, as a catadromous fish, has been studied for decades to reveal the mechanisms of osmoregulation. These studies, however, have been limited by the lack of a genomic database to decipher the mechanism of osmoregulation at a molecular level. In this study, using high throughput transcriptomic and proteomic technologies, we have provided the first genome-wide study to identify hyperosmotic responsive proteins in the gills of the Japanese eel. Deep sequencing using the 454 platform produced over 660,000 reads with a mean length of 385 bp. For the proteomic study, we collected gill samples from three different treatment groups of fish that had fully adapted to FW/SW or were transferred from FW to SW for 6h. The respective group of gill proteins were extracted and labeled using an isobaric tag for relative and absolute quantitation (iTRAQ) using LTQ-Orbitrap, a high resolution mass spectrometer. Among the 1519 proteins identified from the gill samples, 96 proteins were differentially expressed between FW and SW adapted fish. Nineteen hyperosmotic responsive proteins were detected (10 up-regulated and 9 down regulated proteins) after 6h post FW to SW transfer. BIOLOGICAL SIGNIFICANCE: The study has provided the most comprehensive, targeted investigation of eel gill proteins to date, and shown the powerfulness of combining transcriptomic and proteomic approaches to provide molecular insights of osmoregulation mechanisms in a non-model organism, eel. PMID- 23735545 TI - Posterior interosseous nerve entrapment after Monteggia fracture-dislocation in children. AB - OBJECTIVE: Although most of nerve injuries associated with Monteggia fracture dislocation in children are neurapraxias and will recover spontaneously after conservative treatment, surgical exploration of the involved nerve is always required in the cases with the entrapment of posterior interosseous nerve (PIN). However, the necessity and time frame for surgical intervention for specific patterns of nerve dysfunction remains controversial. The aim of the report is to observe and understand the pathology of PIN injury associated with Monteggia fracture-dislocation in children, and to propose the possible indication for the exploration of nerve. METHODS: Eight cases, six boys and two girls, with Monteggia fracture-dislocation complicated by PIN injury, managed operatively at the authors?Hospital from 2007 to 2008 were retrospectively reviewed. All the patients underwent the attempted closed reduction before they received exploration of PIN, with open reduction and internal fixation or successful closed reduction. RESULTS: The PIN was found to be trapped acutely posterior to the radiocapitellar joint in 4 out of 5 Type III Bado's Monteggia fractures. In the remaining cases, since there were longer time intervals from injury to operation, chronic compressive changes and epineural fibrosis of radial nerve were visualized. After a microsurgical neurolysis performed, the complete recovery in the nerve function was obtained in all the cases during the follow up. CONCLUSION: The findings from this study suggest that every case of type III Monteggia fracture-dislocation with decreased or absent function of muscles innervated by PIN and an irreducible radial head in children should be viewed as an indication for immediate surgical exploration of the involved nerve to exclude a potential PIN entrapment. PMID- 23735546 TI - Influence of acute ethanol intoxication on neuronal apoptosis and Bcl-2 protein expression after severe traumatic brain injury in rats. AB - OBJECTIVE: To study the influence and mechanism of acute ethanol intoxication (AEI) on rat neuronal apoptosis after severe traumatic brain injury (TBI). METHODS: Ninety-six Sprague-Dawley rats were randomly divided into four groups: normal control, AEI-only, TBI-only and TBI+AEI (n equal to 24 for each). Severe TBI model was developed according to Feeney's method. Rats in TBI+AEI group were firstly subjected to AEI, and then suffered head trauma. In each group, animals were sacrificed at 6 h, 24 h, 72 h, and 168 h after TBI. The level of neuronal apoptosis and the expression of Bcl-2 protein were determined by TUNEL assay and immunohistochemical method, respectively. RESULTS: Apoptotic cells mainly distributed in the cortex and white matter around the damaged area. Neuronal apoptosis significantly increased at 6 h after trauma and peaked at 72 h. Both the level of neuronal apoptosis and expression of Bcl-2 protein in TBI-only group and TBI+AEI group were higher than those in control group (P less than 0.05). Compared with TBI-only group, the two indexes were much higher in TBI+AEI group at all time points (P less than 0.05). CONCLUSION: Our findings suggest that AEI can increase neuronal apoptosis after severe TBI. PMID- 23735547 TI - An epidemiologic survey of road traffic accidents in Iran: analysis of driver related factors. AB - OBJECTIVE: Road traffic accident (RTA) and its related injuries contribute to a significant portion of the burden of diseases in Iran. This paper explores the association between driver-related factors and RTA in the country. METHODS: This cross-sectional study was conducted in Iran and all data regarding RTAs from March 20, 2010 to June 10, 2010 were obtained from the Traffic Police Department. We included 538 588 RTA records, which were classified to control for the main confounders: accident type, final cause of accident, time of accident and driver related factors. Driver-related factors included sex, educational level, license type, type of injury, duration between accident and getting the driving license and driver's error type. RESULTS: A total of 538 588 drivers (91.83% male, sex ratio of almost 13:1) were involved in the RTAs. Among them 423 932 (78.71%) were uninjured; 224 818 (41.74%) had a diploma degree. Grade 2 driving license represented the highest proportion of all driving licenses (290 811, 54.00%). The greatest number of accidents took place at 12:00-13:59 (75 024, 13.93%). The proportion of drivers involved in RTAs decreased from 15.90% in the first year of getting a driving license to 3.13% after 10 years'of driving experience. Neglect of regulations was the commonest cause of traffic crashes (345 589, 64.17%). Non observance of priority and inattention to the front were the most frequent final causes of death (138 175, 25.66% and 129 352, 24.02%, respectively). We found significant association between type of accident and sex, education, license type, time of accident, final cause of accident, driver's error as well as duration between accident and getting the driving license (all P less than 0.001). CONCLUSION: Our results will improve the traffic law enforcement measures, which will change inappropriate behavior of drivers and protect the least experienced road users. PMID- 23735548 TI - Effect of Advanced Trauma Life Support program on medical interns' performance in simulated trauma patient management. AB - OBJECTIVE: Since appropriate and time-table methods in trauma care have an important impact on patients'outcome, we evaluated the effect of Advanced Trauma Life Support (ATLS) program on medical interns' performance in simulated trauma patient management. METHODS: A descriptive and analytical study before and after the training was conducted on 24 randomly selected undergraduate medical interns from Imam Reza Hospital in Mashhad, Iran. On the first day, we assessed interns' clinical knowledge and their practical skill performance in confronting simulated trauma patients. After 2 days of ATLS training, we performed the same study and evaluated their score again on the fourth day. The two findings, pre- and post- ATLS periods, were compared through SPSS version 15.0 software. P values less than 0.05 were considered statistically significant. RESULTS: Our findings showed that interns'ability in all the three tasks improved after the training course. On the fourth day after training, there was a statistically significant increase in interns' clinical knowledge of ATLS procedures, the sequence of procedures and skill performance in trauma situations (P less than 0.001, P equal to 0.016 and P equal to 0.01 respectively). CONCLUSION: ATLS course has an important role in increasing clinical knowledge and practical skill performance of trauma care in medical interns. PMID- 23735549 TI - Craniocerebral injuries in war against terrorism --- a contemporary series from Pakistan. AB - OBJECTIVE: Terrorism-related bomb attacks on civilian population have increased dramatically over the last decade. Craniocerebral injuries secondary to improvised explosive devices have not been widely reported in the context of unarmored civilians. This series intends to report the spectrum of these injuries secondary to suicidal and implanted bombs as encountered at the Aga Khan University Hospital, Pakistan (AKUH). Further, a few pertinent management guidelines have also been discussed. METHODS: The hospital database and clinical coding during a 5-year period were examined for head injuries secondary to terrorism-associated blasts. In addition to patient demographics, data analysis for our series included initial Glasgow Coma Scale, presenting neurological complaints, associated non-neurological injuries, management (conservative or operative) to associated complications, and discharge neurological status. RESULTS: A total of 16 patients were included in this series. Among them 9 were victims of suicidal blasts while 7 were exposed to implanted devices. The patients presented with diverse patterns of injury secondary to a variety of shrapnel. A follow-up record was available for 12 of the 16 patients (mean follow up: 7.8 months), with most patients having no active complaints. CONCLUSION: The results of this series show that civilian victims of suicidal and improvised bombings present with a wide range of neurological symptoms and injury patterns, which often differ from the neurological injuries incurred by military personnel in similar situations, and thereby often require individualized care. PMID- 23735550 TI - Prevention of bone loss by injection of insulin-like growth factor-1 after sciatic neurectomy in rats. AB - OBJECTIVE: Injection of insulin-like growth factor-1 (IGF-1) can prevent bone loss in sciatic nerve transaction rats. We try to investigate the action mechanism of IGF-1 on bone formation. METHODS: A total of 40 adult male Spragne Dawley rats were divided into two groups (experimental group and control group) with 20 animals in each. Sciatic neurectomy was performed to model disuse osteoporosis in all rats. IGF-1 was administered in experimental group with the dose of 100 microgramme/kilogram per day for 3 days. Meanwhile, the rats in control group were treated with saline. Bone mineral density was measured by dual energy X-ray absorptiometry 4 and 6 weeks after neurectomy respectively. Expression of Osterix and Runx2 was determined by reverse transcription polymerase chain reaction (RT-PCR) assay. RESULTS: There was a significant increase in the bone mineral density of experimental group compared with control group. There was a significant decrease in the level of receptor activator of nuclear factor-kappaB-ligand but an increase in the level of osteoprotegerin 4 and 6 weeks after neurectomy in the experimental group compared with control one. The expression of Osterix and Runx2 was up-regulated in the bone marrow of experimental group compared with control group. CONCLUSION: IGF-1 can increase bone formation by stimulation of osteoblast number and activity, and reduce bone resorption by restriction of differentiation of osteoclast, suggesting that IGF-1 may improve the therapeutic efficacy for disuse osteoporosis. PMID- 23735552 TI - Modern concepts of transport in multiple trauma: a narrative review. AB - Multiple variables can influence triage decision in multiple trauma. Recognition of priorities and selection of the destination can be successfully achieved by field triage and individualized clinical judgment. This narrative review summarizes the new options and protocols for transport of injured subjects. There are four levels of emergency medical providers including first responders and three levels of emergency medical technicians. Two distinct accepted protocols for transport are known as scoop and run and treat and then transfer. The former provides minimum lifesaving treatment at the scene of accident followed by transferring the patient(s) as soon as possible, and the latter mainly emphasizes the need for complete stabilization as a prerequisite for safe transport. The destination and mode of transport are selected according to clinical capabilities of the receiving hospital, transfer time from the scene to the facility, patient's medical condition, accessibility of the scene, and weather. Two common methods of transfer are ground transport, including various type of ambulances, and air medical transport, i.e. helicopter and airplane. PMID- 23735551 TI - Long-term effects of mustard gas on respiratory system of Iranian veterans after Iraq-Iran war: a review. AB - To review long-term respiratory effects of mustard gas on Iranian veterans having undergone Iraq-Iran war. Electronic databases of Scopus, Medline, ISI, IranMedex, and Irandoc sites were searched. We accepted articles published in scientific journals as a quality criterion.The main pathogenic factors are free radical mediators. Prevalence of pulmonary involvement is approximately 42.5%. The most common complaints are cough and dyspnea. Major respiratory complications are chronic obstructive pulmonary disease, bronchiectasis, and asthma. Spirometry results can reveal restrictive and obstructive pulmonary disease. Plain chest X ray does not help in about 50% of lung diseases. High-resolution CT of the lung is the best modality for diagnostic assessment of parenchymal lung and bronchi. There is no definite curative treatment for mustard lung. The effective treatment regimens consist of oxygen administration, use of vaporized moist air, respiratory physiotherapy, administration of mucolytic agents, bronchodilators, corticosteroids, and long-acting beta-2 agonists, antioxidants, surfactant, magnesium ions, therapeutic bronchoscopy, laser therapy, placement of respiratory stents, early tracheostomy in laryngospasm, and ultimately lung transplantation. High-resolution CT of the lung is the most accurate modality for the evaluation of the lung parenchyma and bronchi. The treatment efficacy of patients exposed to mustard gas depends on patient conditions (acute or chronic, upper or lower respiratory tract involvement). There are various treatment protocols, but unfortunately none of them is definitely curable. PMID- 23735553 TI - Electroversion in treatment of arrhythmia in a patient with Wolff-Parkinson-White syndrome and cervical spinal cord injury. AB - We report electroversion in treatment of atrial fibrillation (AF) and atrioventricular nodal reentry tachycardia (AVNRT) in a patient with Wolff Parkinson-White syndrome and cervical spinal cord injury. At first, the patient sustained respiratory failure and weak cough reflex, thereafter repeated bronchoscopy was used to aspirate the sputum as well as control the pneumonia, which resulted in arrhythmia (AF and AVNRT). Two doses of intravenous amiodarone failed to correct the arrhythmia. After restoration of sinus rhythm by electroversion, he was successfully weaned from mechanical ventilation and discharged from the intensive care unit without recurrent arrhythmia. PMID- 23735554 TI - Traumatic L5 over S1 spondyloptosis without neurological involvement managed nonoperatively: a case report. AB - High-grade spondylolisthesis is very rare. We came across a case of high-grade spondylolisthesis at the L5-S1 level in a 32-year-old manual labourer who was hit by a heavy object on his flexed back. The patient presented to us with persistent deformity in the back. He complained of back pain on prolonged standing and after moderate work. Because of that he was unable to return to his work. On clinical examination there was a large step in the lower lumbar region. Detailed neurological evaluation of the lower limbs did not reveal any sensory or motor deficit, neither did bowel or bladder involvement. Radiographic examination showed L5 over S1 traumatic spondyloptosis. CT scan revealed that neural canal was in normal width. MRI confirmed spondyloptosis of L5 over S1 without any compromise of the spinal canal and with normal-looking cauda. Concerning the delayed presentation and no neurological deficit, the patient was managed conservatively after thorough counsel. At 6 months, the patient returned to his work and at the latest follow-up (15 months) he was free from back pain. Conservative means of treatment can lead to satisfactory outcome, especially when the patient has delayed presentation. PMID- 23735555 TI - Ipsilateral dislocation of the radial head associated with fracture of distal end of the radius: a case report and review of the literature. AB - Dislocation of the radial head in adults is uncommon. A simultaneous dislocation of the radial head and fracture of the ipsilateral distal end of radius with no other associated injuries is extremely rare. As far as we know, such an injury after an unusual mode of injury has been seldom reported in the English literature. We report such a case without any associated injuries or comorbidity. Closed reduction was performed within two hours after injury and results were satisfactory. Immobilisation was continued for 3 weeks. Gradual mobilisation was started after removal of the plaster under the supervision of a physiotherapist. At 6 months'follow-up, the patient had no residual pain at the elbow with full flexion and extension. Almost full supination with a restriction of last 10 degrees of pronation was achieved. There was no evidence of instability of the elbow. PMID- 23735556 TI - Delayed migration of K-wire into popliteal fossa used for tension band wiring of patellar fracture. AB - Breakage of K-wires and stainless steel wires which are used for fracture fixation is not uncommon, but migration is rare. We report a case of migration of broken K-wire used for patella tension band wiring to the popliteal fossa. The broken hardware was removed surgically. We would like to suggest that K-wire and wire fixation used for treatment of patellar fractures can migrate into the posterior compartment of the knee and cause clinical symptoms. Close clinical and radiological follow-up after internal fixation to identify the presence of hardware breakage or movement and removal of wires once fracture has united can avert such complications. PMID- 23735557 TI - Scaphoid dislocation with hamate fracture and proximal migration of distal carpal row. AB - Scaphoid dislocation is a rare injury. Traditionally it has been classified into isolated dislocation and dislocation associated with axial carpal disruption. We present a unique case of scaphoid dislocation associated with proximal migration of the entire distal carpal row as a single unit and hamate fracture with no axial carpal disruption. This injury complex has not been previously described in the literature. The purpose of this case report is to emphasize that in absence of axial carpal dissociation with scaphoid dislocation, a careful evaluation of injury to other bones should be done and treated accordingly to maximize the chances of favourable outcome with reconstructive surgery. PMID- 23735558 TI - Robust hopping based on virtual pendulum posture control. AB - A new control approach to achieve robust hopping against perturbations in the sagittal plane is presented in this paper. In perturbed hopping, vertical body alignment has a significant role for stability. Our approach is based on the virtual pendulum concept, recently proposed, based on experimental findings in human and animal locomotion. In this concept, the ground reaction forces are pointed to a virtual support point, named virtual pivot point (VPP), during motion. This concept is employed in designing the controller to balance the trunk during the stance phase. New strategies for leg angle and length adjustment besides the virtual pendulum posture control are proposed as a unified controller. This method is investigated by applying it on an extension of the spring loaded inverted pendulum (SLIP) model. Trunk, leg mass and damping are added to the SLIP model in order to make the model more realistic. The stability is analyzed by Poincare map analysis. With fixed VPP position, stability, disturbance rejection and moderate robustness are achieved, but with a low convergence speed. To improve the performance and attain higher robustness, an event-based control of the VPP position is introduced, using feedback of the system states at apexes. Discrete linear quartic regulator is used to design the feedback controller. Considerable enhancements with respect to stability, convergence speed and robustness against perturbations and parameter changes are achieved. PMID- 23735559 TI - Total shoulder arthroplasty versus hemiarthroplasty in patients with shoulder osteoarthritis: a meta-analysis of randomized controlled trials. AB - OBJECTIVES: Total shoulder arthroplasty (TSA) and hemiarthroplasty (HA) are treatment choices for end-stage shoulder osteoarthritis. The decision of whether to use TSA or HA is controversial. The objective of this study was to compare the effects of TSA and HA for shoulder osteoarthritis. METHODS: We conducted a search for clinical studies that had been published in any language in December 2012 or before. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and several other databases. Randomized and quasi-randomized controlled clinical studies that evaluated different methods were included. At least two review authors independently performed the study selection, data collection, and data extraction. The software Revman 5.1 was used for the statistical analysis. RESULTS: This study included 4 clinical trials. Two of the trials were published clinical trials, and the other 2 clinical trials were presented as unpublished abstracts. A total of 146 patients with 153 shoulders were included in the trials. Compared with HA, TSA presents with a higher UCLA shoulder scale (MD 3.10, 95% CI 1.13-5.08) and a higher ASES (MD 10.17, 95% CI 1.40-18.87). There was no significant difference between TSA and HA for revision (RR 0.35, 95% CI 0.10-1.19), WOOS (MD 9.10, 95% CI -2.72 to 20.92), and incidence of instability (RR 0.88, 95% CI 0.19-3.98). HA had a lower operation time (MD 39.00, 95% CI 17.05-60.95). CONCLUSION: The available evidence suggests that TSA is more effective than HA for patients with shoulder arthritis. PMID- 23735561 TI - A new perspective on the autonomic nervous system. PMID- 23735560 TI - Follow-the-leader cell migration requires biased cell-cell contact and local microenvironmental signals. AB - Directed cell migration often involves at least two types of cell motility that include multicellular streaming and chain migration. However, what is unclear is how cell contact dynamics and the distinct microenvironments through which cells travel influence the selection of one migratory mode or the other. The embryonic and highly invasive neural crest (NC) are an excellent model system to study this question since NC cells have been observed in vivo to display both of these types of cell motility. Here, we present data from tissue transplantation experiments in chick and in silico modeling that test our hypothesis that cell contact dynamics with each other and the microenvironment promote and sustain either multicellular stream or chain migration. We show that when premigratory cranial NC cells (at the pre-otic level) are transplanted into a more caudal region in the head (at the post-otic level), cells alter their characteristic stream behavior and migrate in chains. Similarly, post-otic NC cells migrate in streams after transplantation into the pre-otic hindbrain, suggesting that local microenvironmental signals dictate the mode of NC cell migration. Simulations of an agent-based model (ABM) that integrates the NC cell behavioral data predict that chain migration critically depends on the interplay of biased cell-cell contact and local microenvironment signals. Together, this integrated modeling and experimental approach suggests new experiments and offers a powerful tool to examine mechanisms that underlie complex cell migration patterns. PMID- 23735562 TI - Complex three-way translocation involving MLL, ELL, RREB1, and CMAHP genes in an infant with acute myeloid leukemia and t(6;19;11)(p22.2;p13.1;q23.3). AB - Rearrangements affecting the MLL gene in hematological malignancies are associated with poor prognosis. Most often they are reciprocal translocations and more rarely complex forms involving at least 3 chromosomes. We describe an unusual case with cutaneous leukemic infiltrates that waxed and waned until progression to acute myeloid leukemia, AML-M5. The leukemic cells harbored a novel apparent 3-way translocation t(6;19;11)(p22.2;p13.1;q23.3). We utilized advanced molecular cytogenetic methods including 24-color karyotyping, high resolution array comparative genomic hybridization (aCGH) and DNA sequencing to characterize the genomic complement in the leukemic cells from aspirated bone marrow cells at AML diagnosis. Karyotyping showed 47,XY,t(6;19;11)(p22;p13;q23),+der(6)t(6;11)(p22;q23)[17]/48,sl,+8[3]/48,sl,+8,de (12)t(1;12)(q11;p13)[3]/ 48,sdl,der(Y)t(Y;1)(q12;q11),+8[7] conferring MLL-ELL fusion. Oligo-aCGH analysis confirmed gains of 6p22qter and 11q23.3qter involving the CMAHP and MLL genes, respectively. DNA sequencing disclosed an additional breakpoint at 6p24.3 (at RREB1 gene). Retrospective fluorescence in situ hybridization revealed presence of the MLL-involving rearrangement in the initial stages of disease before clear morphological signs of bone marrow involvement. The patient responded well to therapy and remains in remission>6 years from diagnosis. This apparent 3-way translocation is remarkable because of its rarity and presentation with myeloid sarcoma, and may, as more cases are characterized, further our understanding onto how such complex translocations contribute to promote leukemogenesis and respond to therapy. PMID- 23735563 TI - 1st World Congress of Children and Youth Health Behaviours. Preface. PMID- 23735564 TI - Nutritional status in preschool children: current trends of mother's body perception and concerns. AB - BACKGROUND: Studies in several countries indicate that parents show little concern and aren't much aware of the nutritional status of their children, and have the tendency to underestimate the overweight which may present a difficulty when promoting healthier life styles. The aim of this study was to identify maternal body image perceptions in preschool children and analyze its relationship with nutritional status and family social demographic variables. METHODS: A transversal and descriptive study was developed in a sample of 1424 preschool children and their mothers living in several parts of Portugal. The children were weighted and measured by trained personnel, the BMI was calculated and the nutritional status was classified according to the NCHS referential (CDC, 2000).(1) Mother's real and ideal body image perception from their children was evaluated according to Collins' body image silhouettes (1991).(2) RESULTS: The ideal and real perception was translated in a negative index on both children's genders, however 67.2% of the mothers revealed accuracy of perception, while 22.3% had a negative and 12.8% a positive discrepancy, being this significant concerning gender and age of the children. Children's actual weight status (ie, 60.2% normal weight, 16.9% overweight, 17.4% obese and 5.5% underweight) was significantly different from their parents' perceptions (ie, 52.3% normal weight, 27.5% overweight 0,6% obesity and 19.6% underweight) explaining in 25.9% the variability of this perception. Globally 42.3% has no discrepancy but 44.3% thinks that children were thin and 13.4% heavier. This difference is significant concerning the age and scholarship of the mothers but has no relation with the income and residence. CONCLUSION: Despite signs of a positive trend, mothers continue to show difficulty in recognizing the children's nutritional status, so effective public health strategies to increase parents' awareness could be the first step in an effort to prevent childhood obesity. PMID- 23735565 TI - Genetic heritage as a risk factor enabling chilhood obesity. AB - INTRODUCTION: Nowadays, it is an evidence that maternal obesity is an important predictor of obesity in the descendants, not being consensual if that influence comes from the interaction between genes and facilitators family contexts or both. OBJECTIVES: 1) To determinate the prevalence of the child overweight; 2) to classify the nutritional status and metabolic risk of the progenitors; 3) to analyze the effect of the markers of the family metabolic risk in the expression of the illness in the child. MATERIAL AND METHODS: Descriptive study composed by 1424 children, average age 4.58 years old and their mothers, average age 34.47 years old, living in several parts of Portugal. The children's anthropometric measures were evaluated and classified according to the NCHS referential (CDC, 2000)(1) and of the progenitors by the orientations of the WHO (2000)(2) and Portugal, DGS (2005).(3) Social demographic data was obtained by filling in the Food Frequency Questionnaire adapted from Rito (2007).(4) RESULTS: The overweight affected 34.3% of the children, (including 17.4% obesity), being the higher values on boys (36.8%) and in 5 year old children (39.5). In 41.9% of the progenitors overweight was noted (12.1% obesity), being higher in mothers with low scholarship, low income, older and living in a rural area. The probability of the child to be overweighted was 1.4 times higher when mothers were overweight, and close to 2 times in the relationship mother/daughter. Others enabling factors were revealed, like weight gain above recommended during pregnancy and a higher weight at birth. CONCLUSIONS: Due to the obtained interferences, it is accepted the existence of enabling factors of maternal and child markers in the development of overweight in the child, so that the prevention of child obesity should consider not only the environmental dimension but also the genetic heritage. PMID- 23735566 TI - Sexual education in school context: the efficience of a training intervention. AB - BACKGROUND: Teenagers are a priority intervention group in sexual education. OBJECTIVES: To promote a model of training intervention based on the debate and critical reflection about sexuality in the context of the classroom, to test its efficiency and characterize teenagers in the sexual context. METHODS: It is a field experimental study with a non probabilistic sample of 56 teenagers (28 in the control and experimental group, respectively) with an average of 15 years of age (sd = 1.191). The evaluation protocol is the questionnaire which allows characterizing social demographic and sexual. It includes the scale of attitudes concerning sexuality,(1) attitudes concerning the birth control pill and condom,(2) scale of knowledge about family planning,(3) scale of knowledge about sexual transmitted infections(4) and scale of motivation to have or not to have sex.(5) RESULTS: Teenagers are an older experimental group, mostly of the male gender and live in a town. They have a dating relationship 39.3% mostly lasting between six months and one year, 35.7% has had sexual intercourse, 21.4% has sexual intercourse in their current dating relationship, 44.4% uses the birth control pill and 55.6% the condom, 67,9% has done emergency contraception and 92.9% considers to be important the use of condom. The training intervention was effective in the attitudes concerning the condom (p=0.045). CONCLUSION: Educating to a conscious sexual life is the responsibility of everyone. The reflexive methodologies must be privileged, allowing the integration of knowledge and the change of attitudes, where the students' part is of maximum importance, being up to them, under supervision of the trainer, to post their doubts and collaborate in the pursuit of answers. PMID- 23735567 TI - Family culture and adolescent sexuality. AB - BACKGROUND: Adolescence is characterized by an increase in autonomy and the transformation of family relationships. Their experience has different meanings in future quality of life. OBJECTIVES: To analyze the relationship between the sociodemographic variables, of Sexual context and attitudes adopted by teenagers facing sexuality with the organizational culture of the family. METHODS: Observational descriptive and correlational, transversal study. The non probabilistic convenience sample consists of 1216 adolescents attending the 9th year of study in Portuguese Public Schools and is part of the project PTDC/CPE CED/103313/2008, the questionnaire applied was family organizational culture of Nave (2007) and attitudes towards sexuality of Nelas et al (2010). RESULTS: The majority lives in a village (47.5% of boys and 50.0% girls) .12.9%of boys do not use condoms in all relationships, and the same applies to 17.8% of girls. They belong mostly (55.8% boys and 49.5% girls) to a family with poor interpersonal relationships culture. The majority (51.8%) males and (58.9%) females have a family with moderate heuristic culture. Boys and girls (33.6% and 36.9%) both demonstrate a predominantly moderate hierarchy family culture and a moderate social goals family culture as well. Adolescents who have a bad attitude towards sexuality, mostly (43.2%) present a weak interpersonal relationships family culture with statistical significance (chi(2)=32,092, p=0.000) and have moderate hierarchy family culture and also moderate social goals family culture, without statistical significance. CONCLUSION: The family that loves, welcomes and cares is the same that educates and informs about sexuality, promoting youth empowerment making them safer, healthier and happier. PMID- 23735568 TI - Medical ontology for treatment of clinical data from children and youth. AB - The use of information technologies in the field of biomedical data management has grown considerably and is today one of the main fields of use of these technologies. There are several advantages arising either to an individual's health or to public health, particularly because access to clinical data become available anywhere access via the Internet or individual health card. This card will contain personal data accessible from a terminal card reader, identical to the citizen card. This work focuses on the development of an ontology of universal data structure so that the information is accessible and organized in the same way, regardless of the system that use them. In this context there is the need to incorporate security mechanisms, the respect of ethical principles underlying the management and maintenance of clinical data, ensuring maximum confidentiality. To develop the proposed ontology, for the treatment of clinical data of children and youth is used as reference bulletin health in Portugal. Using this structure, it follows the clear and unambiguous identification of the fields required for registration of clinical information, standardized in a relational model. To ensure the confidentiality of data, identification of the individual is only the number of national health system and are not recorded on the card personal data such as name, address or contact forms. PMID- 23735569 TI - Higher doses of erythropoietin-stimulating agents and hyporesponsiveness to their effects are associated with increased mortality among prevalent hemodialysis patients. AB - BACKGROUND: Attempts to achieve near-normal hemoglobin levels have been associated with higher mortality among chronic kidney disease patients. Evidence suggests a higher mortality rate for those with resistance to erythropoietin stimulating agents (ESA). We investigated the association between responsiveness to ESA, dose of ESA and mortality in our hemodialysis population. METHODS: A retrospective cohort study of chronic hemodialysis patients receiving dialysis was conducted at the University of Virginia facilities. We collected data on patient demographics, comorbidities, dialysis vintage, vascular access type, body weight, ESA dose and hemoglobin, as well as data on known risk factors for ESA hyporesponsiveness. Vital status was determined 30 months later. The association between ESA responsiveness and mortality was investigated by using the Cox proportional hazard model adjusting for demographics, comorbidities, access type, dialysis adequacy, serum albumin, serum parathyroid hormone and ferritin concentrations. RESULTS: A total of 606 patients were included. The overall 30 month mortality was 35.8%. Compared to those in the lowest tertile of ESA hyporesponsiveness, patients in the middle and upper tertiles had significantly higher mortality (hazard ratio, HR: 1.64, 95% CI: 1.14-2.37, and HR: 2.08, 95% CI: 1.46-2.97, respectively). In the Cox proportional hazard model each unit increment in the ESA resistance index was associated with an HR of 2.27 (95% CI: 1.60-3.23) for mortality. In this model each 1-unit increment in ESA dose/kg or each 100-MUg increment in absolute darbepoetin alfa dose were associated with a 9% increased risk of mortality (HR: 1.09, 95% CI: 1.04-1.13, and HR: 1.09, 95% CI: 1.03-1.15, respectively). CONCLUSIONS: Among prevalent hemodialysis patients, a higher degree of resistance to and higher doses of ESA are associated with increased mortality. PMID- 23735570 TI - Body enhancement through female genital cosmetic surgery creates ethical and rights dilemmas. AB - Female genital cosmetic surgery is surgery performed on a woman within a normal range of variation of human anatomy. The issues are heightened by a lack of long term and substantive evidence-based literature, conflict of interest from personal financial gain through performing these procedures, and confusion around macroethical and microethical domains. It is a source of conflict and controversy globally because the benefit and harm of offering these procedures raise concerns about harmful cultural views, education, and social vulnerability of women with regard to both ethics and human rights. The rights issues of who is defining normal female anatomy and function, as well as the economic vulnerability of women globally, bequeath the profession a greater responsibility to ensure that there is adequate health and general education-not just among patients but broadly in society-that there is neither limitation nor interference in the decision being made, and that there are no psychological disorders that could be influencing such choices. PMID- 23735571 TI - Pivotal role of oxidative stress in tumor metastasis under diabetic conditions in mice. AB - Diabetic patients are reported to have a high incidence and mortality of cancer, but little is known about the linkage. In this study, we investigated whether high oxidative stress is involved in the acceleration of tumor metastasis in diabetic mice. Murine melanoma B16-BL6 cells stably labeled with firefly luciferase (B16-BL6/Luc) were inoculated into the tail vein of streptozotocin (STZ)-treated or untreated mice. A luciferase assay demonstrated that tumor cells were present largely in the lung of untreated mice, whereas large numbers of tumor cells were detected in both the lung and liver of STZ-treated mice. Repeated injections of polyethylene glycol-conjugated catalase (PEG-catalase), a long-circulating derivative, reduced the elevated fasting blood glucose levels and plasma lipoperoxide levels of STZ-treated mice, but had no significant effects on these parameters in untreated mice. In addition, the injections significantly reduced the number of tumor cells in the lung and liver in both untreated and STZ-treated mice. Culture of B16-BL6/Luc cells in medium containing over 45 mg/dl glucose hardly affected the proliferation of the cells, whereas the addition of plasma of STZ-treated mice to the medium significantly increased the number of cells. Plasma samples of STZ-treated mice receiving PEG-catalase exhibited no such effect on proliferation. These findings indicate that a hyperglycemia-induced increase in oxidative stress is involved in the acceleration of tumor metastasis, and the removal of systemic hydrogen peroxide by PEG-catalase can inhibit the progression of diabetic conditions and tumor metastasis in diabetes. PMID- 23735572 TI - Carbon nanotube-protein carriers enhance size-dependent self-adjuvant antibody response to haptens. AB - Carbon nanotubes (CNTs) are nanomaterials with interesting emerging applications. Their properties make CNTs excellent candidates for use as new nanovehicles in drug delivery, immunization and diagnostics. In the current study, we assessed the immune-response-amplifying properties of CNTs to haptens by using azoxystrobin, the first developed strobilurin fungicide, as a model analyte. An azoxystrobin derivative bearing a carboxylated spacer arm (hapten AZc6) was covalently coupled to bovine serum albumin (BSA), and the resulting BSA-AZc6 conjugate was covalently linked to four functionalized CNTs of different shapes and sizes, varying in diameter and length. These four types of CNT-based constructs were obtained using efficient, fast, and easy functionalization procedures based on microwave-assisted chemistry. New Zealand rabbits and BALB/c mice were immunized with BSA-AZc6 alone and with the four CNT-BSA-AZc6 constructs, both with and without Freund's adjuvant. The IgG-type antibody responses were assessed in terms of the titer and affinity, paying special attention to the relationship between the immune response and the size and shape of the employed CNTs. Immunization with CNT-BSA-AZc6 resulted in enhanced titers and excellent affinities for azoxystrobin. More important, remarkable IgG responses were obtained even in the absence of an adjuvant, thus proving the self adjuvanting capability of CNTs. Immunogens were able to produce strong anti azoxystrobin immune responses in rabbits even when administered at a BSA-AZc6 conjugate dose as low as 0.05 MUg. The short and thick CNT-BSA-AZc6 construct produced the best antibody response under all tested conditions. PMID- 23735573 TI - Site-specific fatty acid-conjugation to prolong protein half-life in vivo. AB - Therapeutic proteins are indispensable in treating numerous human diseases. However, therapeutic proteins often suffer short serum half-life. In order to extend the serum half-life, a natural albumin ligand (a fatty acid) has been conjugated to small therapeutic peptides resulting in a prolonged serum half-life via binding to patients' serum albumin in vivo. However, fatty acid-conjugation has limited applicability due to lack of site-specificity resulting in the heterogeneity of conjugated proteins and a significant loss in pharmaceutical activity. In order to address these issues, we exploited the site-specific fatty acid-conjugation to a permissive site of a protein, using copper-catalyzed alkyne azide cycloaddition, by linking a fatty acid derivative to p-ethynylphenylalanine incorporated into a protein using an engineered pair of yeast tRNA/aminoacyl tRNA synthetase. As a proof-of-concept, we show that single palmitic acid conjugated to superfolder green fluorescent protein (sfGFP) in a site-specific manner enhanced a protein's albumin-binding in vitro about 20 times and the serum half life in vivo 5 times when compared to those of the unmodified sfGFP. Furthermore, the fatty acid conjugation did not cause a significant reduction in the fluorescence of sfGFP. Therefore, these results clearly indicate that the site specific fatty acid-conjugation is a very promising strategy to prolong protein serum half-life in vivo without compromising its folded structure and activity. PMID- 23735574 TI - PEG length and chemical linkage controls polyacridine peptide DNA polyplex pharmacokinetics, biodistribution, metabolic stability and in vivo gene expression. AB - The pharmacokinetics (PK), biodistribution and metabolism of non-viral gene delivery systems administered systemically are directly related to in vivo efficacy. The magnitude of luciferase expression in the liver of mice following a tail vein dose of a polyplex, composed of 1 MUg of pGL3 in complex with a polyethylene glycol (PEG) polyacridine peptide, followed by a delayed hydrodynamic (HD) stimulation (1-9 h), depends on the HD stimulation delay time and the structure of the polyacridine peptide. As demonstrated in the present study, the PEG length and the type of chemical linkage joining PEG to the polyacridine peptide dramatically influence the in vivo gene transfer efficiency. To understand how PEG length, linkage and location influence gene transfer efficiency, detailed PK, biodistribution and HD-stimulated gene expression experiments were performed on polyplexes prepared with an optimized polyacridine peptide modified through a single terminal Cys or Pen (penicillamine) with a PEG chain of average length of 2, 5, 10, 20, or 30 kDa. The chemical linkage was examined by attaching PEG(5 kDa) to the polyacridine peptide through a thiol thiol (SS), thiol-maleimide (SM), thiol-vinylsulfone (SV), thiol-acetamide (SA), penicillamine-thiol-maleimide (PM) or penicillamine-thiol-thiol (PS). The influence of PEG location was analyzed by attaching PEG(5 kDa) to the polyacridine peptide through a C-terminal, N-terminal, or a middle Cys residue. The results established rapid metabolism of polyplexes containing SV and SA chemical linkages that leads to a decreased polyplex PK half-life and a complete loss of HD-stimulated gene expression at delay times of 5 h. Conversely, polyplexes containing PM, PS, and SM chemical linkages were metabolically stable, allowing robust HD-stimulated expression at delay times up to 5h post-polyplex administration. The location of PEG(5 kDa) within the polyacridine peptide exerted only a minor influence on the gene transfer of polyplexes. However, varying the PEG length from 2, 5, 10, 20, or 30 kDa dramatically altered polyplex biodistribution, with a 30 kDa PEG maximally blocking liver uptake to 13% of dose, while maintaining the ability to mediate HD-stimulated gene expression. The combination of results establishes important relationships between PEGylated polyacridine peptide structure, physical properties, in vivo metabolism, PK and biodistribution resulting in an optimal PEG length and linkage that leads to a robust HD-stimulated gene expression in mice. PMID- 23735575 TI - [Major therapeutic advances and new perspectives in onco-hematology]. AB - Hematology Oncology has a rich history including few crucial therapeutic innovations. These were possible because of the evolution of the cell and molecular biology allowing a better understanding of basic mechanisms of cancerogenesis. We propose here to summarize the most important therapeutic innovations since the beginning of Hematology/Oncology history. We also describe evolution of therapeutic strategies themselves. New insights and therapeutic perspectives for next future are also discussed. PMID- 23735576 TI - Laboratory diagnosis of herpesvirus infections in patients with Pemphigus vulgaris lesions. AB - BACKGROUND/AIMS: Pemphigus vulgaris (PV) is an autoimmune disorder that has an etiology impacted by genetic and exogenous factors. Viral infections, in particular herpesvirus infections, have been identified as possible PV triggers which in addition cause serious complications in these patients. This study investigates the frequency of herpesvirus infections in patients with PV lesions. METHODS: Polymerase chain reaction and DNA sequence analyses were used to determine the presence of herpes simplex virus (HSV)-1/2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus types 6, 7, and 8 (HHV-6, HHV-7, and HHV-8) DNA in 105 mucosal and/or skin swabs harvested from 23 patients presenting with PV lesions. RESULTS: Thirty-six samples collected from 17 patients were positive for at least 1 virus; 3 were positive for HSV-1, 2 for HSV-2, 2 for CMV, and 7 each for HHV-6 and HHV-7. Coinfections were observed in 15 samples. Infections with VZV, EBV, HHV-6A, and HHV-8 were not detected. Herpesvirus infections were detected in 21% (13/62) of reactivated lesions, 54.5% (18/33) in persistent lesions, 40% (2/5) in exacerbated lesions, and 60% (3/5) in lesions in remission. CONCLUSION: PV lesions which do not show improvement following administration of adequate immunosuppressive therapy should be screened for the presence of herpesvirus infections. PMID- 23735577 TI - Are there any surgical and radiological correlations to the level of ligation of the inferior mesenteric artery after sigmoidectomy for cancer? AB - INTRODUCTION: The Societe Francaise de Chirurgie Digestive and the American Society of Colon and Rectal Surgeons recommend a ligation at the origin of the primary feeding vessel for sigmoid cancer to ensure optimal lymphadenectomy. We evaluated the correlation between the level of ligation defined by the surgeon and the real level of ligation visualized on postoperative CT scan. PATIENTS AND METHODS: From December 2004 to August 2010, in a series of 146 patients undergoing colectomy for sigmoid cancer, 51 (19 women) CT measurements (visualization of the left colonic artery (LCA), length of the arterial stump) were performed by a radiologist blinded to operative data. RESULTS: This series comprised 63% of men with a mean age of 69 years. A correlation was demonstrated between the level of ligation assessed by the surgeon and the real level of ligation demonstrated on postoperative CT scan in 41% of cases. No risk factors for absence of correlation were identified (laparoscopy, gender, BMI, emergency, and ASA score). In the "no correlation" group, the site of ligation was overestimated in 70% of cases. No significant difference was observed between the "correlation" and "no correlation" groups for lymphadenectomy (21.6 and 18 lymph nodes, p=0.5593) or 5-year overall survival (71.4 and 93.1 months, p=0.57). CONCLUSION: In conclusion, the surgical and radiological correlations are low as the intraoperative estimation of the level of IMA ligation was correlated with CT findings in less than 50% of cases. No risk factors for non-correlation were identified, and there was no impact on lymphadenectomy. Overestimation of the level of ligation was the most frequent situation but did not appear to have any impact on tumor staging or on patient management in this group of patients. PMID- 23735578 TI - The plasminogen activation system: new targets in lung inflammation and remodeling. AB - The plasminogen activation system (PAS) and the plasmin it forms have dual roles in chronic respiratory diseases including asthma, chronic obstructive pulmonary disease and interstitial lung disease. Whilst plasmin-mediated airspace fibrinolysis is beneficial, interstitial plasmin contributes to lung dysfunction because of its pro-inflammatory and tissue remodeling activities. Recent studies highlight the potential of fibrinolytic agents, including small molecule inhibitors of plasminogen activator inhibitor-1 (PAI-1), as treatments for chronic respiratory disease. Current data also suggest that interstitial urokinase plasminogen activator is an important mediator of lung inflammation and remodeling. However, further preclinical characterization of uPA as a drug target for lung disease is required. Here we review the concept of selectively targeting the contributions of PAS to treat chronic respiratory disease. PMID- 23735579 TI - Protein-protein interactions as druggable targets: recent technological advances. AB - Classical target-based drug discovery, where large chemical libraries are screened using inhibitory assays for a single target, has struggled to find ligands that inhibit protein-protein interactions (PPI). Nevertheless, in the past decade there have been successes that have demonstrated that PPI can be useful drug targets, and the field is now evolving fast. This review focuses on the new approaches and concepts that are being developed to tackle these challenging targets: the use of fragment based methods to explore the chemical space, stapled peptides to regulate intracellular PPI, alternatives to competitive inhibition and the use of antibodies to enable small molecule discovery for these targets. PMID- 23735580 TI - Is plasma cell-free DNA really a useful marker for diagnosis and treatment of trauma patients? AB - INTRODUCTION: Plasma cell-free DNA (cfDNA) of trauma patients has been widely investigated, but it has not been resolved whether cfDNA can be used as a non invasive, rapid and sensitive marker of injury. Here we evaluated serum cfDNA in patients after injury and assessed the relationship between cfDNA levels and clinical prognosis. METHODS: Fifty-six trauma patients formed three groups (minor, moderate and severe) according to Injury Severity Score (ISS), 33 of these cases were also divided according to microbiological and clinical evidence of infection. Plasma cfDNA and other indices were measured 1-6h, 24-36 h and 60 90 h after injury. RESULTS: The severe and moderate injury groups showed significantly higher positive percentage cfDNA than in the control (p<0.001, p=0.004). Positive plasma cfDNA samples were higher 1-6 h after injury than 24-48 h and 60-90 h, and the mean plasma cfDNA concentrations at 60-90 h were higher than that at the earlier two time points but not significantly. The ISS of the infected group was significantly higher than in the non-infected group (p=0.02). cfDNA was found in 48.5% penetrating trauma samples, significantly higher than that in blunt injury (17.4%) (p=0.024). CONCLUSIONS: Plasma cfDNA is a potential marker for trauma prognosis especially death, after severe injury, but its sensitivity presents limitations for clinical use. No evidence was found to relate plasma cfDNA to infection. Circulating cfDNA seems to be connected with injury type and mode, open wounds and surgical operations, which may be the primary reasons for plasma cfDNA increase. PMID- 23735581 TI - Characterization and simulation of optical sensors. AB - Numerical simulation is gradually becoming an advantage in active safety. This is why the development of realistic numerical models enabling to substitute real truth by simulated truth is primordial. In order to provide an accurate and cost effective solution to simulate real optical sensor behavior, the software Pro SiVICTM has been developed. Simulations with the software Pro-SiVICTM can replace real tests with optical sensors and hence allow substantial cost and time savings during the development of solutions for driver assistance systems. An optical platform has been developed by IFSTTAR (French Institute of Science and Technology for Transport, Development and Networks) to characterize and validate any existing camera, in order to measure their characteristics as distortion, vignetting, focal length, etc. By comparing real and simulated sensors with this platform, this paper demonstrates that Pro-SiVICTM accurately reproduces real sensors' behavior. PMID- 23735582 TI - Characteristics of group A Streptococcus strains circulating during scarlet fever epidemic, Beijing, China, 2011. AB - Scarlet fever is one of a variety of diseases caused by group A Streptococcus (GAS). During 2011, a scarlet fever epidemic characterized by peak monthly incidence rates 2.9-6.7 times higher than those in 2006-2010 occurred in Beijing, China. During the epidemic, hospital-based enhanced surveillance for scarlet fever and pharyngitis was conducted to determine characteristics of circulating GAS strains. The surveillance identified 3,359 clinical cases of scarlet fever or pharyngitis. GAS was isolated from 647 of the patients; 76.4% of the strains were type emm12, and 17.1% were emm1. Almost all isolates harbored superantigens speC and ssa. All isolates were susceptible to penicillin, and resistance rates were 96.1% to erythromycin, 93.7% to tetracycline, and 79.4% to clindamycin. Because emm12 type GAS is not the predominant type in other countries, wider surveillance for the possible spread of emm12 type GAS from China to other countries is warranted. PMID- 23735583 TI - Altered affective, executive and sensorimotor resting state networks in patients with pediatric mania. AB - BACKGROUND: The aim of the present study was to map the pathophysiology of resting state functional connectivity accompanying structural and functional abnormalities in children with bipolar disorder. METHODS: Children with bipolar disorder and demographically matched healthy controls underwent resting-state functional magnetic resonance imaging. A model-free independent component analysis was performed to identify intrinsically interconnected networks. RESULTS: We included 34 children with bipolar disorder and 40 controls in our analysis. Three distinct resting state networks corresponding to affective, executive and sensorimotor functions emerged as being significantly different between the pediatric bipolar disorder (PBD) and control groups. All 3 networks showed hyperconnectivity in the PBD relative to the control group. Specifically, the connectivity of the dorsal anterior cingulate cortex (ACC) differentiated the PBD from the control group in both the affective and the executive networks. Exploratory analysis suggests that greater connectivity of the right amygdala within the affective network is associated with better executive function in children with bipolar disorder, but not in controls. LIMITATIONS: Unique clinical characteristics of the study sample allowed us to evaluate the pathophysiology of resting state connectivity at an early state of PBD, which led to the lack of generalizability in terms of comorbid disorders existing in a typical PBD population. CONCLUSION: Abnormally engaged resting state affective, executive and sensorimotor networks observed in children with bipolar disorder may reflect a biological context in which abnormal task-based brain activity can occur. Dual engagement of the dorsal ACC in affective and executive networks supports the neuroanatomical interface of these networks, and the amygdala's engagement in moderating executive function illustrates the intricate interplay of these neural operations at rest. PMID- 23735584 TI - Dopamine and light: dissecting effects on mood and motivational states in women with subsyndromal seasonal affective disorder. AB - BACKGROUND: Despite evidence that bright light can improve mood, the neurobiology remains poorly understood. Some evidence implicates the catecholamines. In the present study, we measured the effects of transiently decreasing dopamine (DA) synthesis on mood and motivational states in healthy women with mild seasonal mood changes who were tested in either bright or dim light. METHODS: On 2 test days, participants slept overnight in a light-controlled room. On the morning of each session, half of the participants awoke to gradual increases of bright light, up to 3000 lux, and half to dim light (10 lux). For all participants, DA was reduced on 1 of the test days using the acute phenylalanine/tyrosine depletion (APTD) method; on the other day, they ingested a nutritionally balanced control mixture (BAL). Beginning 4 hours postingestion, participants completed subjective mood questionnaires, psychological tests and a progressive ratio breakpoint task during which they worked for successive units of $5. RESULTS: Thirty-two women participated in our study. The APTD lowered mood, agreeableness, energy and the willingness to work for monetary reward. The effects on energy and motivation were independent of light, while the effects on mood and agreeableness were seen in the dim condition only, being prevented by bright light. LIMITATIONS: Acute phenylalanine/tyrosine depletion might affect systems other than DA. The sample size was small. CONCLUSION: These results suggest that increased DA function may be responsible for some of the beneficial effects of light, while adding to the evidence that the neurobiology of mood and motivational states can be dissociated. PMID- 23735586 TI - The use of molecular and cytogenetic methods as a valuable tool in the detection of chromosomal abnormalities in horses: a case of sex chromosome chimerism in a Spanish purebred colt. AB - Chromosomal abnormalities associated to sex chromosomes are reported as a problem more common than believed to be in horses. Most of them remain undiagnosed due to the complexity of the horse karyotype and the lack of interest of breeders and veterinarians in this type of diagnosis. Approximately 10 years ago, the Spanish Purebred Breeders Association implemented a DNA paternity test to evaluate the pedigree of every newborn foal. All candidates who showed abnormal or uncertain results are routinely submitted to cytogenetical analysis to evaluate the presence of chromosomal abnormalities. We studied the case of a foal showing 3 and even 4 different alleles in several loci in the short tandem repeat (STR) based DNA parentage test. To confirm these results, a filiation test was repeated using follicular hair DNA showing normal results. A complete set of conventional and molecular cytogenetic analysis was performed to determine their chromosomal complements. C-banding and FISH had shown that the foal presents a sex chimerism 64,XX/64,XY with a cellular percentage of approximately 70/30, diagnosed in blood samples. The use of a diagnostic approach combining routine parentage QF-PCR based STR screening tested with classical or molecular cytogenetic analysis could be a powerful tool that allows early detection of foals that will have a poor or even no reproductive performance due to chromosomal abnormalities, saving time, efforts and breeders' resources. PMID- 23735585 TI - In vivo identification of periodontal progenitor cells. AB - The periodontal ligament contains progenitor cells; however, their identity and differentiation potential in vivo remain poorly characterized. Previous results have suggested that periodontal tissue progenitors reside in perivascular areas. Therefore, we utilized a lineage-tracing approach to identify and track periodontal progenitor cells from the perivascular region in vivo. We used an alpha-smooth muscle actin (alphaSMA) promoter-driven and tamoxifen-inducible Cre system (alphaSMACreERT2) that, in combination with a reporter mouse line (Ai9), permanently labels a cell population, termed 'SMA9'. To trace the differentiation of SMA9-labeled cells into osteoblasts/cementoblasts, we utilized a Col2.3GFP transgene, while expression of Scleraxis-GFP was used to follow differentiation into periodontal ligament fibroblasts during normal tissue formation and remodeling following injury. In uninjured three-week-old SMA9 mice, tamoxifen labeled a small population of cells in the periodontal ligament that expanded over time, particularly in the apical region of the root. By 17 days and 7 weeks after labeling, some SMA9-labeled cells expressed markers indicating differentiation into mature lineages, including cementocytes. Following injury, SMA9 cells expanded, and differentiated into cementoblasts, osteoblasts, and periodontal ligament fibroblasts. SMA9-labeled cells represent a source of progenitors that can give rise to mature osteoblasts, cementoblasts, and fibroblasts within the periodontium. PMID- 23735587 TI - Exploring the connections between traumatic brain injury caregiver mental health and family dynamics in Mexico City, Mexico. AB - OBJECTIVE: To examine the patterns of family dynamics that are most associated with the mental health of traumatic brain injury (TBI) caregivers from Mexico. It was hypothesized that healthier family dynamics would be associated with better caregiver mental health. DESIGN: A cross-sectional study of self-reported data collected from TBI caregivers through the Mexican National Institute of Rehabilitation in Mexico City, Mexico, the premier public medical facility in Mexico that provides rehabilitation services to patients with various disabilities. SETTING: One public outpatient medical and rehabilitation facility. PARTICIPANTS: Sixty-eight caregivers of individuals with moderate-to-severe TBI from Mexico City, Mexico, were related to an individual with TBI who was >=3 months after injury, a primary caregiver for >=3 months, familiar with the patient's history, and without neurologic or psychiatric conditions. The average (standard deviation) age of caregivers was 50.94 +/- 12.85 years), and 82% were women. METHODS: The caregivers completed Spanish versions of instruments that assessed their own mental health and family dynamics. MAIN OUTCOME MEASUREMENTS: Outcomes assessed included family dynamics (Family Adaptability and Cohesion Evaluation Scale-Fourth Edition; Family Communication Scale; Family Satisfaction Scale; Family Assessment Device-General Functioning; and Relationship-Focused Coping Scale), and caregiver mental health (Patient Health Questionnaire-9, Zarit Burden Interview, and Satisfaction with Life Scale). RESULTS: Results of canonical correlation analyses suggested that caregiver mental health and family dynamics were positively related, with a large effect size. Caregivers with high family satisfaction and cohesion tended to have a low burden and high satisfaction with life. In addition, caregiver depression and burden were positively related to each other and were both inversely related to caregiver satisfaction with life. CONCLUSIONS: TBI caregiver interventions in Latino populations would likely benefit from including programming or techniques to improve family dynamics, especially family cohesion, given the strong potentially reciprocal influence of these dynamics on caregiver mental health. PMID- 23735588 TI - ADP-induced platelet aggregation and thrombin generation are increased in Essential Thrombocythemia and Polycythemia Vera. AB - INTRODUCTION: Essential Thrombocythemia (ET) and Polycythemia Vera (PV) patients are characterized by an increased rate of thrombotic complications and by several abnormalities of platelets, more pronounced in JAK2V617F positive patients. The aim of this study was to characterize the platelet aggregation as well as the platelet procoagulant potential induced by several different agonists in ET and PV patients. MATERIALS AND METHODS: Venous blood samples were obtained from 65 ET and 51 PV patients. Whole blood impedance aggregometry was utilized to characterize platelet aggregation induced by collagen, ADP, thrombin receptor activating peptide and arachidonic acid, while the Calibrated Automated Thrombogram (CAT) assay was used to determine the thrombin generation (TG) potential induced by ADP in platelet-rich plasma. CAT assay was also performed in the presence of annexin V to evaluate the contribution of platelet phospholipids to TG. RESULTS AND CONCLUSIONS: ADP-induced platelet aggregation and TG were significantly increased in ET and PV patients compared to controls. The highest values were observed in JAK2V617F positive patients and in patients on aspirin. In these subjects, annexin V was less effective in inhibiting both basal and ADP induced TG. This study demonstrates for first time that platelets from ET and PV patients are more responsive to the ADP stimulus, in terms of both increased platelet aggregation, and enhanced TG, particularly in the JAK2V617F positive patients. Our data support the hypothesis that the use of ADP receptor inhibitors, in addition to aspirin, might be considered in the prevention of thrombosis in these conditions, by allowing a more complete inhibition of platelet functions. PMID- 23735589 TI - Postpartum wound and bleeding complications in women who received peripartum anticoagulation. AB - INTRODUCTION: The objective of this study was to compare wound and bleeding complications between women who received anticoagulation after cesarean delivery due to history of prior venous thromboembolic disease, arterial disease, or being a thrombophilia carrier with adverse pregnancy outcome, to women not receiving anticoagulation. METHODS: Women in the Duke Thrombosis Center Registry who underwent cesarean delivery during 2003-2011 and received postpartum anticoagulation (anticoagulation group, n=77), were compared with a subset of women who delivered during the same time period, but did not receive anticoagulation (no anticoagulation group, n=77). The no anticoagulation group comprised women who were matched to the anticoagulation group by age, body mass index, type of cesarean (no labor vs. labor), and date of delivery. Bleeding and wound complications were compared between the two groups. A multivariable logistic regression model was constructed to determine if anticoagulation was an independent predictor of wound complication. RESULTS: Women who received anticoagulation during pregnancy had a greater incidence of wound complications compared to those who did not (30% vs. 8%, p<0.001). Using multivariable logistic regression, while controlling for race, diabetes, chorioamnionitis, and aspirin use, anticoagulation predicted the development of any wound complication (OR 5.8, 95% CI 2.2, 17.6), but there were no differences in the mean estimated blood loss at delivery (782 vs. 778 ml, p=0.91), change in postpartum hematocrit (5.4 vs. 5.2%, p=0.772), or percent of women receiving blood products (6.5 vs. 1.3%, p=0.209) between the two groups. CONCLUSIONS: Anticoagulation following cesarean delivery is associated with an increased risk of post-cesarean wound complications, but not other postpartum bleeding complications. PMID- 23735590 TI - Epstein-Barr virus-positive nodal peripheral T cell lymphomas: clinicopathologic and gene expression profiling study. AB - Epstein-Barr virus-positive peripheral T cell lymphoma, not otherwise specified (EBV+ PTCL-NOS), in which virtually all neoplastic T cells harbor EBV, is a very rare disease with poor prognosis. To analyze the clinicopathologic characteristics and gene expression profile, we retrospectively collected six cases of EBV+ PTCL-NOS with no known primary immunodeficiency. The patients were 5 men and 1 woman, their age ranging from 48 years to 88 years (median 61.5 years). Lymphadenopathy was the most common presentation. Four patients had underlying disease, including HBV carrier, HCV infection, diabetes mellitus, and prostate cancer. All patients showed fatal clinical course in spite of chemotherapy. Histopathologically, monotonous infiltration of atypical lymphocytes of small to medium size was shown in four patients and medium to large tumor cells in two patients. Five patients showed CD4-/CD8+/bF-1+ phenotype with TIA-1 expression. In gene expression analysis using mRNA microarray, genes differentially expressed in EBV+ PTCL-NOS compared to normal reactive lymph nodes included 1515 genes (Mann-Whitney U-test p<0.05, folder change >=4 times). Enriched functional annotation terms by DAVID were mostly related to immune response, defense response, cell-to-cell signaling, and membrane signaling. Especially, the genes involved in B cell differentiation or activation were mostly down-regulated, and T cell activation was mostly suppressed by down regulation of activation genes and up-regulation of regulatory genes. Genes associated with cytotoxic activity were mostly up-regulated. Based on its peculiar clinical, histopathologic, and gene expression findings in EBV+ PTCL NOS, we suggest EBV+ PTCL-NOS as a distinct disease entity from PTCL-NOS. In this study, the finding that most significantly enriched the functional term was immune response, suggesting a specific relation between EBV infection and alteration of immune response in the patients with EBV+ PTCL-NOS. PMID- 23735591 TI - Membrane associated complexes in calcium dynamics modelling. AB - Mitochondria not only govern energy production, but are also involved in crucial cellular signalling processes. They are one of the most important organelles determining the Ca(2+) regulatory pathway in the cell. Several mathematical models explaining these mechanisms were constructed, but only few of them describe interplay between calcium concentrations in endoplasmic reticulum (ER), cytoplasm and mitochondria. Experiments measuring calcium concentrations in mitochondria and ER suggested the existence of cytosolic microdomains with locally elevated calcium concentration in the nearest vicinity of the outer mitochondrial membrane. These intermediate physical connections between ER and mitochondria are called MAM (mitochondria-associated ER membrane) complexes. We propose a model with a direct calcium flow from ER to mitochondria, which may be justified by the existence of MAMs, and perform detailed numerical analysis of the effect of this flow on the type and shape of calcium oscillations. The model is partially based on the Marhl et al model. We have numerically found that the stable oscillations exist for a considerable set of parameter values. However, for some parameter sets the oscillations disappear and the trajectories of the model tend to a steady state with very high calcium level in mitochondria. This can be interpreted as an early step in an apoptotic pathway. PMID- 23735592 TI - Gelatin embedding for the preparation of thermoreversible or delicate scaffolds for histological analysis. AB - Thermoreversible hydrogels for tissue engineering (TE) purposes have gained increased attention in recent years as they can be combined with cells and drugs and directly injected into the body. Following the fate of transplanted cells in situ is essential in characterizing their distribution and survival, as well as the expression of specific markers or cell-matrix interactions. Existing histological embedding methods, such as paraffin wax embedding, can mechanically damage some biomaterials during processing. In this study, we describe a broadly applicable preparation protocol that allows the handling of delicate, thermoreversible scaffolds for histological sectioning. The gelatin solution permits the embedding of samples at 37 degrees C, which suits the solid phase of most TE scaffolds. A thermoreversible scaffold of polycaprolactone microparticles, combined with poly(polyethylene glycol methacrylate ethyl ether) and containing human adipose-derived stem cells, was prepared for histology by an initial gelatin embedding step in addition to the standard cryosectioning and paraffin processing protocols. Sections were evaluated by hematoxylin eosin staining and immunostaining for human vimentin. The gelatin embedding retained the scaffold particles and permitted the complete transfer of the construct. After rapid cooling, the solid gelatin blocks could be cryosectioned and paraffin infiltrated. In contrast to direct cryosectioning or paraffin infiltration, the extended protocol preserved the scaffold structure as well as the relevant cell epitopes, which subsequently allowed for immunostaining of human cells within the material. The gelatin embedding method proposed is a generalizable alternative to standard preparations for histological examination of a variety of delicate samples. PMID- 23735593 TI - Safety of cycloserine and terizidone for the treatment of drug-resistant tuberculosis: a meta-analysis. AB - Although cycloserine (CS) is recommended by the World Health Organization as a second-line agent for the treatment of multidrug-resistant tuberculosis (MDR-TB), safety concerns have impeded its uptake by several national TB programmes. Terizidone (TRD), a structural analogue of cycloserine, may be better tolerated. To assess the safety of CS and TRD for TB treatment, a systematic review and meta analysis were conducted. From articles published up to December 2011, 27 studies with 2164 patients were included in our review of CS use. The pooled estimate for the frequencies of any adverse drug reaction (ADR) from CS was 9.1% (95%CI 6.4 11.7); it was 5.7% (95%CI 3.7-7.6) for psychiatric ADRs, and 1.1% (95%CI 0.2-2.1) for central nervous system (CNS) related ADRs. TRD showed no better to moderately better safety than CS in a systematic review of the available literature. The published evidence suggests that CS is associated with a higher frequency of psychiatric and CNS-related ADRs than other second-line drugs. While data were limited, treatment discontinuation rates appeared to be manageable. There were no significant differences in tolerability by region, study period or combination. As countries review and revise their treatment programmes, CS, and potentially TRD, should be included in MDR-TB treatment regimens. Adequate information on possible ADRs should be provided to patients, their families and attending health care workers. Greater attention to MDR-TB patients' mental health and a significant increase in resources devoted to pharmacovigilance and treatment of MDR-TB are essential. PMID- 23735594 TI - Therapy of anemia: is it only a number to reach or are there other variables to control? AB - Following the publication of the TREAT study, the treatment of anemia in patients with chronic kidney disease (CKD) has become much more complicated than before. The nephrologist needs to analyze the individual patient and prescribe the best treatment option for that patient. Treatment individualization has thus become the mainstay of anemia management. This paradigm needs to take into account the hemoglobin (Hb) level at the start and during erythropoiesis-stimulating agent (ESA) therapy, ESA dose, patient comorbidities and concomitant iron therapy. All these factors are strictly interrelated. Caution is suggested when using ESA at high dose, especially in patients with comorbidities and/or in those who are hyporesponsive to treatment. According to KDIGO guidelines, Hb levels should not exceed the value of 11.5 g/dl during ESA therapy. Recently, iron therapy has received growing attention in an effort to use the lowest possible dose of ESA. However, the long-term risk in maintaining CKD patients with very high ferritin values is still unknown. PMID- 23735595 TI - [Nonagenerian patients in a general hospital in Spain]. PMID- 23735596 TI - [Visual cues as a therapeutic tool in Parkinson's disease. A systematic review]. AB - Sensory stimuli or sensory cues are being used as a therapeutic tool for improving gait disorders in Parkinson's disease patients, but most studies seem to focus on auditory stimuli. The aim of this study was to conduct a systematic review regarding the use of visual cues over gait disorders, dual tasks during gait, freezing and the incidence of falls in patients with Parkinson to obtain therapeutic implications. We conducted a systematic review in main databases such as Cochrane Database of Systematic Reviews, TripDataBase, PubMed, Ovid MEDLINE, Ovid EMBASE and Physiotherapy Evidence Database, during 2005 to 2012, according to the recommendations of the Consolidated Standards of Reporting Trials, evaluating the quality of the papers included with the Downs & Black Quality Index. 21 articles were finally included in this systematic review (with a total of 892 participants) with variable methodological quality, achieving an average of 17.27 points in the Downs and Black Quality Index (range: 11-21). Visual cues produce improvements over temporal-spatial parameters in gait, turning execution, reducing the appearance of freezing and falls in Parkinson's disease patients. Visual cues appear to benefit dual tasks during gait, reducing the interference of the second task. Further studies are needed to determine the preferred type of stimuli for each stage of the disease. PMID- 23735597 TI - The effectiveness of a Chinese midwives' antenatal clinic service on childbirth outcomes for primipare: a randomised controlled trial. AB - BACKGROUND: Antenatal care is an important component of maternity care. In many parts of the world, midwives are the primary caregivers for childbearing women, providing a high level of continuity of care during a normal pregnancy. While in China, obstetricians are the primary providers of antenatal care for all childbearing women; and midwives only provide intrapartum care to labouring women. Today midwifery as a profession in China has been marginalised. Pregnant women usually lack individualised continuity of care from midwives during the perinatal period. There have been few randomised controlled trials of midwifery care practice in mainland China. OBJECTIVE: (1) To develop and implement a model of Chinese midwives' antenatal clinic service and (2) to explore its effect on childbirth outcomes, psychological state and satisfaction, for primiparae. DESIGN AND METHODS: Two-group randomised controlled trial. One hundred and ten pregnant women were assessed for eligibility and invited to participate in either the intervention group (midwives' antenatal clinic service) or the control group (routine antenatal care) in the Obstetrics and Gynaecology Hospital of Fudan University from September 2011 to December 2011. Baseline data were collected, and then women were randomised to individual midwives' antenatal clinic care (intervention group) or regular antenatal clinic service by obstetricians and obstetric nurse (control group). The research hypothesis was that compared with regular obstetrician-led antenatal care, the midwives' antenatal clinic service would decrease the caesarean section rate, produce more favourable birth outcomes and women's greater satisfaction with care. Data were collected by retrospective review of case records and self-report questionnaires. The sample size of 110 was calculated to identify a decrease in caesarean birth from 70% to 40%. Birth outcomes, satisfaction and anxiety score in the two groups were compared. SETTING: The midwives' antenatal clinic in the Obstetrics and Gynaecology Hospital of Fudan University, Shanghai, China. PARTICIPANTS: 55 women, attending the midwives' antenatal clinic (the intervention group) and 55 women, entering the control group. RESULTS: Women in the intervention group were more likely than women in the control group to have a vaginal birth (35 [66.04%] versus 23 [43.40%]; 95% CI for difference 3.69-41.60). Women in the intervention group had a higher perinatal satisfaction but lower anxiety score than those in the control group. No differences were seen in neonatal Apgar score and in the amount of bleeding 2h post partum. CONCLUSION AND IMPLICATIONS FOR PRACTICE: The midwives' antenatal clinic can decrease the rate of caesarean section and enhance women's satisfaction with midwifery care. Further research needs to be conducted to implement this model of care more widely. We will attempt to make midwifery care a true choice for Chinese women. PMID- 23735598 TI - In vitro antimicrobial activity of squalamine derivatives against mycobacteria. PMID- 23735599 TI - [At the crossroads of cancer]. AB - Since the introduction of the concept of immunosurveillance in 1970 by Macfarlane Burnet and Lewis Thomas, cancer immunology has known a significant revolution and an explosion of discoveries. In this regard, manipulation of the immune system in cancer pathology has been a succession of enthusiasms and failures. Thanks to the fundamental achievements during the past three decades, non-specific passive immunotherapy of cancer has shifted to active specific immunotherapy. Thanks to the immunological arsenal (tumor peptides, dendritic cells), the clinical trials have increased but the results were not encouraging. It became clear that the escape of immunosurveillance by tumor cells is under the control of the complex tumor microenvironment and its heterogeneity, complexity and plasticity. The future of immunotherapy lies in an integrative approach to simultaneously boost the immune system and target the tumor microenvironment or combine immunotherapy with conventional treatments. In this review, we will focus on the development of cancer immunotherapy, its realities, failure and hope it raises as the fourth modality of cancer therapy. PMID- 23735600 TI - Increased risk for premolar tooth loss in shortened dental arches. AB - OBJECTIVES: To assess sustainability of shortened dental arches (SDA) by determining time to 'first restorative intervention' of teeth and time to 'tooth loss' and comparing these outcomes with complete dental arches (CDA) and SDA plus removable dental prostheses (RDP). METHODS: Data (follow-up time ranged from 27.4 (SD 7.1) to 35.0 (SD 5.6) years; max. follow up: 45.8 years) from patient records of 59 subjects (23 SDA, 23 CDA, and 13 SDA plus RDP) participating in a prospective cohort study on shortened dental arches (SDA) were analysed. Group effects on survival were analysed using Cox regression models; where appropriate Kaplan-Meier analyses were done. RESULTS: Compared to SDA subjects, CDA subjects had a lower risk to receive a first restorative intervention in anterior teeth (HR=0.377; 95% CI [0.205-0.695]) and premolars (HR=0.470; 95% CI [0.226-0.977]). CDA subjects had a lower risk to lose premolars compared to SDA subjects (HR=0.130; 95% CI [0.053-0.319]). Risk for 'first restorative intervention' and for 'tooth loss' did not significantly differ between SDA with and without RDP. CONCLUSIONS: SDA subjects had an increased risk to lose premolars and to receive a first time restoration in anterior teeth and premolars compared to CDA subjects. SDA subjects with RDP had no increased risk to receive a first restorative intervention or for tooth loss compared to SDA without RDP. CLINICAL RELEVANCE: Subjects with shortened dental arches can be discerned as enduring at risk patients. It is therefore recommended that shortened dental arch subjects receive intensive and continuous care to prevent further tooth loss. PMID- 23735601 TI - Mechanical and physical properties of silorane and methacrylate-based composites. AB - OBJECTIVES: This study measured the degree of conversion (DC), sorption, solubility and microhardness of methacrylate (Filtek Z250 and Filtek Z350XT) and silorane-based composites (Filtek P90). METHODS: DC was measured using near infrared spectroscopy immediately and 24h after the photoactivation. Sorption and solubility measurements were performed after 24h, 4 weeks and 12 weeks of storage in water. Knoop microhardness was measured after 24h and after thermal cycling. The data were statistically analyzed using ANOVA followed by Tukey's, Tamhane or paired t-tests (alpha=0.05). RESULTS: The DC for P90 (37.22+/-1.46) was significantly lower than the Z250 (71.44+/-1.66) and Z350 (71.76+/-2.84). Water sorption was highest in the Z250 and lowest in the P90. All the tested composites exhibited similar values after 24h of immersion, and no significant differences were observed. No significant differences were observed between the solubilities of the P90 composite (12 weeks) and the Z250 or Z350 composites (4 weeks). KHN values were less elevated for the P90 composite and similar for the Z250 and Z350 composites. An effect of thermal cycling on KHN values was observed for all the composites (p<0.001). CONCLUSIONS: Silorane produced the lowest DC and KHN values and exhibited lower water sorption and solubility compared to methacrylate-based composites. These differences suggest that silorane composites exhibit better hydrolytic stability after 3 months of water immersion compared to conventional methacrylate-based composites. CLINICAL SIGNIFICANCE: Silorane had higher hydrolytic stability after 3 months of water immersion than the methacrylate based resins, despite the lower values of DC and KHN recorded. PMID- 23735602 TI - Diagnostic value of bladder tumor fibronectin in patients with bladder tumor: a systematic review with meta-analysis. AB - OBJECTIVES: Bladder tumor fibronectin (BTF) has been related as a promising biomarker for the early diagnosis of bladder tumor. The meta-analysis was used to establish the diagnostic value of bladder tumor fibronectin in diagnosing bladder tumor. METHODS: Relevant literatures evaluating the value of BTF in the diagnosis of bladder tumor were searched in PubMed, Embase, China National Knowledge Infrastructure (CNKI), Technology of Chongqing (VIP), and Wan Fang Data. Summary estimates were used to evaluate the value of BTF in the diagnosis of bladder tumor by using the Meta-DiSc and STATA 11.0 statistical software. RESULTS: The meta-analysis included 5 studies (649 patients, 291 controls). The summary estimates revealed that the pooled sensitivity was 81% (95% confidence interval [CI]: 74%-85.1%) and specificity was 80% (95%CI 74%-84%). In addition, the area under the summary ROC curve (AUC) was 0.86 (95%CI 0.82-0.89). CONCLUSION: BTF is a potential marker for the diagnosis of bladder tumor, and more prospective studies are needed in the future. PMID- 23735603 TI - High flow arteriovenous malformation in the neck. PMID- 23735604 TI - Chronic neck hematoma from a papillary carcinoma of the thyroid. PMID- 23735605 TI - Factors affecting the complications of pneumatic lithotripsy for the treatment of ureteral stones with different localizations: a multivariate analysis of complications. AB - OBJECTIVE: To evaluate the complications of ureterorenoscopy (URS) using the modified Clavien classification system for ureteral stones with different localizations. PATIENTS AND METHODS: From February 2001 to January 2010, a total of 1,926 patients underwent URS for the treatment of ureteral stones with different localizations. The complications were evaluated according to the modified Clavien system. Univariate and multivariate analyses were conducted to identify risk factors affecting the complication rates. RESULTS: The patient cohort included 1,212 males and 714 females with a mean age of 47.8 +/- 14.3 years (range 15-86). The success rate was 95.7%. The overall complication rate was 9.3%. Univariate analysis revealed that solitary kidney, stone burden, bilaterality, stone localization (proximal to the iliac crest) and stone impaction significantly affected the complication rates. Multivariate analysis revealed that preoperative shock wave lithotripsy treatment, stone impaction, multiplicity, proximal localization and stone burden were significant parameters affecting the occurrence of complications (relative risks of 6.5, 4.3, 3.3, 2.4 and 2.0, respectively). CONCLUSIONS: URS is a safe and minimally invasive procedure with a high success rate and low-grade, self-limiting complications. Preoperative shock wave lithotripsy treatment, stone impaction, multiplicity, proximal localization and stone burden were independent risk factors for the development of complications. PMID- 23735606 TI - Transmission potential of Rift Valley fever virus over the course of the 2010 epidemic in South Africa. AB - A Rift Valley fever (RVF) epidemic affecting animals on domestic livestock farms was reported in South Africa during January-August 2010. The first cases occurred after heavy rainfall, and the virus subsequently spread countrywide. To determine the possible effect of environmental conditions and vaccination on RVF virus transmissibility, we estimated the effective reproduction number (Re) for the virus over the course of the epidemic by extending the Wallinga and Teunis algorithm with spatial information. Re reached its highest value in mid-February and fell below unity around mid-March, when vaccination coverage was 7.5%-45.7% and vector-suitable environmental conditions were maintained. The epidemic fade out likely resulted first from the immunization of animals following natural infection or vaccination. The decline in vector-suitable environmental conditions from April onwards and further vaccination helped maintain Re below unity. Increased availability of vaccine use data would enable evaluation of the effect of RVF vaccination campaigns. PMID- 23735607 TI - Pyrolysis of waste tyres: a review. AB - Approximately 1.5 billion tyres are produced each year which will eventually enter the waste stream representing a major potential waste and environmental problem. However, there is growing interest in pyrolysis as a technology to treat tyres to produce valuable oil, char and gas products. The most common reactors used are fixed-bed (batch), screw kiln, rotary kiln, vacuum and fluidised-bed. The key influence on the product yield, and gas and oil composition, is the type of reactor used which in turn determines the temperature and heating rate. Tyre pyrolysis oil is chemically very complex containing aliphatic, aromatic, hetero atom and polar fractions. The fuel characteristics of the tyre oil shows that it is similar to a gas oil or light fuel oil and has been successfully combusted in test furnaces and engines. The main gases produced from the pyrolysis of waste tyres are H(2), C(1)-C(4) hydrocarbons, CO(2), CO and H(2)S. Upgrading tyre pyrolysis products to high value products has concentrated on char upgrading to higher quality carbon black and to activated carbon. The use of catalysts to upgrade the oil to a aromatic-rich chemical feedstock or the production of hydrogen from waste tyres has also been reported. Examples of commercial and semi commercial scale tyre pyrolysis systems show that small scale batch reactors and continuous rotary kiln reactors have been developed to commercial scale. PMID- 23735609 TI - Clinical course of children with nutcracker syndrome. AB - OBJECTIVE: To evaluate the clinical properties of patients with nutcracker syndrome (NCS). MATERIALS AND METHODS: The medical records of the patients with NCS were retrospectively investigated, and the patients' sex, age, presenting symptoms, urinalysis findings, associated diseases, and body mass indexes were recorded. RESULTS: A total of 23 nonconsanguineous patients (11 male and 12 female patients, mean age 141 +/- 36 months). Two patients had posterior NCS. Seventeen patients presented with 1 or >1 symptom. Fatigue and lassitude (n = 1), flank pain (n = 8), abdominal pain (n = 7), varicocele (n = 2), and macroscopic hematuria (n = 9) were the presenting symptoms. Only 6 patients had received a diagnosis of NCS from the urinalysis findings, which revealed microscopic hematuria or non-nephrotic proteinuria. The urinalysis findings disclosed isolated proteinuria in 6, hematuria plus proteinuria in 8, and macroscopic hematuria in 9 patients. Orthostatic proteinuria was detected in 7 patients. In patients with regressed hematuria and proteinuria, the body mass index was markedly increased at the end of the follow-up period relative to at diagnosis (at diagnosis 16.9 +/- 4.0 kg/m(2); at the end of the follow-up period 18.6 +/- 4.6 kg/m(2); P = .028). CONCLUSION: The diagnosis of NCS should be considered in the presence of symptoms such as proteinuria and hematuria and should be absolutely ruled out before attempting renal biopsy. An apparent correlation between an increased body mass index and regression of symptoms was seen. PMID- 23735608 TI - OPG and sRANKL serum levels and incident hip fracture in postmenopausal Caucasian women in the Women's Health Initiative Observational Study. AB - PURPOSE: The osteoprotogerin/receptor activator of NF-kappa beta/receptor activator of NF-kappa beta ligand (OPG/RANK/RANKL) pathway plays a critical role in bone remodeling. This study investigated associations between serum levels of OPG, soluble RANKL (sRANKL), and the ratio of OPG/sRANKL to risk of incident hip fracture. METHODS: A nested case-control study was conducted among postmenopausal, Caucasian women aged 50-79 at baseline (1993-1998), followed for hip fracture through March 2005 in the Women's Health Initiative Observational Study. 400 incident hip fracture cases were selected and individually matched to 400 controls with no prior fracture or incident hip fracture. Matching factors were baseline age, enrollment date and hormone therapy (HT) exposure. Baseline serum OPG and sRANKL levels were measured using high sensitivity ELISA. Odds ratios were computed for quartiles of each biomarker adjusting for matching factors and hip fracture risk factors. RESULTS: Serum OPG was significantly associated with older age, low physical activity and poorer physical function in control women. sRANKL was inversely associated with total calcium intake in control women, but not associated with age or other fracture risk factors. The odds ratio for hip fracture comparing the highest to lowest quartiles of OPG was 2.28 (95% confidence interval (CI), 1.45-3.61) after adjusting for the matching variables (p-value for linear trend <0.001), and 1.87 (95% CI, 1.15-3.04; p for linear trend=0.02) after adjusting for self-rated health status, physical activity and physical functioning. No significant associations between sRANKL or the ratio of OPG/sRANKL and hip fracture risk were observed. CONCLUSION: Serum OPG levels were independently associated with a nearly twofold increased risk of hip fracture in postmenopausal women. PMID- 23735610 TI - Should follow-up biopsies for men on active surveillance for prostate cancer be restricted to limited templates? AB - OBJECTIVE: To investigate if prostate biopsy templates with fewer cores can be used during active surveillance (AS) for prostate cancer. METHODS: At present, we use an AS protocol template (ASPT) consisting of 13-17 cores. We hypothesize in the setting of known cancer, sextant (6 cores) or standard extended (10-12 cores) templates, could be used with similar effect. We identified patients in our referral institution database (1997-2009) with entry prostate-specific antigen <10 ng/mL, stage <=cT2, Gleason sum <=6, <=3 cores positive for cancer, <50% of single core involved, and age <=75 years (N = 272). Patients fulfilling standard criteria for pathologic reclassification (N = 94) at any follow-up biopsy were selected for evaluation. By mapping tumor location on the pathologic reclassification determining biopsy, hypothetical scenarios of sextant or standard extended templates (SET) were compared with our ASPT and examined for frequency of cancer detection and pathologic reclassification. RESULTS: For the 94 patients analyzed, the median number of cores taken was 9.7 (6-22) at baseline and 15 (14-17) for the reclassification biopsy. The median time between baseline and the pathologic reclassification determining biopsy was 15.4 months. Analysis of subgroupings showed that sextant template would identify 84% of cancers and 47.9% of the reclassification events, whereas SET detected 99% of cancers and 81.9% of patients who pathologically reclassified. When only considering Gleason sum >=7 related progression events, SET found 16.2% less (n = 57) compared with ASPT (n = 68). CONCLUSION: When monitoring patients on AS, a 13-17 core template detects more pathologic reclassification than standard sextant (18.1%) or extended (52.1%) biopsy templates. PMID- 23735611 TI - Differentiation of epididymitis and appendix testis torsion by clinical and ultrasound signs in children. AB - OBJECTIVE: To identify the signs that can help to differentiate torsion of the appendix testis (AT) and epididymitis and to establish the incidence of the various pathologic entities in boys with an acute scrotum. MATERIALS AND METHODS: A retrospective study was performed of the data from all boys treated at our institute from January 2008 to January 2012 for the diagnosis of an "acute scrotum." The clinical and, if available, ultrasound findings were documented. Differences between groups were calculated using a chi-square test or analysis of variance and classification and regression tree analysis. RESULTS: A total of 241 boys with acute scrotal pain were included and underwent surgical exploration. Of the 241 boys, 163 (70%) had AT, 44 (18.5%) had epididymitis, 31 (13.3%) had testicular torsion, and 3 (1.3%) had idiopathic scrotal edema. The incidence of AT was significantly increased in the colder months (P = .01). We found that AT and epididymitis shared several aspects but differed regarding dysuria (epididymitis, P <=.001), a painful epididymis on palpation (epididymitis, P = .028), increased epididymal echogenicity (epididymitis, P = .043), augmented peritesticular perfusion (epididymitis, P = .05), and a positive blue dot sign (AT, P <.001). The classification and regression tree analysis showed that the presence of dysuria, a positive blue dot sign, and a painful epididymis are the best factors for distinguishing AT and epididymitis. CONCLUSION: Most children with an acute scrotum will have AT or epididymitis. It will be possible to differentiate most cases using the clinical and ultrasound findings. In our study, the best predictors were dysuria, a painful epididymis on palpation, and altered epididymal echogenicity and increased peritesticular perfusion found on ultrasound studies for epididymitis and a positive blue dot sign for AT. PMID- 23735612 TI - Conserved variation: identifying patterns of stability and variability in BCR and TCR V genes with different diversity and richness metrics. AB - The immune system can detect most invading pathogens. The potential for detection of pathogens is dependent on the somatic diversity of the immune repertoires. While it is known that this somatic diversity is carefully generated, it is unclear how the diversity is distributed in the different genes encoding receptors of immune cells. Utilizing different metrics for richness and diversity at the level of small sequence fragments, we present here an analysis of the entire known human germline repertoire as represented by the sequences from the ImMunoGeneTics database of immune receptors. We have developed a fragment sequence quantification analysis to track variation of repertoires with different degrees of precision. Somatic diversity has previously been functionally characterized mostly by division of the V gene sequences into the more conserved and invariant framework (FR) of the receptor and more varied complementarity determining regions (CDR), that interact with the antigen. We find that CDR and FR can be explicitly identified with our sequence fragment diversity quantification technique. In terms of diversity, CDR and FR are especially distinct in B cell V genes. T cell V genes show less of the CDR/FR periodicity but are more diverse overall. Our analysis further shows that there are other areas of diversity outside the CDR and FR that are found widely dispersed in T cell receptor V genes and more tightly focused in FR1 and FR3 in the B cell receptor V genes. The diversity we observe is not dependent on allelic differences nor is this diversity segregated by individual V gene families. We would thus expect that each individual exhibit a diversity equivalent to that of the entire potential repertoire. PMID- 23735614 TI - Comparative organization and gene expression profiles of the porcine pseudoautosomal region. AB - The pseudoautosomal region (PAR) has important biological functions in spermatogenesis, male fertility and early development. Even though pig (Sus scrofa, SSC) is an agriculturally and biomedically important species, and its genome is sequenced, current knowledge about the porcine PAR is sparse. Here we defined the PAR in SSCXp/Yp by demarcating the sequence of the pseudoautosomal boundary at X:6,743,567 bp in intron 3-4 of SHROOM2 and showed that SHROOM2 is truncated in SSCY. Cytogenetic mapping of 20 BAC clones containing 15 PAR and X specific genes revealed that the pig PAR is largely collinear with other mammalian PARs or Xp terminal regions. The results improved the current SSCX sequence assembly and facilitated distinction between the PAR and X-specific genes to study their expression in adult and embryonic tissues. A pilot analysis showed that the PAR genes are expressed at higher levels than X-specific genes during early development, whereas the expression of PAR genes was higher at day 60 compared to day 26, and higher in embryonic tissues compared to placenta. The findings advance the knowledge about the comparative organization of the PAR in mammals and suggest that the region might have important functions in early development in pigs. PMID- 23735613 TI - Hyperactivation of the cognitive control network in cocaine use disorders during a multisensory Stroop task. AB - BACKGROUND: It has been suggested that individuals with cocaine use disorders (chronic cocaine abusers, CCA) have impairments in cognitive control, which likely contribute to impairments in decision making around drug use and relapse. However, deficits in cognitive control have currently only been studied under conditions of unisensory stimulation, which may not be reflective of more realistic multisensory drug cues. METHODS: The current study employed functional magnetic resonance imaging (fMRI) to measure neuronal activity during a multisensory numeric Stroop task. RESULTS: Despite few differences in reaction time, recently abstinent CCA (N=14) exhibited increased activation in prefrontal cortex, striatum and thalamus during cognitive control relative to a group of carefully matched controls (N=16). Importantly, these neuronal differences were relatively robust in classifying patients from controls (approximately 90% accuracy) and evident during conditions of both low (slow stimulus presentation rate) and relatively high (faster stimulus presentation rate) cognitive demand. In addition, CCA also failed to deactivate the default-mode network during high frequency visual trials. CONCLUSIONS: In summary, current results indicate compensatory activation within the cognitive control network in recently abstinent CCA to achieve similar levels of behavioral performance. PMID- 23735615 TI - Proposed classification of the feline "complex" mammary tumors as ductal and intraductal papillary mammary tumors. AB - When compared with the canine species, feline mammary tumors (FMTs) are much less heterogeneous, with a predominance of simple malignant neoplasm. Benign FMTs are rare, and it is unclear if complex and mixed tumors exist in the feline. In this study, we selected for immunohistochemical analyses 12 FMTs that had unusual histologic features. A group of 8 (2 benign and 6 malignant) FMTs showed a biphasic epithelial/myoepithelial population and a very regular cord-like distribution in a "Chinese lettering" pattern, within ectatic ducts. A second group (2 benign and 2 malignant) had an intraductal epithelial papillary growth pattern with a basally located monolayer of myoepithelial cells and a supporting fibrovascular stroma. The myoepithelial component always produced a standard immunohistochemical signature. All malignancies were grade I, and the subjects were all alive at 1 year postdiagnosis. On the basis of their morphology, we propose that they be classified as feline ductal adenoma/carcinoma and feline intraductal papillary adenoma/carcinoma, respectively. They overlap with their canine counterparts and lack the typical myoepithelial differentiation patterns seen in canine complex neoplasms, and therefore, the term complex should be avoided in felines. This study will add new information on FMT classification and be useful for prognostic studies. PMID- 23735617 TI - Digital squamous cell carcinoma in dogs: epidemiological, histological, and immunohistochemical study. AB - Squamous cell carcinoma represents 47.4% of all malignant canine digital lesions, but despite its frequency, there are few published studies available. Pathology submission records of 154 cases and follow-up of 49 animals were analyzed. On the 49 cases, histological evaluation was performed of the differentiation degree, mitotic index, presence of emboli, and immunohistochemical expression of vimentin and E-cadherin. The mean (SD) age of affected animals was 10.2 (2.3) years; no sex predisposition was recorded. Beauceron and Briard were 2 new overrepresented breeds. Dark-haired animals comprised 97 of 105 (92%); 94 dogs of 125 (75.2%) belonged to large and giant breeds. The forelimb was affected twice more than the hind limb. Probable metastases were observed in 4 dogs; new tumor development was recorded in 11 of 49 (22.4%). Epidemiologic factors, histological grade, mitotic index, and expression of immunohistochemical markers seemed not to be related to the clinical outcome. PMID- 23735616 TI - Experimental infection of bar-headed geese (Anser indicus) and ruddy shelducks (Tadorna ferruginea) with a clade 2.3.2 H5N1 highly pathogenic avian influenza virus. AB - Since 2005, clade 2.2 H5N1 highly pathogenic avian influenza (HPAI) viruses have caused infections and morbidity among numerous species of wild waterfowl in Eurasia and Africa. However, outbreaks associated with clade 2.3.2 viruses have increased since 2009, and viruses within this clade have become the dominant strain of the H5N1 HPAI virus detected in wild birds, reaching endemic status in domestic birds in select regions of Asia. To address questions regarding the emergence and expansion of clade 2.3.2 viruses, 2 waterfowl species repeatedly involved in outbreaks of H5N1 HPAI viruses, bar-headed geese (Anser indicus) and ruddy shelducks (Tadorna ferruginea), were inoculated with a representative virus. All of 3 infected ruddy shelducks exhibited neurologic signs and died within 4 to 5 days. Two of 3 infected bar-headed geese had transient weakness but all survived. Viral shedding was predominately via the oropharynx and was detected from 1 to 7 days after inoculation. The severity and distribution of microscopic lesions corresponded with clinical disease and influenza-specific immunohistochemical staining of neurons. The predominant lesions were in the brain and were more severe in ruddy shelducks. Increased caspase-3 reactivity in the brains of all infected birds suggests a role for apoptosis in H5N1 HPAI virus pathogenesis in these species. These results demonstrate that similar to clade 2.2 viruses, a clade 2.3.2 H5N1 HPAI virus is neurotropic in some waterfowl species and can lead to neurologic disease with varying clinical outcomes. This has implications for the role that wild waterfowl may play in transmission of this virus in endemic regions. PMID- 23735618 TI - Canine melanoma diagnosis: RACK1 as a potential biological marker. AB - Melanoma diagnosis in dogs can be challenging due to the variety of histological appearances of canine melanocytic neoplasms. Markers of malignancy are needed. Receptor for activated C-kinase 1 (RACK1) was found to characterize melanomas in other mammals. We investigated the value of RACK1 detection in the classification of 19 cutaneous and 5 mucosal melanocytic neoplasms in dogs. These tumors were categorized as melanocytomas or benign and melanomas or malignant after evaluation of their morphology, mitotic index, and Ki-67 growth fraction. Using immunofluorescence, we confirmed microphthalmia-associated transcription factor (MITF) as a marker of normal and transformed melanocytic cells in dog tissues. All control (n = 10) and tumoral (n = 24) samples stained positively for MITF (34/34, 100%). Whereas RACK1 was not detected in healthy skin melanocytes, melanocytic lesions were all positive for RACK1 signal (24/24, 100%). RACK1 cytoplasmic staining appeared with 2 distinct distribution patterns: strong, diffuse, and homogeneous or granular and heterogeneous. All melanoma samples (13/13, 100%) stained homogeneously for RACK1. All melanocytomas (11/11, 100%) stained heterogeneously for RACK1. Immunohistochemistry was less consistent than immunofluorescence for all labelings in melanocytic lesions, which were often very pigmented. Thus, the fluorescent RACK1-MITF labeling pattern helped to distinguish melanomas from melanocytomas. Furthermore, RACK1 labeling correlated with 2 of 11 morphological features linked to malignancy: cell and nuclear size. These results suggest that RACK1 may be used as a marker in dog melanomas. PMID- 23735619 TI - Diagnostic performance evaluation of a computer-aided simple triage system for coronary CT angiography in patients with intermediate risk for acute coronary syndrome. AB - RATIONALE AND OBJECTIVES: Given the significance of coronary artery disease as the most important socioeconomic health care problem in the Western World, the application of computer-aided simple triage (CAST) systems to this disease would be desirable. MATERIALS AND METHODS: In total, 93 patients with acute chest pain and an intermediate risk score for acute coronary syndrome underwent coronary computed tomography angiography (cCTA). Among those, 74 were of adequate image quality for automated analysis by a commercially available CAST system (COR Analyzer, RCADIA, Haifa, Israel). CAST findings were compared to human expert interpretation for the detection of significant stenosis (>=50%) in the left main, left anterior descending, circumflex, right coronary artery, or arterial branches. Further, one inexperienced observer evaluated all studies for significant stenoses alone and after 1 month guided by a CAST system as an initial read. RESULTS: Human expert interpretation identified 37/74 patients with stenosis >=50%, whereas the CAST detected 45 patients. The CAST system demonstrated a sensitivity of 100%/79% and a specificity of 78%/89% on a per patient/per-vessel level, respectively. With CAST, the inexperienced readers' per vessel sensitivity and positive predictive values significantly improved (P = .011, P = .009) from 69% and 41% to 91% and 74%, respectively. CONCLUSIONS: The investigated CAST system for automatic stenosis detection can accurately identify patients with coronary artery stenosis >=50% and may be of use as initial interpretation and triage of cCTA studies as well as a second reader for inexperienced readers, in absence of expert readers. PMID- 23735623 TI - A biomimetic physiological model for human adipose tissue by adipocytes and endothelial cell cocultures with spatially controlled distribution. AB - An in vitro model that recapitulates the characteristics of native human adipose tissue would largely benefit pathology studies and therapy development. In this paper, we fabricated a physiological model composed of both human adipocytes and endothelial cells with spatially controlled distribution that biomimics the structure and composition of human adipose tissue. Detailed studies into the cell cell interactions between the adipocytes and endothelial cells revealed a mutual enhanced effect which resembles the in vivo routine. Furthermore, comparisons between planar coculture and model coculture demonstrated improved adipocyte function as well as endothelial cell proliferation under the same conditions. This research provided a reliable model for human adipose tissue development studies and potential obesity-related therapy development. PMID- 23735624 TI - Low-protein diet or nutritional therapy in chronic kidney disease? AB - The use of a low-protein diet in treating chronic kidney disease dates back many decades. Initially, the low intake of proteins was used to reduce uremic symptoms. Thereafter, the hope of significantly slowing and even halting the progression of renal failure toward dialysis grew among nephrologists. This proved not to be effective and the low-protein diet was largely abandoned. This review focuses on the reasons why a low-protein diet, and mainly comprehensive nutritional therapy, should still be considered a cornerstone in the treatment of chronic renal failure. PMID- 23735625 TI - Failure mode and effect analysis applied to the procedure for intrathecal chemotherapy. PMID- 23735627 TI - A primer for quality improvement in primary care. PMID- 23735626 TI - Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries. AB - Cryptococcal meningitis is the leading cause of adult meningitis in sub-Saharan Africa, and contributes up to 20% of AIDS-related mortality in low-income and middle-income countries every year. Antifungal treatment for cryptococcal meningitis relies on three old, off-patent antifungal drugs: amphotericin B deoxycholate, flucytosine, and fluconazole. Widely accepted treatment guidelines recommend amphotericin B and flucytosine as first-line induction treatment for cryptococcal meningitis. However, flucytosine is unavailable in Africa and most of Asia, and safe amphotericin B administration requires patient hospitalisation and careful laboratory monitoring to identify and treat common side-effects. Therefore, fluconazole monotherapy is widely used in low-income and middle-income countries for induction therapy, but treatment is associated with significantly increased rates of mortality. We review the antifungal drugs used to treat cryptococcal meningitis with respect to clinical effectiveness and access issues specific to low-income and middle-income countries. Each drug poses unique access challenges: amphotericin B through cost, toxic effects, and insufficiently coordinated distribution; flucytosine through cost and scarcity of registration; and fluconazole through challenges in maintenance of local stocks--eg, sustainability of donations or insufficient generic supplies. We advocate ten steps that need to be taken to improve access to safe and effective antifungal therapy for cryptococcal meningitis. PMID- 23735628 TI - New Dutch government: strong primary care close to the people. PMID- 23735629 TI - Are prescribing initiatives readily transferable across classes: the case of generic losartan in Scotland? AB - BACKGROUND: There are on-going initiatives in Scotland to improve the quality and efficiency of prescribing in primary care. Activities to enhance prescribing of angiotensin-converting enzyme inhibitors (ACEIs) versus angiotensin receptor blockers (ARBs) include prescribing guidance, guidelines, benchmarking, prescribing targets and financial incentives. These measures stabilised reimbursed expenditure for renin-angiotensin inhibitor drugs between 2001 and 2007 despite a 159% increase in volumes. Generic losartan was included in the Drug Tariff from July 2010. As there is no appreciable difference between ARBs, and the prices of generic losartan are falling, health boards should be actively encouraging its prescribing. AIM: To primarily assess changes in utilisation patterns of losartan versus other ARBs after July 2010. Second, to assess the utilisation of generic versus originator losartan. METHOD: We used an interrupted time series analysis of ARB utilisation, measured in defined daily doses (DDDs) before and after July 2010. Utilisation data were obtained from the NHS National Services Scotland Corporate Warehouse. RESULTS: There was no significant change in the utilisation pattern of losartan or other ARBs combined before or after the introduction of generic losartan. Losartan accounted for 32% of total ARBs 12 months after listing. Between 98 and 99% of losartan was prescribed generically. In March 2012, the price of losartan was 88% below prepatent prices with potential savings of ?8m per year. CONCLUSION: Specific measures are needed to change prescribing habits especially with complex messages. The cost of deriving savings must be weighed against other quality initiatives and other ARBs losing or shortly losing their patents. PMID- 23735631 TI - The status of accreditation in primary care. AB - BACKGROUND: One method utilised to improve the quality of health care is accreditation. Although accreditation has been extensively used in the acute care sector, its presence in primary care is limited and so is our understanding of its nature, uptake and associated outcomes. Because acute care and primary care environments are vastly different, our understanding of acute care accreditation cannot simply be translated to primary care. AIM: The purpose of this paper was to explore the current state of primary care accreditation. METHODS: An extensive search was completed examining peer-reviewed and grey literature. In addition, interviews with key stakeholders involved in primary care accreditation were undertaken. RESULTS: From the 501 reviewed abstracts, 62 papers were used in this review in addition to 72 sources from grey literature. Eight interviews were also held with key informants. CONCLUSIONS: In this review of the available literature of accreditation within primary care, it was found that accreditation in this sector is generally non-government funded and voluntary with some countries offering financial incentives. It was evident that there is a dearth of research on the nature and uptake of accreditation in this sector, along with how accreditation affects outcomes of care, whether it is an effective method to improve quality, perceptions of care, healthcare utilisation and costs. These findings imply that further research is required to examine the possible impact accreditation may have on health care within primary care. PMID- 23735630 TI - Group supervision for general practitioners: a case study. AB - AIM: Group supervision is a sparsely researched method for professional development in general practice. The aim of this study was to explore general practitioners' (GPs') experiences of the benefits of group supervision for improving the treatment of mental disorders. METHODS: One long-established supervision group was studied closely for six months by observing the group sessions, and by interviewing GPs and their supervisors, individually and collectively. The interviews were recorded digitally and transcribed verbatim. The data were analysed using systematic text condensation. RESULTS: The GPs found participation in a supervision group to be a meaningful and professionally valuable activity. They experienced that supervision had improved their psychiatric skills, and that they had become more confident in carrying out talking therapies. Improvements in referral letters were also reported in relation to the communication with local community psychiatry centres. Furthermore, the GPs experienced that supervision had a positive 'spill-over effect' on everyday consultations, and that the supervision group became a forum for coping with other difficulties in their professional life as well. Trust and continuity were considered important prerequisites for disclosing and discussing professional problems. CONCLUSION: The results of this study indicate that participation in a supervision group can be beneficial for maintaining and developing GPs' skills in dealing with patients with mental health problems. Group supervision influenced other areas of GPs' professional lives as well. However, more studies are needed to assess the impact of supervision groups. PMID- 23735632 TI - Application of a case-control design to the analysis of drop-outs from integrated behavioural health care. AB - BACKGROUND: Case-control designs are rarely employed in quality improvement investigations. The reason for the study was two-fold: (1) to demonstrate the feasibility of the method in a practice setting, and (2) because drop-outs from this programme had not previously been investigated. METHODS: Drop-out was defined as termination due to non-contact after two consecutive months. Fifty drop-outs were randomly selected from all cases discharged from the programme during the period 1 March 2008 to 28 February 2012. Fifty controls were randomly selected from among those discharged patients who did not drop out due to non contact. RESULTS: Dropping out was significantly associated with female sex (P = 0.015), younger age (P = 0.000) and treatment site (P = 0.004). Sites still in the shake-down period had higher drop-out rates. Depression diagnosis and severity were not significant. CONCLUSIONS: The case-control design is an efficient approach to retrospective analysis of discrete quality indicators. PMID- 23735633 TI - Breast cancer screening: an ethical dilemma, or an opportunity for openness? AB - The NHS Breast Screening Programme was hailed as a life-saver when it was set up, but research has raised concerns about efficacy and levels of harm. The honesty and adequacy of screening information was challenged: proof of the '1400 lives a year saved' claim was not offered and some serious harms were not mentioned. The report of the independent review of breast screening exposed grave concerns, but brought more controversy. Doctors, patients and the doctor/patient relationship may be adversely affected. PMID- 23735634 TI - Harnessing information technology to innovate in primary care. AB - BACKGROUND: The health sector's capacity to meet the changing needs of patients is being questioned. This has significant implications for patients, carers, health services and those who hold the public purse. It is therefore important to bolster its capacity to serve a greater proportion of people in need of health care, opportunities for which might be facilitated by information technology (IT). AIM: To identify strategies to bolster the capacity of the primary care sector to deploy and innovate with IT. METHODS: Three discussion groups comprising clinicians, regulatory agents, innovators and academics from each Australian state. Themes discussed included: (1) health problems that can be readily solved by IT, (2) clinician engagement with IT, (3) experiences with IT implementation, (4) engagement with hard-to-reach groups, and (5) social media use. RESULTS: Although participants were aware of the issues surrounding the use of IT, including limited evidence and reduced data integrity, they were equally aware of the opportunities afforded by IT. With appropriate support, they indicated that IT could help to innovate and reinvigorate the primary care sector. This could be demonstrated via research, initiatives that improve governance arrangements (within and beyond the primary care sector), programmes that enhance care delivery and consumer empowerment initiatives. CONCLUSION: Clinicians are rarely included as part of teams developing innovations, and technology is not always tailored for clinical practice or tested on clinical outcomes. Technical and access issues continue to hamper dissemination of innovation. The need for leadership in developing IT healthcare solutions remains paramount, with the organisation best able to negotiate with the key stakeholders at the helm. PMID- 23735635 TI - Physician cardiovascular disease risk factor management: practice analysis in Japan versus the USA. AB - BACKGROUND: There is a 42% lower cardiovascular disease (CVD) death rate in Japan compared with the USA. Do physicians report differences in practice management of CVD risk factors in the two countries that might contribute to this difference? AIMS: CVD risk factor management reported by Japanese versus US primary care physicians was studied. METHODS: We undertook a descriptive study. An internet based survey was conducted with physicians from each country. A convenience sample from the Shiga Prefecture in Japan and the state of Ohio in the USA resulted in 48 Japanese and 53 US physicians completing the survey. RESULTS: The survey group may not be representative of a larger sample. The survey demonstrated that 98% of responding Japanese physicians spend <10 minutes performing a patient visit, while 76% of US physicians spend 10 to 20 minutes (P < 0.0001) managing CVD risk factors. Eighty-seven percent of Japanese physicians (vs. 32% of US physicians) see patients in within three months for follow-up (P < 0.0001). Sixty-one percent of Japanese physicians allocate < 30% of visit time to patient education, whereas 60% of US physicians spend > 30% of visit time on patient education (P < 0.0001). Prescriptions are renewed very frequently by Japanese physicians (83% renewing less than monthly) compared with 75% of US physicians who renew medications every one to six months (P < 0.0001). Only 20% of Japanese physicians use practice guidelines routinely compared with 50% of US physicians (P = 0.0413). US physicians report disparities in care more frequently (P < 0.0001). Forty-three percent of Japanese (vs. 10% of US) physicians believe that they have relative freedom to practise medicine (P < 0.0001). CONCLUSION: Many factors undoubtedly affect CVD in different countries. The dominant ones include social determinants of health, genetics, public health and overall culture (which in turn determine diet, exercise and other factors). Yet the medical care system is an expensive component of society and its role in managing CVD risk factors deserves study. This descriptive report poses questions that require a more definitive study either with a more representative sample or direct observation of physician practices. US physicians responding to the survey reported greater administrative efforts, frustration and disparities in their practice, yet they followed practice guidelines more carefully. Japanese physicians responding reported focusing on quick, frequent visits that may have been more medication oriented, expecting more patient responsibility in self care, which may have resulted in better chronic disease management. There may be differences in CVD risk factor management by primary care physicians in Japan versus the USA. PMID- 23735636 TI - Effect of travel on influenza epidemiology. AB - To assess the attack and incidence rates for influenza virus infections, during October 2006-October 2007 we prospectively studied 1,190 adult short-term travelers from the Netherlands to tropical and subtropical countries. Participants donated blood samples before and after travel and kept a travel diary. The samples were serologically tested for the epidemic strains during the study period. The attack rate for all infections was 7% (86 travelers) and for influenza-like illness (ILI), 0.8%. The incidence rate for all infections was 8.9 per 100 person-months and for ILI, 0.9%. Risk factors for infection were birth in a non-Western country, age 55-64 years, and ILI. In 15 travelers with fever or ILI, influenza virus infection was serologically confirmed; 7 of these travelers were considered contagious or incubating the infection while traveling home. Given the large number of travelers to (sub)tropical countries, travel-related infection most likely contributes to importation and further influenza spread worldwide. PMID- 23735637 TI - Patterning the dorsal-ventral axis of the wasp Nasonia vitripennis. AB - Regulatory networks composed of interacting genes are responsible for pattern formation and cell type specification in a wide variety of developmental contexts. Evolution must act on these regulatory networks in order to change the proportions, distribution, and characteristics of specified cells. Thus, understanding how these networks operate in homologous systems across multiple levels of phylogenetic divergence is critical for understanding the evolution of developmental systems. Among the most thoroughly characterized regulatory networks is the dorsal-ventral patterning system of the fly Drosophila melanogaster. Due to the thorough understanding of this system, it is an ideal starting point for comparative analyses. Here we report an analysis of the DV patterning system of the wasp, Nasonia vitripennis. This wasp undergoes a mode of long germ embryogenesis that is superficially nearly identical to that of Drosophila, but one that was likely independently derived. We have found that while the expression of genes just prior to the onset of gastrulation is almost identical in Nasonia and Drosophila, both the upstream network responsible for generating this pattern, and the downstream morphogenetic movements that it sets in motion, are significantly diverged. From this we conclude that many network structures are available to evolution to achieve particular developmental ends. PMID- 23735638 TI - FOXP3 demethylation as a means of identifying quantitative defects in regulatory T cells in acute coronary syndrome. AB - OBJECTIVE: The contribution of regulatory T cells (Tregs) to the pathogenesis of acute coronary syndrome (ACS) remains poorly understood. One core obstacle is the lack of Treg-specific markers. A highly conserved CpG enriched element in forkhead box P3 intron 1 (FOXP3 i l) is unmethylated only in Tregs, and measuring the unmethylation of FOXP3 i l can be used to identify the role of Tregs in clinical diseases. This study investigated whether analyzing the demethylation status of FOXP3 i 1 is a more reliable means than using Treg-specific surface markers in ACS. METHODS AND RESULTS: We evaluated circulating Tregs percentages on different levels including cell frequencies (CD4(+)CD25(hi)FOXP3(+)Tregs and CD4(+)CD25(hi)CD45(+)naive Tregs) or FOXP3 mRNA, FOXP3 i 1 demethylation status and related cytokine secretion in 89 patients with ACS and 35 controls. FOXP3 i 1 demethylation assay showed that the amount of Tregs in ACS patients was significantly reduced than that in controls (p = 0.0005). However, flow cytometry analysis did not identify any reduction of CD4(+)CD25(hi)FOXP3(+)Tregs in ACS patients. Notably, younger patients had higher percentage of CD4(+)CD25(hi)FOXP3(+)Tregs but decreased percentage of CD4(+)CD25(hi)CD45(+)naive Tregs than either controls or older patients. Furthermore, a DNA hypomethylation agent increased the amount of CD4(+)CD25(hi)FOXP3(+)Tregs and Tregs related cytokine IL-10 and suppressed the production of pro-inflammatory cytokine interferon-gamma by inducing FOXP3 i 1 demethylation in vitro. CONCLUSIONS: A quantitative defect of Tregs, suggestive of decreased peripheral tolerance, could be a potential hallmark of ACS disease. Targeting FOXP3 i l demethylation might elevate the inhibitory activity of Tregs in ACS. PMID- 23735639 TI - Obesity paradox in peripheral vascular disease. PMID- 23735640 TI - Lipoprotein lipase gene polymorphism rs1059611 functionally influences serum lipid concentrations. AB - OBJECTIVE: Dozens of single nucleotide polymorphisms (SNPs) in the lipoprotein lipase (LPL) gene have been reported to be associated with lipid concentrations. The aim of this study was to validate the association between rs1059611 in the LPL gene and serum lipid concentrations in the Chinese Han population and explore the biological relevance. METHODS: A total of 5664 participants were recruited and genotyped for the SNP. Gene expression levels of LPL in blood cells were evaluated by real-time PCR and western blotting analysis. The functional potential of the SNP was examined by luciferase reporter assay and electrophoretic mobility-shift assay (EMSA). RESULTS: We observed significant associations between rs1059611 and increased HDL-C (P = 5.65 * 10(-5)) and decreased TG concentrations (P = 2.68 * 10(-7)). We also found that participants with the C allele had higher mRNA expression level (P = 0.0334) and protein expression level (P = 0.0641) of LPL. The luciferase activity of the rs1059611 T construct was 0.69-fold of the rs1059611 C construct (P = 0.0009). The EMSA showed that the binding of the transcription factor(s) differed for the alleles of the SNP. CONCLUSION: The results of our study demonstrated that rs1059611 was associated with HDL-C and TG concentrations in Chinese Han population and might have a functional effect on the transcription of LPL by differential binding of transcription factors. PMID- 23735642 TI - Intravenous pamidronate treatment in children with moderate-to-severe osteogenesis imperfecta started under three years of age. AB - OBJECTIVE: Evaluate clinical outcome of early cyclic intravenous pamidronate treatment in children with moderate-to-severe osteogenesis imperfecta (OI), commenced before three years of age. METHODS: A retrospective review of 17 patients with moderate-to-severe OI. Development, anthropometry, fracture history, bone mineral density (BMD) and biochemistry were collected at baseline, 12 and 24 months. RESULTS: Four had OI type I, eleven had type III, one OI-FKBP10 type and one OI type V. Mean age at start of pamidronate was 14 +/- 11 months. Pamidronate ranged from 6 to 12 mg/kg/year. No adverse reaction apart from fever and vomiting was noted. Long bone fracture decreased from a mean of 10.4/year to 1.2/year after 12 months and 1.4/year after 24 months (p = 0.02). Lumbar spine age- and height-matched BMD Z-scores increased (p < 0.005). Sixteen with vertebral compression fractures at baseline all showed improved vertebral shape (p < 0.001). Concavity index, likewise, improved (p < 0.005). Motor milestones compared to historical data show earlier attainment in rolling over, crawling, pulling to stand and walking independently but not sitting. CONCLUSION: Cyclic intravenous pamidronate, started under 3 years of age in children with moderate to-severe OI, was well tolerated and associated with an increase in lumbar spine BMD, reduced fracture frequency, vertebral remodelling and attainment of motor milestones at an earlier age. PMID- 23735643 TI - [The French Comprehensive Cancer Centers in the French oncology landscape]. AB - For more than 60 years, the French Comprehensive Cancer Centers participate in public hospital service and are exclusively dedicated to the fight against cancer. This article returns on their history, their model, their group strategy with the creation of UNICANCER, their place in French cancer research and treatments today, their contribution to the cancer plans and the challenges and issues they will face in the next 10 years. PMID- 23735641 TI - Fine-tuned shuttles for bone morphogenetic proteins. AB - Bone morphogenetic proteins (BMPs) are potent secreted signaling factors that trigger phosphorylation of Smad transcriptional regulators through receptor complex binding at the cell-surface. Resulting changes in target gene expression impact critical cellular responses during development and tissue homeostasis. BMP activity is tightly regulated in time and space by secreted modulators that control BMP extracellular distribution and availability for receptor binding. Such extracellular regulation is key for BMPs to function as morphogens and/or in the formation of morphogen activity gradients. Here, we review shuttling systems utilized to control the distribution of BMP ligands in tissue of various geometries, developing under different temporal constraints. We discuss the biological advantages for employing specific strategies for BMP shuttling and roles of varied ligand forms. PMID- 23735644 TI - Comparison of short- and long-term outcomes of percutaneous coronary intervention for chronic total occlusions between patients aged >=75 years and those aged <75 years. AB - Few reports are available on the safety and efficacy of percutaneous coronary intervention (PCI) for chronic total occlusions (CTOs) in older patients. In the present study, 284 patients who underwent PCI for CTOs were retrospectively evaluated by comparing the characteristics of 67 patients aged >=75 years (the older group) and 217 patients aged <75 years (the younger group). Technical success was achieved in 77% of the patients in the older group and 79% of those in the younger group (p = 0.66). No significant differences were observed between the 2 groups in terms of the incidence of procedural complications. In the older group, a comparison between the patients with successful and failed PCI revealed significantly superior 3-year cardiac survival (97.6% vs 76.9%, p = 0.005). The 3 year cardiac survival of those with successful PCI was similar to that observed in the younger group. On multivariate analysis, successful PCI was found to be associated with a lower incidence of cardiac death in the older group (hazard ratio 0.09, 95% confidence interval 0.01 to 0.91, p = 0.042). In conclusion, this single-center, observational study suggests that PCI for CTOs can be performed with a high rate of procedural success and acceptably low mortality and morbidity in older patients, resulting in improved cardiac survival. Thus, PCI for CTO lesions should be included among the treatment strategies for older patients. PMID- 23735645 TI - Flow-mediated vasodilation as a predictor of therapeutic response to midodrine hydrochloride in children with postural orthostatic tachycardia syndrome. AB - This study was designed to explore the value of flow-mediated vasodilation (FMD) as a predictor of therapeutic response to midodrine hydrochloride (MD) in children with postural orthostatic tachycardia syndrome (POTS). One hundred and eight children diagnosed with POTS and 20 healthy control children were enrolled. All children with POTS received MD and were followed up for 3 months. FMD of brachial artery for each participant was measured by vascular ultrasound. Symptom scores, FMD values, and head-up test (HUT)/head-up tilt test (HUTT) outcomes were investigated before and after treatment. A receiver operating characteristic curve was used to explore the value of FMD as a predictor. Baseline FMD (%) and increased heart rate (beats per minute) during HUT/HUTT were significantly greater in children with POTS compared with control children (FMD: 11 +/- 3% vs 6 +/- 2%, p <0.001; increased heart rate: 38 +/- 9 vs 7 +/- 7 beats/min, p <0.001, respectively). Before treatment, MD responders had greater FMD values than MD nonresponders (p <0.05). Symptom scores, excessive increases in heart rate during HUT, and increased FMD values were all reduced significantly after treatment (all p <0.05). The receiver operating characteristic curve for the predictive value of FMD showed the area under the curve to be 0.790 (95% confidence interval: 0.679 to 0.902; p <0.001) at 1-month and 0.803 (95% confidence interval: 0.669 to 0.936; p <0.01) at 3-month therapy. FMD of 9.85% had a high sensitivity (1-month therapy: 71.6%; 3-month therapy: 74.4%) and specificity (1-month therapy 77.8%; 3 month therapy: 80%). In conclusion, FMD is a predictor of the efficacy of MD for treating children with POTS. PMID- 23735646 TI - Long-term outcomes after percutaneous coronary intervention for chronic total occlusion (from the CREDO-Kyoto registry cohort-2). AB - Despite improving success rate of percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) lesions, the clinical benefit of recanalization of CTO is still a matter of debate. Of 13,087 patients who underwent PCI in the CREDO-Kyoto registry cohort-2, 1,524 patients received PCI for CTO (CTO-PCI). Clinical outcomes were compared between 1,192 patients with successful CTO-PCI and 332 patients with failed CTO-PCI. In-hospital death tended to occur less frequently in the successful CTO-PCI group than in the failed CTO-PCI group (1.4% vs 3.0%, p = 0.053). Through 3-year follow-up, the cumulative incidence of all cause death was not significantly different between the successful and failed CTO PCI groups (9.0% vs 13.1%, p = 0.18), whereas the cumulative incidence of cardiac death was significantly less in the successful CTO-PCI group than in the failed CTO-PCI group (4.5% vs 8.4%, p = 0.03). However, after adjusting confounders, successful CTO-PCI was associated with lesser risk for neither all-cause death (hazard ratio 0.93, 95% confidence interval 0.64 to 1.37, p = 0.69) nor cardiac death (hazard ratio 0.71, 95% confidence interval 0.44 to 1.16, p = 0.16). The cumulative incidence of coronary artery bypass grafting (CABG) was remarkably less in patients with successful PCI compared with those with failed PCI (1.8% vs 19.6%, p <0.0001). In conclusion, successful CTO-PCI compared with failed PCI was not associated with lesser risk for 3-year mortality. However, successful CTO-PCI was associated with significantly less subsequent CABG. PMID- 23735647 TI - Plasma vitamin D-binding protein and risk of heart failure in male physicians. AB - Previous studies have suggested that vitamin D deficiency might contribute to the pathogenesis of heart failure (HF); however, limited data are available on the association of vitamin D-binding protein (VDBP)--a major transport protein for vitamin D--and the development of HF. Thus, we investigated whether plasma VDBP is inversely associated with HF risk. Using a prospective nested case-control design, we selected 464 cases and 464 matched controls from the Physicians' Health Study for the present analyses. VDBP was determined using an enzyme-linked immunoassay. Self-reported HF was obtained through annual follow-up questionnaires and validated in a subsample by a review of the medical records. We used conditional logistic regression analyses to compute the adjusted odds ratios. The mean age was 58.6 years, and the median VDBP was 307.8 MUg/ml (interquartile range 265.2 to 354.6). Plasma VDBP was not associated with HF in our study. Across the consecutive quintiles of VDBP, the odds ratio was 1.0 (95% confidence interval [CI] reference), 1.05 (95% CI 0.66 to 1.65), 1.28 (95% CI 0.80 to 2.06), 1.07 (95% CI 0.65 to 1.75), and 1.28 (95% CI 0.76 to 2.15); p for linear trend = 0.41, after adjustment for matching factors, body mass index, diabetes, atrial fibrillation, hypertension, and high-sensitivity C-reactive protein. In conclusion, our data have shown no significant association between the plasma levels of VDBP and HF risk in apparently healthy male physicians. PMID- 23735648 TI - Validation and quantification of genetic determinants of lipoprotein-a levels and predictive value for angiographic coronary artery disease. AB - Lipoprotein(a) (Lp[a]) has gained attention as a heritable coronary artery disease (CAD) risk factor and therapeutic target. Two genetic variants in the LPA gene have been reported to influence Lp(a) levels and increase CAD risk. The aim of this study was to prospectively test these variants for their associations with Lp(a) and CAD risk. Participants (n = 1,400) in the Intermountain Heart Collaborative Study Registry who had Lp(a) cholesterol levels determined at coronary angiography were genotyped for rs3798220 and rs1045587 in LPA. Variants were detected by Taqman polymerase chain reaction. Chi-square and linear and logistic regression tests were used as appropriate among genotypes for Lp(a) and angiographic CAD. Age averaged 63 years; 65% were men; and severe CAD was present in 57%, mild CAD in 12%, and no CAD in 31%. Minor allele frequencies were 0.023 for rs3798220 and 0.090 for rs10455872. In multivariate modeling, only rs10455872 (odds ratio [OR] 2.33, 95% confidence interval [CI] 1.67 to 3.33, p = 1.75 * 10 9) and rs3798220 (OR 1.99, 95% CI 0.99 to 4.00, p = 0.065) contributed to the prediction of elevated Lp(a) cholesterol. Lp(a) cholesterol was weakly associated with CAD (OR 1.17, 95% CI 1.00 to 1.37, p = 0.055). Rs10455872 strongly predicted prevalent CAD (per allele OR 1.43, 95% CI 1.07 to 1.91, p = 0.0172); the effect size for the rare rs3798220 variant was similar (dominant OR 1.47, 95% CI 0.81 to 2.67, p = 0.20), but power was limited to demonstrate significance. The combined genotype explained only a small percentage (<=4%) of variability in Lp(a) cholesterol and prevalence of angiographic CAD. In conclusion, heritable contributions of LPA rs10455872 and rs3798220 to Lp(a) cholesterol levels and to angiographic CAD were prospectively assessed in this study. The percentage of intersubject variability in Lp(a) cholesterol and the percentage of prevalent CAD explained were small. PMID- 23735649 TI - A simple echocardiographic method to estimate pulmonary vascular resistance. AB - Pulmonary hypertension includes heterogeneous diagnoses with distinct hemodynamic pathophysiologic features. Identifying elevated pulmonary vascular resistance (PVR) is critical for appropriate treatment. We reviewed data from patients seen at referral pulmonary hypertension clinics who had undergone echocardiography and right-side cardiac catheterization within 1 year. We derived equations to estimate PVR using the ratio of estimated pulmonary artery (PA) systolic pressure (PASPDoppler) to right ventricular outflow tract velocity time integral (VTI). We validated these equations in a separate sample and compared them with a published model based on the ratio of the transtricuspid flow velocity to right ventricular outflow tract VTI (model 1, Abbas et al 2003). The derived models were as follows: PVR = 1.2 * (PASP/right ventricular outflow tract VTI) (model 2) and PVR = (PASP/right ventricular outflow tract VTI) + 3 if notch present (model 3). The cohort included 217 patients with mean PA pressure of 45.3 +/- 11.9 mm Hg, PVR of 7.3 +/- 5.0 WU, and PA wedge pressure of 14.8 +/- 8.1 mm Hg. Just >1/3 had a PA wedge pressure >15 mm Hg (35.5%) and 82.0% had PVR >3 WU. Model 1 systematically underestimated catheterization estimated PVR, especially for those with high PVR. The derived models demonstrated no systematic bias. Model 3 correlated best with PVR (r = 0.80 vs r = 0.73 and r = 0.77 for models 1 and 2, respectively). Model 3 had superior discriminatory power for PVR >3 WU (area under the curve 0.946) and PVR >5 WU (area under the curve 0.924), although all models discriminated well. Model 3-estimated PVR >3 was 98.3% sensitive and 61.1% specific for PVR >3 WU (positive predictive value 93%; negative predictive value 88%). In conclusion, we present an equation to estimate the PVR, using the ratio of PASPDoppler to right ventricular outflow tract VTI and a constant designating presence of right ventricular outflow tract VTI midsystolic notching, which provides superior agreement with catheterization estimates of PVR across a wide range of values. PMID- 23735650 TI - Fabrication of nanofibrous scaffold using a PLA and hagfish thread keratin composite; its effect on cell adherence, growth, and osteoblast differentiation. AB - Electrospinning is a useful method for the production of nanofibrous scaffolds in the field of tissue engineering. Keratin has been used as a biomaterial for electrospinning and can be used in a variety of biomedical applications because it is a natural protein, giving it the ability to improve cell affinity of scaffolds. In this study, keratin was extracted from hagfish slime thread (H keratin) and blended with polylactic acid (PLA) polymer solution to construct a nanofibrous scaffold. Wool keratin (W-keratin) was used as a control for the comparison of morphological, physical, and biological properties. The results of Fourier transform infrared spectroscopy showed the presence of both W-keratin and H-keratin in the electrospun PLA/keratin. Observations with a scanning electron microscope revealed that PLA, PLA/W-keratin, and PLA/H-keratin had similar average diameters (~800 nm). Cell attachment experiments showed that MG-63 cells adhered more rapidly and spread better onto PLA/H-keratin than onto the pure PLA or PLA/W-keratin. Cell proliferation assay, DNA content, live/dead, and alkaline phosphatase activity assays showed that PLA/H-keratin scaffolds could accelerate the viability, proliferation, and osteogenesis of MG-63 cells relative to pure PLA or PLA/W-keratin nanofibrous scaffolds. These findings suggest that H-keratin can improve cellular attraction and has great potential to be used as a biomaterial in bone tissue engineering. PMID- 23735652 TI - Electrical features of eighteen automated external defibrillators: a systematic evaluation. AB - AIM: Assessment and comparison of the electrical parameters (energy, current, first and second phase waveform duration) among eighteen AEDs. METHOD: Engineering bench tests for a descriptive systematic evaluation in commercially available AEDs. AEDs were tested through an ECG simulator, an impedance simulator, an oscilloscope and a measuring device detecting energy delivered, peak and average current, and duration of first and second phase of the biphasic waveforms. All tests were performed at the engineering facility of the Lombardia Regional Emergency Service (AREU). RESULTS: Large variations in the energy delivered at the first shock were observed. The trend of current highlighted a progressive decline concurrent with the increases of impedance. First and second phase duration varied substantially among the AEDs using the exponential biphasic waveform, unlike rectilinear waveform AEDs in which phase duration remained relatively constant. CONCLUSIONS: There is a large variability in the electrical features of the AEDs tested. Energy is likely not to be the best indicator for strength dose selection. Current and shock duration should be both considered when approaching the technical features of AEDs. These findings may prompt further investigations to define the optimal current and duration of the shock waves to increase the success rate in the clinical setting. PMID- 23735651 TI - Use of impedance threshold device in conjunction with our novel adhesive glove device for ACD-CPR does not result in additional chest decompression. AB - OBJECTIVE: To evaluate the hemodynamic effects of using an adhesive glove device (AGD) to perform active compression-decompression CPR (AGD-CPR) in conjunction with an impedance threshold device (ITD) in a pediatric cardiac arrest model. DESIGN: Controlled, randomized animal study. METHODS: In this study, 18 piglets were anesthetized, ventilated, and continuously monitored. After 3min of untreated ventricular fibrillation, animals were randomized (6/group) to receive either standard CPR (S-CPR), active compression-decompression CPR via adhesive glove device (AGD-CPR) or AGD-CPR along with an ITD (AGD-CPR+ITD) for 2min at 100 120compressions/min. AGD is delivered using a fingerless leather glove with a Velcro patch on the palmer aspect and the counter Velcro patch adhered to the pig's chest. Data (mean+/-SD) were analyzed using one-way ANOVA with pair wise multiple comparisons to assess differences between groups. p-Value<=0.05 was considered significant. RESULTS: Both AGD-CPR and AGD-CPR+ITD groups produced lower intrathoracic pressure (IttP, mmHg) during decompression phase (-13.4+/ 6.7, p=0.01 and -11.9+/-6.5, p=0.01, respectively) in comparison to S-CPR (-0.3+/ 4.2). Carotid blood flow (CBF, % of baseline mL/min) was higher in AGD-CPR and AGD-CPR+ITD (respectively 64.3+/-47.3%, p=0.03 and 67.5+/-33.1%, p=0.04) as compared with S-CPR (29.1+/-12.5%). Coronary perfusion pressure (CPP, mmHg) was higher in AGD-CPR and AGD-CPR+ITD (respectively 19.7+/-4.6, p=0.04 and 25.6+/ 12.1, p=0.02) when compared to S-CPR (9.6+/-9.1). There was no statistically significant difference between AGD-CPR and AGD-CPR+ITD groups with reference to intra-thoracic pressure, carotid blood flow and coronary perfusion pressure. CONCLUSION: Active compression decompression delivered by this simple and inexpensive adhesive glove device resulted in improved cerebral blood flow and coronary perfusion pressure. There was no statistically significant added effect of ITD use along with AGD-CPR on the decompression of the chest. PMID- 23735653 TI - Haemophilus influenzae serotype a invasive disease, Alaska, USA, 1983-2011. AB - Before introduction of Haemophilus influenzae type b (Hib) vaccines, rates of Hib disease in Alaska's indigenous people were among the highest in the world. Vaccination reduced rates dramatically; however, invasive H. influenzae type a (Hia) disease has emerged. Cases of invasive disease were identified through Alaska statewide surveillance during 1983-2011. Of 866 isolates analyzed for serotype, 32 (4%) were Hia. No Hia disease was identified before 2002; 32 cases occurred during 2002-2011 (p<0.001). Median age of case-patients was 0.7 years; 3 infants died. Incidence of Hia infection (2002-2011) among children <5 years was 5.4/100,000; 27 cases occurred in Alaska Native children (18/100,000) versus 2 cases in non-Native children (0.5/100,000) (risk ratio = 36, p<0.001). From 12/2009 to 12/2011, 15 cases of Hia disease occurred in southwestern Alaska (in children <5 years, rate = 204/100,000). Since introduction of the Hib conjugate vaccine, Hia infection has become a major invasive bacterial disease in Alaska Native children. PMID- 23735654 TI - Personal daily dialysis: the evolution of the artificial kidney. AB - To improve hemodialysis (HD) patients' clinical tolerance and quality of life, a new paradigm of technological evolution of the artificial kidney needs to be addressed at this point. Compared to the second law of thermodynamics, if HD is a barrier against entropy increase, personal daily dialysis (PDD), taking account of multidimensional treatment parameters specific to the patient, can be a new treatment option. Here, we review currently used HD equipment and competing technologies of the wearable artificial kidney (WAK) for future application to PDD. Biofeedback control during HD personalizes treatment parameters such as blood volume changes, thermal energy balance and biochemical variables in well defined ranges and tries to deliver the targeted treatment dose without intradialytic hypotension. Miniaturized devices such as WAK could also meet the needs of patients by providing mobility, the possibility of normal social activities and flexibility of treatment schedule. So far, many studies have shown the future direction of renal replacement therapy for chronic patients: personalization and daily treatment. PDD might require a new index including a biological plan for recovery of homeostasis and a strategy toward long-term rehabilitation of the patient. The concept of entropy includes these multidimensional factors, and the artificial kidney should be evolved to minimize the increase in entropy of the patient. PMID- 23735655 TI - MEK1 and MEK2 differentially control the duration and amplitude of the ERK cascade response. AB - The Raf/MEK/ERK cascade is one of the most studied and important signal transduction pathways. However, existing models largely ignore the existence of isoforms of the constituent kinases and their interactions. Here, we propose a model of the ERK cascade that includes heretofore neglected differences between isoforms of MEK. In particular, MEK1 is subject to a negative feedback from activated ERK, which is further conferred to MEK2 via hetero-dimerization. Specifically, ERK phosphorylates MEK1 at the residue Thr292, hypothetically creating an additional phosphatase binding site, accelerating MEK1 and MEK2 dephosphorylation. We incorporated these recently discovered interactions into a mathematical model of the ERK cascade that reproduces the experimental results of Catalanotti et al (2009 Nature Struct. Mol. Biol. 16 294-303) and Kamioka et al (2010 J. Biol. Chem. 285 33540-8). Furthermore, the model allows for predictions regarding the differences in the catalytic activity and function of the MEK isoforms. We propose that the MEK1/MEK2 ratio regulates the duration of the response, which increases with the level of MEK2 and decreases with the level of MEK1. In turn, the amplitude of the response is controlled by the total amount of the two isoforms. We confirm the proposed model structure performing a random parameter sampling, which led us to the conclusion that the sampled parameters, selected to properly reproduce wild-type (WT) cell behavior, to allow for qualitative reproduction of differences in behavior WT cells and cell mutants studied experimentally. PMID- 23735657 TI - Circulating concentrations of leptin, ovarian follicle number, and oocyte lipid content and active mitochondria, in Zebu crossbred cows maintained on standard or improved nutrition. AB - Zebu (Bos indicus) crossbred beef cows (Droughtmaster) were maintained long-term (16 months) on standard nutrition (SN) or improved nutrition (IN). Cows on IN had better body condition and greater (P<0.05) circulating concentrations of leptin than cows on SN (0.7+/-0.1n/ml and 1.7+/-0.1n/ml, respectively). There were no outstanding differences between SN and IN cows in basal number of ovarian follicles (<=4mm, 5-8mm, and >=9mm) and there were also no differences in number of oocytes recovered by oocyte pick-up. Cows on IN had a greater (P<0.05) number of total follicles after stimulation with FSH than cows on SN. Oocytes from cows on IN had greater (P<0.05) lipid content than cows on SN (-0.23+/-0.16 and 0.20+/ 0.18 arbitrary units, respectively) and oocytes of the former cows also tended to have more active mitochondria, although this was not significant. Cows on IN showed a positive relationship (R(2)=0.31, P<0.05) between plasma leptin and oocyte lipid content. Lipids are utilized by oocytes during high energy consumptive processes including fertilization and early cleavage. The greater lipid content of oocytes from IN cows could therefore confer a reproductive advantage. The present study has shown relationships between nutrition, body condition, circulating leptin, and oocyte lipid content, but a clear cause-and effect requires further investigation in the cow. PMID- 23735656 TI - Diagnostic, functional, and therapeutic roles of microRNA in allergic diseases. AB - Allergic inflammation is accompanied by the coordinated expression of a myriad of genes and proteins that initiate, sustain, and propagate immune responses and tissue remodeling. MicroRNAs (miRNAs) are a class of short single-stranded RNA molecules that posttranscriptionally silence gene expression and have been shown to fine-tune gene transcriptional networks because single miRNAs can target hundreds of genes. Considerable attention has been focused on the key role of miRNAs in regulating homeostatic immune architecture and acquired immunity. Recent studies have identified miRNA profiles in multiple allergic inflammatory diseases, including asthma, eosinophilic esophagitis, allergic rhinitis, and atopic dermatitis. Specific miRNAs have been found to have critical roles in regulating key pathogenic mechanisms in allergic inflammation, including polarization of adaptive immune responses and activation of T cells (eg, miR-21 and miR-146), regulation of eosinophil development (eg, miR-21 and miR-223), and modulation of IL-13-driven epithelial responses (eg, miR-375). This review discusses recent advances in our understanding of the expression and function of miRNAs in patients with allergic inflammation, their role as disease biomarkers, and perspectives for future investigation and clinical utility. PMID- 23735659 TI - Complete testicular epididymal dissociation in the abdominal cryptorchid testis. AB - AIM: To document the incidence of complete testicular epididymal dissociation (CTED) in the cryptorchid testis and evaluate its operative outcome. METHODS: The presence of CTED was noted prospectively in cases of undescended testis and the operative findings were studied. RESULTS: CTED was encountered in 11 testes in 10 boys out of 29 intra-abdominal testes among the 142 undescended testes (8%) operated. Ages of patients varied from 18 months-14 years (median 4.5 years). All 11 testes were intra-abdominal. In 5 out of 11 testes, the dissociation was associated with a wide separation of the epididymis and testis. The dissociated epididymis was in the scrotum attached to the gubernaculum while the testis was intra-abdominal. One case had bilateral CTED. Successful subdartos orchidopexy was done for 8 testes, 6 after Prentiss maneuver. Two gonads were fixed just below the pubic tubercle. Orchiectomy was done in one case with a small sized testis with a short gonadal vessel. CONCLUSION: CTED was encountered in 8% of cases of cryptorchidism. A palpable nubbin-like tissue in the scrotal sac in the presence of CTED may suggest a descended dissociated epididymis with an intra abdominal testis. Successful subdartos orchidopexy was possible in 73% of testes with CTED. PMID- 23735658 TI - Immunolocalisation and oestrogen regulation of small proline-rich protein 2a protein in the mouse uterus. AB - Small proline-rich protein 2a (Sprr2a) is one of the structural components of the cornified keratinocyte cell envelope that contributes to form a protective barrier in the skin against dehydration and environmental stress. Interestingly, Sprr2a mRNA is detected in the mouse uterus and is regulated by 17beta-oestradiol (E2). In the present study, we investigated the effects of E2 and oestrogenic compounds on the regulation and localisation of Sprr2a protein in the mouse uterus. Immunohistochemical staining revealed that Sprr2a protein is detected only in the adult uterus, and not in the ovary, oviduct or testis. We also demonstrated that Sprr2a protein is tightly regulated by E2 in the mouse uterus and exclusively detected in luminal and glandular epithelial cells. Furthermore, Sprr2a is dose-dependently induced by oestrogenic compounds such as bisphenol A and 4-tert-octylphenol. Collectively, our studies suggest that Sprr2a protein may have a unique function in physiological events in the mouse uterus and can be used as an indicator to detect compounds with oestrogenic activity in the mouse uterus. PMID- 23735660 TI - The role of elastin and collagen in the softening behavior of the human thoracic aortic media. AB - In a previous study we were able to accurately fit experimental data on arterial tissues at supra-physiological loads using a material model that accounts for softening/damage only in the portion of the model associated with the collagen fibers (Weisbecker et al., 2012). Naturally, this result leads to the hypothesis that the softening behavior is related only to the collagen fibers, and not to the matrix material. In this study we test this hypothesis by conducting uniaxial extension tests on elastase and collagenase treated tissues and on untreated control specimens from the media of human thoracic aortas. We relate structural changes in the tissue after enzyme treatment to changes in the corresponding mechanical behavior. Collagenase treated tissue does not exhibit any softening behavior under quasi-static cyclic loading, a result supporting our hypothesis. Conversely, elastase treated tissue exhibits continuous softening under the same loading conditions, indicating that the integrity of the tissue is destroyed upon removal of the elastin. Finally, we fit isotropic and anisotropic constitutive models to the mechanical response of the collagenase treated arterial tissue, while our anisotropic model better approximates the response of collagenase treated arterial tissues, we show that an isotropic matrix model is sufficient to accurately reproduce the mechanical response of untreated control specimens, consistent with current practice in the literature. PMID- 23735661 TI - A rare case of Moyamoya syndrome in a beta-thalassemia major patient. PMID- 23735662 TI - [Abdominal pain]. PMID- 23735663 TI - [The national union for private hospital oncology]. AB - In the French health system, social security is the same for both public and private hospitals regardless of their status. In terms of number of patients screened, diagnosed, or treated, independant medicine is the most important sector in the French oncology. The multitude of organizations representing private hospitals or independant oncologists, physicians, radiologists or pathologists have a common organization, the National Union for Private Hospital Oncology (UNHPC). It bases its action on two founding postulates to ensure the quality of the oncology practice : the medical and managerial cultures are complementary and should be articulated ; the quality of organizations is as important as professional competence. PMID- 23735664 TI - Zinc supplementation inhibits the increase in osteoclastogenesis and decrease in osteoblastogenesis in streptozotocin-induced diabetic rats. AB - Zinc (Zn) has been shown to stimulate bone formation and inhibit osteoclastic bone resorption and osteoclastogenesis. However, the effects of Zn on bone metabolism in diabetic animals remain to be clarified in vivo. Here, the effects of Zn supplementation on bone metabolism, including osteoclastogenesis and osteoblastogenesis, were investigated using streptozotocine (STZ)-induced diabetic rats. Zn-supplemented water (7.5 mg/L) was given for 1 week to diabetic rats injected with STZ (30 mg/kg body weight) 1 week earlier. The Zn supplement prevented a decrease in the activity and mRNA of alkaline phosphatase (ALP), osteocalcin mRNA, and hydroxyproline and calcium levels, and an increase in the activity and mRNA of tartrate-resistant acid phosphatase (TRAP) and cathepsin K in the proximal tibia of diabetic rats. Histological analysis revealed that the Zn supplement inhibited the diabetes-induced increase and decrease in the number of osteoclasts and osteoblasts, respectively, in the metaphysis of the proximal tibia. The increase in mRNA levels of receptor for activation of NF-kappaB (RANK), c-fos, c-jun, TRAP, and cathepsin K and decrease in the expression of Runx2, Dlx5, osterix, ALP, osteocalcin, and collagen were prevented by the supplement. The decrease in beta-catenin, phosphorylated GSK3beta, phosphorylated Akt, insulin-like growth factor 1 (IGF-1), and IGF-1 receptor (IGF-1R) protein levels in diabetic rats was also inhibited, although Zn did not affect the diabetes-increased gene and protein expression of Sost and Dkk1. These results suggested that Zn prevented the diabetes-induced increase in osteoclastogenesis and decrease in osteoblastogenesis by inhibiting RANK expression and stimulating IGF-1/IGF-1R/Akt/GSK3beta/beta-catenin signaling, respectively. PMID- 23735665 TI - The rising tide of overweight among Kuwaiti children: study from Al-Adan Hospital, Kuwait. AB - OBJECTIVE: This study was designed to screen patients who sought medical services in the Pediatric Outpatient Department, Al-Adan Hospital, Kuwait for overweight. SUBJECTS AND METHODS: Body mass index (BMI) was used to screen 361 children (<=10 years old) for risk of overweight and overweight (BMI between 85th and 94th, and >=95th percentile, respectively). Overweight children were fully examined and abdominal ultrasound was done for each of them. RESULTS: Of the 361 children, 52 (14.41%) and 77 (21.33%) were at risk of overweight and overweight, respectively. There was a slight male predominance for overweight (40 males, 51.95%, compared to 37 females, 48.05%) and within the overweight category; 28 males (70%) and 26 females (70.27%) were above 6 years of age. In overweight children over 6 years, 4 (7.41%) had hepatomegaly with fatty changes and 3 (5.56%) had blood pressure above the 95th percentile for age and sex. CONCLUSION: Childhood overweight at Al Adan Hospital was high and increased with age. Hence childhood screening for overweight is recommended at an early age because it is an important risk factor of chronic diseases. PMID- 23735666 TI - Trials and tribulations: the professional development of surgical trialists-does it really have to be painful and haphazard? PMID- 23735667 TI - Postoperative fluid collections after colon resection: the utility of clinical assessment. AB - BACKGROUND: Computed tomography (CT) scans often identify postoperative fluid collections of uncertain clinical relevance. METHODS: Consecutive adult patients undergoing colorectal resection and postoperative CT scan from January 1, 2000 to December 31, 2008, at a university teaching hospital were identified from a prospective database. A host of clinical and CT findings were recorded. Fisher's exact test and logistic regression with univariate and multivariate analysis were used to assess the predictive value of clinical and radiologic variables. RESULTS: Nine hundred six patients had a colon resection during the study period. Fifty-four patients had a postoperative fluid collection, of which 36 were found to be abscesses. Only high clinical suspicion of an abscess predicted the presence of an abscess (P = .009); of the radiologic criteria, only proximity to the anastomosis was predictive (P = .05). CONCLUSIONS: Clinical judgment is superior to radiologic and individual clinical parameters. This finding has the potential to prevent many unnecessary procedures. PMID- 23735668 TI - Endoscopic stenting for gastric outlet obstruction in patients with unresectable antro pyloric cancer. Systematic review of the literature and final results of a prospective study. The point of view of a surgical group. AB - BACKGROUND: The authors report the final results of a prospective single-center randomized study whose aim was to compare the endoscopic placement of self expandable stents with open surgical gastroenterostomy to relieve gastric outlet obstruction (GOO) in patients with advanced antropyloric adenocarcinoma. A systematic review of the medical literature from December 1999 to December 2011 was carried out to determine the results of endoscopic stenting in patients with GOO from unresectable primary cancer of the antropyloric region. METHODS: In the prospective study, 18 patients with advanced adenocarcinoma of the antropyloric region and symptoms of GOO were enrolled. In 9 patients, self-expandable stents were placed, and in 9 patients, open surgical gastroenterostomy was performed. Patients were followed until death. Six hundred seventy-two patients with primary unresectable cancer of the antropyloric region and GOO syndrome who underwent endoscopic stenting were identified from the literature. RESULTS: In the prospective study of 18 patients, there was no case of postprocedural mortality. Efficient gastric emptying resumed more quickly in patients who received stents, although 3 months after the procedures, there was no difference between the 2 groups. Mean crude survival was 258 days in patients who received stents and 283 days in those who underwent surgical gastroenterostomy (P = NS). In patients who underwent stent placement, there were 2 cases of stent migration and 2 cases of food impaction, which were resolved with endoscopy at a mean follow-up of 70 days. In the 672 patients from the literature, operative mortality and morbidity were very low. In prospective studies, complications related to stents were more common than previously thought. CONCLUSIONS: Endoscopic placement of metallic stents offers an effective therapy in patients with advanced primary adenocarcinoma of the antropyloric region and poor general condition. In patients with longer life expectancies, the form of therapy should be chosen individually, considering that surgical gastroenterostomy has fewer complications in the medium term and that in patients with endoscopic stenting, very careful follow-up is required, with the possibility of new operative endoscopy in half of the patients. PMID- 23735669 TI - Perioperative outcomes after totally robotic gastric bypass: a prospective nonrandomized controlled study. AB - BACKGROUND: Perioperative short-term outcomes could be improved after totally robotic Roux-en-Y gastric bypass (TR-RYGBP) compared with conventional laparoscopic gastric bypass. METHODS: This is a nonrandomized controlled prospective study (N = 200) to evaluate perioperative short-term outcomes. The primary endpoint was to investigate risk factors for 30-day surgical complications. RESULTS: Mean total operative time was shorter in patients who underwent TR-RYGBP (130 vs 147 minutes; P < .0001). However, postoperative surgical complications rate (13% vs 1%; P = .001), and mean overall hospital stay (9.3 vs 6.7 days; P < .0001) were higher after TR-RYGBP. By multivariate analysis, robotic surgery (hazard ratio [HR] = 15.1; 95% confidence interval [CI], 2.8 to 280; P = .01), and conversion to laparotomy (HR = 18.8; 95% CI, 1.7 to 250.8; P = .014) were independent risk factors for 30-day surgical complications. CONCLUSIONS: Although robotic gastric bypass reduces mean operative time, TR-RYGBP is associated with an increased postoperative surgical complications rate and longer hospitalization. PMID- 23735670 TI - Toggle switch: noise determines the winning gene. AB - Bistable regulatory elements enhance heterogeneity in cell populations and, in multicellular organisms, allow cells to specialize and specify their fate. Our study demonstrates that in a system of bistable genetic switch, the noise characteristics control in which of the two epigenetic attractors the cell population will settle. We focus on two types of noise: the gene switching noise and protein dimerization noise. We found that the change of magnitudes of these noise components for one of the two competing genes introduces a large asymmetry of the protein stationary probability distribution and changes the relative probability of individual gene activation. Interestingly, an increase of noise associated with a given gene can either promote or suppress the activation of the gene, depending on the type of noise. Namely, each gene is repressed by an increase of its gene switching noise and activated by an increase of its protein product dimerization noise. The observed effect was found robust to the large, up to fivefold deviations of the model parameters. In summary, we demonstrated that noise itself may determine the relative strength of the epigenetic attractors, which may provide a unique mode of control of cell fate decisions. PMID- 23735671 TI - Ethical considerations in the management of amyotrophic lateral sclerosis. AB - This article examines some of the ethical concerns relevant for the management of amyotrophic lateral sclerosis (ALS). We emphasize the importance for providing a competent assessment of the clinical deficit to correctly identify the disease and to avoid incorrect diagnoses. Conveying the diagnosis to the patient and their family requires empathy and it is important to remain supportive and positive, even in the face of this incurable disease. The essence of care in ALS is to permit the patient to have optimal function for their level of ability. This may require the use of gastrostomy and non-invasive or permanent ventilation. Employment of a multi-disciplinary team will permit optimization of patient care to achieve a good quality of life for as long as possible. The patient should also be informed of the risks associated with unproven therapies and the risks and potential benefits of therapeutic trials. The wishes of patients in regard to gastrostomy, long-term ventilation and end-of life decisions must be considered in an unbiased fashion. Recent advances in the genetics of familial ALS (FALS) have demonstrated some overlap between FALS, sporadic ALS and fronto-temporal lobar dementia (FTLD). The interpretation and dissemination of the results of genetic testing although important can induce confusion, considerable anxiety and guilt in patients and their families and proper counseling is imperative. PMID- 23735672 TI - Role of glia in the regulation of gonadotropin-releasing hormone neuronal activity and secretion. AB - Gonadotropin-releasing hormone (GnRH) neurons are the final common pathway for the central control of reproduction. The coordinated and timely activation of these hypothalamic neurons, which determines sexual development and adult reproductive function, lies under the tight control of a complex array of excitatory and inhibitory transsynaptic inputs. In addition, research conducted over the past 20 years has unveiled the major contribution of glial cells to the control of GnRH neurons. Glia use a variety of molecular and cellular strategies to modulate GnRH neuronal function both at the level of their cell bodies and at their nerve terminals. These mechanisms include the secretion of bioactive molecules that exert paracrine effects on GnRH neurons, juxtacrine interactions between glial cells and GnRH neurons via adhesive molecules and the morphological plasticity of the glial coverage of GnRH neurons. It now appears that glial cells are integral components, along with upstream neuronal networks, of the central control of GnRH neuronal function. This review attempts to summarize our current knowledge of the mechanisms used by glial cells to control GnRH neuronal activity and secretion. PMID- 23735673 TI - Penicillium species-induced granuloma in a cat resulting in chronic lower urinary tract disease. AB - A 5-year-old, female neutered Persian cat was admitted to the Small Animal Hospital (Chulalongkorn University, Bangkok, Thailand) with clinical signs of dysuria, haematuria and partial urethral obstruction that had manifested over several months. The animal also had hyperkalaemia and severe azotaemia at the time of presentation. Urinalysis showed haematuria, pyuria and the presence of several transitional cells. In addition, ultrasonography demonstrated an extraluminal mass between the neck of urinary bladder and the colon. Fine-needle aspiration of the mass revealed a fungal form with branching and septate hyphae. Consequently, itraconazole treatment was prescribed and clinical signs of improvement were seen after 7 days. However, 1 month later, the cat died of acute anaemia. Necropsy revealed the presence of extraluminal multifocal fungal granuloma at the neck of the urinary bladder, and contracted kidneys. Histopathological analysis of the fungal granuloma was found to be composed of branching, septate hyphal fungi together with inflammatory cells. Subsequent fungal culture and identification revealed this to be a species of Penicillium. PMID- 23735674 TI - Application of the single blood sample method to estimate feline glomerular filtration rate in a clinically relevant situation. AB - To compare glomerular filtration rate (GFR) estimated by a single blood sample method, the non-ionic contrast medium iodixanol (40 mg I/kg) and the standard GFR tracer inulin (50 mg/kg) were co-administered as a bolus intravenous injection to 12 cats, followed by blood collection 60 and 90 mins later. Serum iodixanol and inulin concentrations were measured separately by high-performance liquid chromatography and colourimetric assay. A correlation (r = 0.90, P <0.01) was noted between GFR values estimated by the single-blood-sample method using iodixanol and inulin, indicating that this procedure can apply to feline GFR estimates, even if different GFR tracers are used. In a feline kidney transplantation study, the GFR was monitored subsequently by this simplified iodixanol method throughout a 750-day observation period with no adverse reactions. The results demonstrate that the simplified method, including the volume of distribution, can be used as an alternative or expedient tool in a clinically relevant situation. PMID- 23735675 TI - Maine Coon renal screening: ultrasonographical characterisation and preliminary genetic analysis for common genes in cats with renal cysts. AB - The objective of this study was to assess the prevalence of renal cysts and other renal abnormalities in purebred Maine Coon cats, and to characterise these through genetic typing. Voluntary pre-breeding screening programmes for polycystic kidney disease (PKD) are offered for this breed throughout Switzerland, Germany and other northern European countries. We performed a retrospective evaluation of Maine Coon screening for renal disease at one institution over an 8-year period. Renal ultrasonography was performed in 187 healthy Maine Coon cats. Renal changes were observed in 27 of these cats. Renal cysts were found in seven cats, and were mostly single and unilateral (6/7, 85.7%), small (mean 3.6 mm) and located at the corticomedullary junction (4/6, 66.7%). Sonographical changes indicating chronic kidney disease (CKD) were observed in 10/187 (5.3%) cats and changes of unknown significance were documented in 11/187 (5.9%) cats. All six cats genetically tested for PKD1 were negative for the mutation, and gene sequencing of these cats did not demonstrate any common genetic sequences. Cystic renal disease occurs with a low prevalence in Maine Coons and is unrelated to the PKD observed in Persians and related breeds. Ultrasonographical findings compatible with CKD are not uncommon in juvenile Maine Coons. PMID- 23735676 TI - Post-operative elimination of sevoflurane anesthetic and hexafluoroisopropanol metabolite in exhaled breath: pharmacokinetic models for assessing liver function. AB - Sevoflurane (SEV), a commonly used anesthetic agent for invasive surgery, is directly eliminated via exhaled breath and indirectly by metabolic conversion to inorganic fluoride and hexafluoroisopropanol (HFIP), which is also eliminated in the breath. We studied the post-operative elimination of SEV and HFIP of six patients that had undergone a variety of surgeries lasting between 2.5 to 8.5 h using exhaled breath analysis. A classical three compartments pharmacokinetic model developed for the study of environmental contaminants was fitted to the breath data. We found that SEV kinetic behavior following surgery (for up to six days) is consistent across all subjects whereas the production and elimination of HFIP varies to some extent. We developed subject specific parameters for HFIP metabolism and interpreted the differences in the context of timing and dose of anesthesia, type of surgery, and specific host factors. We propose methods for assessing individual patient liver function using SEV as a probe molecule for assessing efficiency of liver metabolism to HFIP. This work is valuable not only for the clinical study of metabolism recovery, but potentially also for the study of the interaction of other manufactured and environmental compounds with human systems biology in controlled exposure and observational studies. PMID- 23735677 TI - Protein production for structural biology: new solutions to new challenges. PMID- 23735678 TI - Montanide ISATM 201 adjuvanted FMD vaccine induces improved immune responses and protection in cattle. AB - Despite significant advancements in modern vaccinology, inactivated whole virus vaccines for foot-and-mouth disease (FMD) remain the mainstay for prophylactic and emergency uses. Many efforts are currently devoted to improve the immune responses and protective efficacy of these vaccines. Adjuvants, which are often used to potentiate immune responses, provide an excellent mean to improve the efficacy of FMD vaccines. This study aimed to evaluate three oil adjuvants namely: Montanide ISA-201, ISA-206 (SEPPIC, France) and GAHOL (an in-house developed oil-adjuvant) for adjuvant potential in inactivated FMD vaccine. Groups of cattle (n=6) were immunized once intramuscularly with monovalent FMDV 'O' vaccine formulated in these adjuvants, and humoral (serum neutralizing antibody, IgG1 and IgG2) and cellular (lymphoproliferation) responses were measured. Montanide ISA-201 adjuvanted vaccine induced earlier and higher neutralizing antibody responses as compared to the two other adjuvants. All the adjuvants induced mainly serum IgG1 isotype antibody responses against FMDV. However, Montanide ISA-201 induced relatively higher IgG2 responses than the other two adjuvants. Lymphoproliferative responses to recall FMDV antigen were relatively higher with Montanide ISA-201, although not always statistically significant. On homologous FMDV challenge at 30 days post-vaccination, 100% (6/6) of the cattle immunized with Montanide-201 adjuvanted vaccine were protected, which was superior to those immunized with ISA-206 (66.6%, 4/6) or GAHOL adjuvanted vaccine (50%, 3/6). Virus replication following challenge infection, as determined by presence of the viral genome in oropharynx and non-structural protein serology, was lowest with Montanide ISA-201 adjuvant. Collectively, these results indicate that the Montanide ISA-201 adjuvanted FMD vaccine induces enhanced immune responses and protective efficacy in cattle. PMID- 23735679 TI - Single multivalent vaccination boosted by trickle larval infection confers protection against experimental lymphatic filariasis. AB - The multivalent vaccine BmHAT, consisting of the Brugia malayi infective larval (L3) antigens heat shock protein12.6 (HSP12.6), abundant larval transcript-2 (ALT 2) and tetraspanin large extra cellular loop (TSP-LEL), was shown to be protective in rodent models from our laboratory. We hypothesize that since these antigens were identified using protective antibodies from immune endemic normal individuals, the multivalent vaccine can be augmented by natural L3 infections providing protection to the vaccinated host. This hypothesis was tested using single dose of DNA and protein or protein alone of the BmHAT vaccination in gerbils followed by live trickle L3 infection as booster dose. Vaccine-induced protection in gerbils was determined by worm establishment, micropore chamber assay and by antibody dependant cell cytotoxicity (ADCC) assay. Results were compared with the traditional prime-boost vaccination regimen. Gerbils vaccinated with BmHAT and boosted with L3 trickle infection were protected 51% (BmHAT DNA protein) and 48% (BmHAT protein) respectively. BmHAT vaccination plus L3 trickle booster generated significant titer of antigen-specific IgG antibodies comparable to the traditional prime boost vaccination approach. BmHAT vaccination plus L3 trickle booster also generated antigen-specific cells in the spleen of vaccinated animals and these cells secreted predominantly IFN-gamma and IL-4 in response to the vaccine antigens. These studies thus show that single dose of BmHAT multivalent vaccination followed by L3 trickle booster infection can confer significant protection against lymphatic filariasis. PMID- 23735680 TI - Vaccination of volunteers with low-dose, live-attenuated, dengue viruses leads to serotype-specific immunologic and virologic profiles. AB - There are currently no vaccines or therapeutics to prevent dengue disease which ranges in severity from asymptomatic infections to life-threatening illness. The National Institute of Allergy and Infectious Diseases (NIAID) Division of Intramural Research has developed live, attenuated vaccines to each of the four dengue serotypes (DENV-1-DENV-4). Two doses (10PFU and 1000PFU) of three monovalent vaccines were tested in human clinical trials to compare safety and immunogenicity profiles. DEN4Delta30 had been tested previously at multiple doses. The three dengue vaccine candidates tested (DEN1Delta30, DEN2/4Delta30, and DEN3Delta30/31) were very infectious, each with a human infectious dose 50%<= 10PFU. Further, infectivity rates ranged from 90 to 100% regardless of dose, excepting DEN2/4Delta30 which dropped from 100% at the 1000PFU dose to 60% at the 10PFU dose. Mean geometric peak antibody titers did not differ significantly between doses for DEN1Delta30 (92 +/- 19 vs. 214 +/- 97, p=0.08); however, significant differences were observed between the 10PFU and 1000PFU doses for DEN2/4Delta30, 19 +/- 9 vs. 102 +/- 25 (p=0.001), and DEN3Delta30/31, 119 +/- 135 vs. 50 +/- 50 (p=0.046). No differences in the incidences of rash, neutropenia, or viremia were observed between doses for any vaccines, though the mean peak titer of viremia for DEN1Delta30 was higher at the 1000PFU dose (0.5 +/- 0 vs. 1.1 +/- 0.1, p=0.007). These data demonstrate that a target dose of 1000PFU for inclusion of each dengue serotype into a tetravalent vaccine is likely to be safe and generate a balanced immune response for all serotypes. PMID- 23735681 TI - Influences of credibility of testimony and strength of statistical evidence on children's and adolescents' reasoning. AB - According to dual-process models that include analytic and heuristic modes of processing, analytic processing is often expected to become more common with development. Consistent with this view, on reasoning problems, adolescents are more likely than children to select alternatives that are backed by statistical evidence. It is shown here that this pattern depends on the quality of the statistical evidence and the quality of the testimonial that is the typical alternative to statistical evidence. In Experiment 1, 9- and 13-year-olds (N=64) were presented with scenarios in which solid statistical evidence was contrasted with casual or expert testimonial evidence. When testimony was casual, children relied on it but adolescents did not; when testimony was expert, both children and adolescents relied on it. In Experiment 2, 9- and 13-year-olds (N=83) were presented with scenarios in which casual testimonial evidence was contrasted with weak or strong statistical evidence. When statistical evidence was weak, children and adolescents relied on both testimonial and statistical evidence; when statistical evidence was strong, most children and adolescents relied on it. Results are discussed in terms of their implications for dual-process accounts of cognitive development. PMID- 23735682 TI - Effect of winter school breaks on influenza-like illness, Argentina, 2005-2008. AB - School closures are used to reduce seasonal and pandemic influenza transmission, yet evidence of their effectiveness is sparse. In Argentina, annual winter school breaks occur during the influenza season, providing an opportunity to study this intervention. We used 2005-2008 national weekly surveillance data of visits to a health care provider for influenza-like illness (ILI) from all provinces. Using Serfling-specified Poisson regressions and population-based census denominators, we developed incidence rate ratios (IRRs) for the 3 weeks before, 2 weeks during, and 3 weeks after the break. For persons 5-64 years of age, IRRs were <1 for at least 1 week after the break. Observed rates returned to expected by the third week after the break; overall decrease among persons of all ages was 14%. The largest decrease was among children 5-14 years of age during the week after the break (37% lower IRR). Among adults, effects were weaker and delayed. Two-week winter school breaks significantly decreased visits to a health care provider for ILI among school-aged children and nonelderly adults. PMID- 23735683 TI - Development of interspecies testicular germ-cell transplantation in flatfish. AB - Interspecific testicular germ cell (TGC) transplantation was investigated in two commercial flatfish species. Testes from donor species (Senegalese sole) were evaluated using classical histological techniques (haematoxylin-eosin staining and haematoxylin-light green-orange G-acid fuchsine staining), in situ hybridisation and immunohistochemical analysis. Both Ssvasa1-2 mRNAs and SsVasa protein allowed the characterisation of TGCs, confirming the usefulness of the vasa gene in the detection of Senegalese sole TGCs. Xenogenic transplants were carried out using TGCs from one-year-old Senegalese sole into turbot larvae. Propidium iodide-SYBR-14 and 4',6'-diamidino-2-phenylindole (DAPI) staining showed that 87.98% of the extracted testicular cells were viable for microinjection and that 15.63% of the total recovered cells were spermatogonia. The vasa gene was characterised in turbot recipients using cDNA cloning. Smvasa mRNA was confirmed as a germ cell-specific molecular marker in this species. Smvasa expression analysis during turbot ontogeny was carried out before Senegalese sole TGC transplants into turbot larvae. Turbot larvae at 18 days after hatching (DAH) proved to be susceptible to manipulation procedures. High survival rates (83.75+/-15.90-100%) were obtained for turbot larvae at 27, 34 and 42 DAH. These data highlight the huge potential of this species for transplantation studies. Quantitative PCR was employed to detect Senegalese sole vasa mRNAs (Ssvasa1-2) in the recipient turbot larvae. The Ssvasa mRNAs showed a significant increase in relative expression in 42-DAH microinjected larvae three weeks after treatment, showing the proliferation of Senegalese sole spermatogonia in transplanted turbot larvae. PMID- 23735684 TI - [Cancer prevention and screening]. AB - We show that cancer mortality is decreasing with time for most sites of cancer, the most notable exception being lung cancer in women. Cancer incidence is a misleading indicator because it can depend on diagnostic procedures, as observed with prostate cancer in men and breast or thyroid cancer in women. Overall these data contradict the alarming information that cancer is on the increase, which is widespread by the media and some health professionals. To be efficient in the prevention of cancer one needs to identify its causes and measure their relative importance. The major causes of cancer in France today are tobacco and alcohol. The variations of the price of tobacco and their effects on sales show the importance of the taxation policy. Cancer screening is practised in a way defying logic : a screening procedure with a demonstrated high efficacy is not part of a national programme whereas a useless and even potentially harmful procedure is very widely used. PMID- 23735685 TI - Requests for malaria prevention advice to Public Health England, Malaria Reference Laboratory: a retrospective observational study. AB - BACKGROUND: The Malaria Reference Laboratory (MRL) provides a specialist advisory service for complex queries from healthcare professionals. This study was conducted to examine the types of queries that general practitioners and nurses ask around malaria prophylaxis, to identify issues which are not obvious from existing easily available sources. METHODS: We reviewed all the faxed requests received over a period of 6 months at the MRL. RESULTS: There were a total of 608 queries (104 concerning children) relating to 450 travellers. 98% of requests were from general practice (GP or practice nurse). The most common enquiries were about travellers to multiple destinations (95/529, 17.96%), prolonged duration of travel (70/529, 13.23%), the immunosuppressed (38/529, 7.18%), potential drug interactions (69/529, 13.04%), pregnancy and conception (36, 6.81%). 79/529 queries related to patients with multiple conditions requiring expert advice from the MRL. 27% of the enquiries could have been answered by consulting the UK malaria prophylaxis guidelines available on the MRL site. CONCLUSION: Most queries where practitioners requested help were not easily answered with existing guidelines. Pregnancy and epilepsy are areas where guidance needs strengthening. Difficulties for practitioners were multifactorial, it would be difficult to address all scenarios in guidelines without making them unwieldy. PMID- 23735686 TI - Leadership, organisational culture and the continuing cultural divide in UK health services. PMID- 23735687 TI - Shifting interventions from specialist to general practitioner is not new. But how realistic is it? PMID- 23735688 TI - Measures of quality, costs and equity in primary health care instruments developed to analyse and compare primary care in 35 countries. AB - BACKGROUND: The Quality and Costs of Primary Care in Europe (QUALICOPC) study aims to analyse and compare how primary health care systems in 35 countries perform in terms of quality, costs and equity. This article answers the question 'How can the organisation and delivery of primary health care and its outcomes be measured through surveys of general practitioners (GPs) and patients?' It will also deal with the process of pooling questions and the subsequent development and application of exclusion criteria to arrive at a set of appropriate questions for a broad international comparative study. METHODS: The development of the questionnaires consisted of four phases: a search for existing validated questionnaires, the classification and selection of relevant questions, shortening of the questionnaires in three consensus rounds and the pilot survey. Consensus was reached on the basis of exclusion criteria (e.g. the applicability for international comparison). Based on the pilot survey, comprehensibility increased and the number of questions was further restricted, as the questionnaires were too long. RESULTS: Four questionnaires were developed: one for GPs, one for patients about their experiences with their GP, another for patients about what they consider important, and a practice questionnaire. The GP questionnaire mainly focused on the structural aspects (e.g. economic conditions) and care processes (e.g. comprehensiveness of services of primary care). The patient experiences questionnaire focused on the care processes and outcomes (e.g. how do patients experience access to care?). The questionnaire about what patients consider important was complementary to the experiences questionnaire, as it enabled weighing the answers from the latter. Finally, the practice questionnaire included questions on practice characteristics. DISCUSSION: The QUALICOPC researchers have developed four questionnaires to characterise the organisation and delivery of primary health care and to compare and analyse the outcomes. Data collected with these instruments will allow us not only to show in detail the variation in process and outcomes of primary health care, but also to explain the differences from features of the (primary) health care system. PMID- 23735689 TI - Are patients' preferences for shifting services from medical specialists to general practitioners related to the type of medical intervention? AB - BACKGROUND: To improve the feasibility of shifting medical specialist to general practitioner (GP) services in patient-centred health care systems, it is important to know how this substitution is valued by patients. However, insight into patients' preferences is lacking. AIM: This study aims to fill this gap by assessing whether patients' preferences for substitution are related to the type of medical intervention. METHODS: Questionnaires were sent to 1000 members of the Dutch Insurants Panel (potential patients). Panel members were asked about their preferences for and use of medical specialist and GP services regarding 11 medical interventions. Six hundred and ninety-four members (69%) responded. We used multilevel multinomial regression to analyse the data. RESULTS: Preferences were significantly related to medical intervention type. GP services were preferred for follow-up treatments (e.g. removing stitches) and non-complex invasive treatments (e.g. removal of lumps), and medical specialist services were preferred for complex invasive treatments (e.g. injection therapy for varicose veins), non-invasive treatments (e.g. start of insulin therapy) and diagnostic examinations (e.g. abdominal ultrasound). Age, effort required to visit a GP, perceived health status and previous treatment experiences also influenced preferences but did not confound the effects of medical intervention type. CONCLUSION: This study provides strong indications that patients' preferences for substitution are influenced by the type of medical intervention. Therefore it seems important that health policy makers, purchasers and practitioners take the preferences of (potential) patients into account. PMID- 23735690 TI - Should there be a Quality and Outcomes Framework domain for osteoarthritis? A cross-sectional survey in general practice. AB - BACKGROUND: Despite being a chronic condition with a high prevalence and significant associated morbidity that is managed predominantly in primary care, osteoarthritis (OA) does not feature in the Quality and Outcomes Framework (QOF) component of the UK general practice contract. The aim of this study was to determine whether general practitioners (GPs) thought OA should be added as a QOF domain, and the potential items for inclusion. METHODS: A cross-sectional postal survey of 2500 UK GPs randomly selected from Binley's database of currently practising GPs was conducted. The survey asked if OA should be added as a domain to QOF, how many points should be allocated to it and what indicators should be included. RESULTS: Responses were received from 768 GPs, of whom 70.4% were male and 89.1% were partners in their practice. The majority (82.6%; n = 602) felt that OA should not be included as a QOF domain. Significant predictors of support for the addition of an OA domain to QOF included having a special interest in musculoskeletal disease (odds ratio [OR] 1.95, 95% confidence interval [CI] 1.26 3.03), a higher research degree (OR 3.98, 95% CI 1.31-12.10) and having read the National Institute for Health and Clinical Excellence (NICE) guidance on the management of OA (OR 1.62, 95% CI 1.04-2.54). Being a GP principal was the only negative association (OR 0.48, 95% CI 0.23-0.99). Preferred potential indicators for an OA QOF were analgesia review, exercise advice and patient education. CONCLUSIONS: The majority of respondents felt that OA should not be included as a QOF domain, although it is unclear whether this reflected views particular to OA, or on the addition of any new domain to QOF. Those supporting an OA QOF domain tended to prefer potential indicators that are in line with current published guidance, despite a significant proportion reporting that they had not read the NICE guidelines on the management of OA. PMID- 23735692 TI - Back pain management in primary care: development and validity of the Patients' and Doctors' Expectations Questionnaire. AB - BACKGROUND: Back pain is a common disorder, with the doctor being the first point of contact for help. Biopsychosocial management of back pain has been shown to be problematic. Meeting patients' expectations is alleged to play a vital role in concordance, adherence and satisfaction. A more potent aspect, however, could be a state of matched patient- doctor expectations with regard to the consultation process and outcome, but this aspect has not been fully investigated and there is currently no valid and specific measure of this dimension. AIM: To report on the development of a newly designed patient and doctor expectations questionnaire that measures the matching of their expectations with regard to the back pain consultation in primary care, and to establish the validity and internal consistency of the new tool. METHODS: A literature review was carried out and a draft 36-item questionnaire was developed. Thirty-eight subjects (7 researchers, 20 patients and 11 doctors) tested the questionnaire. Each subject gave feedback on the questionnaire design and was also asked to fill in a previously validated tool, the Patients' Intentions Questionnaire (PIQ), to establish the concurrent validity of the newly designed expectations questionnaire. Construct validity was established by calculating the Spearman correlation coefficient, and Cronbach's alpha was computed to reflect the internal consistency of the instrument. FINDINGS: The results of the validity questionnaire showed that the questionnaire was perceived as simple, clear and easy to understand and appropriate to the intended aim. Spearman correlation coefficients between the Patients' Expectations Questionnaire and PIQ showed significant correlation ( r = 0.65), reflecting good concurrent validity, while Cronbach's alpha was 0.831, reflecting good internal consistency. CONCLUSION: The newly designed questionnaire showed good face, content and construct validity as well as good internal consistency, and thus can be used as a valid and reliable measure for back pain-specific expectations of the process and outcome of the consultation in primary care settings. PMID- 23735691 TI - How physician and community pharmacist perceptions of the community pharmacist role in Australian primary care influence the quality of collaborative chronic disease management. AB - BACKGROUND: Community pharmacists (CPs) have been changing their role to focus on patient-centred services to improve the quality of chronic disease management (CDM) in primary care. However, CPs have not been readily included in collaborative CDM with other primary care professionals such as physicians. There is little understanding of the CP role change and whether it affects the utilisation of CPs in primary care collaborative CDM. AIM: To explore physician and CP perceptions of the CP's role in Australian primary care and how these perceptions may influence the quality of physician/CP CDM programmes. METHODS: Data were collected from physicians and CPs using semi-structured interviews. A qualitative methodology utilising thematic analysis was employed during data analysis. Qualitative methodology trustworthiness techniques, negative case analysis and member checking were utilised to substantiate the resultant themes. RESULTS: A total of 22 physicians and 22 CPs were interviewed. Strong themes emerged regarding the participant perceptions of the CP's CDM role in primary care. The majority of interviewed physicians perceived that CPs did not have the appropriate CDM knowledge to complement physician knowledge to provide improved CDM compared with what they could provide on their own. Most of the interviewed CPs expressed a willingness and capability to undertake CDM; however, they were struggling to provide sustainable CDM in the business setting within which they function in the primary care environment. CONCLUSIONS: Role theory was selected as it provided the optimum explanation of the resultant themes. First, physician lack of confidence in the appropriateness of CP CDM knowledge causes physicians to be confused about the role CPs would undertake in a collaborative CDM that would benefit the physicians and their patients. Thus, by increasing physician awareness of CP CDM knowledge, physicians may see CPs as suitable CDM collaborators. Second, CPs are experiencing role conflict and stress in trying to change their role. Strengthening the service business model may reduce these CP role issues and allow CPs to reach their full potential in CDM and improve the quality of collaborative CDM in Australian primary care. PMID- 23735693 TI - Frameworks for improvement: clinical audit, the plan-do-study-act cycle and significant event audit. AB - This is the first in a series of articles about quality improvement tools and techniques. We explore common frameworks for improvement, including the model for improvement and its application to clinical audit, plan-do-study-act (PDSA) cycles and significant event analysis (SEA), examining the similarities and differences between these and providing examples of each. PMID- 23735694 TI - Screening for atrial fibrillation in patients aged 65 years or over attending annual flu vaccination clinics at a single general practice. AB - BACKGROUND: Atrial fibrillation (AF) is a common, treatable cause of stroke. Screening is recommended at influenza vaccination ('flu') clinics, but not implemented nationally. OBJECTIVES: We aimed to determine if screening for AF by pulse assessment of those aged >= 65 years attending flu vaccination is effective, practical and feasible. The success of screening was determined by discovery of undiagnosed cases, estimating the prevalence of undiagnosed AF, assessing the accuracy of a second-year General Practice Specialty Trainee (GPST2) and interpretative software at diagnosing AF on electrocardiography (ECG), completion without disrupting routine practice, estimating cost effectiveness and guiding future screening. DESIGN: Patients >= 65 years old attending flu clinics were screened. Patients with an irregular pulse had an ECG, with interpretation by the GPST2, interpretative automated software and a reporting service. RESULTS: A total of 573 patients were screened, identifying 95 patients with an irregular pulse: 21 had prior AF, 5 were < 65 years old and 1 had a previous myocardial infarction (MI); 68 were invited for ECG, of whom 39 attended; 2 new cases of AF were diagnosed. Pre-screening AF prevalence was 12.2% in those aged >= 75 years, and 12.4% after screening. A new case was discovered for every 286 patients screened. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 100% for the GPST2 and interpretative software for ECG diagnosis of AF versus cardiological assessment. Identifying a new case cost approximately L234. Limitations included low uptake of ECG appointments, and delayed and low completion of ECGs, leading to missed AF diagnoses. CONCLUSIONS: Screening was ineffective. ECG immediately after pulse assessment is essential. Screening was acceptable to patients but required additional resources. Age groups 65-74 and >= 85 years were not adequately screened using flu clinics. Novel methods screening older, non-attending patients are required. Practices should introduce annual pulse checks into chronic disease templates and prompts for those aged >= 65 years attending surgery. Additional screening should target practices with low AF prevalence or poor rates of opportunistic screening. PMID- 23735695 TI - FGF23: a mature renal and cardiovascular risk factor? AB - High FGF23 predicts renal function loss in chronic kidney disease (CKD) patients and graft failure in transplant patients. FGF23, parathyroid hormone and serum phosphate are all interrelated but among these CKD-MBD biomarkers only FGF23 is independently related with CKD progression. High FGF23 associates with endothelial dysfunction in CKD patients and in elderly individuals in the general population. Furthermore, independently of serum phosphate, high FGF23 associates with mortality and left ventricular hypertrophy in dialysis patients and with atherosclerosis in elderly individuals in the general population. FGF23 also predicts a high risk for death and cardiovascular events in predialysis CKD patients and in subjects with coronary artery disease. A recent trial in CKD patients showed that low phosphate intake associated with a phosphate binder produces a 35% decrease in plasma FGF23. Yet in this and in another trial testing several phosphate binders, FGF23 levels remained well beyond the upper limit of the normal range. Of note, in this latter study, calcification of the coronary arteries and abdominal aorta actually increased, rather than decreased, during treatment with these drugs in the face of evidence of negative phosphate balance and amelioration of hyperparathyroidism. Mechanistic studies are still needed before testing the hypothesis that FGF23 is implicated in a causal manner in cardiovascular and renal diseases. Given the modest effects of phosphate binders on serum FGF23 in CKD patients, pharmacologic interventions antagonizing the effects of this growth factor rather than phosphate-lowering interventions should be put in place to properly test this hypothesis in the clinical scenario in CKD. PMID- 23735697 TI - High glucose modulates IL-6 mediated immune homeostasis through impeding neutrophil extracellular trap formation. AB - Neutrophils serve as an active constituent of innate immunity and are endowed with distinct ability for producing neutrophil extracellular traps (NETs) to eliminate pathogens. Earlier studies have demonstrated a dysfunction of the innate immune system in diabetic subjects leading to increased susceptibility to infections; however, the influence of hyperglycemic conditions on NETs is unknown. In the present study we demonstrate that (a) NETs are influenced by glucose homeostasis, (b) IL-6 is a potent inducer of energy dependent NET formation and (c) hyperglycemia mimics a state of constitutively active pro inflammatory condition in neutrophils leading to reduced response to external stimuli making diabetic subjects susceptible to infections. PMID- 23735696 TI - Estradiol negatively modulates the pleiotropic actions of orphanin FQ/nociceptin at proopiomelanocortin synapses. AB - Orphanin FQ/nociceptin (OFQ/N) inhibits the activity of proopiomelanocortin (POMC) neurons located in the hypothalamic arcuate nucleus (ARH) that regulate female sexual behavior and energy balance. We tested the hypothesis that estradiol modulates the ability of OFQ/N to pre- and postsynaptically decrease the excitability of these cells. To this end, whole-cell patch-clamp recordings were performed in hypothalamic slices prepared from ovariectomized rats, including some that were injected with the retrograde tracer Fluorogold in the medial preoptic nucleus (MPN) to label the POMC neurons regulating sexual receptivity. OFQ/N (1 uM) evoked a robust outward current in ARH neurons from vehicle-treated animals that was blocked by the opioid receptor-like (ORL)1 receptor antagonist UFP-101 (100 nM) and the G protein-gated, inwardly rectifying K+ (GIRK-1) channel blocker tertiapin (10 nM). OFQ/N also produced a decrease in the frequency of glutamatergic, miniature excitatory postsynaptic currents (mEPSCs), which was also antagonized by UFP-101. Estradiol benzoate (2 ug) increased basal mEPSC frequency and markedly diminished both the OFQ/N-induced activation of postsynaptic GIRK-1 channel currents and the presynaptic inhibition of glutamatergic neurotransmission. These effects were observed in identified POMC neurons, including eight that projected to the MPN. Taken together, these data reveal that estradiol attenuates the pleiotropic inhibitory actions of OFQ/N on POMC neurons: presynaptically through reducing the OFQ/N inhibition of glutamate release and postsynaptically by reducing ORL1 signaling through GIRK channels. As such, they impart critical insight into a mechanism for estradiol to increase the activity of POMC neurons that inhibit sexual receptivity. PMID- 23735698 TI - How crowded is the prokaryotic cytoplasm? AB - We consider biomacromolecular crowding within the cytoplasm of prokaryotic cells as a two-phase system of 'supercrowded' cytogel and 'dilute' cytosol; we simplify and quantify this model for a coccoid cell over a wide range of biomacromolecular crowding. The key result shows that the supercrowded cytogel extends the vectorial character of the plasma membrane deeper into the cytoplasm by about 20 70 nm. We discuss useful physiological insights that this model gives into the functioning of a prokaryotic cell on the micrometer scale. PMID- 23735699 TI - Imaging of heme/hemeproteins in nucleus of the living cells expressing heme binding nuclear receptors. AB - Several factors involved in the core circadian rhythm are PAS domain proteins, one of which, neuronal PAS2 (NPAS2), contains a heme-binding motif. It is thought that heme controls the transcriptional activity of core circadian factors BMAL1 NPAS2, and that the heme-binding nuclear receptor REV-erbalpha negatively regulates the expression of BMAL1. To examine the role of heme in the nucleus, we expressed nuclear hemeproteins including the nuclear localization signal-added cytoglobin, NPAS2 and REV-erbalpha. Then, the living cells expressing these proteins were treated with 2',7'-dichlorodihydrofluorescin diacetate (DCFH-DA). The fluorescent signal derived from DCFH-DA was observed in the nucleus. When the cells were cultured with hemin, the signal of heme in the nucleus increased. Considering that DCFH-DA reacted with heme, we propose that the use of DCFH-DA could be useful in detection of the heme moiety of hemeprotein in vivo. PMID- 23735700 TI - A large number of receptors may reduce cellular response time variation. AB - Cells often have tens of thousands of receptors, even though only a few activated receptors can trigger full cellular responses. Reasons for the overabundance of receptors remain unclear. We suggest that, under certain conditions, the large number of receptors can result in a competition among receptors to be the first to activate the cell. The competition decreases the variability of the time to cellular activation, and hence results in a more synchronous activation of cells. We argue that, in simple models, this variability reduction does not necessarily interfere with the receptor specificity to ligands achieved by the kinetic proofreading mechanism. Thus cells can be activated accurately in time and specifically to certain signals. We predict the minimum number of receptors needed to reduce the coefficient of variation for the time to activation following binding of a specific ligand. Furthermore, we predict the maximum number of receptors so that the kinetic proofreading mechanism still can improve the specificity of the activation. These predictions fall in line with experimentally reported receptor numbers for multiple systems. PMID- 23735701 TI - Distinguishing pulmonary hypertension in interstitial lung disease by ventilation and perfusion defects measured by cardiopulmonary exercise testing. AB - BACKGROUND: Pulmonary hypertension (PH) is common in interstitial lung disease (ILD). Since cardiopulmonary exercise testing (CPET) is useful in understanding the pathophysiology of respiratory disorders and can distinguish between ventilation and perfusion (V/Q) defects, it may have a role in the detection of PH in ILD. We evaluated whether CPET can detect PH through analysis of V/Q defects in ILD. OBJECTIVES: We aimed to use CPET to determine if there are changes in the ventilation and the activity pattern of mixed-expired carbon dioxide pressure (PECO2) and end-tidal carbon dioxide pressure (PetCO2) in ILD patients with and without PH. METHODS: A retrospective chart review was done of all patients who received lung transplants at the Columbia University Medical Center between 2000 and 2011 with the diagnosis of ILD. CPETs were performed during the 2 years prior to transplantation; right heart catheterizations and pulmonary function tests were performed within 4 months of CPET. RESULTS: The ILD patients with PH demonstrated significantly lower PetCO2 and PECO2 during certain levels of exercise with a distinctive activity pattern for PECO2/PetCO2. CONCLUSIONS: Evaluation of V/Q defects through the PECO2 and PetCO2 patterns on CPET in ILD patients can distinguish between patients with and without PH. PMID- 23735702 TI - Impact of geriatric risk factors on pegylated liposomal doxorubicin tolerance and efficacy in elderly metastatic breast cancer patients: final results of the DOGMES multicentre GINECO trial. AB - BACKGROUND: Metastatic breast cancer chemotherapy in the elderly is considered effective in carefully selected patients, but there is little data regarding its effect in vulnerable patients. METHODS: We evaluated tumour response (primary endpoint), feasibility and outcomes after six courses of an adapted dose of pegylated liposomal doxorubicin (PLD) (40 mg/m(2) every 28 days) as first-line chemotherapy for hormone-resistant MBC. RESULTS: Of 60 patients >70 years (median 77 years), 15% had performance status >=2 and 73% had visceral metastases. Geriatric assessment included: >=2 comorbidities, 42%; >=1 deficiency in Activities of Daily Living (ADL), 10% and Instrumental ADL (IADL), 82%; living in residential homes, 12%; albumin <35 g/L, 17%; body mass index (BMI) <21, 20%; depression, 17%; and lymphocytes <=1 * 10(3)/mm(3), 27%. Complete response, partial response and stable disease were observed in 5%, 15% and 60%, respectively, but only 48% completed six cycles. Treatment discontinuations were mostly due to disease progression (18%) and non-haematological (NH) toxicities (22%). Eight patients died during treatment (three possibly related to PLD), and 15 had unplanned hospital admissions. Exploratory analyses to identify geriatric covariates associated with treatment outcomes revealed severe haematological toxicities significantly correlated with lymphocytes <=1 * 10(3)/mm(3). NH toxicities correlated with age >=80 years and living in residential homes. Progression-free survival (median 6.1 months) decreased with age, deficiency in IADL, cardiac dysfunction and living in residential homes. Overall survival (median 15.7 months) also decreased with living in residential homes. CONCLUSION: Despite manageable haematological toxicities and expected response rates, PLD feasibility was poor in unselected elderly patients. PMID- 23735704 TI - Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study. AB - BACKGROUND: Everolimus (EVE; an inhibitor of mammalian target of rapamycin [mTOR]) enhances treatment options for postmenopausal women with hormone-receptor positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer (ABC) who progress on a non-steroidal aromatase inhibitor (NSAI). This is especially true for patients with visceral disease, which is associated with poor prognosis. The BOLERO-2 (Breast cancer trial of OraLEveROlimus-2) trial showed that combination treatment with EVE and exemestane (EXE) versus placebo (PBO)+EXE prolonged progression-free survival (PFS) by both investigator (7.8 versus 3.2 months, respectively) and independent (11.0 versus 4.1 months, respectively) central assessment in postmenopausal women with HR(+), HER2(-) ABC recurring/progressing during/after NSAI therapy. The BOLERO-2 trial included a substantial proportion of patients with visceral metastases (56%). METHODS: Prespecified exploratory subgroup analysis conducted to evaluate the efficacy and safety of EVE+EXE versus PBO+EXE in a prospectively defined subgroup of patients with visceral metastases. FINDINGS: At a median follow-up of 18 months, EVE+EXE significantly prolonged median PFS compared with PBO+EXE both in patients with visceral metastases (N=406; 6.8 versus 2.8 months) and in those without visceral metastases (N=318; 9.9 versus 4.2 months). Improvements in PFS with EVE+EXE versus PBO+EXE were also observed in patients with visceral metastases regardless of Eastern Cooperative Oncology Group performance status (ECOG PS). Patients with visceral metastases and ECOG PS 0 had a median PFS of 6.8 months with EVE+EXE versus 2.8 months with PBO+EXE. Among patients with visceral metastases and ECOG PS >=1, EVE+EXE treatment more than tripled median PFS compared with PBO+EXE (6.8 versus 1.5 months). INTERPRETATION: Adding EVE to EXE markedly extended PFS by >=4 months among patients with HR(+) HER2(-) ABC regardless of the presence of visceral metastases. PMID- 23735703 TI - A randomised trial comparing preoperative to perioperative chemotherapy in early stage non-small-cell lung cancer (IFCT 0002 trial). AB - HYPOTHESIS: There will be a detectable increase in overall survival (OS) using preoperative (PRE) as opposed to perioperative (PERI) chemotherapy in resectable StageI-II non-small-cell lung cancer (NSCLC). METHODS: This multicenter, open label, randomised trial with a 2*2 factorial design first compared two chemotherapy strategies (PRE versus PERI), then two chemotherapy regimens (gemcitabine-cisplatin [GP] versus paclitaxel-carboplatin [TC]). The PRE group received two preoperative cycles followed by two additional preoperative cycles, while the PERI group underwent two preoperative cycles followed by two postoperative cycles, the 3rd and 4th cycles being given only to responders in both cases. RESULTS: A total of 528 patients were randomised, 267 of which were assigned to the PRE group and 261 to the PERI group. Three-year OS did not differ between the two groups (67.4% and 67.7%, respectively; hazard ratio (HR)=1.01 [0.79-1.30], p=0.92), nor did 3-year disease-free survival, response rates, toxicity, or postoperative mortality. Pathological complete response was observed in 22 (8.2%) and 16 patients (6.1%), respectively. Although quality of life did not differ significantly, chemotherapy compliance was significantly higher in the PRE group. The proportion of responders who received Cycles 3 and 4 was significantly higher in the PRE group (90.4% versus 75.2%, p=0.001). In responders, the dose intensity of Cycles 3 and 4 was higher in the PRE group than in the PERI group (mean relative dose intensity of 90.4% versus 82.6%, respectively; p=0.0007). There was no difference between GP and TC in 3-year OS (HR=0.97 [95% confidence interval (CI): 0.76-1.25], p=0.80) or response rates. However, the regimens' toxicity profiles differed. CONCLUSIONS: This study failed to demonstrate any difference in survival between patients receiving preoperative and perioperative chemotherapy in early-stage NSCLC. The increase from two to four preoperative chemotherapy cycles did not increase the pathological response rate. PMID- 23735705 TI - A cutaneous lymphoma international prognostic index (CLIPi) for mycosis fungoides and Sezary syndrome. AB - BACKGROUND: There is no prognostic index for primary cutaneous T-cell lymphomas such as mycosis fungoides (MF) and Sezary syndrome (SS). METHOD: Two prognostic indices were developed for early (IA-IIA) and late stage (IIB-IVB) disease based on multivariate data from 1502 patients. End-points included overall survival (OS) and progression free survival (PFS). External validation included 1221 patients. FINDINGS: Significant adverse prognostic factors at diagnosis consisted of male gender, age >60, plaques, folliculotropic disease and stage N1/Nx for early stage, and male gender, age >60, stages B1/B2, N2/3 and visceral involvement for late stage disease. Using these variables we constructed two separate models each defined using 3 distinct groups for early and late stage patients: 0-1 (low risk), 2 (intermediate risk), and 3-5 factors (high risk). 10 year OS in the early stage model was 90.3% (low), 76.2% (intermediate) and 48.9% (high) and for the late stage model 53.2% (low), 19.8% (intermediate) and 15.0% (high). For the validation set significant differences in OS and PFS in early stage patients (both p<0.001) were also noted. In late stage patients, only OS differed between the groups (p=0.002). INTERPRETATION: This proposed cutaneous lymphoma prognostic index provides a model for prediction of OS in early and late stage MF/SS enabling rational therapeutic choices and patient stratification in clinical trials. PMID- 23735706 TI - Brain-heart coupling at the P300 latency is linked to anterior cingulate cortex and insula--a cardio-electroencephalographic covariance tracing study. AB - Prior work on the coupling of cortical and cardiac responses to feedback demonstrated that feedback-evoked single-trial EEG magnitudes 300 ms post stimulus predict the degree of subsequent cardiac acceleration. The main goal of the current study was to explore the neural sources of this phenomenon using (a) independent component analysis in conjunction with dipole fitting and (b) low resolution electromagnetic tomography (LORETA) in N=14 participants who performed a gambling task with feedback presented after each trial. It was shown that independent components localized near anterior cingulate cortex produced robust within-subjects correlations with feedback-evoked heart-period, suggesting that anterior cingulate cortex activity 300ms after feedback presentation predicts the strength of subsequent cardiac acceleration. Moreover, interindividual differences in evoked left insular cortex LORETA-estimated activity at around 300ms moderated within-subjects EEG-heart period correlations. These results suggest that key regions of central autonomic control are involved in cortico cardiac coupling evoked by feedback stimuli. PMID- 23735707 TI - Relations among EEG-alpha asymmetry, BIS/BAS, and dispositional optimism. AB - Past research has been unable to address whether the activity in the frontal hemispheres is related to the direction of motivation (approach versus withdrawal) or valence of emotion (positive versus negative). The present study was an attempt to address this question by using a standardized low-resolution brain electromagnetic tomography (sLORETA) which provides EEG localization measures that are independent of the recording reference. Resting EEG, self report measures of Behavioral Activation and Inhibition System (BAS and BIS) strength, dispositional optimism and a measure of hedonic tone, were collected from 51 unselected undergraduates. Three measures of cortical activation were obtained: (a) alpha asymmetry at conventional scalp sites, (b) anterior and posterior source alpha asymmetries (sLORETA method), (c) posterior versus frontal delta and theta activity. Both alpha asymmetry measures (conventional EEG and sLORETA) yielded significant frontal and parietal asymmetry correlation patterns. Neither measure identified significant associations between resting posterior versus frontal delta and theta activity personality traits. Higher BAS was uniquely related to greater left-sided activation in the middle frontal gyrus (BA11). Optimism was associated with higher activations in the left-superior frontal gyrus (BA10) and in the right-posterior cingulate cortex (BA31). PMID- 23735708 TI - Who is honest and why: baseline activation in anterior insula predicts inter individual differences in deceptive behavior. AB - Humans engage in deceptive behavior that negatively affects others. The propensity to deceive is, however, characterized by vast inter-individual heterogeneity that is poorly understood. Attempts to investigate the origins of this heterogeneity have so far mainly relied on subjective measures and have shown little predictive power. Here, we used resting electroencephalography to measure objective and stable individual differences in neural baseline activation in combination with an ecologically valid deception paradigm. Results showed that task-independent baseline activation in the anterior insula, a brain area implicated in mapping internal bodily states and in representing emotional arousal and conscious feelings, predicts individuals' propensity for deceptive behavior. The higher the neural baseline activation in this area is, the lower individuals' propensity to deceive. Moreover, results provide evidence that high baseline activation in the anterior insula is associated with negative affect and dispositional tendencies to avoid aversive emotional situations. These results provide converging neural and psychological evidence that individuals might avoid a deceptive act due to a highly active negative emotional system which would make a deceptive act too stressful and bothersome. PMID- 23735709 TI - Self- or parent report of (co-occurring) internalizing and externalizing problems, and basal or reactivity measures of HPA-axis functioning: a systematic evaluation of the internalizing-hyperresponsivity versus externalizing hyporesponsivity HPA-axis hypothesis. AB - BACKGROUND: Previous research findings on the link between adolescents' psychopathology and hypothalamic-pituitary-adrenal (HPA) axis activity have been heterogeneous. METHOD: Adolescents (n=211) with a preadolescent DSM-IV diagnosis participated in a lab-based social stress task. Saliva cortisol was assessed at awakening and during social stress. It was investigated if continuous measures of internalizing and externalizing problems and their interaction, using both self- and parent report, were associated with basal or reactivity measures of HPA-axis functioning. RESULTS: During social stress, an enhanced total release of cortisol was associated with self-reported internalizing problems and a blunted total release of cortisol with self-reported externalizing problems. Post hoc analyses revealed that the association between enhanced cortisol output and internalizing problems held for boys but not for girls. Associations with morning cortisol measures were overall weak. CONCLUSIONS: Only in the context of stress, and particularly when based on self-report, blunted cortisol output was associated with externalizing and enhanced cortisol output with internalizing problems. Our broad approach demonstrates the importance of who reports on psychopathology, the use of dimensional measures of psychopathology, simultaneous analysis of internalizing and externalizing problems, and the use of awakening and social stress related measures of cortisol. PMID- 23735710 TI - Gerontology found me: gaining understanding of advanced practice nurses in geriatrics. AB - Examining the meanings of the experiences of advanced practice nurses (APNs) who chose to work with older adults and why they continue to work with this population was the focus of this hermeneutic qualitative research study. Twelve geriatric APNs currently practicing in two South Central states were interviewed using an open-ended interview guide. Using Gadamerian hermeneutics, the researchers identified Gerontology Found Me as the significant expression that reflected the fundamental meaning of the experience as a whole. Four themes emerged that further described the meanings of the participants' personal, educational, and professional experiences: Becoming a Gerontology Nurse, Being a Gerontology Nurse, Belonging to Gerontology, and Bringing Others to Gerontology. This study concluded that APNs' personal and professional experiences were more influential than educational experiences to become geriatric nurses, and having these personal and professional experiences of being in relationship with older individuals further contributed to their choice of gerontology. PMID- 23735711 TI - Enhancing patient-centered care: pilot study results of a community care team intervention. AB - Health care reform focuses on primary care and development of Health Care Homes to improve patient-centered chronic illness care. This pilot study evaluated a community care team intervention that linked chronically ill older patients, support persons, and nurse care coordinators from a Health Care Home with community resources using an adaptation of the Wraparound process. A pragmatic clinical trial design was used. Patient-centered chronic illness care; physical, mental, and social health; service use; and study feasibility were evaluated. Differences between groups were compared using two-sample t, Wilcoxon rank sum, chi-square, or Fisher's exact tests. At 3 months, the intervention group reported higher patient-centered chronic illness care (mean total Patient Assessment of Chronic Illness Care change scores were 0.39 for the intervention group and -0.11 for the control group, p = .03). Results indicate that the integrated community care team intervention is a promising strategy to support patient-centered chronic illness care. PMID- 23735712 TI - Quadcopter control in three-dimensional space using a noninvasive motor imagery based brain-computer interface. AB - OBJECTIVE: At the balanced intersection of human and machine adaptation is found the optimally functioning brain-computer interface (BCI). In this study, we report a novel experiment of BCI controlling a robotic quadcopter in three dimensional (3D) physical space using noninvasive scalp electroencephalogram (EEG) in human subjects. We then quantify the performance of this system using metrics suitable for asynchronous BCI. Lastly, we examine the impact that the operation of a real world device has on subjects' control in comparison to a 2D virtual cursor task. APPROACH: Five human subjects were trained to modulate their sensorimotor rhythms to control an AR Drone navigating a 3D physical space. Visual feedback was provided via a forward facing camera on the hull of the drone. MAIN RESULTS: Individual subjects were able to accurately acquire up to 90.5% of all valid targets presented while travelling at an average straight-line speed of 0.69 m s(-1). SIGNIFICANCE: Freely exploring and interacting with the world around us is a crucial element of autonomy that is lost in the context of neurodegenerative disease. Brain-computer interfaces are systems that aim to restore or enhance a user's ability to interact with the environment via a computer and through the use of only thought. We demonstrate for the first time the ability to control a flying robot in 3D physical space using noninvasive scalp recorded EEG in humans. Our work indicates the potential of noninvasive EEG based BCI systems for accomplish complex control in 3D physical space. The present study may serve as a framework for the investigation of multidimensional noninvasive BCI control in a physical environment using telepresence robotics. PMID- 23735713 TI - Spatiotemporal dynamics of dengue epidemics, southern Vietnam. AB - An improved understanding of heterogeneities in dengue virus transmission might provide insights into biological and ecologic drivers and facilitate predictions of the magnitude, timing, and location of future dengue epidemics. To investigate dengue dynamics in urban Ho Chi Minh City and neighboring rural provinces in Vietnam, we analyzed a 10-year monthly time series of dengue surveillance data from southern Vietnam. The per capita incidence of dengue was lower in Ho Chi Minh City than in most rural provinces; annual epidemics occurred 1-3 months later in Ho Chi Minh City than elsewhere. The timing and the magnitude of annual epidemics were significantly more correlated in nearby districts than in remote districts, suggesting that local biological and ecologic drivers operate at a scale of 50-100 km. Dengue incidence during the dry season accounted for 63% of variability in epidemic magnitude. These findings can aid the targeting of vector control interventions and the planning for dengue vaccine implementation. PMID- 23735714 TI - Intermittent kangaroo mother care: a NICU protocol. AB - The practice of kangaroo mother care (KMC) is steadily increasing in high-tech settings due to its proven benefits for both infants and parents. In spite of that, clear guidelines about how to implement this method of care are lacking, and as a consequence, some restrictions are applied in many neonatal intensive care units (NICUs), preventing its practice. Based on recommendations from the Expert Group of the International Network on Kangaroo Mother Care, we developed a hospital protocol in the neonatal unit of the Institute for Maternal and Child Health in Trieste, Italy, a level 3 unit, aimed to facilitate and promote KMC implementation in high-tech settings. Our guideline is therefore proposed, based both on current scientific literature and on practical considerations and experience. Future adjustments and improvements would be considered based on increasing clinical KMC use and further knowledge. PMID- 23735715 TI - Production of chimeric embryos by aggregation of bovine egfp eight-cell stage blastomeres with two-cell fused and asynchronic embryos. AB - Embryo disaggregation allows the production of two to four identical offspring from a single cow embryo. In addition, embryo complementation has become the technique of choice to demonstrate the totipotency of embryonic stem cells and induced pluripotent stem cells. Therefore, the aim of this study was to generate a new and simple method by aggregation in the well-of-the-well system to direct each single enhanced green fluorescent protein (egfp) eight-cell blastomere derived from bovine in vitro fertilization embryos to the inner cell mass (ICM) of chimeras produced with fused and asynchronic embryos. To this end, the best conditions to generate in vitro fertilization-fused embryos were determined. Then, the fused (F) and nonfused (NF) embryos were aggregated in two distinct conditions: synchronically (S), with both transgenic and F embryos produced on the same day, and asynchronically (AS), with transgenic embryos produced one day before F embryos. The highest fusion and blastocysts rates were obtained with two pulses of 40 V. The 2ASF and 2ASNF groups showed the best number of blastocysts expressing the EGFP protein (48% and 41%, respectively). Furthermore, the 2ASF group induced the highest localization rates of the egfp-expressing blastomere in the ICM (6/13, 46% of ICM transgene-expressing blastocysts). This technique will have great application for multiplication of embryos of high genetic value or transgenic embryos and also with the generation of truly bovine embryonic stem cells and induced pluripotent stem cells. PMID- 23735717 TI - Effect of peripheral arterial disease and race on survival after coronary artery bypass grafting. AB - BACKGROUND: Although peripheral arterial disease (PAD) is more prevalent among blacks, the effect of race on long-term survival after coronary artery bypass grafting (CABG) has not been examined in this population. METHODS: A retrospective cohort study was conducted of CABG patients between 1992 and 2011. Long-term survival was compared in patients with and without PAD and stratified by race. Hazard ratios (HR) and 95% confidence intervals were computed using a Cox regression model. RESULTS: Of 13,053 patients who underwent CABG, 1,501 (11%) had PAD, comprising 311 blacks and 1,190 whites. Median follow-up was 8.3 years. Long-term survival differed by race (no PAD: HR, 1.0; white PAD: adjusted HR, 1.5, 95% confidence interval, 1.4 to 1.6; black PAD: adjusted HR, 2.1, 95% confidence interval, 1.8 to 2.5; p < 0.0001 for trend). CONCLUSIONS: Risk of death after CABG was comparatively higher among black PAD patients. This finding provides useful outcome information for surgeons and their patients. PMID- 23735716 TI - Interleukin-1 Beta induces an inflammatory phenotype in human aortic valve interstitial cells through nuclear factor kappa Beta. AB - BACKGROUND: Mechanisms of inflammation have been implicated in the pathogenesis of aortic stenosis. When stimulated, human aortic valve interstitial cells (AVICs) have been shown to become inflammatory cells. Increased levels of interleukin (IL)-1beta have been found in the leaflets of stenotic aortic valves. The purpose of this study was to determine the effects of IL-1beta on isolated human AVICs and to determine the intracellular signaling pathway by which the effects are mediated. The results of this study demonstrated that IL-1beta induces an inflammatory phenotype in human AVICs. METHODS: Human AVICs were isolated from normal aortic valves from explanted hearts of patients undergoing cardiac transplantation (n = 4) and grown in culture. When grown to confluence, the cells were treated with IL-1beta (10 ng/mL). Cell culture media was analyzed for IL-6, IL-8, and monocyte chemoattractant protein-1 (enzyme-linked immunosorbent assay). Cell lysates were analyzed for intercellular adhesion molecule-1 (immunoblot). Inhibition of nuclear factor-kappabeta was by Bay 11 7085 (5 MUM). Inhibition of extracellular signal regulated kinase-1/2 was by PD098059 (20 nM). Statistics were by analysis of variance, with p less than 0.05 significant. RESULTS: Interluekin-1beta induced an inflammatory phenotype in human AVICs. The IL-1beta stimulation resulted in significantly increased production of the inflammatory cytokines, IL-6 and IL-8, the chemokine monocyte chemoattractant protein-1, and intercellular adhesion molecule-1. Inhibition of nuclear factor-kappabeta prevented these changes, whereas inhibition of extracellular signal regulated kinase-1/2 had no effect. CONCLUSIONS: Interleukin 1beta induced an inflammatory phenotype in human AVICs, which was prevented by inhibition of nuclear factor-kappabeta. These data implicate IL-1beta in the pathogenesis of aortic stenosis. PMID- 23735718 TI - Determinants of nutrition appointment attendance among male veterans attending Veterans Health Administration clinics. AB - OBJECTIVE: To identify determinants of nutrition appointment attendance among male veterans attending outpatient Veterans Health Administration clinics. METHODS: Sequential use of qualitative and quantitative methods. Individual, semi structured interviews and a mail survey were used to identify factors associated with outpatient nutrition appointment attendance. RESULTS: Qualitative analysis of 17 interviews revealed 6 themes reflecting rationales for missed appointments: travel difficulty, forgetting the appointment, competing demands, scheduling difficulty, knowledge not new or useful, and lack of provider support. Analysis of 349 returned surveys indicated past attendance history, health status, and participation in the referral and scheduling process correlated to appointment attendance (P < .05). Regression analysis substantiated the importance of social support (P < .05). CONCLUSIONS AND IMPLICATIONS: Veterans Health Administration patients should participate in the referral and scheduling process. Social support, perceived health status, and past attendance history are important considerations for patient and provider to address. PMID- 23735719 TI - Modeling the cadmium balance in Australian agricultural systems in view of potential impacts on food and water quality. AB - The historical build up and future cadmium (Cd) concentrations in top soils and in crops of four Australian agricultural systems are predicted with a mass balance model, focusing on the period 1900-2100. The systems include a rotation of dryland cereals, a rotation of sugarcane and peanuts/soybean, intensive dairy production and intensive horticulture. The input of Cd to soil is calculated from fertilizer application and atmospheric deposition and also examines options including biosolid and animal manure application in the sugarcane rotation and dryland cereal production systems. Cadmium output from the soil is calculated from leaching to deeper horizons and removal with the harvested crop or with livestock products. Parameter values for all Cd fluxes were based on a number of measurements on Australian soil-plant systems. In the period 1900-2000, soil Cd concentrations were predicted to increase on average between 0.21 mg kg(-1) in dryland cereals, 0.42 mg kg(-1) in intensive agriculture and 0.68 mg kg(-1) in dairy production, which are within the range of measured increases in soils in these systems. Predicted soil concentrations exceed critical soil Cd concentrations, based on food quality criteria for Cd in crops during the simulation period in clay-rich soils under dairy production and intensive horticulture. Predicted dissolved Cd concentrations in soil pore water exceed a ground water quality criterion of 2 MUg l(-1) in light textured soils, except for the sugarcane rotation due to large water leaching fluxes. Results suggest that the present fertilizer Cd inputs in Australia are in excess of the long-term critical loads in heavy-textured soils for dryland cereals and that all other systems are at low risk. Calculated critical Cd/P ratios in P fertilizers vary from <50 to >1000 mg Cd kg P(-1) for the different soil, crop and environmental conditions applied. PMID- 23735720 TI - Occurrence and behavior of natural and anthropogenic (emerging and historical) halogenated compounds in marine biota from the Coast of Concepcion (Chile). AB - Fifty-five biota samples from the Coast of Concepcion (Chile) were analyzed for PBDEs, emerging brominated FRs, halogenated norbornenes and naturally-occurring MeO-PBDEs. PBDEs, MeO-PBDEs and halogenated norbornenes were detected at concentration levels ranging from 11 to 170, nd to 118 and nd to 5.8 ng/g lw, respectively. However, emerging brominated FRs such as decabromodiphenylethane (DBDPE), hexabromobenzene (HBB) and pentabromoethylbenzene (PBEB) were not detected in any sample. Bioaccumulation and bioconcentration processes were evaluated for the different families of compounds. Biomagnification factors (BMFs) were calculated, and some PBDE congeners (BDE-28, BDE-183 and BDE-209) as well as MeO-PBDEs presented BMF>1, being values of the naturally occurring MeO PBDEs higher than those obtained for PBDEs. As regards halogenated norbornenes, BMF<1 were found. PMID- 23735721 TI - Chemical and biological treatment technologies for leather tannery chemicals and wastewaters: a review. AB - Although the leather tanning industry is known to be one of the leading economic sectors in many countries, there has been an increasing environmental concern regarding the release of various recalcitrant pollutants in tannery wastewater. It has been shown that biological processes are presently known as the most environmental friendly but inefficient for removal of recalcitrant organics and micro-pollutants in tannery wastewater. Hence emerging technologies such as advanced oxidation processes and membrane processes have been attempted as integrative to biological treatment for this sense. This paper, as the-state-of the-art, attempts to revise the over world trends of treatment technologies and advances for pollution prevention from tannery chemicals and wastewater. It can be elucidated that according to less extent advances in wastewater minimization as well as in leather production technology and chemicals substitution, biological and chemical treatment processes have been progressively studied. However, there has not been a full scale application yet of those emerging technologies using advanced oxidation although some of them proved good achievements to remove xenobiotics present in tannery wastewater. It can be noted that advanced oxidation technologies integrated with biological processes will remain in the agenda of the decision makers and water sector to apply the best prevention solution for the future tanneries. PMID- 23735722 TI - Insulin resistance, incident cardiovascular diseases, and decreased kidney function among nondiabetic American Indians: the Strong Heart Study. AB - OBJECTIVE: Prevalence of insulin resistance is high in the American Indian population, likely as a result of the high prevalence of obesity. This condition may be influential for clinical outcomes such as cardiovascular disease (CVD) and decreased kidney function. RESEARCH DESIGN AND METHODS: Normal glucose tolerant (NGT) participants free of hypertension and CVD at the baseline examination (1989 1992) (N=964) of the Strong Heart Study were selected to explore the cross sectional association between insulin resistance quantified by homeostasis model assessment (HOMA-IR) and demographic, behavioral, and cardiometabolic variables. The longitudinal association between baseline HOMA-IR and the development of CVD was also explored. The longitudinal association between baseline HOMA-IR and the development of high urinary albumin-to-creatinine ratio was explored among nondiabetic participants (N=1,401). RESULTS: Cross-sectionally, HOMA-IR was associated with sex, residence location, smoking, and high-risk cardiometabolic profile. Prospectively, insulin resistance is associated with the development of CVD and decreased kidney function in this population. CONCLUSIONS: Insulin resistance may have an important role in the pathogenesis of CVD and chronic kidney disease. Since obesity contributes to the development of insulin resistance, intervention focusing on modifiable factors such as physical activity and weight control may reduce the development of these diseases. PMID- 23735723 TI - Favorable effects of insulin sensitizers pertinent to peripheral arterial disease in type 2 diabetes: results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. AB - OBJECTIVE: The aim of this manuscript was to report the risk of incident peripheral arterial disease (PAD) in a large randomized clinical trial that enrolled participants with stable coronary artery disease and type 2 diabetes and compare the risk between assigned treatment arms. RESEARCH DESIGN AND METHODS: The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial randomly assigned participants to insulin sensitization (IS) therapy versus insulin-providing (IP) therapy for glycemic control. Results showed similar 5 year mortality in the two glycemic treatment arms. In secondary analyses reported here, we examine the effects of treatment assignment on the incidence of PAD. A total of 1,479 BARI 2D participants with normal ankle-brachial index (ABI) (0.91 1.30) were eligible for analysis. The following PAD-related outcomes are evaluated in this article: new low ABI<=0.9, a lower-extremity revascularization, lower-extremity amputation, and a composite of the three outcomes. RESULTS: During an average 4.6 years of follow-up, 303 participants experienced one or more of the outcomes listed above. Incidence of the composite outcome was significantly lower among participants assigned to IS therapy than those assigned to IP therapy (16.9 vs. 24.1%; P<0.001). The difference was significant in time to-event analysis (hazard ratio 0.66 [95% CI 0.51-0.83], P<0.001) and remained significant after adjustment for in-trial HbA1c (0.76 [0.59-0.96], P=0.02). CONCLUSIONS: In participants with type 2 diabetes who are free from PAD, a glycemic control strategy of insulin sensitization may be the preferred therapeutic strategy to reduce the incidence of PAD and subsequent outcomes. PMID- 23735725 TI - Comorbid diabetes and COPD: impact of corticosteroid use on diabetes complications. AB - OBJECTIVE: To identify if there is a dose-dependent risk of diabetes complications in patients treated with corticosteroids who have both diabetes and chronic obstructive pulmonary disorder (COPD). RESEARCH DESIGN AND METHODS: A retrospective study of administrative claims data from the Australian Government Department of Veterans' Affairs, from 1 July 2001 to 30 June 2008, of diabetes patients newly initiated on metformin or sulfonylurea. COPD was identified by dispensings of tiotropium or ipratropium in the 6 months preceding study entry. Total corticosteroid use (inhaled and systemic) in the 12 months after study entry was determined. The outcome was time to hospitalization for a diabetes related complication. Competing risks and Cox proportional hazard regression analyses were conducted with adjustment for a number of covariates. RESULTS: A total of 18,226 subjects with diabetes were identified, of which 5.9% had COPD. Of those with COPD, 67.2% were dispensed corticosteroids in the 12 months from study entry. Stratification by dose of corticosteroids demonstrated a 94% increased likelihood of hospitalization for a diabetes complication for those who received a total defined daily dose (DDD) of corticosteroids>=0.83/day (subhazard ratio 1.94 [95% CI 1.14-3.28], P=0.014), by comparison with those who did not receive a corticosteroid. Lower doses of corticosteroid (<0.83 DDD/day) were not associated with an increased risk of diabetes-related hospitalization. CONCLUSIONS: In patients with diabetes and COPD, an increased risk of diabetes related hospitalizations was only evident with use of high doses of corticosteroids. This highlights the need for constant revision of corticosteroid dose in those with diabetes and COPD, to ensure that the minimally effective dose is used, together with review of appropriate response to therapy. PMID- 23735726 TI - REDEEM: a pragmatic trial to reduce diabetes distress. AB - OBJECTIVE: To compare three interventions to reduce diabetes distress (DD) and improve self-management among non-clinically depressed adults with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS: In REDEEM, 392 adults with T2DM and DD were randomized to computer-assisted self-management (CASM), CASM plus DD-specific problem solving (CAPS), or a computer-administered minimal supportive intervention. Primary outcomes were Diabetes Distress Scale (DDS) total, the Emotional Burden (EB) and Regimen Distress (RD) DDS subscales, and diet, exercise, and medication adherence. RESULTS: Significant and clinically meaningful reductions in DD (DDS, EB, and RD) and self-management behaviors occurred in all three conditions (P < 0.001), with no significant between-group differences. There was, however, a significant group * baseline distress interaction (P < 0.02), in which patients with high baseline RD in the CAPS condition displayed significantly larger RD reductions than those in the other two conditions. RD generated the most distress and displayed the greatest distress reduction as a result of intervention. The pace of DD reduction varied by patient age: older patients demonstrated significant reductions in DD early in the intervention, whereas younger adults displayed similar reductions later. Reductions in DD were accompanied by significant improvements in healthy eating, physical activity, and medication adherence, although not by change in HbA1c. CONCLUSIONS: DD is malleable and highly responsive to intervention. Interventions that enhance self-management also reduce DD significantly, but DD-specific interventions may be necessary for patients with high initial levels of DD. Future research should identify the minimal, most cost-effective interventions to reduce DD and improve self-management. PMID- 23735724 TI - Intensive structured self-monitoring of blood glucose and glycemic control in noninsulin-treated type 2 diabetes: the PRISMA randomized trial. AB - OBJECTIVE: We aimed to evaluate the added value of intensive self-monitoring of blood glucose (SMBG), structured in timing and frequency, in noninsulin-treated patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The 12-month, randomized, clinical trial enrolled 1,024 patients with noninsulin-treated type 2 diabetes (median baseline HbA1c, 7.3% [IQR, 6.9-7.8%]) at 39 diabetes clinics in Italy. After standardized education, 501 patients were randomized to intensive structured monitoring (ISM) with 4-point glycemic profiles (fasting, preprandial, 2-h postprandial, and postabsorptive measurements) performed 3 days/week; 523 patients were randomized to active control (AC) with 4-point glycemic profiles performed at baseline and at 6 and 12 months. Two primary end points were tested in hierarchical order: HbA1c change at 12 months and percentage of patients at risk target for low and high blood glucose index. RESULTS: Intent-to-treat analysis showed greater HbA1c reductions over 12 months in ISM (-0.39%) than in AC patients (-0.27%), with a between-group difference of -0.12% (95% CI, -0.210 to -0.024; P=0.013). In the per-protocol analysis, the between-group difference was -0.21% (-0.331 to -0.089; P=0.0007). More ISM than AC patients achieved clinically meaningful reductions in HbA1c (>0.3, >0.4, or >0.5%) at study end (P<0.025). The proportion of patients reaching/maintaining the risk target at month 12 was similar in ISM (74.6%) and AC (70.1%) patients (P=0.131). At visits 2, 3, and 4, diabetes medications were changed more often in ISM than in AC patients (P<0.001). CONCLUSIONS: Use of structured SMBG improves glycemic control and provides guidance in prescribing diabetes medications in patients with relatively well-controlled noninsulin-treated type 2 diabetes. PMID- 23735729 TI - Blood pressure variability in chronic kidney disease patients. AB - 'Usual' blood pressure (BP) levels are known to be directly related to cardiovascular (CV) risk in the general population and patients with essential hypertension. However, there is increasing evidence that, apart from usual BP, BP variability across visits may also be an important risk factor for death and CV events in healthy subjects and in essential hypertensive patients. In chronic kidney disease (CKD) patients the relationship between hypertension and clinical outcome is still controversial. Moreover, high visit-to-visit BP variability was very recently found to predict death and CV events in this high-risk patient population. This review focuses on the available evidence about the link between high visit-to-visit BP variability and clinical outcomes in CKD patients and describes some hypothetical mechanisms that could explain such a relationship. PMID- 23735728 TI - Inflammation and cognitive dysfunction in type 2 diabetic carotid endarterectomy patients. AB - OBJECTIVE: Type 2 diabetic patients have a high incidence of cerebrovascular disease, elevated inflammation, and high risk of developing cognitive dysfunction following carotid endarterectomy (CEA). To elucidate the relationship between inflammation and the risk of cognitive dysfunction in type 2 diabetic patients, we aim to determine whether elevated levels of systemic inflammatory markers are associated with cognitive dysfunction 1 day after CEA. RESEARCH DESIGN AND METHODS: One hundred fifteen type 2 diabetic CEA patients and 156 reference surgical patients were recruited with written informed consent in this single center cohort study. All patients were evaluated with an extensive battery of neuropsychometric tests. Preoperative monocyte counts, HbA1c, C-reactive protein (CRP), intercellular adhesion molecule 1, and matrix metalloproteinase 9 activity levels were obtained. RESULTS: In a multivariate logistic regression model constructed to identify predictors of cognitive dysfunction in type 2 diabetic CEA patients, each unit of monocyte counts (odds ratio [OR] 1.76 [95% CI 1.17 2.93]; P=0.005) and CRP (OR 1.17 [1.10-1.29]; P<0.001) was significantly associated with higher odds of developing cognitive dysfunction 1 day after CEA in type 2 diabetic patients. CONCLUSIONS: Type 2 diabetic patients with elevated levels of preoperative systemic inflammatory markers exhibit more cognitive dysfunction 1 day after CEA. These observations have implications for the preoperative medical management of this high-risk group of surgical patients undergoing carotid revascularization with CEA. PMID- 23735727 TI - Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. AB - OBJECTIVE: To examine the effect of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on the major components of renal glucose reabsorption (decreased maximum renal glucose reabsorptive capacity [TmG], increased splay, and reduced threshold), using the pancreatic/stepped hyperglycemic clamp (SHC) technique. RESEARCH DESIGN AND METHODS: Subjects with type 2 diabetes (n=12) and matched healthy subjects (n=12) underwent pancreatic/SHC (plasma glucose range 5.5-30.5 mmol/L) at baseline and after 7 days of dapagliflozin treatment. A pharmacodynamic model was developed to describe the major components of renal glucose reabsorption for both groups and then used to estimate these parameters from individual glucose titration curves. RESULTS: At baseline, type 2 diabetic subjects had elevated TmG, splay, and threshold compared with controls. Dapagliflozin treatment reduced the TmG and splay in both groups. However, the most significant effect of dapagliflozin was a reduction of the renal threshold for glucose excretion in type 2 diabetic and control subjects. CONCLUSIONS: The SGLT2 inhibitor dapagliflozin improves glycemic control in diabetic patients by reducing the TmG and threshold at which glucose is excreted in the urine. PMID- 23735730 TI - [Immune-checkpoints: the new anti-cancer immunotherapies]. AB - The immune system plays a dual role against cancer: it prevents tumor cell outgrowth and also sculpts the immunogenicity of the tumor cells. Cancer cells are able to escape from the immune system by inhibiting T lymphocytes activation. New immunotherapies have been developped to target these T lymphocytes activation modulators: the immune checkpoints. These novel therapies are showing promising results with durable objective responses in some patients. Ipilimumab (anti CTLA4) was the first of these new therapeutics to be approved by the FDA in March 2011 for advanced melanoma and other immunomodulators trials are ongoing in other cancers with similar encouraging results like with the anti PD-1/PD-L1. These drugs are already challenging our future practice like for evaluation of tumor response or for management of immune related toxicities. Many immune checkpoints have been identified and could potentially be targeted. Future studies will help to identify predictive factors but also to coordinate these new immunotherapies with our classic treatment strategies. PMID- 23735731 TI - Assessment of bone marrow infiltration diagnosed by flow cytometry in canine large B cell lymphoma: prognostic significance and proposal of a cut-off value. AB - The aims of this study were to assess the prognostic significance of bone marrow (BM) infiltration in canine large B cell lymphoma (LBCL) and to establish cut-off values for designating the BM as infiltrated by lymphoid blasts. The degree of BM infiltration by large CD21 positive cells in dogs with LBCL was assessed by flow cytometry (FC) and related to time to progression (TTP) and lymphoma-specific survival (LSS). Forty-six dogs were prospectively enrolled, staged and treated with a dose-intense chemotherapeutic protocol. BM infiltration was directly correlated with peripheral blood infiltration (P=0.001), high lactate dehydrogenase activity (P=0.0024) and substage b disease (P<0.001). In the univariate analysis, there was a significant association between BM infiltration diagnosed by FC and both TTP (P=0.001) and LSS (P<0.001). Substage was the only factor associated with TTP in the multivariate analysis (P=0.002), whereas substage (P<0.001) and anaemia (P=0.008) were associated with LSS. A cut-off of 3% BM infiltration had the strongest prognostic value, since it discriminated between dogs with a poorer prognosis (median TTP 69 days; median LSS 155 days) and dogs with a better prognosis (median TTP 149 days; median LSS 322 days). BM analysis is an essential step in the staging of LBCL. The presence of BM infiltration by FC at diagnosis is a negative prognostic indicator in canine LBCL. PMID- 23735732 TI - Resveratrol ameliorates subacute intestinal ischemia-reperfusion injury. AB - BACKGROUND: Resveratrol has been shown to attenuate reactive oxygen species formation and protect against ischemia-reperfusion (I/R) injury. However, the effects of resveratrol against subacute intestinal I/R injury are not clearly elucidated. Therefore, this study was designed to investigate the effects and possible protective mechanisms of resveratrol on subacute intestinal I/R injury in mice. METHODS: BALB/c mice were subjected to 1 h ischemia by occluding the superior mesenteric artery and 24 h reperfusion. Histologic injury; myeloperoxidase, superoxide dismutase, and glutathione peroxidase activity; malondialdehyde level; inducible nitric oxide synthase (iNOS), Ac-NF-kappaBp65, and sirtuin 1 (SIRT1) expression; NF-kappaB translocation; and nitric oxide (NO) production were examined in treated with or without resveratrol in the absence or presence of pharmacologic inhibitors. RESULTS: Resveratrol significantly ameliorated subacute intestinal I/R injury accompanied with the decrease of NO production as well as iNOS expression. In addition, resveratrol obviously upregulated the expression of SIRT1 and inhibited the activity of NF-kappaB. After application of iNOS inhibitor S-methylisothiourea and NF-kappaB inhibitor pyrrolidine dithiocarbamate, the protective effect of resveratrol was significantly augmented by attenuating iNOS and NO production, indicating that resveratrol exerted its protective effect on intestinal I/R injury via NF-kappaB mediated iNOS pathway. Furthermore, the protective effect of resveratrol was correlated with SIRT1, because application of SIRT1 inhibitor nicotinamide strikingly weakened the protective effect of resveratrol. CONCLUSIONS: Taken together, our findings showed that resveratrol protects intestinal subacute I/R injury via the SIRT1-NF-kappaB pathway in an iNOS-NO-dependent manner. Therefore, resveratrol has a potential clinical prospect for further development of anti injury therapy. PMID- 23735733 TI - Fatal influenza A(H1N1)pdm09 encephalopathy in immunocompetent man. AB - We report an immunocompetent patient who had fatal encephalopathy after mild influenza. He rapidly died after unusual symptoms related to intracerebral thrombosis and hemorrhage. A brain biopsy specimen was positive for influenza A(H1N1)pdm09 virus RNA, but a lung biopsy specimen and cerebrospinal spinal fluid samples were negative. PMID- 23735734 TI - Incidence and patterns of mandibular fractures during a 5-year period in a London teaching hospital. AB - We retrospectively evaluated mandibular fractures in patients who presented to a London teaching hospital between June 2005 and May 2010. A total of 1261 patients sustained 1994 mandibular fractures (mean 1.6, range 1-5). The incidence of mandibular fracture was higher in male patients (87%) than in females (13%) (male:female ratio 6.6:1), and the peak incidence was during the third decade for both genders. The most common site of fracture was the angle (30%), followed by the parasymphysis (27%), and condyle (27%). Overall, interpersonal violence was the most common cause (72%) followed by falls (18%). In male patients, the most common cause was interpersonal violence (77%); in females it was a fall (46%). The anatomical sites of fracture reflected their cause. Interpersonal violence typically resulted in fractures of the angle (36%) while road traffic accidents and falls resulted in condylar fractures (28% and 53%, respectively). A total of 66 (5%) patients sustained other maxillofacial fractures and 37 (3%) presented with non-maxillofacial fractures. Our findings are consistent with trends reported in other urban centres. PMID- 23735735 TI - Prostaglandin E receptor subtype EP4 agonist serves better to protect cochlea than prostaglandin E1. AB - OBJECTIVE: The present study aimed to examine whether an E-prostanoid receptor 4 (EP4) agonist has superior protective effects to those of prostaglandin E1 (PGE1) in a guinea pig model of noise trauma. METHODS: Drugs were locally applied on the round window membrane of guinea pig cochleae, followed by exposure of the test animals to intense noise. Protective effects mediated by an EP4 agonist were compared with those mediated by PGE1. Auditory function was monitored by measurements of the auditory brainstem response (ABR), and histological damage was assessed by immunohistochemical analysis of cochlear specimens. RESULTS: Animals treated with an EP4 agonist exhibited significantly better hearing recovery than those pretreated with PGE1. Histologically, the numbers of remaining outer hair cells in cochleae treated with the EP4 agonist were significantly higher than in those treated with PGE1. CONCLUSION: The selective activation of EP4 has a stronger protective effect on cochleae against noise trauma than does the broad activation of EPs by PGE1. PMID- 23735736 TI - Performance-based financing with GAVI health system strengthening funding in rural Cambodia: a brief assessment of the impact. AB - INTRODUCTION: Though Cambodia made impressive gains in immunization coverage between the years 2000 and 2005, it recognized several health system challenges to greater coverage of immunization and sustainability. The Global Alliance for Vaccines and Immunization (GAVI) opened a Health System Strengthening (HSS) funding window in 2006. To address the health system challenges, Cambodia has been receiving the GAVI HSS fund since October 2007. The major component of the support is performance-based financing (PBF) for maternal, neonatal and child health (MNCH) services. OBJECTIVE: To examine the impact of the PBF scheme on MNCH services and administrative management in rural Cambodia. METHODS: Quantitative and qualitative studies were conducted in Kroch Chhmar Operational District (OD), Cambodia. Quantitative analyses were conducted on the trends of the numbers of MNCH services. A brief analysis was conducted using qualitative data. RESULTS: After the commencement of the PBF support, the volume of MNCH services was significantly boosted. In addition, strengthened financial and operational management was observed in the study area. However, the quality of the MNCH services was not ensured. Technical assistance, rather than the PBF scheme, was perceived by stakeholders to play a vital role in increasing the quality of the services. DISCUSSION: To improve the quality of the health services provided, it is better to include indicators on the quality of care in the PBF scheme. Mutual co-operation between PBF models and technical assistance may ensure better service quality while boosting the quantity. A robust but feasible data validation mechanism should be in place, as a PBF could incentivize inaccurate reporting. The capacity for financial management should be strengthened in PBF recipient ODs. To address the broader aspects of MNCH, a balanced input of resources and strengthening of all six building blocks of a health system are necessary. PMID- 23735737 TI - Relationship between professional antenatal care and facility delivery: an assessment of Colombia. AB - The determinants of maternal and child health have been the recurrent topics of study in developing countries. Using the Demographic and Health Survey (2010) of Colombia, this study aimed to identify the determinants for professional antenatal care and institutional delivery, taking into account the interdependence of these two decisions, which we consider using a bivariate probit model. This study found that when certain factors affecting both the decision to seek prenatal care and giving birth in a hospital are neglected, the results of the estimates are inefficient. Estimates show that the effects of education, parity, regional location and economic status on institutional delivery tend to be underestimated in a univariate probit model. The results indicate that economic status, level of education, parity and medical-insurance affiliation influenced the joint likelihood of accessing professional antenatal care and delivering in a health facility. An important finding is that mothers with a higher level of education are 9 percentage points more likely to access these two health services compared with mothers who are illiterate. Another observed finding is the regional disparities. The evidence indicates that mothers in the Pacific Region, the poorest region of Colombia, are 6 percentage points less likely to access such services. Thus, the results indicate that the Colombian health policy should emphasize increasing the level of schooling of mothers and establish health facilities in the poorest regions of the country to ensure that women in need are provided with social health insurance. PMID- 23735738 TI - How to (or not to) ... measure performance against the Abuja target for public health expenditure. AB - In 2001, African heads of state committed 'to set a target of allocating at least 15% of our annual budget to the improvement of the health sector'. This target has since been used as a benchmark to hold governments accountable. However, it was never followed by a set of guidelines as to how it should be measured in practice. This article sets out some of the areas of ambiguity and argues for an interpretation which focuses on actual expenditure, rather than budgets (which are theoretical), and which captures areas of spending that are subject to government discretion. These are largely domestic sources, but include budget support, which is externally derived but subject to Ministry of Finance sectoral allocation. Theoretical and practical arguments in favour of this recommendation are recommended using a case study from Sierra Leone. It is recommended that all discretionary spending by government is included in the numerator and denominator when calculating performance against the target, including spending by all ministries on health, social health insurance payments, debt relief funds and budget support. Conversely, all forms of private payment and earmarked aid should be excluded. The authors argue that the target, while an important vehicle for tracking political commitment to the sector, should be assessed intelligently by governments, which have legitimate wider public finance objectives of maximizing overall social returns, and should be complemented by a wider range of indicators, to avoid distortions. PMID- 23735739 TI - Time-ordered product expansions for computational stochastic system biology. AB - The time-ordered product framework of quantum field theory can also be used to understand salient phenomena in stochastic biochemical networks. It is used here to derive Gillespie's stochastic simulation algorithm (SSA) for chemical reaction networks; consequently, the SSA can be interpreted in terms of Feynman diagrams. It is also used here to derive other, more general simulation and parameter learning algorithms including simulation algorithms for networks of stochastic reaction-like processes operating on parameterized objects, and also hybrid stochastic reaction/differential equation models in which systems of ordinary differential equations evolve the parameters of objects that can also undergo stochastic reactions. Thus, the time-ordered product expansion can be used systematically to derive simulation and parameter-fitting algorithms for stochastic systems. PMID- 23735740 TI - Active surveillance for influenza A virus among swine, midwestern United States, 2009-2011. AB - Veterinary diagnostic laboratories identify and characterize influenza A viruses primarily through passive surveillance. However, additional surveillance programs are needed. To meet this need, an active surveillance program was conducted at pig farms throughout the midwestern United States. From June 2009 through December 2011, nasal swab samples were collected monthly from among 540 groups of growing pigs and tested for influenza A virus by real-time reverse transcription PCR. Of 16,170 samples, 746 were positive for influenza A virus; of these, 18.0% were subtype H1N1, 16.0% H1N2, 7.6% H3N2, and 14.5% (H1N1)pdm09. An influenza (H3N2) and (H1N1)pdm09 virus were identified simultaneously in 8 groups. This active influenza A virus surveillance program provided quality data and increased the understanding of the current situation of circulating viruses in the midwestern US pig population. PMID- 23735741 TI - Synthesis and optimization of a novel series of HCV NS3 protease inhibitors: 4 arylproline analogs. AB - In this report we describe the synthesis and evaluation of diverse 4-arylproline analogs as HCV NS3 protease inhibitors. Introduction of this novel P2 moiety opened up new SAR and, in combination with a synthetic approach providing a versatile handle, allowed for efficient exploitation of this novel series of NS3 protease inhibitors. Multiple structural modifications of the aryl group at the 4 proline, guided by structural analysis, led to the identification of analogs which were very potent in both enzymatic and cell based assays. The impact of this systematic SAR on different drug properties is reported. PMID- 23735742 TI - Design, synthesis and antibacterial evaluation of novel AHL analogues. AB - Two series of novel AHL analogues were designed, synthesized and evaluated for antibacterial activity under cell membrane conditions in vitro. Analogues 4a-c and 4g-m presented potent activity against Gram-positive bacteria. Especially the analogue 4l exerted the most potent inhibition against Bacillus subtilis with MIC50 value of 1.443MUg/ml. To our surprise, analogues 6a-c and 6g showed weak inhibition against Gram-negative bacteria with MIC50 values ranging from 17.589 to 67.840MUg/ml. This was the first report about synthesis and antibacterial evaluation in vitro of AHL analogues containing dithioester linkage. PMID- 23735744 TI - BACE1 inhibitors: a head group scan on a series of amides. AB - A series of amides bearing a variety of amidine head groups was investigated as BACE1 inhibitors with respect to inhibitory activity in a BACE1 enzyme as well as a cell-based assay. Determination of their basicity as well as their properties as substrates of P-glycoprotein revealed that a 2-amino-1,3-oxazine head group would be a suitable starting point for further development of brain penetrating compounds for potential Alzheimer's disease treatment. PMID- 23735743 TI - HIV/AIDS eradication. AB - Antiretroviral therapy can inhibit HIV replication in patients and prevent progression to AIDS. However, it is not curative. Here we provide an overview of what antiretroviral drugs do and how the virus persists during therapy in rare reservoirs, such as latently infected CD4+ T cells. We also outline several innovative methods that are currently under development to eradicate HIV from infected individuals. These strategies include gene therapy approaches intended to create an HIV-resistant immune system, and activation/elimination approaches directed towards flushing out latent virus. This latter approach could involve the use of novel chemically synthesized analogs of natural activating agents. PMID- 23735745 TI - HS-1793, a recently developed resveratrol analogue protects rat heart against hypoxia/reoxygenation injury via attenuating mitochondrial damage. AB - Resveratrol is known to exert a cardioprotective effect against hypoxia/reoxygenation (H/R) injury. HS-1793 is a novel, more stable resveratrol analog, but its cardioprotective effects were unknown. The present study aimed to test the cardioprotective effect of HS-1793 against H/R injury and investigate the role of mitochondria in Sprague Dawley rat heart damage using an ex vivo Langendorff system. HS-1793 ameliorated H/R-induced mitochondrial dysfunction by reducing mitochondrial reactive oxygen species production, improving mitochondrial oxygen consumption and suppressing mitochondrial calcium (Ca(2+)) overload during reperfusion. Moreover, HS-1793-treated rat heart showed reduced infarct size. Our data suggest that HS-1793 can protect cardiac against mitochondrial damage following H/R, thereby suppressing injury. PMID- 23735746 TI - Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. AB - BACKGROUND & AIMS: Little is known about the efficacy of golimumab, a fully human monoclonal antibody to tumor necrosis factor (TNF) -alpha, for treatment of ulcerative colitis (UC). We evaluated subcutaneous golimumab induction therapy in TNF-alpha antagonist-naive patients with moderate-to-severe UC despite conventional treatment. METHODS: We integrated double-blind phase 2 dose-finding and phase 3 dose-confirmation trials in a study of 1064 adults with UC (Mayo score: 6-12; endoscopic subscore >= 2; 774 patients in phase 3). Patients were randomly assigned to groups given golimumab doses of 100 mg and then 50 mg (phase 2 only), 200 mg and then 100 mg, or 400 mg and then 200 mg, 2 weeks apart. The phase 3 primary end point was week-6 clinical response. Secondary end points included week-6 clinical remission, mucosal healing, and Inflammatory Bowel Disease Questionnaire (IBDQ) score change. RESULTS: In phase 2, median changes from baseline in the Mayo score were -1.0, -3.0, -2.0, and -3.0, in the groups given placebo, 100 mg/50 mg, 200/100 mg, and 400/200 mg golimumab, respectively. In phase 3, rates of clinical response at week 6 were 51.0% and 54.9% among patients given 200 mg/100 mg and 400 mg/200 mg golimumab, respectively, vs 30.3% among those given placebo (both, P <= .0001). Rates of clinical remission and mucosal healing and mean changes in IBDQ scores were significantly greater in both golimumab groups vs the placebo group (P <= .0014, all comparisons). Rates of serious adverse events were 6.1% and 3.0%, and rates of serious infection were 1.8% and 0.5%, in the placebo and golimumab groups, respectively. One patient in the 400 mg/200 mg group died as a result of surgical complications of an ischiorectal abscess. CONCLUSIONS: Treatment with subcutaneous golimumab induces clinical response, remission, and mucosal healing, and increases quality of life in larger percentages of patients with active UC than placebo. ClinicalTrials.gov Number: NCT00487539. PMID- 23735747 TI - Intrapericardial and intrapleural administration of rituximab to a patient with marginal zone lymphoma. AB - The addition of rituximab to standard chemotherapy has improved the results of the treatment of B cell non-Hodgkin's lymphomas. Under specific circumstances, it can be administered locally, as an alternative to systemic administration. We administered rituximab intrapericardially in an attempt to control pericardial effusion. We report the case of an 85-year-old woman, diagnosed with marginal zone lymphoma, who developed heart failure due to lymphomatous infiltration of the pericardium. We discuss in detail the possibility of intrapericardial treatment of such patients. The patient received rituximab intrapericardially at a dose of 100 mg in addition to systemic rituximab, cyclophosphamide, vincristine and prednisone immunochemotherapy. The treatment proved to be safe and effective. The patient has remained in good health for more than 3 years at the time of writing. Intrapericardial administration of rituximab may be a valuable therapeutic option for patients with lymphoma that involves the pericardium and heart. PMID- 23735748 TI - Hemocompatibility and anti-biofouling property improvement of poly(ethylene terephthalate) via self-polymerization of dopamine and covalent graft of zwitterionic cysteine. AB - Inspired by the composition of adhesive proteins in mussels, we used self polymerized dopamine to form a thin and surface-adherent polydopamine layer onto poly(ethylene terephthalate) (PET) sheet, followed by covalent grafting cysteine (Cys) to improve hemocompatibility and anti-biofouling property. The obtained surfaces were characterized by water contact angle measurements (WCA), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), and X-ray photoelectron spectroscopy (XPS) analysis. The results of platelet adhesion and protein adsorption tests showed that cysteine immobilized PET was endowed with improved resistance to nonspecific protein adsorption and platelet adhesion. The results of hemolysis rate test showed cysteine grafted PET (PET-g-Cys) had low hemolytic ability. Cell assay results showed that PET-g-Cys surface could greatly inhibit HeLa cell adhesion. These works provide an ideal hemocompatible and antifouling surface for biomedical applications. PMID- 23735749 TI - Intestinal epithelium-derived galectin-9 is involved in the immunomodulating effects of nondigestible oligosaccharides. AB - Dietary intervention using nondigestible oligosaccharides, short-chain galacto oligosaccharides (scGOS)/long-chain fructo-oligosaccharides (lcFOS), in combination with Bifidobacterium breve M-16V prevents allergic disease involving galectin-9. In addition, apical TLR9 signaling contributes to intestinal homeostasis. We studied the contribution of galectin-9 secreted by intestinal epithelial cells (IEC; HT-29 and T84) in Th1 and regulatory T-cell (Treg) polarization in vitro. IEC were grown in transwell filters, cocultured with CD3/CD28-activated human peripheral blood mononuclear cells (PBMC) and apically exposed to genomic DNA derived from B. breve M-16V or synthetic TLR9 ligand in the absence or presence of scGOS/lcFOS. Cytokine production and T-cell phenotype were determined and galectin expression by IEC was assessed. Galectin-9 was neutralized using lactose or a TIM-3-Fc fusion protein. IEC exposed to DNA from B. breve M-16V or TLR9 ligand in the presence of scGOS/lcFOS enhanced IFN-gamma secretion by PBMC and increased the percentage of Th1 and Treg cells. Expression and secretion of galectin-9 by IEC was increased and neutralization of galectin-9 prevented the induction of IFN-gamma secretion and also suppressed the production of IL-10 by PBMC. Furthermore, we show that galectin-9 induces Treg and Th1 polarization through interaction with antigen-presenting cells. Our findings show that galectin-9 secreted by IEC apically exposed to TLR9 ligand in the presence of scGOS/lcFOS is involved in Th1 and Treg polarization and may be a promising target to prevent or treat allergic disease. PMID- 23735750 TI - Impact of experience when using the Rapid Upper Limb Assessment to assess postural risk in children using information and communication technologies. AB - The Rapid Upper Limb Assessment (RULA) is an observation-based screening tool that has been used to assess postural risks of children in school settings. Studies using eye-tracking technology suggest that visual search strategies are influenced by experience in the task performed. This study investigated if experience in postural risk assessments contributed to differences in outcome scores on the RULA and the visual search strategies utilized. While wearing an eye-tracker, 16 student occupational therapists and 16 experienced occupational therapists used the RULA to assess 11 video scenarios of a child using different mobile information and communication technologies (ICT) in the home environment. No significant differences in RULA outcome scores, and no conclusive differences in visual search strategies between groups were found. RULA can be used as a screening tool for postural risks following a short training session regardless of the assessor's experience in postural risk assessments. PMID- 23735751 TI - Effect of food/oral-simulating liquids on dynamic mechanical thermal properties of dental nanohybrid light-cured resin composites. AB - OBJECTIVE: The purpose of this work was the study of the effect of food/oral simulating liquids on the dynamic mechanical thermal properties (viscoelastic properties) of current commercial dental light-cured resin composites characterized as nanohybrids. These nanohybrids were Grandio, Protofill-nano and Tetric EvoCeram. METHODS: The properties were determined under dry conditions (1h at 37 degrees C after light-curing) and also after storage in dry air, distilled water, artificial saliva SAGF((r)) or ethanol/water solution (75 vol%) at 37 degrees C for up 1, 7, 30 or 90 days. Dynamic mechanical thermal analysis tests were performed on a Diamond Dynamic Mechanical Analyzer in bending mode. A frequency of 1Hz and a temperature range of 25-185 degrees C were applied, while the heating rate of 2 degrees C/min was selected to cover mouth temperature and the materials' likely Tg. RESULTS: Storage modulus, loss modulus and tangent delta were plotted against temperature over this period. The Tg of composites was obtained as the temperature indicated by tandelta peak. Moreover, the maximum height of tandelta peak, the width at the half of tandelta maximum and a parameter known as "zeta" parameter were determined. All composites analyzed 1h after light-curing and 1 day in air or in food/oral simulating liquids showed two Tg. All composites stored for 7, 30 or 90 days in any medium showed unique Tg value. Also among the various properties studied the most sensible in the structural changes of composites seems to be the Tg. SIGNIFICANCE: Storage of composites in dry air at 37 degrees C which is very close to their Tg (40 degrees C) for 1 or 7 days caused post curing reactions, while storage for 30 or 90 days has no further effect on composites. Storage in water or artificial saliva 37 degrees C for 1 or 7 days caused post curing reactions, while storage for 30 or 90 days seems to cause plasticization effect affecting some parameters analogously. Storage in ethanol/water solution (75vol%) 37 degrees C for 1 or 7 days caused also post curing reactions, while storage for 30 or 90 days caused plasticization and/or probable oxidation/hydrolysis of polymeric network. PMID- 23735752 TI - 3D full field strain analysis of polymerization shrinkage in a dental composite. AB - OBJECTIVE: The objective of this research was to study the polymerization shrinkage in a dental composite using 3D digital image correlation (DIC). METHODS: Using 2 coupled cameras, digital images were taken of bar-shaped composite (Premise Universal Composite; Kerr) specimens before light curing and after for 10 min. Three-dimensional DIC was used to assess in-plane and out-of plane deformations associated with polymerization shrinkage. RESULTS: The results show the polymerization shrinkage to be highly variable with the peak values occurring 0.6-0.8mm away from the surface. Volumetric shrinkage began to significantly decrease at 3.2mm from the specimen surface and reached a minimum at 4mm within the composite. Approximately 25-30% of the strain registered at 5 min occurred after light-activation. Application of 3D DIC dental applications can be performed without the need for assumptions on the deformation field. SIGNIFICANCE: Understanding the local deformations and strain fields from the initial polymerization shrinkage can lead to a better understanding of the composite material and interaction with surrounding tooth structure, aiding in their further development and clinical prognosis. PMID- 23735753 TI - Kinin-B2 receptor exerted neuroprotection after diisopropylfluorophosphate induced neuronal damage. AB - The kinin-B2 receptor (B2BKR) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation. Recently, functions for this receptor in brain development and protection against glutamate-provoked excitotoxicity have been proposed. Here, we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model. Following slice perfusion for 10min with diisopropylfluorophosphate (DFP) to initiate the noxious stimulus, responses of pyramidal neurons upon an electric impulse were reduced to less than 30% of control amplitudes. Effects on synaptic elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with DFP. Accordingly, bradykinin-induced population spike recovery was abolished by HOE-140, a B2BKR antagonist. However, the kinin-B1 receptor (B1BKR) agonist Lys-des-Arg(9)-bradykinin, inducing the phosphorylation of mitogen-activated protein kinase (MEK/MAPK) and cell death, abolished bradykinin-mediated neuroprotection, an effect, which was reverted by the ERK inhibitor PD98059. In agreement with pivotal B1BKR functions in this process, antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity. On the other hand pralidoxime, an oxime, reactivating acetylcholinesterase (AChE) after organophosphate poisoning, induced population spike recovery after DFP exposure in the presence of bradykinin and Lys-des Arg(9)-bradykinin. Lys-des-Arg(9)-bradykinin did not revert protection exerted by pralidoxime, however when instead bradykinin and Ly-des-Arg(9)-bradykinin were superfused together, recovery of population spikes diminished. These findings again confirm the neuroprotective feature of bradykinin, which is, diminished by its endogenous metabolites, stimulating the B1BKR, providing a novel understanding of the physiological roles of these receptors. PMID- 23735754 TI - Characterising effects of impact velocity on brain and behaviour in a model of diffuse traumatic axonal injury. AB - The velocity of impact between an object and the human head is a critical factor influencing brain injury outcomes but has not been explored in any detail in animal models. Here we provide a comprehensive overview of the interplay between impact velocity and injury severity in a well-established weight-drop impact acceleration (WDIA) model of diffuse brain injury in rodents. We modified the standard WDIA model to produce impact velocities of 5.4, 5.85 and 6.15 m/s while keeping constant the weight and the drop height. Gradations in impact velocity produced progressive degrees of injury severity measured behaviourally, electrophysiologically and anatomically, with the former two methods showing greater sensitivity to changes in impact velocity. There were impact velocity dependent reductions in sensorimotor performance and in cortical depth-related depression of sensory cortex responses; however axonal injury (demonstrated by immunohistochemistry for beta-amyloid precursor protein and neurofilament heavy chain) was discernible only at the highest impact velocity. We conclude that the WDIA model is capable of producing graded axonal injury in a repeatable manner, and as such will prove useful in the study of the biomechanics, pathophysiology and potential treatment of diffuse axonal injury. PMID- 23735755 TI - HIV-related travel restrictions: trends and country characteristics. AB - INTRODUCTION: Increasingly, HIV-seropositive individuals cross international borders. HIV-related restrictions on entry, stay, and residence imposed by countries have important consequences for this mobile population. Our aim was to describe the geographical distribution of countries with travel restrictions and to examine the trends and characteristics of countries with such restrictions. METHODS: In 2011, data presented to UNAIDS were used to establish a list of countries with and without HIV restrictions on entry, stay, and residence and to describe their geographical distribution. The following indicators were investigated to describe the country characteristics: population at mid-year, international migrants as a percentage of the population, Human Development Index, estimated HIV prevalence (age: 15-49), presence of a policy prohibiting HIV screening for general employment purposes, government and civil society responses to having non-discrimination laws/regulations which specify migrants/mobile populations, government and civil society responses to having laws/regulations/policies that present obstacles to effective HIV prevention, treatment, care, and support for migrants/mobile populations, Corruption Perception Index, and gross national income per capita. RESULTS: HIV-related restrictions exist in 45 out of 193 WHO countries (23%) in all regions of the world. We found that the Eastern Mediterranean and Western Pacific Regions have the highest proportions of countries with these restrictions. Our analyses showed that countries that have opted for restrictions have the following characteristics: smaller populations, higher proportions of migrants in the population, lower HIV prevalence rates, and lack of legislation protecting people living with HIV from screening for employment purposes, compared with countries without restrictions. CONCLUSION: Countries with a high proportion of international migrants tend to have travel restrictions - a finding that is relevant to migrant populations and travel medicine providers alike. Despite international pressure to remove travel restrictions, many countries continue to implement these restrictions for HIV-positive individuals on entry and stay. Since 2010, the United States and China have engaged in high profile removals. This may be indicative of an increasing trend, facilitated by various factors, including international advocacy and the setting of a UNAIDS goal to halve the number of countries with restrictions by 2015. PMID- 23735756 TI - Event-related brain potential evidence for animacy processing asymmetries during sentence comprehension. AB - The animacy distinction is deeply rooted in the language faculty. A key example is differential object marking, the phenomenon where animate sentential objects receive specific marking. We used event-related potentials to examine the neural processing consequences of case-marking violations on animate and inanimate direct objects in Spanish. Inanimate objects with incorrect prepositional case marker 'a' ('al suelo') elicited a P600 effect compared to unmarked objects, consistent with previous literature. However, animate objects without the required prepositional case marker ('el obispo') only elicited an N400 effect compared to marked objects. This novel finding, an exclusive N400 modulation by a straightforward grammatical rule violation, does not follow from extant neurocognitive models of sentence processing, and mirrors unexpected "semantic P600" effects for thematically problematic sentences. These results may reflect animacy asymmetry in competition for argument prominence: following the article, thematic interpretation difficulties are elicited only by unexpectedly animate objects. PMID- 23735757 TI - Stroke-associated pneumonia: major advances and obstacles. AB - BACKGROUND: Stroke-associated pneumonia (SAP) has been implicated in the morbidity, mortality and increased medical cost after acute ischemic stroke. The annual cost of SAP during hospitalization in the United States approaches USD 459 million. The incidence and prognosis of SAP among intensive care unit (ICU) patients have not been thoroughly investigated. We reviewed the pathophysiology, microbiology, incidence, risk factors, outcomes and prophylaxis of SAP with special attention to ICU studies. METHODS: To determine the incidence, risk factors and prognosis of acute SAP, PubMed was searched using the terms 'pneumonia' AND 'neurology intensive unit' and the MeSH terms 'stroke' AND 'pneumonia'. Non-English literature, case reports and chronic SAP studies were excluded. Studies were classified into 5 categories according to the setting they were performed in: neurological intensive care units (NICUs), medical intensive care units (MICUs), stroke units, mixed studies combining more than one setting or when the settings were not specified and rehabilitation studies. RESULTS: The incidences of SAP in the following settings were: NICUs 4.1-56.6%, MICUs 17-50%, stroke units 3.9-44%, mixed studies 3.9-23.8% and rehabilitation 3.2-11%. The majority of NICU and MICU studies were heterogeneous including different neurovascular diseases, which partly explains the wide range of SAP incidence. The higher incidence in the majority of ICU studies compared to stroke units or acute floor studies is likely explained by the presence of mechanical ventilation, higher stroke severity causing higher rates of aspiration and stroke induced immunodepression among ICU patients. The short-term mortality of SAP was increased among the mixed and stroke unit studies ranging between 10.1 and 37.3%. SAP was associated with worse functional outcome in the majority of stroke unit and floor studies. Mortality was less consistent among NICU and MICU studies. This difference could be due to the heterogeneity of ICU studies and the effect of small sample size or other independent risk factors for mortality such as the larger neurological deficit, mechanical ventilation, and age, which may simultaneously increase the risk of SAP and mortality confounding the outcomes of SAP itself. The pathophysiology of SAP is likely explained by aspiration combined with stroke-induced immunodepression through complex humeral and neural pathways that include the hypothalamic-pituitary-adrenal axis, parasympathetic and sympathetic systems. CONCLUSIONS: A unified definition of SAP, strict inclusion criteria, and the presence of a long-term follow-up need to be applied to the future prospective studies to better identify the incidence and prognosis of SAP, especially among ICU patients. PMID- 23735759 TI - [ICAN (intensive care medicine, surgery, anesthesia and emergency medicine): a new section of SGUM (Swiss Ultrasound Medicine Society)]. PMID- 23735758 TI - Pharmacokinetic study of the structural components of adenosine diphosphate encapsulated liposomes coated with fibrinogen gamma-chain dodecapeptide as a synthetic platelet substitute. AB - Fibrinogen gamma-chain (dodecapeptide HHLGGAKQAGDV, H12)-coated, ADP-encapsulated liposomes [H12-(ADP)-liposomes] were developed as a synthetic platelet alternative that specifically accumulates at bleeding sites as the result of interactions with activated platelets via glycoprotein IIb/IIIa and augments platelet aggregation by releasing ADP. The aim of this study is to characterize the pharmacokinetic properties of H12-(ADP)-liposomes and structural components in rats, and to predict the blood retention of H12-(ADP)-liposomes in humans. With use of H12-(ADP)-liposomes in which the encapsulated ADP and liposomal membrane cholesterol were radiolabeled with (14)C and (3)H, respectively, it was found that the time courses for the plasma concentration curves of (14)C and (3)H radioactivity showed that the H12-(ADP)-liposomes remained intact in the blood circulation for up to 24 hours after injection, and were mainly distributed to the liver and spleen. However, the (14)C and (3)H radioactivity of H12-(ADP) liposomes disappeared from organs within 7 days after injection. The encapsulated ADP was metabolized to allantoin, which is the final metabolite of ADP in rodents, and was mainly eliminated in the urine, whereas the cholesterol was mainly eliminated in feces. In addition, the half-life of the H12-(ADP)-liposomes in humans was predicted to be approximately 96 hours from pharmacokinetic data obtained for mice, rats, and rabbits using an allometric equation. These results suggest that the H12-(ADP)-liposome has potential with proper pharmacokinetic and acceptable biodegradable properties as a synthetic platelet substitute. PMID- 23735760 TI - [Giant cell arteritis]. PMID- 23735762 TI - [Contraception - where ultrasound is of significant support]. AB - The use of ultrasound is already routine in contraceptive procedures. One of the best examples is the transvaginal assessment of the IUD position. But ultrasound may improve safety and comfort to contraceptive procedures too, e. g. transabdominally guided IUD insertion may not only help avoiding perforation but also painful moments. In case of lost threads transabdominally guided IUD extraction might be completed successfully without any kind of anesthesia. Furthermore, a subcutaneous contraceptive implant, if not palpable, might be localized and extracted by transcutaneous ultrasound guidance during local anesthesia. PMID- 23735763 TI - [Transcutaneous sonography of gastrointestinal tumours]. AB - This pictorial essay shows typical sonographic findings of gastrointestinal tumors from the esophagus to the rectum. The results are often incidental findings in routine examinations and demonstrate that the investigation of the GI tract should always be part of abdominal sonography. Special tips like the examination of the stomach filled with liquid are required particularly in targeted questions. PMID- 23735764 TI - [Jaundice and pathological liver values]. AB - Jaundice corresponds to elevated bilirubin- levels, whereat one has to distinguish between direct and indirect serum-bilirubin. In the present Mini Review causes and differential diagnosis of jaundice are outlined. Ultrasound diagnostic plays a major role in identifying intrahepatic or extrahepatic jaundice. Attention is given to the differential diagnosis of elevated liver enzymes in presence of jaundice, pointing out the distinction between hepatocellular and cholestatic parameters as well as the differentiation in acute or chronic increase. Moreover, the consequences of liver enzyme elevations including further diagnostic procedures, are highlighted. Finally, possibilities and limitations of modern diagnostic tests for liver fibrosis are briefly overviewed. PMID- 23735765 TI - [The focal renal lesions]. AB - The focal renal lesions are altogether common. Most frequently are found Columna Bertini hypertrophies (so called pseudotumors) and simple renal cysts. The role of sonography in the practice is to distinguish pseudotumors from real renal tumors, and simple renal cysts from complex cysts. The differentiation of complex renal cysts is possible with the help of the CEUS (= contrast enhanced ultrasound) and other imaging modalities such as CT or MRI. In these cases, the CEUS imaging agent has clear advantages over CT and MRI, because it is composed of gas bubbles, which are only slightly smaller than red blood cells and remains exclusively intravascularly while the CT and MRI contrast agents diffuse into the interstitial space without any real perfusion. The real tumors can be differentiated from certain focal non-tumorous changes based on the ultrasound and clinic. The further differentiation of individual kidney tumors and metastases using ultrasound, MRI, CT and CEUS is only partly possible. In all uncertain or unclear cases, therefore, an open or ultrasound-guided biopsy is useful. PMID- 23735766 TI - [Medical assessment of pleural thickening]. PMID- 23735767 TI - [Exacerbation of chronic lower back pain with an unexpected twist]. AB - We report a case of an 88-year old male patient with known chronic lower back pain who presented in late August with progressive pain in his right knee and lower leg as well as paraesthesias. Diagnostic work-up revealed an acute Lyme Borreliosis. PMID- 23735768 TI - [Clarithromycin increases the risk of cardiovascular events]. PMID- 23735769 TI - [Eyes open - possible association between aspirin and age-related macular degeneration]. PMID- 23735771 TI - [CME ultrasound diagnosis 52. Pain in the neck area. Subacute de Quervain thyroiditis]. PMID- 23735774 TI - Impulsive compulsive behaviors in Japanese Parkinson's disease patients and utility of the Japanese version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease. AB - BACKGROUND: In order to evaluate impulsive compulsive behaviors (ICBs), such as pathological gambling, compulsive sexual behavior, compulsive buying, compulsive eating, punding, and dopamine dysregulation syndrome (DDS) in Japanese Parkinson's disease (PD) patients, we constructed a Japanese version of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease (J-QUIP) and evaluated the utility of the J-QUIP in Japanese PD patients. METHODS: J-QUIP was administered to 121 PD patients. Diagnoses of ICBs were made via interview of patients or their caregivers. Subsequently, in order to evaluate risk factors related to these conditions, we evaluated demographic and clinical characteristics, clinical features, and medications utilized. RESULTS: We were able to administer the J-QUIP to 118 of 121 PD patients (97.5%). Sensitivity and specificity of J-QUIP were similar to that reported for the original version of QUIP. In our study, the actual prevalence of each disorder diagnosed via interview was as follows: pathological gambling (6.5%), compulsive sexual behavior (3.2%), compulsive buying (3.2%), compulsive eating (3.2%), punding (6.5%), and DDS (2.2%). Significantly risk factors for these conditions were younger age (p=0.047), earlier age of disease onset (p=0.015), longer PD duration (p=0.001), total levodopa equivalent dose (p=0.006), and dosage of levodopa (p=0.019). CONCLUSIONS: We evaluated the prevalence of ICBs in Japanese PD patients along with factors associated with these behaviors via J-QUIP. PMID- 23735775 TI - Introduction to the special section on Robert Lisak's contributions to neuroimmunology. PMID- 23735776 TI - Aquaporin-4 antibody negative recurrent isolated optic neuritis: clinical evidence for disease heterogeneity. AB - Recurrent optic neuritis is frequently observed in multiple sclerosis (MS) and is a typical finding in neuromyelitis optica (NMO). Patients that lack further evidence of demyelinating disease are diagnosed with RION (recurrent isolated optic neuritis) or CRION (chronic relapsing inflammatory neuropathy) if they require immunosuppressive therapy to prevent further relapses. The etiology and disease course of this rare condition are not well defined. We studied a series of 10 patients who presented with recurrent episodes of isolated optic neuritis (ON, n=57) and were followed over a median of 3.5 years. Visual acuity was severely reduced at the nadir of the disease (20/200 to 20/800). All patients had MRI non-diagnostic for MS/NMO and were aquaporin-4 antibody negative. Six patients fulfilled the CRION criteria. In two of these a single ON followed by a long disease-free interval preceded development of CRION for years, suggesting the conversion of an initially "benign" isolated ON into the chronic relapsing course. Cerebrospinal fluid (CSF) analysis revealed mild pleocytosis in 5 patients, identical oligoclonal bands in serum and CSF were observed in 2 patients, while the others remained negative. In conclusion, recurrent ON is a disease entity that requires aggressive glucocorticoid and eventually long-term immunosuppressive therapy to prevent substantial visual impairment. PMID- 23735777 TI - Pathology and disease mechanisms in different stages of multiple sclerosis. AB - In this review the differences in pathology and disease mechanisms between early and late stages of multiple sclerosis are discussed. The data suggest that affection of the brain is different, depending on the location of lesions, on the stage of the disease, when lesions arise, and on inter-individual differences between patients. We suggest that in the early stage of the disease new lesions are formed by new waves of inflammatory cells, entering the central nervous system from the circulation and giving rise to focal demyelinated plaques in the white and gray matter. In contrast, at late stages of the disease inflammation decreases, but the susceptibility of the target tissue for neurodegeneration increases. New data suggest that mitochondrial injury, mediated through oxidative injury, is in the center of the pathogenetic events leading to brain damage in multiple sclerosis patients. PMID- 23735778 TI - Experimental evidence supporting isometric functioning of the extrinsic toe flexors during gait. AB - BACKGROUND: The extrinsic toe flexors, flexor hallucis longus and flexor digitorum longus, play an important role in stabilizing the longitudinal arch and supporting high forefoot loads during the stance phase of gait. It was hypothesized that these muscles function isometrically during stance, a strategy thought to provide efficient energy transfer across adjoining body segments, but one for which there is little direct experimental evidence in vivo or in situ. METHODS: Eight lower extremity cadavers were loaded into a robotic apparatus that simulates the kinematics and extrinsic muscle activity of the foot and distal tibia during the stance phase of gait. Instantaneous tendon excursions and forces of the extrinsic toe flexors, as well as plantar pressure distributions during stance, were measured under two muscle control strategies: (1) force feedback control, where tendon forces were matched to forces predicted from normal electromyographic patterns and (2) isometric displacement control, where the representative myotendinous junction was held in a constant location. RESULTS: Tendon excursions of the flexor hallucis longus (7.18 (1.75)mm) and flexor digitorum longus (6.32 (1.74)mm) under force feedback control were small relative to optimal muscle fiber length (13.6% and 14.2%, respectively). Instantaneous tendon forces and plantar pressure variables were not different (P=0.112-0.912) between the two different muscle control strategies for either muscle. INTERPRETATION: These findings suggest that the extrinsic toe flexors function isometrically during the stance phase of gait in vivo. PMID- 23735779 TI - Reemergence of recombinant vaccine-derived polioviruses in healthy children, Madagascar. PMID- 23735780 TI - Foodborne botulism in Canada, 1985-2005. AB - During 1985-2005, a total of 91 laboratory-confirmed outbreaks of foodborne botulism occurred in Canada; these outbreaks involved 205 cases and 11 deaths. Of the outbreaks, 75 (86.2%) were caused by Clostridium botulinum type E, followed by types A (7, 8.1%) and B (5, 5.7%). Approximately 85% of the outbreaks occurred in Alaska Native communities, particularly the Inuit of Nunavik in northern Quebec and the First Nations population of the Pacific coast of British Columbia. These populations were predominantly exposed to type E botulinum toxin through the consumption of traditionally prepared marine mammal and fish products. Two botulism outbreaks were attributed to commercial ready-to-eat meat products and 3 to foods served in restaurants; several cases were attributed to non-Native home prepared foods. Three affected pregnant women delivered healthy infants. Improvements in botulism case identification and early treatment have resulted in a reduction in the case-fatality rate in Canada. PMID- 23735781 TI - Spectroscopic characterization of protein-wrapped single-wall carbon nanotubes and quantification of their cellular uptake in multiple cell generations. AB - We study the spectral characteristics of bovine serum albumin (BSA) protein conjugated single-wall carbon nanotubes (SWNTs), and quantify their uptake by macrophages. The binding of BSA onto the SWNT surface is found to change the protein structure and to increase the doping of the nanotubes. The G-band Raman intensity follows a well-defined power law for SWNT concentrations of up to 33 microg ml(-1) in aqueous solutions. Subsequently, in vitro experiments demonstrate that incubation of BSA-SWNT complexes with macrophages affects neither the cellular growth nor the cellular viability over multiple cell generations. Using wide spot Raman spectroscopy as a fast, non-destructive method for statistical quantification, we observe that macrophages effectively uptake BSA-SWNT complexes, with the average number of nanotubes internalized per cell remaining relatively constant over consecutive cell generations. The number of internalized SWNTs is found to be approximately 30 10(6) SWNTs/cell for a 60 mm( 2) seeding density and approximately 100 x 10(6) SWNTs/cell for a 200 mm(-2) seeding density. Our results show that BSA-functionalized SWNTs are an efficient molecular transport system with low cytotoxicity maintained over multiple cell generations. PMID- 23735782 TI - Population-expression models of immune response. AB - The immune response to a pathogen has two basic features. The first is the expansion of a few pathogen-specific cells to form a population large enough to control the pathogen. The second is the process of differentiation of cells from an initial naive phenotype to an effector phenotype which controls the pathogen, and subsequently to a memory phenotype that is maintained and responsible for long-term protection. The expansion and the differentiation have been considered largely independently. Changes in cell populations are typically described using ecologically based ordinary differential equation models. In contrast, differentiation of single cells is studied within systems biology and is frequently modeled by considering changes in gene and protein expression in individual cells. Recent advances in experimental systems biology make available for the first time data to allow the coupling of population and high dimensional expression data of immune cells during infections. Here we describe and develop population-expression models which integrate these two processes into systems biology on the multicellular level. When translated into mathematical equations, these models result in non-conservative, non-local advection-diffusion equations. We describe situations where the population-expression approach can make correct inference from data while previous modeling approaches based on common simplifying assumptions would fail. We also explore how model reduction techniques can be used to build population-expression models, minimizing the complexity of the model while keeping the essential features of the system. While we consider problems in immunology in this paper, we expect population-expression models to be more broadly applicable. PMID- 23735784 TI - Pulmonary artery pressure correlates directly with spleen volume in non splenectomized hemoglobin E/beta-thalassemia patients. PMID- 23735783 TI - Effects of transfer-oriented curriculum on multiple behaviors in the Netherlands. AB - Many school health promotion curricula address a single health behavior, without paying attention to potential learning effects in associated behavioral domains. We developed an innovative curriculum about smoking and safe sex that also focused on promoting students' transfer of knowledge, skills and attitudes to other domains. In a quasi-experimental study involving 1107 students (Grades 7 and 8) in the Netherlands, the curriculum was compared with regular lessons about smoking and safe sex. The central research questions were to what extent the transfer-oriented curriculum: (i) had effects on psychosocial determinants and behaviors in the domains of smoking and safe sex, (ii) had effects on determinants and behaviors in three domains about which no lessons were taught (consumption of alcohol, fruit and breakfast). Multi-level analyses showed that the answer to both questions is positive. The results indicate that a transfer approach may have surplus value over the classic domain-specific approach and warrant further elaboration in the future. PMID- 23735786 TI - Evolution of lactic acid bacteria in the order Lactobacillales as depicted by analysis of glycolysis and pentose phosphate pathways. AB - Lactic acid bacteria (LAB) represent a functional group of bacteria that are fundamental in human nutrition because of their prominent role in fermented food production and their presence as commensals in the gut. LAB co-evolution and niche-adaptation have been analyzed in several phylogenomic studies due to the availability of complete genome sequences. The aim of this study was to provide novel insights into LAB evolution through the comparative analysis of the metabolic pathways related to carbohydrate metabolism. The analysis was based on 42 LAB genome sequences of representative strains belonging to Enterococcaceae, Lactobacillaceae, Leuconostocaceae and Streptococcaceae. A reference phylogenetic tree was inferred from concatenation of 42 ribosomal proteins; then 42 genes belonging to the Embden-Meyerhof-Parnas (or glycolysis; EMPP) and pentose phosphate (PPP) pathways were analyzed in terms of their distribution and organization in the genomes. Phylogenetic analyses confirmed the paraphyly of the Lactobacillaceae family, while the distribution and organization of the EMPP and PPP genes revealed the occurrence of lineage-specific trends of gene loss/gain within the two metabolic pathways examined. In addition, the investigation of the two pathways as structures resulting from different evolutionary processes provided new information concerning the genetic bases of heterofermentative/homofermentative metabolism. PMID- 23735787 TI - CLN6 disease caused by the same mutation originating in Pakistan has varying pathology. AB - The neuronal ceroid lipofuscinoses (NCLs), the most common neurodegenerative diseases in children, are characterised by storage of autofluorescent material that has a characteristic ultrastructure. We report two families with variant late infantile NCL, both originating from Pakistan. Probands from both families were homozygous for the same mutation (c.316dupC) but had variable pathology to that currently thought to be typical for CLN6 disease, late infantile variant. The observed pathology of one proband resembled condensed fingerprints, previously described in late infantile CLN7 and CLN8 diseases, and pathology from the second proband was thought to be absent even after repeated skin biopsy, but observed after review. This mutation is the most common NCL mutation in families originating from Pakistan and could be prioritised for testing. Finally, this report contains the first prenatal diagnosis for late infantile CLN6 disease, initially made on the basis of EM and now confirmed by mutation analysis. PMID- 23735785 TI - miRNA-548c: a specific signature in circulating PBMCs from dilated cardiomyopathy patients. AB - High fidelity genome-wide expression analysis has strengthened the idea that microRNA (miRNA) signatures in peripheral blood mononuclear cells (PBMCs) can be potentially used to predict the pathology when anatomical samples are inaccessible like the heart. PBMCs from 48 non-failing controls and 44 patients with relatively stable chronic heart failure (ejection fraction of <= 40%) associated with dilated cardiomyopathy (DCM) were used for miRNA analysis. Genome wide miRNA-microarray on PBMCs from chronic heart failure patients identified miRNA signature uniquely characterized by the downregulation of miRNA-548 family members. We have also independently validated downregulation of miRNA-548 family members (miRNA-548c & 548i) using real time-PCR in a large cohort of independent patient samples. Independent in silico Ingenuity Pathway Analysis (IPA) of miRNA 548 targets shows unique enrichment of signaling molecules and pathways associated with cardiovascular disease and hypertrophy. Consistent with specificity of miRNA changes with pathology, PBMCs from breast cancer patients showed no alterations in miRNA-548c expression compared to healthy controls. These studies suggest that miRNA-548 family signature in PBMCs can therefore be used to detect early heart failure. Our studies show that cognate networking of predicted miRNA-548 targets in heart failure can be used as a powerful ancillary tool to predict the ongoing pathology. PMID- 23735788 TI - Integration process of biodiesel production from filamentous oleaginous microalgae Tribonema minus. AB - Biodiesel production from microalgae has been receiving considerable attention. Past studies mainly relied on tiny sized single-cell oleaginous microalgal species, the biodiesel based on filamentous oleaginous microalgae was rarely reported. Thus, integrated process of biodiesel production from filamentous oleaginous microalgal strain Tribonema minus was studied in this work. The filamentous microalgae was cultivated for 21 days in 40 L glass panel, microalgae cells was harvested by DAF without any flocculants after the lipid content was 50.23%. After that, total lipid was extracted by subcritical ethanol from wet algal paste and 44.55% of crude lipid was triacylglycerols. Two-step catalytic conversion of pre-esterification and transesterification was adopted to convert the crude algal oil to biodiesel. The conversion rate of triacylglycerols reached 96.52% under the methanol to oil molar ratio of 12:1 during catalysis with 2% potassium hydroxide at 65 degrees C for 30 min. The biodiesel product from T. minus conformed to Chinese National Standards. PMID- 23735789 TI - Application potential of a newly isolated indigenous aerobic denitrifier for nitrate and ammonium removal of eutrophic lake water. AB - The aim of this work was to evaluate the utilization potential of a newly isolated indigenous aerobic denitrifier, Pseudomonas stutzeri strain T1, for nitrogen removal from the eutrophic Lake Taihu in China. The strain was capable of conducting heterotrophic nitrification-aerobic denitrification and had both excellent nitrate and ammonium removal without nitrite build-up. The characteristics of P. stutzeri strain T1 were studied under different cultural conditions. Furthermore, under the optimized cultivation conditions, strain T1 was added into the water samples from Lake Taihu, the ammonium and nitrate removal rates of the strain reached to 60% and 75%, respectively. Via adding this strain, the water qualities of the sample ameliorated from Grade V to Grade II. Thus, the strain T1 should be an useful biological tool to remediate eutrophic lakes and do not meet acclimation problems. PMID- 23735790 TI - Characterization of bacterial communities in hybrid upflow anaerobic sludge blanket (UASB)-membrane bioreactor (MBR) process for berberine antibiotic wastewater treatment. AB - Biodegradation of berberine antibiotic was investigated in upflow anaerobic sludge blanket (UASB)-membrane bioreactor (MBR) process. After 118days of operation, 99.0%, 98.0% and 98.0% overall removals of berberine, COD and NH4(+)-N were achieved, respectively. The detailed composition of the established bacterial communities was studied by using 16S rDNA clone library. Totally, 400 clones were retrieved and grouped into 186 operational taxonomic units (OTUs). UASB was dominated by Firmicutes and Bacteroidetes, while Proteobacteria, especially Alpha- and Beta-proteobacteria were prevalent in the MBRs. Clostridium, Eubacterium and Synergistes in the UASB, as well as Hydrogenophaga, Azoarcus, Sphingomonas, Stenotrophomonas, Shinella and Alcaligenes in the MBRs were identified as potential functional species in biodegradation of berberine and/or its metabolites. The bacterial community compositions in two MBRs were significantly discrepant. However, the identical functions of the functional species ensured the comparable pollutant removal performances in two bioreactors. PMID- 23735791 TI - Need for optimizing catalyst loading for achieving affordable microbial fuel cells. AB - Microbial fuel cell (MFC) technology is a promising technology for electricity production together with simultaneous water treatment. Catalysts play an important role in deciding the MFC performance. In most reports, effect of catalyst - both type and quantity is not optimized. In this paper, synthesis of nanorods of MnO2-catalyst particles for application in Pt-free MFCs is reported. The effect of catalyst loading i.e., weight ratio, with respect to conducting element and binder has been optimized by employing large number of combinations. Using simple theoretical model, it is shown that too high (or low) concentration of catalysts result in loss of MFC performance. The operation of MFC has been investigated using domestic wastewater as source of bio-waste for obtaining real world situation. Maximum power density of ~61 mW/m(2) was obtained when weight ratio of catalyst and conducting species was 1:1. Suitable reasons are given to explain the outcomes. PMID- 23735792 TI - Characterization and interactions of anodic isolates in microbial fuel cells explored for simultaneous electricity generation and Congo red decolorization. AB - To investigate functions and interactions of predominant microorganisms in microbial fuel cells (MFCs) for simultaneous electricity generation and Congo red decolorization, four strains were isolated from the anodic biofilm, and identified as Pseudomonas (M-P and I-P), Bacillus (M-B) and Aquamicrobium (I-A). Higher maximum power density (by 158.2% and 58.1%) but lower Congo red decolorization rate (by 3.2% and 5.9%) were achieved in MFCs using pure cultures I-P and M-P as inoculums than those using I-A and M-B, respectively. By comparing MFCs using co-cultures with those using pure cultures (M-P&B versus M-B and M-P, I-P&A versus I-A and I-P), the maximum power density of MFCs using co-cultures increased 82.0%, 15.1%, 94.6% and -24.6% (minus meant decreased), but decolorization rate decreased 33.3%, 29.4%, 7.9% and 5.0%, respectively. The results indicated specific interaction could enhance the performance of MFCs and might benefit the development of bio-process controlling. PMID- 23735793 TI - Optimization of supercritical methanol reactive extraction by response surface methodology and product characterization from Jatropha curcas L. seeds. AB - In this study, optimization of supercritical reactive extraction directly from Jatropha seeds in a high pressure batch reactor using Response Surface Methodology (RSM) coupled with Central Composite Rotatable Design (CCRD) was performed. Four primary variables (methanol to solid ratio (SSR), reaction temperature, time and CO2 initial pressure) were investigated under the proposed constraints. It was found that all variables had significant effects towards fatty acid methyl esters (FAME) yield. Moreover, three interaction effects between the variables also played a major role in influencing the final FAME yield. Optimum FAME yield at 92.0 wt.% was achieved under the following conditions: 5.9 SSR, 300 degrees C, 12.3 min and 20 bar CO2. Final FAME product was discovered to fulfil existing international standard. Preliminary characterization analysis proved that the solid residue can be burnt as solid fuel in the form of biochar while the liquid product can be separated as specialty chemicals or burned as bio-oil for energy production. PMID- 23735794 TI - Real-time estimation of glucose concentration in algae cultivation system using Raman spectroscopy. AB - This work proposes a soft-sensor design for real-time estimation of glucose concentration under mixotrophic conditions using Raman spectroscopy. The suggested approach applies a Rolling-Circle Filter (RCF), Partial Least Squares (PLS), and a successive Savitzky-Golay (SG) smoothing filter. RCF is used to remove the background effects of Raman spectrum in the pre-processing step. PLS is used to reduce the dimensionality of spectrum data and relate them to the concentration. The SG filter is further employed as a post-processing step in a successive manner to adjust predicted glucose concentrations. Two sets of experiments using artificial assays and samples from a microalgae cultivation system were performed for verification. The proposed approach showed improved prediction performances compared to other data processing and regression techniques. PMID- 23735795 TI - Hydrothermal carbonization of agricultural residues. AB - The work presented in this article addresses the application of hydrothermal carbonization (HTC) to produce a solid fuel named HTC-Biochar, whose characteristics are comparable to brown coal. Several batch HTC experiments were performed using agricultural residues (AR) as substrates, commonly treated in farm-based biogas plants in Germany. Different AR were used in different combinations with other biomass residues. The biogas potential from the resulting process water was also determined. The combination of different AR lead to the production of different qualities of HTC-Biochars as well as different mass and energy yields. Using more lignocellulosic residues lead to higher mass and energy yields for the HTC-Biochar produced. Whilst residues rich in carbohydrates of lower molecular weight such as corn silage and dough residues lead to the production of a HTC-Biochar of better quality and more similar to brown coal. Process water achieved a maximum of 16.3 L CH4/kg FM (fresh matter). PMID- 23735796 TI - Luminescent photobioreactor design for improved algal growth and photosynthetic pigment production through spectral conversion of light. AB - Growth characteristics of two strains of microalgae in bubble column photobioreactors were investigated under different cultivation conditions. Chlorella vulgaris and Gloeothece membranacea were cultivated in luminescent acrylic photobioreactors at different seed culture densities. Luminescent acrylic photobioreactors in blue, green, yellow, orange, and red colours capable of spectral conversion of light were used. The results indicated that the red luminescent photobioreactor enhanced biomass production in both strains of microalgae while pigmentation was induced under different light colours. Green light promoted chlorophyll production in C. vulgaris however chlorophyll production in G. membranacea cultures was less influenced by the light condition or culture density. Phycobiliproteins were the dominant pigments in G. membranacea and red light favoured synthesis of these pigments. PMID- 23735797 TI - Comparison of process configurations for ethanol production from acid- and alkali pretreated corncob by Saccharomyces cerevisiae strains with and without beta glucosidase expression. AB - beta-Glucosidase was shown to have synergistic effects with commercial cellulase in the hydrolysis of acid- and alkali-pretreated corncob, especially at the dose of 5 U/g biomass and 5 or 10 FPU/g biomass. An integrating yeast strain 45# expressing beta-glucosidase was constructed that utilized cellobiose quickly and efficiently. Process configurations were compared under conditions of 10% solid content, 10 FPU cellulase/g biomass, 5 U beta-glucosidase/g biomass (only used for parental strain W303-1A), 1g/kg yeast loading and 3.3g/kg urea supplementation. While separate hydrolysis and fermentation was optimal for W303 1A and the ethanol titer and yield reached 3.22 g/100g and 75.6% (expressed as a percentage of the theoretical yield), respectively, simultaneous saccharification and fermentation was optimal for strain 45# and the ethanol titer and yield reached 3.31 g/100g and 77.7%, respectively. These results are valuable in optimization of the process configuration and improving the yeast strain selected for cellulosic ethanol production. PMID- 23735798 TI - Evaluating the recovery performance of the ANAMMOX process following inhibition by phenol and sulfide. AB - In this study, the recovery performance of two anaerobic ammonium oxidation (ANAMMOX) reactors (R1, R2) that were previously subjected to phenol and sulfide for nearly 200 days with respective levels of 12.5-50 and 8-40 mg L(-1) and then operated in the absence of these suppressors was investigated. High nitrogen removal rates of greater than 36 kg-Nm(-3)d(-1) were achieved through the 81 and 75 days restoration of R1 and R2, respectively. The recovery performance was determined by specific sludge removal rate, heme c contents, specific ANAMMOX activity, settling properties and morphology of ANAMMOX granules. In addition, the modified Boltzmann model, the modified Gompertz model and the modified Logistic model were applied to simulate recovery performance. The modified Boltzmann model was found to be appropriate for predicting recovery performance of the phenol-inhibited reactor, while the modified Logistic model effectively simulated the recovery performance of the sulfide suppressed reactor. PMID- 23735799 TI - Optimized simultaneous saccharification and co-fermentation of rice straw for ethanol production by Saccharomyces cerevisiae and Scheffersomyces stipitis co culture using design of experiments. AB - Herein an ethanol production process from rice straw was optimized. Simultaneous saccharification and co-fermentation (SSCF) using Saccharomyces cerevisiae and Scheffersomyces stipitis co-culture was carried out to enhance ethanol production. The optimal saccharification solid loading was 5%. Key fermentation parameters for co-culture including cell ratio, agitation rate and temperature was rationally optimized using design of experiment (DoE). Optimized co-culture conditions for maximum ethanol production efficiency were at S. cerevisiae:S. stipitis cell ratio of 0.31, agitation rate of 116 rpm and temperature of 33.1 degrees C. The optimized SSCF process reached ethanol titer of 15.2g/L and ethanol yield of 99% of theoretical yield, consistent with the DoE model prediction. Moreover, SSCF process under high biomass concentration resulted in high ethanol concentration of 28.6g/L. This work suggests the efficiency and scalability of the developed SSCF process which could provide an important basis for the economic feasibility of ethanol production from lignocelluloses. PMID- 23735800 TI - Effect of powdered activated carbon technology on short-cut nitrogen removal for coal gasification wastewater. AB - A combined process consisting of a powdered activated carbon technology (PACT) and short-cut biological nitrogen removal reactor (SBNR) was developed to enhance the removal efficiency of the total nitrogen (TN) from the effluent of an upflow anaerobic sludge bed (UASB) reactor, which was used to treat coal gasification wastewater (CGW). The SBNR performance was improved with the increasing of COD and TP removal efficiency via PACT. The average removal efficiencies of COD and TP in PACT were respectively 85.80% and 90.30%. Meanwhile, the NH3-N to NO2-N conversion rate was achieved 86.89% in SBNR and the total nitrogen (TN) removal efficiency was 75.54%. In contrast, the AOB in SBNR was significantly inhibited without PACT or with poor performance of PACT in advance, which rendered the removal of TN. Furthermore, PAC was demonstrated to remove some refractory compounds, which therefore improved the biodegradability of the coal gasification wastewater. PMID- 23735801 TI - Efficient production of polymer-grade D-lactate by Sporolactobacillus laevolacticus DSM442 with agricultural waste cottonseed as the sole nitrogen source. AB - In this study, we show that Sporolactobacillus laevolacticus DSM442 can produce d lactate by using cottonseed as the sole nitrogen source. The cottonseed was enzymatically hydrolyzed and simultaneously utilized during d-lactate fermentation. Under optimal conditions, a high d-lactic acid concentration (144.4 g/L) was obtained in a fed-batch fermentation within 35 h, with an average productivity of 4.13 g/(Lh) and a yield of 0.96 g/g glucose. The optical purity of d-lactic acid in the broth was 99.3%, which meets the requirement for use in lactic acid polymerization. Our study represents a cost-effective method for polymer-grade d-lactate production using cheap agricultural wastes. PMID- 23735802 TI - Mediators-assisted reductive biotransformation of tetrabromobisphenol-A by Shewanella sp. XB. AB - The anaerobic biotransformation of tetrabromobisphenol A (TBBPA) was mainly observed in the consortia so far. The role of redox mediators in anaerobic TBBPA biotransformation by Shewanella sp. distributed widely in environments was investigated for the first time. The results showed the flavins secretion of Shewanella sp. XB was highly dependent on initial TBBPA concentration. The corresponding first-order rate constants (k) of TBBPA transformation decreased to 0.007 d(-1) when TBBPA concentration increased up to 80 mg/L. Moreover, the removal rate of TBBPA (80 mg/L) was significantly enhanced in treatments amended with cyanocobalamin, riboflavin, 2-hydroxy-1,4-naphthoquinone and Aldrich humic acid with k values of 0.42, 0.19, 0.16, and 0.07 d(-1), respectively. In addition, some redox proteins were secreted and played a role in flavins-mediated extracellular biotransformation of TBBPA by Shewanella sp. XB. These findings are beneficial to better understand TBBPA fate in natural environments and to develop efficient biotreatment strategies of TBBPA pollutions. PMID- 23735803 TI - Pre-treatment of lignocellulosic biomass using ionic liquids: wheat straw fractionation. AB - This work is devoted to study pre-treatment methodologies of wheat straw with 1 ethyl-3-methylimidazolium acetate ([emim][CH3COO]) and subsequent fractionation to cellulose, hemicellulose and lignin. The method developed and described here allows the separation into high purity carbohydrate and lignin fractions and permits an efficient IL recovery. A versatility of the established method was confirmed by the IL reuse. The fractionation of completely dissolved biomass led to cellulose-rich and hemicellulose-rich fractions. A high purity lignin was also achieved. To verify the potential further applicability of the obtained carbohydrate-rich fractions, and to evaluate the pre-treatment efficiency, the cellulose fraction resulting from the treatment with [emim][CH3COO] was subjected to enzymatic hydrolysis. Results showed a very high digestibility of the cellulose samples and confirmed a high glucose yield for the optimized pre treatment methodology. PMID- 23735804 TI - The HIV-1-containing macrophage compartment: a perfect cellular niche? AB - Macrophages are a major target of HIV-1 infection and are believed to act as viral reservoirs and mediators of HIV-1-associated neurological damage. These pathological roles may be associated with the ability of the virus to assemble and accumulate in apparently intracellular compartments in macrophages. These so called virus-containing compartments were initially thought to be late endosomes or multivesicular bodies, but it has since been shown that they are distinct structures that have complex three-dimensional morphology, a unique set of protein markers, and features such as a near-neutral pH and frequent connections to the extracellular milieu. These features appear to protect HIV-1 from hostile elements both within and outside the cell. This review discusses the cellular and molecular characteristics of HIV-1-containing compartments in macrophages and how they offer a safe haven for the virus, with important consequences for pathogenesis. PMID- 23735805 TI - Molecular layer heterotopia of the cerebellar vermis in mutant and transgenic mouse models on a C57BL/6 background. AB - C57BL/6 mice exhibit spontaneous cerebellar malformations consisting of heterotopic neurons and glia in the molecular layer of the vermis (Tanaka and Marunouchi, 2005; Mangaru et al., 2013). Malformations are only found between folia VIII and IX and are indicative of deficits of neuronal migration during cerebellar development. In the present report we test the prediction that mutant and transgenic mouse models on a C57BL/6 background will also exhibit these same cerebellar malformations. Consistent with our hypothesis, we found that 2 spontaneous mutant models of Parkinson's disease on a C57BL/6 background had cerebellar malformations. In addition, we found that numerous transgenic mouse lines on a full or partial C57BL/6 background including eGFP-, YFP- and Cre transgenic mice also exhibited heterotopia. These data suggest that histological analyses be performed in studies of cerebellar function or development when using C57BL/6 or other mice on this background in order for correct interpretation of research results. PMID- 23735806 TI - Responsive neurostimulation for the treatment of medically intractable epilepsy. AB - With an annual incidence of 50/100,000 people, nearly 1% of the population suffers from epilepsy. Treatment with antiepileptic medication fails to achieve seizure remission in 20-30% of patients. One treatment option for refractory epilepsy patients who would not otherwise be surgical candidates is electrical stimulation of the brain, which is a rapidly evolving and reversible adjunctive therapy. Therapeutic stimulation can involve direct stimulation of the brain nuclei or indirect stimulation of peripheral nerves. There are three stimulation modalities that have class I evidence supporting their uses: vagus nerve stimulation (VNS), stimulation of the anterior nuclei of the thalamus (ANT), and, the most recently developed, responsive neurostimulation (RNS). While the other treatment modalities outlined deliver stimulation regardless of neuronal activity, the RNS administers stimulation only if triggered by seizure activity. The lower doses of stimulation provided by such responsive devices can not only reduce power consumption, but also prevent adverse reactions caused by continuous stimulation, which include the possibility of habituation to long-term stimulation. RNS, as an investigational treatment for medically refractory epilepsy, is currently under review by the FDA. Eventually systems may be developed to enable activation by neurochemical triggers or to wirelessly transmit any information gathered. We review the mechanisms, the current status, the target options, and the prospects of RNS for the treatment of medically intractable epilepsy. PMID- 23735807 TI - Histone deactylase inhibitor SAHA induces a synergistic HIV-1 reactivation by 12 O-tetradecanoylphorbol-13-acetate in latently infected cells. AB - OBJECTIVES: Recent studies have reported that human immunodeficiency virus type 1 (HIV-1) proviruses are strongly suppressed in the unique epigenetic environments caused by chromatin modifications such as acetylation and methylation. Therefore, optimized therapeutic strategies directed against the virus reservoir using these epigenetic modifying agents (EMAs) should cure HIV infection. METHODS: Cytotoxicity and HIV-1 reactivation were determined using the PrestoBlueTM Cell Viability Reagent and p24 HIV ELISA, respectively. RESULTS: EMAs, including histone deacetylase inhibitors (VPA and SAHA), DNA methyltransferase inhibitor (5'-Aza-CdR), histone methyltransferase inhibitor (ADOX) and 12-O tetradecanoylphorbol-13-acetate (TPA), were used to reactivate proviruses in HIV 1 latently infected cells. The effect of monotreatment with these EMAs on HIV-1 reactivation was VPA or SAHA > 5'-Aza-CdR > ADOX. Even though cotreatment with these potential HIV-1 reactivating agents did not show any significant reactivation effects in HIV-1 latently infected cells, employing SAHA under TPA treatment demonstrated a dramatic synergistic effect on purging HIV-1 proviruses in all HIV-1 latently infected cells via the ERK and AP-1 pathways. CONCLUSIONS: These results suggest that the combined approaches of EMAs, cotreatment of SAHA and TPA, could provide an effective way to lead a decline of HIV-1 reservoirs in patients. PMID- 23735808 TI - Fingertip replantation at the eponychial level with venous anastomosis: an anatomic study and clinical application. AB - We present an anatomic study of the vein distribution at the eponychial level, in order to standardize outpatient fingertip replantation. The cross sectional anatomy of 100 fingers was studied by dissection following dye injection. The distribution of the veins >0.3 mm was recorded on a pie-chart. Thirty fingers in 27 patients with fingertip amputations at the eponychial level were replanted by anastomosis of the palmar subcutaneous veins, to reconstruct the venous reflux of the amputated digits. The operations were aided by the anatomical study and confirmed that the palmar area is the preferred site for venous anastomosis Following a distal finger amputation at the level of the eponychial fold we propose starting the search for veins between the 3 to 5 o'clock or 7 to 9 o'clock positions, as these are the areas where there are most likely to be suitable veins. PMID- 23735809 TI - Variability in local pressures under digital tourniquets. AB - The UK National Patient Safety Agency issued a rapid response report in 2009 following reports of complications related to digital tourniquet use and inadvertent retention. In their guidance, they recommend the use of CE marked digital tourniquets and advise against the use of surgical gloves. There are a number of different commercially available non-pneumatic digital tourniquets, but little clear data relating to their comparable physical properties, clinical efficacy or safety. The aim of this study was to investigate the variability of pressures exerted by non-pneumatic digital tourniquets. A Tekscan FlexiForce((r)) force sensor was used to measure applied force and to calculate the surface pressures under: the Toe-niquetTM; T-RingTM and surgical glove 'roll down' tourniquets in finger models. The lowest mean pressures were produced by the larger glove sizes (size 8) (25 mmHg), while the highest pressures were produced by the Toe-niquet (1560 mmHg). There was a significant overall difference in pressures exerted under tourniquets when comparing tourniquet type (p<0.001) and finger size (p<0.001) with these techniques. It is difficult to anticipate and regulate pressures generated by non-pneumatic tourniquets. Safe limits for application time and surface pressures are difficult to define. Further work is required to model the pressure effects of commercially available digital tourniquets and to identify which are most effective but safe. PMID- 23735810 TI - Effect of triggering and entrapment on tendon gliding properties following digital flexor tendon laceration: in vitro study on turkey tendon. AB - The optimal management of partial flexor tendon laceration is controversial and remains a clinical challenge. Abnormal tendon gliding (triggering and entrapment) was assessed at the A2 pulley in 40 turkey tendons in three groups: intact, partially divided (palmar or lateral), and trimmed. Testing was of gliding resistance and friction coefficient at 30 degrees and 70 degrees of flexion, loaded with 2 and 4 N. We observed for triggering and entrapment. The changes in gliding properties were compared and analysed using Wilcoxon matched pair testing. A significant difference was found in the change in gliding properties of intact to lacerated and lacerated to trimmed tendons and between tendons that glided normally compared with those exhibiting triggering or entrapment. This suggests that palmar and lateral lacerations which, through clinical examination and visualization, are found to glide normally should be treated with early mobilization. However, partial lacerations that exhibit triggering or entrapment should be trimmed. PMID- 23735811 TI - Complications of acute stroke and the occurrence of early seizures. AB - BACKGROUND: Seizures are common neurological consequences of stroke. Although a number of factors including stroke severity on admission, cortical involvement, and stroke subtype have been consistently associated with post-stroke seizures, the effect that medical and neurological complications of stroke, occurring in the very acute phase, might have on such a risk has never been adequately explored. In the present study we aimed at determining the extent to which complications within the first week of stroke influence the risk of early seizures (ES). METHODS: Data of consecutive patients with first-ever acute stroke included in the Brescia Stroke Registry were analyzed. ES (<=7 days) were recorded and correlated with demographic data, disease characteristics, risk factors, and prespecified medical and neurological stroke complications in a multivariate path analysis model. RESULTS: 516 patients with first-ever acute stroke were eligible for inclusion in the present study. Of them, 436 patients had ischemic stroke (IS) [64 (14.6%) with hemorrhagic transformation (HT)] and 80 had intracerebral hemorrhage (ICH). Twenty patients (3.9%) developed ES. Patients with ES had a higher burden of complications compared with those without (30 vs. 4.2%, for patients with >6 complications). Lesion type, stroke complications, and lesion site were directly related to the risk of seizure occurrence (OR, 0.24; 95% CI, 0.07-0.80 for IS vs. ICH; OR, 1.57; 95% CI, 1.21-2.01 for any increase of 1 in the number of complications; OR, 0.15; 95% CI, 0.04-0.56 for subcortical lesions vs. cortical lesions). Complications appeared also to mediate the indirect effect of lesion type on the occurrence of ES (OR, 0.75; 95% CI, 0.60 0.94). No significant difference on the risk of ES was observed when HT and ICH were compared. The total effect of lesion type was 0.25 * 0.75 = 0.18, corresponding to (1-0.18) = 82% lower risk of ES for IS as compared to ICH. CONCLUSION: Although major determinants of ES are nonmodifiable, preventable and treatable medical and neurologic complications within the first week of stroke increase the risk of ES and mediate the effect of established predictors on the propensity to post-stroke epilepsy. Future epidemiologic studies aimed at investigating post-stroke seizures should include precise information on these complications. PMID- 23735812 TI - The oxidant scavenging capacity of the oral Mycoplasma salivarium. AB - OBJECTIVE: Mycoplasma salivarium is a human oral potential pathogen that preferentially resides in dental plaques and gingival sulci. It has been suggested that this organism may play an etiological role in inflammatory processes in the oral cavity. The aim of this work was to determine whether M. salivarium possesses a potent oxidant scavenging capacity (OSC). DESIGN: The OSC of M. salivarium was quantified by a highly sensitive luminal-dependent chemiluminescence assay in the presence of cocktails that induced a constant flux of luminescence resulting from the generation of peroxide, hydroxyl radical (cocktail A) and NO, superoxide and peroxynitrites (cocktail B). RESULTS: M. salivarium markedly reduced oxidative stress by scavenging both free reactive oxygen and nitrogen species. The OSC of M. salivarium was much higher than that of other Mycoplasma species. Most of M. salivarium OSC was confined to the cytosolic fraction and was markedly increased in the presence of tannic acid, red blood cells or mucin. The cytosolic OSC of M. salivarium was heat stable and not affected by sodium azide or prolonged proteolysis. However, it was markedly decreased upon dialysis, suggesting that the major reducing activity is not enzymatic but rather, a low molecular weight compound(s). CONCLUSIONS: The ability of M. salivarium to scavenge oxidants may play a role in the survival and pathogenicity of this microorganism. The enhanced OSC of M. salivarium in the presence of tannic acid, red blood cells or mucin might have a significant importance to assess complex interactions with polyphenols from nutrients, salivary proteins and red blood cells extravasated from injured capillaries during infection and inflammation in oral tissues. PMID- 23735813 TI - Testing the validity, reliability and utility of the Self-Administration of Medication (SAM) tool in patients undergoing rehabilitation. AB - BACKGROUND: Determination of patients' ability to self-administer medications in the hospital has largely been determined using the subjective judgment of health professionals. OBJECTIVES: To examine the validity, reliability and utility of the Self-Administration of Medication (SAM) tool as an objective means to determine patients' ability to self-administer in a rehabilitation unit of a public teaching hospital in Melbourne, Australia. METHODS: To assess validity of the SAM tool, associations were examined between the total SAM tool score and of the patients' competence to self-administer from the perceptions of the tool administrator, patients and nurses. Validity also was determined from a principal component analysis. Pearson correlations were calculated for how SAM scores related to scores obtained from the Functional Independence Measure (FIM) and Barthel Score Index (BSI). To assess the SAM tool's reliability, a Cronbach's alpha coefficient was calculated. Utility of the SAM tool was evidenced by documenting its administration time. RESULTS: One hundred patients participated in this study. The SAM tool had a Cronbach's alpha coefficient of 0.75 and took a mean time of 5.36 min to complete. The capability to self-medicate section of the SAM tool had strong correlations with the FIM (r = 0.485) and BSI (r = 0.472) data, respectively, and the total SAM tool had moderate and strong correlations with the nurses' (r = 0.315) and tool administrator's (r = 0.632) perceptions of patients' ability to self-administer, respectively. Bland-Altman and ROC curve analyses showed poor agreement between the total SAM tool score and the nurses' perceptions. CONCLUSIONS: The SAM tool demonstrated acceptable overall internal consistency. It only requires a short time to be completed and is more objective than seeking out health professionals' perceptions. Additional research is needed to further validate this approach to determining patients' ability to self medicate. PMID- 23735814 TI - Effects of species-specific leaf characteristics and reduced water availability on fine particle capture efficiency of trees. AB - Trees can improve air quality by capturing particles in their foliage. We determined the particle capture efficiencies of coniferous Pinus sylvestris and three broadleaved species: Betula pendula, Betula pubescens and Tilia vulgaris in a wind tunnel using NaCl particles. The importance of leaf surface structure, physiology and moderate soil drought on the particle capture efficiencies of the trees were determined. The results confirm earlier findings of more efficient particle capture by conifers compared to broadleaved plants. The particle capture efficiency of P. sylvestris (0.21%) was significantly higher than those of B. pubescens, T. vulgaris and B. pendula (0.083%, 0.047%, 0.043%, respectively). The small leaf size of P. sylvestris was the major characteristic that increased particle capture. Among the broadleaved species, low leaf wettability, low stomatal density and leaf hairiness increased particle capture. Moderate soil drought tended to increase particle capture efficiency of P. sylvestris. PMID- 23735815 TI - Ecological risk of estrogenic endocrine disrupting chemicals in sewage plant effluent and reclaimed water. AB - The long-term ecological risk of micropollutants, especially endocrine disrupting chemicals (EDCs) has threatened reclaimed water quality. In this study, estrogenic activity and ecological risk of eight typical estrogenic EDCs in effluents from sewage plants were evaluated. The estrogenic activity analysis showed that steroidal estrogens had the highest estrogenic activity (ranged from 10(-1) to 10(3) ng-E2/L), phenolic compounds showed weaker estrogenic activity (mainly ranged from 10(-3) to 10 ng-E2/L), and phthalate esters were negligible. The ecological risk of the estrogenic EDCs which was characterized by risk quotient ranged from 10(-4) to 10(3), with an order in descending: steroids estrogens, phenolic compounds and phthalate esters. The eight estrogenic EDCs were scored and sorted based on the comparison of the estrogenic activity and the ecological risk, suggesting that 17alpha-ethynylestradiol (EE2), estrone (E1) and estradiol (E2) should be the priority EDCs to control in municipal sewage plants. PMID- 23735816 TI - Does thermal history influence the tolerance of temperate gorgonians to future warming? AB - To date, several studies have provided evidence that thermal stress affects the growth, survival and physiology of tropical and temperate macroinvertebrate species. However, few studies have focused on subtidal temperate species and the potential differential thermal tolerances of populations dwelling under contrasting temperature conditions. To assess the role that environmental history has on the response of the temperate gorgonian Eunicella singularis to thermal stress, we compared populations dwelling in the coldest and warmest areas of the NW Mediterranean Sea. Our results show that E. singularis populations from both areas exhibited a high resistance to thermal stress; however, populations from warmer areas had an increased tolerance to thermal stress. Specifically, the upper thermal limits found for cold and warm populations were 28 and 29 degrees C, respectively. The higher resistance of E. singularis colonies to thermal stress found in this study compared to the field temperature conditions during recent mass mortality events highlights that performing further thermotolerance experiments under contrasting levels of feeding is necessary to fully assess the tolerance thresholds displayed by both study populations. To our knowledge, this study provides the first evidence for the role of thermal history in shaping the thermotolerance responses of Mediterranean marine invertebrates dwelling under contrasting temperature environments. PMID- 23735817 TI - Evaluation of WHO immunologic criteria for treatment failure: implications for detection of virologic failure, evolution of drug resistance and choice of second line therapy in India. AB - INTRODUCTION: Routine HIV viral load (VL) testing is not available in India. We compared test performance characteristics of immunologic failure (IF) against the gold standard of virologic failure (VF), examined evolution of drug resistance among those who stayed on a failing regimen because they did not meet criteria for IF and assessed implications for second-line therapy. METHODS: Participants on first-line highly active antiretroviral therapy (HAART) in Bangalore, India, were monitored for 24 months at six-month intervals, with CD4 count, VL and genotype, if VL>1000 copies/ml. Standard WHO criteria were used to define IF; VF was defined as having two consecutive VL>1000 copies/ml or one VL>10,000 copies/ml. Resistance was assessed using standard International AIDS Society-USA (IAS-USA) recommendations. RESULTS: Of 522 participants (67.6% male, mean age of 37.5; 85.1% on nevirapine-based and 40.4% on d4T-containing regimens), 57 (10.9%) had VF, 38 (7.3%) had IF and 13 (2.5%) had both VF and IF. The sensitivity of immunologic criteria to detect VF was 22.8%, specificity was 94.6% and positive predictive value was 34.2%. Forty-four participants with VF only continued on their failing first-line regimen; by the end of the study period, 90.9% had M184V, 63.6% had thymidine analogue mutations (TAMs), 34.1% had resistance to tenofovir, and 63.6% had resistance to etravirine. CONCLUSIONS: WHO IF criteria have low sensitivity for detecting VF, and the presence of IF poorly predicts VF. Relying on CD4 counts leads to unnecessary switches to second-line HAART and continuation of failing regimens, jeopardizing future therapeutic options. Universal access to VL monitoring would avoid costly switches to second-line HAART and preserve future treatment options. PMID- 23735818 TI - A single formula to describe radiation-induced protein relocalization: towards a mathematical definition of individual radiosensitivity. AB - Immunofluorescence with antibodies against DNA damage repair and signaling protein is revolutionarising the estimation of the genotoxic risk. Indeed, a number of stress response proteins relocalize in nucleus as identifiable foci whose number, pattern and appearance/disappearance rate depend on several parameters such as the stress nature, dose, time and individual factor. Few authors proposed biomathematical tools to describe them in a unified formula that would be relevant for all the relocalizable proteins. Based on our two previous reports in this Journal (Foray et al., 2005; Gastaldo et al., 2008), we considered that foci response to stress is composed of a recognition and a repair phase, both described by an inverse power function provided from a Euler's Gamma distribution. The resulting unified formula called "Bodgi's function" is able to describe appearance/disappearance kinetics of nuclear foci after any condition of genotoxic stress. By applying the Bodgi's formula to DNA damage repair data from 45 patients treated with radiotherapy, we deduced a classification of human radiosensitivity based on objective molecular criteria, notably like the number of unrepaired DNA double-strand breaks and the radiation-induced nucleo-shuttling of the ATM kinase. PMID- 23735819 TI - Cardiovascular toxicity of epoetin-alfa in patients with chronic kidney disease. AB - BACKGROUND: Recombinant erythropoietin has become a routine component of care of patients with chronic kidney disease reducing the need for blood transfusions but raising the risks for cardiovascular events. We undertook this secondary analysis of subjects enrolled in the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial to examine the interrelationships between epoetin alfa maintenance doses utilized and achieved hemoglobin (Hb) irrespective of treatment target and randomized allocation. METHODS: We performed a post hoc analysis from the CHOIR trial. Inclusion criteria were Hb <11.0 g/dl and estimated glomerular filtration rates of 15-50 ml/min/1.73 m(2). To be included in the present analysis, subjects needed to be free of the composite event at 4 months, receive epoetin-alfa, and have >=1 postbaseline Hb measurement. The mean weekly dose of epoetin-alfa received up to the time of first event or censure was the main exposure variable, while the achieved Hb at month 4 was the confounder representing the subject's underlying response to treatment. The primary outcome was the composite of death, heart failure hospitalization, stroke, or myocardial infarction. A Cox proportional hazard regression model was used in time-to-event analysis. RESULTS: Among 1,244 subjects with complete data, the average weekly dose of epoetin-alfa ranged 143.3-fold from 133 to 19,106 units/week at the time of first event or censure. Cox proportional hazard analysis found that those in the middle tertile of Hb achieved (>11.5 to <12.7 g/dl) and the lowest tertile of epoetin-alfa dose exposure level (<5,164 units/week) had the lowest risk. Irrespective of Hb achieved, the relative risk in the highest tertile (>10,095 units/week) of epoetin-alfa dose exposure level was significantly escalated (hazard ratios ranged from 2.536 to 3.572, p < 0.05, when compared to the group of middle Hb tertile and lowered dose tertile). In a multivariable model that adjusted for achieved Hb, albumin, cholesterol, age, prior heart failure, prior stroke, prior deep venous thrombosis, atrial fibrillation or malignancy, the average weekly dose had a significant (p = 0.005) relative risk of 1.067 per 1,000 units of epoetin-alfa for the primary end point. CONCLUSIONS: In the CHOIR trial, average epoetin-alfa doses >10,095 units/week were associated with increased risks for cardiovascular events irrespective of the Hb achieved within the first 4 months of treatment. These data suggest the weekly epoetin-alfa dose and not the Hb achieved was a principal determinant in the primary outcome observed implicating a cardiovascular toxicity of this erythrocyte-stimulating agent. PMID- 23735820 TI - Hepatitis E outbreak, Dadaab refugee camp, Kenya, 2012. PMID- 23735821 TI - Serum protein identification and quantification of the corona of 5, 15 and 80 nm gold nanoparticles. AB - When nanoparticles (NP) enter the body they come into contact with body fluids containing proteins which can adsorb to their surface. These proteins may influence the NP interactions with the biological vicinity, eventually determining their biological fate inside the body. Adsorption of the most abundantly binding proteins was studied after an in vitro 24 hr incubation of monodisperse, negatively charged 5, 15 and 80 nm gold spheres (AuNP) in mouse serum by a two-step analysis: proteomic protein identification and quantitative protein biochemistry. The adsorbed proteins were separated from non-adsorbed proteins by centrifugation and gel electrophoresis and identified using a MALDI TOF-MS-Proteomics-Analyzer. Quantitative analysis of proteins in gel bands by protein densitometry, required the focus on predominantly binding serum proteins. Numerous proteins adsorbed to the AuNP depending on their size, e.g., apolipoproteins or complement C3. The qualitative and quantitative amount of adsorbed proteins differed between 5, 15 and 80 nm AuNP. Band intensities of adsorbed proteins decreased with increasing AuNP sizes based not only on their mass but also on their surface area. Summarizing, the AuNP surface is covered with serum proteins containing transport and immune related proteins among others. Hence, protein binding depends on the size, surface area and curvature of the AuNP. PMID- 23735822 TI - Molecular mechanisms of depression: perspectives on new treatment strategies. AB - Depression is a multicausal disorder and has been associated with the risk to develop cancer, dementia, diabetes, epilepsy and stroke. As a metabolic disorder depression has been associated with obesity, diabetes, insulin sensitivity, neuropeptide Y, glucose regulation, poor glycemic control, glucagone-like peptide 1, cholezystokinin, ghrelin, leptin, the endocannabinoid system, insulin-like growth factor and gastrin-releasing peptide. As a cardiovascular disease a close relationship exists between depression and blood pressure, heart rate, norepinephrine, sympathetic tone, vascular resistance, blood viscosity, plasma volume, intima thickness and atherosclerosis. Additionally blood coagulation, fibrinolysis, D-dimers, plasminogen activator inhibitor-1 protein, platelet activation, VEGF, plasma nitric oxide and its synthase are changed in depressed patients. As an endocrinological and stress disorder depression has been connected with the concentration of free T4, TSH, CRH, arginine vasopressin, corticotrophin, corticosteroid release and ACTH. Depression as an inflammatory disorder is mediated by pro-inflammatory cytokines, interleukin-1, interleukin-6, TNF-alpha, soluble interleukin-2 receptors, interferon-alpha, interleukin 8, interleukin-10, hs-CRP, acute phase proteins, haptoglobin, toll like receptor 4, interleukin-1beta, mammalian target of rapamycin pathway, substance P, cyclooxygenase-2, prostaglandin-E2, lipid peroxidation levels and acid sphingomyelinase. Nutritional factors might influence depression risk, i.e. the consumption of folate, omega-3 fatty acids, monounsaturated fatty acids, olive oil, fish, fruits, vegetables, nuts, legumes, vitamin B6 and vitamin B12. The neurodegenerative hypothesis of depression explains decreased hippocampal volumes in depressed patients and changes of neurotrophic support by BDNF, erythropoietin, GDNF, FGF-2, NT3, NGF and growth hormone. In this context, a fast neuroprotective and antidepressant effect has also been observed by ketamine, which acts via the glutamatergic system. Hence, GABA, AMPA, EAAT, NMDA- and metabotropic glutamate receptors (mGluR1 to mGluR8) have gained interest in depression recently. Alternative, causative or also easy available treatment strategies beyond serotonin and noradrenaline reuptake inhibition might be a major topic of future psychiatric care. In this review, an attempt is made to overview concepts of the disease and search for perspectives on antidepressant treatment strategies beyond approved medications. PMID- 23735823 TI - Discrete model of periodic pattern formation through a combined autocrine juxtacrine cell signaling. AB - We model the formation of periodic patterns of gene expression in epithelial cell sheets driven by autocrine signaling coupled to juxtacrine lateral inhibition. The mathematical model is based on a continuous description of the extracellular matrix and a discrete cell-level description of the layer of cells, coupling the dynamics of diffusible ligands to the threshold-controlled cell-autonomous regulation with randomly fluctuating production rates. The results of numerical simulations indicate that propagating signaling waves emerge in a certain parametric domain, leading to the formation of a variety of either periodic or irregular patterns. For some selections of parameters, a propagating stripe of uniform expression leaves in its wake stationary periodic arrays. Coupling of autocrine and juxtacrine cell communication is essential for the pattern regularity and for the selection of expression patterns. Moreover, weak but non vanishing noise levels are essential for the formation of regular patterns. Additional autocrine and cell-autonomous regulatory interactions can be introduced to increase the spacing of a periodic pattern. PMID- 23735824 TI - Procedural Variations in the Stroop and the Symbol Digit Modalities Test: impact on patients with multiple sclerosis. AB - Decreased information processing speed is often cited as the primary cognitive deficit occurring in conjunction with multiple sclerosis (MS). Two common tools for assessing this deficit are the Stroop Test and the Symbol Digit Modalities Test (SDMT). However, there are procedural variations in these rapid serial processing (RSP) tests pertaining to the response format (e.g., verbal or manual) and the administration format (e.g., paper-based or computerized). The present study was designed to assess whether such variations impact MS patients' and healthy individuals' performance on these tests. In Experiment 1, we showed that response formats in which either the experimenter or the participant was responsible for advancing the items on computerized versions of the Stroop Test and the SDMT were basically equivalent in terms of distinguishing between patients and controls. In Experiment 2, we found differences between administration formats that appear to interact with some of the disease-related features of MS. Understanding how procedural variations differentially impact patients and controls can be useful for interpreting what RSP tests reveal about the cognitive impact of MS. PMID- 23735825 TI - (+)-Altholactone exhibits broad spectrum immune modulating activity by inhibiting the activation of pro-inflammatory cytokines in RAW 264.7 cell lines. AB - An evaluation of Indonesian plants to identify compounds with immune modulating activity revealed that the methanolic extract of an Alphonsea javanica Scheff specimen possessed selective anti-inflammatory activity in a nuclear factor-kappa B (NF-kappaB) luciferase and MTT assay using transfected macrophage immune (Raw264.7) cells. A high-throughput LC/MS-ELSD based library approach of the extract in combination with the NF-kappaB and MTT assays revealed the styryl lactone (+)-altholactone (2) was responsible for the activity. Compound 2, its acetylated derivate (+)-3-O-acetylaltholactone (3), and the major compound of this class, (+)-goniothalmin (1), were further evaluated to determine their anti inflammatory potential in the NF-kappaB assay. Concentration-response studies of 1-3 indicated that only 2 possessed NF-kappaB based anti-inflammatory activity. Compound 2 reduced the LPS-induced NO production, phosphorylation of IkappaBalpha, and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) using Western blot analysis. Further studies using qPCR indicated 2 reduced the expression of eight pro-inflammatory cytokines/enzymes (0.8-5.0MUM) which included: COX-2, iNOS, IP-10, IL-1beta, MCP-1, GCS-F, IL-6 and IFN-beta. These results indicated that 2 displays broad spectrum immune modulating activity by functioning as an anti-inflammatory agent against LPS induced NF-kappaB signaling. Conversely the selective cytotoxicity and in vivo anti-tumor and anti-inflammatory activity previously reported for 1 do not appear to arise from a mechanism that is linked to the NF-kappaB immune mediated pathway. PMID- 23735826 TI - Novel synthetic acridine derivatives as potent DNA-binding and apoptosis-inducing antitumor agents. AB - Acridine derivatives have been explored as DNA-binding anticancer agents. Some derivatives show undesired pharmacokinetic properties and new derivatives need to be explored. In this work, a series of novel acridine analogues were synthesized by modifying previously unexplored linkers between the acridine and benzene groups and their antiproliferative activity and the DNA-binding ability were evaluated. Among these derivatives, compound 5c demonstrated DNA-binding capability and topoisomerase I inhibitory activity. In K562 cell lines, 5c induced apoptosis through mitochondria-dependent intrinsic pathways. These data suggested that compound 5c and other acridine derivatives with modified linkers between the acridine and benzene groups might be potent DNA-binding agents. PMID- 23735827 TI - Pt(II) complexes with (N,N') or (C,N,E)(-) (E=N,S) ligands: cytotoxic studies, effect on DNA tertiary structure and structure-activity relationships. AB - The cytotoxic activity of two series of platinum(II) complexes containing the polyfunctional imines R(1)-CHN-R(2) [R(1)=phenyl or ferrocenyl unit and R(2)=(CH2)n-CH2-NMe2 where n=1 or 2) (1 and 2) or C6H4-2-SMe (3)] acting as a bidentate (N,N') (4-7) or terdentate [C(phenyl or ferrocenyl),N,N'](-) (8-10) or [C(ferrocenyl),N,S](-) ligand (11) in front of A549 lung, MDA-MB231 breast and HCT116 colon human adenocarcinoma cell lines is reported. The results reveal that most of the platinum(II) complexes are active against the three assayed lines and compounds 6, 7 and the platinacycles 10 and 11 exhibit a remarkable antiproliferative activity, even greater than cisplatin itself, in the cisplatin resistant HCT116 human cancer cell line. Electrophoretic DNA migration studies showed that most of them modify the DNA tertiary structure in a similar way as the reference cisplatin. Solution studies of a selection of the most relevant complexes have also been performed in order to test: (a) their stability in the aqueous biological medium and/or the formation of biologically active species and (b) their proclivity to react with 9-methylguanine (9-MeG), as a model nucleobase. Computational studies at DFT level have also been performed in order to explain the different solution behaviour of the complexes and their proclivity to react with the nucleobase. PMID- 23735828 TI - Identification of 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6 dihydropyrazolo[3,4-c]carbazoles as new Pim kinase inhibitors. AB - New 1,6-dihydropyrazolo[4,3-c]carbazoles and 3,6-dihydropyrazolo[3,4-c]carbazoles were prepared and evaluated for their Pim kinase inhibitory potencies as well as their antiproliferative activities toward two prostatic cancer cell lines. Pyrazolocarbazole 15a was found to be a potent Pim kinase modulator with inhibitory potency toward the three isoforms. Compound 6c strongly inhibited Pim 3 with weaker effect toward Pim-1 and Pim-2, and thus could be used as an interesting molecular tool to study Pim-3 biological functions. PMID- 23735829 TI - Synthesis and biological evaluation of novel tamoxifen analogues. AB - A collection of compounds, structurally related to the anticancer drug tamoxifen, used in breast cancer therapy, were designed and synthesized as potential anticancer agents. McMurry coupling reaction was used as the key synthetic step in the preparation of these analogues and the structural assignment of E, Z isomers was determined on the basis of 2D-NOESY experiments. The compounds were evaluated for their antiproliferative activity on breast cancer (MCF-7), cervix adenocarcinoma (HeLa) and biphasic mesothelioma (MSTO-211H) human tumor cell lines. The estrogen like properties of the novel compounds were compared with those of the untreated controls using an estrogen responsive element-based (ERE) luciferase reporter assay and compared to 17beta-estradiol (E2). Finally, with the aim to correlate the antiproliferative activity with an intracellular target(s), the effect on relaxation activity of DNA topoisomerases I and II was assayed. PMID- 23735830 TI - Synthesis and biological evaluation of 4,5-dihydro-1H-pyrazole derivatives as potential nNOS/iNOS selective inhibitors. Part 2: Influence of diverse substituents in both the phenyl moiety and the acyl group. AB - In a preliminary article, we reported a series of 4,5-dihydro-1H-pyrazole derivatives as neuronal nitric oxide synthase (nNOS) inhibitors. Here we present the data about the inhibition of inducible nitric oxide synthase (iNOS) of these compounds. In general, we can confirm that these pyrazoles are nNOS selective inhibitors. In addition, taking these compounds as a reference, we have designed and synthesized a series of new derivatives by modification of the heterocycle in 1-position, and by introduction of electron-donating or electron-withdrawing substituents in the aromatic ring. These derivatives have been evaluated as nNOS and iNOS inhibitors in order to identify new compounds with improved activity and selectivity. Compound 3r, with three methoxy electron-donating groups in the phenyl moiety, is the most potent nNOS inhibitor, showing good selectivity nNOS/iNOS. PMID- 23735832 TI - Exploring DOXP-reductoisomerase binding limits using phosphonated N-aryl and N heteroarylcarboxamides as DXR inhibitors. AB - DOXP-reductoisomerase (DXR) is a validated target for the development of antimalarial drugs to address the increase in resistant strains of Plasmodium falciparum. Series of aryl- and heteroarylcarbamoylphosphonic acids, their diethyl esters and disodium salts have been prepared as analogues of the potent DXR inhibitor fosmidomycin. The effects of the carboxamide N-substituents and the length of the methylene linker have been explored using in silico docking studies, saturation transfer difference NMR spectroscopy and enzyme inhibition assays using both EcDXR and PfDXR. These studies indicate an optimal linker length of two methylene units and have confirmed the importance of an additional binding pocket in the PfDXR active site. Insights into the constraints of the PfDXR binding site provide additional scope for the rational design of DXR inhibitors with increased ligand-receptor interactions. PMID- 23735833 TI - Pharmacokinetics and pharmacodynamics of orally administered clonidine: a model based approach. AB - BACKGROUND/AIMS: The oral clonidine test is a diagnostic procedure performed in children with suspected growth hormone (GH) deficiency. It is associated with untoward effects, including bradycardia, hypotension and sedation. Serum clonidine levels have not previously been assessed during this test. METHODS: In 40 children referred for an oral clonidine test, blood samples were drawn for clonidine and GH. Vital statistics and sedation scores were recorded until 210 min post-dose. We explored the relationship between clonidine concentrations and effects such as GH peak and blood pressure. RESULTS: Of 40 participants, 5 children were GH deficient. Peak clonidine concentrations of 0.846 +/- 0.288 ng/ml were reached after 1 h. Serum levels declined slowly, with concentrations of 0.701 +/- 0.189 ng/ml 210 min post-dose. A large interindividual variation of serum levels was observed. During the procedure, systolic blood pressure dropped by 12.8%, diastolic blood pressure by 19.7% and heart rate by 8.4%. Moderate sedation levels were observed. Concentration-effect modeling showed that the amount of GH available for secretion as determined by previous bursts was an important factor influencing GH response. CONCLUSION: Clonidine concentrations during the test were higher than necessary according to model-based predictions. A lower clonidine dose may be sufficient and may produce fewer side effects. PMID- 23735834 TI - 11C-Acetate clearance as an index of oxygen consumption of the right myocardium in idiopathic pulmonary arterial hypertension: a validation study using 15O labeled tracers and PET. AB - Idiopathic pulmonary arterial hypertension (IPAH) results in increased right ventricular (RV) workload and oxygen demand. It has been shown that myocardial oxygen consumption (MVO2) of the hypertrophied right ventricle of IPAH patients can be measured using PET and (15)O-labeled tracers. This method is, however, not very suitable for routine clinical practice. The purpose of the present study was to assess whether MVO2 can also be determined in the right ventricle of IPAH patients from the clearance of (11)C-acetate, a simple method that is in use for MVO2 measurements of the left myocardium. METHODS: Seventeen of 26 IPAH patients performed the total PET study. Nine other patients were scanned only for (11)C acetate. (15)O-H2O, (15)O-O2, and (15)O-CO scans were used to derive RV flow, oxygen extraction fraction, and blood volume, respectively, from which RV MVO2 was calculated. The rate of clearance determined by monoexponential curve fitting (K(mono)) and the efflux rate constant k2 were derived from the (11)C-acetate scan. The RV rate-pressure product was also determined by means of right heart catheterization, as an index of the RV MVO2, and was calculated as the product of systolic pulmonary artery pressure and heart rate. RESULTS: Both (11)C-acetate clearance rates, K(mono) (R(2) = 0.41, P = 0.006) and k2 (R(2) = 0.45, P = 0.003), correlated with RV MVO2. They also correlated with RV rate-pressure product (K(mono), R(2) = 0.41, P = 0.0005; k2, R(2) = 0.48, P < 0.0001). CONCLUSION: (11)C-acetate clearance rates correlated moderately with quantitative RV MVO2 measurements in IPAH. Therefore, (11)C-acetate PET can be used only as an index of RV oxidative metabolism in IPAH patients. PMID- 23735835 TI - Transthyretin-thyroid hormone internalization by trophoblasts. AB - Normal fetal neurological development depends on a regulated supply of maternal thyroid hormone (TH). We have previously demonstrated that transthyretin (TTR) a TH binding protein, is synthesized, secreted and internalized by trophoblast cells and may provide a route for the transfer of TH from mother to fetus. Our objective was to determine if a member of the low-density lipoprotein receptor family mediates TTR or TTR-TH internalization. TTR-TH internalization by JEG-3 cells is reduced in the presence of receptor associated protein (RAP) or albumin suggesting that TTR-TH is internalized through an LDL-receptor dependent endocytic process. PMID- 23735831 TI - Recent syntheses of PI3K/Akt/mTOR signaling pathway inhibitors. AB - This review focuses on the syntheses of PI3K/Akt/mTOR inhibitors that have been reported outside of the patent literature in the last 5years but is largely centered on synthetic work reported in 2011 and 2012. While focused on syntheses of inhibitors, some information on in vitro and in vivo testing of compounds is also included. Many of these reported compounds are reversible, competitive adenosine triphosphate (ATP) binding inhibitors, so given the structural similarities of many of these compounds to the adenine core, this review presents recent work on inhibitors based on where the synthetic chemistry was started, that is, inhibitor syntheses which started with purines/pyrimidines are followed by inhibitor syntheses which began with pyridines, pyrazines, azoles, and triazines then moves to inhibitors which bear no structural resemblance to adenine: liphagal, wortmannin and quercetin analogs. The review then finishes with a short section on recent syntheses of phosphotidyl inositol (PI) analogs since competitive PI binding inhibitors represent an alternative to the competitive ATP binding inhibitors which have received the most attention. PMID- 23735836 TI - Efficient cytosolic delivery mediated by polymersomes facilely prepared from a degradable, amphiphilic, and amphoteric copolymer. AB - To solve problems in polymersome preparation caused by liposolubility of copolymers and to improve the cytosolic delivery efficiency of polymersomes to drugs, a lipopolysaccharide-amine (LPSA) copolymer with amphotericity and amphiphilicity is developed. LPSA contains two hydrophilic oppositely charged blocks (anionic oxidized alginate (OA), cationic polyethyleneimine (PEI 1.8 k)) and one hydrophobic block (cholesteryl), where OA is the backbone and cholesteryl grafted PEI is the side chain. The two hydrophilic blocks first guarantee that LPSA will dissolve in water, and then help polymersome formation via electrostatic interactions to generate water insoluble interpolyelectrolyte complexes, which supplement the hydrophobic part to reach the right hydrophilicity/hydrophobicity ratio, and thus realize a one-step self-assembly of polymersomes in water. Our results show LPSA nanopolymersomes (LNPs) have low cytotoxicity and degradability, and an excellent ability to enter cells. TEM observation demonstrates that LNPs are entrapped in endosomes after endocytosis, and are then released to cytosols because of their strong endosomal escape capacity. As an example of cytosolic delivery to bioactive molecules, pDNA is delivered in mesenchymal stem cells, and more than 95% of cells express a large target protein, indicating that LNPs have high cytosolic delivery efficiency. Our study provides a novel, easy, and universal method to design copolymers for the preparation of polymersomes as efficient cytosolic delivery nanocarriers. PMID- 23735838 TI - Comparison of different breast planning techniques and algorithms for radiation therapy treatment. AB - This work aims at investigating the impact of treating breast cancer using different radiation therapy (RT) techniques--forwardly-planned intensity modulated, f-IMRT, inversely-planned IMRT and dynamic conformal arc (DCART) RT- and their effects on the whole-breast irradiation and in the undesirable irradiation of the surrounding healthy tissues. Two algorithms of iPlan BrainLAB treatment planning system were compared: Pencil Beam Convolution (PBC) and commercial Monte Carlo (iMC). Seven left-sided breast patients submitted to breast-conserving surgery were enrolled in the study. For each patient, four RT techniques--f-IMRT, IMRT using 2-fields and 5-fields (IMRT2 and IMRT5, respectively) and DCART - were applied. The dose distributions in the planned target volume (PTV) and the dose to the organs at risk (OAR) were compared analyzing dose-volume histograms; further statistical analysis was performed using IBM SPSS v20 software. For PBC, all techniques provided adequate coverage of the PTV. However, statistically significant dose differences were observed between the techniques, in the PTV, OAR and also in the pattern of dose distribution spreading into normal tissues. IMRT5 and DCART spread low doses into greater volumes of normal tissue, right breast, right lung and heart than tangential techniques. However, IMRT5 plans improved distributions for the PTV, exhibiting better conformity and homogeneity in target and reduced high dose percentages in ipsilateral OAR. DCART did not present advantages over any of the techniques investigated. Differences were also found comparing the calculation algorithms: PBC estimated higher doses for the PTV, ipsilateral lung and heart than the iMC algorithm predicted. PMID- 23735837 TI - Effects of three times weekly eight-hour nocturnal hemodialysis on volume and nutritional status. AB - BACKGROUND: This prospective cohort study compared the changes in body water composition and nutritional parameters measured with multifrequency bioimpedance analysis between 8-hour three times weekly nocturnal hemodialysis (NHD) and 4 hour conventional hemodialysis (CHD) patients. PATIENTS AND METHODS: 55 patients on CHD and 57 patients on NHD were included in the study. Multifrequency bioimpedance analysis was performed at baseline and at the 12th month. The primary outcomes of the study were changes in extracellular water (ECW), fat mass, dry lean mass and phase angle. Secondary outcomes of the study included changes in blood pressure and biochemical parameters related to nutrition and inflammation. RESULTS: ECW/height values decreased in the NHD group, while they increased in the CHD group. Fat mass, dry lean mass, and serum albumin increased and high sensitive CRP decreased in the NHD group but did not change in the CHD group. When changes in parameters from baseline to the 12th month between the groups were compared, NHD was associated with improvement in volume parameter including ECW/height (difference -0.44 l/m, p < 0.001). Change in blood pressure was not different between the groups, however requirement for antihypertensive medication decreased from 26.5 to 8.5% in the NHD group (p = 0.002). NHD was also associated with increases in fat mass (difference 1.8 kg, p < 0.001), dry lean mass (difference 0.6 kg, p = 0.006), serum albumin (difference 0.19 g/dl, p < 0.001) and cholesterol (difference 18.8 mg, p < 0.001). Phase angle values decreased in the CHD group but did not change in the NHD group (difference between the groups 0.37 degrees , p = 0.04). CONCLUSION: This study revealed that longer HD facilitates volume control and improves nutritional status. PMID- 23735839 TI - Identification of genes influencing formation of the Type III Brush Hair in Yangtze River Delta white goats by differential display of mRNA. AB - Yangtze River Delta white goat is an exclusive indigenous Chinese goat breeds that can produce Brush Hair specialized in making valuable writing brush. The high-grade (Type III) Brush Hair is conical coarse hair but with a tip, which only grows in the cervical carina and back regions of Yangtze River Delta white goats. Screening of genes influencing the formation of Type III Brush Hair was conducted using differential display of mRNA technique in skin including the hair follicles of different goat groups and the differential bands were identified using reverse Northern dot blot, and the positive bands were subsequently cloned and sequenced. The results showed that 20 differentially displayed bands were obtained, seven of which were identified positive as expressed in skin. Three of these seven cDNAs were homologous to certain sequences from GenBank and the other four were respectively homologous to CKLF-like MARVEL transmembrane domain containing 3 (CMTM3), S100 calcium binding protein A4 (S100A4), protein kinase inhibitor gamma (PKIG) and fibulin 1-D. The study would provide a new view to elucidate their roles in hair growth and hair follicle cycle and increase our understanding of the formation of Type III Brush Hair. PMID- 23735840 TI - SUZ12 depletion suppresses the proliferation of gastric cancer cells. AB - BACKGROUND/AIMS: SUZ12 and EZH2 are two main components of polycomb repressive complex 2 (PRC2) that is known to be of great importance in tumorigenesis. EZH2 has been reported to play a vital role in pathogenesis of human cancer. However, whether SUZ12 has equivalent roles in tumorigenesis has not been demonstrated. Here, we investigated a possible role of SUZ12 for the proliferation of gastric cancer cells. METHODS: Western-blot analysis was used to detected the levels of SUZ12, H3K27me3, EZH2 and p27 in ten gastric cell lines. SUZ12 was depleted by RNA interference. Cell cycle was detected by flow cytometry. Luciferase assays was to analyze whether miR-200b directly regulate SUZ12. RESULTS: We found that SUZ12 depletion mediated by RNA interference (RNAi) led to a reduction of gastric cell numbers and arrested the cell cycle at G1/S point. As an important G1/S phase inhibitory gene, p27 is re-induced to some extent by SUZ12 knockdown. Furthermore, we demonstrated that SUZ12 was directly downregulated by miR-200b. CONCLUSION: We provide evidence suggesting that SUZ12 may be a potential therapeutic target for gastric cancer. PMID- 23735841 TI - Sublingual microvascular glycocalyx dimensions in lacunar stroke patients. AB - BACKGROUND: Cerebral small vessel disease is thought to result from endothelial dysfunction. The glycocalyx, lining the endothelium, is a major determinant of endothelial function. The glycocalyx is partially accessible to flowing red blood cells at its luminal side, called the perfused boundary region (PBR). Glycocalyx damage results in increased PBR, which can be measured in the sublingual microvasculature. We tested whether PBR is increased in patients with cerebral small vessel disease, i.e. lacunar stroke patients, and further distinguished patients with presence of white matter lesions as a sign of extensive cerebral small vessel disease. METHODS: We used sidestream dark field imaging of the sublingual microcirculation in 31 lacunar stroke patients (6 with and 25 without white matter lesions) and 19 healthy controls. In each subject, automatic image analyzing software analyzed PBR in more than 3,000 vessel segments and the average dimension of glycocalyx PBR was determined in vessel segments with a diameter of 5-25 MUm. RESULTS: PBR did not differ between lacunar stroke patients and healthy controls (2.10 +/- 0.25 vs. 2.08 +/- 0.24 MUm, p = 0.8). However, lacunar stroke patients with white matter lesions had an increased PBR compared with both healthy controls (2.35 +/- 0.23 vs. 2.08 +/- 0.24 MUm, p = 0.03) and patients without white matter lesions (2.04 +/- 0.22 MUm, p = 0.004). CONCLUSIONS: White matter lesions are associated with an increase in the red blood cell permeable part of the sublingual microvascular glycocalyx in lacunar stroke patients. This implicates compromised glycocalyx barrier properties, which is consistent with impaired endothelial function in lacunar stroke patients with white matter lesions. PMID- 23735842 TI - Regional impact of exposure to a polychlorinated biphenyl and polychlorinated dibenzofuran mixture from contaminated rice oil on stillbirth rate and secondary sex ratio. AB - Yusho disease, a polychlorinated biphenyl (PCB) and polychlorinated dibenzofuran (PCDF) mixed poisoning caused by contaminated rice oil, occurred in Japan in 1968. The evidence on reproductive outcome is limited. We therefore evaluated the regional impact of the exposure to the PCB and PCDF mixture on stillbirth rate and secondary sex ratio among the residents in two severely affected areas. We selected the regionally-affected towns of Tamanoura (n=4390 in 1970) and Naru (n=6569) in Nagasaki Prefecture, Japan, for study. We obtained data on stillbirths (spontaneous/artificial) and live-born births (total/male/female) from 1958 to 1994. For a decade and a half after the exposure, an increase in the rate of spontaneous stillbirths coincided with a decrease in the male sex ratio. Compared with the years 1958-1967, the ratios for spontaneous stillbirth rates were 2.16 (95% confidence interval: 1.58 to 2.97) for 1968-1977 and 1.80 (95% confidence interval: 1.25 to 2.60) for 1978-1987. The sex ratio (male proportion) was 0.483 (95% confidence interval: 0.457 to 0.508) in the first 10years after exposure. Exposure to a mixture of PCBs and PCDFs affected stillbirth and sex ratio for a decade and a half after the exposure. PMID- 23735843 TI - Effects of chronic mild stress on rats selectively bred for behavior related to bipolar disorder and depression. AB - To test the possibility that chronic mild stress (CMS) might be unreliable in producing its often-intended outcome (i.e., decreased preference for sucrose, hypothesized to represent depression-relevant anhedonia) because it is typically applied to "normal" rats, a CMS procedure was applied to rats that may possess genetic susceptibility to affective disorders, having had been selectively-bred to show behavior indicative of such disorders. These rat lines were: Hyperactive (HYPER) rats, which show characteristics of bipolar disorder, Swim-test Susceptible (SUS) and Swim-test Resistant (RES) rats, being susceptible or resistant to effects of stress in the swim test, Swim High-active (SwHi) and Swim Low-active (SwLo) rats, which innately show high or low activity in the swim test. These selectively-bred lines were compared to normal, non-selectively bred (NS) rats. During CMS, HYPER rats, both females and males, as well as RES and SwHi rats, showed reduced consumption of a palatable 2% sucrose solution, and reduced preference for sucrose (vs. water) in comparison to non-stressed rats (no CMS) of the same lines. In contrast, CMS produced no decrease in sucrose consumption or in preference for sucrose in normal NS rats, and actually a caused a slight increase in sucrose consumption and preference in male NS rats. Other measures that indicate depression - food intake and motor activity in the home cage - were also assessed. SwLo and SwHi showed greater sensitivity to having their home-cage ambulatory activity reduced by CMS than did NS rats, but no other such differences relative to NS rats were seen for these other measures; thus, changes in sucrose intake or preference could not be explained by a change in caloric intake. These results suggest that the genetic attributes of animals can influence the outcome of CMS, and that the application of CMS to normal, non selected rats may account, at least in part, for the unreliability of CMS in decreasing consumption of palatable substances and decreasing preference for such substances. PMID- 23735844 TI - The ventral hippocampus NMDA receptor/nitric oxide/guanylate cyclase pathway modulates cardiovascular responses in rats. AB - The hippocampus is a limbic structure that is involved in the expression of defensive reactions and autonomic changes in rats. The injection of L-glutamate (L-glu) into the ventral hippocampus (VH) decreases blood pressure and heart rate in anesthetized rats. Activation of NMDA receptors in the VH increases the production of nitric oxide (NO), leading to guanylate cyclase activation. The hypothesis of the present study was that a local NMDA receptor-NO-guanylate cyclase interaction mediates the cardiovascular effects of microinjection of L glu into the VH. Microinjection of increasing doses of L-glu (30, 60 and 200 nmol/200 nL) into the VH of conscious rats caused dose-related pressor and tachycardiac responses. The cardiovascular effects of L-glu were abolished by local pretreatment with: the glutamate receptor antagonist AP-7 (0.4 nmol); the selective neuronal NO synthase (nNOS) inhibitor N(omega)-Propyl-L-arginine (0.04 nmol); the NO scavenger C-PTIO (2 nmol) or the guanylate cyclase inhibitor 1H [1,2,4] oxadiazolol [4,3-a]quinoxalin-1-one (2 nmol). Moreover, these cardiovascular responses were blocked by intravenous pretreatment with: the ganglionic blocker mecamylamine (2mg/Kg); the nonselective beta-adrenergic receptor antagonist propranolol (2mg/Kg); the beta1-adrenergic receptor selective antagonist atenolol (1mg/kg). However, pretreatment with the selective alpha1 adrenergic receptor antagonist prazosin (0,5mg/kg) caused only a small reduction in the pressor response, without affecting the L-glu evoked tachycardia. In conclusion, our results suggest that cardiovascular responses caused by L-glu microinjection into the VH are mediated by NMDA glutamate receptors and involve local nNOS and guanylate cyclase activation. Moreover, these cardiovascular responses are mainly mediated by cardiac sympathetic nervous system activation, with a small involvement of the vascular sympathetic nervous system. PMID- 23735845 TI - Temporary reduction of radiation does not permanently reduce flavonoid glycosides and phenolic acids in red lettuce. AB - Applying transparent daytime screens in greenhouses in cool seasons reduces the amount of energy needed for heating, but also the solar radiation available for crops. This can reduce yield and product quality of leafy vegetables because of constrained photosynthesis and altered biosynthesis. To study this, we cultivated five-week old red leaf lettuce (Lactuca sativa L.) for four weeks in growth chambers under a photosynthetic photon flux density (PPFD) of 225 and 410 MUmol m(-2) s(-1), respectively. Some plants were exchanged between radiation intensities after two weeks. We investigated the concentration of five flavonoid glycosides, three caffeic acid derivatives, reducing sugars as well as plant growth. Remarkably, no significant influence of radiation intensity on the concentration of phenolic acids or anthocyanin glycosides was observed. In contrast, quercetin and luteolin glycoside concentration was between 14 and 34% lower in plants growing under lower compared to higher PPFD. Already after two weeks of cultivation, plants grown under lower PPFD contained less quercetin and luteolin glycosides but they completely compensated if subsequently transferred to higher PPFD until harvest. Hence, marketable lettuce heads which experienced temporary shading followed by an unshaded phase did not contain lower concentrations of flavonoid glycosides or phenolic acids. Also, there was no reduction of head mass in this variant. Our results suggest that saving energy in early growth stages is feasible without losses in yield or health promoting phenolic substances. In addition, there was a close correlation between the concentration of reducing sugars and some flavonoid glycosides, indicating a close metabolic connection between their biosynthesis and the availability of carbohydrates. PMID- 23735846 TI - Evaluation of renal function tests by age and sex to determine emergency department patients' eligibility for cardiac computed tomography. AB - BACKGROUND: Coronary computed tomography angiography (CCTA) can be used for low risk chest pain patients, but presents a risk of contrast-induced nephropathy. OBJECTIVE: We compared, by age and sex, the percent of patients who would become ineligible for CCTA based on serum creatinine (SCr) and glomerular filtration rate (GFR) cutoff points. METHODS: All adult patients who presented to the Emergency Department (ED) with chest pain were screened using their first ED SCr as part of the ROMICAT (Rule Out Myocardial Infarction Using Computer Assisted Tomography) study. This was a secondary analysis of the screening logs of that study. The Modification of Diet in Renal Disease formula was applied to calculate estimated GFR and the percent of patients, by age and sex, meeting commonly applied exclusion criteria using selected SCr and GFR cutoff values. This was our primary outcome. RESULTS: Of 2398 patients screened, 384 (16%) were excluded for high-risk features or technical limitations of CCTA, leaving 2014 patients who were studied; 56% were male. For all cutoff points of SCr (>=1.3 mg/dL, >=1.5 mg/dL, >=1.8 mg/dL), the percent of males excluded significantly exceeded that of females (p < 0.0001 [28.6% males to 18.5% females]; p < 0.0001 [17.4% males to 11.2% females]; p = 0.0004 [10.1% males to 5.8% females], respectively). Conversely, for two of the three cutoff points of GFR (<=60 mL/min/1.73 m(2) and <=45 mL/min/1.73 m(2)), the percent of females excluded significantly exceeded that of males (p < 0.0001 [33.6% females to 25.4% males] and p = 0.0015 [17.6% males to 12.5% females], respectively). CONCLUSIONS: The choice of SCr or GFR to screen patients for CCTA selectively excludes either males or females, respectively. Therefore, individual physicians and institutions must understand the impact of both renal function tests and cutoff points when identifying patients who may be eligible for CCTA. PMID- 23735847 TI - Hyperkalemic paralysis: an elective abortion gone wrong. AB - BACKGROUND: Commonly used abortion agents carry potentially serious side effects for the mother. It is important for emergency physicians to be aware of the medications used in elective abortions from the late first trimester to term. If digoxin is used as an abortifacient, it is injected intrafetally or intraplacentally. With this method there is a chance of extraplacental injection, resulting in maternal systemic digoxin toxicity and serious morbidity or death. OBJECTIVES: This report presents a case report, discusses the risks of digoxin induced abortion, and teaches the reader about the abortifacient agents currently in use, along with their associated complications. CASE REPORT: This is a case of a 28-year-old pregnant woman of approximately 20 weeks gestation, who presented with severe muscular weakness and respiratory failure requiring intubation. She was subsequently found to have hyperkalemic paralysis from digoxin toxicity after an extraplacental injection during the first step of a two-part elective abortion. CONCLUSIONS: It is important for emergency physicians to be aware of the various late first-trimester to term abortifacient agents and procedures being used in obstetrical/gynecological practice, and the potential risks of these interventions. Digoxin toxicity or hyperkalemia should be suspected when a patient presents with severe weakness and respiratory distress after an attempted abortion. PMID- 23735848 TI - A case of vaginal bleeding: a new complication of an advanced technique. PMID- 23735849 TI - Survival of acute hypernatremia due to massive soy sauce ingestion. AB - BACKGROUND: Intentional massive sodium chloride ingestions are rare occurrences and are often fatal. OBJECTIVES: There are a variety of treatment recommendations for hypernatremia, ranging from dialysis to varying rates of correction. We report a case of acute severe hypernatremia corrected with rapid free-water infusions that, to our knowledge, has not been previously reported. CASE REPORT: A 19-year-old man presented to the Emergency Department in a comatose state with seizure-like activity 2 hours after ingesting a quart of soy sauce. He was administered 6 L of free water over 30 min and survived neurologically intact without clinical sequelae. Corrected for hyperglycemia, the patient's peak serum sodium was 196 mmol/L, which, to our knowledge, is the highest documented level in an adult patient to survive an acute sodium ingestion without neurologic deficits. CONCLUSION: Emergency physicians should consider rapidly lowering serum sodium with hypotonic intravenous fluids as a potential management strategy for acute severe hypernatremia secondary to massive salt ingestion. PMID- 23735850 TI - Acute dyspnea in a welder. PMID- 23735851 TI - Fit yourself and take your lungs to heart. PMID- 23735852 TI - Sub-15 nm linewidth gratings using roll-to-roll nanoimprinting and plasma trimming to fabricate flexible wire-grid polarizers with low colour shift. AB - Sub-15 nm-wide gratings with a high aspect ratio of up to 16:1 were fabricated using roll-to-roll nanoimprinting and plasma trimming to achieve high optical performance (up to 12 000:1 extinction ratio with an average transmittance of 82%) and low colour shift (transmittance variation less than 3%) flexible wire grid polarizers for display applications. We applied two imprint platforms onto glass and plastic substrates to identify the optical properties and characteristics of each fabrication process. To enhance the tolerance, reproducibility, and optical performance of the process, the grating profile symmetry and varying residual layer thicknesses were precisely simulated and controlled to achieve the design targets. PMID- 23735854 TI - Elevated testosterone levels in HIV-infected men: case report and a retrospective chart review. AB - Little is known about HIV-infected patients with serum testosterone levels in high normal to elevated ranges. An HIV-infected patient with hepatitis C and unexplained high serum testosterone levels prompted a retrospective chart review into the association of hepatitis C and serum testosterone levels greater than 1000 ng/mL in our clinic. The charts of 1419 male HIV patients were reviewed. Out of 1419 patients, 159 (11%) met the criteria for data analysis. A total of 8 patients had serum testosterone levels greater than 1000 ng/mL. There was no significant correlation between hepatitis C antibody positivity or presence of hepatitis C viremia as measured by viral load, nor was there any significant correlation with CD4+ cell counts. We found a weak positive association between years since reported diagnosis of HIV and high testosterone levels. PMID- 23735853 TI - A survey of a small sample of emergency department and admitted patients asking whether they expect to be tested for HIV routinely. AB - OBJECTIVES: Many US HIV-positive patients are unaware of their infection. Although there are multiple studies assessing the acceptance of testing, there are none that assess the patient's expectations of routine HIV testing. METHODS: Through a prospective, cross-sectional, unfunded, convenience sample survey, we assessed the patient's expectation of testing at a regional medical center serving an indigent population. Also, we compared the providers' predictions of the proportion of patients expecting a test. RESULTS: Of the 69 patients, 23% expected a test. The only factor that correlated with this was their desire to be tested (P = .004). Providers' (N = 59) mean prediction was that 21% of the patients expected a test (range: 0%-100%). The proportion of emergency department (ED) patients wanting a test was 52% (of 30) and internal medicine inpatients were 44% (of 39). CONCLUSIONS: Nearly a quarter of patients expected routine HIV testing. This finding should encourage a review of policies promoting HIV testing, especially within the ED. PMID- 23735855 TI - Airborne outreach: building HIV capacity and strengthening health care systems in rural Botswana. AB - There is a paucity of research demonstrating how HIV-funded services in Africa have improved equity and access to non-HIV services for both HIV-infected and uninfected patients. In this short communication, we describe the impact of an airborne outreach program to provide HIV services to high-HIV burden health facilities in rural Botswana. The analysis demonstrates how this HIV-funded program enhanced access to essential subspecialist services at several rural health facilities across Botswana. PMID- 23735856 TI - Performance of KCl:Eu2+ storage phosphor dosimeters for low-dose measurements. AB - Recent research has demonstrated that europium doped potassium chloride (KCl:Eu(2+)) storage phosphor material has the potential to become the physical foundation of a novel and reusable dosimetry system using either film-like devices or devices similar to thermoluminescent dosimeter chips. The purposes of this work are to quantify the performance of KCl:Eu(2+) prototype dosimeters for low-dose measurements and to demonstrate how it can be incorporated into clinical application for in vivo peripheral dose measurements. Pellet-style KCl:Eu(2+) dosimeters, 6 mm in diameter, and 1 mm thick, were fabricated in-house for this study. The dosimeters were read using a laboratory photostimulated luminescence detection system. KCl:Eu(2+) prototype storage phosphor dosimeter was capable of measuring a dose-to-water as low as 0.01 cGy from a 6 MV photon beam with a signal-to-noise ratio greater than 6. A pre-readout thermal annealing procedure enabled the dosimeter to be read within an hour post-irradiation. After receiving large accumulated doses (~10 kGy), the dosimeters retained linear response in the low-dose region with only a 20% loss of sensitivity comparing to a fresh sample (zero Gy history). The energy dependence encountered during low-dose peripheral measurements could be accounted for via a single point outside-field calibration per each beam quality. With further development the KCl:Eu(2+-)-based dosimeter could become a versatile and durable dosimetry tool with large dynamic range (sub cGy to 100 Gy). PMID- 23735857 TI - Linking genomic lesions with minimal residual disease improves prognostic stratification in children with T-cell acute lymphoblastic leukaemia. AB - Multiple lesions in genes that are involved in cell cycle control, proliferation, survival and differentiation underlie T-cell acute lymphoblastic leukaemia (T ALL). We translated these biological insights into clinical practice to improve diagnostic work-ups and patient management. Combined interphase fluorescence in situ hybridization (CI-FISH), single nucleotide polymorphism (SNP), and gene expression profiles (GEP) were applied in 51 children with T-ALL who were stratified according to minimal residual disease (MRD) risk categories (AIEOP-BFM ALL2000). CI-FISH identified type A abnormalities in 90% of patients. Distribution of each was in line with the estimated incidence in childhood T-ALL: 37.5% TAL/LMO, 22.5% HOXA, 20% TLX3, 7.5% TLX1, and 2.5% NKX2-1. GEP predictions concurred. SNP detected type B abnormalities in all cases, thus linking type A and B lesions. This approach provided an accurate, comprehensive genomic diagnosis and a complementary GEP-based classification of T-ALL in children. Dissecting primary and secondary lesions within MRD categories could improve prognostic criteria for the majority of patients and be a step towards personalized diagnosis. PMID- 23735858 TI - Does a patent foramen ovale influence cognitive function in dialysis patients? AB - BACKGROUND: Patients with chronic kidney disease on dialysis treatment have poorer cognitive function than age- and sex-matched controls. One proposed mechanism is cerebral microembolisation due to material from the dialysis circuit crossing a patent foramen ovale (PFO). METHODS: Cognitive testing was carried out in haemodialysis (HD) patients and peritoneal dialysis (PD) patients. Transthoracic echocardiography was used to identify PFO. Follow-up testing 1 year later enabled comparison of cognitive decline between patients with and without a PFO, and between those undergoing different dialysis modalities. RESULTS: 80 patients (aged 60.4 +/- 15.0 years) were recruited (51 HD patients and 29 PD controls). A PFO was found in 21% of patients. 83% of dialysis patients suffered a decline in one or more cognitive function tests over 1 year. There was a significant difference in only one test between HD patients with or without a PFO. PD patients showed a more rapid cognitive decline than those on HD. CONCLUSIONS: Cognitive decline in dialysis patients is rapid and affects most patients. The presence of a PFO made only subtle differences to the rates of cognitive decline during 1 year of follow-up. Patients with a PFO should not be prevented from considering HD because of concerns of cerebral decline due to microembolisation. PMID- 23735860 TI - When should we measure lipoprotein (a)? AB - Recently published epidemiological and genetic studies strongly suggest a causal relationship of elevated concentrations of lipoprotein (a) [Lp(a)] with cardiovascular disease (CVD), independent of low-density lipoproteins (LDLs), reduced high density lipoproteins (HDL), and other traditional CVD risk factors. The atherogenicity of Lp(a) at a molecular and cellular level is caused by interference with the fibrinolytic system, the affinity to secretory phospholipase A2, the interaction with extracellular matrix glycoproteins, and the binding to scavenger receptors on macrophages. Lipoprotein (a) plasma concentrations correlate significantly with the synthetic rate of apo(a) and recent studies demonstrate that apo(a) expression is inhibited by ligands for farnesoid X receptor. Numerous gaps in our knowledge on Lp(a) function, biosynthesis, and the site of catabolism still exist. Nevertheless, new classes of therapeutic agents that have a significant Lp(a)-lowering effect such as apoB antisense oligonucleotides, microsomal triglyceride transfer protein inhibitors, cholesterol ester transfer protein inhibitors, and PCSK-9 inhibitors are currently in trials. Consensus reports of scientific societies are still prudent in recommending the measurement of Lp(a) routinely for assessing CVD risk. This is mainly caused by the lack of definite intervention studies demonstrating that lowering Lp(a) reduces hard CVD endpoints, a lack of effective medications for lowering Lp(a), the highly variable Lp(a) concentrations among different ethnic groups and the challenges associated with Lp(a) measurement. Here, we present our view on when to measure Lp(a) and how to deal with elevated Lp(a) levels in moderate and high-risk individuals. PMID- 23735859 TI - The use of cholinesterase inhibitors and the risk of myocardial infarction and death: a nationwide cohort study in subjects with Alzheimer's disease. AB - AIMS: Cholinesterase inhibitors (ChEIs) are used for symptomatic treatment of Alzheimer's disease. These drugs have vagotonic and anti-inflammatory properties that could be of interest also with respect to cardiovascular disease. This study evaluated the use of ChEIs and the later risk of myocardial infarction and death. METHODS AND RESULTS: The cohort consisted of 7073 subjects (mean age 79 years) from the Swedish Dementia Registry with the diagnoses of Alzheimer's dementia or Alzheimer's mixed dementia since 2007. Cholinesterase inhibitor use was linked to diagnosed myocardial infarctions (MIs) and death using national registers. During a mean follow-up period of 503 (range 0-2009) days, 831 subjects in the cohort suffered MI or died. After adjustment for confounders, subjects who used ChEIs had a 34% lower risk for this composite endpoint during the follow-up than those who did not [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.56-0.78]. Cholinesterase inhibitor use was also associated with a lower risk of death (HR: 0.64, 95% CI: 0.54-0.76) and MI (HR: 0.62, 95% CI: 0.40-0.95) when analysed separately. Subjects taking the highest recommended ChEI doses (donepezil 10 mg, rivastigmine >6 mg, galantamine 24 mg) had the lowest risk of MI (HR: 0.35, 95% CI: 0.19-0.64), or death (HR: 0.54, 95% CI: 0.43-0.67) compared with those who had never used ChEIs. CONCLUSION: Cholinesterase inhibitor use was associated with a reduced risk of MI and death in a nationwide cohort of subjects diagnosed with Alzheimer's dementia. These associations were stronger with increasing ChEI dose. PMID- 23735861 TI - Prevalence of 25-OH vitamin D deficiency in a population of hemodialysis patients and efficacy of an oral ergocalciferol supplementation regimen. AB - BACKGROUND/AIMS: Optimal dosing regimens for 25-OH vitamin D (VitD) deficiency are unknown in hemodialysis (HD) patients. Our aim was to evaluate the efficacy of prescribing ergocalciferol supplementation based on KDOQI guidelines for chronic kidney disease (CKD) stages III-IV in HD patients. METHODS: We conducted a retrospective study of 96 urban, predominately African-American HD patients at a single-center dialysis unit with VitD insufficiency or deficiency treated with ergocalciferol. Patients were classified as either compliant or non-compliant with supplementation as determined by review of pharmacy records. The primary outcome was VitD levels 6 months after initiation of treatment and secondary outcomes were VitD levels at 11 months, bone/mineral and anemia parameters. RESULTS: The population was predominately African-American (69%) and Hispanic (28%). There were 61 individuals in the compliant group and 35 individuals in the non-compliant group. The compliant group was older but otherwise similar in demographics and co-morbid conditions to the non-compliant group. After 6 months of treatment, the compliant group had a significant increase in VitD level (14.7 +/- 6.0 to 28.7 +/- 10.0 ng/ml, p < 0.0001) compared to the non-compliant group (14.7 +/- 5.5 to 14.8 +/- 7.1 ng/ml, p = 0.95). There were no differences in the incidence of hypercalcemia between the two groups. Except for a decrease in phosphorus in the compliant group (5.6 +/- 1.6 to 4.9 +/- 1.7 mg/dl, p = 0.004), there were no significant difference in bone/mineral or anemia parameters including dosing of darbepoetin. CONCLUSION: An ergocalciferol-prescribing strategy using the KDOQI guidelines for stage III-IV kidney disease in HD patients with VitD deficiency or insufficiency is inadequate to achieve repletion or maintenance of normal VitD levels. PMID- 23735862 TI - PIKfyve sensitivity of hERG channels. AB - BACKGROUND/AIMS: Human ether-a-go-go (hERG) channels contribute to cardiac repolarization and participate in the regulation of tumor cell proliferation. Mutations in hERG channels may cause long QT syndrome and sudden cardiac death due to ventricular arrhythmias. HERG channel activity is up-regulated by the serum- and glucocorticoid-inducible kinase isoforms SGK1 and SGK3. Related kinases are protein kinase B (PKB/Akt) isoforms. SGK's and PKB/Akt's activate phosphatidylinositol-3-phosphate-5-kinase PIKfyve, which in turn up-regulates several carriers and channels. An effect of PIKfyve on hERG channels, has, however, never been shown. The present study thus explored the putative influence of PIKfyve on hERG channel expression and activity. METHODS: hERG channels were expressed in Xenopus oocytes with or without PIKfyve and/or PKB, expression of endogenous and injected hERG quantified by RT-PCR, and hERG channel activity determined utilizing dual electrode voltage clamp. Moreover, hERG protein abundance in the cell membrane was visualized utilizing specific antibody binding and subsequent confocal microscopy and quantified by chemiluminescence. RESULTS: Coexpression of wild type PIKfyve increased hERG channel activity in hERG expressing Xenopus oocytes. hERG channel activity was further increased by coexpression of PKB, an effect augmented by additional coexpression of PIKfyve, but not by additional coexpression of PKB/Akt-resistant PIKfyve mutant PIKfyve(S318A). Coexpression of PIKfyve increased hERG channel protein abundance in the cell membrane. Inhibition of hERG channel insertion into the cell membrane by Brefeldin A (5 uM) resulted in a decline of current, which was similar in Xenopus oocytes expressing hERG together with PIKfyve and in Xenopus oocytes expressing hERG alone. CONCLUSION: hERG is up-regulated by PIKfyve, which is in turn activated by PKB/Akt. PMID- 23735863 TI - Histopathological findings of an uncommon co-infection: Echinococcus vogeli, HIV, hepatitis C virus, and hepatitis B virus. AB - Our work represents the first case report of polycystic echinococcosis co infection with HIV, hepatitis C virus (HCV), and hepatitis B virus (HBV). Structural liver alterations were found to be related to parasitic structures and necroinflammatory foci (karyopyknosis, karyorrhexis, and karyolysis), consistent with Echinococcus vogeli. Visceral adipose tissue and intrahepatic triglyceride droplets (macrovesicular and microvesicular steatosis) indicated abnormal fat anabolism, which probably resulted from both viral-induced hepatopathy and drug related toxicity. In summary, our results suggest that the observed liver abnormalities reflected the coincident exposure to hepatotropic viruses and parasites causing polycystic echinococcosis and were not indicative of opportunistic relationships among these pathogens. PMID- 23735864 TI - Wild poliovirus importation, Central African Republic. PMID- 23735865 TI - Bedrails rise again? PMID- 23735866 TI - Variable coordination of eye and head movements during the early development of attention: a longitudinal study of infants aged 12-36 months. AB - This longitudinal study investigated the effects of attentional development on peripheral stimulus localization by analyzing the eye and head movements of toddlers as they matured from 12 to 36 months. On each trial of an experiment, a central fixation point and a 30 degrees peripheral stimulus were presented, such that in the gap condition the fixation disappeared 300 ms before the peripheral stimulus, whereas in the no-overlap condition it disappeared simultaneously as the peripheral stimulus, and in the overlap condition the fixation remained present when the peripheral target occurred. Results showed that eye and head movement latencies were highly correlated in all conditions and ages. However, at 12 months, head movements were as fast as eye movements, whereas during the subsequent development, eye movements became increasingly faster than head movements. These findings are indicative of a transition between 12 and 36 months due either to a change in attentional control, or to changes in the size of the visual field in which only eye movements occur. PMID- 23735867 TI - [Bacteremia caused by Escherichia coli and Klebsiella pneumoniae producing extended-spectrum betalactamases: mortality and readmission-related factors]. AB - BACKGROUND AND OBJECTIVE: The incidence of bloodstream-infections caused by extended-spectrum betalactamases (ESBL)-producing bacteria has increased exponentially. The objective of this study is to determine the factors related to mortality and readmission in these patients. PATIENTS AND METHODS: Socio epidemiological, clinical and laboratory data has been collected (from January, 1st 2008 to April, 31th 2011). They were classified as nosocomial, healthcare associated or community-acquired data. A descriptive research was conducted to determine the main differences in terms of responsible bacteria and variables associated with mortality and readmission rates. The following techniques were used to compare variables: Student's t-test, one-way ANOVA test, chi(2)-test and Fisher's exact test. A logistic-regression analysis was performed to identify variables independently related to mortality and readmission, using SPSS((r)) statistics software v18. RESULTS: A total of 68 patients were included in the study: 73.5% of the infections were caused by Escherichia coli (E. coli), and 26.5% by Klebsiella pneumoniae (K. pneumoniae). Nosocomial origin, critical condition of patients, and abdominal location were more frequent when K. pneumoniae was isolated; urinary tract was the most frequent site of E. coli infections. The in-hospital mortality reached 20.6%, and 24% during the follow-up period. The main factor associated to in-hospital mortality was previous antibiotic treatment (OR 8.37; CI 95%: 1.094-64.091); within the follow-up period, the first mortality factor was central venous catheterization (OR 8.416; CI 95%: 1.367-51.821). Readmission was required in 55.5% of patients. The main variables associated were nosocomial origin (OR 4.801; CI 95%: 1.057-21.802) and previous antibiotic treatment (OR 4.715; CI 95%: 1.125-19.766). Inadequate antibiotic treatment was not associated with increased mortality or readmission. Conclusions ESBL-producing E. coli and K. pneumoniae bloodstream-infections are linked to a high mortality and readmission risk. Previous antibiotic treatment is the main factor associated to a poor outcome. PMID- 23735868 TI - Hydrogen sulfide inhibits abnormal proliferation of lymphocytes via AKT/GSK3beta signal pathway in systemic lupus erythematosus patients. AB - BACKGROUND/AIM: The abnormal activation of the AKT/GSK3beta signal pathway in lymphocytes from systemic lupus erythematosus (SLE) patients plays an important role in the pathogenesis of the disease. Recently Hydrogen sulfide (H2S) has been recognized as a crucial gaseous signaling molecule, involved in regulation of cell proliferation. However, the role of H2S in regulating the abnormal activation of lymphocytes from SLE patients has not been established. This study was conducted to investigate the effect of H2S on lymphocytes and to explore the mechanisms involved. METHODS: The lymphocytes were isolated from SLE patients with or without renal disease and healthy controls. The cells were treated as indicated in each experiment. Cell viability was analyzed by CCK-8. Cell cycle distribution was determined by flow cytometry. Western blot was used to detect the expression of phosphorylated AKT (ser473), GSK3beta (ser9) and CDK2, p27(Kip1) and p21(WAF1/CIP1). RESULTS: Our findings showed that proliferation of lymphocytes was stimulated following treatment with NaHS (a H2S donor) at low NaHS concentrations (<1mM) but inhibited at high NaHS concentrations (>2mM). Similar results were observed using GYY4137, which is a slow-releasing H2S donor. Pretreatment of lymphocytes from SLE patients with NaHS at high concentrations prior to exposure to phytohemagglutinin (PHA) significantly attenuated proliferation, evidenced by decrease in cell viability and S phase distribution of cell cycle. Pretreatment with NaHS decreased PHA-induced expression of CDK2, phosphorylation levels of AKT (ser473) and GSK3beta (ser9) and increased the expression of p27(Kip1) and p21(WAF1/CIP1). Moreover, pretreatment with NaHS blunted the stimulation of SLE lymphocyte proliferation by GSK3beta inhibitor lithium chloride. CONCLUSION: These results demonstrate that H2S inhibits the abnormal activation of lymphocytes from SLE patients throuqh the AKT/GSK3beta signal pathway. PMID- 23735869 TI - Current world literature. PMID- 23735872 TI - The narratives of abused children who have survived attempted filicide. AB - Child abuse is a social problem that receives much attention from policy makers, practitioners, and researchers. This alarming phenomenon generates many consequences for children, their families, and society as a whole; one tragic consequence of child abuse is filicide. Because of the unfortunate circumstances surrounding such events, children are hushed by their perpetrators, whether abusers or killers, and we are thus denied the opportunity to hear their voices and to promote understanding of the phenomenon. The aim of the current study is to explore in depth the patterns and themes that can be found in the narratives of children who survived a murder attempt by one of their parents. Content analysis was performed on seven investigative interviews with children using thematic analysis. Five key categories were determined based on the children's narratives: (a) many bad things have happened to me, (b) this was not the first time I was abused by my parent, (c) I am concerned about my parent, (d) I am alive thanks to my siblings, and (e) it is hard to remember what exactly happened. This study contributes to the understanding of child physical abuse and filicide. The discussion integrated conclusions for policy makers and practitioners who seek methods of addressing child abuse as well as determining whether and how filicide can be prevented. PMID- 23735871 TI - Association of perpetrator relationship to abusive head trauma clinical outcomes. AB - The diagnosis of abusive head trauma (AHT) remains a significant public health problem with limited prevention success. Providing protection from further harm is often challenged by the difficulty in identifying the alleged perpetrator (AP) responsible for this pediatric trauma. The objective of this study was to evaluate demographic and clinical characteristics of children with AHT and the relationship between APs and their victims in a large, multi-site sample. Understanding the AHT risks from various caregivers may help to inform current prevention strategies. A retrospective review of all cases of AHT diagnosed by child protection teams (CPT) from 1/1/04 to 6/30/09 at four children's hospitals was conducted. Clinical characteristics of children with AHT injured by non parental perpetrators (NPP) were compared to parental perpetrators (PP). There were 459 children with AHT; 313 (68%) had an identified AP. The majority of the 313 children were <1 year of age (76%), Caucasian (63%), male (58%), receiving public assistance (80%), and presented without a history of trauma (62%); mortality was 19%. Overall, APs were: father (53%), parent partner (22%), mother (8%), babysitter (8%), other adult caregiver (5%); NPP accounted for 39% of APs. NPPs were more likely to cause AHT in children >= 1 year (77% vs. 23%, p<0.001) compared to PP. Independent associations to NPP included: older child, absence of a history of trauma, retinal hemorrhages, and male perpetrator gender. While fathers were the most common AP in AHT victims, there is a significant association for increased risk of AHT by NPPs in the older child, who presents with retinal hemorrhages, in the hands of a male AP. Further enhancement of current prevention strategies to address AHT risks of non-parental adults who provide care to children, especially in the post-infancy age seems warranted. PMID- 23735873 TI - Extrapolation and phase correction of non-uniformly broadened signals. AB - The initial part of FID-signals cannot always be acquired experimentally. This is particularly true for signals characterised by strong inhomogeneous broadening, such as those in porous materials, e.g. cements, soils and rocks, those measured by portable NMR-apparatus, or EPR-signals. Here we report on a numerical method we designed to extrapolate those initial missing parts, i.e. to retrieve their amplitude and phase. Should the entire signal be available from an experiment, the algorithm can still be used as an automatic phase-corrector and a low-pass filter. The method is based on the use of cardinal series, applies to any oversampled signals and requires no prior knowledge of the system under study. We show that the method can also be used to restore entire one-dimensional MRI-data sets from those in which less than half of the k-space was sampled, thus not only potentially allowing to speed up data acquisition - when extended to two or three dimensions, but also to circumvent phase-distortions usually encountered when exploring the k-space near its origin. PMID- 23735874 TI - New insights into mycotoxin mixtures: the toxicity of low doses of Type B trichothecenes on intestinal epithelial cells is synergistic. AB - Deoxynivalenol (DON) is the most prevalent trichothecene mycotoxin in crops in Europe and North America. DON is often present with other type B trichothecenes such as 3-acetyldeoxynivalenol (3-ADON), 15-acetyldeoxynivalenol (15-ADON), nivalenol (NIV) and fusarenon-X (FX). Although the cytotoxicity of individual mycotoxins has been widely studied, data on the toxicity of mycotoxin mixtures are limited. The aim of this study was to assess interactions caused by co exposure to Type B trichothecenes on intestinal epithelial cells. Proliferating Caco-2 cells were exposed to increasing doses of Type B trichothecenes, alone or in binary or ternary mixtures. The MTT test and neutral red uptake, respectively linked to mitochondrial and lysosomal functions, were used to measure intestinal epithelial cytotoxicity. The five tested mycotoxins had a dose-dependent effect on proliferating enterocytes and could be classified in increasing order of toxicity: 3-ADON<15-ADON~DON15% in 29% of patients. Over median follow-up of 12 months, the median rate of change in RDW was 0.2% per month, and 51 (29%) patients died. On multivariate survival analyses, baseline RDW >= 15.5% predicted death (adjusted HR 2.70, 95% CI 1.40 to 5.22, p=0.003) independently of LVEF, transfemoral approach, baseline pulmonary artery systolic pressure, moderate/severe mitral regurgitation and body mass index. A greater rate of increase in RDW over time was associated with increased mortality (adjusted HR 1.11, 95% CI 1.04 to 1.18, p=0.001) independently of baseline RDW and other significant temporal variables including a change in creatinine, bilirubin, mean cell haemoglobin concentration or urea. An increase in RDW>0.1%/month was associated with a twofold increased risk of mortality. CONCLUSIONS: Baseline RDW >= 15.5% and a rising RDW over time strongly correlate to an increased risk of death post-TAVI, and could be used to refine risk stratification. Investigating and ameliorating the causes of RDW expansion may improve survival. PMID- 23735936 TI - Comparing the decline in coronary heart disease and stroke mortality in neighbouring countries with different healthcare systems. AB - OBJECTIVE: To examine age and gender specific trends in coronary heart disease (CHD) and stroke mortality in two neighbouring countries, the Republic of Ireland (ROI) and Northern Ireland (NI). DESIGN: Epidemiological study of time trends in CHD and stroke mortality. SETTING/PATIENTS: The populations of the ROI and NI, 1985-2010. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Directly age standardised CHD and stroke mortality rates were calculated and analysed using joinpoint regression to identify years where the slope of the linear trend changed significantly. This was performed separately for specific age groups (25-54, 55 64, 65-74 and 75-84 years) and by gender. Annual percentage change (APC) and 95% CIs are presented. RESULTS: There was a striking similarity between the two countries, with percentage change between 1985 and 1989 and between 2006 and 2010 of 67% and 69% in CHD mortality, and 64% and 62% in stroke mortality for the ROI and NI, respectively. However, joinpoint analysis identified differences in the pace of change between the two countries. There was an accelerated pace of decline (negative APC) in mortality for both CHD and stroke in both countries from the mid-1990s (APC ROI -8% (95% CI -9.5 to 6.5) and NI -6.6% (-6.9 to 6.3)), but the accelerated decrease started later for CHD mortality in the ROI. In recent years, a levelling off in CHD mortality was observed in the 25-54 year age group in NI and in stroke mortality for men and women in the ROI. CONCLUSIONS: While differences in the pace of change in mortality were observed at different time points, similar, substantial decreases in CHD and stroke mortality were achieved between 1985 and 1989 and between 2006 and 2010 in the ROI and NI despite important differences in health service structures. There is evidence of a levelling in mortality rates in some groups in recent years. PMID- 23735937 TI - A new transventricular aproach for pulmonary valve implantation in a patient with severe valve disease after tetralogy-of-Fallot repair. PMID- 23735938 TI - Congenital aortopulmonary window; an unusual cause of breathlessness. PMID- 23735939 TI - The efficiency of cardiovascular risk assessment: do the right patients get statin treatment? AB - OBJECTIVE: To evaluate targeting of statin prescribing for primary prevention to those with high cardiovascular disease (CVD) risk. DESIGN: Two cohort studies including the general population and initiators of statins aged 35-74 years. SETTING: UK primary care records in the Clinical Practice Research Datalink. PATIENTS: 3.8 million general population patients and 300 914 statin users. INTERVENTION: Statin prescribing. MAIN OUTCOME MEASURES: Statin prescribing by CVD risk; observed 5-year CVD risks; variability between practices. RESULTS: Statin prescribing increased substantially over time to patients with high 10 year CVD risk (>= 20%): 7.0% of these received a statin prior to 2007, and 30.4% in 2007 onwards. Prescribing to patients with low risk (<15%) also increased (from 1.9% to 5.0%). Only about half the patients initiating statin treatment were high risk according to CVD risk score. The 5-year CVD risks, as observed during statin treatment, reduced over calendar time (from 17.0% to 7.1%). There was a large variation between general practices in the percentage of high-risk patients prescribed a statin in 2007 onwards, ranging from 8.2% to 61.5%. For low risk patients, these varied from 2.1% to 29.1%. CONCLUSIONS: There appeared to be substantive overuse in low CVD risk and underuse in high CVD risk (600 000 and 850 000 patients, respectively, in the UK since 2007). There is wide variation between practices in statin prescribing to patients at high CVD risk. There is a clear need for randomised trials for the best strategy to target statin treatment and manage CVD risk for primary prevention. PMID- 23735940 TI - Biomarker discordance during tumor progression. PMID- 23735941 TI - Significance of biomarker discordance in breast cancer from the pathologist's perspective. AB - Information on hormone receptor and human epidermal growth factor receptor 2 (HER2) is important for making optimal therapeutic decisions for breast cancer patients. Discordance in these biomarkers between primary breast carcinomas and corresponding metastases is well documented and may lead to changes in management option. The underlying mechanisms of biomarker discordance are complicated and multifactorial. Whereas biologic evolution, intratumoral heterogeneity, and subclonal selection may account for discordance, variations in sampling, processing, staining procedure and interpretation are the important contributory yet controllable factors. This article reviews the effects of different factors on the biomarker discordance, the clinical significance and the importance of standardizing methodology and interpretation criteria. PMID- 23735942 TI - Biomarker discordance: why it occurs and why it is important. AB - Although the analysis of hormone receptors and HER-2/neu has usually been performed on primary tumors only, a growing body of evidence suggests that substantial discordance exists between primary and metastatic disease for estrogen receptors (30-40%) and HER-2/neu (10-30%). This discordance may reflect alterations in pathologic assessment techniques, changes between primary and metastatic breast cancer, differences within a heterogenous tumor, or the effect of treatment. The etiology of discordance is poorly understood and frequently may reflect tumor heterogeneity along with lack of standardized preanalytic and analytic variables. Standardization of diagnostic variables can improve diagnostic reproducibility. Because of the emergence of targeted hormonal and HER 2/neu therapies, tumor biomarkers assume a pivotal role in treatment decisions. The loss of sensitivity to hormones or HER-2/neu may suggest tumor resistance; whereas, the acquisition of hormone receptors and HER-2/neu provides potential new treatment targets which can improve overall patient outcomes. PMID- 23735943 TI - Biomarker discordance: prospective and retrospective evidence that biopsy of recurrent disease is of clinical utility. AB - Prospective studies of biomarker status in primary and recurrent or metastatic breast cancer have confirmed the findings of historical retrospective studies which demonstrate that for biomarkers which influence routine clinical practice, Estrogen Receptor (ER), Progesterone Receptor (PR) and Human Epidermal growth factor Receptor type 2 (HER2), biopsy of recurrent or metastatic disease is essential not only to confirm the presence of malignancy but to guide targeted medical therapy. Historically, discordance rates for the expression of receptors between primary and metastatic tumors, though variable, may have led to suboptimal treatment for a significant proportion of patients. While changes in PR are most common, changes in ER (positive to negative or less frequently negative to positive) and the less common changes in HER2 (usually gain of HER2 amplification) influence subsequent therapy for 1 in 6 patients and may thus impact upon survival. Recognition of the potential for heterogeneity within the primary, between metastatic sites and over time requires further prospective study in breast cancer where the comparability of metastases from multiple sites and the need to biopsy successive recurrences have been less well documented. Recent prospective studies confirm the retrospective evidence that optimal patient care requires appropriate biopsy and pathological assessment of recurrent or metastatic breast cancer. PMID- 23735944 TI - Biomarker discordance pre and post neoadjuvant chemotherapy in breast cancer. AB - With the increasing use of neoadjuvant chemotherapy it is increasingly being observed that differences in the status of molecular markers may exist between core biopsy specimens and the residual disease in the breast post chemotherapy. Several hypotheses have been postulated to explain the biomarker discordance observed following neoadjuvant chemotherapy including intratumor heterogeneity, technical variance in the assays used to assess biomarkers and a genetic switch in the biology of the disease. Here we review published data looking at discordance of biomarkers following neoadjuvant chemotherapy and the prognostic and therapeutic implications of the observed discordance. We will review some of the biological explanations to account for the observed discordance and will look at its impact on the role of the pathologist as well as propose essential components required in a pathology report issued for patients receiving neoadjuvant chemotherapy that would help the medical oncologist in treatment planning. PMID- 23735945 TI - Change in HER2 status during breast tumor progression. AB - The HER2 status of breast cancers is routinely assessed using the testing algorithm standardized by the American Society of Clinical Oncology and the College of American Pathologists, which includes immunohistochemical analysis of HER2 protein expression and fluorescence in situ hybridization (FISH) analysis of HER2 gene copy number. Studies have suggested that HER2 status may differ between primary and metastatic tumors. Furthermore, studies have suggested that trastuzumab may convert HER2 status from positive in a primary tumor to negative in a metastatic site. Assessment of HER2 status is affected by aspects of the pathologic analysis, including the method of tumor sampling, the method of specimen fixation, whether immunohistochemical or FISH analysis is used. In this review, we discuss the clinical significance of HER2 discordance in breast cancer. Moreover, the importance of tumor sample handling in assessing HER2 positivity. PMID- 23735951 TI - Can hospital discharge databases be used to follow ischemic stroke incidence? AB - BACKGROUND AND PURPOSE: Because acute ischemic strokes (ISs) are mainly hospitalized, hospital discharge data could be used to routinely follow their incidence management. We aimed to assess sensitivity and positive predictive value of the French hospital discharge database (HDD) to identify patients with acute IS using a prospective and exhaustive cohort (AVC69) of acute IS cases. METHODS: A selection algorithm based on IS diagnosis coded with the International Classification of Diseases (ICD-10) and cerebral imaging codes was used to identify all hospital stays with the primary diagnosis of IS in the HDD of the university hospitals of the Rhone area. Cases identified through HDD search were compared with IS cases identified through an exhaustive cohort study conducted in the Rhone district and confirmed on medical records review. RESULTS: There were 465 confirmed cases of IS hospitalized in 1 of the 4 university hospitals during the study period. The HDD search identified 313 among those (true-positive cases) but missed 152 cases (false-negative cases). The sensitivity of the HDD search was 67.3% (95% confidence interval, 63.1-71.5), and the positive predictive value was 95.1% (95% confidence interval, 92.8-97.4). Additionally, HDD search retrieved 16 cases, which were not eventually IS (false positives). Sensitivity was better when patients were hospitalized in neurological departments. CONCLUSIONS: The lack of sensitivity to identify acute IS patients through HDD search does not seem to be accurate enough to validate the use of these data for incidence estimates. Efforts have to be made to improve the coding quality. PMID- 23735952 TI - Stroke tracked by administrative coding data: is it fair? PMID- 23735953 TI - Multicenter prospective cohort study on volume management after subarachnoid hemorrhage: hemodynamic changes according to severity of subarachnoid hemorrhage and cerebral vasospasm. AB - BACKGROUND AND PURPOSE: Systemic circulation management has not been established for patients with poor grade aneurysmal subarachnoid hemorrhage (SAH) or delayed cerebral ischemia (DCI) after SAH. The aims of the study were to examine hemodynamic variables in these patients and to establish treatment strategies. METHODS: A multicenter prospective cohort study of hemodynamic variables from days 1 to 14 was performed using a transpulmonary thermodilution system (PiCCO Plus). Parameters were analyzed by Mann-Whitney test. Multivariate analysis was performed to identify parameters involved in onset of DCI. RESULTS: The subjects were 204 patients, including 138 with poor grade SAH (World Federation of Neurological Surgeons grades IV and V) and 52 who developed DCI. The extravascular lung water index, pulmonary vascular permeability index, and systemic vascular resistance index were significantly greater in patients with poor grade SAH compared with those with good grade SAH (World Federation of Neurological Surgeons I-III) on day 2 (P=0.049, P=0.039, and P=0.038). Cardiac index was significantly lower in patients with poor grade SAH on days 1 and 2 (P=0.027 and P=0.011). In patients with DCI, the global end-diastolic volume index was significantly lower than in those without DCI on days 3 to 5 (P=0.0053; P=0.048; and P=0.048). In multivariate analysis, median global end-diastolic volume index, cardiac index, and systemic vascular resistance index at an early stage of SAH (days 3-6) were independently related to onset of DCI (P=0.023, P=0.013, and P=0.003). CONCLUSIONS: Patients with poor grade SAH developed heart failure-like afterload mismatch at an early stage, and those with DCI had decreased global end-diastolic volume index (hypovolemia) in the early stage of SAH. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: UMIN000003794. PMID- 23735954 TI - Response to letter regarding article, "patient-reported measures provide unique insights into motor function after stroke". PMID- 23735955 TI - Multimodal imaging in rats reveals impaired neurovascular coupling in sustained hypertension. AB - BACKGROUND AND PURPOSE: Arterial hypertension is an important risk factor for cerebrovascular diseases, such as transient ischemic attacks or stroke, and represents a major global health issue. The effects of hypertension on cerebral blood flow, particularly at the microvascular level, remain unknown. METHODS: Using the spontaneously hypertensive rat (SHR) model, we examined cortical hemodynamic responses on whisker stimulation applying a multimodal imaging approach (multiwavelength spectroscopy, laser speckle imaging, and 2-photon microscopy). We assessed the effects of hypertension in 10-, 20-, and 40-week-old male SHRs and age-matched male Wistar Kyoto rats (CTRL) on hemodynamic responses, histology, and biochemical parameters. In 40-week-old animals, losartan or verapamil was administered for 10 weeks to test the reversibility of hypertension induced impairments. RESULTS: Increased arterial blood pressure was associated with a progressive impairment in functional hyperemia in 20- and 40-week-old SHRs; baseline capillary red blood cell velocity was increased in 40-week-old SHRs compared with age-matched CTRLs. Antihypertensive treatment reduced baseline capillary cerebral blood flow almost to CTRL values, whereas functional hyperemic signals did not improve after 10 weeks of drug therapy. Structural analyses of the microvascular network revealed no differences between normo- and hypertensive animals, whereas expression analyses of cerebral lysates showed signs of increased oxidative stress and signs of impaired endothelial homeostasis upon early hypertension. CONCLUSIONS: Impaired neurovascular coupling in the SHR evolves upon sustained hypertension. Antihypertensive monotherapy using verapamil or losartan is not sufficient to abolish this functional impairment. These deficits in neurovascular coupling in response to sustained hypertension might contribute to accelerate progression of neurodegenerative diseases in chronic hypertension. PMID- 23735956 TI - Progression of carotid plaque volume predicts cardiovascular events. AB - BACKGROUND AND PURPOSE: Carotid ultrasound evaluation of intima-media thickness (IMT) and plaque burden has been used for risk stratification and for evaluation of antiatherosclerotic therapies. Increasing evidence indicates that measuring plaque burden is superior to measuring IMT for both purposes. We compared progression/regression of IMT, total plaque area (TPA), and total plaque volume (TPV) as predictors of cardiovascular outcomes. METHODS: IMT, TPA, and TPV were measured at baseline in 349 patients attending vascular prevention clinics; they had TPA of 40 to 600 mm(2) at baseline to qualify for enrollment. Participants were followed up for <=5 years (median, 3.17 years) to ascertain vascular death, myocardial infarction, stroke, and transient ischemic attacks. Follow-up measurements 1 year later were available in 323 cases for IMT and TPA, and in 306 for TPV. RESULTS: Progression of TPV predicted stroke, death or TIA (Kaplan-Meier logrank P=0.001), stroke/death/MI (P=0.008) and Stroke/Death/TIA/Myocardial infarction (any Cardiovascular event) (P=0.001). Progression of TPA weakly predicted Stroke/Death/TIA (P=0.097) but not stroke/death/MI (P=0.59) or any CV event (P=0.143); likewise change in IMT did not predict Stroke/Death/MI (P=0.13) or any CV event (P=0.455 ). In Cox regression, TPV progression remained a significant predictor of events after adjustment for coronary risk factors (P=0.001) but change in TPA did not. IMT change predicted events in an inverse manner; regression of IMT predicted events (P=0.004). CONCLUSIONS: For assessment of response to antiatherosclerotic therapy, measurement of TPV is superior to both IMT and TPA. PMID- 23735958 TI - Letter by Stinear and Byblow regarding article, "patient-reported measures provide unique insights into motor function after stroke". PMID- 23735957 TI - Prospective, randomized, open-label phase II trial on concomitant intraventricular fibrinolysis and low-frequency rotation after severe subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: The goal of this randomized, open-label phase II study was to investigate the effect of concomitant low-frequency head-motion therapy and intraventricular fibrinolysis in patients after surgical or endovascular treatment for aneurysmal subarachnoid hemorrhage. METHODS: Sixty patients experiencing subarachnoid hemorrhage were randomized into treatment with intraventricular application of recombinant tissue-type plasminogen activator and lateral rotational therapy (experimental) or treatment as usual (control). The primary end point was defined as functional outcome, measured by Glasgow Outcome Scale at discharge and at 3-month follow-up. Clot clearance rate, radiographic features of delayed cerebral ischemia, and posthemorrhagic hydrocephalus were defined as secondary end points. RESULTS: The majority of patients (78.3%) experienced severe subarachnoid hemorrhage. Although there was a higher incidence of subgaleal hematomas in the experimental group, there was no difference in the incidence of adverse or severe adverse events between the 2 groups. Despite significantly higher clot clearance rates, there was no beneficial effect on the incidence of delayed cerebral ischemia and poor functional outcome, as well as posthemorrhagic hydrocephalus after experimental treatment. CONCLUSIONS: Despite the ineffectiveness on reduction of delayed cerebral ischemia or poor functional outcome, intraventricular fibrinolysis and kinetic therapy seems to be a safe and effective concept for therapeutic reduction of subarachnoid clot in a patient collective experiencing predominantly severe subarachnoid hemorrhage. Therefore, future studies should investigate this treatment in a larger patient collective with a lower degree of primary brain injury and until full clot clearance on serial imaging. CLINICAL TRIAL REGISTRATION URL: http://www.controlled trials.com. Unique identifier: ICRCTN13230264. PMID- 23735960 TI - Pandemic controllability: a concept to guide a proportionate and flexible operational response to future influenza pandemics. AB - The 2009 H1N1 influenza pandemic posed challenges for governments worldwide. Strategies designed to limit community transmission, such as antiviral deployment, were largely ineffective due to both feasibility constraints and the generally mild nature of disease, resulting in incomplete case ascertainment. Reviews of national pandemic plans have identified pandemic impact, primarily linked to measures of transmissibility and severity, as a key concept to incorporate into the next generation of plans. While an assessment of impact provides the rationale under which interventions may be warranted, it does not directly provide an assessment on whether particular interventions may be effective. Such considerations motivate our introduction of the concept of pandemic controllability. For case-targeted interventions, such as antiviral treatment and post-exposure prophylaxis, we identify the visibility and transmissibility of a pandemic as the key drivers of controllability. Taking a case-study approach, we suggest that high-impact pandemics, for which control is most desirable, are likely uncontrollable with case-targeted interventions. Strategies that do not rely on the identification of cases may prove relatively more effective. By introducing a pragmatic framework for relating the assessment of impact to the ability to mitigate an epidemic (controllability), we hope to address a present omission identified in pandemic response plans. PMID- 23735959 TI - National health insurance and life satisfaction in late life: longitudinal findings from a natural experiment in Taiwan. AB - BACKGROUND: To determine whether the availability of National Health Insurance (NHI) is associated with a longitudinal increase in life satisfaction among older Taiwanese adults. METHODS: This study used data from the Taiwan Longitudinal Study on Aging, a nationally representative sample (n = 3778) of older adults aged 60 and above. Participants were interviewed prior to the establishment of NHI and on multiple occasions thereafter over the next 18 years. Growth curve models were employed to estimate the NHI effects on life satisfaction across various pre-NHI insurance groups over time while taking concurrent medical care utilization and health status into consideration. RESULTS: While somewhat complex and explained in detail herein, multivariate analyses found a significant increase in life satisfaction among older Taiwanese adults over the 12-year period since the establishment of NHI. Further, while the pre-NHI uninsured had a significantly lower level of life satisfaction than the pre-NHI insured government employees (beta = -1.78, P < 0.05), even after controlling for concurrent medical care utilization and health status, the difference in life satisfaction was significantly reduced by NHI over time. CONCLUSIONS: NHI reduces the barriers to medical care utilization and improves life satisfaction among older Taiwanese adults, particularly for individuals who were uninsured prior to NHI. PMID- 23735961 TI - Co-testing for detection of high-grade cervical intraepithelial neoplasia and cancer compared with cytology alone: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Human papillomavirus (HPV) DNA testing combined with cytology has been recommended as a primary cervical cancer screening strategy. METHODS: PubMed/MEDLINE, Embase, the Cochrane Library and the NIH trial registry were searched for randomized controlled trials comparing co-testing with cytology alone for the detection of high-grade CIN lesions and cancers. Of 1156 articles identified, four met inclusion criteria. The performance of co-testing and cytology alone was compared at baseline screening, second round screening and overall. Cumulative meta-analysis, Begg's test, Egger's test and sensitivity analysis were performed. RESULTS: At baseline, co-testing was associated with a significantly higher detection rate of CIN 2+ [risk ratio (RR) = 1.41, 95% confidence interval (CI): 1.12, 1.76] and a non-significantly higher CIN 3+ detection rate (RR = 1.15, 95% CI: 0.99, 1.33). At second round screening, co testing was associated with significantly lower detection rates of both CIN 2+ and CIN 3+ (RR = 0.77, 95% CI: 0.63, 0.93; RR = 0.68, 95% CI: 0.55, 0.85). The overall detection rate did not differ between co-testing and cytology alone for CIN 2+ (RR: 1.19, 95% CI: 0.99, 1.46) or CIN3+ (RR: 0.99, 95% CI: 0.87, 1.14). CONCLUSION: Co-testing increases the detection of CIN2+ lesions at baseline and significantly decreases the detection rates of CIN2+ or CIN3+ lesions at subsequent screening compared with cytology alone. PMID- 23735962 TI - Cell projections and extracellular matrix cross the interstitial interface within the renal stem/progenitor cell niche: accidental, structural or functional cues? AB - BACKGROUND: During nephron induction, morphogenetic molecules are reciprocally exchanged between epithelial and mesenchymal stem/progenitor cells within the renal stem/progenitor cell niche. That these molecules remain concentrated, it is assumed that both cell populations stand in close contact to each other. However, recently published data illustrate that epithelial and mesenchymal cells are separated by an astonishingly wide interstitial interface. METHODS: To gain deeper morphological insights into the spatial distribution of mesenchymal and epithelial stem/progenitor cells, the embryonic zone of neonatal rabbit kidney was fixed either with glutaraldehyde (GA) or in a combination with cupromeronic blue, ruthenium red or tannic acid. Transmission electron microscopy was then performed on exactly orientated sections. RESULTS: Conventional fixation with GA illustrates that epithelial and mesenchymal stem/progenitor cells are separated by a bright but inconspicuously looking interstitial interface. In contrast, fixation of specimens in GA containing cupromeronic blue, ruthenium red or tannic acid elucidates that part of the interstitial interface exhibits a special extracellular matrix extending like woven strands between mesenchymal and epithelial stem/progenitor cells. In parallel, filigree projections from mesenchymal stem/progenitor cells cross the interstitial interface to penetrate the basal lamina of epithelial cells. Fusion of the plasma membranes cannot be observed. Instead, touching mesenchymal cell projections form a cone at the contact site with tunneling nanotubes. CONCLUSIONS: The results demonstrate that the contact between mesenchymal and epithelial stem/progenitor cells does not form accidentally but physiologically and appears to belong to a suspected system involved in the exchange of morphogenetic information. PMID- 23735963 TI - The Affordable Care Act, Medicare spending, and the case manager. AB - At first blush, it looks like there is welcome relief from the upward growth of Medicare spending. It is important for the case manager to look at the big picture, as there are other reasons for this downward trend, including recovery audit contractor "take backs" and cost shifting to hospitals and Medicare beneficiaries. PMID- 23735964 TI - Case management provider profile: Ellen Lipkus "bringing it all to case management". PMID- 23735965 TI - Applications of comparative effectiveness research to case management. AB - PURPOSE/OBJECTIVES: This article is intended to update case managers on recent advances in comparative effectiveness research (CER) led by the Agency for Healthcare Research and Quality. The article explores potential implications and applications of CER findings to case management practice. PRIMARY PRACTICE SETTINGS: All case management settings. FINDINGS/CONCLUSIONS: An ongoing national movement to advance CER is intended to provide health care professionals with answers to questions about which diagnostic methods, therapies, devices, and services, among the available alternatives for a given disease or condition, may be most effective and safe for individual patients. IMPLICATIONS FOR CASE MANAGEMENT: Knowledge and application of CER findings may benefit case managers in their roles of improving resource utilization, controlling costs, providing stewardship, coordinating care, educating patients, and promoting treatment adherence and self-sufficiency. The findings from a 2013 study on the comparative effectiveness of outpatient case management programs have implications for improving case management models, reinforcing standards in the profession, and advancing research in the field. Continuing education on CER is important for promoting positive values and appropriate applications of its findings to case management practice. PMID- 23735967 TI - Designing the role of the embedded care manager. AB - PURPOSE/OBJECTIVES: : The role of the professional case manager is changing rapidly. Health reform has called upon the industry to ensure that care is delivered in an efficient, effective, and high-quality and low cost manner. As a means to achieve this objective, health plans and health systems are moving the care manager out of a centralized location within their organizations to "embedding" them into physician offices. This move enables the care manager to work alongside the primary care physicians and their high-risk patients. This article discusses the framework for designing and implementing an embedded care manager role into a physician practice. Key elements of the program are discussed. IMPLICATIONS FOR CARE MANAGEMENT:: Historically care management has played a foundational role in improving the quality of care for individuals and populations via the efficient and effective use of resources. Now with the goals of health care reform, a successful transition from a volume-based to value-based reimbursement system requires primary care physicians to welcome care managers into their practices to improve patient care, quality, and costs through care coordination across health care settings and populations. PRIMARY PRACTICE SETTING(S): : As patient-centered medical homes and integrated delivery systems formulate their plans for population health management, their efforts have included embedding a care manager in the primary practice setting. Having care managers embedded at the physician offices increases their ability to collaborate with the physician and their staff in the implementation and monitoring care plans for their patients. FINDINGS/CONCLUSIONS: : Implementing an embedded care manager into an existing physician's practice requires the following:Although the embedded care manager is a highly evolving role, physician groups are beginning to realize the benefits from their care management collaborations. Examples cited include improved outreach and coordination, patient adherence to care plans, and improved quality of life. PMID- 23735969 TI - Strengthening role clarity in acute care nurse case managers: application of the synergy model in staff development. AB - PURPOSE OF STUDY: The purpose of this quality improvement study was to evaluate the impact of a novel educational intervention on nurse case managers' (NCMs') perceived role ambiguity, role conflict, and use of nursing competencies. Specific aims were to apply the American Association of Critical-Care Nurses Synergy Model for Patient Care to determine the use of the model's nurse competencies in acute care case management, to pilot test the feasibility of using widely available basic computer technologies to facilitate NCMs' orientation in acute care settings, and to establish the foundation for future work in developing an evidence-based orientation program for new NCMs based on a nursing conceptual framework. PRIMARY PRACTICE SETTINGS: Two acute care community hospitals in northeastern Ohio, both part of a large national hospital corporation. METHODOLOGY AND SAMPLE: The sample consisted of NCMs who were actively employed in 1 of 2 acute care hospitals and voluntarily agreed to participate in this quality improvement study. Data on perceived role conflict and role ambiguity, perceived use of nurse competencies in bedside nursing and in case management, demographics, and evaluative feedback were collected using Google Docs. The intervention consisted of a series of four self-paced computer based learning modules that provided participants with an introduction to acute care nursing case management based on the American Association of Critical-Care Nurses Synergy Model. RESULTS: Four of the 6 role ambiguity subscale item scores revealed reductions in role ambiguity after the educational intervention. A statistically significant decrease in one role conflict item was observed. Participants rated the use of all nurse competencies as higher in case management than in bedside nursing practice; the variance between the two further increased after the intervention. Statistically significant differences in the use of clinical judgment, advocacy/moral agency, and caring practices were identified. Participants reported that the educational content would be valuable for new NCMs transitioning from bedside clinical practice. The addition of case studies or clinical scenarios illustrating each nurse competency was suggested. Testing of the Synergy Model-based education modules with novice case managers actively transitioning from the bedside to a case management role will be the next step in the development of this program. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: : The use of widely available computer technologies to deliver introductory case management orientation content is feasible, although conversion to a web-based platform is recommended. Evidence-based strategies to prepare NCMs for expanded competency in clinical judgment, advocacy/moral agency, and caring practices are needed. PMID- 23735970 TI - Promoting a health work environment: addressing harassment and the "charged" workplace. PMID- 23735971 TI - Who knew? Innovation and transformation within acute care case management. PMID- 23735972 TI - Integrity and accountability the omnibus final rule: part I. PMID- 23735973 TI - Work activity modification: using physical and occupational therapists to accelerate the return to work process. PMID- 23735974 TI - The ABCs of labor market surveys for certified rehabilitation counselors: eligibility criteria for the certified rehabilitation counselor. PMID- 23735975 TI - Domain-like ultra-thin layers deposited electrochemically from carbazole functionalized perylene bisimides for electron collection in inverted photovoltaic cells. AB - Domain-like ultra-thin layers deposited electrochemically on an ITO electrode from perylene bisimide derivatives are found to improve the electron collection effectively in inverted photovoltaic cells. PMID- 23735976 TI - Posttraumatic stress disorder in female cancer patients: an inappropriate diagnosis in oncology? PMID- 23735978 TI - Isostructural salts of the same complex showing contrasting thermal spin crossover mediated by multiple phase changes. AB - Two salts of [FeL2](2+) (L = 2,6-bis[5-methyl-1H-pyrazol-3-yl]pyridine) are isostructural under ambient conditions but show different thermal spin-crossover behaviour, involving a variety of crystallographic phase changes. PMID- 23735977 TI - TRF1 is a stem cell marker and is essential for the generation of induced pluripotent stem cells. AB - TRF1 is a component of the shelterin complex that protects chromosome ends. TRF1 deficiency leads to early embryonic lethality and to severe organ atrophy when deleted in adult tissues. Here we generate a reporter mouse carrying a knock-in eGFP-TRF1 fusion allele to study the role of TRF1 in stem cell biology and tissue homeostasis. We find that eGFP-TRF1 expression in mice is maximal in known adult stem cell compartments and show that TRF1 ensures their functionality. eGFP-TRF1 is highly expressed in induced pluripotent stem cells, uncoupled from the telomere elongation associated with reprogramming. Selection of eGFP-TRF1-high induced pluripotent stem cells correlates with higher pluripotency as indicated by their ability to form teratomas and chimeras. We further show that TRF1 is necessary for both induction and maintenance of pluripotency, and that TRF1 is a direct transcriptional target of Oct3/4. PMID- 23735979 TI - Joint statement on mechanical circulatory support in children: a consensus review from the Pediatric Cardiac Intensive Care Society and Extracorporeal Life Support Organization. PMID- 23735980 TI - Clinical management of the extracorporeal membrane oxygenation circuit. AB - The clinical management of patients on extracorporeal membrane oxygenation should be standardized and follow clear guidelines or protocols. However, due to the diversity of cannulation strategies and the complex situations that extracorporeal membrane oxygenation is now used in, each extracorporeal membrane oxygenation program has developed its own clinical management strategies. These vary widely across the globe. Extracorporeal membrane oxygenation provides partial or complete support of ventilation and oxygenation, as well as univentricular or biventricular support of myocardial function, either individually or in combination. High-flow extracorporeal membrane oxygenation can also provide circulatory support in profound vasoplegic shock. Improvements in technology and greater understanding of disease pathophysiology, coupled to refinements in technology, which lessen the adverse interaction between the circuit and the patient, all contribute to fewer mechanical and patient complications on extracorporeal membrane oxygenation. Earlier and more appropriate use of extracorporeal membrane oxygenation has been associated with improved patient outcomes. These clinical management strategies are reviewed in this article, part of the Pediatric Cardiac Intensive Care Society/Extracorporeal Life Support Organization Joint Statement on Mechanical Circulatory Support. PMID- 23735981 TI - Pediatric ventricular assist devices. AB - The field of pediatric mechanical circulatory support with ventricular assist devices has lagged significantly behind that of adult patients. However, there is increasing attention on the emerging field of pediatric ventricular assist device support. In this review, part of the Pediatric Cardiac Intensive Care Society/Extracorporeal Life Support Organization Joint Consensus Statement on Mechanical Circulatory Support, we discuss several important aspects of pediatric ventricular assist device, focusing on biomechanics and selection of the most appropriate device. PMID- 23735982 TI - Clinical management of pediatric ventricular assist devices. AB - Mechanical circulatory support is an invaluable tool in the care of children with severe refractory cardiac failure. As the field of mechanical circulatory support has evolved in children, the frequency of ventricular assist device use has been increasing steadily with excellent results. Ventricular assist devices are being used with increasing frequency in children with cardiac failure refractory to medical therapy for primary treatment as a long-term bridge to recovery or transplantation. This review, part of the Pediatric Cardiac Intensive Care Society/Extracorporeal Life Support Organization Joint Consensus Statement on Mechanical Circulatory Support, focuses on ventricular assist device implantation and management, as well as anticipation and management of complications. PMID- 23735983 TI - An overview of mechanical circulatory support in children. AB - OBJECTIVE: For children with severe heart failure in whom medical management has failed, mechanical circulatory support in the form of either extracorporeal membrane oxygenation or ventricular assist device represents life-sustaining therapy. This review provides an overview of these two modalities, including a discussion of indications, contraindications, timing, and device selection, as part of the Pediatric Cardiac Intensive Care Society/Extracorporeal Life Support Organization Joint Statement on Mechanical Circulatory Support. DATA SOURCES, STUDY SELECTION, DATA EXTRACTION: PubMed was searched using the following terms: ECMO, extracorporeal membrane oxygenation, ventricular assist device, VAD, and pediatric. Case reports, single-center series, multicenter studies, and registry reports were reviewed. CONCLUSIONS: The two technologies have unique advantages and disadvantages and may be considered complementary devices, although they are frequently used in sequence. Either modality may be used as bridge-to-transplant or bridge-to-recovery, and the choice of device and device timing is influenced by the acuity of illness, comorbidities, potential for recovery, and anticipated duration of support. PMID- 23735984 TI - Anticoagulation for pediatric mechanical circulatory support. AB - Extracorporeal life support applications have evolved considerably in recent years. However, the blood-biomaterial interface remains incompletely understood, and management of the acute inflammatory response and coagulation pathways continues to be challenging. At present, the gold standard for anticoagulation is unfractionated heparin. Since the inception of extracorporeal life support, the mainstay for anticoagulation monitoring has been activated clotting time. However, alongside the technological evolution in extracorporeal life support, the methods for monitoring heparin have also become more sophisticated, adding additional layers of complexity to creating an ideal safe protocol for anticoagulation during extracorporeal life support. To address this, the Extracorporeal Life Support Organization has formed an Anticoagulation Task Force to help direct both a consensus statement and potential guidelines within which the multiple monitoring methods can be customized for extracorporeal life support. One key question that remains in the use of these monitoring methods is whether the objective during extracorporeal life support is to anticoagulate the circuit to prevent thrombus formation within the extracorporeal device or whether it is to systemically anticoagulate the patient. This review details all current monitoring methods and highlights how they can be used during pediatric mechanical circulatory support. PMID- 23735985 TI - Medical and nursing care of the child on mechanical circulatory support. AB - OBJECTIVES: To review the medical and nursing care of children receiving mechanical circulatory support as part of the Pediatric Cardiac Intensive Care Society/Extracorporeal Life Support Organization Joint Statement on Mechanical Circulatory Support. DATA SOURCES/STUDY SELECTION/DATA EXTRACTION/DATA SYNTHESIS: This is a general review of current issues of medical and nursing care of children on mechanical circulatory support. It consists of knowledge gained from practical experience combined with supporting evidence and/or discussion of controversies for which evidence exists or is inconclusive. The scope of this review includes assessment and monitoring, cardiovascular, pulmonary, and renal and fluid management, as well as infection prevention and treatment, neurological, and nutritional considerations. Physical and psychological care is discussed, as well as ethical and practical issues regarding termination of support. CONCLUSIONS: There are unique aspects to the medical and nursing care of a patient requiring mechanical circulatory support. Preserving the possibility for cardiac recovery when possible and preventing damage to noncardiac organs are essential to maximizing the probability that patients will have quality survival following support with a mechanical circulatory support device. PMID- 23735986 TI - Pediatric extracorporeal life support in specialized situations. AB - OBJECTIVES: The purpose of this review was to provide a systematic review of the literature regarding the use of extracorporeal life support (ECLS) in various specialized conditions, as part of the Pediatric Cardiac Intensive Care Society/Extracorporeal Life Support Organization Joint Statement on Mechanical Circulatory Support. DATA SOURCES: MEDLINE and PubMed. STUDY SELECTION: Searches for published abstracts and articles were conducted using the following MeSH terms: extracorporeal life support, extracorporeal membrane oxygenation, or mechanical support, and pediatric or children. DATA EXTRACTION: Abstracts of all articles including case reports were reviewed; the full article was reviewed if the abstract indicated that it focused on extracorporeal life support for conditions other than primary respiratory disease or persistent pulmonary hypertension of the newborn and described outcomes such as survival to hospital discharge. Studies with potential overlapping patients were highlighted in the review process and summary results. DATA SYNTHESIS: Classification of recommendations and level of evidence are expressed in the American College of Cardiology Foundation/American Heart Association format. CONCLUSIONS: The majority of specialized situations where extracorporeal life support is used fall into the category of class II-III evidence. Class I indications for extracorporeal life support in the pediatric population include myocarditis and in the context of acute interventions in the cardiac catheterization laboratory. PMID- 23735987 TI - Partial mechanical circulatory support in children. AB - Partial mechanical support devices are capable of partially unloading only one ventricle, often the systemic one, in the setting of acute circulatory failure. They are rarely used in the pediatric population, as the mode of circulatory failure in patients with congenital heart disease often involves biventricular or a predominantly right ventricular component. The devices include intra-aortic balloon pumping, Impella, TandemHeart, and CentriMag. They are rarely used as a bridge-to-recovery, but more often as a bridge-to-decision, or bridge-to conversion to full mechanical support systems, such as extracorporeal membrane oxygenation or ventricular assist devices. Currently, lack of availability of more complete support devices, cost issues, or lack of infrastructure and personnel may still be indications to continue using partial mechanical support as opposed to more complete forms of biventricular circulatory support. PMID- 23735988 TI - Recurrent or prolonged mechanical circulatory support: bridge to recovery or road to nowhere? AB - Remarkable outcomes have been reported after prolonged mechanical circulatory support in the pediatric population, but there is yet no clear delineation of the duration beyond which supporting a child becomes futile. The likelihood of survival in patients supported on extracorporeal membrane oxygenation for respiratory failure decreases with the length of support. However, extracorporeal membrane oxygenation can be successfully used in these patients for long periods (weeks to months) provided adequate support is maintained without complications. This is not the case with cardiac failure and mechanical circulatory support.Extracorporeal membrane oxygenation is usually the initial form of mechanical circulatory support used in patients with primary refractory myocardial dysfunction. There is evidence and consensus that if the patient shows no signs of recovery after a maximum duration of 2 weeks, he or she should be transitioned to a ventricular assist device, which allows prolonged support. In post-cardiac surgery patients, survival is only anecdotal beyond 12 days of extracorporeal membrane oxygenation support, and myocardial recovery is exceptionally rare after this time period unless new diagnoses and management strategies are formulated.Repeat extracorporeal membrane oxygenation should generally not be offered to patients unless it is established that support was withdrawn prematurely or a new intervention is planned. Repeat extracorporeal membrane oxygenation may achieve some improvement in early survival, but the long term outcomes of survivors are so poor that these attempts cannot be generally recommended unless organ transplantation is an option. PMID- 23735989 TI - Extracorporeal membrane oxygenation circuitry. AB - The extracorporeal membrane oxygenation circuit is made of a number of components that have been customized to provide adequate tissue oxygen delivery in patients with severe cardiac and/or respiratory failure for a prolonged period of time (days to weeks). A standard extracorporeal membrane oxygenation circuit consists of a mechanical blood pump, gas-exchange device, and a heat exchanger all connected together with circuit tubing. Extracorporeal membrane oxygenation circuits can vary from simple to complex and may include a variety of blood flow and pressure monitors, continuous oxyhemoglobin saturation monitors, circuit access sites, and a bridge connecting the venous access and arterial infusion limbs of the circuit. Significant technical advancements have been made in the equipment available for short- and long-term extracorporeal membrane oxygenation applications. Contemporary extracorporeal membrane oxygenation circuits have greater biocompatibility and allow for more prolonged cardiopulmonary support time while minimizing the procedure-related complications of bleeding, thrombosis, and other physiologic derangements, which were so common with the early application of extracorporeal membrane oxygenation. Modern era extracorporeal membrane oxygenation circuitry and components are simpler, safer, more compact, and can be used across a wide variety of patient sizes from neonates to adults. PMID- 23735990 TI - Outcomes following extracorporeal membrane oxygenation in children with cardiac disease. AB - Extracorporeal membrane oxygenation is a commonly used form of mechanical circulatory support in children with congenital or acquired heart disease and cardiac failure refractory to conventional medical therapies. In children with heart disease who suffer cardiac arrest, extracorporeal membrane oxygenation has been successfully used to provide cardiopulmonary support when conventional resuscitation has failed to establish return of spontaneous circulation. Survival to hospital discharge for children with heart disease support is approximately 40% but varies widely based on age, indication for support, and underlying cardiac disease. Although extracorporeal membrane oxygenation is lifesaving in many instances, it is associated with many complications and is expensive. Thus, a clear understanding of survival to discharge and long-term functional and neurologic outcomes are essential to guide the use of extracorporeal membrane oxygenation now and in the future. This review, part of the Pediatric Cardiac Intensive Care Society/Extracorporeal Life Support Organization Joint Statement on Mechanical Circulatory Support, summarizes current knowledge on short- and long-term outcomes for extracorporeal membrane oxygenation used to support children with cardiac disease. PMID- 23735991 TI - Setup and maintenance of extracorporeal life support programs. AB - Setting up an extracorporeal life support program requires motivated experts, institutional commitment, and an interprofessional team of healthcare providers with dedicated time, space, and resources. This article provides guidance on the key steps involved in the process of developing a sustainable extracorporeal membrane oxygenation program, based on guidelines from the Extracorporeal Life Support Organization and from an international perspective. PMID- 23735992 TI - Pediatric mechanical circulatory support: future directions. AB - The field of extracorporeal support is moving forward rapidly. New technology, improved experience with a variety of patients, and successful outcomes in groups previously excluded from extracorporeal life support are increasing the use of this technique in patient support. Although initial reports of outcome are encouraging, they are often taken from single-center reports or large databases without specific detail to answer many of the relevant questions or for eras that do not reflect the effects of new technology. Collaboration between investigators, rigorous scientific data collection and analysis, and careful short- and long-term outcomes for patients receiving extracorporeal life support are imperative to avoid improper use of this high-resource, high-cost technology and to establish the efficacy of new devices and techniques. Bleeding and thrombosis remain devastating complications and efforts to reduce complications and improve anticoagulation regimens or eliminate the need for anticoagulation would be of major benefit to the field. PMID- 23735995 TI - Synthesis and luminescence mechanism of multicolor-emitting g-C3N4 nanopowders by low temperature thermal condensation of melamine. AB - Graphite like C3N4 (g-C3N4) was synthesized facilely via the low temperature thermal condensation of melamine between 300-650 degrees C. The results showed that the products maintained as melamine when the temperature is below 300 degrees C. With the increase of temperature, the products were transformed into carbon nitride and amorphous g-C3N4 successively. The morphology of products was changed from spherical nanoparticles of melamine into layer carbon nitride and g C3N4 with the increase of temperature. The photoluminescence spectra showed that the carbon nitride products have continuous tunable photoluminescence properties in the visible region with increasing temperature. With the help of steady state, transient state time-resolved photoluminescence spectra and Raman microstructural characterization, a novel tunable photoluminescence mechanism was founded systematically, which is mainly related to the two dimensional pi-conjugated polymeric network and the lone pair of the carbon nitride. PMID- 23735996 TI - Postmenopausal bleeding and corticosteroids. PMID- 23735998 TI - Surgical ablation of atrial fibrillation during mitral valve repair: a cure for arrhythmia? PMID- 23735997 TI - Impacts of chronic low-level nicotine exposure on Caenorhabditis elegans reproduction: identification of novel gene targets. AB - Effects and mechanisms of chronic exposure to low levels of nicotine is an area fundamentally important however less investigated. We employed the model organism Caenorhabditis elegans to investigate potential impacts of chronic (24h) and low nicotine exposure (6.17-194.5 MUM) on stimulus-response, reproduction, and gene expressions. Nicotine significantly affects the organism's response to touch stimulus (p=0.031), which follows a dose-dependent pattern. Chronic nicotine exposure promotes early egg-laying events and slightly increased egg productions during the first 72 h of adulthood. The expressions of 10 (egl-10, egl-44, hlh 14, ric-3, unc-103, unc-50, unc-68, sod-1, oxi-1, and old-1) out of 18 selected genes were affected significantly. Other tested genes were cat-4, egl-19, egl-47, egl-5, lin-39, unc-43, pink-1, and age-1. Changes in gene expression were more evident at low dosages than at relatively high levels. Genes implicated in reproduction, cholinergic signaling, and stress response were regulated by nicotine, suggesting widespread physiological impacts of nicotine. PMID- 23735999 TI - Crimean-Congo hemorrhagic fever Asia-2 genotype, Pakistan. PMID- 23736000 TI - Asymptomatic cerebral microbleeds in adult patients with moyamoya disease: a prospective cohort study with 2 years of follow-up. AB - OBJECTIVE: Risk factors for cerebral microbleeds (CMBs) in moyamoya disease (MMD) remain unknown, and whether the presence or distribution of CMBs is related to the subsequent hemorrhagic events needs to be confirmed. This study aimed to investigate the relationship between intracranial vascular morphology and the incidence/distribution patterns of CMBs as well as to determine the outcome in adult patients with MMD. METHODS: Eighty-five consecutive adult patients with MMD were prospectively evaluated by 3.0-tesla high-intensity susceptibility-weighted magnetic resonance imaging and catheter-based digital subtraction angiography from June 2009 to January 2012. The differences in intracranial angiography (Suzuki stages, posterior cerebral artery stages, and angiographic features of the anterior choroidal and posterior communicating arteries) and clinical parameters (age, gender, hemorrhagic onset, antiplatelet treatment, systolic/diastolic blood pressure, diabetes, and plasma fibrinogen) among various CMB distribution patterns were analyzed with multinomial logistic regression. Moreover, after a median follow-up of 23 months, the relationship between CMB distribution patterns and subsequent intraventricular hemorrhage was also analyzed with Kaplan-Meier survival analysis and a Cox proportional hazards model. RESULTS: Forty-five female and 40 male patients were finally enrolled in the study with an average age of 41.4 +/- 12.7 years. Thirty-one CMB foci were detected in 24 (28.2%) patients. Most of the lesions (n = 22, 71.0%) were located in the region of deep and periventricular white matter (DPWM). Dilation and extension of anterior choroidal and posterior communicating arteries (AChA-PComA) was found to be an independent risk factor associated with the CMBs located in DPWM (p = 0.045; odds ratio 3.39, 95% CI 1.03-11.19). Patients with DPWM CMBs showed a statistically higher likelihood of subsequent intraventricular hemorrhage compared to patients without CMB foci and with CMBs in other regions (p = 0.014) during the follow-up period. Multivariable analysis suggested that DPWM CMBs were independent predictors of subsequent intraventricular hemorrhage (p = 0.028; hazard ratio 5.53, 95% CI 1.20-25.41). CONCLUSIONS: Dilation and extension of AChA-PComA is a determinant of CMBs involved in DPWM. CMBs in DPWM are probably predictors of subsequent intraventricular hemorrhage. PMID- 23736001 TI - Progress and prospects in stem cell therapy and drug discovery. PMID- 23736002 TI - Progress and prospects in stem cell therapy. AB - In the past few years, progress being made in stem cell studies has incontestably led to the hope of developing cell replacement based therapy for diseases deficient in effective treatment by conventional ways. The induced pluripotent stem cells (iPSCs) are of great interest of cell therapy research because of their unrestricted self-renewal and differentiation potentials. Proof of principle studies have successfully demonstrated that iPSCs technology would substantially benefit clinical studies in various areas, including neurological disorders, hematologic diseases, cardiac diseases, liver diseases and etc. On top of this, latest advances of gene editing technologies have vigorously endorsed the possibility of obtaining disease-free autologous cells from patient specific iPSCs. Here in this review, we summarize current progress of stem cell therapy research with special enthusiasm in iPSCs studies. In addition, we compare current gene editing technologies and discuss their potential implications in clinic application in the future. PMID- 23736003 TI - Mesenchymal stem cells: a new trend for cell therapy. AB - Mesenchymal stem cells (MSCs), the major stem cells for cell therapy, have been used in the clinic for approximately 10 years. From animal models to clinical trials, MSCs have afforded promise in the treatment of numerous diseases, mainly tissue injury and immune disorders. In this review, we summarize the recent opinions on methods, timing and cell sources for MSC administration in clinical applications, and provide an overview of mechanisms that are significant in MSC mediated therapies. Although MSCs for cell therapy have been shown to be safe and effective, there are still challenges that need to be tackled before their wide application in the clinic. PMID- 23736004 TI - Establishment of a human colorectal cancer cell line P6C with stem cell properties and resistance to chemotherapeutic drugs. AB - AIM: Cancer stem cells have the capacity to initiate and sustain tumor growth. In this study, we established a CD44(+) colorectal cancer stem cell line with particular emphasis on its self-renewal capacity, enhanced tumor initiation and drug resistance. METHODS: Fresh colon cancer and paired normal colon tissues were collected from 13 patients who had not received chemotherapy or radiotherapy prior to surgery. Among the 6 single-cell derived clones, only the P6C cell line was cultured for more than 20 passages in serial culture and formed holoclones with high efficiency, and then the stemness gene expression, colony formation, tumorigenicity and drug sensitivities of the P6C cell line were examined. RESULTS: Stemness proteins, including c-Myc, Oct3/4, Nanog, Lgr5, and SOX2, were highly expressed in the P6C cell line. Oct3/4-positive P6C cells mostly generated holoclones through symmetric division, while a small number of P6C cells generated meroclones through asymmetric division. P6C cells stably expressed CD44 and possessed a high capacity to form tumor spheres. A single cell-derived sphere was capable of generating xenograft tumors in nude mice. Compared to SW480 and HCT116 colorectal cancer cells, P6C cells were highly resistant to Camptothecin and 5-fluorouracil, the commonly used chemotherapeutic agents to treat colorectal cancers. CONCLUSION: We established a colorectal cancer stem cell line P6C with a high tumorigenic capacity and the characteristics of normal stem cells. It will benefit the mechanistic studies on cancer stem cells and the development of drugs that specifically target the cancer stem cells. PMID- 23736005 TI - Identification of a small molecule 1,4-bis-[4-(3-phenoxy-propoxy)-but-2-ynyl] piperazine as a novel inhibitor of the transcription factor p53. AB - AIM: To identify novel small compound inhibitor of p53 protein. METHODS: Mouse embryonic fibroblasts (MEF) and mouse embryonic stem (ES) cells were tested. Cell proliferation rate was determined using a Cell Proliferation Kit. The mRNA and protein levels of p53-related genes were measured using real-time PCR and Western blotting, respectively. Global response in the p53 signaling network was analyzed using Illumina whole-genome expression BeadChips. RESULTS: Treatment of MEF cells with a small molecule 1,4-bis-[4-(3-phenoxy-propoxy)-but-2-ynyl]-piperazine (G5) at 10 MUmol/L for 24 h markedly reduced the mRNA and protein levels of the p53 downstream genes MDM2 and p21. In G5-treated ES cells, a total of 372 differentially expressed genes were identified, and 18 among them were direct downstream genes of p53; 6 out of 9 p53-repressed genes were upregulated, and 5 out of 9 p53-activated genes were downregulated. In both MEF cells and ES cells, treatment of with G5 (10 MUmol/L) up to 48 h neither affected the proliferation rate nor caused morphological alterations. CONCLUSION: G5 inhibits p53 activity and simultaneously preserves the normal growth and proliferation of cells, therefore is a new compound for studies of p53-mediated cell manipulation. PMID- 23736006 TI - Genetic variation in the beta 3-adrenoreceptor gene (Trp64Arg polymorphism) and its influence on anthropometric parameters and insulin resistance under a high monounsaturated versus a high polyunsaturated fat hypocaloric diet. AB - OBJECTIVE: The aim of our study was to investigate the role of Trp64Arg polymorphism of the beta 3-adrenergic receptor (beta 3-AR) gene on metabolic changes and weight loss secondary to a high monounsaturated fat versus a high polyunsaturated fat hypocaloric diet in obese subjects. MATERIAL AND METHODS: A population of 260 obese subjects was analyzed. In the basal visit, patients were randomly allocated for 3 months to either diet M (high monounsaturated fat hypocaloric diet) or diet P (high polyunsaturated fat hypocaloric diet). RESULTS: There were no significant differences between the positive effects (on weight, body mass index, waist circumference, fat mass) in either genotype group with both diets. With diet P and in genotype Trp64Trp, glucose levels (-6.7 +/- 12.1 vs. -1.2 +/- 2.2 mg/dl; p < 0.05), total cholesterol (-11.2 +/- 8.1 vs. -1.0 +/- 7.1 mg/dl; p < 0.05), low-density lipoprotein (LDL) cholesterol (-9.7 +/- 10.1 vs. -2.2 +/- 8.1 mg/dl; p < 0.05), triglycerides (-11.7 +/- 13.1 vs. +1.7 +/- 10.3 mg/dl; p < 0.05), homeostasis model assessment for insulin resistance (HOMA R; -0.7 +/- 1.1 vs. -0.3 +/- 2.1 units; p < 0.05) and insulin levels (-1.8 +/- 4.6 vs. -1.0 +/- 9.1 mIU/l; p < 0.05) decreased. CONCLUSION: The metabolic effect of weight reduction by the two hypocaloric diets is greatest in subjects with the normal homozygous beta 3-AR gene. Improvements in total cholesterol, LDL cholesterol, triglyceride, glucose, insulin and HOMA-R levels were better than in the heterozygous group. PMID- 23736008 TI - Better neonatal outcomes: oxygen, surfactant and drug delivery. Preface. PMID- 23736009 TI - The surfactant system protects both fetus and newborn. AB - Surfactant complex and its individual components decrease surface tension, silence inflammatory responses, bind and destroy air-borne microbes, facilitate phagocytosis by alveolar macrophages and bind endogenous and exogenous molecules. Surfactant components generally decrease harmful inflammatory responses. New exogenous surfactants and new indications for surfactant therapy remain to be studied. At term the pool of human surfactant from developing airways extends to the amniotic cavity and to the gastrointestinal tract. Preterm labor-inducing inflammatory ligands (interleukin-1 or lipopolysaccharide) cause a robust induction of surfactant complex and lower the risk of respiratory distress syndrome (RDS). The effect of antenatal glucocorticoid therapy is complementary. According to transgenic experiments or genetic evidence in humans, surfactant proteins A, D or C (SP-A, SP-D, SP-C), expressed in fetal tissue, influence the onset of term or preterm labor. After birth, the surface tension-reducing and the inflammation-silencing effects of exogenous and endogenous surfactant are complementary. Surfactant proteins influence the genetic predisposition of RDS, bronchopulmonary dysplasia (BPD) and airway infections in early infancy. Moderate to severe BPD has a strong genetic predisposition. Deleterious mutations of SP-B, ABCA3 or SP-C cause congenital interstitial lung disease that mimics the phenotype of established severe BPD. I propose that lung surfactant protects both the fetus and the newborn. Surfactant ameliorates inflammatory responses that are harmful to the mother, fetus and infant. In chorioamnionitis, inflammatory ligands are carried from the fetal membranes to the alveolar space via amniotic fluid and developing airways. They induce surfactant synthesis and secretion. Surfactant ameliorates severe inflammatory responses in fetal compartments and promotes spontaneous preterm birth. PMID- 23736010 TI - New generation synthetic surfactants. AB - The treatment of preterm newborn rabbits with synthetic surfactants containing simple phospholipid mixtures and peptides gives similar tidal volumes to treatment with poractant alfa (Curosurf(r)). The addition of both surfactant protein B and C analogs to the phospholipid mixture will stabilize the alveoli, measured as lung gas volumes at end expiration, even if no positive end expiratory pressure is applied. The effect on lung gas volumes seems to depend on the structure of the peptides as well as the phospholipid composition. It seems that synthetic surfactants containing two peptides and a more complex phospholipid composition will be able to replace natural surfactants within the near future, but more experiments need to be performed before any conclusion can be drawn about the ideal composition of this new generation of synthetic surfactants. PMID- 23736011 TI - Optimization of airway medications in the infant. AB - Airway medications are frequently used in the care of the sick neonate. The most prominent airway medication, surfactant for respiratory distress syndrome, will be discussed elsewhere in this issue of Neonatology. Other indications for airway medications have included the prevention and treatment of bronchopulmonary dysplasia, pulmonary hypertension, persistent atelectasis, transient tachypnea of the newborn and upper airway edema. Indications such as the prevention of bronchopulmonary dysplasia are currently the focus of a large multicenter international trial. Other indications require further study. PMID- 23736012 TI - Common hemodynamic problems in the neonate. AB - Hemodynamic problems are common in neonatal intensive care. They occur in the context of incomplete myocardial and vascular development and in cardiovascular responses to interventions which are, as a result, limited and often uncertain and unpredictable. In this review, I outline the hemodynamic features of 4 neonatal conditions which often require intervention: (1) persistent pulmonary hypertension of the newborn, (2) cardiogenic shock (most commonly in the context of hypoxic ischemic injury), (3) sepsis and (4) low blood pressure in the transitional period of the extremely preterm infant. I also look at the evidence which exists for effective interventions and the most important research questions for the future. PMID- 23736013 TI - Oxygen targets for preterm infants. AB - Retinopathy of prematurity (ROP) was first observed soon after the widespread introduction of oxygen therapy into neonatal care. Early trials suggested that restricting oxygen supplementation could reduce ROP without other consequences, but when oxygen restriction became widespread, increased mortality was observed. These observations were made before continuous monitoring of oxygenation was possible. New trial evidence from masked randomized controlled trials of different pulse oximeter oxygen saturation (SpO2) target ranges now shows that targeting lower SpO2 levels reduces ROP but is associated with significantly increased mortality. These results illustrate the importance of randomized trials because, prior to these recent studies, trends in practice based on observational data were favouring lower SpO2. Follow-up data may yet further inform clinical practice. PMID- 23736014 TI - Abstracts of the 28th International Workshop on Surfactant Replacement, May 31 June 1, 2013, Helsinki, Finland. PMID- 23736015 TI - European consensus guidelines on the management of neonatal respiratory distress syndrome in preterm infants--2013 update. AB - Despite recent advances in the perinatal management of neonatal respiratory distress syndrome (RDS), controversies still exist. We report updated recommendations of a European Panel of expert neonatologists who developed consensus guidelines after critical examination of the most up-to-date evidence in 2007 and 2010. This second update of the guidelines is based upon published evidence up to the end of 2012. Strong evidence exists for the role of antenatal steroids in RDS prevention, but it is still not clear if the benefit of repeated courses on respiratory outcomes outweighs the risk of adverse outcomes in the short and long term. Many practices involved in preterm neonatal stabilization at birth are not evidence based, including oxygen administration and positive pressure lung inflation, and they may at times be harmful. Surfactant replacement therapy is crucial in the management of RDS but the best preparation, optimal dose and timing of administration at different gestations is not completely clear. In addition, use of very early continuous positive airway pressure (CPAP) has altered the indications for prophylactic surfactant administration. Respiratory support in the form of mechanical ventilation may be lifesaving but can cause lung injury, and protocols should be directed at avoiding mechanical ventilation where possible by using non-invasive respiratory support such as CPAP. For babies with RDS to have best outcomes, it is essential that they have optimal supportive care, including maintenance of normal body temperature, proper fluid management, good nutritional support, appropriate management of the ductus arteriosus and support of the circulation to maintain adequate tissue perfusion. PMID- 23736016 TI - S100P enhances the chemosensitivity of human gastric cancer cell lines. AB - BACKGROUND: The effect of the protein S100P on biological characteristics of cancer is not clear, especially in gastric cancer. We previously showed that S100P positive gastric cancer patients have a better cumulative survival than S100P negative patients. OBJECTIVE: To study the possible mechanisms of S100P enhanced the chemosensitivity to oxaliplatin in gastric cancer cell lines. METHODS: S100P was overexpressed in vitro by plasmid transfection and downregulated by siRNA transfection in the BGC823 and SGC7901 gastric cancer cell lines. Cell survival rate, changes in the chemoresistance gene, such as GST-pi, MDR1, MRP1, Topo-II, MVP and BCRP, intake of anticancer drug were measured after oxaliplatin treatment. RESULTS: In SGC7901 cells, MTT assay indicated that increased S100P expression levels decreased the survival rate and decreased S100P expression levels increased the survival rate. In BGC823 and SGC7901 cell lines, mRNA of MDR1, a chemoresistance genes, was decreased in cells that overexpressed S100P, and increased in cells with downregulation of S100P. Intracellular accumulation of platinum increased in cells with overexpressed S100P, and decreased in cells with S100P downregulation. CONCLUSIONS: S100P contributes to oxaliplatin chemosensitivity in gastric cell lines by increasing drug inflow. It might also be a novel independent prognostic factor in gastric cancer patients who receive adjuvant chemotherapy with oxaliplatin. PMID- 23736017 TI - The effects of hematological parameters and tumor-infiltrating lymphocytes on prognosis in patients with gastric cancer. AB - BACKGROUND: It is well known that tumor-infiltrating lymphocytes (TIL) and, to a lesser extent, peripheral hematologic parameters from patients with cancer have to effect on prognosis. The aim of this study was to evaluate the effect of hematologic parameters and TIL on prognosis of patients with gastric cancer. METHODS: 236 patients who had diagnosed as gastric adenocarcinoma. All hematologic parameters were noted at the time of diagnosis. The number of lymphocyte aggregates as well as the number of lymphocytes within these agregat was counted.The prognostic significance and correlations of high neutrophil lymphocyte ratio (NLR) together with TIL, was evaluated by multivaried analysis. RESULTS: The cut-off values of NLR and derived NLR (dNLR) were 3.8 and 2. The NLR was independently associated with survival (P < 0.001). dNLR was not independently associated with overall survival. No significant advantages for overall survival were found for the high TIL (p: 0.372). It was not determined correlation between TIL - NLR and TIL-lymphoid aggregate density (respectivly, P: 0.104; P: 0.246). CONCLUSIONS: The results suggest that the elevated NLR predicts poor overall survival following at the time diagnosis for all stage gastric cancer. dNLR was not independently associated with overall survival. There is insufficient evidence to the assesment of TIL by a nonspesific method. Therefore further studies is required, to confirm our hypothesis in larger patient cohorts. PMID- 23736018 TI - Correlation between telomerase activity and matrix metalloproteinases 2 expression in gastric cancer. AB - OBJECTIVE: To investigate the relationship between telomerase activity (TA) and matrix metallo proteinases 2 (MMP-2) on malignant behavior and prognosis predictable value in gastric cancer. METHODS: Telomerase activity and MMP-2 protein expressions were tested in 40 gastric surgical resected cancer samples and the clinicopathological data of enrolled patients were obtained to get correlation analysis results. RESULTS: The expression of telomerase was up regulated with infiltrating depth, lymph node metastasis and stage (P < 0.01). Positive expression rate of MMP-2 in gastric cancer tissues was 44.35%, negative in normal gastric tissues. Multivariate analysis of Logistic regression showed telomerase activity and MMP-2 expression were hazardous makers correlated with infiltrating depth (P < 0.05). CONCLUSION: Combined detections of telomerase activity and MMP2 protein could identify patients at high risk in disease recurrence and prognosis more efficiently. PMID- 23736019 TI - A meta-analysis of the association between glutathione S-transferase P1 gene polymorphism and the risk of adenocarcinomas of lung cancer. AB - BACKGROUND: Results of the published reports on the relationship between glutathione S-transferase P1 (GSTP1) gene polymorphism and the adenocarcinomas of lung cancer are still debated. OBJECTIVE: This meta-analysis was performed to evaluate the association between GSTP1 A/G gene polymorphism and the risk of adenocarcinomas of lung cancer. METHODS: The association investigations were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. RESULTS: 16 reports were included into this meta-analysis for the association of GSTP1 A/G gene polymorphism and the risk of adenocarcinomas of lung cancer. The G allele and GG genotype were not associated with the susceptibility of risk of adenocarcinomas. Furthermore, in the sensitivity analysis, the results were similar with those from the non sensitivity analysis. CONCLUSIONS: GSTP1 G allele or GG genotype is not a biomarker to be associated with the susceptibility of adenocarcinomas of lung cancer. PMID- 23736020 TI - High expression of truncated GLI3 is associated with poor overall survival in patients with non-small cell lung cancer. AB - BACKGROUND: The hedgehog (Hh) pathway is involved in embryogenesis and organogenesis. GLI3 is one of the zinc-finger transcription factors in the Hh signaling pathway, which exist in both full-length (GLI3FL) and truncated (GLI3TR) forms. We investigated GLI3 expression in patients with non-small cell lung cancer (NSCLC). The role of GLI3 in lung carcinogenesis and its correlation with clinicopathological factors and overall survival (OS) in patients with NSCLC were explored. METHODS: GLI3FL and GLI3TR expression were analyzed immunohistochemically in 330 and 352 evaluable NSCLC tissues respectively. The association between GLI3FL and GLI3TR expression and clinicopathological parameters and OS were statistically analyzed. RESULTS: GLI3FL immunohistochemical staining could be observed in the cytoplasm, while GLI3TR staining could be observed in nucleus of malignant epithelial cells. High level expression of GLI3FL and GLI3TR were 52.7% and 45.2% respectively. GLI3FL was not significantly correlated with any clinicopathological parameter and survival. However, high-expression of GLI3TR was significantly associated with lymph node metastasis (P = 0.013) and poor OS (28.4 vs. 40.8 months, P = 0.010). In patients with adenocarcinoma of high and low GLI3TR expression, the median OS were 25.7 and 50.6 months respectively (P = 0.004). Multivariate analysis showed that GLI3TR expression (P = 0.036), tumor differentiation (P < 0.001), disease stage (P < 0.001) were independent prognostic factors for patients with NSCLC. CONCLUSION: Overexpression of GLI3TR in NSCLC, especially in adenocarcinoma, is associated with poor prognosis. GLI3TR expression is an independent prognostic factor in OS. GLI3TR may play an important role in the tumorigenesis of NSCLC. PMID- 23736021 TI - Diagnostic value of the FHIT and p16 mRNA loss and the K-ras gene mutation in pleural fluids for malignant pleural effusion. AB - Inactivation of the tumor suppressor genes and activation of oncogenes are involved in the development of cancer. The aim of this study was to evaluate the diagnostic value of the fragile histidine triad (FHIT) and p16 mRNA loss and the K-ras gene mutation in distinguishing malignant from benign pleural effusion. A total of 50 patients with malignant pleural effusion and 30 patients with benign pleural effusion were enrolled in this study. All pleural fluid specimens were evaluated in parallel by cytology, reverse transcriptase-PCR for the loss of FHIT and p16 mRNA, and PCR-SSCP (single-stranded conformation polymorphism) for the mutation of K-ras gene. The detection rates of FHIT and p16 mRNA loss were significantly higher in malignant than in benign pleural effusion (P < 0.001 and P = 0.001). The K-ras mutations were more frequent in malignant than benign pleural effusion (P = 0.006). The sensitivity and specificity were 58% and 93% for FHIT loss, 48% and 90% for p16 loss, and 44% and 87% for the K-ras mutation, respectively. In combined evaluation with both FHIT and p16 loss, the sensitivity was 68%, and specificity was 90%. The combination of the three molecular markers reached 74% sensitivity, whereas the combined use of the cytology and the three markers increased the diagnostic yield of the former by 38%. More than one third of cytology negative malignant pleural effusion could be identified by at least one of the three markers. These results suggest that the detection of FHIT and p16 mRNA loss and the k-ras gene mutation in pleural fluid could be helpful adjunct to cytology in the diagnosis of malignant pleural effusion. PMID- 23736022 TI - Transcriptional expression of glioma chemotherapy drugs associated marker molecules in gliomas and normal brain tissues. AB - Currently, the transcript abundance of key enzymes for chemotherapy drug metabolism, which may help in predicting the efficacy of a drug, can easily be detected in tumor tissues. However, there has been little research on the enzymes involved in the chemotherapy of gliomas. This study aimed to detect and compare the abundance of glioma chemotherapy drug-associated marker molecules in both gliomas and normal brain tissues and among gliomas of different grades. We examined the transcript abundance of four such marker molecules, MGMT, ERCC1, Topo IIalpha and Stathmin, in 46 glioma and 6 normal brain tissues. We also compared the abundance of these molecules in normal brain tissues and glioma tissues with different malignancy grades. Furthermore, we described the variation of these molecules in different grades of gliomas by calculating the ratio of their maximum to their minimum. The transcript abundance of MGMT and ERCC1 was significantly higher in normal brain tissues than in glioma tissues. However, the opposite result was observed for Topo IIalpha. For Stathmin, no significant differences between normal brain tissues and gliomas tissues were found. For all 4 marker molecules, no significant differences were detected between grades of glioma. All four molecules exhibited wide variation in abundance, fluctuating significantly between gliomas. These results suggest that individualized detection and medication may be beneficial for treatment. PMID- 23736023 TI - Continuing friendship in the face of European destruction and European construction: the European conference on psychosomatic research. PMID- 23736024 TI - The basis for limited specificity and MHC restriction in a T cell receptor interface. AB - alphabeta T cell receptors (TCRs) recognize peptides presented by major histocompatibility complex (MHC) proteins using multiple complementarity determining region (CDR) loops. TCRs display an array of poorly understood recognition properties, including specificity, crossreactivity and MHC restriction. Here we report a comprehensive thermodynamic deconstruction of the interaction between the A6 TCR and the Tax peptide presented by the class I MHC HLA-A*0201, uncovering the physical basis for the receptor's recognition properties. Broadly, our findings are in conflict with widely held generalities regarding TCR recognition, such as the relative contributions of central and peripheral peptide residues and the roles of the hypervariable and germline CDR loops in engaging peptide and MHC. Instead, we find that the recognition properties of the receptor emerge from the need to engage the composite peptide/MHC surface, with the receptor utilizing its CDR loops in a cooperative fashion such that specificity, crossreactivity and MHC restriction are inextricably linked. PMID- 23736025 TI - Risk of infections in renal cell carcinoma (RCC) and non-RCC patients treated with mammalian target of rapamycin inhibitors. AB - BACKGROUND: Mammalian target of rapamycin (mTOR) inhibitors are used in a variety of malignancies. Infections have been reported with these drugs. We performed an up-to-date meta-analysis to further characterise the risk of infections in cancer patients treated with these agents. METHODS: Pubmed and oncology conferences' proceedings were searched for studies from January 1966 to June 2012. Studies were limited to phase II and III randomised controlled trials (RCTs) of everolimus or temsirolimus reporting on cancer patients with adequate safety profiles. Summary incidences, relative risks (RRs), and 95% confidence intervals (CIs) were calculated. RESULTS: A total of 3180 patients were included. The incidence of all-grade and high-grade infections due to mTOR inhibitors was 33.1% (95% CI, 24.5-43.0%) and 5.6% (95% CI, 3.8-8.3%), respectively. Compared with controls, the RR of all-grade and high-grade infections due to mTOR inhibitors was 2.00 (95% CI, 1.76-2.28, P<0.001) and 2.60 (95% CI, 1.54-4.41, P<0.001), respectively. Subgroup analysis found no difference in incidences or risks between everolimus and temsirolimus or between different tumour types (renal cell carcinoma (RCC) vs non-RCC). Infections included respiratory tract (61.7%), genitourinary (29.4%), skin/soft tissue (4.2%), and others (4.9%). CONCLUSION: Treatment with mTOR inhibitors is associated with a significant increase in risk of infections. Close monitoring for any signs of infections is warranted. PMID- 23736026 TI - Comment on 'Elevated preoperative neutrophil/lymphocyte ratio is associated with poor prognosis in soft-tissue sarcoma patients': neutrophil to lymphocyte ratio may be predictor of mortality in patients with soft-tissue sarcoma. PMID- 23736027 TI - Vitamin C intake and breast cancer mortality in a cohort of Swedish women. AB - BACKGROUND: Vitamin C may influence cancer progression through its antioxidant properties. However, the evidence from observational epidemiologic studies on vitamin C intake and survival following breast cancer diagnosis is not consistent, and the safety of vitamin C supplements following breast cancer diagnosis has not been extensively studied. METHODS: Using a food-frequency questionnaire we investigated whether vitamin C intake was associated with survival among 3405 women diagnosed with invasive breast cancer in the Swedish Mammography Cohort. RESULTS: From 1987-2010, there were 1055 total deaths with 416 deaths from breast cancer. Women in the highest quartile of pre-diagnosis vitamin C intake had an adjusted HR (95% CI) of breast cancer death of 0.75 (0.57 0.99) compared with those in the lowest quartile (Ptrend=0.03). There was a borderline significant association between vitamin C intake and total mortality (HR=0.84; 95% CI=0.71-1.00; Ptrend=0.08). Among 717 breast cancer cases for whom post-diagnosis supplement use was available, there was no association between vitamin C supplement use (~1000 mg) and breast cancer-specific mortality (HR=1.06; 95% CI=0.52-2.17). CONCLUSION: Our findings suggest that dietary vitamin C intake before breast cancer diagnosis may be associated with breast cancer survival. In addition, post-diagnosis vitamin C supplementation at the level observed in our population was not associated with survival. PMID- 23736028 TI - Functional and cancer genomics of ASXL family members. AB - Additional sex combs-like (ASXL)1, ASXL2 and ASXL3 are human homologues of the Drosophila Asx gene that are involved in the regulation or recruitment of the Polycomb-group repressor complex (PRC) and trithorax-group (trxG) activator complex. ASXL proteins consist of ASXN, ASXH, ASXM1, ASXM2 and PHD domains. ASXL1 directly interacts with BAP1, KDM1A (LSD1), NCOA1 and nuclear hormone receptors (NHRs), such as retinoic acid receptors, oestrogen receptor and androgen receptor. ASXL family members are epigenetic scaffolding proteins that assemble epigenetic regulators and transcription factors to specific genomic loci with histone modifications. ASXL1 is involved in transcriptional repression through an interaction with PRC2 and also contributes to transcriptional regulation through interactions with BAP1 and/or NHR complexes. Germ-line mutations of human ASXL1 and ASXL3 occur in Bohring-Opitz and related syndromes. Amplification and overexpression of ASXL1 occur in cervical cancer. Truncation mutations of ASXL1 occur in colorectal cancers with microsatellite instability (MSI), malignant myeloid diseases, chronic lymphocytic leukaemia, head and neck squamous cell carcinoma, and liver, prostate and breast cancers; those of ASXL2 occur in prostate cancer, pancreatic cancer and breast cancer and those of ASXL3 are observed in melanoma. EPC1-ASXL2 gene fusion occurs in adult T-cell leukaemia/lymphoma. The prognosis of myeloid malignancies with misregulating truncation mutations of ASXL1 is poor. ASXL family members are assumed to be tumour suppressive or oncogenic in a context-dependent manner. PMID- 23736030 TI - Reply: comment on 'Elevated preoperative neutrophil/lymphocyte ratio is associated with poor prognosis in soft-tissue sarcoma patients'. PMID- 23736029 TI - Expression of neutrophil gelatinase-associated lipocalin in colorectal neoplastic progression: a marker of malignant potential? AB - BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) has a diverse functional repertoire, involved in the innate immune response as well as cell growth and differentiation. Expression has been linked to malignant disease development and progression. METHODS: Neutrophil gelatinase-associated lipocalin expression was assessed immunohistochemically in 98 colorectal neoplastic lesions (52 cancer polyps (CaPs) and 46 sporadic adenoma/adjacent normal mucosa paired specimens) to investigate association with adenoma progression and early colorectal carcinogenesis. RESULTS: Within CaPs, all adenomatous and carcinomatous epithelium expressed NGAL, with 92% (43 out of 47) and 58% (19 out of 33) epithelial positivity, respectively, as well as positive stromal cell expression. This was significantly increased compared with normal mucosal epithelium (P=0.0001). Neutrophil gelatinase-associated lipocalin positivity was also identified in sporadic low-grade adenomas, in both the epithelial and stromal compartments as compared with adjacent normal mucosa (P=0.0001 and 0.0002), and this increased along with adenoma size >1 cm (P=0.03). CONCLUSION: Neutrophil gelatinase-associated lipocalin is expressed by the majority of human neoplastic colorectal lesions. This phenotypic switch occurs at an early stage in neoplastic progression with clear differential expression between normal mucosa and adenomatous polyps, rather than further downstream in disease progression at the adenoma-carcinoma transformation. Thus, NGAL expression is not a useful biomarker for determining disease progression from adenomatous to malignant colorectal neoplasia. PMID- 23736031 TI - p28, a first in class peptide inhibitor of cop1 binding to p53. AB - BACKGROUND: A 28 amino-acid (aa) cell-penetrating peptide (p28) derived from azurin, a redox protein secreted from the opportunistic pathogen Pseudomonas aeruginosa, produces a post-translational increase in p53 in cancer cells by inhibiting its ubiquitination. METHODS: In silico computational simulations were used to predict motifs within the p53 DNA-binding domain (DBD) as potential sites for p28 binding. In vitro direct and competitive pull-down studies as well as western blot and RT-PCR analyses were used to validate predictions. RESULTS: The L1 loop (aa 112-124), a region within the S7-S8 loop (aa 214-236) and T140, P142, Q144, W146, R282 and L289 of the p53DBD were identified as potential sites for p28 binding. p28 decreased the level of the E3 ligase COP1 >80%, in p53wt and p53mut cells with no decrease in COP1 in p53dom/neg or p53null cells. Brief increases in the expression of the E3 ligases, TOPORS, Pirh2 and HDM2 (human double minute 2) in p53wt and p53mut cells were in response to sustained increases in p53. CONCLUSION: These data identify the specific motifs within the DBD of p53 that bind p28 and suggest that p28 inhibition of COP1 binding results in the sustained, post-translational increase in p53 levels and subsequent inhibition of cancer cell growth independent of an HDM2 pathway. PMID- 23736032 TI - Multidisciplinary decisions in breast cancer: does the patient receive what the team has recommended? AB - BACKGROUND: A multidisciplinary team (MDT) approach to breast cancer management is the gold standard. The aim is to evaluate MDT decision making in a modern breast unit. METHODS: All referrals to the breast MDT where breast cancer was diagnosed from 1 July 2009 to 30 June 2011 were included. Multidisciplinary team decisions were compared with subsequent patient management and classified as concordant or discordant. RESULTS: Over the study period, there were 3230 MDT decisions relating to 705 patients. Overall, 91.5% (2956 out of 3230) of decisions were concordant, 4.5% (146 out of 3230), were discordant and 4% (128 out of 3230) had no MDT decision. Of 146 discordant decisions, 26 (17.8%) were considered 'unjustifiable' as there was no additional information available after the MDT to account for the change in management. The remaining 120 discordant MDT decisions were considered 'justifiable', as management was altered due to patient choice (n=61), additional information available after MDT (n=54) or MDT error (n=5). CONCLUSION: The vast majority of MDT decisions are implemented. Management alteration was most often due to patient choice or additional information available after the MDT. A minority of management alterations were 'unjustifiable' and the authors recommend that any patient whose treatment is subsequently changed should have MDT rediscussion prior to treatment. PMID- 23736033 TI - Integrated and mutated forms of Merkel cell polyomavirus in non-small cell lung cancer. PMID- 23736034 TI - Merkel cell polyomavirus and non-small cell lung cancer. PMID- 23736035 TI - Cancer chemoprevention: a rapidly evolving field. AB - Cancer chemoprevention involves the chronic administration of a synthetic, natural or biological agent to reduce or delay the occurrence of malignancy. The potential value of this approach has been demonstrated with trials in breast, prostate and colon cancer. The paradigm for developing new chemopreventive agents has changed markedly in the last decade and now involves extensive preclinical mechanistic evaluation of agents before clinical trials are instituted and a focus on defining biomarkers of activity that can be used as early predictors of efficacy. This review will summarise the current status of the field of chemoprevention and highlight potential new developments. PMID- 23736037 TI - Chronic kidney disease: old outcomes and new answers. PMID- 23736036 TI - Pharmacogenetic variants in the DPYD, TYMS, CDA and MTHFR genes are clinically significant predictors of fluoropyrimidine toxicity. AB - BACKGROUND: Fluoropyrimidine drugs are extensively used for the treatment of solid cancers. However, adverse drug reactions are a major clinical problem, often necessitating treatment discontinuation. The aim of this study was to identify pharmacogenetic markers predicting fluoropyrimidine toxicity. METHODS: Toxicity in the first four cycles of 5-fluorouracil or capecitabine-based chemotherapy were recorded for a series of 430 patients. The association between demographic variables, DPYD, DPYS, TYMS, MTHFR, CDA genotypes, and toxicity were analysed using logistic regression models. RESULTS: Four DPYD sequence variants (c.1905+1G>A, c.2846A>T, c.1601G>A and c.1679T>G) were found in 6% of the cohort and were significantly associated with grade 3-4 toxicity (P<0.0001). The TYMS 3' untranslated region del/del genotype substantially increased the risk of severe toxicity (P=0.0123, odds ratio (OR)=3.08, 95% confidence interval (CI): 1.38 6.87). For patients treated with capecitabine, a MTHFR c.1298CC homozygous variant genotype predicted hand-foot syndrome (P=4.1 * 10-6, OR=9.99, 95% CI: 3.84-27.8). The linked CDA c.-92A>G and CDA c.-451C>T variants predicted grade 2 4 diarrhoea (P=0.0055, OR=2.3, 95% CI: 1.3-4.2 and P=0.0082, OR=2.3, 95% CI: 1.3 4.2, respectively). CONCLUSION: We have identified a panel of clinically useful pharmacogenetic markers predicting toxicity to fluoropyrimidine therapy. Dose reduction should be considered in patients carrying these sequence variants. PMID- 23736038 TI - Silica-supported Ti chloride tetrahydrofuranates, precursors of Ziegler-Natta catalysts. AB - The structural and electronic properties of silica-supported titanium chloride tetrahydrofuranates samples, obtained by impregnating a polymer-grade dehydroxylated silica with TiCl4(thf)2 and TiCl3(thf)3 complexes, precursors of Ziegler-Natta catalysts, are investigated by means of FT-IR, XAS, XES and diffuse reflectance UV-Vis spectroscopy, coupled with DFT calculations. The properties of the two silica-supported samples are very similar, irrespective of the starting precursor. In both cases, most of the chlorine ligands originally surrounding the Ti sites are substituted by oxygen ligands upon grafting on silica. As a consequence, the electronic properties of silica-supported Ti sites are largely different from those of the corresponding precursors, and in both cases most of the grafted Ti sites have a formal oxidation state of +4. The whole set of experimental data provide evidence that mono-nuclear Ti species are mainly present at the silica surface. PMID- 23736039 TI - Predictors and timing of recanalization in intracranial carotid artery and siphon dissection: an ultrasound follow-up study. AB - BACKGROUND: Intra- and extracranial internal carotid artery dissections (ICD) are two different pathological conditions. Extracranial dissection is considered to be among the most frequent causes of stroke in the young and the segment generally reopens in 2 out of 3 cases, completely or partially, within 6 months. Intracranial ICD (IICD) is considered a rare occurrence in stroke and, accordingly, there are few systematic published data. However, it is a clinically significant condition that may cause severely disabling ischemic stroke or subarachnoid hemorrhage. In the past, sole availability of invasive imaging methods for its detection may have induced an underreporting. The aim of the study was to analyze ultrasound findings, timing and predictors of recanalization in patients with IICD. METHODS: IICD acute patients admitted to our Stroke Unit were submitted to carotid sonographic seriated monitoring, daily for the 1st week after symptom onset, at day 14, at month 1 and every 3 months thereafter up to a follow-up of 4 years. Contrast carotid ultrasound was performed in patients with persistent occlusion after month 1. RESULTS: Fourteen acute patients with IICD were enrolled. Extracranial internal carotid patency was observed in 8 patients at first ultrasound scans; all of these showed complete intracranial recanalization within the 1st week and oral anticoagulants were withdrawn after 6 months. Conversely, in 6 patients retrograde extracranial internal carotid thrombosis was immediately observed, since the first ultrasound scans. In 4 of these the occlusion persisted after 4 years while 2 of them had only a partial recanalization, with evidence at contrast ultrasound of still late remodeling processes in the extracranial thrombus up to 2 years after the first observation; for this reason, in these 2 patients anticoagulation was not discontinued, while in the 4 patients with persistent, stable, occlusion, therapy was suspended 1 year after the diagnosis. CONCLUSIONS: Identification of the site of dissection - i.e. extra- versus intracranial - is fundamental in clinical studies for outcome and prognosis evaluation. Carotid ultrasound strict surveillance is important to monitor eventual recanalization in patients with ICD, even in a late phase. Retrograde internal carotid thrombosis seems to be correlated with persistent occlusion and partial recanalization. Remodeling of thrombotic material in the internal carotid artery may, however, continue for up to 2 years. In these cases, contrast ultrasound evidence of thrombus morphological changes may support the decision to continue anticoagulation. PMID- 23736041 TI - Wetting on flexible hydrophilic pillar-arrays. AB - Dynamic wetting on the flexible hydrophilic pillar-arrays is studied using large scale molecular dynamics simulations. For the first time, the combined effect of the surface topology, the intrinsic wettability and the elasticity of a solid on the wetting process is taken into consideration. The direction-dependent dynamics of both liquid and pillars, especially at the moving contact line (MCL), is revealed at atomic level. The flexible pillars accelerate the liquid when the liquid approaches, and pin the liquid when the liquid passes. The liquid deforms the pillars, resulting energy dissipation at the MCL. Scaling analysis is performed based on molecular kinetic theory and validated by our simulations. Our results may expand our knowledge of wetting on pillars and assisting the future design of active control of wetting in practical applications. PMID- 23736042 TI - Surgical RF ablation of atrial fibrillation in patients undergoing mitral valve repair for Barlow disease. AB - OBJECTIVES: At present, limited experience exists on the treatment of atrial fibrillation (AF) in patients undergoing mitral valve repair (MVR) for Barlow disease. The aim of this investigation was to prospectively evaluate the radiofrequency ablation of AF in patients undergoing MVR for severe regurgitation due to Barlow disease. METHODS: From January 1, 2007 to December 31, 2010, out of 85 consecutive patients with Barlow disease, 27 with AF underwent RF ablation associated with MVR. They were examined every 4 months in the first year after surgery and thereafter twice yearly. RESULTS: At follow-up, AF was observed in 4/25 (16.0%). NYHA (New York Heart Association) functional class improved significantly, with no patients in class III or IV (before surgery, 81.5% had been). Otherwise, among 58 patients in sinus rhythm, 6 (11%) developed AF during follow-up. No clinical or echocardiographic predictive factor was found in this subgroup. CONCLUSIONS: Results from our investigation suggest that radiofrequency ablation of AF in patients with Barlow disease undergoing MVR for severe regurgitation is effective and should be considered in every patient with Barlow disease and AF undergoing valve surgical repair. PMID- 23736043 TI - Postnatal systemic inflammation exacerbates impairment of hippocampal synaptic plasticity in an animal seizure model. AB - OBJECTIVE: To investigate the effects of systemic inflammation in the critical postnatal stages on neurophysiological actions of immune processes and neural plasticity in adult rats after kainic acid (KA)-induced seizures. METHODS: To determine changes in hippocampal synaptic plasticity after postnatal central nervous system inflammatory responses and seizure attacks, we performed intraperitoneal injections of lipopolysaccharide (LPS) in postnatal Sprague Dawley rats on day 14 (P14) to induce central nervous system inflammation. We then used a KA tail vein injection on P35 to induce seizure attacks. We compared the variability in synaptic plasticity in the hippocampal Schaffer collateral-CA1 region of seizure animals with or without LPS-induced inflammation preconditioning. RESULTS: P14 injection of LPS increased susceptibility to seizures, while treatment with KA on P35 induced seizures. Long-term potentiation (LTP) of the Schaffer collateral-CA1 region was impaired in seizure animals, and this effect was more pronounced in the P14 LPS injection group. Fluoro-Jade staining revealed an increase in degenerated hippocampal CA1 pyramidal cells in the P14 LPS injection group. Cytokine expression in the hippocampus in the pre-, peri- and postictus periods was greater in P14 LPS rats than in saline-treated rats. CONCLUSIONS: Intraperitoneal LPS injection on P14 induces higher cytokine secretion after KA-induced seizures, enhancing neuronal excitability, shortening seizure onset time and exacerbating neuronal degeneration and impairment of LTP formation in the hippocampal Schaffer collateral-CA1 region. Central nervous system inflammation during critical stages of childhood development could disrupt the balance needed for neurophysiological actions of immune processes, producing direct, pernicious effects on memory, neural plasticity and neurogenesis into adulthood. PMID- 23736044 TI - Seasonal changes of total body water and water intake in Shetland ponies measured by an isotope dilution technique. AB - Water is an essential nutrient necessary to support life, and adequate water supply is crucial for animal survival and productivity. The present study was designed to determine seasonal changes in the water metabolism of horses under outdoor conditions. Total body water (TBW) and total water intake (TWI) of 10 adult Shetland pony mares were estimated at monthly intervals for 14 mo by using the deuterium dilution technique. During the last 4 mo, 5 ponies were fed restrictively to simulate natural feed shortage in winter, and 5 ponies served as controls. The TBW (kg) was closely related to body mass [TBW (kg) = -2.86 + 0.67 * body mass (kg); P < 0.001; n = 105] explaining 86% of the variation. In contrast to TBW (kg), TBW (%) remained relatively stable across all measurements (57.8 to 71.2%). The TWI showed an increase in summer and a decrease in winter [TWI (mL.kg(-1).d(-1)) = 15.07 + 23.69 * month - 1.45 * month(2) (R(2) = 0.64, P < 0.01)]. However, TWI measured at ambient temperatures (Ta) < 0 degrees C did not follow the same trend as TWI at Ta > 0 degrees C. Therefore, removing TWI values measured at Ta < 0 degrees C from the analysis resulted in high correlations with locomotor activity (r = 0.87), Ta (r = 0.86), and resting heart rate (r = 0.88). The multiple regression among TWI, Ta, and heart rate explained 84% of the variation in TWI [TWI (mL.kg(-1).d(-1)) = -13.38 + 1.77 * heart rate (beats/min) + 2.11 * Ta ( degrees C); P < 0.001]. Feed restriction had no effect on TWI and TBW. The TBW content was unaffected by season and physical activity. The established regression equation for TBW and body mass can be used to predict TBW from body mass in ponies under field conditions. The comparison of TWI with published data on drinking water intake revealed that ponies had 1.7 to 5.1 times greater total water intakes when other sources of water such as feed and metabolic water were included. The TWI was highly influenced by environmental conditions and metabolic rate. Contrary to expectation, water supply during the cold seasons might be more critical than under summer conditions when water content of grass is high to allow for the compensation of limited availability of drinking water. PMID- 23736045 TI - Blending of soluble corn fiber with pullulan, sorbitol, or fructose attenuates glycemic and insulinemic responses in the dog and affects hydrolytic digestion in vitro. AB - The objective of these experiments was to measure in vitro hydrolytic digestion and glycemic and insulinemic responses of select carbohydrate blends, all containing the novel carbohydrate soluble corn fiber (SCF). Two SCF that varied in their method of production were used to formulate the carbohydrate blends. One set of blends contained a SCF that was spray dried (SCFsd) and then blended with different amounts of either pullulan, sorbitol, or fructose. The other set of blends contained a SCF produced using longer evaporation time (SCF) and then blended with different ratios of pullulan, sorbitol, and fructose. Free sugar concentrations found in the individual SCFsd and SCF substrates were low but varied. Spray-dried soluble corn fiber had a reduced free sugar concentration compared with SCF (2.8 vs. 14.2%). Glucose was the main free sugar found in both SCFsd and SCF but at different concentrations (2.7 vs. 12.7%, respectively). The majority of the SCFsd blends were completely hydrolyzed to their monosaccharide components. Glucose accounted for most of the hydrolyzed monosaccharides for SCFsd and all the SCFsd blends. Hydrolyzed monosaccharide concentrations for the SCF:pullulan:sorbitol:fructose blends followed similar trends to the SCFsd blends where greater percentages of fructose and sorbitol resulted in decreased (P < 0.05) hydrolyzed monosaccharide concentrations. The SCFsd blends had intermediate to high amounts of monosaccharides released as a result of in vitro hydrolytic digestion. The SCFsd:pullulan blends were more digestible in vitro (approximately 91%; P < 0.05) than SCFsd:fructose or SCFsd:sorbitol. Total released monosaccharides were high in SCFsd blends containing either 50% fructose or sorbitol, but the combination resulted in reduced concentrations of glucose released (P < 0.05). The SCF:pullulan:sorbitol:fructose blends also had intermediate to high released monosaccharides as a result of in vitro hydrolytic digestion. All SCF blends resulted in decreased glycemic and insulinemic responses compared with the maltodextrin control (P < 0.05) using a canine model. The addition of pullulan reduced the glycemic response compared with maltodextrin at all concentrations, but only 50:50 SCFsd:pullulan resulted in a reduction of the glycemic response compared with SCFsd alone (P < 0.05). The addition of fructose and sorbitol in the blends had the greatest impact on glycemic and insulinemic responses, even at concentrations as low as 5% of the blends. Overall, SCF and their blends may prove beneficial as components of low glycemic foodstuffs. PMID- 23736046 TI - Maximum permissible load weight of a Taishuh pony at a trot. AB - The aim of this study was to determine the loading capacity of a trotting Taishuh pony by gait analysis using a motion analysis system. Seven Taishuh Ponies (5 mares and 2 geldings) and their rider were fitted with a marker (70 mm in diameter placed on their chest) and recorded by 2 high-resolution digital DVD cameras (at a sampling frequency of 60 Hz) as they were trotting along a straight course. Each horse performed 7 tests: 1 test with a loaded weight of 70 kg, 5 tests with random loaded weights between 80 kg and 120 kg, and a final test with a loaded weight of 70 kg again. Three-dimensional movements of each marker were analyzed using motion capture system. The time series of the vertical displacements of the marker was subjected to spectrum analysis by the maximum entropy method, and the autocorrelation coefficient was calculated. The first 2 peaks of the autocorrelation were defined as symmetry and regularity of the gait, and the sum of symmetry and regularity was defined as stability. The cross spectrum analysis (Blackman-Tukey method) also was performed to analyze the time lag and cross-correlation coefficient between the time series of both pony and rider. Among ponies, symmetry in the 120 kg test (0.54) was significantly lower than that in the first 70 kg test (0.75, P < 0.05) and stabilities in the 100 kg (1.17) and 120 kg (1.17) tests were significantly less than that in the first 70 kg (1.46, P < 0.05). Regarding the rider, there were no significant differences in symmetry, regularity, and stability between loaded weights. The time lag between the time series of horse and rider in the 120 kg test (47.6 ms) was significantly greater than that in the first 70 kg (14.3 ms, P < 0.05) test. These results suggests that the maximum permissible load weight of the Taishuh pony trotting at 3.0 m/s over a short distance was less than 100 kg, which is 43% of the BW. PMID- 23736048 TI - Effect of gestating sow body condition, feed refusals, and group housing on growth and feed intake in grower-finishing pigs. AB - The main focus of this study was to identify sow gestation features that affect growth rate (GR) and feed intake (FI) of their offspring during grower-finishing stage. Because the sow provides a specific environment to her offspring during gestation, certain features (e.g., BW of the sow), feed refusals or gestation group, may affect her ability to deliver and feed a healthy litter. Data on 17,743 grower-finishing pigs, coming from 604 sires and 681 crossbred sows, were obtained from the Institute for Pigs Genetics. Sow gestation features were collected during multiple gestations and divided into 3 clusters describing i) sow body condition (i.e., BW, backfat, and gestation length), ii) sow feed refusals (FR), the difference between offered and eaten feed during 3 periods of gestation: 1 to 28, 25 to 50, 45 to 80 d, and iii) sow group features (i.e., number of sows, and average parity). Sow gestation features were added to the base model 1 at a time to study their effect on GR and FI. Significant gestation features (P < 0.1) were fitted simultaneously in animal model to investigate whether they could explain common litter and permanent sow effects. Gestation length had effect on GR [1.4 (g/d)/d; P = 0.04] and FI [6.8 (g/d)/d; P = 0.007]. Body weights of the sow at insemination [0.07 (g/d)/kg; P = 0.08], at farrowing [0.14 (g/d)/kg; P < 0.0001], and after lactation [0.1 (g/d)/kg; P = 0.003] had effect on GR. Sow parturition-lactation loss in backfat thickness and weight were not significant for GR and FI. Days with FR during 25 to 50 and 45 to 80 d of gestation and average FR during 45 to 80 d of gestation had negative effect on GR and when substantially increased had also a positive effect on FI. Sow FR from 1 to 28 d of gestation were not significant. Number of sows in gestation group had effect on FI [-9 (g/d)/group member; P = 0.04] and day sow entered group had an effect on GR [-0.9 (g/d)/day; P = 0.04]. Sow gestation features explained 1 to 3% of the total variance in grower-finishing pigs. Gestation features did explain phenotypic variance due to permanent sow and part of phenotypic variance due to common litter effects for FI but not for GR. PMID- 23736047 TI - Triennial Reproduction Symposium: the ovarian follicular reserve in cattle: what regulates its formation and size? AB - The ovarian follicular reserve has been linked to fertility in cattle. Young adult cattle with low vs. high numbers of antral follicles >= 3 mm in diameter in follicular waves also have fewer preantral follicles and decreased fertility. This underscores the importance of understanding the factors that regulate early follicular development and establish the ovarian follicular reserve, but little is known about how the follicular reserve is first established. In ruminants and humans, follicles form during fetal life, but there is a gap (about 50 d in cattle) between the appearance of the first primordial follicles and the first growing, primary follicles. In this review we present evidence that in cattle, fetal ovarian steroids (i.e., estradiol and progesterone) are negative regulators of both follicle formation and of the acquisition by newly formed follicles of the capacity to activate (i.e., initiate growth). The results indicate that capacity to activate is linked to the completion of meiotic prophase I by the oocyte. The inhibitory effects of estradiol on follicle activation were found to be reversible and correlated with inhibition of the progression of meiotic prophase I. Fetal bovine ovaries produce steroid hormones and production varies considerably during gestation and in a pattern consistent with the hypothesis that they inhibit follicle formation and capacity of newly formed follicles to activate in vivo. However, little was known about how steroid production is regulated. In our studies, both LH and FSH stimulated progesterone and estradiol production by ovarian pieces in vitro. The addition of testosterone to the culture medium enhanced estradiol production, especially when FSH was also present, but inhibited progesterone production, even in the presence of gonadotropins. Evidence is also presented for effects of maternal nutrition and health and for potential effects of estrogenic endocrine-disrupting chemicals on the size of the ovarian follicular reserve established during fetal life. In summary, fetal ovarian steroids may be important regulators of the early stages of follicular development in cattle. Therefore, external factors that alter steroid production or action may affect the size of the ovarian follicular reserve. PMID- 23736049 TI - Greenhouse gas emissions from swine operations: evaluation of the Intergovernmental Panel on Climate Change approaches through meta-analysis. AB - The objective was to provide a systematic review of the literature on greenhouse gas (GHG) emissions from swine operations, with a meta-analysis that integrates results of independent studies. A total of 53 studies that measured GHG emissions from swine operations were included in the analyses. Results showed that the Intergovernmental Panel on Climate Change (IPCC) approaches were effective in estimating the overall CH4 and N2O emission levels from swine operations, but the variation of the measured emissions is not adequately captured. An overestimation by the IPCC approaches for CH4 emissions was observed for swine buildings with pit systems in European studies and the average percentage relative difference (PRD) between the measured and the IPCC values is -21.1%. The observed CH4 emissions from lagoons were lower than the IPCC estimated values and the average PRD is -33.9%. In North American studies the observed N2O emission factors for swine buildings with pit systems were significantly lower than the IPCC default values whereas in European studies they were significantly greater than the IPCC default values. The measured CH4 and N2O emissions were significantly affected by stage of production (P = 0.05 and <0.01, respectively) and geographic regions (P = 0.04 and 0.02, respectively). The IPCC approaches were effective in simulating the effect of temperature on CH4 emissions from outdoor slurry storage facilities whereas they could overestimate CH4 emissions from lagoons at low temperatures. The CH4 emissions from pits inside swine buildings were not significantly affected by average ambient temperatures. A positive relationship between diet CP content and CH4 emissions was confirmed in the meta-analysis. The obtained knowledge can be helpful in efforts to improve estimation of GHG emissions from swine operations. PMID- 23736050 TI - Practical implementation of cost-effective genomic selection in commercial pig breeding using imputation. AB - Genomic selection can be implemented in pig breeding at a reduced cost using genotype imputation. Accuracy of imputation and the impact on resulting genomic breeding values (gEBV) was investigated. High-density genotype data was available for 4,763 animals from a single pig line. Three low-density genotype panels were constructed with SNP densities of 450 (L450), 3,071 (L3k) and 5,963 (L6k). Accuracy of imputation was determined using 184 test individuals with no genotyped descendants in the data but with parents and grandparents genotyped using the Illumina PorcineSNP60 Beadchip. Alternative genotyping scenarios were created in which parents, grandparents, and individuals that were not direct ancestors of test animals (Other) were genotyped at high density (S1), grandparents were not genotyped (S2), dams and granddams were not genotyped (S3), and dams and granddams were genotyped at low density (S4). Four additional scenarios were created by excluding Other animal genotypes. Test individuals were always genotyped at low density. Imputation was performed with AlphaImpute. Genomic breeding values were calculated using the single-step genomic evaluation. Test animals were evaluated for the information retained in the gEBV, calculated as the correlation between gEBV using imputed genotypes and gEBV using true genotypes. Accuracy of imputation was high for all scenarios but decreased with fewer SNP on the low-density panel (0.995 to 0.965 for S1) and with reduced genotyping of ancestors, where the largest changes were for L450 (0.965 in S1 to 0.914 in S3). Exclusion of genotypes for Other animals resulted in only small accuracy decreases. Imputation accuracy was not consistent across the genome. Information retained in the gEBV was related to genotyping scenario and thus to imputation accuracy. Reducing the number of SNP on the low-density panel reduced the information retained in the gEBV, with the largest decrease observed from L3k to L450. Excluding Other animal genotypes had little impact on imputation accuracy but caused large decreases in the information retained in the gEBV. These results indicate that accuracy of gEBV from imputed genotypes depends on the level of genotyping in close relatives and the size of the genotyped dataset. Fewer high-density genotyped individuals are needed to obtain accurate imputation than are needed to obtain accurate gEBV. Strategies to optimize development of low-density panels can improve both imputation and gEBV accuracy. PMID- 23736051 TI - Isoleucine requirement of pigs weighing 8 to 18 kg fed blood cell-free diets. AB - The aim of the present study was to determine the minimum requirement of Ile in young pigs, enabling feeding of balanced low-CP diets. Most previous studies have used experimental diets that included blood cells, which are particularly high in Leu and known to antagonize the use of Ile. One week after weaning at d 28, 100 crossbred female pigs weighing 7.9 +/- 0.7 kg were allocated to 1 of 5 dietary treatments. Diets were formulated to contain 1.15 g standardized ileal digestible (SID) Lys/MJ NE and were free of blood cells. The SID Ile was 0.42, 0.47, 0.53, 0.58, and 0.62 relative to Lys. The other indispensable AA were supplied according to requirements. Representative samples from the 5 diets were analyzed in 4 replicates at 3 different laboratories. The pigs were fed ad libitum and individually housed in 7 identical rooms during a 21-d period. At d 0, 7, 14, and 21, the pigs were weighed, and feed intake was determined. At d 15, blood samples were collected from the jugular vein to determine the plasma urea and free AA content. There were differences among the 3 laboratories in the analyzed content of several AA, and also Ile and Lys showed a large variation within the diets, which may cause variation in published requirement estimates. The concentration of Ile in plasma increased linearly (P < 0.01), and Lys in plasma decreased linearly (P = 0.02) with increasing SID Ile:Lys. A tendency for a linear decrease in plasma concentration was found for Thr (P = 0.10). Both ADFI and ADG were reduced when Ile was supplied above the Ile requirement estimate. Quadratic regression curves on ADFI, ADG, and G:F all showed the maximum at 0.52 SID Ile:Lys. Modeling with 2-sloped quadratic broken-line curves showed the maximum at 0.50, 0.53, and 0.54 SID Ile:Lys for ADFI, ADG, and G:F, respectively. In conclusion, the average estimation of requirement in this dose-response study using blood cell-free diets was 0.52 SID Ile:Lys during a 21-d experimental period from 8 kg BW. PMID- 23736052 TI - The change in differing leukocyte populations during vaccination to bovine respiratory disease and their correlations with lung scores, health records, and average daily gain. AB - Bovine respiratory disease (BRD) is the most economically important disease in U.S. feedlots. Infection can result in morbidity, mortality, and reduced average daily gain. Cheap and reliable genetic methods of prediction and protection from BRD would be highly advantageous to the industry. The immune response may correlate with BRD incidence. Cattle (n = 2,182) were vaccinated against common viral and bacterial pathogens of BRD. Two blood samples were collected, one during booster vaccination and one 21d later, enabling 3 phenotypes for each trait [prebooster (pre), postbooster (post), and delta (post minus pre)]. From the blood samples innate and adaptive responses [counts of white blood cells (WBC), neutrophils, lymphocytes, monocytes, eosinophils, and basophils] were measured. In addition, feedlot ADG and binary traits [health records (HR; 0 = healthy, 1 = ill) and lung scores (LS; collected at harvest; 0 = no lesions, 1 = lesions)] were also recorded. Traits ADG, HR, and LS have all been significantly correlated with infection to BRD. In this investigation we aimed to find correlations between the immune response and ADG, HR, and LS to find an easily measurable trait that would be a good predictor of BRD resistance after vaccination. The results showed an average positive delta for the innate immune response (eosinophils, basophils, neutrophils), whereas the adaptive immune response had an average negative delta (lymphocytes). Overall, we discovered that the immune responses had moderately high heritabilities (h(2); lowest: delta monocytes, 0.21 +/- 0.05; greatest: pre lymphocytes: 0.5 +/- 0.05), with lymphocytes having the greatest h(2) throughout the study (h(2) >= 0.41). All genetic correlations were calculated using bivariate REML models. Although LS did not significantly correlate with any of the immune phenotypes, both ADG (post lymphocytes, -0.24 +/- 0.12) and HR (pre eosinophils, -0.67 +/- 0.29; delta WBC, 0.5 +/- 0.24, and delta lymphocytes, -0.67 +/- 0.21) did. All the significant genetic correlations with HR were negative; resistance to BRD appears to be a function of greater delta lymphocytes and WBC. The increase in eosinophils may potentially link its role in decreasing lymphocytes. These results may enable producers to predict if revaccination, quarantine, and breeding of animals is required to reduce the incidence of BRD postvaccination. In addition, immunological phenotypes maybe used to aid genomic selection indices to select animals with greater rates of protection after BRD vaccination. PMID- 23736053 TI - Thermal manipulation of the embryo modifies the physiology and body composition of broiler chickens reared in floor pens without affecting breast meat processing quality. AB - Selection in broiler chickens has increased muscle mass without similar development of the cardiovascular and respiratory systems, resulting in limited ability to sustain high ambient temperatures. The aim of this study was to determine the long-lasting effects of heat manipulation of the embryo on the physiology, body temperature (Tb), growth rate and meat processing quality of broiler chickens reared in floor pens. Broiler chicken eggs were incubated in control conditions (37.8 degrees C, 56% relative humidity; RH) or exposed to thermal manipulation (TM; 12 h/d, 39.5 degrees C, 65% RH) from d 7 to 16 of embryogenesis. This study was planned in a pedigree design to identify possible heritable characters for further selection of broiler chickens to improve thermotolerance. Thermal manipulation did not affect hatchability but resulted in lower Tb at hatching and until d 28 post-hatch, with associated changes in plasma thyroid hormone concentrations. At d 34, chickens were exposed to a moderate heat challenge (5 h, 32 degrees C). Greater O2 saturation and reduced CO2 partial pressure were observed (P < 0.05) in the venous blood of TM than in that of control chickens, suggesting long-term respiratory adaptation. At slaughter age, TM chickens were 1.4% lighter and exhibited 8% less relative abdominal fat pad than controls. Breast muscle yield was enhanced by TM, especially in females, but without significant change in breast meat characteristics (pH, color, drip loss). Plasma glucose/insulin balance was affected (P < 0.05) by thermal treatments. The heat challenge increased the heterophil/lymphocyte ratio in controls (P < 0.05) but not in TM birds, possibly reflecting a lower stress status in TM chickens. Interestingly, broiler chickens had moderate heritability estimates for the plasma triiodothyronine/thyroxine concentration ratio at d 28 and comb temperature during the heat challenge on d 34 (h(2) > 0.17). In conclusion, TM of the embryo modified the physiology of broilers in the long term as a possible adaptation for heat tolerance, without affecting breast meat quality. This study highlights the value of 2 new heritable characters involved in thermoregulation for further broiler selection. PMID- 23736054 TI - Estimation of standardized phosphorus retention for inorganic phosphate sources in broilers. AB - Two experiments were conducted to estimate standardized P retention (SPR) values of dicalcium phosphate (DCP), monocalcium phosphate (MCP), and monopotassium phosphate (MKP) in broilers. In total, ninety-six 22-d-old male broilers with similar BW (780 g average) were used in each experiment. The chicks were randomly allotted to 1 of 4 treatments (P-free, DCP, MCP, or MKP diets) with 6 replicate cages of 4 chicks each in a completely randomized design. After 3-d acclimation, chicks were fasted for 24 h and then fed P-free, DCP, MCP, or MKP diets for 4 h in Exp. 1 or 72 h in Exp. 2. Excreta samples were collected for a total of 28 or 52 h (24 or 48 h after feed withdrawal) in Exp. 1 and 96 or 120 h (24 or 48 h after feed withdrawal) in Exp. 2, respectively. The excreta collection time of 52 h in Exp. 1 or 96 h in Exp. 2 was adequate for the estimation of SPR. The estimated basal endogenous P losses (EPL) in chicks fed the P-free diet were 109 +/- 4 mg/52 h per bird and 49.2 +/- 4.0 mg/96 h per bird in Exp. 1 and 2, respectively. The SPR values of inorganic phosphate sources corrected by the above basal EPL differed (P < 0.001) in Exp. 2 but not in Exp. 1. However, these SPR values were very similar between the 2 experiments with 68.7, 69.8, or 76.6% in Exp. 1 and 71.8, 70.6, or 78.3% in Exp. 2 for DCP, MCP, or MKP, respectively. The results from the current study indicated that, compared with the 72-h feeding and 96-h excreta collection procedure, the 4-h feeding and 52-h excreta collection procedure was a relatively quicker time- and labor-saving method for estimating the SPR values of inorganic P sources in broilers. The estimated SPR values of commonly used inorganic P sources (MCP and DCP) were about 70%. PMID- 23736055 TI - A genomewide association study identified CYP2J2 as a gene controlling serum vitamin D status in beef cattle. AB - Vitamin D is an important modulator of calcium homeostasis and has several effects on the immune system. The objective of the study was to estimate its heritability and to identify genomic regions associated with concentration of circulating 25-hydroxyvitamin D (25OHD) in beef cattle. Status of vitamin D was measured in crossbred animals from Cycle VII of the United States Meat Animal Research Center (USMARC) Germplasm Evaluation Project. Progeny were born from March through May in 2008 and in 2010. Heritability was estimated and a genomewide association study was conducted on the concentration of 25OHD measured in 1,432 animals at preconditioning and 1,333 animals at weaning. Genotyping of the population was done by imputing from the parental generation genotyped with a high density array (777,000 SNP) to a target population genotyped with a medium density SNP array (50,000 SNP). After imputation, 675,018 SNP were used in the genomewide association study. Heritability of concentration of circulating 25OHD in cattle at preconditioning and at weaning was 0.41 +/- 0.08 and 0.32 +/- 0.11, respectively. A region on chromosome 3 was associated with circulating 25OHD. The region on BTA3 had 7 SNP significantly (P < 7.4 * 10(-8)) associated at the genomewide level with serum concentrations of serum 25OHD. Genomewide significant SNP spanned the region between 84.93 and 86.65 megabases (Mb); however, 6 SNP reside between 86.64 and 86.65 Mb. The gene CYP2J2 was identified as a candidate gene associated with concentrations of serum 25OHD in cattle. This is 1 of 6 enzymes involved in metabolizing vitamin D to 25OHD. Results from the present study suggest that CYP2J2 is a gene controlling serum 25OHD concentrations in cattle. CYP2J2 should be considered a prime candidate for understanding both genetic and physiological factors affecting serum 25OHD concentrations in cattle and, therefore, vitamin D status. PMID- 23736056 TI - Effects of feeding system and slaughter age on the growth and carcass characteristics of tropical-breed steers. AB - This study aimed to compare the growth performances and carcass characteristics of tropical-breed steers reared in 2 contrasted feeding systems (indoor vs. pasture) and slaughtered at different ages (early vs. late). A total of 309 Creole steers (growing at an initial BW of 173 +/- 3 kg and an initial age of 252 +/- 4 d) were used over a continuous 12-yr study. Indoor steers were housed in a cattle shed, fed fresh-cut grass plus concentrate, and slaughtered at 14.5 or 17.1 +/- 0.1 mo of age. Pasture steers were pasture grazed without supplemental feed, and slaughtered at 17.6 and 21.2 +/- 0.1 mo of age. Indoor-fed steers had a greater ADG (786 vs. 517 +/- 29 g*d(-1); P < 0.0001) and more carcass fat (164 vs. 145 +/- 4.5 g*kg(-1); P = 0.001) than pasture-fed steers. Late-slaughtered steers had decreased ADG (630 vs. 673 +/- 27 g*d(-1); P = 0.001) but greater dressing percentages (hot dressing percentage = 55.7 vs. 54.7 +/- 0.34%; chilled dressing percentage = 54.5 vs. 53.4 +/- 0.34%; P < 0.0001) than early-slaughtered steers. The interaction between feeding system and slaughter age was significant for carcass tissue composition. Whole-carcass muscle content was greater in late slaughtered steers than early-slaughtered steers, especially in pasture-fed steers (720 vs. 698 +/- 6.0 g*kg(-1); P < 0.0001), but less so in indoor-fed steers (707 vs. 700 +/- 5.9 g*kg(-1); P = 0.046). Furthermore, increasing slaughter age had no effect on carcass fat in indoor-fed steers (162 vs. 166 +/- 4.8 g*kg(-1); P = 0.342), but decreased carcass fat in pasture-fed steers (150 vs. 140 +/- 5.0 g*kg(-1); P = 0.014). The results showed that slaughter age and feeding system are 2 major factors that independently affect most of the growth and carcass traits of tropical-breed steers but jointly influence tissue deposition. Our study found that in tropical-breed steers that are grazing, late slaughtering grazing steers increased carcass muscle content without extra fat, thus yielding a carcass quality better suited to consumer choices. PMID- 23736059 TI - Potential benefits of genomic selection on genetic gain of small ruminant breeding programs. AB - In conventional small ruminant breeding programs, only pedigree and phenotype records are used to make selection decisions but prospects of including genomic information are now under consideration. The objective of this study was to assess the potential benefits of genomic selection on the genetic gain in French sheep and goat breeding designs of today. Traditional and genomic scenarios were modeled with deterministic methods for 3 breeding programs. The models included decisional variables related to male selection candidates, progeny testing capacity, and economic weights that were optimized to maximize annual genetic gain (AGG) of i) a meat sheep breeding program that improved a meat trait of heritability (h(2)) = 0.30 and a maternal trait of h(2) = 0.09 and ii) dairy sheep and goat breeding programs that improved a milk trait of h(2) = 0.30. Values of +/-0.20 of genetic correlation between meat and maternal traits were considered to study their effects on AGG. The Bulmer effect was accounted for and the results presented here are the averages of AGG after 10 generations of selection. Results showed that current traditional breeding programs provide an AGG of 0.095 genetic standard deviation (sigmaa) for meat and 0.061 sigmaa for maternal trait in meat breed and 0.147 sigmaa and 0.120 sigmaa in sheep and goat dairy breeds, respectively. By optimizing decisional variables, the AGG with traditional selection methods increased to 0.139 sigmaa for meat and 0.096 sigmaa for maternal traits in meat breeding programs and to 0.174 sigmaa and 0.183 sigmaa in dairy sheep and goat breeding programs, respectively. With a medium sized reference population (nref) of 2,000 individuals, the best genomic scenarios gave an AGG that was 17.9% greater than with traditional selection methods with optimized values of decisional variables for combined meat and maternal traits in meat sheep, 51.7% in dairy sheep, and 26.2% in dairy goats. The superiority of genomic schemes increased with the size of the reference population and genomic selection gave the best results when nref > 1,000 individuals for dairy breeds and nref > 2,000 individuals for meat breed. Genetic correlation between meat and maternal traits had a large impact on the genetic gain of both traits. Changes in AGG due to correlation were greatest for low heritable maternal traits. As a general rule, AGG was increased both by optimizing selection designs and including genomic information. PMID- 23736060 TI - Genetic analysis of vibriosis and viral nervous necrosis resistance in Atlantic cod (Gadus morhua L.) using a cure model. AB - The aim of this study was to investigate whether observed time-until-death of Atlantic cod (Gadus morhua L.) juveniles in separate challenge tests with Vibrio anguillarum (causes vibriosis) and nodavirus [causes viral nervous necrosis (VNN)] are due to differences in susceptibility (whether at risk or not) or increased endurance (individual hazard, given that the animal is susceptible) using a cure mixture (CURE) model with Gibbs sampling. Observed time-until-death, prepared as sequential binary records, were analyzed with the CURE model and results were compared with cross-sectional threshold (SIMPLE) and an ordinary longitudinal survival score (NAIVE) model (i.e., assuming that all animals are susceptible). Overall mortality at the end of the test was 86 and 71% for vibriosis and VNN, respectively. But the CURE model estimated 92 and 82% of the population to be susceptible to vibriosis and VNN, respectively. Hence, a substantial fraction among the survivors were considered to be susceptible but with high endurance. The underlying heritability of susceptibility was moderate for vibriosis (0.33) and extremely high for VNN (0.91), somewhat greater compared with classical SIMPLE model (0.19 and 0.76 for vibriosis and VNN, respectively), analyzing end survival as a cross-sectional binary trait. Estimates of the underlying heritability were low for single test-day scores of both endurance (0.02 and 0.15 for vibriosis and VNN, respectively) in the CURE model and for the NAIVE model (0.02 and 0.18 for vibriosis and VNN, respectively). Based on the CURE model, the genetic correlation between susceptibility and endurance was low to moderately positive and significantly different from unity (P < 0.01) for both vibriosis (0.13) and VNN (0.47). Estimated breeding values from the SIMPLE and NAIVE models showed moderate to high correlations (0.41 to 0.96) with EBV for susceptibility and endurance in the CURE model. The analyses indicate that susceptibility and endurance are apparently distinct genetic traits. Still, the genetic variation estimated in the SIMPLE and NAIVE models seems to a large extent to be controlled by susceptibility and an efficient genetic selection for reduced susceptibility to vibriosis and VNN is therefore likely feasible even when using classical (noncure) models. Earlier termination of the challenge test or back truncation of survival data is not recommended as this likely shifts the focus of selection towards endurance rather than susceptibility. PMID- 23736061 TI - Candidate genes and single nucleotide polymorphisms associated with variation in residual feed intake in beef cattle. AB - The candidate gene approach was used to identify genes associated with residual feed intake (RFI) in beef steers. The approach uses prior knowledge of gene functions to predict their biological role in the variation observed in a trait. It is suited to identify genes associated with complex traits where each gene has a relatively small effect. First, positional candidate genes were identified within the genomic positions of previously reported QTL associated with component traits related to RFI such as dry matter intake (DMI), growth, feed conversion ratio (FCR), average daily gain (ADG), and energy balance. Secondly, the positional candidate genes were prioritized into functional candidate genes according to their biological functions and their relationship with the biological processes associated with RFI including carbohydrate, fat and protein metabolism, thermoregulation, immunity and muscle activity. Single nucleotide polymorphisms (SNPs) located within the functional candidate genes were identified using mRNA sequences and prioritized into functional classes such as non-synonymous (nsSNP), synonymous (sSNP) or intronic SNP. A total of 117 nsSNP were considered as functional SNP and genotyped in steers at the University of Alberta ranch in Kinsella. Multiple marker association analysis in ASReml was performed using RFI data obtained from 531 beef steers. Twenty-five SNP were significantly associated with RFI (P < 0.05) accounting for 19.7% of the phenotypic variation. Using SIFT program to predict the effect of the SNP on the function of the corresponding protein, 3 of the 25 SNP were predicted to cause a significant effect on protein function (P < 0.05). One of the 3 SNP was located in the GHR gene and was also associated with a significant effect on the tertiary structure of the GHR protein (P < 0.05) as modeled using SWISSModel software. Least square means for each genotype were estimated and an over-dominance effect was observed for the SNP located in the GHR, CAST, ACAD11 and UGT3A1 genes. In addition, 2 other SNP showed a dominance effect and 3 genes had an additive effect. Gene network analysis performed in Ingenuity pathway analysis (IPA) software (Ingenuity Systems, www.ingenuity.com) indicated that the significant genes were involved in biological pathways such as lipid, protein and energy metabolism, electron transport and membrane signaling. The genes in this study, if validated in other beef cattle populations, may be useful for marker assisted selection for feed efficiency. PMID- 23736062 TI - Linkage disequilibrium and haplotype block structure in six commercial pig lines. AB - Linkage disequilibrium (LD) across the genome is critical information for association studies and genomic selection because it determines the number of SNP that should be used for a successful association analysis and genomic selection. Linkage disequilibrium also influences the accuracy of genomic breeding values. Some studies have demonstrated that SNP in strong LD are organized into discrete blocks of haplotypes, which are separated by possibly hot spots of recombination. To reduce the number of markers needed to be genotyped for association mapping, a set of SNP can be selected that labels all haplotype blocks. We estimated the LD, calculated the average haplotype block size for 6 pig lines, and compared the block size between lines. Six commercial pig lines were genotyped using the Illumina PorcineSNP60 (number of markers M = 62,163) Genotyping BeadChip (Illumina Inc.); on average, a panel of 37,623 SNP with an average minor allelic frequency (MAF) of 0.283 was included in the analysis. The LD declined as a function of distance. All pig lines had an average r(2) above 0.3 for markers 100 to 150 apart. The estimated average block size was 394.885 kb, and blocks between 100 and 400 kb were most prominent (49.96%) in all lines. These results showed that the extent of LD in pigs is much larger than in the cattle population, in accordance with the genetic map length of pigs, which is much shorter than cattle. The evaluated lines have 2,640 to 3,037 blocks, covering 45% of the pig genome, on average. Differences in haplotype block size between lines were observed for some chromosomes (i.e., SSC 3, 5, 7, 13, 14, and 18), which provide a direction for future studies of haplotype block conservation or divergence across lines. PMID- 23736063 TI - A safe scene? PMID- 23736064 TI - Technical evaluation of the novel preanalytical module on instrumentation laboratory ACL TOP: advancing automation in hemostasis testing. AB - Automation in hemostasis testing is entering an exciting and unprecedented phase. This study was planned to assess the performance of the new preanalytical module on the hemostasis testing system Instrumentation Laboratory ACL TOP. The evaluation included interference studies to define reliable thresholds for rejecting samples with significant concentrations of interfering substances; within-run imprecision studies of plasma indices on four different interference degrees for each index; comparison studies with reference measures of hemolysis index, bilirubin, and triglycerides on clinical chemistry analyzers; and calculation of turnaround time with and without automatic performance of preanalytical check. The upper limits for sample rejection according to our interference studies were 3.6 g/L for hemoglobin, 13.6 mg/dL for bilirubin, and 1454 mg/dL for triglycerides. We found optimal precision for all indices (0.6% to 3.1% at clinically relevant thresholds) and highly significant correlations with reference measures on clinical chemistry analyzers (from 0.985 to 0.998). The limited increase of turnaround time (i.e., +3% and +5% with or without cap piercing), coupled with no adjunctive costs over performance of normal coagulation assays, contribute to make the automatic check of plasma indices on ACL TOP a reliable and practical approach for improving testing quality and safeguarding patient safety. PMID- 23736065 TI - Changes in major charge transport by molecular spatial orientation in graphene channel field effect transistors. AB - Changes in major charge transport of graphene channel transistors in terms of the spatial orientation of adsorbed functional molecules were demonstrated. In contrast to the horizontally (physically) bound molecules, the vertically (chemically) bound molecules did not change major charge carriers of graphene channels, revealing the molecular orientation-dependent doping effects. PMID- 23736066 TI - Imino phenoxide complexes of niobium and tantalum as catalysts for the polymerization of lactides, epsilon-caprolactone and ethylene. AB - Imino phenoxide complexes of Nb and Ta show precise control towards the solvent free ring-opening polymerization of lactides (LA) and epsilon-caprolactone (CL). There is a close proximity between the observed number average molecular weight (M(n)) and theoretical molecular weight and the molecular weight distributions (MWDs) were found to be narrow. Analysis of low molecular weight oligomers of LA synthesized from these compounds revealed that the ligand is incorporated as one of the end terminal groups in the polymer chain. In addition, these complexes were realized to be precatalysts for the polymerization of ethylene. PMID- 23736068 TI - Toxicity following laundry detergent pod ingestion. AB - Laundry detergent pods (LDPs) have only recently become available in the United States, and there has been increasing concern regarding pediatric ingestions of them. We describe a 15-month-old female infant who ingested an LDP and had a depressed level of consciousness, metabolic acidosis, pulmonary toxicity, and swallowing difficulties. It is currently unclear what the exact etiologic agent(s) is responsible for the toxicity associated with LDPs. The case demonstrates the potential for significant toxicity following the ingestion of an LDP. Clearly, measures should be taken to avoid ingestions of these products. PMID- 23736069 TI - Laundry detergent "pod" ingestions: a case series and discussion of recent literature. AB - OBJECTIVES: The objectives of this study were to present and explore the clinical presentation of the increasingly common pediatric exposure to the widely available single-use laundry packets or "laundry pods." METHODS: This is a case report of 4 pediatric patients with significant toxicity due to laundry pod detergent exposure and a review of the available literature including abstract only publications. RESULTS: An unexpectedly severe clinical pattern was noted; 3 of the 4 children required intubation for management, airway injury was noted in 1 of them, and 2 of them had hospital courses of at least 1 week. The literature suggests that laundry pod exposures are associated with increased morbidity compared to traditional laundry detergent exposures. To date, no specific contaminant or component has been identified as being responsible for the injury, although some evidence points to the surfactant component. CONCLUSIONS: A different approach to the triage and management of pediatric exposures to laundry detergent pod ingestions is required compared with nonpod ingestions. Although the exact cause is not known, practitioners should be vigilant for rapid onset of neurological impairment and inability to protect the airway in addition to its caustic effects. PMID- 23736070 TI - Acute renal failure in a child with thrombocytopenic purpura caused by acute Epstein-Barr virus infection after treatment with anti-D immunoglobulin. AB - Immune thrombocytopenia (ITP) in children is usually a benign, self-limiting disorder. An acute Epstein-Barr virus (EBV) infection usually causes atypical lymphocytosis and mild decrease in platelets. Severe thrombocytopenia is an extremely rare complication. Anti-D immunoglobulin has been used for treatment of ITP in Rh(D)-positive nonsplenectomized patients. Severe hemolysis and acute renal failure are extremely rare complications that may be aggravated by the presence of an acute EBV infection. It is believed that anti-D immunoglobulin triggers an unusual virus-induced immune response causing hemolysis. We present a 4-year-old girl with ITP caused by an acute EBV infection that developed acute kidney injury following treatment with anti-D immunoglobulin. The patient recovered completely from thrombocytopenia and renal dysfunction. Intravascular hemolysis and acute kidney injury are consistent with anti-D immunoglobulin mechanism of action. Pediatric patients treated with anti-D immunoglobulin for ITP should be closely monitored for signs and symptoms of hemolysis that may be aggravated by the presence of EBV infection leading to impaired renal function. PMID- 23736071 TI - A rare adverse effect of metronidazole: nervous system symptoms. AB - Metronidazole, as a 5-nitroimidazole compound, is effective on anaerobic bacteria and protozoon diseases. Mostly, metronidazole is a tolerable drug but rarely presents serious adverse effects on the nervous system. In case of these adverse effects, treatment must be stopped.In this report, a 3-year-old child hospitalized because of diarrhea is presented. During the metronidazole treatment, loss of sight, vertigo, ataxia, and headache occurred as the adverse effects. By this report, we want to express the rare adverse effects of drugs in the differential diagnoses of nervous system diseases. PMID- 23736072 TI - Recurrent intussusception. AB - Recurrent intussusception is defined as an occurrence of intussusception of a bowel loop in a patient with a prior resolution of intussusception, either spontaneously or with an intervention. It is not rare to develop a subsequent episode after a successful reduction of intussusception. We report the cases of 2 children who presented to the emergency department with recurrent intussusception and review the pertinent literature. PMID- 23736073 TI - Chronic valproic acid intoxication. AB - Valproic acid intoxication may be associated with cerebral, cardiovascular, respiratory, gastrointestinal, and hematologic complications. We report a case of a 7-year-old girl, epilepsy-treated chronically with valproic acid, sulthiame, and clonazepam, who presented to the emergency room because of a global deterioration during the preceding 2 months, including poorer feeding and worsened general responsiveness. The girl was later diagnosed to have chronic valproic acid intoxication. PMID- 23736074 TI - Bacterial meningitis post-PCV7: declining incidence and treatment. AB - The epidemiology of bacterial meningitis in the United States has changed tremendously in the past 20 years. Since the introduction of the Haemophilus influenzae type b vaccine in 1988, the incidence of H. influenzae type b meningitis has declined by at least 97%, and Streptococcus pneumoniae has emerged as the most common etiologic agent. The PCV7 (7-valent pneumococcal conjugate vaccine [Prevnar]; Wyeth Pharmaceuticals) vaccine, which targets 7 pneumococcal serotypes, was introduced in 2000 and has had an enormous impact on both the incidence and epidemiology of bacterial meningitis. This article reviews the impact of the PCV7 vaccine and the most up-to-date evidence on diagnosis and empiric therapy of suspected bacterial meningitis in the current day. PMID- 23736076 TI - Pediatric emergency medicine: legal briefs. PMID- 23736077 TI - Household "HazMat". Pediatric exploratory ingestion of a single-use detergent sac. PMID- 23736078 TI - ECGs in the ED. PMID- 23736080 TI - Physostigmine reverses disturbances of the intestinal microcirculation during experimental endotoxemia. AB - Intestinal microcirculatory disturbances play an important role in the pathophysiology of sepsis. A neural anti-inflammatory pathway has been suggested as a potential target for therapy that may dampen systemic inflammation. The aim of this study is to investigate the effects of physostigmine, a cholinesterase inhibitor, on the intestinal microcirculation and vascular contractility in experimental endotoxemia. Endotoxemia was induced in Lewis rats by intravenous lipopolysaccharide (LPS) administration. Animals were treated with either physostigmine or saline (control) following LPS challenge. The intestinal microcirculation, including leukocyte-endothelial interaction, functional capillary density (FCD) and non-perfused capillary density (NCD), was examined by intravital microscopy (IVM) 2 hours after LPS administration. The impact of physostigmine on vascular contractility of rat aortic rings was examined by in vitro myography. Physostigmine significantly reduced the number of adhering leukocytes in intestinal submucosal venules (V1 venules: -61%, V3 venules: -36%) of LPS animals. FCD was significantly increased by physostigmine treatment (circular muscle layer: +180%, longitudinal muscle layer: +162%, mucosa: +149%). Low concentrations of physostigmine produced significant contraction of aortic ring preparations, whereas high concentrations produced relaxation. In conclusion, physostigmine treatment significantly improved the intestinal microcirculation in experimental endotoxemia by reducing leukocyte adhesion and increasing FCD. PMID- 23736079 TI - Inhibition of glutathione biosynthesis alters compartmental redox status and the thiol proteome in organogenesis-stage rat conceptuses. AB - Developmental signals that control growth and differentiation are regulated by environmental factors that generate reactive oxygen species (ROS) and alter steady-state redox environments in tissues and fluids. Protein thiols are selectively oxidized and reduced in distinct spatial and temporal patterns in conjunction with changes in glutathione/glutathione disulfide (GSH/GSSG) and cysteine/cystine (Cys/CySS) redox potentials (E(h)) to regulate developmental signaling. The purpose of this study was to measure compartment-specific thiol redox status in cultured organogenesis-stage rat conceptuses and to evaluate the impact of thiol oxidation on the redox proteome. The visceral yolk sac (VYS) has the highest initial (0 h) total intracellular GSH (GSH+2GSSG) concentration (5.5 mM) and the lowest Eh (-223 mV) as determined by HPLC analysis. Total embryo (EMB) GSH concentrations ranged lower (3.2 mM) and were only slightly more oxidized than the VYS. Total GSH concentrations in yolk sac fluid (YSF) and amniotic fluid (AF) are >500-fold lower than in tissues and are highly oxidized (YSF E(h)=-121 mV and AF E(h)=-49 mV). Steady-state total Cys concentrations (Cys+2CySS) were significantly lower than GSH in tissues but were otherwise equal in VYS and EMB near 0.5 mM. On gestational day 11, total GSH and Cys concentrations in EMB and VYS increase significantly over the 6h time course while E(h) remains relatively constant. The Eh (GSH/GSSG) in YSF and AF become more reduced over time while E(h) (Cys/CySS) become more oxidized. Addition of L buthionine-S,R-sulfoximine (BS0) to selectively inhibit GSH synthesis and mimic the effects of some GSH-depleting environmental chemicals significantly decreased VYS and EMB GSH and Cys concentrations and increased Eh over the 6h exposure period, showing a greater overall oxidation. In the YSF, BSO caused a significant increase in total Cys concentrations to 1.7 mM but did not significantly change the E(h) for Cys/CySS. A significant net oxidation was seen in the BSO-treated AF compartment after 6 h. Biotinylated iodoacetamide (BIAM) labeling of proteins revealed the significant thiol oxidation of many EMB proteins following BSO treatment. Quantitative changes in the thiol proteome, associated with developmentally relevant pathways, were detected using isotope coded affinity tag (ICAT) labeling and mass spectroscopy. Adaptive pathways were selectively enriched with increased concentrations of proteins involved in mRNA processing (splicesome) and mRNA stabilization (glycolysis, GAPDH), as well as protein synthesis (aminoacyl-tRNA) and protein folding (antigen processing, Hsp70, protein disulfide isomerase). These results show the ability of chemical and environmental modulators to selectively alter compartmental intracellular and extracellular GSH and Cys concentrations and change their corresponding E(h) within the intact viable conceptus. The altered E(h) were also of sufficient magnitude to alter the redox proteome and change relative protein concentrations, suggesting that the mechanistic links through which environmental factors inform and regulate developmental signaling pathways may be discovered using systems developmental biology techniques. PMID- 23736081 TI - Oxygen promotes biofilm formation of Shewanella putrefaciens CN32 through a diguanylate cyclase and an adhesin. AB - Although oxygen has been reported to regulate biofilm formation by several Shewanella species, the exact regulatory mechanism mostly remains unclear. Here, we identify a direct oxygen-sensing diguanylate cyclase (DosD) and reveal its regulatory role in biofilm formation by Shewanella putrefaciens CN32 under aerobic conditions. In vitro and in vivo analyses revealed that the activity of DosD culminates to synthesis of cyclic diguanylate (c-di-GMP) in the presence of oxygen. DosD regulates the transcription of bpfA operon which encodes seven proteins including a large repetitive adhesin BpfA and its cognate type I secretion system (TISS). Regulation of DosD in aerobic biofilms is heavily dependent on an adhesin BpfA and the TISS. This study offers an insight into the molecular mechanism of oxygen-stimulated biofilm formation by S. putrefaciens CN32. PMID- 23736082 TI - Hypothalamic proteoglycan syndecan-3 is a novel cocaine addiction resilience factor. AB - Proteoglycans like syndecan-3 have complex signaling roles in addition to their function as structural components of the extracellular matrix. Here, we show that syndecan-3 in the lateral hypothalamus has an unexpected new role in limiting compulsive cocaine intake. In particular, we observe that syndecan-3 null mice self-administer greater amounts of cocaine than wild-type mice. This effect can be rescued by re-expression of syndecan-3 in the lateral hypothalamus with an adeno-associated viral vector. Adeno-associated viral vector delivery of syndecan 3 to the lateral hypothalamus also reduces motivation for cocaine in normal mice. Syndecan-3 limits cocaine intake by modulating the effects of glial-cell-line derived neurotrophic factor, which uses syndecan-3 as an alternative receptor. Our findings indicate syndecan-3-dependent signaling as a novel therapeutic target for the treatment of cocaine addiction. PMID- 23736084 TI - Chronological age affects the permeation of fentanyl through human skin in vitro. AB - AIM: To study the influence of chronological age on fentanyl permeation through human skin in vitro using static diffusion cells. Elderly individuals are known to be more sensitive to opioids and obtain higher plasma concentrations following dermal application of fentanyl compared to younger individuals. The influence of age - as an isolated pharmacokinetic term - on the absorption of fentanyl has not been previously studied. METHOD: Human skin from 30 female donors was mounted in static diffusion cells, and samples were collected during 48 h. Donors were divided into three age groups: <30 years of age (n = 6), >=30 and <60 years of age (n = 18) and >=60 years of age (n = 6). RESULTS: The youngest group had a significantly higher mean absorption (3,100 ng/cm(2)) than the two other groups (2,000 and 1,475 ng/cm(2), respectively) and a significant larger AUC (young age group: 9,393 ng; middle and old age groups: 5,922 and 4,050 ng, respectively). Furthermore, the lag time and absorption rate were different between the three groups, with a significantly higher rate in the young participants versus the oldest participants. CONCLUSION: We demonstrate that fentanyl permeates the skin of young individuals in greater amounts and at a higher absorption rate than in middle-aged and old individuals in vitro. PMID- 23736083 TI - Do patients who take part in stroke research differ from non-participants? Implications for generalizability of results. AB - BACKGROUND: Stroke is one of the most disabling neurological conditions. Clinical research is vital for expanding knowledge of treatment effectiveness among stroke patients. However, evidence begins to accumulate that stroke patients who take part in research represent only a small proportion of all stroke patients. Research participants may also differ from the broader patient population in ways that could potentially distort treatment effects reported in therapeutic trials. The aims of this study were to estimate the proportion of stroke patients who take part in clinical research studies and to compare demographic and clinical profiles of research participants and non-participants. METHODS: 5,235 consecutive patients admitted to the Stroke Care Unit of the Royal Melbourne Hospital, Melbourne, Australia, for stroke or transient ischaemic attack between January 2004 and December 2011 were studied. The study used cross-sectional design. Information was collected on patients' demographic and socio-economic characteristics, risk factors, and comorbidities. Associations between research participation and patient characteristics were initially assessed using chi(2) or Mann-Whitney tests, followed by a multivariable logistic regression analysis. The logistic regression analysis was carried out using generalised estimating equations approach, to account for patient readmissions during the study period. RESULTS: 558 Stroke Care Unit patients (10.7%) took part in at least one of the 33 clinical research studies during the study period. Transfer from another hospital (OR = 0.35, 95% CI 0.22-0.55), worse premorbid function (OR = 0.61, 95% CI 0.54-0.70), being single (OR = 0.61, 95% CI 0.44-0.84) or widowed (OR = 0.77, 95% CI 0.60-0.99), non-English language (OR = 0.67, 95% CI 0.53-0.85), high socio economic status (OR = 0.74, 95% CI 0.59-0.93), residence outside Melbourne (OR = 0.75, 95% CI 0.60-0.95), weekend admission (OR = 0.78, 95% CI 0.64-0.94), and a history of atrial fibrillation (OR = 0.79, 95% CI 0.63-0.99) were associated with lower odds of research participation. A history of hypertension (OR = 1.50, 95% CI 1.08-2.07) and current smoking (OR = 1.23, 95% CI 1.01-1.50) on the other hand were associated with higher odds of research participation. CONCLUSIONS: The results of this study indicate that stroke patients who take part in clinical research do not represent 'typical' patient admitted to a stroke unit. The imbalance of prognostic factors between stroke participants and non-participants has serious implications for interpretation of research findings reported in stroke literature. This study provides insights into clinical, demographic, and socio-economic characteristics of stroke patients that could potentially be targeted to enhance generalizability of stroke research studies. Given the imbalance of prognostic factors between research participants and non participants, future studies need to examine differences in stroke outcomes of these groups of patients. PMID- 23736085 TI - Genomics and proteomics: how long do we need to reach clinical results? AB - BACKGROUND: Discovery of the ideal biomarker for clinical care remains a major challenge. Recent progress in genomic and proteomic technologies has allowed the identification of thousands of potential markers, although the benefits of these findings in clinical routine use are not completely evident yet. METHODS: Major genomics and proteomics approaches are outlined and their clinical applications are described. Future developments in clinical nephrology are discussed. CONCLUSION: Genomics and proteomics technologies, used to measure gene expression at the transcript and at the protein levels, provide complementary information, which paves the way for systems biology. The fields of genomics and proteomics continue to develop rapidly, and it is evident that there is great potential for their ability to predict diseases and outcomes. However, there are several tasks that must be accomplished to convert all these '-omics' approaches into clinical practice. Collaboration between clinicians, scientists and healthcare funding organizations together with specific guideline development and high-throughput analytical automation will be crucial to reach the final potential of these technologies. PMID- 23736086 TI - Reply to: does the abbreviation 'H' in HELLP syndrome mean haemolysis or hypertension? PMID- 23736087 TI - A single intraperitoneal injection of ketamine does not affect spatial working, reference memory or neurodegeneration in adult mice: An animal study. AB - BACKGROUND: Ketamine is an anaesthetic and analgesic drug used in research and clinical practice. Little is known about the effects of different doses of this drug on memory and brain cellular death. OBJECTIVE: To study the effects of different doses of ketamine on working and reference memory, and neurodegeneration in adult mice. DESIGN: A randomised study. SETTINGS: The study was carried out in a basic science laboratory, between March 2011 and August 2012. ANIMALS: Forty-eight 7-month-old, male C57BL/6 mice were used. INTERVENTION: Animals received a single intraperitoneal injection of physiological saline solution or one of three doses of ketamine (25, 75 or 150 mg kg(-1)). Each group consisted of 12 animals (seven animals for behavioural tests and five animals for histopathological and immunohistochemical studies). The animals used for histopathology studies were sacrificed 3 h after anaesthesia. MAIN OUTCOME MEASURES: Working and reference memories were assessed using the radial-maze test over 12 consecutive days. The equilibrium was tested using the vertical pole (4 and 24 h after injection), whereas locomotion was assessed using the open field (24, 48 and 72 h after injection). Histopathological (haematoxylin eosin staining) and immunohistochemical analyses (procaspase-3 and activated caspase-3 detections) were performed 3 h after injection to assess neurodegeneration in the retrosplenial and visual cortices, pyramidal cell layer of the cornu Ammonis 1 and cornu Ammonis 3 areas of the hippocampus, in the granular layer of the dentate gyrus, in the laterodorsal thalamic nucleus, striatum and accumbens nucleus. RESULTS: No significant differences were observed between the groups regarding the number of dead cells and cells showing positive immune-reactivity in the different regions of the brain studied. The performance in the vertical pole test and the number of reference and working memory errors in the radial-maze were similar in all groups. Nevertheless, the animals treated with ketamine 75 mg kg(-1) were transiently more active, walking a greater total distance at a greater speed in the open field than other groups (power of 0.96). CONCLUSION: These data indicate that a single intraperitoneal injection of ketamine at subanaesthetic and anaesthetic doses does not impair working memory, reference memory or neurodegeneration in adult mice, but an intermediate dose of ketamine produces transitory hyperlocomotion. PMID- 23736088 TI - Effects of balanced hydroxyethyl starch solutions on gut mucosal microcirculation and exhaled nitric oxide in septic rats: A randomised, animal study. AB - CONTEXT: Balanced hydroxyethyl starch (HES) solutions with a molecular weight of 130 kDa (tetrastarches) are frequently used in clinical practice. These solutions are derived either from waxy maize or potato starch and they are not bioequivalent. OBJECTIVES: Investigation of the effects of waxy maize-derived and potato-derived starches on intestinal microcirculation and pulmonary inflammation in experimental sepsis. DESIGN: A randomised (three groups), blinded animal study. SETTING: Animal experimental facility in a university hospital. ANIMALS: Twenty-one male Sprague-Dawley rats weighing 275 to 300 g. INTERVENTION: Sepsis was induced by caecal ligation and puncture. Animals received balanced crystalloid infusion (6 ml kg h) for 23 h followed by randomised 1 h bolus infusion (30 ml kg h) of crystalloid: balanced crystalloid solution or waxy maize starch: 6% wt/vol HES 130/0.4 or potato starch: 6% wt/vol HES 130/0.42. Results are presented as median (interquartiles). MAIN OUTCOME MEASURES: Using intravital microscopy, mucosal perfusion was assessed by intercapillary area (ICA) between all perfused capillaries (ICAtotal) and continuously perfused capillaries only (ICAcont). Mucosal blood flow was calculated from arteriolar diameter and red blood cell velocity. Intestinal wall 3-nitrotyrosine (3-NTint) content and exhaled nitric oxide (exNO), to indicate pulmonary inflammation, were measured. RESULTS: Both tetrastarches improved capillary perfusion compared to the crystalloid group, as indicated by reduced ICAtotal [crystalloid 1054 (905 to 1211) MUm; waxy maize starch 789 (744 to 940) MUm, P <0.05; potato starch 674 (536 to 693) MUm, P < 0.05] and reduced ICAcont [crystalloid 1060 (996 to 1340) MUm; waxy maize starch 860 (793 to 975) MUm, P <0.05; potato starch 701 (558 to 728) MUm, P <0.05]. Mucosal blood flow and systemic blood pressure did not differ significantly between groups. 3-NTint was comparable among all groups. exNO was significantly reduced from 11.1 (5.0 to 16.5) ppb to 4.2 (4.0 to 4.8) ppb in the waxy maize group, whereas no significant difference was detected in the potato starch group 6.2 (4.8 to 10.5). CONCLUSION: Bolus infusion of balanced 6% wt/vol tetrastarches augments mucosal capillary perfusion. Pulmonary inflammation in sepsis is differentially influenced by tetrastarches produced from different raw materials. PMID- 23736089 TI - Tracheal intubation in the ice-pick position with video laryngoscopes: a randomised controlled trial in a manikin. AB - CONTEXT: Tracheal intubation in nonstandardised positions is associated with a higher risk of tube misplacement and may have deleterious consequences for patients. Video laryngoscopes for tracheal intubation facilitate both glottic view and success rates. However, their use in the ice-pick position has not been evaluated. OBJECTIVE: To evaluate the role of video laryngoscopes for tracheal intubation in the ice-pick position. DESIGN: A randomised, controlled manikin trial. SETTING: A standardised airway manikin was placed in the corner of a room. Tracheal intubation was only possible from the lower right side of the manikin. In randomised order, participants used a standard Macintosh laryngoscope and GlideScope Ranger, Storz C-MAC, Pentax AWS, Airtraq and McGrath Series5 video laryngoscopes. Statistical analysis was performed using the Wilcoxon signed-rank and McNemar's tests; A P value of less than 0.05 was deemed statistically significant. PARTICIPANTS: Twenty anaesthesiologists, all emergency medicine board-certified. MAIN OUTCOME MEASURES: Time to first ventilation (primary); time to glottic view and confirmation of tube position (secondary). RESULTS: Successful ventilation was achieved most rapidly with the Macintosh laryngoscope (36.1 +/- 13.4 s; reference method), followed by the Airtraq (38.4 +/- 36.3 s; P = n.s.), Pentax AWS (51.6 +/- 43.3 s; P = n.s.) and Storz C-Mac (62.7 +/- 49.7 s; P = n.s.). The use of the GlideScope Ranger (79.8 +/- 61.9 s, P = 0.01) and McGrath series5 (79.8 +/- 58.5 s, P = 0.023) resulted in significantly longer times. When comparing overall intubation success, the rate of successful tracheal intubation was higher with the Airtraq than with the McGrath Series5 (P = 0.031; all others n.s.). CONCLUSION: The use of video laryngoscopes did not result in higher success rates or faster tracheal intubation in the ice-pick position when compared with conventional laryngoscopy in this manikin study. TRIAL REGISTRATION: www.clinicaltrials.gov, NCT01210105. PMID- 23736090 TI - Difficult diagnosis of malignant hyperthermia during laparoscopic surgery. PMID- 23736091 TI - Implementation of a structured information transfer checklist improves postoperative data transfer after congenital cardiac surgery. AB - BACKGROUND: During one hospital stay, a patient can be cared for by five different units. With patient transfer from one unit to another, it is of prime importance to convey a complete picture of the patient's situation to minimise the risk of medical errors and to provide optimal patient care. OBJECTIVE(S): This study was designed to test the hypothesis that the implementation of a standardised checklist used during verbal patient handover could improve postoperative data transfer after congenital cardiac surgery. DESIGN: Prospective, pre/postinterventional clinical study. SETTING: Cardiac centre of a university hospital. PATIENTS: Forty-eight patients younger than 16 years undergoing heart surgery. INTERVENTIONS: A standardised checklist was developed containing all data that, according to the investigators, should be communicated during the handover of a paediatric cardiac surgery patient from the operating room to the ICU. MAIN OUTCOME MEASURES: Data transfer during the postoperative handover before and after implementation of the checklist was evaluated. Duration of handover, number of interruptions, number of irrelevant data and number of confusing pieces of information were noted. Assessment of the handover process by ICU medical and nursing staff was quantified. RESULTS: After implementation of the information transfer checklist, the overall data transfer increased from 48 to 73% (P < 0.001). The duration of data transfer decreased from a median (range) of 6 (2 to 16) to 4 min (2 to 19) (P = 0.04). The overall handover assessment by the intensive care nursing staff improved significantly after implementation of the checklist. CONCLUSION: Implementation of an information transfer checklist in postoperative paediatric cardiac surgery patients resulted in a more complete transfer of information, with a decrease in the handover duration. PMID- 23736092 TI - Anaesthesia management of patients with airway susceptibilities: what have we learnt from animal models? AB - Anaesthesia management of patients with airway susceptibility remains a challenge in daily clinical practice due to the increased risk of perioperative bronchospasm. Therefore, understanding the mechanisms participating in the interaction between anaesthetic drugs and the lungs is essential in providing the optimal care for patients with chronic lung diseases. Experimental studies performed on various animal models mimicking airway susceptibility have played a key role in understanding the pathogenesis of lung diseases and have characterised the different pathways involved in the altered airway and lung tissue responses to anaesthetic agents. This narrative review highlights the progress that has been achieved by investigations in animal models and discusses the potential translation of these experimental findings to the clinical setting. The application of animal models with normal and allergically sensitised airways demonstrated that volatile and intravenous anaesthetic agents, muscle relaxants, analgesics and local anaesthetics exert their pulmonary effects via different neurosensorial pathways and through activating various receptors in the lungs. Attention is drawn to the significant differences in the pulmonary effects of anaesthetic agents between lungs with normal and those with susceptible airways. Extrapolating clear-cut conclusions from animal research to clinical practices should be made with caution, particularly for muscle relaxants, opioids and local anaesthetics wherein complex pathophysiological mechanisms are responsible for the potential respiratory effects of these agents. Animal models are of great importance in evaluating the potential interaction between anaesthetic drugs and the lungs, in identifying the pathways involved and in targeting preventive or treatment strategies to the lung compartment primarily involved. PMID- 23736093 TI - Comparison of four facial muscles, orbicularis oculi, corrugator supercilii, masseter or mylohyoid, as best predictor of good conditions for intubation: a randomised blinded trial. AB - CONTEXT: Monitoring of facial muscles after neuromuscular blockade can give an early indication of respiratory muscle readiness for tracheal intubation. OBJECTIVE: To assess which facial muscle, the orbicularis oculi, corrugator supercilii, masseter or the mylohyoid, is the best predictor of readiness for intubation after rocuronium. DESIGN: Prospective, randomised, blinded trial. SETTING: Single centre: Seoul, Korea, from August 2012 to November 2012. PATIENTS: Two hundred and eighty-eight patients aged 22 to 64 years were randomised to one of eight study groups: orbicularis oculi, corrugator supercilii, masseter and mylohyoid for rocuronium 0.6 or 1.2 mg kg. INTERVENTION: The maximum twitch depression at the eyelid (orbicularis oculi), the superciliary arch (corrugator supercilii), the cheek (masseter) and the submental triangle (mylohyoid) was assessed after rocuronium 0.6 and 1.2 mg kg. Endotracheal intubation was performed after maximal neuromuscular blockade, and intubating conditions were appraised. MAIN OUTCOME MEASURES: The onset time of rocuronium and the quality of the intubation conditions were assessed. RESULTS: The onset times in the orbicularis oculi, corrugator supercilii and masseter were significantly faster than that in the mylohyoid (P < 0.001). 'Clinically acceptable' intubation conditions were significantly enhanced in the mylohyoid (94%) compared with those in the orbicularis oculi (80%) and masseter (78%) after rocuronium 0.6 mg kg (P < 0.05), and no difference with corrugator supercilii (92%). Despite differences in onset time of orbicularis oculi and masseter compared to mylohyoid (P < 0.05), intubating conditions were similar among the four muscles after rocuronium 1.2 mg kg. CONCLUSION: Following rocuronium 0.6 mg kg at similar depths of anaesthesia, the monitoring of the corrugator supercilii provided the best balance of a shorter onset time while maintaining 'clinically acceptable' intubation conditions. TRIAL REGISTRATION: IRB File No.: HYUH 2012-07 009. PMID- 23736094 TI - Impact of haemoglobin concentration on cardiovascular outcome after vascular surgery: a retrospective observational cohort study. AB - BACKGROUND: Although low preoperative haemoglobin (Hb) concentration is a well known risk factor for adverse outcome, little is known about decreases in Hb and postoperative Hb concentrations. OBJECTIVES: The aim of this study was to evaluate the prognostic impact of both pre- and postoperative Hb concentrations (divided into low, intermediate and high tertiles) as well as Hb decrease, defined as preoperative minus postoperative Hb (g dl(-1)), on postoperative cardiovascular events in vascular surgery patients. DESIGN: A retrospective observational cohort study. SETTING: Erasmus University Medical Centre, Rotterdam, the Netherlands, from 1 January 2002 to 31 December 2011. PATIENTS: One thousand four hundred and eighty-four patients underwent elective open or endovascular abdominal aortic repair (aneurysm or stenosis), lower extremity arterial repair or carotid surgery. Patients for whom pre or postoperative Hb concentrations were not available were excluded. MAIN OUTCOME MEASURES: The study endpoint was 30-day postoperative cardiovascular events, including myocardial infarction, heart failure, arrhythmias, stroke, asymptomatic troponin-T release and cardiovascular death. RESULTS: In 1041 patients, both pre and postoperative Hb concentrations were available. Thirty-day cardiovascular events occurred in 221 (21%) patients. Multivariable logistic regression analyses, adjusting for age, sex, Revised Cardiac Risk Index (high-risk surgery, coronary heart disease, heart failure, cerebrovascular disease, diabetes mellitus, renal insufficiency), hypertension and hypercholesterolaemia, demonstrated that low preoperative Hb (8.7 to 12.9 g dl(-1)) was associated with 30-day events [odds ratio (OR) 1.7; 95% confidence interval (CI) 1.1 to 2.5]. Intermediate (10.6 to 12.1 g dl(-1)) and low (7.4 to 10.5 g dl(-1)) postoperative Hb and Hb decrease were also associated with an independently increased risk of 30-day events (intermediate Hb: OR 1.7; 95% CI 1.1 to 2.7; low Hb: OR 3.1; 95% CI 2.0 to 4.8; and Hb decrease: OR 1.2; 95% CI 1.1 to 1.3, respectively). Sensitivity analyses excluding patients with transfusions (n=314) demonstrated that only postoperative Hb concentrations remained associated with a high risk of 30-day cardiovascular events (intermediate Hb: OR 1.8; 95% CI 1.0 to 3.3 and low Hb: OR 2.0; 95% CI 1.0 to 4.0). CONCLUSION: Pre and postoperative Hb concentrations and Hb decrease are all related to 30-day cardiovascular events in elective vascular surgery patients. Postoperative Hb concentrations are the strongest predictor of 30-day cardiovascular events. PMID- 23736095 TI - The antinociceptive effect of systemic administration of a combination of low dose tramadol and dexmedetomidine in a rat model of bone cancer pain. AB - BACKGROUND: Multiple factors are involved in the mechanism of bone cancer pain. Treatment with a single drug is not adequate to target all of the different mechanisms. OBJECTIVE: To study the analgesic effect of a combination of low-dose dexmedetomidine (DEX) and tramadol (TRA) on bone cancer pain in rats. DESIGN: A randomised, controlled study. SETTING: Central Laboratory of Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai China, from July 2011 to June 2012. ANIMALS: Adult female Wistar rats weighing 180 to 200g. INTERVENTIONS: Rats with bone cancer were divided into five groups based on drug treatment (n=12 for each group): T5 group (TRA 5 mg kg), T10 group (TRA 10 mg kg), D1 group (DEX 1 MUg kg), T5+D1 group (TRA 5 mg kg+DEX 1MUg kg) and IS (isotonic saline 0.5 ml) group. MAIN OUTCOME MEASURES: The mechanical threshold and spontaneous paw withdrawal were measured in all groups. RESULTS: Both the T5+D1 group and T10 group showed a significantly increased mechanical threshold and a lower incidence of spontaneous paw withdrawal compared with the IS group. Interestingly, there was no significant difference between the T5+D1 and T10 groups. CONCLUSION: We found that a combination of DEX and TRA at low doses provided equal or superior analgesic effects on bone cancer pain compared to high-dose TRA alone. Our animal data might indicate the clinical administration of these two drugs in bone cancer pain therapy. PMID- 23736096 TI - Effects of deltamethrin on biometric parameters and liver biomarkers in common carp (Cyprinus carpio L.). AB - The present study is aimed to evaluate the effect of sublethal exposure to the pyrethroid pesticide deltamethrin, according to biometric parameters and important liver biomarkers in the common carp (Cyprinus carpio). Fish were exposed for 4, 15 and 30 days to deltamethrin mixed to the aquaria water at the concentrations of 0.08, 0.4 and 0.8MUg/L. The exposure did not affect fish biometric parameters. Glutathione-S-transferase (GST) activity in liver (hepatopancreas) increased in fish exposed to the high concentration of pesticide only after 30 days when compared to controls. A significant increase of malondialdehyde (MDA) content (79.4% and 90.2% of control) was remarked after 15 and 30 days of exposure to the highest concentration of pesticide. Catalase activities (CAT) went up after 4 days of was to the concentration of 0.4MUg/L and 0.8MUg/L and at 15 days of exposure to 0.4MUg/L. The most significant change of glutathione reductase (GR) activity was recorded at the fourth day, when GR activity was significantly increased after exposure to the concentrations of 0.4MUg/L and 0.8MUg/L of deltamethrin. PMID- 23736097 TI - Neurotoxicity of dibutyl phthalate in brain development following perinatal exposure: a study in rats. AB - Dibutyl-phthalate (DBP) is a ubiquitous environmental contaminant. However, its neurotoxic effects on neonatal, immature or mature brains remain unclear. Here, we aimed to investigate the neurotoxicity of perinatal exposure of DBP on rodent offspring animals. Pregnant rats received intragastric DBP (500mg/kg body weight) daily from gestational day (GD) 6 to postnatal day (PND) 21. Animals in the control group received the same volume of edible corn oil. Brain sections or tissues from offspring rats on PND5, PND21 and PND60 were collected for analysis. Histological examination demonstrated that perinatal exposure of DBP resulted in hippocampal neuron loss and structural alternation in neonatal and immature offspring rats (PND5 and PND21), while no significant change was found in mature rats (PND60). DBP exposure induced cell apoptosis in hippocampal neurons of these neonatal and immature animals, as evidenced by the increased number of TUNEL positive and Annexin V-propidium iodide (PI) positive cells and up-regulated caspase-3 activity. Moreover, DBP exposure decreased the expression of synaptophysin in the hippocampus and reduced both the slope and amplitude of field excitatory postsynaptic potentials (fEPSPs). DBP also impaired the spatial learning and memory of offspring rats. However, no significant difference in the susceptibility to DBP-induced neurotoxicity was found between male and female offspring rats. Our findings indicated that perinatal exposure of DBP could induce neurotoxicity in neonatal and immature offspring animals, but had no influence on mature animals after DBP withdrawal. These results may provide basic experimental evidence for better understanding the neurotoxic effects of DBP on neonatal, immature and mature brains. PMID- 23736098 TI - Noncompaction in mitochondrial myopathy: visible on microscopy but absent on macroscopic inspection. AB - OBJECTIVES: Disappearance of left ventricular hypertrabeculation (LVHT) over time has been occasionally recognized, but absence on echocardiography and autopsy and presence on histological examination after autopsy has not been reported. METHODS: Routine investigations such as chocardiography, cardiac MRI and coronary angiography were applied. Autopsy studies included macroscopic inspection and dissection but also histological work-up. RESULTS: In a 64-year-old male, LVHT was diagnosed at age 51 years during diagnostic work-up for hypertrophic cardiomyopathy. He had a history of mitochondrial myopathy which was diagnosed long before the cardiac problem became evident. Thickening of the left ventricular myocardium increased over years, resulting also in thickening of the trabeculations and the disappearance of the intertrabecular recesses. This is why LVHT was no longer visible on echocardiography shortly before death at age 64 years. The autopsy revealed that macroscopically no LVHT was visible but upon histological work-up the preformed recesses were still visible but had become unfolded. CONCLUSIONS: This case shows that LVHT may disappear due to thickening of the trabeculations but may remain visible on postmortem histological examination in patients with hypertrophic cardiomyopathy from a mitochondrial myopathy. PMID- 23736100 TI - Systems pharmacology in drug discovery and therapeutic insight for herbal medicines. AB - Systems pharmacology is an emerging field that integrates systems biology and pharmacology to advance the process of drug discovery, development and the understanding of therapeutic mechanisms. The aim of the present work is to highlight the role that the systems pharmacology plays across the traditional herbal medicines discipline, which is exemplified by a case study of botanical drugs applied in the treatment of depression. First, based on critically examined pharmacology and clinical knowledge, we propose a large-scale statistical analysis to evaluate the efficiency of herbs used in traditional medicines. Second, we focus on the exploration of the active ingredients and targets by carrying out complex structure-, omics- and network-based systematic investigations. Third, specific informatics methods are developed to infer drug disease connections, with purpose to understand how drugs work on the specific targets and pathways. Finally, we propose a new systems pharmacology method, which is further applied to an integrated platform (Herbal medicine Systems Pharmacology) of blended herbal medicine and omics data sets, allowing for the systematization of current and traditional knowledge of herbal medicines and, importantly, for the application of this emerging body of knowledge to the development of new drugs for complex human diseases. PMID- 23736101 TI - Dosimetric parameters predictive of acute gastrointestinal toxicity in patients with anal carcinoma treated with concurrent chemotherapy and intensity-modulated radiation therapy. AB - OBJECTIVE: To determine the dosimetric parameters predictive of acute gastrointestinal (GI) toxicity in anal cancer patients treated with intensity modulated radiotherapy (IMRT) and concurrent chemotherapy. METHODS: Fifty-eight anal cancer patients were treated with concurrent chemotherapy and IMRT. The bowel was delineated on the planning CT and included the intestinal cavity. Regression models with multiple independent predictors were used to test associations of clinical factors and dosimetric parameters with clinically significant GI toxicity (grade >=3). Significant dosimetric factors were fitted to a normal tissue complication probability curve using a logit function and subsequently analyzed at multiple bowel volumes to determine the threshold for clinically significant GI toxicity. RESULTS: Two patients (3.4%) experienced no acute GI toxicity, whereas 20 (34.5%) experienced grade 1 toxicity, 20 (34.5%) experienced grade 2, 16 (27.6%) experienced grade 3 and none experienced grade 4. Analysis showed that the volumes of bowel receiving 30 Gy (V30) and 40 Gy (V40) both correlated with clinically significant acute GI toxicity. In patients whose V30 was >310 cm(3), the rate of clinically significant acute GI toxicity was 38.9%, compared to 9.1% if V30 was <=310 cm(3) (p = 0.016). If V40 was <=70 cm(3), the rate of acute grade >=3 toxicity was 6.3%, versus 35.7% if V40 was >70 cm(3) (p = 0.045). CONCLUSION: This analysis demonstrates that the bowel dosimetric parameters are associated with clinically significant acute GI toxicity when IMRT is used in the management of anal cancer patients. PMID- 23736102 TI - Bayesian analysis of biogeography when the number of areas is large. AB - Historical biogeography is increasingly studied from an explicitly statistical perspective, using stochastic models to describe the evolution of species range as a continuous-time Markov process of dispersal between and extinction within a set of discrete geographic areas. The main constraint of these methods is the computational limit on the number of areas that can be specified. We propose a Bayesian approach for inferring biogeographic history that extends the application of biogeographic models to the analysis of more realistic problems that involve a large number of areas. Our solution is based on a "data augmentation" approach, in which we first populate the tree with a history of biogeographic events that is consistent with the observed species ranges at the tips of the tree. We then calculate the likelihood of a given history by adopting a mechanistic interpretation of the instantaneous-rate matrix, which specifies both the exponential waiting times between biogeographic events and the relative probabilities of each biogeographic change. We develop this approach in a Bayesian framework, marginalizing over all possible biogeographic histories using Markov chain Monte Carlo (MCMC). Besides dramatically increasing the number of areas that can be accommodated in a biogeographic analysis, our method allows the parameters of a given biogeographic model to be estimated and different biogeographic models to be objectively compared. Our approach is implemented in the program, BayArea. PMID- 23736103 TI - When outgroups fail; phylogenomics of rooting the emerging pathogen, Coxiella burnetii. AB - Rooting phylogenies is critical for understanding evolution, yet the importance, intricacies and difficulties of rooting are often overlooked. For rooting, polymorphic characters among the group of interest (ingroup) must be compared to those of a relative (outgroup) that diverged before the last common ancestor (LCA) of the ingroup. Problems arise if an outgroup does not exist, is unknown, or is so distant that few characters are shared, in which case duplicated genes originating before the LCA can be used as proxy outgroups to root diverse phylogenies. Here, we describe a genome-wide expansion of this technique that can be used to solve problems at the other end of the evolutionary scale: where ingroup individuals are all very closely related to each other, but the next closest relative is very distant. We used shared orthologous single nucleotide polymorphisms (SNPs) from 10 whole genome sequences of Coxiella burnetii, the causative agent of Q fever in humans, to create a robust, but unrooted phylogeny. To maximize the number of characters informative about the rooting, we searched entire genomes for polymorphic duplicated regions where orthologs of each paralog could be identified so that the paralogs could be used to root the tree. Recent radiations, such as those of emerging pathogens, often pose rooting challenges due to a lack of ingroup variation and large genomic differences with known outgroups. Using a phylogenomic approach, we created a robust, rooted phylogeny for C. burnetii. [Coxiella burnetii; paralog SNPs; pathogen evolution; phylogeny; recent radiation; root; rooting using duplicated genes.]. PMID- 23736104 TI - Parsimonious inference of hybridization in the presence of incomplete lineage sorting. AB - Hybridization plays an important evolutionary role in several groups of organisms. A phylogenetic approach to detect hybridization entails sequencing multiple loci across the genomes of a group of species of interest, reconstructing their gene trees, and taking their differences as indicators of hybridization. However, methods that follow this approach mostly ignore population effects, such as incomplete lineage sorting (ILS). Given that hybridization occurs between closely related organisms, ILS may very well be at play and, hence, must be accounted for in the analysis framework. To address this issue, we present a parsimony criterion for reconciling gene trees within the branches of a phylogenetic network, and a local search heuristic for inferring phylogenetic networks from collections of gene-tree topologies under this criterion. This framework enables phylogenetic analyses while accounting for both hybridization and ILS. Further, we propose two techniques for incorporating information about uncertainty in gene-tree estimates. Our simulation studies demonstrate the good performance of our framework in terms of identifying the location of hybridization events, as well as estimating the proportions of genes that underwent hybridization. Also, our framework shows good performance in terms of efficiency on handling large data sets in our experiments. Further, in analysing a yeast data set, we demonstrate issues that arise when analysing real data sets. Although a probabilistic approach was recently introduced for this problem, and although parsimonious reconciliations have accuracy issues under certain settings, our parsimony framework provides a much more computationally efficient technique for this type of analysis. Our framework now allows for genome-wide scans for hybridization, while also accounting for ILS. PMID- 23736105 TI - A review of warfarin dosing with concurrent acetaminophen therapy. AB - Warfarin is frequently used for the prevention and treatment of thromboembolism, yet it is associated with numerous drug interactions. Regarding over-the-counter pain medications, the preferred analgesic for those patients who are taking warfarin is acetaminophen. There are, however, reports of elevation in the international normalized ratio (INR) in those patients taking concurrent warfarin and acetaminophen. For those practitioners who manage warfarin therapy, there is little guidance regarding management of the drug-drug interaction between warfarin and acetaminophen. This review seeks to evaluate the drug interaction between warfarin and acetaminophen and provides recommendations for concurrent use of these drugs. PMID- 23736106 TI - A series of 3D lanthanide frameworks constructed from aromatic multi-carboxylate ligand: structural diversity, luminescence and magnetic properties. AB - Reactions of lanthanide(III) nitrates with multi-donor carboxylate ligand in the presence of oxalate anion afforded four new lanthanide coordination polymers with three dimensional (3D) frameworks, namely, {[Ln2(DPPA)2(MU2-C2O4)(H2O)2].2H2O}n (Ln = Nd (1), Sm (2)) and [Ln2(HDPPA)2(DPPA)2]n (Ln = Tb (3), Yb (4)), (H3DPPA = 3-(4-hydroxyl pyridinium-1-yl) phthalic acid and H2C2O4 = oxalic acid). Compounds 1 and 2 are isostructural and isomorphous, featuring oxalate pillared binodal (4,5)-connected porous 3D framework with intersected 1D channels, in which the coordinated and lattice waters are accommodated. The complexes 3 and 4 are also isostructural, but featuring a (4,6)-connected 3D network based on a rectangular window composed of {Ln(HDPPA)}(+) extended anion chains, further interlinked by DPPA. The Tb(III) analogue exhibits intense characteristic green photoluminescence employing DPPA as an antenna. While Sm(III) compound 2 mainly involves ligand-to-ligand charge transfer. Variable-temperature susceptibility analyses of complexes 1 (Nd), 2 (Sm) and 3 (Tb) revealed that depopulation of the Stark levels together with weak antiferromagnetic interactions between the lanthanide ions lead to a continuous decrease in chi(M)T when the samples are cooled from 300 to 2 K. PMID- 23736108 TI - Association analysis of tapasin polymorphisms with aspirin-exacerbated respiratory disease in asthmatics. AB - BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is characterized by the development of airway obstruction in asthmatic individuals following the ingestion of aspirin or other nonsteroidal anti-inflammatory drugs. TAPBP (TAP binding protein, tapasin) is upregulated by eicosanoids, which act as potent inflammatory molecules in aspirin-related reactions. Thus, functional alterations in the TAPBP gene may contribute toward AERD. OBJECTIVES: We examined the relationship between the single nucleotide polymorphisms on the TAPBP gene and AERD. MATERIALS AND METHODS: A group of asthmatic patients (n=1252) underwent the oral aspirin challenge. Oral aspirin challenge reactions were categorized into two groups as follows: 15% or greater decreases in forced expiratory volume in 1 s or naso-ocular and skin reactions (AERD), or 15% or less decreases in forced expiratory volume in 1 s without naso-ocular and skin reactions (aspirin-tolerant asthma). Five single nucleotide polymorphisms of the TAPBP gene were genotyped. RESULTS: Logistic regression analysis showed that the minor allele frequencies of TAPBP rs2071888 C>G (Thr260Arg) on exon 4 (P>0.05), which was in absolute linkage disequilibrium with rs1059288 T>C on 3'UTR, were significantly higher in the AERD group than in the aspirin-tolerant asthma group, and the P values remained significant after multiple comparisons (Pcorr=0.006, odds ratio: 1.37, 95% confidence interval: 1.11-1.69, additive model; Pcorr=0.009, odds ratio: 1.52, 95% confidence interval: 1.14-2.03, dominant model). Alpha-helical wheel plotting showed that 260Arg had greater hydrophilic helical property than 260Thr. CONCLUSION: TAPBP polymorphisms may play a role in the development of AERD. PMID- 23736110 TI - Insulin resistance and the metabolic syndrome are associated with arterial stiffness in patients with chronic kidney disease. AB - BACKGROUND: Insulin resistance (IR) and the metabolic syndrome (MetS) may contribute to cardiovascular risk in chronic kidney disease (CKD). We examine the association between IR and vascular function in CKD. Furthermore, we define the prevalence of MetS and examine the association between defining MetS and vascular function. METHODS: This cross-sectional study of 71 stage 3-4 CKD subjects assessed arterial stiffness (pulse wave velocity (PWV) and endothelial dysfunction (ED). IR was assessed using Homeostasis Model Assessment-IR (HOMA IR). MetS was defined by the unified International Diabetes Federation and American Heart Association/National Heart Lung and Blood Institute criteria. RESULTS: CKD subjects with HOMA-IR score above the median had significantly higher body mass index and waist circumference. They also had higher PWV, higher triglycerides with lower high-density lipoprotein concentration (P < 0.05). Age, systolic blood pressure, and HOMA-IR were independently associated with PWV, even after exclusion of diabetic subjects (n = 16) (P <= 0.05). MetS was more prevalent in CKD (78.9%) than controls (2.5%). MetS in CKD was associated with increased PWV (MetS(+) geometric mean = 9.5 m/s, 95% confidence interval (95% CI) = 8.9-10.2 m/s; vs. MetS(-) 8.1 m/s, 95% CI = 7.1-9.3 m/s; P = 0.03) but not ED. In a multiple logistic regression analysis, PWV higher than the median was independently associated with dysglycemia. CONCLUSIONS: IR is independently associated with arterial stiffness, even in nondiabetic CKD. MetS is common and identified a subgroup of CKD patients with increased arterial stiffness, which is associated with dysglycemia. PMID- 23736109 TI - Blood pressure after recent stroke: baseline findings from the secondary prevention of small subcortical strokes trial. AB - BACKGROUND: Hypertension is the most powerful risk factor for stroke. The aim of this study was to characterize baseline blood pressure in participants in the Secondary Prevention of Small Subcortical Strokes trial. METHODS: For this cross sectional analysis, participants were categorized by baseline systolic blood pressure (SBP) < 120, 120-139, 140-159, 160-179, and >= 180 mm Hg and compared on demographic and clinical characteristics. Predictors of SBP < 140 mm Hg were examined. RESULTS: Mean SBP was 143+/-19 mm Hg while receiving an average of 1.7 antihypertensive medications; SBP >= 140 mm Hg for 53% and >= 160 mm Hg for 18% of the 3,020 participants. Higher SBP was associated with a history of hypertension and hypertension for longer duration (both P < 0.0001). Higher SBPs were associated with more extensive white matter disease on magnetic resonance imaging (P < 0.0001). There were significant differences in entry-level SBP when participants were categorized by race and region (both P < 0.0001). Black participants were more likely to have SBP >= 140 mm Hg. Multivariable logistic regression showed an independent effect for region with those from Canada more likely (odds ratio = 1.7; 95% confidence interval, 1.29, 2.32) to have SBP < 140 mm Hg compared with participants from United States. CONCLUSIONS: In this cohort with symptomatic lacunar stroke, more than half had uncontrolled hypertension at approximately 2.5 months after stroke. Regional, racial, and clinical differences should be considered to improve control and prevent recurrent stroke. PMID- 23736111 TI - Exercise training reduces peripheral arterial stiffness and myocardial oxygen demand in young prehypertensive subjects. AB - BACKGROUND: Large artery stiffness is a major risk factor for the development of hypertension and cardiovascular disease. Persistent prehypertension accelerates the progression of arterial stiffness. METHODS: Forty-three unmedicated prehypertensive (systolic blood pressure (SBP) = 120-139 mm Hg or diastolic blood pressure (DBP) = 80-89 mm Hg) men and women and 15 normotensive time-matched control subjects (NMTCs; n = 15) aged 18-35 years of age met screening requirements and participated in the study. Prehypertensive subjects were randomly assigned to a resistance exercise training (PHRT; n = 15), endurance exercise training (PHET; n = 13) or time-control group (PHTC; n = 15). Treatment groups performed exercise training 3 days per week for 8 weeks. Pulse wave analysis, pulse wave velocity (PWV), and central and peripheral blood pressures were evaluated before and after exercise intervention or time-matched control. RESULTS: PHRT and PHET reduced resting SBP by 9.6+/-3.6mm Hg and 11.9+/-3.4mm Hg, respectively, and DBP by 8.0+/-5.1mm Hg and 7.2+/-3.4mm Hg, respectively (P < 0.05). PHRT and PHET decreased augmentation index (AIx) by 7.5% +/- 2.8% and 8.1% +/- 3.2% (P < 0.05), AIx@75 by 8.0% +/- 3.2% and 9.2% +/- 3.8% (P < 0.05), and left ventricular wasted pressure energy, an index of extra left ventricular myocardial oxygen requirement due to early systolic wave reflection, by 573+/-161 dynes s/cm(2) and 612+/-167 dynes s/cm(2) (P < 0.05), respectively. PHRT and PHET reduced carotid-radial PWV by 1.02+/-0.32 m/sec and 0.92+/-0.36 m/sec (P < 0.05) and femoral-distal PWV by 1.04+/-0.31 m/sec and 1.34+/-0.33 m/sec (P < 0.05), respectively. No significant changes were observed in the time-control groups. CONCLUSIONS: This study suggests that both resistance and endurance exercise alone effectively reduce peripheral arterial stiffness, central blood pressures, augmentation index, and myocardial oxygen demand in young prehypertensive subjects. PMID- 23736112 TI - Effects of antihypertensive drugs on central blood pressure in humans: a preliminary observation. AB - BACKGROUND: Central blood pressure (BP) is considered a better predictor of cardiovascular events than brachial BP. Modifications of central, beyond brachial BP, can be assessed by pressure amplification, a potential new cardiovascular risk factor. Comparison between drugs' effect on central hemodynamics has been poorly studied. Our aim was to assess the hemodynamic effect of a 12-week treatment with amlodipine 5mg, or candesartan 8mg, or indapamide sustained release 1.5mg, in comparison with placebo. METHODS: We analyzed 145 out-patients with essential hypertension in primary prevention enrolled in the Natrilix SR Versus Candesartan and Amlodipine in the Reduction of Systolic Blood Pressure in Hypertensive Patients (X-CELLENT) study, a multicenter, randomized, double blinded, placebo-controlled trial. Arterial stiffness, central BP, pressure amplification, and wave reflection were measured by applanation tonometry. RESULTS: Baseline characteristics of patients were homogeneous between groups. After treatment, we found that active drugs produced similar reduction of both central and peripheral BPs, with no significant interdrug differences (all P < 0.05; excluded peripheral pulse pressure, compared with placebo). Second, amlodipine (1.9% +/- 15.3%), candesartan (3.0% +/- 14.6%) and indapamide (4.1% +/ 14.4%) all increased pulse pressure amplification, but only indapamide was statistically different from placebo (P = 0.02). Finally, no significant changes were observed on pulse wave velocity, heart rate, and augmentation index. CONCLUSIONS: The 3 antihypertensive drugs similarly reduced peripheral and central BP, as compared with placebo, but a significant increase in pulse pressure amplification was obtained only with indapamide, independently of arterial stiffness modifications. REGISTRATION NUMBER: 3283161 by BIOPHARMA. PMID- 23736113 TI - New-concept batteries based on aqueous Li+/Na+ mixed-ion electrolytes. AB - Rechargeable batteries made from low-cost and abundant materials operating in safe aqueous electrolytes are attractive for large-scale energy storage. Sodium ion battery is considered as a potential alternative of current lithium-ion battery. As sodium-intercalation compounds suitable for aqueous batteries are limited, we adopt a novel concept of Li(+)/Na(+) mixed-ion electrolytes to create two batteries (LiMn2O4/Na0.22MnO2 and Na0.44MnO2/TiP2O7), which relies on two electrochemical processes. One involves Li(+) insertion/extraction reaction, and the other mainly relates to Na(+) extraction/insertion reaction. Two batteries exhibit specific energy of 17 Wh kg(-1) and 25 Wh kg(-1) based on the total weight of active electrode materials, respectively. As well, aqueous LiMn2O4/Na0.22MnO2 battery is capable of separating Li(+) and Na(+) due to its specific mechanism unlike the traditional "rocking-chair" lithium-ion batteries. Hence, the Li(+)/Na(+) mixed-ion batteries offer promising applications in energy storage and Li(+)/Na(+) separation. PMID- 23736114 TI - Nonvolatile liquid anthracenes for facile full-colour luminescence tuning at single blue-light excitation. AB - Nonvolatile room-temperature luminescent molecular liquids are a new generation of organic soft materials. They possess high stability, versatile optical properties, solvent-free fluid behaviour and can effectively accommodate dopant dye molecules. Here we introduce an approach to optimize anthracene-based liquid materials, focussing on enhanced stability, fluorescence quantum yield, colour tunability and processability, with a view to flexible electronic applications. Enveloping the anthracene core in low-viscosity branched aliphatic chains results in stable, nonvolatile, emissive liquid materials. Up to 96% efficient energy transfer-assisted tunable emission is achieved by doping a minute amount of acceptor dye in the solvent-free state. Furthermore, we use a thermoresponsive dopant to impart thermally controllable luminescence colours. The introduced strategy leading to diverse luminescence colours at a single blue-light excitation can be an innovative replacement for currently used luminescent materials, providing useful continuous emissive layers in developing foldable devices. PMID- 23736115 TI - Paricalcitol and cardiorenal outcome: from the IMPACT study to clinical practice. AB - Chronic kidney disease mineral bone disorders (CKD-MBD) encompass laboratory, vascular and bone abnormalities that might portend a poor prognosis in CKD. In spite of a great effort in elucidating the CKD-MBD natural history and pathogenesis, the underlying mechanisms are still largely unknown. However, a deficit in vitamin D is commonly reported as one of the first steps in CKD-MBD, and numerous epidemiological studies have associated serum vitamin D levels with different markers of cardiovascular disease and the risk of death in different populations. We herein summarize current evidence that links vitamin D deficiency to an adverse outcome and the results of the most recent clinical trials that have investigated the impact of paricalcitol supplementation on hard outcome in CKD patients. PMID- 23736116 TI - Electronic excited states of guanine-cytosine hairpins and duplexes studied by fluorescence spectroscopy. AB - Guanine-cytosine hairpins, containing a hexaethylene glycol bridge, are studied by steady-state fluorescence spectroscopy and time-correlated single photon counting; their properties are compared to those of duplexes with the same sequence. It is shown that, both in hairpins and in duplexes, base pairing induces quenching of the pipi* fluorescence, the quantum yield decreasing by at least two orders of magnitude. When the size of the systems increases from two to ten base pairs, a fluorescent component decaying on the nanosecond time-scale appears at energy higher than that stemming from the bright states of non interacting mono-nucleotides (ca. 330 nm). For ten base pairs, this new fluorescence forms a well-defined band peaking at 305 nm. Its intensity is about 20% higher for the hairpin compared to the duplex. Its position (red-shifted by 1600 cm(-1)) and width (broader by 1800 cm(-1) FWHM) differ from those observed for large duplexes containing 1000 base pairs, suggesting the involvement of electronic coupling. Fluorescence anisotropy reveals that the excited states responsible for high energy emission are not populated directly upon photon absorption but are reached during a relaxation process. They are assigned to charge transfer states. According to the emerging picture, the amplitude of conformational motions determines whether instantaneous deactivation to the ground state or emission from charge transfer states will take place, while pipi* fluorescence is associated to imperfect base-pairing. PMID- 23736117 TI - Revealing the enhanced catalytic activity of nitrogen-doped carbon nanotubes for oxidative dehydrogenation of propane. AB - Bulk nitrogen doping can efficiently improve the catalytic performance of carbon nanotubes (CNT) in oxidative dehydrogenation of propane (ODH). The graphitic nitrogen plays a determining role in enhancing their activity by speeding up the activation of oxygen and decreasing the overall activation energy of the reaction. PMID- 23736118 TI - Correlation between levels of circulating adipokines and adiponectin/resistin index with carotid intima-media thickness in hypertensive type 2 diabetic patients. AB - BACKGROUND: Hypoadiponectinemia and hyperresistinemia are associated with cardiovascular disease. The increase in the carotid intima-media thickness (CIMT) assessed by B-mode ultrasound has been directly associated with increased risk of myocardial infarction and stroke. OBJECTIVE: To evaluate the correlation between adipokine levels with CIMT in hypertensive type 2 diabetic patients. METHODS: Serum levels of adiponectin and resistin levels were measured by ELISA in 30 type 2 diabetic patients with never-treated hypertension and in age-matched healthy controls. The CIMT (B-mode color imaging of extracranial carotid arteries using high-resolution ultrasound) was also obtained. The relationship between adipokine levels and the adiponectin/resistin index with the CIMT was assessed by the Pearson correlation coefficient test. RESULTS: Adiponectin was lower (p < 0.05), and resistin higher (p < 0.01) in patients than in controls, CIMT correlated positively with resistin (R = 0.45, p < 0.02) and the adiponectin/resistin index (R = 0.58, p < 0.001), but not with adiponectin levels (r = -0.11, p > 0.1) in patients. Whereas only adiponectin levels correlated - negatively - with CIMT (r = -0.39, p < 0.02) in controls. CONCLUSION: Our results shown that the adiponectin/resistin index seems to be more strongly associated with atherosclerosis than adipokine levels, and may be used as a reliable marker of cardiovascular risk in type 2 diabetic hypertensive patients. PMID- 23736120 TI - Longer weekly sleep duration predicts greater 3-month BMI reduction among obese adolescents attending a clinical multidisciplinary weight management program. AB - AIMS: To determine whether baseline levels of self-reported sleep and sleep problems among obese adolescents referred to an outpatient multidisciplinary family-based weight management program predict reduction in BMI 3 months later. METHODS: A retrospective medical chart review was conducted for 83 obese adolescents. The following baseline variables were extracted: self-reported sleep duration (weekdays and weekends), and presence of snoring, daytime fatigue, suspected sleep apnea, and physician-diagnosed sleep apnea. Anthropometric data at baseline and 3 months were also collected. RESULTS: On average, adolescents reported significantly less sleeping on weeknights (7.7 +/- 1.3 h) compared to weekend nights (10.0 +/- 1.8 h), t(82) = 10.5, p = 0.0001. Reduction in BMI after 3 months of treatment was predicted by more weekly sleep at baseline (R2 = 0.113, F(1, 80) = 10.2, p = 0.002). Adolescents who reduced their BMI by >=1 kg/m2 reported greater weekly sleep at baseline compared to adolescents who experienced <1 kg/m2 reduction (60.7 +/- 7.5 h vs. 56.4 +/- 8.6 h; F(1, 80) = 5.7, p = 0.02). CONCLUSION: Findings from this study, though correlational, raise the possibility that increased duration of sleep may be associated with weight loss among obese adolescents enrolled in a weight management program. Evidence-based behavioral techniques to improve sleep hygiene and increase sleep duration should be explored in pediatric weight management settings. PMID- 23736119 TI - Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens. AB - There is accumulating evidence that the nucleus accumbens (NAc) has an important role in the pathophysiology of depression. As the NAc is a key component in the neural circuitry of reward, it has been hypothesized that anhedonia, a core symptom of depression, might be related to dysfunction of this brain region. Neuronal morphology and expression of plasticity-related molecules were examined in the NAc of rats displaying anhedonic behavior (measured in the sucrose consumption test) in response to chronic mild stress. To demonstrate the relevance of our measurements to depression, we tested whether the observed changes were sensitive to reversal with antidepressants (imipramine and fluoxetine). Data show that animals displaying anhedonic behavior display an hypertrophy of medium spiny neurons in the NAc and, in parallel, have increased expression of the genes encoding for brain-derived neurotrophic factor, neural cell adhesion molecule and synaptic protein synapsin 1. Importantly, the reversal of stress-induced anhedonia by antidepressants is linked to a restoration of gene expression patterns and dendritic morphology in the NAc. Using an animal model of depression, we show that stress induces anhedonic behavior that is associated with specific changes in the neuronal morphology and in the gene-expression profile of the NAc that are effectively reversed after treatment with antidepressants. PMID- 23736122 TI - Diagnostic accuracy of CT perfusion imaging for detecting acute ischemic stroke: a systematic review and meta-analysis. AB - BACKGROUND: The aim of the current study was to determine the sensitivity and specificity of CT perfusion (CTP) for the detection of ischemic stroke by performing a systematic review and meta-analysis of published reports. METHODS: We searched PubMed, Embase and the Cochrane library using the terms 'perfusion computed tomography', 'ischemic stroke' and synonyms. We included studies that: (1) reported original data, (2) studied the diagnostic value of CTP for detecting ischemic stroke, (3) used MRI-DWI, follow-up MRI or follow-up CT as the reference standard, (4) included at least 10 patients who were suspected of ischemic stroke, and (5) reported the number of true positives, true negatives, false positives and false negatives for the diagnosis of ischemic stroke. RESULTS: Fifteen studies were finally included in the current review with a total of 1,107 patients. A pooled analysis resulted in a sensitivity of 80% (95% confidence interval, CI: 72-86%) and a specificity of 95% (95% CI: 86-98%). Almost two thirds of the false negatives were due to small lacunar infarcts; the remaining false negatives were mostly due to limited coverage. CONCLUSIONS: The current systematic review shows that CTP has a high sensitivity and a very high specificity for detecting infarcts. PMID- 23736123 TI - All-solution processed polymer light-emitting diode displays. AB - Adopting the emerging technology of printed electronics in manufacturing novel ultrathin flat panel displays attracts both academic and industrial interests because of the challenge in the device physics and the potential of reducing production costs. Here we produce all-solution processed polymer light-emitting diode displays by solution-depositing the cathode and utilizing a multifunctional buffer layer between the cathode and the organic layers. The use of ink-jetted conducting nanoparticles as the cathode yields high-resolution cathode patterns without any mechanical stress on the organic layers. The buffer layer, which offers the functions of solvent-proof electron injection and proper affinity, is fabricated by mixing the water/alcohol-soluble polymer and a curable epoxy adhesive. Our 1.5-inch polymer light-emitting diode displays are fabricated without any dead pixels or dead lines. The all-solution process eliminates the need for high vacuum for thermal evaporation of the cathode, which paves the way to industrial roll-to-roll manufacturing of flat panel displays. PMID- 23736125 TI - Acute ischaemic stroke: highlighting the need for early intervention. PMID- 23736126 TI - The prevalence and distribution of non-communicable diseases and their risk factors in Kasese district, Uganda. AB - BACKGROUND: To date there has been no population-based survey of the major risk factors for non-communicable diseases (NCD) in Uganda. Hospital-based data from urban centres report an increasing burden of NCDs in Uganda. This population based survey aimed to describe the prevalence of risk factors for NCDs in a rural Ugandan district. METHODS: The survey was conducted using the WHO STEPwise approach to surveillance of non-communicable diseases (STEPS) methodology. Participants (n = 611) were residents of the Kasese district selected in a one step, complete survey of a rural district. Standardised international protocols were used to record history of disease, and measure behavioural risk factors (smoking, alcohol consumption, fruit and vegetable consumption, physical activity), physical characteristics [weight, height, waist and hip circumferences, blood pressure (BP)], fasting blood glucose (BG) and total cholesterol (TC) levels. Data were analysed using simple descriptive analysis. RESULTS: In this sample, the prevalence of hypertension (systolic BP >= 140 mmHg and/or diastolic BP >= 90 mmHg) was 22.1% for men and 20.5% for women. Fifteen per cent of men and 16.8% of women were overweight [body mass index (BMI) >= 25 kg/m(2)] and 4.9% of men and 9.0% of women were obese (BMI >= 30 kg/m(2)). Nine per cent of participants were diabetic, 7.2% ate five or more combined servings of fruit per day while only 1.2% ate five or more combined servings of vegetables per day. Fifty-one per cent of the population were physically inactive and 9.6% were daily smokers. Thirty-one per cent of females had fasting blood sugar levels (FBS) >= 6.1 mmol/l while 10% of males had FBS > 6.1 mmol/l. CONCLUSION: This study presents evidence on the magnitude of NCDs, their risk factors and gender distribution in a rural population in Uganda, a poor country in east-central Africa. These data, when combined with urban population data, could be useful in the formulation and advocacy of NCD policy and plans of action in Uganda. PMID- 23736127 TI - Modulation of haemodynamics, endogeneous antioxidant enzymes, and pathophysiological changes by selective inhibition of angiotensin II type 1 receptors in pressureoverload rats. AB - BACKGROUND: Constriction of the thoracic or abdominal aorta provides an experimental model of pressure-overload cardiac hypertrophy. Blockade of AT1 receptors is beneficial in preventing target-organ damage in hypertension. OBJECTIVE: To examine the effect of angiotensin II receptor antagonists on blood pressure, endogenous antioxidant enzyme and histopathological changes in pressure overload rats. METHODS: Pressure overload was produced by abdominal aortic banding (AAB) using a blunt 22-guage needle in male rats as a model of cardiac hypertrophy. After surgery, the AAB-induced hypertension (AABIH) rats were treated with losartan 40 mg/kg/day, candesartan 10 mg/kg/day, irbesartan 10 mg/kg/day per os for 16 weeks. At 16 weeks of surgery, the rats were observed for general characteristics and mortality, and we determined non-invasive blood pressure (NIBP), endogenous antioxidant enzyme catalase and superoxide dismutase (SOD) activities, and histology of the target organs. RESULTS: In the AABIH group, significant increase in systolic blood pressure was observed from weeks 3 to 16 compared with the control group, along with reduced serum catalase and SOD activities. The treated groups showed significant reduction in systolic BP and increase in serum SOD and catalase activities. The histological changes induced in the target organs, namely heart, liver, kidneys and thoracic aorta in the AABIH rats were attenuated in the treated rats. CONCLUSION: Blockade of the AT1 receptor caused an improvement in the myocardial antioxidant reserve and decreased oxidative stress in the hypertensive rats, which was evidenced by the protection observed in the treatment groups. PMID- 23736128 TI - Cardiomyopathies and myocardial disorders in Africa: present status and the way forward. PMID- 23736129 TI - Hypertension and associated factors in older adults in South Africa. AB - BACKGROUND: Older adults are disproportionately affected by hypertension, which is an established risk factor for cardiovascular disease. Little attention has been focused on hypertension and associated factors among older adults in Africa. Therefore, this study aimed to investigate the prevalence and associated factors of hypertension in a national sample of older South Africans who participated in the Study of Global Ageing and Adults' Health (SAGE) in 2008. METHODS: In 2008 we conducted a national, population-based, cross-sectional study of a sample of 3 840 subjects aged 50 years or older in South Africa. The questionnaire included socio-demographic characteristics, health variables, and anthropometric and blood pressure measurements. RESULTS: The prevalence of hypertension in the sample population was 77.3% (male 74.4%, female 79.6%). The rates of awareness, treatment and control among the hypertensive participants were 38.1, 32.7 and 17.1%, respectively. The results of multivariate logistic regression analysis revealed that the prevalence of hypertension was associated with being in the Coloured population group, having had a stroke, being overweight or obese and having had five or more out-patients care visits in the past 12 months. Hypertension was inversely associated with current alcohol use. CONCLUSION: This study revealed high rates of hypertension among older adults (50 years and more) in South Africa, which puts them at risk for cardiovascular disease. The percentages of hypertensive subjects who were aware, treated and controlled were very low. These data underscore the urgent need to strengthen the public health education and blood pressure-monitoring systems to better manage hypertension among older adults in South Africa. PMID- 23736130 TI - Neonatal circulatory failure due to acute hypertensive crisis: clinical and echocardiographic clues. AB - OBJECTIVE: Circulatory failure due to acute arterial hypertension in the neonatal period is rare. This study was undertaken to assess the clinical and echocardiographic manifestations of circulatory failure resulting from acute neonatal hypertensive crisis. METHODS: Neonatal and cardiology databases from 2007 to 2010 were reviewed. An established diagnosis of circulatory failure due to neonatal hypertension before the age of 14 days was required for inclusion. Six patients were identified. RESULTS: Five patients presented with circulatory failure due to an acute hypertensive crisis. The median age at presentation was 8.5 days (range: 6.0-11.0) with a median body weight of 3.58 kg (range: 0.86 4.70). Echocardiography demonstrated mild left ventricular dysfunction [median shortening fraction (SF) 25%, range 10-30] and mild aortic regurgitation in 83% (5/6) of patients. One patient with left ventricular dysfunction (SF = 17%) had a large apical thrombus. Two patients were hypotensive, and hypertension only became evident after restoration of cardiac output. Administration of intravenous milrinone was successful, with rapid improvement of the clinical condition. Left ventricular function normalised in all survivors. CONCLUSION: Early neonatal circulatory collapse due to arterial hypertension is a rare but potentially life threatening condition. At presentation, hypotension, especially in the presence of a dysfunctional left ventricle, does not exclude a hypertensive crisis being the cause of circulatory failure. The echocardiographic presence of mild aortic regurgitation combined with left ventricular hypocontractility in a structurally normal heart should alert the physician to the presence of underlying hypertension. PMID- 23736131 TI - Decreased vascular contractility induced by hemin is associated with a reduced rho-kinase activity. AB - OBJECTIVES: In this study, the role of rho-kinase activity in the modulation of vascular contractility induced by hemin, a heme oxygenase inducer, was investigated. METHODS: Aortic rings from Wistar rats were incubated in physiological saline solution (PSS) containing hemin at 10-(4) M for six hours then contracted with phenylephrine, and a dose-response curve was established. The effect of Y-27632, a rho-kinase inhibitor, on the relaxation of the pre contracted aortic rings was then studied. RESULTS: Incubation of the aortic rings in hemin induced an increased expression of heme oxygenase 1 (HO-1). A reduction in the contractile force of aortic rings incubated in hemin was observed in response to phenylephrine. Y-27632 at a concentration of 10-(6) M induced a 36% relaxation of the control aortic rings but only a 20% relaxation in aortic rings treated with hemin. CONCLUSION: These data suggest that the decreased vascular contractility induced by hemin could, in part, result from an inhibition of rho kinase activity. PMID- 23736132 TI - Cardiovascular complications in newly diagnosed rheumatic heart disease patients at Mulago Hospital, Uganda. AB - BACKGROUND: Complications of rheumatic heart disease are associated with severe morbidity and mortality in developing countries where the disease prevalence remains high. Due to lack of screening services, many patients present late, with severe valve disease. In Uganda, the disease and its complications are still not well studied. OBJECTIVE: To profile and describe cardiovascular complications in newly diagnosed rheumatic heart disease patients attending the Mulago National Referral Hospital in Uganda. METHODS: This was a cross-sectional study where consecutive, newly diagnosed rheumatic heart disease patients were assessed and followed up for complications, such as heart failure, pulmonary hypertension, atrial fibrillation, recurrence of acute rheumatic fever, and stroke. RESULTS: A total of 309 (115 males and 196 females) definite rheumatic heart disease patients aged 15-60 years were enrolled in the study and analysed. Complications occurred in 49% (152/309) of the newly diagnosed rheumatic heart disease cases, with heart failure (46.9%) the most common complication, followed by pulmonary arterial hypertension (32.7%), atrial fibrillation (13.9%), recurrence of acute rheumatic fever (11.4%), infective endocarditis (4.5%) and stroke (1.3%). Atrial fibrillation and acute rheumatic fever were the most common complications associated with heart failure. CONCLUSION: In this study we found that about 50% of newly diagnosed rheumatic heart disease patients in Uganda presented with complications. Heart failure and pulmonary arterial hypertension were the most commonly observed complications. PMID- 23736134 TI - Successes, failures, challenges and ground-breaking research: messages from the 6th World Congress of Paediatric Cardiology and Cardiac Surgery. PMID- 23736133 TI - Management of ischaemic stroke in the acute setting: review of the current status. AB - Acute ischaemic stroke can be treated by clot busting and clot removal. Thrombolysis using intravenous recombinanttissue plasminogen activator (IV r-TPA) is the current gold standard for the treatment of acute ischaemic stroke (AIS). The main failure of this type of treatment is the short time interval from stroke onset within which it has to be used for any benefit. The evidence is that IV r TPA has to be used within 4.5 hours. Other modalities of treatment are not as effective and need more scrutiny and examination. The available modalities are intra-arterial thrombolysis and clot-retrieval devices. Not unexpectedly, recanalisation treatments have flourished at a rapid rate. Although vessel recanalisation is vital to increasing the possibility of significant tissue reperfusion, clinical trials need to emphasise functional outcomes rather than reperfusion/recanalisation rates to adequately assess success of these devices/techniques. Our view is that until these treatments become proven in large-scale studies, a greater endeavour should be made in resource-limited settings to expand facilities to enable intravenous r-tPA treatment within the 4.5-hour period following onset of stroke. The resources required are small with the main costs being a CT scan of the brain and the cost of r-tPA. This can easily be done in any emergency facility in any part of the world. What is needed is public awareness, and campaigns of 'stroke attack' should be revisited, especially in the resource-limited context. This approach at present will halt to some extent the stroke pandemic that we are facing. PMID- 23736135 TI - NICD risk factors in a high-HIV-prevalence rural setting. PMID- 23736136 TI - Higher statin doses linked to acute kidney injury: South African experts comment on clinical implications. PMID- 23736137 TI - Treating hypertension in the elderly, even whiteh-coat hypertension, is essential. PMID- 23736138 TI - Use new antiplatelet therapies consistently in clinical practice. PMID- 23736139 TI - "Colloid twice daily" is not fluid resuscitation! Inappropriate inclusion of clinical trials in meta-analyses may distract from gaps in evidence. PMID- 23736140 TI - Harm associated with 6 % tetrastarch 130 kDa [hydroxyethyl starch (HES) 130/0.4 and 130/0.42] is robust to sensitivity analysis by excluding Dolecek et al. PMID- 23736141 TI - Altered neutrophil counts at diagnosis of invasive meningococcal infection in children. AB - BACKGROUND: Invasive meningococcal infections can be devastating. Substantial endotoxemia releases mature and immature neutrophils. Endothelial margination of mature neutrophils may increase the immature-to-total neutrophil ratio (ITR). These changes have not been previously well-described in invasive meningococcal disease. METHODS: Using 2001 to 2011 data from the US Multicenter Meningococcal Surveillance Study, the diagnostic sensitivity and clinical correlates of white blood cell count, absolute neutrophil count (ANC), immature neutrophil count (INC) and ITR were evaluated alone and in combination at the time of diagnosis of invasive meningococcal disease. RESULTS: Two hundred sixteen patients were evaluated: meningococcemia (65), meningitis (145) and other foci (6). ANC <=1000/mm(3) or >=10,000/mm(3) was present in 137 (63%), INC >=500/mm(3) in 170 (79%) and ITR >=0.20 in 139 (64%). One or more of these 3 criteria were met in 204 of the 216 (94%). Results were similar for meningococcemia and meningitis subgroups. All 13 cases with mildest disease met 1 or more of the 3 criteria. Eight children presented with ANCs <1000/mm(3): 3 of them died and a fourth required partial amputation in all 4 limbs. CONCLUSIONS: Invasive meningococcal disease is characterized by striking abnormalities in ANC, INC and/or ITR. Neutropenia was associated with a poor prognosis. Notably, without INCs, 37% of cases would have been missed. Automated methods not measuring immature white blood cells should be avoided when assessing febrile children. Serious infection should be considered when counts meet any of the 3 criteria. PMID- 23736142 TI - Relationship with original pathogen in recurrence of acute otitis media after completion of amoxicillin/clavulanate: bacterial relapse or new pathogen. AB - OBJECTIVE: We sought to determine whether recurrent acute otitis media (rAOM) occurring within 30 days of amoxicillin/clavulanate treatment was caused by bacterial relapse or new pathogens. METHODS: Pneumococcal conjugate vaccinated children, age 6-36 months, enrolled in a prospective, longitudinal study experiencing rAOM<1 month after completing amoxicillin/clavulanate therapy were studied. AOM episodes occurred between June 2006 and November 2012. Multilocus sequence typing was used to genotype isolates. RESULTS: Sixty-six children were in the study cohort; 63 otopathogens were recovered from middle ear fluid after tympanocentesis. Nontypeable Haemophilus influenzae (NTHi) accounted for 47% of initial AOMs versus 15% by Streptococcus pneumoniae (Spn), P<0.0001. NTHi accounted for 42% of rAOM versus 24% by Spn (P value=0.04). NTHi was the main otopathogen that caused true bacteriologic relapses (77%). beta-lactamase producing NTHi and penicillin nonsusceptible Spn were not more common in rAOM than initial AOM infections. Among 21 paired (initial and rAOM events) NTHi isolates genotyped, 13 (61.9%) were the same organism; 1 of 9 (11.1%) of paired Spn isolates was the same (P value=0.017). rAOM occurring within a week of stopping amoxicillin/clavulanate was a different pathogen in 21% of cases, 8-14 days later in 33%, 15-21 days in 41% and 22-30 days in 57% (P=0.04). CONCLUSIONS: In amoxicillin/clavulanate-treated children, NTHi was the main otopathogen that caused true bacteriologic relapses. New pathogens causing rAOM versus persistence of the initial pathogen significantly increased week to week. Neither relapses nor new infections were caused more frequently by beta-lactamase producing NTHi or penicillin nonsusceptible Spn. PMID- 23736143 TI - Routine deworming of children at deployed military healthcare facilities. AB - The World Health Organization advocates mass antihelminthic treatment of school age children in areas of high prevalence of soil-transmitted helminths. Soil transmitted helminths prevalence in Afghanistan is 20-50%, but a high proportion of children do not attend school, so may be missed by deworming programs. The primary function of military medical assets in a theater of war is to provide life, limb and eyesight saving treatment. Additional humanitarian aid in the form of nonemergency treatment has also been provided in Afghanistan for thousands of civilian children. Children represent 3-15% of the patients treated at deployed military medical facilities. We report on recent experience of deployed surgical teams in southern Afghanistan who have noticed high levels of soil-transmitted helminths in war-injured patients. Military medical assets may provide an opportunity to integrate a policy of deworming of children into existing programs of humanitarian support. This would not be a substitute for mass deworming programs, but a supplementation. PMID- 23736146 TI - The relationship between structure and activity of MoO3-CeO2 catalysts for NO removal: influences of acidity and reducibility. AB - The SCR activities of MoO3-CeO2 catalysts are enhanced by both Lewis and Bronsted acidities provided by surface cerium atoms and amorphous MoO3 structures, respectively, but are suppressed by stable adsorbed nitrate or nitrite species on the defect sites of CeO2. PMID- 23736144 TI - Vitamin D-related host genetic variants alter HIV disease progression in children. AB - BACKGROUND: Vitamin D deficiency is common in HIV infection and has been associated with advanced disease. This study investigated whether vitamin D related genetic variants were associated with disease progression in HIV-infected children. METHODS: The Fok-I (C/T), Bsm-I (G/A), GC (A/C), DHCR7 (G/T) and CYP2R1 (G/A) genetic variants were detected by real-time polymerase chain reaction in HIV-infected children who participated in the Pediatric AIDS Clinical Trials Group P152 and P300 protocols, which predated the availability of effective combination antiretroviral therapy. The primary endpoints included time to progression to the first HIV-related disease endpoint (>=2 opportunistic infection, weight growth failure) or death, which constituted the progression free survival. Analyses were performed for age>2 years and <=2 years separately adjusting for race and treatment effect. RESULTS: Of the 998 children evaluated, 139 experienced HIV disease progression. For children>2 years, rapid disease progression was associated with the DHCR7 G allele compared with the T allele (G/G vs. T/T: hazard ratio [HR]=5.0, P = 0.035; G/T vs. T/T: HR=4.5, P=0.042; G/G+G/T vs. T/T: HR=4.8, P=0.036) and the Bsm-I A allele compared with the G allele (A/G vs. G/G: HR=2.2, P=0.014 and A/G+A/A vs. G/G: HR=2.0, P=0.026). In children<=2 years, the Bsm-I A allele increased the risk of disease progression in Hispanics (A/A vs. G/A+G/G: HR=2.8, P=0.03 and A/A vs. G/G: HR=2.8, P=0.046) and whites (A/A vs. G/G: HR=6.6, P=0.025 and A/A vs. G/A+G/G: HR=3.6, P=0.038). CONCLUSIONS: Vitamin D-related host genetic variants that alter the availability and activity of vitamin D are associated with risk of HIV disease progression in children and may vary by age and race. PMID- 23736147 TI - Total lipid management and cardiovascular disease in the dyslipidemia international study. AB - OBJECTIVES: Despite statin use, many patients with cardiovascular disease (CVD) are not achieving treatment goals. An international observational study was performed to estimate the prevalence of residual lipid abnormalities in statin treated patients with CVD to assess whether lipid management requires improvement. METHODS: Fasting plasma concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides were recorded in 11,104 patients with atherosclerotic CVD and >=3 months of statin therapy. RESULTS: LDL-C and total cholesterol were not at goal levels in 41 and 46% of all patients, respectively; for patients with peripheral artery disease (PAD) only, 59 and 65%, respectively, were not at goal, and in those with coronary heart disease only, 38 and 42%, respectively, were not at goal. Patients with cerebrovascular disease only were least frequently observed to have low HDL-C (24%) and elevated triglycerides (36%). Overall, elevated LDL-C was the most frequent lipid anomaly observed, and preexisting heart failure was strongly and positively associated with dyslipidemia. CONCLUSIONS: Approximately two fifths of statin-treated patients with CVD are not reaching lipid goals or have abnormal lipid levels, while patients with PAD could particularly benefit from improved lipid management. In addition to targeting LDL-C, new evidence based approaches are needed to target low HDL-C and elevated triglycerides. PMID- 23736148 TI - Liver stiffness measurement versus liver biopsy to predict survival and decompensations of cirrhosis among HIV/hepatitis C virus-coinfected patients. AB - OBJECTIVE: To compare the prognostic performance of liver biopsy with that of liver stiffness measurement (LSM) to predict survival and liver decompensations among HIV/hepatitis C virus (HCV)-coinfected patients. DESIGN: Retrospective cohort study. METHODS: Cohort of 297 HIV/HCV-coinfected patients, who underwent a liver biopsy and LSM separated by 12 months or less, followed in 10 Spanish tertiary care centers from December 2005 to December 2011 (median follow-up, 5 years; interquartile range, 4.2-5.4 years). Liver biopsies were staged following the Scheuer's score. LSM was obtained by hepatic transient elastometry. A survival analysis was carried out and the integrated discrimination improvement was computed to compare the ability of the survival models to predict outcomes. The incidence of death from any cause and of development of the first decompensation of cirrhosis was calculated. RESULTS: Overall mortality rate was 1.63 [95% confidence interval (CI) 1.06-2.49] per 100 person-years. The adjusted hazard ratio [AHR (95% CI)] of baseline fibrosis (per stage of fibrosis) was 1.52 (1.08-2.15, P=0.017) and of LSM (per 5 kPa increase) 1.28 (1.12-1.46, P<0.001). LSM including models yielded a performance 3.9% better than the liver biopsy based models (P=0.072). For the prediction of liver decompensations, the AHR (95% CI) of baseline fibrosis by liver biopsy (per stage of fibrosis) was 1.67 (1.15 2.43, P=0.007) and of LSM (per 5 kPa increase) 1.37 (1.21-1.54, P<0.001). LSM based models yielded a performance 8.4% better than the liver biopsy-based models (P=0.045). CONCLUSION: LSM-based prediction achieves a similar yield than liver biopsy-based models to predict overall mortality in HIV/HCV-coinfected patients. Models including LSM could predict better liver decompensations than liver biopsy. PMID- 23736153 TI - Organometallic precursors of nano-objects, a critical view. AB - The synthesis of nanoparticles has experienced a huge development over the past 20 years. However, this development has remained relatively limited to a few classes of nanomaterials such as iron oxides, semi-conducting oxides, plasmonic nanoparticles (essentially Au) and quantum dots. In these cases, a physical chemistry approach and standard recipes allow a good control of the size and shape of the resulting nano-objects. However, organometallic precursors have emerged as an important class allowing the preparation of a large variety of nano objects, concerning a large number of elements and displaying a clean and controllable surface and therefore good physical and chemical properties. This perspective article is mostly devoted to the research efforts carried out by our group on the search for new classes of precursors and on the importance of knowing their exact structure and the molecular chemistry involved prior to the fabrication of the nano-objects. PMID- 23736151 TI - Improvements in virological control among women conceiving on combination antiretroviral therapy in Western Europe. AB - Among 396 HIV-infected women conceiving on combination antiretroviral therapy and enrolled in the European Collaborative Study in 2000-2011, the proportion with virological failure (>200 copies/ml after >=24 weeks of treatment) declined substantially from 34% in 2000-2001 to 3% in 2010-2011. In adjusted analyses, younger women and those with at least two children were at increased risk of virological failure, highlighting the importance of close monitoring and adherence support. PMID- 23736152 TI - Hepatitis C virus reinfection incidence and treatment outcome among HIV-positive MSM. AB - OBJECTIVE: Liver disease secondary to hepatitis C virus (HCV) infection in the context of HIV infection is one of the leading non-AIDS causes of death. Sexual transmission of HCV infection among HIV-positive MSM appears to be leading to increased reports of acute HCV infection. Reinfection after successful treatment or spontaneous clearance is reported among HIV-positive MSM but the scale of reinfection is unknown. We calculate and compare HCV reinfection rates among HIV positive MSM after spontaneous clearance and successful medical treatment of infection. DESIGN: Retrospective analysis of HIV-positive MSM with sexually acquired HCV who subsequently spontaneously cleared or underwent successful HCV treatment between 2004 and 2012. RESULTS: Among 191 individuals infected with HCV, 44 were reinfected over 562 person-years (py) of follow-up with an overall reinfection rate of 7.8/100 py [95% confidence interval (CI) 5.8-10.5]. Eight individuals were subsequently reinfected a second time at a rate of 15.5/100 py (95% CI 7.7-31.0). Combining all reinfections, 20% resulted in spontaneous clearance and treatment sustained viral response rates were 73% (16/22) for genotypes one and four and 100% (2/2) for genotypes two and three. Among 145 individuals with a documented primary infection, the reinfection rate was 8.0 per 100 py (95% CI 5.7-11.3) overall, 9.6/100 py (95% CI 6.6-14.1) among those successfully treated and 4.2/100 py (95% CI 1.7-10.0) among those who spontaneously cleared. The secondary reinfection rate was 23.2/100 py (95% CI 11.6-46.4). CONCLUSION: Despite efforts at reducing risk behaviour, HIV-positive MSM who clear HCV infection remain at high risk of reinfection. This emphasizes the need for increased sexual education, surveillance and preventive intervention work. PMID- 23736149 TI - Association of early HIV viremia with mortality after HIV-associated lymphoma. AB - OBJECTIVE: To examine the association between early HIV viremia and mortality after HIV-associated lymphoma. DESIGN: Multicenter observational cohort study. SETTING: Center for AIDS Research Network of Integrated Clinical Systems cohort. PARTICIPANTS: HIV-infected patients with lymphoma diagnosed between 1996 and 2011, who were alive 6 months after lymphoma diagnosis and with at least two HIV RNA values during the 6 months after lymphoma diagnosis. EXPOSURE: Cumulative HIV viremia during the 6 months after lymphoma diagnosis, expressed as viremia copy-6 months. MAIN OUTCOME MEASURE: All-cause mortality between 6 months and 5 years after lymphoma diagnosis. RESULTS: Of 224 included patients, 183 (82%) had non Hodgkin lymphoma (NHL) and 41 (18%) had Hodgkin lymphoma. At lymphoma diagnosis, 105 (47%) patients were on antiretroviral therapy (ART), median CD4+ cell count was 148 cells/MUl (interquartile range 54-322), and 33% had suppressed HIV RNA (<400 copies/ml). In adjusted analyses, mortality was associated with older age [adjusted hazard ratio (AHR) 1.37 per decade increase, 95% CI 1.03-1.83], lymphoma occurrence on ART (AHR 1.63, 95% CI 1.02-2.63), lower CD4+ cell count (AHR 0.75 per 100 cells/MUl increase, 95% CI 0.64-0.89), and higher early cumulative viremia (AHR 1.35 per log10 copies * 6-months/ml, 95% CI 1.11-1.65). The detrimental effect of early cumulative viremia was consistent across patient groups defined by ART status, CD4+ cell count, and histology. CONCLUSION: Exposure to each additional 1-unit log10 in HIV RNA throughout the 6 months after lymphoma diagnosis was associated with a 35% increase in subsequent mortality. These results suggest that early and effective ART during chemotherapy may improve survival. PMID- 23736154 TI - Synergistic interactions between camptothecin and EGFR or RAC1 inhibitors and between imatinib and Notch signaling or RAC1 inhibitors in glioblastoma cell lines. AB - PURPOSE: The current treatment strategies for glioblastoma have limited health and survival benefits for the patients. A common obstacle in the treatment is chemoresistance. A possible strategy to evade this problem may be to combine chemotherapeutic drugs with agents inhibiting resistance mechanisms. The aim with this study was to identify molecular pathways influencing drug resistance in glioblastoma-derived cells and to evaluate the potential of pharmacological interference with these pathways to identify synergistic drug combinations. METHODS: Global gene expressions and drug sensitivities to three chemotherapeutic drugs (imatinib, camptothecin and temozolomide) were measured in six human glioblastoma-derived cell lines. Gene expressions that correlated to drug sensitivity or resistance were identified and mapped to specific pathways. Selective inhibitors of these pathways were identified. The effects of six combinations of inhibitors and chemotherapeutic drugs were evaluated in glioblastoma-derived cell lines. Drug combinations with synergistic effects were also evaluated in non-cancerous epithelial cells. RESULTS: Four drug combinations had synergistic effects in at least one of the tested glioblastoma-derived cell lines; camptothecin combined with gefitinib (epidermal growth factor receptor inhibitor) or NSC 23766 (ras-related C3 botulinum toxin substrate 1 inhibitor) and imatinib combined with DAPT (Notch signaling inhibitor) or NSC 23766. Of these, imatinib combined with DAPT or NSC 23766 did not have synergistic effects in non-cancerous epithelial cells. Two drug combinations had at least additive effects in one of the tested glioblastoma-derived cell lines; temozolomide combined with gefitinib or PF-573228 (focal adhesion kinase inhibitor). CONCLUSION: Four synergistic and two at least additive drug combinations were identified in glioblastoma-derived cells. Pathways targeted by these drug combinations may serve as targets for future drug development with the potential to increase efficacy of currently used/evaluated chemotherapy. PMID- 23736155 TI - Importance of standardizing the dose in hyperthermic intraperitoneal chemotherapy (HIPEC): a pharmacodynamic point of view. PMID- 23736157 TI - Reynaldo Martorell, Editorial Board member, EJCN. PMID- 23736156 TI - The effectiveness of a structured education pulmonary rehabilitation programme for improving the health status of people with moderate and severe chronic obstructive pulmonary disease in primary care: the PRINCE cluster randomised trial. AB - OBJECTIVE: To evaluate the effectiveness of a structured education pulmonary rehabilitation programme on the health status of people with chronic obstructive pulmonary disease (COPD). DESIGN: Two-arm, cluster randomised controlled trial. SETTING: 32 general practices in the Republic of Ireland. PARTICIPANTS: 350 participants with a diagnosis of moderate or severe COPD. INTERVENTION: Experimental group received a structured education pulmonary rehabilitation programme, delivered by the practice nurse and physiotherapist. Control group received usual care. MAIN OUTCOME MEASURE: Health status as measured by the Chronic Respiratory Questionnaire (CRQ) at baseline and at 12-14 weeks postcompletion of the programme. RESULTS: Participants allocated to the intervention group had statistically significant higher mean change total CRQ scores (adjusted mean difference (MD) 1.11, 95% CI 0.35 to 1.87). However, the CI does not exclude a smaller difference than the one that was prespecified as clinically important. Participants allocated to the intervention group also had statistically significant higher mean CRQ Dyspnoea scores after intervention (adjusted MD 0.49, 95% CI 0.20 to 0.78) and CRQ Physical scores (adjusted MD 0.37, 95% CI 0.14 to 0.60). However, CIs for both the CRQ Dyspnoea and CRQ Physical subscales do not exclude smaller differences as prespecified as clinically important. No other statistically significant differences between groups were seen. CONCLUSIONS: A primary care based structured education pulmonary rehabilitation programme is feasible and may increase local accessibility to people with moderate and severe COPD. TRIAL REGISTRATION: ISRCTN52403063. PMID- 23736158 TI - Nanomolar cholera toxin inhibitors based on symmetrical pentavalent ganglioside GM1os-sym-corannulenes. AB - Eight symmetric and pentavalent corannulene derivatives were functionalized with galactose and the ganglioside GM1-oligosaccharide (GM1os) via copper-catalyzed alkyne-azide cycloaddition (CuAAC) reactions. The compounds were evaluated for their ability to inhibit the binding of the pentavalent cholera toxin to its natural ligand, ganglioside GM1. In this assay, all ganglioside GM1os-sym corannulenes proved to be highly potent nanomolar inhibitors of cholera toxin. PMID- 23736160 TI - Safety in healthcare and home care: a permanent improvement process. PMID- 23736159 TI - Causal information on children's attitudes and behavioural intentions toward a peer with obesity. AB - BACKGROUND: This study examined the effect of types of causal information about overweight on children's attitudes and intentions toward a peer presented as overweight. METHODS: Participants (N = 176) were randomly assigned to read a vignette of an overweight peer in one of three conditions, which varied in the explanatory information provided for the aetiology of the peer's overweight condition: biological, environmental or no causal information, along with a vignette of an average-weight peer. RESULTS: The provision of information that the overweight was the result of biological factors and of no causal information yielded more positive attitudes toward the overweight peer compared to those who were provided with environmental information. Information on overweight had no impact on behavioural intentions. A social desirability bias was found for each of the three experimental conditions and for the average weight condition. CONCLUSION: Information explaining overweight had a minimal positive effect on attitudes and no effect on intentions toward an overweight peer. PMID- 23736161 TI - Safe to Sleep public education campaign. PMID- 23736162 TI - A home healthcare and school of pharmacy partnership to reduce falls. AB - Much emphasis has been placed on the impact of falls among older adults, and the relationship between polypharmacy and falls in community-dwelling elders. As home healthcare agencies' critical role in the continuum of care is recognized, so is the responsibility for ensuring that quality patient outcomes are achieved resulting in reduced hospitalizations. As we examined the factors involved in falls and hospitalizations with our home care population, it became evident that the pharmacist plays a critical role in helping to ensure that risk factors associated with falls are minimized through a thorough medication therapy review, completed in collaboration with the case manager and the physician. This project was initiated to positively impact patient outcomes by identifying potential medication issues in those patients who were also identified as high fall risk. PMID- 23736164 TI - Head, neck, and oral cancer update. AB - Although the overall incidence of head, neck, and oral cancer has been decreasing, oral and neck cancer caused by the human papillomavirus (HPV) has risen. This article discusses statistics, risk factors, causes, pathophysiology, treatments, and the home healthcare and hospice nursing implications for these patients. A real-life patient's journey through neck cancer caused by HPV is presented. PMID- 23736166 TI - Research on family caregivers: understanding levels of burden and how to provide assistance. AB - This article focuses on issues and research related to informal caregivers. The first 2 profiled studies looked at caregiver burden with 1 study conducted in the United States and the other in Thailand. Caregiver burden refers to the physical and emotional risks facing caregivers who are taking care of a relative or friend. Both found that the level of caregiver burden was related more to caregiver perception and attitude than to patient disease or other patient characteristic. Other important findings can be found in the summaries in this research brief. The third article profiles an investigation that was part of the Resources for Enhancing Alzheimer's Caregiver Health (REACH II) initiative. Amanda Elliott and colleagues provide evidence of an intervention that was successful in improving caregiver health. The fourth write-up summarizes an important meta-analysis recently published on evaluating the effectiveness of family caregiver interventions on reducing behavioral and psychological symptoms in people with dementia and reducing caregiver negative reactions to these symptoms. Interested readers are encouraged to read the original articles for more details. PMID- 23736167 TI - Thinking outside the box: a performance improvement model with 10 best practices to reduce hospitalizations. PMID- 23736168 TI - The challenges patients experience in speaking about death. PMID- 23736169 TI - Abstracts of the 22nd European Stroke Conference. London, United Kingdom. May 28 31, 2013. PMID- 23736171 TI - Vascular angiotensin II type 2 receptor attenuates atherosclerosis via a kinin/NO dependent mechanism. AB - INTRODUCTION: The angiotensin II (Ang II) type 1 receptor exerts pro-atherogenic action by augmenting oxidative stress, whereas the Ang II type 2 receptor (AT2) mediated effect on atherosclerosis remains controversial. MATERIALS AND METHODS: AT2 transgenic (AT2-Tg) mice, which overexpress AT2 in their vascular smooth muscle cells, were crossed with apoE-deficient (apoE(-/-)) mice to generate AT2 transgenic apoE(-/-) mice (AT2-Tg/apoE(-/-)). RESULTS: A subpressor dose of Ang II infusion exaggerated atherosclerosis development in apoE(-/-) mice, which was markedly suppressed in AT2-Tg/apoE(-/-) mice. Inhibitors of nitric oxide (NO) synthase (L-NAME) or bradykinin type 2 receptor completely abolished AT2-mediated anti-atherogenic actions. The vascular cell adhesion molecule-1 expression levels and degree of monocyte/macrophage accumulation in the intima were also considerably reduced in AT2-Tg/apoE(-/-) mice; these phenomena were completely reversed by L-NAME treatment. Ang II infusion significantly enhanced the accumulation of dihydroethidium-positive mononuclear cells in the intima and mRNA expression levels of Nox2, a phagocytic cell-type NADPH oxidase subunit in apoE( /-) mice, which was completely inhibited in AT2-Tg/apoE(-/-) mice. CONCLUSIONS: Vascular AT2 stimulation exerts anti-atherogenic actions in an endothelial kinin/NO-dependent manner, and its anti-oxidative effect is likely to be exerted by inhibiting the accumulation of superoxide-producing mononuclear leukocytes. PMID- 23736172 TI - Receptivity to weight management interventions among hospitalized obese patients: an untapped opportunity. AB - OBJECTIVES: Hospitalized obese patients rarely receive counseling about weight loss. Specific patient preferences regarding inpatient weight loss interventions have not been systematically investigated. The objective of the study was to describe the preferences of hospitalized obese patients for weight loss interventions and to identify predictors of receptivity to such offerings. METHODS: A total of 204 individuals with a body mass index (BMI) >=30 kg/m (mean BMI 38.1 kg/m) admitted to the hospital medicine service in spring 2011 were surveyed at bedside for this cross-sectional study. The study population was predominantly white (67%) and women (62%), and their mean age was 55 years. RESULTS: Although 82% expressed a desire for providers to discuss weight loss during hospitalization, nearly all (92%) of the patients reported that providers did not address this subject. Logistic regression analysis tested demographic variables and obesity-related health beliefs as predictors of receptivity to inpatient weight loss interventions. The recognition of their own obesity and belief that weight loss would prolong life were significantly associated with receptivity to specific interventions, over and above objectively measured BMI in adjusted models. CONCLUSIONS: Receptivity to inpatient weight loss interventions varies considerably among hospitalized obese patients. The most important determinants that predict the level of receptivity were related to weight-related beliefs and perceptions. Future inpatient weight loss interventions could be targeted to patients with truthful health beliefs and perceptions about obesity. PMID- 23736173 TI - Commentary on "receptivity to weight management interventions among hospitalized obese patients: an untapped opportunity". PMID- 23736174 TI - Clinical outcomes of a veterans affairs outpatient antimicrobial treatment program. AB - OBJECTIVES: The outpatient parenteral antibiotic therapy (OPAT) program of the Portland Veterans Affairs Medical Center (PVAMC), which has a self-administration model, is staffed by visiting nurses from a specialist infusion company. This study evaluates the clinical outcomes of these patients. METHODS: This study was a retrospective chart review of 262 patients at PVAMC who had received OPAT between 2007 and 2009. Patients were included only if they received ongoing care at PVAMC. The data collected included conditions and organisms being treated and types and durations of antibiotics used. Clinical cure was defined as documented cure at the end of treatment and 90 days post-OPAT. RESULTS: One hundred ninety patients of 262 were analyzed. The mean age was 63.2 years. Diabetes was the main comorbid factor (17%). The most common indications for OPAT were osteomyelitis (38%), urinary tract infection (23%), and skin and soft tissue infection (12.6%). Mixed bacterial culture (26%) and Staphylococcus aureus (31%) were the most common organisms treated. Vancomycin was the most frequently used antibiotic (26%) followed by ceftriaxone (12%). The median duration of OPAT was 30 days. The rate of clinical cure at end of treatment observed for all infections treated was 78%, which then decreased to 58% at 90 days post-OPAT (P < 0.001). Patients with diabetes and osteomyelitis had an increased risk of relapse at 90 days post-OPAT on multivariate analysis (P = 0.025). CONCLUSIONS: An OPAT program using a self administration model treating patients who were military veterans had successful outcomes. Patients with diabetes and osteomyelitis had worse clinical outcomes 90 days after the completion of OPAT therapy. PMID- 23736175 TI - Findings and patterns on MRI and MR spectroscopy in neonates after therapeutic hypothermia for hypoxic ischemic encephalopathy treatment. AB - OBJECTIVES: The purpose of this study is to describe the findings and patterns of injury on magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) after whole-body hypothermia treatment for neonatal hypoxic ischemic encephalopathy. METHODS: A retrospective review of consecutive term neonates treated with whole-body hypothermia was performed. Data recorded included demographics and MRI and MRS findings, and day of life (DOL) studies were performed. Injury patterns were classified on MRI as deep, cortical, mixed, or diffuse. The relative apparent diffusion coefficient (rADC) was plotted against DOL scanned and the presence of lactate was recorded. RESULTS: MRI was performed in 44 infants, 34 of whom also underwent MRS. MRI was abnormal in 32% of neonates, 29.5% of whom were imaged at DOL 4 to 8. rADC values were lowest in neonates scanned on DOL 4 and 5 and remained low up to DOL 8. The deep brain nuclei were involved in hypoxic ischemic encephalopathy in 93% of neonates with abnormal MRIs and lactate was identified on MRS in 18% of neonates between DOL 4 and 8. CONCLUSIONS: MRI performed after therapeutic cooling was abnormal in 29.5% of neonates scanned on DOL 4 to 8. Deep nuclear injury was identified in 93% of neonates. Lactate was present on MRS in 18% of neonates, and rADC values were most reduced on MRI between DOL 4 and 8. PMID- 23736176 TI - Surgical treatment of lung cancer in octogenarians. AB - BACKGROUND: As the population ages, octogenarians are becoming the fastest growing patient demographic for non-small-cell lung cancer. We examined lobectomies and 30-day outcomes in this group compared with younger patients to gain insight into the optimal treatment for this challenging group. METHODS: We analyzed data from the American College of Surgeons National Quality Improvement Program for patients with lung cancer undergoing lobectomy during calendar years 2005-2010. We compared clinical risk factors, intraoperative factors, and 30-day operative mortality and major morbidity in octogenarians versus younger patients undergoing either open traditional thoracotomy (OPEN) or video-assisted (VATS) pulmonary lobar resection. RESULTS: Of 2171 patients who had lobar resections for lung cancer, 245 (11%) were octogenarians. Six hundred eight lobectomies (28.0%) were VATS procedures and 1563 (72.0%) were OPEN procedures. The VATS rate increased as patient age increased (34% VATS for octogenarians vs 27% for patients younger than 80 years; P = 0.01). Thoracic surgeons performed VATS with greater frequency compared with general surgeons, especially in octogenarians (41% VATS for thoracic surgeons vs 29% for general surgeons; P < 0.001). Univariate analysis suggests significantly increased major morbidity (pulmonary, renal, and sepsis), but not operative mortality in octogenarians; however, multivariate predictors of major morbidity include OPEN procedures, preoperative decreased functional status, history of chronic obstructive pulmonary disease, preoperative sepsis, prior radiation, diabetes, and dyspnea on exertion (all P < 0.05), but they do not include advanced age. CONCLUSIONS: Comorbidities predict most increased morbidity in octogenarians, and advanced age per se is not an important multivariate predictor of postoperative morbidity or mortality. The frequency of VATS lobectomy increased with increasing patient age, and VATS predisposes to decreased morbidity in octogenarians. PMID- 23736177 TI - Patient-centered approach to ensuring appropriateness of care through blood management. AB - BACKGROUND: Concerns have been raised about the safety and efficacy of blood transfusions. Blood products are in demand and a decreasing supply is projected, with resource conservation a global concern. A consultant group determined that the transfusion rate at Mease Countryside Hospital was higher than an average baseline. METHODS: A process-improvement project was initiated using a multidisciplinary team approach to improve blood utilization and ensure appropriateness in transfusion practice. The foundation of this project was to create new guidelines for transfusion; provide detailed education, communication, reporting, and feedback; and develop criteria to ensure compliance. RESULTS: The mean monthly usage of red blood cell units per 1000 inpatient discharges between April 2010 and October 2011 was 321.4 compared with 212.0 for the 5 months after implementation. The mean monthly number of patients transfused per 1000 inpatient discharges from April 2010 to October 2011 was 135.2 compared with 90.2 after implementation. In both cases, this reduction was found to be statistically significant at a 95% confidence level (P = 0.000 in both respects). CONCLUSIONS: The success of this project was the result of careful planning and execution, administrative support, physician leadership, and teamwork. Blood management includes strategies to avoid inappropriate transfusions and proactively treat anemia. Anemia management should be based on the patient's symptoms, laboratory values, and clinical assessment. Treatment of anemia should encompass a patient centered approach, with the aim of promoting patient safety and minimizing the risk from exposure to blood products. PMID- 23736178 TI - Can in-hospital urinary catheterization rates be reduced with benefits outweighing the risks? AB - Urinary catheterization has risks and its use should be limited because it is the main cause of healthcare-associated urinary tract infection. Other risks are the potential for urethral injuries and the possibility that the catheter will be left in permanently. Rates of urinary catheterization in internal medicine departments generally range from 8% to 20%, with higher rates in older adult patients. Various attempts have been made to decrease catheterization rates with variable success. A major problem is that the guidelines and criteria for urinary catheterization are inconsistent and open to variable interpretations. More restrictive criteria based on observable patient benefit can reduce rates of urinary catheterization and may improve patient care. PMID- 23736179 TI - Commentary on "can in-hospital urinary catheterization rates be reduced with benefits outweighing the risks?". PMID- 23736180 TI - Primer in health information exchange for the emergency physician: benefits and barriers. AB - For various reasons, patients seek care at different hospitals within a region, resulting in fragmented medical records at the point of care. In the emergency department, this is a particularly important issue because the emergency department provides open access to all patients and requires rapid high-stakes decision making to function well. To address these issues and as a result of federal initiatives, health information exchanges (HIEs) have been designed and implemented in various regions throughout the United States to promote health information sharing. The use of HIEs has been demonstrated to lower costs and avoid duplicative testing and treatment; however, obstacles such as physician usage characteristics and institutional concerns regarding information sharing exist and must be addressed before full implementation and adoption of HIEs among institutions take place. Further research is needed to describe the benefits of HIEs and how they can affect these barriers. PMID- 23736181 TI - Commentary on "primer in health information exchange for the emergency physician: benefits and barriers". PMID- 23736182 TI - Digoxin: time to reconsider its role in atrial fibrillation? PMID- 23736183 TI - Evidence-based medicine and digoxin. PMID- 23736184 TI - Silver-catalysed trifluoromethylation of arenes at room temperature. AB - A variety of heteroarenes and electron rich arenes can be trifluoromethylated at room temperature with TMSCF3, catalytic silver and PhI(OAc)2. PMID- 23736185 TI - Is it my mother? PMID- 23736186 TI - [Omega-3 fatty acids--both food and medicine]. PMID- 23736187 TI - [Rituximab and neutropenia]. PMID- 23736191 TI - [Good advice for possible whistleblowers]. PMID- 23736192 TI - [Remember mental health]. PMID- 23736193 TI - Use of emergency medical services by patients encompassed by the Regular GP scheme. AB - BACKGROUND: Norwegian emergency medical services are used with frequency, often in relation to conditions that could wait until the next day to be handled by the patient's regular GP (RGP). We investigated whether there are characteristics of particular GPs that may help explain why patients on their list use the emergency medical services. MATERIAL AND METHODS: We used data from the billing cards for 2008 from all emergency doctors, linked to information from the Regular GP database and Statistics Norway, for a total of 4,097 RGPs. For each RGP we estimated a contact rate: The total number of contacts reported for their list patients (identified by their personal ID numbers), divided by the length of the RGP's list. This rate was subsequently analysed with regard to characteristics of the RGP (bivariate analyses and multiple logistic regression). RESULTS: The average contact rate amounted to 27.4 contacts per 100 list patients, with significant variation between the RGPs (the 25th percentile was 17.8 contacts and the 75th percentile 33.1). Patients of male RGPs, young RGPs and immigrant RGPs used the emergency medical services more frequently than patients of female RGPs, older RGPs and Norwegian RGPs. Patients from long lists, single-doctor practices and open lists used the emergency medical services less frequently than patients from short lists, group practices and closed lists. The contact rate was higher in rural municipalities than in urban areas. INTERPRETATION: The large variations in the use of emergency medical services indicate that more RGPs should take measures to improve accessibility for emergency calls during the daytime. PMID- 23736194 TI - Which GPs are staffing the emergency medical services? AB - BACKGROUND: Approximately half of all accident and emergency medical (A&E) services are provided by regular general practitioners (RGPs). We wished to find out which RGPs staff the A&E services. MATERIAL AND METHOD: The material comprises billing cards from all A&E doctors in 2008, linked to information from Statistics Norway and the Regular GP database. We estimated the proportion of various RGPs who staff the A&E roster and how many patient contacts they had while on duty. The same variables describing the RGPs were used in a multivariate logistic regression analysis, in which the dependent variable was whether the RGPs were on the emergency service roster or not. RESULTS: Altogether 53% of the RGPs were on the emergency service roster, and accounted for 47% of all patient contacts. The RGPs were older than other emergency doctors (44 years as opposed to 34 years), and included a smaller proportion of women (33% as opposed to 44%). Immigrants accounted for 23% of the RGPs and 21% of the other emergency doctors. Women RGPs were on A&E duty less frequently than their male counterparts in all age groups, and they also had fewer patient contacts (206 and 374). The participation rate decreased in proportion to the doctors' age, increasing list length and increasing centrality. Immigrant RGPs with a short time of residence in Norway had the highest frequency of on-call duty (81%). INTERPRETATION: The number of women RGPs is increasing, and it is therefore likely that the frequency of on-call duty among RGPs will decrease further. However, the immigrants are providing a significant contribution to maintaining the A&E scheme. PMID- 23736195 TI - [Fish and omega-3 fatty acids and heart failure]. AB - BACKGROUND: Oily fish are the main source of marine omega-3 fatty acids, which have beneficial cardiovascular effects. The article gives an overview of studies of the effects of fish and omega-3 fatty acids on the risk of heart failure and on mortality in heart failure patients. MATERIAL AND METHOD: The article is based on selected literature from personal archives, references collected from relevant articles in personal archives and on publications found through PubMed searches. RESULTS: Recent observational studies have indicated that a high intake of fish and marine omega-3-fatty acids as well as increased plasma concentrations of the same fatty acids can reduce both the incidence of heart failure and mortality among elderly people with heart failure, with or without a previous myocardial infarction. A clinical, placebo-controlled study of around 7,000 elderly heart failure patients found a 9% reduction in mortality after treatment with omega-3 fatty acids. The omega-3 fatty acids were additional to other heart failure treatment. The beneficial effects of oily fish and omega-3 fatty acids appear to be associated with a number of haemodynamic and biological mechanisms. INTERPRETATION: A high intake of fish and marine omega-3 fatty acids seems to provide protection against the development of heart failure as well as reducing the mortality of manifest heart failure. PMID- 23736196 TI - [Effect and occurrence of synthetic cannabinoids]. AB - BACKGROUND: ''Spice'' is the term used for various products that contain synthetic cannabinoids. In recent years a growing number of products have been reported on the illegal market, also in Norway. The substances are sold over the internet as 'legal' cannabis. A number of the substances have gradually been classified as narcotics, also in Norway, but new variants continue to be developed. An overview is provided here of current knowledge of the efficacy and occurrence of synthetic cannabinoids. METHOD: The article is based on a discretionary selection of relevant articles found by means of a literature search in PubMed and on reports from Norwegian and European authorities and research institutions. RESULTS: Synthetic cannabinoids are a large group of drugs of abuse that have an effect similar to cannabis, but may be considerably more potent. The contents of the various Spice products vary with respect to potency, purity and the number and types of additives, and this implies a risk of unintentional overdose. There are reports from abroad of cardiac infarction in teenagers, severe psychoses, anxiety, unconsciousness and deaths following use. INTERPRETATION: Synthetic cannabinoids are marketed over the internet as legal and harmless cannabis, but can cause severe intoxication and death. There is a considerable need for more knowledge about the action and harmful effects of these substances. PMID- 23736197 TI - Synthetic cannabis. PMID- 23736198 TI - [A man in his 70s with abdominal pain and weight loss]. PMID- 23736199 TI - Secure electronic exchange of pathology reports. PMID- 23736200 TI - Hospital-based forensic psychiatric observation pursuant to Section 167 of the Criminal Procedure Act. PMID- 23736201 TI - [Prevalence--not reserved for the sick?]. PMID- 23736205 TI - Sphingosine 1-phosphate in renal diseases. AB - Because of its highly bioactive properties sphingosine 1-phosphate (S1P) is an attractive target for the treatment of several diseases. Since the expression of sphingosine kinases as well as S1P receptors was demonstrated in the kidney, questions about the physiological and pathophysiological functions of S1P in this organ have been raised. In this review, we summarize the current state of knowledge about S1P-mediated functions in the kidney. A special focus is put on S1P modulated signal transduction in renal glomerular and tubular cells and consequences for the development and treatment of several kidney diseases, diabetic nephropathy, glomerulonephritis, ischemia-reperfusion injury, as well as for Wilms tumor progression. PMID- 23736206 TI - Does molecular electronics compute? PMID- 23736208 TI - Wiring molecules into circuits. PMID- 23736207 TI - A brief history of molecular electronics. PMID- 23736209 TI - Visions for a molecular future. PMID- 23736211 TI - Magnetic domain walls: traps with potential. PMID- 23736212 TI - Thermal transport: naturally glassy crystals. PMID- 23736213 TI - Microcavity polaritons: a new type of light switch. PMID- 23736214 TI - Quantum dots: and then there were three. PMID- 23736216 TI - Experiences, considerations and emotions relating to cardiogenetic evaluation in relatives of young sudden cardiac death victims. AB - Relatives of young sudden cardiac death (SCD) victims are at increased risk of carrying a potentially fatal inherited cardiac disease. Hence, it is recommended to perform an autopsy on the victim and to refer his or her relatives to a cardiogenetics clinic for a full evaluation to identify those at risk and allow preventive measures to be taken. However, at present, the number of families attending a cardiogenetics clinic after the SCD of a young relative is low in the Netherlands. We performed a qualitative study and report on the experiences and attitudes of first-degree relatives who attended a cardiogenetics clinic for evaluation. In total, we interviewed nine first-degree relatives and one spouse of seven SCD victims about their experiences, considerations and emotions before attendance and at the first stage of the cardiogenetic evaluation before DNA results were available. Interviews were transcribed verbatim and analysed. Medical professionals did not have an important role in informing or referring relatives to a cardiogenetics clinic. Importantly, all participants indicated that they would have appreciated a more directive approach from medical professionals, because their mourning process hampered their own search for information and decision-making. A need to understand the cause of death and wanting to prevent another SCD event occurring in the family were the most important reasons for attending a clinic. There are possibilities to improve the information process and better support their decision-making. The multidisciplinary cardiogenetic evaluation was appreciated, but could be improved by minor changes in the way it is implemented. PMID- 23736215 TI - Single-molecule junctions beyond electronic transport. AB - The idea of using individual molecules as active electronic components provided the impetus to develop a variety of experimental platforms to probe their electronic transport properties. Among these, single-molecule junctions in a metal-molecule-metal motif have contributed significantly to our fundamental understanding of the principles required to realize molecular-scale electronic components from resistive wires to reversible switches. The success of these techniques and the growing interest of other disciplines in single-molecule-level characterization are prompting new approaches to investigate metal-molecule-metal junctions with multiple probes. Going beyond electronic transport characterization, these new studies are highlighting both the fundamental and applied aspects of mechanical, optical and thermoelectric properties at the atomic and molecular scales. Furthermore, experimental demonstrations of quantum interference and manipulation of electronic and nuclear spins in single-molecule circuits are heralding new device concepts with no classical analogues. In this Review, we present the emerging methods being used to interrogate multiple properties in single molecule-based devices, detail how these measurements have advanced our understanding of the structure-function relationships in molecular junctions, and discuss the potential for future research and applications. PMID- 23736217 TI - Clinical utility gene card for: hereditary thrombocythemia. PMID- 23736218 TI - Accurate prediction of a minimal region around a genetic association signal that contains the causal variant. AB - In recent years, genome-wide association studies have been very successful in identifying loci for complex traits. However, typically these findings involve noncoding and/or intergenic SNPs without a clear functional effect that do not directly point to a gene. Hence, the challenge is to identify the causal variant responsible for the association signal. Typically, the first step is to identify all genetic variation in the locus region, usually by resequencing a large number of case chromosomes. Among all variants, the causal one needs to be identified in further functional studies. Because the experimental follow up can be very laborious, restricting the number of variants to be scrutinized can yield a great advantage. An objective method for choosing the size of the region to be followed up would be highly valuable. Here, we propose a simple method to call the minimal region around a significant association peak that is very likely to contain the causal variant. We model linkage disequilibrium (LD) in cases from the observed single SNP association signals, and predict the location of the causal variant by quantifying how well this relationship fits the data. Simulations showed that our approach identifies genomic regions of on average ~50 kb with up to 90% probability to contain the causal variant. We apply our method to two genome-wide association data sets and localize both the functional variant REP1 in the alpha synuclein gene that conveys susceptibility to Parkinson's disease and the APOE gene responsible for the association signal in the Alzheimer's disease data set. PMID- 23736219 TI - Clinical utility gene card for: arrhythmogenic right ventricular cardiomyopathy (ARVC). PMID- 23736222 TI - Abstracts of the XXIV Nordic Baltic Congress of Cardiology 2013. Oslo, Norway . June 13-15, 2013. PMID- 23736220 TI - A novel method, the Variant Impact On Linkage Effect Test (VIOLET), leads to improved identification of causal variants in linkage regions. AB - The Human Genome Project was expected to individualize medicine by rapidly advancing knowledge of common complex disease through discovery of disease causing genetic variants. However, this has proved challenging. Although linkage analysis has identified replicated chromosomal regions, subsequent detection of causal variants for complex traits has been limited. One explanation for this difficulty is that utilization of association to follow up linkage is problematic given that linkage and association are not required to co-occur. Indeed, co occurrence is likely to occur only in special circumstances, such as Mendelian inheritance, but cannot be universally expected. To overcome this problem, we propose a novel method, the Variant Impact On Linkage Effect Test (VIOLET), which differs from other quantitative methods in that it is designed to follow up linkage by identifying variants that influence the variance explained by a quantitative trait locus. VIOLET's performance was compared with measured genotype and combined linkage association in two data sets with quantitative traits. Using simulated data, VIOLET had high power to detect the causal variant and reduced false positives compared with standard methods. Using real data, VIOLET identified a single variant, which explained 24% of linkage; this variant exhibited only nominal association (P=0.04) using measured genotype and was not identified by combined linkage association. These results demonstrate that VIOLET is highly specific while retaining low false-negative results. In summary, VIOLET overcomes a barrier to gene discovery and thus may be broadly applicable to identify underlying genetic etiology for traits exhibiting linkage. PMID- 23736223 TI - CH4 combustion cycles at Pd/Al2O3--important role of support and oxygen access. AB - This research is focused on the analysis of adsorbed CH4 intermediates at oxidized Pd9 nanoparticles supported on gamma-alumina. From first-principle density functional theory calculations, several configurations, charge transfer and electronic density of states have been analyzed in order to determine feasible paths for the oxidation process. Methane oxidation cycles have been considered as a further step at differently oxidized Pd nanoparticles. For low oxidized Pd nanoparticles, activation of methane is observed, whereby hydrogen from methane is adsorbed at one oxygen atom. This reaction is exothermic with adsorption energy equal to -0.38 eV. In a subsequent step, desorption of two water molecules is observed. Additionally, a very interesting structural effect is evident, mainly Pd-carbide formation, which is also an exothermic reaction with an energy of -0.65 eV. Furthermore, oxidation of such carbidized Pd nanoparticles leads to CO2 formation, which is an endothermic reaction. Important result is that the support is involved in CO2 formation. A different mechanism of methane oxidation has been found for highly oxidized Pd nanoparticles. When the Pd nanoparticle is more strongly exposed to oxidative conditions, adsorption of methane is also possible, but it will proceed with carbonic acid production at the interface between Pd nanoparticles and support. However, this step is endothermic. PMID- 23736221 TI - The sex-specific associations of the aromatase gene with Alzheimer's disease and its interaction with IL10 in the Epistasis Project. AB - Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimer's disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG=1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor=1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions ,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD. PMID- 23736224 TI - Diverse deep-sea fungi from the South China Sea and their antimicrobial activity. AB - We investigated the diversity of fungal communities in nine different deep-sea sediment samples of the South China Sea by culture-dependent methods followed by analysis of fungal internal transcribed spacer (ITS) sequences. Although 14 out of 27 identified species were reported in a previous study, 13 species were isolated from sediments of deep-sea environments for the first report. Moreover, these ITS sequences of six isolates shared 84-92 % similarity with their closest matches in GenBank, which suggested that they might be novel phylotypes of genera Ajellomyces, Podosordaria, Torula, and Xylaria. The antimicrobial activities of these fungal isolates were explored using a double-layer technique. A relatively high proportion (56 %) of fungal isolates exhibited antimicrobial activity against at least one pathogenic bacterium or fungus among four marine pathogenic microbes (Micrococcus luteus, Pseudoaltermonas piscida, Aspergerillus versicolor, and A. sydowii). Out of these antimicrobial fungi, the genera Arthrinium, Aspergillus, and Penicillium exhibited antibacterial and antifungal activities, while genus Aureobasidium displayed only antibacterial activity, and genera Acremonium, Cladosporium, Geomyces, and Phaeosphaeriopsis displayed only antifungal activity. To our knowledge, this is the first report to investigate the diversity and antimicrobial activity of culturable deep-sea-derived fungi in the South China Sea. These results suggest that diverse deep-sea fungi from the South China Sea are a potential source for antibiotics' discovery and further increase the pool of fungi available for natural bioactive product screening. PMID- 23736225 TI - The Helicobacter pylori protein CagM is located in the transmembrane channel that is required for CagA translocation. AB - Helicobacter pylori (H. pylori) is a human gastric pathogen that colonizes the stomach in more than 50 % of the world's human population. Infection with this bacterium can induce several gastric diseases ranging from gastritis to peptic ulcer and gastric cancer. Virulent H. pylori isolates harboring the cag pathogenicity island (cag PAI), which encodes a Type IV Secretion System (T4SS), form a pilus for the injection of its major virulence protein CagA into gastric cells. Several cag PAI genes have been identified as homologues of T4SS genes from Agrobacterium tumefaciens, while the other members in cag PAI still have no known function. We studied one of such proteins with unknown function, CagM, which was predicted to have a putative N-terminal signal sequence and at least three transmembrane helices. To determine the subcellular localization of CagM, we performed a cell fractionation procedure and produced rabbit anti-CagM polyclonal antibodies for immunoblotting assays. Furthermore, we generated an isogenic DeltacagM mutant to investigate the ability of CagA translocation compared with the wild-type NCTC 11637 strain using GES-1 and MKN-45 cell infection experiments. Our results indicated that CagM was mainly located in the bacterial membrane, partially located in the periplasm, and essential for CagA translocation both in GES-1 and MKN-45 cells, which suggested that CagM was one of the core members of Cag T4SS and localized in the transmembrane channel. PMID- 23736228 TI - Effect of reannealing temperature on characteristics of nanocrystalline Sn-doped In2O3 thin films for organic photovoltaic cell applications. AB - In this study, nanocrystalline Sn-doped In(2)O(3) (ITO) films were deposited by electron beam evaporation technique and were annealed in air atmosphere from 300 degrees C to 500 degrees C for 30 min. Then, the annealed ITO films in air at 450 degrees C were reannealed in vacuum for 1 h at different temperatures from 300 degrees C to 500 degrees C. The effects of reannealing temperature on structural, electrical, and optical properties of the ITO films were investigated. Increasing reannealing temperature from 300 degrees C to 500 degrees C reduced sheet resistance of ITO thin films from 38 to 12(Omega/sq). The highest transparency over the visible wavelength region of spectrum (95%) was obtained for reannealed films at 450 degrees C. The optimum reannealing temperature for these films is 450 degrees C. Refractive index at 550 nm and porosity for ITO films reannealed at 450 degrees C were 1.92% and 21.2%, respectively. The allowed direct bandgap at different reannealing temperature was evaluated to be in the range of 4.1-4.28 eV. X-ray diffraction results showed that the reannealed films were polycrystalline and a rise in grain size was observed in them. The average grain size in the films reannealed in vacuum at 450 degrees C is about 48.6 nm. Atomic force microscope images indicated that the grain size and root-mean-square roughness films depend on the reannealing temperature. It has been found that reannealing temperature is a key factor in controlling the structural, electrical, and optical properties of ITO films. The power conversion efficiency of the device with ITO films reannealed at 450 degrees C is 1.22% and it is about 58% higher than that of the device without it. This indicates that this film is a promising transparent electrode for organic photovoltaic cells. PMID- 23736229 TI - Two important mechanisms damaging KH2PO4 crystal processed by ultraprecision fly cutting and their relationships with cutting parameters. AB - Mid-frequency waviness and subsurface crack are two fundamental factors that damage KH(2)PO(4) (KDP) crystal processed by ultraprecise fly cutting. In this paper, the motif theory and the Fourier model method are used to analyze the influence of the two factors on the laser-induced damage threshold (LIDT) of KDP. Research results indicate that the modulation degrees increase nearly linearly when the waviness amplitude and subsurface crack depth increase, and, meanwhile, the LIDT tends to decrease. The two factors have different effects during different stages of KDP failure. The mean amplitudes of waviness and subsurface damage depth have similar changing regulations with different feeds. From the machining perspective, we need not necessarily know which is more dangerous, because when one factor is controlled, the other one will also be restrained at the same time. In general, smaller feed and cutting depth are benefits for improving the LIDT of KDP. PMID- 23736230 TI - Displacement sensor for indoor machine calibrations. AB - This paper presents a simple displacement sensor for indoor machine calibrations. The sensor, which is placed in the path of a diverging laser beam, consists of two plane mirror pieces laterally displaced with the line joining their centers initially held perpendicular to the optical axis of the beam during the displacement of the sensor with one of the mirrors always traveling along the optical axis of the laser beam. The optical signals from the two mirrors are combined and a simple detector at the interference plane counts the fringes during the sensor displacement. The sensor could be mounted on the moving head of any mechanical machine, e.g., the lathe machine for displacement calibration. The device has been tested over a range of 10 cm beyond a distance of 150 cm from a diverging laser source giving an accuracy of 1.1015 MUm. Theoretical modeling, simulation, and experimental results are presented which establish that the proposed sensor can be used as a promising displacement measuring device. PMID- 23736227 TI - Examining perceived stereotype threat among overweight/obese adults using a multi threat framework. AB - OBJECTIVE: The Multi-Threat Framework accounts for potentially different forms of stereotype threat that differ in target (i.e., the individual or the group) and source (i.e., the self or others). This investigation examined how these different forms of perceived stereotype threat were related to concepts, such as group identity, stereotype endorsement, stigma consciousness, etc., among overweight and obese individuals. METHOD: 216 adults completed an online survey. Participants' mean age was 23.6 (SD 10.1; range 18-64) years and mean BMI was 31.6 (SD 7.5) kg/m2. RESULTS: Participants reported a history of feeling threatened by stereotypes related to weight. When reflecting on past experiences of perceived stereotype threat, participants reported greater levels of self/own stereotype threat compared to group stereotype threat. Level of stereotype threat was related to a number of personal characteristics (i.e., sex, BMI) and individual factors (i.e., group identity, stigma consciousness, fear of fat). CONCLUSION: Individuals who are overweight report a history of being threatened by negative stereotypes. The findings support the Multi-Threat Framework for stereotype threat based on body weight. Overweight individuals' susceptibility to stereotype threat may vary systematically depending on several factors. Future research should examine weight-related stereotypes' impact on cognitive and behavioral outcomes. PMID- 23736231 TI - High-sensitivity SrTiO3 photodetectors with paralleled multiple interdigital electrode cells. AB - We report high-sensitivity SrTiO(3) photoconductive detectors with multiple photoelectric cells connected in parallel. The photocurrent of the detectors increases significantly with an increase of the cell number. The photocurrent responsivity of the detector with three cells can reach 237 mA/W at 10 V bias under illumination of the 375 nm laser, and the corresponding quantum efficiency is 77% at 10 V bias. Furthermore, a transient photovoltaic signal with a rise time of ~490 ps and a full width at half-maximum of ~900 ps is obtained. These results demonstrate that the present devices with further improvement of performance have great potential application in high-sensitivity and ultrafast ultraviolet photodetectors. PMID- 23736232 TI - Limited-view photoacoustic imaging based on an iterative adaptive weighted filtered backprojection approach. AB - An iterative adaptive weighted filtered backprojection (FBP) approach was applied to our photoacoustic imaging (PAI) of the optical absorption in biological tissues from limited-view data. By using an image-based adaptive weighted PAI reconstruction, we can modify the defect of the artifacts degrading the quality of the image. Results of numerical simulations demonstrated that the proposed algorithm was superior to FBP in terms of both accuracy and robustness to noise. Reconstructed images of biological tissues agreed well with the structures of the samples. The resolution of the PAI system with the proposed method was experimentally demonstrated to be better than 0.14 mm. By using the proposed method, the imaging quality of the PAI system can be improved. PMID- 23736233 TI - Parallel on-axis phase-shifting holographic phase microscopy based on reflective point-diffraction interferometer with long-term stability. AB - Parallel on-axis two-step phase-shifting reflective point-diffraction interferometry for holographic phase microscopy based on Michelson architecture is proposed. A cube beamsplitter splits the object wave into two copies within the two arms. The reference wave is rebuilt by low-pass filtering with a pinhole masked mirror. Both object and reference waves are split into two beams by a grating in a 4f imaging system; thus, two interferograms with quadrature phase shift can be acquired simultaneously with the aid of polarization elements. The approach has the merit of nanometers-scale phase stability over hours due to its quasi-common-path geometry. It can make full use of camera spatial bandwidth while its temporal resolution is as fast as the camera frame rate. Phase imaging on microscale specimen is implemented, and the experimental results demonstrate that the proposed approach is suitable for investigating dynamic processes. PMID- 23736234 TI - Ultrahigh sensing based on feedback double ring configuration beyond the limitation of quality factor on sensitivity. AB - In this article, we present a simple method to realize a sensor of ultrahigh sensitivity and compact size by employing a feedback double ring resonator. We demonstrate that this method has not only a higher sensitivity than an optimal add-drop resonator (ADR), but also a relatively high performance when the Q factor drops. Furthermore, we show that this sensing system can overcome the limitation of Q factor on system sensitivity by 2 orders of magnitude in comparison to the corresponding ADR. Thus, the proposal in this paper provides a promising and feasible scheme to realize a highly effective sensor that is weakly dependent on the Q factor of the system. PMID- 23736235 TI - Improving accuracy of distance measurements based on an optoelectronic oscillator by measuring variation of fiber delay. AB - The ultra-long optical fiber of an optoelectronic oscillator (OEO) and the high spectral purity of its high frequency oscillation signal open the possibility of high-accuracy distance measurements at a long range. However, the longer the fiber length in an OEO, the more prone the system is to surrounding disturbance, which in turn leads to fluctuation of the loop delay and a reduction in distance measurement accuracy. In this paper, an intensity modulated light signal is combined with the light signal of an OEO in terms of wavelength division multiplexing (WDM) and is propagated through the fiber. The phase shift has been measured in real time to compensate for variations in fiber delay. With this method, experimental results showed a standard deviation of 14.8 MUm. PMID- 23736236 TI - Optical trapping map of dielectric spheres. AB - Many applications use a focused Gaussian laser beam to manipulate spherical dielectric particles. The axial trapping efficiency of this process is a function of (i) the particle radius r, (ii) the ratio of the refractive index of particle over the medium, and (iii) the numerical aperture of the delivered light beam. During what we believe is the first comprehensive simulation of its kind, we uncovered optical trapping regions in the three-dimensional (3D) parameter space forming an iso-surface landscape with ridge-like contours. Using specific points in the parameter space, we drew attention to difficulties in using the trapping efficiency and stiffness metrics in defining how well particles are drawn into and held in the trap. We have proposed an alternative calculation based on the maximum forward and restoration values of the trapping efficiency in the axial sense, called the trapping quality. We also discuss the manner in which the ridge regions may be harnessed for effective particle sorting, how the optical trapping blind spots can be used in applications that seek to eschew photothermal damage, and how trapping can proceed when many parameters change, such as when swelling occurs. PMID- 23736237 TI - Experimental investigation of the quality of ghost imaging via sparsity constraints. AB - Sampling number and detection signal-to-noise ratio (SNR) are two major factors influencing imaging quality. Combining the image's sparsity in the representation basis with the ghost imaging (GI) approach, GI via sparsity constraints (GISC) can nonlocally image the object even when the measurement number is far fewer than the Nyquist criteria required for the conventional GI reconstruction algorithm. The influence of receiving the system's numerical aperture and detection SNR in the test path to GISC is studied through experiments. It is also shown that the quality of GISC depends on the object's sparse representation basis. PMID- 23736238 TI - Interferometric characterization and modeling of pathlength errors resulting from beamwalk across mirror surfaces in LISA. AB - An alternative payload concept with in-field pointing for the laser interferometer space antenna utilizes an actuated mirror in the telescope for beam tracking to the distant satellite. This actuation generates optical pathlength variations due to the resulting beamwalk over the surface of subsequent optical components, which could possibly have a detrimental influence on the accuracy of the measurement instrument. We have experimentally characterized such pathlength errors caused by a lambda/10 mirror surface and used the results to validate a theoretical model. This model is then applied to predict the impact of this effect for the current optical design of the LISA off axis wide-field telescope. PMID- 23736239 TI - Radiometric calibration and noise estimation of acousto-optic tunable filter hyperspectral imaging systems. AB - The accuracy of the radiometric response of acousto-optic tunable filter (AOTF) hyperspectral imaging systems is crucial for obtaining reliable measurements. It is therefore important to know the radiometric response and noise characteristics of the hyperspectral imaging system used. A radiometric model of an AOTF hyperspectral imaging system composed of an imaging sensor radiometric model (CCD, CMOS, and sCMOS) and an AOTF light transmission model is proposed. Using the radiometric model, a method for obtaining the fixed pattern noise (FPN) of the imaging system by displacing and imaging an illuminated reference target is developed. Methods for estimating the temporal noise of the imaging system, using the photon transfer method, and for correcting FPN are also presented. Noise estimation and image restoration methods were tested on an AOTF hyperspectral imaging system. The results indicate that the developed methods can accurately calculate temporal and FPN, and can effectively correct the acquired images. After correction, the signal-to-noise ratio of the acquired images was shown to increase by 26%. PMID- 23736240 TI - Refraction-enhanced backlit imaging of axially symmetric inertial confinement fusion plasmas. AB - X-ray backlit radiographs of dense plasma shells can be significantly altered by refraction of x rays that would otherwise travel straight-ray paths, and this effect can be a powerful tool for diagnosing the spatial structure of the plasma being radiographed. We explore the conditions under which refraction effects may be observed, and we use analytical and numerical approaches to quantify these effects for one-dimensional radial opacity and density profiles characteristic of inertial-confinement fusion (ICF) implosions. We also show how analytical and numerical approaches allow approximate radial plasma opacity and density profiles to be inferred from point-projection refraction-enhanced radiography data. This imaging technique can provide unique data on electron density profiles in ICF plasmas that cannot be obtained using other techniques, and the uniform illumination provided by point-like x-ray backlighters eliminates a significant source of uncertainty in inferences of plasma opacity profiles from area-backlit pinhole imaging data when the backlight spatial profile cannot be independently characterized. The technique is particularly suited to in-flight radiography of imploding low-opacity shells surrounding hydrogen ice, because refraction is sensitive to the electron density of the hydrogen plasma even when it is invisible to absorption radiography. It may also provide an alternative approach to timing shockwaves created by the implosion drive, that are currently invisible to absorption radiography. PMID- 23736241 TI - Ground-based lidar for atmospheric boundary layer ozone measurements. AB - Ground-based lidars are suitable for long-term ozone monitoring as a complement to satellite and ozonesonde measurements. However, current ground-based lidars are unable to consistently measure ozone below 500 m above ground level (AGL) due to both engineering issues and high retrieval sensitivity to various measurement errors. In this paper, we present our instrument design, retrieval techniques, and preliminary results that focus on the high-temporal profiling of ozone within the atmospheric boundary layer (ABL) achieved by the addition of an inexpensive and compact mini-receiver to the previous system. For the first time, to the best of our knowledge, the lowest, consistently achievable observation height has been extended down to 125 m AGL for a ground-based ozone lidar system. Both the analysis and preliminary measurements demonstrate that this lidar measures ozone with a precision generally better than +/-10% at a temporal resolution of 10 min and a vertical resolution from 150 m at the bottom of the ABL to 550 m at the top. A measurement example from summertime shows that inhomogeneous ozone aloft was affected by both surface emissions and the evolution of ABL structures. PMID- 23736243 TI - Binary coded triangular fringes for 3-D surface-shape measurement. AB - We present a method for synthesizing triangular intensity fringes as a way to solve the problems caused by projector/camera gamma nonlinearity in triangular pattern phase-shifting profilometry. The fringe generation technique consists of projecting and acquiring a temporal sequence of strictly binary color patterns (code gray), whose (adequately weighted) average leads to triangular fringe patterns with the required number of bits, which allows a reliable three dimensional profile reconstruction using these methods. Validation experiments are presented. PMID- 23736242 TI - Synthesis of computer-generated spherical hologram of real object with 360 degrees field of view using a depth camera. AB - A method for synthesizing a 360 degrees computer-generated spherical hologram of real-existing objects is proposed. The whole three-dimensional (3-D) information of a real object is extracted by using a depth camera to capture multiple sides of the object. The point cloud sets which are obtained from corresponding sides of the object surface are brought into a common coordinate system by point cloud registration process. The modeled 3-D point cloud is then processed by hidden point removal method in order to identify visible point set for each spherical hologram point. The hologram on the spherical surface is finally synthesized by accumulating spherical waves from visible object points. By reconstructing partial region of the calculated spherical hologram, the corresponding view of the 3-D real object is obtained. The principle is verified via optical capturing using a depth camera and numerical reconstructions. PMID- 23736244 TI - Theoretical and experimental study on passively Q-switched intracavity frequency doubled solid-state yellow Raman lasers. AB - Normalized space-dependent rate equations of passively Q-switched intracavity frequency-doubled Raman lasers are deduced for the first time. The normalized rate equations are solved numerically to investigate the influences of the normalized variables on the yellow laser performance. The LD end-pumped passively Q-switched Nd:YAG/SrWO(4)/KTP/Cr:YAG yellow Raman laser is realized, and the maximum yellow laser output power is 350 mW with the incident pump power of 5.9 W with Cr:YAG of 85% initial transmission. The theoretical analysis and optimization are taken out for the experiment, and the theoretical results are in accordance with the experimental ones. PMID- 23736245 TI - Polarization-dependent in-line quasi-Michelson interferometer based on PM-PCF reflection. AB - An in-line fiber quasi-Michelson interferometer (IFQMI) working on reflection is proposed and experimentally demonstrated. The sensing head is fabricated by splicing a section of polarization-maintaining photonic crystal fiber (PM-PCF) with a lead-in single mode fiber (SMF). Some cladding modes are excited into the PM-PCF via the mismatch-core splicing interface between PM-PCF and SMF. Besides, two orthogonal polarized-modes are formed due to the inherent multiholes cladding structure of the PM-PCF. A well-defined interference pattern is obtained as the result of cladding-orthogonal modes interference. The IFQMI with 20 cm long PM PCF is proposed for strain and torsion measurements. A strain sensitivity of -1.3 pm/MUepsilon and a torsion sensitivity of -19.17 pm/deg are obtained, respectively. The proposed device with 10 cm long PM-PCF exhibits a considered temperature sensitivity of 9.9 pm/ degrees C. The IFQMI has a compact structure and small size, making it a good candidate for multiparameter measurements. PMID- 23736246 TI - Overview of laser systems for the Orion facility at the AWE. AB - The commissioning of the Orion laser facility at the Atomic Weapons Establishment (AWE) in the UK has recently been completed. The facility is a twelve beam Nd:glass-based system for studying high energy density physics. It consists of ten frequency-tripled beam-lines operating with nanosecond pulses, synchronized with two beam-lines with subpicosecond pulses, each capable of delivering 500 J to target. One of the short pulse beams has the option of frequency doubling, at reduced aperture, to yield up to 100 J at 527 nm in a subpicosecond pulse with high temporal contrast. An extensive array of target diagnostics is provided. This article describes the laser design and commissioning and presents key performance data of the facility's laser systems. PMID- 23736247 TI - Cascaded diffractive optical elements for improved multiplane image reconstruction. AB - Computer-generated phase-only diffractive optical elements in a cascaded setup are designed by one deterministic and one stochastic algorithm for multiplane image formation. It is hypothesized that increasing the number of elements as wavefront modulators in the longitudinal dimension would enlarge the available solution space, thus enabling enhanced image reconstruction. Numerical results show that increasing the number of holograms improves quality at the output. Design principles, computational methods, and specific conditions are discussed. PMID- 23736248 TI - Submicrometer grating light bar for a color-separation backlight. AB - A light bar patterned using a submicrometer grating was designed to replace conventional dye color filters for color liquid crystal displays. The light bar generates color rays by transmitting them from side-lit color light-emitting diodes through the submicrometer grating. These angular color rays are then redirected by a V-grooved light guide, and then converged by a lens array and mapped to corresponding subpixel positions to efficiently display color images. The results show that 106% of the National Television System Committee (NTSC) color space in a blue-green-red-green (B-G-R-G) repeating pattern display pixel layout can be achieved. PMID- 23736249 TI - Peano-like paths for subaperture polishing of optical aspherical surfaces. AB - Polishing can be more uniform if the polishing path provides uniform coverage of the surface. It is known that Peano paths can provide uniform coverage of planar surfaces. Peano paths also contain short path segments and turns: (1) all path segments have the same length, (2) path segments are mutually orthogonal at the turns, and (3) path segments and turns are uniformity distributed over the domain surface. These make Peano paths an attractive candidate among polishing tool paths because they enhance multidirectional approaches of the tool to each surface location. A method for constructing Peano paths for uniform coverage of aspherical surfaces is proposed in this paper. When mapped to the aspherical surface, the path also contains short path segments and turns, and the above attributes are approximately preserved. Attention is paid so that the path segments are still well distributed near the vertex of the surface. The proposed tool path was used in the polishing of a number of parabolic BK7 specimens using magnetorheological finishing (MRF) and pitch with cerium oxide. The results were rather good for optical lenses and confirm that a Peano-like path was useful for polishing, for MRF, and for pitch polishing. In the latter case, the surface roughness achieved was 0.91 nm according to WYKO measurement. PMID- 23736250 TI - Generalized diffractive optical elements with asymmetric harmonic response and phase control. AB - We report a method to generate phase-only diffractive beam splitters allowing asymmetry of the target diffracted orders, as well as providing a tailored phase difference between the diffracted orders. We apply a well-established design method that requires the determination of a set of numerical parameters, and avoids the use of image iterative algorithms. As a result, a phase lookup table is determined that can be used for any situation where a first-order (blazed) diffractive element is modified to produce higher orders with desired intensity and/or phase relation. As examples, we demonstrate the phase difference control on triplicators, as well as on other generalized diffractive elements like bifocal Fresnel lenses and phase masks for the generation of vortex beams. Results are experimentally demonstrated by encoding the calculated phase pattern onto parallel-aligned liquid crystal spatial light modulators. PMID- 23736251 TI - In praise of reviewers. AB - Applied Optics Editor-in-Chief, Joseph N. Mait, comments on the value of peer review in improving the work published by authors. PMID- 23736252 TI - Supraspinatus tendon and subacromial space parameters measured on ultrasonographic imaging in subacromial impingement syndrome. AB - PURPOSE: To characterize the supraspinatus tendon thickness, subacromial space, and the relationship between tendon thickness and subacromial space to further elucidate the mechanisms of subacromial impingement syndrome. METHODS: In a single-blind cross-sectional study, subjects were recruited with subacromial impingement syndrome (n = 20) and asymptomatic controls (n = 20) matched for age, gender, and hand dominance. Ultrasound images were collected using a 4-12-MHz linear transducer in B-mode of the supraspinatus tendon in the transverse (short axis) and the anterior aspect of the subacromial space outlet. Using image callipers, measurements of tendon thickness were taken at 3 points along the tendon and averaged for a single thickness measure. The subacromial space outlet was measured via the acromiohumeral distance (AHD) defined by the inferior acromion and superior humeral head. The occupation ratio was calculated as the tendon thickness as a percentage of AHD. RESULTS: The subacromial impingement syndrome group had a significantly thicker tendon (mean difference = 0.6 mm, p = 0.048) and a greater tendon occupation ratio (mean difference = 7.5 %, p = 0.014) compared to matched controls. There were no AHD group differences. CONCLUSIONS: The supraspinatus tendon was thicker and occupied a greater percentage of AHD, supporting an intrinsic mechanism. An extrinsic mechanism of tendon compression is theoretically supported, but future imaging studies need to confirm direct compression with elevation. Treatment to reduce tendon thickness may reduce symptoms, and surgical intervention to increase subacromial space may be considered if tendon compression can be verified. PMID- 23736253 TI - Traumatic tibialis anterior tendon rupture: treatment with a two-stage silicone tube and an interposition hamstring tendons graft protocol. AB - A novel technique for managing ruptured tibialis anterior tendon complicated by infection and tendon substance loss in a young adult is described. A two-stage reconstruction technique with a silicon tube and tendon autograft was performed. At first, after local control of the infection, scar excision and placement of a silicone tube was performed. Ten weeks later, ipsilateral hamstrings tendons were harvested and bridged the 7 cm tendon gap. Eighteen months later, the patient has excellent clinical and functional outcome. PMID- 23736254 TI - MR-arthrography assessment after repair of chronic meniscal tears. AB - PURPOSE: The aims of this study were to assess the healing rate of repair of chronically torn meniscal tear with MR-arthrography and to evaluate the relationship between the clinical and the radiographic outcomes and the impact of the meniscal section on healing. METHODS: MR-arthrography was performed at a median of 10.5 months (range 6-55) after surgery in 28 patients and healing assessed using Henning's criteria. All lesions were chronic (>3 months). Repairs were carried out at a median 14 months (range 6-80) from initial diagnosis. Eleven patients (39%) had ACL ligament reconstruction as well. All lesions were located in the red or red-white zone. Patients were followed for a median of 18.5 months (range 8-68). Functional outcomes were evaluated using Barrett's healing criteria, Lysholm and Tegner score pre- and postoperatively. RESULTS: Clinical healing of the lesion according to Barrett's criteria was achieved in 24 patients (85.7%). Both Lysholm and Tegner scores improved significantly after the surgery (p < 0.05). According to Henning's criteria, 15 of the menisci healed completely (53.5%), 10 partially (35.7%) and 3 failed (10.8%). There was no significant difference between the healing process in the posterior horn and the body of the meniscus (n.s.). No correlation was found between the healing results and the clinical scores. ACL reconstruction did not influence the healing process (n.s.). Patients waiting more than 1 year from lesion to surgery seem to have a higher rate of failure (p = 0.02). CONCLUSIONS: The results found suggest good short term clinical and anatomic outcomes post-repair of meniscal lesions, despite their chronic nature. Longer waiting times may have negative effects on the healing process. Partial healing occurred often, but the meniscus was painless and stable. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 23736255 TI - Expression of insulin-like growth factor type 1 receptor and myosin heavy chain in rabbit's rotator cuff muscle after injection of adipose-derived stem cell. AB - PURPOSE: This study was performed to evaluate the effects of adipose-derived mesenchymal stem cells (ADMSC) in a subacute rotator cuff tear model of a rabbit by way of comparing the expression of insulin-like growth factor 1 receptor (IGF 1R) and myosin heavy chain (MyHC) in the ADMSC injected muscle and control. METHODS: Supraspinatus tears were created in both shoulders of 11 rabbits, and rotator cuff repair was performed after 3 weeks. At the time of repair, each side of the shoulders was randomly selected, and the injection of the ADMSCs at the muscle belly near musculotendinous junction (injection side) and saline to the contralateral side (control side) was performed. After 3 weeks, we randomly assigned 5 rabbits to the immunohistochemistric analysis and 6 to Western blot analysis. RESULTS: Expression of both IGF-1R (95 kD) and MyHC (200 kD) at the injection side was significantly elevated compared to control side (both p = 0.028). Immunohistochemistry showed that staining areas of both IGF-1R and MyHC were overlapped with staining of ADMSCs. CONCLUSION: The injection of ADMSCs resulted in high expression of IGF-1R and MyHC in subacute rotator cuff tear and repaired model in rabbit compared to control side. Therefore, the injected ADMSCs may assist in regeneration of the rotator cuff muscle by way of insulin-like growth factor 1 (IGF-1) signalling pathway. This result may suggest another solution to facilitate the recovery of rotator cuff muscle and to improve the result of rotator cuff repair by ADMSC injection via IGF-1 pathway, which is one of the potent anabolic pathways. PMID- 23736256 TI - Growing vertical ZnO nanorod arrays within graphite: efficient isolation of large size and high quality single-layer graphene. AB - We report a unique strategy for efficiently exfoliating large size and high quality single-layer graphene directly from graphite into DMF dispersions by growing ZnO nanorod arrays between the graphene layers in graphite. PMID- 23736258 TI - Prevalence and prognostic impact of lymphadenectomy and lymph node metastasis in clinically early-stage ovarian clear cell carcinoma. AB - OBJECTIVES: The objective of this study was to estimate the prevalence and prognostic impact of lymphadenectomy and lymph node involvement in patients with ovarian clear cell carcinoma (OCCC) grossly confined to the ovary. METHODS: Patients with a diagnosis of OCCC grossly confined to the ovary were identified from Surveillance, Epidemiology, and End Results program from 1988 to 2007. Only surgically treated patients were included. Statistical analysis using Student t test, Kaplan-Meier survival methods, and Cox proportional hazards regression were performed. RESULTS: One thousand eight hundred ninety-seven patients with OCCC who have undergone surgical treatment and deemed at time of the surgery to have disease grossly confined to the ovary were included: 538 (28.3%) had no lymphadenectomy (LND -1), and 1359 (71.7%) had lymphadenectomy. Of the 1359 patients who had lymphadenectomy, 1298 (95.5%) were International Federation of Gynecology and Obstetrics (FIGO) surgical stage I (LND +1), and 61 (4.5%) were upstaged to FIGO stage IIIC due to nodal metastasis (LND +3C). The 5-year disease specific survival was 84.9% for LND -1, 88.0% for LND +1, and 65.0% for LND +3C (P < 0.001). Among those with histologically negative lymph nodes, the 5-year disease-specific survival was 85% for patients with 1 to 10 nodes removed, and 91% for those with more than 10 nodes removed (P = 0.054). On multivariate analysis after controlling for stage, age, and race, lymph node metastasis was an independent predictor of poor disease-specific survival (hazard ratio, 3.1; 95% confidence interval, 1.86-5.28; P < 0.001). On other hand, there was a trend toward an improved survival when more extensive lymphadenectomy is performed in patients with histologically negative nodes (1-10 vs >10 nodes), but it did not reach statistical significance (hazard ratio, 0.71; 95% confidence interval, 0.49 1.02; P = 0.064). CONCLUSIONS: Lymph node metastasis was uncommon in patients diagnosed with OCCC grossly confined to the ovary; however, patients with positive nodes were more likely to die compared to those with negative nodes. More extensive lymphadenectomy plays an important role in providing accurate staging and prognostic information. PMID- 23736262 TI - Melanoma Task Force (META) Project in Italy: methodology. AB - A nationwide survey of the diagnostic-therapeutic models used in Italian hospitals for the treatment of melanoma was performed. The study was conducted using paper-assisted personal interviews in hospitals throughout the country [De Vaus DA: Surveys in Social Research, ed 4. London, Routledge, 1995]. Face-to-face interviews were conducted by interviewers specialized in medical research. These 45-minute interviews took place in the office/clinic of the interviewee, during which the interviewer compiled and checked questionnaires for completeness and accuracy. In each hospital, clinicians responsible for the diagnosis, therapy or follow-up phases of melanoma care were interviewed according to their area of expertise. When possible, interviewees included a dermatologist, a surgeon and an oncologist from each hospital. PMID- 23736259 TI - The ALS8 protein VAPB interacts with the ER-Golgi recycling protein YIF1A and regulates membrane delivery into dendrites. AB - The vesicle-associated membrane protein (VAMP) associated protein B (VAPB) is an integral membrane protein localized to the endoplasmic reticulum (ER). The P56S mutation in VAPB has been linked to motor neuron degeneration in amyotrophic lateral sclerosis type 8 (ALS8) and forms ER-like inclusions in various model systems. However, the role of wild-type and mutant VAPB in neurons is poorly understood. Here, we identified Yip1-interacting factor homologue A (YIF1A) as a new VAPB binding partner and important component in the early secretory pathway. YIF1A interacts with VAPB via its transmembrane regions, recycles between the ER and Golgi and is mainly localized to the ER-Golgi intermediate compartments (ERGICs) in rat hippocampal neurons. VAPB strongly affects the distribution of YIF1A and is required for intracellular membrane trafficking into dendrites and normal dendritic morphology. When VAPB-P56S is present, YIF1A is recruited to the VAPB-P56S clusters and loses its ERGIC localization. These data suggest that both VAPB and YIF1A are important for ER-to-Golgi transport and that missorting of YIF1A may contribute to VAPB-associated motor neuron disease. PMID- 23736263 TI - Diagnostic services for melanoma in Italy. AB - OBJECTIVE: To evaluate organizational structure and diagnostic procedures used by the Italian hospital network for identifying cutaneous melanoma. METHODS: A nationwide survey of a representative sample of centers was conducted. RESULTS: Diagnosis occurs mainly in ambulatory dermatology clinics (91%). In all high volume hospitals, clinical and dermoscopic examination is available at first consultation or as an additional service, compared to 89% of low-volume hospitals. Computer-assisted videodermoscopy is available in 75% of hospitals, with a statistically significant difference between high- and low-volume hospitals (86 vs. 62%; p < 0.001). First consultation is generally an integrated clinical/dermoscopic evaluation (55% of high-volume centers vs. 47% of low-volume hospitals); digital evaluation is available for monitoring suspicious lesions and high-risk patients in 25% of high-volume centers versus 19% of low-volume centers. CONCLUSIONS: The organizational structure and diagnostic procedures in Italian hospitals are in line with modern diagnostic procedures for early diagnosis of melanoma. Dermatologists have a central role in managing diagnosis of primitive melanoma. PMID- 23736261 TI - Autolysosomal beta-catenin degradation regulates Wnt-autophagy-p62 crosstalk. AB - The Wnt/beta-catenin signalling and autophagy pathways each play important roles during development, adult tissue homeostasis and tumorigenesis. Here we identify the Wnt/beta-catenin signalling pathway as a negative regulator of both basal and stress-induced autophagy. Manipulation of beta-catenin expression levels in vitro and in vivo revealed that beta-catenin suppresses autophagosome formation and directly represses p62/SQSTM1 (encoding the autophagy adaptor p62) via TCF4. Furthermore, we show that during nutrient deprivation beta-catenin is selectively degraded via the formation of a beta-catenin-LC3 complex, attenuating beta catenin/TCF-driven transcription and proliferation to favour adaptation during metabolic stress. Formation of the beta-catenin-LC3 complex is mediated by a W/YXXI/L motif and LC3-interacting region (LIR) in beta-catenin, which is required for interaction with LC3 and non-proteasomal degradation of beta catenin. Thus, Wnt/beta-catenin represses autophagy and p62 expression, while beta-catenin is itself targeted for autophagic clearance in autolysosomes upon autophagy induction. These findings reveal a regulatory feedback mechanism that place beta-catenin at a key cellular integration point coordinating proliferation with autophagy, with implications for targeting these pathways for cancer therapy. PMID- 23736260 TI - Wnt/beta-catenin signalling induces MLL to create epigenetic changes in salivary gland tumours. AB - We show that activation of Wnt/beta-catenin and attenuation of Bmp signals, by combined gain- and loss-of-function mutations of beta-catenin and Bmpr1a, respectively, results in rapidly growing, aggressive squamous cell carcinomas (SCC) in the salivary glands of mice. Tumours contain transplantable and hyperproliferative tumour propagating cells, which can be enriched by fluorescence activated cell sorting (FACS). Single mutations stimulate stem cells, but tumours are not formed. We show that beta-catenin, CBP and Mll promote self-renewal and H3K4 tri-methylation in tumour propagating cells. Blocking beta catenin-CBP interaction with the small molecule ICG-001 and small-interfering RNAs against beta-catenin, CBP or Mll abrogate hyperproliferation and H3K4 tri methylation, and induce differentiation of cultured tumour propagating cells into acini-like structures. ICG-001 decreases H3K4me3 at promoters of stem cell associated genes in vitro and reduces tumour growth in vivo. Remarkably, high Wnt/beta-catenin and low Bmp signalling also characterize human salivary gland SCC and head and neck SCC in general. Our work defines mechanisms by which beta catenin signals remodel chromatin and control induction and maintenance of tumour propagating cells. Further, it supports new strategies for the therapy of solid tumours. PMID- 23736264 TI - Management of small and intermediate congenital nevi: a nationwide survey in Italy. AB - OBJECTIVE: Small- and intermediate-sized congenital nevi (SCN and ICN) undergo periodic clinical monitoring or surgical excision. We analyzed the management of SCN and ICN in the Italian hospital network. METHODS: A nationwide survey of a representative sample of centers was conducted. Data were analyzed grouping centers by melanoma incidence into high-volume (>25 diagnoses per year) and low volume (<= 25 diagnoses per year). RESULTS: In the pediatric population, 11% of SCN and 22% of ICN are excised, the remainder undergoing clinical monitoring at intervals of 6 months to 2 years (SCN) and of 6 months to 1 year (ICN). In adults, 24% of SCN and 41% of ICN are excised. Clinical monitoring of SCN varies from 6-monthly (most common among low-volume hospitals) to every 2 years; preferred strategies for ICN are follow-up at 1 year (51%) or follow-up at 6 months (42%). For prophylactic surgery, complete excision is preferred. CONCLUSIONS: The Italian hospital network values management and treatment of SCN and ICN. In most cases natural evolution prompts prophylactic excision. Clinical examination is an important monitoring tool, though follow-up frequency depends on the clinician's experience and practice. PMID- 23736265 TI - Impact of mole mapping in the Italian health system. AB - OBJECTIVE: To analyze routine clinical management of atypical melanocytic lesions through monitoring or surgery in Italian hospitals. METHODS: A nationwide survey of clinical practices was conducted. RESULTS: Digital monitoring is performed in most Italian hospitals and is preferred over excision for single atypical melanocytic lesions in 82% of hospitals. For multiple atypical lesions, 60% of high-volume hospitals prefer digital monitoring to surgical excision (40%). There is a statistically significant difference between high- and low-volume hospitals (60 vs. 39%; p = 0.003). Digital monitoring is performed at mean intervals of 4/5 months for both types of lesions. CONCLUSIONS: We show an asymmetric relation between application of the method and practical impact based on available clinical evidence. Although digital monitoring provides better characterization of the evolution of melanocytic lesions, our results indicate that the advantages and limitations of this method require further investigation. PMID- 23736266 TI - Surgical management of suspicious melanocytic lesions in Italy. AB - OBJECTIVE: In melanoma, the surgical approach is important for both diagnosis and therapy. Although surgery is relatively simple, the methods should be performed by experts in melanoma management. We analyze the techniques and methods used in the Italian hospital network for suspicious skin lesions and confirmed melanomas. METHODS: A nationwide survey was conducted of a representative sample of 120 hospitals with >= 200 beds. RESULTS: Excision biopsies remove suspected melanomas. However, some approaches to excision margins and sentinel lymph node procedures differ from international protocols. Overall, 21% of centers perform excisional biopsy of a suspicious lesion using 1 cm margins, and 22% of centers perform sentinel node procedures concurrently with removal of primary melanoma. CONCLUSIONS: Standardized treatment protocols are needed for suspicious lesions and clinically evident melanoma, particularly regarding the critical aspect of excision margins. The sentinel lymph node procedure may be distorted by initial margins that are too wide. PMID- 23736267 TI - Diagnostic and therapeutic approaches in Italian hospitals: adjuvant and metastatic therapy in melanoma. AB - Melanoma incidence and mortality rates are rising in Italy, indicating that more effective treatments are required both in the adjuvant and metastatic settings. We analyzed clinical practices in the adjuvant and metastatic settings by conducting a nationwide survey of clinicians responsible for managing melanoma treatment and follow-up in a representative sample of Italian hospitals. 95% of participating hospitals completed the panel of questions on adjuvant and metastatic treatment, making it likely that these results give a realistic picture of treatment and follow-up of melanoma patients in Italy. In low-volume hospitals (<25 new melanoma diagnoses yearly) adjuvant therapy was significantly more used than in large-volume hospitals for patients in stage III and IV (82 versus 66% and 56 versus 30%, respectively), and only 11% of patients were enrolled in clinical trials. In the metastatic setting dacarbazine was the preferred first-line treatment (32%) followed by polychemotherapy (23%); 12% of patients were enrolled in clinical trials and less than 10% received interleukin 2, usually subcutaneously. The information provided by this study was used by the Italian Melanoma Intergroup to improve the quality of care and to redirect financial resources. PMID- 23736268 TI - Surgical treatment of melanoma: a survey of Italian hospitals. AB - Surgery is the first option for treating melanoma regardless of stage at presentation. We surveyed a representative sample of hospitals to evaluate management and quality of surgical indications for melanoma in Italy. At analysis, hospitals were grouped into high- or low-volume centers, with the population median of 25 diagnoses serving as the cut-off. Surgery for primary melanoma was similar between hospital groups. More high-volume centers were organized to perform sentinel node biopsy (91 vs. 56%). There were no major differences between high- and low-volume centers concerning the surgical approach to stage III and IV disease. PMID- 23736269 TI - Follow-up of melanoma: a survey of Italian hospitals. AB - Follow-up is managed internally in 94% of centers and is programmed according to international guidelines in 52% of high-volume hospitals (>25 melanoma diagnoses per year); the remainder use internal guidelines; fewer low-volume centers (<= 25 diagnoses per year) have internal guidelines (25%, p = 0.001). Instrumental examinations for stage III and IV disease are similar, while the examination interval changes from 3/4 months for stage III to 2/3 months for stage IV, and use of PET/CT increases from 44 to 54%. Overall, thoracic and abdominal CT is used most for follow-up in stage III (83%), while bone scintigraphy is used more commonly in low-volume centers (41 vs. 19%, p = 0.003), despite similar use of PET/CT (48 vs. 41%). Brain CT or MRI is more common in high-volume centers (63 vs. 39%, p > 0.0001), as is echography of draining lymph nodes (71 vs. 52%, p = 0.01). Hepatic/abdominal echography and thoracic radiography are used in about 50% of centers, regardless of type. In stage IV, use of bone scintigraphy is similar among groups (ca. 40%); brain CT/NMR use increases from 51 to 64% and is more common in high-volume centers (p = 0.03). Lymph node echography is more common in high-volume centers (56 vs. 39%, p = 0.03). PMID- 23736272 TI - Melanoma management in Italy: learning from practice. A survey from the Intergruppo Italiano Melanoma. PMID- 23736273 TI - Detection of Cryptosporidium and Giardia (oo)cysts by IFA, PCR and LAMP in surface water from Rasht, Iran. AB - BACKGROUND: Cryptosporidium and Giardia in water supplies is acknowledged as a public health problem. In the present study, we applied immunofluorescence assay (IFA), PCR and loop-mediated isothermal amplification (LAMP) for the detection of the two protozoa. METHODS: Over a period of 12 months, surface water samples were collected from two rivers in the north of Iran, and filtrated by 142 mm membrane filters. At each sampling point 10 L water were used for IFT and the10 L were analysed using molecular methods. RESULTS: In 15/40 samples, (oo)cysts were detected by one of the IFA, PCR or LAMP methods. Five samples that were Cryptosporidium-negative by IFA were positive by LAMP. A total of 10 out of 13 samples that were Giardia-positive by IFA were also positive by PCR. IFA revealed high levels of Giardia, with 1-1800 cysts and 1-16 Cryptosporidium oocysts detected per 10 L. CONCLUSION: The study reveals that the investigated water supplies were contaminated by Cryptosporidium and Giardia. The LAMP assay has advantages for detection and screening of these protozoa at relatively low concentration in water samples. The three assays applied are complimentary but no single one will give the true prevalence of these parasites in surface water samples. However, each method has its own advantages and disadvantages dependent of the aim and the study design; a combination of detection methods should be applied to discover whether water is, or is not, contaminated with (oo)cysts. This is the first report on the occurrence of (oo)cysts in Iranian surface waters to compare the results of parasite detection obtained with the different methods. PMID- 23736274 TI - Circulating tumor cells in metastatic colorectal cancer: do we need an alternative cutoff? AB - PURPOSE: To assess the prognostic and predictive value of circulating tumor cells (CTCs) in metastatic colorectal cancer (mCRC) irrespective of detection level. MATERIALS AND METHODS: We evaluated the prognostic and predictive significance of CTC count at baseline and under treatment in 119 mCRC subjects and compared the standard cutoff (>=3 CTCs/7.5 mL to >=1 CTCs/7.5 mL). RESULTS: An overall comparison was made between patients with 0, 1-2 and >=3 CTC (median PFS 8, 4 and 5 months, respectively). Two poor prognostic groups were found, including patients with >=1 CTCs before and during treatment and patients with 0 CTC at baseline who converted to >=1 CTCs (p = 0.014). CONCLUSIONS: The presence of at least 1 CTC at baseline count is predictive for poor prognosis in mCRC patients. Patients with 1-2 CTC should be switched from the favorable prognostic group- conventionally defined by the presence of <3 CTC--to the unfavorable, deserving a more careful monitoring. PMID- 23736275 TI - Performance of response scales of activity and functional measures of ankylosing spondylitis: numerical rating scale versus visual analog scale. AB - The aim of this study was to compare the performance characteristics of two answer modalities for BASDAI and BASFI in patients with AS and to show validity and reliability of NRS in Turkish version. BASDAI and BASFI were simultaneously employed with a 10-cm VAS and an 11-point NRS. Internal consistency was assessed by using Cronbach's alpha coefficients. Testing was performed on baseline and next day under standardized conditions. Construct validity was determined by association of these measures with ASDAS, DFI, global disease activity, pain scores, ASQOL, HAQ, and SF-36. We also tested the ability of NRS version of BASDAI and BASFI to detect changes. A total 114 patients with AS according to the modified New York criteria were included. There was a good agreement between the total scores of each instrument on day 0 (ICC values were 0.894-0.934). Scores of the both answering modality of each instrument were correlated with ASDAS-CRP, and the scores of DFI, patient global assessment of disease activity and patient reported pain, ASQOL, HAQ. Response time for BASDAI and BASFI was significantly shorter in NRS answer modality (P < 0.001). Our patients found NRS modality more comprehensible and easier to understand (P < 0.001). Our results showed the validity of NRS version of BASDAI and BASFI and provided an evidence for using these questionnaires in 11-point NRS answer modality in Turkish AS patients. PMID- 23736276 TI - Evaluation of mean platelet volume in familial Mediterranean fever; insight from the methodological aspect. PMID- 23736277 TI - Differential effect of orexin-1 and CRF-1 antagonism on stress circuits: a fMRI study in the rat with the pharmacological stressor Yohimbine. AB - Translational approaches to study the neural substrates of stress and assess the mechanistic efficacy of novel anti-anxiety agents necessitate the use of stressors with a similar degree of saliency across species. The alpha-2 adrenoreceptor antagonist yohimbine represents an attractive experimental tool owing to its well-documented stress-inducing properties in humans and laboratory species. We investigated the neural substrates engaged by yohimbine in the rat brain by using functional magnetic resonance imaging and mapped their modulation by neurotransmitter systems involved in stress responses. Yohimbine elicited a composite pattern of brain activation, highlighting the recruitment of cortico striato-thalamic regions and extra-hypothalamic stress neurocircuits. This effect was strongly attenuated by the alpha-2-adrenoceptor agonist medetomidine and by the dopamine (DA) D1 receptor antagonist SCH23390, thus revealing a primary contribution of both norepinephrine and DA on the neurofunctional cascade elicited by the drug. Pretreatment with the corticotrophin-releasing factor type 1 receptor (CRF1R) antagonist CP154,526 produced a region-dependent inhibition of yohimbine-induced activation in the amygdala, striatum, and cingulate cortex, while the orexin type-1 receptor (OX1R) antagonists GSK1059865 robustly inhibited the response in fronto-hippocampal regions as well as in several key components of the extended amygdala. CP154,526 and GSK1059865 did not prevent yohimbine induced plasma corticosterone release, a finding that corroborates a central origin of the effects mapped. Our findings provide novel insight into the brain substrates and neurochemical mediators engaged by the stress-inducing agent yohimbine. The differential pattern of inhibition produced by CRF1R and OX1R antagonists suggests that these two neuropeptide systems can modulate the functional response to stress via distinct central neural pathways. PMID- 23736278 TI - Electrochemical synthesis of vertically aligned zinc nanowires using track-etched polycarbonate membranes as templates. AB - In the present paper, vertically aligned arrays of zinc nanowires were synthesized by electrochemical deposition into ion track-etched polycarbonate membranes in the ionic liquid electrolyte 1-ethyl-3-methylimidazolium trifluoromethylsulfonate ([EMIm]TfO)/Zn(TfO)2. Cyclic voltammetry and chronoamperometry were performed to investigate the electrochemical growth of zinc nanowires inside of the membranes. The transport processes and mechanisms of the nanowire growth in the membranes are also discussed. A supporting zinc or copper layer was deposited on the sputtered side in order to make the back layer thick enough to stabilize the wires. Zinc nanowires with a diameter of 90 nm and a length of up to 18 MUm were obtained after removing the template. Furthermore, short nanowires with lengths less than 5 MUm and a sandwich-like structure with nanowires in the middle were also synthesized. Vertically aligned zinc nanowire structures on such a substrate might be a potential anode candidate for future generation lithium ion batteries. PMID- 23736279 TI - A systematic review of reported cases involving psychotic symptoms worsened by aripiprazole in schizophrenia or schizoaffective disorder. AB - RATIONALE: Numerous case reports have suggested that aripiprazole can worsen psychotic symptoms in schizophrenia. OBJECTIVES: We reviewed reported cases which have suggested that aripiprazole can worsen psychotic symptoms in schizophrenia and evaluated each regarding quality of the causal relationship. METHODS: A systematic literature search was conducted on August 18, 2012, using the PubMed and the EMBASE. Twenty-two cases met the following inclusion criteria: (1) diagnosis of schizophrenia or schizoaffective disorder, (2) worsening of psychotic symptoms associated with aripiprazole, and (3) aripiprazole dose <= 30 mg/day. Information about the causal relationship between aripiprazole and increased psychotic symptoms was extracted. The quality of the causal relationship was evaluated according to the modified guidelines for evaluation of drug-associated events and classified as "questionable," "moderately suggestive," or "highly suggestive." RESULTS: Patients were chronic in at least 15 cases, and prior antipsychotic dose exceeded recommended guidelines in 19 cases. Psychotic symptoms worsened after simply adding aripiprazole to the current regimen in eight cases. Besides psychotic symptoms, increasing agitation (nine cases), aggression (11 cases), and/or activation (seven cases) were reported. Clinical resolution occurred after aripiprazole discontinuation in eight cases. Regarding causal relationship, 11 cases were classified as "highly suggestive," three as "moderately suggestive," and eight as "questionable". CONCLUSIONS: Clinicians should be vigilant when adding aripiprazole to patients with chronic schizophrenia also receiving relatively high doses of other antipsychotics, and discontinuation of aripiprazole should be considered if psychotic symptoms and/or agitation/aggression/activation increase. PMID- 23736282 TI - Are nonesterified fatty acids protective in chronic allograft nephropathy? PMID- 23736281 TI - SSR504734 enhances basal expression of prepulse inhibition but exacerbates the disruption of prepulse inhibition by apomorphine. AB - RATIONALE: Inhibition of glycine transporter 1 (GlyT1) elevates extracellular glycine and can thus increase N-methyl-D-aspartate receptor (NMDAR) excitability in the brain. The potent GlyT1 inhibitor, SSR504734, has also been shown to potentiate the behavioral effects of direct and indirect dopamine agonists. Thus, an acute systemic dose of SSR504734 was sufficient to exacerbate the motor stimulant effect of the dopamine releaser amphetamine in C57BL/6 mice, even though SSR504734 alone exerted no significant effect on motor activity. OBJECTIVES: Here, we explore if SSR504734 might modulate dopamine-dependent sensory gating in the paradigm of prepulse inhibition (PPI) of the acoustic startle reflex. METHODS: Experiment 1 characterized the effect of SSR504734 (10 and 30 mg/kg i.p.) on PPI expression when administered alone. Experiments 2 and 3 investigated the impact of SSR504734 when administered in conjunction with the dopamine receptor agonist, apomorphine (1 and 2 mg/kg s.c.), which is known to reliably disrupt PPI. RESULTS: When administered alone, acute SSR504734 enhanced PPI only at 30 mg/kg--a dose that has been shown to improve cognitive functions including working memory, which has been linked to enhanced NMDAR function resulting from the elevation of extracellular glycine. However, this effect did not allow SSR504734 to antagonize the PPI-disruptive effect of apomorphine. At the lower dose of 10 mg/kg--that was insufficient to enhance PPI when administered alone--SSR504734 even exacerbated the deleterious effect of apomorphine on PPI. CONCLUSIONS: The therapeutic potential of GlyT1 inhibition against distinct behavioral/cognitive deficiency might require different magnitudes of GlyT1 inhibition. PMID- 23736284 TI - Isoflavonoids of the leguminosae. AB - This account describes 275 new isoflavonoids published between 2008 and 2011 as constituents of the Leguminosae, commenting on their source, identification, biological activity, synthesis, and ecological or chemosystematic significance. Applications of hyphenated analytical techniques to the characterisation of Leguminosae isoflavonoids are also reviewed, together with advances in biosynthetic studies. A checklist of new compounds by species is given, and 226 references are cited. PMID- 23736285 TI - Novel quorum-sensing peptides mediating interspecies bacterial cell death. AB - ABSTRACT Escherichia coli mazEF is a toxin-antitoxin stress-induced module mediating cell death. It requires the quorum-sensing signal (QS) "extracellular death factor" (EDF), the penta-peptide NNWNN (EcEDF), enhancing the endoribonucleolytic activity of E. coli toxin MazF. Here we discovered that E. coli mazEF-mediated cell death could be triggered by QS peptides from the supernatants (SN) of the Gram-positive bacterium Bacillus subtilis and the Gram negative bacterium Pseudomonas aeruginosa. In the SN of B. subtilis, we found one EDF, the hexapeptide RGQQNE, called BsEDF. In the SN of P. aeruginosa, we found three EDFs: the nonapeptide INEQTVVTK, called PaEDF-1, and two hexadecapeptides, VEVSDDGSGGNTSLSQ, called PaEDF-2, and APKLSDGAAAGYVTKA, called PaEDF-3. When added to a diluted E. coli cultures, each of these peptides acted as an interspecies EDF that triggered mazEF-mediated death. Furthermore, though their sequences are very different, each of these EDFs amplified the endoribonucleolytic activity of E. coli MazF, probably by interacting with different sites on E. coli MazF. Finally, we suggest that EDFs may become the basis for a new class of antibiotics that trigger death from outside the bacterial cells. IMPORTANCE Bacteria communicate with one another via quorum sensing signal (QS) molecules. QS provides a mechanism for bacteria to monitor each other's presence and to modulate gene expression in response to population density. Previously, we added E. coli EDF (EcEDF), the peptide NNWNN, to this list of QS molecules. Here we extended the group of QS peptides to several additional different peptides. The new EDFs are produced by two other bacteria, Bacillus subtilis and Pseudomonas aeruginosa. Thus, in this study we established a "new family of EDFs." This family provides the first example of quorum-sensing molecules participating in interspecies bacterial cell death. Furthermore, each of these peptides provides the basis of a new class of antibiotics triggering death by acting from outside the cell. PMID- 23736286 TI - Human cytomegalovirus (HCMV) glycoprotein gB promotes virus entry in trans acting as the viral fusion protein rather than as a receptor-binding protein. AB - ABSTRACT Human cytomegalovirus (HCMV) glycoproteins gB and gH/gL are both necessary and sufficient for cell-cell fusion. However, it is not clear what roles these glycoproteins play in virus entry, whether acting directly in membrane fusion or in binding receptors. With other herpesviruses, it appears that gB is the fusion protein and is triggered by gH/gL, which, in some cases, binds receptors. However, for HCMV, there is published evidence that gB binds cellular ligands necessary to promote virus entry into or signaling of cells. Most mechanistic information on herpesvirus fusion proteins involves cell-cell fusion assays, which do not allow a determination of whether gB or gH/gL in the virion envelope must be oriented toward cellular membranes that contain receptors. Here, we showed that HCMV virions lacking gB were unable to enter normal cells but entered cells that expressed gB. Analyses of gB mutants lacking the cytoplasmic domain or with substitutions in putative "fusion loops" provided evidence that gB fusion activity was required for this "entry in trans." In gB mediated entry in trans, gB is oriented toward the virion envelope that apparently lacks receptors, arguing against an essential role for gB in binding receptors or signaling molecules. In contrast, particles lacking gH/gL did not enter cells expressing gH/gL, apparently because gH/gL must be oriented toward cellular membranes (which have receptors). Coupled with our previous interference studies, in which gH/gL expressed in cells blocked HCMV entry, our findings here support the hypothesis that HCMV gH/gL binds cellular receptors before triggering gB, which acts as the fusion protein. IMPORTANCE Human cytomegalovirus (HCMV) produces major disease in neonates and immunosuppressed transplant patients. As with other herpesviruses, HCMV requires two membrane glycoproteins, gB and gH/gL, to enter host cells. However, it has not been clear how gB and gH/gL function in two steps of the HCMV entry pathway, i.e., (i) binding of cellular receptors and (ii) fusion of the virion envelope with cellular membranes. There are studies that suggest that HCMV gB is required for receptor binding and other studies suggesting that gH/gL is the receptor binding protein and gB is the fusion protein. Here, we show that HCMV virions lacking gB can enter cells that express gB in cellular membranes. In contrast, virus particles lacking gH/gL could not enter cells expressing gH/gL. Our study supports the hypothesis that gB is the fusion protein and gH/gL acts upstream of gB to bind receptors and then activate gB for fusion. PMID- 23736287 TI - Imaging the transport dynamics of single alphaherpesvirus particles in intact peripheral nervous system explants from infected mice. AB - ABSTRACT Alphaherpesvirus particles travel long distances in the axons of neurons using host microtubule molecular motors. The transport dynamics of individual virions in neurons have been assessed in cultured neurons, but imaging studies of single particles in tissue from infected mice have not been reported. We developed a protocol to image explanted, infected peripheral nervous system (PNS) ganglia and associated innervated tissue from mice infected with pseudorabies virus (PRV). This ex vivo preparation allowed us to visualize and track individual virions over time as they moved from the salivary gland into submandibular ganglion neurons of the PNS. We imaged and tracked hundreds of virions from multiple mice at different time points. We quantitated the transport velocity, particle stalling, duty cycle, and directionality at various times after infection. Using a PRV recombinant that expressed monomeric red fluorescent protein (mRFP)-VP26 (red capsid) and green fluorescent protein (GFP)-Us9 (green membrane protein), we corroborated that anterograde transport in axons occurs after capsids are enveloped. We addressed the question of whether replication occurs initially in the salivary gland at the site of inoculation or subsequently in the neurons of peripheral innervating ganglia. Our data indicate that significant amplification of infection occurs in the peripheral ganglia after transport from the site of infection and that these newly made particles are transported back to the salivary gland. It is likely that this reseeding of the infected gland contributes to massive invasion of the innervating PNS ganglia. We suggest that this "round-trip" infection process contributes to the characteristic peripheral neuropathy of PRV infection. IMPORTANCE Much of our understanding of molecular mechanisms of alphaherpesvirus infection and spread in neurons comes from studying cultured primary neurons. These techniques enabled significant advances in our understanding of the viral and neuronal components needed for efficient replication and directional spread between cells. However, in vitro systems cannot recapitulate the environment of innervated tissue in vivo with associated defensive properties, such as innate immunity. Therefore, in this report, we describe a system to image the progression of infection by single virus particles in tissue harvested from infected animals. We explanted intact innervated tissue from infected mice and imaged fluorescent virus particles in infected axons of the specific ganglionic neurons. Our measurements of virion transport dynamics are consistent with published in vitro results. Importantly, this system enabled us to address a fundamental biological question about the amplification of a herpesvirus infection in a peripheral nervous system circuit. PMID- 23736289 TI - Discrimination of premalignant lesions and cancer tissues from normal gastric tissues using Raman spectroscopy. AB - The feasibility of early detection of gastric cancer using near-infrared (NIR) Raman spectroscopy (RS) by distinguishing premalignant lesions (adenomatous polyp, n=27) and cancer tissues (adenocarcinoma, n=33) from normal gastric tissues (n=45) is evaluated. Significant differences in Raman spectra are observed among the normal, adenomatous polyp, and adenocarcinoma gastric tissues at 936, 1003, 1032, 1174, 1208, 1323, 1335, 1450, and 1655 cm(-1). Diverse statistical methods are employed to develop effective diagnostic algorithms for classifying the Raman spectra of different types of ex vivo gastric tissues, including principal component analysis (PCA), linear discriminant analysis (LDA), and naive Bayesian classifier (NBC) techniques. Compared with PCA-LDA algorithms, PCA-NBC techniques together with leave-one-out, cross-validation method provide better discriminative results of normal, adenomatous polyp, and adenocarcinoma gastric tissues, resulting in superior sensitivities of 96.3%, 96.9%, and 96.9%, and specificities of 93%, 100%, and 95.2%, respectively. Therefore, NIR RS associated with multivariate statistical algorithms has the potential for early diagnosis of gastric premalignant lesions and cancer tissues in molecular level. PMID- 23736288 TI - Natural genetic variation of Xanthomonas campestris pv. campestris pathogenicity on arabidopsis revealed by association and reverse genetics. AB - ABSTRACT The pathogenic bacterium Xanthomonas campestris pv. campestris, the causal agent of black rot of Brassicaceae, manipulates the physiology and the innate immunity of its hosts. Association genetic and reverse-genetic analyses of a world panel of 45 X. campestris pv. campestris strains were used to gain understanding of the genetic basis of the bacterium's pathogenicity to Arabidopsis thaliana. We found that the compositions of the minimal predicted type III secretome varied extensively, with 18 to 28 proteins per strain. There were clear differences in aggressiveness of those X. campestris pv. campestris strains on two Arabidopsis natural accessions. We identified 3 effector genes (xopAC, xopJ5, and xopAL2) and 67 amplified fragment length polymorphism (AFLP) markers that were associated with variations in disease symptoms. The nature and distribution of the AFLP markers remain to be determined, but we observed a low linkage disequilibrium level between predicted effectors and other significant markers, suggesting that additional genetic factors make a meaningful contribution to pathogenicity. Mutagenesis of type III effectors in X. campestris pv. campestris confirmed that xopAC functions as both a virulence and an avirulence gene in Arabidopsis and that xopAM functions as a second avirulence gene on plants of the Col-0 ecotype. However, we did not detect the effect of any other effector in the X. campestris pv. campestris 8004 strain, likely due to other genetic background effects. These results highlight the complex genetic basis of pathogenicity at the pathovar level and encourage us to challenge the agronomical relevance of some virulence determinants identified solely in model strains. IMPORTANCE The identification and understanding of the genetic determinants of bacterial virulence are essential to be able to design efficient protection strategies for infected plants. The recent availability of genomic resources for a limited number of pathogen isolates and host genotypes has strongly biased our research toward genotype-specific approaches. Indeed, these do not consider the natural variation in both pathogens and hosts, so their applied relevance should be challenged. In our study, we exploited the genetic diversity of Xanthomonas campestris pv. campestris, the causal agent of black rot on Brassicaceae (e.g., cabbage), to mine for pathogenicity determinants. This work evidenced the contribution of known and unknown loci to pathogenicity relevant at the pathovar level and identified these virulence determinants as prime targets for breeding resistance to X. campestris pv. campestris in Brassicaceae. PMID- 23736290 TI - Phase-function corrected diffusion model for diffuse reflectance of a pencil beam obliquely incident on a semi-infinite turbid medium. AB - Oblique incidence reflectometry (OIR) is an established technique for the estimation of tissue optical properties. However, a sensing footprint of a few transport mean-free paths is often needed when diffusion-regime-based algorithms are used. Smaller-footprint probes require improved light-propagation models and inversion schemes for diffuse reflectance close to the point of entry but might enable micro-endoscopic form factors for clinical assessments of cancers and precancers. The phase-function corrected diffusion theory presented by Vitkin et al. [Nat. Commun. 2, 587 (2011)] to the case of pencil beams obliquely incident on a semi-infinite turbid medium is extended. The model requires minimal computational resources and offers improved accuracy over more traditional diffusion-theory approximations models when validated against Monte Carlo simulations. The computationally efficient nature of the models lends itself to rapid fitting procedures for inverse problems. The analytical model is used in a nonlinear fitting algorithm to demonstrate the recovery of optical properties using a measurement footprint that is significantly smaller than needed in previous diffusion-regime OIR methods. PMID- 23736291 TI - Endoplasmic reticulum stress and apoptosis contribute to the pathogenesis of dominantly inherited isolated GH deficiency due to GH1 gene splice site mutations. AB - Dominantly inherited isolated GH deficiency is mainly caused by a heterozygous donor site mutation of intron 3 in the GH1 gene. An exon 3 deletion in GH (del32 71 GH) is produced from a mutant allele, whereas wild-type GH is produced from the other allele. Several studies have demonstrated a dominant negative effect of del32-71 GH on wild-type GH secretion, but the precise molecular mechanisms remain unclear. We hypothesized that unfolded del32-71 GH accumulates in the endoplasmic reticulum (ER) and causes ER stress and apoptosis in somatotrophs, promoting GH deficiency. To evaluate del32-71 GH-mediated ER stress, we established GH4C1 cell lines with doxycycline (dox)-controlled del32-71 GH expression. In 20 of 23 dox-controlled cell lines, the concentration of wild-type GH in the culture medium significantly decreased with del32-71 GH induction, demonstrating the dominant negative effect of this mutant. Cell viability, mRNA abundance of ER stress-response genes, caspase activation, and DNA fragmentation were evaluated in 5 dox-controlled cell lines selected as cellular models. In 4 of the 5 cell lines, del32-71 GH induction decreased cell viability, increased expression of 3 major ER stress response pathways (PRKR-like endoplasmic reticulum kinase [PERK], activating transcription factor-6 [ATF6], and inositol requirement 1 [IRE1]), and induced caspase-3 and caspase-7 activation. In 1 of the 4 cell lines, DNA fragmentation was demonstrated. Finally, overexpression of XBP1(S), a nuclear transcription factor downstream of IRE1, completely reversed the observed caspase activation. These data suggested that del32-71 GH-mediated ER stress and apoptosis contributed to the decrease in wild-type GH secretion observed in GH deficiency due to the GH1 gene slice-site mutations. PMID- 23736292 TI - Global but not gonadotrope-specific disruption of Bmal1 abolishes the luteinizing hormone surge without affecting ovulation. AB - Although there is evidence for a circadian regulation of the preovulatory LH surge, the contributions of individual tissue clocks to this process remain unclear. We studied female mice deficient in the Bmal1 gene (Bmal1(-/-)), which is essential for circadian clock function, and found that they lack the proestrous LH surge. However, spontaneous ovulation on the day of estrus was unaffected in these animals. Bmal1(-/-) females were also deficient in the proestrous FSH surge, which, like the LH surge, is GnRH-dependent. In the absence of circadian or external timing cues, Bmal1(-/-) females continued to cycle in constant darkness albeit with increased cycle length and time spent in estrus. Because pituitary gonadotropes are the source of circulating LH and FSH, we assessed hypophyseal circadian clock function and found that female pituitaries rhythmically express clock components throughout all cycle stages. To determine the role of the gonadotrope clock in the preovulatory LH and FSH surge process, we generated mice that specifically lack BMAL1 in gonadotropes (GBmal1KO). GBmal1KO females exhibited a modest elevation in both proestrous and baseline LH levels across all estrous stages. BMAL1 elimination from gonadotropes also led to increased variability in estrous cycle length, yet GBmal1KO animals were otherwise reproductively normal. Together our data suggest that the intrinsic clock in gonadotropes is dispensable for LH surge regulation but contributes to estrous cycle robustness. Thus, clocks in the suprachiasmatic nucleus or elsewhere must be involved in the generation of the LH surge, which, surprisingly, is not required for spontaneous ovulation. PMID- 23736293 TI - Redundancy in Kiss1 expression safeguards reproduction in the mouse. AB - Kisspeptin (Kiss1) signaling to GnRH neurons is widely acknowledged to be a prerequisite for puberty and reproduction. Animals lacking functional genes for either kisspeptin or its receptor exhibit low gonadotropin secretion and infertility. Paradoxically, a recent study reported that genetic ablation of nearly all Kiss1-expressing neurons (Kiss1 neurons) does not impair reproduction, arguing that neither Kiss1 neurons nor their products are essential for sexual maturation. We posited that only minute quantities of kisspeptin are sufficient to support reproduction. If this were the case, animals having dramatically reduced Kiss1 expression might retain fertility, testifying to the redundancy of Kiss1 neurons and their products. To test this hypothesis and to determine whether males and females differ in the required amount of kisspeptin needed for reproduction, we used a mouse (Kiss1-CreGFP) that has a severe reduction in Kiss1 expression. Mice that are heterozygous and homozygous for this allele (Kiss1(Cre/+) and Kiss1(Cre/Cre)) have ~50% and 95% reductions in Kiss1 transcript, respectively. We found that although male Kiss1(Cre/Cre) mice sire normal-sized litters, female Kiss1(Cre/Cre) mice exhibit significantly impaired fertility and ovulation. These observations suggest that males require only 5% of normal Kiss1 expression to be reproductively competent, whereas females require higher levels for reproductive success. PMID- 23736294 TI - Cocaine- and amphetamine-regulated transcript is a potent stimulator of GnRH and kisspeptin cells and may contribute to negative energy balance-induced reproductive inhibition in females. AB - Cocaine- and amphetamine-regulated transcript (CART) is a hypothalamic neuropeptide implicated in both metabolic and reproductive regulation, raising the possibility that CART plays a role in reproductive inhibition during negative metabolic conditions. The current study characterized CART's regulatory influence on GnRH and kisspeptin (Kiss1) cells and determined the sensitivity of different CART populations to negative energy balance. CART fibers made close appositions to 60% of GnRH cells, with the majority of the fibers (>80%) originating from the arcuate nucleus (ARH) CART/pro-opiomelanocortin population. Electrophysiological recordings in GnRH-green fluorescent protein rats demonstrated that CART postsynaptically depolarizes GnRH cells. CART fibers from the ARH were also observed in close contact with Kiss1 cells in the ARH and anteroventral periventricular nucleus (AVPV). Recordings in Kiss1-GFP mice demonstrated CART also postsynaptically depolarizes ARH Kiss1 cells, suggesting CART may act directly and indirectly, via Kiss1 populations, to stimulate GnRH neurons. CART protein and mRNA levels were analyzed in 2 models of negative energy balance: caloric restriction (CR) and lactation. Both CART mRNA levels and the number of CART-immunoreactive cells were suppressed in the ARH during CR but not during lactation. AVPV CART mRNA was suppressed during CR, but not during lactation when there was a dramatic increase in CART-immunoreactive cells. These data suggest differing regulatory signals of CART between the models. In conclusion, both morphological and electrophysiological methods identify CART as a novel and potent stimulator of Kiss1 and GnRH neurons and suppression of CART expression during negative metabolic conditions could contribute to inhibition of the reproductive axis. PMID- 23736295 TI - 3,5-T2 is an alternative ligand for the thyroid hormone receptor beta1. AB - Several liganded nuclear receptors have alternative ligands acting in a tissue specific fashion and playing important biological roles. We present evidence that 3,5-diiodothyronine (T(2)), a naturally occurring iodothyronine that results from T(3) outer-ring deiodination, is an alternative ligand for thyroid hormone receptor beta1 (TRbeta1). In tilapia, 2 TRbeta isoforms differing by 9 amino acids in the ligand-binding domain were cloned. Binding and transactivation studies showed that T(2) activates the human and the long tilapia TRbeta1 isoform, but not the short one. A chimeric human TRbeta1 (hTRbeta1) that contained the 9-amino-acid insert showed no response to T(2), suggesting that the conformation of the hTRbeta1 naturally allows T(2) binding and that other regions of the receptor are implicated in TR activation by T(2). Indeed, further analysis showed that the N terminus is essential for T(2)-mediated transactivation but not for that by T(3) in the long and hTRbeta1, suggesting a functional interaction between the N-terminal domain and the insertion in the ligand-binding domain. To establish the functional relevance of T(2)-mediated TRbeta1 binding and activation, mRNA expression and its regulation by T(2) and T(3) was evaluated for both isoforms. Our data show that long TRbeta1expression is 10(6)-fold higher than that of the short isoform, and T(3) and T(2) differentially regulate the expression of these 2 TRbeta1 isoforms in vivo. Taken together, our results prompted a reevaluation of the role and mechanism of action of thyroid hormone metabolites previously believed to be inactive. More generally, we propose that classical liganded receptors are only partially locked to very specific ligands and that alternative ligands may play a role in the tissue-specific action of receptors. PMID- 23736297 TI - Cardiac alpha-actin over-expression therapy in dominant ACTA1 disease. AB - More than 200 mutations in the skeletal muscle alpha-actin gene (ACTA1) cause either dominant or recessive skeletal muscle disease. Currently, there are no specific therapies. Cardiac alpha-actin is 99% identical to skeletal muscle alpha actin and the predominant actin isoform in fetal muscle. We previously showed cardiac alpha-actin can substitute for skeletal muscle alpha-actin, preventing the early postnatal death of Acta1 knock-out mice, which model recessive ACTA1 disease. Dominant ACTA1 disease is caused by the presence of 'poison' mutant actin protein. Experimental and anecdotal evidence nevertheless indicates that the severity of dominant ACTA1 disease is modulated by the relative amount of mutant skeletal muscle alpha-actin protein present. Thus, we investigated whether transgenic over-expression of cardiac alpha-actin in postnatal skeletal muscle could ameliorate the phenotype of mouse models of severe dominant ACTA1 disease. In one model, lethality of ACTA1(D286G). Acta1(+/-) mice was reduced from ~59% before 30 days of age to ~12%. In the other model, Acta1(H40Y), in which ~80% of male mice die by 5 months of age, the cardiac alpha-actin transgene did not significantly improve survival. Hence cardiac alpha-actin over-expression is likely to be therapeutic for at least some dominant ACTA1 mutations. The reason cardiac alpha-actin was not effective in the Acta1(H40Y) mice is uncertain. We showed that the Acta1(H40Y) mice had endogenously elevated levels of cardiac alpha-actin in skeletal muscles, a finding not reported in dominant ACTA1 patients. PMID- 23736296 TI - Glucocorticoid-dependent hippocampal transcriptome in male rats: pathway-specific alterations with aging. AB - Although glucocorticoids (GCs) are known to exert numerous effects in the hippocampus, their chronic regulatory functions remain poorly understood. Moreover, evidence is inconsistent regarding the long-standing hypothesis that chronic GC exposure promotes brain aging/Alzheimer disease. Here, we adrenalectomized male F344 rats at 15 months of age, maintained them for 3 months with implanted corticosterone (CORT) pellets producing low or intermediate (glucocorticoid receptor-activating) blood levels of CORT, and performed microarray/pathway analyses in hippocampal CA1. We defined the chronic GC dependent transcriptome as 393 genes that exhibited differential expression between intermediate and low CORT groups. Short-term CORT (4 days) did not recapitulate this transcriptome. Functional processes/pathways overrepresented by chronic CORT-up-regulated genes included learning/plasticity, differentiation, glucose metabolism, and cholesterol biosynthesis, whereas processes overrepresented by CORT-down-regulated genes included inflammatory/immune/glial responses and extracellular structure. These profiles indicate that GCs chronically activate neuronal/metabolic processes while coordinately repressing a glial axis of reactivity/inflammation. We then compared the GC transcriptome with a previously defined hippocampal aging transcriptome, revealing a high proportion of common genes. Although CORT and aging moved expression of some common genes in the same direction, the majority were shifted in opposite directions by CORT and aging (eg, glial inflammatory genes down-regulated by CORT are up-regulated with aging). These results contradict the hypothesis that GCs simply promote brain aging and also suggest that the opposite direction shifts during aging reflect resistance to CORT regulation. Therefore, we propose a new model in which aging related GC resistance develops in some target pathways, whereas GC overstimulation develops in others, together generating much of the brain aging phenotype. PMID- 23736299 TI - Ablation of P2X7 receptor exacerbates gliosis and motoneuron death in the SOD1 G93A mouse model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurological disorder characterized by selective degeneration of upper and lower motoneurons. The primary triggers for motoneuron degeneration are still unknown, but inflammation is considered an important contributing factor. P2X7 receptor is a key player in microglia response to toxic insults and was previously shown to increase pro inflammatory actions of SOD1-G93A ALS microglia. We therefore hypothesized that lack of P2X7 receptor could modify disease features in the SOD1-G93A mice. Hetero and homozygous P2X7 receptor knock-out SOD1-G93A mice were thus generated and analysed for body weight, disease onset and progression (by behavioural scores, grip and rotarod tests) and survival. Although the lifespan of P2X7(+/-) and P2X7(-/-)/SOD1-G93A female mice was extended by 6-7% with respect to SOD1-G93A mice, to our surprise the clinical onset was significantly anticipated and the disease progression worsened in both male and female P2X7(-/-)/SOD1-G93A mice. Consistently, we found increased astrogliosis, microgliosis, motoneuron loss, induction of the pro-inflammatory markers NOX2 and iNOS and activation of the MAPKs pathway in the lumbar spinal cord of end-stage P2X7(-/-)/SOD1-G93A mice. These results show that the constitutive deletion of P2X7 receptor aggravates the ALS pathogenesis, suggesting that the receptor might have beneficial effects in at least definite stages of the disease. This study unravels a complex dual role of P2X7 receptor in ALS and strengthens the importance of a successful time window of therapeutic intervention in contrasting the pathology. PMID- 23736298 TI - The DcpS inhibitor RG3039 improves survival, function and motor unit pathologies in two SMA mouse models. AB - Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein due to the functional loss of the SMN1 gene and the inability of its paralog, SMN2, to fully compensate due to reduced exon 7 splicing efficiency. Since SMA patients have at least one copy of SMN2, drug discovery campaigns have sought to identify SMN2 inducers. C5-substituted quinazolines increase SMN2 promoter activity in cell-based assays and a derivative, RG3039, has progressed to clinical testing. It is orally bioavailable, brain-penetrant and has been shown to be an inhibitor of the mRNA decapping enzyme, DcpS. Our pharmacological characterization of RG3039, reported here, demonstrates that RG3039 can extend survival and improve function in two SMA mouse models of varying disease severity (Taiwanese 5058 Hemi and 2B/- SMA mice), and positively impacts neuromuscular pathologies. In 2B/- SMA mice, RG3039 provided a >600% survival benefit (median 18 days to >112 days) when dosing began at P4, highlighting the importance of early intervention. We determined the minimum effective dose and the associated pharmacokinetic (PK) and exposure relationship of RG3039 and DcpS inhibition ex vivo. These data support the long PK half-life with extended pharmacodynamic outcome of RG3039 in 2B/- SMA mice. In motor neurons, RG3039 significantly increased both the average number of cells with gems and average number of gems per cell, which is used as an indirect measure of SMN levels. These studies contribute to dose selection and exposure estimates for the first studies with RG3039 in human subjects. PMID- 23736302 TI - Descriptive study of electromagnetic wave distribution for various seating positions: using digital textbooks. AB - To better understand environmental electromagnetic wave exposure during the use of digital textbooks by elementary school students, we measured numeric values of the electromagnetic fields produced by tablet personal computers (TPCs). Specifically, we examined the distribution of the electromagnetic waves for various students' seating positions in an elementary school that uses digital textbooks. Electric and magnetic fields from TPCs were measured using the HI-3603 Visual Display Terminal/ Very Low Frequency (VDT/VLF) radiation measurement system. Electromagnetic field values from TPCs measured at a student's seat and at a teacher's computer were deemed not harmful to health. However, electromagnetic field values varied based on the distance between students, other electronic devices such as a desktop computers, and student posture while using a TPC. Based on these results, it is necessary to guide students to observe proper posture and to arrange seats at an appropriate distance in the classroom. PMID- 23736300 TI - Coronary heart disease is associated with a mutation in mitochondrial tRNA. AB - Coronary heart disease (CHD) is the leading cause of death worldwide. Mitochondrial genetic determinant for the development of CHD remains poorly explored. We report there the clinical, genetic, molecular and biochemical characterization of a four-generation Chinese family with maternally inherited CHD. Thirteen of 32 adult members in this family exhibited variable severity and age-at-onset of CHD. Mutational analysis of their mitochondrial genomes identified the tRNA(Thr) 15927G>A mutation belonging to the Eastern Asian haplogroup B5. The anticipated destabilization of a highly conserved base-pairing (28C-42G) by the 15927G>A mutation affects structure and function of tRNA(Thr). Northern analysis revealed ~80% decrease in the steady-state level of tRNA(Thr) in the mutant cell lines carrying the 15927G>A mutation. The 15927G>A mutation changed the conformation of tRNA(Thr), as suggested by slower electrophoretic mobility of mutated tRNA with respect to the wild-type molecule. In addition, ~39% reduction in aminoacylated efficiency of tRNA(Thr) was observed in mutant cells derived from this Chinese family. An in vivo mitochondrial protein labeling analysis showed ~53% reduction in the rate of mitochondrial translation in mutant cells. The impaired mitochondrial protein synthesis leads to defects in overall respiratory capacity or malate/glutamate-promoted respiration or succinate/glycerol-3-phosphate-promoted respiration, or N,N,N',N'-tetramethyl pphenylenediamine/ascorbate-promoted respiration in mutant cells. An increasing production of reactive oxygen species was observed in the mutant cells carrying the 15927G>A mutation. These results provide the direct evidence that the tRNA(Thr) 15927G>A mutation is associated with CHD. Our findings may provide new insights into pathophysiology and intervention targets of this disorder. PMID- 23736301 TI - Mitochondrial damage revealed by immunoselection for ALS-linked misfolded SOD1. AB - Mutant superoxide dismutase 1 (SOD1) selectively associates with spinal cord mitochondria in rodent models of SOD1-mediated amyotrophic lateral sclerosis. A portion of mutant SOD1 exists in a non-native/misfolded conformation that is selectively recognized by conformational antibodies. Misfolded SOD1 is common to all mutant SOD1 models, is uniquely found in areas affected by the disease and is considered to mediate toxicity. We report that misfolded SOD1 recognized by the antibody B8H10 is present in greater abundance in mitochondrial fractions of SOD1(G93A) rat spinal cords compared with oxidized SOD1, as recognized by the C4F6 antibody. Using a novel flow cytometric assay, we detect an age-dependent deposition of B8H10-reactive SOD1 on spinal cord mitochondria from both SOD1(G93A) rats and SOD1(G37R) mice. Mitochondrial damage, including increased mitochondrial volume, excess superoxide production and increased exposure of the toxic BH3 domain of Bcl-2, tracks positively with the presence of misfolded SOD1. Lastly, B8H10 reactive misfolded SOD1 is present in the lysates and mitochondrial fractions of lymphoblasts derived from ALS patients carrying SOD1 mutations, but not in controls. Together, these results highlight misfolded SOD1 as common to two ALS rodent animal models and familial ALS patient lymphoblasts with four different SOD1 mutations. Studies in the animal models point to a role for misfolded SOD1 in mitochondrial dysfunction in ALS pathogenesis. PMID- 23736305 TI - Reducing anastomotic leakage by reinforcement of colorectal anastomosis with cyanoacrylate glue. AB - INTRODUCTION: Technical failure of sutured or stapled anastomoses may lead to anastomotic leakage, which is one of the most important complications after colorectal surgery. Cyanoacrylate glue (CA) provides strong mechanical attachment, making it a good candidate for suture reinforcement. This study aimed to demonstrate that CA is the most important factor in the strength of a sealed colorectal anastomosis, in both normal and insufficient anastomoses. METHODS: Ex vivo porcine colorectal segments were resected. A 1-layer continuous anastomosis or an insufficient 6-interrupted-suture anastomosis was created, and the baseline anastomotic bursting pressure (ABP) was measured. The primary anastomosis was then reinforced either by CA or with 4 additional interrupted sutures, further inverting the anastomosis. After reinforcement a second ABP test was performed. RESULTS: Thirty-two segments were used. Reinforcing the anastomosis by CA significantly increased ABP in both normal and insufficient anastomoses when compared to the primary anastomosis (p < 0.05 for all groups); no significant difference in ABP was found between normal and insufficient anastomosis groups after CA reinforcement. Anastomotic reinforcement with CA was not inferior to the reinforcement with sutures in both normal and insufficient anastomoses, and had significantly fewer ABP variances in normal anastomosis groups (p = 0.042). CONCLUSION: Reinforcing a colorectal anastomosis with CA increases its mechanical strength in both normal and technically insufficient situations, which may contribute to the reduction of anastomotic leakage. CA is promising for anastomotic reinforcement based on mechanical improvement of the anastomosis, and in vivo studies are needed to evaluate its biological effects. PMID- 23736309 TI - Evidence of confinement of the pi plasmon in periodically rippled graphene on Ru(0001). AB - High-resolution electron energy loss spectroscopy has been used to study the electronic response of periodically rippled monolayer graphene grown on Ru(0001). A plasmonic mode, assigned to the pi plasmon, has been observed at around 6 eV. The dispersion curve of this collective mode indicates plasmon confinement within the hills of the ripples. Moreover, we found that the corrugation of the graphene sheet also significantly affects the damping processes of the pi plasmon. PMID- 23736307 TI - Endogenous ABA concentration and cytoplasmic membrane fluidity in microspores of oilseed rape (Brassica napus L.) genotypes differing in responsiveness to androgenesis induction. AB - KEY MESSAGE: A better understanding of androgenesis with a focus on the changes in plasma membrane fluidity and endogenous ABA content affecting embryogenesis induction in microspore suspension of B. napus. Changes in plasma membrane fluidity (MF) and ABA content associated with androgenesis induction were under the study. Both parameters were monitored in microspores of two Brassica napus L. genotypes differing in their response to androgenic induction under heat (1 day at 32 degrees C). MF was assessed by DPH method. ABA content was evaluated by ELISA. Heat caused microspores' plasma membrane to become more rigid. Lower MF in microspores of 'DH 4079' (of high androgenic potential) seems to maintain proper cell protection and leads to efficient embryogenesis induction. Plasma membrane remodelling coincided with changes of ABA content in microspores and in the culture medium in both genotypes. ABA concentration (MUM) and ABA content (fmol per 10(4) microspores or pmol g(-1) FW) were for the first time measured in microspores. ABA concentration (MUM) in microspores and in the culture medium (nM) differed significantly for the genotype and the treatment. The interaction between both variables was also significant. In general, ABA content ranged from <3.5 to 87.1 fmol per 10(4) microspores. The highest content of ABA was detected in 'DH 4079' microspores at 32 degrees C. Assuming a mean microspores' radius of 10 MUm, it corresponds to ABA concentration of 2.1 MUM. Heat shock resulted in quantum of medium pH reduction (0.1-0.2) and increased levels of ABA in microspores and in the medium of both tested genotypes. However, heat induced increase of ABA content in microspores of non-responsive 'Campino' had no clear cut impact, on androgenesis induction efficiency, which suggests a more complex mechanism of process initiation. PMID- 23736306 TI - Genetic epidemiology of cardiometabolic risk factors and their clustering patterns in Mexican American children and adolescents: the SAFARI Study. AB - Pediatric metabolic syndrome (MS) and its cardiometabolic components (MSCs) have become increasingly prevalent, yet little is known about the genetics underlying MS risk in children. We examined the prevalence and genetics of MS-related traits among 670 non-diabetic Mexican American (MA) children and adolescents, aged 6-17 years (49 % female), who were participants in the San Antonio Family Assessment of Metabolic Risk Indicators in Youth study. These children are offspring or biological relatives of adult participants from three well-established Mexican American family studies in San Antonio, TX, at increased risk of type 2 diabetes. MS was defined as >=3 abnormalities among 6 MSC measures: waist circumference, systolic and/or diastolic blood pressure, fasting insulin, triglycerides, HDL cholesterol, and fasting and/or 2-h OGTT glucose. Genetic analyses of MS, number of MSCs (MSC-N), MS factors, and bivariate MS traits were performed. Overweight/obesity (53 %), pre-diabetes (13 %), acanthosis nigricans (33 %), and MS (19 %) were strikingly prevalent, as were MS components, including abdominal adiposity (32 %) and low HDL-cholesterol (32 %). Factor analysis of MS traits yielded three constructs: adipo-insulin-lipid, blood pressure, and glucose factors, and their factor scores were highly heritable. MS itself exhibited 68 % heritability. MSC-N showed strong positive genetic correlations with obesity, insulin resistance, inflammation, and acanthosis nigricans, and negative genetic correlation with physical fitness. MS trait pairs exhibited strong genetic and/or environmental correlations. These findings highlight the complex genetic architecture of MS/MSCs in MA children, and underscore the need for early screening and intervention to prevent chronic sequelae in this vulnerable pediatric population. PMID- 23736310 TI - Immediate implant placement without bone grafting: a retrospective study of 110 cases with 5 years of follow-up. AB - PURPOSE: Immediate implant placement not only reduces the number of surgeries necessary but also decreases the treatment time and treatment costs. The purpose of the study was to present the clinical results of 110 cases of immediate implant placement without using graft materials at the end of 5 years. MATERIALS AND METHODS: One hundred and ten implants in 72 patients were included in the study. Inclusion criteria for the patients were presence of at least 2 mm of bone beyond the root apex, the absence of acute signs of infection or inflammation in the treatment area, and the absence of systemic pathologies that would contraindicate bone healing around implants. In cases where bone grafting was necessary, the implant was excluded from the study. RESULTS: Healing progressed uneventfully in 105 cases. Four implants were lost as a result of infection in the first 3 months and 1 implant was lost 1 year after the functional loading of the prosthesis. The soft tissue anatomy was clinically acceptable in all patients. The implants that were placed in the extraction sockets of infectious teeth had also acceptable survival rates and clinical success. CONCLUSION: With proper patient selection, immediate implant placement without bone grafting has predictable survival rates and clinical success. PMID- 23736311 TI - Diphosphonate immobilization on hydroxyapatite-coated titanium--method description. AB - PURPOSE: The aim of this study was to promote the immobilization of a bone activity biomodulator (diphosphonate) on titanium, commonly used in implant dentistry, to provide a local method of delivering this drug during the osseointegration process. METHODS: The implant material used in this study was commercially wrought titanium (Ticp), 99.9 mass%, grade II. From this material, discs of 15 mm diameter and 1 mm thick were fabricated. These discs underwent 3 sequential surface modification processes: (a) acid-etching, (b) hydroxyapatite coating, and (c) immersion in disodium pamidronate solution. Scanning electron microscopy, X-ray fluorescence, and X-ray diffraction analyses were carried out to characterize the surface created. RESULTS: The results of these analyses demonstrate that the acid-etching process, followed by the sintering of hydroxyapatite particles and immersion in a solution of disodium pamidronate were effective for diphosphonate immobilization on the titanium surface. CONCLUSIONS: The methodology used in this study allows us to conclude that immersion of hydroxyapatite-coated titanium in a solution of diphosphonate was efficient to promote the immobilization of this drug on the titanium surface. PMID- 23736312 TI - Comparison of histological and three-dimensional characteristics of porous titanium granules and deproteinized bovine particulate grafts used for sinus floor augmentation in humans: a pilot study. AB - PURPOSE: Slow-resorbing deproteinized bovine bone grafts have presented high success rates when used for sinus augmentation. However, histologic evaluation shows that this material is eventually excreted as a result of a foreign body reaction. The purpose of this study was to compare and to evaluate the performance of a recently introduced particulate porous graft material, consisting of pure titanium granule (PTG) to the deproteinized bovine bone grafts, when used as a sinus augmentation material. MATERIALS AND METHODS: To understand the histological aspects of PTG, deproteinized bovine particulates (Bio-Oss) and PTG were placed contralaterally as sinus grafting materials in 2 patients. After 9 months, biopsies were performed for histologic and 3 dimensional analysis. RESULTS: Both materials were in contact with newly formed bone. The Bio-Oss showed signs of foreign body reaction. In contrast, bone filled the space between the single PTG particulates, and no foreign body reaction was observed. CONCLUSIONS: From a bone formation perspective, PTG grafts were comparable with the commonly used Bio-Oss grafts and may be regarded as a possible alternative for permanent grafting in sinus augmentation. PMID- 23736313 TI - Fluorescence amplified detection of proteases by the catalytic activation of a semisynthetic sensor. AB - A general approach to mimic the sensing scheme of allosteric enzymes is developed. Through the covalent labeling of a sulfonamide inhibitor to the enzyme HCAII via SNAP-tag protein, the enzyme is rendered inactive. Catalytic activation is triggered only when a protease is present to cleave the recognized peptide sequence. PMID- 23736314 TI - Effects of acute oral naltrexone on the subjective and physiological effects of oral D-amphetamine and smoked cocaine in cocaine abusers. AB - Despite the prevalent worldwide abuse of stimulants, such as amphetamines and cocaine, no medications are currently approved for treating this serious public health problem. Both preclinical and clinical studies suggest that the opioid antagonist naltrexone (NTX) is effective in reducing the abuse liability of amphetamine, raising the question of whether similar positive findings would be obtained for cocaine. The purpose of this study was to evaluate the ability of oral NTX to alter the cardiovascular and subjective effects of D-amphetamine (D AMPH) and cocaine (COC). Non-treatment-seeking COC users (N=12) completed this 3 week inpatient, randomized, crossover study. Participants received 0, 12.5, or 50 mg oral NTX 60 min before active or placebo stimulant administration during 10 separate laboratory sessions. Oral AMPH (0, 10, and 20 mg; or all placebo) was administered in ascending order within a laboratory session using a 60-min interdose interval. Smoked COC (0, 12.5, 25, and 50 mg; or all placebo) was administered in ascending order within a laboratory session using a 14-min interdose interval. Active COC and AMPH produced dose-related increases in cardiovascular function that were of comparable magnitude. In contrast, COC, but not AMPH, produced dose-related increases in several subjective measures of positive drug effect (eg, high, liking, and willingness to pay for the drug). NTX did not alter the cardiovascular effects of AMPH or COC. NTX also did not alter positive subjective ratings after COC administration, but it did significantly reduce ratings of craving for COC and tobacco during COC sessions. These results show that (1) oral AMPH produces minimal abuse-related subjective responses in COC smokers, and (2) NTX reduces craving for COC and tobacco during COC sessions. Future studies should continue to evaluate NTX as a potential anti-craving medication for COC dependence. PMID- 23736316 TI - Reduction of the diffraction in strongly resonant thin-film Fabry-Perot filters between single-mode fibers. AB - Simulations show that the cumbersome diffraction losses occurring in narrow bandpass thin-film Fabry-Perot filters (TF-FP filters) inserted between two narrow-core optical fibers are strongly reduced by introducing into the filter a pair of film materials with high refraction index contrast. They are even further reduced by transforming the optically resonant layers of the filter into gradient index photo-refractive resonant lenses. This permits the design of compact TF-FP filters between fibers with passbands as narrow as those of TF-FP filters deposited on bulk substrates. PMID- 23736317 TI - Refractive index measurement by fiber point diffraction longitudinal shearing interferometry. AB - A refractive index measurement method by measuring the longitudinal displacement of a point light source (PLS) after passing through a plane-parallel-plate sample is proposed. The displacement is derived by applying two point-diffraction longitudinal shearing interferometric measurements if the distance from the PLS to the exit pupil is predetermined. With two fibers to simulate the ideal PLS, an experimental system for solid and liquid sample tests is proposed to verify the principle. The experimental results indicate that its accuracy is in the order of 10(-4). Ways to improve the accuracy are discussed based on the detailed error analysis. PMID- 23736315 TI - Interactions between the lateral habenula and the hippocampus: implication for spatial memory processes. AB - The lateral habenula (LHb) is an epithalamic structure connected with both the basal ganglia and the limbic system and that exerts a major influence on midbrain monoaminergic nuclei. The current view is that LHb receives and processes cortical information in order to select proper strategies in a variety of behavior. Recent evidence indicates that LHb might also be implicated in hippocampus-dependent memory processes. However, if and how LHb functionally interacts with the dorsal hippocampus (dHPC) is still unknown. We therefore performed simultaneous recordings within LHb and dHPC in both anesthetized and freely moving rats. We first showed that a subset of LHb cells were phase-locked to hippocampal theta oscillations. Furthermore, LHb generated spontaneous theta oscillatory activity, which was highly coherent with hippocampal theta oscillations. Using reversible LHb inactivation, we found that LHb might regulate dHPC theta oscillations. In addition, we showed that LHb silencing altered performance in a hippocampus-dependent spatial recognition task. Finally, increased coherence between LHb and dHPC was positively correlated to the memory performance in this test. Collectively, these results suggest that LHb functionally interacts with the hippocampus and is involved in hippocampus dependent spatial information processing. PMID- 23736318 TI - Coherence scanning interferometry: linear theory of surface measurement. AB - The characterization of imaging methods as three-dimensional (3D) linear filtering operations provides a useful way to compare the 3D performance of optical surface topography measuring instruments, such as coherence scanning interferometry, confocal and structured light microscopy. In this way, the imaging system is defined in terms of the point spread function in the space domain or equivalently by the transfer function in the spatial frequency domain. The derivation of these characteristics usually involves making the Born approximation, which is strictly only applicable to weakly scattering objects; however, for the case of surface scattering, the system is linear if multiple scattering is assumed to be negligible and the Kirchhoff approximation is assumed. A difference between the filter characteristics derived in each case is found. However this paper discusses these differences and explains the equivalence of the two approaches when applied to a weakly scattering object. PMID- 23736319 TI - Design and performance of an absolute gas refractometer based on a synthetic pseudo-wavelength method. AB - We present a refractometer that is capable of measuring the refractive index of gases with an unambiguous range of 1.000395 and an uncertainty of 3.14*10(-8) at 633 nm. The measurement range was extended via the combination of the vacuum cells according to the proposed synthetic pseudo-wavelength (SPW) method. The basic principles of the SPW method and the design of the gas refractometer are presented in detail. The performance of the refractometer was verified in the measurements of dry air, nitrogen gas, and ambient air under different environmental conditions. No gas-filling or pumping processes were required during the measurements; so one measurement could be completed within 70 s. Compared with existing refractometers, the method reported here holds advantages in its large unambiguous measuring range, fast speed, high accuracy, and simple instrumentation design. PMID- 23736320 TI - Hybrid optical system for three-dimensional shape acquisition. AB - Hybrid concepts are often used to improve existing methods in many fields. We developed a hybrid optical system that consists of multiple color cameras and one depth camera to make up the concavity problem of the visual hull construction. The heterogeneous data from the color cameras and the depth camera is fused in an effective way. The experimental results show that the proposed hybrid system can reconstruct concave objects successfully by combining the visual hull and the depth data. PMID- 23736321 TI - Design analysis of a fiber-bundle-based mobile free-space optical link with wavelength diversity. AB - This paper reports on a simulation-based investigation of a wavelength diverse free-space optical link with an emphasis on identifying design choices that optimize the performance of the system under different operating scenarios. The simulation incorporates experimental data into the theoretical calculations for optical propagation to better describe the performance of the physical designs. The performance is evaluated in terms of the coverage area at the receiver, which is a measure of misalignment tolerance and is dependent not only on wavelength but on other key parameters, such as link length, transmitted power, the pattern of transmitters, beam divergence, and the receiver construction. The investigation finds that the coverage area of the receiver can be optimized for a given wavelength by proper choices of these parameters, and that parameter choices exist that minimize the change in performance when switching between wavelengths or for variations in link parameters. The interrelationships among key parameters and their impact on the potential system performance are investigated. The results provide guidance on the further development of the overall system. PMID- 23736322 TI - Coupling of surface plasmon with InGaAs/GaAs quantum well emission by gold nanodisk arrays. AB - Enhancement of photoluminescence (PL) intensity from InGaAs/GaAs quantum well (QW) is achieved experimentally by coupling surface plasmon (SP) resonance with QW emission. The SP resonance is generated by fabricating a periodic Au nanodisk array on top of InGaAs/GaAs QW structure. A thin layer of SiO(2) between Au nanodisk and GaAs surface has been employed to achieve easy adjustment of the SP resonance. A 4.16 fold enhancement of PL intensity was observed. Theoretical simulation results match well with the experimental results and confirm that the PL emission is enhanced by SP coupling with the fabricated structure. PMID- 23736323 TI - Theoretical and experimental investigation of infrared properties of tapered silver/silver halide-coated hollow waveguides. AB - Silver/silver halide-coated hollow-glass waveguides (HGWs) are capable of low loss, broadband transmission at infrared wavelengths with the advantage of optical response tunability through alteration of a number of key design parameters. Generally, the design of circular HGWs has primarily involved optimization of the waveguide bore size and deposited film structure in order to obtain the desired optical response, with the waveguide bore size being held constant as a function of length. In this study, the effects of HGW structures consisting of linearly tapered inner diameters on the optical response at infrared wavelengths are theoretically and experimentally investigated. Theoretical analysis involving numerical ray optics methods accounting for the dynamic nature of bore size, and consequently light propagation, along the waveguide length is presented and compared to experimental results in order to gain a deeper understanding of these atypical HGW structures. PMID- 23736324 TI - Femtosecond-laser micromachined optical waveguides in Bi4Ge3O12 crystals. AB - The optical waveguides in Bi(4)Ge(3)O(12) (BGO) crystals in both depressed cladding and dual-line configurations have been produced using femtosecond-laser micromachining. The guiding properties and thermal stabilities of the BGO waveguides have been investigated for both geometries, showing different performance of the fabricated structures. Both depressed-cladding and dual-line waveguides support guidance along both TE and TM polarizations. Thermal annealing treatments up to 600 degrees C reduce the propagation loss of dual-line waveguides to as low as 0.5 dB/cm, while the cladding waveguide is only stable under thermal treatment not higher than 260 degrees C, reaching a propagation loss of 2.1 dB/cm. PMID- 23736325 TI - Morphology evolution of fused silica surface during ion beam figuring of high slope optical components. AB - Ultra-precision and ultra-smooth surfaces are vitally important for some high performance optical systems. Ion beam figuring (IBF) is a well-established, highly deterministic method for the final precision figuring of extremely high quality optical surfaces, whereas ion sputtering induced smoothing, or roughening for nanoscale surface morphology, strongly depends on the processing conditions. Usually, an improper machining method would arouse the production of nanoscale patterns leading to the coarsening of the optical surface. In this paper, the morphology evolution mechanism on a fused silica surface during IBF of high-slope optical components has been investigated by means of atomic force microscopy. Figuring experiments are implemented on two convex spherical surfaces by using different IBF methods. Both of their surface errors are rapidly reduced to 1.2 nm root mean square (RMS) after removing similar deep material, but their surfaces are characterized with obviously different nanoscale morphologies. The experimental results indicate that the ion incidence angle dominates the microscopic morphology during the IBF process. At near-normal incidence, fused silica achieves an ultra-smooth surface with an RMS roughness value R(q) down to 0.1 nm, whereas nanoscale ripple patterns are observed at a large incidence angle with an R(q) value increasing to more than 0.9 nm. Additionally, the difference of incidence angles on various machined areas would influence the uniformity of surface quality, resulting from the interplay between the smoothing and roughening effects induced by ion sputtering. PMID- 23736326 TI - Profile measurement of glass sheet using multiple wavelength backpropagation interferometry. AB - Multiple-wavelength backpropagation interferometry based on a spectral interferometer is proposed for measuring thin glass sheets with nanometer accuracy. The multiwavelength backpropagation method introduced to the spectral interferometer eliminates time-encoded wavelength sweeping and mechanical scanning, which enables high-speed profile measurements. The applicability of the proposed method is experimentally demonstrated through cross-sectional profile and vibrating surface displacement measurements of a glass sheet. PMID- 23736327 TI - Study of frequency stabilization for electro-optical Q-switched radio-frequency excited waveguide CO2 laser using build-up time method. AB - An electro-optical Q-switched RF-excited Z-fold CO(2) waveguide laser was designed, which can output a Q-switched laser and a cavity-dumped laser synchronously. The build-up time method is presented to stabilize the laser frequency. A closed-loop control system was designed to keep the laser oscillating at the peak of the gain curve by measuring the pulse build-up time continuously and controlling the cavity length. In the experiment, the variations for the pulse build-up time and cavity-dumped laser output power with time were recorded in a period of time. The frequency fluctuation is less than +/-16 MHz. PMID- 23736328 TI - Design of a compact silicon-based slot-waveguide crossing. AB - A design scheme for silicon-based slot-waveguide crossing using a slot-to-strip mode converter (at each port) and a strip-multimode-waveguide (SMW) crossing is proposed. The guided modes of the input slot-waveguide are first efficiently transformed into that of the single-mode strip waveguide by using the mode converter, and then enter into the SMW, where fields converge at the center of the intersection due to the multimode interference effect. Consequently, the size of the input beam is much smaller than the width of the SMW at the crossing center, leading to the significant reduction of the crosstalk (CT) and radiation loss. The numerical results show that a slot-waveguide crossing operating at a wavelength of 1.55 MUm with the insertion loss (IL), CT, and reflection (RT) of 0.086, -35.58, and -27.51 dB, respectively, is achieved. Moreover, the IL, CT, and RT as functions of the structural parameters together with the operating wavelength are analyzed in detail by using a finite-difference time domain method, and their fabrication tolerances are presented. In addition, the evolution of the injected fields along the propagation distance through the slot waveguide crossing is also demonstrated. PMID- 23736329 TI - Investigation of the effect of noncircular scatterers on the band structure of anisotropic photonic crystal slabs. AB - Using the supercell approach based on the plane wave expansion method, we analyze the photonic bandgap (PBG) of square and triangular photonic crystal slabs composed of air holes in an anisotropic tellurium background with SiO(2) as cladding material. Two shapes (square and hexagonal) are considered for air holes. We discuss the maximization of the full PBG width as a function of noncircular air hole parameters, their orientation, and also slab thickness. The numerical results show that both structures represent a full PBG with noticeable width, which can be helpful for designing optical devices. PMID- 23736330 TI - S-band multiwavelength Brillouin/Raman distributed Bragg reflector fiber lasers. AB - A multiwavelength Brillouin/Raman distributed Bragg reflector fiber laser operating in the S-band region is proposed and demonstrated. The laser uses a 7.7 km long dispersion-shifted fiber with an effective mode area of 15 MUm(2) as the Brillouin and Raman gain media simultaneously. Two 1420 nm laser diodes with a combined power of 372 mW are used as pump sources, while a fiber Bragg grating with a center wavelength of 1500 nm is used as a reflector in the cavity. The setup is capable of generating 6 clearly defined Stokes lines at the highest pump power, spanning from 1499.8 to 1500.3 nm with the even Stokes having relatively higher peak powers, between 1.4 and 3.5 dBm as compared to the odd Stokes, which have peak powers between -4.7 and -5.0 dBm. The output of the laser is very stable and shows little to no fluctuations over a monitoring period of 50 min. PMID- 23736331 TI - Electric-field-induced optical path length change in LiNbO3:MgO crystals: spatial anisotropy analysis. AB - In this paper we describe the methodology behind the calculation of the indicative surfaces (ISs) of the electric-field-induced optical path length change (EFIOPC) in anisotropic crystal materials accounting for the piezoelectric deformation. It is considered in detail for a particular case of 3m point group symmetry and applied to LiNbO(3) single crystals doped with 7 mol. % MgO (hereafter LiNbO(3):MgO). The contribution of the inverse piezoelectricity into EFIOPC appears to be considerable and, in many cases, modifying, for instance, the spherical coordinates of the extreme directions or even leading to the appearance of new directional maxima on relevant ISs. The ISs of EFIOPC are of considerable practical importance as they allow us to determine an optimal geometry for electro-optic coupling. The spatial anisotropic analysis of EFIOPC in LiNbO(3):MgO crystals suggests that the lowest effective driving voltage is provided by electro-optic cells representing the rectangular slabs of X/50 degrees crystal cut. The modulation efficiency of such electro-optic cells is about 1.5 times better than ones fabricated in the usual way (i.e., as rectangular crystal slabs with the faces parallel to the principal crystallographic directions). PMID- 23736332 TI - Characteristics of multiwavelength L-band Brillouin-Raman fiber laser under forward and backward pumped environment. AB - We experimentally investigate the performance of L-band multiwavelength Brillouin Raman fiber laser (MBRFL) under forward and backward pumped environments utilizing a linear cavity. A short length of 1.18 km dispersion compensating fiber is used as a nonlinear gain medium for both Brillouin and Raman gain. Experimental results indicate that the gain in the copumped laser configuration is higher than the gain in the counterpumped configuration. A stable and constant number of Brillouin Stokes lines up to 23 Stokes, with channel spacing of 0.08 nm and more than 20 dB of optical signal to noise ratio, can be generated as well as tuning over 20 nm in the L-band region from 1570 to 1590 nm. The laser generating the Brillouin Stokes lines exhibits flat amplitude bandwidth and high average output power of 0.8 and 1.6 dBm for the copropagation and counterpropagation pumps, respectively. Moreover, the tuning range bandwidth of the MBRFL can be predicted from the oscillated Brillouin pump gain profile. PMID- 23736333 TI - Real-time monitoring of railway traffic using slope-assisted Brillouin distributed sensors. AB - The application of a Brillouin distributed sensor for the monitoring of railway traffic is presented in this work. The field test is performed on the Italian regional line San Severo-Peschici, operated by Ferrovie del Gargano. A single mode optical fiber sensor was attached along a rail length of about 60 m. The strain associated with train passage was acquired along the monitored rail length at 31 Hz acquisition rate and 1 m spatial resolution. The data acquired by the sensor demonstrates its capability of retrieving useful information in railway traffic monitoring, such as train identification, axle counting, speed detection, and dynamic load calculation. PMID- 23736334 TI - Image analysis through feature extraction by using top-hat transform-based morphological contrast operator. AB - Image decomposition and reconstruction is an important way for image analysis. To be effective for image decomposition and reconstruction, a method using extracted features through top-hat transform-based morphological contrast operator (MCOTH) is proposed in this paper. First, the morphological contrast operator constructed using the top-hat transforms is discussed. Then, extracting the bright and dark image features in the result of MCOTH is given. Based on the extracted bright and dark image features, the original images are decomposed into multiscale complete decompositions using multiscale structuring elements. After processing the decomposed images following different application purposes, the final result image can be reconstructed from the processed decomposition images. To verify the effectiveness of the proposed image analysis method through image decomposition and reconstruction, the application of image enhancement and fusion are discussed. The experimental results show that because the proposed image decomposition and reconstruction method reasonably decomposes the original image into complete decomposition with useful image features at different scales, the useful image features could be easily used for different applications. After the useful image features are processed, the final result image could be reconstructed. Moreover, different types of images are used in the experiments of image enhancement and fusion, and the results are effective. Therefore, the proposed image decomposition and reconstruction method in this paper are effective methods for image analysis and could be widely used in different applications. PMID- 23736335 TI - Digital holography simulations and experiments to quantify the accuracy of 3D particle location and 2D sizing using a proposed hybrid method. AB - The accuracy of digital in-line holography to detect particle position and size within a 3D domain is evaluated with particular focus placed on detection of nonspherical particles. Dimensionless models are proposed for simulation of holograms from single particles, and these models are used to evaluate the uncertainty of existing particle detection methods. From the lessons learned, a new hybrid method is proposed. This method features automatic determination of optimum thresholds, and simulations indicate improved accuracy compared to alternative methods. To validate this, experiments are performed using quasi stationary, 3D particle fields with imposed translations. For the spherical particles considered in experiments, the proposed hybrid method resolves mean particle concentration and size to within 4% of the actual value, while the standard deviation of particle depth is less than two particle diameters. Initial experimental results for nonspherical particles reveal similar performance. PMID- 23736336 TI - Regularized image reconstruction for continuously self-imaging gratings. AB - In this paper, we demonstrate two image reconstruction schemes for continuously self-imaging gratings (CSIGs). CSIGs are diffractive optical elements that generate a depth-invariant propagation pattern and sample objects with a sparse spatial frequency spectrum. To compensate for the sparse sampling, we apply two methods with different regularizations for CSIG imaging. The first method employs continuity of the spatial frequency spectrum, and the second one uses sparsity of the intensity pattern. The two methods are demonstrated with simulations and experiments. PMID- 23736337 TI - Measuring the lens focal length by laser reflection-confocal technology. AB - A laser reflection-confocal focal-length measurement (LRCFM) is proposed for the high-accuracy measurement of lens focal length. LRCFM uses the peak points of confocal response curves to precisely identify the lens focus and vertex of the lens last surface. LRCFM then accurately measures the distance between the two positions to determine the lens focal length. LRCFM uses conic fitting, which significantly enhances measurement accuracy by inhibiting the influence of environmental disturbance and system noise on the measurement results. The experimental results indicate that LRCFM has a relative expanded uncertainty of less than 0.0015%. Compared with existing measurement methods, LRCFM has high accuracy and a concise structure. Thus, LRCFM is a feasible method for high accuracy focal-length measurements. PMID- 23736338 TI - Supercontinuum generation from a multiple-ring-holes tellurite microstructured optical fiber pumped by a 2 MUm mode-locked picosecond fiber laser. AB - Supercontinuum (SC) generation from a highly nonlinear tellurite microstructured optical fiber with multiple rings of holes was demonstrated by pumping with a 2 MUm mode-locked picosecond fiber laser. The chromatic dispersion of the fiber was measured with a homemade white-light spectral interferometer in a wide wavelength range and agreed with the theoretical calculation. Although the pumped wavelength was far from the zero dispersion wavelength, with flat dispersion profile of the fiber in the anomalous dispersion, the SC could be expanded from 650 to 2850 nm with launched pulse energy of several hundred picojoules. Simulations of SC generation agreed with the experimental results. PMID- 23736339 TI - Temperature-dependent Sellmeier equations for rare-earth sesquioxides. AB - High-power lasers are making increasing demands on laser hosts especially in the area of thermal management. Traditional hosts, such as YAG, are unsuitable for many high-power applications and therefore, new hosts are being developed including rare-earth sesquioxides. We report new measurements of the refractive indices of these materials as functions of wavelength and temperature, which will aid in the design of laser cavities and other nonlinear optical elements. PMID- 23736340 TI - Antireflection coatings optimized for single-cycle THz pulses. AB - We show that a single-layer antireflection coating on a THz source of high refractive index can substantially increase the transmission of emitted THz pulses. Calculations indicate that the optimum coating thickness depends on the exact shape of the generated THz waveform and whether the transmitted waveform is to be optimized for the highest peak (temporal) amplitude, peak spectral amplitude, or pulse energy. We experimentally demonstrate a 15% increase in peak amplitude, a 33% increase in peak spectral amplitude, and a 48% increase in energy for a 100 MUm thick fused silica AR coating on a lithium niobate crystal used as THz emitter. PMID- 23736341 TI - Impact of optical feedback on current-induced polarization behavior of 1550 nm vertical-cavity surface-emitting lasers. AB - Polarization switching (PS) between two orthogonal linearly polarized fundamental modes is experimentally observed in commercial free-running 1550 nm vertical cavity surface-emitting lasers (VCSELs) (Raycan). The characteristics of this PS are strongly modified after introducing a polarization-preserved (PP) or polarization-orthogonal (PO) optical feedback. Under the case that the external cavity is approximately 30 cm, the PP optical feedback results in the PS point shifting toward a lower injection current, and the region within which the two polarization modes coexist is enlarged with the increase of the PP feedback strength. Under too-strong PP feedback levels, the PS disappears. The impact of PO optical feedback on VCSEL polarization behavior is quite similar to that of PP optical feedback, but larger feedback strength is needed to obtain similar results. PMID- 23736342 TI - Synthesis method from low-coherence digital holograms for improvement of image quality in holographic display. AB - In holographic displays, it is undesirable to observe the speckle noises with the reconstructed images. A method for improvement of reconstructed image quality by synthesizing low-coherence digital holograms is proposed. It is possible to obtain speckleless reconstruction of holograms due to low-coherence digital holography. An image sensor records low-coherence digital holograms, and the holograms are synthesized by computational calculation. Two approaches, the threshold-processing and the picking-a-peak methods, are proposed in order to reduce random noise of low-coherence digital holograms. The reconstructed image quality by the proposed methods is compared with the case of high-coherence digital holography. Quantitative evaluation is given to confirm the proposed methods. In addition, the visual evaluation by 15 people is also shown. PMID- 23736343 TI - Plasma debris sputter resistant x-ray mirror. AB - A diamond-like carbon (DLC) mirror, used as a grazing incident mirror in a plasma x-ray source, exhibits a high resistance to plasma debris sputtering. Good mirror reflectivity at a wavelength of 13.5 nm was confirmed using synchrotron radiation at the NewSUBARU facility. The erosion rate due to plasma debris sputtered at the incident debris angle of 20 degrees was measured using a laser-produced Xe plasma source developed by the authors. The results indicate that the DLC film has a 5- and 15-fold higher sputtering resistance compared to films made of the traditional mirror materials Ru and Au, respectively. Because the DLC mirror retains a high sputtering resistance to Sn ions, it may be effective in Sn plasma source applications. We conclude that a grazing incident x-ray mirror coated with DLC can be of use as a plasma debris sputtering resistant mirror. PMID- 23736344 TI - Gaussian beam radius measurement with a knife-edge: a polynomial approximation to the inverse error function. AB - A method for approximating the inverse error function involved in the determination of the radius of a Gaussian beam is proposed. It is based on a polynomial inversion that can be developed to any desired degree, according to an a priori defined error budget. Analytic expressions are obtained and used to determine the radius of a TEM(oo) He-Ne laser beam from intensity measurements experimentally obtained by using the knife edge method. The error and the interval of validity of the approximation are determined for polynomials of different degrees. The analysis of the theoretical and experimental errors is also presented. PMID- 23736345 TI - Temperature control of water-based substances by CO2 laser for medical applications. AB - Temperature of water-based substances is investigated by aiming a pulsed CO(2) laser beam at the water-air surface. This method of controlling temperature is believed to be flexible in medical applications as it avoids the use of thermal devices, which are often cumbersome and generate rather larger temperature swing with time. The control of temperature in this laser method is modeled by the heat conduction equation. In this investigation, it is assumed that the energy delivered by the CO(2) laser is confined within a very thin surface layer of roughly 10 MUm. It is shown that the temperature can be very well controlled by a CO(2) laser at a steady temperature, and we demonstrate that the method can be adapted to work in tandem with another laser beam. PMID- 23736346 TI - Beam profile for the Herschel-SPIRE Fourier transform spectrometer. AB - One of the instruments on board the Herschel Space Observatory is the Spectral and Photometric Imaging Receiver (SPIRE). SPIRE employs a Fourier transform spectrometer with feed-horn-coupled bolometers to provide imaging spectroscopy. To interpret the resultant spectral images requires knowledge of the wavelength dependent beam, which in the case of SPIRE is complicated by the use of multimoded feed horns. In this paper we describe a series of observations and the analysis conducted to determine the wavelength dependence of the SPIRE spectrometer beam profile. PMID- 23736347 TI - Robustness analysis of an intensity modulated fiber-optic position sensor with an image sensor readout system. AB - An intensity modulated fiber-optic position sensor, based on a fiber-to-bundle coupling and a readout system using a CMOS image camera together with fast routines for position extraction and calibration, is presented and analyzed. The proposed system eliminates alignment issues otherwise associated with coupling based fiber-optic sensors, still keeping the sensing point free from detector electronics. In this study the robustness of the system is characterized through simulations of the system performance, and the outcome is compared with experimental results. It is shown that knowledge of the shape of the coupled power distribution is the single most important factor for high performance of the system. Further it is experimentally shown that the position extraction error can be improved down to the theoretical limit by employing a modulation function model well fitted to the real coupled power distribution. PMID- 23736348 TI - Experimental demonstration of a high-sensitivity humidity sensor based on an Agarose-coated transmission-type photonic crystal fiber interferometer. AB - We present a detailed study of a high-sensitivity relative humidity (RH) sensor based on Agarose-coated transmission type photonic crystal fiber interferometer for what is the first time to our knowledge. The sensor shows a wavelength shift of approximately 56 nm for a humidity change of 58% RH. The repeatability of the coating layer formation and the evolution of the coating layers on passing the device though Agarose solution multiple times are studied in detail by observing the spectral shift resulting from the effect on the effective index of the cladding mode. Also, a detailed study is reported of the sensor performance in terms of its sensitivity, repeatability, and long-term stability. The sensor shows a linear response for an RH change in the range of 40%-80% RH with a humidity resolution of 0.017% RH and a higher humidity resolution of 0.007% RH in the range 80%-95% RH. The measurement accuracy of the sensor in the RH range 40% 80% is +/-2% RH, and in the range 80%-95%, the accuracy is about +/-1% RH. The response time of the sensor is 86 ms, when RH jumps from 50% to 90%. The temperature dependence of the sensor is found to be ~0.27 nm/ degrees C, which is quite small compared to the RH sensitivity of the sensor. PMID- 23736350 TI - A new approach for quantitative analysis of L-phenylalanine using a novel semi sandwich immunometric assay. AB - Here, we describe a novel method for L-phenylalanine analysis using a sandwich type immunometric assay approach for use as a new method for amino acid analysis. To overcome difficulties of the preparation of high-affinity and selectivity monoclonal antibodies against L-phenylalanine and the inability to use sandwich type immunometric assays due to their small molecular weight, three procedures were examined. First, amino groups of L-phenylalanine were modified by "N-Fmoc-L cysteine" (FC) residues and the derivative (FC-Phe) was used as a hapten. Immunization of mice with bovine serum albumin/FC-Phe conjugate successfully yielded specific monoclonal anti-FC-Phe antibodies. Second, a new derivatization reagent, "biotin linker conjugate of FC-Phe N-succinimidyl ester" (FC(Biotin) NHS), was synthesized to convert L-phenylalanine to FC-(Biotin)-Phe as a hapten structure. The biotin moiety linked to the thiol group of cysteine formed a second binding site for streptavidin/horseradish peroxidase (HRP) conjugates for optical detection. Third, a new semi-sandwich-type immunometric assay was established using pre-derivatized L-phenylalanine, the monoclonal anti-FC-Phe antibody, and streptavidin/HRP conjugate (without second antibody). Using the new "semi-sandwich" immunometric assay system, a detection limit of 35 nM (60 amol per analysis) and a detection range of 0.1-20 MUM were attained using a standard L-phenylalanine solution. Rat plasma samples were analyzed to test reliability. Intra-day assay precision was within 6% of the coefficient of variation; inter day variation was 0.1%. The recovery rates were from 92.4 to 123.7%. This is the first report of the quantitative determination of L-phenylalanine using a reliable semi-sandwich immunometric assay approach and will be applicable to the quantitative determination of other amino acids. PMID- 23736349 TI - Comparison of ventilation and voice outcomes between unilateral laryngeal pacing and unilateral cordotomy for the treatment of bilateral vocal fold paralysis. AB - BACKGROUND/AIMS: Rehabilitation of the bilaterally paralyzed human larynx remains a complex clinical problem. Conventional treatment generally involves surgical enlargement of the compromised airway, but often with resultant dysphonia and risk of aspiration. In this retrospective study, we compared one such treatment, posterior cordotomy, with unilateral laryngeal pacing: reanimation of vocal fold opening by functional electrical stimulation of the posterior cricoarytenoid muscle. METHODS: Postoperative peak inspiratory flow (PIF) values and overall voice grade ratings were compared between the two surgical groups, and pre- and postoperative PIF were compared within the pacing group. RESULTS: There were 5 patients in the unilateral pacing group and 12 patients in the unilateral cordotomy group. Within the pacing group, postoperative PIF values were significantly improved from preoperative PIF values (p = 0.04) without a significant effect on voice (grade; p = 0.62). Within the pacing group, the mean postoperative PIF value was significantly higher than that in the cordotomy group (p = 0.05). Also, the mean postoperative overall voice grade values in the pacing group were significantly lower (better) than those of the cordotomy group (p = 0.03). CONCLUSION: Unilateral pacing appears to be an effective treatment superior to posterior cordotomy with respect to postoperative ventilation and voice outcome measures. PMID- 23736351 TI - Cost-effectiveness of hand-assisted retroperitoneoscopic versus standard laparoscopic donor nephrectomy: a randomized study. AB - BACKGROUND: Live kidney donation has a clear economical benefit over dialysis and deceased-donor transplantation. Compared with mini-incision open donor nephrectomy, laparoscopic donor nephrectomy (LDN) is considered cost-effective. However, little is known on the cost-effectiveness of hand-assisted retroperitoneoscopic donor nephrectomy (HARP). This study evaluated the cost effectiveness of HARP versus LDN. METHODS: Alongside a randomized controlled trial, the cost-effectiveness of HARP versus LDN was assessed. Eighty-six donors were included in the LDN group and 82 in the HARP group. All in-hospital costs were recorded. During follow-up, return-to-work and other societal costs were documented up to 1 year. The EuroQol-5D questionnaire was administered up to 1 year postoperatively to calculate quality-adjusted life years (QALYs). RESULTS: Mean total costs from a healthcare perspective were $8935 for HARP and $8650 for LDN (P = 0.25). Mean total costs from a societal perspective were $16,357 for HARP and $16,286 for LDN (P = 0.79). On average, donors completely resumed their daytime jobs on day 54 in the HARP group and on day 52 in the LDN group (P = 0.65). LDN resulted in a gain of 0.005 QALYs. CONCLUSIONS: Absolute costs of both procedures are very low and the differences in costs and QALYs between LDN and HARP are very small. Other arguments, such as donor safety and pain, should determine the choice between HARP and LDN. PMID- 23736352 TI - Lung transplantation after lung volume reduction surgery. AB - BACKGROUND: Lung volume reduction surgery (LVRS) as a bridge to lung transplantation was first advocated in 1995 and published studies have supported the concept but with limited data. The risk-benefit tradeoffs of the combined procedure have not been thoroughly examined, although substantial information regarding LVRS has emerged. METHODS: Of 177 patients who underwent lung transplantation for end-stage emphysema between 2002 and 2009 at our center, 25 had prior LVRS (22 bilateral and 3 unilateral). Lung transplantation was performed 22.9+/-15.9 months after LVRS. We compared in-hospital morbidity, functional capacity, and long-term outcomes of patients who underwent LVRS before lung transplantation with a matched cohort of patients without prior LVRS to assess the influence of LVRS on posttransplantation morbidity and mortality. RESULTS: The incidence of postoperative bleeding requiring reexploration and the incidence of renal dysfunction requiring dialysis were higher in patients with LVRS before lung transplantation. Posttransplantation peak forced expiratory volume in 1 s was worse in patients with LVRS before lung transplantation (56.7% vs. 78.8%; P<0.05). Five-year survival was not significantly different (59.7% in patients with LVRS before lung transplantation vs. 66.2% in patients with lung transplantation alone). In multivariate analysis, age more than 65 years, prolonged cardiopulmonary bypass time, and severe pulmonary hypertension were significant predictors for mortality (P<0.05). CONCLUSIONS: Although LVRS remains a viable option as a bridge to lung transplantation in appropriately selected patients, LVRS before lung transplantation can impart substantial morbidity and compromised functional capacity after lung transplantation. LVRS should not be easily considered as a bridge to transplantation for all lung transplant candidates. PMID- 23736353 TI - Urine but not serum soluble urokinase receptor (suPAR) may identify cases of recurrent FSGS in kidney transplant candidates. AB - BACKGROUND: Recently, serum soluble urokinase receptor (suPAR) has been proposed as a cause of two thirds of cases of focal segmental glomerulosclerosis (FSGS). It was noted to be uniquely elevated in cases of primary FSGS, with higher levels noted in cases that recurred after transplantation. It is also suggested as a possible target and marker of therapy. METHODS: We studied serum and urine suPAR from pretransplantation banked samples from 86 well-characterized kidney transplant recipients and 10 healthy controls to determine its prognostic utility. Causes of native kidney disease were primary FSGS, diabetic nephropathy, membranous nephropathy, immunoglobulin A nephropathy, and autosomal dominant polycystic kidney disease. suPAR was measured using a commercially available enzyme-linked immunosorbent assay kit. Urinary suPAR was indexed to creatinine. RESULTS: Both serum and urine suPAR correlated with proteinuria and albuminuria. Serum suPAR was found to be elevated in all transplant candidates with advanced renal disease compared with healthy controls and could not differentiate disease diagnosis. Urine suPAR was elevated in cases of recurrent FSGS compared with all other causes of end-stage renal disease. Recurrent FSGS cases had substantially higher proteinuria compared with all other cases. However, elevated urinary suPAR showed a trend in providing additional prognostic information beyond proteinuria in the small cohort of recurrent FSGS cases. CONCLUSION: In advanced renal disease, elevated serum suPAR is not unique to FSGS cases. Urinary suPAR appears to be higher in cases of FSGS destined for recurrence and merits further evaluation. PMID- 23736354 TI - Increased fibroblast growth factor 21 expression in high-fat diet-sensitive non human primates (Macaca mulatta). AB - OBJECTIVE: Fibroblast growth factor 21 (FGF21) is a metabolic regulator of glucose and lipid metabolism. The physiological role of FGF21 is not yet fully elucidated, however, administration of FGF21 lowers blood glucose in diabetic animals. Moreover, increased levels of FGF21 are found in obese and diabetic rodents and humans compared with lean/non-diabetic controls. METHODS: Adult male rhesus macaque monkeys were chronically maintained on a high-fat diet (HFD) or a standard diet (control, CTR). Plasma levels of FGF21, triglycerides and cholesterol were measured and body weight was record. Glucose-stimulated insulin secretion (GSIS) and glucose clearance was determined during an intravenous glucose tolerance test. Furthermore, expression of FGF21 and its receptors were determined in liver, pancreas, three white adipose tissues (WATs) and two skeletal muscles. RESULTS: A cohort of the high-fat fed monkeys responded to the HFD with increasing body weight, plasma lipids, total cholesterol, GSIS and decreased glucose tolerance. These monkeys were termed HFD sensitive. Another cohort of monkeys did not become obese and maintained normal insulin sensitivity. These animals were defined as HFD resistant. Plasma FGF21 levels were significantly increased in all HFD fed monkeys compared with the CTR group. The HFD-sensitive monkeys showed a significant increase in FGF21 mRNA expression in all examined tissues compared with CTR, whereas FGF21 expression in the HFD resistant group was only increased in the liver, pancreas and the retroperitoneal WAT. In the WAT, the co-receptor beta-klotho was downregulated in the HFD sensitive monkeys compared with the HFD-resistant group. CONCLUSION: This study demonstrates that HFD changes FGF21 and FGF21 receptor expression in a tissue specific manner in rhesus monkeys; differential regulation is moreover observed between HFD-sensitive and -resistant monkeys. Monkeys that maintain normal levels of the FGF21 co-receptor beta-klotho in the WAT on HFD were protected toward development of dyslipidemia and hyperglycemia. PMID- 23736355 TI - Short-term aerobic exercise training increases postprandial pancreatic polypeptide but not peptide YY concentrations in obese individuals. AB - OBJECTIVE: Short-term exercise training improves glycemic control, but the effect of short-term training on postprandial satiety peptide responses or perceived satiety remains unknown. We tested the hypothesis that short-term aerobic exercise training (15 days) would alter postprandial pancreatic and gut peptide (pancreatic polypeptide (PP) and peptide YY (PYY)) responses and perceived appetite and satiety in obese individuals. SUBJECTS: Thirteen healthy obese men and women (age: 42+/-2 years; body mass index: 30-45 kg m(-2)). MEASUREMENTS: Subjects were studied before and after 15 days of training (walking 1 h at 70-75% VO(2peak)). On the study day, subjects consumed 1500 kcal as six meals (250 kcal: 9 g protein, 40 g carbohydrate, 6 g fat), while blood samples and satiety measurements were taken at baseline and every 20 min for 12 h. Blood was analyzed for PP, PYY, glucose and insulin levels. Appetite and satiety was assessed with a visual analog scale throughout the day. RESULTS: Incremental area under the curve (iAUC) for PP increased significantly with training (pre: 2788+/-753; post: 3845+/-830 pg ml(-1).per min for 12 h; P<0.001), but there was no difference in the PP response to each meal. The initial PP response to the first meal increased (DeltaPP(min 20-0): pre 86+/-25; post 140+/-36 pg ml(-1); P<0.05) with training. PYY iAUC showed no significant changes with training but showed a significant main effect of time across meals, with the largest response being to the first meal (P<0.005). There were no changes in satiety, glucose or insulin levels with training. CONCLUSION: Short-term exercise training increases postprandial PP concentrations in obese individuals; however, PYY levels and glycemic control remain unaffected. Both PP and PYY show meal-induced increases at all meals, but PYY has a greater response at the first meal with reduced responses at subsequent meals. PMID- 23736356 TI - Parental smoking during pregnancy and risk of overweight and obesity in the daughter. AB - OBJECTIVE: Emerging evidence suggests that prenatal exposures may affect long term health outcomes. In utero exposure to smoking is associated with an increased risk of overweight and obesity in children and adolescents. However, few studies have examined how prenatal exposure to parental smoking influences the risk of obesity during adulthood and whether these associations are independent of childhood and adolescent adiposity. The aim of the current study was to investigate whether prenatal exposure to parental smoking influences body size during adulthood and whether any association may be mediated by childhood and adolescent body size. METHODS: We investigated the association between parental smoking during pregnancy and the risk of being overweight and obese during adulthood and at age 18 and adiposity during childhood among 35 370 participants in the Nurses' Health Study II. Data on smoking during pregnancy and socioeconomic variables were provided by the mothers, and anthropometric data and adult risk factors were reported by participants. RESULTS: After adjustment for socioeconomic and behavioral variables, maternal smoking during pregnancy was associated with adiposity at ages 5-10, 18 and during adulthood. For age 18 overweight, the odd ratios, ORs (95% confidence intervals, CIs) for 1-14, 15-24 and 25+cigarettes per day were 1.13 (1.18-1.50), 1.40 (1.20-1.64) and 1.15 (0.79 1.69), and for obesity were 1.41 (1.14-1.75), 1.69 (1.31-2.18) and 2.36 (1.44 3.86). The corresponding ORs (95% CIs) for obesity during adulthood were 1.26 (1.16-1.37), 1.46 (1.30-1.63) and 1.43 (1.10-1.86). Risk of adiposity was not increased among daughters whose mothers stopped smoking during the first trimester (OR (95% CI) for overweight (1.03 (95% CI 0.90-1.17)) and for obesity (1.12 (95% CI 0.97-1.30)). Women whose fathers smoked during pregnancy were also at an increased risk of being overweight and obese during adulthood with covariate-adjusted ORs (95% CIs) for obesity of 1.19 (1.11-1.29) for 1-14 cigarettes per day, 1.27 (1.18-1.37) for 15-24 cigarettes per day and 1.40 (1.27 1.54) for 25+ cigarettes per day compared with fathers who did not smoke (Ptrend<0.0001). Paternal smoking during pregnancy was also associated with an increased risk of obesity at age 18 among those whose fathers smoked 15 or more cigarettes per day but was not associated with childhood body size. CONCLUSIONS: Maternal smoking during pregnancy was associated in a dose-response manner with overweight and obesity in the daughter across adolescence and adult life. Smoking cessation during the first trimester appears to mitigate this excess risk.Paternal smoking was also associated with the risk of being overweight and obese of the adult daughter and this association persisted after adjustment for maternal smoking. PMID- 23736357 TI - The effect of the home environment on physical activity and dietary intake in preschool children. AB - BACKGROUND: The effects of the home environment on child health behaviors related to obesity are unclear. PURPOSE: To examine the role of the home physical activity (PA) and food environment on corresponding outcomes in young children, and assess maternal education/work status as a moderator. METHODS: Overweight or obese mothers reported on the home PA and food environment (accessibility, role modeling and parental policies). Outcomes included child moderate-vigorous PA (MVPA) and sedentary time derived from accelerometer data and two dietary factors ('junk' and healthy food intake scores) based on factor analysis of mother reported food intake. Linear regression models assessed the net effect (controlling for child demographics, study arm, supplemental time point, maternal education/work status, child body mass index and accelerometer wear time (for PA outcomes)) of the home environment on the outcomes and moderation by maternal education/work status. Data were collected in North Carolina from 2007 to 2011. RESULTS: Parental policies supporting PA increased MVPA time, and limiting access to unhealthy foods increased the healthy food intake score. Role modeling of healthy eating behaviors increased the healthy food intake score among children of mothers with no college education. Among children of mothers with no college education and not working, limiting access to unhealthy foods and role modeling reduced 'junk' food intake scores whereas parental policies supporting family meals increased 'junk' food intake scores. CONCLUSIONS: To promote MVPA, parental policies supporting child PA are warranted. Limited access to unhealthy foods and role modeling of healthy eating may improve the quality of the child's food intake. PMID- 23736359 TI - Risk of symptomatic gallstones and cholecystectomy after a very-low-calorie diet or low-calorie diet in a commercial weight loss program: 1-year matched cohort study. AB - BACKGROUND: Concern exists regarding gallstones as an adverse event of very-low calorie diets (VLCDs; <800 kcal per day). OBJECTIVE: To assess the risk of symptomatic gallstones requiring hospital care and/or cholecystectomy in a commercial weight loss program using VLCD or low-calorie diet (LCD). DESIGN: A 1 year matched cohort study of consecutively enrolled adults in a commercial weight loss program conducted at 28 Swedish centers between 2006 and 2009. A 3-month weight loss phase of VLCD (500 kcal per day) or LCD (1200-1500 kcal per day) was followed by a 9-month weight maintenance phase. Matching (1:1) was performed by age, sex, body mass index, waist circumference and gallstone history (n=3320:3320). Gallstone and cholecystectomy data were retrieved from the Swedish National Patient Register. RESULTS: One-year weight loss was greater in the VLCD than in the LCD group (-11.1 versus -8.1 kg; adjusted difference, -2.8 kg, 95% CI -3.1 to -2.4; P<0.001). During 6361 person-years, 48 and 14 gallstones requiring hospital care occurred in the VLCD and LCD groups, respectively, (152 versus 44/10 000 person-years; hazard ratio, 3.4, 95% CI 1.8-6.3; P<0.001; number-needed to-harm, 92, 95% CI 63-168; P<0.001). Of the 62 gallstone events, 38 (61%) resulted in cholecystectomy (29 versus 9; hazard ratio, 3.2, 95% CI 1.5-6.8; P=0.003; number-needed-to-harm, 151, 95% CI 94-377; P<0.001). Adjusting for 3 month weight loss attenuated the hazard ratios, but the risk remained higher with VLCD than LCD for gallstones (2.5, 95% CI 1.3-5.1; P=0.009) and became borderline for cholecystectomy (2.2, 95% CI 0.9-5.2; P=0.08). CONCLUSION: The risk of symptomatic gallstones requiring hospitalization or cholecystectomy, albeit low, was 3-fold greater with VLCD than LCD during the 1-year commercial weight loss program. PMID- 23736358 TI - Identification of optimal reference genes for RT-qPCR in the rat hypothalamus and intestine for the study of obesity. AB - BACKGROUND: Obesity has a complicated metabolic pathology, and defining the underlying mechanisms of obesity requires integrative studies with molecular end points. Real-time quantitative PCR (RT-qPCR) is a powerful tool that has been widely utilized. However, the importance of using carefully validated reference genes in RT-qPCR seems to have been overlooked in obesity-related research. The objective of this study was to select a set of reference genes with stable expressions to be used for RT-qPCR normalization in rats under fasted vs re-fed and chow vs high-fat diet (HFD) conditions. DESIGN: Male long-Evans rats were treated under four conditions: chow/fasted, chow/re-fed, HFD/fasted and HFD/re fed. Expression stabilities of 13 candidate reference genes were evaluated in the rat hypothalamus, duodenum, jejunum and ileum using the ReFinder software program. The optimal number of reference genes needed for RT-qPCR analyses was determined using geNorm. RESULTS: Using geNorm analysis, we found that it was sufficient to use the two most stably expressed genes as references in RT-qPCR analyses for each tissue under specific experimental conditions. B2M and RPLP0 in the hypothalamus, RPS18 and HMBS in the duodenum, RPLP2 and RPLP0 in the jejunum and RPS18 and YWHAZ in the ileum were the most suitable pairs for a normalization study when the four aforementioned experimental conditions were considered. CONCLUSIONS: Our study demonstrates that gene expression levels of reference genes commonly used in obesity-related studies, such as ACTB or RPS18, are altered by changes in acute or chronic energy status. These findings underline the importance of using reference genes that are stable in expression across experimental conditions when studying the rat hypothalamus and intestine, because these tissues have an integral role in the regulation of energy homeostasis. It is our hope that this study will raise awareness among obesity researchers on the essential need for reference gene validation in gene expression studies. PMID- 23736360 TI - Timing of the introduction of complementary feeding and risk of childhood obesity: a systematic review. AB - The World Health Organisation recommends exclusive breastfeeding until 6 months of age and continued breastfeeding until 2 years of age or beyond. Appropriate complementary foods should be introduced in a timely fashion, beginning when the infant is 6 months old. In developing countries, early or inappropriate complementary feeding may lead to malnutrition and poor growth, but in countries such as the United Kingdom and United States of America, where obesity is a greater public health concern than malnutrition, the relationship to growth is unclear. We conducted a systematic review of the literature that investigated the relationship between the timing of the introduction of complementary feeding and overweight or obesity during childhood. Electronic databases were searched from inception until 30 September 2012 using specified keywords. Following the application of strict inclusion/exclusion criteria, 23 studies were identified and reviewed by two independent reviewers. Data were extracted and aspects of quality were assessed using an adapted Newcastle-Ottawa scale. Twenty-one of the studies considered the relationship between the time at which complementary foods were introduced and childhood body mass index (BMI), of which five found that introducing complementary foods at <3 months (two studies), 4 months (2 studies) or 20 weeks (one study) was associated with a higher BMI in childhood. Seven of the studies considered the association between complementary feeding and body composition but only one study reported an increase in the percentage of body fat among children given complementary foods before 15 weeks of age. We conclude that there is no clear association between the timing of the introduction of complementary foods and childhood overweight or obesity, but some evidence suggests that very early introduction (at or before 4 months), rather than at 4-6 months or >6 months, may increase the risk of childhood overweight. PMID- 23736361 TI - Vitamin D deficiency in childhood obesity is associated with high levels of circulating inflammatory mediators, and low insulin sensitivity. AB - HYPOTHESIS: Childhood obesity is accompanied by low-grade systemic inflammation, which contributes to the development of insulin resistance and cardiovascular complications later in life. As vitamin D exhibits profound immunomodulatory functions and vitamin D deficiency is highly prevalent in childhood obesity, we hypothesized that vitamin D deficiency in childhood obesity coincides with enhanced systemic inflammation and reduced insulin sensitivity. METHODS: In a cross-sectional study of 64 obese and 32 healthy children aged 6-16 years, comprehensive profiling of 32 circulating inflammatory mediators was performed, together with assessment of 25-hydroxyvitamin D (25(OH)D) levels and measures for insulin sensitivity. RESULTS: Severe vitamin D insufficiency, which is further referred to as vitamin D deficiency, was defined as a 25(OH)D level <=37.5 nmol l(-1), and was highly prevalent in obese (56%) versus healthy control children (16%). Throughout the study, 25(OH)D-deficient children were compared with the other children, including 25(OH)D insufficient (37.5-50 nmol l(-1)) and 25(OH)D sufficient children (>=50 nmol l(-1)). First, 25(OH)D-deficient obese children showed a lower insulin sensitivity than other obese children, as measured by a lower quantitative insulin sensitivity check index. Second, the association between 25(OH)D deficiency and insulin resistance in childhood obesity was confirmed with multiple regression analysis. Third, 25(OH)D-deficient obese children showed higher levels of the inflammatory mediators cathepsin S, chemerin and soluble vascular adhesion molecule (sVCAM), compared with the other obese children. Finally, hierarchical cluster analysis revealed an over-representation of 25(OH)D deficiency in obese children expressing inflammatory mediator clusters with high levels of cathepsin S, sVCAM and chemerin. CONCLUSION: 25(OH)D deficiency in childhood obesity was associated with enhanced systemic inflammation and reduced insulin sensitivity. The high cathepsin S and sVCAM levels may reflect activation of a pro-inflammatory, pro-diabetic and atherogenic pathway, which could be inhibited by vitamin D supplementation. PMID- 23736362 TI - Waist circumference to assess reversal of insulin resistance following weight reduction after bariatric surgery: cohort and cross-sectional studies. AB - OBJECTIVE: To validate the use of waist circumference to assess reversal of insulin resistance after weight loss induced by bariatric surgery. DESIGN: In cross-sectional studies, threshold values for insulin resistance were determined with homeostasis model assessment of insulin resistance (HOMA-IR) (algorithm based on fasting plasma glucose and insulin) in 1018 lean subjects and by hyperinsulinemic euglycemic clamp (clamp) in 26 lean women. In a cohort study on 211 patients scheduled for bariatric surgery, HOMA-IR and waist circumference were measured before and 1.5-3 years after weight reduction. In a subgroup of 53 women, insulin sensitivity was also measured using clamp. RESULTS: The threshold for insulin resistance (90th percentile) was 2.21 (mg dl(-1) fasting glucose * mU l(-1) fasting insulin divided by 405) for HOMA-IR and 6.118 (mg glucose per kg body weight per minute) for clamp. Two methods to assess reversal of insulin resistance by measuring waist circumference were used. A single cutoff value to <100 cm for waist circumference was associated with reversal of insulin resistance with an odds ratio (OR) of 49; 95% confidence interval (CI)=7-373 and P=0.0002. Also, a diagram based on initial and weight loss-induced changes in waist circumference in patients turning insulin sensitive predicted reversal of insulin resistance following bariatric surgery with a very high OR (32; 95% CI=4 245; P=0.0008). Results with the clamp cohort were similar as with HOMA-IR analyses. CONCLUSIONS: Reversal of insulin resistance could either be assessed by a diagram based on initial waist circumference and reduction of waist circumference, or by using 100 cm as a single cutoff for waist circumference after weight reduction induced by bariatric surgery. PMID- 23736363 TI - Addiction potential of phentermine prescribed during long-term treatment of obesity. AB - OBJECTIVE: To investigate if phentermine treatment induces phentermine abuse, psychological dependence (addiction) or phentermine drug craving in overweight, obese and weight loss maintenance patients. To investigate whether amphetamine like withdrawal occurs after abrupt cessation of long-term phentermine treatment. DESIGN: Clinical intervention trial with interruption of phentermine treatment in long-term patients. SUBJECTS: 269 obese, overweight or formerly obese subjects (age: 20-88 years, BMI: 21-74 kg m(-2)) treated with phentermine long-term (LTP, N=117), 1.1-21.1 years, or short-term (ATP, N=152), 4-22 days, with phentermine doses of 18.75-112.5 (LTP) and 15-93.75 (ATP) mg per day. MEASUREMENTS: Module K of the Mini International Neuropsychiatric Interview modified for phentermine (MINI-SUD), Severity of Dependence Scale (SDS), 45-item Cocaine Craving Questionnaire-NOW (CCQ-NOW) modified for phentermine (PCQ-NOW), and Amphetamine Withdrawal Questionnaire (AWQ) modified for phentermine (PWQ). RESULTS: MINI-SUD interviews were negative for phentermine abuse or psychological dependence in all LTP patients. SDS examination scores were low for all LTP and ATP patients, indicating they were not psychologically dependent upon phentermine. PCQ-NOW scores were low for all LTP and ATP patients, indicating neither short-term nor long-term phentermine treatment had induced phentermine craving. Other than an increase in hunger or eating, amphetamine-like withdrawal symptoms did not occur upon abrupt phentermine cessation as measured by sequential PWQ scores. CONCLUSIONS: Phentermine abuse or psychological dependence (addiction) does not occur in patients treated with phentermine for obesity. Phentermine treatment does not induce phentermine drug craving, a hallmark sign of addiction. Amphetamine-like withdrawal does not occur upon abrupt treatment cessation even at doses much higher than commonly recommended and after treatment durations of up to 21 years. PMID- 23736364 TI - DNA hypomethylation of inflammation-associated genes in adipose tissue of female mice after multigenerational high fat diet feeding. AB - OBJECTIVE: Maternal obesity significantly increases the susceptibility of offspring to develop obesity and chronic diseases in adulthood. The offspring of obese mothers are shown to prefer high fat diet (HFD) due to their altered neural circuitry, creating a 'feed-forward cycle' across generations. We hypothesized that the 'feed-forward cycle' caused by multigenerational HFD feeding would have exacerbated effects in adipose tissue of the offspring. METHODS: Three generations (F0, F1 and F2) of HFD (60% Kcal fat)-fed and corresponding normal chow (NC)-fed C57BL/6 mice were generated. Body weight (BW) and food intake were monitored weekly. Parametrial adipose tissue (pAT) weight and endocrine parameters were measured in 9-month-old female offspring. Gene expression microarray, quantitative RT-PCR and bisulfite sequencing were performed using pAT. RESULTS: BW and pAT weight increased in female mice across generations under continuous HFD stress, with the most severe phenotype found in the F2 generation. Genes involved in inflammatory response showed increased expression across generations in the pAT, accompanied by increased macrophage infiltration. The promoters of Toll-like receptor 1 (Tlr1), Tlr2 and linker for activation of T cells (Lat) were hypomethylated in the HF groups compared with the NC group, with additional hypomethylation on some specific CpG sites in the F2 generation. CONCLUSIONS: A feed-forward cycle exists in female mice after continuous HFD stress as demonstrated by increased adiposity and progressive inflammation in adipose tissue across generations. DNA hypomethylation over generations lead to epigenetically altered expression of Tlr1, Tlr2 and Lat, which may contribute to the inflammation in adipose tissue. Our study provides a potential mechanism for enhanced inflammation in adipose tissue under multigenerational HFD-fed stress. PMID- 23736366 TI - Glucose-dependent insulinotropic polypeptide has impaired effect on abdominal, subcutaneous adipose tissue metabolism in obese subjects. AB - OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) appears to have a role in lipid metabolism. Recently, we showed that GIP in combination with hyperinsulinemia and hyperglycemia increases triglyceride uptake in abdominal, subcutaneous adipose tissue in lean humans. It has been suggested that increased GIP secretion in obesity will promote lipid deposition in adipose tissue. In light of the current attempts to employ GIP antagonists in the treatment and prevention of human obesity, the present experiments were performed in order to elucidate whether the adipose tissue lipid metabolism would be enhanced or blunted during a GIP, hyperinsulinemic and hyperglycemic (HI-HG) clamp in obese subjects with either normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). DESIGN: Sixteen obese (BMI>30 kg m(-2)) subjects were divided into two groups, based on their plasma glucose response to an oral glucose challenge: (i) NGT and (ii) IGT. Abdominal, subcutaneous adipose tissue lipid metabolism was studied by conducting measurements of arteriovenous concentrations of metabolites and regional adipose tissue blood flow (ATBF) during GIP (1.5 pmol kg(-1) min( 1)) in combination with a HI-HG clamp. RESULTS: In both groups, ATBF responses were significantly lower than what we have found previously in healthy, lean subjects (P<0.0001). The flow response was significantly lower in the IGT group than in the NGT group (P=0.03). It was not possible to show any increase in the lipid deposition in adipose tissue under the applied experimental conditions and likewise the circulating triglyceride (TAG) concentrations remained constant. CONCLUSION: The applied GIP, HI-HG clamp did not induce any changes in TAG uptake in adipose tissue in obese subjects. This may be due to a blunted increase in ATBF. These experiments therefore suggest that GIP does not have a major role in postprandial lipid metabolism in obese subjects. PMID- 23736365 TI - Food environment and socioeconomic status influence obesity rates in Seattle and in Paris. AB - OBJECTIVE: To compare the associations between food environment at the individual level, socioeconomic status (SES) and obesity rates in two cities: Seattle and Paris. METHODS: Analyses of the SOS (Seattle Obesity Study) were based on a representative sample of 1340 adults in metropolitan Seattle and King County. The RECORD (Residential Environment and Coronary Heart Disease) cohort analyses were based on 7131 adults in central Paris and suburbs. Data on sociodemographics, health and weight were obtained from a telephone survey (SOS) and from in-person interviews (RECORD). Both studies collected data on and geocoded home addresses and food shopping locations. Both studies calculated GIS (Geographic Information System) network distances between home and the supermarket that study respondents listed as their primary food source. Supermarkets were further stratified into three categories by price. Modified Poisson regression models were used to test the associations among food environment variables, SES and obesity. RESULTS: Physical distance to supermarkets was unrelated to obesity risk. By contrast, lower education and incomes, lower surrounding property values and shopping at lower-cost stores were consistently associated with higher obesity risk. CONCLUSION: Lower SES was linked to higher obesity risk in both Paris and Seattle, despite differences in urban form, the food environments and in the respective systems of health care. Cross-country comparisons can provide new insights into the social determinants of weight and health. PMID- 23736367 TI - Predictors of body composition and body energy changes in response to chronic overfeeding. AB - OBJECTIVE: We have previously shown that 24 young lean men (12 pairs of identical twins) subjected to a standardized 353 MJ (84 000 kcal) overfeeding protocol over 100 days exhibited individual differences in body weight and composition gains. The mean (+s.d.) gains in fat mass (FM) and fat-free mass (FFM) were 5.4+1.9 kg and 2.7+1.5 kg for a total body energy (BE) gain of 221+75 MJ, representing 63% of the energy surplus consumed. We report here on the most important baseline correlates of these overfeeding-induced changes with the aim of identifying biomarkers of the response. RESULTS: Baseline maximal oxygen uptake per kg body mass was negatively correlated with gains in weight, FM and BE (all P<0.05). Enzyme activities indicative of skeletal muscle oxidative potential correlated with gains in FM and BE (all P<0.05). Baseline thyroid-stimulating hormone levels in response to thyrotropin-releasing hormone stimulation correlated positively with changes in FM-to-FFM ratio (P<0.05). Plasma concentrations of androstenediol sulfate, dehydroepiandrosterone and 17-hydroxy pregnenolone were negatively correlated with gains in FM and BE (0.01=3 servings per day of total dairy had 0.10 kg (+/-0.04) smaller annualized increment of weight (P(trend)=0.04) than those consuming <1 serving per day. Higher total dairy intake was also marginally associated with less WC gain (P(trend)=0.05). Similarly, participants who consumed >=3 servings per week of yogurt had a 0.10 kg (+/-0.04) and 0.13 cm (+/-0.05) smaller annualized increment of weight (P(trend)=0.03) and WC (P(trend)=0.008) than those consuming <1 serving per week, respectively. Skim/low-fat milk, cheese, total high-fat or total low-fat dairy intake were not associated with long-term change in weight or WC. CONCLUSION: Further longitudinal and interventional studies are warranted to confirm the beneficial role of increasing total dairy and yogurt intake, as part of a healthy and calorie-balanced dietary pattern, in the long-term prevention of gain in weight and WC. PMID- 23736372 TI - Improvements in hippocampal-dependent memory and microglial infiltration with calorie restriction and gastric bypass surgery, but not with vertical sleeve gastrectomy. AB - BACKGROUND: Much recent evidence suggest that obesity and related comorbidities contribute to cognitive decline, including the development of non age-related dementia and Alzheimer's disease. Obesity is a serious threat to public health, and few treatments offer proven long-term weight loss. In fact, bariatric surgery remains the most effective long-term therapy to reduce weight and alleviate other aspects of the metabolic syndrome (MetS). Unlike the demonstrated benefits of caloric restriction to prevent weight gain, few if any studies have compared various means of weight loss on central nervous system function and hippocampal dependent cognitive processes. DESIGN AND RESULTS: Our studies comprise the first direct comparisons of caloric restriction to two bariatric surgeries (Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG)) on cognitive function. Weight loss following caloric restriction, RYGB and VSG was associated with generalized improvements in metabolic health and hippocampal-dependent learning, as measured in the radial arm maze and spontaneous alternation tests. However, VSG-treated rats exhibited deficits on spatial learning tasks in the Morris water maze. In addition, whereas VSG animals had elevated hippocampal inflammation, comparable to that of obese controls, RYGB and calorie-restricted (pair-fed, PF) controls exhibited an amelioration of inflammation, as measured by the microglial protein ionized calcium binding adaptor molecule 1 (IBA1). We also assessed whether GHR (ghrelin) replacement would attenuate hippocampal inflammation in VSG, as post-surgical GHR levels are significantly reduced in VSG relative to RYGB and PF rats. However, GHR treatment did not attenuate the hippocampal inflammation. CONCLUSION: Although VSG was comparably effective at reducing body weight and improving glucose regulation as RYGB, VSG did not appear to confer an equal benefit on cognitive function and markers of inflammation. PMID- 23736373 TI - Functional thermogenic beige adipogenesis is inducible in human neck fat. AB - BACKGROUND: Recent studies suggest human neck brown adipose tissue (BAT) to consist of 'brown adipocyte (BA)-like' or beige adipocytes. However, little is known about their thermogenic function. Within the beige adipocyte transcriptome, fibroblast growth factor-21 (FGF21) is a gene whose protein product acts as an adipokine, regulating cold-induced thermogenesis in animals. Here, we explored (i) the adipogenic potential, thermogenic function and FGF21 secretory capacity of beige adipocytes derived from human neck fat and (ii) the role of FGF21 in modulating adipose bioenergetics. METHODS: Progenitors isolated from human cervical fat were differentiated into adipocytes with either a BA-like or white adipocyte (WA) phenotype. FGF21 secretion was measured by enzyme-linked immuosorbent assay. Real-time PCR/western blotting was used to determine cellular mRNA/protein levels. Extracellular flux bioanalyzer was used to quantify adipocyte oxygen consumption and fatty acid oxidation. Adipocyte heat production was measured by infrared thermography. RESULTS: Under hormonal manipulation, primary human neck pre-adipocytes differentiated into adipocytes with either BA like or WA phenotypes, on gene/protein and functional levels. BA-like cells expressed beige but not classic BA markers. During BA differentiation, FGF21 gene expression and secretion were increased, and were augmented following norepinephrine exposure (a cold mimic in vitro). Differentiated WA expressed beta klotho, a critical co-factor mediating FGF21 action. Treatment of WA with FGF21 induced UCP1 expression and increased oxygen consumption, respiratory uncoupling, norepinephrine-mediated thermogenesis, fatty acid oxidation and heat production, thus recapitulating the association between cold-induced FGF21 secretion and cold induced thermogenesis in vivo. CONCLUSION: Beige adipocytes are thermogenic in humans. FGF21 is a beige adipokine capable of promoting a brown fat-like thermogenic program in WAs. SIGNIFICANCE: This study provides first evidence of inducible functional thermogenic beige adipogenesis in human neck fat. FGF21 holds promise as a cold-induced beige adipokine with metabolic benefits of therapeutic relevance through browning of white adipose tissue. PMID- 23736374 TI - Neighborhood built and social environment characteristics: a multilevel analysis of associations with obesity among children and their parents. AB - OBJECTIVE: To examine associations between characteristics of neighborhood built and social environments and likelihood of obesity among family triads living at the same residential address and to explore whether these associations differ between family members. METHODS: Data were from the baseline wave of QUALITY (Quebec Adipose and Lifestyle Investigation in Youth), an ongoing study on the natural history of obesity in 630 Quebec youth aged 8-10 years with a parental history of obesity. Weight and height were measured in children and both biological parents and body mass index was computed. Residential neighborhood environments were characterized using a Geographic Information System and in person neighborhood audits. Principal components analysis allowed for identification of overarching neighborhood indicators including poverty, prestige, level of urbanicity, traffic, physical disorder and deterioration, and pedestrian friendliness. Multilevel logistic regressions were used to examine associations between neighborhood indicators and obesity within multiple family members residing at the same address while controlling for household-level sociodemographic variables. RESULTS: A total of 417 families were included in the analysis. Families residing in lower and average prestige neighborhoods were more likely to be obese (odds ratio (OR)=1.69, 95% confidence interval (CI): 1.16, 2.44, and OR=1.51, 95% CI: 1.09, 2.11, respectively) than those residing in higher prestige neighborhoods. Residing in lower traffic neighborhoods was associated with less obesity (OR=0.69, 95% CI: 0.50, 0.95). Other neighborhood indicators may have differential effects across family members. For example, as neighborhood poverty increased, obesity was more likely among children but less likely among fathers and no different for mothers. CONCLUSION: Findings indicate that some shared neighborhood exposures are associated with greater risk of obesity for entire families whereas other exposures may heighten obesity risk in some but not all family members. Patterns may reflect differences in the way in which family members use residential neighborhood environments. PMID- 23736375 TI - Multi-sequence whole-brain intracranial vessel wall imaging at 7.0 tesla. AB - OBJECTIVES: Intracranial vessel wall magnetic resonance imaging (MRI) may improve the diagnosis of vessel wall abnormalities. Current methods are hampered by limited coverage and few contrast weightings. We present a multi-sequence protocol with whole-brain coverage for vessel wall imaging on 7.0-T MRI. METHODS: A modified magnetisation-preparation inversion recovery turbo-spin-echo (MPIR TSE) sequence was used to obtain proton density (PD)-, T1-, and T2-weighting with 190-mm whole-brain coverage. Three observers independently scored the visibility of arterial vessel walls in five healthy volunteers, and compared the conspicuity and image contrast of all sequences. Clinical applicability was demonstrated in 17 patients with cerebrovascular disease. RESULTS: Conspicuity was good for all acquisitions, with best scores for the original limited-coverage sequence, followed by whole-brain coverage T2-, PD- and T1-weighted sequences, respectively. Mean vessel wall/background MR signal intensity ratios for all whole-brain sequences were similar, with higher scores for the limited-coverage MPIR-TSE sequence. Signal intensity ratios were highest in patients, for the whole-brain T1-weighted sequence. CONCLUSIONS: The whole-brain multi-sequence vessel wall protocol can assess intracranial arterial vessel walls with full brain coverage, for different image contrast weightings. These sequences could eventually characterise intracranial vessel wall abnormalities similar to current techniques for assessing carotid artery plaques. KEY POINTS: - Intracranial vessel wall imaging using MRI improves diagnosis of cerebrovascular diseases. - Conventional 7-T MRI sequences cannot image the whole cerebral arterial tree. - New whole-brain 7-T MRI sequences compare favourably with smaller-coverage sequences. - These whole-brain sequences can demonstrate the entire cerebral arterial tree. - These sequences should help in the diagnosis of vessel wall abnormalities. PMID- 23736377 TI - Abstracts of the 48th Congress of the European Society for Surgical Research. May 29-June 1, 2013. Istanbul, Turkey. PMID- 23736376 TI - Does obesity preclude lumbar puncture with a standard spinal needle? The use of computed tomography to measure the skin to lumbar subarachnoid space distance in the general hospital population. AB - OBJECTIVES: Failed lumbar puncture (LP) is a common indication for referral for radiologically guided LP. This study aims to evaluate what percentage of the hospital population would fail an LP using a standard 9-cm needle because of obesity and a skin to subarachnoid space distance greater than 9 cm. METHODS: Images of 402 consecutive patients undergoing computed tomography of the abdomen and pelvis were reviewed. Skin to subarachnoid space distance was calculated using sagittal images. A survey was conducted among junior hospital doctors to assess their experience of performing lumbar puncture in obese patients. RESULTS: Four hundred patients were included. Fifty-five patients (13.8 %) had a skin to subarachnoid space distance greater than 9 cm. Intra-abdominal fat, subcutaneous fat and abdominal girth correlated with distance between the skin and subarachnoid space. Among junior doctors, 68.3 % (n = 41) reported LP failure on an obese patient; 78.4 % (n = 47) were unaware of the existence of a longer needle and 13.3 % (n = 8) had experience using a longer needle. CONCLUSIONS: A significant proportion of the hospital population will fail LP with a standard length spinal needle. Selecting a longer needle may be sufficient to successfully complete LP in obese patients. KEY POINTS: * Lumbar puncture failure commonly leads to referral for an image-guided procedure * Standard lumbar puncture may fail in 13.8 % of patients due to obesity * 78.4 % of trainee doctors are unaware of the existence of longer spinal-needles * Using longer spinal needles may allow successful LP in obese patients. PMID- 23736378 TI - Long-term treatment effects of the FR-2 appliance: a prospective evalution 7 years post-treatment. AB - AIM: To examine the long-term effects induced by treatment with the function regulator (FR-2) appliance 7 years post-treatment compared with untreated class II subjects. SUBJECTS AND METHODS: The FR-2 sample was collected prospectively and comprised 17 subjects (10 boys and 7 girls, mean age 10.8 years) who were treated with the FR-2 appliance for 1.7 years and re-evaluated 7.1 years after treatment. The step-by-step mandibular advancement was performed gradually (increments up to 3-4 mm), until a 'super class I' molar relationship was obtained. The control group consisted of 17 class II subjects (9 boys and 8 girls, mean age 11.3 years) with class II malocclusion, excessive overjet, and class II molar relationship, matched to the treated group as to ages at all times, gender distribution, and stages of skeletal maturity (evaluated by the cervical vertebral maturation method). The lateral cephalograms were analysed at T1 (initial), T2 (final), and T3 (7.1 years post-treatment). The compatibility between the groups and the comparisons of their changes at T1-T2, T2-T3, and T1 T3 intervals were examined by independent sample t-tests (P < 0.05). RESULTS: FR 2 treatment provided a significant improvement in the maxillomandibular relationship due to an increase in mandibular length compared with controls, which remained stable over time. Also overjet, overbite, and molar relationship corrections demonstrated stability. Among dentoalveolar changes, only the increased mesial movement of the mandibular molars in the FR-2 group demonstrated stability. CONCLUSIONS: Correction of class II malocclusion remained stable 7 years after FR-2 treatment mainly due to the stability of the skeletal changes. PMID- 23736379 TI - ICAM-2 and lipid rafts disappear from the basal plasma membrane of uterine epithelial cells during early pregnancy in rats. AB - Adhesion molecules are redistributed in rat uterine epithelial cells (UECs) during early pregnancy for endometrial receptivity and implantation. Intercellular adhesion molecule-2 (ICAM-2) is located as an oligomer on the basal plasma membrane of non-receptive UECs on day 1 of pregnancy and colocalizes with the lipid raft marker flotillin-2. At the time of implantation in rats and in ovariectomized rats primed with progesterone, ICAM-2 disappears from the basal plasma membrane and lipid rafts redistribute to the apical membrane. The loss of ICAM-2 might render UECs less adherent to the underlying basal lamina and more prone to apoptosis. Flotillin-2 in the apical plasma membrane at the time of implantation might provide an anchoring point for several adhesion molecules that are known to localize to this region at this time. We suggest that flotillin-2 is involved with adhesion between UECs and the implanting blastocyst, whereas ICAM-2 is associated with the ability for UECs to be removed at the time of implantation. PMID- 23736380 TI - Fine structure and primary sensory projections of sensilla located in the labial palp pit organ of Helicoverpa armigera (Insecta). AB - The fine structure and primary sensory projections of sensilla located in the labial-palp pit organ of the cotton bollworm Helicoverpa armigera (Insecta, Lepidoptera) are investigated by scanning electron and transmission electron microscopy combined with confocal laser scanning microscopy. The pit organ located on the third segment of the labial palp is about 300 MUm deep with a 60 MUm-wide opening, each structure containing about 1200 sensilla. Two sensillum types have been found, namely hair-shaped and club-shaped sensilla, located on the upper and lower half of the pit, respectively. Most sensilla possess a single dendrite. The dendrite housed by the club-shaped sensilla is often split into several branches or becomes lamellated in the outer segment. As reported previously, the sensory axons of the sensilla in the labial pit organ form a bundle entering the ipsilateral side of the subesophageal ganglion via the labial palp nerve and project to three distinct areas: the labial pit organ glomerulus in each antennal lobe, the subesophageal ganglion and the ventral nerve cord. In the antennal lobe, the labial pit organ glomerulus is innervated by sensory axons from the labial pit organ only; no antennal afferents target this unit. One neuron has been found extending fine processes into the subesophageal ganglion and innervating the labial palp via one branch passing at the base of the labial palp nerve. The soma of this assumed motor neuron is located in the ipsilateral cell body layer of the subesophageal ganglion. Our results provide valuable knowledge concerning the neural circuit encoding information about carbon dioxide and should stimulate further investigations directed at controlling pest species such as H. armigera. PMID- 23736381 TI - Pluripotent stem cell transcription factors during human odontogenesis. AB - Stem cells are capable of generating various cell lines and can be obtained from adult or embryonic tissues for clinical therapies. Stem cells from deciduous dental pulp are among those that are easily obtainable from adult tissues and have been widely studied because of their ability to differentiate into a variety of cell lines in the presence of various chemical mediators. We have analyze the expression of several proteins related to the differentiation and proliferative potential of cell populations that compose the tooth germ of human fetuses. We evaluate 20 human fetuses of both genders. After being paraffin-embedded, cap and bell stages of tooth germ development were subjected to immunohistochemistry for the following markers: Oct-4, Nanog, Stat-3 and Sox-2. The studied antibodies showed nuclear or cytoplasmic immunnostaining within various anatomical structures and with various degrees of expression, indicating the action of these proteins during tooth development. We conclude that the interrelationship between these transcription factors is complex and associated with self-renewal and cell differentiation. Our results suggest that the expression of Oct-4, Nanog, Sox-2 and Stat-3 are related to differentiation in ameloblasts and odontoblasts. PMID- 23736383 TI - Triterpenoids. AB - This review covers the isolation and structure determination of triterpenoids including squalene derivatives, lanostanes, holostanes, cycloartanes, cucurbitanes, dammaranes, euphanes, tirucallanes, tetranortriterpenoids, quassinoids, lupanes, oleananes, friedelanes, ursanes, hopanes, onoceranes and saponins; 308 references are cited. PMID- 23736382 TI - Distribution of mRNA transcripts and translation activity in skeletal myofibers. AB - We examine the distribution of gene products in skeletal myofibers, which are highly differentiated multinucleated cells exhibiting a specific cellular architecture. In situ hybridization studies of adult rat myofibers with a single nucleus infected with influenza virus suggested that the viral mRNA products were distributed beneath the sarcolemma around the nucleus of origin. In situ hybridization studies with a poly-T oligonucleotide probe to detect endogenous mRNAs indicated their concentration around the nuclei and distribution beneath the sarcolemma in a cross-striated fashion at the A-I junctions (costamers). Labeling with bromouridine resulted in a similar distribution pattern. The ribosomal distribution pattern indicated concentration around the myonuclei but an intracellular component was also seen. Localization of the translating ribosomes by puromycylation revealed prominent spots perinuclearly and in the core regions of the myofibers. These spots flanked Golgi elements. Our results thus suggest that the total mRNA pool is heavily concentrated within the perinuclear and subsarcolemmal regions. However, the ribosomes and the translational activity did not follow this distribution pattern, so the mRNA transcripts were not restricted to a region beneath the sarcolemma. Furthermore, experiments utilizing green fluorescent protein showed the rapid movement of proteins within the endomembrane system, which thus facilitated proteins to reach their site of function irrespective of the site of synthesis. PMID- 23736384 TI - Empyema due to severe Pasteurella multocida treated with quinolone: a case report. AB - Pasteurella multocida (PM) is gram-negative coccobacillus that is commonly acquired through a cat scratch or bite. The standard antibiotic of choice for treating PM is penicillin. We present a case of PM empyema in a penicillin allergic 56-year-old female who has a history of contact with domestic cats and is known to have chronic obstructive pulmonary disease and a chronic history of smoking. The patient was treated successfully with Levofloxacin as alternative treatment to penicillin. PMID- 23736385 TI - Strong enhancement of light absorption and highly directive thermal emission in graphene. AB - Graphene is a two-dimensional material with exotic electronic, optical and thermal properties. The optical absorption in monolayer graphene is limited by the fine structure constant alpha. Here we demonstrated the strong enhancement of light absorption and thermal radiation in homogeneous graphene. Numerical simulations show that the light absorbance can be controlled from near zero to 100% by tuning the Fermi energy. Moreover, a set of periodically located absorption peaks is observed at near grazing incidence. Based on this unique property, highly directive comb-like thermal radiation at near-infrared frequencies is demonstrated. PMID- 23736386 TI - Rapid fabrication of surface micro/nano structures with enhanced broadband absorption on Cu by picosecond laser. AB - A surface micro/nano structuring technique was demonstrated by utilizing a picosecond laser beam to rapidly modify the optical property of copper surfaces with a scanning speed up to tens of millimeters per second. Three kinds of surface micro/nanostructures corresponding to three levels of reflectance were produced which are obviously different from those induced by a femtosecond or nanosecond laser. Specifically, a porous coral-like structure results in over 97% absorptivity in the visible spectral region and over 90% absorptivity in average in the UV, visible, and NIR regions (250 - 2500 nm). Potential applications may include solar energy absorbers, thermal radiation sources, and radiative heat transfer devices. PMID- 23736387 TI - Phase errors in high line density CGH used for aspheric testing: beyond scalar approximation. AB - One common way to measure asphere and freeform surfaces is the interferometric Null test, where a computer generated hologram (CGH) is placed in the object path of the interferometer. If undetected phase errors are present in the CGH, the measurement will show systematic errors. Therefore the absolute phase of this element has to be known. This phase is often calculated using scalar diffraction theory. In this paper we discuss the limitations of this theory for the prediction of the absolute phase generated by different implementations of CGH. Furthermore, for regions where scalar approximation is no longer valid, rigorous simulations are performed to identify phase sensitive structure parameters and evaluate fabrication tolerances for typical gratings. PMID- 23736388 TI - Cascaded Mach-Zehnder wavelength filters in silicon photonics for low loss and flat pass-band WDM (de-)multiplexing. AB - We present 1-to-8 wavelength (de-)multiplexer devices based on a binary tree of cascaded Mach-Zehnder-like lattice filters, and manufactured using a 90 nm CMOS integrated silicon photonics technology. We demonstrate that these devices combine a flat pass-band over more than 50% of the channel spacing with low insertion loss of less than 1.6 dB, and have a small device size of approximately 500 * 400 um. This makes this type of filters well suited for application as WDM (de-)multiplexer in silicon photonics transceivers for optical data communication in large scale computer systems. PMID- 23736389 TI - Demonstration of Silicon-on-insulator mid-infrared spectrometers operating at 3.8 MUm. AB - The design and characterization of silicon-on-insulator mid-infrared spectrometers operating at 3.8 MUm is reported. The devices are fabricated on 200 mm SOI wafers in a CMOS pilot line. Both arrayed waveguide grating structures and planar concave grating structures were designed and tested. Low insertion loss (1.5-2.5 dB) and good crosstalk characteristics (15-20 dB) are demonstrated, together with waveguide propagation losses in the range of 3 to 6 dB/cm. PMID- 23736390 TI - Nonlinear amplification of side-modes in frequency combs. AB - We investigate how suppressed modes in frequency combs are modified upon frequency doubling and self-phase modulation. We find, both experimentally and by using a simplified model, that these side-modes are amplified relative to the principal comb modes. Whereas frequency doubling increases their relative strength by 6 dB, the growth due to self-phase modulation can be much stronger and generally increases with nonlinear propagation length. Upper limits for this effect are derived in this work. This behavior has implications for high precision calibration of spectrographs with frequency combs used for example in astronomy. For this application, Fabry-Perot filter cavities are used to increase the mode spacing to exceed the resolution of the spectrograph. Frequency conversion and/or spectral broadening after non-perfect filtering reamplify the suppressed modes, which can lead to calibration errors. PMID- 23736391 TI - Interplay between localization and absorption in disordered waveguides. AB - This work presents results of ab-initio simulations of continuous wave transport in disordered absorbing waveguides. Wave interference effects cause deviations from diffusive picture of wave transport and make the diffusion coefficient position- and absorption-dependent. As a consequence, the true limit of a zero diffusion coefficient is never reached in an absorbing random medium of infinite size, instead, the diffusion coefficient saturates at some finite constant value. Transition to this absorption-limited diffusion exhibits a universality which can be captured within the framework of the self-consistent theory (SCT) of localization. The results of this work (i) justify use of SCT in analyses of experiments in localized regime, provided that absorption is not weak; (ii) open the possibility of diffusive description of wave transport in the saturation regime even when localization effects are strong. PMID- 23736392 TI - Improved electroluminescence from ZnO light-emitting diodes by p-type MgZnO electron blocking layer. AB - We report on the effect of a p-type MgZnO electron blocking layer (EBL) on the electroluminescence from n-type ZnO/undoped ZnO/p-type ZnO light-emitting diodes (LEDs). The p-type Mg(0.1)Zn(0.9)O EBL was introduced between the undoped and p type ZnO layers. The p-type Mg(0.1)Zn(0.9)O EBL increased the ultraviolet emission by 140% at 60 mA and decreased the broad deep-level emission from ZnO LEDs. The calculated band structures and carrier distribution in ZnO LEDs show that p-type Mg(0.1)Zn(0.9)O EBL effectively suppresses the electron overflow from undoped ZnO to p-type ZnO and increases the hole concentration in the undoped ZnO layer. PMID- 23736393 TI - Tuning the phase sensitivity of a double-lambda system with a static magnetic field. AB - We study the effect of a DC magnetic field on the phase sensitivity of a double lambda system coupled by two laser fields, a probe and a pump. It is demonstrated that the gain and the refractive index of the probe can be controlled by either the magnetic field or the relative phase between the two laser fields. More interestingly, when the system reduces to a single-lambda system, turning on the magnetic field transforms the system from a phase-insensitive process to a phase sensitive one. In the pulsed-probe regime, we observed switching between slow and fast light when the magnetic field or the relative phase was adjusted. Experiments using a coated 87Rb vapor cell produced results in good agreement with our numerical simulation. This work provides a novel and simple means to manipulate phase sensitive electromagnetically-induced-transparency or four-wave mixing, and could be useful for applications in quantum optics, nonlinear optics and magnetometery based on such systems. PMID- 23736394 TI - Generalized Pseudo-Unit-Cell model for long-wavelength optical phonons of multinary mixed crystals: application to A(x)B(1-x)C(y)D(1-y) type mixed crystals. AB - Long-wavelength optical phonons in multinary mixed crystals are studied based on the Pseudo-Unit-Cell model. A unitary matrix method is developed to calculate the eigenfrequencies of optical phonons in multinary mixed crystals. The analytical expressions of oscillator strengths and dielectric constants of the multinary mixed crystals are obtained as a function of the phonon frequencies. The results indicate that the composition dependence of oscillator strengths shows clearly the phonon-mode behaviors of the mixed crystals. The theory and calculation method can be applied to any type of multinary mixed crystals. It is found that there is a composition independent point for the dielectric constant of quaternary mixed crystals. PMID- 23736395 TI - Dressed multi-wave mixing process with Rydberg blockade. AB - We investigate the way to control multi-wave mixing (MWM) process in Rydberg atoms via the interaction between Rydberg blockade and light field dressing effect. Considering both of the primary and secondary blockades, we theoretically study the MWM process in both diatomic and quadratomic systems, in which the enhancement, suppression and avoided crossing can be affected by the atomic internuclear distance or external electric field intensity. In the diatomic system, we also can eliminate the primary blockade by the dressing effect. Such investigations have potential applications in quantum computing with Rydberg atom as the carrier of qubit. PMID- 23736396 TI - Ion beam lithography for Fresnel zone plates in X-ray microscopy. AB - Fresnel Zone Plates (FZP) are to date very successful focusing optics for X-rays. Established methods of fabrication are rather complex and based on electron beam lithography (EBL). Here, we show that ion beam lithography (IBL) may advantageously simplify their preparation. A FZP operable from the extreme UV to the limit of the hard X-ray was prepared and tested from 450 eV to 1500 eV. The trapezoidal profile of the FZP favorably activates its 2nd order focus. The FZP with an outermost zone width of 100 nm allows the visualization of features down to 61, 31 and 21 nm in the 1st, 2nd and 3rd order focus respectively. Measured efficiencies in the 1st and 2nd order of diffraction reach the theoretical predictions. PMID- 23736398 TI - Phase-matching spectral phase measurement and domain period reconstruction of aperiodic quasi-phase matched gratings by nonlinear spectral interferometry. AB - We experimentally measured the phase-matching spectral phases of aperiodic quasi phase matched gratings for the first time (to the best of our knowledge) by nonlinear spectral interferometry. The retrieved information is useful in determining the temporal shape of the nonlinearly converted ultrafast signal and reconstructing the slowly-varying domain period distribution. The method is nondestructive, fast, sensitive, accurate, and applicable to different nonlinear materials. Compared to taking microscopic images of the etched crystal surface, our method can directly measure the domain period distribution in the crystal interior and is free of the artificial random duty period error due to image concatenation. PMID- 23736397 TI - Raman signal enhancement via elastic light scattering. AB - The enhanced generation of a spontaneous Raman signal by way of elastic scattering is demonstrated. Using Monte Carlo simulations, we show that elastic scattering, by increasing the path length of light through the medium, enhances the generation of a Raman signal. This is investigated over a large parameter space, demonstrating that this effect is robust, and providing additional physical insight into the dynamics of light propagation in a turbid medium. Both the temporal and spatial profiles of the Raman signal are shown to depend heavily on the amount of scattering present. PMID- 23736399 TI - High speed multispectral fluorescence lifetime imaging. AB - We report a spectrally resolved fluorescence lifetime imaging system based on time gated single photon detection with a fixed gate width of 200 ps and 7 spectral channels. Time gated systems can operate at high count rates but usually have large gate widths and sample only part of the fluorescence decay curve. In the system presented in this work, the fluorescence signal is sampled using a high speed transceiver. An error analysis is carried out to characterize the performance of both lifetime and spectral detection. The effect of gate width and spectral channel width on the accuracy of estimated lifetimes and spectral widths is described. The performance of the whole instrument is evaluated at count rates of up to 12 MHz. Accurate fluorescence lifetimes (error < 2%) are recorded at count rates as high as 5 MHz. This is limited by the PMT performance, not by the electronics. Analysis of the large spectral lifetime image sets is challenging and time-consuming. Here, we demonstrate the use of lifetime and spectral phasors for analyzing images of fibroblast cells with 2 different labeled components. The phasor approach provides a fast and intuitive way of analyzing the results of spectrally resolved fluorescence lifetime imaging experiments. PMID- 23736400 TI - Optical forces in twisted split-ring-resonator dimer stereometamaterials. AB - We numerically investigate the optical forces in stereometamaterials composed of two-dimensional arrays of two spatially stacked split ring resonators with a twisted angle. At the hybridized magnetic resonances, we obtain both attractive and repulsive relative optical forces, which can be further exploited to control the separation between the two split ring resonators. Due to the strongest inductive coupling achieved for a twist angle of 180 degrees , an attractive relative force as high as ~1200 piconewtons is realized at illumination intensities of 50 mW/um(2). We show that a quasi-static dipole-dipole interaction model could predict well the characteristic and magnitude of the relative optical forces. We also demonstrate that although the optical force exerted on each of the split ring resonators could be oriented in a direction opposite to the propagation wave vector, the mass center of the two resonators is always pushed away from the light source. PMID- 23736401 TI - All-optical, thermo-optical path length modulation based on the vanadium-doped fibers. AB - This paper presents an all-fiber, fully-optically controlled, optical-path length modulator based on highly absorbing optical fiber. The modulator utilizes a high power 980 nm pump diode and a short section of vanadium-co-doped single mode fiber that is heated through absorption and a non-radiative relaxation process. The achievable path length modulation range primarily depends on the pump's power and the convective heat-transfer coefficient of the surrounding gas, while the time response primarily depends on the heated fiber's diameter. An absolute optical length change in excess of 500 um and a time-constant as short as 11 ms, were demonstrated experimentally. The all-fiber design allows for an electrically passive and remote operation of the modulator. The presented modulator could find use within various fiber-optics systems that require optical (remote) path length control or modulation. PMID- 23736402 TI - Fluorescent stereo microscopy for 3D surface profilometry and deformation mapping. AB - Recently, mechanobiology has received increased attention. For investigation of biofilm and cellular tissue, measurements of the surface topography and deformation in real-time are a pre-requisite for understanding the growth mechanisms. In this paper, a novel three-dimensional (3D) fluorescent microscopic method for surface profilometry and deformation measurements is developed. In this technique a pair of cameras are connected to a binocular fluorescent microscope to acquire micrographs from two different viewing angles of a sample surface doped or sprayed with fluorescent microparticles. Digital image correlation technique is used to search for matching points in the pairing fluorescence micrographs. After calibration of the system, the 3D surface topography is reconstructed from the pair of planar images. When the deformed surface topography is compared with undeformed topography using fluorescent microparticles for movement tracking of individual material points, the full field deformation of the surface is determined. The technique is demonstrated on topography measurement of a biofilm, and also on surface deformation measurement of the biofilm during growth. The use of 3D imaging of the fluorescent microparticles eliminates the formation of bright parts in an image caused by specular reflections. The technique is appropriate for non-contact, full-field and real-time 3D surface profilometry and deformation measurements of materials and structures at the microscale. PMID- 23736403 TI - Inner structure detection by optical tomography technology based on feedback of microchip Nd:YAG lasers. AB - We describe a new optical tomography technology based on feedback of microchip Nd:YAG lasers. In the case of feedback light frequency-shifted, light can be magnified by a fact of 10(6) in the Nd:YAG microchip lasers, which makes it possible to realize optical tomography with a greater depth than current optical tomography. The results of the measuring and imaging of kinds of samples are presented, which demonstrate the feasibility and potential of this approach in the inner structure detection. The system has a lateral resolution of ~1 MUm, a vertical resolution of 15 MUm and a longitudinal scanning range of over 10mm. PMID- 23736404 TI - Size-dependent permittivity and intrinsic optical anisotropy of nanometric gold thin films: a density functional theory study. AB - Physical properties of materials are known to be different from the bulk at the nanometer scale. In this context, the dependence of optical properties of nanometric gold thin films with respect to film thickness is studied using density functional theory (DFT). We find that the in-plane plasma frequency of the gold thin film decreases with decreasing thickness and that the optical permittivity tensor is highly anisotropic as well as thickness dependent. Quantitative knowledge of planar metal film permittivity's thickness dependence can improve the accuracy and reliability of the designs of plasmonic devices and electromagnetic metamaterials. The strong anisotropy observed may become an alternative method of realizing indefinite media. PMID- 23736405 TI - Enhanced optical forces in integrated hybrid plasmonic waveguides. AB - We demonstrate gradient optical forces in metal-dielectric hybrid plasmonic waveguides (HPWG) for the first time. The magnitude of optical force is quantified through excitation of the nanomechanical vibration of the suspended waveguides. Integrated Mach-Zehnder interferometry is utilized to transduce the mechanical motion and characterize the propagation loss of the HPWG. Compared with theory, the experimental results have confirmed the optical force enhancement, but also suggested a significantly higher optical loss in HPWG. The excessive loss is attributed to metal surface roughness and other non-idealities in the device fabrication process. PMID- 23736407 TI - In-fiber directional coupler for high-sensitivity curvature measurement. AB - A curvature fiber optic sensor using a two-core fiber (TCF) is proposed and demonstrated. The TCF is designed to operate as a directional coupler with one core located exactly at the center of the fiber and the other off-axis, but close to the center of the fiber. This design allows straightforward splicing of the TCF to single mode fibers (SMF), and alignment of the off-axis core is not strictly required for optimum operation. The sensor is fabricated by simply splicing a 5 cm long section of TCF between two SMF sections, which provides a sinusoidal spectral response. When the fiber is bent, the coupling parameters are modified due to stress-optic and effective length effects, effectively blue shifting the sinusoidal spectral response of the sensor and allowing for the measurement of curvature. The sensor exhibits linear response and a sensitivity of -137.87 nm/m(-1) for curvature ranging from 0 to 0.27 m(-1), making it suitable to measure small curvatures with high sensitivity. PMID- 23736408 TI - All-optical bistability and switching near the Dirac point of a 2-D photonic crystal. AB - We investigate all-optical switching at the guided mode resonances originating near the Dirac point of a finite, 2-D photonic crystal consisting of a square lattice of dielectric columns possessing a cubic nonlinearity. The peculiar field localization properties of these Dirac-point guided mode resonances conspire to yield extremely low switching threshold at near-to-normal incidence for remarkably low filling factors of the nonlinear material. PMID- 23736409 TI - 50-Gb/s ring-resonator-based silicon modulator. AB - We achieved 50-Gb/s operation of a ring-resonator-based silicon modulator for the first time. The pin-diode phase shifter, which consists of a side-wall-grating waveguide, was loaded into the ring resonator. The forward-biased operation mode was applied, which exhibited a V(pi)L as small as 0.28 V . cm at 25 GHz. The driving voltage and optical insertion loss at 50-Gb/s were 1.96 V(pp) and 5.2 dB, respectively. PMID- 23736410 TI - Ultralow-energy and high-contrast all-optical switch involving Fano resonance based on coupled photonic crystal nanocavities. AB - We experimentally and theoretically clarified that a Fano resonant system based on a coupled optical cavity has better performance when used as an all-optical switch than a single cavity in terms of switching energy, contrast, and operation bandwidth. We successfully fabricated a Fano system consisting of doubly coupled photonic-crystal (PhC) nanocavities, and demonstrated all-optical switching for the first time. A steep asymmetric transmission spectrum was clearly observed, thereby enabling a low-energy and high-contrast switching operation. We achieved the switching with a pump energy of a few fJ, a contrast of more than 10 dB, and an 18 ps switching time window. These levels of performance are actually better than those for Lorentzian resonance in a single cavity. We also theoretically investigated the achievable performance in a well-designed Fano system, which suggested a high contrast for the switching of more than 20 dB in a fJ energy regime. PMID- 23736411 TI - Design and fabrication of a planar PDMS transmission grating microspectrometer. AB - We describe the monolithic integration of microfluidic channels, optical waveguides, a collimating lens and a curved focusing transmission grating in a single PDMS-based microsystem. All optical and fluidic components of the device were simultaneously formed in a single layer of high refractive index (n~1.43) PDMS by soft lithography. Outer layers of lower-index (n~1.41) PDMS were subsequently added to provide optical and fluidic confinement. Here, we focus on the design and characterization of the microspectrometer part, which employs a novel self-focusing strategy based on cylindrical facets, and exhibits resolution <10 nm in the visible wavelength range. The dispersive behavior of the grating was analyzed both experimentally and using numerical simulations, and the results are in good agreement with simplified analytical predictions. PMID- 23736412 TI - Phase-shift formed in a long period fiber grating and its application to the measurements of temperature and refractive index. AB - A novel approach to calibrate a phase-shift formed in a long-period fiber grating (LPG) is firstly proposed and numerically demonstrated, which is based on the use of either intensity- or wavelength-interrogation technique to the main loss-peak of the phase-shift LPG in the spectrum. Moreover, by using a CO2 laser with high-repetition-rate pulses emission, an equivalent phase-shift is successfully created at middle of the LPG. As an application of the proposed calibration scheme, measurement for the temperature and the refractive index of the ambient solution has been proposed and successfully demonstrated by using a phase-shifted LPG. PMID- 23736413 TI - In fiber Bragg grating twist sensor based on analysis of polarization dependent loss. AB - In this paper, a new technique exploiting the polarization properties of normal fiber Bragg grating (FBG) for twist sensing is firstly proposed and experimentally demonstrated. The evolution of the polarization dependent loss (PDL) response of the FBG with respect to the twist is studied. The physical model is presented and a numerical simulation based on the transfer matrix method is used to calculate the PDL spectrum of the twisted FBG. The theoretical and experimental results suggest that the PDL response of the FBG have higher twist sensitivities than that of the reflected or transmitted amplitude spectra. Based on comprehensive analysis of the resonant wavelength and the amplitude of the two main lobes of the PDL spectrum, this sensor can measure twist angle and determine twist direction simultaneously. Moreover, the performance of the sensor is not affected by strain and temperature variations. PMID- 23736414 TI - Wavelength reuse in a bidirectional UWB over fiber system. AB - Wavelength reuse in a bidirectional UWB over fiber system using a polarization modulator (PolM) and an electro-absorption modulator (EAM) is proposed and experimentally demonstrated. Since the PolM functions as a special phase modulator that supports phase modulation along the two principal axes with opposite modulation indices and the EAM is a polarization-independent component, the signals due to the phase-modulation to intensity-modulation (PM-IM) conversion along the two orthogonal directions in the upstream link will be complementary and cancelled out, thus the impact of the downstream signal to the upstream transmission due to the PM-IM conversion is fully eliminated. Error-free bidirectional transmission of a 1.25-Gbps UWB signal over 17 km single-mode fiber (SMF) is demonstrated. A power penalty due to the wavelength reuse for upstream transmission is measured to be as low as 0.2 dB. PMID- 23736415 TI - Fundaments of optical far-field subwavelength resolution based on illumination with surface waves. AB - We present a general discussion about the fundamental physical principles involved in a novel class of optical superlenses that permit to realize in the far-field direct non-scanning images with subwavelength resolution. Described superlenses are based in the illumination of the object under observation with surface waves excited by fluorescence, the enhanced transmission of fluorescence via coupling with surface waves, and the occurrence of far-field coherence related fluorescence diffraction phenomena. A Fourier optics description of the image formation based on illumination with surface waves is presented, and several recent experimental realizations of this technique are discussed. Our theoretical approach explains why images with subwavelength resolution can be formed directly in the microscope camera, without involving scanning or numerical post-processing. While resolution of the order of lambda/7 has been demonstrated using the described approach, we anticipate that deeper optical subwavelength resolution should be expected. PMID- 23736416 TI - Phase-stable source of polarization-entangled photons in a linear double-pass configuration. AB - We demonstrate a compact, robust, and highly efficient source of polarization entangled photons, based on linear bi-directional down-conversion in a novel 'folded sandwich' configuration. Bi-directionally pumping a single periodically poled KTiOPO(4) (ppKTP) crystal with a 405-nm laser diode, we generate entangled photon pairs at the non-degenerate wavelengths 784 nm (signal) and 839 nm (idler), and achieve an unprecedented detection rate of 11.8 kcps for 10.4 MUW of pump power (1.1 million pairs / mW), in a 2.9-nm bandwidth, while maintaining a very high two-photon entanglement quality, with a Bell-state fidelity of 99.3 +/- 0.3%. PMID- 23736417 TI - Efficient numerical method for analyzing optical bistability in photonic crystal microcavities. AB - Nonlinear optical effects can be enhanced by photonic crystal microcavities and be used to develop practical ultra-compact optical devices with low power requirements. The finite-difference time-domain method is the standard numerical method for simulating nonlinear optical devices, but it has limitations in terms of accuracy and efficiency. In this paper, a rigorous and efficient frequency domain numerical method is developed for analyzing nonlinear optical devices where the nonlinear effect is concentrated in the microcavities. The method replaces the linear problem outside the microcavities by a rigorous and numerically computed boundary condition, then solves the nonlinear problem iteratively in a small region around the microcavities. Convergence of the iterative method is much easier to achieve since the size of the problem is significantly reduced. The method is presented for a specific two-dimensional photonic crystal waveguide-cavity system with a Kerr nonlinearity, using numerical methods that can take advantage of the geometric features of the structure. The method is able to calculate multiple solutions exhibiting the optical bistability phenomenon in the strongly nonlinear regime. PMID- 23736418 TI - The study of optical band edge property of bismuth oxide nanowires alpha-Bi2O3. AB - The alpha-phase Bi(2)O(3) (alpha-Bi(2)O(3)) is a crucial and potential visiblelight photocatalyst material needless of intentional doping on accommodating band gap. The understanding on fundamental optical property of alpha-Bi(2)O(3) is important for its extended applications. In this study, bismuth oxide nanowires with diameters from tens to hundreds nm have been grown by vapor transport method driven with vapor-liquid-solid mechanism on Si substrate. High-resolution transmission electron microscopy and Raman measurement confirm alpha phase of monoclinic structure for the as-grown nanowires. The axial direction for the as-grown nanowires was along < 122 >. The band-edge structure of alpha-Bi(2)O(3) has been probed experimentally by thermoreflectance (TR) spectroscopy. The direct band gap was determined accurately to be 2.91 eV at 300 K. Temperaturedependent TR measurements of 30-300 K were carried out to evaluate temperature-energy shift and line-width broadening effect for the band edge of alpha-Bi(2)O(3) thin-film nanowires. Photoluminescence (PL) experiments at 30 and 300 K were carried out to identify band-edge emission as well as defect luminescence for the alpha-Bi(2)O(3) nanowires. On the basis of experimental analyses of TR and PL, optical characteristics of direct band edge of alpha Bi(2)O(3) nanowires have thus been realized. PMID- 23736419 TI - Size dependence of surface plasmon modes in one-dimensional plasmonic crystal cavities. AB - The characteristics of surface plasmon polaritons (SPPs) confined in a one dimensional plasmonic crystal (1D-PlC) cavity are investigated using a cathodoluminescence (CL) detection system equipped with a 200 keV scanning transmission electron microscope (STEM). The dispersion curves of SPPs near the Gamma point are derived from the angle-resolved CL spectra, and the SPP cavity modes are observed inside the band gap region. The mode number and wavenumber of the cavity modes are determined from the beam scan CL spectral images. The energy of the cavity mode depends on the cavity length and the angular distribution of the emission from the cavity changes with the mode number of the cavity mode. We also reveal that the phase shift due to the reflection at the cavity edge changes significantly with the resonant energy. PMID- 23736420 TI - Integration of liquid crystal elements for creating an infrared Lyot filter. AB - An infrared Lyot filter was fabricated by integrating a polarization beam splitter and two retarders into a single device. A liquid crystal layer was constructed between two silicon pentaprisms that were designed suitably so that light was incident on this layer at 28 degrees . At this angle, the liquid crystal transmitted p-polarized light (Brewster's angle) and reflected s polarized light (total internal reflection). The p- or s-polarized light was directed to another liquid crystal layer (retarder) between the prism and a mirror, which induced a wavelength-dependent retardation in the reflection process. Consequently, the light that returned to the beam splitter was transmitted or reflected depending on wavelength. PMID- 23736421 TI - Micro-strain sensing using wrinkled stiff thin films on soft substrates as tunable optical grating. AB - We report a strain sensing approach that utilizes wrinkled patterns on poly (dimethylsiloxane) (PDMS) as an optical grating to measure thermally-induced strain of different materials. The mechanism for the strain sensing and the effect of PDMS grating on strain sensing are discussed. By bonding the PDMS grating onto a copper or silicon substrate, the coefficient of thermal expansion (CTE) of the substrates can be deduced by measuring the diffraction angle change due to the change in PDMS grating periodicity when thermal strain is introduced. The measured CTEs agree well with the known reference values. PMID- 23736422 TI - Ultra-low crosstalk, CMOS compatible waveguide crossings for densely integrated photonic interconnection networks. AB - We explore the design space for optimizing CMOS compatible waveguide crossings on a silicon photonics platform. This paper presents simulated and experimental excess loss and crosstalk suppression data for vertically integrated silicon nitride over silicon-on-insulator waveguide crossings. Experimental results show crosstalk suppression exceeding -49/-44 dB with simulation results as low as -65/ 60 dB for the TE/TM mode in a waveguide crossing with a 410 nm vertical gap. PMID- 23736423 TI - Experimental and numerical studies of mode-locked fiber laser with large normal and anomalous dispersion. AB - An ytterbium-doped mode-locked fiber laser was demonstrated with a chirped fiber Bragg grating for dispersion management. The cavity net dispersion could be changed from large normal dispersion (2.4 ps(2)) to large anomalous dispersion ( 2.0 ps(2)), depending on the direction of the chirped Bragg grating in laser cavity. The proposed fiber lasers with large normal dispersion generated stable pulses with a pulse width of <1.1 ns and a pulse energy of 1.5 nJ. The laser with large anomalous dispersion generated wavelength-tunable soliton with a pulse width of 2.7 ps and pulse energy of 0.13 nJ. A theoretical model was established and used to verify the experimental observations. PMID- 23736424 TI - Simple magneto-optic transition metal models for time-domain simulations. AB - Efficient modelling of the magneto-optic effects of transition metals such as nickel, cobalt and iron is a topic of growing interest within the nano-optics community. In this paper, we present a general discussion of appropriate material models for the linear dielectric properties for such metals, provide parameter fits and formulate the anisotropic response in terms of auxiliary differential equations suitable for time-domain simulations. We validate both our material models and their implementation by comparing numerical results obtained with the Discontinuous Galerkin time-domain (DGTD) method to analytical results and previously published experimental data. PMID- 23736425 TI - Investigations of single-frequency Raman fiber amplifiers operating at 1178 nm. AB - We report on core-pumped single-stage and two-stage polarization-maintaining single-frequency Raman fiber amplifiers (RFAs). For a counter-pumped single-stage RFA, commercial-off-the shelf (COTS) single-mode fiber was utilized to generate 10 W of output power at 1178 nm through the application of a two-step thermal gradient in order to suppress SBS. The relatively high output can be explained by the Brillouin gain spectrum (BGS) of the COTS fiber. A pump-probe characterization of the BGS of the fiber provided a Brillouin gain coefficient of 1.2 * 10(-11) m/W with a FWHM of 78 MHz for the gain bandwidth. A fiber cutback study was also conducted to investigate the signal output at SBS threshold as a function of pump power for optimal length. This study revealed a linear dependence, which is in agreement with the theoretical prediction. Furthermore, we present numerical simulations indicating that substantial power scaling can be achieved by seeding at a higher power. Consequently, we constructed a two-stage RFA in order to achieve seed powers at the 1 W level. By utilizing an acoustically tailored fiber possessing a lower Brillouin gain coefficient than the COTS fiber and by seeding at higher powers, 22 W of single-frequency 1178 nm output was obtained from a counter-pumped two-stage RFA. Finally, we show that the single-frequency spectral bandwidth could not be maintained when a similar co pumped two-stage RFA was utilized. PMID- 23736426 TI - Modeling of transient modal instability in fiber amplifiers. AB - A model of transient modal instability in fiber amplifiers is presented. This model combines an optical beam propagation method that incorporates laser gain through local solution of the rate equations and refractive index perturbations caused by the thermo-optic effect with a time-dependent thermal solver with a quantum defect heating source term. This model predicts modal instability a fiber amplifier operating at 241, 270, and 287 Watts of output power characterized by power coupling to un-seeded modes, the presence of stable and unstable regions within the fiber, and rapid intensity variations along the fiber. The instability becomes more severe as the power is increased. PMID- 23736427 TI - Viewing-angle enlargement in holographic augmented reality using time division and spatial tiling. AB - Viewing angle enlargement is essential for SLM-based 3D holographic display. An idea of constructing equivalent-curved-SLM-array (ECSA) is proposed by linear phase factor superimposition. Employing the time division and spatial tiling (TDST) techniques, an ECSA-based horizontal 4f optical system is designed and built. The horizontal viewing angle of a single SLM is increased to 3.6 times when retaining the same hologram area. An interlaced holographic display technique is developed to remove the flicker effect. Holographic augmented reality is performed using the TDST system. Floating holographic 3D image with parallax and accommodation effects is achieved. Both TDST and interlaced technique may extend to multiple SLMs system to achieve larger viewing angle. PMID- 23736428 TI - In-line phase sensitive amplifier based on PPLN waveguides. AB - We demonstrate a chi(2)-based in-line PSA with a carrier-recovery and phase locking system for a phase shift keying (PSK) signal. By doubling the signal phase using a wavelength conversion technique, the carrier was recovered from a PSK signal. The carrier phase was synchronized to a local oscillator using optical injection locking. Phase sensitive amplification with a wide phase sensitive dynamic range of 20 dB was achieved using degenerate parametric amplification in a periodically poled LiNbO(3) (PPLN) waveguide. The phase regeneration effect was examined for a degraded signal by means of constellation analyses and bit-error rate measurements. The in-line PSA also operated successfully as a repeater amplifier in a 160 km fiber link without a power penalty. Finally, we demonstrate the regeneration of non-linear impairments induced by fiber non-linearity. PMID- 23736429 TI - Characterization of a spectrograph based hyperspectral imaging system. AB - A significant part of the uniformity degradation in the acquired hyperspectral images can be attributed to the coregistration distortions and spectrally and spatially dependent resolution arising from the misalignments and the operation principle of the spectrograph based hyperspectral imaging system. The aim of this study was the development and validation of a practical method for characterization of the geometric coregistration distortions and position dependent resolution. The proposed method is based on modeling the imaging system response to several affordable reference objects. The results of the characterization can be used for calibration of the acquired images or as a tool for assessment of the expected errors in various hyperspectral imaging systems. PMID- 23736430 TI - Resonant absorption and scattering suppression of localized surface plasmons in Ag particles on green LED. AB - The metallic-structure dependent localized surface plasmons (LSPs) coupling behaviors with InGaN QWs in a green LED epitaxial wafer are investigated by optical transmission, scanning electron microscopy (SEM) and photoluminescence (PL) measurements. Ag nanoparticles (NPs) are formed by thermal annealing Ag layer on the green LED wafer. SEM images show that for higher annealing temperature and/or thicker deposited Ag layer, larger Ag NPs can be produced, leading to the redshift of absorption peaks in the transmission spectra. Time resolved PL (TRPL) measurements indicate when LSP-MQW coupling occurs, PL decay rate is greatly enhanced especially at the resonant wavelength 560 nm. However, the PL intensity is suppressed by 3.5 folds compared to the bare LED. The resonant absorption and PL suppression are simulated by three dimension finite difference-time-domain (FDTD), which suggests that Ag particle with smaller size and lower height lead to the larger dissipation of LSP. PMID- 23736431 TI - Characteristics of microfiber Fabry-Perot resonators fabricated by UV exposure. AB - We inscribe a Fabry-Perot (FP) resonator in the microfiber utilizing the 193-nm UV exposure and the phase mask technique. Some new characteristics including strong polarization dependence and large spectral dispersion in contrast to the conventional counterparts are measured, which are attributed to the two-fold symmetry of index change in the grating and the dispersion of the effective grating length, respectively. The thinner microfiber can generally generate stronger polarization dependence. The FP spectral dependencies on external strain, temperature, and refractive index are also investigated. Our fabricated structures can have potential of acting as photonic sensors or polarization related filters. PMID- 23736432 TI - Lasing through a strongly-coupled mode by intra-cavity pumping. AB - We demonstrate room temperature lasing through the polaritonic mode of a J aggregate microcavity in which losses from exciton-exciton annihilation and slow polariton relaxation typical of direct J-aggregate excitation are circumvented via intra-cavity pumping. The pumping scheme utilizes an organic dye layer (DCM) within the cavity with an emission band overlapping the entire lower J-aggregate polariton branch spectrum, hence forcing DCM lasing to occur through the strongly coupled mode. This cavity architecture, which separates strong coupling and gain into two materials, presents a general and flexible design for polariton devices and allows for the use of a wide range of materials, organic and inorganic, to be integrated into the cavity. PMID- 23736433 TI - Imaging of director fields in liquid crystals using stimulated Raman scattering microscopy. AB - We demonstrate an approach for background-free three-dimensional imaging of director fields in liquid crystals using stimulated Raman scattering microscopy. This imaging technique is implemented using a single femtosecond pulsed laser and a photonic crystal fiber, providing Stokes and pump frequencies needed to access Raman shifts of different chemical bonds of molecules and allowing for chemically selective and broadband imaging of both pristine liquid crystals and composite materials. Using examples of model three-dimensional structures of director fields, we show that the described technique is a powerful tool for mapping of long-range molecular orientation patterns in soft matter via polarized chemical selective imaging. PMID- 23736434 TI - Determination of surface nematic liquid crystal anchoring strength using nano scale surface grooves. AB - Based on several nano-scale groove models, we propose a new technique to simultaneously determine the azimuthal and polar surface anchoring strengths of nematic liquid crystal (LC). The optical analysis of LCs on a grooved surface made by nanoimprinting lithography was performed on special alignment material, using a typical rubbing process. In our approach, using a polarizing microscope, we can determine the LC alignment exactly as it is in a parallel state, rather than a twisted state. This simple proposed method gives an accurate value of the surface LC anchoring of various surfaces, as well as simultaneously measuring the azimuthal and polar anchoring energy. PMID- 23736435 TI - Plasmon assisted thermal modulation in nanoparticles. AB - Single-particle interactions hold the promise of nanometer-scale devices in areas such as data communications and storage, nanolithography, waveguides, renewable energy and therapeutics. We propose that the collective electronic properties possessed by noble metal nanoparticles may be exploited for device actuation via the unapparent mechanism of plasmon-assisted heat generation and flux. The temperature dependence of the dielectric function and the thermal transport properties of the particles play the central role in the feasibility of the thermally-actuated system, however the behavior of these thermoplasmonic processes is unclear. We experimentally and computationally analyzed modulation via thermoplasmonic processes on a test system of gold (Au) nano-islands. Modulation and energy transport in discontinuous domains exhibited quantitatively different characteristics compared to thin films. The results have implications for all surface plasmon based nano-devices where inevitable small-scale thermal processes are present. PMID- 23736436 TI - Fano resonance of nanoparticles embedded in Fabry-Perot cavities. AB - We present an optical structure, which consists of metal nanoparticles embedded in Fabry-Perot (F-P) cavity, to investigate the Fano resonance, which originates from the interaction between F-P mode and the plasmon modes supported by the nanoparticles. The coupling system is modeled theoretically by coupled-mode theory in time domain and the transmission properties are demonstrated numerically by the finite-difference time-domain method. The charge distribution features of the nanoparticle plasmon modes are further characterized by using boundary integral equation technology. Results show that the F-P modes can be used to active the optical inactive surface plasmon modes by breaking the mode symmetry. PMID- 23736437 TI - Electromagnetically induced transparency and slow light in two-mode optomechanics. AB - We theoretically demonstrate the mechanically mediated electromagnetically induced transparency in a two-mode cavity optomechanical system, where two cavity modes are coupled to a common mechanical resonator. When the two cavity modes are driven on their respective red sidebands by two pump beams, a transparency window appears in the probe transmission spectrum due to destructive interference. Under this situation the transmitted probe beam can be delayed as much as 4 MUs, which can be easily controlled by the power of the pump beams. PMID- 23736438 TI - Three-dimensional light-scattering and deformation of individual biconcave human blood cells in optical tweezers. AB - For studying the elastic properties of a biconcave red blood cell using the dual trap optical tweezers without attaching microbeads to the cell, we implemented a three-dimensional finite element simulation of the light scattering and cell's deformation using the coupled electromagnetic and continuum mechanics modules. We built the vector field of the trapping beams, the cell structure layout, the hyperelastic and viscoelastic cell materials, and we reinforced the constraints on the cell constant volume in the simulation. This computation model can be useful for studying the scattering and the other mechanical properties of the biological cells. PMID- 23736439 TI - Total variation minimization approach in in-line x-ray phase-contrast tomography. AB - The reconstruction problem in in-line X-ray Phase-Contrast Tomography is usually approached by solving two independent linearized sub-problems: phase retrieval and tomographic reconstruction. Both problems are often ill-posed and require the use of regularization techniques that lead to artifacts in the reconstructed image. We present a novel reconstruction approach that solves two coupled linear problems algebraically. Our approach is based on the assumption that the frequency space of the tomogram can be divided into bands that are accurately recovered and bands that are undefined by the observations. This results in an underdetermined linear system of equations. We investigate how this system can be solved using three different algebraic reconstruction algorithms based on Total Variation minimization. These algorithms are compared using both simulated and experimental data. Our results demonstrate that in many cases the proposed algebraic algorithms yield a significantly improved accuracy over the conventional L2-regularized closed-form solution. This work demonstrates that algebraic algorithms may become an important tool in applications where the acquisition time and the delivered radiation dose must be minimized. PMID- 23736440 TI - Amplification of ultra-short optical pulses in a two-pump fiber optical parametric chirped pulse amplifier. AB - We demonstrate with realistic numerical simulations that fiber optical parametric chirped pulse amplification is able to amplify ultra-short optical pulses. Such amplifiers driven by two-pump waves can amplify pulse bandwidth twice as large as the one of a single pump configuration. We show that pulses as short as 50 fs can be directly amplified. In addition, we take benefit from the saturation regime to achieve spectral broadening which makes possible to reduce pulse duration down to 15 fs. PMID- 23736441 TI - Subsurface defects of fused silica optics and laser induced damage at 351 nm. AB - Many kinds of subsurface defects are always present together in the subsurface of fused silica optics. It is imperfect that only one kind of defects is isolated to investigate its impact on laser damage. Therefore it is necessary to investigate the impact of subsurface defects on laser induced damage of fused silica optics with a comprehensive vision. In this work, we choose the fused silica samples manufactured by different vendors to characterize subsurface defects and measure laser induced damage. Contamination defects, subsurface damage (SSD), optical thermal absorption and hardness of fused silica surface are characterized with time-of-flight secondary ion mass spectrometry (TOF-SIMS), fluorescence microscopy, photo-thermal common-path interferometer and fully automatic micro hardness tester respectively. Laser induced damage threshold and damage density are measured by 351 nm nanosecond pulse laser. The correlations existing between defects and laser induced damage are analyzed. The results show that Cerium element and SSD both have a good correlation with laser-induced damage thresholds and damage density. Research results evaluate process technology of fused silica optics in China at present. Furthermore, the results can provide technique support for improving laser induced damage performance of fused silica. PMID- 23736442 TI - A simple, flexible and automatic 3D calibration method for a phase calculation based fringe projection imaging system. AB - An important step of phase calculation-based fringe projection systems is 3D calibration, which builds up the relationship between an absolute phase map and 3D shape data. The existing 3D calibration methods are complicated and hard to implement in practical environments due to the requirement of a precise translating stage or gauge block. This paper presents a 3D calibration method which uses a white plate with discrete markers on the surface. Placing the plate at several random positions can determine the relationship of absolute phase and depth, as well as pixel position and X, Y coordinates. Experimental results and performance evaluations show that the proposed calibration method can easily build up the relationship between absolute phase map and 3D shape data in a simple, flexible and automatic way. PMID- 23736443 TI - Accurate holographic imaging of colloidal particle pairs by Rayleigh-Sommerfeld reconstruction. AB - In-line holographic optical imaging has the unique capability of high speed imaging in three dimensions at rates limited only by the imaging rate of the camera used. In this technique the 3D data is recorded on the detector in a form of a hologram generated by diffraction between the scattered and unscattered light passing through the sample. For dilute samples of single particles or a small cluster of particles, this technique was shown to result in particle tracking with spatial positioning accuracy of a few nanometers. For dense suspension only approximate reconstruction were achieved with systematic axial positioning errors. We propose a scheme to extend accurate holographic microscopy to dense suspensions, by calibrating the Rayleigh-Sommerfeld reconstruction algorithm against Lorentz-Mie scattering theory. We perform this calibration both numerically and experimentally and define the parameter space in which accurate imaging is achieved, and in which numerical calibration holds. We demonstrate the validity of our approach by imaging two attached particles and measuring the distance between their centers with 36 nm accuracy. A difference of 50 nm in particle diameter is easily measured. PMID- 23736444 TI - Optical phased array using high contrast gratings for two dimensional beamforming and beamsteering. AB - We have developed a microelectromechanical system (MEMS) optical phased array incorporating a high-index-contrast subwavelength grating (HCG) for beamforming and beamsteering in a range of +/- 1.26 degrees * 1.26 degrees . Our approach needs only a thin single-layer HCG made of silicon, considerably improving its speed thanks to the low mass, and is suitable for high optical power applications. The measured resonant frequency of HCG is 0.32 MHz. PMID- 23736445 TI - Electromagnetically induced grating in asymmetric quantum wells via Fano interference. AB - We propose a scheme for obtaining an electromagnetically induced grating in an asymmetric semiconductor quantum well (QW) structure via Fano interference. In our structure, owing to Fano interference, the diffraction intensity of the grating, especially the first-order diffraction, can be significantly enhanced. The diffraction efficiency of the grating can be controlled efficiently by tuning the control field intensity, the interaction length, the coupling strength of tunneling, etc. This investigation may be used to develop novel photonic devices in semiconductor QW systems. PMID- 23736446 TI - Gas phase thermometry of hot turbulent jets using laser induced phosphorescence. AB - The temperature distributions of heated turbulent jets of air were determined using two dimensional (planar) laser induced phosphorescence. The jets were heated to specific temperature increments, ranging from 300 - 850 K and several Reynolds numbers were investigated at each temperature. The spectral ratio technique was used in conjunction with thermographic phosphors BAM and YAG:Dy, individually. Single shot and time averaged results are presented as two dimensional stacked images of turbulent jets. YAG:Dy did not produce a high enough signal for single shot measurements. The results allowed for a direct comparison between BAM and YAG:Dy, revealing that BAM is more suitable for relatively lower temperature, fast and turbulent regimes and that YAG:Dy is more suited to relatively higher temperature, steady flow situations. PMID- 23736447 TI - An energy-efficient and elastic optical multiple access system based on coherent interleaved frequency division multiple access. AB - This paper proposes a novel bandwidth-elastic and energy-efficient passive optical network (PON) based on the coherent interleaved frequency division multiple access (IFDMA) scheme. We experimentally demonstrate the coherent IFDMA PON uplink transmission up-to 30 Gbps over a 30 km standard single-mode fiber with 2 * optical network units (ONUs). A low-complexity digital carrier synchronization technique enables multiple access of the ONUs on the basis of 78.1 MHz narrow band orthogonal subcarriers without any guard-bands. PMID- 23736448 TI - Gain-switched all-fiber laser with narrow bandwidth. AB - Gain-switching of a CW fiber laser is a simple and cost-effective approach to generate pulses using an all-fiber system. We report on the construction of a narrow bandwidth (below 0.1 nm) gain-switched fiber laser and optimize the pulse energy and pulse duration under this constraint. The extracted pulse energy is 20 MUJ in a duration of 135 ns at 7 kHz. The bandwidth increases for a higher pump pulse energy and repetition rate, and this sets the limit of the output pulse energy. A single power amplifier is added to raise the peak power to the kW-level and the pulse energy to 230 MUJ while keeping the bandwidth below 0.1 nm. This allows frequency doubling in a periodically poled lithium tantalate crystal with a reasonable conversion efficiency. PMID- 23736449 TI - Reducing residual amplitude modulation in electro-optic phase modulators by erasing photorefractive scatter. AB - Residual amplitude modulation (RAM) is an unwanted noise source in electro-optic phase modulators. The analysis presented shows that while the magnitude of the RAM produced by a MgO:LiNbO(3) modulator increases with intensity, its associated phase becomes less well defined. This combination results in temporal fluctuations in RAM that increase with intensity. This behavior is explained by the presented phenomenological model based on gradually evolving photorefractive scattering centers randomly distributed throughout the optically thick medium. This understanding is exploited to show that RAM can be reduced to below the 10( 5) level by introducing an intense optical beam to erase the photorefractive scatter. PMID- 23736450 TI - Nanoscale optical properties of metal nanoparticles probed by Second Harmonic Generation microscopy. AB - We report spatial and vectorial imaging of local fields' confinement properties in metal nanoparticles with branched shapes, using Second Harmonic Generation (SHG) microscopy. Taking advantage of the coherent nature of this nonlinear process, the technique provides a direct evidence of the coupling between the excitation polarization and both localization and polarization specificities of local fields at the sub-diffraction scale. These combined features, which are governed by the nanoparticles' symmetry, are not accessible using other contrasts such as linear optical techniques or two-photon luminescence. PMID- 23736451 TI - Hybrid femtosecond/picosecond rotational coherent anti-Stokes Raman scattering temperature and concentration measurements using two different picosecond duration probes. AB - A hybrid fs/ps pure-rotational CARS scheme is characterized in furnace-heated air at temperatures from 290 to 800 K. Impulsive femtosecond excitation is used to prepare a rotational Raman coherence that is probed with a ps-duration beam generated from an initially broadband fs pulse that is bandwidth limited using air-spaced Fabry-Perot etalons. CARS spectra are generated using 1.5- and 7.0-ps duration probe beams with corresponding coarse and narrow spectral widths. The spectra are fitted using a simple phenomenological model for both shot-averaged and single-shot measurements of temperature and oxygen mole fraction. Our single shot temperature measurements exhibit high levels of precision and accuracy when the spectrally coarse 1.5-ps probe beam is used, demonstrating that high spectral resolution is not required for thermometry. An initial assessment of concentration measurements in air is also provided, with best results obtained using the higher resolution 7.0-ps probe. This systematic assessment of the hybrid CARS technique demonstrates its utility for practical application in low temperature gas-phase systems. PMID- 23736452 TI - Hollow core photonic crystal fiber as a reusable Raman biosensor. AB - We report that a single hollow core photonic crystal fiber (HC-PCF) can be used for repetitive characterization of multiple samples by Raman spectroscopy. This was achieved by integrating the HC-PCF to a differential pressure system that allowed effective filling, draining and re-filling of samples into a HC-PCF under identical optical conditions. Consequently, high-quality and reliable spectral data could be obtained which were suitable for multivariate analysis (partial least squares). With the present scheme, we were able to accurately predict different concentrations of heparin and adenosine in serum. Thus the detection scheme as presented here paves a path for the inclusion of HC-PCFs in point-of care technologies and environmental monitoring where rapid sample characterization is of utmost importance. PMID- 23736453 TI - Study of EEPN mitigation using modified RF pilot and Viterbi-Viterbi based phase noise compensation. AB - We propose--as a modification of the optical (RF) pilot scheme--a balanced phase modulation between two polarizations of the optical signal in order to generate correlated equalization enhanced phase noise (EEPN) contributions in the two polarizations. The method is applicable for n-level PSK system. The EEPN can be compensated, the carrier phase extracted and the nPSK signal regenerated by complex conjugation and multiplication in the receiver. The method is tested by system simulations in a single channel QPSK system at 56 Gb/s system rate. It is found that the conjugation and multiplication scheme in the Rx can mitigate the EEPN to within 1/2 orders of magnitude. Results are compared to using the Viterbi Viterbi algorithm to mitigate the EEPN. The latter method improves the sensitivity more than two orders of magnitude. Important novel insight into the statistical properties of EEPN is identified and discussed in the paper. PMID- 23736454 TI - Concentration of broadband terahertz radiation using a periodic array of conically tapered apertures. AB - We describe the optical concentration properties of periodic arrays of conically tapered metallic apertures measured using terahertz (THz) time-domain spectroscopy. As a first step in this process, we optimize the geometrical properties of individual apertures, keeping the output aperture diameter fixed, and find that the optimal taper angle is 30 degrees . A consequence of increasing the taper angle is that the effective cutoff frequency red shifts, which can be readily explained using conventional waveguide theory. We then fabricate and measure the transmission properties of a periodic (hexagonal) array of optimized tapered apertures. In contrast to periodic arrays of subwavelength apertures in thin metal films, which are characterized by narrowband transmission resonances associated with the periodic spacing, here we observe broadband enhanced transmission above the effective cutoff frequency. Further enhancement in the concentration capabilities of the array can be achieved by tilting the apertures towards the array center, although the optical throughput of individual tapered apertures is reduced with increasing tilt angle. Finally, we discuss possible future directions that utilize cascaded structures, as a means for obtaining further enhancement in the amplitude of the transmitted THz radiation. PMID- 23736455 TI - The effects of multiple scattering to optical forces on a sphere in an evanescent field. AB - In this paper we discuss the effects of multiple scattering to the optical forces on a particle by an evanescent field. We show that the iterative method to process the effects of the interaction between the particle and a plane surface is invalid when the radius of particle is large or when the structural resonance of the particle occurs. By using the generalized minimum residual method to solve the set of equations directly, the divergence appears in the iterative method can be removed completely. As an illustrative example, we discussed the effects of multiple scattering to optical forces on a particle in an evanescent field from an incident plane wave. The interpretations of numerical results are presented in detail. PMID- 23736457 TI - Polymer stabilized liquid crystal phase shifter for terahertz waves. AB - We propose an electrically tunable phase shifter for terahertz frequencies. The device is based on a polymer stabilized liquid crystal which allows for a simple device geometry. The polymer stabilized liquid crystal enables continuous tuning of the introduced phase shift with only one pair of electrodes. By characterizing the device with terahertz time-domain spectroscopy we demonstrate a phase shift up to 2.5 terahertz, only slightly changed properties of the neat liquid crystal and significantly reduced response times. PMID- 23736456 TI - Sensing the wavefront of x-ray free-electron lasers using aerosol spheres. AB - Characterizing intense, focused x-ray free electron laser (FEL) pulses is crucial for their use in diffractive imaging. We describe how the distribution of average phase tilts and intensities on hard x-ray pulses with peak intensities of 10(21) W/m(2) can be retrieved from an ensemble of diffraction patterns produced by 70 nm-radius polystyrene spheres, in a manner that mimics wavefront sensors. Besides showing that an adaptive geometric correction may be necessary for diffraction data from randomly injected sample sources, our paper demonstrates the possibility of collecting statistics on structured pulses using only the diffraction patterns they generate and highlights the imperative to study its impact on single-particle diffractive imaging. PMID- 23736458 TI - Direct generation of a first-Stokes vortex laser beam from a self-Raman laser. AB - We demonstrate the direct generation of a first-order LG(01) Laguerre Gaussian (vortex) mode operating at the first-Stokes wavelength of a diode end-pumped, Nd:GdVO(4) self-Raman laser. To the best of our knowledge, this is the first report of intracavity stimulated Raman scattering (SRS) being used as a method for frequency conversion of a vortex laser beam and it is effective in enabling the frequency-converted (Stokes) beam to have the same LG(01) mode as the fundamental beam. PMID- 23736459 TI - Robustness to mechanical perturbations of center-launching technique for transparent board-to-board and data server interconnects. AB - Center-launching technique appears as a promising method to allow single-mode propagation in multi-mode fibers, guaranteeing full transparency to the transmitted optical signal also for applications in board-to-board and data server interconnects. In this paper we show that this technique is robust to mechanical perturbations up to about 1 kHz, demonstrating that the vibrations do not affect the transmission performances. Different experimental configurations are tested in order to exclude multimode propagation and to confirm the only fundamental mode propagation. Finally, a theoretical discussion comments the experimental results. PMID- 23736460 TI - A 1014 nm linearly polarized low noise narrow-linewidth single-frequency fiber laser. AB - We present the demonstration of a compact linearly polarized low noise narrow linewidth single-frequency fiber laser at 1014 nm. The compact fiber laser is based on a 5-mm-long homemade Yb(3+)-doped phosphate fiber. Over 164 mW stable continuous-wave single transverse and longitudinal mode lasing at 1014 nm has been achieved. The measured relative intensity noise is less than -135 dB/Hz at frequencies of over 2.5 MHz. The signal-to-noise ratio of the laser is larger than 70 dB, and the linewidth is less than 7 kHz, while the obtained linear polarization extinction ratio is higher than 30 dB. PMID- 23736461 TI - Comparison of different simulation methods for effective medium computer generated holograms. AB - The arrangement of binary subwavelength structures is a promising alternative to the conventional multiheight level technique to generate computer generated holograms (CGHs). However, the current heuristic design approach leads to a slight mismatch between the target signal and experimental data. To evaluate this deviation, a diffractive beam splitter design is investigated rigorously using a finite-difference time-domain (FDTD) method. Since the use of a rigorous Maxwell equation solver like FDTD requires a massive computational effort, an alternative scalar approach, a fast Fourier transform beam propagation method (FFT-BPM), is investigated with a substantial higher computing speed, showing still a good agreement with the FDTD simulation and experimental data. Therefore, an implementation of this scalar approach into the CGH design process offers the possibility to significantly increase the accuracy. PMID- 23736462 TI - High-accuracy measurement of the 113Cd+ ground-state hyperfine splitting at the milli-Hertz level. AB - We have developed a microwave frequency standard based on the 15.2 GHz ground stated hyperfine transition of (113)C(+) ions. Using a laser-cooled ion cloud trapped in a linear quadrupole Paul trap, the clock transition frequency is measured to be 15 199 862 855.0125(87) Hz, with an accuracy at the 10(-13) level. The main errors are from the microwave frequency reference used in the experiment. The precision is improved by nearly two orders of magnitude than that reported before. PMID- 23736463 TI - Design of large-bandwidth single-mode operation waveguides in silicon three dimensional photonic crystals using two guided modes. AB - We report on the design of silicon three-dimensional (3D) photonic crystal (PC) waveguides with a combination of acceptor-type and donor-type line defects. Tuning the width of the acceptor-type line defect allows the waveguide to support two guided modes, which enable single-mode propagation over 98.7% of the complete photonic bandgap (cPBG). In addition, we demonstrate that the frequency ranges for single-mode propagation can be extended to the entire range of the cPBG by further tuning the thickness of the layers in which the donor-type line defects are located. The wide ranges of available frequencies for single mode propagation enable flexible design of 3D PC components and will provide a route towards future 3D photonic circuits. PMID- 23736464 TI - Ramsey spectroscopy of high-contrast CPT resonances with push-pull optical pumping in Cs vapor. AB - We report on the detection of high-contrast and narrow Coherent Population Trapping (CPT) Ramsey fringes in a Cs vapor cell using a simple-architecture laser system. The latter allows the combination of push-pull optical pumping (PPOP) and a temporal Ramsey-like pulsed interrogation. An originality of the optics package is the use of a single Mach-Zehnder electro-optic modulator (MZ EOM) both for optical sidebands generation and light switch for pulsed interaction. Typical Ramsey fringes with a linewidth of 166 Hz and a contrast of 33 % are detected in a cm-scale buffer-gas filled Cs vapor cell. This technique could be interesting for the development of high-performance and low power consumption compact vapor cell clocks based on CPT. PMID- 23736465 TI - Laser operation of a Tm:Y2O3 planar waveguide. AB - We demonstrate the first Tm-doped yttria planar waveguide laser to our knowledge, grown by pulsed laser deposition. A maximum output power of 35 mW at 1.95 MUm with 9% slope efficiency was achieved from a 12 MUm-thick film grown on a Y(3)Al(5)O(12) substrate. PMID- 23736467 TI - Physical optimization of quantum error correction circuits with spatially separated quantum dot spins. AB - We propose an efficient protocol for optimizing the physical implementation of three-qubit quantum error correction with spatially separated quantum dot spins via virtual-photon-induced process. In the protocol, each quantum dot is trapped in an individual cavity and each two cavities are connected by an optical fiber. We propose the optimal quantum circuits and describe the physical implementation for correcting both the bit flip and phase flip errors by applying a series of one-bit unitary rotation gates and two-bit quantum iSWAP gates that are produced by the long-range interaction between two distributed quantum dot spins mediated by the vacuum fields of the fiber and cavity. The protocol opens promising perspectives for long distance quantum communication and distributed quantum computation networks. PMID- 23736466 TI - Wide-field computational color imaging using pixel super-resolved on-chip microscopy. AB - Lens-free holographic on-chip imaging is an emerging approach that offers both wide field-of-view (FOV) and high spatial resolution in a cost-effective and compact design using source shifting based pixel super-resolution. However, color imaging has remained relatively immature for lens-free on-chip imaging, since a 'rainbow' like color artifact appears in reconstructed holographic images. To provide a solution for pixel super-resolved color imaging on a chip, here we introduce and compare the performances of two computational methods based on (1) YUV color space averaging, and (2) Dijkstra's shortest path, both of which eliminate color artifacts in reconstructed images, without compromising the spatial resolution or the wide FOV of lens-free on-chip microscopes. To demonstrate the potential of this lens-free color microscope we imaged stained Papanicolaou (Pap) smears over a wide FOV of ~14 mm(2) with sub-micron spatial resolution. PMID- 23736468 TI - Highly efficient color filter array using resonant Si3N4 gratings. AB - We demonstrate the design and fabrication of a highly efficient guided-mode resonant color filter array. The device is designed using numerical methods based on rigorous coupled-wave analysis and is patterned using UV-laser interferometric lithography. It consists of a 60-nm-thick subwavelength silicon nitride grating along with a 105-nm-thick homogeneous silicon nitride waveguide on a glass substrate. The fabricated device exhibits blue, green, and red color response for grating periods of 274, 327, and 369 nm, respectively. The pixels have a spectral bandwidth of ~12 nm with efficiencies of 94%, 96%, and 99% at the center wavelength of blue, green, and red color filter, respectively. These are higher efficiencies than reported in the literature previously. PMID- 23736469 TI - Terahertz single pixel imaging with an optically controlled dynamic spatial light modulator. AB - We present a single pixel terahertz (THz) imaging technique using optical photoexcitation of semiconductors to dynamically and spatially control the electromagnetic properties of a semiconductor mask to collectively form a THz spatial light modulator (SLM). By co-propagating a THz and collimated optical laser beam through a high-resistivity silicon wafer, we are able to modify the THz transmission in real-time. By further encoding a spatial pattern on the optical beam with a digital micro-mirror device (DMD), we may write masks for THz radiation. We use masks of varying complexities ranging from 63 to 1023 pixels and are able to acquire images at speeds up to 1/2 Hz. Our results demonstrate the viability of obtaining real-time and high-fidelity THz images using an optically controlled SLM with a single pixel detector. PMID- 23736470 TI - Visible cathodoluminescence of quantum dot films by direct irradiation of electron beam and its materialization as a field emission device. AB - The field emission (FE) device based on quantum dot (QD) films as a cathodoluminescent (CL) material has not emerged yet due to the relatively low quantum efficiency and weak photostability of nanocrystals (NCs). Here we improve film stability and luminescence yields by preparing neat films of well-packed core-multishell QDs using spray coating method and then using low-temperature atomic layer deposition (ALD) to infill the pores of these films with metal oxides to produce inorganic nanocomposites. The ALD coatings to protect oxidation and degradation by electrons prevent internal atomic and molecular diffusion and decrease surface trap densities of QD films. Furthermore, the CL of the core multishell QD films is 2.4 times higher than before ALD infilling. We fabricate the FE device by combining cathode structure with carbon nanotube (CNT) emitters and anode plates with QD thin film and successfully can get brilliant images of the light-emitting FE device. Our research opens a way for developing new quantum optoelectronics with high-performance. PMID- 23736471 TI - Femtosecond laser induced surface swelling in poly-methyl methacrylate. AB - We show that surface swelling is the first step in the interaction of a single femtosecond laser pulse with PMMA. This is followed by perforation of the swollen structure and material ejection. The size of the swelling and the perforated hole increases with pulse energy. After certain energy the swelling disappears and the interaction is dominated by the ablated hole. This behaviour is independent of laser polarization. The threshold energy at which the hole size coincides with size of swelling is 1.5 times that of the threshold for surface swelling. 2D molecular dynamics simulations show surface swelling at low pulse energies along with void formation below the surface within the interaction region. Simulations show that at higher energies, the voids coalesce and grow, and the interaction is dominated by material ejection. PMID- 23736472 TI - Image restoration through thin turbid layers by correlation with a known object. AB - A method to recover the image of an object behind thin turbid layers is developed by wavefront shaping technique. The optimized wavefront is generated by modulating the scattering light of a known object with a spatial light modulator. A Pearson Correlation Coefficient is introduced as a cost function for the optimization. A beam scanning method based on optical memory effect is proposed to further enlarge the Field-of-View (FOV). The experimental results show good fidelity and large FOV of the recovered image. PMID- 23736473 TI - 10.9 W kHz-linewidth one-stage all-fiber linearly-polarized MOPA laser at 1560 nm. AB - An all-fiber 10.9 W single-frequency one-stage linearly-polarized master oscillator power amplifier (MOPA) laser at 1560 nm has been demonstrated. The laser linewidth is less than 3.5 kHz and the polarization-extinction ratio (PER) is greater than 24 dB. The measured signal-to-noise ratio (SNR) is higher than 70 dB and the optical-to-optical conversion efficiency is 29.5%. No obvious stimulated Brillouin scattering and the devastating effects of unwanted coupling light were observed. PMID- 23736474 TI - Use of a gold reflecting-layer in optical antenna substrates for increase of photoluminescence enhancement. AB - We report on a straightforward way to increase the photoluminescence enhancement of nanoemitters induced by optical nanotantennas. The nanoantennas are placed above a gold film-silica bilayer, which produces a drastic increase of the scattered radiation power and near field enhancement. We demonstrate this increase via photoluminescence enhancement using an organic emitter of low quantum efficiency, Tetraphenylporphyrin (TPP). An increase of the photoluminescence enhancement by a factor larger than three is observed compared to antennas without the reflecting-layer. In addition, we study the possibility of influencing the polarization of the light emitted by utilizing asymmetry of dimer antennas. PMID- 23736475 TI - Characterization of nonlinear saturation and mode-locking potential of ionically doped colored glass filter for short-pulse fiber lasers. AB - The nonlinear saturable absorption of an ionically-doped colored glass filter is measured directly using a Z-scan technique. For the first time, we demonstrate the potential of this material as a saturable asborber in fiber lasers. We achieve mode-locking of an ytterbium doped system. Mode-locking of cavities with all-positive and net-negative group velocity dispersion are demonstrated, achieving pulse durations of 60 ps and 4.1 ps, respectively. This inexpensive and optically robust material, with the potential for broadband operation, could surplant other saturable absorber devices in affordable mode-locked fiber lasers. PMID- 23736476 TI - Multi-wavelength Erbium-doped fiber laser based on four-wave-mixing effect in single mode fiber and high nonlinear fiber. AB - A multi-wavelength Erbium-doped fiber (EDF) laser based on four-wave-mixing is proposed and experimentally demonstrated. The 5 km single mode fiber in the cavity enhances the four-wave-mixing to suppress the homogenous broadening of the erbium-doped fiber and get the stable multi-wavelength comb. The lasing stability is investigated. When the pump power is 300 mW, the fiber laser has 5-lasing lines and the maximum fluctuation of the output power is about 3.18 dB. At the same time, a laser with 110 m high nonlinear fiber (HNFL) is demonstrated. When the pump power is 300 mW, it has 7-lasing lines (above -30 dBm) and the maximum fluctuation is 0.18dB. PMID- 23736477 TI - Optimization of excitation-emission band-pass filter for visualization of viable bacteria distribution on the surface of pork meat. AB - A novel method of optically reducing the dimensionality of an excitation-emission matrix (EEM) by optimizing the excitation and emission band-pass filters was proposed and applied to the visualization of viable bacteria on pork. Filters were designed theoretically using an EEM data set for evaluating colony-forming units on pork samples assuming signal-to-noise ratios of 100, 316, or 1000. These filters were evaluated using newly measured EEM images. The filters designed for S/N = 100 performed the best and allowed the visualization of viable bacteria distributions. The proposed method is expected to be a breakthrough in the application of EEM imaging. PMID- 23736478 TI - A 3D tunable and multi-frequency graphene plasmonic cloak. AB - We demonstrate the possibility of cloaking three-dimensional objects at multi frequencies in the far-infrared part of the spectrum. The proposed cloaking mechanism exploits graphene layers wrapped around the object to be concealed. Graphene layers are doped via a variable external voltage difference permitting continuous tuning of the cloaking frequencies. Particularly, two configurations are investigated: (i) Only one graphene layer is used to suppress the scattering from a dielectric sphere. (ii) Several of these layers biased at different gate voltages are used to achieve a multi-frequency cloak. These frequencies can be set independently. The proposed cloak's functionality is verified by near- and far-field computations. By considering geometry and material parameters that are realizable by practical experiments, we contribute to the development of graphene based plasmonic applications that may find use in disruptive photonic technologies. PMID- 23736479 TI - Near-infrared femtosecond laser-triggered nanoperforation of hollow microcapsules. AB - Fabrication of a nanopore in a hollow microcapsule was demonstrated using near infrared femtosecond laser irradiation. The shape of the irradiated microcapsules was kept spherical except for a pore in the shell owing to the nonthermal processing by a femtosecond laser. The simulation results for the near-field and far-field scattering around a microcapsule revealed that highly-enhanced optical intensity can be generated at a spot on the shell of a microcapsule, which would in turn contribute to localized ablation. To the best of our knowledge, this is the first demonstration of the nanoperforation of transparent hollow microcapsules by a near-infrared laser without any doping with absorbing metals or dyes that may cause cell toxicity. The presented method is a promising approach for safer drug delivery and the controlled release of therapeutic drugs. PMID- 23736480 TI - Backscatter digital holography of microparticles. AB - This work investigates a method for digital holographic imaging of microparticles. Traditional digital holographic techniques use a particle's forward scattered light to form the hologram, whereas here we use the backscattered light. Images of a particle are then computationally reconstructed from the backscatter hologram, and several examples of such reconstructions are presented. A potential advantage of this technique is that the backscatter holograms may be more sensitive to particle-surface details. PMID- 23736481 TI - Polarization characteristics of Whispering-Gallery-Mode fiber lasers based on evanescent-wave-coupled gain. AB - The polarization characteristics of Whispering-Gallery-Mode (WGM) fiber lasers based on evanescent-wave-coupled gain are investigated. For the laser gain is excited by side-pumping scheme, it is found that the polarization property of lasing emission is simply dependent on the polarized states of the pump beams. The polarization property of lasing emission depends on the propagating situation of the pump beams in an optical fiber if the laser gain is excited by evanescent wave pumping scheme, that is, if the pump beams within the fiber are meridional beams, the lasing emission is a transverse electric (TE) wave that forms a special radial polarization emission. However, if the pump beams within the fiber are skew beams, both transverse magnetic (TM) and TE waves exist simultaneously in lasing emission that forms a special axially and radially mixed polarization emission. Pumped by skew beams, the wave-number differences between TE and TM waves are also investigated quantitatively, the results demonstrate that the wave number difference decreases with the increase of the fiber diameter and the refractive index (RI) of the cladding solution. The observed polarization characteristics have been well explained based on lasing radiation mechanism of WGM fiber laser of gain coupled by evanescent wave. PMID- 23736482 TI - Diode-pumped continuous wave and passively Q-switched Tm,Ho:LLF laser at 2 um. AB - A compact diode-pumped continuous wave and passively Q-switched Tm,Ho:LuLiF(4) laser is demonstrated. The maximal output power of 381 mW at 2069 nm in continuous wave regime is obtained at an absorbed pump power of 1.5 W. By using a Cr(2+):ZnS saturable absorber, the maximum Q-switched average output power of 74 mW is obtained at 2055 nm. The pulse width and pulse energy are almost independent of the absorbed pump power, with the maximal values of 1.2 MUs and of 13 MUJ respectively. The pulse repetition frequency can be tuned almost linearly from 1 to 5.8 kHz by changing the absorbed pump power. Furthermore, a comparative analysis of laser performances with different output couplers is first carried out. PMID- 23736483 TI - Intense ultra-broadband down-conversion in co-doped oxide glass by multipolar interaction process. AB - We report that Eu(2+) can be an efficient sensitizer for Yb(3+) and a broadband absorber for blue solar spectra in the host of oxide glass. The greenish 4f -> 5d transition of Eu(2+) and the characteristic near-infrared emission of Yb(3+) were observed, with the blue-light of xenon lamp excitation. The 5d energy can be adjusted by the host and the energy transfer efficiency can be enhanced. The quantum efficiency is up to 163.8%. Given the broad excitation band, high absorption coefficient and excellent mechanical, thermal and chemical stability, this system can be useful as down-conversion layer for solar cells. PMID- 23736484 TI - Full field vertical scanning in short coherence digital holographic microscope. AB - In Digital holography Microscopes (DHM) implemented in the so-called "off axis" configuration, the object and reference wave fronts are not co-planar but form an angle of a few degrees. This results into two main drawbacks. First, the contrast of the interference is not uniform spatially when the light source has low coherence. The interference contrast is optimal along a line, but decreases when moving away from it, resulting in a lower image quality. Second, the non coplanarity between the coherence plane of both wavefronts impacts the coherence vertical scanning measurement mode: when the optical path difference between the signal and the reference beam is changed, the region of maximum interference contrast shifts laterally in the plane of the objective. This results in more complex calculations to extract the topography of the sample and requires scanning over a much larger vertical range, leading to a longer measurement time. We have previously shown that by placing a volume diffractive optical element (VDOE) in the reference arm, the wavefront can be made coplanar with the object wavefront and the image plane of the microscope objective, resulting in a uniform and optimal interferogram. In this paper, we demonstrate a vertical scanning speed improvement by an order of magnitude. Noise in the phase and intensity images caused by scattering and non-uniform diffraction in the VDOE is analyzed quantitatively. Five VDOEs were fabricated with an identical procedure. We observe that VDOEs introduce a small intensity non-uniformity in the reference beam which results in a 20% noise increase in the extracted phase image as compared to the noise in extracted phase image when the VDOE is removed. However, the VDOE has no impact on the temporal noise measured from extracted phase images. PMID- 23736485 TI - The role of light-induced nanostructures in femtosecond laser micromachining with vector and scalar pulses. AB - In this article we compare the results of micromachining of fused silica and silicon with tightly focused scalar (viz., circularly and linearly polarized) and vector (viz., azimuthally and radially polarized) femtosecond laser pulses. We show that drilling with radially polarized pulses produces holes with smoother and better-delineated walls compared with the other polarizations used, whereas linearly polarized pulses can machine 20-nm wide single grooves in fused silica when the electric field of the pulse is aligned perpendicular to the cutting direction. The observed polarization-controlled micromachining is due to the formation of sub-diffraction-limited nanostructures that are optically produced in the multi-pulse irradiation regime. PMID- 23736486 TI - Sensing and transmission characteristics of a rocking filter fabricated in a side hole fiber with zero group birefringence. AB - We report on sensing and transmission characteristics of rocking filters fabricated in a silica side-hole fiber with group birefringence changing its sign at certain wavelength (lambda(G = 0)), which corresponds to parabolic-like spectral dependence of beat length. Unusual birefringence dispersion of the side hole fiber is induced by an elliptical germanium doped core located in a narrow glass bridge between two holes. Rocking filters fabricated in such a fiber have two resonances of the same order located on both sides of lambda(G = 0). The sensitivity of both resonances has an opposite sign, which makes it possible to double the response of the rocking filter by applying the differential interrogation scheme. We demonstrate that in this way a pressure sensitivity of the rocking filter can be enlarged to 132 nm/MPa. We also show that by fabricating the rocking filter with a period close to maximum beat length a coupling between polarization modes can be obtained in a broad band reaching 240 nm. PMID- 23736487 TI - Mode transition in complex refractive index coated single-mode-multimode-single mode structure. AB - By coating a single-mode-multimode-single-mode (SMS) structure with a high refractive index thin-film it is possible to obtain a transition of modes for specific combinations of thin-film thickness, thin-film refractive index and surrounding medium refractive index, which permits to develop devices with a high sensitivity to specific parameters. In order to gain a better knowledge of the phenomenon the experimental results are corroborated numerically with the Transfer-Matrix-Method. The influence of losses in the thin-film has also been studied. The results obtained prove that a thin-film coated SMS structure is a simple and cost-effective platform for development of sensors and optical filters. PMID- 23736488 TI - Field-flattened, ring-like propagation modes. AB - We present a method for designing optical fibers that support field-flattened, ring-like higher order modes, and show that the effective and group indices of its modes can be tuned by adjusting the widths of the guide's field-flattened layers or the average index of certain groups of layers. The approach provides a path to fibers that have simultaneously large mode areas and large separations between the propagation constants of their modes. PMID- 23736489 TI - Theoretical investigation of ultracompact and athermal Si electro-optic modulator based on Cu-TiO2-Si hybrid plasmonic donut resonator. AB - An ultracompact silicon electro-optic modulator operating at 1550-nm telecom wavelengths is proposed and analyzed theoretically, which consists of a Cu-TiO(2) Si hybrid plasmonic donut resonator evanescently coupled with a conventional Si channel waveguide. Owing to a negative thermo-optic coefficient of TiO(2) (~-1.8 * 10(-4) K(-1)), the real part of effective modal index of the curved Cu-TiO(2) Si hybrid waveguide can be temperature-independent (i.e., athermal) if the TiO(2) interlayer and the beneath Si core have a certain thickness ratio. A voltage applied between the ring-shaped Cu cap and a cylinder metal electrode positioned at the center of the donut,--which makes Ohmic contact to Si, induces a ~1-nm thick free-electron accumulation layer at the TiO(2)/Si interface. The optical field intensity in this thin accumulation layer is significantly enhanced if the accumulation concentration is sufficiently large (i.e., > ~6 * 10(20) cm(-3)), which in turn modulates both the resonance wavelengths and the extinction ratio of the donut resonator simultaneously. For a modulator with the total footprint inclusive electrodes of ~8.6 MUm(2), 50-nm-thick TiO(2), and 160-nm-thick Si core, FDTD simulation predicts that it has an insertion loss of ~2 dB, a modulation depth of ~8 dB at a voltage swing of ~6 V, a speed-of-response of ~35 GHz, and a switching energy of ~0.45 pJ/bit, and it is athermal around room temperature. The modulator's performances can be further improved by optimization of the coupling strength between the bus waveguide and the donut resonator. PMID- 23736490 TI - Phase-sensitive frequency conversion of quadrature modulated signals. AB - Two mechanisms that can make frequency conversion based on nonlinear mixing dependent on the phase of the input signal are identified. A novel phase-to polarization converter that converts the orthogonal phase components of an input signal to two orthogonally polarized outputs is proposed. The operation of this scheme and a previously reported scheme at an increased symbol rate are simulated with semiconductor optical amplifiers (SOAs) as the nonlinear devices. Experimental results demonstrate the effectiveness of SOAs for nonlinear mixing over a wide range of wavelengths and difference frequencies and confirm the accuracy of the numerical model. PMID- 23736491 TI - Two-wire terahertz fibers with porous dielectric support. AB - A novel plasmonic THz fiber is described that features two metallic wires that are held in place by the porous dielectric cladding functioning as a mechanical support. This design is more convenient for practical applications than a classic two metal wire THz waveguide as it allows direct manipulations of the fiber without the risk of perturbing its core-guided mode. Not surprisingly, optical properties of such fibers are inferior to those of a classic two-wire waveguide due to the presence of lossy dielectric near an inter-wire gap. At the same time, composite fibers outperform porous fibers of the same geometry both in bandwidth of operation and in lower dispersion. Finally, by increasing cladding porosity one can consistently improve optical properties of the composite fibers. PMID- 23736492 TI - Super-Gaussian apodization in ground based telescopes for high contrast coronagraph imaging. AB - We introduce the use of Super-Gaussian apodizing functions in the telescope pupil plane and/or the coronagraph Lyot plane to improve the imaging contrast in ground based coronagraphs. We describe the properties of the Super-Gaussian function, we estimate its second-order moment in the pupil and Fourier planes and we check it as an apodizing function. We then use Super-Gaussian function to apodize the telescope pupil, the coronagraph Lyot plane or both of them. The result is that a proper apodizing masks combination can reduce the exoplanet detection distance up to a 45% with respect to the classic Lyot coronagraph, for moderately aberrated wavefronts. Compared to the prolate spheroidal function the Super-Gaussian apodizing function allows the planet light up to 3 times brighter. An extra help to increase the extinction rate is to perform a frame selection (Lucky Imaging technique). We show that a selection of the 10% best frames will reduce up to a 20% the detection angular distance when using the classic Lyot coronagraph but that the reduction is only around the 5% when using an apodized coronagraph. PMID- 23736493 TI - Light curtain for 2D large-area object detection. AB - Fluorescent foils are used with silicon photodiodes for large-area detection of objects, when combined with lasers forming a light curtain. An object entering the detection area penetrates the light curtain and casts shadows onto the fluorescent foils. Using a simple mathematical algorithm, the position of the object is detected with high speed. The device is suitable for security applications and can be used as a touch input device for computers, gaming and presentations. PMID- 23736494 TI - On-chip quasi-digital optical switch using silicon microring resonator-coupled Mach-Zehnder interferometer. AB - In this work, we demonstrate thermo-optical quasi-digital optical switch (q-DOS) using silicon microring resonator-coupled Mach-Zehnder interferometer. The optical transmission spectra show box-like response with 1-dB and 3-dB bandwidths of ~1.3 nm and ~1.6 nm, respectively. Such broadband flat-top optical response improves the tolerance to the light source wavelength fluctuation of +/- 6 A and temperature variation of +/- 6 degrees C. Dynamic characterizations show the device with switching power of ~37 mW, switching time of ~7 MUs, and on/off ratio of > 30 dB. For performance comparison, we also demonstrate a carrier injection based electro-optical q-DOS by integrating lateral P-i-N junction with the microring resonator, which significantly reduces power consumption to ~12 mW and switching time to ~0.7 ns only. PMID- 23736495 TI - 50-Gb/s silicon optical modulator with traveling-wave electrodes. AB - We demonstrate silicon Mach-Zehnder Interferometer (MZI) optical modulator with 50.1-Gb/s data rate and 5.56 dB dynamic extinction ratios. The phase shifter is composed by a 4 mm-long reverse-biased p-n junction with a modulation efficiency (V(pi) . L(pi)) of ~26.7 V . mm and phase shifter loss of ~1.04 dB/mm at V(bias) = -6 V. The measured electro-optic bandwidth reaches 25.6 GHz at V(bias) = -5 V. Compensation doping method and low loss traveling-wave electrodes are utilized to improve the modulator performance. Measurement result demonstrates that reasonable choosing of working point and doping profile of the silicon optical modulator is critical in order to match the performance requirement of the real application. PMID- 23736496 TI - Second harmonic generation in isotropic media: six-wave mixing of optical vortices. AB - Optical vortex light can be up-converted into a second harmonic output in an isotropic medium, in which such conversion is normally forbidden, through six wave mixing. The involvement of orbital angular momentum is tackled for the case of a Laguerre-Gaussian pump comprising l = 1 photons. By calculating quantum amplitudes for the emergent radiation states, utilizing a state-sequence method, the analysis identifies the characteristics of the emission and an entangled distribution of conserved orbital momentum. A distinctive conical spread affords a potential means of resolving the individual angular momentum content. PMID- 23736497 TI - CMOS compatible horizontal nanoplasmonic slot waveguides TE-pass polarizer on silicon-on-insulator platform. AB - An ultra-compact broadband TE-pass polarizer was proposed and demonstrated on the silicon-on-insulator (SOI) platform, using the horizontal nanoplasmonic slot waveguide (HNSW). Detailed design principle was presented, taking advantage of the distinct confinement region of the TE and TM modes in the HNSW. TM mode cut off could be achieved when waveguide width was below 210 nm. Proof-of-concept devices were subsequently fabricated in a CMOS-compatible process. The optimized device had an active region length of 1 MUm, three orders of magnitude smaller than similar device previously demonstrated on the SOI platform. More than 16 dB polarization extinction ratio was achieved across 80 nm wavelength range, with a relatively low insertion loss of 2.2dB. The compact device size and excellent broadband performance could provide a simple yet satisfactory solution to the polarization dependent performance drawback of the silicon photonics devices on the SOI platform. PMID- 23736498 TI - Thulium-doped all-fiber laser mode-locked by CVD-graphene/PMMA saturable absorber. AB - We report an all-fiber Tm-doped fiber laser mode-locked by graphene saturable absorber. The laser emits 1.2 ps pulses at 1884 nm center wavelength with 4 nm of bandwidth and 20.5 MHz mode spacing. The graphene layers were grown on copper foils by chemical vapor deposition (CVD) and transferred onto the fiber connector end. Up to date this is the shortest reported pulse duration achieved from a Tm doped laser mode-locked by graphene saturable absorber. Such cost-effective and stable fiber lasers might be considered as sources for mid-infrared spectroscopy and remote sensing. PMID- 23736499 TI - Modified convolution method to reconstruct particle hologram with an elliptical Gaussian beam illumination. AB - Application of the modified convolution method to reconstruct digital inline holography of particle illuminated by an elliptical Gaussian beam is investigated. Based on the analysis on the formation of particle hologram using the Collins formula, the convolution method is modified to compensate the astigmatism by adding two scaling factors. Both simulated and experimental holograms of transparent droplets and opaque particles are used to test the algorithm, and the reconstructed images are compared with that using FRFT reconstruction. Results show that the modified convolution method can accurately reconstruct the particle image. This method has an advantage that the reconstructed images in different depth positions have the same size and resolution with the hologram. This work shows that digital inline holography has great potential in particle diagnostics in curvature containers. PMID- 23736500 TI - Selective detection of sub-atto-molar Streptavidin in 10(13)-fold impure sample using photonic crystal nanolaser sensors. AB - Biosensors selectively detecting a very small amount of biomarker protein in human blood are desired for early and reliable diagnoses of severe diseases. This paper reports the detection of protein (streptavidin: SA) in ultra-low concentration, with an ultra-high selectivity against contaminants, using photonic crystal nanolasers. For biotin-modified nanolasers in pure water with SA, an extremely-low detection limit of 16 zM is evaluated. Even in a mixture with 1 MUM bovine serum albumin as the contaminant, 100 zM SA is detected, meaning a selectivity of 10(13). These are remarkable capabilities that are promising for practical biosensing in the medical applications mentioned above. PMID- 23736501 TI - Rapid spectral-domain localization. AB - We present a method to dynamically image structures at nanometer spatial resolution with far-field instruments. We propose the use of engineered nanoprobes with distinguishable spectral responses and the measurement of coherent scattering, rather than fluorescence. Approaches such as PALM/STORM have relied on the rarity of emission events in time to distinguish signals from distinct probes. By distinguishing signals in the spectral domain, we enable the acquisition of data in a multiplex fashion and thus circumvent the fundamental problem of slow data acquisition of current techniques. The described method has the potential to image dynamic systems with a spatial resolution only limited to the size of the scattering probes. PMID- 23736502 TI - Emission properties of ns and ps laser-induced soft x-ray sources using pulsed gas jets. AB - The influcence of the pulse duration on the emission characteristics of nearly debris-free laser-induced plasmas in the soft x-ray region (lambda ~ 1-5 nm) was investigated, using six different target gases from a pulsed jet. Compared to ns pulses of the same energy, a ps laser generates a smaller, more strongly ionized plasma, being about 10 times brighter than the ns laser plasma. Moreover, the spectra are considerably shifted towards shorter wavelengths. Electron temperatures and densities of the plasma are obtained by comparing the spectra with model calculations using a magneto-hydrodynamic code. PMID- 23736503 TI - Fabrication of nitrogen vacancy color centers by femtosecond pulse laser illumination. AB - We report on a novel method to fabricate single, multiple and large-area high density ensembles of nitrogen vacancy (NV) color centers in synthetic type Ib bulk diamond by femtosecond laser illumination. Electron beams generated in propagation of intense infrared laser pulses in air sputtered on a diamond sample under high temperature aroused by the laser illumination, creating NV color centers. Typical photoluminescence (PL) spectra of NV centers could be observed on the illuminated spots. Photon streams from individual photoluminescent points exhibited anti-bunching effect by the second-order correlation measurement, evidencing single and multiple photon-emitters around the laser illuminated spots. PMID- 23736504 TI - The three-electron bond =Si2 nanosphere lithography and dry-etch process. Focused-ion-beam (FIB)-deposited Pt was contacted to both ends of the nanorod LEDs, producing bright electroluminescence from the LEDs under forward bias conditions. The turn on voltage in these nanorod LEDs was higher (13 V) than in companion thin film devices (3 V) and this can be attributed to the high contact resistance between the FIB-deposited Pt and nanorod LEDs and the damage induced by inductively coupled plasma and Ga + -ions. Our method to obtain uniform MQW nanorod LEDs shows promise for improving the reproducibility of nano-optoelectronics. PMID- 23736511 TI - Performance evaluation of reflective electro-absorption modulator based optical source using a broadband light seed source for colorless WDM-PON applications. AB - The performance of reflective electro-absorption modulator (R-EAM) based optical source has been evaluated for the use in high-capacity wavelength-division multiplexed passive optical networks (WDM-PONs). In our measurements, a broadband light source (BLS) was used as a seeding source for the cost-effective implementation of R-EAM based optical source. At first, a bit-error rate (BER) floor at 10(-6) was observed even in a back-to-back configuration with the BLS seeded R-EAM source. This is mainly because of the excess intensity noise (EIN) within BLS and the signal-to-noise ratio (SNR) degradation induced by a high insertion loss of R-EAM. To mitigate both effects of EIN and SNR degradation, a reflective semiconductor optical amplifier (RSOA) was also used for the implementation of our BLS seeded R-EAM source. Then, we have evaluated the impact of various noises, such as EIN, chromatic dispersion of transmission fiber and in band crosstalk, on the system's performance using our BLS seeded R-EAM optical source. From the results, we have found that a 3-dB bandwidth of the BLS seeded R EAM optical source should be wider than ~0.8 nm to achieve an error-free transmission of 1.25 Gb/s signal. We have also confirmed that there was a trade off between the dispersion- and the in-band crosstalk-induced penalties due to the wide source bandwidth of our BLS seeded R-EAM source, like the cases of BLS seeded RSOA and Fabry-Perot laser diode (FP-LD) sources. PMID- 23736512 TI - Mode demultiplexer using angularly multiplexed volume holograms. AB - This study proposes a volume holographic demultiplexer (VHDM) for extracting the spatial modes excited in a multimode fiber. A unique feature of the demultiplexer is that it can separate a number of multiplexed modes output from a fiber in different directions by using multi-recorded holograms without beam splitters, which results in a simple configuration as compared with that using phase plates instead of holograms. In this study, an experiment is conducted to demonstrate the basic operations for three LP mode groups to confirm the performance of the proposed VHDM and to estimate the signal-to-crosstalk noise ratio (SNR). As a result, an SNR of greater than 20 dB is obtained. PMID- 23736513 TI - Enhancement of graphene visibility on transparent substrates by refractive index optimization. AB - Optical reflection microscopy is one of the main imaging tools to visualize graphene microstructures. Here is reported a novel method that employs refractive index optimization in an optical reflection microscope, which greatly improves the visibility of graphene flakes. To this end, an immersion liquid with a refractive index that is close to that of the glass support is used in-between the microscope lens and the support improving the contrast and resolution of the sample image. Results show that the contrast of single and few layer graphene crystals and structures can be enhanced by a factor of 4 compared to values commonly achieved with transparent substrates using optical reflection microscopy lacking refractive index optimization. PMID- 23736514 TI - Numerical modeling of fiber lasers with long and ultra-long ring cavity. AB - We highlight two important aspects related to a mathematical modeling of pulsed fiber lasers with long and ultra-long ring cavity -impact of an initial noise and a cavity length on generation of single optical pulses. Using as an example a simple scalar model of a ring fiber laser that describes the radiation build-up from noise and the following intra-cavity pulse dynamics during a round trip we study dependence of generated pulse characteristics on the resonator length in the range from 30 m up to 2 km. PMID- 23736515 TI - Temporally focused wide-field two-photon microscopy: paraxial to vectorial. AB - Temporal focusing allows for optically sectioned wide-field microscopy. The optical sectioning arises because this method takes a pulsed input beam, stretches the pulses by diffracting off a grating, and focuses the stretched pulses such that only at the focal plane are the pulses re-compressed. This approach generates nonlinear optical processes at the focal plane and results in depth discrimination. Prior theoretical models of temporal focusing processes approximate the contributions of the different spectral components by their mean. This is valid for longer pulses that have narrower spectral bandwidth but results in a systematic deviation when broad spectrum, femtosecond pulses are used. Further, prior model takes the paraxial approximation but since these pulses are focused with high numerical aperture (NA) objectives, the effects of the vectorial nature of light should be considered. In this paper we present a paraxial and a vector theory of temporal focusing that takes into account the finite spread of the spectrum. Using paraxial theory we arrive at an analytical solution to the electric field at the focus for temporally focused wide-field two photon (TF2p) microscopy as well as in the case of a spectrally chirped input beam. We find that using paraxial theory while accounting for the broad spectral spread gives results almost twice vector theory. Experiment results agree with predictions of the vector theory giving an axial full-width half maximum (FWHM) of 2.1 MUmand1.8 MUmrespectively as long as spectral spread is taken into account. Using our system parameters, the optical sectioning of the TF2p microscope is found to be 8 MUm. The optical transfer function (OTF) of a TF2p microscope is also derived and is found to pass a significantly more limited band of axial frequencies than a point scanning two-photon (2p) microscope or a single photon (1p) confocal microscope. PMID- 23736516 TI - Cardiorespiratory and neurological effects of morphine and butorphanol in Bos taurus. PMID- 23736517 TI - Postcastration analgesia in ponies using buprenorphine hydrochloride. AB - Buprenorphine has recently obtained UK Marketing Authorisation for horses. The analgesic effects are long lasting, and have considerable potential for postoperative pain relief. This observer blinded, randomised study aimed to evaluate postsurgical analgesia in ponies premedicated with buprenorphine prior to castration under intravenous anaesthesia. Ponies received either 0.01 mg/kg bodyweight (BW) buprenorphine (group B) or an equivalent volume of 5 per cent glucose (group C) given intravenously before induction of anaesthesia. Pain was assessed and recorded using dynamic interactive visual analogue scores (DIVAS 0 100) and a Simple Descriptive Scale (SDS 0-3) (high scores=most pain) before and 1, 3, 6, 9, 12 and 24 hours after anaesthesia. Rescue analgesia was given if DIVAS>40 mm. Data were analysed using the Mann-Whitney U test at P<0.05. Median (range) areas under the curve for DIVAS were 63 (0-383) mm hour in group B and 209 (0-391) mm hour in group C (P=0.0348). The SDS was lower in group B than in group C (P=0.038). Three group B and five group C animals required rescue analgesia. Buprenorphine did not produce any serious adverse effects. Buprenorphine at 0.01 mg/kg BW intravenously administered before anaesthesia provided near-comprehensive postoperative analgesia after surgical castration in ponies. PMID- 23736518 TI - Deep digital flexor tendon injury within the hoof capsule; does lesion type or location predict prognosis? AB - The type and location of deep digital flexor tendon (DDFT) lesions may be important in predicting outcome. The objectives of this study were to determine the frequency of different types of DDFT lesions within the hoof capsule and to determine whether lesion type predicts return to athletic activity. Lesions of the DDFT were divided into: core lesions, dorsal border lesions and parasagittal splits. Lesion location was documented, and follow-up information was obtained by telephone survey at least 18 months after diagnosis. Of 168 horses with primary DDFT injury, 54 horses had dorsal border lesions, 59 had parasagittal splits and 55 had core lesions. Twenty-five per cent of all horses returned to previous levels of athletic activity within 18 months of MRI evaluation. Horses with complete splits or core lesions of the DDFT were significantly less likely to return to some level of athletic activity than horses with dorsal border lesions P<0.001. Dorsal border lesions of the DDFT appear to have a better prognosis than core lesions or parasagittal splits. This study provides additional information that may help clinicians predict the prognosis for different types of DDFT injury. PMID- 23736520 TI - Interventional cardiology: Indications for renal denervation: a balanced approach? AB - Renal denervation for the treatment of resistant hypertension is approved in Europe and is being studied in the USA. A newly published ESC consensus document integrates all the published data on this procedure, and summarizes how best to define, evaluate, and follow up patients who are candidates for the procedure. PMID- 23736519 TI - Statins in the primary prevention of cardiovascular disease. AB - Statins are widely used in the evidence-based lowering of cardiovascular disease (CVD) risk. The use of these drugs for secondary prevention of CVD is well founded, but their expanding use in primary prevention--in individuals without documented CVD--has raised some concerns. Firstly, evidence suggests that, in primary prevention, statins substantially decrease CVD morbidity, but only moderately reduce CVD mortality. Secondly, long-term statin use might cause adverse effects, such as incident diabetes mellitus. Thirdly, the cost effectiveness of such a strategy is unclear, and has to be balanced against the risk of 'overmedicating' the general population. Data clearly support the use of statins for primary prevention in high-risk individuals, in whom the strategy is cost-effective and the benefits exceed the risks. Whether primary prevention is beneficial in individuals at low or moderate risk is not certain. Therefore, the prescription of statins for primary prevention should be individualized on the basis of clinical judgment, particularly for low-risk individuals. In appropriately selected individuals, statins should also be used for primary prevention of ischaemic stroke and transient ischaemic attack. PMID- 23736521 TI - Device therapy: increased number of complications with dual-chamber ICDs. PMID- 23736523 TI - Cue-dependent memory-based smooth-pursuit in normal human subjects: importance of extra-retinal mechanisms for initial pursuit. AB - Using a cue-dependent memory-based smooth-pursuit task previously applied to monkeys, we examined the effects of visual motion-memory on smooth-pursuit eye movements in normal human subjects and compared the results with those of the trained monkeys. These results were also compared with those during simple ramp pursuit that did not require visual motion-memory. During memory-based pursuit, all subjects exhibited virtually no errors in either pursuit-direction or go/no go selection. Tracking eye movements of humans and monkeys were similar in the two tasks, but tracking eye movements were different between the two tasks; latencies of the pursuit and corrective saccades were prolonged, initial pursuit eye velocity and acceleration were lower, peak velocities were lower, and time to reach peak velocities lengthened during memory-based pursuit. These characteristics were similar to anticipatory pursuit initiated by extra-retinal components during the initial extinction task of Barnes and Collins (J Neurophysiol 100:1135-1146, 2008b). We suggest that the differences between the two tasks reflect differences between the contribution of extra-retinal and retinal components. This interpretation is supported by two further studies: (1) during popping out of the correct spot to enhance retinal image-motion inputs during memory-based pursuit, pursuit eye velocities approached those during simple ramp-pursuit, and (2) during initial blanking of spot motion during memory based pursuit, pursuit components appeared in the correct direction. Our results showed the importance of extra-retinal mechanisms for initial pursuit during memory-based pursuit, which include priming effects and extra-retinal drive components. Comparison with monkey studies on neuronal responses and model analysis suggested possible pathways for the extra-retinal mechanisms. PMID- 23736524 TI - Effects of muscle vibration on multi-finger interaction and coordination. AB - The purpose of this study was to investigate the effects of changes in the proprioceptive signals induced by muscle vibration on multi-finger interaction and coordination. We hypothesized that unintended force production by non instructed fingers (enslaving) would increase with muscle vibration while synergy indices during steady-state force production would drop. The framework of the uncontrolled manifold hypothesis was used to quantify indices of multi-finger synergies stabilizing total force during steady-state force production and anticipatory changes in these indices (anticipatory synergy adjustments, ASAs) in preparation to a quick force pulse production with and without hand-muscle vibration at 80 Hz. The dominant hands of twelve healthy right-handed subjects were tested under three conditions: no vibration, vibration of the palmar surface of the hand, and vibration of the forearm applied over the flexor muscles. There were no significant effects of vibration on maximal voluntary force. The magnitude of enslaving was larger during vibration of the hand compared to the other two conditions. During steady-state force production, strong synergies stabilizing total force were seen in all three conditions; however, indices of force-stabilizing synergies were lower during vibration of the hand. Prior to the force pulse initiation, the synergy index started to drop earlier and over a larger magnitude without vibration compared to either vibration condition. Effects of vibration on enslaving and synergy index may be due to diffuse reflex effects of the induced afferent activity on alpha-motoneuronal pools innervating the extrinsic flexor compartments. We conclude that multi-finger synergies are not based on signals from muscle receptors. The smaller synergy indices and ASAs may reflect supraspinal effects of the vibration-induced afferent activity, in particular its interactions with trans-thalamic loops. PMID- 23736525 TI - Magnetism and spin dynamics of novel encapsulated iron oxide superparamagnetic nanoparticles. AB - Encapsulated Fe3O4 nanoparticles of average diameters d = 12 nm are obtained by coprecipitation, in the presence of 2-methoxyethanol hemiester of poly(maleic anhydride-alt-butyl vinyl ether) 5% grafted with poly(ethylene glycol) (VP-MAG nanoparticles). A complete characterization of nude and encapsulated nanoparticles through structural techniques (namely XRD, TEM, SEM), Raman spectroscopy and magnetic measurements has been performed. These nanoparticles compared with commercial compounds (ENDOREM(r)) present superparamagnetic behavior and nuclear relaxivities that make them promising as magnetic resonance imaging (MRI) contrast agents (CAs). We found that our nanostructures exhibit r2 relaxivity higher than those of commercial CAs over the whole frequency range. The MRI efficiency of our samples was related to their microstructural and magnetic properties. PMID- 23736526 TI - Intramolecular [2+2+2] cycloaddition of bis(propargylphenyl)carbodiimides: synthesis of L-shaped pi-extended compounds with pyrrolo[1,2-a][1,8]naphthyridine corner units. AB - L-shaped pi-extended penta-, hexa-, and heptacycles with a pyrrolo[1,2 a][1,8]naphthyridine junction were prepared from N,N'-bis[2-(2-alkyn-1 yl)phenyl]carbodiimides or their naphthyl analogs via Rh(I)-catalyzed intramolecular [2+2+2] cycloaddition and dehydrogenative aromatization. These L shaped compounds emit sky-blue, yellow-green, or golden-orange fluorescence, with high quantum yields. PMID- 23736528 TI - BeCAS: biomedical concept recognition services and visualization. AB - SUMMARY: The continuous growth of the biomedical scientific literature has been motivating the development of text-mining tools able to efficiently process all this information. Although numerous domain-specific solutions are available, there is no web-based concept-recognition system that combines the ability to select multiple concept types to annotate, to reference external databases and to automatically annotate nested and intercepted concepts. BeCAS, the Biomedical Concept Annotation System, is an API for biomedical concept identification and a web-based tool that addresses these limitations. MEDLINE abstracts or free text can be annotated directly in the web interface, where identified concepts are enriched with links to reference databases. Using its customizable widget, it can also be used to augment external web pages with concept highlighting features. Furthermore, all text-processing and annotation features are made available through an HTTP REST API, allowing integration in any text-processing pipeline. AVAILABILITY: BeCAS is freely available for non-commercial use at http://bioinformatics.ua.pt/becas. CONTACTS: tiago.nunes@ua.pt or jlo@ua.pt. PMID- 23736527 TI - Clinical and pathological nodal staging score for urothelial carcinoma of the bladder: an external validation. AB - PURPOSE: Radical cystectomy (RC) and pelvic lymph node dissection (LND) are standard treatments for muscle-invasive urothelial carcinoma of the bladder. Lymph node staging is a prerequisite for clinical decision-making regarding adjuvant chemotherapy and follow-up regimens. Recently, the clinical and pathological nodal staging scores (cNSS and pNSS) were developed. Prior to RC, cNSS determines the minimum number of lymph nodes required to be dissected; pNSS quantifies the accuracy of negative nodal staging based on pT stage and dissected LNs. cNSS and pNSS have not been externally validated, and their relevance for prediction of cancer-specific mortality (CSM) has not been assessed. METHODS: In this retrospective study of 2,483 RC patients from eight German centers, we externally validated cNSS and pNSS and determined their prediction of CSM. All patients underwent RC and LND. Median follow-up was 44 months. cNSS and pNSS sensitivities were evaluated using the original beta-binominal models. Adjusted proportional hazards models were calculated for pN0 patients to assess the predictive value of cNSS and pNSS for CSM. RESULTS: cNSS and pNSS both pass external validation. Adjusted for other clinical parameters, cNSS can predict outcome after RC. pNSS has no independent impact on prediction of CSM. The retrospective design is the major limitation of the study. CONCLUSIONS: In the present external validation, we confirm the validity of both cNSS and pNSS. cNSS is an independent predictor of CSM, thus rendering it useful as a tool for planning the extent of LND. PMID- 23736529 TI - Isaac: ultra-fast whole-genome secondary analysis on Illumina sequencing platforms. AB - SUMMARY: An ultrafast DNA sequence aligner (Isaac Genome Alignment Software) that takes advantage of high-memory hardware (>48 GB) and variant caller (Isaac Variant Caller) have been developed. We demonstrate that our combined pipeline (Isaac) is four to five times faster than BWA + GATK on equivalent hardware, with comparable accuracy as measured by trio conflict rates and sensitivity. We further show that Isaac is effective in the detection of disease-causing variants and can easily/economically be run on commodity hardware. AVAILABILITY: Isaac has an open source license and can be obtained at https://github.com/sequencing. PMID- 23736530 TI - Whole-Genome rVISTA: a tool to determine enrichment of transcription factor binding sites in gene promoters from transcriptomic data. AB - SUMMARY: We have developed a web-based query tool, Whole-Genome rVISTA (WGRV), that determines enrichment of transcription factors (TFs) and associated target genes in sets of co-regulated genes. WGRV enables users to query databases containing pre-computed genome coordinates of evolutionarily conserved transcription factor binding sites in the proximal promoters (from 100 bp to 5 kb upstream) of human, mouse and Drosophila genomes. TF binding sites are based on position-weight matrices from the TRANSFAC Professional database. For a given set of co-regulated genes, WGRV returns statistically enriched and evolutionarily conserved binding sites, mapped by the regulatory VISTA (rVISTA) algorithm. Users can then retrieve a list of genes from the query set containing the enriched TF binding sites and their location in the query set promoters. Results are exported in a BED format for rapid visualization in the UCSC genome browser. Flat files of mapped conserved sites and their genomic coordinates are also available for analysis with stand-alone software. AVAILABILITY: http://genome.lbl.gov/cgi bin/WGRVistaInputCommon.pl. PMID- 23736531 TI - NGS++: a library for rapid prototyping of epigenomics software tools. AB - MOTIVATION: The development of computational tools to enable testing and analysis of high-throughput-sequencing data is essential to modern genomics research. However, although multiple frameworks have been developed to facilitate access to these tools, comparatively little effort has been made at implementing low-level programming libraries to increase the speed and ease of their development. RESULTS: We propose NGS++, a programming library in C++11 specialized in manipulating both next-generation sequencing (NGS) datasets and genomic information files. This library allows easy integration of new formats and rapid prototyping of new functionalities with a focus on the analysis of genomic regions and features. It offers a powerful, yet versatile and easily extensible interface to read, write and manipulate multiple genomic file formats. By standardizing the internal data structures and presenting a common interface to the data parser, NGS++ offers an effective framework for epigenomics tool development. AVAILABILITY: NGS++ was written in C++ using the C++11 standard. It requires minimal efforts to build and is well-documented via a complete docXygen guide, online documentation and tutorials. Source code, tests, code examples and documentation are available via the website at http://www.ngsplusplus.ca and the github repository at https://github.com/NGS-lib/NGSplusplus. CONTACT: nicolas.gevry@usherbrooke.ca or arnaud.droit@crchuq.ulaval.ca. PMID- 23736532 TI - Identification of deleterious synonymous variants in human genomes. AB - MOTIVATION: The prioritization and identification of disease-causing mutations is one of the most significant challenges in medical genomics. Currently available methods address this problem for non-synonymous single nucleotide variants (SNVs) and variation in promoters/enhancers; however, recent research has implicated synonymous (silent) exonic mutations in a number of disorders. RESULTS: We have curated 33 such variants from literature and developed the Silent Variant Analyzer (SilVA), a machine-learning approach to separate these from among a large set of rare polymorphisms. We evaluate SilVA's performance on in silico 'infection' experiments, in which we implant known disease-causing mutations into a human genome, and show that for 15 of 33 disorders, we rank the implanted mutation among the top five most deleterious ones. Furthermore, we apply the SilVA method to two additional datasets: synonymous variants associated with Meckel syndrome, and a collection of silent variants clinically observed and stratified by a molecular diagnostics laboratory, and show that SilVA is able to accurately predict the harmfulness of silent variants in these datasets. AVAILABILITY: SilVA is open source and is freely available from the project website: http://compbio.cs.toronto.edu/silva CONTACT: silva-snv@cs.toronto.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23736533 TI - EcoGene-RefSeq: EcoGene tools applied to the RefSeq prokaryotic genomes. AB - SUMMARY: EcoGene.org is a genome database and website dedicated to Escherichia coli K-12 substrain MG1655 that is revised daily using information derived from the biomedical literature and in-house analysis. EcoGene is a major source of annotation updates for the MG1655 Genbank record, one of only a few Genbank genome records that are updated by a community effort. The Reference Sequence (RefSeq) database, built by The National Center for Biotechnology Information, comprises a set of duplicate Genbank genome records that can be modified by the NCBI staff annotators. EcoGene-RefSeq is being developed as a stand-alone internet resource to facilitate the usage of EcoGene-based tools on any of the >2400 completed prokaryotic genome records that are currently available at the RefSeq database. AVAILABILITY: The web interface of EcoGene-RefSeq is available at http://www.ecogene.org/refseq. CONTACT: krudd@med.miami.edu or j.zhou1@miami.edu. PMID- 23736534 TI - Circulating microRNA changes in heart failure patients treated with cardiac resynchronization therapy: responders vs. non-responders. AB - AIMS: MicroRNAs (miRNAs) play an important role in the pathogenesis of structural alterations of the failing heart through their ability to regulate negatively the expression levels of genes that govern the process of adaptive and maladaptive cardiac remodelling. We studied whether LV reverse remodelling after CRT was associated with changes of circulating miRNAs in patients with heart failure (HF) and dyssynchrony. METHODS AND RESULTS: A prospective, non-randomized self-control trial was performed in 81 patients with HF eligible for CRT. At baseline, to select the HF miRNA profile, we evaluated the expression of 84 miRNAs (implicated in the pathogenesis of structural alterations of the failing heart) in three groups of patients: healthy subjects (healthy group, n = 15); patients with HF (HF group, n = 81); and patients without HF matched for age, sex, and concomitant disease with HF patients (control group, n = 60). At 12 months, the selected miRNA profile was evaluated in plasma from responder (n = 55) and non-responder HF patients (n = 26) to CRT. In the test cohort, the HF patients were characterized by lower expression of 48 miRNAs (all P < 0.04) as compared with healthy subjects. In the validation cohort, the HF patients were characterized by lower expression of 24 miRNAs (all P < 0.03) as compared with control patients. At 12 months, 55 patients (68%) were considered responders and 26 non-responders to CRT (32%). Responders showed an increase in expression of 19 miRNAs (all P < 0.03) compared with baseline expression, whereas in the non-responders we observed an increase of six miRNAs (all P < 0.05) compared with baseline expression. At follow-up, miRNAs were differentially expressed between responders and non-responders. The responders were characterized by higher expression of five miRNAs (miRNA-26b-5p, miRNA-145-5p, miRNA-92a-3p, miRNA-30e-5p, and miRNA 29a-3p; P < 0.01 for all) as compared with non-responders. CONCLUSIONS: In responders, reverse remodelling is associated with favourable changes in miRNAs that regulate cardiac fibrosis, apoptosis, and hypertrophy. PMID- 23736535 TI - Limited utility of current MRI criteria for distinguishing multiple sclerosis from common mimickers: primary and secondary CNS vasculitis, lupus and Sjogren's syndrome. AB - BACKGROUND: Magnetic resonance imaging (MRI) criteria play an important role in making an earlier diagnosis of multiple sclerosis (MS) in patients presenting with clinically isolated syndrome. OBJECTIVE: The objective of this paper is to determine whether MRI criteria may be used to distinguish MS from primary and secondary central nervous system (CNS) vasculitis, lupus, and Sjogren's syndrome. METHODS: MRI criteria were applied retrospectively to images for patients with clinically definite MS (CDMS), primary CNS vasculitis, secondary CNS vasculitis, and autoimmune disorders including systemic lupus erythematosus (SLE) and Sjogren's syndrome. Classical statistics and Bayesian analyses were performed. RESULTS: Overall modified Barkhof's MRI criteria were statistically significant in distinguishing CDMS (60%) from SLE/Sjogren's syndrome (17%, p = 0.0173) but not in distinguishing CDMS from primary CNS vasculitis (50%, p = 0.7376) or secondary CNS vasculitis (58%, p = 1.0000). Four of the five other MRI criteria tested were demonstrated to be superior to modified Barkhof's criteria in predicting MS: nine or more T2 lesions (a component of Barkhof's criteria), one or more ovoid periventricular T2 lesions, one or more perpendicular periventricular T2 lesions, and one or more T2 lesions larger than 6 mm. CONCLUSIONS: MRI criteria, including the modified Barkhof's criteria, were unsuccessful in distinguishing MS from primary CNS vasculitis or secondary CNS vasculitis and mildly successful in distinguishing MS from SLE/Sjogren's syndrome. PMID- 23736536 TI - CRYAB modulates the activation of CD4+ T cells from relapsing-remitting multiple sclerosis patients. AB - BACKGROUND: Suppression of activation of pathogenic CD4(+) T cells is a potential therapeutic intervention in multiple sclerosis (MS). We previously showed that a small heat shock protein, CRYAB, reduced T cell proliferation, pro-inflammatory cytokine production and clinical signs of experimental allergic encephalomyelitis, a model of MS. OBJECTIVE: We assessed whether the ability of CRYAB to reduce the activation of T cells translated to the human disease. METHODS: CD4(+) T cells from healthy controls and volunteers with MS were activated in vitro in the presence or absence of a CRYAB peptide (residues 73 92). Parameters of activation (proliferation rate, cytokine secretion) and tolerance (anergy, activation-induced cell death, microRNAs) were evaluated. RESULTS: The secretion of pro-inflammatory cytokines by CD4(+) T cells was decreased in the presence of CRYAB in a subset of relapsing-remitting multiple sclerosis (RRMS) participants with mild disease severity while no changes were observed in healthy controls. Further, there was a correlation for higher levels of miR181a microRNA, a marker upregulated in tolerant CD8(+) T cells, in CD4(+) T cells of MS patients that displayed suppressed cytokine production (responders). CONCLUSION: CRYAB may be capable of suppressing the activation of CD4(+) T cells from a subset of RRMS patients who appear to have less disability but similar age and disease duration. PMID- 23736537 TI - Silencing of ghrelin receptor expression inhibits endometrial cancer cell growth in vitro and in vivo. AB - Ghrelin is a 28-amino acid peptide hormone produced predominantly in the stomach but also in a range of normal cell types and tumors, where it has endocrine, paracrine, and autocrine roles. Previously, we have demonstrated that ghrelin has proliferative and antiapoptotic effects in endometrial cancer cell lines, suggesting a potential role in promoting tumor growth. In the present study, we investigated the effect of ghrelin receptor, GHSR, and gene silencing in vitro and in vivo and characterized ghrelin and GHSR1a protein expression in human endometrial tumors. GHSR gene silencing was achieved in the Ishikawa and KLE endometrial cancer cell lines, using a lentiviral short-hairpin RNA targeting GHSR. The effects of GHSR1a knockdown were further analyzed in vivo using the Ishikawa cell line in a NOD/SCID xenograft model. Cell proliferation was reduced in cultured GHSR1a knockdown Ishikawa and KLE cells compared with scrambled controls in the absence of exogenously applied ghrelin and in response to exogenous ghrelin (1,000 nM). The tumor volumes were reduced significantly in GHSR1a knockdown Ishikawa mouse xenograft tumors compared with scrambled control tumours. Using immunohistochemistry, we demonstrated that ghrelin and GHSR1a are expressed in benign and cancerous glands in human endometrial tissue specimens, although there was no correlation between the intensity of staining and cancer grade. These data indicate that downregulation of GHSR expression significantly inhibits endometrial cancer cell line and mouse xenograft tumour growth. This is the first preclinical evidence that downregulation of GHSR may be therapeutic in endometrial cancer. PMID- 23736538 TI - Activation of the amino acid response modulates lineage specification during differentiation of murine embryonic stem cells. AB - In somatic cells, a collection of signaling pathways activated by amino acid limitation have been identified and referred to as the amino acid response (AAR). Despite the importance of possible detrimental effects of nutrient limitation during in vitro culture, the AAR has not been investigated in embryonic stem cells (ESC). AAR activation caused the expected increase in transcription factors that mediate specific AAR pathways, as well as the induction of asparagine synthetase, a terminal AAR target gene. Neither AAR activation nor stable knockdown of activating transcription factor (Atf) 4, a transcriptional mediator of the AAR, adversely affected ESC self-renewal or pluripotency. Low-level induction of the AAR over a 12-day period of embryoid body differentiation did alter lineage specification such that the primitive endodermal, visceral endodermal, and endodermal lineages were favored, whereas mesodermal and certain ectodermal lineages were suppressed. Knockdown of Atf4 further enhanced the AAR induced increase in endodermal formation, suggesting that this phenomenon is mediated by an Atf4-independent mechanism. Collectively, the results indicate that, during differentiation of mouse embryoid bodies in culture, the availability of nutrients, such as amino acids, can influence the formation of specific cell lineages. PMID- 23736540 TI - Important role of ventromedial hypothalamic carnitine palmitoyltransferase-1a in the control of food intake. AB - Carnitine palmitoyltransferase-1 (CPT-1) liver isoform, or CPT-1a, is implicated in CNS control of food intake. However, the exact brain nucleus site(s) in mediating this action of CPT-1a has not been identified. In this report, we assess the role of CPT-1a in hypothalamic ventromedial nucleus (VMN). We stereotaxically injected an adenoviral vector containing CPT-1a coding sequence into the VMN of rats to induce overexpression and activation of CPT-1a. The VMN selective activation of CPT-1a induced an orexigenic effect, suggesting CPT-1a in the VMN is involved in the central control of feeding. Intracerebroventricular administration of etomoxir, a CPT-1 inhibitor, decreases food intake. Importantly, in the animals with VMN overexpression of a CPT-1a mutant that antagonizes the CPT-1 inhibition by etomoxir, the anorectic response to etomoxir was attenuated. This suggests that VMN is involved in mediating the anorectic effect of central inhibition of CPT-1a. In contrast, arcuate nucleus (Arc) overexpression of the mutant did not alter etomoxir-induced inhibition of food intake, suggesting that Arc CPT-1a does not play significant roles in this anorectic action. Furthermore, in the VMN, CPT-1a appears to act downstream of hypothalamic malonyl-CoA action of feeding. Finally, we show that in the VMN CPT 1 activity was altered in concert with fasting and refeeding states, supporting a physiological role of CPT-1a in mediating the control of feeding. All together, CPT-1a in the hypothalamic VMN appears to play an important role in central control of food intake. VMN-selective modulation of CPT-1a activity may therefore be a promising strategy in controlling food intake and maintaining normal body weight. PMID- 23736539 TI - Interactions between p-Akt and Smad3 in injured muscles initiate myogenesis or fibrogenesis. AB - In catabolic conditions such as aging and diabetes, IGF signaling is impaired and fibrosis develops in skeletal muscles. To examine whether impaired IGF signaling initiates muscle fibrosis, we generated IGF-IR(+/-) heterozygous mice by crossing loxP-floxed IGF-IR (exon 3) mice with MyoD-cre mice. IGF-IR(+/-) mice were studied because we were unable to obtain homozygous IGF-IR-KO mice. In IGF-IR(+/ ) mice, both growth and expression of myogenic genes (MyoD and myogenin; markers of satellite cell proliferation and differentiation, respectively) were depressed. Likewise, in injured muscles of IGF-IR(+/-) mice, there was impaired regeneration, depressed expression of MyoD and myogenin, and increased expression of TGF-beta1, alpha-SMA, collagen I, and fibrosis. To uncover mechanisms stimulating fibrosis, we isolated satellite cells from muscles of IGF-IR(+/-) mice and found reduced proliferation and differentiation plus increased TGF-beta1 production. In C2C12 myoblasts (a model of satellite cells), IGF-I treatment inhibited TGF-beta1-stimulated Smad3 phosphorylation, its nuclear translocation, and expression of fibronectin. Using immunoprecipitation assay, we found an interaction between p-Akt or Akt with Smad3 in wild-type mouse muscles and in C2C12 myoblasts; importantly, IGF-I increased p-Akt and Smad3 interaction, whereas TGF-beta1 decreased it. Therefore, in muscles of IGF-IR(+/-) mice, the reduction in IGF-IR reduces p-Akt, allowing for dissociation and nuclear translocation of Smad3 to enhance the TGF-beta1 signaling pathway, leading to fibrosis. Thus, strategies to improve IGF signaling could prevent fibrosis in catabolic conditions with impaired IGF signaling. PMID- 23736541 TI - Effects of transaldolase exchange on estimates of gluconeogenesis in type 2 diabetes. AB - Transaldolase (TA) exchange overestimates gluconeogenesis measured with deuterated water (2H2O). However, it is unknown whether TA differs in people with type 2 diabetes (T2DM). 2H2O was ingested, and [1-13C]acetate and [3-3H]glucose were infused in T2DM (n = 10) and healthy nondiabetic (ND; n = 8) subjects. TA was assessed from the ratio of 13C3 to 13C4 glucose enrichment (13C3/13C4) measured by 13C NMR. Glucose turnover was measured before (~16-h fast) and during hyperglycemic (~10 mM) moderate-dose insulin (~0.35 mU.kg-1.min-1) clamp. 13C3/13C4 in T2DM vs. ND was <1.0 and not different at baseline and clamp, indicating equivalent TA. To determine whether incomplete triose phosphate isomerase (TPI) exchange contributed to asymmetric 13C3/13C4, [U-13C]glycerol was infused in lieu of [1-13C]acetate during a separate visit in a subset of ND (n = 7) subjects. Ratio of 13C3/13C4 obtained following either tracer was <1.0 at baseline and during clamp, indicating that TPI exchange was essentially complete and did not contribute to asymmetric glucose enrichment. Uncorrected and corrected rates of gluconeogenesis were no different (P = not significant) in T2DM vs. ND both at baseline and during clamp. TA correction resulted in equivalent estimates of corrected gluconeogenesis in T2DM and ND that were ~25 35% lower than uncorrected gluconeogenesis both at baseline and during the clamp. The asymmetric enrichment of glucose from 13C-gluconeogenic tracers is attributable to TA exchange and can be utilized to correct for TA exchange. In conclusion, TA exchange does not differ between T2DM and ND under fasting or hyperglycemic clamp conditions, and the 2H2O method continues to provide an accurate estimation of gluconeogenesis. PMID- 23736543 TI - Characterization of a novel genetically obese mouse model demonstrating early onset hyperphagia and hyperleptinemia. AB - Obesity is a critical risk factor for the development of metabolic syndrome, and many obese animal models are used to investigate the mechanisms responsible for the appearance of symptoms. To establish a new obese mouse model, we screened ~13,000 ICR mice and discovered a mouse demonstrating spontaneous obesity. We named this mouse "Daruma" after a traditional Japanese ornament. Following the fixation of the genotype, these animals exhibited obese phenotypes according to Mendel's law of inheritance. In the Daruma mouse, the leptin receptor gene sequence carried two base mutations that are good candidates for the variation(s) responsible for the obese phenotype. The Daruma mice developed characteristic visceral fat accumulation at 4 wk of age, and the white adipose and liver tissues exhibited increases in cell size and lipid droplets, respectively. No histological abnormalities were observed in other tissues of the Daruma mice, even after the mice reached 25 wk of age. Moreover, the onset of impaired leptin signaling was early and manifested as hyperleptinemia and hyperinsulinemia. Pair feeding completely inhibited obesity, although these mice rapidly developed hyperphagia and obesity followed by hyperleptinemia when pair feeding ceased and free-access feeding was permitted. Therefore, the Daruma mice exhibited unique characteristics and may be a good model for studying human metabolic syndrome. PMID- 23736542 TI - Na+/H+ exchanger 1 inhibition reverses manifestation of peripheral diabetic neuropathy in type 1 diabetic rats. AB - Evidence for an important role for Na(+)/H(+) exchangers in diabetic complications is emerging. The aim of this study was to evaluate whether Na(+)/H(+) exchanger 1 inhibition reverses experimental peripheral diabetic neuropathy. Control and streptozotocin-diabetic rats were treated with the specific Na(+)/H(+) exchanger 1 inhibitor cariporide for 4 wk after 12 wk without treatment. Neuropathy end points included sciatic motor and sensory nerve conduction velocities, endoneurial nutritive blood flow, vascular reactivity of epineurial arterioles, thermal nociception, tactile allodynia, and intraepidermal nerve fiber density. Advanced glycation end product and markers of oxidative stress, including nitrated protein levels in sciatic nerve, were evaluated by Western blot. Rats with 12-wk duration of diabetes developed motor and sensory nerve conduction deficits, thermal hypoalgesia, tactile allodynia, and intraepidermal nerve fiber loss. All these changes, including impairment of nerve blood flow and vascular reactivity of epineurial arterioles, were partially reversed by 4 wk of cariporide treatment. Na(+)/H(+) exchanger 1 inhibition was also associated with reduction of diabetes-induced accumulation of advanced glycation endproduct, oxidative stress, and nitrated proteins in sciatic nerve. In conclusion, these findings support an important role for Na(+)/H(+) exchanger 1 in functional, structural, and biochemical manifestations of peripheral diabetic neuropathy and provide the rationale for development of Na(+)/H(+) exchanger 1 inhibitors for treatment of diabetic vascular and neural complications. PMID- 23736544 TI - One year of sitagliptin treatment protects against islet amyloid-associated beta cell loss and does not induce pancreatitis or pancreatic neoplasia in mice. AB - The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin is an attractive therapy for diabetes, as it increases insulin release and may preserve beta-cell mass. However, sitagliptin also increases beta-cell release of human islet amyloid polypeptide (hIAPP), the peptide component of islet amyloid, which is cosecreted with insulin. Thus, sitagliptin treatment may promote islet amyloid formation and its associated beta-cell toxicity. Conversely, metformin treatment decreases islet amyloid formation by decreasing beta-cell secretory demand and could therefore offset sitagliptin's potential proamyloidogenic effects. Sitagliptin treatment has also been reported to be detrimental to the exocrine pancreas. We investigated whether long-term sitagliptin treatment, alone or with metformin, increased islet amyloid deposition and beta-cell toxicity and induced pancreatic ductal proliferation, pancreatitis, and/or pancreatic metaplasia/neoplasia. hIAPP transgenic and nontransgenic littermates were followed for 1 yr on no treatment, sitagliptin, metformin, or the combination. Islet amyloid deposition, beta-cell mass, insulin release, and measures of exocrine pancreas pathology were determined. Relative to untreated mice, sitagliptin treatment did not increase amyloid deposition, despite increasing hIAPP release, and prevented amyloid induced beta-cell loss. Metformin treatment alone or with sitagliptin decreased islet amyloid deposition to a similar extent vs untreated mice. Ductal proliferation was not altered among treatment groups, and no evidence of pancreatitis, ductal metaplasia, or neoplasia were observed. Therefore, long-term sitagliptin treatment stimulates beta-cell secretion without increasing amyloid formation and protects against amyloid-induced beta-cell loss. This suggests a novel effect of sitagliptin to protect the beta-cell in type 2 diabetes that appears to occur without adverse effects on the exocrine pancreas. PMID- 23736545 TI - Adipose tissue inflammation contributes to short-term high-fat diet-induced hepatic insulin resistance. AB - High-fat feeding for 3-4 days impairs glucose tolerance and hepatic insulin sensitivity. However, it remains unclear whether the evolving hepatic insulin resistance is due to acute lipid overload or the result of induced adipose tissue inflammation and consequent dysfunctional adipose tissue-liver cross-talk. In the present study, feeding C57Bl6/J mice a fat-enriched diet [high-fat diet (HFD)] for 4 days induced glucose intolerance, hepatic insulin resistance (as assessed by hyperinsulinemic euglycemic clamp studies), and hepatic steatosis as well as adipose tissue inflammation (i.e., TNFalpha expression) compared with standard chow-fed mice. Adipocyte-specific depletion of the antiapoptotic/anti inflammatory factor Fas (CD95) attenuated adipose tissue inflammation and improved glucose tolerance as well as hepatic insulin sensitivity without altering the level of hepatic steatosis induced by HFD. In summary, our results identify adipose tissue inflammation and resulting dysfunctional adipose tissue liver cross-talk as an early event in the development of HFD-induced hepatic insulin resistance. PMID- 23736548 TI - Co-occurrence patterns of Bornean vertebrates suggest competitive exclusion is strongest among distantly related species. AB - Assessing the importance of deterministic processes in structuring ecological communities is a central focus of community ecology. Typically, community ecologists study a single taxonomic group, which precludes detection of potentially important biotic interactions between distantly related species, and inherently assumes competition is strongest between closely related species. We examined distribution patterns of vertebrate species across the island of Borneo in Southeast Asia to assess the extent to which inter-specific competition may have shaped ecological communities on the island and whether the intensity of inter-specific competition in present-day communities varies as a function of evolutionary relatedness. We investigated the relative extent of competition within and between species of primates, birds, bats and squirrels using species presence-absence and attribute data compiled for 21 forested sites across Borneo. We calculated for each species pair the checkerboard unit value (CU), a statistic that is often interpreted as indicating the importance of interspecific competition. The percentage of species pairs with significant CUs was lowest in within-taxon comparisons. Moreover, for invertebrate-eating species the percentage of significantly checkerboarded species pairs was highest in comparisons between primates and other taxa, particularly birds and squirrels. Our results are consistent with the interpretation that competitive interactions between distantly related species may have shaped the distribution of species and thus the composition of Bornean vertebrate communities. This research highlights the importance of taking into account the broad mammalian and avian communities in which species occur for understanding the factors that structure biodiversity. PMID- 23736549 TI - Soil microbial responses to warming and increased precipitation and their implications for ecosystem C cycling. AB - A better understanding of soil microbial ecology is critical to gaining an understanding of terrestrial carbon (C) cycle-climate change feedbacks. However, current knowledge limits our ability to predict microbial community dynamics in the face of multiple global change drivers and their implications for respiratory loss of soil carbon. Whether microorganisms will acclimate to climate warming and ameliorate predicted respiratory C losses is still debated. It also remains unclear how precipitation, another important climate change driver, will interact with warming to affect microorganisms and their regulation of respiratory C loss. We explore the dynamics of microorganisms and their contributions to respiratory C loss using a 4-year (2006-2009) field experiment in a semi-arid grassland with increased temperature and precipitation in a full factorial design. We found no response of mass-specific (per unit microbial biomass C) heterotrophic respiration to warming, suggesting that respiratory C loss is directly from microbial growth rather than total physiological respiratory responses to warming. Increased precipitation did stimulate both microbial biomass and mass specific respiration, both of which make large contributions to respiratory loss of soil carbon. Taken together, these results suggest that, in semi-arid grasslands, soil moisture and related substrate availability may inhibit physiological respiratory responses to warming (where soil moisture was significantly lower), while they are not inhibited under elevated precipitation. Although we found no total physiological response to warming, warming increased bacterial C utilization (measured by BIOLOG EcoPlates) and increased bacterial oxidation of carbohydrates and phenols. Non-metric multidimensional scaling analysis as well as ANOVA testing showed that warming or increased precipitation did not change microbial community structure, which could suggest that microbial communities in semi-arid grasslands are already adapted to fluctuating climatic conditions. In summary, our results support the idea that microbial responses to climate change are multifaceted and, even with no large shifts in community structure, microbial mediation of soil carbon loss could still occur under future climate scenarios. PMID- 23736550 TI - Discreteness of the set of radiant point sources: a physical feature of the second-order wave-fronts. AB - The non-paraxial phase-space representation of diffraction of optical fields in any state of spatial coherence has been successfully modeled by assuming a discrete set of radiant point sources at the aperture plane instead of a continuous wave-front. More than a mere calculation strategy, this discreteness seems to be a physical feature of the field, independent from the sampling procedure of the modeling. PMID- 23736551 TI - An intense elastico-mechanoluminescence material CaZnOS:Mn2+ for sensing and imaging multiple mechanical stresses. AB - The elastico-mechanoluminescence (EML) properties of CaZnOS:Mn2+ are investigated. The CaZnOS:Mn2+/epoxy resin composite can simultaneously "feel" (sense) and "see" (image) various types of mechanical stress over a wide energy and frequency range (ultrasonic vibration, impact, friction and compression) as an intense red emission (610 nm) from Mn2+ ions. Further, the accurate linear relation between emission intensity and different stress parameters (intensity, energy and deformation rate) are confirmed. The EML mechanism is explained using a piezoelectrically induced trapped carrier excitation mode. All the results imply that CaZnOS:Mn2+ has potential as a stress probe to sense and image multiple mechanical stresses and decipher the stress intensity distribution. PMID- 23736552 TI - Polarization distribution control of parallel femtosecond pulses with spatial light modulators. AB - A parallel femtosecond pulse irradiation method using a computer-generated hologram displayed on a spatial light modulator provides the advantages of high throughput and high energy-use efficiency. Polarization control of the femtosecond pulse enables some unique properties, for example, selective excitation of an anisotropic molecule, focusing at a size beyond the diffraction limit owing to the longitudinal vector component of a radially polarized beam focused by a high-numerical-aperture objective lens, and fabrication of periodic nanostructures with femtosecond laser light. In this study, we propose a parallel femtosecond laser irradiation system with arbitrary polarization distribution control using a pair of spatial light modulators. By using the system, the interval between the diffraction spots was the closest yet reported by avoiding mutual interference among their side lobes. The interval was improved to half compared with our previous work. We also demonstrated the parallel fabrication of periodic nanostructures with orientation control, which, to our knowledge, is the first reported demonstration of its kind. PMID- 23736553 TI - Active-grating monochromator for the spectral selection of ultrashort pulses. AB - Active gratings have been used to realize a grazing-incidence double-grating monochromator for the spectral selection of ultrashort pulses while preserving the temporal duration by compensating for the pulse-front tilt. The active grating consists of a bimorph deformable mirror on the top of which a diffraction grating with laminar profile is realized by UV lithography. The time-delay compensated configuration has been tested with ultrashort pulses at 800 nm. The feasibility of this configuration for the extreme-ultraviolet spectral region has been demonstrated by ray tracing studies. PMID- 23736554 TI - Single pulse coherence measurements in the water window at the free-electron laser FLASH. AB - The spatial coherence of free-electron laser radiation in the water window spectral range was studied, using the third harmonic (lambda<(3rd) = 2.66 nm) of DESY's Free-electron LASer in Hamburg (FLASH). Coherent single pulse diffraction patterns of 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC) multilamellar lipid stacks have been recorded. The intensity histogram of the speckle pattern around the first lamellar Bragg peak, corresponding to the d = 5 nm periodicity of the stack, reveals an average number of transverse modes of M- = 3.0 of the 3rd harmonic. Using the lipid stack as a 'monochromator', pulse-to-pulse fluctuations in the third harmonic lambda(3rd) have been determined to be 0.033 nm. PMID- 23736555 TI - A semi-analytical total suspended sediment retrieval model in turbid coastal waters: a case study in Changjiang River Estuary. AB - A simple semi-analytical model to estimate total suspended sediment matter (3S) was established for estimating TSM concentrations in Changjiang River Estuary. The results indicate that 3S model with near-infrared wavelengths provide good estimates of TSM concentrations in the study region. Furthermore, the applicability of 3S model was evaluated using an independent data set taken from Oujiang river estuary during September 2012. The results indicate that providing an available atmospheric correction scheme for satellite imagery, the 3S model could be used for quantitative monitoring of TSM concentration in coastal waters, even though local bio-optical information is still needed to reinitialize the model. PMID- 23736556 TI - Coherence theory of a laser beam passing through a moving diffuser. AB - We present the general coherence theory for laser beams passing through a moving diffuser. The temporal coherence of laser beams passing through a moving diffuser depends on two characteristic temporal scales: the laser coherence time and the mean time it takes the diffuser to move past a phase correlation area. In most applications, the former is much shorter than the latter. Our theoretical analysis shows the spatial coherence area of light scattered from a moving diffuser decreases while the coherence time remains unchanged. The conclusion has been confirmed by experiments using a Michelson interferometer and it is not in accordance with the original coherence theory in which both the temporal and spatial coherence of light scattered by a moving diffuser decrease. We also developed a method based on the theory of eigenvalues to calculate the speckle contrast on a screen illuminated by light transmitted through a moving diffuser. PMID- 23736557 TI - Micro-focusing of attosecond pulses by grazing-incidence toroidal mirrors. AB - The design of optical systems for micro-focusing of extreme-ultraviolet (XUV) attosecond pulses through grazing-incidence toroidal mirrors is presented. Aim of the proposed configuration is to provide a micro-focused image through a high demagnification of the XUV source with the following characteristics: i) almost negligible aberrations; ii) long exit arm to easily accommodate at the output the experimental setups required for the applications of the focused attosecond pulses; iii) possibility to have an intermediate region where the XUV beam is collimated, in order to insert a plane split-mirror for the generation of two XUV pulse replicas to be used in a XUV-pump/XUV-probe setup. We present the analytical and numerical study of two optical configurations characterized by two sections based on the use of toroidal mirrors. The first section provides a demagnified image of the source in an intermediate focus that is free from defocusing but has a large coma aberration. The second section consists of a relay mirror that is mounted in Z-shaped geometry with respect to the previous one, in order to give a stigmatic image with a coma that is opposite to that provided by the first section. An example is provided to demonstrate the capability to achieve spot sizes in the 5-15 MUm range with a demagnification higher than 10 in a compact envelope. PMID- 23736558 TI - Investigation on LD end-pumped passively Q-switched c-cut Nd: YVO4 self-Raman laser. AB - The compact LD end-pumped passively Q-switched c-cut Nd:YVO4/Cr4+:YAG self-Raman laser is realized, and its output performance is investigated in detail. The maximum average output power at 1178nm is 800mW with the pulse repetition frequency of 44kHz and pulse width of 2.6ns, and the first Stokes conversion efficiency is 10.1%. The outputs of fundamental and first Stokes laser are found to be linearly polarized along the diagonals of the rectangular cross section of the c-cut Nd:YVO4 crystal, and the polarization mode competition is observed in the outputs of fundamental and first Stokes laser. PMID- 23736559 TI - Measurement of the chirp characteristics of linearly chirped pulses by a frequency domain interference method. AB - A linear optical technique for chirp characteristics measurement based on frequency domain interference is developed. This technique can be applied to measure the temporal structure of linearly chirped pulses which have become increasingly important in ultrafast optics. To confirm this technique, an experiment is carried out to measure the chirp rate and duration of a picosecond chirped pulse with an imaging spectrometer. PMID- 23736560 TI - A comparative study on reflection of nanosecond Nd-YAG laser pulses in ablation of metals in air and in vacuum. AB - A comparative study on reflection of nanosecond Nd-YAG laser pulses in ablation of aluminum in air and in vacuum under the same other experimental conditions is performed. We find that, hemispherical total reflectivity of aluminum undergoes a sharp drop at the plasma formation threshold both in the air and in vacuum. The initial large value (0.8) of aluminum reflectivity decreases to a level of about 0.14 and 0.24 for ablation in the air and in vacuum, respectively. These decreased reflectivity values remain virtually unchanged with further increasing laser fluence. The reflectivity drop in the air is observed to be sharper than in vacuum. Our study indicates that the reflectivity drop is predominantly caused by absorption of the laser light in plasma. Nano/micro-structural defects present on practical sample surfaces play the important role in the plasma formation, especially for the ablation in the air, where the plasma formation threshold is found to be by a factor of 3 smaller than in vacuum. PMID- 23736561 TI - Nonlinear transmission properties of hydrogenated amorphous silicon core fibers towards the mid-infrared regime. AB - The nonlinear transmission properties of hydrogenated amorphous silicon (a-Si:H) core fibers are characterized from the near-infrared up to the edge of the mid infrared regime. The results show that this material exhibits linear losses on the order of a few dB/cm, or less, over the entire wavelength range, decreasing down to a value of 0.29 dB/cm at 2.7MUm, and negligible nonlinear losses beyond the two-photon absorption (TPA) edge ~ 1.7MUm. By measuring the dispersion of the nonlinear Kerr and TPA parameters we have found that the nonlinear figure of merit (FOM(NL)) increases dramatically over this region, with FOM(NL) > 20 around 2MUm and above. This characterization demonstrates the potential for a-Si:H fibers and waveguides to find use in nonlinear applications extending beyond telecoms and into the mid-infrared regime. PMID- 23736562 TI - Retrieval and analysis of a polarized high-spectral-resolution lidar for profiling aerosol optical properties. AB - Taking advantage of the broad spectrum of the Cabannes-Brillouin scatter from atmospheric molecules, the high spectral resolution lidar (HSRL) technique employs a narrow spectral filter to separate the aerosol and molecular scattering components in the lidar return signals and therefore can obtain the aerosol optical properties as well as the lidar ratio (i.e., the extinction-to backscatter ratio) which is normally selected or modeled in traditional backscatter lidars. A polarized HSRL instrument, which employs an interferometric spectral filter, is under development at the Zhejiang University (ZJU), China. In this paper, the theoretical basis to retrieve the aerosol lidar ratio, depolarization ratio and extinction and backscatter coefficients, is presented. Error analyses and sensitivity studies have been carried out on the spectral transmittance characteristics of the spectral filter. The result shows that a filter that has as small aerosol transmittance (i.e., large aerosol rejection rate) and large molecular transmittance as possible is desirable. To achieve accurate retrieval, the transmittance of the spectral filter for molecular and aerosol scattering signals should be well characterized. PMID- 23736563 TI - Phase locking of multiple optical fiber channels for a slow-light-enabled laser radar system. AB - Phase control is crucial to the operation of coherent beam combining systems, whether for laser radar or high-power beam combining. We have recently demonstrated a design for a multi-aperture, coherently combined, synchronized- and phased-array slow light laser radar (SLIDAR) that is capable of scanning in two dimensions with dynamic group delay compensation. Here we describe in detail the optical phase locking system used in the design. The phase locking system achieves an estimated Strehl ratio of 0.8, and signals from multiple emitting apertures are phase locked simultaneously to within pi/5 radians (1/10 wave) after propagation through 2.2 km of single-mode fiber per channel. Phase locking performance is maintained even as two independent slow light mechanisms are utilized simultaneously. PMID- 23736564 TI - Extended theory of soft x-ray reflection for realistic lamellar multilayer gratings. AB - An extended set of coupled wave equations were derived to describe non-idealized lamellar multilayer grating structures with properties as obtained with state-of the-art fabrication techniques. These generalized equations can include all relevant effects describing the influence of passivation and contamination layers, non-rectangular lamel profiles and sidewall scalloping. The calculations showed that passivation and contamination plays an important role in that it may significantly reduce peak reflectivity. However, we also derived a condition for layer thicknesses having negligible effects. Slightly positive tapered lamel profiles are shown to further reduce the bandwidth as compared to a rectangular lamel profile, whereas negative tapers significantly increased the bandwidth. The influence of intriguing effects, such as the sidewall scalloping caused by Bosch Deep Reactive Ion Etching, are also modeled. We identified the signature of such scalloping as additional side peaks in the reflectivity spectrum and present parameters with which these can be effectively suppressed. PMID- 23736565 TI - ASE and parasitic lasing in thin disk laser with anti-ASE cap. AB - The amplified spontaneous emission (ASE) and parasitic lasing (PL) effects in thin disk laser with an anti-ASE cap have been investigated in detail by measuring both time-resolved radiated intensity at longer axis of elliptical pump profile (dominant ASE direction) and small signal gain (SSG) in laser amplifier. A cryogenically-cooled total-reflection active-mirror laser consisting of 9.8 at.% doped, 0.6-mm thick Yb:YAG and un-doped YAG trapezoidal ceramics cap was used as a sample. The phased transitions from spontaneous emission (SE) to ASE and from ASE to PL have been unambiguously observed. For several pump beam diameters, the ASE gain parameter g(0)l(ASE) at ASE threshold was about 3, and the SSG coefficient was down to about 65% until PL started. To the best of our knowledge, this is the first quantitative characterization of the ASE/PL effects in the thin disk laser with an anti-ASE cap. PMID- 23736566 TI - Double-sided polarization-independent plasmonic absorber at near-infrared region. AB - A double-sided polarization-independent plasmonic absorber is proposed and numerically investigated. Distinct from previously studied absorbers, it could absorb light incident from both sides of the surface through an ultrathin three layer metal-insulator-metal nanostructure. Patterned metal particles are adopted instead of metal films in this absorber. It shows a high absorbance over a wide incident-angle range at near-infrared region. For electromagnetic waves incident from different sides of the structure, the maximum absorption locates at different wavelengths due to asymmetry. The effective medium theory demonstrates that the whole structure exhibits different impedances for both top and bottom incidences. This double-sided-absorption characteristic could lead to potential applications in thermal emitters, sensing, etc. PMID- 23736567 TI - Optical multi-hysteresises and quasi-solitons in nonlinear plasma. AB - An overdense plasma layer irradiated by intense light can exhibit dramatic nonlinear-optical effects due to a relativistic mass-effect of free electrons: highly-multiple hysteresises of reflection and transition, and emergence of immobile waves of large amplitude. Those are trapped quasi-soliton spikes sustained by a weak pumping having a tiny fraction of their peak intensity once they have been excited first by higher power pumping. The phenomenon persists even in the layers with "soft", wash-out boundaries, as well as in a semi infinite plasma with low absorption. PMID- 23736568 TI - Nonlinear Digital Back Propagation compensator for coherent optical OFDM based on factorizing the Volterra Series Transfer Function. AB - We introduce an efficient and accurate nonlinear compensator (NLC) for digital back-propagation (DBP) of coherent optical OFDM receivers, based on a factorization procedure for the Volterra Series Transfer Function (VSTF) with 3N degrees of freedom for N frequency samples. The O(N2) nonlinear compensation complexity of generic Volterra evaluation (normalized per-subcarrier) is reduced to 28 + 6logN. Our analysis and simulations indicate that this NLC system outperforms previous VSTF-based non-linear compensation methods. Compared to a most recent VSTF-based method, the new method incurs 52% extra computational complexity in return for improved nonlinear tolerance of ~2 dB for the particular analyzed link. PMID- 23736569 TI - A unit structure Rochon prism based on the extraordinary refraction of uniaxial birefringent crystals. AB - Based on the Fermat's principle, the universal theory of refraction and reflection of extraordinary rays (e-rays) in the uniaxial crystal is formulated. Using this theory, a new unit structure prism is designed, and its properties are studied. Based on the theoretical results, such a prism is achieved experimentally by using the Iceland crystal. In both theoretical and experimental studies, this new prism shows excellent polarization splitting performances such as big and adjustable splitting angle, comparing to the conventional Rochon prism. For the sample prism with the optical axis angle of 45 degrees , the splitting angle reaches 19.8 degrees in the normal incidence, and the maximum splitting angle reaches 28.44 degrees while the incidence angle is -4 degrees . PMID- 23736570 TI - Optical coherenscopy based on phase-space tomography. AB - Partially coherent light provides attractive benefits in imaging, beam shaping, free-space communications, random medium monitoring, among other applications. However, the experimental characterization of the spatial coherence is a difficult problem involving second-order statistics represented by four dimensional functions that cannot be directly measured and analyzed. In addition, real-world applications usually require quantitative characterization of the local spatial coherence of a beam in the absence of a priori information, together with fast acquisition and processing of the experimental data. Here we propose and experimentally demonstrate a technique that solves this problem. It comprises an optical setup developed for automatized video-rate measurement and a method -phase-space tomographic coherenscopy- allowing parallel data acquisition, processing, and analysis. This technique significantly simplifies the spatial coherence analysis and opens up new perspectives for the development of tools exploiting the degrees of freedom hidden into light coherence. PMID- 23736572 TI - Strong coupling of in-plane propagating plasmon modes and its control. AB - We show anti-crossings due to strong in-plane coupling of grating excited propagating plasmon modes in dielectric-metal-dielectric structure with 2D dielectric pattern on top. Grating coupled propagating plasmon modes along with their complete dispersion in the measurement range and all different sample orientations are calculated first. Further a coupled mode theory is presented for the specific geometry presented here. Experimentally measured anti-crossing widths are compared with those calculated by coupled mode theory. It is shown that the coupling strength of the plasmon modes and thus the anti-crossing width can be controlled by the orientation of the sample. PMID- 23736573 TI - Longitudinal polarized focusing of radially polarized sinh-Gaussian beam. AB - We consider the focusing performance of a radially polarized sinh-Gaussian beam. The sinh-Gaussian beam can be considered as superposition of a series of eccentric Gaussian beam. Based on the Richards-Wolf formulas, high beam quality and subwavelength focusing are achieved for the radially polarized incident sinh Gaussian beam. Therefore, sinh-Gaussian beam can be applied in the focusing system with high numerical aperture to achieve focusing with superresolution. PMID- 23736574 TI - Two dimensional interferometric optical trapping of multiple particles and Escherichia coli bacterial cells using a lensed multicore fiber. AB - Two dimensional interferometric trapping of multiple microspheres and Escherichia coli has been demonstrated using a multicore fiber lensed with an electric arc fusion splicer. Light was coupled evenly into all four cores using a diffractive optical element. The visibility of the fringes and also the appearance of the lattice can be altered by rotating a half wave-plate. As a result the particles can be manipulated from one dimensional trapping to two dimensional trapping or a variety of different two dimensional arrangements. The ability to align bacterial populations has potential application for quorum sensing, floc and biofilm and, metabolic co-operation studies. PMID- 23736575 TI - Long-period gratings inscribed in photonic crystal fiber by symmetric CO2 laser irradiation. AB - Long-period gratings (LPGs) inscribed in endlessly single mode (ESM) photonic crystal fibers (PCFs) with symmetric and asymmetric CO2 laser irradiation are investigated both numerically and experimentally. Parallel results from conventional single mode fibers (SMFs) are presented for comparison. Theoretical predictions, transmission measurements, and near-field imaging indicate that, regardless of the fiber type, symmetric index perturbation induced by laser irradiation with the aid of a 120 degrees gold-coated reflecting mirror results in LP(0n) symmetric mode coupling, while asymmetric irradiation without using the mirror leads to LP(1n) asymmetric mode coupling. Our results show that, because of the azimuthally anisotropic hexagonal cladding structure, symmetric irradiation yields far more reproducible LPGs in PCFs than asymmetric irradiation. On the other hand, the irradiation symmetry has little effect on the reproducibility of LPGs inscribed in SMFs due to the isotropy of its all-solid cladding structure. PMID- 23736576 TI - Silicon-organic hybrid (SOH) IQ modulator using the linear electro-optic effect for transmitting 16QAM at 112 Gbit/s. AB - Advanced modulation formats call for suitable IQ modulators. Using the silicon-on insulator (SOI) platform we exploit the linear electro-optic effect by functionalizing a photonic integrated circuit with an organic chi(2)-nonlinear cladding. We demonstrate that this silicon-organic hybrid (SOH) technology allows the fabrication of IQ modulators for generating 16QAM signals with data rates up to 112 Gbit/s. To the best of our knowledge, this is the highest single polarization data rate achieved so far with a silicon-integrated modulator. We found an energy consumption of 640 fJ/bit. PMID- 23736577 TI - Method for modeling additive color effect in photonic polycrystals with form anisotropic elements: the case of Entimus imperialis weevil. AB - The calculation of the reflectance of photonic crystals having form-birefringent anisotropic elements in the crystal unit cell, such as cylinders, often turns out to be problematic, especially when the reflectance spectrum has to be computed according to different crystal orientations as in polycrystals for instance. The method we propose here solves this problem in the specific case of photonic crystals whose periodicities are such that there are no diffraction orders except Bragg reflection in the visible range. For a given crystal orientation, the crystal is sliced into layers and the periodic spatial variations of the dielectric function epsilon are homogenized. Thanks to that homogenization, the calculation can be performed using standard thin film computation codes. In order to demonstrate the usefulness of our method, we applied it to the case of a natural photonic polycrystal found on the cuticle of Entimus imperialis weevil which is a remarkable example of additive color effect. Although each photonic crystal grain of the polycrystal produces a single bright iridescent color, a non iridescent green matt coloration is perceived by the human eye due to multiscale averaging effects. PMID- 23736578 TI - Phase registration based on matching of phase distribution characteristics and its application in FDOCT. AB - Phase fluctuations in a two-transverse-dimensional scanning Fourier domain optical coherence tomography (FDOCT) seriously affect in vivo phase related applications. The phase difference between two A-scans sampled at the same scanning position or adjacent scanning position is acquired by matching of the phase distribution characteristics on the surface of two A-scans. Finger and palm scanning experiments are performed and defocused images of finger and palm are recovered based on Fresnel scalar diffraction algorithm by using phase compensated OCT complex signals. To further prove the performance of the proposed method, human eye scanning experiments are also performed and blood flow images of retina are extracted from the phase registration results. The accurate, fast and simple phase compensation method is critical for in vivo phase related applications. PMID- 23736579 TI - Bi-material terahertz sensors using metamaterial structures. AB - In this paper we report on the design, fabrication and characterization of terahertz (THz) bi-material sensors with metamaterial absorbers. MEMS fabrication friendly SiOx and Al are used to maximize the bimetallic effect and metamaterial absorption at 3.8 THz, the frequency of a quantum cascade laser illumination source. Sensors with different configurations were fabricated and the measured absorption is near 100% and responsivity is around 1.2 deg/MUW, which agree well with finite element simulations. The results indicate the potential of using these detectors to fabricate focal plane arrays for real time THz imaging. PMID- 23736580 TI - Intracavity absorption spectroscopy with a turbulent detuned actively mode-locked Ti:sapphire laser. AB - Intracavity laser absorption spectroscopy (ICLAS) is an extremely sensitive method for the detection of very weak absorptions. However, the conventional use of multimode lasers has thus far significantly reduced its ability to detect in situ molecules and its sensitivity. We propose the use of a new type of laser that overcomes these limitations: the turbulent detuned actively mode-locked (TDAM) Ti:sapphire laser, which owing to its short coherence length, eliminates harmful intracavity interferences. The proposed technique called TDAM-ICLAS is furthermore highly sensitive to intracavity absorption, continuously tunable and has no frequency chirp. PMID- 23736581 TI - Cross-band relative absorption technique for the measurement of molecular mixing ratios. AB - We describe a new method for the measurement of molecular mixing ratios called Cross-Band Relative Absorption (CoBRA). The proposed method is based on relative measurements in different molecular bands referenced to a band of O2 with properly selected wavelength combinations providing high level of cancelation in temperature sensitivities. The CoBRA approach is particularly promising for satellite based remote sensing of molecular mixing ratios of the atmospheric trace gases. Very low temperature sensitivities and the potential of achieving close weighting function matching for the measurement and reference wavelengths are the main advantages of the method. The effectiveness of CoBRA approach is demonstrated for the retrieval of CO2 mixing ratios (XCO2) with application to the ASCENDS mission. PMID- 23736582 TI - Four-in-one interferometer for coherent and self-coherent detection. AB - A compact micro-optical interferometer is presented that combines two optical 90 degrees hybrids or, alternatively, four delay interferometers into one interferometer structure sharing one tunable delay line. The interferometer can function as a frontend of either a coherent receiver or of a self-coherent receiver by adjusting the waveplates and the delay line. We built a prototype on a LIGA bench. We characterized the device and demonstrated its functionality by successful reception of a 112 Gbit/s signal. PMID- 23736583 TI - Overcoming temporal polarization instabilities from the latent birefringence in all-normal dispersion, wave-breaking-extended nonlinear fiber supercontinuum generation. AB - The intrinsic weak birefringence in all-normal dispersion highly nonlinear fiber, particularly ultra-high-numerical-aperture fiber, generates supercontinuum with long term polarization instabilities, even for seed pulses launched along the perceived slow axis of the fiber. Highly co/anti-correlated fluctuations in energy between regions of power spectral density mask the extent of the spectral noise in total integrated power measurements. The instability exhibits a seed pulse power threshold above which the output polarization state of the supercontinuum seeds from noise. Eliminating this instability through the utilization of nonlinear fiber with a large designed birefringence, encourages the exploration of compression schemes and seed sources. Here, we include an analysis of the difficulties for seeding supercontinuum with the highly attractive ANDi-type lasers. Lastly, we introduce an intuitive approach for understanding supercontinuum development and evolution. By modifying the traditional characteristic dispersion and nonlinear lengths to track pulse properties within the nonlinear fiber, we find simple, descriptive handles for supercontinuum evolution. PMID- 23736584 TI - Heterodyne common-path grating interferometer with Littrow configuration. AB - This paper presents a heterodyne common-path grating interferometer with Littrow configuration (HCGIL). The HCGIL can effectively overcome environmental disturbance effect and the DC offset and the amplitude variation of the measurement signals. Experimental results match well with the HP5529A results for long-range measurements. Results also show that the estimated measurement resolution is 0.15 +/- 0.027 nm. The stability of the HCGIL is -0.41 +/- 0.23 nm. Therefore, the HCGIL has potential for subnanometer resolution and long-range applications. PMID- 23736585 TI - Self-locked optical parametric oscillation in a CMOS compatible microring resonator: a route to robust optical frequency comb generation on a chip. AB - We report a novel geometry for OPOs based on nonlinear microcavity resonators. This approach relies on a self-locked scheme that enables OPO emission without the need for thermal locking of the pump laser to the microcavity resonance. By exploiting a CMOS-compatible microring resonator, we achieve oscillation featured by a complete absence of "shutting down", i.e. the self-terminating behavior that is a very common and detrimental occurrence in externally pumped OPOs. Further, our scheme consistently produces very wide bandwidth (>300nm, limited by our experimental set-up) combs that oscillate at a spacing equal to the FSR of the micro cavity resonance. PMID- 23736586 TI - Homodyne laser Doppler vibrometer on silicon-on-insulator with integrated 90 degree optical hybrids. AB - A miniaturized homodyne laser Doppler vibrometer (LDV) with a compact 90 degrees optical hybrid is experimentally demonstrated on a CMOS compatible silicon-on insulator (SOI) platform. Optical components on this platform usually have inadequate suppressions of spurious reflections, which significantly influence the performance of the LDV. Numerical compensation methods are implemented to effectively decrease the impact of these spurious reflections. With the help of these compensation methods, measurements for both super-half-wavelength and sub half-wavelength vibrations are demonstrated. Results show that the minimal detectable velocity is around 1.2 MUm/s. PMID- 23736587 TI - Nanophotonic computational design. AB - In contrast to designing nanophotonic devices by tuning a handful of device parameters, we have developed a computational method which utilizes the full parameter space to design linear nanophotonic devices. We show that our method may indeed be capable of designing any linear nanophotonic device by demonstrating designed structures which are fully three-dimensional and multi modal, exhibit novel functionality, have very compact footprints, exhibit high efficiency, and are manufacturable. In addition, we also demonstrate the ability to produce structures which are strongly robust to wavelength and temperature shift, as well as fabrication error. Critically, we show that our method does not require the user to be a nanophotonic expert or to perform any manual tuning. Instead, we are able to design devices solely based on the user's desired performance specification for the device. PMID- 23736588 TI - Exceptional points in extraordinary optical transmission through dual subwavelength metallic gratings. AB - Complex metamaterials with multiple optical resonances in constituent elements possess many similarities with open quantum systems that can be described by non Hermitian Hamiltonian. By analogy with a two-state open quantum system, we show that a classic analogue of exceptional points can be observed in the transmission spectra of dual subwavelength metallic gratings. Anti-crossing (crossing) between the two branches lambda(R) of extraordinary optical transmission, with crossing (anti-crossing) of the corresponding widths Gamma(R), is observed in the parameter space spanned by the lateral displacement L and the angle of incidence phi0. Exchanges of field patterns and phases, and the variation of field profile when circling the exceptional point are discussed. This work highlights the potential to transfer the concepts and applications from open quantum systems to optical metamaterials. PMID- 23736589 TI - High-sensitivity temperature sensor using the ultrahigh order mode-enhanced Goos Hanchen effect. AB - A high-sensitivity temperature sensor based on the enhanced Goos-Hanchen effect in a symmetrical metal-cladding waveguide is theoretically proposed and experimentally demonstrated. Owing to the high sensitivity of the ultrahigh-order modes, any minute variation of the refractive index and thickness in the guiding layer induced by the thermo-optic and thermal expansion effects will easily give rise to a dramatic change in the position of the reflected light. In our experiment, a series of Goos-Hanchen shifts are measured at temperatures varying from 50.0 degrees C to 51.2 degrees C with a step of 0.2 degrees C. The sensor exhibits a good linearity and a high resolution of approximately 5*10(-3) degrees C. Moreover, there is no need to employ any complicated optical equipment and servo techniques, since our transduction scheme is irrelevant to the light source fluctuation. PMID- 23736590 TI - Tunable coupling-induced transparency band due to coupled localized electric resonance and quasiguided photonic mode in hybrid plasmonic system. AB - A numerical and theoretical study is presented on the exhibition of tunable narrow band coupled-induced transparency phenomenon in a hybrid waveguide-plasmon system consisting of gold twin nanowires array embedded in a slab waveguide. We show that, at slightly non-normal incidence, a properly designed splitting of transmission with narrow transparency peaks may occur at a given wavelength, depending on the angle of incidence. This leads to the wavelength-selective high quality coupled-induced transparency resonance at optical frequencies. By adjusting the gap distance of the pair gratings, the coupled-induced transparency band can be switched between on-state and off-state, which provides us possibilities to develop controllable plasmonic functional devices employing plasmonic nanostructures. PMID- 23736591 TI - Linear dispersive pre-defined peak amplitude modulation of spectrally modulated Airy-based pulses. AB - Spectrally modulated Airy-based pulses peak amplitude modulation (PAM) in linear dispersive media is investigated, designed, and numerically simulated. As it is shown here, it is possible to design the spectral modulation of the initial Airy based pulses to obtain a pre-defined PAM profile as the pulse propagates. Although optical pulses self-amplitude modulation is a well-known effect under non-linear propagation, the designed Airy-based pulses exhibit PAM under linear dispersive propagation. This extraordinary linear propagation property can be applied in many kinds of dispersive media, enabling its use in a broad range of experiments and applications. PMID- 23736592 TI - Long distance fiber Bragg grating strain sensor interrogation using a high speed Raman-based Fourier domain mode-locked fiber laser with recycled residual Raman pump. AB - We propose a novel fiber Bragg grating (FBG) sensor interrogation using a Raman based Fourier-domain mode locking (FDML) fiber laser for a high speed and long distance measurement. A residual Raman pump after the generation of the Raman based FDML fiber laser is recycled for secondary signal amplification in a 2-m erbium-doped fiber (EDF) to further enhance the output power. The chromatic dispersion is precisely controlled to suppress the phase noise in the FDML laser cavity, resulting in the improvement of an R-number of 1.43 mm/dB. After recycling residual pump, we achieve the 40-km round trip transmission of the sensing probe signal with a high scan rate of 30.8 kHz. With 205-mW residual pump power, the bandwidth and the maximum gain are measured to be more than 50 nm, 10.3 dB at 1550 nm, respectively. The sensitivity of the proposed Raman-based FDML fiber laser to strain is also measured, which are 0.81 pm/MUstrain in the spectral domain and 0.19 ns/MUstrain in the time domain, respectively. PMID- 23736593 TI - Transformation of light backscattering phase matrices of crystal clouds depending on the zenith sensing angle. AB - Problems encountered in the interpretation of results of laser sensing of crystal clouds are considered. The parameters characterizing the cloud particle orientation are determined through the backscattering phase matrix elements. It is demonstrated how these parameters are related to the probability density of particle distribution over the spatial orientation angles. Trends in the change of the backscattering phase matrices attendant to variations of the zenith sensing angle are shown on the example of a monodisperse ice particle ensemble. PMID- 23736594 TI - Ampere force based magnetic field sensor using dual-polarization fiber laser. AB - A magnetic field sensor is proposed by placing a dual-polarization fiber grating laser under a copper wire. With a perpendicular magnetic field applied, an electrical current flowing through the copper wire can generate Ampere force to squeeze the fiber grating laser, resulting in the birefringence change inside the laser cavity and hence the change of the beat note frequency. When an alternating current is injected into the copper wire, the magnetic field induced beat note frequency change can be discriminated from environment disturbances. A novel fiber-optic magnetic field sensor is therefore demonstrated with high sensitivity and inherent immunity to disturbances. PMID- 23736595 TI - Experimental generation of arbitrarily shaped diffractionless superoscillatory optical beams. AB - We present, theoretically and experimentally, diffractionless optical beams displaying arbitrarily-shaped sub-diffraction-limited features known as superoscillations. We devise an analytic method to generate such beams and experimentally demonstrate optical superoscillations propagating without changing their intensity distribution for distances as large as 250 Rayleigh lengths. Finally, we find the general conditions on the fraction of power that can be carried by these superoscillations as function of their spatial extent and their Fourier decomposition. Fundamentally, these new type of beams can be utilized to carry sub-wavelength information for very large distances. PMID- 23736596 TI - Block-wise phase switching for double-sideband direct detected optical OFDM signals. AB - We propose phase switching for either main-carrier or subcarriers of two consecutive signal blocks to achieve fading-free double-sideband direct-detection (DD). The proposed approach has twice of the electrical spectral efficiency (SE) of offset OFDM, and the same electrical SE as single-side band (SSB) OFDM. With this scheme, 40-Gb/s DD-OOFDM is successfully received over 80-km SSMF with single polarization and single detector. PMID- 23736597 TI - Statistical behavior analysis and precision optimization for the laser stripe center detector based on Steger's algorithm. AB - Triangulation laser range scanning, which has been wildly used in various applications, can reconstruct the 3D geometric of the object with high precision by processing the image of laser stripe. The unbiased line extractor proposed by Steger is one of the most commonly used algorithms in laser stripe center extraction for its precision and robustness. Therefore, it is of great significance to assess the statistical performance of the Steger method when it is applied on laser stripe with Gaussian intensity profile. In this paper, a statistical behavior analysis for the laser stripe center extractor based on Steger method has been carried out. Relationships between center extraction precision, image quality and stripe characteristics have been examined analytically. Optimal scale of Gaussian smoothing kernel can be determined for each laser stripe image to achieve the highest precision according to the derived formula. Flexible three-step noise estimation procedure has been proposed to evaluate the center extraction precision of a typical triangulation laser scanning system by simply referring to the acquired images. The validity of our analysis has been verified by experiments on both artificial and natural images. PMID- 23736598 TI - Direct characterization of linear-optical networks. AB - We introduce an efficient method for fully characterizing multimode linear optical networks. Our approach requires only a standard laser source and intensity measurements to directly and uniquely determine all moduli and non trivial phases of the matrix describing a network. We experimentally demonstrate the characterization of a 6*6 fiber-optic network and independently verify the results via nonclassical two-photon interference. PMID- 23736599 TI - Theoretical models for beam quality evaluation of fiber supercontinuum sources. AB - We propose three theoretical models to evaluate the beam quality of the fiber supercontinuum source as a whole. New definitions of spectral centroid and three factors to evaluate the beam quality of supercontinuum source are introduced. Based on the three factors some supercontinuum sources with different output power and spectra obtained from the experiment are calculated numerically. All the results denote that the three models are feasible and useful for the beam quality evaluation and comparison of the fiber supercontinuum sources as a whole with considering the power spectral distribution and propagation modes. PMID- 23736600 TI - Loss compensation by spasers in plasmonic systems. AB - We show that in plasmonic systems, exact loss compensation can be achieved with the help of spasers pumped over a wide range of pumping values both below and above the spasing threshold. We demonstrate that the difference between spaser operation below and above the spasing threshold vanishes, when the spaser is synchronized by an external field. As the spasing threshold loses its significance, a new pumping threshold, the threshold of loss compensation, arises. Below this threshold, which is smaller than the spasing threshold, compensation is impossible at any frequency of the external field. PMID- 23736601 TI - Plasmonic gap-mode nanocavities with metallic mirrors in high-index cladding. AB - We theoretically analyze plasmonic gap-mode nanocavities covered by a thick cladding layer at telecommunication wavelengths. In the presence of high-index cladding materials such as semiconductors, the first-order hybrid gap mode becomes more promising for lasing than the fundamental one. Still, the significant mirror loss remains the main challenge to lasing. Using silver coatings within a decent thickness range at two end facets, we show that the reflectivity is substantially enhanced above 95 %. At a coating thickness of 50 nm and cavity length of 1.51 MUm, the quality factor is about 150, and the threshold gain is lower than 1500 cm(-1). PMID- 23736602 TI - Surface-plasmon-enhanced GaN-LED based on a multilayered M-shaped nano-grating. AB - A multilayered metallic M-shaped nano-grating is proposed to enhance the internal quantum efficiency, light extraction efficiency and surface-plasmon (SP) extraction efficiency of the gallium nitride-based light emitting diodes. This structure is fabricated by the low-cost nano-imprint lithography. The suitable grating based on quasi-symmetrical-waveguide structure has a high transmission in the visible region. The properties of SP mode and the Purcell effect in this type of LED is investigated. The experimental results demonstrate that its peak photoluminescence intensity of the proposed LED is over 10 times greater than that from a naked GaN-LED without any nanostructure. PMID- 23736603 TI - Randomization of gold nano-brick arrays: a tool for SERS enhancement. AB - Surface enhanced Raman scattering (SERS) was measured on periodic and randomly arranged patterns of Au nano-bricks (rectangular parallelepipeds). Resonant SERS conditions were investigated of a near-IR dye deposited on nanoparticles. Random mixtures of Au nano-bricks with different aspect ratio R showed stronger SERS enhancement as compared to periodic patterns with constant aspect ratio (R varies from 1 to 4). SERS mapping revealed up to ~ 4 times signal increase at the hot spots. Experimental observation is verified by numerical modeling and is qualitatively consistent with generic scaling arguments of interaction between plasmonic nanoparticles. The effect of randomization on the polarization selectivity for the transverse and longitudinal modes of nano-bricks is shown. PMID- 23736604 TI - Raman optical activity by coherent anti-Stokes Raman scattering spectral interferometry. AB - We demonstrate a method to measure Raman optical activity (ROA) by using coherent anti-Stokes Raman scattering (CARS) spectral interferometry. An extremely weak chirality-induced CARS field is amplified through the interference with a strong CARS field generated from an external reference and is extracted by the Fourier transformation. In this interferometric coherent Raman optical activity (iCROA), both the sign and the magnitude of optical active non-resonant background susceptibility can be directly determined. Measurement of a CARS-ROA spectrum with less artifact is obtained because a broad offset artifact due to optical rotatory dispersion is clearly distinguished in iCROA. PMID- 23736605 TI - On-chip low loss heralded source of pure single photons. AB - A key obstacle to the experimental realization of many photonic quantum-enhanced technologies is the lack of low-loss sources of single photons in pure quantum states. We demonstrate a promising solution: generation of heralded single photons in a silica photonic chip by spontaneous four-wave mixing. A heralding efficiency of 40%, corresponding to a preparation efficiency of 80% accounting for detector performance, is achieved due to efficient coupling of the low-loss source to optical fibers. A single photon purity of 0.86 is measured from the source number statistics without narrow spectral filtering, and confirmed by direct measurement of the joint spectral intensity. We calculate that similar high-heralded-purity output can be obtained from visible to telecom spectral regions using this approach. On-chip silica sources can have immediate application in a wide range of single-photon quantum optics applications which employ silica photonics. PMID- 23736606 TI - Ultrahigh refractive index sensitivity of TE-polarized electromagnetic waves in graphene at the interface between two dielectric media. AB - The behavior of the TE and TM electromagnetic waves in graphene at the interface between two semi-infinite dielectric media is studied. The dramatic influence on the TE waves propagation even at very small changes in the optical contrast between the two dielectric media is predicted. Frequencies of the TE waves are found to lie only in the window determined by the contrast. We consider this effect in connection with the design of graphene-based optical gas sensor. Near the frequency, where the imaginary part of the conductivity of graphene becomes zero, ultrahigh refractive index sensitivity and very low detection limit are revealed. The considered graphene-based optical gas sensor outperforms characteristics of modern volume refractive index sensors by several orders of magnitude. PMID- 23736607 TI - Digital projection photochemical etching defines gray-scale features. AB - We demonstrate a maskless photochemical etching method that is capable of performing one-step etching of multi-level structures. This method uses a digital projector to focus an image onto the sample and define the etching pattern. By combining digital projection photochemical etching with diffraction phase microscopy, etch heights can be measured in situ in a non-destructive manner. This method is single shot, eliminating the need for expensive gray-scale masks or laser scanning methods. The etch rate is studied as a function of the wavelength and irradiance of the projected light. A lateral etch resolution of 2 MUm is demonstrated by etching selected portions of the USAF-1951 target. Micropillars, multi-level plateaus, and an Archimedean spiral are etched, each in a single processing step, to illustrate the unique capabilities. PMID- 23736608 TI - Spatially dispersive amplification in a 12-core fiber and femtosecond pulse synthesis by coherent spectral combining. AB - A compact scheme is demonstrated for amplification and synthesis of ultrashort pulses by fiber amplifiers. Femtosecond pulses are split in 12 different spectral bands which are amplified separately in the 12 cores of a multicore ytterbium doped fiber. Combining the amplifier outputs together with the intensity and phase management of the spectral bands lead to short pulse synthesis with adjustable pulse shape. The scheme gave an x 92 enhancement in amplified power before the onset of nonlinear effects by comparison with standard stretcher free amplification in a single core fiber. PMID- 23736609 TI - Simple and compact V-cavity semiconductor laser with 50*100 GHz wavelength tuning. AB - We report simple and compact V-cavity semiconductor laser capable of full-band wavelength tuning. A half-wave coupler is used to obtain high side-mode suppression ratio (SMSR) without any grating or epitaxial regrowth. Temperature induced gain spectrum shift is employed in combination with the Vernier tuning mechanism to extend the wavelength tuning range beyond the free spectral range limit. Wavelength tuning of 50 channels at 100GHz spacing with SMSR up to 38 dB has been demonstrated. We show that with a temperature variation of 35 degrees C, the tuning range can be extended by about 15 nm, in contrast to 0.1 nm/ degrees C for thermo-optic tuning range in grating based lasers. At a fixed temperature, consecutive wavelength tuning of 31 channels was achieved. The response time of the channel switching under the current-tuning regime is measured to be about 20MUs. The large tuning range that can cover the full C-band will enable such a simple, compact and potentially low-cost tunable laser to be used in wavelength agile access and data center networks. PMID- 23736610 TI - High-bandwidth squeezed light at 1550 nm from a compact monolithic PPKTP cavity. AB - We report the generation of squeezed vacuum states of light at 1550 nm with a broadband quantum noise reduction of up to 4.8 dB ranging from 5 MHz to 1.2 GHz sideband frequency. We used a custom-designed 2.6 mm long biconvex periodically poled potassium titanyl phosphate (PPKTP) crystal. It featured reflectively coated end surfaces, 2.26 GHz of linewidth and generated the squeezing via optical parametric amplification. Two homodyne detectors with different quantum efficiencies and bandwidths were used to characterize the non-classical noise suppression. We measured squeezing values of up to 4.8 dB from 5 to 100 MHz and up to 3 dB from 100 MHz to 1.2 GHz. The squeezed vacuum measurements were limited by detection loss. We propose an improved detection scheme to measure up to 10 dB squeezing over 1 GHz. Our results of GHz bandwidth squeezed light generation provide new prospects for high-speed quantum key distribution. PMID- 23736611 TI - Vertically stacked microring waveguides for coupling between multiple photonic planes. AB - We present a design for a low-footprint optical interconnect that efficiently couples between two photonic planes with significant vertical separation up to 10 MUm and a footprint less than 10 MUm * 10 MUm. The device may be used to connect between deposited passive waveguide devices in the upper plane and active devices on a substrate. The design is based on a vertical stack of coupled ring resonators. We demonstrate basic feasibility of the design and estimates of device performance based on numerical simulation. A matrix model is presented to estimate spectral performance as a function of several design parameters. PMID- 23736612 TI - Translation position determination in ptychographic coherent diffraction imaging. AB - Accurate knowledge of translation positions is essential in ptychography to achieve a good image quality and the diffraction limited resolution. We propose a method to retrieve and correct position errors during the image reconstruction iterations. Sub-pixel position accuracy after refinement is shown to be achievable within several tens of iterations. Simulation and experimental results for both optical and X-ray wavelengths are given. The method improves both the quality of the retrieved object image and relaxes the position accuracy requirement while acquiring the diffraction patterns. PMID- 23736613 TI - Advanced perturbation technique for digital backward propagation in WDM systems. AB - An improved digital backward propagation (DBP) is proposed to compensate inter nonlinear effects and dispersion jointly in WDM systems based on an advanced perturbation technique (APT). A non-iterative weighted concept is presented to replace the iterative in analytical recursion expression, which can dramatically simplify the complexity and improve accuracy compared to the traditional perturbation technique (TPT). Furthermore, an analytical recursion expression of the output after backward propagation is obtained initially. Numerical simulations are executed for various parameters of the transmission system. The results indicate that the advanced perturbation technique will relax the step size requirements and reduce the oversampling factor when launch power is higher than -2 dBm. We estimate this technique will reduce computational complexity by a factor of around seven with respect to the conventional DBP. PMID- 23736614 TI - A novel method for combating dispersion induced power fading in dispersion compensating fiber. AB - We experimentally investigate the performance of 60 GHz double sideband (DSB) radio over fiber (RoF) links that employ dispersion compensating fiber (DCF). Error free transmission of 3 Gbps signals over 1 m of wireless distance is reported. In order to overcome experimentally observed chromatic dispersion (CD) induced power fading of radio frequency (RF) signal, we propose a method for improvement of RF carrier-to-noise (C/N) ratio through introduction of a degree of RF frequency tunability. Overall results improve important aspects of directly modulated RoF systems and demonstrate the feasibility of high carrier frequency and wide bandwidth RF signals delivery in RoF links including DCF fiber. Error free performance that we obtain for 3 Gbps amplitude shift-keying (ASK) signals enables uncompressed high-definition 1080p video delivery. PMID- 23736615 TI - High-frequency self-induced oscillations in a silicon nanocavity. AB - We show that self-induced oscillations at frequencies above GHz and with a high spectral purity can be obtained in a silicon photonic crystal nanocavity under optical pumping. This self-pulsing results from the interplay between the nonlinear response of the cavity and the photon cavity lifetime. We provide a model to analyze the mechanisms governing the onset of self-pulsing, the amplitudes of both fundamental and harmonic oscillations and their dependences versus input power and oscillation frequency. Theoretically, oscillations at frequencies higher than 50 GHz could be achieved in this system. PMID- 23736616 TI - Selective synthesis of Sb2S3 nanoneedles and nanoflowers for high performance rigid and flexible photodetectors. AB - Needle-like and flower-like antimony sulfide nanostructures were synthesized and applied for both rigid and flexible photodetectors. Rigid photodetectors based on both nanostructures have the features of linear photocurrent characteristics, low linear dynamic range and good sensitivity to light intensity. Especially, the rigid Sb2S3 nanoflowers photodetector has high photoresponse characteristics and its response time and decay time were found to be relatively fast as 6 ms and 10 ms respectively. The flexible Sb2S3 nanoflowers photodetector has high flexible, light-weight and adequate bendability with a response time of about 0.09 s and recovery time of 0.27 s. Our results revealed that the rigid and flexible photodetectors based on Sb2S3 nanostructures have great potential in next generation optoelectronic devices. PMID- 23736617 TI - Low cost wafer metrology using a NIR low coherence interferometry. AB - In this investigation, a low cost Si wafer metrology system based on low coherence interferometry using NIR light is proposed and verified. The whole system consists of two low coherence interferometric principles: low coherence scanning interferometry (LCSI) for measuring surface profiles and spectrally resolved interferometry (SRI) to obtain the nominal optical thickness of the double-sided polished Si wafer. The combination of two techniques can reduce the measurement time and give adequate dimensional information of the Si wafer. The wavelength of the optical source is around 1 MUm, for which transmission is non zero for undoped silicon and can be also detected by a typical CCD camera. Because of the typical CCD camera, the whole system can be constructed inexpensively. PMID- 23736618 TI - Temperature and multi-species measurements by supercontinuum absorption spectroscopy for IC engine applications. AB - The first supercontinuum (SC) absorption spectroscopy measurements showing the feasibility of quantitative temperature evaluation are presented to the best of the authors' knowledge. Temperature and multi-species measurements were carried out at a detection rate of ~2 MHz in a high-temperature flow cell within a temperature range from 450 K to 750 K at 0.22 MPa, representing conditions during the suction and compression stroke in an internal combustion (IC) engine. The broadband SC pulses were temporally dispersed into fast wavelength sweeps, covering the overtone absorption bands 2nu(1), 2nu(3), nu(1) + nu(3) of H2O and 3nu(3) of CO2 in the near-infrared region from 1330 nm to 1500 nm. The temperature information is inferred from the peak ratio of a temperature sensitive (1362.42 nm) and insensitive (1418.91 nm) absorption feature in the nu(1) + nu(3) overtone bands of water. The experimental results are in very good agreement with theoretical intensity ratios calculated from absorption spectra based on HiTran data. PMID- 23736619 TI - 14XX nm-wavelength electrically-pumped VECSELs fabricated by wafer fusion. AB - We report on the design, fabrication and characterization of electrically pumped vertical external cavity surface emitting lasers (EP-VECSELs) emitting at 1470 nm. We demonstrate 6.2 mW of CW output power, which represents the highest power value reported so far for EP-VECSELs in the 14XX nm and 15XX nm wavelength bands. PMID- 23736620 TI - III-V-on-silicon multi-frequency lasers. AB - Compact multi-frequency lasers are realized by combining III-V based optical amplifiers with silicon waveguide optical demultiplexers using a heterogeneous integration process based on adhesive wafer bonding. Both devices using arrayed waveguide grating routers as well as devices using ring resonators as the demultiplexer showed lasing with threshold currents between 30 and 40 mA and output powers in the order of a few mW. Laser operation up to 60 degrees C is demonstrated. The small bending radius allowable for the silicon waveguides results in a short cavity length, ensuring stable lasing in a single longitudinal mode, even with relaxed values for the intra-cavity filter bandwidths. PMID- 23736621 TI - The intra-cavity phase anisotropy and the polarization flipping in HeNe laser. AB - The effect of intra-cavity phase anisotropy on polarization flipping induced by optical feedback is experimentally and theoretically investigated. In experiments, we place a polarizer in feedback cavity to induce polarization flipping. The polarization flipping doesn't occur when the angle between polarizer axis and laser polarization approaches 45 degrees . It is found that the larger the phase anisotropy is, the more easily the polarization flipping happens. As the intra-cavity phase anisotropy is increased, polarization flipping always occurs when the angle between polarizer axis and laser polarization is changed from 0 degrees to 90 degrees . This indicates that the phase anisotropy of the laser cavity contributes to the polarization flipping. It is necessary to keep certain phase anisotropy for the lasers used for polarization control. PMID- 23736622 TI - Hybrid phase-change plasmonic crystals for active tuning of lattice resonances. AB - Tunable lattice resonances are demonstrated in a hybrid plasmonic crystal incorporating the phase-change material Ge2Sb2Te5 (GST) as a 20-nm-thick layer sandwiched between a gold nanodisk array and a quartz substrate. Non-volatile tuning of lattice resonances over a range Deltalambda of about 500 nm (1.89 um to 2.27 um) is achieved experimentally via intermediate phase states of the GST layer. This work demonstrates the efficacy and ease of resonance tuning via GST in the near infrared, suggesting the possibility to design broadband non-volatile tunable devices for optical modulation, switching, sensing and nonlinear optical devices. PMID- 23736624 TI - A detailed study of resonance-assisted evanescent interference lithography to create high aspect ratio, super-resolved structures. AB - Higher resolution demands for semiconductor lithography may be fulfilled by higher numerical aperture (NA) systems. However, NAs more than the photoresist refractive index (~1.7) cause surface confinement of the image. In this paper we describe how evanescent wave coupling to effective gain medium surface states beneath the imaging layer can counter this problem. We experimentally demonstrate this at lambda = 405 nm using hafnium oxide on SiO2 to enhance the image depth of a 55-nm line and space pattern (numerical aperture of 1.824) from less than 40 nm to more than 90 nm. We provide a design example at lambda = 193 nm, where a layer of sapphire on SiO2 counters image decay by an effective-gain-medium resonance phenomena allowing evanescent interferometric lithography to create high aspect ratio structures at NAs of 1.85 (26-nm resolution) and beyond. PMID- 23736623 TI - Elastico-mechanoluminescence in CaZr(PO4)2:Eu2+ with multiple trap levels. AB - We report on a novel elastico-mechanoluminescence (EML) phosphor of CaZr(PO4)2:Eu2+ for simultaneous luminescent sensing and imaging to mechanical load by the light-emitting of Eu2+ ions. The EML properties of CaZr(PO4)2:Eu2+ show an intense luminance (above 15 mcd m(-2)), a low load threshold (below 5 N), a broad measurement range for the dynamic load (up to 2000 N), and an accurate linear relationship of EML intensity against the applied load. The excellent EML characteristics are considered to originate from the piezoelectric crystal structure and the multiple trap levels with appropriate depths. An EML mechanism based on the electrons as the main charge carriers is proposed. PMID- 23736625 TI - Supercritical xenon-filled hollow-core photonic bandgap fiber. AB - We demonstrate that filling a hollow-core photonic-bandgap fiber with supercritical xenon creates a medium with a controllable density up to several hundred times that at STP, while working at room temperature. The high compressibility of the supercritical fluid allows rapid tuning of the spectral guidance window by making small changes of gas pressure near the critical point. We discuss potential applications of this system in linear and nonlinear optics. PMID- 23736626 TI - Polarization filter characters of the gold-coated and the liquid filled photonic crystal fiber based on surface plasmon resonance. AB - The polarization filter characters of a gold-coated and liquid-filled photonic crystal fiber are studied using the finite element method. Results show that the resonance strength and wavelengths are different in two polarized directions. Filling liquid of refractive index n=1.33 (purified water) in holes in longitudinal direction can increase the loss of core mode polarized in the y direction around the resonance peak. The resonance strength is much stronger in y polarized direction than in x-polarized direction. The resonance strength can achieve 508dB/cm in y-polarized direction at the communication wavelength of 1311nm in one of our structures. Moreover, the full width half maximum is only 20nm. Such a small number makes such photonic crystal fibers promising candidate to filter devices. A liquid filled PCF of the small hole in the fiber core is designed and we find that filling liquid increases the resonance strength peak by thirty eight percent for the y-polarized resonance point. PMID- 23736627 TI - Thermal lensing analysis of TGG and its effect on beam quality. AB - An analysis is presented of a TGG crystal rod under high power laser operation. A semianalytical thermal analysis is investigated to obtain the temperature profile and thermal lensing effect in a TGG crystal upon incidence of a high power laser light. By solving the heat transfer equation for the TGG crystal and taking the Gaussian beam transverse intensity profile as the heat source, the optical path difference due to induced thermal effects was obtained. Moreover, a detailed model for the dependence of thermal lensing and beam degradation which takes into account up to the fifth-order spherical aberration is presented. Based on this model, it is shown that up to a critical value of the beam power the degradation of the beam is not significant. The experimental results on thermal lensing and degradation on beam quality of a high power laser passing through a TGG crystal rod are in agreement with the main results from our model. PMID- 23736628 TI - Intrinsic stability of quantum cascade lasers against optical feedback. AB - We study the time dependence of the optical power emitted by terahertz and mid-IR quantum cascade lasers in presence of optical reinjection and demonstrate unprecedented continuous wave (CW) emission stability for strong feedback. We show that the absence of coherence collapse or other CW instabilities typical of diode lasers is inherently associated with the high value of the photon to carrier lifetime ratio and the negligible linewidth enhancement factor of quantum cascade lasers. PMID- 23736629 TI - Snapshot 3D optical coherence tomography system using image mapping spectrometry. AB - A snapshot 3-Dimensional Optical Coherence Tomography system was developed using Image Mapping Spectrometry. This system can give depth information (Z) at different spatial positions (XY) within one camera integration time to potentially reduce motion artifact and enhance throughput. The current (x,y,lambda) datacube of (85*356*117) provides a 3D visualization of sample with 400 MUm depth and 13.4 MUm in transverse resolution. Axial resolution of 16.0 MUm can also be achieved in this proof-of-concept system. We present an analysis of the theoretical constraints which will guide development of future systems with increased imaging depth and improved axial and lateral resolutions. PMID- 23736630 TI - Highly efficient Yb3+-doped channel waveguide laser at 981 nm. AB - Channel waveguide lasers operating at 981 nm are demonstrated in KY(1-x y)Gd(x)Lu(y)(WO4)2:Yb3+ waveguides grown by liquid phase epitaxy onto undoped KY(WO4)2 substrates and microstructured by Ar+ beam etching. Under pumping at 934 nm of samples with different waveguide geometry and outcoupling degree, a record high slope efficiency of 76% versus absorbed pump power and a record-high output power of 650 mW for rare-earth-ion-doped microstructured channel waveguide lasers is achieved. The laser performance is compared to that of the same devices when pumping at 981 nm and lasing near 1025 nm. PMID- 23736631 TI - Experimental wavelet based denoising for indoor infrared wireless communications. AB - This paper reports the experimental wavelet denoising techniques carried out for the first time for a number of modulation schemes for indoor optical wireless communications in the presence of fluorescent light interference. The experimental results are verified using computer simulations, clearly illustrating the advantage of the wavelet denoising technique in comparison to the high pass filtering for all baseband modulation schemes. PMID- 23736632 TI - Investigating the resonance spectrum of optical frequency combs in fiber-optic cavities. AB - We report a detailed theoretical and experimental study of fiber-optic cavities under broadband excitation by mode-locked laser combs. We calculate the effects of fiber dispersion on the cavity transmission. For any integer ratio between the comb repetition rate and cavity free spectral range, the theoretical resonant output spectrum exhibits a narrow group of resonant teeth, surrounded by minor, unevenly spaced resonances. Also, the central resonance can be rapidly and precisely tuned over the entire comb span by only acting on its repetition rate. Experimental observations are provided by a single-mode fiber ring and a telecom wavelength comb laser. The resulting spectral pattern agrees very well with our theoretical prediction, allowing a thorough characterization of the cavity dispersion and opening new perspectives for comb spectroscopy in dielectric resonators. PMID- 23736633 TI - Optical bistability in subwavelength compound metallic grating. AB - We have investigated the optical bistability behavior based on an electromagnetically induced reflection (EIR) effect in a compound metallic grating consisting of subwavelength slits and Kerr nonlinear nanocavities embedded in a metallic film. The theoretical and simulation results show that a narrow peak in the broad reflection dip possesses a red-shift with increasing the refractive index of coupled nanocavities. Importantly, we have obtained an obvious optical bistability with threshold intensity about ten times lower than that of metallic grating coated by nonlinear material. The results indicate that our structure may find excellent applications for nonlinear plasmonic devices, especially optical switches and modulators. PMID- 23736634 TI - Two-axis MEMS scanner with transfer-printed high-reflectivity, broadband monolithic silicon photonic crystal mirrors. AB - We present a two-axis electrostatic MEMS scanner with high-reflectivity monolithic single-crystal-silicon photonic crystal (PC) mirrors suitable for applications in harsh environments. The reflective surfaces of the MEMS scanner are transfer-printed PC mirrors with low polarization dependence, low angular dependence, and reflectivity over 85% in the wavelength range of 1490nm~1505nm and above 90% over the wavelength band of 1550~1570nm. In static mode, the scanner has total scan range of 10.2 degrees on one rotation axis and 7.8 degrees on the other. Dynamic operation on resonance increase the scan range to 21 degrees at 608Hz around the outer rotation axis and 9.5 degrees at 1.73kHz about the inner rotation axis. PMID- 23736635 TI - Tailored bandgaps: iterative algorithms of diffractive optics. AB - A diffractive optics design method based on a phase retrieval algorithm and carrier grating coding is modified to enable designing of photonic bandgap reflectances. Discrete and continuous signals are designed for a fiber grating to demonstrate the capability of the approach. The method is proved a versatile tool for synthesizing reflectance spectra of periodic structures. PMID- 23736636 TI - High power, continuous-wave ytterbium-doped fiber laser tunable from 976 to 1120 nm. AB - We report on a linearly-polarized, continuous-wave Ytterbium-doped fiber laser continuously tunable on the fly over an unprecedented emission bandwidth ranging from 976 nm to 1120 nm and delivering a minimum of 10 W and a maximum of 41 W. Additionally, the bandwidth of the system can be tuned from 100 pm to more than 1 nm at all wavelengths. PMID- 23736637 TI - Light-sheet microscopy in thick media using scanned Bessel beams and two-photon fluorescence excitation. AB - In this study we show that it is possible to successfully combine the benefits of light-sheet microscopy, self-reconstructing Bessel beams and two-photon fluorescence excitation to improve imaging in large, scattering media such as cancer cell clusters. We achieved a nearly two-fold increase in axial image resolution and 5-10 fold increase in contrast relative to linear excitation with Bessel beams. The light-sheet penetration depth could be increased by a factor of 3-5 relative to linear excitation with Gaussian beams. These finding arise from both experiments and computer simulations. In addition, we provide a theoretical description of how these results are composed. We investigated the change of image quality along the propagation direction of the illumination beams both for clusters of spheres and tumor multicellular spheroids. The results reveal that light-sheets generated by pulsed near-infrared Bessel beams and two photon excitation provide the best image resolution, contrast at both a minimum amount of artifacts and signal degradation along the propagation of the beam into the sample. PMID- 23736638 TI - Temporal mode selectivity by frequency conversion in second-order nonlinear optical waveguides. AB - We explore theoretically the feasibility of using frequency conversion by sum- or difference-frequency generation, enabled by three-wave-mixing, for selectively multiplexing orthogonal input waveforms that overlap in time and frequency. Such a process would enable a drop device for use in a transparent optical network using temporally orthogonal waveforms to encode different channels. We model the process using coupled-mode equations appropriate for wave mixing in a uniform second-order nonlinear optical medium pumped by a strong laser pulse. We find Green functions describing the process, and employ Schmidt (singular-value) decompositions thereof to quantify its viability in functioning as a coherent waveform discriminator. We define a selectivity figure of merit in terms of the Schmidt coefficients, and use it to compare and contrast various parameter regimes via extensive numerical computations. We identify the most favorable regime (at least in the case of no pump chirp) and derive the complete analytical solution for the same. We bound the maximum achievable selectivity in this parameter space. We show that including a frequency chirp in the pump does not improve selectivity in this optimal regime. We also find an operating regime in which high-efficiency frequency conversion without temporal-shape selectivity can be achieved while preserving the shapes of a wide class of input pulses. The results are applicable to both classical and quantum frequency conversion. PMID- 23736639 TI - Spectrally modulated stimulated Raman scattering imaging with an angle-to wavelength pulse shaper. AB - The stimulated Raman scattering signal is often accompanied by unwanted background arising from other pump-probe modalities. We demonstrate an approach to overcome this challenge based on spectral domain modulation, enabled by a compact, cost-effective angle-to-wavelength pulse shaper. The pulse shaper switches between two spectrally narrow windows, which are cut out of a broadband femtosecond pulse and selected for on- and off- Raman resonance excitation, at 2.1 MHz frequency for detection of stimulated Raman scattering signal. Such spectral modulation reduced the unwanted pump-probe signals by up to 20 times and enabled stimulated Raman scattering imaging of molecules in a pigmented environment. PMID- 23736640 TI - Mechanical reinforcement fibers produced by gel-spinning of poly-acrylic acid (PAA) and graphene oxide (GO) composites. AB - Graphene oxide (GO) with extraordinary chemical, thermal and mechanical properties offers possibilities in a variety of applications. Many materials have been fabricated through physical blending of GO with other materials, while, the chemical functionalization of GO has generally been considered challenging. Here, we report the preparation of a novel GO-functionalized fibrous material in which individual compliant GO sheets are cross-linked by PAA chains in a near-vertical fashion. This new fibrous material outperforms many other common fibers in stiffness and strength. Combined with straightforward manufacturing methods, the fibers should find applications in a wide range of areas. PMID- 23736641 TI - Hypertension and experimental stroke therapies. AB - Hypertension is an established target for long-term stroke prevention but procedures for management of hypertension in acute stroke are less certain. Here, we analyze basic science data to examine the impact of hypertension on candidate stroke therapies and of anti-hypertensive treatments on stroke outcome. METHODS: Data were pooled from 3,288 acute ischemic stroke experiments (47,899 animals) testing the effect of therapies on infarct size (published 1978-2010). Data were combined using meta-analysis and meta-regression, partitioned on the basis of hypertension, stroke model, and therapy. RESULTS: Hypertensive animals were used in 10% of experiments testing 502 therapies. Hypertension was associated with lower treatment efficacy, especially in larger infarcts. Overall, anti hypertensives did not provide greater benefit than other drugs, although benefits were evident in hypertensive animals even when given after stroke onset. Fifty eight therapies were tested in both normotensive and hypertensive animals: some demonstrated superior efficacy in hypertensive animals (hypothermia) while others worked better in normotensive animals (tissue plasminogen activator, anesthetic agents). DISCUSSION: Hypertension has a significant effect on the efficacy of candidate stroke drugs: standard basic science testing may overestimate the efficacy which could be reasonably expected from certain therapies and for hypertensive patients with large or temporary occlusions. PMID- 23736642 TI - Investigation of whole-brain white matter identifies altered water mobility in the pathogenesis of high-altitude headache. AB - Elevated brain water is a common finding in individuals with severe forms of altitude illness. However, the location, nature, and a causative link between brain edema and symptoms of acute mountain sickness such as headache remains unknown. We examined indices of brain white matter water mobility in 13 participants after 2 and 10 hours in normoxia (21% O2) and hypoxia (12% O2) using magnetic resonance imaging. Using a whole-brain analysis (tract-based spatial statistics (TBSS)), mean diffusivity was reduced in the left posterior hemisphere after 2 hours and globally reduced throughout cerebral white matter by 10 hours in hypoxia. However, no changes in T2 relaxation time (T2) or fractional anisotropy were observed. The TBSS identified an association between changes in mean diffusivity, fractional anisotropy, and T2 both supra and subtentorially after 2 and 10 hours, with headache score after 10 hours in hypoxia. Region of interest-based analyses generally confirmed these results. These data indicate that acute periods of hypoxemia cause a shift of water into the intracellular space within the cerebral white matter, whereas no evidence of brain edema (a volumetric enlargement) is identifiable. Furthermore, these changes in brain water mobility are related to the intensity of high-altitude headache. PMID- 23736643 TI - Ketosis proportionately spares glucose utilization in brain. AB - The brain is dependent on glucose as a primary energy substrate, but is capable of utilizing ketones such as beta-hydroxybutyrate and acetoacetate, as occurs with fasting, starvation, or chronic feeding of a ketogenic diet. The relationship between changes in cerebral metabolic rates of glucose (CMRglc) and degree or duration of ketosis remains uncertain. To investigate if CMRglc decreases with chronic ketosis, 2-[(18)F]fluoro-2-deoxy-D-glucose in combination with positron emission tomography, was applied in anesthetized young adult rats fed 3 weeks of either standard or ketogenic diets. Cerebral metabolic rates of glucose (MUmol/min per 100 g) was determined in the cerebral cortex and cerebellum using Gjedde-Patlak analysis. The average CMRglc significantly decreased in the cerebral cortex (23.0+/-4.9 versus 32.9+/-4.7) and cerebellum (29.3+/-8.6 versus 41.2+/-6.4) with increased plasma ketone bodies in the ketotic rats compared with standard diet group. The reduction of CMRglc in both brain regions correlates linearly by ~9% for each 1 mmol/L increase of total plasma ketone bodies (0.3 to 6.3 mmol/L). Together with our meta-analysis, these data revealed that the degree and duration of ketosis has a major role in determining the corresponding change in CMRglc with ketosis. PMID- 23736644 TI - Resistance of optogenetically evoked motor function to global ischemia and reperfusion in mouse in vivo. AB - Recently we have shown that despite reperfusion, sensory processing exhibits persistent deficits after global ischemia in a mouse in vivo model. We now address how motor output, specifically cortically evoked muscle activity, stimulated by channelrhodopsin-2 is affected by global ischemia and reperfusion. We find that the light-based optogenetic motor map recovers to 80% within an hour. Moreover, motor output recovers relatively faster and more completely than the sensory processing after 5-minute period of global ischemia. Our results suggest a differential sensitivity of sensory and motor systems to the effects of global ischemia and reperfusion that may have implications for rehabilitation. PMID- 23736645 TI - Breast cancer: Timing of sentinel-node biopsy. PMID- 23736646 TI - Biomarkers: New VEGF model-based biomarker. PMID- 23736647 TI - Surgery: Cetuximab--an option for unresectable CRC liver metastases. PMID- 23736649 TI - Feasibility study of the pharmacology of local application of amifostine (WR 2721) to the buccal mucosa in guinea pigs. AB - BACKGROUND/AIMS: We have undertaken this study to investigate the feasibility of topical application of the radioprotective compound WR-2721 to the buccal mucosa. METHODS: Saliva samples were collected from 5 volunteers and were reconstituted in 3 amifostine solutions. Measurements of amifostine and WR-1065 contents were performed at 6 different time points. Young-adult guinea pigs were topically administered amifostine 50 and 100 mg to each buccal mucosa. At 0, 15 and 30 min after application, the blood samples obtained from the heart and the buccal tissues were prepared for the analysis of amifostine and WR-1065. RESULTS: There was no significant difference between the 3 concentrations of amifostine in saliva in vitro at any of the 6 study time points (p > 0.05). No WR-1065 was detected in saliva. In the guinea pigs from groups A and B, there were significant differences in concentrations of amifostine and WR-1065 in the tissues between the 0-min and 15-min subgroups and between the 0-min and 30-min subgroups (p < 0.05). The concentrations of amifostine and WR-1065 from the 15 min and 30-min subgroups did not differ statistically (p > 0.05). CONCLUSIONS: It is feasible to administer topical amifostine (WR-2721) to mucosa to prevent radiation-induced oral mucositis, and systemic absorption is negligible. Relatively high concentrations of amifostine in human saliva in vitro were maintained, although some inconsistent changes are observed. PMID- 23736648 TI - Clinical trials of human papillomavirus vaccines and beyond. AB - Human papillomavirus (HPV) is the most common sexually transmitted infectious agent; its 14 oncogenic types are causally associated with 5-10% of all cancers. The major structural HPV protein self-assembles into immunogenic virus-like particles. Two licensed HPV vaccines--the bivalent vaccine comprising HPV types 16 and 18, and the quadrivalent vaccine comprising HPV types 6, 11, 16 and 18- have proven to be safe and efficacious against 6-month-persistent cervical infections of HPV16 and HPV18 and associated precancerous lesions, and both have efficacies of 90-100%. Among baseline HPV-negative adolescent females, vaccine efficacies against the immediate precursor of cervical cancer (intraepithelial neoplasia grade 3) irrespective of HPV type are 93.2% and 43.0% for the bivalent and quadrivalent vaccines, respectively. The quadrivalent vaccine is efficacious (>75% vaccine efficacy) against any of the more-severe precursors of vulval, vaginal and anal cancers. A strong increase in vaccine efficacy with increasing severity of the precancerous lesion is explained by accumulation of the most oncogenic HPV types 16 and 18 in these lesions. Therefore, prophylactic HPV vaccination will exceed the best results from screening for cancer. With the extremely efficacious prophylactic HPV vaccines, the focus of organized intervention (vaccination and screening) programmes should, however, shift from reducing the HPV disease burden to controlling the prevalence of oncogenic HPV (and nononcogenic HPV) types. Eradication of the major oncogenic HPV types should be pursued. PMID- 23736650 TI - Tandem nucleophilic addition-Oppenauer oxidation of aromatic aldehydes to aryl ketones with triorganoaluminium reagents. AB - In the presence of pinacolone, the in situ prepared triorganoaluminium reagents reacted with aromatic aldehydes to give ketones in moderate to high yield. We propose that the products are formed via a tandem organoaluminium reagents addition-Oppenauer oxidation sequence. PMID- 23736651 TI - Can SNOMED CT as implemented in New South Wales, Australia be used for road trauma injury surveillance in emergency departments? AB - The introduction of Systematized Nomenclature of Medicine - Clinical Terms (SNOMED CT) for diagnosis coding in emergency departments (EDs) in New South Wales (NSW) has implications for injury surveillance abilities. This study aimed to assess the consequences of its introduction, as implemented as part of the ED information system in NSW, for identifying road trauma-related injuries in EDs. It involved a retrospective analysis of road trauma-related injuries identified in linked police, ED and mortality records during March 2007 to December 2009. Of all SNOMED CT codes in the principal provisional diagnosis field, between 53.7% and 78.4% referred to the type of injury or symptom experienced by the individual. Of the road users identified by police, 3.2% of vehicle occupants, 6% of motorcyclists, 10.0% of pedal cyclists and 5.2% of pedestrians were identified using SNOMED CT codes in the principal provisional diagnosis field. The introduction of SNOMED CT may provide flexible terminologies for clinicians. However, unless carefully implemented in information systems, its flexibility can lead to mismatches between the intention and actual use of defined data fields. Choices available in SNOMED CT to indicate symptoms, diagnoses, or injury mechanisms need to be controlled and these three concepts need to be retained in separate data fields to ensure a clear distinction between their classifications in the ED. PMID- 23736652 TI - Moving health promotion communities online: a review of the literature. AB - There is a need to enhance the effectiveness and reach of complex health promotion initiatives by providing opportunities for diverse health promotion practitioners and others to interact in online settings. This paper reviews the existing literature on how to take health promotion communities and networks into online settings. A scoping review of relevant bodies of literature and empirical evidence was undertaken to provide an interpretive synthesis of existing knowledge on the topic. Sixteen studies were identified between 1986 and 2007. Relatively little research has been conducted on the process of taking existing offline communities and networks into online settings. However, more research has focused on offline (i.e. not mediated via computer networks); 'virtual' (purely online with no offline interpersonal contact); and 'multiplex' communities (i.e. those that interact across both online and offline settings). Results are summarised under three themes: characteristics of communities in online and offline settings; issues in moving offline communities online, and designing online communities to match community needs. Existing health promotion initiatives can benefit from online platforms that promote community building and knowledge sharing. Online e-health promotion settings and communities can successfully integrate with existing offline settings and communities to form 'multiplex' communities (i.e. communities that operate fluently across both online and offline settings). PMID- 23736653 TI - Discretionary use of family practice information systems: an empirical examination in Turkey. AB - This study examined the antecedents and consequences of the discretionary use of the family practice information systems (FPIS) by family physicians in Turkey. A structured survey was conducted among family physicians located in Kahramanmaras, a southern province in Turkey. The partial least squares (PLS) method was used to analyse the survey data. Findings showed that (1) physicians' discretionary use of FPIS is positively related to their perceived value of patient care; (2) physicians' computer self-efficacy is positively related to their discretionary use of FPIS; (3) physicians' innovativeness in information technology (IT) is positively related to their computer self-efficacy; and (4) physicians' innovativeness in IT does not significantly impact on their discretionary use of FPIS. The present study's findings revealed that physicians should be adequately informed about the discretionary use of FPIS, and policies should be established to improve family physicians' understanding and competence of information systems, including computer self-efficacy. PMID- 23736654 TI - Mining association rules between abnormal health examination results and outpatient medical records. AB - Currently, interpretation of health examination reports relies primarily on the physician's own experience. If health screening data could be integrated with outpatient medical records to uncover correlations between disease and abnormal test results, the physician could benefit from having additional reference resources for medical examination report interpretation and clinic diagnosis. This study used the medical database of a regional hospital in Taiwan to illustrate how association rules can be found between abnormal health examination results and outpatient illnesses. The rules can help to build up a disease prevention knowledge database that assists healthcare providers in follow-up treatment and prevention. Furthermore, this study proposes a new algorithm, the data cutting and sorting method, or DCSM, in place of the traditional Apriori algorithm. DCSM significantly improves the mining performance of Apriori by reducing the time to scan health examination and outpatient medical records, both of which are databases of immense sizes. PMID- 23736655 TI - Road traffic noise and annoyance: a quantification of the effect of quiet side exposure at dwellings. AB - Previous studies indicate that residents may benefit from a "quiet side" to their dwellings. The influence of the level of road traffic noise exposure at the least exposed side on road traffic noise annoyance was studied in Amsterdam, The Netherlands. Road traffic noise exposure was assessed at the most and least exposed facade (Lden,most and Lden,least respectively) of dwellings for subjects in a population based survey (N = 1,967). It was investigated if and to what extent relative quietness at the least exposed facade affected the level of road traffic noise annoyance by comparing two groups: (1) The subgroup with a relatively quiet facade; (2) the subgroup without a relatively quiet facade (large versus small difference in exposure between most and least exposed facade; DIF >= 10 dB and DIF < 10 dB respectively). In addition, it was investigated if and to what extent Lden,least affected the level of road traffic noise annoyance. Results indicate a significantly lower road traffic noise annoyance score at a given Lden,most, in the subgroup with DIF >= 10 dB versus DIF < 10 dB. Furthermore, results suggest an effect of Lden,least independent of Lden,most. The estimated size of the effect expressed in an equivalent change in Lden,most approximated 5 dB for both the difference between the two subgroups (DIF >= 10 dB and DIF < 10 dB), and for a 10 dB change in Lden,least. PMID- 23736657 TI - Knowledge, attitude and practices (KAP) survey on water, sanitation and hygiene in selected schools in Vhembe District, Limpopo, South Africa. AB - This study assessed the knowledge, attitude and practices (KAP) of learners on issues related to water, sanitation and hygiene in selected schools in Vhembe District, South Africa. The methodology relied on a questionnaire, an inspection of sanitary facilities and discussion with the school authorities. The data was analyzed using the Statistical Package for Social Science. The study revealed that the level of knowledge about waterborne diseases was relatively high (76.7 +/- 1.75%), but knowledge on transmission routes was inadequate. The majority of the respondents had no knowledge when it comes to water-based diseases and their prevention (78.4 +/- 1.71%).The attitude and practice on hygiene was also found to be high (91.40 +/- 1.16%). Some schools from the urban area had proper handwashing facilities, but there was no soap available. The borehole water quality for rural schools appeared clear, but the microbial quality was unknown. The water supply and sanitation facilities were inadequate in rural schools, with no handwashing areas and no sanitary bins for girls. Some schools had toilets with broken doors which did not offer privacy. The only water tap, located at the centre of the school premises, was not enough for the whole school community. PMID- 23736656 TI - Levels of pesticides and their metabolites in Wistar rat amniotic fluids and maternal urine upon gestational exposure. AB - Concentrations of pesticides and selected metabolites in rat urine and amniotic fluid were determined as biomarker upon oral administration of Wistar rats to two pesticide mixtures consisting of three to five pesticides (bitertanol, propiconazole, cypermethrin, malathion, and terbuthylazine). The pesticides and their metabolites were found in rat amniotic fluid and urine, generally in dose response concentrations in relation to dosage. The measurement of the substances in the amniotic fluid indicated that the fetus was exposed to the pesticides as well as their metabolites. Moreover, the pesticides detected in urine demonstrated the exposure as well as the ability of the rat to excrete these compounds. PMID- 23736658 TI - Haemodynamic predictors of a penetrating atherosclerotic ulcer rupture using fluid-structure interaction analysis. AB - We present preliminary data on the flow-induced haemodynamic and structural loads exerted on a penetrating atherosclerotic aortic ulcer (PAU). Specifically, one way fluid-structure interaction analysis was performed on the aortic model reconstructed from a 66-year-old male patient with a PAU that evolved into an intramural haematoma and rupture of the thoracic aorta. The results show that elevated blood pressure (117 mmHg) and low flow velocity at the aortic wall (0.15 m/s(2)) occurred in the region of the PAU. We also found a low value of time averaged wall shear stress (1.24 N/m(2)) and a high value of the temporal oscillation in the wall shear stress (oscillatory shear index = 0.13) in the region of the PAU. After endovascular treatment, these haemodynamic parameters were distributed uniformly on the luminal surface of the stent graft. These findings suggest that wall shear stress could be considered one of the major haemodynamic factors indicating the structural fragility of the PAU wall, which ultimately lead to PAU growth and rupture. PMID- 23736660 TI - Even small aneurysms can bleed: a ruptured small idiopathic aneurysm of the internal thoracic artery. AB - Internal thoracic artery (ITA) aneurysms are rare, but a rupture is potentially fatal. Most cases of ITA aneurysms are iatrogenic, caused by, for instance, previous sternotomy or pacemaker implantation. Other known aetiologies are vasculopathies, either of inflammatory origin or as part of connective tissue disorders like Marfan's syndrome, Ehler-Dahnlos syndrome or neurofibromatosis Type 1. Idiopathic ITA aneurysms are exceedingly scarce. The present case illustrates an unusual scenario, which posed diagnostic challenges, where spontaneous rupture of an idiopathic or possibly very late post-traumatic aneurysm of the left ITA led to a life-threatening bleeding, successfully treated by endovascular coiling with standby preparation for conversion to open surgery. This case demonstrates the importance of the careful interpretation of radiological findings and the significance of multidisciplinary collaboration between radiologist and clinician. PMID- 23736661 TI - Is it safe to divide and ligate the left innominate vein in complex cardiothoracic surgeries? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether it is safe to divide the left innominate vein (LIV) in aortic arch surgery to improve access. Altogether, 228 relevant papers were found using the reported search, of which nine represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Following LIV division, the venous drainage takes place via multiple collateral systems such as the azygous/hemiazygous, the internal mammary veins, the lateral thoracic and superficial thoracoabdominal veins, vertebral venous plexus as well as the transverse sinus. The possible complications are mainly left upper limb swelling and neurological symptoms. In one case series of 14 patients, the LIV was divided and ligated to facilitate the exposure for aortic arch surgery. More than 2-year follow-up did not reveal upper limb oedema or neurological symptoms. In two cohorts of 52 patients, the LIV was ligated prior to the superior vena cava (SVC) resection for malignancy. During the mid-term follow-up, no neurological or upper limb symptoms were reported. Although in two studies with 72 and 70 patients undergoing SVC resection it was not specified how many of them had LIV ligation, no relevant complications were reported. In a report, LIV occlusion was observed in 4 patients undergoing left internal jagular vein catheterization for haemodialysis. The reported symptom was left arm swelling with no neurological problems. In a cohort of 18 patients undergoing SVC resection for malignancy and major vein reconstruction, 7 patients underwent ligation of the LIV with no neurological symptoms. It was also concluded that reconstruction of the LIV is not consistent with favourable patency. In a case series of 10 patients with central venous obstruction, collateral pathways to conduct efficient venous drainage were mapped. We conclude that division of the LIV is safe in selected patients and operations. Patients will initially have symptoms of central vein obstruction, but these will decrease with conservative management as collaterals form. PMID- 23736659 TI - Pre-existing endothelial cell activation predicts vasoplegia after mitral valve surgery. AB - OBJECTIVES: Post-cardiac surgery vasoplegia is a common complication of cardiac surgery, characterized by profound loss of systemic vascular resistance. This results in severe hypotension, high cardiac output and metabolic acidosis reflecting inadequate tissue perfusion. The pathophysiological mechanisms underlying this syndrome remain unknown. We hypothesized that this vasoplegia reflects endothelial dysfunction, either as pre-existing condition or as a consequence of the surgical procedure. METHODS: To examine these mechanisms, six established and distinct markers of endothelial cell activation were measured pre and perioperatively in patients undergoing mitral valve surgery. Arterial (radial artery) and myocardial venous blood samples (coronary sinus) were collected simultaneously over the reperfused heart at various time points during the first hour after reperfusion. Additional samples were collected at baseline (brachial vein) and 1 day post-reperfusion (radial artery). Post-cardiac surgery vasoplegia was defined as a mean arterial blood pressure of <60 mmHg, with a cardiac index of >=2.2 l/min/m(2) treated with continuous intravenous administration of norepinephrine. RESULTS: No myocardial release of endothelial cell activation markers was observed upon reperfusion in patients with vasoplegia (n = 15; mean age 71 years, 73% male). In contrast, in patients without vasoplegia (n = 24; mean age 64 years, 54% male), reperfusion was characterized by a myocardial release of three endothelial cell activation markers. Myocardial von Willebrand Factor propeptide, osteoprotegerin and interleukin-8 were increased 107% (P < 0.001), 106% (P = 0.02) and 116% (P = 0.009), respectively, compared with arterial levels upon reperfusion. Similar systemic levels of all markers were found upon reperfusion in both groups, except for 120% increased soluble P-selectin (sP-selectin) levels in vasoplegia patients (P = 0.03). Remarkably, postoperative vasoplegia was identified with baseline von Willebrand Factor propeptide levels with a cut-off value of 11.9 nM as well as with baseline sP-selectin levels with a cut-off value of 64.4 ng/ml. CONCLUSIONS: Pre-existing endothelial cell activation, reflected by higher baseline von Willebrand Factor propeptide and sP-selectin levels, is a predisposing factor for post-cardiac surgery vasoplegia. The pre-existing endothelial cell activation may have resulted in desensibilization of endothelium in patients who develop vasoplegic syndrome, resulting in no myocardial release of endothelial cell activation markers upon reperfusion. PMID- 23736662 TI - [Therapy-resistant swelling of the upper eyelid in childhood]. AB - HISTORY: Swelling of the upper eyelid in childhood is caused by a variety of diseases and is very often generated by inflammation but orbital tumors should always be considered in the differential diagnostics. METHODS: We report about a 4-year-old girl with a drug-resistant swelling of the upper eyelid and ptosis of the right eye. This case report demonstrates the route from initial clinical examination to diagnosis and additionally reviews the current status of therapeutic options. RESULTS: After magnetic resonance imaging (MRI) and diagnostic excision, Langerhans cell histiocytosis (LCH) could be histologically proven. Visual acuity and levator muscle function improved from 0.5 to 1.25 and from 2 mm to 12 mm, respectively, by amblyopic prophylaxis and immunosuppressive therapy. CONCLUSIONS: Persistent and drug-resistant swelling of the upper eyelid in childhood is also strongly suspicious for tumors. The suspicion of rare orbital tumors in children can be frequently substantiated by MRI. Biopsy and histological diagnosis are essential to plan adequate treatment and to estimate the prognosis. Particularly in Langerhans cell histiocytosis the methods of choice for over 10 years are specific immunochemical procedures (detection of protein s100 and CD1a). PMID- 23736664 TI - Analysis of intact bacteria using rapid evaporative ionisation mass spectrometry. AB - An identification system for microorganisms based on recently developed rapid evaporative ionisation mass spectrometry (REIMS) is presented. Nine bacterial species cultured on various growth media were correctly identified to family-, genus-, and species-level based on their different mass spectral fingerprints using a cross-validated maximum margin criterion model. PMID- 23736663 TI - Glia co-culture with neurons in microfluidic platforms promotes the formation and stabilization of synaptic contacts. AB - Two novel microfluidic cell culture schemes, a vertically-layered set-up and a four chamber set-up, were developed for co-culturing central nervous system (CNS) neurons and glia. The cell chambers in these devices were separated by pressure enabled valve barriers, which permitted us to control communication between the two cell types. The unique design of these devices facilitated the co-culture of glia with neurons in close proximity (~50-100 MUm), differential transfection of neuronal populations, and dynamic visualization of neuronal interactions, such as the development of synapses. With these co-culture devices, initial synaptic contact between neurons transfected with different fluorescent markers, such as green fluorescent protein (GFP) and mCherry-synaptophysin, was imaged using high resolution fluorescence microscopy. The presence of glial cells had a profound influence on synapses by increasing the number and stability of synaptic contacts. Interestingly, as determined by liquid chromatography-ion mobility-mass spectrometry, neuron-glia co-cultures produced elevated levels of soluble factors compared to that secreted by individual neuron or glia cultures, suggesting a potential mechanism by which neuron-glia interactions could modulate synaptic function. Collectively, these results show that communication between neurons and glia is critical for the formation and stability of synapses and point to the importance of developing neuron-glia co-culture systems such as the microfluidic platforms described in this study. PMID- 23736665 TI - Hyperbaric oxygen therapy and trauma. Foreword. PMID- 23736666 TI - Hyperbaric oxygen therapy: an introduction. AB - Hyperbaric oxygen therapy has a rich and diverse history, both in the United States and around the world. From its early uses in war to the building of bridges, and through many introductions to innovations in the medical community, it has been debated and modified until its ultimate acceptance in multiple areas of patient care. Numerous areas of patient care use hyperbaric therapy, from wound care to military applications, in both single monoplace chambers and multipatient settings in larger chambers. This article provides an overview on the history, trial and error, and modern development of hyperbaric oxygen in clinical care therapies in 21st century medicine and nursing. PMID- 23736667 TI - Use of hyperbaric oxygenation in neonatal patients: a pilot study of 8 patients. AB - This article presents a pilot study to determine the value of hyperbaric oxygenation (HBO2) in the acute management of neonatal hypoxia (hypoxic ischemic encephalopathy) and necrotizing enterocolitis. Neonates with hypoxic-ischemic encephalopathy and NE were treated in a Sechrist monoplace chamber. Electroencephalogram, evoked potential, ophthalmic evaluation, ultrasonograph, laboratory exams, and radiographs were obtained before and after HBO2. Treatment protocol was 2.0 atm abs/45 minutes. Preventive myringotomies were conducted in all patients. A follow-up was done at 3 and 6 months. All patients (n = 8) were ventilator-dependent and required bag-valve-mask ventilation by a neonatologist during the treatment. All showed a resolution after HBO2. There was also a dramatic improvement (P < .05) in hemoglobin, hematocrit, total proteins, serum sodium, triglycerides, and pH. There were favorable changes in all other studies although they did not meet statistical significance. There was a marked reduction of the morbidity and mortality. There were no adverse effects on the ophthalmologic or Central Nervous System. When used promptly, HBO2 can modify the local and systemic inflammatory response caused by intestinal inflammation or cerebral or systemic hypoxia. It helps to preserve the marginal tissue and recover the ischemic and metabolic penumbra. This pilot study suggests that HBO2 could be a safe and effective treatment in the acute management of neonatal necrotizing enterocolitis or hypoxic ischemic encephalopathy. There is a need for a prospective, randomized, controlled, and double-blinded study to determine the real use of HBO2 in these cases. PMID- 23736668 TI - Mechanisms of action of hyperbaric oxygenation in stroke: a review. AB - This article outlines the therapeutic mechanisms of hyperbaric oxygenation in acute stroke, based on information obtained from peer-reviewed medical literature. Hyperbaric oxygen is an approved treatment modality for ischemia reperfusion injury in several conditions. It maintains the viability of the marginal tissue, reduces the mitochondrial dysfunction, metabolic penumbra, and blocks inflammatory cascades observed in acute stroke. Basic and clinical data suggest that hyperbaric oxygen could be a safe and effective treatment option in the management of acute stroke. Further work is needed to clarify its clinical utility when applied within the treatment window of "gold standard" treatments (<3-5 hours). PMID- 23736669 TI - The role of hyperbaric oxygen therapy in crush injuries. AB - Hyperbaric oxygen therapy has been approved for primary or adjunctive care in 14 indications. A hyperbaric environment exists when a patient's whole body is physically exposed to 100% oxygen and pressure that is greater than one atmosphere absolute. Hyperbaric oxygen therapy works through the ideal gas laws and is effective as an adjunctive therapy in the treatment of crush injuries. Oxygen is considered a drug and can have contraindications and adverse effects. Hyperbaric therapy works through several different mechanisms in the crush injury. Effects of hyperoxygenation, reduction of edema, infection control enhancement, blood vessel and collagen formation, and reduction of free radicals and reperfusion injury help in healing in patient with crush injuries. PMID- 23736670 TI - The relationship between arterial carbon dioxide tension and end-tidal carbon dioxide tension in intubated adults with traumatic brain injuries who required emergency craniotomies. AB - Anesthetic management of patients who have suffered traumatic brain injuries can be challenging. We investigated the relationship between arterial to end-tidal carbon dioxide partial pressure gradients (Pa-etCO2) and 3 predictor variables: (1) injury severity score, (2) use of positive end-expiratory pressure, and (3) presence of rib fractures. Using a convenient sampling method, we sampled 56 patients who arrived to the operating room intubated after traumatic brain injuries between 2005 and 2011. Two groups were compared retrospectively: those with Pa-etCO2 greater than 10 mm Hg (case group) (n = 37) and those with Pa-etCO2 gradients of 10 mm Hg or less (control group) (n = 19). Descriptive and inferential statistics were employed to identify any differences between the groups. Stepwise regression was also performed. Cross tabulation analysis revealed that injury severity score of 30 or more was a predictor of Pa-etCO2 gradient. Stepwise regression analysis revealed the presence of rib fracture and body mass index to be significant predictors of Pa-etCO2 gradient (P < .011). This study identified coexisting conditions in which the patients' Pa-etCO2 gradients were large. Results showed that injury severity score of 30 or more, the presence of rib fractures, and higher body mass index were statistically significant predictors of Pa-etCO2 gradients greater than 10 mm Hg. These observations should be considered when evaluating PetCO2 in conjunction with arterial blood gas analysis to determine optimal ventilation status of these patients. PMID- 23736671 TI - Hyperbaric nursing. AB - The varied clinical applications for hyperbaric oxygen therapy have led to the development of a unique, highly skilled nursing specialty of hyperbaric nursing. The ever-increasing availability of hyperbaric medicine and the broadening scope of clinical indications have fueled the need for highly skilled hyperbaric nurses. PMID- 23736672 TI - Transient ischemic attack after hot bath in a patient with Moyamoya disease. PMID- 23736673 TI - Primary coenzyme Q10 (CoQ 10) deficiencies and related nephropathies. AB - Oxidative phosphorylation (OXPHOS) is a metabolic pathway that uses energy released by the oxidation of nutrients to generate adenosine triphosphate (ATP). Coenzyme Q10 (CoQ10), also known as ubiquinone, plays an essential role in the human body not only by generating ATP in the mitochondrial respiratory chain but also by providing protection from reactive oxygen species (ROS) and functioning in the activation of many mitochondrial dehydrogenases and enzymes required in pyrimidine nucleoside biosynthesis. The presentations of primary CoQ10 deficiencies caused by genetic mutations are very heterogeneous. The phenotypes related to energy depletion or ROS production may depend on the content of CoQ10 in the cell, which is determined by the severity of the mutation. Primary CoQ10 deficiency is unique among mitochondrial disorders because early supplementation with CoQ10 can prevent the onset of neurological and renal manifestations. In this review I summarize primary CoQ10 deficiencies caused by various genetic abnormalities, emphasizing its nephropathic form. PMID- 23736676 TI - Observational monitoring of clinical signs during the last stage of habituation in a wild western gorilla group at Bai Hokou, Central African Republic. AB - Anthropozoonotic disease transmission to great apes is a critical conservation concern, and has raised ethical doubts regarding ape habituation. We monitored over a 3-year period clinical signs within a group of wild western gorillas (G. gorilla) undergoing habituation at Bai Hokou, Central African Republic. The majority of observations consisted of singular coughs and sneezes among the gorillas. These were the only clinical signs that significantly and positively increased over the years. No changes in the demography of the study group were observed. While clinical signs are not necessarily indicative of 'disease' or other health-related problems, we discuss how long-term records of clinical signs provide useful information when health monitoring, and the importance of the rigid application of preventive disease transmission protocols. PMID- 23736674 TI - Urinary concentration: different ways to open and close the tap. AB - Nephrogenic diabetes insipidus (NDI) provides an excellent model for the benefits and insights that can be gained from studying rare diseases. The discovery of underlying genes identified key molecules involved in urinary concentration, including the type 2 vasopressin receptor AVPR2 and the water channel AQP2, which constitute obvious pharmacologic targets. Subsequently developed drugs targeting AVPR2 not only provide potential benefit to some patients with NDI, but are now used for much more common clinical applications as diverse as nocturnal enuresis and heart failure. Yet, the story is still evolving: clinical observations and animal experiments continue to discover new ways to affect urinary concentration. These novel pathways can potentially be exploited for therapeutic gain. Here we review the (patho)physiology of water homoeostasis, the current status of clinical management, and potential new treatments. PMID- 23736677 TI - Synthesis of Ag nanoclusters by a pH-dependent etching method in aqueous solution. AB - We developed a pH-dependent etching method for the synthesis of stable fluorescent silver nanoclusters (AgNCs) in aqueous solution. The AgNCs emit at 530 nm when excited at 380 nm and can be used for Hg(2+) detection with a low detection limit and high selectivity. PMID- 23736678 TI - Normal intracranial periarterial enhancement on pediatric brain MR imaging. AB - INTRODUCTION: Large/medium vessel vasculitis is an important etiology of childhood stroke. Early research suggests vessel wall enhancement on postcontrast MRI may be a marker of intracranial vasculitis yet no systematic descriptions of normal periarterial enhancement exist in the literature. The aim was to describe normal periarterial enhancement in the pediatric population. METHODS: We included all children who had an MR scan between January 2007 and December 2010, with normal parenchymal imaging, no clinical concern of vasculopathy, and axial and coronal postcontrast fat-saturated T1-weighted images with 3-mm slice thickness. Intensity of periarterial enhancement was graded on a three-point scale by two investigators for all intracranial large and medium arteries. RESULTS: A total of 44 patients aged 4 months to 16 years were included. Inter- and intra-rater reliability in enhancement grading was high (all kappa >0.65). Thin, linear, noncircumferential periarterial enhancement was common and usually symmetrical. It was most commonly prominent in the cavernous and petrous segments of the internal carotid artery and the M1 segment of the middle cerebral artery. Periarterial enhancement was rarely observed at segments surrounded by CSF, including supraclinoid segments of the internal carotid arteries, P1 segments of the posterior cerebral arteries, V4 segments of the vertebral artery, and the basilar arteries. CONCLUSION: Normal periarterial enhancement is common and usually symmetrical along major intracranial arteries but rarely seen around arterial segments bordered by CSF. Knowledge of these findings may be useful for a sensitive and specific interpretation of MR scans of patients with clinical concerns of vasculitis. PMID- 23736679 TI - Methylation analysis of tumor suppressor genes in endometroid carcinoma of endometrium using MS-MLPA. AB - BACKGROUND: Epigenetic changes are considered to be a frequent event during tumor development. Hypermethylation of promoter CpG islands represents an alternative mechanism for inactivation of tumor suppressor genes, DNA repair genes, cell cycle regulators and transcription factors. The aim of this study was to investigate promoter methylation of specific genes in endometrial cancer by comparison with normal endometrial tissue. MATERIALS AND METHODS: We used MS-MLPA (Methylation-specific Multiplex ligation-dependent probe amplification) to compare the methylation status of 59 tissue samples of endometroid type of endometrial carcinoma with 20 control samples of non-neoplastic endometrium. RESULTS: Using 15% cut-off for methylation, we observed significantly higher methylation in the CDH13 gene in endometrial cancer group. We observed significantly higher methylation in both WT1 and GATA5 genes in IB stage of endometroid carcinoma. We also observed significantly higher methylation in GATA5 gene in the group of poorly differentiated endometroid carcinoma. CONCLUSION: The findings suggest the importance of hypermethylation of CDH13, WT1 and GATA5 genes in endometrial carcinogenesis and could have implications for future diagnostic and therapeutic strategies of endometrial cancer based on epigenetic changes. PMID- 23736680 TI - DNA repair: A sensor for chromatin damage. PMID- 23736682 TI - Meiosis: A kinesin on foreign tracks. PMID- 23736681 TI - Macrodomain-containing proteins: regulating new intracellular functions of mono(ADP-ribosyl)ation. AB - ADP-ribosylation of proteins was first described in the early 1960's, and today the function and regulation of poly(ADP-ribosyl)ation (PARylation) is partially understood. By contrast, little is known about intracellular mono(ADP ribosyl)ation (MARylation) by ADP-ribosyl transferase (ART) enzymes, such as ARTD10. Recent findings indicate that MARylation regulates signalling and transcription by modifying key components in these processes. Emerging evidence also suggests that specific macrodomain-containing proteins, including ARTD8, macroD1, macroD2 and C6orf130, which are distinct from those affecting PARylation, interact with MARylation on target proteins to 'read' and 'erase' this modification. Thus, studying macrodomain-containing proteins is key to understanding the function and regulation of MARylation. PMID- 23736683 TI - Synthetic mammalian transgene negative autoregulation. AB - Biological networks contain overrepresented small-scale topologies, typically called motifs. A frequently appearing motif is the transcriptional negative feedback loop, where a gene product represses its own transcription. Here, using synthetic circuits stably integrated in human kidney cells, we study the effect of negative-feedback regulation on cell-wide (extrinsic) and gene-specific (intrinsic) sources of uncertainty. We develop a theoretical approach to extract the two noise components from experiments and show that negative feedback results in significant total noise reduction by reducing extrinsic noise while marginally increasing intrinsic noise. We compare the results to simple negative regulation, where a constitutively transcribed transcription factor represses a reporter protein. We observe that the control architecture also reduces the extrinsic noise but results in substantially higher intrinsic fluctuations. We conclude that negative feedback is the most efficient way to mitigate the effects of extrinsic fluctuations by a sole regulatory wiring. PMID- 23736684 TI - Attenuation of conducted vasodilation in skeletal muscle arterioles during hyperhomocysteinemia. AB - BACKGROUND: Vasomotor responses conducted from terminal arterioles to proximal vessels may contribute to match tissue demands and blood supply during skeletal muscle contraction. Conduction of vasodilatation (CVD) from distal resistance arterioles to the proximal arterioles and feeding arteries during metabolic demand is mediated by intercellular gap junctions in the vascular endothelium. The role of hyperhomocysteinemia (HHcy) in the musculoskeletal system during CVD is unclear. We hypothesize that during HHcy, there is impaired CVD due to decreased expression of endothelial-associated connexins and thus decreased tissue perfusion to the contracting skeletal muscles. METHODS: CVD studies were performed in a gluteus maximus muscle preparation of wild-type (C57BL6/J) and CBS /+ (HHcy) mice using intravital microscopy. Expression of connexins and myostatin protein (an antiskeletal muscle statin) was studied by Western blot and immunohistochemistry methods. Tissue perfusion to acetylcholine was assessed by the laser Doppler technique. RESULTS: There was decreased CVD and tissue perfusion in response to acetylcholine in CBS-/+ mice compared to wild-type controls. There was decreased expression of connexins 37, 40 and 43 and increased expression of myostatin in CBS-/+ mice compared to wild-type controls. CONCLUSION: Our findings suggest that CVD in skeletal muscle is decreased during HHcy due to decreased expression of gap junction connexins. PMID- 23736685 TI - The Greater Metropolitan Medical Alumni Council (GMMAC): the realization of a need. AB - OBJECTIVE: The greater New York metropolitan area includes 8 medical schools. Their alumni association (AA) presidents formed a council 6 years ago, meeting 3 times a year to share ideas and identify best practices to solve mutual problems challenging students and alumni. METHODS: A survey of the 8 medical AAs was conducted; all responded, and the results constitute the data in this report. RESULTS: Mean AA membership was 2509 or 33% of mean alumni populations (7489). Two AAs conferred membership at graduation; hence, 100% of alumni were AA members. Omitting these 2 AAs reduced mean participation to 1722 or 23%. Alumni association support staff averaged 3.8 persons (range, 1-7 persons). The 2 most frequently cited AA challenges were membership and fund-raising. All AAs had annual or biennial reunions and considered the reunion to be a major commitment of resources. Despite this commitment, mean reunion attendance was only 242 alumni (range, 40-500 alumni) or 7.3% of alumni in anniversary years (5-year intervals). The mean number of alumni who contributed annually to their alma mater through its AA was 1936 alumni (range, 500-3500 alumni), or 26% (range, 5% 47%). Medical AAs reported mean assets of $2,755,000 (range, $6475-$11,000,000). The mean AA budget was $298,750, of which 65% (range, 13%-100%) was devoted to "medical student support". The most frequently cited student activities were "career night" (100%), "white coat ceremonies" (63%), medical equipment (stethoscopes, etc, 50%), and alumni host programs (38%). Eleven additional medical student activities received financial support from the 8 AAs in varying proportions. CONCLUSIONS: Each AA in the Greater Metropolitan Medical Alumni Council has derived significant benefit from the application of best practices to its individual problem set. In particular, a nascent AA developed significant momentum in its formation and development by its participation in the Greater Metropolitan Medical Alumni Council. Additionally, these data provide a foundation for the development of best practices within medical school AA for optimizing support of student programs and alumni participation. Stronger AAs will translate into enhanced support of educational programs for medical students. We urge formation of similar medical AA organizations in other metropolitan areas. PMID- 23736686 TI - Economic impact of switching from an open to a closed enteral nutrition feeding system in an acute care setting. AB - BACKGROUND: This study compared an open-system (OS) enteral nutrition (EN) delivery system with a closed system (CS). Factors evaluated included nursing time for administration, patient safety factors, and cost of formula and supplies. MATERIALS AND METHODS: This study analyzed the cost of formula and supplies in 1 major academic medical center. Data were collected on patients requiring EN in acute care settings. Information collected included formula type and amount of formula ordered and delivered. RESULTS: The average daily cost to feed each adult patient using delivered volume with the OS was $3.84 compared with $4.31 if the patient had been receiving EN from a CS. Considering waste costs, the average cost to feed increased to $4.21 compared with $4.80, respectively. After factoring in increased nursing time with the OS, the cost increased to $9.83. For pediatric patients, formula delivery reached 1 L in only 2% of patient days. The average cost to feed each patient each day using actual delivered volume was $1.89 in the OS and $1.94 in the CS. When factoring in the cost of waste, those costs increased to $2.12 and $3.30, respectively. After factoring in increased nursing time with the OS, the cost increased to $8.92. CONCLUSION: Due to the higher contract price and increased waste of the CS formulas compared with the OS formulas, a higher daily average cost for formula delivered may be incurred by switching to a CS. However, the CS is more cost effective when factoring in nursing time. PMID- 23736687 TI - Response: efficacy of erythropoietin combined with enteral nutrition for the treatment of anemia in Crohn's disease. PMID- 23736688 TI - Phospholipids at the interface: current trends and challenges. AB - Phospholipids are one of the major structural elements of biological membranes. Due to their amphiphilic character, they can adopt various molecular assemblies when dispersed in water, such as bilayer vesicles or micelles, which give them unique interfacial properties and render them very attractive in terms of foam or emulsion stabilization. This article aims at reviewing the properties of phospholipids at the air/water and oil/water interfaces, as well as the recent advances in using these natural components as stabilizers, alone or in combination with other compounds such as proteins. A discussion regarding the challenges and opportunities offered by phospholipids-stabilized structure concludes the review. PMID- 23736689 TI - Photochemical production and behavior of hydroperoxyacids in heterotrophic bacteria attached to senescent phytoplanktonic cells. AB - The photooxidation of cellular monounsaturated fatty acids was investigated in senescent phytoplanktonic cells (Emiliania huxleyi) and in their attached bacteria under laboratory controlled conditions. Our results indicated that UV visible irradiation of phytodetritus induced the photooxidation of oleic (produced by phytoplankton and bacteria) and cis-vaccenic (specifically produced by bacteria) acids. These experiments confirmed the involvement of a substantial singlet oxygen transfer from senescent phytoplanktonic cells to attached bacteria, and revealed a significant correlation between the concentration of chlorophyll, a photosensitizer, in the phytodetritus and the photodegradation state of bacteria. Hydroperoxyacids (fatty acid photoproducts) appeared to be quickly degraded to ketoacids and hydroxyacids in bacteria and in phytoplanktonic cells. This degradation involves homolytic cleavage (most likely induced by UV and/or transition metal ions) and peroxygenase activity (yielding epoxy acids). PMID- 23736690 TI - Genome-wide investigation of multifocal and unifocal prostate cancer-are they genetically different? AB - Prostate cancer is widely observed to be biologically heterogeneous. Its heterogeneity is manifested histologically as multifocal prostate cancer, which is observed more frequently than unifocal prostate cancer. The clinical and prognostic significance of either focal cancer type is not fully established. To investigate prostate cancer heterogeneity, the genetic profiles of multifocal and unifocal prostate cancers were compared. Here, we report observations deduced from tumor-tumor comparison of copy number alteration data of both focal categories. Forty-one fresh frozen prostate cancer foci from 14 multifocal prostate cancers and eight unifocal prostate cancers were subjected to copy number variation analysis with the Affymetrix SNP 6.0 microarray tool. With the investigated cases, tumors obtained from a single prostate exhibited different genetic profiles of variable degrees. Further comparison identified no distinct genetic pattern or signatures specific to multifocal or unifocal prostate cancer. Our findings suggest that samples obtained from multiple sites of a single unifocal prostate cancer show as much genetic heterogeneity and variability as separate tumors obtained from a single multifocal prostate cancer. PMID- 23736691 TI - Versatile redox chemistry complicates antioxidant capacity assessment: flavonoids as milieu-dependent anti- and pro-oxidants. AB - Some antioxidants have been shown to possess additional pro-oxidant effects. Diverse methodologies exist for studying redox properties of synthetic and natural chemicals. The latter are substantial components of our diet. Exploration of their contribution to life-extending or -compromising effects is mandatory. Among reactive oxygen species (ROS), hydroxyl radical (*OH) is the most damaging species. Due to its short half-life, the assay has to contain a specific generation system. Plants synthesize flavonoids, phenolic compounds recognized as counter-agents to coronary heart disease. Their antioxidant activities are affected by their hydroxylation patterns. Moreover, in the plant, they mainly occur as glycosides. We chose three derivatives, quercetin, luteolin, and rutin, in attempts to explore their redox chemistry in contrasting hydrogen peroxide environments. Initial addition of hydrogen peroxide in high concentration or gradual development constituted a main factor affecting their redox chemical properties, especially in case of quercetin. Our study exemplifies that a combination of a chemical assay (deoxyribose degradation) with an electrochemical method (square-wave voltammetry) provides insightful data. The ambiguity of the tested flavonoids to act either as anti- or pro-oxidant may complicate categorization, but probably contributed to their evolution as components of a successful metabolic system that benefits both producer and consumer. PMID- 23736692 TI - Peptide induced crystallization of calcium carbonate on wrinkle patterned substrate: implications for chitin formation in molluscs. AB - We here present the nucleation and growth of calcium carbonate under the influence of synthetic peptides on topographically patterned poly(dimethylsiloxane) (PDMS) substrates, which have a controlled density of defects between the wrinkles. Experiments with two lysine-rich peptides derived from the extracellular conserved domain E22 of the mollusc chitin synthase Ar CS1, AKKKKKAS (AS8) and EEKKKKKES (ES9) on these substrates showed their influence on the calcium carbonate morphology. A transition from polycrystalline composites to single crystalline phases was achieved with the peptide AS8 by changing the pH of the buffer solution. We analyzed three different pH values as previous experiments showed that E22 interacts with aragonite biominerals more strongly at pH 7.75 than at pH 9.0. At any given pH, crystals appeared in characteristic morphologies only on wrinkled substrates, and did not occur on the flat, wrinkle-free PDMS substrate. These results suggest that these wrinkled substrates could be useful for controlling the morphologies of other mineral/peptide and mineral/protein composites. In nature, these templates are formed enzymatically by glycosyltransferases containing pH-sensitive epitopes, similar to the peptides investigated here. Our in vitro test systems may be useful to gain understanding of the formation of distinct 3D morphologies in mollusc shells in response to local pH shifts during the mineralization of organic templates. PMID- 23736693 TI - Prevention of intra-abdominal adhesion by bi-layer electrospun membrane. AB - The aim of this study was to compare the anti-adhesion efficacy of a bi-layer electrospun fibrous membrane consisting of hyaluronic acid-loaded poly(epsilon caprolactone) (PCL) fibrous membrane as the inner layer and PCL fibrous membrane as the outer layer with a single-layer PCL electrospun fibrous membrane in a rat cecum abrasion model. The rat model utilized a cecal abrasion and abdominal wall insult surgical protocol. The bi-layer and PCL membranes were applied between the cecum and the abdominal wall, respectively. Control animals did not receive any treatment. After postoperative day 14, a visual semiquantitative grading scale was used to grade the extent of adhesion. Histological analysis was performed to reveal the features of adhesion tissues. Bi-layer membrane treated animals showed significantly lower adhesion scores than control animals (p < 0.05) and a lower adhesion score compared with the PCL membrane. Histological analysis of the bi layer membrane treated rat rarely demonstrated tissue adhesion while that of the PCL membrane treated rat and control rat showed loose and dense adhesion tissues, respectively. Bi-layer membrane can efficiently prevent adhesion formation in abdominal cavity and showed a significantly decreased adhesion tissue formation compared with the control. PMID- 23736694 TI - Use of heat stress responsive gene expression levels for early selection of heat tolerant cabbage (Brassica oleracea L.). AB - Cabbage is a relatively robust vegetable at low temperatures. However, at high temperatures, cabbage has disadvantages, such as reduced disease tolerance and lower yields. Thus, selection of heat-tolerant cabbage is an important goal in cabbage breeding. Easier or faster selection of superior varieties of cabbage, which are tolerant to heat and disease and have improved taste and quality, can be achieved with molecular and biological methods. We compared heat-responsive gene expression between a heat-tolerant cabbage line (HTCL), "HO", and a heat sensitive cabbage line (HSCL), "JK", by Genechip assay. Expression levels of specific heat stress-related genes were increased in response to high-temperature stress, according to Genechip assays. We performed quantitative RT-PCR (qRT-PCR) to compare expression levels of these heat stress-related genes in four HTCLs and four HSCLs. Transcript levels for heat shock protein BoHsp70 and transcription factor BoGRAS (SCL13) were more strongly expressed only in all HTCLs compared to all HSCLs, showing much lower level expressions at the young plant stage under heat stress (HS). Thus, we suggest that expression levels of these genes may be early selection markers for HTCLs in cabbage breeding. In addition, several genes that are involved in the secondary metabolite pathway were differentially regulated in HTCL and HSCL exposed to heat stress. PMID- 23736696 TI - Inhibition effects of a synthesized novel 4-aminoantipyrine derivative on the corrosion of mild steel in hydrochloric acid solution together with quantum chemical studies. AB - 1,5-Dimethyl-4-((2-methylbenzylidene)amino)-2-phenyl-1H-pyrazol-3(2H)-one (DMPO) was synthesized to be evaluated as a corrosion inhibitor. The corrosion inhibitory effects of DMPO on mild steel in 1.0 M HCl were investigated using electrochemical impedance spectroscopy (EIS), potentiodynamic polarization, open circuit potential (OCP) and electrochemical frequency modulation (EFM). The results showed that DMPO inhibited mild steel corrosion in acid solution and indicated that the inhibition efficiency increased with increasing inhibitor concentration. Changes in the impedance parameters suggested an adsorption of DMPO onto the mild steel surface, leading to the formation of protective films. The novel synthesized corrosion inhibitor was characterized using UV-Vis, FT-IR and NMR spectral analyses. Electronic properties such as highest occupied molecular orbital energy, lowest unoccupied molecular orbital energy (EHOMO and ELUMO, respectively) and dipole moment (MU) were calculated and discussed. The results showed that the corrosion inhibition efficiency increased with an increase in the EHOMO values but with a decrease in the ELUMO value. PMID- 23736695 TI - Myricetin-mediated lifespan extension in Caenorhabditis elegans is modulated by DAF-16. AB - Myricetin is a naturally occurring flavonol found in many plant based food sources. It increases the lifespan of Caenorhabditis elegans, but the molecular mechanisms are not yet fully understood. We have investigated the impact of this flavonoid on the transcription factors DAF-16 (C. elegans FoxO homologue) and SKN 1 (Nrf2 homologue), which have crucial functions in the regulation of ageing. Myricetin is rapidly assimilated by the nematode, causes a nuclear translocation of DAF-16 but not of SKN-1, and finally prolongs the mean adult lifespan of C. elegans by 32.9%. The lifespan prolongation was associated with a decrease in the accumulation of reactive oxygen species (ROS) detected by DCF. Myricetin also decreases the formation of lipofuscin, a pigment consisting of highly oxidized and cross-linked proteins that is considered as a biomarker of ageing in diverse species. The lifespan extension was completely abolished in a daf-16 loss-of function mutant strain (CF1038). Consistently with this result, myricetin was also not able to diminish stress-induced ROS accumulation in the mutant. These results strongly indicate that the pro-longevity effect of myricetin is dependent on DAF-16 and not on direct anti-oxidative effects of the flavonoid. PMID- 23736697 TI - Individual and joint impacts of ethanol use, BMI, age and gender on serum gamma glutamyltransferase levels in healthy volunteers. AB - Excessive ethanol consumption, obesity and increasing age may all lead to increased serum levels of gamma-glutamyltransferase (GGT) enzyme, which plays a key role in the metabolism of extracellular reduced glutathione. However, as yet, the interactions between the various modulators of GGT activities have remained poorly defined. We analyzed data from 15,617 apparently healthy individuals (7254 men and 8363 women, mean age 46 +/- 13 years, range 25-74 years) who participated in a national cross-sectional health survey in Finland between 1997 and 2007. All subjects underwent detailed clinical examinations and interviews, including the amount of ethanol use and smoking habits. GGT levels were measured from all participants, and the individual and joint impacts of the different study variables on GGT levels were assessed. Significant individual effects were noted for ethanol use (p < 0.001), body mass index (BMI) (p < 0.001), age (p < 0.001) and smoking (p < 0.001). In men, significant two-factor interactions occurred between ethanol use and age (p < 0.020). Among those over 40 years of age, ethanol consumption was found to be a stronger determinant of increased GGT levels than in men below 40 years, whereas in the latter age group, BMI was found to predominate. In women, a significant two-factor interaction occurred between ethanol and BMI (p = 0.010), whereas it did not with ethanol use and age. The data underscores the role of ethanol consumption and age as major determinants of increased GGT levels in men, whereas in women, a relatively stronger impact was noted for ethanol intake and BMI. In light of the ability of GGT enzyme to modulate crucial redox-sensitive functions, the present findings also support the use of GGT as a biomarker of oxidative stress. PMID- 23736698 TI - Enhanced inhibition of prostate tumor growth by dual targeting the androgen receptor and the regulatory subunit type ialpha of protein kinase a in vivo. AB - Progression to castration resistance is a major problem in the treatment of advanced prostate cancer and is likely to be driven by activation of several molecular pathways, including androgen receptor (AR) and cyclic AMP-dependent protein kinase A (PKA). In this study, we examined the therapeutic efficacy of a combined inhibition of the AR and the regulatory subunit type Ialpha (RIalpha) of protein kinase A with second generation antisense oligonucleotides (ODNs) in androgen-sensitive LNCaP and castration-resistant LNCaPabl tumors in vivo. We found that targeting the AR alone inhibited LNCaP, as well as LNCaPabl tumors. Combined inhibition resulted in an improved response over single targeting and even a complete tumor remission in LNCaPabl. Western blot analysis revealed that both ODNs were effective in reducing their target proteins when administered alone or in combination. In addition, treatment with the ODNs was associated with an induction of apoptosis. Our data suggest that dual targeting of the AR and PKARIalpha is more effective in inhibiting LNCaP and LNCaPabl tumor growth than single treatment and may give a treatment benefit, especially in castration resistant prostate cancers. PMID- 23736699 TI - Expression of the secondary granule proteins major basic protein 1 (MBP-1) and eosinophil peroxidase (EPX) is required for eosinophilopoiesis in mice. AB - Eosinophil activities are often linked with allergic diseases such as asthma and the pathologies accompanying helminth infection. These activities have been hypothesized to be mediated, in part, by the release of cationic proteins stored in the secondary granules of these granulocytes. The majority of the proteins stored in these secondary granules (by mass) are major basic protein 1 (MBP-1) and eosinophil peroxidase (EPX). Unpredictably, a knockout approach targeting the genes encoding these proteins demonstrated that, unlike in mice containing a single deficiency of only MBP-1 or EPX, the absence of both granule proteins resulted in the near complete loss of peripheral blood eosinophils with no apparent impact on any other hematopoietic lineage. Moreover, the absence of MBP 1 and EPX promoted a concomitant loss of eosinophil lineage-committed progenitors in the marrow, identifying a specific blockade in eosinophilopoiesis as the causative event. Significantly, this blockade of eosinophilopoiesis is also observed in ex vivo cultures of marrow progenitors and is not rescued in vivo by adoptive bone marrow engraftment, suggesting a cell-autonomous defect in marrow progenitors. These observations implicate a role for granule protein gene expression as a regulator of eosinophilopoiesis and provide another strain of mice congenitally deficient of eosinophils. PMID- 23736700 TI - Salmonella engineered to express CD20-targeting antibodies and a drug-converting enzyme can eradicate human lymphomas. AB - Escape from immune detection favors both tumor survival and progression, and new approaches to circumvent this are essential to combat cancers. Nonvirulent, tumor tropic bacteria, such as Salmonella typhimurium, can unmask a tumor by transforming it into a site of inflammation; however, the nonspecific invasiveness of Salmonella leads to off-target effects diluting its therapeutic efficacy and making its use in human patients inherently risky. Here, we demonstrate that Salmonella tumor specificity can be significantly improved via a surface-expressed single-domain antibody directed to a tumor-associated antigen (CD20). Antibody-dependent bacterial targeting specifies the infection of CD20+ lymphoma cells in vitro and in vivo, while significantly diminishing nonspecific cell invasion. Indeed, CD20-targeted Salmonella was less generally invasive, even in organs that normally serve as physiological reservoirs. Furthermore, tumor specific Salmonella engineered to carry the herpes simplex virus thymidine kinase prodrug-converting enzyme effectively treats human lymphoma xenografts when coadministered intratumorally or intravenously with ganciclovir in mice lacking a functional adaptive immune system. Therefore, tumor-targeted Salmonella could prove effective even in those patients displaying a debilitated immune system, which is often the case with late-stage cancers. Altogether, antibody-displaying Salmonella vectors can mediate a tumor-specific response and rejection with few detectable adverse effects while specifically delivering cytotoxic payloads. PMID- 23736701 TI - Risk profile and clinical outcome of symptomatic subsegmental acute pulmonary embolism. AB - The clinical significance of subsegmental pulmonary embolism (SSPE) remains to be determined. This study aimed to investigate whether SSPE forms a distinct subset of thromboembolic disease compared with more proximally located pulmonary embolism (PE). We analyzed 3728 consecutive patients with clinically suspected PE. SSPE patients were contrasted to patients with more proximal PE and to patients in whom suspected PE was ruled out, in regards of the prevalence of thromboembolic risk factors and the 3-month risks of recurrent venous thromboembolism (VTE) and mortality. PE was confirmed in 748 patients, of whom 116 (16%) had SSPE; PE was ruled out in 2980 patients. No differences were seen in the prevalence of VTE risk factors, the 3-month risk of recurrent VTE (3.6% vs 2.5%; P = .42), and mortality (10.7% vs 6.5%; P = .17) between patients with SSPE and those with more proximal PE. When compared with patients without PE, aged >60 years, recent surgery, estrogen use, and male gender were found to be independent predictors for SSPE, and patients with SSPE were at an increased risk of VTE during follow-up (hazard ratio: 3.8; 95% CI: 1.3-11.1). This study indicates that patients with SSPE mimic those with more proximally located PE in regards to their risk profile and clinical outcome. PMID- 23736702 TI - Solitary diverticular type V bile duct cyst. AB - Bile duct cysts are a rare form of biliary disease characterized by single or multiple dilations anywhere along the biliary tree. Todani Type V bile duct cysts are intrahepatic and typically involve multiple fusiform dilations. We present the case of a neonate with an unusual prenatally identified solitary diverticular type V bile duct cyst that was evaluated, monitored, and subsequently resected with right lobectomy at the age of 6 months. The importance of imaging in diagnosis and approaches to management are discussed. PMID- 23736705 TI - The cover. The fish bucket. PMID- 23736707 TI - Pure food well cooked. PMID- 23736708 TI - Addiction: White House seeks "third way": policy emphasizes prevention, treatment, recovery. PMID- 23736709 TI - Zolpidem-related surge in emergency department visits. PMID- 23736720 TI - Maternal folic acid supplementation and risk of autism. PMID- 23736721 TI - Maternal folic acid supplementation and risk of autism--reply. PMID- 23736722 TI - Meta-analyses of hydroxyethyl starch for volume resuscitation. PMID- 23736723 TI - Meta-analyses of hydroxyethyl starch for volume resuscitation--reply. PMID- 23736724 TI - Ethics of parsimonious medicine. PMID- 23736725 TI - Ethics of parsimonious medicine--reply. PMID- 23736726 TI - Retinal vessel leakage at high altitude. PMID- 23736729 TI - The morality of using mortality as a financial incentive: unintended consequences and implications for acute hospital care. PMID- 23736730 TI - The future of quality measurement for improvement and accountability. PMID- 23736731 TI - Synthesizing evidence: shifting the focus from individual studies to the body of evidence. PMID- 23736732 TI - A piece of my mind. A view from the safety net. PMID- 23736733 TI - Roux-en-Y gastric bypass vs intensive medical management for the control of type 2 diabetes, hypertension, and hyperlipidemia: the Diabetes Surgery Study randomized clinical trial. AB - IMPORTANCE: Controlling glycemia, blood pressure, and cholesterol is important for patients with diabetes. How best to achieve this goal is unknown. OBJECTIVE: To compare Roux-en-Y gastric bypass with lifestyle and intensive medical management to achieve control of comorbid risk factors. DESIGN, SETTING, AND PARTICIPANTS: A 12-month, 2-group unblinded randomized trial at 4 teaching hospitals in the United States and Taiwan involving 120 participants who had a hemoglobin A1c (HbA1c) level of 8.0% or higher, body mass index (BMI) between 30.0 and 39.9, C peptide level of more than 1.0 ng/mL, and type 2 diabetes for at least 6 months. The study began in April 2008. INTERVENTIONS: Lifestyle-intensive medical management intervention and Roux-en-Y gastric bypass surgery. Medications for hyperglycemia, hypertension, and dyslipidemia were prescribed according to protocol and surgical techniques that were standardized. MAIN OUTCOMES AND MEASURES: Composite goal of HbA1c less than 7.0%, low-density lipoprotein cholesterol less than 100 mg/dL, and systolic blood pressure less than 130 mm Hg. RESULTS: All 120 patients received the intensive lifestyle-medical management protocol and 60 were randomly assigned to undergo Roux-en-Y gastric bypass. After 12-months, 28 participants (49%; 95% CI, 36%-63%) in the gastric bypass group and 11 (19%; 95% CI, 10%-32%) in the lifestyle-medical management group achieved the primary end points (odds ratio [OR], 4.8; 95% CI, 1.9-11.7). Participants in the gastric bypass group required 3.0 fewer medications (mean, 1.7 vs 4.8; 95% CI for the difference, 2.3-3.6) and lost 26.1% vs 7.9% of their initial body weigh compared with the lifestyle-medical management group (difference, 17.5%; 95% CI, 14.2%-20.7%). Regression analyses indicated that achieving the composite end point was primarily attributable to weight loss. There were 22 serious adverse events in the gastric bypass group, including 1 cardiovascular event, and 15 in the lifestyle-medical management group. There were 4 perioperative complications and 6 late postoperative complications. The gastric bypass group experienced more nutritional deficiency than the lifestyle-medical management group. CONCLUSIONS AND RELEVANCE: In mild to moderately obese patients with type 2 diabetes, adding gastric bypass surgery to lifestyle and medical management was associated with a greater likelihood of achieving the composite goal. Potential benefits of adding gastric bypass surgery to the best lifestyle and medical management strategies of diabetes must be weighed against the risk of serious adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00641251. PMID- 23736734 TI - Bariatric surgery for weight loss and glycemic control in nonmorbidly obese adults with diabetes: a systematic review. AB - IMPORTANCE: Bariatric surgery is beneficial in persons with a body mass index (BMI) of 35 or greater with obesity-related comorbidities. There is interest in using these procedures in persons with lower BMI and diabetes. OBJECTIVE: To assess the association between bariatric surgery vs nonsurgical treatments and weight loss and glycemic control among patients with diabetes or impaired glucose tolerance and BMI of 30 to 35. EVIDENCE REVIEW: PubMed, EMBASE, and Cochrane Library databases were searched from January 1985 through September 2012. Of 1291 screened articles, we included 32 surgical studies, 11 systematic reviews on nonsurgical treatments, and 11 large nonsurgical studies published after those reviews. Weight loss, metabolic outcomes, and adverse events were abstracted by 2 independent reviewers. FINDINGS: Three randomized clinical trials (RCTs) (N = 290; including 1 trial of 150 patients with type 2 diabetes and mean BMI of 37, 1 trial of 80 patients without diabetes [38% with metabolic syndrome] and BMI of 30 to 35, and 1 trial of 60 patients with diabetes and BMI of 30 to 40 [13 patients with BMI <35]) found that surgery was associated with greater weight loss (range, 14.4-24 kg) and glycemic control (range, 0.9-1.43 point improvements in hemoglobin A1c levels) during 1 to 2 years of follow-up than nonsurgical treatment. Indirect comparisons of evidence from observational studies of bariatric procedures (n ~ 600 patients) and meta-analyses of nonsurgical therapies (containing more than 300 RCTs) support this finding at 1 or 2 years of follow-up. However, there are no robust surgical data beyond 5 years of follow-up on outcomes of diabetes, glucose control, or macrovascular and microvascular outcomes. In contrast, some RCT data of nonsurgical therapies show benefits at 10 years of follow-up or more. Surgeon-reported adverse events were low (eg, hospital deaths of 0.3%-1.0%), but data were from select centers and surgeons. Long-term adverse events are unknown. CONCLUSIONS AND RELEVANCE: Current evidence suggests that, when compared with nonsurgical treatments, bariatric surgical procedures in patients with a BMI of 30 to 35 and diabetes are associated with greater short-term weight loss and better intermediate glucose outcomes. Evidence is insufficient to reach conclusions about the appropriate use of bariatric surgery in this population until more data are available about long-term outcomes and complications of surgery. PMID- 23736735 TI - Increasingly sensitive assays for cardiac troponins: a review. AB - Cardiac troponins are the preferred biomarkers for diagnosis of myocardial infarction because of their high sensitivity and specificity for myocardial injury. However, acute and chronic conditions distinct from acute coronary syndromes (ACS) commonly lead to small elevations in troponin levels, with few data available regarding management of care for patients with such conditions. Recently developed highly sensitive troponin assays will likely lead to a substantial increase in the proportion of detectable troponin levels attributable to non-ACS conditions. Novel algorithms with highly sensitive assays, incorporating baseline troponin values and changes in values over 1 to 2 hours, may allow rapid exclusion of myocardial infarction and help to address specificity concerns but must be validated in appropriate target populations. Enhanced detection of very low troponin levels with highly sensitive assays has made feasible several potential new indications for troponin testing, including in the ambulatory setting, where assessment for low-level chronic myocardial injury may enhance risk stratification for heart failure and cardiac death. PMID- 23736736 TI - Resuscitation strategies in trauma. PMID- 23736737 TI - Treating diabetes with surgery. PMID- 23736738 TI - JAMA patient page. Ear problems in children. PMID- 23736739 TI - The role of private pesticide vendors in preventing access to pesticides for self poisoning in rural Sri Lanka. AB - In 15% to 20% of self-poisoning cases, the pesticides used are purchased from shops just prior to ingestion. We explored how pesticide vendors interacted with customers at risk of self-poisoning to identify interventions to prevent such poisonings. Two strategies were specifically discussed: selling pesticides only to farmers bearing identity cards or customers bearing pesticide 'prescriptions'. Vendors reported refusing to sell pesticides to people thought to be at risk of self-poisoning, but acknowledged the difficulty of distinguishing them from legitimate customers; vendors also stated they did want to help to improve identification of such customers. The community did not blame vendors when pesticides used for self-poison were purchased from their shops. Vendors have already taken steps to restrict access, including selling low toxic products, counselling and asking customer to return the next day. However, there was little support for the proposed interventions of 'identity cards' and 'prescriptions'. Novel public health approaches are required to complement this approach. PMID- 23736740 TI - Determination of thermodynamic and transport parameters of naphthenic acids and organic process chemicals in oil sand tailings pond water. AB - Oil sand tailings pond water contains naphthenic acids and process chemicals (e.g., alkyl sulphates, quaternary ammonium compounds, and alkylphenol ethoxylates). These chemicals are toxic and can seep through the foundation of the tailings pond to the subsurface, potentially affecting the quality of groundwater. As a result, it is important to measure the thermodynamic and transport parameters of these chemicals in order to study the transport behavior of contaminants through the foundation as well as underground. In this study, batch adsorption studies and column experiments were performed. It was found that the transport parameters of these chemicals are related to their molecular structures and other properties. The computer program (CXTFIT) was used to further evaluate the transport process in the column experiments. The results from this study show that the transport of naphthenic acids in a glass column is an equilibrium process while the transport of process chemicals seems to be a non equilibrium process. At the end of this paper we present a real-world case study in which the transport of the contaminants through the foundation of an external tailings pond is calculated using the lab-measured data. The results show that long-term groundwater monitoring of contaminant transport at the oil sand mining site may be necessary to avoid chemicals from reaching any nearby receptors. PMID- 23736742 TI - Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer. AB - BACKGROUND: The correlation between progression-free survival (PFS) or time to progression (TTP) and overall survival (OS) has been evaluated in patients with advanced gastric cancer (AGC) who received first-line chemotherapy. No corresponding analysis has been done in patients who have undergone second-line chemotherapy. METHODS: We evaluated the correlation between PFS, TTP, objective response rate (ORR), disease control rate (DCR), and OS in patients with AGC who underwent second-line chemotherapy. Correlations were evaluated by Spearman rank correlation coefficient (rho). RESULTS: Sixty-four trials, including 10 randomized studies, were selected for analysis. Median PFS/TTP moderately correlated with OS (rho = 0.56). The correlation tended to be stronger in non Asian trials (rho = 0.74) than in Asian trials (rho = 0.37). ORR and DCR did not strongly correlate with OS (rho = 0.38 for ORR; rho = 0.54 for DCR). The hazard ratio of PFS and OS in each of the arms of the 10 randomized studies also showed a low correlation (rho = 0.36). CONCLUSIONS: PFS/TTP, ORR, and DCR did not correlate sufficiently with OS to be used as surrogate endpoints in patients with AGC who have undergone second-line chemotherapy. Further research is needed based on individual patient data from ongoing randomized trials. PMID- 23736741 TI - Three-year outcomes of a phase II study of adjuvant chemotherapy with S-1 plus docetaxel for stage III gastric cancer after curative D2 gastrectomy. AB - BACKGROUND: We have previously reported the superior feasibility and safety of adjuvant S-1 plus docetaxel in patients with stage III gastric cancer during a prospective phase II study. We report 3-year follow-up data on patients enrolled in this study. PATIENTS AND METHODS: Fifty-three patients with histologically confirmed stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were enrolled into this study. They received oral S-1 (80 mg/m(2)/day) for 2 consecutive weeks and intravenous docetaxel (40 mg/m(2)) on day 1, repeated every 3 weeks (one cycle). Treatment was initiated within 45 days after surgery and repeated for four cycles, followed by S-1 monotherapy (4 weeks on, 2 weeks off) until 1 year after surgery. Three-year overall survival (OS) and disease-free survival (DFS) were evaluated. RESULTS: The OS rate at 3 years was 78.4 % [95 % confidence interval (CI), 67.9-90.6 %] and the DFS rate at 3 years was 66.2 % (95 % CI, 54.4-80.7 %). Subgroup analyses according to disease stage showed a 3-year OS and DFS rate of 85.7 % (95 % CI, 74.9-98.1 %) and 70.8 % (95 % CI, 57.1-87.8 %) for stage IIIA, and 62.5 % (95 % CI, 42.8-91.4 %) and 56.2 % (95 % CI, 36.5-86.7 %) for stage IIIB, respectively. CONCLUSIONS: On the basis of 3 year follow-up data, postoperative adjuvant therapy with S-1 plus docetaxel yielded promising OS and DFS in stage IIIA gastric cancer patients who had undergone D2 gastrectomy. We believe that this regimen is a candidate for future phase III trials studying the optimal adjuvant chemotherapy regimen for stage III gastric cancer. PMID- 23736743 TI - Standard, mini, ultra-mini, and micro percutaneous nephrolithotomy: what is next? A novel labeling system for percutaneous nephrolithotomy according to the size of the access sheath used during procedure. PMID- 23736744 TI - A prospective photographic study of the ocular fundus in obstructive sleep apnea. AB - BACKGROUND: The prevalence of optic nerve and retinal vascular changes within the obstructive sleep apnea (OSA) population are not well-known, although it has been postulated that optic nerve ischemic changes and findings related to an elevated intracranial pressure may be more common in OSA patients. We prospectively evaluated the ocular fundus in unselected patients undergoing overnight diagnostic polysomnography (PSG). METHODS: Demographic data, medical/ocular history, and nonmydriatic fundus photographs were prospectively collected in patients undergoing PSG at our institution and reviewed for the presence of optic disc edema for which our study was appropriately powered a priori. Retinal vascular changes were also evaluated. OSA was defined using the measures of both sleep-disordered breathing and hypoxia. RESULTS: Of 250 patients evaluated in the sleep center, fundus photographs were performed on 215 patients, among whom 127 patients (59%) had an apnea/hypopnea index (AHI) >= 15 events per hour, including 36 with severe OSA. Those with AHI <15 served as the comparison group. None of the patients had optic disc edema (95% confidence interval [CI]: 0%-3%). There was no difference in rates of glaucomatous appearance or pallor of the optic disc among the groups. Retinal arteriolar changes were more common in severe OSA patients (odds ratio: 1.09 per 5 unit increase in AHI; 95% CI, 1.02-1.16; P = 0.01), even after controlling for mean arterial blood pressure. CONCLUSIONS: We did not find an increased prevalence of optic disc edema or other optic neuropathies in our OSA population. However, retinal vascular changes were more common in patients with severe OSA, independent of blood pressure. PMID- 23736745 TI - CuI-catalyzed and air promoted oxidative cyclization for one-pot synthesis of polyarylated oxazoles. AB - A facile CuI-catalyzed and air promoted oxidative cyclization was developed for the synthesis of polyarylated oxazoles. By virtue of this method, a variety of arylated oxazoles could be easily synthesized from readily available starting materials at room temperature in air. PMID- 23736746 TI - [Palliative medicine and teaching]. PMID- 23736747 TI - [Implementation of intersectional field 13: a survey of medical faculties in Germany]. AB - BACKGROUND: In 2013 palliative medicine (PM) will be integrated into the undergraduate curriculum as part of the mandatory education in German medical universities. The aim of this study is to determine the current state of implementation at German medical faculties (MF). METHODS: All German MFs were contacted using a written postal survey in June 2012. RESULTS: A total of 32 out of 36 MFs participated. Teaching staff consists of 15 or more lecturers in 8 MFs (30 %) and includes psychologists in 24 MFs (75 %) and also nurses in 18 MFs (56 %). Participating physicians are specialized in anesthesiology, internal medicine and general medicine. Teaching staff include palliative outpatient (20 MFs, 63 %) and consultation services (22 MFs, 69 %). Bedside teaching is provided in 15 MFs (47 %). Multiple choice tests are the major form of assessment (29 MFs, 84 %). The total number of teaching units in PM is between 12 and 43 and is usually provided at the end of medical school education. Nurses are employed in the education significantly more in MFs with a chair in PM. General practitioners were engaged only by faculties without a chair in PM. CONCLUSIONS: The implementation of the mandatory training in PM at MFs in Germany is inhomogeneous. Further steps include in particular the development of a competence-based curriculum and assessment. PMID- 23736748 TI - Influence of parental occupation on access to specialised treatment for paediatric chronic pain: a retrospective study. AB - BACKGROUND: The purpose of this study was to determine patients' travel distances to a tertiary paediatric pain clinic and to analyse the association between travel distance and the parents' occupational skill level and the patients' pain characteristics. PATIENTS AND METHODS: The retrospective study consisted of 2,248 children assessed at the first evaluation. All children (0-20 years) who visited the clinic during a 5-year period (2005-2010) were enrolled in this study. RESULTS: The mean travel distance was 81 km, and the 80 % catchment area was 109 km. Children of parents with a high occupational skill level had a 1.5-fold higher probability of travelling from outside the catchment area. The 80 % catchment area increased constantly with increasing occupational skill level. Additional significant factors for greater distance travelled were high impairment, musculoskeletal pain, long pain duration and a high number of previous physician contacts. CONCLUSION: The association between travel distance and parental occupational skill level suggests that there is social injustice due to access barriers based on socioeconomic deprivation and education. An increase in the number of health care facilities for chronic pain in children would be a first step in rectifying this injustice. PMID- 23736749 TI - [Medical education and communication in primary pain treatment: clinical relevance and pedagogic challenge]. AB - The term education can be understood here as informing the patient about the symptoms of the disease and the treatment. Patients with chronic pain require comprehensible information from the physician and beyond that esteem, encouragement and participation in decision-making processes. A successful patient-physician interaction is a quality ensuring element of the first degree. Imparting information in this context is of special importance which is not only derived from legal and ethical obligations but also from the scientifically proven therapeutic efficacy. A successful communication and relaying of information promotes motivation (compliance) and therapeutic effectiveness from both parties. Comprehensible explanations on biopsychosocial pain, interdisciplinary diagnostics and multimodal pain therapy reduce misunderstandings, false expectations and premature termination of therapy. The explanation of the biopsychosocial pain model opens for the patient a holistic view of the phenomenon of chronic pain and promotes self-help strategies. The question as to how and what should be imparted is not only a question of temporal resources but also represents a pedagogic challenge. The contents and experience imparted in the education are only substantially effective if they lead to a feeling of being personally affected due to being close to real life and plausibility and if the resulting multimodal treatment options can be implemented in the daily routine. The communicative duties of a physician are demanding and require practical training as can be reflected and practiced in the form of train the-trainer seminars, workshops and Balint groups. It has been proven that competence in counselling techniques also has a positive effect on the experience of the physician in his profession. Pain patients can profit from information flyers, internet and interactive computer-based consulting systems if they fulfil basic standards, including topicality, neutrality, biopsychosocial understanding of disease and preventive information. PMID- 23736751 TI - A transdiagnostic internet-based maintenance treatment enhances the stability of outcome after inpatient cognitive behavioral therapy: a randomized controlled trial. AB - BACKGROUND: High relapse rates following acute treatment for common mental health disorders support the importance of developing maintenance phase interventions. Internet-based interventions have been effective for a broad range of mental disorders, but less is known about their potential to enhance long-term outcomes of traditional face-to-face therapy. Therefore, the goal of the present study was to evaluate a transdiagnostic Internet-based maintenance treatment (TIMT) with the purpose of fostering long-term effects of inpatient psychotherapy. METHOD: In this pragmatic randomized controlled trial, a sample of 400 inpatients with affective, neurotic, and/or behavioral disorders was assigned to either 12 weeks of TIMT + treatment as usual (TAU) or to TAU-only following hospital discharge. TIMT consists of a self-management module, asynchronous patient-coach communication, online patient support group, and online-based monitoring of psychopathological symptoms. Self-ratings of psychopathological symptoms were conducted at the beginning of inpatient treatment (t1), at discharge from inpatient treatment/start of TIMT (t2), and at 3-month (t3) and 12-month follow ups (t4). RESULTS: The TIMT + TAU group was superior to the TAU-only group with regard to differences in change of general psychopathological symptom severity from discharge to 3- and 12-month follow-up. Moreover, participants of the TIMT + TAU group showed less frequent symptom deteriorations and were more often in remission/recovery than controls. CONCLUSION: TIMT effectively enhances long-term outcome of inpatient psychotherapy. PMID- 23736754 TI - Neural coding: timing is key in the olfactory system. PMID- 23736764 TI - Subtilomycin: a new lantibiotic from Bacillus subtilis strain MMA7 isolated from the marine sponge Haliclona simulans. AB - Bacteriocins are attracting increased attention as an alternative to classic antibiotics in the fight against infectious disease and multidrug resistant pathogens. Bacillus subtilis strain MMA7 isolated from the marine sponge Haliclona simulans displays a broad spectrum antimicrobial activity, which includes Gram-positive and Gram-negative pathogens, as well as several pathogenic Candida species. This activity is in part associated with a newly identified lantibiotic, herein named as subtilomycin. The proposed biosynthetic cluster is composed of six genes, including protein-coding genes for LanB-like dehydratase and LanC-like cyclase modification enzymes, characteristic of the class I lantibiotics. The subtilomycin biosynthetic cluster in B. subtilis strain MMA7 is found in place of the sporulation killing factor (skf) operon, reported in many B. subtilis isolates and involved in a bacterial cannibalistic behaviour intended to delay sporulation. The presence of the subtilomycin biosynthetic cluster appears to be widespread amongst B. subtilis strains isolated from different shallow and deep water marine sponges. Subtilomycin possesses several desirable industrial and pharmaceutical physicochemical properties, including activity over a wide pH range, thermal resistance and water solubility. Additionally, the production of the lantibiotic subtilomycin could be a desirable property should B. subtilis strain MMA7 be employed as a probiotic in aquaculture applications. PMID- 23736765 TI - The extract of Rhodobacter sphaeroides inhibits melanogenesis through the MEK/ERK signaling pathway. AB - Reducing hyperpigmentation has been a big issue for years. Even though pigmentation is a normal mechanism protecting skin from UV-causing DNA damage and oxidative stress, it is still an aesthetic problem for many people. Bacteria can produce some compounds in response to their environment. These compounds are widely used in cosmetic and pharmaceutical applications. Some probiotics have immunomodulatory activities and modulate the symptoms of several diseases. Previously, we found that the extracts of Rhodobacter sphaeroides (LycogenTM) inhibited nitric oxide production and inducible nitric-oxide synthase expression in activated macrophages. In this study, we sought to investigate an anti melanogenic signaling pathway in alpha-melanocyte stimulating hormone (alpha-MSH) treated B16F10 melanoma cells and zebrafish. Treatment with LycogenTM inhibited the cellular melanin contents and expression of melanogenesis-related protein, including microphthalmia-associated transcription factor (MITF) and tyrosinase in B16F10 cells. Moreover, LycogenTM reduced phosphorylation of MEK/ERK without affecting phosphorylation of p38. Meanwhile, LycogenTM decreased zebrafish melanin expression in a dose-dependent manner. These findings establish LycogenTM as a new target in melanogenesis and suggest a mechanism of action through the ERK signaling pathway. Our results suggested that LycogenTM may have potential cosmetic usage in the future. PMID- 23736766 TI - Effect of astaxanthin on human sperm capacitation. AB - In order to be able to fertilize oocytes, human sperm must undergo a series of morphological and structural alterations, known as capacitation. It has been shown that the production of endogenous sperm reactive oxygen species (ROS) plays a key role in causing cells to undergo a massive acrosome reaction (AR). Astaxanthin (Asta), a photo-protective red pigment belonging to the carotenoid family, is recognized as having anti-oxidant, anti-cancer, anti-diabetic and anti inflammatory properties and is present in many dietary supplements. This study evaluates the effect of Asta in a capacitating buffer which induces low ROS production and low percentages of acrosome-reacted cells (ARC). Sperm cells were incubated in the presence or absence of increasing concentrations of Asta or diamide (Diam) and analyzed for their ROS production, Tyr-phosphorylation (Tyr-P) pattern and percentages of ARC and non-viable cells (NVC). Results show that Asta ameliorated both sperm head Tyr-P and ARC values without affecting the ROS generation curve, whereas Diam succeeded in enhancing the Tyr-P level but only of the flagellum without increasing ARC values. It is suggested that Asta can be inserted in the membrane and therefore create capacitation-like membrane alteration which allow Tyr-P of the head. Once this has occurred, AR can take place and involves a higher numbers of cells. PMID- 23736767 TI - Self-modulated band gap in boron nitride nanoribbons and hydrogenated sheets. AB - Using hybrid density functional theory calculations with van der Waals correction, we show that polar boron nitride (BN) nanoribbons can be favorably aligned via substantial hydrogen bonding at the interfaces, which induces significant interface polarizations and sharply reduces the band gap of insulating ribbons well below the silicon range. The interface polarization can strongly couple with carrier doping or applied electric fields, yielding not only enhanced stability but also widely tunable band gap for the aligned ribbons. Furthermore, similar layer-by-layer alignment also effectively reduces the band gap of a 2D hydrogenated BN sheet and even turns it into metal. This novel strategy for band gap control appears to be general in semiconducting composite nanostructures with polar nonbonding interfaces and thus offers unique opportunities for developing nanoscale electronic and optical devices. PMID- 23736768 TI - Anorectal malformation associated with a mutation in the P63 gene in a family with split hand-foot malformation. AB - PURPOSE: The aims of this study were to identify the mutation gene of a Chinese family with anorectal malformation (ARM) associated with split hand-foot malformation and to determine the spatiotemporal expression of the mutated gene during hindgut and anorectum development in human embryos. METHOD: A Chinese family with intrafamilial clinically variable manifestation was analyzed and primers were designed for exons 3-14 of P63, DLX5, DLX6, DAC, and HOXD13 as candidate genes and direct sequence analysis of the exons was performed. Immunohistochemical study of mutated gene in the hindgut and anorectum of human embryos of 4th-10th weeks was performed. RESULT: Affected individuals were found to have an Arg227Gln P63 gene mutation. From the 4th-10th weeks of gestation of the human embryo, the P63-positive cells were mainly located on the epithelium of the apical urorectal septum, hindgut, and cloacal membrane. After the anorectum ruptured during the 8th week, the P63 remained strongly immunoreactive on the epithelium of the anal canal and urethra, but the mucous membrane of the rectum exhibited no reaction. CONCLUSIONS: The mutation identified strongly suggests a causal relationship between the ARM phenotype and P63. The expression of P63 was persistently active during the dynamic and incessant septation of the cloaca and hindgut, suggesting that P63 may play a pivotal role in the morphogenesis of the hindgut and anorectum. PMID- 23736769 TI - Vitamin D status and cardiometabolic assessment in infancy. AB - BACKGROUND: Infants are at risk of vitamin D insufficiency, owing to their limited exposure to direct sunlight and the low levels of vitamin D in breast milk. Although vitamin D insufficiency has been associated with cardiometabolic risk factors in children, these associations have not been studied in infants, despite their unique risks. Therefore, we sought to determine whether vitamin D status was associated with cardiometabolic measures in infants. METHODS: Ninety nine full-term infants were evaluated at the age of 1 y with measurement of 25 hydroxy vitamin D (25-OH-D) and an array of traditional (fasting glucose, insulin, low-density-lipoprotein cholesterol, high-density-lipoprotein cholesterol, triglycerides) and emerging (C-reactive protein, adiponectin, leptin) cardiometabolic risk factors. On the basis of 25-OH-D levels, infants were classified as vitamin D sufficient (n = 59), vitamin D insufficient (n = 29), or vitamin D deficient (n = 11). RESULTS: Duration of exclusive breastfeeding and prevalence of nonwhite ethnicity were highest in the vitamin D deficient group (P = 0.05 and 0.03, respectively). Current use of vitamin D supplementation was highest in the sufficient group (P = 0.02). Of note, however, there were no significant differences among the three groups in any of the cardiometabolic risk factors, on both unadjusted and covariate-adjusted analyses. CONCLUSION: Vitamin D insufficiency/deficiency is not associated with an adverse cardiometabolic risk factor profile in 1-y-old infants. PMID- 23736771 TI - In situ potential distribution measurement in an all-vanadium flow battery. AB - An experimental method for measurement of local redox potential within multilayer electrodes was developed and applied to all-vanadium redox flow batteries (VRFBs). Through-plane measurement at the positive side reveals several important phenomena including potential distribution, concentration distribution of active species and the predominant reaction location within the porous carbon electrodes. PMID- 23736770 TI - Viscera and muscle protein synthesis in neonatal pigs is increased more by intermittent bolus than by continuous feeding. AB - BACKGROUND: Continuous and intermittent bolus orogastric feedings are strategies used in infants unable to tolerate normal feeds. METHODS: To determine the effects of feeding modality on protein synthesis in different tissues, neonatal pigs received a balanced formula by orogastric tube as an intermittent bolus feed every 4 h or as a continuous infusion, or were fasted overnight. RESULTS: As compared with fasting, protein synthesis in gastrocnemius, masseter, and soleus muscles; left ventricle; liver; pancreas; jejunum; and kidney increased in bolus- and continuously fed pigs, but the greatest increase occurred after a bolus meal. Tuberous sclerosis complex (TSC2), the proline-rich AKT substrate of 40 kDa (PRAS40), eukaryotic initiation factor (eIF) 4E binding protein (4EBP1), and ribosomal protein S6 kinase 1 (S6K1) phosphorylation in all tissues, and the proportion of ribosomal protein S4 in liver polysomes were enhanced 90 min following the bolus meal but not immediately before the meal or during continuous feeding. Eukaryotic elongation factor 2 (eEF2) and eIF2alpha phosphorylation were unaffected by feeding. CONCLUSION: These results suggest that intermittent bolus feeding increases protein synthesis in muscles of different fiber types and visceral tissues to a greater extent than continuous feeding by stimulating translation initiation. PMID- 23736772 TI - Complex distal humerus fractures-comparison of polyaxial locking and nonlocking screw configurations-a preliminary biomechanical study. AB - OBJECTIVE: The investigation hypothesized that in current anatomical precontoured plates, angular stability plays only a minor role for the efficacy of the osteosynthesis at the distal humerus. METHODS: An AO C2.3 fracture model was simulated and osteosynthesis performed with plates positioned in parallel. System rigidity and median fatigue limit were analyzed in artificial bones and the cycles to failure in cadaver specimens. Loads were applied in anterior-posterior direction (75 degrees flexion) and axial direction (5 degrees flexion). Four composite bone groups were investigated as follows: (1) 2.7 mm polyaxial locking screws, (2) 3.5 mm polyaxial locking screws, (3) 3.5 mm polyaxial locking screws and a gap bridging screw, and (4) 2.7 mm nonlocking screws. Two cadaver groups were investigated with 3.5 mm diameter polyaxial locking (5) versus nonlocking screws (6). RESULTS: There were no differences in stiffness found between the locking versus nonlocking constructs in artificial (1) versus (4) and in cadaver bones (5) versus (6). The larger screw diameter of 3.5 mm in combination with a gap bridging screw significantly increased construct stiffness by 25% (3). The median fatigue limit was significantly increased using larger screw diameters (2) and a gap bridging screw (3). In cadaver bones, the polyaxial locking screws constructs (5) resisted higher peak loads and more cycles until failure compared with nonlocking constructs (6). CONCLUSIONS: System stiffness increases with larger screw diameters and becomes significant with additional gap bridging screws in artificial bones. The use of polyaxial locking screws in anatomical adapted plates becomes more important in poor bone quality. PMID- 23736773 TI - Operationalising concordance: testing the utility of Bech's pharmacopsychometric triangle. PMID- 23736775 TI - A Short-activating RNA Oligonucleotide Targeting the Islet beta-cell Transcriptional Factor MafA in CD34(+) Cells. AB - Upon functional loss of insulin producing islet beta-cells, some patients with diabetes become dependent on life-long insulin supplementation therapy. Bioengineering surrogate insulin producing cells is an alternative replacement strategy. We have developed a novel approach using short-activating RNA oligonucleotides to differentiate adult human CD34(+) cells into insulin secreting cells. By transfecting RNA to increase transcript levels of the master regulator of insulin biosynthesis, v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), several pancreatic endodermal genes were upregulated during the differentiation procedure. These included Pancreatic and duodenal homeobox gene-1 (PDX1), Neurogenin 3, NeuroD, and NK6 homeobox 1 (NKx6-1). Differentiated CD34(+) cells also expressed glucokinase, glucagon-like peptide 1 receptor (GLP1R), sulfonylurea receptor-1 (SUR1) and phogrin-all essential for glucose sensitivity and insulin secretion. The differentiated cells appropriately processed C-peptide and insulin in response to increasing glucose stimulation as shown by enzyme linked immunosorbent assay (ELISA), fluorescence-activated cell sorting analysis, western blotting, and immunofluorescence staining. We provide a new approach using short-activating RNA in developing insulin producing surrogate cells for treating diabetes.Molecular Therapy - Nucleic Acids (2013) 2, e97; doi:10.1038/mtna.2013.23; advance online publication 4 June 2013. PMID- 23736776 TI - Temporal changes in climatic variables and their impact on crop yields in southwestern China. AB - Knowledge of variability in climatic variables changes and its impact on crop yields is important for farmers and policy makers, especially in southwestern China where rainfed agriculture is dominant. In the current study, six climatic parameters (mean temperature, rainfall, relative humidity, sunshine hours, temperature difference, and rainy days) and aggregated yields of three main crops (rice: Oryza sativa L., oilseed rape: Brassica napus L., and tobacco: Nicotiana tabacum L.) during 1985-2010 were collected and analyzed for Chongqing-a large agricultural municipality of China. Climatic variables changes were detected by Mann-Kendall test. Increased mean temperature and temperature difference and decreased relative humidity were found in annual and oilseed rape growth time series (P<0.05). Increased sunshine hours were observed during the oilseed rape growth period (P<0.05). Rainy days decreased slightly in annual and oilseed rape growth time series (P<0.10). Correlation analysis showed that yields of all three crops could benefit from changes in climatic variables in this region. Yield of rice increased with rainfall (P<0.10). Yield of oilseed rape increased with mean temperature and temperature difference but decreased with relative humidity (P<0.01). Tobacco yield increased with mean temperature (P<0.05). Path analysis provided additional information about the importance and contribution paths of climatic variables to crop yields. Temperature difference and sunshine hours had higher direct and indirect effects via other climatic variables on yields of rice and tobacco. Mean temperature, relative humidity, rainy days, and temperature difference had higher direct and indirect effects via others on yield of oilseed rape. PMID- 23736774 TI - Efficient Biodistribution and Gene Silencing in the Lung epithelium via Intravenous Liposomal Delivery of siRNA. AB - RNA interference (RNAi) may provide a therapeutic solution to many pulmonary epithelium diseases. However, the main barrier to the clinical use of RNAi remains the lack of efficient delivery vectors. Research has mainly concentrated on the intranasal route of delivery of short interfering RNA (siRNA) effector molecules for the treatment of respiratory diseases. However, this may be complicated in a diseased state due to the increased fluid production and tissue remodeling. Therefore, we investigated our hydration of a freeze-dried matrix (HFDM) formulated liposomes for systemic delivery to the lung epithelium. Here, we show that 45 +/- 2% of epithelial murine lung cells receive siRNA delivery upon intravenous (IV) liposomal administration. Furthermore, we demonstrate that liposomal siRNA delivery resulted in targeted gene and protein knockdown throughout the lung, including lung epithelium. Taken together, this is the first description of lung epithelial delivery via cationic liposomes, and provides a proof of concept for the use of IV liposomal RNAi delivery to specifically knockdown targeted genes in the respiratory system. This approach may provide an attractive alternate therapeutic delivery strategy for the treatment of lung epithelium diseases.Molecular Therapy - Nucleic Acids (2013) 2, e96; doi:10.1038/mtna.2013.22; published online 4 June 2013. PMID- 23736777 TI - Uric acid levels and all-cause mortality in peritoneal dialysis patients. AB - BACKGROUND: Epidemiological studies have shown that hyperuricemia is associated with all-cause and cardiovascular mortality in chronic kidney disease (CKD) and hemodialysis patients. Our study investigated the influence of serum uric acid (UA) levels on survival in peritoneal dialysis (PD) patients. METHODS: This was a retrospective study involving 156 subjects who had undergone PD. The patient demographics, etiology of ESRD, comorbid conditions and other laboratory parameters were collected. The subjects were divided into three groups according to their serum UA concentrations (group 1, the lowest quartile; group 2, the middle quartiles; group 3, the highest quartile). The risk of death was calculated using a multivariate Cox regression model. RESULTS: There were 41 deaths during a follow-up period of 31.3+/-17.5 months. Compared with group 2, which had a mortality rate of 5.7 per 1000 person-months, the mortality rates were higher in group 1 (14.3 per 1000 person-months, p<0.05) and group 3 (13.3 per 1000 person-months, p<0.05). A multivariable Cox regression model revealed that age, serum albumin, diabetes mellitus (DM), hypertensive nephropathy, residual renal function and UA group were factors associated with mortality in the PD patients. Using group 2 as a reference, the hazard ratio (HR) of mortality was found to be 1.15 (95% confidence interval [CI] 0.20-2.57, p>0.05) for group 1 and 2.96 (95% CI 1.29-6.80, p=0.01) for group 3. CONCLUSIONS: In PD patients, a higher serum UA level is related to increased mortality and is an independent risk factor for all-cause mortality. Uric acid levels and all-cause mortality in peritoneal dialysis patients. PMID- 23736778 TI - Aliskiren, a direct renin inhibitor, improves vascular endothelial function in patients on hemodialysis independent of antihypertensive effect ~ a pilot study~. AB - AIMS: Aliskiren inhibits the first step in the renin-angiotensin system (RAS) and recently has been shown to modulate vascular diseases via RAS-dependent and independent pathways. This study aimed to determine the effect of aliskiren associated direct renin inhibition on endothelial function in patients on hemodialysis via flow-mediated dilatation (FMD) and platelet-derived microparticles (PDMP), as biomarkers of atherosclerosis. METHODS: A 12-week prospective study was performed with 24 patients on hemodialysis who were administered 150 mg orally aliskiren once daily for 12 weeks. RESULTS: No significant difference were observed between pre-dialysis, home, and weekly averaged blood pressure at baseline and at 12 weeks (151.5 +/- 8.5/80.9 +/- 12.9 mmHg vs 150.3 +/- 15.3/78.9 +/- 21.2 mmHg, 151.4 +/- 9.7/82.3 +/- 14.7 mmHg vs 151.2 +/- 17.7/81.4 +/- 10.6 mmHg, and 156.0 +/- 18.3/81.9 +/- 9.4 mmHg vs 152.5 +/- 18.9/81.7 +/- 12.3 mmHg, respectively). FMD significantly increased from 2.54% +/- 1.45% at baseline to 3.11% +/- 1.37% at 12 weeks (P = 0.0267), and PDMP significantly decreased from 13.9 +/- 5.8 U/mL at baseline to 10.9 +/- 4.5 U/mL at 12 weeks (P = 0.0002). CONCLUSION: Aliskiren improved vascular endothelial function and platelet-endothelium activation in patients on hemodialysis independent of antihypertensive effect. PMID- 23736779 TI - Proteinuria as a risk factor for decline in residual renal function in non diabetic peritoneal dialysis patients. AB - BACKGROUND: Preservation of residual renal function (RRF) is a major issue for patients on peritoneal dialysis (PD). Whether proteinuria is associated with a decline in RRF in patients on PD remains unclear. PATIENTS AND METHODS: We reviewed the medical records at the Yeungnam University Hospital in Korea and identified patients who started PD between June 1995 and August 2011. A total of 147 non-diabetic patients were enrolled in the study. The patients were divided into 3 groups with respect to the tertile of initial proteinuria level: Low (n = 49; <320 mg/day), Middle (n = 49; 320-822 mg/day), and High groups (n = 49; >822 mg/day). RESULTS: The mean patient age was 50.2 +/- 15.0 years in the Low tertile, 50.2 +/- 15.4 years in the Middle tertile, and 49.0 +/- 15.1 years in the High tertile. Decline in RRF during follow-up period was greater in the High tertile than that in the other tertiles (P = 0.001). The proportion of patients with RRF >50% of baseline at 24 months after the initiation of PD was 83% in the Low tertile, 66% in the Middle tertile, and 40% in the High tertile (P < 0.001). The multivariate analysis after adjusting for initial RRF, age, gender, underlying disease of end-stage renal disease except diabetes mellitus, PD modality, use of icodextrin, PD-associated peritonitis, and tertile of the initial proteinuria level revealed that High tertile of the initial proteinuria level was associated with a decline in RRF (hazard ratios: 2.442 for the Middle tertile, P = 0.007 ; 3.713 for the Low tertile, P < 0.001). CONCLUSION: The present study demonstrates that proteinuria may be is associated with a rapid decline in RRF in non-diabetic patients on PD, although the potential role of additional factors should be further investigated in prospective studies. PMID- 23736780 TI - Effects of magnoline on P-selectin's expression in diabetic rats and its reno protection. AB - BACKGROUND AND OBJECTIVE: Magnoline is an active ingredient of magnolia fargesii with anti-inflammatory and anti-platelet effects. The objective is to explore the renoprotection of magnoline in diabetic rats and its effects on P-selectin. METHODS: Thirty-six rats were randomized into 4 groups-normal control group (C), diabetic group (D), small-dose magnoline treatment group (M1) and large-dose magnoline treatment group (M2) (n=9 in each group). Streptozotocin was selected to construct diabetic rat model, and group M1 and group M2 were treated with magnoline 0.5mg/Kg.d and 2mg/Kg.d respectively. Urinary albumin excretion rate, renal function, levels of P-selectin and TGF-beta1 were observed after 16 weeks. RESULTS: Levels of albuminuria and serum creatinine of group M1 (1078.9 +/- 77.3MUg/24h, 29.7 +/- 3.9MUmol/L) and M2 (852.9 +/- 80.1MUg/24h, 30.9 +/- 2.9MUmol/L) were lower than group D (1572.8 +/- 176.2MUg/24h, 39.4 +/- 4.1MUmol/L) (P <0.05). Serum levels of P-selectin in group M1 and M2 were lower than group D (P <0.05). The renal expression of P-selectin and TGF-beta1 in group M1 and M2 were significantly attenuated respectively. CONCLUSIONS: Magnoline has reno-protective effects on diabetic rats which may be related to the inhibition of P-selectin. PMID- 23736781 TI - Clinically useful dilution factors for iodine and gadolinium contrast material: an animal model of pediatric digital subtraction angiography using state-of-the art flat-panel detectors. AB - BACKGROUND: Iodinated and gadolinium contrast agents pose some risk for certain pediatric patients, including allergic-like reactions, contrast-induced nephropathy (CIN) and nephrogenic systemic fibrosis (NSF). Digital flat-panel detectors enhance image quality during angiography and might allow use of more dilute contrast material to decrease risk of complications that might be dose dependent, such as CIN and NSF. OBJECTIVE: To assess the maximum dilution factors for iodine- and gadolinium-based contrast agents suitable for vascular imaging with fluoroscopy and digital subtraction angiography (DSA) on digital flat-panel detectors in an animal model. MATERIALS AND METHODS: We performed selective catheterization of the abdominal aorta, renal artery and common carotid artery on a rabbit. In each vessel we performed fluoroscopy and DSA during contrast material injection using iodinated and gadolinium contrast material at 100%, 80%, 50%, 33% and 20% dilutions. An image quality score (0 to 3) was assigned by each of eight evaluators. Intracorrelation coefficient, paired t-test, one-way repeated analysis of variance, Spearman correlation and receiver operating characteristic curve analysis were applied to the data. RESULTS: Overall the image quality scores correlated linearly with dilution levels. For iodinated contrast material, the optimum cut-off level for DSA when a score of at least 2 is acceptable is above 33%; it is above 50% when a score of 3 is necessary. For gadolinium contrast material, the optimum cut-off for DSA images is above 50% when a score of at least 2 is acceptable and above 80% when a score of 3 is necessary. CONCLUSION: Knowledge of the relationship between image quality and contrast material dilution might allow a decrease in overall contrast load while maintaining appropriate image quality when using digital flat-panel detectors. PMID- 23736782 TI - Greater gains in strength and power with intraset rest intervals in hypertrophic training. AB - We sought to determine if hypertrophic training with intraset rest intervals (ISRs) produced greater gains in power compared with traditional rest (TRD) hypertrophic training. Twenty-two men (age 25 +/- 5 years, height 179.71 +/- 5.04 cm, weight 82.1 +/- 10.6 kg, 6.5 +/- 4.5 years of training) matched according to baseline characteristics were assigned to 12 weeks of training using TRD or ISR. Body composition, strength (1-repetition maximum [1RM] bench and squat), and power output (60% 1RM bench and squat, and vertical jump) were assessed at baseline, 4, 8, and 12 weeks. Determination of myosin heavy chain (MHC) percentage from the vastus lateralis was performed pretraining and posttraining. Body composition was analyzed by analysis of variance, whereas performance measures and MHC were analyzed by analysis of covariance with baseline values as the covariate. Data are presented as mean +/- SD changes pre to post. The ISR produced greater power output in bench (TRD 32.8 +/- 53.4 W; ISR 83.0 +/- 49.9 W, p = 0.020) and vertical jump (TRD 91.6 +/- 59.8 W; ISR 147.7 +/- 52.0 W; p = 0.036) with squat power approaching significance (TRD 204.9 +/- 70.2 W; ISR 282.1 +/- 104.2 W; p = 0.053) after post hoc analysis (p < 0.10). The ISR produced greater gains in bench (TRD 9.1 +/- 3.7 kg; ISR 15.1 +/- 8.3 kg; p = 0.010) and squat (TRD 48.5 +/- 17.4 kg; ISR 63.8 +/- 12.0 kg; p = 0.002) strength. Both protocols produced significant gains in lean mass with no significant differences between groups (1.6 +/- 2.1 kg; p = 0.869). The MHCIIx percentage decreased ( 31.0 +/- 24.5%; p = 0.001), whereas the MHCIIA percentage increased (28.9 +/- 28.5%; p = 0.001) with no significant differences between groups. Results indicate that hypertrophy training with ISR produces greater gains in strength and power, with similar gains in lean mass and MHC alterations as TRD. The ISR may be best used in hypertrophic training for strength and power sports. PMID- 23736783 TI - Specimen-specific predictions of contact stress under physiological loading in the human hip: validation and sensitivity studies. AB - Hip osteoarthritis may be initiated and advanced by abnormal cartilage contact mechanics, and finite element (FE) modeling provides an approach with the potential to allow the study of this process. Previous FE models of the human hip have been limited by single specimen validation and the use of quasi-linear or linear elastic constitutive models of articular cartilage. The effects of the latter assumptions on model predictions are unknown, partially because data for the instantaneous behavior of healthy human hip cartilage are unavailable. The aims of this study were to develop and validate a series of specimen-specific FE models, to characterize the regional instantaneous response of healthy human hip cartilage in compression, and to assess the effects of material nonlinearity, inhomogeneity and specimen-specific material coefficients on FE predictions of cartilage contact stress and contact area. Five cadaveric specimens underwent experimental loading, cartilage material characterization and specimen-specific FE modeling. Cartilage in the FE models was represented by average neo-Hookean, average Veronda Westmann and specimen- and region-specific Veronda Westmann hyperelastic constitutive models. Experimental measurements and FE predictions compared well for all three cartilage representations, which was reflected in average RMS errors in contact stress of less than 25%. The instantaneous material behavior of healthy human hip cartilage varied spatially, with stiffer acetabular cartilage than femoral cartilage and stiffer cartilage in lateral regions than in medial regions. The Veronda Westmann constitutive model with average material coefficients accurately predicted peak contact stress, average contact stress, contact area and contact patterns. The use of subject- and region-specific material coefficients did not increase the accuracy of FE model predictions. The neo-Hookean constitutive model underpredicted peak contact stress in areas of high stress. The results of this study support the use of average cartilage material coefficients in predictions of cartilage contact stress and contact area in the normal hip. The regional characterization of cartilage material behavior provides the necessary inputs for future computational studies, to investigate other mechanical parameters that may be correlated with OA and cartilage damage in the human hip. In the future, the results of this study can be applied to subject-specific models to better understand how abnormal hip contact stress and contact area contribute to OA. PMID- 23736784 TI - Bioactive secondary metabolites of a marine Bacillus sp. inhibit superoxide generation and elastase release in human neutrophils by blocking formyl peptide receptor 1. AB - It is well known that overwhelming neutrophil activation is closely related to acute and chronic inflammatory injuries. Formyl peptide receptor 1 (FPR1) plays an important role in activation of neutrophils and may represent a potent therapeutic target in inflammatory diseases. In the present study, we demonstrated that IA-LBI07-1 (IA), an extract of bioactive secondary metabolites from a marine Bacillus sp., has anti-inflammatory effects in human neutrophils. IA significantly inhibited superoxide generation and elastase release in formyl-L methionyl-L-leucyl-L-phenylalanine (FMLP)-activated neutrophils, but failed to suppress the cell responses activated by non-FPR1 agonists. IA did not alter superoxide production and elastase activity in cell-free systems. IA also attenuated the downstream signaling from FPR1, such as the Ca2+, MAP kinases and AKT pathways. In addition, IA inhibited the binding of N-formyl-Nle-Leu-Phe-Nle Tyr-Lys-fluorescein, a fluorescent analogue of FMLP, to FPR1 in human neutrophils and FPR1-transfected HEK293 cells. Taken together, these results show that the anti-inflammatory effects of IA in human neutrophils are through the inhibition of FPR1. Also, our data suggest that IA may have therapeutic potential to decrease tissue damage induced by human neutrophils. PMID- 23736785 TI - (89)Zr, a radiometal nuclide with high potential for molecular imaging with PET: chemistry, applications and remaining challenges. AB - Molecular imaging-and especially Positron Emission Tomography (PET)-is of increasing importance for the diagnosis of various diseases and thus is experiencing increasing dissemination. Consequently, there is a growing demand for appropriate PET tracers which allow for a specific accumulation in the target structure as well as its visualization and exhibit decay characteristics matching their in vivo pharmacokinetics. To meet this demand, the development of new targeting vectors as well as the use of uncommon radionuclides becomes increasingly important. Uncommon nuclides in this regard enable the utilization of various selectively accumulating bioactive molecules such as peptides, antibodies, their fragments, other proteins and artificial structures for PET imaging in personalized medicine. Among these radionuclides, 89Zr (t1/2 = 3.27 days and mean Ebeta+ = 0.389 MeV) has attracted increasing attention within the last years due to its favorably long half-life, which enables imaging at late time-points, being especially favorable in case of slowly-accumulating targeting vectors. This review outlines the recent developments in the field of 89Zr labeled bioactive molecules, their potential and application in PET imaging and beyond, as well as remaining challenges. PMID- 23736786 TI - The design and synthesis of a new class of RTK/HDAC dual-targeted inhibitors. AB - Over the years, the development of targeted medicines has made significant achievements. As a typical example, receptor tyrosine kinases (RTK) inhibitors have become important chemotherapy drugs for a variety of cancers. However, the effectiveness of these agents is always hindered by poor response rates and acquired drug resistance. In order to overcome these limitations, several dual targeted inhibitors with quinazoline core were designed and synthesized. Though these compounds can simultaneously inhibit histone deacetylases (HDAC) as well as RTK, the structure-activity relationship (SAR) is still not clear enough. To further explore this type of dual-targeted inhibitors, a new class of quinazoline derivatives were designed and synthesized. Their activity evaluations include in vitro inhibitory activity of HDAC, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). The SAR study indicated that the introduction of polar group such as hydroxamate on the 4-position of the quinazoline core is more likely to provide a potent HDACi/HER2i hybrid rather than HDACi/EGFRi molecule. PMID- 23736787 TI - The development, physicochemical characterisation and in vitro drug release studies of pectinate gel beads containing Thai mango seed kernel extract. AB - Pectinate gel beads containing Thai mango seed kernel extract (MSKE, cultivar 'Fahlun') were developed and characterised for the purpose of colon-targeted delivery. The MSKE-loaded pectinate beads were prepared using ionotropic gelation with varying pectin-to-MSKE ratios, MSKE concentrations, and concentrations of two cross-linkers (calcium chloride and zinc acetate). The formulated beads were spherical in shape and ranged in size between 1.13 mm and 1.88 mm. Zinc-pectinate (ZPG) beads containing high amounts of MSKE showed complete entrapment efficiency (EE) of MSKE (100%), while calcium-pectinate (CPG) beads demonstrated 70% EE. The in vitro release tests indicated that MSKE-loaded CPG beads were unstable in both simulated gastric medium (SGM) and simulated intestinal medium (SIM), while MSKE loaded ZPG beads were stable in SIM but unable to prevent the release of MSKE in SGM. The protection of ZPG beads with gastro-resistant capsules (Eudragit(r) L 100-55) resulted in stability in both SGM and SIM; they disintegrated immediately in simulated colonic medium containing pectinolytic enzymes. MSKE-loaded ZPG beads were stable at 4, 25 and 45 degrees C during the study period of four months. The present study revealed that ZPG beads in enteric-coated capsules might be a promising carrier for delivering MSKE to the colon. PMID- 23736788 TI - A microfluidic chip using phenol formaldehyde resin for uniform-sized polycaprolactone and chitosan microparticle generation. AB - This study develops a new solvent-compatible microfluidic chip based on phenol formaldehyde resin (PFR). In addition to its solvent-resistant characteristics, this microfluidic platform also features easy fabrication, organization, decomposition for cleaning, and reusability compared with conventional chips. Both solvent-dependent (e.g., polycaprolactone) and nonsolvent-dependent (e.g., chitosan) microparticles were successfully prepared. The size of emulsion droplets could be easily adjusted by tuning the flow rates of the dispersed/continuous phases. After evaporation, polycaprolactone microparticles ranging from 29.3 to 62.7 MUm and chitosan microparticles ranging from 215.5 to 566.3 MUm were obtained with a 10% relative standard deviation in size. The proposed PFR microfluidic platform has the advantages of active control of the particle size with a narrow size distribution as well as a simple and low cost process with a high throughput. PMID- 23736789 TI - Isocyanate-functionalized chitin and chitosan as gelling agents of castor oil. AB - The main objective of this work was the incorporation of reactive isocyanate groups into chitin and chitosan in order to effectively use the products as reactive thickening agents in castor oil. The resulting gel-like dispersions could be potentially used as biodegradable lubricating greases. Three different NCO-functionalized polymers were obtained: two of them by promoting the reaction of chitosan with 1,6-hexamethylene diisocyanate (HMDI), and the other by using chitin instead of chitosan. These polymers were characterized through 1H-NMR, FTIR and thermogravimetric analysis (TGA). Thermal and rheological behaviours of the oleogels prepared by dispersing these polymers in castor oil were studied by means of TGA and small-amplitude oscillatory shear (SAOS) measurements. The evolution and values of the linear viscoelasticity functions with frequency for NCO-functionalized chitosan- and chitin-based oleogels are quite similar to those found for standard lubricating greases. In relation to long-term stability of these oleogels, no phase separation was observed and the values of viscoelastic functions increase significantly during the first seven days of ageing, and then remain almost constant. TGA analysis showed that the degradation temperature of the resulting oleogels is higher than that found for traditional lubricating greases. PMID- 23736790 TI - One-step biofunctionalization of quantum dots with chitosan and N-palmitoyl chitosan for potential biomedical applications. AB - Carbohydrates and derivatives (such as glycolipids, glycoproteins) are of critical importance for cell structure, metabolism and functions. The effects of carbohydrate and lipid metabolic imbalances most often cause health disorders and diseases. In this study, new carbohydrate-based nanobioconjugates were designed and synthesized at room temperature using a single-step aqueous route combining chitosan and acyl-modified chitosan with fluorescent inorganic nanoparticles. N palmitoyl chitosan (C-Pal) was prepared aiming at altering the lipophilic behavior of chitosan (CHI), but also retaining its reasonable water solubility for potential biomedical applications. CHI and C-Pal were used for producing biofunctionalized CdS quantum dots (QDs) as colloidal water dispersions. Fourier transform infrared spectroscopy (FTIR), thermal analysis (TG/DSC), surface contact angle (SCA), and degree of swelling (DS) in phosphate buffer were used to characterize the carbohydrates. Additionally, UV-Visible spectroscopy (UV-Vis), photoluminescence spectroscopy (PL), dynamic light scattering (DLS), scanning and transmission electron microscopy (SEM/TEM) were used to evaluate the precursors and nanobioconjugates produced. The FTIR spectra associated with the thermal analysis results have undoubtedly indicated the presence of N-palmitoyl groups "grafted" to the chitosan chain (C-Pal) which significantly altered its behavior towards water swelling and surface contact angle as compared to the unmodified chitosan. Furthermore, the results have evidenced that both CHI and C-Pal performed as capping ligands on nucleating and stabilizing colloidal CdS QDs with estimated average size below 3.5 nm and fluorescent activity in the visible range of the spectra. Therefore, an innovative "one-step" process was developed via room temperature aqueous colloidal chemistry for producing biofunctionalized quantum dots using water soluble carbohydrates tailored with amphiphilic behavior offering potential applications as fluorescent biomarkers in the investigation of glycoconjugates for the nutrition, biology, pharmaceutical, and medicine fields. PMID- 23736791 TI - New Lignans from the Leaves and Stems of Kadsura philippinensis. AB - Three novel C19 homolignans, taiwankadsurins D (1), E (2) and F (4), and two new C18 lignans kadsuphilins N (3) and O (5) were isolated from the aerial parts of Taiwanese medicinal plant Kadsura philippinensis. The structures of compounds 1-5 were determined by spectroscopic analyses, especially 2D NMR techniques. The structure of compound 5 was further confirmed by X-ray crystallographic analysis. Compounds 1 and 2 have a 3,4-{1'-[(Z)-2''-methoxy-2''-oxoethylidene]}-pentano(2,3 dihydrobenzo[b]furano)-3-(2'''-methoxycarbonyl-2'''-hydroxy-2''',3'-epoxide) skeleton. PMID- 23736792 TI - Indomethacin inhibits cancer cell migration via attenuation of cellular calcium mobilization. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) were shown to reduce the risk of colorectal cancer recurrence and are widely used to modulate inflammatory responses. Indomethacin is an NSAID. Herein, we reported that indomethacin can suppress cancer cell migration through its influence on the focal complexes formation. Furthermore, endothelial growth factor (EGF)-mediated Ca2+ influx was attenuated by indomethacin in a dose dependent manner. Our results identified a new mechanism of action for indomethacin: inhibition of calcium influx that is a key determinant of cancer cell migration. PMID- 23736793 TI - Platelet-rich plasma in patients with tibiofemoral cartilage degeneration. AB - INTRODUCTION: Recently an articular cartilage repair has been given much attention in the orthopaedic field. Cartilage regeneration capacity is very limited. Optimal approach seems to be a delivery of natural growth factors. Autologous platelet-rich plasma (PRP) contains proliferative and chemoattractant growth factors. The objective of the present study was to determine if PRP can increase tibiofemoral cartilage regeneration and improve knee function. MATERIALS AND METHODS: Fifty consecutive and strictly selected patients, affected by Grade II or III chondromalatia, underwent 1 year treatment (9 injections) with autologous PRP in a liquid form with 2.0 to 2.5-fold platelets concentration. Outcome measures included the Lysholm, Tegner, IKDC, and Cincinnati scores. Magnetic resonance imaging was used to evaluate cartilage thickness and degree of degeneration. RESULTS: The study demonstrated significant improvement in Lysholm (p < 0.05), Tegner (p < 0.05), IKDC (p < 0.05), and Cincinnati (p < 0.05) scores. Results improved at 12-month follow-up. Cartilage assessment revealed no significant cartilage regeneration (p < 0.05). There were no adverse events reported. CONCLUSIONS: PRP significantly reduced pain and improved quality of live in patients with low degree of cartilage degeneration. Magnetic resonance imaging did not confirmed any significant cartilage condition improvement. PMID- 23736795 TI - Helicobacter pylori infection is positively associated with gallstones: a large scale cross-sectional study in Japan. AB - BACKGROUND: Our aim is to elucidate causative factors for gallstones, especially focusing on Helicobacter pylori (HP) infection. METHODS: We analyzed 15,551 Japanese adults who had no history of gastrectomy, cholecystectomy, HP eradication, and didn't use proton pump inhibitors, anti-diabetic drugs, or anti cholesterol drugs. 1,057 subjects who previously had HP eradication were analyzed separately. RESULTS: Gallstones were detected in 409 of 8,625 men (4.74%) and 285 of 6,926 women (4.11%) by ultrasonography. Among the 25 factors univariately analyzed, age, HP infection, alcohol intake, weight, body mass index (BMI), and 14 blood test values (AST, ALT, ALP, gamma-GTP, T-Chol, HDL-Chol, LDL-Chol, TG, TP, Hb, HbA1c, pepsinogen I, pepsinogen II, and pepsinogen I/II ratio) displayed significant association with gallstones (p < 0.05), whereas gender, smoking, height, and three blood test values (Alb, T-Bil, MCV) did not. Multivariate analysis showed that age, gender, alcohol intake, BMI, gamma-GTP, LDL-Chol, TP, and HP infection had significant association (p < 0.05). Successive multiple logistic regression analysis calculating odds ratio (OR) and standardized coefficients (beta) showed that age (OR/beta = 1.57/0.450), BMI (OR/beta = 1.30/0.264), HP infection (OR/beta = 1.51/0.206), lower alcohol intake (OR/beta = 1.33/0.144), gamma-GTP (OR/beta = 1.15/0.139), and pepsinogen I/II ratio (OR/beta = 1.08/0.038) have significant positive association with gallstones, whereas gender does not. The gallstone prevalence among HP-negative, HP-eradicated, and HP-positive subjects was 3.81, 4.73 and 6.08%, respectively. The matched analysis controlling age, BMI, gamma-GTP, alcohol intake, pepsinogen I/II ratio and gender also demonstrated that gallstone prevalence among HP-eradicated subjects was significantly lower compared with HP-positive subjects (p < 0.05). CONCLUSIONS: HP infection is positively associated with gallstones. HP eradication may lead to prevention of gallstones. PMID- 23736794 TI - Management controversies in Barrett's oesophagus. AB - The management of Barrett's oesophagus and associated neoplasia has evolved considerably in recent years. Modern endoscopic strategies including endoscopic resection and mucosal ablation can eradicate dysplastic Barrett's and prevent progression to invasive oesophageal cancer. However, several aspects of Barrett's management remain controversial including the stage in the disease process at which to intervene, and the choice of endoscopic or surgical therapy. A review of articles pertaining to the management of Barrett's oesophagus with or without associated neoplasia, was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Medline, Embase and Cochrane databases were searched to identify literature relevant to eight pre defined areas of clinical controversy. The following search terms were used: Barrett's oesophagus; dysplasia; intramucosal carcinoma; endotherapy; endoscopic resection; ablation; oesophagectomy. A significant body of evidence exists to support early endoscopic therapy for high-grade dysplasia (HGD). Although not supported by randomised controlled trial evidence, endoscopic therapy is now favoured ahead of oesophagectomy for most patients with HGD. Focal intramucosal (T1a) carcinomas can be managed effectively using endoscopic and surgical therapy, however surgery should be considered the first line therapy where there is submucosal invasion (T1b). Treatment of low grade dysplasia is not supported at present due to widespread over-reporting of the disease. The role of surveillance endoscopy in non-dysplastic Barrett's remains controversial. PMID- 23736796 TI - Pancreatobiliary reflux in individuals with a normal pancreaticobiliary junction: a prospective multicenter study. AB - BACKGROUND: Pancreatobiliary reflux (PBR) can occur in individuals without pancreaticobiliary maljunction. The aim of this study was to elucidate the incidence of PBR in individuals with a normal pancreaticobiliary junction and its impact on the biliary tree. METHODS: Data were prospectively collected from 15 centers on 420 patients with a morphologically normal pancreaticobiliary junction who had undergone bile sampling and measurement of the biliary amylase level. We investigated the incidence and predictive factors for high biliary amylase levels (HBAL), as well as the relationship of HBAL with biliary malignancy. RESULTS: Twenty-three patients (5.5%) showed HBAL (>=10,000 IU/L). Univariate analysis showed that risk factors for the elevation of biliary amylase levels were the existence of a relatively long common channel (>=5 mm), acute pancreatitis, and papillitis. Multivariate analysis revealed that only the existence of a relatively long common channel was a significant factor for PBR. Biliary amylase levels in patients with a relatively long common channel were significantly higher than in patients without a long common channel (12,333 vs. 2,070 IU/L, P = 0.001). The incidence of HBAL (P < 0.001), as well as the overall biliary amylase levels (P = 0.007) were significantly higher in patients with gallbladder cancer than in those without gallbladder cancer. CONCLUSIONS: The PBR was frequently observed in individuals with a relatively long common channel. Patients showing HBAL with normal pancreaticobiliary junction are at high risk for gallbladder cancer. PMID- 23736798 TI - Few-layered CoHPO4 . 3H2O ultrathin nanosheets for high performance of electrode materials for supercapacitors. AB - Ultrathin cobalt phosphate (CoHPO4 . 3H2O) nanosheets are successfully synthesized by a one pot hydrothermal method. Novel CoHPO4 . 3H2O ultrathin nanosheets are assembled for constructing the electrodes of supercapacitors. Benefiting from the nanostructures, the as-prepared electrode shows a specific capacitance of 413 F g(-1), and no obvious decay even after 3000 charge-discharge cycles. Such a quasi-two-dimensional material is a new kind of supercapacitor electrode material with high performance. PMID- 23736797 TI - Clinical significance and evolution of hepatic HBsAg expression in HBeAg-positive patients receiving interferon therapy. AB - BACKGROUND: Serum hepatitis B surface antigen (HBsAg) level is important in the management of chronic hepatitis B (CHB). However, it is unclear whether serum HBsAg reflects its expression in liver and the hepatic HBsAg evolution following interferon therapy. METHODS: Forty-five HBeAg-positive CHB patients receiving interferon-based therapy within a randomized, controlled, multicenter study during 1998-1999 were included. The hepatic HBsAg expressions were categorized into cytoplasmic, inclusion, marginal and negative patterns by immunohistochemical staining. The HBsAg-positive hepatocytes were quantified by image-based cytometry and correlated to HBV serological and virological profiles for clinical implications. The evolution of hepatic HBsAg levels was analyzed among 22 patients with paired liver biopsies before and after interferon therapy, sequentially. RESULTS: There was a positive correlation between pretreatment serum HBsAg and hepatic HBsAg levels (r = 0.67, P < 0.0001). The hepatic HBsAg expression pattern significantly evolved from cytoplasmic/inclusion pattern to marginal/negative pattern after interferon treatment. The serum HBV-DNA, HBsAg and hepatic HBsAg levels all decreased significantly after interferon therapy. Among 36 % patients with HBeAg loss after therapy, pretreatment hepatic HBsAg levels were significantly lower compared with those without HBeAg loss. After multivariate analysis, low pretreatment hepatic HBsAg levels rather than serum HBsAg titers were associated with a higher rate of HBeAg loss (OR: 4.97, 95 % CI: 1.12-22.00, P = 0.035). CONCLUSIONS: The serum HBsAg level positively reflects the HBsAg level in liver which evolves significantly after interferon therapy. A lower hepatic HBsAg level is associated with HBeAg loss after interferon treatment. Hepatic HBsAg may have clinical significance in CHB patients receiving interferon treatment. PMID- 23736799 TI - A highly sensitive resonance Rayleigh scattering method to discriminate a parallel-stranded G-quadruplex from DNA with other topologies and structures. AB - The RRS intensities are significantly increased only when a parallel-stranded G quadruplex is added to Mg(2+) solution owing to the formation of G-wires between them, but the others cannot. So, we constructed a new and highly sensitive RRS method to discriminate a parallel-stranded G-quadruplex from DNA with other topologies and structures. PMID- 23736801 TI - Nearly 40% of hospitals missed emergency department waiting time target in last quarter, show figures. PMID- 23736800 TI - Facile, scalable synthesis of edge-halogenated graphene nanoplatelets as efficient metal-free eletrocatalysts for oxygen reduction reaction. AB - A series of edge-selectively halogenated (X = Cl, Br, I) graphene nanoplatelets (XGnPs = ClGnP, BrGnP, IGnP) were prepared simply by ball-milling graphite in the presence of Cl2, Br2 and I2, respectively. High BET surface areas of 471, 579 and 662 m(2)/g were observed for ClGnP, BrGnP and IGnP, respectively, indicating a significant extent of delamination during the ball-milling and subsequent workup processes. The newly-developed XGnPs can be well dispersed in various solvents, and hence are solution processable. Furthermore, XGnPs showed remarkable electrocatalytic activities toward oxygen reduction reaction (ORR) with a high selectivity, good tolerance to methanol crossover/CO poisoning effects, and excellent long-term cycle stability. First-principle density-functional calculations revealed that halogenated graphene edges could provide decent adsorption sites for oxygen molecules, in a good agreement with the experimental observations. PMID- 23736802 TI - Reply: To PMID 22964522. PMID- 23736804 TI - Real-time guidewire localization using impedance-based electroanatomic mapping: experimental results and clinical validation during cryoballoon ablation of atrial fibrillation. AB - AIMS: Cryoballoon ablation is an emerging therapy for atrial fibrillation (AF). However, the Arctic Front cryoballoon (Medtronic) cannot be localized on current electroanatomic mapping (EAM) systems. We describe a technique to visualize guidewires in an impedance-based EAM system. METHODS AND RESULTS: A novel technique for real-time guidewire localization in an EAM (Ensite Velocity, St Jude Medical) was prospectively evaluated among patients referred for cryoballoon AF ablation. The guidewire was visualized as an 'orb' on the EAM and localization in each of the pulmonary veins (PVs) compared with orthogonal fluoroscopy, contrast venography, and intra-cardiac echocardiography. Application of the technique in 21 consecutive patients [median age 58 (interquartile range 21); 71.4% male; 85.7% paroxysmal AF] demonstrated agreement with respect to guidewire localization in 82 of 82 (100%) PVs. Discrimination of guidewire position in the left atrial appendage from the left PVs was also demonstrated. When compared with 21 consecutive cryoballoon procedures over the same time period in which the technique was not used, fluoroscopy time was reduced [median 53.2 (25.9) vs. 72.3 (47.6) min, P = 0.008], and a trend towards reduced radiation exposure [median 372 (656.0) vs. 581 (849.9) mGy, P = 0.08] was noted, without effect on acute procedural or mid-term endpoints. Ex vivo assessment of the technique in a saline bath left atrial model demonstrated that the 'orb' localizes to the centroid of the exposed portion of the guidewire. CONCLUSION: This simple, novel technique provides real-time, accurate guidewire localization to enable guidewire and catheter navigation during cryoballoon AF ablation. PMID- 23736803 TI - Aerosol transmission is an important mode of influenza A virus spread. AB - Influenza A viruses are believed to spread between humans through contact, large respiratory droplets and small particle droplet nuclei (aerosols), but the relative importance of each of these modes of transmission is unclear. Volunteer studies suggest that infections via aerosol transmission may have a higher risk of febrile illness. Here we apply a mathematical model to data from randomized controlled trials of hand hygiene and surgical face masks in Hong Kong and Bangkok households. In these particular environments, inferences on the relative importance of modes of transmission are facilitated by information on the timing of secondary infections and apparent differences in clinical presentation of secondary infections resulting from aerosol transmission. We find that aerosol transmission accounts for approximately half of all transmission events. This implies that measures to reduce transmission by contact or large droplets may not be sufficient to control influenza A virus transmission in households. PMID- 23736805 TI - Open-irrigated laser catheter ablation: relationship between the level of energy, myocardial thickness, and collateral damages in a dog model. AB - AIMS: To evaluate laser lesion formation in the beating hearts of dogs by using an open-irrigated electrode-laser mapping and ablation heart catheter. METHODS AND RESULTS: A total of 50 laser applications at 15 W (n = 31) and 20 W (n = 19) for 10-50 s, with an irrigation flow of 35 mL/min were aimed at the right (n = 15) and left (n = 9) atrial, right (n = 15) and left (n = 11) ventricular walls in five dogs (6-16/dog), by using an open-irrigated laser ablation catheter. The 1064 nm diode laser was provided with a light control system, a Flowmeter, and a transoesophageal laser sensor. Lesions were measured and were evaluated morphometrically. Transmural lesions were achieved in seconds regardless of the level of energy applied. Laser applications at 15 W > 10 s aimed at the atrial walls produced collateral lesions to the lung or to the oesophagus. Laser applications at 20 W > 30 s aimed at the ventricular walls may result in steam pop with intramural cavitations and arrhythmias. Collateral damages to the oesophagus occurred only when the transoesophageal light sensor was deactivated. CONCLUSION: To avoid unwanted effects during laser catheter ablation by using an open-irrigated laser catheter energy delivery must be adapted to the thickness of the myocardial wall. Light control system and a transoesophageal light sensor may help reduce the risks of myocardial and collateral damages. PMID- 23736806 TI - A survey of German centres performing invasive electrophysiology: structure, procedures, and training positions. AB - AIMS: To provide a nationwide survey (and reference for the future) on cardiac electrophysiologists, types and numbers of invasive electrophysiological procedures, and training opportunities in 2010. METHODS AND RESULTS: German cardiology centres performing invasive electrophysiology were identified from quality reports and contacted to fill a questionnaire. A majority of 122 centres (65%) responded. Electrophysiology (ablation procedures and device therapy) was mainly part of a cardiology department (82%), and only in 9% independent (own budget). In only 58% of the centres, (at least) two physicians were present during catheter ablations. Although in 2010, women represented 59.4% of physicians <35 years old, only 26% of physicians in electrophysiology training were female. In total, 33 420 catheter ablations were performed with a median number of 180 per centre. Atrial fibrillation (AF) was the most common arrhythmia invasively treated (35%). At least 50 AF ablations were performed in 53% of the centres. Of the centres performing AF ablations, consecutive left atrial arrhythmias were treated by catheter ablation only in 75%, and only 44% had in house surgical backup. Only one-fourth of the 122 centres fulfilled all requirements for training centre accreditation according to the European Heart Rhythm Association and the German Cardiac Society. CONCLUSION: The results indicate a high number of electrophysiology centres and procedures in Germany. Atrial fibrillation was the most common arrhythmia invasively treated. An increasing demand for catheter ablation is likely, but training opportunities are limited. Women are clearly underrepresented. A co-operation of higher and lower volume electrophysiology centres may be necessary for training purposes. PMID- 23736807 TI - Cardiac resynchronization therapy in pacemaker-dependent patients with left ventricular dysfunction. AB - AIMS: Heart failure and left ventricular (LV) systolic dysfunction (LVSD) are common in patients with permanent pacemakers. The aim was to determine if cardiac resynchronization therapy (CRT) at the time of pulse generator replacement (PGR) is of benefit in patients with unavoidable RV pacing and LVSD. METHODS AND RESULTS: Fifty patients with unavoidable RV pacing, LVSD, and mild or no symptoms of heart failure, listed for PGR were randomized 1 : 1 to either standard RV-PGR (comparator) or CRT. The primary endpoint was the difference in change in LV ejection fraction (LVEF) between RV-PGR and CRT groups from baseline to 6 months. Secondary endpoints included peak oxygen consumption, quality of life, and N terminal pro-B-type natriuretic peptide (NT-proBNP) levels. At 6 months there was a difference in change in median (interquartile range) LVEF [9 (6-12) vs. -1.5 ( 4.5 to -0.8)%; P < 0.0001] between the CRT and RV-PGR arms. There were also improvements in exercise capacity (P = 0.007), quality of life (P = 0.03), and NT proBNP (P = 0.007) in those randomized to CRT. After 809 (729-880) days, 17 patients had died or been hospitalized (6 in CRT group and 11 in the comparator RV-PGR group) and two patients in the RV-PGR arm had required CRT for deteriorating heart failure. Patients with standard RV-PGR had more days in hospital during follow-up than those in the CRT group [4 (2-7) vs. 11 (6-16) days; P = 0.047]. CONCLUSION: Performing CRT in pacemaker patients with unavoidable RV pacing and LVSD but without severe symptoms of heart failure, at the time of PGR, improves cardiac function, exercise capacity, quality of life, and NT-pro-BNP levels. PMID- 23736808 TI - Extremely abnormal location of the coronary sinus ostium. PMID- 23736809 TI - Time-dependent effect of cardiac resynchronization therapy on ventricular repolarization and ventricular arrhythmias. AB - AIMS: Cardiac resynchronization therapy (CRT) improves the clinical status of patients with congestive heart failure, although left ventricular epicardial pacing may increase transmural dispersion of repolarization (TDR). The aim of this study was to investigate the time-dependent effect of CRT on ventricular repolarization and ventricular arrhythmia at mid-term follow-up. METHODS AND RESULTS: The study group consisted of 84 patients treated with CRT. Twelve-lead electrocardiogram was digitally recorded and Tpeak-to-Tend interval (Tp-e) was measured at baseline, 1 week, 1 month, and 3, 6, and 12 months after device implantation. We determined the time-dependent changes in Tp-e, ventricular tachycardia and ventricular fibrillation (VT/VF) during 12 months of follow-up, in both CRT responders and non-responders. Seventeen of 84 patients (20%) had VT/VF during first year. Six of those 17 patients (35%) experienced VT/VF within 1 month of implantation and diminished over time. Tp-e decreased significantly at 6 and 12 months after implantation compared with 1 week [108 +/- 14 ms at 1 week vs. 97 +/- 21 ms at 6 months (P = 0.03) and 95 +/- 19 ms at 12 months (P = 0.01)]. Responders demonstrated a greater time-dependent reduction of Tp-e at 6 and 12 months of CRT and had a lower rate of VT/VF compared with non-responders (log-rank test, P = 0.004). CONCLUSION: Transmural dispersion of repolarization and the number of patients with VT/VF decreased over time after CRT. Patients with reverse remodelling demonstrated a lower rate of VT/VF and a greater time dependent reduction of TDR. PMID- 23736810 TI - A preliminary investigation of depression and kidney functioning in patients with chronic kidney disease. AB - BACKGROUND: The incidence and prevalence of Chronic Kidney Disease (CKD) is growing rapidly. Understanding the factors associated with declining renal function is of clinical significance. The current study's main goal was to identify variables that could predict decline in glomerular filtration rate (GFR) over time in outpatients with varying stages of CKD. METHODS: Seventy CKD patients completed psychological questionnaires and medical variables were extracted from the medical charts. Follow-up GFR was collected 6 months later. CKD patients with elevated depression scores were compared to patients with subclinical depression on medical and psychological variables. RESULTS: Average Beck Depression Inventory (BDI) score was 10.0 +/- 7.8, placing the mean below the cut-off for clinical elevation. GFR was significantly different for the two groups (nondepressed, 40.0 +/- 11.3 vs. depressed 29.6 +/- 8.9; p < 0.05). Similarly, patients with elevated depression scores reported lower quality of life (Short Form 36 Health Survey; p < 0.05) inferior social support (Interpersonal Support Evaluation List; p < 0.05), and worse community integration (Community Integration Questionnaire; p < 0.05). Utilizing a regression, with a model correcting for baseline GFR, the BDI explained 19% of the variance in GFR score (t = -2.0, p < 0.05) for subjects with decreased GFR. CONCLUSIONS: Increased levels of preexisting depression were associated with inferior quality of life, social support and kidney functioning. Depression scores explained a significant amount of variance in GFR scores at 6 months even when corrected for baseline variability. Elevated depression scores are prevalent in CKD populations and further research on the impact of depression interventions is warranted. PMID- 23736811 TI - Effect of systemic lipopolysaccharide-induced inflammation on cytokine levels in the murine cochlea: a pilot study. AB - The objective was to detect changes in cytokine expression within cochleae in a murine model of systemic inflammation, with or without aminoglycoside exposure. Four groups of mice received 1 of the following: saline only, systemic bacterial lipopolysaccharides (LPS) for 6 hours to induce endotoxemia and inflammatory responses, systemic gentamicin for 3 hours, or both treatments. After exsanguination, pooled cochleae (4/group) were processed for enzyme-linked immunosorbent assay (ELISA) for 16 cytokines. Gentamicin alone did not change cochlear cytokine levels, while LPS (+/- gentamicin) substantially elevated cochlear expression of several cytokines, particularly interleukin-1alpha, interleukin-6, monocyte chemotactic protein-1, macrophage inflammatory protein 1alpha, and RANTES. Since cytokines increase blood-brain barrier permeability, we hypothesize that cytokine-enhanced permeability of the blood-labyrinth barrier (BLB) could potentiate aminoglycoside-induced ototoxicity. This pilot study demonstrated the feasibility of detecting cytokine expression in murine cochleae using ELISA and facilitates future studies investigating BLB permeability in animal models of systemic inflammation. PMID- 23736813 TI - Effects on diversity of soil fungal community and fate of an artificially applied Beauveria bassiana strain assessed through 454 pyrosequencing. AB - The entomopathogenic fungus Beauveria bassiana is widely used as a biological control agent (BCA) for insect pest control, with fungal propagules being either incorporated into the potting media or soil or sprayed directly onto the foliage or soil. To gain a better understanding of entomopathogenic fungal ecology when applied as a BCA to the soil environment, a case study using tag-encoded 454 pyrosequencing of fungal ITS sequences was performed to assess the fate and potential effect of an artificially applied B. bassiana strain on the diversity of soil fungal communities in an agricultural field in India. Results show that the overall fungal diversity was not influenced by application of B. bassiana during the 7 weeks of investigation. Strain-specific microsatellite markers indicated both an establishment of the applied B. bassiana strain in the treated plot and its spread to the neighboring nontreated control plot. These results might be important for proper risk assessment of entomopathogenic fungi-based BCAs. PMID- 23736814 TI - Recent clinical trials evaluating benefit of drug therapy for modification of HDL cholesterol. AB - PURPOSE OF REVIEW: To highlight the recent data evaluating pharmacological manipulation of HDL cholesterol (HDL-C) and examine whether medication-induced changes were associated with improved clinical outcomes and reduced short-term and long-term cardiovascular risks. The review focuses on the studies with niacin and the new cholesteryl ester transfer protein (CETP) inhibitors torcetrapib, dalcetrapib, anacetrapib and evacetrapib. RECENT FINDINGS: Several large randomized clinical trials have evaluated drug therapy on HDL-C and cardiovascular outcomes. Two studies have evaluated the clinical outcomes following HDL-C raising with niacin. Data from the Heart Protection 2 Treatment of HDL to Reduce the Incidence of Vascular Events and The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health trials both demonstrated no clinical benefit from use of niacin therapy when added to background statin therapy with regard to short-term and long-term cardiovascular risk reduction. Both studies demonstrated excess side effects from use of niacin. A number of clinical trials have evaluated HDL-C modification from use of a CETP inhibitor. All of the studies have demonstrated significant increases in HDL-C. To date, the outcome data are not favorable. Use of torcetrapib was associated with excess mortality. Use of dalcetrapib had no effect on short-term and long-term cardiovascular events. Two outcome studies with anacetrapib and evacetrapib are ongoing and will report out in a few years' time. SUMMARY: Pharmacological manipulation of HDL-C has not improved the cardiovascular outcomes. Several agents have caused harm or unacceptable side effects. Further studies are needed before one can recommend the use of additional lipid-modifying therapies beyond statins. PMID- 23736812 TI - Epigenetic modulation of signal transduction pathways in HPV-associated HNSCC. AB - OBJECTIVE: Human papilloma virus (HPV) positive and HPV negative head and neck squamous cell cancer (HNSCC) are biologically distinct with a prognostic advantage for HPV positive patients compared to HPV negative cases. DNA promoter methylation is central to human diseases such as cancer, including HNSCC, with reported genome-wide hypomethylaton and promoter hypermethylation in HPV positive HNSCC tumors. The goal of this study was to identify differentially methylated genes in HPV positive versus HPV negative primary HNSCC genomes with clues to signaling networks. STUDY DESIGN: Laboratory-based study. SETTING: Primary care academic health care system. SUBJECTS AND METHODS: DNA from 4 HPV positive and 4 HPV negative freshly frozen primary HNSCC were subject to comprehensive genome wide methylation profiling. Differentially methylated gene lists were examined using the Signal Transduction Pathways (canonical) filter in the Genomatix Pathway System (GePS). RESULTS: Twofold methylation differences were observed between HPV positive and HPV negative cases for 1168 genes. Pathway analysis applied to investigate the biological role of the 1168 differentially methylated genes revealed 8 signal transduction pathways forming a network of 66 genes, of which 62% are hypermethylated. CONCLUSION: Our study reveals a predominant hypermethylation profile for genes in signal transduction pathways of HPV positive HNSCC tumor genomes. Because signaling events in the cell play a critical role in the execution of key biological functions, insights into how complex cellular signaling cascades and networks may be programmed in HNSCC are likely to be critical in the development of new biological agents designed to hit multiple targets. PMID- 23736815 TI - Ovarian hormones and vascular disease. AB - PURPOSE OF REVIEW: Observational studies have shown benefit of hormone therapy, particularly estrogen, in women who begin treatment in the perimenopausal/early postmenopausal period, whereas randomized controlled trials of such therapy in older postmenopausal women have reported harm. These apparently paradoxical findings have led to the 'timing hypothesis' which proposes that estrogen signaling is altered in older women, converting vasoprotective to vasotoxic effects. We reviewed recent literature on age-dependent effects of hormones (particularly estrogen) on the vasculature of women and the fundamental cellular/molecular mechanisms responsible for those effects. RECENT FINDINGS: Observational studies have shown that early menopause is associated with adverse cardiovascular disease outcomes and that starting hormone therapy in the perimenopausal period reduces these outcomes. Mechanistic studies have shown that estrogen modulates injury-induced inflammation, growth factor expression, and oxidative stress in arteries and vascular smooth muscle cells isolated from young women but that these vasoprotective mechanisms are lost in women who are aged and/or deprived of estrogen for prolonged periods of time. SUMMARY: The vasoprotective effects of estrogen are age-dependent and disappear with aging and/or estrogen deprivation. Future studies designed to preserve the vasoprotective effects of estrogen in older women are needed and may lead to innovative approaches to improving women's cardiovascular health. PMID- 23736816 TI - Is chlorthalidone better than hydrochlorothiazide in reducing cardiovascular events in hypertensives? AB - PURPOSE OF REVIEW: Hydrochlorthiazide (HCTZ) is the tenth most commonly prescribed drug in recent data. Although no head-to-head trials compare HCTZ with the uncommonly prescribed chlorthalidone (CTDN) in reducing cardiovascular events (CVEs), numerous other data are available. RECENT FINDINGS: Head-to-head trials have shown CTDN's superiority in antihypertensive potency, particularly during the critical nighttime period (SBP difference 7.1 mmHg), due to the differences in duration of action (16-24 h for HCTZ versus 48-72 h for CTDN). In an observational cohort study, compared with HCTZ, CTDN was associated with lower left ventricular hypertrophy. In another observational cohort analysis (n = 12,866), the percentage risk reduction in CVEs from CTDN versus HCTZ was 21 [95% confidence interval (CI) 8-32], P = 0.002. In network meta-analyses of randomized trials (n = 50,946), CTDN was superior to HCTZ in reducing congestive heart failure and in reducing all CVEs: percentage risk reduction 21 (95% CI 12-28), P < 0.0001. A statistically significant reduction in CVEs by CTDN versus HCTZ persisted even when reduction in office SBP produced by the two diuretics was identical, further strengthening the case for CTDN. SUMMARY: Direct and indirect evidence demonstrates that CTDN is superior to HCTZ in reducing CVEs and is congruent with the recent changes in the guidelines for hypertension management. PMID- 23736817 TI - Serum urate: a biomarker or treatment target in pediatric hypertension? AB - PURPOSE OF REVIEW: Studies have shown an association between hyperuricemia and essential hypertension in children, presenting the possibility for serum uric acid level to serve as a biomarker for diagnosis and potential treatment target. RECENT FINDINGS: The proposed mechanism of uric acid-induced hypertension is biphasic, with a reversible early phase, implying added significance for new onset hypertension. Current evidence shows a strong correlation between uric acid level and essential hypertension, supporting its use in diagnosis. Small studies have shown that the use of uric acid-lowering agents allopurinol and probenecid can lower blood pressure in adolescents. These medications require further study in large populations and careful consideration of their side-effect profiles prior to clinical use as antihypertensive agents. Recent studies have also linked dietary fructose intake to hyperuricemia and hypertension, but the clinical effect of fructose reduction on blood pressure has not been confirmed. SUMMARY: Current evidence supports use of serum uric acid level as a biomarker for diagnosis of essential hypertension in children. More research is needed to evaluate the utility of pharmacologic and nonpharmacologic means of serum uric acid reduction prior to clinical use as a therapy for hypertension. PMID- 23736818 TI - What should be the blood pressure target for patients with chronic kidney disease? AB - PURPOSE OF REVIEW: Persons with chronic kidney disease (CKD) exhibit a disproportionate burden of elevated blood pressure (BP) with a high prevalence of premature end-stage renal disease and cardiovascular events. RECENT FINDINGS: Results of recent randomized controlled clinical trials suggest that most patients with reduced estimated glomerular filtration rate (eGFR) and hypertension experience optimal clinical outcomes when SBP is less than 140 mmHg and DBP is less than 90 mmHg. The benefit of additional lowering of SBP to less than 130 mmHg and DBP to less than 80 mmHg remains controversial, and appears to be of most benefit to the subset of CKD patients with proteinuria (>300 mg/day). The combination of a diuretic and an angiotensin receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI) has demonstrated particular promise in patients with reduced eGFR and proteinuria. SUMMARY: A practical approach in clinical practice for the treatment of elevated BP in persons with CKD is to achieve a BP less than 140/90 mmHg with a combination of diuretic and an ARB or ACEI. Consideration for a lower BP goal and other therapeutic and nontherapeutic interventions can be made based on the cause of CKD, presence of proteinuria, or other coexisting medical conditions. PMID- 23736819 TI - New therapies to reduce low-density lipoprotein cholesterol. AB - PURPOSE OF REVIEW: Lipid-lowering is an intervention that reduces atherosclerosis and its complications. Statins currently form the standard of care but are not able to reduce low-density lipoprotein cholesterol (LDL-C) adequately in all patients - particularly those with familial hypercholesterolaemia and those with statin intolerance. RECENT FINDINGS: Combination therapy with statins is well established and ezetimibe is often used as an additional LDL-C-lowering agent reducing LDL-C by 20%. However, its clinical efficacy still remains controversial. Newer, more potent methods of LDL-C reduction are in development. Both lomitapide, a microsomal transfer protein inhibitor (MTPI), and mipomersen, an antisense oligonucleotide (ASO), have been shown to improve LDL-C levels by 25 50% in patients with homozygous familial hypercholesterolaemia. In patients with heterozygous familial hypercholesterolaemia or statin intolerance antibody-based inhibitors of preprotein convertase subtilisin/kexin 9 (PCSK9) produce reductions in LDL-C of 30-65%. Cholesterol ester transfer protein inhibitors (CETPIs) reduce LDL-C by 30-40% as well as raising levels of high-density lipoprotein cholesterol (HDL-C) and may also have a role as additional LDL-C-reducing drugs. SUMMARY: Surrogate outcome trials will be required with lomitapide or mipomersen to confirm their effects in homozygous familial hypercholesterolaemia and clinical endpoint trials will be needed for PCSK9 and CETPIs if these are to be used widely. PMID- 23736821 TI - Current world literature. PMID- 23736820 TI - High-density lipoprotein cholesterol raising: does it matter? AB - PURPOSE OF REVIEW: Cardiovascular disease (CVD) is the leading cause of morbidity and premature mortality in Europe and the United States, and is increasingly common in developing countries. High-density lipoprotein cholesterol (HDL-C) is an independent risk factor for CVD and is superior to low-density lipoprotein cholesterol (LDL-C) as a predictor of cardiovascular events. The residual risk conferred by low HDL-C in patients with a satisfactory LDL-C was recently highlighted by the European Atherosclerosis Society. Despite the lack of randomized controlled trials, it has been suggested that raising the level of HDL C should be considered as a therapeutic strategy in high-risk patients because of the strong epidemiological evidence, compelling biological plausibility, and both experimental and clinical research supporting its cardioprotective effects. RECENT FINDINGS: Three recent large randomized clinical trials investigating the effect of HDL-C raising with niacin and dalcetrapib in statin-treated patients failed to demonstrate an improvement in cardiovascular outcomes. SUMMARY: There is evidence to support the view that HDL functionality and the mechanism by which a therapeutic agent raises HDL-C are more important than plasma HDL-C levels. Future therapeutic agents will be required to improve this functionality rather than simply raising the cholesterol cargo. PMID- 23736823 TI - Atrial natriuretic peptide reduces hepatic ischemia-reperfusion injury in rabbits. AB - PURPOSE: Atrial natriuretic peptide (ANP) has been known to be protective against hepatic ischemia/reperfusion injury. The purpose of this study was to verify the hypothesis that ANP conserves microvascular circulation and reduces ischemia reperfusion injury in the in vivo rabbit model. METHODS: With IRB approval, 30 male Japanese white rabbits under pentobarbital anesthesia were studied. These animals were randomly assigned to the following three groups (n = 10 each): control, ANP, and sham group. Animals in the ANP group received continuous infusion of ANP at 0.1 MUg/kg/min throughout the study period. Animals in control and ANP groups underwent 90 min of partial hepatic ischemia by clamping the right hepatic artery and portal vein. Descending aortic blood flow (AoF) was monitored with a transit-time ultrasound flowmeter. Hepatic tissue microvascular blood flow (HTBF) at both right (ischemic) and left (nonischemic) lobe was intermittently evaluated with the hydrogen clearance method. After 180 min of reperfusion, hepatic injury was determined with serum AST and ALT. Galactose clearance of reperfused right lobe was also measured as an indicator of hepatic metabolic function. Histopathological change and the number of apoptotic hepatocytes were also evaluated. RESULTS: Systemic hemodynamic data including mean arterial pressure, heart rate, and AoF did not differ among the three groups during the study period. ANP attenuated ischemia-induced right HTBF decrease. ANP also suppressed histopathological degeneration, apoptosis, and decline in galactose clearance after reperfusion. CONCLUSIONS: ANP attenuated hepatic microvascular dysfunction and hepatocyte injury after reperfusion without significant hemodynamic change. PMID- 23736824 TI - Postoperative analgesia after modified radical mastectomy: the efficacy of interscalene brachial plexus block. AB - PURPOSE: In the present study, we evaluated the effects of interscalene brachial plexus block on postoperative pain relief and morphine consumption after modified radical mastectomy (MRM). METHODS: Sixty ASA I-III patients scheduled for elective unilateral MRM under general anesthesia were included. They were randomly allocated into two groups: group 1 (n = 30), single-injection ipsilateral interscalene brachial plexus block; group 2 (n = 30), control group. Postoperative analgesia was provided with IV PCA morphine during 24 h postoperatively. Pain intensity was assessed with the visual analogue scale (VAS). Morphine consumption, side effects of opioid, antiemetic requirement, and complications associated with interscalene block were recorded. RESULTS: VAS scores were significantly lower in group 1, except in the first postoperative 24 h (p < 0.007). The patients without block consumed more morphine [group 1, 5 (0 40) mg; group 2, 22 (6-48) mg; p = 0.001]. Rescue morphine requirements were also higher in the postoperative first hour in group 2 (p = 0.001). Nausea and antiemetic requirements were significantly higher in group 2 (p = 0.03 and 0.018). Urinary retention was observed in 1 patient in group 2 and signs of Horner's syndrome in 2 patients in group 1. CONCLUSIONS: The optimal method has not been defined yet for acute pain palliation after MRM. Our study demonstrated that the use of interscalene block in patients undergoing MRM improved pain scores and reduced morphine consumption during the first 24 h postoperatively. The block can be a good alternative to other invasive regional block techniques used for postoperative pain management after MRM. PMID- 23736825 TI - Computed tomography for planning transcatheter aortic valve replacement. AB - Transcatheter aortic valve replacement (TAVR) is rapidly becoming a widely used alternative to surgical aortic valve replacement (SAVR) in patients with severe aortic stenosis at high surgical risk. In these patients, TAVR has been associated with markedly improved survival and relief from symptoms. Despite a very-high risk patient profile, recent multicenter registries have confirmed the safety and efficacy of this procedure. Moreover, the randomized, controlled PARTNER (Placement of AoRTic TraNscathetER Valves) trial has confirmed both the superiority of TAVR over medical treatment in patients not considered to be candidates for standard SAVR and the noninferiority of TAVR compared with SAVR in high-risk patients. The TAVR procedure requires a comprehensive preinterventional diagnostic workup. Above all, detailed information on the anatomy of the aortic annulus (AA) and the relation of the AA to the coronary arteries is essential to avoid complications. So far, no imaging reference standard for AA sizing has been established. Echocardiography, catheter angiography, and computed tomography angiography are widely and often complementarily used imaging techniques for this purpose. Compared with 2-dimensional imaging techniques, computed tomography (CT) has been proven to provide comprehensive information on AA anatomy and geometry, supporting appropriate patient selection and prosthesis sizing. In addition, CT is gaining an increasing role in evaluating the vascular access route before the procedure. This article describes the rapidly emerging role of CT in the context of pre-TAVR assessment. PMID- 23736826 TI - Peculiarities of enhancing resistant starch in ruminants using chemical methods: opportunities and challenges. AB - High-producing ruminants are fed high amounts of cereal grains, at the expense of dietary fiber, to meet their high energy demands. Grains consist mainly of starch, which is easily degraded in the rumen by microbial glycosidases, providing energy for rapid growth of rumen microbes and short-chain fatty acids (SCFA) as the main energy source for the host. Yet, low dietary fiber contents and the rapid accumulation of SCFA lead to rumen disorders in cattle. The chemical processing of grains has become increasingly important to confer their starch resistances against rumen microbial glycosidases, hence generating ruminally resistant starch (RRS). In ruminants, unlike monogastric species, the strategy of enhancing resistant starch is useful, not only in lowering the amount of carbohydrate substrates available for digestion in the upper gut sections, but also in enhancing the net hepatic glucose supply, which can be utilized by the host more efficiently than the hepatic gluconeogenesis of SCFA. The use of chemical methods to enhance the RRS of grains and the feeding of RRS face challenges in the practice; therefore, the present article attempts to summarize the most important achievements in the chemical processing methods used to generate RRS, and review advantages and challenges of feeding RRS to ruminants. PMID- 23736828 TI - Benzyne cycloaddition onto carbon nanohorns. AB - A facile approach for the covalent functionalization of carbon nanohorns (CNHs) based on the benzyne cycloaddition reaction is presented. The benzynes were in situ generated from either anthranilic acid by decomposition of the internal benzenediazonium-2-carboxylate or from 2-(trimethylsilyl)-phenyl triflate by fluoride ion attack at the silicon atom followed by displacement of the trimethylsilyl group under mild conditions. Moreover, the functionalization reaction was tested and performed under conventional conditions as well as under microwave irradiation. Modified CNHs possessing fused rings onto their graphitic skeleton were fully characterized by means of complementary spectroscopic techniques, thermogravimetric analysis, electron microscopy and light scattering. Moreover, Sonogashira coupling with propargyl alcohol followed by condensation with thioctic acid, to the iodo-modified CNHs obtained from the cycloaddition reaction of 2-amino-5-iodobenzoic acid with CNHs, resulted in the preparation of a new CNH-based material in which endocyclic disulfides are extended from the fused rings onto CNHs. The latter moieties were used to immobilize gold nanoparticles, furnishing the CNH-Au(nano) hybrid material, in which the former were identified with the aid of UV-Vis and EDX spectroscopy. PMID- 23736827 TI - Observation of human retinal remodeling in octogenarians with a resveratrol based nutritional supplement. AB - PURPOSE: Rare spontaneous remissions from age-related macular degeneration (AMD) suggest the human retina has large regenerative capacity, even in advanced age. We present examples of robust improvement of retinal structure and function using an OTC oral resveratrol (RV) based nutritional supplement called Longevinex(r) or L/RV (circa 2004, Resveratrol Partners, LLC, Las Vegas, NV, USA). RV, a polyphenolic phytoalexin caloric-restriction mimic, induces hormesis at low doses with widespread beneficial effects on systemic health. RV alone inhibits neovascularization in the murine retina. Thus far, published evidence includes L/RV mitigation of experimentally induced murine cardiovascular reperfusion injury, amelioration of human atherosclerosis serum biomarkers in a human Japanese randomized placebo controlled trial, modulation of micro RNA 20b and 539 that control hypoxia-inducing-factor (HIF-1) and vascular endothelial growth factor (VEGF) genes in the murine heart (RV inhibited micro RNA20b 189-fold, L/RV 1366-fold). Little is known about the effects of L/RV on human ocular pathology. METHODS: Absent FDA IRB approval, but with permission from our Chief of Staff and medical center IRB, L/RV is reserved for AMD patients, on a case-by-case compassionate care basis. Patients include those who progress on AREDS II type supplements, refuse intra-vitreal anti-VEGF injections or fail to respond to Lucentis(r), Avastin(r) or Eylea(r). Patients are clinically followed traditionally as well as with multi-spectral retinal imaging, visual acuity, contrast sensitivity, cone glare recovery and macular visual fields. Three cases are presented. RESULTS: Observed dramatic short-term anti-VEGF type effect including anatomic restoration of retinal structure with a suggestion of improvement in choroidal blood flow by near IR multispectral imaging. The visual function improvement mirrors the effect seen anatomically. The effect is bilateral with the added benefit of better RPE function. Effects have lasted for one year or longer when taken daily, at which point one patient required initiation of anti-VEGF agents. Unanticipated systemic benefits were observed. CONCLUSIONS: Preliminary observations support previous publications in animals and humans. Restoration of structure and visual function in octogenarians with daily oral consumption of L/RV is documented. Applications include failure on AREDS II supplements, refusing or failing conventional anti-VEGF therapy, adjunct therapy to improve RPE function, and compassionate use in medically underserved or economically depressed third-world countries. PMID- 23736829 TI - Association of Helicobacter pylori positivity with the symptoms in patients with hyperemesis gravidarum. AB - PURPOSE: To investigate the relationship between Helicobacter pylori (Hp) positivity and the severity of symptoms of nausea and vomiting in patients diagnosed with hyperemesis gravidarum (HG). DESIGN: Prospective controlled. METHODS: Ninety patients with the diagnosis of HG below the 20th week gestation, who had no additional disease and 50 pregnant women with no complaints were enrolled in the study. According to the severity of symptoms, the patients were divided into three groups as group I, II and III (mild, moderate and severe, respectively). The Rhode's scoring system was used to determine the severity of HG symptoms. HpIgG and IgM levels were determined in the blood samples and Hp DNA positivity with PCR was investigated in the saliva. RESULTS: In accordance with the Rhode's scoring system, 15.5 % of the pregnant women had mild, 58.9 % had moderate, and 25.6 % had severe symptoms (group I, II and III, respectively). HpIgG was determined as positive in 78.6, 84.9 and 82.6 % in groups I, II and III, respectively. HpIgM positivity was determined as 26.1 % only in group III (p = 0.847). HpDNA was determined as 7.2, 3.8, and 91.3 % in group I, II, and III, respectively (p<0.01). While HpIgG was positive in 60 %, HpDNA was found to be positive in 2 % and HpIgM was found to be negative in all the pregnant women in the control group. CONCLUSION: A positive relationship between the symptoms of HG and Hp positivity was determined using PCR. PMID- 23736830 TI - Message from new Editor-in-Chief--Prof. Olaf Ortmann. PMID- 23736831 TI - Increased serotonin receptor 1A binding in major depressive disorder after psychotherapy, but not after SSRI pharmacotherapy, is related to improved social functioning capacity. PMID- 23736832 TI - Hospital Survey on Patient Safety Culture in Slovenia: a psychometric evaluation. AB - OBJECTIVE: To study the psychometric properties of a translated version of the Agency for Healthcare Research and Quality Hospital Survey on Patient Safety Culture (HSOPSC) in the Slovenian setting. DESIGN: A cross-sectional psychometric study including principal component and confirmatory factor analysis. The percentage of positive responses for the 12 dimensions (42 items) of patient safety culture and differences at unit and hospital-level were calculated. SETTING: Three acute general hospitals. PARTICIPANTS: Census of clinical and non clinical staff (n = 976). MAIN OUTCOME MEASURES: Model fit, internal consistency and scale score correlations. RESULTS: Principal component analysis showed a 9 factor model with 39 items would be appropriate for a Slovene sample, but a Satorra-Bentler scaled chi(2) difference test demonstrated that the 12-factor model fitted Slovene data significantly better. Internal consistency was found to be at an acceptable level. Most of the relationships between patient safety culture dimensions were strong to moderate. The relationship between all 12 dimensions and the patient safety grade was negative. The unit-level dimensions of patient safety were perceived better than the dimensions at the hospital level. CONCLUSION: The original 12-factor model for the HSOPSC was a good fit for a translated version of the instrument for use in the Slovene setting. PMID- 23736833 TI - Quality of gastric cancer care in designated cancer care hospitals in Japan. AB - OBJECTIVE: To develop a set of process-of-care quality indicators (QIs) that would cover a wide range of gastric cancer care modalities and to examine the current state of the quality of care provided by designated cancer care hospitals in Japan. DESIGN: A retrospective medical record review. SETTING: Eighteen designated cancer care hospitals throughout Japan. PARTICIPANTS: A total of 1685 patients diagnosed with gastric cancer in 2007. MAIN OUTCOME MEASURES: Provision of care to eligible patients as described in the 29 QIs, which were developed using an adaptation of the RAND/UCLA (University of California, Los Angeles) appropriateness method by a panel of nationally recognized experts in Japan. RESULTS: Overall, the patients received 68.3% of the care processes recommended by the QIs. While 'deep venous thrombosis prophylaxis before major surgery' was performed for 99% of the cases, 'documentation before endoscopic resection' was completed for only 12% of the cases. The chemotherapy care was less likely to meet the QI standards (61%) than pre-therapeutic care (76%), surgical treatment (66%) and endoscopic resection (71%; overall difference: P < 0.001). A comparison based on the types of care showed that documentation and patient explanation were performed less frequently (60 and 53%, respectively) than were diagnostic and therapeutic processes as recommended in the QIs (85%; overall P < 0.001). CONCLUSIONS: Although many required care processes were provided, some areas with room for improvement were revealed, especially with respect to chemotherapy, documentation and patient explanation. Continuous efforts to improve the quality and develop a system to monitor this progress would be beneficial in Japan. PMID- 23736835 TI - RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy. PMID- 23736834 TI - Utilization of non-US educated nurses in US hospitals: implications for hospital mortality. AB - OBJECTIVE: To determine whether, and under what circumstance, US hospital employment of non-US-educated nurses is associated with patient outcomes. DESIGN: Observational study of primary data from 2006 to 2007 surveys of hospital nurses in four states (California, Florida, New Jersey and Pennsylvania). The direct and interacting effects of hospital nurse staffing and the percentage of non-US educated nurses on 30-day surgical patient mortality and failure-to-rescue were estimated before and after controlling for patient and hospital characteristics. PARTICIPANTS: Data from registered nurse respondents practicing in 665 hospitals were pooled with patient discharge data from state agencies. MAIN OUTCOMES MEASURE(S): Thirty-day surgical patient mortality and failure-to-rescue. RESULTS: The effect of non-US-educated nurses on both mortality and failure-to-rescue is nil in hospitals with lower than average patient to nurse ratios, but pronounced in hospitals with average and poor nurse to patient ratios. In hospitals in which patient-to-nurse ratios are 5:1 or higher, mortality is higher when 25% or more nurses are educated outside of the USA than when <25% of nurses are non-US educated. Moreover, the effect of having >25% non-US-educated nurses becomes increasingly deleterious as patient-to-nurse ratios increase beyond 5:1. CONCLUSIONS: Employing non-US-educated nurses has a negative impact on patient mortality except where patient-to-nurse ratios are lower than average. Thus, US hospitals should give priority to achieving adequate nurse staffing levels, and be wary of hiring large percentages of non-US-educated nurses unless patient-to nurse ratios are low. PMID- 23736836 TI - Hybrid charge transfer complexes based on archaeal glycolipids wrapping single walled carbon nanotubes. AB - SWNTs have been functionalized with an archaeal glycolipid which wraps around the nano-objects in a single layer or bilayer, as a function of the nanotube diameter. Hydrogen bonds between the lipid glucose rings and the aromatic SWNT walls are involved in the formation of hybrid complexes resulting in electron transfer from the glycolipid to the nanotubes. PMID- 23736837 TI - Visualization of rodent brain tumor angiogenesis and effects of antiangiogenic treatment using 3D DeltaR2-MUMRA. AB - Understanding of structural and functional characteristics of the vascular microenvironment in gliomas and the impact of antiangiogenic treatments is essential for developing better therapeutic strategies. Although a number of methods exist in which this process can be studied experimentally, no single noninvasive test has the capacity to provide information concerning both microvascular function and morphology. The purpose of present study is to demonstrate the feasibility of using a novel three-dimensional DeltaR2-based microscopic magnetic resonance angiography (3D DeltaR2-MUMRA) technique for longitudinal imaging of tumor angiogenesis and monitoring the effects of antiangiogenic treatment in rodent brain tumor models. Using 3D DeltaR2-MUMRA, a generally consistent early pattern of vascular development in gliomas was revealed, in which a single feeding vessel was visualized first (arteriogenesis), followed by sprouting angiogenesis. Considerable variability of the tumor associated vasculature was then noted at later stages of tumor evolution. DeltaR2 MUMRA revealed that anti-vascular endothelial growth factor treatment induced a rapid and significant alteration of the intratumoral angiogenic phenotype. In summary, 3D DeltaR2-MUMRA enables high-resolution visualization of tumor associated vessels while simultaneously providing functional information on the tumor microvasculature. It can serve as a useful tool for monitoring both the temporal evolution of tumor angiogenesis and the impact of antiangiogenic therapies. PMID- 23736838 TI - Highly sensitive and selective gas sensor using hydrophilic and hydrophobic graphenes. AB - New hydrophilic 2D graphene oxide (GO) nanosheets with various oxygen functional groups were employed to maintain high sensitivity in highly unfavorable environments (extremely high humidity, strong acidic or basic). Novel one-headed polymer optical fiber sensor arrays using hydrophilic GO and hydrophobic reduced graphene oxide (rGO) were carefully designed, leading to the selective sensing of volatile organic gases for the first time. The two physically different surfaces of GO and rGO could provide the sensing ability to distinguish between tetrahydrofuran (THF) and dichloromethane (MC), respectively, which is the most challenging issue in the area of gas sensors. The eco-friendly physical properties of GO allowed for faster sensing and higher sensitivity when compared to previous results for rGO even under extreme environments of over 90% humidity, making it the best choice for an environmentally friendly gas sensor. PMID- 23736839 TI - New insights in regulation of calcium homeostasis. AB - PURPOSE OF REVIEW: Regulation of calcium homeostasis during a lifetime is a complex process reflecting a balance among intestinal calcium absorption, bone calcium influx and efflux, and renal calcium excretion. Perturbations can result in hypocalcemia or hypercalcemia and adaptations in calcium handling must occur during growth and aging. RECENT FINDINGS: Study of the calcium sensing receptor in the thick ascending limb of Henle and TRPV5 in the distal tubule continues to provide insights into regulation of renal calcium excretion. Hypercalcemia induced secretion of calcitonin via activation of the calcium-sensing receptor may protect against the development of hypercalcemia. A calcilytic was shown to increase serum calcium by decreasing renal calcium excretion. Ezrin, a cross linking protein important for renal phosphate handling, is also involved in the regulation of intestinal calcium absorption. Increased 1,25-hydroxyvitamin D (1,25D) values were shown to protect against the development of hypocalcemia by increasing calcium efflux and decreasing calcium influx in bone. Finally, fibroblast growth factor 23 stimulation, which should result in suppression of 1,25D, was shown to be prevented in a model of vitamin D deficiency in which maintenance of 1,25D is important in minimizing hypocalcemia. SUMMARY: Recent information has provided new insights on how intestinal, bone and renal mechanisms are regulated to maintain calcium homeostasis. PMID- 23736840 TI - Nephrolithiasis and loss of kidney function. AB - PURPOSE OF REVIEW: The prevalence of nephrolithiasis has been on the rise over recent decades. There have also been extensive efforts to identify risk factors for chronic kidney disease (CKD). The purpose of this review is to highlight recent evidence on the association of nephrolithiasis with the development of CKD and end-stage renal disease (ESRD). RECENT FINDINGS: Several epidemiologic studies over the past decade assessed the relationship between history of nephrolithiasis and CKD. Across several studies, patients with nephrolithiasis had about a two-fold higher risk for decreased renal function or need for renal replacement therapy. This risk appears to be independent of risk factors for CKD that are common in stone formers such as hypertension and diabetes mellitus. Specific risk factors for CKD in stone formers include recurrent urinary tract infections, struvite and possibly uric acid stone composition, symptomatic stones, solitary kidney, ileal conduit, neurogenic bladder, and hydronephrosis. SUMMARY: Recent evidence has shown a consistent relationship between nephrolithiasis history and an increased risk of CKD and ESRD. Understanding the characteristics that predispose to CKD may better inform how to optimally manage patients with nephrolithiasis and prevent this complication. PMID- 23736841 TI - Use of phosphate binders in chronic kidney disease. AB - PURPOSE OF REVIEW: Hyperphosphatemia is a paradigmatic finding in late-stage chronic kidney disease (CKD) and consistently associated with adverse outcomes. Preclinical and epidemiological studies strongly support a causative role of hyperphosphatemia for cardiovascular complications, especially with regard to vascular, valvular and soft-tissue calcifications, and for subsequent mortality. Therefore, phosphate management is thought to play a pivotal role in health and longevity of CKD patients. In this regard, phosphate binders are considered the prime option; however, dietary phosphate restriction and intensified dialysis are also valuable supportive tools. RECENT FINDINGS: Studies on available calcium free phosphate binders demonstrate potential to interfere with phosphate regulatory factors, such as fibroblast growth factor-23 (FGF23). Magnesium containing phosphate binding may possess a pleiotropic potential due to its calcification inhibitory properties. Novel phosphate lowering compounds, including colestilan, iron-containing binders and nicotinamide, are underway to extend the armamentarium of phosphate-lowering strategies. An open question remains when to therapeutically counteract phosphate retention by binders. A recent prospective randomized trial in patients with moderate CKD (stages 3b-4) and phosphate levels in the upper normal range demonstrated only moderate reductions in serum phosphate levels, no effects on FGF23, but increased vascular calcification progression with active treatment versus placebo. Another small trial in patients with similar renal function given diets containing approximately 1 g of calcium and 1.4 g of phosphate per day showed neutral calcium and phosphate balances, whereas addition of calcium carbonate as a phosphate binder only caused a positive calcium, but no negative phosphate balance. SUMMARY: Adequate phosphate management in end-stage CKD remains a mainstay of our therapeutic approaches in this population, and additional promising drugs are in development and may shortly be available. The timing and indication for phosphate-lowering strategies in predialysis CKD is currently unclear. PMID- 23736842 TI - Slit2-Robo signaling: a novel regulator of vascular injury. AB - PURPOSE OF REVIEW: Vascular injury is a common contributor to, and complication of, kidney disease. Given the prevalence and importance of vascular injury in renal disease, interest has grown in a novel signaling pathway first identified in developing neurons that also has widespread effects on vascular structure and function, comprising the secreted ligand Slit2 and its cognate Roundabout (Robo) receptors. RECENT FINDINGS: Although initially discovered as a modulator of neuronal migration during development, the Slit2-Robo signaling pathway has recently been found to regulate the structure and function of various subsets of vascular cells and circulating hematopoietic cells that interact with the vessel wall. Through the regulation of intermediate signaling enzymes that control the organization of the actin cytoskeleton, Slit2 and its Robo receptors regulate such diverse processes as angiogenesis, endothelial permeability, vascular smooth muscle cell migration, and thrombosis. SUMMARY: Recent advances in our understanding of Slit2-Robo signaling have provided novel insights into the pathophysiology of vascular injury that is commonly associated with renal disease. These insights have created potential opportunities for the development of new therapies targeting vascular injury associated with renal disease. PMID- 23736843 TI - Osmoregulation, vasopressin, and cAMP signaling in autosomal dominant polycystic kidney disease. AB - PURPOSE OF REVIEW: Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited nephropathy. This review will focus on the vasopressin and 3'-5'-cyclic adenosine monophosphate (cAMP) signaling pathways in ADPKD and will discuss how these insights offer new possibilities for the follow-up and treatment of the disease. RECENT FINDINGS: Defective osmoregulation is an early manifestation of ADPKD and originates from both peripheral (renal effect of vasopressin) and central (release of vasopressin) components. Copeptin, which is released from the vasopressin precursor, may identify ADPKD patients at risk for rapid disease progression. Increased levels of cAMP in tubular cells, reflecting modifications in intracellular calcium homeostasis and abnormal stimulation of the vasopressin V2 receptor (V2R), play a central role in cystogenesis. Blocking the V2R lowers cAMP in cystic tissues, slows renal cystic progression and improves renal function in preclinical models. A phase III clinical trial investigating the effect of the V2R antagonist tolvaptan in ADPKD patients has shown that this treatment blunts kidney growth, reduces associated symptoms and slows kidney function decline when given over 3 years. SUMMARY: These advances open perspectives for the understanding of cystogenesis in ADPKD, the mechanisms of osmoregulation, the role of polycystins in the brain, and the pleiotropic action of vasopressin. PMID- 23736844 TI - Current world literature. Mineral metabolism. Renal pathophysiology. PMID- 23736846 TI - Asymmetric construction of fluorinated imidazolidines via Cu(I)-catalyzed exo' selective 1,3-dipolar cycloaddition of azomethine ylides with fluorinated imines. AB - Expedient access to optically active fluorinated 2,4-trans-imidazolidines was successfully developed via Cu(I)-catalyzed exo'-selective 1,3-DC of azomethine ylides with fluorinated imines. PMID- 23736848 TI - Photo-switched self-assembly of a gemini alpha-helical peptide into supramolecular architectures. AB - An azobenzene-linked symmetrical gemini alpha-helical peptide was designed and prepared to realize the light-switched self-assembly. With the reversible molecular structure transition between Z- and U-structures, the morphology of the self-assembled gemini alpha-helical peptide can reversibly change between nanofibers and nanospheres in acidic medium, and between nanospheres and vesicles in basic medium. PMID- 23736847 TI - Relationship between neovascularization and degenerative changes in herniated lumbar intervertebral discs. AB - PURPOSE: Lumbar disc degeneration may be associated with intensity of neovascularization in disc herniations. Our study was designed to evaluate how much the severity of histodegeneration is related to the development of neovascularization and to the level of pleiotrophin in the herniated lumbar discs. METHODS: Surgically excised lumbar disc specimens were obtained from 29 patients with noncontained (i.e., extruding through the posterior longitudinal ligament) and 21 patients with contained disc herniations. The histodegeneration scores and levels of neovascularization were estimated according to semiquantitative analysis in lumbar disc and endplate samples. Immunohistochemical staining were performed to identify the newly formed blood vessels and to detect the presence of pleiotrophin in the specimens. RESULTS: Higher levels of disc and endplate neovascularity were registered in noncontained herniations. The level of neovascularization was significantly related to the score of histodegeneration in the herniated disc tissues but not in the endplate specimens. Both contained and noncontained herniations had the highest values of histodegeneration in conjunction with the highest level of neovascularization but the relations between neovascularity and degenerative changes remained to be significant only in the group of noncontained herniations. Registration or frequency of pleiotrophin positive cells did not correlate significantly with histodegeneration or level of neovascularization in the disc samples. CONCLUSION: Severe histodegeneration of the lumbar disc herniations is associated with enhanced neovascularization and potentially also spontaneous regression of the herniated tissue. PMID- 23736849 TI - An integral model for target tracking based on the use of a WSN. AB - The use of wireless sensor networks (WSN) in tracking applications is growing at a fast pace. In these applications, the sensor nodes discover, monitor and track an event or target object. A significant number of proposals relating the use of WSNs for target tracking have been published to date. However, they either focus on the tracking algorithm or on the communication protocol, and none of them address the problem integrally. In this paper, a comprehensive proposal for target detection and tracking is discussed. We introduce a tracking algorithm to detect and estimate a target location. Moreover, we introduce a low-overhead routing protocol to be used along with our tracking algorithm. The proposed algorithm has low computational complexity and has been designed considering the use of a mobile sink while generating minimal delay and packet loss. We also discuss the results of the evaluation of the proposed algorithms. PMID- 23736850 TI - Non-invasive continuous glucose monitoring with multi-sensor systems: a Monte Carlo-based methodology for assessing calibration robustness. AB - In diabetes research, non-invasive continuous glucose monitoring (NI-CGM) devices represent a new and appealing frontier. In the last years, some multi-sensor devices for NI-CGM have been proposed, which exploit several sensors measuring phenomena of different nature, not only for measuring glucose related signals, but also signals reflecting some possible perturbing processes (temperature, blood perfusion). Estimation of glucose levels is then obtained combining these signals through a mathematical model which requires an initial calibration step exploiting one reference blood glucose (RBG) sample. Even if promising results have been obtained, especially in hospitalized volunteers, at present the temporal accuracy of NI-CGM sensors may suffer because of environmental and physiological interferences. The aim of this work is to develop a general methodology, based on Monte Carlo (MC) simulation, to assess the robustness of the calibration step used by NI-CGM devices against these disturbances. The proposed methodology is illustrated considering two examples: the first concerns the possible detrimental influence of sweat events, while the second deals with calibration scheduling. For implementing both examples, 45 datasets collected by the Solianis Multisensor system are considered. In the first example, the MC methodology suggests that no further calibration adjustments are needed after the occurrence of sweat events, because the "Multisensor+model" system is able to deal with the disturbance. The second case study shows how to identify the best time interval to update the model's calibration for improving the accuracy of the estimated glucose. The methodology proposed in this work is of general applicability and can be helpful in making those incremental steps in NI-CGM devices development needed to further improve their performance. PMID- 23736851 TI - Simultaneous/selective detection of dopamine and ascorbic acid at synthetic zeolite-modified/graphite-epoxy composite macro/quasi-microelectrodes. AB - The present paper aims to miniaturize a graphite-epoxy and synthetic zeolite modified graphite-epoxy composite macroelectrode as a quasi-microelectrode aiming in vitro and also, envisaging in vivo simultaneous electrochemical detection of dopamine (DA) and ascorbic acid (AA) neurotransmitters, or DA detection in the presence of AA. The electrochemical behavior and the response of the designed materials to the presence of dopamine and ascorbic acid without any protective membranes were studied by cyclic voltammetry and constant-potential amperometry techniques. The catalytic effect towards dopamine detection was proved for the synthetic zeolite-modified graphite-epoxy composite quasi-microelectrode, allowing increasing the sensitivity and selectivity for this analyte detection, besides a possible electrostatic attraction between dopamine cation and the negative surface of the synthetic zeolite and electrostatic repulsion with ascorbic acid anion. Also, the synthetic zeolite-modified graphite-epoxy composite quasi-microelectrode gave the best electroanalytical parameters for dopamine detection using constant-potential amperometry, the most useful technique for practical applications. PMID- 23736852 TI - An optimized handover scheme with movement trend awareness for body sensor networks. AB - When a body sensor network (BSN) that is linked to the backbone via a wireless network interface moves from one coverage zone to another, a handover is required to maintain network connectivity. This paper presents an optimized handover scheme with movement trend awareness for BSNs. The proposed scheme predicts the future position of a BSN user using the movement trend extracted from the historical position, and adjusts the handover decision accordingly. Handover initiation time is optimized when the unnecessary handover rate is estimated to meet the requirement and the outage probability is minimized. The proposed handover scheme is simulated in a BSN deployment area in a hospital environment in UK. Simulation results show that the proposed scheme reduces the outage probability by 22% as compared with the existing hysteresis-based handover scheme under the constraint of acceptable handover rate. PMID- 23736853 TI - TREFEX: trend estimation and change detection in the response of MOX gas sensors. AB - Many applications of metal oxide gas sensors can benefit from reliable algorithms to detect significant changes in the sensor response. Significant changes indicate a change in the emission modality of a distant gas source and occur due to a sudden change of concentration or exposure to a different compound. As a consequence of turbulent gas transport and the relatively slow response and recovery times of metal oxide sensors, their response in open sampling configuration exhibits strong fluctuations that interfere with the changes of interest. In this paper we introduce TREFEX, a novel change point detection algorithm, especially designed for metal oxide gas sensors in an open sampling system. TREFEX models the response of MOX sensors as a piecewise exponential signal and considers the junctions between consecutive exponentials as change points. We formulate non-linear trend filtering and change point detection as a parameter-free convex optimization problem for single sensors and sensor arrays. We evaluate the performance of the TREFEX algorithm experimentally for different metal oxide sensors and several gas emission profiles. A comparison with the previously proposed GLR method shows a clearly superior performance of the TREFEX algorithm both in detection performance and in estimating the change time. PMID- 23736856 TI - Raman spectroscopy of serum: an exploratory study for detection of oral cancers. AB - Early diagnosis of oral cancers, one of the major cancers, is of utmost importance as 5-year disease-free survival rates are some of the lowest, despite advances in treatment and surgical modalities. In vivo Raman spectroscopy has shown efficacy in the detection of normal, premalignant and malignant lesions and even of early changes such as cancer-field-effects/malignancy-associated-changes. However, the need for a dedicated instrument and stringent laboratory conditions, at all diagnostic centers, limits wide screening applications of this method. In light of this, it is pertinent to explore ex vivo samples like serum due to its ease of collection, storage, transport and analysis at a centralized facility. Hence, Raman studies were carried out on serum from 14 buccal mucosa and 40 tongue cancers as well as 16 healthy control samples. Spectral features indicate differential contributions of proteins, DNA, and amino acids like Phe, Trp and Tyr and beta-carotene in the analyzed groups. Highly intense Raman bands assigned to beta-carotene could be due to resonance Raman, and were observed in all sera with the highest relative intensity in normal samples. Higher DNA and protein content were observed in the mean cancer spectra. Principal component-linear discriminant analysis (PC-LDA) followed by cross-validation using leave-one-out cross-validation (LOOCV) were employed for data analysis which was carried out both spectra- and patient-wise. Findings indicate the possibility of classifying normal and oral cancer sera in both these approaches; however, the patient-wise approach could be the preferred mode for prospective studies. Besides, a tendency of classification for buccal mucosa and tongue cancers was also observed. Prospective validation of these results on a large sample size may help in the translation of this methodology to clinics. PMID- 23736854 TI - Optoacoustic imaging and tomography: reconstruction approaches and outstanding challenges in image performance and quantification. AB - This paper comprehensively reviews the emerging topic of optoacoustic imaging from the image reconstruction and quantification perspective. Optoacoustic imaging combines highly attractive features, including rich contrast and high versatility in sensing diverse biological targets, excellent spatial resolution not compromised by light scattering, and relatively low cost of implementation. Yet, living objects present a complex target for optoacoustic imaging due to the presence of a highly heterogeneous tissue background in the form of strong spatial variations of scattering and absorption. Extracting quantified information on the actual distribution of tissue chromophores and other biomarkers constitutes therefore a challenging problem. Image quantification is further compromised by some frequently-used approximated inversion formulae. In this review, the currently available optoacoustic image reconstruction and quantification approaches are assessed, including back-projection and model-based inversion algorithms, sparse signal representation, wavelet-based approaches, methods for reduction of acoustic artifacts as well as multi-spectral methods for visualization of tissue bio-markers. Applicability of the different methodologies is further analyzed in the context of real-life performance in small animal and clinical in-vivo imaging scenarios. PMID- 23736855 TI - Stac3 is a component of the excitation-contraction coupling machinery and mutated in Native American myopathy. AB - Excitation-contraction coupling, the process that regulates contractions by skeletal muscles, transduces changes in membrane voltage by activating release of Ca(2+) from internal stores to initiate muscle contraction. Defects in excitation contraction coupling are associated with muscle diseases. Here we identify Stac3 as a novel component of the excitation-contraction coupling machinery. Using a zebrafish genetic screen, we generate a locomotor mutation that is mapped to stac3. We provide electrophysiological, Ca(2+) imaging, immunocytochemical and biochemical evidence that Stac3 participates in excitation-contraction coupling in muscles. Furthermore, we reveal that a mutation in human STAC3 is the genetic basis of the debilitating Native American myopathy (NAM). Analysis of NAM stac3 in zebrafish shows that the NAM mutation decreases excitation-contraction coupling. These findings enhance our understanding of both excitation-contraction coupling and the pathology of myopathies. PMID- 23736857 TI - Hypertriglyceridemic waist is associated with increased carotid atherosclerosis in chronic kidney disease patients. AB - BACKGROUND: Patients with chronic kidney disease (CKD) have an unacceptably high risk of death, primarily as a result of cardiovascular disease (CVD). The 'hypertriglyceridemic waist' phenotype has been proposed as a simple and strong predictor of CVD risk. Therefore, we investigated the relationship between the hypertriglyceridemic waist phenotype and carotid atherosclerosis in CKD patients. METHODS: In a cross-sectional study, we enrolled 785 prevalent CKD patients [416 males, aged 44.6 years (21.7-69.4), glomerular filtration rate 52.5 ml/min/1.73 m(2) (5.3-119.4)]. We divided the patients into three groups: group 1: waist circumference >90 cm in men or >85 cm in women and triglycerides >=2 mmol/l (n = 109); group 3: waist circumference <=90 cm in men or <=85 cm in women and triglycerides <2 mmol/l (n = 379), and group 2: the remaining patients (n = 297). Routine biochemical parameters and carotid artery intima-media thickness (IMT) were measured. RESULTS: The prevalence of the hypertriglyceridemic waist phenotypes was 13.8% in the CKD patients. Triglyceride, total cholesterol, HDL cholesterol and LDL-cholesterol concentrations in group 1 were significantly higher than those in group 3. Carotid artery IMT of the hypertriglyceridemic waist group was the highest. CONCLUSION: The hypertriglyceridemic waist phenotype was associated with worse carotid atherosclerosis in CKD patients. This suggests that the hypertriglyceridemic waist phenotype may be useful for predicting CVD risk in CKD patients. PMID- 23736858 TI - Effects of low-fat diet on serum lipids in premenopausal and postmenopausal women: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: This study aims to conduct a meta-analysis to evaluate the effects of a low-fat diet, in comparison with participants' usual diet, on serum lipids in premenopausal and postmenopausal women. METHODS: Ten electronic databases were searched for relevant articles reporting randomized controlled trials through August 31, 2012, including PubMed/Medline, EMBASE, Cochrane Library, CINAHL, Web of Science, SCOPUS, ProQuest Dissertations and Theses, SinoMed, CNKI (Chinese database), and WanFang (Chinese database). This systematic review and meta analysis, which evaluated the effects of a low-fat diet, in comparison with the participants' usual diet, was conducted according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. All analyses were performed using RevMan version 5 (Cochrane Collaboration). RESULTS: From 512 potentially relevant publication citations reviewed, 8 randomized clinical trials were included in the meta-analysis, representing 22 groups (11 intervention groups and 11 control groups). A total of 1,536 women (900 in the intervention group and 636 in the control group) met the inclusion criteria. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) values changed more favorably in participants randomized to low-fat diets than in participants randomized to their usual diets. Low-fat diet was found to induce significant reductions in TC (random-effects model: mean difference [MD], -0.49 mmol/L; 95% CI, -0.69 to -0.29; I = 42%; Peffect < 0.00001), HDL-C (MD, -0.12 mmol/L; 95% CI, -0.20 to -0.05; I = 49%; Peffect = 0.00006), and LDL-C (MD, -0.24 mmol/L; 95% CI, -0.38 to -0.09; I = 42%; Peffect = 0.001) for two groups. For subgroup analysis, low-fat diet was efficacious in reducing TC, HDL-C, and LDL-C in premenopausal women but did not significantly reduce the same outcomes in postmenopausal women. However, there were also no statistically significant differences in triglycerides (TG) and TC-to-HDL-C ratio between a low-fat diet and the participants' usual diet (TG: MD, 0.04 mmol/L; 95% CI, -0.02 to 0.11; I = 0%; Peffect = 0.16; TC-to-HDL-C ratio: MD, 0.08 mmol/L; 95%, CI -0.21 to 0.36; I = 0%; Peffect = 0.59) in two groups. CONCLUSIONS: Overall results suggest that a low-fat diet is efficacious in reducing the concentrations of TC, HDL-C, and LDL-C but not in reducing TG and TC-to-HDL-C ratio in women. A low-fat diet is efficacious in reducing TC, HDL-C, and LDL-C in premenopausal women. Additional studies are needed to further address its effects on postmenopausal women. PMID- 23736859 TI - Which is worse: old or obese? PMID- 23736860 TI - Collagen cross-links as a marker for subclinical atherosclerosis in postmenopausal women. AB - OBJECTIVE: This study aimed to examine the utility of pyridinoline (Pyd) and deoxypyridinoline (Dpd) cross-links in the detection of subclinical atherosclerosis in postmenopausal women with or without osteoporosis. METHODS: We measured Pyd, Dpd, carotid intima-media thickness (CIMT), fasting total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and blood pressure in 59 healthy postmenopausal women: 30 had normal bone mineral density (group I) and the remaining 29 had osteoporosis or osteopenia (group II) according to World Health Organization criteria. RESULTS: There were no statistically significant differences in age, duration of menopause, age at menopause, lipid profile, body mass index, Pyd level, Dpd level, and Pyd-to-Dpd ratio between the groups (P > 0.05). No significant difference in CIMT was found when groups I and II were compared (P = 0.538). No statistically significant differences in Pyd level, Dpd level, and Pyd to-Dpd ratio were found when women with CIMT higher than 5 mm and women with CIMT of 5 mm or less were compared in groups I and II (P > 0.05). However, significantly declined Dpd level and increased Pyd-to-Dpd ratio were found in women with CIMT higher than 5 mm when compared with women with CIMT of 5 mm or less. CIMT was found to be negatively correlated with Dpd level (r = -0.346, P = 0.007) and to be positively correlated with the Pyd-to-Dpd ratio (r = 0.702, P < 0.001). CONCLUSIONS: The increase in the Pyd-to-Dpd ratio, irrespective of the participants' bone mineral density, may have predictive value in the determination of subclinical atherosclerosis in postmenopausal women. PMID- 23736861 TI - Frequency and determinants of urogenital symptoms in postmenopausal Islamic women. AB - OBJECTIVE: The objective of this study was to evaluate the frequency of genitourinary symptoms and their relationships with several factors in a large cohort of postmenopausal women in Turkey. METHODS: We performed a cross-sectional study to review genitourinary complaints among 1,328 postmenopausal women; 1,071 of these women were enrolled in the study. They were questioned about their vaginal and urinary symptoms, and the relationships between these symptoms and their demographic characteristics were evaluated. RESULTS: The most common vaginal and urinary symptoms were dryness (n = 358; 33.4%) and nocturia (n = 421; 39.3%), respectively. Cigarette smoking and regular exercise were not associated with any vaginal symptoms (P > 0.05), with the exception of an association between regular exercise and vaginal dryness (P = 0.026). Nocturia was more common in women older than 60 years (P = 0.001) and in obese women (P = 0.013). Based on multiple binary logistic regression analysis, lower educational status (primary school vs secondary school or higher) and higher parity were the factors most significantly associated with the appearance of at least three vaginal symptoms. Lower educational status was associated with vaginal pain (P = 0.002; odds ratio [OR], 1.75), itching (P < 0.001; OR, 1.23), and discharge (P = 0.011; OR, 1.46). Higher parity was associated with vaginal itching (P < 0.001; OR, 1.23), discharge (P = 0.07; OR, 1.18), and burning (P = 0.012; OR, 1.16). Body mass index (BMI) was the only factor that was significantly associated with the appearance of at least three urinary symptoms, with each one-unit increase in BMI increasing the risk of urgency (P < 0.001; OR, 1.06), nocturia (P < 0.001; OR, 1.06), and frequency (P = 0.009; OR, 1.04). CONCLUSIONS: We identify associations between the frequency of genitourinary complaints and educational status, parity, and BMI. There is no association between regular exercise and urogenital symptoms. However, prospective studies are needed to evaluate the effects of regular exercise on urogenital symptoms. When examining postmenopausal women with risk factors for urinary and vaginal symptoms, clinicians should evaluate these symptoms more thoroughly to facilitate earlier treatment. PMID- 23736862 TI - Clarifying Vaginal Atrophy's Impact on Sex and Relationships (CLOSER) survey: emotional and physical impact of vaginal discomfort on North American postmenopausal women and their partners. AB - OBJECTIVE: This study aims to determine the emotional and physical impact of vaginal atrophy on North American postmenopausal women and their male partners. METHODS: A weighted sample of 1,000 married or cohabiting North American postmenopausal women aged 55 to 65 years with vaginal discomfort and 1,000 male partners of postmenopausal women aged 55 to 65 years who experienced vaginal discomfort participated in the Clarifying Vaginal Atrophy's Impact on Sex and Relationships (CLOSER) online survey to determine the impact of vaginal discomfort and local estrogen therapy on intimacy, relationships, and women's self-esteem. RESULTS: Vaginal discomfort caused most surveyed North American women to avoid intimacy (58%), experience loss of libido (64%), and experience pain associated with sex (64%). Most surveyed North American men also believed that vaginal discomfort caused their partners to avoid intimacy (78%), experience loss of libido (52%), and find sex painful (59%). Approximately 30% of North American women and men cited vaginal discomfort as the reason they ceased having sex altogether. North American women who used local estrogen therapy to treat their vaginal discomfort reported less painful sex (56%), more satisfying sex (41%), and improved sex life (29%). Most men reported looking forward to having sex (57%) because of their partner's use of local estrogen therapy. CONCLUSIONS: Local estrogen therapy ameliorates the negative impact of vaginal atrophy on the intimate relationships of North American postmenopausal women and their male partners. Additional education and awareness efforts about the symptoms of and available treatments for vaginal atrophy may be of further benefit to North American partners. PMID- 23736863 TI - The role of antibiotic therapy and nasal packing in septoplasty. AB - Both systemic antibiotic therapy and nasal packing are used frequently in septoplasty. Nevertheless, there is still great disagreement among authors around the real advantages with regard to the efficacy of both of these procedures in septal surgery. The aim of the present review was to evaluate the more recent data published on this topic. One appropriate string was run on PubMed to retrieve articles dealing with the topics mentioned above. A double cross-check was performed on citations and full-text articles found using the selected inclusion and exclusion criteria. Overall, the articles we analyzed indicated the poor utility of routine antibiotic therapy and nasal packing during septoplasty, the latter procedure producing more complications than advantages. In conclusion, on the basis of the recent literature, the use of systemic antibiotic prophylaxis and nasal packing in septal surgery seems to be a non-rational procedure. PMID- 23736864 TI - Critical role of nutrition in improving quality of care: an interdisciplinary call to action to address adult hospital malnutrition. AB - The current era of healthcare delivery, with its focus on providing high-quality, affordable care, presents many challenges to hospital-based health professionals. The prevention and treatment of hospital malnutrition offer a tremendous opportunity to optimize the overall quality of patient care, improve clinical outcomes, and reduce costs. Unfortunately, malnutrition continues to go unrecognized and untreated in many hospitalized patients. This article represents a call to action from the interdisciplinary Alliance to Advance Patient Nutrition to highlight the critical role of nutrition intervention in clinical care and to suggest practical ways to promptly diagnose and treat malnourished patients and those at risk for malnutrition. We underscore the importance of an interdisciplinary approach to addressing malnutrition both in the hospital and in the acute posthospital phase. It is well recognized that malnutrition is associated with adverse clinical outcomes. Although data vary across studies, available evidence shows that early nutrition intervention can reduce complication rates, length of hospital stay, readmission rates, mortality, and cost of care. The key is to systematically identify patients who are malnourished or at risk and to promptly intervene. We present a novel care model to drive improvement, emphasizing the following 6 principles: (1) create an institutional culture where all stakeholders value nutrition, (2) redefine clinicians' roles to include nutrition care, (3) recognize and diagnose all malnourished patients and those at risk, (4) rapidly implement comprehensive nutrition interventions and continued monitoring, (5) communicate nutrition care plans, and (6) develop a comprehensive discharge nutrition care and education plan. PMID- 23736865 TI - MR findings of primary choroid plexus papilloma of the cerebellopontine angle: report of three cases and literature reviews. PMID- 23736866 TI - Pitfall of fluid-attenuated inversion recovery (FLAIR) MR imaging in acute stroke does magnetic field strength influence the tissue clock? PMID- 23736867 TI - Hyperreninemic hypoaldosteronism in combat-related posttraumatic stress disorder. PMID- 23736868 TI - Surface code implementation of block code state distillation. AB - State distillation is the process of taking a number of imperfect copies of a particular quantum state and producing fewer better copies. Until recently, the lowest overhead method of distilling states produced a single improved [formula: see text] state given 15 input copies. New block code state distillation methods can produce k improved [formula: see text] states given 3k + 8 input copies, potentially significantly reducing the overhead associated with state distillation. We construct an explicit surface code implementation of block code state distillation and quantitatively compare the overhead of this approach to the old. We find that, using the best available techniques, for parameters of practical interest, block code state distillation does not always lead to lower overhead, and, when it does, the overhead reduction is typically less than a factor of three. PMID- 23736869 TI - The rediscovered Hula painted frog is a living fossil. AB - Amphibian declines are seen as an indicator of the onset of a sixth mass extinction of life on earth. Because of a combination of factors such as habitat destruction, emerging pathogens and pollutants, over 156 amphibian species have not been seen for several decades, and 34 of these were listed as extinct by 2004. Here we report the rediscovery of the Hula painted frog, the first amphibian to have been declared extinct. We provide evidence that not only has this species survived undetected in its type locality for almost 60 years but also that it is a surviving member of an otherwise extinct genus of alytid frogs, Latonia, known only as fossils from Oligocene to Pleistocene in Europe. The survival of this living fossil is a striking example of resilience to severe habitat degradation during the past century by an amphibian. PMID- 23736870 TI - Dynamic cervical plate versus static cervical plate in the anterior cervical discectomy and fusion: a systematic review. AB - STUDY DESIGN AND OBJECTIVE: This study performs a systematic review to compare the functional outcomes and complications between the dynamic cervical plate and static cervical plate in patients with the anterior cervical discectomy and fusion (ACDF). The common static cervical plates have been widely used in the ACDF. It can successfully increase the fusion rate and decrease the surgery failure. Recently, the dynamic plate has been identified as another safe and efficient option for the better fusion rate by promoting load sharing across the construct. However, the proposed benefits have been largely theoretical, and there is considerable controversy as to which plate is a better option for reconstruction after ACDF. METHODS: We searched the Cochrane Library, EMBASE, PubMed, and CBM to identify the clinical studies regarding the comparison of dynamic cervical plate with fixed cervical plate in the ACDF. Reports not available in English were excluded. The quality of the included studies was critically assessed, and the data analysis was performed by the Cochrane Collaboration's RevMan 4.2. We defined statistical significance as a P value <0.05. RESULTS: Five studies were included in this systematic review. In the final analysis, there were 172 patients in the dynamic cervical plate and 143 in the static cervical group. Four studies compared the clinical and radiographic outcomes between the two plate groups in the one-level or two-level fusion segmentation patients, while one studied the patients with the multiple levels. The similar clinical outcomes between the two cervical plate systems were reported in two studies. However, another study suggested that a better clinical outcome was found in the dynamic plate group for the multiple-level fusion patients, although the similar clinical outcome was found in the one-level fusion patients. The two RCT studies with the same clinical data reported that four patients in the static group developed hardware complications, while there was no implant complication in the dynamic group. CONCLUSION: The clinical outcome was similar in ACDF for one-level fusion patients, although the hardware failure rate was higher in ACDF with static plates. PMID- 23736871 TI - Dynamic development of the protein corona on silica nanoparticles: composition and role in toxicity. AB - The formation and composition of the protein corona on silica (SiO2) nanoparticles (NP) with different surface chemistries was evaluated over time. Native SiO2, amine (-NH2) and carboxy (-COO(-)) modified NP were examined following incubation in mammalian growth media containing fetal bovine serum (FBS) for 1, 4, 24 and 48 hours. The protein corona transition from its early dynamic state to the later more stable corona was evaluated using mass spectrometry. The NP diameter was 22.4 +/- 2.2 nm measured by scanning transmission electron microscopy (STEM). Changes in hydrodynamic diameter and agglomeration kinetics were studied using dynamic light scattering (DLS). The initial surface chemistry of the NP played an important role in the development and final composition of the protein corona, impacting agglomeration kinetics and NP toxicity. Particle toxicity, indicated by changes in membrane integrity and mitochondrial activity, was measured by lactate dehydrogenase (LDH) release and tetrazolium reduction (MTT), respectively, in mouse alveolar macrophages (RAW264.7) and mouse lung epithelial cells (C10). SiO2-COO(-) NP had a slower agglomeration rate, formed smaller aggregates, and exhibited lower cytotoxicity compared to SiO2 and SiO2-NH2. Composition of the protein corona for each of the three NP was unique, indicating a strong dependence of corona development on NP surface chemistry. This work underscores the need to understand all aspects of NP toxicity, particularly the influence of agglomeration on effective dose and particle size. Furthermore, the interplay between materials and local biological environment is emphasized and highlights the need to conduct toxicity profiling under physiologically relevant conditions that provide an appropriate estimation of material modifications that occur during exposure in natural environments. PMID- 23736872 TI - The catabolism of 2,4-xylenol and p-cresol share the enzymes for the oxidation of para-methyl group in Pseudomonas putida NCIMB 9866. AB - Pseudomonas putida NCIMB 9866 utilizes p-cresol or 2,4-xylenol as a sole carbon and energy source. Enzymes catalyzing the oxidation of the para-methyl group of p cresol have been studied in detail. However, those responsible for the oxidation of the para-methyl group in 2,4-xylenol catabolism are still not reported. In this study, real-time quantitative PCR analysis indicated pchC- and pchF-encoded p-cresol methylhydroxylase (PCMH) and pchA-encoded p-hydroxybenzaldehyde dehydrogenase (PHBDD) in p-cresol catabolism were also likely involved in the catabolism of 2,4-xylenol. Enzyme activity assays and intermediate identification indicated that the PCMH and PHBDD catalyzed the oxidations of 2,4-xylenol to 4 hydroxy-3-methylbenzaldehyde and 4-hydroxy-3-methylbenzaldehyde to 4-hydroxy-3 methylbenzoic acid, respectively. Furthermore, the PCMH-encoding gene pchF was found to be necessary for the catabolism of 2,4-xylenol, whereas the PHBDD encoding gene pchA was not essential for the catabolism by gene knockout and complementation. Analyses of the maximum specific growth rate (MU m) and specific activity of the gene-knockout strain to different intermediates revealed the presence of other enzyme(s) with PHBDD activity in strain 9866. However, PHBDD played a major role in the catabolism of 2,4-xylenol in contrast to the other enzyme(s). PMID- 23736873 TI - Solid-state fermentation of industrial solid wastes from the fruits of milk thistle Silybum marianum for feed quality improvement. AB - The industrial solid wastes generated during the production of silymarin from the fruits of milk thistle Silybum marianum was used as the substrate. Preparation and evaluation of the feeds produced by solid-state fermentation (SSF) of the industrial solid wastes was carried out. The protein content of the fermented feed (FF) from a combination of Aspergillus niger and Candida tropicalis was the highest among the examined strains. The optimal process parameters for protein enrichment with SSF using A. niger and C. tropicalis included incubation temperature of 30.8 degrees C, fermentation time of 87.0 h, and initial moisture content of 59.7 %. Under these conditions, the value additions of FF occurred. The fiber of FF was decreased by 25.07 %, while the digestibility of protein, protein content, and the ratio of total essential amino acids to total amino acids were increased by 79.85, 16.22, and 8.21 %, respectively. The analysis indicated that FF contained 1.44 mg/kg flavonoids and 0.5 mg/kg silybin, which significantly increased by 2.42 and 1.63 times, respectively than those in unfermented substrates. FF recorded reduced molecular weight of proteins from 20.1 to 44.3 kDa to below 14.3 kDa. The results of feeding trial of FF replacement with soybean meal in broilers diets for 8 weeks showed that FF significantly improved carcass characteristics including abdominal fat rate, serum biochemical parameters including aspartate transaminase, blood urea nitrogen and high density lipoprotein cholesterol, and immune responses of broilers. A potential feed quality improvement was achieved through mixed strains SSF of industrial solid wastes of S. marianum fruits. PMID- 23736874 TI - Atrial fibrillation ablation in patients with gastroesophageal reflux disease or irritable bowel syndrome-the heart to gut connection! AB - PURPOSE: An association between atrial fibrillation (AF) and gastroesophageal reflux disease (GERD) and/or irritable bowel syndrome (IBS) is increasingly being identified; yet the role of radiofrequency catheter ablation (RFA) of AF has not been systematically evaluated in these patient populations. METHODS: We performed a prospective matched case-control study of AF patients with GERD and/or IBS who underwent RFA for AF in two centers in North America. AF patients with GERD and/or IBS (gastrointestinal [GI] group) were matched by age, gender, and type of AF at each of the centers with an equal number of AF patients without GERD or IBS (non-GI group). RESULTS: Sixty patients were included in the study with 30 in each group. Mean age of the population was 45 years with 14 (47 %) males and 21 (87 %) patients with paroxysmal AF in each group. More patients in the GI group had identifiable GI triggers for AF episodes. During RFA, more patients in the GI group had a "vagal response" compared to non-GI group (60 vs 13 %; p < 0.001). Left atrial scar as identified by electroanatomical mapping was more common in patients in the non-GI group compared to the GI group (57 vs 27 %; p = 0.018). At 1-year follow-up, 56 (93 %) of the patients were free from AF with no difference between both groups. CONCLUSIONS: Majority of AF patients with GERD and/or IBS have triggered AF and a positive vagal response during RFA. RFA is equally effective in this patient population when compared to those without GERD or IBS. PMID- 23736875 TI - Early palliative care for patients with advanced cancer: how to make it work? AB - PURPOSE OF REVIEW: As the benefit of early palliative care for the quality of life of patients with advanced cancer is currently receiving widespread recognition, cancer specialists increasingly inquire about the practical implications of this concept. This publication presents the available information about how to provide early palliative care for patients with advanced cancer. RECENT FINDINGS: Oncologists and other cancer specialists provide general palliative care from the time of diagnosis of incurable cancer together with the patients' family doctors. This includes basic assessment of symptoms and distress, their initial management as well as sensitive communication with the patient, including advance care planning and end-of-life issues and hope. The additional integration of a specialized palliative care team early in the care trajectory has been found to be beneficial for quality of life and survival. This concept is known as 'early palliative care' or 'early integration' and has become recommended by institutions such as the American Society of Clinical Oncology. SUMMARY: Palliative care is warranted from the time of diagnosis of incurable cancer. From this early stage, palliative care consists of general palliative care provided by cancer specialists and family doctors and additional support of a specialized palliative care program. Guidance from different guidelines is presented alongside practical recommendations derived from our experience with an early palliative care program for comprehensive cancer care over the last 7 years. PMID- 23736876 TI - The impact of infectious diseases consultation on oncology practice. AB - PURPOSE OF REVIEW: Traditional utilization of infectious diseases consultants by oncologists ranges from inpatient management of a variety of acute infectious syndromes to management of ambulatory patients with acute or chronic infections; however, there is a paucity of data to evaluate in which circumstances the impact of infectious diseases input may be most valuable. RECENT FINDINGS: Data derived from the general population of patients emphasize the value of infectious diseases consultation in specific infections, such as Staphylococcus aureus bacteremia, candidemia, and hepatitis C virus infection. In addition, infectious diseases involvement has been associated with greater adherence to guidelines (up to 34% increase), more appropriate antibiotic utilization (up to 52% increase in appropriate duration), decreased cost and complications of care, and lower mortality (up to 17% decrease). Recent studies suggest that bedside, formal infectious diseases consultation is more optimal than informal interactions (e.g., e-mail, telephone, other). Furthermore, infectious diseases consultants play central roles in antibiotic stewardship, infection control, and quality improvement, particularly in oncology centers. SUMMARY: Infectious diseases consultants contribute value in various inpatient and outpatient infections, decreasing mortality, cost, and complications. PMID- 23736877 TI - Psychological interventions to reduce pain in patients with cancer. AB - PURPOSE OF REVIEW: To review relevant studies about psychological interventions among patients with cancer pain. RECENT FINDINGS: We used MEDLINE as a source of studies on psychological interventions between January 2012 and December 2012. Most studies were randomized, but there was no homogeneity in terms of psychological intervention types or pain evaluation. SUMMARY: Not all studies with psychological interventions measured pain as a primary outcome; pain was measured inconsistently across studies, pain raters were rarely blinded, few studies carefully described the other treatments (pharmacological or not), and patients were observed for only a limited period of time. Despite these limitations, the positive findings of this review advance support for the importance of psychological interventions on reducing pain among patients with cancer, and for the implementation of quality-controlled psychosocial interventions as part of a multimodal approach to the management of pain. PMID- 23736878 TI - Immunotherapy of sarcomas. AB - PURPOSE OF REVIEW: To describe the current advances in immunotherapy and how they can be applied to sarcoma. This review will discuss the recent literature and selected clinical trials. Evidence supporting treatment with immunotherapy alone in sarcoma will be reviewed, as will the potential incorporation of immunotherapy into treatment for sarcoma. RECENT FINDINGS: Sarcoma, cancer of the connective tissues, frequently strikes young people, comprising a large percentage of cancer in children and young adults, but may occur at any age. Although molecularly targeted inhibitors are of great interest in treating sarcoma patients, immunotherapy is emerging as a plausible therapeutic modality because of the recent advances in other cancer types that may be translated to sarcoma. The licensing of ipilimumab and sipuleucel-T for cancer, and the remarkable success of immunotherapy for some childhood cancers, suggest a role for immunotherapy in the treatment of tumors like sarcoma. SUMMARY: Sarcoma is a disease for which new treatments are needed. Immunotherapies have different mechanisms of action from most current therapies and could work in concert with them. Recent advances in sarcoma biology and cancer immunotherapy suggest that our knowledge of the immune system has reached the point where it can be used to augment both targeted and multimodality therapy for sarcoma. PMID- 23736879 TI - Current world literature. PMID- 23736882 TI - Sensitivity of activatable reactive oxygen species probes by fluorescence spectroelectrochemistry. AB - We have developed a new analytical method of evaluating activatable fluorescent probes for ROS detection using integrated fluorescence spectroelectrochemistry. The Tafel formalism was applied to describe the process of the probes' oxidation under electrochemical conditions and identify a novel parameter defined as the threshold oxidation potential. This potential can serve as an approximation to the equilibrium potential and can be utilized for determining the sensitivity of a probe to oxidation. Based upon the measured values of threshold potentials, the order of sensitivity towards oxidation among several commonly used probes was determined to be the following (from highest to lowest): 2,7 dihydrodichlorofluorescein > dihydroethidium > dihydrorhodamine 123 > dihydrorhodamine 6G. The presented approach opens up a new direction in synthesizing and screening novel ROS probes with a well-defined sensitivity for in vitro and in vivo applications. PMID- 23736881 TI - Regulation of human cytomegalovirus transcription in latency: beyond the major immediate-early promoter. AB - Lytic infection of differentiated cell types with human cytomegalovirus (HCMV) results in the temporal expression of between 170-200 open reading frames (ORFs). A number of studies have demonstrated the temporal regulation of these ORFs and that this is orchestrated by both viral and cellular mechanisms associated with the co-ordinated recruitment of transcription complexes and, more recently, higher order chromatin structure. Importantly, HCMV, like all herpes viruses, establishes a lifelong latent infection of the host--one major site of latency being the undifferentiated haematopoietic progenitor cells resident in the bone marrow. Crucially, the establishment of latency is concomitant with the recruitment of cellular enzymes that promote extensive methylation of histones bound to the major immediate early promoter. As such, the repressive chromatin structure formed at the major immediate early promoter (MIEP) elicits inhibition of IE gene expression and is a major factor involved in maintenance of HCMV latency. However, it is becoming increasingly clear that a distinct subset of viral genes is also expressed during latency. In this review, we will discuss the mechanisms that control the expression of these latency-associated transcripts and illustrate that regulation of these latency-associated promoters is also subject to chromatin mediated regulation and that the instructive observations previously reported regarding the negative regulation of the MIEP during latency are paralleled in the regulation of latent gene expression. PMID- 23736883 TI - Vagus somatosensory evoked potentials are delayed in Alzheimer's disease, but not in major depression. AB - In Alzheimer's disease (AD), the degeneration of brainstem nuclei is different from major depression (MD). Thus, vagus somatosensory evoked potentials (VSEP) proposed for the functional assessment of brainstem nuclei should show prolonged latencies in AD but not in MD. In 55 AD patients, 57 MD patients and two age matched control groups evoked potentials were recorded upon stimulation of the auricular branch of the vagus nerve. In the AD, not in the MD group, latencies were significantly longer as compared to controls. Thus, the method of VSEP could contribute to the important differential diagnosis of AD and MD in elderly patients. PMID- 23736884 TI - Group psychoeducation normalizes cortisol awakening response in stabilized bipolar patients under pharmacological maintenance treatment. PMID- 23736885 TI - Motivators to participation in actual HIV vaccine trials. AB - An examination of actual HIV vaccine trials can contribute to an understanding of motivators for participation in these studies. Analysis of these motivators reveals that they can be categorized as social and personal benefits. Social benefits are generally altruistic, whereas personal benefits are psychological, physical, and financial. In this systematic review, the authors performed a literature search for actual preventive HIV vaccine trials reporting motivators to participation. Of studies conducted in the Organization for Economic Co operation and Development (OECD) countries, the authors retrieved 12 studies reporting on social benefits and seven reporting on personal benefits. From the non-OECD countries, nine studies reported on social benefits and eight studies on personal benefits. Social benefits were most frequently described on macroscopic, altruistic levels. Personal benefits were most frequently psychological in nature. Rates of participation were compared between the OECD and the non-OECD countries. Knowledge of actual motivators in specific countries and regions can help target recruitment in various types of actual HIV vaccine trials. PMID- 23736887 TI - Urban characteristics attributable to density-driven tie formation. AB - Motivated by empirical evidence on the interplay between geography, population density and societal interaction, we propose a generative process for the evolution of social structure in cities. Our analytical and simulation results predict both super-linear scaling of social-tie density and information contagion as a function of the population. Here we demonstrate that our model provides a robust and accurate fit for the dependency of city characteristics with city size, ranging from individual-level dyadic interactions (number of acquaintances, volume of communication) to population level variables (contagious disease rates, patenting activity, economic productivity and crime) without the need to appeal to heterogeneity, modularity, specialization or hierarchy. PMID- 23736886 TI - Novel n-3 immunoresolvents: structures and actions. AB - Resolution of inflammation is now held to be an active process where autacoids promote homeostasis. Using functional-metabololipidomics and in vivo systems, herein we report that endogenous n-3 docosapentaenoic (DPA) acid is converted during inflammation-resolution in mice and by human leukocytes to novel n-3 products congenerous to D-series resolvins (Rv), protectins (PD) and maresins (MaR), termed specialized pro-resolving mediators (SPM). The new n-3 DPA structures include 7,8,17-trihydroxy-9,11,13,15E,19Z-docosapentaenoic acid (RvD1(n-3 DPA)), 7,14-dihydroxy-8,10,12,16Z,19Z-docosapentaenoic acid (MaR1(n-3 DPA)) and related bioactive products. Each n-3 DPA-SPM displayed protective actions from second organ injury and reduced systemic inflammation in ischemia reperfusion. The n-3 DPA-SPM, including RvD1(n-3 DPA) and MaR1(n-3 DPA), each exerted potent leukocyte directed actions in vivo. With human leukocytes each n-3 DPA-SPM reduced neutrophil chemotaxis, adhesion and enhanced macrophage phagocytosis. Together, these findings demonstrate that n-3 DPA is converted to novel immunoresolvents with actions comparable to resolvins and are likely produced in humans when n-3 DPA is elevated. PMID- 23736888 TI - Painful pelvic recurrence of rectal cancer: percutaneous radiofrequency ablation treatment. AB - PURPOSE: To retrospectively evaluate the feasibility and efficacy of computed tomography (CT)-guided radiofrequency thermal ablation (RFA) in reducing the pain in patients with painful pelvic recurrence of rectal cancer ineligible for surgical resection. MATERIAL AND METHODS: Twelve consecutive patients (10 men and 2 women; mean age 67 +/- 10 years) with painful pelvic recurrence of rectal cancer underwent CT-guided RFA treatments under conscious sedation. At baseline, in all patients pelvic-sacral pain was classified as severe by Visual Analog Scale (VAS; VAS score >=75 mm). The tumor density and carcinoembryionic antigen (CEA) serum level averages were 46 +/- 7 HU and 15.7 +/- 9.3 ng/mL, respectively. Clinical outcome was evaluated by VAS with a mean follow-up period of 23 months. RESULTS: All RFA sessions were completed and well tolerated. Morbidity consisted of recto-vesical fistula (8 %) and rectal abscess (8 %). 1 month after RFA procedure, complete lack of enhancement was obtained in 7 cases (58 %). A significant difference in HU and CEA serum level averages between baseline and 1 month post-RFA was revealed (p < 0.000 and p < 0.002, respectively). A significant reduction in pain was obtained: VAS score was significantly different between baseline and the clinical evaluations at week 1 and month 3, 6, 12, and 22) (p < 0.000). At the end of follow-up, 11 patients (92 %) were symptom free. CONCLUSIONS: CT-guided RFA of painful pelvic recurrence of rectal cancer can be considered as a feasible and effective treatment for reducing the pain in selected cases. PMID- 23736889 TI - Usefulness of laparoscopic subtotal cholecystectomy with operative cholangiography for severe cholecystitis. AB - PURPOSE: Cholecystectomy can become hazardous when inflammation develops, leading to anatomical changes in Calot's triangle. We attempted to study the safety and efficacy of laparoscopic subtotal cholecystectomy (LSC) to decrease the incidence of complications and the rate of conversion to open surgery. METHODS: Patients who underwent LSC between January 2005 and December 2008 were evaluated retrospectively. The operations were performed laparoscopically irrespective of the grade of inflammation estimated preoperatively. However, patients with severe inflammation of the gallbladder underwent LSC involving resection of the anterior wall of the gallbladder, removal of all stones and placement of an infrahepatic drainage tube. To prevent intraoperative complications, including bile duct injury, intraoperative cholangiography was performed. RESULTS: LSC was performed in 26 elective procedures among 26 patients (eight females, 18 males). The median patient age was 69 years (range 43-82 years). The median operative time was 125 min (range 60-215 min) and the median postoperative inpatient stay was 6 days (range 3-21 days). Cholangiography was performed during surgery in 24 patients. One patient underwent postoperative endoscopic sphincterotomy for a retained common bile duct stone that was found on cholangiography during surgery. Neither complications nor conversion to open surgery were encountered in this study. CONCLUSIONS: LSC with the aid of intraoperative cholangiography is a safe and effective treatment for severe cholecystitis. PMID- 23736892 TI - Pd(OAc)2-catalyzed regioselective aromatic C-H bond fluorination. AB - A novel Pd(OAc)2-NFSI-TFA system was developed for the highly selective ortho monofluorination directed by diverse aryl-N-heterocyclic directing groups e.g., quinoxaline, pyrazole, benzo[d]oxazole, and pyrazine derivatives. A Pd(II/IV) catalytic cycle was proposed based on the ESI-MS/MS studies. PMID- 23736890 TI - Regulating surgical oncotaxis to improve the outcomes in cancer patients. AB - Excessive surgical stress and postoperative complications cause a storm of perioperative cytokine release, which has been shown to enhance tumor metastasis in experimental models. We have named this phenomenon "surgical oncotaxis". The mechanisms that underpin this process are thought to be excessive corticosteroid secretion, coagulopathy in the peripheral vasculature, immune suppression and excessive production of reactive oxygen species. Nuclear factor-kappa B (NFkB) activation plays a key role in these mechanisms. Minimally invasive surgical techniques should be used, and postoperative complications should be avoided whenever possible to lessen the impact of surgical oncotaxis. Furthermore, there may be a role for a small preoperative dose of corticosteroid or the use of free radical scavengers in the perioperative period. Recently, there has been a great deal of interest in omega-3 fatty acid, because it regulates NFkB activation. The use of multimodal treatments that regulate surgical oncotaxis may be as important as chemotherapy for determining the outcome of patients with cancer undergoing surgery. PMID- 23736891 TI - Developing the skill of laryngeal mask insertion: prospective single center study. AB - BACKGROUND: Laryngeal mask insertion (LMI) represents a fundamental skill for anesthesiologists in routine management as well as in difficult airway situations. This study aimed to evaluate the time needed by first year anesthesiology residents to perform 40 LMIs and assessed the associated success rates and the number of attempts needed for successful LMI. METHODS: This prospective single center study evaluated the number of work days, the success rate and the attempts needed for successful LMI (LMA ProSealTM) in consecutive blocks of five LMI procedures and the related difficulties and complications. RESULTS: From 2007 to 2010 a total of 10 anesthesiology resident physicians were evaluated consecutively. These residents needed a mean of 18.3 +/- 4.1 (mean +/- standard deviation) working days to successfully perform 40 LMIs. The LMI success rate after the first 5 LMIs increased steadily up to the results after 40 LMIs per resident (LMI success rate within 1 attempt 72 versus 86 %, p = 0.09, LMI success rate within all LMI attempts 74 versus 96 %, p = 0.001). The mean number of attempts required until successful LMI decreased from 1.45 +/- 0.82 after the first 5 LMIs to 1.16 +/- 0.37 after 40 LMIs (p = 0.03). The most common difficulties associated with unsuccessful LMI by residents that led to handing over to an experienced colleague were small oral aperture (9.8 %), short thick neck, large tongue, blood/mucus in the mouth or throat (each 7.3 %) and retrognathy (4.9 %). CONCLUSIONS: The increasing LMI success rate and the decreasing rate of LMI attempts for successful airway management correlated to a learning curve and development of LMI dexterity over time. PMID- 23736893 TI - Taming furfuryl cations for the synthesis of privileged structures and novel scaffolds. AB - Furfuryl cations are generated via a highly efficient bismuth-catalyzed reaction of furfuryl alcohols. This systematic study provides insight on the reactivity profile of furfuryl cations towards nucleophilic substitution reactions. Novel C C, C-N, C-O and C-S bond forming reactions of furfuryl cations have been developed, thus providing access to a diverse array of building blocks for further manipulations. PMID- 23736894 TI - Mycocrystallization of gold ions by the fungus Cylindrocladium floridanum. AB - The size and morphology determines the thermodynamic, physical and electronic properties of metal nanoparticles. The extracellular synthesis of gold nanoparticles by fungus, Cylindrocladium floridanum, which acts as a source of reducing and stabilizing agent has been described. The synthesized nanoparticles were characterized using techniques such as UV-Vis spectroscopy, X-ray diffraction (XRD), scanning electron microscopy, energy dispersive X-ray analysis (EDAX), and high-resolution transmission electron microscopy (HR-TEM). Based on the evidence of HR-TEM, the synthesized particles were found to be spherical with an average size of 19.05 nm. Powder XRD pattern proved the formation of (111) oriented face-centered cubic crystals of metallic gold. This microbial approach by fungus for the green synthesis of spherical gold nanoparticles has many advantages such as economic viability, scaling up and environment friendliness. PMID- 23736895 TI - Degradation of lindane and endosulfan by fungi, fungal and bacterial laccases. AB - The ability of two white-rot fungi (Trametes versicolor and Pleurotus ostreatus) and one brown-rot fungus (Gloeophyllum trabeum) to degrade two organochlorine insecticides, lindane and endosulfan, in liquid cultures was studied and dead fungal biomass was examined for adsorption of both insecticides from liquid medium. Lindane and endosulfan were also treated with fungal laccase and bacterial protein CotA, which has laccase activities. The amount of degraded lindane and endosulfan increased with their exposure period in the liquid cultures of both examined white-rot fungi. Endosulfan was transformed to endosulfan sulphate by T. versicolor and P. ostreatus. A small amount of endosulfan ether was also detected and its origin was examined. Degradation of lindane and endosulfan by a brown rot G. trabeum did not occur. Mycelial biomasses of all examined fungi have been found to adsorb lindane and endosulfan and adsorption onto fungal biomass should therefore be considered as a possible mechanism of pollutant removal when fungal degradation potentials are studied. Bacterial protein CotA performed more efficient degradation of lindane and endosulfan than fungal laccase and has shown potential for bioremediation of organic pollutants. PMID- 23736896 TI - Methylovorus sp. MP688 exopolysaccharides contribute to oxidative defense and bacterial survival under adverse condition. AB - Methylovorus sp. MP688 is an aerobic bacterium that can grow on reduced C1 compounds such as methanol, being regarded as an attractive producer for many commercial materials including polysaccharides. The aim of the study was to learn more information about the biochemical and physiological functions of extracellular polysaccharides (EPS) produced by Methylovorus sp. MP688. Firstly, gene clusters involved in EPS synthesis were identified by whole genome sequence analysis. Then EPS produced by Methylovorus sp. MP688 were isolated and purified by centrifugation, precipitation and deproteinization. Purified EPS displayed antioxidant activity towards DPPH free radical, hydroxyl radical and superoxide anion radical. Glucose, galactose and mannose were identified to be main component monosaccharides in EPS. One mutant with defect in EPS production was obtained by knocking out epsA gene within EPS synthesis cluster. Strain with deletion of epsA exhibited compromised growth ability in the presence of oxidative stress due to the sharp reduction in EPS synthesis. Meanwhile, the intracellular antioxidant scavengers were activated to a higher level in order to counteract with the excess harmful radicals. In addition, EPS were assimilated by Methylovorus sp. MP688 to survive under disadvantage condition when the preferred carbon source was exhausted. It was reasonable to conclude that EPS produced by Methylovorus sp. MP688 contributed to oxidative defense and bacterial survival under adverse condition. PMID- 23736897 TI - Corneal collagen cross-linking in the stabilization of PRK, LASIK, thermal keratoplasty, and orthokeratology. AB - PURPOSE OF REVIEW: To describe the use of corneal collagen cross-linking (CXL) and its efficacy in the stabilization of keratorefractive procedures, including PRK, laser in-situ keratomileusis (LASIK), thermal keratoplasty, and orthokeratology. RECENT FINDINGS: Since its introduction, CXL has quickly gained interest in the treatment of ectactic disorders due to its ability to increase the biomechanical stability of the cornea. In its earliest use, it has shown to be effective in the treatment of both keratoconus and post-LASIK ectasia. More recent studies of CXL in combination with keratorefractive procedures have shown varying degrees of success. SUMMARY: CXL with PRK has shown to be effective in slowing or halting the progression of keratoconus, pellucid marginal degeneration, and post-LASIK ectasia, in addition to potentially decreasing or delaying the need for penetrating keratoplasty. Several small case series have also demonstrated improved stability and efficacy of PRK and LASIK when combined with CXL, as well as a potentially decreased risk of postprocedure ectasia. In conjunction with thermokeratoplasty and orthokeratology, CXL has shown improved but only temporary results in the treatment of keratoconus. Future studies are needed to determine the efficacy and long-term stability of CXL in combination with keratorefractive procedures, as well as to address possible complications. PMID- 23736898 TI - A graphene-based label-free voltammetric immunosensor for sensitive detection of the egg allergen ovalbumin. AB - A graphene-based label-free voltammetric immunosensor for the sensitive detection of the egg white allergen ovalbumin has been developed. Graphene-modified screen printed carbon electrodes have been covalently functionalized using electrochemical reduction of in situ generated aryl diazonium salt forming a carboxyphenyl film on the graphene surface. The blocking property of the carboxyphenyl film grafted on to the graphene electrodes using different cyclic voltammetry cycles has been characterized using differential pulse voltammetry in [Fe(CN)6](3-/4-) solution. Then, the terminal carboxylic groups on the graphene surface were activated using EDC/NHS and used to immobilize the ovalbumin antibody and construct the immunosensor. The fabrication steps of the immunosensor have also been characterized using differential pulse voltammetry. The decrease in the [Fe(CN)6](3-/4-) reduction peak current after the immunochemical reaction with ovalbumin has been used for the ovalbumin detection. The developed immunosensor has been used for ovalbumin detection in the concentration range of 1 pg mL(-1) to 0.5 MUg mL(-1) with a detection limit of 0.83 pg mL(-1) in PBS buffer. The food matrix effect studied with ovalbumin spiked cake extract showed a good percentage of recovery, indicating the possible applicability of the developed immunosensor in real food samples. PMID- 23736900 TI - Pathways to certifications in physical medicine and rehabilitation in the United States: past, present, and future. AB - This article describes the certification pathways for Physiatrists in the United States, reviews the licensure, certification and accreditation pathways for rehabilitation facilities in the United States, examines the evolving models of health care in the United States, evaluates the impact of health care reform within the United States with particular emphasis on the intrinsic value of Physiatric services, and discusses how the intersection of certification, accreditation and emerging models of care in the United States present opportunities for Physiatrists instead of threats. These principles and practices should be relevant to Physiatrists and physiatric programs globally. PMID- 23736901 TI - Obesity: a disabling disease or a condition favoring disability? PMID- 23736902 TI - Rationale for hospital-based rehabilitation in obesity with comorbidities. AB - Severely obese patients affected by two or more chronic conditions which could mutually influence their outcome and disability can be defined as "complex" patients. The presence of multiple comorbidities often represents an obstacle for being admitted to clinical settings for the treatment of metabolic diseases. On the other hand, clinical Units with optimal standards for the treatment of pathological conditions in normal-weight patients are often structurally and technologically inadequate for the care of patients with extreme obesity. The aims of this review paper were to review the intrinsic (anthropometrics, body composition) and extrinsic (comorbidities) determinants of disability in obese patients and to provide an up-to-date definition of hospital-based multidisciplinary rehabilitation programs for severely obese patients with comorbidities. Rehabilitation of such patients require a here-and-now multidimensional, comprehensive approach, where the intensity of rehabilitative treatments depends on the disability level and severity of comorbidities and consists of the simultaneous provision of physiotherapy, diet and nutritional support, psychological counselling, adapted physical activity, specific nursing in hospitals with appropriate organizational and structural competences. PMID- 23736899 TI - The diverse functional LINCs of the nuclear envelope to the cytoskeleton and chromatin. AB - The nuclear envelope (NE) is connected to the different types of cytoskeletal elements by linker of nucleoskeleton and cytoskeleton (LINC) complexes. LINC complexes exist from yeast to humans, and have preserved their general architecture throughout evolution. They are composed of SUN and KASH domain proteins of the inner and the outer nuclear membrane, respectively. These SUN KASH bridges are used for the transmission of forces across the NE and support diverse biological processes. Here, we review the function of SUN and KASH domain proteins in various unicellular and multicellular species. Specifically, we discuss their influence on nuclear morphology and cytoskeletal organization. Further, emphasis is given on the role of LINC complexes in nuclear anchorage and migration as well as in genome organization. PMID- 23736903 TI - Outpatient rehabilitation outcomes in obese patients with orthopedic conditions. AB - BACKGROUND: Obesity is related to the development of functional and mobility impairment, musculoskeletal pain and orthopedic problems. Irrespective of age, obese children and adults have impaired walking capacity and body transfer ability, and difficulties navigating obstacle courses or community spaces. Obesity is related to relative strength deficits, musculoskeletal pain, kinesiophobia, low self-efficacy and a decline in quality of life. AIM: This review provides an update of the available evidence for the efficacy of outpatient rehabilitation programs for the treatment of disabling obesity. RESULTS: Outpatient rehabilitation programs can effectively improve muscle strength, self-confidence and physical function. Key rehabilitation components should include aerobic exercise (AX), resistance exercise (RX) and cognitive strategies to cope with the unique challenges posed by obesity. Available high quality evidence indicates that 3-18 month rehabilitation programs that included aerobic and strengthening exercise (2-3 days per week) with caloric restriction (typically 500-750 kcal deficit/ day), elicited the best changes in functional performance measures compared with exercise or diet alone. CONCLUSION: Comprehensive outpatient rehabilitation interventions coupled with diet can catalyze lifestyle patterns that improve and preserve physical function over the life span. PMID- 23736904 TI - Rehabilitation needs after bariatric surgery. AB - BACKGROUND: Bariatric surgery has grown from an obscure experimental procedure to one of the most popular operations in the world. Such accelerated progress left many gaps, notably concerning subsequent rehabilitation needs of this population. AIM: In the present study, a brief description of both the patients and the interventions is provided, along with potentially disabling features especially concerning the locomotor system, which has received comparatively little attention . DESIGN: Based on reported protocols and actual experience, major issues are addressed. SETTING: Bariatric patients are initially managed in the hospital, however long-term and even lifetime needs may be recognized, requiring major lifestyle and physical activity changes. These have to be focused in all settings, inside and outside the healthcare institutions. POPULATION: Initially only adults were considered bariatric candidates, however currently also adolescents and the elderly are admitted in many centers. RESULTS: Bariatric weight loss is certainly successful for remission or prevention of metabolic, cardiovascular and cancer comorbidities. Yet benefits for bones, joints and muscles, along with general physical performance are still incompletely established. This should be no reason for denying continued care to such individuals, within the context of well-designed protocols, as available evidence points toward favorable rehabilitation in the realms of physical, social and workplace activities. CONCLUSION: The importance of a physiatric curriculum in medical schools has been emphasized. Even more crucial is the presence of such a specialists in obesity and bariatric teams, a requirement recognized in a few countries but not in others. CLINICAL REHABILITATION IMPACT: The relevance of obesity as a disabling condition is reviewed, along with the positive changes induced by surgical weight loss. Although obesity alleviation is a legitimate end point it is not a sufficient one. The shortcomings of such result from the point of view of physical normalization are outlined, and recommendations are suggested. PMID- 23736905 TI - Intrinsic radiative lifetime derived via absorption cross section of one dimensional excitons. AB - Intrinsic radiative lifetime is an essential physical property of low-dimensional excitons that represents their optical transition rate and wavefunction, which directly measures the probability of finding an electron and a hole at the same position in an exciton. However, the conventional method that is used to determine this property via measuring the temperature-dependent photoluminescence (PL) decay time involves uncertainty due to various extrinsic contributions at high temperatures. Here, we propose an alternative method to derive the intrinsic radiative lifetime via temperature-independent measurement of the absorption cross section and transformation using Einstein's A-B-coefficient equations derived for low-dimensional excitons. We experimentally verified our approach for one-dimensional (1D) excitons in high-quality 14 * 6 nm(2) quantum wires by comparing it to the conventional approach. Both independent evaluations showed good agreement with each other and with theoretical predictions. This approach opens a promising path to studying low-dimensional exciton physics. PMID- 23736906 TI - Pelagicola litorisediminis sp. nov., a novel alphaproteobacterium isolated from tidal flat sediment. AB - A Gram-negative, aerobic, non-motile and rod-shaped or ovoid bacterial strain, designated D1-W8(T), was isolated from a tidal flat on the South Sea in South Korea. Strain D1-W8(T) was found to grow optimally at 25 degrees C, at pH 7.0 8.0 and in the presence of 2.0-3.0 % (w/v) NaCl. Neighbour-joining, maximum likelihood and maximum-parsimony phylogenetic trees based on 16S rRNA gene sequences revealed that strain D1-W8(T) clustered with the type strain of Pelagicola litoralis showing 97.1 % sequence identity. 16S rRNA gene sequences of the type strains of other species exhibited lower similarity values. Strain D1 W8(T) was determined to contain Q-10 as the predominant ubiquinone and C18:1 omega7c as the predominant fatty acid. The major polar lipids of strain D1-W8(T) were identified as phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, one unidentified aminolipid and one unidentified lipid. The DNA G+C content of strain D1-W8(T) was determined to be 57.9 mol% and its DNA DNA relatedness value with the type strain of P. litoralis was 17 %. The differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, revealed that strain D1-W8(T) is separate from P. litoralis. On the basis of the data presented, strain D1-W8(T) is considered to represent a novel species of the genus Pelagicola, for which the name Pelagicola litorisediminis sp. nov. is proposed. The type strain is D1-W8(T) (= KCTC 32327(T) = CECT 8287(T)). PMID- 23736908 TI - Haematological improvement as a beneficial effect during deferasirox treatment in transfusion-dependent patients with myelodysplastic syndrome. PMID- 23736907 TI - Kinetics and thermodynamics of glycans and glycoproteins binding to Holothuria scabra lectin: a fluorescence and surface plasmon resonance spectroscopic study. AB - Holothuria scabra produces a monomeric lectin (HSL) of 182 kDa. HSL showed strong antibacterial activity and induced bacterial agglutination under in vitro conditions, indicating its role in animals' innate immune responses. Very few lectins have been reported from echinoderms and none of these lectins have been explored in detail for their sugar-binding kinetics. Affinity, kinetics and thermodynamic analysis of glycans and glycoproteins binding to HSL were studied by fluorescence and surface plasmon resonance spectroscopy. Lectin binds with higher affinity to O-linked than N-linked asialo glycans, and the affinities were relatively higher than that for sialated glycans and glycoproteins. T-antigen alpha-methyl glycoside was the most potent ligand having the highest affinity (Ka 8.32 *10(7) M(-1)). Thermodynamic and kinetic analysis indicated that the binding of galactosyl Tn-antigen and asialo glycans is accompanied by an enthalpic contribution in addition to higher association rate coupled by low activation energy for the association process. Presence of sialic acid or protein matrix inhibits binding. Higher affinity of HSL for O-glycans than N-glycans had biological implications; since HSL specifically recognizes bacteria, which have mucin or O-glycan cognate on their cell surfaces and play a major role in animal innate immunity. Since, HSL had higher affinity to T-antigen, makes it a useful tool for cancer diagnostic purpose. PMID- 23736909 TI - A cure for post-radiation proctitis? PMID- 23736910 TI - A new strategy to identify rare blood donors: single polymerase chain reaction multiplex SNaPshot reaction for detection of 16 blood group alleles. AB - BACKGROUND: As an alternative to phenotyping, large-scale DNA-based assays, which are feasible for high-throughput donor red blood cell typing, were developed for determination of blood group polymorphisms. However, high-throughput genotyping platforms based on these technologies are still expensive and the inclusion of single nucleotide polymorphisms and analysis of the alleles depend on the manufacturer's determination. To overcome this limitation and in order to develop an assay to enable the screening of rare donors, we developed a SNaPshot assay for analysis of nine single nucleotide polymorphisms related to antigens that are difficult to assess using conventional serology. MATERIALS AND METHODS: The single polymerase chain reaction multiplex SNaPshot reaction was optimized to identify nine single nucleotide polymorphisms determining 16 alleles: KEL*3/KEL*4, KEL*6/KEL*7, DI*1/DI*2, DI*3/DI*4, YT*1/YT*2, CO*1/CO*2, DO*1/DO*2, DO*4, DO*5. We designed a single multiplex PCR with primers encompassing the blood group single nucleotide polymorphisms and performed an internal reaction with probe primers able to discriminate the alleles after fragment analysis. The SNaPshot assay was validated with 140 known alleles previously determined by PCR restriction fragment length polymorphism. RESULTS: We were able to simultaneous detect nine single nucleotide polymorphisms defining 16 blood group alleles on an assay based on a multiplex PCR combined with a single base extension using genomic DNA. DISCUSSION: This study demonstrates a robust genotyping strategy for conducting rare donor screening which can be applied in blood centers and could be an important tool for identifying antigen-negative donors and, therefore, for providing rare blood. PMID- 23736911 TI - Prophylactic efficacy and pharmacokinetically guided dosing of a von Willebrand factor/factor VIII concentrate in adults and children with von Willebrand's disease undergoing elective surgery: a pooled and comparative analysis of data from USA and European Union clinical trials. AB - BACKGROUND: Surgical intervention may pose significant risk of life-threatening bleeding in patients with von Willebrand's disease; prophylactic treatment with von Willebrand factor/factor VIII concentrate is generally indicated for von Willebrand's disease characterized by moderate to severe qualitative and quantitative deficiencies of Willebrand factor to raise and maintain both Willebrand factor and FVIII at haemostatic levels for surgical prophylaxis. MATERIALS AND METHODS: Since prospective clinical data in such situations were lacking, two recent, prospective, multicentre studies evaluated the prophylactic perioperative use of the on Willebrand factor/ factor VIII concentrates, Humate P(r) and Haemate P. Despite some differences in the two studies, one conducted in the USA (n =35) and one in the European Union (n =27), the designs were similar enough to allow for a limited pooled analysis of data. In both studies, preoperative loading doses and subsequent maintenance doses were calculated using individual subject-derived incremental in vivo recovery values, although von Willebrand factor:ristocetin cofactor and FVIII:coagulation activity target levels differed between the protocols. Efficacy was rated daily by the investigator as excellent, good, moderate, or poor. RESULTS: Overall haemostatic efficacy (rating of excellent/good), assessed 24 hours after the last infusion (USA) or taken as the worst rating between surgery and day 14 (EU), was achieved in 95% of the pooled population of 62 adults and children. Efficacy did not appear to be affected by dosing variations. The rate of possibly related adverse events was low (8 subjects; 13%); one of these events was considered serious (pulmonary embolism). DISCUSSION: This pooled analysis of a relatively large number of patients for a rare disease confirms the feasibility of pharmacokinetically guided dosing of von Willebrand factor/factor VIII concentrate and highlights its efficacy and safety in the prevention of excessive perioperative bleeding. PMID- 23736912 TI - Idiopathic thrombocytopenic purpura resistant to eltrombopag, but cured with romiplostim. PMID- 23736913 TI - Detection of functional vitamin B12 and folate deficiencies, while serum levels are normal. PMID- 23736914 TI - A possible role of soluble HLA-I molecule in the immunomodulatory effects of therapeutic apheresis. PMID- 23736915 TI - Outcome in moderate haemophilia: back to the past? Remarks on haemophilia A classification and treatment. PMID- 23736916 TI - Impact of changes to policy for Mexican risk travel on Canadian blood donor deferrals. AB - BACKGROUND: Travel to malaria risk areas such as Mexico is a common source of donor deferral in Canada. On February 21st, 2011 the deferrable regions in Mexico were revised to permit donation if donors travelled to the state of Quintana Roo, Mexico, a popular ocean-side resort area. MATERIALS AND METHODS: Canadian travel data and malaria deferral rates since 2007 were plotted to examine trends. Deferral records in one centre were accessed from January to April, 2011 to tabulate travel destinations of deferred donors immediately before and after the change. RESULTS: Travel to Mexico and the Caribbean accounts for 63% of general population travel, and travel to Mexico has been increasing (P <0.05). Deferral for short-term malaria risk travel has a strong seasonal trend with peaks in the winter and troughs in the summer. Approximately 36,000 fewer donations were lost following the change, a reduction of 37% from the previous year. Deferrals in one centre increased for Caribbean/Central America after the change (P <0.05) consistent with the seasonal trend, but decreased for Mexico (P <0.05). DISCUSSION: Deferrals for malaria risk travel are substantial. Careful revision and refinement of risk areas of travel can significantly reduce the burden of deferral. PMID- 23736917 TI - A possible case of Chagas disease reactivation after a bone marrow transplant. PMID- 23736918 TI - Probable hepatitis C virus transmission from a seronegative blood donor via cellular blood products. PMID- 23736919 TI - Gene frequencies of human platelet alloantigens 1-5 in two Arab populations. AB - BACKGROUND: Polymorphisms of the human platelet alloantigens (HPA) arise from single base pair substitutions in alleles and lead to changes in amino acids of glycoproteins expressed on platelets. The aim of this study was to determine the gene frequencies of the five common HPA (HPA-1 to -5) in Egyptians and Jordanians and to compare these data with those established for other populations. MATERIALS AND METHODS: HPA genotyping was done by polymerase chain reaction with sequence specific primers. RESULTS: The gene frequencies obtained in Egyptians were: HPA 1a/b, 0.767/0.233; HPA-2a/b, 0.759/0.241; HPA-3a/b, 0.704/0.296; HPA-4a/b, 1/0; HPA-5a/b, 0.728/0.272, while the frequencies in Jordanians were: HPA-1a/b, 0.821/0.179; HPA-2a/b, 0.877/0.123; HPA-3a/b, 0.660/0.340; HPA-4a/b, 1/0; HPA 5a/b, 0.795/0.205. The observed gene frequencies in both populations were in Hardy-Weinberg equilibrium. The gene frequencies for HPA-2b and HPA-5b among Egyptians were the highest reported among Arabs. Except for HPA-2, there were no significant differences in the distribution of HPA-1 to -5 between the two populations. CONCLUSION: The distributions of HPA alleles among Egyptians and Jordanians are similar to those reported for other Arabs. This study reports the first data on gene frequencies of HPA in Egyptians and Jordanians. PMID- 23736921 TI - Preoperative autologous blood donation in lower limb arthroplasty surgery: has the time come for its retirement? PMID- 23736920 TI - T-regulatory cell-mediated immune tolerance as a potential immunotherapeutic strategy to facilitate graft survival. PMID- 23736922 TI - Blood management and transfusion strategies in 600 patients undergoing total joint arthroplasty: an analysis of pre-operative autologous blood donation. AB - BACKGROUND: Blood loss during total joint arthroplasty strongly influences the time to recover after surgery and the quality of the recovery. Blood conservation strategies such as pre-operative autologous blood donation and post-operative cell salvage are intended to avoid allogeneic blood transfusions and their associated risks. Although widely investigated, the real effectiveness of these alternative transfusion practices remains controversial. MATERIALS AND METHODS: The surgery reports of 600 patients undergoing total joint arthroplasty (312 hip and 288 knee replacements) were retrospectively reviewed to assess transfusion needs and related blood management at our institute. Evaluation parameters included post-operative blood loss, haemoglobin concentration measured at different time points, ASA score, and blood transfusion strategies. RESULTS: Autologous blood donation increased the odds of receiving a red blood cell transfusion. Reinfusion by a cell salvage system of post-operative shed blood was found to limit adverse effects in cases of severe post-operative blood loss. The peri-operative net decrease in haemoglobin concentration was higher in patients who had predeposited autologous blood than in those who had not. DISCUSSION: The strengths of this study are the high number of cases and the standardised procedures, all operations having been performed by a single orthopaedic surgeon and a single anaesthesiologist. Our data suggest that a pre-operative autologous donation programme may often be useless, if not harmful. Conversely, the use of a cell salvage system may be effective in reducing the impact of blood transfusion on a patient's physiological status. Basal haemoglobin concentration emerged as a useful indicator of transfusion probability in total joint replacement procedures. PMID- 23736924 TI - A report of a rare case of autoimmune haemolytic anaemia in a patient with Hodgkin's disease in whom routine serology was negative. PMID- 23736923 TI - Ulinastatin, a protease inhibitor, may inhibit allogeneic blood transfusion associated pro-inflammatory cytokines and systemic inflammatory response syndrome and improve postoperative recovery. AB - BACKGROUND: The aim of this study was to investigate the effects of ulinastatin, a protease inhibitor, and blood transfusion on perioperative surgical complications, changes of systemic inflammatory response syndrome (SIRS) scores, and levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha) in patients undergoing liver resection. MATERIALS AND METHODS: Patients aged 18-65 years were enrolled and divided into four groups (12 patients in each group): a control group, a group given ulinastatin (UTI group), a group given blood transfusion (BT group), and a group given both blood transfusion and ulinastatin (BT+UTI group). Patients were randomised to receive ulinastatin or not, whereas blood transfusion was administered based on a transfusion trigger. Ulinastatin was given at a dose of 100,000 units/10 kg, infused 15 min before allogeneic blood transfusion or after completion of the liver resection. The patients were followed up for 3 days to record surgical complications, SIRS scores and levels of IL-6, IL-8 and TNF-alpha. RESULTS: Forty four patients were included in the data analysis. The SIRS rate (SIRS scores>=2) was significantly higher in the BT groups than in the control group at 6 hours and on day 3 after surgery and was significantly lower in the BT+UTI group than in the BT group on day 3 after surgery. Allogeneic blood transfusion significantly increased and ulinastatin significantly decreased postoperative levels of IL-6, IL-8, and TNF-alpha. The length of stay in hospital was significantly longer in the BT groups than in the control group but was not significantly different between the BT+UTI and BT groups. CONCLUSION: A single dose of ulinastatin before allogeneic blood transfusion may lower the rate of postoperative SIRS and levels of IL-6, IL-8 and TNF-alpha associated with allogeneic blood transfusion and improve patients' postoperative recovery. PMID- 23736925 TI - Antiplatelet agents in clinical practice and their haemorrhagic risk. PMID- 23736927 TI - Voluntary non-remunerated blood donation and reasons for donating: is there room for philosophy? PMID- 23736926 TI - Infusible platelet membrane as a platelet substitute for transfusion: an overview. PMID- 23736928 TI - Pleural tissue repair with cord blood platelet gel. AB - BACKGROUND: Prolonged air leak is the major cause of morbidity after pulmonary resection. In this study we used in vitro and in vivo experiments to investigate an innovative approach based on the use of human umbilical cord blood platelet gel. MATERIALS AND METHODS: In vitro, a scratch assay was performed to test the tissue repair capability mediated by cord blood platelet gel compared to the standard culture conditions using human primary mesothelial cells. In vivo, an iatrogenic injury was made to the left lung of 54 Wistar rats. Cord blood platelet gel was placed on the injured area only in treated animals and at different times histological changes and the presence of pleural adhesions were evaluated. In addition, changes in the pattern of soluble inflammatory factors were investigated using a multiplex proteome array. RESULTS: In vitro, mesothelial cell damage was repaired in a shorter time by cord blood platelet gel than in the control condition (24 versus 35 hours, respectively). In vivo, formation of new mesothelial tissue and complete tissue recovery were observed at 45+/-1 and 75+/-1 hours in treated animals and at 130+/-2.5 and 160+/-6 hours in controls, respectively. Pleural adhesions were evident in 43% of treated animals compared to 17% of controls. No complications were observed. Interestingly, some crucial soluble factors involved in inflammation were significantly reduced in treated animals. DISCUSSION: Cord blood platelet gel accelerates the repair of pleural damage and stimulates the development of pleural adhesions. Both properties could be particularly useful in the management of prolonged air leak, and to reduce inflammation. PMID- 23736929 TI - Haemostasis and immunity: cross-talking systems? PMID- 23736930 TI - The prevention of adverse reactions to transfusions in patients with haemoglobinopathies: a proposed algorithm. AB - BACKGROUND: Transfusion therapy remains the main treatment for patients with severe haemoglobinopathies, but can cause adverse reactions which may be classified as immediate or delayed. The use of targeted prevention with drugs and treatments of blood components in selected patients can contribute to reducing the development of some reactions.The aim of our study was to develop an algorithm capable of guiding behaviours to adopt in order to reduce the incidence of immediate transfusion reactions. MATERIALS AND METHODS: Immediate transfusion reactions occurring over a 7-year period in 81 patients with transfusion dependent haemoglobinopathies were recorded. The patients received transfusions with red cell concentrates that had been filtered prestorage. Various measures were undertaken to prevent transfusion reactions: leucoreduction, washing the red blood cells, prophylactic administration of an antihistamine (loratidine 10 mg tablet) or an antipyretic (paracetamol 500 mg tablet). RESULTS: Over the study period 20,668 red cell concentrates were transfused and 64 adverse transfusion reactions were recorded in 36 patients. The mean incidence of reactions in the 7 years of observation was 3.10/00. Over the years the incidence gradually decreased from 6.80/00 in 2004 to 0.90/00 in 2010. DISCUSSION: Preventive measures are not required for patients who have an occasional reaction, because the probability that such a type of reaction recurs is very low. In contrast, the targeted use of drugs such as loratidine or paracetamol, sometimes combined with washing and/or double filtration of red blood cells, can reduce the rate of recurrent (allergic) reactions to about 0.90/00. The system for detecting adverse reactions and training staff involved in transfusion therapy are critical points for reliable collection of data and standardisation of the detection system is recommended for those wanting to monitor the incidence of all adverse reactions, including minor ones. PMID- 23736931 TI - Ethical and legal aspects of refusal of blood transfusions by Jehovah's Witnesses, with particular reference to Italy. PMID- 23736932 TI - Low perception of sexual behaviours at risk for human immunodeficiency virus infection among blood donors who call the AIDS/STI Help Line in Italy. AB - BACKGROUND: In Italy, the circulation of human immunodeficiency virus (HIV) has expanded to include population groups that do not perceive themselves to be "at risk" of HIV infection and who do not even consider undergoing HIV testing. The aim of this study was to describe the socio-demographic and behavioural characteristics, and perceived risk of HIV infection in a sample of blood donors who reported never having been tested for HIV. MATERIALS AND METHODS: A questionnaire was administered to a sample of donors who called the Italian National AIDS/STI Help Line and reported never having been tested for HIV. RESULTS: The study sample consisted of 164 blood donors: 29.3% had given blood in the preceding 2 years. With regards to at-risk behaviours, 39.6% of the donors interviewed were heterosexuals who had sexual contacts with multiple partners, and 5.5% were men who had sex with multiple male partners. Sexual contacts with female sex workers were reported by 11.6% of first-time donors and 25.7% of repeat donors. Of the 164 donors interviewed, 125 (76.2%) said that the main reason that they had never been tested for HIV was that they did not consider themselves at risk. Among these, 56 (44.8%) reported that they would have sexual contacts with a sex worker, 52 (41.6%) reported that they would have sexual contacts with someone having more than one sexual partner, and 36 (28.8%) reported that they would have sexual contacts without using a condom. DISCUSSION: All the donors interviewed reported that they had never been tested for HIV despite the fact that they had been certainly been tested upon blood donation. These results show that some sexual behaviours may not be perceived as behaviours at risk for acquiring HIV infection. These findings suggest that not all blood donors are knowledgeable about HIV risk behaviours and that an explicit pre donation questionnaire and effective counselling continue to be important for the selection of candidate donors. PMID- 23736933 TI - Automated red cell exchange: a simplified formula for how many red cell units to exchange and validity of haemoglobin S levels measured one to two hours later. PMID- 23736934 TI - Waldenstrom's macroglobulinaemia complicated by pure red cell aplasia: a case report. PMID- 23736935 TI - The relationship between Chagas disease and immunosuppressive therapy. PMID- 23736936 TI - Arginase as a new concern in blood transfusion. PMID- 23736938 TI - Surgical consideration of cervical dumbbell tumors. AB - BACKGROUND: Nineteen patients with cervical dumbbell tumors treated surgically were analyzed retrospectively. METHODS: Surgical strategies for dumbbell tumor were discussed from the perspective of safe, less-invasive surgery. RESULTS: Patients included 6 men and 13 women, with a mean age at the time of surgery of 48.3 years (range, 25-70 years). Underlying pathologies included 16 schwannomas, 2 neurofibromas, and 1 double tumor (schwannoma and meningioma). According to Eden's classification, one patient was classified as Type 1, 5 as Type 2, 8 as Type 3, and 5 as Type 4. In 13 cases, tumors were excised through the posterior approach alone, compared to five cases using the anterior approach. One case was excised using combined anterior and posterior approaches. Facetectomy was not performed in 18 cases. In one case, the facet joint on one side had already destroyed and needed instrumentation. Tumors were totally excised in all cases. Postoperatively, the patients did not display any further neurological deficit, with the exception of transient radiculopathy in two patients. Major surgical complications and cerebrospinal fluid leakage were not seen. Tumor recurrence and spinal segmental instability were not found during follow-up period (mean, 41.6 months). CONCLUSIONS: Dumbbell tumor surgery requires sufficient debulking of the epidural and paravertebral mass, using intraoperative nerve stimulation and Doppler ultrasonography to detect the vertebral artery. When using a posterior approach, recapping laminoplasty using an ultrasonic bone curette is very useful to remove tumor without sacrificing facet joints. PMID- 23736939 TI - Endoscopic endonasal trans-sphenoidal approach for pituitary adenomas: is one nostril enough? AB - BACKGROUND: Over the past decade, the endoscopic endonasal trans-sphenoidal approach has been used to resect pituitary adenomas. However, in the use of this procedure, some research teams prefer a two-nostril method, whereas other groups are in favor of the one-nostril method. Here, we present a series of pituitary adenomas and try to confirm whether or not one nostril is enough for endoscopic resection of most pituitary adenomas. METHODS: A total of 250 consecutive patients who underwent an endoscopic endonasal trans-sphenoidal approach were reviewed retrospectively, of which 200 were via the unilateral nostril (group 1) and 50 were via bilateral nostrils (group 2). Surgical and clinical outcomes were analyzed. RESULTS: For microadenomas, intrasellar macroadenomas and macroadenomas with moderate extrasellar extension, the prevalence of gross total resection (GTR), hormonal outcome and visual improvement were similar between the two groups. The one-nostril group had better results for duration of surgery and blood loss, with fewer rhinological complications. However, for macroadenomas with extensive extrasellar invasion, GTR was obtained in two of seven patients in group 2 but none in group 1. CONCLUSION: The one-nostril method, which is relatively fast and minimally invasive, is adequate for endoscopic resection of most pituitary adenomas with moderate extension. PMID- 23736940 TI - Single nucleotide polymorphism typing with massively parallel sequencing for human identification. AB - The Ion AmpliSeqTM HID single nucleotide polymorphism (SNP) panel, a primer pool of 103 autosomal SNPs and 33 Y-SNPs, was evaluated using the Ion 314TM Chip on the Ion PGMTM Sequencer with four DNA samples. The study focused on the sequencing of DNA at three different initial target quantities, related interpretation issues, and concordance of results with another sequencing platform, i.e., Genome Analyzer IIx. With 10 ng of template DNA, all genotypes at the 136 SNPs were detected. With 1 ng of DNA, all SNPs were detected and one SNP locus in one sample showed extreme heterozygote imbalance on allele coverage. With 100 pg of DNA, an average of 1.6 SNP loci were not detected, and an average of 4.3 SNPs showed heterozygote imbalance. The average sequence coverage was 945 600* at autosomal SNPs and 465-209* at Y-SNPs for 10 ng-100 pg of DNA. The average heterozygote allele coverage ratio was 89.6-61.8 % for 10 ng-100 pg of DNA. At 10 ng of DNA, all genotypes of the 95 SNPs shared between the two different sequencing platforms were concordant except for one SNP, rs1029047. The error was due to the misalignment of a flanking homopolymer. Overall, the data support that genotyping a large battery of SNPs is feasible with massively parallel sequencing. With barcode systems, better allele balance, and specifically designed alignment software, a more comprehensive rapid genotyping and more cost-effective results may be obtained from multiple samples in one analysis than are possible with current typing and capillary electrophoresis systems. PMID- 23736941 TI - Human deforestation outweighs future climate change impacts of sedimentation on coral reefs. AB - Near-shore coral reef systems are experiencing increased sediment supply due to conversion of forests to other land uses. Counteracting increased sediment loads requires an understanding of the relationship between forest cover and sediment supply, and how this relationship might change in the future. Here we study this relationship by simulating river flow and sediment supply in four watersheds that are adjacent to Madagascar's major coral reef ecosystems for a range of future climate change projections and land-use change scenarios. We show that by 2090, all four watersheds are predicted to experience temperature increases and/or precipitation declines that, when combined, result in decreases in river flow and sediment load. However, these climate change-driven declines are outweighed by the impact of deforestation. Consequently, our analyses suggest that regional land-use management is more important than mediating climate change for influencing sedimentation of Malagasy coral reefs. PMID- 23736942 TI - [Eustachian tube function tests: an update]. AB - There are many diverse methods for the assessment of Eustachian tube (ET) function. Clinical studies have demonstrated good results for several clinical tests, tympanometry and a number of manometric approaches, such as the nine-step test. The relevance of tubomanometry according to Esteve requires further investigation. MRI studies in particular have considerably enhanced our knowledge of ET function. Endoscopy and conventional Schuller radiography are routinely employed in the clinic. The pressure chamber is ideal for simulating the most diverse test conditions, but it is only used experimentally. Sonotubometry has both the potential and the necessary level of technical advancement for a broader clinical application. The majority of investigations have demonstrated that there is no single valid method. There is currently no technique available that is capable of reflecting all aspects of ET function. Although several methods have found clinical application, a commonly accepted golden standard for ET testing still has to be established. Further clinical studies are necessary to generate an adequate amount of data pertaining to the various ET function tests. PMID- 23736943 TI - "If i wasn't this robust": patients' expectations and experiences at the Outcome Measures in Rheumatology Conference 2010. AB - BACKGROUND: Patients are incidentally involved in scientific conferences as collaborating partners. Little is known about how they engage with researchers. OBJECTIVE: The purpose of this study was to explore the expectations and experiences of new patients to better understand the specific features of collaborative research during conferences in its complexity. STUDY DESIGN: After a thematic literature review, we conducted fourteen interviews with eight delegates: four men and four women with three rheumatic diseases and representing five countries. They participated for the first time in the biannual conference on Outcome Measures in Rheumatology (OMERACT) in 2010. Data were subjected to a thematic content analysis. RESULTS: Before the conference, patient participants had felt privileged to be invited but felt insufficiently prepared and uncertain about what was expected from their participation. They had anticipated a learning experience and had hoped to be able to make a contribution. Most experienced the conference program as physically and mentally challenging, partially due to poor moderation or lack of individual support. They doubted their input had been beneficial. After the conference these patients also described their participation as having been a valuable, meaningful, and learning experience. Although they presumed that they had not been very productive, they expected their contribution would be more effective at future conferences. CONCLUSIONS: Patient delegates attending a scientific conference need clear information about their role prior to the event. Personalized support and a facilitative moderation style during sessions are advantageous for maximizing valuable contributions. Participation leads to personal learning curves and various benefits. PMID- 23736944 TI - Facilitative effects of VNS on the motor threshold: implications for its antidepressive mode of action? AB - In the present study, the effects of vagus nerve stimulation (VNS) on the resting motor threshold (rMT) of patients treated with repetitive transcranial magnetic stimulation were evaluated. Patients showed a significant decrease in the rMT during VNS-on stimulation. VNS was the only significant factor affecting rMT changes and did not appear to be a static variable. Further studies should focus on the effect of VNS on neural neurogenesis in depressive disorders, and the effects of other treatment options for major depressive disorder on the rMT should also be determined. PMID- 23736946 TI - Postweaning social isolation exacerbates neurotoxic effects of the NMDA receptor antagonist MK-801 in rats. AB - The glutamate hypothesis of schizophrenia postulates NMDA receptor hypofunction as important pathophysiological mechanism. In rodents, NMDA receptor antagonists induce together with psychosis-like effects cortical injury. Stress during adolescence can trigger schizophrenia by unknown mechanisms. Here we show in rats that juvenile chronic isolation significantly increases MK-801-triggered expression of heat shock protein 70, a marker of neuronal injury, in the retrosplenial cortex. These data suggest an additive effect of juvenile stress and NMDA receptor blockade, with possible relevance for schizophrenia. PMID- 23736947 TI - Neuron specific enolase and serum remain unaffected by ultra high frequency left prefrontal transcranial magnetic stimulation in patients with depression: a preliminary study. AB - Serum levels of neuron specific enolase (NSE) and protein S-100 were analysed in 22 patients with depression, who got repetitive transcranial magnetic stimulation (rTMS) for 3 weeks with ultra high frequency stimulation or sham. NSE and S-100 at baseline and after 3 weeks did not differ between the groups. Neither in the ultra high frequency group, nor in the sham group a difference between baseline and end could be found. No evidence for a significant rise in brain damage markers in rTMS was found in this preliminary study. PMID- 23736948 TI - Educational and behavioural interventions for anticoagulant therapy in patients with atrial fibrillation. AB - BACKGROUND: Current guidelines recommend oral anticoagulation therapy for patients with atrial fibrillation who are at moderate-to-high risk of stroke, however anticoagulation control (time in therapeutic range (TTR)) is dependent on many factors. Educational and behavioural interventions may impact on patients' ability to maintain their International Normalised Ratio (INR) control. OBJECTIVES: To evaluate the effects on TTR of educational and behavioural interventions for oral anticoagulation therapy (OAT) in patients with atrial fibrillation (AF). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and the Database of Abstracts of Reviews of Effects (DARE) in The Cochrane Library (2012, Issue 7 of 12), MEDLINE Ovid (1950 to week 4 July 2012), EMBASE Classic + EMBASE Ovid (1947 to Week 31 2012), PsycINFO Ovid (1806 to 2012 week 5 July) on 8 August 2012 and CINAHL Plus with Full Text EBSCO (to August 2012) on 9 August 2012. We applied no language restrictions. SELECTION CRITERIA: The primary outcome analysed was TTR. Secondary outcomes included decision conflict (patient's uncertainty in making health-related decisions), percentage of INRs in the therapeutic range, major bleeding, stroke and thromboembolic events, patient knowledge, patient satisfaction, quality of life (QoL), and anxiety. DATA COLLECTION AND ANALYSIS: The two review authors independently extracted data. Where insufficient data were present to conduct a meta-analysis, effect sizes and confidence intervals (CIs) of the included studies were reported. Data were pooled for two outcomes, TTR and decision conflict. MAIN RESULTS: Eight trials with a total of 1215 AF patients (number of AF participants included in the individual trials ranging from 14 to 434) were included within the review. Studies included education, decision aids, and self monitoring plus education.For the primary outcome of TTR, data for the AF participants in two self-monitoring plus education trials were pooled and did not favour self-monitoring plus education or usual care in improving TTR, with a mean difference of 6.31 (95% CI -5.63 to 18.25). For the secondary outcome of decision conflict, data from two decision aid trials favoured usual care over the decision aid in terms of reducing decision conflict, with a mean difference of -0.1 (95% CI -0.2 to -0.02). AUTHORS' CONCLUSIONS: This review demonstrated that there is insufficient evidence to draw definitive conclusions regarding the impact of educational or behavioural interventions on TTR in AF patients receiving OAT. Thus, more trials are needed to examine the impact of interventions on anticoagulation control in AF patients and the mechanisms by which they are successful. It is also important to explore the psychological implications for patients suffering from this long-term chronic condition. PMID- 23736949 TI - Adenosine and verapamil for no-reflow during primary percutaneous coronary intervention in people with acute myocardial infarction. AB - BACKGROUND: Primary percutaneous coronary intervention (PPCI) is the preferred treatment for ST segment elevation myocardial infarction. Although there is restoration of coronary flow after PPCI, impaired myocardial perfusion (known as no-reflow) is frequently observed, and is related to poor clinical outcomes. In order to overcome this phenomenon, drugs have been tried as adjunctive treatments to PPCI. Among them, verapamil and adenosine are two of the most promising drugs. There are no systematic reviews of these two drugs in people with acute myocardial infarction (AMI) undergoing PPCI. OBJECTIVES: To study the impact of adenosine and verapamil on people with AMI who are undergoing PPCI. SEARCH METHODS: We searched the following databases in February 2012: the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, Web of Science and BIOSIS, China National Knowledge Infrastructure, Clinical Trials registers (Clinical Trials.gov, Current Controlled Trials, Australian & New Zealand Clinical Trials Registry, the WHO International Clinical Trials Registry Platform). We also handsearched the American Journal of Cardiology. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) where adenosine or verapamil was the primary intervention. Participants were individuals diagnosed with AMI who were undergoing PPCI. DATA COLLECTION AND ANALYSIS: Two review authors collected studies and extracted data. Where necessary, we contacted the trial authors to obtain the relevant information. We calculated risk ratios (RRs), P values, and 95% confidence intervals (CIs) of dichotomous data. MAIN RESULTS: We included 10 RCTs involving 939 participants in our review. Nine RCTs were associated with adenosine and one with verapamil. We considered the overall risk of bias of included studies to be moderate. There was no evidence that adenosine reduced short-term all-cause mortality (RR 0.61, 95% CI 0.23 to 1.61, P = 0.32), long-term all-cause mortality (RR 1.20, 95% CI 0.27 to 5.22, P = 0.81), short-term non-fatal myocardial infarction (RR 1.38, 95% 0.28 to 6.96, P = 0.69) or the incidence of angiographic no-reflow (TIMI flow grade < 3 after PPCI: RR 0.72, 95% CI 0.49 to 1.07, P = 0.11, and myocardial blush grade (MBG) 0 to 1 after PPCI: RR 0.96, 95% CI 0.76 to 1.22, P=0.75). But the incidence of adverse events with adenosine, such as bradycardia (RR 6.57, 95% CI 2.94 to 14.67, P<0.00001), hypotension (RR 11.43, 95% CI 2.75 to 47.57, P=0.0008) and atrioventricular (AV) block (RR 6.67, 95% CI 1.52 to 29.21, P=0.01) was significantly increased.Meta-analysis of verapamil as treatment for no-reflow during PPCI was not calculated due to lack of data. AUTHORS' CONCLUSIONS: We found no evidence that adenosine and verapamil as treatments for no-reflow during PPCI can reduce all-cause mortality, non-fatal myocardial infarction or the incidence of angiographic no-reflow (TIMI flow grade < 3 and MBG 0 to1), but there was some evidence of increased adverse events. Further clinical research into adenosine and verapamil is needed because of the limited numbers of included trials and participants. PMID- 23736950 TI - Increased consumption of fruit and vegetables for the primary prevention of cardiovascular diseases. AB - BACKGROUND: There is increasing evidence that high consumption of fruit and vegetables is beneficial for cardiovascular disease (CVD) prevention. OBJECTIVES: The primary objective is to determine the effectiveness of i) advice to increase fruit and vegetable consumption ii) the provision of fruit and vegetables to increase consumption, for the primary prevention of CVD. SEARCH METHODS: We searched the following electronic databases: The Cochrane Library (2012, issue 9 CENTRAL, HTA, DARE, NEED), MEDLINE (1946 to week 3 September 2012); EMBASE (1980 to 2012 week 39) and the Conference Proceedings Citation Index - Science on ISI Web of Science (5 October 2012). We searched trial registers, screened reference lists and contacted authors for additional information where necessary. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials with at least three months follow-up (follow-up was considered to be the time elapsed since the start of the intervention) involving healthy adults or those at high risk of CVD. Trials investigated either advice to increase fruit and vegetable intake (via any source or modality) or the provision of fruit and vegetables to increase intake. The comparison group was no intervention or minimal intervention. Outcomes of interest were CVD clinical events (mortality (CVD and all-cause), myocardial infarction (MI), coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA), angiographically defined angina pectoris, stroke, carotid endarterectomy, peripheral arterial disease (PAD)) and major CVD risk factors (blood pressure, blood lipids, type 2 diabetes). Trials involving multifactorial lifestyle interventions (including different dietary patterns, exercise) or where the focus was weight loss were excluded to avoid confounding. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data and assessed the risk of bias. Trials of provision of fruit and vegetables were analysed separately from trials of dietary advice. MAIN RESULTS: We identified 10 trials with a total of 1730 participants randomised, and one ongoing trial. Six trials investigated the provision of fruit and vegetables, and four trials examined advice to increase fruit and vegetable consumption.The ongoing trial is examining the provision of an avocado-rich diet.The number and type of intervention components for provision, and the dietary advice provided differed between trials.None of the trials reported clinical events as they were all relatively short term. There was no strong evidence for effects of individual trials of provision of fruit and vegetables on cardiovascular risk factors, but trials were heterogeneous and short term. Furthermore, five of the six trials only provided one fruit or vegetable. Dietary advice showed some favourable effects on blood pressure (systolic blood pressure (SBP): mean difference (MD) -3.0 mmHg (95% confidence interval (CI) -4.92 to -1.09), diastolic blood pressure (DBP): MD -0.90 mmHg (95% CI -2.03 to 0.24)) and low-density lipoprotein (LDL) cholesterol but analyses were based on only two trials. Three of the 10 included trials examined adverse effects, which included increased bowel movements, bad breath and body odour. AUTHORS' CONCLUSIONS: There are very few studies to date examining provision of, or advice to increase the consumption of, fruit and vegetables in the absence of additional dietary interventions or other lifestyle interventions for the primary prevention of CVD. The limited evidence suggests advice to increase fruit and vegetables as a single intervention has favourable effects on CVD risk factors but more trials are needed to confirm this. PMID- 23736952 TI - Sensitive magnetic control of ensemble nuclear spin hyperpolarization in diamond. AB - Dynamic nuclear polarization, which transfers the spin polarization of electrons to nuclei, is routinely applied to enhance the sensitivity of nuclear magnetic resonance. This method is particularly useful when spin hyperpolarization can be produced and controlled optically or electrically. Here we show complete polarization of nuclei located near optically polarized nitrogen-vacancy centres in diamond. Close to the ground-state level anti-crossing condition of the nitrogen-vacancy electron spins, (13)C nuclei in the first shell are polarized in a pattern that depends sensitively upon the magnetic field. Based on the anisotropy of the hyperfine coupling and of the optical polarization mechanism, we predict and observe a reversal of the nuclear spin polarization with only a few millitesla change in the magnetic field. This method of magnetic control of high nuclear polarization at room temperature can be applied in sensitivity enhanced nuclear magnetic resonance of bulk nuclei, nuclear-based spintronics, and quantum computation in diamond. PMID- 23736951 TI - Intravenous infusion of phage-displayed antibody library in human cancer patients: enrichment and cancer-specificity of tumor-homing phage-antibodies. AB - Phage display is a powerful method for target discovery and selection of ligands for cancer treatment and diagnosis. Our goal was to select tumor-binding antibodies in cancer patients. Eligibility criteria included absence of preexisting anti-phage-antibodies and a Stage IV cancer status. All patients were intravenously administered 1 * 10(11) TUs/kg of an scFv library 1 to 4 h before surgical resection of their tumors. No significant adverse events related to the phage library infusion were observed. Phage were successfully recovered from all tumors. Individual clones from each patient were assessed for binding to the tumor from which clones were recovered. Multiple tumor-binding phage-antibodies were identified. Soluble scFv antibodies were produced from the phage clones showing higher tumor binding. The tumor-homing phage-antibodies and derived soluble scFvs were found to bind varying numbers (0-5) of 8 tested normal human tissues (breast, cervix, colon, kidney, liver, spleen, skin, and uterus). The clones that showed high tumor-specificity were found to bind corresponding tumors from other patients also. Clone enrichment was observed based on tumor binding and DNA sequence data. Clone sequences of multiple variable regions showed significant matches to certain cancer-related antibodies. One of the clones (07 2,355) that was found to share a 12-amino-acid-long motif with a reported IL-17A antibody was further studied for competitive binding for possible antigen target identification. We conclude that these outcomes support the safety and utility of phage display library panning in cancer patients for ligand selection and target discovery for cancer treatment and diagnosis. PMID- 23736953 TI - Rigid organic nanotubes obtained from phenylene-butadiynylene macrocycles. AB - Rigid organic nanotubes were prepared from six-membered phenylene-butadiynylene macrocycles through topochemical polymerization in the xerogel state. All six butadiyne units underwent polymerization, thus creating rigid nanotubes with six polydiacetylene chains lying parallel, one relative to each other. PMID- 23736954 TI - Managing alcohol abuse. PMID- 23736955 TI - Decrease in cytosine methylation at CpG island shores and increase in DNA fragmentation during zebrafish aging. AB - Age-related changes in DNA methylation have been demonstrated in mammals, but it remains unclear as to the generality of this phenomenon in vertebrates, which is a criterion for the fundamental cause of senescence. Here we showed that the zebrafish genome gradually and clearly lost methylcytosine in somatic cells, but not in male germ cells during aging, and that age-dependent hypomethylation preferentially occurred at a particular domain called the CpG island shore, which is associated with vertebrates' genes and has been shown to be hypomethylated in humans with age. We also found that two CpG island shores hypomethylated in zebrafish oocytes were de novo methylated in fertilized eggs, which suggests that the zebrafish epigenome is reset upon fertilization, enabling new generations to restart with a heavily methylated genome. Furthermore, we observed an increase in cleavage of the zebrafish genome to an oligonucleosome length in somatic cells from the age of 12 months, which is suggestive of an elevated rate of apoptosis in the senescent stage. PMID- 23736956 TI - The use of Ginkgo biloba in healthy elderly. AB - To promote health-conscious behavior in the aging society and gain insight into the sources of knowledge on which preventive strategies are based, analyzing the behavior of elderly people who are recognized as highly health conscious may be useful. We focused on the use of Ginkgo biloba, which is commonly considered to be effective in preventing cognitive decline and dementia, among elderly adults. A total of 1,672 questionnaires were distributed among geriatric participants (60 94 years) who attended university lectures at 22 universities throughout Germany. Response rate was 36.1 %. We collected data on demographic characteristics, preventive strategies (use of Ginkgo and other supplements), health-conscious behavior, sources of knowledge concerning health behavior, and factors associated with the participants' concept of aging. The prevalence of Ginkgo use was 15.3 %. Ginkgo was assumed to be effective for cognitive enhancement and the treatment of cognitive decline by two thirds of the surveyed participants and one third believed Ginkgo to be effective for preventing dementia. Ginkgo use was significantly higher among participants using natural remedies and herbal and food supplements. The use of Ginkgo was recommended by physicians (57.3 %), chemists (16 %), and healthcare magazines (10.7 %). Food supplements were taken by 65.8 % of the sample: this percentage was significantly higher among subjects who exhibited health-conscious behavior. "Knowledge" about strategies to enhance cognition or prevent cognitive decline among the elderly do not appear to be evidence based. Thus, there is a need to establish reliable and independent sources of scientific information for healthcare professionals and the general public. PMID- 23736957 TI - [Early detection of colorectal cancer: role of endoscopy and imaging]. AB - Colorectal cancer is one of the leading causes of cancer-related morbidity and mortality. Colorectal cancer commonly develops slowly via adenomatous polyps, a process usually requiring >= 10 years. This allows for early detection. Endoscopic polypectomy and surgery of early disease can reduce the incidence and mortality of colorectal cancer. Both hemoccult testing and colonoscopy are the most widely used tests for colorectal cancer screening; however, colonoscopy has the highest sensitivity for colorectal neoplasia. Sigmoidoscopy is not commonly used for screening in Germany. Colon contrast enema is no longer recommended for screening. As colonoscopy serves as a diagnostic and therapeutic tool and is the reference method in hemoccult and sigmoidoscopy studies, it is viewed as the gold standard for the diagnosis of colonic disease. New methods including capsule colonoscopy and virtual colonoscopy have great potential but are currently not recommended for early detection of colonic neoplasia. PMID- 23736958 TI - [Rational CT imaging in cardiology]. AB - Due to continuous technical developments computed tomography (CT) is increasingly being used for cardiac diagnostics, especially for diagnosis of coronary artery disease (CAD) or less commonly for evaluation of coronary artery anomalies, cardiac valves or cardiac function. Because CT exposes patients to ionizing radiation it should only be performed in patients with a clear indication. Calcium scoring for example may improve risk stratification in asymptomatic patients with an intermediate risk profile or coronary CT angiography may be used to exclude or confirm obstructive CAD in symptomatic patients at intermediate cardiovascular risk. However, other patients, such as symptomatic patients with high cardiovascular risk should not be examined using CT. Therefore, a reasonable use of CT in cardiology requires a differentiated selection of patients. PMID- 23736959 TI - [Rational radiological diagnostics of pneumonia]. AB - As one of the most common infectious diseases pneumonia is associated with a high morbidity and mortality. A rapid and rational diagnostic work-up is crucial to improve patient prognosis and outcome. The diagnosis of pneumonia requires the detection of pulmonary infiltrates; therefore, radiological methods are a key part of the diagnostic algorithm to demonstrate the presence of infiltrates and to confirm the diagnosis. The accepted standard method is chest X-ray at two levels, posteroanterior (PA) and lateral radiographs. Computed tomography is mainly used for immunocompromised patients, patients with pre-existing structural lung disease, therapy refractory pneumonia and in the differential diagnosis of suspected underlying diseases, such as pulmonary embolism or malignancy. Increasing evidence suggests that lung ultrasound is a promising, precise technology which is readily available and with no irradiation of patient. PMID- 23736960 TI - [Rational imaging of metastasized tumor diseases]. AB - Most anticancer medications are effective only in subgroups of patients. Despite considerable improvements in histopathological and molecular pathological diagnostics, tumor response in the individual patient still remains unpredictable. Measuring tumor shrinkage by cross-sectional imaging procedures in patients with metastatic cancer represents the current standard for documenting the effectiveness of anticancer therapy. In addition to the large number of different imaging procedures computed tomography (CT) is certainly the best established and most widely available technique for assessing tumor response. This manuscript reviews the necessity and rationality of imaging procedures for monitoring tumor response in patients with metastatic cancer. PMID- 23736961 TI - [Dyspnea and weight loss in a 70-year-old man]. AB - A 70-year-old man presented with subacute dyspnea, cough, weight loss, and mild fever. Blood analysis revealed an elevated C-reactive protein level. Chest x-ray and CT of the chest showed alveolar opacities with a migratory tendency during the clinical course. After extensive diagnostics, treatment with prednisolone under the presumed diagnosis of a cryptogenic organizing pneumonia was started, which lead to a rapid clinical response. PMID- 23736962 TI - Variations in the mRNA expression of poly(ADP-ribose) polymerases, poly(ADP ribose) glycohydrolase and ADP-ribosylhydrolase 3 in breast tumors and impact on clinical outcome. AB - In order to assess the variation in expression of poly(ADP-ribose) polymerase (PARP) family members and the hydrolases that degrade the poly(ADP-ribose) polymers they generate and possible associations with classical pathological parameters, including long-term outcome, the mRNA levels of PARP1, PARP2, PARP3, poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribosylhydrolase 3 (ARH3) were examined using quantitative reverse transcription polymerase chain reaction in 443 unilateral invasive breast cancers and linked to hormonal status, tumor proliferation and clinical outcome. PARP1 mRNA levels were the highest among these five genes in both normal and tumor tissues, with a 2.45-fold higher median level in tumors compared to normal tissues. Tumors (34.1%) showed PARP1 overexpression (>3 fold relative to normal breast tissues) compared to underexpression (<0.33 fold) in only 0.5%. This overexpression was seen in all breast tumor subgroups, with the highest fraction (51%) seen in the HR positive/ERBB2-positive subgroup and was not highly associated with any other classical predictive factors. No correlation was seen between PARP1 mRNA and PARP 1 protein levels in a subset of 31 tumors. PARP3 was underexpressed in 10.4% of tumors, more frequently in the HR-negative tumors (25.4%) than the HR-positive tumors (5.9%). This PARP3 underexpression was mutually exclusive with a PARP1 overexpression. PARP2 levels were unchanged between normal and tumor tissues and few tumors showed overexpression of PARG (3.8%) or ARH3 (3.4%). Within the subgroup of triple negative tumors, PARG mRNA levels below the median were associated with a higher risk of developing metastases (p = 0.039) raising the possibility this might be marker of clinical outcome. PMID- 23736963 TI - Fear of deportation is not associated with medical or dental care use among Mexican-origin farmworkers served by a federally-qualified health center--faith based partnership: an exploratory study. AB - Migrant and seasonal farmworkers face many health risks with limited access to health care and promotion services. This study explored whether fear of deportation (as a barrier), and church attendance (as an enabling factor), were associated with medical and dental care use among Mexican-origin farmworkers. Interviews were conducted with 179 farmworkers who attended mobile services provided by a local federally-qualified health center (FQHC) in partnership with area churches, during the 2007 agricultural season. The majority of respondents (87 %) were afraid of being deported, and many (74 %) attended church. Although about half of participants reported poor/fair physical (49 %) and dental (58 %) health, only 37 % of farmworkers used medical care and 20 % used dental care during the previous year. Fear of deportation was not associated with use of medical or dental care; while church attendance was associated with use of dental care. Findings suggest that despite high prevalence of fear of deportation, support by FQHCs and churches may enable farmworkers to access health care services. PMID- 23736964 TI - Increasing colonoscopy screening for Latino Americans through a patient navigation model: a randomized clinical trial. AB - Latinos have a higher rate of mortality and lower rate of colorectal cancer (CRC) screening than most racial groups in the United States. This study examines the predictors of screening colonoscopy (SC) for CRC among Latinos in a patient navigation (PN) intervention. Participants were randomized to either a culturally targeted PN group (n = 225) or a standard PN group (n = 167). Each completed an interview assessing sociodemographic and intrapersonal information. There was no difference in SC completion between PN groups (80.9 and 79.0 %). Logistic regression revealed that low language acculturation (OR = 2.22) and annual income above $10,000 (OR = 1.97) were independent predictors of completion. Both standard and culturally-targeted PN successfully increased SC completion by nearly 30 % above the recent estimation for physician-referred patients. Our findings suggest a need to further reduce barriers to SC in low income and highly acculturated Latino groups. PMID- 23736965 TI - Genetic mapping of agenesis of the third molars in mice. AB - EL/Sea mice are characterized by 100% incidence of agenesis of the third molars (M3). In a previous study, chromosomal mapping of the ninth generation EL/Sea congenic strains revealed a major locus for agenesis of M3, designated am3, in the 125-137 Mbp region of chromosome 3. In the present study, to determine the precise location of the am3 locus, we produced further generations of the EL/Sea congenic strains for am3 in which the restricted interval on chromosome 3 of EL/Sea was replaced by a MSM/Msf-derived homolog. The eleventh generation congenic mice that were either heterozygous or homozygous for the MSM/Msf-derived interval exhibited a significant decrease in the incidence of M3 agenesis (p < 0.00001). Results confined the am3 locus to an interval of 1 Mbp on chromosome 3, demonstrating that Lef1, one of the essential transcription factors for early tooth development, is the strongest candidate for am3. PMID- 23736966 TI - Voclosporin food effect and single oral ascending dose pharmacokinetic and pharmacodynamic studies in healthy human subjects. AB - Voclosporin (VCS) is a novel calcineurin (CN) inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. These studies evaluated the single ascending dose pharmacokinetics (PK) and pharmacodynamics (PD, CN activity) of VCS and the effect of food. VCS was administered orally in single doses of 0.25 through 4.5 mg/kg in 62 subjects in the single ascending dose study and as a single oral 1.5 mg/kg dose to 18 subjects after fasting, consumption of a low-fat and high-fat meal. Non-compartmental PK, PD, and PKPD correlation were evaluated. Following single oral doses, systemic exposure increased in a linear manner and demonstrated 1:1 dose-proportional, first-order linear PK above 1.5 mg/kg. VCS inhibited CN activity in a dose-related fashion with maximal inhibition peaking at 3.0 mg/kg. PKPD correlation indicated an EC50 of 78.3 +/- 6.8 ng/mL. Administration of VCS with a low-fat and high-fat meal decreased C(max) by 29% and 53%, respectively, and AUC(inf) by 15% and 25%, respectively. Following ascending single doses of VCS, exposure increased in a linear fashion. A food effect on exposure was demonstrated, with a more pronounced effect following a high-fat meal. VCS concentrations were also found to correlate with CN activity. PMID- 23736967 TI - Other aspects of Ambroise Pare's life. PMID- 23736968 TI - Comment on Brunnekreef et al.: Is etoricoxib effective in preventing heterotopic ossification after primary total hip arthroplasty? PMID- 23736969 TI - [Repositioning options with percutaneous dorsal stabilization. For burst fractures of the thoracolumbar junction]. AB - BACKGROUND: The purpose of this investigation was to evaluate the options of percutaneous systems for reducing relevant posttraumatic kyphosis in spinal burst fractures. Clinical advantages of percutaneous techniques are evident from the literature and a disadvantage can be a lack of repositioning options in reducing the fracture kyphosis. Better results seem to be possible with new techniques and especially monoaxial percutaneous screws. PATIENTS AND METHODS: A total of 70 patients with burst fractures (AO type Magerl A3.1-A3.3) of the thoracolumbar spine were treated with a special percutaneous reduction technique in the Trauma Clinic in Murnau (BGU) Germany between July 2009 and March 2011. Posttraumatic, intraoperative and postoperative kyphosis was measured in computed tomography (CT) scans in monosegmental and bisegmental angles. Two different percutaneous fixation systems were compared for reduction. Statistical analyses were carried out with Student's t-test. RESULTS: We found a highly significant difference between preoperative and postoperative kyphosis angles but no differences in reduction between the two percutaneous systems. In 39 cases additional reconstruction of the anterior column was necessary because of a ventral defect. In comparison to the MCS 2 study of the German Society of Trauma Surgery (DGU) we found no differences in postoperative kyphosis angles (3 degrees ). CONCLUSION: A significant reduction of posttraumatic kyphosis of thoracolumbar burst fractures is possible with percutaneous techniques. Prerequisites are percutaneous monoaxial screws and tools and a special percutaneous technique as described. PMID- 23736970 TI - [Medical and sociodemographic aspects of domestic violence. Systematic evaluation of patient data from the emergency department of a maximum care hospital]. AB - BACKGROUND: Injuries due to domestic violence are a frequent occurrence in emergency departments. Although domestic violence has been well analyzed from the sociological point of view, medical data concerning patterns of injuries are rare. METHODS: Victims of domestic violence who presented at the emergency department of a maximum care hospital were included in the study. Sociodemographic data and patterns of injuries were documented. RESULTS: Of the patients who presented at the emergency room 1.4 % suffered injuries due to domestic violence and 70 % were women who had been predominantly attacked by the (ex) partner. The male victims were predominantly attacked by friends. In 88 % the head and neck were involved. Male patients were attacked with objects (as a kind of weapon) more frequently than women. A migration background was documented in 45 % of the female and 30 % of the male patients. CONCLUSION: Patterns can be easily recognized: the victims were predominantly female and were attacked by the (ex) partner. Injuries were localized to the upper part of the body. No excessive violence with life-threatening or fatal injuries was observed. PMID- 23736971 TI - A choice that matters? Smulation study on the impact of direct meta-analysis methods on health economic outcomes. AB - BACKGROUND: Decision-analytic cost-effectiveness (CE) models combine many different parameters like transition probabilities, event probabilities, utilities and costs, which are often obtained after meta-analysis. The method of meta-analysis may affect the CE estimate. AIM: Our aim was to perform a simulation study that compares the performance of different methods of meta analysis, especially with respect to model-based health economic (HE) outcomes. METHODS: A reference patient population of 50,000 was simulated from which sets of samples were drawn. Each sample drawn represented a clinical trial comparing two fictitious interventions. In several scenarios, the heterogeneity between these trials was varied, by drawing one or more of the trials from predefined subpopulations. Parameter estimates from these trials were combined using frequentist fixed (FFE) and random effects (FRE), and Bayesian fixed (BFE) and random effects (BRE) meta-analysis. The pooled parameter estimates were entered into a probabilistic cost-effectiveness Markov model. The four methods of meta analysis resulted in different parameter estimates and HE outcomes, which were compared with the true values in the reference population. Performance statistics were: (1) the percentage of repetitions that the confidence interval of the probabilistic sensitivity analysis covers the true value (coverage), (2) the difference between the estimated and true value (bias), (3) the mean absolute value of the bias (MAD) and (4) the percentage of repetitions that result in a statistically significant difference between the two interventions (statistical power). As the differences between methods could be due to chance, we repeated every step of the analysis 1,000 times to study whether differences were systematic. RESULTS: FFE, FRE and BFE lead to different parameter estimates, but, when entered into the model, they do not lead to large differences in the point estimates of the HE outcomes, even in scenarios where we built in heterogeneity. Random effects methods do not necessarily reduce bias when heterogeneity is added to the trials, and may even increase bias in certain situations. BRE tends to overestimate uncertainty reflected in the CE acceptability curve. CONCLUSION: FFE, FRE and BFE lead to comparable HE outcomes. BRE tends to overestimate uncertainty. Based on this study, we recommend FRE as the preferred method of meta-analysis. PMID- 23736972 TI - Sub-threshold cognitive impairment in multiple sclerosis: the association with cognitive reserve. AB - Multiple sclerosis (MS) patients with high premorbid intellect have the advantage of cognitive reserve that may mitigate the effects of cognitive decline. A fall off in cognition may nevertheless still occur, even should it fail to meet global impairment thresholds. The present cross-sectional study explores the neurologic and behavioral characteristics of this little known group of patients. A consecutive sample of 144 MS patients underwent neuropsychological testing with the minimal assessment of cognitive function in the MS (MACFIMS) battery. Premorbid IQ was assessed with the ANART reading test. A validated algorithm based on ANART errors and verbal fluency scores was used to predict whether current cognitive function matched premorbid estimates. Three MS groups were thus defined: cognitively intact (n = 53), impaired (n = 46) and cognitively intact on the MACFIMS, but falling short of premorbid predictions (n = 45). Patients who were cognitively intact on the MACFIMS but fell short of verbal fluency predictions had higher premorbid IQ (p = 0.007) and lower EDSS (p = 0.002) than cognitively impaired, but not intact patients. They outperformed impaired patients on every MACFIMS variable, but were more impaired than intact patients on the Paced Auditory Serial Addition Test-3 (PASAT-3) (p = 0.009). They were more likely to be employed (48.9%) than the impaired (26.1%) group (p = 0.025). We defined a group of MS patients deemed cognitively intact on conventional neuropsychological testing, but who, nevertheless, had deficits relative to premorbid intellectual abilities. The high premorbid IQ in this group does not prevent, but 'softens' the impact of cognitive decline. These findings provide novel evidence supporting cognitive reserve as a protective factor in relation to cognitive dysfunction in MS. PMID- 23736973 TI - Validation of the German version of the extended ALS functional rating scale as a patient-reported outcome measure. AB - The revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is a well-established rating instrument to assess the functional status of ALS patients. A recent innovation was the addition of three further items designed to improve its sensitivity at lower levels of physical function (ALSFRS-Extension, ALSFRS-EX). Neither the ALSFRS-R nor the ALSFRS-EX has been validated in German yet. The aim of the present study was the validation of the German version of a self-administered form of the ALSFRS-EX. Seventy-six patients participated in the study. Psychometric analysis included reliability assessment and factorial analysis. To evaluate convergent validity, correlations between ALSFRS-EX items and the MRC score, spasticity, tongue movement, pulmonary function, ALSAQ-40 and Borg dyspnoea scales (upright and supine) were performed. Internal consistency as measured by Cronbach's alpha (total scale 0.868, subscales 0.690-0.938) and corrected item to total correlations (all above 0.50) was high. Test-retest reliability assessed by Spearman's rho (0.882-0.972) and Cohen's Kappa (0.63 0.92) was also high. Principal component analysis with varimax rotation yielded a four-factor solution accounting for approximately 79% of the variance. Clinical parameters were strongly correlated with respective items and subscores of the ALSFRS-EX (muscle strength 0.568-0.833 p < 0.01; spasticity -0.236 to -0.376 p < 0.05; tongue movement 0.437-0.818 p < 0.01; pulmonary function 0.485-0.577 p < 0.01). ALSAQ-40 and Borg score correlated highly with the corresponding ALSFRS-EX items. The German self-report version of the ALSFRS-EX possesses very good psychometric properties similar to the original scale including high internal consistency and test-retest reliability as well as excellent convergent validity. PMID- 23736974 TI - Brain structural and functional abnormalities in Fahr's disease: a report of two cases. PMID- 23736976 TI - Conversion of a heme-based oxygen sensor to a heme oxygenase by hydrogen sulfide: effects of mutations in the heme distal side of a heme-based oxygen sensor phosphodiesterase (Ec DOS). AB - The heme-based oxygen-sensor phosphodiesterase from Escherichia coli (Ec DOS), is composed of an N-terminal heme-bound oxygen sensing domain and a C-terminal catalytic domain. Oxygen (O2) binding to the heme Fe(II) complex in Ec DOS substantially enhances catalysis. Addition of hydrogen sulfide (H2S) to the heme Fe(III) complex in Ec DOS also remarkably stimulates catalysis in part due to the heme Fe(III)-SH and heme Fe(II)-O2 complexes formed by H2S. In this study, we examined the roles of the heme distal amino acids, M95 (the axial ligand of the heme Fe(II) complex) and R97 (the O2 binding site in the heme Fe(II)-O2 complex) of the isolated heme-binding domain of Ec DOS (Ec DOS-PAS) in the binding of H2S under aerobic conditions. Interestingly, R97A and R97I mutant proteins formed an oxygen-incorporated modified heme, verdoheme, following addition of H2S combined with H2O2 generated by the reactions. Time-dependent mass spectroscopic data corroborated the findings. In contrast, H2S did not interact with the heme Fe(III) complex of M95H and R97E mutants. Thus, M95 and/or R97 on the heme distal side in Ec DOS-PAS significantly contribute to the interaction of H2S with the Fe(III) heme complex and also to the modification of the heme Fe(III) complex with reactive oxygen species. Importantly, mutations of the O2 binding site of the heme protein converted its function from oxygen sensor to that of a heme oxygenase. This study establishes the novel role of H2S in modifying the heme iron complex to form verdoheme with the aid of reactive oxygen species. PMID- 23736975 TI - Dystonic opisthotonus: a "red flag" for neurodegeneration with brain iron accumulation syndromes? AB - Back arching was reported in one of the very first patients with neurodegeneration with brain iron accumulation syndrome (NBIAs) published in 1936. However, recent reports have mainly focused on the genetic and imaging aspects of these disorders, and the phenotypic characterization of the dystonia has been lost. In evaluating patients with NBIAs in our centers, we have observed that action-induced dystonic opisthotonus is a common and characteristic feature of NBIAs. Here, we present a case series of patients with NBIAs presenting this feature demonstrated by videos. We suggest that dystonic opisthotonus could be a useful "red flag" for clinicians to suspect NBIAs, and we discuss the differential diagnosis of this feature. This would be particularly useful in identifying patients with NBIAs and no iron accumulation as yet on brain imaging (for example, as in phospholipase A2, group IV (cytosolic, calcium-independent) [PLA2G6]-related disorders), and it has management implications. PMID- 23736977 TI - New diterpenoids with estrogen sulfotransferase inhibitory activity from Leonurus sibiricus L. AB - Four new diterpenoids (1-4), along with eight known diterpenoids (5-12) were isolated from the acetone extract of Leonurus herb (aerial parts of Leonurus sibiricus L.). The structures of the compounds were determined by spectroscopic methods. Among the isolated compounds, compounds 2, 3, 8, 9 and 10 showed inhibitory activity against human liver cytosol estrogen sulfotransferase (E-ST), which plays a key role in the maintenance of cellular estrogen levels. Compound 2 showed the strongest activity with an IC50 value of 7.9 MUM, which is comparable to the activity of the positive control, meclofenamic acid (IC50 5.4 MUM). PMID- 23736978 TI - Molecular characterization of a porcine kobuvirus variant strain in China. AB - In this study, we report the complete nucleotide sequence of porcine kobuvirus CH/HZ/2011 (CH/HZ) isolated from infected piglets in China. Dendrograms indicated that CH/HZ is closely related to other porcine kobuviruses. The complete genome sequence of CH/HZ has an adenine insertion at position 124, an 18-nt deletion in the 5'UTR, and a 90-nt deletion in the 2B coding region. A neighbor-joining tree based on the VP1 gene indicated that 31 porcine kobuvirus strains are divided into four clusters (Thai-Japanese group, Hungarian group, Chinese group I and Chinese group II). The strain CH/HZ was included in Chinese group II. PMID- 23736979 TI - Porcine CD74 is involved in the inflammatory response activated by nuclear factor kappa B during porcine circovirus type 2 (PCV-2) infection. AB - Human CD74 induces a signalling cascade that results in the activation of nuclear factor kappa B (NF-kappaB); however, porcine CD74 has not been widely studied. In this study, we show that porcine CD74 is mainly expressed in cells of the macrophage lineage and can be induced by lipopolysaccharide (LPS), polyinosinic acid-polycytidylic acid [Poly(I:C)], and infection with porcine circovirus type 2 (PCV2) in vitro. In addition, we confirmed that porcine CD74 can activate NF kappaB by promoting IkappaBalpha degradation and nuclear translocation of p65. Furthermore, the transcription of NF-kappaB-regulated genes [Interleukin-6 (IL 6), Interleukin-8 (IL-8), and COX-2] was upregulated in response to the overexpression of porcine CD74. In general, porcine CD74 significantly enhanced the inflammatory response by regulating the NF-kappaB signalling pathway during PCV2 infection, which suggests that porcine CD74 may be implicated in the pathogenesis of PCV2 infection. PMID- 23736980 TI - Ferromagnetic superexchange in a 1D -[La(III)-radical]- coordination polymer. AB - The first coordination polymer of a bridging radical 1,2,3,5-dithiadiazolyl ligand is reported. Upon coordination with the La(hfac)3 fragment, the paramagnetic 4-(benzoxazol-2'-yl)-1,2,3,5-dithiadiazolyl (boaDTDA) ligand forms a one-dimensional (1D) alternating -[La(hfac)3-boaDTDA]n- polymer exhibiting ferromagnetic (FM) coupling between the radicals, mediated through the diamagnetic La(III) ion (hfac = 1,1,1,5,5,5-hexafluoroacetylacetonato). PMID- 23736983 TI - Reply to the letter by Yang et al. RE: acute myeloid leukemia associated with FGFR1 abnormalities. PMID- 23736984 TI - Different solvates of the dinuclear cyclometallated gold(I) complex [Au2(MU-2 C6H4AsMe2)2]: a computational study insight into solvent-effected optical properties. AB - Two solvates of an arsena-aura-metallocyclic molecule, which, apart from the different solvents, have the same molecular stoichiometry, display different optical properties. We develop an ab initio model, benchmarked against X-ray diffraction experiment, to explore the possible causes of this change in behavior. We study the bonding and electronic properties of the crystals, their local environments, and consider possible effects of the solvents used for crystallization. PMID- 23736985 TI - A prospective randomized controlled trial of semi-mechanical versus hand-sewn or circular stapled esophagogastrostomy for prevention of anastomotic stricture. PMID- 23736986 TI - Laparoscopy-assisted hybrid left-side donor hepatectomy. AB - BACKGROUND: Laparoscopic liver resection developed for live liver donors has the advantage of reducing the physical and mental stress in donors. However, its safety and efficacy still remain to be established. We aimed to evaluate the feasibility, safety and efficacy of laparoscopy-assisted hybrid donor hepatectomy (LADH) to obtain left side grafts. PATIENTS AND METHODS: A total of 31 consecutive live liver donors of left side liver grafts underwent LADH, including left lateral segmentectomy (n = 17) and left liver resection with or without the caudate lobe (n = 14) (LADH group). We compared the clinical data between the LADH group and the group of donors in whom traditional open donor hepatectomy was performed to procure the liver graft (open donor hepatectomy [ODH] group, n = 79). RESULTS: Laparoscopy-assisted hybrid donor hepatectomy was feasible in all patients, and there was no mortality over a follow-up period of 13.9 +/- 9.8 months. The operative time to procure a left-lobe graft was significantly longer in the LADH group (510 +/- 90 min) than in the ODH group (P < 0.001). A large right lobe on CT (RPv distance) was identified as a significant risk factor for prolonged operative time (P = 0.007). Evaluation using the SF36-v2 questionnaire revealed faster recovery of the physical component summary score and bodily pain score in the LADH group than in the ODH group. CONCLUSIONS: Laparoscopy-assisted hybrid donor hepatectomy for procuring left side grafts was safe and effective up to the left liver with the caudate lobe. Left-lobe LADH in donors with a large right lobe should be carefully planned in view of the potential surgical difficulty. PMID- 23736987 TI - Prenatal morphogenesis of mammary glands in mouse and rabbit. AB - Our understanding of prenatal morphogenesis of mammary glands has recently greatly advanced. This review focuses on morphogenesis proper, as well as cellular processes and tissue interactions involved in the progression of the embryonic mammary gland through sequential morphogenic stages in both the mouse and rabbit embryo. We provide a synthesis of both historical and more recent studies of embryonic mammary gland development, as well as arguments to revise old concepts about mechanisms of mammary line and rudiment formation. Finally, we highlight outstanding issues that remain to be addressed. PMID- 23736988 TI - How do amino acid substitutions affect the amyloidogenic properties and seeding efficiency of prion peptides. AB - The amino acid sequences in the amyloidogenic region (amino acids 108-144) of several mammalian prion proteins were compared and variations were found to occur at residues 109 (M or L), 112 (M or V), 129 (M, V, or L), 135 (N or S), 138 (M, L, or I), 139 (M or I), and 143 (N or S). Using the bovine PrP peptide (residues 108-144 based on the numbering of the human prion protein sequence) as a control peptide, several peptides with one amino acid differing from that of the bovine PrP peptide at residues 109, 112, 135, 138, 139, or 143 and several mammalian PrP peptides were synthesized, and the effects of these amino acid substitutions on the amyloidogenic properties of these peptides were compared and discussed on the basis of the chemical and structural properties of amino acids. Our results showed that the V112M substitution accelerated nucleation of amyloidogenesis, while the N143S and I139M substitutions retarded nucleation. These effects tended to cancel each other out when two substitutions with opposite effects were present on the same peptide. Moreover, acceleration or inhibition of nucleation was not necessarily correlated with effect on seeding efficiency. Using amyloid fibrils prepared from the bovine PrP peptide as seeds, the seeding efficiency for the monomer peptides with the M129L, S135N, N143S, or I139M substitution was decreased compared to that for bPrP peptide. Of all the mammalian peptides used in this study, the dog, mule deer, and pig PrP peptides had the lowest seeding efficiencies. PMID- 23736989 TI - Interconception care for women with a history of gestational diabetes for improving maternal and infant outcomes. AB - BACKGROUND: Gestational diabetes mellitus (GDM) is associated with adverse health outcomes for both mother and infant both perinatally and long-term. Women with a history of GDM are at risk of recurrence in subsequent pregnancies and may benefit from intervention in the interconception period to improve maternal and infant health outcomes. OBJECTIVES: To investigate the effects of interconception care for women with a history of GDM on maternal and infant health outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2013). SELECTION CRITERIA: Randomised controlled trials, including quasi-randomised controlled trials and cluster-randomised trials evaluating any protocol of interconception care with standard care or other forms of interconception care for women with a history of GDM in a previous pregnancy on maternal and infant health outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility. In future updates of this review, at least two review authors will extract data and assess the risk of bias of included studies. MAIN RESULTS: One ongoing trial was identified. No eligible completed trials were identified. AUTHORS' CONCLUSIONS: The role of interconception care for women with a history of gestational diabetes remains unclear. Randomised controlled trials are required evaluating different forms and protocols of interconception care for these women on perinatal and long-term maternal and infant health outcomes, acceptability of such interventions and cost effectiveness. PMID- 23736991 TI - Correlation of optical coherence tomography parameters with clinical and radiological progression in patients with symptomatic optic pathway gliomas. AB - PURPOSE: To study the optical coherence tomography (OCT) characteristics in children with optic pathway glioma (OPG) to determine if OCT changes occur alongside clinical/radiological changes at diagnosis and during the second-year follow-up. METHODS: Twenty-three patients (38 eyes) diagnosed with symptomatic OPG in a single institution were enrolled in this longitudinal observational cohort study. Complete ophthalmologic evaluation, including determination of visual acuity, visual fields, retinal nerve fiber layer ,and posterior pole retinal thickness scanning with spectral-domain optical coherence tomography, and neuroimaging was performed at the time of diagnosis and 6 months and 1 and 2 years after presentation. Patients who experienced visual decline or radioagraphic tumor enlargement of the OPG were classified as progressors. OCT data were compared between progressors and nonprogressors. RESULTS: The average age at diagnosis was 5.8 years. All patients were followed up for 24 months. Five patients (21%) (eight eyes) had clinical or radiological progression of their OPG during follow-up and were classified as progressors. Mean changes in average nerve fiber layer and posterior pole retinal thickness were significantly higher for progressors compared with nonprogressors (P < 0.001). The area under the receiver operator characteristic curves comparing average nerve fiber layer and posterior pole retinal thinning between the progressors and nonprogressors were 0.94 and 0.95 respectively. CONCLUSIONS: Optical coherence tomography of average nerve fiber layer and posterior pole retinal thickness may be helpful in monitoring OPG. PMID- 23736992 TI - Clinical failure analysis of contemporary ceramic-on-ceramic total hip replacements. AB - The present study investigates the performance of ceramic-on-ceramic total hip replacements by combining a retrieval analysis with a survivorship analysis to elucidate mechanisms that led to clinical failure. Semiquantitative surface damage assessment, contact profilometry, contour measurements, and scanning electron microscopy were performed to characterize the types and quantify the extent of surface damage on the retrieved ceramic components. The implantation period was positively correlated with both damage scores of the femoral heads (R = 0.573, p < 0.001) and the acetabular cups (R = 0.592, p < 0.001). Increased maximal out-of-roundness values of the femoral heads correlated with both increased metal transfer damage score (R = 0.384, p = 0.023) and increased stripe damage score (R = 0.729, p <= 0.001) of the acetabular liners. The damage rate (damage score/year) for both the retrieved heads and acetabular liners was at least 2.2-fold greater at inclination angles of >45 degrees than the damage rate at inclination angles of <=45 degrees . For the retrieved femoral heads only, the linear wear rate of 25.5 +/- 21.3 um/year at inclination angles of >45 degrees was 6-fold greater than the linear wear rate of 4.2 +/- 2.3 um/year at inclination angles of <=45 degrees . Metal transfer on the ceramic bearing surface could possibly contribute to fluid-film starvation and, in combination with an increased inclination angle, may facilitate an adhesive wear mechanism associated with stripe surface damage. At our institution, the clinical survivorship of ceramic-on-ceramic total hip replacements was 98.9% (a total of 9 out of 815 patients were revised within 10 years after total hip arthroplasty) with revision as the end point, suggesting their safe use in younger patients. PMID- 23736993 TI - Contribution of posterolateral corner structures to knee joint translational and rotational stabilities: a computational study. AB - It has been reported that posterolateral corner structures, including the lateral collateral ligament, the popliteus tendon, and the popliteofibular ligament, may play important roles in reducing external rotational and posterior translational instabilities. However, there are few studies focusing on the quantitative influence of posterolateral corner structures on knee joint stability, due to the difficulty of controlling experimental conditions. In this study, a knee model that included posterolateral corner structures was developed. It was validated by comparison to previous experimental studies using the posterior drawer test, dial test, and varus stress test. The posterior translation, external rotation, and varus rotation were then predicted in order to investigate the contribution of posterolateral corner structures to translational and rotational stabilities. Our results indicate that posterolateral corner structures, including the popliteofibular ligament and the popliteus tendon, could contribute to posterior translational and external rotational stabilities, as clinical observations had suggested. Therefore, the addition of posterolateral corner structures to knee joint models may improve the utility of such models. PMID- 23736994 TI - Evaluation of phytochemical-incorporated porous polymeric sponges for bone tissue engineering: a novel perspective. AB - Porous polymeric scaffolds are extensively studied for delivery of bone growth factors. Since phytochemicals are known to produce changes in cell signalling and other metabolic pathways, osteogenic phytochemicals, that is, extracts of Cissus quadrangularis and Butea monosperma, are incorporated into sulphonated poly(aryl ether ketone) sponges. The results have shown that the scaffolds with phytochemicals enhanced the proliferation and alkaline phosphatase activity of the cells compared to cells treated on scaffolds without phytochemicals. Hence, these phytochemicals can be evaluated to augment, if not substitute the use of bone morphogenetic proteins in scaffolds. PMID- 23736995 TI - An in vitro approach to the evaluation of foot-ankle kinematics: performance evaluation of a custom-built gait simulator. AB - Despite their well-known limitations, in vitro experiments have several benefits over in vivo techniques when exploring foot biomechanics under conditions characteristic of gait. In this study, we present a new setup for dynamic in vitro gait simulation that integrates a numerical model for generating the tibial kinematics control input, and we present an innovative methodology to measure full three-dimensional joint kinematics during gait simulations. The gait simulator applies forces to the tendons. Tibial kinematics in the sagittal plane is controlled using a numerical model that takes into account foot morphology. The methodology is validated by comparing joint rotations measured during gait simulation with those measured in vivo. In addition, reliability and accuracy of the control system as well as simulation input and output repeatability are quantified. The results reflect good control performance and repeatability of the control inputs, vertical ground reaction force, center of pressure displacement, and joint rotations and translations. In addition, there is a good correspondence to in vivo kinematics for most patterns of motion at the ankle, subtalar, and Chopart's joints. Therefore, these results show the relevance and validity of including specimen-specific information for defining the control inputs. PMID- 23736996 TI - Progressive cognitive dysfunction in spinocerebellar ataxia type 3. AB - BACKGROUND: Although it is well established that there is cognitive dysfunction in spinocerebellar ataxia type 3 (SCA3), it is unknown whether cognition deteriorates with disease progression. We therefore prospectively studied cognitive function in patients with SCA3. METHODS: Eleven patients with SCA3 were assessed using an extensive neuropsychological test battery and retested after 3.5 +/- 0.4 years. RESULTS: In addition to ataxia and motor control, verbal learning and verbal and figural memory deteriorated significantly during the follow-up period. An increase in depressive symptoms was not observed. CONCLUSIONS: The observation that memory and learning abilities deteriorated with disease progression suggests that cognitive dysfunction is an integral part of SCA3. Because the applied tests for memory function did not require motor responses, cognitive decline cannot be attributed to progressive cerebellar ataxia. The deterioration of verbal and figural memory can be explained either by extracerebellar pathology or by disruption of cerebellar-cerebral circuitries. PMID- 23736997 TI - CYP2C19 2 predicts substantial tamoxifen benefit in postmenopausal breast cancer patients randomized between adjuvant tamoxifen and no systemic treatment. AB - Estrogen catabolism is a major function of CYP2C19. The effect of CYP2C19 polymorphisms on tamoxifen sensitivity may therefore not only be mediated by a variation in tamoxifen metabolite levels but also by an effect on breast cancer risk and molecular subtype due to variation in lifelong exposure to estrogens. We determined the association between these polymorphisms and tamoxifen sensitivity in the context of a randomized trial, which allows for the discernment of prognosis from prediction. We isolated primary tumor DNA from 535 estrogen receptor-positive, stages I-III, postmenopausal breast cancer patients who had been randomized to tamoxifen (1-3 years) or no adjuvant therapy. Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of CYP2C19 2 and CYP2C19 17. Hazard ratios and interaction terms were calculated using multivariate Cox proportional hazard models, stratified for nodal status. Tamoxifen benefit was not significantly affected by CYP2C19 17. Patients with at least one CYP2C19 2 allele derived significantly more benefit from tamoxifen (HR 0.26; p = 0.001) than patients without a CYP2C19 2 allele (HR 0.68; p = 0.18) (p for interaction 0.04). In control patients, CYP2C19 2 was an adverse prognostic factor. In conclusion, breast cancer patients carrying at least one CYP2C19 2 allele have an adverse prognosis in the absence of adjuvant systemic treatment, which can be substantially improved by adjuvant tamoxifen treatment. PMID- 23736998 TI - Serum thymidine kinase activity compared with CA 15-3 in locally advanced and metastatic breast cancer within a randomized trial. AB - The primary objective was to estimate serum thymidine kinase 1 (TK1) activity, reflecting total body cell proliferation rate including cancer cell proliferation, in women with loco regional inoperable or metastatic breast cancer participating in a prospective and randomized study. Secondary objectives were to analyze TK1 in relation to progression-free survival (PFS), overall survival (OS), therapy response and other tumour characteristics, including CA 15-3, widely used as a standard serum marker for disease progression. TK1 and CA 15-3 were analysed in 198 serum samples collected prospectively from women included in the randomized TEX trial between December 2002 and June 2007. TK1 activity was determined by the ELISA based DiviTumTM assay, and CA 15-3 analyses was generated with the electrochemiluminescence immunoassay Cobas Elecsys CA 15-3 II. High pre treatment TK1 activity predicted shorter PFS (10 vs. 15 months p = 0.02) and OS (21 vs. 38 months, p < 0.0001), respectively. After adjustment for age, metastatic site and study treatment TK1 showed a trend as predictor of PFS (p = 0.059) and was an independent prognostic factor for OS, (HR 1.81, 95 % confidence interval (CI) 1.26-2.61, p = 0.001). There was a trend of shortened OS for women with high CA 15-3 (p = 0.054) in univariate analysis, but not after adjustment for the above mentioned covariates. Both TK1 (p = 0.0011) and CA 15-3 (p = 0.0004) predicted response to treatment. There were statistically different distributions of TK1 and CA 15-3 in relation to the site of metastases. TK1 activity measured by DiviTumTM predicted therapy response, PFS and OS in loco regional inoperable or disseminated breast cancer. These results suggest that this factor is a useful serum marker. In the present material, a prognostic value of CA 15-3 could not be proven. PMID- 23736999 TI - [Co(I)(CN)2(CO)3]-, a new discovery from an 80-year-old reaction. AB - A systematic study of the 80-year-old simple and fundamental reaction of cobalt(II) salt with cyanide under one atmosphere CO was carried out and two novel Co(I) complexes were isolated in the absence of hydroxide. These complexes are the first structurally characterized mixed cobalt CO-CN(-) compounds. PMID- 23737000 TI - Noun imageability facilitates the acquisition of plurals: survival analysis of plural emergence in children. AB - Some research in child language suggests that semantically general verbs appear in grammatical structures earlier than semantically complex, specific ones. The present study examines whether this was the case in nouns, using imageability as a proxy measure of semantic generality. Longitudinal corpus data from 12 children from the Manchester corpus in CHILDES were used to obtain information on the first occurrence of plurals. A total of 3,560 uninflected nouns were identified in the corpora, of which 1,202 were observed in the plural. Survival analyses indicated that the chance of observing a plural form increases with the imageability rating of the noun, even after accounting for the age of acquisition of the uninflected noun, maternal input frequency, and word length. Noun imageability thus facilitates the acquisition of plural forms. This finding contradicts the observations from verbs, and indicates that the acquisition of grammar is facilitated by high imageability rather than semantic generality. PMID- 23737001 TI - Lessons learnt from the human infections of avian-origin influenza A H7N9 virus: live free markets and human health. PMID- 23737002 TI - Nuclear proteome profile of C57BL/6J mouse liver. AB - The liver proteome can serve as a reference to better understand both disease mechanisms and possible therapeutics, since the liver is an important organ in the body that performs a large number of tasks. Here we identify the organelle proteome of C57BL/6J mouse liver nuclei as a promising strategy to enrich low abundance proteins, in the sense that analysis of whole liver cells is rather complex for current techniques and may not be suitable for proteins with low abundance. Evaluation of nucleus integrity and purity was performed to demonstrate the effectiveness of the optimized isolation procedure. The extracted nuclear proteins were identified by 2-DE MS analyses, and a total of 748 proteins were identified. Bioinformatic analyses were performed to demonstrate the physicochemical properties, cellular locations and functions of the proteins. PMID- 23737003 TI - Soil microbial properties under different vegetation types on Mountain Han. AB - This study investigated the influence of broadleaf and conifer vegetation on soil microbial communities in a distinct vertical distribution belt in Northeast China. Soil samples were taken at 0-5, 5-10 and 10-20 cm depths from four vegetation types at different altitudes, which were characterized by poplar (Populus davidiana) (1250-1300 m), poplar (P. davidiana) mixed with birch (Betula platyphylla) (1370-1550 m), birch (B. platyphylla) (1550-1720 m), and larch (Larix principis-rupprechtii) (1840-1890 m). Microbial biomass and community structure were determined using the fumigation-extraction method and phospholipid fatty acid (PLFA) analysis, and soil fungal community level physiological profiles (CLPP) were characterized using Biolog FF Microplates. It was found that soil properties, especially soil organic carbon and water content, contributed significantly to the variations in soil microbes. With increasing soil depth, the soil microbial biomass, fungal biomass, and fungal catabolic ability diminished; however, the ratio of fungi to bacteria increased. The fungal ratio was higher under larch forests compared to that under poplar, birch, and their mixed forests, although the soil microbial biomass was lower. The direct contribution of vegetation types to the soil microbial community variation was 12%. If the indirect contribution through soil organic carbon was included, variations in the vegetation type had substantial influences on soil microbial composition and diversity. PMID- 23737004 TI - Activities of principal photosynthetic enzymes in green macroalga Ulva linza: functional implication of C4 pathway in CO2 assimilation. AB - The green-tide-forming macroalga Ulva linza was profiled by transcriptome sequencing to ascertain whether the alga carries both C3 and C4 photosynthesis genes. The key enzymes involved in C4 metabolism including pyruvate orthophosphate dikinase (PPDK), phosphoenolpyruvate carboxylase (PEPC), and phosphoenolpyruvate carboxykinase (PCK) were found. When measured under normal and different stress conditions, expression of rbcL was higher under normal conditions and lower under the adverse conditions, whereas that of PPDK was higher under some adverse conditions, namely desiccation, high salinity, and low salinity. Both ribulose-1, 5-biphosphate carboxylase (RuBPCase) and PPDK were found to play a role in carbon fixation, with significantly higher PPDK activity across the stress conditions. These results suggest that elevated PPDK activity alters carbon metabolism in U. linza leading to partial operation of the C4 carbon metabolism, a pathway that, under stress conditions, probably contributes to the hardy character of U. linza and thus to its wide distribution. PMID- 23737005 TI - Proton versus photon radiation therapy for patients with high-risk neuroblastoma: the need for a customized approach. AB - BACKGROUND: Proton therapy for treatment for high-risk neuroblastoma may offer sparing of organs at risk (OAR) when compared to intensity-modulated X-ray therapy (IMXT). PROCEDURE: Double-scattered proton plans and IMXT plans delivering 2,160 cGy to the primary tumor site and other residual disease were developed for 13 consecutive HR-NBL patients. Radiation doses to target volumes and OAR were calculated to determine the optimal modality for each. RESULTS: All patients received radiation (5/13 >= 2 sites). No patient has experienced local recurrence or clinical organ toxicity. Coverage was excellent using both protons and IMXT: median % dose delivered to 95% clinical target volume was 99% and 100%, respectively. For nine patients with lateralized disease, proton therapy offered sparing of the contralateral kidney both with regard to median dose and dose to 20% (median <1 cGy vs. 362 cGy, P = 0.01; median 100 cGy vs. 634 cGy, P = 0.02, respectively). Proton therapy did not reduce ipsilateral kidney dose, and for 2 select patients with lateralized disease IMXT improved overall bilateral renal sparing. Proton therapy improved median bowel (median 33 cGy vs. 590 cGy, P = 0.01), total body (median <1 cGy vs. 30 cGy, P = 0.15), and liver dose (median <1 cGy vs. 529, P < 0.001). When chest RT was required, proton therapy decreased median heart dose and mean lung dose. CONCLUSIONS: For most patients (11/13), proton therapy offered the optimal combination of target coverage and organ sparing, and is a feasible treatment for HR-NBL. We recommend a customized approach with careful evaluation of renal dosimetry; IMXT may be preferred for select patients. PMID- 23737007 TI - Functional (psychogenic) symptoms in Parkinson's disease. AB - It has been reported that patients who have Parkinson's disease have a high prevalence of somatisation (functional neurological symptoms) compared with patients who have other neurodegenerative conditions. Numerous explanations have been advanced for this phenomenon. Here, with illustrative cases, we discuss this topic, including its clinical importance, and suggest a link between the pathophysiology of Parkinson's disease and the proposed propensity to develop functional symptoms. PMID- 23737006 TI - Blood pressure regulation IX: cerebral autoregulation under blood pressure challenges. AB - Cerebral autoregulation (CA) is integral to the delicate process of maintaining stable cerebral perfusion and brain tissue oxygenation against changes in arterial blood pressure. The last four decades has seen dramatic advances in understanding CA physiology, and the role that CA might play in the causation and progression of disease processes that affect the cerebral circulation such as stroke. However, the translation of these basic scientific advances into clinical practice has been limited by the maintenance of old constructs and because there are persistent gaps in our understanding of how this vital vascular mechanism should be quantified. In this review, we re-evaluate relevant studies that challenge established paradigms about how the cerebral perfusion pressure and blood flow are related. In the context of blood pressure being a major haemodynamic challenge to the cerebral circulation, we conclude that: (1) the physiological properties of CA remain inconclusive, (2) many extant methods for CA characterisation are based on simplistic assumptions that can give rise to misleading interpretations, and (3) robust evaluation of CA requires thorough consideration not only of active vasomotor function, but also the unique properties of the intracranial environment. PMID- 23737008 TI - Case report: Macrodont mandibular second premolars, a hereditary dental anomaly. AB - BACKGROUND: Macrodontia or megadontia is a rare dental anomaly that refers to teeth that appear larger than normal. Generalised macrodontia may be associated with certain medical conditions and syndromes. Isolated macrodontia involves single teeth, might be the result of teeth fusion and is mainly seen in the incisor area. CASE REPORTS: This paper describes two unrelated cases presenting with bilateral macrodont second lower premolars and the treatment provided. One case demonstrated the anomaly in both the patient and his father. CONCLUSION: This case report suggests for the first time in the literature the genetic aetiology and heritability, as a possible autosomal dominant trait, of this rare dental anomaly. PMID- 23737009 TI - Evaluation of the tooth brushing skills in children aged 6-12 years. AB - AIM: To evaluate the tooth brushing skills in children aged between 6 and 12 years and its relation with age, type of grip used, duration of brushing and gender. METHOD: A total of 105 children aged between 6 and 12 years were divided into seven groups and their plaque scores, type of grip used and duration of brushing were assessed. RESULTS: The most preferred grip was the distal oblique (58.1 %). Oblique, distal oblique and power grips were more efficient (plaque reduction up to 70 %). Plaque removal efficacy improved with age (57 % in 6-year olds and 82 % in 12-year-old children). Plaque reduction was greater when the duration of brushing was longer (82 % plaque reduction when the brushing time was >2.5 min). Overall, the mean duration of tooth brushing in children aged 6-12 years was 1.71 min (103 s). CONCLUSIONS: Tooth brushing skills improved with age and the duration of tooth brushing made a significant difference to the oral hygiene status of the child. The type of grip used and gender did not influence tooth brushing ability in this group of children. Tooth brushing skills were low in children younger than 10 years of age. Hence, parental supervision is considered necessary and recommended until 10 years of age. PMID- 23737010 TI - [Computed tomography angiography as the basis for optimized therapy planning before endovascular aneurysm repair (EVAR)]. AB - Computed tomography angiography (CTA) of the aorta is an accepted standard diagnostic procedure for preoperative evaluation and planning of endovascular treatment of abdominal aortic aneurysms (endovascular aortic repair EVAR). The CTA method delivers all relevant anatomical and morphological information on the underlying pathology of the aorta and pelvic axes. Various software solutions are available for multiplanar reconstruction of the CT data for exact measurement of the access routes and landing zones and are essential components of individualized operation planning. The synthesis of all CT-based information allows a safe and exactly targeted release of the stent graft in the aorta. Furthermore, the periprocedural radiation dose can be reduced by a precise preoperative planning of the positions to be irradiated during implantation. PMID- 23737011 TI - A longitudinal study of maternal attachment and infant developmental outcomes. AB - Extant research has demonstrated that compared to adults with insecure attachment styles, more securely attached parents tend to be more responsive, sensitive, and involved parents, resulting in improved outcomes for their children. Less studied is the influence of a mother's attachment style on her attachment to her unborn child during pregnancy and the consequent developmental outcomes of the child during early childhood. Thus, the aim of this prospective longitudinal study was to examine the relationship between maternal-fetal attachment (MFA) during pregnancy and infant and toddler outcomes and the role of mothers' attachment style on early childhood developmental outcomes in an economically disadvantaged sample of women and their children. Gamma regression modeling demonstrated that an avoidant maternal attachment style (b = .98, 95 % CI [.97, .98], p < 0.001) and post-partum depressive symptomatology (b = .97, 95 % CI [.96-.99], p = 0.03) were significant predictors of early childhood development. Women demonstrating higher avoidant attachment styles and greater depressive symptomatology were more likely to have children demonstrating early childhood developmental delays than those women with less avoidant attachment styles and less depressive symptomatology. Furthermore, women reporting higher MFA during pregnancy had more secure attachment styles, and their children had more optimal early childhood development than those women reporting lower MFA and less secure attachment styles. Findings have implications for enhancing early intervention programs aimed at improving maternal and childhood outcomes. An earlier identification of disruptions in attachment may be beneficial in tailoring interventions focused on the mother-child dyad. PMID- 23737012 TI - Characteristics of perinatal women seeking treatment for marijuana abuse in a community-based clinic. AB - In the US, marijuana continues to be the most frequently used illicit drug among women of childbearing age, including pregnant and postpartum women. Given the critical window for treatment during the perinatal period, more information is needed about the characteristics of women who abuse marijuana and about their unique needs with the goal of improving clinical services and outcomes for both women and their infants. OBJECTIVES: To (1) identify a profile of perinatal women seeking treatment for primarily marijuana abuse and (2) report birth outcomes in a subset of pregnant women with marijuana abuse. METHODS: This retrospective clinical chart review study examined 67 adult perinatal women patients (54 % ethnic minority) who attended an inner-city, hospital-affiliated outpatient program specializing in substance abuse treatment for women. Of all pregnant women, 26 % reported positive urine screens during the first trimester, 41 % during the second trimester, and 27 % during the third trimester. While the subset of pregnant women was small, exploratory results suggest that infants whose mothers continued to use marijuana during their pregnancies were born at a lower gestational age than mothers who abstained; t(29) = 2.04, p <0.05. CONCLUSION: Identifying potential barriers to treatment could help improve retention in community-based treatment programs during pregnancy and the postpartum period. PMID- 23737014 TI - This is the tenth issue within the series of special issues dedicated to "Bioanalysis" and thus, to some extent, a jubilee issue. Introduction. PMID- 23737013 TI - This issue continues the series of special issues on "Bioanalysis". Introduction. PMID- 23737015 TI - Identification of stromal differentially expressed proteins in the colon carcinoma by quantitative proteomics. AB - Tumor microenvironment plays very important roles in the carcinogenesis. A variety of stromal cells in the microenvironment have been modified to support the unique needs of the malignant state. This study was to discover stromal differentially expressed proteins (DEPs) that were involved in colon carcinoma carcinogenesis. Laser capture microdissection (LCM) was captured and isolated the stromal cells from colon adenocarcinoma (CAC) and non-neoplastic colon mucosa (NNCM) tissues, respectively. Seventy DEPs were identified between the pooled LCM enriched CAC and NNCM stroma samples by iTRAQ-based quantitative proteomics. Gene Ontology (GO) relationship analysis revealed that DEPs were hierarchically grouped into 10 clusters, and were involved in multiple biological functions that were altered during carcinogenesis, including extracellular matrix organization, cytoskeleton, transport, metabolism, inflammatory response, protein polymerization, and cell motility. Pathway network analysis revealed 6 networks and 56 network eligible proteins with Ingenuity pathway analysis. Four significant networks functioned in digestive system development and its function, inflammatory disease, and developmental disorder. Eight DEPs (DCN, FN1, PKM2, HSP90B1, S100A9, MYH9, TUBB, and YWHAZ) were validated by Western blotting, and four DEPs (DCN, FN1, PKM2, and HSP90B1) were validated by immunohistochemical analysis. It is the first report of stromal DEPs between CAC and NNCM tissues. It will be helpful to recognize the roles of stromas in the colon carcinoma microenvironment, and improve the understanding of carcinogenesis in colon carcinoma. The present data suggest that DCN, FN1, PKM2, HSP90B1, S100A9, MYH9, TUBB, and YWHAZ might be the potential targets for colon cancer prevention and therapy. PMID- 23737021 TI - Radiofrequency ablation of liver tumors in combination with local OK-432 injection prolongs survival and suppresses distant tumor growth in the rabbit model with intra- and extrahepatic VX2 tumors. AB - PURPOSE: To evaluate survival and distant tumor growth after radiofrequency ablation (RFA) and local OK-432 injection at a single tumor site in a rabbit model with intra- and extrahepatic VX2 tumors and to examine the effect of this combination therapy, which we termed immuno-radiofrequency ablation (immunoRFA), on systemic antitumor immunity in a rechallenge test. METHODS: Our institutional animal care committee approved all experiments. VX2 tumors were implanted to three sites: two in the liver and one in the left ear. Rabbits were randomized into four groups of seven to receive control, RFA alone, OK-432 alone, and immunoRFA treatments at a single liver tumor at 1 week after implantation. Untreated liver and ear tumor volumes were measured after the treatment. As the rechallenge test, tumors were reimplanted into the right ear of rabbits, which survived the 35 weeks and were followed up without additional treatment. Statistical significance was examined by log-rank test for survival and Student's t test for tumor volume. RESULTS: Survival was significantly prolonged in the immunoRFA group compared to the other three groups (P < 0.05). Untreated liver and ear tumor sizes became significantly smaller after immunoRFA compared to controls (P < 0.05). In the rechallenge test, the reimplanted tumors regressed without further therapy compared to the ear tumors of the control group (P < 0.05). CONCLUSION: ImmunoRFA led to improved survival and suppression of distant untreated tumor growth. Decreases in size of the distant untreated tumors and reimplanted tumors suggested that systemic antitumor immunity was enhanced by immunoRFA. PMID- 23737022 TI - Ethanolamine oleate sclerotherapy combined with transarterial embolization using n-butyl cyanoacrylate for extracranial arteriovenous malformations. AB - PURPOSE: This study was designed to assess the safety and effectiveness of ethanolamine oleate (EO) sclerotherapy combined with transarterial embolization using a liquid adhesive agent (n-butyl cyanoacrylate, NBCA) for treatment of extracranial arteriovenous malformations (AVMs). METHODS: Twenty-four patients with symptomatic AVMs in the head and neck (n = 15), extremity (n = 5), and trunk (n = 4) with a mean age of 44 years (range, 18-78) treated with EO sclerotherapy were retrospectively assessed. AVMs were classified according to the angiographic morphology of the nidus. There were 7 type II (arteriolovenous fistulae), 6 type IIIa (arteriolovenulous fistulae with nondilated fistula), and 11 type IIIb (arteriolovenulous fistulae with dilated fistula). Transarterial embolization using NBCA was performed to reduce arterial flow before sclerotherapy. EO mixed with contrast material was delivered by percutaneous direct puncture or by catheterization into the draining vein under balloon occlusion. RESULTS: Three (13%) of 24 patients were cured, 17 (71%) had partial remission, and 4 (16%) no remission. Treatment was considered effective (cure and partial remission) in 20 patients (83%). Four patients (16%) experienced transient minor complications, including self-healing skin ulcer (n = 3) and localized deep venous thrombosis (n = 1). There were no major complications. CONCLUSIONS: EO sclerotherapy combined with transarterial embolization using NBCA is safe and effective for treating extracranial AVMs with an acceptable risk of minor complications. PMID- 23737023 TI - Deep pelvic postprostatectomy pseudoaneurysm treated by transrectal ultrasound guided thrombin injection. PMID- 23737024 TI - Saccular aneurysm of superior vena cava treated with percutaneous, transcatheter thrombin injection. AB - We report the case of successful endovascular treatment of large saccular aneurysm of SVC in a patient with vascular malformation of right hand and chest. Considering the high risk of surgery, the patient was referred for percutaneous intervention. Venography showed communication between the aneurysm and SVC, just below brachiocephalic confluence. That is why the decision of balloon-protected transcatheter thrombin injection was made. Selective catheter was placed in the aneurysm and balloon occlusion catheter in SVC. Both catheters were withdrawn right after thrombin injection. During follow-up, aneurysm slightly enlarged in early observation and after a year shrinkage was observed. PMID- 23737025 TI - Synchronous and metachronous malignancies: analysis of the Minneapolis Veterans Affairs (VA) tumor registry. AB - PURPOSE: Multiple primary malignancies (MPMs) are increasing as cancer survivorship improves. A large analysis of the SEER database estimates that approximately 16 % of new cancers reported to their registry represent a second or higher order malignancy. The purpose of this study is to estimate the number of MPM diagnoses and to define differences in synchronous and metachronous cancers in the Veterans Affairs (VA) population. METHODS: The primary objective of this study was to determine the proportion of second or higher order cancers diagnosed at the Minneapolis VA Medical Center from 1 January 2005 to 31 December 2009. The secondary objectives were to analyze and compare correlative demographic, exposure, clinical, and tumor data among those with synchronous and metachronous malignancies. We included any patient with a diagnosis of a malignant cancer during the study period. RESULT: A total of 4,449 patients were diagnosed with malignancies during the study period. Of these, 506 patients (11.4 % of cancer diagnoses) had a diagnosis of a second or higher order malignancy. Of the 506 patients, 124 (24.3 %) had synchronous malignancies and 383 (75.5 %) had metachronous malignancies. The most common malignancy pairing was prostate cancer with bladder/ureter cancer (12 %) of MPM diagnoses. Differences between patients with synchronous and metachronous second occurrences were identified. CONCLUSION: Multiple primary malignancies are a growing area of interest in cancer survivorship. At our institution, approximately 1 in 9 new cancer diagnoses during the 5-year study period represented second-order malignancies. Our data suggest that the VA population is at risk of developing second primary cancers. Further analysis of this population to identify unique risk factors is warranted. PMID- 23737028 TI - Do reproductive and hormonal risk factors for breast cancer associate with attendance at mammography screening? AB - PURPOSE: To determine whether reproductive and hormonal risk factors for breast cancer associate with mammography attendance. METHODS: We linked data from the Malmo Diet and Cancer Study to the Malmo mammography register (Sweden, 1992 2009). We analyzed 11,409 women (age 44-72) who were free of breast cancer at study entry and a total of 69,746 screening invitations. Generalized Estimating Equations were used to account for repeated measures within subjects. Models were adjusted for age and other sociodemographic factors. RESULTS: In this study cohort, mammography screening attendance ranged from 87.6 to 94.5% between calendar years, with an average attendance of 92%. Higher attendance was found among women who had given birth to fewer than three children (ORs ranging between 1.15 and 1.37) and had used oral contraceptives (OC) within the last decade (OR = 1.22, 95% CI 1.07-1.38) and for a longer period (OR = 1.13, 95% CI 1.01-1.27). A lower odds of attendance was found among post-menopausal women (OR = 0.86, 95% CI 0.77-0.96). Age < 13 at menarche, age >= 30 at first childbirth, age >= 55 at menopause, age < 20 at first OC use, nulliparity, breastfeeding, and hormone replacement therapy were not associated with mammography attendance. CONCLUSION: Reproductive and hormonal risk factors for breast cancer have little effect on mammography screening attendance. This may indicate a potential for under screening of some women at higher risk. PMID- 23737027 TI - Pregnancy-related characteristics and breast cancer risk. AB - Breast tissues undergo extensive physiologic changes during pregnancy, which may affect breast carcinogenesis. Gestational hypertension, preeclampsia/eclampsia, gestational diabetes, pregnancy weight gain, and nausea and vomiting (N&V) during pregnancy may be indicative of altered hormonal and metabolic profiles and could impact breast cancer risk. Here, we examined associations between these characteristics of a woman's pregnancy and her subsequent breast cancer risk. Participants were parous women that were recruited to a population-based case control study (Western New York Exposures and Breast Cancer Study). Cases (n = 960), aged 35-79 years, had incident, primary, histologically confirmed breast cancer. Controls (n = 1,852) were randomly selected from motor vehicle records (< 65 years) or Medicare rolls (>= 65 years). Women were queried on their lifetime pregnancy experiences. Multivariable-adjusted logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). N&V during pregnancy was inversely associated with breast cancer risk. Relative to those who never experienced N&V, ever experiencing N&V was associated with decreased risk (OR 0.69, 95% CI 0.56-0.84) as were increased N&V severity (p trend < 0.001), longer duration (p trend < 0.01), and larger proportion of affected pregnancies (p trend < 0.0001) among women with >= 3 pregnancies. Associations were stronger for more recent pregnancies (< 5 years). Findings did not differ by menopausal status or breast cancer subtype including estrogen receptor and HER2 expression status. Other pregnancy characteristics examined were not associated with risk. We observed strong inverse associations between pregnancy N&V and breast cancer risk. Replication of these findings and exploration of underlying mechanisms could provide important insight into breast cancer etiology and prevention. PMID- 23737026 TI - Prostate cancer chemoprevention in men of African descent: current state of the art and opportunities for future research. AB - Prostate cancer is the most frequently diagnosed malignancy in men. However, African American/Black men are 60 % more likely to be diagnosed with and 2.4 times more likely to die from prostate cancer, compared to Non-Hispanic White men. Despite the increased burden of this malignancy, no evidence-based recommendation regarding prostate cancer screening exists for the high-risk population. Moreover, in addition to screening and detection, African American men may constitute a prime population for chemoprevention. Early detection and chemoprevention may thus represent an integral part of prostate cancer control in this population. Importantly, recent research has elucidated biological differences in the prostate tumors of African American compared to European American men. The latter may enable a more favorable response in African American men to specific chemopreventive agents that target relevant signal transduction pathways. Based on this evolving evidence, the aims of this review are threefold. First, we aim to summarize the biological differences that were reported in the prostate tumors of African American and European American men. Second, we will review the single- and multi-target chemopreventive agents placing specific emphasis on the pathways implicated in prostate carcinogenesis. And lastly, we will discuss the most promising nutraceutical chemopreventive compounds. Our review underscores the promise of chemoprevention in prostate cancer control, as well as provides justification for further investment in this filed to ultimately reduce prostate cancer morbidity and mortality in this high-risk population of African American men. PMID- 23737029 TI - Brain abnormalities and neurodevelopmental delay in congenital heart disease: systematic review and meta-analysis. AB - OBJECTIVES: Studies have demonstrated an association between congenital heart disease (CHD) and neurodevelopmental delay. Neuroimaging studies have also demonstrated a high incidence of preoperative brain abnormalities. The aim of this study was to perform a systematic review to quantify the non-surgical risk of brain abnormalities and of neurodevelopmental delay in infants with CHD. METHODS: MEDLINE, EMBASE and The Cochrane Library were searched electronically without language restrictions, utilizing combinations of the terms congenital heart, cardiac, neurologic, neurodevelopment, magnetic resonance imaging, ultrasound, neuroimaging, autopsy, preoperative and outcome. Reference lists of relevant articles and reviews were hand-searched for additional reports. Cohort and case-control studies were included. Studies reporting neurodevelopmental outcomes and/or brain lesions on neuroimaging in infants with CHD before heart surgery were included. Cases of chromosomal or genetic abnormalities, case reports and editorials were excluded. Between-study heterogeneity was assessed using the I(2) test. RESULTS: The search yielded 9129 citations. Full text was retrieved for 119 and the following were included in the review: 13 studies (n = 425 cases) reporting on brain abnormalities either preoperatively or in those who did not undergo congenital cardiac surgery and nine (n = 512 cases) reporting preoperative data on neurodevelopmental assessment. The prevalence of brain lesions on neuroimaging was 34% (95% CI, 24-46; I(2) = 0%) in transposition of the great arteries, 49% (95% CI, 25-72; I(2) = 65%) in left-sided heart lesions and 46% (95% CI, 40-52; I(2) =18.1%) in mixed/unspecified cardiac lesions, while the prevalence of neurodevelopmental delay was 42% (95% CI, 34-51; I(2) = 68.9). CONCLUSIONS: In the absence of chromosomal or genetic abnormalities, infants with CHD are at increased risk of brain lesions as revealed by neuroimaging and of neurodevelopmental delay. These findings are independent of the surgical risk, but it is unclear whether the time of onset is fetal or postnatal. PMID- 23737030 TI - Antispasmodics for labour. AB - BACKGROUND: Prolonged labour can lead to increased maternal and neonatal mortality and morbidity due to increased risks of maternal exhaustion, postpartum haemorrhage and sepsis, fetal distress and asphyxia and requires early detection and appropriate clinical response. The risks for complications of prolonged labour are much greater in poor resource settings. Active management of labour versus physiological, expectant management, has shown to decrease the occurrence of prolonged labour. Administering antispasmodics during labour could also lead to faster and more effective dilatation of the cervix. Interventions to shorten labour, such as antispasmodics, can be used as a preventative or a treatment strategy in order to decrease the incidence of prolonged labour. As the evidence to support this is still largely anecdotal around the world, there is a need to systematically review the available evidence to obtain a valid answer. OBJECTIVES: To assess the effects of antispasmodics on labour in term pregnancies. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (28 February 2013), the ProQuest dissertation and thesis database, the dissertation database of the University of Stellenbosch and Google Scholar (28 February 2013) and reference lists of articles. We also contacted pharmaceutical companies and experts in the field. We did not apply language restrictions. SELECTION CRITERIA: Randomised controlled trials comparing antispasmodics with placebo or no medication in women with term pregnancies. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts and selected studies for inclusion, assessed risk of bias and extracted data. Data were checked for accuracy. We contacted trial authors when data were missing. MAIN RESULTS: Twenty-one trials (n = 3286) were included in the review. Seventeen trials (n = 2617) were included in the meta-analysis. Antispasmodics used included valethamate bromide, hyoscine butyl-bromide, drotaverine hydrochloride, rociverine and camylofin dihydrochloride. Most studies included antispasmodics as part of their package of active management of labour. Overall, the quality of studies was poor, as only four trials were assessed as low risk of bias. Thirteen trials (n = 1995) reported on the duration of first stage of labour, which was significantly reduced by an average of 74.34 minutes when antispasmodics were administered (mean difference (MD) -74.34 minutes; 95% confidence Interval (CI) 98.76 to -49.93). Seven studies (n = 797) reported on the total duration of labour, which was significantly reduced by an average of 85.51 minutes (MD -85.51 minutes; 95% CI -121.81 to -49.20). Six studies (n = 820) had data for the outcome: rate of cervical dilatation. Administration of antispasmodics significantly increased the rate of cervical dilatation by an average of 0.61 cm/hour (MD 0.61 cm/hour; 95% CI 0.34 to 0.88). Antispasmodics did not affect the duration of second and third stage of labour. The rate of normal vertex deliveries was not affected either. Only one study explored pain relief following administration of antispasmodics and no conclusions can be drawn on this outcome. There was significant heterogeneity for most outcomes and therefore, we undertook random-effects meta-analysis. Subgroup analysis was undertaken to explore heterogeneity, but remained largely unexplained. Maternal and neonatal adverse events were reported inconsistently. The main maternal adverse event reported was tachycardia. No serious neonatal adverse events were reported. AUTHORS' CONCLUSIONS: There is low quality evidence that antispasmodics reduce the duration of first stage of labour and increase the cervical dilatation rate. There is very low quality evidence that antispasmodics reduce the total duration of labour. There is moderate quality evidence that antispasmodics do not affect the rate of normal vertex deliveries. There is insufficient evidence to make any conclusions regarding the safety of these drugs for both mother and baby. Large, rigorous randomised controlled trials are needed to evaluate the effect of antispasmodics on prolonged labour and to evaluate their effect on labour in a context of expectant management of labour. PMID- 23737031 TI - Elective preterm birth for fetal gastroschisis. AB - BACKGROUND: Gastroschisis is an uncommon congenital defect of the anterior abdominal wall that results in herniation of intestinal loops outside the abdominal cavity. Babies with gastroschisis generally do well, but there remains a mortality rate of 5% to 10% and some require prolonged parenteral nutrition and intensive care. Significant injury to the exposed bowel may occur in-utero, and earlier birth may reduce this, improve long-term outcomes and reduce complications, such as necrotising enterocolitis. However, it may also increase complications related to prematurity. There is a lack of published data in this area. OBJECTIVES: To assess the effects of elective preterm birth for fetal gastroschisis in pregnancies complicated by this condition. The mode of birth may be either vaginal or by caesarean section, but this review is studying only timing, not the route, of birth. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (16 January 2013). SELECTION CRITERIA: Individual patient randomised controlled trials of planned preterm birth in pregnancies complicated by fetal gastroschisis, diagnosed by ultrasound scanning in time for preterm birth to be an option, and without other fetal anomalies. The intervention is planned preterm birth, prior to 37 weeks and 0 days' gestation, versus planned later birth, at or after 37 weeks and 0 days' gestation (mode of birth is not part of the intervention).We did not include quasi-randomised controlled trials and cluster trials. Cross-over trials are not appropriate for this condition. Studies that were presented in abstract form only were eligible for inclusion, providing that the population included women with pregnancies affected by fetal gastroschisis, the interventions were defined and the treatment selection was randomised. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed for inclusion the one trial identified as a result of the search strategy and assessed trial quality. Two review authors extracted data and checked it for accuracy. MAIN RESULTS: We included one study, involving 40 infants and 42 women. The trial was underpowered to detect clinically important outcome differences between the two policies. There were no significant benefits or adverse effects of elective preterm birth at 36 weeks' gestation for fetal gastroschisis. The primary outcomes were caesarean section and neonatal survival to discharge. Two babies died after birth but before discharge in the elective (intervention) group versus none in the spontaneous group (risk ratio (RR) 5.00; 95% confidence interval (CI) 0.26 to 98.00; one study, n = 40). Seven women (33%) in the elective group and nine women (43%) in the spontaneous group delivered by caesarean section (RR 0.78; 95% CI 0.36 to 1.70).Similarly, for the secondary outcomes, there were no statistical differences in birthweight, ventilation requirements, necrotising enterocolitis and requirement for repeat surgery between the two groups. None of our prespecified maternal secondary outcomes were reported in the included study.We also examined gestational age at birth as a non-prespecified outcome. There was a difference in gestational age at birth between the two arms of the trial (35.8 weeks (SD 0.7) in the elective group and 36.7 (SD 1.5) in the spontaneous group. Possible reasons for this small mean difference include a trend towards spontaneous preterm birth in pregnancies complicated by fetal gastroschisis. AUTHORS' CONCLUSIONS: This review is unable to draw any firm conclusions regarding preterm birth for infants with gastroschisis. It is not possible to say whether the intervention is beneficial or harmful for these babies or their mothers. Only one small trial is included. Further research is needed in this area. PMID- 23737032 TI - Levonorgestrel-releasing intrauterine system for atypical endometrial hyperplasia. AB - BACKGROUND: Endometrial carcinoma is the most common gynaecologic malignancy in the world and develops through preliminary stages of endometrial hyperplasia. Typical endometrial hyperplasia suggests a significant pre-malignant state with frank progression to endometrial carcinoma. Because atypical endometrial hyperplasia tends to occur at a young age, it has become increasingly important and necessary to find a safe and effective fertility-sparing treatment with better tolerability and fewer side effects than the options for treatment that are currently available. The levonorgestrel-releasing intrauterine system has already been used to provide endometrial protection in women with breast cancer who are on adjuvant tamoxifen. The antiproliferative function of levonorgestrel is thought to reduce the risk of endometrial hyperplasia. OBJECTIVES: To determine the efficacy and safety of the levonorgestrel-releasing intrauterine system in reversing atypical endometrial hyperplasia. SEARCH METHODS: In November 2012 we searched the Cochrane Menstrual Disorders and Subfertility Review Group Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library; MEDLINE; EMBASE; and the China National Knowledge Infrastructure for relevant trials. Attempts were made to identify trials from references in published studies. We also searched for ongoing trials in five major clinical trials registries. SELECTION CRITERIA: Randomised controlled trials (RCTs) of the levonorgestrel-releasing intrauterine system (LNG-IUS) versus progestin therapy in women with a confirmed histological diagnosis of simple or complex endometrial hyperplasia with atypia. DATA COLLECTION AND ANALYSIS: No eligible study was found. MAIN RESULTS: We did not identify any studies which met our full inclusion criteria. AUTHORS' CONCLUSIONS: There is no evidence available from randomised controlled trials regarding the efficacy and safety of the levonorgestrel-releasing intrauterine system (LNG-IUS) for atypical endometrial hyperplasia. RCTS are required to determine whether the LNG-IUS is safe and effective for treating atypical endometrial hyperplasia. PMID- 23737033 TI - Hormone therapy for sexual function in perimenopausal and postmenopausal women. AB - BACKGROUND: The perimenopausal and postmenopausal periods are associated with many symptoms, including sexual complaints. OBJECTIVES: To assess the effect of hormone therapy (HT) on sexual function in perimenopausal and postmenopausal women. SEARCH METHODS: We searched for articles in the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov, Current Controlled Trials, WHO International Clinical Trials Registry Platform, ISI Web of Knowledge and OpenGrey. The last search was performed in December 2012. SELECTION CRITERIA: We included randomised controlled trials comparing HT to either placebo or no intervention (control). We considered as HT estrogens alone; estrogens in combination with progestogens; synthetic steroids (for example tibolone); or selective estrogen receptor modulators (SERMs) (for example raloxifene, bazedoxifene). Studies of other drugs possibly used in the relief of menopausal symptoms were excluded. We included studies that evaluated sexual function using any validated assessment tool. The primary outcome was a composite score for sexual function and the scores for individual domains (arousal and sexual interest, orgasm, and pain) were secondary outcomes. Studies were selected by two authors independently. DATA COLLECTION AND ANALYSIS: Data were independently extracted by two authors and checked by a third. Risk of bias assessment was performed independently by two authors. We contacted study investigators as required. Data were analysed using standardized mean difference (SMD) and relative risk (RR). We stratified the analysis by participant characteristics with regard to menopausal symptoms. The overall quality of the evidence for the primary outcome was evaluated using the GRADE criteria. MAIN RESULTS: The search retrieved 2351 records from which 27 studies (16,393 women) were included. The 'symptomatic or early post-menopausal' subgroup included nine studies: perimenopausal women (one study), up to 36 months postmenopause (one study), up to five years postmenopause (one study), experiencing vasomotor or other menopausal symptoms (five studies), or experiencing hot flushes and sexual dysfunction (one study). The 'unselected postmenopausal women' subgroup included 18 studies, which included women regardless of menopausal symptoms and permitted the inclusion of women with more than five years since the final menstrual period. No studies were restricted to women with sexual dysfunction. Only five studies evaluated sexual function as a primary outcome. Eighteen studies were deemed at high risk of bias, and the other nine studies were at unclear risk of bias. Twenty studies received commercial funding.Findings for sexual function (measured by composite score):For estrogens alone versus control, in symptomatic or early postmenopausal women the SMD and 95% CI were compatible with a small to moderate benefit in sexual function for the HT group (SMD 0.38, 95% CI 0.23 to 0.54, P < 0.00001, 3 studies, 699 women, I2 = 55%, high-quality evidence). In unselected postmenopausal women, the 95% CI was compatible with no effect to a small benefit (SMD 0.16, 95% CI -0.02 to 0.34, P = 0.08, 2 studies, 478 women, I2 = 44%, low-quality evidence). The subgroups were not pooled because of considerable heterogeneity.For estrogens combined with progestogens versus control, in symptomatic or early postmenopausal women the 95% CI was compatible with a small to moderate benefit for sexual function in the HT group (SMD 0.42, 95% CI 0.19 to 0.64, P = 0.0003, 1 study, 335 women, moderate-quality evidence). In unselected postmenopausal women, the 95% CI was compatible with no effect to a small benefit (SMD 0.09, 95% CI -0.02 to 0.20, P = 0.10, 3 studies, 1314 women, I2 = 0%, moderate-quality evidence). The subgroups were not pooled because of considerable heterogeneity.For tibolone versus control, in symptomatic or early postmenopausal women the 95% CI was compatible with no effect to a small benefit for sexual function in the HT group (SMD 0.13, 95% CI 0.00 to 0.26, P = 0.05, 1 study, 883 women, low-quality evidence). In unselected postmenopausal women, the 95% CI was compatible with no effect to a moderate benefit (SMD 0.38, 95% CI 0.04 to 0.71, P = 0.03, 2 studies, 142 women, I2 = 0%, low-quality evidence). In the combined analysis, the 95% CI was compatible with no effect to a small benefit (SMD 0.17, 95% CI 0.04 to 0.29, P = 0.008, 3 studies, 1025 women, I2 = 20%).For SERMs versus control, in symptomatic or early postmenopausal women the 95% CI was compatible with no effect to a moderate benefit for sexual function in the HT group (SMD 0.23, 95% CI -0.04 to 0.50, P = 0.09, 1 study, 215 women, low-quality evidence). In unselected postmenopausal women, the 95% CI was compatible with small harm to a small benefit (SMD 0.04, 95% CI -0.20 to 0.29, P = 0.72, 1 study, 283 women, low-quality evidence). In the combined analysis, the 95% CI was compatible with no effect to a small benefit (SMD 0.13, 95% CI -0.05 to 0.31, P = 0.16, 2 studies, 498 women, I2 = 2%).A comparison of SERMs combined with estrogens versus control was only evaluated in symptomatic or early postmenopausal women. The 95% CI was compatible with no effect to a small benefit for sexual function in the HT group (SMD 0.21, 95% CI 0.00 to 0.43, P = 0.05, 1 study, 542 women, moderate-quality evidence). AUTHORS' CONCLUSIONS: HT treatment with estrogens alone or in combination with progestogens was associated with a small to moderate improvement in sexual function, particularly in pain, when used in women with menopausal symptoms or in early postmenopause (within five years of amenorrhoea), but not in unselected postmenopausal women. Evidence regarding other HTs (synthetic steroids and SERMs) is of low quality and we are uncertain of their effect on sexual function. The current evidence does not suggest an important effect of tibolone or of SERMs alone or combined with estrogens on sexual function. More studies evaluating the effect of synthetic steroids, SERMS and the association of SERM + estrogens would improve the quality of the evidence for the effect of these treatments on sexual function in peri and postmenopausal women. Future studies should also evaluate the effect of HT solely among women with sexual complaints. PMID- 23737034 TI - Overexpression of metastasis-associated in colon cancer-1 associated with poor prognosis in patients with esophageal cancer. AB - Recent studies have shown that expression of metastasis-associated in colon cancer-1(MACC1) is observed in different types of cancer and plays an important role in tumor metastasis. However, the expression of MACC1 and its possible role in esophageal cancer remains unknown. In this study, we determined the expression of MACC1 in esophageal cancer by utilizing immunohistochemistry and analyzed the relationship between the expression and esophageal cancer prognosis. Immunohistochemistry results showed that 47 of 85 cancer lesions (55.2 %) were stained positive, and high expression of MACC1 was correlated with the node metastasis and TNM stage (P < 0.05). The Kaplan-Meier survival curve showed that patients with high MACC1 expression had significantly reduced overall 5-year survival rates (P = 0.004). Cox regression analysis revealed that high expression of MACC1 was associated with increased risk of death (hazard ratio [HR] =2.25) in patients with esophageal cancer. These findings suggested that high expression of MACC1 was correlated with progression and metastasis of esophageal cancer and might serve as a novel prognostic marker for patients with esophageal cancer. PMID- 23737035 TI - Laparoscopic versus open radical hysterectomy in patients with stage IB2 and IIA2 cervical cancer. AB - OBJECTIVES: To compare survival and surgical outcomes of laparoscopic (LRH) and open radical hysterectomy (ORH) in patients with stage IB2 and IIA2 cervical cancer. METHODS: A retrospective analysis was performed on 303 patients with stage IB2 and IIA2 cervical cancer who underwent LRH (n = 115) or ORH (n = 188). RESULTS: Two patients (1.7%) in the LRH group required conversion to laparotomy. There was no difference with respect to operating time, perioperative change in hemoglobin level, and need for transfusion. However, in the LRH group, estimated blood loss (P = 0.003) was significantly lower, time to recovery of bowel movement (P < 0.001) and length of postoperative hospital stay (P < 0.001) were significantly shorter, and postoperative complications were significantly less frequent (P = 0.036). The 5-year disease-free survival was 78% in the LRH group and 77% in the ORH group (P = 0.718), and 5-year overall survival was 83% in both groups (P = 0.746). There were no differences in pattern of recurrence (P = 0.225) and median time to recurrence (12 vs. 13 months; P = 0.240). CONCLUSIONS: LRH has similar therapeutic efficacy to ORH in patients with bulky early-stage cervical cancer. However, LRH has more favorable surgical outcomes. Therefore, LRH is not only a reasonable alternative to ORH but also the preferred surgical procedure for these patients. PMID- 23737036 TI - Place of death, and its relation with underlying cause of death, in Parkinson's disease, motor neurone disease, and multiple sclerosis: a population-based study. AB - BACKGROUND: Little is known about place of death in chronic neurological diseases. Mortality statistics are ideal for examining trends in place of death, but analyses are limited by coding rule changes. AIM: To examine the relationship between place of death and underlying cause of death in Parkinson's disease, multiple sclerosis and motor neurone disease and the impact of coding rule changes on analysis of place of death. DESIGN: Population-based study. Proportion ratios for death in hospice, home, care home and hospital were calculated according to underlying cause of death, using multivariable Poisson regression. PARTICIPANTS: Deaths in England (1993-2010) with any mention of Parkinson's disease, multiple sclerosis or motor neurone disease as a cause of death, identified from national mortality data. RESULTS: In this study, 125,242 patients with Parkinson's disease, 23,501 with multiple sclerosis, and 27,030 with motor neurone disease were included. Home deaths ranged from 9.7% (Parkinson's disease) to 27.1% (motor neurone disease), hospice deaths ranged from 0.6% (Parkinson's disease) to 11.2% (motor neurone disease) and hospital deaths ranged from 43.4% (Parkinson's disease) to 55.8% (multiple sclerosis). In Parkinson's disease and multiple sclerosis, cancer as underlying cause of death increased likelihood of hospice death (proportion ratio (PR): 18.8, 95% confidence interval (CI) = 16.1 22.0; 8.88, 95% CI = 7.49-10.5) and home death (PR: 1.91, 95% CI = 1.80-2.04; 1.71, 95% CI = 1.56-1.88). Dementia as underlying cause of death increased likelihood of care home death in Parkinson's disease (PR: 1.25, 95% CI = 1.19 1.32), multiple sclerosis (PR: 1.73, 95% CI = 1.22-2.45) and motor neurone disease (PR: 2.36, 95% CI = 1.31-4.27). CONCLUSIONS: Underlying cause of death has a marked effect on place of death. The effects of coding rule changes are an essential consideration for all research using underlying cause of death to study place of death. PMID- 23737039 TI - Bonhoeffer and universal health care as a human right. AB - Bonhoeffer gave a theocentric basis for human rights, as God is the ground of ethics. In our earthly world, the "ultimate" must be prepared by what is "penultimate." That includes humanity's natural life and bodily wholeness, leading to human duties crafted by human reason. Nowadays, biblical texts should not be used as partisan weapons attacking government provision of health care, since all Scripture (even the Law) is seen as a Christ-centered focus on human redemption. Thus, Bonhoeffer implies a right to universal health care, but leaves entirely open which practical structures may best provide it. PMID- 23737040 TI - Recent developments in the coordination chemistry of multidentate ligands featuring a boron moiety. AB - Synergistic effects between a transition metal and an appropriate ligand are required to promote a desired catalytic reaction. Ancillary ligands, provided by the versatile functionality of certain elements, give rise to an almost infinite potential for catalytic applications. Recently, the study of the synergistic effect between transition metals and boron has become easy on account of the development of various rigid multidentate frameworks. In this Review, we mainly focus on the chemistry of sigma-acceptor (Z-type) borane ligands, particularly the key achievements of their unique reactivity and catalytic applications. Conceptually, the unique character of sigma-acceptor borane ligands provides a new strategy for developing remarkable reactivity and novel catalytic applications. This study discusses recent developments in the field in this context. The chemistry of boron-based multidentate ligands that involve a covalent M-B bond such as the boryl ligand (-BR2), in which a boron moiety serves as a strong electron-donating ligand, is also rapidly developing. The effect of the boryl ligand on a metal center is totally different from that of the borane ( BR3) ligand, and different boron-based functionalities confer opposing electronic properties to the metal center. The interesting character of boryl-based chelating ligands augments their unique coordination chemistry, which is also summarized in this context. PMID- 23737037 TI - Wnt signaling in the pathogenesis of human HIV-associated pain syndromes. AB - Many synaptic plasticity-related signaling pathways have been identified as important regulators of the pathogenesis of chronic pain in animal models. However, their relevance to human pathological pain is rarely confirmed rigorously. Recent studies suggest that Wnt signaling plays critical roles in synaptic plasticity and is dysregulated in the spinal cord dorsal horn (SDH) of different mouse pain models. In this study, we compared the protein levels of Wnt ligands, Wnt receptors and their downstream effector proteins in the SDH from non HIV patients, HIV patients who developed chronic pain ('pain-positive' HIV patients), and HIV patients who did not develop chronic pain ('pain-negative' HIV patients). Our results indicate that many Wnt ligands and downstream effector proteins were specifically up-regulated in the SDH of 'pain-positive' HIV patients but not in the 'pain-negative' HIV patients. These findings describe an HIV pain-associated activation of Wnt signaling in the SDH of human patients. Given the established role of Wnt signaling in the regulation of synaptic plasticity, these results suggest that the activated Wnt signaling might contribute to the expression of the synaptic plasticity in the SDH during the pathogenesis of HIV-associated chronic pain. PMID- 23737041 TI - Iterative cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for recurrent peritoneal metastases. AB - BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) achieves disease control within the peritoneum but recurrences occur. This study examines the outcomes of iterative CRS (iCRS) HIPEC for treatment of recurrent peritoneal metastases. METHODS: Patients who underwent iCRS in a single tertiary referral center were identified from a prospective database. Safety analysis was performed and clinicopathological variables were analyzed to assess factors predictive of major morbidity and survival. RESULTS: The demographics of patients who underwent primary cytoreductive surgery (pCRS) (n = 466) and iCRS (n = 79) were balanced between groups. pCRS was shown to require more blood transfusion (P = 0.019) and albumin use (P = 0.013). The mortality and major complication rates were comparable (1.2% vs. 0%; P = 0.600, and 42% vs. 41%; P = 0.806). Residual pneumothorax occurred more frequently after pCRS (12% vs. 4%; P = 0.030). Factors associated with major complications after iCRS include use of HIPEC (P = 0.042) and length of hospital stay (P = 0.024). The overall median survival was 48 months and 5-year survival was 34%. By cancer type, the 3-year survival was 0%, 74%, 80%, and 72% for colorectal, appendiceal pseudomyxoma, peritoneal mesothelioma, and appendix cancer, respectively. Independent predictors of survival include age (P = 0.049), interval between pCRS and iCRS (P = 0.008), small bowel resection (P < 0.001), and use of HIPEC (P = 0.005). CONCLUSION: Iterative CRS achieved further peritoneal disease control without adverse effects on morbidity. Patients with appendiceal tumors and peritoneal mesothelioma appear to benefit most after iCRS. Intraoperative HIPEC remains important in the repetoire of managing these patients. PMID- 23737042 TI - The protective effect of crocin on the amyloid fibril formation of Abeta42 peptide in vitro. AB - Abeta is the main constituent of the amyloid plaque found in the brains of patients with Alzheimer's disease. There are two common isoforms of Abeta: the more common form, Abeta40, and the less common but more amyloidogenic form, Abeta42. Crocin is a carotenoid from the stigma of the saffron flower and it has many medicinal properties, including antioxidant effects. In this study, we examined the potential of crocin as a drug candidate against Abeta42 amyloid formation. The thioflavin T-binding assay and electron microscopy were used to examine the effects of crocin on the extension and disruption of Abeta42 amyloids. To further investigate the relationship between crocin and Abeta42 structure, we analyzed peptide conformation using the ANS-binding assay and circular dichroism (CD) spectroscopy. An increase in the thioflavin T fluorescence intensity upon incubation revealed amyloid formation in Abeta42. It was found that crocin has the ability to prevent amyloid formation by decreasing the fluorescence intensity. Electron microscopy data also indicated that crocin decreased the amyloid fibril content of Abeta. The ANS-binding assay showed that crocin decreased the hydrophobic area in incubated Abeta42. CD spectroscopy results also showed that the peptide undergoes a structural change to alpha helical and beta-turn. Our study shows that the anti-amyloidogenic effect of crocin may be exerted not only by the inhibition of Abeta amyloid formation but also by the disruption of amyloid aggregates. Therefore, crocin could be essential in the search for therapies inhibiting aggregation or disrupting aggregation. PMID- 23737043 TI - The ORP basis set designed for optical rotation calculations. AB - Details of generation of the optical rotation prediction (ORP) basis set developed for accurate optical rotation (OR) calculations are presented. Specific rotation calculations carried out at the density functional theory (DFT) level for model chiral methane molecule, fluorooxirane, methyloxirane, and dimethylmethylenecyclopropane reveal that the ORP set outperforms larger basis sets, among them the aug-cc-pVTZ basis set of Dunning (J. Chem. Phys. 1989, 90, 1007) and the aug-pc-2 basis set of Jensen (J. Chem. Phys. 2002, 117, 9234; J. Chem. Theory Comput. 2008, 4, 719). It is shown to be an attractive choice also in the case of larger systems, namely norbornanone, beta-pinene, trans-pinane, and nopinone. The ORP basis set is further used in OR calculations for 24 other systems, and the results are compared to the aug-cc-pVDZ values. Whenever large discrepancies of results are observed, the ORP values are in an excellent agreement with the aug-cc-pVTZ results. The ORP basis set enables accurate specific rotation calculations at a reduced cost and thus can be recommended for routine DFT OR calculations, also for large and conformationally flexible molecules. PMID- 23737044 TI - Depression and frailty in elderly patients. PMID- 23737045 TI - Use of the Geriatric Anxiety Inventory-short form as a screening tool for detection of generalised anxiety in a memory clinic population. PMID- 23737046 TI - The block suppression test uncovers specific inhibitory deficits in mild cognitive impairment. PMID- 23737047 TI - Introduction: the structural basis of virus function. AB - Viruses may be regarded as dynamic nucleoprotein assemblies capable of assisted multiplication within cells, and of propagation between cells and organisms. Infectious virus particles (virions) assembled in a host cell are dynamic, generally metastable particles: They are robust enough to protect the viral genome outside the cell, but are also poised to undergo structural changes and execute mechanochemical actions required for infection of other cells. This chapter provides an introduction to the structural and physical biology of viruses by including: (i) an elementary overview on virions and the structural basis of virus function; (ii) a concise summary on basic techniques used in structural or physical virology; (iii) brief structure-based general descriptions of the different stages in the virus cycle, especially those in which virions and/or their components are involved. These contents may facilitate a better understanding of the specialized subjects treated in the rest of the book. This chapter is also intended as a "road map" to help interconnect and integrate in a single picture the different topics described in depth in the 21 monographic chapters in this book. PMID- 23737048 TI - The basic architecture of viruses. AB - Viruses are elegant macromolecular assemblies and constitute a paradigm of the economy of genomic resources; they must use simple general principles and a very limited number of viral components to complete their life cycles successfully. Viruses need only one or a few different capsid structural subunits to build an infectious particle, which is made possible because of two reasons: extensive use of symmetry and built-in conformational flexibility. Although viruses from the numerous virus families come in many shapes and sizes, two major types of symmetric assemblies are found: icosahedral and helical particles. The enormous diversity of virus structures might be derived from one or a limited number of basic schemes that has become more complex by consecutive incorporation of structural elements. The intrinsic structural polymorphism of the viral proteins and other observations indicate that capsids are dynamic structures. Study of virus structures is required to understand structure-function relationships in viruses, including those related to morphogenesis and antigenicity. These structural foundations can be extended to other macromolecular complexes that control many fundamental processes in biology. PMID- 23737049 TI - Conventional electron microscopy, cryo-electron microscopy and cryo-electron tomography of viruses. AB - Electron microscopy (EM) techniques have been crucial for understanding the structure of biological specimens such as cells, tissues and macromolecular assemblies. Viruses and related viral assemblies are ideal targets for structural studies that help to define essential biological functions. Whereas conventional EM methods use chemical fixation, dehydration, and staining of the specimens, cryo-electron microscopy (cryo-EM) preserves the native hydrated state. Combined with image processing and three-dimensional reconstruction techniques, cryo-EM provides 3D maps of these macromolecular complexes from projection images, at subnanometer to near-atomic resolutions. Cryo-EM is also a major technique in structural biology for dynamic studies of functional complexes, which are often unstable, flexible, scarce or transient in their native environments. As a tool, cryo-EM complements high-resolution techniques such as X-ray diffraction and NMR spectroscopy; these synergistic hybrid approaches provide important new information. Three-dimensional cryo-electron tomography goes further, and allows the study of viruses not only in their physiological state, but also in their natural environment in the cell, thereby bridging structural studies at the molecular and cellular levels. PMID- 23737050 TI - X-ray crystallography of viruses. AB - For about 30 years X-ray crystallography has been by far the most powerful approach for determining virus structures at close to atomic resolutions. Information provided by these studies has deeply and extensively enriched and shaped our vision of the virus world. In turn, the ever increasing complexity and size of the virus structures being investigated have constituted a major driving force for methodological and conceptual developments in X-ray macromolecular crystallography. Landmarks of new virus structures determinations, such as the ones from the first animal viruses or from the first membrane-containing viruses, have often been associated to methodological breakthroughs in X-ray crystallography. In this chapter we present the common ground of proteins and virus crystallography with an emphasis in the peculiarities of virus studies. For example, the solution of the phase problem, a central issue in X-ray diffraction, has benefited enormously from the presence of non-crystallographic symmetry in virus crystals. PMID- 23737051 TI - Nuclear magnetic resonance spectroscopy to study virus structure. AB - Nuclear magnetic resonance (NMR) is a spectroscopic technique based in the absorption of radiofrequency radiation by atomic nuclei in the presence of an external magnetic field. NMR has followed a "bottom-up" approach to solve the structures of isolated domains of viral proteins, including capsid protein subunits. NMR has been instrumental to describe conformational changes in viral proteins and nucleic acids, showing the presence of dynamic equilibria which are thought to be important at different stages of the virus life cycle; in this sense, NMR is also the only technique currently available to describe, in atomic detail, the conformational preferences of natively unfolded viral proteins. NMR has also complemented X-ray crystallography and has been combined with electron microscopy to obtain pseudo-atomic models of entire virus capsids. Finally, the joint use of liquid and solid-state NMR has allowed the identification of conformational changes in intact viral capsids on insertion in host membranes. PMID- 23737052 TI - Fluorescence, circular dichroism and mass spectrometry as tools to study virus structure. AB - Fluorescence and circular dichroism, as analytical spectroscopic techniques, and mass spectrometry as an analytical tool to determine the molecular mass, provide important biophysical approaches in structural virology. Although they do not provide atomic, or near-atomic, details as electron microscopy, X-ray crystallography or nuclear magnetic resonance spectroscopy can do, they do provide important insights into virus particle composition, structure, conformational stability and dynamics, assembly and maturation, and interactions with other viral and cellular biomolecules. They can be used also to investigate the molecular determinants of virus particle structure and properties, and the changes induced in them by external factors. In this chapter, I describe the physical bases of these three techniques, and some examples on how they have helped us to understand virus particle structure and physicochemical properties. PMID- 23737053 TI - Combined approaches to study virus structures. AB - A virus particle must work as a safe box for protecting its genome, but at the same time it has to undergo dramatic conformational changes in order to preserve itself by propagating in a cell infection. Thus, viruses are miniaturized wonders whose structural complexity requires them to be investigated by a combination of different techniques that can tackle both static and dynamic processes. In this chapter we will illustrate how major structural techniques such as X-ray crystallography and electron microscopy have been and can be combined with other techniques to determine the structure of complex viruses. The power of these hybrid method approaches are revealed through the various examples provided. PMID- 23737054 TI - Atomic force microscopy of viruses. AB - Atomic force microscopy (AFM) is a helpful tool to acquire nanometric-resolution images, and also to perform a certain physical characterization of specimens, including their stiffness and mechanical resilience. Besides of the wide range of applications, from materials science to biology, this technique works in a variety of conditions as long as the sample is supported on a solid surface, in air, ultra high vacuum or, most importantly for virus research, in liquids. The adaptability of this technique is also fostered by the variety of sizes of the specimens that it can dealt with, such as atoms, molecules, molecular complexes including viruses and cells, and the possibility to observe dynamic processes in real time. Indeed, AFM facilitates single molecule experiments enabling not only to see but also to touch the material under study (i.e., to undertake mechanical manipulations), and constitutes a fundamental source of information for material characterization. In particular, the study of the mechanical properties at the nanoscale of viruses and other biomolecular aggregates, is providing an important set of data which help to elaborate mechano-chemical structure/function models of molecular biomachines, expanding and complementing the information obtained by other structural techniques. PMID- 23737055 TI - Optical tweezers to study viruses. AB - A virus is a complex molecular machine that propagates by channeling its genetic information from cell to cell. Unlike macroscopic engines, it operates in a nanoscopic world under continuous thermal agitation. Viruses have developed efficient passive and active strategies to pack and release nucleic acids. Some aspects of the dynamic behavior of viruses and their substrates can be studied using structural and biochemical techniques. Recently, physical techniques have been applied to dynamic studies of viruses in which their intrinsic mechanical activity can be measured directly. Optical tweezers are a technology that can be used to measure the force, torque and strain produced by molecular motors, as a function of time and at the single-molecule level. Thanks to this technique, some bacteriophages are now known to be powerful nanomachines; they exert force in the piconewton range and their motors work in a highly coordinated fashion for packaging the viral nucleic acid genome. Nucleic acids, whose elasticity and condensation behavior are inherently coupled to the viral packaging mechanisms, are also amenable to examination with optical tweezers. In this chapter, we provide a comprehensive analysis of this laser-based tool, its combination with imaging methods and its application to the study of viruses and viral molecules. PMID- 23737056 TI - Assembly of simple icosahedral viruses. AB - Icosahedral viruses exhibit elegant pathways of capsid assembly and maturation regulated by symmetry principles. Assembly is a dynamic process driven by consecutive and genetically programmed morphogenetic interactions between protein subunits. The non-symmetric capsid subunits are gathered by hydrophobic contacts and non-covalent interactions in assembly intermediates, which serve as blocks to build a symmetric capsid. In some cases, non-symmetric interactions among intermediates are involved in assembly, highlighting the remarkable capacity of capsid proteins to fold into demanding conformations compatible with a closed protein shell. In this chapter, the morphogenesis of structurally simple icosahedral viruses, including representative members of the parvoviruses, picornaviruses or polyomaviruses as paradigms, is described in some detail. Icosahedral virus assembly may occur in different subcellular compartments and involve a panoplia of cellular and viral factors, chaperones, and protein modifications that, in general, are still poorly characterized. Mechanisms of viral genome encapsidation may imply direct interactions between the genome and the assembly intermediates, or active packaging into a preformed empty capsid. High stability of intermediates and proteolytic cleavages during viral maturation usually contribute to the overall irreversible character of the assembly process. These and other simple icosahedral viruses were pioneer models to understand basic principles of virus assembly, continue to be leading subjects of morphogenetic analyses, and have inspired ongoing studies on the assembly of larger viruses and cellular and synthetic macromolecular complexes. PMID- 23737057 TI - Structure and assembly of complex viruses. AB - Viral particles consist essentially of a proteinaceous capsid protecting a genome and involved also in many functions during the virus life cycle. In simple viruses, the capsid consists of a number of copies of the same, or a few different proteins organized into a symmetric oligomer. Structurally complex viruses present a larger variety of components in their capsids than simple viruses. They may contain accessory proteins with specific architectural or functional roles; or incorporate non-proteic elements such as lipids. They present a range of geometrical variability, from slight deviations from the icosahedral symmetry to complete asymmetry or even pleomorphism. Putting together the many different elements in the virion requires an extra effort to achieve correct assembly, and thus complex viruses require sophisticated mechanisms to regulate morphogenesis. This chapter provides a general view of the structure and assembly of complex viruses. PMID- 23737058 TI - Nucleic acid packaging in viruses. AB - Viruses protect their genetic information by enclosing the viral nucleic acid inside a protein shell (capsid), in a process known as genome packaging. Viruses follow essentially two main strategies to package their genome: Either they co assemble their genetic material together with the capsid protein, or they assemble first an empty shell (procapsid) and then pump the genome inside the capsid with a molecular motor that uses the energy released by ATP hydrolysis. During packaging the viral nucleic acid is condensed to very high concentration by its careful arrangement in concentric layers inside the capsid. In this chapter we will first give an overview of the different strategies used for genome packaging to discuss later some specific virus models where the structures of the main proteins involved, and the biophysics underlying the packaging mechanism, have been well documented. PMID- 23737059 TI - Virus maturation. AB - The formation of infectious virus particles is a highly complex process involving a series of sophisticated molecular events. In most cases, the assembly of virus structural elements results in the formation of immature virus particles unable to initiate a productive infection. Accordingly, for most viruses the final stage of the assembly pathway entails a set of structural transitions and/or biochemical modifications that transform inert precursor particles into fully infectious agents. In this chapter, we review the most relevant maturation mechanisms involved in the generation of infectious virions for a wide variety of viruses. PMID- 23737060 TI - Virus morphogenesis in the cell: methods and observations. AB - Viruses carry out many of their activities inside cells, where they synthesise proteins that are not incorporated into viral particles. Some of these proteins trigger signals to kidnap cell organelles and factors which will form a new macro structure, the virus factory, that acts as a physical scaffold for viral replication and assembly. We are only beginning to envisage the extraordinary complexity of these interactions, whose characterisation is a clear experimental challenge for which we now have powerful tools. Conventional study of infection kinetics using virology, biochemistry and cell biology methods can be followed by genome-scale screening and global proteomics. These are important new technologies with which we can identify the cell factors used by viruses at different stages in their life cycle. Light microscopy, electron microscopy and electron tomography, together with labelling methods for molecular mapping in situ, show immature viral intermediates, mature virions and recruited cell elements in their natural environment. This chapter describes how these methods are being used to understand the cell biology of viral morphogenesis and suggests what they might achieve in the near future. PMID- 23737061 TI - Virus-receptor interactions and receptor-mediated virus entry into host cells. AB - The virus particles described in previous chapters are vehicles that transmit the viral genome and the infection from cell to cell. To initiate the infective cycle, the viral genome must therefore translocate from the viral particle to the cytoplasm. Via distinct proteins or motifs in their outermost shell, the particles attach initially to specific molecules on the host cell surface. These virus receptors thus mediate penetration of the viral genome inside the cell, where the intracellular infective cycle starts. The presence of these receptors on the cell surface is a principal determinant of virus host tropism. Viruses can use diverse types of molecules to attach to and enter into cells. In addition, virus-receptor recognition can evolve over the course of an infection, and virus variants with distinct receptor-binding specificities and tropism can appear. The identification of virus receptors and the characterization of virus-receptor interactions have been major research goals in virology for the last two decades. In this chapter, we will describe, from a structural perspective, several virus receptor interactions and the active role of receptor molecules in virus entry. PMID- 23737062 TI - Entry of enveloped viruses into host cells: membrane fusion. AB - Viruses are intracellular parasites that hijack the cellular machinery for their own replication. Therefore, an obligatory step in the virus life cycle is the delivery of the viral genome inside the cell. Enveloped viruses (i.e., viruses with a lipid envelope) use a two-step procedure to release their genetic material into the cell: (i) they first bind to specific surface receptors of the target cell membrane and then, (ii) they fuse the viral and cell membranes. This last step may occur at the cell surface or after internalization of the virus particle by endocytosis or by some other route (e.g., macropinocytosis). Remarkably, the virus-cell membrane fusion process goes essentially along the same intermediate steps as other membrane fusions that occur for instance in vesicular fusion at the nerve synapsis or cell-cell fusion in yeast mating. Specialized viral proteins, fusogens, promote virus-cell membrane fusion. The viral fusogens experience drastic structural rearrangements during fusion, liberating the energy required to overcome the repulsive forces that prevent spontaneous fusion of the two membranes. This chapter describes the different types of viral fusogens and their mode of action, as are currently known. PMID- 23737063 TI - Bacteriophage receptor recognition and nucleic acid transfer. AB - Correct host cell recognition is important in the replication cycle for any virus, including bacterial viruses. This essential step should occur before the bacteriophage commits to transfer its genomic material into the host. In this chapter we will discuss the proteins and mechanisms bacteriophages use for receptor recognition (just before full commitment to infection) and nucleic acid injection, which occurs just after commitment. Some bacteriophages use proteins of the capsid proper for host cell recognition, others use specialised spikes or fibres. Usually, several identical recognition events take place, and the information that a suitable host cell has been encountered is somehow transferred to the part of the bacteriophage capsid involved in nucleic acid transfer. The main part of the capsids of bacteriophages stay on the cell surface after transferring their genome, although a few specialised proteins move with the DNA, either forming a conduit, protecting the nucleic acids after transfer and/or functioning in the process of transcription and translation. PMID- 23737064 TI - Mechanical properties of viruses. AB - Structural biology techniques have greatly contributed to unveil the relationships between structure, properties and functions of viruses. In recent years, classic structural approaches are being complemented by single-molecule techniques such as atomic force microscopy and optical tweezers to study physical properties and functions of viral particles that are not accessible to classic structural techniques. Among these features are mechanical properties such as stiffness, intrinsic elasticity, tensile strength and material fatigue. The field of virus mechanics is contributing to materials science by investigating some physical parameters of "soft" biological matter and biological nano-objects. Virus mechanics studies are also starting to unveil the biological implications of physical properties of viruses. Growing evidence indicate that viruses are subjected to internal and external forces, and that they may have adapted to withstand and even use those forces. This chapter describes what is known on the mechanical properties of virus particles, their structural determinants, and possible biological implications, of which several examples are provided. PMID- 23737065 TI - Theoretical studies on assembly, physical stability and dynamics of viruses. AB - All matter has to obey the general laws of physics and living matter is not an exception. Viruses have not only learnt how to cope with them, but have managed to use them for their own survival. In this chapter we will review some of the exciting physics behind viruses and discuss simple physical models that can shed some light on different aspects of the viral life cycle and viral properties. In particular, we will focus on how the structure and shape of the capsid, its assembly and stability, and the entry and exit of viral particles and their genomes can be understood using fundamental physics theories. PMID- 23737066 TI - Antiviral agents: structural basis of action and rational design. AB - During the last 30 years, significant progress has been made in the development of novel antiviral drugs, mainly crystallizing in the establishment of potent antiretroviral therapies and the approval of drugs inhibiting hepatitis C virus replication. Although major targets of antiviral intervention involve intracellular processes required for the synthesis of viral proteins and nucleic acids, a number of inhibitors blocking virus assembly, budding, maturation, entry or uncoating act on virions or viral capsids. In this review, we focus on the drug discovery process while presenting the currently used methodologies to identify novel antiviral drugs by using a computer-based approach. We provide examples illustrating structure-based antiviral drug development, specifically neuraminidase inhibitors against influenza virus (e.g. oseltamivir and zanamivir) and human immunodeficiency virus type 1 protease inhibitors (i.e. the development of darunavir from early peptidomimetic compounds such as saquinavir). A number of drugs in preclinical development acting against picornaviruses, hepatitis B virus and human immunodeficiency virus and their mechanism of action are presented to show how viral capsids can be exploited as targets of antiviral therapy. PMID- 23737067 TI - Design of novel vaccines based on virus-like particles or chimeric virions. AB - Virus-like particles (VLPs) are formed by viral structural proteins that, when overexpressed, spontaneously self-assemble into particles that are antigenically indistinguishable from infectious virus or subviral particles. VLPs are appealing as vaccine candidates because their inherent properties (i.e., virus-sized, multimeric antigens, highly organised and repetitive structure, not infectious) are suitable for the induction of safe and efficient humoral and cellular immune responses. VLP-based vaccines have already been licensed for human and veterinary use, and many more vaccine candidates are currently in late stages of evaluation. Moreover, the development of VLPs as platforms for foreign antigen display has further broadened their potential applicability both as prophylactic and therapeutic vaccines. This chapter provides an overview on the design and use of VLPs for the development of new generation vaccines. PMID- 23737068 TI - Nanoscale science and technology with plant viruses and bacteriophages. AB - Nanoscale science refers to the study and manipulation of matter at the atomic and molecular scales, including nanometer-sized single objects, while nanotechnology is used for the synthesis, characterization, and for technical applications of structures up to 100 nm size (and more). The broad nature of the fields encompasses disciplines such as solid-state physics, microfabrication, molecular biology, surface science, organic chemistry and also virology. Indeed, viruses and viral particles constitute nanometer-sized ordered architectures, with some of them even able to self-assemble outside cells. They possess remarkable physical, chemical and biological properties, their structure can be tailored by genetic engineering and by chemical means, and their production is commercially viable. As a consequence, viruses are becoming the basis of a new approach to the manufacture of nanoscale materials, made possible only by the development of imaging and manipulation techniques. Such techniques reach the scale of single molecules and nanoparticles. The most important ones are electron microscopy and scanning probe microscopy (both awarded with the Nobel Prize in Physics 1986 for the engineers and scientists who developed the respective instruments). With nanotechnology being based more on experimental than on theoretical investigations, it emerges that physical virology can be seen as an intrinsic part of it. PMID- 23737069 TI - Electronic excitation and structural relaxation of the adenine dinucleotide in gas phase and solution. AB - The excited states and potential surfaces of the adenine dinucleotide are analyzed in gas phase and in solution using a correlated ab initio methodology in a QM/MM framework. In agreement with previous studies, a rather flat S1 surface with a number of minima of different character is found. Specifically, our results suggest that exciplexes with remarkably short intermolecular separation down to ~2.0 A are formed. A detailed analysis shows that due to strong orbital interactions their character differs significantly from any states present in the Franck-Condon region. The lowest S1 energy minimum is a pipi* exciplex with only a small amount of charge transfer. It possesses appreciable oscillator strength with a polarization almost perpendicular to the planes of the two adenine molecules. PMID- 23737070 TI - Vanadyl acetylacetonate upregulates PPARgamma and adiponectin expression in differentiated rat adipocytes. AB - Vanadium compounds are promising agents in the therapeutic treatment of diabetes mellitus, but their mechanism of action has not been fully elucidated. The current work investigated the effects of vanadyl acetylacetonate, VO(acac)2, on peroxisome-proliferator-activated receptor gamma (PPARgamma) and adiponectin, which are important targets of antidiabetic drugs. The experimental results revealed that vanadyl complexes increased the expression and multimerization of adiponectin in differentiated rat adipocytes. VO(acac)2 caused activation of p38 mitogen-activated protein kinase (MAPK) and AMP-activated protein kinase (AMPK) and elevation of PPARgamma levels. The specific inhibitors SB203580 (p38 MAPK inhibitor) and T0070907 (PPARgamma inhibitor) decreased the expression of adiponectin; however, compound C (AMPK inhibitor) did not significantly reduce the expression of adiponectin. In addition, vanadyl complexes induced protein protein interaction between PPARgamma and a vanadium-binding chaperone, heat shock protein 60 kDa. Overall, our results suggest that vanadyl complexes may upregulate PPARgamma by suppressing PPARgamma degradation, and thus stimulate adiponectin expression and multimerization. The present work has provided new insights into the mechanism of the antidiabetic actions of vanadium compounds. PMID- 23737071 TI - Resolving bony abnormality evolves to diffuse large B-cell lymphoma. AB - Primary lymphoma of bone is a rare malignancy that can mimic infection and benign bone lesions radiographically. Malignant conversion of osseous lesions has been reported; evolution to lymphoma has not. We describe an adolescent male diagnosed with atypical osteoid osteoma who, despite near resolution of bony changes involving the anterior tibia, was diagnosed with monostotic diffuse large B-cell lymphoma four years later. Indolent lymphoma of the initial lesion is unlikely. This case highlights the importance of clinical suspicion of malignancy even with recurrence of similar clinical presentation and hints at possible osseous microenvironment abnormalities predisposing to the development of lymphoma. PMID- 23737073 TI - QTL mapping of stalk bending strength in a recombinant inbred line maize population. AB - Stalk bending strength (SBS) is a reliable indicator for evaluating stalk lodging resistance of maize plants. Based on biomechanical considerations, the maximum load exerted to breaking (F max), the breaking moment (M max) and critical stress (sigma max) are three important parameters to characterize SBS. We investigated the genetic architecture of SBS by phenotyping F max, M max and sigma max of the fourth internode of maize plants in a population of 216 recombinant inbred lines derived from the cross B73 * Ce03005 evaluated in four environments. Heritability of F max, M max and sigma max was 0.81, 0.79 and 0.75, respectively. F max and sigma max were positively correlated with several other stalk characters. By using a linkage map with 129 SSR markers, we detected two, three and two quantitative trait loci (QTL) explaining 22.4, 26.1 and 17.2 % of the genotypic variance for F max, M max and sigma max, respectively. The QTL for F max, M max and sigma max located in adjacent bins 5.02 and 5.03 as well as in bin 10.04 for F max were detected with high frequencies in cross-validation. As our QTL mapping results suggested a complex polygenic inheritance for SBS-related traits, we also evaluated the prediction accuracy of two genomic prediction methods (GBLUP and BayesB). In general, we found that both explained considerably higher proportions of the genetic variance than the values obtained in QTL mapping with cross validation. Nevertheless, the identified QTL regions could be used as a starting point for fine mapping and gene cloning. PMID- 23737074 TI - The effect of day-neutral mutations in barley and wheat on the interaction between photoperiod and vernalization. AB - Vernalization-2 (Vrn-2) is the major flowering repressor in temperate cereals. It is only expressed under long days in wild-type plants. We used two day-neutral (photoperiod insensitive) mutations that allow rapid flowering in short or long days to investigate the day length control of Vrn-2. The barley (Hordeum vulgare) early maturity8 (eam8) mutation affects the barley ELF3 gene. eam8 mutants disrupt the circadian clock resulting in elevated expression of Ppd-H1 and the floral activator HvFT1 under short or long days. When eam8 was crossed into a genetic background with a vernalization requirement Vrn-2 was expressed under all photoperiods and the early flowering phenotype was partially repressed in unvernalized (UV) plants, likely due to competition between the constitutively active photoperiod pathway and the repressing effect of Vrn-2. We also investigated the wheat (Triticum aestivum) Ppd-D1a mutation. This differs from eam8 in causing elevated levels of Ppd-1 and TaFT1 expression without affecting the circadian clock. We used genotypes that differed in "short-day vernalization". Short days were effective in promoting flowering in individuals wild type at Ppd-D1, but not in individuals that carry the Ppd-D1a mutation. The latter showed Vrn-2 expression in short days. In summary, eam8 and Ppd-D1a mimic long days in terms of photoperiod response, causing Vrn-2 to become aberrantly expressed (in short days). As Ppd-D1a does not affect the circadian clock, this also shows that clock regulation of Vrn-2 operates indirectly through one or more downstream genes, one of which may be Ppd-1. PMID- 23737075 TI - Preventing depression in homes for older adults: are effects sustained over 2 years? AB - OBJECTIVES: The objective of this study was to evaluate the 2-year effects of a stepped-care programme to prevent the onset of a major depressive disorder (MDD) in older people living in residential homes. METHODS: A 2-year follow-up study of a pragmatic randomised controlled trial was conducted in 14 residential homes in the Netherlands. A total of 185 residents (Center for Epidemiologic Studies Depression Scale score >7), who did not meet the diagnostic criteria for MDD, were randomised to a stepped-care programme (n = 93) or to usual care (n = 92). Stepped-care participants sequentially underwent watchful waiting, a self-help intervention, life review and a consultation with the general practitioner. The primary outcome measure was the incidence of MDD during a period of 2 years, according to the Mini International Neuropsychiatric Interview. RESULTS: After 2 years, the incidence of MDD was not significantly reduced in the intervention group compared with the control group (incidence rate ratio: 0.98; 95% confidence interval (CI) [0.54, 1.81]). However, in the completer analysis, on the basis of 79 residents who completed the 2-year measurements, there was a significant difference in favour of the intervention group (incidence rate ratio: 0.53; 95% CI [0.32, 0.87]). Dropout percentages were high (44%), mostly accounted for by illness and death (68%). CONCLUSION: A minority of residents had benefit from the intervention that sustained after 2 years in the completer group. Yet, these findings cannot be generalised as the majority of the residents did not opt for participation in the project and many dropped out. Ways should be sought to motivate residents with depressive symptoms to engage in preventive interventions. PMID- 23737076 TI - The ecdysone receptor (ScEcR-A) binds DNA puffs at the start of DNA amplification in Sciara coprophila. AB - The steroid hormone ecdysone induces DNA amplification and subsequent DNA puff formation in late fourth larval instar salivary gland polytene chromosomes of the fungus fly, Sciara coprophila. Previous in vitro studies on DNA puff II/9A in Sciara demonstrated that the ecdysone receptor (ScEcR-A) efficiently binds an ecdysone response element adjacent to the origin recognition complex binding site within the II/9A amplification origin, implying a role for ScEcR-A in amplification. Here, we extrapolate the molecular details from locus II/9A to the rest of the genome using immunofluorescence with a ScEcR-A-specific antibody. ScEcR-A binds all DNA puff sites just as amplification begins and persists throughout the processes of amplification, transcription, and puffing. Ecdysone injections into pre-amplification stage larvae prematurely induce both DNA amplification and ScEcR-A binding to DNA puff sites. These data are consistent with a direct role for ScEcR-A in DNA amplification. PMID- 23737077 TI - Inhibition of lactoperoxidase-catalyzed oxidation by imidazole-based thiones and selones: a mechanistic study. AB - Herein, we describe the synthesis and biomimetic activity of a series of N,N disubstituted thiones and selones that contain an imidazole pharmacophore. The N,N-disubstituted thiones do not show any inhibitory activity towards LPO catalyzed oxidation reactions, but their corresponding N,N-disubstituted selones exhibit inhibitory activity towards LPO-catalyzed oxidation reactions. Substituents on the N atom of the imidazole ring appear to have a significant effect on the inhibition of LPO-catalyzed oxidation and iodination reactions. Selones 16, 17, and 19, which contain methyl, ethyl, and benzyl substituents, exhibit similar inhibition activities towards LPO-catalyzed oxidation reactions with IC50 values of 24.4, 22.5, and 22.5 MUM, respectively. However, their activities are almost three-fold lower than that of the commonly used anti thyroid drug methimazole (MMI). In contrast, selone 21, which contains a N CH2CH2OH substituent, exhibits high inhibitory activity, with an IC50 value of 7.2 MUM, which is similar to that of MMI. The inhibitory activity of these selones towards LPO-catalyzed oxidation/iodination reactions is due to their ability to decrease the concentrations of the co-substrates (H2O2 and I2), either by catalytically reducing H2O2 (anti-oxidant activity) or by forming stable charge-transfer complexes with oxidized iodide species. The inhibition of LPO catalyzed oxidation/iodination reactions by N,N-disubstituted selones can be reversed by increasing the concentration of H2O2. Interestingly, all of the N,N disubstituted selones exhibit high anti-oxidant activities and their glutathione peroxidase (GPx)-like activity is 4-12-fold higher than that of the well-known GPx-mimic ebselen. These experimental and theoretical studies suggest that the selones exist as zwitterions, in which the imidazole ring contains a positive charge and the selenium atom carries a large negative charge. Therefore, the selenium moieties of these selones possess highly nucleophilic character. The (77)Se NMR chemical shifts for the selones show large upfield shift, thus confirming the zwitterionic structure in solution. PMID- 23737078 TI - Lithium polysulfidophosphates: a family of lithium-conducting sulfur-rich compounds for lithium-sulfur batteries. AB - Sulfur-rich lithium polysulfidophosphates (LPSPs) act as an enabler for long lasting and efficient lithium-sulfur batteries. LPSPs have ionic conductivities of 3.0*10(-5) S cm(-1) at 25 degrees C, which is 8 orders of magnitude higher than that of Li2S. The high lithium ion conductivity imparts excellent cycling performance, and the batteries are configured in an all-solid state, which promises safe cycling with metallic lithium anodes. PMID- 23737079 TI - In-vivo occlusal caries prevention by pulsed CO2 -laser and fluoride varnish treatment--a clinical pilot study. AB - BACKGROUND AND OBJECTIVES: High caries prevalence in occlusal pits and fissures warrants novel prevention methods. An 86% reduction in dental enamel smooth surface demineralization in-vivo following short-pulsed 9.6 um-CO(2) -laser irradiation was recently reported. The objective of this study was to conduct a blinded 12-month-pilot clinical trial of occlusal pit and fissure caries inhibition using the same CO(2) -laser irradiation conditions. STUDY DESIGN/MATERIALS AND METHODS: Twenty subjects, average age 14 years, were recruited. At baseline, second molars were randomized into test and control groups, assessed by International Caries Detection & Assessment System (ICDAS II), SOPROLIFE light-induced fluorescence evaluator in daylight and blue fluorescence mode and DIAGNOdent. An independent investigator irradiated test molars with a CO(2) -laser, wavelength 9.6 um, pulse-duration 20 us, pulse repetition-rate 20 Hz, beam diameter 800 um, average fluence 4.5 +/- 0.5 J/cm(2), 20 laser pulses per spot. At 3-, 6- and 12-month recall teeth were assessed by ICDAS, SOPROLIFE and DIAGNOdent. All subjects received fluoride varnish applications at baseline and 6-month recall. RESULTS: All subjects completed the 3-month, 19 the 6-month and 16 the 12-month recall. At all recalls average ICDAS scores had decreased for the test and increased for the control fissures (laser vs. control, 3-month: -0.10 +/- 0.14, 0.30 +/- 0.18, P > 0.05; 6-month: -0.26 +/- 0.13, 0.47 +/- 0.16, P = 0.001; 12-month: -0.31 +/- 0.15, 0.75 +/- 0.17, P < 0.0001; mean +/- SE, unpaired t-test) being statistically significantly different at 6- and 12-month recalls. SOPROLIFE daylight evaluation revealed at 6- and 12 months statistically significant differences in changes between baseline and recall for test and control molars, respectively (laser vs. control, 6-month: 0.22 +/- 0.13, 0.17 +/- 0.09, P = 0.02; 12-month: 0.28 +/- 0.19, 0.25 +/- 0.17, P = 0.03). For SOPROLIFE blue-fluorescence evaluation mean changes in comparison to baseline for the control and the laser treated teeth were also statistically significant for the 6- and 12-month recall. CONCLUSION: Specific microsecond short-pulsed 9.6 um CO(2) -laser irradiation markedly inhibits caries progression in pits and fissures in comparison to fluoride varnish alone over 12 months. PMID- 23737080 TI - Vitamin C transporter gene (SLC23A1 and SLC23A2) polymorphisms, plasma vitamin C levels, and gastric cancer risk in the EPIC cohort. AB - Vitamin C is known to protect mucosal tissues from oxidative stress and inhibit nitrosamine formation in the stomach. High consumption of fruits, particularly citrus, and higher circulating vitamin C concentrations may be inversely associated with gastric cancer (GC) risk. We investigated 20 polymorphisms in vitamin C transporter genes SCL23A1 and SCL23A2 and GC risk in 365 cases and 1,284 controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. We also evaluated the association between these polymorphisms and baseline plasma vitamin C levels in a subset of participants. Four SNPs were predictors of plasma vitamin C levels (SLC23A1 rs11950646 and rs33972313; SLC23A2 rs6053005 and rs6133175) in multivariable linear regression models. One SNP (SLC23A2 rs6116569) was associated with GC risk, in particular non-cardia GC (OR = 1.63, 95 % CI = 1.11-2.39, based on 178 non-cardia cases), but this association was attenuated when plasma vitamin C was included in the logistic regression model. Haplotype analysis of SLC23A1 yielded no associations with GC. In SLC23A2, one haplotype was associated with both overall and non cardia GC, another haplotype was associated with GC overall, and a third was associated with intestinal-type GC. Common variants in SLC23A1 and SLC23A2 may influence plasma vitamin C concentration independent of dietary intake, and variation in SLC23A2 may influence GC risk. Additional prospective studies in large populations and consortia are recommended. Investigation of variation in vitamin C transporter genes may shed light on the preventative properties of vitamin C in gastric carcinogenesis. PMID- 23737081 TI - Calibrated predictions for multivariate competing risks models. AB - Prediction models for time-to-event data play a prominent role in assessing the individual risk of a disease, such as cancer. Accurate disease prediction models provide an efficient tool for identifying individuals at high risk, and provide the groundwork for estimating the population burden and cost of disease and for developing patient care guidelines. We focus on risk prediction of a disease in which family history is an important risk factor that reflects inherited genetic susceptibility, shared environment, and common behavior patterns. In this work family history is accommodated using frailty models, with the main novel feature being allowing for competing risks, such as other diseases or mortality. We show through a simulation study that naively treating competing risks as independent right censoring events results in non-calibrated predictions, with the expected number of events overestimated. Discrimination performance is not affected by ignoring competing risks. Our proposed prediction methodologies correctly account for competing events, are very well calibrated, and easy to implement. PMID- 23737083 TI - Acting on anger: social anxiety modulates approach-avoidance tendencies after oxytocin administration. AB - Oxytocin attenuates responses to stress and threat (e.g., by fostering social approach in animals), but direct investigations of whether the hormone also facilitates approach-related social behaviors in humans are lacking. To assess approach-avoidance tendencies, we had participants respond to images of happy and angry faces with direct or averted gaze by either pulling a joystick toward themselves (approach) or pushing it away from themselves (avoidance). When given a placebo, participants' action tendencies were typical, with happy faces eliciting approach responses and angry faces eliciting avoidance responses. However, 24 IU of oxytocin moderated these tendencies, with the inclination to approach angry faces with direct gaze being negatively related to social anxiety. The results demonstrate that oxytocin facilitates approach in humans in response to social threat, which verifies its anxiolytic potential. Moreover, they underscore the moderating role of dispositional factors reported in endocrine research and their therapeutic implications. PMID- 23737082 TI - Trans fat supplementation increases UV-radiation-induced oxidative damage on skin of mice. AB - We evaluated the influence of fish oil (FO, rich in n-3 FA), soybean oil (SO, rich in n-6 FA) and hydrogenated vegetable fat (HVF, rich in trans FA) on the oxidative status and viability of skin cells of mice exposed to ultraviolet radiation (UVR). Mice were supplemented with FO, SO or HVF for three months and exposed to UVR (2.72 mJ/cm(2)) for 2 days. One day after the last UVR session, the FO group showed higher levels of n-3 fatty acids (FA), while the HVF showed higher incorporation of trans FA (TFA) in dorsal skin. UVR increased lipid peroxidation and protein carbonyl levels of the HVF and to a lesser extent of the control and SO groups. Although all irradiated groups showed increased skin thickness, this increase was slighter in FO mice. UVR exposure reduced skin cell viability of the control, SO and HVF groups, while FO prevented this. Catalase activity was reduced independently of the supplementation and SOD level was increased in C and FO groups after UVR exposure; FO prevented the UVR-induced increase in glutathione levels, which was observed in skin of the control, SO and HVF mice. Our results showed the beneficial effects of FO supplementation, as well as the harmful effects of trans FA, whose intensity can increase vulnerability to skin diseases. PMID- 23737084 TI - Expression of peroxiredoxins I and IV in multiple myeloma: association with immunoglobulin accumulation. AB - B cell malignancies are classified according to the postulated differentiation stage of the originating cell. During differentiation, structural and molecular changes occur to support massive processing of immunoglobulin in the endoplasmic reticulum (ER) of plasma cells at the final stage. When overloaded, the ER generates unfolded proteins and hydrogen peroxide (H2O2), which may cause cell death. Peroxiredoxins (Prxs) I and IV belong to a family of proteins able to catalyze peroxide detoxification. Here, we investigated a potential association of these enzymes with immunoglobulin production in B cell neoplasms. Our results demonstrated that the expression of Prx IV was induced as cells became competent to synthesize immunoglobulin light chains, as observed by immunohistochemistry in tissue sections of B cell neoplasms and also by qPCR and Western blotting analyses in malignant B cell lines. Prx I was frequently highly expressed, indicating additional regulatory processes besides ER activity. Results obtained exclusively with myeloma cells have shown that expression of Prxs I and IV, both at mRNA and protein levels, was associated with light chain secretion quantified by ELISA. We suggest that Prxs I and IV may provide survival advantages for terminally differentiated neoplastic B cells by the elimination of H2O2 and, in the case of Prx IV, by the conversion of this toxic in a functional agent driving oxidative protein folding in the ER. In this sense, multiple myeloma and lymphomas demonstrated to synthesize immunoglobulin chains may benefit from strategic therapies targeting the adaptive pathway to ER stress, including inhibition of Prxs I and IV activity. PMID- 23737085 TI - The snail Theba pisana as an indicator of soil contamination by trace elements: potential exposure for animals and humans. AB - BACKGROUND: The ability of snails to accumulate trace elements is well known. We analysed the snail Theba pisana as an indicator of soil contamination by trace elements after a mine spill accident, to assess the exposure of animal and human consumption. Snails were collected in autumn and spring, when they are most active. RESULTS: In general, trace elements in the soft tissues reached greater concentrations in the contaminated soils than in the non-contaminated soils, although significant differences were only found for As, Cd, Cu Fe and Hg. Cadmium content in tissues, with a maximum value of 10 mg kg-1 (dry matter), was the most worrying result. Trace element concentrations in the snail bodies were still of concern for human consumption; As and Cd concentrations were sometimes higher than the maximum concentration authorised in foodstuffs. Generally, nutritional status of the contaminated snails was not altered; concentrations of the main nutrients (Ca, K, Mg, P and S) were similar to those of the non contaminated snails. CONCLUSIONS: Results reveal a potential risk for animal and human consumption of T. pisana. It seems thus advisable to avoid collecting this species for human consumption in the affected area. Periodic monitoring is recommended to assess the evolution of potential risk for animal consumption. PMID- 23737086 TI - Tyrosine supplementation for phenylketonuria. AB - BACKGROUND: Phenylketonuria is an inherited disease for which the main treatment is the dietary restriction of the amino acid phenylalanine. The diet has to be initiated in the neonatal period to prevent or reduce mental handicap. However, the diet is very restrictive and unpalatable and can be difficult to follow. A deficiency of the amino acid tyrosine has been suggested as a cause of some of the neuropsychological problems exhibited in phenylketonuria. Therefore, this review aims to assess the efficacy of tyrosine supplementation for phenylketonuria. OBJECTIVES: To assess the effects of tyrosine supplementation alongside or instead of a phenylalanine-restricted diet for people with phenylketonuria, who commenced on diet at diagnosis and either continued on the diet or relaxed the diet later in life. To assess the evidence that tyrosine supplementation alongside, or instead of a phenylalanine-restricted diet improves intelligence, neuropsychological performance, growth and nutritional status, mortality rate and quality of life. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register which is comprised of references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings. Additional studies were identified from handsearches of the Journal of Inherited Metabolic Disease (from inception in 1978 to 1998). The manufacturers of prescribable dietary products used in the treatment of phenylketonuria were also contacted for further references.Date of the most recent search of the Group's Inborn Errors of Metabolism Trials Register: 28 June 2012. SELECTION CRITERIA: All randomised or quasi-randomised trials investigating the use of tyrosine supplementation versus placebo in people with phenylketonuria in addition to, or instead of, a phenylalanine-restricted diet. People treated for maternal phenylketonuria were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the trial eligibility, methodological quality and extracted the data. MAIN RESULTS: Six trials were found, of which three trials reporting the results of a total of 56 participants, were suitable for inclusion in the review. The blood tyrosine concentrations were significantly higher in the participants receiving tyrosine supplements than those in the placebo group, mean difference 23.46 (95% confidence interval 12.87 to 34.05). No significant differences were found between any of the other outcomes measured. AUTHORS' CONCLUSIONS: From the available evidence no recommendations can be made about whether tyrosine supplementation should be introduced into routine clinical practice. Further randomised controlled studies are required to provide more evidence. PMID- 23737087 TI - Palivizumab for prophylaxis against respiratory syncytial virus infection in children with cystic fibrosis. AB - BACKGROUND: Respiratory syncytial virus infection causes acute lung infection in infants and young children worldwide, resulting in considerable morbidity and mortality. Children with cystic fibrosis are prone to recurrent lung inflammation, bacterial colonisation and subsequent chronic airway disease, putting them at risk for severe respiratory syncytial virus infections requiring intensive care and respiratory support. No treatment currently exists, hence prevention is important. Palivizumab is effective in reducing respiratory syncytial virus hospitalisation rates and is recommended for prophylaxis in high risk children with other conditions. It is unclear if palivizumab can prevent respiratory syncytial virus hospitalisations and intensive care unit admissions in children with cystic fibrosis. OBJECTIVES: To determine the efficacy and safety of palivizumab (Synagis((r))) compared with placebo, no prophylaxis or other prophylaxis, in preventing hospitalisation and mortality from respiratory syncytial virus infection in children with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register and scanned references of the eligible study and related reviews.Date of last search: 11 October 2012. SELECTION CRITERIA: Randomised and quasi-randomised studies. DATA COLLECTION AND ANALYSIS: The authors independently extracted data and assessed risk of bias. MAIN RESULTS: One study (186 infants up to two years old) comparing five monthly doses of palivizumab (N = 92) to placebo (N = 94) over one respiratory syncytial virus season was identified and met our inclusion criteria. At six months follow-up, one participant in each group was hospitalised due to respiratory syncytial virus; there were no deaths in either group. In the palivizumab and placebo groups, 86 and 90 children experienced any adverse event, while five and four children had related adverse events respectively. Nineteeen children receiving palivizumab and 16 receiving placebo suffered serious adverse events; one participant receiving palivizumab discontinued due to this. At 12 months follow-up, there were no significant differences between groups in number of Pseudomonas bacterial colonisations or change in weight-to-height ratio. AUTHORS' CONCLUSIONS: We identified one randomised controlled trial comparing five monthly doses of palivizumab to placebo in infants up to two years old with cystic fibrosis. While the overall incidence of adverse events was similar in both groups, it is not possible to draw firm conclusions on the safety and tolerability of respiratory syncytial virus prophylaxis with palivizumab in infants with cystic fibrosis. Six months after treatment, the authors reported no clinically meaningful differences in outcomes. Additional randomised studies are needed to establish the safety and efficacy of palivizumab in children with cystic fibrosis. PMID- 23737088 TI - Timing of dornase alfa inhalation for cystic fibrosis. AB - BACKGROUND: Inhalation of the enzyme dornase alfa reduces sputum viscosity and improves clinical outcomes of people with cystic fibrosis. OBJECTIVES: To determine the effect of timing of dornase alfa inhalation on measures of clinical efficacy in people with cystic fibrosis (in relation to airway clearance techniques or time of day). SEARCH METHODS: Relevant randomised and quasi randomised controlled trials were identified from the Cochrane Cystic Fibrosis Trials Register, Physiotherapy Evidence Database (PEDro), and international CF conference proceedings.Date of the most recent search: 22 February 2013. SELECTION CRITERIA: Any trial of dornase alfa in people with cystic fibrosis where timing of inhalation was the randomised element in the study with either: inhalation before compared to after airway clearance techniques; or morning compared to evening inhalation. DATA COLLECTION AND ANALYSIS: Both authors independently selected trials, assessed risk of bias and extracted data with disagreements resolved by discussion. Relevant data were extracted and, where possible, meta-analysed. MAIN RESULTS: We identified 99 trial reports representing 48 studies, of which five studies (providing data on 122 participants) met our inclusion criteria. All five studies used a cross-over design. Intervention periods ranged from two to eight weeks. Four trials compared dornase alfa inhalation before versus after airway clearance techniques. Inhalation after instead of before airway clearance did not significantly change FEV1. Similarly, FVC and quality of life were not significantly affected; FEF25 was significantly worse with dornase alfa inhalation after airway clearance, MD 0.17 litres (95% CI -0.28 to -0.05), based on the pooled data from two small studies in children (7 to 19 years) with well-preserved lung function. All other secondary outcomes were statistically non-significant.In one trial, morning versus evening inhalation had no impact on lung function or symptoms. AUTHORS' CONCLUSIONS: The current evidence derived from a small number of participants does not indicate that inhalation of dornase alfa after airway clearance techniques is more or less effective than the traditional recommendation to inhale nebulised dornase alfa 30 minutes prior to airway clearance techniques, for most outcomes. For children with well-preserved lung function, inhalation before airway clearance may be more beneficial for small airway function than inhalation after. However, this result relied on a measure with high variability and studies with variable follow up. In the absence of strong evidence to indicate that one timing regimen is better than another, the timing of dornase alpha inhalation can be largely based on pragmatic reasons or individual preference with respect to the time of airway clearance and time of day. Further research is warranted. PMID- 23737089 TI - Antibiotic adjuvant therapy for pulmonary infection in cystic fibrosis. AB - BACKGROUND: Cystic fibrosis is a multi-system disease characterised by the production of thick secretions causing recurrent pulmonary infection, often with unusual bacteria. This leads to lung destruction and eventually death through respiratory failure. There are no antibiotics in development that exert a new mode of action and many of the current antibiotics are ineffective in eradicating the bacteria once chronic infection is established. Antibiotic adjuvants - therapies that act by rendering the organism more susceptible to attack by antibiotics or the host immune system, by rendering it less virulent or killing it by other means, are urgently needed. OBJECTIVES: To determine if antibiotic adjuvants improve clinical and microbiological outcome of pulmonary infection in people with cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis Trials Register which is compiled from database searches, hand searches of appropriate journals and conference proceedings.Date of most recent search: 26 July 2012.We also searched MEDLINE (all years) on 23 February 2013 and ongoing trials registers on 13 February 2013. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials of a therapy exerting an antibiotic adjuvant mechanism of action compared to placebo or no therapy for people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: The authors independently assessed and extracted data from identified studies. MAIN RESULTS: We identified eighteen studies of which four are included that examined antibiotic adjuvant therapies, three studies are ongoing. The included studies involve the assessment of beta carotene, garlic and zinc supplementation and KB001 (a biological agent). No therapy demonstrated a significant effect upon pulmonary function, pulmonary exacerbations or quality of life. The study of zinc supplementation reports a reduction in the requirement of oral antibiotics but not of intravenous antibiotics, an effect that is difficult to understand. AUTHORS' CONCLUSIONS: We could not identify an antibiotic adjuvant therapy that could be recommended for the treatment of lung infection in those with cystic fibrosis. The emergence of increasingly resistant bacteria makes the reliance on antibiotics alone challenging for cystic fibrosis teams. There is a need to explore alternative strategies, such as the use of adjuvant therapies. Further research is required to provide future therapeutic options. PMID- 23737091 TI - How do we define complete remission for acute myeloid leukemia in the current era? Results of an international survey. PMID- 23737092 TI - Rituximab-based pre-emptive treatment of molecular relapse in follicular and mantle cell lymphoma. AB - Pre-emptive rituximab (pRTX) might represent an effective approach for patients with follicular (FL) and mantle cell lymphoma (MCL) experiencing molecular relapse (M-rel). However, available experience is still limited. We retrospectively collected FL and MCL cases that underwent pRTX with four weekly rituximab infusions (375 mg/m2) due to molecular persistence or M-rel. M-rel was assessed using nested polymerase chain reaction (PCR) and real-time quantitative PCR using the Bcl-1/IGH, Bcl-2/IGH or the immunoglobulin heavy chain rearrangement. Twenty-three occurrences of M-rel or persistence were treated in 18 patients (nine MCL and nine FL). The pRTX reinduced molecular remission (MR) in 17/23 cases (7/9 FL and 10/14 MCL). The median time to MR reinduction was 4.5 months (range 3-12), and the median duration of the first MR reinduction was 34 months (range 12-72). In five MCL cases, pRTX was used to treat subsequent M rels, with success in four cases. No clinical relapses were seen within 2 years of successful reinduction of MR. Progression-free survival after pRTX was 64 % at a median follow-up of 6 years. pRTX was feasible and safe and effectively reinduced MR in FL and MCL patients (74 %). Prospective trials are needed to verify the clinical benefit of similar approaches. PMID- 23737090 TI - Recombinant growth hormone therapy for cystic fibrosis in children and young adults. AB - BACKGROUND: Cystic fibrosis is an inherited condition causing disease most noticeably in the lungs, digestive tract and pancreas. People with cystic fibrosis often have malnutrition and growth delay. Adequate nutritional supplementation does not improve growth optimally and hence an anabolic agent, recombinant growth hormone, has been proposed as a potential intervention. OBJECTIVES: To evaluate the effectiveness and safety of recombinant human growth hormone therapy in improving lung function, quality of life and clinical status of children and young adults with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Date of latest search: 15 May 2013.We conducted a search of relevant endocrine journals and proceedings of the Endocrinology Society meetings using Scopus and Proceedings First. Date of latest search: 15 March 2012. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of all preparations of recombinant growth hormone compared to either no treatment, or placebo, or each other at any dose (high-dose and low-dose) or route and for any duration, in children or young adults aged up to 25 years diagnosed with cystic fibrosis (by sweat test or genetic testing). DATA COLLECTION AND ANALYSIS: Two authors independently screened papers, extracted trial details and assessed their risk of bias. MAIN RESULTS: Four controlled trials were included in this review (with 161 participants in total), each with an unclear risk of bias. Analysis of data obtained from these trials shows improvement in height for all comparisons, but improvements in weight and lean tissue mass were only reported in the comparison of standard dose recombinant growth hormone versus no treatment. There is moderate improvement in one parameter of pulmonary function tests, functional vital capacity (per cent predicted) when comparing standard dose recombinant growth hormone and no treatment. Little evidence was found for improvement in quality of life. An improvement in fasting blood glucose levels was reported when comparing rhGH to placebo only. Exercise capacity improved in participants receiving standard dose recombinant growth hormone versus no treatment, but not for any other comparison. There is insufficient evidence to conclude any changes in hospitalisations, antibiotic use or significant adverse effects. AUTHORS' CONCLUSIONS: Recombinant growth hormone therapy is effective in improving the intermediate outcomes in height, weight and lean tissue mass when compared with no treatment. One measure of pulmonary function test showed moderate improvement. No significant changes in quality of life, clinical status or side-effects were observed in this review. Long-term, well-designed randomised controlled trials of recombinant growth hormone therapy in patients with cystic fibrosis are required prior to evaluation of human growth hormone treatment for routine use in patients. PMID- 23737093 TI - A mimicking "multiple liver metastasis" of breast cancer by recurrent B lymphoblastic leukemia. PMID- 23737094 TI - Anatomical considerations for reconstruction of the Lisfranc ligament. AB - BACKGROUND: The Lisfranc ligament is important in supporting the arch of the foot. Injury to this ligament causes pain and deformity of the foot. METHODS: We studied the Lisfranc ligament and its surrounding anatomical structures in detail, and examined the route for reconstruction and the thickness of the ligament for optimum reconstruction. 78 feet of 39 cadavers were used for systematic dissection. Of the cadavers 17 were males and 22 were females; their ages ranged from 60 to 99 years (mean age 84.5 years). RESULTS: The Lisfranc ligament is a fasciculated interosseous ligament that binds the lateral surface of C1 and the medial surface of M2. It has one to four fasciculi; the mean number of fasciculi is 2.0 and the cross-sectional area is 88 mm(2). The ideal reconstruction is such that the center of the ligament is positioned 5.9 mm distally from the C2-M2 joint surface on M2, and at a position 8.6 mm centrally from the C1-M1 joint surface on C1. The reconstruction would also be ideal if positioned at the same level as the C2-M2 joint surface on C1, horizontal to the plantar surface from the medial surface of C1 toward M2. This is the route for anatomical reconstruction of the Lisfranc ligament. CONCLUSION: Our results reveal some important aspects of anatomical and physiological ligament reconstruction. PMID- 23737095 TI - Dasatinib plus chemotherapy to achieve full donor chimerism and complete molecular remission in a child with relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia. PMID- 23737096 TI - Imaging and tracking of bone marrow-derived immune and stem cells. AB - Bone marrow (BM)-derived stem and immune cells play critical roles in maintaining the health, regeneration, and repair of many tissues. Given their important functions in tissue regeneration and therapy, tracking the dynamic behaviors of BM-derived cells has been a long-standing research goal of both biologists and engineers. Because of the complex cellular-level processes involved, real-time imaging technologies that have sufficient spatial and temporal resolution to visualize them are needed. In addition, in order to track cellular dynamics, special attention is needed to account for changes in the microenvironment where the cells reside, for example, tissue contraction, stretching, development, etc. In this chapter, we introduce methods for real-time imaging and longitudinal tracking of BM-derived immune and stem cells in in vivo three-dimensional (3-D) tissue environments with an integrated optical microscope. The integrated microscope combines multiple imaging functions derived from optical coherence tomography (OCT) and multiphoton microscopy (MPM), including optical coherence microscopy (OCM), microvasculature imaging, two-photon excited fluorescence (TPEF), and second harmonic generation (SHG) microscopy. Short- and long-term tracking of the dynamic behavior of BM-derived cells involved in cutaneous wound healing and skin grafting in green fluorescent protein (GFP) BM-transplanted mice is demonstrated. Methods and algorithms for nonrigid registration of time-lapse images are introduced, which allows for long-term tracking of cell dynamics over several months. PMID- 23737097 TI - A high content imaging-based approach for classifying cellular phenotypes. AB - Current methods to characterize cell-biomaterial interactions are population based and rely on imaging or biochemical analysis of end-point biological markers. The analysis of stem cells in cultures is further challenged by the heterogeneous nature and divergent fates of stem cells, especially in complex, engineered microenvironments. Here, we describe a high content imaging-based platform capable of identifying cell subpopulations based on cell phenotype specific morphological descriptors. This method can be utilized to identify microenvironment-responsive morphological descriptors, which can be used to parse cells from a heterogeneous cell population based on emergent phenotypes at the single-cell level and has been successfully deployed to forecast long-term cell lineage fates and screen regenerative phenotype-prescriptive biomaterials. PMID- 23737099 TI - Chondrogenic potential of human dermal fibroblasts in a contractile, soft, self assembling, peptide hydrogel. AB - The present paper describes a simple approach to obtain three-dimensional (3D) cartilage constructs using human normal dermal fibroblasts (hNDFs) cultured in a self-assembling peptide nanofibre scaffold. During the first days of culture, the 3D constructs underwent morphological changes consisting of a substantial contraction process that ended in a small compact structure. During this process the system became sensitive to induction with standard chondrogenic medium, evidenced by the expression of specific markers of mature cartilage. First, it was detected that the samples become highly stained with toluidine blue dye over time (40-50 days), indicating that the system produced significantly high amounts of glycosaminoglycans. By quantitative PCR, it was confirmed that the system significantly upregulated the expression of the proteoglycan aggrecan, a good indicator of cartilage commitment. Moreover, collagen type II was upregulated at protein level, confirming that the system differentiated to a chondrocyte-like construct. Additionally, during the first days of culture in control medium analysed hNDFs proliferation capacity in this 3D system was analysed. This platform could be used in the future to obtain an autologous source of cells from a simple patient skin biopsy, which could be easily translated into a low-cost and effective regenerative therapy. PMID- 23737100 TI - Fluorene-based co-polymer with high hole mobility and device performance in bulk heterojunction organic solar cells. AB - A new donor-acceptor polymer based on 9,9-dioctylfluorene is synthesized and tested in organic photovoltaic devices. Results show that the polymer exhibits good solubility in a range of organic solvents and has a high hole mobility. When blended with a PC70 BM acceptor and fabricated into a bulk heterojunction, photovoltaic devices having a maximum power conversion efficiency (PCE) of 6.2% and a peak external quantum efficiency of 74% are created. Such efficiencies are realized without any necessity for solvent additives or thermal annealing protocols. PMID- 23737101 TI - Er:YAG laser activation of sodium hypochlorite for root canal soft tissue dissolution. AB - BACKGROUND AND OBJECTIVE: The aim of this in vitro study was to investigate the effect of Er:YAG laser irradiation on the ability of sodium hypochlorite (NaOCl) to dissolve soft tissue during endodontic procedures. MATERIALS AND METHODS: Two acrylic glass plates, each containing a semi-canal, were bolted together to form a complete canal. This geometry permitted one semi-canal to be filled with fine liver sausage of bovine origin dyed by methylene blue and the other with NaOCl (4.00-4.99% available chlorine; Sigma-Aldrich Corporation, St. Louis, MA), which was then activated by Er:YAG laser irradiation (KEY Laser 3; KaVo, Biberach, Germany) using a plain-ended fiber tip and a range of output energy and repetition rate. To achieve relatively low output energy from high input energy, the laser beam was attenuated by placing glass slides in the beam path. The resultant images acquired were analyzed using pixel-based analysis. Samples were statistically analyzed (two-way ANOVA, P < 0.05, univariate, bifactorial; IBM SPSS Statistics 19, SPSS Inc., Chicago, IL). RESULTS: Both output energy and repetition rate significantly influenced the tissue dissolution ability of NaOCl (P < 0.05). CONCLUSION: Within the limitations of this in vitro study, we conclude that laser activation of NaOCl at 200 mW output power leads to effective soft tissue dissolution. This finding can be of use to endodontists pursuing effective soft tissue dissolution from their irrigants. PMID- 23737102 TI - "Magic" surface clustering of borazines driven by repulsive intermolecular forces. AB - It's a kind of magic: Hydroxy pentaaryl borazine molecules self-assemble into small clusters (see structure) on Cu(111) surfaces, whereas with symmetric hexaaryl borazine molecules large islands are obtained. Simulations indicate that the observed "magic" cluster sizes result from long-range repulsive Coulomb forces arising from the deprotonation of the B-OH groups of the hydroxy pentaaryl borazine. PMID- 23737103 TI - Surgical and catheter procedures in adult congenital heart disease: simple national statistics of the UK tell us something. AB - Published national statistics for the last decade in the UK were utilized to figure out the reality of interventions in adolescents and adults with congenital heart disease. There was a clear indication of increase in the number of procedures of some specific types, such as pulmonary valve replacement and other heart valve surgery. Intervention for closure of inter-atrial communication was another entity that showed a marked rise in numbers during the last 10 years. Overall survival rates at 30 days and 1 year were encouraging, including those for relatively uncommon procedures. On the basis of growing understanding and meticulous investigation into every aspect of this field, clinical practice in adults with congenital heart disease is likely directed to a promising future. PMID- 23737105 TI - Two new neolignans from Patrinia scabra with potent cytotoxic activity against HeLa and MNK-45 cells. AB - Two new neolignans, patrineolignan A (1) and patrineolignan B (2), together with seven known lignans, were isolated from the 90 % aqueous EtOH extract of the roots of Patrinia scabra. Their structures were elucidated on the basis of spectroscopic data (HRESIMS, IR, 1D and 2D NMR) and comparison with literature data. The two new neolignans were evaluated in vitro for cytotoxic properties against human cervical carcinoma HeLa cell line and gastric carcinoma MNK-45 cell line using the microculture tetrazolium assay, and both 1 and 2 exhibited strongly cytotoxic activity against the two tumor cell lines. PMID- 23737104 TI - Techniques and results in the management of multiple muscular trabecular ventricular septal defects. AB - The management of patients with multiple muscular trabecular ventricular septal defects (VSDs) remains controversial. In the past two decades, innovative techniques including a right ventricular apical infundibulotomy and transcatheter, intraoperative and perventricular device closure have been exploited, and essential right atrial approach and limited apical left ventriculotomy have also been refined. However, specific management guidelines for this difficult disease have not been established. In this article, the benefits and drawbacks of each technique are reviewed and discussed. Primary repair for infants with multiple muscular trabecular VSDs was associated with good late outcomes. The right atrial approach was satisfactory for all muscular VSDs, excluding apical defects that were well seen through a limited apical ventriculotomy. Surgical closure of apical defects could be achieved safely and completely in early infancy through a limited apical left ventriculotomy or a right ventricular apical infundibulotomy. Further follow-up and prudent evaluations of ventriculotomy-associated morbidities are needed. Pulmonary artery banding should be limited to a small infant with complex associated defects. Percutaneous device closure, the most desirable option, is impractical due to limitations between the delivery system and access route. Intraoperative device closure appears less successful than device closure in the catheterization laboratory. Perventricular device closure has a significant advantage of being a non-bypass procedure approach. A less invasive strategy for "true" Swiss cheese septum is needed. All may have an important role, and results obtained by using these techniques are encouraging. These hybrid approaches will promise future success on management guidelines of multiple muscular trabecular VSDs. PMID- 23737106 TI - Anticancer activities of some newly synthesized pyrazole and pyrimidine derivatives. AB - A series of pyrazolopyridine and pyridopyrimidine derivatives 2-6 were newly synthesized using 3,5-bisarylmethylene-1-methylpiperidone as the starting material. The anticancer activities of the synthesized compounds were evaluated using 59 different human tumor cell lines, representing cancers of CNS, ovary, renal, breast, colon, lung, leukemia, and melanoma, prostate as well as kidney. Some of the tested compounds, especially those with a fluorine substituent at the para-position in the phenyl ring and those with a pyridopyrimidine-2-thione with a free -NH or -SH, exhibited greater in vitro anti-tumor activities at low concentrations (log 10 [GI50] = -4.6) against the human tumor cell lines. Additionally, some of the compounds had moderate inhibitory effects on the growth of the cancer cell lines. The detailed synthesis, spectroscopic data and antitumor properties of the synthesized compounds are reported. PMID- 23737107 TI - Individual characteristics and use of maternal and child health services by adolescent mothers in Niger. AB - Despite high rates of early childbearing, maternal mortality, and under-five mortality, little is known about factors that affect access of teenage mothers to maternal and child health (MCH) services in Niger. This paper explores potential factors associated with the utilization of MCH care services by adolescent mothers. Using the third wave of the Niger demographic and health survey (NDHS) 2006, we estimate three multivariate logistic regression models to assess individual characteristics associated with the utilization of antenatal care (ANC) and safe delivery care services among adolescent women, as well as full immunization received by children born to adolescent mothers. The analytical sample includes 934 adolescent mothers out of 1,835 respondents aged 15-19, and within this group, 493 mother-child dyads for children aged 12-59 months. Possessing any level of education was found associated with the increased use of all three selected MCH services, while urban residence and higher income were associated with the increased use of two of three MCH services studied. Higher birth order plus a birth interval more than 2 years for the most recent birth appeared associated with the lower probability of antenatal care visits and safe delivery care. This study finds that women who attended at least four ANC visits were more likely to experience safe delivery care, and the children whose mothers had safe delivery care were more likely to receive full immunization. Therefore, an effective program should be designed to promote a continuum of MCH care with special attention to adolescent women who are uneducated, poor and residing in rural areas. PMID- 23737108 TI - Altering the rate of glucose release from starch-based foods by spray-drying with an extract from barley. AB - BACKGROUND: Health outcomes associated with sustained elevated blood glucose may be better managed by limiting glucose availability for uptake. Glucose release from consumed starch may be altered using various methods, but many are not suitable for high-carbohydrate foods. This study describes an approach to protect starch granules, while generally maintaining their physical characteristics, with an extract from barley using spray-drying. RESULTS: The use of the extract resulted in the coating of the starch granules with a film-like material composed of beta-glucans and proteins. This coincided with a reduction in starch digestion and a significant increase in the indigestible (resistant) starch component. Substitution of the starch component in a model snack bar by the coated starch was also associated with lowering starch digestion in the bar. CONCLUSION: The barley extract provides a physical barrier that may limit the exposure of starch to the digestive enzymes and water, with a consequent reduction in starch digestion and the rate of glucose release. It is possible, therefore, to produce wheat starch with lower digestibility and glucose release rate that may be used as a healthier substitute in high-carbohydrate foods by coating the granules with polymers extracted from barley cereals through spray-drying. PMID- 23737109 TI - Mobility histories of 7th-9th century AD people buried at early medieval Bamburgh, Northumberland, England. AB - Early Medieval England is described historically as a time when people migrated from the Continent to English shores. This study tests the hypothesis that those buried in the Bowl Hole cemetery, Bamburgh, Northumberland were nonlocally born, because of its royal status. Ninety-one male and female adult, and nonadult, skeletons were studied. Isotope ratios of strontium ((87) Sr/(86) Sr) and oxygen (delta(18) O) were generated for 78 individuals (28 females, 27 males, five "adults," 18 nonadults). The mean Sr value for human enamel was 0.71044, standard deviation (sd) 0.001, and the mean O (deltaw) value is -5.90/00, sd 1.60/00. Additionally, animal tooth enamel (mean Sr value 0.710587, sd 0.001; mean O value -6.50/00, sd 1.50/00), local soil (mean Sr value 0.709184, sd 0.0006), snail shells (mean Sr value 0.708888, sd 0.0001), and soil samples from a 5 km transect heading inland (mean Sr value 0.709121, sd 0.0003), were analyzed for an indication of the isotopic composition of bioavailable Sr in the modern environment and to assess the impact of sea-spray; water samples from a well, local rivers, and standing water were analyzed for local delta(18) O values (mean O value -6.40/00, relative to VSMOW, sd 2.80/00). Over 50% of those buried at Bamburgh were nonlocal. All ages and both sexes produced "nonlocal" signatures; some suggested childhood origins in Scandinavia, the southern Mediterranean or North Africa. Stature and other indicators of health status indicated differences in quality of life between local and migrant groups. These differences did not extend to burial practices. PMID- 23737110 TI - The status of serum vitamin D in patients attending a general rheumatology clinic in the UK. AB - Vitamin D deficiency may be involved in the pathogenesis of several inflammatory conditions. This study aimed to determine the status of vitamin D in the rheumatology patients who were diagnosed with different rheumatic, inflammatory and non-inflammatory diseases. In this cross-sectional observational study, we reviewed the levels of serum vitamin D in patients who attended the general rheumatology clinics for the first time between May 2012 and October 2012. A total of 61 patients were included in this study. Twenty-five patients (41 %) had vitamin D insufficiency and two patients (3.3 %) were vitamin D deficient. Sixteen patients had an inflammatory condition and vitamin D was low in five patients (31 %). Among the 45 patients who had a non-inflammatory rheumatic condition, 20 patients (44 %) had low vitamin D. There was no significant statistical difference (P = 0.3) in the incidence of low vitamin D between the two groups. We found no significant correlation either between CRP and vitamin D (r = -0.02 (95 % confidence interval -0.28 to 0.23), P = 0.8). In this limited study, which was undertaken in the summer months, we concluded that there was no significant difference in vitamin D status between patients with inflammatory and non-inflammatory rheumatic conditions. PMID- 23737111 TI - Cognitive performance is of clinical importance, but is unrelated to pain severity in women with chronic fatigue syndrome. AB - In various chronic pain populations, decreased cognitive performance is known to be related to pain severity. Yet, this relationship has not been investigated in patients with chronic fatigue syndrome (CFS). This study investigated the relationship between cognitive performance and (1) pain severity, (2) level of fatigue, and (3) self-reported symptoms and health status in women with CFS. Examining the latter relationships is important for clinical practice, since people with CFS are often suspected to exaggerate their symptoms. A sample of 29 female CFS patients and 17 healthy controls aged 18 to 45 years filled out three questionnaires (Medical Outcomes Study 36-Item Short-Form Health Survey, Checklist Individual Strength (CIS), and CFS Symptom List) and performed three performance-based cognitive tests (psychomotor vigilance task, Stroop task, and operation span task), respectively. In both groups, pain severity was not associated with cognitive performance. In CFS patients, the level of fatigue measured with the CFS Symptom List, but not with the CIS, was significantly correlated with sustained attention. Self-reported mental health was negatively correlated with all investigated cognitive domains in the CFS group. These results provide evidence for the clinical importance of objectively measured cognitive problems in female CFS patients. Furthermore, a state-like measure (CFS Symptom List) appears to be superior over a trait-like measure (CIS) in representing cognitive fatigue in people with CFS. Finally, the lack of a significant relationship between cognitive performance and self-reported pain severity suggests that pain in CFS might be unique. PMID- 23737112 TI - [Vena cava filters in pulmonary embolism: temporary or permanent?--Cava filters have to be removed early]. PMID- 23737114 TI - [Branch retinal vein occlusion in a 20-year-old patient]. AB - HISTORY: A 20-year-old patient from India was referred because visual acuity of the left eye had deteriorated four weeks ago. A left branch retinal vein occlusion (BRVO) had been diagnosed in an external eye clinic. INVESTIGATIONS: His best corrected visual acuity was 1,0 in the right eye but only 0.3 in the left. Intraocular pressure was normal. Fundoscopy of the left eye confirmed the finding of a left BRVO. Fluorescein angiography showed evidence of a retinal vasculitis resulting in an ischemic BRVO. Full blood count showed leucocytosis. Chest X-ray, thoracic CT and an Interferon-Gamma Release Assay (IGRA) were suggestive of systemic tuberculosis (TB). TREATMENT AND COURSE: Antituberculosis treatment with ethambutol, isoniazid, rifampicin and pyrazinamide was administered for 4 months followed by maintenace therapy of isoniazid and ethambutol for 6 months. 6 months after treatment visual acuity of the left eye had improved; the findings of lung TB had regressed. CONCLUSION: BRVO associated with ocular TB is a rare presentation of retinal vasculitis. This rare manifestation of a BRVO emphasizes the need of thorough systemic evaluation in young patients with BRVO. PMID- 23737113 TI - [Diagnostic accuracy of a standardized carbohydrate-rich breakfast compared to an oral glucose tolerance test in occupational medicine]. AB - BACKGROUND: Increasing prevalence of type 2 diabetes mellitus is not only a problem for the health care system but also impairs working environment. In order to reduce costs by illness and early retirement and the development of diabetic complications occupational medicine is important for early diabetes detection. However, the diagnostic gold standard, oral glucose tolerance test (oGTT), is rarely accepted. Aim of our investigation was to evaluate diagnostic accuracy of a standardizable and cost-effective test-breakfast in comparison to oGTT which might be accepted in workplace. METHODS: During a workplace health promotion program diagnostic accuracy (sensitivity and specificity) of a test-breakfast (index test) was analyzed in a random-cross-over-design with healthy volunteers in comparison to an oGTT (reference test). RESULTS: 278 subjects participated and rated the health promotion program to be useful (99%). 74% stated that they preferred the test-breakfast in contrast to the oGTT. Both screening methods showed comparable plasma glucose and insulin curves. The plasma glucose levels measured capillary and venously during test-breakfast and oGTT were very consistent. Differences were only seen for the 2 h plasma glucose values in the fully adjusted model. The test-breakfast demonstrated high sensitivity and specificity for diabetes diagnosis compared to the reference test with highly comparable results, i. e. 8 persons (2,9%) newly diagnosed with diabetes by the test-breakfast vs. 7 (2,5%) by oGTT. CONCLUSION: A test-breakfast seems to be a useful first screening instrument to increase the compliance of occupational health promotions and might improve early diabetes diagnosis. PMID- 23737115 TI - [57-year-old patient after attempted suicide. Severe accidental hypothermia]. PMID- 23737116 TI - [Electrical cardioversion for non-valvular atrial fibrillation--underestimated risk for thromboembolic complications?]. AB - Electrical cardioversions are performed to restore sinus rhythm in patients with non-valvular atrial fibrillation to improve symptoms. It has been known for decades that cardioversion without adequate anticoagulation for 3-4 weeks prior to and for 4 weeks after cardioversion results in thromboembolic complication of about 5%. It is much less known that cardioversion is also associated with a higher risk of thromboembolism (stroke, peripheral embolism) in patients treated with usual anticoagulation. The control arms (warfarin) of the three studies with the new anticoagulants dabigatran, rivaroxaban, and apixaban for the prevention of thromboembolism in non-valvular atrial fibrillation report a monthly thromboembolic risk of 0,13-0,2%. The risk for thromboembolic complication in the month following cardioversion is about three to six times higher than without cardioversion in patients with non-valvular atrial fibrillation treated with usual anticoagulation. Since most cardioversions are performed by DC shock it is not known whether electrical and pharmacological cardioversions carry the same risk for thromboembolism. Although thromboembolic complications do not often occur following cardioversion the increased risk due to this procedure should be acknowledged. Strict anticoagulation (e. g. INR value > 2,5) in the first 10-14 days following cardioversion could possibly minimize the risk of thromboembolism. PMID- 23737117 TI - [Safety aspects of parenteral iron supplementation therapies in patients with chronic kidney disease]. AB - Iron deficiency often occurs in patients with chronic kidney disease and can be effectively treated with parenteral supplementation of iron. In these patients, prompt application of iron therapy can help to reduce the dependence of erythropoietin-stimulating agents and effectively treat anemia. Correct evaluation of iron metabolism in CKD patients can be difficult. Duration of and response to therapy should always be considered while planning parenteral supplementation of iron. The main safety aspects of parenteral iron preparations relate to their possible anaphylactic potential and the potential induction of oxidative stress due to the release of free iron. However, parenteral iron supplementation is usually safe and without major side effects. Regarding current data, none of the iron preparations is showing definitive superiority. Although uncommon, iron preparations containing dextran can lead to severe side effects, therefore these preparations appear to have an inferior safety profile. Due to limited data, a comparison of third-generation iron preparations with previous preparations is not possible. Recently, for the first time, the third generation iron preparation ferumoxytol has been directly compared to iron sucrose. From this data and others, it remains unclear whether third generation iron preparations show safety-relevant superiority. PMID- 23737118 TI - [Long non-coding RNAs as central regulators of hematopoiesis and leukemogenesis]. PMID- 23737119 TI - [Pain medication for children and adolescents in primary care]. PMID- 23737120 TI - Evaluation of three-dimensional porous chitosan-alginate scaffolds in rat calvarial defects for bone regeneration applications. AB - This study investigated the use of three-dimensional porous chitosan-alginate (CA) scaffolds for critical size calvarial defect (diameter, 5.0 mm) repair in Sprague-Dawley rats. CA scaffolds have been used for in vitro culture of many cell types and demonstrated osteogenesis in ectopic locations in vivo, but have yet to be evaluated for functional bone tissue engineering applications. CA scaffolds demonstrated the ability to support undifferentiated mesenchymal stem cells (MSCs) in culture for 14 days in vitro and promoted spherical morphology. In vivo tests were performed using CA scaffolds and CA scaffolds with treatments including undifferentiated MSCs, bone marrow aspirate, and bone morphogenetic protein-2 (BMP-2) growth factor in comparison to unfilled bone defect used as a control. The samples were analyzed with MicroCT, histology, and immunohistochemical staining at 4 and 16 weeks. Partial defect closure was observed in all experimental groups at 16 weeks, with the greatest defect closure (71.56 +/- 19.74%) in the animal group treated with CA scaffolds with BMP-2 (CA + BMP-2). The experimental samples demonstrated osteogenesis in histology and immunohistochemical staining, with the CA + BMP-2 group, showing the greatest level of osteogenesis. Tissue engineered CA scaffolds show promise in reconstruction of critical size bone defects. PMID- 23737121 TI - A dynamic distention protocol for whole-organ bladder decellularization: histological and biomechanical characterization of the acellular matrix. AB - A combined physical-chemical protocol for whole full-thickness bladder decellularization is proposed, based on organ cyclic distention through repeated infusion/withdrawal of the decellularization agents through the urethra. The dynamic decellularization was intended to enhance cell removal efficiency, facilitating the delivery of detergents within the inner layers of the tissue and the removal of cell debris. The use of mild chemical detergents (hypotonic solution and non-ionic detergent) was employed to limit adverse effects upon matrix 3D ultrastructure. Inspection of the presence of residual DNA and RNA was carried out on decellularized matrices to verify effective cell removal. Histological investigation was focused on assessing the retention of adequate structural and functional components that regulate the biomechanical behaviour of the acellular tissue. Biomechanical properties were evaluated through uniaxial tensile loading tests of tissue strips and through ex vivo filling cystometry to evaluate the whole-organ mechanical response to a physiological-like loading state. According to our results, a dynamic decellularization protocol of 17 h duration with a 5 ml/min detergent infusion flow rate revealed higher DNA removal efficiency than standard static decellularization, resulting in residual DNA content < 50 ng/mg dry tissue weight. Furthermore, the collagen network and elastic fibres distribution were preserved in the acellular ECM, which exhibited suitable biomechanical properties in the perspective of its future use as an implant for bladder augmentation. PMID- 23737122 TI - Proof-of-concept of a laser mounted endoscope for touch-less navigated procedures. AB - BACKGROUND AND OBJECTIVES: During navigated procedures a tracked pointing device is used to define target structures in the patient to visualize its position in a registered radiologic data set. When working with endoscopes in minimal invasive procedures, the target region is often difficult to reach and changing instruments is disturbing in a challenging, crucial moment of the procedure. We developed a device for touch less navigation during navigated endoscopic procedures. MATERIALS AND METHODS: A laser beam is delivered to the tip of a tracked endoscope angled to its axis. Thereby the position of the laser spot in the video-endoscopic images changes according to the distance between the tip of the endoscope and the target structure. A mathematical function is defined by a calibration process and is used to calculate the distance between the tip of the endoscope and the target. The tracked tip of the endoscope and the calculated distance is used to visualize the laser spot in the registered radiologic data set. RESULTS: In comparison to the tracked instrument, the touch less target definition with the laser spot yielded in an over and above error of 0.12 mm. The overall application error in this experimental setup with a plastic head was 0.61 +/- 0.97 mm (95% CI -1.3 to +2.5 mm). CONCLUSION: Integrating a laser in an endoscope and then calculating the distance to a target structure by image processing of the video endoscopic images is accurate. This technology eliminates the need for tracked probes intraoperatively and therefore allows navigation to be integrated seamlessly in clinical routine. However, it is an additional chain link in the sequence of computer-assisted surgery thus influencing the application error. PMID- 23737123 TI - Pucker sign in proximal humeral fractures: implications on management. AB - Fracture of the surgical neck of humerus in young patients is a relatively rare injury. We reviewed the available material on the topic and identified puckering at the shoulder in high-energy fracture of the surgical neck as a finding which has been reported infrequently but signifies a need for open reduction. We present a review of the literature on the subject and our similar experience in two young males who had puckering and ecchymosis at the shoulder. PMID- 23737124 TI - New device for single-stage in-office secondary tracheoesophageal puncture: animal studies. AB - BACKGROUND: A new device is described for secondary tracheoesophageal puncture (TEP). We hypothesize that the device can be used to create the puncture, size, and insert the voice prosthesis in antegrade fashion in a single procedure suitable for office-based use. METHODS: A measurement and insertion device (MAID) was designed with the hypothesis in mind and tested on 3 pigs while they were under general anesthesia. RESULTS: The procedure was easy and successful in all 3 animals. The MAID allowed measurement of tracheoesophageal wall thickness and antegrade insertion of voice prosthesis with a single device. Transnasal esophagoscopy (TNE) allowed visualization of markings on the MAID within the esophagus to facilitate sizing. Intraesophageal visualization using TNE also enabled accurate positioning, reduced risk of posterior esophageal wall injury, and practically eliminated false passage formation. CONCLUSION: We believe the MAID can facilitate single-stage office-based secondary TEP in postlaryngectomy patients. PMID- 23737125 TI - Microwave-assisted synthesis and biological evaluation of some benzimidazole derivatives containing a 1,2,4-triazol ring. AB - A new series of 2-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole derivatives containing a 1,2,4-triazole ring were synthesized via microwave technique. This efficient procedure provides pure products within a few minutes. The newly synthesized compounds were confirmed by (1) H NMR and (13) C NMR spectra and they were screened for their lipase inhibition and antioxidant activities. Compounds 4a, 4b, 5a, and 5b showed very good scavenging activity. PMID- 23737126 TI - Characterization and source apportionment of water pollution in Jinjiang River, China. AB - Characterizing water quality and identifying potential pollution sources could greatly improve our knowledge about human impacts on the river ecosystem. In this study, fuzzy comprehensive assessment (FCA), pollution index (PI), principal component analysis (PCA), and absolute principal component score-multiple linear regression (APCS-MLR) were combined to obtain a deeper understanding of temporal spatial characterization and sources of water pollution with a case study of the Jinjiang River, China. Measurement data were obtained with 17 water quality variables from 20 sampling sites in the December 2010 (withered water period) and June 2011 (high flow period). FCA and PI were used to comprehensively estimate the water quality variables and compare temporal-spatial variations, respectively. Rotated PCA and receptor model (APCS-MLR) revealed potential pollution sources and their corresponding contributions. Application results showed that comprehensive application of various multivariate methods were effective for water quality assessment and management. In the withered water period, most sampling sites were assessed as low or moderate pollution with characteristics pollutants of permanganate index and total nitrogen (TN), whereas 90% sites were classified as high pollution in the high flow period with higher TN and total phosphorus. Agricultural non-point sources, industrial wastewater discharge, and domestic sewage were identified as major pollution sources. Apportionment results revealed that most variables were complicatedly influenced by industrial wastewater discharge and agricultural activities in withered water period and primarily dominated by agricultural runoff in high flow period. PMID- 23737127 TI - Planted floating bed performance in treatment of eutrophic river water. AB - The objective of the study was to treat eutrophic river water using floating beds and to identify ideal plant species for design of floating beds. Four parallel pilot-scale units were established and vegetated with Canna indica (U1), Accords calamus (U2), Cyperus alternifolius (U3), and Vetiveria zizanioides (U4), respectively, to treat eutrophic river water. The floating bed was made of polyethylene foam, and plants were vegetated on it. Results suggest that the floating bed is a viable alternative for treating eutrophic river water, especially for inhibiting algae growth. When the influent chemical oxygen demand (COD) varied from 6.53 to 18.45 mg/L, total nitrogen (TN) from 6.82 to 12.25 mg/L, total phosphorus (TP) from 0.65 to 1.64 mg/L, and Chla from 6.22 to 66.46 g/m(3), the removal of COD, TN, TP, and Chla was 15.3%-38.4%, 25.4%-48.4%, 16.1% 42.1%, and 29.9 %-88.1%, respectively. Ranked by removal performance, U1 was best, followed by U2, U3, and U4. In the floating bed, more than 60% TN and TP were removed by sedimentation; plant uptake was quantitatively of low importance with an average removal of 20.2% of TN and 29.4% of TP removed. The loss of TN (TP) was of the least importance. Compared with the other three, U1 exhibited better dissolved oxygen (DO) gradient distributions, higher DO levels, higher hydraulic efficiency, and a higher percentage of nutrient removal attributable to plant uptake; in addition, plant development and the volume of nutrient storage in the C. indica tissues outperformed the other three species. C. indica thus could be selected when designing floating beds for the Three Gorges Reservoir region of P. R. China. PMID- 23737128 TI - Identification of molecular-adsorption geometries and intermolecular hydrogen bonding configurations by in situ STM manipulation. AB - Don't be dim! By combining the technique with DFT calculations, STM manipulation was extended to the probing of intermolecular hydrogen-bonding configurations in self-assembled nanostructures. It was also possible to convert one configuration into another in a controlled fashion through the careful manipulation of a particular structural unit (see picture). PMID- 23737129 TI - Reply to the letter to the editor on: Use of bronchial blockers for single-lung ventilation in infants and children. PMID- 23737130 TI - Use of bronchial blockers for single-lung ventilation in infants and children. PMID- 23737131 TI - Complex fetal ovarian cysts cause problems even after regression. AB - PURPOSE: Fetal ovarian cysts' size and nature are considered as the most important factors for determining the treatment modality. When to perform an intervention and to which fetal ovarian cysts has not been clarified yet. We herein present our experience with fetal ovarian cysts. Materials and METHODS: The hospital records of 38 ovarian cysts (27 simple and 11 complex) were evaluated retrospectively. The prenatal and postnatal outcomes of the cysts were investigated. RESULTS: Prenatally at the 37 fetuses, 38 fetal ovarian cysts were evaluated retrospectively. There were 27 simple and 11 complex fetal ovarian cysts followed by prenatally and postnatally. None of the simple fetal ovarian cysts underwent in utero torsion. Postnatally, 23 simple ovarian cysts were regressed within 3 months. Four patients with simple ovarian cysts larger than 4 cm were operated. During follow-up period, seven complex ovarian cysts regressed, one complex ovarian cyst complicated with intestinal obstruction underwent surgery, and three complex ovarian cysts did not regress and they were operated. Three out of seven complex ovarian cysts that were initially regressed presented with intestinal obstruction and oophorectomy plus adhesiolysis were performed. Surgical treatment was required in 7 out of 11 (64%) complex ovarian cysts. CONCLUSION: Complex ovarian cysts lead to problems even after regression in the postnatal period and require operative intervention sooner or later. PMID- 23737132 TI - Long-term outcome of esophageal anastomosis. AB - After repair of esophageal atresia (EA) in a newborn, esophageal dysmotility presenting as dysphagia and symptomatic gastroesophageal reflux are common. Significant esophageal morbidity associated with EA extends into adulthood. In adulthood approximately one-fifth of the patients have developed epithelial metaplastic changes, one-third of these have intestinal metaplasia (Barrett esophagus). Surgical complications, increasing age, and impaired esophageal motility predict the development of epithelial metaplasia after repair of EA. To date, worldwide, eight cases of esophageal cancer have been reported in young adults treated for EA. Incidence of esophageal cancer after EA repair is very much likely to increase in the future. Life-long endoscopic follow-up is warranted in patients with EA. PMID- 23737133 TI - Vacuolar protein sorting 4B, an ATPase protein positively regulates the progression of NSCLC via promoting cell division. AB - Vacuolar protein sorting 4B (VPS4B), a member of ATPase family proteins, plays a crucial role in lysosome-dependent degradation. Recently, it was found that VPS4B could negatively regulate breast cancer progression through promoting lysosomal dependent degradation for EGFR. Nevertheless, other studies found that VPS4B was also essential for cell division and mitosis through insuring the maintenance of centrosome and spindle assembly. Thus, the role of VPS4B in cancer biology remains under debate. In this study, we analyzed the clinical significance of VPS4B in NSCLC. The expression of VPS4B was evaluated by Western blot in 8 paired fresh NSCLC tissues and immunohistochemistry on 105 paraffin-embedded slices. VPS4B was highly expressed in NSCLC and significantly associated with NSCLCs tumor size, histological differentiation, clinical stage and Ki-67. Besides, high VPS4B expression was an independent prognostic factor for NSCLC patients' poor survival. To determine whether VPS4B could regulate the proliferation of NSCLC cells, we knocked down the expression of VPS4B and analyzed the proliferation of A549 NSCLC cells using Western blot, CCK8 and flow cytometry assays, which together indicated that loss of VPS4B could inhibit cell cycle progress. These data suggest that VPS4B may promote the progression of NSCLC and be a biotarget for NSCLCs therapy. PMID- 23737134 TI - Differentiation of hUC-MSC into dopaminergic-like cells after transduction with hepatocyte growth factor. AB - Parkinson's disease (PD) is a common neurodegenerative condition causing significant disability and thus negatively impacting quality of life. The recent advent of stem cell-based therapy has heralded the prospect of a potential restorative treatment option for PD. In particular, mesenchymal stem cells derived from human umbilical cord (hUC-MSCs) have great potential for developing a therapeutic agent as such. Furthermore, hepatocyte growth factor (HGF), which shows mitogenic and morphogenetic activities in a variety of cells, including MSC, and may be implicated in the pathophysiology of PD. As such, HGF may represent a new therapeutic target for the disease. In this study, we successfully isolated and facilitated the transduction of an adenoviral vector expressing HGF (Ad-HGF) into isolated hUC-MSCs. Following transduction, the hUC MSCs can differentiate into dopaminergic neuron-like cells secreting dopamine, tyrosine hydroxylase, and dopamine transporter. Our data suggest that hUC-MSCs have the ability to differentiate into dopaminergic neurons after transduction with Ad-HGF, providing encouraging evidence to further explore this approach to the treatment of PD. PMID- 23737135 TI - The association between estrogen receptor alpha polymorphisms and the risk of prostate cancer in Slovak population. AB - The aim of our study was to evaluate the effect of two polymorphisms in the estrogen receptor alpha, PvuII and XbaI, on the development of prostate cancer within Slovak population, as well as their correlation with selected clinical characteristics. The study was performed using 311 prostate cancer patients and 256 healthy male controls. Both polymorphisms were significantly associated with higher risk of prostate cancer development. At the same time, the CC genotype of PvuII polymorphism (OR = 1.98; 95% CI 0.94-4.21; p = 0.05) and the AG genotype of XbaI polymorphism (OR = 1.74; 95% CI 1.0-3.02; p = 0.04) significantly contributed to the development of low-grade carcinoma, while the AG and GG genotypes of the XbaI polymorphism contributed mainly to the development of high grade prostate cancer (OR = 1.83; 95% CI 1.12-3.01; p = 0.01 and OR = 2.13; 95% CI 1.06-4.19; p = 0.03, respectively). Similarly, the AG and GG genotypes of XbaI polymorphism showed significant association with prostate cancer in patients with serum PSA level >=10 ng/ml. Both polymorphisms were found at the same time to be more frequent in patients diagnosed before the age of 60. We conclude on the basis of these results that PvuII and XbaI polymorphisms of estrogen receptor alpha might be associated with prostate cancer risk within Slovak population. Although this is a pilot study and, as such, more detailed investigations are needed to confirm the role of these polymorphisms in prostate cancer development and progression within said Slovak population, our results might still provide a valuable basis for further research with larger patient groups. PMID- 23737136 TI - The effect of partial outlet obstruction on calpain and phospholipase-2 activities: analyzed by severity and duration. AB - In an attempt to better understand the two pathways that lead to bladder decompensation following partial obstruction in rabbits one of which is caused by calcium-activated enzymes and the other by oxidative stress, calpain and phospholipase A2 (PLA2) biochemical assays were conducted to see how bladder decompensation is mediated by these two calcium-activated enzymes. Partial outlet obstructions of varying durations (4, 8, and 12 weeks plus controls) were performed on 32 New Zealand white rabbits. The rabbits were also grouped by severity: control, mild, intermediate, and severe. The activities of Calpain and PLA2 on the muscle tissue of the bladders were analyzed. A stronger correlation was seen between activities and severities as opposed to between activities and durations for both PLA2 and calpain. The activity for PLA2 increased dramatically from control to mild and then stayed constant for both intermediate and severe obstructions. Calpain activity increased steadily from control to mild to intermediate to severe. Based on the increase in levels of the calcium-dependent enzymes, it was clearly shown that calcium levels increased in all stages of bladder decompensation most notably with the mild obstructions. Based on previous studies in which nitrotyrosine and dinitrophenol levels did not increase in mildly obstructed rabbits, the calcium overload pathway may predominate in mild decompensation because cells in mildly obstructed bladders are better able to cope with oxidative stress than increased calcium levels. PMID- 23737137 TI - Matrix metalloproteinase-2 (MMP-2) generates soluble HLA-G1 by cell surface proteolytic shedding. AB - Human leukocyte antigen-G (HLA-G) molecules are non-classical HLA class I antigens with an important role in pregnancy immune regulation and inflammation control. Soluble HLA-G proteins can be generated through two mechanisms: alternative splicing and proteolytic release, which is known to be metalloprotease mediated. Among this class of enzymes, matrix metalloproteinases (MMPs) might be involved in the HLA-G1 membrane cleavage. Of particular interest are MMP-2 and MMP-9, which regulate the inflammatory process by cytokine and chemokine modulation. We evaluated the effect of MMP-9 and MMP-2 on HLA-G1 membrane shedding. In particular, we analyzed the in vitro effect of these two gelatinases on the secretion of HLA-G1 via proteolytic cleavage in 221-G1 transfected cell line, in JEG3 cell line, and in peripheral blood mononuclear cells. The results obtained by both cell lines showed the role of MMP-2 in HLA-G1 shedding. On the contrary, MMP-9 was not involved in this process. In addition, we identified three possible highly specific cleavage sites for MMP-2, whereas none were detected for MMP-9. This study suggests an effective link between MMP-2 and HLA-G1 shedding, increasing our knowledge on the regulatory machinery beyond HLA-G regulation in physiological and pathological conditions. PMID- 23737138 TI - Limited utility of tartrate-resistant acid phosphatase isoform 5b in assessing response to therapy in osteoporosis. AB - BACKGROUND: Tartrate-resistant acid phosphatase isoform 5b (TRACP5b) is a serum bone resorption marker. Our aim was to investigate its utility in monitoring metabolic bone disease. METHODS: Serum TRACP5b, C-terminal cross-linking telopeptide of type I collagen, urine N-terminal cross-linking telopeptide of type I collagen and free deoxypyridinoline were measured pre- and post-treatment with a parathyroid hormone analogue [PTH (1-34)] (n = 14) or a bisphosphonate (N BP) (n = 8). TRACP5b, bone alkaline phosphatase (bone ALP), 25-hydroxyvitamin D (25OHD) and parathyroid hormone (PTH) were measured in 100 osteoporosis patients on prolonged bisphosphonate therapy. RESULTS: Changes in TRACP5b were smaller in magnitude but mimicked those of other bone resorption markers. Absolute changes in TRACP5b and the other resorption markers correlated significantly (p < 0.001). In patients on long-term bisphosphonates, TRACP5b and bone ALP levels were not suppressed. Vitamin D status was consistent with the level of supplementation. CONCLUSION: TRACP5b has limited utility as a single marker of metabolic bone disease treatment. PMID- 23737140 TI - Presence of human papillomaviruses and p16 expression in hypopharyngeal cancer. AB - BACKGROUND: Patients with hypopharyngeal cancer have a 5-year survival of only 15% to 30%. Human papillomavirus (HPV) is a risk factor and a favorable prognostic factor for oropharyngeal carcinoma and p16 has been suggested as a surrogate marker for HPV-induced cancer. However, few studies have been performed on HPV and p16 in hypopharyngeal cancer. METHODS: One hundred nine pretreatment hypopharyngeal cancer biopsies were analyzed for presence of HPV and p16 overexpression, and the results were correlated to patient survival. RESULTS: Of 109 tumors, 7 were HPV-positive (4 HPV16) and 18 overexpressed p16. There was some correlation between survival and HPV status, but not with regard to p16 expression. Notably, all patients with HPV16-positive tumors, also overexpressing p16, lived tumor free for more than 3 years. CONCLUSION: Our results indicate that HPV-induced hypopharyngeal cancer is rare and that p16 is not a suitable biomarker for presence of HPV in this tumor type. PMID- 23737141 TI - DNABind: a hybrid algorithm for structure-based prediction of DNA-binding residues by combining machine learning- and template-based approaches. AB - Accurate prediction of DNA-binding residues has become a problem of increasing importance in structural bioinformatics. Here, we presented DNABind, a novel hybrid algorithm for identifying these crucial residues by exploiting the complementarity between machine learning- and template-based methods. Our machine learning-based method was based on the probabilistic combination of a structure based and a sequence-based predictor, both of which were implemented using support vector machines algorithms. The former included our well-designed structural features, such as solvent accessibility, local geometry, topological features, and relative positions, which can effectively quantify the difference between DNA-binding and nonbinding residues. The latter combined evolutionary conservation features with three other sequence attributes. Our template-based method depended on structural alignment and utilized the template structure from known protein-DNA complexes to infer DNA-binding residues. We showed that the template method had excellent performance when reliable templates were found for the query proteins but tended to be strongly influenced by the template quality as well as the conformational changes upon DNA binding. In contrast, the machine learning approach yielded better performance when high-quality templates were not available (about 1/3 cases in our dataset) or the query protein was subject to intensive transformation changes upon DNA binding. Our extensive experiments indicated that the hybrid approach can distinctly improve the performance of the individual methods for both bound and unbound structures. DNABind also significantly outperformed the state-of-art algorithms by around 10% in terms of Matthews's correlation coefficient. The proposed methodology could also have wide application in various protein functional site annotations. DNABind is freely available at http://mleg.cse.sc.edu/DNABind/. PMID- 23737143 TI - Evaluation of immobilization in external rotation after primary traumatic anterior shoulder dislocation: 5-year results. AB - BACKGROUND: It is still not clear which method is the most efficient for treating primary traumatic anterior shoulder dislocation. Immobilization in external rotation has become increasingly discussed within the last 10 years. The aim of this study was to evaluate the rate of recurrence and clinical outcome of the immobilization in external rotation after primary traumatic anterior dislocation within a midterm period of 5 years. Additionally, a summary of literature is given according to the present knowledge of this issue. METHODS: From May 2004 to May 2006, 28 patients with primary traumatic anterior shoulder dislocations were included in a prospective MRI-controlled study. After a follow-up of 5 years, the recurrence rate and clinical outcomes of the patients were evaluated using clinical scores (Constant and Murley score, Western Ontario Shoulder Instability Index, Rowe score). RESULTS: After 5 years, 26 patients (93 %; males, n = 25; female, n = 1; mean age, 29.3 years) were interviewed concerning re-dislocations. In the meantime, four patients (15 %) experienced a re-dislocation (o 12.2 months) after the end of the immobilization. Overall, 21 patients (75 %) were included in a clinical follow-up (CM score: o 92.8 points; Western Ontario Shoulder Instability Index: o 87 %; Rowe score (in 17 patients): o 94.2 points). Upon clinical examination, unidirectional anterior instability was found in one patient, which corresponds to an overall instability rate of 19 % within the examined patient population including the re-dislocations. CONCLUSIONS: Immobilization in external rotation shows satisfactory results after 5 years in regard to recurrence and instability rates and clinical outcomes. The data show that with immobilization in external rotation, re-dislocations occur within the first 2 years. PMID- 23737142 TI - Agent-based modeling: a systematic assessment of use cases and requirements for enhancing pharmaceutical research and development productivity. AB - A crisis continues to brew within the pharmaceutical research and development (R&D) enterprise: productivity continues declining as costs rise, despite ongoing, often dramatic scientific and technical advances. To reverse this trend, we offer various suggestions for both the expansion and broader adoption of modeling and simulation (M&S) methods. We suggest strategies and scenarios intended to enable new M&S use cases that directly engage R&D knowledge generation and build actionable mechanistic insight, thereby opening the door to enhanced productivity. What M&S requirements must be satisfied to access and open the door, and begin reversing the productivity decline? Can current methods and tools fulfill the requirements, or are new methods necessary? We draw on the relevant, recent literature to provide and explore answers. In so doing, we identify essential, key roles for agent-based and other methods. We assemble a list of requirements necessary for M&S to meet the diverse needs distilled from a collection of research, review, and opinion articles. We argue that to realize its full potential, M&S should be actualized within a larger information technology framework--a dynamic knowledge repository--wherein models of various types execute, evolve, and increase in accuracy over time. We offer some details of the issues that must be addressed for such a repository to accrue the capabilities needed to reverse the productivity decline. PMID- 23737144 TI - Proteomic analysis of the enzymes involved in the starch biosynthesis of maize with different endosperm type and characterization of the starch. AB - BACKGROUND: The characterization of starch maize with different endosperm type and the proteomic analysis of its biosynthetic enzymes at 20 and 50 days after pollination (DAP) was carried out. RESULTS: There were differences between both endosperm types at 20 DAP, mainly in starch accumulation, amylose content, granule size and crystallinity percentage, whereas at 50 DAP the differences found were not relevant in the case of starch content, granule size, chain length distribution and thermal properties. SSSI, SBEIIb and GBSSI enzymes were identified; however, SBEIIb was only identified in two samples: floury endosperm at 20 DAP and vitreous at 50 DAP. CONCLUSION: Starch did not show differences in its morphological or structural characteristics in either endosperm on reaching maturity. Starch biosynthetic enzymes identified by matrix-assisted laser desorption/ionization-time of flight did not show a relationship to starch structure. PMID- 23737145 TI - Neanderthal teeth from Moula-Guercy, Ardeche, France. AB - Here we describe dental remains from a Neanderthal fossil assemblage from Moula Guercy, France. Our report demonstrates that the Moula-Guercy hominid remains contribute important morphological, developmental, and behavioral data to understanding Neanderthal evolutionary history. We include gross comparative morphological descriptions and enamel surface microstructure and microwear data. These teeth reveal numerous characteristics that are diagnostic of Neanderthals and provide no evidence for the presence of any other hominid taxa. Enamel growth increment data from the Moula-Guercy specimens yield evidence of a Neanderthal pattern of development, although at the lower end of the range of variation. The presence of a significant number of linear enamel hypoplasias indicates that these individuals were stressed during childhood. Molar microwear data suggest that these Neanderthals did not differ significantly from modern humans in terms of the fracture properties of the food they were consuming. The incisor microwear and macro striations provide evidence that these individuals may have been using their anterior teeth as tools, similar to the practices of several modern human populations such as the Inuit, Ipiutak, and Australian Aboriginals, and reminiscent of evidence from other Neanderthals from Krapina, Croatia, as well as the 600,000 year old hominids from Sima de los Huesos, Spain. Am J Phys Anthropol 151:477-491, 2013.(c) 2013 Wiley Periodicals, Inc. PMID- 23737146 TI - Effect of partially protected butyrate used as feed additive on growth and intestinal metabolism in sea bream (Sparus aurata). AB - Butyrate is a short-chain fatty acid extensively used in animal nutrition since it promotes increases in body weight and other multiple beneficial effects on the intestinal tract. Although such effects have been demonstrated in several species, very few studies have assessed them in fish. On the other hand, little is known about the metabolic processes underlying these effects. In the present work, growth parameters and changes in more than 80 intestinal metabolites (nucleotides, amino acids and derivatives, glycolytic intermediates, redox coenzymes and lipid metabolism coenzymes) have been quantified in juvenile sea bream fed a butyrate-supplemented diet. Results showed a significant increase in the weight of fish receiving butyrate, while metabolomics provided some clues on the suggested effects of this feed additive. It seems that butyrate increased the availability of several essential amino acids and nucleotide derivatives. Also, the energy provision for enteric cells might have been enhanced by a decrease in glucose and amino acid oxidation related to the use of butyrate as fuel. Additionally, butyrate might have increased transmethylation activity. This work represents an advance in the knowledge of the metabolic consequences of using butyrate as an additive in fish diets. PMID- 23737147 TI - Pro-oxidant and antioxidant responses in the liver and kidney of wild Goodea gracilis and their relation with halomethanes bioactivation. AB - In mammals, it has been shown that halomethanes (HM) are bioactivated by enzymes such as CYP 2E1 and the theta isoform of GST to produce reactive metabolites. However, in fish, little information is available, although HM can form autochthonously in aquatic environments. This study assessed the effect of HM in dusky splitfin (Goodea gracilis) from three lakes of the Valley of Mexico by analysing specific HM biomarkers as well as a broad range of biomarkers. The concentration of HM was a function of its half-life (higher in deep waters), while its precursors and solar radiation are secondary factors that determine its concentration. The kidney showed higher basal metabolism than the liver, probably because of its function as a haematopoietic and filtration organ. Using integrated biological response version 2 (IBRv2), it was found that the hepatic and renal O2. content is a pro-oxidant force capable of inducing oxidative stress (ROOH, TBARS and RC=O). Early damage was found to be dependent on low concentrations of HM in Major Lake, whereas late damage was observed in fish exposed to higher concentrations of HM in Zumpango Lake and Ancient Lake. The activities of enzymes involved in antioxidant defence seemed to be inefficient. The quantitative assessment of biomarkers (ANOVA) and the estimate of parameter A obtained from IBRv2 provided different information. However, the data support the greater predictive power of IBRv2, but it requires a series of interrelated biomarkers to infer these possibilities. G. gracilis presents marked patterns of adaptation, which are dependant on the HM concentrations in environmental mixtures, although the response is complex and many toxicants could induce similar responses. PMID- 23737148 TI - Dietary fish oil replacement with palm or poultry oil increases fillet oxidative stability and decreases liver glutathione peroxidase activity in barramundi (Lates calcarifer). AB - Complete dietary fish oil replacement with palm or poultry oil in barramundi (Lates calcarifer) had no detrimental effects on growth or hepatosomatic index of juvenile fish up to an average size of ~50 g. However, it significantly decreased the omega-3 (n-3) long-chain polyunsaturated fatty acid content of the fish muscle (fillet) lipids. This was particularly true for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) which are recognised for their health beneficial effects in the human diet. As a result of their decreased EPA and DHA content, the peroxidation index of the muscle lipids was also decreased. This was associated with increased simulated retail storage shelf life as indicated by decreased thiobarbituric acid reactive substances in muscle samples from fish fed the palm or poultry oil-based diets. Concomitantly, glutathione peroxidase (GPx) activity, but not glutathione S-transferase (GST) activity or reduced glutathione concentration, was significantly reduced in the liver of barramundi fed the palm or poultry oil-based diets as compared with the fish fed the fish oil-based diet. Furthermore, GPx and GST activity were very low in muscle, much lower than in gastrointestinal tract, liver or swim bladder. Therefore, we propose that liver GPx activity may be a good predictor of fillet shelf life in barramundi and other fish species. PMID- 23737149 TI - Effects of pH on uranium uptake and oxidative stress responses induced in Arabidopsis thaliana. AB - Uranium (U) causes oxidative stress in Arabidopsis thaliana plants grown at pH 5.5. However, U speciation and its toxicity strongly depend on environmental parameters, for example pH. It is unknown how different U species determine U uptake and translocation within plants and how they might affect the oxidative defense mechanisms of these plants. The present study analyzed U uptake and oxidative stress-related responses in A. thaliana (Columbia ecotype) under contrasted U chemical speciation conditions. The 18-d-old seedlings were exposed for 3 d to 25 uM U in a nutrient solution of which the pH was adjusted to 4.5, 5.5, 6.5, or 7.5. Results indicate that there is a different rate of U uptake and translocation at the different pHs, with high uptake and low translocation at low pH and lower uptake but higher translocation at high pH. After U exposure, an increased glutathione reductase activity and total glutathione concentration were observed in U-exposed roots, pointing toward an important role for glutathione in the root defense system against U either by chelation or by antioxidative defense mechanisms. In leaves, antioxidative defense mechanisms were activated on U exposure, indicated by increased superoxide dismutase and catalase activity. As it seems that U toxicity is influenced by pH, it is important to consider site specific characteristics when making U risk assessments. PMID- 23737150 TI - Is pericardiocentesis needed for preventing hypoplastic lung in case with massive pericardial effusion? PMID- 23737152 TI - Prenatal screening for Down syndrome in pregnancies at risk for alpha thalassemia. PMID- 23737153 TI - A tin-free regioselective radical de-O-benzylation by an intramolecular hydrogen atom transfer on carbohydrate templates. PMID- 23737154 TI - Lower GI bleeding: epidemiology and management. AB - Gastrointestinal (GI) bleeding from the colon is a common reason for hospitalization and is becoming more common in the elderly. While most cases will cease spontaneously, patients with ongoing bleeding or major stigmata of hemorrhage require urgent diagnosis and intervention to achieve definitive hemostasis. Colonoscopy is the primary modality for establishing a diagnosis, risk stratification, and treating some of the most common causes of colonic bleeding, including diverticular hemorrhage which is the etiology in 30% of cases. Other interventions, including angiography and surgery, are usually reserved for instances of bleeding that cannot be stabilized or allow for adequate bowel preparation for colonoscopy. We discuss the colonoscopic diagnosis, risk stratification, and definitive treatment of colonic hemorrhage in patients presenting with severe hematochezia. PMID- 23737155 TI - [Cost evaluation of a model for integrated care of seriously mentally ill patients]. AB - BACKGROUND: The model for integrated care (IC) of those seriously mentally ill patients insured with the DAK-Gesundheit health insurance and various Betriebskrankenkassen (members of the VAG Mitte) from the regions Berlin, Brandenburg, Lower Saxony and Bremen allows a complex treatment in the outpatient setting which consists of psychiatrists, general practitioners and clinicians, psychiatric nursing, sociotherapy (only in Berlin), internal medicine quality circles, orientation on treatment guidelines and conceptual consensus with the relevant care clinics. The aim of the evaluation is to illustrate the health economic effects of IC. METHODS: In the period from 2006 to 2010 insured members of the DAK-Gesundheit and other involved health insurance companies with a serious mental illness, a significant impairment of social functioning and the need to be treated to avoid or substitute an in-hospital stay were included in the integrated care. The cost perspective was that of the statutory health insurance companies. For the health economic evaluation, the utilisation of continuous IC over 18 months was compared to the last 18 months prior to the inclusion in IC. The clinical findings were gathered quarterly during the IC using CGI (Clinical Global Impressions) and GAF (Global Assessment of Functioning Scale). RESULTS: A total of 1 364 patients receiving IC in 66 doctor's practices were documented (of those, 286 had diagnoses of ICD-10 F2, 724 ICD-10 F32-F39). The median age was 48.8 years, 69% were female. 24% had their own source of income, 40% were on the pension, and the rest of the patients were receiving transfer benefits in some form. In 54% of the cases IC was used to avoid an in hospital stay, in 46% of the cases to substitute an in-hospital stay. The degree of the CGI was 5.5 on average at the time of inclusion and the GAF score was 36.5 on average. The 226 patients with continuous documentation over 18 months were included in the health economic analysis. The number of days spent in hospital was lower during the IC period as compared to the 18 months prior to IV (11.8 vs. 28.6 days, p<0.001), the inpatient costs were lower (5 929 +/- 13 837 Euro vs. 2 458 +/- 6 940 Euro, p<0.001), the total was not significantly changed (7 777 +/- 14 263 Euro vs. 7 321 +/- 7 910 Euro, p=0.65). The substantial reduction of inpatient costs was compensated by the additional costs for medication and the costs of the complex outpatient care. Results were comparable for the 2 subgroups of schizophrenic/schizoaffective (n=66, 40.9 vs. 17.9 days, p=0.03; inpatient cost 9 009 +/- 15 677 Euro vs. 3 650 +/- 8 486 Euro, p=0.02; total expenditures 11 789 +/- 15 975 Euro vs. 9 623 +/- 9 262 Euro, p=0.33) and unipolar depressive patients (n=90, 29.8 vs. 9.8 days, p=0.006; inpatient cost 5 664 +/- 14 921 Euro vs. 1 967 +/- 5 276 Euro, p=0.02; total expenditures 7 146 +/- 15 164 Euro vs. 6 234 +/- 6 292 Euro, p=0.57). CONCLUSION: The IC was able to considerably reduce the utilisation of inpatient treatment through offering a complex range of services in the outpatient setting and allowed for a weight-shift in a low threshold comprehensive care structure without an increase in costs from the statutory health insurance companies' perspective. For a detailed description of clinical effects further studies are required. PMID- 23737156 TI - Computer-assisted diagnosis of monocular elevation deficiency. AB - Our aim is to demonstrate the benefits of using a computer model to support the clinical diagnosis of complex eye motility disorders. For diagnosis and differential diagnosis we compared the clinical data of a patient with suspected monocular elevation deficiency (MED) and the corresponding computer simulation with the simulations of rectus superior palsy, vertical Duane miswiring syndrome and two simulations of asymmetric gaze palsy. We used our biomechanical eye model SEE-KID for the computer simulations, which is partly based on ideas and concepts of the software system OrbitTM by Joel Miller. A young patient with the clinical characteristics of congenital MED, unilateral limitation of up-gaze above midline, with accompanying ptosis on the affected right side, mild head posture, chin-up position, partial binocular functions and Bell's phenomenon was examined. Pupillary situation, cover test, version and duction movements, saccadic test, Parks-Bielschowsky phenomenon and head tilt test, stereopsis test, Bagolini striated lens test and forced duction test were assessed. Up to the age of 5 years we used the prism cover test in the nine main gaze positions; later we switched to the Hess-Lancaster test for analyzing deviations. We also used our computer model for evaluating the diagnosis and for differential diagnosis of our patient. The simulation results from the SEE-KID model support the diagnosis of supranuclear MED, which can be achieved in the model by varying central innervations, contrary to the modification of muscle forces in the simulation of a rectus superior palsy. It is necessary to distinguish between supranuclear, nuclear, interstitial or peripheral lesions with regard to monocular elevation deficit. Simulations of patients with similar pathologies in a way that the simulations correspond to the patient-measured values support (beside the clinical signs) the diagnosis of supranuclear or infranuclear lesions. PMID- 23737157 TI - Cross-talk between the ligand- and DNA-binding domains of estrogen receptor. AB - Estrogen receptor alpha (ERalpha) is a hormone-responsive transcription factor that contains several discrete functional domains, including a ligand-binding domain (LBD) and a DNA-binding domain (DBD). Despite a wealth of knowledge about the behaviors of individual domains, the molecular mechanisms of cross-talk between LBD and DBD during signal transduction from hormone to DNA-binding of ERalpha remain elusive. Here, we apply a multiscale approach combining coarse grained (CG) and atomistically detailed simulations to characterize this cross talk mechanism via an investigation of the ERalpha conformational landscape. First, a CG model of ERalpha is built based on crystal structures of individual LBDs and DBDs, with more emphasis on their interdomain interactions. Second, molecular dynamics simulations are implemented and enhanced sampling is achieved via the "push-pull-release" strategy in the search for different LBD-DBD orientations. Third, multiple energetically stable ERalpha conformations are identified on the landscape. A key finding is that estradiol-bound LBDs utilize the well-described activation helix H12 to pack and stabilize LBD-DBD interactions. Our results suggest that the estradiol-bound LBDs can serve as a scaffold to position and stabilize the DBD-DNA complex, consistent with experimental observations of enhanced DNA binding with the LBD. Final assessment using atomic-level simulations shows that these CG-predicted models are significantly stable within a 15-ns simulation window and that specific pairs of lysine residues in close proximity at the domain interfaces could serve as candidate sites for chemical cross-linking studies. Together, these simulation results provide a molecular view of the role of ERalpha domain interactions in response to hormone binding. PMID- 23737158 TI - Randomized prospective crossover study of interstim lead wire placement with curved versus straight stylet. AB - AIMS: To assess whether InterStim lead wire placement with the curved stylet achieves motor response at lower amplitudes compared to straight stylet use. METHODS: This was a prospective, randomized, crossover study of patients scheduled for InterStim lead wire placement. All patients underwent lead wire testing with both the curved and straight stylets. Patients were randomized to determine stylet order, and then crossed-over to the alternate. Intra operatively, the amplitude achieving motor response at each electrode was recorded. The stylet with lowest overall amplitudes was used for final placement. Primary outcome measure was amplitude requirement in the two deepest (0 and 1) electrodes. Secondary outcomes included amplitudes at the number 2 and 3 electrodes, combined amplitudes, stylet order, and adverse outcomes. RESULTS: Forty-two patients were enrolled, 40 of whom were included in the final analysis. Mean age was 69 years (SD = 12.8) and mean BMI 27 (SD = 5.6). Indications for placement included: urge urinary incontinence (N = 26), urge/frequency (N = 25), non-obstructive urinary retention (N = 5), and fecal incontinence (N = 10). There were no significant differences between randomized groups. Regardless of order, the curved stylet achieved a motor response at lower amplitudes in the deepest electrodes (P < 0.001). Combined amplitudes of all electrodes were also significantly lower with the curved stylet (P < 0.001). Subsequently, 88% underwent final "optimal" placement with curved stylet (N = 35). CONCLUSIONS: The curved stylet for InterStim lead wire placement consistently achieved motor response at lower amplitudes. A brief intra-operative exchange of stylets represents a minor procedural alteration that could maximize Implantable Pulse Generator battery life and facilitate programming. PMID- 23737159 TI - A hypothetical protocol for the provisional use of perfusion imaging with exercise stress testing. AB - BACKGROUND: Previous literature suggests that the results of myocardial perfusion imaging (MPI) add little to the prognosis of patients who exercise >10 metabolic equivalents (METS) during stress testing. With this in mind, we attempted to determine if a provisional injection protocol could be developed in which a patient would not receive an injection of radioisotope if adequate exercise was achieved without symptoms and a negative ECG response. This protocol would save a substantial amount of time, radiation exposure, and cost. METHODS: All patients who underwent a stress SPECT MPI over a 6.5-year period from 2004 to 2010 were included. Patients who would have been considered for a standby injection protocol were: exercise stress, age < 65, no known coronary artery disease (CAD), and an interpretable ECG. Patients were retrospectively divided into two groups based on whether they would have received radioisotope or not. Criteria for not injecting included a maximal predicted heart rate >= 85%, >=10 METS of exercise, no symptoms of chest pain or shortness of breath, and no ECG changes (ST depression or arrhythmia). The two groups were then compared based on MPI results and all-cause mortality derived from the Social Security Death Index. RESULTS: A total of 24,689 patients underwent SPECT MPI during this period, and 5,352 would have been eligible for a provisional injection protocol. There were 3,791 (70.8%), who would have been injected and 1,561 (29.2%), who would not have been. Perfusion results were abnormal in 5.9% of non-injected group compared to 14.4% in those who would have been injected. After a mean follow-up of 60.6 +/- 21.4 months, 1.1% had died in the non-injected cohort compared to 2.2% in the injected group. CONCLUSION: A provisional injection protocol defined as age < 65, normal rest ECG, no history of CAD, and high level exercise with a negative ECG response and no symptoms has a very low 5-year all-cause mortality and low yield of MPI. If adopted it would decrease radiation exposure and save time and health care costs without jeopardizing prognosis. PMID- 23737160 TI - High-efficiency SPECT MPI: comparison of automated quantification, visual interpretation, and coronary angiography. AB - BACKGROUND: Recently introduced high-efficiency (HE) SPECT cameras with solid state CZT detectors have been shown to decrease imaging time and reduce radiation exposure to patients. An automated, computer-derived quantification of HE MPI has been shown to correlate well with coronary angiography on one HE SPECT camera system (D-SPECT), but has not been compared to visual interpretation on any of the HE SPECT platforms. METHODS: Patients undergoing a clinically indicated Tc 99m sestamibi HE SPECT (GE Discovery 530c with supine and prone imaging) study over a 1-year period followed by a coronary angiogram within 2 months were included. Only patients with a history of CABG surgery were excluded. Both MPI studies and coronary angiograms were reinterpreted by blinded readers. One hundred and twenty two very low (risk of CAD < 5%) or low (risk of CAD < 10%) likelihood subjects with normal myocardial perfusion were used to create normal reference limits. Computer-derived quantification of the total perfusion deficit at stress and rest was obtained with QPS software. The visual and automated MPI quantification were compared to coronary angiography (>=70% luminal stenosis) by receiver operating curve (ROC) analysis. RESULTS: Of the 3,111 patients who underwent HE SPECT over a 1-year period, 160 patients qualified for the correlation study (66% male, 52% with a history of CAD). The ROC area under the curve (AUC) was similar for both the automated and the visual interpretations using both supine only and combined supine and prone images (0.69-0.74). Using thresholds determined from sensitivity and specificity curves, the automated reads showed higher specificity (59%-67% vs 27%-60%) and lower sensitivity (71% 72% vs 79%-93%) than the visual reads. By including prone images sensitivity decreased slightly but specificity increased for both. By excluding patients with known CAD and cardiomyopathies, AUC and specificity increased for both techniques (0.72-0.82). The use of a difference score to evaluate ischemic burden resulted in lower sensitivities but higher specificities for both automated and visual quantification. There was good agreement between the visual interpretation and automated quantification in the entire cohort of 160 unselected consecutive patients (r = 0.70-0.81, P < .0001). CONCLUSIONS: Automated and visual quantification of high-efficiency SPECT MPI with the GE Discovery camera provides similar overall diagnostic accuracy when compared to coronary angiography. There was good correlation between the two methods of assessment. Combined supine and prone stress imaging provided the best diagnostic accuracy. PMID- 23737161 TI - Comparison of attenuation, dual-energy-window, and model-based scatter correction of low-count SPECT to 82Rb PET/CT quantified myocardial perfusion scores. AB - BACKGROUND: New reconstruction algorithms allow reduction in acquisition times or the amount of injected radioactivity. We examined the impact of different corrections on low-count clinical SPECT myocardial perfusion images (MPI) and compared to (82)Rb PET/CT. We compared no corrections (NC) to attenuation correction (AC) with and without scatter correction by either a dual-energy window (AC-DEW) or model-based (AC-ESSE) approach. All reconstructions included resolution recovery. METHODS: 56 patients were imaged using a standard rest/stress Tc-99m-tetrofosmin MPI SPECT/CT protocol with an additional half-time acquisition. A (82)Rb-rest/stress PET/CT MPI was acquired within 4 weeks. Reconstruction methods were compared using summed rest/stress/difference scores from an objective algorithm (SRS/SSS/SDS). RESULTS: The SRS and SSS for NC were significantly (P < .01) higher than for AC, but well correlated (r >= 0.87). The correlation in SRS/SSS among AC, AC-DEW, and AC-ESSE was excellent (r >= 0.98). AC-ESSE and AC-DEW had higher SRS (P <= .05) than AC, but the SDS values were not significantly different. Concordance with PET normal/abnormal classification was 76% for NC and >=85% for the AC methods. CONCLUSION: AC significantly improves the accuracy of low-count myocardial perfusion SPECT half-time imaging for the detection of disease compared to NC. Compared to PET, there was no significant difference among AC, AC-DEW, and AC-ESSE. PMID- 23737162 TI - Highly athletic terrestrial mammals: horses and dogs. AB - Evolutionary forces drive beneficial adaptations in response to a complex array of environmental conditions. In contrast, over several millennia, humans have been so enamored by the running/athletic prowess of horses and dogs that they have sculpted their anatomy and physiology based solely upon running speed. Thus, through hundreds of generations, those structural and functional traits crucial for running fast have been optimized. Central among these traits is the capacity to uptake, transport and utilize oxygen at spectacular rates. Moreover, the coupling of the key systems--pulmonary-cardiovascular-muscular is so exquisitely tuned in horses and dogs that oxygen uptake response kinetics evidence little inertia as the animal transitions from rest to exercise. These fast oxygen uptake kinetics minimize Intramyocyte perturbations that can limit exercise tolerance. For the physiologist, study of horses and dogs allows investigation not only of a broader range of oxidative function than available in humans, but explores the very limits of mammalian biological adaptability. Specifically, the unparalleled equine cardiovascular and muscular systems can transport and utilize more oxygen than the lungs can supply. Two consequences of this situation, particularly in the horse, are profound exercise-induced arterial hypoxemia and hypercapnia as well as structural failure of the delicate blood-gas barrier causing pulmonary hemorrhage and, in the extreme, overt epistaxis. This chapter compares and contrasts horses and dogs with humans with respect to the structural and functional features that enable these extraordinary mammals to support their prodigious oxidative and therefore athletic capabilities. PMID- 23737163 TI - Determinants of pulmonary blood flow distribution. AB - The primary function of the pulmonary circulation is to deliver blood to the alveolar capillaries to exchange gases. Distributing blood over a vast surface area facilitates gas exchange, yet the pulmonary vascular tree must be constrained to fit within the thoracic cavity. In addition, pressures must remain low within the circulatory system to protect the thin alveolar capillary membranes that allow efficient gas exchange. The pulmonary circulation is engineered for these unique requirements and in turn these special attributes affect the spatial distribution of blood flow. As the largest organ in the body, the physical characteristics of the lung vary regionally, influencing the spatial distribution on large-, moderate-, and small-scale levels. PMID- 23737164 TI - Hypoxic pulmonary hypertension of the newborn. AB - Hypoxic pulmonary hypertension of the newborn is characterized by elevated pulmonary vascular resistance and pressure due to vascular remodeling and increased vessel tension secondary to chronic hypoxia during the fetal and newborn period. In comparison to the adult, the pulmonary vasculature of the fetus and the newborn undergoes tremendous developmental changes that increase susceptibility to a hypoxic insult. Substantial evidence indicates that chronic hypoxia alters the production and responsiveness of various vasoactive agents such as endothelium-derived nitric oxide, endothelin-1, prostanoids, platelet activating factor, and reactive oxygen species, resulting in sustained vasoconstriction and vascular remodeling. These changes occur in most cell types within the vascular wall, particularly endothelial and smooth muscle cells. At the cellular level, suppressed nitric oxide-cGMP signaling and augmented RhoA-Rho kinase signaling appear to be critical to the development of hypoxic pulmonary hypertension of the newborn. PMID- 23737165 TI - Growth factors and cytokines in acute lung injury. AB - Cytokines and growth factors play an integral role in the maintenance of immune homeostasis, the generation of protective immunity, and lung reparative processes. However, the dysregulated expression of cytokines and growth factors in response to infectious or noxious insults can initiate and perpetuate deleterious lung inflammation and fibroproliferation. In this article, we will comprehensively review the contribution of individual cytokines and growth factors and cytokine networks to key pathophysiological events in human and experimental acute lung injury (ALI), including inflammatory cell recruitment and activation, alveolar epithelial injury and repair, angiogenesis, and matrix deposition and remodeling. The application of cytokines/growth factors as prognostic indicators and therapeutic targets in human ALI is explored. PMID- 23737166 TI - Gaseous therapeutics in acute lung injury. AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain major causes of morbidity and mortality in critical care medicine despite advances in therapeutic modalities. ALI can be associated with sepsis, trauma, pharmaceutical or xenobiotic exposures, high oxygen therapy (hyperoxia), and mechanical ventilation. Of the small gas molecules (NO, CO, H2S) that arise in human beings from endogenous enzymatic activities, the physiological significance of NO is well established, whereas that of CO or H2S remains controversial. Recent studies have explored the potential efficacy of inhalation therapies using these small gas molecules in animal models of ALI. NO has vasoregulatory and redox-active properties and can function as a selective pulmonary vasodilator. Inhaled NO (iNO) has shown promise as a therapy in animal models of ALI including endotoxin challenge, ischemia/reperfusion (I/R) injury, and lung transplantation. CO, another diatomic gas, can exert cellular tissue protection through antiapoptotic, anti-inflammatory, and antiproliferative effects. CO has shown therapeutic potential in animal models of endotoxin challenge, oxidative lung injury, I/R injury, pulmonary fibrosis, ventilator-induced lung injury, and lung transplantation. H2S, a third potential therapeutic gas, can induce hypometabolic states in mice and can confer both pro- and anti-inflammatory effects in rodent models of ALI and sepsis. Clinical studies have shown variable results for the efficacy of iNO in lung transplantation and failure for this therapy to improve mortality in ARDS patients. No clinical studies have been conducted with H2S. The clinical efficacy of CO remains unclear and awaits further controlled clinical studies in transplantation and sepsis. PMID- 23737169 TI - Hyperbaric conditions. AB - Exposure to elevated ambient pressure (hyperbaric conditions) occurs most commonly in underwater diving, during which respired gas density and partial pressures, work of breathing, and physiological dead space are all increased. There is a tendency toward hypercapnia during diving, with several potential causes. Most importantly, there may be reduced responsiveness of the respiratory controller to rising arterial CO2, leading to hypoventilation and CO2 retention. Contributory factors may include elevated arterial PO2, inert gas narcosis and an innate (but variable) tendency of the respiratory controller to sacrifice tight control of arterial CO2 when work of breathing increases. Oxygen is usually breathed at elevated partial pressure under hyperbaric conditions. Oxygen breathing at modest hyperbaric pressure is used therapeutically in hyperbaric chambers to increase arterial carriage of oxygen and diffusion into tissues. However, to avoid cerebral and pulmonary oxygen toxicity during underwater diving, both the magnitude and duration of oxygen exposure must be managed. Therefore, most underwater diving is conducted breathing mixtures of oxygen and inert gases such as nitrogen or helium, often simply air. At hyperbaric pressure, tissues equilibrate over time with high inspired inert gas partial pressure. Subsequent decompression may reduce ambient pressure below the sum of tissue gas partial pressures (supersaturation) which can result in tissue gas bubble formation and potential injury (decompression sickness). Risk of decompression sickness is minimized by scheduling time at depth and decompression rate to limit tissue supersaturation or size and profusion of bubbles in accord with models of tissue gas kinetics and bubble formation and growth. PMID- 23737170 TI - Exercise: Kinetic considerations for gas exchange. AB - The activities of daily living typically occur at metabolic rates below the maximum rate of aerobic energy production. Such activity is characteristic of the nonsteady state, where energy demands, and consequential physiological responses, are in constant flux. The dynamics of the integrated physiological processes during these activities determine the degree to which exercise can be supported through rates of O2 utilization and CO2 clearance appropriate for their demands and, as such, provide a physiological framework for the notion of exercise intensity. The rate at which O2 exchange responds to meet the changing energy demands of exercise--its kinetics--is dependent on the ability of the pulmonary, circulatory, and muscle bioenergetic systems to respond appropriately. Slow response kinetics in pulmonary O2 uptake predispose toward a greater necessity for substrate-level energy supply, processes that are limited in their capacity, challenge system homeostasis and hence contribute to exercise intolerance. This review provides a physiological systems perspective of pulmonary gas exchange kinetics: from an integrative view on the control of muscle oxygen consumption kinetics to the dissociation of cellular respiration from its pulmonary expression by the circulatory dynamics and the gas capacitance of the lungs, blood, and tissues. The intensity dependence of gas exchange kinetics is discussed in relation to constant, intermittent, and ramped work rate changes. The influence of heterogeneity in the kinetic matching of O2 delivery to utilization is presented in reference to exercise tolerance in endurance-trained athletes, the elderly, and patients with chronic heart or lung disease. PMID- 23737167 TI - Pulmonary vascular disease related to hemodynamic stress in the pulmonary circulation. AB - Hemodynamic stress in the pulmonary vessel is directly linked to the development of vascular remodeling and dysfunction, ultimately leading to pulmonary hypertension. Recently, some advances have been made in our molecular understanding of the exogenous upstream stimuli that initiate hemodynamic pertubations as well as the downstream vasoactive effectors that control these responses. However, much still remains unknown regarding how these complex signaling pathways connect in order to result in these characteristic pathophysiological changes. This chapter will describe our current understanding of and needed areas of research into the clinical, physiological, and molecular changes associated with pressure/volume overload in the pulmonary circulation. PMID- 23737171 TI - Distribution of perfusion. AB - Local driving pressures and resistances within the pulmonary vascular tree determine the distribution of perfusion in the lung. Unlike other organs, these local determinants are significantly influenced by regional hydrostatic and alveolar pressures. Those effects on blood flow distribution are further magnified by the large vertical height of the human lung and the relatively low intravascular pressures in the pulmonary circulation. While the distribution of perfusion is largely due to passive determinants such as vascular geometry and hydrostatic pressures, active mechanisms such as vasoconstriction induced by local hypoxia can also redistribute blood flow. This chapter reviews the determinants of regional lung perfusion with a focus on vascular tree geometry, vertical gradients induced by gravity, the interactions between vascular and surrounding alveolar pressures, and hypoxic pulmonary vasoconstriction. While each of these determinants of perfusion distribution can be examined in isolation, the distribution of blood flow is dynamically determined and each component interacts with the others so that a change in one region of the lung influences the distribution of blood flow in other lung regions. PMID- 23737168 TI - The adventitia: Essential role in pulmonary vascular remodeling. AB - A rapidly emerging concept is that the vascular adventitia acts as a biological processing center for the retrieval, integration, storage, and release of key regulators of vessel wall function. It is the most complex compartment of the vessel wall and comprises a variety of cells including fibroblasts, immunomodulatory cells, resident progenitor cells, vasa vasorum endothelial cells, and adrenergic nerves. In response to vascular stress or injury, resident adventitial cells are often the first to be activated and reprogrammed to then influence tone and structure of the vessel wall. Experimental data indicate that the adventitial fibroblast, the most abundant cellular constituent of adventitia, is a critical regulator of vascular wall function. In response to vascular stresses such as overdistension, hypoxia, or infection, the adventitial fibroblast is activated and undergoes phenotypic changes that include proliferation, differentiation, and production of extracellular matrix proteins and adhesion molecules, release of reactive oxygen species, chemokines, cytokines, growth factors, and metalloproteinases that, collectively, affect medial smooth muscle cell tone and growth directly and that stimulate recruitment and retention of circulating inflammatory and progenitor cells to the vessel wall. Resident dendritic cells also participate in "sensing" vascular stress and actively communicate with fibroblasts and progenitor cells to simulate repair processes that involve expansion of the vasa vasorum, which acts as a conduit for further delivery of inflammatory/progenitor cells. This review presents the current evidence demonstrating that the adventitia acts as a key regulator of pulmonary vascular wall function and structure from the "outside in." PMID- 23737173 TI - Mechanical and structural plasticity. AB - Excessive narrowing of the airways due to airway smooth muscle (ASM) contraction is a major cause of asthma exacerbation. ASM is therefore a direct target for many drugs used in asthma therapy. The contractile mechanism of smooth muscle is not entirely clear. A major advance in the field in the last decade was the recognition and appreciation of the unique properties of smooth muscle- mechanical and structural plasticity, characterized by the muscle's ability to rapidly alter the structure of its contractile apparatus and cytoskeleton and adapt to the mechanically dynamic environment of the lung. This article describes a possible mechanism for smooth muscle to adapt and function over a large length range by adding or subtracting contractile units in series spanning the cell length; it also describes a mechanism by which actin-myosin-actin connectivity might be influenced by thin and thick filament lengths, thus altering the muscle response to mechanical perturbation. The new knowledge is extremely useful for our understanding of ASM behavior in the lung and could provide new and more effective targets for drugs aimed at relaxing the muscle or keeping the muscle from excessive shortening in the asthmatic airways. PMID- 23737174 TI - Smooth muscle cell hypertrophy, proliferation, migration and apoptosis in pulmonary hypertension. AB - Pulmonary hypertension is a multifactorial disease characterized by sustained elevation of pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP). Central to the pathobiology of this disease is the process of vascular remodelling. This process involves structural and functional changes to the normal architecture of the walls of pulmonary arteries (PAs) that lead to increased muscularization of the muscular PAs, muscularization of the peripheral, previously nonmuscular, arteries of the respiratory acinus, formation of neointima, and formation of plexiform lesions. Underlying or contributing to the development of these lesions is hypertrophy, proliferation, migration, and resistance to apoptosis of medial cells and this article is concerned with the cellular and molecular mechanisms of these processes. In the first part of the article we focus on the concept of smooth muscle cell phenotype and the difficulties surrounding the identification and characterization of the cell/cells involved in the remodelling of the vessel media and we review the general mechanisms of cell hypertrophy, proliferation, migration and apoptosis. Then, in the larger part of the article, we review the factors identified thus far to be involved in PH intiation and/or progression and review and discuss their effects on pulmonary artery smooth muscle cells (PASMCs) the predominant cells in the tunica media of PAs. PMID- 23737175 TI - Pulmonary circulation in extreme environments. AB - The pulmonary circulation is subject to direct challenge from both altered pressure and altered gravity. To efficiently exchange gas, the pulmonary capillaries must be extremely thin-walled and directly exposed to the alveolar space. Thus, alterations in ambient pressure are directly transmitted to the capillaries with the potential to alter pulmonary blood flow. To produce ventilation, the mammalian lung must expand and contract, and so it is a highly compliant structure. Thus, because the capillaries are contained in the alveolar walls, alterations in the apparent gravitational force deform the lung and directly affect pulmonary blood flow both through lung deformation and through changes in the hydrostatic pressure distribution in the lung. High gravitational forces are encountered in the aviation environment, while gravity is absent in spaceflight. Diving subjects the lung to large increases in ambient pressure, while large reductions in pressure occur, often associated with alterations in oxygen level and airway pressure, in aviation. This article reviews the effects of alterations in both gravity and ambient pressure on the pulmonary circulation. PMID- 23737176 TI - Gas exchange under altered gravitational stress. AB - Efficient gas exchange in the lung depends on the matching of ventilation and perfusion. However, the human lung is a readily deformable structure and as a result gravitational stresses generate gradients in both ventilation and perfusion. Nevertheless, the lung is capable of withstanding considerable change in the applied gravitational load before pulmonary gas exchange becomes impaired. The postural changes that are part of the everyday existence for most bipedal species are well tolerated, as is the removal of gravity (weightlessness). Increases in the applied gravitational load result only in a large impairment in pulmonary gas exchange above approximately three times that on the ground, at which point the matching of ventilation to perfusion is so impaired that efficient gas exchange is no longer possible. Much of the tolerance of the lung to alterations in gravitation stress comes from the fact that ventilation and perfusion are inextricably coupled. Deformations in the lung that alter ventilation necessarily alter perfusion, thus maintaining a degree of matching and minimizing the disruption in ventilation to perfusion ratio and thus gas exchange. PMID- 23737172 TI - Environmental perturbations: Obesity. AB - Obesity currently affects about one-third of the U.S. population, while another one-third is overweight. The importance of obesity for certain conditions such as heart disease and type 2 diabetes is well appreciated. The effects of obesity on the respiratory system have received less attention and are the subject of this article. Obesity alters the static mechanical properties of the respiratory system leading to a reduction in the functional residual capacity (FRC) and the expiratory reserve volume (ERV). There is substantial variability in the effects of obesity on FRC and ERV, at least some of which is related to the location rather than the total mass of adipose tissue. Obesity also results in airflow obstruction, which is only partially attributable to breathing at low lung volume, and can also promote airway hyperresponsiveness and asthma. Hypoxemia is common is obesity and correlates well with FRC, as well as with measures of abdominal obesity. However, obese subjects are usually eucapnic, indicating that hypoventilation is not a common cause of their hypoxemia. Instead, hypoxemia results from ventilation-perfusion mismatch caused by closure of dependent airways at FRC. Many obese subjects complain of dyspnea either at rest or during exertion, and the dyspnea score also correlates with reductions in FRC and ERV. Weight reduction should be encouraged in any symptomatic obese individual, since virtually all of the respiratory complications of obesity improve with even moderate weight loss. PMID- 23737177 TI - Endothelial cell energy metabolism, proliferation, and apoptosis in pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) is a fatal disease characterized by impaired regulation of pulmonary hemodynamics and excessive growth and dysfunction of the endothelial cells that line the arteries in PAH lungs. Establishment of methods for culture of pulmonary artery endothelial cells from PAH lungs has provided the groundwork for mechanistic translational studies that confirm and extend findings from model systems and spontaneous pulmonary hypertension in animals. Endothelial cell hyperproliferation, survival, and alterations of biochemical-metabolic pathways are the unifying endothelial pathobiology of the disease. The hyperproliferative and apoptosis-resistant phenotype of PAH endothelial cells is dependent upon the activation of signal transducer and activator of transcription (STAT) 3, a fundamental regulator of cell survival and angiogenesis. Animal models of PAH, patients with PAH, and human PAH endothelial cells produce low nitric oxide (NO). In association with the low level of NO, endothelial cells have reduced mitochondrial numbers and cellular respiration, which is associated with more than a threefold increase in glycolysis for energy production. The shift to glycolysis is related to low levels of NO and likely to the pathologic expression of the prosurvival and proangiogenic signal transducer, hypoxia-inducible factor (HIF)-1, and the reduced mitochondrial antioxidant manganese superoxide dismutase (MnSOD). In this article, we review the phenotypic changes of the endothelium in PAH and the biochemical mechanisms accounting for the proliferative, glycolytic, and strongly proangiogenic phenotype of these dysfunctional cells, which consequently foster the panvascular progressive pulmonary remodeling in PAH. PMID- 23737178 TI - Spatial distribution of ventilation and perfusion: mechanisms and regulation. AB - With increasing spatial resolution of regional ventilation and perfusion, it has become more apparent that ventilation and blood flow are quite heterogeneous in the lung. A number of mechanisms contribute to this regional variability, including hydrostatic gradients, pleural pressure gradients, lung compressibility, and the geometry of the airway and vascular trees. Despite this marked heterogeneity in both ventilation and perfusion, efficient gas exchange is possible through the close regional matching of the two. Passive mechanisms, such as the shared effect of gravity and the matched branching of vascular and airway trees, create efficient gas exchange through the strong correlation between ventilation and perfusion. Active mechanisms that match local ventilation and perfusion play little if no role in the normal healthy lung but are important under pathologic conditions. PMID- 23737179 TI - Hibernation and gas exchange. AB - Hibernation in endotherms and ectotherms is characterized by an energy-conserving metabolic depression due to low body temperatures and poorly understood temperature-independent mechanisms. Rates of gas exchange are correspondly reduced. In hibernating mammals, ventilation falls even more than metabolic rate leading to a relative respiratory acidosis that may contribute to metabolic depression. Breathing in some mammals becomes episodic and in some small mammals significant apneic gas exchange may occur by passive diffusion via airways or skin. In ectothermic vertebrates, extrapulmonary gas exchange predominates and in reptiles and amphibians hibernating underwater accounts for all gas exchange. In aerated water diffusive exchange permits amphibians and many species of turtles to remain fully aerobic, but hypoxic conditions can challenge many of these animals. Oxygen uptake into blood in both endotherms and ectotherms is enhanced by increased affinity of hemoglobin for O2 at low temperature. Regulation of gas exchange in hibernating mammals is predominately linked to CO2/pH, and in episodic breathers, control is principally directed at the duration of the apneic period. Control in submerged hibernating ectotherms is poorly understood, although skin-diffusing capacity may increase under hypoxic conditions. In aerated water blood pH of frogs and turtles either adheres to alphastat regulation (pH ~8.0) or may even exhibit respiratory alkalosis. Arousal in hibernating mammals leads to restoration of euthermic temperature, metabolic rate, and gas exchange and occurs periodically even as ambient temperatures remain low, whereas body temperature, metabolic rate, and gas exchange of hibernating ectotherms are tightly linked to ambient temperature. PMID- 23737180 TI - Carbon monoxide transport and actions in blood and tissues. AB - This chapter will discuss the transport of carbon monoxide (CO) from the environment to the tissues of the body and physiological effects on blood-borne cells and perivascular tissues. It will review the physiology of CO exchange between alveolar gas and pulmonary capillary blood, dynamics of hemoglobin transport, the effects of CO on blood elements, and the effects of CO on extravascular tissues at the capillary bed. Effects of CO from exogenous and endogenous sources on the activities of different proteins will be reviewed. Because CO binds competitively to heme-containing proteins its effects depend on CO concentration relative to alternative ligands. Therefore, some discussion is devoted to how nitric oxide and hydrogen sulfide influence CO effects. PMID- 23737181 TI - Diving mammals. AB - The ability of diving mammals to forage at depth on a breath hold of air is dependent on gas exchange, both in the lung and in peripheral tissues. Anatomical and physiological adaptations in the respiratory system, cardiovascular system, blood and peripheral tissues contribute to the remarkable breath-hold capacities of these animals. The end results of these adaptations include efficient ventilation, enhanced oxygen storage, regulated transport and delivery of respiratory gases, extreme hypoxemic/ischemic tolerance, and pressure tolerance. PMID- 23737182 TI - Genomics and proteomics of pulmonary vascular disease. AB - Study of RNA and proteins in cells of both normal and diseased tissues is providing researchers with new knowledge of disease pathologies. While still in its early stages, high-throughput expression analysis is improving our understanding of the pathogenesis of pulmonary arterial hypertension (PAH). While many studies have used microarray and proteomic analyses as "hypothesis generating" tools, the technologies also have potential to identify and quantify biomarkers of disease. To date, many of the published studies have examined gene expression profiles of tissue biopsies, others have utilized cells from peripheral blood. Microarray technology has been employed successfully in the investigation of a diverse array of human diseases. The potential of high throughput expression analysis to improve our understanding of the pathogenesis of PAH is highlighted in this review. Proteomic studies of PAH and pulmonary vascular diseases in general have been little utilized thus far. To date, such studies are few and no consistent biomarker has emerged from studies of either plasma or blood cells from idiopathic pulmonary arterial hypertension (IPAH) patients. The studies of both lung tissue and lymphocytes are perhaps more revealing and suggest that changes in the cytoskeletal machinery may play a role in the pathogenesis of idiopathic pulmonary arterial hypertension. The oncology literature has demonstrated the utility of gene microarray analysis to predict important outcomes such as response to therapy and survival. It is likely that in the near future, gene microarrays and proteomic analyses will also be employed in a pharmacogenomics approach in PAH, helping to identify the most appropriate therapies for individual patients. PMID- 23737183 TI - Microgravity. AB - Gravity profoundly affects the overall mechanics of the respiratory system. Functional residual capacity, when measured in sustained microgravity, is intermediate to that present in the standing and supine postures in 1G, consistent with early modeling studies. This change occurs almost exclusively through changes in the abdominal compliance and thus in the volume of the abdominal compartment, with the rib cage being relatively unaffected by gravity. Microgravity leaves vital capacity unaltered once the initial translocation of blood into the thorax is corrected by homeostatic mechanisms, but residual volume is reduced, likely through a more uniform distribution of alveolar size permitting deflation to a lower overall lung volume. Expiratory flows are unaffected by microgravity provided they are measured following normalization of the intrathoracic blood volume. During sleep in microgravity, there is an almost complete abolition of obstructive sleep apnea events. PMID- 23737184 TI - Right ventricle in pulmonary hypertension. AB - During heart development chamber specification is controlled and directed by a number of genes and a fetal heart gene expression pattern is revisited during heart failure. In the setting of chronic pulmonary hypertension the right ventricle undergoes hypertrophy, which is likely initially adaptive, but often followed by decompensation, dilatation and failure. Here we discuss differences between the right ventricle and the left ventricle of the heart and begin to describe the cellular and molecular changes which characterize right heart failure. A prevention and treatment of right ventricle failure becomes a treatment goal for patients with severe pulmonary hypertension it follows that we need to understand the pathobiology of right heart hypertrophy and the transition to right heart failure. PMID- 23737185 TI - Nitric oxide transport in blood: a third gas in the respiratory cycle. AB - The trapping, processing, and delivery of nitric oxide (NO) bioactivity by red blood cells (RBCs) have emerged as a conserved mechanism through which regional blood flow is linked to biochemical cues of perfusion sufficiency. We present here an expanded paradigm for the human respiratory cycle based on the coordinated transport of three gases: NO, O2, and CO2. By linking O2 and NO flux, RBCs couple vessel caliber (and thus blood flow) to O2 availability in the lung and to O2 need in the periphery. The elements required for regulated O2-based signal transduction via controlled NO processing within RBCs are presented herein, including S-nitrosothiol (SNO) synthesis by hemoglobin and O2-regulated delivery of NO bioactivity (capture, activation, and delivery of NO groups at sites remote from NO synthesis by NO synthase). The role of NO transport in the respiratory cycle at molecular, microcirculatory, and system levels is reviewed. We elucidate the mechanism through which regulated NO transport in blood supports O2 homeostasis, not only through adaptive regulation of regional systemic blood flow but also by optimizing ventilation-perfusion matching in the lung. Furthermore, we discuss the role of NO transport in the central control of breathing and in baroreceptor control of blood pressure, which subserve O2 supply to tissue. Additionally, malfunctions of this transport and signaling system that are implicated in a wide array of human pathophysiologies are described. Understanding the (dys)function of NO processing in blood is a prerequisite for the development of novel therapies that target the vasoactive capacities of RBCs. PMID- 23737187 TI - Lateral gradients significantly enhance static magnetic field-induced inhibition of pain responses in mice--a double blind experimental study. AB - Recent research demonstrated that exposure of mice to both inhomogeneous (3-477 mT) and homogeneous (145 mT) static magnetic fields (SMF) generated an analgesic effect toward visceral pain elicited by the intraperitoneal injection of 0.6% acetic acid. In the present work, we investigated behavioral responses such as writhing, entry avoidance, and site preference with the help of a specially designed cage that partially protruded into either the homogeneous (ho) or inhomogeneous (inh) SMF. Aversive effects, cognitive recognition of analgesia, and social behavior governed mice in their free locomotion between SMF and sham sides. The inhibition of pain response (I) for the 0-5, 6-20, and 21-30 min periods following the challenge was calculated by the formula I = 100 (1 - x/y) in %, where x and y represent the number of writhings in the SMF and sham sides, respectively. In accordance with previous measurements, an analgesic effect was induced in exposed mice (Iho = 64%, P < 0.0002 and Iinh = 62%, P < 0.002). No significant difference was found in the site preference (SMFho, inh vs. sham) indicating that SMF is neither aversive nor favorable. Comparison of writhings observed in the sham versus SMF side of the cage revealed that SMF exposure resulted in significantly fewer writhings than sham (Iho = 64%, P < 0.004 and Iinh = 81%, P < 0.03). Deeper statistical analysis clarified that the lateral SMF gradient between SMF and sham sides could be responsible for most of the analgesic effect (Iho = 91%, P < 0.02 and Iinh = 54%, P < 0.02). PMID- 23737186 TI - Stress transmission within the cell. AB - An outstanding problem in cell biology is how cells sense mechanical forces and how those forces affect cellular functions. During past decades, it has become evident that the deformable cytoskeleton (CSK), an intracellular network of various filamentous biopolymers, provides a physical basis for transducing mechanical signals into biochemical responses. To understand how mechanical forces regulate cellular functions, it is necessary to first understand how the CSK develops mechanical stresses in response to applied forces, and how those stresses are propagated through the CSK where various signaling molecules are immobilized. New experimental techniques have been developed to quantify cytoskeletal mechanics, which together with new computational approaches have given rise to new theories and models for describing mechanics of living cells. In this article, we discuss current understanding of cell biomechanics by focusing on the biophysical mechanisms that are responsible for the development and transmission of mechanical stresses in the cell and their effect on cellular functions. We compare and contrast various theories and models of cytoskeletal mechanics, emphasizing common mechanisms that those theories are built upon, while not ignoring irreconcilable differences. We highlight most recent advances in the understanding of mechanotransduction in the cytoplasm of living cells and the central role of the cytoskeletal prestress in propagating mechanical forces along the cytoskeletal filaments to activate cytoplasmic enzymes. It is anticipated that advances in cell mechanics will help developing novel therapeutics to treat pulmonary diseases like asthma, pulmonary fibrosis, and chronic obstructive pulmonary disease. PMID- 23737189 TI - IFNG polymorphisms are associated with tuberculosis in Han Chinese pediatric female population. AB - Host genetic factors play a major role in determining differential susceptibility to human tuberculosis (TB), a re-emerging infectious disease throughout the world. Genetic variations in the IFNG gene coding for interferon gamma (IFN gamma), have been identified in TB patients. To investigate the association of the IFNG polymorphisms with TB susceptibility in Chinese pediatric population. A case-control study of 189 TB patients and 164 controls was performed using single nucleotide polymorphism (SNP) analysis. Genomic DNA was extracted from leukocytes in peripheral blood. Three SNPs of IFNG, including -1616C/T (rs2069705), +874A/T (rs2430561), and +3234C/T (rs2069718), were selected for genotyping and analysis. The +874A and +3234C alleles were more frequent among TB patients (P = 0.108 and P = 0.088), especially in females (both P = 0.029), although this difference was not significant since Bonferroni corrected significance threshold was 0.025 (two of three SNPs were found to be in linkage disequilibrium). More pronounced differences for the +874 and +3234 polymorphisms were found under the genotype comparison between TB cases and controls in the total population [P = 0.026 (borderline non-significance) and P = 0.020, respectively], and in the female subgroup (P = 0.020 and P = 0.020). The dominant model of inheritance was shown to be significant for +874A and +3234C alleles (both P = 0.019) in the female subgroup. The +874A and +3234C alleles were more frequently found in extrapulmonary TB patients than in controls (P = 0.039). Haplotype analysis carried out on these three SNPs showed the TTT haplotype to be more frequent in controls than in TB cases, and this difference showed a strong significance (P = 0.005). The +874A and +3234C alleles may be related to TB susceptibility in the female subgroup in the Chinese pediatric population of North China. The higher rate of +874A (known to correlate with lower IFN-gamma expression) in the extrapulmonary TB subgroup suggests a sufficient IFN-gamma expression to be not only an important factor for the onset of TB disease but also for limiting its dissemination to lungs. PMID- 23737188 TI - Post-transplant lymphoproliferative disease (PTLD): risk factors, diagnosis, and current treatment strategies. AB - Post-transplant lymphoproliferative diseases (PTLD) are heterogeneous lymphoid disorders ranging from indolent polyclonal proliferations to aggressive lymphomas that complicate solid organ or hematopoietic transplantation. Risk factors for PTLD include viral infections, degree of immunosuppression, recipient age and race, allograft type, and host genetic variations. Clinically, extra-nodal disease is common including 10-15 % presenting with central nervous system (CNS) disease. Most PTLD cases are B cell (5-10 % T/NK cell or Hodgkin lymphoma), while over one-third are EBV-negative. World Health Organization (WHO) diagnostic categories are: early lesions, polymorphic, and monomorphic PTLD; although in practice, a clear separation is not always possible. Therapeutically, reduction in immunosuppression remains a mainstay, and recent data has documented the importance of rituximab +/- combination chemotherapy. Therapy for primary CNS PTLD should be managed according to immunocompetent CNS paradigms. Finally, novel treatment strategies for PTLD have emerged, including adoptive immunotherapy and rational targeted therapeutics (e.g., anti-CD30 based therapy and downstream signaling pathways of latent membrane protein-2A). PMID- 23737190 TI - Current tissue engineering strategies in anterior cruciate ligament reconstruction. AB - Rupture of the anterior cruciate ligament (ACL) is one of the most common ligamentous injuries of the knee. Limitations of allografts and autografts in ACL reconstruction as well as recent advancements in biology and materials science have spurred interest in developing tissue-engineered ACL replacements that have the potential to mimic the native ACL in terms of both biological and mechanical properties. This article reviews the current literature regarding contemporary tissue engineering strategies. The four basic components of tissue engineering, biomaterial scaffolds, cell sources, growth factors, and mechanical stimuli, as applied to the development of tissue-engineered ACL replacement grafts, will be systematically addressed. In addition, animal models that have been used to test these tissue-engineered ACL replacements will also be reviewed. To date, there is no tissue-engineered ACL construct that has been successfully implanted in humans. We expect that continued progress in designing a viable tissue-engineered ACL replacement will accompany rapidly advancing techniques in materials science and biology. PMID- 23737191 TI - Patients with difficult-to-treat depression do not exhibit an increased frequency of CYP2D6 allele duplication. AB - The insufficient response of patients to antidepressant medications may result from several factors, including altered drug metabolism. CYP2D6 genotyping may help assess the possible factors that contribute to difficult-to-treat depression. The aim of our study was to determine the frequency of CYP2D6 allelic variants and the prevalence of predicted CYP2D6 phenotypes in patients who were suffering from difficult-to-treat depression and compare the data with those for the healthy population of Hungary.55 patients who failed to respond to 2 or more adequate trials of different CYP2D6-dependent antidepressants were selected for genotyping.The prevalence of the predicted CYP2D6 phenotypes in the patient population was 1.8% for the UMs, 80.0% for EMs, 3.6% for IMs and 14.5% for PMs compared with 1.9% for UMs, 83.3% for EMs, 6.5% for IMs and 8.3% for PMs in the Hungarian population.The CYP2D6 allele frequencies and the predicted phenotype distributions in patients with difficult-to-treat depression were not significantly different to those found in the healthy population of Hungary. The cumulative frequency of the CYP2D6*1XN, *2XN and *35XN alleles was 0.9% in the patient population -suggesting that CYP2D6 duplication or multiplication does not play a significant role in antidepressant pharmacotherapy failure in this patient sample. The cumulative frequency of the non-functional alleles (33.5%) and the prevalence of the genetically determined PM phenotype (14.5%) were relatively high in the patient group. These figures draw attention to the possibility of unrecognised and non-reported side effects and non-adherence to drug treatment. PMID- 23737192 TI - TDM in Saxonia (Germany). AB - Conca et al. complain insufficient TD use in Italy. This survey suggests that the situation and possibly also the reasons are similar in the German Federal Republic. PMID- 23737193 TI - Structural basis for the beta-lactamase activity of EstU1, a family VIII carboxylesterase. AB - EstU1 is a unique family VIII carboxylesterase that displays hydrolytic activity toward the amide bond of clinically used beta-lactam antibiotics as well as the ester bond of p-nitrophenyl esters. EstU1 assumes a beta-lactamase-like modular architecture and contains the residues Ser100, Lys103, and Tyr218, which correspond to the three catalytic residues (Ser64, Lys67, and Tyr150, respectively) of class C beta-lactamases. The structure of the EstU1/cephalothin complex demonstrates that the active site of EstU1 is not ideally tailored to perform an efficient deacylation reaction during the hydrolysis of beta-lactam antibiotics. This result explains the weak beta-lactamase activity of EstU1 compared with class C beta-lactamases. Finally, structural and sequential comparison of EstU1 with other family VIII carboxylesterases elucidates an operative molecular strategy used by family VIII carboxylesterases to extend their substrate spectrum. PMID- 23737194 TI - Regioselectively functionalized pyridines from sustainable resources. PMID- 23737195 TI - Inert gas transport in blood and tissues. AB - This article establishes the basic mathematical models and the principles and assumptions used for inert gas transfer within body tissues-first, for a single compartment model and then for a multicompartment model. From these, and other more complex mathematical models, the transport of inert gases between lungs, blood, and other tissues is derived and compared to known experimental studies in both animals and humans. Some aspects of airway and lung transfer are particularly important to the uptake and elimination of inert gases, and these aspects of gas transport in tissues are briefly described. The most frequently used inert gases are those that are administered in anesthesia, and the specific issues relating to the uptake, transport, and elimination of these gases and vapors are dealt with in some detail showing how their transfer depends on various physical and chemical attributes, particularly their solubilities in blood and different tissues. Absorption characteristics of inert gases from within gas cavities or tissue bubbles are described, and the effects other inhaled gas mixtures have on the composition of these gas cavities are discussed. Very brief consideration is given to the effects of hyper- and hypobaric conditions on inert gas transport. PMID- 23737196 TI - Pulmonary vascular diseases. AB - Diseases of the pulmonary vasculature are a cause of increased pulmonary vascular resistance (PVR) in pulmonary embolism, chronic thromboembolic pulmonary hypertension (CTEPH), and pulmonary arterial hypertension or decreased PVR in pulmonary arteriovenous malformations on hereditary hemorrhagic telangiectasia, portal hypertension, or cavopulmonary anastomosis. All these conditions are associated with a decrease in both arterial PO2 and PCO2. Gas exchange in pulmonary vascular diseases with increased PVR is characterized by a shift of ventilation and perfusion to high ventilation-perfusion ratios, a mild to moderate increase in perfusion to low ventilation-perfusion ratios, and an increased physiologic dead space. Hypoxemia in these patients is essentially explained by altered ventilation-perfusion matching amplified by a decreased mixed venous PO2 caused by a low cardiac output. Hypocapnia is accounted for by hyperventilation, which is essentially related to an increased chemosensitivity. A cardiac shunt on a patent foramen ovale may be a cause of severe hypoxemia in a proportion of patients with pulmonary hypertension and an increase in right atrial pressure. Gas exchange in pulmonary arteriovenous malformations is characterized by variable degree of pulmonary shunting and/or diffusion-perfusion imbalance. Hypocapnia is caused by an increased ventilation in relation to an increased pulmonary blood flow with direct peripheral chemoreceptor stimulation by shunted mixed venous blood flow. PMID- 23737197 TI - Gas exchange consequences of left heart failure. AB - This review explores the pathophysiology of gas exchange abnormalities arising consequent to either acute or chronic elevation of pulmonary venous pressures. The initial experimental studies of acute pulmonary edema outlined the sequence of events from lymphatic congestion with edema fluid to frank alveolar flooding and its resultant hypoxemia. Clinical studies of acute heart failure (HF) suggested that hypoxemia was associated only with the final stage of alveolar flooding. However, in patients with chronic heart failure and normal oxygenation, hypoxemia could be produced by the administration of potent pulmonary vasodilators, suggesting that hypoxic pulmonary vasoconstriction is an important reflex for these patients. Patients with chronic left HF commonly manifest a reduced diffusing capacity, an abnormality that appears to be a consequence of chronic elevation of left atrial pressure. That reduction in diffusing capacity does not appear to be primarily attributable to increases in lung water but is improved by any sustained treatment that improves overall cardiac function. Patients with heart failure may also manifest an abnormally elevated VE/VCO2 during exercise, and that exercise ventilation abnormality arises as a consequence of both alveolar hyperventilation and elevated physiologic dead space. That elevated exercise VE/VCO2 in an HF patient has proven to be a powerful predictor of an adverse outcome and hence it has received sustained attention in the HF literature. At least three of the classes of drugs used to treat HF will normalize the exercise VE/VCO2, suggesting that the excessive ventilation response may be linked to elevated sympathetic activity. PMID- 23737198 TI - Ventilation-induced lung injury. AB - Mechanical ventilation (MV) is, by definition, the application of external forces to the lungs. Depending on their magnitude, these forces can cause a continuum of pathophysiological alterations ranging from the stimulation of inflammation to the disruption of cell-cell contacts and cell membranes. These side effects of MV are particularly relevant for patients with inhomogeneously injured lungs such as in acute lung injury (ALI). These patients require supraphysiological ventilation pressures to guarantee even the most modest gas exchange. In this situation, ventilation causes additional strain by overdistension of the yet non-injured region, and additional stress that forms because of the interdependence between intact and atelectatic areas. Cells are equipped with elaborate mechanotransduction machineries that respond to strain and stress by the activation of inflammation and repair mechanisms. Inflammation is the fundamental response of the host to external assaults, be they of mechanical or of microbial origin and can, if excessive, injure the parenchymal tissue leading to ALI. Here, we will discuss the forces generated by MV and how they may injure the lungs mechanically and through inflammation. We will give an overview of the mechanotransduction and how it leads to inflammation and review studies demonstrating that ventilator-induced lung injury can be prevented by blocking pathways of mechanotransduction or inflammation. PMID- 23737199 TI - Gas exchange in disease: asthma, chronic obstructive pulmonary disease, cystic fibrosis, and interstitial lung disease. AB - Ventilation-perfusion (VA/Q) inequality is the underlying abnormality determining hypoxemia and hypercapnia in lung diseases. Hypoxemia in asthma is characterized by the presence of low VA/Q units, which persist despite improvement in airway function after an attack. This hypoxemia is generally attenuated by compensatory redistribution of blood flow mediated by hypoxic vasoconstriction and changes in cardiac output, however, mediator release and bronchodilator therapy may cause deterioration. Patients with chronic obstructive pulmonary disease have more complex patterns of VA/Q inequality, which appear more fixed, and changes in blood flow and ventilation have less benefit in improving gas exchange efficiency. The inability of ventilation to match increasing cardiac output limits exercise capacity as the disease progresses. Deteriorating hypoxemia during exacerbations reflects the falling mixed venous oxygen tension from increased respiratory muscle activity, which is not compensated by any redistribution of VA/Q ratios. Shunt is not a feature of any of these diseases. Patients with cystic fibrosis (CF) have no substantial shunt when managed according to modern treatment regimens. Interstitial lung diseases demonstrate impaired oxygen diffusion across the alveolar-capillary barrier, particularly during exercise, although VA/Q inequality still accounts for most of the gas exchange abnormality. Hypoxemia may limit exercise capacity in these diseases and in CF. Persistent hypercapnic respiratory failure is a feature of advancing chronic obstructive pulmonary disease and CF, closely associated with sleep disordered breathing, which is not a prominent feature of the other diseases. Better understanding of the mechanisms of hypercapnic respiratory failure, and of the detailed mechanisms controlling the distribution of ventilation and blood flow in the lung, are high priorities for future research. PMID- 23737200 TI - Urea transport in the kidney. AB - Urea transport proteins were initially proposed to exist in the kidney in the late 1980s when studies of urea permeability revealed values in excess of those predicted by simple lipid-phase diffusion and paracellular transport. Less than a decade later, the first urea transporter was cloned. Currently, the SLC14A family of urea transporters contains two major subgroups: SLC14A1, the UT-B urea transporter originally isolated from erythrocytes; and SLC14A2, the UT-A group with six distinct isoforms described to date. In the kidney, UT-A1 and UT-A3 are found in the inner medullary collecting duct; UT-A2 is located in the thin descending limb, and UT-B is located primarily in the descending vasa recta; all are glycoproteins. These transporters are crucial to the kidney's ability to concentrate urine. UT-A1 and UT-A3 are acutely regulated by vasopressin. UT-A1 has also been shown to be regulated by hypertonicity, angiotensin II, and oxytocin. Acute regulation of these transporters is through phosphorylation. Both UT-A1 and UT-A3 rapidly accumulate in the plasma membrane in response to stimulation by vasopressin or hypertonicity. Long-term regulation involves altering protein abundance in response to changes in hydration status, low protein diets, adrenal steroids, sustained diuresis, or antidiuresis. Urea transporters have been studied using animal models of disease including diabetes mellitus, lithium intoxication, hypertension, and nephrotoxic drug responses. Exciting new animal models are being developed to study these transporters and search for active urea transporters. Here we introduce urea and describe the current knowledge of the urea transporter proteins, their regulation, and their role in the kidney. PMID- 23737201 TI - Neural control of renal function. AB - The kidney is innervated with efferent sympathetic nerve fibers that directly contact the vasculature, the renal tubules, and the juxtaglomerular granular cells. Via specific adrenoceptors, increased efferent renal sympathetic nerve activity decreases renal blood flow and glomerular filtration rate, increases renal tubular sodium and water reabsorption, and increases renin release. Decreased efferent renal sympathetic nerve activity produces opposite functional responses. This integrated system contributes importantly to homeostatic regulation of sodium and water balance under physiological conditions and to pathological alterations in sodium and water balance in disease. The kidney contains afferent sensory nerve fibers that are located primarily in the renal pelvic wall where they sense stretch. Stretch activation of these afferent sensory nerve fibers elicits an inhibitory renorenal reflex response wherein the contralateral kidney exhibits a compensatory natriuresis and diuresis due to diminished efferent renal sympathetic nerve activity. The renorenal reflex coordinates the excretory function of the two kidneys so as to facilitate homeostatic regulation of sodium and water balance. There is a negative feedback loop in which efferent renal sympathetic nerve activity facilitates increases in afferent renal nerve activity that in turn inhibit efferent renal sympathetic nerve activity so as to avoid excess renal sodium retention. In states of renal disease or injury, there is activation of afferent sensory nerve fibers that are excitatory, leading to increased peripheral sympathetic nerve activity, vasoconstriction, and increased arterial pressure. Proof of principle studies in essential hypertensive patients demonstrate that renal denervation produces sustained decreases in arterial pressure. PMID- 23737202 TI - Experimental and transgenic models of pulmonary hypertension. AB - Pulmonary hypertension in human patients can result from increased pulmonary vascular tone, pressure transferred from the systemic circulation, dropout of small pulmonary vessels, occlusion of vessels with thrombi or intimal lesions, or some combination of all of these. Different animal models have been designed to reflect these different mechanistic origins of disease. Pulmonary hypertension models may be roughly grouped into tone-related models, inflammation-related models, and genetic models with unusual or mixed mechanism. Models of tone generally use hypoxia as a base, and then modify this with either genetic modifications (SOD, NOS, and caveolin) or with drugs (Sugen), although some genetic modifications of tone-related pathways can result in spontaneous pulmonary hypertension (Hph-1). Inflammation-related models can use either toxic chemicals (monocrotaline, bleomycin), live pathogens (stachybotrys, schistosomiasis), or genetic modifications (IL-6, VIP). Additional genetic models rely on alterations in metabolism (adiponectin), cell migration (S100A4), the serotonin pathway, or the BMP pathway. While each of these shares molecular and pathologic symptoms with different classes of human pulmonary hypertension, in most cases the molecular etiology of human pulmonary hypertension is unknown, and so the relationship between any model and human disease is unclear. There is thus no best animal model of pulmonary hypertension; instead, investigators must select the model most related to the specific pathology they are studying. PMID- 23737204 TI - Gas mixing in the airways and airspaces. AB - Basic physical concepts of diffusion, convection, and dispersion pertaining to gas transport in the human airways are reviewed. Their incorporation into quantitative models of gas mixing is presented, also illustrating the crucial interaction of gas transport equations with the model geometry. Model simulations are confronted with the available experimental gas mixing indices such as the phase III slope obtained in normal human lungs, with some pertinent examples in laboratory animals and in human lung disease. The use of inert gases with differing diffusion coefficients and their associated phase III slope provides invaluable experimental information on gas mixing in the lungs, with the concept of the diffusion front playing a central role. Sources of inter- and intraregional ventilation heterogeneity can be related to the location of the diffusion front, which offers the possibility to distinguish between ventilation heterogeneity proximal to the diffusion front (driven by convection between lung units larger than acini) and more peripheral ventilation heterogeneity (driven by diffusion-convection interaction mainly within the acinus). While specific ventilation distribution and flow asynchrony co-act to generate convection dependent ventilation heterogeneity, local structural asymmetry of the acinar air spaces is sufficient to generate diffusion-convection-dependent ventilation heterogeneity. The remaining hiatus in our understanding of ventilation heterogeneity in the human lung is described, together with some potential perspectives for its investigation. PMID- 23737205 TI - Acute lung injury and pulmonary vascular permeability: use of transgenic models. AB - Acute lung injury is a general term that describes injurious conditions that can range from mild interstitial edema to massive inflammatory tissue destruction. This review will cover theoretical considerations and quantitative and semi quantitative methods for assessing edema formation and increased vascular permeability during lung injury. Pulmonary edema can be quantitated directly using gravimetric methods, or indirectly by descriptive microscopy, quantitative morphometric microscopy, altered lung mechanics, high-resolution computed tomography, magnetic resonance imaging, positron emission tomography, or x-ray films. Lung vascular permeability to fluid can be evaluated by measuring the filtration coefficient (Kf) and permeability to solutes evaluated from their blood to lung clearances. Albumin clearances can then be used to calculate specific permeability-surface area products (PS) and reflection coefficients (sigma). These methods as applied to a wide variety of transgenic mice subjected to acute lung injury by hyperoxic exposure, sepsis, ischemia-reperfusion, acid aspiration, oleic acid infusion, repeated lung lavage, and bleomycin are reviewed. These commonly used animal models simulate features of the acute respiratory distress syndrome, and the preparation of genetically modified mice and their use for defining specific pathways in these disease models are outlined. Although the initiating events differ widely, many of the subsequent inflammatory processes causing lung injury and increased vascular permeability are surprisingly similar for many etiologies. PMID- 23737203 TI - Mechanics of the nucleus. AB - The nucleus is the distinguishing feature of eukaryotic cells. Until recently, it was often considered simply as a unique compartment containing the genetic information of the cell and associated machinery, without much attention to its structure and mechanical properties. This article provides compelling examples that illustrate how specific nuclear structures are associated with important cellular functions, and how defects in nuclear mechanics can cause a multitude of human diseases. During differentiation, embryonic stem cells modify their nuclear envelope composition and chromatin structure, resulting in stiffer nuclei that reflect decreased transcriptional plasticity. In contrast, neutrophils have evolved characteristic lobulated nuclei that increase their physical plasticity, enabling passage through narrow tissue spaces in their response to inflammation. Research on diverse cell types further demonstrates how induced nuclear deformations during cellular compression or stretch can modulate cellular function. Pathological examples of disturbed nuclear mechanics include the many diseases caused by mutations in the nuclear envelope proteins lamin A/C and associated proteins, as well as cancer cells that are often characterized by abnormal nuclear morphology. In this article, we will focus on determining the functional relationship between nuclear mechanics and cellular (dys-)function, describing the molecular changes associated with physiological and pathological examples, the resulting defects in nuclear mechanics, and the effects on cellular function. New insights into the close relationship between nuclear mechanics and cellular organization and function will yield a better understanding of normal biology and will offer new clues into therapeutic approaches to the various diseases associated with defective nuclear mechanics. PMID- 23737207 TI - Regulation of mitochondrial biogenesis and GLUT4 expression by exercise. AB - Endurance exercise training can induce large increases mitochondria and the GLUT4 isoform of the glucose transporter in skeletal muscle. For a long time after the discovery in the 1960s that exercise results in an increase in muscle mitochondria, there was no progress in elucidation of the mechanisms involved. The reason for this lack of progress was that nothing was known regarding how expression of the genes-encoding mitochondrial proteins is coordinately regulated. This situation changed rapidly after discovery of transcription factors that control transcription of genes-encoding mitochondrial proteins and, most importantly, the discovery of peroxisome proliferator-gamma coactivator 1alpha (PGC-1alpha). This transcription coactivator binds to and activates transcription factors that regulate transcription of genes-encoding mitochondrial proteins. Thus, PGC-1alpha activates and coordinates mitochondrial biogenesis. It is now known that exercise rapidly activates and induces increased expression of PGC-1alpha. The exercise-generated signals that lead to PGC-1alpha activation and increased expression are the increases in cytosolic Ca(2+) and decreases in ATP and creatine phosphate (~P). Ca(2+) mediates its effect by activating CAMKII, while the decrease in ~P mediates its effect via activation of AMPK. Expression of the GLUT4 isoform of the glucose transporter is regulated in parallel with mitochondrial biogenesis via the same signaling pathways. This review describes what is known regarding the regulation of mitochondrial biogenesis and GLUT4 expression by exercise. A major component of this review deals with the physiological and metabolic consequences of the exercise-induced increase in mitochondria and GLUT4. PMID- 23737210 TI - Complexity and emergent phenomena. AB - Complex biological systems operate under non-equilibrium conditions and exhibit emergent properties associated with correlated spatial and temporal structures. These properties may be individually unpredictable, but tend to be governed by power-law probability distributions and/or correlation. This article reviews the concepts that are invoked in the treatment of complex systems through a wide range of respiratory-related examples. Following a brief historical overview, some of the tools to characterize structural variabilities and temporal fluctuations associated with complex systems are introduced. By invoking the concept of percolation, the notion of multiscale behavior and related modeling issues are discussed. Spatial complexity is then examined in the airway and parenchymal structures with implications for gas exchange followed by a short glimpse of complexity at the cellular and subcellular network levels. Variability and complexity in the time domain are then reviewed in relation to temporal fluctuations in airway function. Next, an attempt is given to link spatial and temporal complexities through examples of airway opening and lung tissue viscoelasticity. Specific examples of possible and more direct clinical implications are also offered through examples of optimal future treatment of fibrosis, exacerbation risk prediction in asthma, and a novel method in mechanical ventilation. Finally, the potential role of the science of complexity in the future of physiology, biology, and medicine is discussed. PMID- 23737211 TI - Molecular physiology of the medullary collecting duct. AB - The mammalian kidney is responsible for a multitude of homeostatic functions, which are mediated by both structural and functional diversity along the renal tubule. In this article, we focus on the major functions of the terminal portion of the renal tubule, the medullary collecting duct system. The role of the medullary collecting ducts in determining the composition of the final urine through controlled water, sodium, chloride, potassium and urea reabsorption, ammonia transport, and acid-base homeostasis is discussed. The molecular identity of the major channels and transporters that contribute to medullary collecting duct function are described in detail, including; aquaporins, urea transporters, the epithelial sodium channel (ENaC), the Na,K-ATPase, H-ATPase, Rh glycoproteins, and sodium bicarbonate transporters. Knowledge gained from studies in knockout mice is also discussed. PMID- 23737212 TI - Mechanotransduction. AB - Physical forces are central players in development and morphogenesis, provide an ever-present backdrop influencing physiological functions, and contribute to a variety of pathologies. Mechanotransduction encompasses the rich variety of ways in which cells and tissues convert cues from their physical environment into biochemical signals. These cues include tensile, compressive and shear stresses, and the stiffness or elastic modulus of the tissues in which cells reside. This article focuses on the proximal events that lead directly from a change in physical state to a change in cell-signaling state. A large body of evidence demonstrates a prominent role for the extracellular matrix, the intracellular cytoskeleton, and the cell matrix adhesions that link these networks in transduction of the mechanical environment. Recent work emphasizes the important role of physical unfolding or conformational changes in proteins induced by mechanical loading, with examples identified both within the focal adhesion complex at the cell-matrix interface and in extracellular matrix proteins themselves. Beyond these adhesion and matrix-based mechanisms, classical and new mechanisms of mechanotransduction reside in stretch-activated ion channels, the coupling of physical forces to interstitial autocrine and paracrine signaling, force-induced activation of extracellular proteins, and physical effects directly transmitted to the cell's nucleus. Rapid progress is leading to detailed delineation of molecular mechanisms by which the physical environment shapes cellular signaling events, opening up avenues for exploring how mechanotransduction pathways are integrated into physiological and pathophysiological cellular and tissue processes. PMID- 23737213 TI - Novel YAP1-TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma. AB - Conventional epithelioid hemangioendotheliomas (EHE) have a distinctive morphologic appearance and are characterized by a recurrent t(1;3) translocation, resulting in a WWTR1-CAMTA1 fusion gene. We have recently encountered a fusion negative subset characterized by a somewhat different morphology, including focally well-formed vasoformative features, which was further investigated for recurrent genetic abnormalities. Based on a case showing strong transcription factor E3 (TFE3) immunoreactivity, fluorescence in situ hybridization (FISH) analysis for TFE3 gene rearrangement was applied to the index case as well as to nine additional cases, selected through negative WWTR1-CAMTA1 screening. A control group, including 18 epithelioid hemangiomas, nine pseudomyogenic HE, and three epithelioid angiosarcomas, was also tested. TFE3 gene rearrangement was identified in 10 patients, with equal gender distribution and a mean age of 30 years old. The lesions were located in somatic soft tissue in six cases, lung in three and one in bone. One case with available frozen tissue was tested by RNA sequencing and FusionSeq data analysis to detect novel fusions. A YAP1-TFE3 fusion was thus detected, which was further validated by FISH and reverse transcription polymerase chain reaction (RT-PCR). YAP1 gene rearrangements were then confirmed in seven of the remaining nine TFE3-rearranged EHEs by FISH. No TFE3 structural abnormalities were detected in any of the controls. The TFE3 rearranged EHEs showed similar morphologic features with at least focally, well formed vascular channels, in addition to a variably solid architecture. All tumors expressed endothelial markers, as well as strong nuclear TFE3. In summary, we are reporting a novel subset of EHE occurring in young adults, showing a distinct phenotype and YAP1-TFE3 fusions. PMID- 23737214 TI - Atomoxetine response in the inattentive and combined subtypes of attention deficit hyperactivity disorder: a retrospective chart review. AB - The DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, 1994, American Psychiatric Association) describes attention deficit hyperactivity disorder (ADHD) as a heterogeneous disorder; providing diagnostic criteria for three subtypes: hyperactive/impulsive (ADHD/HI), inattentive (ADHD/I), and combined type (ADHD/C). Differences among the subtypes are well defined, but there may be also differences in terms of treatment responses. The aim of this study is to assess the responses of ADHD/I and ADHD/C to atomoxetine treatment. The medical records of the January-June 2012 term, first time referrals to outpatient clinic, were reviewed, and 37 ADHD diagnosed primary school age children (18 ADHD/I, 19 ADHD/C) that were treated with atomoxetine were determined. Thirty-five of them who completed 8 weeks of treatment duration were recruited for the study. The children with an ADHD medication use history in 2 months time prior to onset of treatment and/or the children receiving additional psychopharmacologic treatment to atomoxetine were excluded. Baseline and eighth week assessment, records were evaluated. Efficacy assessments included Turgay DSM IV ADHD Screening and Rating Scale parent and teacher forms (T-DSM-IV) and Clinical Global Impression Scale-Severity and Improvement subscales. Safety assessments included laboratory and body weight assessments, ECG, heart rate, and blood pressure evaluations (baseline and eighth week) along a scale filled by the parents at the eighth week to review side effects. Atomoxetine was found to be effective in both ADHD/I and ADHD/C groups. Atomoxetine also decreased the opposition defiance subscale scores of T-DSM-IV (both parent and teacher forms), whereas it was not found to make statistically significant difference in the conduct disorder subscale scores. Mean difference in 8-week time in T-DSM-IV hyperactivity subscale and total scores of parent and teacher forms; inattention subscale scores of only parent forms and the CGI- severity subscale scores; differed significantly among the ADHD/I and ADHD/C groups; that ADHD/C types responded better to medication. Results of this study revealed that atomoxetine is effective both in ADHD/I and ADHD/C subtypes. ADHD/C types may be responding better to atomoxetine treatment than the ADHD/I subtypes. PMID- 23737209 TI - The kallikrein-kinin system as a regulator of cardiovascular and renal function. AB - Autocrine, paracrine, endocrine, and neuroendocrine hormonal systems help regulate cardio-vascular and renal function. Any change in the balance among these systems may result in hypertension and target organ damage, whether the cause is genetic, environmental or a combination of the two. Endocrine and neuroendocrine vasopressor hormones such as the renin-angiotensin system (RAS), aldosterone, and catecholamines are important for regulation of blood pressure and pathogenesis of hypertension and target organ damage. While the role of vasodepressor autacoids such as kinins is not as well defined, there is increasing evidence that they are not only critical to blood pressure and renal function but may also oppose remodeling of the cardiovascular system. Here we will primarily be concerned with kinins, which are oligopeptides containing the aminoacid sequence of bradykinin. They are generated from precursors known as kininogens by enzymes such as tissue (glandular) and plasma kallikrein. Some of the effects of kinins are mediated via autacoids such as eicosanoids, nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), and/or tissue plasminogen activator (tPA). Kinins help protect against cardiac ischemia and play an important part in preconditioning as well as the cardiovascular and renal protective effects of angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor blockers (ARB). But the role of kinins in the pathogenesis of hypertension remains controversial. A study of Utah families revealed that a dominant kallikrein gene expressed as high urinary kallikrein excretion was associated with a decreased risk of essential hypertension. Moreover, researchers have identified a restriction fragment length polymorphism (RFLP) that distinguishes the kallikrein gene family found in one strain of spontaneously hypertensive rats (SHR) from a homologous gene in normotensive Brown Norway rats, and in recombinant inbred substrains derived from these SHR and Brown Norway rats this RFLP cosegregated with an increase in blood pressure. However, humans, rats and mice with a deficiency in one or more components of the kallikrein-kinin system (KKS) or chronic KKS blockade do not have hypertension. In the kidney, kinins are essential for proper regulation of papillary blood flow and water and sodium excretion. B2-KO mice appear to be more sensitive to the hypertensinogenic effect of salt. Kinins are involved in the acute antihypertensive effects of ACE inhibitors but not their chronic effects (save for mineralocorticoid-salt-induced hypertension). Kinins appear to play a role in the pathogenesis of inflammatory diseases such as arthritis and skin inflammation; they act on innate immunity as mediators of inflammation by promoting maturation of dendritic cells, which activate the body's adaptive immune system and thereby stimulate mechanisms that promote inflammation. On the other hand, kinins acting via NO contribute to the vascular protective effect of ACE inhibitors during neointima formation. In myocardial infarction produced by ischemia/reperfusion, kinins help reduce infarct size following preconditioning or treatment with ACE inhibitors. In heart failure secondary to infarction, the therapeutic effects of ACE inhibitors are partially mediated by kinins via release of NO, while drugs that activate the angiotensin type 2 receptor act in part via kinins and NO. Thus kinins play an important role in regulation of cardiovascular and renal function as well as many of the beneficial effects of ACE inhibitors and ARBs on target organ damage in hypertension. PMID- 23737215 TI - Is there a role for DHEA supplementation in women with diminished ovarian reserve? AB - PURPOSE: Poor ovarian reserve and poor ovarian response presents a challenge to IVF centers. Dehydroepiandrosterone (DHEA) supplementation is increasingly being used by many IVF centers around the world in poor responders despite the lack of convincing data. We therefore examined the rationale for the use of DHEA in poor responders, address the relevant studies, present new data, and address its potential mechanisms of action. METHODS: All published articles on the role of DHEA in infertile women from 1990 to April 2013 were reviewed. RESULTS: Several studies have suggested an improvement in pregnancy rates with the use of DHEA. Potential mechanisms include improved follicular steroidogenesis, increased IGF 1, acting as a pre-hormone for follicular testosterone, reducing aneuploidy, and increasing AMH and antral follicle count. While the role of DHEA is intriguing, evidence-based recommendations are lacking. CONCLUSIONS: While nearly 25 % of IVF programs use DHEA currently, large randomized prospective trials are sorely needed. Until (and if) such trials are conducted, DHEA may be of benefit in suitable, well informed, and consented women with diminished ovarian reserve. PMID- 23737217 TI - Primary hypertension in children and adolescents is an immuno-metabolic disease with hemodynamic consequences. AB - With the rise in obesity epidemic primary hypertension (PH) is now one of the most common chronic diseases in adolescence. In contrast to hypertensive adults, hypertensive children usually are not exposed to other comorbidities such as diabetes, chronic kidney disease and atherosclerosis. Thus, PH in children and adolescents can be treated as the early stage of development of cardiovascular disease. There is increasing amount of data indicating that PH is not only hemodynamic phenomenon but a complex syndrome involving disturbed activity of sympathetic nervous system, metabolic abnormalities and activation of innate and adaptive immune system. We discuss results of the studies on clinical, metabolic and immunological phenotype of hypertensive children, associations between metabolic and immunological abnormalities with target organ damage and results of antihypertensive treatment. PMID- 23737206 TI - Physiology of endothelin and the kidney. AB - Since its discovery in 1988 as an endothelial cell-derived peptide that exerts the most potent vasoconstriction of any known endogenous compound, endothelin (ET) has emerged as an important regulator of renal physiology and pathophysiology. This review focuses on how the ET system impacts renal function in health; it is apparent that ET regulates multiple aspects of kidney function. These include modulation of glomerular filtration rate and renal blood flow, control of renin release, and regulation of transport of sodium, water, protons, and bicarbonate. These effects are exerted through ET interactions with almost every cell type in the kidney, including mesangial cells, podocytes, endothelium, vascular smooth muscle, every section of the nephron, and renal nerves. In addition, while not the subject of the current review, ET can also indirectly affect renal function through modulation of extrarenal systems, including the vasculature, nervous system, adrenal gland, circulating hormones, and the heart. As will become apparent, these pleiotropic effects of ET are of fundamental physiologic importance in the control of renal function in health. In addition, to help put these effects into perspective, we will also discuss, albeit to a relatively limited extent, how alterations in the ET system can contribute to hypertension and kidney disease. PMID- 23737216 TI - Supplementation with low concentrations of melatonin improves nuclear maturation of human oocytes in vitro. AB - PURPOSE: Studies in bovine and porcine have indicated that melatonin (MT) could induce meiotic maturation of immature oocytes in vitro. The object of the current study was to investigate if MT could ameliorate human oocytes maturation during rescue in vitro maturation (IVM). METHODS: Two hundred seventy eight germinal vesicle (GV) oocytes and 451 (MI) metaphase I oocytes were vitrified, thawed and then matured in vitro. All the oocytes were randomly allocated into six groups in which the oocytes were cultured in medium supplemented with different concentrations of MT (0, 10(-2), 1, 10(2), 10(4), 10(6) nM) and nuclear maturation was evaluated at 6 h, 12 h, 18 h, 24 h and 48 h of culture. RESULTS: The optimal MT concentration for both GV and MI oocytes was 1 nM. At 24 h of culture, nuclear maturation rate of MI oocytes cultured in 1 nM MT medium was significantly higher than other groups (P < 0.05); Nuclear maturation rate of GV oocytes cultured in 1 nM MT medium was also significantly higher than the control group (P < 0.05). On the other hand, decreased nuclear maturation rate was observed in the high MT concentration group (10(6) nM). CONCLUSIONS: The current study demonstrated that low concentration of exogenous MT could ameliorate nuclear maturation of human oocyte during rescue IVM, while high concentration of MT presented negative effects. PMID- 23737218 TI - The sympathetic nervous system in chronic kidney disease. AB - Accumulating evidence has shown that the sympathetic nervous system plays an important role in the pathophysiology and progression of several chronic disorders, e.g., arterial hypertension, cardiac arrhythmias, heart failure, and in particular chronic kidney disease (CKD). Experimental and clinical studies provide evidence that sympathetic inhibition using either sympatholytic pharmacotherapy or catheter-based renal denervation has beneficial effects in patients with CKD. Randomized clinical trials are needed to characterize the underlying pathophysiological mechanisms, and systematically evaluate the therapeutic effects of sympathetic inhibition in this high-risk patient population. In this review current knowledge of the role of the sympathetic nervous system in the development and progression of CKD will be summarized, and novel treatment options targeting sympathetic nervous system activity will be discussed. PMID- 23737221 TI - Automatic remote monitoring: is there a need? PMID- 23737220 TI - Recombinant human bone morphogenetic protein-type 2 (rhBMP-2) enhances local bone formation in the lumbar spine of osteoporotic sheep. AB - The failure of orthopedic implants in osteoporotic patients is attributed to the lack of sufficient bone stock and regenerative capacity but most treatments for osteoporosis fail to address this issue. rhBMP-2 is known to promote bone formation under normal conditions but has not been used clinically in the osteoporotic condition. Osteoporosis was induced in 19 ewes using ovariectomy, low calcium diet, and steroid injection. After induction, the steroid was withdrawn and pellets containing inert carrier with rhBMP-2 in either slow or fast-release formulation were implanted into the lumbar vertebrae of each animal. After 2, 3, and 6 months the spines were harvested and assessed for changes in BMD and histomorphometric indices. BMD did not change after cessation of steroid treatment. After 2 months BV/TV increased in the vicinity of the pellets containing the fast-release rhBMP-2 and was sustained for the duration of the study. Focal voids surrounding all implants, particularly the slow-release formulation, were observed initially but resolved with time. Increased BV/TV adjacent to rhBMP-2 pellets suggests it could be used for localized treatment of osteoporosis. Refinement of the delivery system and supplementary treatments may be necessary to overcome the initial catabolic effects of rhBMP-2. PMID- 23737208 TI - Reactive oxygen species: impact on skeletal muscle. AB - It is well established that contracting muscles produce both reactive oxygen and nitrogen species. Although the sources of oxidant production during exercise continue to be debated, growing evidence suggests that mitochondria are not the dominant source. Regardless of the sources of oxidants in contracting muscles, intense and prolonged exercise can result in oxidative damage to both proteins and lipids in the contracting myocytes. Further, oxidants regulate numerous cell signaling pathways and modulate the expression of many genes. This oxidant mediated change in gene expression involves changes at transcriptional, mRNA stability, and signal transduction levels. Furthermore, numerous products associated with oxidant-modulated genes have been identified and include antioxidant enzymes, stress proteins, and mitochondrial electron transport proteins. Interestingly, low and physiological levels of reactive oxygen species are required for normal force production in skeletal muscle, but high levels of reactive oxygen species result in contractile dysfunction and fatigue. Ongoing research continues to explore the redox-sensitive targets in muscle that are responsible for both redox regulation of muscle adaptation and oxidant-mediated muscle fatigue. PMID- 23737222 TI - Recommendations for post-implant monitoring of patients with cardiovascular implantable electronic devices: where do we stand today? PMID- 23737223 TI - Remote follow-up and continuous remote monitoring, distinguished. AB - Remote device management involves remote follow-up (which replace periodic in clinic device interrogations for assessing device function), remote monitoring (with unscheduled transmissions of alerts such as atrial fibrillation), and patient-initiated interrogations (that are initiated manually due to a perceived or real clinical event). This article overviews the different aspects related to these functions. PMID- 23737224 TI - Role of home monitoring in children with implantable cardioverter defibrillators for Brugada syndrome. AB - AIMS: Implementation of remote home monitoring systems (HM) in clinical practice has become undoubtedly an added value for all patients with implantable cardiac devices. The aim of this study was to investigate the impact of HM in a population of children with Brugada syndrome (BS) who received an implantable cardioverter defibrillator (ICD). METHODS AND RESULTS: Eleven children (age between 6 months and 18 years) implanted with an ICD were followed either by means of HM and with conventional in-hospital visits in our centre. Alerts and/or device-related clinical events were recorded, analysed, and subsequent clinical decisions were made if needed. During an average observation time of 26 months a total of 16 relevant alerts (13 pre-emptive alerts) were recorded in seven patients of our population. One patient experienced appropriate therapies for life-threatening ventricular arrhythmias. Three patients experienced inappropriate therapies due to supraventricular tachycardia and lead dislodgement. By means of HM two patients were discovered to have lead problems because of dislodgement or lead fracture. Mean anticipation of treatment based on the alerts was 76 +/- 59 days. CONCLUSION: Remote monitoring systems substantially improve the proper management of children with BS. PMID- 23737225 TI - Automatic remote home monitoring of implantable cardioverter defibrillator lead and generator function: a system that tests itself everyday. AB - The implantation of cardiac electronic devices (CIEDs) has increased exponentially over the last decade in response to widening indications. Assessment of post-implant system performance is an important responsibility but challenging in view of increasing volume, device complexity, and advisory notices. Automatic remote home monitoring (HM) may satisfy these difficult monitoring demands. When tested, HM enhanced the discovery of system issues (even when asymptomatic) and enabled prompt clinical decisions regarding conservative vs. surgical management. This form of remote monitoring may form a device management model in which near-continuous remote surveillance of CIED performance is combined with automatic self-declaration of system problems, enabling prompt medical decisions. The ability to collect detailed device-specific data, with component function assessed daily, sets a precedent for longitudinal evaluation of lead and generator performance. These characteristics have significant ramifications for CIEDs in general and patient safety. PMID- 23737226 TI - Remote monitoring as a key innovation in the management of cardiac patients including those with implantable electronic devices. AB - This Introduction to the Supplement provides a brief history of remote monitoring, discusses its current status, and indicates the bright future that it possesses with a broad application in many branches of cardiology, at least including arrhythmias, heart failure, and ischaemic heart disease in addition to the management of implantable electronic devices. PMID- 23737227 TI - Expert commentary: how well has the call from Heart Rhythm Society/European Heart Rhythm Association for improved device monitoring been answered? AB - This commentary highlights the benefits of remote device monitoring and explores some of the challenges implementation of this technology worldwide. PMID- 23737228 TI - Disease management: atrial fibrillation and home monitoring. AB - Device-detected atrial fibrillation (AF) episodes predict poor clinical outcome regardless of symptoms. Potential benefits of remote monitoring are early arrhythmia detection and patient continuous monitoring. Several studies of device remote monitoring consistently demonstrated that AF represents the most common clinical alert and that detailed information on arrhythmia onset, duration, and burden as well as on the ventricular rate may be early available for clinical evaluation. Reaction time to AF alerts was very short in all series involving either pacemakers or defibrillators and action ability of AF alerts was very high. In the Home Guide Registry, in which 1650 patients were enrolled, AF was detected in 16.3% of patients and represented 36% of all cardiovascular events during the follow-up. Timely anticoagulation introduction in asymptomatic patients may impact on the stroke rate. According to the results of repeated Monte Carlo simulations based on a real population of 166 patients, daily monitoring may reduce the 2-year stroke risk by 9-18% with an absolute reduction of 0.2-0.6%, compared with conventional inter-visit intervals of 6-12 months. In the COMPAS trial, the incidence of hospitalizations for atrial arrhythmias and related stroke was significantly higher in the control group than in the remote monitoring group. Major questions will be addressed by the ongoing IMPACT trial in which a remote monitoring guided anticoagulation strategy based on AF detection will be compared with a physician-directed standard strategy. In patients with heart failure, AF early detection combined with other indexes may help prevent hospitalizations. PMID- 23737229 TI - Disease management: remote monitoring in heart failure patients with implantable defibrillators, resynchronization devices, and haemodynamic monitors. AB - Heart failure represents a major public health concern, associated with high rates of morbidity and mortality. A particular focus of contemporary heart failure management is reduction of hospital admission and readmission rates. While optimal medical therapy favourably impacts the natural history of the disease, devices such as cardiac resynchronization therapy devices and implantable cardioverter defibrillators have added incremental value in improving heart failure outcomes. These devices also enable remote patient monitoring via device-based diagnostics. Device-based measurement of physiological parameters, such as intrathoracic impedance and heart rate variability, provide a means to assess risk of worsening heart failure and the possibility of future hospitalization. Beyond this capability, implantable haemodynamic monitors have the potential to direct day-to-day management of heart failure patients to significantly reduce hospitalization rates. The use of a pulmonary artery pressure measurement system has been shown to significantly reduce the risk of heart failure hospitalization in a large randomized controlled study, the CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial. Observations from a pilot study also support the potential use of a left atrial pressure monitoring system and physician-directed patient self-management paradigm; these observations are under further investigation in the ongoing LAPTOP-HF trial. All these devices depend upon high-intensity remote monitoring for successful detection of parameter deviations and for directing and following therapy. PMID- 23737230 TI - Remote monitoring and the twin epidemics of atrial fibrillation and chronic heart failure. PMID- 23737231 TI - Workflow, time and patient satisfaction from the perspectives of home monitoring. AB - Remote monitoring of cardiac implantable electronic devices improves device surveillance and patient clinical management. The greatest challenge in implementing remote monitoring in standard practice is the need to develop new organizational models, capable of combining clinical effectiveness, low resource consumption, and patient acceptance. Since 2005, we developed a new model based on 'Primary Nursing' in which each patient is assigned to a nurse responsible for continuity of care. The model is essentially based on a cooperative interaction between the roles of an expert reference nurse and a responsible physician with an agreed list of respective tasks and responsibilities. After a pilot experience, the model was tested in a wide registry, the HomeGuide Registry, in which 1650 patients were enrolled. In this setting, remote monitoring sensitivity in detecting major cardiovascular events was very high (84%) with a positive predictive value of 97%. Overall, 95% of asymptomatic and 73% of actionable events were detected during remote monitoring sessions with a median reaction time of 3 days. Manpower was remarkably low: 55.5 min per health personnel per month every 100 patients. The strongest points of this model include strict definition of workflow, early reaction, traceability, continuity of care, maintaining human relationship with the patient. This model has been tested successfully even in a multicentre setting in the Model Project Monitor Centre study, in which one monitor centre screened daily remote monitoring data from nine satellite clinics. PMID- 23737232 TI - Cost efficiency and reimbursement of remote monitoring: a US perspective. AB - Demographic and technological changes are driving increased utilization of cardiac implantable electronic devices (CIEDs) remote monitoring. In the USA, fee for-service model of healthcare delivery, services rendered are valued based upon time, intensity, and technical or practice expense costs. As a consequence of this perspective, and to contain spending, Medicare has grouped physician services into families. Spending within each family of services must, by law, remain budget neutral. Cardiac implantable electronic devices monitoring services, remote and in-person, are grouped into one family. As the volume of services within this family increases, the individual encounters are destined to be discounted into ever decreasing portions. However, if the value of remote monitoring is demonstrated to extend beyond the previous boundaries of in-person interrogations, a rational request can be made to reconsider the relative value of remote monitoring. Outcome data supporting the value-added benefits of remote monitoring are rapidly accumulating, including (i) patient convenience, with reduced use of office services, (ii) equal safety compared with in-person evaluation, (iii) shorter detection time to actionable events (arrhythmias, cardiovascular disease progression, and device malfunction), (iv) reduced length of stay for hospitalizations, (v) reduced inappropriate shocks, (vi) increased battery longevity, and (vii) a relative reduction in the risk of death. Fully automatic wireless technology, only recently widely implemented, will add considerable clinical efficiencies and further increase the value of remote monitoring. The U.S. challenge will be to appropriately define the relative value of CIEDs remote monitoring now that outcome data have demonstrated its value extends beyond in-person interrogation. PMID- 23737233 TI - Remote monitoring costs, benefits, and reimbursement: a European perspective. AB - AIMS: To provide a European perspective on reimbursement issues surrounding remote monitoring of cardiac implantable electronic devices in view of the anticipated costs and benefits. METHODS AND RESULTS: Review of recent literature addressing clinical, economic, sociocultural, and technological factors associated with remote monitoring. When healthcare transformation is urgently needed, remote monitoring offers opportunities to innovate and cope with escalating costs and constrained resources, while improving patient safety, quality, and access to care as reflected in clinical studies. The introduction of remote monitoring into daily practice requires analysis of reimbursement policies to address funding scope, payment method, payer, price and allocation, and alignment with health system objectives and goals to ensure financial and operational sustainability of resources, infrastructure, and processes. Remote monitoring policies should gradually transition from activity-based, added-value services in a care-and-cure setting, to performance and outcome-oriented highlighting prevention, surveillance, and empowerment. By encouraging and rewarding innovation and interoperability, proprietary remote monitoring technologies can open up using standards and connect to support a growing evidence base that guides clinical decision support and planning of future policies. CONCLUSION: Careful planning, sharing of experiences, and gradual adoption of reimbursement models that focus on outcome, performance, and cost effectiveness are key aspects of containing escalating costs and improving quality and access to healthcare. Despite differences in health systems and payment methods in Europe, policy-makers, professional societies, payers, providers, and the industry need to join forces to transform healthcare and make innovation happen. PMID- 23737234 TI - Current clinical evidence for remote patient management. AB - Pacemaker (PM) and implantable cardioverter defibrillator (ICD) patients are ideally suited to remote management in the form of remote follow-up as well as of remote monitoring, which are both acts of telemedicine. Large randomized trials, such as TRUST, COMPAS, CONNECT, ECOST and EVOLVO, and the huge ALTITUDE registry provided a high level of evidence for the multiple advantages of remote management. These trials demonstrated the capability of early detection of events, the ability to reduce the incidence of inappropriate shocks and also of all charged shocks and this despite fewer in-clinic visits for the patients. The studies also demonstrated the safety of remote management of ICD and PM patients and moreover its positive impact on the survival of patients. Thereby, remote monitoring is clinically much more effective and efficient than conventional follow-up. PMID- 23737235 TI - Remote monitoring of cardiac implantable devices in the Asia-Pacific. AB - Remote monitoring of pacemakers and implantable cardioverter defibrillators (ICDs) has emerged as a tool to replace regular follow-up of such devices, and to detect hardware failure, arrhythmias, and heart failure decompensation. The Asia Pacific region is a geographically diverse area, with widely different cardiac device implant rates and expertise. However, common to all countries, distance and logistic for patients to reach an expert monitoring centre for routine follow up are significant, and in some countries, this will likely be replaced by remote monitoring. Unscheduled visits such as for the treatment of atrial fibrillation and ICD shocks will be expedited. There has been an increase in both pacemaker and ICD implant rates in Asia-Pacific, due to an ageing population and improvement in economic condition. Among the countries, Australia and Japan are the major users of remote monitoring. According to the statistics of the suppliers, in Australia, up to 15% of pacemakers, 40% ICD, and 30% cardiac resynchronization therapy (CRT)/cardiac resynchronization therapy defibrillator (CTRD) are remotely monitored. The corresponding numbers for Japan are 5, 50, and 50% respectively. The monitoring personnel include nurses, technicians, and doctors, either from local centre or from device companies. Cost, lack of reimbursement, and logistic support are major issues in widespread application of remote monitoring technology. In conclusion, remote monitoring is increasing in Asia-Pacific region despite the increase in cost. Implantable cardioverter defibrillators and CRT/CRTDs are more likely than pacemakers to be enabled with remote monitoring. PMID- 23737236 TI - Automatic remote monitoring: milestones reached, paths to pave. PMID- 23737237 TI - Pathophysiology of infective endocarditis. AB - Infective endocarditis (IE) is an uncommon infection, occurring as a complication in varying percentages of bacteremic episodes. The ability of an organism to cause endocarditis is the result of an interplay between the predisposing structural abnormalities of the cardiac valve for bacterial adherence, the adhesion of circulating bacteria to the valvular surface, and the ability of the adherent bacteria to survive on the surface and propagate as vegetation or systemic emboli. Certain bacteria, if present in the bloodstream, may colonize the initially sterile vegetation composed of fibrin and platelets; bacterial growth enlarges the vegetation, further impeding blood flow and inciting inflammation that involves the vegetation and adjacent endothelium. The true incidence of endocarditis complicating each of the bacterial species causing IE is difficult to estimate. About 20 %-30 % of individuals with community-acquired staphylococcal bacteremia develop IE [1, 2]. PMID- 23737238 TI - ClogP(alk): a method for predicting alkane/water partition coefficient. AB - Alkane/water partition coefficients (P(alk)) are less familiar to the molecular design community than their 1-octanol/water equivalents and access to both data and prediction tools is much more limited. A method for predicting alkane/water partition coefficient from molecular structure is introduced. The basis for the ClogP(alk) model is the strong (R2 = 0.987) relationship between alkane/water partition coefficient and molecular surface area (MSA) that was observed for saturated hydrocarbons. The model treats a molecule as a perturbation of a saturated hydrocarbon molecule with the same MSA and uses increments defined for functional groups to quantify the extent to which logP(alk) is perturbed by the introduction each functional group. Interactions between functional groups, such as intramolecular hydrogen bonds are also parameterized within a perturbation framework. The functional groups and interactions between them are specified substructurally in a transparent and reproducible manner using SMARTS notation. The ClogP(alk) model was parameterized using data measured for structurally prototypical compounds that dominate the literature on alkane/water partition coefficients and then validated using an external test set of 100 alkane/water logP measurements, the majority of which were for drugs. PMID- 23737240 TI - Investigation of the porous structure of cellulosic substrates through confocal laser scanning microscopy. AB - At the most fundamental level, saccharification occurs when cell wall degrading enzymes (CWDEs) diffuse, bind to and react on readily accessible cellulose fibrils. Thus, the study of the diffusive behavior of solutes into and out of cellulosic substrates is important for understanding how biomass pore size distribution affects enzyme transport, binding, and catalysis. In this study, fluorescently labeled dextrans with molecular weights of 20, 70, and 150 kDa were used as probes to assess their diffusion into the porous structure of filter paper. Fluorescence microscopy with high numerical aperture objectives was used to generate high temporal and spatial resolution datasets of probe concentrations versus time. In addition, two diffusion models, including a simple transient diffusion and a pore grouping diffusion models, were developed. These models and the experimental datasets were used to investigate solute diffusion in macro- and micro-pores. Nonlinear least squares fitting of the datasets to the simple transient model yielded diffusion coefficient estimates that were inadequate for describing the initial fast diffusion and the later slow diffusion rates observed; on the other hand, nonlinear least squares fitting of the datasets to the pore grouping diffusion model yielded estimations of the micro-pore diffusion coefficient that described the inherently porous structure of plant-derived cellulose. In addition, modeling results show that on average 75% of the accessible pore volume is available for fast diffusion without any significant pore hindrance. The method developed can be applied to study the porous structure of plant-derived biomass and help assess the diffusion process for enzymes with known sizes. PMID- 23737239 TI - A biodegradable thermoset polymer made by esterification of citric acid and glycerol. AB - A new biomaterial, a degradable thermoset polymer, was made from simple, economical, biocompatable monomers without the need for a catalyst. Glycerol and citric acid, nontoxic and renewable reagents, were crosslinked by a melt polymerization reaction at temperatures from 90 to 150 degrees C. Consistent with a condensation reaction, water was determined to be the primary byproduct. The amount of crosslinking was controlled by the reaction conditions, including temperature, reaction time, and ratio between glycerol and citric acid. Also, the amount of crosslinking was inversely proportional to the rate of degradation. As a proof-of-principle for drug delivery applications, gentamicin, an antibiotic, was incorporated into the polymer with preliminary evaluations of antimicrobial activity. The polymers incorporating gentamicin had significantly better bacteria clearing of Staphylococcus aureus compared to non-gentamicin gels for up to 9 days. PMID- 23737241 TI - Large-scale analysis of the dynamics of enzymes. AB - Protein enzymes enable the cell to execute chemical reactions in short time by accelerating the rate of the reactions in a selective manner. The motions or dynamics of the enzymes are essential for their function. Comparison of the dynamics of a set of 1247 nonhomologous enzymes was performed. For each enzyme, the slowest modes of motion are calculated using the Gaussian network model (GNM) and they are globally aligned. Alignment is done using the dynamic programming algorithm of Needleman and Wunsch, commonly used for sequence alignment. Only 96 pairs of proteins were identified to have three similar GNM slow modes with 63 of them having a similar structure. The most frequent slowest mode of motion describes a two domains anticorrelated motion that characterizes at least 23% of the enzymes. Therefore, dynamics uniqueness cannot be accounted for by the slowest mode itself but rather by the combination of several slow modes. Different quaternary structure packing can restrain the motion of enzyme subunits differently and may serve as another mechanism that increases the dynamics uniqueness. PMID- 23737242 TI - Antibacterial activity of a lectin-like Burkholderia cenocepacia protein. AB - Bacteriocins of the LlpA family have previously been characterized in the gamma proteobacteria Pseudomonas and Xanthomonas. These proteins are composed of two MMBL (monocot mannose-binding lectin) domains, a module predominantly and abundantly found in lectins from monocot plants. Genes encoding four different types of LlpA-like proteins were identified in genomes from strains belonging to the Burkholderia cepacia complex (Bcc) and the Burkholderia pseudomallei group. A selected recombinant LlpA-like protein from the human isolate Burkholderia cenocepacia AU1054 displayed narrow-spectrum genus-specific antibacterial activity, thus representing the first functionally characterized bacteriocin within this beta-proteobacterial genus. Strain-specific killing was confined to other members of the Bcc, with mostly Burkholderia ambifaria strains being susceptible. In addition to killing planktonic cells, this bacteriocin also acted as an antibiofilm agent. PMID- 23737244 TI - Sexual dysfunction related to psychotropic drugs: a critical review part II: antipsychotics. AB - Sexual dysfunction is a potential side effect of antipsychotic drugs: this article presents a critical review of the current literature. Although many studies have been published on the subject, only some used a validated sexual function rating scale and most lacked either a baseline or placebo control or both. In addition, many of the studies on sexual dysfunction associated with antipsychotic medication are limited by other methodological flaws. However, there is consistent evidence to suggest that a large number of antipsychotic drugs adversely affect one or more of the 3 phases of sexual response (desire, arousal and orgasm). Among the antipsychotics, the so called "prolactin-raising" are probably most associated with sexual dysfunction, even if further studies to confirm this are needed: the reviewed literature shows no consistent evidence that any one antipsychotic drug has a significantly superior side effect profile over another and current information on this topic is often based on methodologically weak research. Clinicians must be aware of drug-induced sexual dysfunction, since its presence can have important consequences for clinical management and compliance. PMID- 23737243 TI - Pharmacodynamic effects of aripiprazole and ziprasidone with respect to p glycoprotein substrate properties. AB - INTRODUCTION: Aripiprazole, an atypical antipsychotic drug with mixed antagonism and agonism on dopamine D2 and serotonin receptors, is a substrate of the efflux transporter P-glycoprotein (P-gp). Here we tested the pharmacodynamic consequences of these properties in a P-gp deficient mouse model by studying the effects of aripiprazole and of ziprasidone on motor coordination. METHODS: The motor behaviour of wild-type (WT) and P-gp deficient [abcb1ab(-/-)] mice was investigated on a RotaRod. Mice received acute injections of either aripirazole or ziprasidone. For comparison, the dopamine receptor antagonist haloperidol and serotonin receptor ligands buspirone and ketanserin were also applied. RESULTS: Pharmacokinetic analyses revealed P-gp activity for aripiprazole and ziprasidone. This was indicated by 3.1- and 1.9-fold higher ratios of brain to plasma concentrations of drugs in knock-out to WT animals. Acute doses of ariprazole or ziprasidone impaired motor behaviour on the RotaRod. Effects were similar after injection of haloperidol, whereas the serotonin receptor ligands buspirone and ketanserin enhanced RotaRod performance. Genotype dependent differences of motor performance were found for aripiprazole but not for ziprasidone. DISCUSSION: Evidence was given that P-gp substrate properties have pharmacodynamic consequences for aripiprazole but not for ziprasidone and thus affect dopamine receptor related motor behaviour. PMID- 23737245 TI - Sexual dysfunction related to psychotropic drugs: a critical review--part I: antidepressants. AB - Sexual dysfunction is a potential side effect of antidepressant drugs: this article presents a critical review of the current literature. Although many studies have been published on this subject, only some have used a validated sexual function rating scale and most lacked either a baseline or placebo control or both. In addition, many of the studies on sexual dysfunction associated with antidepressants are limited by other methodological flaws. However, there is consistent evidence to suggest that antidepressant medication adversely affects one or more of the 3 phases of sexual response (desire, arousal and orgasm). Antidepressants with strong serotonergic properties have the highest rate of sexual side effects. Clinicians must be aware of drug-induced sexual dysfunction, since its presence can have important consequences on clinical management and compliance. PMID- 23737246 TI - Association between pulmonary hypertension and an atrial septal defect. PMID- 23737248 TI - Facile monolayer formation on SiO2 surfaces via organoboron functionalities. AB - More than they appear on the surface: The treatment of SiO2 nanoparticles under mild conditions with two organoboron derivatives led to boron-containing monolayers with different types of surface species (see picture) through the direct formation of Si-O-B bonds. The organoboron-modified SiO2 NPs showed selective reactivity towards diols. PMID- 23737247 TI - Anatomical characterization of athetotic and spastic cerebral palsy using an atlas-based analysis. AB - PURPOSE: To analyze diffusion tensor imaging (DTI) in two types of cerebral palsy (CP): the athetotic-type and the spastic-type, using an atlas-based anatomical analysis of the entire brain, and to investigate whether these images have unique anatomical characteristics that can support functional diagnoses. MATERIALS AND METHODS: We retrospectively analyzed the DTI of seven children with athetotic type, 11 children with spastic-type, and 20 healthy control children, all age matched. The severity of motor dysfunction was evaluated with the Gross Motor Function Classification System (GMFCS). The images were normalized using a linear transformation, followed by large deformation diffeomorphic metric mapping. For 205 parcellated brain areas, the volume, fractional anisotropy, and mean diffusivity were measured. Principal component analysis (PCA) was performed for the Z-scores of these parameters. RESULTS: The GMFCS scores in athetotic-type were significantly higher than those in spastic-type (P < 0.001). PCA extracted anatomical components that comprised the two types of CP, as well as the severity of motor dysfunction. In the athetotic group, the abnormalities were more severe than in the spastic group. In the spastic group, significant changes were concentrated in the lateral ventricle and periventricular structures. CONCLUSION: Our results quantitatively delineated anatomical characteristics that reflected the functional findings in two types of CP. PMID- 23737249 TI - Adduction moment increases with age in healthy obese individuals. AB - There is a need to understand how obesity and aging interact to cause an increased risk of medial knee osteoarthritis (OA). This study tested whether the knee adduction and flexion moments increase with age in healthy normal-weight and obese adults, as well as the mechanism of this increase. We analyzed whether ground reaction force magnitude, knee alignment, step width, toe-out angle, body volume distribution, and limb position (knee position relative to the pelvis center) are associated with the adduction moment and whether these variables also change with age. Ninety-six healthy volunteers (60 normal-weight and 36 obese) were tested using marker-based gait analysis; knee alignment was based on marker positions during quiet standing. Adduction moment increased with age in obese (R(2) = 0.19), but not in normal-weight individuals (R(2) = 0.01); knee flexion moment did not change with age in either group. In the obese, only knee alignment and limb position were related to the adduction moment (R(2) = 0.19 and 0.51), but only limb position changed with age (R(2) = 0.26). The resulting increase in adduction moment suggests greater medial compartment loads, which may combine with elevated levels of inflammation to contribute to the increased risk of medial OA in this population. PMID- 23737250 TI - Receptor for complement peptide C3a: a therapeutic target for neonatal hypoxic ischemic brain injury. AB - Complement is an essential component of inflammation that plays a role in ischemic brain injury. Recent reports demonstrate novel functions of complement in normal and diseased CNS, such as regulation of neurogenesis and synapse elimination. Here, we examined the role of complement-derived peptide C3a in unilateral hypoxia-ischemia (HI), a model of neonatal HI encephalopathy. HI injury was induced at postnatal day 9 (P9), and loss of hippocampal tissue was determined on P31. We compared WT mice with transgenic mice expressing C3a under the control of glial fibrillary acidic protein promoter, which express biologically active C3a only in CNS and without the requirement of a priori complement activation. Further, we injected C3a peptide into the lateral cerebral ventricle of mice lacking the C3a receptor (C3aR) and WT mice and assessed HI induced memory impairment 41 d later. We found that HI-induced tissue loss in C3a overexpressing mice was reduced by 50% compared with WT mice. C3a peptide injected 1 h after HI protected WT but not C3aR-deficient mice against HI-induced memory impairment. Thus, C3a acting through its canonical receptor ameliorates behavioral deficits after HI injury, and C3aR is a novel therapeutic target for the treatment of neonatal HI encephalopathy. PMID- 23737251 TI - The adolescent and young adult with cancer: state of the art--brain tumor. AB - The management of adolescents and young adults with brain tumors, which consist of many different histologic subtypes, continues to be a challenge. Better outcome with a decrease of the side effects of the disease and therapy and improvement of quality of life has been demonstrated in recent decades for some tumors. Significant differences in survival and cure are also observed between adult and pediatric tumors of the same histologic grade. Genetic, developmental, and environmental factors likely influence the type of tumor and response observed, even though no clear pathologic features differentiate these lesions among children, adolescents, and adults. Similarly, treatment strategies are not identical among these populations; most patients receive surgery, followed by radiation therapy and multiagent chemotherapy. Advances in understanding the biology underlying the distribution of tumors in adolescents and young adults may influence the development of prospective trials. A more individualized view of these tumors will likely influence stratification of patients in future studies as well as selection for targeted agents. Accordingly, outcomes may improve and long-term morbidities may decrease. PMID- 23737252 TI - Semi-rational engineering of cytochrome P450sca-2 in a hybrid system for enhanced catalytic activity: insights into the important role of electron transfer. AB - Hybrid P450 systems in which P450 monooxygenases are reconstituted with non native or surrogate redox partners have become important for the engineering of this class of versatile enzymes. P450sca-2 from Streptomyces carbophilus stereoselectively hydroxylates mevastatin to yield pravastatin, a cholesterol lowering drug. While S. carbophilus has been successfully applied in the industrial biotransformation process for pravastatin, the molecular study and engineering of P450sca-2 has been very limited. We have previously established a functional P450sca-2/Pdx/Pdr hybrid system. In this study, on the basis of a more active P450sca-2 mutant (R8-5C), five sites located in the substrate binding pocket, substrate access entrance, and presumed Pdx interaction interface were rationally chosen, and systematically subjected to site-directed saturation mutagenesis (SDSM), and three rounds of iterative saturation mutagenesis (ISM). A best mutant (Variant III) was obtained, which showed a whole cell biotransformation activity (377.5 mg/L) and an overall apparent k(cat) (6.37 min 1) that was 7.1- and 10.0-fold that of the starting template R8-5C, respectively. Kinetic characterization revealed that most of the improvements seen for the SDSM and ISM mutants came from enhanced overall electron transfer, with the two sites at the interface between P450sca-2 and Pdx (T119 and N363) being most critical. Our study underscores the important role of electron transfer in a hybrid P450 system, and also demonstrates the utility of ISM in optimizing the redox partner interface. This should facilitate engineering of this and other important hybrid P450 systems. PMID- 23737253 TI - SNCA rs356219 variant increases risk of sporadic Parkinson's disease in ethnic Chinese. AB - Alpha-synuclein gene (SNCA) polymorphisms have been associated with Parkinson's disease (PD). A recently published genome-wide association study (GWAS) meta analysis from the USA and Europe found a strong association between SNCA rs356219 and PD. Considering the population-specific heterogeneity, we investigated the role of SNCA rs356219 as PD susceptibility in a large Han Chinese population of 685 patients and 569 controls. The SNCA rs356219-G allele was found to increase the risk to develop PD (OR = 1.81, 95% CI: 1.54-2.13, P = 5.71E-13). The meta analysis revealed that the frequency of AG + GG genotypes higher in PD than in control subjects (OR = 1.85, 95% CI: 1.56-2.19, P = 0.00001) in the Asian population. PD patients with AG + GG genotypes were associated with earlier age at onset compared with those with AA genotype. No such significant association was observed in the clinical presentation for gender, age at onset, and onset symptoms. Our study provides strong support for the susceptibility role of SNCA rs356219 in sporadic PD in a Han Chinese population from mainland China and the meta-analysis also revealed a similar finding in the Asian population. PMID- 23737254 TI - Physics-based protein structure refinement through multiple molecular dynamics trajectories and structure averaging. AB - We used molecular dynamics (MD) simulations for structure refinement of Critical Assessment of Techniques for Protein Structure Prediction 10 (CASP10) targets. Refinement was achieved by selecting structures from the MD-based ensembles followed by structural averaging. The overall performance of this method in CASP10 is described, and specific aspects are analyzed in detail to provide insight into key components. In particular, the use of different restraint types, sampling from multiple short simulations versus a single long simulation, the success of a quality assessment criterion, the application of scoring versus averaging, and the impact of a final refinement step are discussed in detail. PMID- 23737255 TI - Salivary IgA response to probiotic bacteria and mutans streptococci after the use of chewing gum containing Lactobacillus reuteri. AB - We investigated whether ingestion of probiotic bacteria could influence salivary IgA levels, specific anti-mutans streptococci IgA levels and specific antibodies towards the ingested probiotic bacterium. The study was a randomised, double blind, placebo-controlled trial, where the test group (n = 11) received twice daily chewing of gum containing Lactobacillus reuteri (2 * 10(8) CFU per dose) and the control group (n = 12) received placebo. Resting saliva was collected before and after 12 weeks of treatment and 4 weeks after end of treatment. Total salivary IgA concentrations were measured by ELISA. Specific IgA reactivity was determined using a whole-cell ELISA. Results were expressed as % IgA per protein in saliva. The level of total IgA% per protein increased significantly between pretreatment levels (13.5%) and follow-up treatment levels (14.4%) within the test group only (P < 0.05). No changes were seen in the control group during the trial. The level of probiotic-reactive antibodies decreased significantly between pre- and post-treatment samples (from 12.2% to 9.0%, P < 0.05) in the test group. Similarly, the level of specific mutans streptococci antibodies decreased significantly between pre- and post-treatment samples (P < 0.05) in the test group only (for Streptococcus mutans from 20.1% to 15.0%; for Streptococcus sobrinus from 7.4% to 5.3%). Ingestion of probiotic bacteria might influence the adaptive immune response of the host. PMID- 23737256 TI - Width of the cervical intervertebral neuroforamina after total disc replacement with the Cerkinetic prosthesis: a three-dimensional simulation using a computer aided design model. AB - INTRODUCTION: Physiological cervical intervertebral motion inherently induces a neuroforaminal volume change. Integration of an artificial motion component within this intervertebral kinematic system may cause neuroforamina to lose their ability for continuous and instantaneous volume adaptation, inducing foraminal stenosis. The purpose of the current study is to virtually simulate a newly developed cervical total disc replacement (TDR) to evaluate the neuroforaminal dimensions at rest and during motion. MATERIALS AND METHODS: In a three dimensional computer-aided design model of the spine, the Cerkinetic (OrthoKinematica Ltd., Haifa, Israel) TDR was virtually implanted at the C5-C6 disc space. The TDR consists of a bearing mechanism with an elliptical protuberance and a recess, allowing a progressive increase of the intervertebral axial spacing in all three dimensions and in line with flexion and extension. Translations are performed in accordance with the physiological forces influencing the disc space and spinal continuum. The minimal proximal neuroforaminal width was defined and evaluated at rest and motion. RESULTS: A progressive increase (15.2% at 6 degrees) in flexion and a decrease (12.3% at 6 degrees) in extension of the neuroforaminal width were observed. With axial motion, a progressive increase (44.6% at 6 degrees) of the right neuroforamen width as well as a decrease of the left neuroforamen width (15.3% at 6 degrees) were seen. CONCLUSION: The TDR under investigation simulates the intervertebral kinematics, allowing a physiological adjustment of the facet joints in rest and motion. This preserves the ability of the neuroforamina to maintain their capability of changing their dimensions. PMID- 23737257 TI - One-pot synthesis of an acid-labile amphiphilic triblock copolymer and its pH responsive vesicular assembly. PMID- 23737258 TI - Quality of labour neuraxial analgesia and maternal satisfaction at a tertiary care teaching hospital: a prospective observational study. AB - PURPOSE: Current labour analgesia practices are evidence-based; however, such evidence often originates in controlled trials, the results of which may not be readily applicable in the context of day-to-day clinical practice. The objective of this study was to evaluate the effectiveness of and maternal satisfaction with the neuraxial labour analgesia regimen provided at a tertiary care teaching hospital. METHODS: All women with a viable pregnancy who requested neuraxial analgesia for labour during November 2011 at our institution were approached to participate in this prospective study. Patients were managed as per departmental routine based on a patient-controlled epidural analgesia regimen with a maintenance solution of 0.0625% bupivacaine and fentanyl 2 MUg.mL(-1). Demographic and obstetric data, characteristics of the neuraxial analgesia, pain scores, side effects, and complications were recorded. After delivery, patients completed a satisfaction questionnaire. RESULTS: All 332 eligible women were approached, and 294 completed the study. Most women received epidural analgesia and considered its placement comfortable. A large number of women reported having experienced pain during the first or second stages of labour (38% and 26%, respectively). Although 24.4% of women required top-ups both by nurses and physicians, adjustment in the local anesthetic maintenance concentration was made in only 7.8% of the cases. Most women (92%) were satisfied with the quality of analgesia. Unintentional dural puncture occurred in three (1%) cases, and there were no cases of intravascular catheter insertion or systemic local anesthetic toxicity. Overweight women (body mass index 25-30 kg.m(-2)) (adjusted odds ratio [AOR] = 2.56; 95% confidence interval [CI]: 1.1 to 5.97), those undergoing induced labour (AOR = 2.4; 95% CI: 1.2 to 5.2), and those requiring top-ups by the anesthesiologist (AOR = 5.08; 95% CI: 2.31 to 11.11) were associated with more dissatisfaction with pain control during the first stage of labour. CONCLUSION: Although our technique with dilute local anesthetic-opioid infusion was considered effective in previous randomized clinical trials, it did not provide sufficient labour analgesia for a large proportion of women. Nevertheless, most women were satisfied with their pain management and childbirth experience. Strategies to individualize care for labour and delivery should be readily available while providing labour analgesia. PMID- 23737259 TI - Enhancement in a brain glioma model: a comparison of half-dose gadobenate dimeglumine versus full-dose gadopentetate dimeglumine at 1.5 and 3 T. AB - PURPOSE: To examine dose reduction comparing enhancement with full-dose gadopentetate dimeglumine (0.1 mmol/kg) to half-dose gadobenate dimeglumine in a rat brain glioma model. MATERIALS AND METHODS: Intra-axial parenchymal brain tumors were implanted in 17 experimental animals. The 13 surviving animals were imaged at 1.5 or 3 T. Either gadopentetate dimeglumine or gadobenate dimeglumine was injected in random order on consecutive days. Tumor signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and contrast enhancement (CE) for each agent were obtained with region of interest analyses and compared. Lesions were confirmed histopathologically. RESULTS: Statistically significantly lower SNR, CNR, and CE parameters were found at both 1.5 and 3 T with half-dose gadobenate dimeglumine relative to full-dose gadopentetate dimeglumine (P < 0.05). SNR on average at 3 T was 70.0 +/- 14.4 for gadopentetate dimeglumine and 57.0 0 +/- 4.8 for gadobenate dimeglumine (P < 0.02). CONCLUSION: Improved r1 relaxivity with gadobenate dimeglumine does not produce adequate half-dose contrast-enhancement relative to full-dose gadopentetate dimeglumine. PMID- 23737260 TI - MUFEA successfully exhibits higher stresses and strains in microdamaged regions of whole vertebrae. AB - Micro-finite element (MUFE) modeling has shown promise in evaluating the structural integrity of trabecular bone. Histologic microcrack analyses have been compared to MUFE models of trabecular bone cores to demonstrate the potential of this technique. To date this has not been achieved in whole bone structures, and comparisons of histologic microcrack and MUFE results have been limited due to challenges in alignment of 2D sections with 3D data sets. The goal of this study was to ascertain if image registration can facilitate determination of a relationship between stresses and strains generated from MUFE models of whole vertebrae and histologically identified microdamage. MUFE models of three whole vertebrae, stained sequentially with calcein and fuchsin, were generated with accurate integration of element sets representing the histologic sections based on volumetric image registration. Displacement boundary conditions were applied to the MUFE models based on registration of loaded and unloaded MUCT images. Histologically labeled damaged regions were found to have significantly higher von Mises stresses and principle strains in the MUFE models, as compared to undamaged regions. This work provides a new robust method for generating and histologically validating MUFE models of whole bones that can represent trabecular damage resulting from complex physiologic loading. PMID- 23737263 TI - Response to Mariani et al.: a second report of PARK2 duplication and developmental delay. PMID- 23737262 TI - Does proximal rectus femoris release influence kinematics in patients with cerebral palsy and stiff knee gait? AB - BACKGROUND: Stiff gait resulting from rectus femoris dysfunction in cerebral palsy commonly is treated by distal rectus femoris transfer (DRFT), but varying outcomes have been reported. Proximal rectus femoris release was found to be less effective compared with DRFT. No study to our knowledge has investigated the effects of the combination of both procedures on gait. QUESTIONS/PURPOSES: We sought to determine whether an additional proximal rectus release affects knee and pelvic kinematics when done in combination with DRFT; specifically, we sought to compare outcomes using the (1) range of knee flexion in swing phase, (2) knee flexion velocity and (3) peak knee flexion in swing phase, and (4) spatiotemporal parameters between patients treated with DRFT, with or without proximal rectus release. Furthermore the effects on (5) anterior pelvic tilt in both groups were compared. METHODS: Twenty patients with spastic bilateral cerebral palsy treated with DRFT and proximal rectus femoris release were matched with 20 patients in whom only DRFT was performed. Standardized three-dimensional gait analysis was done before surgery, at 1 year after surgery, and at a mean of 9 years after surgery. Basic statistics were done to compare the outcome of both groups. RESULTS: The peak knee flexion in swing was slightly increased in both groups 1 year after surgery, but was not different between groups. Although there was a slight but not significant decrease found the group with DRFT only, there was no significant difference at long-term followup between the groups. Timing of peak knee flexion, range of knee flexion, and knee flexion velocity improved significantly in both groups, and in both groups a slight deterioration was seen with time; there were no differences in these parameters between the groups at any point, however. There were no group differences in spatiotemporal parameters at any time. There were no significant differences in the long-term development of anterior pelvic tilt between the groups. CONCLUSIONS: The results of our study indicate that the short- and long-term influences of adding proximal rectus femoris release on the kinematic effects of DRFT and on pelvic tilt in children with cerebral palsy are negligible. LEVEL OF EVIDENCE: Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 23737264 TI - Production of non-proteinogenic amino acids from alpha-keto acid precursors with recombinant Corynebacterium glutamicum. AB - In the present work, Corynebacterium glutamicum was metabolically engineered for the enantioselective synthesis of non-proteinogenic amino acids as valuable building blocks for pharmaceuticals and agrochemicals. The novel bio-catalytic activity of C. glutamicum was obtained by heterologous expression of the branched chain aminotransferase IlvE from Escherichia coli. Upon this modification, the recombinant cells converted the alpha-keto acid precursor 2-(3-hydroxy-1 adamantyl)-2-oxoethanoic acid (HOAE) into the corresponding amino acid 2-(3 hydroxy-1-adamantyl)-(2S)-amino ethanoic acid (HAAE). Similarly, also L-tert leucine could be obtained from trimethyl pyruvate indicating a broader applicability of the novel strategy. In both cases, the amino group donor glutamate was supplied from the endogenous metabolism of the recombinant producer. Hereby, the uptake of the precursor and secretion of the product was supported by an enhanced cell permeability through treatment of ethambutol, which inhibits arabinosyl transferases involved in cell wall biosynthesis. The excretion of HAAE into the reaction medium was linked to the secretion of glutamate, indicating a similar mechanism for the export of both compounds. On the other hand, the efflux of L-tert-leucine appeared to be driven by active transport. Subsequent bioprocess engineering enabled HAAE and L-tert-leucine to be produced at a rate of 0.21 and 0.42 mmol (g dry cells)-1 h-1, respectively up to a final product titer of 40 mM. Beyond the given examples, integrated metabolic and cell envelop engineering might extend the production of a variety of other non-proteinogenic amino acids as well as chiral amines by C. glutamicum. PMID- 23737266 TI - Managing unscheduled bleeding in non-pregnant premenopausal women. PMID- 23737265 TI - Differences in recognition of wild-type and lipoprotein-deficient strains of oral Streptococci in vitro and in vivo. AB - Whole cells of wild-type strains of Streptococcus gordonii and Streptococcus mutans induced Toll-like receptor 2 (TLR2)-mediated nuclear factor-kappaB (NF kappaB) activation, whereas those of lipoprotein (LP)-deficient strains did not. All strains upregulated the proliferation of TLR2(+/+) splenocytes more strongly than TLR2(-/-) splenocytes. However, significant differences were not observed between the cytokine-inducing activities of wild-type and LP-deficient strains toward TLR2(+/+) and TLR2(-/-) splenocytes. Muramyl dipeptide as well as whole cells not only induced nucleotide-binding oligomerization domain 2 (NOD2) mediated activation of NF-kappaB but also enhanced the proliferation of TLR2(-/-) as well as TLR2(+/+) splenocytes. Wild-type strains of these streptococci were more resistant to clearance from blood and organs (liver and spleen) in TLR2(+/+) but not TLR2(-/-) mice and induced production of larger amounts of blood TNF alpha than the LP-deficient strains. Wild-type strains of both species adhered to human vascular endothelial cells more strongly than did the LP-deficient strains. Thus, this study suggested that LP plays an important role in the recognition of these streptococci by the host in vivo as well as in vitro and that these streptococci possess some components recognized by NOD2 and/or TLR2 that are involved in the mitogenic activity toward splenocytes. PMID- 23737267 TI - Do trusts ensure their workers are immune to measles, mumps, and rubella? PMID- 23737268 TI - Family and friends tests may not give us the answers we're looking for. PMID- 23737269 TI - Family and friends test is inappropriate for patients with cancer. PMID- 23737270 TI - Let the patient evolution continue. PMID- 23737271 TI - Value of a well organised team approach in primary care in managing patients with multimorbidity. PMID- 23737272 TI - Might doctors follow lawyers in plain English campaign? PMID- 23737273 TI - For whom was article on investigating suspected heart failure intended? PMID- 23737274 TI - What does article on investigating suspected heart failure add to current practice? PMID- 23737275 TI - Authors' reply to Davie and to Broughton and colleagues. PMID- 23737276 TI - Scotland's geographical disadvantage in the devolved NHS systems. PMID- 23737277 TI - Where is the evidence based on hard endpoints for the safety and effectiveness of sitagliptin in type 2 diabetes? PMID- 23737278 TI - Empowerment is inappropriate for equal citizens. PMID- 23737279 TI - Positive predictive value is poor in low risk populations seen in universal screening for HIV infection. PMID- 23737280 TI - Authors' reply to de Oliveira. PMID- 23737281 TI - Patient participation in decision making may raise cost of care, study shows. PMID- 23737282 TI - Contraception in Copenhagen. PMID- 23737283 TI - Study finds small association between statin use and musculoskeletal conditions. PMID- 23737284 TI - Architect of DSM-5 rejects claims it will lead to labelling of more people as mentally ill. PMID- 23737285 TI - A reliable method to quantify sildenafil and its metabolite N-demethylsildenafil by HPLC in plasma of children. AB - The aim of this study was to develop a simple method for quantifying plasma levels of sildenafil and its metabolite by liquid chromatography with a C18 reverse-phase column and UV detection. For both compounds, linearity was assessed in the range from 10 and 1 000 ng . ml-1 and had correlation coefficients of r=0.995 and r=0.997 for sildenafil and its metabolite, respectively. The inter- and intra-day coefficients of variation was<5.3%. The limits of detection and quantification were 1 and 10 ng . ml-1. Drug levels were determined satisfactorily in two patients. A simple and reliable method was developed for use in children with Pulmonary Arterial Hypertension under treatment with sildenafil. PMID- 23737286 TI - Differential cochlear implant outcomes in older adults. AB - OBJECTIVES/HYPOTHESIS: The goals of this study were to analyze whether cochlear implant (CI) users over 65 years of age have different surgical and audiological outcomes when compared to younger adult CI users and to identify reasons for these possible differences. STUDY DESIGN: Retrospective single-institution study. METHODS: Records of 113 postlingually deafened adults with unilateral cochlear implants were reviewed. Preoperative and postoperative speech perception scores, and medical and epidemiological data were recorded and analyzed. RESULTS: Speech perception ability was significantly poorer in CI users over 65 years of age compared to younger adult patients (P = .012). Patients over the age of 80 years accounted for these findings (P = .017). Older patients were less likely to have a family history of hearing deficits. A history of noise exposure and idiopathic cause of hearing loss did not correlate with audiological outcomes. A family history of hearing loss was associated with a trend toward better speech recognition (P = .062). Older patients did not experience more vestibular symptoms or other complications compared to younger patients. CONCLUSIONS: Patients over the age of 80 years had lower speech perception scores than other adult CI recipients but did not have higher rates of dizziness or vertigo after surgery. A family history of hearing loss was associated with a trend toward better speech recognition, possibly representing a new prognostic variable. These findings provide important information that will aid clinicians in counseling older CI candidates. PMID- 23737288 TI - Polymorphism rs7214723 in CAMKK1 and lung cancer risk in Chinese population. AB - Polymorphism rs7214723 was reported to be associated with lung cancer risk in UK Caucasians and caused the E375G substitution of CAMKK1 which plays important role in the calcium/calmodulin-dependent kinase cascade. To analyze rs7214723 in CAMKK1 and lung cancer risk in a Chinese population, SNPscan(TM) was used to genotype polymorphism rs7214723 in 961 lung cancer cases and 999 control subjects. The frequencies of the TT, TC, and CC genotypes of CAMKK1 rs7214723 were 43.3, 42.6, and 14.0 % in controls, and 41.1, 48.0, and 10.9 % in cases, respectively (P = 0.025). Compared with the CC genotype, TC genotype was associated with increased risk of lung cancer (OR 1.500, 95 % CI 1.112-2.022) after adjustment for age, gender, smoking status, and family history. The T allele of rs7214723 is the risk allele for lung carcinogenesis in dominant model (OR 1.354, 95 % CI 1.020-1.797). In stratified analysis, the risk effect of the TC genotype of rs7214723 was more evident in subgroups of those who had never been smokers (OR 1.556, 95 % CI 1.074-2.254). For the population without a family history of cancer, both the TT (OR 1.488, 95 % CI 1.050-2.109) and TC (OR 1.668, 95 % CI 1.180-2.357) carrier had an increased lung cancer risk. E375 is located in the kinase domain of CAMKK1, and E375G may change the electrical charge at the surface and decrease the kinase activity. Polymorphism rs7214723 in CAMKK1 might contribute to the risk of lung cancer in Chinese populations. The T allele is a risk allele in lung carcinogenesis. PMID- 23737287 TI - Current understanding of the role and targeting of tumor suppressor p53 in glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is the most common primary malignancy in the brain and confers a uniformly poor prognosis. Despite decades of research on the topic, limited progress has been made to improve the poor survival associated with this disease. GBM arises de novo (primary GBM) or via dedifferentiation of lower grade glioma (secondary GBM). While distinct mutations are predominant in each subtype, alterations of tumor suppressor p53 are the most common, seen in 25-30 % of primary GBM and 60-70 % of secondary GBM. Various roles of p53 that protect against neoplastic transformation include modulation of cell cycle, DNA repair, apoptosis, senescence, angiogenesis, and metabolism, resulting in an extremely complex signaling network. Mutations of p53 in GBM are most common in the DNA binding domain, namely within six hotspot mutation sites (codons 175, 245, 248, 249, 273, and 282). These alterations generally result in loss-of-function, gain of-function, and dominant-negative mutational effects for p53, however, the distinct effect of these mutation types in GBM pathogenesis remain unclear. Signaling alterations downstream from p53 (e.g., MDM2, MDM4, INK4/ARF), p53 isoforms (e.g., p63, p73), and microRNAs (e.g., miR-34) also play critical roles in modulating the p53 pathway. Despite novel mouse models of GBM showing that p53 combined with other mutation generate tumors de novo, the role of p53 as a molecular marker of GBM remains controversial with most studies failing to show an association with prognosis. Regarding treatment in GBM, p53 targeted-gene therapy and vaccinations have reached phase I clinical trials while therapeutic drugs are still in preclinical development. This review aims to discuss the most recent findings regarding the impact of p53 mutations on GBM pathogenesis, prognosis, and treatment. PMID- 23737289 TI - Prognostic significance of VEGF immunohistochemical expression in oral cancer: a meta-analysis of the literature. AB - Vascular endothelial growth factor (VEGF) is considered as a prime mediator of angiogenesis and has been implicated in carcinogenesis and metastasis. Various studies examined the relationship between VEGF protein overexpression with the clinical outcome in patients with oral cancer, but yielded conflicting results. Electronic databases updated to March 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between VEGF overexpression and survival of patients with oral cancer. Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of 17 studies (n = 1,207 patients) that evaluated the correlation between VEGF overexpression detected by immunohistochemistry and survival in patients with oral cancer. Combined hazard ratios suggested that VEGF overexpression had an unfavorable impact on overall survival (hazard ratio [HR] = 1.89; 95 % confidence interval [CI], 1.24-2.55) and disease-free survival (HR = 2.08; 95 % CI, 1.14-3.02) in patients with oral cancer: 1.77 (1.09-1.44) in oral squamous cell carcinoma (SCC) patients and 4.28 (1.35-7.21) in adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma (MEC) of the salivary glands. No significant heterogeneity was observed among all studies. VEGF overexpression indicates a poor prognosis for patients with oral SCC, ACC, and MEC of the salivary glands. PMID- 23737290 TI - Prognostic significance of mammalian sterile 20-like kinase 1 in breast cancer. AB - Mammalian sterile 20-like kinase 1 (Mst1) has been proved in the process of apoptosis and tumor suppression. The aim of the study was to investigate the expression of Mst1 in breast cancer and to evaluate its prognostic significance. The expression of Mst1 was examined in 110 breast cancer patients by immunohistochemistry, in which 80 (72.7 %) were defined as positive for Mst1 expression. Patients with negative expression of Mst1 had poor overall survival, comparing with those with positive expression using Kaplan-Meier survival analysis (P = 0.009). Multivariate analysis using Cox proportional hazards model showed that Mst1 expression was a significant independent prognostic factor in breast cancer (P = 0.030). Our results presented the tumor suppressive role of Mst1, and confirmed Mst1 was a prognostic factor in human breast cancer. PMID- 23737291 TI - Value of diffusion-weighted MR imaging performed with quantitative apparent diffusion coefficient values for cervical lymphadenopathy. AB - PURPOSE: To assess diffusion-weighted magnetic resonance imaging (DWI-MRI) performed with apparent diffusion coefficient (ADC) values for the detection of cervical lymphadenopathy. MATERIALS AND METHODS: Studies evaluating DWI-MRI for the detection of cervical lymphadenopathy were systematically searched for in the MEDLINE, EMBASE, Cancerlit, and Cochrane Library and other database from January 1995 to November 2010. By node-based data analyses, Cochrane methodology was used for the results of this meta-analysis. RESULTS: Eight studies enrolling a total of 229 individuals were eligible for inclusion. Significant differences were found between malignant nodes and benign nodes of the mean ADC value (WMD [weighted-mean difference]: 1.19, 95% CI: [1.02, 1.35] * 10(-3) mm(2) /s, [P < 0.05]). In the secondary outcomes, significant differences were found between lymphomatous nodes and benign nodes (WMD: 1.33, 95% CI: [0.89, 1.77] * 10(-3) mm(2) /s), and nodes originating from highly or moderately differentiated cancer (WMD: 0.24, 95% CI: [0.21, 0.28] * 10(-3) mm(2) /s, [P < 0.05]), and nodes originating from poorly differentiated cancers (WMD: 0.10, 95% CI: [0.06, 0.14] * 10(-3) mm(2) /s, [P < 0.05]). CONCLUSION: DWI-MRI performed with ADC values shows significant differences among malignant nodes, lymphomatous nodes, and benign nodes in cervical lymphadenopathy. PMID- 23737293 TI - A conserved tyrosine in ferritin is a molecular capacitor. AB - A highly conserved tyrosine residue of unknown function is present in the vicinity of the di-iron catalytic center of the ubiquitous iron-storage protein ferritin. The di-iron center with a gateway FeII/FeIII-binding site nearby provides the vital iron-storage mechanism of the protein. It is believed that, in eukaryotic ferritin, this center catalyzes simultaneous oxidation of two FeII ions, whereas in microbial ferritin it catalyzes simultaneous oxidation of three FeII ions. To understand the role of the conserved tyrosine, we studied the intermediates and products that are formed during catalysis of FeII oxidation in the di-iron catalytic centers of the hyperthermophilic archaeal Pyrococcus furiosus ferritin and of eukaryotic human H ferritin. Based on our spectroscopic studies and modeling, we propose a merger of the models for eukaryotic and bacterial ferritin into a common mechanism of FeII oxidation in which the conserved tyrosine acts as a single-electron molecular capacitor to facilitate oxidation of FeII. PMID- 23737292 TI - Integrin-mediated interactions with extracellular matrix proteins for nucleus pulposus cells of the human intervertebral disc. AB - The extracellular matrix (ECM) of the human intervertebral disc is rich in molecules that interact with cells through integrin-mediated attachments. Porcine nucleus pulposus (NP) cells have been shown to interact with laminin (LM) isoforms LM-111 and LM-511 through select integrins that regulate biosynthesis and cell attachment. Since human NP cells lose many phenotypic characteristics with age, attachment and interaction with the ECM may be altered. Expression of LM-binding integrins was quantified for human NP cells using flow cytometry. The cell-ECM attachment mechanism was determined by quantifying cell attachment to LM 111, LM-511, or type II collagen after functionally blocking specific integrin subunits. Human NP cells express integrins beta1, alpha3, and alpha5, with over 70% of cells positive for each subunit. Blocking subunit beta1 inhibited NP cell attachment to all substrates. Blocking subunits alpha1, alpha2, alpha3, and alpha5 simultaneously, but not individually, inhibits NP cell attachment to laminins. While integrin alpha6beta1 mediated porcine NP cell attachment to LM 111, we found integrins alpha3, alpha5, and beta1 instead contributed to human NP cell attachment. These findings identify integrin subunits that may mediate interactions with the ECM for human NP cells and could be used to promote cell attachment, survival, and biosynthesis in cell-based therapeutics. PMID- 23737294 TI - Outcome comparison between younger and older patients undergoing intracranial meningioma resections. AB - Studies directly comparing the outcomes of intracranial meningioma resection between elderly and younger patients are currently limited. This study aimed to assess the perioperative complications, mortalities and functional outcomes in these two groups. Consecutive elderly patients (aged >= 65) and tumor-location matched younger patients who underwent intracranial meningioma resections were retrospectively reviewed. Outcomes were assessed at 30-day, 90-day, 6-month and 1 year. We used a standardized classification of operative complications, and conducted subgroup analyses based on tumor location [convexity, parasagittal and falcine (CPF) as one group; skull base (SB) as another]. There were 92 patients in each group. The mean age was 74.6 +/- 6.4 years in the elderly and 49.3 +/- 10.1 years in the younger groups. The cumulative 30-day, 90-day and 1-year mortality rates were 0, 2.2 and 4.3 % for the elderly, respectively, and 1.1 % for all time points in the young. These differences were not statistically significant. Overall, the elderly suffered from more perioperative complications (P = 0.010), and these were mostly minor complications according to the classification of operative complications. However, these differences were observed only in the SB but not in the CPF subgroup. More elderly patients had impaired functional outcome 1-year after surgery. Significantly more elderly patients had new neurological deficits 1-year after surgery (26.1 vs. 6.6 %; P = 0.001). Comparable mortality rates were observed in elderly and younger patients. However, the elderly had more minor complications and poorer functional outcomes. Patient selection remains key to good clinical outcome. PMID- 23737295 TI - CHO cell line specific prediction and control of recombinant monoclonal antibody N-glycosylation. AB - Here we demonstrate that it is possible to predict and control N-glycan processing of a secreted recombinant monoclonal antibody during manufacturing process development using a combination of statistical modelling and comparative measurement of cell surface glycans using fluorescent lectins. Using design of experiments--response surface modelling (DoE-RSM) methodology to adjust the relative media concentrations of known metabolic effectors of galactosylation (manganese, galactose, and uridine) we have shown that beta1,4-galactosylation of the same recombinant IgG4 monoclonal antibody produced by different CHO cell lines can be precisely controlled in a cell line specific manner. For two cell lines, monoclonal antibody galactosylation could be increased by over 100% compared to control, non-supplemented cultures without a reduction in product titre and with minimal effect on cell growth. Analysis of galactosylation effector interactions by DoE-RSM indicated that Mn2+ alone was necessary but not sufficient to improve galactosylation, and that synergistic combinations of Gal and Urd were necessary to maximize galactosylation, whilst minimizing the deleterious effect of Urd on cell growth. To facilitate rapid cell culture process development we also tested the hypothesis that substrate-level control of cellular galactosylation would similarly affect both cell surface and secreted monoclonal antibody glycans, enabling facile indirect prediction of product glycan processing. To support this hypothesis, comparative quantitation of CHO cell surface beta1,4-galactosylation by flow cytometry using fluorescent derivatives of RCA and ConA lectins revealed that substrate-controlled variation in monoclonal antibody galactosylation and cell surface galactosylation were significantly correlated. Taken together, these data show that precision control of a complex, dynamic cellular process essential for the definition of protein product molecular heterogeneity and bioactivity is possible. Moreover, real-time, or near real-time control can be enabled by facile, rapid measurement of cell surface biomarkers of cellular biosynthetic capability. PMID- 23737296 TI - Emotion regulation difficulties mediate associations between betrayal trauma and symptoms of posttraumatic stress, depression, and anxiety. AB - Emotion regulation difficulties following trauma exposure have received increasing attention among researchers and clinicians. Previous work highlights the role of emotion regulation difficulties in multiple forms of psychological distress and identifies emotion regulation capacities as especially compromised among survivors of betrayal trauma: physical, sexual, or emotional maltreatment perpetrated by someone to whom the victim is close, such as a parent or partner. It is unknown, however, whether links between emotion regulation difficulties and psychological symptoms differ following exposure to betrayal trauma as compared with other trauma types. In the present study, 593 male and female university undergraduates completed the Difficulties with Emotion Regulation Scale (Gratz & Roemer, 2004), the Brief Betrayal Trauma Scale (Goldberg & Freyd, 2006), the Impact of Event Scale (Horowitz, Wilner, & Alvarez, 1979), and the Trauma Symptom Checklist (Elliott & Briere, 1992). A path analytic model demonstrated that betrayal trauma indirectly impacted symptoms of intrusion (beta = .11), avoidance (beta = .13), depression (beta = .17), and anxiety (beta = .14) via emotion regulation difficulties, an effect consistent with mediation. Emotion regulation difficulties did not mediate the relationship between other trauma exposure and psychological symptoms. Results may inform treatment-matching efforts, and suggest that emotion regulation difficulties may constitute a key therapeutic target following betrayal trauma. PMID- 23737297 TI - A prospective study on the association between caregiver psychological symptomatology and symptom clusters of pediatric posttraumatic stress disorder. AB - This study investigated the influence of caregiver psychological symptoms on posttraumatic stress disorder (PTSD) symptoms in traumatized children. One hundred eleven children and caretakers were assessed in this study. Children (N = 59) with a history of exposure to interpersonal violence were evaluated for reexperiencing, avoidance/numbing, and hyperarousal symptom clusters using the Clinician-Administered PTSD Scale for Children and Adolescents (CAPS-CA). The 52 primary caregivers were evaluated using the Symptom Checklist-90-Revised (SCL-90 R) on 9 domains of psychological symptomatology: anxiety, depression, hostility, interpersonal sensitivity, obsessive-compulsive disorder, paranoid ideation, phobic anxiety, psychoticism, and somatization. At 14-month follow-up, 45 of the children were re-evaluated with the CAPS-CA. Caregiver psychological symptoms in the domains of anxiety, depression, interpersonal sensitivity, obsessive compulsive disorder, and paranoid ideation were associated with less improvement in total pediatric PTSD symptoms. Analysis of PTSD symptoms by cluster showed that greater caregiver symptomatology in the domains of anxiety, depression, interpersonal sensitivity, and obsessive-compulsive disorder were associated with less improvement in the hyperarousal symptom cluster. These results suggest caregiver symptomatology may be specifically associated with hyperarousal symptoms in pediatric trauma. PMID- 23737298 TI - How prevalent is resilience following sexual assault?: comment on steenkamp et Al. (2012). AB - Steenkamp, Dickstein, Salters-Pedneault, Hofmann, and Litz (2012) analyzed latent trajectories of posttraumatic stress disorder (PTSD) symptoms on data obtained in the early months following a single-incident sexual assault. In contrast to previous studies of potentially traumatic events, they did not observe a trajectory of minimal symptoms or resilience, which they argued occurred because sexual assault involves more severe and direct trauma exposure than examined in previous studies. Although sexual assault is an aversive and challenging event, it seems highly unlikely that at least some sexual assault survivors would not be resilient. Steenkamp et al.'s failure to observe resilience can easily be explained on purely methodological grounds. Most notably, their findings were probably heavily influenced by sampling bias. Additionally, their sample size was too small and had too much missing data for the kinds of latent trajectory modeling they attempted. PMID- 23737299 TI - What is the typical response to sexual assault? Reply to Bonanno (2013). AB - We respond to Bonanno's (2013) comment on our longitudinal evaluation of sexual assault survivors. Bonanno posits that minor disruption in functioning is the modal response to any stressor or trauma, yet most women we studied had marked initial symptoms in the immediate months following assault, which gradually improved over time. We argue that sexual violence is one example of intentional and malicious victimization, which differs from other experiences studied by Bonanno, such as spinal cord injury. Our study also differed from most previous studies in that it specifically examined the acute reactions period, which is the only period that can distinguish between resilience and recovery: Both trajectories ultimately involve good adaptation, but are distinguished by the degree of initial postevent disruption. We address Bonanno's contention that our results should be dismissed on methodological and statistical grounds. Our findings suggest that prior research about the frequency of resilience may in part be confounded by the degree and type of stress exposure. PMID- 23737300 TI - Attachment narratives in refugee children: interrater reliability and qualitative analysis in pilot findings from a two-site study. AB - Although forced migration research on refugee family functioning clearly points to the potential breakdown of parental availability and responsiveness in the context of cumulative migration stressors, studies exploring attachment security in refugee children are surprisingly lacking so far. The authors report their findings from a 2-site, small-scale administration of an attachment measure, adapted for use with refugee children aged between 4 and 9 years from a reliable and validated doll-play procedure. We evaluated interrater reliability and conducted a qualitative analysis of refugee children's narrative response to identify migration-specific representational markers of attachment quality. The level of agreement among 3 independent coders ranged between .54 to 1.00 for both study samples, providing initial psychometric evidence of the measure's value in assessing child attachment security in this population. The exploratory analysis of migration-related narrative markers pointed to specific parameters to be used in parent-child observational assessments in future validation of the attachment measure, such as parental withdrawal or trauma-communication within the parent child dyad. PMID- 23737301 TI - A prospective study of the effects of breastfeeding and FADS2 polymorphisms on cognition and hyperactivity/attention problems. AB - Breastfeeding has been associated with improved cognitive functioning. There is a beneficial effect on IQ, and possibly on associated phenotypes such as attention problems. It has been suggested that the effect on IQ is moderated by polymorphisms in the FADS2 gene, which is involved in fatty acid metabolism. In this study we tested the relation between breastfeeding and FADS2 polymorphisms on the one hand and IQ, educational attainment, overactivity, and attention problems on the other hand. IQ at age 5, 7, 10, 12, and/or 18 (n = 1,313), educational attainment at age 12 (n = 1,857), overactive behavior at age 3 (n = 2,560), and attention problems assessed at age 7, 10, and 12 years (n = 2,479, n = 2,423, n = 2,226) were predicted by breastfeeding and two SNPs in FADS2 (rs174575 and rs1535). Analyses were performed using structural equation modeling. After correction for maternal education, a main effect of breastfeeding was found for educational attainment at age 12 and overactive behavior at age 3. For IQ, the effect of breastfeeding across age was marginally significant (P = 0.05) and amounted to 1.6 points after correcting for maternal education. Neither a main effect of the FADS2 polymorphisms nor an interaction with breastfeeding was detected for any of the phenotypes. This developmentally informed study confirms that breastfeeding is associated with higher educational attainment at age 12, less overactive behavior at age 3 and a trend toward higher IQ after correction for maternal education. In general, the benefits of breastfeeding were small and did not interact with SNPs in FADS2. PMID- 23737302 TI - Leaf extract of Azadirachta indica (neem): a potential antibiofilm agent for Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is well known for its ability to form biofilm on indwelling medical devices. These biofilms are difficult to remove because of their high tolerance to conventional antibiotics. Therefore, there is a need to look for alternative agents such as medicinal plants, which can eradicate or inhibit biofilm effectively. This study evaluated the role of neem in inhibiting biofilm formation by P aeruginosa Factors contributing to adherence and biofilm formation were also studied. Results demonstrated that neem leaves extract was quite effective in disrupting formation and structure of biofilms. Moreover, the level of exopolysaccharide, alginate, hydrophobic interactions and uroepithelial cell attachment, which contributes to biofilm formation, was also affected significantly. Results confirm the effectiveness of neem extract in inhibiting biofilm formation. Such studies can lead to the discovery of safe antimicrobial drugs from natural sources without the risk of resistance. PMID- 23737303 TI - Coexpression of CPR from various origins enhances biotransformation activity of human CYPs in S. pombe. AB - Cytochrome P450 enzymes (CYPs or P450s) are the most important enzymes involved in the phase I metabolism of drugs (and other xenobiotics) in humans, and the corresponding drug metabolites are needed as reference substances for their structural confirmation and for pharmacological or toxicological characterization. We have previously shown that biotechnological synthesis of such metabolites is feasible by whole-cell biotransformation with human CYPs recombinantly expressed in the fission yeast Schizosaccharomyces pombe. It was the aim of this study to compare the activity of seven human microsomal CYPs (CYP2C9, CYP2D6, CYP3A4, CYP3A5, CYP3A7, CYP17, and CYP21) upon coexpression with NADPH-cytochrome P450 oxidoreductases (CPRs) from various origins, namely, human CPR (hCPR) and its homologues from fission yeast (ccr1) and the bishop's weed Ammi majus (AmCPR), respectively. For this purpose, 28 recombinant strains were needed, with five of them having been constructed previously and 23 strains being newly constructed. Bioconversion experiments showed that coexpression of a CPR does not only influence the reaction rate but, in some cases, also exerts an influence on the metabolite pattern. For CYP3A enzymes, coexpression of hCPR yielded the best results, while for another two, hCPR was equally helpful as ccr1 (both CYP17 and CYP21) or AmCPR (CYP17 only), respectively. Interestingly, CYP2D6 displayed its highest activity when coexpressed with ccr1 and CYP2C9 with AmCPR. These results corroborate the view of CPR as a well-suited bio-brick in synthetic biology for the construction of artificial enzyme complexes. PMID- 23737304 TI - Coexpression of the pyrroloquinoline quinone and glucose dehydrogenase genes from Serratia marcescens CTM 50650 conferred high mineral phosphate-solubilizing ability to Escherichia coli. AB - The genes gdh and pqqABCDE encoding glucose dehydrogenase and its pyrroloquinoline quinone cofactor were cloned from the mineral phosphate solubilizing (MPS) bacterium Serratia marcescens CTM 50650. We investigated, for the first time, the impact of their coexpression in Escherichia coli on MPS ability. The production of recombinant PQQGDH conferred high MPS activity to the engineered E. coli. In fact, the amounts of soluble phosphorus (P) produced from tricalcium phosphate, hydroxyapatite, and Gafsa rock phosphate (GRP) were 574, 426, and 217 mg/L, respectively. In an attempt to increase the soluble P concentration, the E. coli strain coexpressing the gdh and pqqABCDE genes was immobilized in agar, calcium alginate, and k-carrageenan and was then further applied in a repeated batch (six batches) fermentation process to solubilize GRP. Compared to other encapsulated systems, alginate cell beads were noted to yield the highest concentration of soluble P, which attained 300 mg/L/batch. MPS efficiency was maximal in the presence of 5 and 40 g/L of GRP and glucose, respectively. PMID- 23737305 TI - Development of an in situ detachment protocol of Vero cells grown on Cytodex1 microcarriers under animal component-free conditions in stirred bioreactor. AB - Subcultivation of Vero cells grown in a proprietary animal component-free medium named IPT-AFM, on microcarriers, was studied. TrypLE Select, a non-animal-derived protease, was used as an alternative to trypsin for cell passaging. We first studied the effect of increasing concentrations of TrypLE Select toward cell growth and then studied the inactivation of the protease using either soybean trypsin inhibitor (STI) or the soy hydrolysate Hypep 1510, in six-well plates. Data showed that cell growth was impaired by residual level of TrypLE Select; STI was identified as an efficient agent to neutralize this effect. To restore cell growth and inactivate TrypLE Select, STI should be added to the medium at least at 0.2 g L(-1). Cells were also grown in spinner flask on 2 g L(-1) Cytodex1 in IPT-AFM. In these conditions, the cell detachment yield was equal to 78 +/- 8 %. Furthermore, cells exhibited a typical growth profile when using the dislodged cells to seed a new culture. A cell detachment yield of 70 +/- 19 % was also achieved when the cells were grown in a 2-L stirred bioreactor in IPT-AFM, on 3 g L(-1) Cytodex1. This protocol can be of great interest to scale-up the process of Vero cells cultivation in IPT-AFM on Cytodex1 from one stirred bioreactor culture to another. PMID- 23737306 TI - Trajectory of parental hope when a child has difficult-to-treat cancer: a prospective qualitative study. AB - OBJECTIVE: This prospective and longitudinal study was designed to further our understanding of parental hope when a child is being treated for a malignancy resistant to treatment over three time points during the first year after diagnosis using a qualitative approach to inquiry. METHODS: We prospectively recruited parents of pediatric cancer patients with a poor prognosis who were treated in the Hematology/Oncology Program at a large children's hospital for this longitudinal grounded theory study. Parents were interviewed at three time points: within 3 months of the initial diagnosis, at 6 months, and at 9 months. Data collection and analysis took place concurrently using line-by-line coding. Constant comparison was used to examine relationships within and across codes and categories. RESULTS: Two overarching categories defining hope as a positive inner source were found across time, but their frequency varied depending on how well the child was doing and disease progression: future-oriented hope and present oriented hope. Under future-oriented hope, we identified the following: hope for a cure and treatment success, hope for the child's future, hope for a miracle, and hope for more quality time with child. Under present-oriented hope, we identified hope for day-to-day/moment-to-moment, hope for no pain and suffering, and hope for no complications. CONCLUSIONS: For parents of children with a diagnosis of cancer with a poor prognosis, hope is an internal resource that can be present and future focused. These views fluctuated over time in response to changes in the child's well-being and disease progression. PMID- 23737307 TI - Platelet concentrates and Achilles tendon healing. PMID- 23737308 TI - In commemorating one thousandth anniversary of the Avicenna's Canon of Medicine: gastric headache, a forgotten clinical entity from the medieval Persia. AB - Although the connection between head and stomach and hence the condition known as "gastric headache" was well known to the ancients, it has received little attention since the early 20th century. Herein, we review the teachings of the medieval Persian physicians about the gastric headache along with the related signs, symptoms, types and causes. The medieval Persian scholars adopted the main ideas of the gastric headache from predecessors in the ancient Greece and Rome, added substantial sub-categories and details to the earlier descriptions and therapeutic options. The medieval Persian physicians' contributions to the concept of gastric headache influenced beyond doubt the later accounts of this condition. PMID- 23737309 TI - Vaccination of diffuse large B- cell lymphoma patients with antigen-primed dendritic cells. AB - Dendritic cells (DCs) are professional antigen presenting cells that have a potential role in the initiating of immune responses. The cell vaccination is a new strategy in treatment of infectious diseases and cancers. In this study, we have generated monocyte-derived dendritic cells of lymphoma patient's peripheral blood mononuclear cells then; these cells were used as vaccine in lymphoma patients. We generated dendritic cell vaccine from lymphoma patient's blood monocytes with human interleukin-4, granulocyte monocyte colony stimulating factor and then, antigen-primed Dcs were administrated subcutaneously close to the inguinal lymph nodes after maturation of dendritic cells. After 7 days, we analyzed immune response in lymphoma patients with determining of LDH, Beta 2 Microglobulin, CD4+T cell percent, CD8+ Tcell percent and Tumor size before and after vaccination. Furthermore, phenotypic and functional analysis of dendritic cells was performed using anti CD83-FITC monoclonal antibodies. Before vaccination, the mean +/- SD of LDH was 530.62+/-140.65 but after vaccination it was 459+/-109.45 that significantly different between experimental groups (P=0.002). In addition, the CD8+ T cells percentage significantly different between two groups (P=0.002). We concluded that the use of dendritic cell probably is one of the suitable noninvasive treatments for lymphoma patients that they have not response to chemical drugs. PMID- 23737310 TI - Comparison of vitamin D3 serum levels in new diagnosed patients with multiple sclerosis versus their healthy relatives. AB - Multiple risk factors are introduced for Multiple Sclerosis (MS). Recent studies have suggested a possible correlation between vitamin D deficiency and an increase risk of MS. This study was therefore undertaken to compare vitamin D levels in new cases of MS and their relatives as healthy controls. Seventy five new diagnosed MS patients and 100 matched healthy controls among their relatives were enrolled in this study. Two groups were matched for gender, age, season in which serum level of vitamin D was checked and region and diet. Serum levels of 25-hydroxy vitamin D was measured, recorded and analyzed. Seventy five patients (57 female and 18 male) and 100 healthy subjects (75 female and 25 male) were enrolled in this study. The mean serum levels of 25-hydroxy vitamin D in case and control groups were 11.31 and 17.9 ng/ml, respectively (P=0.003). Compared to the healthy subject, serum levels of vitamin D were significantly lower in patients with MS. This difference was only significant in women. Observed difference of vitamin D levels of both groups were significant in summer. This study continues to support the role of vitamin D deficiency in MS. PMID- 23737311 TI - The association of Helicobacter pylori infection with Hashimoto's thyroiditis. AB - Autoimmune thyroid diseases (ATD) are multifactorial conditions that result from genetic predisposition in combination with environmental risk factors. Helicobacter pylori infection as an environmental risk factor has been proposed to imitate the antigenic components of the thyroid cell membrane and may play a leading role in the onset of the autoimmune diseases, such as Hashimoto thyroiditis. The aim of this study was to investigate the association between Helicobacter pylori (HP) infection and Hashimoto's thyroiditis (HT). The participants in this case-control study included 43 patients affected by Hashimoto's thyroiditis, and 40 healthy individuals without history of autoimmune disease as the control group. Anti HP IgG and anti-TPO antibodies were determined using ELISA method. Results were considered positive when the IgG anti-HP value was higher than 30 IU/ml and the anti-TPO autoantibody value was higher than 75 IU/ml. The mean TSH level was 18.3+/-16.8 IU/ml for patients and 2.8+/-1.2 IU/ml for the control group (P<0.001). 46.5% of the patient group and 10.8% of the control group were infected with HP. The association between HP and Hashimoto's thyroiditis was statistically significant (Odds Ratio=7.2, 95%, Confidence Interval: 2.0- 28.8, P<0.001). The findings show that, there is an association between HP and Hashimoto's thyroiditis. To establish a definite correlation between them, more detailed studies with a more specialized examination and precise consideration regarding species of HP, genetic polymorphism of the host and investigation of environmental factors are needed. PMID- 23737312 TI - Risk factors for neonatal mortality among very low birth weight neonates. AB - The objective of this study is to determine risk factors causing increase in very low birth way (VLBW) neonatal mortality. The medical files of all neonates weighing <=1500 g, born in Vali-e-Asr hospital (2001-2004) were studied. Two groups of neonates (living and dead) were compared up to the time of hospital discharge or death. A total of 317 neonates were enrolled. A meaningful relationship existed between occurrence of death and low gestational age (P=0.02), low birth weight, lower than 1000 g (P=0.001), Apgar score <6 at 5th minutes (P=0.001), resuscitation at birth (P=0.001), respiratory distress syndrome (P=0.001) need for mechanical ventilation (P=0.001), neurological complications (P=0.001) and intraventricular hemorrhage (P=0.001). Regression analysis indicated that each 250 g weight increase up to 1250 g had protective effect, and reduced mortality rate. The causes of death of those neonates weighting over 1250 g should be sought in factors other than weight. Survival rate was calculated to be 80.4% for neonates weighing more than 1000 g. The most important high risk factors affecting mortality of neonates are: low birth weight, need for resuscitation at birth, need for ventilator use and intraventricular hemorrhage. PMID- 23737313 TI - Evaluation of the normal fetal kidney length and its correlation with gestational age. AB - A true estimation of gestational age (GA) plays an important role in quality maternity care and scheduling the labor date. This study aimed to evaluate the normal fetal kidney length (KL) and its correlation with GA. A cross-sectional study on 92 pregnant women between 8th and 10th week of gestation with normal singleton pregnancy underwent standard ultrasound fetal biometry and kidney length measurement. univariate and multivariate linear regression analysis was used to create a predictive equation to estimate GA on the KL and fetobiometry parameters. A significant correlation was found between GA and KL (r=0.83, P<0.002). The best GA predictor was obtained by combining head circumference, fetal biparietal diameter, femur length and KL with a standard error (SE) about 14.2 days. Our findings showed that KL measurements combination with other fetal biometric parameters could predict age of pregnancy with a better precision. PMID- 23737314 TI - Predictive value of having positive family history of cardiovascular disorders, diabetes mellitus, dyslipidemia, and hypertension in non-alcoholic fatty liver disease patients. AB - In the present study, we examined the relationship between family history of cardiovascular diseases (CVD), dyslipidemia, hypertension, and diabetes with laboratorial abnormalities and syndromes in Iranian patients with non-alcoholic fatty liver disease (NAFLD). A total of 332 NAFLD patients from our outpatient clinic were consecutively entered into analysis. Exclusion criteria were having diabetes mellitus and fasting blood glucose over 126, active hepatitis B virus infection, having HCV positive serology, and to be under corticosteroid therapy. Family history of CVD, diabetes, dyslipidemia, and hypertension were taken from patients and related to the study variables. Family history of cardiovascular diseases (CVD) was associated with low HDL levels (P=0.05). Patients with positive family history of diabetes mellitus were significantly more likely to have AST/ALT levels proportion of higher than one (P=0.044). Family history of dyslipidemia was a predictor for hypertriglyceridemia (P=0.02), higher prothrombin time levels (P=0.013), lower albumin (P=0.024) and T4 (P=0.043) levels. Family history of hypertension was associated with dysglycemia/diabetes (P=0.038), high ALT (P=0.008), and low TIBC (P=0.007) and albumin levels (P=0.001). Family history for CVD, diabetes, dyslipidemia, and hypertension were of clinical importance in the Iranian patients with NAFLD. We therefore recommend that physicians should precisely get family history of main disorders in all NAFLD patients; and to pay more attention to those having the mentioned family histories. Further studies with larger patient population and prospective approach are needed for confirming our findings. PMID- 23737315 TI - Serum ox-LDL level is reduced with the extent of stenosis in coronary arteries. AB - Oxidized LDL (ox-LDL) lipoproteins are proposed as important modified particles triggering pro-inflammatory events through receptor-mediated pathways. We evaluated the circulating ox-LDL level on the concept that the chronic immune events may affect ox-LDL clearance as the vessel stenosis develops in coronary arteries. One hundred sixty five subjects underwent coronary angiography and then, subdivided into four subgroups controls (n=85); SVD, 2VD and 3VD (n=80). The serum ox-LDL level and other biochemical parameters were measured using ELISA method and routine laboratory techniques, respectively. The serum ox-LDL level in the control group (4.81+/-1.41 mU/mg) was significantly higher than patients (4.28+/-1.73 mU/mg, P<0.05). The ox-LDL/LDL ratio was conversely reduced with the extent of stenosis as compared with the controls (P<0.05). Furthermore, no difference was observed in the ox-LDL/LDL ratio between the 2VD and 3VD patients. We suggested the atherosclerosis process increases the total clearing capacities of the circulating ox-LDL particles. PMID- 23737316 TI - On pump versus off pump coronary artery bypass surgery in patients over seventy years old with triple vessels disease and severe left ventricle dysfunction: focus on early clinical outcomes. AB - Cardiovascular disease is the leading reason of morbidity in older people. Coronary artery bypass graft (CABG) surgery is the most common type of operations in world. This study was designed to characterize comparison of early clinical outcome following on pump vs. off pump in patients over 70 years old with triple vessels disease and severe left ventricle dysfunction. 80 patients were divided into two groups: In group A (n=40) on pump CABG was performed with hypothermic cardiopulmonary bypass and cold blood cardioplegic arrest and in group B (n=40) the patients had off pump coronary artery bypass (OPCAB) surgery. Exclusion criteria included emergency or urgent operation, combined valve surgery, history of renal insufficiency (Cr >2 mg/dl), stroke. Early postoperative complications such as occurrence, duration and frequency of recurrence of atrial fibrillation were recorded. All patients underwent Holter monitoring after ICU discharge during their hospital stay. The average age of patients was 79.5+/-7.5 years. Post operative atrial fibrillation (POAF) occurred in 24 cases (30%); 17 cases (42.5%) related to on pump CABG group and 7 cases (17.5%) related to OPCAB group (P=0.03). The frequency of the recurrence of AF in the on pump group was 3.8+/ 1.3 days and in the off pump group was 2.4+/-1.1 days (P=0.02). ICU stay in on pump group was 3.6+/-1.80 days, while for the off pump was 2.5+/-0.6 days (P=0.001). Also hospital stay duration was 8.5+/-2.1 days for the on pump group compared to the other group that was 6.34+/-1.06 days. Off pump in patients over 70 years old with triple vessels disease and severe LV dysfunction is safer than on pump and can reduce POAF, ICU and hospital stay and some early surgical complications. PMID- 23737317 TI - Immediate, short, intermediate and long-term results of balloon valvuloplasty in congenital pulmonary valve stenosis. AB - Transluminal balloon valvuloplasty is an alternative to surgical valvotomy for congenital pulmonary valve stenosis. The aim of this study was to evaluate the long term results (to 13.5 years) of balloon pulmonary valvuloplasty. From June 1998 to January 2012, percutaneous balloon pulmonary valvuloplasty for congenital pulmonary valve stenosis was performed in 98 patients (50 males, 48 females, with a median age of 6.75 years) underwent balloon valvuloplasty of pulmonary valve stenosis. Follow-up was performed based on the Doppler echocardiographic data and clinical findings. Forty three of ninety eight patients were 10 years of age or older. The mean peak to peak pressure gradient across pulmonary valve before and immediately after balloon pulmonary valvuloplasty (BPV) was 88.7+/-36.4 mmHg and 21.8+/-15.9 mmHg (P<0.001) respectively. Doppler pressure gradient across pulmonary valve before BPV, at 3 month (short term), at 1 year (intermediate term) and long-term follow-up were 93.2+/-41.3 mmHg, 18.7+/-15.8 mmHg (P<0.001), 15.8+/-13.1 mmHg (P<0.001) and 13.6+/-7.4 mmHg (P<0.017) respectively. Mild pulmonary regurgitation (PR) was observed in 55 (57%) patients immediately after BPV and 30 (31%) patients at late follow up. Rupture of the right ventricular outflow tract was the major complication in two patients with fatal event. Short, intermediate and long-term results of BPV for typical valvular pulmonary stenosis are excellent. Therefore, it can be considered as treatment of choice for patients with typical valvular pulmonary stenosis. PMID- 23737318 TI - Diffuse pigmentation of back and arms: macular amyloidosis or other? AB - The study was undertaken to answer the question that how many patients with pigmentation of back and arms actually have amyloid deposits in pathology. 44 patients presenting with diffuse pigmentation of back and arms (DPOBA) were selected. Skin biopsies were performed in all cases from the affected sites. On all formalin fixed and paraffin embedded specimens, the following histochemical stains were performed: Haematoxylin and eosin (H&E), Congo red and immunohistochemical staining using anti-cytokeratin monoclonal antibody. In 9 of 44 cases (20%), amyloid deposits were found. In the remaining 35 cases (80%), H&E, Congo red and immunohistochemical staining failed to show any amyloid deposition. We were unable to find amyloid deposition in most of the patients presented with DPOBA. It seems that the signs may be attributable other disorders with similar clinical but different pathophysiologic aspects. PMID- 23737319 TI - Hematoma of rectus sheath following subcutaneous enoxaparin injection. AB - Anticoagulation drugs are frequently used to prevent deep vein thrombosis in high risk patients. Subcutaneous low molecular weight heparin (LMWH) is increasingly used in both hospitalized patients and outpatient settings. This necessitates familiarity of both health care providers and patients with such treatment and vigilance on possible complications. Here we present a case of hematoma of rectus sheath that occurred following subcutaneous injection of enoxaparin and was successfully treated with conservative management. PMID- 23737320 TI - An unusual combination of parathyroid adenoma, medullary and papillary thyroid carcinoma. AB - The coexistence of medullary thyroid carcinoma (MTC), papillary thyroid carcinoma (PTC) and parathyroid adenoma is an uncommon clinical entity. Here, we report a case of MTC, PTC, and parathyroid adenoma diagnosed incidentally on a routine physical examination of the neck for the work-up of diabetes. The patient had neither symptoms of hypercalcemia nor those related to MTC and PTC. PMID- 23737321 TI - A rare case of aplasia cutis congenita. AB - Aplasia cutis congenita is a rare anomaly presenting with the absence of skin. No definite etiology is available. The most common site is the scalp. We present an instance with ACC occurring symmetrically in both sides of the body from chest to flank. PMID- 23737322 TI - Genetics of mondini malformation. PMID- 23737323 TI - Conservative versus surgical treatment for chronic anal idiopathic fissure: a prospective randomized trial. AB - Anal fissure is a tear in the lining of the anal canal distal to the dentate line, which most commonly occurs in the posterior midline. Anal fissure was defined chronic if the patient presented with history of anal pain during defecation for at least 2 months with the observation of sphincter fibers at the base of the lesion. One hundred and forty-two consecutive patients with a chronic anal fissure with hypertonicity of internal sphincter on proctological examination were selected for this study from October 2008 to October 2010. Patients enrolled for the study were randomized to two groups by using a computer generated list. Patients who underwent lateral internal sphincterotomy (LIS) were operated as day surgery procedures under local or epidural anesthesia. Patients randomized to conservative treatment were prescribed to use warm anal dilator with a nifedipine ointment 5 min twice daily for 4 weeks. Patients were clinically examined after 2, 4 and 8 weeks of treatment to evaluate if there was complete healing of the fissure. All patients were required to record pain after the first defecation, on 3rd and 7th postoperative day on a self-administered VAS scale in cm (0-10). Sixty-eight patients were randomly assigned to LIS, 74 to the conservative approach. Fifty-one patients of topical nifedipine group (68.9 %) and 60 patients of LIS group (88.2 %) presented an anal fissure healed at 8 weeks with a p value of 0.0077. As regards post-operative pain, 43 patients of LIS group (63.2 %) and 25 patients of topical nifedipine group (33.7 %) referred first defecation as painless. In the topical nifedipine group 43 (58.1 %) after 3 days since treatment and 35 (47.3 %) after 7 days had pain. In the LIS group 22 (32.3 %) after 3 days and 9 (13.2 %) after 7 days referred pain. There was no statistical difference between LIS and topical nifedipine group concerning side effects. Lateral internal sphincterotomy is an effective, less painful, fast recovery treatment for chronic anal fissure. Incontinence rate is overestimated and often the fear of a continence disturbance, albeit with a low incidence following surgery, may obscure the need to relieve symptoms which may be so severe as to make the patient's life intolerable. PMID- 23737324 TI - Is speech language pathologist evaluation necessary in the nonoperative treatment of head and neck cancer? PMID- 23737325 TI - Neuronal autophagy: self-eating or self-cannibalism in Alzheimer's disease. AB - Autophagy is a major intracellular degeneration pathway involved in the elimination and recycling of damaged organelles and long-lived proteins by lysosomes. Many of the pathological factors, which trigger neurodegenerative diseases, can perturb the autophagy activity, which is associated with misfolded protein aggregates accumulation in these disorders. Alzheimer's disease, the first neurodegenerative disorder between dementias, is characterized by two aggregating proteins, beta-amyloid peptide (plaques) and tau-protein (tangles). In Alzheimer's disease autophagosomes dynamically form along neurites within neuronal cells and in synapses but effective clearance of these structures needs retrograde transportation towards the neuronal soma where there is a major concentration of lysosomes. Maturation of autophago-lysosomes and their retrograde trafficking are perturbed in Alzheimer's disease, which causes a massive concentration of autophagy elements along degenerating neurites. Transportation system is disturbed along defected microtubules in Alzheimer's disease brains. tau-protein has been found to control the stability of microtubules, however, phosphorylation of tau-protein or an increase in the total level of tau-protein can cause dysfunction of neuronal cells microtubules. Current evidence has shown that autophagy is developing in Alzheimer's disease brains because of ineffective degradation of autophagosomes, which hold amyloid precursor protein-rich organelles and secretases important for beta-amyloid peptides generation from amyloid precursor. The combination of raised autophagy induction and abnormal clearance of beta-amyloid peptide-generating autophagic vacuoles creates circumstances helpful for beta-amyloid peptide aggregation and accumulation in Alzheimer's disease. However, the key role of autophagy in Alzheimer's disease development is still under consideration today. One point of view suggests that abnormal autophagy induction causes a concentration of autophagic vacuoles rich in amyloid precursor protein, beta-amyloid peptide and the elements crucial for its formation, whereas other hypothesis points to marred autophagic clearance or even decrease in autophagic effectiveness playing a role in maturation of Alzheimer's disease. In this review we present the recent evidence linking autophagy to Alzheimer's disease and the role of autophagic regulation in the development of full-blown Alzheimer's disease. PMID- 23737326 TI - Microhomology-mediated intron loss during metazoan evolution. AB - How introns are lost from eukaryotic genomes during evolution remains an enigmatic question in biology. By comparative genome analysis of five Caenorhabditis and eight Drosophila species, we found that the likelihood of intron loss is highly influenced by the degree of sequence homology at exon intron junctions: a significant elevated degree of microhomology was observed for sequences immediately flanking those introns that were eliminated from the genome of one or more subspecies. This determinant was significant even at individual nucleotides. We propose that microhomology-mediated DNA repair underlies this phenomenon, which we termed microhomology-mediated intron loss. This hypothesis is further supported by the observations that in both species 1) smaller introns are preferentially lost over longer ones and 2) genes that are highly transcribed in germ cells, and are thus more prone to DNA double strand breaks, display elevated frequencies of intron loss. Our data also testify against a prominent role for reverse transcriptase-mediated intron loss in metazoans. PMID- 23737327 TI - Genome-wide characterization of adaptation and speciation in tiger swallowtail butterflies using de novo transcriptome assemblies. AB - Hybrid speciation appears to be rare in animals, yet characterization of possible examples offers to shed light on the genomic consequences of this unique phenomenon, as well as more general processes such as the role of adaptation in speciation. Here, we first generate transcriptome assemblies for a putative hybrid butterfly species, Papilio appalachiensis, its parental species, P. glaucus and P. canadensis, and an outgroup, P. polytes. Then, we use these data to infer genome-wide patterns of introgression and genomic mosaicism using both phylogenetic and population genetic approaches. Our results reveal that there is little genetic divergence among all three of the focal species, but the subset of gene trees that strongly support a specific tree topology suggest widespread sharing of genetic variation between P. appalachiensis and both parental species, likely as a result of hybrid speciation. We also find evidence for substantial shared genetic variation between P. glaucus and P. canadensis, which may be due to gene flow or ancestral variation. Consistent with previous work, we show that P. applachiensis is more similar to P. canadensis at Z-linked genes and more similar to P. glaucus at mitochondrial genes. We also identify a variety of targets of adaptive evolution, which appear to be enriched for traits that are likely to be important in the evolution of this butterfly system, such as pigmentation, hormone sensitivity, developmental processes, and cuticle formation. Overall, our results provide a genome-wide portrait of divergence and introgression associated with adaptation and speciation in an iconic butterfly radiation. PMID- 23737328 TI - Spliced DNA sequences in the Paramecium germline: their properties and evolutionary potential. AB - Despite playing a crucial role in germline-soma differentiation, the evolutionary significance of developmentally regulated genome rearrangements (DRGRs) has received scant attention. An example of DRGR is DNA splicing, a process that removes segments of DNA interrupting genic and/or intergenic sequences. Perhaps, best known for shaping immune-system genes in vertebrates, DNA splicing plays a central role in the life of ciliated protozoa, where thousands of germline DNA segments are eliminated after sexual reproduction to regenerate a functional somatic genome. Here, we identify and chronicle the properties of 5,286 sequences that putatively undergo DNA splicing (i.e., internal eliminated sequences [IESs]) across the genomes of three closely related species of the ciliate Paramecium (P. tetraurelia, P. biaurelia, and P. sexaurelia). The study reveals that these putative IESs share several physical characteristics. Although our results are consistent with excision events being largely conserved between species, episodes of differential IES retention/excision occur, may have a recent origin, and frequently involve coding regions. Our findings indicate interconversion between somatic--often coding--DNA sequences and noncoding IESs, and provide insights into the role of DNA splicing in creating potentially functional genetic innovation. PMID- 23737329 TI - Strain optimization for efficient isobutanol production using Corynebacterium glutamicum under oxygen deprivation. AB - Microbial production of isobutanol is made difficult by the chemical's high cell toxicity. Corynebacterium glutamicum, inherently one of the more isobutanol tolerant industrial microorganisms, exhibits unprecedented productivity under oxygen deprivation, potentially allowing for high productivity of such toxic chemicals as isobutanol. Here, we show that development of C. glutamicum strains proficient in isobutanol production depends not only on modulating the activity of 2-keto acid decarboxylase (KDC) and isobutanol dehydrogenase (IBDH) and suppressing by-product formation, but also on optimizing the production process to eschew product inhibition. Isobutanol production under oxygen deprivation reached 343 mM (3.2% v/v) in strain IBU5 expressing kivd (encoding KDC) under the control of ldhA promoter and adhP (encoding IBDH from Escherichia coli MG1655) under the control of gapA promoter. This productivity is double the previously reported best productivity of 1.6% (v/v) and exceeds the 2.5% (v/v) limit beyond which cell growth becomes too severely suppressed. Irrespective, a cumulative 56.5% improvement on yield was possible with the combined effects of disruption of the ppc gene, encoding phosphoenolpyruvate carboxylase (PEPC), use of a NAD+ specific mutant acetohydroxyacid isomeroreductase (AHAIR), and overexpression of select glycolytic genes. Using oleyl alcohol to continuously extract the isobutanol from reaction mixture and tripling the cell concentration in the reaction mixture to 60 g dry cell/L stretched the yield to 78.1% and volumetric productivity to 981 mM (9.1% v/v). PMID- 23737330 TI - Polyamines are oncometabolites that regulate the LIN28/let-7 pathway in colorectal cancer cells. AB - Polyamine metabolism is a highly coordinated process that is essential for normal development and neoplastic growth in mammals. Although polyamine metabolism is a validated pathway for prevention of carcinogenesis, the mechanisms by which polyamines elicit their tumorigenic effects are poorly understood. In this study, we investigated the role of polyamine metabolism in colon cancer by screening a non-coding RNA (ncRNA) platform to identify polyamine responsive signaling nodes. We report that multiple non-coding RNAs are altered by polyamine depletion including induction of microRNA (miRNA) let-7i, a member of the tumor suppressive let-7 family. The let-7 family targets several RNAs for translational repression, including the growth-associated transcription factor HMGA2 and is negatively regulated by the pluripotency factor LIN28. Depletion of polyamines using difluoromethylornithine (DFMO) or genetic knockdown of the polyamine-modified eukaryotic translation initiation factor 5A isoforms 1 and 2 (eIF5A1/2) resulted in robust reduction of both HMGA2 and LIN28. Locked nucleic acid (LNA) oligonucleotides targeting the seed region of the let-7 family rescued the expression of HMGA2, but not LIN28, in both DFMO-treated and eIF5A1/2 knockdown cultures. Our findings suggest that polyamines are oncometabolites that influence specific aspects of tumorigenesis by regulating pluripotency associated factors, such as LIN28, via an eIF5A-dependent but let-7-independent mechanism while the expression of proliferation-related genes regulated by let-7, such as HMGA2, is mediated through microRNA mediated repression. Therefore, manipulating polyamine metabolism may be a novel method of targeting the LIN28/let-7 pathway in specific disease states. PMID- 23737332 TI - Key aspects of antimicrobial stewardship. PMID- 23737333 TI - Antimicrobial de-escalation strategies in hospitalized patients with pneumonia, intra-abdominal infections, and bacteremia. AB - Increasing numbers of serious hospital/healthcare- or community-acquired infections are caused by resistant (often multi-drug resistant) bacterial pathogens. Because delayed or ineffective initial therapy can have severe negative consequences, patients at risk for these types of infections typically receive initial empiric antibiotic therapy with a broad-spectrum regimen covering the most likely pathogens, based on local surveillance data and risk factors for infection with a resistant microorganism. While improving the likelihood of a successful outcome, use of broad-spectrum, often high-dose, empiric antimicrobial therapy also creates pressure for the selection or development of resistant microorganisms, as well as increasing costs and possibly exposing patients to adverse events or collateral damage such as Clostridium difficile-associated disease. De-escalation is a strategy that attempts to balance the competing aims of providing initial empiric therapy that is appropriate and covers the likely pathogens, and limiting antimicrobial exposure and increased risk for emergence of resistant pathogens. More specifically, the de-escalation strategy involves collection of cultures for later microbiological assessment before initiating broad-spectrum empiric therapy covering the most likely pathogens, with the intention of streamlining or de-escalating to a more narrow-spectrum antimicrobial regimen 2-3 days later if warranted by clinical status and culture results. In some cases, negative culture results and subsequent clinical review may allow for termination of initial empiric therapy. In this manner, de escalation enables more effective targeting of the causative pathogen(s), elimination of redundant therapy, a decrease in antimicrobial pressure for emergence of resistance, and cost savings. This article examines application of the de-escalation strategy to 3 case patients, one with healthcare-associated pneumonia, another with complicated intra-abdominal infection, and a third with central line-associated bacteremia. Journal of Hospital Medicine 2012;7:S13-S21. (c) 2012 Society of Hospital Medicine. PMID- 23737334 TI - Empiric antibiotic selection strategies for healthcare-associated pneumonia, intra-abdominal infections, and catheter-associated bacteremia. AB - Initial selection and early deployment of appropriate/adequate empiric antimicrobial therapy is critical to minimize the significant morbidity and mortality associated with hospital- or healthcare-associated infections (HAIs). Initial empiric therapy that inadequately covers the pathogen(s) causing a serious HAI has been associated with increased mortality, longer hospital stay, and elevated healthcare costs. Moreover, subsequent modification of initial inadequate therapy, later in the disease process when culture results become available, may not remedy the impact of the initial choice. Because of this, it is important that initial empiric therapy covers the most likely pathogens associated with infection in a particular patient, even if this initial regimen turns out to be unnecessarily broad, based on subsequent culture results. The current paradigm for management of serious HAIs is to initiate empiric therapy with a broad-spectrum regimen covering likely pathogens, based on local surveillance and susceptibility data, and presence of risk factors for involvement of a resistant microorganism. Subsequent modification (de-escalation) of the initial regimen becomes possible later, when culture results are available and clinical status can be better assessed, 2 to 4 days after initiation of empiric therapy. When possible, de-escalation and other steps to modify antimicrobial exposure are important for minimizing risk of antimicrobial resistance development. This article examines the general process for selection of initial empiric antibiotic therapy for patients with HAIs, illustrated through 3 case studies dealing with healthcare-associated pneumonia, complicated intra abdominal infection, and catheter-associated bacteremia, respectively. Journal of Hospital Medicine 2012;7:S2-S12. (c) 2012 Society of Hospital Medicine. PMID- 23737336 TI - Infections, bacterial resistance, and antimicrobial stewardship: the emerging role of hospitalists. AB - The care of patients with serious infections both within and outside healthcare settings is increasingly complicated by the high prevalence of resistant or multidrug-resistant (MDR) pathogens. Moreover, infections caused by MDR versus susceptible bacteria or other pathogens are associated with significantly higher mortality, length of hospital stay, and healthcare costs. Antimicrobial misuse or overuse is the primary driver for development of antimicrobial resistance, suggesting that better use of antimicrobials will translate into improved patient outcomes, more efficient use of hospital resources, and lowered healthcare costs. Antimicrobial stewardship refers to the various practices and procedures utilized to optimize antimicrobial use. The primary goal of antimicrobial stewardship is to improve patient outcomes and lower antimicrobial resistance and other unintended consequences of antimicrobial therapy. Secondary goals are to reduce length of hospital stays and healthcare-related costs. Hospitalists are increasingly involved in the care of hospitalized patients throughout the United States. Expertise in managing conditions requiring hospitalization, and experience in quality improvement across a wide range of clinical conditions, make hospitalists well positioned to participate in the development and implementation of hospital-based antimicrobial stewardship programs designed to improve patient outcomes, reduce antimicrobial resistance, and provide more efficient and lower-cost hospital care. Journal of Hospital Medicine 2012;7:S34 S43. (c) 2012 Society of Hospital Medicine. PMID- 23737337 TI - Chemokine CCL28 induces apoptosis of decidual stromal cells via binding CCR3/CCR10 in human spontaneous abortion. AB - Spontaneous abortion is the most common complication of pregnancy. Immune activation and the subsequent inflammation-induced tissue injury are often observed at the maternal-fetal interface as the final pathological assault in recurrent spontaneous abortion. However, the precise mechanisms responsible for spontaneous abortion involving inflammation are not fully understood. Chemokine CCL28 and its receptors CCR3 and CCR10 are important regulators in inflammatory process. Here, we examined the expression of CCL28 and its receptors in decidual stromal cells (DSCs) by immunochemistry and flow cytometry (FCM), and compared their expression level in DSCs from normal pregnancy versus spontaneous abortion, and their relationship to inflammatory cytokines production by DSCs. We further analyzed regulation of the pro-inflammatory cytokines on CCL28 expression in DSCs by real-time polymerase chain reaction, In-cell Western and FCM. The effects of CCL28-CCR3/CCR10 interaction on DSC apoptosis was investigated by Annexin V staining and FCM analysis or DAPI staining and nuclear morphology. Higher levels of the inflammatory cytokines interleukin (IL)-1beta, IL-17A and tumor necrosis factor-alpha, and increased CCR3/CCR10 expression were observed in DSCs from spontaneous abortion compared with normal pregnancy. Treatment with inflammatory cytokines differently affected CCL28 and CCR3/CCR10 expression in DSCs. Human recombinant CCL28 promoted DSC apoptosis, which was eliminated by pretreatment with neutralizing antibodies against CCR3/CCR10 and CCL28. However, CCL28 did not affect DSC growth. These results suggest that the inflammation-promoted up regulation of CCL28 and its receptors interaction in DSCs is involved in human spontaneous abortion via inducing DSC apoptosis. PMID- 23737338 TI - Influence of weather on daily symptoms of pain and fatigue in female patients with fibromyalgia: a multilevel regression analysis. AB - OBJECTIVE: Although patients with fibromyalgia often report that specific weather conditions aggravate their symptoms, empirical studies have not conclusively demonstrated such a relationship. Our aim was to examine the association between weather conditions and daily symptoms of pain and fatigue in fibromyalgia, and to identify patient characteristics explaining individual differences in weather sensitivity. METHODS: Female patients with fibromyalgia (n = 333, mean age 47.0 years, mean time since diagnosis 3.5 years) completed questions on pain and fatigue on 28 consecutive days. Daily weather conditions, including air temperature, sunshine duration, precipitation, atmospheric pressure, and relative humidity, were obtained from the Royal Netherlands Meteorological Institute. Multilevel regression analysis was applied. RESULTS: In 5 (10%) of 50 analyses, weather variables showed a significant but small effect on either pain or fatigue. In 10 analyses (20%), significant, small differences between patients were observed in the random effects of the weather variables, suggesting that symptoms of patients were, to a small extent, differentially affected by some weather conditions, for example, high pain with either low or high atmospheric pressure. These individual differences were explained neither by demographic, functional, or mental patient characteristics, nor by season or weather variation during the assessment period. CONCLUSION: There is more evidence against than in support of a uniform influence of weather on daily pain and fatigue in female patients with fibromyalgia. Although individuals appear to be differentially sensitive to certain weather conditions, there is no indication that specific patient characteristics play a role in weather sensitivity. PMID- 23737339 TI - Effect of hyperoxia on the viability and proliferation of the primary type II alveolar epithelial cells. AB - To observe the effect of hyperoxia on the growth of type II alveolar epithelial cells (AEC II). The lungs of 19-day gestation fetal rats were primary cultured and the AEC II were purified by differential adhesion method. The cells were divided into control (normoxia) group and hyperoxia group. The cell growth, cell viability, cell apoptosis, and cell cycle were examined at 2, 4, 6, and 8 days of normoxia or hyperoxia exposure. The number of cells in hyperoxia-exposed group significantly decreased as compared to those of air control group. Number of cells in hyperoxia group was the highest at day 2 of exposure and gradually decreased with time. The viability of cells exposed to hyperoxia was substantially reduced compared with cells exposed to air. Percentage of cells in G1 phase and S phase in hyperoxia group increased gradually with increase in exposure duration and significant differences were seen at day 4 and day 6 compared with either the preceding time points and also with corresponding air exposed cells. The percentage of both early apoptotic cells (Annexin-V(+)/PI(-)) and late apoptotic cells and necrotic cells (Annexin-V(+)/PI(+)) increased significantly in cells exposed to hyperoxia compared with cells exposed to air. Hyperoxia inhibits proliferation, viability and growth of AEC II and promotes apoptosis. PMID- 23737340 TI - A possible role of Aspergillus niger mitochondrial cytochrome c in malachite green reduction under calcium chloride stress. AB - In previous work, decolorization of malachite green (MG) was studied in Aspergillus niger in the presence and absence of calcium chloride stress. Decolorization took place within 24 h, and a signal transduction process that initiated MG decolorization was suggested to be involved. In the present study, further investigation of the relationship between calcium chloride stress and enhanced MG biodegradation was conducted at the sub-cellular level. MG-NADH reductase activity, a key enzyme in MG decolorization, was produced as decolorization commenced, and enzyme activity increased threefold upon exposure to calcium chloride. Inhibitors of cytochrome p450, Ca(2+) channel activity as well as activity of the signaling protein phosphoinositide 3-kinase were tested. All three activities were inhibited to different extents resulting in reduced MG decolorization. Spectral analysis of the mitochondrial fraction showed a heme signal at 405 nm and A405/A280 ratio that is characteristic of the porphoryin ring of cytochromes. There were no peaks detected for cytochromes a or b, but a shoulder appearing at 550 nm was observed, which suggested that cytochrome c is involved; the absorbance for cytochrome c doubled after calcium chloride stress supporting this idea. MG decolorization took place via a series of demethylation steps, and cytotoxicity analysis revealed a decrease in the toxicity associated with generation of leucomalachite green. PMID- 23737341 TI - ROCK is involved in vimentin phosphorylation and rearrangement induced by dengue virus. AB - Our previous study showed that dengue virus 2 (DENV2) infection induces rearrangement of vimentin into dense structures at the perinuclear area. However, the underlying mechanism of this phenomenon is poorly characterized. In the present work, we found that vimentin and Ser71 phosphorylated vimentin display similar distributions in DENV2-infected cells. DENV2 infection also induced ROCK activation and phosphorylation of vimentin at Ser71 as the DENV2 infection progressed. Furthermore, Ser71 phosphorylation and vimentin rearrangement induced by DENV2 infection were blocked by the ROCK inhibitor Y-27632. In addition, DENV2 led to endoplasmic reticulum (ER) redistribution in the perinuclear region of the host cells, which was partially blocked by pretreatment with Y-27632. Together, these data support indicate that ROCK may have a role in governing regulating vimentin and ER rearrangement during DENV2 infection. We hypothesize that DENV2 infection, via ROCK activation, induces both vimentin rearrangement and ER redistribution around the perinuclear region, which may play a structural role in anchoring DENV2 to replication sites. PMID- 23737342 TI - Efficacy of chemotherapy combined with targeted arterial infusion of verapamil in patients with advanced gastric cancer. AB - The present study evaluated the efficacy of chemotherapy combined with targeted arterial infusion of verapamil in patients with advanced gastric cancer. Forty patients were enrolled. Targeted arterial infusion of verapamil was done once a month, 3-5 times per patient, along with chemotherapy. After 2 bouts of combined treatment, the efficacy was evaluated. Primary gastric tumor was confirmed in 38/40 patients, and unconfirmed in 2/40 patients due to adhesion of tumors to surrounding tissue. Combined treatment was administered in 38 patients with defined tumors. Complete response to the treatment was in 5/38 (13.1 %) patients, partial response in 27/38 (71.1 %) patients, stable disease in 4/38 (10.5 %) patients, and progressive disease in 2/38 (5.26 %) patients. The effective rate (i.e., complete + partial response) comprised 84.2 %. There were 31 patients with liver metastases; 10/31 (32.3 %) patients showed complete response, 16/31 (51.6 %) patients showed partial response, 3/31 (9.7 %) patients had stable disease, and 2/31 (6.5 %) patients had progressive disease. The effective rate in these patients was 83.8 %. Thirty-seven patients were followed up, and 27/37 (73.0 %) patients were alive for 6 months or longer, 19/37 (51.3 %) for 12 months, 8 (35.1 %) for 18 months, and 8/37 (21.6 %) for 24 months. In conclusion, in patients with advanced gastric cancer, chemotherapy is more effective when combined with targeted arterial infusion of verapamil, leading to extended patients' survival and improved quality of life. PMID- 23737343 TI - Target to start clinical trials within 70 days of approval will take time to achieve, admits minister. PMID- 23737344 TI - States that opt out of Medicaid expansion stand to lose billions. PMID- 23737345 TI - Ocular disposition of the hemiglutarate ester prodrug of ?9-Tetrahydrocannabinol from various ophthalmic formulations. AB - PURPOSE: The overall goal of this project is to enhance ocular delivery of ?(9) Tetrahydrocannabinol (THC) through the topical route. METHODS: Solubility, stability and in vitro transcorneal permeability of the relatively hydrophilic hemiglutarate ester derivative, THC-HG, was studied in the presence of surfactants. The solutions were characterized with respect to micelle size, zeta potential and solution viscosity. In vivo studies were carried out in New Zealand albino rabbits. A previously reported promising THC-HG ion-pair formulation was also studied in vivo. RESULTS: Aqueous solubility and stability and in vitro transcorneal permeability of THC-HG was enhanced significantly in the presence of surfactants. THC levels in the ocular tissues (except cornea) were found to be below detection limits from mineral oil, surfactant or emulsion based formulations containing THC. In contrast, micellar and ion pair based THC-HG formulations produced significantly higher total THC concentrations in the anterior ocular chamber. CONCLUSION: In this study, although delivery of THC to the anterior chamber ocular tissues could be significantly increased through the prodrug and formulation approaches tested, further studies are needed to increase penetration to the back-of-the eye. PMID- 23737346 TI - Application of hematological toxicity modeling in clinical development of abexinostat (S-78454, PCI-24781), a new histone deacetylase inhibitor. AB - PURPOSE: A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the thrombocytopenia (dose-limiting toxicity) of abexinostat, a new histone deacetylase inhibitor. An optimal administration schedule of the drug was determined using a simulation-based approach. METHODS: Early PK and PK/PD data were analysed using a sequential population modeling approach (NONMEM 7), allowing for the description of a PK profile and platelet-count decrease after abexinostat administration with various administration schedules. Simulations of platelet count with several administration schedules over 3-week treatment cycles (ASC) and over a day (ASD) were computed to define the optimal schedule that limits the depth of thrombocytopenia. RESULTS: An intermediate PK/PD model accurately described the data. The administration of abexinostat during the first 4 days of each week in a 3-week cycle resulted in fewer adverse events (with no influence of ASD on platelet count profiles), and corresponded to the optimal treatment schedule. This administration schedule was clinically evaluated in a phase I clinical trial and allowed for the definition of a new maximum tolerated dose (MTD), leading to a nearly 30% higher dose-intensity than that of another previously tested schedule. Lastly, a final model was built using all of the available data. CONCLUSIONS: The final model, characterizing the dose-effect and the dose-toxicity relationships, provides a useful modeling tool for clinical drug development. PMID- 23737348 TI - CSF viral escape in a patient with HIV-associated neurocognitive disorder. PMID- 23737347 TI - Pharmacokinetic interactions of CEP-1347 and atazanavir in HIV-infected patients. AB - CEP-1347 is a potent inhibitor of mixed lineage kinase (MLK), which was investigated for ameliorating HIV-associated neurocognitive disorders. CEP-1347 and atazanavir pharmacokinetics were determined when CEP-1347 50 mg twice daily was administered to HIV-infected patients (n = 20) receiving combination antiretroviral therapy including atazanavir and ritonavir (ATV/RTV, 300/100 mg) once daily continuously. Co-administration of CEP-1347 and ATV/RTV resulted with significant changes in pharmacokinetics of ATV but not RTV. Specifically, an increase in ATV accumulation ratio of 15 % (p = 0.007) and a prolongation of T(1/2) from 12.7 to 15.9 h (p = 0.002) were observed. The results suggested that co-administration of CEP-1347 with ATV/RTV in HIV-infected patients might result in limited impact on ATV but not on RTV pharmacokinetics. PMID- 23737349 TI - 1H NMR metabolite fingerprinting as a new tool for body fluid identification in forensic science. AB - In this feasibility study, we propose, for the first time, (1)H NMR spectroscopy coupled with mathematical strategies as a valid tool for body fluid (BF) trace identification in forensic science. In order to assess the ability of this approach to identify traces composed either by a single or by two different BFs, samples of blood, urine, saliva, and semen were collected from different donors, and binary mixtures were prepared. (1)H NMR analyses were carried out for all samples. Spectral data of the whole set were firstly submitted to unsupervised principal component analysis (PCA); it showed that samples of the same BF cluster well on the basis of their characterizing molecular components and that mixtures exhibit intermediate characteristics among BF typologies. Furthermore, samples were divided into a training set and a test set. An average NMR spectral profile for each typology of BF was obtained from the training set and validated as representative of each BF class. Finally, a fitting procedure, based on a system of linear equations with the four obtained average spectral profiles, was applied to the test set and the mixture samples; it showed that BFs can be unambiguously identified, even as components of a mixture. The successful use of this mathematical procedure has the advantage, in forensics, of overcoming bias due to the analyst's personal judgment. We therefore propose this combined approach as a valid, fast, and non-destructive tool for addressing the challenges in the identification of composite traces in forensics. PMID- 23737350 TI - Cholesteatoma in cleft lip and palate: a population-based follow-up study of children after ventilation tubes. AB - OBJECTIVES/HYPOTHESIS: To investigate the association of cleft conditions and the development of secondary cholesteatoma following middle ear ventilation tube insertion (MEVTI) in children. STUDY DESIGN: A retrospective cohort study of all children born after 1980 who underwent at least one MEVTI in a Western Australian hospital from 1980 to 2009 using administrative health data. METHODS: The timing and number of MEVTIs, adenoidectomy, type of cleft conditions and cholesteatoma were identified along with demographic variables. Flexible parametric proportional hazards models and hazard functions using age as a time scale were used to estimate the relative rate of developing cholesteatoma. RESULTS: There were 56,949 children who underwent at least one MEVTI during the study period. There were 869 (1.5%) children who also had a diagnosis of a cleft condition. Overall, 594 (1.0%) children developed a secondary cholesteatoma. After taking length of follow-up into account, 6.9% (95% confidence interval [CI], 5.0-9.6) of children with cleft conditions developed cholesteatoma by 18 years of age compared to 1.5% (95% CI, 1.3-1.6) of children without cleft conditions. After adjusting for demographic and clinical variables, children with cleft conditions developed cholesteatoma 7.5 (95% CI, 3.8-18.2) times faster after first MEVTI compared to children without cleft conditions, although by the third MEVTI this difference was no longer statistically significant (P = .257). The rate of developing cholesteatoma in 2005 to 2009 was 0.5 (95% CI, 0.3-0.8) times that of 1980 to 1990. CONCLUSIONS: Children with cleft conditions are at increased risk of developing cholesteatoma compared to other children who had one or two MEVTIs, although the overall rate of cholesteatoma is declining. PMID- 23737351 TI - A metabolite of daidzein, 6,7,4'-trihydroxyisoflavone, suppresses adipogenesis in 3T3-L1 preadipocytes via ATP-competitive inhibition of PI3K. AB - SCOPE: Daidzein is one of the major soy isoflavones. Following ingestion, daidzein is readily metabolized in the liver and converted into hydroxylated metabolites. One such metabolite is 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF), which has been the focus of recent studies due to its various health benefits, however, its anti-adipogenic activity has not been investigated. Our objective was to determine the effects of 6,7,4'-THIF on adipogenesis in 3T3-L1 preadipocytes and elucidate the mechanisms of action involved. METHODS AND RESULTS: Adipogenesis was stimulated in 3T3-L1 preadipocytes. Both 6,7,4'-THIF and daidzein were treated in the presence and absence of mixture of isobutylmethylxanthine, dexamethasone, and insulin (MDI). We observed that 6,7,4' THIF, but not daidzein, inhibited MDI-induced adipogenesis significantly at 40 and 80 MUM, associated with decreased peroxisome proliferator-activated receptor gamma and C/EBP-alpha protein expression. 6,7,4'-THIF significantly suppressed MDI-induced lipid accumulation in the early stage of adipogenesis, attributable to a suppression of cell proliferation and the induction of cell cycle arrest. We also determined that 6,7,4'-THIF, but not daidzein, attenuated phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. 6,7,4'-THIF was found to inhibit PI3K activity via direct binding in an ATP-competitive manner. CONCLUSION: Our results suggest that 6,7,4'-THIF suppresses adipogenesis in 3T3 L1 preadipocytes by directly targeting PI3K. Soy isoflavones like 6,7,4'-THIF may have potential for development into novel treatment strategies for chronic obesity. PMID- 23737352 TI - Recurrence of high-risk bladder cancer: a population-based analysis. AB - BACKGROUND: Patients with bladder cancer are apt to develop multiple recurrences that require intervention. The recurrence, progression, and bladder cancer related mortality rates were examined in a cohort of individuals with high-grade non-muscle-invasive bladder cancer. METHODS: Using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data, subjects were identified who had a diagnosis of high-grade, non-muscle-invasive disease in 1992 to 2002 and who were followed until 2007. Multivariate competing-risks regression analyses were then used to examine recurrence, progression, and bladder cancer-related mortality rates. RESULTS: Of 7410 subjects, 2897 (39.1%) experienced a recurrence without progression, 2449 (33.0%) experienced disease progression, of whom 981 succumbed to bladder cancer. Using competing-risks regression analysis, the 10 year recurrence, progression, and bladder cancer-related mortality rates were found to be 74.3%, 33.3%, and 12.3%, respectively. Stage T1 was the only variable associated with a higher rate of recurrence. Women, black race, undifferentiated grade, and stage Tis and T1 were associated with a higher risk of progression and mortality. Advanced age (>= 70) was associated with a higher risk of bladder cancer-related mortality. CONCLUSIONS: Nearly three-fourths of patients diagnosed with high-risk bladder cancer will recur, progress, or die within 10 years of their diagnosis. Even though most patients do not die of bladder cancer, the vast majority endures the morbidity of recurrence and progression of their cancer. Increasing efforts should be made to offer patients intravesical therapy with the goal of minimizing the incidence of recurrences. Furthermore, the high recurrence rate seen during the first 2 years of diagnosis warrants an intense surveillance schedule. PMID- 23737353 TI - Interaction between noise and cigarette smoking for the outcome of hearing loss among women: a population-based study. AB - BACKGROUND: We investigated the interaction between exposure to noise and smoking in relation to prevalence of hearing loss among women. METHODS: A sample of women aged 20-49 years (n = 1,723) from a population-based cross-sectional study carried out in Brazil in 2006 was examined. Hearing loss was assessed using a yes no validated question. Biological interaction was analyzed using the additive scale and measured with interaction contrast ratio (ICR) and assessment of dose response relationship. RESULTS: The combined effect of exposure to noise and cigarette smoking on hearing loss (adjusted prevalence ratio (PRadj) = 3.94, 95% confidence interval (CI): 2.81, 5.52) was greater than expected based on the additive single effects of smoking (PRadj = 1.39, 95% CI: 1.07, 1.81) and noise (PRadj = 2.66, 95% CI: 1.86, 3.82). ICR estimates were not statistically significant. The prevalence of hearing loss among noise-exposed women increased with duration of smoking (P trend = 0.026), number of cigarettes smoked per day (P trend = 0.034), cumulative tobacco use (P trend = 0.030), and early age at smoking initiation (P trend = 0.047). CONCLUSIONS: Noise and smoking may have a combined effect on hearing loss but further studies are still needed. A dose response relation of smoking for the noise effect among women is suggested. PMID- 23737354 TI - Systematic selection of metalloporphyrin-based catalysts for oxygen reduction by modulation of the donor-acceptor intermolecular hardness. AB - Incisive modulation of the intermolecular hardness between metalloporphyrins and O2 can lead to the identification of promising catalysts for oxygen reduction. The dependency of the electrocatalytic reduction of O2 by metalloporphyrins on the nature of the central metal yields a volcano-type curve, which is rationalized to be in accordance with the Sabatier principle by using an approximation of the electrophilicity of the complexes. By using electrochemical and UV/Vis data, the influence of a selection of meso-substituents on the change in the energy for the pi->pi* excitation of manganese porphyrins was evaluated allowing one to quantitatively correlate the influence of the various ligands on the electrocatalysis of O2 reduction by the complexes. A manganese porphyrin was identified that electrocatalyzes the reduction of oxygen at low overpotentials without generating hydrogen peroxide. The activity of the complex became remarkably enhanced upon its pyrolysis at 650 degrees C. PMID- 23737356 TI - Macular Carotenoids Conference - Cambridge, United Kingdom, July 10-12, 2013. PMID- 23737355 TI - Molecular mechanisms of meditation. AB - Meditation is a complex process involving change in cognition, memory, and social and emotional control, and causes improvement in various cardiovascular, neurological, autoimmune, and renal pathologies. Meditation also become widely used in medical and psychological treatment therapies for stress-related physical and mental disorders. But still, biological mechanisms in terms of effect on brain and body are poorly understood. This paper explains the basic changes due to meditation in cerebral cortex, prefrontal area, cingulate gyrus, neurotransmitters, white matter, autonomic nervous system, limbic system, cytokines, endorphins, hormones, etc. The following is a review of the current literature regarding the various neurophysiological mechanisms, neuro-endocrine mechanisms, neurochemical substrates, etc. that underlies the complex processes of meditation. PMID- 23737358 TI - Smokers can use nicotine replacement products to reduce harm, says NICE. PMID- 23737359 TI - The bizarreness effect: evidence for the critical influence of retrieval processes. AB - People show better memory for bizarre sentences relative to common sentences, a finding referred to as the bizarrness effect. Interestingly, this effect is typically only obtained using a mixed-list design, in which participants study common and bizarre sentences in the same list. This bizarreness effect in mixed list designs has been explained as the result of both enhanced encoding processes and efficient retrieval processes. The present experiment was designed to isolate the unique contributions of the retrieval context to the bizarreness effect. Participants studied common sentences in one room under one set of instructions, and bizarre sentences in another room under another set of instructions. At test, participants recalled the common and bizarre sentences either together or separately. The results showed that the bizarreness effect was only obtained when participants recalled the common and bizarre items together; no bizarreness advantage emerged when participants were required to recall the common and bizarre items separately. These results suggest that differential encoding processes are not necessary for explaining the bizarreness effect in memory. Rather, retrieval of the mixed-list context appears to be critical for obtaining the effect. PMID- 23737360 TI - Targeted liposome-loaded microbubbles for cell-specific ultrasound-triggered drug delivery. AB - One of the main problems in cancer treatment is disease relapse through metastatic colonization, which is caused by circulating tumor cells (CTCs). This work reports on liposome-loaded microbubbles targeted to N-cadherin, a cell-cell adhesion molecule expressed by CTCs. It is shown that such microbubbles can indeed bind to N-cadherin at the surface of HMB2 cells. Interestingly, in a mixture of cells with and without N-cadherin expression, binding of the liposome loaded microbubbles mainly occurs to the N-cadherin-expressing cells. Importantly, applying ultrasound results in the intracellular delivery of a model drug (loaded in the liposomes) in the N-cadherin-expressing cells only. As described in this paper, such liposome-loaded microbubbles may find application as theranostics and in devices aimed for the specific killing of CTCs in blood. PMID- 23737361 TI - Short-term outcomes and cost of care of treatment of head and neck paragangliomas. AB - OBJECTIVES/HYPOTHESIS: To characterize contemporary treatment of head and neck paragangliomas and the effect of treatment on postoperative complications, length of stay, and costs. STUDY DESIGN: Retrospective cross-sectional study. METHODS: Discharge data from the Nationwide Inpatient Sample for 7,791 patients who underwent endovascular or surgical treatment of head and neck paragangliomas between 1993 and 2008 were analyzed using cross tabulations and multivariate regression modeling. RESULTS: Surgery only was performed in 91% of cases, embolization alone was performed in 4% of cases, and both embolization and surgery were performed in 5% of cases. Postoperative surgical complications were significantly more likely in patients undergoing embolization and surgery during the same admission (odds ratio [OR], 2.3; P = .031), whereas acute medical complications were more likely in patients undergoing embolization only (OR, 3.9; P = .001). Embolization alone was specifically associated with an increased risk of acute renal failure (OR, 8.2; P = .026) and pneumonia (OR, 3.9; P = .001). Cranial nerve injury was associated with increased odds of dysphagia (OR, 8.5; P = .004), and dysphagia was associated with increased odds of voice disturbance (OR, 5.1; P = .004). Embolization, with or without surgery during the same admission, was associated with significantly increased hospital-related costs, after controlling for all other variables. CONCLUSIONS: Endovascular treatment of head and neck paragangliomas is associated with an increase in complications and hospital-related costs. Although these findings may reflect larger tumor size and comorbidity in patients selected for embolization, these data suggest a need to reexamine the benefits and cost-effectiveness of embolization in surgical patients. PMID- 23737362 TI - 3He NMR: from free gas to its encapsulation in fullerene. AB - The (3)He nuclear magnetic shieldings were calculated for single helium atom, its dimer, simple models of fullerene cages (He@Cn), and single wall carbon nanotubes. The performances of several levels of theory (HF, MP2, DFT-VSXC, CCSD, CCSD(T), and CCSDT) were tested. Two sets of polarization-consistent basis sets were used (pcS-n and aug-pcS-n), and an estimate of (3)He nuclear magnetic shieldings in the complete basis set limit using a two-parameter fit was established. Theoretical (3)He results reproduced accurately previously reported theoretical values for helium gas, dimer, and helium probe inside several fullerene cages. Excellent agreement with experimental values was achieved. (3)He nuclear magnetic shieldings of single helium atom approaching various points of benzene ring were tested, and an impact of (3)He confinement within fullerene cages of different size on the (3)He chemical shift was determined. PMID- 23737363 TI - Congenital chylous ascites and lymphedema in Down's syndrome: authors' reply. PMID- 23737364 TI - Incidence and etiology of acute kidney injury in Southern India: author's reply. PMID- 23737365 TI - Treatment of relapsed/refractory langerhans cell histiocytosis: a single centre experience. PMID- 23737366 TI - Hyperleukocytosis: emergency management : correspondence. PMID- 23737367 TI - Hyperleukocytosis: emergency management : authors' reply. PMID- 23737368 TI - Congenital chylous ascites and lymphedema in Down's syndrome: correspondence. PMID- 23737369 TI - Structure-dependent electronic nature of star-shaped oligothiophenes, probed by ensemble and single-molecule spectroscopy. AB - We have investigated the photophysical properties of star-shaped oligothiophenes with three terthiophene arms (meta to each other, S3) or six terthiophene arms (ortho-, meta-, and para-arranged, S6) connected to an ethynylbenzene core to elucidate the relationship between their molecular structure and electronic properties by using a combination of ensemble and single-molecule spectroscopic techniques. We postulate two different conformations for molecules S3 and S6 on the basis of the X-ray structure of hexakis(5-hexyl-2-thienlyethynyl)benzene and suggest the coexistence of these conformers by using spectroscopic methods. From the steady-state spectroscopic data of compound S6, we show that the exciton is delocalized over the core structure, but that the meta-linkage in compound S3 prevents the electronic communication between the arms. However, in single molecule spectroscopic measurements, we observed that some molecules of compound S3 showed long fluorescence lifetimes (about 1.4 ns) in the fluorescence intensity trajectories, which indicated that pi electrons were delocalized along the meta linker. Based on these observations, we suggest that the delocalized exciton is intensely sensitive towards the dihedral angle between the core and the adjacent thiophene ring, as well as to the substituted position of the terthiophene arms. Our results highlight that the fluorescence lifetimes of compounds S3 and S6 are strongly correlated with the spatial location of their excitons, which is mainly affected by their conformation, that is, whether the innermost thiophene rings are facing each other or not. More interestingly, we observed that the difference between the degrees of ring-torsional flexibility of compounds S3 and S6 results in their sharply contrasting fluorescence properties, such as a change in fluorescence intensity as a function of temperature. PMID- 23737372 TI - Rapid decline in lung function in coal miners: evidence of disease in small airways. AB - BACKGROUND: Coal mine dust exposure can cause both pneumoconiosis and chronic airflow limitation. The contributions of various pathophysiologic mechanisms to dust-related lung function decrements remain unclear. METHODS: Clinical and physiological findings were assessed for 15 underground coal miners who had demonstrated accelerated FEV1 losses (decliners) over 6-18 years. Decliners' findings were evaluated in comparison to a group of 11 miners who had shown relatively stable lung function (referents) during the same period. RESULTS: At follow-up examination, the decliners showed significantly greater mean airway resistance (10.47 vs. 6.78 cmH2 O/L/s; P = 0.05) and more air trapping (RV/TLC = 37.5 vs. 29.1%; P < 0.01) compared to the referents. Decliners also demonstrated more evidence of small airways dysfunction and tended to have more bronchospasm than the referent group. Total lung capacity, lung compliance, diffusing capacity, and chest radiography did not differ significantly between the two groups. After cessation of mine dust exposures, the decliners' mean rate of FEV1 loss normalized. CONCLUSION: In a series of working coal miners, accelerated lung function declines were associated with air trapping and evidence of small airways dysfunction. A preventive benefit from controlling dust exposures was suggested. PMID- 23737374 TI - Assessment of genetic markers and glioblastoma stem-like cells in activation of dendritic cells. AB - Glioblastoma (GBM) is the most common and aggressive intraparenchymal primary brain tumor in adults. The principal reasons for the poor outcomes of GBM are the high rates of recurrence and resistance to chemotherapy. The aim of this study was to determine the role of tailored cellular therapy for GBM with a poor prognosis and compare the activity of dendritic cells (DCs) that have encountered GBM cells. Detecting the correlations between methylation and expression of MGMT and PTEN genes and GBM cancer stem cells (CSCs) markers after co-cultures with a mononuclear cell cocktail are also aims for this study. Allogenic umbilical cord blood (UCB)-derived DCs were labeled with the CD11a and CD123 for immature DCs, and CD80 and CD11c for mature DCs. CD34, CD45, and CD56 cells were isolated from allogenic UCB for using in DCs maturation. GBM CSCs were detected with CD133/1 and CD111 antibodies after co-culture studies. DC activation was carried out via GBM cells including CD133 and CD111 cells and a mononuclear cells cocktail including CD34, CD45, and CD56 natural killer cells. Real-time PCR was performed to detect the expression and promoter methylation status of PTEN and MGMT genes. The expression of CSCs markers was found in all GBM cases, and a statistically significant correlation was found among them after co-culture studies. The most pronounced affinity of DCs to GBM cells was observed at dilutions between 1/4 and 1/256 in co-cultures. There was a statistically significant correlation between cellularity and granularity ratios for CD123 and CD11c. PTEN and MGMT gene expression and methylation values were evaluated with respect to CSCs expression and no statistical significance was found. Activation of DCs might associate with CSCs and the mononuclear cells cocktail including CD34, CD45, and CD56 cells which were obtained from allogenic UCB. PMID- 23737376 TI - Screening for MRSA and isolating carriers doesn't reduce ICU infections. PMID- 23737375 TI - Comprehensive genome- and transcriptome-wide analyses of mutations associated with microsatellite instability in Korean gastric cancers. AB - Microsatellite instability (MSI) is a critical mechanism that drives genetic aberrations in cancer. To identify the entire MS mutation, we performed the first comprehensive genome- and transcriptome-wide analyses of mutations associated with MSI in Korean gastric cancer cell lines and primary tissues. We identified 18,377 MS mutations of five or more repeat nucleotides in coding sequences and untranslated regions of genes, and discovered 139 individual genes whose expression was down-regulated in association with UTR MS mutation. In addition, we found that 90.5% of MS mutations with deletions in gene regions occurred in UTRs. This analysis emphasizes the genetic diversity of MSI-H gastric tumors and provides clues to the mechanistic basis of instability in microsatellite unstable gastric cancers. PMID- 23737377 TI - Visible-light-induced disruption of diselenide-containing layer-by-layer films: toward combination of chemotherapy and photodynamic therapy. AB - A photoresponsive polyelectrolyte multilayer film containing a diselenide functional group is fabricated using an unconventional layer-by-layer method. The polycation backbone is constructed through copolymerization of di-(1 hydroxylundecyl) diselenide and 1,4-bis(2-hydroxyethyl)piperazine with 2,4 diisocyanatotoluene. A common polyanion poly(styrene sulfonate) is selected as the polyanion. The obtained film can be gradually disrupted under the irradiation of mild visible light, and this process can be monitored with UV-vis spectroscopy. The residue of the film is estimated to be 17% after 5 h of irradiation. The intensity of the visible light can be as low as 50 mW cm-2, which is even weaker than the sunlight. The cytotoxicity of the building blocks is evaluated in MTT assays using human hepatic cell line (L-02), and the results are satisfactory. Further tests show that cells can grow in a regular manner on this film, indicating good biocompatibility. In addition, the film can be used to achieve cargo loading and controlled release. Considering that light can not only trigger controlled release but also act as part of the therapy itself (photodynamic therapy), this system shows hope for further development into a platform for the combination of chemotherapy and photodynamic therapy, especially for applications concerning skin. PMID- 23737378 TI - Is there a "July effect" for head and neck cancer surgery? AB - OBJECTIVES/HYPOTHESIS: A "July effect" of increased complications when new trainees begin residency has been reported widely by the media. We sought to determine the effect of admission month on in-hospital mortality, complications, length of hospitalization, and costs for patients undergoing head and neck cancer (HNCA) surgery. STUDY DESIGN: Retrospective cross-sectional study. METHODS: Discharge data from the Nationwide Inpatient Sample for 48,263 patients who underwent an ablative procedure for a malignant oral cavity, laryngeal, hypopharyngeal, or oropharyngeal neoplasm in 2005 to 2008 were analyzed using cross-tabulations and multivariate regression modeling. RESULTS: There were 3,812 cases admitted in July (8%). July admission was significantly associated with Medicaid (RRR 1.40, P = 0.011) or self-pay payor status (RRR 1.40, P = 0.022), medium hospital bed size (RRR 1.63, P = 0.033) and large hospital bed size (RRR 1.73, P = 0.013). There was no association between July admission and other patient or hospital demographic characteristics. Major procedures and comorbidity were significantly associated with in-hospital death, surgical and medical complications, length of hospitalization, and costs, but no association was found for July admission, July through September discharge, or teaching hospital status and short-term morbidity or mortality. Teaching hospitals and large hospital bed size were predictors of increased length of hospitalization and costs; and private, for profit hospitals were additionally associated with increased costs. No interaction between July admission and teaching hospitals was found for any of the outcome variables studied. CONCLUSIONS: These data do not support evidence of a "July effect" or an increase in morbidity or mortality at teaching hospitals providing HNCA surgical care. PMID- 23737379 TI - Editorial. International health planning management. PMID- 23737380 TI - Hyper-stasis as opposed to hyper-activism: the politics of health policy in the USA set against England. AB - This paper considers health policy-making in the USA with England as comparator. It contrasts policy inertia in US healthcare despite crisis with hyper-activity in perpetual 'reform' in England despite absence of crisis in the NHS. It does so from the standpoint of political science and political economy. I suggest that 'path-dependency', the view that past policy constrains future policy, lacks explanatory power and that wider and deeper explanations must be sought. The USA's apparent path dependency is in fact a story of political economy and power, buttressed by institutions. England's apparent lack of path-dependency in promulgating NHS reform is in fact a story of executive hyper-activism which is oblivious to how implementation will obviate its prescriptions. This failure of 'reform' in the NHS is not a symptom of concealed path-dependency but a sign of pragmatism by those charged with implementation. In the USA, the durability of its various systems of healthcare is by contrast a sign of pragmatism not being adequate to achieve health sector reform. In the USA, a weak state is unable to manage healthcare reform which would actually benefit US capitalism as a whole. In the UK, a strong state has created and developed the NHS to the benefit of capital through the economical provision of healthcare to the workforce. Such an 'investment state' is a testimony to the continuing validity of the neo-Marxist argument that social investment and social expenses are an important and functional component of the capitalist state. PMID- 23737383 TI - Facile and rapid oxidation fabrication of BiOCl hierarchical nanostructures with enhanced photocatalytic properties. PMID- 23737382 TI - Heterologous vaccination against human tuberculosis modulates antigen-specific CD4+ T-cell function. AB - Heterologous prime-boost strategies hold promise for vaccination against tuberculosis. However, the T-cell characteristics required for protection are not known. We proposed that boost vaccines should induce long-lived functional and phenotypic changes to T cells primed by Bacille Calmette Guerin (BCG) and/or natural exposure to mycobacteria. We characterized changes among specific CD4(+) T cells after vaccination with the MVA85A vaccine in adults, adolescents, and children. CD4(+) T cells identified with Ag85A peptide-bearing HLA class II tetramers were characterized by flow cytometry. We also measured proliferative potential and cytokine expression of Ag85A-specific CD4(+) T cells. During the effector phase, MVA85A-induced specific CD4(+) T cells coexpressed IFN-gamma and IL-2, skin homing integrins, and the activation marker CD38. This was followed by contraction and a transition to predominantly IL-2-expressing, CD45RA(-) CCR7(+) CD27(+) or CD45RA(+) CCR7(+) CD27(+) specific CD4(+) T cells. These surface phenotypes were similar to Ag85A-specific T cells prior to MVA85A. However, functional differences were observed postvaccination: specific proliferative capacity was markedly higher after 6-12 months than before vaccination. Our data suggest that MVA85A vaccination may modulate Ag85A-specific CD4(+) T-cell function, resulting in greater recall potential. Importantly, surface phenotypes commonly used as proxies for memory T-cell function did not associate with functional effects of vaccination. PMID- 23737387 TI - Targeting premeal anxiety in eating disordered clients and normal controls: a preliminary investigation into the use of mindful eating vs. distraction during food exposure. AB - OBJECTIVE: Studies have demonstrated that negative affect increases prior to food intake in individuals diagnosed with an eating disorder. Mindfulness has been supported empirically to treat experiential avoidance stemming from anxiety. Thus, the current objective in this study is to empirically compare mindfulness vs. thought suppression invention during a food exposure in both clinical and nonclinical samples. METHOD: In a 2 (Group: clinical vs. nonclinical) * 2 (INTERVENTION: mindfulness vs. distraction) counterbalanced within treatment design, the current investigation sought to determine the differential effectiveness of a brief mindfulness intervention vs. a brief distraction intervention in women diagnosed with AN and BN in a clinical and nonclinical sample during a food exposure. RESULTS: Results indicated that the eating disorder group reported a significant increase in negative affect after the mindfulness intervention as compared to the distraction intervention, whereas the nonclinical group reported a significant decrease in negative affect after the mindfulness intervention as compared to the distraction intervention. DISCUSSION: Preliminary findings suggest that clinicians may want to proceed cautiously when using mindful eating in those with severe eating disorders during the early stages of food exposure. Limitations and future directions are discussed. PMID- 23737385 TI - Pharmaceutical follow-up for patients on rituximab therapy for non-Hodgkin lymphoma: what is the evidence? AB - BACKGROUND: Introduction of the monoclonal antibody rituximab to chemotherapy regimens has substantially improved disease-free and overall survival in patients with non-Hodgkin lymphomas (NHL). The short-term safety of this drug has been widely reported, but there are few data on long-term safety, which suggests that these patients require prolonged follow-up. AIM OF THE REVIEW: To review the literature on follow-up models, with a focus on the safety of rituximab therapy for diffuse large B-cell lymphoma and follicular lymphoma. METHOD: The Cochrane Library, Embassy, Lilacs, Medline, and Scirus databases were searched for systematic reviews and randomized controlled trials. Furthermore, textbooks and journals on pharmaceutical care and institutional websites were searched for patient management recommendations. The outcomes were follow-up models and grade 3, 4, and 5 adverse reactions. RESULTS: Five systematic reviews and eight clinical trials or updates describing patient follow-up or reporting adverse reactions were identified. Only one systematic review and seven clinical trials reported follow-up routines for patients receiving rituximab, including information on staging, frequency of reassessment, and laboratory tests, as well as pre-infusion care and management of acute or delayed adverse reactions. Five systematic reviews and four clinical trials reported data on statistically significant adverse reactions (fever, leukopenia, infection). Four guidelines or institutional protocols for treatment and follow-up were identified, as well as seven studies describing experiences in the implementation of pharmaceutical care for oncology patients, but none were specifically focused on follow-up of patients receiving rituximab for NHL. CONCLUSION: Although some systematic reviews and clinical trials contain guidance on follow-up of patients receiving rituximab for NHL, there are no validated strategies for systematic follow-up of these patients with a focus on safety. As there are few data on long-term safety profile of these novel treatments, monitoring strategies should be developed and implemented to ensure safe and optimized use of drugs recently added to the therapeutic arsenal of clinical oncology. PMID- 23737388 TI - Toxicity and adherence to treatment for latent tuberculosis infection in patients with hematologic malignancies. AB - PURPOSE: Oncohematological patients undergoing chemotherapy who have latent tuberculosis infection (LTBI) are at a high risk of developing active tuberculosis (TB). The identification and treatment of these patients can prevent LTBI progressing to active TB. This study analyzed the degree of adherence with and safety of the treatment of latent tuberculosis infection (TLTBI) in oncohematological patients undergoing antineoplastic chemotherapy. METHODS: This is a retrospective study of a cohort of oncohematological patients receiving TLTBI and antineoplastic chemotherapy simultaneously, between January 2007 and June 2010. The proportions of toxicity and adherence to TLTBI in these patients were compared with a non-oncohematological control group, matched for age, sex, and year in which the TLTBI was started. In addition, a minimum 2-year follow-up was carried out for all patients. RESULTS: A total of 105 patients who received TLTBI were included, 21 of whom had received antineoplastic chemotherapy simultaneously. The mean age of the patients was 63 years. There were no significant baseline differences in transaminase values. The percentages of patients completing treatment were 76.2% in the control group and 71.4% in the oncohematological group [risk ratio (RR): 1.07, 95% confidence interval (CI): 0.79-1.43]. The voluntary dropout proportion was similar in both groups (12.3 vs. 11.8%, RR: 1.05, 95% CI: 0.25-4.42). Treatment was discontinued because of toxicity in three oncohematological patients and in 11 patients from the control group (RR: 1.14; 95% CI: 035-3.66). No patient developed TB during the follow-up period. CONCLUSION: The safety of TLTBI is not influenced by simultaneous antineoplastic chemotherapy in oncohematological patients. PMID- 23737389 TI - Development and validation of the cough severity index: a severity index for chronic cough related to the upper airway. AB - OBJECTIVES/HYPOTHESIS: To develop and validate a cough severity index (CSI) which quantifies patients' symptoms associated with upper airway chronic cough and to provide a tool for treatment outcome measures. METHODS: Two hundred patients who had a complaint of chronic cough and/or dyspnea were given a 49- item questionnaire developed through a clinical consensus of the most common symptoms of chronic cough of upper airway origin. The instrument was reduced to 10 questions using statistical methodology. Fifty subsequent patients were given the CSI to measure test-retest reliability at two different moments in time. Twenty healthy controls (HC) were given the instrument to obtain validity. An additional 95 participants provided pre- and posttreatment outcomes using the CSI. RESULTS: Principle Component Analysis (PCA) revealed a single factor with the original 49 questions. A combination of PCA, rank-ordering item-total correlation and communality, as well as clinical consensus further reduced the questionnaire to 10 items. Internal consistency of the CSI was 0.97. Test-retest reliability was r = 0.83. An r = 0.60 for divergent validity between the CSI and the Cough-Specific Quality-of-Life Questionnaire (CQLQ) demonstrated two fairly separate instruments, although both measured cough. Mann-Whitney test was significant between symptomatic patients and healthy controls (P < 0.0004). The results of 20 HC showed a mean of 0.45 (standard deviation = 1.39). Results for treatment outcomes revealed significance with the Wilcoxon test (P < 0.0001) and paired samples t test showed significantly different correlations between pre- and postmeasures. CONCLUSION: The CSI is a short, simple instrument that can be used in the clinical setting to quantify a patient's symptoms of chronic cough of upper airway origin. It represents a statistically reliable, valid, and clinically relevant instrument that can be used to measure treatment outcomes for chronic cough. PMID- 23737390 TI - Long-term efficacy and safety of Zotarolimus-eluting stent in patients with diabetes mellitus: pooled 5-year results from the ENDEAVOR III and IV trials. AB - OBJECTIVE: To assess long-term outcomes of Endeavor Zotarolimus-eluting stent (E ZES) implantation in patients with diabetes mellitus (DM). BACKGROUND: Patients with DM and coronary artery disease have lower restenosis with drug-eluting stent (DES) compared with bare-metal stents. Recent data suggest that the E-ZES is inferior to other DES in this population. METHODS: Patient-level data for 601 patients with DM from the ENDEAVOR III and ENDEAVOR IV trials were pooled, of which 337 were treated with E-ZES and 264 were treated with other DES. The primary outcome was target vessel failure (TVF) in the course of 5 years. Outcomes are reported as rates using Kaplan-Meier (KM) survival method and differences between E-ZES and other stent types (sirolimus-eluting stent or paclitaxel-eluting stent) were compared using the log-rank statistic. The independent effect of stent type on TVF was assessed using Cox proportional hazards regression. RESULTS: Baseline characteristics were similar between the groups. Five-year TVF KM rate estimate was numerically lower for E-ZES, but the difference did not reach statistical significance (20.2 vs. 26.9%, P = 0.065). The 5-year KM rate estimates of major adverse cardiac events (17.7 vs. 26.6%, P = 0.012), death (7.6 vs. 15.0%, P = 0.004), and myocardial infarction (1.3 vs. 5.1%, P = 0.011) were also lower for E-ZES versus other DES. CONCLUSIONS: Patients with DM implanted with E-ZES have favorable long-term outcomes compared to first-generation DES. Long-term performance of DES should be assessed routinely and may differ from initial performance. PMID- 23737394 TI - Submerged discontent and patterns of accommodation: a case study of doctors' pay in two public hospitals in China. AB - The article evaluates submerged discontent among Chinese public hospital doctors (Note1) regarding their pay and patterns of accommodation, including doctors' responses through formal and informal actions in the context of health service marketization. On the basis of a case study of two public hospitals, the article illustrates the dynamical impact of marketization on Chinese doctors' pay-related dissatisfaction and health service employment relationship. Because of the authoritarian management and compliant trade unions, the conflict between doctors and hospitals is unable to be accommodated through collective methods. Instead, doctors' discontent is often channelled through informal, individual and subtle activities. Meanwhile, doctors' professional society is gradually influential, showing its potential of developing doctors' group identity and protecting members' interests in future. PMID- 23737393 TI - Angiogenesis and intramembranous osteogenesis. AB - BACKGROUND: Angiogenesis is likely critical for the process of intramembranous osteogenesis; however, the developmental relationship between blood vessels and bone mineralization is not well studied within intramembranous bones. Given its importance, changes in angiogenesis regulation are likely to contribute to evolutionarily and medically relevant craniofacial variation. RESULTS: We summarize what is known about the association between angiogenesis and intramembranous osteogenesis, supplementing with information from the better studied processes of endochondral ossification and distraction osteogenesis. Based on this review, we introduce a model of angiogenesis during early intramembranous osteogenesis as well as a series of null hypotheses to be tested. CONCLUSIONS: This model can serve as a basis of future research on the spatio temporal association and regulatory interactions of mesenchymal, vascular, and bone cells, which will be required to illuminate the potential effects of angiogenesis dysregulation on craniofacial skeletal phenotypes. PMID- 23737395 TI - Ursolic acid promotes cancer cell death by inducing Atg5-dependent autophagy. AB - Ursolic acid (UA) has been reported to possess anticancer activities. Although some of the anticancer activities of UA have been explained by its apoptosis inducing properties, the mechanisms underlying its anticancer actions are largely unknown. We have found that UA-activated autophagy induced cytotoxicity and reduced tumor growth of cervical cancer cells TC-1 in a concentration-dependent manner. UA did not induce apoptosis of TC-1 cells in vitro as determined by annexin V/propidium iodide staining, DNA fragmentation, and Western blot analysis of the apoptosis-related proteins. We found that UA increased punctate staining of light chain 3 (LC3), which is an autophagy marker. LC3II, the processed form of LC3I which is formed during the formation of double membranes, was induced by UA treatment. These results were further confirmed by transmission electron microscopy. Wortmannin, an inhibitor of autophagy, and a small interfering RNA (siRNA) for autophagy-related genes (Atg5) reduced LC3II and simultaneously increased the survival of TC-1 cells treated with UA. We also found that LC3II was significantly reduced and that survival was increased in Atg5-/- mouse embryonic fibroblast (MEF) cells compared to Atg5+/+ MEF cells under UA treatment. However, silencing BECN1 by siRNA affected neither the expression of LC3II nor the survival of TC-1 cells under UA treatment. These results suggest that autophagy is a major mechanism by which UA kills TC-1 cells. It is Atg5 rather than BECN1 that plays a crucial role in UA-induced autophagic cell death in TC-1 cells. The activation of autophagy by UA may become a potential cancer therapeutic strategy complementing the apoptosis-based therapies. Furthermore, regulation of Atg5 may improve the efficacy of UA in cancer treatment. PMID- 23737396 TI - Screening for breast cancer with mammography. AB - BACKGROUND: A variety of estimates of the benefits and harms of mammographic screening for breast cancer have been published and national policies vary. OBJECTIVES: To assess the effect of screening for breast cancer with mammography on mortality and morbidity. SEARCH METHODS: We searched PubMed (22 November 2012) and the World Health Organization's International Clinical Trials Registry Platform (22 November 2012). SELECTION CRITERIA: Randomised trials comparing mammographic screening with no mammographic screening. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. Study authors were contacted for additional information. MAIN RESULTS: Eight eligible trials were identified. We excluded a trial because the randomisation had failed to produce comparable groups.The eligible trials included 600,000 women in the analyses in the age range 39 to 74 years. Three trials with adequate randomisation did not show a statistically significant reduction in breast cancer mortality at 13 years (relative risk (RR) 0.90, 95% confidence interval (CI) 0.79 to 1.02); four trials with suboptimal randomisation showed a significant reduction in breast cancer mortality with an RR of 0.75 (95% CI 0.67 to 0.83). The RR for all seven trials combined was 0.81 (95% CI 0.74 to 0.87). We found that breast cancer mortality was an unreliable outcome that was biased in favour of screening, mainly because of differential misclassification of cause of death. The trials with adequate randomisation did not find an effect of screening on total cancer mortality, including breast cancer, after 10 years (RR 1.02, 95% CI 0.95 to 1.10) or on all cause mortality after 13 years (RR 0.99, 95% CI 0.95 to 1.03).Total numbers of lumpectomies and mastectomies were significantly larger in the screened groups (RR 1.31, 95% CI 1.22 to 1.42), as were number of mastectomies (RR 1.20, 95% CI 1.08 to 1.32). The use of radiotherapy was similarly increased whereas there was no difference in the use of chemotherapy (data available in only two trials). AUTHORS' CONCLUSIONS: If we assume that screening reduces breast cancer mortality by 15% and that overdiagnosis and overtreatment is at 30%, it means that for every 2000 women invited for screening throughout 10 years, one will avoid dying of breast cancer and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress including anxiety and uncertainty for years because of false positive findings. To help ensure that the women are fully informed before they decide whether or not to attend screening, we have written an evidence-based leaflet for lay people that is available in several languages on www.cochrane.dk. Because of substantial advances in treatment and greater breast cancer awareness since the trials were carried out, it is likely that the absolute effect of screening today is smaller than in the trials. Recent observational studies show more overdiagnosis than in the trials and very little or no reduction in the incidence of advanced cancers with screening. PMID- 23737397 TI - Psychological interventions for women with metastatic breast cancer. AB - BACKGROUND: Psychological symptoms are associated with metastatic breast cancer. This is the basis for exploring the impact of psychological interventions on psychosocial and survival outcomes. One early study appeared to show significant survival and psychological benefits from psychological support while subsequent studies have revealed conflicting results. This review is an update of a Cochrane review first published in 2004 and previously updated in 2007. OBJECTIVES: To assess the effects of psychological interventions on psychosocial and survival outcomes for women with metastatic breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group Specialised Register, MEDLINE (OvidSP), EMBASE (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCO), online trials and research registers in June/July 2011. Further potentially relevant studies were identified from handsearching references of previous trials, systematic reviews and meta analyses. SELECTION CRITERIA: Randomised controlled trials (RCTs) and cluster RCTs of psychological interventions, which recruited women with metastatic breast cancer. Outcomes selected for analyses were overall survival, psychological outcomes, pain, quality of life, condition-specific outcome measures, relationship and social support measures, and sleep quality. Studies were excluded if no discrete data were available on women with metastatic breast cancer. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data and assessed the quality of the studies using the Cochrane Collaboration risk of bias tool. Where possible, authors were contacted for missing information. Data on the nature and setting of the intervention, relevant outcome data, and items relating to methodological quality were extracted. Meta-analyses was performed using a random-effects or fixed-effect Mantel-Haenszel model, depending on expected levels of heterogeneity. MAIN RESULTS: Ten RCTs with 1378 women were identified. Of the seven RCTs on group psychological interventions, three were on cognitive behavioural therapy and four were on supportive expressive group therapy. The remaining three studies were individual based and the types of psychological interventions were not common to either cognitive behavioural or supportive-expressive therapy. A clear pattern of psychological outcomes could not be discerned as a wide variety of outcome measures and durations of follow-up were used in the included studies. The overall effect of the psychological interventions across six studies, on one-year survival, favoured the psychological intervention group with an odds ratio (OR) of 1.46 (95% confidence interval (CI) 1.07 to 1.99). Pooled data from four studies did not show any survival benefit at five-years follow-up (OR 1.03, 95% CI 0.42 to 2.52). There was evidence of a short-term benefit for some psychological outcomes and improvement in pain scores. AUTHORS' CONCLUSIONS: Psychological interventions appear to be effective in improving survival at 12 months but not at longer-term follow-up, and they are effective in reducing psychological symptoms only in some of the outcomes assessed in women with metastatic breast cancer. However, findings of the review should be interpreted with caution as there is a relative lack of data in this field, and the included trials had reporting or methodological weaknesses and were heterogeneous in terms of interventions and outcome measures. PMID- 23737399 TI - Heterobimetallic cuprates consisting of a redox-switchable, silicon-based metalloligand: synthesis, structures, and electronic properties. AB - A series of bimetallic silyl halido cuprates consisting of the new tripodal silicon-based metalloligand [kappa(3)N-Si(3,5-Me2pz)3Mo(CO)3](-) is presented (pz = pyrazolyl). This metalloligand is straightforwardly accessible by reacting the ambidentate ligand tris(3,5-dimethylpyrazolyl)silanide ({Si(3,5-Me2pz)3}(-)) with [Mo(CO)3(eta(6)-toluene)]. The compound features a fac-coordinated tripodal chelating ligand and an outward pointing, "free" pyramidal silyl donor, which is easily accessible for a secondary coordination to other metal centers. Several bimetallic silyl halido cuprates of the general formula [CuX{MU kappa(1)Si:kappa(3)N-Si(3,5-Me2pz)3Mo(CO)3}](-) (X = Cl, Br, I) have been synthesized. The electronic and structural properties of these complexes were probed in detail by X-ray diffraction analysis, electrospray mass spectrometry, infrared-induced multiphoton dissociation studies, cyclic voltammetry, spectroelectrochemistry, gas-phase photoelectron spectroscopy, as well as UV/Vis and fluorescence spectroscopy. The heterobimetallic complexes contain linear two coordinate copper(I) entities with the shortest silicon-copper distances reported so far. Oxidation of the anionic complexes in methylene chloride and acetonitrile solutions at E(1/2)(0( = -0.60 and -0.44 V (vs. ferrocene/ferrocenium (Fc/Fc(+))), respectively, shows substantial reversibility. Based on various results obtained from different characterization methods, as well as density functional theory calculations, these oxidation events were attributed to the Mo(0)/Mo(I) redox couple. PMID- 23737400 TI - Rapid blood pressure lowering may improve haemorrhagic stroke outcomes. PMID- 23737401 TI - Grandparent-grandchild family capital and self-rated health of older rural Chinese adults: the role of the grandparent-parent relationship. AB - OBJECTIVES: This study tested the relationship between grandparent-grandchild family capital and self-rated health of older rural Chinese adults and the mediating role of the grandparent-parent relationship in terms of grandparent grandchild family capital and self-rated health. METHODS: Data were derived from a random sample of 1,027 adults aged 60 and older who were interviewed in the rural Chaohu region in 2009. Structural equation modeling was used to examine the direct effect of grandparent-grandchild family capital in terms of relations with the first child's family on self-rated health among respondents, as well as the mediating effect of the grandparent-parent relationship. RESULTS: The results showed the direct effect of grandparent-grandchild family capital on self-rated health of older rural Chinese adults. The grandparent-parent relationship had a partial mediation effect on the relationship between grandparent-grandchild family capital and self-rated health of respondents. DISCUSSION: Grandparent grandchild family capital had a unique direct effect on the self-rated health of older rural Chinese adults, enriching our theoretical understanding of sources of family capital and their impacts in a collectivist cultural context that emphasizes intergenerational interaction and exchange. The findings also highlighted the mediation effects of grandparent-parent relationships on the relationship between grandparent-grandchild family capital and self-rated health of older rural Chinese adults, supporting the "grandchild-as-linkage" hypothesis in understanding the social determination of self-rated health in China. PMID- 23737402 TI - PAX5 somatic mutation is rare in multiple myelomas and non-Hodgkin lymphomas of Korean patients. PMID- 23737403 TI - National trends in thyroid surgery and the effect of volume on short-term outcomes. AB - OBJECTIVES/HYPOTHESIS: To characterize contemporary patterns of thyroid surgical care and the effect of volume status on surgical care and short-term outcomes. STUDY DESIGN: Retrospective cross-sectional study. METHODS: Discharge data from the Nationwide Inpatient Sample for 871,644 patients who underwent surgery for thyroid disease in 1993 through 2008 were analyzed using cross-tabulations and multivariate regression modeling. RESULTS: Surgical cases increased from 364,288 in 1993 through 2000 to 507,356 in 2001 through 2008, with an increase in thyroid cancer surgical cases from 28% to 34%. Cases performed by high-volume surgeons increased from 12% in 1993 through 2000 to 25% in 2001 through 2008, whereas cases performed by very-low volume surgeons decreased from 51% to 34% (P < .001). Cases performed at high-volume hospitals increased from 14% in 1993 through 2000 to 29% in 2001 through 2008, whereas cases performed at very-low volume hospitals decreased from 46% to 33% (P < .001). High-volume surgeons were significantly more likely to perform total thyroidectomy (odds ratio [OR] = 1.4, P < .001) and had a lower incidence of recurrent laryngeal nerve injury (OR = 0.7, P = .024), hypocalcemia (OR = 0.7, P = .002), and in-hospital death (OR = 0.3, P = .004). High-volume hospital care was not associated with extent of surgery, postoperative morbidity, or mortality after adjusting for surgeon volume. After controlling for other variables, thyroid surgery in 2001 through 2008 was associated with an increase in cases performed by low-volume (relative risk ratio [RRR] = 1.5, P < .001), intermediate-volume (RRR = 1.7, P < .001), and high volume surgeons (RRR = 2.1, P < .001), high-volume hospitals (RRR = 2.0, P = .008), total thyroidectomy (RRR = 2.1, P < .001), and neck dissection (RRR = 1.3, P = .016). CONCLUSIONS: These data reflect changing trends in the surgical management of thyroid disease, with meaningful differences in the type of surgical care provided by high-volume surgeons. PMID- 23737404 TI - Impact of impaired renal function on the pharmacokinetics of the antiepileptic drug lacosamide. AB - BACKGROUND AND OBJECTIVE: The antiepileptic drug lacosamide is eliminated predominantly via the kidneys. Therefore, an evaluation of the impact of renal impairment on its pharmacokinetic profile is an important component of its safety assessment. The objective of this study was to evaluate the pharmacokinetic profile of lacosamide among individuals with renal impairment (mild, moderate, or severe) and among patients with end-stage renal disease (ESRD), including those on hemodialysis. METHODS: This was an open-label, Phase I trial. The pharmacokinetics of a single oral 100-mg lacosamide dose were evaluated in five groups of participants: healthy controls, patients with mild, moderate, or severe renal impairment, and patients with ESRD (with and without hemodialysis). RESULTS: Forty participants completed the trial, eight in each group. In healthy volunteers, renal clearance accounted for approximately 30 % of total body clearance [geometric mean 0.5897 l/h (coefficient of variation 37.9 %) vs 2.13 l/h (20.8 %)]. With severe renal impairment, renal clearance was approximately 11 % of total body clearance [0.1428 l/h (31.8 %) vs 1.34 l/h (26.9 %)]. Terminal half-life and systemic exposure were increased with renal impairment, while total body clearance, renal clearance, and urinary excretion were decreased. Strong positive correlations between creatinine clearance, renal clearance, and urinary excretion were observed. Among patients with ESRD, approximately 50 % of lacosamide was cleared from systemic circulation by 4-h hemodialysis. In patients with essentially no renal clearance, nonrenal clearance was still present (1.1 l/h). Lacosamide was well tolerated by healthy volunteers and patients. CONCLUSIONS: In patients with mild-to-moderate renal impairment, lacosamide dose adjustment is not necessary, because total body clearance decreased by only approximately 20 %. Dose adjustment, however, is required for patients with severe renal impairment. Hemodialysis removes approximately 50 % of lacosamide from plasma; therefore, dose supplementation following hemodialysis should be considered. PMID- 23737405 TI - Exploring the impacts of personal factors on self-leadership in a hospital setting. AB - Self-leadership may be defined as a self-effecting process that individuals experience by maintaining the motivation they require for fulfilling their roles and duties. The self-leadership process comprises three key strategies: behaviour oriented strategies, natural reward strategies and constructive thought pattern strategies. What is intended herein is to inquire about the implementation of self-leadership within organisations and to examine the effects of such variables as age, gender, total terms of employment, marital status and education on self leadership strategies. The primary data collection instrument was a survey distributed to 450 personnel working at a state hospital in Kirikkale, Turkey, and feedback thereto was received from 308 (68.4%) of those surveyed. As a result of the findings taken from the analyses, age, total terms of employment and receipt of education in leadership affect the use of self-leadership strategies. Although age and total terms of employment display a negative-directional correlation with the self-leadership strategies, female employees and those who receive education in leadership are more inclined towards self-leadership strategies. PMID- 23737406 TI - Influence of chlorhexidine on dentin adhesive interface micromorphology and nanoleakage expression of resin cements. AB - This study focused on adhesive interface morphologic characterization and nanoleakage expression of resin cements bonded to human dentin pretreated with 1% chlorhexidine (CHX). Thirty-two non-carious human third molars were ground flat to expose superficial dentin. Resin composite blocks were luted to the exposed dentin using one conventional (RelyX ARC) and one self-adhesive resin cement (RelyX U100), with/without CHX pretreatment. Four groups (n = 8) were obtained: control groups (ARC and U100); experimental groups (ARC/CHX and U100/CHX) were pretreated with 1% CHX prior to the luting process. After storage in water for 24 h, the bonded teeth were sectioned into 0.9 * 0.9 mm(2) sticks producing a minimum of 12 sticks per tooth. Four sticks from each tooth were prepared for hybrid layer evaluation by scanning electron microscope analysis. The remaining sticks were immersed in silver nitrate for 24 h for either nanoleakage evaluation along the bonded interfaces or after rupture. Nanoleakage samples were carbon coated and examined using backscattered electron mode. Well-established hybrid layers were observed in the groups luted with RelyX ARC. Nanoleakage evaluation revealed increase nanoleakage in groups treated with CHX for both resin cements. Group U100/CHX exhibited the most pronouncing nanoleakage expression along with porous zones adjacent to the CHX pretreated dentin. The results suggest a possible incompatibility between CHX and RelyX U100 that raises the concern that the use of CHX with self-adhesive cements may adversely affect resin-dentin bond. PMID- 23737407 TI - "Clinical judgment" and the DSM-5 diagnosis of major depression. PMID- 23737408 TI - The DSM-5: Classification and criteria changes. AB - The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) marks the first significant revision of the publication since the DSM-IV in 1994. Changes to the DSM were largely informed by advancements in neuroscience, clinical and public health need, and identified problems with the classification system and criteria put forth in the DSM-IV. Much of the decision-making was also driven by a desire to ensure better alignment with the International Classification of Diseases and its upcoming 11th edition (ICD-11). In this paper, we describe select revisions in the DSM-5, with an emphasis on changes projected to have the greatest clinical impact and those that demonstrate efforts to enhance international compatibility, including integration of cultural context with diagnostic criteria and changes that facilitate DSM-ICD harmonization. It is anticipated that this collaborative spirit between the American Psychiatric Association (APA) and the World Health Organization (WHO) will continue as the DSM-5 is updated further, bringing the field of psychiatry even closer to a singular, cohesive nosology. PMID- 23737410 TI - Cognitive and social factors influencing clinical judgment in psychiatric practice. PMID- 23737409 TI - Future perspectives on the treatment of cognitive deficits and negative symptoms in schizophrenia. AB - Drug discovery based on classic models for cognitive impairment and negative symptoms of schizophrenia have met with only modest success. Because cognitive impairment and negative symptoms may result from disruptions in neurodevelopment, more complex developmental models that integrate environmental and genetic risk factors are needed. In addition, it has become clear that biochemical pathways involved in schizophrenia form complex, interconnected networks. Points at which risk factors converge, such as brain-derived neurotrophic factor (BDNF) and protein kinase B (AKT), and from which processes involved in neuroplasticity diverge, are of particular interest for pharmacologic interventions. This paper reviews elements of neurodevelopmental models for cognitive deficits and negative symptoms of schizophrenia with the aim of identifying potential targets for interventions. PMID- 23737411 TI - The past, present and future of psychiatric diagnosis. PMID- 23737412 TI - Beyond DSM and ICD: introducing "precision diagnosis" for psychiatry using momentary assessment technology. PMID- 23737414 TI - Pediatric psychopharmacology: Too much and too little. PMID- 23737413 TI - Pediatric psychopharmacology: too much or too little? AB - This paper provides a selective overview of the past, present and future of pediatric psychopharmacology. The acceptance of medication use in child psychiatry was based on the results of double-blind, placebo-controlled trials documenting the efficacy of drug treatments for attention-deficit/hyperactivity disorder, enuresis, depression, anxiety disorders, obsessive-compulsive disorder and psychoses. This period of success was followed by a series of challenges, including a growing awareness of the long-term adverse effects of medications and of the inadequacy of long-term drug surveillance. There is great concern today that children are being overtreated with medication, especially in the US. Further advances in pediatric psychopharmacology may come from examination of large medical data sets including both pharmacological and psychiatric information, which could lead to drug repurposing, as well as from preclinical translational studies such as those using human induced pluripotent stem cells. PMID- 23737415 TI - What's next for developmental psychiatry? PMID- 23737416 TI - Prescribing of psychotropic medications to children and adolescents: quo vadis? PMID- 23737417 TI - Child neuropsychopharmacology: good news... the glass is half full. PMID- 23737418 TI - From too much and too little towards stratified psychiatry and pathophysiology. PMID- 23737419 TI - A European perspective on paedo-psychiatric pharmacoepidemiology. PMID- 23737420 TI - Do we face the same dilemma on pediatric psychopharmacology in low and middle income countries? PMID- 23737421 TI - Child psychopharmacology: how much have we progressed? PMID- 23737422 TI - Psychopharmacological treatments in children and adolescents. Adequate use or abuse? PMID- 23737423 TI - The efficacy of psychotherapy and pharmacotherapy in treating depressive and anxiety disorders: a meta-analysis of direct comparisons. AB - Although psychotherapy and antidepressant medication are efficacious in the treatment of depressive and anxiety disorders, it is not known whether they are equally efficacious for all types of disorders, and whether all types of psychotherapy and antidepressants are equally efficacious for each disorder. We conducted a meta-analysis of studies in which psychotherapy and antidepressant medication were directly compared in the treatment of depressive and anxiety disorders. Systematic searches in bibliographical databases resulted in 67 randomized trials, including 5,993 patients that met inclusion criteria, 40 studies focusing on depressive disorders and 27 focusing on anxiety disorders. The overall effect size indicating the difference between psychotherapy and pharmacotherapy after treatment in all disorders was g=0.02 (95% CI: -0.07 to 0.10), which was not statistically significant. Pharmacotherapy was significantly more efficacious than psychotherapy in dysthymia (g=0.30), and psychotherapy was significantly more efficacious than pharmacotherapy in obsessive-compulsive disorder (g=0.64). Furthermore, pharmacotherapy was significantly more efficacious than non-directive counseling (g=0.33), and psychotherapy was significantly more efficacious than pharmacotherapy with tricyclic antidepressants (g=0.21). These results remained significant when we controlled for other characteristics of the studies in multivariate meta-regression analysis, except for the differential effects in dysthymia, which were no longer statistically significant. PMID- 23737424 TI - Early childhood sexual abuse increases suicidal intent. AB - Childhood sexual abuse has been consistently associated with suicidal behavior. We studied suicide attempt features in depressed individuals sexually abused as children. On average, sexual abuse started before age 9. It frequently coexisted with physical abuse. Suicide attempters more often had personality disorders and had endured abuse for longer, but did not differ in terms of other clinical characteristics from non-attempters. Earlier onset of sexual abuse and its duration were associated with more suicide attempts. However, when personality disorders were included in the regression model, only these disorders predicted number of attempts. The severity of sexual abuse and the coexistence of physical abuse were correlated with age at first suicide attempt. However, only severity of sexual abuse was marginally associated with age at first suicide attempt in the regression model. Finally, the earlier the age of onset of sexual abuse, the higher the intent, even after controlling for age, sex and personality disorders. This suggests that the characteristics of childhood sexual abuse, especially age of onset, should be considered when studying the risk for suicidal behavior in abused populations. PMID- 23737426 TI - Priorities for mental health research in Europe: A survey among national stakeholders' associations within the ROAMER project. AB - Within the ROAMER project, funded by the European Commission, a survey was conducted with national associations/organizations of psychiatrists, other mental health professionals, users and/or carers, and psychiatric trainees in the 27 countries of the European Union, aiming to explore their views about priorities for mental health research in Europe. One hundred and eight associations/organizations returned the questionnaire. The five most frequently selected research priorities were early detection and management of mental disorders, quality of mental health services, prevention of mental disorders, rehabilitation and social inclusion, and new medications for mental disorders. All these areas, except the last one, were among the top ten research priorities according to all categories of stakeholders, along with stigma and discrimination. These results seem to support the recent argument that some rebalancing in favor of psychosocial and health service studies may be needed in psychiatric research. PMID- 23737425 TI - Personal stigma in schizophrenia spectrum disorders: a systematic review of prevalence rates, correlates, impact and interventions. AB - A systematic electronic PubMed, Medline and Web of Science database search was conducted regarding the prevalence, correlates, and effects of personal stigma (i.e., perceived and experienced stigmatization and self-stigma) in patients with schizophrenia spectrum disorders. Of 54 studies (n=5,871), published from 1994 to 2011, 23 (42.6%) reported on prevalence rates, and 44 (81.5%) reported on correlates and/or consequences of perceived or experienced stigmatization or self stigma. Only two specific personal stigma intervention studies were found. On average, 64.5% (range: 45.0-80.0%) of patients perceived stigma, 55.9% (range: 22.5-96.0%) actually experienced stigma, and 49.2% (range: 27.9-77.0%) reported alienation (shame) as the most common aspect of self-stigma. While socio demographic variables were only marginally associated with stigma, psychosocial variables, especially lower quality of life, showed overall significant correlations, and illness-related factors showed heterogeneous associations, except for social anxiety that was unequivocally associated with personal stigma. The prevalence and impact of personal stigma on individual outcomes among schizophrenia spectrum disorder patients are well characterized, yet measures and methods differ significantly. By contrast, research regarding the evolution of personal stigma through the illness course and, particularly, specific intervention studies, which should be conducted utilizing standardized methods and outcomes, are sorely lacking. PMID- 23737427 TI - DSM-5 grief scorecard: Assessment and outcomes of proposals to pathologize grief. PMID- 23737428 TI - Understanding Breivik and Sandy Hook: sin and sickness? PMID- 23737429 TI - Community mental health care in South Asia. PMID- 23737430 TI - Management of the psychosocial effects of economic crises. PMID- 23737431 TI - Mental health and psychosocial support interventions for survivors of sexual and gender-based violence during armed conflict: a systematic review. PMID- 23737432 TI - Technique optimization of orbital atherectomy in calcified peripheral lesions of the lower extremities: the CONFIRM series, a prospective multicenter registry. AB - OBJECTIVES: The purpose of CONFIRM registry series was to evaluate the use of orbital atherectomy (OA) in peripheral lesions of the lower extremities, as well as optimize the technique of OA. BACKGROUND: Methods of treating calcified arteries (historically a strong predictor of treatment failure) have improved significantly over the past decade and now include minimally invasive endovascular treatments, such as OA with unique versatility in modifying calcific lesions above and below-the-knee. METHODS: Patients (3135) undergoing OA by more than 350 physicians at over 200 US institutions were enrolled on an "all-comers" basis, resulting in registries that provided site-reported patient demographics, ABI, Rutherford classification, co-morbidities, lesion characteristics, plaque morphology, device usage parameters, and procedural outcomes. RESULTS: Treatment with OA reduced pre-procedural stenosis from an average of 88-35%. Final residual stenosis after adjunctive treatments, typically low-pressure percutaneous transluminal angioplasty (PTA), averaged 10%. Plaque removal was most effective for severely calcified lesions and least effective for soft plaque. Shorter spin times and smaller crown sizes significantly lowered procedural complications which included slow flow (4.4%), embolism (2.2%), and spasm (6.3%), emphasizing the importance of treatment regimens that focus on plaque modification over maximizing luminal gain. CONCLUSION: The OA technique optimization, which resulted in a change of device usage across the CONFIRM registry series, corresponded to a lower incidence of adverse events irrespective of calcium burden or co-morbidities. PMID- 23737435 TI - Transporting and shielding photosensitisers by using water-soluble organometallic cages: a new strategy in drug delivery and photodynamic therapy. AB - Skin photosensitivity remains one of the main limitations in photodynamic therapy. In this Concept article a strategy to overcome this limitation is described, in which the photosensitizer is hidden inside the hydrophobic cavity of a water-soluble organometallic cage. The metallacage not only protects the photosensitizer from light, it also facilitates its delivery to cancer cells. PMID- 23737434 TI - Deficiency of Kruppel-like factor KLF4 in mammary tumor cells inhibits tumor growth and pulmonary metastasis and is accompanied by compromised recruitment of myeloid-derived suppressor cells. AB - Increasing evidence indicates that myeloid-derived suppressor cells (MDSCs) negatively regulate immune responses during tumor progression, inflammation and infection. However, the underlying molecular mechanisms of their development and mobilization remain to be fully delineated. Kruppel-like factor KLF4 is a transcription factor that has an oncogenic function in breast cancer development, but its function in tumor microenvironment, a critical component for tumorigenesis, has not been examined. By using a spontaneously metastatic 4T1 breast cancer mouse model and an immunodeficient NOD/SCID mouse model, we demonstrated that KLF4 knockdown delayed tumor development and inhibited pulmonary metastasis, which accompanied by decreased accumulation of MDSCs in bone marrow, spleens and primary tumors. Mechanistically, we found that KLF4 knockdown resulted in a significant decrease of circulating GM-CSF, an important cytokine for MDSC biology. Consistently, recombinant GM-CSF restored the frequency of MDSCs in purified bone marrow cells incubated with conditioned medium from KLF4 deficient cells. In addition, we identified CXCL5 as a critical mediator to enhance the expression and function of GM-CSF. Reduced CXCL5 expression by KLF4 knockdown in primary tumors and breast cancer cells was correlated with a decreased GM-CSF expression in our mouse models. Finally, we found that CXCL5/CXCR2 axis facilitated MDSC migration and that anti-GM-CSF antibodies neutralized CXCL5-induced accumulation of MDSCs. Taken together, our data suggest that KLF4 modulates maintenance of MDSCs in bone marrow by inducing GM-CSF production via CXCL5 and regulates recruitment of MDSCs into the primary tumors through the CXCL5/CXCR2 axis, both of which contribute to KLF4-mediated mammary tumor development. PMID- 23737436 TI - Is surgery necessary for all vocal fold polyps? PMID- 23737438 TI - No benefit from early tracheotomy in mechanically ventilated ICU patients? PMID- 23737437 TI - Recent developments in drug therapy for Cushing's disease. AB - Cushing's disease (CD) is a rare endocrine disorder that is caused by an adrenocorticotropin (ACTH)-producing pituitary adenoma that chronically stimulates adrenocortical cortisol production. CD is primarily treated by transsphenoidal surgery, resulting in long-term biochemical remission in approximately 60-90% of the patients. Patients who are ineligible for surgery or have undergone unsuccessful surgery are candidates for drug therapy. Medical treatment can aim to inhibit the excess ACTH production at the level of the pituitary adenoma, to decrease adrenocortical steroidogenesis or to antagonize the effects of cortisol at the level of its receptor. In recent years, a number of studies have been published that evaluated the efficacy of medical therapy, either as monotherapy or combination therapy, in patients with CD. In particular, the effects of the somatostatin analog pasireotide and the glucocorticoid receptor antagonist mifepristone have been investigated in two large clinical trials. Moreover, the first clinical experiences with the novel steroidogenesis inhibitor LCI699 and the pituitary-directing retinoic acid have become available. Finally, an in vitro study with gefitinib, an epidermal growth factor receptor antagonist, showed promising results that warrant further exploration. In this review, the efficacy and limitations of drugs that have been used in the treatment of CD will be discussed as well as recent developments with respect to new pituitary- and adrenal-targeting compounds. PMID- 23737439 TI - Sclerostin regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2. AB - The osteocyte product sclerostin is emerging as an important paracrine regulator of bone mass. It has recently been shown that osteocyte production of receptor activator of NF-kappaB ligand (RANKL) is important in osteoclastic bone resorption, and we reported that exogenous treatment of osteocytes with sclerostin can increase RANKL-mediated osteoclast activity. There is good evidence that osteocytes can themselves liberate mineral from bone in a process known as osteocytic osteolysis. In the current study, we investigated sclerostin stimulated mineral dissolution by human primary osteocyte-like cells (hOCy) and mouse MLO-Y4 cells. We found that sclerostin upregulated osteocyte expression of carbonic anhydrase 2 (CA2/Car2), cathepsin K (CTSK/Ctsk), and tartrate-resistant acid phosphatase (ACP5/Acp5). Because acidification of the extracellular matrix is a critical step in the release of mineral from bone, we further examined the regulation by sclerostin of CA2. Sclerostin stimulated CA2 mRNA and protein expression in hOCy and in MLO-Y4 cells. Sclerostin induced a decrease in intracellular pH (pHi) in both cell types as well as a decrease in extracellular pH (pHo) and the release of calcium ions from mineralized substrate. These effects were reversed in the co-presence of the carbonic anhydrase inhibitor, acetozolamide. Car2-siRNA knockdown in MLO-Y4 cells significantly inhibited the ability of sclerostin to both reduce the pHo and release calcium from a mineralized substrate. Knockdown in MLO-Y4 cells of each of the putative sclerostin receptors, Lrp4, Lrp5 and Lrp6, using siRNA, inhibited the sclerostin induction of Car2, Catk and Acp5 mRNA, as well as pHo and calcium release. Consistent with this activity of sclerostin resulting in osteocytic osteolysis, human trabecular bone samples treated ex vivo with recombinant human sclerostin for 7 days exhibited an increased osteocyte lacunar area, an effect that was reversed by the co-addition of acetozolamide. These findings suggest a new role for sclerostin in the regulation of perilacunar mineral by osteocytes. PMID- 23737440 TI - Joseph Rudinger memorial lecture: discovery and applications of cyclotides. AB - Cyclotides are plant-derived peptides of approximately 30 amino acids that have the characteristic structural features of a head-to-tail cyclized backbone and a cystine knot arrangement of their three conserved disulfide bonds. This article gives a personal account of the discovery of cyclotides, their characterization and their applications, based on work carried out in my laboratory over the last 20 years. It describes some of the background to their discovery and focuses on how their unique structural features lead to exceptional stability. This stability and their amenability to chemical synthesis have made it possible to use cyclotides as templates in protein engineering and drug design applications. These applications complement the interest in cyclotides deriving from their unique structures and natural function as host defense molecules. PMID- 23737441 TI - Diagnostic accuracy of intravascular ultrasound-derived minimal lumen area compared with fractional flow reserve--meta-analysis: pooled accuracy of IVUS luminal area versus FFR. AB - INTRODUCTION: Although intravascular ultrasound minimal luminal area (IVUS-MLA) is one of many anatomic determinants of lesion severity, it has been proposed as an alternative to fractional flow reserve (FFR) to assess severity of coronary artery disease. OBJECTIVE: Pool the diagnostic performance of IVUS-MLA and determine its overall accuracy to predict the functional significance of coronary disease using FFR (0.75 or 0.80) as the gold standard. METHODS: Studies comparing IVUS and FFR to establish the best MLA cutoff value that correlates with significant coronary stenosis were reviewed from a Medline search using the terms "fractional flow reserve" and "ultrasound." DerSimonian Laird method was applied to obtain pooled accuracy. RESULTS: Eleven clinical trials, including two left main (LM) trials (total N = 1,759 patients, 1,953 lesions) were included. The weighted overall mean MLA cutoff was 2.61 mm(2) in non-LM trials and 5.35 mm(2) in LM trials. For non-LM lesions, the pooled sensitivity of MLA was 0.79 (95% CI = 0.76-0.83) and specificity was 0.65 (95% CI = 0.62-0.67). Positive likelihood ratio (LR) was 2.26 (95% CI = 1.98-2.57) and LR- was 0.32 (95% CI = 0.24-0.44). Area under the summary receiver operator curve for all trials was 0.848. Pooled LM trials had better accuracy: sensitivity = 0.90, specificity = 0.90, LR+ = 8.79, and LR- = 0.120. CONCLUSION: Given its limited pooled accuracy, IVUS-MLA's impact on clinical decision in this scenario is low and may lead to misclassification in up to 20% of the lesions. Pooled analysis points toward lower MLA cutoffs than the ones used in current practice. PMID- 23737442 TI - You can teach an old dog new tricks: angiopoietin-1 instructs Tie2(pos) myeloid cells to promote neovascularization in ischemic limbs. PMID- 23737445 TI - SPACER: Server for predicting allosteric communication and effects of regulation. AB - The SPACER server provides an interactive framework for exploring allosteric communication in proteins with different sizes, degrees of oligomerization and function. SPACER uses recently developed theoretical concepts based on the thermodynamic view of allostery. It proposes easily tractable and meaningful measures that allow users to analyze the effect of ligand binding on the intrinsic protein dynamics. The server shows potential allosteric sites and allows users to explore communication between the regulatory and functional sites. It is possible to explore, for instance, potential effector binding sites in a given structure as targets for allosteric drugs. As input, the server only requires a single structure. The server is freely available at http://allostery.bii.a-star.edu.sg/. PMID- 23737446 TI - Density-dependent cooperative non-specific binding in solid-phase SELEX affinity selection. AB - The non-specific binding of undesired ligands to a target is the primary factor limiting the enrichment of tight-binding ligands in affinity selection. Solution phase non-specific affinity is determined by the free-energy of ligand binding to a single target. However, the solid-phase affinity might be higher if a ligand bound concurrently to multiple adjacent immobilized targets in a cooperative manner. Cooperativity could emerge in this case as a simple consequence of the relationship between the free energy of binding, localization entropy and the spatial distribution of the immobilized targets. We tested this hypothesis using a SELEX experimental design and found that non-specific RNA aptamer ligands can concurrently bind up to four bead-immobilized peptide targets, and that this can increase their effective binding affinity by two orders-of-magnitude. Binding curves were quantitatively explained by a new statistical mechanical model of density-dependent cooperative binding, which relates cooperative binding to both the target concentration and the target surface density on the immobilizing substrate. Target immobilization plays a key role in SELEX and other ligand enrichment methods, particularly in new multiplexed microfluidic purification devices, and these results have strong implications for optimizing their performance. PMID- 23737447 TI - Cooperative working of bacterial chromosome replication proteins generated by a reconstituted protein expression system. AB - Replication of all living cells relies on the multirounds flow of the central dogma. Especially, expression of DNA replication proteins is a key step to circulate the processes of the central dogma. Here we achieved the entire sequential transcription-translation-replication process by autonomous expression of chromosomal DNA replication machineries from a reconstituted transcription translation system (PURE system). We found that low temperature is essential to express a complex protein, DNA polymerase III, in a single tube using the PURE system. Addition of the 13 genes, encoding initiator, DNA helicase, helicase loader, RNA primase and DNA polymerase III to the PURE system gave rise to a DNA replication system by a coupling manner. An artificial genetic circuit demonstrated that the DNA produced as a result of the replication is able to provide genetic information for proteins, indicating the in vitro central dogma can sequentially undergo two rounds. PMID- 23737448 TI - GalaxyRefine: Protein structure refinement driven by side-chain repacking. AB - The quality of model structures generated by contemporary protein structure prediction methods strongly depends on the degree of similarity between the target and available template structures. Therefore, the importance of improving template-based model structures beyond the accuracy available from template information has been emphasized in the structure prediction community. The GalaxyRefine web server, freely available at http://galaxy.seoklab.org/refine, is based on a refinement method that has been successfully tested in CASP10. The method first rebuilds side chains and performs side-chain repacking and subsequent overall structure relaxation by molecular dynamics simulation. According to the CASP10 assessment, this method showed the best performance in improving the local structure quality. The method can improve both global and local structure quality on average, when used for refining the models generated by state-of-the-art protein structure prediction servers. PMID- 23737449 TI - antiSMASH 2.0--a versatile platform for genome mining of secondary metabolite producers. AB - Microbial secondary metabolites are a potent source of antibiotics and other pharmaceuticals. Genome mining of their biosynthetic gene clusters has become a key method to accelerate their identification and characterization. In 2011, we developed antiSMASH, a web-based analysis platform that automates this process. Here, we present the highly improved antiSMASH 2.0 release, available at http://antismash.secondarymetabolites.org/. For the new version, antiSMASH was entirely re-designed using a plug-and-play concept that allows easy integration of novel predictor or output modules. antiSMASH 2.0 now supports input of multiple related sequences simultaneously (multi-FASTA/GenBank/EMBL), which allows the analysis of draft genomes comprising multiple contigs. Moreover, direct analysis of protein sequences is now possible. antiSMASH 2.0 has also been equipped with the capacity to detect additional classes of secondary metabolites, including oligosaccharide antibiotics, phenazines, thiopeptides, homo-serine lactones, phosphonates and furans. The algorithm for predicting the core structure of the cluster end product is now also covering lantipeptides, in addition to polyketides and non-ribosomal peptides. The antiSMASH ClusterBlast functionality has been extended to identify sub-clusters involved in the biosynthesis of specific chemical building blocks. The new features currently make antiSMASH 2.0 the most comprehensive resource for identifying and analyzing novel secondary metabolite biosynthetic pathways in microorganisms. PMID- 23737450 TI - webPDBinder: a server for the identification of ligand binding sites on protein structures. AB - The webPDBinder (http://pdbinder.bio.uniroma2.it/PDBinder) is a web server for the identification of small ligand-binding sites in a protein structure. webPDBinder searches a protein structure against a library of known binding sites and a collection of control non-binding pockets. The number of similarities identified with the residues in the two sets is then used to derive a propensity value for each residue of the query protein associated to the likelihood that the residue is part of a ligand binding site. The predicted binding residues can be further refined using conservation scores derived from the multiple alignment of the PFAM protein family. webPDBinder correctly identifies residues belonging to the binding site in 77% of the cases and is able to identify binding pockets starting from holo or apo structures with comparable performances. This is important for all the real world cases where the query protein has been crystallized without a ligand and is also difficult to obtain clear similarities with bound pockets from holo pocket libraries. The input is either a PDB code or a user-submitted structure. The output is a list of predicted binding pocket residues with propensity and conservation values both in text and graphical format. PMID- 23737451 TI - Real-time single-molecule tethered particle motion analysis reveals mechanistic similarities and contrasts of Flp site-specific recombinase with Cre and lambda Int. AB - Flp, a tyrosine site-specific recombinase coded for by the selfish two micron plasmid of Saccharomyces cerevisiae, plays a central role in the maintenance of plasmid copy number. The Flp recombination system can be manipulated to bring about a variety of targeted DNA rearrangements in its native host and under non native biological contexts. We have performed an exhaustive analysis of the Flp recombination pathway from start to finish by using single-molecule tethered particle motion (TPM). The recombination reaction is characterized by its early commitment and high efficiency, with only minor detraction from 'non-productive' and 'wayward' complexes. The recombination synapse is stabilized by strand cleavage, presumably by promoting the establishment of functional interfaces between adjacent Flp monomers. Formation of the Holliday junction intermediate poses a rate-limiting barrier to the overall reaction. Isomerization of the junction to the conformation favoring its resolution in the recombinant mode is not a slow step. Consistent with the completion of nearly every initiated reaction, the chemical steps of strand cleavage and exchange are not reversible during a recombination event. Our findings demonstrate similarities and differences between Flp and the mechanistically related recombinases lambda Int and Cre. The commitment and directionality of Flp recombination revealed by TPM is consistent with the physiological role of Flp in amplifying plasmid DNA. PMID- 23737452 TI - The RNA polymerase trigger loop functions in all three phases of the transcription cycle. AB - The trigger loop (TL) forms a conserved element in the RNA polymerase active centre that functions in the elongation phase of transcription. Here, we show that the TL also functions in transcription initiation and termination. Using recombinant variants of RNA polymerase from Pyrococcus furiosus and a reconstituted transcription system, we demonstrate that the TL is essential for initial RNA synthesis until a complete DNA-RNA hybrid is formed. The archaeal TL is further important for transcription fidelity during nucleotide incorporation, but not for RNA cleavage during proofreading. A conserved glutamine residue in the TL binds the 2'-OH group of the nucleoside triphosphate (NTP) to discriminate NTPs from dNTPs. The TL also prevents aberrant transcription termination at non terminator sites. PMID- 23737453 TI - Absence of pharmacokinetic and pharmacodynamic interactions between almorexant and warfarin in healthy subjects. AB - BACKGROUND AND OBJECTIVE: Almorexant is the first representative of the new class of orexin receptor antagonists, which could become a new treatment option for insomnia. The present study investigated the potential interaction between almorexant and warfarin. METHODS: In this open-label, two-way crossover, drug drug interaction study, healthy male subjects received, in a randomized fashion, almorexant 200 mg once daily for 10 days and a single dose of 25 mg warfarin co administered on day 5 (treatment A) and a single dose of 25 mg warfarin on day 1 (treatment B). Serial blood samples for warfarin pharmacokinetics and pharmacodynamics were drawn during both treatments. RESULTS: Of the 14 enrolled subjects, one withdrew due to an adverse event and 13 completed the study. Almorexant had no effect on the pharmacokinetics of warfarin. The geometric mean ratios (90% confidence interval) for the area under the plasma concentration-time curve to infinity (AUC0-infinity) of S- and R-warfarin were 0.99 (0.89, 1.09) and 1.05 (0.95, 1.16), respectively, and for the maximum plasma concentration (Cmax) were 0.99 (0.86, 1.14) and 1.00 (0.88, 1.13), respectively. The main pharmacodynamic variable was the AUC for the international normalized ratio (AUCINR). Almorexant had no effect on this variable as demonstrated by a geometric mean ratio of 0.99 (0.82, 1.19). Secondary pharmacodynamic variables including maximum effect (Emax), the time to the maximum INR, and factor VII plasma concentrations were also not affected by almorexant. CONCLUSION: No dose adjustment of warfarin is necessary when concomitantly administered with almorexant. PMID- 23737454 TI - Evaluation of crushed ticagrelor tablet doses: recovery following crushing and naso-gastric tube passage ex vivo. AB - BACKGROUND: Orally available ticagrelor in combination with low-dose aspirin (75 100 mg/day) is indicated for adult patients with acute coronary syndromes. However, patients with swallowing difficulties may be unable to consume the currently available 90-mg tablet. It is hypothesized that ticagrelor could be given to this patient cohort as a crushed dose administered either orally or via a naso-gastric (NG) tube. OBJECTIVES: To investigate the potential use of crushed ticagrelor tablets (90- and 180-mg doses) for oral dose or NG tube administration. METHODS: Ticagrelor tablets (90 or 180 mg [two 90-mg tablets]) were prepared to emulate oral and NG tube administration by similar methods. For the oral dose, ticagrelor tablets were crushed using a mortar and pestle and transferred to a dosing cup. 100 mL of water was added to the mortar, stirred, and the contents were transferred to the dosing cup and stirred to form a suspension. At this stage, where the suspension would normally be administered to a patient, it was collected for high performance liquid chromatography (HPLC) analysis. The mortar was then flushed with 100 mL of water, and the contents were again transferred to the dosing cup, stirred, and collected for HPLC analysis. For the NG dose, polyvinylchloride, polyurethane, and silicone size CH10 NG tubes were used. The tablets were crushed using a mortar and pestle, diluted with 50 mL of water, and stirred. At this stage, where the suspension would normally be administered to a patient through an NG tube using a syringe, it was collected for HPLC analysis. The mortar was then flushed with two additional 50 mL aliquots of water and the contents were passed through the NG tube. HPLC analysis examined the recoverability of ticagrelor in each of the dose suspensions and flushes and the stability of the suspension when held in a syringe for up to 2 h. RESULTS: One or two crushed 90-mg ticagrelor tablets, prepared for either oral or NG tube administration, delivers a mean dose of >=97% of the original tablet. No degradation of the suspensions was detected after ticagrelor had been held in the syringe for up to 2 h. CONCLUSION: Although not an approved method of administration, these results suggest that ticagrelor tablets can be crushed and prepared for oral administration or for administration via an NG tube. From a clinical perspective, a syringe hold-time of up to 2 h should allow for enough time between preparation and administration (orally or via an NG tube) of the dispersed tablets to the patient. Future studies are required to test the effect of crushed dosing on pharmacokinetic and pharmacodynamic parameters. PMID- 23737455 TI - Tissue metabolite profiling identifies differentiating and prognostic biomarkers for prostate carcinoma. AB - Metabolomic research offers a deeper insight into biochemical changes in cancer metabolism and is a promising tool for identifying novel biomarkers. We aimed to evaluate the diagnostic and prognostic potential of metabolites in prostate cancer (PCa) tissue after radical prostatectomy. In matched malignant and nonmalignant prostatectomy samples from 95 PCa patients, aminoadipic acid, cerebronic acid, gluconic acid, glycerophosphoethanolamine, 2-hydroxybehenic acid, isopentenyl pyrophosphate, maltotriose, 7-methylguanine and tricosanoic acid were determined within a global metabolite profiling study using gas chromatography/liquid chromatography-mass spectrometry. The data were related to clinicopathological variables like prostate volume, tumor stage, Gleason score, preoperative prostate-specific antigen and disease recurrence in the follow-up. All nine metabolites showed higher concentrations in malignant than in nonmalignant samples except for gluconic acid and maltotriose, which had lower levels in tumors. Receiver -operating characteristics analysis demonstrated a significant discrimination for all metabolites between malignant and nonmalignant tissue with a maximal area under the curve of 0.86 for tricosanoic acid, whereas no correlation was observed between the metabolite levels and the Gleason score or tumor stage except for gluconic acid. Univariate Cox regression and Kaplan Meier analyses showed that levels of aminoadipic acid, gluconic acid and maltotriose were associated with the biochemical tumor recurrence (prostate specific antigen > 0.2 ng/mL). In multivariate Cox regression analyses, aminoadipic acid together with tumor stage and Gleason score remained in a model as independent marker for prediction of biochemical recurrence. This study proved that metabolites in PCa tissue can be used, in combination with traditional clinicopathological factors, as promising diagnostic and prognostic tools. PMID- 23737456 TI - Prevalence and incidence of hypoparathyroidism in the United States using a large claims database. AB - Hypoparathyroidism is a rare endocrine disorder whose incidence and prevalence have not been well defined. This study aimed to 1) estimate the number of insured adult patients with hypoparathyroidism in the United States and 2) obtain physician assessment of disease severity and chronicity. Prevalence was estimated through calculation of diagnoses of hypoparathyroidism in a large proprietary health plan claims database over a 12-month period from October 2007 through September 2008 and projected to the US insured population. Incidence was also calculated from the same database by determining the proportion of total neck surgeries resulting in either transient (<=6 months) or chronic (>6 months) hypoparathyroidism. A physician primary market research study was conducted to assess disease severity and determine the percentage of new nonsurgical patients with hypoparathyroidism. Incidence data were entered into an epidemiologic model to derive an estimate of prevalence. The diagnosis-based prevalence approach estimated 58,793 insured patients with chronic hypoparathyroidism in the United States. The surgical-based incidence approach yielded 117,342 relevant surgeries resulting in 8901 cases over 12 months. Overall, 7.6% of surgeries resulted in hypoparathyroidism (75% transient, 25% chronic). The prevalence of chronic hypoparathyroidism among insured patients included in the surgical database was estimated to be 58,625. The physician survey found that 75% of cases treated over the past 12 months were reported due to surgery and, among all thyroidectomies and parathyroidectomies and neck dissections performed in a year, 26% resulted in transient hypoparathyroidism and 5% progressed to a chronic state. In conclusion, the two claims-based methods yielded similar estimates of the number of insured patients with chronic hypoparathyroidism in the United States (~58,700). The physician survey was consistent with those calculations and confirmed the burden imposed by hypoparathyroidism. PMID- 23737457 TI - Observer-rated pain assessment instruments improve both the detection of pain and the evaluation of pain intensity in people with dementia. AB - BACKGROUND: Observer-rated pain assessment instruments for people with dementia have proliferated in recent years and are mainly effective in identifying the presence of pain. The objective of this study was to determine whether these tools can also be used to evaluate intensity of pain. METHOD: Quasi-experimental design. Cognitively intact [Mini Mental State Examination (MMSE) >= 24, n = 60] and impaired people (MMSE < 20, n = 65) in nursing home facilities took part in the study. Participants were observed at rest and during a movement protocol. Directly afterwards, the observer, blinded to cognitive status, completed three behavioural pain assessment instruments (Abbey Pain Scale, Pain Assessment in Advanced Dementia Scale (PAINAD), Non-communicative Patient's Pain Assessment Instrument (NOPPAIN) ], before interviewing the resident about pain self-report. RESULTS: Significant correlations were found between observer-rated and self rated measures of pain and were stronger in persons with dementia than in cognitively intact adults. Discriminant function analysis (DFA) revealed: (1) that the use of observer-rated instruments improved recognition of the presence or absence of pain by up to 25.4% (in dementia) and 28.3% (in cognitively intact adults) above chance; and (2) the same instruments improved the classification of residents into the correct self-reported level of pain intensity by up to 42.5% (in dementia) and 34.1% (in cognitively intact adults) above chance. However, DFA also reveals a considerable rate of 'false alarms' for pain in cognitively intact and 'misses' in cognitively impaired people. CONCLUSIONS: The use of the Abbey Pain Scale, PAINAD or NOPPAIN improves both the recognition of pain presence/absence as well as rating pain severity in older people with impaired cognition. PMID- 23737458 TI - The current state of medical simulation in interventional cardiology: a clinical document from the Society for Cardiovascular Angiography and Intervention's (SCAI) Simulation Committee. AB - OBJECTIVES: To assess the current use and application of simulators in interventional cardiology. BACKGROUND: Despite a paucity of data on the efficacy of simulation in medicine, cardiovascular simulation training is now a mandated part of cardiovascular fellowship training. Additionally, simulators have been endorsed by the Food and Drug Administration as a way to teach physicians new and novel procedures. We sought to establish the current use of simulators in cardiovascular medicine. METHODS: A systematic review was done of available training programs, and currently existing data regarding simulation training. A panel of experts was convened to review this data and provide recommendations as how simulation should be used in the field of interventional cardiology. RESULTS: This document provides a comprehensive review of the current state of simulation and how we as a society must formulate well validated studies to more closely examine and explore how this technology can be further studied and validated. CONCLUSIONS: Simulation will likely take on a larger role in cardiovascular training and maintenance of certification, but at the current time lacks a large body of evidence for its use. PMID- 23737460 TI - Daily use of sunscreen prevents ageing of the skin. PMID- 23737462 TI - Review on pharmacological pain management in trauma patients in (pre-hospital) emergency medicine in the Netherlands. AB - Pain is one of the main complaints of trauma patients in (pre-hospital) emergency medicine. Significant deficiencies in pain management in emergency medicine have been identified. No evidence-based protocols or guidelines have been developed so far, addressing effectiveness and safety issues, taking the specific circumstances of pain management of trauma patients in the chain of emergency care into account. The aim of this systematic review was to identify effective and safe initial pharmacological pain interventions, available in the Netherlands, for trauma patients with acute pain in the chain of emergency care. Up to December 2011, a systematic search strategy was performed with MeSH terms and free text words, using the bibliographic databases CINAHL, PubMed and Embase. Methodological quality of the articles was assessed using standardized evaluation forms. Of a total of 2328 studies, 25 relevant studies were identified. Paracetamol (both orally and intravenously) and intravenous opioids (morphine and fentanyl) proved to be effective. Non-steroidal anti-inflammatory drugs (NSAIDs) showed mixed results and are not recommended for use in pre-hospital ambulance or (helicopter) emergency medical services [(H)EMS]. These results could be used for the development of recommendations on evidence-based pharmacological pain management and an algorithm to support the provision of adequate (pre-hospital) pain management. Future studies should address analgesic effectiveness and safety of various drugs in (pre-hospital) emergency care. Furthermore, potential innovative routes of administration (e.g., intranasal opioids in adults) need further exploration. PMID- 23737459 TI - Tyrosine kinase inhibition increases functional parkin-Beclin-1 interaction and enhances amyloid clearance and cognitive performance. AB - Tyrosine kinase inhibitors (TKIs) are effective therapies for leukaemia. Alzheimer is a neurodegenerative disease characterized by accumulation of beta amyloid (plaques) and hyper-phosphorylated Tau (tangles). Here we show that AD animals have high levels of insoluble parkin and decreased parkin-Beclin-1 interaction, while peripheral administration of TKIs, including Nilotinib and Bosutinib, increases soluble parkin leading to amyloid clearance and cognitive improvement. Blocking Beclin-1 expression with shRNA or parkin deletion prevents tyrosine kinase (TK) inhibition-induced amyloid clearance, suggesting that functional parkin-Beclin-1 interaction mediates amyloid degradation. Isolation of autophagic vacuoles (AVs) in AD mouse brain shows accumulation of parkin and amyloid, consistent with previous results in AD brains, while Bosutinib and Nilotinib increase parkin-Beclin-1 interaction and result in protein deposition in the lysosome. These data suggest that decreased parkin solubility impedes parkin-Beclin-1 interaction and amyloid clearance. We identified two FDA-approved anti-cancer drugs as potential treatment for AD. PMID- 23737463 TI - Tetsuo Nozoe's "Autograph Books by Chemists 1953-1994": an essay. PMID- 23737466 TI - Lack of reliable evidence for a distinctive epsilon4-related cognitive phenotype that is independent from clinical diagnostic status: findings from the Australian Imaging, Biomarkers and Lifestyle Study. AB - Individuals who carry the apolipoprotein E epsilon4 polymorphism have an increased risk of late-onset Alzheimer's disease. However, because possession of the epsilon4 allele confers an increased risk for the diagnosis of dementia, it has proven problematic in older individuals to dissociate the influence of epsilon4 on cognitive capacity per se as distinct from its influence on clinical diagnostic status. We report a statistical approach that attempts to partial out the influence of diagnostic group membership (Alzheimer's disease, mild cognitive impairment, healthy control) from the influence of apolipoprotein epsilon4 genetic status on cognitive functioning. The cognitive phenotype hypothesis predicts that epsilon4-positive individuals will show cognitive deficits (relative to matched epsilon4-negative individuals) independent of the development of Alzheimer's disease. By contrast, the prodromal/preclinical Alzheimer's disease hypothesis proposes that the effect of apolipoprotein E status on cognitive performance is a function of the increased risk of dementia in individuals with the epsilon4 allele. We evaluated these hypotheses in the Australian Imaging, Biomarkers and Lifestyle cohort (n = 1112). We first determined whether previously reported findings concerning epsilon4 status and age-related neuropsychological performance could be explained by the inadvertent recruitment of people with mild cognitive impairment into the healthy control group. We then tested each diagnostic group in isolation to identify any neuropsychological patterns that may be attributed to the epsilon4 allele. Finally, as interactions between the epsilon4 allele and age have previously been reported in cognitive functioning within healthy elderly populations, we attempted to determine whether the inclusion of mild cognitively impaired individuals in the sample may drive this relationship. An extensive battery of standardized, well-validated neuropsychological tasks was administered to a final sample of 764 healthy control subjects, 131 individuals with mild cognitive impairment and 168 individuals with Alzheimer's disease. The effect of the epsilon4 allele on cognitive performance was assessed using a statistical mediation analysis and supplemented with Bayesian methods to address a number of the limitations associated with Fisherian/Neyman-Pearsonian significance testing. Our findings support the prodromal/preclinical Alzheimer's disease hypothesis and do not support the concept of a distinctive epsilon4-related cognitive phenotype. PMID- 23737468 TI - Impact of acute exposure to high altitude on anterior chamber geometry. AB - PURPOSE: This study aimed to quantify the impact of exposure to high altitude on individual layers of the cornea in regard to central corneal thickness (CCT) and the geometry of the anterior chamber angle (ACA). This work is related to the Tubingen High Altitude Ophthalmology study. METHODS: Anterior segment spectral domain optical coherence tomography was used to quantify changes in individual corneal layers and to study ACA and angle opening distance (AOD). Peripheral oxygen saturation, heart rate, and scores of acute mountain sickness (AMS) were assessed in 14 healthy subjects at baseline (341 m) and altitude (4559 m) for respective correlations. RESULTS: Longitudinal analysis revealed a significant (P < 0.05) increase of CCT during altitude exposure (CCT(baseline) = 539.27 +/- 32.30 MUm; CCT(day1) = 558.87 +/- 29.39 MUm; CCT(day3) = 567.17 +/- 33.40 MUm; mean +/- SD) due to stromal edema. This change was completely reversible upon descent. Geometric measures of aqueous outflow structures remained consistent with no significant changes in AOD or ACA. Incidence of AMS on day 1 was 64% followed by a decrease in AMS scores over time spent at high altitude; while AMS correlated significantly with stromal edema formation just after arrival (r = 0.71; P = 0.01), no correlation was found on day 3 (r = 0.05; P = 0.87); no correlations were found for vital parameters. CONCLUSIONS: Significant stromal edema was found during exposure to high altitude in healthy subjects. This seems to occur due to decreased atmospheric pressure under hypoxia but independent of systemic acclimatization. Other measures of anterior chamber geometry remained stable during the challenge to hypoxic conditions at high altitude. PMID- 23737469 TI - Automated segmentation of pathological cavities in optical coherence tomography scans. AB - PURPOSE: To develop and evaluate a method for automated segmentation and quantitative analysis of pathological cavities in the retina visualized by spectral-domain optical coherence tomography (SD-OCT) scans. METHODS: The algorithm is based on the segmentation of the gray-level intensities within a B scan by a k-means cluster analysis and subsequent classification by a k-nearest neighbor algorithm. Accuracy was evaluated against three clinical experts using 130 bullous cavities identified on eight SD-OCT B-scans of three patients with wet age-related macular degeneration (AMD) and five patients with X-linked retinoschisis, as well as on one volume scan of a patient with X-linked retinoschisis. The algorithm calculated the surface area of the cavities for the B-scans and the volume of all cavities for the volume scan. In order to validate the applicability of the algorithm in clinical use, we analyzed 31 volume scans taken over the course of 4 years for one AMD patient with a serous retinal detachment. RESULTS: Discrepancies in area measurements between the segmentation results of the algorithm and the experts were within the range of the area deviations among the experts. Volumes interpolated from the B-scan series of the volume scan were comparable among experts and algorithm (0.249 mm3 for the algorithm, 0.271 mm3 for expert 1, 0.239 mm3 for expert 2, and 0.262 mm3 for expert 3). Volume changes of the serous retinal detachment were quantifiable. CONCLUSIONS: The segmentation algorithm represents a method for the automated analysis of large numbers of volume scans during routine diagnostics and in clinical trials. PMID- 23737470 TI - Comparative assessment for the ability of Cirrus, RTVue, and 3D-OCT to diagnose glaucoma. AB - PURPOSE: We compared the ability of circumpapillary retinal nerve fiber layer (cpRNFL) thickness and macular parameters obtained by three spectral-domain optical coherence tomography (SD-OCT) instruments to detect glaucoma. METHODS: We enrolled 87 normal eyes and 145 glaucomatous eyes (75 early glaucomatous eyes (EGs), mean deviation > -6 dB). Each participant was imaged using Cirrus, RTVue, and 3D-OCT to evaluate the average and quadrant cpRNFL thicknesses. The macular retinal nerve fiber layer (mRNFL), ganglion cell layer plus inner plexiform layer (GCL/IPL), and mRNFL + GCL/IPL (ganglion cell complex [GCC]) thicknesses were analyzed. The areas under the receiver operating characteristic curves (AUCs) were compared among the instruments. RESULTS: These instruments revealed similar AUCs for the average cpRNFL and GCC thicknesses in EGs, and total all-stage glaucomatous eyes (TGs). RTVue showed better performance in the nasal cpRNFL thickness than Cirrus and 3D-OCT, and better performance in the temporal cpRNFL thickness than 3D-OCT in TGs. RTVue had a higher AUC for the superior GCC thickness compared to Cirrus and 3D-OCT in EGs, and TGs. Cirrus had higher AUCs for GCL/IPL parameters in TGs, and lower AUCs for the mRNFL parameters in EGs and TGs compared to 3D-OCT. CONCLUSIONS: The average cpRNFL and GCC thicknesses measured using these OCT instruments exhibited similar abilities in the diagnosis of glaucoma, and RTVue exhibited better diagnostic abilities than Cirrus and 3D OCT for nasal cpRNFL, and superior GCC thicknesses. The diagnostic performance of Cirrus and 3D-OCT was different for GCL/IPL and mRNFL parameters. (http://www.umin.ac.jp/ctr number, UMIN000006900.) PMID- 23737471 TI - Longitudinal hemodynamic changes within the optic nerve head in experimental glaucoma. AB - PURPOSE: To characterize longitudinal changes in basal blood flow (BF) of the optic nerve head (ONH) during progression of structural damage in experimental glaucoma (EG). METHODS: Unilateral elevation of IOP was induced in 15 adult rhesus macaques by laser treatment to the trabecular meshwork. Prior to and after laser, retinal nerve fiber layer thickness (RNFLT) and ONH BF were measured biweekly by spectral-domain optical coherence tomography and a laser speckle flowgraphy device (LSFG), respectively. RESULTS: Average postlaser IOP was 20.2 +/- 5.9 mm Hg in EG eyes and 12.3 +/- 2.6 mm Hg in control eyes (P < 0.0001). Longitudinal changes in basal ONH BF were strongly associated with changes in RNFLT as EG progressed from early through moderately advanced stages of damage, with Pearson correlation coefficients ranging from 0.64 to 0.97 (average = 0.81) and an average slope of 1.0. During early stage (RNFLT loss < 10%), basal ONH BF was mildly increased (9% +/- 10%, P = 0.004) relative to baseline and compared with fellow controls (P = 0.02). Basal ONH BF declined continuously throughout subsequent stages in EG eyes reaching 25.0% +/- 9.6% (P < 0.0001) below baseline at the final stage studied (RNFLT loss > 40%). In fellow control eyes, there was no significant change in basal ONH BF over time (P = 0.27). CONCLUSIONS: In EG based on chronic mild-to-moderate IOP elevation, a two-phase pattern of ONH BF alteration was observed. ONH BF increased during the earliest stage (while RNFLT was within 10% of baseline) followed by a linear decline that was strongly correlated with loss of RNFLT. PMID- 23737472 TI - Optical coherence tomography-assisted enhanced depth imaging of central serous chorioretinopathy. AB - PURPOSE: To describe characteristics of central serous chorioretinopathy (CSC) imaged by optical coherence tomography-assisted enhanced depth imaging (EDI-OCT). METHODS: The prospective observational case series study consisted of patients with acute or chronic CSC. All subjects underwent fundus fluorescein angiography, indocyanine green angiography (ICGA), and EDI-OCT. RESULTS: The study included 68 eyes (68 patients) with 35 eyes showing signs of acute CSC. Mean subfoveal choroidal thickness, 478 +/- 114 MUm, was larger than the normative value from the beijing eye study 2011 (254 +/- 107 MUm) on the same ethnic group. In the hyperfluorescent ICGA areas, EDI-OCT revealed a thinning of the inner choroidal layers and enlargement of the underlying hyporeflective lumina in all eyes. the diameter of the hyporeflective lumina (mean: 330 +/- 103 MUm) was significantly (P < 0.001) associated with subfoveal choroidal thickness (correlation coefficient [r]: 0.68). An RPE detachment was detected in 36 (53%) eyes. A double layer sign defined as an undulated RPE layer and intact underlying Bruch's membrane (seen in 51 [75%] eyes) was significantly (P = 0.025) more often in the chronic CSC group (29/33; 87%) than in the acute CSC group (22/35; 63%). Prevalence of an RPE microrip (8/68 [12%] eyes) did not differ (P = 0.14) between the chronic CSC group (6/33; 18%) and the acute CSC group (2/35; 5.7%). CONCLUSIONS: CSC is characterized by a thinned inner choroidal layer and enlarged underlying hyporeflective choroidal lumina in all eyes, in addition to a dome shaped RPE elevation, a double-layer sign of the RPE/Bruch's membrane complex, and RPE microrips in some eyes. EDI-OCT may be helpful in the diagnosis of CSC. PMID- 23737473 TI - Myopia, axial length, and age-related cataract: the Singapore Malay eye study. AB - PURPOSE: To describe the associations of myopia and axial length (AL) with age related cataract in an Asian population in Singapore. METHODS: A population-based cross-sectional study that examined 3280 (78.7% response) adults of Malay ethnicity aged 40 to 80 years. Refractive error was determined by subjective refraction and AL was measured using the Zeiss IOL-Master. Digital slit lamp and retroillumination lens photographs were taken and graded for age-related nuclear, cortical, and posterior subcapsular (PSC) cataract following the Wisconsin system. RESULTS: After excluding eyes with prior refractive or cataract surgery, 5474 eyes with gradable lens photographs were analyzed. In multivariate analyses adjusting for age, sex, body mass index, systolic blood pressure, glycosylated hemoglobin, smoking status, and education, myopia (spherical equivalent less than -0.5 diopter [D]) was associated with an increased prevalence of nuclear (OR: 4.99, 95% CI: 3.72-6.69) and PSC cataract (OR: 1.34, 95% CI: 1.30-1.39) but not with cortical cataract (OR: 0.85, 95% CI: 0.68-1.08) compared with emmetropia. Per-millimeter increase in AL was not associated with any of the three cataract subtypes. When myopia was defined as spherical equivalent of less than -5.0 D to 6.0 D, the OR of myopia for PSC cataract increased dramatically. CONCLUSIONS: Our study shows that myopia, but not AL, was associated with nuclear cataract, supporting the concept of index myopia with aging. Myopia, especially high myopia, may predispose to PSC cataract formation. Clinically, ophthalmologists should be aware that risk of PSC cataract appears to vary by refractive status. PMID- 23737474 TI - Apoptotic and proliferative defects characterize ocular development in a microphthalmic BMP model. AB - PURPOSE: Vision is critically dependent on ocular size, which is regulated by environmental and genetic factors. Mutation of human Growth and Differentiation Factor 6 (GDF6) or zebrafish gdf6a results in a spectrum of small eye phenotypes (microphthalmia, anophthalmia, and coloboma). However, current models do not explain their etiology fully. As such, analyses of apoptosis and cell cycle regulation were undertaken in a zebrafish gdf6a mutant. METHODS: Microarray analysis was performed at 2 days after fertilization to uncover novel gdf6a dependent cell cycle regulators. Altered expression of Gdf6a targets was confirmed by in situ hybridization, and resulting changes in cell proliferation were assessed by phosphohistone H3 immunohistochemistry. Analysis of apoptosis was evaluated through activated Caspase 3 immunohistochemistry and chemical inhibitors of cell death. RESULTS: Reduced numbers of retinal progenitor cells are observed at 24 hours post fertilization (hpf), resulting in microphthalmic eyes in gdf6a(-/-) embryos. At 28 hpf, a wave of apoptosis occurs; however, apoptosis inhibition does not rescue eye size, indicating a limited contribution. Mutants display altered proliferation and expression levels of cell cycle regulators, including members of the forkhead box i (foxi) transcription factor family expressed in the ciliary marginal zone. Notably, inhibition of foxi2 in gdf6a(-/-) embryos further reduces eye size. CONCLUSIONS: These data support a model whereby the gdf6a(-/-)-induced microphthalmia is based on early regulation of retinal progenitor cell number, and later by regulation of proliferation in the ciliary marginal zone. Foxi genes represent downstream effectors of Gdf6a function in the CMZ required for eye size determination. PMID- 23737475 TI - Adiponectin-induced dilation of isolated porcine retinal arterioles via production of nitric oxide from endothelial cells. AB - PURPOSE: Adiponectin, an important adipocytokine secreted by adipocytes, has anti inflammatory and atheroprotective effects on vascular tissue via the adiponectin receptor (adipoR). However, the action of adiponectin in the retinal microcirculation is unknown. We examined the direct effect and underlying mechanism of the vasomotor action of adiponectin in porcine retinal arterioles. METHODS: Porcine retinal arterioles (internal diameter, 60-90 MUm) were isolated, cannulated, and pressurized (55 cmH2O) without flow in this in vitro study. Videomicroscopic techniques were used to record changes in diameter in response to adiponectin. RESULTS: The retinal arterioles dilated in a dose-dependent (0.125-7.5 MUg/mL) manner in response to adiponectin. The vasodilation decreased significantly after removal of the endothelium. N(G)-nitro-L-arginine methyl ester (a nitric oxide [NO] synthase inhibitor), 1H-1,2,4-oxadia-zolo[4,3 a]quinoxalin-1-one (a soluble guanylyl cyclase inhibitor), but not wortmannin (a phosphatidylinositol 3-kinase inhibitor) inhibited the effect of adiponectin induced vasodilation comparable with that of denudation. Pretreatment with compound C, an activated protein kinase (AMPK) inhibitor, partially but significantly reduced vasodilation. Incubation with GW6471, a peroxisome proliferator-activated receptor blocker, did not significantly inhibit vasodilation by adiponectin. AdipoR1 and adipoR2 immunoreactions were observed in the endothelium of retinal arterioles. CONCLUSIONS: Adiponectin elicits mainly endothelium-dependent dilation of the retinal arterioles. Endothelium-dependent vasodilation likely induced by adiponectin results from NO via activation of guanylyl cyclase that is partially dependent on AMPK activity. Understanding the effect of adiponectin on the retinal vasculature may help improve potential therapies for retinal vascular disorders, especially diabetic retinopathy in patients with type 2 diabetes mellitus. PMID- 23737476 TI - The pupil light reflex in Leber's hereditary optic neuropathy: evidence for preservation of melanopsin-expressing retinal ganglion cells. AB - PURPOSE: To investigate the pupillary light reflex (PLR) of patients with severe loss of vision due to Leber's Hereditary Optic Neuropathy (LHON) in the context of a proposed preservation of melanopsin-expressing retinal ganglion cells (mRGCs). METHODS: Ten LHON patients (7 males; 51.6 +/- 14.1 years), with visual acuities ranging from 20/400 to hand motion perception and severe visual field losses, were tested and compared with 16 healthy subjects (7 males; 42.15 +/- 15.4 years) tested as controls. PLR was measured with an eye tracker and the stimuli were controlled with a Ganzfeld system. Pupil responses were measured monocularly, to 1 second of blue (470 nm) and red (640 nm) flashes with 1, 10, 100, and 250 cd/m2 luminances. The normalized amplitude of peak of the transient PLR and the amplitude of the sustained PLR at 6 seconds after the flash offset were measured. In addition, optical coherence topography (OCT) scans of the peripapillary retinal nerve fiber layer were obtained. RESULTS: The patient's peak PLR responses were on average 15% smaller than controls (P < 0.05), but 5 out of 10 patients had amplitudes within the range of controls. The patients' sustained PLRs were comparable with controls at lower flash intensities, but on average, 27% smaller to the 250 cd/m2 blue light, although there was considerable overlap with the PLR amplitudes of control. All patients had severe visual field losses and the retinal nerve fiber layer thickness was reduced to a minimum around the optic disc in 8 of the 10 patients. CONCLUSIONS: The PLR is maintained overall in LHON patients despite the severity of optic atrophy. These results are consistent with previous evidence of selective preservation of mRGCs. PMID- 23737477 TI - Staphylococcus aureus corneal infections: effect of the Panton-Valentine leukocidin (PVL) and antibody to PVL on virulence and pathology. AB - PURPOSE: Community-associated methicillin-resistant Staphylococcus aureus strains expressing Panton-Valentine leukocidin (PVL) are associated with severe skin and soft tissue infections, necrotizing pneumonia, and eye infections. We determined PVL's toxicity on infected mouse and cultured human corneal epithelial cells and the role of PVL and antibody to PVL in pathogenesis of murine keratitis. METHODS: Cytotoxicity on corneas and corneal epithelial cells was evaluated by LDH assays. Scratched corneas of female A/J mice were inoculated with approximately 107 CFU/eye of either WT S. aureus, isogenic DeltaPVL, or strains overproducing PVL. Antibodies to PVL or control sera were topically applied to infected corneas 0, 24, and 32 hours postinfection, corneas scored for pathology and tissue levels of S. aureus were determined. RESULTS: PVL expression augmented the cytotoxicity of S. aureus on infected mouse corneas and human cultured corneal epithelial cells. Variable effects on leukocyte recruitment, pathogenesis, and immunity were obtained in the in vivo studies. Inactivation of PVL in USA300 strains caused reduced pathology and bacterial counts. Results were variable when comparing WT and DeltaPVL USA400 strains, while USA400 strains overproducing PVL caused increased bacterial burdens. Topical treatment with polyclonal antibody to PVL yielded significant reductions in corneal pathology and bacterial CFU in corneas infected with USA300 strains, whereas effects were inconsistent in eyes infected with USA400 strains. CONCLUSIONS: PVL enhanced the virulence of a subset of MRSA strains in a keratitis model. Coupled with a variable effect of antibody treatment, it appears that PVL plays an inconsistent role in pathogenesis and immunity to S. aureus corneal infection. PMID- 23737478 TI - Elevation of conjunctival epithelial CD45INTCD11b+CD16+CD14- neutrophils in ocular Stevens-Johnson syndrome and toxic epidermal necrolysis. AB - PURPOSE: Ocular complications related to Stevens-Johnson Syndrome (SJS)-Toxic Epidermal Necrolysis (TEN) may persist and progress after resolution of systemic disease. This is thought to be related in part to persistent ocular innate-immune signaling. In this study, our aim was to characterize infiltrative conjunctival cellular profiles during acute (<12 months) and chronic (>12 months) disease. METHODS: Consecutive patients presenting with SJS-TEN over a 12-month period were followed for 1 year. Detailed clinical examination and conjunctival impression cell recovery was analyzed by flow cytometry for the presence of intraepithelial leukocytes and compared with healthy controls (n = 21). RESULTS: Ten patients were recruited of whom six had acute disease and five were classified as TEN (SCORTEN = 1, n = 4). Conjunctival inflammation was graded as absent/mild in a total of nine patients; but despite this, evidence of fornix shrinkage was observed in nine subjects. This inversely correlated with disease duration (P < 0.05). A reduction in percentage of CD8alphabeta(+) T cells compared with controls (80% vs. 57%; P < 0.01) was associated with a corresponding increase in the number/percentage of CD45(INT)CD11b(+)CD16(+)CD14(-) neutrophils (186 vs. 3.4, P < 0.01, 31% vs. 0.8%, P < 0.001). Neutrophils inversely correlated with disease duration (r = -0.71, P = 0.03), yet there was no absolute change in the CD8alphabeta(+) or neutrophil populations during the study period (P = 1.0). CONCLUSIONS: These data highlight that a neutrophilic infiltrate is present in mildly inflamed or clinically quiescent conjunctival mucosa in patients with ocular SJS-TEN, where neutrophil numbers inversely correlate with disease duration. Neutrophil persistence endorses the hypothesis of an unresolved innate inflammatory process that might account for disease progression. PMID- 23737479 TI - Effective childhood cancer treatment: the impact of large scale clinical trials in Germany and Austria. AB - In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease-specific first-line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five-year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995. Today, treatment intensity is tailored to the individual patient's risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals. PMID- 23737480 TI - Incidence and outcomes of patients with late recurrence of Wilms' tumor. AB - BACKGROUND: Most relapses from Wilms' tumor occur within 2 years from diagnosis. This study aims to describe the incidence and outcome of patients who experienced a late recurrence (LR) more than 5 years after diagnosis across several clinical trials, and to develop evidence-based recommendations for follow-up surveillance. METHODS: Available records on children with Wilms' tumor enrolled onto 10 national or international cooperative clinical trials were reviewed to identify patients who experienced a LR. RESULTS: Seventy of 13,330 (0.5%) patients with Wilms' tumor experienced a LR. No gender bias was observed. Median time elapsing between initial Wilms' tumor diagnosis and first recurrence was 13.2 years (range: 5.1-17.3 years). Initial tumor stage was: stage I (15); stage II (19); stage III (14); stage IV (8); bilateral disease stage V (14). The most frequent sites of relapse were--abdomen: 21, lungs: 20, and contralateral kidney: 15. Thirty-five children died of disease progression. Recurrence in the contralateral kidney was associated with a better outcome (13/15 patients alive), while initial tumor stage did not seem to influence the post-recurrence outcome. Therapies administered at recurrence varied between centers, preventing any conclusion about the best salvage treatment. CONCLUSIONS: LR of Wilms' tumor is rare and associated with similar outcome to those experiencing earlier recurrence. The low rate of LR does not justify prolonged monitoring. Further study of the biology of these tumors may give us some insights in regards to mechanisms on tumor cell dormancy or cancer stem cell maintenance. PMID- 23737481 TI - A systematic review regarding the association of illness perception and survival among end-stage renal disease patients. AB - BACKGROUND: End-stage renal disease (ESRD) patients have increased mortality and morbidity. According to Leventhal's self-regulation model, these patients mentally develop illness representations and coping strategies in order to better understand their condition. Mental representations seem to be an important factor for clinical and psychosocial outcomes. We aimed to systematically review all available data regarding the association between illness perception and survival/mortality among ESRD patients receiving dialysis treatment. METHODS: This is a systematic review of prospective observational studies, evaluating illness perception and its association with survival/mortality in ESRD dialysis stage patients. We searched CENTRAL in the Cochrane Library until August 2012, MEDLINE from 1950, EMBASE from 1980, PsychINFO from 1967 and additional sources to identify all records evaluating illness perception and clinical outcomes in this population. Two authors assessed potential citations for eligibility and quality and extracted all data. The studied intervention was the application of the most commonly used questionnaires for assessing illness perception. The main outcomes were survival and mortality. RESULTS: We identified five studies evaluating the relationship between illness perception and survival/mortality in ESRD patients receiving dialysis treatment. All included studies were prospective observational ones. Four studies showed that a negative perception of illness is associated with increased risk of death and one study failed to find any association between illness perception and mortality. This is the first systematic search that analysed the existing data showing an association between illness representation and survival/mortality among these patients. The main limitation of this review includes the design of the included studies (prospective observational studies without a non-exposed control group). CONCLUSIONS: This study implies that patient's outcome may be improved by changes in illness perception and designing appropriate interventions. We conclude that these findings constitute an important indication for future research in this field (high-quality randomized trials) and for future implementation of effective interventions that could improve this patients' outcome. PMID- 23737482 TI - Cost of peritoneal dialysis and haemodialysis across the world. AB - Peritoneal dialysis (PD) as a modality is underutilized in most parts of the world today despite several advantages including the possibility of it being offered in the remotest of locations and being significantly more affordable than haemodialysis (HD) in most cases. In this article, we will compare the cost of HD and PD in several countries to demonstrate that PD is less than, or at least as expensive as, HD. A thorough literature survey of EMBASE and PUBMED was conducted; 78 articles which compared the annual PD and annual HD costs were finally selected. Careful attention was paid to the methodology followed by each study and the year it was published in. Our final calculations included 46 countries (20 developed and 26 developing). We found that the cost of HD was between 1.25 and 2.35 times the cost of PD in 22 countries (17 developed and 5 developing), between 0.90 and 1.25 times the cost of PD in 15 countries (2 developed and 13 developing), and between 0.22 and 0.90 times the cost of PD in 9 countries (1 developed and 8 developing). From our analysis, it is evident that most developed countries can provide PD at a lesser expense to the healthcare system than HD. The evidence on developing countries is more mixed, but in most cases PD can be provided at a similar cost where economies of scale have been achieved, either by local production or by low import duties on PD equipment. PMID- 23737483 TI - Renal centre characteristics and physician practice patterns associated with home dialysis use. AB - BACKGROUND: There is a wide variation in home dialysis use (peritoneal dialysis and home haemodialysis) between renal centres. This study identifies which centre characteristics and practice patterns are associated with home dialysis use. METHODS: An observational study of all UK patients starting renal replacement therapy (RRT) in 2007-2008 using patient characteristics from the UK Renal Registry (UKRR) and renal centre characteristics ascertained from a national survey. Multilevel logistic regression was used to examine the association between patient and centre characteristics and home dialysis uptake. RESULTS: Twenty-six per cent of 11 913 patients used home dialysis and survey responses were available from every renal centre. After taking into account patient factors, several centre factors were associated with a higher probability of home dialysis: physicians aspiring to a higher 'ideal' peritoneal dialysis rate (odds ratio, OR 1.21, 95% CI 1.06-1.37, P = 0.003 per 10% increase in 'ideal' percentage), early use of peritoneal dialysis (PD, OR 1.52, 95% CI 1.18-1.95, P < 0.001), use of home visits to educate patients pre-dialysis (OR 1.39, 95% CI 1.05 1.83, P = 0.02) and to provide trouble-shooting advice for existing home dialysis patients (OR 1.63, 95% CI 1.11-2.42, P = 0.01). Using videos/DVDs as part of the pre-dialysis education programme was associated with a lower probability of home dialysis, but this was correlated with lower levels of physician enthusiasm (r = 0.48, P < 0.001). After adjustment for this, the association disappeared (OR 0.77, 95% CI 0.55-1.07, P = 0.1). CONCLUSIONS: Home dialysis use is associated with modifiable centre factors as well as individual patient characteristics. PMID- 23737484 TI - Obesity and nephrology: results of a knowledge and practice pattern survey. AB - BACKGROUND: Obesity, the largest epidemic of modern time, carries a markedly increased risk of type-2 diabetes, cancer, fatty liver, sleep apnea, hypertension, dyslipidemia and atherosclerotic cardiovascular disease. In addition, obesity increases the risk of chronic kidney disease (CKD) and its progression to end-stage renal disease (ESRD). There are limited data regarding the basic knowledge of nephrologists on how to assess and manage obesity in the setting of CKD. METHODS: To learn more about practice patterns among nephrologists, a survey on obesity was published online in NDT-Educational between 8 November 2012 and 31 January 2013. Three-hundred and ninety-nine responses were received mostly from nephrologists in Europe (57%), South and Central America (12%) and the Middle East (10%). The majority practiced in clinical nephrology (64%) and outpatient dialysis clinics (23%). Whereas 54% of the participants worked in hospitals, 31% worked in academic centers. RESULTS: Most participants stated that the number of obese patients has increased both among their CKD stage 2-5 patients and in their dialysis clinics during the last 10 years. For routine estimation of body fat content in the dialysis clinic, the majority of nephrologists (43%) still rely on the body mass index (BMI). A majority (72%) does not think that weight gain should be promoted in dialysis patients with a BMI of <35 kg/m(2). The survey also showed that 30% of the responders did not have any predetermined cut-off level for BMI. However, 29% used a cut-off level of 35 kg/m(2) and 27% used a cut-off level of 30 kg/m(2) for approval for kidney transplantation in their clinics. CONCLUSIONS: The level of understanding of the intricacies of obesity in the setting of CKD needs improvement among nephrologists. Similarly, there is no consensus regarding weight management strategies in CKD patients with obesity. Studies are needed in this orphan area of renal research. PMID- 23737485 TI - Potent immunomodulatory effects of the trifunctional antibody catumaxomab. AB - Catumaxomab (CatmAb), a trifunctional bispecific antibody directed against the epithelial cell adhesion molecule (EpCAM) and the T-cell antigen CD3, is approved as intraperitoneal therapy for the treatment of malignant ascites in patients with EpCAM-positive carcinomas. The immunomonitoring results of a phase II/III study using CatmAb revealed a tumoricidal effect associated with reduced VEGF levels, CD69-expressing T cells, and the release of T-helper cell (TH)-1 cytokines. We comprehensively dissected the immunomodulatory effects of the CatmAb on the major subsets of malignant ascites-infiltrating leukocytes and the molecular fingerprint of tumor cell death. Herein we show that in the presence of EpCAM-positive tumor targets, CatmAb markedly enhanced T-cell activation [CD69, CD107A (LAMP1), HLA-DR and PD-1(PDCD1) expression] and stimulated inflammatory CD4(+) TH1 and CD8(+) TH1 to release IFN-gamma but failed to trigger TH17 cells. Engagement of CD16-expressing cells caused upregulation of TRAIL (TNFSF10) and costimulatory CD40 and CD80 molecules. CatmAb promoted tumor cell death associated with ATP release and strongly synergized with oxaliplatin for the exposure of the three hallmarks of immunogenic cell death (calreticulin, HMGB1, and ATP). These findings warrant validation as potential biomarkers of efficacy of CatmAb. PMID- 23737486 TI - A renewable tissue resource of phenotypically stable, biologically and ethnically diverse, patient-derived human breast cancer xenograft models. AB - Breast cancer research is hampered by difficulties in obtaining and studying primary human breast tissue, and by the lack of in vivo preclinical models that reflect patient tumor biology accurately. To overcome these limitations, we propagated a cohort of human breast tumors grown in the epithelium-free mammary fat pad of severe combined immunodeficient (SCID)/Beige and nonobese diabetic (NOD)/SCID/IL-2gamma-receptor null (NSG) mice under a series of transplant conditions. Both models yielded stably transplantable xenografts at comparably high rates (~21% and ~19%, respectively). Of the conditions tested, xenograft take rate was highest in the presence of a low-dose estradiol pellet. Overall, 32 stably transplantable xenograft lines were established, representing 25 unique patients. Most tumors yielding xenografts were "triple-negative" [estrogen receptor (ER)-progesterone receptor (PR)-HER2+; n = 19]. However, we established lines from 3 ER-PR-HER2+ tumors, one ER+PR-HER2-, one ER+PR+HER2-, and one "triple-positive" (ER+PR+HER2+) tumor. Serially passaged xenografts show biologic consistency with the tumor of origin, are phenotypically stable across multiple transplant generations at the histologic, transcriptomic, proteomic, and genomic levels, and show comparable treatment responses as those observed clinically. Xenografts representing 12 patients, including 2 ER+ lines, showed metastasis to the mouse lung. These models thus serve as a renewable, quality-controlled tissue resource for preclinical studies investigating treatment response and metastasis. PMID- 23737487 TI - C-RAF mutations confer resistance to RAF inhibitors. AB - Melanomas that contain B-RAF(V600E) mutations respond transiently to RAF and MEK inhibitors; however, resistance to these agents remains a formidable challenge. Although B- or C-RAF dysregulation represents prominent resistance mechanisms, resistance-associated point mutations in RAF oncoproteins are surprisingly rare. To gain insights herein, we conducted random mutagenesis screens to identify B- or C-RAF mutations that confer resistance to RAF inhibitors. Whereas bona fide B RAF(V600E) resistance alleles were rarely observed, we identified multiple C-RAF mutations that produced biochemical and pharmacologic resistance. Potent C-RAF resistance alleles localized to a 14-3-3 consensus binding site or a separate site within the P loop. These mutations elicited paradoxical upregulation of RAF kinase activity in a dimerization-dependent manner following exposure to RAF inhibitors. Knowledge of resistance-associated C-RAF mutations may enhance biochemical understanding of RAF-dependent signaling, anticipate clinical resistance to novel RAF inhibitors, and guide the design of "next-generation" inhibitors for deployment in RAF- or RAS-driven malignancies. PMID- 23737489 TI - Re-evaluation of nondiagnostic biopsies of suspected low-grade glioma using isocitrate dehydrogenase 1 mutation immunohistochemistry. PMID- 23737488 TI - Synergy between the ectoenzymes CD39 and CD73 contributes to adenosinergic immunosuppression in human malignant gliomas. AB - BACKGROUND: The importance of ectoenzymes CD39 and CD73 in mediating adenosinergic immunosuppression has been recognized, but their roles in human malignant glioma-associated immunosuppression remain largely unknown. METHODS: In this study, the ectoenzyme characteristics of malignant glioma cells and infiltrating CD4(+) T lymphocytes isolated from newly diagnosed malignant glioma patients were investigated. The ectoenzyme activities of both cell populations were determined by nucleotide hydrolysis assay. The immunosuppressive property of the CD39-CD73 synergic effect was evaluated via responder T-cell proliferation assay. RESULTS: We observed that CD39(-)CD73(+) glioma cells and infiltrating CD4(+)CD39(high)CD73(low) T lymphocytes exhibited 2 distinct but complementary ectoenzyme phenotypes, which were further verified by enzyme activity assay. The nucleotide hydrolysis cascade was incomplete unless CD39 derived from T lymphocytes and CD73 collaborated synergistically. We demonstrated that increased suppression of responder CD4(+) T-cell proliferation suppression was induced by CD4(+)CD39(+) T cells in the presence of CD73(+) glioma cells, which could be alleviated by the CD39 inhibitor ARL67156, the CD73 inhibitor APCP, or the adenosine receptor A2aR antagonist SCH58261. In addition, survival analysis suggested that CD73 downregulation was a positive prognostic factor related to the extended disease-free survival of glioblastoma patients. CONCLUSIONS: Our data indicate that glioma-derived CD73 contributes to local adenosine-mediated immunosuppression in synergy with CD39 from infiltrating CD4(+)CD39(+) T lymphocytes, which could become a potential therapeutic target for treatment of malignant glioma and other immunosuppressive diseases. PMID- 23737490 TI - Spread of oqxAB in Salmonella enterica serotype Typhimurium predominantly by IncHI2 plasmids. AB - OBJECTIVES: To investigate the prevalence and genetic environment of the multiresistance gene oqxAB in Salmonella enterica serotype Typhimurium isolated from food-producing animals. METHODS: In this study, 63 Salmonella enterica serotype Typhimurium isolates were analysed for the presence of plasmid-mediated quinolone resistance determinants and mutations in the quinolone resistance determining region by molecular methods (PCR/sequencing). The oqxAB-positive isolates were typed by pulsed-field gel electrophoresis (PFGE). Plasmids carrying oqxAB were studied by conjugation/transformation, replicon typing, Southern hybridization, long-range PCR and restriction fragment length polymorphism (RFLP). RESULTS: The oqxAB, aac(6')-Ib-cr and qnrS1 genes were present alone or in combination in 20 (31.7%), 23 (36.5%) and 1 (1.6%) isolate, respectively. The oqxAB-positive isolates were clonally related, as determined by PFGE. All of the oqxAB-aac(6')-Ib-cr-positive isolates carried transferable IncHI2-type plasmids containing an oqxAB cassette and an incomplete class 1 integron harbouring aac(6')-Ib-cr, blaOXA-1, catB3, arr3, qacEDelta1 and sul1. Meanwhile, 6 of 15 plasmids carrying both oqxAB and aac(6')-Ib-cr showed identical RFLP patterns. CONCLUSIONS: The results suggest that both clonal expansion and horizontal transmission of IncHI2-type plasmids containing oqxAB and aac(6')-Ib-cr may be involved in the spread of oqxAB in Salmonella Typhimurium isolates in food producing animals in China. There is a great need to monitor the potential dissemination of this multiresistance gene. PMID- 23737492 TI - Endovascular reconstruction of vertebral artery occlusion prior to basilar thrombectomy in a series of six patients presenting with acute symptomatic basilar thrombosis. AB - INTRODUCTION AND PURPOSE: Symptomatic acute basilar thrombosis is associated with a high mortality rate. Aggressive endovascular management has led to survival rates of 35-50%. We report the largest series of endovascular reconstruction of occluded dominant vertebral arteries prior to basilar thrombectomy. MATERIALS AND METHODS: A prospective database since August 2010 of all neuroendovascular interventions was mined for patients undergoing basilar artery thrombolysis from which a group with vertebral artery reconstruction was selected. Patient charts were retrospectively reviewed for relevant clinical, technical, and outcome data. RESULTS: From August 2010 to September 2012, six patients were identified who underwent vertebral reconstruction prior to basilar thrombectomy. Patients ranged in age from 42 to 57 years (mean 51 years). Mean time from symptoms until recanalization was approximately 6 h. Angiographic Thrombolysis in Cerebral Infarction IIB reconstitution of the basilar trunk was achieved in all cases. There were no technical complications. Two patients had care withdrawn secondary to massive completed brainstem infarction and poor neurological status post intervention. Three patients are now independent at 12, 14, and 31 months, respectively. One patient, after a follow-up of only 8 months, has achieved a modified Rankin Scale score of 3. CONCLUSIONS: Complete vertebral occlusion below a basilar thrombus can be recanalized prior to thrombectomy. In this case series, 100% of the acutely occluded vertebral arteries could be opened using either anterograde or retrograde access. However, basilar thrombosis continues to be a devastating illness, with one-third of the patients in this series dying of progressive infarction despite angiographic patency of the large conduit vessels with technical complications. PMID- 23737494 TI - Biomechanical factors in cardiovascular disease. PMID- 23737493 TI - The valosin-containing protein promotes cardiac survival through the inducible isoform of nitric oxide synthase. AB - AIMS: Expression of the heat shock protein 22 (Hsp22) in the heart stimulates cardiac cell survival through activation of the Akt pathway and expression of the inducible nitric oxide (NO) synthase (iNOS), the mediator of ischaemic preconditioning and the most powerful prophylaxis against cardiac cell death. The goal of the present study was to elucidate the downstream effector by which Hsp22 and Akt increase iNOS expression. We tested both in vivo and in vitro the hypothesis that such an effector is the valosin-containing protein (VCP), an Akt substrate, which activates the transcription factor NF-kappaB, using a transgenic mouse with cardiac-specific over-expression of Hsp22, as well as isolated rat cardiac myocytes. METHODS AND RESULTS: Using two-dimensional gel electrophoresis and mass spectrometry combined with immunoprecipitation, we found that Hsp22 and Akt co-localize and interact together with VCP. Adeno-mediated over-expression of VCP in isolated cardiac myocytes activated NF-kappaB and dose-dependently increased the expression of iNOS, which was abolished upon NF-kappaB inhibition. Over-expression of a dominant-negative (DN) mutant of VCP did not increase iNOS expression. VCP, but not its DN mutant, protected against chelerythrine-induced apoptosis, which was suppressed by inhibition of either NF-kappaB or iNOS. VCP mediated activation of the NF-kappaB/iNOS pathway was also prevented upon inhibition of Akt. CONCLUSION: We conclude that the Akt substrate, VCP, mediates the increased expression of iNOS downstream from Hsp22 through an NF-kappaB dependent mechanism. PMID- 23737495 TI - NLRP3 in myocardial ischaemia-reperfusion injury: inflammasome-dependent or independent role in different cell types. PMID- 23737497 TI - Environmental cost of conservation victories. PMID- 23737496 TI - Age-related differences in the disposition of nicotine and metabolites in rat brain and plasma. AB - INTRODUCTION: Studies have evaluated the behavioral and neurochemical impact of nicotine administration in rodents. However, the distribution of nicotine and metabolites in rat brain and plasma as a function of age has not been investigated. This is a significant issue because human adolescents have a greater risk for developing nicotine addiction than adults, and reasons underlying this observation have not been fully determined. Thus, in this present study, we evaluated the impact of the transition from adolescence (postnatal day [PND 40]) to adulthood (PND 90) on nicotine distribution in rats. METHODS: PND 40, 60, and 90 rats received a single injection of (-) nicotine (0.8 mg/kg, subcutaneously). Liquid chromatography tandem-mass spectrometry was used to measure concentration of nicotine and metabolites in selected biological matrices. RESULTS: Nicotine, cotinine, and nornicotine were detected in rat striata and frontal cortex 30 min, 1 hr, 2 hr, and 4 hr after a single administration. These and several additional metabolites (nicotine-1'-oxide, cotinine-N-oxide, norcotinine, and trans-3'-hydroxycotinine) were also detected in plasma at these same timepoints. The mean concentration of nicotine in brain and plasma was lower in PND 40 versus PND 90 rats. In contrast, the mean concentration of nornicotine was higher in the plasma and brain of PND 40 versus PND 90 rats. CONCLUSIONS: Nicotine and metabolite distribution differs between adolescent and adult rats. These data suggest that adolescent rats metabolize nicotine to some metabolites faster than adult rats. Further studies are needed to investigate the potential correlation between age, drug distribution, and nicotine addiction. PMID- 23737498 TI - Whole-climate experiments for peatlands. PMID- 23737500 TI - Trafficking of plant vacuolar invertases: from a membrane-anchored to a soluble status. Understanding sorting information in their complex N-terminal motifs. AB - Vacuolar invertases (VIs) are highly expressed in young tissues and organs. They may have a substantial regulatory influence on whole-plant metabolism as well as on photosynthetic efficiency. Therefore, they are emerging as potentially interesting biotechnological targets to increase plant biomass production, especially under stress. On the one hand, VIs are well known as soluble and extractable proteins. On the other hand, they contain complex N-terminal propeptide (NTPP) regions with a basic region (BR) and a transmembrane domain (TMD). Here we analyzed in depth the Arabidopsis thaliana VI2 (AtVI2) NTPP by mutagenesis. It was found that correct sorting to the lytic vacuole (LV) depends on the presence of intact dileucine (SSDALLPIS), BR (RRRR) and TMD motifs. AtVI2 remains inserted into membranes on its way to the LV, and the classical sorting pathway (endoplasmic reticulum->Golgi->LV) is followed. However, our data suggest that VIs might follow an alternative, adaptor protein 3 (AP3)-dependent route as well. Membrane-anchored transport and a direct recognition of the dileucine motif in the NTPP of VIs might have evolved as a simple and more efficient sorting mechanism as compared with the vacuolar sorting receptor 1/binding protein of 80 kDa (VSR1/BP80)-dependent sorting mechanism followed by those proteins that travel to the vacuole as soluble proteins. PMID- 23737501 TI - Arabitol provided by lichenous fungi enhances ability to dissipate excess light energy in a symbiotic green alga under desiccation. AB - Lichens are drought-resistant symbiotic organisms of mycobiont fungi and photobiont green algae or cyanobacteria, and have an efficient mechanism to dissipate excess captured light energy into heat in a picosecond time range to avoid photoinhibition. This mechanism can be assessed as drought-induced non photochemical quenching (d-NPQ) using time-resolved fluorescence spectroscopy. A green alga Trebouxia sp., which lives within a lichen Ramalina yasudae, is one of the most common green algal photobionts. This alga showed very efficient d-NPQ under desiccation within the lichen thallus, whereas it lost d-NPQ ability when isolated from R. yasudae, indicating the importance of the interaction with the mycobiont for d-NPQ ability. We analyzed the water extracts from lichen thalli that enhanced d-NPQ in Trebouxia. Of several sugar compounds identified in the water extracts by nuclear magnetic resonance (NMR), mass spectrometry (MS) and gas chromatography (GC) analyses, only d-arabitol recovered d-NPQ in isolated Trebouxia to a level similar to that detected for R. yasudae thallus. Other sugar compounds did not help the expression of d-NPQ at the same concentrations. Thus, arabitol is essential for the expression of d-NPQ to dissipate excess captured light energy into heat, protecting the photobiont from photoinhibition. The relationship between mycobionts and photobionts is, therefore, not commensalism, but mutualism with each other, as shown by d-NPQ expression. PMID- 23737502 TI - A novel astaxanthin-binding photooxidative stress-inducible aqueous carotenoprotein from a eukaryotic microalga isolated from asphalt in midsummer. AB - Water-soluble orange carotenoid proteins (OCPs) that bind 3'-hydroxyechinenone are found in cyanobacteria, and are thought to play a key role in photoprotection. The distribution of OCPs in eukaryotes remains largely unknown. In this study, we identified a novel OCP that predominantly binds astaxanthin from a eukaryotic microalga, strain Ki-4, isolated from a dry surface of heated asphalt in midsummer. A purified astaxanthin-binding OCP, named AstaP, shows high solubility in water with an absorption peak at 484 nm, and possesses a heat stable activity that quenches singlet oxygen. The deduced amino acid sequence of AstaP comprises an N-terminal hydrophobic signal peptide, fasciclin domains found in secreted and cell surface proteins, and N-linked glycosylation sites, the first example of a carotenoprotein among fasciclin family proteins. AstaP homologs of unknown function are distributed mainly in organisms from the hydrosphere, such as marine bacteria, cyanobacteria, sea anemone and eukaryotic microalgae; however, AstaP exhibits a unique extraordinarily high isoelectric point (pI) value among homologs. The gene encoding AstaP, as well as the AstaP peptide, is expressed abundantly under conditions of dehydration and salt stress in conjunction with high light exposure. As a unique aqueous carotenoprotein, AstaP will provide a novel function of OCPs in protection against extreme photooxidative stresses. PMID- 23737503 TI - Targeting of the MNK-eIF4E axis in blast crisis chronic myeloid leukemia inhibits leukemia stem cell function. AB - Chronic myeloid leukemia responds well to therapy targeting the oncogenic fusion protein BCR-ABL1 in chronic phase, but is resistant to treatment after it progresses to blast crisis (BC). BC is characterized by elevated beta-catenin signaling in granulocyte macrophage progenitors (GMPs), which enables this population to function as leukemia stem cells (LSCs) and act as a reservoir for resistance. Because normal hematopoietic stem cells (HSCs) and LSCs depend on beta-catenin signaling for self-renewal, strategies to specifically target BC will require identification of drugable factors capable of distinguishing between self-renewal in BC LSCs and normal HSCs. Here, we show that the MAP kinase interacting serine/threonine kinase (MNK)-eukaryotic translation initiation factor 4E (eIF4E) axis is overexpressed in BC GMPs but not normal HSCs, and that MNK kinase-dependent eIF4E phosphorylation at serine 209 activates beta-catenin signaling in BC GMPs. Mechanistically, eIF4E overexpression and phosphorylation leads to increased beta-catenin protein synthesis, whereas MNK-dependent eIF4E phosphorylation is required for nuclear translocation and activation of beta catenin. Accordingly, we found that a panel of small molecule MNK kinase inhibitors prevented eIF4E phosphorylation, beta-catenin activation, and BC LSC function in vitro and in vivo. Our findings identify the MNK-eIF4E axis as a specific and critical regulator of BC self-renewal, and suggest that pharmacologic inhibition of the MNK kinases may be therapeutically useful in BC chronic myeloid leukemia. PMID- 23737505 TI - Sustained reductions in emergency department laboratory test orders: impact of a simple intervention. AB - OBJECTIVES: To determine whether a pathology request form allowing interns and residents to order only a limited range of laboratory blood tests prior to consultation with a registrar or consultant can reduce test ordering in an emergency department (ED). METHODS: A prospective before-and-after study in an adult tertiary-referral teaching hospital ED was conducted. A pathology request form with a limited list of permissible tests was implemented for use by junior medical officers. Tests for patients 16 years and older presenting in a 20-week pre-intervention period from 19 January 2009 were compared with those in a corresponding 20-week post-intervention period from 18 January 2010. Main outcome measures were the number and cost of blood tests ordered. RESULTS: 24 652 and 25 576 presentations were analysed in the pre- and post-intervention periods, respectively. The mean number of blood tests ordered per 100 ED presentations fell by 19% from 172 in the pre- to 140 in the post-intervention period (p=0.001). The mean cost of blood tests ordered per 100 ED presentations fell by 17% from $A3177 in the pre- to $A2633 in the post-intervention period (p=0.001). There were falls in the number of coagulation profiles (11.1 vs 4.8/100 patients), C-reactive protein (5.6 vs 2.7/100 patients), erythrocyte sedimentation rate (2.5 vs 1.3/100 patients) and thyroid function tests (2.2 vs 1.6/100 patients). CONCLUSIONS: Pathology request forms limiting tests that an intern and resident may order prior to consultation with a registrar or consultant are an effective low maintenance method for reducing laboratory test ordering in the ED that is sustainable over 12 months. PMID- 23737504 TI - Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function. AB - Aberrant signaling by oncogenic mutant rat sarcoma (Ras) proteins occurs in ~15% of all human tumors, yet direct inhibition of Ras by small molecules has remained elusive. Recently, several small-molecule ligands have been discovered that directly bind Ras and inhibit its function by interfering with exchange factor binding. However, it is unclear whether, or how, these ligands could lead to drugs that act against constitutively active oncogenic mutant Ras. Using a dynamics-based pocket identification scheme, ensemble docking, and innovative cell-based assays, here we show that andrographolide (AGP)--a bicyclic diterpenoid lactone isolated from Andrographis paniculata--and its benzylidene derivatives bind to transient pockets on Kirsten-Ras (K-Ras) and inhibit GDP-GTP exchange. As expected for inhibitors of exchange factor binding, AGP derivatives reduced GTP loading of wild-type K-Ras in response to acute EGF stimulation with a concomitant reduction in MAPK activation. Remarkably, however, prolonged treatment with AGP derivatives also reduced GTP loading of, and signal transmission by, oncogenic mutant K-RasG12V. In sum, the combined analysis of our computational and cell biology results show that AGP derivatives directly bind Ras, block GDP-GTP exchange, and inhibit both wild-type and oncogenic K-Ras signaling. Importantly, our findings not only show that nucleotide exchange factors are required for oncogenic Ras signaling but also demonstrate that inhibiting nucleotide exchange is a valid approach to abrogating the function of oncogenic mutant Ras. PMID- 23737506 TI - Antidepressant medication in patients with advanced cancer--an observational study. AB - OBJECTIVE: Literature reviews suggest limited evidence of efficacy of antidepressant medication in patients with advanced cancer. This study was carried out to observe the longitudinal effect of antidepressant medication in a cohort of advanced cancer patients. METHOD: Patients were recruited from hospice day care settings and followed up longitudinally by series of measures for depression for 6 months or until death. RESULTS: Six hundred and twenty nine patients recruited. One hundred and fifty six patients in total (25%) were receiving antidepressant medication for a median of 9.5 weeks (range 0-36 weeks) and a mean of 12.2 weeks. There was no significant difference in scores on depression measures over time for patients receiving antidepressant medication. CONCLUSION: Antidepressant medication for advanced cancer patients appeared to have little impact on depression scores. We postulate the holistic approaches within hospice day care may in themselves be interventions for depression thereby masking effect of pharmacological treatment. Further research should explore multi-intervention models for management of depression in advanced cancer. PMID- 23737508 TI - Graves' disease and atrial thrombus. PMID- 23737507 TI - The advantages of a consultant led primary percutaneous coronary intervention service on patient outcome. AB - BACKGROUND: Mortality among emergency medical admissions has been reported to be higher when patients are admitted to hospital at nights and weekends. AIM: We studied the outcome of ST elevation myocardial infarction (STEMI) patients presenting at different times to our centre with 24/7 primary percutaneous coronary intervention (PPCI) service. METHODS: We divided all patients who underwent PPCI between September 2009 and November 2011 into three groups according to the time of admission as group 1: in-hours (0800-1800 h weekdays), group 2: out-of-hours (1800- 0800 h weekdays) and group 3: weekends (Sat to Mon 0800-0800 h). RESULTS: A total of 605 (41.1%), 397 (27%) and 469 (31.9%) were included in group 1, 2 and 3, respectively. Apart from cardiogenic shock (8.9%, 5.5% and 7.7%, P = 0.05) and door to balloon time (median 29, 33 and 36 min, P < 0.0001), there was no significant difference noted in the baseline and procedural characteristics between the groups. In-hospital mortality (4.6%, 4.3% and 5.3%, P = 0.5), 30-day mortality (6.4%, 6.3% and 7%, P = 0.7), 30-day stent thrombosis (0.8%, 0.8% and 0.2%, P = 0.1) and 1-year mortality (10.7%, 10.8% and 9.8%, P = 0.7) were no difference between the groups. On logistic regression analysis, out of-hours and weekend admissions were not found to be a predictor of both 30-day and 1-year mortality. CONCLUSION: In this consecutive series of patients admitted to a high volume PPCI centre, there was no difference in mortality when patients were admitted at different times. The involvement of senior medical staff early in the patients' admission may have contributed to these consistent outcomes. PMID- 23737509 TI - Atrial fibrillation as a risk factor for cognitive impairment: a semi-systematic review. AB - It is unclear if atrial fibrillation (AF) is an independent risk factor for cognitive impairment. This review evaluates the available evidence and provides an overview of the association between AF and cognitive function. Electronic database searches, January 1990 to December 2012, identified 271 studies comparing the incidence of cognitive impairment and/or dementia in patients with/without AF. Cognitive function was diagnosed by a physician using the mini mental state examination (MMSE) or other established diagnostic criteria. Studies with <20 participants and without direct comparison to controls in sinus rhythm were excluded. There were no restrictions on the basis of age, language or study design. Full texts of 11 studies were obtained. Eight studies (three cross sectional, two case-control and three prospective cohorts) reported an association between cognitive decline and AF. Among cross-sectional studies, patients with AF had a 1.7 (95% CI 1.2-2.5) to 3.3 (95% CI 1.6-6.5) greater risk of cognitive impairment, and a 2.3-fold (95% CI 1.4-3.7) increased risk of dementia, compared to patients in sinus rhythm. There was marked heterogeneity in the design, size and quality of studies and reporting of the data which precluded formal meta-analysis. Eight studies reported an association between AF and cognitive impairment and/or dementia, but the magnitude of risk varied. Further large-scale prospective studies are needed to establish whether AF is a risk factor for cognitive decline, utilizing objective measures of cognitive function and neuropsychological testing, and to investigate the potential benefit of anticoagulation on reducing cognitive impairment and development of dementia. PMID- 23737510 TI - Efficacy and safety of mirtazapine in fibromyalgia syndrome patients: a randomized placebo-controlled pilot study. AB - BACKGROUND: Data from an open-label trial suggest that mirtazapine might prove useful in treatment of fibromyalgia syndrome (FMS). OBJECTIVE: To obtain preliminary efficacy data of mirtazapine for estimation of sample size requirements for a Phase 2 clinical trial in FMS. METHODS: This 13-week randomized controlled trial compared the effects of mirtazapine 15 mg/day, mirtazapine 30 mg/day, and placebo in 40 patients with FMS. The primary outcomes were change in Pain Visual Analog Scale (PVAS) and proportion of pain responders (>=30% PVAS reduction). Secondary outcomes included scores from the Jenkins Sleep Scale (JSS), Patient Global Impression of Change (PGIC), Fibromyalgia Impact Questionnaire (FIQ), Hamilton Depression Rating Scale (HAM-D), Patient Global Assessment, and self-reported adverse events. RESULTS: Significant within-group PVAS reductions from baseline were observed in all 3 groups, with the greatest improvement in the mirtazapine 30-mg group (p < 0.005); between-group difference was not significant. The proportion of pain responders did not meet significance criteria (66.67% for mirtazapine 30 mg, 50% for mirtazapine 15 mg, 41.67% for placebo). Significant within-group improvement in JSS scores was seen for mirtazapine 30 mg (p < 0.01) and mirtazapine 15 mg (p < 0.05). Between-group comparison achieved significance for JSS item 3, waking several times per night (p < 0.05). On the PGIC, 72.73% felt better with both mirtazapine dosages compared with 50% for placebo. Within-group FIQ responses indicated improvement in only mirtazapine-treated groups, whereas within-group improvement for HAM-D and Patient Global Assessment was observed in all groups. Based on our findings, the sample size requirement (80% power, 5% type I error) should be 83 per group to detect PVAS change difference between mirtazapine 30 mg and placebo. Common mirtazapine-related adverse events were increased appetite and weight gain. CONCLUSIONS: Patients with FMS taking mirtazapine exhibited within-group significant improvement in most of the measured outcomes. Between-group analysis was predictably compromised by the small sample size. Mirtazapine was well tolerated. Further study with a larger sample size is likely to be useful. PMID- 23737511 TI - Posaconazole therapeutic drug monitoring in pediatric patients and young adults with cancer. AB - BACKGROUND: Limited information exists regarding the use of posaconazole for treating systemic fungal infections in children, adolescents, and young adults with cancer. At St. Jude Children's Research Hospital, the recommended posaconazole dose in patients weighing less than 34 kg is 18-24 mg/kg daily, given in 4 divided doses. For patients aged 13 years or older or those weighing 34 kg or more, the recommended dose is 800 mg daily, given orally in 4 divided doses. OBJECTIVE: To determine whether the current posaconazole dosing guidelines achieve target posaconazole plasma concentrations of 0.7 MUg/mL or greater. METHODS: This retrospective clinical study examined data from patients who received treatment-dose posaconazole and had at least 1 posaconazole plasma concentration measurement. RESULTS: Data from 33 patients who received posaconazole for the treatment of fungal infections were analyzed. The median age of patients was 11.5 years (range 0.5-23.2). Twenty-one of 33 patients (63.6%) had posaconazole concentrations of 0.7 MUg/mL or greater (median 1.4; range 0.7 2.98) at the first measurement. The median posaconazole dosage referenced to total body weight in these patients was 20 mg/kg/day. Patients with concentrations less than 0.7 MUg/mL (median 0.4; range 0.025-0.69) received lower posaconazole dosages when referenced to body weight (median 12.9 mg/kg/day; p = 0.02). Of the 12 patients with concentrations less than 0.7 MUg/mL, 7 (58.3%) were aged 13 years or older. CONCLUSIONS: The current dosing approach for posaconazole yielded therapeutic plasma concentrations more frequently in patients younger than 13 years than in those 13 years or older. This difference may be related to the practice of capping adolescent and young adult doses at the suggested maximum adult daily dose. Therefore, we recommend weight-based dosing in all pediatric, adolescent, and young adult patients with cancer, with routine therapeutic drug monitoring to ensure adequate concentrations. PMID- 23737512 TI - Apparent argatroban resistance in a patient with elevated factor VIII levels. AB - OBJECTIVE: To report a case in which there was a lack of activated partial thromboplastin time (aPTT) correlation with plasma argatroban concentrations in a patient with elevated factor VIII levels who was diagnosed with heparin-induced thrombocytopenia (HIT). CASE SUMMARY: A 59-year-old female with a history significant for basal cell carcinoma was transferred from an outside hospital and underwent resection of a third ventricle mass. The postoperative hospital course was complicated by subdural hematoma, HIT, and pulmonary embolism. Upon initiation of argatroban, we faced difficulty in maintaining therapeutic aPTT values despite administration of significantly higher than usual doses of argatroban (up to 7 MUg/kg/min). A coagulation abnormality was suspected and an argatroban concentration was obtained; results showed an elevated level of 2.2 MUg/mL (therapeutic range 0.4-1.2), with a corresponding aPTT of 53.1 seconds. A coagulopathy workup revealed an excess of factor VIII activity. Thereafter, argatroban concentrations were used for dose adjustments and the infusion was titrated to a final rate of 2.75 MUg/kg/min. DISCUSSION: The lack of correlation of aPPT values with argatroban administration has not been described in the literature and, to our knowledge, similar cases have not been reported. We were unable to achieve an increase in aPTT, despite aggressive argatroban dosing in a patient with increased factor VIII activity. A definitive mechanism for this is not entirely known; however, it is thought to be secondary to contributing underlying causes such as excessive clotting factors, circulating inflammatory proteins, or other aspects. CONCLUSIONS: With the initiation of argatroban therapy, particular attention should be given to ensure that aPTTs correlate with dosing to prevent life-threatening bleeding complications. Excessive argatroban dosing requirements should prompt further investigation into potential confounders such as elevated factor VIII levels. PMID- 23737513 TI - Medication errors in HIV-infected hospitalized patients: a pharmacist's impact. AB - BACKGROUND: Treatment with highly active antiretroviral therapy (HAART) decreases morbidity and mortality associated with HIV infection. Unfortunately, HAART medication errors are prevalent in hospitalized patients with HIV infection. Appropriate regimen administration and adherence are essential for treatment success. OBJECTIVE: To assess the impact of pharmacist interventions on the rate of medication errors in HIV-infected hospitalized patients who had been prescribed HAART in the outpatient setting. METHODS: Hospitalized patients aged 18 years or older receiving HAART and/or opportunistic infection (OI) prophylaxis were screened for inclusion. Data collection for each enrolled patient included demographic information, pertinent laboratory results, and inpatient and outpatient medication regimens. Patient medication profiles were reviewed within 72 hours of admission. HAART and/or OI prophylaxis errors were classified by type and frequency. Following the pharmacist intervention, prescribers' responses to each recommendation and the estimated time per intervention were recorded. RESULTS: Eighty-six patients were included in this investigation and 210 HAART and OI prophylaxis errors were documented. Of patients receiving HAART and/or OI prophylaxis, 54.7% had at least 1 medication error on admission. An average of 2.4 errors per patient was identified. Dose omission (45.5%) was the most common error type among combined HAART and OI prophylaxis regimens, followed by incorrect regimen (17.1%) and incorrect dose (15.1%). Prescribers accepted 90% of pharmacist recommendations. A pharmacist was able to amend 94.7% of correctable HAART errors, as well as 89.9% of correctable combined HAART and OI prophylaxis errors. An estimated 18.5 minutes of pharmacist time were spent per patient requiring an intervention. CONCLUSIONS: A clinical pharmacist's targeted review of outpatient-prescribed HAART and/or OI primary prophylaxis regimens of hospitalized HIV-infected patients can reduce most medication errors during hospitalization. PMID- 23737514 TI - Plan B and the German Catholic bishops. AB - Germany's Catholic bishops recently ruled that levonorgestrel emergency contraception (EC) was acceptable for prevention of pregnancy in the case of rape. The ruling represents a significant change in Catholic doctrine that has been opposed to most forms of birth control. In their ruling the bishops cited a lack of evidence that levonorgestrel EC acts as an abortifacient. This case serves as a reminder of the need for bioethics to be based on current scientific literature as well as articles of faith and morals. PMID- 23737515 TI - Aclidinium bromide: an alternative long-acting inhaled anticholinergic in the management of chronic obstructive pulmonary disease. AB - OBJECTIVE: To evaluate the efficacy and safety of aclidinium bromide, a novel, long-acting inhaled muscarinic receptor antagonist approved by the Food and Drug Administration (FDA) in July 2012, as a treatment in the management of moderate to severe chronic obstructive pulmonary disease (COPD). DATA SOURCES: Literature was identified through PubMed/MEDLINE (2000-March 2013) and International Pharmaceutical Abstracts using the search terms aclidinium, COPD, chronic bronchitis, emphysema, anticholinergic, and muscarinic antagonist. In addition, US government websites, including fda.gov and clinicaltrials.gov, were reviewed for pertinent information. Forest Laboratories, Inc provided previously unpublished clinical trial data. All reference citations from identified publications were reviewed for possible inclusion. STUDY SELECTION AND DATA EXTRACTION: All identified Phase 1, 2a, 2b, and 3 studies evaluating the safety and efficacy of aclidinium bromide were reviewed. DATA SYNTHESIS: Once- and twice daily aclidinium bromide was assessed for efficacy and safety in patients with moderate to severe COPD. In comparison to placebo, aclidinium significantly improves trough and peak forced expiratory volume in 1 second (FEV1). Significant increases in trough and peak FEV1 were sustainable for up to 64 weeks. In addition to improvement in trough and peak FEV1, twice-daily aclidinium 400 MUg induced clinically meaningful improvements in the health status of patients with moderate to severe COPD. Aclidinium was generally well tolerated, with headache, cough, diarrhea, and nasopharyngitis the most common treatment-related adverse effects noted in clinical trials. Aclidinium did not demonstrate a difference in the incidence of systemic anticholinergic-associated adverse effects in comparison to placebo or active comparator. CONCLUSIONS: Aclidinium bromide is a novel, inhaled, long-acting anticholinergic that, when administered at the FDA approved dose, safely produces clinically and statistically significant bronchodilation and improves health status in patients with moderate to severe COPD. Long-term clinical trials assessing the efficacy and safety of aclidinium are warranted. PMID- 23737516 TI - Intravenous sodium bicarbonate therapy in severely acidotic diabetic ketoacidosis. AB - BACKGROUND: The use of intravenous bicarbonate in diabetic ketoacidosis (DKA) may be considered for patients with a pH less than 6.9 according to the American Diabetes Association. The impact of this therapy on resolution of acidosis in patients with DKA is unclear. OBJECTIVE: To determine whether the use of intravenous bicarbonate therapy was associated with improved outcomes in patients with severe DKA who were seen in the emergency department. METHODS: This review was conducted from 2007 to 2011 in the emergency department of a tertiary teaching hospital. Adults diagnosed with DKA with an initial pH less than 7.0 were included. Patients were stratified into 2 groups based on receipt of intravenous bicarbonate. The primary study outcome was time to resolution of acidosis, defined as return to pH greater than 7.2. Secondary outcomes included length of stay; continuous infusion insulin use; and intravenous fluid, po tas si um, and insulin requirements within the first 24 hours of hospital admission, beginning upon admittance to the emergency department. We also conducted a subgroup analysis of patients with an initial pH less than 6.9. RESULTS: There was no significant difference in time to resolution of acidosis (8 hours vs 8 hours; p = 0.7) or time to hospital discharge (68 hours vs 61 hours; p = 0.3) between patients who received intravenous bicarbonate (n = 44) compared with those who did not (n = 42). The median dose of intravenous bicarbonate was 100 mEq (100-150) for patients who received intravenous bicarbonate. Insulin and fluid requirements in the first 24 hours were significantly higher in patients who received intravenous bicarbonate compared with those who did not (100 units vs 86 units; p = 0.04 and 7.6 L vs 7.2 L; p = 0.01, respectively). There was no significant difference in hours of continuous insulin infusion (27 hours vs 26 hours; p = 0.09) or potassium requirements in the first 24 hours of hospital stay (135 mEq vs 120 mEq; p = 0.84). CONCLUSIONS: Intravenous bicarbonate therapy did not decrease time to resolution of acidosis or time to hospital discharge for patients with DKA with an initial pH less than 7.0. PMID- 23737517 TI - Impact of severe hypothyroidism on cyclophosphamide disposition and routes of metabolism and transport in a patient with treatment-resistant lupus nephritis. AB - OBJECTIVE: To report what we believe to be the first case of severe hypothyroidism with reduced drug metabolism and transport activity. CASE SUMMARY: A 32-year-old African American woman with a history of treatment-resistant lupus nephritis and concurrent hypothyroidism was participating in a clinical study to evaluate cyclophosphamide pharmacokinetics in patients with glomerulonephritis due to lupus nephritis and small-vessel vasculitis. Thyroid-stimulating hormone levels ranged from 60 to 300 MUIU/mL, despite high doses of thyroid replacement hormone (levothyroxine 400 MUg twice weekly). The pharmacokinetics of the probe drug cocktail (flurbiprofen/fexofenadine) were altered, with formation clearance of flurbiprofen (CYP2C9 function) lower in our patient versus the average value in our study cohort, suggesting a reduction in activity. The area under the concentration-time curve from 0 to 24 hours for fexofenadine (transporter function) was 2-fold higher in our patient compared to that of other study patients. Pharmacokinetic data showed markedly decreased cyclophosphamide clearance and exposure to 4-hydroxycyclophosphamide, as well as a reduced metabolic ratio of 4-hydroxycyclophosphamide to cyclophosphamide. DISCUSSION: Previous cases of altered pharmacokinetics and toxicity of medications in patients with mild to moderate thyroid dysfunction have been published. Our case evaluated the impact of a severe form of hypothyroidism on cyclophosphamide pharmacokinetics and probe drug metabolism and transport. If changes were not demonstrated at the extreme spectrum of hypothyroidism, there would be little concern for changes in patients with less severe disease. Profound hypothyroidism likely contributed to the patient's poor response to cyclophosphamide treatment through its influence on CYP isoenzymes responsible for the activation to 4 hydroxycyclophosphamide and possibly through reduced transport function. CONCLUSIONS: Clinicians should monitor for significant hypothyroidism in patients who are prescribed drugs (eg, cyclophosphamide) that require metabolic conversion to form active therapeutic moieties. PMID- 23737519 TI - Anti-antimicrobial peptides: folding-mediated host defense antagonists. AB - Antimicrobial or host defense peptides are innate immune regulators found in all multicellular organisms. Many of them fold into membrane-bound alpha-helices and function by causing cell wall disruption in microorganisms. Herein we probe the possibility and functional implications of antimicrobial antagonism mediated by complementary coiled-coil interactions between antimicrobial peptides and de novo designed antagonists: anti-antimicrobial peptides. Using sequences from native helical families such as cathelicidins, cecropins, and magainins we demonstrate that designed antagonists can co-fold with antimicrobial peptides into functionally inert helical oligomers. The properties and function of the resulting assemblies were studied in solution, membrane environments, and in bacterial culture by a combination of chiroptical and solid-state NMR spectroscopies, microscopy, bioassays, and molecular dynamics simulations. The findings offer a molecular rationale for anti-antimicrobial responses with potential implications for antimicrobial resistance. PMID- 23737518 TI - Diaminothiazoles modify Tau phosphorylation and improve the tauopathy in mouse models. AB - Although Tau accumulation is a feature of several neurodegenerative conditions, treatment options for these conditions are nonexistent. Targeting Tau kinases represents a potential therapeutic approach. Small molecules in the diaminothiazole class are potent Tau kinase inhibitors that target CDK5 and GSK3beta. Lead compounds from the series have IC50 values toward CDK5/p25 and GSK3beta in the low nanomolar range and no observed toxicity in the therapeutic dose range. Neuronal protective effects and decreased PHF-1 immunoreactivity were observed in two animal models, 3*Tg-AD and CK-p25. Treatment nearly eliminated Sarkosyl-insoluble Tau with the most prominent effect on the phosphorylation at Ser-404. Treatment also induced the recovery of memory in a fear conditioning assay. Given the contribution of both CDK5/p25 and GSK3beta to Tau phosphorylation, effective treatment of tauopathies may require dual kinase targeting. PMID- 23737520 TI - The Drosophila platelet-derived growth factor and vascular endothelial growth factor-receptor related (Pvr) protein ligands Pvf2 and Pvf3 control hemocyte viability and invasive migration. AB - Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) family members are essential and evolutionary conserved determinants of blood cell development and dispersal. In addition, VEGFs are integral to vascular growth and permeability with detrimental contributions to ischemic diseases and metastatic cancers. The PDGF/VEGF-receptor related (Pvr) protein is implicated in the migration and trophic maintenance of macrophage-like hemocytes in Drosophila melanogaster embryos. pvr mutants have a depleted hemocyte population and a breakdown in hemocyte distribution. Previous studies suggested redundant functions for the Pvr ligands, Pvf2 and Pvf3 in the regulation of hemocyte migration, proliferation, and size. However, the precise roles that Pvf2 and Pvf3 play in hematopoiesis remain unclear due to the lack of available mutants. To determine Pvf2 and Pvf3 functions in vivo, we generated a genomic deletion that simultaneously disrupts Pvf2 and Pvf3. From our studies, we identified contributions of Pvf2 and Pvf3 to the Pvr trophic maintenance of hemocytes. Furthermore, we uncovered a novel role for Pvfs in invasive migrations. We showed that Pvf2 and Pvf3 are not required for the directed migration of hemocytes, but act locally in epithelial cells to coordinate trans-epithelial migration of hemocytes. Our findings redefine Pvf roles in hemocyte migration and highlight novel Pvf roles in hemocyte invasive migration. These new parallels between the Pvr and PDGF/VEGF pathways extend the utility of the Drosophila embryonic system to dissect physiological and pathological roles of PDGF/VEGF-like growth factors. PMID- 23737521 TI - Identification of a novel endoplasmic reticulum stress response element regulated by XBP1. AB - Understanding the regulatory mechanisms mediating PRNP gene expression is highly relevant to elucidating normal cellular prion protein (PrP) function(s) and the transmissibility of prion protein neurodegenerative diseases. Here, luciferase reporter assays showed that an endoplasmic reticulum stress element (ERSE)-like element, CCAAT-N26-CCACG in the human PRNP promoter, is regulated by ER stress and X-box-binding protein 1 (XBP1) but not by activating transcription factor 6 alpha (ATF6alpha). Bioinformatics identified the ERSE-26 motif in 37 other human genes in the absence of canonical ERSE sites except for three genes. Several of these genes are associated with a synaptic function or are involved in oxidative stress. Brefeldin A, tunicamycin, and thapsigargin ER stressors induced gene expression of PRNP and four randomly chosen ERSE-26-containing genes, ERLEC1, GADD45B, SESN2, and SLC38A5, in primary human neuron cultures or in the breast carcinoma MCF-7 cell line, although the level of the response depends on the gene analyzed, the genetic background of the cells, the cell type, and the ER stressor. Overexpression of XBP1 increased, whereas siRNA knockdown of XBP1 considerably reduced, PRNP and ERLEC1 mRNA levels in MCF-7 cells. Taken together, these results identify a novel ER stress regulator, which implicates the ER stress response in previously unrecognized cellular functions. PMID- 23737522 TI - Divergent sequence tunes ligand sensitivity in phospholipid-regulated hormone receptors. AB - The members of the NR5A subfamily of nuclear receptors (NRs) are important regulators of pluripotency, lipid and glucose homeostasis, and steroidogenesis. Liver receptor homologue 1 (LRH-1; NR5A2) and steroidogenic factor 1 (SF-1; NR5A1) have therapeutic potential for the treatment of metabolic and neoplastic disease; however, a poor understanding of their ligand regulation has hampered the pursuit of these proteins as pharmaceutical targets. In this study, we dissect how sequence variation among LRH-1 orthologs affects phospholipid (PL) binding and regulation. Both human LRH-1 (hLRH-1) and mouse LRH-1 (mLRH-1) respond to newly discovered medium chain PL agonists to modulate lipid and glucose homeostasis. These PLs activate hLRH-1 by altering receptor dynamics in a newly identified alternate activation function region. Mouse and Drosophila orthologs contain divergent sequences in this region potentially altering PL driven activation. Structural evidence suggests that these sequence differences in mLRH-1 and Drosophila FTZ-f1 (dmFTZ-f1) confer at least partial ligand independence, making them poor models for hLRH-1 studies; however, the mechanisms of ligand independence remain untested. We show using structural and biochemical methods that the recent evolutionary divergence of the mLRH-1 stabilizes the active conformation in the absence of ligand, yet does not abrogate PL-dependent activation. We also show by mass spectrometry and biochemical assays that FTZ-f1 is incapable of PL binding. This work provides a structural mechanism for the differential tuning of PL sensitivity in NR5A orthologs and supports the use of mice as viable therapeutic models for LRH-1-dependent diseases. PMID- 23737523 TI - The chlorite dismutase (HemQ) from Staphylococcus aureus has a redox-sensitive heme and is associated with the small colony variant phenotype. AB - The chlorite dismutases (C-family proteins) are a widespread family of heme binding proteins for which chemical and biological roles remain unclear. An association of the gene with heme biosynthesis in Gram-positive bacteria was previously demonstrated by experiments involving introduction of genes from two Gram-positive species into heme biosynthesis mutant strains of Escherichia coli, leading to the gene being renamed hemQ. To assess the gene product's biological role more directly, a Staphylococcus aureus strain with an inactivated hemQ gene was generated and shown to be a slow growing small colony variant under aerobic but not anaerobic conditions. The small colony variant phenotype is rescued by the addition of exogenous heme despite an otherwise wild type heme biosynthetic pathway. The DeltahemQ mutant accumulates coproporphyrin specifically under aerobic conditions. Although its sequence is highly similar to functional chlorite dismutases, the HemQ protein has no steady state reactivity with chlorite, very modest reactivity with H2O2 or peracetic acid, and no observable transient intermediates. HemQ's equilibrium affinity for heme is in the low micromolar range. Holo-HemQ reconstituted with heme exhibits heme lysis after <50 turnovers with peroxide and <10 turnovers with chlorite. The heme-free apoprotein aggregates or unfolds over time. IsdG-like proteins and antibiotic biosynthesis monooxygenases are close sequence and structural relatives of HemQ that use heme or porphyrin-like organic molecules as substrates. The genetic and biochemical data suggest a similar substrate role for heme or porphyrin, with possible sensor regulator functions for the protein. HemQ heme could serve as the means by which S. aureus reversibly adopts an SCV phenotype in response to redox stress. PMID- 23737524 TI - Roles of long-range electrostatic domain interactions and K+ in phosphoenzyme transition of Ca2+-ATPase. AB - Sarcoplasmic reticulum Ca(2+)-ATPase couples the motions and rearrangements of three cytoplasmic domains (A, P, and N) with Ca(2+) transport. We explored the role of electrostatic force in the domain dynamics in a rate-limiting phosphoenzyme (EP) transition by a systematic approach combining electrostatic screening with salts, computer analysis of electric fields in crystal structures, and mutations. Low KCl concentration activated and increasing salt above 0.1 m inhibited the EP transition. A plot of the logarithm of the transition rate versus the square of the mean activity coefficient of the protein gave a linear relationship allowing division of the activation energy into an electrostatic component and a non-electrostatic component in which the screenable electrostatic forces are shielded by salt. Results show that the structural change in the transition is sterically restricted, but that strong electrostatic forces, when K(+) is specifically bound at the P domain, come into play to accelerate the reaction. Electric field analysis revealed long-range electrostatic interactions between the N and P domains around their hinge. Mutations of the residues directly involved and other charged residues at the hinge disrupted in parallel the electric field and the structural transition. Favorable electrostatics evidently provides a low energy path for the critical N domain motion toward the P domain, overcoming steric restriction. The systematic approach employed here is, in general, a powerful tool for understanding the structural mechanisms of enzymes. PMID- 23737525 TI - Mammalian adenylyl cyclase-associated protein 1 (CAP1) regulates cofilin function, the actin cytoskeleton, and cell adhesion. AB - CAP (adenylyl cyclase-associated protein) was first identified in yeast as a protein that regulates both the actin cytoskeleton and the Ras/cAMP pathway. Although the role in Ras signaling does not extend beyond yeast, evidence supports that CAP regulates the actin cytoskeleton in all eukaryotes including mammals. In vitro actin polymerization assays show that both mammalian and yeast CAP homologues facilitate cofilin-driven actin filament turnover. We generated HeLa cells with stable CAP1 knockdown using RNA interference. Depletion of CAP1 led to larger cell size and remarkably developed lamellipodia as well as accumulation of filamentous actin (F-actin). Moreover, we found that CAP1 depletion also led to changes in cofilin phosphorylation and localization as well as activation of focal adhesion kinase (FAK) and enhanced cell spreading. CAP1 forms complexes with the adhesion molecules FAK and Talin, which likely underlie the cell adhesion phenotypes through inside-out activation of integrin signaling. CAP1-depleted HeLa cells also had substantially elevated cell motility as well as invasion through Matrigel. In summary, in addition to generating in vitro and in vivo evidence further establishing the role of mammalian CAP1 in actin dynamics, we identified a novel cellular function for CAP1 in regulating cell adhesion. PMID- 23737526 TI - Streptococcus pneumoniae serotype 11D has a bispecific glycosyltransferase and expresses two different capsular polysaccharide repeating units. AB - Streptococcus pneumoniae (pneumococcus) expresses a capsular polysaccharide (CPS) that protects against host immunity and is synthesized by enzymes in the capsular polysaccharide synthesis (cps) locus. Serogroup 11 has six members (11A to -E) and the CPS structure of all members has been solved, except for serotype 11D. The cps loci of 11A and 11D differ by one codon (N112S) in wcrL, which putatively encodes a glycosyltransferase that adds the fourth sugar of the CPS repeating unit (RU). Gas chromatography and nuclear magnetic resonance analysis revealed that 11A and 11D PSs contain identical CPS RUs that contain alphaGlc as the fourth sugar. However, ~25% of 11D CPS RUs contain instead alphaGlcNAc as the fourth sugar, suggesting that 11D wcrL encodes a bispecific glycosyltransferase. To test the hypothesis that codon 112 of WcrL determines enzyme specificity, and therefore the fourth sugar in the RU, we generated three isogenic pneumococcal strains with 11A cps loci containing wcrL encoding Ser-112 (MBO128) or Ala-112 (MBO130). MBO128 was serologically and biochemically identical to serotype 11D. MBO130 has a unique serologic profile; has as much alphaGlcNAc as 11F, 11B, and 11C CPS do; and may represent a new serotype. These findings demonstrate how pneumococci alter their CPS structure and their immunologic properties with a minimal genetic change. PMID- 23737527 TI - Transforming growth factor-beta induces transcription factors MafK and Bach1 to suppress expression of the heme oxygenase-1 gene. AB - Transforming growth factor-beta (TGF-beta) has multiple functions in embryogenesis, adult homeostasis, tissue repair, and development of cancer. Here, we report that TGF-beta suppresses the transcriptional activation of the heme oxygenase-1 (HO-1) gene, which is implicated in protection against oxidative injury and lung carcinogenesis. HO-1 is a target of the oxidative stress responsive transcription factor Nrf2. TGF-beta did not affect the stabilization or nuclear accumulation of Nrf2 after stimulation with electrophiles. Instead, TGF-beta induced expression of transcription factors MafK and Bach1. Enhanced expression of either MafK or Bach1 was enough to suppress the electrophile inducible expression of HO-1 even in the presence of accumulated Nrf2 in the nucleus. Knockdown of MafK and Bach1 by siRNA abolished TGF-beta-dependent suppression of HO-1. Furthermore, chromatin immunoprecipitation assays revealed that Nrf2 substitutes for Bach1 at the antioxidant response elements (E1 and E2), which are responsible for the induction of HO-1 in response to oxidative stress. On the other hand, pretreatment with TGF-beta suppressed binding of Nrf2 to both E1 and E2 but marginally increased the binding of MafK to E2 together with Smads. As TGF-beta is activated after tissue injury and in the process of cancer development, these findings suggest a novel mechanism by which damaged tissue becomes vulnerable to oxidative stress and xenobiotics. PMID- 23737528 TI - The NAD+ synthesis enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT1) regulates ribosomal RNA transcription. AB - The chromosomal region encoding the nuclear NAD(+) synthesis enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT1) is frequently deleted in human cancer. We describe evidence that NMNAT1 interacts with the nucleolar repressor protein nucleomethylin and is involved in regulating rRNA transcription. NMNAT1 binds to nucleomethylin and is recruited into a ternary complex containing the NAD(+)-dependent deacetylase SirT1. NMNAT1 expression stimulates the deacetylase function of SirT1. Knockdown of NMNAT1 enhances rRNA transcription and promotes cell death after nutrient deprivation. Furthermore, NMNAT1 expression is induced by DNA damage and plays a role in preventing cell death after damage. Heterozygous deletion of NMNAT1 in lung tumor cell lines correlates with low expression level and increased sensitivity to DNA damage. These results suggest that NMNAT1 deletion in tumors may contribute to transformation by increasing rRNA synthesis, but may also increase sensitivity to nutrient stress and DNA damage. PMID- 23737529 TI - An uncharacterized member of the ribokinase family in Thermococcus kodakarensis exhibits myo-inositol kinase activity. AB - Here we performed structural and biochemical analyses on the TK2285 gene product, an uncharacterized protein annotated as a member of the ribokinase family, from the hyperthermophilic archaeon Thermococcus kodakarensis. The three-dimensional structure of the TK2285 protein resembled those of previously characterized members of the ribokinase family including ribokinase, adenosine kinase, and phosphofructokinase. Conserved residues characteristic of this protein family were located in a cleft of the TK2285 protein as in other members whose structures have been determined. We thus examined the kinase activity of the TK2285 protein toward various sugars recognized by well characterized ribokinase family members. Although activity with sugar phosphates and nucleosides was not detected, kinase activity was observed toward d-allose, d-lyxose, d-tagatose, d talose, d-xylose, and d-xylulose. Kinetic analyses with the six sugar substrates revealed high Km values, suggesting that they were not the true physiological substrates. By examining activity toward amino sugars, sugar alcohols, and disaccharides, we found that the TK2285 protein exhibited prominent kinase activity toward myo-inositol. Kinetic analyses with myo-inositol revealed a greater kcat and much lower Km value than those obtained with the monosaccharides, resulting in over a 2,000-fold increase in kcat/Km values. TK2285 homologs are distributed among members of Thermococcales, and in most species, the gene is positioned close to a myo-inositol monophosphate synthase gene. Our results suggest the presence of a novel subfamily of the ribokinase family whose members are present in Archaea and recognize myo-inositol as a substrate. PMID- 23737530 TI - Nuclear factor of activated T cells c1 mediates p21-activated kinase 1 activation in the modulation of chemokine-induced human aortic smooth muscle cell F-actin stress fiber formation, migration, and proliferation and injury-induced vascular wall remodeling. AB - Recent literature suggests that cyclin-dependent kinases (CDKs) mediate cell migration. However, the mechanisms were not known. Therefore, the objective of this study is to test whether cyclin/CDKs activate Pak1, an effector of Rac1, whose involvement in the modulation of cell migration and proliferation is well established. Monocyte chemotactic protein 1 (MCP1) induced Pak1 phosphorylation/activation in human aortic smooth muscle cells (HASMCs) in a delayed time-dependent manner. MCP1 also stimulated F-actin stress fiber formation in a delayed manner in HASMCs, as well as the migration and proliferation of these cells. Inhibition of Pak1 suppressed MCP1-induced HASMC F actin stress fiber formation, migration, and proliferation. MCP1 induced cyclin D1 expression as well as CDK6 and CDK4 activities, and these effects were dependent on activation of NFATc1. Depletion of NFATc1, cyclin D1, CDK6, or CDK4 levels attenuated MCP1-induced Pak1 phosphorylation/activation and resulted in decreased HASMC F-actin stress fiber formation, migration, and proliferation. CDK4, which appeared to be activated downstream of CDK6, formed a complex with Pak1 in response to MCP1. MCP1 also activated Rac1 in a time-dependent manner, and depletion/inhibition of its levels/activation abrogated MCP1-induced NFATc1 cyclin D1-CDK6-CDK4-Pak1 signaling and, thereby, decreased HASMC F-actin stress fiber formation, migration, and proliferation. In addition, smooth muscle specific deletion of NFATc1 led to decreased cyclin D1 expression and CDK6, CDK4, and Pak1 activities, resulting in reduced neointima formation in response to injury. Thus, these observations reveal that Pak1 is a downstream effector of CDK4 and Rac1-dependent, NFATc1-mediated cyclin D1 expression and CDK6 activity mediate this effect. In addition, smooth muscle-specific deletion of NFATc1 prevented the capacity of vascular smooth muscle cells for MCP-1-induced activation of the cyclin D1-CDK6-CDK4-Pak1 signaling axis, affecting their migration and proliferation in vitro and injury-induced neointima formation in vivo. PMID- 23737531 TI - Interaction of aryl hydrocarbon receptor-interacting protein-like 1 with the farnesyl moiety. AB - Aryl hydrocarbon receptor-interacting protein-like 1 (AIPL1) is a photoreceptor specific chaperone of the visual effector enzyme phosphodiesterase-6 (PDE6). AIPL1 has been shown to bind the farnesylated PDE6A subunit. Mutations in AIPL1 are thought to destabilize PDE6 and thereby cause Leber congenital amaurosis type 4 (LCA4), a severe form of childhood blindness. Here, we examined the solution structure of AIPL1 by small angle x-ray scattering. A structural model of AIPL1 with the best fit to the scattering data features two independent FK506-binding protein (FKBP)-like and tetratricopeptide repeat domains. Guided by the model, we tested the hypothesis that AIPL1 directly binds the farnesyl moiety. Our studies revealed high affinity binding of the farnesylated-Cys probe to the FKBP-like domain of AIPL1, thus uncovering a novel function of this domain. Mutational analysis of the potential farnesyl-binding sites on AIPL1 identified two critical residues, Cys-89 and Leu-147, located in close proximity in the structure model. The L147A mutation and the LCA-linked C89R mutation prevented the binding of the farnesyl-Cys probe to AIPL1. Furthermore, Cys-89 and Leu-147 flank the unique insert region of AIPL1, deletion of which also abolished the farnesyl interaction. Our results suggest that the binding of PDE6A farnesyl is essential to normal function of AIPL1 and its disruption is one of the mechanisms underlying LCA. PMID- 23737532 TI - Hsp110 is a bona fide chaperone using ATP to unfold stable misfolded polypeptides and reciprocally collaborate with Hsp70 to solubilize protein aggregates. AB - Structurally and sequence-wise, the Hsp110s belong to a subfamily of the Hsp70 chaperones. Like the classical Hsp70s, members of the Hsp110 subfamily can bind misfolding polypeptides and hydrolyze ATP. However, they apparently act as a mere subordinate nucleotide exchange factors, regulating the ability of Hsp70 to hydrolyze ATP and convert stable protein aggregates into native proteins. Using stably misfolded and aggregated polypeptides as substrates in optimized in vitro chaperone assays, we show that the human cytosolic Hsp110s (HSPH1 and HSPH2) are bona fide chaperones on their own that collaborate with Hsp40 (DNAJA1 and DNAJB1) to hydrolyze ATP and unfold and thus convert stable misfolded polypeptides into natively refolded proteins. Moreover, equimolar Hsp70 (HSPA1A) and Hsp110 (HSPH1) formed a powerful molecular machinery that optimally reactivated stable luciferase aggregates in an ATP- and DNAJA1-dependent manner, in a disaggregation mechanism whereby the two paralogous chaperones alternatively activate the release of bound unfolded polypeptide substrates from one another, leading to native protein refolding. PMID- 23737533 TI - Orm proteins integrate multiple signals to maintain sphingolipid homeostasis. AB - Sphingolipids are structural components of membranes, and sphingolipid metabolites serve as signaling molecules. The first and rate-limiting step in sphingolipid synthesis is catalyzed by serine palmitoyltransferase (SPT). The recently discovered SPT-associated proteins, Orm1 and Orm2, are critical regulators of sphingolipids. Orm protein phosphorylation mediating feedback regulation of SPT activity occurs in response to multiple sphingolipid intermediates, including long chain base and complex sphingolipids. Both branches of the TOR signaling network, TORC1 and TORC2, participate in regulating sphingolipid synthesis via Orm phosphorylation in response to sphingolipid intermediates as well as nutritional conditions. Moreover, sphingolipid synthesis is regulated in response to endoplasmic reticulum (ER) stress by activation of a calcium- and calcineurin-dependent pathway via transcriptional induction of ORM2. Conversely, the calcium- and calcineurin-dependent pathway signals ER stress response upon lipid dysregulation in the absence of the Orm proteins to restore ER homeostasis. PMID- 23737534 TI - Sex-specific transcriptional responses of the zebrafish (Danio rerio) brain selenoproteome to acute sodium selenite supplementation. AB - The potential benefits of selenium (Se) supplementation are currently under investigation for prevention of certain cancers and treatment of neurological disorders. However, little is known concerning the response of the brain to increased dietary Se under conditions of Se sufficiency, despite the majority of Se supplementation trials occurring in healthy, Se sufficient subjects. We evaluated the transcriptional response of Se-dependent genes, selenoproteins and the genes necessary for their synthesis (the selenoproteome), in the zebrafish (Danio rerio) brain to supplementation with nutritionally relevant levels of dietary Se (sodium selenite) during conditions of assumed Se sufficiency. We first used a microarray approach to analyze the response of the brain selenoproteome to dietary Se supplementation for 14 days and then assessed the immediacy and time-scale transcriptional response of the brain selenoproteome to 1, 7, and 14 days of Se supplementation by quantitative real-time PCR (qRT-PCR). The microarray approach did not indicate large-scale influences of Se on the brain transcriptome as a whole or the selenoproteome specifically; only one nonselenoproteome gene (si:ch73-44m9.2) was significantly differentially expressed. Our qRT-PCR results, however, indicate that increases of dietary Se cause small, but significant transcriptional changes within the brain selenoproteome, even after only 1 day of supplementation. These responses were dynamic over a short period of supplementation in a manner highly dependent on sex and the duration of Se supplementation. In nutritional intervention studies, it may be necessary to utilize methods such as qRT-PCR, which allow larger sample sizes, for detecting subtle transcriptional changes in the brain. PMID- 23737535 TI - Human coronary artery perivascular adipocytes overexpress genes responsible for regulating vascular morphology, inflammation, and hemostasis. AB - Inflammatory cross talk between perivascular adipose tissue and the blood vessel wall has been proposed to contribute to the pathogenesis of atherosclerosis. We previously reported that human perivascular (PV) adipocytes exhibit a proinflammatory phenotype and less adipogenic differentiation than do subcutaneous (SQ) adipocytes. To gain a global view of the genomic basis of biologic differences between PV and SQ adipocytes, we performed genome-wide expression analyses to identify differentially expressed genes between adipocytes derived from human SQ vs. PV adipose tissues. Although >90% of well-expressed genes were similarly regulated, we identified a signature of 307 differentially expressed genes that were highly enriched for functions associated with the regulation of angiogenesis, vascular morphology, inflammation, and blood clotting. Of the 156 PV upregulated genes, 59 associate with angiogenesis, vascular biology, or inflammation, noteworthy of which include TNFRSF11B (osteoprotegerin), PLAT, TGFB1, THBS2, HIF1A, GATA6, and SERPINE1. Of 166 PV downregulated genes, 21 associated with vascular biology and inflammation, including ANGPT1, ANGPTL1, and VEGFC. Consistent with the emergent hypothesis that PV adipocytes differentially regulate angiogenesis and inflammation, cell culture-derived adipocyte-conditioned media from PV adipocytes strongly enhanced endothelial cell tubulogenesis and monocyte migration compared with media from SQ adipocytes. These findings demonstrate that PV adipocytes have the potential to significantly modulate vascular inflammatory crosstalk in the setting of atherosclerosis by their ability to signal to both endothelial and inflammatory cells. PMID- 23737536 TI - Image noise reduction algorithm for digital subtraction angiography: clinical results. AB - PURPOSE: To test the hypothesis that an image noise reduction algorithm designed for digital subtraction angiography (DSA) in interventional neuroradiology enables a reduction in the patient entrance dose by a factor of 4 while maintaining image quality. MATERIALS AND METHODS: This clinical prospective study was approved by the local ethics committee, and all 20 adult patients provided informed consent. DSA was performed with the default reference DSA program, a quarter-dose DSA program with modified acquisition parameters (to reduce patient radiation dose exposure), and a real-time noise-reduction algorithm. Two consecutive biplane DSA data sets were acquired in each patient. The dose-area product (DAP) was calculated for each image and compared. A randomized, blinded, offline reading study was conducted to show noninferiority of the quarter-dose image sets. Overall, 40 samples per treatment group were necessary to acquire 80% power, which was calculated by using a one-sided alpha level of 2.5%. RESULTS: The mean DAP with the quarter-dose program was 25.3% +/- 0.8 of that with the reference program. The median overall image quality scores with the reference program were 9, 13, and 12 for readers 1, 2, and 3, respectively. These scores increased slightly to 12, 15, and 12, respectively, with the quarter-dose program imaging chain. CONCLUSION: In DSA, a change in technique factors combined with a real-time noise-reduction algorithm will reduce the patient entrance dose by 75%, without a loss of image quality. PMID- 23737537 TI - Pulmonary nodules in patients with primary malignancy: comparison of hybrid PET/MR and PET/CT imaging. AB - PURPOSE: To assess diagnostic sensitivity of radial T1-weighted gradient-echo (radial volumetric interpolated breath-hold examination [VIBE]) magnetic resonance (MR) imaging, positron emission tomography (PET), and combined simultaneous PET and MR imaging with an integrated PET/MR system in the detection of lung nodules, with combined PET and computed tomography (CT) as a reference. MATERIALS AND METHODS: In this institutional review board-approved HIPAA compliant prospective study, 32 patients with tumors who underwent clinically warranted fluorine 18 ((18)F) fluorodeoxyglucose (FDG) PET/CT followed by PET/MR imaging were included. In all patients, the thorax station was examined with free breathing radial VIBE MR imaging and simultaneously acquired PET data. Presence and size of nodules and FDG avidity were assessed on PET/CT, radial VIBE, PET, and PET/MR images. Percentage of nodules detected on radial VIBE and PET images was compared with that on PET/MR images by using generalized estimating equations. Maximum standardized uptake value (SUVmax) in pulmonary nodules with a diameter of at least 1 cm was compared between PET/CT and PET/MR imaging with Pearson rank correlation. RESULTS: A total of 69 nodules, including 45 FDG-avid nodules, were detected with PET/CT. The sensitivity of PET/MR imaging was 70.3% for all nodules, 95.6% for FDG-avid nodules, and 88.6% for nodules 0.5 cm in diameter or larger. PET/MR imaging had higher sensitivity than PET for all nodules (70.3% vs 61.6%, P = .002) and higher sensitivity than MR imaging for FDG avid nodules (95.6% vs 80.0%, P = .008). There was a significantly strong correlation between SUVmax of pulmonary nodules obtained with PET/CT and that obtained with PET/MR imaging (r = 0.96, P < .001). CONCLUSION: Radial VIBE and PET data acquired simultaneously with PET/MR imaging have high sensitivity in the detection of FDG-avid nodules and nodules 0.5 cm in diameter or larger, with low sensitivity for small non-FDG-avid nodules. PMID- 23737538 TI - Markers of good performance in mammography depend on number of annual readings. AB - PURPOSE: To explore relationships between reader performance and reader characteristics in mammography for specific radiologist groupings on the basis of annual number of readings. MATERIALS AND METHODS: The institutional review board approved the study and waived the need for patient consent to use all images. Readers gave informed consent. One hundred sixteen radiologists independently reviewed 60 mammographic cases: 20 cases with cancer and 40 cases with normal findings. Readers located any visualized cancer, and levels of confidence were scored from 1 to 5. A jackknifing free response operating characteristic (JAFROC) method was used, and figures of merit along with sensitivity and specificity were correlated with reader characteristics by using Spearman techniques and standard multiple regressions. RESULTS: Reader performance was positively correlated with number of years since qualification as a radiologist (P <= .01), number of years reading mammograms (P <= .03), and number of readings per year (P <= .0001). The number of years since qualification as a radiologist (P <= .004) and number of years of reading mammograms (P <= .002) were negatively related to JAFROC values for radiologists with annual volumes of less than 1000 mammographic readings. For individuals with more than 5000 mammographic readings per year, JAFROC values were positively related to the number of years that the reader was qualified as a radiologist (P <= .01), number of years of reading mammograms (P <= .002), and number of hours per week of reading mammograms (P <= .003). Number of mammographic readings per year was positively related with JAFROC scores for readers with an annual volume between 1000 and 5000 readings (P <= .03). Differences in JAFROC scores appear to be more related to specificity than location sensitivity, with the former demonstrating significant relationships with four of the five characteristics analyzed, whereas no relationships were shown for the latter. CONCLUSION: Radiologists' determinants of performance are associated with annual reading volumes. Ability to recognize normal images is a discriminating factor in individuals with a high volume of mammographic readings. PMID- 23737539 TI - Frequency of atlantoaxial calcium pyrophosphate dihydrate deposition at CT. AB - PURPOSE: To determine (a) the prevalence of atlantoaxial calcium pyrophosphate dihydrate (CPPD) crystal deposition in a population of patients undergoing computed tomography (CT) for acute trauma and (b) the association between atlantoaxial CPPD crystal deposition and retro-odontoid soft-tissue thickness. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review board, and the requirement to obtain informed consent was waived. In 513 consecutive patients, CT scans of the cervical spine obtained for acute trauma were retrospectively reviewed for the presence of atlantoaxial CPPD crystal deposition, and the maximal thickness of the retro-odontoid soft tissues was measured. The relationships among imaging findings, age, and sex were assessed with the t test, the chi(2) test, Spearman correlation, and logistic and linear regression models as appropriate. RESULTS: The overall prevalence of atlantoaxial CPPD crystal deposition was 12.5% (64 of 513 patients), and prevalence increased with age (P < .0001, logistic regression coefficient). In patients aged 60 years and older, the prevalence of CPPD crystal deposition was 34% (58 of 170 patients). In patients aged 80 years and older, the prevalence of CPPD crystal deposition was 49% (37 of 75 patients). There was a positive correlation between age and retro-odontoid soft-tissue thickness (Spearman rho = 0.48, P < .0001). The mean retro-odontoid soft-tissue thickness in patients with CPPD crystal deposition was greater than that in patients without CPPD crystal deposition (3.4 mm vs 2.2 mm, respectively; P < .0001, t test). CONCLUSION: CPPD crystal deposition in the cervical spine is seen with a higher prevalence than previously reported. CPPD crystal deposition shows a positive correlation with age and retro-odontoid soft-tissue thickening. PMID- 23737540 TI - Relevance of spinal cord abnormalities to clinical disability in multiple sclerosis: MR imaging findings in a large cohort of patients. AB - PURPOSE: To determine whether spinal cord atrophy differs among disease subtypes in multiple sclerosis (MS) and whether it offers diagnostic and clinical correlative information beyond that provided by other magnetic resonance (MR) imaging markers. MATERIALS AND METHODS: The institutional review board approved the study; all subjects gave written informed consent. Upper cervical cord cross sectional area (UCCA), brain and spinal cord lesion loads, and brain atrophy were measured in 440 patients with MS (311 with relapsing-remitting [RR] MS, 92 with secondary-progressive [SP] MS, and 37 with primary-progressive [PP] MS) studied in two centers. Disability was scored with the Expanded Disability Status Scale (EDSS), the timed 25-foot walk test (TWT), and the nine-hole peg test. UCCA was compared between groups with the Mann-Whitney U test. Correlations were assessed with the Spearman rho test. Multivariate associations between UCCA and clinical and other MR imaging parameters, including number of hypointense brain lesions on T1-weighted MR images, presence of diffuse abnormalities, and number of involved segments in the spinal cord, were assessed by using multiple linear regression, adjusted for study center site. RESULTS: The UCCA in patients with SP MS (median, 79 mm(2); interquartile range, 72.4-84.9 mm(2)) and PP MS (median, 77.3 mm(2); interquartile range, 69-82.5 mm(2)) was significantly smaller (P < .001) than that in patients with RR MS (median, 84 mm(2); interquartile range, 78.7-89.3 mm(2)). UCCA was inversely correlated with EDSS score, TWT, and nine-hole peg test findings (rho <= -0.29, P < .001 for all comparisons). UCCA, number of hypointense brain lesions on T1-weighted MR images, presence of diffuse abnormalities, and number of involved segments in the spinal cord were found to be significant explanatory factors for clinical disability (R(2) = 0.564). The UCCA and the number of hypointense brain lesions on T1-weighted images were the strongest MR imaging parameters for explaining physical disability, as measured with the EDSS. CONCLUSION: Spinal cord abnormalities have a strong effect on clinical disability in MS. MR imaging-derived UCCA was found to be the most significant spinal cord parameter for explaining EDSS score. PMID- 23737541 TI - A standardized assessment of thyroid nodules in children confirms higher cancer prevalence than in adults. AB - CONTEXT: Thyroid cancer is the most common endocrine malignancy, but due to its rare occurrence in the pediatric population, the cancer risk of childhood thyroid nodules is incompletely defined, and optimal management of children with suspected nodules is debated. OBJECTIVE: The aim was to study the presenting features and cancer risk of sporadic childhood thyroid nodules using a standardized clinical assessment and management plan. DESIGN AND SETTING: Boston Children's Hospital and Brigham and Women's Hospital collaborated to create a multidisciplinary pediatric thyroid nodule clinic and implement a standardized assessment plan. Upon referral for a suspected nodule, serum TSH was measured and hypothyrotropinemic patients underwent (123)I scintigraphy. All others underwent thyroid ultrasonography, and if this confirmed nodule(s) >= 1 cm, ultrasound guided fine-needle aspiration was performed. Medical records were retrospectively reviewed and compared to a control population of 2582 adults evaluated by identical methods. PATIENTS AND RESULTS: Of 300 consecutive children referred for the initial evaluation of suspected thyroid nodules from 1997 to 2011, 17 were diagnosed with autonomous nodules by scintigraphy. Neck ultrasonography performed in the remainder revealed that biopsy was unnecessary in over half, either by documenting only sub-centimeter nodules or showing that no nodule was present. A total of 125 children met criteria for thyroid biopsy, which was performed without complication. Their rate of cancer was 22%, significantly higher than the adult rate of 14% (P = .02). CONCLUSIONS: Neck ultrasonography and biopsy were key to the evaluation of children with suspected thyroid nodules. Although the relative cancer prevalence of sonographically confirmed nodules >= 1 cm is higher in pediatric patients than adults, most children referred for suspected nodules have benign conditions, and efforts to avoid unnecessary surgery in this majority are warranted. PMID- 23737542 TI - Subclinical hypothyroidism and indices for metabolic syndrome in Japanese women: one-year follow-up study. AB - CONTEXT: Subclinical hypothyroidism (SCH) and metabolic syndrome (MetS) increase with age; however, their relationship remains unclear. OBJECTIVE: Our objective was to investigate the relationship between SCH and indices of metabolic syndrome and follow up subjects for 1 year. DESIGN: Cross-sectional and longitudinal follow-up studies of cases were collected from Takasaki Hidaka Hospital between 2003 and 2007. PARTICIPANTS: Overall, 11 498 participants of health checkups were analyzed. The mean age was 48 +/- 9 years. MAIN OUTCOME MEASURES: The relationship between SCH and indices of MetS were examined. RESULTS: Serum free T4 levels were lower in women than men in most of the age groups, and the prevalence of SCH, 6.3% in women vs 3.4% in men, increased with age, reaching 14.6% in 70-year-old women. Multivariate logistic-regression analyses revealed that waist circumference and the serum triglyceride and low-density lipoprotein cholesterol levels were significantly higher in subjects with SCH than without among women. Reflecting these findings, the adjusted odds ratio of MetS in patients with SCH was higher than in the euthyroid subjects in women with an odds ratio of 2.7 (95% confidence interval 1.1-5.6; P = .017) but not in men. Furthermore, progression from euthyroid into SCH resulted in a significant increase in the serum triglyceride levels but not low-density lipoprotein cholesterol in women. CONCLUSION: Japanese women exhibited a high prevalence of SCH associated with low free T4 levels. There was a strong association between SCH and several indices of metabolic syndrome in women. SCH may affect serum triglyceride levels and be a risk factor for metabolic syndrome. PMID- 23737543 TI - Endoscopic vs microsurgical transsphenoidal surgery for acromegaly: outcomes in a concurrent series of patients using modern criteria for remission. AB - CONTEXT: It is unclear whether endoscopic transsphenoidal surgery (ETSS) or microsurgical transsphenoidal surgery (MTS) is a superior surgical approach for pituitary adenomas. OBJECTIVE: The objective of the study was to compare the outcome of surgery with ETSS and MTS by experienced pituitary surgeons using criteria of remission using current consensus criteria for acromegaly. DESIGN AND SETTING: This was a retrospective review of prospectively recorded outcomes. The study was conducted at a tertiary referral center. Patients, Interventions, and Outcome Measures: Remission was defined as a normal IGF-I level and either suppressed GH less than 0.4 ng/mL during an oral glucose tolerance test or random GH less than 1.0 ng/mL. The Youden indices were calculated to determine the optimal cutoffs for using immediate postoperative GH levels to predict the results of later testing for remission. RESULTS: Preoperative demographics and tumor characteristics were not significantly different between patients undergoing ETSS (72 patients) or MTS (41 patients). Overall, postoperative remission was achieved in 20 of 23 microadenomas (87%) and 59 of 90 macroadenomas (66%). Remission rates and perioperative complications were not significantly different between ETSS and MTS groups, except for self-reported sinusitis and alterations in taste or smell, which were significantly higher in patients treated with ETSS. Preoperative variables predicting remission in multivariate analysis included GH less than 45 ng/mL [odds ratio (OR) 6.4, P = .010)] and Knosp score of 0-2 (OR 6.8, P < .001). Postoperative in-hospital GH less than 1.15 ng/mL provided the best predictor of remission (OR 7.7, P < .001; sensitivity of 73%, specificity of 85%) defined by follow-up testing. CONCLUSIONS: Outcomes of transsphenoidal surgery for acromegaly by experienced pituitary surgeons do not differ between endoscopic and microscopic techniques. Regardless of the mode of resection, patients with high preoperative GH levels and Knosp scores are less likely to achieve remission. An immediate postoperative GH level of less than 1.15 ng/mL provides the best immediate predictor of remission, but long-term outcomes are indicated. PMID- 23737544 TI - The relationship between informal caregiving and mortality: an analysis using the ONS Longitudinal Study of England and Wales. AB - BACKGROUND: Many studies have suggested that caregiving has a detrimental impact on health. However, these conclusions are challenged by research which finds evidence of a comparative survivorship advantage, as well as work which controls for group differences in the demand for care. METHODS: We use a large record linkage study of England and Wales to investigate the mortality risks of carers identified in the 2001 Census. The analysis focuses on individuals aged 35-74 living with others in private households and a distinction is made between those providing 1-19 and 20 or more hours of care per week. Logit models identify differences in carers' health at baseline and postcensal survival is analysed using Cox proportional hazards models. RESULTS: 12.2% of study members reported providing 1-19 h of care and 5.4% reported providing 20 or more hours. While carers were significantly more likely to report poorer health at baseline, survival analyses suggested that they were at a significantly lower risk of dying. This comparative advantage also held when the analyses were restricted to individuals living with at least one person with poor health. CONCLUSIONS: The comparative mortality advantage revealed in this analysis challenges common characterisations of carers' health and draws attention to important differences in the way carers are defined in existing analyses. The survival results are consistent with work using similar data for Northern Ireland. However, the study also affords more uniform conclusions about carers' baseline health and this provides grounds for questioning existing hypotheses about the reasons for this advantage. PMID- 23737545 TI - Effects of smoking, depression, and anxiety on mortality in COPD patients: a prospective study. AB - BACKGROUND: Smoking, depression, and anxiety increase the risk of death in patients with COPD, but the combined effect of these factors is unknown. We assessed the interactive effects of smoking, depression, and anxiety on mortality in patients with COPD. METHODS: We collected and analyzed data from 7,787 subjects with COPD, in 14 rural communities, from May 2008 to May 2012, and used logistic regression to evaluate the interactions and relative excess risk due to interaction (RERI). We applied the attributable proportion of interaction and the synergy index to evaluate the additive interactions of the factors. RESULTS: In our COPD subjects the interaction of current smoking and depression symptoms increased the death risk by 3.8-fold (odds ratio 3.78, 95% CI 2.51-5.05), with significant biological interactions (RERI 1.74, 95% CI 0.51-2.99, attributable proportion 0.48, 95% CI 0.13-0.85, synergy index 2.98, 95% CI 1.44-4.56). The biological interactions increased with increasing years or pack-years of smoking: for subjects with >= 30 years of smoking: RERI 1.80, 95% CI 1.05-2.75, attributable proportion 0.48, 95% CI 0.15-0.82, synergy index 2.85, 95% CI 1.75 3.96; for subjects with >= 40 pack-years of smoking: RERI 3.11, 95% CI 1.54-4.71, attributable proportion 0.60, 95% CI 0.31-0.91, synergy index 4.00, 95% CI 2.84 5.26. Similarly, the combined effect of current smoking and anxiety symptoms increased the death risk by 4.3-fold (odds ratio 4.27, 95% CI 95% CI 2.96-5.59), with significant biological interactions (RERI 1.51, 95% CI 0.31-2.74, attributable proportion 0.46, 95% CI 0.11-0.87, synergy index 2.89, 95% CI 1.31 4.51). The biological interactions also increased with increasing years or pack years of smoking: for subjects with >= 30 years of smoking: RERI 1.41, 95% CI 0.45-2.43, attributable proportion 0.45, 95% CI 0.12-0.81, synergy index 2.88, 95% CI 1.24-5.98; for subjects with >= 40 pack-years of smoking: RERI 3.15, 95% CI 2.07-4.61, attributable proportion 0.55, 95% CI 0.21-0.94, synergy index 3.00, 95% CI 1.45-4.75. CONCLUSIONS: Smoking, depression, and anxiety are associated with higher risk of death in patients with COPD. The risk of death, depression, and anxiety increases with increasing duration of smoking (years) and cigarette pack-years. Chinese Clinical Trials Registration ChiCTR-TRC-12001958. PMID- 23737546 TI - Noninvasive ventilation for acute hypercapnic respiratory failure: intubation rate in an experienced unit. AB - BACKGROUND: Failure of noninvasive ventilation (NIV) is common in patients with COPD admitted to the ICU for acute hypercapnic respiratory failure (AHRF). We aimed to assess the rate of NIV failure and to identify early predictors of intubation under NIV in patients admitted for AHRF of all origins in an experienced unit. METHODS: This was an observational cohort study using data prospectively collected over a 3-year period after the implementation of a nurse driven NIV protocol in a 24-bed medical ICU of a French university hospital. RESULTS: Among 242 subjects receiving NIV for AHRF (P(aCO2) > 45 mm Hg), 67 had cardiogenic pulmonary edema (CPE), 146 had acute-on-chronic respiratory failure (AOCRF) (including 99 subjects with COPD and 47 with other chronic respiratory diseases), and 29 had non-AOCRF (mostly pneumonia). Overall, the rates of intubation and ICU mortality were respectively 15% and 5%. The intubation rates were 4% in CPE, 15% in AOCRF, and 38% in non-AOCRF (P < .001). After adjustment, non-AOCRF was independently associated with NIV failure, as well as acidosis (pH < 7.30) and severe hypoxemia (P(aO2)/F(IO2) <= 200 mm Hg) after 1 hour of NIV initiation, whereas altered consciousness on admission and ventilatory settings had no influence on outcome. CONCLUSIONS: With a nurse-driven NIV protocol, the intubation rate was reduced to 15% in patients receiving NIV for AHRF, with a mortality rate of only 5%. Whereas the risk of NIV failure is associated with hypoxemia and acidosis after initiation of NIV, it is also markedly influenced by the presence or absence of an underlying chronic respiratory disease. PMID- 23737547 TI - Impact of bronchodilator responsiveness on quality of life and exercise capacity in patients with COPD. AB - BACKGROUND: Bronchial variability in COPD patients may be a phenotypic feature associated with clinical characteristics and differential treatment response. We analyzed whether symptoms, quality of life, and exercise capacity varied in COPD patients as a function of bronchodilator test results, and compared responses to an exercise program. METHODS: A positive bronchodilator test result was defined as FVC and/or FEV1 improvement of > 12% plus > 200 mL after 400 MUg of salbutamol. We studied 198 COPD subjects: 94 with positive reversibility, and 104 with negative reversibility. Training sessions were carried out on 3 non consecutive days each week, for 12 weeks, and consisted of a combination of resistance and strength training. Subjects were evaluated on 2 consecutive days at baseline, and at the end of the 12-week training program. RESULTS: Those with positive reversibility had shorter time to exhaustion in the endurance test (19.1 +/- 12.6 min vs 24.5 +/- 14.5 min, P = .03), shorter shuttle walk test distance (380.6 +/- 158.2 m vs 438.5 +/- 149.1 m, P = .02), and lower Chronic Respiratory Disease Questionnaire scores (18.7 +/- 4.6 vs 19.8 +/- 4.3, P = .01). There were no significant differences in peak exercise, peripheral muscle strength, dyspnea, or improvement after exercise training. CONCLUSIONS: Compared to COPD subjects with negative reversibility, those with positive reversibility walked for shorter distances, and had shorter endurance times and worse quality of life, but the improvements after exercise training were similar. PMID- 23737548 TI - Effect of high-flow nasal cannula on thoraco-abdominal synchrony in adult critically ill patients. AB - BACKGROUND: High-flow nasal cannula (HFNC) creates positive oropharyngeal airway pressure and improves oxygenation. It remains unclear, however, whether HFNC improves thoraco-abdominal synchrony in patients with mild to moderate respiratory failure. Using respiratory inductive plethysmography, we investigated the effects of HFNC on thoraco-abdominal synchrony. METHODS: We studied 40 adult subjects requiring oxygen therapy in the ICU. Low-flow oxygen (up to 8 L/min) was administered via oronasal mask for 30 min, followed by HFNC at 30-50 L/min. Respiratory inductive plethysmography transducer bands were circumferentially placed: one around the rib cage, and one around the abdomen. We measured the movement of the rib-cage and abdomen, and used the sum signal to represent tidal volume (V(T)) during mask breathing, and at 30 min during HFNC. We calculated the ratio of maximum compartmental amplitude (MCA) to V(T), and the phase angle. We assessed arterial blood gas and vital signs at each period, and mouth status during HFNC. We used multiple regression analysis to identify factors associated with improvement in thoraco-abdominal synchrony. RESULTS: During HFNC, breathing frequency significantly decreased from 25 breaths/min (IQR 22-27 breaths/min) to 21 breaths/min (IQR 18-24 breaths/min) (P < .001), and MCA/VT (P < .001) and phase angle (P = .047) significantly improved. CONCLUSIONS: HFNC improved thoraco abdominal synchrony in adult subjects with mild to moderate respiratory failure. PMID- 23737550 TI - Acetylation of Ets-1 is the key to chromatin remodeling for miR-192 expression. AB - By regulating gene expression, microRNAs (miRNAs) play pivotal roles in physiological and pathological processes. However, the regulation of miRNAs is elusive. miR-192 is a key regulator of renal fibrosis and hypertrophy in diabetic nephropathy. Natarajan et al. showed that the miR-192 gene contains an upstream region with Ets-1 and Smad3 binding sites. In control cells, all Ets-1 sites were occupied, resulting in a locked chromatin structure that kept miR-192 expression low. In response to transforming growth factor-beta (TGF-beta) stimulation, Smad3 and Akt were activated, and the latter further activated p300 to induce partial acetylation and dissociation of Ets-1 and the recruitment of Smad3 to the miR-192 gene, inducing transient miR-192 expression. During prolonged TGF-beta treatment, p300 acetylated histone and Ets-1, resulting in complete dissociation of Ets-1 and the opening of the chromatin for sustained miR-192 expression. Thus, transcription factors and chromatin remodeling control microRNA gene expression in a dynamic, coordinated fashion. PMID- 23737549 TI - White matter microstructure in individuals at clinical high risk of psychosis: a whole-brain diffusion tensor imaging study. AB - BACKGROUND: The study of individuals at clinical high risk (CHR) for psychosis provides an important opportunity for unraveling pathological mechanisms underlying schizophrenia and related disorders. A small number of diffusion tensor magnetic resonance imaging (DTI) studies in CHR samples have yielded anatomically inconsistent results. The present study is the first to apply tract based spatial statistics (TBSS) to perform a whole-brain DTI analysis in CHR subjects. METHODS: A total of 28 individuals meeting CHR criteria and 34 healthy controls underwent DTI. TBSS was used for a group comparison of fractional anisotropy (FA), as well as axial, radial, and mean diffusivity (AD, RD, and MD). Conversion to psychosis was monitored during a mean follow-up period of 12.3 months. RESULTS: The rate of conversion to psychosis was relatively low (4%). TBSS revealed increased MD in several clusters in the right hemisphere, most notably in the superior longitudinal fasciculus (SLF), posterior corona radiata, and corpus callosum (splenium and body). Increased RD was restricted to a smaller area in the posterior parietal lobe. CONCLUSION: We present further evidence that white matter microstructure is abnormal in CHR individuals, even in a sample in which the vast majority do not transition to psychosis over the following year. In accord with previous studies on CHR individuals and patients with early-onset schizophrenia, our findings suggest an important pathological role for the parietal lobe and especially the SLF. The latter is known to undergo particularly dynamic microstructural changes during adolescence and early adulthood, a critical phase for the development of psychotic illness. PMID- 23737551 TI - TGF-beta induces acetylation of chromatin and of Ets-1 to alleviate repression of miR-192 in diabetic nephropathy. AB - MicroRNAs (miRNAs), such as miR-192, mediate the actions of transforming growth factor-beta1 (TGF-beta) related to the pathogenesis of diabetic kidney diseases. We found that the biphasic induction of miR-192 expression by TGF-beta in mouse renal glomerular mesangial cells initially involved the Smad transcription factors, followed by sustained expression that was promoted by acetylation of the transcription factor Ets-1 and of histone H3 by the acetyltransferase p300, which was activated by the serine and threonine kinase Akt. In mesangial cells from Ets 1-deficient mice or in cells in which Ets-1 was knocked down, basal amounts of miR-192 were higher than those in control cells, but sustained induction of miR 192 by TGF-beta was attenuated. Furthermore, inhibition of Akt or ectopic expression of dominant-negative histone acetyltransferases decreased p300 mediated acetylation and Ets-1 dissociation from the miR-192 promoter and prevented miR-192 expression in response to TGF-beta. Activation of Akt and p300 and acetylation of Ets-1 and histone H3 were increased in glomeruli from diabetic db/db mice compared to nondiabetic db/+ mice, suggesting that this pathway may contribute to diabetic nephropathy. These findings provide insight into the regulation of miRNAs through signaling-mediated changes in transcription factor activity and in epigenetic histone acetylation under normal and disease states. PMID- 23737553 TI - In vivo phosphoproteomics analysis reveals the cardiac targets of beta-adrenergic receptor signaling. AB - beta-Blockers are widely used to prevent cardiac arrhythmias and to treat hypertension by inhibiting beta-adrenergic receptors (betaARs) and thus decreasing contractility and heart rate. betaARs initiate phosphorylation dependent signaling cascades, but only a small number of the target proteins are known. We used quantitative in vivo phosphoproteomics to identify 670 site specific phosphorylation changes in murine hearts in response to acute treatment with specific betaAR agonists. The residues adjacent to the regulated phosphorylation sites exhibited a sequence-specific preference (R-X-X-pS/T), and integrative analysis of sequence motifs and interaction networks suggested that the kinases AMPK (adenosine 5'-monophosphate-activated protein kinase), Akt, and mTOR (mammalian target of rapamycin) mediate betaAR signaling, in addition to the well-established pathways mediated by PKA (cyclic adenosine monophosphate dependent protein kinase) and CaMKII (calcium/calmodulin-dependent protein kinase type II). We found specific regulation of phosphorylation sites on six ion channels and transporters that mediate increased ion fluxes at higher heart rates, and we showed that phosphorylation of one of these, Ser(92) of the potassium channel KV7.1, increased current amplitude. Our data set represents a quantitative analysis of phosphorylated proteins regulated in vivo upon stimulation of seven-transmembrane receptors, and our findings reveal previously unknown phosphorylation sites that regulate myocardial contractility, suggesting new potential targets for the treatment of heart disease and hypertension. PMID- 23737554 TI - Limits to sustained energy intake. XIX. A test of the heat dissipation limitation hypothesis in Mongolian gerbils (Meriones unguiculatus). AB - We evaluated factors limiting lactating Mongolian gerbils (Meriones unguiculatus) at three temperatures (10, 21 and 30 degrees C). Energy intake and daily energy expenditure (DEE) increased with decreased ambient temperature. At peak lactation (day 14 of lactation), energy intake increased from 148.7+/-5.7 kJ day(-1) at 30 degrees C to 213.1+/-8.2 kJ day(-1) at 21 degrees C and 248.7+/-12.3 kJ day(-1) at 10 degrees C. DEE increased from 105.1+/-4.0 kJ day(-1) at 30 degrees C to 134.7+/-5.6 kJ day(-1) at 21 degrees C and 179.5+/-8.4 kJ day(-1) at 10 degrees C on days 14-16 of lactation. With nearly identical mean litter sizes, lactating gerbils at 30 degrees C exported 32.0 kJ day(-1) less energy as milk at peak lactation than those allocated to 10 or 21 degrees C, with no difference between the latter groups. On day 14 of lactation, the litter masses at 10 and 30 degrees C were 12.2 and 9.3 g lower than those at 21 degrees C, respectively. Lactating gerbils had higher thermal conductance of the fur and lower UCP-1 levels in brown adipose tissue than non-reproductive gerbils, independent of ambient temperature, suggesting that they were attempting to avoid heat stress. Thermal conductance of the fur was positively related to circulating prolactin levels. We implanted non reproductive gerbils with mini-osmotic pumps that delivered either prolactin or saline. Prolactin did not influence thermal conductance of the fur, but did reduce physical activity and UCP-1 levels in brown adipose tissue. Transferring lactating gerbils from warm to hot conditions resulted in reduced milk production, consistent with the heat dissipation limit theory, but transferring them from warm to cold conditions did not elevate milk production, consistent with the peripheral limitation hypothesis, and placed constraints on pup growth. PMID- 23737552 TI - The deubiquitinase A20 mediates feedback inhibition of interleukin-17 receptor signaling. AB - The proinflammatory cytokine interleukin-17 (IL-17) is the signature cytokine of the T helper 17 (TH17) subset of CD4(+) T cells, and antibodies targeting IL-17 or the IL-17 receptor (IL-17R) show clinical efficacy in several autoimmune diseases. Although important for protective immunity against microorganisms, IL 17 causes collateral damage in inflammatory settings. TNFAIP3 encodes the deubiquitinase A20 and is genetically linked to numerous autoimmune syndromes. A20, a potent inhibitor of tumor necrosis factor-alpha signaling, removes ubiquitin from signaling intermediates upstream of nuclear factor kappaB (NF kappaB), thereby dampening NF-kappaB-mediated inflammation. We demonstrated that IL-17 stimulates TNFAIP3 expression. Enhanced IL-17-mediated induction of genes encoding proinflammatory factors, including IL-6 and various chemokines, occurred upon knockdown of A20 with short inhibitory RNA or in A20(-/-) cells. A20 associated with the E3 ubiquitin ligase TRAF6 (tumor necrosis factor receptor associated factor 6) in an IL-17-dependent manner and restricted the IL-17 dependent activation of NF-kappaB and mitogen-activated protein kinases. A20 interacted directly with the distal domain of IL-17RA, a previously defined inhibitory domain. Together, these data describe a mechanism of restraining IL-17 signaling and reveal an aspect of A20 activity that may help to explain its role in autoimmunity in humans. PMID- 23737555 TI - Specific response to herbivore-induced de novo synthesized plant volatiles provides reliable information for host plant selection in a moth. AB - Animals depend on reliable sensory information for accurate behavioural decisions. For herbivorous insects it is crucial to find host plants for feeding and reproduction, and these insects must be able to differentiate suitable from unsuitable plants. Volatiles are important cues for insect herbivores to assess host plant quality. It has previously been shown that female moths of the Egyptian cotton leafworm, Spodoptera littoralis (Lepidoptera: Noctuidae), avoid oviposition on damaged cotton Gossypium hirsutum, which may mediated by herbivore induced plant volatiles (HIPVs). Among the HIPVs, some volatiles are released following any type of damage while others are synthesized de novo and released by the plants only in response to herbivore damage. In behavioural experiments we here show that oviposition by S. littoralis on undamaged cotton plants was reduced by adding volatiles collected from plants with ongoing herbivory. Gas chromatography-electroantennographic detection (GC-EAD) recordings revealed that antennae of mated S. littoralis females responded to 18 compounds from a collection of headspace volatiles of damaged cotton plants. Among these compounds, a blend of the seven de novo synthesized volatile compounds was found to reduce oviposition in S. littoralis on undamaged plants under both laboratory and ambient (field) conditions in Egypt. Volatile compounds that are not produced de novo by the plants did not affect oviposition. Our results show that ovipositing females respond specifically to the de novo synthesized volatiles released from plants under herbivore attack. We suggest that these volatiles provide reliable cues for ovipositing females to detect plants that could provide reduced quality food for their offspring and an increased risk of competition and predation. PMID- 23737556 TI - The effect of flow speed and body size on Karman gait kinematics in rainbow trout. AB - We have little understanding of how fish hold station in unsteady flows. Here, we investigated the effect of flow speed and body size on the kinematics of rainbow trout Karman gaiting behind a 5 cm diameter cylinder. We established a set of criteria revealing that not all fish positioned in a vortex street are Karman gaiting. By far the highest probability of Karman gaiting occurred at intermediate flow speeds between 30 and 70 cm s(-1). We show that trout Karman gait in a region of the cylinder wake where the velocity deficit is about 40% of the nominal flow. We observed that the relationships between certain kinematic and flow variables are largely preserved across flow speeds. Tail-beat frequency matched the measured vortex shedding frequency, which increased linearly with flow speed. Body wave speed was about 25% faster than the nominal flow velocity. At speeds where fish have a high probability of Karman gaiting, body wavelength was about 25% longer than the cylinder wake wavelength. Likewise, the lateral (i.e. cross-stream) amplitude of the tail tip was about 50% greater than the expected lateral spacing of the cylinder vortices, while the body center amplitude was about 70% less. Lateral body center acceleration increased quadratically with speed. Head angle decreased with flow speed. While these values are different from those found in fish swimming in uniform flow, the strategy for locomotion is the same; fish adjust to increasing flow by increasing their tail-beat frequency. Body size also played a role in Karman gaiting kinematics. Tail-beat amplitudes of Karman gaiting increased with body size, as in freestream swimming, but were almost three times larger in magnitude. Larger fish had a shorter body wavelength and slower body wave speed than smaller fish, which is a surprising result compared with freestream swimming, where body wavelength and wave speed increased with size. In contrast to freestream swimming, tail-beat frequency for Karman gaiting fish did not depend on body size and was a function of the vortex shedding frequency. PMID- 23737557 TI - Precision of archerfish C-starts is fully temperature compensated. AB - Hunting archerfish precisely adapt their predictive C-starts to the initial movement of dislodged prey so that turn angle and initial speed are matched to the place and time of the later point of catch. The high accuracy and the known target point of the starts allow a sensitive straightforward assay of how temperature affects the underlying circuits. Furthermore, archerfish face rapid temperature fluctuations in their mangrove biotopes that could compromise performance. Here, we show that after a brief acclimation period the function of the C-starts was fully maintained over a range of operating temperatures: (i) full responsiveness was maintained at all temperatures, (ii) at all temperatures the fish selected accurate turns and were able to do so over the full angular range, (iii) at all temperatures speed attained immediately after the end of the C-start was matched - with equal accuracy - to 'virtual speed', i.e. the ratio of remaining distance to the future landing point and remaining time. While precision was fully temperature compensated, C-start latency was not and increased by about 4 ms per 1 degrees C cooling. Also, kinematic aspects of the C start were only partly temperature compensated. Above 26 degrees C, the duration of the two major phases of the C-start were temperature compensated. At lower temperatures, however, durations increased similar to latency. Given the accessibility of the underlying networks, the archerfish predictive start should be an excellent model to assay the degree of plasticity and functional stability of C-start motor patterns. PMID- 23737558 TI - Wind induces variations in spider web geometry and sticky spiral droplet volume. AB - Trap building by animals is rare because it comes at a substantial cost. Using materials with properties that vary across environments maintains trap functionality. The sticky spiral silks of spider orb webs are used to catch flying prey. Web geometry, accompanied by compensatory changes in silk properties, may change across environments to sustain web functionality. We exposed the spider Cyclosa mulmeinensis to wind to test whether wind-induced changes in web geometry are accompanied by changes in aggregate silk droplet morphology, axial thread width or spiral stickiness. We compared: (i) web catching area, (ii) length of total silks, (iii) mesh height, (iv) number of radii, (v) aggregate droplet morphology and (vi) spiral thread stickiness, between webs made by spiders exposed to wind and those made by spiders not exposed to wind. We interpreted co-variation in droplet morphology or spiral stickiness with web capture area, mesh height or spiral length as the silk properties functionally compensating for changes in web geometry to reduce wind drag. Wind-exposed C. mulmeinensis built webs with smaller capture areas, shorter capture spiral lengths and more widely spaced capture spirals, resulting in the expenditure of less silk. Individuals that were exposed to wind also deposited larger droplets of sticky silk but the stickiness of the spiral threads remained unchanged. The larger droplets may be a product of a greater investment in water, or low molecular weight compounds facilitating atmospheric water uptake. Either way, droplet dehydration in wind is likely to be minimized. PMID- 23737559 TI - The evolution of active vibrissal sensing in mammals: evidence from vibrissal musculature and function in the marsupial opossum Monodelphis domestica. AB - Facial vibrissae, or whiskers, are found in nearly all extant mammal species and are likely to have been present in early mammalian ancestors. A sub-set of modern mammals, including many rodents, move their long mystacial whiskers back and forth at high speed whilst exploring in a behaviour known as 'whisking'. It is not known whether the vibrissae of early mammals moved in this way. The grey short-tailed opossum, Monodelphis domestica, is considered a useful species from the perspective of tracing the evolution of modern mammals. Interestingly, these marsupials engage in whisking bouts similar to those seen in rodents. To better assess the likelihood that active vibrissal sensing was present in ancestral mammals, we examined the vibrissal musculature of the opossum using digital miscroscopy to see whether this resembles that of rodents. Although opossums have fewer whiskers than rats, our investigation found that they have a similar vibrissal musculature. In particular, in both rats and opossums, the musculature includes both intrinsic and extrinsic muscles with the intrinsic muscles positioned as slings linking pairs of large vibrissae within rows. We identified some differences in the extrinsic musculature which, interestingly, matched with behavioural data obtained through high-speed video recording, and indicated additional degrees of freedom for positioning the vibrissae in rats. These data show that the whisker movements of opossum and rat exploit similar underlying mechanisms. Paired with earlier results suggesting similar patterns of vibrissal movement, this strongly implies that early therian (marsupial and placental) mammals were whisking animals that actively controlled their vibrissae. PMID- 23737560 TI - Bilateral flight muscle activity predicts wing kinematics and 3-dimensional body orientation of locusts responding to looming objects. AB - We placed locusts in a wind tunnel using a loose tether design that allowed for motion in all three rotational degrees of freedom during presentation of a computer-generated looming disc. High-speed video allowed us to extract wing kinematics, abdomen position and 3-dimensional body orientation. Concurrent electromyographic (EMG) recordings monitored bilateral activity from the first basalar depressor muscles (m97) of the forewings, which are implicated in flight steering. Behavioural responses to a looming disc included cessation of flight (wings folded over the body), glides and active steering during sustained flight in addition to a decrease and increase in wingbeat frequency prior to and during, respectively, an evasive turn. Active steering involved shifts in bilateral m97 timing, wing asymmetries and whole-body rotations in the yaw (psi), pitch (chi) and roll (eta) planes. Changes in abdomen position and hindwing asymmetries occurred after turns were initiated. Forewing asymmetry and changes in eta were most highly correlated with m97 spike latency. Correlations also increased as the disc approached, peaking prior to collision. On the inside of a turn, m97 spikes occurred earlier relative to forewing stroke reversal and bilateral timing corresponded to forewing asymmetry as well as changes in whole-body rotation. Double spikes in each m97 occurred most frequently at or immediately prior to the time the locusts turned, suggesting a behavioural significance. These data provide information on mechanisms underlying 3-dimensional flight manoeuvres and will be used to drive a closed loop flight simulator to study responses of motion sensitive visual neurons during production of realistic behaviours. PMID- 23737561 TI - Effects of intraspecific variation in reproductive traits, pectoral fin use and burst swimming on metabolic rates and swimming performance in the Trinidadian guppy (Poecilia reticulata). AB - There is considerable intraspecific variation in metabolic rates and locomotor performance in aquatic ectothermic vertebrates; however, the mechanistic basis remains poorly understood. Using pregnant Trinidadian guppies (Poecilia reticulata), a live-bearing teleost, we examined the effects of reproductive traits, pectoral fin use and burst-assisted swimming on swimming metabolic rate, standard metabolic rate (O2std) and prolonged swimming performance (Ucrit). Reproductive traits included reproductive allocation and pregnancy stage, the former defined as the mass of the reproductive tissues divided by the total body mass. Results showed that the metabolic rate increased curvilinearly with swimming speed. The slope of the relationship was used as an index of swimming cost. There was no evidence that reproductive traits correlated with swimming cost, O2std or Ucrit. In contrast, data revealed strong effects of pectoral fin use on swimming cost and Ucrit. Poecilia reticulata employed body-caudal fin (BCF) swimming at all tested swimming speeds; however, fish with a high simultaneous use of the pectoral fins exhibited increased swimming cost and decreased Ucrit. These data indicated that combining BCF swimming and pectoral fin movement over a wide speed range, presumably to support swimming stability and control, is an inefficient swimming behaviour. Finally, transition to burst assisted swimming was associated with an increase in aerobic metabolic rate. Our study highlights factors other than swimming speed that affect swimming cost and suggests that intraspecific diversity in biomechanical performance, such as pectoral fin use, is an important source of variation in both locomotor cost and maximal performance. PMID- 23737562 TI - Hummingbird feather sounds are produced by aeroelastic flutter, not vortex induced vibration. AB - Males in the 'bee' hummingbird clade produce distinctive, species-specific sounds with fluttering tail feathers during courtship displays. Flutter may be the result of vortex shedding or aeroelastic interactions. We investigated the underlying mechanics of flutter and sound production of a series of different feathers in a wind tunnel. All feathers tested were capable of fluttering at frequencies varying from 0.3 to 10 kHz. At low airspeeds (Uair) feather flutter was highly damped, but at a threshold airspeed (U*) the feathers abruptly entered a limit-cycle vibration and produced sound. Loudness increased with airspeed in most but not all feathers. Reduced frequency of flutter varied by an order of magnitude, and declined with increasing Uair in all feathers. This, along with the presence of strong harmonics, multiple modes of flutter and several other non linear effects indicates that flutter is not simply a vortex-induced vibration, and that the accompanying sounds are not vortex whistles. Flutter is instead aeroelastic, in which structural (inertial/elastic) properties of the feather interact variably with aerodynamic forces, producing diverse acoustic results. PMID- 23737563 TI - Superficial neuromasts facilitate non-visual feeding by larval striped bass (Morone saxatilis). AB - To investigate whether mechanoreception is used in non-visual feeding in larval striped bass (Morone saxatilis), the ontogeny of superficial neuromasts along the lateral line was described using the vital stain FM1-43FX and fluorescent microscopy. The number of neuromasts visible along one flank increased from 11 at first feeding [5 to 7 days post-hatch (dph)] to >150 by the juvenile stage (27 dph). A neomycin dose response (0, 1, 2 and 5 mmol l(-1)) was evaluated for neuromast ablation of bass aged 10, 13, 17 and 20 dph. Using these same age groups, the ability of bass to catch Artemia salina prey in both dark and light tank-based feeding trials was compared between larvae with neuromasts ablated using neomycin (5 mmol l(-1)) and controls. Neomycin significantly reduced the incidence of feeding in the light and dark. Among larvae that fed, those in the dark treated with neomycin caught fewer Artemia (~5 prey h(-1); P<0.05) than controls (16 prey h(-1) at 10 dph; 72 prey h(-1) at 20 dph). In the light, by contrast, neomycin treatment had no significant effect on prey capture by larvae age 13 to 20 dph, but did inhibit feeding of 10 dph larvae. Verification that neomycin was specifically ablating the hair cells of superficial neuromasts and not affecting either neuromast innervation, olfactory pits, or taste cells was achieved by a combination of staining with FM1-43FX and immunocytochemistry for tubulin and the calcium binding proteins, S100 and calretinin. PMID- 23737564 TI - Long-day photoperiod interacts with vasopressin and food restriction to modulate reproductive status and vasopressin receptor expression of male golden spiny mice. AB - We tested the effects of photoperiod, water and food availability on body mass, reproductive status and arginine vasopressin receptor 1A (Avpr1a) mRNA expression in males of desert-adapted golden spiny mice, Acomys russatus. In Experiment 1, males were acclimated to short-day (SD; 8 h:16 h light:dark) or long-day (LD; 16 h:8 h light:dark) photoperiods with either saline (control) or vasopressin treatment for 3 weeks. The results of this experiment revealed that under control conditions, SD mice increased body mass by ~5% while LD mice decreased it by ~4%. SD photoperiod had no effect on reproductive status and leptin levels, whereas LD males increased testes mass and serum testosterone, but the photoperiod had no effect on leptin levels. Vasopressin administration decreased LD-induced reproductive enhancement. Because no consistent effect of SD treatment was found on reproductive status, Experiment 2 was carried out only on LD-acclimated males kept under 75% food restriction (decrease from ad libitum) with saline or leptin treatment. Body mass, testes mass, serum testosterone, leptin concentrations and Avpr1a mRNA expression were measured. Food restriction remarkably decreased body mass, with a more potent effect in leptin-treated males, showing enhanced reproductive status and a significant increase in serum leptin compared with controls. Avpr1a expression was significantly upregulated in LD, vasopressin treated and food-restricted males, with higher levels in the hypothalamus compared with the testes. We conclude that in A. russatus, LD photoperiod interacts with water and food availability to advance reproductive responses. Avpr1a is suggested to integrate nutritional and osmotic signals to optimize reproduction by modulating reproductive and energetic neuroendocrine axes at the central level. The interaction between photoperiod and other environmental cues is of an adaptive value to desert-adapted small rodents for timing reproduction in unpredictable ecosystems such as extreme deserts. PMID- 23737565 TI - Structural resonance and mode of flutter of hummingbird tail feathers. AB - Feathers can produce sound by fluttering in airflow. This flutter is hypothesized to be aeroelastic, arising from the coupling of aerodynamic forces to one or more of the feather's intrinsic structural resonance frequencies. We investigated how mode of flutter varied among a sample of hummingbird tail feathers tested in a wind tunnel. Feather vibration was measured directly at ~100 points across the surface of the feather with a scanning laser Doppler vibrometer (SLDV), as a function of airspeed, Uair. Most feathers exhibited multiple discrete modes of flutter, which we classified into types including tip, trailing vane and torsional modes. Vibratory behavior within a given mode was usually stable, but changes in independent variables such as airspeed or orientation sometimes caused feathers to abruptly 'jump' from one mode to another. We measured structural resonance frequencies and mode shapes directly by measuring the free response of 64 feathers stimulated with a shaker and recorded with the SLDV. As predicted by the aeroelastic flutter hypothesis, the mode shape (spatial distribution) of flutter corresponded to a bending or torsional structural resonance frequency of the feather. However, the match between structural resonance mode and flutter mode was better for tip or torsional mode shapes, and poorer for trailing vane modes. Often, the 3rd bending structural harmonic matched the expressed mode of flutter, rather than the fundamental. We conclude that flutter occurs when airflow excites one or more structural resonance frequencies of a feather, most akin to a vibrating violin string. PMID- 23737566 TI - Agitation after minor trauma: combativeness as a cardinal catatonic feature. AB - Catatonia is a syndrome of motor dysregulation, usually associated with psychiatric, neurological, systemic and drug-related diseases. Retarded and excited types exist, both of which often go unrecognised in clinical practice. We describe a 64-year-old woman who gradually developed insomnia, started communicating less, complained of feeling restless and ended up injuring relatives. Initiation of symptoms followed a fibula fracture. The patient was diagnosed with excited-type catatonia with prominent combativeness because of minor trauma and rapidly recovered after lorazepam treatment instatement. Our case demonstrates that catatonia can follow minor traumatic injury and how excited-type catatonic features may go unrecognised in general practitioner and specialist settings. Moreover, we show that catatonia may be recurrent, necessitating long-term treatment and very gradual lorazepam tapering. PMID- 23737567 TI - Cardiogenic shock in a neonate. AB - We describe a case of a healthy male full-term neonate, 21 days old, admitted to the emergency room, presenting a severe cardiovascular collapse with an initial sinus rhythm. The first diagnostic hypothesis was of septic shock, having antibiotics, fluid resuscitation, inotropic drugs and ventilatory support started immediately. After achieving haemodynamic stability, a new cardiovascular collapse occurred with supraventricular tachycardia (SVT). The latter was successfully treated and the neonate did not suffer any organ damage. Cardiogenic shock should be considered despite being a much rarer cause of shock in neonates. SVT is promptly diagnosed when a cardiorespiratory monitor is available; however, the intermittent occurrence of the tachycardia episodes makes this diagnosis more difficult to recognise and manage. PMID- 23737568 TI - Successfully treated bilateral renal artery stenosis in a patient with coronary artery disease. AB - Renal artery stenosis (RAS) is the most common cause of secondary hypertension and accounts for approximately 1-3% of all causes of hypertension. Over 90% of RASs are caused by atherosclerosis; atherosclerotic RAS is increasingly common in aging populations, particularly elderly people with diabetes, hyperlipidaemia, aortoiliac occlusive disease, coronary artery disease or hypertension. Three therapeutic options are currently available for patients with renovascular hypertension: medical antihypertensive therapy, surgical revascularisation and transluminal angioplasty including stent implantation. We present in this report a male patient with bilateral severe ostial stenosis and coronary artery disease, and who was successfully treated with renal stent implantation in one session. PMID- 23737569 TI - Use of the AngioJet percutaneous thrombectomy system for the treatment of acute Budd-Chiari syndrome. AB - A 31-year-old woman presented to our emergency department with an acute liver injury secondary to acute Budd-Chiari (BC) syndrome from hepatic vein thrombosis. After a thorough discussion of the risks involved, we proceeded to treatment with a novel approach, performing a mechanical hepatic vein thrombectomy with the AngioJet percutaneous thrombectomy system. Restoration of hepatic vein flow was confirmed with on-table Doppler ultrasound. There were no complications following the procedure. The patient was initiated on anticoagulation, and showed progressive clinical and laboratory improvement. She was discharged home on day 20 with normal liver function and biochemistry. This is the first reported case of successful mechanical thrombectomy in acute BC syndrome without the addition of angioplasty or chemical thrombolysis. PMID- 23737570 TI - Aneurysmal coronary cameral fistula. AB - A 26-year-old asymptomatic man, being medically managed for ventricular septal defect since childhood, presented to the outpatient clinic for a second opinion. Clinically, he was well built with normal vital signs. Cardiac auscultation was significant for a diastolic murmur over the praecordium. An ECG showed non specific ST changes, and a subsequent transthoracic echocardiography performed revealed diastolic flow from the left ventricular (LV) anteroseptal wall into the LV cavity. A diagnosis of coronary-cameral fistula was confirmed by a multidetector CT which showed a 2.5*2 cm aneurysmal left anterior descending artery fistula to the LV. In addition to starting aspirin, transcatheter closure with occlusion device was considered knowing the potential risk of thrombus formation in the aneurysm and subsequent systemic embolisation. The patient however refused any percutaneous or surgical intervention. He remains asymptomatic 1 year after returning to his home country. PMID- 23737571 TI - Anticoagulation-induced spontaneous intramural small bowel haematomas. AB - Small intestinal intramural haematomas may develop spontaneously, especially in patients with deranged clotting function. We present a case of a 57-year-old man who developed abdominal pain in the setting of abnormal clotting function secondary to an inadvertent warfarin overdose. A CT scan showed thickening of parts of the distal ileum, terminal ileum and duodenum. Dilation of the small bowel proximal to the thickening was also reported, indicative of a degree of small bowel obstruction. The patient was treated conservatively with a nasogastric tube and intravenous fluids. His anticoagulation was fully reversed with fresh frozen plasma and vitamin K. The patient remained well 6 months following discharge, with well-controlled anticoagulation levels and resolution of the findings on CT. PMID- 23737572 TI - Tubercular retinal vasculitis. AB - Intraocular tuberculosis (TB) infection can have different clinical manifestations including retinal vasculitis. It more frequently involves the veins and is associated with retina haemorrhages and neovascularisation. The diagnosis may be difficult and presumptive being based on clinical findings and evidence of systemic TB infection. The authors present a case of a 61-year-old woman with blurred vision and floaters in her left eye for 6 years, associated with recurrent vitreous haemorrahages. A temporal branch retinal vein occlusion was presumed. Four years later her right eye was also involved. Her best corrected visual acuity (BCVA) was 20/50 in both eyes. Fundoscopic examination showed bilateral venous occlusion with vascular staining on fluorescein angiography suggestive of vasculitis secondary to Eales Disease (ED). The interferon gamma release assay (IGRA-QuantiFERON-TB Gold) was positive and antituberculosis treatment (ATT) was started. Her final BCVA was 20/20 bilaterally, without recurrences over a follow-up of 15 months. The use of ATT is likely to reduce recurrent vitreous haemorrhages and eliminate future recurrences. PMID- 23737573 TI - Prenatal diagnosis of caudal dysplasia sequence associated with undiagnosed type I diabetes. AB - Caudal regression or caudal dysplasia sequence (CDS) is a rare congenital malformation, which includes a wide spectrum of musculoskeletal abnormalities involving the lumbosacral spine, pelvis and lower limbs. It can be associated to visceral defects in various degrees. Maternal diabetes, genetic predisposition and vascular hypoperfusion have been suggested as possible causative factors. Women with diabetes who are dependent on insulin are 200-400 times more likely to have a child with caudal regression, making CDS the most characteristic fetal abnormality of diabetic embryopathy. Prenatal diagnosis is possible by ultrasonographic examination. The sonographic findings include abrupt interruption of the lumbar spine and 'Buddha or frog position' of the lower limbs. MRI has demonstrated the level of the vertebral anomalies as well as the associated abnormalities and this is crucial because the prognosis of this condition depends on the severity of the lesion and the presence of associated disorders. PMID- 23737574 TI - Primary ileocaecal B-cell non-Hodgkin lymphoma (NHL): a rare underlying cause of right iliac fossa pain. AB - Primary gastrointestinal non-Hodgkin lymphomas (NHL) account for about 0.9% of all gastrointestinal tract tumours. They are usually associated with ulcerative colitis, Crohn's disease, previous radiotherapy, renal transplantation and AIDS. We present a 36-year-old immunocompetent man, previously well with abdominal pain, weight loss and palpable mass in the right iliac fossa. A CT scan of the abdomen showed a thickening of the terminal ileum and the caecum with characteristic aneurysmal luminal dilation. Given the patient's presentation and radiology findings, a right hemicolectomy was performed. The suspected diagnosis of NHL, which was based on the imaging findings, was confirmed at histological analysis. PMID- 23737575 TI - Hepatic subcapsular haematoma in a premature newborn. AB - Subcapsular haematoma of the liver rarely occurs in neonates and the diagnosis is often missed or delayed. It is a catastrophic condition that can be caused by maternal, placentar or fetal factors. A high index of suspicion is essential for early identification and stabilisation of babies with such a pathology. In a newborn with hypovolemic shock and abdominal distension, haemoperitoneum should be suspected and, along with exclusion of other aetiologies, supportive therapy should be instituted. The hepatic subcapsular haematoma has a non-specific presentation, and should be considered in very low birth weight infants with hypovolemic shock. Abdominal ultrasonography is the investigation of choice. It can delineate the lesion well, differentiate it from neoplasms, rule out rupture and aid in serial follow-up. We report a premature newborn who had this uncommon condition in the early neonatal period and survived without sequelae. PMID- 23737576 TI - Splenic injury after colonoscopy requiring splenectomy. AB - We present a case of a middle-aged woman, who presented with abdominal pain less than 24 h following an uneventful colonoscopy for rectal bleeding. Initial diagnosis was thought to be colonic perforation. An urgent CT scan performed owing to dropping haemoglobin and blood pressure revealed a large perisplenic haematoma. An urgent laparotomy was performed in which the patient had a total blood loss of 2500 ml and required splenectomy. The patient recovered well postoperatively.Colonoscopy is a commonly performed procedure in which complications of perforation and bleeding are well recognised. This case represents one of the rare but serious complications that endoscopists and patients should be aware of to aid prevention and early diagnosis. PMID- 23737577 TI - An unusual aetiology for internuclear ophthalmoplegia. AB - Typical causes of internuclear ophthalmoplegia (INO) include arterial infarcts, demyelinating conditions, inflammation and trauma. We here report the unique case of a 33-year-old man with INO of the right eye caused by infarction of the right midbrain, confirmed by diffusion-weighted MRI. At presentation he displayed impaired adduction of the right eye with normal movement of the left. CT angiogram revealed an underlying developmental venous anomaly (DVA), raising the concern of venous infarction. His symptoms improved with aggressive management of blood pressure and risk factors. The patient had vascular risk factors-smoking, hypertension and dyslipidaemia-and we theorise that the hyalinised and inelastic walls of our patient's DVA were more vulnerable to the thrombogenic effects of his risk factors, predisposing him to this event. Venous infarcts owing to DVA are rare. To our knowledge INO secondary to venous infarct has not been reported, and should be considered in the differential of such cases. PMID- 23737578 TI - Craniopharyngioma and epidermoid tumour in same child: a rare association. AB - Simultaneous occurrence of histologically different primary brain tumours is rare, and its preoperative diagnosis is still challenging. The explanations for the simultaneous occurrence of different primary intracranial tumours in the absence of phacomatoses or prior radiation exposure are at present hypothetical, and these tumours could be simply coincidental. Herein, we report a case of a boy presenting with features of raised intracranial pressure and right-sided sensorineural hearing loss. Brain MRI revealed two different neoplastic pathologies at different sites: an intrasellar and suprasellar craniopharyngioma and a right cerebello-pontine angle epidermoid. To the best of our knowledge, this is the first report in literature of a craniopharyngioma coexisting with an epidermoid, in the same individual. PMID- 23737579 TI - Normal functioning single system ectopic ureter draining into a Gartner's cyst: laparoscopic management. AB - Association of single system ectopic ureter with normal functioning bilateral kidney and absence of congenital anomalies is very rarely reported in the literature. We are reporting for the first time a case of this type of anomaly in which uretral ectopia was draining into a Gartner's cyst and was managed by laparoscopy. A 16 year girl presented with normal voiding with continuous dribbling since birth. Voiding cystourethrogram, intravenous urogram, cystovaginoscopy and retrograde contrast study confirmed the diagnosis. Ultrasound of the whole abdomen and physical examination ruled out any associated congenital anomalies. Transperitoneal laparoscopic ureteric reimplantation was performed and distal stump was ligated. On follow-up at 3 months she was completely dry; her vaginoscopy showed disappearance of cystic bulge and her voiding cystourethrogram showed normal study without any reflux. When single system ectopic ureter opens into small-to-moderate size wide opened mouth vaginal Gartner's cyst, laparoscopic ureteric reimplantation and ligation of distal stump is an appropriate procedure. PMID- 23737580 TI - Fixed functional space maintainer: novel aesthetic approach for missing maxillary primary anterior teeth. AB - The first-line treatment of non-restorable traumatically injured or carious deciduous teeth is extraction which may be a curse for the future dentition as well as social activity of a child. Various therapeutic modalities from removable partial dentures to fixed space maintainer can be used for replacement of such lost teeth. Two types of fixed aesthetic space maintainers for replacing premature loss of maxillary deciduous incisors in 4-year-old children are discussed. PMID- 23737581 TI - Atypical histiocytic granuloma of tongue. AB - A 40-year-old male patient presented with a 3-week history of a painless ulcer on the dorsum of the tongue. He was a chronic smoker since the age of 15 years. The ulcer was well-defined, non-tender and indurated. An incisional biopsy was performed and the diagnosis of atypical histiocytic granuloma was made after histopathological examination. The lesion resolved spontaneously after the incisional biopsy and the patient was on follow-up for 6 months and no recurrences were observed. Here we report a rare case of atypical histiocytic granuloma. Hence, it must be borne in mind in the differential diagnosis of ulcers on the tongue. PMID- 23737582 TI - Aesthetic management of a complicated crown fracture: a multidisciplinary approach. AB - A predictable aesthetic restoration is not limited to the restored teeth; it has to include the gingival unit and its interface with the teeth involved. Orthodontic forced eruption may be a suitable approach without risking the aesthetic appearance in tooth fracture below the gingival attachment or alveolar bone crest. It is a well-documented clinical method for altering the relation between a non-restorable tooth and its attachment apparatus, elevating sound tooth material from within the alveolar socket to create a ferrule effect which is considered to be crucial for the optimal biomechanical behaviour of restored teeth. This report presents the reconstruction of a traumatised and fractured left maxillary lateral incisor by building a cast core with a cast post to perform orthodontic extrusion before placing porcelain fused to metal crown as the final restoration. PMID- 23737583 TI - Primary parapharyngeal and skull base synovial sarcoma in a 13-year-old boy with neurofibromatosis radiologically misdiagnosed as a benign lesion. AB - Synovial sarcoma is a rare form of malignant tumour and accounting approximately for 8% of all soft tissue sarcomas. Head and neck synovial sarcomas are uncommon and parapharyngeal space involvement is extremely rare. We report a case of synovial sarcoma in the parapharyngeal space of a 13-year-old boy with a history of neurofibromatosis presented with odynophagia, ptosis and left submandibular mass. The lesion extended from retrostyloid parapharyngeal space to the skull base and foramen jugular superiorly. The first clinical and radiological impressions were carotid jugular related tumours such as schwannoma and paraganglioma. PMID- 23737584 TI - Percutaneous ablation of functioning adenoma in a patient with a single adrenal gland. AB - The conventional treatment of functioning adrenal adenomas is laparoscopic resection. Since the 1990s, radiofrequency ablation has been increasingly applied to the treatment of tumours of the liver, lungs and musculoskeletal system. However, the use of radiofrequency ablation to treat adrenal nodules is still an uncommon procedure, particularly in aldosterone-producing adenomas. We report the case of a 35-year-old male patient with resistant hypertension, hypokalaemia and aldosterone-producing adenoma in a single adrenal gland. The patient underwent CT guided percutaneous radiofrequency ablation. Clinical, laboratory and MRI follow up data indicated excellent response to treatment. This case report is the first in the literature to describe the use of CT-guided percutaneous radiofrequency ablation in the treatment of a functioning adrenal adenoma in a patient with a single adrenal gland. PMID- 23737585 TI - Ocular argyrosis in a jeweller. PMID- 23737586 TI - Haemophilus parainfluenzae prosthetic valve endocarditis complicated by septic emboli to brain. AB - A 51-year-old man with a history of injection drug use presented to the emergency roomwith fevers, chills and headaches. Five months earlier, he had undergone bioprosthetic aortic valve replacement for infective endocarditis owing to Corynebacterium auricumosum involving a bicuspid aortic valve. Blood cultures obtained during current hospitalisation grew Haemophilus parainfluenzae and patient underwent a transesophageal echocardiogram that revealed a large mitral valve vegetation. Owing to persistent headache and right lower extremity weakness, MRI of the brain was performed which demonstrated multifocal, acute infarctions secondary to septic embolisation. He was initiated on parenteral antibiotics and experienced no further neurological setbacks. After 2 weeks of antibiotic therapy, he underwent bioprosthetic aortic and mitral valve replacement, aortic root debridement and replacement, and reconstruction of the intravalvular fibrosa without complication. He was discharged to a skilled nursing facility to complete six more weeks of intravenous ceftriaxone. PMID- 23737587 TI - Condylus tertius and episodic vertigo: is there an association? PMID- 23737588 TI - Mediastinal lipoblastoma: unexpected finding of a chest infection. AB - A 2-year-old boy was presented with symptoms of chest infection. The chest radiograph showed a large mediastinal mass, which led to further investigations including biopsy of the tumour. Histopathological analysis revealed a diagnosis of lipoblastoma. We highlight the imaging appearance of the lesion. Although histopathological analysis is required for the confirmation of the diagnosis, cross-sectional imaging is useful in evaluating the extent of the tumour for surgical planning. PMID- 23737589 TI - Thyroid associated orbitopathy. AB - Thyroid-associated orbitopathy (TAO) is a self-limiting auto-immune condition usually associated with Grave's disease. It is characterised by ocular pain, eyelid swelling, chemosis, proptosis and keratopathy. As the mechanism for ophthamoplegia and optic neuropathy is the orbital swelling leading to mechanical restriction of ocular muscles and compression of optic nerve, one expects proptosis rather than ptosis in TAO. We describe a case of a young adult woman who presented with acute onset restriction of movement along with partial ptosis and severe diminution of vision in left eye. The MRI of orbit revealed significant swelling of recti along with signal alteration consistent with TAO. The radio-isotope thyroid scan revealed thyroiditis, and thyroid peroxidase (TPO) antibody was significantly high; hence, the diagnosis of Hashimoto thyroiditis was considered. A course of intravenous methylprednisolone followed by oral steroid was administered, which produced marked improvement in vision and extraocular movement. PMID- 23737590 TI - A rare cause of secondary hypertension: median arcuate ligament compression of the renal artery diagnosed by CT angiography. PMID- 23737591 TI - Situs inversus totalis, oesophageal atresia and tracheo-oesophageal fistula. PMID- 23737592 TI - Primary malignant melanoma of uterine cervix with probable origin from benign cervical melanosis. AB - We report a case of primary malignant melanoma of cervix which is a rare malignancy with only around 60 cases being reported. This patient presented with bleeding per vaginum. A large exophytic growth from cervix with black discolouration was seen. International Federation of Gynaecology and Obsterics (FIGO) staging was stage IIa. Histoimmunocytology confirmed the diagnosis of malignant melanoma of cervix. S-100 and HMB-45 are reliable markers for cervical melanomas. We attempted Wertheim's hysterectomy; but, due to extensive disease, paravescical and pararectal fossae could not be dissected and we had to perform type I hysterectomy. The patient was started on adjuvant chemotherapy with dacarbazine. Despite counselling, she refused a complete course of chemotherapy and died after 6 months. Radical surgery, chemotherapy and immunotherapy are the therapeutic modalities used. In bulky disease, neoadjuvant chemotherapy should be considered to reduce the tumour bulk and facilitate required surgery. Prognosis is poor and unpredictable. PMID- 23737593 TI - Management of an infant having natal teeth. AB - Eruption of teeth at or immediately after birth is a relatively rare phenomenon. These teeth are known as 'natal' teeth if present at birth and 'neonatal' teeth if they erupt during the first 30 days of life. Natal teeth might resemble normal primary dentition in size and shape; however, the teeth are often smaller, conical and yellowish and have hypoplastic enamel and dentin with poor or absent root formation. Complications include difficulty and discomfort during suckling, sublingual ulceration, laceration of the mother's breasts and aspiration of the teeth. These situations would warrant extraction. If the tooth does not interfere with breast feeding and is otherwise asymptomatic, no treatment is necessary. Negative cultural attitudes towards natal teeth demand good parental counselling and vigilant management in relation to child protection. Both general practice dentists and paediatric dental specialists may be involved in the supervision or treatment of patients with natal and neonatal teeth. PMID- 23737594 TI - Taurodontism in deciduous molars. AB - Taurodont teeth are characterised by large pulp chambers at the expense of roots. An enlarged pulp chamber, apical displacement of the pulpal floor and no constriction at the level of the cement-enamel junction are the characteristic features of taurodont tooth. It appears more frequently as an isolated anomaly but its association with syndromes and other abnormalities have also been reported. Permanent dentition is more commonly affected than deciduous dentition. This paper presents a case report of taurodontism in relation to mandibular deciduous second molars. PMID- 23737595 TI - Inflammatory myopathy as the initial presentation of cryoglobulinaemic vasculitis. AB - Cryoglobulinaemic vasculitis is characterised by immunoglobulin deposition at low temperatures. The most common manifestations are cutaneous involvement, arthralgias, Raynaud's phenomenon, peripheral neuropathy and renal disease. Myopathy is unusual and only a few cases have been reported. Here, we present a 31-year-old woman who developed progressive muscle weakness involving upper and lower extremities, dysphagia, paraesthesias and palpable purpura. Diagnostic studies revealed elevated creatine kinase, diffuse myopathic and sensorimotor axonal neuropathy on electromyography and nerve conduction studies, and inflammatory myopathy on muscle biospsy. Cryoglobulin levels were elevated on two occasions. She responded favourably to cyclophosphamide and high-dose corticosteroids. Cyclophosphamide was continued for 1 year followed by methotrexate. Prednisone was gradually tapered and discontinued 1 year later. She remained in clinical remission after 4 years of follow-up. This case suggests that cryoglobulinaemia should be considered in the differential diagnosis of a patient presenting with inflammatory myopathy. PMID- 23737596 TI - Costal osteoid osteoma with chest pain. PMID- 23737597 TI - Endovascular repair of a double-lumen dissecting aneurysm. AB - Treating dissections and dissecting aneurysms requires maintenance of flow through the true lumen and exclusion of the false lumen from the circulation. A dissecting aneurysm of the vertebral artery presented with both a true and false lumen within the aneurysmal sac. Stenting of the true lumen followed by coil embolization of both lumens was performed. Management options and decision-making are discussed for this unique situation. PMID- 23737598 TI - A review of social inclusion measures. AB - BACKGROUND: Social inclusion is crucial to mental health and well-being and is emphasised in Australia's Fourth National Mental Health Plan. There is a recognition that a measure of social inclusion would complement the suite of outcome measures that is currently used in public sector mental health services. This paper is an initial scope of candidate measures of social inclusion and considers their suitability for this purpose. METHODS: We identified potential measures through searches of PsycINFO and Medline and a more general Internet search. We extracted descriptive and evaluative information on each measure identified and compared this information with a set of eight criteria. The criteria related to the measure's inclusion of four domains of social inclusion outlined in Australia's Fourth National Mental Health Plan, its usability within the public mental health sector and its psychometric properties. RESULTS: We identified 10 candidate measures of social inclusion: the Activity and Participation Questionnaire (APQ-6); the Australian Community Participation Questionnaire (ACPQ); the Composite Measure of Social Inclusion (CMSI); the EMILIA Project Questionnaire (EPQ); the Evaluating Social Inclusion Questionnaire (ESIQ); the Inclusion Web (IW); the Social and Community Opportunities Profile (SCOPE); the Social Inclusion Measure (SIM); the Social Inclusion Questionnaire (SIQ); and the Staff Survey of Social Inclusion (SSSI). After comparison with the eight review criteria, we determined that the APQ-6 and the SCOPE-short form show the most potential for further testing. CONCLUSIONS: Social inclusion is too important not to measure. This discussion of individual-level measures of social inclusion provides a springboard for selecting an appropriate measure for use in public sector mental health services. It suggests that there are two primary candidates, but neither of these is quite fit-for-purpose in their current form. Further exploration will reveal whether one of these is suitable, whether another measure might be adapted for the current purpose or whether a new, specifically designed measure needs to be developed. PMID- 23737599 TI - Clinical correlates of nucleus accumbens volume in drug-naive, adult patients with obsessive-compulsive disorder. AB - BACKGROUND: Reward-processing deficits have been demonstrated in obsessive compulsive disorder (OCD) and this has been linked to ventral striatal abnormalities. However, volumetric abnormalities of the nucleus accumbens (NAcc), a key structure in the reward pathway, have not been examined in OCD. We report on the volumetric abnormalities of NAcc and its correlation with illness severity in drug-naive, adult patients with OCD. METHOD: In this cross-sectional study of case-control design, the magnetic resonance imaging (MRI) 1.5-T (1-mm) volume of NAcc was measured using 3D Slicer software in drug-naive OCD patients (n = 44) and age, sex and handedness-matched healthy controls (HCs) (n = 36) using a valid and reliable method. OCD symptoms were assessed using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) Symptom checklist and severity and the Clinical Global Impression-Severity (CGI-S) scale. RESULTS: There was no significant difference in NAcc volumes on either side between OCD patients and HCs (F = 3.45, p = 0.07). However, there was significant negative correlation between the right NAcc volume and Y-BOCS compulsion score (r = -0.48, p = 0.001). CONCLUSIONS: Study observations suggest involvement of the NAcc in the pathogenesis of OCD, indicating potential reward-processing deficits. Correlation between the right NAcc volume deficit and severity of compulsions offers further support for this region as a candidate for deep brain stimulation treatment in OCD. PMID- 23737600 TI - Personality and psychopathology: mapping the MMPI-2-RF on Cloninger's psychobiological model of personality. AB - This study investigates the relationship between the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) and the Temperament and Character Inventory (TCI) in a combined data set (N = 491) of patients with a broad range of psychiatric disorders (n = 286) as well as alcohol use disorder (n = 205). We examined bivariate correlations between both measures. The MMPI-2-RF scales relate to the TCI dimensions as was hypothesized, and relationships between both measurements were largely similar for psychiatric patients and alcohol-dependent patients. Theoretical and clinical implications are considered. PMID- 23737601 TI - Bacillus anthracis cell wall peptidoglycan but not lethal or edema toxins produces changes consistent with disseminated intravascular coagulation in a rat model. AB - BACKGROUND: Disseminated intravascular coagulation (DIC) appears to be important in the pathogenesis of Bacillus anthracis infection, but its causes are unclear. Although lethal toxin (LT) and edema toxin (ET) could contribute, B. anthracis cell wall peptidoglycan (PGN), not the toxins, stimulates inflammatory responses associated with DIC. METHODS AND RESULTS: To better understand the pathogenesis of DIC during anthrax, we compared the effects of 24-hour infusions of PGN, LT, ET, or diluent (control) on coagulation measures 6, 24, or 48 hours after infusion initiation in 135 rats. No control recipient died. Lethality rates (approximately 30%) did not differ among PGN, LT, and ET recipients (P = .78). Thirty-three of 35 deaths (94%) occurred between 6 and 24 hours after the start of challenge. Among challenge components, PGN most consistently altered coagulation measures. Compared with control at 6 hours, PGN decreased platelet and fibrinogen levels and increased prothrombin and activated partial thromboplastin times and tissue factor, tissue factor pathway inhibitor, protein C, plasminogen activator inhibitor (PAI), and thrombin-antithrombin complex levels, whereas LT and ET only decreased the fibrinogen level or increased the PAI level (P <= .05). Nearly all effects associated with PGN infusion significantly differed from changes associated with toxin infusion (P <= .05 for all comparisons except for PAI level). CONCLUSION: DIC during B. anthracis infection may be related more to components such as PGN than to LT or ET. PMID- 23737602 TI - A FimH inhibitor prevents acute bladder infection and treats chronic cystitis caused by multidrug-resistant uropathogenic Escherichia coli ST131. AB - BACKGROUND: Escherichia coli O25b:H4-ST131 represents a predominant clone of multidrug-resistant uropathogens currently circulating worldwide in hospitals and the community. Urinary tract infections (UTIs) caused by E. coli ST131 are typically associated with limited treatment options and are often recurrent. METHODS: Using established mouse models of acute and chronic UTI, we mapped the pathogenic trajectory of the reference E. coli ST131 UTI isolate, strain EC958. RESULTS: We demonstrated that E. coli EC958 can invade bladder epithelial cells and form intracellular bacterial communities early during acute UTI. Moreover, E. coli EC958 persisted in the bladder and established chronic UTI. Prophylactic antibiotic administration failed to prevent E. coli EC958-mediated UTI. However, 1 oral dose of a small-molecular-weight compound that inhibits FimH, the type 1 fimbriae adhesin, significantly reduced bacterial colonization of the bladder and prevented acute UTI. Treatment of chronically infected mice with the same FimH inhibitor lowered their bladder bacterial burden by >1000-fold. CONCLUSIONS: In this study, we provide novel insight into the pathogenic mechanisms used by the globally disseminated E. coli ST131 clone during acute and chronic UTI and establish the potential of FimH inhibitors as an alternative treatment against multidrug-resistant E. coli. PMID- 23737603 TI - Immunological characterization of bronchoalveolar lavage fluid in patients with acute pulmonary coccidioidomycosis. AB - BACKGROUND: The specific cellular immunological characteristics of bronchoalveolar lavage (BAL) fluid in acute pulmonary coccidioidomycosis have not been defined. METHODS: BAL fluid from patients living in a coccidioidomycosis endemic region of Arizona who were undergoing bronchoscopy because of pulmonary infiltrates was analyzed. Mononuclear cells from BAL fluid and peripheral blood mononuclear cells (PBMCs) were incubated with the coccidioidal antigen T27K in vitro, and cellular immunological assays were performed. RESULTS: Forty-six patients were studied. Twelve received a diagnosis of acute pulmonary coccidioidomycosis, 17 received other diagnoses, and 17 had no diagnosis established. There was an increased proportion of polyfunctional CD8(+) T cells after antigen stimulation from subjects with coccidioidomycosis as compared to those with another diagnosis (P = .025). In cells collected from BAL fluid and in PBMCs, the concentrations of interferon gamma, tumor necrosis factor alpha, and interleukin 17 (IL-17) were all significantly increased in samples from those with acute pulmonary coccidioidomycosis, compared with the other 2 groups (for all, P<.05). CONCLUSIONS: When incubated in vitro with a coccidioidal antigen preparation, cells from both BAL fluid and peripheral blood obtained from patients with pulmonary coccidioidomycosis demonstrated specific cellular immune responses, including expression of IL-17. PMID- 23737605 TI - Early palliative intervention for patients with advanced cancer. AB - BACKGROUND: Early palliative intervention in advanced cancer patients with metastatic non-small-cell-lung cancer has been shown to improve survival time. Possibly, palliative intervention at the time of outpatient care further improves patient survival time. OBJECTIVE: We performed a comparative study of late and early referrals of patients with advanced cancer to clarify the appropriate time for palliative intervention and the improvement in survival time. METHODS: Two hundred and one cancer patients, all since deceased, who were treated in our department over a period of 4 years were divided into two groups: patients who experienced outpatient services for <7 days (late referral group, 64 patients) and those who experienced outpatient services for >=7 days (early referral group, 137 patients). Survival time, duration of chemotherapy and post-progression survival were retrospectively analyzed through examination of medical records. RESULTS: Survival time of the early referral group was longer than that of the late referral group in all the cases (19.0 vs. 6.5 months, P < 0.001). Survival time in advanced non-small-cell lung cancer was 3.5 and 14.0 months (P = 0.010) and 16.5 and 20.9 months (P = 0.039) in advanced colorectal cancer, respectively. There was no significant difference in gastric cancer (P = 0.310). Post progression survival in each group was 0.7 and 2.7 months (P = 0.018) in non small-cell lung cancer. CONCLUSIONS: The results of this study suggested that early outpatient referral and palliative intervention leads to improvement of the outcome in patients with advanced non-small-cell lung cancer and colorectal cancer. A prospective comparative study is warranted. PMID- 23737604 TI - Impaired pulmonary nitric oxide bioavailability in pulmonary tuberculosis: association with disease severity and delayed mycobacterial clearance with treatment. AB - BACKGROUND: Nitric oxide (NO), a key macrophage antimycobacterial mediator that ameliorates immunopathology, is measurable in exhaled breath in individuals with pulmonary tuberculosis. We investigated relationships between fractional exhale NO (FENO) and initial pulmonary tuberculosis severity, change during treatment, and relationship with conversion of sputum culture to negative at 2 months. METHODS: In Papua, we measured FENO in patients with pulmonary tuberculosis at baseline and serially over 6 months and once in healthy controls. Treatment outcomes were conversion of sputum culture results at 2 months and time to conversion of sputum microscopy results. RESULTS: Among 200 patients with pulmonary tuberculosis and 88 controls, FENO was lower for patients with pulmonary tuberculosis at diagnosis (geometric mean FENO, 12.7 parts per billion [ppb]; 95% confidence interval [CI], 11.6-13.8) than for controls (geometric mean FENO, 16.6 ppb; 95% CI, 14.2-19.5; P = .002), fell further after treatment initiation (nadir at 1 week), and then recovered by 6 months (P = .03). Lower FENO was associated with more-severe tuberculosis disease, with FENO directly proportional to weight (P < .001) and forced vital-capacity (P = .001) and inversely proportional to radiological score (P = .03). People whose FENO increased or remained unchanged by 2 months were 2.7-fold more likely to achieve conversion of sputum culture than those whose FENO decreased (odds ratio, 2.72; 95% CI, 1.05-7.12; P = .04). CONCLUSIONS: Among patients with pulmonary tuberculosis, impaired pulmonary NO bioavailability is associated with more severe disease and delayed mycobacterial clearance. Measures to increase pulmonary NO warrant investigation as adjunctive tuberculosis treatments. PMID- 23737606 TI - Cancer cachexia pathophysiology and translational aspect of herbal medicine. AB - About half of all cancer patients show a syndrome of cachexia, characterized by anorexia and loss of adipose tissue and skeletal muscle mass. Numerous cytokines have been postulated to play a role in the etiology of cancer cachexia. Cytokines can elicit effects that mimic leptin signaling and suppress orexigenic ghrelin and neuropeptide Y signaling, inducing sustained anorexia and cachexia not accompanied by the usual compensatory response. Furthermore, cytokines have been implicated in the induction of cancer-related muscle wasting. In particular, tumor necrosis factor-alpha, interleukin-1, interleukin-6 and interferon-gamma have been implicated in the induction of cancer-related muscle wasting. Cytokine induced skeletal muscle wasting is probably a multifactorial process, which involves a depression in protein synthesis, an increase in protein degradation or a combination of both. Cancer patients suffer from the reduction in physical function, tolerance to anti-cancer therapy and survival, while many effective chemotherapeutic agents for cancer are burdened by toxicities that can reduce patient's quality of life or hinder their effective use. Herbal medicines have been widely used to help improve such conditions. Recent studies have shown that herbal medicines such as rikkunshito enhance ghrelin signaling and consequently improve nausea, appetite loss and cachexia associated with cancer or cancer chemotherapy, which worsens the quality of life and life expectancy of the patients. The multicomponent herbal medicines capable of targeting multiple sites could be useful for future drug discovery. Mechanistic studies and identification of active compounds could lead to new discoveries in biological and biomedical sciences. PMID- 23737607 TI - Targeted group-based interventions in schools to promote emotional well-being: a systematic review. AB - The school environment offers significant opportunities to deliver psychological interventions to groups of young people in the UK. However, the nature and effectiveness of programmes are not consistently documented. This systematic review aimed to identify and examine group-based interventions delivered in UK schools. Sixteen papers describing eight interventions were included. It was found that nurture groups have an immediate positive impact on the social and emotional well-being of young people. Results from follow-up studies are less clear, and limited by a high level of sample attrition. The findings reported in relation to social and emotional aspects of learning, cognitive, behavioural and social skills based interventions were limited as each intervention is only evaluated by one paper. The review highlighted a need to implement well-designed, longitudinal studies with larger samples in order to evaluate which interventions are effective in UK schools. PMID- 23737608 TI - Statutory health assessments for pre-school foster children fail to screen accurately for mental health disorders. AB - The aim of this study was to determine the diagnostic accuracy of statutory health assessments in identifying existing mental health disorders in pre-school foster children. It was examined whether a foster carer completed screening instrument could enhance accuracy. A representative sample of 43 pre-schoolers under the care of one inner-city local authority underwent comprehensive multidimensional mental health assessments as the reference standard. Statutory health assessments gave false negative results for 65% (95% confidence interval (CI) 44-82%) of children diagnosed with at least one mental health disorder according to the reference standard and 18% (95% CI 3-52%) of children with developmental delay. The Ages & Stages Questionnaire completed by the foster carers failed to identify 65% (95% CI 44-82%) of the children with diagnosed mental health disorders. There was no evidence of selective underreporting by foster carers in relation to specific diagnostic categories. In conclusion, statutory health assessments in their current form may fail to identify the majority of pre-school foster children with mental health disorders. Adding a screening instrument to the assessment process may not be adequate to improve diagnostic accuracy. PMID- 23737609 TI - Measuring mental health in Indigenous young people: a review of the literature from 1998-2008. AB - BACKGROUND: Indigenous young people are disproportionately exposed to risk factors for poor mental health. Methodologically rigorous research will be critical in the development and evaluation of prevention and treatment programs. Research examining the mental health of Indigenous young people may have been undermined by poor measurement. The extent to which research has used measures with adequate psychometrics is unknown. METHODS: MEDLINE, PsychINFO and PUBMED databases, were systematically searched to identify papers published between 1998 2008 measuring the mental health of Indigenous young people from Australia, Canada, New Zealand or the US. Data extracted included type of mental health instrument, psychometric analyses reported and results. RESULTS: Fifty-four relevant studies were identified. Seventy-nine mental health instruments were used, and 18% were bespoke. Only 14% of instruments had been validated for the relevant Indigenous population. Few studies reported assessment of the reliability or validity of instruments. Data about both the reliability and validity of 10 measures were reported. None of the measures met the standards set by the review. Evidence of at least one type of reliability and validity was demonstrated for six measures. CONCLUSIONS: From 1998-2008 few studies of mental health in Indigenous young people used measurement instruments with previously determined reliability and validity. PMID- 23737610 TI - Feeding forward to a 'miracle day' - a pilot study of video feedforward in reactive attachment disorder. AB - Video feedforward is a solution-focused intervention used to improve desired behaviour. We present two case studies of using video feedforward in reactive attachment disorder. Children with reactive attachment disorder, their caregivers and their clinician completed storyboards of behaviours desired during a 'miracle day' and filmed the individual scenes. These scenes were edited to a prolonged sequence of successful behaviour which was fed back to the child and their caregiver using principles of video interaction guidance. Families reported major improvements in the targeted behaviours, usually within a week of filming the 'miracle day'. PMID- 23737611 TI - Viral encephalitis and its management through advanced molecular diagnostic methods: a review. PMID- 23737612 TI - Neonatal "seizure" while riding in a car: a peculiar but key episode for diagnosis of benign neonatal sleep myoclonus. PMID- 23737613 TI - Do specialty courts achieve better outcomes for children in foster care than general courts? AB - OBJECTIVE: This study assessed the effects of unified family and drug treatment courts (DTCs) on the resolution of cases involving foster care children and the resulting effects on school performance. METHOD: The first analytic step was to assess the impacts of presence of unified and DTCs in North Carolina counties on time children spent in foster care and the type of placement at exit from foster care. In the second step, the same data on foster care placements were merged with school records for youth in Grades 3-8 in public schools. The effect of children's time in foster care and placement outcomes on school performance as measured by math and reading tests, grade retention, and attendance was assessed using child fixed-effects regression. RESULTS: Children in counties with unified family courts experienced shorter foster care spells and higher rates of reunification with parents or primary caregivers. Shorter foster care spells translated into improved school performance measured by end-of-grade reading and math test scores. Adult DTCs were associated with lower probability of reunification with parents/primary caregivers. CONCLUSION: The shortened time in foster care implies an efficiency gain attributable to unified family courts, which translate into savings for the court system through the use of fewer resources. Children also benefit through shortened stays in temporary placements, which are related to some improved educational outcomes. PMID- 23737614 TI - From vision to change: educational initiatives and research at the intersection of physics and biology. PMID- 23737615 TI - Integration of physics and biology: synergistic undergraduate education for the 21st century. AB - This is an exciting time to be a biologist. The advances in our field and the many opportunities to expand our horizons through interaction with other disciplines are intellectually stimulating. This is as true for people tasked with helping the field move forward through support of research and education projects that serve the nation's needs as for those carrying out that research and educating the next generation of biologists. So, it is a pleasure to contribute to this edition of CBE-Life Sciences Education. This column will cover three aspects of the interactions of physics and biology as seen from the viewpoint of four members of the Division of Undergraduate Education of the National Science Foundation. The first section places the material to follow in context. The second reviews some of the many interdisciplinary physics-biology projects we support. The third highlights mechanisms available for supporting new physics-biology undergraduate education projects based on ideas that arise, focusing on those needing and warranting outside support to come to fruition. PMID- 23737616 TI - On the edge of mathematics and biology integration: improving quantitative skills in undergraduate biology education. PMID- 23737617 TI - Biology education research: lessons and future directions. PMID- 23737618 TI - Physics and biology collaborate to color the world. PMID- 23737620 TI - Interdisciplinarity: the right people, a supportive place, and a program emerges. PMID- 23737621 TI - Preparing high school students for the interdisciplinary nature of modern biology. PMID- 23737622 TI - A problem with STEM. PMID- 23737623 TI - How can we improve problem solving in undergraduate biology? Applying lessons from 30 years of physics education research. AB - If students are to successfully grapple with authentic, complex biological problems as scientists and citizens, they need practice solving such problems during their undergraduate years. Physics education researchers have investigated student problem solving for the past three decades. Although physics and biology problems differ in structure and content, the instructional purposes align closely: explaining patterns and processes in the natural world and making predictions about physical and biological systems. In this paper, we discuss how research-supported approaches developed by physics education researchers can be adopted by biologists to enhance student problem-solving skills. First, we compare the problems that biology students are typically asked to solve with authentic, complex problems. We then describe the development of research validated physics curricula emphasizing process skills in problem solving. We show that solving authentic, complex biology problems requires many of the same skills that practicing physicists and biologists use in representing problems, seeking relationships, making predictions, and verifying or checking solutions. We assert that acquiring these skills can help biology students become competent problem solvers. Finally, we propose how biology scholars can apply lessons from physics education in their classrooms and inspire new studies in biology education research. PMID- 23737624 TI - Competency-based reforms of the undergraduate biology curriculum: integrating the physical and biological sciences. AB - The National Experiment in Undergraduate Science Education project funded by the Howard Hughes Medical Institute is a direct response to the Scientific Foundations for Future Physicians report, which urged a shift in premedical student preparation from a narrow list of specific course work to a more flexible curriculum that helps students develop broad scientific competencies. A consortium of four universities is working to create, pilot, and assess modular, competency-based curricular units that require students to use higher-order cognitive skills and reason across traditional disciplinary boundaries. Purdue University; the University of Maryland, Baltimore County; and the University of Miami are each developing modules and case studies that integrate the biological, chemical, physical, and mathematical sciences. The University of Maryland, College Park, is leading the effort to create an introductory physics for life sciences course that is reformed in both content and pedagogy. This course has prerequisites of biology, chemistry, and calculus, allowing students to apply strategies from the physical sciences to solving authentic biological problems. A comprehensive assessment plan is examining students' conceptual knowledge of physics, their attitudes toward interdisciplinary approaches, and the development of specific scientific competencies. Teaching modules developed during this initial phase will be tested on multiple partner campuses in preparation for eventual broad dissemination. PMID- 23737625 TI - Biology and physics competencies for pre-health and other life sciences students. AB - The recent report on the Scientific Foundations for Future Physicians (SFFP) and the revised Medical College Admissions Test (MCAT) reframe the preparation for medical school (and other health professional schools) in terms of competencies: what students should know and be able to do with that knowledge, with a strong emphasis on scientific inquiry and research skills. In this article, we will describe the thinking that went into the SFFP report and what it says about scientific and quantitative reasoning, focusing on biology and physics and the overlap between those fields. We then discuss how the SFFP report set the stage for the discussion of the recommendations for the revised MCAT, which will be implemented in 2015, again focusing the discussion on biology and physics. Based on that framework, we discuss the implications for undergraduate biology and physics education if students are to be prepared to demonstrate these competencies. PMID- 23737626 TI - Learning each other's ropes: negotiating interdisciplinary authenticity. AB - A common feature of the recent calls for reform of the undergraduate biology curriculum has been for better coordination between biology and the courses from the allied disciplines of mathematics, chemistry, and physics. Physics has lagged behind math and chemistry in creating new, biologically oriented curricula, although much activity is now taking place, and significant progress is being made. In this essay, we consider a case study: a multiyear conversation between a physicist interested in adapting his physics course for biologists (E.F.R.) and a biologist interested in including more physics in his biology course (T.J.C.). These extended discussions have led us both to a deeper understanding of each other's discipline and to significant changes in the way we each think about and present our classes. We discuss two examples in detail: the creation of a physics problem on fluid flow for a biology class and the creation of a biologically authentic physics problem on scaling and dimensional analysis. In each case, we see differences in how the two disciplines frame and see value in the tasks. We conclude with some generalizations about how biology and physics look at the world differently that help us navigate the minefield of counterproductive stereotypical responses. PMID- 23737627 TI - A framework for analyzing interdisciplinary tasks: implications for student learning and curricular design. AB - The national conversation around undergraduate science instruction is calling for increased interdisciplinarity. As these calls increase, there is a need to consider the learning objectives of interdisciplinary science courses and how to design curricula to support those objectives. We present a framework that can help support interdisciplinary design research. We developed this framework in an introductory physics for life sciences majors (IPLS) course for which we designed a series of interdisciplinary tasks that bridge physics and biology. We illustrate how this framework can be used to describe the variation in the nature and degree of interdisciplinary interaction in tasks, to aid in redesigning tasks to better align with interdisciplinary learning objectives, and finally, to articulate design conjectures that posit how different characteristics of these tasks might support or impede interdisciplinary learning objectives. This framework will be useful for both curriculum designers and education researchers seeking to understand, in more concrete terms, what interdisciplinary learning means and how integrated science curricula can be designed to support interdisciplinary learning objectives. PMID- 23737628 TI - Toward university modeling instruction--biology: adapting curricular frameworks from physics to biology. AB - University Modeling Instruction (UMI) is an approach to curriculum and pedagogy that focuses instruction on engaging students in building, validating, and deploying scientific models. Modeling Instruction has been successfully implemented in both high school and university physics courses. Studies within the physics education research (PER) community have identified UMI's positive impacts on learning gains, equity, attitudinal shifts, and self-efficacy. While the success of this pedagogical approach has been recognized within the physics community, the use of models and modeling practices is still being developed for biology. Drawing from the existing research on UMI in physics, we describe the theoretical foundations of UMI and how UMI can be adapted to include an emphasis on models and modeling for undergraduate introductory biology courses. In particular, we discuss our ongoing work to develop a framework for the first semester of a two-semester introductory biology course sequence by identifying the essential basic models for an introductory biology course sequence. PMID- 23737629 TI - Advantages and challenges of using physics curricula as a model for reforming an undergraduate biology course. AB - We report on the development of a life sciences curriculum, targeted to undergraduate students, which was modeled after a commercially available physics curriculum and based on aspects of how people learn. Our paper describes the collaborative development process and necessary modifications required to apply a physics pedagogical model in a life sciences context. While some approaches were easily adapted, others provided significant challenges. Among these challenges were: representations of energy, introducing definitions, the placement of Scientists' Ideas, and the replicability of data. In modifying the curriculum to address these challenges, we have come to see them as speaking to deeper differences between the disciplines, namely that introductory physics--for example, Newton's laws, magnetism, light--is a science of pairwise interaction, while introductory biology--for example, photosynthesis, evolution, cycling of matter in ecosystems--is a science of linked processes, and we suggest that this is how the two disciplines are presented in introductory classes. We illustrate this tension through an analysis of our adaptations of the physics curriculum for instruction on the cycling of matter and energy; we show that modifications of the physics curriculum to address the biological framework promotes strong gains in student understanding of these topics, as evidenced by analysis of student work. PMID- 23737630 TI - From F = ma to flying squirrels: curricular change in an introductory physics course. AB - We present outcomes from curricular changes made to an introductory calculus based physics course whose audience is primarily life sciences majors, the majority of whom plan to pursue postbaccalaureate studies in medical and scientific fields. During the 2011-2012 academic year, we implemented a Physics of the Life Sciences curriculum centered on a draft textbook that takes a novel approach to teaching physics to life sciences majors. In addition, substantial revisions were made to the homework and hands-on components of the course to emphasize the relationship between physics and the life sciences and to help the students learn to apply physical intuition to life sciences-oriented problems. Student learning and attitudinal outcomes were assessed both quantitatively, using standard physics education research instruments, and qualitatively, using student surveys and a series of postsemester interviews. Students experienced high conceptual learning gains, comparable to other active learning-based physics courses. Qualitatively, a substantial fraction of interviewed students reported an increased interest in physics relative to the beginning of the semester. Furthermore, more than half of students self-reported that they could now relate physics topics to their majors and future careers, with interviewed subjects demonstrating a high level of ability to come up with examples of how physics affects living organisms and how it helped them to better understand content presented in courses in their major. PMID- 23737631 TI - Using assessments to investigate and compare the nature of learning in undergraduate science courses. AB - Assessments and student expectations can drive learning: students selectively study and learn the content and skills they believe critical to passing an exam in a given subject. Evaluating the nature of assessments in undergraduate science education can, therefore, provide substantial insight into student learning. We characterized and compared the cognitive skills routinely assessed by introductory biology and calculus-based physics sequences, using the cognitive domain of Bloom's taxonomy of educational objectives. Our results indicate that both introductory sequences overwhelmingly assess lower-order cognitive skills (e.g., knowledge recall, algorithmic problem solving), but the distribution of items across cognitive skill levels differs between introductory biology and physics, which reflects and may even reinforce student perceptions typical of those courses: biology is memorization, and physics is solving problems. We also probed the relationship between level of difficulty of exam questions, as measured by student performance and cognitive skill level as measured by Bloom's taxonomy. Our analyses of both disciplines do not indicate the presence of a strong relationship. Thus, regardless of discipline, more cognitively demanding tasks do not necessarily equate to increased difficulty. We recognize the limitations associated with this approach; however, we believe this research underscores the utility of evaluating the nature of our assessments. PMID- 23737632 TI - Developing and assessing curriculum on the physics of medical instruments. AB - Undergraduate educational settings often struggle to provide students with authentic biologically or medically relevant situations and problems that simultaneously improve their understanding of physics. Through exercises and laboratory activities developed in an elective Physics in Biomedicine course for upper-level biology or pre-health majors at Portland State University, we aim to teach fundamental physical concepts, such as light absorption and emission and atomic energy levels, through analysis of biological systems and medical devices. The activities address the properties of electromagnetic waves as they relate to the interaction with biological tissue and make links between physics and biomedical applications such as microscopy or laser eye surgery. We report on the effect that engaging students in tasks with actual medical equipment has had on their conceptual understanding of light and spectroscopy. These initial assessments indicate that students' understanding improves in some areas as a result of taking the course, but gains are not uniform and are relatively low for other topics. We also find a promising "nonshift" in student attitudes toward learning science as a result of taking the course. A long-term goal of this work is to develop these materials to the extent that they can eventually be imported into an introductory curriculum for life sciences majors. PMID- 23737634 TI - Context dependence of students' views about the role of equations in understanding biology. AB - Students' epistemological views about biology--their ideas about what "counts" as learning and understanding biology--play a role in how they approach their courses and respond to reforms. As introductory biology courses incorporate more physics and quantitative reasoning, student attitudes about the role of equations in biology become especially relevant. However, as documented in research in physics education, students' epistemologies are not always stable and fixed entities; they can be dynamic and context-dependent. In this paper, we examine an interview with an introductory student in which she discusses the use of equations in her reformed biology course. In one part of the interview, she expresses what sounds like an entrenched negative stance toward the role equations can play in understanding biology. However, later in the interview, when discussing a different biology topic, she takes a more positive stance toward the value of equations. These results highlight how a given student can have diverse ways of thinking about the value of bringing physics and math into biology. By highlighting how attitudes can shift in response to different tasks, instructional environments, and contextual cues, we emphasize the need to attend to these factors, rather than treating students' beliefs as fixed and stable. PMID- 23737633 TI - Using a physics experiment in a lecture setting to engage biology students with the concepts of Poiseuille's law. AB - Biology students enrolled in a typical undergraduate physiology course encounter Poiseuille's law, a physics equation that describes the properties governing the flow of blood through the circulation. According to the equation, a small change in vessel radius has an exponential effect on resistance, resulting in a larger than expected change in blood flow. To help engage students in this important concept, we performed a physics experiment as a lecture demonstration to mimic the original research by the 19th-century French scientist. We tested its impact as a research project and found that students who viewed the demonstration reacted very positively and showed an immediate increase in test performance, while the control group was able to independently "catch up" at the fourth week posttest. We further examined whether students' math skills mapped to learning gains. The students with lower math scores who viewed the demonstration had slightly more improvement in test performance than those students who did not view the demonstration. Our data suggest that watching a lecture demonstration may be of even greater benefit to biology students with lower math achievement. PMID- 23737635 TI - The effects of the SUN project on teacher knowledge and self-efficacy regarding biological energy transfer are significant and long-lasting: results of a randomized controlled trial. AB - Biological energy flow has been notoriously difficult to teach. Our approach to this topic relies on abiotic and biotic examples of the energy released by moving electrons in thermodynamically spontaneous reactions. A series of analogical model-building experiences was supported with common language and representations including manipulatives. These materials were designed to help learners understand why electrons move in a hydrogen explosion and hydrogen fuel cell, so they could ultimately understand the rationale for energy transfer in the mitochondrion and the chloroplast. High school biology teachers attended a 2-wk Students Understanding eNergy (SUN) workshop during a randomized controlled trial. These treatment group teachers then took hydrogen fuel cells, manipulatives, and other materials into their regular biology classrooms. In this paper, we report significant gains in teacher knowledge and self-efficacy regarding biological energy transfer in the treatment group versus randomized controls. Significant effects on treatment group teacher knowledge and self efficacy were found not only post-SUN workshop but even 1 yr later. Teacher knowledge was measured with both a multiple-choice exam and a drawing with a written explanation. Teacher confidence in their ability to teach biological energy transfer was measured by a modified form of the Science Teaching Efficacy Belief Instrument, In-Service A. Professional development implications regarding this topic are discussed. PMID- 23737636 TI - The trouble with chemical energy: why understanding bond energies requires an interdisciplinary systems approach. AB - Helping students understand "chemical energy" is notoriously difficult. Many hold inconsistent ideas about what energy is, how and why it changes during the course of a chemical reaction, and how these changes are related to bond energies and reaction dynamics. There are (at least) three major sources for this problem: 1) the way biologists talk about chemical energy (which is also the way we talk about energy in everyday life); 2) the macroscopic approach to energy concepts that is common in physics and physical sciences; and 3) the failure of chemistry courses to explicitly link molecular with macroscopic energy ideas. From a constructivist perspective, it is unlikely that students can, without a coherent understanding of such a central concept, attain a robust and accurate understanding of new concepts. However, changes are on the horizon, guided by the increasing understanding that difficult concepts require coherent, well-designed learning progressions and the new National Research Council Framework for K-12 Science Education. We provide supporting evidence for our assertions and suggestions for an interdisciplinary learning progression designed to better approach the concept of bond energies, a first step in an understanding chemical energy and behavior of reaction systems that is central to biological systems. PMID- 23737639 TI - Navicular subluxation as a radiographic finding in Charcot neuroarthropathy. AB - BACKGROUND: Treatment of patients with Charcot midfoot destruction is a difficult and increasingly common clinical problem. The pathoanatomical features of Charcot neuropathy have been evaluated in only a few studies. This study evaluated whether medial navicular subluxation (adduction of the navicular on the talus) is a radiographic finding present in patients with Charcot neuroarthropathy. METHODS: A retrospective review of 143 consecutive patients diagnosed with Charcot arthropathy of the foot from January 2004 to May 2011 was performed. Patients were identified based on a clinical diagnosis code 713.5 during an outpatient clinic visit with 2 surgeons at a single institution. After exclusion criteria were applied, a series of radiographs of 50 feet in 40 patients were compared with radiographs from an age-matched control group. Radiographic data including talonavicular coverage angle and talonavicular uncoverage percentage were collected. RESULTS: The mean talonavicular coverage angle of the Charcot arthropathy group was 1.5 degrees and of the control group 12.1 degrees (P < .05). The talonavicular uncoverage value for the Charcot arthropathy group was 12.2% and for the control group 22.0% (P < .001). CONCLUSIONS: Medial navicular subluxation was a radiographic finding that was more commonly present in patients with Charcot arthropathy than in a matched control group. It is theorized that this finding is attributable to an unopposed pull of the posterior tibial tendon on the destabilized navicular. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 23737640 TI - Patient disclosure of medical misdeeds. AB - Modern patients walk a tightrope between respecting medical authority and acting as knowledgeable advocates regarding health issues, with the agency and responsibilities that come with this. This article uses conversation analysis to explore this balance in relation to patient disclosures of medical misdeeds in video-recorded primary care medical visits (e.g., taking another's prescription medication or failing to adhere to a healthy lifestyle or prescription regimen). We focus on patient-initiated disclosures. We show that disclosures are used (1) where patients are seeking physician assessment of their behavior, (2) where patients are proposing the etiology of a health problem, and (3) where patients are lobbying for a particular treatment outcome. We argue that disclosures of medical misdeeds are an important but understudied domain of conduct in which patients show awareness of their own agency over, and responsibility for, their healthcare and respect for the physician's medical authority. PMID- 23737641 TI - Rasayana drugs from the Ayurvedic system of medicine as possible radioprotective agents in cancer treatment. AB - The use of ionizing radiation, which is the cornerstone of cancer treatment, is compromised by the radiosensitivity of normal tissues. A chemical that can give selective benefit to the normal cells against the deleterious effects of ionizing radiation has been a long-sought goal. However, most of the compounds studied have shown inadequate clinical application owing to their inherent toxicity, undesirable side effects, and high cost. Studies carried out in the past 2 decades have shown that some of the classical Indian Ayurvedic drugs (Amritaprasham, Ashwagandha Rasayana, Brahma Rasayana, Chyavanprasha, Narasimha Rasayana, and Triphala Churna) possess radioprotective effects. In the current review, an attempt is made to summarize the radioprotective observations of these Ayurvedic drugs and the mechanisms responsible for the radioprotective effects. PMID- 23737642 TI - ATP is required and advances cytokine-induced gap junction formation in microglia in vitro. AB - Microglia are the immune cells in the central nervous system. After injury microglia release bioactive molecules, including cytokines and ATP, which modify the functional state of hemichannels (HCs) and gap junction channels (GJCs), affecting the intercellular communication via extracellular and intracellular compartments, respectively. Here, we studied the role of extracellular ATP and several cytokines as modulators of the functional state of microglial HCs and GJCs using dye uptake and dye coupling techniques, respectively. In microglia and the microglia cell line EOC20, ATP advanced the TNF-alpha/IFN-gamma-induced dye coupling, probably through the induction of IL-1beta release. Moreover, TNF alpha/IFN-gamma, but not TNF-alpha plus ATP, increased dye uptake in EOC20 cells. Blockade of Cx43 and Panx1 HCs prevented dye coupling induced by TNF-alpha/IFN gamma, but not TNF-alpha plus ATP. In addition, IL-6 prevented the induction of dye coupling and HC activity induced by TNF-alpha/IFN-gamma in EOC20 cells. Our data support the notion that extracellular ATP affects the cellular communication between microglia through autocrine and paracrine mechanisms, which might affect the timing of immune response under neuroinflammatory conditions. PMID- 23737644 TI - Glucagon-like peptide-1 triggers protective pathways in pancreatic beta-cells exposed to glycated serum. AB - Advanced glycation end products (AGEs) might play a pathophysiological role in the development of diabetes and its complications. AGEs negatively affect pancreatic beta-cell function and the expression of transcriptional factors regulating insulin gene. Glucagon-like peptide-1 (GLP-1), an incretin hormone that regulates glucose homeostasis, might counteract the harmful effects of AGEs on the beta cells in culture. The aim of this study was to identify the intracellular mechanisms underlying GLP-1-mediated protection from AGE-induced detrimental activities in pancreatic beta cells. HIT-T15 cells were cultured for 5 days with glycated serum (GS, consisting in a pool of AGEs), in the presence or absence of 10 nmol/L GLP-1. After evaluation of oxidative stress, we determined the expression and subcellular localization of proteins involved in maintaining redox balance and insulin gene expression, such as nuclear factor erythroid derived 2 (Nrf2), glutathione reductase, PDX-1, and MafA. Then, we investigated proinsulin production. The results showed that GS increased oxidative stress, reduced protein expression of all investigated factors through proteasome activation, and decreased proinsulin content. Furthermore, GS reduced ability of PDX-1 and MafA to bind DNA. Coincubation with GLP-1 reversed these GS-mediated detrimental effects. In conclusion, GLP-1, protecting cells against oxidants, triggers protective intercellular pathways in HIT-T15 cells exposed to GS. PMID- 23737643 TI - Neuropathic pain in animal models of nervous system autoimmune diseases. AB - Neuropathic pain is a frequent chronic presentation in autoimmune diseases of the nervous system, such as multiple sclerosis (MS) and Guillain-Barre syndrome (GBS), causing significant individual disablement and suffering. Animal models of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN) mimic many aspects of MS and GBS, respectively, and are well suited to study the pathophysiology of these autoimmune diseases. However, while much attention has been devoted to curative options, research into neuropathic pain mechanisms and relief has been somewhat lacking. Recent studies have demonstrated a variety of sensory abnormalities in different EAE and EAN models, which enable investigations of behavioural changes, underlying mechanisms, and potential pharmacotherapies for neuropathic pain associated with these diseases. This review examines the symptoms, mechanisms, and clinical therapeutic options in these conditions and highlights the value of EAE and EAN animal models for the study of neuropathic pain in MS and GBS. PMID- 23737645 TI - Prostaglandin D(2) in inflammatory arthritis and its relation with synovial fluid dendritic cells. AB - Prostaglandin (PG)D2 has been shown to be an active agent in the resolution of experimentally induced inflammation. This study was undertaken to determine the presence of PGD2 in chronic joint effusions and to explore the potential contributions of dendritic cells (DC) and monocytes to the intra-articular synthesis of PGD2. Synovial fluid (SF) was obtained from patients with inflammatory arthritis and knee effusions. PGD2 and PGE2 were detected in SF by ultrahigh-performance tandem mass spectrometry. Cellular fractions in SF were separated by density-gradient centrifugation and flow cytometry. The expression of hematopoietic prostaglandin D-synthase (hPGDS) and PGE-synthase (PGES) mRNA was determined by RT-PCR. Both PGD2 and PGE2 were detected in blood and SF, with PGD2 being more abundant than PGE2 in SF. mRNA for hPGDS was more abundant in SF mDCs than SF monocytes (P < 0.01) or PB monocytes (P < 0.001). SF mDC expressed significantly more hPGDS than PGES. Expressions of PGD2 and hPGDS were inversely associated with serum C-reactive protein (P < 0.01) and erythrocyte sedimentation rate (P < 0.01). The findings suggest that synovial DCs may be an important source of hPGDS and that systemic disease activity may be influenced by actions of PGD2 in RA and other arthropathies. PMID- 23737646 TI - Evaluation of clinical and immunological responses: a 2-year follow-up study in children with allergic rhinitis due to house dust mite. AB - Background. Allergic rhinitis is a disease with polarization towards Th2 and a defect of regulatory T cells. Immunological changes have been reported after immunotherapy treatment. However, there is not much known about the natural course of allergic rhinitis with respect to clinical manifestation and the relation with immunological responses. Objective. To evaluate clinical symptoms of allergic rhinitis, in relation to in vivo allergen-specific skin responses and in vitro allergen-specific effector and regulatory T cells determined at baseline and after two years. Methods. From a large trial, 59 children were randomly selected. The following variables were compared: clinical symptoms, allergen skin tests, specific IgE, T-cell proliferation, IL-5, IL-13, IFN-gamma, IL-10, TGF beta, CD4(+)CD25(hi) cells, and Foxp3 expression. Results. Allergic symptoms had decreased after two years. Whereas skin test reactions correlated between years 0 and 2, there was no change in the size of the reaction. Also, proinflammatory reactions did not change after two years, with a positive correlation between years 0 and 2. No relevant changes were observed with respect to regulatory cells. Conclusion. Whereas, comparable to immunotherapy, allergic complaints decrease, the immunological changes of specific T-cell activity (both effector cells and regulator cells) which are observed after immunotherapy, do not change. PMID- 23737647 TI - Pre- and posttherapy assessment of intestinal soluble mediators in IBD: where we stand and future perspectives. AB - Inflammatory bowel disease (IBD) is a chronic inflammatory condition characterized by an abnormal immune response against food or bacterial antigens in genetically predisposed individuals. Several factors of innate and adaptive immune system take part in the inflammatory process, probably actively contributing in endoscopic and histological healing at molecular level. Although it is difficult to discriminate whether they are primary factors in determining these events or they are secondarily involved, it would be interesting to have a clear map of those factors in order to have a restricted number of potentially "good candidates" for mucosal healing. The present review will present a class of these factors and their modulation in course of therapy, starting from pathogenic studies involving several treatments associated with good clinical outcomes. This approach is meant to help in the difficult task of identifying "good candidates" for healing signatures, which could also be possible new therapeutic targets for clinical management of IBD patients. PMID- 23737648 TI - IL-1 beta and IL-6 upregulation in children with H1N1 influenza virus infection. AB - The role of cytokines in relation to clinical manifestations, disease severity, and outcome of children with H1N1 virus infection remains thus far unclear. The aim of this study was to evaluate interleukin IL-1 beta and IL-6 plasma expressions and their association with clinical findings, disease severity, and outcome of children with H1N1 infection. We prospectively evaluated 15 children with H1N1 virus infection and 15 controls with lower respiratory tract infections (LRTI). Interleukin plasma levels were measured using immunoenzymatic assays. Significantly higher levels of IL-1 beta and IL-6 were detected in all patients with H1N1 virus infection compared to controls. It is noteworthy to mention that in H1N1 patients with more severe clinical manifestations of disease IL-1 beta and IL-6 expressions were significantly upregulated compared to H1N1 patients with mild clinical manifestations. In particular, IL-6 was significantly correlated with specific clinical findings, such as severity of respiratory compromise and fever. No correlation was found between interleukin expression and final outcome. In conclusion, H1N1 virus infection induces an early and significant upregulation of both interleukins IL1 beta and IL-6 plasma expressions. The upregulation of these cytokines is likely to play a proinflammatory role in H1N1 virus infection and may contribute to airway inflammation and bronchial hyperreactivity in these patients. PMID- 23737649 TI - Protective effect of short-term genistein supplementation on the early stage in diabetes-induced renal damage. AB - Hyperglycemia-induced oxidative stress has been concerned in the development of diabetic nephropathy (DN), which may cause kidney damage associated with inflammation and fibrosis. This study has been conducted to investigate the role of genistein supplementation in an acute DN state. Mice with FBG levels more than 250 mg/dL after alloxan injection (single i.p., 150 mg/kg) were considered as diabetic. Diabetic mice (DM) were further subdivided according to their FBG levels, medium-high FBG (DMMH < 450 mg/dL) and high FBG (DMH; 450 mg/dL) and were administrated by an AIG-93G diet supplemented with different doses of genistein (0, 0.025 or 0.1%). After 2 weeks' treatment, the levels of kidney malondialdehyde (MDA), blood urea nitrogen (BUN), and plasma creatinine and lipid profiles, as well as oxidative stress and inflammation-related markers, were measured (P < 0.05). Genistein supplementation improved levels of FBG in the DMMH groups, but not in the DMH group, regardless of the treatment dose. Moreover, the supplementation attenuated kidney oxidative stress indicated by MDA, BUN, and plasma creatinine. In addition, genistein treatment decreased inflammatory markers such as nuclear factor kappa B (p65), phosphorylated inhibitory kappa B alpha, C-reactive protein, monocyte chemotactic protein-1, cyclooxygenase-2, and tumor necrosis factor-alpha and improved oxidative stress markers (nuclear related factor E2, heme oxygenase-1, glutathione peroxidase, and superoxide dismutase isoforms) in treatment groups, regardless of the genistein treatment dose. Furthermore, genistein supplementation inhibited the fibrosis-related markers (protein kinase C, protein kinase C-beta II, and transforming growth factor-beta I) in the DN state. However, 0.1% genistein supplementation in diabetes with high FBG levels selectively showed a preventive effect on kidney damage. These results suggest that genistein might be a good protective substance for DN through regulation of oxidative stress and inflammation. In particular, genistein is more efficient in diabetes patients with medium-high blood glucose levels. Finally, it is required to establish the beneficial dosage of genistein according to blood glucose levels. PMID- 23737650 TI - Increased expression of VEGF and CD31 in postradiation rectal tissue: implications for radiation proctitis. AB - Background. Inflammation mediators related to radiation proctitis are partially elucidated, and neovascularization is thought to play a key role. Objectives. To investigate the expression of vascular endothelial growth factor (VEGF) and CD31 as angiogenetic markers in postradiation rectal tissue. Methods. Rectal mucosa biopsies from 11 patients who underwent irradiation for prostate cancer were examined immunohistochemically for the expression of VEGF and CD31 at three time settings-before, at the completion of, and 6 months after radiotherapy. VEGF expressing vascular endothelial cells and CD31 expressing microvessels were counted separately in 10 high-power fields (HPFs). VEGF vascular index (VEGF-VI) and microvascular density (MVD) were calculated as the mean number of VEGF positive cells per vessel or the mean number of vessels per HPF, respectively. Histological features were also evaluated. Results. VEGF-VI was significantly higher at the completion of radiotherapy (0.17 +/- 0.15 versus 0.41 +/- 0.24, P = 0.001) declining 6 months after. MVD increased significantly only 6 months after radiotherapy (7.3 +/- 3.2 versus 10.5 +/- 3.1, P < 0.005). The histopathological examination revealed inflammatory changes at the completion of radiotherapy regressing in the majority of cases 6 months after. Conclusions. Our results showed that in postradiation rectal biopsy specimens neoangiogenesis seems to be inflammation-related and constitutes a significant postradiation component of the tissue injury. PMID- 23737651 TI - NAG-1/GDF15 transgenic mouse has less white adipose tissue and a reduced inflammatory response. AB - NAG-1/GDF15 is a TGF- beta superfamily member with poorly characterized biological activity proposed to inhibit inflammatory cytokine production. Transgenic mice expressing human NAG-1/GDF15 (NAG-1 (Tg/Lox) ) are leaner with lower body weight and are resistant to chemically or genetically induced intestinal tumors. Because of the link between obesity, inflammation, and cancer, we examined whether these mice exhibit a reduced response to inflammatory stimuli. The NAG-1 (Tg/Lox) mice had a reduced inflammatory response to LPS based on the serum levels of cytokines KC, IL-6, MCP-1, and TNF alpha . In contrast to literature reports and our in vivo results, NAG-1 did not inhibit LPS-induced cytokine expression in vitro in RAW264.7 cells, mouse peritoneal macrophages, or mouse liver Kupffer cells, suggesting that NAG-1/GDF15 does not directly inhibit LPS-induced inflammatory cytokine production. However, NAG-1 (Tg/Lox) mice have less white adipose tissue, the major source of inflammatory adipokines including leptin. Basal and LPS-treated serum leptin and mRNA levels in the adipose tissue of NAG-1 (Tg/Lox) mice were lower than those in WT mice. We propose that the reduced white adipose tissue and reduced leptin expression may be responsible, in part, for the reduced inflammatory response to LPS and the decrease in intestinal tumors observed in NAG-1 (Tg/Lox) mice. PMID- 23737652 TI - Paradoxical glucose-sensitizing yet proinflammatory effects of acute ASP administration in mice. AB - Acylation stimulating protein (ASP) is an adipokine derived from the immune complement system, which stimulates fat storage and is typically increased in obesity, type 2 diabetes, and cardiovascular disease. Using a diet-induced obesity (DIO) mouse model, the acute effects of ASP on energy metabolism and inflammatory processes in vivo were evaluated. We hypothesized that ASP would specifically exert proinflammatory effects. C57Bl/6 wild-type mice were put on a high-fat-high-sucrose diet for 12 weeks. Mice were then subjected to both glucose and insulin tolerance tests, each manipulation being preceded by recombinant ASP or vehicle (control) bolus injection. ASP supplementation increased whole-body glucose excursion, and this was accomplished with reduced concomitant insulin levels. However, ASP did not directly alter insulin sensitivity. ASP supplementation induced a proinflammatory phenotype, with higher levels of cytokines including IL-6 and TNF-alpha in plasma and in adipose tissue, liver, and skeletal muscle mRNA. Additionally, ASP increased M1 macrophage content of these tissues. ASP exerted a direct concentration-dependent role in the migration and M1 activation of cultured macrophages. Altogether, the in vivo and in vitro experiments demonstrate that ASP plays a role in both energy metabolism and inflammation, with paradoxical whole-body glucose-sensitizing yet proinflammatory effects. PMID- 23737653 TI - Update on the protective molecular pathways improving pancreatic beta-cell dysfunction. AB - The primary function of pancreatic beta-cells is to produce and release insulin in response to increment in extracellular glucose concentrations, thus maintaining glucose homeostasis. Deficient beta-cell function can have profound metabolic consequences, leading to the development of hyperglycemia and, ultimately, diabetes mellitus. Therefore, strategies targeting the maintenance of the normal function and protecting pancreatic beta-cells from injury or death might be crucial in the treatment of diabetes. This narrative review will update evidence from the recently identified molecular regulators preserving beta-cell mass and function recovery in order to suggest potential therapeutic targets against diabetes. This review will also highlight the relevance for novel molecular pathways potentially improving beta-cell dysfunction. PMID- 23737654 TI - Probiotics in the management of lung diseases. AB - The physiology and pathology of the respiratory and gastrointestinal tracts are closely related. This similarity between the two organs may underlie why dysfunction in one organ may induce illness in the other. For example, smoking is a major risk factor for COPD and IBD and increases the risk of developing Crohn's disease. Probiotics have been defined as "live microorganisms which, when administered in adequate amounts, confer health benefits on the host." In model systems probiotics regulate innate and inflammatory immune responses. Commonly used probiotics include lactic acid bacteria, particularly Lactobacillus, Bifidobacterium, and Saccharomyces, and these are often used as dietary supplements to provide a health benefit in gastrointestinal diseases including infections, inflammatory bowel disease, and colon cancer. In this respect, probiotics probably act as immunomodulatory agents and activators of host defence pathways which suggest that they could influence disease severity and incidence at sites distal to the gut. There is increasing evidence that orally delivered probiotics are able to regulate immune responses in the respiratory system. This review provides an overview of the possible role of probiotics and their mechanisms of action in the prevention and treatment of respiratory diseases. PMID- 23737656 TI - Multicenter Randomized Trial of 10-French versus 11.5-French Plastic Stents for Malignant Biliary Obstruction. AB - Background. There is little prospective data on whether bigger plastic stents are better for patients with malignant biliary obstruction with jaundice. Goals. Multicenter prospective study to compare technical success, clinical response, stent occlusion, and patient survival in patients with malignant biliary obstruction randomized to 10-French or 11.5-French plastic stent. Study. Patients with malignant biliary obstruction were randomized to 10-French or 11.5-French biliary stents. Patients were prospectively assessed for stent occlusion, stent related interventions, hospital stay, and change in bilirubin. Main outcome measurements included technical success, clinical response, rates of stent occlusion, and survival. Results. 234 patients (47 hilar and 187 common bile duct strictures) were randomized. Outcomes were similar for the 10-French and 11.5 French groups (technical success 99.1% versus 97.4%, P = 0.37). Overall, median stent survival was 213 days, but there was no statistically significant difference in stent survival between 10-French and 11.5-French stents (149 versus 258 days, P = 0.16). Stent survival was significantly longer when placed for common bile duct versus hilar strictures (231 versus 115 days, P = 0.049). Conclusions. The theoretical advantage of improved bile flow for the 11.5-French stent does not translate into more prolonged patency, better clinical response, and longer patient survival than the 10-French stent. PMID- 23737657 TI - Diamond burr superficial keratectomy with mitomycin C for corneal scarring and high corneal astigmatism after pterygium excision. AB - BACKGROUND: The purpose of this paper is to report the successful treatment of corneal scarring and high corneal astigmatism secondary to previous pterygium surgery with diamond burr superficial keratectomy using mitomycin C. METHODS: Four patients with corneal scarring and high corneal astigmatism related to previous pterygium surgery underwent diamond burr superficial keratectomy with application of mitomycin C. Anterior segment photography and corneal topographic analysis were obtained preoperatively and postoperatively in all patients. RESULTS: Six months after surgery, corneal astigmatism and corneal aberrations were reduced in all patients. A clear cornea was achieved in all cases. No complications were noted during the follow-up period. CONCLUSION: Diamond burr superficial keratectomy with application of mitomycin C is a potentially effective and simple procedure for treating patients with corneal scarring and high corneal astigmatism secondary to previous pterygium surgery. PMID- 23737655 TI - Role of scavenger receptors in glia-mediated neuroinflammatory response associated with Alzheimer's disease. AB - It is widely accepted that cells serving immune functions in the brain, namely, microglia and astrocytes, are important mediators of pathological phenomena observed in Alzheimer's disease. However, it is unknown how these cells initiate the response that results in cognitive impairment and neuronal degeneration. Here, we review the participation of the immune response mediated by glial cells in Alzheimer's disease and the role played by scavenger receptors in the development of this pathology, focusing on the relevance of class A scavenger receptor (SR-A) for A beta clearance and inflammatory activation of glial cell, and as a potential target for Alzheimer's disease therapy. PMID- 23737658 TI - Ultra-widefield fluorescein angiography of white without pressure. AB - PURPOSE: To describe ultra-widefield fluorescein angiography (UWFA) findings in eyes with white without pressure (WWOP) and in eyes without any obvious peripheral chorioretinal disease, and to determine if a difference exists between these two groups. METHODS: A retrospective review of 379 eyes undergoing diagnostic UWFA using the Optos 200Tx imaging system. Eyes were excluded if the quality of the color photograph or UWFA prevented reliable evaluation. Eyes were also excluded if there was any evidence of peripheral retinal or choroidal disease, which was thought to have an effect on UWFA (eg, peripheral background diabetic or hypertensive retinopathy, vein occlusion, or any other peripheral vascular disorder). Eyes were determined to have WWOP, based on a dilated fundus examination and color fundus photography that contained areas of peripheral retinal whitening consistent with the diagnosis. UWFA was evaluated by trained masked graders, and determined to have or not have peripheral vascular leakage and/or staining. RESULTS: Of the 379 eyes evaluated, 45 eyes were included in the study. Twelve eyes were determined to have peripheral WWOP; 33 eyes did not have WWOP on examination or color fundus photography. Three common UWFA peripheral patterns were visualized. Eyes with and without WWOP were grouped into one of three patterns. The majority of eyes without WWOP demonstrated UWFA pattern one (69.7%), while those in the WWOP group demonstrated pattern three (50%). The distribution of UWFA patterns is statistically different between those with and without WWOP (P = 0.002). In eyes without WWOP, in patients with no documented systemic microvascular disease (diabetes, hypertension), 71.4% of eyes had UWFA pattern one while 14.3% had both patterns two and three. CONCLUSION: This study is one of the first to specifically evaluate peripheral vascular leakage/staining in eyes with WWOP as well as in eyes without any obvious peripheral chorioretinal disease. We demonstrate that a significant portion of WWOP eyes exhibit peripheral findings on UWFA (pattern one) compared to eyes without WWOP. Importantly, even in eyes that are apparently unremarkable in the periphery on exam and color photography, UWFA can still show peripheral vascular abnormalities. These results warrant further investigation. PMID- 23737659 TI - Azithromycin: assessment of intrinsic cytotoxic effects on corneal epithelial cell cultures. AB - PURPOSE: To compare the cytotoxic effects of preservative-free azithromycin on corneal epithelial cells in vivo with those of preservative-free netilmicin and levofloxacin, and the preservative benzalkonium chloride (BAK). METHODS: Rabbit corneal epithelial cells in vitro were incubated for 15 minutes or 6 hours with commercially available ophthalmic preservative-free netilmicin 0.3%, levofloxacin 0.3%, or azithromycin 1.5% preparations or different concentrations of unpreserved azithromycin and different concentrations of BAK. Qualitative analysis was undertaken using phase-contrast optics to examine the morphological aspects of cell cultures and quantitative analysis was undertaken by measuring the release of the cytoplasmic enzyme lactate dehydrogenase into the medium immediately and 24 hours after exposure to drugs. Finally, we observed the wound healing rate of mechanically injured corneal epithelial cells exposed to each antibiotic ophthalmic preparation for 48 hours. RESULTS: Our results show that both the commercially available unpreserved mono-dose preparation of azithromycin and ophthalmic preparations of azithromycin up to a concentration of 1.5% were virtually devoid of harmful effects under our experimental conditions. This was not significantly different from the results obtained for the other antibiotic preparations (P > 0.05) tested, but was unlike the results obtained for BAK. Azithromycin 1.5% also showed good recovery properties after a mechanical wound test. CONCLUSION: Under our experimental conditions, unpreserved azithromycin 1.5% showed a much lower toxicity than BAK and did not interfere with the wound healing process. PMID- 23737660 TI - Development of a robust cell-based high-throughput screening assay to identify targets of HIV-1 viral protein R dimerization. AB - Targeting protein-protein interactions (PPI) is an emerging field in drug discovery. Dimerization and PPI are essential properties of human immunodeficiency virus (HIV)-1 proteins, their mediated functions, and virus biology. Additionally, dimerization is required for the functional interaction of HIV-1 proteins with many host cellular components. In this study, a bimolecular fluorescence complementation (BiFC)-based screening assay was developed that can quantify changes in dimerization, using HIV-1 viral protein R (Vpr) dimerization as a "proof of concept." Results demonstrated that Venus Vpr (generated by BiFC Vpr constructs) could be competed off in a dose-dependent manner using untagged, full-length Vpr as a competitor molecule. The change in signal intensity was measured quantitatively through flow cytometry and fluorescence microscopy in a high content screening assay. High content imaging was used to screen a library of small molecules for an effect on Vpr dimerization. Among the tested molecules, a few of the small molecules demonstrate an effect on Vpr dimerization in a dose dependent manner. PMID- 23737661 TI - Fluocinolone acetonide intravitreal implant for the treatment of diabetic macular edema. AB - Diabetic macular edema (DME) remains one of the leading causes of moderate to severe vision loss. Although laser photocoagulation was the standard of care for several years, few patients achieved significant improvements in visual acuity. As a result, several pharmacotherapies and surgeries have been investigated. The fluocinolone acetonide devices are one of the latest therapies considered for the treatment of DME. Despite bringing significant improvements in visual acuity, fluocinolone devices are associated with cataract formation, increased intraocular pressure (IOP), and surgery to lower IOP. Due to the risk of complications, fluocinolone acetonide devices should be considered only in cases refractive to first-line therapies. In this review, we evaluate current and emerging therapies for DME, with special emphasis on fluocinolone acetonide intravitreal devices. PMID- 23737662 TI - Impact of reducing dosing frequency on adherence to oral therapies: a literature review and meta-analysis. AB - OBJECTIVES: To assess the impact of reduced frequency of oral therapies from multiple-dosing schedules to a once-daily (OD) dosing schedule on adherence, compliance, persistence, and associated economic impact. METHODS: A meta-analysis was performed based on relevant articles identified from a comprehensive literature review using MEDLINE(r) and Embase(r). The review included studies assessing adherence with OD, twice-daily (BID), thrice-daily (TID), and four times daily (QID) dosing schedules and costs associated with optimal/suboptimal adherence among patients with acute and chronic diseases. Effect estimates across studies were pooled and analyzed using the DerSimonian and Laird random-effect model. RESULTS: Forty-three studies met inclusion criteria, and meta-analyzable data were available from 13 studies. The overall results indicated that OD schedules were associated with higher adherence rates (odds ratio [OR] 3.07, 95% confidence interval [CI] 1.80-5.23; P < 0.001 for OD versus > OD dosing) and compliance rates (OR 3.50, 95% CI 1.73-7.08; P < 0.001 for OD versus > OD dosing); persistence rates showed the same direction but were not statistically significant (OR 1.43, 95% CI 0.62-3.29; P = 0.405 for OD versus BID dosing). Results for each of the conditions were consistent with those observed overall with respect to showing the benefits of less frequent dosing. From a health economic perspective, higher adherence rates with OD relative to multiple dosing in a number of conditions were consistently associated with corresponding lower costs of health care resources utilization. CONCLUSION: Current meta-analyses suggested that across acute and chronic disease states, reducing dosage frequency from multiple dosing to OD dosing may improve adherence to therapies among patients. Improving adherence may result in subsequent decreases in health care costs. PMID- 23737663 TI - Sex inequality, high transport costs, and exposed clinic location: reasons for loss to follow-up of clients under prevention of mother-to-child HIV transmission in eastern Uganda - a qualitative study. AB - BACKGROUND: In Iganga, Uganda, 45% of women who tested HIV-positive during antenatal care between 2007 and 2010 were lost to follow-up (LTFU). We explored reasons for LTFU during prevention of mother-to-child transmission (PMTCT) from a client perspective in eastern Uganda, where antiretroviral therapy (ART) awareness is presumably high. METHODS: Seven key informant interviews and 20 in depth interviews, including both clients who had been retained under PMTCT care and those LTFU during PMTCT were held. Ten focus-group discussions involving a total of 112 participants were also conducted with caretakers/ relatives of the PMTCT clients. Content analysis was performed to identify recurrent themes. RESULTS: Our findings indicate that LTFU during PMTCT in eastern Uganda was due to sex inequality, high transport costs to access the services, inadequate posttest counseling, lack of HIV status disclosure, and the isolated/exposed location of the ART clinic, which robs the clients of their privacy. CONCLUSION: There is a need for approaches that empower women with social capital, knowledge, and skills to influence health-seeking practices. There is also a need to train low-ranking staff and take PMTCT services closer to the clients at the lower level units to make them affordable and accessible to rural clients. Posttest counseling should be improved to enable PMTCT clients to appreciate the importance of PMTCT services through increasing the number of staff in antenatal care to match the client numbers for improved quality. The counseling should emphasize HIV status disclosure to partners and encourage partner escort for antenatal care visits for further counseling. The exposed and isolated ART clinic should be integrated with the other regular outpatient services to reduce the labeling stigma. PMID- 23737664 TI - User assessment of Norditropin NordiFlex((r)), a new prefilled growth hormone pen: a Phase IV multicenter prospective study. AB - BACKGROUNDAIM: In growth disorders, ensuring long-term growth hormone therapy (GHT) remains a challenge that might compromise the clinical outcome. Consequently, strategies aiming at alleviating the burden of daily injection might improve the treatment benefit. The study reported here was performed to assess the ease of use of Norditropin NordiFlex((r)) (Novo Nordisk, Princeton, NJ, USA) compared with that of the devices previously used in children treated with GHT with recombinant somatropin. METHODS: This Phase IV prospective, multicenter, open-label study was conducted in France. All patients received Norditropin NordiFlex for 6 weeks. Oral questionnaires were administered by the physician to the patients and/or the parents at inclusion and at the final visit. RESULTS: This study included 103 patients aged between 6 and 17 years. The patients assessed Norditropin NordiFlex as significantly easier to use than their previous device (median value = 7.5, P < 0.001). Almost three-quarters of patients (64.4%) preferred Norditropin NordiFlex to their previous device. Among physicians and nurses, 73% assessed Norditropin NordiFlex training as "very easy" and 26% as "easy." Norditropin NordiFlex improved patient autonomy, with 41% of patients able to self-inject the treatment. CONCLUSION: This study has shown that Norditropin NordiFlex is reliable, safe, and easy to use and most study patients preferred it to their previous device. These characteristics may improve the adherence to GHT. PMID- 23737665 TI - Polyethylenimine600-beta-cyclodextrin: a promising nanopolymer for nonviral gene delivery of primary mesenchymal stem cells. AB - Genetically modified mesenchymal stem cells (MSCs) have great potential in the application of regenerative medicine and molecular therapy. In the present manuscript, we introduce a nanopolymer, polyethylenimine600-beta-cyclodextrin (PEI600-beta-CyD), as an efficient polyplex-forming plasmid delivery agent with low toxicity and ideal transfection efficiency on primary MSCs. PEI600-beta-CyD causes significantly less cytotoxicity and apoptosis on MSCs than 25 kDa high molecular-weight PEI (PEI25kDa). PEI600-beta-CyD also exhibits similar transfection efficiency as PEI25kDa on MSCs, which is higher than that of PEI600Da. Quantum dot-labeled plasmids show that PEI600-beta-CyD or PEI25kDa delivers the plasmids in a more scattered manner than PEI600Da does. Further study shows that PEI600-beta-CyD and PEI25kDa are more capable of delivering plasmids into the cell lysosome and nucleus than PEI600Da, which correlates well with the results of their transfection-efficiency assay. Moreover, among the three vectors, PEI600-beta-CyD has the most capacity of enhancing the alkaline phosphatase activity of MSCs by transfecting bone morphogenetic protein 2, 7, or special AT-rich sequence-binding protein 2. These results clearly indicate that PEI600-beta-CyD is a safe and effective candidate for the nonviral gene delivery of MSCs because of its ideal inclusion ability and proton sponge effect, and the application of this nanopolymer warrants further investigation. PMID- 23737666 TI - Preparation and controlled-release studies of a protocatechuic acid magnesium/aluminum-layered double hydroxide nanocomposite. AB - In the study reported here, magnesium/aluminum (Mg/Al)-layered double hydroxide (LDH) was intercalated with an anticancer drug, protocatechuic acid, using ion exchange and direct coprecipitation methods, with the resultant products labeled according to the method used to produce them: "PANE" (ie, protocatechuic acid Mg/Al nanocomposite synthesized using the ion-exchange method) and "PAND" (ie, protocatechuic acid-Mg/Al nanocomposite synthesized using the direct method), respectively. Powder X-ray diffraction and Fourier transform infrared spectroscopy confirmed the intercalation of protocatechuic acid into the inter galleries of Mg/Al-LDH. The protocatechuic acid between the interlayers of PANE and PAND was found to be a monolayer, with an angle from the z-axis of 8 degrees for PANE and 15 degrees for PAND. Thermogravimetric and differential thermogravimetric analysis results revealed that the thermal stability of protocatechuic acid was markedly enhanced upon intercalation. The loading of protocatechuic acid in PANE and PAND was estimated to be about 24.5% and 27.5% (w/w), respectively. The in vitro release study of protocatechuic acid from PANE and PAND in phosphate-buffered saline at pH 7.4, 5.3, and 4.8 revealed that the nanocomposites had a sustained release property. After 72 hours incubation of PANE and PAND with MCF-7 human breast cancer and HeLa human cervical cancer cell lines, it was found that the nanocomposites had suppressed the growth of these cancer cells, with a half maximal inhibitory concentration of 35.6 MUg/mL for PANE and 36.0 MUg/mL for PAND for MCF-7 cells, and 19.8 MUg/mL for PANE and 30.3 MUg/mL for PAND for HeLa cells. No half maximal inhibitory concentration for either nanocomposite was found for 3T3 cells. PMID- 23737667 TI - Understanding the wetting properties of nanostructured selenium coatings: the role of nanostructured surface roughness and air-pocket formation. AB - Wetting properties of biomaterials, in particular nanomaterials, play an important role, as these influence interactions with biological elements, such as proteins, bacteria, and cells. In this study, the wetting phenomenon of titanium substrates coated with selenium nanoparticles was studied using experimental and mathematical modeling tools. Importantly, these selenium-coated titanium substrates were previously reported to increase select protein adsorption (such as vitronectin and fibronectin), to decrease bacteria growth, and increase bone cell growth. Increased selenium nanoparticle coating density resulted in higher contact angles but remained within the hydrophilic regime. This trend was found in disagreement with the Wenzel model, which is widely used to understand the wetting properties of rough surfaces. The trend also did not fit well with the Cassie-Baxter model, which was developed to understand the wetting properties of composite surfaces. A modified wetting model was thus proposed in this study, to understand the contributing factors of material properties to the hydrophilicity/hydrophobicity of these nanostructured selenium-coated surfaces. The analysis and model created in this study can be useful in designing and/or understanding the wetting behavior of numerous biomedical materials and in turn, biological events (such as protein adsorption as well as bacteria and mammalian cell functions). PMID- 23737668 TI - Influence of hydrophilic additives on the supersaturation and bioavailability of dutasteride-loaded hydroxypropyl-beta-cyclodextrin nanostructures. AB - The objectives of this study were to develop a novel solid dutasteride formulation with improved physicochemical properties and oral bioavailability, and to examine the correlation between its in vitro dissolution and in vivo pharmacokinetic parameters. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) nanostructures with or without hydrophilic additives were manufactured using the supercritical antisolvent process. The dutasteride-loaded HP-beta-CD nanoparticles formed aggregates with a mean particle size of less than 160 nm and a specific surface area greater than 100 m(2)/g. Increases in the supersaturation and dissolution rate for dutasteride were dependent on the type of additive; increases in maximum solubility and extended supersaturation were observed in dutasteride-loaded HP-beta-CD nanostructures with hydroxypropylmethyl cellulose, whereas the dissolution rate was the highest for nanostructures containing d alpha-tocopheryl polyethylene glycol 1000 succinate. In rats, the oral bioavailability of dutasteride increased with the supersaturation induced by the HP-beta-CD nanostructures. In addition, compared with the in vitro drug release rate, the in vivo pharmacokinetic parameters were more closely correlated with in vitro parameters related to supersaturation (solubility). Further, the bioavailability of the dutasteride-loaded HP-beta-CD nanostructures with hydroxypropylmethyl cellulose was similar to that of the commercially available soft gelatin capsule (Avodart(r)). In conclusion, preparation of dutasteride loaded HP-beta-CD nanostructures using the supercritical antisolvent process affords a viable alternative solid dosage form for dutasteride. PMID- 23737669 TI - The in vitro sustained release profile and antitumor effect of etoposide-layered double hydroxide nanohybrids. AB - Magnesium-aluminum layered double hydroxides intercalated with antitumor drug etoposide (VP16) were prepared for the first time using a two-step procedure. The X-ray powder diffraction data suggested the intercalation of VP16 into layers with the increased basal spacing from 0.84-1.18 nm was successful. Then, it was characterized by X-ray powder diffraction, Fourier transform infrared spectroscopy, thermogravimetry and differential thermal analysis, and transmission electron microscopy. The prepared nanoparticles, VP16-LDH, showed an average diameter of 62.5 nm with a zeta potential of 20.5 mV. Evaluation of the buffering effect of VP16-LDH indicated that the nanohybrids were ideal for administration of the drugs that treat human stomach irritation. The loading amount of intercalated VP16 was 21.94% and possessed a profile of sustained release. The mechanism of VP16-LDH release in the phosphate buffered saline solution at pH 7.4 is likely controlled by the diffusion of VP16 anions from inside to the surface of LDH particles. The in vitro cytotoxicity and antitumor assays indicated that VP16-LDH hybrids were less toxic to GES-1 cells while exhibiting better antitumor efficacy on MKN45 and SGC-7901 cells. These results imply that VP16-LDH is a potential antitumor drug for a broad range of gastric cancer therapeutic applications. PMID- 23737670 TI - Development of biodegradable methylprednisolone microparticles for treatment of articular pathology using a spray-drying technique. AB - In this work, microparticles were prepared by spray-drying using albumin, chondroitin sulfate, and hyaluronic acid as excipients to create a controlled release methylprednisolone system for use in inflammatory disorders such as arthritis. Scanning electron microscopy demonstrated that these microparticles were almost spherical, with development of surface wrinkling as the methylprednisolone load in the formulation was increased. The methylprednisolone load also had a direct influence on the mean diameter and zeta potential of the microparticles. Interactions between formulation excipients and the active drug were evaluated by x-ray diffraction, differential scanning calorimetry, and thermal gravimetric analysis, showing limited amounts of methylprednisolone in a crystalline state in the loaded microparticles. The encapsulation efficiency of methylprednisolone was approximately 89% in all formulations. The rate of methylprednisolone release from the microparticles depended on the initial drug load in the formulation. In vitro cytotoxic evaluation using THP-1 cells showed that none of the formulations prepared triggered an inflammatory response on release of interleukin-1beta, nor did they affect cellular viability, except for the 9.1% methylprednisolone formulation, which was the maximum test concentration used. The microparticles developed in this study have characteristics amenable to a therapeutic role in inflammatory pathology, such as arthritis. PMID- 23737671 TI - Abundance of Flt3 and its ligand in astrocytic tumors. AB - BACKGROUND: Molecular targeted therapies for astrocytic tumors are the subject of growing research interest, due to the limited response of these tumors, especially glioblastoma multiforme, to conventional chemotherapeutic regimens. Several of these approaches exploit the inhibition of receptor tyrosine kinases. To date, it has not been elucidated if fms-like tyrosine kinase-3 (Flt3) and its natural ligand (Flt3L) are expressed in astrocytic tumors, although some of the clinically intended small-molecule receptor tyrosine kinase inhibitors affect Flt3, while others do not. More importantly, the recent proof of principle for successful stimulation of the immune system against gliomas in preclinical models via local Flt3L application requires elucidation of this receptor tyrosine kinase pathway in these tumors in more detail. This therapy is based on recruitment of Flt3-positive dendritic cells, but may be corroborated by activity of this signaling pathway in glioma cells. METHODS: Receptor and ligand expression was analyzed by real-time polymerase chain reaction in 31 astrocytic tumors (six diffuse and 11 anaplastic astrocytomas, 14 glioblastomas) derived from patients of both genders and in glioblastoma cell lines. The two most common activating mutations of the Flt3 gene, ie, internal tandem duplication and D835 point mutation, were assessed by specific polymerase chain reaction. RESULTS: A relatively high abundance of Flt3L mRNA (4%-6% of the reference, b2 microglobulin) could be demonstrated in all tumor samples. Flt3 expression could generally be demonstrated by 40 specific polymerase chain reaction cycles and gel electrophoresis in 87% of the tumors, including all grades, although the small quantities of the receptor did not allow reliable quantification. Expression of both mRNAs was verified in the cell lines, excluding a derivation solely from contaminating lymphocytes or macrophages. No activating mutations were found. CONCLUSION: Our results warrant further analysis of endogenous Flt3 signaling in these tumors prior to application of immunotherapy in human patients. PMID- 23737672 TI - Nanoparticle albumin-bound paclitaxel combined with cisplatin as the first-line treatment for metastatic esophageal squamous cell carcinoma. AB - Esophageal cancer is a major health hazard in many parts of the world and is often diagnosed late. The objective of this study was to explore the efficacy and safety of nanoparticle albumin-bound paclitaxel (Nab-PTX) combined with cisplatin (DDP) in patients with metastatic esophageal squamous cell carcinoma (ESCC). Patients with histologically confirmed ESCC were treated with Nab-PTX 250 mg/m(2) and DDP 75 mg/m(2) intravenously on day 1, every 21 days. Evaluation was performed after every two cycles of therapy and the therapy was continued until disease progression or unacceptable toxicity. From April 2010 to December 2012, 33 patients were enrolled. Ten patients had recurrent and metastatic tumors after surgery and 23 patients were diagnosed with unresectable metastatic disease. Patients received a median of four cycles of therapy (ranging from two to six cycles). Twenty patients achieved partial response and nine patients achieved stable disease; no complete response was observed. The objective response rate was 60.6% and the disease control rate was 87.9%. The median progression-free survival was 6.2 months (95% confidence interval: 4.0 to 8.4 months) and the median overall survival was 15.5 months (95% CI: 7.6 to 23.4 months). Only four patients experienced grade 3 adverse events, including vomiting, neutropenia, and sensory neuropathy. The most common adverse events were nausea/vomiting (81.8%), neutropenia (63.6%), leucopenia (48.5%), anemia (24.2%) and sensory neuropathy (24.2%). In conclusion, the combination of Nab-PTX and DDP is a highly effective and well-tolerated first-line treatment in metastatic ESCC. PMID- 23737674 TI - Rheumatoid arthritis is an autoimmune disease caused by periodontal pathogens. AB - A statistically significant association between periodontal disease (PD) and systemic diseases has been identified. Rheumatoid arthritis (RA), which is a chronic inflammatory joint disease, exhibits similar characteristics and pathogenesis to PD. The association between RA and PD has been investigated, and numerous publications on this subject exist. Approximately 20 bacterial species have been identified as periodontal pathogens, and these organisms are linked to various types of PD. The most analyzed species of periodontopathic bacteria are Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia, and Aggregatibacter actinomycetemcomitans. Antibodies and DNA from these oral pathogens have been isolated from the sera and synovial fluids of RA patients. This rapid communication describes the role of periodontal pathogens in the etiopathogenesis of RA. PMID- 23737675 TI - Effectiveness of exercise on cognitive impairment and Alzheimer's disease. AB - Physical activity has a protective effect on brain function in older people. Here, we briefly reviewed the studies and results related to the effects of exercise on cognitive impairment and Alzheimer's disease. The main findings from the current body of literature indicate positive evidence for structured physical activity (cardiorespiratory and resistance exercise) as a promising non pharmacological intervention for preventing cognitive decline. More studies are needed to determine the mechanisms involved in this preventative effect, including on strength, cardiorespiratory, and other types of exercise. Thus, the prevention of Alzheimer's disease may depend on healthy lifestyle habits, such as a structured physical fitness program. PMID- 23737676 TI - Clinical outcome of incidentally discovered small renal cell carcinoma after delayed surgery. AB - BACKGROUND: This study was undertaken to investigate the growth rate and clinical outcome of patients with a small renal mass (SRM) after delayed surgery. METHODS: We reviewed the clinical records of 34 patients with SRMs <= 4 cm at diagnosis, who underwent delayed surgical intervention during surveillance from January 2000 to December 2011. Radiographic evaluations using computed tomography (CT) scan and magnetic resonance imaging (MRI) were performed at least every 6 months, and the tumor size was determined at least twice. RESULTS: The mean follow-up time was 26.6 +/- 18.6 months and mean tumor doubling time was 23.4 +/- 16.0 months. Histopathological analysis revealed that 32 of the 34 patients were malignant in pT1aN0M0. Only one patient showed tumor recurrence, who subsequently died due to tumor progression. CONCLUSION: The growth rate of the small renal mass was slow in the majority of our patients. Delayed intervention does not have a detrimental effect on cancer-specific outcomes. PMID- 23737677 TI - Determinants of condom use by men in extramarital relationships in Nigeria. AB - BACKGROUND: Extramarital sex is a high-risk behavior in terms of Human Immunodeficiency Virus (HIV) transmission, yet condom use in extramarital relationships is an understudied area in Africa, and Nigeria in particular, where such liaisons are not uncommon. This study highlights key determinants of condom use among men who engage in extramarital sex in Nigeria. METHODS: Results are based on a subsample of 642 married men from a combined dataset from three waves of the National HIV/AIDS and Reproductive Health Survey (NARHS), a set of multiround nationally representative surveys. Logistic regression was employed to explore possible determinants of condom use in extramarital sex. The motivation, opportunity, and ability model was applied in selecting the determinants. RESULTS: HIV risk-reduction knowledge was found not to be associated with condom use. At the full logistic regression model, being of the Yoruba tribe, having no misconception about HIV transmission, ability to discuss condom use, and ability to wear condoms were the key variables significantly associated with condom use in extramarital sex. CONCLUSION: Implementing HIV risk-reduction behavior change requires more than knowledge. Behavioral skills in condom use are critical. Intervention efforts should move away from knowledge about risk to concentrate on improving skills on how to discuss condom use and wear condoms correctly. PMID- 23737678 TI - Burden of vasomotor symptoms in France, Germany, Italy, Spain, and the United Kingdom. AB - BACKGROUND: Several studies have documented a significant association between vasomotor symptoms (VMS) and a decrement in health outcomes among postmenopausal women, but these studies have mostly focused on the US. The aim of the current study was to broaden this investigation by examining the burden of VMS symptoms in the European Union with respect to both humanistic and economic outcomes. METHODS: All women aged 40-75 years who completed the 2010 5EU (France, Germany, Italy, Spain, and the UK) National Health and Wellness Survey were identified as potential respondents and invited to participate in an additional cross sectional, Internet-based survey. Only postmenopausal women from 5EU were included in the current analyses (n = 3801). VMS was assessed using the Menopausal Rating Scale, and was used in multiple regression models as the primary predictor of health status (EQ-5D-3L), work productivity loss, and the number of physician visits due to menopause. RESULTS: Over half (50.3%) of postmenopausal women experienced either mild (24.6%), moderate (17.6%), or severe (8.1%) VMS. Controlling for confounding variables, mild (b = -0.03, P < 0.05), moderate (b = -0.07, P < 0.05), and severe VMS (b = -0.17, P < 0.05) were each associated with worse health utilities relative to women without VMS. Similarly, increased resource use (b = 1.04-2.39, all P < 0.05), overall work impairment (b = 8.71-19.69, all P < 0.05), and activity impairment (b = 11.22-24.54, all P < 0.05) were also observed as VMS severity increased (with each b representing the difference between each level of severity and the reference category). CONCLUSION: These results suggest a high prevalence of VMS in Western Europe. These symptoms are also associated with both humanistic and economic outcomes. Improved management of VMS may be able to increase the health status and ability to work productively as well as reduce societal direct costs. PMID- 23737679 TI - Preventing ovarian cancer by salpingectomy. PMID- 23737680 TI - Opportunistic salpingectomy: the way forward-response to Steven Narod. PMID- 23737681 TI - Salpingectomy to prevent ovarian cancer: A Countercurrents Series. PMID- 23737682 TI - Fallopian tube removal: "stic-ing" it to ovarian cancer: what is the utility of prophylactic tubal removal? PMID- 23737683 TI - The potential role for acupuncture in treating symptoms in patients with lung cancer: an observational longitudinal study. AB - BACKGROUND: Most lung cancer patients experience multiple symptoms related either to the disease or its treatment. The commonly reported symptoms are pain, depression, anxiety, nausea, and poor well-being. The aim of the present study was to evaluate the effect of acupuncture as a potential treatment modality in symptomatic lung cancer patients. METHODS: This prospective observational study enrolled 33 lung cancer patients from the Peter Brojde Lung Cancer Centre between August 2010 and May 2012. All patients received 45-minute sessions of acupuncture, 1-2 times weekly for a minimum of 4 sessions. Symptom severity was assessed using the Edmonton Symptom Assessment System (esas) before and after completion of acupuncture. RESULTS: The study cohort included 30 patients with non-small- cell lung cancer and 3 with small-cell lung cancer. Mean age was 62 years (range: 36-88 years); 17 of the patients were women. Most of the patients had advanced-stage cancer (73%) and good performance status (Eastern Cooperative Oncology Group 0-1: 88%). Of these patients, 67% received anticancer treatment (chemotherapy or radiotherapy, or both) with acupuncture. Of the remaining 10 patients, 8 received acupuncture after a complete surgical resection of their tumour, and because of their advanced age, 2 received acupuncture and best supportive care. The median number of acupuncture sessions was 7 (interquartile range: 4-13 sessions). Statistically significant improvements in pain, appetite, nausea, nervousness, and well-being were observed. A clinically important improvement (2 points on the esas) was reported by 61% of patients for pain and by 33% for well-being. A significant positive correlation between improved well being and the number of acupuncture sessions was observed. This correlation remained significant even after controlling for treatment and narcotic use. Receiver operating characteristic analysis demonstrated that a minimum of 6 acupuncture sessions are required for a 70% chance of a clinically important improvement in well-being. CONCLUSIONS: The present study is the first to demonstrate that acupuncture may be an effective approach for improving symptoms in particular, pain and well-being-in lung cancer patients. Acupuncture is a safe and minimally invasive procedure, and it is potentially useful even in patients undergoing anticancer treatment. PMID- 23737684 TI - Responses by breast and prostate cancer patients to out-of-pocket costs in Newfoundland and Labrador. AB - PURPOSE: Cancer patients face substantial care-related out-of-pocket (oop) costs that may influence treatment decisions, attitudes, and use of drug- or appointment-related cost-saving strategies. We examined the relationship between oop costs and care-related responses by patients. METHODS: We surveyed 170 prostate and 131 breast cancer patients presenting at clinics or support groups, or listed on the cancer registry in Newfoundland and Labrador. RESULTS: In the 3 month period before the survey, 18.8% of prostate and 25.2% of breast cancer patients had oop costs greater than $500. Those oop costs consumed more than 7.5% of quarterly household income for 15.9% of prostate and 19.1% of breast cancer patients. Few patients (8.8% prostate, 15.3% breast) ever adopted any drug- or appointment-related cost-saving strategy. Few patients (7.2% prostate, 9.6% breast) said oop costs influenced treatment decisions, told their physicians about their oop costs (27.0% prostate, 21.1% breast), or were aware of available financial assistance programs (27.3% prostate, 36.9% breast). Compared with patients having low or moderate oop costs (22.9% prostate, 16.7% breast, and 25.7% prostate, 58.3% breast respectively), a larger proportion of prostate (56.0%) and breast (58.3%) cancer patients with high oop costs said that those costs created stress. Among prostate cancer patients, a larger proportion of those having high oop costs (compared with low or moderate costs) used drug related (22.2% vs. 3.3% and 9.6% respectively) and appointment-related (11.1% vs. 1.1% and 3.8% respectively) cost-saving strategies, said oop costs created an unusual amount of stress (48.0% vs. 18.4% and 10.4%), and had difficulty paying those costs (29.2% vs. 6.2% and 10.4%). CONCLUSIONS: For a small group of breast and prostate cancer patients, oop costs are high, but rarely lead to the use of care-related cost-saving strategies or influence care decisions. PMID- 23737685 TI - Clinical information available to oncologists in surgically treated rectal cancer: room to improve. AB - INTRODUCTION: In rectal cancer, decisions about the use of adjuvant and neoadjuvant treatment rely on clinical information from a variety of sources. Currently, the quality and accuracy of the aggregate of this clinical information is unclear. The objectives of the present study were to evaluate the completeness and quality of clinical information available to oncologists managing rectal cancer. METHODS: All patients diagnosed with rectal cancer in Nova Scotia between 2001 and 2005 were identified through the provincial cancer registry. The registry was linked to other administrative databases to obtain demographic, diagnostic, and treatment data. Patients undergoing radiation oncology consultation were identified, and a standardized review of the cancer centre chart was performed on a random sample, stratified by year. RESULTS: For the 222 patients reviewed, the relevant endoscopy report was present in 113 cases (51%). The level of the tumour was documented in 75% of those reports, and colonoscopy completeness, in 81%. The relevant operative report was available in 192 cases (87%). Tumour level was described in 59% of those reports, and local extension, in 73%. Elements of total mesorectal excision were partially described in 97%. In pathology reports (10% of which were synoptic), we observed significant variability in the presence of important elements. Reporting of those elements was significantly better in the synoptic pathology reports. CONCLUSIONS: Clinical information related to adjuvant and neoadjuvant therapy decision-making in rectal cancer is often not available or incomplete. A synoptic reporting system in endoscopy, surgery, and pathology could potentially be a beneficial tool in rectal cancer care. PMID- 23737686 TI - Examining the use of salpingectomy with hysterectomy in Canada. PMID- 23737687 TI - Real-world impact of granulocyte-colony stimulating factor on febrile neutropenia. AB - BACKGROUND: Primary prophylaxis with granulocyte colony-stimulating factors (pp-g csf) is recommended in patients undergoing chemotherapy carrying a febrile neutropenia (fn) risk of 20% or more. In the present study, we examined clinical practice patterns and the impact of pp-g-csf on fn incidence in women with early stage breast cancer (ebc) treated with modern adjuvant chemotherapy (act). METHODS: This single-centre retrospective cohort study of women with ebc, who were identified from the pharmacy database and who received at least 1 cycle of modern act from January 2009 to December 2011, was conducted at the Cancer Centre of Southeastern Ontario. Data on patient demographics, pathology, stage distribution, chemotherapy, pp-g-csf use, dose reductions, chemotherapy delays, treatment discontinuation, relative dose intensity, and fn events were collected. Chi-square tests, t-tests, univariate and multivariate logistic regression analyses, and nonparametric Mann-Whitney U-tests were used for data analysis. RESULTS: Of the 239 women eligible for analysis, 145 (61%) received pp-g-csf, and 50 (21%) developed at least 1 episode of fn. Use of pp-g-csf was associated with a significantly lower rate of fn (14% vs. 31%, p = 0.002) and trends to fewer dose delays (17% vs. 27%, p = 0.060) and dose reductions (19% vs. 25%, p = 0.28). Among women receiving pp-g-csf, higher fn rates were associated with an age of 65 years or older, taxane-based chemotherapy, and prophylaxis with filgrastim. CONCLUSIONS: Clinical practice patterns at our institution showed that more than 50% of ebc patients treated with modern act received pp-g-csf, which led to fewer fn episodes and increased delivery of planned act. The observed high fn risk despite pp-g-csf was linked to older age, taxane-based chemotherapy, and filgrastim. PMID- 23737688 TI - Axillary lymph node status, adjusted for pathologic complete response in breast and axilla after neoadjuvant chemotherapy, predicts differential disease-free survival in breast cancer. AB - BACKGROUND: Our retrospective study in breast cancer patients evaluated whether integrating subtype and pathologic complete response (pcr) information into axillary lymph node restaging after neoadjuvant chemotherapy (nac) adds significance to its prognostic values. METHODS: Patients included in the analysis had stage ii or iii disease, with post-nac axillary lymph node dissection (alnd), without sentinel lymph node biopsy before completion of nac, with definitive subtyping data and subtype-oriented adjuvant treatments. The ypN grading system was used to restage axillary lymph node status, and ypN0 was adjusted by pcr in both breast and axilla into ypN0(pcr) and ypN0(non-pcr). Univariate and multivariate survival analyses were performed. RESULTS: Among the 301 patients analyzed, 145 had tumours that were hormone receptor-positive (hr+) and negative for the human epidermal growth factor receptor (her2-), 101 had tumours that were positive for her2 (her2+), and 55 had tumours that were triple-negative. The rate of pcr in both breast and axilla was 11.7%, 43.6%, and 25.5% respectively for the 3 subtypes. Compared with the non-pcr patients, the pcr patients had better disease-free survival (dfs) and overall survival (os): p = 0.002 for dfs and p = 0.011 for os. In non-pcr patients, dfs and os were similar in the ypN0(non-pcr) and ypN1 subgroups, and in the ypN2 and ypN3 subgroups. We therefore grouped the ypN grading results into ypN0(pcr) (n = 75), ypN0- 1(non-pcr) (n = 175), and ypN2 3 (n = 51). In those groups, the 3-year dfs was 98%, 91%, and 56%, and the 3-year os was 100%, 91%, and 82% respectively. The differences in dfs and os between those three subgroups were significant (all p < 0.05 in paired comparisons). Multivariate Cox regression showed that subtype and ypN staging adjusted by pcr were the only two independent factors predicting dfs. CONCLUSIONS: Axillary lymph node status after nac, adjusted for pcr in breast and axilla, predicts differential dfs in patients without prior sentinel lymph node biopsy. PMID- 23737689 TI - A comparison of patient knowledge of clinical trials and trialist priorities. AB - BACKGROUND: Recruitment to clinical trials remains poor, and patient knowledge of clinical trials is one barrier to recruitment. To identify knowledge deficits, we conducted and compared surveys measuring actual patient knowledge and clinical trialist priorities for patient knowledge. METHODS: Consenting patients at a tertiary cancer centre answered a survey that included 2 opinion questions about their own knowledge and willingness to join a trial, and22 knowledge questions. Clinical researchers at the centre were asked 13 questions about the importance of various trials factors. RESULTS: Of 126 patients surveyed, 16% had joined a clinical trial, and 42% had a secondary school education or less. The mean correct response rate on the knowledge questions was 58%. Higher rates of correct responses were associated with lower age (p = 0.05), greater education (p = 0.006), prior trial participation (p < 0.001), agreement or strong agreement with perceived understanding of trials (p < 0.001), and willingness to join a clinical trial (p = 0.002). Trialists valued an understanding of the rationale for clinical trials and of randomization, placebo, and patient protection, but those particular topics were poorly understood by patients. CONCLUSIONS: Patient knowledge about clinical trials is poor, including knowledge of several concepts ranked important by clinical trialists. The findings suggest that when developing education interventions, emphasis should be placed on the topics most directly related to patient care, and factors such as age and education level should be considered. PMID- 23737690 TI - Continued success in providing timely palliative radiation therapy at the Rapid Response Radiotherapy Program: a review of 2008-2012. AB - OBJECTIVE: We set out to review the Rapid Response Radiotherapy Program (rrrp). METHODS: We retrospectively reviewed a prospective database of patients referred to the rrrp between August 1, 2008, and June 30, 2012, extracting patient demographics, case dispositions, and wait times in days from referral to consultation and from consultation to treatment. RESULTS: Of 2742 patients referred to the rrrp, 1458 (53%) were men, and 1284 (47%) were women. Median age was 64 years. The most prevalent primary cancer sites were lung (33%), breast (21%), and prostate (17%). The most common reasons for referral were bone metastases (53%) and brain metastases (21%). Palliative radiation therapy was given to 1890 patients. The median wait time from referral to consultation was 3 days. Among treated patients, 60% were treated on the day of their consultation, and 33%, within 1-6 days. CONCLUSIONS: The rrrp continues to deliver timely palliative radiation therapy to patients, comparable to earlier reviews. The continued success of the rrrp will remain a model for future rapid-access palliative radiation therapy clinics. PMID- 23737691 TI - Factors influencing the quality of local management of ductal carcinoma in situ: a cohort study. AB - BACKGROUND: Guidelines recommend radiotherapy (rt) after breast-conserving surgery (bcs) for optimal control of ductal carcinoma in situ (dcis). The aim of the present study was to characterize the rates of rt consideration and administration, and to identify factors influencing those rates in a cohort of women diagnosed between 1998 and 2005 in Quebec. METHODS: Quebec's medical service claims and discharge abstract database were used. Using consultation for rt as an indicator for rt consideration, odds ratios (ors) and 95% confidence intervals (cis) were estimated using a generalized estimating equations regression model. RESULTS: Of 4139 women analyzed (mean age: 58 years), 3435 (83%) received a consultation for rt, and 3057 of them (89%) proceeded with treatment. The rate of rt consideration increased by 7.1% over the study period, with notable differences in the various age groups. Relative to women 50-69 years of age, the ors for being considered for rt were, respectively, 0.89 (95% ci: 0.71 to 1.12), 0.71 (95% ci: 0.55 to 0.92), and 0.20 (95% ci: 0.14 to 0.31) for women younger than 50, 70-79, and 80 years of age and older. Distance to a designated breast care centre lowered the probability of rt consideration, but the presence of comorbidities did not. A surgeon's volume of bcss increased the probability of being considered for rt by 7% for every 10 such procedures performed (or: 1.07; 95% ci: 1.04 to 1.11). CONCLUSIONS: Consideration for rt has increased over time. However, older women (despite being in good health) and those living far from a designated breast care centre or having a low-case-volume surgeon were less likely to be considered for rt. PMID- 23737692 TI - Management of renal collecting duct carcinoma: a systematic review and the McMaster experience. AB - INTRODUCTION: Collecting duct carcinoma (cdc) is a rare, aggressive form of renal carcinoma that presents at an advanced stage and has a poor prognosis. Little is known concerning the optimal management of cdc. We present the results of a systematic review addressing the management of cdc and the McMaster University cdc series. METHODS: The medline, Cochrane Library, and embase databases and conference proceedings were searched to identify studies relating to the management of cdc. Included studies reported on a minimum of 10 subjects receiving a single intervention. Series in which an evaluation of therapeutic effectiveness was not possible were excluded. The McMaster University (Hamilton, Ontario) series of 6 cases of cdc were retrospectively reviewed. RESULTS: We identified 3 studies relevant to the management of cdc that included a total of 72 patients. A gemcitabine-cisplatin or -carboplatin regimen resulted in a 26% objective response rate in 23 patients with metastatic cdc. Two additional studies indicated that 49 patients treated with immunotherapy achieved no response. In the McMaster series, cytoreductive nephrectomy was performed in 4 of 6 patients. In 2 patients, mvac therapy (methotrexate-vinblastine-doxorubicin cisplatin) achieved no response. No significant therapeutic complications occurred, but survival was poor (median: 11 months; range: 10-33 months). CONCLUSIONS: Our review and clinical experience suggest that the current standard of care for metastatic cdc is a gemcitabine-cisplatin regimen. PMID- 23737693 TI - A pan-Canadian practice guideline and algorithm: screening, assessment, and supportive care of adults with cancer-related fatigue. AB - PURPOSE: The purpose of the present systematic review was to develop a practice guideline to inform health care providers about screening, assessment, and effective management of cancer-related fatigue (crf) in adults. METHODS: The internationally endorsed adapte methodology was used to develop a practice guideline for pan-Canadian use. A systematic search of the literature identified a broad range of evidence: clinical practice guidelines, systematic reviews, and other guidance documents on the screening, assessment, and management of crf. The search included medline, embase, cinahl, the Cochrane Library, and other guideline and data sources to December 2009. RESULTS: Two clinical practice guidelines were identified for adaptation. Seven guidance documents and four systematic reviews also provided supplementary evidence to inform guideline recommendations. Health professionals across Canada provided expert feedback on the adapted recommendations in the practice guideline and algorithm through a participatory external review process. CONCLUSIONS: Practice guidelines can facilitate the adoption of evidence-based assessment and interventions for adult cancer patients experiencing fatigue. Development of an algorithm to guide decision-making in practice may also foster the uptake of a guideline into routine care. PMID- 23737694 TI - Surgical margins and handling of soft-tissue sarcoma in extremities: a clinical practice guideline. AB - QUESTIONS: In limb salvage surgery for extremity soft-tissue sarcoma (sts), what is an adequate surgical margin?What is the appropriate number of samples to take from the margins of a surgical resection specimen?What is the appropriate handling of surgical resection specimens? BACKGROUND: Surgery is the primary treatment for extremity sts. The combination of radiotherapy with surgery allows for limb salvage by using radiation to biologically "sterilize" microscopic extensions of tumour and to spare neurovascular and osseous structures. Adjuvant chemotherapy in sts-except for rhabdomyosarcoma and Ewing sarcoma-continues to be controversial. METHODS: The medline and embase databases (1975 to June 2011) and the Cochrane Library were searched for pertinent studies. The Web sites of the main guideline organizations and the American Society of Clinical Oncology conference proceedings (2007-2010) were also searched. RESULTS AND CONCLUSIONS: Thirty-three papers, including four guidelines, one protocol, and one abstract, were eligible for inclusion. The data suggest that patients with clear margins have a better prognosis, but no prospective studies have indicated how wide margins should be. In limb-salvage surgery for extremity sts, the procedure should be planned to achieve a clear margin. However, to preserve functionality, surgery may result in a very close (<1 cm) or even microscopically positive margin. In this circumstance, the use of preoperative or postoperative radiation should be considered. No studies described the optimal number of tissue sections required to assess adequacy of excision nor the appropriate handling of surgical resection specimens. The Sarcoma Disease Site Group made its recommendations based on expert opinion and consensus. PMID- 23737696 TI - A pilot study examining the unmet needs of cancer survivors living with polypathology. AB - With improved average longevity, the issue of polypathology in the cancer population is of growing importance, because it will increasingly affect more people. The present study piloted two self-report surveys aiming to provide preliminary data on the nature of polypathology and supportive care needs (met and unmet) of cancer survivors. Survivors were recruited from outpatient clinics at the Princess Margaret Hospital in Toronto and were asked to complete and give feedback on the surveys. Of a convenience sample of 88 survivors, almost three quarters (73%) reported having polypathology, and 64% had at least 1 unmet need. Results also suggest that those with the highest number of needs were more likely to have polypathology. Our study invites further assessments with self-report surveys of the complex picture that arises when cancer is not the only disease affecting a person. It also highlights the need for innovative supportive services to address patient needs. PMID- 23737695 TI - Liver resection for colorectal cancer metastases. AB - QUESTIONS: Should surgery be considered for colorectal cancer (crc) patients who have liver metastases plus (a) pulmonary metastases, (b) portal nodal disease, or (c) other extrahepatic metastases (ehms)?What is the role of chemotherapy in the surgical management of crc with liver metastases in (a) patients with resectable disease in the liver, or (b) patients with initially unresectable disease in the liver that is downsized with chemotherapy ("conversion")?What is the role of liver resection when one or more crc liver metastases have radiographic complete response (rcr) after chemotherapy? PERSPECTIVES: Advances in chemotherapy have improved survival in crc patients with liver metastases. The 5-year survival with chemotherapy alone is typically less than 1%, although two recent studies with folfox or folfoxiri (or both) reported rates of 5%-10%. However, liver resection is the treatment that is most effective in achieving long-term survival and offering the possibility of a cure in stage iv crc patients with liver metastases. This guideline deals with the role of chemotherapy with surgery, and the role of surgery when there are liver metastases plus ehms. Because only a proportion of patients with crc metastatic disease are considered for liver resection, and because management of this patient population is complex, multidisciplinary management is required. METHODOLOGY: Recommendations in the present guideline were formulated based on a prepublication version of a recent systematic review on this topic. The draft methodology experts, and external review by clinical practitioners. Feedback was incorporated into the final version of the guideline. PRACTICE GUIDELINE: These recommendations apply to patients with liver metastases from crc who have had or will have a complete (R0) resection of the primary cancer and who are being considered for resection of the liver, or liver plus specific and limited ehms, with curative intent. 1(a). Patients with liver and lung metastases should be seen in consultation with a thoracic surgeon. Combined or staged metastasectomy is recommended when, taking into account anatomic and physiologic considerations, the assessment is that all pulmonary metastases can also be completely removed. Furthermore, liver resection may be indicated in patients who have had a prior lung resection, and vice versa.1(b). Routine liver resection is not recommended in patients with portal nodal disease. This group includes patients with radiologically suspicious portal nodes or malignant portal nodes found preoperatively or intraoperatively. Liver plus nodal resection, together with perioperative systemic therapy, may be an option-after a full discussion with the patient-in cases with limited nodal involvement and with metastases that can be completely resected.1(c). Routine liver resection is not recommended in patients with nonpulmonary ehms. Liver plus extrahepatic resection, together with perioperative systemic therapy, may be an option-after a full discussion with the patient-for metastases that can be completely resected.2(a). Perioperative chemotherapy, either before and after resection, or after resection, is recommended in patients with resectable liver metastatic disease. This recommendation extends to patients with ehms that can be completely resected (R0). Risks and potential benefits of perioperative chemotherapy should be discussed for patients with resectable liver metastases. The data on whether patients with previous oxaliplatin-based chemotherapy or a short interval from completion of adjuvant therapy for primary crc might benefit from perioperative chemotherapy are limited.2(b). Liver resection is recommended in patients with initially unresectable metastatic liver disease who have a sufficient downstaging response to conversion chemotherapy. If complete resection has been achieved, postoperative chemotherapy should be considered.3. Surgical resection of all lesions, including lesions with rcr, is recommended when technically feasible and when adequate functional liver can be left as a remnant. When a lesion with rcr is present in a portion of the liver that cannot be resected, surgery may still be a reasonable therapeutic strategy if all other visible disease can be resected. Postoperative chemotherapy might be considered in those patients. Close follow-up of the lesion with rcr is warranted to allow localized treatment or further resection for an in situ recurrence. PMID- 23737697 TI - Spontaneous regression of metastatic melanoma after inoculation with tetanus diphtheria-pertussis vaccine. AB - Spontaneous regression of metastatic melanoma is an exceedingly rare event, with only 76 well-documented cases in the literature since 1866. Here, we present the case of a patient who developed metastatic melanoma despite interferon therapy and who then achieved spontaneous regression shortly after a reaction to tetanus diphtheria-pertussis vaccination. A common theme among these cases is the development of febrile illness before remission of the malignant disease. A brief overview of proposed mechanisms for these miraculous recoveries is presented, including a highlight on the potential role of the herv-k-mel viral marker, a nona- or decapeptide that appears in most melanomas, with homologies to peptides in pathogenic microorganisms. PMID- 23737698 TI - Liposomal doxorubicin plus radiofrequency ablation for complete necrosis of a hepatocellular carcinoma. AB - Radiofrequency ablation (rfa) is a standard treatment for small, unresectable hepatocellular carcinomas (hccs). However, rfa for larger tumours is less successful, and intravenous lyso-thermosensitive liposomal doxorubicin during rfa is one technique postulated to potentially address that limitation. This drug plus-device combination therapy was used to completely treat a hcc in a patient who underwent liver transplantation 79 days later. PMID- 23737699 TI - Comment on "Clinical features and course of brain metastases in colorectal cancer: an experience from a single institution". PMID- 23737700 TI - Response to Bernardi and colleagues. PMID- 23737702 TI - Impact of unplanned excision on prognosis of patients with extremity soft tissue sarcoma. AB - Unplanned excision of soft tissue sarcomas (STSs) outside comprehensive tumor management centers necessitates the need for wide reexcision to achieve adequate margins. We retrospectively reviewed medical records of 135 patients with STS operated at our hospital with the goal of examining outcomes, in terms of local recurrence (LR) and metastasis rate (MR), of reexcision following unplanned excision of STS and comparing results with those of first-time planned surgery. Eighty-four patients had their first-time surgery and 51 patients had come to us following unplanned excision at prereferral hospital. Mean age of all patients was 41.8 +/- 21.9 years. The LR and MR was 14.3% and 8.3%, respectively, in patients undergoing first resection, whereas it was 21.4% and 13.7%, respectively, in patients undergoing revision surgery. Average duration from previous unplanned excision was 8 months. Twelve patients were referred immediately after excised specimen revealed STS, while 39 patients presented after evident local recurrence. Wide reexcision was attempted in 48 patients while three patients need amputation. Adjuvant radiotherapy was administered in all patients undergoing limb-sparing surgery. Ten patients needed adjuvant chemotherapy. We conclude that wide reexcision of STS has poorer outcomes compared to planned excision. Therefore, patients with soft tissue masses should be managed by multidisciplinary oncology team at specialized cancer centers. PMID- 23737703 TI - Do malignant bone tumors of the foot have a different biological behavior than sarcomas at other skeletal sites? AB - We analyze the delay in diagnosis and tumor size of malignant bone tumors of the foot in a retrospective study. We compared the oncological and surgical long-term results with identical tumor at other anatomical sites in order to analyze the biological behavior of sarcomas that are found in the foot. Thirty-two patients with a histologically proven malignant bone tumor (fifteen chondrosarcomas, nine osteosarcomas, and eight Ewing sarcomas) between the years 1969 and 2008 were included. The median follow-up was 11.9 years. The overall median time gap between the beginning of symptoms and diagnosis in the study group was 10 months. Ewing sarcoma presented with the longest delay in diagnosis (median of 18 months), followed by osteosarcoma (median of 15 months) and chondrosarcoma (median of 7.5 months). The delay in diagnosis of these tumors was significantly longer than that of equivalent tumors at other skeletal sites, but the 5- and 10 year survival rates and the occurrence of distant metastases were comparable. In contrast, the average size of foot tumors was 5- to 30-fold less than that of tumors analyzed at other skeletal sites. This study indicates that sarcomas of the foot demonstrate a distinct biological behavior compared to the same tumor types at other skeletal sites. PMID- 23737704 TI - Biomarkers of periodontal tissue remodeling during orthodontic tooth movement in mice and men: overview and clinical relevance. AB - Biologically active substances are expressed by cells within the periodontium in response to mechanical stimuli from orthodontic appliances. Several possible biomarkers representing biological modifications during specific phenomena as simile-inflammatory process, bone resorption and formation, periodontal ligament changes, and vascular and neural responses are proposed. Citations to potentially published trials were conducted by searching PubMed, Cochrane databases, and scientific textbooks. Additionally, hand searching and contact with experts in the area were undertaken to identify potentially relevant published and unpublished studies. Selection criteria were as follows: animal models involving only mice and rats undergoing orthodontic treatment; collection of gingival crevicular fluid (GCF) as a noninvasively procedure for humans; no other simultaneous treatment that could affect experimental orthodontic movement. The data suggest that knowledge of the remodeling process occurring in periodontal tissues during orthodontic and orthopedic therapies may be a clinical usefulness procedure leading to proper choice of mechanical stress to improve and to shorten the period of treatment, avoiding adverse consequences. The relevance for clinicians of evaluating the rate of some substances as valid biomarkers of periodontal effects during orthodontic movement, by means of two models of study, mice and men, is underlined. PMID- 23737705 TI - Roquefort cheese proteins inhibit Chlamydia pneumoniae propagation and LPS induced leukocyte migration. AB - Inflammation in atherosclerosis, which could be associated with some subclinical infections such as C. pneumoniae, is one of the key factors responsible for the development of clinical complications of this disease. We report that a proprietary protein extract isolated from Roquefort cheese inhibits the propagation of C. pneumoniae in a human HL cell line in a dose-dependent manner, as revealed by the immunofluorescence analysis. These changes were accompanied by a significant reduction in the infective progeny formation over the protein extract range of 0.12-0.5 MUg/mL. Moreover, short term feeding of mice with Roquefort cheese (twice, 10 mg per mouse with an interval of 24 hours) led to the inhibition of the migration of peritoneal leukocytes caused by intraperitoneal injection of E. coli lipopolysaccharide. These changes were complemented by a reduction in neutrophil count and a relative increase in peritoneal macrophages, suggesting that ingestion of Roquefort could promote regenerative processes at the site of inflammation. The ability of this protein to inhibit propagation of Chlamydia infection, as well as the anti-inflammatory and proregenerative effects of Roquefort itself, may contribute to the low prevalence of cardiovascular mortality in France where consumption of fungal fermented cheeses is the highest in the world. PMID- 23737706 TI - Intracranial cysts: an imagery diagnostic challenge. AB - Intracerebral cysts and cystic appearing intracerebral masses are common findings at routine cerebral imaging examination. We discuss here the most interesting aspects of some intracerebral cysts encountered in medical practice in terms of imaging, clinical and pathological description, and problems of differential diagnosis. On an almost routine basis, the neurologists have to deal with such differentials. Therefore, we aim to mention here some of the frequently encountered diagnosis problems when a patient presents with a cystic cerebral mass. PMID- 23737707 TI - Mortality predicted accuracy for hepatocellular carcinoma patients with hepatic resection using artificial neural network. AB - The aim of this present study is firstly to compare significant predictors of mortality for hepatocellular carcinoma (HCC) patients undergoing resection between artificial neural network (ANN) and logistic regression (LR) models and secondly to evaluate the predictive accuracy of ANN and LR in different survival year estimation models. We constructed a prognostic model for 434 patients with 21 potential input variables by Cox regression model. Model performance was measured by numbers of significant predictors and predictive accuracy. The results indicated that ANN had double to triple numbers of significant predictors at 1-, 3-, and 5-year survival models as compared with LR models. Scores of accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC) of 1-, 3-, and 5-year survival estimation models using ANN were superior to those of LR in all the training sets and most of the validation sets. The study demonstrated that ANN not only had a great number of predictors of mortality variables but also provided accurate prediction, as compared with conventional methods. It is suggested that physicians consider using data mining methods as supplemental tools for clinical decision-making and prognostic evaluation. PMID- 23737708 TI - Coexisting disorders and problems in preschool children with autism spectrum disorders. AB - OBJECTIVES: To analyze cooccurring disorders and problems in a representative group of 198 preschool children with autism spectrum disorders (ASD) who had had interventions at a specialized habilitation center. METHODS: Parents and children were seen by a research team. Data were based on parental interviews, pediatric assessments, and tests of the child. Information on autistic symptoms, general cognitive function, speech and language, motor function, epilepsy, vision, hearing, activity level, behavior, and sleep was collected. RESULTS: Three ASD categories were used: (1) autistic disorder (AD), (2) autistic-like condition (ALC) or Asperger syndrome, and (3) one group with autistic symptoms/traits but not entirely all its criteria met for ASD. Children with autism had a mean of 3.2 coexisting disorders or problems, the ALC/Asperger group had a mean of 1.6, and children with autistic traits had a mean of 1.6. The most common disorder/problems in the total group pertained to language problems (78%), intellectual disability (ID) (49%), below average motor function (37%), and severe hyperactivity/ADHD (33%). CONCLUSIONS: The results accord with the concept of early symptomatic syndromes eliciting neurodevelopmental clinical examination (ESSENCE), and highlight the need of considering ASD in a broad perspective taking also other cooccurring developmental disorders into account. PMID- 23737709 TI - Classification in networked data with heterophily. AB - In the real world, a large amount of data can be described by networks using relations between data. The data described by networks can be called networked data. Classification is one of the main tasks in analyzing networked data. Most of the previous methods find the class of the unlabeled node using the classes of its neighbor nodes. However, in the networks with heterophily, most of connected nodes belong to different classes. It is hard to get the correct class using the classes of neighbor nodes, so the previous methods have a low level of performance in the networks with heterophily. In this paper, a probabilistic method is proposed to address this problem. Firstly, the class propagating distribution of the node is proposed to describe the probabilities that its neighbor nodes belong to each class. After that, the class propagating distributions of neighbor nodes are used to calculate the class of the unlabeled node. At last, a classification algorithm based on class propagating distribution is presented in the form of matrix operations. In empirical study, we apply the proposed algorithm to the real-world datasets, compared with some other algorithms. The experimental results show that the proposed algorithm performs better when the networks are of heterophily. PMID- 23737710 TI - The clinical efficiency of positive airway pressure treatment. AB - OBJECTIVES: The aim of this study was to evaluate the clinical efficiency and compliance of positive airway pressure (PAP) treatment. MATERIALS AND METHODS: This study was conducted on moderate-severe obstructive sleep apnea syndrome (OSAS) patients who admitted to Ankara Numune Hospital Sleep Center between 2008 and 2012. Seventy-five patients with moderate-severe OSAS who were using PAP treatment regularly were enrolled in the study. Patient's usage data, Epworth sleepiness scale (ESS) scores, and the differences in complaints of OSAS were recorded. RESULTS: The overall complaints were improved when compared to pretreatment period. Particularly there was improvement in apnea, snoring, excessive daytime sleepiness, fatigue, and sleep quality. CONCLUSION: PAP is effective in reducing symptoms in people with moderate and severe OSAS. To inform the patients with details and the creation of strategies for close followup are necessary for improving the compliance of the patients. TRIAL REGISTRATION NUMBER: ACTRN12613000373774. PMID- 23737711 TI - Discovering weighted patterns in intron sequences using self-adaptive harmony search and back-propagation algorithms. AB - A hybrid self-adaptive harmony search and back-propagation mining system was proposed to discover weighted patterns in human intron sequences. By testing the weights under a lazy nearest neighbor classifier, the numerical results revealed the significance of these weighted patterns. Comparing these weighted patterns with the popular intron consensus model, it is clear that the discovered weighted patterns make originally the ambiguous 5SS and 3SS header patterns more specific and concrete. PMID- 23737712 TI - The effect of mirtazapine on cisplatin-induced oxidative damage and infertility in rat ovaries. AB - Cisplatin causes infertility due to ovarian toxicity. The toxicity mechanism is unknown, but evidence suggests oxidative stress. In this study, the effect of mirtazapine on cisplatin-induced infertility and oxidative stress in rats was investigated. 64 female rats were divided into 4 groups of 16. Except for the controls that received physiologic saline only, all were administered with cisplatin (5 mg/kg i.p.) and mirtazapine (15 mg/kg p.o.) or mirtazapine (30 mg/kg p.o.) for 10 days. After this period, six rats from each group were randomly selected, and malondialdehyde (MDA), myeloperoxidase (MPO), nitric oxide (NO), total gluthatione (tGSH), gluthatione peroxidase (GPx), superoxide dismutase (SOD), and 8-hydroxy-2 deoxyguanine (8-OH Gua) levels were measured in their ovarian tissues. Reproductive functions of the remaining rats were examined for 6 months. The MDA, MPO, NO groups and 8-OH Gua levels were higher in the cisplatin treated groups than the controls, which was not observed in the mirtazapine and cisplatin groups. GSH, GPx, and SOD levels were reduced by cisplatin, which was prevented by mirtazapine. Cisplatin caused infertility by 70%. The infertility rates were, respectively, 40% and 10% for the 15 and 30 mg/kg mirtazapine administered groups. In conclusion, oxidative stress induced by cisplatin in the rat ovary tissue causes infertility in the female rats. Mirtazapine reverses this in a dose-dependent manner. PMID- 23737713 TI - Immunohistochemical and molecular characterization of the human periosteum. AB - PURPOSE: The aim of the present study was to characterize the cell of the human periosteum using immunohistological and molecular methods. METHODS: Phenotypic properties and the distribution of the cells within the different layers were investigated with immunohistochemical staining techniques and RT-PCR, focussing on markers for stromal stem cells, osteoblasts, osteoclasts and immune cells. RESULTS: Immunohistochemical results revealed that all stained cells were located in the cambium layer and that most cells were positive for vimentin. The majority of cells consisted of stromal stem cells and osteoblastic precursor cells. The density increased towards the deeper layers of the cambium. In addition, cells positive for markers of the osteoblast, chondrocyte, and osteoclast lineages were found. Interestingly, there were MHC class II-expressing immune cells suggesting the presence of dendritic cells. Using lineage-specific primer pairs RT-PCR confirmed the immunofluorescence microscopy results, supporting that human periosteum serves as a reservoir of stromal stem cells, as well as cells of the osteoblastic, and the chondroblastic lineage, osteoclasts, and dendritic cells. CONCLUSION: Our work elucidates the role of periosteum as a source of cells with a high regenerative capacity. Undifferentiated stromal stem cells as well as osteoblastic precursor cells are dominating in the cambium layer. A new outlook is given towards an immune response coming from the periosteum as MHC II positive immune cells were detected. PMID- 23737714 TI - Evaluation of functional lower urinary tract dysfunction in children: are the physicians complying with the current guidelines? AB - OBJECTIVE: To elucidate whether the diagnostic and treatment approaches of the physicians for functional lower urinary tract dysfunction (LUTD) in children is complying with the current guidelines. MATERIAL AND METHODS: We have conducted an internet-based national survey for the physicians from different departments randomly sampled from the database of Turkish Paediatric Urology Society. Participants were asked to answer two-page questionnaire consisting of 4 main sections: "demography," "working conditions," "daily practice," and "scientific knowledge." Kruskal Wallis and multiple logistic regression were used for statistical analyses. RESULTS: Of the 117 departments a total of 93 have completed the survey (n: 58 urology; n: 35 paediatric nephrology). Routine use of a questionnaire with validated symptom scoring system was found to be 13.9%. Of the participants, only 38.7% were asking all of the patients to fill the bladder diary. During treatment, only 24.7% were applying standard urotherapy for every patient. Almost half of the clinicians (45.1%) believed that they were personally insufficient during the evaluation of those children. Finally, 86% reported that children with LUTD were not adequately approached. CONCLUSIONS: Evaluation of LUTD in children is not complying with the current guidelines. General approach for those children needs to be revisited by the clinicians. PMID- 23737715 TI - To identify the important soil properties affecting dinoseb adsorption with statistical analysis. AB - Investigating the influences of soil characteristic factors on dinoseb adsorption parameter with different statistical methods would be valuable to explicitly figure out the extent of these influences. The correlation coefficients and the direct, indirect effects of soil characteristic factors on dinoseb adsorption parameter were analyzed through bivariate correlation analysis, and path analysis. With stepwise regression analysis the factors which had little influence on the adsorption parameter were excluded. Results indicate that pH and CEC had moderate relationship and lower direct effect on dinoseb adsorption parameter due to the multicollinearity with other soil factors, and organic carbon and clay contents were found to be the most significant soil factors which affect the dinoseb adsorption process. A regression is thereby set up to explore the relationship between the dinoseb adsorption parameter and the two soil factors: the soil organic carbon and clay contents. A 92% of the variation of dinoseb sorption coefficient could be attributed to the variation of the soil organic carbon and clay contents. PMID- 23737716 TI - Heme iron content in lamb meat is differentially altered upon boiling, grilling, or frying as assessed by four distinct analytical methods. AB - Lamb meat is regarded as an important source of highly bioavailable iron (heme iron) in the Iranians diet. The main objective of this study is to evaluate the effect of traditional cooking methods on the iron changes in lamb meat. Four published experimental methods for the determination of heme iron were assessed analytically and statistically. Samples were selected from lambs' loin. Standard methods (AOAC) were used for proximate analysis. For measuring heme iron, the results of four experimental methods were compared regarding their compliance to Ferrozine method which was used for the determination of nonheme iron. Among three cooking methods, the lowest total iron and heme iron were found in boiling method. The heme iron proportions to the total iron in raw, boiled lamb meat and grilled, were counted as 65.70%, 67.75%, and 76.01%, receptively. Measuring the heme iron, the comparison of the methods in use showed that the method in which heme extraction solution was composed of 90% acetone, 18% water, and 2% hydrochloric acid was more appropriate and more correlated with the heme iron content calculated by the difference between total iron and nonheme iron. PMID- 23737717 TI - Establishing an efficient way to utilize the drought resistance germplasm population in wheat. AB - Drought resistance breeding provides a hopeful way to improve yield and quality of wheat in arid and semiarid regions. Constructing core collection is an efficient way to evaluate and utilize drought-resistant germplasm resources in wheat. In the present research, 1,683 wheat varieties were divided into five germplasm groups (high resistant, HR; resistant, R; moderate resistant, MR; susceptible, S; and high susceptible, HS). The least distance stepwise sampling (LDSS) method was adopted to select core accessions. Six commonly used genetic distances (Euclidean distance, Euclid; Standardized Euclidean distance, Seuclid; Mahalanobis distance, Mahal; Manhattan distance, Manhat; Cosine distance, Cosine; and Correlation distance, Correlation) were used to assess genetic distances among accessions. Unweighted pair-group average (UPGMA) method was used to perform hierarchical cluster analysis. Coincidence rate of range (CR) and variable rate of coefficient of variation (VR) were adopted to evaluate the representativeness of the core collection. A method for selecting the ideal constructing strategy was suggested in the present research. A wheat core collection for the drought resistance breeding programs was constructed by the strategy selected in the present research. The principal component analysis showed that the genetic diversity was well preserved in that core collection. PMID- 23737718 TI - Improving Vector Evaluated Particle Swarm Optimisation by incorporating nondominated solutions. AB - The Vector Evaluated Particle Swarm Optimisation algorithm is widely used to solve multiobjective optimisation problems. This algorithm optimises one objective using a swarm of particles where their movements are guided by the best solution found by another swarm. However, the best solution of a swarm is only updated when a newly generated solution has better fitness than the best solution at the objective function optimised by that swarm, yielding poor solutions for the multiobjective optimisation problems. Thus, an improved Vector Evaluated Particle Swarm Optimisation algorithm is introduced by incorporating the nondominated solutions as the guidance for a swarm rather than using the best solution from another swarm. In this paper, the performance of improved Vector Evaluated Particle Swarm Optimisation algorithm is investigated using performance measures such as the number of nondominated solutions found, the generational distance, the spread, and the hypervolume. The results suggest that the improved Vector Evaluated Particle Swarm Optimisation algorithm has impressive performance compared with the conventional Vector Evaluated Particle Swarm Optimisation algorithm. PMID- 23737719 TI - Effect of metakaolin on strength and efflorescence quantity of cement-based composites. AB - This study investigated the basic mechanical and microscopic properties of cement produced with metakaolin and quantified the production of residual white efflorescence. Cement mortar was produced at various replacement ratios of metakaolin (0, 5, 10, 15, 20, and 25% by weight of cement) and exposed to various environments. Compressive strength and efflorescence quantify (using Matrix Laboratory image analysis and the curettage method), scanning electron microscopy, and X-ray diffraction analysis were reported in this study. Specimens with metakaolin as a replacement for Portland cement present higher compressive strength and greater resistance to efflorescence; however, the addition of more than 20% metakaolin has a detrimental effect on strength and efflorescence. This may be explained by the microstructure and hydration products. The quantity of efflorescence determined using MATLAB image analysis is close to the result obtained using the curettage method. The results demonstrate the best effectiveness of replacing Portland cement with metakaolin at a 15% replacement ratio by weight. PMID- 23737720 TI - Comment on "Berberine and its emerging benefits in psychiatric conditions especially Alzheimer's disease". PMID- 23737721 TI - Characterization of activated carbons from oil-palm shell by CO2 activation with no holding carbonization temperature. AB - Activated carbons can be produced from different precursors, including coals of different ranks, and lignocellulosic materials, by physical or chemical activation processes. The objective of this paper is to characterize oil-palm shells, as a biomass byproduct from palm-oil mills which were converted into activated carbons by nitrogen pyrolysis followed by CO2 activation. The effects of no holding peak pyrolysis temperature on the physical characteristics of the activated carbons are studied. The BET surface area of the activated carbon is investigated using N2 adsorption at 77 K with selected temperatures of 500, 600, and 700 degrees C. These pyrolysis conditions for preparing the activated carbons are found to yield higher BET surface area at a pyrolysis temperature of 700 degrees C compared to selected commercial activated carbon. The activated carbons thus result in well-developed porosities and predominantly microporosities. By using this activation method, significant improvement can be obtained in the surface characteristics of the activated carbons. Thus this study shows that the preparation time can be shortened while better results of activated carbon can be produced. PMID- 23737722 TI - Survival analysis by penalized regression and matrix factorization. AB - Because every disease has its unique survival pattern, it is necessary to find a suitable model to simulate followups. DNA microarray is a useful technique to detect thousands of gene expressions at one time and is usually employed to classify different types of cancer. We propose combination methods of penalized regression models and nonnegative matrix factorization (NMF) for predicting survival. We tried L1- (lasso), L2- (ridge), and L1-L2 combined (elastic net) penalized regression for diffuse large B-cell lymphoma (DLBCL) patients' microarray data and found that L1-L2 combined method predicts survival best with the smallest logrank P value. Furthermore, 80% of selected genes have been reported to correlate with carcinogenesis or lymphoma. Through NMF we found that DLBCL patients can be divided into 4 groups clearly, and it implies that DLBCL may have 4 subtypes which have a little different survival patterns. Next we excluded some patients who were indicated hard to classify in NMF and executed three penalized regression models again. We found that the performance of survival prediction has been improved with lower logrank P values. Therefore, we conclude that after preselection of patients by NMF, penalized regression models can predict DLBCL patients' survival successfully. PMID- 23737724 TI - Clustering-based multiple imputation via gray relational analysis for missing data and its application to aerospace field. AB - A large number of scientific researches and industrial applications commonly suffer from missing data. Some inappropriate techniques of missing value treatment compromise data quality, which detrimentally influences the knowledge discovery. In this paper, we propose a missing data completion method named CBGMI. Firstly, it separates the nonmissing data instances into several clusters by excluding the missing-valued entries. Then, it utilizes the entropy of the proximal category for each incomplete instance in terms of the similarity metric based on gray relational analysis. Experiments on UCI datasets and aerospace datasets demonstrate that the superiority of our algorithm to other approaches on validity. PMID- 23737723 TI - Recent advances in DENV receptors. AB - Dengue is an old disease caused by the mosquito-borne dengue viruses (DENVs), which have four antigenically distinct serotypes (DENV1-4). Infection by any of them can cause dengue fever (DF) and/or a more serious disease, that is, dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). In recent decades, incidence of dengue disease has increased 30-fold, putting a third to half of the world's population living in dengue-endemic areas at high infection risk. However, the pathogenesis of the disease is still poorly understood. The virus binding with its host cell is not only a first and critical step in their replication cycle but also a key factor for the pathogenicity. In recent years, there have been significant advances in understanding interactions of DENVs with their target cells such as dendritic cells (DC), macrophages, endothelial cells, and hepatocytes. Although DENVs reportedly attach to a variety of receptors on these cells, consensus DENV receptors have not been defined. In this review, we summarize receptors for DENVs on different cells identified in recent years. PMID- 23737725 TI - Risk prison and hepatitis B virus infection among inmates with history of drug injection in Isfahan, Iran. AB - OBJECTIVES: Hepatitis B virus (HBV) is a health problem among injection drug users (IDUs) in prison. The aim of this study is to evaluate the association of factors of incarceration with HBV infection in prisoners with history of drug injection in Isfahan, Iran. METHODS: In a cross-sectional study, all IDUs inmates were enrolled. Sociodemographic characteristics and associated risk factors were obtained. Blood samples were collected and serological markers for HBV were analyzed. For data analysis, odds ratio and logistic regression were used. RESULTS: Of the IDUs inmates, 970 subjects participated in the study. History of imprisonment (OR: 1.82, 95% CI: 1.28-2.57), multiple incarceration (OR: 1.43, 95% CI: 1.01-2.02), and total duration of imprisonment (OR: 2.70, 95% CI: 1.94-3.74) were significantly associated with prevalence of HBV among IDUs inmates. Multivariate analysis of associated factors showed that only total duration of incarceration is significantly associated with HBV infection. CONCLUSION: In conclusion, according to our results, multiple and duration of incarcerations will be considered as important risk factors of HBV infection in IDUs inmates. This fact makes it important to set some screening and prevention programs in prisons to decrease the risk of being infected and prevent the transmission of these diseases. PMID- 23737726 TI - Effect of humidity and hydrophobicity on the tribological properties of self assembled monolayers. AB - The tribological properties of two distinctive alkanethiol SAMs, 16 mercaptohexadecanoic acid (MHA) and 1-octadecanethiol (ODT), on gold substrates in various humidity conditions were examined by lateral force microscopy (LFM). The results suggest that hydrophobic ODT SAM is insensitive to humidity. The difference of lateral force signal is within +/-10% regardless of humidity. The lateral force signal of hydrophilic MHA SAMs has a significant decrease in signal in humid environments. The influence of bulk water was also investigated by LFM. By imaging under water, the capillary force is eliminated on ODT SAMs, which leads to a lower lateral force. However, the lateral force image was reversed on MHA SAMs, which suggested that hydrophobic forces dominated in water. PMID- 23737727 TI - Evaluation of combination effects of ethanolic extract of Ziziphus mucronata Willd. subsp. mucronata Willd. and antibiotics against clinically important bacteria. AB - A pragmatic approach to the treatment of infectious diseases with multicausal agents and prevention of the development of resistant isolates is the combination of herbal remedies with the first-line antimicrobial agents to which most of them have become resistant. This study evaluated the interactions between the ethanolic bark extract of Ziziphus mucronata with known antimicrobial agents in vitro. In this study, the results showed that varied zones of inhibitions (ZME chloramphenicol (17-42 mm), ZME-amoxicillin (17-35 mm), ZME-tetracycline (17-36 mm), ZME-ciprofloxacin (20-41 mm), ZME-nalidixic acid (17-34 mm), and ZME kanamycin (17-38 mm)) were produced by the antibacterial combinations. At the highest combined concentrations, 12 isolates (ZME-ciprofloxacin) > 10 isolates (ZME-chloramphenicol) = (ZME-kanamycin) > 6 isolates (ZME-amoxicillin) = (ZME nalidixic acid) and 5 isolates (ZME-tetracycline) were inhibited with zones of inhibition greater than 20 +/- 1.0 mm. Although the agar diffusion assay suggested that the interactions between the ethanolic extract of Z. mucronata and the antibiotics were both synergistic and additive in nature, the fractional inhibitory concentration indices (FICI) showed that the interactions were synergistic (54.17%), additive (27.78%), indifferent (16.67%), and antagonistic (1.39%). While the fractional inhibitory concentration indices (FICIs) for synergism ranged between 0.00391 and 0.5, that of additivity ranged between 0.516 and 1.0, indifferences ranged between 1.062 and 3.0 and antagonistic interaction was 5.0. The synergistic effects implied that the antibacterial combinations would be more effective and useful in the treatment of multicausal and multidrug resistant bacteria than a single monotherapy of either antibacterial agent. PMID- 23737728 TI - RNA editing and drug discovery for cancer therapy. AB - RNA editing is vital to provide the RNA and protein complexity to regulate the gene expression. Correct RNA editing maintains the cell function and organism development. Imbalance of the RNA editing machinery may lead to diseases and cancers. Recently, RNA editing has been recognized as a target for drug discovery although few studies targeting RNA editing for disease and cancer therapy were reported in the field of natural products. Therefore, RNA editing may be a potential target for therapeutic natural products. In this review, we provide a literature overview of the biological functions of RNA editing on gene expression, diseases, cancers, and drugs. The bioinformatics resources of RNA editing were also summarized. PMID- 23737729 TI - Anxiolytic-like actions of fatty acids identified in human amniotic fluid. AB - Eight fatty acids (C12-C18) were previously identified in human amniotic fluid, colostrum, and milk in similar proportions but different amounts. Amniotic fluid is well known to be the natural environment for development in mammals. Interestingly, amniotic fluid and an artificial mixture of fatty acids contained in amniotic fluid produce similar anxiolytic-like actions in Wistar rats. We explored whether the lowest amount of fatty acids contained in amniotic fluid with respect to colostrum and milk produces such anxiolytic-like effects. Although a trend toward a dose-response effect was observed, only an amount of fatty acids that was similar to amniotic fluid fully mimicked the effect of diazepam (2 mg/kg, i.p.) in the defensive burying test, an action devoid of effects on locomotor activity and motor coordination. Our results confirm that the amount of fatty acids contained in amniotic fluid is sufficient to produce anxiolytic-like effects, suggesting similar actions during intrauterine development. PMID- 23737730 TI - Hysteresis modeling of magnetic shape memory alloy actuator based on Krasnosel'skii-Pokrovskii model. AB - As a new type of intelligent material, magnetically shape memory alloy (MSMA) has a good performance in its applications in the actuator manufacturing. Compared with traditional actuators, MSMA actuator has the advantages as fast response and large deformation; however, the hysteresis nonlinearity of the MSMA actuator restricts its further improving of control precision. In this paper, an improved Krasnosel'skii-Pokrovskii (KP) model is used to establish the hysteresis model of MSMA actuator. To identify the weighting parameters of the KP operators, an improved gradient correction algorithm and a variable step-size recursive least square estimation algorithm are proposed in this paper. In order to demonstrate the validity of the proposed modeling approach, simulation experiments are performed, simulations with improved gradient correction algorithm and variable step-size recursive least square estimation algorithm are studied, respectively. Simulation results of both identification algorithms demonstrate that the proposed modeling approach in this paper can establish an effective and accurate hysteresis model for MSMA actuator, and it provides a foundation for improving the control precision of MSMA actuator. PMID- 23737731 TI - Changes of substance P in the crevicular fluid in relation to orthodontic movement preliminary investigation. AB - Substance P (SP) is a tachykinin released from both the central and the peripheral endings of primary afferent neurons and functions as a neurotransmitter. As a transmitter signaling pain, substance P is involved in nociception and is an extremely potent vasodilator. We found several studies about this neuropeptide especially in relation to parodontology and a few orthodontic reviews. This is because in the past the importance of this neuropeptide in dental element undergoing periodontal inflammation was observed. The aims of the present pilot study was to investigate whether the substance P was present in gingival crevicular fluid in dental elements undergoing orthodontic treatment with Invisalign technique compared to teeth belonging to the same series but not undergoing orthodontic movement. We analysed gengival crevicular fluid (GCF) collected from four young subjects, using a paper cone for a time of 60 seconds. The results showed that SP is present in the gengival sulcus in elements undergoing orthodontic forces during treatment with Invisalign technique and not in the control teeth. During the literature analysis, we have found a lot of papers describing involvement of SP in periodontitis and inflammatory diseases, but further studies are needed in order to demonstrate the role of this neuropeptide during teeth movement. PMID- 23737732 TI - Pathogenesis and novel treatment from the mouse model of type 2 diabetic nephropathy. AB - Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease worldwide. However, current treatments remain suboptimal. Many factors, such as genetic and nongenetic promoters, hypertension, hyperglycemia, the accumulation of advanced glycation end products (AGEs), dyslipidemia, and albuminuria/proteinuria itself, influence the progression of this disease. It is important to determine the molecular mechanisms and treatment of this disease. The development of diabetes results in the formation of AGEs, oxidative stress, and the activation of the renin-angiotensin-aldosterone system (RAAS) within the kidney, which promotes progressive inflammation and fibrosis, leading to DN and declining renal function. A number of novel therapies have also been tested in the experimental diabetic model, including exercise, inhibitors of the RAAS (angiotensin type 1 receptor blockers (ARB), angiotensin-converting enzyme (ACE) inhibitors), inhibitors of AGE (pyridoxamine), peroxisome proliferator-activated receptor (PPAR) gamma agonists (pioglitazone), inhibitors of lipid accumulation (statins and eicosapentaenoic acid (EPA)), and the vitamin D analogues. This review summarizes the advances in knowledge gained from our studies and therapeutic interventions that may prevent this disease. PMID- 23737733 TI - A novel method for the accurate evaluation of Poisson's ratio of soft polymer materials. AB - A new method with a simple algorithm was developed to accurately measure Poisson's ratio of soft materials such as polyvinyl alcohol hydrogel (PVA-H) with a custom experimental apparatus consisting of a tension device, a micro X-Y stage, an optical microscope, and a charge-coupled device camera. In the proposed method, the initial positions of the four vertices of an arbitrarily selected quadrilateral from the sample surface were first measured to generate a 2D 1st order 4-node quadrilateral element for finite element numerical analysis. Next, minimum and maximum principal strains were calculated from differences between the initial and deformed shapes of the quadrilateral under tension. Finally, Poisson's ratio of PVA-H was determined by the ratio of minimum principal strain to maximum principal strain. This novel method has an advantage in the accurate evaluation of Poisson's ratio despite misalignment between specimens and experimental devices. In this study, Poisson's ratio of PVA-H was 0.44 +/- 0.025 (n = 6) for 2.6-47.0% elongations with a tendency to decrease with increasing elongation. The current evaluation method of Poisson's ratio with a simple measurement system can be employed to a real-time automated vision-tracking system which is used to accurately evaluate the material properties of various soft materials. PMID- 23737734 TI - Differences and similarities among parotoid macrogland secretions in South American toads: a preliminary biochemical delineation. AB - Amphibians are known by cutaneous glands, spread over the skin, containing toxins (proteins, peptides, biogenic amines, steroidal bufadienolides, and alkaloids) used as chemical defense against predators and microbial infection. Toads are characterized by the presence of parotoid macroglands. The common toads have lately been divided into two genera: Bufo (Europe, Asia, and Africa) and Rhinella (South America). Basal Rhaebo genus is exclusively of Central America and Amazon region. Although Rhinella and Rhaebo are related, species may share differences due to the diversity of environments that they live in. In this work, we have performed a biochemical characterization of the components of the poison of eight Rhinella species and one Rhaebo by means of RP-HPLC with either UV or MS detection and by SDS-PAGE, in order to verify whether phylogenetic and biological differences, such as habitat, diet, and defensive strategies, between them may also be reflected in poison composition. Although some components were common among the secretions, we were able to identify exclusive molecules to some species. The fact that closely related animals living in different habitats secrete different molecules into the skin is an indication that biological features, and not only evolution, seem to directly influence the skin secretion composition. PMID- 23737736 TI - Grand challenges: integrating mental health services into priority health care platforms. PMID- 23737735 TI - Molecular imaging of experimental abdominal aortic aneurysms. AB - Current laboratory research in the field of abdominal aortic aneurysm (AAA) disease often utilizes small animal experimental models induced by genetic manipulation or chemical application. This has led to the use and development of multiple high-resolution molecular imaging modalities capable of tracking disease progression, quantifying the role of inflammation, and evaluating the effects of potential therapeutics. In vivo imaging reduces the number of research animals used, provides molecular and cellular information, and allows for longitudinal studies, a necessity when tracking vessel expansion in a single animal. This review outlines developments of both established and emerging molecular imaging techniques used to study AAA disease. Beyond the typical modalities used for anatomical imaging, which include ultrasound (US) and computed tomography (CT), previous molecular imaging efforts have used magnetic resonance (MR), near infrared fluorescence (NIRF), bioluminescence, single-photon emission computed tomography (SPECT), and positron emission tomography (PET). Mouse and rat AAA models will hopefully provide insight into potential disease mechanisms, and the development of advanced molecular imaging techniques, if clinically useful, may have translational potential. These efforts could help improve the management of aneurysms and better evaluate the therapeutic potential of new treatments for human AAA disease. PMID- 23737737 TI - Biases in the experimental annotations of protein function and their effect on our understanding of protein function space. AB - The ongoing functional annotation of proteins relies upon the work of curators to capture experimental findings from scientific literature and apply them to protein sequence and structure data. However, with the increasing use of high throughput experimental assays, a small number of experimental studies dominate the functional protein annotations collected in databases. Here, we investigate just how prevalent is the "few articles - many proteins" phenomenon. We examine the experimentally validated annotation of proteins provided by several groups in the GO Consortium, and show that the distribution of proteins per published study is exponential, with 0.14% of articles providing the source of annotations for 25% of the proteins in the UniProt-GOA compilation. Since each of the dominant articles describes the use of an assay that can find only one function or a small group of functions, this leads to substantial biases in what we know about the function of many proteins. Mass-spectrometry, microscopy and RNAi experiments dominate high throughput experiments. Consequently, the functional information derived from these experiments is mostly of the subcellular location of proteins, and of the participation of proteins in embryonic developmental pathways. For some organisms, the information provided by different studies overlap by a large amount. We also show that the information provided by high throughput experiments is less specific than those provided by low throughput experiments. Given the experimental techniques available, certain biases in protein function annotation due to high-throughput experiments are unavoidable. Knowing that these biases exist and understanding their characteristics and extent is important for database curators, developers of function annotation programs, and anyone who uses protein function annotation data to plan experiments. PMID- 23737739 TI - Rocky mountain conference on bioinformatics celebrates 10 years. PMID- 23737738 TI - Computational assessment of the cooperativity between RNA binding proteins and MicroRNAs in Transcript Decay. AB - Transcript degradation is a widespread and important mechanism for regulating protein abundance. Two major regulators of transcript degradation are RNA Binding Proteins (RBPs) and microRNAs (miRNAs). We computationally explored whether RBPs and miRNAs cooperate to promote transcript decay. We defined five RBP motifs based on the evolutionary conservation of their recognition sites in 3'UTRs as the binding motifs for Pumilio (PUM), U1A, Fox-1, Nova, and UAUUUAU. Recognition sites for some of these RBPs tended to localize at the end of long 3'UTRs. A specific group of miRNA recognition sites were enriched within 50 nts from the RBP recognition sites for PUM and UAUUUAU. The presence of both a PUM recognition site and a recognition site for preferentially co-occurring miRNAs was associated with faster decay of the associated transcripts. For PUM and its co-occurring miRNAs, binding of the RBP to its recognition sites was predicted to release nearby miRNA recognition sites from RNA secondary structures. The mammalian miRNAs that preferentially co-occur with PUM binding sites have recognition seeds that are reverse complements to the PUM recognition motif. Their binding sites have the potential to form hairpin secondary structures with proximal PUM binding sites that would normally limit RISC accessibility, but would be more accessible to miRNAs in response to the binding of PUM. In sum, our computational analyses suggest that a specific set of RBPs and miRNAs work together to affect transcript decay, with the rescue of miRNA recognition sites via RBP binding as one possible mechanism of cooperativity. PMID- 23737740 TI - Coordination of rapid sphingolipid responses to heat stress in yeast. AB - The regulatory roles of sphingolipids in diverse cell functions have been characterized extensively. However, the dynamics and interactions among the different sphingolipid species are difficult to assess, because de novo biosynthesis, metabolic inter-conversions, and the retrieval of sphingolipids from membranes form a complex, highly regulated pathway system. Here we analyze the heat stress response of this system in the yeast Saccharomyces cerevisiae and demonstrate how the cell dynamically adjusts its enzyme profile so that it is appropriate for operation under stress conditions before changes in gene expression become effective. The analysis uses metabolic time series data, a complex mathematical model, and a custom-tailored optimization strategy. The results demonstrate that all enzyme activities rapidly increase in an immediate response to the elevated temperature. After just a few minutes, different functional clusters of enzymes follow distinct activity patterns. Interestingly, starting after about six minutes, both de novo biosynthesis and all exit routes from central sphingolipid metabolism become blocked, and the remaining metabolic activity consists entirely of an internal redistribution among different sphingoid base and ceramide pools. After about 30 minutes, heat stress is still in effect and the enzyme activity profile is still significantly changed. Importantly, however, the metabolites have regained concentrations that are essentially the same as those under optimal conditions. PMID- 23737741 TI - A two-stage cascade model of BOLD responses in human visual cortex. AB - Visual neuroscientists have discovered fundamental properties of neural representation through careful analysis of responses to controlled stimuli. Typically, different properties are studied and modeled separately. To integrate our knowledge, it is necessary to build general models that begin with an input image and predict responses to a wide range of stimuli. In this study, we develop a model that accepts an arbitrary band-pass grayscale image as input and predicts blood oxygenation level dependent (BOLD) responses in early visual cortex as output. The model has a cascade architecture, consisting of two stages of linear and nonlinear operations. The first stage involves well-established computations local oriented filters and divisive normalization-whereas the second stage involves novel computations-compressive spatial summation (a form of normalization) and a variance-like nonlinearity that generates selectivity for second-order contrast. The parameters of the model, which are estimated from BOLD data, vary systematically across visual field maps: compared to primary visual cortex, extrastriate maps generally have larger receptive field size, stronger levels of normalization, and increased selectivity for second-order contrast. Our results provide insight into how stimuli are encoded and transformed in successive stages of visual processing. PMID- 23737742 TI - A mechanical design principle for tissue structure and function in the airway tree. AB - With every breath, the dynamically changing mechanical pressures must work in unison with the cells and soft tissue structures of the lung to permit air to efficiently traverse the airway tree and undergo gas exchange in the alveoli. The influence of mechanics on cell and tissue function is becoming apparent, raising the question: how does the airway tree co-exist within its mechanical environment to maintain normal cell function throughout its branching structure of diminishing dimensions? We introduce a new mechanical design principle for the conducting airway tree in which mechanotransduction at the level of cells is driven to orchestrate airway wall structural changes that can best maintain a preferred mechanical microenvironment. To support this principle, we report in vitro radius-transmural pressure relations for a range of airway radii obtained from healthy bovine lungs and model the data using a strain energy function together with a thick-walled cylinder description. From this framework, we estimate circumferential stresses and incremental Young's moduli throughout the airway tree. Our results indicate that the conducting airways consistently operate within a preferred mechanical homeostatic state, termed mechanical homeostasis, that is characterized by a narrow range of circumferential stresses and Young's moduli. This mechanical homeostatic state is maintained for all airways throughout the tree via airway wall dimensional and mechanical relationships. As a consequence, cells within the airway walls throughout the airway tree experience similar oscillatory strains during breathing that are much smaller than previously thought. Finally, we discuss the potential implications of how the maintenance of mechanical homeostasis, while facilitating healthy tissue-level alterations necessary for maturation, may lead to airway wall structural changes capable of chronic asthma. PMID- 23737744 TI - Experimental evolution of pathogenesis: "patient" research. PMID- 23737743 TI - Critical role of transient activity of MT1-MMP for ECM degradation in invadopodia. AB - Focal degradation of extracellular matrix (ECM) is the first step in the invasion of cancer cells. MT1-MMP is a potent membrane proteinase employed by aggressive cancer cells. In our previous study, we reported that MT1-MMP was preferentially located at membrane protrusions called invadopodia, where MT1-MMP underwent quick turnover. Our computer simulation and experiments showed that this quick turnover was essential for the degradation of ECM at invadopodia (Hoshino, D., et al., (2012) PLoS Comp. Biol., 8: e1002479). Here we report on characterization and analysis of the ECM-degrading activity of MT1-MMP, aiming at elucidating a possible reason for its repetitive insertion in the ECM degradation. First, in our computational model, we found a very narrow transient peak in the activity of MT1-MMP followed by steady state activity. This transient activity was due to the inhibition by TIMP-2, and the steady state activity of MT1-MMP decreased dramatically at higher TIMP-2 concentrations. Second, we evaluated the role of the narrow transient activity in the ECM degradation. When the transient activity was forcibly suppressed in computer simulations, the ECM degradation was heavily suppressed, indicating the essential role of this transient peak in the ECM degradation. Third, we compared continuous and pulsatile turnover of MT1-MMP in the ECM degradation at invadopodia. The pulsatile insertion showed basically consistent results with the continuous insertion in the ECM degradation, and the ECM degrading efficacy depended heavily on the transient activity of MT1-MMP in both models. Unexpectedly, however, low-frequency/high-concentration insertion of MT1-MMP was more effective in ECM degradation than high-frequency/low concentration pulsatile insertion even if the time-averaged amount of inserted MT1-MMP was the same. The present analysis and characterization of ECM degradation by MT1-MMP together with our previous report indicate a dynamic nature of MT1-MMP at invadopodia and the importance of its transient peak in the degradation of the ECM. PMID- 23737745 TI - Membrane assembly during the infection cycle of the giant Mimivirus. AB - Although extensively studied, the structure, cellular origin and assembly mechanism of internal membranes during viral infection remain unclear. By combining diverse imaging techniques, including the novel Scanning-Transmission Electron Microscopy tomography, we elucidate the structural stages of membrane biogenesis during the assembly of the giant DNA virus Mimivirus. We show that this elaborate multistage process occurs at a well-defined zone localized at the periphery of large viral factories that are generated in the host cytoplasm. Membrane biogenesis is initiated by fusion of multiple vesicles, ~70 nm in diameter, that apparently derive from the host ER network and enable continuous supply of lipid components to the membrane-assembly zone. The resulting multivesicular bodies subsequently rupture to form large open single-layered membrane sheets from which viral membranes are generated. Membrane generation is accompanied by the assembly of icosahedral viral capsids in a process involving the hypothetical major capsid protein L425 that acts as a scaffolding protein. The assembly model proposed here reveals how multiple Mimivirus progeny can be continuously and efficiently generated and underscores the similarity between the infection cycles of Mimivirus and Vaccinia virus. Moreover, the membrane biogenesis process indicated by our findings provides new insights into the pathways that might mediate assembly of internal viral membranes in general. PMID- 23737746 TI - Murinization of internalin extends its receptor repertoire, altering Listeria monocytogenes cell tropism and host responses. AB - Listeria monocytogenes (Lm) is an invasive foodborne pathogen that leads to severe central nervous system and maternal-fetal infections. Lm ability to actively cross the intestinal barrier is one of its key pathogenic properties. Lm crosses the intestinal epithelium upon the interaction of its surface protein internalin (InlA) with its host receptor E-cadherin (Ecad). InlA-Ecad interaction is species-specific, does not occur in wild-type mice, but does in transgenic mice expressing human Ecad and knock-in mice expressing humanized mouse Ecad. To study listeriosis in wild-type mice, InlA has been "murinized" to interact with mouse Ecad. Here, we demonstrate that, unexpectedly, murinized InlA (InlA(m)) mediates not only Ecad-dependent internalization, but also N-cadherin-dependent internalization. Consequently, InlA(m)-expressing Lm targets not only goblet cells expressing luminally-accessible Ecad, as does Lm in humanized mice, but also targets villous M cells, which express luminally-accessible N-cadherin. This aberrant Lm portal of entry results in enhanced innate immune responses and intestinal barrier damage, both of which are not observed in wild-type Lm infected humanized mice. Murinization of InlA therefore not only extends the host range of Lm, but also broadens its receptor repertoire, providing Lm with artifactual pathogenic properties. These results challenge the relevance of using InlA(m)-expressing Lm to study human listeriosis and in vivo host responses to this human pathogen. PMID- 23737747 TI - Antibody quality and protection from lethal Ebola virus challenge in nonhuman primates immunized with rabies virus based bivalent vaccine. AB - We have previously described the generation of a novel Ebola virus (EBOV) vaccine platform based on (a) replication-competent rabies virus (RABV), (b) replication deficient RABV, or (c) chemically inactivated RABV expressing EBOV glycoprotein (GP). Mouse studies demonstrated safety, immunogenicity, and protective efficacy of these live or inactivated RABV/EBOV vaccines. Here, we evaluated these vaccines in nonhuman primates. Our results indicate that all three vaccines do induce potent immune responses against both RABV and EBOV, while the protection of immunized animals against EBOV was largely dependent on the quality of humoral immune response against EBOV GP. We also determined if the induced antibodies against EBOV GP differ in their target, affinity, or the isotype. Our results show that IgG1-biased humoral responses as well as high levels of GP-specific antibodies were beneficial for the control of EBOV infection after immunization. These results further support the concept that a successful EBOV vaccine needs to induce strong antibodies against EBOV. We also showed that a dual vaccine against RABV and filoviruses is achievable; therefore addressing concerns for the marketability of this urgently needed vaccine. PMID- 23737748 TI - Activation of the NLRP3 inflammasome by IAV virulence protein PB1-F2 contributes to severe pathophysiology and disease. AB - The ability for a host to recognize infection is critical for virus clearance and often begins with induction of inflammation. The PB1-F2 of pathogenic influenza A viruses (IAV) contributes to the pathophysiology of infection, although the mechanism for this is unclear. The NLRP3-inflammasome has been implicated in IAV pathogenesis, but whether IAV virulence proteins can be activators of the complex is unknown. We investigated whether PB1-F2-mediated activation of the NLRP3 inflammasome is a mechanism contributing to overt inflammatory responses to IAV infection. We show PB1-F2 induces secretion of pyrogenic cytokine IL-1beta by activating the NLRP3-inflammasome, contributing to inflammation triggered by pathogenic IAV. Compared to infection with wild-type virus, mice infected with reverse engineered PB1-F2-deficient IAV resulted in decreased IL-1beta secretion and cellular recruitment to the airways. Moreover, mice exposed to PB1-F2 peptide derived from pathogenic IAV had enhanced IL-1beta secretion compared to mice exposed to peptide derived from seasonal IAV. Implicating the NLRP3-inflammasome complex specifically, we show PB1-F2 derived from pathogenic IAV induced IL-1beta secretion was Caspase-1-dependent in human PBMCs and NLRP3-dependent in mice. Importantly, we demonstrate PB1-F2 is incorporated into the phagolysosomal compartment, and upon acidification, induces ASC speck formation. We also show that high molecular weight aggregated PB1-F2, rather than soluble PB1-F2, induces IL-1beta secretion. Furthermore, NLRP3-deficient mice exposed to PB1-F2 peptide or infected with PB1-F2 expressing IAV were unable to efficiently induce the robust inflammatory response as observed in wild-type mice. In addition to viral pore forming toxins, ion channel proteins and RNA, we demonstrate inducers of NLRP3-inflammasome activation may include disordered viral proteins, as exemplified by PB1-F2, acting as host pathogen 'danger' signals. Elucidating immunostimulatory PB1-F2 mediation of NLRP3-inflammasome activation is a major step forward in our understanding of the aetiology of disease attributable to exuberant inflammatory responses to IAV infection. PMID- 23737749 TI - Identification of a functional type VI secretion system in Campylobacter jejuni conferring capsule polysaccharide sensitive cytotoxicity. AB - The pathogen Campylobacter jejuni is the principal cause of bacterial food-borne infections. The mechanism(s) that contribute to bacterial survival and disease are still poorly understood. In other bacterial species, type VI secretion systems (T6SS) are increasingly recognized to contribute to bacterial pathogenesis by toxic effects on host cells or competing bacterial species. Here we report the presence of a functional Type VI secretion system in C. jejuni. Proteome and genetic analyses revealed that C. jejuni strain 108 contains a 17-kb T6SS gene cluster consisting of 13 T6SS-conserved genes, including the T6SS hallmark genes hcp and vgrG. The cluster lacks an ortholog of the ClpV ATPase considered important for T6SS function. The sequence and organization of the C. jejuni T6SS genes resemble those of the T6SS located on the HHGI1 pathogenicity island of Helicobacter hepaticus. The C. jejuni T6SS is integrated into the earlier acquired Campylobacter integrated element CJIE3 and is present in about 10% of C. jejuni isolates including several isolates derived from patients with the rare clinical feature of C. jejuni bacteremia. Targeted mutagenesis of C. jejuni T6SS genes revealed T6SS-dependent secretion of the Hcp needle protein into the culture supernatant. Infection assays provided evidence that the C. jejuni T6SS confers contact-dependent cytotoxicity towards red blood cells but not macrophages. This trait was observed only in a capsule-deficient bacterial phenotype. The unique C. jejuni T6SS phenotype of capsule-sensitive contact mediated hemolysis represents a novel evolutionary pathway of T6SS in bacteria and expands the repertoire of virulence properties associated with T6SS. PMID- 23737750 TI - Type I interferon programs innate myeloid dynamics and gene expression in the virally infected nervous system. AB - Viral infections of central nervous system (CNS) often trigger inflammatory responses that give rise to a wide range of pathological outcomes. The CNS is equipped with an elaborate network of innate immune sentinels (e.g. microglia, macrophages, dendritic cells) that routinely serve as first responders to these infections. The mechanisms that underlie the dynamic programming of these cells following CNS viral infection remain undefined. To gain insights into this programming, we utilized a combination of genomic and two-photon imaging approaches to study a pure innate immune response to a noncytopathic virus (lymphocytic choriomeningitis virus) as it established persistence in the brain. This enabled us to evaluate how global gene expression patterns were translated into myeloid cell dynamics following infection. Two-photon imaging studies revealed that innate myeloid cells mounted a vigorous early response to viral infection characterized by enhanced vascular patrolling and a complete morphological transformation. Interestingly, innate immune activity subsided over time and returned to a quasi-normal state as the virus established widespread persistence in the brain. At the genomic level, early myeloid cell dynamics were associated with massive changes in CNS gene expression, most of which declined over time and were linked to type I interferon signaling (IFN-I). Surprisingly, in the absence of IFN-I signaling, almost no differential gene expression was observed in the nervous system despite increased viral loads. In addition, two photon imaging studies revealed that IFN-I receptor deficient myeloid cells were unresponsive to viral infection and remained in a naive state. These data demonstrate that IFN-I engages non-redundant programming responsible for nearly all innate immune activity in the brain following a noncytopathic viral infection. This Achilles' heel could explain why so many neurotropic viruses have acquired strategies to suppress IFN-I. PMID- 23737751 TI - Rapid quantification of the latent reservoir for HIV-1 using a viral outgrowth assay. AB - HIV-1 persists in infected individuals in a stable pool of resting CD4(+) T cells as a latent but replication-competent provirus. This latent reservoir is the major barrier to the eradication of HIV-1. Clinical trials are currently underway investigating the effects of latency-disrupting compounds on the persistence of the latent reservoir in infected individuals. To accurately assess the effects of such compounds, accurate assays to measure the frequency of latently infected cells are essential. The development of a simpler assay for the latent reservoir has been identified as a major AIDS research priority. We report here the development and validation of a rapid viral outgrowth assay that quantifies the frequency of cells that can release replication-competent virus following cellular activation. This new assay utilizes bead and column-based purification of resting CD4(+) T cells from the peripheral blood of HIV-1 infected patients rather than cell sorting to obtain comparable resting CD4(+) T cell purity. This new assay also utilizes the MOLT-4/CCR5 cell line for viral expansion, producing statistically comparable measurements of the frequency of latent HIV-1 infection. Finally, this new assay employs a novel quantitative RT-PCR specific for polyadenylated HIV-1 RNA for virus detection, which we demonstrate is a more sensitive and cost-effective method to detect HIV-1 replication than expensive commercial ELISA detection methods. The reductions in both labor and cost make this assay suitable for quantifying the frequency of latently infected cells in clinical trials of HIV-1 eradication strategies. PMID- 23737752 TI - Global properties and functional complexity of human gene regulatory variation. AB - Identification and functional interpretation of gene regulatory variants is a major focus of modern genomics. The application of genetic mapping to molecular and cellular traits has enabled the detection of regulatory variation on genome wide scales and revealed an enormous diversity of regulatory architecture in humans and other species. In this review I summarise the insights gained and questions raised by a decade of genetic mapping of gene expression variation. I discuss recent extensions of this approach using alternative molecular phenotypes that have revealed some of the biological mechanisms that drive gene expression variation between individuals. Finally, I highlight outstanding problems and future directions for development. PMID- 23737753 TI - Using extended genealogy to estimate components of heritability for 23 quantitative and dichotomous traits. AB - Important knowledge about the determinants of complex human phenotypes can be obtained from the estimation of heritability, the fraction of phenotypic variation in a population that is determined by genetic factors. Here, we make use of extensive phenotype data in Iceland, long-range phased genotypes, and a population-wide genealogical database to examine the heritability of 11 quantitative and 12 dichotomous phenotypes in a sample of 38,167 individuals. Most previous estimates of heritability are derived from family-based approaches such as twin studies, which may be biased upwards by epistatic interactions or shared environment. Our estimates of heritability, based on both closely and distantly related pairs of individuals, are significantly lower than those from previous studies. We examine phenotypic correlations across a range of relationships, from siblings to first cousins, and find that the excess phenotypic correlation in these related individuals is predominantly due to shared environment as opposed to dominance or epistasis. We also develop a new method to jointly estimate narrow-sense heritability and the heritability explained by genotyped SNPs. Unlike existing methods, this approach permits the use of information from both closely and distantly related pairs of individuals, thereby reducing the variance of estimates of heritability explained by genotyped SNPs while preventing upward bias. Our results show that common SNPs explain a larger proportion of the heritability than previously thought, with SNPs present on Illumina 300K genotyping arrays explaining more than half of the heritability for the 23 phenotypes examined in this study. Much of the remaining heritability is likely to be due to rare alleles that are not captured by standard genotyping arrays. PMID- 23737755 TI - Side effects: substantial non-neutral evolution flanking regulatory sites. PMID- 23737754 TI - Strong purifying selection at synonymous sites in D. melanogaster. AB - Synonymous sites are generally assumed to be subject to weak selective constraint. For this reason, they are often neglected as a possible source of important functional variation. We use site frequency spectra from deep population sequencing data to show that, contrary to this expectation, 22% of four-fold synonymous (4D) sites in Drosophila melanogaster evolve under very strong selective constraint while few, if any, appear to be under weak constraint. Linking polymorphism with divergence data, we further find that the fraction of synonymous sites exposed to strong purifying selection is higher for those positions that show slower evolution on the Drosophila phylogeny. The function underlying the inferred strong constraint appears to be separate from splicing enhancers, nucleosome positioning, and the translational optimization generating canonical codon bias. The fraction of synonymous sites under strong constraint within a gene correlates well with gene expression, particularly in the mid-late embryo, pupae, and adult developmental stages. Genes enriched in strongly constrained synonymous sites tend to be particularly functionally important and are often involved in key developmental pathways. Given that the observed widespread constraint acting on synonymous sites is likely not limited to Drosophila, the role of synonymous sites in genetic disease and adaptation should be reevaluated. PMID- 23737756 TI - GLIS3, a susceptibility gene for type 1 and type 2 diabetes, modulates pancreatic beta cell apoptosis via regulation of a splice variant of the BH3-only protein Bim. AB - Mutations in human Gli-similar (GLIS) 3 protein cause neonatal diabetes. The GLIS3 gene region has also been identified as a susceptibility risk locus for both type 1 and type 2 diabetes. GLIS3 plays a role in the generation of pancreatic beta cells and in insulin gene expression, but there is no information on the role of this gene on beta cell viability and/or susceptibility to immune- and metabolic-induced stress. GLIS3 knockdown (KD) in INS-1E cells, primary FACS purified rat beta cells, and human islet cells decreased expression of MafA, Ins2, and Glut2 and inhibited glucose oxidation and insulin secretion, confirming the role of this transcription factor for the beta cell differentiated phenotype. GLIS3 KD increased beta cell apoptosis basally and sensitized the cells to death induced by pro-inflammatory cytokines (interleukin 1beta + interferon-gamma) or palmitate, agents that may contribute to beta cell loss in respectively type 1 and 2 diabetes. The increased cell death was due to activation of the intrinsic (mitochondrial) pathway of apoptosis, as indicated by cytochrome c release to the cytosol, Bax translocation to the mitochondria and activation of caspases 9 and 3. Analysis of the pathways implicated in beta cell apoptosis following GLIS3 KD indicated modulation of alternative splicing of the pro-apoptotic BH3-only protein Bim, favouring expression of the pro-death variant BimS via inhibition of the splicing factor SRp55. KD of Bim abrogated the pro-apoptotic effect of GLIS3 loss of function alone or in combination with cytokines or palmitate. The present data suggest that altered expression of the candidate gene GLIS3 may contribute to both type 1 and 2 type diabetes by favouring beta cell apoptosis. This is mediated by alternative splicing of the pro-apoptotic protein Bim and exacerbated formation of the most pro-apoptotic variant BimS. PMID- 23737757 TI - Cell polarity and patterning by PIN trafficking through early endosomal compartments in Arabidopsis thaliana. AB - PIN-FORMED (PIN) proteins localize asymmetrically at the plasma membrane and mediate intercellular polar transport of the plant hormone auxin that is crucial for a multitude of developmental processes in plants. PIN localization is under extensive control by environmental or developmental cues, but mechanisms regulating PIN localization are not fully understood. Here we show that early endosomal components ARF GEF BEN1 and newly identified Sec1/Munc18 family protein BEN2 are involved in distinct steps of early endosomal trafficking. BEN1 and BEN2 are collectively required for polar PIN localization, for their dynamic repolarization, and consequently for auxin activity gradient formation and auxin related developmental processes including embryonic patterning, organogenesis, and vasculature venation patterning. These results show that early endosomal trafficking is crucial for cell polarity and auxin-dependent regulation of plant architecture. PMID- 23737758 TI - DNA binding of the cell cycle transcriptional regulator GcrA depends on N6 adenosine methylation in Caulobacter crescentus and other Alphaproteobacteria. AB - Several regulators are involved in the control of cell cycle progression in the bacterial model system Caulobacter crescentus, which divides asymmetrically into a vegetative G1-phase (swarmer) cell and a replicative S-phase (stalked) cell. Here we report a novel functional interaction between the enigmatic cell cycle regulator GcrA and the N6-adenosine methyltransferase CcrM, both highly conserved proteins among Alphaproteobacteria, that are activated early and at the end of S phase, respectively. As no direct biochemical and regulatory relationship between GcrA and CcrM were known, we used a combination of ChIP (chromatin immunoprecipitation), biochemical and biophysical experimentation, and genetics to show that GcrA is a dimeric DNA-binding protein that preferentially targets promoters harbouring CcrM methylation sites. After tracing CcrM-dependent N6 methyl-adenosine promoter marks at a genome-wide scale, we show that these marks recruit GcrA in vitro and in vivo. Moreover, we found that, in the presence of a methylated target, GcrA recruits the RNA polymerase to the promoter, consistent with its role in transcriptional activation. Since methylation-dependent DNA binding is also observed with GcrA orthologs from other Alphaproteobacteria, we conclude that GcrA is the founding member of a new and conserved class of transcriptional regulators that function as molecular effectors of a methylation dependent (non-heritable) epigenetic switch that regulates gene expression during the cell cycle. PMID- 23737759 TI - CDK4 T172 phosphorylation is central in a CDK7-dependent bidirectional CDK4/CDK2 interplay mediated by p21 phosphorylation at the restriction point. AB - Cell cycle progression, including genome duplication, is orchestrated by cyclin dependent kinases (CDKs). CDK activation depends on phosphorylation of their T loop by a CDK-activating kinase (CAK). In animals, the only known CAK for CDK2 and CDK1 is cyclin H-CDK7, which is constitutively active. Therefore, the critical activation step is dephosphorylation of inhibitory sites by Cdc25 phosphatases rather than unrestricted T-loop phosphorylation. Homologous CDK4 and CDK6 bound to cyclins D are master integrators of mitogenic/oncogenic signaling cascades by initiating the inactivation of the central oncosuppressor pRb and cell cycle commitment at the restriction point. Unlike the situation in CDK1 and CDK2 cyclin complexes, and in contrast to the weak but constitutive T177 phosphorylation of CDK6, we have identified the T-loop phosphorylation at T172 as the highly regulated step determining CDK4 activity. Whether both CDK4 and CDK6 phosphorylations are catalyzed by CDK7 remains unclear. To answer this question, we took a chemical-genetics approach by using analogue-sensitive CDK7(as/as) mutant HCT116 cells, in which CDK7 can be specifically inhibited by bulky adenine analogs. Intriguingly, CDK7 inhibition prevented activating phosphorylations of CDK4/6, but for CDK4 this was at least partly dependent on its binding to p21 (cip1) . In response to CDK7 inhibition, p21-binding to CDK4 increased concomitantly with disappearance of the most abundant phosphorylation of p21, which we localized at S130 and found to be catalyzed by both CDK4 and CDK2. The S130A mutation of p21 prevented the activating CDK4 phosphorylation, and inhibition of CDK4/6 and CDK2 impaired phosphorylations of both p21 and p21-bound CDK4. Therefore, specific CDK7 inhibition revealed the following: a crucial but partly indirect CDK7 involvement in phosphorylation/activation of CDK4 and CDK6; existence of CDK4-activating kinase(s) other than CDK7; and novel CDK7-dependent positive feedbacks mediated by p21 phosphorylation by CDK4 and CDK2 to sustain CDK4 activation, pRb inactivation, and restriction point passage. PMID- 23737760 TI - Interactions with iridophores and the tissue environment required for patterning melanophores and xanthophores during zebrafish adult pigment stripe formation. AB - Skin pigment patterns of vertebrates are a classic system for understanding fundamental mechanisms of morphogenesis, differentiation, and pattern formation, and recent studies of zebrafish have started to elucidate the cellular interactions and molecular mechanisms underlying these processes. In this species, horizontal dark stripes of melanophores alternate with light interstripes of yellow or orange xanthophores and iridescent iridophores. We showed previously that the highly conserved zinc finger protein Basonuclin-2 (Bnc2) is required in the environment in which pigment cells reside to promote the development and maintenance of all three classes of pigment cells; bnc2 mutants lack body stripes and interstripes. Previous studies also revealed that interactions between melanophores and xanthophores are necessary for organizing stripes and interstripes. Here we show that bnc2 promotes melanophore and xanthophore development by regulating expression of the growth factors Kit ligand a (Kitlga) and Colony stimulating factor-1 (Csf1), respectively. Yet, we found that rescue of melanophores and xanthophores was insufficient for the recovery of stripes in the bnc2 mutant. We therefore asked whether bnc2-dependent iridophores might contribute to stripe and interstripe patterning as well. We found that iridophores themselves express Csf1, and by ablating iridophores in wild-type and mutant backgrounds, we showed that iridophores contribute to organizing both melanophores and xanthophores during the development of stripes and interstripes. Our results reveal an important role for the cellular environment in promoting adult pigment pattern formation and identify new components of a pigment-cell autonomous pattern-generating system likely to have broad implications for understanding how pigment patterns develop and evolve. PMID- 23737761 TI - Role of Peroxisome Proliferator-Activated Receptor beta/delta and B-Cell Lymphoma 6 in Regulation of Genes Involved in Metastasis and Migration in Pancreatic Cancer Cells. AB - PPARbeta/delta is a ligand-activated transcription factor that regulates various cellular functions via induction of target genes directly or in concert with its associated transcriptional repressor, BCL-6. Matrix remodeling proteinases are frequently over-expressed in pancreatic cancer and are involved with metastasis. The present study tested the hypothesis that PPARbeta/delta is expressed in human pancreatic cancer cells and that its activation could regulate MMP-9, decreasing cancer cells ability to transverse the basement membrane. In human pancreatic cancer tissue there was significantly higher expression of MMP-9 and PPARbeta/delta, and lower levels of BCL-6 mRNA. PPARbeta/delta activation reduced the TNF alpha -induced expression of various genes implicated in metastasis and reduced the invasion through a basement membrane in cell culture models. Through the use of short hairpin RNA inhibitors of PPARbeta/delta, BCL-6, and MMP-9, it was evident that PPARbeta/delta was responsible for the ligand-dependent effects whereas BCL-6 dissociation upon GW501516 treatment was ultimately responsible for decreasing MMP-9 expression and hence invasion activity. These results suggest that PPARbeta/delta plays a role in regulating pancreatic cancer cell invasion through regulation of genes via ligand-dependent release of BCL-6 and that activation of the receptor may provide an alternative therapeutic method for controlling migration and metastasis. PMID- 23737763 TI - Time course of the development of nonalcoholic Fatty liver disease in the Otsuka long-evans Tokushima Fatty rat. AB - Nonalcoholic fatty liver disease (NAFLD) is considered a hepatic manifestation of metabolic syndrome. In this study, we investigated histological and biochemical changes in NAFLD and the gene expression involving de novo lipogenesis in Otsuka Long-Evans Tokushima fatty (OLETF) rats. We used OLETF rats and Long-Evans Tokushima Otsuka (LETO) rats as animal models of NAFLD and as controls, respectively. Consistent observations were made at 4-week intervals up to 50 weeks of age, and all rats were fed ad libitum with standard food. Biochemical and histological changes were observed, and gene expression involved in de novo lipogenesis was measured using real-time polymerase chain reactions. As a results hepatic micro- and macrovesicular steatosis and hepatocyte ballooning were evident in the OLETF rats at 22-38 weeks of age but disappeared after 42 weeks; no fibrosis or collagen deposition was observed. Gene expression involved in de novo lipogenesis followed a pattern similar to that of the histological changes. In conclusion, in the absence of dietary manipulation, hepatic steatosis in OLETF rats is evident at 22-38 weeks and declines after 42 weeks. Therefore, OLETF rats at 22-38 weeks are recommended as animal models of hepatic steatosis. PMID- 23737764 TI - Mucosal barrier in ulcerative colitis and Crohn's disease. AB - Background. The mucus layer in the gastrointestinal tract plays important role in host innate defense, regulation of secretion, and absorption processes, maintaining colonization resistance, which composes the integrity of protective mucus barrier in the large intestine. Investigations of mucin expression in the colon mucosa can improve the understanding of protective function of mucosal barrier in ulcerative colitis (UC) and Crohn's disease (CD). Materials and Methods. 77 patients with UC and CD were examined. Histological analysis of colon mucosa was done by standard method (haematoxylin-eosin, alcian blue at pH 1.0 and 2.5 to determine sulfated and nonsulfated glycosaminoglycans and glycoproteins, and goblet cells). To characterize the mucus production the PAS-reaction was performed. Immunohistochemistry was performed using monoclonal mouse antibodies raised against MUC2, MUC3, MUC4, and TFF3 (USBiological, USA). Results. The moderate expression of MUC2 and MUC3 (50.0% and 32.1%, P = 0.03) and high expression of MUC4 and TFF3 in the colon mucosa were observed in all patients with CD. The intensive labeling of MUC4 and TFF3 occurred more often (42.9% and 57.1%, P = 0.03) in patients with CD. The level of expression of secretory MUC2 and transmembrane MUC3 and MUC4 in all patients with UC was low, up to its complete absence (59.2% and 53.1% cases, P = 0.05). TFF3 expression had high and medium staining intensity in patients with UC. Conclusions. Different types of mucins synthesis, secretion, and expression were found in patients with UC and CD. The expression of mucin MUC2, MUC3, MUC4, and TFF3 correlated with the activity of disease and the extent of the inflammatory process in the large intestine. The most pronounced alteration of mucins expression was observed in patients with severe UC and CD. PMID- 23737762 TI - Functional Role of PPARs in Ruminants: Potential Targets for Fine-Tuning Metabolism during Growth and Lactation. AB - Characterization and biological roles of the peroxisome proliferator-activated receptor (PPAR) isotypes are well known in monogastrics, but not in ruminants. However, a wealth of information has accumulated in little more than a decade on ruminant PPARs including isotype tissue distribution, response to synthetic and natural agonists, gene targets, and factors affecting their expression. Functional characterization demonstrated that, as in monogastrics, the PPAR isotypes control expression of genes involved in lipid metabolism, anti inflammatory response, development, and growth. Contrary to mouse, however, the PPARgamma gene network appears to controls milk fat synthesis in lactating ruminants. As in monogastrics, PPAR isotypes in ruminants are activated by long chain fatty acids, therefore, making them ideal candidates for fine-tuning metabolism in this species via nutrients. In this regard, using information accumulated in ruminants and monogastrics, we propose a model of PPAR isotype driven biological functions encompassing key tissues during the peripartal period in dairy cattle. PMID- 23737765 TI - Precancerous lesions in colorectal cancer. AB - Colorectal cancer (CRC) is the third most common cause of cancer death in the world. The incidence rate (ASR) and age distribution of this disease differ between most of African-Middle-Eastern (AMAGE) and North America and Europe for many reasons. However, in all areas, "CRC" is considered as one of the most preventable cancers, because it might develop from variant processes like polyps and IBD in addition to the genetic pathogenesis which became very well known in this disease. We tried in this paper to review all the possible reasons of the differences in incidence and age between the west and AMAGE. Also we reviewed all the mutations that lead to the hereditary and familiar clustering of this disease with the correlations with the surrounding food and environment of different areas. Then, we focused on the precancerous pathology of this disease with special focusing on early detection depending on new endoscopy technology and most important genetic studies. We lastly reviewed the evidence of some of the surveillance and put suggestions about future surveillance programs and how important those programs are on the psychological aspect of the patients and their families. PMID- 23737766 TI - EUS-Guided Vascular Procedures: A Literature Review. AB - Endoscopic ultrasound (EUS) is continuously stepping into the therapeutic arena, simultaneously evolving in different directions, such as the management of pancreatic and biliary diseases, celiac neurolysis, delivering local intratumoral therapy, and EUS-guided endosurgery. EUS-guided vascular procedures are also challenging, considering the variety of vascular pathology, proximity of the vascular structures to the GI tract wall, high resolution, and real-time guidance offering an attractive access route and precise delivery of the intervention. The literature on vascular therapeutic EUS demonstrates techniques for the management of upper GI variceal and nonvariceal bleeding, pseudoaneurysms, and coiling and embolization procedures, as well as the creation of intrahepatic portosystemic shunts. The paucity of studies, diversity of study designs, and the number of animal model studies hamper a systematic approach to the conclusion and decision making important to clinicians and healthcare policy makers. Nevertheless, theoretical benefits and findings up to date concerning technical feasibility, efficacy, and safety of the procedures drive further research and development in this rather young therapeutic arena. PMID- 23737767 TI - Interactions among Low Dose of Methotrexate and Drugs Used in the Treatment of Rheumatoid Arthritis. AB - Methotrexate (MTX) is a nonbiological disease-modifying antirheumatic drug that has shown both a good control of clinical disease and a good safety. Usually drug drug interactions (DDIs) represent the most limiting factor during the clinical management of any disease, in particular when several drugs are coadministered to treat the same disease. In this paper, we report the interactions among MTX and the other drugs commonly used in the management of rheumatoid arthritis. Using Medline, PubMed, Embase, Cochrane libraries, and Reference lists, we searched for the articles published until June 30, 2012, and we reported the most common DDIs between MTX and antirheumatic drugs. In particular, clinically relevant DDIs have been described during the treatment with MTX and NSAIDs, for example, diclofenac, indomethacin, or COX-2 inhibitors, and between MTX and prednisone or immunosuppressant drugs (e.g., leflunomide and cyclosporine). Finally, an increase in the risk of infections has been recorded during the combination treatment with MTX plus antitumor necrosis factor- alpha agents. In conclusion, during the treatment with MTX, DDIs play an important role in both the development of ADRs and therapeutic failure. PMID- 23737768 TI - Reverse engineering sparse gene regulatory networks using cubature kalman filter and compressed sensing. AB - This paper proposes a novel algorithm for inferring gene regulatory networks which makes use of cubature Kalman filter (CKF) and Kalman filter (KF) techniques in conjunction with compressed sensing methods. The gene network is described using a state-space model. A nonlinear model for the evolution of gene expression is considered, while the gene expression data is assumed to follow a linear Gaussian model. The hidden states are estimated using CKF. The system parameters are modeled as a Gauss-Markov process and are estimated using compressed sensing based KF. These parameters provide insight into the regulatory relations among the genes. The Cramer-Rao lower bound of the parameter estimates is calculated for the system model and used as a benchmark to assess the estimation accuracy. The proposed algorithm is evaluated rigorously using synthetic data in different scenarios which include different number of genes and varying number of sample points. In addition, the algorithm is tested on the DREAM4 in silico data sets as well as the in vivo data sets from IRMA network. The proposed algorithm shows superior performance in terms of accuracy, robustness, and scalability. PMID- 23737769 TI - Determination of pesticide residues in cannabis smoke. AB - The present study was conducted in order to quantify to what extent cannabis consumers may be exposed to pesticide and other chemical residues through inhaled mainstream cannabis smoke. Three different smoking devices were evaluated in order to provide a generalized data set representative of pesticide exposures possible for medical cannabis users. Three different pesticides, bifenthrin, diazinon, and permethrin, along with the plant growth regulator paclobutrazol, which are readily available to cultivators in commercial products, were investigated in the experiment. Smoke generated from the smoking devices was condensed in tandem chilled gas traps and analyzed with gas chromatography-mass spectrometry (GC-MS). Recoveries of residues were as high as 69.5% depending on the device used and the component investigated, suggesting that the potential of pesticide and chemical residue exposures to cannabis users is substantial and may pose a significant toxicological threat in the absence of adequate regulatory frameworks. PMID- 23737770 TI - Photoperiod-Dependent Effects of 4-tert-Octylphenol on Adherens and Gap Junction Proteins in Bank Vole Seminiferous Tubules. AB - In the present study we evaluated in vivo and in vitro effects of 4-tert octylphenol (OP) on the expression and distribution of adherens and gap junction proteins, N-cadherin, beta -catenin, and connexin 43 (Cx43), in testes of seasonally breeding rodents, bank voles. We found that in bank vole testes expression and distribution of N-cadherin, beta -catenin, and Cx43 were photoperiod dependent. Long-term treatment with OP (200 mg/kg b.w.) resulted in the reduction of junction proteins expressions (P < 0.05, P < 0.01) and their delocalization in the testes of males kept in long photoperiod, whereas in short day animals slight increase of Cx43 (P < 0.05), N-cadherin, and beta -catenin (statistically nonsignificant) levels was observed. Effects of OP appeared to be independent of FSH and were maintained during in vitro organ culture, indicating that OP acts directly on adherens and gap junction proteins in the testes. An experiment performed using an antiestrogen ICI 182,780 demonstrated that the biological effects of OP on beta -catenin and Cx43 involve an estrogen receptor mediated response. Taken together, in bank vole organization of adherens and gap junctions and their susceptibility to OP are related to the length of photoperiod. Alterations in cadherin/catenin and Cx43-based junction may partially result from activation of estrogen receptor alpha and/or beta signaling pathway. PMID- 23737771 TI - Significant independent predictors of vitamin d deficiency in inpatients and outpatients of a nephrology unit. AB - Aims. Kidney disease was found to be a major risk factor for vitamin D deficiency in a population study of patients hospitalized. The aims of the study were to describe the prevalence of vitamin D deficiency inpatients and outpatients in a nephrology department during fall and to evaluate effect of assessing serum 25 hydroxyvitamin D (25(OH)D) levels and previous supplementation of cholecalciferol on vitamin D status. Methods. We studied 280 subjects in total, between October and January. The subjects were recruited from the following two groups: (a) inpatients and (b) outpatients in nephrology unit. We examined previous documentary evidence of vitamin D supplementation of the patients. Results. The prevalence of vitamin D deficiency among these 280 patients was 62,1% (174 patients). Fifty-three patients (18.9%) had severe vitamin D deficiency, 121 patients (43.2%) moderate vitamin D deficiency, and 66 patients (23.6%) vitamin D insufficiency. In logistic regression analysis female gender, not having vitamin D supplementation history, low serum albumin, and low blood urea nitrogen levels were significant independent predictors of vitamin D deficiency while no association of vitamin D deficiency with diabetes mellitus, serum creatinine, eGFR, and being hospitalized was found. Conclusion. Vitamin D deficiency, seems to be an important problem in both inpatients and outpatients of nephrology. Monitoring serum 25(OH)D concentrations regularly and replacement of vitamin D are important. Women in Turkey are at more risk of deficiency and may therefore need to consume higher doses of vitamin D. PMID- 23737772 TI - Association between Endocrine Disrupting Phenols in Colostrums and Maternal and Infant Health. AB - Bisphenol A (BPA) and alkylphenols (APs) are well-known endocrine disrupting chemicals (EDCs) which may threat the next generations' health. We performed biomonitoring of these phenols in colostrums to assess risk of the phenols in breast-fed neonates. Study subjects were the lactating mothers who delivered babies within 2 weeks (N = 325; 30.67 +/- 3.45 years) and their neonates (N = 326; embryonic period, 39.1 +/- 1.5 weeks). BPA, nonylphenol (NP), and octylphenol (OP) in colostrums were quantified with LC/MS/MS. Information for environmental exposure sources of the phenols was obtained by questionnaires. As results, median level of BPA in colostrums was 7.8 ng/mL, while most NP or OP was not detected. Regarding health risks of phenols, levels of total NP in colostrums were elevated among sick mothers with toxemia, thyroid disorders, gastritis, and so forth than health mothers (3.51 +/- 4.98 versus 2.04 +/- 3.71 ng/mL, P = 0.02). Dairy products intake and detergents use were positively correlated with total BPA levels (Ps < 0.05). In conclusion, we estimate most neonates who are exposed to BPA rather than NP or OP via colostrums and recommend continuous biomonitoring of the phenols to clarify their suspected health risk on neonates and pregnant or gestation mothers. PMID- 23737773 TI - Hepatic Steatosis, Carbohydrate Intake, and Food Quotient in Patients with NAFLD. AB - Is steatosis related to the spontaneous carbohydrate intake in patients with NAFLD? We performed dietary records for 24 patients with NAFLD, 3 months after their liver biopsy was performed and before the deliverance of a dietary advice. The food quotient, indicator of the proportion of calories from carbohydrates, was calculated as (1.00*% calories from carbohydrates/100) + (0.70*% calories from lipids/100) + (0.81*% calories from proteins/100). The associations between diet variables and steatosis% on the hepatic biopsies were tested by regression analysis, and diet variables were compared according to the presence of fibrosis. The subjects displayed a large range of steatosis, 50.5% +/- 25.5 [10-90], correlated with their energy intake (1993 +/- 597 kcal/d, r = 0.41, P < 0.05) and food quotient (0.85 +/- 0.02, r = 0.42, P < 0.05), which remained significant with both variables by a multivariate regression analysis (r = 0.51, P < 0.05). For the 17/24 patients with a hepatic fibrosis, the energy intake was lower (fibrosis: 1863 +/- 503 versus others: 2382 +/- 733 kcal/d, P < 0.05), and their food quotients did not differ from patients without fibrosis. Hepatic steatosis was related to the energy and carbohydrate intakes in our patients; the role of dietary carbohydrates was detectable in the range of usual carbohydrate intake: 32% to 58% calories. PMID- 23737775 TI - Inflammatory factors and exercise in chronic kidney disease. AB - Patients with chronic kidney disease frequently present with chronic elevations in markers of inflammation, a condition that appears to be exacerbated by disease progression and onset of haemodialysis. Systemic inflammation is interlinked with malnutrition and muscle protein wasting and is implicated in a number of morbidities including cardiovascular disease: the most common cause of mortality in this population. Research in the general population and other chronic disease cohorts suggests that an increase in habitual activity levels over a prolonged period may help redress basal increases in systemic inflammation. Furthermore, those populations with the highest baseline levels of systemic inflammation appear to have the greatest improvements from training. On the whole, the activity levels of the chronic kidney disease population reflect a sedentary lifestyle, indicating the potential for increasing physical activity and observing health benefits. This review explores the current literature investigating exercise and inflammatory factors in the chronic kidney disease population and then attempts to explain the contradictory findings and suggests where future research is required. PMID- 23737774 TI - Assessment and molecular actions of endocrine-disrupting chemicals that interfere with estrogen receptor pathways. AB - In all vertebrate species, estrogens play a crucial role in the development, growth, and function of reproductive and nonreproductive tissues. A large number of natural or synthetic chemicals present in the environment and diet can interfere with estrogen signaling; these chemicals are called endocrine disrupting chemicals (EDCs) or xenoestrogens. Some of these compounds have been shown to induce adverse effects on human and animal health, and some compounds are suspected to contribute to diverse disease development. Because xenoestrogens have varying sources and structures and could act in additive or synergistic effects when combined, they have multiple mechanisms of action. Consequently, an important panel of in vivo and in vitro bioassays and chemical analytical tools was used to screen, evaluate, and characterize the potential impacts of these compounds on humans and animals. In this paper, we discuss different molecular actions of some of the major xenoestrogens found in food or the environment, and we summarize the current models used to evaluate environmental estrogens. PMID- 23737776 TI - Comparison of a multiple daily insulin injection regimen (glargine or detemir once daily plus prandial insulin aspart) and continuous subcutaneous insulin infusion (aspart) in short-term intensive insulin therapy for poorly controlled type 2 diabetes patients. AB - Aims. To examine the potential differences between multiple daily injection (MDI) regimens based on new long-acting insulin analogues (glargine or detemir) plus prandial insulin aspart and continuous subcutaneous insulin aspart infusion (CSII) in patients with poorly controlled type 2 diabetes. Methods. Patients (n = 119) with poorly controlled type 2 diabetes of a duration exceeding five years were randomly assigned into three groups: Group A treated with CSII using insulin aspart; Group B treated with glargine-based MDI and Group C treated with detemir based MDI. Results. Good glycemic control was achieved by patients in Group A in a significantly shorter duration than patients in Groups B and C. Total daily insulin, basal insulin dose and dose per kg body weight in Group A were significantly less than those in Groups B and C. Daily blood glucose fluctuation in Group A was significantly less than that in Groups B and C. There were no differences between Groups B and C. Conclusions. Aspart-based CSII may achieve good blood glucose control with less insulin doses over a shorter period compared with glargine or detemir-based MDI. No differences between glargine- and detemir based MDI were detected in poorly controlled subjects with type 2 diabetes. PMID- 23737777 TI - Dietary calcium intake and calcium supplementation in hungarian patients with osteoporosis. AB - Purpose. Adequate calcium intake is the basis of osteoporosis therapy-when this proves insufficient, even specific antiosteoporotic agents cannot exert their actions properly. Methods. Our representative survey analyzed the dietary intake and supplementation of calcium in 8033 Hungarian female and male (mean age: 68 years) (68.01 (CI95: 67.81-68.21)) patients with osteoporosis. Results. Mean intake from dietary sources was 665 +/- 7.9 mg (68.01 (CI95: 67.81-68.21)) daily. A significant positive relationship could be detected between total dietary calcium intake and lumbar spine BMD (P = 0.045), whereas such correlation could not be demonstrated with femoral T-score. Milk consumption positively correlated with femur (P = 0.041), but not with lumbar BMD. The ingestion of one liter of milk daily increased the T-score by 0.133. Average intake from supplementation was 558 +/- 6.2 mg (68.01 (CI95: 67.81-68.21)) daily. The cumulative dose of calcium-from both dietary intake and supplementation-was significantly associated with lumbar (r = 0.024, P = 0.049), but not with femur BMD (r = 0.021, P = 0.107). The currently recommended 1000-1500 mg total daily calcium intake was achieved in 34.5% of patients only. It was lower than recommended in 47.8% of the cases and substantially higher in 17.7% of subjects. Conclusions. We conclude that calcium intake in Hungarian osteoporotic patients is much lower than the current recommendation, while routinely applied calcium supplementation will result in inappropriately high calcium intake in numerous patients. PMID- 23737778 TI - Glucocorticoid-induced bone loss is associated with abnormal intravertebral areal bone mineral density distribution. AB - Individuals with glucocorticoid-induced osteoporosis experience vertebral fractures at an increased rate and at higher vertebral areal bone mineral density (aBMD) than individuals with primary osteoporosis. Standard posteroanterior- (PA ) projection dual energy X-ray absorptiometry (DXA) lacks the diagnostic sensitivity required for reliable estimation of vertebral fracture risk in individuals. Assessment of subregional vertebral aBMD using lateral-projection DXA may improve the predictive value of DXA parameters for fracture. One hundred and four individuals were recruited and grouped for this study: primary osteoporosis with no history of vertebral fracture (n = 43), glucocorticoid induced bone loss (n = 13), and healthy controls (n = 48). Standard PA-projection and supine-lateral scans were performed, and lateral scans were analysed according to an established protocol to measure aBMD within 6 subregions. Main effects for subregion and group were assessed and observed, by ANCOVA. Ratios were calculated between subregions and compared between groups, to overcome the potentially confounding influence of variability in subregional geometry. Significantly lower values were observed in the glucocorticoid group for the ratios of (i) anterior subregion: whole vertebral body and (ii) posterior: whole vertebral body when compared to the primary osteoporosis and control groups (P < 0.05). Lower anterior subregional aBMD in individuals on glucocorticoid therapy may help to explain the increased vertebral fracture risk in this patient group. PMID- 23737779 TI - Endocrine actions of osteocalcin. AB - Osteocalcin is the most abundant noncollagenous protein of bone matrix. Once transcribed, this protein undergoes posttranslational modifications within osteoblastic cells before its secretion, including the carboxylation of three glutamic residues in glutamic acid, which is essential for hydroxyapatite binding and deposition in the extracellular matrix of bone. Recent provocative data from experimental observations in mice showed that the circulating undercarboxylated fraction of osteocalcin increases insulin secretion and sensitivity, lowers blood glucose, and decreases visceral fat in both genders, while it enhances testosterone production by the testes in males. Moreover, both total and undercarboxylated osteocalcins increase following physical activity with potential positive effects on glucose tolerance. Despite that these evidences have been only in part confirmed in humans, further prospective investigations are needed to definitively establish the endocrine role of osteocalcin both in the general population and cohorts of patients with diabetes or other metabolic disorders. PMID- 23737780 TI - Intrahepatic Lipid Content and Insulin Resistance Are More Strongly Associated with Impaired NEFA Suppression after Oral Glucose Loading Than with Fasting NEFA Levels in Healthy Older Individuals. AB - Introduction. The mechanisms underlying the association between insulin resistance and intrahepatic lipid (IHL) accumulation are not completely understood. We sought to determine whether this association was explained by differences in fasting non-esterified fatty acid (NEFA) levels and/or NEFA suppression after oral glucose loading. Materials and Methods. We performed a cross-sectional analysis of 70 healthy participants in the Hertfordshire Physical Activity Trial (39 males, age 71.3 +/- 2.4 years) who underwent oral glucose tolerance testing with glucose, insulin, and NEFA levels measured over two hours. IHL was quantified with magnetic resonance spectroscopy. Insulin sensitivity was measured with the oral glucose insulin sensitivity (OGIS) model, the leptin: adiponectin ratio (LAR), and the homeostasis model assessment (HOMA). Results. Measures of insulin sensitivity were not associated with fasting NEFA levels, but OGIS was strongly associated with NEFA suppression at 30 minutes and strongly inversely associated with IHL. Moreover, LAR was strongly inversely associated with NEFA suppression and strongly associated with IHL. This latter association (beta = 1.11 [1.01, 1.21], P = 0.026) was explained by reduced NEFA suppression (P = 0.24 after adjustment). Conclusions. Impaired postprandial NEFA suppression, but not fasting NEFA, contributes to the strong and well-established association between whole body insulin resistance and liver fat accumulation. PMID- 23737781 TI - A Novel, Homozygous c.1502T>G (p.Val501Gly) Mutation in the Thyroid peroxidase Gene in Malaysian Sisters with Congenital Hypothyroidism and Multinodular Goiter. AB - Congenital hypothyroidism (CH) with multinodular goiter (MNG) is uncommonly seen in children. However, CH associated with goiter is often caused by defective Thyroid peroxidase (TPO) gene. In this study, we screened for mutation(s) in the TPO gene in two siblings with CH and MNG and their healthy family members. The two sisters, born to consanguineous parents, were diagnosed with CH during infancy and received treatment since then. They developed MNG during childhood despite adequate L-thyroxine replacement and negative thyroid antibody screening. PCR-amplification of all exons using flanking primers followed by DNA sequencing revealed that the two sisters were homozygous for a novel c.1502T>G mutation. The mutation is predicted to substitute valine for glycine at a highly conserved amino acid residue 501 (p.Val501Gly). Other healthy family members were either heterozygotes or mutation-free. The mutation was not detected in 50 healthy unrelated individuals. In silico analyses using PolyPhen-2 and SIFT predicted that the p.Val501Gly mutation is functionally "damaging." Tertiary modeling showed structural alterations in the active site of the mutant TPO. In conclusion, a novel mutation, p.Val501Gly, in the TPO gene was detected expanding the mutation spectrum of TPO associated with CH and MNG. PMID- 23737782 TI - Maternal thyroid dysfunction and neonatal thyroid problems. AB - Aim. To investigate obstetric features of pregnant women with thyroid disorders and thyroid function tests of their newborn infants. Methods. Women with hypothyroidism and having anti-thyroglobulin (ATG) and anti-thyroid peroxidase (anti-TPO) antibodies were assigned as group I, women with hypothyroidism who did not have autoantibodies were assigned as group II, and women without thyroid problems were assigned as group III. Results. Pregnant women with autoimmune hypothyroidism (group I) had more preterm delivery and their babies needed more frequent neonatal intensive care unit (NICU) admission. In group I, one infant was diagnosed with compensated hypothyroidism and one infant had transient hyperthyrotropinemia. Five infants (23.8%) in group II had thyroid-stimulating hormone (TSH) levels >20 mIU/mL. Only two of them had TSH level >7 mIU/L at the 3rd postnatal week, and all had normal free T4 (FT4). Median maternal TSH level of these five infants with TSH >20 mIU/mL was 6.6 mIU/mL. In group III, six infants (6.5%) had TSH levels above >20 mIU/mL at the 1st postnatal week. Conclusion. Infants of mothers with thyroid problems are more likely to have elevated TSH and higher recall rate on neonatal thyroid screening. Women with thyroid disorders and their newborn infants should be followed closely for both obstetrical problems and for thyroid dysfunction. PMID- 23737783 TI - Tumor-associated macrophages in glioma: friend or foe? AB - Tumor-associated macrophages (TAMs) contribute substantially to the tumor mass of gliomas and have been shown to play a major role in the creation of a tumor microenvironment that promotes tumor progression. Shortcomings of attempts at antiglioma immunotherapy may result from a failure to adequately address these effects. Emerging evidence supports an independent categorization of glioma TAMs as alternatively activated M2-type macrophages, in contrast to classically activated proinflammatory M1-type macrophages. These M2-type macrophages exert glioma-supportive effects through reduced anti-tumor functions, increased expression of immunosuppressive mediators, and nonimmune tumor promotion through expression of trophic and invasion-facilitating substances. Much of our work has demonstrated these features of glioma TAMs, and together with the supporting literature will be reviewed here. Additionally, the dynamics of glioma cell-TAM interaction over the course of tumor development remain poorly understood; our efforts to elucidate glioma cell-TAM dynamics are summarized. Finally, the molecular pathways which underlie M2-type TAM polarization and gene expression similarly require further investigation, and may present the most potent targets for immunotherapeutic intervention. Highlighting recent evidence implicating the transcription factor STAT3 in immunosuppressive tumorigenic glioma TAMs, we advocate for gene array-based approaches to identify yet unappreciated expression regulators and effector molecules important to M2-type glioma TAMs polarization and function within the glioma tumor microenvironment. PMID- 23737784 TI - Predictive Factors of Response in HER2-Positive Breast Cancer Treated by Neoadjuvant Therapy. AB - Since 2005, major progresses have been made in the neoadjuvant treatment of HER2 positive breast cancer. Trastuzumab introduction associated with chemotherapy has been the first major step leading to the improvement of the complete pathological response rate and, like in the adjuvant studies, better survivals. Dual HER2 blockade has been the next step and trastuzumab is associated now with other anti HER2 therapies like lapatinib or pertuzumab, the latter being much more easy to use in combination with chemotherapy. Additional knowledge is necessary to better define within the HER2 tumor subgroup which patients could benefit more from targeted therapies. Different biomarkers have been studied to predict the response after anti-HER2 neoadjuvant therapies but until now none has been validated. PMID- 23737786 TI - Electronic Properties of TiO2 Nanoparticles Films and the Effect on Apatite Forming Ability. AB - Nanoparticle-covered electrodes have altered properties as compared to conventional electrodes with same chemical composition. The changes originate from the large surface area and enhanced conduction. To test the mineralization capacity of such materials, TiO2 nanoparticles were deposited on titanium and gold substrates. The electrochemical properties were investigated using cyclic voltammetry and impedance spectroscopy while the mineralization was tested by immersion in simulated body fluid. Two types of nucleation and growth behaviours were observed. For smooth nanoparticle surfaces, the initial nucleation is fast with the formation of few small nuclei of hydroxyapatite. With time, an amorphous 2D film develops with a Ca/P ratio close to 1.5. For the rougher surfaces, the nucleation is delayed but once it starts, thick layers are formed. Also the electronic properties of the oxides were shown to be important. Both density of states (DOS) in the bandgap of TiO2 and the active area were determined. The maximum in DOS was found to correlate with the donor density (N d ) and the active surface area. The results clearly show that a rough surface with high conductivity is beneficial for formation of thick apatite layers, while the nanoparticle covered electrodes show early nucleation but limited apatite formation. PMID- 23737785 TI - Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. AB - Background. In the last decades, thyroid cancer incidence has continuously and sharply increased all over the world. This review analyzes the possible reasons of this increase. Summary. Many experts believe that the increased incidence of thyroid cancer is apparent, because of the increased detection of small cancers in the preclinical stage. However, a true increase is also possible, as suggested by the observation that large tumors have also increased and gender differences and birth cohort effects are present. Moreover, thyroid cancer mortality, in spite of earlier diagnosis and better treatment, has not decreased but is rather increasing. Therefore, some environmental carcinogens in the industrialized lifestyle may have specifically affected the thyroid. Among potential carcinogens, the increased exposure to medical radiations is the most likely risk factor. Other factors specific for the thyroid like increased iodine intake and increased prevalence of chronic autoimmune thyroiditis cannot be excluded, while other factors like the increasing prevalence of obesity are not specific for the thyroid. Conclusions. The increased incidence of thyroid cancer is most likely due to a combination of an apparent increase due to more sensitive diagnostic procedures and of a true increase, a possible consequence of increased population exposure to radiation and to other still unrecognized carcinogens. PMID- 23737787 TI - Crevicular Alkaline Phosphatase Activity and Rate of Tooth Movement of Female Orthodontic Subjects under Different Continuous Force Applications. AB - Purpose. This study is aimed to compare the effects of two different orthodontic forces on crevicular alkaline phosphatase activity, rate of tooth movement, and root resorption. Materials and Methods. Twelve female subjects of class II division 1 malocclusion participated. Maxillary canines with bonded fixed appliances acted as the tested teeth, while their antagonists with no appliances acted as the controls. Canine retraction was performed using nickel titanium coil spring that delivered forces of 100 gm or 150 gm to either side. Crevicular fluid was analyzed for ALP activity, and study models were casted to measure tooth movements. Root resorption was assessed using periapical radiographs before and after the force application. Results. ALP activity at the mesial sites peaked at week 1 for 150 gm group with significant differences when compared with the 100 gm group. Cumulative canine movements were significantly greater in the 150 gm force (2.10 +/- 0.50 mm) than in the 100 gm force (1.57 +/- 0.44 mm). No root resorption was in the maxillary canines after retraction. Conclusions. A force of 150 gm produced faster tooth movements and higher ALP activity compared with the 100 gm group and had no detrimental effects such as root resorption. PMID- 23737788 TI - Strain Distribution in a Kennedy Class I Implant Assisted Removable Partial Denture under Various Loading Conditions. AB - Purpose. This in vitro study investigates how unilateral and bilateral occlusal loads are transferred to an implant assisted removable partial denture (IARPD). Materials and Methods. A duplicate model of a Kennedy class I edentulous mandibular arch was made and then a conventional removable partial denture (RPD) fabricated. Two Straumann implants were placed in the second molar region, and the prosthesis was modified to accommodate implant retained ball attachments. Strain gages were incorporated into the fitting surface of both the framework and acrylic to measure microstrain ( MU Strain). The IARPD was loaded to 120Ns unilaterally and bilaterally in three different loading positions. Statistical analysis was carried out using SPSS version 18.0 (SPSS, Inc., Chicago, IL, USA) with an alpha level of 0.05 to compare the maximum MU Strain values of the different loading conditions. Results. During unilateral and bilateral loading the maximum MU Strain was predominantly observed in a buccal direction. As the load was moved anteriorly the MU Strain increased in the mesial area. Unilateral loading resulted in a twisting of the structure and generated a strain mismatch between the metal and acrylic surfaces. Conclusions. Unilateral loading created lateral and vertical displacement of the IARPD. The curvature of the dental arch resulted in a twisting action which intensified as the unilateral load was moved anteriorly. PMID- 23737790 TI - Measurement of primary and secondary stability of dental implants by resonance frequency analysis method in mandible. AB - Background. There is no doubt that the success of the dental implants depends on the stability. The aim of this work was to measure the stability of dental implants prior to loading the implants, using a resonance frequency analysis (RFA) by Osstell mentor device. Methods. Ten healthy and nonsmoker patients over 40 years of age with at least six months of complete or partial edentulous mouth received screw-type dental implants by a 1-stage procedure. RFA measurements were obtained at surgery and 1, 2, 3, 4, 5, 7, and 11 weeks after the implant surgery. Results. Among fifteen implants, the lowest mean stability measurement was for the 4th week after surgery in all bone types. At placement, the mean ISQ obtained with the magnetic device was 77.2 with 95% confidence interval (CI) = 2.49, and then it decreased until the 4th week to 72.13 (95% CI = 2.88), and at the last measurement, the mean implant stability significantly (P value <0.05) increased and recorded higher values to 75.6 (95% CI = 1.88), at the 11th week. Conclusions. The results may be indicative of a period of time when loading might be disadvantageous prior to the 4th week following implant placement. These suggestions need to be further assessed through future studies. PMID- 23737789 TI - The impact of edentulism on oral and general health. AB - An adequate dentition is of importance for well-being and life quality. Despite advances in preventive dentistry, edentulism is still a major public health problem worldwide. In this narrative review, we provide a perspective on the pathways that link oral to general health. A better understanding of disease indicators is necessary for establishing a solid strategy through an organized oral health care system to prevent and treat this morbid chronic condition. PMID- 23737791 TI - Application of dispersive liquid-liquid microextraction with graphite furnace atomic absorption spectrometry for determination of trace amounts of zinc in water samples. AB - A selective and simple method for separation and preconcentration of zinc ions was developed by using dispersive liquid-liquid microextraction. Parameters that have an effect on the microextraction efficiency such as volume of extraction and disperser solvent, extraction time, and adding salt were investigated. Under optimum conditions, a preconcentration factor of 250 was obtained. The limit of detection (LOD) obtained under the optimal conditions was 0.09 ng mL(-1). The linearity of method was obtained in range of 0.2-50 ng mL(-1) with a correlation coefficient (r) of 0.9974. The relative standard deviation for 10 replicate determinations at 1.0 ng mL(-1) of zinc was 2.53%. The proposed method was successfully applied to the analysis of zinc in water sample. PMID- 23737792 TI - Fibrin and collagen differentially but synergistically regulate sprout angiogenesis of human dermal microvascular endothelial cells in 3-dimensional matrix. AB - Angiogenesis is a highly regulated event involving complex, dynamic interactions between microvascular endothelial cells and extracellular matrix (ECM) proteins. Alteration of ECM composition and architecture is a hallmark feature of wound clot and tumor stroma. We previously reported that during angiogenesis, endothelial cell responses to growth factors are modulated by the compositional and mechanical properties of a surrounding three-dimensional (3D) extracellular matrix (ECM) that is dominated by either cross-linked fibrin or type I collagen. However, the role of 3D ECM in the regulation of angiogenesis associated with wound healing and tumor growth is not well defined. This study investigates the correlation of sprout angiogenesis and ECM microenvironment using in vivo and in vitro 3D angiogenesis models. It demonstrates that fibrin and type I collagen 3D matrices differentially but synergistically regulate sprout angiogenesis. Thus blocking both integrin alpha v beta 3 and integrin alpha 2 beta 1 might be a novel strategy to synergistically block sprout angiogenesis in solid tumors. PMID- 23737793 TI - Prevalence of K-RAS Codons 12 and 13 Mutations in Locally Advanced Head and Neck Squamous Cell Carcinoma and Impact on Clinical Outcomes. AB - Background. RAS gene mutations have an impact on treatment response and overall prognosis for certain types of cancer. Objectives. To determine the prevalence and impact of K-RAS codons 12 and 13 mutations in patients with locally advanced HNSCC treated with primary or adjuvant chemo-radiation. Methods. 428 consecutive patients were treated with chemo-radiation therapy and followed for a median of 37 months. From these, 199 paraffin embedded biopsy or surgical specimens were retrieved. DNA was isolated and analyzed for K-RAS mutational status. Results. DNA extraction was successful in 197 samples. Of the 197 specimens, 3.5% presented K-RAS codon 12 mutations. For mutated cases and non-mutated cases, complete initial response to chemoradiation therapy was 71 and 73% (P = 0.32). LRC was respectively 32 and 83% (P = 0.03), DFS was 27 and 68% (P = 0.12), distant metastasis-free survival was 100 and 81% (P = 0.30) and OS was 57 and 65% (P = 0.14) at three years. K-Ras codon 13 analysis revealed no mutation. Conclusion. K-RAS codon 12 mutational status, although not associated with a difference in response rate, may influence the failure pattern and the type of therapy offered to patients with HNSCC. Our study did not reveal any mutation of K-RAS codon 13. PMID- 23737794 TI - Diagnosis and management of extracranial head and neck schwannomas: a review of 27 cases. AB - Objectives. Clinical records of 27 patients with extracranial head and neck schwannoma were retrospectively reviewed. Methods. Ultrasonography (US) was performed in all cases. Seven patients underwent CT. Twenty-five patients underwent MRI. Fine needle aspiration cytology (FNAC) was performed for 12 of the 27 patients. Clinical history, surgical data, and postoperative morbidity were analyzed. Results. The images of US showed a well-defined, hypoechoic, primarily homogeneous solid mass. At CT, only one of 7 cases (14%) was able to suggest the diagnosis of schwannoma. At MRI, twenty of 25 cases (80%) suggested the diagnosis of schwannoma. Only three of 12 cases (25%) displayed a specific diagnosis of schwannoma rendered on FNAC. The distribution of 27 nerves of origin was 10 (37%) vagus nerves, 6 (22%) sympathetic trunks, 5 (19%) cervical plexuses, 3 (11%) brachial plexuses, 2 (7%) hypoglossal nerves, and 1 (4%) accessory nerve. Complete tumor resection was performed in 11 patients, and intracapsular enucleation of the tumor was performed in 16 patients. The rate of nerve palsy was 100 (11/11) and 31% (5/16). Conclusions. MRI is sensitive and specific in the diagnosis of schwannoma. Intracapsular enucleation was an effective and feasible method for preserving the neurological functions. PMID- 23737795 TI - What works and what does not: a discussion of popular approaches for the abandonment of female genital mutilation. AB - The prevalence of Female Genital Mutilation (FGM) is reducing in almost all countries in which it is a traditional practice. There are huge variations between countries and communities though, ranging from no change at all to countries and communities where the practice has been more than halved from one generation to the next. Various interventions implemented over the last 30-40 years are believed to have been instrumental in stimulating this reduction, even though in most cases the decrease in prevalence has been slow. This raises questions about the efficacy of interventions to eliminate FGM and an urgent need to channel the limited resources available, where it can make the most difference in the abandonment of FGM. This paper is intended to contribute to the design of more effective interventions by assessing existing knowledge of what works and what does not and discusses some of the most common approaches that have been evaluated: health risk approaches, conversion of excisers, training of health professionals as change agents, alternative rituals, community-led approaches, public statements, and legal measures. PMID- 23737796 TI - Women's Attitudes towards the Option to Choose between Karyotyping and Rapid Targeted Testing during Pregnancy. AB - Objectives. Pregnant women, referred because of an increased risk of fetal Down syndrome, who underwent an invasive prenatal procedure were offered a choice between karyotyping and rapid targeted testing. This study aims to assess women's attitudes and experiences towards what option to choose. Methods. A retrospective multicentre survey (2008-2010) was conducted among 1370 women. General questions were asked about decision making issues, followed by personal questions about their experiences in choice making, test preference, influence of others, and possible regrets. Results. In total, 90.1% of the respondents (N = 825) indicated that pregnant women are able to choose, although 33.1% stated that the choice can best be made by a professional. 18.4% indicated that making a choice places a burden on women. In 96.4%, respondents preferred to have the option to choose again in case of a next pregnancy, whereas 2.7% preferred the choice to be made by a professional. Regret was indicated by 1.2%. Decision making was influenced by others in 64.9%. A slightly higher preference for karyotyping was indicated by 52.7% of the respondents. Conclusions. Positive attitudes and experiences were expressed towards the option to choose. Respondents took decisions freely, although sometimes influenced by a partner or a professional, to follow their individual perspectives. PMID- 23737797 TI - Postcoital haemoptysis: a case report and a review of the literature. AB - Haemoptysis is rarely reported following coitus, and cardiac decompensation has been mostly implicated in the aetiology. We present a 53-year-old Nigerian, known hypertensive diabetic woman with background ischaemic heart disease who presented with postcoital haemoptysis of one-year duration. Echocardiography revealed combined ischaemic and mitral valvular heart disease, probably of rheumatic aetiology. There has been no previous report in an African population. This case illustrates the need to rule out coitus as a rare but potential cause of haemoptysis in middle aged patients with underlying cardiac pathologies and the need for an extensive cardiac workup in a population with predominantly pulmonary causes of haemoptysis. PMID- 23737798 TI - Renal cell carcinoma with intraluminal spread of the entire upper urinary tract. AB - We describe an unusual case of renal cell carcinoma (RCC) involving the entire upper urinary tract. A 51-year-old female was referred to us because of macroscopic hematuria. Computed tomography revealed a renal tumor filling renal pelvis and ureter, which turned to be a clear cell RCC after nephroureterectomy. PMID- 23737799 TI - Combined awake craniotomy with endoscopic port surgery for resection of a deep seated temporal lobe glioma: a case report. AB - The authors describe the combination of awake craniotomy and minimally invasive endoscopic port surgery to resect a high-grade glioma located near eloquent structures of the temporal lobe. Combined minimally invasive techniques such as these may facilitate deep tumor resection within eloquent regions of the brain, allowing minimum white matter dissection. Technical aspects of this procedure, a case outcome involving this technique, and the direction of further investigations for the utility of these techniques are discussed. PMID- 23737800 TI - Minimally invasive direct repair of bilateral lumbar spine pars defects in athletes. AB - Spondylolysis of the lumbar spine has traditionally been treated using a variety of techniques ranging from conservative care to fusion. Direct repair of the defect may be utilized in young adult patients without significant disc degeneration and lumbar instability. We used minimally invasive techniques to place pars interarticularis screws with the use of an intraoperative CT scanner in three young adults, including two athletes. This technique is a modification of the original procedure in 1970 by Buck, and it offers the advantage of minimal muscle dissection and optimal screw trajectory. There were no intra- or postoperative complications. The detailed operative procedure and the postoperative course along with a brief review of pars interarticularis defect treatment are discussed. PMID- 23737801 TI - A case of spontaneous ruptured solid pseudopapillary tumor of pancreas resected by laparoscopic surgery. AB - Solid pseudopapillary tumor (SPT) is an uncommon neoplasm of the pancreas. A rare case of spontaneous rupture of SPT is reported. A 13-year-old female felt acute abdominal pain without blunt abdominal trauma. Enhanced computed tomography (CT) revealed a tumor in the pancreas tail with fluid collection around it. The tumor was diagnosed as SPT with hemoperitoneum associated with spontaneous rupture. The bleeding was stopped conservatively and she was referred for surgery at three months after the rupture. At that time, CT revealed a tumor 4 cm in diameter, which protruded from pancreas tail without distant metastases. Since peritoneal dissemination was not seen on intraoperative exploration, laparoscopic enucleation was performed. Pathologically, the tumor was diagnosed as SPT with rupture of the capsule of tumor, and complete resection was confirmed. The patient has been followed up for two years, and she is alive without recurrence. PMID- 23737803 TI - Progenitor Cell Therapy to Treat Acute Myocardial Infarction: The Promise of High Dose Autologous CD34(+) Bone Marrow Mononuclear Cells. AB - ST elevation myocardial infarction (STEMI) is associated with an increased risk for congestive heart failure and long-term mortality despite the widespread use of thrombolysis and catheter-based revascularization. The need for improved post STEMI therapies has led to a surge of novel therapeutics, especially regenerative approaches using autologous mononuclear cells. Indeed, the past decade has been marked by a number of human trials studying the safety and efficacy of progenitor cell delivery in the post-STEMI setting. While a variety of cell types and delivery techniques have been utilized, directed therapy to the infarct-related artery has been the most widely used approach. From over 1300 subjects randomized in these studies, there is sufficient evidence to conclude that cell therapy after STEMI is uniformly safe, while the efficacy of this intervention for improving outcomes is less clear. Recent meta-analyses have highlighted the importance of both timing of cell delivery, as well as the type, quantity, and mobility of delivered cells as determinants of response. Here, we show the case in which higher doses of CD34(+) cells, which are more potent in terms of their migratory capacity, offer the best hope for preserving cardiac function following STEMI. PMID- 23737804 TI - Short-Term Effects of Pacifier Texture on NNS in Neurotypical Infants. AB - The dense representation of trigeminal mechanosensitive afferents in the lip vermilion, anterior tongue, intraoral mucosa, and temporomandibular joint allows the infant's orofacial system to encode a wide range of somatosensory experiences during the critical period associated with feed development. Our understanding of how this complex sensorium processes texture is very limited in adults, and the putative role of texture encoding in the infant is unknown. The purpose of this study was to examine the short-term effects of a novel textured pacifier experience in healthy term infants (N = 28). Nonnutritive suck (NNS) compression pressure waveforms were digitized in real time using a variety of custom-molded textured pacifiers varying in spatial array density of touch domes. MANCOVA, adjusted for postmenstrual age at test and sex, revealed that infants exhibited an increase in NNS burst attempts at the expense of a degraded suck burst structure with the textured pacifiers, suggesting that the suck central pattern generator (sCPG) is significantly disrupted and reorganized by this novel orocutaneous experience. The current findings provide new insight into oromotor control as a function of the oral somatosensory environment in neurotypically developing infants. PMID- 23737805 TI - Normal Thymic Size and Low Rate of Infections in Human Donor Milk Fed HIV-Exposed Uninfected Infants from Birth to 18 Months of Age. AB - Objective. To evaluate the immune function in HIV-exposed uninfected (HIV-EU) infants fed human donor milk. Methods. Ultrasound-obtained thymic index (Ti), T lymphocyte subsets, and the number of infections were examined from birth to 18 months of age in 18 HIV-EU infants. The infants were compared to a cohort of 47 term, HIV-unexposed breastfed or formula-fed infants. Results. The thymic size at 12 months of age was not significantly different between the HIV-EU group and the control infants (P = 0.56). At 4 months of age, the HIV-EU infants had significantly fewer infections than the control infants (P < 0.001). Furthermore, in the control group, the infants exclusively breastfed at 4 months of age had significantly fewer infections at 8 months when compared to age-matched formula fed infants (P = 0.001). Conclusion. HIV-EU infants fed human donor milk have normal growth of thymus and contract fewer infections than other healthy infants. This finding along with fewer infections in exclusively breastfed infants compared to formula-fed infants supports the beneficial effect of human milk on the immune system. We suggest, when breastfeeding is not possible, that providing human donor milk to vulnerable groups of infants will be beneficial for their maturing immune system. PMID- 23737806 TI - Nociceptin Signaling Involves a Calcium-Based Depolarization in Tetrahymena thermophila. AB - Tetrahymena thermophila are free-living, ciliated eukaryotes. Their behavioral response to stimuli is well characterized and easily observable, since cells swim toward chemoattractants and avoid chemorepellents. Chemoattractant responses involve increased swim speed or a decreased change in swim direction, while chemorepellent signaling involves ciliary reversal, which causes the organism to jerk back and forth, swim in small circles, or spin in an attempt to get away from the repellent. Many food sources, such as proteins, are chemoattractants for these organisms, while a variety of compounds are repellents. Repellents in nature are thought to come from the secretions of predators or from ruptured organisms, which may serve as "danger" signals. Interestingly, several peptides involved in vertebrate pain signaling are chemorepellents in Tetrahymena, including substances P, ACTH, PACAP, VIP, and nociceptin. Here, we characterize the response of Tetrahymena thermophila to three different isoforms of nociceptin. We find that G-protein inhibitors and tyrosine kinase inhibitors do not affect nociceptin avoidance. However, the calcium chelator, EGTA, and the SERCA calcium ATPase inhibitor, thapsigargin, both inhibit nociceptin avoidance, implicating calcium in avoidance. This result is confirmed by electrophysiology studies which show that 50 MUM nociceptin-NH2 causes a sustained depolarization of approximately 40 mV, which is eliminated by the addition of extracellular EGTA. PMID- 23737807 TI - The distributional characteristics of heavy metal in Jiangsu Province Shoal Sea. AB - After the analysis of surface samples and core samples collected in Xinyanggang tidal land, the contents of Pb, Cu, Zn, and Cr were obtained and analyzed in this paper. The heavy metal accumulation rule and pollution status were studied by Index of geo-accumulation, latent ecological risk index method, and elements accumulation index method. The research suggests that (1) the contents of heavy metal Pb, Cu, Zn, and Cr in Xinyanggang tidal land have the same change trend, and such trend remains unchanged after the data were normalized, while the fluctuation range becomes smaller. (2) After analyzing the heavy metal content in the surface samples, it was revealed that the contents of heavy metals are getting lower from high tidal zone to low tidal zone, but the ranges of the change were different. Cu, Ni, and Zn emerge obvious decline from supratidal zone to subtidal zone, while the changes of Cr and Pb are not obvious. (3) Pb and Cr contents in Xinyanggang tidal land present accumulative character, as Pb in Xinyanggang is 3 times as much as the local background value, whose EF reaches 3.774. (4) RI value in Xinyanggang is 23.552, which indicates that though Xinyanggang tidal land has some heavy metal pollution and accumulation, there are no ecosystem risks, and the whole Xinyanggang core area environment quality is relatively good. PMID- 23737808 TI - Prevalence and characteristics of abuse experiences and depression symptoms among injection drug-using female sex workers in Mexico. AB - This mixed methods study examined the prevalence and characteristics of physical and sexual abuse and depression symptoms among 624 injection drug-using female sex workers (FSW-IDUs) in Tijuana and Ciudad Juarez, Mexico; a subset of 47 from Tijuana also underwent qualitative interviews. Linear regressions identified correlates of current depression symptoms. In the interviews, FSW-IDUs identified drug use as a method of coping with the trauma they experienced from abuse that occurred before and after age 18 and during the course of sex work. In a multivariate linear regression model, two factors-ever experiencing forced sex and forced sex in the context of sex work-were significantly associated with higher levels of depression symptoms. Our findings suggest the need for integrated mental health and drug abuse services for FSW-IDUs addressing history of trauma as well as for further research on violence revictimization in the context of sex work in Mexico. PMID- 23737809 TI - Why do some employees fall into and fail to exit a job-lock situation? AB - Previous studies have paid little attention to the employees' ability to exit a job-lock situation and factors that determine this ability. It remains unclear why some employees who experience job lock are able to exit this state while others remain in job lock. We use longitudinal data to identify employees who have fallen in the state of job lock and their subsequent behavior-exiting or remaining in job lock. By use of a first-order Markov transition models, we analyze the relevance of sociodemographic features, employment, occupational, sectoral, and contextual factors, as well as personality characteristics in explaining the transition or its absence. Overall the results show that both demographic factors and work-related aspects increase the likelihood that an employee enters the long-term job lock state (especially for older, married, full time employed, those in a craft occupation and governmental sector, and in a region with high unemployment). Mental health problems and personality characteristics (low peak-end self-esteem and decisional procrastination) have a significant effect on the probability to stay in long-term job lock. On the contrary, having a managerial, service, or associate occupation, working in the private sector, and having promotion opportunities increase the chance of an exit from the state of job lock. PMID- 23737812 TI - Interferon- gamma triggers hepatic stellate cell-mediated immune regulation through MEK/ERK signaling pathway. AB - Hepatic stellate cells (HSCs) interact with immune cells to actively participate in regulating immune response in the liver which is mediated by the effector molecules, including B7-H1. We demonstrated here that expression of B7-H1 on HSCs was markedly enhanced by interferon-(IFN-) gamma stimulation. IFN- gamma stimulated HSCs inhibited T-cell proliferation via induction of T-cell apoptosis (22.1% +/- 1.6%). This immunosuppressive effect was inhibited by preincubation with an anti-B7-H1 antibody, or inhibitor of the MEK/ERK pathway inhibited IFN- gamma mediated expression of B7-H1. Thus, regulation of B7-H1 expression on HSCs by IFN- gamma represents an important mechanism that regulates immune responses in the liver favoring tolerogenicity rather than immunogenicity. Involvement of MEK/ERK pathway provides a novel target for therapeutic approaches. PMID- 23737810 TI - Neonatal immune adaptation of the gut and its role during infections. AB - The intestinal tract is engaged in a relationship with a dense and complex microbial ecosystem, the microbiota. The establishment of this symbiosis is essential for host physiology, metabolism, and immune homeostasis. Because newborns are essentially sterile, the first exposure to microorganisms and environmental endotoxins during the neonatal period is followed by a crucial sequence of active events leading to immune tolerance and homeostasis. Contact with potent immunostimulatory molecules starts immediately at birth, and the discrimination between commensal bacteria and invading pathogens is essential to avoid an inappropriate immune stimulation and/or host infection. The dysregulation of these tight interactions between host and microbiota can be responsible for important health disorders, including inflammation and sepsis. This review summarizes the molecular events leading to the establishment of postnatal immune tolerance and how pathogens can avoid host immunity and induce neonatal infections and sepsis. PMID- 23737813 TI - Regulatory T cells in allogeneic stem cell transplantation. AB - Growing evidence suggests that cellular adoptive immunotherapy is becoming an attractive though challenging approach in regulating tumor immunity and alloresponses in clinical transplantation. Naturally arising CD4+CD25+Foxp3+ regulatory T cells (Treg) have emerged as a key component in this regard. Over the last decade, a large body of evidence from preclinical models has demonstrated their crucial role in auto- and tumor immunity and has opened the door to their "first-in-man" clinical application. Initial studies in clinical allogeneic stem cell transplantation are very encouraging and may pave the way for other applications. Further improvements in Treg ex vivo or in vivo expansion technologies will simplify their global clinical application. In this review, we discuss the current knowledge of Treg biology and their potential for cell-based immunotherapy in allogeneic stem cell transplantation. PMID- 23737814 TI - Trichostatin A promotes the generation and suppressive functions of regulatory T cells. AB - Regulatory T cells are a specific subset of lymphocytes that suppress immune responses and play a crucial role in the maintenance of self-tolerance. They can be generated in the thymus as well as in the periphery through differentiation of naive CD4(+) T cells. The forkhead box P3 transcription factor (Foxp3) is a crucial molecule regulating the generation and function of Tregs. Here we show that the foxp3 gene promoter becomes hyperacetylated in in vitro differentiated Tregs compared to naive CD4(+) T cells. We also show that the histone deacetylase inhibitor TSA stimulated the in vitro differentiation of naive CD4(+) T cells into Tregs and that this induction was accompanied by a global increase in histone H3 acetylation. Importantly, we also demonstrated that Tregs generated in the presence of TSA have phenotypical and functional differences from the Tregs generated in the absence of TSA. Thus, TSA-generated Tregs showed increased suppressive activities, which could potentially be explained by a mechanism involving the ectonucleotidases CD39 and CD73. Our data show that TSA could potentially be used to enhance the differentiation and suppressive function of CD4(+)Foxp3(+) Treg cells. PMID- 23737815 TI - Enhanced antidepressant-like effects of electroacupuncture combined with citalopram in a rat model of depression. AB - Currently, antidepressants are the dominative treatment for depression, but they have limitations in efficacy and may even produce troublesome side effects. Electroacupuncture (EA) has been reported to have therapeutic benefits in the treatment of depressive disorders. The present study was conducted to determine whether EA could enhance the antidepressant efficacy of a low dose of citalopram (an SSRI antidepressant) in the chronic unpredictable stress-induced depression model rats. Here, we show that a combined treatment with 2 Hz EA and 5 mg/kg citalopram for three weeks induces a significant improvement in depressive-like symptoms as detected by sucrose preference test, open field test, and forced swimming test, whereas these effects were not observed with either of the treatments alone. Further investigations revealed that 2 Hz EA plus 5 mg/kg citalopram produced a remarkably increased expression of BDNF and its receptor TrkB in the hippocampus compared with those measured in the vehicle group. Our findings suggest that EA combined with a low dose of citalopram could produce greater therapeutic effects, thereby, predictive of a reduction in drug side effects. PMID- 23737816 TI - Enhancement of Lymphangiogenesis In Vitro via the Regulations of HIF-1alpha Expression and Nuclear Translocation by Deoxyshikonin. AB - The objectives of this study were to determine the effects of deoxyshikonin on lymphangiogenesis. Deoxyshikonin enhanced the ability of human dermal lymphatic microvascular endothelial cells (HMVEC-dLy) to undergo time-dependent in vitro cord formation. Interestingly, an opposite result was observed in cells treated with shikonin. The increased cord formation ability following deoxyshikonin treatment correlated with increased VEGF-C mRNA expression to higher levels than seen for VEGF-A and VEGF-D mRNA expression. We also found that deoxyshikonin regulated cord formation of HMVEC-dLy by increasing the HIF-1 alpha mRNA level, HIF-1 alpha protein level, and the accumulation of HIF-1 alpha in the nucleus. Knockdown of the HIF-1 alpha gene by transfection with siHIF-1 alpha decreased VEGF-C mRNA expression and cord formation ability in HMVEC-dLy. Deoxyshikonin treatment could not recover VEGF-C mRNA expression and cord formation ability in HIF-1 alpha knockdown cells. This indicated that deoxyshikonin induction of VEGF C mRNA expression and cord formation in HMVEC-dLy on Matrigel occurred mainly via HIF-1 alpha regulation. We also found that deoxyshikonin promoted wound healing in vitro by the induction of HMVEC-dLy migration into the wound gap. This study describes a new effect of deoxyshikonin, namely, the promotion of cord formation by human endothelial cells via the regulation of HIF-1 alpha . The findings suggest that deoxyshikonin may be a new drug candidate for wound healing and treatment of lymphatic diseases. PMID- 23737811 TI - Human polyomavirus reactivation: disease pathogenesis and treatment approaches. AB - JC and BK polyomaviruses were discovered over 40 years ago and have become increasingly prevalent causes of morbidity and mortality in a variety of distinct, immunocompromised patient cohorts. The recent discoveries of eight new members of the Polyomaviridae family that are capable of infecting humans suggest that there are more to be discovered and raise the possibility that they may play a more significant role in human disease than previously understood. In spite of this, there remains a dearth of specific therapeutic options for human polyomavirus infections and an incomplete understanding of the relationship between the virus and the host immune system. This review summarises the human polyomaviruses with particular emphasis on pathogenesis in those directly implicated in disease aetiology and the therapeutic options available for treatment in the immunocompromised host. PMID- 23737817 TI - Brain responses to acupuncture are probably dependent on the brain functional status. AB - In recent years, neuroimaging studies of acupuncture have explored extensive aspects of brain responses to acupuncture in finding its underlying mechanisms. Most of these studies have been performed on healthy adults. Only a few studies have been performed on patients with diseases. Brain responses to acupuncture in patients with the same disease at different pathological stages have not been explored, although it may be more important and helpful in uncovering its underlying mechanisms. In the present study, we used fMRI to compare brain responses to acupuncture in patients with Bell's palsy at different pathological stages with normal controls and found that the brain response to acupuncture varied at different pathological stages of Bell's palsy. The brain response to acupuncture decreased in the early stages, increased in the later stages, and nearly returned to normal in the recovered group. All of the changes in the brain response to acupuncture could be explained as resulting from the changes in the brain functional status. Therefore, we proposed that the brain response to acupuncture is dependent on the brain functional status, while further investigation is needed to provide more evidence in support of this proposition. PMID- 23737818 TI - Low-Level Laser-Accelerated Peripheral Nerve Regeneration within a Reinforced Nerve Conduit across a Large Gap of the Transected Sciatic Nerve in Rats. AB - This study proposed a novel combination of neural regeneration techniques for the repair of damaged peripheral nerves. A biodegradable nerve conduit containing genipin-cross-linked gelatin was annexed using beta-tricalcium phosphate (TCP) ceramic particles (genipin-gelatin-TCP, GGT) to bridge the transection of a 15 mm sciatic nerve in rats. Two trigger points were irradiated transcutaneously using 660 nm of gallium-aluminum arsenide phosphide (GaAlAsP) via laser diodes for 2 min daily over 10 consecutive days. Walking track analysis showed a significant improvement in sciatic functional index (SFI) (P < 0.01) and pronounced improvement in the toe spreading ability of rats undergoing laser stimulation. Electrophysiological measurements (peak amplitude and area) illustrated by compound muscle action potential (CMAP) curves demonstrated that laser stimulation significantly improved nerve function and reduced muscular atrophy. Histomorphometric assessments revealed that laser stimulation accelerated nerve regeneration over a larger area of neural tissue, resulting in axons of greater diameter and myelin sheaths of greater thickness than that observed in rats treated with nerve conduits alone. Motor function, electrophysiological reactions, muscular reinnervation, and histomorphometric assessments all demonstrate that the proposed therapy accelerated the repair of transected peripheral nerves bridged using a GGT nerve conduit. PMID- 23737819 TI - Beta-Glucan-Rich Extract from Pleurotus sajor-caju (Fr.) Singer Prevents Obesity and Oxidative Stress in C57BL/6J Mice Fed on a High-Fat Diet. AB - Mushrooms have been used in folk medicine for thousands of years. In this study, the effect of beta -glucan-rich extract of P. sajor-caju (GE) on lipid lowering and antioxidant potential was assessed in C57BL/6J mice fed on a high-fat diet. Obesity was induced in C57BL/6J mice by feeding a high-fat diet. The control groups in this study were ND (for normal diet) and HFD (for high-fat diet). The treated groups were ND240 (for normal diet) (240 mg/kg b.w) and HFD60, HFD120, and HFD240 (for high-fat diet), where the mice were administrated with three dosages of GE (60, 120, and 240 mg GE/kg b.w). Metformin (2 mg/kg b.w) served as positive control. GE-treated groups showed significantly reduced body weight, serum lipid, and liver enzymes levels. GE also attenuated protein carbonyl and lipid hydroperoxide levels by increasing the enzymic antioxidants (SOD, CAT, and GPx) activities in the mice. GE-treated groups induced the expression of hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) while downregulated the expression of peroxisome proliferator-activated receptor gamma (PPAR- gamma ), sterol regulatory binding protein-1c (SREBP-1c), and lipoprotein lipase (LPL). Hence, GE prevented weight gain in the mice by inducing lipolysis and may be valuable in the formulation of adjuvant therapy for obesity. PMID- 23737820 TI - Evaluation of the Hypoglycemic Properties of Anacardium humile Aqueous Extract. AB - The antihyperglycemic effects of several plant extracts and herbal formulations which are used as antidiabetic formulations have been described and confirmed to date. The main objective of this work was to evaluate the hypoglycemic activity of the aqueous extract of Anacardium humile. Although the treatment of diabetic animals with A. humile did not alter body weight significantly, a reduction of the other evaluated parameters was observed. Animals treated with A. humile did not show variation of insulin levels, possibly triggered by a mechanism of blood glucose reduction. Levels of ALT (alanine aminotransferase) decreased in treated animals, suggesting a protective effect on liver. Levels of cholesterol were also reduced, indicating the efficacy of the extract in reestablishing the balance of nutrients. Moreover, a kidney protection may have been achieved due to the partial reestablishment of blood glucose homeostasis, while no nephrotoxicity could be detected for A. humile. The obtained results demonstrate the effectiveness of A. humile extracts in the treatment of alloxan-induced diabetic rats. Therefore, A. humile aqueous extract, popularly known and used by diabetic patients, induced an improvement in the biochemical parameters evaluated during and following treatment of diabetic rats. Thus, a better characterization of the medicinal potential of this plant will be able to provide a better understanding of its mechanisms of action in these pathological processes. PMID- 23737821 TI - A promise in the treatment of endometriosis: an observational cohort study on ovarian endometrioma reduction by N-acetylcysteine. AB - Urged by the unmet medical needs in endometriosis treatment, often with undesirable side effects, and encouraged by N-acetylcysteine (NAC) efficacy in an animal model of endometriosis and by the virtual absence of toxicity of this natural compound, we performed an observational cohort study on ovarian endometriosis. NAC treatment or no treatment was offered to 92 consecutive Italian women referred to our university hospital with ultrasound confirmed diagnosis of ovarian endometriosis and scheduled to undergo laparoscopy 3 months later. According to patients acceptance or refusal, NAC-treated and untreated groups finally comprised 73 and 72 endometriomas, respectively. After 3 months, within NAC-treated patients cyst mean diameter was slightly reduced (-1.5 mm) versus a significant increase (+6.6 mm) in untreated patients (P = 0.001). Particularly, during NAC treatment, more cysts reduced and fewer cysts increased their size. Our results are better than those reported after hormonal treatments. Twenty-four NAC-treated patients-versus 1 within controls-cancelled scheduled laparoscopy due to cysts decrease/disappearance and/or relevant pain reduction (21 cases) or pregnancy (1 case). Eight pregnancies occurred in NAC-treated patients and 6 in untreated patients. We can conclude that NAC actually represents a simple effective treatment for endometriosis, without side effects, and a suitable approach for women desiring a pregnancy. PMID- 23737822 TI - Blockade of Airway Inflammation by Kaempferol via Disturbing Tyk-STAT Signaling in Airway Epithelial Cells and in Asthmatic Mice. AB - Asthma is characterized by bronchial inflammation causing increased airway hyperresponsiveness and eosinophilia. The interaction between airway epithelium and inflammatory mediators plays a key role in the asthmatic pathogenesis. The in vitro study elucidated inhibitory effects of kaempferol, a flavonoid found in apples and many berries, on inflammation in human airway epithelial BEAS-2B cells. Nontoxic kaempferol at <=20 MU M suppressed the LPS-induced IL-8 production through the TLR4 activation, inhibiting eotaxin-1 induction. The in vivo study explored the demoting effects of kaempferol on asthmatic inflammation in BALB/c mice sensitized with ovalbumin (OVA). Mouse macrophage inflammatory protein-2 production and CXCR2 expression were upregulated in OVA-challenged mice, which was attenuated by oral administration of >=10 mg/kg kaempferol. Kaempferol allayed the airway tissue levels of eotaxin-1 and eotaxin receptor CCR3 enhanced by OVA challenge. This study further explored the blockade of Tyk STAT signaling by kaempferol in both LPS-stimulated BEAS-2B cells and OVA challenged mice. LPS activated Tyk2 responsible for eotaxin-1 induction, while kaempferol dose-dependently inhibited LPS- or IL-8-inflamed Tyk2 activation. Similar inhibition of Tyk2 activation by kaempferol was observed in OVA-induced mice. Additionally, LPS stimulated the activation of STAT1/3 signaling concomitant with downregulated expression of Tyk-inhibiting SOCS3. In contrast, kaempferol encumbered STAT1/3 signaling with restoration of SOCS3 expression. Consistently, oral administration of kaempferol blocked STAT3 transactivation elevated by OVA challenge. These results demonstrate that kaempferol alleviated airway inflammation through modulating Tyk2-STAT1/3 signaling responsive to IL-8 in endotoxin-exposed airway epithelium and in asthmatic mice. Therefore, kaempferol may be a therapeutic agent targeting asthmatic diseases. PMID- 23737824 TI - Tongue color analysis for medical application. AB - An in-depth systematic tongue color analysis system for medical applications is proposed. Using the tongue color gamut, tongue foreground pixels are first extracted and assigned to one of 12 colors representing this gamut. The ratio of each color for the entire image is calculated and forms a tongue color feature vector. Experimenting on a large dataset consisting of 143 Healthy and 902 Disease (13 groups of more than 10 samples and one miscellaneous group), a given tongue sample can be classified into one of these two classes with an average accuracy of 91.99%. Further testing showed that Disease samples can be split into three clusters, and within each cluster most if not all the illnesses are distinguished from one another. In total 11 illnesses have a classification rate greater than 70%. This demonstrates a relationship between the state of the human body and its tongue color. PMID- 23737823 TI - Predicting the Drug Safety for Traditional Chinese Medicine through a Comparative Analysis of Withdrawn Drugs Using Pharmacological Network. AB - As the major issue to limit the use of drugs, drug safety leads to the attrition or failure in clinical trials of drugs. Therefore, it would be more efficient to minimize therapeutic risks if it could be predicted before large-scale clinical trials. Here, we integrated a network topology analysis with cheminformatics measurements on drug information from the DrugBank database to detect the discrepancies between approved drugs and withdrawn drugs and give drug safety indications. Thus, 47 approved drugs were unfolded with higher similarity measurements to withdrawn ones by the same target and confirmed to be already withdrawn or discontinued in certain countries or regions in subsequent investigations. Accordingly, with the 2D chemical fingerprint similarity calculation as a medium, the method was applied to predict pharmacovigilance for natural products from an in-house traditional Chinese medicine (TCM) database. Among them, Silibinin was highlighted for the high similarity to the withdrawn drug Plicamycin although it was regarded as a promising drug candidate with a lower toxicity in existing reports. In summary, the network approach integrated with cheminformatics could provide drug safety indications effectively, especially for compounds with unknown targets or mechanisms like natural products. It would be helpful for drug safety surveillance in all phases of drug development. PMID- 23737825 TI - Investigation of the Effect of Rice Wine on the Metabolites of the Main Components of Herbal Medicine in Rat Urine by Ultrahigh-Performance Liquid Chromatography-Quadrupole/Time-of-Flight Mass Spectrometry: A Case Study on Cornus officinalis. AB - Ultrahigh-performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-QTOF/MS) was developed for rapid and sensitive analysis of the effect of rice wine on the metabolites of the main components of herbal medicine in rat urine. Using Cornus officinalis as a model of herbal medicine, the metabolite profiles of crude and processed (steaming the crude drug presteeped in rice wine) Cornus officinalis extracts in rat urine were investigated. The metabolites of Cornus officinalis were identified by using dynamic adjustment of the fragmentor voltage to produce structure-relevant fragment ions. In this work, we identified the parent compounds and metabolites of crude and processed Cornus officinalis in rats. In total, three parent compounds and seventeen new metabolites of Cornus officinalis were found in rats. The contents of the parent compounds and metabolites in vivo varied significantly after intragastric (i.g.) administration of aqueous extracts of crude and processed Cornus officinalis. Data from this study suggests that UPLC-QTOF/MS could be used as a potential tool for uncovering the effects of excipients found in the metabolites of the main components of herbal medicine, in vivo, to predict and discover the processing mechanisms of herbal medicine. PMID- 23737826 TI - Chinese Herbal Medicine (Zi Shen Qing) for Mild-to-Moderate Systematic Lupus Erythematosus: A Pilot Prospective, Single-Blinded, Randomized Controlled Study. AB - Objective. The aim of this study is to investigate the effectiveness and safety of a Chinese herbal formula Zi Shen Qing (ZSQ) in the treatment of systematic lupus erythematosus (SLE) in Chinese patients. Methods. A randomized controlled trial was conducted over 12 weeks in 84 Chinese patients who reported total scores of SLE Disease Activity Index-2000 (SLEDAI-2000) was from 5 to 14. The primary outcome was the changes of the SLEDAI-2000. The secondary outcomes included score changes of Chinese Medicine Syndromes (CMS), the changes of steroid dosage, the incidence of disease flare-up and biologic markers. Results. ZSQ significantly reduced SLEDAI-2000, the total scores of CMS in the treatment group compared with the controlled group (P < 0.05). Superiority of ZSQ over controlled group was also observed with greater improvement in the withdrawal dosage of corticosteroids and the incidence of disease flare-up (P < 0.05). There were no serious adverse events, and safety indices of whole blood counts, renal and liver functions were normal, both before and after the treatment. Conclusion. ZSQ is safe and effective for decreasing SLE disease activity and withdrawal dosage of corticosteroids in the mild to moderate SLE patients with "Deficiency of Qi and Yin" Pattern. PMID- 23737827 TI - The rs1142345 in TPMT Affects the Therapeutic Effect of Traditional Hypoglycemic Herbs in Prediabetes. AB - Therapeutic interventions in prediabetes are important in the primary prevention of type 2 diabetes (T2D) and its chronic complications. However, little is known about the pharmacogenetic effect of traditional herbs on prediabetes treatment. A total of 194 impaired glucose tolerance (IGT) subjects were treated with traditional hypoglycemic herbs (Tianqi Jiangtang) for 12 months in this study. DNA samples were genotyped for 184 mutations in 34 genes involved in drug metabolism or transportation. Multinomial logistic regression analysis indicated that rs1142345 (A > G) in the thiopurine S-methyltransferase (TPMT) gene was significantly associated with the hypoglycemic effect of the drug (P = 0.001, FDR P = 0.043). The "G" allele frequencies of rs1142345 in the healthy (subjects reverted from IGT to normal glucose tolerance), maintenance (subjects still had IGT), and deterioration (subjects progressed from IGT to T2D) groups were 0.094, 0.214, and 0.542, respectively. Binary logistic regression analysis indicated that rs1142345 was also significantly associated with the hypoglycemic effect of the drug between the healthy and maintenance groups (P = 0.027, OR = 4.828) and between the healthy and deterioration groups (P = 0.001, OR = 7.811). Therefore, rs1142345 was associated with the clinical effect of traditional hypoglycemic herbs. Results also suggested that TPMT was probably involved in the pharmacological mechanisms of T2D. PMID- 23737829 TI - Assessing the metabolic effects of aromatherapy in human volunteers. AB - Aromatherapy, a form of complementary and alternative medicine (CAM) that uses essential oils through inhalation, is believed to enhance physical and spiritual conditions. Although clinical studies suggest that the use of essential oils may have therapeutic potential, evidence for the efficacy of aromatherapy in treating medical conditions remains poor, with a particular lack of studies employing rigorous analytical methods that capture its identifiable impact on human biology. Here, we report a comprehensive metabolomics study that reveals metabolic changes in people after exposed to aroma inhalation for 10 continuous days. In this study, the metabolic alterations in urine of 31 females with mild anxiety symptoms exposed to aerial diffusion of aromas were measured by GC-TOF-MS and UPLC-Q-TOF-MS analyses. A significant alteration of metabolic profile in subjects responsive to essential oil was found, which is characterized by the increased levels of arginine, homocysteine, and betaine, as well as decreased levels of alcohols, carbohydrates, and organic acids in urine. Notably, the metabolites from tricarboxylic acid (TCA) cycle and gut microbial metabolism were significantly altered. This study demonstrates that the metabolomics approach can capture the subtle metabolic changes resulting from exposure to essential oils, which may lead to an improved mechanistic understanding of aromatherapy. PMID- 23737830 TI - Comparison of electroacupuncture in restrained and unrestrained rat models. AB - Acupuncture and electroacupuncture (EA) are widely used to treat a variety of diseases including pain. In preclinical research, EA is usually applied by inserting acupuncture needles into the hindlimbs of rats restrained in small tubes or bags. This restrained model of EA not only causes stress-like behaviors but also is limited in stimulating locations and intensities. In 2004, a novel, unrestrained model of EA was introduced. However, these two EA methods have never been directly compared regarding their analgesic effects and other features such as stress. In the present study, we reported similar analgesic effects between restrained and unrestrained EA in rats of acute inflammatory pain induced by intraplantar injection of CFA. In addition, rats receiving unrestrained EA showed less significant stress-like behaviors and tolerated higher current intensity. These advantages suggest that this unrestrained EA method can replace the traditional restrained procedure with similar analgesic effects and allow for more choices of stimulating intensities and locations. PMID- 23737828 TI - Treating type 2 diabetes mellitus with traditional chinese and Indian medicinal herbs. AB - Type II diabetes mellitus (T2DM) is a fast-growing epidemic affecting people globally. Furthermore, multiple complications and comorbidities are associated with T2DM. Lifestyle modifications along with pharmacotherapy and patient education are the mainstay of therapy for patients afflicted with T2DM. Western medications are frequently associated with severe adverse drug reactions and high costs of treatment. Herbal medications have long been used in the treatment and prevention of T2DM in both traditional Chinese medicine (TCM) and traditional Indian medicine (TIM). This review examines in vivo, in vitro, and clinical evidence supporting the use of various herbs used in TCM and TIM. The problems, challenges, and opportunities for the incorporation of herbal frequently used in TCM and TIM into Western therapy are presented and discussed. PMID- 23737831 TI - An Engineered Arginase FC Protein Inhibits Tumor Growth In Vitro and In Vivo. AB - Arginine is a semiessential amino acid required for the growth of melanoma and hepatocellular carcinoma, and the enzymatic removal of arginine by pegylated arginine deiminase (ADI) or arginase is being tested clinically. Here, we report a genetically engineered arginase FC fusion protein exhibiting a prolonged half life and enhanced efficacy. The use of this enzyme to treat different tumor lines both inhibited cell proliferation and impaired cellular migration in vitro and in vivo. Our data reinforce the hypothesis that nutritional depletion is a key strategy for cancer treatment. PMID- 23737832 TI - Inhibition of Neuroinflammation in LPS-Activated Microglia by Cryptolepine. AB - Cryptolepine, an indoloquinoline alkaloid in Cryptolepis sanguinolenta, has anti inflammatory property. In this study, we aimed to evaluate the effects of cryptolepine on lipopolysaccharide (LPS)- induced neuroinflammation in rat microglia and its potential mechanisms. Microglial activation was induced by stimulation with LPS, and the effects of cryptolepine pretreatment on microglial activation and production of proinflammatory mediators, PGE2/COX-2, microsomal prostaglandin E2 synthase and nitric oxide/iNOS were investigated. We further elucidated the role of Nuclear Factor-kappa B (NF- kappa B) and the mitogen activated protein kinases in the antiinflammatory actions of cryptolepine in LPS stimulated microglia. Our results showed that cryptolepine significantly inhibited LPS-induced production of tumour necrosis factor-alpha (TNF alpha ), interleukin-6 (IL-6), interleukin-1beta (IL-1 beta ), nitric oxide, and PGE2. Protein and mRNA levels of COX-2 and iNOS were also attenuated by cryptolepine. Further experiments on intracellular signalling mechanisms show that I kappa B independent inhibition of NF- kappa B nuclear translocation contributes to the anti-neuroinflammatory actions of cryptolepine. Results also show that cryptolepine inhibited LPS-induced p38 and MAPKAPK2 phosphorylation in the microglia. Cell viability experiments revealed that cryptolepine (2.5 and 5 MU M) did not produce cytotoxicity in microglia. Taken together, our results suggest that cryptolepine inhibits LPS-induced microglial inflammation by partial targeting of NF- kappa B signalling and attenuation of p38/MAPKAPK2. PMID- 23737833 TI - Functional Recovery after Scutellarin Treatment in Transient Cerebral Ischemic Rats: A Pilot Study with (18) F-Fluorodeoxyglucose MicroPET. AB - Objective. To investigate neuroprotective effects of scutellarin (Scu) in a rat model of cerebral ischemia with use of (18)F-fluorodeoxyglucose ((18)F-FDG) micro positron emission tomography (microPET). Method. Middle cerebral artery occlusion was used to establish cerebral ischemia. Rats were divided into 5 groups: sham operation, cerebral ischemia-reperfusion untreated (CIRU) group, Scu-25 group (Scu 25 mg/kg/d), Scu-50 group (Scu 50 mg/kg/d), and nimodipine (10 mg/Kg/d). The treatment groups were given for 2 weeks. The therapeutic effects in terms of cerebral infarct volume, neurological deficit scores, and cerebral glucose metabolism were evaluated. Levels of vascular density factor (vWF), glial marker (GFAP), and mature neuronal marker (NeuN) were assessed by immunohistochemistry. Results. The neurological deficit scores were significantly decreased in the Scu 50 group compared to the CIRU group (P < 0.001). (18)F-FDG accumulation in the ipsilateral cerebral infarction increased steadily over time in Scu-50 group compared with CIRU group (P < 0.01) and Scu-25 group (P < 0.01). Immunohistochemical analysis demonstrated Scu-50 enhanced neuronal maturation. Conclusion. (18)F-FDG microPET imaging demonstrated metabolic recovery after Scu 50 treatment in the rat model of cerebral ischemia. The neuroprotective effects of Scu on cerebral ischemic injury might be associated with increased regional glucose activity and neuronal maturation. PMID- 23737834 TI - The history of inpatient care in german departments focussing on natural healing. AB - We describe historic developments of inhouse facilities for natural healing in this paper, which were mainly located in German speaking regions. The naturopathic movement is a relabeling of the hydropathic movement in Germany, which was supported by a considerable proportion of the population in Germany during the mid 19th century. Due to the fact that hydropathic treatments were provided by nonmedical healers, discriminated as "quacks", there was continuous hostility between hydropathy/naturopathy and medicine. However, among the many establishments providing inhouse treatment for acute and chronic diseases over weeks there were some which were controlled by medical doctors in the 20th century and some which were implemented by government. In many of the establishments there were approaches for measuring usefulness of the treatments, some of which have been initiated explicitly for that purpose. PMID- 23737835 TI - Oleanolic Acid diminishes liquid fructose-induced Fatty liver in rats: role of modulation of hepatic sterol regulatory element-binding protein-1c-mediated expression of genes responsible for de novo Fatty Acid synthesis. AB - Oleanolic acid (OA), contained in more than 1620 plants and as an aglycone precursor for naturally occurred and synthesized triterpenoid saponins, is used in China for liver disorders in humans. However, the underlying liver-protecting mechanisms remain largely unknown. Here, we found that treatment of rats with OA (25 mg/kg/day, gavage, once daily) over 10 weeks diminished liquid fructose induced excess hepatic triglyceride accumulation without effect on total energy intake. Attenuation of the increased vacuolization and Oil Red O staining area was evident on histological examination of liver in OA-treated rats. Hepatic gene expression profile demonstrated that OA suppressed fructose-stimulated overexpression of sterol regulatory element-binding protein-(SREBP-) 1/1c mRNA and nuclear protein. In accord, overexpression of SREBP-1c-responsive genes responsible for fatty acid synthesis was also downregulated. In contrast, overexpressed nuclear protein of carbohydrate response element-binding protein and its target genes liver pyruvate kinase and microsomal triglyceride transfer protein were not altered. Additionally, OA did not affect expression of peroxisome proliferator-activated receptor-gamma- and -alpha and their target genes. It is concluded that modulation of hepatic SREBP-1c-mediated expression of the genes responsible for de novo fatty acid synthesis plays a pivotal role in OA elicited diminishment of fructose-induced fatty liver in rats. PMID- 23737836 TI - Optimizing combinations of flavonoids deriving from astragali radix in activating the regulatory element of erythropoietin by a feedback system control scheme. AB - Identifying potent drug combination from a herbal mixture is usually quite challenging, due to a large number of possible trials. Using an engineering approach of the feedback system control (FSC) scheme, we identified the potential best combinations of four flavonoids, including formononetin, ononin, calycosin, and calycosin-7-O- beta -D-glucoside deriving from Astragali Radix (AR; Huangqi), which provided the best biological action at minimal doses. Out of more than one thousand possible combinations, only tens of trials were required to optimize the flavonoid combinations that stimulated a maximal transcriptional activity of hypoxia response element (HRE), a critical regulator for erythropoietin (EPO) transcription, in cultured human embryonic kidney fibroblast (HEK293T). By using FSC scheme, 90% of the work and time can be saved, and the optimized flavonoid combinations increased the HRE mediated transcriptional activity by ~3-fold as compared with individual flavonoid, while the amount of flavonoids was reduced by ~10-fold. Our study suggests that the optimized combination of flavonoids may have strong effect in activating the regulatory element of erythropoietin at very low dosage, which may be used as new source of natural hematopoietic agent. The present work also indicates that the FSC scheme is able to serve as an efficient and model-free approach to optimize the drug combination of different ingredients within a herbal decoction. PMID- 23737837 TI - Antiteratogenic Effects of beta-Carotene in Cultured Mouse Embryos Exposed to Nicotine. AB - After maternal intake, nicotine crosses the placental barrier and causes severe embryonic disorders and fetal death. In this study, we investigated whether beta carotene has a beneficial effect against nicotine-induced teratogenesis in mouse embryos (embryonic day 8.5) cultured for 48 h in a whole embryo culture system. Embryos exposed to nicotine (1 mM) exhibited severe morphological anomalies and apoptotic cell death, as well as increased levels of TNF- alpha , IL-1 beta , and caspase 3 mRNAs, and lipid peroxidation. The levels of cytoplasmic superoxide dismutase (SOD), mitochondrial manganese-dependent SOD, cytosolic glutathione peroxidase (GPx), phospholipid hydroperoxide GPx, hypoxia inducible factor 1 alpha , and Bcl-x L mRNAs decreased, and SOD activity was reduced compared to the control group. However, when beta -carotene (1 * 10(-7) or 5 * 10(-7) MUM) was present in cultures of embryos exposed to nicotine, these parameters improved significantly. These findings indicate that beta -carotene effectively protects against nicotine-induced teratogenesis in mouse embryos through its antioxidative, antiapoptotic, and anti-inflammatory activities. PMID- 23737838 TI - Resveratrol Impedes the Stemness, Epithelial-Mesenchymal Transition, and Metabolic Reprogramming of Cancer Stem Cells in Nasopharyngeal Carcinoma through p53 Activation. AB - Cancer stem cells (CSCs) are able to self-renew and are refractory to cancer treatment. To investigate the effects of resveratrol on CSCs of nasopharyngeal carcinoma (NPC), we employed a behavior selection strategy to isolate CSCs based on radioresistance, chemoresistance, and tumor sphere formation ability. These NPC CSCs displayed stem cell properties and underwent metabolic shift to predominately rely on glycolysis for energy supply. Intriguingly, we found that resveratrol turned off the metabolic switch, increased the reactive oxygen species (ROS) level, and depolarized mitochondrial membranes. These alterations in metabolism occurred concomitantly with the suppression of CSC properties including resistance to therapy, self-renewal capacity, tumor initiation capacity, and metastatic potential in NPC CSCs. We found that resveratrol impeded CSC properties through the activation of p53 and this effect could be reversed by knockdown of p53. Furthermore, resveratrol suppressed the stemness and EMT through reactivating p53 and inducing miR-145 and miR-200c, which were downregulated in NPC CSCs. In conclusion, we demonstrated that resveratrol employed the p53 pathway in regulating stemness, EMT, and metabolic reprogramming. Further investigation of the molecular mechanism of p53 activation by resveratrol may provide useful information for the development of novel therapies for cancer treatment through targeting to CSCs. PMID- 23737839 TI - Research on zheng classification fusing pulse parameters in coronary heart disease. AB - This study was conducted to illustrate that nonlinear dynamic variables of Traditional Chinese Medicine (TCM) pulse can improve the performances of TCM Zheng classification models. Pulse recordings of 334 coronary heart disease (CHD) patients and 117 normal subjects were collected in this study. Recurrence quantification analysis (RQA) was employed to acquire nonlinear dynamic variables of pulse. TCM Zheng models in CHD were constructed, and predictions using a novel multilabel learning algorithm based on different datasets were carried out. Datasets were designed as follows: dataset1, TCM inquiry information including inspection information; dataset2, time-domain variables of pulse and dataset1; dataset3, RQA variables of pulse and dataset1; and dataset4, major principal components of RQA variables and dataset1. The performances of the different models for Zheng differentiation were compared. The model for Zheng differentiation based on RQA variables integrated with inquiry information had the best performance, whereas that based only on inquiry had the worst performance. Meanwhile, the model based on time-domain variables of pulse integrated with inquiry fell between the above two. This result showed that RQA variables of pulse can be used to construct models of TCM Zheng and improve the performance of Zheng differentiation models. PMID- 23737840 TI - Inhibitory Effects of Standardized Extracts of Phyllanthus amarus and Phyllanthus urinaria and Their Marker Compounds on Phagocytic Activity of Human Neutrophils. AB - The standardized methanol extracts of Phyllanthus amarus and P. urinaria, collected from Malaysia and Indonesia, and their isolated chemical markers, phyllanthin and hypophyllanthin, were evaluated for their effects on the chemotaxis, phagocytosis and chemiluminescence of human phagocytes. All the plant extracts strongly inhibited the migration of polymorphonuclear leukocytes (PMNs) with the Malaysian P. amarus showing the strongest inhibitory activity (IC50 value, 1.1 u g/mL). There was moderate inhibition by the extracts of the bacteria engulfment by the phagocytes with the Malaysian P. amarus exhibiting the highest inhibition (50.8% of phagocytizing cells). The Malaysian P. amarus and P. urinaria showed strong reactive oxygen species (ROS) inhibitory activity, with both extracts exhibiting IC50 value of 0.7 u g/mL. Phyllanthin and hypophyllanthin exhibited relatively strong activity against PMNs chemotaxis, with IC50 values slightly lower than that of ibuprofen (1.4 u g/mL). Phyllanthin exhibited strong inhibitory activity on the oxidative burst with an IC50 value comparable to that of aspirin (1.9 u g/mL). Phyllanthin exhibited strong engulfment inhibitory activity with percentage of phagocytizing cells of 14.2 and 27.1% for neutrophils and monocytes, respectively. The strong inhibitory activity of the extracts was due to the presence of high amounts of phyllanthin and hypophyllanthin although other constituents may also contribute. PMID- 23737841 TI - A meta-analysis of randomized controlled trials on acupuncture for amblyopia. AB - Objective. To assess the evidence of efficacy and safety of acupuncture for amblyopia and analyze the current situation of its clinical setting. Methods. We systemically searched Wanfang, Chongqing Weipu Database for Chinese Technical Periodicals (VIP), China National Knowledge Infrastructure (CNKI), and PubMed. Published randomized controlled trials (RCT) and controlled clinical trials (CCT) that evaluated the effect of acupuncture for amblyopia compared with conventional treatment were identified. The methodological quality of the included trials was assessed based on the Jadad scale. Data synthesis was facilitated using RevMan 5.1. Results. Fourteen trials involving 2662 participants satisfied the minimum criteria for meta-analysis. The evidence showed that the total effective rate of treatment within the group receiving acupuncture was higher than that in conventional group; there were statistically significant differences between groups (polled random effects model (RR) = 1.17, 95% confidence interval (1.11, 1.24), Z = 5.56, P < 0.00001). Conclusion. The total effective rate of acupuncture for amblyopia was significantly superior to conventional treatment, indicating that acupuncture was a promising treatment for amblyopia. However, due to the limited number of CCTs and RCTs, especially those of large sample size and multicenter randomized controlled studies that were quantitatively insufficient, we could not reach a completely affirmative conclusion until further studies of high quality are available. PMID- 23737842 TI - Fucoidan inhibits the growth of hepatocellular carcinoma independent of angiogenesis. AB - Some sulphated polysaccharides can bind bFGF but are unable to present bFGF to its high-affinity receptors. Fucoidan, a sulphated polysaccharide purified from brown algae, which has been used as an anticancer drug in traditional Chinese medicine for hundreds of years, exhibits a variety of anticancer effects, including the induction of the apoptosis and autophagy of cancer cells, the inhibition of the growth of cancer cells, the induction of angiogenesis, and the improvement of antitumour immunity. Our research shows that fucoidan dose not inhibit the expressions of VEGF, bFGF, IL-8, and heparanase in HCC cells and/or tumour tissues. Moreover, fucoidan exhibited low affinity for bFGF and could not block the binding of bFGF to heparan sulphated. Although fucoidan had no effect on angiogenesis and apoptosis in vivo, this drug significantly inhibited the tumour growth and the expression of PCNA. These results suggest that fucoidan exhibits an anticancer effect in vivo at least partly through inhibition of the proliferation of HCC cells, although it is unable to suppress the angiogenesis induced by HCC. PMID- 23737843 TI - Recent progress of propolis for its biological and chemical compositions and its botanical origin. AB - Propolis is the generic name given to the product obtained from resinous substances, which is gummy and balsamic and which is collected by bees from flowers, buds, and exudates of plants. It is a popular folk medicine possessing a broad spectrum of biological activities. These biological properties are related to its chemical composition and more specifically to the phenolic compounds that vary in their structure and concentration depending on the region of production, availability of sources to collect plant resins, genetic variability of the queen bee, the technique used for production, and the season in which propolis is produced. Many scientific articles are published every year in different international journal, and several groups of researchers have focused their attention on the chemical compounds and biological activity of propolis. This paper presents a review on the publications on propolis and patents of applications and biological constituents of propolis. PMID- 23737844 TI - Metabonomic strategy to the evaluation of chinese medicine compound danshen dripping pills interfering myocardial ischemia in rats. AB - Coronary heart disease (CHD) is one of the highest mortality diseases in the world. Traditional Chinese medicine compound Danshen dripping pills (CDDPs) have currently made a great achievement in treating CHD. However, the therapeutic mechanism of CDDP is often poorly interpreted. In this study, a GC-MS-based metabonomic study was conducted to assess the holistic efficacy of CDDP for myocardial infarction in male Sprague-Dawley rats, which were divided into the control group, the sham group, the model group, the control + CDDP group, and the model + CDDP, with CDDP at a dose of 107 mg/kg.d (equal to 1.8 mL/kg.d). The metabonomic findings demonstrated great differences of metabolic pattern among sham, model, and the model + CDDP in the orthogonal partial least squares discriminant analysis (OPLS-DA) models, which coordinated well with the assessment of plasma biochemistry and histopathological assay. Differentially expressed metabolites suggested that energy metabolism, glycolysis, and lipid metabolism might be disrupted by myocardial infarction. Both the potential metabolic biomarkers and the biochemical histopathological indices were regulated effectively by CDDP. PMID- 23737846 TI - Electroacupuncture and Brain Protection against Cerebral Ischemia: Specific Effects of Acupoints. AB - Electroacupuncture (EA) has been shown to increase cerebral blood flow (CBF) and reduce ischemic infarction in the rat model of cerebral ischemia (middle cerebral artery occlusion, MCAO). Since multiple acupoints are recommended to treat cerebral ischemia, we performed this study to investigate if there is any variation in EA protection against cerebral ischemia with the stimulation of certain "acupoints" in rats. One hour of right MCAO with an 85% reduction of blood flow induced an extensive infarction (32.9% +/- 3.8% of the brain), serious neurological deficits (scale = 6.0 +/- 0.5, on a scale of 0-7), and a 17% (10 out of 60) mortality. EA, with a sparse-dense wave (5 Hz/20 Hz) at 1.0 mA for 30 minutes, at Du 20 and Du 26 greatly reduced the infarction to 4.5% +/- 1.5% (P < 0.01), significantly improved neurological deficit (scale = 1.0 +/- 0.5, P < 0.01), and decreased the death rate to 7% (2 out of 30, P < 0.01). Similarly, EA at left LI 11 & PC 6 reduced the infarct volume to 8.6% +/- 3.8% (P < 0.01), improved the neurological deficit (scale = 2.0 +/- 1.0, P < 0.01), and decreased the death rate to 8% (2 out of 24, P < 0.01). In sharp contrast, EA at right LI 11 & PC 6 did not lead to any significant changes in the infarct volume (33.4% +/ 6.3%), neurological deficit (scale = 6.5 +/- 0.5), and the death rate (20%, 5 out of 24). EA at left GB 34 & SP 6, also had an inconspicuous effect on the ischemic injury. EA at Du 20 & Du 26 or at left LI 11 & PC 6 instantaneously induced a significant increase in cerebral blood flow. Neither EA at right LI 11 & PC 6 nor at GB 34 & SP 6 increased cerebral blood flow. These results revealed that the EA protection against cerebral ischemia is relatively acupoint specific. PMID- 23737845 TI - Preventive and prophylactic mechanisms of action of pomegranate bioactive constituents. AB - Pomegranate fruit presents strong anti-inflammatory, antioxidant, antiobesity, and antitumoral properties, thus leading to an increased popularity as a functional food and nutraceutical source since ancient times. It can be divided into three parts: seeds, peel, and juice, all of which seem to have medicinal benefits. Several studies investigate its bioactive components as a means to associate them with a specific beneficial effect and develop future products and therapeutic applications. Many beneficial effects are related to the presence of ellagic acid, ellagitannins (including punicalagins), punicic acid and other fatty acids, flavonoids, anthocyanidins, anthocyanins, estrogenic flavonols, and flavones, which seem to be its most therapeutically beneficial components. However, the synergistic action of the pomegranate constituents appears to be superior when compared to individual constituents. Promising results have been obtained for the treatment of certain diseases including obesity, insulin resistance, intestinal inflammation, and cancer. Although moderate consumption of pomegranate does not result in adverse effects, future studies are needed to assess safety and potential interactions with drugs that may alter the bioavailability of bioactive constituents of pomegranate as well as drugs. The aim of this review is to summarize the health effects and mechanisms of action of pomegranate extracts in chronic inflammatory diseases. PMID- 23737847 TI - Inclusion Complex of Zerumbone with Hydroxypropyl- beta -Cyclodextrin Induces Apoptosis in Liver Hepatocellular HepG2 Cells via Caspase 8/BID Cleavage Switch and Modulating Bcl2/Bax Ratio. AB - Zerumbone (ZER) isolated from Zingiber zerumbet was previously encapsulated with hydroxypropyl- beta -cyclodextrin (HP beta CD) to enhance ZER's solubility in water, thus making it highly tolerable in the human body. The anticancer effects of this new ZER-HP beta CD inclusion complex via apoptosis cell death were assessed in this study for the first time in liver hepatocellular cells, HepG2. Apoptosis was ascertained by morphological study, nuclear stain, and sub-G1 cell population accumulation with G2/M arrest. Further investigations showed the release of cytochrome c and loss of mitochondrial membrane potential, proving mitochondrial dysfunction upon the ZER-HP beta CD treatment as well as modulating proapoptotic and anti-apototic Bcl-2 family members. A significant increase in caspase 3/7, caspase 9, and caspase 8 was detected with the depletion of BID cleaved by caspase 8. Collectively, these results prove that a highly soluble inclusion complex of ZER-HP beta CD could be a promising anticancer agent for the treatment of hepatocellular carcinoma in humans. PMID- 23737848 TI - Neurobiological foundations of acupuncture: the relevance and future prospect based on neuroimaging evidence. AB - Acupuncture is currently gaining popularity as an important modality of alternative and complementary medicine in the western world. Modern neuroimaging techniques such as functional magnetic resonance imaging, positron emission tomography, and magnetoencephalography open a window into the neurobiological foundations of acupuncture. In this review, we have summarized evidence derived from neuroimaging studies and tried to elucidate both neurophysiological correlates and key experimental factors involving acupuncture. Converging evidence focusing on acute effects of acupuncture has revealed significant modulatory activities at widespread cerebrocerebellar brain regions. Given the delayed effect of acupuncture, block-designed analysis may produce bias, and acupuncture shared a common feature that identified voxels that coded the temporal dimension for which multiple levels of their dynamic activities in concert cause the processing of acupuncture. Expectation in acupuncture treatment has a physiological effect on the brain network, which may be heterogeneous from acupuncture mechanism. "Deqi" response, bearing clinical relevance and association with distinct nerve fibers, has the specific neurophysiology foundation reflected by neural responses to acupuncture stimuli. The type of sham treatment chosen is dependent on the research question asked and the type of acupuncture treatment to be tested. Due to the complexities of the therapeutic mechanisms of acupuncture, using multiple controls is an optimal choice. PMID- 23737849 TI - The cardioprotective effects of citric Acid and L-malic Acid on myocardial ischemia/reperfusion injury. AB - Organic acids in Chinese herbs, the long-neglected components, have been reported to possess antioxidant, anti-inflammatory, and antiplatelet aggregation activities; thus they may have potentially protective effect on ischemic heart disease. Therefore, this study aims to investigate the protective effects of two organic acids, that is, citric acid and L-malic acid, which are the main components of Fructus Choerospondiatis, on myocardial ischemia/reperfusion injury and the underlying mechanisms. In in vivo rat model of myocardial ischemia/reperfusion injury, we found that treatments with citric acid and L malic acid significantly reduced myocardial infarct size, serum levels of TNF alpha, and platelet aggregation. In vitro experiments revealed that both citric acid and L-malic acid significantly reduced LDH release, decreased apoptotic rate, downregulated the expression of cleaved caspase-3, and upregulated the expression of phosphorylated Akt in primary neonatal rat cardiomyocytes subjected to hypoxia/reoxygenation injury. These results suggest that both citric acid and L-malic acid have protective effects on myocardial ischemia/reperfusion injury; the underlying mechanism may be related to their anti-inflammatory, antiplatelet aggregation and direct cardiomyocyte protective effects. These results also demonstrate that organic acids, besides flavonoids, may also be the major active ingredient of Fructus Choerospondiatis responsible for its cardioprotective effects and should be attached great importance in the therapy of ischemic heart disease. PMID- 23737850 TI - The In Vitro Antimicrobial Activity of Lavandula angustifolia Essential Oil in Combination with Other Aroma-Therapeutic Oils. AB - The antimicrobial activity of Lavandula angustifolia essential oil was assessed in combination with 45 other oils to establish possible interactive properties. The composition of the selected essential oils was confirmed using GC-MS with a flame ionization detector. The microdilution minimum inhibitory concentration (MIC) assay was undertaken, whereby the fractional inhibitory concentration (SigmaFIC) was calculated for the oil combinations. When lavender oil was assayed in 1 : 1 ratios with other oils, synergistic (26.7%), additive (48.9%), non interactive (23.7%), and antagonistic (0.7%) interactions were observed. When investigating different ratios of the two oils in combination, the most favourable interactions were when L. angustifolia was combined with Cinnamomum zeylanicum or with Citrus sinensis, against C. albicans and S. aureus, respectively. In 1 : 1 ratios, 75.6% of the essential oils investigated showed either synergistic or additive results, lending in vitro credibility to the use of essential oil blends in aroma-therapeutic practices. Within the field of aromatherapy, essential oils are commonly employed in mixtures for the treatment of infectious diseases; however, very little evidence exists to support the use in combination. This study lends some credence to the concomitant use of essential oils blended with lavender. PMID- 23737851 TI - Effect of electroacupuncture on rat ischemic brain injury: importance of stimulation duration. AB - We explored the optimal duration of electroacupuncture (EA) stimulation for protecting the brain against ischemic injury. The experiments were carried out in rats exposed to right middle cerebral artery occlusion (MCAO) for 60 min followed by 24-hr reperfusion. EA was delivered to "Shuigou" (Du 26) and "Baihui" (Du 20) acupoints with sparse-dense wave (5/20 Hz) at 1.0 mA for 5, 15, 30, and 45 min, respectively. The results showed that 30 min EA, starting at 5 minutes after the onset of MCAO (EA during MCAO) or 5 minutes after reperfusion (EA after MCAO), significantly reduced ischemic infarct volume, attenuated neurological deficits, and decreased death rate with a larger reduction of the ischemic infarction in the former group. Also in the group of EA during MCAO, this protective benefit was positively proportional to the increase in the period of stimulation, that is, increased protection in response to EA from 5- to 30-min stimulation. In all groups, EA induced a significant increase in cerebral blood flow and promoted blood flow recovery after reperfusion, and both blood flow volume and blood cell velocity returned to the preischemia level in a short period of time. Surprisingly, EA for 45 min did not show reduction in the neurological deficits or the infarct volume and instead demonstrated an increase in death rate in this group. Although EA for 45 min still increased the blood flow during MCAO, it led to a worsening of perfusion after reperfusion compared to the group subjected only to ischemia. The neuroprotection induced by an "optimal" period (30 min) of EA was completely blocked by Naltrindole, a delta -opioid receptor (DOR) antagonist (10 mg/kg, i.v.). These findings suggest that earlier EA stimulation leads to better outcomes, and that EA-induced neuroprotection against ischemia depends on an optimal EA-duration via multiple pathways including DOR signaling, while "over-length" stimulation exacerbates the ischemic injury. PMID- 23737852 TI - The effects of xuefu zhuyu and shengmai on the evolution of syndromes and inflammatory markers in patients with unstable angina pectoris after percutaneous coronary intervention: a randomised controlled clinical trial. AB - We evaluated the effects of the Xuefu Zhuyu capsule (XFZY) and the Shengmai capsule (SM) on the evolution of syndromes and inflammatory markers in patients with unstable angina pectoris (UAP) after percutaneous coronary intervention (PCI). Ninety patients with UAP after PCI were randomly and equally assigned to three groups: the XFZY group, the SM group, and the placebo group, with 30 patients in each group. Six syndrome factors (including Qi deficiency, yin deficiency, yang deficiency, blood stasis, phlegm, and Qi stagnation) and 4 inflammatory markers (high-sensitivity C-reactive protein (Hs-CRP), endothelins-1 (ET-1), matrix metalloproteinases-9 (MMP-9), and homocysteine (Hcy)) were observed at week 0 and at the 1st, 4th and 12th weeks. In conclusion, the evolution of syndromes present in patients with UAP after PCI followed these trends (1) The deficiency syndromes gradually increased during a 12-week period, but the excess syndromes first gradually decreased and then mildly increased after PCI. (2) XFZY and SM can prevent excess syndromes from increasing in the later stages and prevent deficiency syndromes from increasing in all stages. (3) XFZY and SMcan reduce the levels of the inflammatory markers, especially in the later stages after PCI. PMID- 23737853 TI - Bioactive Fraction of Geopropolis from Melipona scutellaris Decreases Neutrophils Migration in the Inflammatory Process: Involvement of Nitric Oxide Pathway. AB - The aim of this study was to evaluate the activity of the ethanolic extract of geopropolis (EEGP) from Melipona scutellaris and its fractions on the modulation of neutrophil migration in the inflammatory process, and the participation of nitric oxide (NO) pathway, as well as to check the chemical profile of the bioactive fraction. EEGP and its aqueous fraction decreased neutrophil migration in the peritoneal cavity and also the interaction of leukocytes (rolling and adhesion) with endothelial cells. The levels of chemokines CXCL1/KC and CXCL2/MIP 2 were not altered after treatment with EEGP and the aqueous fraction. It was found that the injection of NO pathway antagonists abolished the EEGP and the aqueous fraction inhibitory activity on the neutrophil migration. The expression of intercellular adhesion molecule type 1 (ICAM-1) was reduced, and nitrite levels increased after treatment with EEGP and aqueous fraction. In the carrageenan-induced paw edema model, EEGP and the aqueous fraction showed antiedema activity. No pattern of flavonoid and phenolic acid commonly found in propolis samples of Apis mellifera could be detected in the aqueous fraction samples. These data indicate that the aqueous fraction found has promising bioactive substances with anti-inflammatory activity. PMID- 23737854 TI - A network pharmacology approach to evaluating the efficacy of chinese medicine using genome-wide transcriptional expression data. AB - The research of multicomponent drugs, such as in Chinese Medicine, on both mechanism dissection and drug discovery is challenging, especially the approaches to systematically evaluating the efficacy at a molecular level. Here, we presented a network pharmacology-based approach to evaluating the efficacy of multicomponent drugs by genome-wide transcriptional expression data and applied it to Shenmai injection (SHENMAI), a widely used Chinese Medicine composed of red ginseng (RG) and Radix Ophiopogonis (RO) in clinically treating myocardial ischemia (MI) diseases. The disease network, MI network in this case, was constructed by combining the protein-protein interactions (PPI) involved in the MI enriched pathways. The therapeutic efficacy of SHENMAI, RG, and RO was therefore evaluated by a network parameter, namely, network recovery index (NRI), which quantitatively evaluates the overall recovery rate in MI network. The NRI of SHENMAI, RG, and RO were 0.865, 0.425, and 0.271 respectively [corrected], which indicated SHENMAI exerts protective effects and the synergistic effect of RG and RO on treating myocardial ischemia disease. The successful application of SHENMAI implied that the proposed network pharmacology-based approach could help researchers to better evaluate a multicomponent drug on a systematic and molecular level. PMID- 23737855 TI - Brazilian green propolis compared to miconazole gel in the treatment of Candida associated denture stomatitis. AB - Aim. To evaluate the efficacy of Brazilian green propolis in comparison to miconazole gel in the treatment of Candida-associated denture stomatitis. Methods. Forty-five denture stomatitis patients, with palatal mucosa erythema levels classified according to Newtons's criteria and with positive culture to Candida spp., were randomly divided into three treatment groups: 15 received miconazole gel 2%, 15 received propolis gel 2,5%, and 15 received propolis 24% for mouthwash. After four daily use lasting two weeks, they were reexamined for the denture stomatitis degree and for a second culture of Candida. The Wilcoxon's test was applied to compare the results of clinical classification of the denture stomatitis and the Candida spp. colonies numbers, before and after each treatment. The Kruskall-Wallis's test was used to compare efficacy among the three treatment groups. Results. There were a significant reduction or complete remission of denture stomatitis (P < 0.05) and a significant decrease of Candida colonies for the three groups (P < 0.05). There was no difference in the efficacy among the treatment groups (P > 0.05). Conclusion. Brazilian green propolis has a similar effect as miconazole in the treatment of Candida-associated denture stomatitis being an alternative in the therapeutics of this condition. PMID- 23737856 TI - Primo vascular system accompanying a blood vessel from tumor tissue and a method to distinguish it from the blood or the lymph system. AB - A primo vessel was observed in the abdominal cavity in the lung cancer mouse model, and its function as an extra metastatic path was observed. In this work, we found a primo vessel accompanying a blood vessel emanating from a tumor in the skin. We also presented simple and efficient criteria to distinguish a primo vessel from a blood or a lymph vessel and from a nerve. The criteria for using DAPI and Phalloidin will be useful in clinical situations to find and identify the primo vessels among the blood vessels, lymph vessels, or nerves in the tissue surrounding a tumor such as a melanoma or breast cancer. PMID- 23737857 TI - Trial-by-trial adaptation of movements during mental practice under force field. AB - Human nervous system tries to minimize the effect of any external perturbing force by bringing modifications in the internal model. These modifications affect the subsequent motor commands generated by the nervous system. Adaptive compensation along with the appropriate modifications of internal model helps in reducing human movement errors. In the current study, we studied how motor imagery influences trial-to-trial learning in a robot-based adaptation task. Two groups of subjects performed reaching movements with or without motor imagery in a velocity-dependent force field. The results show that reaching movements performed with motor imagery have relatively a more focused generalization pattern and a higher learning rate in training direction. PMID- 23737858 TI - Power analysis of C-TDT for small sample size genome-wide association studies by the joint use of case-parent trios and pairs. AB - In family-based genetic association studies, it is possible to encounter missing genotype information for one of the parents. This leads to a study consisting of both case-parent trios and case-parent pairs. One of the approaches to this problem is permutation-based combined transmission disequilibrium test statistic. However, it is still unknown how powerful this test statistic is with small sample sizes. In this paper, a simulation study is carried out to estimate the power and false positive rate of this test across different sample sizes for a family-based genome-wide association study. It is observed that a statistical power of over 80% and a reasonable false positive rate estimate can be achieved even with a combination of 50 trios and 30 pairs when 2% of the SNPs are assumed to be associated. Moreover, even smaller samples provide high power when smaller percentages of SNPs are associated with the disease. PMID- 23737859 TI - Discrimination between Alzheimer's disease and mild cognitive impairment using SOM and PSO-SVM. AB - In this study, an MRI-based classification framework was proposed to distinguish the patients with AD and MCI from normal participants by using multiple features and different classifiers. First, we extracted features (volume and shape) from MRI data by using a series of image processing steps. Subsequently, we applied principal component analysis (PCA) to convert a set of features of possibly correlated variables into a smaller set of values of linearly uncorrelated variables, decreasing the dimensions of feature space. Finally, we developed a novel data mining framework in combination with support vector machine (SVM) and particle swarm optimization (PSO) for the AD/MCI classification. In order to compare the hybrid method with traditional classifier, two kinds of classifiers, that is, SVM and a self-organizing map (SOM), were trained for patient classification. With the proposed framework, the classification accuracy is improved up to 82.35% and 77.78% in patients with AD and MCI. The result achieved up to 94.12% and 88.89% in AD and MCI by combining the volumetric features and shape features and using PCA. The present results suggest that novel multivariate methods of pattern matching reach a clinically relevant accuracy for the a priori prediction of the progression from MCI to AD. PMID- 23737860 TI - Computational models of articular cartilage. PMID- 23737861 TI - Statistical evaluation of a fully automated mammographic breast density algorithm. AB - Visual assessments of mammographic breast density by radiologists are used in clinical practice; however, these assessments have shown weaker associations with breast cancer risk than area-based, quantitative methods. The purpose of this study is to present a statistical evaluation of a fully automated, area-based mammographic density measurement algorithm. Five radiologists estimated density in 5% increments for 138 "For Presentation" single MLO views; the median of the radiologists' estimates was used as the reference standard. Agreement amongst radiologists was excellent, ICC = 0.884, 95% CI (0.854, 0.910). Similarly, the agreement between the algorithm and the reference standard was excellent, ICC = 0.862, falling within the 95% CI of the radiologists' estimates. The Bland-Altman plot showed that the reference standard was slightly positively biased (+1.86%) compared to the algorithm-generated densities. A scatter plot showed that the algorithm moderately overestimated low densities and underestimated high densities. A box plot showed that 95% of the algorithm-generated assessments fell within one BI-RADS category of the reference standard. This study demonstrates the effective use of several statistical techniques that collectively produce a comprehensive evaluation of the algorithm and its potential to provide mammographic density measures that can be used to inform clinical practice. PMID- 23737862 TI - Numerical simulations of MREIT conductivity imaging for brain tumor detection. AB - Magnetic resonance electrical impedance tomography (MREIT) is a new modality capable of imaging the electrical properties of human body using MRI phase information in conjunction with external current injection. Recent in vivo animal and human MREIT studies have revealed unique conductivity contrasts related to different physiological and pathological conditions of tissues or organs. When performing in vivo brain imaging, small imaging currents must be injected so as not to stimulate peripheral nerves in the skin, while delivery of imaging currents to the brain is relatively small due to the skull's low conductivity. As a result, injected imaging currents may induce small phase signals and the overall low phase SNR in brain tissues. In this study, we present numerical simulation results of the use of head MREIT for brain tumor detection. We used a realistic three-dimensional head model to compute signal levels produced as a consequence of a predicted doubling of conductivity occurring within simulated tumorous brain tissues. We determined the feasibility of measuring these changes in a time acceptable to human subjects by adding realistic noise levels measured from a candidate 3 T system. We also reconstructed conductivity contrast images, showing that such conductivity differences can be both detected and imaged. PMID- 23737863 TI - Cardiac stem cells in patients with heart disease. AB - The heart has been regarded as a terminally differentiated organ for decades. There are numerous indicators for the potency of myocardial regeneration, which opens up new avenues for the treatment of heart disease. Cardiac stem cells (CSCs) have been discovered in the human heart and they play a vital role in myocardial regeneration. This review discusses the distribution, properties and proliferation of CSCs in the myocardium of patients with heart disease. Additionally, the potency of myocardial regeneration in patients with heart disease is discussed. PMID- 23737864 TI - Magnetic resonance imaging and thallium-201 scintigraphy for the diagnosis of localized pigmented villonodular synovitis arising from the elbow: A case report and review of the literature. AB - Pigmented villonodular synovitis (PVNS) arising from the elbow joint is extremely rare; only 24 cases have been reported. It is extremely difficult to differentiate PVNS from other soft tissue tumors on the basis of imaging findings alone. Therefore, a biopsy is required for definitive diagnosis. A 20-year-old female reported a mass on her right elbow. Physical examination revealed a tumor measuring 3.0x3.0 cm. Magnetic resonance imaging (MRI) revealed that the signal intensity of the tumor was isointense to muscle on T1-weighted images; however, it was hyper- or isointense to muscle on T2-weighted images. In images obtained by gadolinium-enhanced MRI, the margin of the tumor was well-contrasted. Thallium (Tl)-201 scintigrams revealed an abnormal accumulation in the area of the mass in the early and delayed phases. On the basis of clinical findings, imaging characteristics and incision biopsy results, localized PVNS was diagnosed and marginal excision was performed. We thus identified an extremely rare case of PVNS arising from the elbow joint. When interpreting Tl-201 images for the assessment of bone and soft tissue lesions, it is important to recognize PVNS as a condition that simulates malignant tumors. Furthermore, PVNS should be considered in the differential diagnosis when increased Tl-201 activity is closely related to the joint. MRI aids in the differentiation by demonstrating features of hemosiderin degradation products. These findings are likely to be extremely helpful in the differential diagnosis of bone and soft tissue tumors. PMID- 23737865 TI - Effects of chemical combinations on the parthenogenetic activation of mouse oocytes. AB - The aim of this study was to identify an optimal method for the parthenogenetic activation of mouse oocytes. Ethanol (EH), strontium chloride (SrCl2) and ionomycin calcium salt were each combined with cytochalasin B to induce the parthenogenetic activation of CD-1(r) mouse oocytes. Among the EH combination groups, the blastocyst formation and hatching rates of the group that was activated with EH and CB for 5 min were significantly higher compared with those of the groups that were activated for 7 and 10 min (P<0.05). Among the SrCl2 combination groups, the blastocyst formation and hatching rates of the group that was activated with SrCl2 and CB for 30 min were significantly higher compared with those of the groups that were activated for 1 and 2 h (P<0.05). Among the ionomycin calcium salt combination groups, the blastocyst formation and hatching rates of the group that was activated with ionomycin and CB for 3 min were higher compared with those of the groups that were activated for 5 and 7 min (P<0.05). Compared with the other two combinations, the experimental indicators of the EH combination groups were notably superior (P<0.05). For combined activation, simultaneous activation with two substances was significantly more effective than successive activation (P<0.05). For combined activation with EH and cytochalasin B in mouse oocytes, 5 min of parthenogenetic activation had significant advantages with regard to cleavage, blastocyst formation and blastocyst hatching rates. In addition, the activation rate of combined activation was higher than that of single activators. For combined activation, the simultaneous application of two activators has a superior effect. PMID- 23737866 TI - Hyperglycemia induces endoplasmic reticulum stress-dependent CHOP expression in osteoblasts. AB - Diabetic osteoporosis is a metabolic bone disease responsible for global health problems. Hyperglycemia induces osteopenia, increases bone fragility and unbalances the coupling of osteoblasts and osteoclasts. The mechanism is, however, unknown. For the purpose of this study, we hypothesized that hyperglycemia destroys endoplasmic reticulum (ER) homeostasis, activates C/EBP homologous protein (CHOP) and induces osteoblast apoptosis under diabetic conditions. Diabetic rats were created by injecting streptozotocin (STZ) 65 mg/kg intraperitoneally and their osteoblasts were cultured under high-glucose medium in vitro. The bone mineral density (BMD) and pathological changes of the rats' femurs were observed. The expression of CHOP in osteoblasts was assayed using immunohistochemistry and western blot analysis. Six weeks after diabetic model establishment, a significant decrease was found in the BMD of the diabetic rat femurs, and the numbers of osteoblasts under cortical bone were also reduced. The expression of the ER stress regulator CHOP in osteoblasts of diabetic rats or high-glucose medium was also elevated (P<0.01). The present results demonstrated that hyperglycemia elevated the expression of CHOP and finally led to osteoporosis. This suggested that elevating the expression of CHOP may play a role in diabetic osteoporosis. PMID- 23737867 TI - Qianliening capsule treats benign prostatic hyperplasia via suppression of the EGF/STAT3 signaling pathway. AB - Benign prostatic hyperplasia (BPH) is a pathological overgrowth of the human prostate. It may cause increased resistance to urine flow through the urethra and occasionally kidney damage, bladder stones and urinary tract infections, and therefore affect the quality of life. Qianliening capsule (QC) is a traditional Chinese formula that has been used clinically in China to treat BPH for a number of years. However, the mechanism of its anti-BPH effect remains largely unknown. We evaluated the therapeutic effect of QC in a rat model of BPH, established by the injection of testosterone following castration, and investigated the underlying molecular mechanism of action. We observed that QC treatment significantly and dose-dependently decreased the prostatic volume (PV) and prostatic index (PI; P<0.05 or P<0.01), and ameliorated the histological damage of the prostate tissue in the BPH rats. In addition, treatment with QC inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), as well as the expression of epidermal growth factor (EGF), epidermal growth factor receptor (EGFR), cyclin D1 and Bcl-2. Our results suggest that suppression of the EGF/STAT3 pathway may be one of the mechanisms by which QC treats BPH. PMID- 23737868 TI - Diagnosis and therapy of acute urolithiasis caused by melamine contamination in infant formula milk. AB - The aim of this study was to determine the clinical characteristics and diagnosis of severe, acute urolithiasis in infants and toddlers, caused by melamine contamination in infant formula milk. The clinical data of 28 patients were collected and analyzed. Among the 28 patients, 17 patients received indwelling ureteral stents by cystoscopy (60.71%) and 5 patients received open surgery to extract calculi (17.86%). Four patients received catheterization or diuretic, anti-inflammatory or antispasmodic treatment (14.28%). Two patients underwent a second open surgery to extract calculi (7.14%). Eventually, the stones were eliminated from 23 patients and 5 patients had residual stones. In the 5 patients with residual stones, 3 patients had kidney stones, hydronephrosis or unilateral ureteral stones, resulting in urinary obstruction following surgery. Urolithiasis in infants and toddlers caused by melamine contamination was diagnosed, with common symptoms, including acute anuria, oliguria and dysurias. Ultrasonic inspection may be used to successfully examine urinary stones. Computed tomography (CT) scanning further detects the position of the stones and the degree of edema. Ureteral stenting via cystoscopy is a useful method, resulting in minimal trauma and a positive prognosis. PMID- 23737869 TI - Effect of limb ischemic preconditioning on myocardial apoptosis-related proteins in ischemia-reperfusion injury. AB - The aim of this study was to investigate the effect of limb ischemic preconditioning (LIPC) on myocardial apoptosis in myocardial ischemia-reperfusion injury (MIRI), as well as the regulation of caspase-3 and the B cell lymphoma 2 (Bcl-2) gene in LIPC. A total of 50 rats were divided randomly into 5 groups (n=10). Four rats in each group were drawn out for detection of apoptosis. The sham, MIRI and LIPC groups underwent surgery without additional treatment. In the LY294002 group, LY294002 preconditioning was administered 15 min before reperfusion. In the LY294002+LIPC group, following LIPC, LY294002 was administered 15 min before reperfusion. The relative expression of myocardial Bcl 2 and caspase-3 mRNA and the apoptotic index for each group were determined by reverse transcription-polymerase chain reaction (RT-PCR) and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL), respectively. The ultrastructure of the cardiac muscle tissues was observed by election microscopy. Compared with the sham group, the expression of caspase-3 mRNA in the MIRI group significantly increased (P<0.05) and the expression of Bcl-2 mRNA clearly decreased. Compared with the MIRI group, LIPC reduced the expression of caspase-3 and increased the expression of Bcl-2 mRNA (P<0.05). There were no significant differences between the LY294002+LIPC group and the MIRI group. Compared with the sham group, the apoptotic index of myocardial cells in the MIRI group significantly increased (P<0.05). Compared with the MIRI group, LIPC significantly decreased the apoptotic index of myocardial cells (P<0.05) and LY294002 increased the apoptotic index of myocardial cells. Compared with the LIPC group, LY294002+LIPC significantly increased the apoptotic index of myocardial cells (P<0.05). There were no significant differences between the LY294002+LIPC and MIRI groups. In conclusion, LIPC increased the expression of Bcl-2 and decreased caspase-3 mRNA and apoptosis in myocardial tissue following MIRI. Therefore, LIPC plays a protective role in myocardial tissue. PMID- 23737870 TI - Analysis and curative effect of ocular ischemic diseases caused by carotid artery stenosis. AB - Carotid artery stenosis is a notable cause of ocular ischemic disease. To analyze the ocular ischemic diseases caused by carotid artery stenosis and to seek effective treatment, a retrospective review of 182 patients with carotid artery stenosis was performed. These patients were administered medical treatment, carotid artery stenting (CAS) or carotid endarterectomy (CEA) and the curative effects of the three different treatments were compared. The results demonstrated that all three treatments helped to improve the disease. Both carotid endarterectomy and carotid artery stenting were more effective than medical treatment (P<0.05). There was no significant difference between carotid endarterectomy and carotid artery stenting (P>0.05). In conclusion, timely diagnosis and suitable treatment for ocular ischemic diseases caused by carotid artery stenosis are necessary due to the complicated clinical manifestation. This study suggested that carotid endarterectomy and carotid artery stenting are effective techniques that may relieve this disease. PMID- 23737871 TI - hsa-miR-203 enhances the sensitivity of leukemia cells to arsenic trioxide. AB - The aim of this study was to investigate the effect of a eukaryotic expression vector expressing hsa-miR-203 on the sensitivity of K562 leukemia cells to arsenic trioxide (ATO) and the possible mechanism of action. The eukaryotic expression vector expressing the hsa-miR-203 plasmid (PmiR-203) was transfected into K562 cells using Lipofectamine 2000. bcr/abl 3' untranslated region (UTR) and bcr/abl mutated 3'UTR dual luciferase report vectors (psi-CHECK-2) were used to validate the regulation of bcr/abl by miR-203. The inhibitory effects of ATO and PmiR-203, used singly or in combination, on cell proliferation were detected by MTT assay. Apoptosis of the K562 cells was detected by flow cytometry using double-staining with Annexin V and propidium iodide (PI). The activities of caspase-3 and caspase-9 were detected by a colorimetric method and the cytochrome c protein levels were detected by western blotting. When used in combination with PmiR-203, the IC50 of ATO was reduced from 6.49 to 2.45 MUg/ml and the sensitivity of cells to ATO increased 2.64-fold. In addition, PmiR-203 and ATO caused growth inhibition, apoptosis and G1-phase arrest in K562 cells. Furthermore, PmiR-203 significantly promoted ATO-mediated growth inhibition and apoptosis, affecting the G1 phase. JC-1 fluorescent staining revealed that the membrane potential of the mitochondria had changed. The activities of caspase-3 and caspase-9 increased, the expression levels of cytochrome c were upregulated and the expression level of bcr/abl mRNA was significantly suppressed. Furthermore, the dual-luciferase reporter vector, containing tandem miR-203 binding sites from the bcr/abl 3'UTR, demonstrated that bcr/abl was directly regulated by miR-203. PmiR-203 sensitized K562 leukemia cells to ATO by inducing apoptosis and downregulating bcr/ abl gene levels. The induction of apoptosis may occur through the mitochondrial pathway. The combination of ATO and PmiR-203 presents therapeutic potential for chronic myelogenous leukemia. PMID- 23737872 TI - Isolating glomeruli from mice: A practical approach for beginners. AB - A modified procedure for Dynabead perfusion was developed to provide a practical methodology for obtaining large quantities of glomeruli from mice with a high purity. The glomeruli may be useful in exploring the mechanism behind glomerular diseases in conjunction with proteomics. The aim of the study was to save on costs and help researchers, particularly beginners, in the practical application of this method in their studies. Kidneys of C57BL/6 mice were perfused via two different techniques with Dynabeads. The purity and structures of the isolated glomeruli were investigated. The amounts of glomerular protein were measured and the costs of kidney and heart perfusions were compared. There was a 100% success rate at all stages involved in separating the glomeruli of mice via kidney perfusion. The isolated glomeruli remained intact and the purity was 96.7+/-1.2%. The average amounts of protein in the isolated glomeruli of 8- and 20-week-old mice were 45.6+/-13.4 and 55.8+/-17.0 MUg, respectively. The cost of glomerular isolation via kidney perfusion was one-fortieth of the cost of isolation via heart perfusion. The described procedure is practical and has a high success rate. The isolated glomeruli of mice were intact and pure and a large quantity was obtained at a lower cost. PMID- 23737873 TI - Effects of imidapril treatment on aquaporin-2 expression in the kidneys and excretion in the urine of hypertensive rats. AB - Renal aquaporin-2 (AQP2) is critical for maintaining water balance and is associated with hypertension. Anti-hypertensive drugs, including imidapril, improve kidney function; however, it remains unclear whether these effects are mediated through the regulation of AQP2. In this study, the effects of imidapril on AQP2 expression in the kidneys and excretion in urine were assessed in hypertensive rats. Hypertension was induced in 24 rats, which were randomized into a control group, treated with water only, and an imidapril treatment group (n=12 per group). Blood and urine samples were collected from all rats to determine blood pressure (BP), serum Na+, urine volume and urine osmolality after 8 weeks of treatment. Molecular and immunological techniques were used to measure the expression of AQP2 in the kidneys. Urine AQP2 concentration was detected by indirect enzyme-linked immunosorbent assay (ELISA). The concentration of plasma arginine vasopressin (AVP), a regulator of AQP2 was detected by radioimmunoassay (RIA). Hypertensive rats treated with imidapril exhibited reduced BP and 24-h urine osmolality, with a concomitant increase in 24-h urine volume, compared with control hypertensive rats (P<0.05). Additionally, the expression of Aqp2 mRNA, detected by RT-PCR, and AQP2 protein, detected by immunohistochemistry and western blotting, in renal tissue significantly decreased (P<0.05). Finally, urine AQP2 concentration increased while plasma AVP concentration decreased following imidapril treatment (P<0.05). These findings indicate that imidapril reduces the expression level of AQP2 in renal tissue and accelerates its excretion. PMID- 23737874 TI - Characteristics of the four subtypes of myelodysplastic/myeloproliferative neoplasms. AB - The aim of the present study was to investigate the characteristics of the four subtypes of myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) in order to improve current knowledge and to aid their diagnosis. A total of 53 cases of MDS/MPNs were analyzed using routine blood cell analysis and morphological, cytogenetic and molecular genetic characteristics were investigated. Numerical data for several groups were compared using a single-factor analysis of variance. The Student-Newman-Keuls test was used to compare the means of two groups. The proportions were compared using a Chi-square test or Fisher's exact test. Analysis of the patients with MDS/MPNs revealed that 46 patients (86.8%) had paleness and fatigue, and blood analysis revealed hemoglobin (Hb) levels of 83.1+/-24.6 g/l, a white blood cell (WBC) count of 19.8+/-8.1*109/l and a platelet (PLT) count of 158.7+/-108.2*1012/l. Immature neutrophils and monocytes were identified in the peripheral blood at levels of 0.058+/-0.031 and 0.152+/ 0.034%, respectively. There were 23 cases (43.4%) with dyserythropoiesis and 36 cases (67.9%) had dysgranulopoiesis. Fifteen cases were immunologically characterized using flow cytometry (FCM), of which 13 cases showed abnormalities on blasts and myelocytes. Karyotyping was performed in 27 cases of MDS/MPN and 12 (44.4%) were identified as abnormal. In 23 cases, testing for BCR/ABL1, AML-ETO, CBF-MYH11A, PML-RARA, E2A-PBX1, TEL-AML1, SIL-TAL1 returned negative results. The JAK2V617F mutation was positive in one of five cases. The majority of MDS/MPN cases had anemia, cytosis, low-grade blasts and immature neutrophils in the peripheral blood and dysplasia in the bone marrow. Immunological abnormalities and abnormal karyotypes occurred frequently in MDS/MPNs and although there were no statistical differences between the four subtypes, these were able to aid diagnosis. No specific molecular abnormalities were identified in MDS/MPNs. PMID- 23737875 TI - Eliminating sedimentation for the treatment of chronic pelvic pain syndrome. AB - The aim of this study was to evaluate the curative effects of eliminating sedimentation inside the prostate via manipulation for the treatment of chronic pelvic pain syndrome (CPPS) using the National Institutes of Health (NIH)-chronic prostatitis symptom index (CPSI) scores. According to the prostatitis classification standard of the NIH, 721 patients with CPPS were divided into groups IIIA and IIIB by prostatic fluid routine examination (EPSRt) and treated using manipulation. The treatment was performed once per 3 days for 3-5 min and 10 treatments were considered to be a period. The EPSRt and NIH-CPSI scores were tested before and at the end of each period following treatment. After 3 treatment periods, the effectiveness and total effectiveness rates of the IIIA group were 72.3 and 15.9%, respectively and those of the IIIB group were 71.8 and 16.3%, respectively. Statistical analysis showed no significant differences between the curative effects in the two groups (P>0.05). The NIH-CPSI scores of the two groups were significantly improved following each treatment period (P<0.01). Eliminating sedimentation using manipulation dispersed the blockage, discharged the turbidity and cleared the gland, leading to the elimination of sedimentation and the relief of sinus hyperemia around the prostate, which significantly improved the clinical symptoms of CPPS and the quality of life of the patients. PMID- 23737876 TI - Saikosaponin A mediates the inflammatory response by inhibiting the MAPK and NF kappaB pathways in LPS-stimulated RAW 264.7 cells. AB - Saikosaponin A (SSA) is a major triterpenoid saponin isolated from Radix bupleuri (RB), a widely used Chinese traditional medicine to treat various inflammation related diseases. The aim of this study was to investigate the anti-inflammatory activity, as well as the molecular mechanism of SSA in lipopolysaccharide (LPS) stimulated RAW 264.7 cells. In this study, we demonstrated that SSA markedly inhibits the expression of certain immune-related cytotoxic factors, including cyclooxygenase-2 (COX-2) and inducible nitric-oxide synthase (iNOS), as well as pro-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6. It also significantly upregulates the expression of IL-10, an important anti-inflammatory cytokine, suggesting its anti inflammatory activity in LPS-stimulated macrophages. We further demonstrated that SSA inhibits the activation of the nuclear factor-kappaB (NF-kappaB) signaling pathway by suppressing the phosphorylation of inhibitory NF-kappaB inhibitor alpha (IkappaBalpha) and thus holding p65 NF-kappaB in the cytoplasm to prevent its translocation to the nucleus. In addition, SSA also inhibits the mitogen activated protein kinase (MAPK) signaling pathway by downregulating the phosphorylation of p38 MAPK, c-Jun N-terminal kinase (c-JNK) and extracellular signal-regulated kinase (ERK), the three key components of the MAPK family. In conclusion, our study demonstrates that SSA has an anti-inflammatory effect by regulating inflammatory mediators and suppressing the MAPK and NF-kappaB signaling pathways in LPS-stimulated RAW 264.7 cells. PMID- 23737877 TI - Platelet count predicts prognosis in operable non-small cell lung cancer. AB - Platelets play a significant role in cancer cell growth, progression and metastasis. However, in non-small cell lung cancer (NSCLC), the association between a patient's platelet count and prognosis has not previously been fully elucidated. The aim of the present study was to investigate the correlation between platelet count, patients' characteristics and prognosis in patients with NSCLC. A total of 510 NSCLC patients were enrolled in the present study. The median platelet count in the NSCLC patients was 203*109/l (95% CI, 115 358*109/l). The median platelet count in T3 and T4 patients was significantly higher than that of T1 and T2 patients (median, 263*109/l and 253.5*109/l vs. 199.5*109/l and 196.5*109/l, respectively; P<0.001). The 3-year cumulative overall survival (OS) probability was 75.3% for patients with normal platelet counts and 59.2% for patients with elevated platelet counts. When compared with the patients with normal platelet counts, the patients with elevated platelet counts had an increased risk of disease progression (HR, 1.568; 95% CI, 1.015 2.453). Pre-operative platelet counts are a novel independent prognostic biomarker in operable NSCLC. PMID- 23737878 TI - Surgical treatment of fibrous dysplasia in the proximal femur. AB - The aim of this study was to summarize oncological and functional results and to investigate surgical treatment methods and efficacies by conducting a retrospective study of patients with fibrous dysplasia (FD) in the proximal femur. A total of 15 patients with FD in the proximal femur were selected. Among them, 12 cases were monostotic and 3 cases were polyostotic. In addition, 2 cases were accompanied by shepherd's crook deformity. All cases received internal fixation following focus curettage and impaction grafting. Among them, valgus osteotomy was conducted for 2 cases of shepherd's crook deformity. All patients were followed up for 12-32 months. For 2 patients with shepherd's crook deformity in the proximal femur, the collodiaphysial angle was recovered after an orthopedic procedure following osteotomy. In addition, no patient presented with postoperative recurrent lesions. At 3 months following surgery, local bone resorption was visible in the bone grafting area. Between 8 and 12 months after surgery, the bones in the bone grafting area had healed, pain had disappeared and gaits were nearly normal. An effective internal fixation following thorough focus curettage and allograft bone transplantation is an effective method of treating FD in the proximal femur. For patients with shepherd's crook deformity, it is also necessary to perform valgus osteotomy to recover hip joint function. PMID- 23737879 TI - A case of ossifying fibroma of the frontal sinus. AB - Ossifying fibroma is a rare benign tumor of the nasal cavity and the paranasal sinus, and is easily misdiagnosed. In the present study, we report the clinical data in the case of a 46-year-old female patient, treated due to 5-day forehead swelling accompanied by dizziness. CT examination revealed dilation of the right frontal sinus, bone wall integration, dense masses in the cavity, multiple punctate calcification foci internally and no nasal obstruction, nasal mucus or epistaxis. After hospitalization, a right frontal sinus fenestration and tumor resection plus nasofrontal duct reconstruction combined with nasal endoscopic frontal recess open surgery was conducted under general anesthesia. Following the tumor resection, the frontal sinus bone lamella was reset and fixed with a titanium bone fixation set. The postoperative pathological diagnosis was of ossifying fibroma. At the postoperative 5-year follow-up there was no tumor recurrence and nasal endoscopy revealed an unobstructed nasofrontal duct opening. PMID- 23737880 TI - The chronergy of recombinant streptokinase thrombolysis in acute myocardial infarction. AB - The aim of this study was to explore the chronergy of intravenous recombinant streptokinase (r-SK) in patients with acute myocardial infarction (AMI). A total of 114 patients were divided into two groups according to the time of AMI onset: the morning onset (6:01-12:00, n=53) and non-morning onset (12:01-06:00, n=61) groups. The recanalization rate was recorded, as well as anticoagulant and fibrinolytic indices. Statistical analysis was performed to evaluate the recanalization rate following thrombolysis, as well as the anticoagulant and fibrinolytic activities. The recanalization rates following thrombolysis in the morning onset and non-morning onset groups were 60.4 and 82.0%, respectively (P<0.05). The level of plasminogen activator inhibitor-1 (PAI-1) antigen was significantly higher in the morning onset group compared with that in the non morning onset group (P<0.05). This indicated a resistance to r-SK thrombolysis in the morning at the early stage of AMI, which possibly correlates with increased PAI-1 antigen levels and activity. PMID- 23737881 TI - Anticoagulation therapy in patients with chronic obstructive pulmonary disease in the acute exacerbation stage. AB - This aim of this study was to investigate the effects of intervention with low molecular-weight heparin calcium on the pulmonary function and blood coagulation function of patients with chronic obstructive pulmonary disease (COPD) in the acute exacerbation stage. A total of 70 patients with COPD in the acute exacerbation stage were selected and randomly divided into the control group (32 cases) and the anticoagulation group (38 cases). The patients of the control group were treated with oxygen therapy, spasmolysis, asthmarelief, cough relief and sputum reduction. The patients in the anticoagulation group, in addition to the conventional therapy used the control group, were also treated with low molecular-weight heparin calcium 4100 AXaIU/time. by abdominal subcutaneous injection once every 12 h. For both groups, one treatment course lasted 10 days. The pulmonary function indicators and blood coagulation indicators of the two groups before and after treatment were determined. Following treatment, the pulmonary function and arterial blood gas indicators of the two groups were significantly better than those before treatment, and the extents of the improvements in the anticoagulation group were significantly greater than those in the control group. The D-dimer level and blood coagulation indicators [international normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen (FIB) concentration] of the anticoagulation group were significantly improved compared with those prior to treatment, but there were no significant differences between these measures before and after treatment for patients in the control group. No serious adverse reaction occurred in the anticoagulation group. Although, the conventional therapy was able to improve the overall condition of patients with COPD, it was not able to effectively improve the hypercoagulative state of the patients' blood. The combination of conventional therapy with low-molecular-weight heparin calcium anticoagulation improved the blood coagulation and pulmonary functions of patients. PMID- 23737882 TI - An Egr-1-specific DNAzyme regulates Egr-1 and proliferating cell nuclear antigen expression in rat vascular smooth muscle cells. AB - The aim of the present study was to transfect rat aortic smooth muscle cells with an early growth response factor-1 (Egr-1)-specific DNAzyme (ED5), to observe its effect on Egr-1 and proliferating cell nuclear antigen (PCNA) expression and to elucidate the mechanism of ED5-mediated inhibition of vascular smooth muscle cell (VSMC) proliferation. VSMCs in primary culture obtained by tissue block adhesion were identified by morphological observation and alpha smooth muscle actin (alpha SM-actin) immunocytochemistry. The cells were then transfected with ED5 or scrambled ED5 (ED5SCR). The three groups of cells used in the present study were the control group, ED5 group and ED5SCR group. The expression levels of Egr-1 and PCNA protein were detected following transfection by analyzing and calculating the integral optical density value in each group. Primary culture of VSMCs and transfection of ED5 and ED5SCR were successfully accomplished. Following stimulation with 10% fetal calf serum, the Egr-1 protein was expressed most strongly at 1 h and demonstrated a declining trend over time; the expression of PCNA protein began at 4 h, peaked at 24 h and then demonstrated a slightly declining trend over time. Compared with the control group and the ED5SCR group, ED5 inhibited the expression of Egr-1 and PCNA (P<0.05). ED5 was able to inhibit the expression of Egr-1 and PCNA proteins in VSMCs to a certain extent and VSMC proliferation in vitro. DNAzyme gene therapy may be useful as a new method for treating vascular proliferative diseases, including atherosclerosis and restenosis. PMID- 23737883 TI - Free dermatoplasty combined with vacuum sealing drainage for the treatment of large-area soft tissue defects accompanied by bone exposure in the lower leg. AB - The aim of this study was to investigate the clinical efficacy of free dermatoplasty combined with vacuum sealing drainage (VSD) for the treatment of large-area soft tissue defects accompanied by bone exposure in the lower leg (crus). Free dermatoplasty combined with VSD was used to treat 36 patients with large-area soft tissue defects accompanied by bone exposure in the lower leg. The areas of the soft tissue defects ranged from 25*12 to 35*30 cm and the areas of exposed bone ranged from 6*4 to 10*6 cm. When evaluated by the open fracture Gustilo classification, 14 cases were of Gustilo type IIIA and 22 cases were of type IIIB. During surgery, adjacent available muscle flaps were transferred to cover the outer areas of the exposed bone and reduce the bone exposure range. Following VSD treatment, granulation tissues grew well and free dermatoplasty combined with VSD was used to treat and repair the wound surfaces. The patients were followed up for 1-5 years (mean duration, 2.5 years). All 36 cases with skin flap grafts survived, the free skin graft texture on the wound surface was good, the recovery of lower limb function was satisfactory and the success rate was 80.56%. Free dermatoplasty combined with VSD used for the treatment of large-area soft tissue defects accompanied by bone exposure in the lower leg may eliminate the need for amputation and complex surgery, and is a simple, fast and effective treatment method. PMID- 23737884 TI - Comparative study of thyroid puncture biopsy guided by contrast-enhanced ultrasonography and conventional ultrasound. AB - The aim of this study was to investigate the application value of thyroid puncture biopsy guided by contrast-enhanced ultrasound (CEUS). A total of 48 patients with 51 solid thyroid nodules (suspected papillary thyroid carcinoma, PTC) were enrolled in the study. Following detection by conventional ultrasonography and CEUS, puncture biopsy of the suspicious lesions guided by conventional ultrasonography and CEUS was conducted, respectively. Then, pathological diagnosis was performed. The number of PTC positive nodules and puncture points detected by the two methods were compared. In 51 nodules with 310 punctures, 44 nodules (86.3%, 44/51) and 240 punctures (77.4%, 240/310) were pathologically diagnosed as PTC. In the 44 nodules diagnosed as PTC, 43 and 34 nodules were detected by CEUS and conventional ultrasound, respectively, with a significant difference between the two methods (P=0.022). Eleven (25%) nodules were independently detected by CEUS. The sensitivity and accuracy of puncture point detection by CEUS (82.9 and 82.6%, respectively) were significantly higher compared with those of conventional ultra-sound (48.3 and 56.5%, respectively; P<0.001). The specificity of puncture points detected by CEUS (81.4%) was significantly lower compared with that by conventional ultrasound (84.3%; P=0.009). Compared with conventional ultrasound, a greater number of PTC-positive nodules were detected by CEUS, with increased sensitivity and accuracy of the puncture points. PMID- 23737885 TI - A case of anaphylactoid purpura nephritis accompanied by pulmonary hemorrhage and review of the literature. AB - Cases of Henoch-Schonlein purpura and purpura nephritis accompanied by pulmonary hemorrhage are rare. Mild cases are easily ignored due to a lack of evident bleeding, and severe cases may be fatal. We have only treated one patient with Henoch-Schonlein nephritis (HSPN), a female child. The clinical manifestations were not evident, however, the imaging manifestations were clear. Finally, the patient was definitively diagnosed with HSPN accompanied by pulmonary hemorrhage. Following treatment with antiinflammatory and steroidal agents, tripterygium glycosides and traditional Chinese medicine, the patient recovered. In the present study, we report the diagnosis and treatment of this disease, with a review of the literature. PMID- 23737886 TI - Effects of renal pelvic high-pressure perfusion on nephrons in a porcine pyonephrosis model. AB - The aim of this study was to investigate the effects of various renal pelvic pressure gradients on nephrons with purulent infection. Five miniature test pigs were selected. One side of the kidney was used to prepare the pyonephrosis model and the other side was used as the healthy control. A piezometer and a water fill tube were inserted into the renal pelvis through the ureter. Prior to perfusion, punctures were made on the healthy and purulent sides of the kidneys to obtain tissues (as controls). Subsequently, a puncture biopsy was conducted on the kidneys at five pressure levels: 10, 20, 30, 40 and 50 mmHg. Once the renal pelvic pressure had increased, the healthy and injured kidneys presented pathological changes, including dilation of the renal tubule and capsule and compression of the renal glomerulus. When the renal pelvic pressure exceeded 20 mmHg, the injured kidney presented more damage. Electron microscopy revealed that the increase in pressure resulted in the following: the podocyte gap widened, the epithelial cells of the renal capsule separated from the basement membrane, the basement membrane thickness became uneven, the continuity of the basement membrane was interrupted at multiple positions and the renal tubule microvillus arrangement became disorganised. The manifestations in the pyonephrosis model were more distinct compared with those in the healthy kidney. As the renal pelvic pressure exceeds 20 mmHg under a renal purulent infection status, the nephrons become damaged. The extent of the damage is aggravated as the pressure is increased. PMID- 23737887 TI - Prevalence and incidence of retinopathy in elderly diabetic patients receiving early diagnosis and treatment. AB - Diabetic retinopathy (DR) is one of the most common and specific complications of diabetes. Thus, intervention is required to lower the incidence and prevalence of sight-threatening retinopathy. The aim of this study was to investigate the prevalence and incidence of diabetic retinopathy in elderly diabetic patients receiving early diagnosis and proper treatment and to explore risk factors for DR. From May 2005 to May 2011, fundus examination was performed for elderly diabetic patients during routine medical examinations. The presence of a microaneurysm or more severe presentations was used to diagnose DR, which was followed by fundus fluorescein angiography. Logistic regression analysis was employed to analyze the risk factors for DR development within 5 years. A total of 2,194 diabetic patients were recruited and followed-up for a mean of 5.8 years. The prevalence of DR was 15.38-16.20% and the incidence of DR was 8.38/1,000 person-years. Logistic multiple stepwise regression revealed that fasting plasma glucose (FPG), mean arterial pressure (MAP), duration of diabetes, body mass index (BMI) and microalbuminuria (MAU) were significantly associated with the occurrence of DR (all P<0.05). In the present study, the prevalence and incidence of DM were higher compared with those reported in the general population; however, the prevalence and incidence of DR were lower compared with those reported in similar studies. This suggests that favorable control of blood glucose, blood pressure and blood lipids effectively prevents the occurrence of DR in diabetic patients. PMID- 23737889 TI - Effect of thalidomide on the proliferation of hepatoma cells assessed by osteopontin levels in nude mice. AB - The aim of the present study was to investigate the inhibitory effects of thalidomide in the hepatocellular carcinoma nude mouse model in order to provide new insights into a comprehensive clinical intervention for hepatocellular carcinoma. MHCC97 cells were routinely cultured, passaged and adjusted to a single cell suspension with a concentration of 2*107/ml. Six-week-old, BALB/C male nude mice were anesthetized and fixed in the prone position, then a subcapsular injection of the single cell suspension was administered into the spleen and their abdomens were closed. A laparotomy and left hepatic lobectomy was performed 14 days later and the abdomens were closed once again. Subsequent to the establishment of the hepatocellular carcinoma model, the nude mice were randomly divided into three groups, each consisting of 12 mice. The early intervention group were immediately provided with the post-operative thalidomide intervention, the late intervention group were provided with the post-operative thalidomide intervention one week subsequent to the surgery, and the negative control group were provided with a placebo intervention (0.9% physiological saline). Each intervention was continuously administered once per day for one week. The osteopontin (OPN) content of the liver tumors was detected using immunohistochemistry. The data were analyzed using an analysis of variance (ANOVA) test. There were significant differences in the OPN levels of the tumors among the early intervention, late intervention and negative control groups. Thalidomide may inhibit the generation of OPN and thereby inhibit the infiltration and metastasis of tumors; the immediate use of thalidomide following hepatectomy in the present study may block the invasion and metasis for liver cancer more effectively. PMID- 23737888 TI - p53 codon 72 polymorphism and breast cancer risk: A meta-analysis. AB - p53 is a tumor suppressor gene and plays important roles in the etiology of breast cancer. Studies have produced conflicting results concerning the role of p53 codon 72 polymorphism (G>C) on the risk of breast cancer; therefore, a meta analysis was performed to estimate the association between the p53 codon 72 polymorphism and breast cancer. Screening of the PubMed database was conducted to identify relevant studies. Studies containing available genotype frequencies of the p53 codon 72 polymorphism were selected and a pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the association. Sixty-one published studies, including 28,539 breast cancer patients and 32,788 controls were identified. The results suggest that variant genotypes are not associated with breast cancer risk (Pro/Pro + Arg/Pro vs. Arg/Arg: OR=1.016, 95% CI=0.931-1.11, P=0.722). The symmetric funnel plot, Egger's test (P=0.506) and Begg's test (P=0.921) were all suggestive of the lack of publication bias. This meta-analysis suggests that the p53 codon 72 Pro/Pro + Arg/Pro genotypes are not associated with an increased risk of breast cancer. To validate the association between the p53 codon 72 polymorphism and breast cancer, further studies with larger numbers of participants worldwide are required. PMID- 23737890 TI - Study on potential role of apolipoprotein E in recurrent pregnancy loss. AB - The role of apolipoprotein E (Apo E) gene polymorphisms in the etiology of recurrent pregnancy loss (RPL) is not clearly understood. We evaluated this polymorphism in unexplained pregnancy losses in a group of Turkish women. In our prospective case-control study, 45 well-characterized RPL cases were examined for their Apo E genotypes, based on restriction fragment length polymorphism analysis of polymerase chain reaction (PCR)-amplified fragments. The observed genotypes were compared with those obtained from equal number matched controls. We observed similar Apo E genotypes and E2, E3 and E4 allele frequency distribution among RPL patients and controls. The allele frequencies obtained in patients and controls, respectively, were as follows: E2=8 (9%) and 12 (13.4%) (P=0.342), E3=66 (73.3%) and 60 (66.6%) (P=0.328) and E4=16 (17.7%) and 18 (20%) (P=0.703). Our data did not support the association of Apo E gene polymorphisms with RPL as reported by previous studies. We endorse adequate characterization of RPL cases and adequate sample size prior to addressing such studies. PMID- 23737891 TI - Liquid nitrogen-cryopreserved tarsal plate and palpebral conjunctival transplantation for the repair of tarsal defects. AB - The objectives of this study were to compare the efficiency of three methods for repairing tarsal defects (glycerine-preserved, alcohol-preserved and cryopreserved tarsal plate and palpebral conjunctival transplantation) based on histopathological changes and apoptosis, and to evaluate the clinical effects of repairing tarsal defects by liquid nitrogen-cryopreserved tarsal plate and palpebral conjunctival transplantation. Forty-eight rabbit eyes with tarsal defects were equally divided into three groups and transplanted with tarsal plates and palpebral conjunctivae under the following conditions: Group 1, liquid nitrogen cryopreservation; Group 2, glycerine preservation; and Group 3, alcohol preservation. Histopathological changes in the transplants were observed by light microscopy 1 week, 1 month and 3 months postoperatively. Apoptosis was assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Clinically, transplantations of liquid nitrogen-cryopreserved tarsal plates and palpebral conjunctivae were performed in 30 eyes (29 cases) to repair tarsal defects caused by the excision of neoplasms. The postoperative inflammatory reaction and number of apoptotic cells in Group 1 were lower compared with those in Groups 2 and 3. Clinically, of the 30 eyes operated on, 14 were cured, 15 improved and 1 failed between 6 and 90 months of follow-up. Liquid nitrogen cryopreserved tarsal plate and palpebral conjunctival transplantation is an easy, feasible and convenient procedure. Its effects are fairly favorable, with only a small rejection rate postoperatively. Therefore, it is an ideal method for repairing tarsal defects. PMID- 23737892 TI - The effect of palonosetron hydrochloride in the prevention of chemotherapy induced moderate and severe nausea and vomiting. AB - The current study aimed to evaluate the efficacy and safety of palonosetron hydrochloride injection for preventing chemotherapy-induced moderate and severe nausea and vomiting. A multi-centered, randomly stratified, double-blind, double dummy, parallel-group and positive-controlled trial was performed. A total of 240 patients who underwent chemotherapy treatment which induced moderate or severe vomiting were divided into the experimental and control groups. Half an hour before chemotherapy, the experimental group received a 0.25-mg palonosetron hydrochloride injection, whereas the control group received a 3-mg granisetron injection. The acute vomiting complete remission rate (CRR) of the experimental group was not significantly different compared with that of the control group (P=0.35). The delayed vomiting CRR of the experimental group was significantly higher compared with that of the control group (P=0.002). No difference in full course vomiting CRR, vomiting control time, treatment failure time or acute nausea CRR was identified between the two groups. No significant differences in adverse events were observed between the experimental group and the control group. No significant differences in adverse reactions occurred between the experimental group and the control group (12.50%). Palonosetron hydrochloride injection had a better effect on delayed vomiting CRR than granisetron hydrochloride injection. The two injections exhibited similar effects on acute vomiting CRR, full course vomiting CRR, vomiting control time, treatment failure time (days), acute nausea CRR and adverse events. PMID- 23737893 TI - Association between plasma soluble P-selectin elements and progressive ischemic stroke. AB - The aim of this study was to analyze the association between plasma-soluble P selectin (sP-selectin) elements and progressive ischemic stroke (PIS) and to explore the pathogenesis of PIS. Patients with acute ischemic stroke who were admitted and hospitalized in the Department of Neurology between August 2010 and August 2011 were used as subjects in this study. The enrolled patients were divided into progressive (58 cases) and non-progressive groups (143 cases), based on changes in disease conditions. The normal control group included 40 cases. The sP-selectin levels and related risk factors of the three groups of patients were compared. sP-selectin levels in the progressive group showed the highest values on day 1 after progression and gradually decreased on days 3, 7 and 14. sP selectin levels in the progressive and non-progressive groups on day 1 were higher compared with those in the control group (P<0.05) and the levels in the progressive group were higher compared with those in the non-progressive group (P<0.05). On days 3 and 7, levels in the progressive group were higher compared with those in the non-progressive group (P<0.05) and on day 14, levels in the progressive group remained higher compared with those in the non-progressive group (P>0.05). On days 1, 3 and 7, sP-selectin levels in the aortic atherosclerosis progressive group were higher compared with those in the aortic atherosclerosis non-progressive group (P<0.05), however on day 14, the difference between the two groups was not statistically significant (P>0.05). P-selectin levels had the most significant impact on the progressive group and the aortic atherosclerosis progressive group. P-selectin levels were high in patients with PIS and even higher in the aortic atherosclerosis progressive group and were closely correlated with the onset time of PIS. PMID- 23737894 TI - NT-ProBNP levels are moderately increased in acute high-altitude pulmonary edema. AB - The aim of the present study was to investigate the effect of B-type natriuretic peptides (BNPs) in acute high-altitude pulmonary edema (HAPE). The study enrolled 46 subjects from lowland Han, including 33 individuals who had acutely ascended to a high altitude (21 individuals with HAPE as the case group and 12 individuals without HAPE as the high-altitude control group) and 13 healthy normal residents as the plain control group. The serum concentrations of N-terminal probrain natriuretic peptide (NT-proBNP), erythropoietin (EPO), vascular endothelial growth factor (VEGF) and nitric oxide (NO) were measured. There were significant differences in the serum concentrations of NT-ProBNP, NO, VEGF and EPO among the three groups. The serum concentrations of NT-ProBNP, EPO and VEGF were significantly higher in the HAPE patients and high-altitude control individuals than those of the plain group. No significant differences were identified between the HAPE patients and the high-altitude control group. In contrast to these three parameters, the serum concentrations of NO in the high-altitude control group were significantly higher than those of the HAPE patients and the plain group, while there were no significant differences in the serum concentrations of NO between the HAPE patients and the plain group. Furthermore, serum concentrations of NT-ProBNP and EPO were significantly reduced following treatment in the HAPE patients, however, no significant changes were identified in VEGF or NO concentrations. BNPs are increased in HAPE with severe hypoxia and right ventricular overload, but are decreased subsequent to treatment. BNPs may therefore be a potential biomarker for the diagnosis and prognosis of HAPE. PMID- 23737895 TI - Associations of plasma atrial natriuretic peptide and electrolyte levels with essential hypertension. AB - This study aimed to investigate the associations among the levels of plasma atrial natriuretic peptide (ANP) and electrolytes and essential hypertension (EH) in Uygur, Han and Kazakh populations in Xinjiang. A total of 724 hypertensive participants of different ethnicities from Xinjiang (208 Uygur, 287 Han and 229 Kazakh) and 741 normal controls (208 Uygur, 267 Han and 266 Kazakh) were enrolled. The associations of ANP with serum potassium, serum sodium and blood pressure were assessed. In the normal control (NT) group, the concentration of ANP was higher in the Uygur population than in the Han population, and the concentration in the Han population was higher than that in the Kazakh population (P<0.05). In the EH group, the serum potassium levels of the Uygur and Han populations were higher than that of the Kazakh population (P<0.05). The ANP concentration in the Uygur ethnic group was higher than that in the Han population, which was in turn higher than that in the Kazakh participants (P<0.05). In the Kazakh population, the serum potassium level was significantly lower in the EH group compared with that in the NT group (P<0.05). The serum potassium level was significantly lower and the ANP concentration significantly higher in the EH group compared with those of NT groups in the Uygur and Han populations (P<0.05). Age and body mass index (BMI) were associated with hypertension in the Uygur, Han and Kazakh populations. Low serum potassium may be a risk factor of hypertension in individuals of Uygur and Kazakh ethnicity. Plasma ANP may be a regulatory factor involved in the development of hypertension in Uygur and Han populations. PMID- 23737896 TI - Mechanically assisted intra-arterial thrombolysis in acute cerebral infarction. AB - The aim of this study was to assess the clinical efficacy and safety of mechanically assisted thrombolysis in the treatment of acute cerebral infarction. Mechanically assisted intra-arterial urokinase thrombolysis was conducted on 28 patients with acute cerebral infarction with a disease onset time of 90-450 min. The maximum level of urokinase was 1,150,000 units. Thrombus disruption with a microwire, retrieval with a microcatheter and stent-assisted revascularization were performed. The recanalization rate, bleeding complications and modified Rankin scale (mRS) score were observed within 3 months of surgery. Our results showed that mechanically assisted thrombolysis was successfully conducted on 23 patients, with a recanalization rate of 82.1% (23/28), average recanalization time of 65.22 min and mRS score <=3.5. Five cases of recanalization were invalid, including 2 cases of mortality, 1 case with an mRS score of 4 and 2 cases with an mRS score <=3. In the recanalization group, the mechanically assisted thrombolysis did not increase the number of bleeding complications. Our study demonstrated that the safety of mechanically assisted thrombolysis for the treatment of acute cerebral infarction is equivalent to that of simple intra arterial thrombolysis, but that the former has a higher efficiency. Mechanically assisted thrombolysis is able to reduce the urokinase dosage and recanalization time, and increase the recanalization rate. PMID- 23737897 TI - Correlation between plasma lipoprotein-associated phospholipase A2 and peripheral arterial disease. AB - Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a recently identified and potentially useful plasma biomarker for cardiovascular diseases. However, its role in peripheral arterial disease (PAD) remains unclear. The objective of this study was to assess the independent association of Lp-PLA2 and other inflammatory markers with the reduced ankle-brachial blood pressure index (ABI), a marker of PAD. We performed a cross-sectional study in 982 individuals aged >=40 years who were recruited from the First Affiliated Hospital of Zhengzhou University. PAD was defined as an ABI <0.9 in at least one leg. The individuals were further divided into two groups, 145 with PAD and 837 without PAD. Following adjustment for traditional cardiovascular risk factors, the odds ratios of PAD when comparing the highest to the lowest quartiles were 3.24 (95% CI, 1.68-3.94) for Lp-PLA2, 2.14 (95% CI, 1.07-3.11) for homocysteine, 1.93 (95% CI, 1.02-4.01) for fibrinogen, 2.26 (95% CI, 1.32-5.74) for apolipoprotein B and 1.3 (95% CI, 0.75 2.49) for high-sensitivity C-reactive protein (hsCRP). When Lp-PLA2 and inflammatory markers were simultaneously included in the full model, the corresponding odds ratios were 1.81 (95% CI, 1.14-3.68) for Lp-PLA2, 1.15 (95% CI, 0.49-2.69) for homocysteine, 1.21 (95% CI, 0.88-5.57) for fibrinogen, 0.98 (95% CI, 0.51-3.85) for apolipoprotein B and 1.23 (95% CI, 1.12-3.51) for hsCRP. Lp-PLA2 levels were significantly and independently associated with PAD following adjustment for other inflammatory markers. These findings reflect the potential role of circulating Lp-PLA2 as a marker of atherosclerosis. PMID- 23737898 TI - Correlation between apoptosis and TGF-beta1 expression in the mucosal epithelium of rat small intestine in a cold stress state. AB - The aim of this study was to investigate the correlation between the expression of transforming growth factor-beta1 (TGF-beta1) in the mucosal tissue of rat small intestine and the apoptosis of epithelial cells in the small intestine in a cold-restraint stress state. Immunohistochemistry was used to detect the expression of TGF-beta1. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) and DNA agarose gel electrophoresis were used to detect apoptosis. After 8 and 12 h of cold-restraint stress, the positive expression rate of TGF-beta1 in the rat small intestine epithelial tissue was 59.09 and 54.16%, respectively. The apoptotic index (AI) of the rat small intestine epithelial cells was 25.69+/-8.09 and 19.65+/-6.61%, respectively. The positive expression rate of TGF-beta1 in the epithelial tissue of the rat small intestine was positively correlated with the AI of the epithelial cells (r=0.980, P<0.05). The epithelial cells of the rat small intestine exhibited apoptosis under cold-restraint stress. TGF-beta1 is one of the key factors that induces apoptosis of the epithelial cells of the rat small intestine. PMID- 23737899 TI - Evaluation of blunt pancreatic injury with contrast-enhanced ultrasonography in comparison with contrast-enhanced computed tomography. AB - The aim of the present study was to evaluate acute blunt pancreatic injury using contrast-enhanced ultrasonography (CEUS) in comparison with contrast-enhanced computed tomography (CECT). Superficial and deep lesions were established by blunt pancreatic injury in 40 Chinese Guangxi Bama miniature pigs. Conventional ultrasound (US), CEUS and CECT were performed to detect traumatic lesions in the pancreas. A total of 40 lesions were established, including 20 deep lesions and 20 superficial lesions. US identified 21 of the 40 lesions, including 7 of the 20 superficial and 14 of the 20 deep lesions. CEUS identified 34 of the 40 lesions, including 14 of the 20 superficial and 20 of the 20 deep lesions. CECT identified 33 of the 40 lesions, including 13 of the 20 superficial and 20 of the 20 deep lesions. The detection rate of acute blunt pancreatic injury using CEUS was significantly higher compared with that using US (85 vs. 52.5%, P<0.05), however there was no significant difference in the detection rate of pancreatic lesions between CEUS and CECT (85 vs. 82.5%, P>0.05). CEUS improves the diagnostic levels of conventional US and is comparable with CECT scans in the diagnosis of blunt pancreatic injury. PMID- 23737900 TI - Establishment and performance assessment of preparation technology of internal quality control products for blood transfusion compatibility testing. AB - The aim of this study was to establish and to optimize the preparation technology of whole blood internal quality control (IQC) products for blood transfusion compatibility testing. Several B-type RhD-negative blood samples collected from healthy donors were mixed. Two groups of whole blood IQC products, namely, the preservative solution group (PS group) and the saline group, were prepared. The agglutination intensity of IQC sample red cells and anti-B antibody, IgM anti-A antibody and reverse-typing A cell, IgG anti-D and O-type RhD-positive red cells, as well as free hemoglobin concentration in the supernatant of the two groups were detected. The erythrocytes in both groups were damaged to a certain extent during storage, but no evident (above moderate) hemolysis was observed in the stored sample within 42 days. The red cells remained structurally complete and the reaction activity of IgG anti-D reagent remained generally unchanged (P>0.05). Although the reaction activity oscillation of IgM anti-A reagent was observed, the agglutination intensity varied within an acceptable range of 1+. No difference was observed between the preparation methods of the samples, i.e., between the erythrocyte washed with saline and the one washed with red cell preservative solution (P>0.05). The long shelf life, low variance between tubes and stable antigen-antibody reaction activity of the whole blood IQC products prepared using the proposed method can meet the requirements of blood transfusion compatibility testing. PMID- 23737901 TI - Preliminary use of a double-echo pulse sequence with 3D ultrashort echo time in the MRI of bones and joints. AB - The aim of the present study was to investigate the application of a double-echo pulse sequence with 3D ultrashort echo time (UTE) in the magnetic resonance imaging (MRI) of bones and joints. In total, 7 healthy volunteers and 1 volunteer with a suspected tear of the lateral meniscus of the left knee joint underwent MRI with a double-echo pulse sequence and 3D UTE. The imaging was performed on the tibial diaphysis, knee joint and ankle of the volunteers and on a segment of porcine fibula in vitro. The echo time of echo 1 (TE1) of the UTE images for the achilles tendon of the ankle joint were set as 0.08, 0.16, 0.24 and 0.35 msec. The maximum intensity projection (MIP) of the difference images created from the primary double-echo images with a TE1 of 0.08 msec were performed on the tendons of the ankle to display their 3D structure. The data were analyzed with a one-way ANOVA and paired-sample t-test. The 3D distribution of the tendons was displayed through MIPs of the difference images created from the primary double-echo images. The cortical bones, periosteum, tendons and menisci of the 8 volunteers appeared as high signal intensities in the UTE pulse sequence. Multiplanar reconstruction followed by subtraction of the primary double-echo images raised the image signal-to-noise (S/N) ratio from 2.80+/-0.75 to 3.76+/-0.88 (t=-4.851, P<0.01). The artifacts appeared more marked as the TE1 was prolonged. A double pulse sequence MRI with 3D UTE may display the short T2 components which are not displayed with a conventional clinical MRI sequence, therefore creating a basis for the further quantification of these tissues. PMID- 23737902 TI - Expression and distribution of dendritic cells in nasal polyps. AB - The aim of the present study was to investigate the expression, distribution and function of dendritic cells (DCs) and to study their role in nasal polyps. The study involved 55 participants, 45 of whom had nasal polyps and were the study group and 10 who had normal inferior turbinates and were the control group. Immunohistochemical staining was used to visualize the expression and distribution of the S-100 protein. A double immunostaining method was used to visualize the CD1a and CD40 expression and the images were analyzed with Axioplan 2 microscopy. The expression level of the S-100 protein in the nasal polyps was higher than that in the normal inferior turbinates with a significant difference (P<0.01). The distribution area, number and density of the double stained cells in the nasal polyps were all greater than in the normal inferior turbinates (P<0.01). The S-100 protein and double stained cells were mainly located in the lamina propria below the mucous membrane. The present study demonstrates that DCs are involved in the pathogenesis of nasal polyps and the presence of CD40 positive DCs suggests that this was related to the reciprocal interaction between the DCs and T lymphocytes. PMID- 23737903 TI - Comparison of treatments for bullous keratopathy in rabbits. AB - The aim of the present study was to compare deep lamellar endothelial keratoplasty (DLEK) and penetrating keratoplasty (PK) treatments for bullous keratopathy (BK). In total, 36 healthy New Zealand white rabbits were randomly divided into 3 groups termed the experimental, DLEK and PK groups. The experimental control group received no treatment. The DLEK and PK groups were observed for corneal astigmatism at 1, 2, or 3 months post-surgery using a corneal topography instrument and a slit lamp microscope. The incidence of immune rejection after 3 months of recovery was determined using hematoxylin and eosin (H&E) staining. The corneal specimens from the surgery groups were compared with those from the control group. In the 12 rabbit eyes that underwent the DLEK surgery, the central cornea became clear after 1 week. After 3 months, these corneas were almost transparent and no eye infections or other complications were observed in 10 of the eyes, while surgical perforations in 2 eyes led to surgical lamellar failure. In the PK surgery group, in which 12 rabbit eyes were also treated, nine were almost transparent after 3 months of recovery, while three eyes were immunologically rejected due to the corneal grafts. The occur-rences of corneal astigmatism that were observed following DLEK and PK treatment were significantly different after 1, 2 and 3 months of recovery (P<0.05). Normal corneal staining was observed in the DLEK and PK rabbits subjected to H&E staining after 3 months of recovery. A BK animal model was established by curetting the Descemet's membrane (DM film). In comparison with PK, DLEK is a superior surgical treatment for BK. PMID- 23737904 TI - Predictors of diffuse-type in-stent restenosis following drug-eluting stent implantation. AB - Diffuse-type in-stent restenosis (ISR) is known to be associated with a higher rate of restenosis than focal-type ISR. Therefore, it is clinically important to identify the determinants of diffuse-type ISR following drug-eluting stent (DES) implantation. We investigated the clinical, procedural and angiographic variables for predicting diffuse-type ISR following DES implantation. A total of 173 ISR lesions in 159 patients (diffuse-type: 61 lesions, focal-type: 112 lesions) following DES implantation from February 2003 to May 2008 were included in this study. Clinical, procedural and quantitative coronary angiographic variables were analyzed to determine predictors of diffuse-type ISR following DES implantation. Univariate analysis showed that the absence of hypertension [odds ratio (OR), 0.493; 95% confidence interval (CI), 1.025-4.103, P=0.042], use of a paclitaxel eluting stent (PES) (OR, 3.318; 95% CI, 1.730-6.365, P<0.001) and smaller post stenting minimal luminal diameter (MLD; OR, 0.368, 95% CI, 0.168-0.808, P=0.013) were significantly associated with diffuse-type ISR. However, use of a PES (OR, 3.957; 95% CI, 1.977-7.922, P<0.001) and smaller post-stenting MLD (OR, 0.320; CI, 0.140-0.731, P=0.007) were only independent predictors of diffuse-type ISR by multivariate analysis. Diabetes was not a predictor of diffuse-type ISR. The use of a PES and the post-stenting MLD were related to diffuse-type ISR following DES implantation. PMID- 23737905 TI - Upregulation of heme oxygenase-1 expression may facilitate memory and learning in mice. AB - Heme oxygenase (HO)-1 is highly expressed in the hippocampus. Its expression is induced by many factors including hemes, whose metabolites play an important role in neuron protection and learning development. In the present study, the correlation between HO-1 and learning ability was investigated in mice. Behavioral tests were used to evaluate the effects of altering HO-1 on learning ability in mature mice. In order to determine the function of HO-1 in the immature mice, a dark-reared model was constructed. Either the HO-1 inducer hemin or the HO-1 inhibitor Zn protoporphyrin IX (ZnPPIX) was injected into the left lateral ventricle prior to a behavior test. Results showed that neither hemin nor ZnPPIX affected the learning ability of adult mice reared in normal conditions. The hippocampal HO-1 of dark-reared mice was decreased while it was increased in the behavioral training group. In general, HO-1 had no effect on established learning ability but it may be upregulated by behavioral training and is beneficial for the development of memory and learning ability in neonatal mice. PMID- 23737906 TI - Protective effect of melatonin against Adriamycin-induced cardiotoxicity. AB - The aim of this in vivo study was to explore the protective properties of melatonin against Adriamycin-induced myocardial toxicity. A rat model of breast cancer was established and the rats were randomly divided into the blank group (Blank), the solvent group [Diss; dehydrated alcohol: physiological saline (1:9)], the Adriamycin group (ADM), the melatonin group (MLT) and the melatonin + Adriamycin group (M+A). The concentrations of lipid peroxide (LPO), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in myocardial tissues were detected, the changes in myocardial tissues were observed using light microscopy and electron microscopy, and the 1-month survival rates of each group of rats were compared. Breast cancer was established in 116 rats. In the ADM group, the concentration of LPO was higher and the concentrations of SOD and GSH-Px were significantly lower than those in the blank group. In the M+A group, compared with the ADM group, the concentration of LPO was lower (P<0.05) and the concentrations of SOD and GSH-Px were higher (P<0.05). It was observed using light and electron microscopy that the myocardial injuries to the M+A group were significantly alleviated in comparison with those in the ADM group; the 1-month survival rate in the M+A group was higher than that in the ADM group. Melatonin may have a protective role in the myocardium by reducing Adriamycin-induced myocardial oxidative damage. PMID- 23737907 TI - Diagnostic value of an ROC curve of the size of the antepartum foramen ovale in the prediction of puerperal atrial septal defect. AB - The aim of this study was to determine the diagnostic value of an ROC curve of the antepartum foramen ovale (AFO) size and the ratio of FO size to aorta (AO) size (FO/AO) for the prediction of puerperal atrial septal defect in different gestational weeks (DGWs). A total of 958 cases were divided into five groups according to number of gestational weeks. Comparisons of FO size, AO size and FO/AO were determined by variance analysis. The correlations between FO size, AO size and gestational age were determined using regression analysis and comparisons between atrial septal defect (ASD) diagnosed in DGWs and normal cardiac FO size and FO/AO were analyzed by t-test. ROC curve analysis was used for FO size and FO/AO to predict the demarcation point of puerperal ASD (pASD). The differences between FO size and AO size in the five groups at DGWs were statistically significant (P=0.000). The sizes of FO and AO increased with gestational age. The differences among pASD, normal cardiac FO size and FO/AO were statistically significant (P=0.000). FO size in the five DGW groups (18-22, 23-26, 27-30, 31-34 and 35-40 weeks) was able to predict the demarcation points of pASD, which were 5.02, 5.15, 6.55, 8.55 and 7.90 mm, respectively. The prediction of pASD with AFO size and FO/AO was accurate and may provide reliable reference values in the clinic. PMID- 23737908 TI - Correlation between microtubule-associated gene expression and chemosensitivity of patients with stage II non-small cell lung cancer. AB - The aim of this study was to explore the correlation between mRNA expression of beta-tubulin-III and stathmin in patients with stage II non-small cell lung cancer (NSCLC) and the chemosensitivity to Navelbine plus cisplatin (NP), as well as to provide a basis for personalized treatment. A single-gene quantitative test was performed to detect the mRNA expression of beta-tubulin-III and stathmin in the tumor tissue of patients with stage II NSCLC. All the patients underwent NP treatment following surgery and were followed-up to record their disease-free survival (DFS) and overall survival (OS). Statistical analyses were conducted to investigate the correlation between beta-tubulin-III and stathmin mRNA expression and DFS and OS in the patients. beta-tubulin-III mRNA expression was associated with OS in the 73 patients (P=0.003) and DFS was correlated with beta-tubulin-III mRNA expression and lymphatic metastasis (P<0.01). Stathmin mRNA expression was not correlated with OS or DFS (P>0.05). OS and DFS were longer in the patients with low beta-tubulin-III mRNA expression than in those with high beta-tubulin III mRNA expression (P<0.01); there was no significant change in OS and DFS between the patients with high and low mRNA expression of stathmin (P>0.05). The mRNA expression levels of beta-tubulin-III in the tumor tissue of patients with stage II NSCLC may be considered as an index of prognosis and chemosensitivity, as well as a reference for personalized chemotherapeutic applications in patients. PMID- 23737909 TI - Ileal interposition surgery-induced improvement of hyperglycemia and insulin resistance in Goto-Kakizaki rats by upregulation of TCF7L2 expression. AB - The aim of this study was to investigate the effects of ileal interposition (IT) on glucose and insulin resistance (IR) in type 2 diabetic mellitus (T2DM), and the role of T-cell factor 7-like 2 (TCF7L2), formerly known as TCF4, in the downregulation of hyperglycemia following IT. Goto-Kakizaki (GK) rats subjected to IT surgery (GK-IT group), GK rats subjected to sham surgery (GK-Sham group) and Wistar (WS) rats subjected to sham surgery (WS-Sham group) were investigated in this study. Fasting plasma glucose, body weight, food intake per 1 kg body weight, insulin and a homeostasis model assessment of insulin resistance (HOMA IR) were measured pre- and post-surgery. The rats were euthanized 28 days post surgery and the pancreas of each rat was dissected. The expression levels of TCF7L2 mRNA and protein were analyzed by quantitative RT-PCR and western blotting, respectively. Our results revealed that IT improved both fasting plasma glucose levels and IR in GK rats by upregulating the expression of the TCF7L2 protein. IT provides a valuable therapeutic option for patients with T2DM. Upregulation of TCF7L2 protein expression may be a possible mechanism underlying the improvement of T2DM following IT. PMID- 23737910 TI - Agnogenic massive pulmonary embolism with syncope as initial symptom: A case report and review of the literature. AB - Pulmonary embolism may escape prompt diagnosis since clinical symptoms and signs are nonspecific. The occurrence of syncope as the sole initial symptom in a previously healthy patient with no predisposing factors to embolism and no hemodynamic instability is extremely rare, which may have been a factor in the delayed diagnosis. We describe a case of agnogenic massive pulmonary embolism with syncope as the initial symptom. A 41-year-old previously healthy female was admitted to the Department of Neurology, Taizhou People's Hospital in March 2012, for two transitory episodes of syncope during a 5-h period. Following admission, chest computed tomography demonstrated embolism in the right main pulmonary and left inferior pulmonary arteries. Color ultrasonography revealed a dilated right ventricle and right heart overload, severe tricuspid regurgitation and severe pulmonary hypertension. Following the final diagnosis, the patient was successfully treated with interventional mechanical thrombectomy combined with thrombolytic therapy with local and systemic low-dose urokinase. We consider that raised awareness and early diagnosis and treatment were key factors in ensuring a satisfactory prognosis. PMID- 23737911 TI - Effect of advanced glycation end products on the expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor proteins in RF/6A cells. AB - The aim of this study was to investigate the effect of advanced glycation end products (AGEs) on the expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) proteins in RF/6A cells cultured in vitro, and to investigate the association between the expression of HIF-1alpha and VEGF proteins. RF/6A cells were cultured in vitro and treated with AGEs and non-glycated albumin control at various concentrations (0, 50, 100, 200, 400 and 800 mg/l) for 24 h. The expression of the VEGF protein was detected by ELISA, and western blot analysis was used to determine the levels of HIF-1alpha protein. The expression of HIF-1alpha and VEGF proteins was significantly higher in the AGE group compared with the non-glycated control group (all P<0.05). With the increase in concentration of AGEs, the expression levels of HIF-1alpha and VEGF protein increased and reached a maximum at 200 mg/l AGE, then decreased at 400 and 800 mg/l. However this effect was not observed in the non-glycated control groups. There was a positive correlation between the expression of HIF-1alpha and VEGF (P<0.05). AGEs induced the expression of HIF-1alpha and VEGF proteins in RF/6A cells in a concentration-dependent manner. AGEs may upregulate the expression of VEGF protein by increasing the levels of HIF-1alpha protein, demonstrating the potential role of HIF-1alpha-targeted therapy in neovascularization. PMID- 23737912 TI - Dynamic changes in HMGB1 levels correlate with inflammatory responses during cardiopulmonary bypass. AB - High mobility group box 1 (HMGB1), which is released by activated immune cells and necrotic cells, has properties similar to those of pro-inflammatory cytokines. Cardiopulmonary bypass (CPB) induces systemic inflammation and aortic cross-clamping induces myocardial ischemia. This study was conducted to observe the dynamic changes of HMGB1 and tumor necrosis factor (TNF)-alpha levels during CPB and to analyze their clinical significance. A total of 78 cases of American Society of Anesthesiologists (ASA) grade II-IV undergoing elective valve replacement under CPB were included in this study. Blood and urine samples were collected after anesthesia prior to surgery (T1), before aortic cross-clamping (T2), after CPB (T3) and on the first day after surgery (T4), as well as the second (T5) and third (T6) day after surgery for determination of the levels of HMGB1, TNF-alpha, alanine aminotransferase (ALT), creatinine (Cr), blood urea nitrogen (BUN), N-acetyl-beta-D-glucosamidase (NAG) and beta2-microglobulin (beta2-MG). Results revealed that: i) the serum levels of HMGB1 elevated as early as T1, increased until reaching a peak at T3, then decreased to a lower level at T4; ii) the serum level of TNF-alpha was low at T1, gradually increased in a similar manner to HMGB1, then decreased following CPB and reached the lowest point at T5; and iii) the levels of HMGB1 were positively correlated with serum TNF-alpha and serum ALT at T3. In conclusion, HMGB1 levels may be used as an indicator of inflammation and may be a novel target for controlling inflammation during CPB. The optimal treatment time is T3 (after CPB). PMID- 23737913 TI - The effects of Gouqi extracts on Morris maze learning in the APP/PS1 double transgenic mouse model of Alzheimer's disease. AB - The present study examined the effects of Gouqi (Lycium barbarum) on the learning and memory abilities of an APP/PS1 double transgenic mouse model of Alzheimer's disease. We employed a Morris water maze to examine the spatial memory in this mice line with or without Gouqi extracts treatment. We identified that 2 weeks of oral administration of Gouqi extracts at 10 mg/kg improved the performance of the APP/PS1 mice in the learning and the memory retrieval phases of the Morris maze. In correlation with this, the levels of Abeta(1-42) in hippocampal tissue were reduced by the Gouqi treatment. We conclude that pharmacological treatment with Gouqi extracts is beneficial at the later stages of Alzheimer's disease. PMID- 23737914 TI - Absorbable implants versus metal implants for the treatment of ankle fractures: A meta-analysis. AB - This meta-analysis was performed to evaluate the efficiency and the safety of absorbable implants. Five major electronic databases (PubMed, Embase, Cochrane Library, SinoMed and Wanfang Data) were systematically searched for randomized controlled trials (RCTs) from their establishment to November 2012. Studies on absorbable implants and metal implants for ankle fractures were selected. The meta-analysis was performed using RevMan 5.1. Ten studies with 762 patients were included and analyzed. Compared with metal implants, absorbable implants used for the internal fixation of ankle fractures produce similar radiographic and functional outcomes (P= 0.52). Normally, removal of the internal fixation is unnecessary (P<0.0001) and the incidence of palpable implants is lower (P=0.02) for absorbable implants. No statistically significant difference was observed between the two groups with regard to foreign body reactions (P=0.07), infection (P= 0.69), osteoarthritis (P= 0.39), pain (P= 0.06), refracture (P=0.67), skin necrosis (P=0.99), deep vein thrombosis (P=0.21) and nerve injury (P=0.94). Absorbable implants used in ankle fractures rarely require reoperation and result in similar functional outcomes and complications compared with metal implants. These characteristics make them efficient and reasonably safe for the treatment of ankle fractures. PMID- 23737915 TI - Symposium on "Developing Clinical Competences - Research and Development Challenges in Germany" March 7 and 8, 2013, Charite - Universitatsmedizin Berlin, ChariteCrossOver. PMID- 23737916 TI - AKWLZ annual meeting 2012 in Witten. PMID- 23737917 TI - Feasibility, acceptance and impact of team-based learning in neurology: a pilot study. AB - BACKGROUND/GOAL: Neurology is rated as one of the most difficult specialties by medical students, as well as by medical practitioners in other areas. Team-based learning (TBL) as a method of active and group-based learning seems to be a suitable method to achieve greater learning success and a better understanding of neurology. METHODS: The TBL neurology course was designed as a supplemental program within the regular neurology course for third-year medical students. This supplemental course consisted of six 90-minute units as a pilot study during the 2011-12 winter semester and was evaluated in terms of time and effort. The acceptance of the TBL concept in general, as well as of the TBL neurology course in particular, was assessed using written evaluations. The results of the final exam were analyzed with regard to participation in TBL and the content imparted therein. RESULTS: The preparation time was approximately 8 hours per unit. The implementation was without difficulty. The high rate of regular attendance and the consistently very positive evaluation results indicated a high acceptance of the TBL concept in general, as well as of the TBL neurology course in particular. TBL participants displayed better results on the final exam in topics also covered in the TBL units. CONCLUSION: The resulting achievement of a subjectively better understanding and a simultaneously higher level of interest in neurology justified the one-time, relatively intense preparation effort for TBL. The high acceptance among students inexperienced in teamwork suggests an unproblematic transfer to other preclinical or clinical courses. The impact on measurably improved results in clinical reasoning and problem-solving skills should be further investigated in the context of controlled studies. PMID- 23737918 TI - Significant improvement of a clinical training course in physical examination after basic structural changes in the teaching content and methods. AB - BACKGROUND: Regular student evaluations at the Technical University Munich indicate the necessity for improvement of the clinical examination course. The aim of this study was to examine if targeted measures to restructure and improve a clinical examination course session lead to a higher level of student satisfaction as well as better self-assessment of the acquired techniques of clinical examination. METHODS: At three medical departments of the Technical University Munich during the 2010 summer semester, the quantitative results of 49 student evaluations (ratings 1-6, German scholastic grading system) of the clinical examination course were compared for a course before and a course after structured measures for improvement. These measures included structured teaching instructions, handouts and additional material from the Internet. RESULTS: 47 evaluations were completed before and 34 evaluations after the measures for improvement. The measures named above led to a significant improvement of the evaluative ratings in the following areas: short introduction to the topic of each clinical examination course (from 2.4+/-1.2 to1.7+/-1.0; p=0.0020) and to basic measures of hygiene (from 3.8+/-1.9 to 2.5+/-1.8; p=0.004), structured demonstration of each clinical examination step (from 2.9+/-1.5 to 1.8+/-1.0; p=0.001), sufficient practice of each clinical examination step (from 3.1+/-1.8 to 2.2+/-1.4; p=0.030) structured feedback on each clinical examination step (from 3.0+/-1.4 to 2.3+/-1.0; p=0.0070), use of handouts (from 5.2+/-1.4 to 1.8+/ 1.4; p<0.001), advice on additional learning material (from 5.0+/-1.4 to 3.4+/ 2.0; p<0.001), general learning experience (from 2.4+/-0.9 to 1.9+/-0.8; p=0.017), and self-assessment of the acquired techniques of clinical examination (from 3.5+/-1.3 to 2.5+/-1.1; p<0.01). CONCLUSION: Structured changes led to significant improvement in the evaluative ratings of a clinical examination course session concerning preparation of the tutors, structure of the course, and confidence in performing physical examinations. PMID- 23737919 TI - Measurement of specific medical school stress: translation of the "Perceived Medical School Stress Instrument" to the German language. AB - OBJECTIVE: Medical students encounter specific stressors during their studies. As a result, they develop anxiety, depression and burnout symptoms more frequently than their similarly aged, but employed counterparts. In 1984, Vitaliano et al. published a 13-item instrument for the measurement of stress specific to medical school: the "Perceived Medical School Stress Instrument" (PMSS). Since then, it has been widely applied and validated in English-speaking countries. No German version of the PMSS exists to date. Thus, our aim was to translate the instrument into the German language in order to be able to measure medical school stress in German-speaking countries. METHOD: The items of the PMSS were translated into German by three separate researchers. The resulting translations were compared and combined with each other to establish a first German version of each item in the PMSS. These items were then translated back into English by two native English speakers to validate the correct primary translation. Based on a revised German version, a cognitive debriefing with 19 German medical students and a theoretical testing on 169 German medical students, the final German translations for each of the 13 items were determined. RESULTS: The PMSS was easily translated into German and there was a high congruency between the primary translations into German and the secondary translations back into English. Incongruities between the translations were solved quickly. The assessment of the German equivalent of the PMSS showed good results regarding its reliability (Cronbach's Alpha 0.81). CONCLUSION: A German version of the PMSS is now available for measuring the medical school related stress in German-speaking countries. PMID- 23737920 TI - Bedside Teaching: general and discipline-specific teacher characteristics, criteria for patient selection and difficulties. AB - OBJECTIVE: With regard to bedside teaching (BST), which has an important function in medical education for practicing history taking and clinical examination, only few studies can be found which define recommendations for its realization. However, difficulties with this teaching method are often reported in evaluations. Hence, the goal of this study is to collect important general requirements for bedside teaching and to identify important aspects of patient selection. METHODS: A newly designed questionnaire with closed and open questions concerning the organisation, the execution and the design of BST as well as patient selection was sent to a total of 134 teachers from the departments of surgery, internal medicine and psychiatry. The collected data were analysed using quantitative and qualitative methods. RESULTS: Teachers from internal medicine were significantly older than teachers from both other disciplines. In surgery, a significantly higher number of hours was taught by younger residents. Patient consent and the match of their diseases to the learning objectives were stated to be the most important factors for patient selection across disciplines. Psychiatrists put significantly more emphasis on patients' German language skills according to their own declaration. By trend, an acute deterioration of the state of health was mentioned more often in surgery to lead to an exclusion from BST. CONCLUSION: With regard to planning of content, organisation and patient selection for BST, aspects mentioned by teachers as well as discipline specific characteristics should be considered for and addressed during teacher trainings. PMID- 23737921 TI - A single standardized practical training for surgical scrubbing according to EN1500: effect quantification, value of the standardized method and comparison with clinical reference groups. AB - The standardized training of practical competences in skills labs is relatively new among German Medical Faculties. The broad acceptance and outstanding evaluation results do not provide objective data on the efficiency and cost efficiency of these trainings. This study aims on the quantification of the teaching effect of the surgical scrubbing technique EN1500 and its comparison with clinical references of OR personnel. METHODS: 161 4(th) year medical students were randomized into intervention and control group. The intervention group received a 45 minute standardized peer-teaching training of practical competences necessary in the OR including the scrubbing according to EN1500. Fluorescence dye was mixed in the disinfectant solution. After hand disinfection, standardized fotographs and semi-automated digital processing resulted in quantification of the insufficiently covered hand area. These results were compared with the control group that received the training after the test. In order to provide information on the achieved clinical competence level, the results were compared with the two clinical reference groups. RESULTS: The intervention group remained with 4,99% (SD 2,34) insufficiently covered hand area after the training compared to the control group 7,33% (SD 3,91), p<0,01. There was no significant difference between control group and reference groups: surgeons 9,32% (SD 4,97), scrub nurses 8,46% (SD 4,66). The student intervention group showed results that were significantly better than the clinical references. The methodic mistake remained negligible. In the sub-group analysis, the students with low or medium experience in surgical scrubbing and hand disinfection derived highest benefit from the training, whereas students with no or high experience did benefit less. All participants showed better results on hand palms compared to back of hand areas. DISCUSSION: A single standardized peer-teaching of surgical scrubbing and hand disinfection according to EN1500 is sufficient to improve the measurable coverage of hand area and reduce the disinfection gap by 1/3. In absolute measures, the competence level of experienced surgeons and scrub nurses is achieved or even exceeded. PMID- 23737922 TI - Evaluation of the peer teaching program at the University Children's Hospital Essen - a single center experience. AB - Since 1986 medical students at the University Children's Hospital Essen are trained as peers in a two week intensive course in order to teach basic paediatric examination techniques to younger students. Student peers are employed by the University for one year. Emphasis of the peer teaching program is laid on the mediation of affective and sensomotorical skills e.g. get into contact with parents and children, as well as manual paediatric examination techniques. The aim of this study is to analyse whether student peers are able to impart specific paediatric examination skills as good as an experienced senior paediatric lecturer. 123 students were randomly assigned to a group with either a senior lecturer or a student peer teacher. Following one-hour teaching-sessions in small groups students had to demonstrate the learned skills in a 10 minute modified OSCE. In comparison to a control group consisting of 23 students who never examined a child before, both groups achieved a significantly better result. Medical students taught by student peers almost reached the same examination result as the group taught by paediatric teachers (21,7+/-4,1 vs. 22,6+/-3,6 of 36 points, p=0,203). Especially the part of the OSCE where exclusively practical skills where examined revealed no difference between the two groups (7,44+/-2,15 vs. 7,97+/-1,87 of a maximum of 16 points, p=0,154). The majority of students (77%) evaluated peer teaching as stimulating and helpful. The results of this quantitative teaching study reveal that peer teaching of selected skills can be a useful addition to classical paediatric teaching classes. PMID- 23737923 TI - The future of graduate medical education in Germany - position paper of the Committee on Graduate Medical Education of the Society for Medical Education (GMA). AB - The German graduate medical education system is going through an important phase of changes. Besides the ongoing reform of the national guidelines for graduate medical education (Musterweiterbildungsordnung), other factors like societal and demographic changes, health and research policy reforms also play a central role for the future and competitiveness of graduate medical education. With this position paper, the committee on graduate medical education of the Society for Medical Education (GMA) would like to point out some central questions for this process and support the current discourse. As an interprofessional and interdisciplinary scientific society, the GMA has the resources to contribute in a meaningful way to an evidence-based and future-oriented graduate medical education strategy. In this position paper, we use four key questions with regards to educational goals, quality assurance, teaching competence and policy requirements to address the core issues for the future of graduate medical education in Germany. The GMA sees its task in contributing to the necessary reform processes as the only German speaking scientific society in the field of medical education. PMID- 23737924 TI - GMA: reaching a zenith and taking part in many competitions. PMID- 23737925 TI - A Hierarchical Bayesian Model for Estimating and Inferring Differential Isoform Expression for Multi-Sample RNA-Seq Data. AB - RNA-Seq has drastically changed our ways of studying transcrip-tomes in providing more precise estimates of gene expression, including isoform-specific expression. Most of the available methods for RNA-Seq data focus on one sample at a time. We present in this paper a Poisson-Gamma hierarchical model for multi-sample RNA-Seq data analysis in order to simultaneously estimate isoform-specific expression and to identify differentially expressed iso-forms. Our model has the advantage of borrowing information across all samples in estimating expression levels, which can improve the estimates drastically, particularly for low abundance isoforms. Furthermore, our hierarchical model has the ability to account for overdispersion in the data and also can incorporate sample-specific covariates in the underlying model, which facilitates the isoform-specific differential expression analysis. Simulation studies demonstrated that this Bayesian multi-sample approach can lead to more precise estimates of isoform-specific expression and higher power to detect differential expression by borrowing information across all samples than single sample analysis, especially for isoforms of low abundance. We further illustrated our methods using the RNA-Seq data of 10 Yoruban and 10 Caucasian individuals. PMID- 23737926 TI - Aging from a global perspective, fall narratives and much more .... PMID- 23737927 TI - Do Antidepressants Lower the Prevalence of Lithium-associated Hypernatremia in the Elderly? A Retrospective Study. AB - BACKGROUND: Clinically important measures of lithium-induced nephrogenic diabetes insipidus (NDI) such as hypernatremia have not been well-studied. This is especially relevant for the elderly who, in comparison to younger adults, may become symptomatic and require hospitalization with relatively small elevations in sodium levels. We hypothesized that antidepressant use, which has been associated with the syndrome of inappropriate antidiuretic hormone secretion, has a protective effect against lithium-associated hypernatremia in the elderly. METHODS: Retrospective cohort study of 55 geriatric psychiatry outpatients followed at tertiary-care hospitals. Patients using lithium and antidepressants were compared with those using lithium alone for prevalence rates of hypernatremia during a 15-year observational period. RESULTS: The prevalence of hypernatremia was less in patients who had concurrent use of lithium and antidepressants, as compared to lithium alone 3/35 (8.6%) vs. 8/20 (40%), OR 0.14, p = .011. CONCLUSIONS: Our results suggest that elderly lithium patients are less likely to develop hypernatremia if they are taking antidepressants concurrently. Whether antidepressants may be useful in the prevention of lithium associated hypernatremia should be assessed in future prospective observational or treatment studies. PMID- 23737928 TI - The value of patient narratives in the assessment of older patients presenting with falls. AB - BACKGROUND PURPOSE: Falls are a common and serious health problem experienced by older persons. The perception and interpretation of the fall experience can influence the long-term consequences of the event. In this pilot study, we explored whether there would be additional value in obtaining a patient narrative as part of the assessment of an older person who had fallen. METHODS: We conducted narrative interviews on a convenience sample of five older patients referred to the Calgary Fall Prevention Clinic (CFPC). Phenomena from the narratives were generated using original audio recordings. A focus group of four CFPC health professionals discussed similarities and differences between the narratives and the CFPC assessments conducted on these subjects without access to the narratives. RESULTS: Patient narratives revealed additional information about the person's emotional response to their falls and overall health status, their strengths that could be utilized in implementing a care plan, and what they had done personally to prevent further falls. CONCLUSIONS: Including patient narratives within standard fall-risk assessments could aid in understanding the emotional impact of falls on older patients and how they might respond to interventions. A challenge would be incorporating this within the time restraints of routine clinical practice. PMID- 23737929 TI - Evaluation of older adults hospitalized with a diagnosis of failure to thrive. AB - BACKGROUND: older adults are sometimes hospitalized with the admission diagnosis of failure to thrive (FTT), often because they are not felt safe to be discharged back to their current living arrangement. It is unclear if this diagnosis indicates primarily a social admission or suggests an acute medical deterioration. The objective of this study was to explore the level of acuity and medical investigations commonly conducted among older hospitalized adults with a diagnosis of FTT. METHODS: We conducted a retrospective cohort study at three hospitals in Calgary, Alberta. Data were extracted from the electronic medical records of the 603 admissions of patients 65 years or older with a diagnosis of FTT between January 2010 and January 2011. Markers of medical acuity were evaluated. RESULTS: The vast majority of patients had short hospital stays. Specialist physicians were consulted for 323 cases (54%). Allied health-care professionals were consulted in 151 cases (25%). While in hospital, patients underwent extensive investigations, including CT scans, ultrasounds, and echo cardiograms. Many patients received IV fluids (71%) and IV antibiotics (35%). CONCLUSIONS: The data suggest that acute illnesses, and not social factors, were the primary reason for admission among those given a diagnosis of FTT. PMID- 23737930 TI - Canadian academy of geriatric psychiatry survey of brief cognitive screening instruments. AB - BACKGROUND: The use of brief cognitive screening instruments is essential in the assessment of dementia. The purpose of this study is to determine the frequency of use and perceived characteristics of cognitive screening instruments among Canadian psychogeriatric clinicians. METHODS: Members of the Canadian Academy of Geriatric Psychiatry (CAGP) and attendees to the 2010 Annual Scientific Meeting were asked to complete a computerized survey. This survey assessed the perceived characteristics and frequency of use of 14 instruments. RESULTS: The survey had a 55% response rate, with a total of 155 respondents. The most commonly used instruments are the Clock Drawing Test (CDT), Mini-Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA), and Delayed Word Recall. Effectiveness, ease of administration, and speed of administration were the perceived characteristics of instruments most correlated with frequency of use. CONCLUSIONS: Consistent with previous surveys, a small number of cognitive screening instruments are used by the majority of clinicians. Use of the CDT and the MMSE were comparable. To our knowledge, this is the first survey demonstrating that the MMSE is not the most commonly used tool, and other, newer instruments like the MoCA, are gaining prominence. PMID- 23737931 TI - Understanding and meeting the needs of the older population: a global challenge. AB - BACKGROUND: In the past century, there has been a significant rise in life expectancy in almost all regions of the world, contributing to an increasingly older population. The aging of the population, in conjunction with urbanization and industrialization, has resulted in an important epidemiological transition marked by a widespread increase in the prevalence of chronic diseases and their sequelae. Current trends suggest that the transition will have a greater impact on developing countries compared to developed countries. An adequate response to the transition requires a strong emphasis on primary prevention and adequate resource allocation. PMID- 23737937 TI - Biological clocks in the duodenum and the diurnal regulation of duodenal and plasma serotonin. AB - Serotonin in blood plasma is primarily synthesized in the duodenum, as brain derived serotonin does not cross the blood-brain barrier. Because serotonin in the brain and retina is synthesized under the control of a circadian clock, we sought to determine if a circadian clock in the duodenum regulates serotonin synthesis and release in blood. We examined gene expression in the duodenum of chickens at different times of the day and found that the duodenum rhythmically expresses molecular circadian clock genes and genes controlling serotonin biosynthesis, specifically tryptophan hydroxylase, in a light dark cycle (LD). Analysis of the duodenum and blood plasma showed that the amount of serotonin in the duodenum varies across the day and that serotonin profiles in blood plasma are also rhythmic in LD, but were not rhythmic in constant darkness. Because serotonin in the gut affects duodenal nutrient absorption and gut motility, the control of serotonin production in the duodenum by LD cycles could provide an additional mechanism by which the external environment controls nutrient uptake and digestive function. The diurnal regulation of plasma serotonin may also serve as an additional biochemical signal in the blood encoding time and could be used by target tissues to indicate the status of nutrient absorption. PMID- 23737938 TI - Embryogenesis of the first circulating endothelial cells. AB - Prior to this study, the earliest appearance of circulating endothelial cells in warm-blooded animals was unknown. Time-lapse imaging of germ-line transformed Tie1-YFP reporter quail embryos combined with the endothelial marker antibody QH1 provides definitive evidence for the existence of circulating endothelial cells - from the very beginning of blood flow. Blood-smear counts of circulating cells from Tie1-YFP embryos showed that up to 30% of blood-borne cells are Tie1 positive; though cells expressing low levels of YFP were also positive for benzidine, a hemoglobin stain, suggesting that these cells were differentiating into erythroblasts. Electroporation-based time-lapse experiments, exclusively targeting the intra-embryonic mesoderm were combined with QH1 immunostaining. The latter antibody marks quail endothelial cells. Together the optical data provide conclusive evidence that endothelial cells can enter blood flow from vessels of the embryo proper, as well as from extra-embryonic areas. When Tie1-YFP positive cells and tissues are transplanted to wild type host embryos, fluorescent cells emigrate from such transplants and join host vessels; subsequently a few YFP cells are shed into circulation. These data establish that entering circulation is a commonplace activity of embryonic vascular endothelial cells. We conclude that in the class of vertebrates most closely related to mammals a normal component of primary vasculogenesis is production of endothelial cells that enter circulation from all vessels, both intra- and extra-embryonic. PMID- 23737939 TI - MstX and a putative potassium channel facilitate biofilm formation in Bacillus subtilis. AB - Biofilms constitute the predominant form of microbial life and a potent reservoir for innate antibiotic resistance in systemic infections. In the spore-forming bacterium Bacillus subtilis, the transition from a planktonic to sessile state is mediated by mutually exclusive regulatory pathways controlling the expression of genes required for flagellum or biofilm formation. Here, we identify mstX and yugO as novel regulators of biofilm formation in B. subtilis. We show that expression of mstX and the downstream putative K+ efflux channel, yugO, is necessary for biofilm development in B. subtilis, and that overexpression of mstX induces biofilm assembly. Transcription of the mstX-yugO operon is under the negative regulation of SinR, a transcription factor that governs the switch between planktonic and sessile states. Furthermore, mstX regulates the activity of Spo0A through a positive autoregulatory loop involving KinC, a histidine kinase that is activated by potassium leakage. The addition of potassium abrogated mstX-mediated biofilm formation. Our findings expand the role of Spo0A and potassium homeostasis in the regulation of bacterial development. PMID- 23737940 TI - Effectiveness of zinc supplementation to full term normal infants: a community based double blind, randomized, controlled, clinical trial. AB - The study was aimed to test whether zinc supplementation, if initiated early, can prevent stunting and promote optimum body composition in full term infants. For this, full term pregnant women from low income urban community were enrolled and were followed-up for 24 months postpartum. Body mass index (BMI) was calculated from maternal weight and height that were collected one month after delivery. Infants' weight, and length, head, chest and mid upper arm circumferences and skin fold thicknesses at triceps, biceps and subscapular area were collected at baseline (before randomization) and once in three months up till 24 months. Three hundred and twenty four infants were randomized and allocated to zinc (163) or placebo (161) groups respectively. Supplementation of zinc was initiated from 4 months of age and continued till children attained 18 months. The control (placebo) group of children received riboflavin 0.5 mg/day, whereas the intervention (zinc) group received 5 mg zinc plus riboflavin 0.5 mg/day. When infants were 18 months old, dietary intakes (in 78 children) were calculated by 24 hour diet recall method and hemoglobin, zinc, copper and vitamin A were quantified in blood samples collected from 70 children. The results showed prevalence of undernutrition (body mass index <18.5) in 37% of the mothers. Mean+/-SD calorie consumption and zinc intakes from diets in infants were 590+/ 282.8 Kcal/day and 0.97+/-0.608 mg/day respectively. Multiple linear regression models demonstrated maternal weight as a strong predictor of infants' weight and length at 18 months of age. As expected, diarrhea duration impacted infants' linear growth and weight gain adversely. Zinc supplementation for a mean period of 190 days, starting from 4 months up to 18 months of age, in full term normal infants, consuming an average energy of 590 Kcal/day, had significant effect on the skin fold thicknesses, but not on their linear growth. TRIAL REGISTRATION: Clinical Trail Registration India (CTRI) CTRI/2012/08/002884. PMID- 23737941 TI - Prior storm experience moderates water surge perception and risk. AB - BACKGROUND: How accurately do people perceive extreme water speeds and how does their perception affect perceived risk? Prior research has focused on the characteristics of moving water that can reduce human stability or balance. The current research presents the first experiment on people's perceptions of risk and moving water at different speeds and depths. METHODS: Using a randomized within-person 2 (water depth: 0.45, 0.90 m) *3 (water speed: 0.4, 0.8, 1.2 m/s) experiment, we immersed 76 people in moving water and asked them to estimate water speed and the risk they felt. RESULTS: Multilevel modeling showed that people increasingly overestimated water speeds as actual water speeds increased or as water depth increased. Water speed perceptions mediated the direct positive relationship between actual water speeds and perceptions of risk; the faster the moving water, the greater the perceived risk. Participants' prior experience with rip currents and tropical cyclones moderated the strength of the actual-perceived water speed relationship; consequently, mediation was stronger for people who had experienced no rip currents or fewer storms. CONCLUSIONS: These findings provide a clearer understanding of water speed and risk perception, which may help communicate the risks associated with anticipated floods and tropical cyclones. PMID- 23737942 TI - Interactive effect of herbivory and competition on the invasive plant Mikania micrantha. AB - A considerable number of host-specific biological control agents fail to control invasive plants in the field, and exploring the mechanism underlying this phenomenon is important and helpful for the management of invasive plants. Herbivory and competition are two of the most common biotic stressors encountered by invasive plants in their recipient communities. We predicted that the antagonistic interactive effect between herbivory and competition would weaken the effect of herbivory on invasive plants and result in the failure of herbivory to control invasive plants. To examine this prediction, thus, we conducted an experiment in which both invasive Mikania micrantha and native Coix lacryma-job i were grown together and subjected to herbivory-mimicking defoliation. Both defoliation and competition had significantly negative effects on the growth of the invader. However, the negative effect of 75% respective defoliation on the above- and below-ground biomass of Mikania micrantha was alleviated by presence of Coix lacryma-jobi. The negative effect of competition on the above- and below ground biomass was equally compensated at 25%, 50% and 100% defoliation and overcompensated at 75% defoliation. The interactive effect was antagonistic and dependent on the defoliation intensity, with the maximum effect at 75% defoliation. The antagonistic interaction between defoliation and competition appears to be able to release the invader from competition, thus facilitating the invasiveness of Mikania, a situation that might make herbivory fail to inhibit the growth of invasive Mikania in the invaded community. PMID- 23737943 TI - Biological networks for predicting chemical hepatocarcinogenicity using gene expression data from treated mice and relevance across human and rat species. AB - BACKGROUND: Several groups have employed genomic data from subchronic chemical toxicity studies in rodents (90 days) to derive gene-centric predictors of chronic toxicity and carcinogenicity. Genes are annotated to belong to biological processes or molecular pathways that are mechanistically well understood and are described in public databases. OBJECTIVES: To develop a molecular pathway-based prediction model of long term hepatocarcinogenicity using 90-day gene expression data and to evaluate the performance of this model with respect to both intra species, dose-dependent and cross-species predictions. METHODS: Genome-wide hepatic mRNA expression was retrospectively measured in B6C3F1 mice following subchronic exposure to twenty-six (26) chemicals (10 were positive, 2 equivocal and 14 negative for liver tumors) previously studied by the US National Toxicology Program. Using these data, a pathway-based predictor model for long term liver cancer risk was derived using random forests. The prediction model was independently validated on test sets associated with liver cancer risk obtained from mice, rats and humans. RESULTS: Using 5-fold cross validation, the developed prediction model had reasonable predictive performance with the area under receiver-operator curve (AUC) equal to 0.66. The developed prediction model was then used to extrapolate the results to data associated with rat and human liver cancer. The extrapolated model worked well for both extrapolated species (AUC value of 0.74 for rats and 0.91 for humans). The prediction models implied a balanced interplay between all pathway responses leading to carcinogenicity predictions. CONCLUSIONS: Pathway-based prediction models estimated from sub chronic data hold promise for predicting long-term carcinogenicity and also for its ability to extrapolate results across multiple species. PMID- 23737944 TI - Characterization of Asia 1 sdAb from camels bactrianus (C. bactrianus) and conjugation with quantum dots for imaging FMDV in BHK-21 cells. AB - Foot-and-mouth disease (FMD), caused by FMD virus (FMDV), is a highly contagious viral disease affecting cloven-hoofed animals. Camelids have a unique immunoglobulin profile, with the smallest functional heavy-chain antibodies (sdAb or VHH) naturally devoid of light chains with antigen-binding capacity. We screened and characterized five sdAbs against FMDV by immunized library from C. bactrianus with Asia 1 virus-like particles (VLPs). Three of five recombinant sdAbs were stably expressed in E.coli, remained highly soluble, and were serotype specific for VP1 protein of FMDV Asia 1 by ELISA. These failed to completely neutralize the Asia 1 virus. According to the KD value of binding affinity to three sdAbs, which ranged from 0.44 to 0.71 nm by SPR, sdAb-C6 was selected and conjugated with Zn/CdSe quantum dots (QDs) to form a QDs-C6 probe, which was used to trace and image the subcellular location of FMDV in BHK-21 cells. The results show that FMD virions were observed from 3 h.p.i., and most of virions were distributed on one side of the nucleus in the cytoplasm. We demonstrate the utility of sdAbs as functionalized QDs are powerful tools for FMDV research. PMID- 23737946 TI - Empirical support for DSM-IV schizoaffective disorder: clinical and cognitive validators from a large patient sample. AB - OBJECTIVE: The diagnosis of schizoaffective disorder has long maintained an uncertain status in psychiatric nosology. Studies comparing clinical and biological features of patients with schizoaffective disorder to patients with related disorders [e.g., schizophrenia and bipolar disorder] can provide an evidence base for judging the validity of the diagnostic category. However, because most prior studies of schizoaffective disorder have only evaluated differences between groups at a static timepoint, it is unclear how these disorders may be related when the entire illness course is taken into consideration. METHODS: We ascertained a large cohort [N = 993] of psychiatric patients with a range of psychotic diagnoses including schizophrenia with no history of major affective episodes [SZ-; N = 371], schizophrenia with a superimposed mood syndrome [SZ+; N = 224], schizoaffective disorder [SAD; N = 129] and bipolar I disorder with psychotic features [BPD+; N = 269]. Using cross sectional data we designed key clinical and neurocognitive dependent measures that allowed us to test longitudinal hypotheses about the differences between these diagnostic entities. RESULTS: Large differences between diagnostic groups on several demographic and clinical variables were observed. Most notably, groups differed on a putative measure of cognitive decline. Specifically, the SAD group demonstrated significantly greater post-onset cognitive decline compared to the BP+ group, with the SZ- and SZ+ group both exhibiting levels of decline intermediate to BPD+ and SAD. CONCLUSIONS: These results suggest that schizoaffective disorder may possess distinct features. Contrary to earlier formulations, schizoaffective disorder may be a more severe form of illness. PMID- 23737945 TI - Characterization and pharmacological properties of a novel multifunctional Kunitz inhibitor from Erythrina velutina seeds. AB - Inhibitors of peptidases isolated from leguminous seeds have been studied for their pharmacological properties. The present study focused on purification, biochemical characterization and anti-inflammatory and anticoagulant evaluation of a novel Kunitz trypsin inhibitor from Erythrina velutina seeds (EvTI). Trypsin inhibitors were purified by ammonium sulfate (30-60%), fractionation followed by Trypsin-Sepharose affinity chromatography and reversed-phase high performance liquid chromatography. The purified inhibitor showed molecular mass of 19,210.48 Da. Furthermore, a second isoform with 19,228.16 Da was also observed. The inhibitor that showed highest trypsin specificity and enhanced recovery yield was named EvTI (P2) and was selected for further analysis. The EvTI peptide fragments, generated by trypsin and pepsin digestion, were further analyzed by MALDI-ToF-ToF mass spectrometry, allowing a partial primary structure elucidation. EvTI exhibited inhibitory activity against trypsin with IC50 of 2.2*10(-8) mol.L(-1) and constant inhibition (Ki) of 1.0*10(-8) mol.L(-1), by a non-competitive mechanism. In addition to inhibit the activity of trypsin, EvTI also inhibited factor Xa and neutrophil elastase, but do not inhibit thrombin, chymotrypsin or peptidase 3. EvTI was investigated for its anti-inflammatory and anti-coagulant properties. Firstly, EvTI showed no cytotoxic effect on human peripheral blood cells. Nevertheless, the inhibitor was able to prolong the clotting time in a dose-dependent manner by using in vitro and in vivo models. Due to anti-inflammatory and anticoagulant EvTI properties, two sepsis models were here challenged. EvTI inhibited leukocyte migration and specifically acted by inhibiting TNF-alpha release and stimulating IFN-alpha and IL-12 synthesis. The data presented clearly contribute to a better understanding of the use of Kunitz inhibitors in sepsis as a bioactive agent capable of interfering in blood coagulation and inflammation. PMID- 23737947 TI - Glucanase induces filamentation of the fungal pathogen Candida albicans. AB - Candida albicans is the most common human fungal pathogen. Many organisms, including C. albicans, secrete glucanases under different environmental conditions. Here, we report a novel role for beta-1, 3- glucanase in inducing Candida albicans to form filaments at 22 degrees C and enhancing filamentation at 37 degrees C in nutrient-rich medium. Quorum sensing, the efg1-signaling and cek1 MAP kinase pathways are involved in this process. Our data suggest that the natural antifungal agent beta-glucanase may support morphologic transformation of Candida albicans at a wide range of ambient temperatures. PMID- 23737948 TI - A simple widespread computer help improves nutrition support orders and decreases infection complications in critically ill patients. AB - AIMS: To assess the impact of a simple computer-based decision-support system (computer help) on the quality of nutrition support orders and patients' outcome in Intensive-Care Unit (ICU). METHODS: This quality-improvement study was carried out in a 16-bed medical-surgical ICU in a French university hospital. All consecutive patients who stayed in ICU more than 10 days with non-oral feeding for more than 5 days were retrospectively included during two 12-month periods. Prescriptions of nutrition support were collected and compared to French national guidelines as a quality-improvement process. A computer help was constructed using a simple Excel-sheet (Microsoft(TM)) to guide physicians' prescriptions according to guidelines. This computer help was displayed in computers previously used for medical orders. Physicians were informed but no systematic protocol was implemented. Patients included during the first (control group) and second period (computer help group) were compared for achievement of nutrition goals and ICU outcomes. RESULTS: The control and computer help groups respectively included 71 and 95 patients. Patients' characteristics were not significantly different between groups. In the computer help group, prescriptions achieved significantly more often 80% of nutrition goals for calorie (45% vs. 79% p<0.001) and nitrogen intake (3% vs. 37%, p<0.001). Incidence of nosocomial infections decreased significantly between the two groups (59% vs. 41%, p = 0.03). Mortality did not significantly differ between control (21%) and computer help groups (15%, p = 0.30). CONCLUSIONS: Use of a widespread inexpensive computer help is associated with significant improvements in nutrition support orders and decreased nosocomial infections in ICU patients. This computer-help is provided in electronic supplement. PMID- 23737949 TI - Testing the utility of an integrated analysis of copy number and transcriptomics datasets for inferring gene regulatory relationships. AB - Correlation patterns between matched copy number variation and gene expression data in cancer samples enable the inference of causal gene regulatory relationships by exploiting the natural randomization of such systems. The aim of this study was to test and verify experimentally the accuracy of a causal inference approach based on genomic randomization using esophageal cancer samples. Two candidates with strong regulatory effects emerging from our analysis are components of growth factor receptors, and implicated in cancer development, namely ERBB2 and FGFR2. We tested experimentally two ERBB2 and three FGFR2 regulated interactions predicted by the statistical analysis, all of which were confirmed. We also applied the method in a meta-analysis of 10 cancer datasets and tested 15 of the predicted regulatory interactions experimentally. Three additional predicted ERBB2 regulated interactions were confirmed, as well as interactions regulated by ARPC1A and FANCG. Overall, two thirds of experimentally tested predictions were confirmed. PMID- 23737950 TI - Novel animal defenses against predation: a snail egg neurotoxin combining lectin and pore-forming chains that resembles plant defense and bacteria attack toxins. AB - Although most eggs are intensely predated, the aerial egg clutches from the aquatic snail Pomacea canaliculata have only one reported predator due to unparalleled biochemical defenses. These include two storage-proteins: ovorubin that provides a conspicuous (presumably warning) coloration and has antinutritive and antidigestive properties, and PcPV2 a neurotoxin with lethal effect on rodents. We sequenced PcPV2 and studied whether it was able to withstand the gastrointestinal environment and reach circulation of a potential predator. Capacity to resist digestion was assayed using small-angle X-ray scattering (SAXS), fluorescence spectroscopy and simulated gastrointestinal proteolysis. PcPV2 oligomer is antinutritive, withstanding proteinase digestion and displaying structural stability between pH 4.0-10.0. cDNA sequencing and protein domain search showed that its two subunits share homology with membrane attack complex/perforin (MACPF)-like toxins and tachylectin-like lectins, a previously unknown structure that resembles plant Type-2 ribosome-inactivating proteins and bacterial botulinum toxins. The protomer has therefore a novel AB toxin combination of a MACPF-like chain linked by disulfide bonds to a lectin-like chain, indicating a delivery system for the former. This was further supported by observing PcPV2 binding to glycocalix of enterocytes in vivo and in culture, and by its hemaggutinating, but not hemolytic activity, which suggested an interaction with surface oligosaccharides. PcPV2 is able to get into predator's body as evidenced in rats and mice by the presence of circulating antibodies in response to sublethal oral doses. To our knowledge, a lectin-pore-forming toxin has not been reported before, providing the first evidence of a neurotoxic lectin in animals, and a novel function for ancient and widely distributed proteins. The acquisition of this unique neurotoxic/antinutritive/storage protein may confer the eggs a survival advantage, opening new perspectives in the study of the evolution of animal defensive strategies. PMID- 23737951 TI - Comparison of coral reef ecosystems along a fishing pressure gradient. AB - Three trophic mass-balance models representing coral reef ecosystems along a fishery gradient were compared to evaluate ecosystem effects of fishing. The majority of the biomass estimates came directly from a large-scale visual survey program; therefore, data were collected in the same way for all three models, enhancing comparability. Model outputs-such as net system production, size structure of the community, total throughput, production, consumption, production to-respiration ratio, and Finn's cycling index and mean path length-indicate that the systems around the unpopulated French Frigate Shoals and along the relatively lightly populated Kona Coast of Hawai'i Island are mature, stable systems with a high efficiency in recycling of biomass. In contrast, model results show that the reef system around the most populated island in the State of Hawai'i, O'ahu, is in a transitional state with reduced ecosystem resilience and appears to be shifting to an algal-dominated system. Evaluation of the candidate indicators for fishing pressure showed that indicators at the community level (e.g., total biomass, community size structure, trophic level of the community) were most robust (i.e., showed the clearest trend) and that multiple indicators are necessary to identify fishing perturbations. These indicators could be used as performance indicators when compared to a baseline for management purposes. This study shows that ecosystem models can be valuable tools in identification of the system state in terms of complexity, stability, and resilience and, therefore, can complement biological metrics currently used by monitoring programs as indicators for coral reef status. Moreover, ecosystem models can improve our understanding of a system's internal structure that can be used to support management in identification of approaches to reverse unfavorable states. PMID- 23737952 TI - Terminal platelet production is regulated by von Willebrand factor. AB - It is established that proplatelets are formed from mature megakaryocytes (MK) as intermediates before platelet production. Recently, the presence of proplatelets was described in blood incubated in static conditions. We have previously demonstrated that platelet and proplatelet formation is upregulated by MK exposure to high shear rates (1800 s(-1)) on immobilized von Willebrand factor (VWF). The purpose of the present study was to investigate whether VWF is involved in the regulation of terminal platelet production in blood. To this end, Vwf (-/-) mice, a model of severe von Willebrand disease, were used to create a situation in which blood cells circulate in a vascular tree that is completely devoid of VWF. Murine platelets were isolated from Vwf (-/-) and Vwf (+/+) blood, exposed to VWF at 1800 s(-1) in a microfluidic platform, and examined by means of videomicroscopy, as well as fluorescence and activation studies. Proplatelets became visible within 5 minutes, representing 38% of all platelets after 12 minutes and 46% after 28 min. The proportion of proplatelets was 1.8-fold higher in blood from Vwf(-/-) mice than from Vwf(+/+) mice, suggesting a role of VWF in vivo. Fragmentation of these proplatelets into smaller discoid platelets was also observed in real-time. Platelets remained fully activatable by thrombin. Compensation of plasmatic VWF following hydrodynamic gene transfer in Vwf(-/-) mice reduced the percentage of proplatelets to wild-type levels. A thrombocytopenic mouse model was studied in the flow system, 7 days after a single 5-FU injection. Compared to untreated mouse blood, a 2-fold increase in the percentage of proplatelets was detected following exposure to 1800 s(-1) on VWF of samples from mice treated with 5-FU. In conclusion, VWF and shear stress together appear to upregulate proplatelet reorganization and platelet formation. This suggests a new function for VWF in vivo as regulator of bloodstream thrombopoiesis. PMID- 23737954 TI - Targeted exome sequencing identified novel USH2A mutations in Usher syndrome families. AB - Usher syndrome (USH) is a leading cause of deaf-blindness in autosomal recessive trait. Phenotypic and genetic heterogeneities in USH make molecular diagnosis much difficult. This is a pilot study aiming to develop an approach based on next generation sequencing to determine the genetic defects in patients with USH or allied diseases precisely and effectively. Eight affected patients and twelve unaffected relatives from five unrelated Chinese USH families, including 2 pseudo dominant ones, were recruited. A total of 144 known genes of inherited retinal diseases were selected for deep exome resequencing. Through systematic data analysis using established bioinformatics pipeline and segregation analysis, a number of genetic variants were released. Eleven mutations, eight of them were novel, in the USH2A gene were identified. Biparental mutations in USH2A were revealed in 2 families with pseudo-dominant inheritance. A proband was found to have triple mutations, two of them were supposed to locate in the same chromosome. In conclusion, this study revealed the genetic defects in the USH2A gene and demonstrated the robustness of targeted exome sequencing to precisely and rapidly determine genetic defects. The methodology provides a reliable strategy for routine gene diagnosis of USH. PMID- 23737953 TI - Increases in the risk of cognitive impairment and alterations of cerebral beta amyloid metabolism in mouse model of heart failure. AB - Epidemiological and clinico-pathological studies indicate a causal relationship between heart disease and Alzheimer's disease (AD). To learn whether heart disease causes an onset of AD, mice with myocardial infarction (MI) and congestive heart failure (HF) were used to test neuropsychiatric and cognitive behaviors as well as for measurements of AD related protein markers. To this end, adult mice were subjected to ligation of left anterior descending artery (LAD) and about two weeks later high-frequency echocardiography was performed to exam the resulting cardiac structure and function. Three months after successful induction of chronic heart failure (CHF) these mice showed an impairment of learning in the Morris Water Maze task. In addition, the expression of selected molecules, which are involved in beta-amyloid metabolism, apoptosis and inflammation on the level of gene transcription and translation, was altered in CHF mice. Our findings provide a plausible explanation that CHF increases the risk of cognitive impairments and alters cerebral beta-amyloid metabolism. In addition, our data indicate that the cerebral compensatory mechanisms in response to CHF are brain area and gender specific. PMID- 23737955 TI - Effectiveness of stereotactic body radiotherapy for hepatocellular carcinoma with portal vein and/or inferior vena cava tumor thrombosis. AB - BACKGROUND: To report the feasibility, efficacy, and toxicity of stereotactic body radiotherapy (SBRT) for the treatment of portal vein tumor thrombosis (PVTT) and/or inferior vena cava tumor thrombosis (IVCTT) in patients with advanced hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Forty-one patients treated with SBRT using volumetric modulated arc therapy (VMAT) for HCC with PVTT/IVCTT between July 2010 and May 2012 were analyzed. Of these, 33 had PVTT and 8 had IVCTT. SBRT was designed to target the tumor thrombosis and deliver a median total dose of 36 Gy (range, 30-48 Gy) in six fractions during two weeks. RESULTS: The median follow-up was 10.0 months. At the time of analysis, 15 (36.6%) achieved complete response, 16 (39.0%) achieved partial response, 7 (17.1%) patients were stable, and three (7.3%) patients showed progressive disease. No treatment-related Grade 4/5 toxicity was seen within three months after SBRT. One patient had Grade 3 elevation of bilirubin. The one-year overall survival rate was 50.3%, with a median survival of 13.0 months. The only independent predictive factor associated with better survival was response to radiotherapy. CONCLUSIONS: VMAT-based SBRT is a safe and effective treatment option for PVTT/IVCTT in HCC. Prospective randomized controlled trials are warranted to validate the role of SBRT in these patients. PMID- 23737957 TI - A novel benzothiazole derivative YLT322 induces apoptosis via the mitochondrial apoptosis pathway in vitro with anti-tumor activity in solid malignancies. AB - Benzothiazole derivatives are known for various biological activities, and their potency in cancer therapy has received considerable attention in recent years. YLT322, a novel synthesized benzothiazole derivative, exhibits potent anti-tumor activity via inducing apoptosis both in vitro and in vivo. In this study, we found that YLT322 showed growth inhibition against a broad spectrum of human cancer cells and induced apoptosis of HepG2 cells in a dose- and time-dependent manner. The occurrence of its apoptosis was associated with activation of caspases-3 and -9, but not caspase-8. YLT322 increased the expression of Bax, decreased the expression of Bcl-2, and induced the release of cytochrome c which activates the mitochondrial apoptotic pathway. The down-regulation of phosphorylated p42/44 MAPK and phosphorylated Akt was also observed. Moreover, YLT322 suppressed the growth of established tumors in xenograft models in mice without obvious side effects. Histological and immunohistochemical analyses revealed an increase in TUNEL and caspase-3-positive cells and a decrease in Ki67 positive cells upon YLT322. These results suggest that YLT322 may be a potential candidate for cancer therapy. PMID- 23737956 TI - Ursolic acid simultaneously targets multiple signaling pathways to suppress proliferation and induce apoptosis in colon cancer cells. AB - Ursolic acid (UA), a natural pentacyclic triterpenoid carboxylic acid distributed in medical herbs, exerts antitumor effects and is emerging as a promising compound for cancer prevention and therapy, but its excise mechanisms of action in colon cancer cells remains largely unknown. Here, we identified the molecular mechanisms by which UA inhibited cell proliferation and induced apoptosis in human colon cancer SW480 and LoVo cells. Treatment with UA led to significant inhibitions in cell viability and clone formation and changes in cell morphology and spreading. UA also suppressed colon cancer cell migration by inhibiting MMP9 and upregulating CDH1 expression. Further studies showed that UA inhibited the phosphorylation of Akt and ERK proteins. Pretreatment with an Akt or ERK-specific inhibitor considerably abrogated the proliferation inhibition by UA. UA also significantly inhibited colon cancer cell COX-2 expression and PGE2 production. Pretreatment with a COX-2 inhibitor (celecoxib) abrogated the UA-induced cell proliferation. Moreover, we found that UA effectively promoted NF-kappaB and p300 translocation from cell nuclei to cytoplasm, and attenuated the p300-mediated acetylation of NF-kappaB and CREB2. Pretreatment with a p300 inhibitor (roscovitine) abrogated the UA-induced cell proliferation, which is reversed by p300 overexpression. Furthermore, UA treatment induced colon cancer cell apoptosis, increased the cleavage of PARP, caspase-3 and 9, and trigged the release of cytochrome c from mitochondrial inter-membrane space into cytosol. These results indicate that UA inhibits cell proliferation and induces apoptosis in colon cancer cells through simultaneous modulation of the multiple signaling pathways such as MMP9/CDH1, Akt/ERK, COX-2/PGE2, p300/NF-kappaB/CREB2, and cytochrome c/caspase pathways. PMID- 23737958 TI - An integrative proteomics and interaction network-based classifier for prostate cancer diagnosis. AB - AIM: Early diagnosis of prostate cancer (PCa), which is a clinically heterogeneous-multifocal disease, is essential to improve the prognosis of patients. However, published PCa diagnostic markers share little overlap and are poorly validated using independent data. Therefore, we here developed an integrative proteomics and interaction network-based classifier by combining the differential protein expression with topological features of human protein interaction networks to enhance the ability of PCa diagnosis. METHODS AND RESULTS: By two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with MS using PCa and adjacent benign tissues of prostate, a total of 60 proteins with the differential expression in PCa tissues were identified as the candidate markers. Then, their networks were analyzed by GeneGO Meta-Core software and three hub proteins (PTEN, SFPQ and HDAC1) were chosen. After that, a PCa diagnostic classifier was constructed by support vector machine (SVM) modeling based on the microarray gene expression data of the genes which encode the hub proteins mentioned above. Validations of diagnostic performance showed that this classifier had high predictive accuracy (85.96~90.18%) and area under ROC curve (approximating 1.0). Furthermore, the clinical significance of PTEN, SFPQ and HDAC1 proteins in PCa was validated by both ELISA and immunohistochemistry analyses. More interestingly, PTEN protein was identified as an independent prognostic marker for biochemical recurrence-free survival in PCa patients according to the multivariate analysis by Cox Regression. CONCLUSIONS: Our data indicated that the integrative proteomics and interaction network-based classifier which combines the differential protein expression and topological features of human protein interaction network may be a powerful tool for the diagnosis of PCa. We also identified PTEN protein as a novel prognostic marker for biochemical recurrence-free survival in PCa patients. PMID- 23737959 TI - Systematics and molecular phylogeny of the family oscarellidae (homoscleromorpha) with description of two new oscarella species. AB - The family Oscarellidae is one of the two families in the class Homoscleromorpha (phylum Porifera) and is characterized by the absence of a skeleton and the presence of a specific mitochondrial gene, tatC. This family currently encompasses sponges in two genera: Oscarella with 17 described species and Pseudocorticium with one described species. Although sponges in this group are relatively well-studied, phylogenetic relationships among members of Oscarellidae and the validity of genus Pseudocorticium remain open questions. Here we present a phylogenetic analysis of Oscarellidae using four markers (18S rDNA, 28S rDNA, atp6, tatC), and argue that it should become a mono-generic family, with Pseudocorticium being synonymized with Oscarella, and with the transfer of Pseudocorticium jarrei to Oscarella jarrei. We show that the genus Oscarella can be subdivided into four clades, each of which is supported by either a small number of morphological characters or by molecular synapomorphies. In addition, we describe two new species of Oscarella from Norwegian fjords: O. bergenensis sp. nov. and O. nicolae sp. nov., and we compare their morphology, anatomy, and cytology with other species in this genus. Internal anatomical characters are similar in both species, but details of external morphology and particularly of cytological characters provide diagnostic features. Our study also confirms that O. lobularis and O. tuberculata are two distinct polychromic sibling species. This study highlights the difficulties of species identification in skeleton-less sponges and, more generally, in groups where morphological characters are scarce. Adopting a multi-marker approach is thus highly suitable for these groups. PMID- 23737960 TI - Increased crown-to-implant ratio may not be a risk factor for dental implant failure under appropriate plaque control. AB - OBJECTIVE: The aim of this study was to evaluate whether increased crown-to implant (C/I) ratio influences implant stability or not under proper healthy control of peri-implant mucosa. The hypothesis of this study is that implant stability can be maintained despite High C/I, under appropriate plaque control. MATERIALS AND METHODS: Five male Beagle-Labrador hybrid dogs (2 years old) were used. Their bilateral mandibular premolar extraction was performed. After allowing 12 weeks for bone healing, 3 types of vertical marginal bone loss were simultaneously prepared randomly. Then, 30 titanium implants were placed in the edentulous areas and defined as High C/I, Mid C/I and Low C/I groups. This time point was designated as the baseline (0 Week). Twelve weeks after implant placement, metal superstructures were cemented to the implants and an occlusal plate was set at the opposite side. At the same time, Calcein green was injected for remodeling evaluation. Implants were loaded by feeding the dogs a hard pellet diet. Tooth brushing was performed 5 days per week during the study to maintain healthy peri-implant mucosa. Twenty-four weeks following implant placement, the interface structure was evaluated clinically, radiologically, and histologically. RESULT: Implant stability quotient (ISQ) increased with time in all 3 groups, without any significant correlation with the C/I value (p >0.05). Moreover, mean marginal bone loss adjacent around implants in all 3 groups ranged between 0.11 and 0.19 mm, with no significant difference (p >0.05). Many fluorescence-labeled bones are shown in the High C/I group. It is considered that high remodeling activity prevent marginal bone loss in the High C/I group and this may provide favorable implant stability under proper plaque control. CONCLUSION: These findings suggest that increased C/I may not be a risk factor for implant failure if the peri-implant mucosa is kept healthy, as was the case in this animal model. PMID- 23737961 TI - Inhibition of TDP-43 aggregation by nucleic acid binding. AB - The aggregation of TAR DNA-binding protein (TDP-43) has been shown as a hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) since 2006. While evidence has suggested that mutation or truncation in TDP-43 influences its aggregation process, nevertheless, the correlation between the TDP-43 aggregation propensity and its binding substrates has not been fully established in TDP-43 proteinopathy. To address this question, we have established a platform based on the in vitro protein expression system to evaluate the solubility change of TDP-43 in response to factors such as nucleotide binding and temperature. Our results suggest that the solubility of TDP-43 is largely influenced by its cognate single-strand DNA (ssDNA) or RNA (ssRNA) rather than hnRNP, which is known to associate with TDP-43 C-terminus. The direct interaction between the refolded TDP-43, purified from E.coli, and ssDNA were further characterized by Circular Dichroism (CD) as well as turbidity and filter binding assay. In addition, ssDNA or ssRNA failed to prevent the aggregation of the F147L/F149L double mutant or truncated TDP-43 (TDP208-414). Consistently, these two mutants form aggregates, in contrast with the wild-type TDP-43, when expressed in Neuro2a cells. Our results demonstrate an intimate relationship between the solubility of TDP-43 and its DNA or RNA binding affinity, which may shed light on the role of TDP-43 in ALS and FTLD. PMID- 23737962 TI - The effects of cadmium exposure on the oxidative state and cell death in the gill of freshwater crab Sinopotamon henanense. AB - We studied here the short-term toxicity effects of Cd on the oxidative state and cell death in the gill of freshwater crab Sinopotamon henanense. Crabs were exposed to Cd that resulted in Cd accumulation and a significant increase in the metallothionein (MT) level in the gill, but MT level increased disproportionally compared to the Cd accumulation with an extension of exposure time. Significant changes in the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were observed. An increase in the levels of reactive oxygen species (ROS) and lipid peroxidation (LPO) was detected that will cause oxidative stress. Histological abnormalities of the gills were discovered, including the expansion of gill cavity, a decrease in the numbers of connection of the upper and the lower of the gill lamellae and epithelial cells, and an increase in the number of hemocytes. The results of a TUNEL test and transmission electron microscope (TEM) showed that more gill cells had apoptotic characteristics after 48 h of Cd treatment compared to the control, but epithelial cell necrosis and inflammatory response appeared only after 72 h. It was concluded that (1) Cd induced the ROS production and accumulation through inhibiting antioxidant enzyme activities and exceeding the saturation values of MT binging; (2) Cd led to lipid peroxidation and histopathological alternations; and (3) Cd induced apoptotic response at short time exposure, followed by necrotic features and inflammatory reaction after longer time exposure. PMID- 23737963 TI - Iron supplementation in suckling piglets: how to correct iron deficiency anemia without affecting plasma hepcidin levels. AB - The aim of the study was to establish an optimized protocol of iron dextran administration to pig neonates, which better meets the iron demand for erythropoiesis. Here, we monitored development of red blood cell indices, plasma iron parameters during a 28-day period after birth (till the weaning), following intramuscular administration of different concentrations of iron dextran to suckling piglets. To better assess the iron status we developed a novel mass spectrometry assay to quantify pig plasma levels of the iron-regulatory peptide hormone hepcidin-25. This hormone is predominantly secreted by the liver and acts as a negative regulator of iron absorption and reutilization. The routinely used protocol with high amount of iron resulted in the recovery of piglets from iron deficiency but also in strongly elevated plasma hepcidin-25 levels. A similar protocol with reduced amounts of iron improved hematological status of piglets to the same level while plasma hepcidin-25 levels remained low. These data show that plasma hepcidin-25 levels can guide optimal dosing of iron treatment and pave the way for mixed supplementation of piglets starting with intramuscular injection of iron dextran followed by dietary supplementation, which could be efficient under condition of very low plasma hepcidin-25 level. PMID- 23737964 TI - 16 kDa heat shock protein from heat-inactivated Mycobacterium tuberculosis is a homodimer - suitability for diagnostic applications with specific llama VHH monoclonals. AB - BACKGROUND: The 16 kDa heat shock protein (HSP) is an immuno-dominant antigen, used in diagnosis of infectious Mycobacterium tuberculosis (M.tb.) causing tuberculosis (TB). Its use in serum-based diagnostics is limited, but for the direct identification of M.tb. bacteria in sputum or cultures it may represent a useful tool. Recently, a broad set of twelve 16 kDa specific heavy chain llama antibodies (VHH) has been isolated, and their utility for diagnostic applications was explored. METHODOLOGY/PRINCIPAL FINDINGS: To identify the epitopes recognized by the nine (randomly selected from a set of twelve 16 kDa specific VHH antibodies) distinct VHH antibodies, 14 overlapping linear epitopes (each 20 amino acid long) were characterized using direct and sandwich ELISA techniques. Seven out of 14 epitopes were recognized by 8 out of 9 VHH antibodies. The two highest affinity binders B-F10 and A-23 were found to bind distinct epitopes. Sandwich ELISA and SPR experiments showed that only B-F10 was suitable as secondary antibody with both B-F10 and A-23 as anchoring antibodies. To explain this behavior, the epitopes were matched to the putative 3D structure model. Electrospray ionization time-of-flight mass spectrometry and size exclusion chromatography were used to determine the higher order conformation. A homodimer model best explained the differential immunological reactivity of A-23 and B-F10 against heat-treated M.tb. lysates. CONCLUSIONS/SIGNIFICANCE: The concentrations of secreted antigens of M.tb. in sputum are too low for immunological detection and existing kits are only used for identifying M.tb. in cultures. Here we describe how specific combinations of VHH domains could be used to detect the intracellular HSP antigen. Linked to methods of pre-concentrating M.tb. cells prior to lysis, HSP detection may enable the development of protein-based diagnostics of sputum samples and earlier diagnosis of diseases. PMID- 23737965 TI - Particle-cell contact enhances antibacterial activity of silver nanoparticles. AB - BACKGROUND: It is generally accepted that antibacterial properties of Ag nanoparticles (AgNPs) are dictated by their dissolved fraction. However, dissolution-based concept alone does not fully explain the toxic potency of nanoparticulate silver compared to silver ions. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we demonstrated that the direct contact between bacterial cell and AgNPs' surface enhanced the toxicity of nanosilver. More specifically, cell-NP contact increased the cellular uptake of particle-associated Ag ions - the single and ultimate cause of toxicity. To prove that, we evaluated the toxicity of three different AgNPs (uncoated, PVP-coated and protein-coated) to six bacterial strains: Gram-negative Escherichia coli, Pseudomonas fluorescens, P. putida and P. aeruginosa and Gram-positive Bacillus subtilis and Staphylococcus aureus. While the toxicity of AgNO3 to these bacteria varied only slightly (the 4-h EC50 ranged from 0.3 to 1.2 mg Ag/l), the 4-h EC50 values of protein-coated AgNPs for various bacterial strains differed remarkably, from 0.35 to 46 mg Ag/l. By systematically comparing the intracellular and extracellular free Ag(+) liberated from AgNPs, we demonstrated that not only extracellular dissolution in the bacterial test environment but also additional dissolution taking place at the particle-cell interface played an essential role in antibacterial action of AgNPs. The role of the NP-cell contact in dictating the antibacterial activity of Ag-NPs was additionally proven by the following observations: (i) separation of bacterial cells from AgNPs by particle-impermeable membrane (cut-off 20 kDa, ~4 nm) significantly reduced the toxicity of AgNPs and (ii) P. aeruginosa cells which tended to attach onto AgNPs, exhibited the highest sensitivity to all forms of nanoparticulate Ag. CONCLUSIONS/SIGNIFICANCE: Our findings provide new insights into the mode of antibacterial action of nanosilver and explain some discrepancies in this field, showing that "Ag-ion" and "particle-specific" mechanisms are not controversial but, rather, are two faces of the same coin. PMID- 23737966 TI - DSG3 facilitates cancer cell growth and invasion through the DSG3-plakoglobin TCF/LEF-Myc/cyclin D1/MMP signaling pathway. AB - Desmoglein 3 (DSG3) is a component of the desmosome, which confers strong cell cell adhesion. Previously, an oncogenic function of DSG3 has been found in head neck cancer (HNC). Here, we investigated how this molecule contributes to the malignant phenotype. Because DSG3 is associated with plakoglobin, we examined whether these phenotypic alterations were mediated through the plakoglobin molecule. Immunoprecipitation and immunofluorescence staining revealed that DSG3 silencing disrupted its interaction with plakoglobin and induced plakoglobin translocation from the cytoplasm to the nucleus. Knockdown of DSG3 significantly increased the interaction of plakoglobin with the transcriptional factor TCF and suppressed the TCF/LEF transcriptional activity. These effects further conferred to reduced expression of the TCF/LEF downstream target genes, including c-myc, cyclin D1, and MMP-7. Functional analyses showed that DSG3 silencing reduced cell growth and arrested cells at G0/G1 phase. Besides, cell migration and invasion abilities were also decreased. These cellular results were confirmed using tumor xenografts in mice, as DSG3 silencing led to the suppressed tumor growth, plakoglobin translocation and reduced expression of TCF/LEF target genes in tumors. Therefore, our study shows that the desmosomal protein DSG3 additionally functions to regulate malignant phenotypes via nuclear signaling. In conclusion, we found that DSG3 functions as an oncogene and facilitates cancer growth and invasion in HNC cells through the DSG3-plakoglobin-TCF/LEF pathway. PMID- 23737967 TI - HLA-DRB1 genotypes and the risk of developing anti citrullinated protein antibody (ACPA) positive rheumatoid arthritis. AB - OBJECTIVE: To provide a table indicating the risk for developing anti citrullinated protein antibody (ACPA) positive rheumatoid arthritis (RA) according to one's HLA-DRB1 genotype. METHODS: We HLA-DRB1 genotyped 857 patients with ACPA positive RA and 2178 controls from South Eastern and Eastern France and calculated Odds Ratios (OR) for developing RA for 106 of 132 possible genotypes accounting for 97% of subjects. RESULTS: HLA-DRB1 genotypic ORs for developing ACPA positive RA range from 28 to 0.19. HLA-DRB1 genotypes with HLA-DRB1*04SE (HLA-DRB1*0404, HLA-DRB1*0405, HLA-DRB1*0408), HLA-DRB1*04?01, HLA-DRB1*01 are usually associated with high risk for developing RA. The second HLA-DRB1 allele in genotype somewhat modulates shared epitope associated risk. We did not identify any absolutely protective allele. Neither the Reviron, nor the du Montcel models accurately explains our data which are compatible with the shared epitope hypothesis and suggest a dosage effect among shared epitope positive HLA DRB1 alleles, double dose genotypes carrying higher ORs than single dose genotypes. CONCLUSION: HLA-DRB1 genotypic risk for developing ACPA positive RA is influenced by both HLA-DRB1 alleles in genotype. We provide an HLA-DRB1 genotypic risk table for ACPA positive RA. PMID- 23737968 TI - Gender disparity between cutaneous and non-cutaneous manifestations of Lyme borreliosis. AB - Cutaneous manifestations of Lyme borreliosis in Europe include erythema migrans (EM) and acrodermatitis chronica atrophicans (ACA); the most common non-cutaneous manifestations are Lyme neuroborreliosis (LNB) and Lyme arthritis. The purpose of this study was to evaluate the gender distribution of patients with these clinical manifestations of Lyme borreliosis. Data on gender were obtained from the clinical records of patients with Lyme borreliosis aged >=15 years who had been evaluated at the University Medical Center Ljubljana, Ljubljana, Slovenia. Among 10,539 patients diagnosed with EM, 6,245 (59.3%) were female and among 506 ACA patients 347 (68.6%) were female. In contrast, among the 60 patients with Lyme arthritis only 15 (25%) were female (p<0.0001 for the comparison of gender with EM or ACA) and among the 130 patients with LNB only 51 (39.2%) were females (p<0.0001for the comparison of gender with EM or ACA). Although the proportion that was female in the LNB group was greater than that of patients with Lyme arthritis, this difference did not reach statistical significance (p = 0.10). Although older individuals are more likely to be female in the general Slovenian population, the age of patients with cutaneous versus non-cutaneous manifestations was not the explanation for the observed differences in gender. In conclusion, patients with cutaneous manifestations of Lyme borreliosis were predominantly female, whereas those with non-cutaneous manifestations were predominantly male. This provocative finding is unexplained but may have direct relevance to the pathogenesis of Lyme borreliosis. PMID- 23737969 TI - Pharmacogenetic study of deferasirox, an iron chelating agent. AB - Transfusion-associated iron overload induces systemic toxicity. Deferasirox, a convenient long acting oral agent, has recently been introduced in clinical practice with a promising efficacy. But there are some patients who experience drug-related toxicities and cannot tolerate it. To investigate effect of genetic variations on the toxicities and find optimal target population, we analyzed the genetic polymorphisms of UDP-glucuronosyltransferase 1A (UGT1A) subfamily, multi drug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). A total of 20 functional genetic polymorphisms were analyzed in 98 patients who received deferasirox to reduce transfusion-induced iron overload. We retrospectively reviewed the medical records to find out the drug-related toxicities. Fifteen (15.3%) patients developed hepatotoxicity. Patients without wild-type allele carrying two MRP2 haplotypes containing -1774 del and/or -24T were at increased risk of developing hepatotoxicity compared to patients with the wild-type allele on multivariate analysis (OR = 7.17, 95% CI = 1.79-28.67, P = 0.005). Creatinine elevation was observed in 9 patients (9.2%). Body weight >=40 kg and homozygosity for UGT1A1*6 were risk factors of creatinine elevation (OR = 8.48, 95% CI = 1.7-43.57, P = 0.010 and OR = 14.17, 95% CI = 1.34-150.35, P = 0.028). Our results indicate that functional genetic variants of enzymes to metabolize and transport deferasirox are associated with drug-related toxicities. Further studies are warranted to confirm the results as the pharmacogenetic biomarkers of deferasirox. PMID- 23737970 TI - Reverse engineering of modified genes by Bayesian network analysis defines molecular determinants critical to the development of glioblastoma. AB - In this study we have identified key genes that are critical in development of astrocytic tumors. Meta-analysis of microarray studies which compared normal tissue to astrocytoma revealed a set of 646 differentially expressed genes in the majority of astrocytoma. Reverse engineering of these 646 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I IV), and 'key genes' within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. All of these genes were up-regulated, except MPP2 (down regulated). These 10 genes were able to predict tumor status with 96-100% confidence when using logistic regression, cross validation, and the support vector machine analysis. Markov genes interact with NFkbeta, ERK, MAPK, VEGF, growth hormone and collagen to produce a network whose top biological functions are cancer, neurological disease, and cellular movement. Three of the 10 genes - EGFR, COL4A1, and CDK4, in particular, seemed to be potential 'hubs of activity'. Modified expression of these 10 Markov Blanket genes increases lifetime risk of developing glioblastoma compared to the normal population. The glioblastoma risk estimates were dramatically increased with joint effects of 4 or more than 4 Markov Blanket genes. Joint interaction effects of 4, 5, 6, 7, 8, 9 or 10 Markov Blanket genes produced 9, 13, 20.9, 26.7, 52.8, 53.2, 78.1 or 85.9%, respectively, increase in lifetime risk of developing glioblastoma compared to normal population. In summary, it appears that modified expression of several 'key genes' may be required for the development of glioblastoma. Further studies are needed to validate these 'key genes' as useful tools for early detection and novel therapeutic options for these tumors. PMID- 23737972 TI - Predicting in-hospital maternal mortality in Senegal and Mali. AB - OBJECTIVE: We sought to identify predictors of in-hospital maternal mortality among women attending referral hospitals in Mali and Senegal. METHODS: We conducted a cross-sectional epidemiological survey using data from a cluster randomized controlled trial (QUARITE trial) in 46 referral hospitals in Mali and Senegal, during the pre-intervention period of the trial (from October 1st 2007 to October 1st 2008). We included 89,518 women who delivered in the 46 hospitals during this period. Data were collected on women's characteristics, obstetric complications, and vital status until the hospital discharge. We developed a tree like classification rule (classification rule) to identify patient subgroups at high risk of maternal in-hospital mortality. RESULTS: Our analyses confirm that patients with uterine rupture, hemorrhage or prolonged/obstructed labor, and those who have an emergency ante-partum cesarean delivery have an increased risk of in-hospital mortality, especially if they are referred from another health facility. Twenty relevant patterns, based on fourteen predictors variables, are used to predict in-hospital maternal mortality with 81.41% sensitivity (95% CI = [77.12%-87.70%]) and 81.6% specificity (95% CI = [81.16%-82.02%]). CONCLUSION: The proposed class association rule method will help health care professionals in referral hospitals in Mali and Senegal to identify mothers at high risk of in hospital death, and can provide scientific evidence on which to base their decisions to manage patients delivering in their health facilities. PMID- 23737971 TI - A new Mint1 isoform, but not the conventional Mint1, interacts with the small GTPase Rab6. AB - Small GTPases of the Rab family are important regulators of a large variety of different cellular functions such as membrane organization and vesicle trafficking. They have been shown to play a role in several human diseases. One prominent member, Rab6, is thought to be involved in the development of Alzheimer's Disease, the most prevalent mental disorder worldwide. Previous studies have shown that Rab6 impairs the processing of the amyloid precursor protein (APP), which is cleaved to beta-amyloid in brains of patients suffering from Alzheimer's Disease. Additionally, all three members of the Mint adaptor family are implied to participate in the amyloidogenic pathway. Here, we report the identification of a new Mint1 isoform in a yeast two-hybrid screening, Mint1 826, which lacks an eleven amino acid (aa) sequence in the conserved C-terminal region. Mint1 826, but not the conventional Mint1, interacts with Rab6 via the PTB domain. This interaction is nucleotide-dependent, Rab6-specific and influences the subcellular localization of Mint1 826. We were able to detect and sequence a corresponding proteolytic peptide derived from cellular Mint1 826 by mass spectrometry proving the absence of aa 495-505 and could show that the deletion does not influence the ability of this adaptor protein to interact with APP. Taking into account that APP interacts and co-localizes with Mint1 826 and is transported in Rab6 positive vesicles, our data suggest that Mint1 826 bridges APP to the small GTPase at distinct cellular sorting points, establishing Mint1 826 as an important player in regulation of APP trafficking and processing. PMID- 23737973 TI - Uncontrolled donors with controlled reperfusion after sixty minutes of asystole: a novel reliable resource for kidney transplantation. AB - BACKGROUND: Organ shortage leads to usage of kidneys from donors after sudden cardiac death, or uncontrolled donors (UDCD). Ischemic injury due to cessation of circulation remains a crucial problem that limits adoption of UDCD. Our clinical investigation was to determine the applicability of kidneys obtained from UDCD and resuscitated by extracorporeal perfusion in situ after 60 minutes of asystole. METHODS: In 2009-2011, organ procurement service of St. Petersburg, obtained kidneys from 22 UDCD with critically expanded warm ischemic time (WIT). No patients were considered as potential organ donors initially. All donors died after sudden irreversible cardiac arrest. Mean WIT was 61.4+/-4.5 minutes. For kidney resuscitation, the subnormothermic extracorporeal abdominal perfusion with thrombolytics and leukocyte depletion was employed. Grafts were transplanted into 44 recipients. The outcomes of transplantation of resuscitated kidneys were compared to outcomes of 87 KTx from 74 brain death donors (BDDs). RESULTS: Immediate functioning of kidney grafts was observed in 21 of the 44 recipients, with no cases of primary non function. By the end of the first post-transplant year there was an acute rejection rate of 9.1% (4 episodes of rejection) in the UDCD group versus 14.2% (13 episodes of rejection) in the BDD group. The actual 1 year graft survival rate was 95.5% (n = 42) in UDCD group, and 94.6% (n = 87) in BDD group. Creatinine levels at the end of the first year were 0.116+/-0.008 and 0.115+/-0.004 mmol/l in UDCD and BDD groups, respectively. CONCLUSIONS: UDCD kidneys with critically expanded WIT could be succefully used for transplantation if in situ organ "resuscitation" perfusion is included into procurement protocol. The results of 1-year follow-up meet the generally accepted criteria for graft survival and function. In situ reperfusion may exert a therapeutic effect on grafts before procurement. This approach could substantially expand the organ donors' pool. PMID- 23737974 TI - Transcriptome analysis in chicken cecal epithelia upon infection by Eimeria tenella in vivo. AB - Coccidiosis, caused by various Eimeria species, is a major parasitic disease in chickens. However, our understanding on how chickens respond to coccidian infection is highly limited at both molecular and cellular levels. The present study employed the Affymetrix chicken genome array and performed transcriptome analysis on chicken cecal epithelia in response to infection for 4.5 days in vivo by the cecal-specific species E. tenella. By Significance Analysis of Microarrays (SAM), we have identified 7,099 probe sets with q-values at <0.05, in which 4,033 and 3,066 genes were found to be up- or down-regulated in response to parasite infection. The reliability of the microarray data were validated by real-time qRT PCR of 20 genes with varied fold changes in expression (i.e., correlation coefficient between microarray and qRT-PCR datasets: R (2) = 0.8773, p<0.0001). Gene ontology analysis, KEGG pathway mapping and manual annotations of regulated genes indicated that up-regulated genes were mainly involved in immunity/defense, responses to various stimuli, apoptosis/cell death and differentiation, signal transduction and extracellular matrix (ECM), whereas down-regulated genes were mainly encoding general metabolic enzymes, membrane components, and some transporters. Chickens mustered complex cecal eipthelia molecular and immunological responses in response to E. tenella infection, which included pathways involved in cytokine production and interactions, natural killer cell mediated cytotoxicity, and intestinal IgA production. In response to the pathogenesis and damage caused by infection, chicken cecal epithelia reduced general metabolism, DNA replication and repair, protein degradation, and mitochondrial functions. PMID- 23737975 TI - The hot pepper (Capsicum annuum) microRNA transcriptome reveals novel and conserved targets: a foundation for understanding MicroRNA functional roles in hot pepper. AB - MicroRNAs (miRNAs) are a class of non-coding RNAs approximately 21 nt in length which play important roles in regulating gene expression in plants. Although many miRNA studies have focused on a few model plants, miRNAs and their target genes remain largely unknown in hot pepper (Capsicum annuum), one of the most important crops cultivated worldwide. Here, we employed high-throughput sequencing technology to identify miRNAs in pepper extensively from 10 different libraries, including leaf, stem, root, flower, and six developmental stage fruits. Based on a bioinformatics pipeline, we successfully identified 29 and 35 families of conserved and novel miRNAs, respectively. Northern blot analysis was used to validate further the expression of representative miRNAs and to analyze their tissue-specific or developmental stage-specific expression patterns. Moreover, we computationally predicted miRNA targets, many of which were experimentally confirmed using 5' rapid amplification of cDNA ends analysis. One of the validated novel targets of miR-396 was a domain rearranged methyltransferase, the major de novo methylation enzyme, involved in RNA-directed DNA methylation in plants. This work provides the first reliable draft of the pepper miRNA transcriptome. It offers an expanded picture of pepper miRNAs in relation to other plants, providing a basis for understanding the functional roles of miRNAs in pepper. PMID- 23737976 TI - Demand and predictors for post-discharge medical counseling in home care patients: a prospective cohort study. AB - RATIONALE: Post-discharge care is challenging due to the high rate of adverse events after discharge. However, details regarding post-discharge care requirements remain unclear. Post-discharge medical counseling (PDMC) by telephone service was set-up to investigate its demand and predictors. METHODS: This prospective study was conducted from April 2011 to March 2012 in a tertiary referral center in northern Taiwan. Patients discharged for home care were recruited and educated via telephone hotline counseling when needed. The patient's characteristics and call-in details were recorded, and predictors of PDMC use and worsening by red-flag sign were analyzed. RESULTS: During the study period, 224 patients were enrolled. The PDMC was used 121 times by 65 patients in an average of 8.6 days after discharge. The red-flag sign was noted in 17 PDMC from 16 patients. Of the PDMC used, 50% (n = 60) were for symptom change and the rest were for post-discharge care problems and issues regarding other administrative services. Predictors of PDMC were underlying malignancy and lower Barthel index (BI). On the other hand, lower BI, higher adjusted Charlson co morbidity index (CCI), and longer length of hospital stay were associated with PDMC and red-flag sign. CONCLUSIONS: Demand for PDMC may be as high as 29% in home care patients within 30 days after discharge. PDMC is needed more by patients with malignancy and lower BI. More focus should also be given to those with lower BI, higher CCI, and longer length of hospital stay, as they more frequently have red flag signs. PMID- 23737977 TI - Mechanistic model of Rothia mucilaginosa adaptation toward persistence in the CF lung, based on a genome reconstructed from metagenomic data. AB - The impaired mucociliary clearance in individuals with Cystic Fibrosis (CF) enables opportunistic pathogens to colonize CF lungs. Here we show that Rothia mucilaginosa is a common CF opportunist that was present in 83% of our patient cohort, almost as prevalent as Pseudomonas aeruginosa (89%). Sequencing of lung microbial metagenomes identified unique R. mucilaginosa strains in each patient, presumably due to evolution within the lung. The de novo assembly of a near complete R. mucilaginosa (CF1E) genome illuminated a number of potential physiological adaptations to the CF lung, including antibiotic resistance, utilization of extracellular lactate, and modification of the type I restriction modification system. Metabolic characteristics predicted from the metagenomes suggested R. mucilaginosa have adapted to live within the microaerophilic surface of the mucus layer in CF lungs. The results also highlight the remarkable evolutionary and ecological similarities of many CF pathogens; further examination of these similarities has the potential to guide patient care and treatment. PMID- 23737978 TI - A quantitative comparison of single-dye tracking analysis tools using Monte Carlo simulations. AB - Single-particle tracking (SPT) is widely used to study processes from membrane receptor organization to the dynamics of RNAs in living cells. While single-dye labeling strategies have the benefit of being minimally invasive, this comes at the expense of data quality; typically a data set of short trajectories is obtained and analyzed by means of the mean square displacements (MSD) or the distribution of the particles' displacements in a set time interval (jump distance, JD). To evaluate the applicability of both approaches, a quantitative comparison of both methods under typically encountered experimental conditions is necessary. Here we use Monte Carlo simulations to systematically compare the accuracy of diffusion coefficients (D-values) obtained for three cases: one population of diffusing species, two populations with different D-values, and a population switching between two D-values. For the first case we find that the MSD gives more or equally accurate results than the JD analysis (relative errors of D-values <6%). If two diffusing species are present or a particle undergoes a motion change, the JD analysis successfully distinguishes both species (relative error <5%). Finally we apply the JD analysis to investigate the motion of endogenous LPS receptors in live macrophages before and after treatment with methyl-beta-cyclodextrin and latrunculin B. PMID- 23737980 TI - If you don't find it often, you often don't find it: why some cancers are missed in breast cancer screening. AB - Mammography is an important tool in the early detection of breast cancer. However, the perceptual task is difficult and a significant proportion of cancers are missed. Visual search experiments show that miss (false negative) errors are elevated when targets are rare (low prevalence) but it is unknown if low prevalence is a significant factor under real world, clinical conditions. Here we show that expert mammographers in a real, low-prevalence, clinical setting, miss a much higher percentage of cancers than are missed when the mammographers search for the same cancers under high prevalence conditions. We inserted 50 positive and 50 negative cases into the normal workflow of the breast cancer screening service of an urban hospital over the course of nine months. This rate was slow enough not to markedly raise disease prevalence in the radiologists' daily practice. Six radiologists subsequently reviewed all 100 cases in a session where the prevalence of disease was 50%. In the clinical setting, participants missed 30% of the cancers. In the high prevalence setting, participants missed just 12% of the same cancers. Under most circumstances, this low prevalence effect is probably adaptive. It is usually wise to be conservative about reporting events with very low base rates (Was that a flying saucer? Probably not.). However, while this response to low prevalence appears to be strongly engrained in human visual search mechanisms, it may not be as adaptive in socially important, low prevalence tasks like medical screening. While the results of any one study must be interpreted cautiously, these data are consistent with the conclusion that this behavioral response to low prevalence could be a substantial contributor to miss errors in breast cancer screening. PMID- 23737979 TI - Intermittent exposure to xenon protects against gentamicin-induced nephrotoxicity. AB - Aminoglycoside antibiotics, especially gentamicin, are widely used to treat Gram negative infections due to their efficacy and low cost. Nevertheless the use of gentamicin is limited by its major side effect, nephrotoxicity. Xenon (Xe) provided substantial organoprotective effects in acute injury of the brain and the heart and protected against renal ischemic-reperfusion injury. In this study, we investigated whether xenon could protect against gentamicin-induced nephrotoxicity. Male Wistar rats were intermittently exposed to either 70% xenon or 70% nitrogen (N2) balanced with 30% oxygen before and during gentamicin administration at a dose of 100 mg/kg for 7 days to model gentamicin-induced kidney injury. We observed that intermittent exposure to Xe provided morphological and functional renoprotection, which was characterized by attenuation of renal tubular damage, apoptosis, and oxidative stress, but not a reduction in inflammation. We also found that Xe pretreatment upregulated hypoxia inducible factor 2alpha (HIF-2alpha) and its downstream effector vascular endothelial growth factor, but not HIF-1alpha. With regard to the three HIF prolyl hydroxylases, Xe pretreatment upregulated prolyl hydroxylase domain containing protein-2 (PHD2), suppressed PHD1, and had no influence on PHD3 in the rat kidneys. Pretreatment with Xe also increased the expression of miR-21, a microRNA known to have anti-apoptotic effects. These results support Xe renoprotection against gentamicin-induced nephrotoxicity. PMID- 23737981 TI - Prevalence of human parvovirus B19, bocavirus, and PARV4 in blood samples from the general population of China and lack of a correlation between parvovirus and hepatitis B co-infection. AB - Few comprehensive studies have investigated viraemia caused by human parvoviruses (HPAVs) in China. A total of 1626 of blood samples were collected from non-HBV and HBV infected Chinese subjects (adults, N = 1279; children, N = 347) from south-western and south-eastern China. DNA from three HPAVs was detected in blood samples using PCR-based assays. The epidemiological profiles and association with HBV co-infection were also analysed. Of the 1626 blood samples tested, 138 (8.49%) were found to exhibit HPAV viraemia, including 3.51% with B19, 3.75% with HBoV and 2.52% with PARV4. The presence of B19 DNA in both child and adult, as well as that of PARV4 DNA in adult,from the south-western region was significantly higher than that from the south-eastern region (P = 0.006 for B19 in children; P = 0.026 for B19 in adults; and P = 0.014 for PARV4 in adult).However, the frequency of HBoV DNA in adults from the south-western region was significantly lower than that observed in adults from the south-eastern region (P = 0.001). Furthermore, HBoV was more prevalence in male (4.9%) than in female (1.4%) individuals. In addition, no significant correlation between HBV and HPAV co-infection was found using serum samples from Chinese adults. In conclusions,the molecular prevalence of three HPAVs in blood samples exhibited variation among different populations depending on area, age and gender; No association between HPAV and HBV infection in adults was found. Our data provide a basis for improving blood safety and preventing HPAV infection in China. PMID- 23737982 TI - Electro-acupuncture stimulation improves spontaneous locomotor hyperactivity in MPTP intoxicated mice. AB - Bradykinesia is one of the major clinical symptoms of Parkinson's disease (PD) for which treatment is sought. In most mouse models of PD, decreased locomotor activity can be reflected in an open field behavioral test. Therefore the open field test provides a useful tool to study the clinic symptoms of PD patients. Our previous work demonstrated that 100 Hz electro-acupuncture (EA) stimulation at ZUSANLI and SANYINJIAO protected the dopaminergic nigrostriatal system of C57BL/6 mice from MPTP toxicity, indicating that acupuncture might be an effective therapy for PD sufferers. In the present study, we investigated the effects of 100 Hz EA stimulation on the spontaneous locomotor activity in MPTP injured mice. Here we found that, in MPTP treated mice, the total movements significantly decreased and the movement time, velocity and distance dramatically increased, although the dopaminergic nigrostriatal system was devastated, revealed by immunohistochemistry and HPLC-ECD. After 12 sessions of 100 Hz EA stimulation, the total movements elevated and the movement time, velocity and distance decreased, in MPTP mice. 100 Hz EA increased striatal dopamine content in MPTP mice by 35.9%, but decreased its striatal dopamine turnover. We assumed that the injury of other regions in the brain, such as the A11 group in diencephalon, might be involved in the hypermotility in MPTP mice. The effects of 100 Hz EA on spontaneous locomotor activity in MPTP mice might not relate with the striatal dopamine, but with its neuroprotective and regulatory effects on motor circuits in the brain. Our study suggests that EA might be a promising treatment for neurological disorders including PD. PMID- 23737983 TI - Eukaryotic translation initiation factor 3 subunit e controls intracellular calcium homeostasis by regulation of cav1.2 surface expression. AB - Inappropriate surface expression of voltage-gated Ca(2+)channels (CaV) in pancreatic beta-cells may contribute to the development of type 2 diabetes. First, failure to increase intracellular Ca(2+) concentrations at the sites of exocytosis impedes insulin release. Furthermore, excessive Ca(2+) influx may trigger cytotoxic effects. The regulation of surface expression of CaV channels in the pancreatic beta-cells remains unknown. Here, we used real-time 3D confocal and TIRFM imaging, immunocytochemistry, cellular fractionation, immunoprecipitation and electrophysiology to study trafficking of L-type CaV1.2 channels upon beta-cell stimulation. We found decreased surface expression of CaV1.2 and a corresponding reduction in L-type whole-cell Ca(2+) currents in insulin-secreting INS-1 832/13 cells upon protracted (15-30 min) stimulation. This internalization occurs by clathrin-dependent endocytosis and could be prevented by microtubule or dynamin inhibitors. eIF3e (Eukaryotic translation initiation factor 3 subunit E) is part of the protein translation initiation complex, but its effect on translation are modest and effects in ion channel trafficking have been suggested. The factor interacted with CaV1.2 and regulated CaV1.2 traffic bidirectionally. eIF3e silencing impaired CaV1.2 internalization, which resulted in an increased intracellular Ca(2+) load upon stimulation. These findings provide a mechanism for regulation of L-type CaV channel surface expression with consequences for beta-cell calcium homeostasis, which will affect pancreatic beta-cell function and insulin production. PMID- 23737984 TI - Effect of propofol in the immature rat brain on short- and long-term neurodevelopmental outcome. AB - BACKGROUND: Propofol is commonly used as sedative in newborns and children. Recent experimental studies led to contradictory results, revealing neurodegenerative or neuroprotective properties of propofol on the developing brain. We investigated neurodevelopmental short- and long-term effects of neonatal propofol treatment. METHODS: 6-day-old Wistar rats (P6), randomised in two groups, received repeated intraperitoneal injections (0, 90, 180 min) of 30 mg/kg propofol or normal saline and sacrificed 6, 12 and 24 hrs following the first injection. Cortical and thalamic areas were analysed by Western blot and quantitative real-time PCR (qRT-PCR) for expression of apoptotic and neurotrophin dependent signalling pathways. Long-term effects were assessed by Open-field and Novel-Object-Recognition at P30 and P120. RESULTS: Western blot analyses revealed a transient increase of activated caspase-3 in cortical, and a reduction of active mitogen-activated protein kinases (ERK1/2, AKT) in cortical and thalamic areas. qRT-PCR analyses showed a down-regulation of neurotrophic factors (BDNF, NGF, NT-3) in cortical and thalamic regions. Minor impairment in locomotive activity was observed in propofol treated adolescent animals at P30. Memory or anxiety were not impaired at any time point. CONCLUSION: Exposing the neonatal rat brain to propofol induces acute neurotrophic imbalance and neuroapoptosis in a region- and time-specific manner and minor behavioural changes in adolescent animals. PMID- 23737985 TI - Serial passaging of Candida albicans in systemic murine infection suggests that the wild type strain SC5314 is well adapted to the murine kidney. AB - The opportunistic fungal pathogen Candida albicans has a remarkable ability to adapt to unfavorable environments by different mechanisms, including microevolution. For example, a previous study has shown that passaging through the murine spleen can cause new phenotypic characteristics. Since the murine kidney is the main target organ in murine Candida sepsis and infection of the spleen differs from the kidney in several aspects, we tested whether C. albicans SC5314 could evolve to further adapt to infection and persistence within the kidney. Therefore, we performed a long-term serial passage experiment through the murine kidney of using a low infectious dose. We found that the overall virulence of the commonly used wild type strain SC5314 did not change after eight passages and that the isolated pools showed only very moderate changes of phenotypic traits on the population level. Nevertheless, the last passage showed a higher phenotypic variability and a few individual strains exhibited phenotypic alterations suggesting that microevolution has occurred. However, the majority of the tested single strains were phenotypically indistinguishable from SC5314. Thus, our findings indicate that characteristics of SC5314 which are important to establish and maintain kidney infection over a prolonged time are already well developed. PMID- 23737986 TI - Elucidating the Pseudomonas aeruginosa fatty acid degradation pathway: identification of additional fatty acyl-CoA synthetase homologues. AB - The fatty acid (FA) degradation pathway of Pseudomonas aeruginosa, an opportunistic pathogen, was recently shown to be involved in nutrient acquisition during BALB/c mouse lung infection model. The source of FA in the lung is believed to be phosphatidylcholine, the major component of lung surfactant. Previous research indicated that P. aeruginosa has more than two fatty acyl-CoA synthetase genes (fadD; PA3299 and PA3300), which are responsible for activation of FAs using ATP and coenzyme A. Through a bioinformatics approach, 11 candidate genes were identified by their homology to the Escherichia coli FadD in the present study. Four new homologues of fadD (PA1617, PA2893, PA3860, and PA3924) were functionally confirmed by their ability to complement the E. coli fadD mutant on FA-containing media. Growth phenotypes of 17 combinatorial fadD mutants on different FAs, as sole carbon sources, indicated that the four new fadD homologues are involved in FA degradation, bringing the total number of P. aeruginosa fadD genes to six. Of the four new homologues, fadD4 (PA1617) contributed the most to the degradation of different chain length FAs. Growth patterns of various fadD mutants on plant-based perfumery substances, citronellic and geranic acids, as sole carbon and energy sources indicated that fadD4 is also involved in the degradation of these plant-derived compounds. A decrease in fitness of the sextuple fadD mutant, relative to the DeltafadD1D2 mutant, was only observed during BALB/c mouse lung infection at 24 h. PMID- 23737987 TI - CKAP2 ensures chromosomal stability by maintaining the integrity of microtubule nucleation sites. AB - Integrity of the microtubule spindle apparatus and intact cell division checkpoints are essential to ensure the fidelity of distributing chromosomes into daughter cells. Cytoskeleton-associated protein 2, CKAP2, is a microtubule associated protein that localizes to spindle poles and aids in microtubule stabilization, but the exact function and mechanism of action are poorly understood. In the present study, we utilized RNA interference to determine the extent to which the expression of CKAP2 plays a role in chromosome segregation. CKAP2-depleted cells showed a significant increase of multipolar mitoses and other spindle pole defects. Notably, when interrogated for microtubule nucleation capacity, CKAP2-depleted cells showed a very unusual phenotype as early as two minutes after release from mitotic block, consisting of dispersal of newly polymerized microtubule filaments through the entire chromatin region, creating a cage-like structure. Nevertheless, spindle poles were formed after one hour of mitotic release suggesting that centrosome-mediated nucleation remained dominant. Finally, we showed that suppression of CKAP2 resulted in a higher incidence of merotelic attachments, anaphase lagging, and polyploidy. Based on these results, we conclude that CKAP2 is involved in the maintenance of microtubule nucleation sites, focusing microtubule minus ends to the spindle poles in early mitosis, and is implicated in maintaining genome stability. PMID- 23737988 TI - Prognostic roles of cross-talk between peritumoral hepatocytes and stromal cells in hepatocellular carcinoma involving peritumoral VEGF-C, VEGFR-1 and VEGFR-3. AB - BACKGROUND: Peritumoral liver tissue could play a potential role in hepatocellular carcinoma (HCC) progression and patient survival via angiogenesis- and lymphangiogensis-related factors. The prognostic role of these factors in hepatocytes and stromal cells in HCC patients after curative resection remains to be explored. METHODS: Tumor tissue and surrounding peritumoral tissue were obtained from 145 resected HCC patients without lymph node metastasis (LNM) and 37 resected HCC patients with LNM. Tissue microarrays were constructed from duplicate cores of tumor tissue and surrounding peritumoral tissue from each resected specimen. Immunohistochemistry and real-time polymerase chain reaction were used to evaluate the expression of vascular endothelial growth factor-A (VEGF-A), VEGF-C, VEGF receptor-1(VEGFR-1), VEGFR-2, and VEGFR-3. Macrophage infiltration was determined by CD68 staining. Correlations between the expression of these factors and overall survival (OS) and time to recurrence (TTR) were studied. RESULTS: The peritumoral expression of VEGF-A, VEGF-C, VEGFR-1, VEGFR-2, and VEGFR-3 were significantly higher than expression of these factors in tumors. VEGFR-1 was mostly located in peritumoral macrophages, while VEGF-C and VEGFR-3 were mostly located in peritumoral hepatocytes. HCC with high peritumoral co expression of VEGF-C, VEGFR-1, and VEGFR-3 was associated with higher peritumoral distribution of macrophages (0.87%+/-0.26% versus 0.45%+/-0.20%), LNM (32.4% versus 12.0%), shorter TTR (10.2 months versus 34.5 months), and poor prognosis (19.4 months versus 49.3 months). CONCLUSION: Expression of VEGF-C, VEGFR-1, and VEGFR-3 in peritumoral liver tissue is associated with a unique type of HCC that has a poorer outcome after hepatectomy. PMID- 23737989 TI - Multiple-locus variable-number tandem-repeat analysis of mycoplasma pneumoniae clinical specimens and proposal for amendment of MLVA nomenclature. AB - Mycoplasma pneumoniae is one of the major respiratory bacterial pathogens that cause pneumonia in humans. Multiple-locus variable-number tandem-repeat analysis (MLVA) is currently the most discriminative method for typing M. pneumoniae strains. To better understand the epidemic of M. pneumoniae-related pneumonia in pediatric patients in Beijing, China, we performed MLVA analysis on 118 specimens collected during an epidemic from 2010-2012. Eleven distinct MLVA types were identified, including four novel types. There was no obvious association of macrolide resistance with any of the genotypes. Considering the instability of VNTR locus Mpn1, we propose an amended MLVA nomenclature system based on the remaining four VNTR loci. PMID- 23737990 TI - Production of cloned pigs with targeted attenuation of gene expression. AB - The objective of this study was to demonstrate that RNA interference (RNAi) and somatic cell nuclear transfer (SCNT) technologies can be used to attenuate the expression of specific genes in tissues of swine, a large animal species. Apolipoprotein E (apoE), a secreted glycoprotein known for its major role in lipid and lipoprotein metabolism and transport, was selected as the target gene for this study. Three synthetic small interfering RNAs (siRNA) targeting the porcine apoE mRNA were tested in porcine granulosa cells in primary culture and reduced apoE mRNA abundance ranging from 45-82% compared to control cells. The most effective sequence was selected for cloning into a short hairpin RNA (shRNA) expression vector under the control of RNA polymerase III (U6) promoter. Stably transfected fetal porcine fibroblast cells were generated and used to produce embryos with in vitro matured porcine oocytes, which were then transferred into the uterus of surrogate gilts. Seven live and one stillborn piglet were born from three gilts that became pregnant. Integration of the shRNA expression vector into the genome of clone piglets was confirmed by PCR and expression of the GFP transgene linked to the expression vector. Analysis showed that apoE protein levels in the liver and plasma of the clone pigs bearing the shRNA expression vector targeting the apoE mRNA was significantly reduced compared to control pigs cloned from non-transfected fibroblasts of the same cell line. These results demonstrate the feasibility of applying RNAi and SCNT technologies for introducing stable genetic modifications in somatic cells for eventual attenuation of gene expression in vivo in large animal species. PMID- 23737991 TI - The red flour beetle as a model for bacterial oral infections. AB - Experimental infection systems are important for studying antagonistic interactions and coevolution between hosts and their pathogens. The red flour beetle Tribolium castaneum and the spore-forming bacterial insect pathogen Bacillus thuringiensis (Bt) are widely used and tractable model organisms. However, they have not been employed yet as an efficient experimental system to study host-pathogen interactions. We used a high throughput oral infection protocol to infect T. castaneum insects with coleopteran specific B. thuringiensis bv. tenebrionis (Btt) bacteria. We found that larval mortality depends on the dietary spore concentration and on the duration of exposure to the spores. Furthermore, differential susceptibility of larvae from different T. castaneum populations indicates that the host genetic background influences infection success. The recovery of high numbers of infectious spores from the cadavers indicates successful replication of bacteria in the host and suggests that Btt could establish infectious cycles in T. castaneum in nature. We were able to transfer plasmids from Btt to a non-pathogenic but genetically well characterised Bt strain, which was thereafter able to successfully infect T. castaneum, suggesting that factors residing on the plasmids are important for the virulence of Btt. The availability of a genetically accessible strain will provide an ideal model for more in-depth analyses of pathogenicity factors during oral infections. Combined with the availability of the full genome sequence of T. castaneum, this system will enable analyses of host responses during infection, as well as addressing basic questions concerning host-parasite coevolution. PMID- 23737992 TI - Dietary carbohydrates modulate Candida albicans biofilm development on the denture surface. AB - The purpose of this study was to investigate whether dietary carbohydrates can modulate the development of Candida albicans biofilms on the denture material surface. Poly (methyl methacrylate) acrylic resin discs were fabricated and had their surface roughness measured. Biofilms of C. albicans ATCC 90028 were developed on saliva-coated specimens in culture medium without (control) or with carbohydrate supplementation by starch, starch+sucrose, glucose, or sucrose for 72 h. The cell count, metabolic activity, biovolume, average thickness, and roughness coefficient were evaluated at the adhesion phase (1.5 h) and after 24, 48, and 72 h. The secretion of proteinases and phospholipases, cell surface energy, and production of extra/intracellular polysaccharides were analyzed after 72 h of biofilm development. Data were analyzed by one- and two-way ANOVA followed by Tukey's test at 5% significance level. In the early stages of colonization (adhesion and 24 h), the glucose group showed the highest cell counts and metabolic activity among the groups (p<0.05). After maturation (48 and 72 h), biofilms exposed to glucose, sucrose, or starch+sucrose showed higher cell counts and metabolic activity than the control and starch groups (p<0.001). Compared to the control group, biofilms developed on starch or starch+sucrose had more proteinase activity (p<0.001), whereas biofilms developed on glucose or sucrose had more phospholipase activity (p<0.05). Exposure to starch+sucrose increased the production of extracellular and intracellular polysaccharides (p<0.05). Biofilms developed on starch or without carbohydrate supplementation presented cells with more hydrophobic behavior compared to the other groups. Confocal images showed hyphae forms on biofilms exposed to starch or starch+sucrose. Within the conditions studied, it can be concluded that dietary carbohydrates can modulate biofilm development on the denture surface by affecting virulence factors and structural features. PMID- 23737993 TI - The good, the bad, and the unknown: quality of clinical laboratories in Kampala, Uganda. AB - BACKGROUND: Clinical laboratories are crucial in addressing the high rates of communicable and non-communicable diseases seen in sub-Saharan Africa (SSA). However, the most basic information, such as the number and quality of clinical laboratories in SSA, is not available. The objective of this study was to create a practical method for obtaining this information in SSA towns and cities using an initial survey in Kampala, Uganda. METHODS: Kampala city was divided into 5 partially-overlapping regions. Each region was assigned to 2-3 surveyors who identified and surveyed laboratories in their respective regions; in person and on foot. A modified version of the World Health Organization - African Region (WHO/AFRO) Laboratory Strengthening Checklist was used to obtain baseline measures of quality for all clinical laboratories within Kampala city. The surveyors also measured other attributes of each laboratory, such as their affiliation (government, private etc), designation (national hospital, district hospital, standalone etc), staff numbers, and type of staff. RESULTS: The survey team identified and surveyed 954 laboratories in Kampala city. 96% of laboratories were private. Only 45 (5%) of the laboratories met or surpassed the lowest quality standards defined by the WHO/AFRO-derived laboratory strengthening tool (1-star). These 45 higher-quality laboratories were, on average, larger and had a higher number of laboratory-specific staff (technologists, phlebotomists etc) than the other 909 laboratories. 688 (72%) of the 954 laboratories were not registered with the Ministry of Health (MoH). CONCLUSIONS: This comprehensive evaluation of the number, scope, and quality of clinical laboratories in Kampala is the first published survey of its kind in sub-Saharan Africa. The survey findings demonstrated that laboratories in Kampala that had qualified personnel and those that had higher testing volumes, tended to be of higher-quality. PMID- 23737994 TI - New tools for targeted disruption of cholinergic synaptic transmission in Drosophila melanogaster. AB - Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels. The alpha7 subtype of nAChRs is involved in neurological pathologies such as Parkinson's disease, Alzheimer's disease, addiction, epilepsy and autism spectrum disorders. The Drosophila melanogaster alpha7 (Dalpha7) has the closest sequence homology to the vertebrate alpha7 subunit and it can form homopentameric receptors just as the vertebrate counterpart. The Dalpha7 subunits are essential for the function of the Giant Fiber circuit, which mediates the escape response of the fly. To further characterize the receptor function, we generated different missense mutations in the Dalpha7 nAChR's ligand binding domain. We characterized the effects of targeted expression of two UAS-constructs carrying a single mutation, D197A and Y195T, as well as a UAS-construct carrying a triple D77T, L117Q, I196P mutation in a Dalpha7 null mutant and in a wild type background. Expression of the triple mutation was able to restore the function of the circuit in Dalpha7 null mutants and had no disruptive effects when expressed in wild type. In contrast, both single mutations severely disrupted the synaptic transmission of Dalpha7-dependent but not glutamatergic or gap junction dependent synapses in wild type background, and did not or only partially rescued the synaptic defects of the null mutant. These observations are consistent with the formation of hybrid receptors, consisting of D197A or Y195T subunits and wild type Dalpha7 subunits, in which the binding of acetylcholine or acetylcholine induced conformational changes of the Dalpha7 receptor are altered and causes inhibition of cholinergic responses. Thus targeted expression of D197A or Y195T can be used to selectively disrupt synaptic transmission of Dalpha7-dependent synapses in neuronal circuits. Hence, these constructs can be used as tools to study learning and memory or addiction associated behaviors by allowing the manipulation of neuronal processing in the circuits without affecting other cellular signaling. PMID- 23737995 TI - Transposon mutagenesis in Bifidobacterium breve: construction and characterization of a Tn5 transposon mutant library for Bifidobacterium breve UCC2003. AB - Bifidobacteria are claimed to contribute positively to human health through a range of beneficial or probiotic activities, including amelioration of gastrointestinal and metabolic disorders, and therefore this particular group of gastrointestinal commensals has enjoyed increasing industrial and scientific attention in recent years. However, the molecular mechanisms underlying these probiotic mechanisms are still largely unknown, mainly due to the fact that molecular tools for bifidobacteria are rather poorly developed, with many strains lacking genetic accessibility. In this work, we describe the generation of transposon insertion mutants in two bifidobacterial strains, B. breve UCC2003 and B. breve NCFB2258. We also report the creation of the first transposon mutant library in a bifidobacterial strain, employing B. breve UCC2003 and a Tn5-based transposome strategy. The library was found to be composed of clones containing single transposon insertions which appear to be randomly distributed along the genome. The usefulness of the library to perform phenotypic screenings was confirmed through identification and analysis of mutants defective in D galactose, D-lactose or pullulan utilization abilities. PMID- 23737996 TI - High quality genome-wide genotyping from archived dried blood spots without DNA amplification. AB - Spots of blood are routinely collected from newborn babies onto filter paper called Guthrie cards and used to screen for metabolic and genetic disorders. The archived dried blood spots are an important and precious resource for genomic research. Whole genome amplification of dried blood spot DNA has been used to provide DNA for genome-wide SNP genotyping. Here we describe a 96 well format procedure to extract DNA from a portion of a dried blood spot that provides sufficient unamplified genomic DNA for genome-wide single nucleotide polymorphism (SNP) genotyping. We show that SNP genotyping of the unamplified DNA is more robust than genotyping amplified dried blood spot DNA, is comparable in cost, and can be done with thousands of samples. This procedure can be used for genome-wide association studies and other large-scale genomic analyses that require robust, high-accuracy genotyping of dried blood spot DNA. PMID- 23737997 TI - Intermedin suppresses pressure overload cardiac hypertrophy through activation of autophagy. AB - Left ventricular hypertrophy is a maladaptive response to pressure overload and an important risk factor for heart failure. Intermedin (IMD), a multi-functional peptide, plays important roles in cardiovascular protection. In this study, we revealed an autophagy-dependent mechanism involved in IMD's protection against cardiac remodeling and cardiomyocyte death in heart hypertrophy. We observed that transverse aortic contraction (TAC) induction, Ang II or ISO exposure induced remarkable increase in the expression of endogenous IMD and its receptor components, CRLR, RAMP1 and RAMP3, in mouse hearts and H9c2 cell cultures, respectively. Furthermore, the heart size, heart weight/body weight ratios, cardiomyocyte size and apoptosis, interstitial collagen, hypertrophic markers including ANP and BNP expression were also significantly increased, which were effectively suppressed by IMD supplementation. In addition, IMD induced capillary angiogenesis and improved functions in hypertrophic hearts. We further observed that IMD induced strong autophagy in hypertrophic hearts and cultured cells, which was paralleling with the decrease in cardiomyocyte size and apoptosis. Furthermore, an autophagy inhibitor, 3-MA, was used to block the IMD-augmented autophagy level, and then the protection of IMD on cardiomyocyte hypertrophy and apoptosis was almost abrogated. We also observed that IMD supplementation stirred intracellular cAMP production, and augmented the ERK1/2 phosphorylation induced by Ang II/ISO exposure in H9c2 cells. In addition, we inhibited PI3K, PKA and MAPK/ERK1/2 signaling pathways by using wortamannin, H89 and PD98059, respectively, in H9c2 cells co-incubating with both IMD and Ang II or ISO, and observed that these inhibitors effectively reduced IMD-augmented autophagy level, but only H89 and PD98059 pre-incubation abrogated the anti-apoptotic action of IMD. These results indicate that the endogenous IMD and its receptor complexes are induced in hypertrophic cardiomyocytes and proposed to play an important role in the pathogenesis of cardiac hypertrophy, and the autophagy stirred by IMD supplementation is involved in its protection against cardiomyocyte hypertrophy and apoptosis through the activation of both cAMP/PKA and MAPK/ERK1/2 pathways. PMID- 23737998 TI - Top-down regulation, climate and multi-decadal changes in coastal zoobenthos communities in two Baltic Sea areas. AB - The structure of many marine ecosystems has changed substantially during recent decades, as a result of overexploitation, climate change and eutrophication. Despite of the apparent ecological and economical importance of coastal areas and communities, this aspect has received relatively little attention in coastal systems. Here we assess the temporal development of zoobenthos communities in two areas on the Swedish Baltic Sea coast during 30 years, and relate their development to changes in climate, eutrophication and top-down regulation from fish. Both communities show substantial structural changes, with a decrease in marine polychaetes and species sensitive to increased water temperatures. Concurrently, opportunistic species tolerant to environmental perturbation have increased in abundance. Species composition show a similar temporal development in both communities and significant changes in species composition occurred in both data sets in the late 1980s and early 1990s. The change in species composition was associated with large scale changes in climate (salinity and water temperature) and to the structure of the local fish community, whereas we found no effects of nutrient loading or ambient nutrient concentrations. Our results suggest that these coastal zoobenthos communities have gone through substantial structural changes over the last 30 years, resulting in communities of different species composition with potentially different ecological functions. We hence suggest that the temporal development of coastal zoobenthos communities should be assessed in light of prevailing climatic conditions considering the potential for top-down effects exerted by local fish communities. PMID- 23737999 TI - Microwell scaffolds for the extrahepatic transplantation of islets of Langerhans. AB - Allogeneic islet transplantation into the liver has the potential to restore normoglycemia in patients with type 1 diabetes. However, the suboptimal microenvironment for islets in the liver is likely to be involved in the progressive islet dysfunction that is often observed post-transplantation. This study validates a novel microwell scaffold platform to be used for the extrahepatic transplantation of islet of Langerhans. Scaffolds were fabricated from either a thin polymer film or an electrospun mesh of poly(ethylene oxide terephthalate)-poly(butylene terephthalate) (PEOT/PBT) block copolymer (composition: 4000PEOT30PBT70) and were imprinted with microwells, ~400 um in diameter and ~350 um in depth. The water contact angle and water uptake were 39+/ 2 degrees and 52.1+/-4.0 wt%, respectively. The glucose flux through electrospun scaffolds was three times higher than for thin film scaffolds, indicating enhanced nutrient diffusion. Human islets cultured in microwell scaffolds for seven days showed insulin release and insulin content comparable to those of free floating control islets. Islet morphology and insulin and glucagon expression were maintained during culture in the microwell scaffolds. Our results indicate that the microwell scaffold platform prevents islet aggregation by confinement of individual islets in separate microwells, preserves the islet's native rounded morphology, and provides a protective environment without impairing islet functionality, making it a promising platform for use in extrahepatic islet transplantation. PMID- 23738000 TI - An RNA aptamer provides a novel approach for the induction of apoptosis by targeting the HPV16 E7 oncoprotein. AB - BACKGROUND: Human papillomavirus 16 (HPV16) is a high-risk DNA tumour virus, which is a major causative agent of cervical cancer. Cellular transformation is associated with deregulated expression of the E6 and E7 oncogenes. E7 has been shown to bind a number of cellular proteins, including the cell cycle control protein pRb. In this study, RNA aptamers (small, single-stranded oligonucleotides selected for high-affinity binding) to HPV16 E7 were employed as molecular tools to further investigate these protein-protein interactions. METHODOLOGY/PRINCIPAL FINDINGS: This study is focused on one aptamer (termed A2). Transfection of this molecule into HPV16-transformed cells resulted in inhibition of cell proliferation (shown using real-time cell electronic sensing and MTT assays) due to the induction of apoptosis (as demonstrated by Annexin V/propidium iodide staining). GST-pull down and bead binding assays were used to demonstrate that the binding of A2 required N-terminal residues of E7 known to be involved in interaction with the cell cycle control protein, pRb. Using a similar approach, A2 was shown to disrupt the interaction between E7 and pRb in vitro. Furthermore, transfection of HPV16-transformed cells with A2 appeared to result in the loss of E7 and rise in pRb levels, as observed by immunoblotting. CONCLUSIONS/SIGNIFICANCE: This paper includes the first characterisation of the effects of an E7 RNA aptamer in a cell line derived from a cervical carcinoma. Transfection of cells with A2 was correlated with the loss of E7 and the induction of apoptosis. Aptamers specific for a number of cellular and viral proteins have been documented previously; one aptamer (Macugen) is approved for clinical use and several others are in clinical trials. In addition to its role as a molecular tool, A2 could have further applications in the future. PMID- 23738001 TI - Global fit analysis of myosin-5b motility reveals thermodynamics of Mg2+ sensitive acto-myosin-ADP states. AB - Kinetic and thermodynamic studies of the mechanochemical cycle of myosin motors are essential for understanding the mechanism of energy conversion. Here, we report our investigation of temperature and free Mg(2+)-ion dependencies of sliding velocities of a high duty ratio class-5 myosin motor, myosin-5b from D. discoideum using in vitro motility assays. Previous studies have shown that the sliding velocity of class-5 myosins obeys modulation by free Mg(2+)-ions. Free Mg(2+)-ions affect ADP release kinetics and the dwell time of actin-attached states. The latter determines the maximal velocity of actin translocation in the sliding filament assay. We measured the temperature dependence of sliding velocity in the range from 5 to 55 degrees C at two limiting free Mg(2+)-ion concentrations. Arrhenius plots demonstrated non-linear behavior. Based on this observation we propose a kinetic model, which explains both sensitivity towards free Mg(2+)-ions and non-linearity of the temperature dependence of sliding velocity. According to this model, velocity is represented as a simple analytical function of temperature and free Mg(2+)-ion concentrations. This function has been applied to global non-linear fit analysis of three data sets including temperature and magnesium (at 20 degrees C) dependence of sliding velocity. As a result we obtain thermodynamic parameters (DeltaH(Mg) and DeltaS(Mg)) of a fast equilibrium between magnesium free (AM.D) and magnesium bound acto-myosin-ADP (AM. Mg(2+)D) states and the corresponding enthalpic barriers associated with ADP release (DeltaH1(?) and DeltaH2(?)). The herein presented integrative approach of data analysis based on global fitting can be applied to the remaining steps of the acto-myosin ATPase cycle facilitating the determination of energetic parameters and thermodynamics of acto-myosin interactions. PMID- 23738002 TI - Nutritionally driven differential gene expression leads to heterochronic brain development in honeybee castes. AB - The differential feeding regimes experienced by the queen and worker larvae of the honeybee Apis mellifera shape a complex endocrine response cascade that ultimately gives rise to differences in brain morphologies. Brain development analyzed at the morphological level from the third (L3) through fifth (L5) larval instars revealed an asynchrony between queens and workers. In the feeding phase of the last larval instar (L5F), two well-formed structures, pedunculi and calyces, are identifiable in the mushroom bodies of queens, both of which are not present in workers until a later phase (spinning phase, L5S). Genome-wide expression analyses and normalized transcript expression experiments monitoring specific genes revealed that this differential brain development starts earlier, during L3. Analyzing brains from L3 through L5S1 larvae, we identified 21 genes with caste-specific transcription patterns (e.g., APC-4, GlcAT-P, fax, kr-h1 and shot), which encode proteins that are potentially involved in the development of brain tissues through controlling the cell proliferation rate (APC4, kr-h1) and fasciculation (GlcAT-P, fax, and shot). Shot, whose expression is known to be required for axon extension and cell proliferation, was found to be transcribed at significantly higher levels in L4 queens compared with worker larvae. Moreover, the protein encoded by this gene was immunolocalized to the cytoplasm of cells near the antennal lobe neuropiles and proximal to the Kenyon cells in the brains of L4 queens. In conclusion, during the larval period, the brains of queens are larger and develop more rapidly than workers' brains, which represents a developmental heterochrony reflecting the effect of the differential feeding regime of the two castes on nervous system development. Furthermore, this differential development is characterized by caste-specific transcriptional profiles of a set of genes, thus pointing to a link between differential nutrition and differential neurogenesis via genes that control cell proliferation and fasciculation. PMID- 23738003 TI - Altered functional connectivity in an aged rat model of postoperative cognitive dysfunction: a study using resting-state functional MRI. AB - BACKGROUND: Postoperative cognitive impairment is a common complication after cardiac and major non-cardiac surgery in the elderly, but its causes and mechanisms remain unclear. The purpose of the current study was to use resting state functional magnetic resonance imaging (fMRI) to explore changes in the functional connectivity, i.e. the synchronization of low frequency fluctuation (LFF), in an animal model of cognitive impairment in aged rats. METHODS: Aged (22 months) rats were anaesthetized with 40 ug/kg fentanyl and 500 ug/kg droperidol (intraperitoneal) for splenectomy. Cognitive function was assessed using Y maze prior to operation and on postoperative days 1, 3 and 9. To evaluate functional connectivity, resting-state fMRI data were acquired using a 3T MR imaging system with a 4 channel phase array rat head coil. RESULTS: Cognitive function was impaired at postoperative days 1 and 3 compared with preoperative. Significant synchronized LFF was detected bilaterally in the primary somatosensory cortex and hippocampus preoperatively. By contrast, no significant LFF synchronization was detected in the right primary somatosensory cortex and right hippocampus on postoperative days 1 and 3, although the pattern of functional connectivity had become almost normal by day 9. CONCLUSION: Splenectomy performed under neuroleptic anaesthesia triggers a cognitive decline that is associated with altered spontaneous neuronal activity in the cortex and hippocampus. PMID- 23738004 TI - Association of TLR4 Gene rs2149356 polymorphism with primary gouty arthritis in a case-control study. AB - BACKGROUND: The toll-like receptor (TLR)4-interleukin1beta (IL1beta) signaling pathway is involved in the monosodium urate (MSU)-mediated inflammation. The aim of this present study was to determine whether the TLR4 gene rs2149356 SNP is associated with gouty arthritis (GA) susceptibility and whether rs2149356 SNP impacts the TLR4-IL1beta signaling pathway molecules expression. METHODS AND FINDINGS: The rs2149356 SNP was detected in 459 GA patients and 669 control subjects (containing 459 healthy and 210 hyperuricemic subjects). Peripheral blood mononuclear cells (PBMCs) TLR4 mRNA and serum IL1beta were measured in different genotype carriers, and correlations between TLR4 gene SNP and TLR4 mRNA, IL1beta were investigated. The frequencies of the genotype and allele were significantly different between the GA and control groups (P<0.01, respectively). The TT genotype was associated with a significantly increased risk of GA (OR = 1.88); this finding was not influenced by making adjustments for the components of possible confounders (adjusted OR = 1.96). TLR4 mRNA and IL1beta were significantly increased in the TT genotype from acute GA patients (P<0.05, respectively), and lipids were significantly different among three genotypes in the GA patients (P<0.05, respectively). CONCLUSIONS: The TLR4 gene rs2149356 SNP might be associated with GA susceptibility, and might participate in regulating immune, inflammation and lipid metabolism. Further studies are required to confirm these findings. PMID- 23738005 TI - Vagal afferent mediates the anorectic effect of peripheral secretin. AB - Secretin (SCT) is a classical peptide hormone that is synthesized and released from the gastrointestinal tract after a meal. We have previously shown that it acts both as a central and peripheral anorectic peptide, and that its central effect is mediated via melanocortin system. As peripheral satiety signals from the gastrointestinal tract can be sent to the brain via the vagal afferent or by crossing the blood-brain barrier (BBB), we therefore sought to investigate the pathway by which peripheral SCT reduces appetite in this study. It is found that bilateral subdiaphragmatic vagotomy and treatment of capsaicin, an excitotoxin for primary afferent neurons, could both block the anorectic effect of peripherally injected SCT. These treatments are found to be capable of blunting i.p. SCT-induced Fos activation in pro-opiomelanocortin (POMC) neurons within the hypothalamic Arcuate Nucleus (Arc). Moreover, we have also found that bilateral midbrain transaction could block feeding reduction by peripheral SCT. Taken together, we conclude that the satiety signals of peripheral SCT released from the gastrointestinal tract are sent via the vagus nerves to the brainstem and subsequently Arc, where it controls central expression of other regulatory peptides to regulate food intake. PMID- 23738006 TI - Associations between handedness and cerebral lateralisation for language: a comparison of three measures in children. AB - It has been known for many years that hand preference is associated with cerebral lateralisation for language, but the relationship is weak and indirect. It has been suggested that quantitative measures of differential hand skill or reaching preference may provide more valid measures than traditional inventories, but to date these have not been validated against direct measures of cerebral lateralisation. We investigated the associations of three different handedness assessments; 1) a hand preference inventory, 2) a measure of relative hand skill, and 3) performance on a reaching task; with cerebral lateralisation for language function as derived from functional transcranial Doppler ultrasound during a language production task, in a group of 57 typically developing children aged from 6 to 16 years. Significant correlations between cerebral lateralisation for language production and handedness were found for a short version of the inventory and for performance on the reaching task. However, confidence intervals for the correlations overlapped and no one measure emerged as clearly superior to the others. The best handedness measures accounted for only 8-16% of the variance in cerebral lateralisation. These findings indicate that researchers should not rely on handedness as an indicator of cerebral lateralisation for language. They also imply that lateralisation of language and motor functions in the human brain show considerable independence from one another. PMID- 23738007 TI - Active suppression induced by repetitive self-epitopes protects against EAE development. AB - BACKGROUND: Autoimmune diseases result from a breakdown in self-tolerance to autoantigens. Self-tolerance is induced and sustained by central and peripheral mechanisms intended to deviate harmful immune responses and to maintain homeostasis, where regulatory T cells play a crucial role. The use of self antigens in the study and treatment of a range of autoimmune diseases has been widely described; however, the mechanisms underlying the induced protection by these means are unclear. This study shows that protection of experimental autoimmune disease induced by T cell self-epitopes in a multimerized form (oligomers) is mediated by the induction of active suppression. PRINCIPAL FINDINGS: The experimental autoimmune encephalomyelitis (EAE) animal model for multiple sclerosis was used to study the mechanisms of protection induced by the treatment of oligomerized T cell epitope of myelin proteolipid protein (PLP139 151). Disease protection attained by the administration of oligomers was shown to be antigen specific and effective in both prevention and treatment of ongoing EAE. Oligomer mediated tolerance was actively transferred by cells from treated mice into adoptive hosts. The induction of active suppression was correlated with the recruitment of cells in the periphery associated with increased production of IL-10 and reduction of the pro-inflammatory cytokine TNF-alpha. The role of suppressive cytokines was demonstrated by the reversion of oligomer-induced protection after in vivo blocking of either IL-10 or TGF-beta cytokines. CONCLUSIONS: This study strongly supports an immunosuppressive role of repeat auto-antigens to control the development of EAE with potential applications in vaccination and antigen specific treatment of autoimmune diseases. PMID- 23738008 TI - The role of mechanical force and ROS in integrin-dependent signals. AB - Cells are exposed to several types of integrin stimuli, which generate responses generally referred to as "integrin signals", but the specific responses to different integrin stimuli are poorly defined. In this study, signals induced by integrin ligation during cell attachment, mechanical force from intracellular contraction, or cell stretching by external force were compared. The elevated phosphorylation levels of several proteins during the early phase of cell attachment and spreading of fibroblast cell lines were not affected by inhibition of ROCK and myosin II activity, i.e. the reactions occurred independently of intracellular contractile force acting on the adhesion sites. The contraction independent phosphorylation sites included ERK1/2 T202/Y204, AKT S473, p130CAS Y410, and cofilin S3. In contrast to cell attachment, cyclic stretching of the adherent cells induced a robust phosphorylation only of ERK1/2 and the phosphorylation levels of the other investigated proteins were not or only moderately affected by stretching. No major differences between signaling via alpha5beta1 or alphavbeta3 integrins were detected. The importance of mitochondrial ROS for the integrin-induced signaling pathways was investigated using rotenone, a specific inhibitor of complex I in the respiratory chain. While rotenone only moderately reduced ATP levels and hardly affected the signals induced by cyclic cell stretching, it abolished the activation of AKT and reduced the actin polymerization rate in response to attachment in both cell lines. In contrast, scavenging of extracellular ROS with catalase or the vitamin C analog Asc-2P did not significantly influence the attachment-derived signaling, but caused a selective and pronounced enhancement of ERK1/2 phosphorylation in response to stretching. In conclusion, the results showed that "integrin signals" are composed of separate sets of reactions triggered by different types of integrin stimulation. Mitochondrial ROS and extracellular ROS had specific and distinct effects on the integrin signals induced by cell attachment and mechanical stretching. PMID- 23738009 TI - Conserved inhibitory mechanism and competent ATP binding mode for adenylyltransferases with Fic fold. AB - The ubiquitous FIC domain is evolutionarily conserved from bacteria to human and has been shown to catalyze AMP transfer onto protein side-chain hydroxyl groups. Recently, it was predicted that most catalytically competent Fic proteins are inhibited by the presence of an inhibitory helix alphainh that is provided by a cognate anti-toxin (class I), or is part of the N- or C-terminal part of the Fic protein itself (classes II and III). In vitro, inhibition is relieved by mutation of a conserved glutamate of alphainh to glycine. For the class III bacterial Fic protein NmFic from Neisseria meningitidis, the inhibitory mechanism has been elucidated. Here, we extend above study by including bacterial class I and II Fic proteins VbhT from Bartonella schoenbuchensis and SoFic from Shewanella oneidensis, respectively, and the respective E->G mutants. Comparative enzymatic and crystallographic analyses show that, in all three classes, the ATP substrate binds to the wild-type FIC domains, but with the alpha-phosphate in disparate and non-competent orientations. In the E->G mutants, however, the tri-phosphate moiety is found reorganized to the same tightly bound structure through a unique set of hydrogen bonds with Fic signature motif residues. The gamma-phosphate adopts the location that is taken by the inhibitory glutamate in wild-type resulting in an alpha-phosphate orientation that can be attacked in-line by a target side-chain hydroxyl group. The latter is properly registered to the Fic active center by main-chain beta-interactions with the beta-hairpin flap. These data indicate that the active site motif and the exposed edge of the flap are both required to form an adenylylation-competent Fic protein. PMID- 23738011 TI - Epidemiology of multidrug-resistant microorganisms among nursing home residents in Belgium. AB - OBJECTIVES: A national survey was conducted to determine the prevalence and risk factors of methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum beta-lactamases-producing Enterobacteriaceae (ESBLE) and vancomycin-resistant enterococci (VRE) among nursing home residents in Belgium. METHODS: A random stratified, national prevalence survey was conducted in nursing home residents who were screened for carriage of ESBLE, MRSA and VRE by multisite enriched culture. Characteristics of nursing homes and residents were collected by a questionnaire survey and were analysed by multilevel logistic regression analysis. RESULTS: Of 2791 screened residents in 60 participating nursing home, the weighted prevalence of ESBLE and MRSA carriage were 6.2% (range: 0 to 20%) and 12.2% (range: 0 to 36%), respectively. No cases of VRE were found. No relationship was found between ESBLE and MRSA prevalence rates within nursing homes and the rate of co-colonization was very low (0.8%). Geographical variations in prevalence of MRSA and ESBLE and in distribution of ESBL types in nursing home residents paralleled that of acute hospitals. Risk factors of ESBLE carriage included previously known ESBLE carriage, male gender, a low level of mobility and previous antibiotic exposure. Risk factors for MRSA colonization were: previously known MRSA carriage, skin lesions, a low functional status and antacid use. CONCLUSIONS: A low prevalence of ESBLE carriage was found in nursing home residents in Belgium. The prevalence of MRSA carriage decreased substantially in comparison to a similar survey conducted in 2005. A low functional status appeared as a common factor for ESBLE and MRSA carriage. Previous exposure to antibiotics was a strong predictor of ESBLE colonization while increased clustering of MRSA carriage suggested the importance of cross transmission within nursing homes for this organism. These results emphasize the need for global coordination of the surveillance of MDRO within and between nursing homes and hospitals. PMID- 23738012 TI - Genetic variations in TERT-CLPTM1L genes and risk of lung cancer in Chinese women nonsmokers. AB - BACKGROUND: The TERT gene is the reverse transcriptase component of telomerase and is essential for the maintenance of telomere DNA length, chromosomal stability and cellular immortality. CLPTM1L gene encodes a protein linked to cisplatin resistance, and it is well conserved and express in various normal or malignant tissues, including lung. METHODS: To test this hypothesis, we genotyped for two significant SNPs TERT-rs2736098 and CLPTM1L-rs4016981 in a case-control study with 501 cancer cases and 576 cancer-free controls in Chinese nonsmoking population. Information concerning demographic and risk factors was obtained for each case and control by a trained interviewer. Gene polymorphisms were determined by TaqMan methodology. RESULTS: We found that the homozygous variant genetic model of TERT gene was associated with a significantly increased risk of lung cancer with adjusted OR of 1.72(95%CI = 1.19-2.51, P = 0.004 for heterogeneity). The joint effect of TERT and CLPTM1L increased risk for lung cancer with adjusted OR is 1.31(95%CI = 1.00-1.74, P = 0.052 for heterogeneity). CONCLUSION: Genetic variants in TERT and CLPTM1L may affect the susceptibility of lung cancer, especially adenocarcinoma in Chinese women nonsmokers. PMID- 23738010 TI - HIV-1 Tat protein increases microglial outward K(+) current and resultant neurotoxic activity. AB - Microglia plays a crucial role in the pathogenesis of HIV-1-associated neurocognitive disorders. Increasing evidence indicates the voltage-gated potassium (Kv) channels are involved in the regulation of microglia function, prompting us to hypothesize Kv channels may also be involved in microglia mediated neurotoxic activity in HIV-1-infected brain. To test this hypothesis, we investigated the involvement of Kv channels in the response of microglia to HIV-1 Tat protein. Treatment of rat microglia with HIV-1 Tat protein (200 ng/ml) resulted in pro-inflammatory microglial activation, as indicated by increases in TNF-alpha, IL-1beta, reactive oxygen species, and nitric oxide, which were accompanied by enhanced outward K(+) current and Kv1.3 channel expression. Suppression of microglial Kv1.3 channel activity, either with Kv1.3 channel blockers Margatoxin, 5-(4-Phenoxybutoxy)psoralen, or broad-spectrum K(+) channel blocker 4-Aminopyridine, or by knockdown of Kv1.3 expression via transfection of microglia with Kv1.3 siRNA, was found to abrogate the neurotoxic activity of microglia resulting from HIV-1 Tat exposure. Furthermore, HIV-1 Tat-induced neuronal apoptosis was attenuated with the application of supernatant collected from K(+) channel blocker-treated microglia. Lastly, the intracellular signaling pathways associated with Kv1.3 were investigated and enhancement of microglial Kv1.3 was found to correspond with an increase in Erk1/2 mitogen-activated protein kinase activation. These data suggest targeting microglial Kv1.3 channels may be a potential new avenue of therapy for inflammation-mediated neurological disorders. PMID- 23738013 TI - Rice mitogen activated protein kinase kinase and mitogen activated protein kinase interaction network revealed by in-silico docking and yeast two-hybrid approaches. AB - Protein-protein interaction is one of the crucial ways to decipher the functions of proteins and to understand their role in complex pathways at cellular level. Such a protein-protein interaction network in many crop plants remains poorly defined owing largely to the involvement of high costs, requirement for state of the art laboratory, time and labour intensive techniques. Here, we employed computational docking using ZDOCK and RDOCK programmes to identify interaction network between members of Oryza sativa mitogen activated protein kinase kinase (MAPKK) and mitogen activated protein kinase (MAPK). The 3-dimentional (3-D) structures of five MAPKKs and eleven MAPKs were determined by homology modelling and were further used as input for docking studies. With the help of the results obtained from ZDOCK and RDOCK programmes, top six possible interacting MAPK proteins were predicted for each MAPKK. In order to assess the reliability of the computational prediction, yeast two-hybrid (Y2H) analyses were performed using rice MAPKKs and MAPKs. A direct comparison of Y2H assay and computational prediction of protein interaction was made. With the exception of one, all the other MAPKK-MAPK pairs identified by Y2H screens were among the top predictions by computational dockings. Although, not all the predicted interacting partners could show interaction in Y2H, yet, the harmony between the two approaches suggests that the computational predictions in the present work are reliable. Moreover, the present Y2H analyses per se provide interaction network among MAPKKs and MAPKs which would shed more light on MAPK signalling network in rice. PMID- 23738014 TI - Extracellular domains of CD8alpha and CD8beta subunits are sufficient for HLA class I restricted helper functions of TCR-engineered CD4(+) T cells. AB - By gene transfer of HLA-class I restricted T-cell receptors (TCRs) (HLA-I-TCR) into CD8(+) as well as CD4(+) T-cells, both effector T-cells as well as helper T cells can be generated. Since most HLA-I-TCRs function best in the presence of the CD8 co-receptor, the CD8alphabeta molecule has to be co-transferred into the CD4(+) T-cells to engineer optimal helper T-cells. In this study, we set out to determine the minimal part of CD8alphabeta needed for optimal co-receptor function in HLA-I-TCR transduced CD4(+) T-cells. For this purpose, we transduced human peripheral blood derived CD4(+) T-cells with several HLA-class I restricted TCRs either with or without co-transfer of different CD8 subunits. We demonstrate that the co-transduced CD8alphabeta co-receptor in HLA-I-TCR transduced CD4(+) T cells behaves as an adhesion molecule, since for optimal antigen-specific HLA class I restricted CD4(+) T-cell reactivity the extracellular domains of the CD8alpha and beta subunits are sufficient. PMID- 23738015 TI - Sleep duration among children 8 months after the 2011 Japan earthquake and tsunami. AB - BACKGROUND: To elucidate relationships between disaster damage conditions and sleep duration among children who survived the 2011 Japan earthquake and tsunami. METHODS: The subjects comprised 12,524 children in kindergartens, elementary schools, and junior high schools in Ishinomaki City, Miyagi Prefecture, Japan. The Post Traumatic Stress Symptoms for Children 15 items (PTSSC-15), a self completion questionnaire on traumatic symptoms, and a sleep questionnaire were distributed to them. A questionnaire regarding disaster damage conditions of the children's homes was distributed to their teachers. Of 12,524, an effective response was obtained from 11,692 (93.3%). RESULTS: Relationships between sleep duration and traumatic symptoms were displayed low correlations. Children with house damage and/or evacuation experiences slept for a significantly shorter time than children without these experiences. CONCLUSION: It is critical not only to examine traumatic symptoms in children but also to collect sleep duration and disaster damage conditions following natural disasters. PMID- 23738016 TI - Statistical analysis and decoding of neural activity in the rodent geniculate ganglion using a metric-based inference system. AB - We analyzed the spike discharge patterns of two types of neurons in the rodent peripheral gustatory system, Na specialists (NS) and acid generalists (AG) to lingual stimulation with NaCl, acetic acid, and mixtures of the two stimuli. Previous computational investigations found that both spike rate and spike timing contribute to taste quality coding. These studies used commonly accepted computational methods, but they do not provide a consistent statistical evaluation of spike trains. In this paper, we adopted a new computational framework that treated each spike train as an individual data point for computing summary statistics such as mean and variance in the spike train space. We found that these statistical summaries properly characterized the firing patterns (e. g. template and variability) and quantified the differences between NS and AG neurons. The same framework was also used to assess the discrimination performance of NS and AG neurons and to remove spontaneous background activity or "noise" from the spike train responses. The results indicated that the new metric system provided the desired decoding performance and noise-removal improved stimulus classification accuracy, especially of neurons with high spontaneous rates. In summary, this new method naturally conducts statistical analysis and neural decoding under one consistent framework, and the results demonstrated that individual peripheral-gustatory neurons generate a unique and reliable firing pattern during sensory stimulation and that this pattern can be reliably decoded. PMID- 23738018 TI - Antibiotic consumption and healthcare-associated infections caused by multidrug resistant gram-negative bacilli at a large medical center in Taiwan from 2002 to 2009: implicating the importance of antibiotic stewardship. AB - BACKGROUND: Better depicting the relationship between antibiotic consumption and evolutionary healthcare-associated infections (HAIs) caused by multidrug resistant Gram-negative bacilli (MDR-GNB) may help highlight the importance of antibiotic stewardship. METHODOLOGY/PRINCIPAL FINDINGS: The correlations between antibiotic consumption and MDR-GNB HAIs at a 2,700-bed primary care and tertiary referral center in Taiwan between 2002 and 2009 were assessed. MDR-GNB HAI referred to a HAI caused by MDR-Enterobacteriaceae, MDR-Pseudomonas aeruginosa or MDR-Acinetobacter spp. Consumptions of individual antibiotics and MDR-GNB HAI series were first evaluated for trend over time. When a trend was significant, the presence or absence of associations between the selected clinically meaningful antibiotic resistance and antibiotic consumption was further explored using cross-correlation analyses. Significant major findings included (i) increased consumptions of extended-spectrum cephalosporins, carbapenems, aminopenicillins/beta-lactamase inhibitors, piperacillin/tazobactam, and fluoroquinolones, (ii) decreased consumptions of non-extended-spectrum cephalosporins, natural penicillins, aminopenicillins, ureidopenicillin and aminoglycosides, and (iii) decreasing trend in the incidence of the overall HAIs, stable trends in GNB HAIs and MDR-GNB HAIs throughout the study period, and increasing trend in HAIs caused by carbapenem-resistant (CR) Acinetobacter spp. since 2006. HAIs due to CR-Acinetobacter spp. was found to positively correlate with the consumptions of carbapenems, extended-spectrum cephalosporins, aminopenicillins/beta-lactamase inhibitors, piperacillin/tazobactam and fluoroquinolones, and negatively correlate with the consumptions of non-extended spectrum cephalosporins, penicillins and aminoglycosides. No significant association was found between the increased use of piperacilllin/tazobactam and increasing HAIs due to CR-Acinetobacter spp. CONCLUSIONS: The trend in overall HAIs decreased and trends in GNB HAIs and MDR-GNB HAIs remained stable over time suggesting that the infection control practice was effective during the study period, and the escalating HAIs due to CR- Acinetobacter spp. were driven by consumptions of broad-spectrum antibiotics other than piperacillin/tazobactam. Our data underscore the importance of antibiotic stewardship in the improvement of the trend of HAIs caused by Acinetobacter spp. PMID- 23738017 TI - Global transcriptional and phenotypic analyses of Escherichia coli O157:H7 strain Xuzhou21 and its pO157_Sal cured mutant. AB - Escherichia coli O157:H7 is an important food-borne pathogen that can cause hemorrhagic colitis and hemolytic-uremic syndrome in humans. pO157_Sal, a novel conjugative plasmid is present in a Chinese O157:H7 outbreak strain Xuzhou21. Here we investigated the phenotypic and transcriptional differences between the wild type strain Xuzhou21 and the pO157_Sal cured mutant strain Xuzhou21m. RNA Seq analysis found that all 52 ORFs encoded on pO157_Sal were transcribed. One hundred and sixty eight chromosomal and pO157 genes were differentially expressed (>=2 fold difference) between Xuzhou21 and Xuzhou21m. Sixty-seven and 101 genes were up-regulated and down-regulated respectively by pO157_Sal including genes related to stress response, adaption and virulence. The plasmid-cured mutant Xuzhou21m grew slower than wild type Xuzhou21 and pO157_Sal plasmid complemented strain Xuzhou21c in M9 medium under the condition of high NaCl or presence of sodium deoxycholate (NaDC), corroborating with the RNA-Seq data. Seven differentially expressed genes are associated with NaDC resistance, including the adenine-specific DNA-methyltransferase gene (dam), multidrug efflux system subunit gene mdtA, hyperosmotically inducible periplasmic protein gene osmY and oxidation-reduction related genes while two differentially expressed genes (osmY and pspD) are likely to be related to resistance to osmotic pressure. A number of differentially expressed genes were virulence associated including four genes encoding T3SS effectors from the chromosome and ehxD from pO157. Through complementation of Xuzhou21m with a plasmid construct carrying the pO157_Sal hha homolog we further showed that the pO157_Sal hha represses the expression of T3SS effectors. These findings demonstrated that the plasmid pO157_Sal affects the transcription of the chromosomal and pO157 plasmid genes and contributes to the enhanced ability to resist stress. We conclude that pO157_Sal plays an important role in regulating global gene expression and affects the virulence and adaptation of E. coli O157:H7. PMID- 23738019 TI - Comparative transcriptome analysis using high papaverine mutant of Papaver somniferum reveals pathway and uncharacterized steps of papaverine biosynthesis. AB - The benzylisoquinoline alkaloid papaverine, synthesized in low amount in most of the opium poppy varieties of Papaver somniferum, is used as a vasodilator muscle relaxant and antispasmodic. Papaverine biosynthesis remains controversial as two different routes utilizing either (S)-coclaurine or (S)-reticuline have been proposed with uncharacterized intermediate steps. In an attempt to elucidate papaverine biosynthesis and identify putative genes involved in uncharacterized steps, we carried out comparative transcriptome analysis of high papaverine mutant (pap1) and normal cultivar (BR086) of P. somniferum. This natural mutant synthesizes more than 12-fold papaverine in comparison to BR086. We established more than 238 Mb transcriptome data separately for pap1 and BR086. Assembly of reads generated 127,342 and 106,128 unigenes in pap1 and BR086, respectively. Digital gene expression analysis of transcriptomes revealed 3,336 differentially expressing unigenes. Enhanced expression of (S)-norcoclaurine-6-O methyltransferase (6OMT), (S)-3'-hydroxy-N-methylcoclaurine 4'-O methyltransferase (4'OMT), norreticuline 7-O-methyltransferase (N7OMT) and down regulation of reticuline 7-O-methyltransferase (7OMT) in pap1 in comparison to BR086 suggest (S)-coclaurine as the route for papaverine biosynthesis. We also identified several methyltransferases and dehydrogenases with enhanced expression in pap1 in comparison to BR086. Our analysis using natural mutant, pap1, concludes that (S)-coclaurine is the branch-point intermediate and preferred route for papaverine biosynthesis. Differentially expressing methyltransferases and dehydrogenases identified in this study will help in elucidating complete biosynthetic pathway of papaverine. The information generated will be helpful in developing strategies for enhanced biosynthesis of papaverine through biotechnological approaches. PMID- 23738020 TI - CNF1 increases brain energy level, counteracts neuroinflammatory markers and rescues cognitive deficits in a murine model of Alzheimer's disease. AB - Overexpression of pro-inflammatory cytokines and cellular energy failure are associated with neuroinflammatory disorders, such as Alzheimer's disease. Transgenic mice homozygous for human ApoE4 gene, a well known AD and atherosclerosis animal model, show decreased levels of ATP, increased inflammatory cytokines level and accumulation of beta amyloid in the brain. All these findings are considered responsible for triggering cognitive decline. We have demonstrated that a single administration of the bacterial E. coli protein toxin CNF1 to aged apoE4 mice, beside inducing a strong amelioration of both spatial and emotional memory deficits, favored the cell energy restore through an increment of ATP content. This was accompanied by a modulation of cerebral Rho and Rac1 activity. Furthermore, CNF1 decreased the levels of beta amyloid accumulation and interleukin-1beta expression in the hippocampus. Altogether, these data suggest that the pharmacological modulation of Rho GTPases by CNF1 can improve memory performances in an animal model of Alzheimer's disease via a control of neuroinflammation and a rescue of systemic energy homeostasis. PMID- 23738022 TI - Contributions of the Guinea worm disease eradication campaign toward achievement of the Millennium Development Goals. PMID- 23738021 TI - A genome-wide screening of potential target genes to enhance the antifungal activity of micafungin in Schizosaccharomyces pombe. AB - Micafungin is a non-reversible inhibitor of 1, 3-beta-D-glucan synthase and interferes with fungal cell wall synthesis. Clinically, micafungin has been shown to be efficacious for the treatment of invasive candidiasis and invasive aspergillosis. However, considering its relatively restricted antifungal spectrum, combination therapy with micafungin plus other agents should be considered in critically ill patients. To identify potential therapeutic targets for syncretic drug combinations that potentiate micafungin action, we carried out a genome-wide screen for altered sensitivity to micafungin by using the model yeast Schizosaccharomyces pombe mutant library. We confirmed that 159 deletion strains in the library are micafungin sensitive and classified them into various functional categories, including cell wall biosynthesis, gene expression and chromatin remodeling, membrane trafficking, signaling transduction, ubiquitination, ergosterol biosynthetic process and a variety of other known functions or still unknown functions. On the other hand, we also investigated the growth inhibitory activities of some well-known drugs in combination with micafungin including antifungal drug amphotericin B, fluconazole and immunosuppressive drug FK506. We found that amphotericin B in combination with micafungin showed a more potent inhibitory activity against wild-type cells than that of micafungin alone, whereas fluconazole in combination with micafungin did not. Also, the immunosuppressive drug FK506 showed synergistic inhibitory effect with micafungin on the growth of wild-type cells, whereas it decreased the inhibitory effect of micafungin in Deltapmk1 cells, a deletion mutant of the cell wall integrity mitogen-activated protein kinase (MAPK) Pmk1. Altogether, our findings provide useful information for new potential drug combinations in the treatment of fungal infections. PMID- 23738023 TI - Potential non-invasive urine-based antigen (protein) detection assay to diagnose active visceral leishmaniasis. PMID- 23738024 TI - Emergence of clinically relevant Non-Tuberculous Mycobacterial infections in Saudi Arabia. AB - BACKGROUND: Non-Tuberculous Mycobacteria (NTM) are emerging around the world due to a higher prevalence of immunosuppressive illness and therapy. Saudi Arabia is not an exception as there have been novel mycobacterial species also identified. In addition, several published case reports from different parts of the country suggest a growing pathogenic potential of NTM. As the first nationwide study, we sought to gain an insight into the species diversity of NTM clinical isolates. METHODOLOGY/PRINCIPAL FINDINGS: During June 2009-July 2010, 95 clinical isolates were collected from tuberculosis reference laboratories in major provinces within Saudi Arabia and subjected to standard line probe assay techniques to identify their species. Diagnostic guidelines of the American Thoracic Society were applied to determine the clinical relevance of respiratory isolates. Species diversity (13 species) was very high and dominated (61.0%) by rapid growing NTM. The major species obtained were Mycobacterium abscessus, M. fortuitum, M. intracellulare followed by M. kansassi, M. gordanae and M. avium. Interestingly this study reports for the first time the clinical relevance of M. celatum, M. xenopi, M. scrofulceum, M. lentiflavum, M. asiaticum and M. simiae in Saudi Arabia. Of the total, 67.1% were clinically relevant respiratory cases, 23.2% were non-respiratory cases and 9.7% were respiratory colonizers. Coexisting illness was reported in 53.7% of the studied cases. The major risk factors observed among the patients were previous history of tuberculosis, chronic obstructive pulmonary disorder and human immunodeficiency virus infection. CONCLUSION/SIGNIFICANCE: The high rates of clinically confirmed respiratory cases suggest that NTM infections are indeed a new challenge to health authorities. The current findings show an opposite picture of the Western world where M. avium complex and particularly slow growing NTM are the most predominant respiratory pathogens. The complexity of species demands an immediate strengthening of the current diagnostic facilities. PMID- 23738025 TI - Cooler temperatures destabilize RNA interference and increase susceptibility of disease vector mosquitoes to viral infection. AB - BACKGROUND: The impact of global climate change on the transmission dynamics of infectious diseases is the subject of extensive debate. The transmission of mosquito-borne viral diseases is particularly complex, with climatic variables directly affecting many parameters associated with the prevalence of disease vectors. While evidence shows that warmer temperatures often decrease the extrinsic incubation period of an arthropod-borne virus (arbovirus), exposure to cooler temperatures often predisposes disease vector mosquitoes to higher infection rates. RNA interference (RNAi) pathways are essential to antiviral immunity in the mosquito; however, few experiments have explored the effects of temperature on the RNAi machinery. METHODOLOGY/PRINCIPAL FINDINGS: We utilized transgenic "sensor" strains of Aedes aegypti to examine the role of temperature on RNA silencing. These "sensor" strains express EGFP only when RNAi is inhibited; for example, after knockdown of the effector proteins Dicer-2 (DCR-2) or Argonaute-2 (AGO-2). We observed an increase in EGFP expression in transgenic sensor mosquitoes reared at 18 degrees C as compared with 28 degrees C. Changes in expression were dependent on the presence of an inverted repeat with homology to a portion of the EGFP sequence, as transgenic strains lacking this sequence, the double stranded RNA (dsRNA) trigger for RNAi, showed no change in EGFP expression when reared at 18 degrees C. Sequencing small RNAs in sensor mosquitoes reared at low temperature revealed normal processing of dsRNA substrates, suggesting the observed deficiency in RNAi occurs downstream of DCR 2. Rearing at cooler temperatures also predisposed mosquitoes to higher levels of infection with both chikungunya and yellow fever viruses. CONCLUSIONS/SIGNIFICANCE: This data suggest that microclimates, such as those present in mosquito breeding sites, as well as more general climactic variables may influence the dynamics of mosquito-borne viral diseases by affecting the antiviral immunity of disease vectors. PMID- 23738026 TI - Genetic and phenotypic characterization of manufacturing seeds for a tetravalent dengue vaccine (DENVax). AB - BACKGROUND: We have developed a manufacturing strategy that can improve the safety and genetic stability of recombinant live-attenuated chimeric dengue vaccine (DENVax) viruses. These viruses, containing the pre-membrane (prM) and envelope (E) genes of dengue serotypes 1-4 in the replicative background of the attenuated dengue-2 PDK-53 vaccine virus candidate, were manufactured under cGMP. METHODOLOGY/PRINCIPAL FINDINGS: After deriving vaccine viruses from RNA transfected Vero cells, six plaque-purified viruses for each serotype were produced. The plaque-purified strains were then analyzed to select one stock for generation of the master seed. Full genetic and phenotypic characterizations of the master virus seeds were conducted to ensure these viruses retained the previously identified attenuating determinants and phenotypes of the vaccine viruses. We also assessed vector competence of the vaccine viruses in sympatric (Thai) Aedes aegypti mosquito vectors. CONCLUSION/SIGNIFICANCE: All four serotypes of master vaccine seeds retained the previously defined safety features, including all three major genetic loci of attenuation, small plaques, temperature sensitivity in mammalian cells, reduced replication in mosquito cell cultures, and reduced neurovirulence in new-born mice. In addition, the candidate vaccine viruses demonstrated greatly reduced infection and dissemination in Aedes aegypti mosquitoes, and are not likely to be transmissible by these mosquitoes. This manufacturing strategy has successfully been used to produce the candidate tetravalent vaccine, which is currently being tested in human clinical trials in the United States, Central and South America, and Asia. PMID- 23738027 TI - Evolutionary dynamics of West Nile virus in the United States, 1999-2011: phylogeny, selection pressure and evolutionary time-scale analysis. AB - West Nile virus (WNV), an arbovirus maintained in a bird-mosquito enzootic cycle, can infect other vertebrates including humans. WNV was first reported in the US in 1999 where, to date, three genotypes belonging to WNV lineage I have been described (NY99, WN02, SW/WN03). We report here the WNV sequences obtained from two birds, one mosquito, and 29 selected human samples acquired during the US epidemics from 2006-2011 and our examination of the evolutionary dynamics in the open-reading frame of WNV isolates reported from 1999-2011. Maximum-likelihood and Bayesian methods were used to perform the phylogenetic analyses and selection pressure analyses were conducted with the HyPhy package. Phylogenetic analysis identified human WNV isolates within the main WNV genotypes that have circulated in the US. Within genotype SW/WN03, we have identified a cluster with strains derived from blood donors and birds from Idaho and North Dakota collected during 2006-2007, termed here MW/WN06. Using different codon-based and branch-site selection models, we detected a number of codons subjected to positive pressure in WNV genes. The mean nucleotide substitution rate for WNV isolates obtained from humans was calculated to be 5.06*10(-4) substitutions/site/year (s/s/y). The Bayesian skyline plot shows that after a period of high genetic variability following the introduction of WNV into the US, the WNV population appears to have reached genetic stability. The establishment of WNV in the US represents a unique opportunity to understand how an arbovirus adapts and evolves in a naive environment. We describe a novel, well-supported cluster of WNV formed by strains collected from humans and birds from Idaho and North Dakota. Adequate genetic surveillance is essential to public health since new mutants could potentially affect viral pathogenesis, decrease performance of diagnostic assays, and negatively impact the efficacy of vaccines and the development of specific therapies. PMID- 23738028 TI - Prevalence and diversity of Bartonella species in commensal rodents and ectoparasites from Nigeria, West Africa. AB - BACKGROUND: Bartonellae are fastidious bacteria causing persistent bacteremia in humans and a wide variety of animals. In recent years there is an increasing interest in mammalian bartonelloses in general and in rodent bartonelloses in particular. To date, no studies investigating the presence of Bartonella spp. in rodents and ectoparasites from Nigeria were carried out. METHODOLOGY/PRINCIPAL FINDINGS: The aim of the current study was to investigate the presence of Bartonella spp. in commensal rodents and their ectoparasites in Nigeria. We report, for the first time, the molecular detection of Bartonella in 26% (46/177) of commensal rodents (Rattus rattus, R. norvegicus and Cricetomys gambianus) and 28% (9/32) of ectoparasite pools (Xenopsylla cheopis, Haemolaelaps spp., Ctenophthalmus spp., Hemimerus talpoides, and Rhipicephalus sanguineus) from Nigeria. Sequence analysis of the citrate synthase gene (gltA) revealed diversity of Bartonella spp. and genotypes in Nigerian rodents and their ectoparasites. Bartonella spp. identical or closely related to Bartonella elizabethae, Bartonella tribocorum and Bartonella grahamii were detected. CONCLUSIONS/SIGNIFICANCE: High prevalence of infection with Bartonella spp. was detected in commensal rodents and ectoparasites from Nigeria. The Bartonella spp. identified were previously associated with human diseases highlighting their importance to public health. Further studies need to be conducted to determine whether the identified Bartonella species could be responsible for human cases of febrile illness in Nigeria. PMID- 23738029 TI - Association between response to albendazole treatment and beta-tubulin genotype frequencies in soil-transmitted helminths. AB - BACKGROUND: Albendazole (ABZ), a benzimidazole (BZ) anthelmintic (AH), is commonly used for treatment of soil-transmitted helminths (STHs). Its regular use increases the possibility that BZ resistance may develop, which, in veterinary nematodes is caused by single nucleotide polymorphisms (SNPs) in the beta-tubulin gene at positions 200, 167 or 198. The relative importance of these SNPs varies among the different parasitic nematodes of animals studied to date, and it is currently unknown whether any of these are influencing BZ efficacy against STHs in humans. We assessed ABZ efficacy and SNP frequencies before and after treatment of Ascaris lumbricoides, Trichuris trichiura and hookworm infections. METHODS: Studies were performed in Haiti, Kenya, and Panama. Stool samples were examined prior to ABZ treatment and two weeks (Haiti), one week (Kenya) and three weeks (Panama) after treatment to determine egg reduction rate (ERR). Eggs were genotyped and frequencies of each SNP assessed. FINDINGS: In T. trichiura, polymorphism was detected at codon 200. Following treatment, there was a significant increase, from 3.1% to 55.3%, of homozygous resistance-type in Haiti, and from 51.3% to 67.8% in Kenya (ERRs were 49.7% and 10.1%, respectively). In A. lumbricoides, a SNP at position 167 was identified at high frequency, both before and after treatment, but ABZ efficacy remained high. In hookworms from Kenya we identified the resistance-associated SNP at position 200 at low frequency before and after treatment while ERR values indicated good drug efficacy. CONCLUSION: Albendazole was effective for A. lumbricoides and hookworms. However, ABZ exerts a selection pressure on the beta-tubulin gene at position 200 in T. trichiura, possibly explaining only moderate ABZ efficacy against this parasite. In A. lumbricoides, the codon 167 polymorphism seemed not to affect drug efficacy whilst the polymorphism at codon 200 in hookworms was at such low frequency that conclusions cannot be drawn. PMID- 23738030 TI - Antibody signature of spontaneous clearance of Chlamydia trachomatis ocular infection and partial resistance against re-challenge in a nonhuman primate trachoma model. AB - BACKGROUND: Chlamydia trachomatis is the etiological agent of trachoma the world's leading cause of infectious blindness. Here, we investigate whether protracted clearance of a primary infection in nonhuman primates is attributable to antigenic variation or related to the maturation of the anti-chlamydial humoral immune response specific to chlamydial antigens. METHODOLOGY/PRINCIPAL FINDINGS: Genomic sequencing of organisms isolated throughout the protracted primary infection revealed that antigenic variation was not related to the inability of monkeys to efficiently resolve their infection. To explore the maturation of the humoral immune response as a possible reason for delayed clearance, sera were analyzed by radioimmunoprecipitation using intrinsically radio-labeled antigens prepared under non-denaturing conditions. Antibody recognition was restricted to the antigenically variable major outer membrane protein (MOMP) and a few antigenically conserved antigens. Recognition of MOMP occurred early post-infection and correlated with reduction in infectious ocular burdens but not with infection eradication. In contrast, antibody recognition of conserved antigens, identified as PmpD, Hsp60, CPAF and Pgp3, appeared late and correlated with infection eradication. Partial immunity to re-challenge was associated with a discernible antibody recall response against all antigens. Antibody recognition of PmpD and CPAF was destroyed by heat treatment while MOMP and Pgp3 were partially affected, indicating that antibody specific to conformational epitopes on these proteins may be important to protective immunity. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that delayed clearance of chlamydial infection in NHP is not the result of antigenic variation but rather a consequence of the gradual maturation of the C. trachomatis antigen specific humoral immune response. However, we cannot conclude that antibodies specific for these proteins play the primary role in host protective immunity as they could be surrogate markers of T cell immunity. Collectively, our results argue that an efficacious subunit trachoma vaccine might require a combination of these antigens delivered in their native conformation. PMID- 23738031 TI - Significance of G-X-W motif in the myocilin olfactomedin domain. PMID- 23738032 TI - Red orange: experimental models and epidemiological evidence of its benefits on human health. AB - In recent years, there has been increasing public interest in plant antioxidants, thanks to the potential anticarcinogenic and cardioprotective actions mediated by their biochemical properties. The red (or blood) orange (Citrus sinensis (L.) Osbeck) is a pigmented sweet orange variety typical of eastern Sicily (southern Italy), California, and Spain. In this paper, we discuss the main health-related properties of the red orange that include anticancer, anti-inflammatory, and cardiovascular protection activities. Moreover, the effects on health of its main constituents (namely, flavonoids, carotenoids, ascorbic acid, hydroxycinnamic acids, and anthocyanins) are described. The red orange juice demonstrates an important antioxidant activity by modulating many antioxidant enzyme systems that efficiently counteract the oxidative damage which may play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes, and cancer. The beneficial effects of this fruit may be mediated by the synergic effects of its compounds. Thus, the supply of natural antioxidant compounds through a balanced diet rich in red oranges might provide protection against oxidative damage under differing conditions and could be more effective than, the supplementation of an individual antioxidant. PMID- 23738033 TI - Diabetic neuropathy and oxidative stress: therapeutic perspectives. AB - Diabetic neuropathy (DN) is a widespread disabling disorder comprising peripheral nerves' damage. DN develops on a background of hyperglycemia and an entangled metabolic imbalance, mainly oxidative stress. The majority of related pathways like polyol, advanced glycation end products, poly-ADP-ribose polymerase, hexosamine, and protein kinase c all originated from initial oxidative stress. To date, no absolute cure for DN has been defined; although some drugs are conventionally used, much more can be found if all pathophysiological links with oxidative stress would be taken into account. In this paper, although current therapies for DN have been reviewed, we have mainly focused on the links between DN and oxidative stress and therapies on the horizon, such as inhibitors of protein kinase C, aldose reductase, and advanced glycation. With reference to oxidative stress and the related pathways, the following new drugs are under study such as taurine, acetyl-L-carnitine, alpha lipoic acid, protein kinase C inhibitor (ruboxistaurin), aldose reductase inhibitors (fidarestat, epalrestat, ranirestat), advanced glycation end product inhibitors (benfotiamine, aspirin, aminoguanidine), the hexosamine pathway inhibitor (benfotiamine), inhibitor of poly ADP-ribose polymerase (nicotinamide), and angiotensin-converting enzyme inhibitor (trandolapril). The development of modern drugs to treat DN is a real challenge and needs intensive long-term comparative trials. PMID- 23738034 TI - Effect of lutein and antioxidant supplementation on VEGF expression, MMP-2 activity, and ultrastructural alterations in apolipoprotein E-deficient mouse. AB - Oxidative stress is involved in the pathogenesis of several diseases such as atherosclerosis and age-related macular degeneration (AMD). ApoE-deficient mice (apoE(-/-)) are a well-established model of genetic hypercholesterolemia and develop retinal alterations similar to those found in humans with AMD. Thus supplementation with lutein or multivitamin plus lutein and glutathione complex (MV) could prevent the onset of these alterations. ApoE(-/-) mice (n = 40, 3 months old) were treated daily for 3 months with lutein (AE-LUT) or MV (two doses): AE-MV15 (15 mg/kg/day) and AE-MV50 (50 mg/kg/day) and were compared to controls with vehicle (AE-C). Wild-type mice (n = 10) were also used as control (WT-C). ApoE(-/-) mice showed higher retinal lipid peroxidation and increased VEGF expression and MMP-2 activity, associated with ultrastructural alterations such as basal laminar deposits, vacuoles, and an increase in Bruch's membrane thickness. While lutein alone partially prevented the alterations observed in apoE(-/-) mice, MV treatment substantially reduced VEGF levels and MMP-2 activity and ameliorated the retinal morphological alterations. These results suggest that oxidative stress in addition to an increased expression and activity of proangiogenic factors could participate in the onset or development of retinal alterations of apoE(-/-) mice. Moreover, these changes could be prevented by efficient antioxidant treatments. PMID- 23738035 TI - Plasma lipoproteins as mediators of the oxidative stress induced by UV light in human skin: a review of biochemical and biophysical studies on mechanisms of apolipoprotein alteration, lipid peroxidation, and associated skin cell responses. AB - There are numerous studies concerning the effect of UVB light on skin cells but fewer on other skin components such as the interstitial fluid. This review highlights high-density lipoprotein (HDL) and low-density lipoprotein (LDL) as important targets of UVB in interstitial fluid. Tryptophan residues are the sole apolipoprotein residues absorbing solar UVB. The UVB-induced one-electron oxidation of Trp produces (*)Trp and (*)O2 (-) radicals which trigger lipid peroxidation. Immunoblots from buffered solutions or suction blister fluid reveal that propagation of photooxidative damage to other residues such as Tyr or disulfide bonds produces intra- and intermolecular bonds in apolipoproteins A-I, A-II, and B100. Partial repair of phenoxyl tyrosyl radicals (TyrO(*)) by alpha tocopherol is observed with LDL and HDL on millisecond or second time scales, whereas limited repair of alpha -tocopherol by carotenoids occurs in only HDL. More effective repair of Tyr and alpha -tocopherol is observed with the flavonoid, quercetin, bound to serum albumin, but quercetin is less potent than new synthetic polyphenols in inhibiting LDL lipid peroxidation or restoring alpha -tocopherol. The systemic consequences of HDL and LDL oxidation and the activation and/or inhibition of signalling pathways by oxidized LDL and their ability to enhance transcription factor DNA binding activity are also reviewed. PMID- 23738036 TI - Age-dependent accumulation of 8-oxoguanine in the DNA and RNA in various rat tissues. AB - The relationship between the oxidative damage of nucleic acids and aging of animals was investigated by analyzing the nucleic acids derived from various tissue specimens of naturally aged Sprague-Dawley (SD) rats. For this purpose, we established an accurate and sensitive isotope-diluted LC-MS/MS method to determine the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGsn) in DNA and 8-oxo-7,8-dihydroguanosine (8-oxo-Gsn) in RNA. An age-dependent increase in oxidative DNA and RNA damage was observed in the various organs examined, including the brain, liver, kidneys, and testes. Similar increases in the 8-oxo dGsn and 8-oxo-Gsn contents were observed in three parts of the brain, the hippocampus, cerebral cortex, and cerebellum, among which, the values for the hippocampus were always the highest. When the oxidized guanosine metabolites were quantified with urine, a similar age-dependent increase was observed for both 8 oxo-dGsn and 8-oxo-Gsn. However, unlike the results of nucleic acid samples derived from the tissues, the amount of 8-oxo-Gsn was significantly higher compared to that of 8-oxo-dGsn, probably reflecting the fact that RNA degradation occurs more frequently than DNA degradation. Our finding indicates that the amount of urinary 8-oxo-Gsn could be considered as a biomarker for the sensitive measurement of oxidative stress and aging. PMID- 23738037 TI - Nrf2 is a protective factor against oxidative stresses induced by diesel exhaust particle in allergic asthma. AB - Epidemiological studies have shown that air pollutants, such as diesel exhaust particle (DEP), are implicated in the increased incidence of allergic airway disorders. In vitro studies of molecular mechanisms have focused on the role of reactive oxygen species generated directly and indirectly by the exposure to DEP. Antioxidants effectively reduce the allergic inflammatory effects induced by DEP both in vitro and in vivo. On the other hand, Nrf2 is a transcription factor essential for the inducible and/or constitutive expression of phase II and antioxidant enzymes. Disruption of Nrf2 enhances susceptibility to airway inflammatory responses and exacerbation of allergic inflammation induced by DEP in mice. Host responses to DEP are regulated by a balance between antioxidants and proinflammatory responses. Nrf2 may be an important protective factor against oxidative stresses induced by DEP in airway inflammation and allergic asthma and is expected to contribute to chemoprevention against DEP health effects in susceptible individuals. PMID- 23738038 TI - Oxidative stress and free-radical oxidation in bcg granulomatosis development. AB - BACKGROUND: Little is known about the role of free-radical and oxidative stress signaling in granuloma maturation and resolution. We aimed to study the activity of free-radical oxidation processes in the dynamics of BCG-induced generalized granulomatosis in mice. METHODS: Chronic granulomatous inflammation was induced in male BALB/c mice by intravenously injecting the BCG vaccine, and the production of oxidative stress (activity of free-radical oxidation processes) and histological changes in the lungs, liver, and peritoneal exudate were measured 3, 30, 60, and 90 days after infection. RESULTS: The tuberculous granuloma numerical density and diameter continuously increased from day 30 to day 90, and the macrophage content within the granulomas progressively diminished with a concomitant elevation in the number of epithelioid cells. The activity of the free-radical oxidation processes in the liver (i.e., the intensity of the homogenate chemiluminescence) reached a maximum at postinfection day 60 and subsequently began to decrease. The peak generation of reactive oxygen species by phagocytes in the peritoneal exudate (measured using flow cytometry) was also shifted in time and fell on day 30. CONCLUSIONS: The rise in the steady-state concentration of H2O2 in the liver of mice with BCG-induced granulomatosis is not related to local H2O2 production by phagocytes, and a decrease in the severity of generalized inflammation precedes the resolution of local inflammation. PMID- 23738039 TI - Effects of single exposure of sodium fluoride on lipid peroxidation and antioxidant enzymes in salivary glands of rats. AB - Many studies suggest that fluoride exposure can inhibit the activity of various enzymes and can generate free radicals, which interfere with antioxidant defence mechanisms in living systems. To further the understanding of this issue, this present study examined the effects of low-dose fluoride treatment on the activity of enzymatic antioxidant superoxide dismutase (SOD) and catalase (CAT), as well as the levels of lipid peroxidation (LPO) in the parotid (PA) and submandibular (SM) salivary glands of rats. Rats were injected with a single dose of sodium fluoride (NaF) (15 mg F(-)/kg b.w.) then euthanized at various time intervals up to 24 hours (h) following exposure. NaF exposure did not cause significant differences in SOD or CAT activity or LPO levels in PA glands compared to control. Conversely, SM glands presented increased SOD activity after 3 h and decreased SOD activity after 1, 12, and 24 h, while LPO was increased after 6, 12, and 24 h of the NaF injection. There were no significant differences in the CAT activity in the groups studied. Our results demonstrated that NaF intoxication caused oxidative stress in salivary glands few hours after administration. These changes were more pronounced in SM than in PA gland. PMID- 23738040 TI - Examining the impact of skin lighteners in vitro. AB - Three cosmetically important skin lightening agents, hydroquinone (HQ), kojic acid (KA), and niacinamide (NA), consume the bulk of successful skin lightening ingredients in cosmetic applications. However, the mechanisms by which these ingredients work are still unclear. In this study, melanocytes and keratinocytes were treated with high, nontoxic doses of HQ, KA, and NA and the cells were examined by human microarrays and protein assays for several important targets including cytotoxicity, melanin expression, tyrosinase gene (TYR) and protein expression, melanocortin-1 receptor (MC1R) gene and protein expression, cytochrome c oxidase-1 (COX1) gene and protein expression, and ferritin (FTH1) gene and protein expression. It was found that all the skin lighteners examined showed marked increases in TYR, COX1, and FTH1 gene and protein expression, but not in MC1R expression in melanocytes. Upregulation of COX1 and FTH1 genes and proteins was common across both cell lines, melanocytes and keratinocytes. The results of the tyrosinase expression were somewhat unexpected. The role of iron in the expression of melanin is somewhat unexplored, but common and strong upregulation of ferritin protein in both types of cells due to the treatments suggests that iron plays a more pivotal role in melanin synthesis than previously anticipated. PMID- 23738041 TI - Site-specific antioxidative therapy for prevention of atherosclerosis and cardiovascular disease. AB - Oxidative stress has been implicated in pathophysiology of aging and age associated disease. Antioxidative medicine has become a practice for prevention of atherosclerosis. However, limited success in preventing cardiovascular disease (CVD) in individuals with atherosclerosis using general antioxidants has prompted us to develop a novel antioxidative strategy to prevent atherosclerosis. Reducing visceral adipose tissue by calorie restriction (CR) and regular endurance exercise represents a causative therapy for ameliorating oxidative stress. Some of the recently emerging drugs used for the treatment of CVD may be assigned as site-specific antioxidants. CR and exercise mimetic agents are the choice for individuals who are difficult to continue CR and exercise. Better understanding of molecular and cellular biology of redox signaling will pave the way for more effective antioxidative medicine for prevention of CVD and prolongation of healthy life span. PMID- 23738042 TI - The NRF2 activation and antioxidative response are not impaired overall during hyperoxia-induced lung epithelial cell death. AB - Lung epithelial and endothelial cell death caused by pro-oxidant insults is a cardinal feature of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) patients. The NF-E2-related factor 2 (NRF2) activation in response to oxidant exposure is crucial to the induction of several antioxidative and cytoprotective enzymes that mitigate cellular stress. Since prolonged exposure to hyperoxia causes cell death, we hypothesized that chronic hyperoxia impairs NRF2 activation, resulting in cell death. To test this hypothesis, we exposed nonmalignant small airway epithelial cells (AECs) to acute (1-12 h) and chronic (36-48 h) hyperoxia and evaluated cell death, NRF2 nuclear accumulation and target gene expression, and NRF2 recruitment to the endogenous HMOX1 and NQO1 promoters. As expected, hyperoxia gradually induced death in AECs, noticeably and significantly by 36 h; ~60% of cells were dead by 48 h. However, we unexpectedly found increased expression levels of NRF2-regulated antioxidative genes and nuclear NRF2 in AECs exposed to chronic hyperoxia as compared to acute hyperoxia. Chromatin Immunoprecipitation (ChIP) assays revealed an increased recruitment of NRF2 to the endogenous HMOX1 and NQO1 promoters in AECs exposed to acute or chronic hyperoxia. Thus, our findings demonstrate that NRF2 activation and antioxidant gene expression are functional during hyperoxia-induced lung epithelial cell death and that chronic hyperoxia does not impair NRF2 signaling overall. PMID- 23738043 TI - Reactive oxygen species and the cardiovascular system. AB - Ever since the discovery of free radicals, many hypotheses on the deleterious actions of reactive oxygen species (ROS) have been proposed. However, increasing evidence advocates the necessity of ROS for cellular homeostasis. ROS are generated as inherent by-products of aerobic metabolism and are tightly controlled by antioxidants. Conversely, when produced in excess or when antioxidants are depleted, ROS can inflict damage to lipids, proteins, and DNA. Such a state of oxidative stress is associated with many pathological conditions and closely correlated to oxygen consumption. Although the deleterious effects of ROS can potentially be reduced by restoring the imbalance between production and clearance of ROS through administration of antioxidants (AOs), the dosage and type of AOs should be tailored to the location and nature of oxidative stress. This paper describes several pathways of ROS signaling in cellular homeostasis. Further, we review the function of ROS in cardiovascular pathology and the effects of AOs on cardiovascular outcomes with emphasis on the so-called oxidative paradox. PMID- 23738045 TI - Adduct of malondialdehyde to hemoglobin: a new marker of oxidative stress that is associated with significant morbidity in preterm infants. AB - Preterm infants (PT) are particularly exposed to oxidative stress (OS), and a blood-sparing marker, the malondialdehyde adduct to hemoglobin (MDA-Hb), may be useful to accurately assess OS-related neonatal morbidity. In a prospective study, MDA-Hb concentrations were assessed in two groups of PT, one with and one without severe neonatal morbidity as estimated by a composite index of severe morbidity (ISM). All PT born in a single tertiary care NICU (<32 weeks and birth weight <1500 g) were consecutively included. MDA-Hb and blood glutathione (GSH) concentrations were measured by liquid chromatography-mass spectrometry during the first 6 weeks of life. Linear regressions and a multilevel model were fitted to study the relationship between MDA-Hb or GSH and ISM. Of the 83 PT (mean +/- SD: 28.3 +/- 2 weeks, 1089 +/- 288 g), 21% presented severe neonatal morbidity. In the multivariate model, MDA-Hb concentrations were significantly higher in the ISM+ group than in the ISM- group during the first 6 weeks of life (P = 0.009). No significant difference in GSH concentrations was observed between groups (P = 0.180). MDA-Hb is a marker of interest for estimating oxidative stress in PT and could be useful to evaluate the impact of strategies to improve perinatal outcomes. PMID- 23738044 TI - The influence of Nrf2 on cardiac responses to environmental stressors. AB - Nrf2 protects the lung from adverse responses to oxidants, including 100% oxygen (hyperoxia) and airborne pollutants like particulate matter (PM) exposure, but the role of Nrf2 on heart rate (HR) and heart rate variability (HRV) responses is not known. We hypothesized that genetic disruption of Nrf2 would exacerbate murine HR and HRV responses to severe hyperoxia or moderate PM exposures. Nrf2(-/ ) and Nrf2(+/+) mice were instrumented for continuous ECG recording to calculate HR and HRV (low frequency (LF), high frequency (HF), and total power (TP)). Mice were then either exposed to hyperoxia for up to 72 hrs or aspirated with ultrafine PM (UF-PM). Compared to respective controls, UF-PM induced significantly greater effects on HR (P < 0.001) and HF HRV (P < 0.001) in Nrf2(-/ ) mice compared to Nrf2(+/+) mice. Nrf2(-/-) mice tolerated hyperoxia significantly less than Nrf2(+/+) mice (~22 hrs; P < 0.001). Reductions in HR, LF, HF, and TP HRV were also significantly greater in Nrf2(-/-) compared to Nrf2(+/+) mice (P < 0.01). Results demonstrate that Nrf2 deletion increases susceptibility to change in HR and HRV responses to environmental stressors and suggest potential therapeutic strategies to prevent cardiovascular alterations. PMID- 23738047 TI - Achieving the balance between ROS and antioxidants: when to use the synthetic antioxidants. AB - Free radical damage is linked to formation of many degenerative diseases, including cancer, cardiovascular disease, cataracts, and aging. Excessive reactive oxygen species (ROS) formation can induce oxidative stress, leading to cell damage that can culminate in cell death. Therefore, cells have antioxidant networks to scavenge excessively produced ROS. The balance between the production and scavenging of ROS leads to homeostasis in general; however, the balance is somehow shifted towards the formation of free radicals, which results in accumulated cell damage in time. Antioxidants can attenuate the damaging effects of ROS in vitro and delay many events that contribute to cellular aging. The use of multivitamin/mineral supplements (MVMs) has grown rapidly over the past decades. Some recent studies demonstrated no effect of antioxidant therapy; sometimes the intake of antioxidants even increased mortality. Oxidative stress is damaging and beneficial for the organism, as some ROS are signaling molecules in cellular signaling pathways. Lowering the levels of oxidative stress by antioxidant supplements is not beneficial in such cases. The balance between ROS and antioxidants is optimal, as both extremes, oxidative and antioxidative stress, are damaging. Therefore, there is a need for accurate determination of individual's oxidative stress levels before prescribing the supplement antioxidants. PMID- 23738046 TI - Ulinastatin suppresses burn-induced lipid peroxidation and reduces fluid requirements in a Swine model. AB - Objective. Lipid peroxidation plays a critical role in burn-induced plasma leakage, and ulinastatin has been reported to reduce lipid peroxidation in various models. This study aims to examine whether ulinastatin reduces fluid requirements through inhibition of lipid peroxidation in a swine burn model. Methods. Forty miniature swine were subjected to 40% TBSA burns and were randomly allocated to the following four groups: immediate lactated Ringer's resuscitation (ILR), immediate LR containing ulinastatin (ILR/ULI), delayed LR resuscitation (DLR), and delayed LR containing ulinastatin (DLR/ULI). Hemodynamic variables, net fluid accumulation, and plasma thiobarbituric acid reactive substances (TBARS) concentrations were measured. Heart, liver, lung, skeletal muscle, and ileum were harvested at 48 hours after burn for evaluation of TBARS concentrations, activities of antioxidant enzymes, and tissue water content. Results. Ulinastatin significantly reduced pulmonary vascular permeability index (PVPI) and extravascular lung water index (ELWI), net fluid accumulation, and water content of heart, lung, and ileum in both immediate or delayed resuscitation groups. Furthermore, ulinastatin infusion significantly reduced plasma and tissue concentrations of TBARS in both immediate or delayed resuscitation groups. Conclusions. These results indicate that ulinastatin can reduce fluid requirements through inhibition of lipid peroxidation. PMID- 23738048 TI - Activation of the Nrf2 pathway by inorganic arsenic in human hepatocytes and the role of transcriptional repressor Bach1. AB - Previous studies have proved that the environmental toxicant, inorganic arsenic, activates nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in many different cell types. This study tried to explore the hepatic Nrf2 pathway upon arsenic treatment comprehensively, since liver is one of the major target organs of arsenical toxicity. Our results showed that inorganic arsenic significantly induced Nrf2 protein and mRNA expression in Chang human hepatocytes. We also observed a dose-dependent increase of antioxidant response element- (ARE-) luciferase activity. Both the mRNA and protein levels of NAD(P)H:quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) were all upregulated dramatically. On the other hand, entry and accumulation of Nrf2 protein in the nucleus, while exportting the transcriptional repressor BTB and CNC homology 1 (Bach1) from nucleus to cytoplasm, were also confirmed by western blot and immunofluorescence assay. Our results therefore confirmed the arsenic-induced Nrf2 pathway activation in hepatocytes and also suggested that the translocation of Bach1 was associated with the regulation of Nrf2 pathway by arsenic. Hepatic Nrf2 pathway plays indispensable roles for cellular defenses against arsenic hepatotoxicity, and the interplay of Bach1 and Nrf2 may be helpful to understand the self-defensive responses and the diverse biological effects of arsenicals. PMID- 23738049 TI - Clinical importance and surgical decision-making regarding proximal resection margin for gastric cancer. AB - Because of the intramural spread of gastric cancer, a sufficient length of a resection margin has to be attained to ensure complete excision of the tumor. There has been debate on an adequate length of proximal resection margin (PRM) and its related issues. Thus, the objective of this article is to review several studies on PRM and to summarize the current evidence on the subject. Although there is some discrepancy in the recommended values for PRM between authors, a PRM of more than 2-3 cm for early gastric cancer and 5-6 cm for advanced gastric cancer is thought to be acceptable. Once the margin is confirmed to be clear, however, the length of PRM measured in postoperative pathologic examination does not affect the patient's survival, even when it is shorter than the recommended values. Hence, the recommendations for PRM length should be applied only to intraoperative decision-making to prevent positive margins on the final pathology. Given that a negative resection margin is the ultimate goal of determining an adequate PRM, development and improvement of reliable methods to confirm a negative resection margin intraoperatively would minimize the extent of surgery and offer a better quality of life to more patients. In the same context, special attention has to be paid to patients who have advanced stage or diffuse type gastric cancer, because they are more likely to have a positive margin. Therefore, a wider excision with intraoperative frozen section (IFS) examination of the resection margin is necessary. Despite all the attempts to avoid positive margins, there is still a certain rate of positive-margin cases. Since the negative impact of a positive margin on prognosis is mostly obvious in low N stage patients, aggressive further management, such as extensive re-operation, is required for these patients. In conclusion, every possible preoperative and intraoperative evaluation should be thoroughly carried out to identify in advance the patients with a high risk of having positive margins; these patients need careful management with a wider excision or an IFS examination to confirm a negative margin during surgery. PMID- 23738050 TI - Evaluation of cystoid macular edema using optical coherence tomography and fundus autofluorescence after uncomplicated phacoemulsification surgery. AB - Aim. To investigate the utility of fundus autofluorescence (FAF) and optical coherence tomography (OCT) in the evaluation of cystoid macular edema (CME) following cataract surgery. Materials and Methods. Forty eyes of 29 patients undergone phacoemulsification, with posterior chamber intraocular lens implantation surgery. Central macular thickness (CMT) of the patients was evaluated using OCT and FAF preoperatively and postoperative 1st, 30th, 60th, 90th, and 180th days. Results. CME was detected in three eyes (7.5%) of two patients using OCT. Hyperautofluorescence (HAF) was detected in two of these three eyes and resolved with treatment. In the remaining 37 eyes without CME, there was a significant increase in visual acuity when compared to preoperative values (P = 0.008) Mean macular thicknesses (MMT) of the eyes without CME were 174 +/- 20 MU m preoperatively and 179 +/- 22 MU m at day 1, 178 +/- 19 MU m at 1st month, and 168 +/- 10 MU m at 6th month postoperatively. In the eyes with CME, the MMTs, measured with OCT were 189 +/- 23 MU m preoperatively and 432 +/- 361 on day 1, 343 +/- 123 MU m at 1st month, 345 +/- 196 at 2nd month, and 200 +/- 36 MU m at 6th month postoperatively. Conclusion. We found a moderate increase in CMT in the first 3 months postoperatively, in the eyes without CME which did not cause visual disturbances. FAF is a noninvasive, rapid method for the evaluation and follow-up of CME following cataract surgery. PMID- 23738052 TI - Flash electroretinography and pattern visual evoked potential changes in ocular hypertension patients. AB - Purpose. To evaluate the changes of flash electroretinography (fERG) and pattern visual evoked potentials (pVEP) in ocular hypertension (OHT) patients. Methods. Twenty-five OHT patients and 30 healthy volunteers were enrolled for this cross sectional study. Opthalmologic examinations, visual field tests, pVEP and fERG were performed. The main outcome measures were the differences between pVEP and fERG parameters. Results. The mean age of OHT patients and volunteers were 57 +/- 12.25 years (range 30-65 years), and 53.25 +/- 12.0 years (range 30-65 years), respectively. The mean amplitude of the pVEP was statistically lower in the OHT group (P < 0.05). Latency of the two groups was different; however, the difference was not statistically significant (P > 0.05). In fERG of OHT group, there was a significant decrease in the amplitude of the oscillatory potentials (Ops), and a significant delay in latency of rod and cone waves (all P < 0.05). There was no significant change in the flicker fERG waves between the two groups (P > 0.05). Conclusions. Although we found a decrease in Ops amplitude and a prolonged latency in flicker fERG, only the decrease in Ops amplitude was statistically significant between the two groups. The amplitude of Ops wave and amplitude of pVEP may reflect early glaucomatous damage in OHT patients. PMID- 23738051 TI - Current surgical options for the management of pediatric glaucoma. AB - Currently, there are numerous choices for the treatment of pediatric glaucoma depending on the type of glaucoma, the age of the patient, and other particularities of the condition discussed in this review. Traditionally, goniotomy and trabeculotomy ab externo have been the preferred choices of treatment for congenital glaucoma, and a variety of adult procedures adapted to children have been utilized for other types of pediatric glaucoma with variable results and complications. More recently, seton implantations of different types have become more popular to use in children, and newer techniques have become available including visualized cannulation and opening of Schlemm's canal, deep sclerectomy, trabectome, and milder more directed cyclodestructive procedures such as endolaser and transcleral diode laser cyclophotocoagulation. This paper reviews the different surgical techniques currently available, their indications, results, and most common complications to allow the surgeon treating these conditions to make a more informed choice in each particular case. Although the outcome of surgical treatment in pediatric glaucoma has improved significantly, its treatment remains challenging. PMID- 23738053 TI - Prevalence of 10-year risk of cardiovascular diseases and associated risks in canadian adults: the contribution of cardiometabolic risk assessment introduction. AB - Background. Cardiovascular disease (CVD) is the leading cause of death in adult Canadians. Cardiometabolic risk (CMR) derived from 10-year risk of cardiovascular diseases and metabolic syndrome (MetS) needs to be evaluated in Canadian adults. Objective. To determine CMR among Canadian adults by sociodemographic and lifestyle characteristics. Subjects and Methods. Data from the Canadian Health Measures Survey (CHMS), Cycle 1, 2007-2009, was used. Framingham Risk Score (FRS) was implemented to predict 10-year risk of CVD, and metabolic syndrome was identified using the most recent criteria. The 10-year risk of CVD was multiplied by 1.5 in individuals with MetS to obtain CMR. Data were weighted and bootstrapped to be able to generalize the results nationally. Results and Conclusion. CMR gave more accurate estimation of 10-year risk of CVD in Canadian adults from 30 to 74 years than using only FRS. The 10-year risk of CVD in Canadian adults significantly increased when CMR was taken into account from 8.10% to 9.86%. The CVD risk increased by increase in age, decrease in education, and decrease in physical activity and in smokers. Canadians with medium risk of CVD consumed significantly less fruit and vegetable juice compared to Canadians with low risk. No other dietary differences were found. PMID- 23738054 TI - Recovery of Extracellular Lipolytic Enzymes from Macrophomina phaseolina by Foam Fractionation with Air. AB - Macrophomina phaseolina was cultivated in complex and simple media for the production of extracellular lipolytic enzymes. Culture supernatants were batch foam fractionated for the recovery of these enzymes, and column design and operation included the use of P 2 frit (porosity 40 to 100 MU m), air as sparging gas at variable flow rates, and Triton X-100 added at the beginning or gradually in aliquots. Samples taken at intervals showed the progress of the kinetic and the efficiency parameters. Best results were obtained with the simple medium supernatant by combining the stepwise addition of small amounts of the surfactant with the variation of the air flow rates along the separation. Inert proteins were foamed out first, and the subsequent foamate was enriched in the enzymes, showing estimated activity recovery (R), enrichment ratio (E), and purification factor (P) of 45%, 34.7, and 2.9, respectively. Lipases were present in the enriched foamate. PMID- 23738056 TI - A Community-Supported Clinic-Based Program for Prevention of Violence against Pregnant Women in Rural Kenya. AB - Objective. Pregnant women are especially vulnerable to adverse outcomes related to HIV infection and gender-based violence (GBV). We aimed at developing a program for prevention and mitigation of the effects of GBV among pregnant women at an antenatal clinic in rural Kenya. Methods. Based on formative research with pregnant women, male partners, and service providers, we developed a GBV program including comprehensive clinic training, risk assessments in the clinic, referrals supported by community volunteers, and community mobilization. To evaluate the program, we analyzed data from risk assessment forms and conducted focus groups (n = 2 groups) and in-depth interviews (n = 25) with healthcare workers and community members. Results. A total of 134 pregnant women were assessed during a 5-month period: 49 (37%) reported violence and of those 53% accepted referrals to local support resources. Qualitative findings suggested that the program was acceptable and feasible, as it aided pregnant women in accessing GBV services and raised awareness of GBV. Community collaboration was crucial in this low-resource setting. Conclusion. Integrating GBV programs into rural antenatal clinics has potential to contribute to both primary and secondary GBV prevention. Following further evaluation, this model may be deemed applicable for rural communities in Kenya and elsewhere in East Africa. PMID- 23738055 TI - Integration of HIV Care with Primary Health Care Services: Effect on Patient Satisfaction and Stigma in Rural Kenya. AB - HIV departments within Kenyan health facilities are usually better staffed and equipped than departments offering non-HIV services. Integration of HIV services into primary care may address this issue of skewed resource allocation. Between 2008 and 2010, we piloted a system of integrating HIV services into primary care in rural Kenya. Before integration, we conducted a survey among returning adults >=18-year old attending the HIV clinic. We then integrated HIV and primary care services. Three and twelve months after integration, we administered the same questionnaires to a sample of returning adults attending the integrated clinic. Changes in patient responses were assessed using truncated linear regression and logistic regression. At 12 months after integration, respondents were more likely to be satisfied with reception services (adjusted odds ratio, aOR 2.71, 95% CI 1.32-5.56), HIV education (aOR 3.28, 95% CI 1.92-6.83), and wait time (aOR 1.97 95% CI 1.03-3.76). Men's comfort with receiving care at an integrated clinic did not change (aOR = 0.46 95% CI 0.06-3.86). Women were more likely to express discomfort after integration (aOR 3.37 95% CI 1.33-8.52). Integration of HIV services into primary care services was associated with significant increases in patient satisfaction in certain domains, with no negative effect on satisfaction. PMID- 23738057 TI - Overcoming Barriers to Family Planning through Integration: Perspectives of HIV Positive Men in Nyanza Province, Kenya. AB - This study explored barriers to and facilitators of using family planning services among HIV-positive men in Nyanza Province, Kenya. From May to June 2010, in-depth interviews were conducted with 30 men receiving care at 15 HIV clinics. The key barriers to the use of family planning included concerns about side effects of contraceptives, lack of knowledge about contraceptive methods, myths and misconceptions including fear of infertility, structural barriers such as staffing shortages at HIV clinics, and a lack of male focus in family planning methods and service delivery. The integration of family planning into HIV clinics including family planning counseling and education was cited as an important strategy to improve family planning receptivity among men. Integrating family planning into HIV services is a promising strategy to facilitate male involvement in family planning. Integration needs to be rigorously evaluated in order to measure its impact on unmet need for contraception among HIV-positive women and their partners and assure that it is implemented in a manner that engages both men and women. PMID- 23738058 TI - Providers' Perspectives on Provision of Family Planning to HIV-Positive Individuals in HIV Care in Nyanza Province, Kenya. AB - Objective. To inform an intervention integrating family planning into HIV care, family planning (FP) knowledge, attitudes and practices, and perspectives on integrating FP into HIV care were assessed among healthcare providers in Nyanza Province, Kenya. Methods. Thirty-one mixed-method, structured interviews were conducted among a purposive sample of healthcare workers (HCWs) from 13 government HIV care facilities in Nyanza Province. Structured questions and case scenarios assessed contraceptive knowledge, training, and FP provision experience. Open-ended questions explored perspectives on integration. Data were analyzed descriptively and qualitatively. Results. Of the 31 HCWs interviewed, 45% reported previous FP training. Few providers thought long-acting methods were safe for HIV-positive women (19% viewed depot medroxyprogesterone acetate as safe and 36% viewed implants and intrauterine contraceptives as safe); fewer felt comfortable recommending them to HIV-positive women. Overall, providers supported HIV and family planning integration, yet several potential barriers were identified including misunderstandings about contraceptive safety, gendered power differentials relating to fertility decisions, staff shortages, lack of FP training, and contraceptive shortages. Conclusions. These findings suggest the importance of considering issues such as patient flow, provider burden, commodity supply, gender and cultural issues affecting FP use, and provider training in FP/HIV when designing integrated FP/HIV services in high HIV prevalence areas. PMID- 23738059 TI - Preoperative hematocrit concentration and the risk of stroke in patients undergoing isolated coronary-artery bypass grafting. AB - Background. Identification and management of risk factors for stroke following isolated coronary artery bypass grafting (CABG) could potentially lower the risk of such serious morbidity. Methods. We retrieved data for 30-day stroke incidence and perioperative variables for patients undergoing isolated CABG and used multivariate logistic regression to assess the adjusted effect of preoperative hematocrit concentration on stroke incidence. Results. In 2,313 patients (mean age 65.9 years, 73.6% men), 43 (1.9%, 95% CI: 1.4-2.5) developed stroke within 30 days following CABG (74.4% within 6 days). After adjustment for a priori defined potential confounders, each 1% drop in preoperative hematocrit concentration was associated with 1.07 (95% CI: 1.01-1.13) increased odds for stroke (men, OR: 1.08, 95% CI: 1.01-1.16; women, OR: 1.02, 95% CI: 0.91-1.16). The predicted probability of stroke for descending preoperative hematocrit concentration exceeded 2% for values <37% (<37% for men (adjusted OR: 2.39, 95% CI: 1.08-5.26) and <38% for women (adjusted OR: 2.52, 95% CI: 0.53-11.98), with a steeper probability increase noted in men). The association between lower preoperative hematocrit concentration and stroke was evident irrespective of intraoperative transfusion use. Conclusion. Screening and management of patients with low preoperative hematocrit concentration may alter postoperative stroke risk in patients undergoing isolated CABG. PMID- 23738060 TI - Staging Laparoscopy in Carcinoma of Stomach: A Comparison with CECT Staging. AB - Background. aim of this study was to compare the role of diagnostic laparoscopy and contrast enhanced computed tomography (CECT) of abdomen in the staging of stomach carcinoma. Methods. This was a prospective study conducted in a tertiary care hospital over a period of two years and included 50 patients of endoscopy and biopsy proven stomach carcinoma that were found to be operable on CECT. Diagnostic laparoscopy was performed in all patients before proceeding to a formal laparotomy. Results. Metastasis was detected at diagnostic laparoscopy in 14 (28%) patients. CECT correctly identified the T stage in 22 (61%) patients. Overall accuracy of CECT for T staging was 74% with a a sensitivity of 65% and a specificity of 79%. Laparoscopy correctly identified the T stage in 26 (72%) patients. Overall accuracy of laparoscopy for T staging was 81% with a sensitivity of 76% and specificity of 86%. the most common N stage on CECT was N0 (50%). CECT correctly identified the N stage in 26 (72%) patients. Overall accuracy of CECT for N staging was 86% with a sensitivity of 50% and a specificity of 90%. the most common N stage on laparoscopy was N0 and N2 (42% each). Laparoscopy correctly identified the N stage in 27 (75%) patients. Overall accuracy of Laparoscopy for N staging was 88% with a sensitivity of 53% and specificity of 91%. Conclusion. Laparoscopy is a valuable technique in staging of stomach carcinoma and has an important role in the detection of intra-abdominal metastasis missed by CECT. PMID- 23738061 TI - Variations in institutional review board approval in the implementation of an improvement research study. AB - The purpose of this paper is to report the variance in institutional review board (IRB) reviews as part of the implementation of a multisite, quality improvement study through the Improvement Science Research Network (ISRN) and recommend strategies successful in procuring timely IRB approval. Using correspondence documents as data sources, the level of review was identified and time to submission, time to approval, and time to study start were analyzed. Thirteen of the 14 IRBs conducted independent reviews of the project. Twelve IRBs approved the study through expedited review while two IRBs reviewed the project at a full board meeting. Lastly, 11 of the 14 sites required documented consent. The greatest delay in approval was seen early on in the IRB process with site PIs averaging 45.1 +/- 31.8 days to submit the study to the IRB. IRB approvals were relatively quick with an average of 14 +/- 5.7 days to approval. The delay in study submission may be attributed to a lack of clear definitions and differing interpretations of the regulations that challenge researchers. PMID- 23738062 TI - A qualitative systematic review of older persons' perceptions of health, ill health, and their community health care needs. AB - The aim of this qualitative systematic review was to report a synthesis of older persons' perceptions of health, ill health, and their community health care needs. The review questions were what characterizes older persons' perceptions of health and ill health? and what are their community health care needs? Ten studies were identified in a systematic search for relevant qualitative papers published between January 2000 and January 2013 in the following electronic databases: PubMed, EBSCOhost/Academic Search Premier, and CINAHL. Publications were evaluated for quality, and a thematic analysis was performed. Two main themes were interpreted on a higher level: reconciliation with how life has become: and desire to regain their identity and sense of self-worth despite disability. Two themes emerged: creating meaning led to the experience of being valued in health care and society and a mental struggle to regain independence with the help of caregivers. Of special interest is the finding of perceptions related to the fear of becoming dependent on caregivers as well as the sorrow and pain caused by encountering caregivers who did not understand their desire to create meaning in their lives or their struggle for autonomy and independency. PMID- 23738063 TI - Improvement in Stress, General Self-Efficacy, and Health Related Quality of Life following Patient Education for Patients with Neuroendocrine Tumors: A Pilot Study. AB - The purpose of the study was to evaluate changes in general self-efficacy, health related quality of life (HRQoL), and stress among patients with neuroendocrine tumors (NET) following a multidisciplinary educational intervention. Forty-one patients were enrolled in this exploratory pilot study. A total of 37 patients completed the full 26-week intervention based on the principles of self-efficacy. General self-efficacy was measured by the General Self-Efficacy Scale, HRQoL was measured with the SF-36, and stress was measured with the Impact of Event Scale. Mixed effect models were used to evaluate changes in general self-efficacy, mental and physical components of HRQoL, and stress adjusting for demographic and clinical variables. Results showed significant improvements in patients' general self-efficacy (beta = 0.71; P < 0.05), physical component scores of HRQoL (beta = 3.09; P < 0.01), and stress (beta = -2.10, P = 0.008). Findings suggest that patients with NET have the capacity to improve their ability to cope with their disease, problem-solve, improve their physical status, and reduce their stress following an educational intervention based on the principles of self-efficacy. These preliminary data provide a basis for future randomized controlled trials to test interventions to improve HRQoL for patients with NET. PMID- 23738064 TI - Translating Research into Practice in Low-Resource Countries: Progress in Prevention of Maternal to Child Transmission of HIV in Nigeria. AB - Background. Research related to prevention of maternal to child transmission (PMTCT) of HIV is dynamic and rapidly changing and has provided evidence-based interventions and policies for practitioners. However, it is uncertain that research and policy guidelines are adequately being disseminated and implemented in resource-constrained countries with the largest burden PMTCT. This study examined current PMTCT practices in 27 public health facilities in Nigeria. Methods. A cross-sectional survey of 231 practicing nurses was conducted. Current PMTCT care practices were evaluated and compared to WHO and national PMTCT policy guidelines. Linear mixed models evaluated the association between PMTCT care practices and training in PMTCT. Results. Most nurses (80%) applied practices involving newborn prophylaxis; yet significant gaps in maternal intrapartum treatment and infant feeding practices were identified. PMTCT training explained 25% of the variance in the application of PMTCT care practices. Conclusion. Key PMTCT practices are not being adequately translated from research into practice. Researchers, policymakers, and clinicians could apply the study findings to address significant knowledge translation gaps in PMTCT. Strategies derived from an implementation science perspective are suggested as a means to improve the translation of PMTCT research into practice in Sub-Saharan African medical facilities. PMID- 23738065 TI - Supporting mothers' engagement in a community-based methadone treatment program. AB - Unmanaged maternal opioid addiction poses health and social risks to both mothers and children in their care. Methadone maintenance treatment (MMT) is a targeted public health service to which nurses and other allied health professionals may refer these high risk families for support. Mothers participating in MMT to manage their addiction and their service providers were interviewed to identify resources to maximize mothers' engagement in treatment and enhance mothers' parenting capacity. Twelve mothers and six service providers were recruited from an outpatient Atlantic Canadian methadone treatment program. Two major barriers to engagement in MMT were identified by both mothers and service providers including (1) the lack of available and consistent childcare while mothers attended outpatient programs and (2) challenges with transportation to the treatment facility. All participants noted the potential benefits of adding supportive resources for the children of mothers involved in MMT and for mothers to learn how to communicate more effectively with their children and rebuild damaged mother-child relationships. The public health benefits of integrating parent-child ancillary supports into MMT for mothers are discussed. PMID- 23738066 TI - Immunisation with BCG in the Maringue District, Sofala Province, Mozambique. AB - Objectives. We evaluated immunisation with Bacille Calmette-Guerin (BCG) among newborns in 2011 in the Maringue District, Sofala Province, Mozambique, which includes seven health units. The study was motivated by the fact that in official reports, immunisation coverage was unreliable (more than 100%). Methods. The office of maternal-child health of the central Maringue-Sede health unit provided the number of live newborns in 2011 at the maternal clinics of the seven health units and an estimate of the number of home deliveries. From vaccination registers, we abstracted records of BCG vaccinations administered in the period 01/01/2011-30/06/2012 to children born in 2011. Results. The number of live newborns was 3,353. Overall, the number of BCG vaccinations administered was 2,893, with a coverage of 86.3%. Conclusion. In this study, we could only calculate an approximate coverage estimate, because of unavailability of adequate individual information. Recording practices should be changed in order to allow use of individual information and linkage across different information sources and thus a more precise vaccination coverage assessment. PMID- 23738067 TI - Sleep, fatigue, and functional health in psychotic patients. AB - This study sought to examine the association between sleep, fatigue, and functional health in psychotic patients. Participants included 93 psychotic inpatients (n = 67 with schizophrenia) who completed the Chalder Fatigue Scale (ChFS), the Fatigue Symptom Inventory (FSI), the Pittsburgh Sleep Quality Index (PSQI), and the SF36 Health Survey. Patients were classified on the basis of their performance on sleep and fatigue measures: 60% reported significant levels of fatigue and 67% significant sleep disturbances. 28.4% reported both, suggesting that fatigue and sleep dysfunctions do not necessarily cooccur. A closer examination of patterns showed that fatigue was only related to qualitative aspects of sleep and not quantifiable aspects of sleep disturbances. The results also showed that functional health was the lowest in patients with high levels of fatigue, compared to patients with sleep problems only or patients with neither symptom. A regression analysis further showed that the size of the contribution of fatigue onto functional health was twice as much as that of sleep dysfunctions. In conclusion, the results show that (i) dissatisfaction with sleep and not sleep itself-is related to fatigue symptoms and that (ii) fatigue is particularly detrimental to functional health, regardless of the presence of sleep dysfunctions. PMID- 23738068 TI - Empirically Based Psychosocial Therapies for Schizophrenia: The Disconnection between Science and Practice. AB - Empirically validated psychosocial therapies for individuals diagnosed with schizophrenia were described in the report of the Schizophrenia Patient Outcomes Research Team (PORT, 2009). The PORT team identified eight psychosocial treatments: assertive community treatment, supported employment, cognitive behavioral therapy, family-based services, token economy, skills training, psychosocial interventions for alcohol and substance use disorders, and psychosocial interventions for weight management. PORT listings of empirically validated psychosocial therapies provide a useful template for the design of effective recovery-oriented mental health care systems. Unfortunately, surveys indicate that PORT listings have not been implemented in clinical settings. Obstacles to the implementation of PORT psychosocial therapy listings and suggestions for changes needed to foster implementation are discussed. Limitations of PORT therapy listings that are based on therapy outcome efficacy studies are discussed, and cross-cultural and course and outcome studies of correlates of recovery are summarized. PMID- 23738069 TI - Advances in quantitative mass spectrometry. PMID- 23738070 TI - GAPDH Pseudogenes and the Quantification of Feline Genomic DNA Equivalents. AB - Quantitative real-time PCR (qPCR) is broadly used to detect and quantify nucleic acid targets. In order to determine cell copy number and genome equivalents, a suitable reference gene that is present in a defined number in the genome is needed, preferably as a single copy gene. For most organisms, a variable number of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) pseudogenes have been reported. However, it has been suggested that a single-copy of the GAPDH pseudogene is present in the feline genome and that a GAPDH assay can therefore be used to quantify feline genomic DNA (gDNA). The aim of this study was to determine whether one or more GAPDH pseudogenes are present in the feline genome and to provide a suitable alternative qPCR system for the quantification of feline cell copy number and genome equivalents. Bioinformatics and sequencing results revealed that not just one but several closely related GAPDH-like sequences were present in the cat genome. We thus identified, developed, optimized, and validated an alternative reference gene assay using feline albumin (fALB). Our data emphasize the need for an alternative reference gene, apart from the GAPDH pseudogene, for the normalization of gDNA levels. We recommend using the fALB qPCR assay for future studies. PMID- 23738071 TI - Pharmacological management of esophageal food bolus impaction. AB - Background. Soft esophageal bolus impaction is an emergency that requires skilled endoscopic removal if persistent obstructive symptoms do not resolve spontaneously after careful observation. Expedited care of these patients is crucial to avoid respiratory and mechanical complications. Other possible options for management include medical agents used to manage it prior to performing endoscopy if access to endoscopy was not available or declined by the patient. Aim. To review the available pharmacological and other nonmedicinal options and their mechanism of relief for soft esophageal impaction. Method. Pubmed, Medline and Ovid were used for search of MESH terms pertinent including "foreign body, esophageal, esophageal bolus and medical" for pharmacological and non medicinial agents used for management of esophageal soft bolus impaction as well as manual review of the cross-references. Results. Several agents were identified including Buscopan, Glucagon, nitrates, calcium channel blockers, and papaveretum. Non medicinal agents are water, effervescent agents, and papain. No evidence was found to suggest preference or effectiveness of use of a certain pharmacological agent compared to others. Buscopan, Glucagon, benzodiazepines, and nitrates were studied extensively and may be used in selected patients with caution. Use of papain is obsolete in management of soft bolus impaction. PMID- 23738072 TI - Healing pathways: a program for women with physical disabilities and depression. AB - Objective. The objective of this study was to test the efficacy of the Healing Pathways (HP) program in reducing clinically significantly depressive symptoms in women with physical disabilities (WPD). Healing Pathways is a peer-implemented group mental health treatment program targeting WPD who have clinically significant cooccurring depressive symptoms. Participants. Eighty women were randomized in this trial. Design. This study used a community-based participatory intervention research design. Using community-based recruiting methods, participants were recruited from Centers for Independent Living, local disability service organizations, via Craig's list as well as other community locations such as grocery stores and bus stops. Women participated in the HP program for 14 weeks. Results. The primary outcome variable for this study was reduction in depressive symptoms as measured by the Center for Epidemiologic Depression Scale (CES-D). We found that there was a significant interaction effect of treatment by time on depression scores, F(3,210) = 9.51, P < 0.0001, partial eta (2) = 0.101. Investigation of the predicted mean profile over time in the intervention group demonstrated that depression scores decreased greatly from baseline to the first posttest and remained stable in the two followups, whereas there was a little change in the mean profile over time in the control group. Conclusion. The HP program has demonstrated initial efficacy in reducing depressive symptoms in women with physical disabilities. PMID- 23738073 TI - Ipilimumab: A First-in-Class T-Cell Potentiator for Metastatic Melanoma. AB - Ipilimumab, a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody that potentiates antitumor T-cell responses, has demonstrated improved survival in previously treated and treatment-naive patients with unresectable stage III/IV melanoma. Survival benefit has also been shown in diverse patient populations, including those with brain metastases. In 2011, ipilimumab (3 mg/kg every 3 weeks for 4 doses) was approved by the Food and Drug Administration for unresectable or metastatic melanoma. Ipilimumab can induce novel response patterns for which immune-related response criteria have been proposed. irAEs are common but are usually low grade; higher grades can be severe and life threatening. irAEs are usually manageable using established guidelines emphasizing vigilance and prompt intervention. This agent provides an additional therapeutic option in metastatic melanoma, and guidelines for management of adverse events facilitate clinical implementation of this new agent. PMID- 23738074 TI - Protein Kinase C epsilon , Which Is Linked to Ultraviolet Radiation-Induced Development of Squamous Cell Carcinomas, Stimulates Rapid Turnover of Adult Hair Follicle Stem Cells. AB - To find clues about the mechanism by which kinase C epsilon (PKC epsilon ) may impart susceptibility to ultraviolet radiation (UVR)-induced development of cutaneous squamous cell carcinomas (SCC), we compared PKC epsilon transgenic (TG) mice and their wild-type (WT) littermates for (1) the effects of UVR exposures on percent of putative hair follicle stem cells (HSCs) and (2) HSCs proliferation. The percent of double HSCs (CD34+ and alpha 6-integrin or CD34+/CD49f+) in the isolated keratinocytes were determined by flow cytometric analysis. Both single and chronic UVR treatments (1.8 kJ/m(2)) resulted in an increase in the frequency of double positive HSCs in PKC epsilon TG mice as compared to their WT littermates. To determine the rate of proliferation of bulge region stem cells, a 5-bromo-2'-deoxyuridine labeling (BrdU) experiment was performed. In the WT mice, the percent of double positive HSCs retaining BrdU label was 28.4 +/- 0.6% compared to 4.0 +/- 0.06% for the TG mice, an approximately 7-fold decrease. A comparison of gene expression profiles of FACS sorted double positive HSCs showed increased expression of Pes1, Rad21, Tfdp1 and Cks1b genes in TG mice compared to WT mice. Also, PKC epsilon over expression in mice increased the clonogenicity of isolated keratinocytes, a property commonly ascribed to stem cells. PMID- 23738075 TI - Nanotechnologies in cancer. PMID- 23738076 TI - MRI-Guided Focused Ultrasound as a New Method of Drug Delivery. AB - Ultrasound-mediated drug delivery under the guidance of an imaging modality can improve drug disposition and achieve site-specific drug delivery. The term focal drug delivery has been introduced to describe the focal targeting of drugs in tissues with the help of imaging and focused ultrasound. Focal drug delivery aims to improve the therapeutic profile of drugs by improving their specificity and their permeation in defined areas. Focused-ultrasound- (FUS-) mediated drug delivery has been applied with various molecules to improve their local distribution in tissues. FUS is applied with the aid of microbubbles to enhance the permeability of bioactive molecules across BBB and improve drug distribution in the brain. Recently, FUS has been utilised in combination with MRI-labelled liposomes that respond to temperature increase. This strategy aims to "activate" nanoparticles to release their cargo locally when triggered by hyperthermia induced by FUS. MRI-guided FUS drug delivery provides the opportunity to improve drug bioavailability locally and therefore improve the therapeutic profiles of drugs. This drug delivery strategy can be directly translated to clinic as MRg FUS is a promising clinically therapeutic approach. However, more basic research is required to understand the physiological mechanism of FUS-enhanced drug delivery. PMID- 23738077 TI - Nanoparticle albumin bound Paclitaxel in the treatment of human cancer: nanodelivery reaches prime-time? AB - Nanoparticle albumin bound paclitaxel (nab-paclitaxel) represents the first nanotechnology-based drug in cancer treatment. We discuss the development of this innovative compound and report the recent changing-practice results in breast and pancreatic cancer. A ground-breaking finding is the demonstration that nab paclitaxel can not only enhance the activity and reduce the toxicity of chromophore-diluted compound, but also exert activity in diseases considered refractory to taxane-based treatment. This is the first clinical demonstration of major activity of nanotechnologically modified drugs in the treatment of human neoplasms. PMID- 23738078 TI - Probiotics as antiviral agents in shrimp aquaculture. AB - Shrimp farming is an aquaculture business for the cultivation of marine shrimps or prawns for human consumption and is now considered as a major economic and food production sector as it is an increasingly important source of protein available for human consumption. Intensification of shrimp farming had led to the development of a number of diseases, which resulted in the excessive use of antimicrobial agents, which is finally responsible for many adverse effects. Currently, probiotics are chosen as the best alternatives to these antimicrobial agents and they act as natural immune enhancers, which provoke the disease resistance in shrimp farm. Viral diseases stand as the major constraint causing an enormous loss in the production in shrimp farms. Probiotics besides being beneficial bacteria also possess antiviral activity. Exploitation of these probiotics in treatment and prevention of viral diseases in shrimp aquaculture is a novel and efficient method. This review discusses the benefits of probiotics and their criteria for selection in shrimp aquaculture and their role in immune power enhancement towards viral diseases. PMID- 23738080 TI - Phase II Study of Bortezomib as a Single Agent in Patients with Previously Untreated or Relapsed/Refractory Acute Myeloid Leukemia Ineligible for Intensive Therapy. AB - We explored the safety and efficacy of bortezomib given as single agent in patients with untreated or relapsed/refractory acute myeloid leukemia (AML), unfit for conventional chemotherapy. Fourteen patients were treated with bortezomib 1.5 mg/m(2) administered twice weekly for two weeks, every 3 weeks. Median age was 70 years (range 60-81) and the median number of cycles delivered was 2 (range 1-4). Of 13 evaluable patients, in 8 (61%), the administration of bortezomib resulted in an antileukemic effect as demonstrated by peripheral blood and/or bone marrow blast reduction. In 4 (50%) of these 8, a decrease by 37% of transfusion requirement was also observed (P = 0.009). Overall median survival was 4 months (range 0.25-10). Neurotoxicity was the most frequent adverse event with 7 of 13 (54%) patients experiencing grades 3-4 peripheral neuropathy. Neurotoxicity led to treatment discontinuation in 4 (57%) of 7. In conclusion, the observed anti-leukemic activity of bortezomib indicates that there is room for designing additional studies in which combination with other chemotherapeutic agents should be considered. Clinical registration no.: EUDRACT 2006-006923-38. PMID- 23738081 TI - HBV perinatal transmission. AB - Hepatitis B is a serious public health problem all around the world. It is a blood-borne and sexually transmitted DNA virus in adults, but mother to child transmission of hepatitis B virus also occurs in infants born to hepatitis B surface antigen positive mothers. PMID- 23738082 TI - Intervertebral disc rehydration after lumbar dynamic stabilization: magnetic resonance image evaluation with a mean followup of four years. AB - Objective. To compare the clinical and radiographic outcomes in patients of different ages who underwent the Dynesys stabilization. Methods. This retrospective study included 72 patients (mean age 61.4 years) with one- or two level lumbar spinal stenosis who underwent laminectomy and the Dynesys (Zimmer Spine, Minneapolis) dynamic stabilization system. Thirty-seven patients were younger than 65-year old while the other 35 were older. Mean followup was 46.7 months. Pre- and postoperative radiographic and clinical evaluations were analyzed. Results. The mean calibrated disc signal (CDS) at the index level was significantly improved from 60.2 +/- 25.2 preoperatively to 66.9 +/- 26.0 postoperatively (P > 0.001). Screw loosening occurred in 22.2% of patients and 5.1% of screws. The improvement in CDS at index level was seen to be significant in younger patients but not in older patients. Overall, the mean visual analogue scale (VAS) of back pain, VAS of leg pain, and the Oswestry disability index (ODI) scores improved significantly after operation. There were no significant differences in pre- and postoperative VAS and ODI and screw loosening rates between the younger and older patients. Conclusions. There is significant clinical improvement after laminectomy and dynamic stabilization for symptomatic lumbar spinal stenosis. Intervertebral disc rehydration was seen in younger patients. PMID- 23738083 TI - A perspective on robotic assistance for knee arthroplasty. AB - Knee arthroplasty is used to treat patients with degenerative joint disease of the knee to reduce pain and restore the function of the joint. Although patient outcomes are generally quite good, there are still a number of patients that are dissatisfied with their procedures. Aside from implant design which has largely become standard, surgical technique is one of the main factors that determine clinical results. Therefore, a lot of effort has gone into improving surgical technique including the use of computer-aided surgery. The latest generation of orthopedic surgical tools involves the use of robotics to enhance the surgeons' abilities to install implants more precisely and consistently. This review presents an evolution of robot-assisted surgical systems for knee replacement with an emphasis on the clinical results available in the literature. Ever since various robotic-assistance systems were developed and used clinically worldwide, studies have demonstrated that these systems are as safe as and more accurate than conventional methods of manual implantation. Robotic surgical assistance will likely result in improved surgical technique and improved clinical results. PMID- 23738079 TI - Dissecting Major Signaling Pathways throughout the Development of Prostate Cancer. AB - Prostate cancer (PCa) is one of the most common malignancies found in males. The development of PCa involves several mutations in prostate epithelial cells, usually linked to developmental changes, such as enhanced resistance to apoptotic death, constitutive proliferation, and, in some cases, to differentiation into an androgen deprivation-resistant phenotype, leading to the appearance of castration resistant PCa (CRPCa), which leads to a poor prognosis in patients. In this review, we summarize recent findings concerning the main deregulations into signaling pathways that will lead to the development of PCa and/or CRPCa. Key mutations in some pathway molecules are often linked to a higher prevalence of PCa, by directly affecting the respective cascade and, in some cases, by deregulating a cross-talk node or junction along the pathways. We also discuss the possible environmental and nonenvironmental inducers for these mutations, as well as the potential therapeutic strategies targeting these signaling pathways. A better understanding of how some risk factors induce deregulation of these signaling pathways, as well as how these deregulated pathways affect the development of PCa and CRPCa, will further help in the development of new treatments and prevention strategies for this disease. PMID- 23738084 TI - Widening Socioeconomic, Racial, and Geographic Disparities in HIV/AIDS Mortality in the United States, 1987-2011. AB - This study examined the extent to which socioeconomic and racial and geographic disparities in HIV/AIDS mortality in the United States changed between 1987 and 2011. Census-based deprivation indices were linked to county-level mortality data from 1987 to 2009. Log-linear, least-squares, and Poisson regression were used to model mortality trends and differentials. HIV/AIDS mortality rose between 1987 and 1995 and then declined markedly for all groups between 1996 and 2011. Despite the steep mortality decline, socioeconomic gradients and racial and geographic disparities in HIV/AIDS mortality increased substantially during the study period. Compared to whites, blacks had 3 times higher HIV/AIDS mortality in 1987 and 8 times higher mortality in 2011. In 1987, those in the most-deprived group had 1.9 times higher HIV/AIDS mortality than those in the most-affluent group; the corresponding relative risks increased to 2.9 in 1998 and 3.6 in 2009. Socioeconomic gradients existed across all race-sex groups, with mortality risk being 8-16 times higher among blacks than whites within each deprivation group. Dramatic reductions in HIV/AIDS mortality represent a major public health success. However, slower mortality declines among more deprived groups and blacks contributed to the widening gap. Mortality disparities reflect inequalities in incidence, access to antiretroviral therapy, and patient survival. PMID- 23738086 TI - Comment on "dental prosthetic status and prosthetic need of the institutionalized elderly living in geriatric homes in mangalore: a pilot study". AB - Public Health Dentistry is a speciality which is targeted towards the larger benefit of community and society. Dental health surveys in specific population groups should be planned adequately and the data should be analyzed in such a way so that it may help in making strategies for the intervention to improve the existing status. This could be only done with the help of proper planning, analysis and interpretation of a sample survey. The present study highlights the research design, statistical and inferential errors in a published work of public health dentistry in order to bring about the common mistakes and errors made. The renewed suggested approach helps in interpreting the results in a better way and makes them objective-oriented. PMID- 23738085 TI - Biomechanics and load resistance of short dental implants: a review of the literature. AB - This paper was aimed to review the studies published about short dental implants. In the focus were the works that investigated the effect of biting forces of the rate of marginal bone resorption around short implants and their survival rates. Bone deformation defined by strain was obviously higher around short implants than the conventional ones. The clinical outcomes of 6 mm short implants after 2 years showed a survival rate of 94% to 95% and lower survival rate (<80%) for 7 mm short implants after 3 to 6 years for single crown restorations. The short implants used for supporting fixed partial prostheses had a survival rate of 98.9%. Short implants can be considered as a good alternative implant therapy to support single crown or partial fixed restorations. PMID- 23738087 TI - Relationship between Subjective Oral Health Status and Lifestyle in Elderly People: A Cross-Sectional Study in Japan. AB - Objective. The aim of this study was to assess the relationship between subjective oral health status and lifestyle in elderly people living in Japan. Methods. Subjects were 5383 inhabitants of the Kagawa Prefecture, Japan, at the age of 75-100. Records of the number of remaining teeth and the data from self reported questionnaire were analyzed statistically. Results. Remaining teeth were significantly correlated to "no current smoking," while not related to other lifestyle. On the other hand, "subjective masticatory ability" defined as a condition allowing chewing all foods well was related to favorable lifestyles. "Subjective masticatory ability" was also related to "not feeling stress," "no deviated food habit" as well as to other good oral health conditions. A logistic regression analysis for "remaining teeth more than 20" revealed a significant relationship between "no current smoking" (OR = 1.582) and "no alcohol drinking" (OR = 0.851). Regarding "subjective masticatory ability," all favorable lifestyles analyzed in this study were found to be significant positive factors. Conclusions. "Subjective masticatory ability" seems to be strongly associated with favorable lifestyles. Therefore, it can be suggested that "subjective masticatory ability" might be a good landmark for quality of life of elderly people in addition to the number of remaining teeth. PMID- 23738088 TI - Oral health behavior of parents as a predictor of oral health status of their children. AB - Introduction. It is widely acknowledged that the behavior of parents affects their children's health. This study aimed to evaluate the relationship between oral health behavior of parents and oral health status and behavior of their children in a sample of preschool children in Iran. Method and Material. A random sample of over-five-year-old preschool children and their parents were enrolled in the study. Selection of schools was by clustering method. Parents were asked to fill a piloted questionnaire which included demographic characteristics, socioeconomic status, oral health behaviors of children and their parents. Oral health status of children was examined. The parent and their children oral health relationship were tested using regression and correlation analysis. Results. About 222 parents and children participated in the study. There was a significant relationship between history of having dental problems in parents and dmft index in their children (P = 0.01). There was a significant relationship between parental frequency of tooth brushing and child frequency of tooth brushing (P = 0.05); however, there was no significant relationship between parental frequency of dental visits and those of their children (P = 0.1). Conclusion. The study concluded that some important health behaviors in parents, such as tooth brushing habits are important determinants of these behaviors in their young children. So promoting parent knowledge and attitude could affect their children oral health behavior and status. PMID- 23738089 TI - Comment on "Computed Tomography Evaluation of Craniomandibular Articulation in Class II Division 1 Malocclusion and Class I Normal Occlusion Subjects in North Indian Population". AB - Clear statement of objective, appropriate location of landmarks and removal of subjective bias in measurement is essential in all kinds of research, especially, orthodontics. The research design should be rationalistic, purposeful, and in accordance with the objectives of the study. In this communication, we highlight the errors in research design, measurement, analysis, and inferences drawn with the help of a published article as the primary source to explain these simple but useful points. PMID- 23738090 TI - Modulating Role of Vitamins C and E against Transport-Induced Stress in Pullets during the Hot-Dry Conditions. AB - The modulating effects of ascorbic acid (AA), vitamin E (E), and a combination of AA and E (AA + E) against eight-hour road transportation stress were investigated in 120 pullets during the hot-dry season. The result obtained showed that handling, loading and transportation induced lymphopenia, neutrophilia, liveweight loss, and mortality, which was alleviated by oral administration of AA, E, and AA + E at doses of 60 mg, 30 mg, and 60 + 30 mg per kg bodyweight, respectively, 30 minutes before being loaded and transported. The meteorological conditions recorded during the study period were higher (P < .05) than the thermoneutral values established for chickens in the zone. In conclusion, the administration of vitamins AA, E, and AA + E, especially AA, ameliorated the risk of adverse effects of handling, loading, transportation, and thermal stress in pullets during the hot-dry season. PMID- 23738091 TI - Single layer centrifugation with androcoll-p can be scaled-up to process larger volumes of boar semen. AB - The objective of this study was to scale-up the procedure for Single Layer Centrifugation (SLC) through Androcoll(TM)-P, as a preliminary step towords processing the whole ejaculate. The first experiment compared Single Layer Centrifugation using 4.5 mL and 15 mL extended ejaculate (SLC-4.5 and SLC-15, resp.), assessing sperm quality by objective motility analysis, morphology, viability, and the production of reactive oxygen species (ROS). In the second experiment, SLC-4.5 was compared to Single Layer Centrifugation with 25 mL extended ejaculate (SLC-25) using motility analysis and morphology. In both experiments, normal morphology and linear motility were significantly higher in the SLC-selected samples than in the uncentrifuged controls (P < .001), whereas total motility and membrane integrity were unchanged. Although ROS production was higher in the SLC-selected samples than in the controls (P < .01), this might have been due to the presence of antioxidants in seminal plasma in the latter. In conclusion, there was no difference in sperm quality between SLC-4.5 and SLC-15 samples, or between SLC-4.5 and SLC-25 samples, indicating that the SLC method can be scaled-up successfully. PMID- 23738092 TI - Characteristics and health of Turkey husbandry in ouake, north-benin. AB - Sanitary constraints of raising turkey in north-west Benin were studied by using a survey and Haemagglutination Inhibition Test (HIT) to detect antibodies of Newcastle Disease (ND) and Avian Influenza (AI). We tested 85 serums from 7- to 24-month-old turkeys raised in 19 farms. ND prevalence rate was 54% but reactions on four sub-types of AI were negative. Mortality rates varied from 55 to 100% for 0-30 day-old flocks; 30% for 1- to 4-month-old; and 15% for older turkeys. Next to ND, probable causes of mortality are Fowl pox, Gumboro disease, scabies, coccidiosis, histomonosis, capillariosis and colibacillosis. Only one farmer who fed and vaccinated the poults, and provided clean housing for them got a lower mortality rate of 11% in turkeys less than 4-month-old. The question remains why most farmers do not apply these simple practices: are they unaware or are the technologies not profitable? PMID- 23738093 TI - Effect of Osmolarity and Density of Colloid Formulations on the Outcome of SLC Selection of Stallion Spermatozoa. AB - The osmolarity and density of colloids used to prepare spermatozoa for assisted reproduction may affect sperm quality in the resultant preparation. In this study, two osmolarities of Androcoll-E for single-layer or density gradient centrifugation of stallion spermatozoa were compared: "normal" (320 mOsm) or "high" (345 mOsm). Mean yields for the two centrifugation techniques did not differ between treatments or osmolarities (single layer centrifugation: 30.19 +/- 16.9 * 10(6) and 25.8 +/- 18.5 * 10(6) spermatozoa; density gradient centrifugation: 31.84 +/- 19.7 * 10(6) and 26.46 +/- 20.0 * 10(6) spermatozoa respectively for the two osmolarities). However, use of the high osmolarity colloid for single layer centrifugation increased the proportion of morphologically normal spermatozoa (P < .05). Therefore, increasing the osmolarity of the colloid formulation may be beneficial for processing ejaculates containing a high proportion of abnormal spermatozoa by SLC. Reducing the density of the colloid used for the SLC substantially increased the yield of motile spermatozoa compared to the normal density colloid (mean +/- SD: 72.6 +/- 28.9 * 10(6) versus 28.9 +/- 24.7 * 10(6)), while also prolonging sperm survival by 24 hours compared to the uncentrifuged ejaculate. This increased yield may render Single Layer Centrifugation practical for use in the field. PMID- 23738094 TI - Prevalence of bovine brucellosis and risk factors assessment in cattle herds in jigawa state. AB - A serological survey of Brucella antibodies was carried out in Jigawa State, northwestern Nigeria to determine the prevalence of the disease and risk factors among some pastoralist cattle herds. A total of 570 cattle of different ages and sexes selected from 20 herds across the four agroecological zones in the state were screened using Rose Bengal Plate test and competitive enzyme immunoassay. From the results 23 cattle (4.04%) were positive by Rose Bengal Plate Test while 22(3.86%) were positive with competitive enzyme immunoassay. The infection rate was higher in females than males. Cattle older than 3 years had a higher prevalence rate compared to age groups 2-3 years, 1-2 years, and less than 1 year. The prevalence rate was higher in cattle densely populated locations. Infection rate differs between herds with larger herds presenting high prevalence due to poor sanitary practice. It is hereby recommended that public enlightenment on adequate control and preventive measures using proper sanitary practice and calf hood vaccination are required. PMID- 23738096 TI - Time exposure period of bovine oocytes to sperm in relation to embryo development rate and quality. AB - The objective of the study was to determine the effect of different bovine gamete coincubation times on fertilization and embryo development performance. In vitro matured COCs were co-incubated with sperm at a concentration of 1.5 * 10(6) spermatozoa/ml in TALP medium for 3 hours (T 3, n = 362), 6 hours (T 6, n = 358), or 18 hours (T 18, n = 350). At the end of the coincubation period COCs from times 3 and 6 groups were post-incubated in a new well of fertilization medium without sperm for additional 15 and 12 h, respectively. Cumulus Oocyte Complexes from the T 18 were co-incubated with the sperm suspension for 18 hours. Presumptive zygotes were cultured for 9 days and embryo development was evaluated on days 2, 8, and 9. Thirty blastocysts from each group were stained and total number of nuclei was recorded. The mean (+/- SEM) percentages of zygotes to develop into >=2 cell stage were 71.9 +/- 5.0; 72.5 +/- 5.3 and 81.2 +/- 6.1 % for T 3, 6, and 18, respectively, on day 2 and they did not differ (P = .3) among groups. The mean percentage of blastocysts developed on day 8 (25.6 +/- 2.8; 24.2 +/- 3.3; 28.4 +/- 4.2 % for T 3, 6, and 18, resp.) did not differ (P = .4) among groups. The total number of embryonic nuclei was greater (P < .05) for the blastocysts produced from the shortest co-incubation time (T 3). PMID- 23738097 TI - Neoplastic and nonneoplastic cutaneous tumors of dogs in grenada, west indies. AB - This retrospective survey was undertaken between 2002 and 2007 on samples from dogs residing in Grenada. The objectives of the study were to identify the most common histologic types of canine cutaneous tumors, determine the relative frequency of each tumor type, and compare results to reports from other regions. In a series of 225 skin masses examined, the proportion of neoplasms was 72% whereas nonneoplastic tumors accounted for 15.6%, and inflammatory conditions constituted 12.4%. There were 10 types of nonneoplastic tumors with hamartomas being the most common (28.5%), followed by sebaceous hyperplasia (25.7%) and fibroepithelial polyps (22.8%). The 10 most common cutaneous neoplasms were hemangiosarcomas (19.1%), histiocytomas (8.6%), melanocytomas (8%), mast cell tumors (6.8%), lipomas (6.8%), hemangiopericytomas (6.2%), papillomas (5.6%), fibrosarcomas (5.6%), hemangiomas (4.9%), and squamous cell carcinomas (4.3%). Tumors of vascular origin and transmissible venereal tumors were more common in dogs in our study than reported from other regions. PMID- 23738098 TI - Detection of paratuberculosis in breeding bulls at pakistani semen production units: a continuous source of threat. AB - Paratuberculosis is a chronic bowel disease of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). Its secretion through semen highlights the importance of paratuberculosis-free breeding bulls. The breeding and teaser bulls at three semen production units (SPUs) located in Punjab, Pakistan, were screened for the presence of antibodies against MAP. A total of 253 samples were collected from SPUs and a commercially available indirect screen ELISA (Is-ELISA) was applied. Is-ELISA detected antibodies in 20 (24.6%), 16 (22.8%), and 17 (16.6%) samples from SPU-I, SPU-II, and SPU-III, respectively. Collectively, seroprevalence of 20.0% (47/235) in breeding bulls and 33.3% (6/18) in teaser bulls was observed, and thus it poses a potential threat of disease spread to a high number of heifers and cows through artificial insemination. Therefore, this paper highlights the presence of the disease for the first time at SPUs and triggers attempts to ascertain the prevalence of paratuberculosis throughout the country. PMID- 23738099 TI - Genetic characterization of porcine circovirus type 2 from pigs with porcine circovirus associated diseases in Argentina. AB - Porcine circovirus type 2 (PCV-2) has been associated with syndromes grouped by the term porcine circovirus associated diseases (PCVAD). The PCV-2 isolates have been grouped into two major groups or genotypes according to their nucleotide sequence of whole genomes and/or ORF-2: PCV-2b, which have, in turn, been subdivided into three clusters (1A-1C), and PCV-2a, which has been subdivided into five clusters (2A-2E). In the present study, we obtained 16 sequences of PCV 2 from different farms from 2003 to 2008, from animals with confirmatory diagnosis of PCVAD. Since results showed an identity of 99.8% among them, they were grouped within a common cluster 1A-B. This preliminary study suggests a stable circulation of PCV-2b among the Argentinean pig population. PMID- 23738100 TI - Our Experience with Left-Sided Abomasal Displacement Correction via the Roll-and Toggle-Pin Suture Procedure according to Grymer/Sterner Model. AB - All over the world, and also in Slovenia, left-sided displacement of the abomasum (LDA) occurs most commonly in large-sized, high-producing adult dairy cows immediately after parturition. Yearly retrospective analyses of our ambulatory records showed significantly increased prevalence of LDA (2000 = 0.9%, 2010 = 3.7%), especially in cows after first parturition. Surgical replacement is now commonly practiced, and many techniques have been devised with emphasis on avoidance of recurrence of the displacement. Because of good results as recorded in the literature and encouragement of Keith E. Sterner, the author of this method, we want to try the right paramedian abomasopexy-Grymer/Sterner model. Since May 2009 till October 2011 109 cows from 46 farms were operated on because of LDA. As many as 44 (40.3%) were affected with LDA after first parturition. The analysis of successful procedure that was carried out 2 months after suture showed that 104 (95.4%) cows were cured. Only 5 (4.5%) cows died within 24 hours after surgery (4 cases of severe toxemia with hypokalemia and one case of acute abomasal hemorrhage were established). Our experience with Grymer/Sterner LDA transfixation sutures proved favorable. Because roll-and-toggle-pin suture technique is rapid and inexpensive we recommend it. PMID- 23738102 TI - Economic and managerial analysis of effective managerial strategies on prevention from ketosis in transition period in shahroud commercial dairy farms. AB - The purpose of this research is to study any effects of managerial strategies on prevention of ketosis metabolic disorder in transition period in Shahroud commercial dairy farms. For this purpose, a questionnaire was prepared in order to obtain required information about the performance of these managerial strategies, performance costs, involvement situation with disorders relying upon clinical signs and treatment and health records, producing and economic situation, and fertility rate and its costs. The considered managerial guidelines include body condition score management or type evaluation in transition period, increase in dry matter intake close to parturition, using propylene glycol, using niacin, and high-quality feeding (the importance of feed quality) in transition period. Finally and upon arrangement of data, it was possible to study any effects of mentioned managerial strategies on related variants through multiple linear regressions. Furthermore, in order to study any relation among variables, we considered Pearson correlation coefficients as well. Finally, it was revealed that any application of managerial strategies for prevention from Ketosis in transition period has a significant effect in betterment of managerial and economic parameters. PMID- 23738101 TI - Disposition Kinetic of Moxifloxacin following Intravenous, Intramuscular, and Subcutaneous Administration in Goats. AB - The present study was carried out to investigate disposition kinetics of moxifloxacin following single-dose intravenous (i.v.), intramuscular (i.m.), and subcutaneous (s.c.) administration at a dose rate of 5 mg/kg of body weight (b.wt.) in goats. Plasma samples collected after treatments were analyzed for drug concentration using high-performance liquid chromatography (HPLC). After i.v. administration, distribution of the drug was rapid and wide as reflected by high steady-state volume of distribution. Drug elimination was relatively faster with a total body clearance of 0.59 +/- 0.03 L/h/kg. Following i.m. injection, the drug has shown the rapid and near-to-complete absorption with bioavailability of 98.20 +/- 3.96 per cent. The maximum plasma drug concentration (Cmax) of 1.21 +/- 0.04 MUg/mL was attained at 1 h (Tmax). The drug was widely distributed as reflected by high apparent volume of distribution. The elimination half-life (t 1/2beta ) of the drug was 6.26 +/- 0.08 h. Following s.c. administration, the drug was rapidly absorbed (Cmax: 1.16 +/- 0.02 MUg/mL; tmax: 1 h) and slowly eliminated from the body. The elimination half-life and total body clearance (ClB) were 5.61 +/- 0.10 h and 0.60 +/- 0.03 L/h/kg, respectively. The bioavailability of moxifloxacin following s.c. administration was 90.44 +/- 3.96 per cent. PMID- 23738095 TI - Origins of injection-site sarcomas in cats: the possible role of chronic inflammation-a review. AB - The etiology of feline injection-site sarcomas remains obscure. Sarcomas and other tumors are known to be associated with viral infections in humans and other animals, including cats. However, the available evidence suggests that this is not the case with feline injection-site sarcomas. These tumors have more in common with sarcomas noted in experimental studies with laboratory animals where foreign materials such as glass, plastics, and metal are the causal agent. Tumors arising with these agents are associated with chronic inflammation at the injection or implantation sites. Similar tumors have been observed, albeit infrequently, at microchip implantation sites, and these also are associated with chronic inflammation. It is suggested that injection-site sarcomas in cats may arise at the administration site as a result of chronic inflammation, possibly provoked by adjuvant materials, with subsequent DNA damage, cellular transformation, and clonal expansion. However, more fundamental research is required to elucidate the mechanisms involved. PMID- 23738103 TI - The benefits of supplementary fat in feed rations for ruminants with particular focus on reducing levels of methane production. AB - Methane (CH4), a highly potent greenhouse gas, has repeatedly been identified as a significant contributor to global warming. In this connection, ruminants, animals that produce large quantities of methane, have been singled out as an area for reduction with regard to their emissions to the atmosphere. In an analysis of recently published data, we identify the underlying mechanisms of methane production in ruminants and focus on the efficacy of different fat sources in terms of their ability to reduce methane production. Specific attention has been placed on in vivo studies involving cattle and sheep, as well as studies based on a large number of animals (>10), recorded over a longer period (>21 days), and employing reliable techniques for the quantification of methane production. Data clearly indicate that supplementary fat, given to ruminants inhibits methane production, with medium-chain fatty acids (laurin, myristic acid) as well as poly-unsaturated fatty acids (linoleic and especially linolenic acid) having a significant effect. It is also apparent that conflicting findings between individual published trials can largely be resolved when one takes into consideration differences in experimental design, the composition of the basic feeds, the fat sources used, and the number of animals involved. PMID- 23738104 TI - Preliminary Finding on Anomalous Cleavage and Degeneration of Intestinal Nematode Eggs (Nematodirus sp.) after Oral Administration of Medium-Chain Fatty Acid in Calves. AB - Medium-chain fatty acids (MCFAs) consisting of 8 to 12 carbons are knowns exhibit antimicrobial activity against bacteria and gut protozoa. However, little information is available on their effect in helminthes. The effect of MCFA on an intestinal nematode (Nematodirus sp.) was therefore evaluated in four calves (4 to 11 month old). Edible fat containing MCFA was administered into the abomasum of the calves by practical stimulation of the reticular groove reflex for 5 days, and the resulting fecal egg shedding was examined. Although MCFA had a weak effect on fecal egg number of Nematodirus sp., morphologically anomalous eggs were observed. Anomalies manifested as degenerated eggs with ova granulation or shell rupture, irregular monocellular egg, and disproportional cleavage at the 2 , 4-cell and subsequent stages, despite normal shedding at 8- or 16-cell stages in most cases. Thus, MCFA administration brought cleavage disturbance and degeneration of Nematodirus sp. eggs. PMID- 23738105 TI - Evaluation of "Indigenous Absorbed ELISA Kit" for the Estimation of Seroprevalence of Mycobacterium avium Subspecies paratuberculosis Antibodies in Human Beings in North India. AB - In present pilot study aimed to estimate, presence of Mycobacterium avium subspecies paratuberculosis (MAP) antibodies in the human serum samples originating from North India using "Indigenous absorbed ELISA kit" (ELISA kit). The phase I, "ELISA kit" was optimized using protoplasmic antigen from native isolate of MAP "Indian Bison type" recovered from the biopsies of Crohn's disease patients. The phase II, sensitivity and specificity of the kit were estimated as 40.0 and 83.3%, respectively, when evaluated in 40 human serum samples (5 Crohn's disease and 22 ulcerative colitis patients and 13 healthy human subjects) with defined MAP status with respect to stool culture. Seroprevalence of MAP antibodies was higher in CD patients (80.0%) as compared to ulcerative colitis patients (4.5%) and normal human subjects (15.3%). The phase III, seroprevalence of MAP antibodies was estimated as 23.4%, on the basis of the screening of 452 human serum samples (without history) from different geographical regions of North India. Region-wise, 34.0, 33.3, 32.8, 25.0, 23.0, 17.7, and 12.5% samples were positive from the states of Punjab, Uttarakhand, New Delhi, Himachal Pradesh, Haryana, Uttar Pradesh and Jammu and Kashmir, respectively. Study reported moderately higher presence of MAP antibodies in human population, which necessitates programs to reduce the bioburden of MAP in the environment and in animal population. PMID- 23738106 TI - Modulating effect of ascorbic Acid on transport-induced immunosuppression in goats. AB - The effect of 12 h road transportation on some basic blood cells and the modulating role of ascorbic acid were investigated in 40 adult Red Sokoto goats during the hot dry season. The animals were divided into two groups, GI (experimental; n = 20) and GII (control; n = 20). Group 1 was administered with ascorbic acid (AA) per os at a dosage rate of 100 mg/kg body weight, while GII was given 10 mL of sterile water per goat. Forty minutes after the administration and loading, the goats were transported for 12 h. The result obtained in GII goats showed that loading, transportation, high ambient temperature (AT), and relative humidity (RH) encountered during transportation induced lymphopenia, neutrophilia, and eosinopenia, which can cause immunosuppression. In GI goats, the administration of AA prior to loading and transportation ameliorated the adverse effects of loading and transportation stress on neutrophil/lymphocyte ratio and eosinopenia of the goats. PMID- 23738107 TI - Effect of tannin-binding agents (polyethylene glycol and polyvinylpyrrolidone) supplementation on in vitro gas production kinetics of some grape yield byproducts. AB - The effects of polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP) on in vitro gas production characteristics, organic matter digestibility (OMD), and metabolizable energy (ME) contents of some grape yield byproducts were investigated. The gas production was recorded after 2, 4, 6, 8, 12, 16, 24, 36, and 48 h of incubation. The gas production profiles in triplicate fitted with equation Y = A (1 - e(-ct)). The data was analyzed using completely randomized design. Total phenol (TP) and total tannin (TT) contents were highest for raisin waste (RW). The TP content (g/kg DM) ranged from 30.1 in grape pomace (GP) to 96.3 in RW, which also had the higher TT (72.1 g/kg DM). The potential gas production (a + b) of DGB, GP, and RW were 239.43, 263.49, and 208.22 mL/g DM, respectively. In the absence of PEG and PVP, rate constant of gas production (c) for GP was highest among the feedstuffs (0.1073 mL/h), but in presence of PEG or PVP, RW had highest fraction (c) among the feedstuffs. Addition of PEG and PVP inactivated effects of tannins and increased gas production, ME, NE1, OMD, and VFA in grape yield byproducts. Addition of PEG and PVP could overcome adverse effects of tannins on nutrient availability as indicated by gas production parameters. PMID- 23738108 TI - An Effort to Isolate Mycobacterium bovis from Environmental Substrates during Investigations of Bovine Tuberculosis Transmission Sites (Cattle Farms and Wildlife Areas) in Michigan, USA. AB - Deer movements on cattle farms, wildlife feeding, and livestock management practices in Michigan are thought to create opportunities for indirect transmission of Mycobacterium bovis via environmental substrates. To confirm the presence of viable M. bovis in the environment, substrates were collected from 13 farms with culture-confirmed M. bovis in cattle and 5 sites with high prevalence of M. bovis in free-ranging deer. None of the samples processed for mycobacterial culture were positive for M. bovis. Agent, host, and landscape-level factors decrease the probability of detecting M. bovis in the environment using conventional mycobacterial culture. Molecular techniques that increase the probability of M. bovis detection in environmental substrates should be applied to known sites of M. bovis transmission in Michigan. In the interim, epidemiological investigations informed by experimental studies will be most effective in characterizing M. bovis persistence in the environment and its role in the indirect interspecies transmission of M. bovis. PMID- 23738110 TI - Ultrasonographic imaging for structural characterization of renal affections and diagnosis of associated chronic renal failure in 10 dogs. AB - The present study comprises of 10 dogs of either sex with primary indication of azotaemia. All the dogs were subjected to detailed clinical, haematobiochemical, urinalysis, and microbiological examination along with radiographical and ultrasonographical examination. Based on the ultrasonographic structural abnormalities, the different renal affections associated with CRF in majority of dogs were diagnosed. The different affections included "end-stage" kidneys (n = 4), hydronephrosis (n = 1), renomegaly (n = 1), nephritis (n = 1), nephrolithiasis (n = 1), nephrocalcinosis (n = 1), and renal cyst (n = 1). The significant ultrasonographic features in these affections included small kidneys with loss of corticomedullary demarcation ("end-stage" kidneys); increased cortical echogenicity (nephritis); dilation of the renal pelvis, separation of the central renal sinus with anechoic space, atrophy of renal medulla, (hydronephrosis); enlarged kidneys with increased overall echogenicity of renal cortex (renomegaly and associated nephritis); hyperechoic-mineralized structure with shadowing (nephrolithiasis); diffuse, small, multiple hyperechoic structures in the renal parenchyma with distal acoustic shadowing (nephrocalcinosis); small spherical intercortical anechoic structures fluid (renal cysts). In the present study, ultrasound proved to be a quick, convenient, and sensitive modality in detecting alterations in renal size and parenchymal architecture. All the dogs so diagnosed with CRF were rendered conservative medical treatment to control clinical signs of uraemia; maintain adequate fluid, electrolyte, and acid/base balance; provide adequate nutrition; minimize progression of renal failure. PMID- 23738109 TI - Effects of heat stress on the well-being, fertility, and hatchability of chickens in the northern Guinea savannah zone of Nigeria: a review. AB - The paper examines heat stress and its adverse effects as a hindrance to profitable poultry production in the tropics, with emphasis on the Northern Guinea Savannah zone of Nigeria. It elucidates the general negative effects of heat stress on physiological parameters of domestic chickens, and the specific impact of the stress on reproduction in the tropics. The deleterious effects are expressed in poor poultry well-being and reproductive performance. It is concluded that measures aimed at alleviating heat stress in domestic chickens must be adopted in order to enhance reproductive and, consequently, efficiency of modern poultry production in the tropics. PMID- 23738111 TI - Single Layer Centrifugation Can Be Scaled-Up Further to Process up to 150 mL Semen. AB - Single-Layer centrifugation has been used to improve the quality of sperm samples in several species. However, where stallion or boar semen is to be used for AI, larger volumes of semen have to be processed than for other species, thus limiting the effectiveness of the original technique. The objective of the present study was to scale up the SLC method for both stallion and boar semen. Stallion semen could be processed in 100 mL glass tubes without a loss of sperm quality, and similarly, boar semen could be processed in 200 mL and 500 mL tubes without losing sperm quality. The results of these preliminary studies are encouraging, and larger trials are underway to evaluate using these methods in the field. PMID- 23738112 TI - Comparative ultrasonographic imaging of spleen and liver in healthy crossbred cows. AB - The present study was undertaken to conduct a comparative ultrasonographic study of the normal bovine spleen and liver. This study was carried out in two phases using 3.5 MHz curvilinear transducer. In first phase of water bath study, bovine spleens and livers were obtained from 3 healthy cadavers and subjected to repeated ultrasonography to study the echotexture. The splenic parenchyma was isoechogenic with greater echogenicity as compared to the liver. Water bath study provided a good learning experience for the comparative analysis of echotexture of the spleen and liver. In second phase, 10 healthy Jersey/Red Sindhi adult nonpregnant cows were subjected to detailed abdominal ultrasonography a number of times to develop the baseline topographical data of the spleen and liver. The dorsal end of the spleen in the cranial intercostal spaces could be clearly seen at the peak of inspiration when the lungs retracted to uncover the parietal surface of the spleen. The ventral end of the spleen, portion of the left lung, and the reticular wall could be scanned in the left 7th to 6th ICS in all the cows, and in the left 5th ICS in 5 cows. The liver was imaged from just behind the 12th to 6th ICS in all the cows easily. The gallbladder was imaged as a tear drop or pear shaped anechogenic structure with a hyperechogenic wall. The location of the gallbladder varied from the 12th to 9th ICS. It was most consistently observed in the 11th ICS (in 7 cows) at a mean distance of 46.3 cm from the dorsal midline. In 3 cows, the gallbladder was also seen ventral to the costal arch. The caudal vena cava was imaged as a triangular anechogenic structure on the dorsal border of the liver in the last 2 intercostal spaces in all the cows. The portal vein was imaged characteristically as a star shaped anechogenic structure with a hyperechogenic wall, ventral to the caudal vena cava, in the last 2 intercostal spaces in all the cows and in the 10th ICS in only 8 cows. It was concluded that a systematic ultrasonography formed a basis for a reliable noninvasive determination of positions and sizes of the normal spleen and liver and their vessels in the bovines. PMID- 23738113 TI - Efficacy and safety of deracoxib for the control of postoperative pain and inflammation associated with dental surgery in dogs. AB - The efficacy and safety of deracoxib administered at 1-2 mg/kg/day for 3 days was assessed for the control of postoperative pain and inflammation associated with dental surgery in dogs. Client-owned dogs scheduled for dental extractions were premedicated with butorphanol and randomly assigned to receive either deracoxib (n = 31) or placebo (n = 31) preoperatively and again once daily for 2 additional days. Dogs were evaluated prior to and after surgery using a modified Glasgow Composite Pain Scale (mGCPS). Dogs could be rescued at any time if they scored >=4 on the mGCPS or in cases of obvious discomfort. Rescued dogs were considered treatment failures for determining treatment response and were removed from the study. Of the 62 dogs enrolled, 57 were usable for the efficacy analyses and all were assessed for safety. Four of 27 deracoxib-treated dogs (14.8%) were rescued compared to 20 of 30 placebo dogs (66.7%) (P = 0.0006). Deracoxib-treated dogs also had numerically lower mGCPS scores. Eight of 31 deracoxib dogs (26%) had adverse events reported compared to 6 of 31 placebo dogs (19%). Results indicate perioperative administration of deracoxib to dogs at 1-2 mg/kg/day for 3 days significantly improves analgesia after dental surgery. PMID- 23738114 TI - Occurrence of granulomas in bovines: an abattoir-based study. AB - The present study was carried out to record the occurrence of naturally occurring granulomas in cattle and buffaloes. Tissues grossly suspected for granulomas were collected from 336 out of 1600 (21%) abattoir cases. The gross features ranged from focal necrosis to large caseated masses, hard nodules, growths and abscesses. Histopathologically, 102 tissue samples (6.38%) were ascertained as granulomas. Majority of the granulomas were found in the liver 42 (41.18%), followed by lungs 22 (20.59%), lymph nodes 11 (10.78%), kidneys 6 (5.88%) and 14 (13.73%) as subcutaneous nodules/growths. Solitary cases were found in tongue, muscle, and urinary bladder, whereas 4 granulomas (3.92%) were found in body cavities. Based on the cellular component, the granulomas were categorized as epithelioid (53%), eosinophilic (37%) and suppurative (10%). Employing special staining techniques, the possible etiology of 75 granulomas could be identified. Among these, 70 granulomas (68.63%) were of infectious nature (parasitic 37 (36.28%), bacterial 32 (31.37%), and fungal 1(0.98%)). Non-infectious granulomas 5 cases (4.90%) included two lipid granulomas (1.96%), two granulomas (1.96%) associated with neoplasms and one (0.31%) associated with renal calculi. In 27 (26.47%) cases, the etiology of the granuloma could not be established and were categorized as granulomas of unknown etiology. PMID- 23738115 TI - An evaluation of the aboistop citronella-spray collar as a treatment for barking of domestic dogs. AB - The aim of our study was to investigate whether citronella-spray collars offer a humane alternative to electric-shock collars to reduce the barking of domestic dogs. The Aboistop collar was applied to seven dogs with problematic barking behaviour by the dogs' owners in a series of case studies concurrently run. Vocalisation of the dogs was recorded in the problem context under baseline conditions, inactive collar conditions, and active collar conditions. The Aboistop collar was effective at reducing problem vocalization for only three of seven dogs and appeared to be most effective for dogs whose problem barking had developed more recently. The collar may be more humane than other punishment methods, but it did produce stress reactions which varied in severity across the dogs. Clinical Relevance. In our study, the collar was applied by the dogs' owners in order to test whether the collar would be effective when used by members of the public. While the results here are preliminary, they suggest that the collar may be effective for some dogs, but not for others, when applied by dog owners for the treatment of problem vocalisation. Further research is required to determine whether the collar could be effective when administered by a trained professional. PMID- 23738116 TI - Effect of antimicrobial Peptide, nisin, on the reproductive functions of rats. AB - Our previous studies have demonstrated that naturally occurring peptide, Nisin possess antibacterial activity and did not interfere with rabbit vaginal mucosa. In this study, the reproductive toxicity of the Nisin in male rats was evaluated. Rats were fed orally with Nisin (10, 25, and 50 mg/kg/day) for 13 weeks. No treatment related mortality was observed. The body weight gain, food consumption and serum biochemical parameters were at par with the control group. Histomorphology of the selected reproductive (testis, epididymis, ventral prostate, and seminal vesicle) and nonreproductive (liver and kidney) tissues was observed to be normal. There was no treatment-related increase or decrease in the expression of testis-specific genes (c-Kit, GATA-1, and HILS-1) and the activity levels of epididymal alpha-glucosidase, ventral prostate alkaline phosphatase (AlP), liver alanine aminotransferase (AlAT) and aspartate aminotransferase (AAT). Fructose and lactic acid levels in the seminal vesicles also remained unchanged. These studies suggest that Nisin did not affect the normal physiology of these organs. In addition, no adverse effects were observed on the reproductive performance of Nisin-treated male rats and their offspring. In conclusion, the current studies support our earlier studies, which demonstrated suitability of Nisin as a safe and effective microbicide. PMID- 23738117 TI - Thiolated carboxymethyl-hyaluronic-Acid-based biomaterials enhance wound healing in rats, dogs, and horses. AB - The progression of wound healing is a complicated but well-known process involving many factors, yet there are few products on the market that enhance and accelerate wound healing. This is particularly problematic in veterinary medicine where multiple species must be treated and large animals heal slower, oftentimes with complicating factors such as the development of exuberant granulation tissue. In this study a crosslinked-hyaluronic-acid (HA-) based biomaterial was used to treat wounds on multiple species: rats, dogs, and horses. The base molecule, thiolated carboxymethyl HA, was first found to increase keratinocyte proliferation in vitro. Crosslinked gels and films were then both found to enhance the rate of wound healing in rats and resulted in thicker epidermis than untreated controls. Crosslinked films were used to treat wounds on forelimbs of dogs and horses. Although wounds healed slower compared to rats, the films again enhanced wound healing compared to untreated controls, both in terms of wound closure and quality of tissue. This study indicates that these crosslinked HA based biomaterials enhance wound healing across multiple species and therefore may prove particularly useful in veterinary medicine. Reduced wound closure times and better quality of healed tissue would decrease risk of infection and pain associated with open wounds. PMID- 23738118 TI - Presence of Infectious Bronchitis Virus Strain CK/CH/LDL/97I in the Middle East. AB - Infectious bronchitis virus (IBV) is a very dynamic and evolving virus, causing major economic losses to the global poultry industry. In early 2011, respiratory disease outbreaks were investigated in Iraq, Jordan, and Saudi Arabia. Five IBV isolates (JOA2, JOA4, Saudi-1, Saudi-2, and Iraqi IBV) were detected by diagnostic-nested nucleocapsid RT-PCR. Strain identification was characterised by sequencing and phylogenetic analysis of the amplified hypervariable region of the spike 1 (S1) gene. These five IBV isolates were found to be of the IBV strain CK/CH/LDL/97I. Nucleotide identity between these five IBV isolates ranged from 96.9% to 99.7%, and between these isolates and the CK/CH/LDL/97I strain in the range of 96.6-99.1%. The sequenced fragment of the S1 gene of the CK/CH/LDL/97I strain had less than 80% nucleotide identity to the IBV vaccine strains commonly used in the Middle East (M41 and H120). The presence of these CK/CH/LDL/97I-like strains may account for vaccination failure against IBV, since all IBV isolates were from vaccinated chickens. In this paper, we documented for the first time the presence of IBV strain CK/CH/LDL/97I in the Middle East. This strain is known to have originated in China and Taiwan. PMID- 23738119 TI - Effect of immunosuppression on newcastle disease virus persistence in ducks with different immune status. AB - This study was carried out to verify the possibility that ducks are sources of Newcastle disease (ND) virus infection for chickens in mixed flocks. Immunosuppressed (IS) and non immunosuppressed (NIS) birds, at three different antibody levels (medium, low and absent) were used; the titres having been induced through vaccination, and Immunosuppression done using dexamethazone. Each of the 3 respective groups was further divided into 2 groups of about 12 ducks each: one challenged with velogenic ND virus; the other not challenged. Selected ducks from all groups had their antibody titres monitored serially using hemagglutination inhibition test, while two birds from each of the challenged groups were killed and respective tissues processed for ND viral recovery, using chicken embryo fibroblasts. In general, antibody titres of IS and NIS challenged ducks were significantly higher than their unchallenged counterparts (P < 0.05). Non-challenged pre-immunised ducks had a progressive decrease in antibody levels; non-immunised ducks did not seroconvert. Newcastle disease virus was isolated from livers and kidneys of the challenged ducks throughout the experimental period; indicating a possibility of viral excretion, especially when the birds are stressed. It, therefore, provides another possible model of viral circulation within mixed flocks. PMID- 23738121 TI - Effects of replacing groundnut cake with blood vegetable waste meal in the diets of weaner rabbits. AB - A total of seventy-two weaner rabbits of eight weeks of age were used to assess the effects of replacing groundnut cake (GNC) with blood vegetable waste meal (BVWM) in the diets of rabbits. The BVWM was fed to replace dietary GNC at 0, 15, 30, and 45%, with GNC being 15% in the control diet. The four experimental diets were fed ad libitum for a period of eight weeks. BVWM was analyzed to contain a crude protein value of 62.35%. There were comparable feed intake values by rabbits on all the diets although the rabbits in the higher replacement levels of BVWM tended to have consumed more of the feed. There were significant increases (P < 0.05) in body weight gain by rabbits as the BVWM level increased in the diet. Similarly, the feed to gain ratio improved and nitrogen digestibility increased (P < 0.05) with higher levels of BVWM in the diet. This study shows that rabbits can tolerate the 45% BVWM replacement of groundnut cake effectively. PMID- 23738122 TI - The effect of a silage inoculant on silage quality, aerobic stability, and meat production on farm scale. AB - The effect of inoculation on nutrient content, fermentation, aerobic stability, and beef cattle performance for whole-plant corn silage treated with a commercial product (blend of homo- and heterofermentative lactic acid bacteria, BSM, blend of Enterococcus faecium, Lactobacillus plantarum, and Lactobacillus brevis, DSM numbers 3530, 19457, and 23231, resp.), was compared to a control treatment with no silage additives (CT). The material had a DM of 323 g/kg, crude protein, and water-soluble carbohydrate concentrations of 87.9 and 110.5 g/kg DM, respectively. BSM increased the fermentation rate with a significantly deeper pH (P < 0.01), a significant increase in the total organic acids concentration (P < 0.05), more lactic acid (P < 0.01), and numerically more acetic acid compared to CT. BSM significantly decreased the concentrations of butyric acid (P < 0.01), ethanol, and ammonia-N compared to the CT. BSM-treated silage decreased DM by 3.0 % (P < 0.01) and had a higher digestible energy and a higher metabolizable energy concentration by 2.3 (P < 0.01) and 1.00 % (P < 0.05), respectively, compared to untreated silage. Aerobic stability improved by more than 2 days in BSM silage. The DM intake of silage treated with BSM increased by 6.14 %, and improved weight gain and the feed conversion by 8.0 (P < 0.01) and 3.4%. PMID- 23738123 TI - An immunohistochemical study on the expression of sex steroid receptors in canine mammary tumors. AB - Steroid hormones are found to play a major role in the genesis and progression of mammary tumors. The aim of this study was to immunohistochemically detect the presence of estrogen receptor alpha (ER alpha ), estrogen receptor beta (ER beta ), and progesterone receptor (PR) and also to study the association between these markers in 29 cases of benign (11) and malignant (18) canine mammary tumors. ER alpha immunostaining was noticed in only one case of carcinosarcoma specifically in the nuclei of epithelial and a few myoepithelial cells. ER beta immunostaining was noticed in the nuclei and cytoplasm of epithelial cells and smooth muscles lining the blood vessels. Immunoexpression of ER beta was 82% in benign tumors and 78% in malignant tumors. PR immunostaining was expressed in the nuclei of epithelial cells in both benign and malignant tumors. Among the 15 PR+ cases, 6 (55%) were of benign type, and 9 (50%) were of malignant type. The most common group of hormone receptor was the ER alpha -/PR+/ER beta + (46%) in benign tumors and ER alpha -/PR-/ER beta + (38%) in malignant tumors. Although there was no significant association between ER alpha and PR with ER beta , the findings indicated that ER beta was consistently expressed in both benign and malignant tumors, irrespective of ER alpha and PR status. PMID- 23738124 TI - Hemoculture and Polymerase Chain Reaction Using Primers TCZ1/TCZ2 for the Diagnosis of Canine and Feline Trypanosomiasis. AB - Introduction. American trypanosomiasis, also known as Chagas disease, is a zoonosis caused by Trypanosoma cruzi (T. cruzi). Dogs and cats participate actively in this parasite's transmission cycle. This study aimed at evaluating the occurrence of T. cruzi in dogs and cats from Botucatu, SP, Brazil, as well as at evaluating the technique of hemoculture in LIT (liver infusion tryptose) medium by polymerase chain reaction (PCR). Methods. Blood samples were collected from 50 dogs and 50 cats in Botucatu-SP, Brazil. For hemoculture, the samples were inoculated in LIT medium, and readings were performed for four months. Upon completion of such period, all the hemocultures were processed for parasitic DNA extraction. The PCR reactions were performed by using primers TCZ1/TCZ2. Results. Ten dogs and ten cats (20%) were positive to PCR, and four dogs and three cats (7%) were positive to hemoculture. Only in a one cat sample (1%) there was confirmation of positive hemoculture by PCR for T. cruzi. Conclusions. Results showed that PCR was a suitable tool for the confirmation of the parasite detection in hemoculture samples, and that dogs and cats from Botucatu, SP, Brazil, are maintaining the role of household reservoirs of T. cruzi, which reinforces the need for constant epidemiologic surveillance for this zoonosis. PMID- 23738125 TI - Incidence of Listeria spp. in Dairy Cows Feed and Raw Milk in Latvia. AB - Feed is a risk factor for poisoning the farm environment thus also fresh milk with pathogenic microorganisms of Listeria genus species. Listeria ivanovii, Listeria innocua, and Listeria seeligeri were isolated from 9.2%, but Listeria monocytogenes from 20.0% of feed samples. Most often different fodders (9.3%) and silage (4.7%) were contaminated with Listeria monocytogenes. Listeria genus species were isolated more often from feed prepared and used in organic dairy farm than from that used in conventional dairy farm, correspondingly 44.4% and 18.3%. No Listeria monocytogenes was found in bulk milk samples of organic dairy farm. PMID- 23738120 TI - Detection and control of prion diseases in food animals. AB - Transmissible spongiform encephalopathies (TSEs), or prion diseases, represent a unique form of infectious disease based on misfolding of a self-protein (PrP(C)) into a pathological, infectious conformation (PrP(Sc)). Prion diseases of food animals gained notoriety during the bovine spongiform encephalopathy (BSE) outbreak of the 1980s. In particular, disease transmission to humans, to the generation of a fatal, untreatable disease, elevated the perspective on livestock prion diseases from food production to food safety. While the immediate threat posed by BSE has been successfully addressed through surveillance and improved management practices, another prion disease is rapidly spreading. Chronic wasting disease (CWD), a prion disease of cervids, has been confirmed in wild and captive populations with devastating impact on the farmed cervid industries. Furthermore, the unabated spread of this disease through wild populations threatens a natural resource that is a source of considerable economic benefit and national pride. In a worst-case scenario, CWD may represent a zoonotic threat either through direct transmission via consumption of infected cervids or through a secondary food animal, such as cattle. This has energized efforts to understand prion diseases as well as to develop tools for disease detection, prevention, and management. Progress in each of these areas is discussed. PMID- 23738126 TI - Response of fumaric Acid addition on methanogenesis, rumen fermentation, and dry matter degradability in diets containing wheat straw and sorghum or berseem as roughage source. AB - An in vitro incubation system was used to evaluate effect of supplementation of fumaric acid at 0, 5, 10, and 15 mM concentration in high-, medium-, and low fiber wheat straw containing total mixed diets with sorghum (Sorghum vulgare) and berseem clover (Trifolium alexandrinum L.) on rumen fermentation, methane production, and gas kinetics parameters. Three types of diets were prepared with different roughage and concentrate ratio (80 : 20, 50 : 50, and 20 : 80) by taking the representative samples. The roughage part composed of wheat straw (70 parts) and sorghum (30 parts) or berseem (30 parts) and the concentrate part composed of maize (33%), GNC (21%), mustard cake (12%), wheat bran (20%), deoiled rice bran (11%), mineral mixture (2%), and salt (1%). Fumaric acid was added in incubation medium to achieve final concentration of 0, 5, 10, and 15 mM. All the treatment combinations were arranged in 4 * 3 factorial designs with three replicates. It was concluded from the study that fumaric acid addition (5-15 mM) in diets varying in roughage to concentrate ratio significantly (P <= 0.05) reduced the methane production without affecting dry matter digestibility and maximum reduction was noticed at 5 mM concentration. PMID- 23738127 TI - Bacteriological quality of abattoir effluents discharged into water bodies in abuja, Nigeria. AB - Bacteriological characteristics of abattoir effluents (wastewater), abattoir water source, and water bodies receiving abattoir wastewater were investigated in Abuja, Nigeria using the multiple-tube fermentation technique. Source of water to the abattoirs and the usage of water bodies receiving abattoir effluents were determined using questionnaires. Bacterial counts ranged from 4.8 * 10(6) to 5.8 * 10(5) /100 mL of total coliform (TC), 8.2 * 10(4) to 3.2 * 10(4)/100 mL of Fecal coliform (FC), 5.2 * 10(4) to 2.0 * 10(4)/100 mL of Fecal streptococcus and 1.2 * 10(4) to 2.0 * 10(3)/100 mL of Escherichia coli for abattoir effluents 6.6 * 10(5) to 6.0 * 10(5)/100 mL of TC, 6.2 * 10(4) to 1.8 * 10(4)/100 mL of FC, 1.8 * 10(4) to 6.0 * 10(3)/100 mL of F. streptococcus, and 4.8 * 10(3) to 6.6 * 10(2)/100 mL of E. coli for water bodies receiving abattoir effluents 100 m downstream. TC bacteria counts for abattoir effluents exceeded recommended limit for discharge into surface water in Nigeria. No significant difference (P < 0.05) was observed between bacterial counts of abattoir effluents and receiving water bodies 100 m downstream: an indication of contamination of receiving water bodies by abattoir effluents and possible public and environmental health hazards. PMID- 23738128 TI - Effect of Aqueous Extract of Telfairia occidentalis Leaf on the Performance and Haematological Indices of Starter Broilers. AB - This experiment was conducted to determine the effect of aqueous extract of Telfairia occidentalis (Fluted Pumpkin) leaf on the performance and haematological indices of starter broilers. A total of 200, 8-day-old broiler chicks were randomly allotted to five (5) treatments, each with 4 replicate groups containing 10 chicks and fed with standard starter broiler diets. Telfaria occidentalis leaves extract (FPLE) was added at 0, 40, 80, 120, and 160 mL/litre of drinking water. Growth performance and haematological indices were evaluated. Results showed that there was significant (P < 0.05) difference in weight gain, feed conversion, and protein efficiency ratios of the birds among the treatments. Birds fed 80 ml FPLE/litre of water had significantly the highest weight gain and the best feed conversion and protein efficiency ratios. There was no significant (P > 0.05) variations in the feed and water intakes of the birds. Results also show no significant (P > 0.05) difference in haematological indices of birds among the treatments. The results of this study indicate that, for enhanced weight gain and feed conversion efficiency, birds should be fed 80 mL FPLE/litre of water. PMID- 23738129 TI - Evaluation of oral robenacoxib for the treatment of postoperative pain and inflammation in cats: results of a randomized clinical trial. AB - The efficacy and safety of robenacoxib were assessed for the control of postoperative pain and inflammation in cats. The study was a multicenter, prospective, randomized, blinded, and parallel group clinical trial. A total of 249 client-owned cats scheduled for forelimb onychectomy plus either ovariohysterectomy or castration surgeries were included. All cats received butorphanol prior to anesthesia and forelimb four-point regional nerve blocks with bupivacaine after induction of general anesthesia. Cats were randomized to receive daily oral tablet robenacoxib, at a mean (range) dosage of 1.84 (1.03 2.40) mg/kg (n = 167), or placebo (n = 82), once prior to surgery and for two days postoperatively. Significantly (P < 0.05) fewer robenacoxib cats received additional analgesia rescue therapy (16.5%) than placebo cats (46.3%). Pain elicited on palpation of the soft tissue incision site, behavior following social interaction, and posture assessed during the first 8 hours after extubation were significantly (P < 0.05) improved in cats receiving robenacoxib. Frequency of reported adverse clinical signs, hematology, serum chemistry and urinalysis variables, and body weight changes weresimilar between groups. In conclusion, robenacoxib was effective and well tolerated in the control of postoperative pain and inflammation in cats undergoing onychectomy with ovariohysterectomy or castration. PMID- 23738130 TI - Bioeconomic performance of pullets and layer hens fed soybean grains-based diets in hot and humid climate. AB - The aim of this paper was to evaluate the effects of toasted soybean grains on bioeconomic performance of pullets and layer hens in hot and humid environment. A total of 972 three-week-old Harco chicks were divided into 12 groups. At starter, pullet and laying phases, birds were fed four diets containing 0% (R0), 5% (R5), 10% (R10), and 15% (R15) of soybean grains. Results showed similar feed intake, body weight gain, laying rate, feed conversion ratio, and mortality rate between dietary treatments at each phase. The egg weight increased significantly in diet R15 (P < 0.05). The use of soybean grains reduced the feed prices. Feeding cost decreased significantly (P < 0.05) during growth and laying phases in soybean grains added diets. Feeds efficiency increased significantly (P < 0.05) with the increase of dietary soybean grains rate. Properly toasted soybean grains can be therefore included up to 15% in heavy line layer hens' diet in tropical conditions. PMID- 23738131 TI - Nephroprotective Effect of POLYCAN on Acute Renal Failure Induced by Cisplatin in Rats. AB - We performed to evaluate the effect of POLYCAN (beta-glucan) on cisplatin-(CDDP )induced acute renal failure (ARF) in rats. POLYCAN was administered orally once a day for 32 days. Each of 8 rats per group was selected based on the body weight (BW) after acclimatization and they were sacrificed at 5 days after CDDP injection. There was significant (P < 0.05) increase of BW after CDDP dosing in all POLYCAN groups than vehicle control and significant (P < 0.01 or P < 0.05) decrease of absolute and relative kidney weight were detected in all POLYCAN groups compared with vehicle control. In addition, serum BUN and creatinine level in all POLYCAN groups were significantly (P < 0.01 or P < 0.05) lower than vehicle control and the percentage of degenerative regions significantly (P < 0.01) decreased in all POLYCAN groups. As the results of CDDP-induced ARF process, dramatic decrease of the BW, increase of the kidney weight, serum BUN, and creatinine level were detected in vehicle control group compared with sham control group. The changes by CDDP-induced ARF process in POLYCAN groups were significantly and dose-dependently improved compared with vehicle control group. Therefore, POLYCAN has enough potential to develop as a new agent of prevention or treatment for ARF. PMID- 23738133 TI - Growth performance of rabbits fed palm-press fibres-based diets. AB - An experiment was carried out to define the optimal rate of palm-press fibres in growing rabbits' diet. In total, 64 weaned rabbits (35 days old) of Beninese breed were divided in 16 groups of 4 rabbits (2 males and 2 females) each. During six weeks, rabbits were fed with 4 complete diets containing 0% (F0, control), 5% (F5), 10% (F10), and 15% (F15) of fibres from a palm oil industry. Results demonstrated that up to 15 of palm-press fibres can be included efficiently in growing rabbits' diet. The daily feed intake was not significantly affected by the diet (P > 0.05). At 13 weeks old, the average live weights of rabbits were 1788.5 g, 1805.0 g, 1718.5 g, and 1801.3 g in respectively, F0, F5, F10 and F15 groups. No mortality of rabbits was recorded. Compared to F0, the feed conversion ratio and feeding cost decreased in the group of rabbits fed F15 diet. The carcass yield was similar between diets. PMID- 23738134 TI - Plasma disposition of conventional and long-acting moxifloxacin in sheep after intravenous administration. AB - This study describes disposition of long-acting moxifloxacin and conventional formulations of moxifloxacin in sheep after intravenous administration in five male sheep. Long acting moxifloxacin solution (10% moxifloxacin in solution with L-arginine, N-butyl alcohol, and benzyl alcohol) and conventional moxifloxacin (10%) were injected in jugular vein. Blood samples were collected from contralateral jugular vein in test tubes containing 30-50 IU heparin (anticoagulant) periodically from 0.083 to 72 h of drug administration. Drug concentrations in plasma were determined using High-Performance Liquid Chromatography (HPLC) with fluorescence detector. The mobile phase consisted of a mixture of buffer (10 gm of tetrabutyl ammonium hydrogen sulphate per liter deionised water) and acetonitrile (80 : 20). The buffer was 0.067M of disodium hydrogen phosphate with pH of 7.5. The flow rate was 1 mL.min(-1) at ambient temperature. The effluent was monitored at 296 nm excitation and 504 nm emissions wavelength. HPLC with fluorescence detector method for plasma moxifloxacin assay was standardized with specific modification for plasma of sheep in the present study. After single-dose intravenous administration of long acting moxifloxacin the plasma concentration of 0.016 +/- 0.001 MU g.mL(-1) was maintained for up to 72 h. Conventional formulation of moxifloxacin remained in body for up to 24 h of drug administration with the level of 0.015 +/- 0.005 MU g.mL(-1). PMID- 23738132 TI - The major histocompatibility complex in bovines: a review. AB - Productivity in dairy cattle and buffaloes depends on the genetic factors governing the production of milk and milk constituents as well as genetic factors controlling disease resistance or susceptibility. The immune system is the adaptive defense system that has evolved in vertebrates to protect them from invading pathogens and also carcinomas. It is remarkable in the sense that it is able to generate an enormous variety of cells and biomolecules which interact with each other in numerous ways to form a complex network that helps to recognize, counteract, and eliminate the apparently limitless number of foreign invading pathogens/molecules. The major histocompatibility complex which is found to occur in all mammalian species plays a central role in the development of the immune system. It is an important candidate gene involved in susceptibility/resistance to various diseases. It is associated with intercellular recognition and with self/nonself discrimination. It plays major role in determining whether transplanted tissue will be accepted as self or rejected as foreign. PMID- 23738135 TI - A Survey for Escherichia coli Virulence Factors in Asymptomatic Free-Ranging Parrots. AB - Parrots in captivity are frequently affected by Escherichia coli (E. coli) infections. The objective of this study was to collect information on the carrier state for E. coli pathotypes in asymptomatic free-ranging parrots. Cloacal swabs were collected from nestlings of Hyacinth, Lear's macaws and Blue-fronted Amazon parrots and tested by polymerase chain reaction (PCR) for virulence factors commonly found in enteropathogenic, avian pathogenic, and uropathogenic E. coli strains. In total, 44 samples were cultured and E. coli isolates were yielded, from which DNA was extracted and processed by PCR. Genes commonly found in APEC isolates from Blue-fronted Amazon parrots and Hyacinth macaws were expressed in 14 of these 44 samples. One atypical EPEC isolate was obtained from a sample from Lear's macaw. The most commonly found gene was the increased serum survival (iss) gene. This is the first report, that describes such pathotypes in asymptomatic free-living parrots. The findings of this study suggest the presence of a stable host/parasite relationship at the time of the sampling brings a new understanding to the role that E. coli plays in captive and wild parrots. Such information can be used to improve husbandry protocols as well as help conservation efforts of free-living populations. PMID- 23738136 TI - A proposed selection index for jersey cattle in zimbabwe. AB - A multitrait selection index (I T ) for Zimbabwean Jersey cattle was constructed. The breeding objective was defined in terms of production and functionality traits. The production component of the index included milk yield (M), butterfat yield (F), protein yield (P), butterfat percent (F%), and protein percent (P%), while the functional component included the somatic cell count (SCC). The index was termed as I T = 0.0004M + 0.0109F + 0.0313P + 1.0004F% + 2.4491P% - 0.1905SCC. The accuracy of the index was 91.1%, and the correlation between this index and the aggregate breeding objective was 0.954. A selection index is more important in the selection of sires and cows. This leads to the greatest genetic progress and hence productivity in the dairy sector. Therefore, the application of the selection index developed is necessary if the dairy cattle industry is to maximise the exploitation of genetics and to improve its relative competitive position. PMID- 23738137 TI - Effect of Withania somnifera Extracts on Some Selective Biochemical, Hematological, and Immunological Parameters in Guinea Pigs Experimental Infected with E. coli. AB - Fifty 1-2-month-old Guinea pigs were divided into 5 equal groups, 10 each. Control (Gp1) did receive neither viable bacteria nor treatment. Each animal from the other groups (Gp2-5) was challenged with (1-2 * 10(8)) viable E. coli in 200 MU L normal saline (0.9%) through IP route. GP2 infected group was treated with 200 MU L saline IP and kept as positive control group. Gp3-4 are infected and treated with Withania somnifera (ethanol root extract) with doses 50 and 100 mg/kg. BW, respectively. Gp5 infected treated group was treated with cefoperazone antibiotic at dose 35 mg/Kg BW. The treatment by drug or the extracted medicinal plant was started 72 h after infection for 7 successive days. Serum and whole blood sample were collected from all groups 14 days after treatment to evaluate some hematological and biochemical changes as well as immunomodulatory cytokine tumor necrosis factor-alpha (TNF- alpha ). Oral treatment of the plant extract caused significant benefit results in infected Guinea pig appeared in the correction of some hematological and biochemical parameters also try to suppressed inflammatory cytokine response represent in TNF- alpha . It could be concluded that W. somnifera extract has potent antibacterial activity, and this appears in the correction with hematological, biochemical, and immunological results. PMID- 23738138 TI - Assessment of Fatty liver syndrome and its predisposing factors in a dairy herd from Venezuela. AB - The present on-farm research evaluated the occurrence of fatty liver syndrome and its predisposing risk factors for multiparous dairy cows from a commercial herd in Venezuela. Liver biopsy samples were collected at 35 days (d) prepartum (Holstein, n = 14; Holstein * Carora crossbred, n = 17) as well as 1 to 7 d (Holstein, n = 8; Holstein * Carora crossbred, n = 11) and 28 to 35 d (Holstein, n = 6; Holstein * Carora crossbred, n = 14) postpartum in order to analyse hepatic triacylglycerols (TAG, % wet basis) and glycogen concentrations. At postpartum, an occurrence of 72.0% for severe fatty liver along with 73.5% of subclinical ketosis (SCK) was found. The multiple regression model that best explained the association between milk production in the previous lactation (MYP) and TAG at first week postpartum was as follows: TAG, % = -11.2 + 3.16 (prepartum body condition) + 0.0009176 (MYP) (R(2) = 0.36, P < 0.05). Logistic regression indicated that Holstein * Carora crossbred cows tended to have 27% higher relative risk than Holstein to experience SCK, whereas prepartum liver TAG greater than 3% tended to be associated with a higher relative risk for SCK compared to cows with TAG <=3%. PMID- 23738140 TI - Histomorphological and Histochemical Observations of the Common Myna (Acridotheres tristis) Tongue. AB - Common myna tongue was studied histomorphologically and histochemically. Four tongues of adult birds were carried out macroscopically and microscopically. The tongue was triangular; the dorsum of the body had median groove. Two to three backward directed papillae were located on each side of the body-base junction. A single transverse row of pharyngeal papillae was located behind the laryngeal cleft. The parakeratinized mucosa covered the entire surface of the tongue except clearly keratinized band on the ventrolateral surface and the conical papillae. Compared with the lateral group (LG), the secretory cells of the medial group (MG) of the anterior lingual glands (ALG) and the posterior lingual glands (PLG) contained large amount of mucin. It was neutral mucin. However, the LG had weak acid mucin with carboxylated group. Meanwhile, the MG of the ALG and the PLG had strong acid mucin with both carboxylated and sulphated groups. In conclusion, the morphological observation of the common myna tongue showed some variation from the other birds. Histochemical results indicated the differences between the LG and MG of the anterior lingual glands. However, no difference was observed between the latter and the PLG. PMID- 23738141 TI - Extravasation injuries in adults. AB - Insertion of an intravascular catheter is one of the most common invasive procedures in hospitals worldwide. These intravascular lines are crucial in resuscitation, allow vital medication to be administered, and can be used to monitor the patients' real-time vital parameters. There is, however, growing recognition of potential risks to life and limb associated with their use. Medical literature is now replete with isolated case reports of complications succinctly described by Garden and Laussen (2004) as "An unending supply of "unusual" complications from central venous catheters." This paper reviews complications of venous and arterial catheters and discusses treatment approaches and methods to prevent complications, based on current evidence and endeavours to provide information and guidance that will enable practitioners to prevent, recognise, and successfully treat extravasation injuries in adults. PMID- 23738142 TI - Transarterial treatment of direct carotid cavernous fistulas with the assistance of undetachable balloons. AB - Directed carotid cavernous fistula means high blood flow shunts between the internal carotid artery and the cavernous sinus. Obstructing the abnormal shunt between the internal carotid artery and the cavernous sinus while preserving the internal carotid artery is the key role in fistula treatment. Transarterial balloon embolization is currently the gold standard treatment for most of the carotid cavernous fistulas. But there are still some technical difficulties in the use of detachable balloon to treat carotid cavernous fistulas. Here, we describe undetachable balloon-assisted technique in the embolization of three patients who got complete immediate occlusion of the shunt and preserved the internal carotid artery at the same time. PMID- 23738139 TI - Breed-predispositions to cancer in pedigree dogs. AB - Cancer is a common problem in dogs and although all breeds of dog and crossbred dogs may be affected, it is notable that some breeds of pedigree dogs appear to be at increased risk of certain types of cancer suggesting underlying genetic predisposition to cancer susceptibility. Although the aetiology of most cancers is likely to be multifactorial, the limited genetic diversity seen in purebred dogs facilitates genetic linkage or association studies on relatively small populations as compared to humans, and by using newly developed resources, genome wide association studies in dog breeds are proving to be a powerful tool for unravelling complex disorders. This paper will review the literature on canine breed susceptibility to histiocytic sarcoma, osteosarcoma, haemangiosarcoma, mast cell tumours, lymphoma, melanoma, and mammary tumours including the recent advances in knowledge through molecular genetic, cytogenetic, and genome wide association studies. PMID- 23738143 TI - Noncoding RNAs in Neurodegenerative Diseases. AB - Noncoding RNAs are widely known for their various essential roles in the development of central nervous system. It involves neurogenesis, neural stem cells generation, maintenance and maturation, neurotransmission, neural network plasticity, formation of synapses, and even brain aging and DNA damage responses. In this review, we will discuss the biogenesis of microRNA, various functions of noncoding RNA's specifically microRNAs (miRNAs) that act as the chief regulators of gene expression, and focus in particular on misregulation of miRNAs which leads to several neurodegenerative diseases as well as its therapeutic outcome. Recent evidences has shown that miRNAs expression levels are changed in patients with neurodegenerative diseases; hence, miRNA can be used as a potential diagnostic biomarker and serve as an effective therapeutic tool in overcoming various neurodegenerative disease processes. PMID- 23738144 TI - The well-being of siblings of individuals with autism. AB - Objective. The purpose of this review of the literature was to summarise studies regarding the psychosocial impact of growing up with a sibling with autism and to identify gaps in the related literature. Methods. Electronic databases were reviewed in order to critically appraise the 14 articles relevant to the topic. The search included a combination of the following key words: autism*, quality of life, well-being, sibling*, ASD, ASD sibling*, family, adjust*, psychological functioning. Results. The majority of studies involved mixed children and adolescent samples, leading to confounding results and an inability to draw accurate conclusions about these distinct life stages. Autism appears to contribute to unique environmental stressors for the typically developing sibling. When experienced in the context of additional demographic risk factors, these stressors can result in difficulties adjusting to the demands of a special needs child. Despite some vulnerability to behavioural and emotional dysfunction in at-risk children, siblings have the potential to not only adjust but to thrive in the face of disability adversity. Conclusion. Growing up with a sibling with autism appears to manifest in both positive and negative outcomes for siblings, depending upon important demographical, family, and individual variables. PMID- 23738146 TI - Thymic Stromal Lymphopoietin Enhances Th2/Th22 and Reduces IL-17A in Protease Allergen-Induced Airways Inflammation. AB - Background. Thymic stromal lymphopoietin (TSLP) is induced in allergic skin and lung inflammation in man and mice. Methods. Allergic lung inflammation induced by two proteases allergens HDM and papain and a classical allergen ovalbumin was evaluated in vivo in mice deficient for TSLPR. Eosinophil recruitment, Th2 and Th17 cytokine and chemokine levels were determined in bronchoalveolar lavage fluid, lung homogenates and lung mononuclear cells ex vivo. Results. Here we report that mice challenged with house dust mite extract or papain in the absence of TSLPR have a drastic reduction of allergic inflammation with diminished eosinophil recruitment in BAL and lung and reduced mucus overproduction. TSLPR deficient DCs displayed diminished OVA antigen uptake and reduced capacity to activate antigen specific T cells. TSLPR deficient mice had diminished proinflammatory IL-1 beta , IL-13, and IL-33 chemokines production, while IL-17A, IL-12p40 and IL-10 were increased. Together with impaired Th2 cytokines, IL-17A expressing TCR beta (+) T cells were increased, while IL-22 expressing CD4(+) T cells were diminished in the lung. Conclusion. Therefore, TSLPR signaling is required for the development of both Th2 and Th22 responses and may restrain IL 17A. TSLP may mediate its effects in part by increasing allergen uptake and processing by DCs resulting in an exacerbated asthma. PMID- 23738147 TI - Assessment of the effects of access count in percutaneous nephrolithotomy on renal functions by technetium-99m-dimercaptosuccinic Acid scintigraphy. AB - Objective. To determine the effects of percutaneous nephrolithotomy on renal functions by using DMSA scintigraphy while considering access counts. Material and Methods. A total of 37 patients who had undergone percutaneous nephrolithotomy were included. Preoperative DMSA scans were performed a day before the surgery, whereas postoperative scans were randomized by evaluating them before (n = 25) and after (n = 12) the 6th postoperative month. Twenty-six of 37 cases underwent percutaneous nephrolithotomy with a single access site and 11 with multiple access sites. Results. There were no significant changes of total renal functions in the whole study group (P = 0.054). In the single access group, total functions were significantly elevated (P = 0.03) In the multiple access group, while treated site functions were significantly decreased (P = 0.01), total functions did not change significantly (P = 0.42). There was an insignificant decrease in those evaluated before the 6th postoperative month (P = 0.27) and an insignificant increase in the others (P = 0.11). Conclusion. We could not find a superiority of single access over multiple accesses. There is a temporary functional loss in the treated site. PMID- 23738148 TI - Subthalamic hGAD65 gene therapy and striatum TH gene transfer in a Parkinson's disease rat model. AB - The aim of the present study is to detect a combination method to utilize gene therapy for the treatment of Parkinson's disease (PD). Here, a PD rat model is used for the in vivo gene therapy of a recombinant adeno-associated virus (AAV2) containing a human glutamic acid decarboxylase 65 (rAAV2-hGAD65) gene delivered to the subthalamic nucleus (STN). This is combined with the ex vivo gene delivery of tyrosine hydroxylase (TH) by fibroblasts injected into the striatum. After the treatment, the rotation behavior was improved with the greatest efficacy in the combination group. The results of immunohistochemistry showed that hGAD65 gene delivery by AAV2 successfully led to phenotypic changes of neurons in STN. And the levels of glutamic acid and GABA in the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNr) were obviously lower than the control groups. However, hGAD65 gene transfer did not effectively protect surviving dopaminergic neurons in the SNc and VTA. This study suggests that subthalamic hGAD65 gene therapy and combined with TH gene therapy can alleviate symptoms of the PD model rats, independent of the protection the DA neurons from death. PMID- 23738149 TI - Case study of ecstatic meditation: fMRI and EEG evidence of self-stimulating a reward system. AB - We report the first neural recording during ecstatic meditations called jhanas and test whether a brain reward system plays a role in the joy reported. Jhanas are Altered States of Consciousness (ASC) that imply major brain changes based on subjective reports: (1) external awareness dims, (2) internal verbalizations fade, (3) the sense of personal boundaries is altered, (4) attention is highly focused on the object of meditation, and (5) joy increases to high levels. The fMRI and EEG results from an experienced meditator show changes in brain activity in 11 regions shown to be associated with the subjective reports, and these changes occur promptly after jhana is entered. In particular, the extreme joy is associated not only with activation of cortical processes but also with activation of the nucleus accumbens (NAc) in the dopamine/opioid reward system. We test three mechanisms by which the subject might stimulate his own reward system by external means and reject all three. Taken together, these results demonstrate an apparently novel method of self-stimulating a brain reward system using only internal mental processes in a highly trained subject. PMID- 23738145 TI - Neurochemical and behavioral features in genetic absence epilepsy and in acutely induced absence seizures. AB - The absence epilepsy typical electroencephalographic pattern of sharp spikes and slow waves (SWDs) is considered to be due to an interaction of an initiation site in the cortex and a resonant circuit in the thalamus. The hyperpolarization activated cyclic nucleotide-gated cationic I h pacemaker channels (HCN) play an important role in the enhanced cortical excitability. The role of thalamic HCN in SWD occurrence is less clear. Absence epilepsy in the WAG/Rij strain is accompanied by deficiency of the activity of dopaminergic system, which weakens the formation of an emotional positive state, causes depression-like symptoms, and counteracts learning and memory processes. It also enhances GABAA receptor activity in the striatum, globus pallidus, and reticular thalamic nucleus, causing a rise of SWD activity in the cortico-thalamo-cortical networks. One of the reasons for the occurrence of absences is that several genes coding of GABAA receptors are mutated. The question arises: what the role of DA receptors is. Two mechanisms that cause an infringement of the function of DA receptors in this genetic absence epilepsy model are proposed. PMID- 23738151 TI - Magnet-retained facial prosthesis combined with maxillary obturator. AB - Prosthetic rehabilitation of the midfacial defects has always perplexed prosthodontists. These defects lead to functional and esthetic deficiencies. The purpose of this clinical case report was the presentation of the prosthetic rehabilitation of an extraoral-intraoral defect using two-piece prosthesis magnetically connected. This prosthesis has dramatically improved the patient's speech, mastication, swallowing, and esthetic. PMID- 23738153 TI - Granuloma annulare, autoimmune thyroiditis, and lichen sclerosus in a woman: randomness or significant association? AB - We report a 60-year-old Caucasian female with a 2-year history of diffused granuloma annulare (GA), who presented for the simultaneous occurrence of genital lichen sclerosus (LS) and autoimmune thyroiditis (AT). In our opinion this combination is not just coincidental but may share similar immunopathological mechanisms. PMID- 23738150 TI - Brain connectivity plasticity in the motor network after ischemic stroke. AB - The motor function is controlled by the motor system that comprises a series of cortical and subcortical areas interacting via anatomical connections. The motor function will be disturbed when the stroke lesion impairs either any of these areas or their connections. More and more evidence indicates that the reorganization of the motor network including both areas and their anatomical and functional connectivity might contribute to the motor recovery after stroke. Here, we review recent studies employing models of anatomical, functional, and effective connectivity on neuroimaging data to investigate how ischemic stroke influences the connectivity of motor areas and how changes in connectivity relate to impaired function and functional recovery. We suggest that connectivity changes constitute an important pathophysiological aspect of motor impairment after stroke and important mechanisms of motor recovery. We also demonstrate that therapeutic interventions may facilitate motor recovery after stroke by modulating the connectivity among the motor areas. In conclusion, connectivity analyses improved our understanding of the mechanisms of motor recovery after stroke and may help to design hypothesis-driven treatment strategies and sensitive measures for outcome prediction in stroke patients. PMID- 23738154 TI - Critical pertussis in a young infant requiring mechanical ventilation. AB - Pertussis may likely be misdiagnosed in its initial or catarrhal phase as a common respiratory infection. The earlier diagnosis of pertussis really depends on the capability of the medical professional especially in the first line public health services. The lack of awareness in diagnosis of severe pertussis as one of the causes of severe respiratory problems may likely misdiagnose pertussis as respiratory failure or even septic shock. In fact, pertussis may manifest as a critical pertussis which can be fatal due to the respiratory failure that require pediatric intensive care unit using mechanical ventilation. We reported a confirmed pertussis case of a 7-weeks-old female infant referred to our tertiary hospital with gasping leading to respiratory failure and septic shock requiring mechanical ventilation, aggressive fluid therapy, and antibiotics. Pertussis was diagnosed late during the course of illness when the patient was hospitalized. Improvement was noted after administering macrolide which gave a good response. Bordetella pertussis isolation from Bordet-Gengou media culture yielded positive result. PMID- 23738155 TI - A case of inoperable malignant insulinoma with resistant hypoglycemia who experienced the most significant clinical improvement with everolimus. AB - Metastatic insulinomas may sometimes present with recurrent life-threatening hypoglycemia episodes. Such patients usually fail to respond to various therapeutic agents which causes constant dextrose infusion requirement. Herein, we present a resistant case of inoperable malignant insulinoma who was treated with many therapeutic agents and interventions including somatostatin analogues, Yttrium-90 radioembolization, everolimus, radiotherapy, and chemoembolization. Close blood sugar monitorization during these therapies showed the most favourable response with everolimus. Everolimus treatment resulted in rapid improvement of hypoglycemia episodes, letting us discontinue dextrose infusion and discharge the patient. However, experience with everolimus in such patients is still limited, and more precise data can be obtained with the increasing use of this agent for neuroendocrine tumours. PMID- 23738156 TI - Chromosome 22q11.2 deletion syndrome presenting as adult onset hypoparathyroidism: clues to diagnosis from dysmorphic facial features. AB - We report a 26-year-old Thai man who presented with hypoparathyroidism in adulthood. He had no history of cardiac disease and recurrent infection. His subtle dysmorphic facial features and mild intellectual impairment were suspected for chromosome 22q11.2 deletion syndrome. The diagnosis was confirmed by fluorescence in situ hybridization, which found microdeletion in 22q11.2 region. The characteristic facial appearance can lead to clinical suspicion of this syndrome. The case report emphasizes that this syndrome is not uncommon and presents as a remarkable variability in the severity and extent of expression. Accurate diagnosis is important for genetic counseling and long-term health supervision by multidisciplinary team. PMID- 23738157 TI - Actinomycosis of cecum associated with entamoeba infection mimicking perforated colon cancer. AB - Actinomycosis is a granulomatous disease caused by Actinomyces that mimics other intra-abdominal pathologies especially neoplasms. Correct diagnosis can be rarely established before radical surgery. On the other hand Entamoeba infection affects a considerable number of people worldwide. To our knowledge only one case has been reported to be affected by both organisms. We report a man who has been operated for a mass in the cecum mimicking a perforated colon cancer. Abdominal CT revealed a mass with features of an invading neoplasm. After radical surgery, definitive pathology revealed that the mass was due to actinomycosis associated with Entamoeba infection. The postoperative period was uneventful and the patient was on long-course antibiotherapy. It is important to consider actinomycosis especially in patients with intra-abdominal masses with unusual aggressiveness to prevent unnecessary surgery. However, surgery can be unavoidable especially in the presence of complicated disease or high index of suspicion for malignancy. PMID- 23738158 TI - Hem-o-Lok Clip in the First Part of Duodenum after Laparoscopic Cholecystectomy. AB - Laparoscopic cholecystectomy (LC) and common bile duct exploration (LCBDE) have become the standard surgical procedure for cholecystolithiasis and choledocholithiasis. During the operation, cystic duct and vessels are usually controlled by Hem-o-Lok clips. We report a case with a complaint of severe abdominal pain for the previous 20 days. Her medical history was unremarkable except for laparoscopic cholecystectomy 8 months ago. In upper gastrointestinal endoscopy, two Hem-o-Lok clips at anterior wall of the first part of duodenum were detected. Therefore, the clip can migrate during postoperative period and Hem-o-Lok is not a very safe ligation method during laparoscopic cholecystectomy. PMID- 23738160 TI - A Unique "Composite" PTLD with Diffuse Large B-Cell and T/Anaplastic Large Cell Lymphoma Components Occurring 17 Years after Transplant. AB - Posttransplant lymphoproliferative disorder (PTLD) comprises a spectrum ranging from polyclonal hyperplasia to aggressive monoclonal lymphomas. The majority of PTLDs are of B-cell origin while T-cell PTLDs and Hodgkin lymphoma-like PTLDs are uncommon. Here, we report a unique case of a 56-year-old man in whom a lymphoma with two distinct components developed as a duodenal mass seventeen years following a combined kidney-pancreas transplant. This PTLD, which has features not previously reported in the literature, consisted of one component of CD20 positive and EBV negative monomorphic diffuse large B-cell lymphoma. The other component showed anaplastic morphology, expressed some but not all T-cell markers, failed to express most B-cell markers except for PAX5, and was diffusely EBV positive. Possible etiologies for this peculiar constellation of findings are discussed and the literature reviewed for "composite-like" lymphomas late in the posttransplant setting. PMID- 23738161 TI - Steroid-resistant extranodal rosai-dorfman disease of cheek mass and ptosis treated with radiation therapy. AB - Background. Rosai-Dorfman Disease (RDD) is rare benign hematologic disorder of histiocytes, which usually manifests as painless lymphadenopathy, fever, leukocytosis and hypergammaglobulinemia. Extranodal RDD has been reported in 43% of cases, with skin as commonly involved site followed by head and neck region. However, soft tissue cheek mass is rare presentation of extra-nodal RDD. Case Presentation. A 26-year-old Saudi man presented with a six-month history of right cheek swelling and left upper eyelid swelling. Physical examination revealed right cheek mass of size 3 * 3 cm and left upper eyelid mass of size 1 * 2 cm and no palpable cervical lymphadenopathy. Incisional biopsy of cheek mass showed positivity for S100 and negativity for CD1a, consistent with extra-nodal RDD. Patient did not respond to systemic steroids and was given radiation therapy to left orbit with minimal response. Then, he was started on chemotherapy Rituximab, cyclophosphamide, vincristine, and prednisolone (RCVP) 8 cycles followed by reirradiation 10 Gy in 10 fractions with 6 MeV electron with complete response. After 12 months of followup, patient had recurrence in right cheek and was started on radiotherapy to the cheek mass. Conclusion. Extra-nodal RDD with involvement of cheek is a rare presentation. Incorporation of S100 and CD1a is helpful in diagnoses of RDD and differentiating it from other benign histiocytosis. Treatment consists of surgery, steroids, chemotherapy, and radiation therapy. PMID- 23738162 TI - Thrombotic thrombocytopenic purpura: a case presenting with acute ischemic colitis. AB - Thrombotic thrombocytopenic purpura (TTP) consists of the pentad of thrombocytopenia, hemolytic anemia, fever, neurologic abnormalities, and renal disease. We present a case report of acute TTP following a bout of ischemic colitis. This report reminds the clinician that ischemic colitis can be an atypical presentation of TTP. The prompt recognition and treatment of this disease process resulted in a good prognosis for our patient. PMID- 23738163 TI - Incidental discovery of a testicular plasmacytoma at initial presentation of multiple myeloma. AB - Testicular plasmacytomas are a rare phenomenon reported in the literature and they can occur as a solitary plasmacytoma, as a recurrence of multiple myeloma, or concurrently in an active myeloma. We report the case of a 43-year-old man who presented with back pain and was diagnosed with multiple myeloma. A CT scan performed to determine the extent of disease revealed an incidental mass in the testicle. Immunohistochemical staining of the mass revealed monoclonal cytolpasmic IgA in the tumor cells and serum studies showed this same immunoglobulin. Following orchiectomy, radiotherapy to the vertebra, chemotherapy with bortezomib, dexamethasone, and doxorubicin, and an autologous bone marrow transplant, the patient is alive twelve months after diagnosis and is in complete remission. PMID- 23738164 TI - Combination Antifungal Therapy in the Treatment of Scedosporium apiospermum Central Nervous System Infections. AB - Treatment of Scedosporium apiospermum central nervous system (CNS) infection typically consists of an azole in combination with surgical debridement. This approach requires prolonged treatment and carries a high associated mortality. We present two cases of the successful treatment of S. apiospermum CNS infections with the combination of voriconazole and terbinafine. PMID- 23738165 TI - Posterior Reversible Encephalopathy Syndrome in a Patient with Newly Diagnosed HIV Infection and End Stage Renal Disease. AB - Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome in which patients present with an acute or subacute clinical presentation of seizures, visual disturbances, headache, and altered mental status. The pathophysiology of PRES may be explained by endothelial dysfunction that leads to transudation of fluids and protein, resulting in vasogenic cerebral edema. PRES is typically associated with many conditions such as hypertension, uremia, immunosuppressive drugs, and sepsis. This is a case report of a 39-year old woman with untreated HIV infection and end-stage renal disease (ESRD) who developed PRES with a normal blood pressure and no other known causes of PRES. Untreated HIV is associated with known endothelial dysfunction and we believe that this, in combination with her untreated end-stage renal disease, contributed to her unique presentation of PRES. Although uncommon in HIV-infected patients and challenging to diagnose, prompt recognition of PRES is critical to provide appropriate care and ensure reversibility of the vasogenic edema seen in PRES. PMID- 23738166 TI - A 17-year-old female with systemic lupus presents with complex movement disorder: possible relationship with antiribosomal p antibodies. AB - Complex movement disorder is a relatively rare presentation of neurolupus. Antiphospholipid antibodies are associated with movement disorders likely via aberrant neuronal stimulation. Antiribosomal P antibodies have been previously associated with neuropsychiatric disorders but their correlation with movement disorder was not previously established. Our case report involves a 17-year-old Caucasian female patient positive for only antiribosomal P antibody and lupus anticoagulant who presented with a sudden onset of complex movement disorder. After complete cessation of physical signs with olanzapine, anticardiolipin and anti- beta 2 glycoprotein I antibodies became positive which indicates a likely discordance between movement disorder and antiphospholipid antibodies. This also indicates a potential causal role of antiribosomal P antibodies in inducing movement disorder. PMID- 23738167 TI - Primary angiitis of the central nervous system: a report of three cases from a single colombian center. AB - The primary angiitis of the central nervous system (PACNS) is an entity with a very low incidence and prevalence. It is not clear why the inflammatory process of this entity is limited to the cerebral vasculature without systemic manifestations. Its clinical manifestations are very heterogeneous and make clinical diagnosis difficult. In most cases, a brain biopsy is required. Only the clinical suspicion and the ability to recognize the possible clinical and imagenological patterns of presentation make an accurate diagnosis possible. The vast majority of the treatment recommendations are given by series of case reports. The following paper described the clinical, imagenological, and histopathological characteristics of three Colombian patients with PACNS. The strategic therapeutic used in shown. PMID- 23738168 TI - Laparoscopic treatment of intrauterine fallopian tube incarceration. AB - Herniation of the pelvic structures into the uterine cavity (appendix vermiformis, small bowel, omentum, or fallopian tube) may occur after uterine perforation. In this paper, we describe one case of intrauterine fallopian tube incarceration treated by means of laparoscopic surgery. PMID- 23738169 TI - A fibroid or cancer? A rare case of mixed choriocarcinoma and epithelioid trophoblastic tumour. AB - Background. Gestational trophoblastic disease (GTD) is a rare complication of pregnancy which is characterised by abnormal growth of the trophoblasts at the placental site. It is categorised into benign and malignant forms, which include hydatidiform moles (HMs) and gestational trophoblastic neoplasia (GTN), respectively. A mixed choriocarcinoma (CC) and epithelioid trophoblastic tumour (ETT) is an extremely rare subgroup of GTN, which is a highly curable but aggressive form of malignancy. Case. We report a case of mixed CC and ETT in a 41 year-old patient who presented with a 2-year history of menorrhagia and fibroid uterus in the absence of previous history of molar pregnancy. She had a 12-year interval between the antecedent pregnancy and presentation. She was treated with intensive regimen of adjuvant chemotherapy, etoposide, methotrexate, and actinomycin-D with etoposide and cisplatin (EMA-EP). She has remained disease free for more than 5 years. Conclusion. This case highlights the importance of considering GTN as one of the differential diagnoses value of beta -HCG in patients presented with menorrhagia and growing fibroids. PMID- 23738170 TI - Stage IAE Follicular Lymphoma of the Breast: Case Report and Review of the Literature. AB - Primary lymphoma of the breast is a rare entity in the field of oncological medicine and represents <0.5% of all breast malignancies. A definitive diagnosis is obtained by excisional biopsy as the clinical and radiographical presentation is similar to the more common primary breast carcinoma. Unlike primary breast carcinoma, localized radiation therapy is the mainstay of treatment. We report on a case of primary follicular lymphoma of the breast in a 67-year-old Caucasian woman treated with localized radiation as well as coinciding literature review regarding outcomes of different treatment modalities. PMID- 23738171 TI - Revision arthroplasty in the haemophiliac patient. AB - Arthroplasty in the haemophiliac patient is associated with higher rates of infection and is traditionally performed in a younger age group. Despite this there is little evidence in the literature regarding revision arthroplasty in this cohort of patients. We describe the case of a periprosthetic fracture in a haemophiliac patient requiring revision arthroplasty, who did not consent to receiving blood products due to religious beliefs, with a successful outcome. PMID- 23738172 TI - Could ossification of the achilles tendon have a hereditary component? AB - Ossification of the Achilles tendon (OTA) is an unusual clinical condition. It is characterized by the presence of an ossified mass within the fibrocartilaginous substance of the Achilles tendon. The etiology of the ossification of the Achilles tendon is unknown. Review of the literature suggests that its etiology is multifactorial. The major contributing factors are trauma and surgery with other minor causes such as systemic diseases, metabolic conditions, and infections. To our knowledge, no previous reports suggest any genetic/hereditary predisposition in OAT. We report 3 siblings who have OAT with no history of any of the aforementioned predisposing factors. Could OAT have a hereditary component as one of its etiologies? PMID- 23738173 TI - Sacral Fracture Nonunion Treated by Bone Grafting through a Posterior Approach. AB - Nonunion of a sacral fracture is a rare but serious clinical condition which can cause severe chronic pain, discomfort while sitting, and significant restriction of the level of activities. Fracture nonunions reportedly occur most often after nonoperative initial treatment or inappropriate operative treatment. We report a case of fracture nonunion of the sacrum and pubic rami that resulted from non operative initial treatment, which was treated successfully using bone grafting through a posterior approach and CT-guided percutaneous iliosacral screw fixation combined with anterior external fixation. Although autologous bone grafting has been the gold standard for the treatment of pelvic fracture nonunions, little has been written describing the approach. We utilized a posterior approach for bone grafting, which could allow direct visualization of the nonunion site and preclude nerve root injury. By this procedure, we were able to obtain the healing of fracture nonunion, leading to pain relief and functional recovery. PMID- 23738174 TI - A rare case of nasopharyngeal pleomorphic adenoma. AB - Salivary gland tumors are rare. The majority of these tumors are benign and about 70% are pleomorphic adenomas (PA). Nasopharynx is an unusual site for the PA tumor. Only six cases are presented in the literature from 1990 to 2011. The diagnosis of this disease is linked to the sum of imaging tests, clinical and histological study of the mass of the above. The radiologic features of noninvasion of surrounding structures give the first clue to the benign lesion. From the review of the literature and our experience is identified as the gold standard in surgical treatment for this condition. Thanks to the endoscopic surgery, we can perform a complete resection of the lesion without damaging adjacent structures. We presented a case of pleomorphic adenoma of nasopharynx with literature review. PMID- 23738175 TI - Endoscopic Resection of Sinonasal Hemangiopericytoma following Preoperative Embolisation: A Case Report and Literature Review. AB - Objectives. Hemangiopericytoma is a rare tumor entity deriving from pericytes. Less than 5% of hemangiopericytoma occur in the nasal cavity and are characterised by a rather benign nature with low tendency of metastasis. However, as the recurrence rate in the literature ranges from 9.5% to 50%-depending on the length of followup-a radical surgical resection is considered as the gold standard treatment. Only a few years ago, a wide external approach, usually via lateral rhinotomy or Caldwell-Luc, was performed. Endoscopic techniques were regarded as appropriate for small low-vascularised tumors only. Methods. We present the case of a 64-year-old patient with an extended sinonasal hemangiopericytoma, who was successfully treated by an endoscopic controlled endonasal tumor resection after embolisation with Onyx. Further, to support the new treatment option, we review the literature concerning all features of sinonasal hemangiopericytomas and their therapeutical management. Results/Conclusion. Onyx, which has not been described in the context of hemangiopericytoma yet, is a very effective embolic agent for a preoperative embolisation of sinonasal hemangiopericytoma allowing a safe endoscopic surgery. PMID- 23738176 TI - Neuroendocrine tumor, well differentiated, of the breast: a relatively high-grade case in the histological subtype. AB - Primary neuroendocrine carcinoma of the breast is a rare entity, comprising <1% of breast carcinomas. Described here is the case of a 78-year-old woman who developed an invasive tumor in the left breast measuring 2.0 cm x 1.5 cm x 1.2 cm. The tumor was composed of only endocrine elements in the invasive part. It infiltrated in a nested fashion with no tubular formation. Intraductal components were present both inside and outside of the invasive portion. Almost all carcinoma cells consisting of invasive and intraductal parts were positive for synaptophysin and neuron-specific enolase. According to the World Health Organization classification 2012, this tumor was subclassified as neuroendocrine tumor, well-differentiated. Among the subgroup, this tumor was relatively high grade because it was grade 3 tumor with a few mitotic figures. Vascular and lymphatic permeation and lymph node metastases were noted. In the lymph nodes, the morphology of the tumor was similar to the primary site. No distant metastasis and no relapse was seen for one year after surgery. The prognosis of neuroendocrine carcinomas is thought to be worse than invasive mammary carcinomas, not otherwise specified. Therefore, immunohistochemistry for neuroendocrine markers is important in the routine practice to prevent overlooking neuroendocrine carcinomas. PMID- 23738178 TI - A Sacral Mass in a Newborn: A Variant of Type II Diastematomyelia with Triple Splitting of the Cord. AB - Ultrasonographic (US) evaluation of spinal anomalies is limited. MRI is increasingly being used in the diagnosis of spinal anomalies. MRI has been able to show clearly the detailed anatomy of this rare case of type II diastematomyelia with triple splitting of the cord. PMID- 23738179 TI - Obturator hernia: a rare case of acute mechanical intestinal obstruction. AB - Obturator hernia is a rare type of pelvic hernia which generally occurs in elderly patients with accompanying diseases. Because it is difficult to diagnose before surgery, the morbidity and mortality rates for obturator hernia are high. The most common symptom is strangulation combined with mechanical intestinal obstruction. PMID- 23738180 TI - Unusual presentation of mediastinal neurogenic tumours. AB - Mediastinal neurogenic tumours generally arise as single benign lesions and their typical location is the costovertebral sulcus. In about 10% of cases mediastinal neurogenic tumours may extend to the spinal canal; occasionally they may extend to the cervical region and, more rarely, may be multiple or associated with other synchronous mediastinal lesions. The treatment of choice is surgical resection. This report describes three cases of unusual presentation of mediastinal benign schwannomas successfully treated at our Hospital. In the first case multiple simultaneous paravertebral lesions were resected through a posterior approach. In the second case a tumour of the posterior mediastinum extending to the cervical region was excised through a one-stage combined supraclavicular incision followed by left mini-invasive video-assisted thoracoscopic surgical techniques. The third case describes a patient with a posterior neurogenic mediastinal tumour with a synchronous parathyroid adenoma of the anterior mediastinum, which were both successfully resected by video-assisted thoracoscopic surgery. PMID- 23738181 TI - A unique cause of intestinal and splenic infarction in a sickle cell trait patient. AB - Sickle-cell trait is a common genetic abnormality in the African American population. A sickle-cell crisis in a patient with sickle-cell trait is uncommon at best. Abdominal painful crises are typical of patients with sickle cell anemia. The treatment for an abdominal painful crisis is usually medical and rarely surgical. We present the case of a cocaine-induced sickle-cell crisis in a sickle-cell trait patient that resulted in splenic, intestinal, and cerebral infarctions and multisystem organ failure necessitating a splenectomy, subtotal colectomy, and small bowel resection. This case highlights the diagnostic dilemma that abdominal pain can present in the sickle-cell population and illustrates the importance of recognizing the potential for traditionally medically managed illnesses to become surgical emergencies. PMID- 23738182 TI - Asymptomatic bone cement pulmonary embolism after vertebroplasty: case report and literature review. AB - Introduction. Acrylic cement pulmonary embolism is a potentially serious complication following vertebroplasty. Case Report. A 70-year-old male patient was treated with percutaneous vertebroplasty for osteoporotic nontraumatic vertebral collapse of L5-S1. Asymptomatic pulmonary cement embolism was detected on routine postoperative chest radiogram and the patient was treated with enoxaparin, amoxicillin, and dexamethasone. At the followup CT scan no further migration of any cement material was reported; and the course was uneventful. Discussion. The frequency of local leakage of bone cement is relatively high (about 80-90%), moreover, the rate of cement leakage into the perivertebral veins (seen in up to 24% of vertebral bodies treated) with consequent pulmonary cement embolism varies from 4.6 to 6.8% (up to 26% in radiologic studies); the risk of embolism is increased with the liquid consistency of the cement and with the treatment of some malignant lesions. Patients may remain asymptomatic and develop no known long-term sequelae. Conclusions. Our ancedotal case illustrates the need for close monitoring of patients undergoing percutaneous vertebroplasty and emphasizes the importance of prompt and correct diagnosis and treatment, even if actually there is no agreement regarding the therapeutic strategy. PMID- 23738183 TI - Abdominal cocoon syndrome (idiopathic sclerosing encapsulating peritonitis): how easy is its diagnosis preoperatively? A case report. AB - The abdominal cocoon syndrome (or idiopathic encapsulating peritonitis) is a rare cause of intestinal obstruction. It has been reported predominantly in adolescent girls living in tropical/subtropical region in which diagnosis is only made at laparotomy in most cases. The cause and pathogenesis of the condition have not been elucidated. Prolonged administration of practalol, meconium peritonitis, and tuberculous infection of the female genital tract have been incriminated as possible causes. The author reports a case of a female patient with recurrent intestinal obstruction treated for years but failed to settle down on conservative treatment during her last hospital admission and had to undergo surgery. Preoperative diagnosis of this syndrome as the cause of her intestinal obstruction was not made until at laparotomy, when a thick fibrotic peritoneal wrapping of the bowel in a concertina-like fashion with some adhesions was found. Excision of this membrane and adhesiolysis were carried out without any need for bowel resection, and this led to relief of the obstruction and patient's complete recovery. Awareness of this benign condition in the differential diagnosis of intestinal obstruction will result in early diagnosis and correct management and prevent unnecessary bowel resections and bad outcomes. PMID- 23738184 TI - Multifocal retroperitoneal sarcoma. AB - Introduction. Retroperitoneal sarcomas comprise a small proportion of all soft tissue sarcomas, and multiple factors influence their clinical behavior. Histopathological type and grade as well as complete surgical resection especially on the first operative attempt are well recognized as the main prognostic factors. Multifocality is another prognostic factor, which compromises therapy and finally makes prognosis worse due to multiple adverse implications. Case Presentation. A rare case of a 65-year-old male patient suffering from a multifocal retroperitoneal liposarcoma successfully treated in our hospital is presented herein. Discussion. Also, general considerations for these tumors are discussed, and especially multifocality is underlined as an ominous sign of retroperitoneal sarcomas behavior. Despite multifocality, once again complete surgical excision remains the mainstay of treatment of these patients, as long as further systemic and local therapies do not provide durable results. PMID- 23738185 TI - Visceral myopathy presenting as acute appendicitis and ogilvie syndrome. AB - Background. Visceral myopathy is rare pathological condition of gastrointestinal tract with uncertain clinical presentation and unknown etiology. It often presents with symptoms of chronic intestinal pseudoobstruction of colon. We report a case of visceral myopathy which presented to us as acute appendicitis and Ogilvie syndrome, and we managed it surgically. Method and Result. A case report of 20-year female clinically presented as acute appendicitis and we performed laparoscopic exploration which revealed inflamed appendix with grossly dilated ascending colon. We performed laparoscopic appendectomy and postoperatively managed the patients with IV fluids, antibiotics, neostigmine, and extended length rectal tube for enema and decompression. During postoperative period, she developed abdomen distension and peritonitis, and we ordered abdomen CT which revealed colon pseudo- obstruction. We performed right hemicolectomy with permanent ileostomy, and the histopathology reports of resected colon were visceral myopathy. Conclusion. Visceral myopathy is very rare group of disease and poorly understood condition that may present with chronic or acute intestinal pseudo-obstruction and often mimic other more common gastrointestinal disease. VM should be considered as differential diagnosis whenever the patient presents with acute appendicitis, uncharacteristic abdominal symptoms, recurrent attacks of abdominal distention, and pain with no radiological evidence of intestinal obstruction. PMID- 23738186 TI - Esophageal gastrointestinal stromal tumor: diagnostic complexity and management pitfalls. AB - Introduction. Gastrointestinal stromal tumors of the esophagus are rare. Case Presentation. This is a case of a 50-year-old male patient who was referred to our department complaining of atypical chest pain. A chest computed tomographic scan and endoscopic ultrasound revealed a submucosal esophageal tumor measuring 5 cm in its largest diameter. Suspecting a leiomyoma, we performed enucleation via right thoracotomy. The pathology report yielded a diagnosis of an esophageal gastrointestinal stromal tumor. The patient has shown no evidence of recurrence one year postoperatively. Conclusions. This report illustrates the complexity and dilemmas inherent in diagnosing and treating esophageal GISTs. PMID- 23738187 TI - Radical chemoradiotherapy for urethral squamous cell carcinoma: two case reports and a review of the literature. AB - Primary urethral squamous cell carcinoma is rare. Its management is particularly challenging owing to the paucity of evidence from randomised trials to inform practice. We report two male and female cases of squamous cell carcinoma of the urethra, which were treated with concomitant cisplatin and radiotherapy. These cases add to the body of case reports that have shown benefit for concomitant chemoradiotherapy in urethral squamous cell carcinoma. They also illustrate that single agent chemotherapy, namely, cisplatin, may be used successfully with limited toxicities. PMID- 23738188 TI - Advanced prostate cancer presenting as hemolytic uremic syndrome. AB - Introduction. Hemolytic uremic syndrome (HUS) is characterized by endothelial dysfunction, consumption thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. HUS generally has a dismal prognosis, except when associated with gastroenteritis caused by verotoxin-producing bacteria. Cancer associated HUS is uncommon, and there are only scarce reports on prostate cancer presenting with HUS. Case Presentation. A 72-year-old man presented to the emergency department with oliguria, hematuria, and hematemesis. Clinical evaluation revealed acute renal failure, hemolysis, normal blood-clotting studies, and prostate-specific antigen value of 1000 ng/mL. The patient was started on hemodialysis, ultrafiltration with plasma exchange, and androgen blockade with bicalutamide and completely recovered from HUS. The authors review the 14 published cases on this association. Conclusion. The association of HUS and prostate cancer occurs more frequently in patients with high-grade, clinically advanced prostate cancer. When readily recognized and appropriately treated, HUS does not seem to worsen prognosis in prostate cancer patients. PMID- 23738189 TI - Lumbar Ureteral Stenosis due to Endometriosis: Our Experience and Review of the Literature. AB - Endometriosis is a chronic gynaecological disorder characterized by the presence of endometrial tissue outside the uterus. The disease most often affects the ovaries, uterine ligaments, fallopian tubes, and cervical-vaginal region. Urinary tract involvement is rare, accounting for around 1%-2% of all cases, of which 84% are in the bladder. We report a case of isolated lumbar ureteral stenosis due to endometriosis in a 37-year-old patient. The patient came to our observation complaining from lumbar back pain and presented with severe fever. The urological examination found monolateral left positive sign of Giordano. Blood tests evidenced marked lymphocytosis and increased valued of C-reactive protein. Urologic ultrasound showed hydronephrosis of first degree in the left kidney and absence of images related to stones bilaterally. Uro-CT scan evidenced ureteral stenosis at the transition between the iliac and pelvic tracts. We addressed the patient to surgery, and performed laparoscopic excision of the paraureteral bulk, endoscopic mechanical ureteral dilation, and stenting. The histological examination evidenced glandular structures lined by simple epithelium and surrounded by stroma. Immunohistochemical test of the glandular epithelium showed positivity for estrogen and progesterone receptors and moreover stromal cells were positive for CD10. The finding suggested a very rare diagnosis of isolated lumbar ureteral endometriosis. PMID- 23738191 TI - Long-term survival of a patient with invasive signet-ring cell carcinoma of the urinary bladder managed by combined s-1 and Cisplatin adjuvant chemotherapy. AB - Primary signet-ring cell carcinoma of the urinary bladder is extremely rare and patient survival is very poor. The disease usually presents at advanced stages because the cancer progresses rapidly. The only option for effective treatment is radical cystectomy, and no effective chemotherapy has been established for this variant. We report a case of signet-ring cell carcinoma of the urinary bladder with a long-term survival of 90 months owing to radical cystectomy and combination adjuvant chemotherapy with S-1 and cisplatin. To our knowledge, this is the first report to demonstrate the long-term therapeutic activity of combination S-1 and cisplatin adjuvant chemotherapy against invasive signet-ring cell carcinoma of the urinary bladder. PMID- 23738192 TI - Effectiveness of cognitive-behavioral therapy modified for inpatients with depression. AB - The effectiveness among inpatients with depression of a modified cognitive behavior therapy (CBT) program was examined. A group of 300 inpatient admissions with a primary diagnosis of depression attending a private psychiatric clinic were assessed at the beginning and end of a two-week CBT program. The effectiveness of the treatment was demonstrated by improvements on the Beck depression inventory (BDI), the health of the nation outcome scales, locus of control of behaviour scale, and the global assessment of function. The changes on the BDI for patients with depression were benchmarked against estimates generated from published studies. The degree of change in a two-week period for inpatients with depression was similar to that observed in efficacy studies of CBT that typically run over a more extended time. Implications for integrating CBT with inpatient services are discussed. PMID- 23738193 TI - Posttraumatic Growth Inventory: Factor Structure in the Context of DSM-IV Traumatic Events. AB - Studies examining the dimensionality of the Posttraumatic Growth Inventory (PTGI) have yielded varying results. To date, no study has investigated the measure's factor structure in the context of DSM-defined traumatic events. The present study examined the structure in an undergraduate student sample (N = 379) reporting DSM-IV Criterion-A potentially traumatic events. Confirmatory factor analysis (CFA) did not support the original five-factor structure. Follow-up exploratory factor analysis and CFA on random halves of the sample showed poor model fit for 1-, 3-, and 7-factor models. Results suggest that the PTGI factor structure is unclear amongst individuals with DSM-IV traumatic events, and continued use of the total score is most appropriate. Future directions including the utility of the PTGI factors are discussed. PMID- 23738194 TI - Coping styles in patients with anxiety and depression. AB - Different individuals use different coping styles to cope with their problems. In patients with anxiety and/or depression, these have important implications. The primary objective of our study was to estimate the frequency of different coping mechanisms used by patients with symptoms of anxiety and depression. A descriptive, cross-sectional survey was conducted and patients with symptoms of anxiety and depression were identified using the Aga Khan University's Anxiety and Depression Scale (AKUADS). Coping styles were determined by using the 28-item Brief COPE inventory. We were able to recruit 162 people. The prevalence of anxiety and depression was found to be 34%. Females were more than 2 times likely to have anxiety and depression (P value = 0.024, OR = 2.62). In patients screening positive for AKUADS, "religion" was the most common coping mechanism identified. "Acceptance", "Use of instrumental support", and "Active coping" were other commonly used coping styles. Our findings suggest that religious coping is a common behavior in patients presenting with symptoms anxiety and depression in Pakistan. Knowledge of these coping styles is important in the care of such patients, as these coping methods can be identified and to some extent modified by the treating clinician/psychiatrist. PMID- 23738195 TI - Eysenck's Two Big Personality Factors and Their Relationship to Depression in Patients with Chronic Idiopathic Pain Disorder: A Clinimetric Validation Analysis. AB - Aim. The clinimetric aspects of Eysenck's two big personality factors (neuroticism and extraversion) were originally identified by principal component analysis but have been insufficiently analysed with item response theory models. Their relationship to states of melancholia and anxiety was subsequently analysed. Method. Patients with chronic idiopathic pain disorder were included in the study. The nonparametric item response model (Mokken) was compared to the coefficient alpha to validate the anxiety and depression subscales within the neuroticism scale and the extraversion and introversion subscales within the extraversion scale. When measuring states of depression and anxiety, the Melancholia Scale and the Hamilton Anxiety Scale were used. Results. We identified acceptable subscales of anxiety and depression in the Eysenck factor of neuroticism and extraversion versus introversion subscales within the Eysenck factor of extraversion. Focusing on the item of "Does your mood often go up and down?" we showed a statistically significant association with melancholia and anxiety for patients with a positive score on this item. Conclusion. Within the Eysenck factor of neuroticism it is important to differentiate between the anxiety and depression subscales. The clinimetric analysis of the Eysenck factor of extraversion identified valid subscales. PMID- 23738196 TI - Validation of Yoruba Version of Family Burden Interview Schedule (Y-FBIS) on Caregivers of Schizophrenia Patients. AB - Objective. To validate the Yoruba version of Family Burden Interview Schedule (Y FBIS) for assessing the burden on caregivers of persons with schizophrenia. Methods. Three hundred and sixty-eight dyads of persons with schizophrenia and their caregivers were recruited from a psychiatric outpatient clinic. The (Y FBIS) and the Yoruba version of the GHQ-12 (Y-GHQ-12) were applied to the caregivers. Patients' level of social functioning was assessed using the Global Assessment of Functioning scale. Results. All (368) caregivers were used for tests of internal consistency, 180 for interrater reliability, and another 180 for test-retest reliability. Internal consistency of the Y-FBIS was demonstrated by a significant Cronbach alpha of between 0.62 and 0.82 for each item. Concurrent validity of the Y-FBIS was illustrated by its significant positive correlation with Y-GHQ-12 (r = 0.633 , P < 0.01). Split-half reliability was 0.849. Intraclass correlation coefficient for the total score of Y-FBIS was 0.849 at 95% confidence interval. Test-retest reliability of individual scales ranged from 0.780 to 0.874 and was 0.830 for total objective scale score. Convergent validity was shown by the significant positive correlation (r = 0.83) between the objective burden score and subjective burden score of Y-FBIS. ROC curve area was 0.981. Conclusion. The Y-FBIS is a valid, reliable, and sensitive instrument for assessing the burden on caregivers of persons with schizophrenia in Nigeria. PMID- 23738197 TI - Psychological symptoms in patients with injury-related chronic pain. AB - Background. Chronic injury-related pain could be influenced by psychological symptoms such as depression, anxiety, and stress that also affect daily life. Methods. Patients with chronic pain caused by an injury (n = 86) aged 18-65 years referred to the Pain Rehabilitation Clinic at the Umea University Hospital answered a set of questionnaires to assess pain intensity, depression, anxiety, posttraumatic stress, sleep disturbance, and fatigue. Results. A significantly higher proportion of women (47.5%) reported depression (Hospital Anxiety and Depression Scale (HAD)) than men (22.2%). In all patients anxiety (HAD) was reported by 39.5% and moderate/severe posttraumatic stress (Impact of Event Scale) by 30.2%. A majority reported sleep disturbance (84.9%) and fatigue (90.7%). Significant relationships were found between posttraumatic stress and depression and anxiety. Conclusion. These findings indicate the importance of assessing and treating psychological symptoms associated with chronic pain as the result of trauma. PMID- 23738198 TI - Emerging psychosis and the family. AB - Schizophrenias hold a special position among psychotic disorders. Schizophrenias often start in early adulthood and bear considerable psychosocial risks and consequences. Several years of nonpsychotic clinical signs and symptoms and growing distress for patient and significant others may pass by before definite diagnosis. Young males in particular often experience their first episode while still living in their primary families. Thus, the whole family system is involved. In worldwide initiatives on early detection and early intervention, near-psychotic prodromal symptoms as well as deficits of thought and perception, observable by the affected person himself, were found to be particularly predictive of psychosis. Various psychological and social barriers as well as ones inherent to the disease impede access to affected persons. Building trust and therapeutic alliance are extremely important for counseling, diagnostics, and therapy. The indication for strategies of intervention differs from the early to the late prodromal stage, depending on proximity to psychosis. For psychotherapy versus pharmacotherapy, the first evidence of effectiveness has been provided. A false-positive referral to treatment and other ethical concerns must be weighed against the risks of delayed treatment. PMID- 23738200 TI - The Influence of Coinfection on Mood States in HTLV-1-Infected Patients. AB - The objective of this study was to discuss the influence of coinfection on mood states (depression and anxiety) in Human T Lymphotropic virus type 1 HTLV-1 infected patients. A cross-sectional study was performed with a sample obtained through a nonprobabilistic technique. A total of 130 patients in treatment at the HTLV Ambulatory of Instituto de Infectologia Emilio Ribas participated in the research, of whom 63 had HAM/TS and 67 were asymptomatic. A sociodemographic survey and the Beck Anxiety and Depression Inventories were used. The results indicated a prevalence of 7.2% for HTLV-1/HIV co-infection, 7.2% for HTLV-1/HCV, and 4.0% for HTLV-1/HIV/HCV. It is possible that the presence of a co-infection causes greater fear and concern about the future than asymptomatic HTLV-1 infection, increasing the observed degree of depression and anxiety. PMID- 23738199 TI - The effect of self-transcendence on depression in cognitively intact nursing home patients. AB - Aims. This study's aim was to test the effects of self-transcendence on depression among cognitively intact nursing home patients. Background. Depression is considered the most frequent mental disorder among the elderly population. Specifically, the depression rate among nursing home patients is three to four times higher than that among community-dwelling elderly. Therefore, finding new and alternative ways to prevent and decrease depression is of great importance for nursing home patients' well-being. Self-transcendence is related to spiritual as well as nonspiritual factors, and it is described as a correlate and resource for well-being among vulnerable populations and at the end of life. Methods. A two-factor construct of the self-transcendence scale (interpersonal and intrapersonal) and the hospital anxiety and depression scale (HADS) was applied. A sample of 202 cognitively intact nursing home patients in central Norway was selected to respond to the questionnaires in 2008/2009. Results. A hypothesized SEM model demonstrated significant direct relationships and total effects of self transcendence on depression. Conclusion and Implication for Practice. Facilitating patients' self-transcendence, both interpersonally and intrapersonally, might decrease depression among cognitively intact nursing home patients. PMID- 23738201 TI - WCST Performance in Schizophrenia and Severe Depression with Psychotic Features. AB - Background. Differentiating between schizophrenia and major depression with psychotic features often reveals diagnostic dilemma. Both share psychotic features and severe impairment in occupational functions. Severe psychomotor retardation, not uncommon in psychotic depression, may simulate negative symptoms of schizophrenia. Our work aims at utilizing Wisconsin Card Sorting Test (WCST) performance as a potential differentiating neurocognitive tool. Subjects and Methods. 60 patients were recruited randomly from the outpatient service at Alexandria University Hospital: 30 patients with schizophrenia and 30 patients with chronic psychotic depression. They were subjected to Clinical Global Impression for Severity (CGI-S) scale and Wisconsin Card Sorting Test (WCST) 128 card computerized version. Results. Both groups were balanced in terms of gender distribution, severity and duration of illness. The study compared all parameters of WCST. Only perseverative errors showed mild significant difference (P < 0.05) that disappeared when applying Bonferroni adaptation, setting significance level at 0.01 instead of 0.05. Conclusion. Performance on WCST is similar in schizophrenia and severe depression with psychotic features in most of the measured parameters and hence could not serve as a supplementary tool differentiating between both diagnoses in our study. PMID- 23738202 TI - Factors Associated with Anxiety and Depression among African American and White Women. AB - Background. We examined factors associated with depression and anxiety in a cohort of low-income Baltimore women. Methods. We used Pathways to Adulthood data, a cohort of adults aged 27 to 33 who were born in Baltimore between 1960 and 1965. Our outcomes were a score of >4 on the General Health Questionnaire (GHQ-28) across the depression or anxiety domains. Linear regression clustered on census tract was used for multivariate analysis. Results. In multivariable analyses, unmarried women, White women, those with lower self-rated health, and younger mothers had higher depression scores. Only lower self-rated health and White race were associated with a higher anxiety score. Neither neighborhood poverty nor racial composition was a predictor for anxiety or depression; however, the significant risk factors cluster in disadvantaged neighborhoods. Conclusion. Our work highlights the importance of universal screening for depression or anxiety with more in-depth surveillance based on risk factors rather than on race. PMID- 23738203 TI - Synergistic Effect between Maternal Infection and Adolescent Cannabinoid Exposure on Serotonin 5HT1A Receptor Binding in the Hippocampus: Testing the "Two Hit" Hypothesis for the Development of Schizophrenia. AB - Infections during pregnancy and adolescent cannabis use have both been identified as environmental risk factors for schizophrenia. We combined these factors in an animal model and looked at their effects, alone and in combination, on serotonin 5HT1A receptor binding (5HT1AR) binding longitudinally from late adolescence to adulthood. Pregnant rats were exposed to the viral mimic poly I:C on embryonic day 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14 days starting on postnatal day (PND) 35. Hippocampal and cortical 5HT1AR binding was quantified autoradiographically using [(3)H]8-OH-DPAT, in late adolescent (PND 55), young adult (PND 65) and adult (PND 90) rats. Descendants of poly I:C treated rats showed significant increases of 15-18% in 5HT1AR in the hippocampus (CA1) compared to controls at all developmental ages. Offspring of poly I:C treated rats exposed to HU210 during adolescence exhibited even greater elevations in 5HT1AR (with increases of 44, 29, and 39% at PNDs 55, 65, and 90). No effect of HU210 alone was observed. Our results suggest a synergistic effect of prenatal infection and adolescent cannabinoid exposure on the integrity of the serotoninergic system in the hippocampus that may provide the neurochemical substrate for abnormal hippocampal-related functions relevant to schizophrenia. PMID- 23738204 TI - The Association between Alcohol Dependence and Depression before and after Treatment for Alcohol Dependence. AB - The presence of depression in alcohol-dependent persons is likely to influence treatment process and outcomes. Identification of depression is important though not every depressed alcohol-dependent person requires treatment with antidepressants. Understanding the association between depression and alcohol dependence is essential for proper management of alcohol dependence. Objectives. To determine the prevalence of depression among alcohol-dependent persons before and after alcohol detoxification and rehabilitation. Design. Clinical trial with pre-/postmeasurements. Method. The CIDI and WHO-ASSIST were administered to 188 alcohol-dependent persons at intake and after six months. A researcher-designed sociodemographic questionnaire was also administered at intake. Results. The prevalence of depression among alcohol-dependent persons is high (63.8%) with a significant association between depression and the mean AUDIT score. At posttest, depressed participants had a statistically significant craving for alcohol. Conclusion. Alcohol dependence is associated with major depression. PMID- 23738205 TI - Comparative evaluation of forced swim test and tail suspension test as models of negative symptom of schizophrenia in rodents. AB - Previous studies have shown that the administration of NMDA antagonist can induce negative symptoms of schizophrenia which can be tested through the enhanced immobility observed in the forced swim test (FST). In the present study, we have compared the effects of acute as well as chronic administration of a noncompetitive NMDA receptor antagonist, ketamine on FST, and another behaviour despair model, tail suspension test (TST). Our observations suggest that chronic ketamine administration induced a state of enhanced immobility in FST, but such findings were not replicated in the TST model. Further, in FST, treatment with clozapine reverses the ketamine-induced immobility in mice, whereas it enhances the immobility duration in the TST model. However, haloperidol showed no protective effects in both models. The data suggests that although both of these tests show common behavioural measure of feeling despair, however, the underlying pathophysiology seems to be different. Hence, forced swim test but not tail suspension test can be used as a model of negative symptom of psychosis in mice. PMID- 23738206 TI - Clozapine augments delta, theta, and right frontal EEG alpha power in schizophrenic patients. AB - Objective. To explore the Quantitative EEG (QEEG) effects of established clozapine therapy regimes compared to those of previous ineffective antipsychotic regimes among 64 chronic (DSM-IV) schizophrenic patients. Methods. Data from 20 EEG channels referenced to linked ears were collected before and during maintenance clozapine therapy (mean duration 1.4 years). Absolute power was calculated in six frequency bands: delta (0.4-3.6 Hz), theta (4.2-7.8 Hz), alpha (8.2-11.8 Hz), beta1 (12.2-15.8 Hz), beta2 (16.2-19.8 Hz), and beta3 (20.2-23.8 Hz). Results. Clozapine augments power globally in the delta and theta bands, but this effect is more pronounced over frontal areas. Beta3 power was reduced. Alpha showed a frontal increase, more pronounced in the right, coupled with a posterior decrease with no net change in overall power. Conclusion. The demonstration of a significant clozapine-induced alpha topographic shift frontally and to the right is a novel discovery that may serve to encourage further investigations of subcortical structures in attempts to better understand the diverse aetiologies and optimal treatments of the schizophrenias. PMID- 23738207 TI - Emotion processing in women with schizophrenia is menstrual cycle phase and affective valence dependent: an FMRI study. AB - Despite a large number of functional neuroimaging investigations of emotion processing in schizophrenia, very few have included women. In the present study 21 schizophrenia and 23 healthy women underwent functional MRI (3T) on two occasions (during the follicular and luteal phase of their menstrual cycle) while viewing blocks of emotionally negative, positive and neutral images. During exposure to negatively charged images patients showed relatively less activations than controls during the luteal phase, but no between-group differences were observed during the follicular phase. In contrast, the exposure to positively valenced material produced no significant interaction, but the main effect of group; schizophrenia patients exhibited less activation than healthy controls during both phases of the menstrual cycle. This is the first study demonstrating that atypical neural activations associated with emotion processing in women diagnosed with schizophrenia depend on the menstrual cycle phase and on the affective valence of presented stimuli. PMID- 23738208 TI - Mental fatigue and cognitive impairment after an almost neurological recovered stroke. AB - Mental fatigue is for many a distressing and long-term problem after stroke. This mental fatigue will make it more difficult for the person to return to work and previous activities. The intention with this study is to investigate mental fatigue in relation to depression and cognitive functions. We examined 24 well rehabilitated stroke subjects, who suffered from mental fatigue one year or more after a stroke, and 24 healthy controls. Subjects were examined using self assessment scales for mental fatigue, depression and anxiety, and cognitive tests. The results showed a highly increased rating for mental fatigue for the stroke group (P < 0.001). These participants also had a significantly higher rating on the depression (P < 0.001) and anxiety (P < 0.001) scales. Furthermore, they had a slower information processing speed (P < 0.001) and made more errors in a demanding attention and speed test (P < 0.05). Among the cognitive tests, processing speed and errors made in an attention and speed test were significant predictors for mental fatigue. We suggest mental fatigue following a stroke to be related to cognitive impairments, primarily information processing speed. Mental fatigue should also be treated as a separate phenomenon and should be differentiated from, and not confused with, depression, even if overlapping symptoms exist. PMID- 23738209 TI - Familial paraphilia: a pilot study with the construction of genograms. AB - Biological factors are likely predisposing and modulating elements in sexually deviant behavior. The observation that paraphilic behavior tends to cluster in some families is intriguing and potentially raises questions as to whether shared genetic factors may play a role in the transmission of paraphilia. This pilot study introduces five families in which we found presence of paraphilia over generations. We constructed genograms on the basis of a standardized family history. Results document the aggregation of sexual deviations within the sample of families and support a clinical/phenomenological heterogeneity of sexual deviation. The concept of paraphilia in relation to phenotypic expressions and the likelihood of a spectrum of related disorders must be clarified before conclusions can be reached as to family aggregation of paraphilia based on biological factors. PMID- 23738210 TI - Evaluation of efficacy, safety, and cognitive profile of amisulpride per se and its comparison with olanzapine in newly diagnosed schizophrenic patients in an 8 week, double-blind, single-centre, prospective clinical trial. AB - Background. Impaired cognitive functions in schizophrenia are the major deciding factors in response to treatment. Conventional antipsychotics have minimal impact on cognitive dysfunctions and are associated with adverse effects. Atypical antipsychotics have shown promise in treatment of cognitive and negative symptoms of schizophrenia. Efforts are underway to find out the best drug amongst atypical antipsychotics. Objective. To compare efficacy, safety, and cognitive profile of amisulpride and olanzapine in the treatment of acute psychotic exacerbations of schizophrenia. Method. A prospective, randomized, double-blind, single-center, 8 week clinical trial we used. Subjects and Treatments. Seventy four patients were treated for two months with either amisulpride (400-800 mg/d) or olanzapine (10 20 mg/d). Statistics. Mann Whitney U test we used for independent samples with P < 0.05 taken as significant. Results. Brief psychiatric rating scale (BPRS) was used as a primary measure of efficacy. Other measures of efficacy and safety were also evaluated. Both amisulpride and olanzapine groups showed equivalent improvement in psychotic symptoms on BPRS scale. Less than five percent of patients suffered adverse effects only to withdraw from the study. Olanzapine group showed statistically significant (P < 0.05) weight gain compared with amisulpride group. Amisulpride group showed significant improvement (P < 0.05) in various cognitive parameters as compared to olanzapine group. PMID- 23738211 TI - The autoimmune model of schizophrenia. AB - Schizophrenia is of mysterious causation. It is not infectious, not congenital, but shows familial aggregation, the Mendelian genetics indicating involvement of multiple codominant genes with incomplete penetrance. This is the pattern for autoimmune diseases, such as Graves' disease of the thyroid, where forbidden clones of B lymphocytes develop, and cause thyrotoxicosis by secreting autoantibodies that react with the thyroid gland's receptor for thyroid stimulating hormone from the pituitary gland. In 1982, Knight postulated that autoantibodies affecting the function of neurons in the limbic region of the brain are a possible cause of schizophrenia. Today, this is even more probable, with genes predisposing to schizophrenia having being found to be immune response genes, one in the MHC and two for antibody light chain V genes. Immune response genes govern the immune repertoire, dictating the genetic risk of autoimmune diseases. The simplest test for an autoimmune basis of schizophrenia would be trial of immunosuppression with prednisone in acute cases. The urgent research need is to find the microbial trigger, as done by Ebringer for rheumatoid arthritis and for ankylosing spondylitis. This could lead to prophylaxis of schizophrenia by vaccination against the triggering microbe. PMID- 23738212 TI - Influence of anxiety and depression on quality of life of people with schizophrenia in the eastern region of poland. AB - Schizophrenia is the most severe and most debilitating mental illness, which is one of the first ten causes of disability in youth and elderly people. Regarding many consequences that schizophrenia brings for individual and social functioning of ill people, their assessment of the quality of their lives seems to be interesting. The aim of this study is to evaluate the incidence and severity of anxiety and depression as well as analysis of the impact level of anxiety and depression on life quality of people with schizophrenia. A group of patients with schizophrenia from psychiatric centers was involved in a study. A set of methods, included: author's questionnaire, the quality of life scale WHOQOL-BREF, and the hospital anxiety and depression scale (HADS). Anxiety disorders occurred in more than 78% of respondents, while depressive disorders in more than half of respondents. The more severe anxiety and depressive disorders, the lower values were observed in all tested components of quality of life. The study of quality of life of the mentally ill patients should be conducted on a continuous basis in order to explore the current factors influencing the improvement of their psychophysical welfare. It is necessary to promote prohealthy mental lifestyle. PMID- 23738213 TI - Monoamine oxidase a and B gene polymorphisms and negative and positive symptoms in schizophrenia. AB - Given that schizophrenia is a heterogeneous disorder, the analysis of clinical characteristics could help to identify homogeneous phenotypes that may be of relevance in genetic studies. Linkage and association studies have suggested that a locus predisposing to schizophrenia may reside within Xp11. We analyzed uVNTR and rs1137070, polymorphisms from MAOA and rs1799836 of MAOB genes to perform single SNP case-control association study in a sample of 344 schizophrenia patients and 124 control subjects. Single polymorphism analysis of uVNTR, rs1137070 and rs1799836 SNPs did not show statistical differences between cases and controls. Multivariate ANOVA analysis of clinical characteristics showed statistical differences between MAOB/rs1799836 and affective flattening scores (F = 4.852, P = 0.009), and significant association between MAOA/uVNTR and affective flattening in female schizophrenia patients (F = 4.236, P = 0.016) after Bonferroni's correction. Our preliminary findings could suggest that severity of affective flattening may be associated by modifier variants of MAOA and MAOB genes in female Mexican patients with schizophrenia. However, further large-scale studies using quantitative symptom-based phenotypes and several candidate variants should be analyzed to obtain a final conclusion. PMID- 23738214 TI - Religiousness, health, and depression in older adults from a brazilian military setting. AB - This study aims to analyze the association between religious attendance, self reported religiousness, depression, and several health factors in 170 older adults from a Brazilian outpatient setting. A comprehensive assessment was conducted including sociodemographic characteristics, religious attendance, self reported religiousness, functional status, depression, pain, hospitalization, and mental status. After adjusting for sociodemographics, (a) higher self-reported religiousness was associated with lower prevalence of smoking, less depressive symptoms, and less hospitalization and (b) higher religious attendance was only associated with less depressive symptoms. Religiousness seems to play a role in depression, smoking, and hospitalization in older adults from a Brazilian outpatient setting. Self-reported religiousness was associated with more health characteristics than religious attendance. PMID- 23738215 TI - T-817MA, but Not Haloperidol and Risperidone, Restores Parvalbumin-Positive gamma -Aminobutyric Acid Neurons in the Prefrontal Cortex and Hippocampus of Rats Transiently Exposed to MK-801 at the Neonatal Period. AB - The number of parvalbumin (PV)-positive gamma -aminobutyric acid (GABA) neurons is decreased in the brain of rats transiently exposed to MK-801, an N-methyl-D aspartate (NMDA) receptor blocker, in the neonatal stage (Uehara et al. (2012)). T-817MA [1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate] is a neuroprotective agent synthesized for the treatment of psychiatric disorders characterized by cognitive disturbances, such as dementia. We herein sought to determine whether T-817MA, haloperidol (HPD), or risperidone (RPD) would ameliorate the decrease in the number of PV-positive GABA neurons in the medial prefrontal cortex (mPFC) and hippocampus of the model animals. Rats were treated with MK-801 (0.2 mg/kg/day) or vehicle on postnatal days (PD) 7-10, and the number of PV-positive neurons in the mPFC and hippocampus were measured on PDs 63. T-817MA (20 mg/kg), HPD (1 mg/kg), or RPD (1 mg/kg) were administered during PDs 49-62. Fourteen-day administration of T-817MA reversed the decrease in the number of PV-positive neurons in the above brain regions of rats given MK-801, whereas HPD and RPD were ineffective. These results indicate that T-817MA provides a novel pharmacologic strategy to enhance cognitive function in patients with schizophrenia. PMID- 23738216 TI - Age of onset of mood disorders and complexity of personality traits. AB - Objective. The aim of the present study is to evaluate the link between the age of onset of mood disorders and the complexity of the personality traits. Methods. 209 patients with major depressive or manic/hypomanic episodes were assessed using the Structured Clinical Interview for DSM Axis I diagnoses and the Millon Clinical Multiaxial Inventory-III (MCMI-III). Results. 17.2% of the patients had no elevated MCMI-III scores, 45.9% had one peak, and 36.9% had a complex personality disorder with two or more elevated scores. Mood disorders onset of 29 years or less was the variable most related to the complexity of personality disorders as indicated from a recursive partitioning analysis. Conclusions. The relationship between mood disorders and personality traits differ in reference to age of onset of the mood disorder. In younger patients, maladaptive personality traits can evolve both in a mood disorder onset and in a complex personality disorder, while the later development of a severe mood disorder can increase the personality symptomatology. Our results suggest a threshold of mood disorder onset higher compared to previous studies. Maladaptive personality traits should be assessed not only during adolescence but also in young adults to identify and treat potential severe mood disorders. PMID- 23738217 TI - A multiple case series analysis of six variants of attentional bias modification for depression. AB - Background. Attention bias modification (ABM) is a new treatment for affective disorders. A meta-analysis of ABM for anxiety disorders showed that the effect size may be large but the number of studies is low. The working mechanism is still unclear, and little is known about the optimal treatment parameters. ABM for depression is much less studied. A few studies claimed positive effects but the sample sizes are low. Furthermore, the treatment parameters varied widely and differed from the anxiety literature. Aim. To select the most promising version of ABM for depression for further evaluation in clinical trials. Methods. Multiple case series design. We tested six versions of ABM that varied on stimulus duration and training direction. Thirty students with mild to moderate symptoms of depression underwent four sessions of ABM. Change of attentional bias was measured during each session. Generalization of treatment effects and the role of awareness of receiving training were also investigated. Results. None of the investigated versions of ABM had a consistent effect on attentional bias. Changes of attentional bias in individual participants the effects did not generalize to untrained stimuli. Conclusion. It is unlikely that any of these ABM versions will have a specific effect on symptoms in controlled studies. PMID- 23738218 TI - Participatory Research for Preventing Pesticide-Related DSH and Suicide in Sundarban, India: A Brief Report. AB - Deliberate self-harm (DSH) is a major public health problem in the Sundarban region, India. This study is aimed to develop a DSH-suicide prevention programme based on the principles of community-based participatory research (CBPR). Perception and opinion of community about the problem of pesticide-related DSH and suicide were elicited in a series of facilitated focus group discussions in Namkhana block of Sundarban region. Based on their suggestion, a broad preventive programme was launched involving the development of information, education, and communication (IEC) and training modules and training of the stakeholders of the block. Most of the members of each target group found that the IEC materials were culture fair (message is acceptable, understandable, and meaningful in the local context) and very useful. Analysis of Dwariknagar BPHC, DSH admission data showed a definite reduction of DSH incidents after this CBPR approach to prevention was initiated. Similar model of DSH prevention in the other blocks of Sundarban region or in agricultural community may help to reduce the enormous mortality and morbidity from pesticide-related DSH and suicide. PMID- 23738219 TI - Scl-90-R symptom profiles and outcome of short-term psychodynamic group therapy. AB - Background. Psychodynamic group psychotherapy may not be an optimal treatment for anxiety and agoraphobic symptoms. We explore remission of SCL-90-R Global Severity Index (GSI) and target symptoms in 39 sessions of psychodynamic group therapy. Methods. SCL-90-R "target symptom" profile and GSI remission according to Danish norms were identified in 239 patients and evaluated according to reliable and clinical significant change. Results. Four major groups of target symptom cases (depression, interpersonal sensitivity, anxiety, and phobic anxiety) covered 95.7% of the sample. As opposite to phobic anxiety and anxiety patients, patients with interpersonal sensitivity obtained overall the most optimal outcome. The phobic anxiety scale, social network support, and years of school education were independent predictors of GSI remission, and a low anxiety score and absence of phobic anxiety target symptoms were independent predictors of remission of target symptom pathology. Conclusions. The negative results as associated with the SCL-90-R phobic anxiety scale and the phobic anxiety target symptom group are largely in agreement with recent studies. In contrast, whatever the diagnoses, patients with interpersonal sensitivity target symptom may be especially suited for psychodynamic group therapy. The SCL-90-R subscales may allow for a more complex symptom-related differentiation of patients compared with both diagnoses and GSI symptom load. PMID- 23738220 TI - Chronic phencyclidine increases synapsin-1 and synaptic adaptation proteins in the medial prefrontal cortex. AB - Phencyclidine (PCP) mimics many aspects of schizophrenia, yet the underlying mechanism of neurochemical adaptation for PCP is unknown. We therefore used proteomics to study changes in the medial prefrontal cortex in animals with PCP induced behavioural deficits. Male Wistar rats were injected with saline or 5 mg/kg phencyclidine for 5 days followed by two days of washout. Spontaneous alternation behaviour was tested in a Y-maze and then proteins were extracted from the medial prefrontal cortex. 2D-DIGE analysis followed by spot picking and protein identification with mass spectrometry then provided a list of differentially expressed proteins. Treatment with 5 mg/kg phencyclidine decreased the percentage of correct alternations in the Y-maze compared to saline-treated controls. Proteomics analysis of the medial prefrontal cortex found upregulation of 6 proteins (synapsin-1, Dpysl3, Aco2, Fscn1, Tuba1c, and Mapk1) and downregulation of 11 (Bin1, Dpysl2, Sugt1, ApoE, Psme1, ERp29, Pgam1, Uchl1, Ndufv2, Pcmt1, and Vdac1). A trend to upregulation was observed for Gnb4 and Capza2, while downregulation trends were noted for alpha-enolase and Fh. Many of the hits in this study concur with recent postmortem data from schizophrenic patients and this further validates the use of phencyclidine in preclinical translational research. PMID- 23738221 TI - The effect of methylated vitamin B complex on depressive and anxiety symptoms and quality of life in adults with depression. AB - Depression, the most common type of mental illness, is the second leading cause of disability and is increasing among Americans. The effect of improved nutrition, particularly with dietary supplements, on depression may provide an alternative to standard medical treatment. Some studies have shown that certain nutrients (e.g., inositol and S-adenosyl methionine) are effective at improving depressed mood, although the results are not unequivocal. The current study was a randomized, double-blind, placebo-controlled trial to evaluate the efficacy of a vitamin B complex nutritional supplement (Max Stress B) for improving depressive and anxiety symptoms according to the Beck Depression and Anxiety Inventories (BDI and BAI) in 60 adults diagnosed with major depression or other forms of depressive disorders. Secondary outcomes included quality of life according to the SF-36. Participants were assessed at baseline and 30- and 60-day followups. Max Stress B showed significant and more continuous improvements in depressive and anxiety symptoms, compared to placebo. Additionally, Max Stress B showed significant improvement on the mental health scale of the SF-36 compared to placebo. Thus, we showed modest utility of Max Stress B to improve mood symptoms and mental health quality of life in adults with depression. PMID- 23738222 TI - Substance abusers in an acute psychiatric facility: a diagnostic and logistic challenge. AB - Acute resident psychiatric facilities in Norway usually get their patients after referral from a medical doctor. Acute psychiatric wards are the only places accepting persons in need of emergency hospitalisation when emergency units in somatic hospitals do not accept the patient. Resident patients at one random chosen day were scrutinized in an acute psychiatric facility with 36 beds serving a catchment area of 165 000. Twenty-five patients were resident in the facility at that particular day. Eight of 25 resident patients (32.0%) in the acute wards were referred for a substance-induced psychosis (SIP). Another patient may also have had a SIP, but the differential diagnostic work was not finished. A main primary diagnosis of substance use was given in the medical reports in only 12.9% of patients during the last year. Given that the chosen day was representative of the year, a majority of patients with substance abuse problems were given other diagnoses. There seems to be a reluctance to declare the primary reason for an acute stay in a third of resident stays. Lack of specialized emergency detoxification facilities may have contributed to the results. PMID- 23738223 TI - The coexistence of psychiatric disorders and intellectual disability in children aged 3-18 years in the barwani district, India. AB - Background. The coexistence of psychiatric disorders in people with intellectual disability (ID) is common. This study determined the prevalence of psychiatric disorders in children with ID in Barwani, India. Method. A total of 262 children with ID were evaluated for psychiatric disorders using the diagnostic criteria outlined in the International Classification of Diseases (ICD-10). Results. Psychiatric disorders appeared in study participants at the following rates: attention deficit hyperactivity disorder (ADHD), 6.5%; autism, 4.2%; anxiety, 2.7%; bipolar disorder, 1.1%; delusional disorder, 0.8%; depression, 2.3%; obsessive-compulsive disorder, 0.8%; schizophrenia, 1.9%; enuresis, 10.3%; epilepsy, 23.7%; and behavioral problems, 80.9%. The prevalence of psychiatric disorders was statistically higher in severely intellectually disabled children (IQ <= 49) than mildly intellectually disabled children (IQ >= 50). Conclusions. There is a higher prevalence of psychiatric disorders in children with ID when their IQ <= 49 compared with ID children whose IQ >= 50. PMID- 23738224 TI - Disrupted central inhibition after transcranial magnetic stimulation of motor cortex in schizophrenia with long-term antipsychotic treatment. AB - Aims. Schizophrenia is a neuropsychiatric disorder associated with mental and motor disturbances. We aimed to investigate motor control, especially central silent period (CSP) in subjects with schizophrenia (n = 11) on long-term antipsychotic treatment compared to healthy controls (n = 9). Methods. Latency and duration of motor evoked potentials (MEPs) and CSPs were measured with the help of single pulse transcranial magnetic stimulation (TMS) and intramuscular electrodes. After stimulation of the dominant and nondominant motor cortex of abductor digiti minimi (ADM) and tibialis anterior (TA) muscle areas, respective responses were measured on the contralateral side. Results. MEPs did not differ significantly between the groups. Multiple CSPs were found predominantly in subjects with schizophrenia, which showed a higher number of CSPs in the dominant ADM and the longest summarized duration of CSPs in the nondominant ADM (P < 0.05) compared to controls. Conclusions. There were multiple CSPs predominantly in the upper extremities and in the dominant body side in subjects with schizophrenia. Behind multiple CSPs may lie an impaired regulation of excitatory or inhibitory neurotransmitter systems in central motor pathways. Further research is needed to clarify the role of the intramuscular recording methods and the effect of antipsychotics on the results. PMID- 23738225 TI - Assessment of behavior abnormalities of corticosteroids in children with nephrotic syndrome. AB - Introduction. The objective of this work was to define the frequency and severity of steroid related behavioral side effects in children with steroid sensitive idiopathic nephrotic syndrome (SSNS) during Treatment for relapse. Methods. 30 pediatric patients with steroid sensitive nephrotic syndrome were studied; known as SSNS at complete remission or low dose of Prednisolone and have relapse on follow up. All children in this study were subjected to full history taking, thorough clinical examination, assessment socioeconomic standard, and assessment of pediatric quality of life, a battery of psychometric tests included pediatric anxiety, depression, and aggression scores. Results. Our results revealed that there are highly significant increase in the mean values of anxiety, depression and aggression among cases starts to appear on week one and extends to three, five and seven weeks compared to baseline. In the seventh week of follow up cases show significant positive correlation between prednisone doses and mean values of anxiety and depression scores and aggression. Conclusion. we concluded that all studied children with SSNS often experience significant problems with anxiety, depression, and increased aggression during high dose steroid therapy. PMID- 23738226 TI - The relationship of affective temperament and emotional-behavioral difficulties to internet addiction in Turkish teenagers. AB - The purpose of this study was to investigate the association of affective temperament profiles and emotional and behavioural characteristics with Internet addiction among high school students. The study sample included 303 high school students. A sociodemographic characteristics data form, internet addiction scale (IAS), the strengths and difficulties questionnaire, and the temperament evaluation of Memphis, Pisa, Paris, and San Diego autoquestionnaire were used to collect data. Of the sample, 6.6% were found to be addicted to Internet. Having a computer in the home (P < 0.001) and using the Internet for more than two years (P < 0.001) were found to be related to higher scores on the IAS. The prevalence rate of anxious temperament for Internet addicts was more than that for nonaddicts (P < 0.001). Dysthymic (r = 0.199; P < 0.01), cyclothymic (r = 0.249; P < 0.01), hyperthymic (r = 0.156; P < 0.01), irritable (r = 0.254; P < 0.01), and anxious (r = 0.205; P < 0.01) temperaments; conduct problems (r = 0.146; P < 0.05), hyperactivity-inattention (r = 0.133; P < 0.05), emotional symptoms (r = 0.138; P < 0.05), and total difficulties (r = 0.160; P < 0.01) were found to be correlated with IAS scores. According to these findings, there is a relation between the Internet addiction and affective temperament profiles, especially with anxious temperament. Furthermore, emotional and behavioural problems are more frequent in adolescents who have problematic Internet use. PMID- 23738227 TI - Evolution of the Macrophage CD163 Phenotype and Cytokine Profiles in a Human Model of Resolving Inflammation. AB - Cantharidin skin blisters were examined over two days to model the acute and resolving phases of inflammation in human skin. Four blisters were created by topical administration of cantharidin (0.1% v/v) to the forearm of healthy volunteers, with IRB approval. Duplicate skin blisters were aspirated at 16 and 40 hours to model the proinflammatory and resolving phases, respectively. There was a significant increase in leukocyte infiltrate at 40 h with appearance of a "resolving macrophage" phenotype CD14(+)CD163(+) by flow cytometry. Neutrophils acquired apoptotic markers at 40 h and were observed to be phagocytosed by macrophagic "Reiter's" cells. Multiplex cytokine analysis demonstrated that monocyte chemoattractant protein (MCP-1/CCL2), interleukin- (IL-) 6, IL-8/CXCL8, macrophage inflammatory protein (MIP1 alpha /CCL3), MIP-1 beta /CCL4, tumor necrosis factor- (TNF-) alpha , and eotaxin (CCL11) were all significantly upregulated at 16 h compared with 40 h. In contrast, immunoregulatory transforming growth factor- (TGF-) beta , macrophage-derived chemokine (MDC/CCL22), and interferon-inducible protein (IP-10/CXCL10) were significantly elevated at 40 h. Our results demonstrate that the phases of inflammation and resolution can be discriminated in a two-day model of dermal wound healing. This confirms and extends our understanding of wound repair in humans and provides a powerful research tool for use in clinical settings and to track the molecular benefits of therapeutic intervention. PMID- 23738228 TI - Curbing Inflammation through Endogenous Pathways: Focus on Melanocortin Peptides. AB - The resolution of inflammation is now known to be an active process, armed with a multitude of mediators both lipid and protein in nature. Melanocortins are peptides endowed with considerable promise with their proresolution and anti inflammatory effects in preclinical models of inflammatory disease, with tissue protective effects. These peptides and their targets are appealing because they can be seen as a natural way of inducing these effects as they harness endogenous pathways of control. Whereas most of the information generated about these mediators derives from several acute models of inflammation (such as zymosan induced peritonitis), there is some indication that these mediators may inhibit chronic inflammation by modulating cytokines, chemokines, and leukocyte apoptosis. In addition, proresolving mediators and their mimics have often been tested alongside therapeutic protocols, hence have been tested in settings more relevant to real life clinical scenarios. We provide here an overview on some of these mediators with a focus on melanocortin peptides and receptors, proposing that they may unveil new opportunities for innovative treatments of inflammatory arthritis. PMID- 23738229 TI - Management of thyroid peroxidase antibody euthyroid women in pregnancy: comparison of the american thyroid association and the endocrine society guidelines. AB - The presence of thyroid autoantibodies is relatively high in women of childbearing age. There is evidence that positive thyroperoxidase antibody even in euthyroid women may increase the risk of spontaneous and recurrent pregnancy loss and preterm delivery. However, the evidence is not enough to justify recommendation on the screening of pregnant women for thyroid autoantibodies or LT4 supplementation for reducing maternal or fetal complications. In this paper we reviewed the related evidence and compared the new guidelines of the American Thyroid Association and Endocrine Society with respect to the screening and management of positive thyroperoxidase antibody in euthyroid pregnant women. As there was no major contradiction or disagreement between the two guidelines, either one of two guidelines may be used by clinicians for the appropriate management of thyroid autoimmunity during pregnancy. PMID- 23738230 TI - Exploring outcome measures for exercise intervention in people with Parkinson's disease. AB - Background. It is widely believed that exercise improves mobility in people with Parkinson's disease (PD). However, it is difficult to determine whether a specific type of exercise is the most effective. The purpose of this study was to determine which outcome measures were sensitive to exercise intervention and to explore the effects of two different exercise programs for improving mobility in patients with PD. Methods. Participants were randomized into either the Agility Boot Camp (ABC) or treadmill training; 4x/week for 4 weeks. Outcome measures were grouped by the International Classification of Function/Disability (ICF). To determine the responsiveness to exercise, we calculated the standardized response means. t-tests were used to compare the relative benefits of each exercise program. Results. Four of five variables at the structure/function level changed after exercise: turn duration (P = 0.03), stride velocity (P = 0.001), peak arm speed (P = 0.001), and horizontal trunk ROM during gait (P = 0.02). Most measures improved similarly for both interventions. The only variable that detected a difference between groups was postural sway in ABC group (F = 4.95; P = 0.03). Conclusion. Outcome measures at ICF body structure/function level were most effective at detecting change after exercise and revealing differences in improvement between interventions. PMID- 23738232 TI - Is weight-bearing asymmetry associated with postural instability after stroke? A systematic review. AB - Introduction. Improvement of postural stability is an important goal during poststroke rehabilitation. Since weight-bearing asymmetry (WBA) towards the nonparetic leg is common, training of weight-bearing symmetry has been a major focus in post-stroke balance rehabilitation. It is assumed that restoration of a more symmetrical weight distribution is associated with improved postural stability. Objective. To determine to what extent WBA is associated with postural instability in people after stroke. Methods. Electronic databases were searched (Cochrane, MEDLINE, EMBASE, and CINAHL) until March 2012. Main Eligibility Criteria. (1) Participants were people after stroke. (2) The association between WBA and postural stability was reported. Quality of reporting was assessed with the STROBE checklist and a related tool for reporting of confounding. Results. Nine observational studies met all criteria. Greater spontaneous WBA was associated with higher center of pressure (COP) velocity and with poorer synchronization of COP trajectories between the legs (two and one studies, resp.). Evidence for associations between WBA and performance on clinical balance tests or falls was weak. Conclusion. Greater WBA after stroke was associated with increased postural sway, but the current literature does not provide evidence for a causal relationship. Further studies should investigate whether reducing WBA would improve postural stability. PMID- 23738233 TI - Characterization of the fungal microbiome (mycobiome) in fecal samples from dogs. AB - The prevalence and phylogenetic description of fungal organisms and their role as part of the intestinal ecosystem have not yet been studied extensively in dogs. This study evaluated the fungal microbiome of 19 dogs (12 healthy dogs and 7 dogs with acute diarrhea) using fungal tag-encoded FLX-Titanium amplicon pyrosequencing. Five distinct fungal phyla were identified, with Ascomycota (medians: 97.9% of obtained sequences in healthy dogs and 98.2% in diseased dogs) and Basidiomycota (median 1.0% in healthy dogs and median 0.5% in diseased dogs) being the most abundant fungal phyla. A total of 219 fungal genera were identified across all 19 dogs with a median (range) of 28 (4-69) genera per sample. Candida was the most abundant genus found in both the diseased dogs (median: 1.9%, range: 0.2%-38.5% of sequences) and healthy dogs (median: 5.2%, range: 0.0%-63.1% of sequences). Candida natalensis was the most frequently identified species. No significant differences were observed in the relative proportions of fungal communities between healthy and diseased dogs. In conclusion, fecal samples of healthy dogs and dogs with acute diarrhea harbor various fungal genera, and their role in gastrointestinal health and disease warrants further studies. PMID- 23738234 TI - E. coli-Derived L-Asparaginase Retains Enzymatic and Cytotoxic Activity In Vitro for Canine and Feline Lymphoma after Cold Storage. AB - Background. L-asparaginase is effective in treating canine and feline lymphoma, however chemotherapy poses a significant financial cost to veterinary clients, limiting therapy for many pets. Single dose vials result in significant drug wastage, and drug shortages limit consistent availability for pets. Hypothesis. E. coli-derived asparaginase retains enzymatic and antineoplastic activity in canine and feline lymphoma cells after cold storage. Methods. E. coli-derived asparaginase was cold-stored: refrigeration (7-14 days) and freezing (14 days-six months, one to three freeze/thaw cycles). Enzymatic activity of asparaginase was measured via a modified asparagine assay. Effects of cold-stored asparaginase on cell proliferation and cytotoxicity were measured in feline (MYA-1, F1B) and canine (17-71, OSW) lymphoma cells. Results. Cold-stored E. coli-derived asparaginase retains antineoplastic activity in all four cell lines tested. Cold stored E. coli-derived L-asparaginase depletes asparagine and retains enzymatic activity. Duration of refrigeration, duration of freezing, and number of freeze thaw cycles have minimal effect on asparaginase enzyme activity. Conclusions and Clinical Importance. This study establishes a scientific basis for long-term cold storage of reconstituted E. coli-derived asparaginase that may result in better utilization of limited drug resources and improve financial feasibility of E. coli-derived asparaginase as a therapeutic option for pets with lymphoma. PMID- 23738231 TI - Rehabilitation with poststroke motor recovery: a review with a focus on neural plasticity. AB - Motor recovery after stroke is related to neural plasticity, which involves developing new neuronal interconnections, acquiring new functions, and compensating for impairment. However, neural plasticity is impaired in the stroke affected hemisphere. Therefore, it is important that motor recovery therapies facilitate neural plasticity to compensate for functional loss. Stroke rehabilitation programs should include meaningful, repetitive, intensive, and task-specific movement training in an enriched environment to promote neural plasticity and motor recovery. Various novel stroke rehabilitation techniques for motor recovery have been developed based on basic science and clinical studies of neural plasticity. However, the effectiveness of rehabilitative interventions among patients with stroke varies widely because the mechanisms underlying motor recovery are heterogeneous. Neurophysiological and neuroimaging studies have been developed to evaluate the heterogeneity of mechanisms underlying motor recovery for effective rehabilitation interventions after stroke. Here, we review novel stroke rehabilitation techniques associated with neural plasticity and discuss individualized strategies to identify appropriate therapeutic goals, prevent maladaptive plasticity, and maximize functional gain in patients with stroke. PMID- 23738235 TI - Rapid Identification of the Multiple Absorbed Bioactive Components and Metabolites in Rat Serum after Oral Administration of Wu-Jia Sheng-Hua Capsule by UPLC-ESI-MS. AB - To identify the compounds absorbed in rat serum after the oral administration of Wu-Jia Sheng-Hua (WJSH) capsule, a traditional Chinese medicine (TCM) compound prescription, an ultraperformance liquid chromatography coupled with electrospray ionization mass spectrometry (UPLC/ESI-MS) method, was established. The chromatographic separation of the absorbed compounds and metabolites was achieved with an ACQUITY UPLC BEH C18 column (2.1 mm * 50 mm, 1.7 MUm) under a gradient elution. The mobile phase was composed of acetonitrile and water buffered with ammonium acetate (10 mM) and formic acid (0.1%, V/V). Twelve absorbed compounds and four metabolites were found. Seven of the absorbed compounds were identified by ESI-MS. The identification of absorbed compounds might be helpful for the better understanding of the mechanisms underlying the pharmacological effects of WJSH capsule. PMID- 23738236 TI - Simultaneous Quantification of Limonin, Two Indolequinazoline Alkaloids, and Four Quinolone Alkaloids in Evodia rutaecarpa (Juss.) Benth by HPLC-DAD Method. AB - A simple and efficient HPLC-DAD (225 nm) method was developed and validated for the simultaneous determination of limonin and six key alkaloids (evodiamine, rutaecarpine, 1-methyl-2-undecyl-4(1H)-quinolone, evocarpine, 1-methy-2-[(6Z,9Z)] 6,9-pentadecadienyl-4-(1H)-quinolone, and dihydroevocarpine) in Evodia rutaecarpa (Juss.) Benth, which has been widely used as one of the Traditional Chinese Medicines. The chromatographic separation was carried out on a Hypersil BDS C18 column, and gradient elution was employed with a mobile phase containing acetonitrile and water. Contents of the analytes in 18 batches of samples were analyzed by ultrasonic extraction with ethanol and water mixture (80 : 20, v/v) followed by HPLC analysis. Separation of the seven analytes was achieved within 60 min with good linearity (r > 0.999). The RSD of both the intraday and interday precision was below 1.85%. The accuracy at different concentrations was within the range of 97.91 to 100.49%. Hierarchical clustering analysis was performed to differentiate and classify the samples based on the contents of the seven constituents. This study indicated that the quality control of E. rutaecarpa could be simplified to the measurement of four constituents, and that limonin, 1 methyl-2-undecyl-4(1H)-quinolone, and dihydroevocarpine should also be served as the chemical markers together with evodiamine for the quality control of Evodia rutaecarpa (Juss.) Benth. PMID- 23738237 TI - Why m.L.T.j. ? PMID- 23738238 TI - Microcirculation in skeletal muscle. AB - The role of microcirculation in skeletal muscle is to provide the supply of oxygen and various nutrients and to remove waste products of muscle metabolism. As skeletal muscles are composed of different fibre types, this review tries to elucidate the question of capillary supply and flow with respect to these. It reviews the current knowledge of structure of microcirculation and its nervous, hormonal, and local (myogenic, metabolic and endothelial) control. It also discuss factors involved in the increase in blood flow and changes in microcirculation occurring during muscle contractions, exercise training, muscle hypertrophy and atrophy, hypoxia, ageing, hypertension, diabetes and limited blood supply. PMID- 23738240 TI - Plantar pressure of clipless and toe-clipped pedals in cyclists - A pilot study. AB - To determine the effect of clipless and toe-clipped pedals on plantar foot pressure while cycling. Seven bikers and 11 healthy volunteers were tested on a Giant ATX Team mountain bike, Tekscan Clinical 5.24 F-scan(r) system with an inner sole pressure sensor, a Tacx Cycle force One Turbo Trainer and a Cateye Mity 8 computerized speedometer were used. The subjects wore Shimano M037 shoes and used a standard clipless and toe-clipped pedal. The seat height was set at 100% of subject's trochanteric height. Plantar pressures were recorded over 12 consecutive crank cycles at a constant speed for each of the power outputs. The videos were analysed to record the pressure exerted at 12 positions on the foot for each variable. Whether there is any dominance of any of the metatarsals, and any difference in plantar pressures between clipped and clipless pedal. There was a significant difference in the pressure at many positions of the foot, but the sites were different for each individual. General regression analysis indicated that pedal type had a statistically significant effect on plantar pressure at the sites of 1(st) metatarsal (p=0.042), 3(rd) metatarsal (p<0.001), 5(th) metatarsal (<0.001), 2(nd) (p=0.018) and 5(th) toe (p<0.001), lateral midfoot (p<0.001) and central heel (p<0.001) areas. Clipless pedals produce higher pressures which are more spread across the foot than toe-clipped pedals. This may have implications for their use in the prevention and/or management of overuse injuries in the knee and foot. PMID- 23738239 TI - Conservative management of rotator cuff tears: literature review and proposal for a prognostic. Prediction Score. AB - Rotator cuff tears are a common cause of pain and shoulder dysfunction. The prevalence of the rotator cuff tears increases with the age reaching the 80% in patients aged more than 80 year. Symptomatic shoulders usually are initially treated conservatively and then, in case of poor outcomes, with surgery. Different parameters are still used to decide between the conservative or surgical treatment in patients with rotator cuff tears. Aim of the current study is to characterize the various features used in decision making and to validate a "Prediction Score" that let us know which patients could have a good and stable outcome with non operative treatment. We enrolled 60 patients (mean age 52 years) with symptomatic rotator cuff tears who were assigned to conservative treatment and were evaluated at 6,9 and 12 months follow-up. We developed a score based on 18 clinical and radiographic parameters. 27 patients ("non conservative") (45%) with a mean prediction score of 16.1 +/- 1.7 interrupted the conservative treatment, while 33 patients ("conservative") (55%) with an average prediction score of 11.3 +/- 1.8 remained conservatively treated at last follow-up. The conservative patients were 14 years older than non conservative patients. According to the results of this study we identified a value of 13 points as a "cut-off" score to predict good results by conservative management of rotator cuff tear. These outcomes support the assumption that a predictive prognostic score may guarantee a rational approach in the management of subjects with RC tears, especially in elderly who continue to have the higher rate of recurrence and therefore could be well treated with standard conservative therapies. PMID- 23738241 TI - Evaluation of a novel topical essential oxygen oil for the treatment of pain in acute tendinopathy and sprains. AB - Topical analgesics may play an increasingly important role in managing acute and chronic pain as acetaminophen, NSAIDs, and opioid drugs come under heightened scrutiny. This article reviews studies about essential oxygen oil, a topical over the-counter (OTC) analgesic new to the American market but available for many years in Europe. Prospective studies evaluating the oil's safety and efficacy in acute and chronic pain patients, a dermatological study in which healthy subjects served as their own controls, and a post-marketing surveillance study were considered. These studies found the novel essential oxygen oil to be safe and effective in a variety of acute and chronic pain syndromes as well as being well tolerated with few side effects. Its mechanism of action is not understood and further study is warranted. Essential oxygen oil is safe and effective for the treatment of pain associated with many common conditions, including tendinopathy, arthritis, sprains, and others. PMID- 23738242 TI - Persistent HyperCKemia in Athletes. AB - We compared the effects of exercise on serum levels of creatin kinase (CK) in athletes with persistent hyperCKemia at rest (CK group) and in healthy athletes (control group). Prospective controlled study. Eighteen male Caucasian athletes with high serum CK levels at rest (CK between 80 and 150 U/L) and 25 male Caucasian athletes with normal serum CK levels at rest (CK between 10 and 80 U/L). MAIN OUTCOME MEASURES: Blood samples were collected at rest, 30 minutes, 6 hours, 24 hours, 48 hours and 72 hours after a progressive cycloergometer test to exhaustion. The levels of serum CK and its isoenzymes were measured. In the control group, serum CK values at rest were normal (48.18 +/- 14.14 U/L). After exercise, they increased slightly, though they always remained <80 U/L, decreasing to the rest level after 48 hours. The CK group had serum CK levels at rest higher than normal (116.56 +/- 33.30 U/L). Serum CK levels were still outwith the normal range after 48 hours (130.11 +/- 46.95 U/L) and 72 hours (116.55 +/- 24.84 U/L). Serum CK levels were significantly different in both groups both before and after progressive cycloergometer test to exhaustion. In athletes with high serum CK levels at rest, serum CK levels remained elevated and had a different kinetics after exercise when compared with healthy athletes. PMID- 23738244 TI - A great day for EFOST. PMID- 23738243 TI - One step open synovectomy without adjuvant therapy for diffuse pigmented villonodular synovitis of the knee in a soccer player. AB - Pigmented villonodular synovitis is a proliferative disease involving joints, bursas and tendon sheaths with typical histological changes in the synovial tissue. A local and diffuse form are described. Aetiology is uncertain, MRI is helpful to establish the diagnosis, which is confirmed with by biopsy. Treatment is based on the principles of tumor resection: arthroscopically in the local form, or by a open synovectomy in the diffuse form, often followed by adjuvant radiotherapy. The rate of recurrence is high, but differs in consideration of the treatment chosen. We report a 35 year old soccer player with diffuse pigmented villonodular synovitis with a history of chronic swelling knee. The patient underwent a one step open synovectomy without adjuvant therapy, with the conservation of the heads of gastrocnemius muscle. At five years of follow-up, the patient had no sign of recurrence of the condition. One step open synovectomy in this patient showed an excellent outcome with the return to his previous sport. The short follow-up and the neoplastic characteristic of the disease cannot exclude the risk of recurrence. PMID- 23738245 TI - Single injection of platelet-rich plasma in a rat Achilles tendon tear model. AB - The purpose of this study was to determine the efficacy of platelet-rich plasma (PRP) 1-injection during an Achilles tendon rat tear model. 80 male adult imbreded rats (Wistar Kyoto), underwent under surgical tendon rupture. 40 Animal (PRP group rats) were given a local injection with 0,25 mL of PRP, and 40 animal (control group) were given the same quantity of control solution. The rats were sacrified at 1, 2, 4 and 6 weeks (each time point, 20 rats of the each group) after surgical tear and tendon tissue was analysed by macroscopic aspect, histology, immunostaining and Real Time (RT)-PCR to evaluate tissue repair. PRP improved tendon remodelling by better coordination of the reconstructive process with earlier formation of tendon-like continuity only in the first week after surgery. However, after 2,4 and 6 weeks, Achilles tendons in the PRP group had no difference compared to the control group. Immunostaining and RT-PCR did not show any difference between PRP treated and untreated group. Based on these findings a single injection of PRP appear not useful for Achilles rat tendon tear. PMID- 23738246 TI - Chronic peripheral administration of serotonin inhibits thyroid function in the rat. AB - We studied the effect of chronic intraperitoneal (ip) administration of serotonin (5-HT) and thyroid function. We injected daily intraperitoneally for 10 days different doses of 5-HT, and measured plasma thyroid hormones and TSH levels. There was a decrease in the plasma levels of T3 and T4 with medium doses of 5-HT (0.2 and 0.4 mg/Kg bw for T3, and 0.2 for T4). No effects were evidenced on the plasma levels of TSH. In normal environmental conditions, the site action of 5-HT outside the blood-brain barrier is active when the 5-HT is injected at defined doses. This is probably a result of down-regulation independent of the hypothalamus-pituitary-thyroid axis. PMID- 23738247 TI - Thicker Achilles tendons are a risk factor to develop Achilles tendinopathy in elite professional soccer players. AB - The primary aim of this prospective cohort study was to compare the incidence of Achilles tendinopathy symptoms in elite soccer players with and without baseline asymptomatic ultrasound abnormalities. This study also investigated the relationship between baseline tendon thickness and development of symptoms. Using ultrasonography, 18 players were examined in 2009 for the existence of hypoechoicity, paratenon blurring, focal thickening and/or neovascularisation, and anteroposterior tendon thickness was measured. Symptom development during the follow-up period was assessed by interview one year later. Baseline mid-tendon thickness was greater (p=0.041) in tendons that experienced symptoms [median (IQR): 0.53 (0.51-0.55) cm] in the following year than tendons remaining asymptomatic [0.48 (0.45-0.52) cm]. No association between the existence of baseline ultrasound signs and development of symptoms in the following year was observed (Chi-Square: 1.180, p=0.277). A thicker baseline mid-tendon thickness was identified as a risk indicator for the development of Achilles tendinopathy in elite soccer players. PMID- 23738248 TI - Muscular damage during telbivudine treatment in a chronic hepatitis B patient. AB - Muscle tissue damage might be related to metabolic and mechanical factors. Certain drugs have been associated with increased blood levels of creatin phospho kinase (CPK) and myoglobin that are biochemical markers of musculoskeletal damage. An increase of CPK plasma levels might suggest severe rhabdomyolysis with possible resulting renal failure. Telbivudine is an antiviral drug indicated for the treatment of chronic hepatitis B (CHB) in adult patients. An increase in CPK plasma levels has been recently described in some telbivudine-treated CHB patients without muscle-skeletal symptoms. In this paper we report a CHB patient that developed a severe increase of CPK plasma levels during telbivudine treatment. Pharmacological evaluation, using the Naranjo probability scale, indicated a probable relationship between telbivudine and CPK increase, so telbivudine was discontinued and replaced with entecavir with a complete resolution of laboratory findings. In conclusion, telbivudine treatment can induce muscular damage in the absence of skeletal injury, therefore we suggest to closely monitor the muscular function of the patients treated with this drug in order to prevent possible major complications. PMID- 23738249 TI - Pilates: how does it work and who needs it? AB - Pilates uses a combination of approximately 50 simple, repetitive exercises to create muscular exertion. Advocates of this system of exercise claim that exercises can be adapted to provide either gentle strength training for rehabilitation or a strenuous workout vigorous enough to challenge skilled athletes. The exercises are designed to increase muscle strength and endurance, as well as flexibility and to improve posture and balance. There is cautious support for the effectiveness of Pilates in improving flexibility, abdominal and lumbo-pelvic stability and muscular activity. Stronger support cannot be given at this point in time primarily due to the limited number of studies and the lack of sound methodology in the published research. However, current research does indicate that there may be applications for this type of intervention in certain clinical populations that are worthy of continued investigation. PMID- 23738250 TI - Why I.s.mu.L.T? PMID- 23738251 TI - Tenocytes, pro-inflammatory cytokines and leukocytes: a relationship? AB - Leukocyte derived pro-inflammatory mediators could be involved in tendon healing and scar formation. Hence, the effect of autologous leukocytes (PBMCs, peripheral blood mononuclear cells and neutrophils) on primary rabbit Achilles tenocytes gene expression was tested in insert assisted co-cultures. Subsequently, tenocytes gene expression of extra-cellular matrix (ECM) components (type I collagen, decorin, fibronectin), the cell-ECM receptor beta1-integrin, the angiogenic factor myodulin, ECM degrading matrix-metalloproteinase (MMP)1 and pro inflammatory cytokines (interleukin [IL]-1beta, tumour necrosis factor [TNFalpha] and IL-6) was analysed. The only significant effect of leukocytes on tenocytes ECM genes expression was a suppression of type I collagen by neutrophils combined with TNFalpha stimulation. The same effect could be observed analysing the beta1 integrin and myodulin gene expression. However, PBMCs up-regulated significantly cytokine and MMP1 gene expression in tenocytes. These in vitro results suggest that mononuclear cells could present an exogenic stimulus for the induction of pro-inflammatory and catabolic mediators in tendon. PMID- 23738252 TI - Experimental basis of the hypotheses on the mechanism of skeletal muscle contraction. AB - With time clever hypotheses may be accepted as "facts" without being supported by solid experimental evidence. In our opinion this happened with muscle contraction where pure suggestions still occupy the scene and delay the progress of the research. Among these suggestions are: 1. the believe that viscosity is irrelevant in the economy of muscle contraction, 2. the concept of the drag stroke, 3. some interpretations of the significance of the Huxley-Simmons manoeuvre, 4. the definition of the load as a force/cross-section without taking into consideration the possible, divergent effects of the infinite mass x acceleration couples. Technical questions are also raised since it is apparent that measuring equipments interfere with the measure itself. PMID- 23738254 TI - Effects of Gaps Induced Into the ACL Tendon Graft on Tendon-Bone Healing in a Rodent ACL Reconstruction Model. AB - Graft necrosis following ACL reconstruction is often associated with the use of autologous grafts. Host cells rather than graft cells contribute to the repair of the tendon-bone interface and the remodeling of the autologous graft. The native tendon-bone interface is not recreated and the biomechanical properties are not restored back to native values. We examined the effects of introducing gaps within the tendon graft prior to ACL reconstruction in a rodent model. We hypothesised that gaps will make physical way for host cells to infiltrate and repopulate the graft and thus enhance healing. Animals were sacrificed at seven, fourteen, and twenty-eight days for biomechanical testing and histology. Our findings indicate that graft necrosis, usually observed in the initial two weeks of the healing process, is averted. Histological observations showed that tendon bone healing stages were hastened however this didn't translate into improved biomechanical properties. PMID- 23738253 TI - Oxidative system in aged skeletal muscle. AB - Aging is an inevitable biological process that is characterized by a general decline in the physiological and biochemical functions of the major systems. In the case of the neuromuscular system, reductions in strength and mobility cause a deterioration in motor performance, impaired mobility and disability. At the cellular level, aging is caused by a progressive decline in mitochondrial function that results in the accumulation of reactive oxygen species (ROS). As the level of oxidative stress in skeletal muscle increases with age, the age process is characterized by an imbalance between an increase in ROS production in the organism, and antioxidant defences as a whole. We have reviewed the literature on oxidative stress in aging human skeletal muscles, and to assesss the impact of differences in physiological factors (sex, fiber composition, muscle type and function). PMID- 23738255 TI - Sternoclavicular joint injuries: a literature review. AB - Traumatic sternoclavicular (SC) joint injuries are rare. The goal of this literature review was to evaluate the available literature on the treatment of traumatic anterior and posterior SC (fracture-) dislocations in adults and children. In adults, anterior dislocations are most commonly treated by nonoperative means. Closed reduction can be attempted but is associated with a high recurrence rate. For posterior dislocations, closed reduction is usually more successful. Children usually present with displaced physeal fractures, as true dislocations probably do not occur in a skeletally immature population. Anterior displacement can easily be reduced but it is difficult, if not impossible, to maintain the reduction. In contrast with the recommendations in adults, ORIF with the use of absorbable sutures can be indicated in these cases. No consensus exists on the recurrence of posterior displacement after closed reduction. If closed reductions fails, operative treatment is indicated, using the same technique as in anterior displacement. PMID- 23738256 TI - Football officials activities during matches: a comparison of activity of referees and linesmen in European, Premiership and Championship matches. AB - We compared the notational activity of 68 referees and 170 referee's assistants or linesmen officiating European matches from UEFA and the Champions League together with matches from the English Premiership and the English Championship competitions during the 2005/2006 football season using a computerised video system. We studied 328 games (14 European matches, UEFA and Champions league, 202 matches from the English Premiership and 112 from the English Championship). Referees covered a mean overall distance of 11.634 km, and assistants 6.508 km per match. Both referees and assistant referees covered significantly shorter distances jogging, running and high speed running in the second half compared to the first. There is a significant negative correlation between the distance covered and activity of officials compared with competition standard. Although we have demonstrated a negative correlation between distance covered and activity and competition standard, the physical activity across all competitions was intense and this reaffirms the high levels of fitness required by officials. PMID- 23738258 TI - ISMuLT Meeting Report. PMID- 23738257 TI - Short-term effectiveness of bi-phase oscillatory waves versus hyperthermia for isolated long head biceps tendinopathy. AB - INTRODUCTION: Long head biceps (LHB) tendinopathy is a common cause of anterior shoulder pain. Isolated LHB pathology is most common among younger people who practise overhead sports. The authors conducted a short-term prospective randomised study to test the effectiveness of two different methods for the treatment of isolated LHB tendinopathy: biphasic oscillatory waves and hyperthermia. STUDY DESIGN: The study is a prospective randomised study (Level II). MATERIAL AND METHODS: The authors identified 20 patients who had clinical and ultrasound (US) evidence of LHB tendinopathy. No patient was a high-level athlete. The patients were randomly assigned to two groups. Group A (10 patients) was treated with bi-phasic oscillatory waves, while Group B received hyperthermia. During the treatment period, no other electromedical therapy, injections with corticosteroids, oral analgesics or nonsteroidal anti inflammatory drugs were allowed. All the patients were assessed at baseline (T0), immediately after the end of the treatment period (T1) and 6 months after the end of treatment (T2) using a visual analogic scale (VAS) and Constant-Murley Score (CMS). Furthermore, all patients underwent US examinations at T0 and at T1. All the US examinations were performed by the same radiologist. RESULTS: The VAS scores showed a highly statistically significant reduction of pain at T1 both in Group A (65%; p=0,004) and in Group B (50%; p=0,0002). The CMS also showed a statistically significant improvement between the pre-intervention, the post treatment and the short-term follow-up in both groups. In addition, the peritendinous fluid evident on US examination at T0 was no longer present in all cases at T1. CONCLUSION: These findings suggest that both bi-phasic oscillatory waves and hyperthermia are able to relieve pain in patients with isolated LHB tendinopathy. This is a Class II level of evidence. PMID- 23738259 TI - Proteomic profiling of skeletal muscle plasticity. AB - One of the most striking physiological features of skeletal muscle tissues are their enormous capacity to adapt to changed functional demands. Muscle plasticity has been extensively studied by histological, biochemical, physiological and genetic methods over the last few decades. With the recent emergence of high throughput and large-scale proteomic techniques, mass spectrometry-based surveys have also been applied to the global analysis of the skeletal muscle protein complement during physiological modifications and pathophysiological alterations. This review outlines and discusses the impact of recent proteomic profiling studies of skeletal muscle transitions, including the effects of chronic electro stimulation, physical exercise, denervation, disuse atrophy, hypoxia, myotonia, motor neuron disease and age-related fibre type shifting. This includes studies on the human skeletal muscle proteome, animal models of muscle plasticity and major neuromuscular pathologies. The biomedical importance of establishing reliable biomarker signatures for the various molecular and cellular transition phases involved in muscle transformation is critically examined. PMID- 23738260 TI - Myofascial force transmission between transferred rat flexor carpi ulnaris muscle and former synergistic palmaris longus muscle. AB - We investigated the extent of mechanical interaction between rat flexor carpi ulnaris (FCU) and palmaris longus (PL) muscles following transfer of FCU to the distal tendons of extensor carpi radialis brevis and longus (ECRB/L) muscles. Five weeks after recovery from surgery, isometric forces exerted at the distal tendons of FCU and PL were quantified at various FCU lengths. PL was kept at a constant length. Changing the muscle-tendon complex length of transferred FCU (by maximally 3.5 mm) decreased PL force significantly (by 7%). A linear relationship was found between changes in FCU muscle belly length, being a measure of muscle relative positions, and PL force. These results indicate that despite transfer of FCU muscle to the extensor side of the forearm, changing FCU length still affects force transmission of its, now, antagonistic PL muscle. We conclude that a transferred muscle may still be mechanically linked to its former synergistic muscles. PMID- 23738261 TI - Conservative management of tendinopathy: an evidence-based approach. AB - Tendinopathy is one of the most frequent overuse injuries associated with sport. It is a failure of a chronic healing response associated with both chronic overloaded and unloaded states. Although several conservative therapeutic options have been proposed, very few of them are supported by randomized controlled trials. Eccentric exercises provide excellent clinical results both in athletic and sedentary patients, with no reported adverse effects. Combining eccentric loading and low-energy shock wave therapy produces higher success rates compared with eccentric training alone or shock wave therapy alone. High-volume injection of normal saline solution, corticosteroids, or anesthetics can reduce pain and improve long-term function in patients with Achilles or patellar tendinopathy. The use of injectable substances such as platelet-rich plasma, autologous blood, polidocanol, and corticosteroids in and around tendons is not support by strong clinical evidence. Further randomized controlled trials are necessary to define the best conservative management of tendinopathy. PMID- 23738263 TI - Anatomic Double Bundle single tunnel Foreign Material Free ACL-Reconstruction - a technical note. AB - The anterior cruciate ligament (ACL) consists of two bundles, the anteromedial (AM) and posterolateral bundle (PM). Double bundle reconstructions appear to give better rotational stability. The usual technique is to make two tunnels in the femur and two in the tibia. This is difficult and in small knees may not even be possible. We have developed a foreign material free press fit fixation for double bundle ACL reconstruction using a single femoral tunnel ((R)). This is based on the ALL PRESS FIT ACL reconstruction. It is suitable for the most common medium and, otherwise difficult, small sizes of knees. METHOD: Using diamond edged wet grinding hollow reamers, bone cylinders in different diameters are harvested from the implantation tunnels of the tibia and femur and used for the press fit fixation. Using the press fit technique the graft is first fixed in tibia. It is then similarly fixed under tension in the femoral side with the knee in 120 degree flexion. This is called Bottom To Top Fixation (BTT). On extending the knee the graft tension is self adapting. Depending on the size of the individual knee, the diameter of the femoral bone plug is varied from 8 to 13 mm to achieve an anatomic spread with a double bundle-like insertion. The tibia tunnel can be applied with two 7 or 8 mm diameter tunnels overlapping to a semi oval tunnel between 10 to 13 mm. RESULTS: Since May 2003 we have carried out ACL reconstructions with Hamstring grafts without foreign material using the ALL PRESS FIT technique. Initially, an 8 mm press fit fixation was used proximally with good results. Since April 2008, the range of diameters was increased up to 13 mm. The results of the Lachman tests have been good to excellent. Results of the Pivot shift test suggested more stability with femoral broader diameters of 9,5 to 13 mm. CONCLUSIONS: The foreign material free fixation of ham-string in the ALL PRESS FIT Bottom To Top Fixation is a successful method for ACL Reconstruction. The Diamond Instruments and tubed guiding devices are precise, reliable and easy to manage. On this basis a double bundle reconstruction is achieved using a single tunnel. A broad anatomic femoral insertion with autogenous bone plugs inserted near the cortex seems to improve rotational stability. PMID- 23738262 TI - Biological effects of extracorporeal shock waves on fibroblasts. A review. AB - Tissue homeostasis is influenced by mechanical forces which regulate the normal function of connective tissues. Mechanotransduction, the process that transforms mechanical stimuli in chemical signals, involves mechanosensory units integrated in cell membrane. The mechanosensory units are able to activate gene expression for growth factors or cytochines as well as to induce a biological event which results in cell proliferation and/or differentiation. In connective tissue the fibroblasts are the cells more represented and are considered as a model of mechanosensitive cells. They are ubiquitous but specific for each type of tissue. Their heterogeneity consists in different morphological features and activity; the common function is the mechanosensitivity, the capacity to adhere to extracellular matrix (ECM) and to each other, the secretion of growth factors and ECM components. Extracorporeal shock waves (ESW) have been recently used to treat damaged osteotendineous tissues. Studies in vitro and in vivo confirmed that ESW treatment enhances fibroblast proliferation and differentiation by activation of gene expression for transforming growth factor beta1 (TGF- beta1) and Collagen Types I and III. In addition, an increase of nitric oxide (NO) release is even reported in early stage of the treatment and the subsequent activation of endothelial nitric oxide synthase (eNOS) and of vascular endothelial growth factor (VEGF) are related to TGF- beta1 rise. The data have been related to the increase of angiogenesis observed in ESW treated tendons, an additional factor in accelerating the repairing process. A suitable treatment condition, characterized by a proper energy/shot number ratio, is the basis of treatment efficacy. Further ESWT applications are suggested in regenerative medicine, in all cases where fibroblast activity and the interaction with connective tissue can be positively influenced. PMID- 23738264 TI - Peroneus longus tear and its relation to the peroneal tubercle: A review of the literature. AB - Tear of the peroneal tendon may occur in different anatomical sites. The most prevalent site is around the lateral malleolus. Tear of the peroneus longus at the level of the peroneal tubercle is unusual. Anatomically, the lateral surface of the calcaneous can be divided into thirds. The middle third includes the peroneal tubercle, which separates the peroneus longus tendon from the peroneus brevis. An anatomic variation of the peroneal tubercle may lead to chronic irritation of the peroneus longus tendon that could ultimately cause a longitudinal tear. We conducted this review aiming to clarify the anatomy, biomechanics of the tendon, and the clinical features of tear of the peroneus longus tendon on the lateral surface of the calcaneous due to an enlarged peroneal tubercle. In addition, we reviewed the diagnostic and treatment options of peroneal tendon tears at this site. PMID- 23738265 TI - Biological aspects of rotator cuff healing. AB - Tendon tears of the rotator cuff show a high prevalence in today's population. Patients suffer from permanent pain and disability, and surgical reconstruction may be the only possibility for abatement. The complex process of tendon-bone healing leads to mechanically inferior scar-tissue, which often results in retears or non-healing. In the current literature, factors such as patients age, sex and fatty muscle infiltration are highly correlated to the presence of rotator cuff tears and the incidence of retears. To improve the tendon tissue quality after surgical reconstructions biologically based strategies with use of growth factors arouse more and more interest in the last years. However, to optimize the treatment of rotator cuff tears the biological background of tears and retears must be investigated in more detail. This article will elucidate different aspects that have an impact on rotator cuff healing and give a brief insight in tendon/ligament cell culture and animal studies focusing on growth factor treatments. PMID- 23738266 TI - Tendon, tendon healing, hyperlipidemia and statins. AB - Both hyperlipidemia and metabolic syndrome have adverse effect on tendon structure. Atorvastatin is most widely used antihyperlipidemic drug. Statins have adverse effects on the tendon. Many studies have analyzed the relationship between atorvastatin and skeletal muscles. Atorvastatin administered after the surgical repair of a ruptured tendon appears to affect revascularization, collagenization, inflammatory cell infiltration, and collagen construction. Therefore, further investigations on the effects of atorvastatin on tendon healing are needed. PMID- 23738267 TI - Syndecans in skeletal muscle development, regeneration and homeostasis. AB - Skeletal muscle is a highly dynamic tissue that can change in size in response to physiological demands and undergo successful regeneration even upon extensive injury. A population of resident stem cells, termed satellite cells, accounts for skeletal muscle plasticity, maintenance and regeneration. Mammalian satellite cells, generated from muscle precursor cells during development, are maintained quiescent in the musculature throughout a lifespan, but ready to activate, proliferate and differentiate into myocytes upon demand. Syndecans are transmembrane heparan sulfate proteoglycans expressed in muscle precursors during embryonic development and in satellite cells during postnatal life. In the last decades a number of crucial functions for syndecans in myogenesis and muscle disease have been described. Here we review the current knowledge of the multiple roles played by syndecans in the skeletal muscle of several animal models and explore future perspectives for human muscle health, with a focus on muscle aging and muscular dystrophy. PMID- 23738268 TI - The meniscal healing process. AB - Meniscus is a difficult structure to repair and replace. An injured or degenerative meniscus promotes osteoarthritic joint changes that should be avoided. Research focused on promoting healing or replacement must cover three different working lines: biology, mechanics and surgical technique. Biology research line looks for specific factors able to develop a collagen tissue in a matrix with cells that joins the edges of the lesion and also looks for factors able to keep the elasticity and able to regenerate the damaged meniscus fibres. On the other side, scaffolds need the adequate viscoelasticity to allow the penetration of vessels and cells to avoid reabsorption. PMID- 23738269 TI - Clinical application of diffusion tensor magnetic resonance imaging in skeletal muscle. AB - Diffusion tensor magnetic resonance imaging (DTI) is increasingly applied in the detection and characterization of skeletal muscle. This promising technique has aroused much enthusiasm and generated high expectations, because it is able to provide some specific information of skeletal muscle that is not available from other imaging modalities. Compared with conventional MRI, DTI could reconstruct the trajectories of skeletal muscle fibers. It makes it possible to non invasively detect several physiological values (diffusion values), like fractional anisotropy (FA) and apparent diffusion coefficient (ADC), which have a great association with the muscle physiology and pathology. Furthermore, other advantages of DTI are the capability of investigating the muscle biomechanics and also investigate the pathological condition of skeletal muscle. Finally, several challenges, which limit the wide application of DTI in skeletal muscle, were discussed. It is believed that this review may arouse in-depth studies on the clinical application of DTI in skeletal muscle in future. PMID- 23738270 TI - How can we strengthen the quadriceps femoris in patients with patellofemoral pain syndrome? AB - PURPOSE: the aim of this article was to review the clinical approach of quadriceps strengthening programmes. METHODS: a literature search was carried out from 1980 up to September 2011. Eligible studies were those that: (1) evaluated the patients with patellofemoral pain syndrome (not healthy or asymptomatic subjects) (2) examined the effect of kinetic chain exercises (3) examined the effect of weight-bearing exercises (4) compared the effect of the combined exercises programme in the treatment of patients with patellofemoral pain syndrome. RESULTS AND CONCLUSION: patients with patellofemoral pain syndrome may tolerate a closed kinetic chain exercises programme better than open kinetic chain. Weight-bearing and non-weight-bearing quadriceps exercises can significantly improve subjective and clinical outcomes in patients with patellofemoral pain syndrome. Combining treatments as an initial approach to treating patellofemoral pain but developing individualized more functional, global treatments are essential. PMID- 23738271 TI - The biological effects of extracorporeal shock wave therapy (eswt) on tendon tissue. AB - There is currently great interest in the use of Extracorporeal Shock Wave Therapy (ESWT) and in clarifying the mechanisms of action in tendon pathologies. The success rate ranges from 60% to 80% in epicondylitis, plantar fasciitis, cuff tendinitis, trocanteritis, Achilles tendinitis or jumper's knee. In contrast to urological treatments (lithotripsy), where shockwaves are used to disintegrate renal stones, in musculoskeletal treatments (orthotripsy), shockwaves are not being used to disintegrate tissues, but rather to microscopically cause interstitial and extracellular biological responses and tissue regeneration. The researchers are interesting to investigate the biological effects which support the clinical successes. Some authors speculated that shockwaves relieve pain in insertional tendinopathy by hyper-stimulation analgesia. Many recent studies demonstrated the modulations of shockwave treatment including neovascularization, differentiation of mesenchymal stem cells and local release of angiogenetic factors. The experimental findings confirm that ESWT decrease the expression of high levels of inflammatory mediators (matrix metalloproteinases and inter leukins). Therefore, ESWT produces a regenerative and tissue-repairing effect in musculoskeletal tissues, not merely a mechanical disintegrative effect as generally before assumed. Based on the encouraging results of clinical and experimental studies, the potential of ESWT appears to be emerging. The promising outcome after this non-invasive treatment option in tendinitis care justifies the indication of shockwave therapy. Further studies have to be performed in order or determine optimum treatment parameters and will bring about an improvement in accordance with evidence-based medicine. Finally, meta-analysis studies are necessary to demonstrate the efficacy and safety of ESWT in treating tendinopathies. PMID- 23738272 TI - Differences among mechanoreceptors in healthy and injured anterior cruciate ligaments and their clinical importance. AB - Mechanoreceptors in an intact Anterior Cruciate Ligament (ACL) contribute towards functional stability of the knee joint. Injury to the ACL not only causes mechanical instability, but also leads to a disturbance in the neuromuscular control of the injured knee due to loss or damage to mechanoreceptors. ACL reconstruction restores proprioceptive potential of the knee to some extent, but the results vary. Although the remnant ACL contains residual mechanoreceptors, the number and functionality of these receptors is dependent, to some extent, on the physical characteristics of the remnant and duration of injury. Remnants, especially that adherent to the PCL, may actually act as a possible source of reinnervation of the graft. These remnants are worth preserving during ACL reconstruction and can play an important role in restoration of proprioception of knee following ACL reconstruction. PMID- 23738273 TI - Achilles tendinopathy in amateur runners: role of adiposity (Tendinopathies and obesity). AB - Obesity is an important risk factor for Achilles tendinopathy, and running is usually carried out to reduce excess body weight. Aim of this study was to evaluate the prevalence of Achilles tendinopathy in young over-weight amateur runners. MALE RUNNERS AND NON RUNNERS WERE RECRUITED AND, IN EACH CATEGORY, DIVIDED IN TWO GROUPS: normal weight, and overweight. Data about Achilles tendon thickness, vascularisation and structural abnormalities were collected using a Power Doppler Ultrasonography device. Achilles tendon thickness was greater in both normal weight or overweight runners, but the difference was significant only in normal weight subjects. In non - runners, thickness was significantly higher only in over-weight subjects. Sonographic abnormalities were significantly prevalent in overweight runners. Running is associated to a physiologic hypertrophy of Achilles tendon in normal weight subjects. Overweight runners may precociously develop tendon abnormalities, due to the increased stress and the unfavourable milieu of repair. PMID- 23738274 TI - Real time evaluation of monolateral clubfoot with sonoelastography. Preliminary results. AB - PURPOSE: to assess the real time elastosonography (RTE) as a primary diagnostic tool for the evaluation of mechanical properties of Achilles tendons in patients affected by not surgically treated monolateral clubfoot. MATERIALS AND METHOD: six patients were evaluated, four males and two females, mean age 1.2 +/- 1.3 months, treated with Ponseti method, and afterward, they underwent RTE examination of the Achilles tendon in club-foot. A following ROI (region of interest) was positioned on the distal third of the tendon and the obtained data was examined retrospectively. RESULTS: in the examined cohort of patients, the mean value ROI 1/mean value ROI 2 ratio was 2.0 +/- 0.18, with an increased red area in the RTE evaluation of the affected tendon, while in the contralateral foot the mean observed value was 2.50 +/- 2.1. CONCLUSION: RTE is a feasible and simple technique, which allows the study of the mechanical properties of Achilles tendons in children with clubfoot. PMID- 23738276 TI - From muscle research to clinical applications: Do glutamate antagonists aid muscle recovery? AB - It has been shown in the rat, that during the first five postnatal days, motoneurons are particularly vulnerable to excitotoxic cell death and glutamate receptors play a significant role in this time-dependent process. Various categories of glutamate blockers (MK-801, Mg, PNQX, DAP-5) have various actions on the respective receptors. Furthermore, the different response between mature and immature motoneurons following injury is attributed to the quantity of glutamate receptors on the cell membrane. The effect of these substances on the recovery of fast and slow muscles after sciatic nerve crush, at critical developmental stages, shows a variable but impressive reversal of the devastating effects on rat muscle properties, which is different between fast and slow muscles. In addition, blocking of NMDA receptors by various substances rescues motoneurons and increases the number of motor units surviving into adulthood. In this way, glutamate receptor blockers may represent a promising therapeutic approach to retain nerve and muscle function during neurodegenerative events. PMID- 23738275 TI - The development of the myotendinous junction. A review. AB - The myotendinous junction (MTJ) is a complex specialized region located at the muscle-tendon interface that represents the primary site of force transmission. Despite their different embryologic origins, muscle and tendon morphogenesis occurs in close spatial and temporal association. After muscle attachment, muscle and tendon constitute a dynamic and functional integrated unit that transduces muscle contraction force to the skeletal system. We review here the current understanding of MTJ formation describing changes during morphogenesis and focusing on the crosstalk between muscle and tendon cells that leads to the development of a functional MTJ. Molecules involved in the formation of the linkage, both at the tendon side and at the muscle side of the junction are described. Much of this knowledge comes from studies using different animal models such as mice, zebrafish and Drosophila where powerful methods for in vivo imaging and genetic manipulations can be used to enlighten this developmental process. PMID- 23738278 TI - The force-length relationship of the cat soleus muscle. AB - According to the force-length relationship, cat soleus optimal sarcomere length should lie between 2.3-2.5MUm. Rack and Westbury (1969) found optimal sarcomere length around 2.8- 3.0MUm. The purpose of this study was to repeat their study to check for these discrepancies between the expected and the measured optimal length. The soleus muscle of both hindlimbs of three cats was supra-maximally stimulated. Isometric forces were measured for lengths ranging from -20 to +20mm relative to the optimal length. Mean sarcomere lengths were obtained by laser diffraction. Fibre length was obtained post-mortem by video analysis and in situ with sonomicrometry crystals. Sarcomere number was determined and in situ sarcomere lengths were calculated. The sarcomere force-length relationship showed an ascending and descending part with a plateau between 2.0-2.4MUm. Peak forces were obtained at smaller average sarcomere lengths than reported by Rack and Westbury and closer to the optimal sarcomere length based on sliding filament considerations. PMID- 23738277 TI - Treatment of adhesive capsulitis: a review. AB - Adhesive capsulitis is a condition "difficult to define, difficult to treat and difficult to explain from the point of view of pathology". This Codman's assertion is still actual because of a variable nomenclature, an inconsistent reporting of disease staging and many types of treatment. There is no consensus on how the best way best to manage patients with this condition, so we want to provide an evidence-based overview regarding the effectiveness of conservative and surgical interventions to treat adhesive capsulitis. PMID- 23738279 TI - The influence of radiofrequency ablation patterns on length, histological and mechanical properties of tendons. AB - The use of radiofrequency ablation for thermomodulation of connective tissues has gained acceptance with some surgeons. It is now mainly used for shoulder instability, and two techniques are commonly applied - ablation in a uniform pattern (paintbrush) and ablation in a linearly dispersed fashion (grid). The use of these techniques for shrinkage of tendons or cruciate ligaments is not widely accepted but may be utilized in selected cases. We assessed the effects of thermo modulation via monopolar radiofrequency ablation using these two techniques on the histological and biomechanical properties of rabbit Achilles tendons. 16 paired rabbit achilles tendons were divided into two treatment groups. Using a Monopolar RF device, eight tendons were treated using the paintbrush technique, and eight using the grid technique. The tendons were shrunk to about 90% of their original length, and the paired tendons were used as control. Following thermomodulation, tendons were pulled to tear using the Instron 4502 (Instron, Mass.) device. We found treated tendons were significantly less resistant to tear when compared to control; the average load to failure of the treatment group was 19.4% lower (p=0.05) than the control group values and the average tissue stiffness in the treatment group was 11.3% lower (p=0.051) than the control group. We found a tendency towards a lower resistance to pull in the tendon group treated using the grid technique. Histological analysis demonstrated areas of collagen denaturation correlated to areas of thermomodulation. A random point of failure was found along the tendons in the paintbrush group whereas the typical point of failure in the grid group was located at the treatment point or at its margins. Our findings demonstrate that use of the grid technique in ablation of tendons creates typical failure points (locus minoris resistenci) which bring about failure and alter the biomechanical properties of the thermomodulated tendons. Thermomodulation of tendons may be used efficiently in selected cases but its detrimental effects to the biomechanical attributes of the tissue should be considered. PMID- 23738280 TI - Chronic insertional Achilles tendinopathy: surgical outcomes. AB - BACKGROUND AND OBJECTIVE: insertional Achilles tendinopathy is a common condition among athletes and joggers. One fifth of the injuries involves the insertion of the tendon. The etiology is either due to mechanical overuse related to sports activity, or a systemic inflammatory disease. The clinical appearance includes pain and movement restriction. The primary treatment is conservative. The surgery referred to in this study (Calcaneal Osteotomy) is performed by decompression of the posterior margin of the calcaneus. If the tendon is degenerative, debridement is needed. There is controversy on the surgical outcome and the surgical approach. A retrospective analytic observational study. METHODS: 20 patients who were diagnosed with IAT (21 feet) and were operated on between the years 2000 2007 by calcaneal osteotomy. MAIN OUTCOME MEASURES: the primary measure of success was diminished pain. It was demonstrated in the AOFAS score and in the VAS scale of pain. RESULTS: the average grade in the AOFAS questionnaire improved by 20 points, and the average grading of pain in the VAS scale was decreased by 4.21. The median satisfaction rate was 8, the average was 5.81. 62% of the patients would repeat the surgery/recommend it. We found a significant relationship (p=0.022) between patients who avoided sports activity while suffering from insertional Achilles tendinopathy and the satisfaction rate from the surgery. CONCLUSIONS: using the calcaneal osteotomy technique as a surgical treatment for IAT is successful, and improves measures of pain and function. Low compliance with avoiding sports activity while suffering from an IAT might lead to a need for surgery. PMID- 23738281 TI - Pectoralis major tendon rupture. Surgical procedures review. AB - Pectoralis major (PM) muscle is the powerful dynamic stabiliser of the shoulder that acts as a flexor, adductor and internal rotator. The rupture of the PM tendon is a relatively rare injury that was firstly described in a French boy by Patissier in 1822 and later, in 1861, by Letenneur who reported another similiar case. To date, over 200 cases have been published. In this article we describe the clinical anatomy and the mechanism of injuries of PM and we review the surgical procedures for acute and chronic ruptures. PMID- 23738282 TI - Shock wave over hand muscles: a neurophysiological study on peripheral conduction nerves in normal subjects. AB - BACKGROUND AND PURPOSE: shock waves are defined as a sequence of single sonic pulses largely used in the treatment of bone and tendon diseases and recently on muscular hypertonia in stroke patients. Our purpose is to investigate the short and long term effect of extra-corporeal shock wave therapy (ESWT) on the peripheral nerve conduction and central conductions from the treated muscles in normal human subjects in order to define safety criteria. METHODS: we studied 10 patients normal subjects. Motor and sensory nerve conduction velocity and F response from right ipothenar eminence (abductor digiti minimi) of the hand was recorded. Furthermore MEP latency and amplitude and central conduction from the same muscles by transcranial magnetic stimulation was evaluated. In all subjects each neurophysiological measures were monitored before, immediately after, 15 minutes and after 30 minutes from the active ESWT treatment (1600 shots with an energy applied of 0.030 mj/mm(2)). RESULTS: no significant short or long term changes were noted in sensory and motor peripheral nerve conduction and in central motor conduction in all the subjects evaluated after ESWT. CONCLUSIONS: the ESWT has no effect on sensory and motor peripheral nerve conduction and in central motor conduction. The ESWT using low level of energy represent a safety method for treating the muscles in human subjects without involvement of motor or sensory nervous trunks. Different mechanisms of action of ESWT are discussed. PMID- 23738283 TI - The morphology and symptom history of the Achilles tendons of figure skaters: an observational study. AB - This cross-sectional study assessed the prevalence of Achilles tendinopathy symptoms and ultrasound (US) abnormalities in male and female ice skaters, and compared this to age-matched controls. The 20 skaters of mean (sd) age 17.3 (7.9) were recruited from British figure skating clubs. The 17 non-skaters of mean age 18.0 (3.7) were recruited from a secondary school and university. Each group had 12 females. All participants completed a questionnaire, and Achilles tendons were ultrasound-scanned for thickening, hypoechoic areas, paratenon blurring and neovascularization. Skaters experienced significantly more lifetime symptoms (p=0.012) than the control group but there were no differences in present symptoms. Mid-tendon longitudinal thickness and the coefficient of variation (CoV) for longitudinal tendon thickness were significantly greater in the skaters (p=0.001 and p=0.017 respectively). No other ultrasound abnormalities were detected in either group. Figure skaters may be at a greater risk of Achilles tendon problems than the general population and have adaptive changes in their tendons. PMID- 23738284 TI - Elbow tendinopathy. AB - Lateral epicondylosis is a common pathology of the upper extremity. The origin of the ECRB is the most commonly cited anatomic location of lateral epicondylosis pathology. Histologic examination shows the features of a failed healing response, with absence of acute inflammatory cells. The typical patient with lateral epicondylosis is an adult in the fourth or fifth decade of life, with no difference about the sex. Diagnosis is based on history and physical examination. The role of imaging is to confirm the diagnosis. The most consistent symptom of lateral epicondylosis is pain over the lateral aspect of the elbow. Therapeutic modalities for lateral epicondylosis vary widely and lack definitive evidence. Open, percutaneous or arthroscopic surgery is recommended when functional disability and pain persist after 6 to 12 months of nonoperative management. Future studies using validated clinical measures and imaging are needed to determine the best management for patients with lateral epicondylosis. PMID- 23738285 TI - Neuromuscular efficiency of the vastus medialis obliquus and postural balance in professional soccer athletes after anterior cruciate ligament reconstruction. AB - The purpose of this study was to evaluate the neuromuscular efficiency of the vastus medialis obliquus and postural balance in high-performance soccer athletes after anterior cruciate ligament (ACL) reconstruction, compared to the uninvolved leg. A cross-sectional study was conducted with 22 male professional soccer players after ACL reconstruction (4-12 months postoperatively). The athletes were submitted to functional rehabilitation with an accelerated protocol on the soccer team. They were evaluated using isokinetic dynamometer, surface electromyography and electronic baropodometer. There was no decrease or difference between neuromuscular efficiency of the VMO when comparing both the limbs after ACL reconstruction in the professional soccer athletes under treatment. The same result was found in postural balance. It can be concluded that the NME of the VMO in the involved member and postural balance were successfully re-established after the reconstruction procedure of the ACL in the sample group studied. PMID- 23738286 TI - Leg extension test, sEMG and vibratory stimuli to assess functional recovery following knee joint surgery. AB - OBJECTIVE: the purpose of this study was to introduce new procedure to determine the magnitude of functional recovery after knee surgery. DESIGN: we compared the performance in the leg extension test and the response in the sEMG activity to vibration in the operated to the non-operated leg. Thirty-eight patients with knee operation and 14 healthy subjects participated in these experiments. RESULTS: during leg extension test, the mechanical power of the operated leg showed a lower value (P<0.001) than the contralateral one, while no differences were noted in the sEMG activity. The sEMG activity during vibration treatment was higher in the operated compared to non-operated leg (P<0.001). It has been suggested that the reduced motility trigger functional adaptations that are exhibited via the vibration test. CONCLUSIONS: results of our study suggest that combination of vibration and sEMG recordings may detect the impairment as well as monitoring progress of the rehabilitation programs. PMID- 23738287 TI - Prospective study of three surgical procedures for long head biceps tendinopathy associated with rotator cuff tears. AB - PURPOSE: simple tenotomy in the treatment of long head biceps (LHB) lesion offers good results, as well as tenotomy/tenodesis. MATERIALS AND METHODS: we prospectively evaluated 252 patients, divided into 3 groups, treated with rotator cuff repair associated with LHB tenotomy or 2 different types of tenodesis in cases where there had been a partial lesion of the LHB or instability of the bicipital groove. We ascertained whether there was residual pain and the presence of the "Popeye sign" in the post-operative stage. RESULTS: patients who underwent tenotomy alone achieved an improvement on the Visual Analogue Scale (VAS), Simple Shoulder Test (SST) and modified UCLA shoulder rating compared to patients who underwent LHB tenodesis. A positive Popeye sign is poorly perceived by patients. CONCLUSION: we considered the LHB tenotomy as treatment of choice for the rotator cuff surgical repair when there was an evident LHB lesion. PMID- 23738288 TI - Clinical review of patients subjected to mini-Mumford arthroscopy. AB - PURPOSE: assessment of the clinical efficacy of isolated arthroscopic mini Mumford surgery, associated with shoulder surgery in patients with degenerative disease of the acromioclavicular joint. MATERIALS AND METHODS: 52 patients (group A) underwent isolated arthroscopic mini-Mumford and 84 (group B) additional arthroscopic surgery of rotator cuff and/or long head of biceps. They were evaluated clinically using Visual Analogue Scale (VAS), Simple Shoulder Test (SST) and Modified UCLA shoulder rating, pre- and post-operatively after a mean period of 18.1 months. RESULTS: the results obtained in groups A and B overlap. DISCUSSION: arthroscopic mini-Mumford is a simple, low-risk procedure, which has proved effective in treating degenerative disease of the acromioclavicular joint, both in isolation and in association with reconstruction of the rotator cuff and/or biceps long head tenotomy. PMID- 23738289 TI - Insertional tendinopathy of the adductors and rectus abdominis in athletes: a review. AB - Insertional tendinopathy of the adductors and rectus abdominis is common in male athletes, especially in soccer players. It may be worsened by physical activity and it usually limits sport performance. The management goal in the acute phase consists of analgesic and anti-inflammatory drugs and physical rehabilitation. In the early stages of rehabilitation, strengthening exercises of adductors and abdominal muscles, such as postural exercises, have been suggested. In the sub acute phase, muscular strength is targeted by overload training in the gym or aquatherapy; core stability exercises seem to be useful in this phase. Finally, specific sport actions are introduced by increasingly complex exercises along with a preventive program to limit pain recurrences. PMID- 23738290 TI - Massive cuff tears treated with arthroscopically assisted latissimus dorsi transfer. Surgical technique. AB - Latissimus dorsi transfer is our preferred treatment for active disabled patients with a posterosuperior massive cuff tear. We present an arthroscopically assisted technique which avoids an incision through the deltoid obtaining a better and faster clinical outcome. The patient is placed in lateral decubitus. After the arthroscopic evaluation of the lesion through a posterior and a posterolateral portal, with the limb in traction we perform the preparation of the greater tuberosity of the humerus. We place the arm in abduction and internal rotation and we proceed to the harvest of the latissimus dorsi and the tendon preparation by stitching the two sides using very resistant sutures. After restoring limb traction, under arthroscopic visualization, we pass a curved grasper through the posterolateral portal by going to the armpit in the space between the teres minor and the posterior deltoid. Once the grasper has exited the access at the level of the axilla we fix two drainage transparent tubes, each with a wire inside, and, withdrawing it back, we shuttle the two tubes in the subacromial space. After tensioning the suture wires from the anterior portals these are assembled in a knotless anchor of 5.5 mm that we place in the prepared site on the greater tuberosity of the humerus. A shoulder brace at 15 degrees of abduction and neutral rotation protect the patient for the first month post-surgery but physical therapy can immediately start. PMID- 23738291 TI - Stem cells for soft injuries. PMID- 23738292 TI - Biological properties of mesenchymal Stem Cells from different sources. AB - Mesenchymal stem cells (MSCs) are adult, nonhematopoietic, stem cells that were initially isolated from bone marrow. Now they can be isolated from almost every tissue of the body. They have the ability to self-renew and differentiate into multiple cell lineage, including bone, chondrocytes, adipocytes, tenocytes and cardiomyocytes, and it makes them an attractive cell source for a new generation of cell-based regenerative therapies. In this review we try to summarize data on sources and the biological properties of MSCs. PMID- 23738293 TI - Tendon stem cells: experimental and clinical perspectives in tendon and tendon bone junction repair. AB - Tendon and tendon-bone junction injuries, while heal, have high re-tear rates. Mesenchymal stem cells (MSCs) have great appeal for the promotion of tendon and tendon-bone junction healing because of their high proliferation rate, multi potency and relative ease of isolation from various tissues. Tendon stem cells have been identified recently and could be an alternative new cell source for tendon and tendon-bone junction repair. In this review, we summarized the in vitro characteristics of tendon stem cells. The evidence supporting the potential use of these cells for tendon and tendon-bone junction repair was presented. In order to therapeutically apply tendon stem cells in the clinical settings, standardization of tendon stem cell culture is essential. Issues relating to the sources, purity, efficacy, safety and delivery of tendon stem cells for tendon and tendon-bone junction repair were summarized and discussed. The direction for future research was suggested. PMID- 23738294 TI - Mesenchymal stem cell responses to mechanical stimuli. AB - Mesenchymal stem cells (MSCs) have the potential to replace or restore the function of damaged tissues and offer much promise in the successful application of tissue engineering and regenerative medicine strategies. Optimising culture conditions for the pre-differentiation of MSCs is a key goal for the research community, and this has included a number of different approaches, one of which is the use of mechanical stimuli. Mesenchymal tissues are subjected to mechanical stimuli in vivo and terminally differentiated cells from the mesenchymal lineage respond to mechanical stimulation in vivo and in vitro. MSCs have also been shown to be highly mechanosensitive and this may present an ideal method for controlling MSC differentiation. Here we present an overview of the response of MSCs to various mechanical stimuli, focusing on their differentiation towards the mesenchymal tissue lineages including bone, cartilage, tendon/ligament, muscle and adipose tissue. More research is needed to elucidate the complex interactions between biochemically and mechanically stimulated differentiation pathways. PMID- 23738295 TI - Biodegradable synthetic scaffolds for tendon regeneration. AB - Tissue regeneration is aimed at producing biological or synthetic scaffolds to be implanted in the body for regenerate functional tissues. Several techniques and materials have been used to obtain biodegradable synthetic scaffolds, on which adhesion, growth, migration and differentiation of human cells has been attempted. Scaffolds for tendon regeneration have been less frequently proposed, because they have a complex hierarchical structure and it is very difficult to mimic their peculiar mechanical properties. In this review, we critically analyzed the proposed materials and fabrication techniques for tendon tissue engineering and we indicated new preparation processes, based on the use of supercritical fluids, to produce scaffolds with characteristics very similar to the native tendon structure. PMID- 23738296 TI - Stem cell therapy of tendinopathies: suggestions from veterinary medicine. AB - The ideal strategy for tendon healing has not been identified to date. Recently, the use of stem cells based therapy has been proposed, due to their ability to proliferate and to differentiate towards specific connective tissues lineages. Embryonic stem cells should be considered the ideal cell source for regenerative therapies, but ethical factors limit their use in humans. Mesenchymal stem cells are more easily available and can be obtained by different sources. Amnion derived stem cells can differentiate towards all three germ layers, and can be used for allogeneic transplantation and stored thanks to cryopreservation. In veterinary medicine, stem cells have been used with encouraging results for the treatment of the Superficial Digital Flexor tendinopathy in the horses. Considering that Superficial Digital Flexor tendinopathy is similar for pathogenesis and histopathology to Achilles tendinopathy in man, this experience can provide supportive data to encourage the use of regenerative therapy in humans. PMID- 23738297 TI - Bioactive factors for tissue regeneration: state of the art. AB - THERE ARE THREE COMPONENTS FOR THE CREATION OF NEW TISSUES: cell sources, scaffolds, and bioactive factors. Unlike conventional medical strategies, regenerative medicine requires not only analytical approaches but also integrative ones. Basic research has identified a number of bioactive factors that are necessary, but not sufficient, for organogenesis. In skeletal development, these factors include bone morphogenetic proteins (BMPs), transforming growth factor beta TGF-beta, Wnts, hedgehogs (Hh), fibroblast growth factors (FGFs), insulin-like growth factors (IGFs), SRY box-containing gene (Sox) 9, Sp7, and runt-related transcription factors (Runx). Clinical and preclinical studies have been extensively performed to apply the knowledge to bone and cartilage regeneration. Given the large number of findings obtained so far, it would be a good time for a multi-disciplinary, collaborative effort to optimize these known factors and develop appropriate drug delivery systems for delivering them. PMID- 23738298 TI - Stem cell research and clinical development in tendon repair. AB - Stem cells are one of the most fascinating areas in regenerative medicine today. They play a crucial role in development and regeneration and are defined as cells that continuously reproduce themselves while maintaining the ability to differentiate into various cell types. Stem cells are found at all developmental stages, from embryonic stem cells (ESCs) which differentiate into all cell types, to adult stem cells (ASCs) which are responsible for tissue regeneration. Studies using animal models have shown promising results following cell therapy for induced injury in musculoskeletal system, including tendon healing, but the results can be variable. Alternative sources for cell therapy in tendon pathology may include ESCs, ASCs (bone marrow, adipose tissue or tendon derived stem cells) or induced pluripotent stem cells (iPSCs). While ethical and safety concerns currently forbid clinical application of ESCs and iPSCs, initial clinical trials with ASCs are promising. PMID- 23738299 TI - The role of microvesicles derived from mesenchymal stem cells in tissue regeneration; a dream for tendon repair? AB - Tendon injuries represent even today a challenge as repair may be exceedingly slow and incomplete. Regenerative medicine and stem cell technology have shown to be of great promise. Here, we will review the current knowledge on the mechanisms of the regenerative potential of mesenchymal stem cells (MSCs) obtained from different sources (bone marrow, fat, cord blood, placenta). More specifically, we will devote attention to the current use of MSCs that have been used experimentally and in limited numbers of clinical cases for the surgical treatment of subchondral-bone cysts, bone-fracture repair and cartilage repair. Based on the recently emerging role in regenerative mechanisms of soluble factors and of extracellular vesicles, we will discuss the potential of non-cellular therapies in horse tendon injuries. PMID- 23738301 TI - Tissue engineering for skeletal muscle regeneration. AB - Stem cells and regenerative medicine have obtained a remarkable consent from the scientific community for their promising ability to recover aged, injured and diseased tissue. However, despite the noteworthy potential, hurdles currently hinder their use and clinical application: cell survival, immune response, tissue engraftment and efficient differentiation. Hence a new interdisciplinary scientific approach, such as tissue engineering, is going deep attempts to mimic neo-tissue-genesis as well as stem cell engraftment amelioration. Skeletal muscle tissue engineering represents a great potentiality in medicine for muscle regeneration exploiting new generation injectable hydrogel as scaffold supporting progenitor/stem cells for muscle differentiation reconstructing the natural skeletal muscle tissue architecture influenced by matrix mechanical and physical property and by a dynamic environment. PMID- 23738300 TI - Mesenchymal stem cell applications to tendon healing. AB - Tendons are often subject to age related degenerative changes that coincide with a diminished regenerative capacity. Torn tendons often heal by forming scar tissue that is structurally weaker than healthy native tendon tissue, predisposing to mechanical failure. There is increasing interest in providing biological stimuli to increase the tendon reparative response. Stem cells in particular are an exciting and promising prospect as they have the potential to provide appropriate cellular signals to encourage neotendon formation during repair rather than scar tissue. Currently, a number of issues need to be investigated further before it can be determined whether stem cells are an effective and safe therapeutic option for encouraging tendon repair. This review explores the in-vitro and invivo evidence assessing the effect of stem cells on tendon healing, as well as the potential clinical applications. PMID- 23738302 TI - Stem cells and tendinopathy: state of the art from the basic science to clinic application. AB - Management of tendinopathies and tendon rupture is challenging. In the last few decades, several emerging strategies including tissue engineering with mesenchymal stem cells have been proposed to enhance tendon healing. They hold the promise to yield more successful outcomes for the management of patients with tendon pathology. Current in vitro studies support the application of these cell based therapies for the regeneration of tendon tissues. However, these cell-based strategies have been investigated only in pre-clinical studies and the role of stem cells needs to be confirmed. We performed a review of the literature to focus on actual knowledge and the future perspectives of stem cells for tendon regeneration and tendon engineering. PMID- 23738303 TI - Mesenchymal stem cells, aging and regenerative medicine. AB - Tissue maintenance and regeneration is dependent on stem cells and increasing evidence has shown to decline with age. Stem cell based-aging is thought to influence therapeutic efficacy. Mesenchymal stromal cells (MSCs) are involved in tissue regeneration. Here, we discuss the effects of age-related changes on MSC properties considering their possible use in research or regenerative medicine. PMID- 23738304 TI - Cell therapy: cGMP facilities and manufacturing. AB - Advanced therapies constitute one of the most complex, organizational, and regulatory areas currently approached by clinical researchers in order to explore new therapeutic applications. Basic scientists and clinicians trying to implement cell therapies into clinical practice, may feel overwhelmed by the apparently endless regulatory requirements that apply. However, regulatory agencies have primary responsibility on patient safety and law enforcement are, and should be, their main considerations. Cell- and tissue-based therapies have the potential to treat many conditions, where present conventional treatments are inadequate. The current approach to cell- and tissue-based therapy development requires using good manufacturing production facilities through master and working cell banks. Facilities need to be purpose-designed and accredited by their national medicinal regulatory body and production scientists need to work in close tandem with quality assurances and ethics committees to absolutely ensure the safety of this cellular products. PMID- 23738305 TI - International differences in sport medicine access and clinical management. AB - I undertook the 2012 ECOSEP travelling fellowship, sponsored by Bauerfeind, between May and August 2012, which involved visiting 5 European sport medicine centres and spending approximately one week in each centre. The 5 centres included: National Track and Field Centre, SEGAS, Thessaloniki, Greece; Professional School in Sport & Exercise Medicine, University of Barcelona, Spain; Sport Medicine Frankfurt Institute, Germany; Isokinetic Medical Group, FIFA Medical Centre of Excellence, Bologna, Italy, and Centre for Sports and Exercise Medicine, Barts and the London School of Medicine and Dentistry, Mile End Hospital, England. Throughout the fellowship, the clinical cases which were routinely encountered were documented. The following sections detail my experiences throughout the fellowship, the sports of the athletes and the injuries which were treated at each of the sport medicine centres during the fellowship visit and the different forms of management employed. PMID- 23738306 TI - Anatomical considerations in hamstring tendon harvesting for anterior cruciate ligament reconstruction. AB - Hamstring tendons are widely used for anterior cruciate ligament (ACL) reconstruction of the knee. Certain anatomical considerations must be taken into account when harvesting the hamstring tendons to be used in ACL reconstruction. These anatomical considerations are discussed in this review article. PMID- 23738307 TI - Biceps instability and Slap type II tear in overhead athletes. AB - Type II lesions are common lesions encountered in overhead athletes with controversies arising in term of timing for treatment, surgical approach, rehabilitation and functional results. The aim of our study was to evaluate the outcomes of arthroscopic repair of type II SLAP tears in overhead athletes, focusing on the time elapsed from diagnosis and treatment, time needed to return to sport, rate of return to sport and to previous level of performance, providing an overview concerning evidence for the effectiveness of different surgical approaches to type II SLAP tears in overhead athletes. A internet search on peer reviewed Journal from 1990, first descriprion of this pathology, to 2012, have been conducted evaluating the outcomes for both isolated Slap II tear overhead athletes and those who presented associated lesions treated. The results have been analyzed according to the scale reported focusing on return to sport and level of activity. Apart from a single study, non prospective level I and II studies were detected. Return to play at the same level ranged form 22% to 94% with different range of technique utilized with the majority of the authors recommending the fixation of these lesions but biceps tenodesis can lead to higher satisfaction racte when directly compated to the anchor fixation. Associated pathologies such as partial or full tickness rotator cuff tear did not clearly affect the outcomes and complications rate. There is no consensus regarding timing and treatment for type II SLAP, especially in overhead athletes who need to regain a high level of performance. PMID- 23738308 TI - Arthroscopic treatment of chronic patellar tendinopathy in high-level athletes. AB - To present the results of arthroscopic treatment of patellar tendinopathy in high level competition athletes. Eleven high-level athletes presented chronic patellar tendinopathy which did not respond to long term conservative treatment. Average age of the patients was 24.8 +/-3.4 years old. All patients received an arthroscopic procedure with osteoplasty of the distal patellar pole, debridement of the underlying Hoffa fat pad and of the degenerated areas of the proximal posterior patella tendon and cauterization of the visible neo-vessels. Mean duration of follow-up was 17.4+/-4 months. Patients showed a major improvement in the Lysholm score from 49.9+/-5.2 to 92.5+/-7 and in the VISA P score from 41.2+/ 5.2 to 86.8+/-14.9 on tenth post-operative week. All patients had returned to sports activities by the twelfth postoperative week. Arthroscopic treatment of chronic patellar tendinopathy found to be a minimal invasive and safe technique which produced satisfactory results. PMID- 23738309 TI - Calcific spurs at the insertion of the Achilles tendon: a clinical and histological study. AB - In active people, insertional calcific tendinopathy (CT) of the Achilles tendon is rare. We evaluated the results of surgical treatment for Achilles tendon CT and analyzed post-surgery Achilles tendon histological features. The study included 36 operations in 34 patients. Twenty-eight (78%) cases had a resection of a Haglund's deformity performed. The mean age of the patients was 42 years (range=23 to 68). Thirteen of the patients were professional athletes and 20 recreational athletes. In twenty-five (69%) cases, the result of surgery was rated good, in nine cases (25%) moderate and in two (6%) cases poor. The mean age of those with a good result was 10 years lower (40 versus 50 years) than those with a moderate result (p=0.0239). Higher athletic activity was also related to a better outcome (p=0.0205). Histology samples showed fast remodellation and stem cell activation. Surgery seemed to result in a good outcome in patients with or without a Haglund's deformity which failed conservative treatment. PMID- 23738310 TI - Vertical or horizontal orientation of foot radiographs does not affect image interpretation. AB - This study determined whether the orientation of dorsoplantar and oblique foot radiographs has an effect on radiograph interpretation. A test set of 50 consecutive foot radiographs were selected (25 with fractures, and 25 normal), and duplicated in the horizontal orientation. The images were randomly arranged, numbered 1 through 100, and analysed by six image interpreters. Vertical and horizontal area under the ROC curve, accuracy, sensitivity and specificity were calculated for each image interpreter. There was no significant difference in the area under the ROC curve, accuracy, sensitivity or specificity of image interpretation between images viewed in the vertical or horizontal orientation. While conventions for display of radiographs may help to improve the development of an efficient visual search strategy in trainees, and allow for standardisation of publication of radiographic images, variation from the convention in clinical practice does not appear to affect the sensitivity or specificity of image interpretation. PMID- 23738311 TI - Hypermobility of the first ray in ballet dancer. AB - Hypermobility of the first ray, which is caused by an instability of the first metatarsocuneiform joint, is one of the factors that induces hallux valgus and can be caused by technical mistakes in ballet practice. Correlation between ballet practice and hypermobility of the first ray. Using a modified Klaue device, mobility of the first metatarsocuneiform joint was measured (hypermobility >= 10mm) in both dorsal and dorso-medial directions in 264 feet in 2 groups of people: ballet dancers (non professional) and a control group of non dancers. 45 degrees mobility is statistically higher than dorsal mobility, and mobility in the ballet dancer group is higher than in the control group, but there is no correlation between hours of ballet and en-pointe shoe practice, and hypermobility of the first ray. First ray hypermobility, and even hallux valgus, in ballet practice is related to anatomical-hereditary factors and to incorrect technical execution. PMID- 23738312 TI - In vitro release and expansion of mesenchymal stem cells by a hyaluronic acid scaffold used in combination with bone marrow. AB - Articular cartilage injuries of the knee are difficult to treat due to the poor healing ability of cartilage and conventional treatment methods often give unsatisfactory results. Mesenchymal Stem Cells (MSCs) have generated interest as an alternative source of cells for cartilage tissue engineering due to their chondrogenic potential and their easy isolation from bone marrow. It has been reported that the use of scaffold in cartilage engineering acts as a support for cell adhesion, keeping the cells in the cartilage defects and therefore facilitating tissue formation, and that Hyaluronic acid (HA) is a molecule of particular interest for producing scaffold for tissue engineering. In this study we evaluated the in vitro selection and expansion of Bone Marrow MSCs (BM-MSCs) and by residual BM+HA membrane (BM-HA-MSCs) used as scaffold. Sixty mL of BM have been aspirated by the posterior iliac crest and HA membrane (Hyalograft-C, Fidia Advanced Biopolimers) was used as scaffold. BM-MSCs were cultured with D-MEM supplemented with Desamethasone, Ascorbic Acid, beta-Transforming Growth Factor and Insulin. When cultured in chondrogenic selective medium MSCs from both BM and HA membrane were able to differentiate into chondrogenesis, but BM-HA-MSCs showed a higher staining intensity than BM-MSCs when they were stained with Toluidine blue. The interaction of MSCs with the HA-scaffold seems to promote by itself chondrogenesis. PMID- 23738313 TI - The meniscus tear. State of the art of rehabilitation protocols related to surgical procedures. AB - Meniscal injuries represent one of the most frequent lesions in sport practicing and in particular in soccer players and skiers. Pain, functional limitation and swelling are typical symptoms associated with meniscal tears. Epidemiological studies showed that all meniscal lesions, in different sports athletes, involves 24% of medial meniscus, while 8% of lateral meniscus and about 20-30% of meniscal lesions are associated with other ligament injuries. Meniscal tears can be treated conservatively or surgically. Surgery leads in many cases to complete resolution of symptoms and allows the return to sport activity. However many studies show that this treatment can induce more frequently the development of degenerative conditions if not correctly associated to a specific rehabilitation protocol. The aim of this article is to compare different timing in specific rehabilitation programs related to the most actual surgical options. PMID- 23738314 TI - Rehabilitation after endoscopically percutaneous intramuscular splintage for vastus medialis partial rupture - A case report and review of the literature. AB - Isolated rupture of the vastus medialis muscle is rare, and surgical repair is recommended. The results of rehabilitation programme after the percutaneous intramuscular splintage of a nearly total vastus medialis muscle tear in a 52 year professional-master degree weight-lifter is presented in this report. PMID- 23738315 TI - Infra-patellar fat pad cysts: a case report and review of the literature. AB - Infra-patellar fat pad cysts are an uncommon type of intra-articular ganglia. We report a case of a young woman with a painful little mass in the anterior aspect of the left knee. Ultrasound revealed a multiloculate cyst, that was initially drained with a spinal needle. Four months later, she had a recurrence of symptoms and a ultrasound guided aspiration was performed. Cytological examination revealed synovial cells, synovial fluid, macrophages and debris: diagnosis was ganglion cyst. We reviewed the literature about infra-patellar fat pad cysts. Clinical diagnosis of an intraarticular cyst is very difficult, but sometimes an infra-patellar fat pad cyst could be suspected because it could be visible and palpable. MRI is the best diagnostic option in all cases. There are several treatment option, operative or conservative. In our opinion ultrasound guided aspiration is the treatment of choice in symptomatic ganglia, because it allows to drain all lacunae, preventing recurrence. PMID- 23738316 TI - Non contact Hamstring injuries in sports. AB - Hamstring muscle injuries are frequent in different sports and are a clinical challenge for Sports Medicine Teams. Injury Mechanics are import to know while assessing the injured athlete. There are at least two distinctly different types of acute hamstring injuries, which are best distinguished by the different injury situations. Classifying the severity of the injury is equally important. Active Range of motion measurements, proper imaging selection and the anatomical location of the injury must be considered. Once the diagnosis is established rehabilitation issues must be considered. Recurrence rate of the injury and prevention are issues that must always be included in our Hamstring Injuries approach as Clinicians. PMID- 23738317 TI - Comparison between extracorporeal shockwave therapy, placebo ESWT and endoscopic plantar fasciotomy for the treatment of chronic plantar heel pain in the athlete. AB - Plantar fasciitis can be a chronic and debilitating condition affecting athletes of all levels. The aim of this study is to compare treatment outcomes for the treatment of chronic plantar fasciitis in athletes, comparing focused extra corporeal sound wave therapy (ESWT) and the surgical endoscopic plantar fasciotomy (EPF). A total of 37 eligible patients were enrolled in the study between May 2006 and December 2008 at a single institution. Patients were either enrolled in the surgical group, or to the ESWT group which included a placebo controlled, randomized group (P-ESWT). Pre and post Visual Analog Scores (VAS) and Roles and Maudlsey (RM) scores were recorded and compared between the three groups. The patient's return to activity (RTA) was also documented. The results showed statistical improvement within the EPF and ESWT groups with both VAS & RM scores, with EPF being significantly better than both ESWT and P-ESWT in terms of treatment outcomes. Patients enrolled in the ESWT were able though to continue with their exercise regimen, while the EPF group was able to return to their athletic activity in an average of 2.8 months. In conclusion, EPF and ESWT are both effective forms of treatment for chronic plantar fasciitis; EPF being superior in outcomes yet ESWT treatment could be preferable since the athlete can remain active during treatment. LEVEL OF EVIDENCE: II. PMID- 23738318 TI - Genome Microscale Heterogeneity among Wild Potatoes Revealed by Diversity Arrays Technology Marker Sequences. AB - Tuber-bearing potato species possess several genes that can be exploited to improve the genetic background of the cultivated potato Solanum tuberosum. Among them, S. bulbocastanum and S. commersonii are well known for their strong resistance to environmental stresses. However, scant information is available for these species in terms of genome organization, gene function, and regulatory networks. Consequently, genomic tools to assist breeding are meager, and efficient exploitation of these species has been limited so far. In this paper, we employed the reference genome sequences from cultivated potato and tomato and a collection of sequences of 1,423 potato Diversity Arrays Technology (DArT) markers that show polymorphic representation across the genomes of S. bulbocastanum and/or S. commersonii genotypes. Our results highlighted microscale genome sequence heterogeneity that may play a significant role in functional and structural divergence between related species. Our analytical approach provides knowledge of genome structural and sequence variability that could not be detected by transcriptome and proteome approaches. PMID- 23738319 TI - Molecular Analysis of Twist1 and FGF Receptors in a Rabbit Model of Craniosynostosis: Likely Exclusion as the Loci of Origin. AB - Craniosynostosis is the premature fusion of the cranial vault sutures. We have previously described a colony of rabbits with a heritable pattern of nonsyndromic, coronal suture synostosis; however, the underlying genetic defect remains unknown. We now report a molecular analysis to determine if four genes implicated in human craniosynostosis, TWIST1 and fibroblast growth factor receptors 1-3 (FGFR1-3), could be the loci of the causative mutation in this unique rabbit model. Single nucleotide polymorphisms (SNPs) were identified within the Twist1, FGFR1, and FGFR2 genes, and the allelic patterns of these silent mutations were examined in 22 craniosynostotic rabbits. SNP analysis of the Twist1, FGFR1, and FGFR2 genes indicated that none were the locus of origin of the craniosynostotic phenotype. In addition, no structural mutations were identified by direct sequence analysis of Twist1 and FGFR3 cDNAs. These data indicate that the causative locus for heritable craniosynostosis in this rabbit model is not within the Twist1, FGFR1, and FGFR2 genes. Although a locus in intronic or flanking sequences of FGFR3 remains possible, no direct structural mutation was identified for FGFR3. PMID- 23738320 TI - Protein-Protein Interactions Inferred from Domain-Domain Interactions in Genogroup II Genotype 4 Norovirus Sequences. AB - Severe gastroenteritis and foodborne illness caused by Noroviruses (NoVs) during the winter are a worldwide phenomenon. Vulnerable populations including young children and elderly and immunocompromised people often require hospitalization and may die. However, no efficient vaccine for NoVs exists because of their variable genome sequences. This study investigates the infection processes in protein-protein interactions between hosts and NoVs. Protein-protein interactions were collected from related Pfam NoV domains. The related Pfam domains were accumulated incrementally from the protein domain interaction database. To examine the influence of domain intimacy, the 7 NoV domains were grouped by depth. The number of domain-domain interactions increased exponentially as the depth increased. Many protein-protein interactions were relevant; therefore, cloud techniques were used to analyze data because of their computational capacity. The infection relationship between hosts and NoVs should be used in clinical applications and drug design. PMID- 23738321 TI - Comparative genomics of cryptosporidium. AB - Until recently, the apicomplexan parasites, Cryptosporidium hominis and C. parvum, were considered the same species. However, the two parasites, now considered distinct species, exhibit significant differences in host range, infectivity, and pathogenicity, and their sequenced genomes exhibit only 95-97% identity. The availability of the complete genome sequences of these organisms provides the potential to identify the genetic variations that are responsible for the phenotypic differences between the two parasites. We compared the genome organization and structure, gene composition, the metabolic and other pathways, and the local sequence identity between the genes of these two Cryptosporidium species. Our observations show that the phenotypic differences between C. hominis and C. parvum are not due to gross genome rearrangements, structural alterations, gene deletions or insertions, metabolic capabilities, or other obvious genomic alterations. Rather, the results indicate that these genomes exhibit a remarkable structural and compositional conservation and suggest that the phenotypic differences observed are due to subtle variations in the sequences of proteins that act at the interface between the parasite and its host. PMID- 23738322 TI - Plant stress and biotechnology. PMID- 23738323 TI - Involvement of Nrf2-mediated upregulation of heme oxygenase-1 in mollugin-induced growth inhibition and apoptosis in human oral cancer cells. AB - Although previous studies have shown that mollugin, a bioactive phytochemical isolated from Rubia cordifolia L. (Rubiaceae), exhibits antitumor effects, its biological activity in oral cancer has not been reported. We thus investigated the effects and putative mechanism of apoptosis induced by mollugin in human oral squamous cell carcinoma cells (OSCCs). Results show that mollugin induces cell death in a dose-dependent manner in primary and metastatic OSCCs. Mollugin induced cell death involved apoptosis, characterized by the appearance of nuclear shrinkage, flow cytometric analysis of sub-G1 phase arrest, and annexin V-FITC and propidium iodide staining. Western blot analysis and RT-PCR revealed that mollugin suppressed activation of NF- kappa B and NF- kappa B-dependent gene products involved in antiapoptosis (Bcl-2 and Bcl-xl), invasion (MMP-9 and ICAM 1), and angiogenesis (FGF-2 and VEGF). Furthermore, mollugin induced the activation of p38, ERK, and JNK and the expression of heme oxygenase-1 (HO-1) and nuclear factor E2-related factor 2 (Nrf2). Mollugin-induced growth inhibition and apoptosis of HO-1 were reversed by an HO-1 inhibitor and Nrf2 siRNA. Collectively, this is the first report to demonstrate the effectiveness of mollugin as a candidate for a chemotherapeutic agent in OSCCs via the upregulation of the HO-1 and Nrf2 pathways and the downregulation of NF- kappa B. PMID- 23738324 TI - Genetic and functional profiling of Crohn's disease: autophagy mechanism and susceptibility to infectious diseases. AB - Crohn's disease is a complex disease in which genome, microbiome, and environment interact to produce the immunological background of the disease. Disease in childhood is more extensive and characterized by a rapid progression, leading to severe repercussions in the course of the disorder. Several genetic variations have been associated with an increased risk of developing the disease and most of these are also implicated in other autoimmune disorders. The gut has many tiers of defense against incursion by luminal microbes, including the epithelial barrier and the innate and adaptive immune responses. Moreover, recent evidence shows that bacterial and viral infections, as well as inflammasome genes and genes involved in the autophagy process, are implicated in Crohn's disease pathogenesis. The aim of this review is to establish how much the diagnostic system can improve, thus increasing the success of Crohn's disease diagnosis. The major expectation for the near future is to be able to anticipate the possible consequences of the disease already in childhood, thus preventing associated complications, and to choose the best treatment for each patient. PMID- 23738325 TI - Cardiac fibroblast-derived extracellular matrix (biomatrix) as a model for the studies of cardiac primitive cell biological properties in normal and pathological adult human heart. AB - Cardiac tissue regeneration is guided by stem cells and their microenvironment. It has been recently described that both cardiac stem/primitive cells and extracellular matrix (ECM) change in pathological conditions. This study describes the method for the production of ECM typical of adult human heart in the normal and pathological conditions (ischemic heart disease) and highlights the potential use of cardiac fibroblast-derived ECM for in vitro studies of the interactions between ECM components and cardiac primitive cells responsible for tissue regeneration. Fibroblasts isolated from adult human normal and pathological heart with ischemic cardiomyopathy were cultured to obtain extracellular matrix (biomatrix), composed of typical extracellular matrix proteins, such as collagen and fibronectin, and matricellular proteins, laminin, and tenascin. After decellularization, this substrate was used to assess biological properties of cardiac primitive cells: proliferation and migration were stimulated by biomatrix from normal heart, while both types of biomatrix protected cardiac primitive cells from apoptosis. Our model can be used for studies of cell-matrix interactions and help to determine the biochemical cues that regulate cardiac primitive cell biological properties and guide cardiac tissue regeneration. PMID- 23738326 TI - Oxidation of marine omega-3 supplements and human health. AB - Marine omega-3 rich oils are used by more than a third of American adults for a wide range of purported benefits including prevention of cardiovascular disease. These oils are highly prone to oxidation to lipid peroxides and other secondary oxidation products. Oxidized oils may have altered biological activity making them ineffective or harmful, though there is also evidence that some beneficial effects of marine oils could be mediated through lipid peroxides. To date, human clinical trials have not reported the oxidative status of the trial oil. This makes it impossible to understand the importance of oxidation to efficacy or harm. However, animal studies show that oxidized lipid products can cause harm. Oxidation of trial oils may be responsible for the conflicting omega-3 trial literature, including the prevention of cardiovascular disease. The oxidative state of an oil can be simply determined by the peroxide value and anisidine value assays. We recommend that all clinical trials investigating omega-3 harms or benefits report the results of these assays; this will enable better understanding of the benefits and harms of omega-3 and the clinical importance of oxidized supplements. PMID- 23738327 TI - Characterization and dynamic behavior of wild yeast during spontaneous wine fermentation in steel tanks and amphorae. AB - We studied the dynamic behavior of wild yeasts during spontaneous wine fermentation at a winery in the Valais region of Switzerland. Wild yeasts in the winery environment were characterized using a PCR-RFLP method. Up to 11 different yeast species were isolated from the vineyard air, whereas only seven were recovered from the grapes surface. We initially investigated a cultureindependent method in pilot-scale steel fermentation tanks and found a greater diversity of yeasts in the musts from two red grape varieties compared to three white grape varieties. We found that the yeasts Metschnikowia pulcherrima, Rhodotorula mucilaginosa, Pichia kluyveri, P. membranifaciens and Saccharomyces cerevisiae remained active at the end of the fermentation. We also studied the dynamic behavior of yeasts in Qvevris for the first time using a novel, highlysensitive quantitative real-time PCR method. We found that non-Saccharomyces yeasts were present during the entire fermentation process, with R. mucilaginosa and P. anomala the most prominent species. We studied the relationship between the predominance of different species and the output of the fermentation process. We identified so-called spoilage yeasts in all the fermentations, but high levels of acetic acid accumulated only in those fermentations with an extended lag phase. PMID- 23738328 TI - Cytotoxicity of ferulic Acid on T24 cell line differentiated by different microenvironments. AB - Ferulic acid (4-hydroxy-3-methoxycinnamic acid) (FA) is a ubiquitous health beneficial phenolic acid. Although FA has shown a diversity of biological activities including anti-inflammatory, antihypercholesterolemic and anticancer bioactivities, studies revealing its adverse effects are accumulating. Recently, 3D-cultures are shown to exhibit uniquely biological behaviors different from that of 2D cultures. To understand whether the cytotoxicity of FA against the T24 cell line (a bladder cancer cell line) in 2D-culture could consistently retain similar bioactivity if cultured in the 3D-systems, we conducted this experiment with 2 mM FA. Much higher cytotoxicity was found for 3D- than 2D-culture, showing (2D vs. 3D): apoptotic rates, 64% and 76%; cell killing rates, 3.00 * 10(5) cells mmol(-1).h(-1) and 2.63 * 10(6) cells mmol(-1).h(-1), attaining a 8.77-fold. FA upregulated the activities at 72 h (2D vs. 3D in folds that of control): SOD, 1.73-folds (P < 0.05) versus 3.18 folds (P < 0.001); and catalase, 2.58 versus 1.33-folds. Comparing to the control (without FA), Bcl-2 was prominently downregulated while Bax, caspase-3 and cleaved caspase-9 were more upregulated in 3D-cultures (P < 0.05). Conclusively, different microenvironments could elicit different biological significance which in part can be ascribed to different mass transport rate. PMID- 23738330 TI - Unraveling the lipolytic activity of thermophilic bacteria isolated from a volcanic environment. AB - In a bioprospecting effort towards novel thermostable lipases, we assessed the lipolytic profile of 101 bacterial strains isolated from the volcanic area of Santorini, Aegean Sea, Greece. Screening of lipase activity was performed both in agar plates and liquid cultures using olive oil as carbon source. Significant differences were observed between the two screening methods with no clear correlation between them. While the percentage of lipase producing strains identified in agar plates was only 17%, lipolytic activity in liquid culture supernatants was detected for 74% of them. Nine strains exhibiting elevated extracellular lipase activities were selected for lipase production and biochemical characterization. The majority of lipase producers revealed high phylogenetic similarity with Geobacillus species and related genera, whilst one of them was identified as Aneurinibacillus sp. Lipase biosynthesis strongly depended on the carbon source that supplemented the culture medium. Olive oil induced lipase production in all strains, but maximum enzyme yields for some of the strains were also obtained with Tween-80, mineral oil, and glycerol. Partially purified lipases revealed optimal activity at 70-80 degrees C and pH 8 9. Extensive thermal stability studies revealed marked thermostability for the majority of the lipases as well as a two-step thermal deactivation pattern. PMID- 23738329 TI - Analytical methodologies for the determination of endocrine disrupting compounds in biological and environmental samples. AB - Endocrine-disruptor compounds (EDCs) can mimic natural hormones and produce adverse effects in the endocrine functions by interacting with estrogen receptors. EDCs include both natural and synthetic chemicals, such as hormones, personal care products, surfactants, and flame retardants, among others. EDCs are characterised by their ubiquitous presence at trace-level concentrations and their wide diversity. Since the discovery of the adverse effects of these pollutants on wildlife and human health, analytical methods have been developed for their qualitative and quantitative determination. In particular, mass-based analytical methods show excellent sensitivity and precision for their quantification. This paper reviews recently published analytical methodologies for the sample preparation and for the determination of these compounds in different environmental and biological matrices by liquid chromatography coupled with mass spectrometry. The various sample preparation techniques are compared and discussed. In addition, recent developments and advances in this field are presented. PMID- 23738331 TI - Genotoxicity of polycyclic aromatic hydrocarbons and nitro-derived in respirable airborne particulate matter collected from urban areas of Rio de Janeiro (Brazil). AB - Air pollution toxic effects are mainly attributed to small inhalable particulates with an aerodynamic diameter of less than 2.5 u m (PM 2.5). Our objective was to investigate mutagenic and clastogenic activity in PM samples collected in Rio de Janeiro. Samples were collected using a high-volume sampler at three sites: with low traffic and (2) and (3) with a heavy traffic. Six polycyclic aromatic hydrocarbons (PAHs) were quantified by gas chromatography/mass spectrometry (GC/MS). Salmonella typhimurium TA98 and the derivative strains YG1021 and YG1024 were used in mutagenicity assays in the presence of organic extracts (10-50 u g/ plate) with and without exogenous metabolization. Allium cepa test was performed to evaluate possible cytotoxic and clastogenic activities. The highest PM 2.5 u m (132.73 u m/m(3)) and PAH values (1.22 ng/m(3) for benzo(a)pyrene) were detected at site 3. High mutagenic frameshift responses in absence and presence of metabolic activation were detected at site 3. The participation of nitroarenes and dinitroarenes was detected in the total mutagenicity of the extracts studied. The cytotoxic effect and the abnormalities detected by Allium cepa test can be attributed to the PAH nitroderivatives in the organic extracts. Evaluation of the genotoxicity of urban airborne particulate matter is important as a basis for decision making by regulatory authorities. PMID- 23738332 TI - Moscatilin inhibits lung cancer cell motility and invasion via suppression of endogenous reactive oxygen species. AB - Lung cancer is the leading cause of death among cancer patients worldwide, and most of them have died from metastasis. Migration and invasion are prerequisite processes associated with high metastasis potential in cancers. Moscatilin, a bibenzyl derivative isolated from the Thai orchid Dendrobium pulchellum, has been shown to have anticancer effect against numerous cancer cell lines. However, little is known regarding the effect of moscatilin on cancer cell migration and invasion. The present study demonstrates that nontoxic concentrations of moscatilin were able to inhibit human nonsmall cell lung cancer H23 cell migration and invasion. The inhibitory effect of moscatilin was associated with an attenuation of endogenous reactive oxygen species (ROS), in which hydroxyl radical (OH(?)) was identified as a dominant species in the suppression of filopodia formation. Western blot analysis also revealed that moscatilin downregulated activated focal adhesion kinase (phosphorylated FAK, Tyr 397) and activated ATP-dependent tyrosine kinase (phosphorylated Akt, Ser 473), whereas their parental counterparts were not detectable changed. In conclusion, our results indicate the novel molecular basis of moscalitin-inhibiting lung cancer cell motility and invasion and demonstrate a promising antimetastatic potential of such an agent for lung cancer therapy. PMID- 23738333 TI - Structural adaptation of cold-active RTX lipase from Pseudomonas sp. strain AMS8 revealed via homology and molecular dynamics simulation approaches. AB - The psychrophilic enzyme is an interesting subject to study due to its special ability to adapt to extreme temperatures, unlike typical enzymes. Utilizing computer-aided software, the predicted structure and function of the enzyme lipase AMS8 (LipAMS8) (isolated from the psychrophilic Pseudomonas sp., obtained from the Antarctic soil) are studied. The enzyme shows significant sequence similarities with lipases from Pseudomonas sp. MIS38 and Serratia marcescens. These similarities aid in the prediction of the 3D molecular structure of the enzyme. In this study, 12 ns MD simulation is performed at different temperatures for structural flexibility and stability analysis. The results show that the enzyme is most stable at 0 degrees C and 5 degrees C. In terms of stability and flexibility, the catalytic domain (N-terminus) maintained its stability more than the noncatalytic domain (C-terminus), but the non-catalytic domain showed higher flexibility than the catalytic domain. The analysis of the structure and function of LipAMS8 provides new insights into the structural adaptation of this protein at low temperatures. The information obtained could be a useful tool for low temperature industrial applications and molecular engineering purposes, in the near future. PMID- 23738335 TI - Evaluation of adverse effects of mutein forms of recombinant human interferon alpha-2b in female swiss webster mice. AB - PURPOSE: We successfully developed recombinant human interferon alpha-2b (rhIFN- alpha 2b) and mutein forms through the site-directed mutagenesis technique. The mutein forms were developed by substituting cysteins at positions 2 and 99 with aspartic acids. The potential adverse effects of these rhIFN- alpha 2bs were assessed by acute and subchronic studies. METHODS: In the acute study, rhIFN- alpha 2bs were subcutaneously administered to mice at a single dose of 97.5 MU g/kg, 975 MU g/kg, and 9.75 mg/kg BW and were observed for 14 days. In the subchronic study, single dose of 1.95 MU g/kg and 19.5 MU g/kg, respectively, was given subcutaneously every 3 days for 45 days. RESULTS: No death as well as abnormality in body weight, behavior, presentation of main organs, and value of plasma SGPT and SGOT was observed. Wild type and mutein rhIFN- alpha 2bs did not show significant adverse effects at dose up to 9.75 mg/kg BW. Administration of these rhIFN- alpha 2bs given repeatedly did not induce any adverse effect. CONCLUSION: These results suggest that our rhIFN- alpha 2bs are safe. However, further study is still needed to clarify the safety issue before use in clinical trial. PMID- 23738334 TI - 2-heptyl-formononetin increases cholesterol and induces hepatic steatosis in mice. AB - Consumption of isoflavones may prevent adiposity, hepatic steatosis, and dyslipidaemia. However, studies in the area are few and primarily with genistein. This study investigated the effects of formononetin and its synthetic analogue, 2 heptyl-formononetin (C7F), on lipid and cholesterol metabolism in C57BL/6J mice. The mice were fed a cholesterol-enriched diet for five weeks to induce hypercholesterolemia and were then fed either the cholesterol-enriched diet or the cholesterol-enriched diet-supplemented formononetin or C7F for three weeks. Body weight and composition, glucose homeostasis, and plasma lipids were compared. In another experiment, mice were fed the above diets for five weeks, and hepatic triglyceride accumulation and gene expression and histology of adipose tissue and liver were examined. Supplementation with C7F increased plasma HDL-cholesterol thereby increasing the plasma level of total cholesterol. Supplementation with formononetin did not affect plasma cholesterol but increased plasma triglycerides levels. Supplementation with formononetin and C7F induced hepatic steatosis. However, formononetin decreased markers of inflammation and liver injury. The development of hepatic steatosis was associated with deregulated expression of hepatic genes involved in lipid and lipoprotein metabolism. In conclusion, supplementation with formononetin and C7F to a cholesterol-enriched diet adversely affected lipid and lipoprotein metabolism in C57BL/6J mice. PMID- 23738336 TI - Revealing the mechanism of in vitro wound healing properties of Citrus tamurana extract. AB - In the present investigation, we examined the effect of Hyuganatsu (Citrus tamurana) extract (HE) on skin fibroblast (TIG-119) proliferation and migration during in vitro wound healing. HE selectively inhibited proliferation of TIG-119 cells at higher concentration (>1.0 mg/mL); at lower concentrations (0.1, 0.25, 0.5, and 0.75 mg/mL), it exhibited linear and time-dependent cell proliferation. In vitro scratch wound healing studies showed that the HE also accelerated the migration of cells towards the wounded region. Cytometric analysis demonstrated that HE extract did not alter G1/0 and S phases of cell cycle in any concentration studied; however, G2/M phases of cell cycle were significantly (P < 0.05) accelerated at 0.75 mg/mL dose. RT-PCR and Western blotting analysis indicated that HE markedly overexpressed levels of Rac-1, Rho-A, and Cdc-42 mRNA and the respective proteins. Cyclin-dependent kinases (Cdk-1 and -2) gene expression activity was significantly (P < 0.05) increased, but protein content decreased during treatment with HE. The induction of Cdk-1 and -2 by HE was abolished by inhibitors, transcription (DRB), and translation (CHX), implying transcriptional regulation that required de novo protein synthesis. PMID- 23738338 TI - Simulation training for acute medical specialist trainees: a pilot. AB - Simulation training is a method of interactive teaching and training for healthcare professionals. Medical education research demonstrates that high fidelity simulation leads to effective learning. Acute Medical Specialist Year Three-plus Trainee (ST3+) doctors are often required to manage high-pressure situations, requiring a combination of clinical and non-clinical abilities. We therefore hypothesised that simulation training could be an ideal training tool for this cohort. We designed a simulation training day for ST3+trainees which exposed them to ethically challenging scenarios. The learning objectives were mapped to the acute medical curriculum, focusing on areas trainees may traditionally describe as either difficult to achieve, or for those for which providing evidence may be challenging. Simulation scenarios and debriefing sessions enabled trainees to explore different views in a protected environment, and feedback was strongly positive. We strongly recommend simulation training as a teaching tool for Acute Medical ST3+ doctors. PMID- 23738339 TI - Guest editors' introduction: Special section on the ACM SIGGRAPH Symposium on Interactive 3D Graphics and Games (I3D 2012). PMID- 23738337 TI - Impact of high glucose and proteasome inhibitor MG132 on histone H2A and H2B ubiquitination in rat glomerular mesangial cells. AB - BACKGROUND: Hyperglycemia plays a pivotal role in the development of diabetic nephropathy (DN) and may be related to epigenetic metabolic memory. One of the most crucial epigenetic mechanisms is histone modification, which is associated with the expression of a fibrosis factor in vascular injury. Aim .In this study, we investigated the ubiquitination of histones H2A and H2B to explore the epigenetic mechanisms of DN. MATERIALS AND METHODS: The GMCs were cultured as follows: normal group, high glucose group, mannitol group, and intervention group. After 12 hr, 24 hr, and 48 hr, histones ubiquitination, transforming growth factor-beta (TGF-beta), and fibronectin (FN) were measured using WB, RT PCR, and IF. RESULT: High glucose can induce the upregulation of FN. H2A ubiquitination in GMCs increased in high glucose group (P < 0.01), whereas it decreased significantly in intervention group (P < 0.05). In contrast, H2B ubiquitination decreased with an increasing concentration of glucose, but it was recovered in the intervention group (P < 0.05). Expression of TGF-beta changed in response to abnormal histone ubiquitination. CONCLUSIONS: The high glucose may induce H2A ubiquitination and reduce H2B ubiquitination in GMCs. The changes of histone ubiquitination may be due in part to DN by activating TGF-beta signaling pathway. PMID- 23738340 TI - Peter Friedrich (1936-2013). PMID- 23738341 TI - Abstracts of Heart Failure Congress 2013. Lisbon, Portugal. May 25-28, 2013. PMID- 23738342 TI - Clinical pathologic conference case 1: a woman with a lump in her cheek. PMID- 23738343 TI - Clinical pathologic conference case 2: a diffuse swelling of the neck. PMID- 23738344 TI - Clinical pathologic conference case 3: Painful, mobile mandibular molar. PMID- 23738345 TI - Clinical pathologic conference case 4: an incidental maxillary sinus finding. PMID- 23738346 TI - Clinical pathologic conference case 5: Unusual severe glossitis. PMID- 23738347 TI - Clinical pathologic conference case 6: a painful multilocular radiolucency. PMID- 23738348 TI - Abstracts of the British Cardiovascular Society Annual Conference. June 3-5, 2013. London, United Kingdom. PMID- 23738349 TI - Abstracts of the Annual Meeting of the Obstetric Anaesthetists' Association. Bournemouth, United Kingdom. May 23-24, 2013. PMID- 23738350 TI - In response. PMID- 23738351 TI - In response. PMID- 23738352 TI - Surgical research abroad. PMID- 23738353 TI - Data loss from time series of pollutants in ambient air exhibiting seasonality: consequences and strategies for data prediction. AB - The effect of data loss on annual average concentrations of seasonal and non seasonal pollutants in ambient air has been investigated. The bias caused to the true annual average has been shown to be significant for measurements of benzo[a]pyrene (BaP) in PM(10) (a highly seasonal pollutant) even when legislative requirements for data capture and time coverage are still met. In order to mitigate this bias, strategies to predict concentrations during periods of lost data have been tested. These have been based on fitting quadratic relationships to available data of BaP in PM(10) at individual monitoring stations on the UK PAH Monitoring Network. The annual average concentration values produced with and without the use of predicted data have been compared to the actual annual averages in the absence of data loss. The use of predicted data is a significant (but not universal) improvement at urban and rural monitoring stations where the data exhibit consistently good fits to the predicted quadratic model. At industrial stations, where the quadratic model fails, the use of predicted data shows no improvement, although the effect of lost data at these sites on the annual average is much less noticeable because of their lack of seasonality. PMID- 23738354 TI - Health risk assessment of occupational exposure to hazardous volatile organic compounds in swine gestation, farrowing and nursery barns. AB - Livestock producers are exposed to a high number of airborne pollutants during their daily duties of cleaning, feeding and maintenance activities. Hazardous air pollutants (HAPs) are a major group of pollutants that may cause cancer or other serious health effects including neurological, respiratory, reproductive and developmental disorders. In this study, health risks of occupational exposure to eight hazardous VOCs (phenol, p-cresol, o/m-cresol, benzene, toluene, ethylbenzene, o-xylene, and m/pxylene) that are most likely to be emitted from swine buildings were assessed using Monte Carlo simulation. The purpose of the study was to calculate emission rates and to quantify cancer and hazard risks of the target VOCs. Cancer and hazard risks were calculated for workers A, B, and C, who spent six hours in the gestation, farrowing and nursery barns, respectively, and one hour in the office space every day. Concentrations of the target VOCs did not exceed their recommended exposure limits (RELs). But, concentrations of p cresol and benzene exceeded their preliminary remediation goals (PRGs). The highest emission rates in mg s(-1) were measured from the gestation rooms while the highest emission rates in mg per s per head were measured from the farrowing rooms. Cancer risks of ethylbenzene, benzene and p-cresol were higher than EPA's benchmark of one per million. Hazard risks of benzene, toluene, p-cresol, and o/m cresol were higher than the maximum acceptable risk threshold (10(-4)). Worker B (farrowing) had the highest cumulative cancer (16.6 in one million) and hazard (11 342 in one million) risks. It was followed by workers A (gestation) and C (nursery). Sensitivity analysis showed that inhalation unit risk (IUR) had the highest impact on cancer risk assessment while recommended exposure limit (REL) had the highest impact on hazard risk assessment. PMID- 23738355 TI - Evaluation of a low-cost commercially available extraction device for assessing lead bioaccessibility in contaminated soils. AB - The U.S. EPA's in vitro bioaccessibility (IVBA) method 9200.1-86 defines a validated analytical procedure for the determination of lead bioaccessibility in contaminated soils. The method requires the use of a custom-fabricated extraction device that uses a heated water bath for sample incubation. In an effort to improve ease of use, increase sample throughput, and reduce equipment acquisition and maintenance costs, an alternative low-cost, commercially available extraction device capable of sample incubation via heated air and end-over-end rotation was evaluated. An intra-laboratory study was conducted to compare lead bioaccessibility values derived using the two extraction devices. IVBA values were not statistically different (alpha = 0.05) between the two extraction devices for any of the soils (n = 6) evaluated in this study, with an average difference in mean lead IVBA of 0.8% (s.d. = 0.5%). The commercially available extraction device was able to generate accurate lead IVBA data as compared to the U.S. EPA's expected value for a National Institute of Standards and Technology standard reference material soil. The relative percent differences between high and low IVBA values for each soil, a measure of instrument precision, were also not statistically different (alpha = 0.05) between the two extraction devices. The statistical agreement of lead IVBA values observed using the two extraction devices supports the use of a low-cost, commercially available extraction device as a reliable alternative to a custom-fabricated device as required by EPA method 9200.1-86. PMID- 23738356 TI - A portable analyser for the measurement of ammonium in marine waters. AB - A portable ammonium analyser was developed and used to measure in situ ammonium in the marine environment. The analyser incorporates an improved LED photodiode based fluorescence detector (LPFD). This system is more sensitive and considerably smaller than previous systems and incorporates a pre-filtering subsystem enabling measurements in turbid, sediment-laden waters. Over the typical range for ammonium in marine waters (0-10 mM), the response is linear (r(2) = 0.9930) with a limit of detection (S/N ratio > 3) of 10 nM. The working range for marine waters is 0.05-10 mM. Repeatability is 0.3% (n =10) at an ammonium level of 2 mM. Results from automated operation in 15 min cycles over 16 days had good overall precision (RSD = 3%, n = 660). The system was field tested at three shallow South Florida sites. Diurnal cycles and possibly a tidal influence were expressed in the concentration variability observed. PMID- 23738357 TI - Factors contributing to hypoxia in a highly turbid, macrotidal estuary (the Gironde, France). AB - Dissolved oxygen (DO) is a fundamental parameter of coastal water quality, as it is necessary to aquatic biota, and it provides an indication of organic matter decomposition in waters and their degree of eutrophication. We present here a 7 year time series of DO concentration and ancillary parameters (river discharge, water level, turbidity, temperature, and salinity) from the MAGEST high-frequency monitoring network, at four automated stations in the central and fluvial regions of the macrotidal Gironde Estuary, one of the largest European estuaries. The spatio-temporal variability of DO at different time scales was first related to the migration and position of the maximum turbidity zone in this extremely turbid estuary. Since 2005, the Gironde Estuary has recorded several borderline hypoxic situations (DO close to 2 mg L(-1)) and a 7 day-long hypoxic event (DO < 2 mg L( 1)) in July 2006. Summer hypoxia occurred exclusively in the fluvial, low salinity, and high turbidity sections of the estuary and was significantly more pronounced in front of the large urban area of Bordeaux (715 000 inhabitants). Detailed analysis of the data at the seasonal, neap-spring and semi-diurnal tidal time scales, reveals that hypoxia in this area occurred: (i) in the maximum turbidity zone; (ii) during the spring to neap tide transition; (iii) at highest water temperature; and (iv) at lowest river discharge; there was also evidence of an additional negative impact of sewage treatment plants of Bordeaux city. Enhancement of respiration by turbidity, temperature and inputs of domestic biodegradable organic matter and ammonia, versus renewal of waters and dispersion of reduced pollutants with the river discharge, appeared as the dominant antagonist processes that controlled the occurrence of summer hypoxia. In the context of long-term environmental changes (increase in temperature and population, decrease in summer river discharge), the occurrence of severe hypoxia could not be excluded in the next decades in the upstream reach of the Gironde Estuary. PMID- 23738358 TI - Size distribution effects of cadmium tellurium quantum dots (CdS/CdTe) immunotoxicity on aquatic organisms. AB - The increasing use of products derived from nanotechnology has raised concern about their potential toxicity to aquatic life. This study sought to examine the comparative immunotoxicity of capped cadmium sulphide/cadmium telluride (CdS/CdTe) quantum dots (QDs) and possible impact of particle/aggregate size on two bivalves (Mytilus edulis and Elliptio complanata) and a fish (Oncorhynchus mykiss). The QDs were dispersed in sterile water and fractionated using a series of micro/ultrafiltration membranes of decreasing pore size: 450 nm, 100 nm, 50 nm, 25 nm, 100 kDa (6.8 nm), 30 kDa (4.6 nm), 10 kDa (3.2 nm) and 1 kDa (1.5 nm). The total concentrations of cadmium and tellurium were determined for the filtered material and for that retained on the filters (retentate). The immunotoxicity was determined by measuring cell viability and phagocytosis. Results revealed that nanoparticles retained on the ultrafilters had a higher Cd/Te ratio compared to the permeate fraction (ratio of 5 and 2 respectively) which could indicate that the CdS core was not associated with the permeable fraction of Cd. Our results demonstrate that the toxicity of CdS/CdTe QDs was concentration and size dependent. Large CdS/CdTe QD aggregates (25 nm < size < 100 nm) reduced phagocytosis more than did smaller nanoparticles (<25 nm). Moreover, our results revealed that the different species responded differently to these fractions. Mytilus edulis hemocytes were less sensitive to CdS/CdTe QDs than the Oncorhynchus mykiss macrophage and Elliptio complanata hemocytes. PMID- 23738359 TI - Organochlorine pesticide (OCP) residues in mountain soils from Tajikistan. AB - The concentrations and spatial distribution of organochlorine pesticides (OCPs) in surface soils of different altitudes (570-4656 m) from Tajikistan were determined. OCPs were detected in all samples with concentrations in the range 52.83-247.98 ng g(-1) dry weight (ng g(-1) dw). Aldrins were the most predominant compounds followed by chlordanes, hexachlorocyclohexanes (HCHs) and endosulfans, while dichlorodiphenyltrichloroethanes (DDTs) and methoxychlor were detected at much lower concentrations. Composition analysis indicated that OCPs mainly came from the atmospheric transport of historically used pesticides. OCP residues in the west and northwest parts of Tajikistan were higher than the east and the southeast due to the proximity to the potential sources and anthropogenic activity intensities around. Additionally, correlation analysis between OCPs and altitudes indicated that the more volatile pollutants, such as HCH isomers, seemed to become enriched more easily in regions with higher altitudes relative to the less volatile ones, such as DDTs. PMID- 23738360 TI - The effect of hospital effluent on antimicrobial resistant E. coli within a municipal wastewater system. AB - There is a concern that hospital effluent potentially containing antimicrobial compounds, antimicrobial resistant (AMR) bacteria and genetic determinants of resistance may contribute to the emergence, dissemination and persistence of AMR bacteria in municipal wastewaters. Hence, it is of interest to investigate the effect, if any, hospital effluent has on the percentage of AMR bacteria within wastewater. Water from two wastewater treatment plants (WWTPs) (one receives and treats hospital effluent (WWTPhe) and the second does not (WWTPc)) were examined for E. coli expressing resistance to seven antimicrobials (ampicillin, streptomycin, cefoxitin, cefotaxime, tetracycline, sulphonamide and ciprofloxacin). A two-sample t-test showed that AMR E. coli are present in WWTP influent and effluent, irrespective of receiving hospital effluent, and are being released into the environment (no statistical difference in count between the two WWTPs). The effect of hospital effluent on resistance varies for each AMR bacteria. Excluding tetracycline, sulphonamide and ciprofloxacin, the results suggest that the release of hospital effluent does not significantly affect the frequency with which AMR E. coli are detected in effluent. For some hospital specific antimicrobial agents, such as ciprofloxacin, the release of hospital effluent is associated with an increased proportion of antimicrobial resistance. The results suggest resistance to AMR E. coli may already be well developed in the community, making the effect of hospital effluent on AMR E. coli indistinguishable. However, for hospital specific antimicrobials, there may be a selective effect and hence limiting the release of hospital effluent containing such antimicrobials may impact the proportion of antimicrobial resistance. This research has provided statistical evidence to support necessary mitigation and remediation of antimicrobial residue release and subsequent resistance in the environment. PMID- 23738361 TI - Health risk assessment for vehicle inspection workers exposed to airborne polycyclic aromatic hydrocarbons (PAHs) in their work place. AB - Inhalatory and dermal exposures of on-duty vehicle inspection workers to polycyclic aromatic hydrocarbons (PAHs) in Beijing were investigated from April 18 to May 17, 2011. Exposure levels to particulate PAHs for the vehicle inspection workers at gasoline, bus and diesel lines were found to be 56.07 ng m( 3), 111.72 ng m(-3) and 199.80 ng m(-3), respectively. A probabilistic risk assessment framework was integrated with the toxic equivalence factors (TEFs) and the incremental lifetime cancer risk (ILCR) approaches to quantitatively estimate the exposure risk for vehicle inspection workers of the three work lines. The median values of inhalation risk were estimated to be 3.7 * 10(-7), 5.0 * 10(-7) and 1.37 * 10(-6), respectively, while the median dermal ILCR values were 7.05 * 10(-6), 6.98 * 10(-6) and 1.28 * 10(-5), respectively for gasoline, bus, and diesel inspection workers. Total ILCR was higher than the acceptable risk level of 10(-6), indicating unacceptable potential cancer risk. PMID- 23738362 TI - Characterization and validation of sampling and analytical methods for mycotoxins in workplace air. AB - Mycotoxins are produced by certain plant or foodstuff moulds under growing, transport or storage conditions. They are toxic for humans and animals, some are carcinogenic. Methods to monitor occupational exposure to seven of the most frequently occurring airborne mycotoxins have been characterized and validated. Experimental aerosols have been generated from naturally contaminated particles for sampler evaluation. Air samples were collected on foam pads, using the CIP 10 personal aerosol sampler with its inhalable health-related aerosol fraction selector. The samples were subsequently solvent extracted from the sampling media, cleaned using immunoaffinity (IA) columns and analyzed by liquid chromatography with fluorescence detection. Ochratoxin A (OTA) or fumonisin and aflatoxin derivatives were detected and quantified. The quantification limits were 0.015 ng m(-3) OTA, 1 ng m(-3) fumonisins or 0.5 pg m(-3) aflatoxins, with a minimum dust concentration level of 1 mg m(-3) and a 4800 L air volume sampling. The methods were successfully applied to field measurements, which confirmed that workers could be exposed when handling contaminated materials. It was observed that airborne particles may be more contaminated than the bulk material itself. The validated methods have measuring ranges fully adapted to the concentrations found in the workplace. Their performance meets the general requirements laid down for chemical agent measurement procedures, with an expanded uncertainty less than 50% for most mycotoxins. The analytical uncertainty, comprised between 14 and 24%, was quite satisfactory given the low mycotoxin amounts, when compared to the food benchmarks. The methods are now user-friendly enough to be adopted for personal workplace sampling. They will later allow for mycotoxin occupational risk assessment, as only very few quantitative data have been available till now. PMID- 23738363 TI - Examining the efficiency of muffle furnace-induced alkaline hydrolysis in determining the titanium content of environmental samples containing engineered titanium dioxide particles. AB - A novel muffle furnace (MF)-based potassium hydroxide (KOH) fusion digestion technique was developed and evaluated for different titanium dioxide materials in various solid matrices. Digestion of different environmental samples containing sediments, clay minerals and humic acid with and without TiO(2) particles was first performed utilizing the MF-based KOH fusion technique and its dissolution efficacy was compared to a Bunsen burner (BB)-based KOH fusion method. The three types of TiO(2) particles (anatase, brookite and rutile) were then digested with the KOH fusion techniques and microwave (MW)-based nitric (HNO3)-hydrofluoric (HF) mixed acid digestion methods. Statistical analysis of the results revealed that Ti recoveries were comparable for the KOH fusion methods (BB and MF). For pure TiO(2) particles, the measured Ti recoveries compared to calculated values were 96%, 85% and 87% for anatase, brookite and rutile TiO(2) materials, respectively, by the MF-based fusion technique. These recoveries were consistent and less variable than the BB-based fusion technique recoveries of 104%, 97% and 72% and MW-based HNO3-HF mixed acids digestion recoveries of 80%, 81% and 14%, respectively, for anatase, brookite and rutile. Ti percent recoveries and measurement precision decreased for both the BB and MF methods when TiO(2) was spiked into sediment, clay minerals, and humic acid. This drop in efficacy was counteracted by more thorough homogenization of the spiked mixtures and by increasing the mass of KOH in the MF fusion process from 1.6 g to 10.0 g. The MF based fusion technique is consistently superior in digestion efficiency for all three TiO(2) polymorphs. The MF-based fusion technique required 20 minutes for digestion of 25 samples (based on in-house Lindberg MF capacity) compared to 8 hours for the same number of samples using the BB-based fusion technique. Thus, the MF-based fusion technique can be used to dissolve a large number of samples in a shorter time (e.g., 500 samples per 8 hours) while conserving energy and eliminating health and safety risks from methods involving HF. PMID- 23738364 TI - Photolysis of brominated flame retardants in textiles exposed to natural sunlight. AB - Photolytic transformation profiles of technical hexabromocyclododecane (HBCD) and technical decabromodiphenyl ether (DecaBDE) in flame-retarded textiles exposed to natural sunlight were compared. Textiles that contained approximately 4% HBCDs by weight showed no substantial loss of any of the HBCD diastereomers during the entire exposure period (371 days), indicating that they were resistant to sunlight, that is, that debromination and isomerization of HBCD diastereomers did not occur under the experimental conditions. Exposure of a textile treated with technical DecaBDE resulted in the formation of polybrominated dibenzofurans (PBDFs) as products of photodecomposition of polybrominated diphenyl ethers present in the technical DecaBDE. After 329 days of exposure, the total PBDF concentration reached a maximum of 27 000 ng g(-1), which was approximately 10 times the initial concentration. During the experiment, di- to hexa-BDF congener concentrations increased continuously. Although the concentrations of PBDFs in the textiles were 4-5 orders of magnitude lower than the concentrations of polybrominated diphenyl ethers, it is important to note that PBDFs were formed as a result of sunlight exposure during normal use of products treated with technical DecaBDE. PMID- 23738365 TI - Polycyclic aromatic hydrocarbons in soils from the Tibetan Plateau, China: distribution and influence of environmental factors. AB - Thirty four sampling sites along an elevation transect in the Tibetan Plateau region were chosen. Soil cores were divided into several layers and a total of 175 horizon soil samples were collected from July to September 2011, for determination of polycyclic aromatic hydrocarbons (PAHs). The measured PAHs concentration in surface soils was 56.26 +/- 45.84 ng g(-1), and the low molecular weight PAHs (2-3 rings) predominated, accounting for 48% and 35%. We analyzed the spatial (altitudinal and vertical) distribution of PAHs in soil, and explored the influence of related environmental factors. Total organic carbon (TOC) showed a controlling influence on the distribution of PAHs. PAH concentrations declined with soil depth, and the composition patterns of PAHs along soil depth indicated that the heavy PAHs tended to remain in the upper layers (0-10 cm), while the light fractions were transported downward more easily. PAHs inventories (8.77-57.92 mg m(-2)) for soil cores increased with mean annual precipitation, while the topsoil concentrations decreased with it. This implies that an increase in precipitation could transfer more PAHs from the atmosphere to the soil and further transport PAHs from the topsoil to deeper layers. PMID- 23738366 TI - Decrease of antiandrogenic activity in gray water and domestic wastewater treated by the MBR process. AB - In order to figure out the variation of the androgens/antiandrogens in wastewater treatment, androgenic/antiandrogenic activities were investigated in two membrane bioreactors (MBR) treating gray water and domestic wastewater, respectively, in Beijing city, China. The androgens and antiandrogens were extracted from water and solid samples by a solid phase extraction (SPE) method and the androgenic/antiandrogenic activities were detected with a recombined androgen receptor (AR) yeast assay. The results showed that there were no androgenic induction activities either in water or in solid samples, but all samples exhibited obvious antiandrogenic activities. The antiandrogenic activities in the suspended solids contributed to 27.4% of the total antiandrogenic activities in gray water and 37.7% in domestic wastewater. Although the concentration of flutamide equivalent (FEQ) of the domestic wastewater (3.1 mg L(-1)) was about three times higher than that of the gray water (1.1 mg L-(1)) in the liquid phase, the effluent FEQ of the two processes was comparable, and the concentrations were 53.7 +/- 2.4 MUg L(-1) and 68.9 +/- 6.0 MUg L(-1), respectively. By mass balance analysis, a total of 1825.2 mg FEQ antiandrogens flowed into the gray water and 4914.1 mg flowed into the domestic wastewater treatment process every day. More than 95% of the influent antiandrogens in the liquid phase was removed in both systems. And only 64.5 mg and 69.0 mg FEQ antiandrogens flowed out of gray water and domestic wastewater treatment processes every day. Biodegradation was considered to be the crucial antiandrogen removal mechanism in MBR, which contributed to 98% of the antiandrogen removal in the gray water treatment plant, and 91% in the domestic wastewater treatment plant. PMID- 23738367 TI - A radiological survey and the impact of the elevated concentrations of (210)Pb and (210)Po released from the iron- and steel-making plant ILVA Taranto (Italy) on the environment and the public. AB - A radiological survey on the iron- and steel-making plant ILVA Taranto (Italy) was mainly focused on contamination source-term investigation and exposure impact evaluation of the volatile radionuclides 210Po and 210Pb. The activity concentrations of 210Po and 210Pb in the raw materials, dust particles, surficial soils and atmospheric particulate samples collected in the area of ILVA Taranto were determined. The results showed that the activity concentrations in the raw materials were in the range of 3.46-17.9 Bq kg(-1) for 210Po and 3.50-16.8 Bq kg( 1) for 210Pb, which could create maximum annual inventories of 2.64 * 1011 Bq of 210Po and 2.71 * 1011 Bq of 210Pb if a total quantity of 22 Mt per year raw materials was consumed in the plant. The activity concentrations in dust particles emitted from the chimney of the ILVA Taranto were in the range of 5.91 85.6 kBq kg(-1) for 210Po and 5.44-34.6 kBq kg(-1) for 210Pb, releasing more 210Po than 210Pb. The activity concentrations in surficial soils were in the range of 49.3-140 Bq kg(-1) for 210Po and 51.6-150 Bq kg(-1) for 210Pb, a variation of the activity concentrations being observable with distance. The activity concentrations in atmospheric particulate were in the range of 43.1-564 MUBq m(-3) for 210Po and 618-1099 MUBq m(-3) for 210Pb, and it was observed that the mass specific activity concentrations of 210Po and 210Pb in the atmospheric particulate are one to three orders of magnitude higher than that found in the top soil. After deduction of the background contribution, about 27.2 MUSv per year of the estimated committed effective dose at mean and 49.2 MUSv per year at maximum could be attributed to 210Po and 210Pb emitted from the chimney of the ILVA Taranto and inhaled by the public in the form of atmospheric particulate, of which about 63.5-69.0% was the contribution of 210Pb. No specific interventions should be required, as far as only inhalation of 210Po and 210Pb are concerned. PMID- 23738368 TI - A new approach to quantify the adaptive potential of gene expression variation in gymnosperms. AB - Variation in patterns of gene expression contributes to phenotypic diversity and can ultimately predict adaptive responses. However, in many cases, the consequences of regulatory mutations on patterns of gene expression and ultimately phenotypic differences remain elusive. A standard way to study the genetic architecture of expression variation in model systems has been to map gene expression variation to genetic loci (Fig. 1a). At the same time, in many nonmodel species, especially for long-lived organisms, controlled crosses are not feasible. If we are to expand our understanding of the role of regulatory mutations on phenotypes, we need to develop new methodologies to study species under ecologically relevant conditions. In this issue of Molecular Ecology, Verta et al. (2013) present a new approach to analyse gene expression variation and regulatory networks in gymnosperms (Fig. 1b). They capitalized on the fact that gymnosperm seeds contain an energy storage tissue (the megagametophyte) that is directly derived from a single haploid cell (the megaspore). The authors identified over 800 genes for which expression segregated in this maternally inherited haploid tissue. Based on the observed segregation patterns, these genes (Mendelian Expression Traits) are most probably controlled by biallelic variants at a single locus. Most of these genes also belonged to different regulatory networks, except for one large group of 180 genes under the control of a putative trans-acting factor. In addition, the approach developed here may also help to uncover the effect of rare recessive mutations, which usually remain hidden in a heterozygous state in diploid individuals. The appeal of the work by Verta et al. (2013) to study gene expression variation is in its simplicity, which circumvents several of the hurdles behind traditional expression quantitative trait locus (eQTL) studies, and could potentially be applied to a large number of species. PMID- 23738369 TI - Levodopa-carbidopa treatment and falsely high urinary dopamine levels. PMID- 23738370 TI - Puny males punch above their weight to preserve genetic diversity in a declining Atlantic salmon population. AB - Many salmonid fish populations have anadromous (i.e. migratory) and nonanadromous individuals co-existing in sympatry. The nonanadromous individuals, frequently males, mature at a much smaller size in freshwater without undergoing marine migrations and often successfully fertilize many eggs laid by anadromous females. Because these small males do not recruit to fisheries, they are often not regarded in high esteem by fishers. In this issue of Molecular Ecology, Johnstone et al. (2013) demonstrate that by substantially contributing to reproduction, such males help maintain genetic diversity in a declining population of Atlantic salmon (Salmo salar). Their results show that estimates of effective population size (Ne), obtained by counting the number of anadromous adults returning from sea and correcting for unequal sex ratios, are lower than estimates generated from genetic markers. Many mechanisms are expected to reduce Ne below the adult census population size (N); the opposite pattern of Ne > N observed by Johnstone et al. (2013) is difficult to explain unless the reproductive effort of nonanadromous males is accounted for. The results have important implications for the conservation of small populations and highlight the challenges of relating Ne to N in organisms with complex life histories. PMID- 23738371 TI - Understanding the genetic basis of invasiveness. AB - Invasive species provide excellent study systems to evaluate the ecological and evolutionary processes that contribute to the colonization of novel environments. While the ecological processes that contribute to the successful establishment of invasive plants have been studied in detail, investigation of the evolutionary processes involved in successful invasions has only recently received attention. In particular, studies investigating the genomic and gene expression differences between native and introduced populations of invasive species are just beginning and are required if we are to understand how plants become invasive. In the current issue of Molecular Ecology, Hodgins et al. (2013) tackle this unresolved question, by examining gene expression differences between native and introduced populations of annual ragweed, Ambrosia artemisiifolia. The study identifies a number of potential candidate genes based on gene expression differences that may be responsible for the success of annual ragweed in its introduced range. Furthermore, genes involved in stress response are over-represented in the differentially expressed gene set. Future experiments could use functional studies to test whether changes in gene expression at these candidate genes do in fact underlie changes in growth characteristics and reproductive output observed in this and other invasive species. PMID- 23738373 TI - In response: clarifications regarding ACCME standards. PMID- 23738372 TI - Clarifications regarding ACCME standards. PMID- 23738374 TI - Abstracts of CARS 2013, Computer Assisted Radiology and Surgery. The 27th International Congress and Exhibition. Heidelberg, Germany. June 26-29, 2013. PMID- 23738375 TI - Abstracts of Albany 2013: the 18th Conversation. June 11-18, 2013. Albany, New York, USA. PMID- 23738376 TI - Abstracts of the 2013 In Vitro Biology Meeting. June 15-19, 2013. Providence, Rhode Island, USA. PMID- 23738377 TI - Retraction. Refining siRNA in vivo transfection: silencing SPHK1 reveals its key role in C5a-induced inflammation in vivo. PMID- 23738378 TI - Surface nanobubbles and micropancakes. PMID- 23738379 TI - Training not required to prescribe sustained-release opioids. PMID- 23738380 TI - Problem of homeless cats the focus of first Research Day. PMID- 23738381 TI - RE: Insensitivity of the in vitro cytokinesis-block micronucleus assay with human lymphocytes for the detection of DNA damage present at the start of the cell culture (Mutagenesis, 27, 743-747, 2012). PMID- 23738382 TI - Assessment of pre-digested piggery wastewater treatment operations with surface flow integrated constructed wetland systems. AB - Non-point source pollution such as land-spreading of nitrogen-rich piggery wastewater poses a significant threat to surface waters. The aim was to examine the treatment of anaerobically digested piggery wastewater using four different meso-scale integrated constructed wetland (ICW) systems planted with Glyceria maxima. Four replicates were used for each system to assess differences due to nutrient loading, hydraulic loading and effluent recycling. All systems were effective in removing total organic nitrogen, ammonia-nitrogen, nitrate-nitrogen and molybdate reactive phosphorus. However, ammonia-nitrogen removal was the greatest challenge for high flow rates (>100 m3/ha/d). Nitrification was higher in summer than winter. Findings show for the first time that effluent recycling within ICW was beneficial to lower ammonia-nitrogen but was associated with higher operational costs. The cost-benefit ratio based on ammonia-nitrogen removal for standard, recycling, high nutrients and high flow rate treatments was 1.08:1.04:1.06:1.00. It follows that a high flow rate was only marginally more cost-effective. PMID- 23738384 TI - Complicated margins. Surgical complications bring in more money: study. PMID- 23738386 TI - A SAGE decision. PMID- 23738385 TI - Albert Szent-Gyorgyi (1893-1986): the scientist who discovered vitamin C. AB - Albert Szent-Gyorgyi, a Hungarian biochemist, discovered vitamin C and rutin (vitamin P). The role of these vitamins in the body and their application to dermatology is vast. For the discovery of vitamin C and the description of oxidation, Albert Szent-Gyorgyi received a Nobel Prize in medicine in 1937. He discovered the role of adenosine triphosphate, actin-myosin, and many phases of the Krebs cycle, and also initiated studies on the influence of free radicals in the formation of tumors. Between 1918 and 1946, he worked in many European research centers and between 1947 and 1986, in the United States. His achievements were made possible due to his perseverance, which allowed him to overcome many maelstroms that plagued his scientific career. PMID- 23738387 TI - Sexual Misconduct: hospital could be liable for failing to supervise medical staff members. Doe v. Borromeo, Nos. 305162, 305163 (Ct. App. Mich.September 20, 2012). PMID- 23738388 TI - Disclosure: hospital avoids having disclosure used against it. Ronan v. Sanford Health, No. 25813 (S.D. February 1, 2012). PMID- 23738389 TI - Medical Malpractice: duty of care may arise from informal contact. Rindsberg v. Neacsu, No. A12A0359 (Ct. App. Ga. July 12, 2012). PMID- 23738390 TI - Mental Health: therapist's sexual relationship with patient may be malpractice. Dupree v. Giugliano, 2011 NY Slip Op. 06471, 87 A. D.3d 975 (NY App. Div. 2011). PMID- 23738391 TI - Rapid synthesis of isoprenoid diphosphates and their isolation in one step using either thin layer or flash chromatography. AB - A rapid procedure for the preparation of short-chain (C s-C.) isoprenoid diphosphates is described . It is based on the method of Cornforth and Popjak [Methods Enzymol., 15 (1969) 359-390] which utilizes bis-triethylammonium phosphate in trichioroacetonitriie as the phosphorylating reagent . The reaction takes place in 15 min, and product isolation, previously requiring several steps, is done in a single step using either preparative thin-layer chromatography or flash chromatography on silica . From a single TLC plate, up to 50 MU mol of pure farnesyl diphosphate (i .e., ca. 20 mg) can be isolated, while up to 1200 MU mol can be isolated using a standard flash chromatography column. PMID- 23738392 TI - Community Transformation Grants. PMID- 23738393 TI - Short-term effects of summer temperatures on mortality in Portugal: a time-series analysis. AB - Heat stress is a current public health concern during the warm months in many urban areas. Climate change and increasing urbanization are expected to worsen this concern, with some locations being more vulnerable than others. The aim of this study was to determine the short-term effect of heat on mortality in the two most populated cities in Portugal: Lisbon and Oporto. Each city was assessed for specific heat stress threshold above which heat-related mortality becomes significant. A Poisson generalized estimating equations (GEE) model was used to estimate the impact of maximum apparent temperature (ATmax) and maximum temperature (Tmax) on daily mortality, in the summer season. Data show ATmax thresholds of 30.4 degrees C for Lisbon and 26.3 degrees C for Oporto, and Tmax thresholds of 29.3 degrees C and 25.0 degrees C, respectively. For every 1 degrees C elevation in ATmax above the city-specific threshold, all-cause mortality rate rose by 7.13% (95% CI: 5.9; 8.4) in Lisbon and 4.31% (95% CI: 3.2; 5.4) in Oporto. The Tmax threshold increases were 5.6% (95% CI: 4.6; 6.6) in Lisbon and 3% (95% CI: 2.0, 3.9) in Oporto. In both cities, stronger associations were found for respiratory diseases and the elderly group was the most vulnerable. This study confirmed that elevated temperatures have a considerable impact on daily mortality frequency in the two most urbanized areas in Portugal. Our results also provide useful data for policymakers to better prepare local actions to mitigate and reduce the health risks associated with high temperatures. PMID- 23738395 TI - The end of insulin? A newly discovered hormone could free diabetics from injections. PMID- 23738394 TI - Impact of road traffic emissions on ambient air quality in an industrialized area. AB - Several epidemiological studies showed a correlation between airborne particulate matter(PM) and the incidence of several diseases in exposed populations. Consequently, the European Commission reinforced the need and obligation of member-states to monitor exposure levels of PM and adopt measures to reduce this exposure. However, in order to plan appropriate actions, it is necessary to understand the main sources of air pollution and their relative contributions to the formation of the ambient aerosol. The aim of this study was to develop a methodology to assess the contribution of vehicles to the atmospheric aerosol,which may constitute a useful tool to assess the effectiveness of planned mitigation actions.This methodology is based on three main steps: (1) estimation of traffic emissions provided from the vehicles exhaust and resuspension; (2) use of the dispersion model TAPM ("The Air Pollution Model") to estimate the contribution of traffic for the atmospheric aerosol; and(3) use of geographic information system (GIS) tools to map the PM10 concentrations provided from traffic in the surroundings of a target area. The methodology was applied to an industrial area, and results showed that the highest contribution of traffic for the PM10 concentrations resulted from dust resuspension and that heavy vehicles were the type that most contributed to the PM10 concentration. PMID- 23738396 TI - 10 question. Harvard professor and global-health activist Paul Farmer on helping Haiti, rethinking aid--and bathroom signs. Interview by Belinda Luscombe. PMID- 23738397 TI - Medicine chest. PMID- 23738398 TI - Breast cancer awareness: why do we need it? PMID- 23738399 TI - A clinical and pathological study of triple negative breast carcinoma: experience of a tertiary care centre in eastern India. AB - Breast cancers which do not express oestrogen, progesterone, or HER-2 neu receptors are known as triple negative breast carcinomas. In western literature they have been found to be extremely aggressive with a poor prognosis. However there is scarcity of data regarding this variety of breast cancer in India.To examine the clinical and pathological character of triple negative breast carcinomas and to compare their characteristics with other variants of breast carcinomas which presented to Medical College, Kolkata, a randomised sample of 72 patients were included with breast cancer attending the department of surgery from January 2008 to June 2008.The clinical and histopathological data along with ER/PR status and HER-2 neu expression examined by immunohistochemical methods were recorded.Twenty patients (27.78%) were found to be triple negative.The mean age at presentation was 35.4 +/- 1.95 years with 17 (85%) out of 20 being premenopausal. At presentation, mean tumour size was 4.7 +/- 0.21 cm. Though 15 patients (75%) presented with stage III disease and 16 patients (80%) had grade III histology, 14 (70%) were node negative and 20 (80%) did not have involvement of nipple areola complex and 19(95%) did not have multicentric disease. Triple negative breast cancer is prevalent in eastern India.They are locally aggressive, common in premenopausal women, but strangely do not tend to present with lymph node involvement or involvement of nipple areola complex. Therefore a more conservative approach might have a role in these seemingly aggressive tumours. PMID- 23738400 TI - A metric analysis of Mumbai region (India) crania. AB - The human skull has been studied both metrically and non- metrically previously. These studies have thrown light on the functional and morphological aspect of the skull. Cranial index and other cranial indices are useful in differentiation of racial and gender difference. As studies on sexual dimorphism of cranium were very few we have taken this study to find out the differences in cranial index, vertical index and transverse vertical index of male and female crania at Mumbai region. This study was carried out on 210 (150 males and 60 females) dry human skulls available in department of anatomy of four Medical Colleges in Mumbai. The mean and SD of cranial index were 74.23 +/- 4.06; for males: 73.19 +/- 3.76, and for females: 76.84 +/- 3.63. The mean and SD of transverse vertical index were 100.84 +/- 6.31; for males: 102.19 +/- 6.15, and for females: 97.46 +/- 5.41. The difference between cranial index (p = 0.000000) and transverse vertical index (p = 0.000019) of male and female skulls were significant. The results of the present study show that majority of male skulls of Mumbai region belong to dolicocephalic group and majority of female skulls to mesocephalic.The result of present study shows that majority of male skulls of Mumbai region belong to acrocranial group (based on transverse vertical index). This data can be useful for forensic medicine experts, plastic surgeons, anatomist and oral surgeons for clinical and research purpose. PMID- 23738401 TI - Pregnancy outcome in pre-operative danazol treatment followed by laparoscopic correction in infertility associated with endometriosis. AB - Probably, more has been written and less has been agreed upon, regarding the pathogenesis of the enigmatic disorder--endometriosis, which is the leading cause of disability in women of reproductive age group, resulting in infertility and pelvic pain. It is an accepted fact that the medical treatment of endometriosis does not help in infertility management, except certain situations like pain, limiting the attempt of pregnancy, or endometriosis presenting with cornual block, due to endosalpingiosis. The usual treatment of infertility being either surgical correction, or assisted reproductive technology procedures. In our patient population, the acceptance of In-vitro fertilisation or embryo transfer is much less, because of its high cost and social taboo. In this series, the improved pregnancy outcome is observed with medical treatment of endometriosis with danazol before and after the laparoscopic correction of the tubo-ovarian relation due to endometriosis or in certain cases of minimal to mild endometriosis, not requiring correction. Out of 722 suspected cases of endometriosis, 576 cases were subjected to prelaparoscopic treatment with danazol, and the result was compared with 424 cases of only laparoscopic treatment, and 216 cases of postlaparoscopic danazol treatment, during the years 2004 to 2008. A total of 1216 cases were included in the study. The initiation of medical treatment in the pre-operative period gives better pregnancy outcome, as compared to only surgical or postsurgical medical treatment. The experience proves that the adjuvant medical treatment with danazol, initiated before laparoscopy in suspected endometriosis cases is useful treatment procedure, to increase the pregnancy rate. PMID- 23738402 TI - Effect of health education on compliance in asthma. AB - Non-compliance is a major problem in the treatment of any chronic disease. Asthma is one such chronic disease where non-compliance is a major problem. Several factors for non-compliance like cost of the drugs and relief of symptoms on taking medications for a short time are common to all chronic diseases but in asthma, inhalational therapy especially in elderly because of senile changes, economic factors and comorbidities is an added factor. Health education can improve the compliance. So a study was undertaken to observe the causes of non compliance in asthmatics, to compare these causes in elderly and young asthmatics and to see the effect of health education on non-compliance in asthmatics. One hundred patients of bronchial asthma, group A consisting 50 patients > or = 65 years old and group B 50 patients < 40 years attending tuberculosis and chest diseases hospital, Patiala were studied. Initial compliance and reasons for non compliance, initial usage of inhalational devices and their techniques of inhalation were studied. Patients were educated on asthma and inhalational techniques.These patients were followed up at 15th day, 1st, 2nd and 3rd months for changes in compliance and lung functions. At the initial stage, non compliance was observed in 30 patients (60%) amongst elderly and only 15 patients (30%) amongst the young. Cause for non-compliance was cost in 6, memory in 11, both cost and memory in 7 and relief of symptoms in 6 in elderly and 4, 0, 0 and 11 in young respectively. Only 23 patients (40%) amongst the elderly and 33 patients (66%) amongst the young were put on inhalational therapy. There were statistically significant differences between elderly and young with respect to all the above factors. Out of these 23 elderly, only 7 (30.4%) were confident of the technique of inhalation and demonstrated it correctly.The health education resulted in significant improvement in compliance in both the groups, but more so in the young. The compliance for medications improved from a baseline of 40% to 88% amongst elderly and from 70% to 96% amongst young. There was an improvement in the confidence and technique of inhalation from 44% to 86% amongst elderly and from 64% to 98% amongst young at follow-ups. Mean PEFR improved statistically significantly from 75.25% to 81.13% in elderly and 84.38% to 89.74% in young asthmatics. However, during the follow-up at 2nd month, it was realised that 7 patients amongst elderly and 1 amongst young could not be sustained on inhalational medications because of the cost factor, therefore they were put on only oral medications which were supplied free of cost to them and thus at followup at 3rd month, these patients were not on inhalational medications any more. PMID- 23738403 TI - Attitude towards psychiatry among medical students. AB - The proportion of medical graduates opting for psychiatry in career has been observed to be distinctly less compared to those choosing other specialties. The study was undertaken to find out the attitudes of newly entrant medical students towards psychiatry in comparison to other specialties. Sixty-two students of first year MBBS were administered a questionnaire to assess their attitudes towards various specialties. Only 1 student (1.5%) opted for psychiatry as a career choice, another 2 students (3%) considered it as a strong possibility, 71.5% negated psychiatry as a career choice. Students rated psychiatry significantly lower than other specialties in regards to financially rewarding, enjoyable and satisfying work, intellectually challenging, scientific basis, prestige among others, lifestyle. Psychiatry was also rated as poor on prospects of having a bright and interesting future. The present study suggests that new entrants in medical college harbour a negative attitude towards psychiatry, which has not changed over the last three to four decades. A conscious effort in trying to make psychiatry an active and interesting component of medical education and an improved portrayal of this field in society thereby reducing stigma associated with it would be of immense importance in generating interest in this field among newly entrant medical students. PMID- 23738404 TI - Lupus glomerulonephritis: a clinicopathological correlation of 93 patients of systemic lupus erythematosus for a follow-up period of three years. AB - A prospective study of 93 patients (female 86, male 7) of systemic lupus erythematosus (SLE) attending NRS Medical College and Hospital was done with special reference to their renal affection. Clinical features were noted and various laboratory parameters including auto-antibodies (ANF, anti ds DNA) were performed. Histopathological study of renal biopsy was carried out both at the time of presentation and subsequently 1 and 3 years later and lupus glomerulonephritis (LN) was categorised according to World Health Organisation (WHO) classification. Among the cases, 43 (46.23%) had some form of renal involvement at presentation. Additional 9 patients (9.68%) developed renal affection during 1 year of follow-up and after 3 years another 11 patients (11.83%) developed renal affection (total 63 cases, 67.74%). Histologically commonest pattern in renal biopsy was WHO class IV (21 cases, out of 63; 33.33%) followed by class III (20 cases; 31.75%). Rebiopsy was done in 33 cases of LN and 19 cases (30.16%) showed transformation from one biopsy class to another during the study period.Thus renal involvement seen in cases of SLE had a whole spectrum of histological pattern.The outcome of renal involvement is unpredictable so also is their tendency to transform from one biopsy class to another, usually from indolent class to the more virulent ones. There is dissociation between clinical finding and histologic severity. Hence renal biopsy should be done in all cases of SLE both initially and during follow-up, regardless of their individual clinical presentation. PMID- 23738405 TI - A sociodemographic study of multidrug resistant tuberculosis cases from DOTS clinics of Kolkata. AB - This cross-sectional, observational study was undertaken to identify rifampicin and INH resistant mycobacteria in the sputum samples of category II treatment failure tuberculosis patients from three 'DOTS' clinics of Kolkata (Ward No 15, 33, 79 of Kolkata Municipal Corporation). Conventional method of culture in solid and liquid media followed by sensitivity testing to rifampicin and INH were done. Age, sex, economic status, nutrition, history of contact, living condition, etc, were taken into consideration. Out of 66 category II treatment failure tuberculosis cases from 3 DOTS clinics, 45 (68.2%) were found to be multidrug resistant (MDR). Among them, 68.9% were male patients and 55.6% were in the economically productive age group. Most of them (73.3%) were malnourished (BMI < 18.5); 62.2% of patients belonged to 'below poverty line' (BPL) category and 82.2% patients lived in overcrowded room. Majority of them (82.3%) either had past history of tuberculosis or history of contact or both.This study also shows that apart from the biological reasons of drug resistance, the sociodemographic and economic factors are no less important for the spread of drug resistant tuberculosis. PMID- 23738406 TI - A study of cutaneous manifestations in HIV infected persons. AB - Skin is one of the major target organs during all stages of HIV. The present study is conducted to know the dermatological manifestations among 181 HIV positive patients over a period of 17 months ie, from 01-03-2006 to 31-08-2007 at Mandya Institute of Medical Sciences, Mandya. Of these 181 patients, skin diseases were seen in 82 patients (45.3%), 41 patients had only one dermatological disease, 25 had two, 10 had three and 6 patients had more than four diseases. It was observed that a total of 45.3% patients among the study group developed mucocutaneous manifestations. Therefore early recognition of mucocutaneous lesions will help in early diagnosis and better management of HIV/AIDS patients. PMID- 23738407 TI - Tuberculosis--a notifiable disease. AB - In a landmark development, the Ministry of Health and Family Welfare, Government of India, has taken important steps to establish the compulsory notification of tuberculosis in the country. A Government Order to this effect was issued on 7 May 2012. In addition to this IMA passed a resolution on TB notification in CWC on 22nd April 2012 at Mumbai: "In conformity with the requirements of ISTC, Indian Medical Association (IMA) desires that Notification of TB patient to the National Programme be made mandatory. IMA also recommends to the medical practitioner to follow the ISTC guidelines in diagnosis and management of TB care". Notification of TB will facilitate early diagnosis and treatment, prevention of MDR and XDR, reduce TB deaths, better quality diagnostic and treatment services for the TB patients. RNTCP will realistically estimateTB burden, plan resources and control measures to commensurate with the actual burden of disease. PMID- 23738408 TI - Evolution of keratoplasty: from darkness to light. AB - The story of the evolution of corneal grafting reads like a modem day epic: Complete with a cast of larger than life heroes, brilliant and heroic feats, inspired by the mundane. The history is also peppered with dismal, heart rending failures, foolhardy ventures, and the ultimate triumph of the indomitable human spirit over all odds. This review aims to highlight the significant milestones in the rich history of corneal transplantation, and to pay tribute to the many inspired and dedicated pioneers in this field for their perseverance and superior wisdom. It is also a salute and memorial to the patients who reposed their trust in the corneal surgeons, subjecting themselves to the trauma of surgery, often with less than optimal results. It was their collective, relentless toil and dynamic vision which has resulted in the state of the art surgical techniques which are the basis of modern day keratoplasty. PMID- 23738409 TI - Smoking and its implications in anaesthesia. AB - Even though there is a general awareness about smoking and its hazards, the problems associated with this unhealthy habit on a patient coming for a surgical procedure which needs anaesthesia is not that widely discussed. This article tries to highlight the importance of cessation of smoking prior to anaesthesia and its effects on various organ systems. Smoking whether active or passive is a well known risk factor for the general health. This in turn has a bad impact on the safety of anaesthesia. There are more than 4000 chemicals in cigarette smoke, including 43 known cancer causing compounds and 400 other toxins, some of which are harmful to the smoker. Some constituents cause cardiovascular problems, increase the blood pressure, heart rate and the systemic vascular resistance. Some cause respiratory problems, Interfering with oxygen uptake, transport and delivery. PMID- 23738410 TI - Xanthogranulomatous pyelonephritis in a male child--a case report with a brief review of literature. AB - Xanthogranulomatous pyelonephritis is a rare type of renal infection characterised by granulomatous inflammation with giant cells and foamy histiocytes.The peak incidence is in the sixth to seventh decade with a female to male ratio of 2:1. It is rare in children. A case of xanthogranulomatous pyelonephritis in a 11-year-old male child who presented with a history of high grade fever and chills for 15 days, right flank pain and progressive pyuria for two months is reported. He had a prior history of surgery for vesical calculus and anterior urethral calculus for which he underwent open cystolithotomy and urethrolithotomy four years back. Although Gram-negative bacilli were isolated from thick pus aspirated from the right renal pelvis under ultrasound guidance, urine and blood culture were sterile. Following a renal biopsy diagnosed as chronic pyelonephritis the patient underwent subscapsular right. nephrectomy. PMID- 23738411 TI - Primary cold agglutinin disease: a case report. AB - Chronic cold agglutinin disease is a subgroup of auto-immune haemolytic anaemia. Primary cold agglutinin disease has traditionally been defined by the absence of any underlying or associated disease. It usually affects elderly. The term cold refers to the fact that the auto-antibody involved reacts with red cells poorly or not at all at 37 degrees C, whereas it reacts strongly at lower temperature. Here a case of severe pallor, jaundice and red colour urine in winter season for last 10 years diagnosed as a case of primary cold agglutinin disease is reported.The patient was managed conservatively. PMID- 23738412 TI - Bactibilia due to enterococcus species in a case of periampullary carcinoma. AB - Biliary obstruction due to pancreaticobiliary malignancy is often accompanied by bactibilia and cholangitis; which are associated with postoperative septic complications and may adversely affect the clinical course. The enterococcus species is most responsible for postoperative complications in patients with malignant biliary obstruction. Here a case of bactibilia in a 60-year-old male patient, admitted with peri-ampullary carcinoma is reported. The bile sent for Gram-stain showed the presence of pus cells and Gram-positive cocci in pairs and the bacteriological culture revealed the growth of Enterococcus faecium. The patient developed fever with chills on the second postoperative day. The blood cultures of the patient showed growth of Enterococcus faecium for which he was given vancomycin. The patient went on to develop a surgical site infection, the wound swab of which revealed the growth of klebsiella species. The patient was treated for the wound infection and was later on discharged after three weeks of hospital stay. The patient was doing well during follow-up with the subsidence of the jaundice and Iiver enzymes. PMID- 23738413 TI - Anaesthetic management of severe hypertrophic obstructive cardiomyopathy with bronchial asthma for emergency caesarean section. AB - A 39-year-old primi and a known case of hypertrophic obstructive cardiomyopathy presented for emergency lower segment caesarean section. She was also an asthmatic with a recent exacerbation. She underwent uneventful lower segment caesarean section under general anaesthesia with lumbar epidural analgesia for postoperative pain relief. Anaesthetic agents and techniques were selected to suit the haemodynamic profile of severe hypertrophic obstructive cardiomyopathy in pregnancy. The case has been reported because of successful outcome in an emergency scenario with such high intraventricular gradients and omissions in the case so that it will be of benefit to readers who may happen to land up in similar situations. PMID- 23738414 TI - Congenital distichiasis treated by a time-based cryosurgical technique--a case report. AB - Congenital distichiasis is a rare eyelid anomaly usually running in a family with some systemic disorders. Isolated congenital distichiasis is very rare. A very rare case of sporadic congenital distichiasis with symmetrical four-lid involvement is reported here. Detailed ophthalmic and systemic examinations failed to reveal any other abnormality. Various modalities of surgical techniques are tried to treat this difficult condition. It was treated by eyelid splitting and double freeze-thaw cryotherapy with anterior lamellar recession but no thermocouple was used. This simple modified technique, ensured excellent functional and cosmetic result with no recurrence in a one year follow-up. PMID- 23738415 TI - Coinfection with dengue and chikungunya--a case report. AB - Dengue fever outbreaks are reported from India since last 10 years. Since 2005, chikungunya is also causing massive outbreaks in India and other parts of Asia. Both viruses are transmitted by aedes genus and both viruses can re-emerge in many regions due to climatic changes. The clinical presentation of both arthropod borne diseases are similar. Here a concomitant infection of chikungunya and dengue is reported in an 8-year-old child. PMID- 23738416 TI - First branchial arch syndrome with central core myopathy presenting with bilateral congenital ptosis. PMID- 23738417 TI - JIMA, August 2012 issue. PMID- 23738418 TI - An outbreak of dengue fever in northern India. PMID- 23738419 TI - ACA sales push begins. Administration launches outreach efforts to educate public on reform. PMID- 23738420 TI - CEO jackpot. Industry executives continue to see big payouts despite spending declines and cost-cutting. AB - Leaders of pharmaceutical companies were among the highest-paid healthcare industry executives in 2012. In that sector, executive compensation packages can be weighted with equity that bring large payouts when the company does well. Dr. George Yancopoulos of Regeneron, left, eamed a salary of $850,000 and a $2 million bonus last year, but came away with benefits totaling $81.6 million with the addition of stock and option awards. PMID- 23738421 TI - Growing scrutiny. Variance in hospital charges raises questions. PMID- 23738422 TI - Psychiatric evolution. DSM-5 changes draw mixed reactions. PMID- 23738423 TI - Pushing for payment. Doctors group aims to get payers to cover lung cancer screenings. PMID- 23738424 TI - Grading grievances. Leapfrog's safety-score program still divisive. PMID- 23738425 TI - At odds over privacy. Rx industry pushes back against refill reminder rule. PMID- 23738426 TI - 'High-stakes' decision. Tuomey's adverse verdict may have lingering effects. PMID- 23738427 TI - 'He was killing throughout'. Author pieces together case of serial-killer nurse. Interview by Joe Carlson. PMID- 23738428 TI - The value in price transparency. It's time for hospitals to look inward for reasons behind cost disparity. PMID- 23738429 TI - Geographic disparity. Excluding some of the poorest from health reform shouldn't be an option. PMID- 23738430 TI - Better care at lower costs. Panelists discuss the challenges of building a broader continuum of care. PMID- 23738431 TI - A new sensory system. Next generations of wireless monitoring technologies--some still years off--promise to transform healthcare. PMID- 23738432 TI - Peer pressures. Use of CEO compensation comparisons draws heightened scrutiny. PMID- 23738433 TI - By the numbers. Top paid execs at publicly traded healthcare industry companies. Ranked by total compensation for 2012 as reported to the U.S. Securities and Exchange Commission. PMID- 23738434 TI - Optical trapping of nanoparticles by ultrashort laser pulses. AB - Optical trapping with continuous-wave lasers has been a fascinating field in the optical manipulation. It has become a powerful tool for manipulating micrometer sized objects, and has been widely applied in physics, chemistry, biology, material, and colloidal science. Replacing the continuous-wave- with pulsed-mode laser in optical trapping has already revealed some novel phenomena, including the stable trap, modifiable trapping positions, and controllable directional optical ejections of particles in nanometer scales. Due to two distinctive features; impulsive peak powers and relaxation time between consecutive pulses, the optical trapping with the laser pulses has been demonstrated to have some advantages over conventional continuous-wave lasers, particularly when the particles are within Rayleigh approximation. This would open unprecedented opportunities in both fundamental science and application. This Review summarizes recent advances in the optical trapping with laser pulses and discusses the electromagnetic formulations and physical interpretations of the new phenomena. Its aim is rather to show how beautiful and promising this field will be, and to encourage the in-depth study of this field. PMID- 23738435 TI - The treatment of Wilson's disease, a rare genetic disorder of copper metabolism. AB - Wilson's disease is a rare autosomal recessive disease characterised by the deposition of copper in the brain, liver; cornea, and other organs. The overload of copper inevitably leads to progressive liver and neurological dysfunction. Copper overload in patients with Wilson's disease is caused by impairment to the biliary route for excretion of dietary copper A combination of neurological, psychiatric and hepatic symptoms can make the diagnosis of Wilson's disease challenging. Most symptoms appear in the second and third decades of life. The disease affects between one in 30,000 and one in 100,000 individuals, and is fatal if left untreated. Five drugs are currently available to treat Wilson's disease: British Anti-Lewisite; D-penicillamine; trientine; zinc sulfate or acetate; and ammonium tetrathiomolybdate. Each drug can reduce copper levels and/or transform copper into a metabolically inert and unavailable form in the patient. The discovery and introduction of these five drugs owes more to the inspiration of a few dedicated physicians and agricultural scientists than to the resources of the pharmaceutical industry. PMID- 23738436 TI - Prediction of protein contacts from correlated sequence substitutions. AB - Recent work has led to a substantial improvement in the accuracy of predictions of contacts between amino acids using evolutionary information derived from multiple sequence alignments. Where large numbers of diverse sequence relatives are available and can be aligned to the sequence of a protein of unknown structure, it is now possible to generate high-resolution models without recourse to the structure of a template. In this review, we describe these exciting new techniques and critically assess the state of the art in contact prediction in light of them. We discuss areas for immediate research and development as well as potential future developments. PMID- 23738437 TI - Antisense RNA regulation and application in the development of novel antibiotics to combat multidrug resistant bacteria. AB - Despite the availability of antibiotics and vaccines, infectious diseases remain one of most dangerous threats to humans and animals. The overuse and misuse of antibacterial agents have led to the emergence of multidrug resistant bacterial pathogens. Bacterial cells are often resilient enough to survive in even the most extreme environments. To do so, the organisms have evolved different mechanisms, including a variety of two-component signal transduction systems, which allow the bacteria to sense the surrounding environment and regulate gene expression in order to adapt and respond to environmental stimuli. In addition, some bacteria evolve resistance to antibacterial agents while many bacterial cells are able to acquire resistance genes from other bacterial species to enable them to survive in the presence of toxic antimicrobial agents. The crisis of antimicrobial resistance is an unremitting menace to human health and a burden on public health. The rapid increase in antimicrobial resistant organisms and limited options for development of new classes of antibiotics heighten the urgent need to develop novel potent antibacterial therapeutics in order to combat multidrug resistant infections. In this review, we introduce the regulatory mechanisms of antisense RNA and significant applications of regulated antisense RNA interference technology in early drug discovery. This includes the identification and evaluation of drug targets in vitro and in vivo, the determination of mode of action for antibiotics and new antibacterial agents, as well as the development of peptide-nucleic acid conjugates as novel antibacterials. PMID- 23738438 TI - Finding research information on the web: how to make the most of Google and other free search tools. AB - The Internet and the World Wide Web has had a major impact on the accessibility of research information. The move towards open access and development of institutional repositories has resulted in increasing amounts of information being made available free of charge. Many of these resources are not included in conventional subscription databases and Google is not always the best way to ensure that one is picking up all relevant material on a topic. This article will look at how Google's search engine works, how to use Google more effectively for identifying research information, alternatives to Google and will review some of the specialist tools that have evolved to cope with the diverse forms of information that now exist in electronic form. PMID- 23738439 TI - Utilisation of biochar and superabsorbent polymers for soil amendment. AB - The application of superabsorbent polymers (SAPs) and/or biochars to stressed lands offer solutions to several critical ecological, energy and economic challenges posed by degraded lands due to human activities. These substances are like, 'artificial humus' as they are hydrophilic and contain carboxylic groups (SAPs) which enable them to bind cations and water and sequester carbon from air to reverse global warming (biochars). Several research studies using these substances point to their ability to increase the plant-available water in the soil which enables the plants to survive longer with water shortage, increase soil fertility and agricultural yields, improve soil structure, aeration and water penetration, reduce use of synthetic fertilisers and pesticides, reduce nitrous oxide and methane emission from soil, reduce nitrate and farm chemicals leaching into watersheds, convert green and brown wastes into valuable resources, and reduce the evapotranspiration rate of the plants. SAPs and biochars induce a significantly higher growth rate in plants; they bind heavy metals and mitigate their action on plants as well as mitigate the effects of salinity. This paper reviews what is known about these claims and considers the wider environmental implications of the adoption of these processess. The intention is not just to summarise the current knowledge but also to identify gaps that require further research. PMID- 23738440 TI - Large Hadron Collider (LHC). PMID- 23738441 TI - Anti-melanogenesis constituents from the seaweed Dictyota coriacea. AB - This study was conducted to identify the anti-melanogenesis constituents from a seaweed Dictyota coriacea (Holmes). Three known compounds, viz. 1,9 dihydroxycrenulide (1), epiloliolide (2) and D-mannitol (3), were isolated from the ethanol extract. The melanin synthesis inhibition activities were evaluated using B16F10 melanoma cells for the isolates. Compared with the positive control, arbutin, compounds 1 and 2 exhibited more potency, showing 27.8 and 22.6% inhibition activities at a substrate concentration of 30 microg/mL. Our studies also indicate that these compounds are not cytotoxic. Hence, they might prove to be useful therapeutic agents for treating hyperpigmentation and effective components of whitening cosmetics. PMID- 23738442 TI - Methyl carnosate, an antibacterial diterpene isolated from Salvia officinalis leaves. AB - Ethanolic extracts of Salvia officinalis leaves demonstrated antibacterial activity against Bacillus cereus. Fractionation of the extracts led to the isolation of the most active antibacterial compound, which, from spectroscopic and LC-MS evidence, was proved to be the diterpene, methyl carnosate. PMID- 23738443 TI - Cytotoxicity of meroterpenoids from Sargassum siliquastrum against human cancer cells. AB - The cytotoxicity of the brown alga Sargassum siliquastrum on human cancer cells (AGS, HT-29, HT-1080, and MCF-7) was investigated. Bioassay-guided fractionation of the crude extracts showed that the 85% aq. methanol (MeOH) fraction was the most toxic. Seven known meroterpenoids (1-7) were isolated from this cytotoxic fraction. Each compound was evaluated for its cytotoxic effect on human cancer cells. Compounds 1, 2, and 4 showed strong cytotoxicity against AGS, HT-29, and HT-1080 cell lines, with IC50 values ranging from 0.5 to 5.7 microg/mL. PMID- 23738444 TI - Isolation of methyl 27-caffeoyloxyoleanolate--a new oleanane Triterpenoid from the roots of Hibiscus vitifolius. AB - A new oleanane triterpenoid, methyl 27-caffeoyloxyoleanolate (2), together with eight known compounds viz. oleanolic acid, kaempferol, quercetin, beta-sitosterol 3-O-beta-D-glucopyranoside, kaempferol-3-O-alpha-D-rhamnopyranoside, gossypin, quercetin-3-O-beta-D-glucopyranoside and mangiferin were isolated from the ethanol extract of roots of Hibiscus vitifolius Linn. The structure of the new compound 2 was elucidated from spectroscopic, ESI-MS and physical data. The eight known compounds were identified by comparison of their physical and spectroscopic data with those reported in the literature. PMID- 23738445 TI - Synthesis and cytotoxic activity of new betulin and betulinic acid esters with conjugated linoleic acid (CLA). AB - The synthesis of new ester derivatives of betulin (3a-c) and betulinic acid (4) with conjugated linoleic acid isomers (CLA; in a mixture of 43.4% 9c, 11t; 49.5% 10t, 12c; 7.1% other isomers) is presented. Esterification was carried out with N,N'-dicyclohexylcarbodiimide (DCC) as the coupling agent in the presence of 4 dimethylamino-pyridine (DMAP) in dichloromethane (or pyridine). The in vitro cytotoxic effect of betulin (1), betulinic acid (2), a mixture of CLA isomers and their derivatives (3a-c, 4) was examined using the MTT assay against four cancer cell lines (P388, CEM/C2, CCRF/CEM and HL-60) and the SRB assay on the HT-29 cell line. Ester 4 was the most active among the esters synthesized against the CEM/C2 cell line with an ID50 value 16.9 +/- 6.5 microg/mL. Betulin (1), betulinic acid (2) and CLA were the most active agents against the cancer cell lines studied. PMID- 23738446 TI - Analysis of pyrrolizidine alkaloids and evaluation of some biological activities of Algerian Senecio delphinifolius (Asteraceae). AB - Although Senecio species are known as sources of potentially toxic pyrrolizidine alkaloids (PAs), some species of this genus are traditionally used as remedies, notably in Algeria. In this paper, the evaluation of biological activities and the analysis of PAs of Algerian specimens of Senecio delphinifolius Vahl are reported. The n-butanolic extract of the herb showed a weak antibacterial effect against Escherichia coli with a MIC of 1 mg/mL, but was inactive against Staphylococcus aureus and Pseudomonas aeruginosa. The n-butanolic extracts of the roots, stems and herb showed a modest antioxidant activity, scavenging the free radical DPPH with respective IC50 values of 55.3, 50.2 and 13.3 microg/mL. A cytotoxic effect against a series of human tumor cell lines was observed with the n-butanolic extract from stems (IC50 ranging between 34 and 88 microg/mL). The herb of the evaluated sample contains 140 ppm of PAs (senecionine, seneciphylline, integerrimine, senkirkine) and PA-related alkaloids (dehydrosenkirkine and neosenkirkine). As the major PAs belong to the toxic series (1,2-unsaturation in the pyrrolizidine cycle and macrocyclic diester), the use of S. delphinifolius should be discouraged in traditional medicine. PMID- 23738447 TI - Berbanine: a new isoquinoline-isoquinolone alkaloid from Berberis vulgaris (Berberidaceae). AB - A new isoquinoline-isoquinolone alkaloid was isolated from the root bark of Berberis vulgaris and named berbanine. The structure was established by spectroscopic methods (including 2D NMR, HR-EI-MS). PMID- 23738448 TI - Dicentrine production in callus and cell suspension cultures of Stephania venosa. AB - The highest dicentrine content (19.5 +/- 0.3 mg/g dry weight) from callus culture of Stephania venosa was achieved from stem segments cultured on MS medium supplemented with TDZ 0.5 mg/L and NAA 1.0 mg/L. Cell suspension cultures were established from callus cultured on MS liquid medium with the same plant growth regulators. Dicentrine production from S. venosa cell suspension cultures was obtained in the range of 15-26 mg/g dry weight. Elicitation in cell suspension cultures by chitosan (50 mg/L) and salicylic acid (2 mg/L) for 6 days significantly increased dicentrine content. Our findings indicate that callus and cell suspension cultures of S. venosa can produce high levels of dicentrine as an alternative source of plant materials. PMID- 23738449 TI - New flavan and alkyl alpha,beta-lactones from the stem bark of Horsfieldia superba. AB - In the present study phytochemical investigation of the methanol extract of the stem bark of Horsfieldia superba led to the isolation of twenty compounds (1-20), of which three (1-3) were new. However, compounds 2 and 3 were previously reported as synthetic alpha,beta-lactones. The compounds were characterized as ( )-3,4',7-trihydroxy-3'-methoxyflavan (1), (-)-5,6-dihydro-6-undecyl-2H-pyran-2 one (2), and (-)-5,6-dihydro-6-tridecyl-2H-pyran-2-one (3). Seventeen other known compounds were also isolated and identified as (-)-viridiflorol (4), hexacosanoic acid (5), beta-sitosterol (6), methyl 2,4-dihydroxy-6-methylbenzoate (methylorsellinate) (7), methyl 2,4-dihydroxy-3,6-dimethylbenzoate (8), (-)-4' hydroxy-7-methoxyflavan (9), (-)-4',7-dihydroxyflavan (10), (-)-4',7-dihydroxy-3' methoxyflavan (11), (+)-3,4',7-trihydroxyflavan (12), (-)-catechin (13), (-) epicatechin (14), (-)-7-hydroxy-3',4'-methylenedioxyflavan (15), 2',3,4 trihydroxy-4'-methoxydihydrochalcone (16), 3',4',7-trihydroxyflavone (17), (+)-4' hydroxy-7-methoxyflavanone (18), hexadecanoic acid (palmitic acid) (19) and 3,4 dihydroxybenzoic acid (20). The structures of the compounds were fully characterized by various physical methods (melting point, optical rotation), spectral (UV, IR, ID and 2D NMR) and mass spectrometric techniques. In vitro assay of compounds 2 and 3 demonstrated moderate cytotoxic activities against human prostate (PC-3), colon (HCT-116) and breast (MCF-7) cancer cells, while the chloroform and ethyl acetate fractions of H. superba were found to exhibit moderate AChE inhibitory activity (IC50 72 and 60 microg/mL). PMID- 23738450 TI - New flavonol triglycosides from the leaves of soybean cultivars. AB - Soybean (Glycine max) is a major crop in the world. Three new flavonol 3-O glycosides, kaempferol 3-O-alpha-L-rhamnopyranosyl-(1 --> 4)-[alpha-L rhamnopyranosyl-(1 --> 6)-beta-D-galactopyranoside] (1), kaempferol 3-O-alpha-L rhamnopyranosyl-(1 --> 4)-[beta-D-glucopyranosyl-(1 --> 6)-beta-D galactopyranoside] (4) and quercetin 3-O-beta-D-glucopyranosyl-(1--> 2)-[alpha-L rhamnopyranosyl-(1 --> 6)-beta-galactopyranoside] (5) were isolated from the leaves of soybean cultivars, together with three known compounds, kaempferol 3-O beta-D-glucopyranosyl-(1 --> 2)-[alpha-L-rhamnopyranosyl-(1--> 6)-beta-D galactopyranoside] (2), kaempferol 3-O-beta-D-glucopyranosyl-(1 --> 2)-[alpha-L rhamnopyranosyl-(1 --> 6)-beta-D-glucopyranoside] (3) and quercetin 3-O-beta-D glucopyranosyl-(1 --> 2)-[alpha-L-rhamnopyranosyl-(1 --> 6)-beta-D glucopyranoside] (6), and also common flavonoids. The isolated compounds possess similar structures and high water solubility, and so it was hard to isolate them (in particular 5 and 6) with a normal preparative HPLC system. Their final purification was achieved by a preparative HPLC system equipped with a recycle device. PMID- 23738451 TI - Melitidin: a flavanone glycoside from Citrus grandis 'Tomentosa'. AB - Citrus grandis 'Tomentosa' is a traditional Chinese medicine, used as an antitussive. In this research, melitidin, a flavanone glycoside, was isolated from this species for the first time by using chromatographic methods. The structure was confirmed through comprehensive analyses of its ultraviolet, infrared, 1H and 13C NMR, HMBC and HMQC spectroscopic and high-resolution mass spectrometric data. Meliditin showed a good antitussive effect on cough induced by citric acid in Guinea pig, suggesting that it was a contributor to the antitussive effect of C. grandis 'Tomentosa'. PMID- 23738452 TI - Two new chalcones from the flowers of Clerodendrum inerme. AB - Two new chalcones, 3-hydroxy-3',4'-dimethoxychalcone (1) and 3,2'-dihydroxy-3',4' dimethoxychalcone (2), were isolated from the flowers of Clerodendrum inerme (L.) Gaertn together with two known flavones, 7-O-methylwogonin (3) and eucalyptin (4). The structures of the new compounds 1 and 2 have been established by extensive 2D-NMR and ESI-TOFMS studies. PMID- 23738453 TI - A novel phenolic compound from Phyllanthus emblica. AB - A new compound, mucic acid 3-O-gallate (1), was isolated from the fruit of Phyllanthus emblica L, together with 5 known compounds (2-6). Their structures were elucidated on the basis of spectroscopic analysis, including 1D and 2D NMR techniques, and by comparison with literature data. PMID- 23738454 TI - Anti-austeric activity of phenolic constituents of seeds of Arctium lappa. AB - From seeds of Arctium lappa L. (Asteraceae) we obtained arctigenin (1), arctiin (2), chlorogenic acid (3), 4,5-dicaffeoylquinic acid (4), 3,5-dicaffeoylquinic acid (5), 3,4-dicaffeoylquinic acid (6), matairesinol (11), isolappaol A (12), lappaol F (14), and lappaol B (15), together with 1:1 mixtures of isolappaol C (7) and lappaol C (8), arctignan E (9) and arctignan D (10), and 12 and lappaol A (13), while 3,3',4'-tri-O-demethylarctigenin (16), 3,3'-di-O-demethyl-4' dehydroxyarctigenin (17), and 3-O-demethylarctigenin (18) were obtained by anaerobic microbiological metabolism of 1. Then, we evaluated the in vitro preferential cytotoxic activity of these pure compounds and 1:1 mixtures, together with enterodiol (19) and enterolactone (20), against human pancreatic cancer PANC-1 cells in nutrient-deprived medium (NDM). Among them, 1 and 18 showed potent activity, with PC50 values of 1.75 and 4.38 microM, respectively, while 11, 15, and 17 showed mild activity with PC50 values of 31.1, 30.9, and 38.7 microM, respectively. By comparing their structures and PC50 values, the following structural moieties could be concluded to be important for the preferential cytotoxicity of 1: 1) the 3-hydroxy-4-methoxyphenyl group at the 2 position on the gamma-butyrolactone ring, 2) the less polar substituent at the 3 position on the gamma-butyrolactone ring, and 3) the gamma-butyrolactone ring. PMID- 23738455 TI - Bioactive lignans from the leaves and stems of Schisandra wilsoniana. AB - Three new dibenzocyclooctadiene lignans, marlignans M-O (1-3), together two known ones, were isolated from the leaves and stems of Schisandra wilsoniana. The structures of 1-3 were elucidated by spectroscopic methods, including extensive 1D- and 2D-NMR techniques. Compound 2 showed anti-HIV-1 activity with an EC50 value of 5.82 microg/mL and a therapeutic index (TI) of more than 12.8. Compound 3 showed obvious bioactivity in inhibiting Epstein-Barr virus early antigen (EBV EA) activation. PMID- 23738456 TI - Antioxidative/acetylcholinesterase inhibitory activity of some Asteraceae plants. AB - The extracts obtained by 80% EtOH from some Asteraceae plants (Calendula officinalis, Inula helenium, Arctium lappa, Artemisia absinthium and Achillea millefolium) were studied. Rosmarinic acid, one of the main compounds identified in all extracts, was determined quantitatively by using HPLC. In addition, spectrophotometric methods were evaluated as an alternative for rosmarinic acid content determination. Total phenolic content was also established for all extracts. A. millefolium extract was found to have the highest content of rosmarinic acid as well as total phenols. All extracts were tested for antioxidant and acetylcholinesterase inhibitory activity. A. millefolium was shown to possess the best antioxidant activity (for all tested methods) as well as acetylcholinesterase inhibitory activity. Highly positive linear relationships were obtained between antioxidant/acetylcholinesterase inhibitory activity and the determined rosmarinic acid content indicating its significance for the observed activities. PMID- 23738457 TI - Antioxidant and antimicrobial activities, and phenolic compounds of selected Inula species from Turkey. AB - Three Inula species, I. viscosa, I. helenium ssp. turcoracemosa and I. montbretiana, collected from different locations of Anatolia were investigated for their antioxidant and antimicrobial potential, and their total phenolic content and phenolic composition. Antioxidant activities of various extracts of the plant parts were measured using DPPH radical scavenging and ABTS assays. Antimicrobial potential of methanol extracts of the plant parts was determined by the agar dilution method against Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and Candida tropicalis. All the extracts were more active against Gram-positive bacteria and yeasts than Gram-negative bacteria. The extracts exhibited antioxidant and antimicrobial activities in different concentrations. Total phenolic concentration of the extracts was estimated with Folin-Ciocalteu reagent using gallic acid as standard. The total phenolic content varied widely in different parts of the three tested Inula species, ranging from 21.1 +/- 0.8 to 190.9 +/- 6.1 mg GAE/g extract. Phenolic components, such as chlorogenic acid, caffeic acid, rutin, myricetin, quercetin, luteolin and kaempferol were quantified by HPLC-DAD in the methanol extracts of the Inula species. It was obvious that the antioxidant and antimicrobial properties of the plants were due to the phenolics. PMID- 23738458 TI - Two new dihydrostilbenoid glycosides isolated from the leaves of Litsea coreana and their anti-inflammatory activity. AB - Two new dihydrostilbenoid glycosides, named 5-(2-phenylethyl)-3-hydroxyphenol-1-O beta-D-glucopyranoside (1) and 6-(2-phenylethyl)-2,4-dihydroxy benzoic acid-2-O beta-D-glucopyranoside (2), together with two known compounds, were isolated from the leaves of Litsea coreana Levl.. Their structures were established on the basis of NMR spectroscopic, MS and chemical data. Biological tests revealed that 1-3 exhibited moderate anti-inflammatory activity through an inhibitory effect on TNF-alpha, IL-1 production from RAW264.7 cell line activated with lipopolysaccharides (LPS). PMID- 23738459 TI - Inhibitory activity of benzophenones from Anemarrhena asphodeloides on pancreatic lipase. AB - Pancreatic lipase is a key enzyme for lipid absorption by hydrolysis of total dietary fats. Therefore, inhibition of pancreatic lipase is suggested to be an effective therapy in the regulation of obesity. The EtOAc-soluble fraction of Anemarrhena asphodeloides rhizomes significantly inhibited pancreatic lipase activity as assessed using porcine pancreatic lipase as an in vitro assay system. Further fractionation of the EtOAc-soluble fraction of A. asphodeloides led to the isolation of a new benzophenone glycoside, zimoside A (1), together with the eleven known compounds iriflophenone (2), 2,4',6-trihydroxy-4-methoxybenzophenone (3), foliamangiferoside A (4), (2,3-dihydroxy-4-methoxyphenyl)(4-hydroxyphenyl) methanone (5), 1,4,5,6,-tetrahydroxyxanthone (6), isosakuranetin (7), 4 hydroxybenzoic acid (8), 4-hydroxyacetophenone (9), vanillic acid (10), tyrosol (11) and 5-hydroxymethyl-2-furaldehyde (12). Among the isolated compounds, 3, 5 and 10 showed significant inhibition of pancreatic lipase activity. PMID- 23738460 TI - Identification and quantification of furanocoumarins in stem bark and wood of eight Algerian varieties of Ficus carica by RP-HPLC-DAD and RP-HPLC-DAD-MS. AB - Furanocoumarins are the major phytoalexins of Ficus carica and are effective natural drug candidates for treatment of several types of cancer and skin disease. The objectives of this study were to analyze and quantify linear furanocoumarins, mainly psoralen and bergapten, in wood and bark of stems from eight Algerian varieties of fig and to establish the differences in the content of these metabolites in the eight local samples. Psoralen and bergapten contents in the stem bark and wood (in microg/g DW) varied respectively from 146.6 to 1110.3 and from 395.7 to 1671.8 for psoralen, and from 114.3 to 524.0 and from 144.2 to 718.6 for bergapten. This study fills a gap in our knowledge of furanocoumarin distribution in different parts of the fig tree. Psoralen and bergapten concentrations were higher in the wood than in the stem bark. Most of the dark fruited fig trees produce these two coumarins more than the green ones. PMID- 23738461 TI - UPLC-Q-TOF/MS coupled with multivariate statistical analysis as a powerful technique for rapidly exploring potential chemical markers to differentiate between radix paeoniae alba and radix paeoniae rubra. AB - To explore rapidly the potential chemical markers for differentiating Radix Paeoniae Alba and Radix Paeoniae Rubra, a method is proposed based on ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) coupled with multivariate statistical analysis. Batches of commercial samples were analyzed by UPLC-Q-TOF/MS. The datasets of t(R)-m/z pair, ion intensities and sample codes were further processed with orthogonal partial least squared discriminant analysis (OPLS-DA) to compare holistically the difference between these two kinds of samples. Then statistics were used to generate an S-plot, in which the variables (t(R)-m/z pair) contributing most to the difference were clearly depicted as points at the two ends of "S", and the components correlated to these ions should be regarded as the chemical markers. The identities of the most changed markers can be identified by comparing the mass/UV spectra and retention times with those of reference compounds and/or tentatively assigned by matching empirical molecular formulae with those of known compounds published in the literature. Using this proposed approach, albflorin, paeoniflorin, oxypaeoniflorin, benzoylpaeoniflorin, galloylalbiflorin and paeoniflorigenone were found to be the differentiating components for discrimination of Radix Paeoniae Alba and Radix Paeoniae Rubra. Moreover, paeoniflorin sulfonate and its isomer, isomaltopaeoniflorin sulfonate, were found to be the characteristic markers for all Radix Paeoniae Alba samples that were processed by sulfurdioxide gas fumigation. The results suggested that this newly established approach could be used to explore rapidly the potential chemical markers for herbs with similar chemical characteristics. PMID- 23738462 TI - Antimicrobial activity of crude methanolic extract from Phyllanthus niruri. AB - The antibacterial efficiency of the methanolic extract of Phyllanthus niruri Linn. was investigated against pathogenic bacteria responsible for common infections of skin, and urinary and gastrointestinal tracts. The extract demonstrated antibacterial activities against all the Gram-positive and Gram negative bacteria tested. The results obtained suggested that at higher concentrations the extract would eradicate the growth of bacterial cells. The bacterial cells, after exposure to the extract, showed complete alteration in their morphology, followed by collapse of the cells beyond repair. The study revealed that the methanolic extract of P. niruri may be an effective antibacterial agent to treat bacterial infections since the extract exhibited significant antimicrobial potency, comparable with that of the standard antibiotic chloramphenicol. PMID- 23738463 TI - Cellulose contents of some abundant Indian seaweed species. AB - Crude cellulose as well as alpha- and beta-celluloses were estimated in thirty four seaweed species of fifteen orders of Chlorophyta, Phaeophyta and Rhodophyta of Indian waters. The greatest yields of crude cellulose and a-cellulose were obtained from Chaetomorpha aerea (approx. 20.0% and 18.5%, respectively), and of beta-cellulose (approx. 3.1%) from Caulerpa imbricata. The lowest crude cellulose, and alpha-and beta-contents were recorded for the calcareous red alga Liagora indica (approx. 0.90%, 0.70% and 0.10%, respectively). There was little variation in cellulose content among the brown algae, while wide variations in the yields were found in the green and red algae. The present work contributes to the repertoire of 67 Indian seaweed species studied to now for their cellulose contents in our laboratory. The combined studies highlight that Chaetomorpha aerea, Acrosiphonia orientalis, Caulerpa taxifolia, Sargassum tenerrimum, Hydroclathrus clathratus and Gelidiella acerosa possess relatively high (> 10%) cellulose contents, which could be of potential utility. PMID- 23738464 TI - Anti-inflammatory potential of silk sericin. AB - Silk sericin was found to suppress the production of pro-inflammatory cytokines, which are related to the inflammatory reaction. The objectives of this study were to investigate the anti-inflammatory effect of sericin in vivo using the carrageenan-induced rat edema model and changes in the histology of tissues. The effects of sericin on the expression of COX-2 and iNOS were also evaluated. Sericin solutions at 0.004-0.080 mg/mL were applied topically to the top of the hind paw and carrageenan (1.0 mg) was injected subcutaneously to the plantar surface of the right hind paw. Our results indicated that sericin significantly reduced the inflammation in rats' paw compared with the negative control (water and acetone) and its effect at 0.080 mg/mL was only slightly lower than that of 1.0% w/v indomethacin. Similar numbers of polymorphonuclear and macrophage cells were found in rats' tissue treated with indomethacin and sericin solution, while the numbers were significantly higher in their absence. The gene expression results by RT-PCR showed that the COX-2 and iNOS genes were down-regulated in samples treated with sericin in a dose dependent manner. These data indicated that the anti-inflammatory properties of sericin may be partly attributable to the suppression of the COX-2 enzyme and nitric oxide production. PMID- 23738465 TI - Composition of essential oil from aerial and underground parts of Geum rivale and G. urbanum growing in Poland. AB - A study of the composition of essential oils from aerial and underground parts of Geum rivale L. and Geum urbanum L. growing in Poland led to the identification of 130 compounds. The main compound of the essential oil from underground parts of G. urbanum was eugenol (69.2%), whereas cis-myrtanal (53.3%) was the major constituent of the essential oil from roots of G. rivale. The essential oils from aerial parts of the plants contained large amounts of aliphatic compounds with (Z)-3-hexenol (38.4%) being the dominant constituent of the essential oil from aerial parts of G. urbanum and 1-octen-3-ol (33.9%) from G. rivale. PMID- 23738466 TI - Volatile composition of six horsetails: prospects and perspectives. AB - Six horsetails were investigated for volatile organic compounds (VOC) by GC-MS using organic solvent extraction. Seventy-five VOC biosynthesized from the shikimic, lipidic and terpenic pathways including isoprenoid derivatives were detected from these putative natural resources. E. palustre var. americana contained mainly lipidic derivatives, i.e., 1-octen-3-ol (mushroom-like odor), (E)-2-hexenoic acid (fruity odor) and (E)-2-hexenal (green odor). Many isoprenoid flavour precursors, i.e., 3-oxo-alpha-ionol (spicy odor) and (E,E)-pseudoionone (balsamic odor), as well as odorous benzenic derivatives, i.e, phenylethanal (hyacinth, lilac note) and 2-phenylethanol (rose odor) contributed to the odor of E. arvense. The volatile pattern of E. telmateia is dominated by high amounts of isoprenoids and benzenic derivatives. The complex volatile profiles of E. hyemale and E. ramosissimum are based on ferulic acid isomers, along with either (E)-2 heptenal (green vegetable-like odor) or 4-vinylguaiacol (spicy clove smoky odor) for E. hyemale and E. ramosissimum, respectively. The broad spectrum of E. scirpioides shows the lowest VOC content with high amount of isoprenoids (46.9%), mainly ionone derivatives. Equisetum resources are of great interest as bioactive litter and new potential functional feed ingredients. PMID- 23738467 TI - Chemical compositions of the rhizome, leaf and stem oils from Malaysian Hornstedtia leonurus. AB - The chemical compositions of the essential oil of the rhizome, leaf and stem of Hornstedtia leonurus Retz., collected from Negeri Sembilan, Malaysia,are reported for the first time. The essential oils were extracted using hydrodistillation and analyzed by gas chromatography (GC-FID) and gas chromatography/mass spectrometry (GC/MS). Seventeen (96.4%), thirteen (89.2%) and nine components (98.8%) were successfully identified from the rhizome, stem and leaf oils, respectively. Phenylpropanoids were found to be the major fraction, with methyleugenol being the most abundant compound in all oils with percentage compositions of 76.4% (rhizome), 80.3% (stem) and 74.5% (leaf). PMID- 23738468 TI - Effect on emotional behavior and stress by inhalation of the essential oil from Chamaecyparis obtusa. AB - Various effects have been reported in the literature for the essential oil from Chamaecyparis obtusa (EOCO), such as antibacterial and antifungal activity. In this study, we examined the effect of EOCO on emotional behavior and stress induced biomarkers. Male ICR mice, aged 5 weeks at the start of each experiment, were individually housed in cages for 1 week. After placing each mouse in a glass container and exposing it to EOCO for 90 min, we then investigated the influence on emotional behavior using the elevated-plus maze (EPM) test, which is one of the evaluation methods for anxiolytic-like behavior. Significant anxiolytic-like effects were observed for the 7.0 mg/L air EOCO (P < 0.05). After the EPM test, mice were dissected and changes in the stress-induced biomarkers within the brain were investigated by examining the amounts of fast nerve growth factor receptor (NGFR) and activity regulated cytoskeletal-associated protein (Arc) gene expression, and brain-derived neurotrophic factor (BDNF) and galactokinase 1 (GLK1) protein expression. Significant increases were observed in the amount of NGFR after inhalation of 7.0 mg/L air EOCO (P < 0.05). These results indicate that EOCO has both anxiolytic-like and stress mitigation effects. PMID- 23738469 TI - Chemical composition and antibacterial activity of rhizome oils from five Hedychium species. AB - The essential oils from rhizomes of five Hedychium species, H. coronarium, H. neocarneum, H. flavescens, H. speciosum and H. stenopetalum (Zingiberaceae), were obtained by hydrodistillation and analyzed by capillary GC and GC/MS. Sixty components were identified and percentage oil yields from the fresh plants ranged from 0.06-0.17 % (v/w). All rhizome oils were rich in terpenes, especially monoterpenes (75.0-95.9 %). The most common compounds in the rhizome oils of Hedychium were beta-pinene, linalool and 1,8-cineole. The essential oils were tested against four bacterial strains. They showed moderate to weak activity against Gram-positive bacteria (inhibition zone 25-13 mm, MIC 0.3-8.3 mg/mL, MBC 0.6-8.3 mg/mL). PMID- 23738470 TI - Chemical composition and antimicrobial activity of three essential oils from Curcuma wenyujin. AB - Curcuma wenyujin is a traditional medicinal plant in China. The non-steamed rhizomes, steamed rhizomes and steamed roots of this plant are used as herbal medicines in three clinics, namely Pian-jiang-huang (PJH), Wen-e-zhu (WEZ), and Wen-yu-jin (WYJ), and are officially listed in the Chinese Pharmacopoeia. The purpose of this study was to conduct a comparative analysis of the three essential oils extracted from the C. wenyujin rhizomes and roots using GC-MS, and in doing so thirty compounds were identified. Principal component analysis (PCA) effectively distinguished the samples taken from the three different groups. Monoterpenoids, including camphene, linalool, camphor, isoborneol, borneol and eucalyptol, were characteristic components of the PJH oil, while beta-elemene, beta-elemenone, gamma-elemene and delta-elemene were typical components of the WEZ oil, and propanenitrile, caryophyllene oxide, (-)-caryophyllene, germacrene B, pogostol and alpha-humulene were representative ingredients of the WYJ oil. The ratio of sesquiterpenoids to monoterpenoids in PJH, WEZ, and WYJ were 2:1, 5:1 and 7:1, respectively. The antimicrobial activities of the three essential oils and of the six main ingredients were tested against two bacterial and one fungal strains using agar diffusion and broth dilution methods. The essential oil of PJH was shown to present a higher antimicrobial activity than that of WEZ and WYJ. Based on the Partial Least Square Model (PLS), the correlation between the antimicrobial activity of the tested oils and the identified chemical components was discussed and potential components of the antimicrobial activity were predicted according to Variable Importance in the Project (VIP) Value. The tested monoterpenes eucalyptol and isoborneol demonstrated a higher inhibitory activity than the sesquiterpenes germacrone, curdione and beta-elemene. Therefore, the potent inhibitory effect of the PJH oil might be attributed to its higher content of monoterpenes. The MIC values for the essential oils and their ingredients ranged from 62.5 to 500 microg/mL. PMID- 23738471 TI - Essential oil composition and antimicrobial activity of aerial parts and ripe fruits of Echinophora spinosa (Apiaceae) from Italy. AB - The chemical composition and antimicrobial activity of the essential oils obtained from the flowering aerial parts and ripe fruits of Echinophora spinosa L. (Apiaceae) from central Italy were analyzed by GC/MS. The major constituents of the oil from the aerial parts were beta-phellandrene (34.7%), myristicin (16.5%), delta3-carene (12.6%), alpha-pinene (6.7%) and alpha-phellandrene (6.2%), and of the oil from the ripe fruits p-cymene (50.2%), myristicin (15.3%), alpha-pinene (15.1%) and alpha-phellandrene (8.1%). The two oils showed good antimicrobial activity against Clostridium difficile, C. perfringens, Enterococcus faecalis, Eubacterium limosum, Peptostreptococcus anaerobius and Candida albicans with MIC values respectively of 0.25, 0.25, 0.25, 0.25, 2.25, and 0.50%, v/v, and 0.13, 0.13, 0.13, 0.13, 2.25, 0.50%, v/v, for aerial parts and ripe fruits respectively. A less significant antimicrobial activity against bifidobacteria and lactobacilli, very important in the intestinal microflora, was also detected, with MIC values higher than 4.0%, v/v. PMID- 23738472 TI - Composition and in vitro anticancer activities of the leaf essential oil of Neolitsea variabillima from Taiwan. AB - This study investigated the chemical composition and in vitro anticancer activities of the essential oil isolated from the leaf of Neolitsea variabillima. The essential oil was isolated using hydrodistillation in a Clevenger-type apparatus, and characterized by GC-FID and GC-MS. Sixty-seven compounds were identified, representing 100% of the oil. The main components identified were trans-beta-ocimene (13.4%), alpha-cadinol (10.5%), terpinen-4-ol (9.3%), tau cadinol (9.2%), beta-caryophyllene (8.8%), and sabinene (6.7%). The anticancer activities of oil were evaluated. The results showed that the oil exhibited cytotoxic activity against human oral, liver, lung, colon, melanoma, and leukemic cancer cells. The presence of beta-caryophyllene, tau-cadinol, and alpha-cadinol significantly contributed to the anticancer activities of N. variabillima leaf oil. PMID- 23738473 TI - Natural products from marine algae of the genus Osmundaria (Rhodophyceae, Ceramiales). AB - The present work is a review of the natural products isolated from red marine algae of the genus Osmundaria (including Vidalia), which intends to encompass their occurrence in the species of this genus, the possible synonymies, their geographic distribution, their structural variety and their biological potential as prototypes for the pharmaceutical industry and as active principles of cosmetics. At the end, we provide a table with these natural products and their biological activities. PMID- 23738474 TI - Phenols, alkaloids and terpenes from medicinal plants with antihypertensive and vasorelaxant activities. A review of natural products as leads to potential therapeutic agents. AB - Numerous studies support the cardiovascular effects of medicinal plants. This review examines plants whose antihypertensive and vasorelaxant effects have been scientifically validated. Our study selected only chemically characterized plants whose mode of action had already been investigated. The aim of the paper is to provide a quick way to identify medicinal plants and their constituents with antihypertensive and vasorelaxant activities. PMID- 23738475 TI - Diosmin--isolation techniques, determination in plant material and pharmaceutical formulations, and clinical use. AB - Diosmin is a naturally occurring flavone glycoside used in the treatment of venous diseases. In this review, we present the clinical aspects of the use of diosmin preparations in venous stasis, hemorrheologic disorders and vein wall remodeling. Because of its multiple applications in biology and its many therapeutic activities, research on isolation and identification of diosmin is of high relevance. The aim of this review is to present an overview of techniques of isolation and separation of diosmin in plant material, pharmaceutical formulations such as Daflon, Diosed and Dioven tablets, and biological fluids. PMID- 23738476 TI - Safety woes. FDA finds deficiencies at 31 compounding factories. PMID- 23738477 TI - Challenging gene patents. Myriad ruling will impact personalized medicine. PMID- 23738478 TI - Targeting disease. Technology is new approach to fighting outbreaks. PMID- 23738479 TI - More cuts ahead? Obama's budget plan opens broader deficit debate. PMID- 23738480 TI - Navigators hit some turbulence. Brokers and agents push for tighter regulation of insurance exchange helpers. PMID- 23738481 TI - Lives at risk. Hospitals face hurdles addressing alarm fatigue. PMID- 23738482 TI - Aggressive cost-cutting. Maryland wants to tie spending increases to economic growth. PMID- 23738483 TI - Behavioral studies. Researchers try to identify what influences change. PMID- 23738484 TI - Gearing up for exchanges. We won't be overwhelmed by new patients: execs. PMID- 23738485 TI - Dissecting the president's budget. Crucial agencies would barely keep up with inflation under Obama's plan. PMID- 23738486 TI - HIPAA as a hurdle. Family members are often barred from becoming engaged in patients' care. PMID- 23738487 TI - Truven Health Analytics 15 Top Health Systems. PMID- 23738489 TI - Medium-size systems. Care management at the core. PMID- 23738488 TI - Large systems. Learning through sharing. PMID- 23738490 TI - Small systems. Making sure they measure up. PMID- 23738491 TI - Painful side effects. Drug-abuse problems evade paltry anti-fraud efforts in Medicare Part D. PMID- 23738492 TI - Largest publicly traded, for-profit hospital chains. Ranked by 2012 revenue (in millions) as reported to the U.S. Securities and Exchange Commission. PMID- 23738493 TI - Can UnitedHealth really fix the system? PMID- 23738494 TI - Goodbye to the surgical mask. Thanks to new government data, patients can now learn the real cost of hospital procedures. PMID- 23738495 TI - The donor-supply electrode enhances performance in colloidal quantum dot solar cells. AB - Colloidal quantum dot (CQD) solar cells combine solution-processability with quantum-size-effect tunability for low-cost harvesting of the sun's broad visible and infrared spectrum. The highest-performing colloidal quantum dot solar cells have, to date, relied on a depleted-heterojunction architecture in which an n type transparent metal oxide such as TiO2 induces a depletion region in the p type CQD solid. These devices have, until now, been limited by a modest depletion region depth produced in the CQD solid owing to limitations in the doping available in TiO2. Herein we report a new device geometry-one based on a donor supply electrode (DSE)-that leads to record-performing CQD photovoltaic devices. Only by employing this new charge-extracting approach do we deepen the depletion region in the CQD solid and thereby extract notably more photocarriers, the key element in achieving record photocurrent and device performance. With the use of optoelectronic modeling corroborated by experiment, we develop the guidelines for building a superior CQD solar cell based on the DSE concept. We confirm that using a shallow-work-function terminal electrode is essential to producing improved charge extraction and enhanced performance. PMID- 23738496 TI - Synthesis and quantitative structure-activity relationship (QSAR) study of novel N-arylsulfonyl-3-acylindole arylcarbonyl hydrazone derivatives as nematicidal agents. AB - In continuation of our program aimed at the discovery and development of natural product-based pesticidal agents, 54 novel N-arylsulfonyl-3-acylindole arylcarbonyl hydrazone derivatives were prepared, and their structures were well characterized by 1H NMR, 13C NMR, HRMS, ESI-MS, and mp. Their nematicidal activity was evaluated against that of the pine wood nematode, Bursaphelenchus xylophilus in vivo. Among all of the derivatives, especially V-12 and V-39 displayed the best promising nematicidal activity with LC50 values of 1.0969 and 1.2632 mg/L, respectively. This suggested that introduction of R1 and R2 together as the electron-withdrawing substituents, R3 as the methyl group, and R4 as the phenyl with the electron-donating substituents could be taken into account for further preparation of these kinds of compounds as nematicidal agents. Six selected descriptors are a WHIM descriptor (E1m), two GETAWAY descriptors (R1m+ and R3m+), a Burden eigenvalues descriptor (BEHm8), and two edge-adjacency index descriptors (EEig05x and EEig13d). Quantitative structure-activity relationship (QSAR) studies demonstrated that the structural factors, such as molecular mass (a negative correlation with the bioactivity) and molecular polarity (a positive correlation with bioactivity), are likely to govern the nematicidal activities of these compounds. For this model, the correlation coefficient (R2(training set)), the leave-one-out cross-validation correlation coefficient (Q2(LOO)), and the 7 fold cross-validation correlation coefficient (Q2(7-fold)) were 0.791, 0.701, and 0.715, respectively. The external cross-validation correlation coefficient (Q2ext) and the root-mean-square error for the test set (RMSE(test set)) were 0.774 and 3.412, respectively. This study will pave the way for future design, structural modification, and development of indole derivatives as nematicidal agents. PMID- 23738497 TI - Nucleophilic addition to silyl-protected five-membered ring oxocarbenium ions governed by stereoelectronic effects. AB - A series of fused-bicyclic acetals containing a disiloxane ring was investigated to evaluate the source of selectivity in silyl-protected 2-deoxyribose systems. The disiloxane ring unexpectedly enables the diaxial conformer of the cation to be stabilized by an electronegative atom at C-3. This low energy conformer subsequently undergoes stereoelectronically controlled nucleophilic addition to give substituted tetrahydrofurans with high diastereoselectivity. PMID- 23738498 TI - Efficiency and air-stability improvement of flexible inverted polymer solar cells using ZnO/poly(ethylene glycol) hybrids as cathode buffer layers. AB - The flexible inverted polymer solar cells composed of poly(3-hexylthiophene) (P3HT):(6,6)-phenyl-C61 butyric acid methyl ester (PC61BM) blends on the flexible poly(ethylene terephthalate) (PET) substrates were fabricated, which showed improving device performance by using solution-processed ZnO/poly(ethylene glycol) (PEG) hybrids as cathode buffer layers compared to the devices using the pristine ZnO as cathode buffer layers. It is mainly attributed to the effective passivation of the ZnO surface traps, suppression of the interfacial charge recombination, decrease of the work function and improvement of the energy-level alignment between ZnO and PC61BM. When the PEG was introduced into the ZnO, the large aggregates was dispersed and yielded large ZnO nanoclusters containing less domain boundaries. The performance of devices with ZnO/PEG6000 (with averaged molecular weight of 6000) hybrids exhibited the best power conversion efficiency (PCE) of 3.3% compared to the devices with ZnO/PEG400 (with averaged molecular weight of 400) and ZnO/PEG20000 (with averaged molecular weight of 20000). It was found that the short PEG backbone (e.g., Mw = 400) containing less oxygen could not effectively passivate ZnO surface traps, meanwhile, longer PEG backbone (e.g., Mw = 20000) could lead to the formation of the charge transport barrier because of the insulating nature of PEG. Furthermore, solar cells with the ZnO/PEG buffer also showed better air-stability. The 23% degradation was observed after 14 days, compared to the 45% degradation of devices with the pristine ZnO buffer. In addition, due to the simplicity and low-temperature process, the ZnO/PEG hybrids can be well-suitable as cathode buffer for large area roll-to roll manufacturing of printed polymer solar cells. PMID- 23738499 TI - Network meta-analysis and the comparison of efficacy and tolerability of anti epileptic drugs for treatment of refractory focal epilepsy. PMID- 23738500 TI - Broad control of disulfide stability through microenvironmental effects and analysis in complex redox environments. AB - Disulfide bonds stabilize the tertiary- and quaternary structure of proteins. In addition, they can be used to engineer redox-sensitive (bio)materials and drug delivery systems. Many of these applications require control of the stability of the disulfide bond. It has recently been shown that the charged microenvironment of the disulfide can be used to alter their stability by ~3 orders of magnitude in a predictable and finely tunable manner at acidic pH. The aim of this work is to extend these findings to physiological pH and to demonstrate the validity of this approach in complex redox milieu. Disulfide microenvironments were manipulated synergistically with steric hindrance herein to control disulfide bond stability over ~3 orders of magnitude at neutral pH. Control of disulfide stability through microenvironmental effects could also be observed in complex redox buffers (including serum) and in the presence of cells. Such fine and predictable control of disulfide properties is not achievable using other existing approaches. These findings provide easily implementable and general tools for controlling the responsiveness of biomaterials and drug delivery systems toward various local endogenous redox environments. PMID- 23738501 TI - Cerebral venous infarction: a potentially avoidable complication of deep brain stimulation surgery. AB - OBJECT: Despite numerous reports on the morbidity and mortality of deep brain stimulation (DBS), cerebral venous infarction has rarely been reported. We present four cases of venous infarct secondary to DBS surgery. METHODS: The diagnosis of venous infarction was based on 1) delayed onset of new neurologic deficits on postoperative day 1 or 2; 2) significant edema surrounding the superficial aspect of the implanted lead, with or without subcortical hemorrhage on CT scan. RESULTS: Four cases (0.8% per lead, 1.3% per patient) of symptomatic cerebral venous infarction were identified out of 500 DBS lead implantation procedures between July 2002 and August 2009. All four patients had Parkinson's disease. Their DBS leads were implanted in the subthalamic nucleus (n = 2), and the globus pallidus internus (n = 2). Retrospective review of the targeting confirmed that the planned trajectory passed within 3 mm of a cortical vein in two cases for which contrast-enhanced preoperative magnetic resonance (MR) imaging was available. In the other two cases, contrasted targeting images were not obtained preoperatively. CONCLUSION: Cerebral venous infarction is a potentially avoidable, but serious complication. To minimize its incidence, we propose the use of high-resolution, contrast-enhanced, T1-weighted MR images to delineate cerebral venous anatomy, along with careful stereotactic planning of the lead trajectory to avoid injury to venous structures. PMID- 23738502 TI - Measurement of cortisol in dog hair: a noninvasive tool for the diagnosis of hypercortisolism. AB - BACKGROUND: The clinical signs of hyperadrenocorticism (hypercortisolism) in dogs are known to be caused by chronic overexposure to glucocorticoids. The quantification of cortisol in serum, saliva or urine reflects the cortisol concentration at the time of sample collection, but in suspected hyperadrenocorticism it may be preferable to examine a long-term parameter of cortisol production. HYPOTHESIS/OBJECTIVES: There is a need for a noninvasive method to monitor the long-term production of cortisol in dogs. It seems possible that measuring cortisol levels in hair could represent such a method. ANIMALS: Hair was collected from 12 dogs with hyperadrenocorticism and from 10 healthy control dogs. METHODS: Immunoreactive cortisol, cortisone and corticosterone concentrations were determined by enzyme immunoassay. High-performance liquid chromatography was performed to test the validity of the cortisol assay. RESULTS: Levels of immunoreactive cortisol, cortisone and corticosterone were significantly higher in dogs with hyperadrenocorticism than in control dogs. The difference was most pronounced for the cortisol level. CONCLUSIONS AND CLINICAL IMPORTANCE: The determination of cortisol in hair offers the advantage that sampling is easier and less invasive than taking blood, urine, faeces or saliva. Measuring cortisol in hair may represent a valuable tool for the diagnosis of hyperadrenocorticism in dogs. PMID- 23738503 TI - Calculating osmotic pressure according to nonelectrolyte Wilson nonrandom factor model. AB - Abstract The osmotic pressure of NaCl solutions was determined by the air humidity in equilibrium (AHE) method. The relationship between the osmotic pressure and the concentration was explored theoretically, and the osmotic pressure was calculated according to the nonelectrolyte Wilson nonrandom factor (N-Wilson-NRF) model from the concentration. The results indicate that the calculated osmotic pressure is comparable to the measured one. PMID- 23738504 TI - Improved oral bioavailability of fexofenadine hydrochloride using lipid surfactants: ex vivo, in situ and in vivo studies. AB - Abstract The aim of the present study was to improve the dissolution, permeability and therefore oral bioavailability of the fexofenadine hydrochloride (FEX), by preparing lipid surfactant based dispersions using self-emulsifying carriers, i.e. Gelucire 44/14 (GLC) and d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS or TPGS). The reprecipitation studies were conducted using these carriers to evaluate inhibition of reprecipitation by maintaining super saturation state. The aqueous solubility of the FEX was increased linearly with increasing GLC, TPGS concentrations as verified by the phase solubility studies. The dispersions of FEX were prepared in different drug/GLC (GD) and drug/TPGS (TD) ratios by melt method and evaluated. The prepared dispersions showed improved dissolution rate in distilled water as dissolution media and highest dissolution rate was achieved with dispersions prepared using TPGS. The solid state characterization was carried by differential scanning calorimetry and scanning electron microscopy indicated reduced crystallinity of the drug. Fourier transform infrared spectroscopy revealed the compatibility of drug with carriers. The ex vivo permeation studies conducted using intestinal gut sac technique, resulted in reduced efflux of the drug by inhibiting intestinal P-glycoprotein from the dispersions. The in situ perfusion studies and in vivo pharmacokinetic studies in male wistar rats showed improved absorption and oral bioavailability from the prepared dispersions as compared to pure drug. PMID- 23738505 TI - Low levels of high-density lipoproteins are associated with acute kidney injury following revascularization for chronic limb ischemia. AB - OBJECTIVES: Perioperative acute kidney injury (AKI) is not uncommon, following revascularization. HDL has been shown to reduce organ injury in animal models. The aim of the study is to examine the association of HDL on AKI in patients undergoing revascularization for chronic limb ischemia. METHODS: All patients who underwent revascularization between June 2001 and December 2009 were analyzed. Patients on dialysis and with incomplete data were excluded. Patients were grouped for HDL < or >=40 mg/dL. Univariate and multivariate analysis were used to identify factors associated with AKI. RESULTS: A total of 684 patients were included. Eighty-two (12.0%) patients developed postoperative AKI (15.7% in low HDL group vs. 6.3% in high HDL group, p < 0.001). The AKI group were more likely to be older (71.5 +/- 10.1 vs. 68.0 +/- 10.8, p = 0.01), ASA 4 class (26% vs. 14%, p < 0.001), to have albumin <3 g/dL (59% vs. 32%, p < 0.001), low HDL levels (79% vs. 58%, p < 0.001), DM (61% vs. 44%, p = 0.005), CAD (67% vs. 55%, p = 0.003), preoperative chronic kidney disease (CKD) stage III-IV (55% vs.39%, p < 0.001), to present with critical limb ischemia (82% vs. 63%, p = 0.001), and to be on ACEI (67% vs. 51%, p = 0.006). Multivariate logistic regression analysis showed low HDL (Odds Ratio (OR) 1.66 [1.23-2.24]) and serum albumin levels <3 g/dL (OR 1.66 [1.29-2.13], p < 0.001) were independently associated with increased odds for developing AKI. Propensity score analyses showed low HDL was independently associated with increased odds of AKI (OR 2.4 (1.4-4.2)). CONCLUSIONS: AKI following revascularization is not uncommon (12.0%), and lower concentrations of HDL and serum albumin are associated with increased odds of postoperative AKI. There was also a trend of higher prevalence of AKI among those with pre-existing CKD. PMID- 23738506 TI - Cs10H[Ga3H8]3: a hydrogenous zintl phase containing propane-like polyanions [Ga3H8]3- and interstitial hydrogen. AB - The hydrogenous Zintl-phase Cs10H[Ga3H8]3 containing propane-like polyanions [Ga3H(D)8](3-) was successfully synthesized by direct hydrogenation of a 1:1 Cs/Ga metal mixture and characterized by powder X-ray and neutron diffraction. The charge of the polyanions is balanced by two different species of cations, hydrogen-centered octahedra [H(D)Cs6](5+) and isolated Cs(+). The structure crystallizes in the hexagonal space group P63/mcm (193) with the cell parameters a = 11.1108(3) A, c = 18.2149(5) A, Z = 2. PMID- 23738507 TI - Diagnostic accuracy of diffuse reflectance imaging for early detection of pre malignant and malignant changes in the oral cavity: a feasibility study. AB - BACKGROUND: Diffusely reflected light is influenced by cytologic and morphologic changes that take place during tissue transformation, such as, nuclear changes, extracellular matrix structure and composition as well as blood flow. Albeit with varying degree of sensitivity and specificity, the properties of diffusely reflected light in discriminating a variety of oral lesions have been demonstrated by our group in multiple studies using point monitoring systems. However, the point monitoring system could not identify the region with the most malignant potential in a single sitting. METHODS: In order to scan the entire lesion, we developed a multi-spectral imaging camera system that records diffuse reflectance (DR) images of the oral lesion at 545 and 575 nm with white light illumination. The diagnostic accuracy of the system for 2-dimensional DR imaging of pre-malignant and malignant changes in the oral cavity was evaluated through a clinical study in 55 patients and 23 healthy volunteers. The DR imaging data were compared with gold standard tissue biopsy and histopathology results. RESULTS: In total 106- normal/clinically healthy sites, 20- pre-malignant and 29- malignant (SCC) sites were compared. While the median pixel value of the R545/R575 image ratio for normal/clinically healthy tissue was 0.87 (IQR = 0.82-0.94), they were 1.35 (IQR = 1.13-1.67) and 2.44 (IQR = 1.78-3.80) for pre-malignant and malignant lesions, respectively. Area under the ROC curve to differentiate malignant from normal/clinically healthy [AUC = 0.99 (95% CI: 0.99-1.00)], pre-malignant from normal/clinically healthy [AUC = 0.94 (95% CI: 0.86-1.00)], malignant from pre malignant [AUC = 0.84 (95% CI: 0.73-0.95)] and pre-malignant and malignant from normal/clinically healthy [AUC = 0.97 (95% CI: 0.94-1.00)] lesions were desirable. CONCLUSION: We find DR imaging to be very effective as a screening tool in locating the potentially malignant areas of oral lesions with relatively good diagnostic accuracy while comparing it to the gold standard histopathology. PMID- 23738508 TI - The key role of Shenyan Kangfu tablets, a Chinese patent medicine for diabetic nephropathy: study protocol for a randomized, double-blind and placebo-controlled clinical trial. AB - BACKGROUND: Diabetic nephropathy (DN) is a major microvascular complication with diabetes. In China, an estimated 34.7 percent of people diagnosed with diabetes have renal complications and a further 50 percent die of renal failure. Hence, identification of alternative treatments for these patients should be given priority. The Shenyan Kangfu tablet (SYKFT) is a new formulation of an existing and widely acclaimed Chinese herbal tea for treating qi-yin deficiency syndrome. Because a considerable portion of DN patients presenting with symptoms of swelling, fatigue and weak limbs would be diagnosed with qi-yin deficiency syndrome according to the traditional Chinese medicine (TCM) diagnostic criteria, we hypothesize that SYKFT may represent a complementary drug for DN patients with the corresponding syndrome. In view of this, we have designed a trial to assess the efficacy and safety of SYKFT for patients with diabetic nephropathy exhibiting signs of qi and yin deficiency. METHODS: This is a multicenter, double blind, randomized controlled trial (RCT). The total target sample size is planned at 80 participants, with a balanced (1:1) treatment allocation. The experimental intervention will be SYKFY plus irbesartan (SI regimen) and the control intervention will be a placebo plus irbesartan (PI regimen). Participants will receive two courses of medication treatment each lasting 8 weeks. The primary outcome will be the composite of the quantitative 24-hour urinary protein level and urinary albumin excretion rate (UAER). Changes in urine albumin-to-creatinine ratio (UACR) and DN staging, and TCM symptom improvement will be the secondary outcome measures. Adverse events (AEs) will be monitored throughout the trial. DISCUSSION: This study will be the first placebo-controlled RCT to assess whether SYKFT plus irbesartan will have beneficial effects on enhancing overall response rate (ORR), changing DN staging, improving clinical symptoms, and reducing the frequency of AEs for DN patients with qi-yin deficiency syndrome. The results of this trial will help to provide evidence-based recommendations for clinicians. PMID- 23738509 TI - Central precocious puberty caused by mutations in the imprinted gene MKRN3. AB - BACKGROUND: The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. METHODS: We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. RESULTS: We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. CONCLUSIONS: Deficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.). PMID- 23738511 TI - In support of SUPPORT--a view from the NIH. PMID- 23738510 TI - A congenital neutrophil defect syndrome associated with mutations in VPS45. AB - BACKGROUND: Neutrophils are the predominant phagocytes that provide protection against bacterial and fungal infections. Genetically determined neutrophil disorders confer a predisposition to severe infections and reveal novel mechanisms that control vesicular trafficking, hematopoiesis, and innate immunity. METHODS: We clinically evaluated seven children from five families who had neutropenia, neutrophil dysfunction, bone marrow fibrosis, and nephromegaly. To identify the causative gene, we performed homozygosity mapping using single nucleotide polymorphism arrays, whole-exome sequencing, immunoblotting, immunofluorescence, electron microscopy, a real-time quantitative polymerase chain-reaction assay, immunohistochemistry, flow cytometry, fibroblast motility assays, measurements of apoptosis, and zebrafish models. Correction experiments were performed by transfecting mutant fibroblasts with the nonmutated gene. RESULTS: All seven affected children had homozygous mutations (Thr224Asn or Glu238Lys, depending on the child's ethnic origin) in VPS45, which encodes a protein that regulates membrane trafficking through the endosomal system. The level of VPS45 protein was reduced, as were the VPS45 binding partners rabenosyn 5 and syntaxin-16. The level of beta1 integrin was reduced on the surface of VPS45-deficient neutrophils and fibroblasts. VPS45-deficient fibroblasts were characterized by impaired motility and increased apoptosis. A zebrafish model of vps45 deficiency showed a marked paucity of myeloperoxidase-positive cells (i.e., neutrophils). Transfection of patient cells with nonmutated VPS45 corrected the migration defect and decreased apoptosis. CONCLUSIONS: Defective endosomal intracellular protein trafficking due to biallelic mutations in VPS45 underlies a new immunodeficiency syndrome involving impaired neutrophil function. (Funded by the National Human Genome Research Institute and others.). PMID- 23738512 TI - Releasing the brake on puberty. PMID- 23738513 TI - The OHRP and SUPPORT. PMID- 23738514 TI - Pandemic influenza viruses--hoping for the road not taken. PMID- 23738515 TI - Characterization of uterine leiomyomas by whole-genome sequencing. AB - BACKGROUND: Uterine leiomyomas are benign but affect the health of millions of women. A better understanding of the molecular mechanisms involved may provide clues to the prevention and treatment of these lesions. METHODS: We performed whole-genome sequencing and gene-expression profiling of 38 uterine leiomyomas and the corresponding myometrium from 30 women. RESULTS: Identical variants observed in some separate tumor nodules suggested that these nodules have a common origin. Complex chromosomal rearrangements resembling chromothripsis were a common feature of leiomyomas. These rearrangements are best explained by a single event of multiple chromosomal breaks and random reassembly. The rearrangements created tissue-specific changes consistent with a role in the initiation of leiomyoma, such as translocations of the HMGA2 and RAD51B loci and aberrations at the COL4A5-COL4A6 locus, and occurred in the presence of normal TP53 alleles. In some cases, separate events had occurred more than once in single tumor-cell lineages. CONCLUSIONS: Chromosome shattering and reassembly resembling chromothripsis (a single genomic event that results in focal losses and rearrangements in multiple genomic regions) is a major cause of chromosomal abnormalities in uterine leiomyomas; we propose that tumorigenesis occurs when tissue-specific tumor-promoting changes are formed through these events. Chromothripsis has previously been associated with aggressive cancer; its common occurrence in leiomyomas suggests that it also has a role in the genesis and progression of benign tumors. We observed that multiple separate tumors could be seeded from a single lineage of uterine leiomyoma cells. (Funded by the Academy of Finland Center of Excellence program and others.). PMID- 23738516 TI - The lectin-like oxidized low-density lipoprotein receptor-1 as therapeutic target for atherosclerosis, inflammatory conditions and longevity. AB - INTRODUCTION: The lectin-like oxidized LDL receptor-1 (LOX-1) is a scavenger receptor and is regarded as a central element in the initiation of endothelial dysfunction and its further progression to atherosclerosis. Increasing numbers of studies suggest that therapeutic strategies to modulate LOX-1 will have a broad spectrum of applications ranging from cardiovascular diseases to longevity. AREAS COVERED: The dual role of LOX-1 as a culprit molecule in the process of atherosclerosis and as a danger signal in various tissues is introduced. The structure of the receptor, its ligands and its modulation by known drugs, by natural products (e.g., statins, imipramine, salicylate-based drugs, procyanidins, curcumin) and by new strategies (antisenseRNA, miRNA, pyrrole imidazol-polyamides, LOX-1 antibodies, lipid apheresis) are described. EXPERT OPINION: Therapeutic approaches via transcript regulation, allowing a modulation of LOX-1, may be an easier and safer strategy than a blockade of the receptor. Considering the wide distribution of LOX-1 on different tissues, research on the mechanisms of LOX-1 modulation by drugs and natural products applying "omic" technologies will not only allow a better understanding of the role of LOX-1 in the processes of atherosclerosis, inflammation and longevity but also support the development of specific LOX-1 modulators, avoiding the initiation of molecular mechanisms which lead to adverse events. PMID- 23738517 TI - Effect of orally administered sodium bicarbonate on caecal pH. AB - REASONS FOR PERFORMING STUDY: Caecal acidosis is a central event in the metabolic cascade that occurs following grain overload. Buffering the caecal acidosis by enterally administered sodium bicarbonate (NaHCO3 ) may be beneficial to affected horses. OBJECTIVES: To determine the effect and duration of enterally administered NaHCO3 on caecal pH in healthy horses. STUDY DESIGN: Experimental study using horses with caecal cannulas. METHODS: Nine horses had been previously fitted with a caecal cannula. Six horses received 1.0 g/kg bwt NaHCO3 and 3 control horses were given 3 l of water via nasogastric tube. Clinical parameters, water consumption, venous blood gases, caecal pH, faecal pH and faecal water content were measured at 6 h intervals over a 36 h study period. RESULTS: Horses that received enterally administered NaHCO3 had significantly increased caecal pH that lasted the duration of the study. Treated horses increased their water intake, and developed metabolic alkalaemia, significantly increased plasma sodium concentrations and significantly decreased plasma potassium concentrations. CONCLUSIONS: Enterally administered NaHCO3 may be beneficial in buffering caecal acidosis. PMID- 23738518 TI - A genome-wide association study for reading and language abilities in two population cohorts. AB - Candidate genes have been identified for both reading and language, but most of the heritable variance in these traits remains unexplained. Here, we report a genome-wide association meta-analysis of two large cohorts: population samples of Australian twins and siblings aged 12-25 years (n = 1177 from 538 families), and a younger cohort of children of the UK Avon Longitudinal Study of Parents and their Children (aged 8 and 9 years; maximum n = 5472). Suggestive association was indicated for reading measures and non-word repetition (NWR), with the greatest support found for single nucleotide polymorphisms (SNPs) in the pseudogene, ABCC13 (P = 7.34 * 10(-8)), and the gene, DAZAP1 (P = 1.32 * 10(-6)). Gene-based analyses showed significant association (P < 2.8 * 10(-6)) for reading and spelling with genes CD2L1, CDC2L2 and RCAN3 in two loci on chromosome 1. Some support was found for the same SNPs having effects on both reading skill and NWR, which is compatible with behavior genetic evidence for influences of reading acquisition on phonological-task performance. The results implicate novel candidates for study in additional cohorts for reading and language abilities. PMID- 23738519 TI - Care for hospitalized patients with unhealthy alcohol use: a narrative review. AB - There is increasing emphasis on screening, brief intervention, and referral to treatment (SBIRT) for unhealthy alcohol use in the general hospital, as highlighted by new Joint Commission recommendations on SBIRT. However, the evidence supporting this approach is not as robust relative to primary care settings. This review is targeted to hospital-based clinicians and administrators who are responsible for generally ensuring the provision of high quality care to patients presenting with a myriad of conditions, one of which is unhealthy alcohol use. The review summarizes the major issues involved in caring for patients with unhealthy alcohol use in the general hospital setting, including prevalence, detection, assessment of severity, reduction in drinking with brief intervention, common acute management scenarios for heavy drinkers, and discharge planning. The review concludes with consideration of Joint Commission recommendations on SBIRT for unhealthy alcohol use, integration of these recommendations into hospital work flows, and directions for future research. PMID- 23738520 TI - Evidence for interplay between genes and parenting on infant temperament in the first year of life: monoamine oxidase A polymorphism moderates effects of maternal sensitivity on infant anger proneness. AB - BACKGROUND: The low expression polymorphism of the MAOA gene in interaction with adverse environments (G * E) is associated with antisocial behaviour disorders. These have their origins in early life, but it is not known whether MAOA G * E occurs in infants. We therefore examined whether MAOA G * E predicts infant anger proneness, a temperamental dimension associated with later antisocial behaviour disorders. In contrast to previous studies, we examined MAOA G * E prospectively using an observational measure of a key aspect of the infant environment, maternal sensitivity, at a specified developmental time point. METHODS: In a stratified epidemiological cohort recruited during pregnancy, we ascertained MAOA status (low vs. high expression alleles) from the saliva of 193 infants, and examined specific predictions to maternal report of infant temperament at 14 months from maternal sensitivity assessed at 29 weeks of age. RESULTS: Analyses, weighted to provide general population estimates, indicated a robust interaction between MAOA status and maternal sensitivity in the prediction of infant anger proneness (p = .003) which became stronger once possible confounders for maternal sensitivity were included in the model (p = .0001). The interaction terms were similar in males (p = .010) and females (p = .016), but the effects were different as a consequence of an additional sex of infant by maternal sensitivity interaction. CONCLUSIONS: This prospective study provides the first evidence of moderation by the MAOA gene of effects of parenting on infant anger proneness, an important early risk for the development of disruptive and aggressive behaviour disorders. PMID- 23738522 TI - Peripheral odontogenic fibroma associated with a dilacerated maxillary central incisor: a case report. AB - The authors report a case of a 16-year-old male with peripheral odontogenic fibroma (POF) in the anterior maxilla associated with dilaceration of a tooth in its vicinity. A solitary, exophytic and sessile growth was present between the maxillary right central and lateral incisors and extended from the labial mucosa to the palatal gingiva. A periapical radiograph of the maxillary right central incisor revealed a shortened and dilacerated root. The growth was excised and sent for histopathologic examination. A diagnosis of POF (World Health Organization type) was rendered. The clinical and microscopic features are discussed. PMID- 23738521 TI - Death certificate completion skills of hospital physicians in a developing country. AB - BACKGROUND: Death certificates (DC) can provide valuable health status data regarding disease incidence, prevalence and mortality in a community. It can guide local health policy and help in setting priorities. Incomplete and inaccurate DC data, on the other hand, can significantly impair the precision of a national health information database. In this study we evaluated the accuracy of death certificates at a tertiary care teaching hospital in a Karachi, Pakistan. METHODS: A retrospective study conducted at Aga Khan University Hospital, Karachi, Pakistan for a period of six months. Medical records and death certificates of all patients who died under adult medical service were studied. The demographic characteristics, administrative details, co-morbidities and cause of death from death certificates were collected using an approved standardized form. Accuracy of this information was validated using their medical records. Errors in the death certificates were classified into six categories, from 0 to 5 according to increasing severity; a grade 0 was assigned if no errors were identified, and 5, if an incorrect cause of death was attributed or placed in an improper sequence. RESULTS: 223 deaths occurred during the study period. 9 certificates were not accessible and 12 patients had incomplete medical records. 202 certificates were finally analyzed. Most frequent errors pertaining to patients' demographics (92%) and cause/s of death (87%) were identified. 156 (77%) certificates had 3 or more errors and 124 (62%) certificates had a combination of errors that significantly changed the death certificate interpretation. Only 1% certificates were error free. CONCLUSION: A very high rate of errors was identified in death certificates completed at our academic institution. There is a pressing need for appropriate intervention/s to resolve this important issue. PMID- 23738523 TI - Bridging the gap between osteoporosis and osteonecrosis of the jaw: preventing and treating BRONJ with MK4. AB - Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an iatrogenic disease and a significant concern to patients and dentists. Bisphosphonates are used for millions of men and women with osteoporosis, with the rationale being that these medications increase bone mineral density and decrease fracture risk. Clinicians will undoubtedly encounter some patients who are taking bisphosphonate medications. Recognizing the risk factors for BRONJ, understanding the pathophysiology of BRONJ, and enacting a reasonable approach to prevent BRONJ in patients is crucial to providing safe and effective treatments. This article proposes a rational approach for moving BRONJ away from a risk management and quality assurance model that is currently being used by dentists, to a preventive model. The role of collagen as postulated in this article cannot be ignored in the pathophysiology and potential prevention and treatment of osteoporosis and BRONJ. Studies from the medical literature support the safety and efficacy of MK4 as a potential therapeutic agent in preventing and treating osteoporosis and BRONJ. While the approach outlined herein requires additional study, the conceptual framework based on a broad review of the osteonecrosis of the jaw (ONJ) literature provides a means to begin to address this situation in a proactive, rather than reactive, way. PMID- 23738525 TI - Nanosized metal oxide and nanobelts prepared by selective dealloying of Ti-based amorphous powders. AB - Two typical nanomaterials, nanosized metal oxides and nanobelts, are obtained in one-pot selective dealloying process by using multiple-component Ti-based amorphous powders as dealloying precursors. The microstructure and photoelectric conversion property of the as-synthesized Zr-doped nanobelts are comprehensively investigated. Particularly, a core-shell structure, for example, residual amorphous alloy as the microsized core and nanosized metal oxide composites (mainly TiO2 and CuO) as the shell, forms as a byproduct of the selective dealloying. These resultant metal oxide composites show large specific surface area, and superior adsorption efficiency and capacity for removing toxic Cr(6+) in aqueous solution. The differences in the standard electrode potentials between the multiple-component elements in amorphous powders trigger their selective dealloying in alkaline solutions. PMID- 23738526 TI - An effective prodrug strategy to selectively enhance ocular exposure of a cannabinoid receptor (CB1/2) agonist. AB - Glaucoma is a leading cause of vision loss and blindness, with increased intraocular pressure (IOP) a prominent risk factor. IOP can be efficaciously reduced by administration of topical agents. However, the repertoire of approved IOP-lowering drug classes is limited, and effective new alternatives are needed. Agonism of the cannabinoid receptors CB1/2 significantly reduces IOP clinically and experimentally. However, development of CB1/2 agonists has been complicated by the need to avoid cardiovascular and psychotropic side effects. 1 is a potent CB1/2 agonist that is highly excluded from the brain. In a phase I study, compound 1 eyedrops were well tolerated and generated an IOP-lowering trend but were limited in dose and exposure due to poor solubility and ocular absorption. Here we present an innovative strategy to rapidly identify compound 1 prodrugs that are efficiently metabolized to the parent compound for improved solubility and ocular permeability while maintaining low systemic exposures. PMID- 23738524 TI - Monofunctional and higher-valent platinum anticancer agents. AB - Platinum compounds represent one of the great success stories of metals in medicine. Following the serendipitous discovery of the anticancer activity of cisplatin by Rosenberg, a large number of cisplatin variants have been prepared and tested for their ability to kill cancer cells and inhibit tumor growth. These efforts continue today with increased realization that new strategies are needed to overcome issues of toxicity and resistance inherent to treatment by the approved platinum anticancer agents. One approach has been the use of so-called "non-traditional" platinum(II) and platinum(IV) compounds that violate the structure-activity relationships that governed platinum drug-development research for many years. Another is the use of specialized drug-delivery strategies. Here we describe recent developments from our laboratory involving monofunctional platinum(II) complexes together with a historical account of the manner by which we came to investigate these compounds and their relationship to previously studied molecules. We also discuss work carried out using platinum(IV) prodrugs and the development of nanoconstructs designed to deliver them in vivo. PMID- 23738527 TI - A method for accounting for maintenance costs in flux balance analysis improves the prediction of plant cell metabolic phenotypes under stress conditions. AB - Flux balance models of metabolism generally utilize synthesis of biomass as the main determinant of intracellular fluxes. However, the biomass constraint alone is not sufficient to predict realistic fluxes in central heterotrophic metabolism of plant cells because of the major demand on the energy budget due to transport costs and cell maintenance. This major limitation can be addressed by incorporating transport steps into the metabolic model and by implementing a procedure that uses Pareto optimality analysis to explore the trade-off between ATP and NADPH production for maintenance. This leads to a method for predicting cell maintenance costs on the basis of the measured flux ratio between the oxidative steps of the oxidative pentose phosphate pathway and glycolysis. We show that accounting for transport and maintenance costs substantially improves the accuracy of fluxes predicted from a flux balance model of heterotrophic Arabidopsis cells in culture, irrespective of the objective function used in the analysis. Moreover, when the new method was applied to cells under control, elevated temperature and hyper-osmotic conditions, only elevated temperature led to a substantial increase in cell maintenance costs. It is concluded that the hyper-osmotic conditions tested did not impose a metabolic stress, in as much as the metabolic network is not forced to devote more resources to cell maintenance. PMID- 23738528 TI - PEG-phosphorylcholine hydrogels as tunable and versatile platforms for mechanobiology. AB - We report here the synthesis of a new class of hydrogels with an extremely wide range of mechanical properties suitable for cell studies. Mechanobiology has emerged as an important field in bioengineering, in part due to the development of synthetic polymer gels and fibrous protein biomaterials to control and quantify how cells sense and respond to mechanical forces in their microenvironment. To address the problem of limited availability of biomaterials, in terms of both mechanical range and optical clarity, we have prepared hydrogels that combine poly(ethylene glycol) (PEG) and phosphorylcholine (PC) zwitterions. Our goal was to create a hydrogel platform that exceeds the range of Young's moduli reported for similar hydrogels, while being simple to synthesize and manipulate. The Young's modulus of these "PEG-PC" hydrogels can be tuned over 4 orders of magnitude, much greater than commonly used hydrogels such as PEG diacrylate, PEG-dimethacrylate, and polyacrylamide, with smaller average mesh sizes and optical clarity. We prepared PEG-PC hydrogels to study how substrate mechanical properties influence cell morphology, focal adhesion structure, and proliferation across multiple mammalian cell lines, as a proof of concept. These novel PEG-PC biomaterials represent a new and useful class of mechanically tunable hydrogels for mechanobiology. PMID- 23738529 TI - C2 subcutaneous stimulation for failed back surgery syndrome: a case report. AB - OBJECTIVE: Failed back surgery syndrome (FBSS) is a term embracing a constellation of conditions that describes persistent or recurring low back pain, with or without sciatica following one or more spine surgeries. It has been shown in animals that electrical stimulation of the high cervical C2 area can suppress pain stimuli derived from the L5-S1 dermatome. It is unknown whether C2 electrical stimulation in humans can be used to treat pain derived from the L5-S1 area, and a case is reported in which subcutaneous C2 is applied to treat FBSS. CASE: A patient presents to the neuromodulation clinic because of FBSS (after three lumbar diskectomies) and noninvasive neuromodulation is performed consisting of transcutaneous electrical nerve stimulation (TENS) at C2. The C2 TENS stimulation is successful in improving pain. It induces paresthesias in the C2 dermatome above a certain amplitude threshold, but does not generate paresthesias in the pain area. However, the patient becomes allergic to the skin applied TENS electrodes and therefore a new treatment strategy is discussed with the patient. A subcutaneous C2 electrode is inserted under local anesthesia, and attached to an external pulse generator. METHODS: Three stimulation designs are tested: a classical tonic stimulation, consisting of 40 Hz stimulation, a placebo, and a burst stimulation, consisting of 40 Hz burst mode, with five spikes delivered at 500 Hz at 1000 MUsec pulse width and 1000 MUsec interspike interval. RESULTS: The patient's stimulation results demonstrate that burst mode is superior to placebo and tonic mode, and she receives a fully implanted C2 electrode connected to an internal pulse generator via an extension wire. CONCLUSION: The burst design is capable of both suppressing the least and worst pain effectively, and she has remained almost pain-free for over three years. PMID- 23738531 TI - Capillaroscopy. AB - Microscopy of the nailfold capillaries has found increasing use in dermatology, rheumatology and angiology particularly as an important tool to distinguish between primary and secondary Raynaud disease. The best evidence is available in systemic sclerosis where specific capillaroscopic patterns have a high positive predictive value for the development of the disease. Conversely, a regular capillary pattern rules out systemic sclerosis with high degree of probability. PRINCE (prognostic index for nailfold capillaroscopic examination) was developed to identify patients at high risk of developing systemic sclerosis. CSURI (capillaroscopic skin ulcer risk index) should predict the risk of developing digital ulcers in patients with systemic sclerosis with high specificity and sensitivity. As a consequence of recent results a pathologic capillary pattern was integrated by the EULAR Scleroderma Trials and Research Group (EUSTAR) in the diagnostic algorithm of the VEDOSS-Project (very early diagnosis of systemic sclerosis). Capillary patterns may correlate with visceral involvement and capillaroscopy thus has the potential as a screening tool to enable early diagnosis of organ involvement in systemic sclerosis. PMID- 23738530 TI - Group trauma-focused cognitive-behavioural therapy with former child soldiers and other war-affected boys in the DR Congo: a randomised controlled trial. AB - BACKGROUND: The Democratic Republic of Congo (DRC) has been home to the world's deadliest conflict since World War II and is reported to have the largest number of child soldiers in the world. Despite evidence of the debilitating impact of war, no group-based mental health or psychosocial intervention has been evaluated in a randomised controlled trial for psychologically distressed former child soldiers. METHOD: A randomised controlled trial involving 50 boys, aged 13-17, including former child soldiers (n = 39) and other war-affected boys (n = 11). They were randomly assigned to an intervention group, or wait-list control group. The intervention group received a 15-session, group-based, culturally adapted Trauma-Focused Cognitive-Behavioural Therapy (TF-CBT) intervention. Assessment interviews were completed at baseline, postintervention and 3-month follow-up (intervention group). RESULTS: Analysis of Covariance (ANCOVA) demonstrated that, in comparison to the wait-list control group, the TF-CBT intervention group had highly significant reductions in posttraumatic stress symptoms, overall psychosocial distress, depression or anxiety-like symptoms, conduct problems and a significant increase in prosocial behaviour (p < .001 for all). Effect sizes were higher when former child soldier scores were separated for sub-analysis. Three-month follow-up of the intervention group found that treatment gains were maintained. CONCLUSIONS: A culturally modified, group-based TF-CBT intervention was effective in reducing posttraumatic stress and psychosocial distress in former child soldiers and other war-affected boys. PMID- 23738532 TI - Meta-analyses of antiepileptic drugs for refractory partial (focal) epilepsy: an observation. PMID- 23738533 TI - Targeting liver X receptors in inflammation. AB - INTRODUCTION: The two oxysterol receptors, 'liver X receptors (LXRs)' LXRalpha and LXRbeta, are amongst the emerging newer drug targets within the nuclear receptor family and targeting LXRs represents novel strategies needed for prevention and treatment of diseases where current therapeutics is inadequate. AREAS COVERED: This review discusses the current understanding of LXR biology with an emphasis on the molecular aspects of LXR signalling establishing their potential as drug targets. Recent advances of their transcriptional mechanisms in inflammatory pathways and their physiological roles in inflammation and immunity are described. EXPERT OPINION: The new discoveries of LXR-regulated inflammatory pathways have ignited new promises for LXRs as drug targets. The broad physiological roles of LXRs involve a high risk of unwanted side effects. Recent insights into LXR biology of the brain indicate a highly important role in neuronal development and a clinical trial testing an LXR agonist reported adverse neurological side effects. This suggests that drug development must focus on limiting the range of LXR signalling - possibly achieved through subtype, tissue specific, promoter specific or pathway specific activation of LXRs where a successful candidate drug must be carefully studied for its effect in the central nervous system. PMID- 23738534 TI - Chemical stability and electrical performance of dual-active-layered zinc-tin oxide/indium-gallium-zinc-oxide thin-film transistors using a solution process. AB - We investigated the chemical stability and electrical properties of dual-active layered zinc-tin-oxide (ZTO)/indium-gallium-zinc-oxide (IGZO) structures (DALZI) with the durability of the chemical damage. The IGZO film was easily corroded or removed by an etchant, but the DALZI film was effectively protected by the high chemical stability of ZTO. Furthermore, the electrical performance of the DALZI thin-film transistor (TFT) was improved by densification compared to the IGZO TFT owing to the passivation of the pin holes or pore sites and the increase in the carrier concentration due to the effect of Sn(4+) doping. PMID- 23738535 TI - Outpatient treatment of the poisoned patients in Iran; may it be a feasible plan? PMID- 23738537 TI - Phenytoin-associated severe hypocalcemia with seizures in a patient with a TSC2 PKD1 contiguous gene syndrome. AB - We report the case of an inaugural episode of generalized seizures in a 40-year old male with a history of chronic kidney disease associated with TSC2-PKD1 contiguous gene syndrome. This patient was under prophylactic treatment of phenytoin since 2 years because of a subarachnoid hemorrhage due to a ruptured cerebral aneurysm. Laboratory results revealed therapeutic range of phenytoin levels, but severe hypocalcemia associated with profound vitamin D deficiency that could not be explained by secondary hyperparathyroidism alone. The interaction of phenytoin on the P-450 cytochromes activity has been demonstrated to accelerate the rate of 25-hydroxivitamin D3 and 1alpha,25-dihydroxivitamin D3 catabolism into inactive metabolites, leading to hypocalcemia. Physicians should be aware of significant phenytoin interactions on vitamin D metabolism which may lead to symptomatic hypocalcemia in patients with chronic kidney disease. PMID- 23738536 TI - A test of current models for the mechanism of milk-lipid droplet secretion. AB - Milk lipid is secreted by a unique process, during which triacylglycerol droplets bud from mammary cells coated with an outer bilayer of apical membrane. In all current schemes, the integral protein butyrophilin 1A1 (BTN) is postulated to serve as a transmembrane scaffold, which interacts either with itself or with the peripheral proteins, xanthine oxidoreductase (XOR) and possibly perilipin-2 (PLIN2), to form an immobile bridging complex between the droplet and apical surface. In one such scheme, BTN on the surface of cytoplasmic lipid droplets interacts directly with BTN in the apical membrane without binding to either XOR or PLIN2. We tested these models using both biochemical and morphological approaches. BTN was concentrated in the apical membrane in all species examined and contained mature N-linked glycans. We found no evidence for the association of unprocessed BTN with intracellular lipid droplets. BTN-enhanced green fluorescent protein was highly mobile in areas of mouse milk-lipid droplets that had not undergone post-secretion changes, and endogenous mouse BTN comprised only 0.5-0.7% (w/w) of the total protein, i.e. over 50-fold less than in the milk lipid droplets of cow and other species. These data are incompatible with models of milk-lipid secretion in which BTN is the major component of an immobile global adhesive complex and suggest that interactions between BTN and other proteins at the time of secretion are more transient than previously predicted. The high mobility of BTN in lipid droplets marks it as a potential mobile signaling molecule in milk. PMID- 23738538 TI - Diabetes severity and the role of leisure time physical exercise on cardiovascular mortality: the Nord-Trondelag Health study (HUNT), Norway. AB - BACKGROUND: Physical activity has been associated with lower cardiovascular mortality in people with diabetes, but how diabetes severity influence this association has not been extensively studied. METHODS: We prospectively examined the joint association of diabetes severity, measured as medical treatment status and disease duration, and physical exercise with cardiovascular mortality. A total of 56,170 people were followed up for 24 years through the Norwegian Cause of Death Registry. Cox proportional adjusted hazard ratios (HRs) with 95% confidence intervals (CI) were estimated. RESULTS: Overall, 7,723 people died from cardiovascular disease during the follow-up. Compared to the reference group of inactive people without diabetes, people with diabetes who reported no medical treatment had a hazard ratio (HR) of 1.65 (95% CI: 1.34, 2.03) if they were inactive and a HR of 0.99 (95% CI: 0.68, 1.45) if they reported >=2.0 hours physical exercise per week. Among people who received oral hypoglycemic drugs or insulin, the corresponding comparison gave HRs of 2.46 (95% CI: 2.08-2.92) and 1.58 (95% CI: 1.21, 2.05), respectively. CONCLUSIONS: The data suggest a more favourable effect of exercise in people with diabetes who used medication than in those who did not, suggesting that physical exercise should be encouraged as a therapeutic measure additional to medical treatment. PMID- 23738539 TI - Bioactive dibenzocyclooctadiene lignans from the stems of Schisandra neglecta. AB - Seven new unusual dibenzocyclooctadiene lignans, neglignans A-G (1-7), together with 16 known dibenzocyclooctadiene lignans, were isolated from the stems of Schisandra neglecta. Compounds 1 and 2 are the first dibenzocyclooctadiene lignans bearing a carboxyl group at C-4, and compounds 3 and 4 are the first 7,8 seco-dibenzocyclooctadiene lignans found from Nature. The new compounds (1-7) and several of the known compounds were evaluated for their anti-HIV activity and cytotoxicity. Compounds 2 and 6 showed anti-HIV-1 activities with therapeutic index values greater than 50, and compound 4 showed cytotoxicity against the NB4 and SHSY5Y cancer cell lines with IC50 values of 2.9 and 3.3 MUM, respectively. PMID- 23738540 TI - Pharmaceutical manufacturing and formulation design. Preface. PMID- 23738541 TI - Combined high resolution NMR and 1H and 17O relaxometric study sheds light on the solution structure and dynamics of the lanthanide(III) complexes of HPDO3A. AB - GdHPDO3A is one of the most used MRI contrast agents (CAs) for clinical use. However, unlike most of the other commercially available Gd-based CAs, only limited information is available on its solution structure and dynamics. 600 MHz high resolution (1)H NMR spectra of nine LnHPDO3A complexes (Ln = Pr, Nd, Eu, Tb, Dy, Ho, Er, Tm, and Yb) have been recorded at 298 K and neutral pH. Because of the low symmetry of the Ln-chelates, each proton gives rise to a different peak. Despite the very crowded spectra, it is possible to detect the presence of two sets of resonances associated with different isomers in solution in slow exchange in the NMR time scale. In principle, the LnHPDO3A complexes may be present in solution as eight isomeric forms (four enantiomeric pairs) differing in the layout of the acetate arms (Delta or Lambda), in the conformation of the macrocyclic ring (deltadeltadeltadelta or lambdalambdalambdalambda) and in the configuration of the chiral center (R or S). 1D- and 2D proton NMR spectra were measured as a function of temperature across the Lanthanide series. The data allow identifying the nature of the most abundant isomeric species in solution (e.g., Lambda(lambdalambdalambdalambda)-R/Lambda(deltadeltadeltadelta)-R and their enantiomeric forms Delta(deltadeltadeltadelta) S/Delta(lambdalambdalambdalambda)-S) and their interconversion process. Analysis of the data led us to identify the presence in solution of a third isomeric species, lacking the coordinated water molecule (q = 0), whose population becomes more relevant for the heavier lanthanides (Ln = Er-Lu). Moreover, we have introduced an innovative way of modeling the thermodynamic equilibrium between the various isomeric forms of LnHPDO3A that can be extended to a number of other systems. This analysis enabled us to calculate the molar fractions of the two isomeric forms for GdHPDO3A (chi = 0.7 and 0.30, for SAP and TSAP, respectively). This information has allowed interpreting the slightly anomalous relaxometric properties of GdHPDO3A. In particular, we observed that the temperature dependence of the (17)O NMR transverse relaxation rate of GdHPDO3A, R2, reveals an unusual trend at low temperatures and at high magnetic field strength (>9.4 T). This behavior has been attributed to the occurrence of a very large difference in the rate of water exchange, k(ex), for the two isomeric species (1/k(ex) = tauM = 640 +/- 35 ns and 8.9 +/- 0.5 ns, for the major and minor isomer respectively). PMID- 23738542 TI - How AIDS invented global health. PMID- 23738543 TI - War and sexual violence--mental health care for survivors. PMID- 23738544 TI - Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. AB - BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73*10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]). PMID- 23738545 TI - Controlled trial of psychotherapy for Congolese survivors of sexual violence. AB - BACKGROUND: Survivors of sexual violence have high rates of depression, anxiety, and post-traumatic stress disorder (PTSD). Although treatment for symptoms related to sexual violence has been shown to be effective in high-income countries, evidence is lacking in low-income, conflict-affected countries. METHODS: In this trial in the Democratic Republic of Congo, we randomly assigned 16 villages to provide cognitive processing therapy (1 individual session and 11 group sessions) or individual support to female sexual-violence survivors with high levels of PTSD symptoms and combined depression and anxiety symptoms. One village was excluded owing to concern about the competency of the psychosocial assistant, resulting in 7 villages that provided therapy (157 women) and 8 villages that provided individual support (248 women). Assessments of combined depression and anxiety symptoms (average score on the Hopkins Symptom Checklist [range, 0 to 3, with higher scores indicating worse symptoms]), PTSD symptoms (average score on the PTSD Checklist [range, 0 to 3, with higher scores indicating worse symptoms]), and functional impairment (average score across 20 tasks [range, 0 to 4, with higher scores indicating greater impairment]) were performed at baseline, at the end of treatment, and 6 months after treatment ended. RESULTS: A total of 65% of participants in the therapy group and 52% of participants in the individual-support group completed all three assessments. Mean scores for combined depression and anxiety improved in the individual support group (2.2 at baseline, 1.7 at the end of treatment, and 1.5 at 6 months after treatment), but improvements were significantly greater in the therapy group (2.0 at baseline, 0.8 at the end of treatment, and 0.7 at 6 months after treatment) (P<0.001 for all comparisons). Similar patterns were observed for PTSD and functional impairment. At 6 months after treatment, 9% of participants in the therapy group and 42% of participants in the individual-support group met criteria for probable depression or anxiety (P<0.001), with similar results for PTSD. CONCLUSIONS: In this study of sexual-violence survivors in a low-income, conflict-affected country, group psychotherapy reduced PTSD symptoms and combined depression and anxiety symptoms and improved functioning. (Funded by the U.S. Agency for International Development Victims of Torture Fund and the World Bank; ClinicalTrials.gov number, NCT01385163.). PMID- 23738547 TI - Images in clinical medicine. Hampton's hump. PMID- 23738546 TI - Response to the AIDS pandemic--a global health model. PMID- 23738548 TI - Clinical problem-solving. Waiting for the other foot to drop. PMID- 23738549 TI - High-frequency oscillation for ARDS. PMID- 23738550 TI - High-frequency oscillation for ARDS. PMID- 23738551 TI - High-frequency oscillation for ARDS. PMID- 23738552 TI - High-frequency oscillation for ARDS. PMID- 23738553 TI - High-frequency oscillation for ARDS. PMID- 23738554 TI - High-frequency oscillation for ARDS. PMID- 23738555 TI - Myths, presumptions, and facts about obesity. PMID- 23738556 TI - Myths, presumptions, and facts about obesity. PMID- 23738557 TI - Myths, presumptions, and facts about obesity. PMID- 23738558 TI - Myths, presumptions, and facts about obesity. PMID- 23738559 TI - Case 4-2013: A man with acute flank pain. PMID- 23738560 TI - Case 4-2013: A man with acute flank pain. PMID- 23738561 TI - When to start ART in Africa. PMID- 23738562 TI - When to start ART in Africa. PMID- 23738563 TI - The Step 2 Clinical Skills exam. PMID- 23738564 TI - The Step 2 Clinical Skills exam. PMID- 23738565 TI - The Step 2 Clinical Skills exam. PMID- 23738566 TI - JC viremia in natalizumab-treated patients with multiple sclerosis. PMID- 23738567 TI - Images in clinical medicine. Scombroid poisoning. PMID- 23738568 TI - The admixture maximum likelihood test to test for association between rare variants and disease phenotypes. AB - BACKGROUND: The development of genotyping arrays containing hundreds of thousands of rare variants across the genome and advances in high-throughput sequencing technologies have made feasible empirical genetic association studies to search for rare disease susceptibility alleles. As single variant testing is underpowered to detect associations, the development of statistical methods to combine analysis across variants - so-called "burden tests" - is an area of active research interest. We previously developed a method, the admixture maximum likelihood test, to test multiple, common variants for association with a trait of interest. We have extended this method, called the rare admixture maximum likelihood test (RAML), for the analysis of rare variants. In this paper we compare the performance of RAML with six other burden tests designed to test for association of rare variants. RESULTS: We used simulation testing over a range of scenarios to test the power of RAML compared to the other rare variant association testing methods. These scenarios modelled differences in effect variability, the average direction of effect and the proportion of associated variants. We evaluated the power for all the different scenarios. RAML tended to have the greatest power for most scenarios where the proportion of associated variants was small, whereas SKAT-O performed a little better for the scenarios with a higher proportion of associated variants. CONCLUSIONS: The RAML method makes no assumptions about the proportion of variants that are associated with the phenotype of interest or the magnitude and direction of their effect. The method is flexible and can be applied to both dichotomous and quantitative traits and allows for the inclusion of covariates in the underlying regression model. The RAML method performed well compared to the other methods over a wide range of scenarios. Generally power was moderate in most of the scenarios, underlying the need for large sample sizes in any form of association testing. PMID- 23738569 TI - Predictors of early post ischemic stroke apathy and depression: a cross-sectional study. AB - BACKGROUND: Apathy and depression are important neuropsychiatric disorders that can occur after a stroke but the etiology and risk factors are not well understood. The purpose of this study was to identify risk factors for apathy and depression following a stroke. METHODS: Patients with an acute stroke who met the inclusion criteria were recruited from our hospital, and general information was recorded from patient charts. The Apathy Evaluation Scale, Clinician Version (AES C) was used to evaluate these patients within 2 weeks after the stroke. The Montreal Cognitive Assessment (MoCA), mini-mental state examination (MMSE), Hamilton Depression Scale (HAMD), Mattis Dementia Rating Scale Initiation/Perseveration subset (MDRS I/P), Frontal Assessment Battery (FAB) and Stroop Color-Word Association Test were employed to evaluate emotion, cognitive function and executive function. The patients were divided into two groups: the apathy group and the non-apathy group. We also divided the patients into two groups based on whether or not they had post-stroke depression. The clinical characteristics and scores on the MoCA, MMSE, HAMD and MDRS I/P were compared between the apathy and non-apathy groups as well as between patients with and without depression. Logistic regression analysis was performed to identify risk factors for apathy and depression following a stroke. RESULTS: A total of 75 patients with acute stroke were recruited. Of these, 25 (33.3%) developed apathy and 12 (16%) developed depression. Multivariate logistic regression analysis indicated that a history of cerebrovascular disease (OR: 6.45, 95% CI: 1.48 28.05, P = 0.013), low HbA1c (OR: 0.31, 95% CI: 0.12-0.81, P = 0.017) and a low MDRS I/P score (OR: 0.84, 95% CI: 0.74, 0.96, P = 0.010) were risk factors for post-stroke apathy. Additionally, multivariate logistic regression indicated that a low MDRS I/P (OR: 0.85, 95% CI: 0.75, 0.97, P = 0.015) was associated with post stroke depression. CONCLUSIONS: Three risk factors for post-stroke apathy were identified as a history of cerebrovascular disease, low HbA1c and lower MDRS I/P scores. A low MDRS I/P score was also identified as a risk factor for post-stroke depression. These results may be useful to clinicians in recognizing and treating apathy and depression in patients after a stroke. PMID- 23738570 TI - Snapshot of the AAOHN Membership-Health Risk Appraisal Priority Areas. AB - A 2012 American Association of Occupational Health Nurses, Inc. (AAOHN) web-based membership survey of 5,138 members was designed to identify occupational health and safety issues facing members. A total of 2,123 members responded to the survey (41% response rate). Of the AAOHN members who responded to this survey, 61% reported health risk appraisal (HRA) priorities for 2012. HRA priority areas are identified among various subgroups of the AAOHN responders in this article. The top three HRA priority areas identified were weight management/nutrition/healthy eating, physical activity, and mental health/stress management. These priority areas were consistent across three industry sectors, three occupational health nurse job titles, and the smallest and largest employers. These results suggest that occupational health nurses should consider prioritizing their employee wellness efforts in these areas. PMID- 23738571 TI - Organophosphate exposure with pseudocholinesterase deficiency. AB - A 36-year-old correctional officer was exposed to lice while at work and self treated with chlorpyrifos, an organophosphate. The correctional officer applied chlorpyrifos to her entire body and did not wash it off for 8 to 12 hours. Eight hours after the initial application, the correctional officer developed abdominal cramps, diarrhea, sweating, excessive salivation, frequent urination, and increased bronchial secretions. After a phone consultation with the occupational health clinic, the correctional officer reported to the emergency department, was diagnosed with organophosphate toxicity, and was treated with atropine. Later testing revealed that the correctional officer had pseudocholinesterase deficiency. PMID- 23738573 TI - Color vision deficiency. AB - Occupational and environmental health nurses can promote awareness of color vision deficiency in the workplace. PMID- 23738574 TI - Factors affecting learning and teaching for medicines supply management training in Pacific Island Countries--a realist review. AB - INTRODUCTION: Limited human resources are a major impediment to achieving the UN health-related Millennium Development Goals in a number of Pacific Island Countries (PICs). Lack of education capacity to support competency development in medicine supply management is one of the main issues affecting workforce development in this region, which is characterised by disparate service delivery due to the range of environments in which supply occurs (ie urban, rural and remote), geographical challenges and cultural practices associated with teaching and learning. The supply of medicines, and an adequate pharmacy workforce with appropriate competencies is crucial to ensuring a well-functioning pharmaceutical system. In this region approximately 80% of patients access healthcare in rural areas without a pharmacist, thus local health personnel must be competent in pharmaceutical management relevant to the local context and culture. A new approach involves a partnership between the UN Population Fund Suva Sub-Regional Office, University of Canberra, Ministry of Health officials and the heath personnel within identified PICs, starting with the need to understand local culture and its impact on learning and teaching, and the mapping of competency requirements and an understanding of currently available information and materials. This information will be used to develop and trial new pedagogical approaches to training health personnel involved in essential medicines supply management, to improve medicines availability for patients in their own environment. The focus of this review was to determine what cultural and learning factors need to be considered when developing a curriculum for South Pacific pharmaceutical health personnel who work across a range of practice environments. METHODS: A 'realist methodology' consisting of a systematic investigation of the published literature and a targeted review of the 'grey' literature was used. All relevant literature was retrieved and coded manually using broad thematic analysis. RESULTS: The combined bibliographic and 'grey' literature search strategy resulted in the inclusion of 17 full text articles, 44 documents and 10 books. The five themes identified as key to optimising the cultural and learning approaches for the study population included recognition of: (1) past regional experiences of health related training; (2) the impact of South Pacific culture on learning styles; (3) the impact of external influences on curriculum; (4) the challenges of open and distance education in the Pacific; and (5) a distinct South Pacific student learning approach. CONCLUSIONS: The results of this 'realist methodology' review provide insights into learning approaches and cultural influences on student learning within PICs. The themes generated will be used to develop a set of principles to inform educators and health personnel involved in pharmaceutical training within PICs. PMID- 23738575 TI - Coarse grained molecular dynamics of engineered macromolecules for the inhibition of oxidized low-density lipoprotein uptake by macrophage scavenger receptors. AB - Atherosclerosis is a condition resulting from the accumulation of oxidized low density lipoproteins (oxLDLs) in arterial walls. Previously developed macromolecules consisting of alkyl chains and polyethylene glycol (PEG) on a mucic acid backbone, termed nanolipoblockers (NLBs) are hypothesized to mitigate the uptake of oxLDL by macrophage scavenger receptors. In this work, we developed a coarse grained model to characterize the interactions between NLBs with a segment of human scavenger receptor A (SR-A), a key receptor domain that regulates cholesterol uptake and foam cell conversion of macrophages, and studied NLB ability to block oxLDL uptake in PBMC macrophages. We focused on four different NLB configurations with variable molecular charge, charge location, and degree of NLB micellization. Kinetic studies showed that three of the four NLBs form micelles within 300 ns and of sizes comparable to literature results. In the presence of SR-A, micelle-forming NLBs interacted with the receptor primarily in an aggregated state rather than as single unimers. The model showed that incorporation of an anionic charge near the NLB mucic acid head resulted in enhanced interaction with the proposed binding pocket of SR-A compared to uncharged NLBs. By contrast, NLBs with an anionic charge located at the PEG tail showed no interaction increase as NLB aggregates were predominately observed to interact away from the oxLDL binding site. Additionally, using two different methods to assess the number of contacts that each NLB type formed with SR-A, we found that the rank order of contacts coincided with our experimental flow cytometry results evaluating the ability of the different NLBs to block the uptake of oxLDL. PMID- 23738576 TI - From immunity to susceptibility: virus resistance induced in tomato by a silenced transgene is lost as TGS overcomes PTGS. AB - Tomato line 30.4 was obtained engineering the nucleocapsid (N) gene of tomato spotted wilt virus into plant genome, and immunity to tomato spotted wilt virus infection of its self-pollinated homozygous progeny was observed. Despite the presence of a high amount of transgenic transcripts, transgenic proteins have not been detected, suggesting a mechanism of resistance mediated by RNA. In the present study, we identify post-transcriptional gene silencing as the main mechanism of resistance, which is able to spread systemically through grafting, and show that the line 30.4 resistant plants produce both 24 and 21-22 nt N-gene specific siRNA classes. The transgenic locus in chromosome 4 shows complex multiple insertions of four T-DNA copies in various orientations, all with 3' end deletions in the terminator and part of the N gene. However, for three of them, polyadenylated transcripts are produced, due to flanking tomato genome sequences acting as alternative terminators. Interestingly, starting at the fifth generation after the transformation event, some individual plants show a tomato spotted wilt virus-susceptible phenotype. The change is associated with the disappearance of transgene-specific transcripts and siRNAs, and with hyper methylation of the transgene, which proceeds gradually through the generations. Once it reaches a critical threshold, the shift from post-transcriptional gene silencing to transcriptional silencing of the transgene eliminates the previously well established virus resistance. PMID- 23738578 TI - A prospective long-term study on the outcome after vagus nerve stimulation at maximally tolerated current intensity in a cohort of children with refractory secondary generalized epilepsy. AB - INTRODUCTION: We report the outcome after vagus nerve stimulation (VNS) in children with secondary generalized epilepsy. METHODS: Twenty-four consecutive children with Lennox-Gastaut or Lennox-like syndrome under the age of 12 years by the time of surgery, who were implanted with a vagus nerve stimulator and had at least two years of postimplantation follow-up, were prospectively included in the study. The generator was turned on using 0.25 mA, 30 Hz, 500 MUsec, 30 sec "on," 5 min "off" stimuli parameters; current was then increased by 0.25 mA every two weeks, until 3.5 mA was reached or adverse effects were noted. RESULTS: Magnetic resonance imaging was normal or showed atrophy in 13 children. Six children got an end-of-study (24 months) postimplantation video-electroencephalogram, and their findings were similar to those before VNS. Quality of life and health measures improved in up to 50% (mean = 25%) in 20 children. Attention was noted to improve in 21 out of the 24 children. Final intensity parameters ranged from 2 to 3.5 mA (mean = 3.1 mA). An implantation effect was noted in 14 out of the 24 children, and lasted a mean of 20.2 days. There were 47 seizure types among the 24 children. An at least 50% seizure frequency reduction was noted in 35 seizure types and 17 seizure types disappeared after VNS. Atypical absence, myoclonic and generalized tonic-clonic seizures were significantly reduced by VNS; tonic and atonic seizures did not improve. Transient seizure frequency worsening was noted in ten of the 24 children, at a mean of 3.1 mA. DISCUSSION: Our study showed that VNS was effective in reducing atypical absence, generalized tonic-clonic, and myoclonic seizures (but not atonic or tonic seizures) in children with Lennox Gastaut or Lennox-like syndrome. A concomitant improvement in attention level and quality of life and health also was noted. Secondary generalized epilepsy represents a subset of good candidates for VNS. PMID- 23738579 TI - Detection of a few metallo-protein molecules using color centers in nanodiamonds. AB - Nanometer-sized diamonds containing nitrogen-vacancy defect centers (NV) are promising nanosensors in biological environments due to their biocompatibility, bright fluorescence, and high magnetic sensitivity at ambient conditions. Here we report on the detection of ferritin molecules using magnetic noise induced by the inner paramagnetic iron as a contrast mechanism. We observe a significant reduction of both coherence and relaxation time due to the presence of ferritin on the surface of nanodiamonds. Our theoretical model is in excellent agreement with the experimental data and establishes this method as a novel sensing technology for proteins. PMID- 23738580 TI - Chemical changes of Angelicae Sinensis Radix and Chuanxiong Rhizoma by wine treatment: chemical profiling and marker selection by gas chromatography coupled with triple quadrupole mass spectrometry. AB - BACKGROUND: Angelicae Sinensis Radix (ASR) and Chuanxiong Rhizoma (CR) can be treated with wine to promote their biological functions in Chinese medicine. Both ASR and CR contain similar volatile chemicals that could be altered after wine treatment. This study aims to identify the differential chemical profiles and to select marker chemicals of ASR and CR before and after wine treatment. METHODS: Chemical analyses were carried out by gas chromatography-triple quadrupole mass spectrometry (GC-QQQ-MS/MS) coupled with multivariate statistical analysis. Characterization of the compositions of essential oils was performed by automated matching to the MS library and comparisons of their mass spectra (NIST08 database). For ferulic acid, butylphthalide, Z-butylidenephthalide, senkyunolide A and Z-ligustilide, the mass spectrometer was operated in electron ionization mode, the selection reaction monitoring mode was used and an evaluation of the stability and sensitivity of the chromatographic system was performed for the tested extraction. RESULTS: Principal component analysis (PCA) simultaneously distinguished ASR and CR from different forms. Ferulic acid, Z butylidenephthalide, Z-ligustilide, butylphthalide and senkyunolide A were screened by PCA loading plots and can be used as chemical markers for discrimination among different groups of samples. CONCLUSION: Different chemical profiles of ASR and CR after wine treatment could be identified by GC-QQQ-MS/MS. The five marker chemicals selected by PCA, namely ferulic acid, butylphthalide, Z butylidenephthalide, senkyunolide A and Z-ligustilide, were sufficient to distinguish between the crude and corresponding wine-treated forms of ASR and CR. PMID- 23738581 TI - Current knowledge on oxidative stress in hepatic ischemia/reperfusion. AB - Ischemia/reperfusion (I/R) injury associated with hepatic resections and liver transplantation remains a serious complication in clinical practice, despite several attempts to solve the problem. The redox balance, which is pivotal for normal function and integrity of tissues, is dysregulated during I/R, leading to an accumulation of reactive oxygen species (ROS). Formation of ROS and oxidant stress are the disease mechanisms most commonly invoked in hepatic I/R injury. The present review examines published results regarding possible sources of ROS and their effects in the context of I/R injury. We also review the effect of oxidative stress on marginal livers, which are more vulnerable to I/R-induced oxidative stress. Strategies to improve the viability of marginal livers could reduce the risk of dysfunction after surgery and increase the number of organs suitable for transplantation. The review also considers the therapeutic strategies developed in recent years to reduce the oxidative stress induced by hepatic I/R, and we seek to explain why some of them have not been applied clinically. New antioxidant strategies that have yielded promising results for hepatic I/R injury are discussed. PMID- 23738583 TI - To bleed or clot? PMID- 23738582 TI - Clarithromycin substantially increases steady-state bosentan exposure in healthy volunteers. AB - AIMS: The aim of this study was to assess the effect of the cytochrome P450 (CYP) 3A4 and organic anion-transporting polypeptide (OATP) 1B1 inhibitor clarithromycin on the pharmacokinetics of bosentan. We also aimed to evaluate the impact of CYP2C9 and SLCO1B1 (encoding for OATP1B1) genotypes and their combination. METHODS: We assessed the effect of the OATP and CYP3A inhibitor clarithromycin on bosentan pharmacokinetics at steady state and concurrently quantified changes of CYP3A activity using midazolam as a probe drug. Sixteen healthy volunteers received therapeutic doses of bosentan (125 mg twice daily) for 14 days and clarithromycin (500 mg twice daily) concomitantly for the last 4 days, and bosentan pharmacokinetics was assessed on days 1, 10 and 14. RESULTS: Clarithromycin significantly increased bosentan area under the plasma concentration-time curve of the dosing interval 3.7-fold and peak concentration 3.8-fold in all participants irrespective of the genotype. Clarithromycin also reduced CYP3A activity (midazolam clearance) in all participants; however, these changes were not correlated to the changes of bosentan clearance. CONCLUSIONS: Clarithromycin substantially increases the exposure to bosentan, suggesting that dose reductions may be necessary. PMID- 23738584 TI - Refining cataract surgery for the developing world. PMID- 23738585 TI - Zn2SnO4 nanowires versus nanoplates: electrochemical performance and morphological evolution during Li-cycling. AB - Zn2SnO4 nanowires have been synthesized directly on stainless steel substrate without any buffer layers by the vapor transport method. The structural and morphological properties are investigated by means of X-ray diffraction (XRD) and transmission electron microscopy (TEM). The electrochemical performance of Zn2SnO4 nanowires is examined by galvanostatic cycling and cyclic voltammetry (CV) measurements in two different voltage windows, 0.005-3 and 0.005-1.5 V vs Li and compared to that of Zn2SnO4 nanoplates prepared by hydrothermal method. Galvanostatic cycling studies of Zn2SnO4 nanowires in the voltage range 0.005-3 V, at a current of 120 mA g(-1), show a reversible capacity of 1000 (+/-5) mAh g( 1) with almost stable capacity for first 10 cycles, which thereafter fades to 695 mAh g(-1) by 60 cycles. Upon cycling in the voltage range 0.005-1.5 V vs Li, a stable, reversible capacity of 680 (+/-5) mAh g(-1) is observed for first 10 cycles with a capacity retention of 58% between 10-50 cycles. On the other hand, Zn2SnO4 nanoplates show drastic capacity fading up to 10 cycles and then showed a capacity retention of 80% and 70% between 10 and 50 cycles when cycled in the voltage range 0.005-1.5 and 0.005-3 V, respectively. The structural and morphological evolutions during cycling and their implications on the Li-cycling behavior of Zn2SnO4 nanowires are examined. The effect of the choice of voltage range and initial morphology of the active material on the Li-cycleabilty is also elucidated. PMID- 23738587 TI - Lipid distribution and influence on hair structure. PMID- 23738586 TI - Intra-oral myofascial therapy versus education and self-care in the treatment of chronic, myogenous temporomandibular disorder: a randomised, clinical trial. AB - BACKGROUND: Myogenous temporomandibular disorders (TMD) are considered to be a common musculoskeletal condition. No studies exist comparing intra-oral myofascial therapies to education, self-care and exercise (ESC) for TMD. This study evaluated short-term differences in pain and mouth opening range between intra-oral myofascial therapy (IMT) and an ESC program. METHODS: Forty-six participants with chronic myogenous TMD (as assessed according to the Research Diagnostic Criteria Axis 1 procedure) were consecutively block randomised into either an IMT group or an ESC group. Each group received two sessions per week (for five weeks) of either IMT or short talks on the anatomy, physiology and biomechanics of the jaw plus instruction and supervision of self-care exercises. The sessions were conducted at the first author's jaw pain and chiropractic clinic in Sydney, Australia. Primary outcome measures included pain at rest, upon opening and clenching, using an eleven point ordinal self reported pain scale. A secondary outcome measure consisted of maximum voluntary opening range in millimetres. Data were analysed using linear models for means and logistic regression for responder analysis. RESULTS: After adjusting for baseline, the IMT group had significantly lower average pain for all primary outcomes at 6 weeks compared to the ESC group (p < 0.001). These differences were not clinically significant but the IMT group had significantly higher odds of a clinically significant change (p < 0.045). There was no significant difference in opening range between the IMT and ESC groups. Both groups achieved statistically significant decreases in all three pain measures at six weeks (p <= 0.05), but only the IMT group achieved clinically significant changes of 2 or more points. CONCLUSION: This study showed evidence of superiority of IMT compared to ESC over the short-term but not at clinically significant levels. Positive changes over time for both IMT and ESC protocols were noted. A longer term, multi-centre study is warranted. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12610000508077. PMID- 23738588 TI - A versatile diphosphine ligand: cis and trans chelation or bridging, with self association through hydrogen bonding. AB - The diphosphine ligand, N,N'-bis(2-diphenylphosphinoethyl)isophthalamide, dpipa, contains two amide groups and can form cis or trans chelate complexes or cis,cis or trans,trans bridged complexes. The amide groups are likely to be involved in intramolecular or intermolecular hydrogen bonding. This combination of properties of the ligand dpipa leads to very unusual structural properties of its complexes, which often exist as mixtures of monomers and dimers in solution. In the complex [Au2(MU-dpipa)2]Cl2, the ligands adopt the trans,trans bridging mode, with linear gold(I) centers, and the amide groups hydrogen bond to the chloride anions. In [Pt2Cl4(MU-dpipa)2], the ligands adopt the cis,cis bridging mode, with square planar platinum(II) centers, and the amide groups form intermolecular hydrogen bonds to the chloride ligands to form a supramolecular one-dimensional polymer. Both the monomeric and dimeric complexes [PtMe2(dpipa)] and [Pt2Me4(MU-dpipa)2] have cis-PtMe2 units with cis chelating or cis,cis bridging dpipa ligands respectively; each forms a supramolecular dimer through hydrogen bonding between amide groups and each contains an unusual NH...Pt interaction. An attempted oxidative addition reaction with methyl iodide gave the complex [PtIMe(dpipa)], which contains trans chelating dpipa, while a reaction with bromine gave a disordered complex with approximate composition [Pt2Me3Br5(MU-dpipa)2], which contains trans,trans bridging dpipa ligands. PMID- 23738589 TI - Lead nephropathy due to Sindoor in India. AB - We report a case of lead nephropathy due to Sindoor treated successfully with steroid, hemodialysis and chelating agent. Diagnosis of lead nephropathy was confirmed by identification of potential sources of lead exposure (Sindoor, 5-10 gm per year for 11 years) indicated by high blood lead level, 95 ug/dL and presence of extrarenal features of lead poisoning (hypertension, anemia, lead line, hyperuricemia). A search for the underlying systemic causes of renal failure yielded no results. A kidney biopsy showed acute or chronic tubule interstitial nephritis with mesangioproliferative glomerulonephritis with no immune deposit on immunofluorescence consistent with lead nephropathy. He was discharged in good health after psychiatric consultation and continued with oral D-Penicillamine with normal renal function tests and urine output. This case identifies Sindoor as a potential lead exposure among Indians and clinicians should be aware of this risk factor and enquire about it when searching a source of lead exposure in high-risk population. PMID- 23738591 TI - Efficacy of methotrexate-loaded poly(epsilon-caprolactone) implants in Ehrlich solid tumor-bearing mice. AB - CONTEXT: Methotrexate (MTX) is used in the treatment of malignancies; however, its clinical application is limited by its toxic dose-related side effects. An alternative to overcome the toxicity of the MTX in healthy tissues is the design of an implantable device capable of controlling the delivery of this drug for an extended period within the tumor site. OBJECTIVE: To develop methotrexate-loaded poly(epsilon-caprolactone) implants (MTX PCL implants) and to demonstrate their efficacy as local drug delivery systems capable of inhibiting Ehrlich solid tumor bearing mice. MATERIALS AND METHODS: MTX PCL implants were produced by the melt molding technique and were characterized by FTIR, WAXS, DSC and SEM. The in vitro and in vivo release of MTX from the PCL implants was also evaluated. The efficacy of implants in inhibiting tumor cells in culture and the solid tumor in a murine model was revealed. RESULTS AND DISCUSSION: The chemical and morphological integrity of the drug was preserved into the polymeric matrix. The in vitro and in vivo release processes of the MTX from the PCL implants were modulated by diffusion. MTX diffused from the implants revealed an antiproliferative effect on tumor cells. Finally, MTX controlled and sustained released from the polymeric implants efficiently reduced 42.7% of the solid tumor in mice paw. CONCLUSION: These implantable devices represented a contribution to improve the efficacy and safety of chemotherapy treatments, promoting long-term local drug accumulation in the targeted site. PMID- 23738590 TI - Identification of minimal human MHC-restricted CD8+ T-cell epitopes within the Plasmodium falciparum circumsporozoite protein (CSP). AB - BACKGROUND: Plasmodium falciparum circumsporozoite protein (CSP) is a leading malaria vaccine candidate antigen, known to elicit protective antibody responses in humans (RTS,S vaccine). Recently, a DNA prime / adenovirus (Ad) vector boost vaccine encoding CSP and a second P. falciparum antigen, apical membrane antigen 1, also elicited sterile protection, but in this case associated with interferon gamma ELISpot and CD8+ T cell but not antibody responses. The finding that CSP delivered by an appropriate vaccine platform likely elicits protective cell mediated immunity provided a rationale for identifying class I-restricted epitopes within this leading vaccine candidate antigen. METHODS: Limited samples of peripheral blood mononuclear cells from clinical trials of the Ad vaccine were used to identify CD8+ T cell epitopes within pools of overlapping 15mer peptides spanning portions of CSP that stimulated recall responses. Computerized algorithms (NetMHC) predicted 17 minimal class I-restricted 9-10mer epitopes within fifteen 15mers positive in ELISpot assay using PBMC from 10 HLA-matched study subjects. Four additional epitopes were subsequently predicted using NetMHC, matched to other study subjects without initial 15mer ELISpot screening. Nine of the putative epitopes were synthesized and tested by ELISpot assay, and six of these nine were further tested for CD8+ T cell responses by ELISpot CD4+ and CD8+ T cell-depletion and flow cytometry assays for evidence of CD8+ T cell dependence. RESULTS: Each of the nine putative epitopes, all sequence-conserved, recalled responses from HLA-matched CSP-immunized research subjects. Four shorter sequences contained within these sequences were identified using NetMHC predictions and may have contributed to recall responses. Five (9-10mer) epitopes were confirmed to be targets of CD8+ T cell responses using ELISpot depletion and ICS assays. Two 9mers among these nine epitopes were each restricted by two HLA supertypes (A01/B07; A01A24/A24) and one 9mer was restricted by three HLA supertypes (A01A24/A24/B27) indicating that some CSP class I-restricted epitopes, like DR epitopes, may be HLA-promiscuous. CONCLUSIONS: This study identified nine and confirmed five novel class I epitopes restricted by six HLA supertypes, suggesting that an adenovirus-vectored CSP vaccine would be immunogenic and potentially protective in genetically diverse populations. PMID- 23738592 TI - Tissue-specific cell wall hydration in sugarcane stalks. AB - Plant cell walls contain water, especially under biological and wet processing conditions. The present work characterizes this water in tissues of sugarcane stalks. Environmental scanning electron microscopy shows tissue deformation upon drying. Dynamic vapor sorption determines the equilibrium and kinetics of moisture uptake. Thermoporometry by differential scanning calorimetry quantifies water in nanoscale pores. Results show that cell walls from top internodes of stalks are more deformable, slightly more sorptive to moisture, and substantially more porous. These differences of top internode are attributed to less lignified walls, which is confirmed by lower infrared spectral signal from aromatics. Furthermore, cell wall nanoscale porosity, an architectural and not directly compositional characteristic, is shown to be tissue-specific. Nanoscale porosities are ranked as follows: pith parenchyma > pith vascular bundles > rind. This ranking coincides with wall reactivity and digestibility in grasses, suggesting that nanoscale porosity is a major determinant of wall recalcitrance. PMID- 23738593 TI - Nationwide time trends in dispensed prescriptions of psychotropic medication for children and adolescents in Denmark. AB - OBJECTIVE: The analysis of time trends in dispensed prescriptions of psychotropic medications for children and adolescents in Denmark. METHOD: The entire data set of the Danish prescription register covering stimulants, antidepressants, antipsychotics, and anxiolytics used in children and adolescents over a 15-year time span from 1996 to 2010 was analyzed. Both non-adjusted age-standardized prevalence rates and adjusted age-standardized prevalence rates considering the increase in patient numbers over time were calculated, and time trends were assessed based on 105908 patient-years. RESULTS: For stimulants, antidepressants, and antipsychotics, the non-adjusted prevalence rates increased significantly. These trends were strongest for the stimulants. However, all adjusted prevalence rates were much lower with the anxiolytics even declining significantly. The prevalence rates of stimulants and antipsychotics were significantly higher among males than females, whereas females received significantly more antidepressants. The increase in prescription rates for both antidepressants and antipsychotics was mainly due to increased use among the 14- to 17-year-olds. Stratification by diagnoses revealed significantly increasing prevalence rates of dispensed antidepressants and antipsychotics in six major diagnostic indications. CONCLUSION: Although increasing, the unadjusted Danish prevalence rates of dispensed prescriptions of psychotropics for children and adolescents are still lower than in many other Western countries. PMID- 23738595 TI - Introducing quality improvement. PMID- 23738594 TI - A range-wide synthesis and timeline for phylogeographic events in the red fox (Vulpes vulpes). AB - BACKGROUND: Many boreo-temperate mammals have a Pleistocene fossil record throughout Eurasia and North America, but only few have a contemporary distribution that spans this large area. Examples of Holarctic-distributed carnivores are the brown bear, grey wolf, and red fox, all three ecological generalists with large dispersal capacity and a high adaptive flexibility. While the two former have been examined extensively across their ranges, no phylogeographic study of the red fox has been conducted across its entire Holarctic range. Moreover, no study included samples from central Asia, leaving a large sampling gap in the middle of the Eurasian landmass. RESULTS: Here we provide the first mitochondrial DNA sequence data of red foxes from central Asia (Siberia), and new sequences from several European populations. In a range-wide synthesis of 729 red fox mitochondrial control region sequences, including 677 previously published and 52 newly obtained sequences, this manuscript describes the pattern and timing of major phylogeographic events in red foxes, using a Bayesian coalescence approach with multiple fossil tip and root calibration points. In a 335 bp alignment we found in total 175 unique haplotypes. All newly sequenced individuals belonged to the previously described Holarctic lineage. Our analyses confirmed the presence of three Nearctic- and two Japan-restricted lineages that were formed since the Mid/Late Pleistocene. CONCLUSIONS: The phylogeographic history of red foxes is highly similar to that previously described for grey wolves and brown bears, indicating that climatic fluctuations and habitat changes since the Pleistocene had similar effects on these highly mobile generalist species. All three species originally diversified in Eurasia and later colonized North America and Japan. North American lineages persisted through the last glacial maximum south of the ice sheets, meeting more recent colonizers from Beringia during postglacial expansion into the northern Nearctic. Both brown bears and red foxes colonized Japan's northern island Hokkaido at least three times, all lineages being most closely related to different mainland lineages. Red foxes, grey wolves, and brown bears thus represent an interesting case where species that occupy similar ecological niches also exhibit similar phylogeographic histories. PMID- 23738596 TI - The GlideScope and the Bonfils is it the device, the operator, or both? PMID- 23738597 TI - Valproic acid and acquired coagulopathy. PMID- 23738598 TI - Preoperative autologous blood transfusion in pediatric craniosynostosis surgery is not without complications, although these may be ameliorated by washing the donated blood. PMID- 23738599 TI - The Fontan patient in the noncardiac setting. PMID- 23738601 TI - Attentional bias and anxiety in individuals with coronary heart disease. AB - This study examined whether in an emotional Stroop task, individuals with coronary heart disease (CHD) would show greater attention towards the threatening words related to their disease than healthy persons, and if such an attentional bias is associated with anxiety. An emotional Stroop task with threatening words related to CHD as well as positive, negative and neutral words was administered to 35 individuals with CHD and 35 healthy controls. Additionally, the original Stroop task, the Beck anxiety inventory and the state-trait anxiety inventory were administered. The results indicated an attentional bias towards threatening words related to CHD in the individuals with CHD. They experienced higher interference than healthy participants from threatening words related to CHD but not from positive or negative words. Moreover, the level of interference was associated with their level of anxiety, and a vicious circle may exist in this association. In addition, results indicated a possible deficit of executive functioning among individuals with CHD. Attentional bias, as well as its association with anxiety, and an indication of deficit in executive functioning among individuals with CHD might be the risk factors for these individuals' quality of life and for further development of their disease. PMID- 23738602 TI - Koebner phenomenon in vitiligo in an Indian population. PMID- 23738603 TI - Genome-wide characterization and expression analysis of genetic variants in sweet orange. AB - Heterozyosity is an important feature of many plant genomes, and is related to heterosis. Sweet orange, a highly heterozygous species, is thought to have originated from an inter-species hybrid between pummelo and mandarin. To investigate the heterozygosity of the sweet orange genome and examine how this heterozygosity affects gene expression, we characterized the genome of Valencia orange for single nucleotide variations (SNVs), small insertions and deletions (InDels) and structural variations (SVs), and determined their functional effects on protein-coding genes and non-coding sequences. Almost half of the genes containing large-effect SNVs and InDels were expressed in a tissue-specific manner. We identified 3542 large SVs (>50 bp), including deletions, insertions and inversions. Most of the 296 genes located in large-deletion regions showed low expression levels. RNA-Seq reads and DNA sequencing reads revealed that the alleles of 1062 genes were differentially expressed. In addition, we detected approximately 42 Mb of contigs that were not found in the reference genome of a haploid sweet orange by de novo assembly of unmapped reads, and annotated 134 protein-coding genes within these contigs. We discuss how this heterozygosity affects the quality of genome assembly. This study advances our understanding of the genome architecture of sweet orange, and provides a global view of gene expression at heterozygous loci. PMID- 23738604 TI - The association between price, competition, and demand factors on private sector anti-malarial stocking and sales in western Kenya: considerations for the AMFm subsidy. AB - BACKGROUND: Households in sub-Saharan Africa are highly reliant on the retail sector for obtaining treatment for malaria fevers and other illnesses. As donors and governments seek to promote the use of artemisinin combination therapy in malaria-endemic areas through subsidized anti-malarials offered in the retail sector, understanding the stocking and pricing decisions of retail outlets is vital. METHODS: A survey of all medicine retailers serving Bungoma East District in western Kenya was conducted three months after the launch of the AMFm subsidy in Kenya. The survey obtained information on each anti-malarial in stock: brand name, price, sales volume, outlet characteristics and GPS co-ordinates. These data were matched to household-level data from the Webuye Health and Demographic Surveillance System, from which population density and fever prevalence near each shop were determined. Regression analysis was used to identify the factors associated with retailers' likelihood of stocking subsidized artemether lumefantrine (AL) and the association between price and sales for AL, quinine and sulphadoxine-pyrimethamine (SP). RESULTS: Ninety-seven retail outlets in the study area were surveyed; 11% of outlets stocked subsidized AL. Size of the outlet and having a pharmacist on staff were associated with greater likelihood of stocking subsidized AL. In the multivariable model, total volume of anti malarial sales was associated with greater likelihood of stocking subsidized AL and competition was important; likelihood of stocking subsidized AL was considerably higher if the nearest neighbour stocked subsidized AL. Price was a significant predictor of sales volume for all three types of anti-malarials but the relationship varied, with the largest price sensitivity found for SP drugs. CONCLUSION: The results suggest that helping small outlets overcome the constraints to stocking subsidized AL should be a priority. Competition between retailers and prices can play an important role in greater adoption of AL. PMID- 23738605 TI - Diagnostic performance of alpha-fetoprotein, lens culinaris agglutinin-reactive alpha-fetoprotein, des-gamma carboxyprothrombin, and glypican-3 for the detection of hepatocellular carcinoma: a systematic review and meta-analysis protocol. AB - BACKGROUND: Diagnosis of early-stage hepatocellular carcinoma (HCC) followed by curative resection or liver transplantation offers the best chance for long-term patient survival. Clinically, ultrasonography has suboptimal sensitivity for detecting early-stage HCC. Several serological tests including alpha-fetoprotein (AFP), the ratio of lens culinaris agglutinin-reactive alpha-fetoprotein to total AFP (AFP-L3/AFP), des-gamma carboxyprothrombin (DCP), and glypican-3 (GPC-3) have been widely investigated as diagnostic biomarkers for early-stage HCC in at-risk populations. However, these tests are not recommended for routine HCC screening. Our objective is to determine the diagnostic performance of AFP, AFP-L3/AFP, DCP, and GPC-3 for the detection of HCC, particularly early-stage tumors meeting the Milan criteria. METHODS/DESIGN: We will include cross-sectional studies that consecutively or randomly recruit target populations. We will search the Cochrane Library, Medline, Embase, Science Citation Index, and the Chinese National Knowledge Infrastructure. We will also search the MEDION and ARIF databases to identify diagnostic systematic reviews that include primary studies. Reference lists of relevant reviews will be searched for additional trials. Language restrictions will not be applied. Two reviewers will independently screen study eligibility and extract data. Methodological quality will be assessed according to the revised tool for the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2). Two authors will apply the QUADAS-2 assessment to all the included studies, and any discrepancies will be resolved by the third author. The following test characteristics will be extracted into 2 * 2 tables for all included studies: true positives, false positives, true negatives, and false negatives. Study-specific estimates of sensitivity and specificity with 95% confidence intervals will be displayed in forest plots. When possible, we will use the bivariate random-effects model or the Rutter and Gatsonis hierarchical summary receiver operating characteristic model for statistical analysis. To investigate heterogeneity, we will include study designs, population characteristics, test characteristics, and types of reference standard as the study-level variables. DISCUSSION: Our systematic review will allow patients, clinicians, and researchers to determine the diagnostic performance of AFP, AFP L3/AFP, DCP, and GPC-3 for the detection of early-stage HCC and the potential roles of these diagnostic biomarkers in the existing diagnostic pathways.Systematic Review Registration: PROSPERO 2013; CRD42013003879. PMID- 23738606 TI - Time of day variation in door-to-balloon time for STEMI patients in Los Angeles County: does time of day make a difference? AB - OBJECTIVE: Evaluate treatment times and clinical outcome in a consecutive series of ST segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI) in Los Angeles County. BACKGROUND: Primary PCI for STEMI is beneficial if performed in a timely manner. Conflicting data exist regarding potential treatment delays for primary PCI performed during off hours. METHODS: The Emergency Medical Services STEMI Receiving Center Database was queried from 2007 to 2009 to identify patients with a pre-hospital ECG showing STEMI who underwent PCI. On-hour PCI (On-hour Group, n = 1324) was defined as PCI occurring from 8 am to 5 pm and off-hour PCI (Off-hour Group, n = 922) was defined as occurring from 5 pm to 8 am. Treatment times, length of stay, vascular complications, achievement of TIMI 3 flow and in-hospital mortality were evaluated. RESULTS: Off-hours PCI occurred in 41% of patients. Medical contact to door time was similar in the Off-hour Group compared to the On-hour Group, 20.7 +/- 14.6 versus 20.3 +/- 12.3 min, respectively, P = 0.47. In patients with available data (n = 1366), the door-to-catheterization laboratory (CL) activation time was significantly shorter in the On-hour Group as compared to the Off-hour Group, -4.9 +/- 11.9 versus -0.2 +/- 27.5 min, respectively, P < 0.0001. Door-to balloon time was significantly longer in the Off-hour Group compared to the On hour Group, 74 +/- 35 versus 60 +/- 26 min respectively, P < 0.0001. Length of stay, vascular complications, final TIMI 3 flow and in-hospital mortality were similar between both groups. CONCLUSIONS: In STEMI patients receiving primary PCI in Los Angeles County, off-hour PCI was common. Short-term clinical outcomes were similar despite longer door-to-balloon time in patients receiving off-hour PCI. The longer door-to-balloon time in the off-hour PCI patients were partly explained by longer door-to-CL activation time. PMID- 23738607 TI - Composition characterization and clinical efficacy study of a salmon egg extract. AB - OBJECTIVE: There is an increasing demand for scientifically documented over-the counter products on the cosmetic market. Salmon eggs are rich in proteins, vitamins and minerals with anti-oxidative and anti-inflammatory properties, as well as free amino acids and lipids documented to be beneficial for skin. Of the fatty acids, several are commonly used as skin penetration enhancers. The unique combination of active substances led us to study whether an extract from salmon eggs could serve as an ingredient for skin care. METHODS: We conducted a double blinded, randomized clinical trial with 66 healthy female volunteers. Efficacy of the salmon egg extract was evaluated at concentrations of 1% and 5% in vehicle formulation, and responses after 7, 14, 28 and 56 days of treatment were compared with baseline. Composition of the extract was analysed to improve the understanding of the effects of the extract on skin. The salmon egg extract was safety-tested by repeat insult patch test. RESULTS: Treatment of facial skin with the salmon egg extract significantly improved all parameters investigated, wrinkles, pigmentation, redness, brightness and hydration and led to global improvement of the facial skin. Efficacy of the extract was dose dependent and time dependent. There were no adverse reactions noted during the course of the repeat insult patch test, demonstrating that the extract causes neither skin irritation nor sensitization. Furthermore, chemical analyses of the extract revealed the composition of a vast number of active substances, including unsaturated fatty acids, vitamins, proteins, minerals, DNA and RNA. CONCLUSION: The salmon egg extract serves as a skin care ingredient that significantly improves characteristics important for perception of skin ageing and health. The efficacy of the treatment is conceivably accounted for by the unique combination of numerous active substances present in the salmon egg extract. PMID- 23738608 TI - A combined experimental and DFT/TD-DFT investigation of structural, electronic, and cation-induced switching of photophysical properties of bimetallic Ru(II) and Os(II) complexes derived from imidazole-4,5-dicarboxylic acid and 2,2' bipyridine. AB - Experimental results coupled with computational studies were utilized to investigate the structural and electronic properties of mixed-ligand bimetallic ruthenium(II) and osmium(II) complexes of composition [(bpy)2M(Imdc)M(bpy)2](+) [M = Ru(II) (1) and M = Os(II) (2)], where H3Imdc = imidazole-4,5-dicarboxylic acid and bpy = 2,2'-bipyridine. The X-ray crystal structures of both the bimetallic complexes were determined which showed that compound 1 crystallizes in monoclinic form with space group P2(1)/c, while 2 is obtained in orthorhombic form with the space group Pca2(1). The optimized geometrical parameters for the complexes computed both in the gas phase and in solution are reported and compared with the single-crystal X-ray data. The absorption spectra, redox behaviors, and luminescence properties of the complexes were thoroughly investigated. The complexes display very intense, ligand-centered absorption bands in the UV and moderately intense MLCT bands in the visible regions. While the Ru(II) complex displays moderately strong luminescence, the corresponding Os(II) complex does not luminesce at room temperature. Both the bimetallic complexes show two successive one-electron reversible metal-centered oxidations. The effect of alkali, alkaline earth, and transition metal cations on the absorption and emission spectral behavior of the complexes has also been studied in detail. As compared to the luminescence intensities and the quantum yields of the free complexes, those of the complexes were enhanced substantially in the presence of selective cations showing cation-induced molecular switching behaviors. Density functional theory (DFT) and time-dependent DFT (TD-DFT) studies provide insight into the nature of the ground and excited states with resulting detailed assignments of the orbitals involved in absorption and emission transitions. In particular, the blue-shifts of the absorption and emission bands in the presence of cations are also reproduced by our calculations. PMID- 23738611 TI - Placenta praevia after prior caesarean section: an exploratory case-control study. AB - OBJECTIVE: To identify additional risk factors for placenta praevia in women with prior caesarean section. METHOD: A retrospective case-control study of 53 cases and 157 controls was performed. Information was obtained from the National Women's database between 2004 and 2009. Cases were defined as women with diagnosed placenta praevia over 20 weeks' gestation and having had one or more prior caesarean sections. Risk factors assessed from the prior caesarean section were (i) type of suture used for hysterotomy closure; (ii) stage of labour; (iii) type of primary surgeon; and (iv) model of funding. Univariate and logistical regression analyses were performed. RESULTS: Use of monofilament suture for hysterotomy closure in prior caesarean section significantly reduced the chance of having placenta praevia in the index pregnancy (adjusted odds ratio 0.26, 95% confidence interval 0.08-0.80), as did prior caesarean being performed in the first stage of labour (aOR 0.36, 95% CI 0.14-0.92). Type of primary surgeon (specialist vs trainee junior doctor), nor model of funding of prior caesarean section (public vs private), was associated with risk of placenta praevia (privately funded specialist aOR 4.75, 95% CI 0.89-25.23 and trainee junior doctor aOR 3.18, 95% CI 0.59-17.28, respectively). CONCLUSION: A prior caesarean section performed in first stage, and monofilament suture for hysterotomy closure, reduced the chance of having placenta praevia in the index pregnancy. PMID- 23738610 TI - Monoclonal antibodies to 65kDa glutamate decarboxylase induce epitope specific effects on motor and cognitive functions in rats. AB - BACKGROUND: Stiff Person Syndrome (SPS) is a rare autoimmune movement disorder characterized by the presence of autoantibodies specific to the smaller isoform of glutamate decarboxylase (GAD65). A pathological role of these antibodies has been suggested by their capacity to inhibit GAD65 enzyme activity and by the observation that rats receiving cerebellar injections of GAD65Ab showed cerebellar motor hyperexcitability. To assess the effect of epitope-specific GAD65Ab on cognitive and motor functions, we conducted behavioral experiments in rats that received cerebellar injections with two distinct monoclonal GAD65Ab (b96.11 and b78). METHODS: Rats received three injections of GAD65Ab b96.11 (5 or 7 MUg), GAD65Ab b78 (5 or 7 MUg), or saline at the level of three cerebellar nuclei. Animals were submitted to neurological evaluation and Morris Water Maze (MWM) test. Cellular internalization of GAD65Ab was analyzed by Flow Cytometry, Fluorescence and Bright Field microscopy. RESULTS: Monoclonal GAD65Ab induced dose-dependent and epitope-specific effects on motor and cognitive functions. Injections of the higher dose altered motor and spatial procedural behaviors, while the lower dose induced only modest cerebellar motor symptoms and did not affect MWM performances. While b96.11 provoked immediate severe effects, which rapidly decreased, b78 induced moderate but prolonged effects. Both GAD65Ab were taken up by live cells in a dose-dependent manner. CONCLUSIONS: Our findings support the hypothesis that epitope-specific GAD65Ab induce cerebellar dysfunction impairing motor and procedural abilities. This is the first demonstration of a critical role of cerebellar nuclei GAD65 enzyme in procedural spatial functions. PMID- 23738609 TI - Prevalence of obesity and associated cardiovascular risk: the DARIOS study. AB - BACKGROUND: To estimate the prevalence of overweight and obesity in the Spanish population as measured with body mass index (BMI), waist circumference (WC) and waist to height ratio (WHtR) and to determine the associated cardiovascular risk factors. METHODS: Pooled analysis with individual data from 11 studies conducted in the first decade of the 21st century. Participants aged 35-74 years were asked about the history of cardiovascular diseases, hypertension, diabetes and hypercholesterolemia. Height, weight, WC, blood pressure, glycaemia, total cholesterol, low-density and high-density lipoprotein cholesterol and coronary risk were measured. The prevalence of overweight (BMI 25-29.9 kg/m(2)), general obesity (BMI >= 30 kg/m(2)), suboptimal WC (>= 80 cm and < 88 in women, >= 94 and < 102 in men), abdominal obesity (WC >=88 cm >=102 cm in women and men, respectively) and WHtR >=0.5 was estimated, standardized for the European population. RESULTS: We included 28,743 individuals. The prevalence of overweight and suboptimal WC was 51% and 30% in men and 36% and 22% in women, respectively; general obesity was 28% in both sexes and abdominal obesity 36% in men and 55% in women. The prevalence of WHtR >=0.5 was 89% and 77% in men and women, respectively. All cardiovascular risk factors were significantly associated with abnormal increased values of BMI, WC and WHtR. Hypertension showed the strongest association with overweight [OR = 1.99 (95% confidence interval 1.81-2.21) and OR = 2.10 (1.91-2.31)]; suboptimal WC [OR = 1.78 (1.60-1.97) and OR = 1.45 (1.26 1.66)], with general obesity [OR = 4.50 (4.02-5.04), and OR = 5.20 (4.70-5.75)] and with WHtR >=0.5 [OR = 2.94 (2.52-3.43), and OR = 3.02 (2.66-3.42)] in men and women respectively, besides abdominal obesity in men only [OR = 3.51 (3.18 3.88)]. Diabetes showed the strongest association with abdominal obesity in women [OR = 3,86 (3,09-4,89). CONCLUSIONS: The prevalence of obesity in Spain was high. Overweight, suboptimal WC, general, abdominal obesity and WHtR >=0.5 was significantly associated with diabetes, hypertension, hypercholesterolemia and coronary risk. The use of lower cut-off points for both BMI and particularly WC and could help to better identify the population at risk and therefore achieve more effective preventive measures. PMID- 23738612 TI - Efficacy and safety of lidocaine for treatment of neonatal seizures. AB - AIM: Treatment of neonatal seizures still relies primarily on phenobarbital, despite an estimated efficacy of less than 50% and concern over neurodegenerative side effects. The objective of this study was to evaluate the efficacy and safety of lidocaine as second-line treatment of neonatal seizures in infants following benzodiazepine treatment but without previous treatment with phenobarbital. METHODS: In a 10-year cohort, a retrospective chart review was conducted for all infants (gestational age >= 37 w, age <= 28 days) who had received lidocaine as second-line treatment of neonatal seizures prior to treatment with phenobarbital between January 2000 and June 2010. Infants were included if they had electroencephalographic seizures. RESULTS: Cessation of seizure activity was seen in 16 of 30 infants based on clinical and electroencephalographic features, and a probable response was seen in an additional 3 of 30 patients. Suspected adverse effects were seen in only one patient, who developed a transient bradycardia. CONCLUSION: Lidocaine has a moderate efficacy as second-line therapy following benzodiazepines for treating neonatal seizures and is not frequently associated with cardiovascular adverse effects. Lidocaine should therefore be considered in the treatment of seizures in the neonatal period to a higher extent than is the case today. PMID- 23738613 TI - Adhesion property profiles of supported thin polymer films. AB - Polymer coatings are frequently utilized to control and modify substrate properties. The performance of the coatings is often determined by the first polymer layers between the substrate and the bulk polymer material, which are termed interphase. Standard methods have failed to completely characterize this interphase, because its properties change significantly over a few nanometers. Here we determine the spatially resolved adhesion properties of the interphase in polyelectrolyte multilayers (PEMs) by desorbing a single polymer covalently bound to an atomic force microscope cantilever tip from PEMs with varying thickness. We show that the adhesion properties of the first few layers (up to three double layers) is dominated by the surface potential of the substrate, while thicker PEMs are controlled by cohesion in between the PEM polymers. For cohesion, the local film conformation is the crucial parameter. This finding is generalized by utilizing oligoelectrolyte multilayer (OEM) as coatings and both hydrophilic and hydrophobic polymers as polymeric force sensors. PMID- 23738614 TI - A C(sp3)-C(sp3) bond forming reductive condensation of alpha-keto esters and enolizable carbon pronucleophiles. AB - The preparation of densely functionalized unsymmetrical 1,4-dicarbonyl structural motifs by a phosphorus(III)-mediated reductive condensation of alpha-keto esters and enolizable carbon pronucleophiles is described. The reaction, which is initiated by Kukhtin-Ramirez addition of commercially available tris(dimethylamino)phosphine to the alpha-keto ester substrate, proceeds rapidly under mild conditions. PMID- 23738615 TI - The utility of the Gilliam autism rating scale for identifying Iranian children with autism. AB - PURPOSE: Screening and assessment tools for developmental disabilities such as autism may need to be adjusted to particular cultures. The aim of this study was to evaluate the use in Iran of a rating scale for autism commonly used in western society. METHOD: A Persian translation of the GARS was completed by parents of 658 children: 442 who had been diagnosed with Autism; 112 intellectually disabled and 102 normally developing. The psychometric properties of the subscales were assessed and comparisons made across the three groups. RESULTS: Factor analysis broadly confirmed the three subscales; each of which had high internal consistency. Individuals with autism were clearly distinguished from the other two groups and a cut-off score was identified that maximised the scale's sensitivity and specificity. Ten items were identified that best discriminated the three groups and these could form the basis for a shorter screening tool as they had good internal reliability and predictive validity. CONCLUSIONS: Iranian parents identified items relating to impaired social interaction and repetitive behaviours as more indicative of autism rather than those relating to communication and language. Attuning screening tools to cultural contexts is an important step towards a better understanding of autism internationally. Implications for Rehabilitation Early identification of autism enables appropriate interventions to be commenced and support offered to families. Screening tools developed in western society needs to be evaluated for their suitability in other cultures internationally as well as with immigrant communities. Iranian professionals working in child development clinics could use the translated version of GARS with some confidence. In addition a shorter screening tool was developed comprising 10 autistic traits that were especially salient to an Iranian culture. PMID- 23738616 TI - Differences in patterns of participation in leisure activities in Swedish children with and without disabilities. AB - PURPOSE: To compare participation in leisure activities between Swedish children with and without disabilities and to examine whether age, gender, presence of disabilities, and mother's educational level influence participation. METHOD: A Swedish version of the Children's Assessment of Participation and Enjoyment was used to study the diversity, intensity, and enjoyment of participation in leisure activities of children aged 6 to 17 years. Fifty-five of the children had disabilities and 337 of the children did not have disabilities. A multiple regression analysis was conducted to explore the impact of age, gender, mother's level of education, and disability on the diversity, intensity, and enjoyment of leisure activities. A t-test for independent samples was used to compare the diversity and intensity of participation between children with and without disabilities. RESULTS: The multiple regression analysis explained 4-36% of the variance of diversity, intensity, and enjoyment. Children with disabilities participated with higher diversity, but with less intensity, than children without disabilities. Younger children had higher levels of enjoyment. CONCLUSIONS: Children with disabilities participated in several different activities, but the presence of a disability was associated with lower intensity of participation. The low explanatory value of the investigated variables indicates that the combined effect of several variables needs to be taken into consideration when designing participation interventions. Implications for Rehabilitation Children with disabilities participated in a high number of activities but with a low intensity compared to children without disabilities. Analysis of the children's personal and environmental barriers and facilitators is critical to providing the therapist with ideas about which strategies should be implemented to increase participation. Assessment and intervention may need to focus on methods for supporting the children's autonomy and on creating goals for intervention that focus on activities that are determined by the child based on their interests and desires. Age and gender influenced the variance in the diversity and enjoyment outcome and the presence of disability was associated with the intensity outcome. Age, gender, parental educational level, and disability only explain a small proportion of the variance in leisure participation patterns. Thus, client-centred and individually tailored interventions are needed that are based on the individual's unique situation. PMID- 23738617 TI - The emerging pattern of disability in Rwanda. AB - PURPOSE: The purpose of this paper is to describe the emerging pattern of disability (activity limitation) in terms of its prevalence, age and gender distribution in Rwanda. METHOD: A door-to-door survey was conducted in all households in villages from two districts selected through a multi-stage sampling procedure. Identified persons were screened for activity limitations using age appropriate instruments developed from domains in the ICF. Proportions were computed and disaggregated by age group, gender, district and activity limitation. A multi-disciplinary rehabilitation team including community members participated in the development of instruments, community mobilisation, data collection and collation. RESULTS: Prevalence rates of 8.6% (Bugesera) and 14.7% (Musanze) were obtained. The prevalence of disability was higher in adults than in children in both districts (10.4% versus 6.6% in Bugesera and 19.6% versus 7.7% in Musanze). Visual limitations occurred the most frequently in both adults and children in both districts. Mobility and mental health limitations also notably contributed to the overall disability burden. CONCLUSION: The prevalence of disability obtained was higher than all previously reported data for Rwanda. Despite the limitations, the findings provide useful information for planning rehabilitation services and to direct future enquiry into the epidemiology of disability in Rwanda. Implications for Rehabilitation It is important to design specific surveys to measure disability using contemporary methods to gauge the situation accurately and qualitatively. Currently, the ICF provides the best framework to describe the epidemiology of disability meaningfully; it enables comparisons within and between countries and regions of the world; and enables the active participation of a wide range of rehabilitation stakeholders including PWDs and lay community members. The vast majority of disabilities in Rwanda are limitations in visual, mobility and mental health functions. PMID- 23738619 TI - Efficacy of falls prevention interventions: protocol for a systematic review and network meta-analysis. AB - BACKGROUND: Falls are a leading cause of morbidity and mortality in older adults. Although numerous trials of falls prevention interventions have been completed, there is extensive variation in their intervention components and clinical context, such that the key elements of an effective falls prevention program remain unclear to patients, clinicians, and policy-makers. Our objective is to identify the most effective interventions and combinations of interventions that prevent falls though a systematic review and meta-analysis, including a network meta-analysis. METHODS/DESIGN: We will search for published (e.g., MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Ageline) and unpublished (e.g., trial registries, dissertations) randomised clinical trials (RCTs) in all languages examining interventions to prevent falls compared to usual care or other falls prevention interventions among adults aged >=65 years from all settings (e.g., community, acute care, long-term care, and rehabilitation). The primary outcomes are number of injurious falls and number of hospitalizations due to falls. Secondary outcomes include falls rate, number of fallers, number of emergency room visits due to falls, number of physician visits due to falls, number of fractures, costs, and number of intervention-related harms (e.g., muscle soreness related to exercise).We will calibrate our eligibility criteria amongst the team and two independent team members will screen the literature search results in duplicate. Conflicts will be resolved through team discussion. A similar process will be used for data abstraction and quality appraisal with the Cochrane risk of bias tool.Our results will be synthesized descriptively and a random effects meta-analysis will be conducted if the studies are deemed methodologically, clinically, and statistically (e.g., I2<60%) similar. If appropriate, a network meta-analysis will be conducted, which will allow the comparison of interventions that have not been compared in head-to-head RCTs, as well as the effectiveness of interventions. DISCUSSION: We will identify the most effective interventions and combinations of interventions that prevent falls in older people. Our results will be used to optimize falls prevention strategies, and our goal is to ultimately improve the health of seniors internationally. TRIAL REGISTRATION: PROSPERO registry number: CRD42013004151. PMID- 23738620 TI - Directed dimerization: an in vivo expression system for functional studies of type II phytochromes. AB - Type II phytochromes (phy) in Arabidopsis form homodimers and heterodimers, resulting in a diverse collection of light-stable red/far-red (R/FR) sensing photoreceptors. We describe an in vivo protein engineering system and its use in characterizing the activities of these molecules. Using a phyB null mutant background, singly and doubly transgenic plants were generated that express fusion proteins containing the phyB-phyE N-terminal photosensory regions (NB-NE PSRs), a nuclear localization sequence, and small yeast protein domains that mediate either homodimerization or heterodimerization. Activity of NB/NB homodimers but not monomeric NB subunits in control of seedling and adult plant responses to R light is demonstrated. Heterodimers of the NB sequence with the chromophoreless NB(C357S) sequence, which mimic phyB Pfr/Pr photo-heterodimers, mediate R sensitivity in leaves and petioles but not hypocotyls. Homodimerization of the NC, ND and NE sequences and directed heterodimerization of these photosensory regions with the NB region reveal form-specific R-induced activities for different type II phy dimers. The experimental approach developed here of directed assembly of defined protein dimer combinations in vivo may be applicable to other systems. PMID- 23738621 TI - In vitro shear stress-induced platelet activation: sensitivity of human and bovine blood. AB - As platelet activation plays a critical role in physiological hemostasis and pathological thrombosis, it is important in the overall hemocompatibility evaluation of new medical devices and biomaterials to assess their effects on platelet function. However, there are currently no widely accepted in vitro test methods to perform this assessment. In an effort to develop effective platelet tests for potential use in medical device evaluation, this study compared the sensitivity of platelet responses to shear stress stimulation of human and bovine blood using multiple platelet activation markers. Fresh whole blood samples anticoagulated with heparin or anticoagulant citrate dextrose, solution A (ACDA) were exposed to shear stresses up to 40 Pa for 2 min using a cone-and-plate rheometer model. Platelet activation was characterized by platelet counts, platelet surface P-selectin expression, and serotonin release into blood plasma. The results indicated that exposure to shear stresses above 20 Pa caused significant changes in all three of the platelet markers for human blood and that the changes were usually greater with ACDA anticoagulation than with heparin. In contrast, for bovine blood, the markers did not change with shear stress stimulation except for plasma serotonin in heparin anticoagulated blood. The differences observed between human and bovine platelet responses suggest that the value of using bovine blood for in vitro platelet testing to evaluate devices may be limited. PMID- 23738622 TI - Relationship between apnoea-hypopnoea index and angiographic?coronary disease phenotypes in patients presenting with acute?myocardial infarction. AB - BACKGROUND: Relationship between obstructive sleep apnoea and atherosclerosis has not been confirmed using coronary angiography. We sought to investigate the relationships between the apnoea-hypopnoea index (AHI) and angiographic coronary disease phenotypes.? METHODS: SYNTAX score, lesion complexity, and thrombus burden grade were determined in 125 patients presenting with acute myocardial infarction and had undergone a screening sleep study. Severe OSA was defined as AHI >= 30.? RESULTS: Most of the recruited patients were male (97.6%). Severe obstructive sleep apnoea was diagnosed in 37% of the patients. The severe obstructive sleep apnoea group (n = 46) was older (P = 0.039) and more obese (P = 0.003) than the non-severe group (n = 79). There was no evidence of difference between the severe and non-severe obstructive sleep apnoea groups with regard to SYNTAX score (P = 0.871), number of complex lesions (P = 0.241), and thrombus burden grade (P = 0.433). Multivariate analysis adjusting for difference in age and body mass index did not change the findings. CONCLUSION: Using the three angiographic scoring systems, we found no association between AHI and angiographic coronary disease phenotypes, suggesting a limited effect of obstructive sleep apnoea on the amount and distribution of coronary plaques in patients presenting with acute myocardial infarction. PMID- 23738623 TI - Stress hyperglycemia in acute ST-segment elevation myocardial infarction is a marker of left ventricular remodeling. AB - INTRODUCTION: Stress hyperglycemia (SH) in STEMI is associated with high risk of in-hospital mortality. It is still controversial if SH is marker of high post hospital risk. OBJECTIVES: The aim was to analyze in-hospital and one-year risk associated with SH in STEMI and to study if SH is marker of LV remodeling. METHODS: We enrolled 275 patients who were admitted with first STEMI and reperfused. Patients were divided according to admission glycemia in three groups: (1) with diabetes mellitus (DM); (2) with SH, without DM and; (3) without both DM and SH. SH was defined as admission blood glucose level >= 8 mmol/l. RESULTS: In-hospital mortality was higher in patients with known DM (5%) and highest in patients with SH without previous DM (9.3%), and only 1.6% in the third group, P < 0.05. In patients without known DM, SH was associated with 6.378 fold higher in-hospital mortality. Total mortality was double in group with SH without DM compared to the third group (13.9% versus 6.3%). EDV changed in patients with SH without DM from 126 +/- 37 to 145 +/- 30 ml after one year, P < 0.05. CONCLUSION: SH is associated with high in-hospital mortality risk and it could be marker of LV remodeling (significant increase of EDV during one year). PMID- 23738624 TI - The road most travelled: the geographic distribution of road traffic injuries in England. AB - BACKGROUND: Both road safety campaigns and epidemiological research into social differences in road traffic injury risk often assume that road traffic injuries occur close to home. While previous work has examined distance from home to site of collision for child pedestrians in local areas, less is known about the geographic distribution of road traffic injuries from other modes. This study explores the distribution of the distance between home residence and collision site (crash distance) by mode of transport, geographic area, and social characteristics in England. METHODS: Using 10 years of road casualty data collected by the police, we examined the distribution of crash distance by age, sex, injury severity, area deprivation, urban/rural status, year, day of week, and, in London only, ethnic group. RESULTS: 54% of pedestrians, 39% of cyclists, 17% of powered two-wheeler riders and 16% of car occupants were injured within 1 km of home. 82% of pedestrians, 83% of cyclists, 54% of powered two-wheeler and 53% of car occupants were injured within 5 km of home. We found some social and geographic differences in crash distance: for all transport modes injuries tended to occur closer to home in more deprived or urban areas; younger and older pedestrians and cyclists were also injured closer to home. Crash distance appears to have increased over time for pedestrian, cyclist and car occupant injuries, but has decreased over time for powered two-wheeler injuries. CONCLUSIONS: Injuries from all travel modes tend to occur quite close to home, supporting assumptions made in epidemiological and road safety education literature. However, the trend for increasing crash distance and the social differences identified may have methodological implications for future epidemiological studies on social differences in injury risk. PMID- 23738625 TI - Identification of a sphingolipid-specific phospholipase D activity associated with the generation of phytoceramide-1-phosphate in cabbage leaves. AB - The structure and biosynthetic route for an unidentified lipid (lipid X) detected by TLC of cabbage (Brassica oleracea) lipids was determined. Lipid X is a phospholipid that is resistant to mild alkali and detectable by MALDI-TOF MS as an adduct with Phos-tag, a phosphate-capture zinc complex. Various alpha-hydroxy fatty acids (16:0, 22:0, 24:0 and 24:1) were detected by GC-MS of fatty acid methyl esters prepared from lipid X. The deacyl derivative of lipid X was determined to be 4-hydroxysphingenine (dehydrophytosphingosine)-1-phosphate by MALDI-TOF MS with Phos-tag. From these results, lipid X was determined to be phytoceramide-1-phosphate (PC1P) with an alpha-hydroxy fatty acid. When cabbage homogenates were incubated, PC1P was formed, with a concomitant decrease in the amount of glycosylinositol phosphoceramide (GIPC). The formation of PC1P from GIPC was confirmed by treatment of purified cabbage GIPC with a membrane fraction of cabbage homogenates. Using a partially purified enzyme fraction, we found that the enzyme hydrolyzes GIPC specifically, but not glycerophospholipids and sphingomyelin. Arabidopsis thaliana also had this enzyme activity. From these results, we conclude that a previously uncharacterized phospholipase D activity that specifically hydrolyzes GIPC produces PC1P in brassicaceous plants. PMID- 23738627 TI - A retrospective audit to examine the effectiveness of preoperative warming on hypothermia in spine deformity surgery patients. AB - BACKGROUND: Hypothermia (core body temperature <36 degrees C) during surgery has been associated with surgical site infection, a major risk in all spine deformity surgeries. Forced air warming is an important method of intraoperative temperature maintenance in children. In mid-2010, we empirically introduced preoperative warming as a strategy to reduce intraoperative hypothermia. OBJECTIVE: We report the prevalence and extent of hypothermia during spine deformity surgeries at our institution and evaluate the effect of the introduction of preoperative warming. METHODS: We performed a retrospective audit of temperature data in children who underwent spine deformity surgeries during two-seven-month periods: November 2011 to June 2012 and 2 years prior to this period (before preoperative warming implementation). Specifically, the following data were obtained: (i) case duration; (ii) first measured temperature; (iii) last measured temperature; (iv) percentage of case spent hypothermic; (v) number of hypothermic episodes per case, and (vi) delay between case start and time of first temperature measured. Data were compared visually and using the Mann Whitney U-test. Confidence intervals (CI) were obtained using the Hodges-Lehmann estimator. RESULTS: Preoperative warming reduced the percentage of case duration spent hypothermic by a median of 111.1 min (P < 0.001, 95% CI 77.1-139.9 min). Additionally, it increased the first measured temperature by a median of 0.5 degrees C (P < 0.001, 95% CI 0.3-0.7 degrees C). The last temperature at the end of the case remained unchanged (P = 0.57, 95% CI -0.2-0.1 degrees C). CONCLUSION: Preoperative warming of children undergoing spine deformity surgery significantly reduces the percentage of case spent hypothermic, thereby potentially reducing risk of perioperative complications. PMID- 23738628 TI - Anatomical location of the medial lemniscus and spinothalamic tract at the pons in the human brain: a diffusion tensor tractography study. AB - Using diffusion tensor tractography, we investigated the anatomical location of medial lemniscus (ML) and spinothalamic tract (STT) at pons. We recruited 47 healthy volunteers. Evaluation of the anatomical location of ML and STT was performed using the highest probabilistic location at the upper, middle, and lower pons. According to findings, MLs were located around the middle to medial one-third, between midline and lateral boundary of pons in the pontine tegmentum and STTs were located posterolaterally to ML. PMID- 23738629 TI - Attentional processes during submaximal exercises. AB - Blood levels of lactate and glucose were measured in 15 healthy male athletes with the purpose of evaluating possible correlation between their blood values and intensity and selectivity of attention, after a 30-min steady-state test performed at 60 and 80% of maximal oxygen consumption (VO2max). On the basis of the results, we conclude that, during aerobic exercise, a worsening of attentional capabilities does not occur unless there is an increase of blood lactate above 4 mmol/l. PMID- 23738630 TI - Whole-mount evaluation of penectomies for penile cancer: feasibility, cost and comparison to routine sectioning. AB - AIMS: Pathological staging in penectomies may be difficult due to the anatomical complexity of penile anatomy, and may be additionally challenging due to the low volume at most institutions. Our study aimed to assess the feasibility of whole mount processing for penectomy specimens. METHODS AND RESULTS: A 7-year retrospective search for partial or radical penectomies identified 55 specimens, which were processed routinely (n = 31) from 2006 to 2009 and whole-mounted (n = 24) from 2010 to 2012. Routine cases used more slides per case compared to whole mounts (mean 10.4 versus 7.2). Recuts occurred more often in routine cases (12.9% versus 0%). More routine cases had additional blocks grossed (19.4% versus 4.2%). Upon review, five discrepancies that impacted pT staging were identified in the routine group, with none in the whole-mount group. The average estimated additional cost for each whole-mount case compared to routine processing was $40.74, with an increased turnaround time of 1 day. CONCLUSIONS: Whole-mounting is a feasible technique for penectomy that can be utilized with minimal increased cost and turnaround time, and may improve staging. Institutions in which whole mounting is already established for other organs, such as prostate, may wish to consider utilizing this format for penectomy specimens. PMID- 23738626 TI - Phylogeography and postglacial expansion of the endangered semi-aquatic mammal Galemys pyrenaicus. AB - BACKGROUND: Species with strict ecological requirements may provide new insights into the forces that shaped the geographic variation of genetic diversity. The Pyrenean desman, Galemys pyrenaicus, is a small semi-aquatic mammal that inhabits clean streams of the northern half of the Iberian Peninsula and is endangered in most of its geographic range, but its genetic structure is currently unknown. While the stringent ecological demands derived from its aquatic habitat might have caused a partition of the genetic diversity among river basins, Pleistocene glaciations would have generated a genetic pattern related to glacial refugia. RESULTS: To study the relative importance of historical and ecological factors in the genetic structure of G. pyrenaicus, we used mitochondrial and intronic sequences of specimens covering most of the species range. We show, first, that the Pyrenean desman has very low levels of genetic diversity compared to other mammals. In addition, phylogenetic and dating analyses of the mitochondrial sequences reveal a strong phylogeographic structure of a Middle Pleistocene origin, suggesting that the main lineages arose during periods of glacial isolation. Furthermore, both the spatial distribution of nuclear and mitochondrial diversity and the results of species distribution modeling suggest the existence of a major glacial refugium in the northwestern part of the Iberian Peninsula. Finally, the main mitochondrial lineages show a striking parapatric distribution without any apparent exchange of mitochondrial haplotypes between the lineages that came into secondary contact (although with certain permeability to nuclear genes), indicating incomplete mixing after the post-glacial recolonization. On the other hand, when we analyzed the partition of the genetic diversity among river basins, the Pyrenean desman showed a lower than expected genetic differentiation among main rivers. CONCLUSIONS: The analysis of mitochondrial and intronic markers in G. pyrenaicus showed the predominant effects of Pleistocene glaciations on the genetic structure of this species, while the distribution of the genetic diversity was not greatly influenced by the main river systems. These results and, particularly, the discovery of a marked phylogeographic structure, may have important implications for the conservation of the Pyrenean desman. PMID- 23738631 TI - Next-generation sequencing in genetic hearing loss. AB - The advent of the $1000 genome has the potential to revolutionize the identification of genes and their mutations underlying genetic disorders. This is especially true for extremely heterogeneous Mendelian conditions such as deafness, where the mutation, and indeed the gene, may be private. The recent technological advances in target-enrichment methods and next generation sequencing offer a unique opportunity to break through the barriers of limitations imposed by gene arrays. These approaches now allow for the complete analysis of all known deafness-causing genes and will result in a new wave of discoveries of the remaining genes for Mendelian disorders. In this review, we describe commonly used genomic technologies as well as the application of these technologies to the genetic diagnosis of hearing loss (HL) and to the discovery of novel genes for syndromic and nonsyndromic HL. PMID- 23738633 TI - Quantification of gold nanoparticle cell uptake under controlled biological conditions and adequate resolution. AB - AIM: We examined cellular uptake mechanisms of fluorescently labeled polymer coated gold nanoparticles (NPs) under different biological conditions by two quantitative, microscopic approaches. MATERIALS & METHODS: Uptake mechanisms were evaluated using endocytotic inhibitors that were tested for specificity and cytotoxicity. Cellular uptake of gold NPs was analyzed either by laser scanning microscopy or transmission electron microscopy, and quantified by means of stereology using cells from the same experiment. RESULTS: Optimal inhibitor conditions were only achieved with chlorpromazine (clathrin-mediated endocytosis) and methyl-beta-cyclodextrin (caveolin-mediated endocytosis). A significant methyl-beta-cyclodextrin-mediated inhibition (63-69%) and chlorpromazine-mediated increase (43-98%) of intracellular NPs was demonstrated with both imaging techniques, suggesting a predominant uptake via caveolin-medicated endocytois. Transmission electron microscopy imaging revealed more than 95% of NPs localized in intracellular vesicles and approximately 150-times more NP events/cell were detected than by laser scanning microscopy. CONCLUSION: We emphasize the importance of studying NP-cell interactions under controlled experimental conditions and at adequate microscopic resolution in combination with stereology. PMID- 23738634 TI - Asymmetric hydrogenation of alkynyl ketones with the eta(6)-arene/TsDPEN ruthenium(II) catalyst. AB - Enantioselective hydrogenation of alkynyl ketones catalyzed by Ru(OTf)(TsDPEN)(eta(6)-p-cymene) (TsDPEN = N-(p-toluenesulfonyl)-1,2 diphenylethylenediamine) affords the propargylic alcohols in up to 97% ee. The alkynyl moieties are left intact in most cases. The reaction can be conducted with a substrate-to-catalyst molar ratio as high as 5000 under 10 atm of H2. The mode of enantioselection is elucidated with the transition state models directed by the CH/pi attractive interaction between the substrate and the catalytic species. PMID- 23738632 TI - Antimicrobial photodynamic therapy with decacationic monoadducts and bisadducts of [70]fullerene: in vitro and in vivo studies. AB - BACKGROUND: Antimicrobial photodynamic therapy uses photosensitizers designed to bind to microorganisms and generate reactive oxygen species when illuminated with visible light. MATERIALS & METHODS: We synthesized a highly water-soluble [70]fullerene monoadduct, C70[>M(C3N6(+)C3)2]-(I(-))10 (LC17), and bisadduct, C70[>M(C3N6(+)C3)2][>M(C3N6C3)2] (LC18), both with a well-defined decacationic quaternary ammonium iodide moiety with ten positive charges per C70 to give water solubility and bacterial binding. We determined the antimicrobial effects against human pathogens, Gram-positive (Staphylococcus aureus) and Gram-negative species (Escherichia coli and Acinetobacter baumannii) when activated by UVA or white light. RESULTS: White light was more effective with LC17, while UVA light was more effective with LC18. Both compounds were effective in a mouse model of Gram negative third-degree burn infections determined by bioluminescence imaging. DISCUSSION & CONCLUSION: We propose that the attachment of an additional deca(tertiary-ethylenylamino)malonate arm to C70 allowed the moiety to act as a potent electron donor and increased the generation yield of hydroxyl radicals under UVA illumination. PMID- 23738635 TI - Psychodermatology services guidance: the report of the British Association of Dermatologists' Psychodermatology Working Party. PMID- 23738636 TI - Patient-reported outcome measures in skin cancer. PMID- 23738637 TI - Biomarkers in hidradenitis suppurativa. PMID- 23738638 TI - Women itch on Venus, Men scratch on Mars. PMID- 23738639 TI - Wet work--home and away.... PMID- 23738640 TI - Maternal and fetal outcome in Swedish women with erythropoietic protoporphyria. AB - BACKGROUND: Painful photosensitivity is characteristic of erythropoietic protoporphyria (EPP). In women, symptoms may be affected by menstrual cycle and pregnancy but very little is known about maternal and fetal outcome. OBJECTIVES: To investigate the impact of menstruation, pregnancy and breast-feeding on photosensitivity and possible effects of EPP on maternal, fetal and neonatal outcome. METHODS: Retrospective study screening all 20 Swedish women alive and older than 18 years diagnosed with EPP with a total of 33 deliveries. Data were retrieved for 19 women and 32 deliveries in medical records and completed by a questionnaire sent to the patients. RESULTS: Photosensitivity worsened in five of 19 (26%) women around menstruation whereas amelioration was reported in 17 of 32 (53%) pregnancies and during 11 of 32 (34%) breast-feeding periods. Fertility rate was normal and there were no maternal or fetal complications apart from minor arterial hypertension in one woman. CONCLUSIONS: The study confirms changes in photosensitivity during menstruation and pregnancy. Amelioration during breast feeding is a new finding. Pregnancy appears safe without increased risks of pregnancy complications or adverse effects on fetal or neonatal health. PMID- 23738641 TI - Effectiveness and safety of fumaric acid esters in children with psoriasis: a retrospective analysis of 14 patients from The Netherlands. AB - BACKGROUND: Fumaric acid esters (FAE) are used as an effective and safe oral treatment for plaque psoriasis in adult patients, but little is known about their efficacy and safety in children with psoriasis. OBJECTIVES: To assess the effectiveness and safety of FAE in the treatment of paediatric psoriasis. METHODS: This is a retrospective analysis of 14 paediatric patients with psoriasis (age <18 years) treated with FAE between 2004 and 2012 at several Dutch university and regional clinics. Patients were identified through databases or registries. RESULTS: The median age at the start of FAE treatment was 15 years (range 8-17 years). The median duration of FAE treatment was 10 months (range 1 80 months), and the median maintenance dosage per day was 360 mg dimethylfumarate (range 240-600 mg). Five patients (36%) achieved a complete clearance of their psoriasis, one patient (7%) had a good improvement, three patients (21%) had a partial response and five patients (36%) were nonresponders. FAE treatment was well tolerated, but two patients (14%) discontinued FAE, one with severe diarrhoea and one with flushes. Five patients (36%) had transient, slightly abnormal laboratory values of liver-function tests or leucocytes that did not necessitate FAE dosage reduction or treatment discontinuation. No serious adverse events occurred. CONCLUSIONS: In this retrospective case series FAE seemed to be an effective and safe treatment for children with psoriasis. FAE may be an attractive therapeutic alternative to the currently used systemic immunosuppressive agents for paediatric patients with psoriasis. Further studies are needed to evaluate the suitability of FAE in paediatric psoriasis. PMID- 23738642 TI - Concurrence of autoantibodies to bullous pemphigoid antigens and desmoglein 3: analysis of pathogenic and nonpathogenic antibodies. PMID- 23738643 TI - Skin self-examination and the ABCDE rule in the early diagnosis of melanoma: is the game over? PMID- 23738644 TI - Skin self-examination and the ABCDE rule in the early diagnosis of melanoma: is the game over? Reply from author. PMID- 23738647 TI - Internet safety education for youth: stakeholder perspectives. AB - BACKGROUND: Internet use is nearly ubiquitous among US youth; risks to internet use include cyberbullying, privacy violations and unwanted solicitation. Internet safety education may prevent these negative consequences; however, it is unclear at what age this education should begin and what group is responsible for teaching this topic. METHODS: Surveys were distributed to key stakeholders in youth safety education including public school teachers, clinicians, parents and adolescents. Surveys assessed age at which internet safety education should begin, as well as experiences teaching and learning internet safety. Surveys of adults assessed willingness to teach internet safety. Finally, participants were asked to identify a group whose primary responsibility it should be to teach internet safety. RESULTS: A total of 356 participants completed the survey (93.4% response rate), including 77 teachers, 111 clinicians, 72 parents and 96 adolescents. Stakeholders felt the optimal mean age to begin teaching internet safety was 7.2 years (SD = 2.5), range 2-15. Internet safety was regularly taught by some teachers (20.8%), few clinicians (2.6%) and many parents (40.3%). The majority of teachers, clinicians and parents were willing to teach internet safety, but all groups surveyed identified parents as having primary responsibility for teaching this topic. CONCLUSIONS: Findings suggest agreement among key stakeholders for teaching internet safety at a young age, and for identifying parents as primary teachers of this topic. Clinicians have a unique opportunity to support parents by providing resources, guidance and support. PMID- 23738646 TI - Cell-based therapy for ischemic stroke. AB - INTRODUCTION: Stroke is a major cause of mortality and disability in adults worldwide. Unfortunately, current therapy which targets vessel recanalization has a narrow treatment window, and at this time neuroprotective approaches are not effective for stroke treatment. However, after stroke the parenchymal and endothelial cells in the central nervous system (CNS) respond in concert to ischemic stressors and create a microenvironment in which successful recovery may ensue. Neurogenesis, synaptogenesis, axonal sprouting, glial cell activation, angiogenesis and vascular remodeling within the brain and the spinal cord are stimulated post stroke. Cell based-therapy amplifies these endogenous restorative effects within the CNS to promote functional outcome. AREAS COVERED: This article reviews current knowledge of cell-based therapy in the adult brain after stroke, including transplanted cell type, benefits and risks, with an emphasis on mechanisms of action. EXPERT OPINION: Experimental studies and clinical trials with cell-based therapy in stroke appear promising. Cell-based therapy is not intended for the replacement of damaged cells, but for the remodeling of the CNS by promoting neuroplasticity, angiogenesis and immunomodulation. However, there are risks associated with the use of cell-based therapy, and adequate evaluation of these potential risks is a prerequisite before clinical application for stroke patients. PMID- 23738648 TI - Health-related quality of life among Norwegian children and adolescents with type 1 diabetes on intensive insulin treatment: a population-based study. AB - AIM: To examine health-related quality of life (HRQOL) in children and adolescents with type 1 diabetes on intensive insulin treatment. METHODS: All children and adolescents with type 1 diabetes above 8 years of age scheduled for follow-up at 21 paediatric departments in Norway, and one of their parents was invited to describe HRQOL by completing DISABKIDS questionnaires. HRQOL was related to sociodemographic factors (i.e. parental economy, education, marital status and to level of physical activity and disease characteristics, obtained from the Norwegian Childhood Diabetes Registry). RESULTS: Nine hundred and thirty seven (48%) and one of their parents responded. Mean duration of diabetes was 4.9 years (SD 3.3), 51% were girls, 56% used insulin pumps, and 44% used multiple insulin injections, predominantly of long-acting and rapid insulin analogues. Mean HbA1c was 8.5% (SD 1.3). Lower HRQOL scores were significantly associated with higher HbA1c, being a girl and experience of diabetes ketoacidosis. Mothers scored lower than fathers on total score and most subscales. No significant differences in scores were found between users of an insulin pump and multi injection treatment. CONCLUSIONS: Health-related quality of life was related to metabolic control and gender, but not to mode of intensified insulin treatment. PMID- 23738649 TI - The use of the Cervilenz device to aid in the diagnosis of premature labor. AB - OBJECTIVE: A short cervix measured by transvaginal ultrasound has been correlated with increased risk for preterm delivery (PTD). Many patients presenting with a complaint of possible premature labor (PL); may not have access to cervical length (CL) screening by ultrasound. Cervilenz is an FDA cleared disposable device for obtaining vaginal CL measurements. This study was conducted to correlate Cervilenz measurements of CL with the occurrence of PTD. METHODS: Women presenting with regular uterine contractions at gestational age (GA) >=22 and <34 weeks with intact membranes and cervical dilation <3 cm were recruited. A speculum examination was performed and Cervilenz measurement of CL was obtained. Patients were treated with tocolytics and/or corticosteroids based upon the attending physician's judgment. The occurrences of PTD as a result of PL or premature rupture of membranes within 7 days, <32 weeks, <34 weeks and <37 weeks, were determined. Patients who were delivered preterm for other maternal or fetal indications were excluded. Negative predictive value (NPV) was calculated. RESULTS: Of the 220 women recruited, 20 were subsequently excluded from analysis because they required PTD for unrelated indications. The mean GA at enrollment was 29.8 +/- 2.8 (SD) weeks. One (0.5%), 2 (1.0%), 4 (2.0%) and 29 (14.5%) women delivered at <=7 days from enrollment, <=32 weeks, <=34 weeks, and <=37 weeks, inclusively. Seventy-seven (38.5%), 39 (19.5%) and 19 (9.5%) women had Cervilenz measurement of <=30, <=25 and <=20 mm, respectively. The NPV for a Cervilenz measurement of >20 mm for delivery at, <=32, <=34 and <=37 weeks were 99.2%, 98.3% and 86.7%, respectively. CONCLUSION: Cervilenz measurement >20 mm appears to have high NPV for PTD prior to 34 weeks. PMID- 23738650 TI - Structural characterization of 2-imidazolones: comparison with their heavier chalcogen counterparts. AB - The molecular structures of 1-t-butyl-1,3-dihydro-2H-imidazol-2-one [H(oim(Bu(t)))], 1-methyl-1,3-dihydro-2H-benzimidazol-2-one [H(obenzim(Me))], 1-t butyl-1,3-dihydro-2H-benzimidazol-2-one [H(obenzim(Bu(t)))], and 1-t-butyl-1,3 dihydro-2H-benzimidazole-2-thione [H(mbenzim(Bu(t)))] have been determined by single crystal X-ray diffraction. Consideration of the C-O bond lengths in the 2 imidazolones, together with the respective values for 2-thiones and 2-selones, indicates that the C-E bonds in these compounds are intermediate between those of formal C-E single and double bonds, an observation that may be rationalized in terms of a significant contribution of zwitterionic structures that feature single C(+)-E(-) dative covalent bonds. In this regard, a natural bond orbital (NBO) analysis of the bonding in H(xim(Bu(t))) derivatives demonstrates that a doubly bonded C?E resonance structure is most significant for the oxygen derivative, whereas singly bonded C(+)-E(-) resonance structures are dominant for the tellurium derivative, despite the fact that oxygen is more electronegative. The C-E bonding in these compounds is, therefore, significantly different from that in chalcogenoformaldehyde derivatives for which the bonding is well represented by a H2C?E double bonded resonance structure. Comparison of the C-E bond lengths of the imidazolechalcogenones with those of C-E single bonds indicates that the C-O bonds are anomalously short. This observation may be rationalized in terms of the oxygen derivative having not only the most significant pi-component but also a substantial ionic component. The latter results from the C-O bond being the most polar due to a substantial polarization of the sigma-bond in the direction of oxygen, which thereby supplements the pi polarization and increases the negative charge on oxygen. In contrast, the sigma polarization for the heavier chalcogens opposes the zwitterionic C(+)-E(-) pi polarization and thereby reduces the negative charge on the chalcogen. As such, the C-E bond becomes less polar as the chalcogen becomes heavier, despite the fact that the zwitterionic C(+)-E(-) contribution increases. PMID- 23738651 TI - Prevalence and type distribution of high-risk human papillomavirus in patients with cervical cancer: a population-based study. AB - BACKGROUND: Cervical cancer is the greater cause of cancer death in women in many developing countries. Persistent infection with human papilloma virus (HPV), primarily high risk types 16 and 18, is recognized as a causal and essential factor for the development of cervical cancer. We aimed to determine the distribution of high-risk HPV genotypes in archival biopsies with cervical carcinoma in patients from Mazandaran Province, Northern Iran. METHODS: A total of 98 paraffin-embedded cervical samples consisted of 63 Squamous Cell Carcinomas (SCC), 4 Adenocarcinomas, 19 Cervical Interaepithelial Neoplasia grade I (CIN-I), 4 CIN-II and 8 CIN-III diagnosed during 2009-2011, were selected to perform high risk HPV genotyping using AmpliSens(R) HPV HCR DNA genotyping kit. The prevalence of HPV infections was assessed in low and high grade cervical lesions by age. RESULTS: Of the 98 cervical samples analysed by DNA PCR, 78 (79.59%) were positive for HPV DNA. HPV was detected in the 52 of SCC, 4 of Adenocarcinomas, 14 of CIN-I, 4 of CIN-II, and 4 of CIN-III for HPV. From the 78 HPV positive samples, 23 (29.5%) samples were positive for HPV type 16, 32 (41%) were positive for HPV 18, 19 (24.4%) were positive for HPV 45, and 4 (5.1%) of cervical specimens were positive for HPV 39. CONCLUSIONS: This study provides valuable baseline data for future assessment of the impact of current prophylactic vaccination programs that is protective against the two most common oncogenic types of HPV found in cervical cancer, HPV-16 and HPV-18, but not against other high-risk mucosal HPVs, 39 and 45, reported in this population. PMID- 23738653 TI - Printable polymer actuators from ionic liquid, soluble polyimide, and ubiquitous carbon materials. AB - We present here printable high-performance polymer actuators comprising ionic liquid (IL), soluble polyimide, and ubiquitous carbon materials. Polymer electrolytes with high ionic conductivity and reliable mechanical strength are required for high-performance polymer actuators. The developed polymer electrolytes comprised a soluble sulfonated polyimide (SPI) and IL, 1-ethyl-3 methylimidazolium bis(trifluoromethanesulfonyl)amide ([C2mim][NTf2]), and they exhibited acceptable ionic conductivity up to 1 * 10(-3) S cm(-1) and favorable mechanical properties (elastic modulus >1 * 10(7) Pa). Polymer actuators based on SPI/[C2mim][NTf2] electrolytes were prepared using inexpensive activated carbon (AC) together with highly electron-conducting carbon such as acetylene black (AB), vapor grown carbon fiber (VGCF), and Ketjen black (KB). The resulting polymer actuators have a trilaminar electric double-layer capacitor structure, consisting of a polymer electrolyte layer sandwiched between carbon electrode layers. Displacement, response speed, and durability of the actuators depended on the combination of carbons. Especially the actuators with mixed AC/KB carbon electrodes exhibited relatively large displacement and high-speed response, and they kept 80% of the initial displacement even after more than 5000 cycles. The generated force of the actuators correlated with the elastic modulus of SPI/[C2mim][NTf2] electrolytes. The displacement of the actuators was proportional to the accumulated electric charge in the electrodes, regardless of carbon materials, and agreed well with the previously proposed displacement model. PMID- 23738652 TI - Overexpression of Smad2 inhibits proliferation of gingival epithelial cells. AB - BACKGROUND AND OBJECTIVE: Spatiotemporal inhibition of apical migration and proliferation of gingival epithelium are significant factors involved in periodontal regeneration. Transforming growth factor beta (TGF-beta) is important in multiple aspects of wound healing, and Smad2, a downstream transcription factor of TGF-beta, has an inhibitory effect on re-epithelialization during gingival wound healing. Therefore, we investigated the effects on migration and proliferation status, and intra/extracellular signaling regulated by Smad2 overexpression in gingival epithelial cells. MATERIAL AND METHODS: Gingival epithelial cells were isolated from the palatal gingival tissue of transgenic mice overexpressing Smad2 driven by the Keratin14 promoter. Smad2 expression was identified by western blotting and immunofluorescence analysis. Scratch assay and 5-bromo-2'-deoxyuridine staining were performed to assess cell migration and proliferation. To inactivate TGF-beta type I receptor, the cultures were supplemented with SB431542. Secreted TGF-beta was quantified by ELISA. Smad2 target gene expression was examined by real-time RT-PCR and in vivo immunofluorescence analysis of gingival junctional epithelium. RESULTS: Smad2 overexpressing cells were confirmed to have significant phosphorylated Smad2 in the nucleus. Scratch assay and 5-bromo-2'-deoxyuridine staining indicated that Smad2-overexpressing cells showed no significant differences in migration, but had reduced proliferation rates compared to wild-type controls. SB431542 significantly inhibited Smad2 phosphorylation, which coincided with restoration of the proliferation rate in Smad2-overexpressing cells. ELISA of TGF-beta release did not show any differences between genotypes. The cell cycle inhibitors, p15 and p21, showed significant upregulation in Smad2-overexpressing cells compared to wild-type controls. Moreover, junctional epithelium of the transgenic mice showed increased expression of P-Smad2, p15 and p21. CONCLUSION: The signaling activation triggered by overexpression of Smad2 was dependent on TGF-beta type I receptor, and the activated Smad2 increased p15 and p21 expression, responsible for inhibiting cell cycle entry, resulting in antiproliferative effects on gingival epithelial cells. Understanding of Smad2 induced signaling would be useful for possible clinical application to regulate gingival epithelial downgrowth. PMID- 23738654 TI - Reverse genetics in complex multigene operons by co-transformation of the plastid genome and its application to the open reading frame previously designated psbN. AB - Reverse genetics approaches have contributed enormously to the elucidation of gene functions in plastid genomes and the determination of structure-function relationships in chloroplast multiprotein complexes. Gene knock-outs are usually performed by disrupting the reading frame of interest with a selectable marker cassette. Site-directed mutagenesis is done by placing the marker into the adjacent intergenic spacer and relying on co-integration of the desired mutation by homologous recombination. These strategies are not applicable to genes residing in large multigene operons or other gene-dense genomic regions, because insertion of the marker cassette into an operon-internal gene or into the nearest intergenic spacer is likely to interfere with expression of adjacent genes in the operon or disrupt cis-elements for the expression of neighboring genes and operons. Here we have explored the possibility of using a co-transformation strategy to mutate a small gene of unknown function (psbN) that is embedded in a complex multigene operon. Although inactivation of psbN resulted in strong impairment of photosynthesis, homoplasmic knock-out lines were readily recovered by co-transformation with a selectable marker integrating >38 kb away from the targeted psbN. Our results suggest co-transformation as a suitable strategy for the functional analysis of plastid genes and operons, which allows the recovery of unselected homoplasmic mutants even if the introduced mutations entail a significant selective disadvantage. Moreover, our data provide evidence for involvement of the psbN gene product in the biogenesis of both photosystem I and photosystem II. We therefore propose to rename the gene product 'photosystem biogenesis factor 1' and the gene pbf1. PMID- 23738655 TI - Pig-related infections. PMID- 23738656 TI - Socio-economic, industrial and cultural parameters of pig-borne infections. AB - The pork-processing industry has been possibly the fastest growing sector of the food industry in recent years. Specialization, genetic homogenization of the pig population, high density of the breeding population, reduced human-animal interactions, slaughter at a lower age and increased international trade of live animals and pork are parameters that affect, positively or negatively, the emergence of novel pig-borne pathogens, many of which are pig-specific, and many of which have significant zoonotic potential, as observed in recent outbreaks of Nipah virus and Streptococcus suis in Southeast Asia and China, respectively. Numerous other pathogens are transmitted to humans through direct contact with or consumption of pig products, and globalization trends in trade and human population movements have resulted in outbreaks of pig-borne diseases even in Muslim countries and in Israel, where pork consumption is religiously prohibited. The role of pigs as potential reservoirs of antibiotic-resistant pathogens or genes encoding resistance, and the role of feral pigs as a reservoir of zoonotic disease, are scientific fields in direct need of further research. PMID- 23738658 TI - Scalability and internal consistency of the German version of the dementia specific quality of life instrument QUALIDEM in nursing homes - a secondary data analysis. AB - BACKGROUND: Quality of life (Qol) is a widely selected outcome in intervention studies. The QUALIDEM is a dementia-specific Qol-instrument from The Netherlands. The aim of this study is to evaluate the scalability and internal consistency of the German version of the QUALIDEM. METHODS: This secondary data analysis is based on a total sample of 634 residents with dementia from 43 nursing homes. The QUALIDEM consists of nine subscales that were applied to a subsample of 378 people with mild to severe dementia and six consecutive subscales that were applied to a subsample of 256 people with very severe dementia. Scalability, internal consistency and distribution scores were calculated for each predefined subscale using the Mokken scale analysis. RESULTS: In people with mild to severe dementia, seven subscales, care relationship, positive affect, negative affect, restless tense behavior, positive self-image, social relations and feeling at home, were scalable (0.31 <= H <= 0.65) and internally consistent (Rho >= 0.62). The subscales social isolation (H = 0.28) and having something to do (H = 0.18) were not scalable and exhibited insufficient reliability scores (Rho <= 0.53). For people with very severe dementia, five subscales, care relationship, positive affect, restless tense behavior, negative affect and social relations, were scalable (0.33 <= H <= 0.65), but only the first three of these subscales showed acceptable internal consistency (Rho 0.59 - 0.86). The subscale social isolation was not scalable (H = 0.20) and exhibited poor internal consistency (Rho = 0.42). CONCLUSIONS: The results show an acceptable scalability and internal consistency for seven QUALIDEM subscales for people with mild to severe dementia and three subscales for people with very severe dementia. The subscales having something to do (mild to severe dementia), negative affect (very severe dementia), social relations (very severe dementia) and social isolation (both versions) produced unsatisfactory results and require revision. PMID- 23738660 TI - Calcium phosphate nanoparticles: a future therapeutic platform for the treatment of osteomyelitis? PMID- 23738661 TI - Iontophoresis for treating nail diseases. PMID- 23738659 TI - Genome-wide association study for backfat thickness in Canchim beef cattle using Random Forest approach. AB - BACKGROUND: Meat quality involves many traits, such as marbling, tenderness, juiciness, and backfat thickness, all of which require attention from livestock producers. Backfat thickness improvement by means of traditional selection techniques in Canchim beef cattle has been challenging due to its low heritability, and it is measured late in an animal's life. Therefore, the implementation of new methodologies for identification of single nucleotide polymorphisms (SNPs) linked to backfat thickness are an important strategy for genetic improvement of carcass and meat quality. RESULTS: The set of SNPs identified by the random forest approach explained as much as 50% of the deregressed estimated breeding value (dEBV) variance associated with backfat thickness, and a small set of 5 SNPs were able to explain 34% of the dEBV for backfat thickness. Several quantitative trait loci (QTL) for fat-related traits were found in the surrounding areas of the SNPs, as well as many genes with roles in lipid metabolism. CONCLUSIONS: These results provided a better understanding of the backfat deposition and regulation pathways, and can be considered a starting point for future implementation of a genomic selection program for backfat thickness in Canchim beef cattle. PMID- 23738662 TI - Peptide nanofibers for controlled growth factor release. PMID- 23738665 TI - Targeting drug delivery systems for circumventing multidrug resistance of cancers. AB - Multidrug resistance is a major obstacle to successful chemotherapy of cancer. To overcome multidrug resistance, our research is to develop new liposome and nanomicelle delivery systems. Investigations are focusing on certain aspects, including resistant cancer cell membranes, cancer stem cells, mitochondria, apoptosis genes, vasculogenic mimicry and heterogeneity of cancer cells. Evaluations have been performed on cancer cells, cancer spheroids and cancer animal models. These nanoscale formulations demonstrated an enhanced chemotherapy efficacy in resistant cancer and cancer stem cells in vitro and in vivo. PMID- 23738666 TI - 3D-fection: cell transfection within 3D scaffolds and hydrogels. AB - BACKGROUND: 3D matrices are widely used as cell growth supports in basic research, regenerative medicine or cell-based drug assays. In order to genetically manipulate cells cultured within 3D matrices, two novel non-viral transfection reagents allowing preparation of matrices for in situ cell transfection were evaluated. RESULTS: Two lipidic formulations, 3D-FectTM and 3D FectINTM, were assessed for their ability to transfect cells cultured within 3D solid scaffolds and 3D hydrogels, respectively. These reagents showed good compatibility with the most widespread types of matrices and enabled transfection of a wide range of mammalian cells of various origins. Classical cell lines, primary cells and stem cells were thus genetically modified while colonizing their growth support. Importantly, this in situ strategy alleviated the need to manipulate cells before seeding them. CONCLUSION: Results presented here demonstrated that 3D-Fect and 3D-FectIN reagents for 3D transfection are totally compatible with cells and do not impair matrix properties. 3D-Fect and 3D-FectIN, therefore, provide valuable tools for achieving localized and sustained transgene expression and should find versatile applications in fundamental research, regenerative medicine and cell-based drug assays. PMID- 23738668 TI - Intracellular delivery of polymeric nanocarriers: a matter of size, shape, charge, elasticity and surface composition. AB - Recent progress in drug discovery has enabled the targeting of specific intracellular molecules to achieve therapeutic effects. These next-generation therapeutics are often biologics that cannot enter cells by mere diffusion. Therefore, it is imperative that drug carriers are efficiently internalized by cells and reach specific target organelles before releasing their cargo. Nanoscale polymeric carriers are particularly suitable for such intracellular delivery. Although size and surface charge have been the most studied parameters for nanocarriers, it is now well appreciated that other properties, for example, particle shape, elasticity and surface composition, also play a critical role in their transport across physiological barriers. It is proposed that a multivariate design space that considers the interdependence of particle geometry with its mechanical and surface properties must be optimized to formulate drug nanocarriers for effective accumulation at target sites and efficient intracellular delivery. PMID- 23738669 TI - Innovative approaches for demonstration of bioequivalence: the US FDA perspective. AB - In this article, the authors will briefly introduce the general concepts and background of bioavailability and bioequivalence (BE), discuss the conventional method for BE demonstration, and present case examples where novel approaches have been adopted by the US FDA for BE demonstration. Here, 'novel approaches' include unconventional BE studies, as well as statistical criteria for comparison. More specifically, biowaivers, methods to demonstrate BE for highly variable drugs and drug products, and narrow therapeutic index drugs, partial AUCs as additional metrics for some modified-release drug products, methods to demonstrate BE for locally acting gastrointestinal, dermatological, nasal and inhalation products, and non-biological complex drug products, and future perspectives in the field of BE assessment will be discussed. Methods adopted by other agencies, such as European Medicines Agency and Health Canada will be compared with the FDA approaches when appropriate. PMID- 23738667 TI - Therapeutic nanomedicine for brain cancer. AB - Malignant brain cancer treatment is limited by a number of barriers, including the blood-brain barrier, transport within the brain interstitium, difficulties in delivering therapeutics specifically to tumor cells, the highly invasive quality of gliomas and drug resistance. As a result, the prognosis for patients with high grade gliomas is poor and has improved little in recent years. Nanomedicine approaches have been developed in the laboratory, with some technologies being translated to the clinic, in order to address these needs. This review discusses the obstacles to effective treatment that are currently faced in the field, as well as various nanomedicine techniques that have been used or are being explored to overcome them, with a focus on liposomal and polymeric nanoparticles. PMID- 23738672 TI - Eradication of an outbreak of vancomycin-resistant Enterococcus (VRE): the cost of a failure in the systematic screening. AB - BACKGROUND: Vancomycin-resistant enterococci (VRE) are still a concern in hospital units tending to seriously ill patients. However, the cost-effectiveness of active surveillance program to identify asymptomatically VRE colonized patient remains debatable. This work aims at evaluating the cost of a failure in the active surveillance of VRE that had resulted in an outbreak in a French University Hospital. FINDINGS: A VRE outbreak was triggered by a failure in the systematic VRE screening in a medico-surgical ward specialised in liver transplantation as a patient was not tested for VRE. This failure was likely caused by the reduction of healthcare resource. The outbreak involved 13 patients. Colonized patients were grouped in a dedicated part of the infectious diseases unit and tended by a dedicated staff. Transmission was halted within two months after discovery of the index case.The direct cost of the outbreak was assessed as the cost of staffing, disposable materials, hygiene procedures, and surveillance cultures.The loss of income from spare isolation beds was computed by difference with the same period in the preceding year. Payments were drawn from the hospital database. The direct cost of the outbreak (2008 Euros) was ?60 524 and the loss of income reached ?110 915. CONCLUSIONS: Despite this failure, the rapid eradication of the VRE outbreak was a consequence of the rapid isolation of colonized patient. Yet, eradicating even a limited outbreak requires substantial efforts and resources. This underlines that special attention has to be paid to strictly adhere to active surveillance program. PMID- 23738673 TI - In vitro performance of Class I and II composite restorations: a literature review on nondestructive laboratory trials--part I. AB - Posterior adhesive restorations are a basic procedure in general dental practices, but their application remains poorly standardized as a result of the number of available options. An abundant number of study hypotheses corresponding to almost unlimited combinations of preparation techniques, adhesive procedures, restorative options, and materials have been described in the literature and submitted to various evaluation protocols. A literature review was thus conducted on adhesive Class I and II restorations and nondestructive in vitro tests using the PubMed/Medline database for the 1995-2010 period. The first part of this review discusses the selected literature related to photoelasticity, finite element analysis (FEM), and microleakage protocols. Based on the aforementioned evaluation methods, the following parameters proved influential: cavity dimensions and design, activation mode (light or chemical), type of curing light, layering technique, and composite structure or physical characteristics. Photoelasticity has various limitations and has been largely (and advantageously) replaced by the FEM technique. The results of microleakage studies proved to be highly inconsistent, and the further use of this technique should be strictly limited. Other study protocols for adhesive Class II restorations were also reviewed and will be addressed in part II of this article, together with a tentative relevance hierarchy of selected in vitro methods. PMID- 23738674 TI - Adverse influence of mixed acidemia on the biocompatibility of continuous veno venous hemofiltration with respect to the lungs. AB - Experimental data indicate that hypercapnic adidosis has anti-inflammatory effects. These anti-inflammatory effects may even be a beneficial property in case of low tidal volume ventilation with consecutive hypercapnic acidosis. It is unclear whether these anti-inflammatory effects predominate in critically ill patients who suffer from multiple pro- and anti-inflammatory insults like extracorporeal organ support (pro-inflammatory), metabolic acidosis (pro- and anti-inflammatory), as well as hypoxia (pro-inflammatory). Eighteen pigs were randomized into three groups, mechanically ventilated and connected to a continuous veno-venous hemofiltration (CVVH) as pro-inflammatory insult. A reference group with normal acid-base state obtained normoventilation; a normoxemic acidemia group obtained normoxemic, mixed acidemia due to infusion of lactic and hyperchloremic acid and low tidal volume ventilation, and in a hypoxemic acidemia group the mixed acidemia was paralleled by hypoxemia. Lung histology including pulmonary leukocyte invasion, blood gases, blood cell counts, and hemodynamics were examined. The histological examination of the lungs of acidemic pigs showed a suppressed invasion of leukocytes and thinner alveolar walls compared with normoventilated and with hypoxemic pigs. Enhanced congestion and alveolar red blood cells (RBCs) combined with an increase of the pulmonary artery pressure were observed in acidemic pigs in comparison with the reference group. Normoxemic acidemia reduced the pro-inflammatory reaction to the CVVH and mechanical ventilation in the ventilated lung areas in the form of pulmonary leukocyte invasion. However, this did not result in reduced scores for lung injury. Instead, an increased score for criteria which represent lung injury (congestion and alveolar RBCs) was observed in acidemic pigs. PMID- 23738670 TI - Noncovalently associated cell-penetrating peptides for gene delivery applications. AB - The use of various cell-penetrating peptides (CPPs) to deliver genetic material for gene therapy applications has been a topic of interest for more than 20 years. The delivery of genetic material by using CPPs can be divided into two categories: covalently bound and electrostatically bound. Complexity of the synthesis procedure can be a significant barrier to translation when using a strategy requiring covalent binding of CPPs. In contrast, electrostatically complexing CPPs with genetic material or with a viral vector is relatively simple and has been demonstrated to improve gene delivery in both in vitro and in vivo studies. This review highlights gene therapy applications of complexes formed noncovalently between CPPs and genetic material or viruses. PMID- 23738675 TI - Effect of retrobulbar nerve block on heart rate variability during enucleation in horses under general anesthesia. AB - OBJECTIVE: Analysis of any effect of retrobulbar block during ocular surgery on heart rate variability and oculocardiac reflex. STUDY DESIGN: Prospective study. ANIMAL STUDIED: Horses (n = 16) undergoing eye enucleation due to chronic ophthalmologic diseases. PROCEDURE: Eye enucleation was performed under general anesthesia. The horses were randomly assigned to the first (inhalation anesthesia only, n = 10) or second group (inhalation and local retrobulbar anesthesia, n = 6). The retrobulbar block was performed using 12 mL of mepivacaine hydrochloride 2%. ECG data were taken by a Telemetric ECG before, during, and after surgery. Heart rate variability was analyzed in the time domain as mean heart rate, mean beat-to-beat interval duration, and standard deviation of continuous beat-to-beat intervals. The frequency domain analysis included the low- and high-frequency components of heart rate variability and the sympathovagal balance (low/high frequency). The low frequency represents mainly sympathetic influences on the heart, whereas high frequency is mediated by the parasympathetic tone. RESULTS: All horses without a retrobulbar block showed a significant decrease in the heart rate during traction on the globe and pressure on the orbital fat pad for homoestasis (P = 0.04). Simultaneously, high-frequency power, as an indicator of vagal stimulation, increased significantly. High-frequency and low-frequency power in the retrobulbar block group increased in five horses, and heart rate decreased in only one horse. Both were not significant within the group, but there was a significant difference between both groups relating to the incidence of heart rate decrease occurring at globe traction. CONCLUSIONS AND CLINICAL RELEVANCE: Heart rate variability is a sensitive, non-invasive parameter to obtain sympathovagal stimulations during general anesthesia. The retrobulbar block can prevent heart rate decrease associated with initiation of the oculocardiac reflex. PMID- 23738676 TI - Prevalence of female subfertility in German gynecological practices. AB - INTRODUCTION: The aim of this study was to calculate the number of women with a subfertility diagnosis in gynecological practices in Germany between 2006 and 2010 based on the data from a large epidemiological database. METHODS: All calculations are based on a representative, epidemiological database called "disease analyzer". Women with a confirmed diagnosis of female infertility (ICD 10: N97) or/and with documentation of procreative management (ICD 10: Z31) were identified. They were summarized under the term "subfertility". RESULTS: In total, data on 1,975,253 female patients with between 2006 and 2010 were included. Estimates for patients with "subfertility" compared to number of women lived in Germany (aged 18-45) was 2.44% (CI: 2.43-2.45) in 2006, 2.52% (CI: 2.51 2.53) in 2007, 2.56% (CI: 2.55-2.57) in 2008, 2.68% (CI: 2.67-2.69) in 2009 and 2.69% (CI: 2.68-2.70) in 2010. The difference was significant (p < 0.01). In total, between 2006 and 2010 an estimated 8.91% of all German women had been diagnosed "subfertile". CONCLUSION: When calculated for 5 years almost 1 out of 10 women aged 18 to 45 was counseled, investigated or treated by her gynecologist for "subfertility". This study provides reliable, representative data on a major healthcare issue in Germany. PMID- 23738677 TI - The effect of Bikram yoga on arterial stiffness in young and older adults. AB - BACKGROUND AND OBJECTIVE: Bikram yoga is the most popular form of hot yoga, despite the limited information available on its cardiovascular benefits. This study sought to determine the effect of Bikram yoga on arterial stiffness and insulin resistance in young and older adults. METHODS: Twenty-four young (mean age+/-standard deviation, 30+/-1 years) and 18 middle-aged and older (mean age, 53+/-2 years) adults completed an 8-week Bikram yoga intervention. Bikram yoga classes were performed for 90 minutes per session, three times per week, in a room heated to 40.5 degrees C with 40%--60% relative humidity. RESULTS: Body mass, body fat percentage, blood pressure, and fasting blood glucose and triglyceride concentrations did not significantly change as a result of the intervention in either the young or the older group. Trunk flexibility, as measured by the sit-and-reach test, increased in both groups (p<0.01). Total (p<0.05) and low-density lipoprotein cholesterol (p<0.05) levels, plasma insulin concentrations (p<0.01), and scores on the homeostatic model of the assessment of insulin resistance (p<0.01) decreased in older adults, whereas total and high density lipoprotein cholesterol concentrations were reduced in young adults (all p<0.05). Carotid artery compliance (p<0.05) was increased and beta-stiffness index decreased in young (p<0.05) but not in older adults. Carotid pulse pressure did not significantly change in either group. CONCLUSION: A relatively short-term Bikram yoga intervention improved arterial stiffness in young but not older adults and significantly reduced insulin resistance index in older but not young adults. PMID- 23738678 TI - The effects of mindfulness training on post-traumatic stress disorder symptoms and heart rate variability in combat veterans. PMID- 23738679 TI - No, there is no conclusive scientific evidence for visualization of meridians at the moment. PMID- 23738681 TI - Western herbal medicine, epigenetics, and endometriosis. AB - Endometriosis is an enigmatic disease characterized by the presence and growth of endometrial-like tissue outside the uterine cavity. The etiology of endometriosis is poorly understood, yet recent evidence suggests that epigenetic aberrations and heritable changes in the genome may be the key to understanding how to approach this disease. Difficulty in long-term management of endometriosis symptoms and unpredictability of treatment outcome necessitate research into other treatment modalities, such as Western herbal medicine. This article reviews commonly used herbs in the treatment of endometriosis, the effects of phytochemical constituents on endometrial cells, and the impact on the epigenome. PMID- 23738680 TI - Effectiveness and acceptance of acupuncture in patients with chronic low back pain: results of a prospective, randomized, controlled trial. AB - OBJECTIVE: To investigate the effectiveness of additional acupuncture in patients with chronic low back pain participating in an inpatient rehabilitation program. DESIGN: Patients were randomly assigned to one of two groups (A and B), both receiving a standard rehabilitation program according to German guidelines. Patients in group A additionally underwent acupuncture twice weekly, conducted by two Chinese physicians with education in Traditional Chinese Medicine (TCM). At the beginning and end of the program, as well as at 3 months after, patients completed questionnaires about health-related quality of life (Short-Form 36 Health Survey [SF-36]), sociodemographic and clinical data, attitude towards TCM, pain, and adverse events. SETTING: Inpatient rehabilitation clinic in Germany. PATIENTS: Patients with chronic low back pain participating in an inpatient rehabilitation program. OUTCOME MEASURES: Acceptance of acupuncture, health related quality of life, and pain/symptoms. RESULTS: One hundred and forty-three patients were analyzed: 74 in group A (intervention) and 69 in group B (controls); 67% were men and 33% were women, with a mean age of 50.7 years. Acceptance of TCM was excellent: 89% of the patients would want TCM to be integrated into standard inpatient rehabilitation, and 83% would even have paid for TCM if necessary. Responses to SF-36 questionnaires showed that group A reported significantly better physical functioning, general health, vitality, and emotional role than group B. Pain outcomes in group A were superior to those in group B. Specifically, pain with sitting/standing, pain upon carrying loads of 10 kg or more, and prickling in hands and feet were significantly diminished. CONCLUSION: Acupuncture was highly accepted and had positive effects in patients with chronic low back pain. These results show that acupuncture can be an effective, well-tolerated therapy with no major adverse events. PMID- 23738682 TI - Decrease in major amputations in Germany. AB - A decrease in rate of amputation has been reported from many countries. This study aims to study the trends in amputation rates in Germany. On the basis of DRG-system, detailed lists of all amputations coded as minor amputations (OPS 5 864) and major amputations (OPS 5-865) performed between 2005 and 2010 were provided by the Federal Statistical Office. There was a significant decrease in age-adjusted major amputation rates per 100 000 population in Germany from 27.0 in 2005 to 22.9 in 2010 (15.2%, P ? 0.001) in males and from 19.7 in 2005 to 14.4 in 2010 (26.9%, P ? 0.001) in females. Overall, minor amputation rates did not show such a decrease but increased in males (from 47.4 in 2005 to 57.8 in 2010, 21.9%, P ? 0.001) and remained almost unchanged in females (23.1 in 2005 and 23.9 in 2010, not significant). Reduction in major amputation rates were even more pronounced in people above 80 years, especially in males from 216 to 150 (30.5%) and in females from 168 to 117 (30.4%). The present data demonstrate an increasing overall burden of foot lesions as indicated by an increase in incidence of minor amputations but an ongoing success in the fight against amputation, resulting in a significant decrease in major amputation rates in Germany, in the 6-year period from 2005 to 2010. PMID- 23738683 TI - Diagnostic and prognostic implications of the PAX8-PPARgamma translocation in thyroid carcinomas-a TMA-based study of 226 cases. AB - AIMS: Follicular thyroid carcinoma (FTC) has been a diagnostic challenge for decades. The PAX8-PPARgamma rearrangement has been detected in FTC and classic papillary thyroid carcinomas (PTCs). The aims of this study were to assess the presence of PAX8-PPARgamma by using tissue microarrays in a large cohort of different thyroid neoplasms, and to assess its diagnostic and prognostic implications. METHODS AND RESULTS: Fluorescence in-situ hybridization (FISH) analysis for PAX8-PPARgamma was performed on 226 thyroid tumours, comprising FTCs (n = 59), PTCs (n = 126), poorly differentiated thyroid carcinomas (PDs; n = 34), follicular thyroid adenomas (FTAs; n = 5), and follicular tumours of unknown malignant potential (FTUMPs; n = 2). PAX8-PPARgamma was detected in 12% of FTCs, 1% of PTCs, 7% of PDs, and in both cases of FTUMP. There was no correlation between the extent of capsular or vascular invasion and PAX8-PPARgamma, or between lymph node or haematogenous metastasis and PAX8-PPARgamma. Overall survival (OS), tumour-specific survival (TSS) and relapse-free-survival (RFS) were not influenced by PAX8-PPARgamma. CONCLUSIONS: In this study, we demonstrate for the first time the presence of PAX8-PPARgamma in PDs and FTUMPs, whereas in FTCs and PTCs the prevalence of PAX8-PPARgamma is lower than previously reported. PAX8-PPARgamma did not correlate with invasiveness or affect prognosis in any tumour type. PMID- 23738684 TI - Human umbilical vein endothelial cells synergize osteo/odontogenic differentiation of periodontal ligament stem cells in 3D cell sheets. AB - BACKGROUND AND OBJECTIVE: To investigate the expression of osteo/odontogenic differentiation markers and vascular network formation in a 3D cell sheet with varying cell ratios of periodontal ligament stem cells (PDLSCs) and human umbilical vein endothelial cells (HUVECs). MATERIAL AND METHODS: Human PDLSCs were isolated and characterized by flow cytometry, and co-cultured with HUVECs for the construction of cell sheets. Both types of cells were seeded on temperature-responsive culture dishes with PDLSCs alone, HUVECs alone and various ratios of the latter cells (1 : 1, 2 : 1, 5 : 1 and 1 : 5) to obtain confluent cell sheets. The expressions of osteo/odontogenic pathway markers, including alkaline phosphatase (ALP), bone sialoprotein (BSP) and runt-related transcription factor 2 (RUNX2), were analyzed at 3 and 7 d using RT-PCR. Further ALP protein quantification was performed at 7 and 14 d using ALP assay. The calcium nodule formation was assessed qualitatively and quantitatively by alizarin red assay. Histological evaluations of three cell sheet constructs treated with different combinations (PDLSC-PDLSC-PDLSC/PDLSC-HUVEC-PDLSC/co culture-co-culture-co-culture) were performed with hematoxylin and eosin and immunofluorescence staining. Statistical analysis was performed using t-test (p < 0.05). RESULTS: Significantly higher ALP gene expression was observed at 3 d in 1 : 1 (PDLSC-HUVEC) (2.52 +/- 0.67) and 5 : 1 (4.05 +/- 1.07) co-culture groups compared with other groups (p < 0.05); this was consistent with ALP protein quantification. However, the expression of BSP and RUNX2 genes was higher at 7 d compared to 3 d. Significant calcium mineralization was detected as quantified by alizarin red assay at 14 d in 1 : 1 (1323.55 +/- 6.54 MUm) and 5 : 1 (994.67 +/- 4.15 MUm) co-cultures as compared with monoculture cell sheets (p < 0.05). Hematoxylin and eosin and CD31 immunostaining clearly exemplified the development of a layered cell sheet structure with endothelial cell islands within the constructed PDLSC-HUVEC-PDLSC and co-culture groups. Furthermore, HUVECs invaded the layered cell sheet, suggestive of rudimentary vascular network initiation. CONCLUSION: This study suggests that the PDLSC-HUVEC co-culture, cell sheet, model exhibits significantly high levels of osteo/odontogenic markers with signs of initial vascular formation. This novel 3D cell sheet-based approach may be potentially beneficial for periodontal regenerative therapy. PMID- 23738685 TI - NHC-catalyzed O-selective addition of nitrosoarenes with aldehydes. AB - An NHC-catalyzed O-selective addition of nitrosoarenes with aldehydes probably upon a dual-activation mode was developed, generating a variety of O-acyl hydroxylamines without any detectable competing amidation byproducts. PMID- 23738686 TI - Administration of alemtuzumab and G-CSF to adults with relapsed or refractory acute lymphoblastic leukemia: results of a phase II study. AB - The outlook for adults with refractory and relapsed acute lymphocytic leukemia (ALL) is poor. CD52 is expressed in most patients with ALL. Alemtuzumab is an anti-CD52 humanized monoclonal antibody. This phase II study assessed the efficacy of alemtuzumab combined with granulocyte-colony stimulating factor (G CSF) to boost antibody-dependent cell cytotoxicity mediated by neutrophils. Twelve patients with relapsed (n = 11) or refractory (n = 1) ALL, including four relapses postallogeneic stem cell transplantation, were treated and monitored between October 2006 and January 2011. Patients received 1 wk of alemtuzumab every other day at increasing doses of 3, 10, and 30 mg to test tolerance and 30 mg three times a week for 12-18 infusions. If in complete remission (CR), patients received maintenance therapy for 1 wk, every 2 months. G-CSF was administered at 5 MUg/kg per day during alemtuzumab administration. The primary endpoint was disappearance of blast cells on a marrow aspirate. CD52 was expressed in all patients. Four patients reached CR. In one additional patient, clearance of blast cells was observed in peripheral blood but not in the marrow. The most frequent adverse events during course 1 of treatment were fever and chills (n = 3), skin rash (n = 3), and bronchospasm (n = 2). Tumor lysis syndrome was observed at treatment initiation in one patient who reached CR. All patients progressed within a few months and all but one died. The surviving patient is still alive after relapse and a second allogeneic stem cell transplantation. This study shows that in relapse/refractory ALL, alemtuzumab with G-CSF can produce good responses of short duration. PMID- 23738688 TI - Flow-directed loading of block copolymer micelles with hydrophobic probes in a gas-liquid microreactor. AB - We investigate the loading efficiencies of two chemically distinct hydrophobic fluorescent probes, pyrene and naphthalene, for self-assembly and loading of polystyrene-block-poly(acrylic acid) (PS-b-PAA) micelles in gas-liquid segmented microfluidic reactors under different chemical and flow conditions. On-chip loading efficiencies are compared to values obtained via off-chip dropwise water addition to a solution of copolymer and probe. On-chip, probe loading efficiencies depend strongly on the chemical probe, initial solvent, water content, and flow rate. For pyrene and naphthalene probes, maximum on-chip loading efficiencies of 73 +/- 6% and 11 +/- 3%, respectively, are obtained, in both cases using the more polar solvent (DMF), an intermediate water content (2 wt % above critical), and a low flow rate (~5 MUL/min); these values are compared to 81 +/- 6% and 48 +/- 2%, respectively, for off-chip loading. On-chip loading shows a significant improvement over the off-chip process where shear-induced formation of smaller micelles enables increased encapsulation of probe. As well, we show that on-chip loading allows off-chip release kinetics to be controlled via flow rate: compared to vehicles produced at ~5 MUL/min, pyrene release kinetics from vehicles produced at ~50 MUL/min showed a longer initial period of burst release, followed by slow release over a longer total period. These results demonstrate the necessity to match probes, solvents, and running conditions to achieve effective loading, which is essential information for further developing these on-chip platforms for manufacturing drug delivery formulations. PMID- 23738687 TI - Hospitalization rates and cost in severe or complicated obesity: an Italian cohort study. AB - BACKGROUND: The economic and social costs of obesity are estimated to be considerable, particularly for inpatient care. The aim of this study was to compare the hospitalization rates of individuals with severe (body mass index [BMI] >=40 kg/m2) or complicated (BMI >=30 kg/m2) obesity with those of the general population in two regions of Northwest Italy, and to describe absolute costs of hospitalization and their determinants. METHODS: Between 1996 and 2002, 6,516 patients who were admitted for the first time to a hospital offering a nutritional rehabilitation programme for obesity were enrolled and followed-up (mean follow-up time: 7.3 years). Standardized hospitalization rates (SHRs) were computed by sex for all-cause and cause-specific hospitalization. The general population of the two regions was used as the reference population. The annual cost of hospitalization was estimated for the study cohort only at the individual level, and its association with different determinants was assessed using a multivariable linear model for longitudinal data. RESULTS: SHRs of the study cohort versus the general population increased for all-cause hospitalization (males: 3.53, 95% CI 3.45-3.61; females: 3.22, 95% CI 3.18-3.26) as well as for most obesity-related conditions. The absolute median annual cost of hospitalization was 2,436 euros for males and 2,293 euros for females. Older age at cohort enrolment, BMI >=40 kg/m2, waist circumference above the median (males: 1.26 metres; females: 1.13 metres), and the presence of co-morbidities, such as cardiovascular diseases, respiratory diseases, cancer, diseases of the musculoskeletal system and connective tissue, and mental disorders, significantly increased the absolute median annual costs of hospitalization. CONCLUSIONS: The economic consequences of high hospitalization rates in obese individuals are relevant. Reducing the occurrence of co-morbidities among obese persons may be one important goal, not only for clinical reasons, but also from a public health point of view. PMID- 23738689 TI - An in vivo expression system for the identification of cargo proteins of vacuolar sorting receptors in Arabidopsis culture cells. AB - Vacuolar sorting receptors (VSRs) are type I integral membrane family proteins that in plant cells are thought to recognize cargo proteins at the late Golgi or trans-Golgi network (TGN) for vacuolar transport via the pre-vacuolar compartment (PVC). However, little is known about VSR cargo proteins in plants. Here we developed and tested an in vivo expression system for the identification of VSR cargos which is based on the premise that the expressed N-terminus of VSRs will be secreted into the culture medium along with their corresponding cargo proteins. Indeed, transgenic Arabidopsis culture cell lines expressing VSR N terminal binding domains (VSRNTs) were shown to secrete truncated VSRs (BP80NT, AtVSR1NT and AtVSR4NT) with attached cargo molecules into the culture medium. Putative cargo proteins were identified through mass spectrometry. Several identified cargo proteins were confirmed by localization studies and interaction analysis with VSRs. The screening strategy described here should be applicable to all VSRs and will help identify and study cargo proteins for individual VSR proteins. This method should be useful for both cargo identification and protein protein interaction in vivo. PMID- 23738691 TI - Repetitive implantations of short- and long-term mechanical circulatory support in acute severe heart failure: pushing the limits? PMID- 23738692 TI - Emerging pathways as individualized therapeutic target of multiple myeloma. AB - INTRODUCTION: Multiple myeloma (MM) is an incurable plasma cell malignancy, which causes significant morbidity due to organ damage and bone tissue destruction. In recent years, novel drugs have become available for MM therapy thanks to the growing knowledge of disease pathobiology. AREAS COVERED: Intrinsic genetic lesions, as well as the bone marrow microenvironment, contribute to the activation of proliferation and survival pathways, impairment of cell death mechanisms and drug resistance. The phosphatidylinositol 3-kinase (PI3K) and the Ras/mitogen-activated protein kinase (MAPK) cascades are the signaling pathways mainly involved in the MM development. In the last decade, several molecules interfering with growth and survival promoting signaling have been developed. EXPERT OPINION: Despite the availability of novel therapeutics, MM still evolves into a drug-resistant phase and most patients die of progressive disease. Therefore, there is an urgent need of novel therapeutic strategies. Among a plethora of new investigational agents, microRNA (miRNA) represents the basis for the design of novel therapeutic strategies which basically rely on miRNA inhibition or miRNA replacement approaches and take benefit respectively from the use of miRNA inhibitors or synthetic miRNAs as well as from lipid-based nanoparticles as carriers for in vivo delivery. PMID- 23738690 TI - Depolarization alters phenotype, maintains plasticity of predifferentiated mesenchymal stem cells. AB - Although adult stem cell transplantation has been implemented as a therapy for tissue repair, it is limited by the availability of functional adult stem cells. A potential approach to generate stem and progenitor cells may be to modulate the differentiated status of somatic cells. Therefore, there is a need for a better understanding of how the differentiated phenotype of mature cells is regulated. We hypothesize that bioelectric signaling plays an important role in the maintenance of the differentiated state, as it is a functional regulator of the differentiation process in various cells and tissues. In this study, we asked whether the mature phenotype of osteoblasts and adipocytes derived from human mesenchymal stem cells (hMSCs) could be altered by modulation of their membrane potential. hMSC-derived osteoblasts and adipocytes were depolarized by treatment with ouabain, a Na(+)/K(+) ATPase inhibitor, or by treatment with high concentrations of extracellular K(+). To characterize the effect of voltage modulation on the differentiated state, the depolarized cells were evaluated for (1) the loss of differentiation markers; (2) the up-regulation of stemness markers and stem properties; and (3) differences in gene expression profiles in response to voltage modulation. hMSC-derived osteoblasts and adipocytes exhibited significant down-regulation of bone and fat tissue markers in response to depolarization, despite the presence of differentiation-inducing soluble factors, suggesting that bioelectric signaling overrides biochemical signaling in the maintenance of cell state. Suppression of the osteoblast or adipocyte phenotype was not accompanied by up-regulation of genes associated with the stem state. Thus, depolarization does not activate the stem cell genetic signature and, therefore, does not induce a full reprogramming event. However, after transdifferentiating the depolarized cells to evaluate for multi-lineage potential, depolarized osteoblasts demonstrated improved ability to achieve correct adipocyte morphology compared with nondepolarized osteoblasts. The present study thus demonstrates that depolarization reduces the differentiated phenotype of hMSC-derived cells and improves their transdifferentiation capacity, but does not restore a stem-like genetic profile. Through global transcript profiling of depolarized osteoblasts, we identified pathways that may mediate the effects of voltage signaling on cell state, which will require a detailed mechanistic inquiry in future studies. PMID- 23738694 TI - The role of mathematical modelling in thermal medicine. PMID- 23738693 TI - Maximizing capture of gene co-expression relationships through pre-clustering of input expression samples: an Arabidopsis case study. AB - BACKGROUND: In genomics, highly relevant gene interaction (co-expression) networks have been constructed by finding significant pair-wise correlations between genes in expression datasets. These networks are then mined to elucidate biological function at the polygenic level. In some cases networks may be constructed from input samples that measure gene expression under a variety of different conditions, such as for different genotypes, environments, disease states and tissues. When large sets of samples are obtained from public repositories it is often unmanageable to associate samples into condition specific groups, and combining samples from various conditions has a negative effect on network size. A fixed significance threshold is often applied also limiting the size of the final network. Therefore, we propose pre-clustering of input expression samples to approximate condition-specific grouping of samples and individual network construction of each group as a means for dynamic significance thresholding. The net effect is increase sensitivity thus maximizing the total co-expression relationships in the final co-expression network compendium. RESULTS: A total of 86 Arabidopsis thaliana co-expression networks were constructed after k-means partitioning of 7,105 publicly available ATH1 Affymetrix microarray samples. We term each pre-sorted network a Gene Interaction Layer (GIL). Random Matrix Theory (RMT), an un-supervised thresholding method, was used to threshold each of the 86 networks independently, effectively providing a dynamic (non-global) threshold for the network. The overall gene count across all GILs reached 19,588 genes (94.7% measured gene coverage) and 558,022 unique co-expression relationships. In comparison, network construction without pre-sorting of input samples yielded only 3,297 genes (15.9%) and 129,134 relationships. in the global network. CONCLUSIONS: Here we show that pre clustering of microarray samples helps approximate condition-specific networks and allows for dynamic thresholding using un-supervised methods. Because RMT ensures only highly significant interactions are kept, the GIL compendium consists of 558,022 unique high quality A. thaliana co-expression relationships across almost all of the measurable genes on the ATH1 array. For A. thaliana, these networks represent the largest compendium to date of significant gene co expression relationships, and are a means to explore complex pathway, polygenic, and pleiotropic relationships for this focal model plant. The networks can be explored at sysbio.genome.clemson.edu. Finally, this method is applicable to any large expression profile collection for any organism and is best suited where a knowledge-independent network construction method is desired. PMID- 23738695 TI - Comparative analysis of mathematical models of cell death and thermal damage processes. AB - The standard method for assessing hyperthermia treatment has been calculation of cumulative equivalent minutes at 43 degrees C, CEM43 and its variations. This parameter normalises treatment thermal histories rather than predicts treatment results. Arrhenius models have been widely used in analysing higher temperature thermal treatments and successfully employed to predict irreversible thermal alterations in structural proteins. Unfortunately, in many, but not all cases they fail to represent thermally induced damage or cell death at hyperthermic temperatures, 43-50 degrees C, exhibiting significant over-prediction of the initial 'shoulder' region. The failure arises from the simplifying assumptions used to derive the irreversible reaction format that has been used in thermal damage studies. Several successful multi-parameter fit methods have been employed to model cell survival data. The two-state statistical thermodynamic model was derived from basic thermodynamic principles. The three-state model results from relaxing the assumptions under the Arrhenius formulation that result in an irreversible reaction. In other cell processes studied in vitro the irreversible Arrhenius model holds, and is sufficient to provide an accurate and useful estimate of thermal damage and cell death. It is essential in numerical model work to include multiple thermal damage processes operating in parallel to obtain a clear image of the likely outcome in tissues. Arrhenius and other C(t) models have that capability, while a single value for CEM43, does not. PMID- 23738696 TI - Arrhenius parameter determination as a function of heating method and cellular microenvironment based on spatial cell viability analysis. AB - PURPOSE: Predictions of injury in response to photothermal therapy in vivo are frequently made using Arrhenius parameters obtained from cell monolayers exposed to laser or water bath heating. However, the impact of different heating methods and cellular microenvironments on Arrhenius predictions has not been thoroughly investigated. This study determined the influence of heating method (water bath and laser irradiation) and cellular microenvironment (cell monolayers and tissue phantoms) on Arrhenius parameters and spatial viability. METHODS: MDA-MB-231 cells seeded in monolayers and sodium alginate phantoms were heated with a water bath for 3-20 min at 46, 50, and 54 degrees C or laser irradiated (wavelength of 1064 nm and fluences of 40 W/cm(2) or 3.8 W/cm(2) for 0-4 min) in combination with photoabsorptive carbon nanohorns. Spatial viability was measured using digital image analysis of cells stained with calcein AM and propidium iodide and used to determine Arrhenius parameters. The influence of microenvironment and heating method on Arrhenius parameters and capability of parameters derived from more simplistic experimental conditions (e.g. water bath heating of monolayers) to predict more physiologically relevant systems (e.g. laser heating of phantoms) were assessed. RESULTS: Arrhenius predictions of the treated area (<1% viable) under-predicted the measured areas in photothermally treated phantoms by 23 mm(2) using water bath treated cell monolayer parameters, 26 mm(2) using water bath treated phantom parameters, 27 mm(2) using photothermally treated monolayer parameters, and 0.7 mm(2) using photothermally treated phantom parameters. CONCLUSIONS: Heating method and cellular microenvironment influenced Arrhenius parameters, with heating method having the greater impact. PMID- 23738699 TI - Cytotoxicity of hepatocellular carcinoma cells to hyperthermic and ablative temperature exposures: in vitro studies and mathematical modelling. AB - PURPOSE: Image-guided ablative therapies use temperatures greater than 45 degrees C to kill abnormal cells. There is limited published data of cell survival after ablative temperature exposures, which is of importance to predict ablation zone dimensions. The objective of this study was to determine and mathematically model survival of hepatocellular carcinoma cells following ablative temperature exposures (45-60 degrees C). MATERIALS AND METHODS: Hepatocellular carcinoma (HCC) cell lines were plated in 96-well plates, and heated between 45 and 60 degrees C for 0-32 min. Heating was applied by a rapid media exchange with heated Hank's balanced salt solution (HBSS) in a temperature controlled water bath. Cell viability was determined by MTS assay. Survival data was modelled by the Arrhenius model, and the thermal isoeffective dose (TID) model where kinetic parameters were determined via non-linear optimisation. RESULTS: Results suggest that the thermal dose based on cumulative equivalent minutes and parameters as used for hyperthermia exposures (<43 degrees C) is not applicable for ablative exposures. We found R = 0.72 for temperatures between 45 60 degrees C for the TID model. The Arrhenius parameters were frequency factor A = 3.25E43 1/s, and activation energy Ea = 281 kJ/mol. These parameters correlate well with a prior study in the same cell line, and with threshold temperatures for necrosis from in vivo studies. CONCLUSIONS: Our results suggest that standard TID model kinetic parameters based on hyperthermia studies, often also used at ablation temperatures, are not applicable at these higher temperatures for HCC cells. PMID- 23738697 TI - Modelling of endoluminal and interstitial ultrasound hyperthermia and thermal ablation: applications for device design, feedback control and treatment planning. AB - Endoluminal and catheter-based ultrasound applicators are currently under development and are in clinical use for minimally invasive hyperthermia and thermal ablation of various tissue targets. Computational models play a critical role in device design and optimisation, assessment of therapeutic feasibility and safety, devising treatment monitoring and feedback control strategies, and performing patient-specific treatment planning with this technology. The critical aspects of theoretical modelling, applied specifically to endoluminal and interstitial ultrasound thermotherapy, are reviewed. Principles and practical techniques for modeling acoustic energy deposition, bioheat transfer, thermal tissue damage, and dynamic changes in the physical and physiological state of tissue are reviewed. The integration of these models and applications of simulation techniques in identification of device design parameters, development of real time feedback-control platforms, assessing the quality and safety of treatment delivery strategies, and optimisation of inverse treatment plans are presented. PMID- 23738698 TI - Computational modelling of microwave tumour ablations. AB - Microwave tissue heating is being increasingly utilised in several medical applications, including focal tumour ablation, cardiac ablation, haemostasis and resection assistance. Computational modelling of microwave ablations is a precise and repeatable technique that can assist with microwave system design, treatment planning and procedural analysis. Advances in coupling temperature and water content to electrical and thermal properties, along with tissue contraction, have led to increasingly accurate computational models. Developments in experimental validation have led to broader acceptability and applicability of these newer models. This review will discuss the basic theory, current trends and future direction of computational modelling of microwave ablations. PMID- 23738701 TI - 2012 Informa-Yamamoto Editor Award winners. PMID- 23738700 TI - Thermal modelling using discrete vasculature for thermal therapy: A review. AB - Reliable temperature information during clinical hyperthermia and thermal ablation is essential for adequate treatment control, but conventional temperature measurements do not provide 3D temperature information. Treatment planning is a very useful tool to improve treatment quality, and substantial progress has been made over the last decade. Thermal modelling is a very important and challenging aspect of hyperthermia treatment planning. Various thermal models have been developed for this purpose, with varying complexity. Since blood perfusion is such an important factor in thermal redistribution of energy in in vivo tissue, thermal simulations are most accurately performed by modelling discrete vasculature. This review describes the progress in thermal modelling with discrete vasculature for the purpose of hyperthermia treatment planning and thermal ablation. There has been significant progress in thermal modelling with discrete vasculature. Recent developments have made real-time simulations possible, which can provide feedback during treatment for improved therapy. Future clinical application of thermal modelling with discrete vasculature in hyperthermia treatment planning is expected to further improve treatment quality. PMID- 23738702 TI - Ultrasonography of the Harderian gland in the rabbit, guinea pig, and chinchilla. AB - OBJECTIVE: To evaluate the Harderian gland in rabbits, guinea pigs, and chinchillas using B-mode ultrasound and to determine normal size and changes in size and/or location in normal and diseased eyes and orbits by ultrasonographic measurements. PROCEDURE: Normal Harderian glands were evaluated ultrasonographically in 20 rabbits, 10 guinea pigs, and eight chinchillas. The Harderian gland was measured ultrasonographically in horizontal and vertical planes. Normal Harderian gland sizes were then compared with sizes in 27 rabbits, 13 guinea pigs, and three chinchillas that had exophthalmos. RESULTS: Harderian glands in normal rabbits were 0.69 +/- 0.07 cm (mean value +/- SD) horizontally and 1.33 +/- 0.14 cm vertically. Harderian glands in normal guinea pigs were 0.58 +/- 0.05 cm horizontally and 0.61 +/- 0.10 vertically. In normal chinchillas, the Harderian glands were 0.53 +/- 0.04 cm horizontally and 0.53 +/- 0.03 cm vertically. Harderian glands were significantly larger in the vertical plane in rabbits with exophthalmos (P = 0.001) and in the horizontal plane in guinea pigs with exophthalmos (P = 0.018). Harderian glands of rabbits with exophthalmos were significantly larger in both diseased and healthy glands in both planes compared with those of normal rabbits. Guinea pigs and chinchillas with exophthalmos had larger Harderian glands bilaterally in only the vertical plane. CONCLUSIONS: Ultrasonography is a valuable diagnostic imaging technique to evaluate the Harderian gland in the rabbit, guinea pig, and chinchilla. Retrobulbar pathologic processes cause enlargement of the Harderian gland, which may be attributable to inflammation or possible obstruction of the excretory ducts. PMID- 23738703 TI - Explaining the social gradient in sickness absence: a study of a general working population in Sweden. AB - BACKGROUND: Some previous studies have proposed potential explanatory factors for the social gradient in sickness absence. Yet, this research area is still in its infancy and in order to comprise the full range of socioeconomic positions there is a need for studies conducted on random population samples. The main aim of the present study was to investigate if somatic and mental symptoms, mental wellbeing, job strain, and physical work environment could explain the association between low socioeconomic position and belonging to a sample of new cases of sick-listed employees. METHODS: This study was conducted on one random working population sample (n = 2763) and one sample of newly sick-listed cases of employees (n = 3044), drawn from the same random general population in western Sweden. Explanatory factors were self-rated 'Somatic and mental symptoms', 'Mental well-being', 'job strain', and 'physical work conditions' (i.e. heavy lifting and awkward work postures). Multiple logistic regression analyses were used. RESULTS: Somatic and mental symptoms, mental well-being, and job strain, could not explain the association between socioeconomic position and sickness absence in both women and men. However, physical work conditions explained the total association in women and much of this association in men. In men the gradient between Non-skilled manual OR 1.76 (1.24;2.48) and Skilled manual OR 1.59 (1.10;2.20), both in relation to Higher non-manual, remained unexplained. CONCLUSIONS: The present study strengthens the scientific evidence that social differences in physical work conditions seem to comprise a key element of the social gradient in sickness absence, particularly in women. Future studies should try to identify further predictors for this gradient in men. PMID- 23738704 TI - CD27+ B cells from a subgroup of common variable immunodeficiency patients are less sensitive to apoptosis rescue regardless of interleukin-21 signalling. AB - Common variable immunodeficiency (CVID) is a primary immunodeficiency characterized by hypogammaglobulinaemia and recurrent infections. Although the underlying cause is unknown, B cells from most CVID patients fail to differentiate to memory or plasma cells. We investigated if increased apoptosis could influence the fate of B cells. For this purpose we activated purified B lymphocytes of CVID patients with a surrogate T-dependent (anti-CD40) or T independent [cytosine-phosphate-guanosine oligodeoxynucleotides (CpG-ODN) or anti immunoglobulin (Ig)M)] stimulus with or without interleukin (IL)-21. We found that CD27(+) B cells were more sensitive than CD27(-) B cells to spontaneous apoptosis and less sensitive to rescue from apoptosis. The addition of IL-21 down modulated the protective effect of all the stimuli on CD27(-) B cells and the protective effect of CpG-ODN and anti-IgM on CD27(+) B cells. In contrast, IL-21 rescued unstimulated CD27(-) B cells and improved the rescue of anti-CD40 stimulated CD27(+) B cells. When we compared patients and controls, mainly CD27(+) B cells from MB0 patients were less sensitive to rescue from apoptosis than those from MB1 patients and controls after activation, irrespective of the IL-21 effect. Increased apoptosis during an immune response could result in lower levels of immunoglobulin production in these patients. PMID- 23738705 TI - In vitro study on the pulmonary cytotoxicity of amiodarone. AB - CONTEXT: Amiodarone (an iodinated benzofuran) is a Class III antiarrhythmic drug that produces significant pulmonary disease. Proposed mechanisms of this cytotoxicity include necrosis, apoptosis, mitochondrial dysfunction and glutathione depletion. OBJECTIVE: This study was designed primarily to explore whether amiodarone impairs lung tissue cellular bioenergetics in BALB/c and Taylor Outbred mice. MATERIALS AND METHODS: Cellular respiration (mitochondrial O2 consumption), ATP, caspase activity and glutathione were measured in lung fragments incubated in vitro with 22 uM amiodarone for several hours. RESULTS: Without amiodarone, lung tissue cellular mitochondrial O2 consumption decayed exponentially with time, showing two distinct phases sharply separated at t >= 150 min. The rate of cellular respiration was 6-10-fold higher in the late phase compared to the early phase (p<0.0001). Lung tissue ATP also decayed exponentially with time, suggesting "uncoupling oxidative phosphorylation" was the responsible mechanism (low cellular ATP with high mitochondrial O2 consumption, resulting in rapid depletion of cellular metabolic fuels). Although intracellular caspase activity increased exponentially with time, the uncoupling was not prevented by the pancaspase inhibitor zVAD-fmk (N-benzyloxycarbonyl-val ala-asp (O-methyl)-fluoromethylketone). The same profiles were noted in the presence of amiodarone; but cellular ATP decayed 50% faster. Cellular glutathione for untreated tissue was 560 +/- 287 pmol mg(-1) (n=12) and for treated tissue was 490 +/- 226 pmol mg(-1) (n=12, p=0.5106). CONCLUSION: Uncoupling oxidative phosphorylation was demonstrated in untreated mouse lung tissues. Amiodarone lowered cellular ATP. Further studies are needed to explore the susceptibility of the lung to these deleterious insults and their relevance to human diseases. PMID- 23738707 TI - On the fate of MRI Gd-based contrast agents in cells. Evidence for extensive degradation of linear complexes upon endosomal internalization. AB - Commercial Gd-containing complexes are often used as MRI reporters in cellular labeling procedures as they are internalized into endosomes by pinocytosis. A methodology has been applied to assess the relative stability of three commercial Gd contrast agents following cellular uptake in fibroblasts and macrophages. It has been found that the acyclic series of Gd MRI contrast agents are degraded much more rapidly than their macrocyclic analogues, following endosomal internalization into living cells. This helps to explain their causal role in the development of nephrogenic systemic fibrosis in renally impaired patients. The methodology has also been applied to assess the fate of Gd-DTPA-BMA-loaded liposomes upon their endosomal internalization. Resistant liposomes prevent the degradation of the complex, whereas liposomes designed to release their payload in the acidic environments show a loss of integrity of Gd-DTPA-BMA analogous to the one observed upon internalization of the free complex. PMID- 23738706 TI - Unique clinicopathological features of metaplastic breast carcinoma compared with invasive ductal carcinoma and poor prognostic indicators. AB - BACKGROUND: Metaplastic breast carcinoma is a rare aggressive malignant neoplasm. The purposes of this study are to review the pathologic features and clinical outcomes of metaplastic breast carcinoma compared to invasive ductal carcinoma and to evaluate the prognosis of metaplastic breast carcinoma. METHODS: The cases of 55 patients with metaplastic breast carcinoma presenting between 1991 and 2006 were analyzed and compared to the cases of 767 age-matched patients with invasive ductal carcinoma from the same time period. RESULTS: The group of patients with metaplastic breast carcinoma presented with a larger tumor size, lower lymph node involvement, higher percentage of triple-negative (estrogen receptor-, progesterone receptor- and human epidermal growth factor receptor-2-negative) cases, and Ki-67 over-expression compared with the group of patients with invasive ductal carcinoma and triple-negative invasive ductal carcinomas. Patients in the metaplastic breast carcinoma group tended to have more local (often chest wall) recurrences (P = 0.038) and distant (often lung) metastases (P = 0.001) than those in the invasive ductal carcinomas group. The prognosis of metaplastic breast carcinoma was poorer than that of invasive ductal carcinoma and triple-negative invasive ductal carcinomas; the 5-year overall survival rate was 54.5% in metaplastic breast carcinoma versus 85.1% in invasive ductal carcinoma, and 73.3% in triple-negative invasive ductal carcinomas (P <0.001). The 5-year disease-free survival rate was 45.5% in metaplastic breast carcinoma versus 71.2% in invasive ductal carcinoma, and 60.3% in triple-negative invasive ductal carcinomas (P <0.001). Multivariate analysis revealed tumor size larger than 5.0 cm, lymph node involvement and Ki-67>=14% were significantly related to 5-year overall survival (P = 0.010; P = 0.010; P = 0.035) and 5-year disease-free survival (P = 0.020; P = 0.018; P = 0.049). CONCLUSIONS: Metaplastic breast carcinoma shows a poorer prognosis than both invasive ductal carcinoma and triple negative invasive ductal carcinomas. Tumor size larger than 5.0 cm, lymph node involvement and Ki-67 >=14% indicate a poor prognosis in patients with metaplastic breast carcinoma. PMID- 23738708 TI - Fluorescence photoactivation by ligand exchange around the boron center of a BODIPY chromophore. AB - Chelation of the boron center of the borondipyrromethene (BODIPY) platform by a catecholate ligand results in effective fluorescence suppression. Electron transfer from the chelating unit to the adjacent chromophore upon excitation is responsible for fluorescence quenching. Under the influence of a photoacid generator, the catecholate chelator can be exchanged with a pair of methoxide ligands. This photoinduced transformation prevents electron transfer and efficiently activates the fluorescence of the BODIPY chromophore. PMID- 23738709 TI - A high-throughput functional screen identifies small molecule regulators of temperature- and mechano-sensitive K2P channels. AB - K2P (KCNK) potassium channels generate "leak" potassium currents that strongly influence cellular excitability and contribute to pain, somatosensation, anesthesia, and mood. Despite their physiological importance, K2Ps lack specific pharmacology. Addressing this issue has been complicated by the challenges that the leak nature of K2P currents poses for electrophysiology-based high-throughput screening strategies. Here, we present a yeast-based high-throughput screening assay that avoids this problem. Using a simple growth-based functional readout, we screened a library of 106,281 small molecules and identified two new inhibitors and three new activators of the mammalian K2P channel K2P2.1 (KCNK2, TREK-1). By combining biophysical, structure-activity, and mechanistic analysis, we developed a dihydroacridine analogue, ML67-33, that acts as a low micromolar, selective activator of temperature- and mechano-sensitive K2P channels. Biophysical studies show that ML67-33 reversibly increases channel currents by activating the extracellular selectivity filter-based C-type gate that forms the core gating apparatus on which a variety of diverse modulatory inputs converge. The new K2P modulators presented here, together with the yeast-based assay, should enable both mechanistic and physiological studies of K2P activity and facilitate the discovery and development of other K2P small molecule modulators. PMID- 23738711 TI - Seroprevalence of Toxocara infection in children from southern Brazil. AB - The seroprevalence of Toxocara canis antibodies in children aged from 1 to 12 yr old was evaluated in Pelotas City, Rio Grande do Sul, Brazil. Human toxocariasis or visceral larva migrans (VLM) was diagnosed with the use of an ELISA based on the T. canis excretory-secretory (TES) antigens; Western blotting was used to confirm the ELISA-positive results. From 427 samples, 50.6% were positive for the presence of anti-TES antibodies. A confirmatory test (Western blot) was carried out on a sample of the ELISA-positive sera (n = 70), and all were positive. The Western blots had specific banding pattern characteristics, where the 30-kDa fraction demonstrated the highest reactivity. This fraction could be important for the specific diagnosis of toxocariasis. PMID- 23738712 TI - Recent developments in the use of differential scanning fluorometry in protein and small molecule discovery and characterization. AB - INTRODUCTION: Despite tremendous advances in the application of biophysical methods in drug discovery, the preponderance of instruments and techniques still require sophisticated analyses by dedicated personnel and/or large amounts of frequently hard-to-produce proteins. A technique which carries the promise of simplicity and relatively low protein consumption is the differential scanning fluorometry (DSF). This technique monitors protein through the use of environmentally sensitive fluorescent dye, in a temperature-ramp regime by observing the gradual exposure to the solvent of otherwise buried hydrophobic faces of protein domains. AREAS COVERED: This review describes recent developments in the field of DSF. This article pays a particular emphasis on the advances published during the 2010 - 2013 period. EXPERT OPINION: There has been a significant diversification of DSF applications beyond initial small molecule discovery into areas such as protein therapeutic development, formulation studies and various mechanistic investigations. This serves as a further indication of the broad penetration of the technique. In the small molecule arena, DSF has expanded toward sophisticated co-dependency MOA tests, demonstrating the wealth of information which the technique can provide. Importantly, the first public deposition of a large screening dataset may enable the use of thermal stabilization data in refining in silico models for small molecule binding. PMID- 23738713 TI - RNA-seq analysis reveals extensive transcriptional plasticity to temperature stress in a freshwater fish species. AB - BACKGROUND: Identifying genes of adaptive significance in a changing environment is a major focus of ecological genomics. Such efforts were restricted, until recently, to researchers studying a small group of model organisms or closely related taxa. With the advent of next generation sequencing (NGS), genomes and transcriptomes of virtually any species are now available for studies of adaptive evolution. We experimentally manipulated temperature conditions for two groups of crimson spotted rainbowfish (Melanotaenia duboulayi) and measured differences in RNA transcription between them. This non-migratory species is found across a latitudinal thermal gradient in eastern Australia and is predicted to be negatively impacted by ongoing environmental and climatic change. RESULTS: Using next generation RNA-seq technologies on an Illumina HiSeq2000 platform, we assembled a de novo transcriptome and tested for differential expression across the treatment groups. Quality of the assembly was high with a N50 length of 1856 bases. Of the 107,749 assembled contigs, we identified 4251 that were differentially expressed according to a consensus of four different mapping and significance testing approaches. Once duplicate isoforms were removed, we were able to annotate 614 up-regulated transfrags and 349 that showed reduced expression in the higher temperature group. CONCLUSIONS: Annotated blast matches reveal that differentially expressed genes correspond to critical metabolic pathways previously shown to be important for temperature tolerance in other fish species. Our results indicate that rainbowfish exhibit predictable plastic regulatory responses to temperature stress and the genes we identified provide excellent candidates for further investigations of population adaptation to increasing temperatures. PMID- 23738714 TI - Effects of glutamine on wound healing. AB - Studies reporting the need for replacing amino acids such as glutamine (Gln), hydroxymethyl butyrate (HMB) and arginine (Arg) to accelerate wound healing are available in the literature. The primary objective of this study was to present the effects of Gln on tissue hydroxyproline (OHP) levels in wound healing. This study was conducted on 30 female Sprague Dawley rats with a mean weight of 230 +/ 20 g. Secondary wounds were formed by excising 2 * 1 cm skin subcutaneous tissue on the back of the rats. The rats were divided into three equal groups. Group C (Control): the group received 1 ml/day isotonic solution by gastric gavage after secondary wound was formed. Group A (Abound): the group received 0.3 g/kg/day/ml Gln, 0.052 g/kg/day/ml HMB and 0.3 g/kg/day/ml Arg by gastric gavage after secondary wound was formed. Group R (Resource): the group received 0.3 g/kg/day/ml Gln by gastric gavage after secondary wound was formed. The OHP levels of the tissues obtained from the upper half region on the 8th day and the lower half region on the 21st day from the same rats in the groups were examined. Statistical analysis was performed using the statistics program SPSS version 17.0. No statistically significant differences were reported with regard to the OHP measurements on the 8th and 21st days (8th day: F = 0.068, P = 0.935 > 0.05; 21st day: F = 0.018, P = 0.983 > 0.05). The increase in mean OHP levels on the 8th and 21st days within each group was found to be statistically significant (F = 1146.34, P = 0.000 < 0.001). We conclude that in adults who eat healthy food, who do not have any factor that can affect wound healing negatively and who do not have large tissue loss at critical level, Gln, Arg and HMB support would not be required to accelerate secondary wound healing. PMID- 23738715 TI - The effects and mechanism of ginsenoside Rg1 on myocardial remodeling in an animal model of chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Recent studies haveshown that ginsenoside Rg1, extracted from the dry roots of Panax notoginseng as a traditional Asian medicine, plays an anti fibrosis role in myocardial remodeling. However, the mechanism still remains unclear. In the present study, we investigate the effect of ginsenoside Rg1on the collagenic remodeling of myocardium in chronic thromboembolic pulmonary hypertension (CTEPH), and its potential mechanism. METHODS: A rat model of CTEPH was established by injecting thrombi through the jugular vein wice in2 weeks. Four weeks later, four groups (Group A: normal rats + normal saline; Group B: normal rats + Rg1; Group C: CTEPH model + normal saline; Group D: CTEPH model + Rg1) were established. Normal saline and Rg1 were administrated by intraperitoneal injection. Ineach group, we measured the hemodynamic parameters, as well as the right ventricle to left ventricle (RV/LV) thickness ratio. Myocardial tissue sections of the RV were stained by hematoxylin-eosin +gentian violet and the morphological characteristics were observed by light microscopy. The matrix metalloproteinases (MMP) -2 and -9 were detected by the western blot. RESULTS: Compared with Group A and Group B, the right ventricular systolic pressure was significantly increased in Group C and significantly decreased in Group D. Compared with Group A and Group B, the RV/LV thickness ratio of the rats was significantly higher in Group C and Group D. There was significant fibrosis with collagen in Group C compared with Group A and Group B, and less significant changes in Group D were observed compared with those in Group C. The expression of MMP-2 and MMP-9 exhibited a significant decrease in Group C and was also significantly decreased in Group D compared withGroup A and Group B. Also, a negative linear relationship was shown between collagen-I and the expression of MMP-2 and MMP-9. CONCLUSIONS: Our animal study showed that ginsenoside Rg1 positively affects myocardial remodeling and pulmonary hemodynamics in CTEPH. Upregulation of the expression of MMP-2 and MMP-9 could explain the beneficial effects of ginsenoside Rg1 in CTEPH. PMID- 23738716 TI - Influence of surface chemistry on particle internalization into giant unilamellar vesicles. AB - Cellular uptake of materials plays a key role in their biomedical applications. In this work, based on the cell-mimic giant unilamellar vesicles (GUVs) and a novel type of microscale materials consisting of stimuli-responsive poly(N isopropylacrylamide) microgel particles and the incorporated lipids, the influence of particle surface chemistry, including hydrophobic/hydrophilic property and lipid decorations, on the adsorption and consequent internalization of particles into GUVs was investigated. It is found that the decoration of particle surface with lipids facilitates the adsorption of particles on GUV membrane. After that, the hydrophobic property of particle surface further triggers the internalization of particles into GUVs. These results demonstrate the importance of surface properties of particles on their interactions with lipid membranes and are helpful to the understanding of cellular uptake mechanism. PMID- 23738717 TI - An analysis of PLAG1 and HMGA2 rearrangements in salivary duct carcinoma and examination of the role of precursor lesions. AB - AIMS: Salivary duct carcinoma (SDC) often arises in pleomorphic adenoma (PA). Putative precursors, including low-grade cribriform cystadenocarcinoma (LGCCC) and ductal carcinoma in-situ (DCIS), are more controversial. Rearrangement of PLAG1 or HMGA2 is seen in 50-70% of PAs, but this has not been investigated in SDC. Using a large collection of SDCs from a single institution, we aimed to study these genes by fluorescence in-situ hybridization (FISH), and to correlate the presence of precursor lesions/intraductal proliferations with gene alterations. METHODS AND RESULTS: Forty-four SDCs were stained for smooth muscle actin, CK14, and p63, and examined with PLAG1 and HMGA2 FISH. Eight cases were SDC ex-PA; ten had a hyalinized nodule (HN), which is suspicious for PA; six arose in association with LGCCC; and twenty were 'de-novo' SDCs. Ten cases had PLAG1 rearrangement/amplification (22.7%) and eight had HMGA2 (18.2%) rearrangement/amplification. The positive cases were four SDC ex-PAs, eight SDCs with an HN, and five 'de-novo' SDCs. Twenty-three SDC ex-PAs were present in total (52.3%). All six SDC ex-LGCCCs were FISH-negative. Myoepithelial staining surrounded all LGCCCs, and demonstrated DCIS in 17 cases. Eleven DCIS lesions were in SDC ex-PAs or FISH-positive 'de-novo' SDCs. These cases represent 'cancerization' of ducts. Only six FISH-negative 'de-novo' SDCs showed DCIS. CONCLUSIONS: A large proportion of SDCs arise in PAs (with or without residual evidence of a PA). A small proportion of SDCs arise in LGCCCs. Cases showing DCIS often represent cancerization. PMID- 23738720 TI - The use of dried cerebrospinal fluid filter paper spots as a substrate for PCR diagnosis of the aetiology of bacterial meningitis in the Lao PDR. AB - We investigated whether dried cerebrospinal fluid (CSF) conserved on filter paper can be used as a substrate for accurate PCR diagnosis of important causes of bacterial meningitis in the Lao PDR. Using mock CSF, we investigated and optimized filter paper varieties, paper punch sizes, elution volumes and quantities of DNA template to achieve sensitive and reliable detection of bacterial DNA from filter paper specimens. FTA Elute Micro CardTM (Whatman, Maidstone, UK) was the most sensitive, consistent and practical variety of filter paper. Following optimization, the lower limit of detection for Streptococcus pneumoniae from dried mock CSF spots was 14 genomic equivalents (GE)/MUL (interquartile range 5.5 GE/MUL) or 230 (IQR 65) colony forming units/mL. A prospective clinical evaluation for S. pneumoniae, S. suis and Neisseria meningitidis was performed. Culture and PCR performed on fresh liquid CSF from patients admitted with a clinical diagnosis of meningitis (n = 73) were compared with results derived from dried CSF spots. Four of five fresh PCR-positive CSF samples also tested PCR positive from dried CSF spots, with one patient under the limit of detection. In a retrospective study of S. pneumoniae samples (n = 20), the median (IQR; range) CSF S. pneumoniae bacterial load was 1.1 * 10(4) GE/MUL (1.2 * 10(5) ; 1 to 6.1 * 10(6) DNA GE/MUL). Utilizing the optimized methodology, we estimate an extrapolated sensitivity of 90%, based on the range of CSF genome counts found in Laos. Dried CSF filter paper spots could potentially help us to better understand the epidemiology of bacterial meningitis in resource-poor settings and guide empirical treatments and vaccination policies. PMID- 23738721 TI - Coupling biorelevant dissolution methods with physiologically based pharmacokinetic modelling to forecast in-vivo performance of solid oral dosage forms. AB - OBJECTIVES: To summarize the basis for and progress with the development of in vitro-in-silico-in-vivo (IV-IS-IV) relationships for oral dosage forms using physiologically based pharmacokinetic (PBPK) modelling, with the focus on predicting the performance of solid oral dosage forms in humans. KEY FINDINGS: Various approaches to forecasting oral absorption have been reported to date. These range from simple dissolution tests, through biorelevant dissolution testing and laboratory simulations of the gastrointestinal (GI) tract, to the use of PBPK modelling to predict oral drug absorption based on the physicochemical parameters of the drug substance. Although each of these approaches can be useful for qualitative predictions, forecasting oral absorption on a quantitative basis with an individual approach is only possible for selected drug/dosage form combinations. By integrating biorelevant dissolution test results with the PBPK models, it has become possible to achieve quantitatively accurate as well as qualitative predictions of plasma profiles after oral dosing for both immediate and modified release formulations. SUMMARY: With further refinement of both the biorelevant dissolution testing methods and the PBPK models, it should be possible to expedite the development and regulatory approval of optimized dosage forms and dosing conditions. PMID- 23738722 TI - Fractal structure determines controlled release kinetics of monolithic osmotic pump tablets. AB - OBJECTIVES: To calculate the fractal dimension values of felodipine osmotic pump tablets during drug dissolution and to characterize the mechanism of the controlled drug release kinetics through three-dimensional fractal data. METHODS: Three-dimensional fractal values of volume (Df,volume ) and surface (Df,surface ) of the tablet core were calculated based on the box counting method. KEY FINDINGS: During the process of release of felodipine, both Df,volume and Df,surface were within the range of 2-3 and then changed markedly after a period of 3.0 h release, corresponding to extensive changes in entire shape, interior porous channels and surface structure of the tablet core. The curve of Df,volume mirrored that for tablet volume, however the curve of Df,surface was quite different from that of the surface area. Results showed that values of Df,surface correlated well with the drug release rate. Df,surface was found to be an efficient fractal parameter that could be used to characterize the complex changes to the tablet core that take place during drug release. CONCLUSIONS: The fractal dimension can be used as a quantitative indicator reflecting the drug release performance and be regarded as a key indicator for the quality control of oral controlled drug delivery systems. PMID- 23738723 TI - Determination of intestinal permeability of rigosertib (ON 01910.Na, Estybon): correlation with systemic exposure. AB - OBJECTIVES: Rigosertib (ON 01910.Na, Estybon) is a novel, anticancer agent undergoing phase 3 clinical trials for a lead indication against myelodysplastic syndromes (MDS). In this research, the permeability of rigosertib was evaluated using the in-situ perfused rat intestine (IPRI) model to support development of an oral formulation for rigosertib for treating cancer patients. METHODS: Experiments (n = 6 per group) were conducted using male Sprague-Dawley rats. Studies evaluated permeability across various intestinal segments and assessed the dose-linearity of absorption over the entire intestinal length. Drug concentrations in the portal and jugular vein were collected to correlate permeability parameters with presystemic and systemic exposure. KEY FINDINGS: Rigosertib permeability was highest in the jejunum, although parameter estimates indicated that rigosertib was a medium permeability compound. The compound displayed nonlinear absorption in the IPRI model, suggesting a saturable transport process. Transport inhibition studies using Caco-2 cells demonstrated that rigosertib was a P-glycoprotein (P-gp) substrate. Absolute bioavailability of rigosertib (10 and 20 mg/kg, 1-h infusion) in rats was estimated to be 10-15%. However, the fraction absorbed in humans predicted from IPRI data (52%) was consistent with published clinical data for rigosertib (35% oral bioavailability). CONCLUSIONS: The results of this research indicated that rigosertib is a promising candidate for oral delivery. Further studies are needed to evaluate the potential impact of P-gp and other intestinal transporters on the oral absorption of this promising anticancer agent. PMID- 23738724 TI - Basolateral glycylsarcosine (Gly-Sar) transport in Caco-2 cell monolayers is pH dependent. AB - OBJECTIVES: Transepithelial di/tripeptide transport in enterocytes occurs via the apical proton-coupled peptide transporter, hPEPT1 (SLC15A1) and a basolateral peptide transporter, which has only been characterized functionally. In this study we examined the pH dependency, substrate uptake kinetics and substrate specificity of the transporter. METHODS: We studied the uptake of [(14) C]Gly-Sar from basolateral solution into Caco-2 cell monolayers grown for 17-22 days on permeable supports, at a range of basolateral pH values. KEY FINDINGS: Basolateral Gly-Sar uptake was pH dependent, with a maximal uptake rate at a basolateral pH of 5.5. Uptake of Gly-Sar decreased in the presence of the protonophore nigericin, indicating that the uptake was proton-coupled. The uptake was saturable, with a maximal flux (Vmax ) of 408 +/- 71, 307 +/- 25 and 188 +/- 19 pmol/cm(2) /min (mean +/- S.E., n = 3) at basolateral pH 5.0, 6.0 and 7.4, respectively. The compounds Gly-Asp, Glu-Phe-Tyr, Gly-Glu-Gly, Gly-Phe-Gly, lidocaine and, to a smaller degree, para-aminohippuric acid were all shown to inhibit the basolateral uptake of Gly-Sar. CONCLUSIONS: The study showed that basolateral Gly-Sar transport in the intestinal cell line Caco-2 is proton coupled. The inhibitor profile indicated that the transporter has broad substrate specificity. PMID- 23738725 TI - Bitterness evaluation of intact and crushed Vesicare orally disintegrating tablets using taste sensors. AB - OBJECTIVE: Vesicare tablets, whose main component is solifenacin succinate, are known to be extremely bitter. The purpose of this study was to evaluate the effect of crushing on the bitterness of the Vesicare orally disintegrating tablets (ODTs). METHOD: Vesicare ODTs and conventional Vesicare tablets (CTs) were crushed either heavily or lightly. The bitterness scores and release rates of sample solutions obtained 5, 10, 30, 60, 90 or 120 s after placing a crushed CT or ODT containing 5 mg solifenacin in 40 ml of water were predicted using two taste sensors (SA402B and a-ASTREE) and HPLC, respectively. The particle size and the surfaces of the crushed tablets were observed microscopically. KEY FINDINGS: The predicted bitterness scores and the drug release rates of CTs were high, irrespective of the degree of crushing. The lightly crushed ODT was predicted to be less bitter than the heavily crushed ODT. In lightly crushed ODTs, spherical particles were observed, about 200 mm in diameter. CONCLUSIONS: The degree of crushing was a critical factor in determining the expression of bitterness by crushed ODTs. When intact tablets of Vesicare must be crushed to adjust the dosage, it is strongly recommended that ODTs be crushed gently. PMID- 23738726 TI - Influence of aminoglycoside antibiotics on chicken cystatin binding to renal brush-border membranes. AB - OBJECTIVES: Drug-induced kidney injury is a serious adverse event which needs to be monitored during aminoglycoside therapy. Urine cystatin C is considered an early and sensitive marker of nephrotoxicity. Cystatin C, a low-molecular-weight serum protein, and basic drugs have a common transport system expressed in the apical membrane of renal proximal tubular cells. The aim of this study was to investigate whether aminoglycoside antibiotics influenced cystatin C binding to the renal brush-border membrane. METHODS: The binding study was performed using a rapid filtration technique and affinity column displacement method. KEY FINDINGS: Concentration-dependent inhibition of chicken cystatin binding to brush-border membranes by gentamicin was observed. The gentamicin interaction with brush border membranes was of relatively low affinity (Ki = 32 MUm) in comparison with the chicken cystatin affinity to the binding sites (Kd = 3.6 MUm). Amikacin and gentamicin were only able to displace chicken cystatin from the chromatographic affinity column in concentrations several times higher than normally found in the tubular fluid during standard aminoglycoside therapy. CONCLUSION: Cystatin reabsorption in the proximal tubule cannot be significantly affected by aminoglycoside antibiotics because of their relatively low affinity to common binding sites on the brush-border membrane. PMID- 23738727 TI - Activation of renal haeme oxygenase-1 alleviates gentamicin-induced acute nephrotoxicity in rats. AB - OBJECTIVES: This study aimed to investigate whether activation of haeme oxygenase (HO)-1 enzyme by haemin would have beneficial effects on the functional and histological outcome against gentamicin-induced renal damage in rats and sought to elucidate the underlying mechanisms of the therapeutic action. METHODS: Nephrotoxicity was induced by injection of gentamicin (80 mg/kg, i.p.) once daily for seven days. Haemin (50 MUmol/kg, i.p.) was given to the control and gentamicin-treated rats in the presence or absence of a HO-1 inhibitor, zinc protoporphyrin IX (ZnPP, 50 MUmol/kg per day, i.p.). KEY FINDINGS: Haemin treatment prevented gentamicin-induced elevated serum creatinine, urinary protein levels and ameliorated the impaired creatinine clearance. Haemin compensated the deficits in antioxidant enzyme activity and attenuated lipid peroxidation along with decreased reactive oxygen species (ROS) production in renal tissues due to gentamicin. Moreover, haemin pre-administration evoked increased renal HO-1 activity. Additionally, haemin significantly attenuated elevated renal tumour necrosis factor-alpha (TNF-alpha), nuclear factor-kappaB (NF-kappaB) levels and caspase-3 activity alongside ameliorating glomerular pathology. These therapeutic effects were abolished by ZnPP pretreatment. CONCLUSIONS: Here is the first evidence demonstrating the protective effect of HO-1 against gentamicin associated nephrotoxicity. Suppression of oxidative/inflammatory insults alongside the corresponding decline of apoptosis were presumably responsible for this renoprotection. PMID- 23738728 TI - Curculigoside promotes osteogenic differentiation of bone marrow stromal cells from ovariectomized rats. AB - OBJECTIVES: Curculigoside, a natural compound isolated from the medicinal plant Curculigo orchioides has been reported to prevent bone loss in ovariectomized rats. However, the underlying molecular mechanisms are largely unknown. This study investigated the effects of curculigoside on proliferation and osteogenic differentiation of bone marrow stromal cells (BMSCs). METHODS: The toxicity, proliferation and osteogenic differentiation of BMSCs cultured with various concentrations (0 as control, 10, 100 and 500 um) of curculigoside were measured by viability assay, MTT analysis, alkaline phosphatase (ALP) activity assay, alizarin red staining and mineralization assay, real-time PCR analysis on osteogenic genes including ALP, type I collagen (Col I), osteocalcin (OCN) and osteoprotegerin (OPG), runt-related transcription factor 2 (Runx2), as well as OPG enzyme-linked immunosorbent assay. KEY FINDINGS: No significant cytotoxicity was observed for BMSCs after supplementation with curculigoside. The proliferation of BMSCs was enhanced after administration of curculigoside, especially 100 um curculigoside. Moreover, the osteogenic gene expression was significantly enhanced with 100 um curculigoside treatment. Importantly, curculigoside significantly increased OPG secretion. CONCLUSIONS: The data indicate that curculigoside could promote BMSC proliferation and induce osteogenic differentiation of BMSCs. The most profound response was observed with 100 um curculigoside. These findings may be valuable for understanding the mechanism of the effect of curculigoside on bone, especially in relation to osteoporosis. PMID- 23738729 TI - Effects of herbal supplements on the bioactivation of chemotherapeutic agents. AB - OBJECTIVES: The aim of this study was to investigate the impact of commercially available, over-the-counter herbal supplements (St John's wort, black cohosh and ginger root extract) on the metabolic activation of tamoxifen and irinotecan. METHODS: Co-incubation of each drug and supplement combination over a range of concentrations was conducted in human liver microsomes and the decrease in the rate of active metabolite formation was monitored using high-performance liquid chromatography tandem mass spectrometry. Data was analysed using non-linear regression analysis and Dixon plots to determine the dominant mechanism of inhibition and to estimate the Ki and IC50 values of the commercial supplements. KEY FINDINGS: The data suggest that black cohosh was the strongest inhibitor tested in this study for both CYP450 and carboxyesterase mediated biotransformation of tamoxifen and irinotecan, respectively, to their active metabolites. St John's wort was a stronger inhibitor compared with ginger root extract for tamoxifen (CYP mediated pathway), while ginger root extract was a stronger inhibitor compared with St John's wort for the carboxyesterase mediated pathway. CONCLUSIONS: Commercially available supplements are widely used by patients and their potential impact on the efficacy of the chemotherapy is often unknown. The clinical significance of these results needs to be evaluated in a comprehensive clinical trial. PMID- 23738730 TI - (S)-[6]-Gingerol inhibits TGF-beta-stimulated biglycan synthesis but not glycosaminoglycan hyperelongation in human vascular smooth muscle cells. AB - OBJECTIVES: (S)-[6]-Gingerol is under investigation for a variety of therapeutic uses. Transforming growth factor (TGF)-beta stimulates proteoglycan synthesis, leading to increased binding of low-density lipoproteins, which is the initiating step in atherosclerosis. We evaluated the effects of (S)-[6]-gingerol on these TGF-beta-mediated proteoglycan changes to explore its potential as an anti atherosclerotic agent. METHODS: Purified (S)-[6]-gingerol was assessed for its effects on proteoglycan synthesis by [(35) S]-sulfate incorporation into glycosaminoglycan chains and [(35) S]-Met/Cys incorporation into proteoglycans and total proteins in human vascular smooth muscle cells. Biglycan level was assessed by real-time quantitative polymerase chain reactions and the effects of (S)-[6]-gingerol on TGF-beta signalling by assessment of the phosphorylation of Smads and Akt by western blotting. KEY FINDINGS: (S)-[6]-Gingerol concentration dependently inhibited TGF-beta-stimulated proteoglycan core protein synthesis, and this was not secondary to inhibition of total protein synthesis. (S)-[6] Gingerol inhibited biglycan mRNA expression. (S)-[6]-Gingerol did not inhibit TGF beta-stimulated glycosaminoglycan hyperelongation or phosphorylation of Smad 2, in either the carboxy terminal or linker region, or Akt phosphorylation. CONCLUSIONS: The activity of (S)-[6]-gingerol to inhibit TGF-beta-stimulated biglycan synthesis suggests a potential role for ginger in the prevention of atherosclerosis or other lipid-binding diseases. The signalling studies indicate a novel site of action of (S)-[6]-gingerol in inhibiting TGF-beta responses. PMID- 23738731 TI - Effect of quercetin on the transport of N-acetyl 5-aminosalicylic acid. AB - OBJECTIVES: The aim of this study was to investigate the transporter-mediated transport of N-acetyl 5-aminosalicylic acid (Ac-5-ASA) and the effect of quercetin on Ac-5-ASA transport. METHODS: Caco-2 cell monolayers grown in Transwells were used to study the transport of Ac-5-ASA in the absence or presence of quercetin, and apical-to-basolateral and basolateral-to-apical apparent permeability (PappAB and PappBA values, respectively) was determined. The effect of transporter inhibitors, such as MK571, quinidine and mitoxantrone, on the transport of Ac-5-ASA was investigated. KEY FINDINGS: In the absence of transporter mediators, the transport of Ac-5-ASA was much higher in the basolateral-to-apical direction than in the opposite direction. The PappBA/PappAB ratio of Ac-5-ASA was 4.89. Quercetin inhibited the apical efflux of Ac-5-ASA and decreased the PappBA/PappAB ratio to 1.05. Of the transporter inhibitors, MK571 decreased the PappBA/PappAB ratio to 1.07; however, neither quinidine nor mitoxantrone had an effect on Ac-5-ASA transport. CONCLUSIONS: Ac-5-ASA was excreted by multidrug resistance-associated protein 2 from Caco-2 cells, and its transport was inhibited by quercetin. Our findings suggest that dose levels of sulfasalazine or 5-aminosalicylic acid can be decreased by coadministration of quercetin, leading to improved pharmaceutical care for inflammatory bowel diseases. PMID- 23738732 TI - Extracts from Epilobium sp. herbs induce apoptosis in human hormone-dependent prostate cancer cells by activating the mitochondrial pathway. AB - OBJECTIVES: The aim of this work was to determine the effect of standardized aqueous extracts from Epilobium angustifolium L., E. parviflorum Schreb. and E. hirsutum L. herbs on the apoptosis of hormone-dependent prostate cancer cells (LNCaP). METHODS: The extracts were characterized using high-performance liquid chromatography-diode array detector coupled with mass spectrometry (HPLC-DAD MS/MS). Apoptosis in the cells was analysed using Annexin V-fluorescein isothiocyanate, and mitochondrial potential, Deltapsim , using JC-1 by flow cytometry. Caspase-3 activity was determined by enzyme-linked immunosorbent assay. KEY FINDINGS: Using the HPLC-DAD-MS/MS method, 38 constituents were characterized. Extracts contained significant amounts of oenothein B as well as flavonoids and phenolic acids. Exposure of LNCaP cells to the extracts (20, 50 and 70 MUg/ml) resulted in a significant increase in the level apoptotic cells, from 2.86 +/- 0.5% (for untreated cells) up to 86.6 +/- 1.0%. All extracts significantly decreased the mitochondrial potential, Deltapsim , resulting in an increase in the activity of caspase-3 from 0.3 +/- 0.07 ng/mg of protein (for untreated cells) up to 1.26 +/- 0.32 ng/mg of protein. CONCLUSIONS: This study demonstrated that Epilobium extracts are active against LNCaP prostate cancer cells and that their apoptotic activity is related to activation of the mitochondrial pathway. The high oenothein B content may influence the biological activity of these plant materials. PMID- 23738734 TI - Herb-drug pharmacokinetic interaction of artificial calculus bovis with diclofenac sodium and chlorpheniramine maleate in rats. AB - OBJECTIVES: To investigate the herb-drug pharmacokinetic interaction of artificial calculus bovis (ACB) with diclofenac sodium (DS) and chlorpheniramine maleate (CPM) in rats. METHODS: A sensitive high-performance liquid chromatography coupled with tandem mass spectrometry method was developed and validated for the simultaneous determination of DS and CPM in rat plasma. The proposed method was successfully applied to compare the herb-drug pharmacokinetic interaction of ACB with DS and CPM in rats following intragastric administration. KEY FINDINGS: The proposed method had good linearity and no endogenous material interfered with the analytes and internal standard peaks. The lower limit of quantification of DS and CPM was 1 and 0.1 ng/ml, respectively. There was no apparent pharmacokinetic interaction between DS and CPM. Co-administration of ACB with DS noticeably increased the area under the concentration-time curve (AUC0 infinity ) and peak plasma concentration (Cmax ) of DS, while the parameters time of peak concentration (Tmax ), clearance (ClZ/F ) and apparent volume of distribution (VZ/F ) of DS significantly decreased. Meanwhile, co-administration of ACB with CPM noticeably increased the Tmax , ClZ/F and VZ/F of CPM. A marked decline in AUC0-infinity and Cmax of CPM occurred in the presence of ACB. CONCLUSIONS: This study indicated that co-administration of ACB with DS and CPM can result in an apparent herb-drug pharmacokinetic interaction in rats. PMID- 23738733 TI - Suramin inhibits PDGF-stimulated receptor phosphorylation, proteoglycan synthesis and glycosaminoglycan hyperelongation in human vascular smooth muscle cells. AB - OBJECTIVES: Suramin is a polysulfonated naphthylurea with antiparasitic and potential antineoplastic activity. Suramin's pharmacological actions, which have not yet been fully elucidated, include antagonism of the action of platelet derived growth factor (PDGF) at its receptor. We investigated the effects of suramin on PDGF-stimulated proteoglycan synthesis. METHODS: Human vascular smooth muscle cells (VSMCs) were incubated in the presence and absence of PDGF and suramin with [(3) H]thymidine or (35) SO4 as radiolabels. Mitogenic response was determined by [(3) H]thymidine incorporation. PDGFbeta receptor phosphorylation was assessed by western blotting. Proteoglycan size and glycosaminoglycan chain synthesis and size were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The Alphascreen phosphotyrosine assay kit was used to investigate PDGFbeta receptor tyrosine kinase inhibition by suramin. KEY FINDINGS: Suramin decreased PDGF-stimulated proliferation, proteoglycan synthesis and GAG chain hyperelongation. Suramin also directly inhibited PDGFbeta receptor kinase activity as well as PDGFbeta receptor phosphorylation in intact VSMCs. CONCLUSIONS: These data show that inhibition of PDGFbeta receptor phosphorylation in intact cells is necessary to define a fully active PDGF antagonist. They also confirm that PDGFbeta receptor kinase activity is necessary for PDGF-mediated atherogenic changes in proteoglycan synthesis and support efforts to develop PDGFbeta receptor antagonists as potential anti-atherosclerotic agents. PMID- 23738735 TI - Multiparametric evaluation of the cytoprotective effect of the Mangifera indica L. stem bark extract and mangiferin in HepG2 cells. AB - OBJECTIVE: Mango (Mangifera indica L.) stem bark extract (MSBE) is a natural product with biological properties and mangiferin is the major component. This paper reported the evaluation of the protective effects of MSBE and mangiferin against the toxicity induced in HepG2 cells by tert-butyl hydroperoxide or amiodarone. METHOD: Nuclear morphology, cell viability, intracellular calcium concentration and reactive oxygen species (ROS) production were measured by using a high-content screening multiparametric assay. KEY FINDINGS: MSBE and mangiferin produced no toxicity below 500 mg/ml doses. A marked recovery in cell viability, which was reduced by the toxicants, was observed in cells pre-exposed to MSBE or mangiferin at 5-100 mg/ml doses. We also explored the possible interaction of both products over P-glycoprotein (P-gp). MSBE and mangiferin above 100 mg/ml inhibited the activity of P-gp in HepG2 cells. CONCLUSIONS: MSBE and mangiferin showed cytoprotective effects of against oxidative damage and mitochondrial toxicity induced by xenobiotics to human hepatic cells but it seemed that other constituents of the extract could contribute to MSBE protective properties. In addition, the drug efflux should be taken into account because of the inhibition of the P-gp function observed in those cells exposed to both natural products. PMID- 23738736 TI - Sesamol prevents doxorubicin-induced oxidative damage and toxicity on H9c2 cardiomyoblasts. AB - OBJECTIVES: Exposure to toxicants like doxorubicin (Dox) damages cellular components by generating reactive oxygen species (ROS). This can be attenuated using free radical scavengers and/or antioxidants. METHODS: Dox-exposed cardiac myoblasts (H9c2 cells) were treated with sesamol (12.5, 25 and 50 MUm), a natural phenolic compound. Intracellular ROS inhibition, cell viability and analysis of antioxidant and biochemical markers such as superoxide dismutase, catalase, glutathione-S-transferase, glutathione peroxidase, reduced/oxidized glutathione, lipid peroxidation and protein carbonyl content were performed. The effect of sesamol treatment on the cytotoxic and genotoxic parameters was studied by monitoring the signalling proteins involved in the apoptotic pathway. KEY FINDINGS: Dox triggered cellular and genetic damage by increasing levels of intracellular ROS, thereby decreasing cell viability and increasing apoptosis. Sesamol reversed the cytotoxic and genotoxic effects of Dox. In addition, sesamol attenuated the pro-apoptotic proteins and improved the anti-apoptotic status. Sesamol pre-treatment also alleviated the disturbed antioxidant milieu by preventing ROS production and improving endogenous enzyme levels. CONCLUSIONS: Among the different doses tested, 50 MUm of sesamol showed maximum protection against Dox-induced oxidative damage. This reflects the significance of sesamol in ameliorating the deleterious effects associated with cancer chemotherapy. PMID- 23738737 TI - Hexokinase mediates stomatal closure. AB - Stomata, composed of two guard cells, are the gates whose controlled movement allows the plant to balance the demand for CO2 for photosynthesis with the loss of water through transpiration. Increased guard-cell osmolarity leads to the opening of the stomata and decreased osmolarity causes the stomata to close. The role of sugars in the regulation of stomata is not yet clear. In this study, we examined the role of hexokinase (HXK), a sugar-phosphorylating enzyme involved in sugar-sensing, in guard cells and its effect on stomatal aperture. We show here that increased expression of HXK in guard cells accelerates stomatal closure. We further show that this closure is induced by sugar and is mediated by abscisic acid. These findings support the existence of a feedback-inhibition mechanism that is mediated by a product of photosynthesis, namely sucrose. When the rate of sucrose production exceeds the rate at which sucrose is loaded into the phloem, the surplus sucrose is carried toward the stomata by the transpiration stream and stimulates stomatal closure via HXK, thereby preventing the loss of precious water. PMID- 23738739 TI - Systematic screening of behavioral responses in two zebrafish strains. AB - Wild-type (WT) zebrafish are commonly used in behavioral tests, but the term WT is not a precise description, and corresponds to many different strains (e.g., AB, TU, WIK, and others). Previous studies compared the physiological, behavioral, or metabolic characteristics of different zebrafish strains (indigenous WT populations versus laboratory WT strains). AB and TU are widely used, but at least one study has demonstrated behavioral differences between them. To choose the most appropriate strain for our experiments, we systematically screened behavioral responses of AB and TU fish in several assays. We analyzed the locomotion activity and responses to a light/dark challenge in adults and larvae, and exploratory behavior and color conditioning in adults. Differences were observed for all tests, the strains displaying particular behavior depending on the tests. As larvae, TU displayed a wider activity range than AB larvae at the onset of locomotor behavior; as adults, TU were more reactive to sudden light transitions and recovered the swimming activity faster in T-maze or homebase release in novel tank tests, whereas AB fish had more contrasted circadian rhythms and performed better in color learning. Strain specific behavior should be considered when designing experiments using behavior. PMID- 23738738 TI - The binding characteristics of isoniazid with copper-zinc superoxide dismutase and its effect on enzymatic activity. AB - BACKGROUND: Isoniazid (INH) is front-line anti-tuberculosis (TB) drugs, which are usually prescribed to TB patients for a total period of 6 months. Antituberculosis drug-induced hepatotoxicity (ATDH) is a serious adverse reaction of TB treatment. It is reported that INH-induced hepatotoxicity is associated with oxidative stress. Superoxide dismutase (SOD, EC 1.15.1.1) is the key enzyme for the protection of oxidative stress, which catalyzes the removal of superoxide radical anion, thereby raising the need to better understand the interaction between INH and SOD. RESULTS: The experimental results showed that the fluorescence intensity of Cu/Zn-SOD regularly decreased owing to form a 1:1 INH SOD complex. According to the corresponding association constants (K SV) between INH and SOD obtained from Stern-Volmer plot, it is shown that values of K A are 1.01 * 10(4), 5.31 * 10(3), 3.33 * 10(3), 2.20 * 10(3) L . mol(-1) at four different temperatures, respectively. The binding constants, binding sites and the corresponding thermodynamic parameters ((Delta) H, (Delta) G and (Delta) S) were calculated. A value of 3.93 nm for the average distance between INH and chromophore of Cu/Zn-SOD was derived from Forster theory of non-radiation energy transfer. The conformational investigation showed that the presence of INH resulted in the microenvironment and conformational changes of Cu/Zn-SOD. In addition, Effects of INH on superoxide dismutase activity was examined. CONCLUSIONS: The results show that the hydrogen bonding and van der Waals forces play major roles in stabilizing the 1:1 INH-SOD complex. After addition of INH during the range of the experiment, the conformation and microenvironment of Cu/Zn-SOD are changed, but the activity of Cu/Zn-SOD is not changed. PMID- 23738740 TI - Abstracts of the Pre-Congress Courses from the 12th International Congress on Implant Prosthodontics. June 6- 8, 2013. Padova, Palazzo della Ragione, Italy. PMID- 23738741 TI - Reducing high calorie snack food in young adults: a role for social norms and health based messages. AB - BACKGROUND: Consumption of high calorie junk foods has increased recently, especially among young adults and higher intake may cause weight gain. There is a need to develop public health approaches to motivate people to reduce their intake of junk food. OBJECTIVE: To assess the effect of health and social norm messages on high calorie snack food intake (a type of junk food) as a function of usual intake of junk food. DESIGN: In a between-subjects design, 129 young adults (45 men and 84 women, mean age = 22.4 years, SD = 4.5) were assigned to one of three conditions: 1) a social norm condition, in which participants saw a message about the junk food eating habits of others; 2) a health condition, in which participants saw a message outlining the health benefits of reducing junk food consumption and; 3) a control condition, in which participants saw a non-food related message. After exposure to the poster messages, participants consumed a snack and the choice and amount of snack food consumed was examined covertly. We also examined whether usual intake of junk food moderated the effect of message type on high calorie snack food intake. RESULTS: The amount of high calorie snack food consumed was significantly lower in both the health and the social norm message condition compared with the control message condition (36% and 28%, both p < 0.05). There was no significant difference in snack food or energy intake between the health and social norm message conditions. There was no evidence that the effect of the messages depended upon usual consumption of junk food. CONCLUSIONS: Messages about the health effects of junk food and social normative messages about intake of junk food can motivate people to reduce their consumption of high calorie snack food. PMID- 23738742 TI - High expression of tocochromanol biosynthesis genes increases the vitamin E level in a new line of giant embryo rice. AB - 'Shangshida No. 5' is a new variety of giant embryo rice derived from a single point mutation of the giant embryo gene (ge) in 'Chao2-10' rice. This study quantified the levels of eight vitamin E homologues (alpha-, beta-, gamma-, and delta-tocopherol and alpha-, beta-, gamma-, and delta-tocotrienol) in brown rice, embryos, endosperm, and developing seeds of giant embryo and normal embryo rice using a normal phase high-performance liquid chromatographic method. Quantitative RT-PCR analysis was conducted to reveal the different expression patterns of the ge gene and tocochromanol biosynthesis genes in developing giant and normal embryo seeds. The total vitamin E content in 'Shangshida No. 5' brown rice was 52.54 mg alpha-tocopherol equivalent (alpha-TE)/kg, of which alpha-tocopherol constituted 49.14 mg/kg, which was approximately 2.2-fold greater than that in 'Chao2-10' brown rice. In giant embryo seeds, the expression level of the ge gene was higher than that in normal embryo seeds during early developmental stages. These results are the first to indicate that coup-regulated expression of the OsHPPD, OsHPT, and OsMPBQ MT2 genes might be the primary reason for the large accumulation of alpha-tocopherol in giant embryo rice seeds. The different transcription pattern of the tocochromanol biosynthesis genes in 'Shangshida No. 5' rice seeds compared with 'Chao2-10' rice seeds is attributable to the ge mutation and the different expression level of the ge gene in giant embryo seeds. PMID- 23738743 TI - Socioeconomic variations in access to smoking cessation interventions in UK primary care: insights using the Mosaic classification in a large dataset of primary care records. AB - BACKGROUND: Smoking prevalence is particularly high amongst more deprived social groups. This cross-sectional study uses the Mosaic classification to explore socioeconomic variations in the delivery and/or uptake of cessation interventions in UK primary care. METHODS: Data from 460,938 smokers registered in The Health Improvement Network between 2008 and 2010 were analysed. Logistic regression was used to calculate odds ratios for smokers having a record of receiving cessation advice or a prescription for a cessation medication during the study period by Townsend quintile and for each of the 11 Mosaic groups and 61 Mosaic types. Both of these measures are area-level indicators of deprivation. Profiles of Mosaic categories were used to suggest ways to target specific groups to increase the provision of cessation support. RESULTS: Odds ratios for smokers having a record of advice or a prescription increased with increasing Townsend deprivation quintile. Similarly, smokers in more deprived Mosaic groups and types were more likely to have a documented cessation intervention. The odds of smokers receiving cessation advice if they have uncertain employment and live in social housing in deprived areas were 35% higher than the odds for successful professionals living in desirable areas (odds ratio (OR) 1.35, 95% confidence interval (CI) 1.20-1.52; absolute risks 57.2% and 50.1% respectively), and those in low-income families living in estate-based social housing were 50% more likely to receive a prescription than these successful professionals (OR 1.50, 95% CI 1.31-1.73; absolute risks 19.5% and 13% respectively). Smokers who did not receive interventions were generally well educated, financially successful, married with no children, read broadsheet newspapers and had broadband internet access. CONCLUSIONS: Wide socioeconomic variations exist in the delivery and/or uptake of smoking cessation interventions in UK primary care, though encouragingly the direction of this variation may help to reduce smoking prevalence-related socioeconomic inequalities in health. Groups with particularly low intervention rates may be best targeted through broadsheet media, the internet and perhaps workplace-based interventions in order to increase the delivery and uptake of effective quit support. PMID- 23738745 TI - Evaluation of intraorbital prosthetic pigmentation using 0.3 and 1.5 Tesla magnetic resonance imaging and computed tomography. AB - PURPOSE: To investigate the magnetic susceptibility artifact associated with pigmented intraorbital prosthetics when performing magnetic resonance imaging (MRI) and computed tomography (CT). Potential artifact reduction techniques were also investigated. STUDY DESIGN: Prospective study. METHODS: Five different colored 20-millimeter small animal silicone intraorbital prosthetics and two equine prosthetics were evaluated using 0.3 and 1.5 Tesla (T) MRI and CT. MRI sequences included T1- (T1WI) and T2-weighted spin echo (T2WI), T2 gradient echo (T2*), short tau inversion recovery (STIR), and fluid-attenuated inversion recovery (FLAIR). When present, artifact size was measured using computerized software by three separate observers. Artifact reduction techniques included alterations in receiver bandwidth, field of view, slice thickness, and matrix size. RESULTS: The ferrous brown-pigmented prosthetic resulted in a magnetic susceptibility artifact with MRI. No artifact was observed on CT images. Interobserver variability was not statistically significant. For both the 0.3T and 1.5T MRI, the T2* sequence exhibited the largest artifact surface area followed by T2WI, T1WI, STIR, and FLAIR. Decreasing slice thickness showed a decrease in artifact size; however, this difference was not statistically significant. CONCLUSIONS: The ferrous substances in the brown intraorbital prosthetic resulted in a significant magnetic susceptibility artifact when performing MRI. Artifact reduction techniques did not significantly decrease artifact surface area. The use of ferrous brown-pigmented prosthetics and their potential to affect future MR imaging studies should be adequately discussed with pet owners. PMID- 23738744 TI - Relationship of CD146 expression to activation of circulating T cells: exploratory studies in healthy donors and patients with connective tissue diseases. AB - The endothelial cell adhesion molecule, CD146, is expressed on ~ 2% of normal circulating T cells, correlating with T cell activation, endothelial interactions and T helper type 17 (Th17) effector functions. In this study, we have characterized CD146 expression in circulating T cells from healthy controls and patients with stable, well-controlled autoimmune connective tissue diseases (CTDs). In vitro, anti-CD3/anti-CD28 stimulation induced CD146 expression in both CD4 and CD8 T cells. In healthy controls and CTD patients, CD146 was associated with expression of recent and chronic activation markers (CD25(+), OX-40(+), CD69(+), CD27(-)) and was confined to CD45RO(+)/RA(-)/CD28(+) populations within the CD4 subset. Except for CD69, these markers were not associated with CD146 in the CD8 subset. Surprisingly, most CTD patients exhibited no T cell hyperactivation ex vivo. In five of five patients with secondary Sjogren's syndrome circulating T cells appeared activated despite therapy, and CD146 up regulation, associated with activation markers, was observed both on CD4 and CD8 T cells. There was no association between CD146 and putative pro-atherogenic T cell subsets. In conclusion, the relationship of CD146 expression to T cell activation differs between T cell subsets in healthy subjects and correlates with systemic hyperactivity, where present, in patients with CTDs, as exemplified by the patients with secondary Sjogren's syndrome in this study. PMID- 23738746 TI - The minipig as an alternative non-rodent model for immunogenicity testing using the TNFalpha blockers adalimumab and infliximab. AB - Immunogenicity is a major issue of concern for monoclonal antibodies used in human diseases and is by default mainly determined in non-human primates (NHP), as target molecules are considered most similar in NHP compared to human. In this manuscript the predictive value of immunogenicity testing in minipigs for human safety is evaluated, as the immune system of the pig is functionally similar to that in other mammalian species. Adalimumab and infliximab (both monoclonal antibodies blocking TNFalpha) were used as model substances. Female Gottingen minipigs (4/group) were treated every other week with low (0.1 mg/kg), mid (1.0 mg/kg), or high dose (5 mg/kg) adalimumab or 5 mg/kg infliximab subcutaneous (SC) over a period of 8 weeks. After first and last dosing, pharmacokinetic analysis was performed. Anti-drug antibodies (ADAs) were measured on several time points. Furthermore, hematology, clinical chemistry, body weight, clinical signs, and histopathology of several organs were evaluated. No signs of toxicity of the treatments were observed in the limited organs and tissues collected. Eleven out of 12 minipigs treated with adalimumab elicited a detectable ADA response. Induction of ADA was correlated with decreased plasma levels of adalimumab. Infliximab clearance was comparable after first and last dose. Therefore, the presence of ADA directed to infliximab was considered highly unlikely. It was concluded that the minipig and NHP showed comparable suitability for immunogenicity prediction in humans. More studies with other biopharmaceutical products are needed to strengthen the status of the minipig as an alternative model for immunotoxicity testing including immunogenicity. PMID- 23738748 TI - Data integrity. PMID- 23738747 TI - Chromatographic determination of nanomolar cyanate concentrations in estuarine and sea waters by precolumn fluorescence derivatization. AB - Recent studies suggest that cyanate (OCN(-)) is a potentially important source of reduced nitrogen (N) available to support the growth of aquatic microbes and, thus, may play a role in aquatic N cycling. However, aquatic OCN(-) distributions have not been previously described because of the lack of a suitable assay for measuring OCN(-) concentrations in natural waters. Previous methods were designed to quantify OCN(-) in aqueous samples with much higher reduced N concentrations (micromolar levels) than those likely to be found in natural waters (nanomolar levels). We have developed a method to quantify OCN(-) in dilute, saline environments. In the method described here, OCN(-) in aqueous solution reacts with 2-aminobenzoic acid to produce a highly fluorescent derivative, 2,4 quinazolinedione, which is then quantified using high performance liquid chromatography. Derivatization conditions were optimized to simultaneously minimize the reagent blank and maximize 2,4-quinazolinedione formation (>90% reaction yield) in estuarine and seawater matrices. A limit of detection (LOD) of 0.4 nM was achieved with only minor matrix effects. We applied this method to measure OCN(-) concentrations in estuarine and seawater samples from the Chesapeake Bay and coastal waters from the mid-Atlantic region. OCN(-) concentrations ranged from 0.9 to 41 nM. We determined that OCN(-) concentrations were stable in 0.2 MUm filtered seawater samples stored at -80 degrees C for up to nine months. PMID- 23738749 TI - Edelfosine and miltefosine effects on lipid raft properties: membrane biophysics in cell death by antitumor lipids. AB - Edelfosine (1-O-octadecyl-2-O-methyl-sn-glycero-phosphocholine) and miltefosine (hexadecylphosphocholine) are synthetic alkylphospholipids (ALPs) that are reported to selectively accumulate in tumor cell membranes, inducing Fas clustering and activation on lipid rafts, triggering apoptosis. However, the exact mechanism by which these lipids elicit these events is still not fully understood. Recent studies propose that their mode of action might be related with alterations of lipid rafts biophysical properties caused by these lipid drugs. To achieve a clear understanding of this mechanism, we studied the effects of pharmacologically relevant amounts of edelfosine and miltefosine in the properties of model and cellular membranes. The influence of these molecules on membrane order, lateral organization, and lipid rafts molar fraction and size were studied by steady-state and time-resolved fluorescence methods, Forster resonance energy transfer (FRET), confocal and fluorescence lifetime imaging microscopy (FLIM). We found that the global membrane and lipid rafts biophysical properties of both model and cellular membranes were not significantly affected by both the ALPs. Nonetheless, in model membranes, a mild increase in membrane fluidity induced by both alkyl lipids was detected, although this effect was more noticeable for edelfosine than miltefosine. This absence of drastic alterations shows for the first time that ALPs mode of action is unlikely to be directly linked to alterations of lipid rafts biophysical properties caused by these drugs. The biological implications of this result are discussed in the context of ALPs effects on lipid metabolism, mitochondria homeostasis modulation, and their relationship with tumor cell death. PMID- 23738750 TI - Screw dislocation driven growth of nanomaterials. AB - Nanoscience and nanotechnology impact our lives in many ways, from electronic and photonic devices to biosensors. They also hold the promise of tackling the renewable energy challenges facing us. However, one limiting scientific challenge is the effective and efficient bottom-up synthesis of nanomaterials. We can approach this core challenge in nanoscience and nanotechnology from two perspectives: (a) how to controllably grow high-quality nanomaterials with desired dimensions, morphologies, and material compositions and (b) how to produce them in a large quantity at reasonable cost. Because many chemical and physical properties of nanomaterials are size- and shape-dependent, rational syntheses of nanomaterials to achieve desirable dimensionalities and morphologies are essential to exploit their utilities. In this Account, we show that the dislocation-driven growth mechanism, where screw dislocation defects provide self perpetuating growth steps to enable the anisotropic growth of various nanomaterials at low supersaturation, can be a powerful and versatile synthetic method for a wide variety of nanomaterials. Despite significant progress in the last two decades, nanomaterial synthesis has often remained an "art", and except for a few well-studied model systems, the growth mechanisms of many anisotropic nanostructures remain poorly understood. We strive to go beyond the empirical science ("cook-and-look") and adopt a fundamental and mechanistic perspective to the anisotropic growth of nanomaterials by first understanding the kinetics of the crystal growth process. Since most functional nanomaterials are in single crystal form, insights from the classical crystal growth theories are crucial. We pay attention to how screw dislocations impact the growth kinetics along different crystallographic directions and how the strain energy of defected crystals influences their equilibrium shapes. Furthermore, such inquiries are supported by detailed structural investigation to identify the evidence of dislocations. The dislocation-driven growth mechanism not only can unify the various explanations behind a wide variety of exotic nanoscale morphologies but also allows the rational design of catalyst-free solution-phase syntheses that could enable the scalable and low cost production of nanomaterials necessary for large scale applications, such as solar and thermoelectric energy conversions, energy storage, and nanocomposites. In this Account, we discuss the fundamental theories of the screw dislocation driven growth of various nanostructures including one-dimensional nanowires and nanotubes, two-dimensional nanoplates, and three-dimensional hierarchical tree-like nanostructures. We then introduce the transmission electron microscopy (TEM) techniques to structurally characterize the dislocation-driven nanomaterials for future searching and identifying purposes. We summarize the guidelines for rationally designing the dislocation-driven growth and discuss specific examples to illustrate how to implement the guidelines. By highlighting our recent discoveries in the last five years, we show that dislocation growth is a general and versatile mechanism that can be used to grow a variety of nanomaterials via distinct reaction chemistry and synthetic methods. These discoveries are complemented by selected examples of anisotropic crystal growth from other researchers. The fundamental investigation and development of dislocation-driven growth of nanomaterials will create a new dimension to the rational design and synthesis of increasingly complex nanomaterials. PMID- 23738752 TI - Interleukin-17-producing cell infiltration in the breast cancer tumour microenvironment is a poor prognostic factor. AB - AIMS: Interleukin-17 (IL-17) is a proinflammatory cytokine that is most prominently produced by T-helper type 17 (Th17) cells, a distinct CD4+ T-helper cell subset. The aim of this study was to investigate the level of IL-17 producing cells in the breast cancer tumour microenvironment and its prognostic role. METHODS AND RESULTS: A total of 207 breast carcinoma specimens were assessed by IL-17 immunohistochemistry, and the findings were correlated with clinicopathological parameters. We found that increased numbers of IL-17 producing cells were correlated with high histological grade, negative ER/PR status, and triple-negative molecular subtypes segregated by immunoprofiles. However, they did not correlate with stage, tumour size, nodal status, HER2 status, or histological type. Patients with tumours with high numbers of IL-17 producing cells had shorter disease-free survival (DFS) than patients with tumours with low numbers of IL-17-producing cells (P < 0.01). In multivariate analysis, high IL-17 level [hazard ratio (HR) 2.24; 95% CI 1.06-4.75], advanced T stage (HR 2.73; 95% CI 1.30-5.73), positive HER2 status (HR 4.88; 95% CI 1.47 16.18) and triple-negative subtype (HR 7.46; 95% CI 1.38-40.36) were significant prognostic factors for DFS. CONCLUSIONS: Our results indicate that a high level of IL-17-producing cells in the breast cancer tumour microenvironment is a poor prognostic factor. PMID- 23738751 TI - Candidiasis drug discovery and development: new approaches targeting virulence for discovering and identifying new drugs. AB - INTRODUCTION: Targeting pathogenetic mechanisms, rather than essential processes, represents a very attractive alternative for the development of new antibiotics. This may be particularly important in the case of antimycotics, due to the urgent need for novel antifungal drugs and the paucity of selective fungal targets. The opportunistic pathogenic fungus Candida albicans is the main etiological agent of candidiasis, the most common human fungal infection. These infections carry unacceptably high mortality rates, a clear reflection of the many shortcomings of current antifungal therapy, including the limited armamentarium of antifungal agents, their toxicity and the emergence of resistance. Moreover, the antifungal pipeline is mostly dry. AREAS COVERED: This review covers some of the most recent progress toward understanding C. albicans pathogenetic processes and how to harness this information for the development of anti-virulence agents. The two principal areas covered are filamentation and biofilm formation, as C. albicans pathogenicity is intimately linked to its ability to undergo morphogenetic conversions between yeast and filamentous morphologies and to its ability to form biofilms. EXPERT OPINION: Filamentation and biofilm formation represent high value targets, yet are clinically unexploited, for the development of novel anti virulence approaches against candidiasis. Although this has proved a difficult task despite increasing understanding at the molecular level of C. albicans virulence, there are some opportunities and prospects for antifungal drug development targeting these two important biological processes. PMID- 23738753 TI - Ejaculatory activities of Allanblackia floribunda stem bark in spinal male rats. AB - CONTEXT: Medicinal plants have become a great source of relief for more 70% of the population in developing countries where access to modern medicine is very limited. Some of these plants are used as aphrodisiac agents. The stem bark of Allanblackia floribunda Oliver (Clusiacea) has been used in Cameroon as an aphrodisiac. OBJECTIVE: This study was designed to assess the effects of Allanblackia floribunda aqueous and ethanol extracts and their potential mechanism on fictive ejaculation in spinal male rats. MATERIALS AND METHODS: Electromyographic activities of the bulbospongiosus muscles were recorded in 24 groups of spinal rats after intravenous administration of aqueous and ethanol extracts (2.5, 10, 20, 40 or 60 mg/kg) from the stem bark of A. floribunda in the presence or absence of dopamine (60 mg/kg). Furthermore, electromyographic activities of the bulbospongiosus muscles were recorded in five groups of spinal rats pre-treated orally during 8 d with extracts (150 and 300 mg/kg) in the presence of dopamine. RESULTS: Sequential treatments of rats with extracts significantly decreased the occurrence of ejaculation induced by dopamine up to 88.94% inhibition. The oral pre-treatment with both extracts significantly decreased the ejaculation induced by dopamine with the highest inhibition of 89.79%. DISCUSSION AND CONCLUSION: Two extracts of A. floribunda used in this study had inhibitory activities on ejaculation. The inhibitory effect of A. floribunda extracts on fictive ejaculation in rat may be directly mediated through dopaminergic pathways. Inhibition of ejaculation caused by these extracts could support its use in patients suffering from rapid ejaculation. PMID- 23738755 TI - Mass-action model analysis of the apparent molar volume and heat capacity of pluronics in water and liposome suspensions at 25 degrees C. AB - Pluronics are block copolymers composed of a central block of polypropylene oxide and two side chains of polyethylene oxide. They are used in water to generate aggregates and gels or added to phospholipid suspensions to prepare microparticles for drug delivery applications. The structure of these systems has been widely investigated. However, little is known about the mechanisms leading to these structures. This investigation compares the apparent molar volumes and heat capacities of Pluronics F38, F108, F127, P85, P104, and P103 at 25 degrees C in water and in the presence of lecithin liposomes. The changes in molar volumes, heat capacities, and enthalpies generated by a mass-action model are in good agreement with the loss of hydrophobic hydration of the polypropylene oxide central block of the Pluronics. However, the molecularity of the endothermic transitions is much smaller than the aggregation numbers reported in the literature for the same systems. It is suggested that Pluronics go through dehydration of their central block to form unimolecular or small entities having a hydrophobic polypropylene oxide core. In water, these entities would assemble athermally to form larger aggregates. In the presence of liposomes, they would be transferred into the hydrophobic lecithin bilayers of the liposomes. Light transmission experiments suggest that the liposome suspensions are significantly altered only when the added Pluronics are in the dehydrated state. PMID- 23738754 TI - Multilocus variable-number-tandem-repeats analysis (MLVA) distinguishes a clonal complex of Clavibacter michiganensis subsp. michiganensis strains isolated from recent outbreaks of bacterial wilt and canker in Belgium. AB - BACKGROUND: Clavibacter michiganensis subsp. michiganensis (Cmm) causes bacterial wilt and canker in tomato. Cmm is present nearly in all European countries. During the last three years several local outbreaks were detected in Belgium. The lack of a convenient high-resolution strain-typing method has hampered the study of the routes of transmission of Cmm and epidemiology in tomato cultivation. In this study the genetic relatedness among a worldwide collection of Cmm strains and their relatives was approached by gyrB and dnaA gene sequencing. Further, we developed and applied a multilocus variable number of tandem repeats analysis (MLVA) scheme to discriminate among Cmm strains. RESULTS: A phylogenetic analysis of gyrB and dnaA gene sequences of 56 Cmm strains demonstrated that Belgian Cmm strains from recent outbreaks of 2010-2012 form a genetically uniform group within the Cmm clade, and Cmm is phylogenetically distinct from other Clavibacter subspecies and from non-pathogenic Clavibacter-like strains. MLVA conducted with eight minisatellite loci detected 25 haplotypes within Cmm. All strains from Belgian outbreaks, isolated between 2010 and 2012, together with two French strains from 2010 seem to form one monomorphic group. Regardless of the isolation year, location or tomato cultivar, Belgian strains from recent outbreaks belonged to the same haplotype. On the contrary, strains from diverse geographical locations or isolated over longer periods of time formed mostly singletons. CONCLUSIONS: We hypothesise that the introduction might have originated from one lot of seeds or contaminated tomato seedlings that was the source of the outbreak in 2010 and that these Cmm strains persisted and induced infection in 2011 and 2012. Our results demonstrate that MLVA is a promising typing technique for a local surveillance and outbreaks investigation in epidemiological studies of Cmm. PMID- 23738756 TI - Getting the inside tract: new frontiers in zebrafish digestive system biology. PMID- 23738757 TI - In vitro and in vivo properties of CD133 expressing cells from human lung cancer cell lines. AB - BACKGROUND: Tumor development is recently hypothesized to depend on a rare cell population with stem cell properties, such cells are called cancer stem cells (CSCs) or tumor-initiating cells (TICs). From various cancer tissues or cancer cell lines, CD133 expressing cells were found to define a unique CSC/TIC phenotype. To study whether that also could be the case in lung cancer, we examined different lung cancer cell lines for CD133 expression. RESULTS: Among the 4 cell lines studied, only the cell line LC-42 expressed CD133. Therefore, LC 42 was further characterized and studied with special emphasis on identifying the presence of CD133+ CSCs/TICs. FACS sorted CD133high and CD133dim subpopulations from LC-42 showed no differences in soft agar colony-forming capacity and spheres forming capacity in serum-free cultures. LC-42 cells contained Side Population (SP), and only SP cells were able to form spheres. Furthermore, Nanog expression was significantly higher in SP than in non-SP. However, no difference was observed of CD133 expression in SP and non-SP. When CD133high and CD133dim cells were serially xeno-transplanted in NOD/SCID mice, both formed tumours similar to their parental LC-42 cells. There were no expression differences for NANOG, OCT4 and SOX2 examined immunohistochemically in the xenografts from both cell fractions. CONCLUSION: Our data do not show a difference in tumorigenic potential of CD133high and CD133dim cells with respect to any of the parameters analyzed in vitro and in vivo, suggesting that CD133 expression is not restricted to cancer initiating cells in the human lung cancer cell line LC-42. PMID- 23738758 TI - Ontogenetic shifts in plant interactions vary with environmental severity and affect population structure. AB - Environmental conditions and plant size may both alter the outcome of inter specific plant-plant interactions, with seedlings generally facilitated more strongly than larger individuals in stressful habitats. However, the combined impact of plant size and environmental severity on interactions is poorly understood. Here, we tested explicitly for the first time the hypothesis that ontogenetic shifts in interactions are delayed under increasingly severe conditions by examining the interaction between a grass, Agrostis magellanica, and a cushion plant, Azorella selago, along two severity gradients. The impact of A. selago on A. magellanica abundance, but not reproductive effort, was related to A. magellanica size, with a trend for delayed shifts towards more negative interactions under greater environmental severity. Intermediate-sized individuals were most strongly facilitated, leading to differences in the size-class distribution of A. magellanica on the soil and on A. selago. The A. magellanica size-class distribution was more strongly affected by A. selago than by environmental severity, demonstrating that the plant-plant interaction impacts A. magellanica population structure more strongly than habitat conditions. As ontogenetic shifts in plant-plant interactions cannot be assumed to be constant across severity gradients and may impact species population structure, studies examining the outcome of interactions need to consider the potential for size- or age-related variation in competition and facilitation. PMID- 23738759 TI - Comparative performance of Thin Layer Agar and Lowenstein-Jensen culture for diagnosis of tuberculosis. AB - Sputum smear microscopy for the diagnosis of tuberculosis (TB) is cheap and simple but its sensitivity is low. Culture on Lowenstein-Jensen (LJ) is more sensitive but it takes a long time to yield results. Thin-Layer Agar (TLA) culture was suggested as an equally sensitive and faster alternative. We evaluated the performance of TLA for diagnosing TB in Jogjakarta, Indonesia. People with suspected TB presenting from July 2010 to July 2011 to two chest clinics of the National TB Control Programme network of Jogjakarta were eligible for inclusion. A sputum sample was sent to the Gadjah Mada University microbiology laboratory for concentration, smearing, Ziehl-Neelsen staining and culture on LJ and TLA. Sensitivity of cultures was evaluated against a composite reference standard (any positive culture). Time to detection of Mycobacteria was recorded. Out of 1414 samples, 164 (12%) were smear positive, 99 (7%) were scanty and 1151 (81%) were negative. On TLA and LJ respectively, 168 (12%) and 149 (11%) samples were positive, 72 (5%) and 32 (2%) were contaminated (kappa = 0.64; 95% CI 0.59-0.69, p <0.01). Using the reference standard, 196 (14%) TB cases were identified. The sensitivity of TLA was 0.86 (95% CI 0.80-0.90), significantly higher (p 0.03) than for LJ (0.76; 95% CI 0.69-0.81). The median time to detection in days was significantly shorter (p <0.01) for TLA (12; 95% CI 11-13) than for LJ (44; 95% CI 43-45). TLA is a rapid and sensitive method for the diagnosis of TB. Implementation studies to evaluate the cost-effectiveness and impact of its introduction into programmatic settings are urgently needed. PMID- 23738760 TI - Mesenchymal stromal cells and kidney transplantation: pretransplant infusion protects from graft dysfunction while fostering immunoregulation. AB - Bone marrow-derived mesenchymal stromal cells (MSC) have emerged as useful cell population for immunomodulation therapy in transplantation. Moving this concept towards clinical application, however, should be critically assessed by a tailor made step-wise approach. Here, we report results of the second step of the multistep MSC-based clinical protocol in kidney transplantation. We examined in two living-related kidney transplant recipients whether: (i) pre-transplant (DAY 1) infusion of autologous MSC protected from the development of acute graft dysfunction previously reported in patients given MSC post-transplant, (ii) avoiding basiliximab in the induction regimen improved the MSC-induced Treg expansion previously reported with therapy including this anti-CD25-antibody. In patient 3, MSC treatment was uneventful and graft function remained normal during 1 year follow-up. In patient 4, acute cellular rejection occurred 2 weeks post transplant. Both patients had excellent graft function at the last observation. Circulating memory CD8(+) T cells and donor-specific CD8(+) T-cell cytolytic response were reduced in MSC-treated patients, not in transplant controls not given MSC. CD4(+) FoxP3(+) Treg expansion was comparable in MSC-treated patients with or without basiliximab induction. Thus, pre-transplant MSC no longer negatively affect kidney graft at least to the point of impairing graft function, and maintained MSC-immunomodulatory properties. Induction therapy without basiliximab does not offer any advantage on CD4(+) FoxP3(+) Treg expansion (ClinicalTrials.gov number: NCT 00752479). PMID- 23738762 TI - Pulmonary large cell carcinoma lacking squamous differentiation is clinicopathologically indistinguishable from solid-subtype adenocarcinoma. AB - CONTEXT: Pulmonary large cell carcinoma (LCC) includes tumors not readily diagnosed as adenocarcinoma (ADC) or squamous cell carcinoma on morphologic grounds, without regard to immunophenotype, according to the World Health Organization (WHO). This ambiguous designation may cause confusion over selection of mutation testing and directed therapies. Several groups have proposed the use of immunohistochemistry (IHC) to recategorize LCC as ADC or squamous cell carcinoma; however, it remains unclear if strictly defined LCCs are a clinicopathologically distinct lung tumor subset. OBJECTIVE: To compare the pathologic, molecular, and clinical features of 2 morphologically similar tumors: solid-subtype ADC and LCC. DESIGN: Tumors were included on the basis of solid growth pattern; tumors with squamous or neuroendocrine differentiation were excluded. Solid ADC (n = 42) and LCC (n = 57) were diagnosed by using WHO criteria (5 intracellular mucin droplets in >=2 high-power fields for solid ADC) and tested for KRAS, EGFR, and ALK alterations. RESULTS: Both solid ADC and LCC groups were dominated by tumors with "undifferentiated"-type morphology and both had a high frequency of thyroid transcription factor 1 expression. KRAS was mutated in 38% of solid ADCs versus 43% of LCCs (P = .62). One ALK-rearranged and 1 EGFR-mutated tumor were detected in the solid ADC and LCC groups, respectively. There were no significant differences in clinical features or outcomes; the prevalence of smoking in both groups was greater than 95%. CONCLUSIONS: Other than a paucity of intracellular mucin, LCC lacking squamous or neuroendocrine differentiation is indistinguishable from solid-subtype ADC. We propose the reclassification of these tumors as mucin-poor solid adenocarcinomas. PMID- 23738761 TI - Trends in laboratory test volumes for Medicare Part B reimbursements, 2000-2010. AB - CONTEXT: Changes in reimbursements for clinical laboratory testing may help us assess the effect of various variables, such as testing recommendations, market forces, changes in testing technology, and changes in clinical or laboratory practices, and provide information that can influence health care and public health policy decisions. To date, however, there has been no report, to our knowledge, of longitudinal trends in national laboratory test use. OBJECTIVE: To evaluate Medicare Part B-reimbursed volumes of selected laboratory tests per 10,000 enrollees from 2000 through 2010. DESIGN: Laboratory test reimbursement volumes per 10,000 enrollees in Medicare Part B were obtained from the Centers for Medicare & Medicaid Services (Baltimore, Maryland). The ratio of the most recent (2010) reimbursed test volume per 10,000 Medicare enrollees, divided by the oldest data (usually 2000) during this decade, called the volume ratio, was used to measure trends in test reimbursement. Laboratory tests with a reimbursement claim frequency of at least 10 per 10,000 Medicare enrollees in 2010 were selected, provided there was more than a 50% change in test reimbursement volume during the 2000-2010 decade. We combined the reimbursed test volumes for the few tests that were listed under more than one code in the Current Procedural Terminology (American Medical Association, Chicago, Illinois). A 2-sided Poisson regression, adjusted for potential overdispersion, was used to determine P values for the trend; trends were considered significant at P < .05. RESULTS: Tests with the greatest decrease in reimbursement volumes were electrolytes, digoxin, carbamazepine, phenytoin, and lithium, with volume ratios ranging from 0.27 to 0.64 (P < .001). Tests with the greatest increase in reimbursement volumes were meprobamate, opiates, methadone, phencyclidine, amphetamines, cocaine, and vitamin D, with volume ratios ranging from 83 to 1510 (P < .001). CONCLUSIONS: Although reimbursement volumes increased for most of the selected tests, other tests exhibited statistically significant downward trends in annual reimbursement volumes. The observed changes in reimbursement volumes may be explained by disease prevalence and severity, patterns of drug use, clinical or laboratory practices, and testing recommendations and guidelines, among others. These data may be useful to policy makers, health systems researchers, laboratory directors, and industry scientists to understand, address, and anticipate trends in laboratory testing in the Medicare population. PMID- 23738763 TI - Digital pathology and federalism. PMID- 23738764 TI - Pathologist workforce in the United States: I. Development of a predictive model to examine factors influencing supply. AB - CONTEXT: Results of prior pathology workforce surveys have varied between a state of equilibrium and predictions of shortage. OBJECTIVE: To assess the current and future supply of pathologists, and apply a dynamic modeling tool for assessing the effects of changing market forces and emerging technologies on the supply of pathologists' services through 2030. DESIGN: Data came from various sources, including the literature, College of American Pathologists' internal data, and primary research through custom-developed surveys for the membership and for pathology practice managers RESULTS: Through 2010, there were approximately 18 000 actively practicing pathologists in the United States (5.7 per 100 000 population), approximately 93% of whom were board certified. Our model projects that the absolute and per capita numbers of practicing pathologists will decrease to approximately 14 000 full-time equivalent (FTE) pathologists or 3.7 per 100 000 in the coming 2 decades. This projection reflects that beginning in 2015, the numbers of pathologists retiring will increase precipitously, and is anticipated to peak by 2021. Including all types of separation, the net pathologist strength will begin falling by year 2015. Unless workforce entry or exit rates change, this trend will continue at least through 2030. These changes reflect the closure of many training programs 2 to 4 decades ago and the substantially decreased number of graduating residents. CONCLUSIONS: This comprehensive analysis predicts that pathologist numbers will decline steadily beginning in 2015. Anticipated population growth in general and increases in disease incidence owing to the aging population, to be presented in a companion article on demand, will lead to a net deficit in excess of more than 5700 FTE pathologists. To reach the projected need in pathologist numbers of nearly 20 000 FTE by 2030 will require an increase from today of approximately 8.1% more residency positions. We believe a pathologist shortage will negatively impact both patient access to laboratory services and health care providers' abilities to deliver more effective health care to their patient populations. PMID- 23738765 TI - Medicine is politics. PMID- 23738766 TI - Do competing demands of physical illness in type 2 diabetes influence depression screening, documentation and management in primary care: a cross-sectional analytic study in Aboriginal and Torres Strait Islander primary health care settings. AB - BACKGROUND: Relatively little is known about how depression amongst people with chronic illness is identified and managed in diverse primary health care settings. We evaluated the role of complex physical needs in influencing current practice of depression screening, documentation and antidepressant prescriptions during a 12-month period, among adults with Type 2 diabetes attending Aboriginal and Torres Strait Islander primary care health centres in Australia. METHODS: We analysed clinical audit data from 44 health centres participating in a continuous quality improvement initiative, using previously reported standard sampling and data extraction protocols. Eligible patients were those with Type 2 diabetes with health centre attendance within the past 12 months. We compared current practice in depression screening, documentation and antidepressant prescription between patients with different disease severity and co-morbidity. We used random effects multiple logistic regression models to adjust for potential confounders and for clustering by health centre. RESULTS: Among the 1174 patients with diabetes included, median time since diagnosis was 7 years, 19% of patients had a co existing diagnosis of Ischaemic Heart Disease and 1/3 had renal disease. Some 70% of patients had HbAc1>7.0%; 65% had cholesterol >4.0 mmol1-1 and 64% had blood pressure>130/80 mmHg. Documentation of screening for depression and of diagnosed depression were low overall (5% and 6% respectively) and lower for patients with renal disease (Adjusted odds ratio [AOR] 0.21; 95% confidence interval [CI] 0.14 to 0.31 and AOR 0.34; 95% CI 0.15 to 0.75), and for those with poorly controlled disease (HbA1c>7.00 (AOR 0.40; 95% CI 0.23 to 0.68 and AOR 0.51; 95% CI 0.30 to 84)). Screening for depression was lower for those on pharmaceutical treatment for glycaemic control compared to those not on such treatment. Antidepressant prescription was not associated with level of diabetes control or disease severity. CONCLUSIONS: Background levels of depression screening and documentation were low overall and significantly lower for patients with greater disease severity. Strategies to improve depression care for vulnerable populations are urgently required. An important first step in the Australian Indigenous primary care context is to identify and address barriers to the use of current clinical guidelines for depression screening and care. PMID- 23738767 TI - Combining Flexi-Seal and negative pressure wound therapy for wound management in Fournier's gangrene. PMID- 23738768 TI - An exploratory study into the unmet supportive needs of breast cancer patients. AB - This study explores the unmet supportive needs of people with breast cancer attending a London NHS Foundation Trust Hospital. A mixed methods approach was used. One hundred and one patients completed a specially designed questionnaire focusing on their concerns in the previous week, and whether they felt they had been offered sufficient support from health professionals. Seven semi-structured interviews were then completed in order to gain insight into the need for future developments of services for patients with breast cancer. Pearson's chi-squared analysis was used to examine whether symptoms reported within 1 year of diagnosis differed from symptoms reported more than 1 year post diagnosis. Fatigue was the most common concern expressed (53%) with no significant difference between the two groups. Emotional concerns and pain were also highly reported (35% and 36%). Only 32% of the questionnaire participants reported that they had been offered support in dealing with their concerns. Most participants (65%) would have liked more support from the healthcare team. From the interviews it was clear that whilst there are gaps in services available, participants were not aware of the range of services already available for people with breast cancer. The results of this study have helped to inform service development, particularly around the management of fatigue. PMID- 23738769 TI - A qualitative study of the coverage of influenza vaccination on Dutch news sites and social media websites. AB - BACKGROUND: Information about influenza and the effectiveness of vaccination against influenza is largely available on the Internet, and may influence individual decision making about participation in future influenza vaccination rounds. E-health information has often been found to be inaccurate, or even to contradict Health Authority recommendations, especially when it concerns controversial topics. METHODS: By means of an online media monitoring programme, Dutch news sites and social media websites were scanned for the Dutch counterparts of the terms influenza, vaccination, vaccine and epidemic during February, March and April 2012. Data were processed with QSR NVivo 8.0 and analysed using a general inductive approach. RESULTS: Three overarching themes were found in both media sources: (1) the (upcoming) influenza epidemic, (2) general information regarding the virus, its prevention and treatment, and (3) uncertainty and mistrust regarding influenza vaccination. Social media tended to report earlier on developments such as the occurrence of an influenza epidemic. The greatest difference was that in social media, influenza was not considered to be a serious disease, and more opposition to the flu shot was expressed in social media, as compared to news media. CONCLUSIONS: News media and social media discussed the same topics regarding influenza, but differed in message tone. Whereas news media reports tended to be more objective and non-judgmental, social media more critically evaluated the harmfulness of influenza and the necessity of the flu shot. Media may influence decision making and behaviours of Internet users and may thereby influence the success of vaccination campaigns and recommendations made by health authorities. Social media may be more of a problem in this sense, since it is neither controlled nor censored. Future research should investigate the actual impact of Internet media on the influenza decision making process of its users. PMID- 23738770 TI - Retrobulbar rhabdomyosarcoma in a neotropical peregrine falcon (Falco peregrinus cassini). AB - A mild swelling of the left periorbital was detected on a routine physical exam of a healthy captive adult peregrine falcon. Despite treatment, the swelling did not subside and within twenty-five days was causing significant exophthalmia and medial deviation of the left globe. A retrobulbar fusiform cell sarcoma was diagnosed with histopathology, then light microscopy and immunohistochemical staining confirmed the diagnosis of a rhabdomyosarcoma. PMID- 23738771 TI - Asymmetric hetero-Diels-Alder reaction of Danishefsky's dienes with alpha carbonyl esters catalyzed by an indium(III)-pybox complex. AB - An efficient catalytic enantioselective hetero-Diels-Alder reaction of Danishefsky's dienes with alpha-carbonyl esters using a chiral In(III)-pybox complex has been demonstrated. This protocol offers several advantages, including mild reaction conditions, relatively low catalyst loading, and good to excellent enantioselectivities. Furthermore, the absolute configurations of the new alkynyl containing products were determined by CD spectra in combination with TD-DFT calculations. PMID- 23738772 TI - Binding and folding of the small bacterial chaperone HdeA. AB - The small pH stress-sensing chaperone HdeA helps pathogenic enteric E. coli survive passage through the severely acidic environment of the mammalian stomach. Under stress conditions, HdeA transitions from an inactive folded dimer to a chaperone-active unfolded monomer to prevent the acid-induced aggregation of periplasmic proteins. Here we use a topology-based Go-like model to delineate the relationship between dimer interface formation and monomer folding and to better understand the structural details of the chaperone activation mechanism. Free energy surfaces show that dimer interface formation and monomer folding proceed concurrently through an on-pathway dimeric intermediate in which one monomer is partially unfolded. The absence of a preexisting fully folded monomer in the proposed binding mechanism is in agreement with HdeA's rapid chaperone response. Binding between unfolded monomers exhibits an enhancement of molecular recognition reminiscent of the fly-casting mechanism. Overall, our simulations further highlight the efficient nature of HdeA's chaperone response and we anticipate that knowledge of a dimeric intermediate will facilitate the interpretation of experimental studies. PMID- 23738774 TI - SERT-to-DAT ratios in early Parkinson's disease do not correlate with the development of dyskinesias. AB - BACKGROUND: Although the treatment of Parkinson's disease (PD) is very effective, in the course of the disease, 40% to 60% of patients develop dyskinesias. The pathophysiology of dyskinesias is still unclear. Results of preclinical research suggest that uptake and uncontrolled release of dopamine by serotonergic neurons is an important factor. Based on this model, we hypothesized that dyskinesias will develop predominantly in PD patients with a relatively preserved serotonergic system. METHODS: Between 1995 and 1998, 50 patients with early-stage untreated PD, diagnosed according to clinical criteria, and reduced striatal [123I]beta-carboxymethyoxy-3-beta-(4-iodophenyl) tropane (CIT) single-photon emission computed tomography (SPECT) binding were recruited. To test our hypothesis, we retrospectively assessed baseline [123I]beta-CIT SPECT scans for striatal dopamine transporter (DAT) and midbrain serotonin transporter (SERT) availability as well as the SERT-to-DAT ratios. We compared these data between patients that developed dyskinesias and patients that did not develop dyskinesias during a mean follow-up of 14.2 years. RESULTS: Approximately half of the PD patients developed dyskinesias. No differences in baseline [123I]beta-CIT DAT availability, SERT availability, or SERT-to-DAT ratios were found between the dyskinetic and non-dyskinetic group. The development of dyskinesias was most strongly associated with the age of onset (P = 0.002). CONCLUSIONS: SERT-to-DAT ratios in early-stage untreated PD do not correlate with the future development of dyskinesias. However, our study does not exclude the possibility that SERT-to DAT ratios increase with disease progression in patients that develop dyskinesias because of a slower rate of degeneration of the serotonergic system. PMID- 23738775 TI - Phenylpropanoids from Podocarpium podocarpum. AB - CONTEXT: Podocarpium podocarpum (DC.) Yang et Huang (Leguminoseae) is a very important Podocarpium species with significant anti-inflammatory, analgesic and anti-pyretic activities, which has not yet been subjected to adequate phytochemical investigation. OBJECTIVE: To isolate and identify bioactive compounds from P. podocarpum. MATERIALS AND METHODS: Ethanol extract of the whole plant of P. podocarpum was subjected to repeated column chromatography. Chemical structures of the compounds were identified by 1D, 2D-NMR spectra and MS data. Human cervical carcinoma (HeLa) and pancreatic carcinoma (PANC-1) cell lines were employed to evaluate the in vitro cytotoxic activity of the isolated constituents at six concentrations (0.001, 0.01, 0.1, 1.0, 10.0, 100.0 MUg/ml). RESULTS: A new phenylpropanoid glycoside, podocarioside A (1), together with four known compounds, (E)-3-(4-hydroxy-3-propoxyphenyl) acrylic acid (2), schizandrin (3), dehydrodiconiferyl alcohol (4) and dihydrodehydrodiconiferyl alcohol (5), were isolated from P. podocarpum. Compounds 1, 3 and 4 showed moderate cytotoxic against HeLa cells with IC50 values of 38.62, 8.64 and 5.85 MUg/mL, respectively, while none exhibited toxicity against PANC-1 cells. DISCUSSION AND CONCLUSION: This is the first report on the isolation and identification of bioactive compounds from P. podocarpum. In vitro cytotoxic assay of the isolated constituents establishes the potential of those components as antitumor agents. PMID- 23738773 TI - Comparative study and meta-analysis of meta-analysis studies for the correlation of genomic markers with early cancer detection. AB - A large number of common disorders, including cancer, have complex genetic traits, with multiple genetic and environmental components contributing to susceptibility. A literature search revealed that even among several meta analyses, there were ambiguous results and conclusions. In the current study, we conducted a thorough meta-analysis gathering the published meta-analysis studies previously reported to correlate any random effect or predictive value of genome variations in certain genes for various types of cancer. The overall analysis was initially aimed to result in associations (1) among genes which when mutated lead to different types of cancer (e.g. common metabolic pathways) and (2) between groups of genes and types of cancer. We have meta-analysed 150 meta-analysis articles which included 4,474 studies, 2,452,510 cases and 3,091,626 controls (5,544,136 individuals in total) including various racial groups and other population groups (native Americans, Latinos, Aborigines, etc.). Our results were not only consistent with previously published literature but also depicted novel correlations of genes with new cancer types. Our analysis revealed a total of 17 gene-disease pairs that are affected and generated gene/disease clusters, many of which proved to be independent of the criteria used, which suggests that these clusters are biologically meaningful. PMID- 23738777 TI - A case of omphalo-ischiopagus (dicephalic dithoracic abdominopagus tetrascelus tetrabrachius) in lambs. AB - This case report describes a rare occurrence of asymmetrical conjoined twinning in lambs in Makurdi (Benue state), Middle Belt region of Nigeria. The conjoined twins were delivered normally by a multiparous ewe of about three and a half years old; the female twins had two complete set of limbs. Barium meal and X-ray revealed abnormalities of the skeletal, digestive, urinary and reproductive systems. This condition is rare in sheep and is to the best of our knowledge the first report of omphalo-ishiopagus (dicephalic dithoracic tetrabrachius) twinned lambs. The condition always leads to death of the twin lambs due to various physical abnormalities. PMID- 23738778 TI - Synthetic ion channels: from pores to biological applications. AB - In this Account, we describe the development of several diverse families of synthetic, membrane-active amphiphiles that form pores and facilitate transport within membrane bilayers. For the most part, the compounds are amphiphiles that insert into the bilayer and form pores either on their own or by self-assembly. The first family of synthetic ion channels prepared in our lab, the hydraphiles, used crown ethers as head groups and as a polar central element. In a range of biophysical studies, we showed that the hydraphiles formed unimolecular pores that spanned the bilayer. They mediated the transport of Na(+) and K(+) but were blocked by Ag(+). The hydraphiles are nonrectifying and disrupt ion homeostasis. As a result, these synthetic ion channels are toxic to various bacteria and yeast, a feature that has been used therapeutically in direct injection chemotherapy. We also developed a family of amphiphilic heptapeptide ion transporters that selected Cl(-) >10-fold over K(+) and showed voltage dependent gating. The formed pores were approximately dimeric, and variations in the N- and C-terminal anchor chains and the acids affected transport rates. Surprisingly, the longer N-terminal anchor chains led to less transport but greater Cl(-) selectivity. A proline residue, which is present in the ClC protein channel's conductance pore, proved to be critical for Cl(-) transport selectivity. Pyrogallol[4]arenes are macrocycles formed by acid-catalyzed condensation of four 1,2,3- trihydroxybenzenes with four aldehydes. The combination of 12 hydroxyl groups on one face of the macrocycle and four pendant alkyl chains conferred considerable amphiphilicity to these compounds. The pyrogallol[4]arenes inserted into bilayer membranes and conducted ions. Based on our experimental evidence, the ions passed through a self-assembled pore comprising four or five amphiphiles rather than passing through the central opening of a single macrocycle. Pyrogallol[4]arenes constructed with branched chains are also amphiphilic and active in membranes. The pyrogallol[4]arene with 3-pentyl sidechains formed a unique nanotube assembly and functioned as an ion channel in bilayer membranes. Finally, we showed that dianilides of either isophthalic or dipicolinic acids, compounds which have been extensively studied as anion binders, can self-assemble to form pores within bilayers. We called these dianilides tris-arenes and have shown that they readily bind to phosphate anions. These structures also mediated the transport of DNA plasmids through vital bilayer membranes in the bacterium Escherichia coli and in the yeast Saccharomyces cerevisiae . This transformation or transfection process occurred readily and without any apparent toxicity or mutagenicity. PMID- 23738776 TI - Metal ions in macrophage antimicrobial pathways: emerging roles for zinc and copper. AB - The immunomodulatory and antimicrobial properties of zinc and copper have long been appreciated. In addition, these metal ions are also essential for microbial growth and survival. This presents opportunities for the host to either harness their antimicrobial properties or limit their availability as defence strategies. Recent studies have shed some light on mechanisms by which copper and zinc regulation contribute to host defence, but there remain many unanswered questions at the cellular and molecular levels. Here we review the roles of these two metal ions in providing protection against infectious diseases in vivo, and in regulating innate immune responses. In particular, we focus on studies implicating zinc and copper in macrophage antimicrobial pathways, as well as the specific host genes encoding zinc transporters (SLC30A, SLC39A family members) and CTRs (copper transporters, ATP7 family members) that may contribute to pathogen control by these cells. PMID- 23738779 TI - Tectorigenin and its inhibitory effects on tumor growth in systemic malignancies. PMID- 23738780 TI - Aerosol generation using nanometer liposome suspensions for pulmonary drug delivery applications. AB - Pulmonary lung targeting finds applications in drug delivery to the lung itself and to other body organs, via blood circulation following transfer across alveolar membranes. Understanding pulmonary drug delivery systems towards improving their efficacy needs identification of particle sizes of relevance and elucidation of links between suspension properties, techniques of atomisation and properties of the generated aerosols. This review article is focussed on understanding the elements of pulmonary drug delivery, specifically related to suspensions of small liposomes. Specific objectives of this review include (a) understanding aerosol particle deposition and absorption on pulmonary surface, (b) links between properties of aerosol generation and colloidal drug carriers used for drug encapsulation, and (c) investigation on the controlled properties of liposome aerosols generated using different atomisation techniques for efficacious aerosol therapy. PMID- 23738782 TI - Correction: Massive right hemothorax as the source of hemorrhagic shock after laparoscopic cholecystectomy - case report of a rare intraoperative complication. PMID- 23738781 TI - Telmisartan protects against microvascular dysfunction during myocardial ischemia/reperfusion injury by activation of peroxisome proliferator-activated receptor gamma. AB - BACKGROUND: We investigated the potential of telmisartan to improve microvascular dysfunction induced by myocardial ischemia/reperfusion (I/R) injury by activating the peroxisome proliferator-activated receptor gamma (PPARG) pathway. METHODS: Forty-eight male rabbits were randomly allocated into sham-operated, I/R, GW9662, telmisartan, telmisartan-GW9662, or candesartan groups. Rabbits were anesthetized, and the left anterior descending coronary artery (LAD) was ligated for 60 minutes. Following reperfusion for 6 hours, angiotensin II content of the heart was determined using radioimmunoassay. Myocardial neutrophil accumulation and microvessel cross-sectional area were examined histologically. Myocardial capillaries were examined with transmission electron microscopy. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the myocardium were measured using enzyme-linked immunosorbent assay. Western blot was utilized for investigating the expression of nuclear factor kappa-light chain-enhancer of activated B cells (NF-kappaB) and PPARG. RESULTS: Angiotensin II concentration was significantly increased in all treatment groups compared with the sham-operated group (P < 0.05, all). Accumulation of polymorphonuclear neutrophils was significantly lower, while microvessel cross-sectional area was significantly higher in the telmisartan, telmisartan-GW9662, and candesartan groups compared with the I/R group (P < 0.05). ICAM-1 and VCAM-1 levels were also significantly lower, and correlated with lower NF-kappaB expression in these groups. The effects were the most significant in the telmisartan group compared with the telmisartan-GW9662 and candesartan groups. Telmisartan significantly increased PPARG protein expression compared with all other groups (P < 0.05, all). CONCLUSIONS: Except for the typical effects of angiotensin II-receptor blocker, telmisartan improved microvascular dysfunction during myocardial I/R injury via the PPARG pathway. PMID- 23738783 TI - Naphthodithiophene-naphthobisthiadiazole copolymers for solar cells: alkylation drives the polymer backbone flat and promotes efficiency. AB - We show that rational functionalization of the naphthodithiophene core in copolymers based on naphthodithiophene and naphthobisthiadiazole improves the solubility without an alteration of the electronic structure. Surprisingly, the introduction of linear alkyl chains brings about a drastic change in polymer orientation into the face-on motif, which is beneficial for the charge transport in solar cells. As a result, the present polymers exhibit high power conversion efficiencies of up to ~8.2% in conventional single-junction solar cells. PMID- 23738784 TI - Altered diurnal variation and localization of clock proteins in the remnant kidney of 5/6 nephrectomy rats. AB - AIM: To investigate the localization and diurnal variation of clock proteins (BMAL1, PER2) and clock output protein (DBP) in the remnant kidney of 5/6 nephrectomy rats (STNx). METHODS: Male wistar rats were randomly divided into sham STNx group (Control) and STNx group. Rats were synchronized 12 weeks to the light: dark cycle 12:12 with light on from 07.00 hours (Zeitgeber time ZT 0). Kidneys were collected to detect the localization and expression rhythm of clock proteins (BMAL1, PER2 and DBP) every 4 h throughout the day by immunohistochemistry and Western blotting. RESULTS: Clock proteins showed diurnal rhythm in the kidney of the control. But diurnal rhythm of clock proteins changed in the STNx rats. Acrophase of BMAL1, DBP and PER2 advanced 4 h, respectively; mesor of clock proteins increased in the STNx rats. BMAL1 was located in endothelial cells of glomerulus and tubular interstitial vasculars, and it was also expressed in nucleus of tubular cells in cortex and medulla. PER2 was mainly expressed in proximal tubular cells at the juncture of cortex and medulla. DBP was widely expressed in the kidney. The localization of BMAL1 and PER2 were changed in remnant kidneys of the STNx group. CONCLUSION: The localization and diurnal variation of BMAL1, DBP and PER2 are changed in remnant kidney of 5/6 nephrectomy rats and are involved in diurnal rhythm of renal function. PMID- 23738785 TI - Prevalence of health-risk behaviours among Canadian post-secondary students: descriptive results from the National College Health Assessment. AB - BACKGROUND: It is important to understand health-risk behaviours among young adults, as modifications in this can enhance and lessen the risk of chronic illness later in life. The purpose of the current study was to determine the prevalence of a broad range of health-risk behaviours among post-secondary students from across Canada, and to determine whether institutional variability exists in the prevalence of these behaviours. METHODS: Data were collected from 8,182 undergraduate students enrolled in one of eight Canadian post-secondary institutions during the fall or spring of 2009, using the National College Health Assessment (NCHA). The NCHA consists of 60 questions, assessing student health status and engagement in various health behaviours. RESULTS: Findings show relatively low prevalence in smoking (13.1%) marijuana (17.5%) or other illicit drug use (3.5%), and risky sexual behaviour (12%). Binge drinking, however, was much higher, with nearly 60% of students consuming more than 5 alcoholic drinks in a single occasion during the past 15 days. Similarly, prevalence rates for physical inactivity (72.2%), inadequate sleep (75.6%) and low fruit and vegetable intake (88.0%) were all high among the student population. Results also found that students in smaller institutions exhibited higher rates of inactivity, binge drinking, and marijuana and illicit drug use compared to institutions having a larger student body. CONCLUSION: Overall, findings point to the need for more concentrated health promotion campaigns, specifically targeting sleep, fruit and vegetables intake, and greater participation in physical activity. Given evidence of some institutional variability, future efforts are warranted in exploring how best to increase institutional commitment for collecting surveillance data on Canadian post-secondary students. PMID- 23738786 TI - A text message based weight management intervention for overweight adults. AB - BACKGROUND: Weight management interventions can be extended using mobile telephone technology to deliver support in real-time, real-world settings. The present study aimed to determine whether text messaging helped patients maintain or lose weight following a weight-loss programme. METHODS: In this controlled study, overweight and obese [body mass index (BMI) >30 kg m(-2) or >28 kg m(-2) with co-morbidities] adults who completed a weight-loss programme participated in an additional 12-week text message intervention [Lifestyle, Eating and Activity Programme (LEAP) Beep]. Patients were allocated goals for steps, fruit, vegetable and breakfast consumption. Patients regularly 'texted' their progress and received tailored practitioner feedback. Pre/post-intervention body weight, waist circumference (WC), BMI, quality of life (QOL), anxiety and depression measurements were compared retrospectively with a control group offered weight checks only. RESULTS: Compared to control (n = 17), the intervention group's (n = 17) body weight, WC and BMI reduced significantly (-1.6 versus 0.7 kg, P = 0.006; -2.2 versus 1.5 cm, P = 0.0005; -0.6 versus 0.7 kg m(-2) , P = 0.03, respectively). QOL and depression scores also improved (-6.8 versus 1 point, P = 0.134; -0.2 versus 0.2 points, P = 0.228). No difference was observed in anxiety scores between the groups. Intervention versus control group follow-up attendance improved significantly (4.4 versus 1.7 attendances, P = 0.0005). CONCLUSIONS: LEAP Beep promoted losses in weight, WC and BMI, and improved QOL parameters and follow-up attendance. Text messaging is a cheap, portable, convenient and innovative medium facilitating goal setting, self-monitoring and information exchange. Further improvements to automation at the same time as maintaining individual support are necessary to ease practitioner burden. Text messaging offers cost-efficient dietetic input, opening up possibilities for practitioner to-patient support and yields positive weight outcomes following initial weight loss. PMID- 23738787 TI - Common arbuscular mycorrhizal networks amplify competition for phosphorus between seedlings and established plants. AB - Common mycorrhizal networks (CMNs) influence competition between plants, but reports regarding their precise effect are conflicting. We studied CMN effects on phosphorus (P) uptake and growth of seedlings as influenced by various disruptions of network components. Tomato (Solanum lycopersicon) seedlings grew into established networks of Rhizophagus irregularis and cucumber (Cucumis sativus) in two experiments. One experiment studied seedling uptake of (32)P in the network in response to cutting of cucumber shoots; the other analysed seedling uptake of P and nitrogen (N) in the presence of intact or severed arbuscular mycorrhizal fungus networks and at two soil P concentrations. Pre established and intact networks suppressed growth of tomato seedlings. Cutting of cucumber shoots mitigated P deficiency symptoms of seedlings, which obtained access to P in the extraradical mycelium and thereby showed improved growth. Solitary seedlings growing in a network patch that had been severed from the CMN also grew much better than seedlings of the corresponding CMN. Interspecific and size-asymmetric competition between plants may be amplified rather than relaxed by CMNs that transfer P to large plants providing most carbon and render small plants P deficient. It is likely that grazing or senescence of the large plants will alleviate the network-induced suppression of seedling growth. PMID- 23738789 TI - Commentary: sugar intolerances in functional gastrointestinal disorders. PMID- 23738790 TI - Commentary: sugar intolerances in functional gastrointestinal disorders - author's reply. PMID- 23738791 TI - Letter: assessment of safety and efficacy of mesalazine in Indian patients with ulcerative colitis. PMID- 23738792 TI - Bifurcated hydrogen bonding and asymmetric fluctuations in a carbohydrate crystal studied via X-ray crystallography and computational analysis. AB - The structure of the O-methyl glycoside of the naturally occurring 6-O-[(R)-1 carboxyethyl]-alpha-D-galactopyranose, C10H18O8, has been determined by X-ray crystallography at 100 K, supplementing the previously determined structure obtained at 293 K (Acta Crystallogr.1996, C52, 2285-2287). Molecular dynamics simulations of this glycoside were performed in the crystal environment with different numbers of units cells included in the primary simulation system at both 100 and 293 K. The calculated unit cell parameters and the intramolecular geometries (bonds, angles, and dihedrals) agree well with experimental results. Atomic fluctuations, including B-factors and anisotropies, are in good agreement with respect to the relative values on an atom-by-atom basis. In addition, the fluctuations increase with increasing simulation system size, with the simulated values converging to values lower than those observed experimentally indicating that the simulation model is not accounting for all possible contributions to the experimentally observed B-factors, which may be related to either the simulation time scale or size. In the simulations, the hydroxyl group of O7 is found to form bifurcated hydrogen bonds with O6 and O8 of an adjacent molecule, with the interactions dominated by the HO7-O6 interaction. Quantum mechanical calculations support this observation. PMID- 23738793 TI - Protocatechuic acid induces angiogenesis through PI3K-Akt-eNOS-VEGF signalling pathway. AB - In this study, we sought to elucidate whether protocatechuic acid contributes to induce angiogenesis as well as its mechanisms. To this end, we examined the role of protocatechuic acid on human brain microvascular endothelial cell line (HBMEC) proliferation, invasion and tube formation in in vitro. For the study of mechanisms involved, the phosphoinositide 3 kinase (PI3K)-Akt inhibitor LY294002, the endothelial nitric oxide synthase (eNOS) inhibitor L-NAME, vascular endothelial growth factor (VEGF), antagonist sFlt-1 and VEGF receptor blocker SU 1498 were used. Proliferation of HBMEC was tested by MTT. Scratch adhesion test was used to assess the ability of invasion. A Matrigel tube formation assay was performed to test capillary tube formation ability. PI3K-Akt-eNOS-VEGF pathway activation in HBMEC was tested by Western blot. Our data suggested that protocatechuic acid induces angiogenesis in vitro by increasing proliferation, invasion and tube formation. VEGF expression was increasing by protocatechuic acid and counteracted by VEGF antagonist sFlt-1, LY294002 and L-NAME in HBMEC. Tube formation was increased by protocatechuic acid and counteracted by VEGF receptor blocker-SU1498, LY294002 and L-NAME. These data suggest that protocatechuic acid may be a candidate therapy for stroke recovery by promoting angiogenesis via a programmed PI3K/Akt/eNOS/VEGF signalling axis. PMID- 23738794 TI - Novel approaches to glioma drug design and drug screening. AB - INTRODUCTION: Gliomas are considered the most malignant form of brain tumors, and ranked among the most aggressive human cancers. Despite advance standard therapy the prognosis for patients with gliomas remains poor. Chemotherapy has played an important role as an adjuvant in treating gliomas. The efficacy of the chemotherapeutic drug is limited due to poor drug delivery and the inherent chemo and radio-resistance. Challenges of the brain cancer therapy in clinical settings are; i) to overcome the chemo- and radio-resistance, ii) to improve drug delivery to tumors and iii) the development of effective drug screening procedures. AREAS COVERED: In this review, the authors discuss clinically important chemotherapeutic agents used for treating malignant gliomas along with novel drug design approaches. The authors, furthermore, discuss the in vitro and in vivo drug screening procedures for the development of novel drug candidates. EXPERT OPINION: The development of novel and highly potent chemotherapeutic agents for both glioma and glioma stem cells (GSCs) is highly important for future brain cancer research. Thus, research efforts should be directed towards developing innovative molecularly targeted antiglioma agents in order to reduce the toxicity and drug resistance which are associated with current forms of therapy. Development of novel pre-clinical drug screening procedures is also very critical for the overall success of brain cancer therapies in clinical settings. PMID- 23738795 TI - Serum and salivary levels of albumin as diagnostic tools for oral pre-malignancy and oral malignancy. AB - The role of oxygen free radicals in the initiation, promotion and progression of carcinogenesis and the protective role of antioxidants has been a subject of much speculation. There are few studies that report evaluation of serum albumin and only one study in which salivary albumin was found and only one study that reports of salivary albumin in oral Leukoplakia and Oral Squamous Cell Carcinoma (OSCC). We evaluated serum and salivary albumin levels in normal individuals, patients with oral pre-malignancy and patients with oral malignancy, and we compared serum and salivary albumin levels in patients with oral pre-malignancy and oral malignancy. Our study comprised 45 subjects separated into three groups of 15: normal healthy, oral pre-malignancy and oral malignancy patients. Venous blood was drawn and unstimulated saliva was collected early in the morning. Albumin levels were estimated using the bromocresol green method. Serum albumin levels decreased in oral pre-malignancy and oral malignancy cases compared to healthy individuals. Salivary albumin levels increased in oral pre-malignancy and oral malignancy cases compared to healthy individuals. Our results suggest that albumin may play a role in early diagnosis and prognosis of oral pre-malignant and oral malignant tissues. PMID- 23738796 TI - Oral factitious injury in a child diagnosed with Kabuki syndrome. AB - Factitious injury or self-injurious behavior is a common manifestation in children affected by neurologic, developmental, or psychiatric disease. The nature and presentation of this behavior in the oral cavity varies among diagnoses, and such behavior can be easily missed. This report describes the presence of self-injurious behavior in a child diagnosed with Kabuki syndrome who presented to a pediatric dentistry referral practice for evaluation of gingival bleeding, and provides a brief overview of the known etiology and management of this challenging condition. Clinicians should be aware of the possibility of self injurious behavior when treating children diagnosed with Kabuki syndrome. PMID- 23738798 TI - Bone-added osteotome sinus floor elevation for the deficient maxillary posterior implant site: case series. AB - Implant placement in the posterior maxillary region is often compromised due to anatomic limitations. Often, factors like inadequate vertical dimension, poor bone quality, and undercuts result in placement of shorter and/or angled implants. The bone-added osteotome sinus floor elevation technique can be employed in many clinical situations that involve minimal bone height, resulting in increased bone height and placement of longer implants. This article will briefly review the literature and provide a detailed description of the technique as well as present multiple cases in which this procedure was used. PMID- 23738797 TI - Reactive oxygen species and antioxidant defense mechanisms in the oral cavity: a literature review. AB - Through dental procedures and environment, periodontal tissues are exposed to many types of reactive oxygen species (ROS). Recently, various forms of antioxidants have been introduced as an approach to fight dental diseases and improve general gingival health. This article focuses on the classification of antioxidants and the link between oxidative stress and periodontal disease. The protective mechanisms of antioxidants and how routine dental procedures may increase ROS is discussed. The final section reviews the effect of tobacco products on gingival health and disease. PMID- 23738799 TI - An exploratory study demonstrating the diagnostic ability of healthcare professionals in primary care using online case studies for common skin conditions. AB - OBJECTIVES: To compare the diagnostic ability of pharmacists, nurses and general practitioners (GPs) for a range of skin conditions. METHODS: An online study comprising 10 specifically developed dermatological case studies containing a digital image of the skin condition and a short case history. A total of 60 participants (20 representing each of pharmacists, GPs and primary care nurses) were required to identify the skin condition as well as the features in the case history that supported the diagnosis and the recommended first-line management approach for the condition. KEY FINDINGS: The mean diagnostic scores for each group were GPs = 8.8 (95% confidence interval, CI, 7.9-9.6), pharmacists = 6.2 (95% CI, 5.4-6.9) and nurses = 7.0 (95% CI, 6.1-7.9). Post hoc analysis revealed that the difference in mean diagnostic scores was significant (P < 0.05) between GPs and both pharmacists and nurses. However, pharmacists' diagnostic accuracy was similar to GPs' for some skin conditions such as tinea corporis, scabies and plantar warts and overall at least 40% of pharmacists correctly identified all conditions. CONCLUSION: This small study has demonstrated that for all of the skin conditions considered, pharmacists' overall diagnostic scores were significantly different from those of GPs but similar to those of nurses for the conditions assessed. However, further work with a larger sample is required to determine the accuracy of these preliminary findings and to establish whether advice given by pharmacists in practice results in the appropriate course of action being taken. PMID- 23738800 TI - Journey through the potential energy surfaces for the isomerization and decomposition reactions of the telluroformaldehyde analogues: H2A?Te and HFA?Te (A = C, Si, and Ge). AB - The unavailability of monomeric heavy ketone analogues has been ascribed to the evanescence of the very reactive A?E double bond (A and E are the heavier group 14 and group 16 elements, respectively). Can the isolation of any of the monomeric telluro-ketones be assisted by an energetic favorability on its potential energy surface (PES)? In this light, the reaction pathways for the isomerization and decomposition reactions of H2A?Te and HFA?Te (A = C, Si, and Ge) molecules on their singlet state PES have been studied using second-order Moller-Plesset perturbation theory (MP2). The barrier heights reported suggest that telluroformaldehyde, silanetellone, and germatellone are kinetically more resistant to unimolecular reactions than the corresponding lighter chalcogen analogues. However, upon replacing a hydrogen atom by fluorine, the barrier heights of most of the isomerization and decomposition reactions are lowered. Among the unimolecular reactions studied for the H2A?Te and HFA?Te (A = C, Si, and Ge) molecules, the decomposition of cis-FGeTeH into HF and GeTe is found to be the most facile reaction, with a barrier height of only 4.6 kcal/mol. We also predict the ground state telluro-ketones to be viable molecules, as they have no imaginary vibrational frequencies and their lowest vibrational frequencies are always >100 cm(-1). In view of the scarcity of information on the chemistry of the mentioned telluro-ketones, the molecular parameters of various isomers and decomposition products have been reported, and should be useful for future experimental investigations. PMID- 23738801 TI - Antimutagenic properties of affinin isolated from Heliopsis longipes extract. AB - CONTEXT: Heliopsis longipes (A. Gray) Blake (Asteraceae), commonly known in Mexico as "chilcuage" or "chilcuan", is widely used as an analgesic and anesthetic agent. Affinin, the major metabolite of this plant, and the ethanol extract of the plant have shown antinociceptive properties in mice. H. longipes plant produces a complex mixture of antioxidant chlorophylls and polyamines as well as a number of possible antimutagens. OBJECTIVE: The current study evaluated the potential utilization of the natural product affinin isolated from H. longipes ethanol extract as an antimutagenic and possibly anticarcinogenic agent. MATERIALS AND METHODS: The Ames assay was used to assess the mutagenic properties of affinin (12.5, 25 and 50 ug/plate) that was added to several mutagens with or without S9 metabolic activation in Salmonella typhimurium (TA98, TA100 and TA102 strains). RESULTS: Heliopsis longipes extract and affinin were not toxic as a reduction in the number of His+ revertant bacteria colonies. Affinin (25 and 50 ug/plate) significantly reduced the frameshift mutations that were generated by 2 aminoanthracene (2AA) (40%) and reduced the oxidative DNA damage generated by norfloxacin (NOR) (37-50%). Affinin possessed antioxidant properties that were able to reduce 2AA- and NOR-induced mutations in S. typhimurium TA98 and TA102, respectively. DISCUSSION AND CONCLUSION: Affinin, the principal metabolite of H. longipes, is not mutagenic and possesses antimutagenic activity. These plants are currently used to treat some pain symptoms in Mexico; and antimutagen activity determined could be important to treat some pain symptoms related to antiradical activity. PMID- 23738802 TI - New susceptibility locus for obesity and dyslipidaemia on chromosome 3q22.3. AB - BACKGROUND: The muscle Ras (MRAS) gene resides on chromosome 3q22.3 and encodes a member of the membrane-associated Ras small GTPase proteins, which function as signal transducers in multiple processes including cell growth and differentiation. Its role in cardiovascular disease is not fully understood yet. In a preliminary study in heterozygous familial hypercholesterolaemia, we identified a locus linking the early onset of coronary artery disease (CAD) to chromosome 3q.22 and elected to sequence the MRAS gene using the MegaBACE DNA analysis system. In the present study, we investigated the association of seven single-nucleotide polymorphisms (SNPs) at this locus with CAD and its dyslipidaemia-related risk traits in 4,650 Saudi angiographed individuals using TaqMan assays by the Applied Biosystems real-time Prism 7900HT Sequence Detection System. RESULTS: Among the studied SNPs, rs6782181 (p = 0.017) and rs9818870T (p = 0.009) were associated with CAD following adjustment for sex, age and other confounding risk factors. The rs6782181_GG also conferred risk for obesity (1,764 cases vs. 2,586 controls) [1.16(1.03-1.30); p = 0.017], hypercholesterolaemia (1,686 vs. 2,744) [1.23(1.02-1.47); p = 0.019], hypertriglyceridaemia (1,155 vs. 3,496) [1.29(1.01-1.45); p = 0.043] and low high-density lipoprotein-cholesterol (lHDL-chol) levels (1,935 vs. 2,401) [1.15(1.02-1.30); p = 0.023] after adjustment. Additionally, rs253662_(CT+TT) [1.16(1.01-1.32); p = 0.030] was associated with lHDL-chol levels. Interestingly, rs253662 (p = 0.014) and rs6782181 (p = 0.019) were protective against acquiring high low-density lipoprotein-cholesterol (hLDL-chol) levels (p = 0.014), while rs1720819 showed similar effects against CAD (p < 0.0001). More importantly, a 7-mer haplotype, ACCTGAC (chi2 = 7.66; p = 0.0056), constructed from the studied SNPs, its 6-mer derivative CCTGAC (chi2 = 6.90; p = 0.0086) and several other shorter derivatives conferred risk for obesity. hLDL-chol was weakly linked to CTAA (chi2 = 3.79; p = 0.052) and CCT (chi2 = 4.32; p = 0.038), while several other haplotypes were protective against both obesity and hLDL-chol level. CONCLUSION: Our results demonstrate that the genomic locus for the MRAS gene confers risk for CAD, obesity and dyslipidaemia and point to the possible involvement of other genes or regulatory elements at this locus, rather than changes in the M-Ras protein function, in these events. PMID- 23738804 TI - Editorial boards and their value to the professions: opening the gates to what is next. PMID- 23738803 TI - When worlds collide: interactions at the interface between biological systems and synthetic cationic conjugated polyelectrolytes and oligomers. AB - This Feature Article focuses on recent progress made in elucidating the intermolecular interactions between a novel class of synthetic phenylene ethynylene (PPE)-based conjugated polyelectrolyte polymers (CPEs) and oligomers (OPEs) and multiscale cellular targets that give rise to their remarkable broad spectrum biocidal activity. We first review the interactions and self-assembly behaviors of the CPEs and OPEs with a set of vital biomolecules, including lipids, proteins, and nucleic acids, that reveal the potential pathways by which synthetic biocidal agents could exert toxicity. An overview of the antimicrobial effects and mechanisms of the CPEs and OPEs on multiple clinically relevant pathogens is then presented, with an emphasis on the morphological damage induced by the biocidal compounds toward the pathogens. Finally, we discuss the cytotoxicity of these materials against mammalian cells and human tissues to explore the potential applications of the CPEs and OPEs as antiseptics. We also pose some unanswered questions about their antimicrobial mechanisms, which provide direction for a future study. PMID- 23738805 TI - Using social media. AB - Social media has become mainstream in both our personal and our professional lives. Some of its uses, including promoting professional development activities, are described in this column. PMID- 23738806 TI - Rapid response systems update. AB - Rapid response is a mature concept that is undergoing metamorphosis. The ideal structure and function of these safety teams has not yet been realized but new developments in the field of rapid response systems are evolving. PMID- 23738807 TI - Videotaping as a learning tool. AB - Philosophically, an assumption exists that equates formal academic education with teaching or presentation ability. Nothing could be further from the truth. . PMID- 23738809 TI - Quantification of 99mTc-DPD concentration in the lumbar spine with SPECT/CT. AB - BACKGROUND: Routine single-photon emission computed tomography (SPECT) currently lacks quantitative information on regional activity concentration (ACC) of the injected tracer (e.g. kBq/ml). Furthermore, little is known on the skeletal absolute concentration of 99mTc-DPD after intravenous injection in bone scintigraphy. The aim of this study is to determine ACC in the healthy lumbar vertebrae of patients using a recently published quantitative SPECT/computed tomography (CT) protocol. METHODS: Lumbar vertebrae ACC estimates were performed in 50 female patients (mean age 69.88 +/- 13.73 years) who had been administered 562.84 +/- 102.33 MBq of 99mTc-DPD and had undergone SPECT acquisition 4 h after the injection. The SPECT/CT system was calibrated against a well counter. Images were reconstructed with Flash3D. ACC and CT tissue density were measured in volumes of interest drawn over the spongious bone tissue of the three lower lumbar vertebral bodies when these exhibited no focal CT or SPECT pathology. RESULTS: Average ACC measured in the normal spongious bone tissue was 48.15 +/- 13.66 kBq/ml (95% confidence interval (CI) 45.81 to 50.50 kBq/ml). This corresponds to a mean standardised uptake value (SUV) of (5.91 +/- 1.54) (95% CI (5.64 to 6.17) SUV). SUV correlated significantly with Hounsfield units (HU) (r = 0.678, p < 0.0001). Significant negative correlations were observed between age and HU (r = -0.650, p < 0.0001) and between age and SUV (r = -0.385, p < 0.0001). CONCLUSIONS: The SUVs determined for 99mTc-DPD uptake 4 h post injection are in the same range as those reported for [18F]fluoride in positron emission tomography. The strong correlation of SUV with bone CT density underlines the physiological significance of this variable. Our data suggest further investigation of the potential value of ACC measurement in the diagnosis of pathological conditions such as osteoporosis or in following up osseous metastases under therapy. PMID- 23738810 TI - The effect of mannosylation of liposome-encapsulated indocyanine green on imaging of sentinel lymph node. AB - The imaging of sentinel lymph nodes (SLN) has been researched for its role in assessing cancer progression and postsurgical lymphedema. Indocyanine green (ICG) is a near-infrared (NIR) optical dye that has been approved by the Food and Drug Administration. It is known that liposome-encapsulated ICG (LP-ICG) has improved stability and fluorescence signal compared with ICG. We designed mannosylated liposome-encapsulated ICG (M-LP-ICG) as an optical contrast agent for SLN. M-LP ICG has a higher UV absorbance spectrum and fluorescence intensity than LP-ICG. The stability of M-LP-ICG measured in 50% fetal bovine serum solution by a dialysis method was better than that of LP-ICG. M-LP-ICG demonstrated a high uptake in RAW 264.7 macrophage cell because the density of mannose is high. There were differences between M-LP-ICG and glucosylated liposome-encapsulated ICG (G LP-ICG), which are geometrical isomers. The result of an inhibition study of M-LP ICG showed a statistically significant decrease in uptake in RAW 264.7 cells after either co-treatment or pre-treatment with D-(+)-mannose as an inhibitor. Results from an in vitro experiment demonstrated that M-LP-ICG was specifically taken up by macrophage cells through the mannose receptor on its surface. The time-series images acquired from a normal mouse model after subcutaneous injection showed that the signal from M-LP-ICG in SLN and other organs appeared early and disappeared quickly in comparison with signals from LP-ICG. Not only the sentinel but also the draining lymph nodes were observed partly in M-LP-ICG. M-LP-ICG appears to increase the specificity of uptake and retention in macrophages, making it a good candidate contrast agent for an optic imaging system for SLN and the lymphatic system. PMID- 23738811 TI - Interleukin-6 neutralization alleviates pulmonary inflammation in mice exposed to cigarette smoke and poly(I:C). AB - Increased systemic and pulmonary levels of IL-6 (interleukin-6) are associated with the severity of exacerbations and decline of lung function in patients with COPD (chronic obstructive pulmonary disease). Whether IL-6 is directly involved or plays a bystander role in the pathophysiology of COPD remains unclear. Here we hypothesized that neutralizing circulating levels of IL-6 would modulate episodes of acute pulmonary inflammation following CS (cigarette smoke) exposure and virus like challenges. For this purpose, we used a model where C57BL/6 mice were exposed to CS twice daily via a nose-only system, and concomitant periodic intranasal challenge with poly(I:C), a synthetic ligand for TLR3 (Toll-like receptor 3) that mimics the encounter with double stranded RNA that is carried by influenza-like viruses. This protocol recapitulates several aspects of acute pulmonary inflammation associated with COPD, including prominent airway neutrophilia, insensitivity to steroid treatment and increased levels of several inflammatory cytokines in BAL (bronchoalveolar lavage) samples. Although IL-6 deficient mice exposed to CS/poly(I:C) developed pulmonary inflammation similar to WT (wild-type) controls, WT mice exposed to CS/poly(I:C) and treated intraperitoneally with IL-6-neutralizing antibodies showed significantly lower blood counts of lymphocytes and monocytes, lower BAL levels of IL-6 and CXCL1 (CXC chemokine ligand 1)/KC (keratinocyte chemoattractant), as well as reduced numbers of BAL neutrophils, lymphocytes and macrophages. Our results thus indicate that the systemic neutralization of IL-6 significantly reduces CS/poly(I:C)-induced pulmonary inflammation, which may be a relevant approach to the treatment of episodes of acute pulmonary inflammation associated with COPD. PMID- 23738812 TI - Structural and physicochemical property relationships of cruciferin homohexamers. AB - Heteromeric cruciferin from wild type (WT) Arabidopsis thaliana and homomeric cruciferin CRUA, CRUB, and CRUC composed of identical subunits obtained from double-knockout mutant lines were investigated for their structural and physicochemical properties. A three-step chromatographic procedure allowed isolation of intact cruciferin hexamers with high purity (>95%). FT-IR and CD analysis of protein secondary structure composition revealed that all cruciferins were folded into higher order structures consisting of 44-50% beta-sheets and 7 9% alpha-helices. The structural and physicochemical properties of homohexameric CRUC deviated from that of CRUA and CRUB and exhibited a compact, thermostable, and less hydrophobic structure, confirming the predictions made using 3D homology structure models. PMID- 23738813 TI - Divergent NHC-catalyzed oxidative transformations of 3-bromoenal: selective synthesis of 2H-pyran-2-ones and chiral dihydropyranones. AB - A selective synthesis of either 2H-pyran-2-ones (4) or chiral dihydropyranones (6) from the same substrates of 3-bromoenals and 1,3-dicarbonyl compounds upon oxidative N-heterocyclic carbene catalysis is presented. It is shown that the oxidative transformation of 3-bromoenals under NHC catalyst can be well controlled to proceed through two pathways, i.e., elimination of reducible beta bromide or by an external oxidant 3, allowing the selective generation two sorts of unsaturated acyl azoliums, respectively. PMID- 23738814 TI - Trifluoromethanesulfonyl hypervalent iodonium ylide for copper-catalyzed trifluoromethylthiolation of enamines, indoles, and beta-keto esters. AB - A novel electrophilic-type trifluoromethylthiolation reagent, a trifluoromethanesulfonyl hypervalent iodonium ylide, was designed and reacted well with various nucleophiles to afford the desired CF3S-substituted products. In situ reduction of the trifluoromethanesulfonyl group to give the trifluoromethylthio group, which is the key step in this process, was realized in the presence of copper(I) chloride. PMID- 23738815 TI - Queer challenges to evidence-based practice. AB - This paper aims to queer evidence-based practice by troubling the concepts of evidence, knowledge and mental illness. The evidence-based narrative that emerged within biomedicine has dominated health care. The biomedical notion of 'evidence' has been critiqued extensively and is seen as exclusive and limiting, and even though the social constructionist paradigm attempts to challenge the authority of biomedicine to legitimate what constitutes acceptable evidence or knowledge for those experiencing mental illness, biomedical notions of evidence appear to remain relatively intact. Queer theory offers theoretical tools to disrupt biomedical norms and challenges biomedical normativity to indicate how marginalisation occurs when normative truths about mental health classify those who differ from the norm as 'ill' or 'disordered'. Queer theory's emphasis on normativity serves the political aim to subvert marginalisation and bring about radical social and material change. Reference will be made to mental health subjects within each discourse by indicating how the body acts as a vehicle for knowing. Deleuzian notions of the rhizome are used as metaphor to suggest a relational approach to knowledge that does away with either/or positions in either biomedical, or queer knowledge to arrive at a both/and position where the biomedical, constructionist and queer are interrelated and entangled in needing the other for their own evolution. However, queer does not ask for assimilation but celebrates difference by remaining outside to disrupt that which is easily overlooked, assumed to be natural or represented as the norm. The task of queer knowledge is to do justice to the lives lived in the name of evidence-based practice and demands that we consider the relations of power where knowledge is produced. This pursuit creates different knowledge spaces where we identify new intersections that allow for socially just understandings of knowing or evidence to emerge. PMID- 23738817 TI - Molecular topography of the MED12-deleted region in smooth muscle tumors: a possible link between non-B DNA structures and hypermutability. AB - BACKGROUND: Deletions of the gene encoding mediator subcomplex 12 (MED12) in human smooth muscle tumors rank among the most frequent genomic alterations in human tumors at all. In a minority of these cases, small deletions are found. In an attempt to delineate key features of the deletions aimed at a better understanding of the molecular pathogenesis of uterine smooth muscle tumors we have analyzed 70 MED12 deletions including 46 cases from the literature and 24 own unpublished cases. RESULTS: The average length of the deletions was 18.7 bp ranging between 2 bp and 43 bp. While in general multitudes of 3 clearly dominated leaving the transcript in frame, deletions of 21, 24, 30, and 33 nucleotides were clearly underrepresented. Within the DNA segment affected deletion breakpoints were not randomly distributed. Most breakpoints clustered within the center of the segment where two peaks of breakpoint clusters could be distinguished. Interestingly, one of these clusters coincides with the loop of a putative folded non-B DNA structure whereas a much lower number of breaks noted in the 5' and 3' stem of the structure forming an intramolecular B-helix. The second cluster mainly consisting of 3' breaks was located in a region downstream adjacent to the stem. CONCLUSION: The present study describes for the first time main characteristics of MED12 deletions occurring in smooth muscle tumors. Interestingly, the non-random distribution of breakpoints within the deletion hotspot region may point to a role of non-canonical DNA structures for the occurrence of these mutations and the molecular pathogenesis of uterine smooth muscle tumors, respectively. PMID- 23738818 TI - Human H5N1 influenza infections in Cambodia 2005-2011: case series and cost-of illness. AB - BACKGROUND: Southeast Asia has been identified as a potential epicentre of emerging diseases with pandemic capacity, including highly pathogenic influenza. Cambodia in particular has the potential for high rates of avoidable deaths from pandemic influenza due to large gaps in health system resources. This study seeks to better understand the course and cost-of-illness for cases of highly pathogenic avian influenza in Cambodia. METHODS: We studied the 18 laboratory confirmed cases of avian influenza subtype H5N1 identified in Cambodia between January 2005 and August 2011. Medical records for all patients were reviewed to extract information on patient characteristics, travel to hospital, time to admission, diagnostic testing, treatment and disease outcomes. Further data related to costs was collected through interviews with key informants at district and provincial hospitals, the Ministry of Health and non-governmental organisations. An ingredient-based approach was used to estimate the total economic cost for each study patient. Costing was conducted from a societal perspective and included both financial and opportunity costs to the patient or carer. Sensitivity analysis was undertaken to evaluate potential change or variation in the cost-of-illness. RESULTS: Of the 18 patients studied, 11 (61%) were under the age of 18 years. The majority of patients (16, 89%) died, eight (44%) within 24 hours of hospital admission. There was an average delay of seven days between symptom onset and hospitalisation with patients travelling an average of 148 kilometres (8-476 km) to the admitting hospital. Five patients were treated with oseltamivir of whom two received the recommended dose. For the 16 patients who received all their treatment in Cambodia the average per patient cost of H5N1 influenza illness was US$300 of which 85.0% comprised direct medical provider costs, including diagnostic testing (41.2%), pharmaceuticals (28.4%), hospitalisation (10.4%), oxygen (4.4%) and outpatient consultations (0.6%). Patient or family costs were US$45 per patient (15.0%) of total economic cost. CONCLUSION: Cases of avian influenza in Cambodia were characterised by delays in hospitalisation, deficiencies in some aspects of treatment and a high fatality rate. The costs associated with medical care, particularly diagnostic testing and pharmaceutical therapy, were major contributors to the relatively high cost-of illness. PMID- 23738820 TI - The discovery of non-adrenergic, non-cholinergic transmission: reply to the criticisms of G. Burnstock (2013) (GB) and Abbracchio et al. (2013) (A et al.) of M. Bennett's (MB) account of this history in Acta Physiol (2013) Feb; 207(2):236 43. PMID- 23738819 TI - Mean platelet volume is decreased in HIV-infected women. AB - OBJECTIVES: HIV infection is associated with higher than expected cardiovascular event rates and lowered platelet counts. These conditions are associated with an elevation of mean platelet volume (MPV). The present study compared MPV in HIV infected and uninfected women and identified factors influencing MPV values in HIV-infected women. METHODS: A total of 234 HIV-infected and 134 HIV-uninfected participants from the Women's Interagency HIV Study (WIHS) had MPV values obtained. HIV-infected women were older, were more likely to have diabetes and had higher triglyceride levels than HIV-uninfected women. RESULTS: The mean platelet count was lower in HIV-infected vs. uninfected women [249 cells/MUL (95% confidence interval (CI) 238, 259 cells/MUL) vs. 276 cells/MUL (95% CI 265, 287 cells/MUL), respectively; P < 0.01]. Adjusted mean MPV values were lower in the HIV-infected than in the uninfected group [8.66 fL (95% CI 8.52, 8.79 fL) vs. 9.05 fL (95% CI 8.87, 9.24 fL), respectively]. In multiple regression analysis, after adjusting for other covariates, MPV was positively associated with platelet count, and negatively with HIV infection (model R2 = 0.20; P < 0.01). In multiple regression analysis confined to HIV-infected women, a lower MPV was independently associated with a history of AIDS-defining illness (R2 = 0.28; P = 0.03), but not with nadir CD4 count or highly active antiretroviral therapy (HAART) use. CONCLUSIONS: HIV-infected women had lower MPV values than uninfected women, suggesting impaired production rather than increased destruction. Higher than expected cardiovascular event rates cannot be attributed to greater platelet reactivity as measured by MPV. PMID- 23738821 TI - Modulation of presynaptic Ca(2+) currents in frog motor nerve terminals by high pressure. AB - Presynaptic Ca(2+) -dependent mechanisms have already been implicated in depression of evoked synaptic transmission by high pressure (HP). Therefore, pressure effects on terminal Ca(2+) currents were studied in Rana pipiens peripheral motor nerves. The terminal currents, evoked by nerve or direct stimulation, were recorded under the nerve perineurial sheath with a loose macropatch clamp technique. The combined use of Na(+) and K(+) channel blockers, [Ca(2+) ]o changes, voltage-dependent Ca(2+) channel (VDCC) blocker treatments and HP perturbations revealed two components of presynaptic Ca(2+) currents: an early fast Ca(2+) current (ICaF ), possibly carried by N-type (CaV 2.2) Ca(2+) channels, and a late slow Ca(2+) current (ICaS ), possibly mediated by L-type (CaV 1) Ca(2+) channels. HP reduced the amplitude and decreased the maximum (saturation level) of the Ca(2+) currents, ICaF being more sensitive to pressure, and may have slightly shifted the voltage dependence. HP also moderately diminished the Na(+) action current, which contributed to the depression of VDCC currents. Computer-based modeling was used to verify the interpretation of the currents and investigate the influence of HP on the presynaptic currents. The direct HP reduction of the VDCC currents and the indirect effect of the action potential decrease are probably the major cause of pressure depression of synaptic release. PMID- 23738822 TI - In vivo analgesic and anti-inflammatory activities of Rosmarinus officinalis aqueous extracts, rosmarinic acid and its acetyl ester derivative. AB - CONTEXT: Despite several pharmacological applications of Rosmarinus officinalis L. (Lamiaceae), studies on its analgesic and anti-inflammatory properties have been scarce. OBJECTIVE: The aim of this work was to use in vivo models to evaluate the analgesic and anti-inflammatory activities of the aqueous extracts obtained from leaves (AEL) and stems (AES) of Rosmarinus officinalis, as well as its isolated compound--rosmarinic acid (RA). We also prepared and assessed the acetyl ester derivative of RA. MATERIALS AND METHODS: The analgesic activity was evaluated using abdominal constriction and formalin tests. For the evaluation of the anti-inflammatory effects, carrageenin-induced paw edema in rats were used. The extracts were used at doses of 100, 200 and 400 mg kg-1 compounds were tested at 10, 20 and 40 mg kg-1. RESULTS: Orally administered AEL, AES and RA were not significantly active at any of the doses tested during the abdominal constriction test; the acetyl ester derivative of RA displayed significant analgesic activity. In the carrageenin-induced paw edema assay, the acetyl derivative of RA at all the tested doses produced significant anti-inflammatory effects and reduced the number of paw licks in the second phase of the formalin test. DISCUSSION AND CONCLUSION: The results suggest that the analgesic effects of the acetyl derivative of RA operate via a peripheral-mediated mechanism. The acetyl ester derivative of RA is potentially applicable as a new lead compound for the management of pain and inflammation. PMID- 23738823 TI - Employment of a needs assessment survey to shape a novel web-based pediatric rheumatology curriculum for primary care providers. AB - BACKGROUND: Pediatric rheumatology faces many challenges due to the shortage of board certified physicians in the field and the imbalance in their geographic distribution. This shortage has required primary care physicians and adult rheumatologists to assume the care of children with rheumatologic diseases, though these physicians report significant discomfort doing so. We are addressing this issue through the development of a novel web-based curriculum aimed at primary care physicians. METHODS: We pursued a needs assessment survey of Vanderbilt pediatric residency graduates (1981-2010) working in primary care. Our goals were to understand their perceptions of what the needs are and what educational interventions would be most effective. RESULTS: Of 152 surveys sent successfully via Survey Monkey, we received 28 responses (18.4%). Responses suggest there to be a discrepancy between physicians' general assessment of their training and their self-reported ability to recognize specific diseases. Nearly 80% of respondents felt that additional education in pediatric rheumatology would improve their ability to co-manage children with the rheumatologist. Action plans for common rheumatologic complaints and potential emergencies were thought to be of potential benefit by a majority of respondents. CONCLUSIONS: We will utilize our survey results to develop a learner centered curriculum to have the highest positive impact in assisting primary care providers in caring for children with rheumatologic diseases. PMID- 23738824 TI - Using Bonferroni, BIC and AIC to assess evidence for alternative biological pathways: covariate selection for the multilevel Embryo-Uterus model. AB - BACKGROUND: IVF treatments for infertility involve the transfer of multiple embryos in any one treatment cycle. When data is available on individual embryos the outcomes of each embryo are only partially observed, as treatment outcome (live birth) is assessed at the patient level. Two-level Embryo-Uterus (EU) models have been developed which assume a biologically plausible mechanism and assume that effects are mediated directly through the embryo (E) and also through the uterine environment (U), represented by two sub-models. This approach potentially allows inference as to the association of patient variables with outcome. However, when the variable is measured at the patient level either additional decisions have to be made in the modelling process as to in which sub model the variable should be included or some model selection algorithm has to be invoked. These uncertainties have limited the practical application of these models. METHODS: We have conducted simulation studies based around realistic parameter values of situations where a putative patient-level variable is being considered for inclusion in an EU model and/or the mechanistic interpretation from the sub-model assignment is of interest. Firstly we explore various strategies for inference for a variable of interest where the sub-model is either pre-specified or considered unknown. Secondly we explore the use of information criteria to select the appropriate sub-model and the strength of evidence for that assignment. These are demonstrated in a reanalysis of a previously published dataset. RESULTS: In the absence of prior evidence for potential prognostic factors measured at the patient level, two single degree-of-freedom likelihood ratio tests with a Bonferroni correction including the variable of interest in first the E then the U sub-model performs well as a statistical test for association with outcome. For model building the information criteria can be used, but large differences are required (>= 6) to provide reasonable evidence of sub-model assignment. Previous interpretations have been over-optimistic. CONCLUSIONS: These results suggest simple strategies and should enable these models to be used more confidently in practical applications. PMID- 23738825 TI - Are all polar molecules hydrophilic? Hydration numbers of ketones and esters in aqueous solution. AB - Hydration numbers of typical polar compounds like ketones and esters in aqueous solution were precisely determined using high-frequency dielectric relaxation techniques up to a frequency of 50 GHz at 25 degrees C. Because the hydration number is one of the most quantitative parameters to demonstrate how much are molecules hydrophilic, it is a critical parameter to determine the hydrophilicity of compounds. Hydration numbers of some ketones bearing carbonyl groups were determined to be ca. 0 irrespective of the species of molecules. Moreover, hydration numbers of some esters were also evaluated to be ca. 0 as well as the ketones. These findings suggested that there is no hydrogen bond formation between the ester group and water molecules, nor is there the hydrogen bond formation between the carbonyl group and water molecules. Consequently, esters and ketones bearing typical polar groups are not classified into hydrophilic compounds, but into "hydroneutral" compounds positioned between hydrophilic and hydrophobic ones. Molecular motions of the examined polar molecules in aqueous solution were well described with single Debye-type rotational relaxation modes without strong interaction between solute and water molecules, and also between solute molecules because of the obtained Kirkwood factor close to unity. This independent rotational mode for the polar compounds results from the hydroneutral characteristics caused by the relationship n(H) = 0. PMID- 23738826 TI - Glycogen Storage Disease type 1a - a secondary cause for hyperlipidemia: report of five cases. AB - BACKGROUND AND AIMS: Glycogen storage disease type Ia (GSD Ia) is a rare metabolic disorder, caused by deficient activity of glucose-6-phosphatase-alpha. It produces fasting induced hypoglycemia and hepatomegaly, usually manifested in the first semester of life. Besides, it is also associated with growth delay, anemia, platelet dysfunction, osteopenia and sometimes osteoporosis. Hyperlipidemia and hyperuricemia are almost always present and hepatocellular adenomas and renal dysfunction frequent late complications. METHODS: The authors present a report of five adult patients with GSD Ia followed in internal medicine appointments and subspecialties. RESULTS: Four out of five patients were diagnosed in the first 6 months of life, while the other one was diagnosed in adult life after the discovery of hepatocellular adenomas. In two cases genetic tests were performed, being identified the missense mutation R83C in one, and the mutation IVS4-3C > G in the intron 4 of glucose-6-phosphatase gene, not previously described, in the other. Growth retardation was present in 3 patients, and all of them had anemia, increased bleeding tendency and hepatocellular adenomas; osteopenia/osteoporosis was present in three cases. All but one patient had marked hyperlipidemia and hyperuricemia, with evidence of endothelial dysfunction in one case and of brain damage with refractory epilepsy in another case. Proteinuria was present in two cases and end-stage renal disease in another case. There was a great variability in the dietary measures; in one case, liver transplantation was performed, with correction of the metabolic derangements. CONCLUSIONS: Hyperlipidemia is almost always present and only partially responds to dietary and drug therapy; liver transplantation is the only definitive solution. Although its association with premature atherosclerosis is rare, there have been reports of endothelial dysfunction, raising the possibility for increased cardiovascular risk in this group of patients. Being a rare disease, no single metabolic center has experience with large numbers of patients and the recommendations are based on clinical experience more than large scale studies. PMID- 23738827 TI - Interspecific vs intraspecific patterns in leaf nitrogen of forest trees across nitrogen availability gradients. AB - Leaf nitrogen content (delta) coordinates with total canopy N and leaf area index (LAI) to maximize whole-crown carbon (C) gain, but the constraints and contributions of within-species plasticity to this phenomenon are poorly understood. Here, we introduce a game theoretic, physiologically based community model of height-structured competition between late-successional tree species. Species are constrained by an increasing, but saturating, relationship between photosynthesis and leaf N per unit leaf area. Higher saturating rates carry higher fixed costs. For a given whole-crown N content, a C gain-maximizing compromise exists between delta and LAI. With greater whole-crown N, both delta and LAI increase within species. However, a shift in community composition caused by reduced understory light at high soil N availability (which competitively favors species with low leaf costs and consequent low optimal delta) counteracts the within-species response, such that community-level delta changes little with soil N availability. These model predictions provide a new explanation for the changes in leaf N per mass observed in data from three dominant broadleaf species in temperate deciduous forests of New England. Attempts to understand large-scale patterns in vegetation often omit competitive interactions and intraspecific plasticity, but here both are essential to an understanding of ecosystem-level patterns. PMID- 23738828 TI - Toroid formation through self-assembly of graft copolymer and homopolymer mixtures: experimental studies and dissipative particle dynamics simulations. AB - Self-assembly of mixture systems containing poly(acrylic acid)-g-poly(gamma benzyl-L-glutamate) graft copolymers (PAA-g-PBLG) and PBLG homopolymers in aqueous solution was investigated by both experiments and computer simulations. It was found that the aggregate morphologies, such as rods, curved rods, and toroids, could be tuned by the homopolymer content. The toroidal micelles with uniform size were formed when the homopolymer content in the hybrid aggregates is higher. The effect of added water content on the toroid formation process was studied. Rods and curved rods were observed sequentially before formation of toroids. We also performed dissipative particle dynamics (DPD) simulations to verify the structure transition and explore the formation mechanism of the toroidal aggregates. The DPD results are in good agreement with the experimental findings and provide additional information such as chain distribution in aggregates, which is difficult to be gained through experiments. On the basis of the experimental and simulation results, the formation mechanism of the toroidal micelles was suggested. PMID- 23738829 TI - Co-occurrence of ACSSuT and cephalosporin resistance phenotypes is mediated by int1-associated elements in nontyphoidal Salmonella enterica from human infections in Spain. AB - A screening of antimicrobial resistance and its genetic determinants has been performed on 300 Salmonella enterica isolates collected during 2004-2008 from human infections in Spain. Salmonella Typhimurium and Salmonella Enteritidis were the major serotypes, which were found with similar frequencies covering 80% of the bacterial collection. Salmonella Typhimurium isolates frequently shared low susceptibility to antimicrobials of the penta-resistance phenotype (ACSSuT) and/or cephalosporin resistance. The ACSSuT profile was found closely linked to int1-associated gene cassettes, with major elements carrying DNA fragments of 1.0 Kb (aadA2 gene) plus 1.2 Kb (blaPSE-1 gene) or 2.0 Kb (aadA1 and blaOXA-1 genes). Among these, ACSSuT and cephalosporin resistances were associated in Salmonella Typhimurium isolates expressing the blaOXA gene. beta-lactamase activities were also detected from isolates carrying blaTEM, blaCMY, or blaSHV, although only the two last genes expressed extended-spectrum beta-lactamases. The clonal analysis of S. enterica strains suggests that both horizontal and vertical transfer mechanisms are involved in the wide dissemination of their antimicrobial resistance. PMID- 23738830 TI - Imaging findings in 14 domestic ferrets (Mustela putorius furo) with lymphoma. AB - Lymphoma is the most common malignant neoplasia in domestic ferrets, Mustela putorius furo. However, imaging findings in ferrets with lymphoma have primarily been described in single case reports. The purpose of this retrospective study was to describe imaging findings in a group of ferrets with confirmed lymphoma. Medical records were searched between 2002 and 2012. A total of 14 ferrets were included. Radiographs (n = 12), ultrasound (n = 14), computed tomography (CT; n = 1), and magnetic resonance imaging (MRI; n = 1) images were available for review. Median age at the time of diagnosis was 5.2 years (range 3.25-7.6 years). Clinical signs were predominantly nonspecific (8/14). The time between the first imaging study and lymphoma diagnosis was 1 day or less in most ferrets (12). Imaging lesions were predominantly detected in the abdomen, and most frequently included intra-abdominal lymphadenopathy (12/14), splenomegaly (8/14), and peritoneal effusion (11/14). Lymphadenopathy and mass lesions were typically hypoechoic on ultrasound. Mild peritoneal effusion was the only detected abnormality in two ferrets. Mild pleural effusion was the most common thoracic abnormality (3/12). Expansile lytic lesions were present in the vertebrae of two ferrets with T3-L3 myelopathy and the femur in a ferret with lameness. Hyperattenuating, enhancing masses with secondary spinal cord compression were associated with vertebral lysis in CT images of one ferret. The MRI study in one ferret with myelopathy was inconclusive. Findings indicated that imaging characteristics of lymphoma in ferrets are similar to those previously reported in dogs, cats, and humans. PMID- 23738831 TI - Alveolar ridge augmentation: comparison of two socket graft materials in implant cases. AB - With the variety of bone grafting materials available and their use around both natural teeth and dental implants, clinicians need to understand not only basic bone biology but also characteristics of different bone grafting materials to make a proper choice when selecting a material for alveolar bone augmentation and implant treatment. The grafting materials used in the maxillofacial region include autogenous bone, allografts, xenografts, alloplastic or synthetic products, and composite grafts (combination of different materials). This case report describes two frequenly used bone graft materials for socket preservation immediately after extraction: Puros(r) (Zimmer Dental Inc, www.zimmerdental.com) (allogeneic) and Bio-Oss(r)(Osteohealth Co, www.osteohealth.comwww.osteohealth.com) (xenogeneic). In the case presented, the authors perform biologic, clinical, radiologic, and histologic analysis of the two grafting materials by placing them side-by-side in the same patient during implant reconstruction. Implant-related phases of bone augmentation are proposed, and an overview of bone grafting materials, specifically Bio-Oss and Puros, is presented. PMID- 23738832 TI - Use of antioxidants in oral healthcare. AB - There is increasing attention to the potential benefit from the use of antioxidants in the field of dental medicine. In general, antioxidants may be available through oral ingestion, diet or vitamin supplements, and in nutraceuticals. In addition, treatment of oral and dental health problems may include drug-free, natural antioxidant remedies that are available in topical oral applications such as mouth rinse, gel, paste, gum, or lozenge compositions. These topical antioxidant remedies help reduce free-radical or reactive-oxygen species, which are causative inflammatory factors in the progression of gingival and periodontal maladies. This review focuses on relationships between antioxidants and free-radical/reactive-oxygen species in the oral environment. PMID- 23738833 TI - An alternative donor site for an epithelialized-free soft-tissue autograft. AB - Typically, epithelialized-free soft-tissue autografts are harvested from the palate, while alternative sites include edentulous ridges and wide zones of gingival tissue. This case report documents the use of the operculum over an erupting molar as an additional harvest site, a technique that may offer certain advantages in younger patients. PMID- 23738834 TI - Evaluation of ABX Pentra DX 120 and Sysmex XE-2100 in umbilical cord blood. AB - INTRODUCTION: Cord blood (CB) is an important source of hematopoietic stem cells and reflects the hematologic status of neonates. ABX Pentra DX 120 (Horiba Medical, Montpellier, France) and Sysmex XE-2100 (Sysmex, Kobe, Japan) were compared in 200 CB specimens. METHODS: Complete blood count parameters including white blood cell (WBC) differential counts were compared between the two analyzers. Double differential matrix (DDX) by ABX Pentra DX 120 and hematopoietic progenitor cell (HPC) by Sysmex XE-2100 were compared with CD34(+) cells by flow cytometry. RESULTS: Most of the parameters showed acceptable correlation between the two analyzers. Although WBC differential of both analyzers showed acceptable correlation with manual counts, mononuclear cells (MNC) by ABX Pentra DX 120 better correlated with manual count than MNC by Sysmex XE-2100. NRBC by Sysmex XE-2100 better correlated with manual count than NRBC by ABX Pentra DX 120. ABX Pentra DX 120 showed better flagging performances. DDX better correlated with CD34(+) cells than HPC. CONCLUSION: Although the results from both analyzers are mostly interchangeable and reliable in CB specimens, flagging performance of ABX Pentra DX 120 seems to be superior to that of Sysmex XE-2100. DDX by ABX Pentra DX 120 would be valuable to evaluate the quality of CB for further therapeutic utilization. PMID- 23738835 TI - Carbocyclization versus oxycyclization on the metal-catalyzed reactions of oxyallenyl C3-linked indoles. AB - The preparation of previously unknown (indol-3-yl)-alpha-allenols and -allenones was accomplished from indole-3-carbaldehydes, through indium-mediated Barbier allenylation reaction taking advantage of the N-(2-pyridyl)sulfonyl group. Metal catalyzed cyclizations of oxyallenyl C3-linked indoles proceeded in two ways depending on the presence or absence of the N-(2-pyridyl)sulfonyl group. For allenols, gold-catalyzed oxycyclization occurred in the presence of the protecting group; in the absence of the protecting group, palladium- and gold catalyzed benzannulations operated. On the contrary, under gold catalysis furyl indoles were obtained as exclusive products from NH-allenones, while 5-endo carbocyclization adducts were the major components starting from N-SO2py protected allenones. These cyclization reactions have been developed experimentally, and their mechanisms have additionally been investigated by a computational study. PMID- 23738836 TI - Sequencing of a novel HLA-DRB1*09:01:07 allele in a Chinese individual. AB - The novel DRB1*09:01:07 allele differs from DRB1*09:01:02 by only one nucleotide substitution in exon 2. PMID- 23738837 TI - Roles of free radicals in type 1 phototherapeutic agents: aromatic amines, sulfenamides, and sulfenates. AB - Detailed analyses of the electron spin resonance (ESR) spectra, cell viability, and DNA degradation studies are presented for the photolyzed Type I phototherapeutic agents: aromatic amines, sulfenamides, and sulfenates. The ESR studies provided evidence that copious free radicals can be generated from these N-H, N-S, and S-O containing compounds upon photoirradiation with UV/visible light. The analyses of spectral data allowed us to identify the free radical species. The cell viability studies showed that these agents after exposure to light exert cytotoxicity to kill cancer cells (U937 leukemia cell lines HTC11, KB, and HT29 cell lines) in a dosage- and time-dependent manner. We examined a possible pathway of cell death via DNA degradation by a plasmid cleavage assay for several compounds. The effects of photosensitization with benzophenone in the presence of oxygen were examined. The studies indicate that planar tricyclic amines and sulfenamides tend to form pi-electron delocalized aminyl radicals, whereas nonplanar ones tend to yield nitroxide radicals resulting from the recombination of aminyl radicals with oxygen. The ESR studies coupled with the results of cell viability measurements and DNA degradation reveal that planar N centered radicals can provide higher potency in cell death and allow us to provide some insights on the reaction mechanisms. We also found the formation of azatropylium cations possessing high aromaticity derived from azepines can facilitate secondary electron transfer to form toxic O2(*-) radicals, which can further exert oxidative stress and cause cell death. PMID- 23738838 TI - unc5c haploinsufficient phenotype: striking similarities with the dcc haploinsufficiency model. AB - DCC and UNC5 homologs (UNC5H) are guidance cue receptors highly expressed by mesocorticolimbic dopamine neurons. We have shown that dcc heterozygous mice exhibit increased dopamine, but not norepinephrine, innervation and function in medial prefrontal cortex. Concomitantly, dcc heterozygotes show blunted mesolimbic dopamine release and behavioral responses to stimulant drugs. These changes appear only in adulthood. Recently, we found an adolescent emergence of UNC5H expression by dopamine neurons and co-expression of DCC and UNC5H by single dopamine cells. Here, we demonstrate selective expression of unc5 homolog c mRNA by dopamine neurons in adulthood. We show that unc5c haploinsufficiency results in diminished amphetamine-induced locomotion in male and female mice. This phenotype is identical to that produced by dcc haploinsufficiency and is observed after adolescence. Notably, and similar to dcc haploinsufficiency, unc5c haploinsufficiency leads to dramatic increases in tyrosine hydroxylase expression in the medial prefrontal cortex, but not in the nucleus accumbens. In contrast, medial prefrontal cortex dopamine-beta-hydroxylase expression is not altered. We confirmed that UNC5C protein is reduced in the ventral tegmental area of unc5c heterozygous mice, but that DCC expression in this region remains unchanged. UNC5C receptors may also play a role in dopamine function and influence sensitivity to behavioral effects of stimulant drugs of abuse, at least upon first exposure. The striking similarities between the dcc and the unc5c haploinsufficient phenotypes raise the possibility that functions mediated by DCC/UNC5C complexes may be at play. PMID- 23738839 TI - Divin: a small molecule inhibitor of bacterial divisome assembly. AB - Bacterial cell division involves the dynamic assembly of division proteins and coordinated constriction of the cell envelope. A wide range of factors regulates cell division--including growth and environmental stresses--and the targeting of the division machinery has been a widely discussed approach for antimicrobial therapies. This paper introduces divin, a small molecule inhibitor of bacterial cell division that may facilitate mechanistic studies of this process. Divin disrupts the assembly of late division proteins, reduces peptidoglycan remodeling at the division site, and blocks compartmentalization of the cytoplasm. In contrast to other division inhibitors, divin does not interact with the tubulin homologue FtsZ, affect chromosome segregation, or activate regulatory mechanisms that inhibit cell division indirectly. Our studies of bacterial cell division using divin as a probe suggest that dividing bacteria proceed through several morphological stages of the cell envelope, and FtsZ is required but not sufficient to compartmentalize the cytoplasmic membrane at the division site. Divin is only moderately toxic to mammalian cells at concentrations that inhibit the growth of clinical pathogens. These characteristics make divin a useful probe for studying bacterial cell division and a starting point for the development of new classes of therapeutic agents. PMID- 23738840 TI - Reducing health inequities: the contribution of core public health services in BC. AB - BACKGROUND: Within Canada, many public health leaders have long identified the importance of improving the health of all Canadians especially those who face social and economic disadvantages. Future improvements in population health will be achieved by promoting health equity through action on the social determinants of health. Many Canadian documents, endorsed by government and public health leaders, describe commitments to improving overall health and promoting health equity. Public health has an important role to play in strengthening action on the social determinants and promoting health equity. Currently, public health services in British Columbia are being reorganized and there is a unique opportunity to study the application of an equity lens in public health and the contribution of public health to reducing health inequities. Where applicable, we have chosen mental health promotion, prevention of mental disorders and harms of substance use as exemplars within which to examine specific application of an equity lens. METHODS/DESIGN: This research protocol is informed by three theoretical perspectives: complex adaptive systems, critical social justice, and intersectionality. In this program of research, there are four inter-related research projects with an emphasis on both integrated and end of grant knowledge translation. Within an overarching collaborative and participatory approach to research, we use a multiple comparative case study research design and are incorporating multiple methods such as discourse analysis, situational analysis, social network analysis, concept mapping and grounded theory. DISCUSSION: An important aim of this work is to help ensure a strong public health system that supports public health providers to have the knowledge, skills, tools and resources to undertake the promotion of health equity. This research will contribute to increasing the effectiveness and contributions of public health in reducing unfair and inequitable differences in health among population groups. As a collaborative effort between public health practitioners/decision makers and university researchers, this research will provide important understanding and insights about the implementation of the changes in public health with a specific focus on health equity, the promotion of mental health and the prevention of harms of substance use. PMID- 23738841 TI - Horizontal transfer of bacterial polyphosphate kinases to eukaryotes: implications for the ice age and land colonisation. AB - BACKGROUND: Studies of online database(s) showed that convincing examples of eukaryote PPKs derived from bacteria type PPK1 and PPK2 enzymes are rare and currently confined to a few simple eukaryotes. These enzymes probably represent several separate horizontal transfer events. Retention of such sequences may be an advantage for tolerance to stresses such as desiccation or nutrient depletion for simple eukaryotes that lack more sophisticated adaptations available to multicellular organisms. We propose that the acquisition of encoding sequences for these enzymes by horizontal transfer enhanced the ability of early plants to colonise the land. The improved ability to sequester and release inorganic phosphate for carbon fixation by photosynthetic algae in the ocean may have accelerated or even triggered global glaciation events. There is some evidence for DNA sequences encoding PPKs in a wider range of eukaryotes, notably some invertebrates, though it is unclear that these represent functional genes.Polyphosphate (poly P) is found in all cells, carrying out a wide range of essential roles. Studied mainly in prokaryotes, the enzymes responsible for synthesis of poly P in eukaryotes (polyphosphate kinases PPKs) are not well understood. The best characterised enzyme from bacteria known to catalyse the formation of high molecular weight polyphosphate from ATP is PPK1 which shows some structural similarity to phospholipase D. A second bacterial PPK (PPK2) resembles thymidylate kinase. Recent reports have suggested a widespread distribution of these bacteria type enzymes in eukaryotes. RESULTS: On - line databases show evidence for the presence of genes encoding PPK1 in only a limited number of eukaryotes. These include the photosynthetic eukaryotes Ostreococcus tauri, O. lucimarinus, Porphyra yezoensis, Cyanidioschyzon merolae and the moss Physcomitrella patens, as well as the amoeboid symbiont Capsaspora owczarzaki and the non-photosynthetic eukaryotes Dictyostelium (3 species), Polysphondylium pallidum and Thecamonas trahens. A second bacterial PPK (PPK2) is found in just two eukaryotes (O. tauri and the sea anemone Nematostella vectensis). There is some evidence for PPK1 and PPK2 encoding sequences in other eukaryotes but some of these may be artefacts of bacterial contamination of gene libraries. CONCLUSIONS: Evidence for the possible origins of these eukaryote PPK1s and PPK2s and potential prokaryote donors via horizontal gene transfer is presented. The selective advantage of acquiring and maintaining a prokaryote PPK in a eukaryote is proposed to enhance stress tolerance in a changing environment related to the capture and metabolism of inorganic phosphate compounds. Bacterial PPKs may also have enhanced the abilities of marine phytoplankton to sequester phosphate, hence accelerating global carbon fixation. PMID- 23738842 TI - Evaluation of oxidative stress and DNA damage in traffic policemen exposed to vehicle exhaust. AB - OBJECTIVE: We aimed to study the genotoxic effects in traffic police who are occupationally exposed due to higher free radical generation. METHODS: Ambient and breathing zone air samples were analyzed blood samples were collected for analysis of antioxidant enzymes Superoxide Dismutase (SOD), Glutathione Peroxidase (GPx) and free radicals - nitric oxide (NO) and malondialdehyde (MDA) levels using a spectrophotometer. DNA damage was measured with the comet assay. RESULTS: Higher levels of benzene (BZ), toluene (TOL), carbon monoxide (CO), benzo([a])pyrene (BaP) and sulfur dioxide (SO2) was observed in traffic police. Elevated levels of NO, MDA and comet tail length and lower SOD and GPx levels observed in traffic police. CONCLUSION: The studied biomarkers, related to oxidative stress and DNA damage positively correlated in traffic police exposed to environmental air pollutants. PMID- 23738843 TI - Phentermine and topiramate extended-release: a new treatment for obesity and its role in a complications-centric approach to obesity medical management. AB - INTRODUCTION: Weight-management options include lifestyle modifications, bariatric surgery and, until recently, limited pharmacotherapy. Phentermine and topiramate extended-release (phentermine/topiramate ER) has recently been approved in the USA for chronic weight management in obese adults and overweight adults with weight-related co-morbidities in conjunction with a reduced-calorie diet and increased physical activity. AREAS COVERED: This review describes the pharmacology and clinical trials data for phentermine/topiramate ER and its role in a complications-centric approach to medical care of the overweight and obese patient. EXPERT OPINION: Phentermine/topiramate ER is an effective and safe weight-loss medication that can produce and sustain approximately 10% loss of body weight. This is a landmark development in the pharmacotherapy of obesity. By offering an effective medical option to complement lifestyle and surgical approaches, phentermine/topiramate ER enables a comprehensive medical model for obesity care. The overall approach to the overweight and obese patient should be to identify individuals who will benefit most from therapy based on cardiometabolic or mechanical complications, establish therapeutic targets and goals for ameliorating these complications and selecting the treatment modality and intensity for weight loss to achieve these goals. This complications-centric model emphasizes weight loss as a tool to ameliorate obesity-related complications and optimizes benefit/risk for achieving the best outcomes in overweight/obese patients. PMID- 23738844 TI - Sum-frequency-generation vibration spectroscopy and density functional theory calculations with dispersion corrections (DFT-D2) for cellulose Ialpha and Ibeta. AB - Sum-frequency-generation (SFG) vibration spectroscopy selectively detects noncentrosymmetric vibrational modes in crystalline cellulose inside intact lignocellulose. However, SFG peak assignment in biomass samples is challenging due to the complexity of the SFG processes and the lack of reference SFG spectra from the two crystal forms synthesized in nature, cellulose Ialpha and Ibeta. This paper compares SFG spectra of laterally aligned cellulose Ialpha and Ibeta crystals with vibration frequencies calculated from density functional theory with dispersion corrections (DFT-D2). Two possible hydrogen-bond networks A and B ( Nishiyama et al. Biomacromolecules 2008 , 9 , 3133 ) were investigated for both polymorphs. From DFT-D2 calculations the energetically favorable structures for cellulose Ialpha and Ibeta had CH2OH groups in tg conformations and network A hydrogen bonding. The calculated frequencies of C-H stretch modes agreed reasonably well with the peak positions observed with SFG and were localized vibrations; thus, peak assignments to specific alkyl groups were proposed. DFT-D2 calculations underestimated the distances between hydrogen-bonded oxygen atoms compared to the experimentally determined values; therefore, the OH stretching calculated frequencies were ~100 cm(-1) lower than observed. The SFG peak assignments through comparison with DFT-D2 calculations will guide the SFG analysis of the crystalline cellulose structure in plant cell walls and lignocellulose biomass. PMID- 23738845 TI - Ipsilateral lower extremity joint involvement increases the risk of poor pain and function outcomes after hip or knee arthroplasty. AB - BACKGROUND: Poor pain and function outcomes are undesirable after an elective surgery such as total hip or knee arthroplasty (THA/TKA). Recent studies have indicated that the presence of contralateral joint influences outcomes of THA/TKA, however the impact of ipsilateral knee/hip involvement on THA/TKA outcomes has not been explored. The objective of this study was to assess the association of ipsilateral knee/hip joint involvement on short-term and medium term pain and function outcomes after THA/TKA. METHODS: In this retrospective study of prospectively collected data, we used the data from the Mayo Clinic Total Joint Registry to assess the association of ipsilateral knee or hip joint involvement with moderate to severe pain and moderate to severe activity limitation at 2-year and 5-year follow-up after primary and revision THA and TKA using multivariable-adjusted logistic regression analyses. RESULTS: At 2 years, 3,823 primary THA, 4,701 primary TKA, 1,218 revision THA and 725 revision TKA procedures were studied. After adjusting for multiple covariates, ipsilateral knee pain was significantly associated with outcomes after primary THA (all P values <0.01): (1) moderate to severe pain: at 2 years, odds ratio (OR), 2.3 (95% confidence interval (CI) 1.5 to 3.6); at 5 years, OR 1.8 (95% CI 1.1 to 2.7); (2) moderate to severe activity limitation: at 2 years, OR 3.1 (95% CI 2.3 to 4.3); at 5 years, OR 3.6 (95% CI 2.6 to 5.0). Ipsilateral hip pain was significantly associated with outcomes after primary TKA (all P values <0.01): (1) moderate to severe pain: at 2 years, OR 3.3 (95% CI 2.3 to 4.7); at 5 years, OR 1.8 (95% CI 1.1 to 2.7); (2) moderate to severe activity limitation: at 2 years, OR 3.6 (95% CI 2.6 to 4.9); at 5 years, OR 2.2 (95% CI 1.6 to 3.2). Similar associations were noted for revision THA and TKA patients. CONCLUSIONS: To the best of our knowledge, this is the first study showing that the presence of ipsilateral joint involvement after THA or TKA is strongly associated with poor pain and function outcomes. A potential way to improve outcomes is to address ipsilateral lower extremity joint involvement. PMID- 23738846 TI - Higher vitamin D levels in HIV-infected out-patients on treatment with boosted protease inhibitor monotherapy. AB - OBJECTIVES: We investigated the vitamin D status of patients receiving frequently used types of combination antiretroviral therapy (cART), including boosted protease inhibitor (PI) monotherapy. METHODS: For this cross-sectional study, out of 450 HIV-infected patients followed in the Hospital Severo Ochoa (Madrid, Spain), we selected 352 patients for whom vitamin D levels had been measured (January 2009 to December 2010). We collected the following data: demographics, cART duration, main cART regimen, viral load (VL), CD4 cell count, and concentrations of 25(OH)-vitamin D [25(OH)-D], parathyroid hormone (PTH), albumin and calcium. Vitamin D status cut-off points were: (1) deficiency (vitDd): 25(OH) D < 20 ng/mL; (2) insufficiency (vitDi): 25(OH)-D from 20 to 29.99 ng/mL; and (3) optimal (vitDo): 25(OH)-D >= 30 ng/mL. RESULTS: The percentages of patients with vitDd, vitDi and vitDo were 44, 27.6 and 28.5%, respectively. Twenty-nine out of 30 (96.7%) Black patients had vitDd or vitDi, vs. 71.6% in the global sample (P < 0.001). Former injecting drug users (IDUs) had a higher prevalence of vitDo (P < 0.001) than patients in other transmission categories. Among patients with vitDd, vitDi and vitDo, the proportions of patients with a VL <= 50 HIV-1 RNA copies/mL were 77.4, 68 and 91%, respectively (P < 0.0001). Of the cART regimens, only boosted PI monotherapy was associated with significant differences in vitamin D levels (P = 0.039). Multivariate logistic regression analysis showed an increased risk of vitDi or vitDd associated with the following variables: Black vs. Caucasian ethnicity [odds ratio (OR) 10.6; 95% confidence interval (CI) 1.2-94; P = 0.033]; heterosexual (OR 2.37; 95% CI 1.13-4.93; P = 0.022) or men who have sex with men (MSM) (OR 3.25; 95% CI 1.25-8.50; P = 0.016) transmission category vs. former IDU; and VL > 50 copies/mL (OR 2.56; 95% CI 1.10-7.25; P = 0.040). A lower risk of vitamin D insufficiency or deficiency was found in patients on boosted PI monotherapy vs. no treatment (OR 0.08; 95% CI 0.01-0.6; P = 0.018). CONCLUSIONS: Our data show an increased risk of vitamin D deficiency or insufficiency in patients with detectable VL and a Black ethnic background. Among cART regimens, boosted PI monotherapy was associated with a lower risk of vitamin D deficiency or insufficiency. The more favourable vitamin D status in former IDUs was probably attributable to a higher frequency of outdoor jobs in this group of patients. PMID- 23738847 TI - Ultrasound appearance of the outer medulla in dogs without renal dysfunction. AB - Ultrasound findings of the canine kidney include a hyperechoic cortex and a hypo to anechoic medulla. In this study, the sonographic appearance of the outer renal medulla in dogs without evidence of renal disease is described. Dogs that underwent abdominal ultrasound over a 6-month period were subjected to review and then divided into six groups based on body weight (kg): < 4.9, 5.0-9.9, 10-19.9, 20-29.9, 30-39.9, and >= 40. Chi-square analysis was used to determine if the frequency of a hyperechoic outer medulla was significantly different between weight groups, sex, and age (P-value < 0.05). Of the 145 dogs that met the inclusion criteria, 45 had a hyperechoic outer medulla relative to the cortex and inner medulla. In the remaining dogs, the outer medulla was isoechoic to the cortex. Dogs less than 5 kg had the highest frequency of a hyperechoic outer medulla (P < 0.0001) and dogs greater than 40 kg did not have a hyperechoic outer medulla (P < 0.0001). Sex had no influence on the presence or absence of the hyperechoic outer medulla; however, younger dogs were overrepresented (6.4 +/- 0.6 years compared with 7.8 +/- 0.4 years; P = 0.04). Ultrasound descriptions of the canine kidney have not taken into account the contributions of the renal cortex and outer medulla. Based on this study of dogs with no clinically significant renal disease, the outer medulla can be isoechoic or hyperechoic to the cortex and a hyperechoic outer medulla is more commonly seen in small breed dogs. PMID- 23738848 TI - Arsenic-bearing calcite in natural travertines: evidence from sequential extraction, MUXAS, and MUXRF. AB - Recent studies demonstrated that synthetic calcite may host considerable amounts of arsenic (As). In this paper, the concentration of As in natural calcite was determined using two novel, specifically designed, sequential extraction procedures. In addition, the oxidation state of As and its distribution between calcite and coexisting Fe-oxyhydroxides was unravelled by MUXRF elemental mapping and As K-edge MUXAS spectroscopy. Our results conclusively demonstrate that arsenic can be found in natural calcite up to 2 orders of magnitude over the normal crustal As abundances. Because of the large diffusion of calcite in the environment, this phase may exert an important control on As geochemistry, mobility, and bioavailability. PMID- 23738849 TI - Phytotoxic allelochemicals from roots and root exudates of Trifolium pratense. AB - Trifolium pratense, a widespread legume forage plant, is reported to exhibit phytotoxic activity on other plants, but the active metabolites have not been clarified so far. A bioassay-guided fractionation of the root extracts led to the isolation of five isoflavonoids, which were elucidated by spectroscopic analysis. All of the purified compounds observably showed phytotoxic activities against Arabidopsis thaliana . Moreover, the inhibitory effects were concentration dependent. The furan ring linked at C-4 and C-2' positions by an oxygen atom and a 1,3-dioxolane at C-4' and C-5' positions are considered to be critical factors for the phytotoxic activity. The concentrations of (6aR,11aR)-maackiain and (6aR,11aR)-trifolirhizin, concluded to be allelochemicals from soil around plants of T. pratense, were determined by HPLC and LC-MS to be 4.12 and 2.37 MUg/g, respectively. These allelochemicals, which showed remarkable activities against the weed Poa annua may play an important role in assisting the widespread occurrence of T. pratense in nature. PMID- 23738850 TI - Evidence for xylooligosaccharide utilization in Weissella strains isolated from Indian fermented foods and vegetables. AB - Six strains isolated from fermented food were identified as Weissella species by 16S rDNA sequencing, clustering with the species pair W. confusa/W. cibaria. The strains were analysed for growth on glucose, xylose and xylooligosaccharides (XOS). All strains were xylose positive using the API CHL 50 test. Growth on XOS was observed for strains 85, 92, 145 and AV1, firstly by optical density measurements in microtitre plates and secondly in batch cultures also confirming concomitant decrease in pH. Analysis of XOS before and after growth established consumption in the DP2-DP5 range in the four XOS-fermenting strains. XOS were consumed simultaneously with glucose, while xylose was consumed after glucose depletion. Cell-associated beta-xylosidase activity was detected in the XOS fermenting strains. Analysis of genomic data suggests this activity to be linked with genes encoding glycoside hydrolases from family 3, 8 or 43. No endo-beta xylanase activity was detectable. Major end products were lactate and acetate. A higher ratio of acetic acid to lactic acid was obtained during growth on XOS compared with growth on glucose. This is the first report on utilization of XOS in Weissella, indicating an increased probiotic potential for XOS-utilizing strains from the species pair W. confusa/W. cibaria, but also showing that XOS utilization is strain dependent for these species. PMID- 23738851 TI - Control of ordering and structure in soft templated mesoporous carbon films by use of selective solvent additives. AB - The structure of ordered mesoporous carbons fabricated using poly(styrene-block N,N,-dimethyl-n-octadecylamine p-styrenesulfonate) (PS-b-PSS-DMODA) as the template and phenolic resin (resol) as the carbon source can be easily manipulated by inclusion of low concentrations of low volatility selective solvents in the casting solution. Casting from neat methyl ethyl ketone yields a disordered structure even upon thermal annealing. However, addition of both dioctyl phthalate (DOP, PS selective) and dimethyl sulfoxide (DMSO, resol and PSS DMODA selective) at modest concentrations to this casting solution provides sufficient mobility to produce highly ordered films with cylindrical mesopores. The DOP acts to swell the hydrophobic domain and can more than double the mesopore size, while the DMSO acts to swell the resol phase. Moreover, the surface area of the mesoporous carbons increases significantly as the meosopore size increases. This is a result of the decrease in wall thickness, which can be ascertained by the constant d-spacing of the mesostructure as the pore size increases. This behavior is counter to the typical effect of pore swelling agents that increase the pore size and decrease the surface area. Moreover, with only 4 wt % DOP/DMSO in the solution (20 wt % relative to solids), the scattering profiles exhibit many orders of diffraction, even upon carbonization, which is not typically observed for soft templated films. Variation in the concentration of DOP and DMSO during casting enables facile tuning of the structure of mesoporous carbon films. PMID- 23738852 TI - Different extraction pretreatments significantly change the flavonoid contents of Scutellaria baicalensis. AB - CONTEXT: Scutellaria baicalensis Georgi (Labiatae) is one of the most commonly used medicinal herbs, especially in traditional Chinese medicine. However, compared to many pharmacological studies of this botanical, much less attention has been paid to the quality control of the herb's pretreatment prior to extract preparation, an issue that may affect therapeutic outcomes. OBJECTIVE: The current study was designed to evaluate whether different pretreatment conditions change the contents of the four major flavonoids in the herb, i.e., two glycosides (baicalin and wogonoside) and two aglycones (baicalein and wogonin). MATERIALS AND METHODS: A high-performance liquid chromatography assay was used to quantify the contents of these four flavonoids. The composition changes of four flavonoids by different pretreatment conditions, including solvent, treatment time, temperature, pH value and herb/solvent ratio were evaluated. RESULTS: After selection of the first order time-curve kinetics, our data showed that at 50 degrees C, 1:5 herb/water (in w/v) ratio and pH 6.67 yielded an optimal conversion rate from flavonoid glycosides to their aglycones. In this optimized condition, the contents of baicalin and wogonoside were decreased to 1/70 and 1/13, while baicalein and wogonin were increased 3.5- and 3.1-fold, respectively, compared to untreated herb. DISCUSSION AND CONCLUSION: The markedly variable conversion rates by different pretreatment conditions complicated the quality control of this herb, mainly due to the high amount of endogenous enzymes of S. baicalensis. Optimal pretreatment conditions observed in this study could be used obtain the highest level of desired constituents to achieve better pharmacological effects. PMID- 23738853 TI - Parasitic infection may be associated with discordant responses to QuantiFERON and tuberculin skin test in apparently healthy children and adolescents in a tuberculosis endemic setting, Ethiopia. AB - BACKGROUND: M. tuberculosis remains one of the world's deadliest pathogens in part because of its ability to establish persistent, latent infections, which can later reactivate to cause disease. In regions of the globe where disease is endemic, as much as 50% of the population is thought to be latently infected, complicating diagnosis and tuberculosis control. The tools most commonly used for diagnosis of latent M. tuberculosis infection are the tuberculin skin test and the newer interferon-gamma release assays, both of which rely on an antigen specific memory response as an indicator of infection. It is clear that the two tests, do not always give concordant results, but the factors leading to this are only partially understood. METHODS: In this study we examined 245 healthy school children aged from 12 to 20 years from Addis Ababa, a tuberculosis-endemic region, characterised them with regard to response in the tuberculin skin test and QuantIFERONTM test and assessed factors that might contribute to discordant responses. RESULTS: Although concordance between the tests was generally fair (90% concordance), there was a subset of children who had a positive QuantIFERONTM result but a negative tuberculin skin test. After analysis of multiple parameters the data suggest that discordance was most strongly associated with the presence of parasites in the stool. CONCLUSIONS: Parasitic gut infections are frequent in most regions where M. tuberculosis is endemic. This study, while preliminary, suggests that the tuberculin skin test should be interpreted with caution where this may be the case. PMID- 23738854 TI - Treatment of refractory venous stasis ulcers with autologous platelet-rich plasma and light-emitting diodes: a pilot study. AB - BACKGROUND: Stasis dermatitis with secondary ulcer formation is not only therapeutically challenging but also significantly decreases the quality of life for affected individuals. Recently, autologous platelet-rich plasma (PRP) has entered the therapeutic regimen for leg ulcers, while light-emitting diodes (LEDs) are now used to accelerate wound healing. OBJECTIVE: To assess the efficacy and safety of autologous PRP with concomitant LED therapy for the treatment of venous stasis dermatitis with secondary ulceration. METHODS AND MATERIALS: In total, 16 Korean patients with ulcers secondary to venous stasis dermatitis were enrolled in this study. Each lesion was treated with autologous PRP weakly, and LED therapy three times per week. Treatments continued for 6 weeks or until the ulcer completely reepithelialized without evidence of drainage. Not only were subjects objectively evaluated by a study investigator, their own subjective satisfaction was also assessed. RESULTS: The combined autologous PRP and LED therapy was well tolerated and safe. A statistically significant improvement was observed post-therapeutically in the clinical parameters of pain, itching, heaviness, paresthesia, cramps, and leg swelling. There was also a significant decrease in ulcer size. None of the patients showed worsening of their venous stasis ulcer. Regarding subject satisfaction with the regimen, 75.0% of participants reported being 'satisfied or very satisfied' with their overall improvement after treatment. No significant adverse effects were observed. CONCLUSION: Combined autologous PRP and LED therapy is a promising conservative combination regimen for treating recalcitrant ulcerating stasis dermatitis. Additional studies comparing combined autologous PRP and LED therapy directly with autologous PRP or LED monotherapies are needed to confirm the results reported here. PMID- 23738855 TI - Prevalence of transfusion-acquired hepatitis C in an Australian bleeding disorders population. AB - In Australia prior to 1992, many patients with bleeding disorders were exposed to hepatitis C through blood products. However, the incidence, complications and response to treatment of chronic hepatitis C (CHC) in this population are poorly characterized. The aim of this study was to examine the prevalence of CHC and response to treatment in an Australian bleeding disorders population. Demographic data, virological data and liver disease status from these 700 patients with inherited bleeding disorders were analysed. Of these 700 patients, 424 (61%) had been tested for CHC infection and 219 (52%) were hepatitis C antibody positive, with the prevalence approaching 100% in patients with severe bleeding disorders. Of 219 patients, 73 (33%) had received treatment for their infection with a response rate of 33/73 (45%) across all genotypes. Of 219 patients, 34 (16%) had spontaneous viral clearance. When measured with transient elastography, 44/98 (45%) patients with CHC had significant liver fibrosis and 15/98 (15%) had liver cirrhosis. Of 130 patients, 38 (29%) with CHC infection had no evidence of follow up with an appropriate clinician in the past 2 years. This study demonstrates that testing for CHC in this population is incomplete and treatment rates are low. Given the substantial morbidity and mortality associated with CHC and new therapeutic options becoming available, it seems important to reengage patients to diagnose, offer treatment and monitor this infection. PMID- 23738856 TI - Multiple episodes of sodium depletion in the rat: a remodeling of the electrical properties of median preoptic nucleus neurons. AB - In rat brain, the detection and integration of chemosensory and neural signals are achieved, inter alia, by the median preoptic nucleus (MnPO) during a disturbance of the hydromineral balance. This is allowed through the presence of the sodium (Na(+) ) sensor neurons. Interestingly, enkephalins and mu-opioid receptors (MU-ORs) are known for their role in ingestive behaviors and have previously been shown to regulate the excitability of MnPO neurons following a single Na(+) depletion. However, little is known about the role of these MU-ORs in the response enhancement following repeated Na(+) challenge. Therefore, we used whole-cell recordings in acute brain slices to determine neuronal plasticity in the electrical properties of the MnPO Na(+) sensor-specific neuronal population following multiple Na(+) depletions. Our results show that the population of Na(+) sensor neurons was represented by 80% of MnPO neurons after a single Na(+) depletion and was reduced after three Na(+) depletions. Interestingly, the subpopulation of Na(+) sensors responding to D-Ala(2) ,N MePhe(4) ,Gly-ol-enkephalin (DAMGO), a specific MU-OR agonist, represented 11% of MnPO neurons after a single Na(+) depletion and the population doubled after three Na(+) depletions. Moreover, Na(+) sensor neurons displayed modifications in the discharge pattern distribution and shape of calcium action potentials after three Na(+) depletions but these changes did not occur in Na(+) sensors responding to DAMGO. Thus, the reinforced MU-OR functionality in Na(+) sensors might take place to control the neuronal hyperexcitability and this plasticity in opioid-sensitive and Na(+) detection MnPO networks might sustain the enhanced salt ingestion induced by repeated exposure to Na(+) depletion. PMID- 23738857 TI - Synthesis of cis-C-iodo-N-tosyl-aziridines using diiodomethyllithium: reaction optimization, product scope and stability, and a protocol for selection of stationary phase for chromatography. AB - The preparation of C-iodo-N-Ts-aziridines with excellent cis-diastereoselectivity has been achieved in high yields by the addition of diiodomethyllithium to N tosylimines and N-tosylimine-HSO2Tol adducts. This addition-cyclization protocol successfully provided a wide range of cis-iodoaziridines, including the first examples of alkyl-substituted iodoaziridines, with the reaction tolerating both aryl imines and alkyl imines. An ortho-chlorophenyl imine afforded a beta-amino gem-diiodide under the optimized reaction conditions due to a postulated coordinated intermediate preventing cyclization. An effective protocol to assess the stability of the sensitive iodoaziridine functional group to chromatography was also developed. As a result of the judicious choice of stationary phase, the iodoaziridines could be purified by column chromatography; the use of deactivated basic alumina (activity IV) afforded high yield and purity. Rearrangements of electron-rich aryl-iodoaziridines have been promoted, selectively affording either novel alpha-iodo-N-Ts-imines or alpha-iodo-aldehydes in high yield. PMID- 23738858 TI - Reduction of two red complex bacteria by sustained-release doxycycline and correlation to improvement in mean pocket depth. AB - OBJECTIVE: The objective was to evaluate the effects of an 8.5% sustained-release doxycycline-containing polymer formulation (SRDF) on deep pockets (pocket depth [PD] >= 7 mm) in chronic periodontitis. Total bacterial counts were used to estimate the number of viable bacteria present before treatment and for up to 6 months posttreatment. METHODS: All sites had PD >= 5 mm and bled on probing in 23 subjects who received treatment with SRDF. There was an average of 8.7 teeth or 23 sites for each subject. One deep pocket (>= 7 mm) in each subject was selected for monitoring. This site was sampled prior to treatment and at 7, 21, 91, and 182 days after SRDF placement. The primary endpoints were changes in the viable counts of two red complex species, Porphyromonas gingivalis and Tannerella forsythia. Secondary endpoints were changes in the number of total anaerobic bacteria recovered and changes in PD. RESULTS: Relative to baseline, SRDF reduced the proportions of P. gingivalis and T. forsythia by 88% and 99%, respectively, at day 7. At the conclusion of the monitoring period--182 days--P. gingivalis and T. forsythia were present but at 19% to 20% of the pretreatment values. Total anaerobic counts were reduced by 96% at day 7; by 87% at day 21; and by 75% and 68% at days 91 and 182, respectively. Mean PD for the sample sites (initially >= 7 mm) was reduced 2 mm by day 21, and this difference persisted throughout the study. CONCLUSIONS: This study demonstrates SRDF has a significant effect, not only statistically but also microbially and clinically, on deep periodontal sites in patients with chronic periodontitis. SRDF significantly reduced the number of red complex bacteria P. gingivalis and T. forsythia, as well as the number of total anaerobic bacteria. By day 21, PD was reduced by 2 mm, and this reduction was maintained for at least 6 months posttherapy. PMID- 23738859 TI - Smile restoration through use of enamel microabrasion associated with tooth bleaching. AB - Enamel microabrasion can eliminate enamel irregularities and discoloration defects, improving the appearance of teeth. This article presents the latest treatment protocol of enamel microabrasion to remove stains on the enamel surface. It has been verified that teeth submitted to microabrasion acquire a yellowish color because of the thinness of the remaining enamel, revealing the color of dentinal tissue to a greater degree. In these clinical conditions, correction of the color pattern of these teeth can be obtained with a considerable margin of clinical success using products containing carbamide peroxide in custom trays. Thus, patients can benefit from combined enamel microabrasion/tooth bleaching therapy, which yields attractive cosmetic results. Esthetics plays an important role in contemporary dentistry, especially because the media emphasizes beauty and health. Currently, in many countries, a smile is considered beautiful if it imitates a natural appearance, with clear, well aligned teeth and defined anatomical shapes. Enamel microabrasion is one technique that can be used to correct discolored enamel. This technique has been elucidated and strongly advocated by Croll and Cavanaugh since 1986, and by other investigators who suggested mechanical removal of enamel stains using acidic substances in conjunction with abrasive agents. Enamel microabrasion is indicated to remove intrinsic stains of any color and of hard texture, and is contraindicated for extrinsic stains, dentinal stains, for patients with deficient labial seals, and in cases where there is no possibility to place a rubber dam adequately during the microabrasion procedure. It should be emphasized that enamel microabrasion causes a microreduction on the enamel surface, and, in some cases, teeth submitted to microabrasion may appear a darker or yellowish color because the thin remaining enamel surface can reveal some of the dentinal tissue color. In these situations, according to Haywood and Heymann in 1989, correction of the color pattern of teeth can be obtained through the use of whitening products containing carbamide peroxide in custom trays. A considerable margin of clinical success has been shown when diligence to at-home protocols is achieved by the patient and supervised by the professional. Considering these possibilities, this article presents the microabrasion technique for removal of stains on dental enamel, followed by tooth bleaching with carbamide peroxide and composite resin restoration, if required. PMID- 23738860 TI - Evaluating extraction sockets in the esthetic zone for immediate implant placement. AB - With the increasing demands of patients and the profession to maximize esthetic outcomes and minimize the number of procedures, clinicians must consider the use of immediate placement of implants into extraction sockets. Despite atraumatic extraction techniques, many cases present with a non-intact extraction socket, with bone deficiency in the coronal or apical aspect of the socket. In cases of immediate placement, an intact socket and guided bone regeneration procedures are often prerequisites to a successful esthetic outcome. In most cases, these grafting techniques can be performed at the time of immediate placement. Certain cases, however, have undergone such extensive bone and soft-tissue destruction that implants cannot be placed immediately and hard- and/or soft-tissue augmentation is required prior to implant placement. This article describes a classification system that considers both hard- and soft-tissue defects and the morphology of the extraction socket for immediate implant placement. Recommendations are made concerning the surgical technique required to treat the hard- and soft-tissue defects based on the socket morphology. PMID- 23738861 TI - Dental root resorption: a review of the literature and a proposed new classification. AB - OBJECTIVE: This article reviews the dental literature pertaining to dental root resorption and proposes a classification system designed to facilitate communication of precise information for each type. DESIGN: A systematic review of the literature using PubMed was performed and supplemented with manual reviews of bibliographies from textbooks. RESULTS: A classification system was developed using etiology and morphologic characteristics of dental root resorption. Various types of dental root resorption were identified. The different forms were organized into dental and non-dental origins and further divided between internal and external resorption along etiologic and morphologic characteristics. CONCLUSIONS: The classification of dental root resorption proposed may assist dentists in the formulation of a differential diagnosis and management of root resorption. PMID- 23738862 TI - Changes in milk proteome and metabolome associated with dry period length, energy balance, and lactation stage in postparturient dairy cows. AB - The early lactation period of dairy cows, which produce high quantities of milk, is normally characterized by an insufficient energy intake to cover milk production and maintenance requirements. Mobilization of body reserves occurs to compensate this negative energy balance (NEB), and probably as a consequence there is a higher susceptibility to diseases and metabolic disorders. There are several diagnostic methods to detect NEB, usually involving ketosis related parameters. Due to the easy availability of milk this is a preferred matrix, but simple and robust predictors of NEB level are missing. To better understand the physiological mechanism of NEB, milk of cows subjected to different dry period lengths, in different energy balance status and lactation stage, were analyzed by untargeted metabolomics and proteomics techniques. Milk of cows in severe NEB showed higher concentrations of acute phase response proteins, unsaturated fatty acids, and galactose-1-phosphate. Improved energy balance (EB) resulted in higher concentration of cholesterol, cholesterol synthesis related proteins, and stomatin. The presence of stomatin and galactose-1-phosphate in milk was strongly dependent on the EB of the cows. These novel and interesting findings warrant more in-depth research to assess their applicability as robust indicators of NEB in milk and to clarify the role of stomatin and galactose-1-phophate in milk of dairy cows in NEB. PMID- 23738863 TI - Transcriptomic characterization of two major Fusarium resistance quantitative trait loci (QTLs), Fhb1 and Qfhs.ifa-5A, identifies novel candidate genes. AB - Fusarium head blight, caused by Fusarium graminearum, is a devastating disease of wheat. We developed near-isogenic lines (NILs) differing in the two strongest known F. graminearum resistance quantitative trait loci (QTLs), Qfhs.ndsu-3BS (also known as resistance gene Fhb1) and Qfhs.ifa-5A, which are located on the short arm of chromosome 3B and on chromosome 5A, respectively. These NILs showing different levels of resistance were used to identify transcripts that are changed significantly in a QTL-specific manner in response to the pathogen and between mock-inoculated samples. After inoculation with F. graminearum spores, 16 transcripts showed a significantly different response for Fhb1 and 352 for Qfhs.ifa-5A. Notably, we identified a lipid transfer protein which is constitutively at least 50-fold more abundant in plants carrying the resistant allele of Qfhs.ifa-5A. In addition to this candidate gene associated with Qfhs.ifa-5A, we identified a uridine diphosphate (UDP)-glycosyltransferase gene, designated TaUGT12887, exhibiting a positive difference in response to the pathogen in lines harbouring both QTLs relative to lines carrying only the Qfhs.ifa-5A resistance allele, suggesting Fhb1 dependence of this transcript. Yet, this dependence was observed only in the NIL with already higher basal resistance. The complete cDNA of TaUGT12887 was reconstituted from available wheat genomic sequences, and a synthetic recoded gene was expressed in a toxin sensitive strain of Saccharomyces cerevisiae. This gene conferred deoxynivalenol resistance, albeit much weaker than that observed with the previously characterized barley HvUGT13248. PMID- 23738865 TI - Toll-like receptor stimulation increases phagocytosis of Cryptococcus neoformans by microglial cells. AB - BACKGROUND: Toll-Like receptors (TLRs) belong to the family of pattern recognition receptors with a crucial function of recognising pathogen-associated molecular patterns (PAMPs). Cryptococcal meningitis is a potentially fatal disease with a high mortality and risk of neurological sequelae. METHODS: We studied the ability of microglial cells to increase the phagocytosis of cryptococci after stimulation with agonists of TLR1/2, TLR3, TLR4 and TLR9. RESULTS: Stimulation of murine microglial cells with these TLR agonists for 24 h increased the phagocytosis of encapsulated Cryptococcus neoformans. Stimulation increased the release of TNF-alpha, CXCL1 (KC), IL-6, IL-10 and MIP-2, which indicated the activation of microglial cells. Unstimulated and TLR agonist stimulated MyD88-deficient cells showed a reduced ability to phagocytose cryptococci compared to their wild-type counterpart. Intracellular killing of cryptococci was also increased in TLR-stimulated cells compared to unstimulated microglial cells. CONCLUSION: Our observation suggests that stimulation of microglial cells by TLR agonists can increase the resistance of the brain against CNS infections caused by Cryptococcus neoformans. This may be of interest when an immunocompromised patient is unable to eliminate Cryptococcus neoformans despite antifungal therapy. PMID- 23738866 TI - Accuracy of CT and MRI for contouring the feline optic apparatus for radiation therapy planning. AB - Consistency and accuracy in normal tissue contouring in radiotherapy planning is important for comparison of dosimetry and toxicity data between studies. The purpose of this study was to determine whether magnetic resonance imaging (MRI) improves the accuracy of optic apparatus contouring as compared with computed tomography (CT) in both normal and acromegalic cats, and to construct a reference contour of the feline optic apparatus. Both CT and MRI were performed on cadavers of four healthy cats, as well as on five radiotherapy patients with feline acromegaly. Contours of the optic apparatus were drawn for each imaging study. The volume, center of mass, and the degree of concordance and mismatch were determined for each, and compared with a reference standard. Precontrast CT was found to overestimate volume as compared with MRI in acromegalic cats; no other statistically significant differences were identified in the volume, concordance index or mismatch index values of normal or acromegalic cats. Contours derived from T2-wieghted MRI were subjectively considered to best match the reference standard. The caudal margin of the optic chiasm and the optic tracts were difficult to confidently contour regardless of which imaging modality and/or sequence was used. In conclusion, findings from the current study supported the use of a combination of CT and MR images and a priori knowledge of the shape of the optic apparatus to guide accurate contouring, especially where image contrast is not sufficient to clearly delineate the margins. Guidelines for feline optic apparatus contouring developed in this study can be used for future studies. PMID- 23738864 TI - UpSETing chromatin during non-coding RNA production. AB - The packaging of eukaryotic DNA into nucleosomal arrays permits cells to tightly regulate and fine-tune gene expression. The ordered disassembly and reassembly of these nucleosomes allows RNA polymerase II (RNAPII) conditional access to the underlying DNA sequences. Disruption of nucleosome reassembly following RNAPII passage results in spurious transcription initiation events, leading to the production of non-coding RNA (ncRNA). We review the molecular mechanisms involved in the suppression of these cryptic initiation events and discuss the role played by ncRNAs in regulating gene expression. PMID- 23738868 TI - Symmetry break of special pair: photochemically induced dynamic nuclear polarization NMR confirms control by nonaromatic substituents. AB - Despite the high structural symmetry of cofactor arrangement and protein environment, light-induced electron transfer in photosynthetic reaction centers (RCs) of the purple bacterium Rhodobacter sphaeroides runs selectively over one of the two branches of cofactors. The origin of this functional symmetry break has been debated for several decades. Recently, a crucial role of the substituents has been proposed by theoretical studies [Yamasaki, H.; Takano, Y.; Nakamura, H. J. Phys. Chem. B 2008, 112, 13923-13933]. Photo-CIDNP (photochemically induced dynamic nuclear polarization) MAS (magic angle spinning) NMR demonstrates that indeed the peripheral atoms show opposite electronic effects on both sides of the special pair. While the aromatic system of P(L) receives electron density from its periphery, the electron density of the aromatic ring of P(M) is decreased. PMID- 23738867 TI - Cysticlean(r) a highly pac standardized content in the prevention of recurrent urinary tract infections: an observational, prospective cohort study. AB - BACKGROUND: The present study was aimed at determining the prophylactic efficacy of American cranberry (AC) extract (Cysticlean(r)) in women with recurrent symptomatic postcoital urinary tract infections (PCUTI), non-consumer of AC extract in the past 3 months before inclusion, and to determine changes in their quality of life (QoL). METHODS: This was a single center, observational, prospective study in a total of 20 women (mean age 35.2 years; 50.0% were married). Patients were followed up for 3 and 6 months during treatment. RESULTS: The number of PCUTIs in the previous 3 months prior to start the treatment with Cysticlean(r) was 2.8+/-1.3 and it was reduced to 0.2+/-0.5 at Month 6 (P<0.0001), which represent a 93% improvement. At baseline, the mean score on the VAS scale (range from 0 to 100) for assessing the QoL was 62.4+/-19.1, increasing to 78.2+/-12.4 at Month 6 (P=0.0002), which represents a 20% improvement. All patients had an infection with positive urine culture at baseline, after 6 months there were only 3 symptomatic infections (P<0.001). The most common bacterium was Escherichia coli. CONCLUSIONS: Prophylaxis with American cranberry extract (Cysticlean(r)) could be an alternative to classical therapies with antibiotics. Further studies are needed to confirm results obtained in this pilot study. PMID- 23738869 TI - Empirical examination of the potential adverse psychological effects associated with pediatric FMRI scanning. AB - BACKGROUND: Over the past decade, the number of functional magnetic resonance imaging (fMRI) studies has increased dramatically. As MRI scans may be anxiety provoking, performing them in a research setting, particularly with children already prone to anxiety, raises questions about ethics as well as methodological feasibility. It is essential to address these questions before expanding the use of this technique to clinical settings, or more widely in the context of pediatric psychopharmacology and biological psychiatry research. The current study investigates the psychological reactions of anxious and non-anxious children and non-anxious adults to an fMRI scan. METHODS: Eighty-seven anxious children, 140 non-anxious children, and 98 non-anxious adults rated their emotional reactions to an fMRI scan. RESULTS: Results indicated that anxious and non-anxious children reported no greater anxiety after fMRI scanning than did adults. In addition, no age-related differences in distress were observed. These data demonstrate that anxious children, healthy children, and healthy adults have similar emotional reactions to fMRI scanning. CONCLUSIONS: The observed findings suggest that the potential for fMRI to produce anxiety should not impede its widespread use in clinical research, psychopharmacology, and biological psychiatry. PMID- 23738870 TI - Priapism associated with risperidone in a 21-year-old male with autism. PMID- 23738871 TI - Pressure induced structure formation in Langmuir monolayers of amphiphilic metallocene diblock copolymers. AB - We present in situ structural investigations of a metal-containing diblock copolymer on a water surface. Monolayers of poly(vinylferrocene-b-(2 vinylpyridine)) (PVFc-b-P2VP) block copolymers are studied in a wide range of compositions by varying molar masses of P2VP with two different molecular weights of PVFc. We focus on the role of the respective block partners, PVFc and P2VP, when compressing the layer on the water surface. Compression isotherms are presented and interpreted in terms of the classical gaseous, expanded, and condensed phases. We calculate isothermal compressibilities, which reveal a minimum value independent of the molar masses of the respective block partners. We find the isotherms to be dominated by P2VP while PVFc barely contribute to the compression behavior due to its rather compact coil structure. We consider the diblock copolymer monolayers as a two-dimensional model system, which is reflected by two-dimensional scaling behavior in the semi dilute and condensed regime. By X-ray reflectometry (XR), we monitor in situ the monolayer structure change with increasing surface pressure Pi and observe the PVFc-b-P2VP separation at high Pi. PMID- 23738872 TI - Deep brain stimulation in cerebral palsy: an opportunity for collaborative research. PMID- 23738873 TI - StAMPP: an R package for calculation of genetic differentiation and structure of mixed-ploidy level populations. AB - Statistical Analysis of Mixed-Ploidy Populations (StAMPP) is a freely available R package for calculation of population structure and differentiation based on single nucleotide polymorphism (SNP) genotype data from populations of any ploidy level, and/or mixed-ploidy levels. StAMPP provides an advance on previous similar software packages, due to an ability to calculate pairwise FST values along with confidence intervals, Nei's genetic distance and genomic relationship matrixes from data sets of mixed-ploidy level. The software code is designed to efficiently handle analysis of large genotypic data sets that are typically generated by high-throughput genotyping platforms. Population differentiation studies using StAMPP are broadly applicable to studies of molecular ecology and conservation genetics, as well as animal and plant breeding. PMID- 23738874 TI - Ethical, scientific and practical standards in clinical practice research. PMID- 23738875 TI - Resistance through a different prism. PMID- 23738876 TI - Biosecurity at equestrian competitions: Olympic legacy? PMID- 23738877 TI - Science in brief: resolving tendon inflammation. A new perspective. PMID- 23738878 TI - Science in brief: the likely role of the central nervous system in bilateral tendinopathy and tendon healing. PMID- 23738879 TI - Cat scratch-induced Pasteurella multocida necrotizing cellulitis in a dog. AB - BACKGROUND: In humans, rapidly developing Pasteurella multocida cellulitis after a cat scratch or bite is a well-known entity that sometimes progresses to necrotizing fasciitis and can be fatal. CASE REPORT: A 3-year-old female spayed whippet dog developed ecchymosis, swelling and pain within 24 h of being scratched by a cat on the ventral thorax. Over the following days, while being treated only with pain medications, the lesions rapidly progressed into haemorrhagic bullae with expanding skin necrosis. A heavy growth of P. multocida was seen on bacterial cultures, and histological examination showed marked, suppurative panniculitis with necrosis of the epidermis, dermis and panniculus. Special histological stains highlighted a moderate amount of Gram-negative coccobacilli admixed with inflammatory cells. Complete resolution was achieved with surgical debridement, skin grafting and intravenous antibiotic treatment. Positive bacterial culture for P. multocida, in conjunction with the history, clinical findings, histology results and the rapid response to therapy, strongly supports a diagnosis of P. multocida necrotizing cellulitis. CONCLUSIONS AND CLINICAL IMPORTANCE: Complications of cat bite-associated P. multocida infections in humans are well known. To the authors' knowledge, this is the first documentation of P. multocida necrotizing cellulitis in a dog following a cat scratch wound. This case highlights the rapidity and severity of P. multocida cellulitis, if not recognized and treated early. Veterinarians should include P. multocida in the differential diagnosis of any local wound infection following a cat scratch. PMID- 23738880 TI - Non-Robertsonian translocation t (2;11) is associated with infertility in an oligospermic man. AB - Infertility is a major health problem which affects approximately 22% of married couples in reproductive age. Chromosomal defects are the most common genetic abnormalities in infertile men, with an incidence of cytogenetic abnormalities ranging from 2.1% to 15.5%. We describe here the clinical and cytogenetic studies carried out in a couple with repeated abortions. Cytogenetic analysis of the couple showed a de novo chromosomal translocation t (2;11)(p14;q21) in the male partner and a normal 46, XX karyotype in the female counterpart. Such an autosomal translocation may lead to the disruption of genes responsible for spermatogenesis or impaired synaptic complex pairing during meiosis resulting in reproductive failure. PMID- 23738881 TI - Postgraduate internal medicine residents' roles at patient discharge - do their perceived roles and perceptions by other health care providers correlate? AB - Knowing one's own role is a key collaboration competency for postgraduate trainees in the Canadian competency framework (CanMEDS(r)). To explore methods to teach collaborative competency to internal medicine postgraduate trainees, baseline role knowledge of the trainees was explored. The perceptions of roles (self and others) at patient discharge from an acute care internal medicine teaching unit amongst 69 participants, 34 physicians (25 internal medicine postgraduate trainees and 9 faculty physicians) and 35 health care professionals from different professions were assessed using an adapted previously validated survey (Jenkins et al., 2001). Internal medicine postgraduate trainees agreed on 8/13 (62%) discharge roles, but for 5/13 (38%), there was a substantial disagreement. Other professions had similar lack of clarity about the postgraduate internal medicine residents' roles at discharge. The lack of interprofessional and intraprofessional clarity about roles needs to be explored to develop methods to enhance collaborative competence in internal medicine postgraduate trainees. PMID- 23738883 TI - Measuring neural representations with fMRI: practices and pitfalls. AB - Recently, there has been a dramatic increase in the number of functional magnetic resonance imaging studies seeking to answer questions about how the brain represents information. Representational questions are of particular importance in connecting neuroscientific and cognitive levels of analysis because it is at the representational level that many formal models of cognition make distinct predictions. This review discusses techniques for univariate, adaptation, and multivoxel analysis, and how they have been used to answer questions about content specificity in different regions of the brain, how this content is organized, and how representations are shaped by and contribute to cognitive processes. Each of the analysis techniques makes different assumptions about the underlying neural code and thus differ in how they can be applied to specific questions. We also discuss the many pitfalls of representational analysis, from the flexibility in data analysis pipelines to emergent nonrepresentational relationships that can arise between stimuli in a task. PMID- 23738882 TI - Gossypetin, a naturally occurring hexahydroxy flavone, ameliorates gamma radiation-mediated DNA damage. AB - PURPOSE: To evaluate the protective effect of gossypetin (GTIN) against gamma (gamma)-radiation-mediated DNA damage. MATERIALS AND METHODS: Increasing concentrations (10-150 MUM) of GTIN were incubated with supercoiled DNA 1 h prior exposure to gamma-radiation in the range of 5-Gy absorbed dose from Co(60) gamma source. To establish the effective protective concentration of GTIN, supercoiled DNA was pre-incubated with 50 MUM of GTIN for 1 h followed by exposure of 5, 10 and 20 Gy doses of gamma-radiation. Moreover, 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical, hydroxyl radical, nitric oxide (NO) scavenging, metal chelating activity and ferric reducing antioxidant power (FRAP) of GTIN were measured and compared with standards. The flowcytometric analysis and radiation-induced genomic DNA damage by comet assay were employed to estimate the level of intracellular reactive oxygen species (ROS) using isolated murine hepatocytes. RESULTS: GTIN was able to effectively scavenge different free radicals in in vitro situations. It could significantly prevent radiation induced supercoiled and genomic DNA damage with reduced comet parameters. It also acted as a potent scavenger of the radiation induced ROS. CONCLUSIONS: GTIN ameliorated radiation induced oxidative stress and DNA damage by its free-radical scavenging activity. PMID- 23738884 TI - Methods for thermal stability enhancement of leaf essential oils and their main constituents from indigenous cinnamon (Cinnamomum osmophloeum). AB - The thermal stability of leaf essential oils from various Cinnamomum osmophloeum and their constituents was investigated for the first time. The results indicated that trans-cinnamaldehyde (Cin) content in eugenol-free essential oil from C. osmophloeum was affected by high temperatures. The retention of Cin (RC) decreased to 17.4% after the essential oil was incubated for 8 h at 100 degrees C. In contrast, essential oils containing eugenol showed greater thermal stability. Seven kinds of antioxidants were added to Cin to improve its thermal stability. Among them, eugenol endowed Cin with the best thermal stability. We also investigated the influence of various amounts of eugenol on the thermal stability of both essential oil and Cin. Both essential oil and Cin showed excellent thermal stability when 0.62 and 2.60% (v/v) eugenol were added. In short, the thermal stability of essential oil and Cin could be effectively improved by adding appropriate amounts of eugenol. PMID- 23738885 TI - Langevin equation path integral ground state. AB - We propose a Langevin equation path integral ground state (LePIGS) approach for the calculation of ground state (zero temperature) properties of molecular systems. The approach is based on a modification of the finite temperature path integral Langevin equation (PILE) method (J. Chem. Phys. 2010, 133, 124104) to the case of open Feynman paths. Such open paths are necessary for a ground state formulation. We illustrate the applicability of the method using model systems and the weakly bound water-parahydrogen dimer. We show that the method can lead to converged zero point energies and structural properties. PMID- 23738886 TI - Child desire in women and men living with HIV attending HIV outpatient clinics: evidence from a European multicentre study. AB - OBJECTIVES: Fertility-related decisions are challenging for women and couples living with HIV, in spite of vertical HIV transmission rates lower than 1% under effective antiretroviral treatment. This multicentre study identified factors influencing child desire of women and men living with HIV in Europe. METHODS: We gathered quantitative data by means of anonymous, self-administered questionnaires distributed through a network of 13 European HIV treatment centres. Data analysis employed descriptive statistics and multivariate logistic regression. RESULTS: The majority of 427 heterosexual HIV-positive study participants were sexually active. Forty-three percent reported a child desire, 28% had unmet family planning needs. Factors independently associated with child desire were: being younger than 36 years for both genders, and having no children for women. Perceived HIV-related discrimination by health care providers was associated negatively with child desire for women, but positively for men. CONCLUSIONS: Many women and men living with HIV in Europe desire children and have fertility intentions, for which they need unbiased support to conceive and deliver safely. Comprehensive and gender-specific sexual and reproductive health counselling, including pre-conception and contraceptive counselling, should be integrated into HIV care delivery. PMID- 23738887 TI - In vitro toxicity assessment of silver nanoparticles in the presence of phenolic compounds--preventive agents against the harmful effect? AB - The increasing commercial use of silver nanoparticles (Ag-NPs) will inevitably lead to elevated silver exposure and thus to potential human health complications. In this study the acute toxicity of Ag-NPs <20 nm alone and upon co-administration with food matrix component phenolic compounds (PCs) on the cell based models of the gastrointestinal tract was investigated. An improved co culture model of Caco-2 and RajiB cells was applied for more precise in vitro simulation of the gastrointestinal tract. The involvement of two major factors contributing to the toxicity of Ag-NPs, i.e. the release of Ag(+) and the induction of oxidative stress, was investigated. Ag-NPs were cytotoxic for Caco-2 cells with an EC50 of ca. 40 ug/ml. Ag-NPs led to oxidative stress starting from ca. 45 ug/ml. The epithelial barrier integrity disruption by Ag-NPs on Caco-2 cell mono- and co-cultures was established by decreased transepithelial electrical resistances and increased passages of Lucifer Yellow, a paracellular marker. Immunofluorescence staining demonstrated that Ag-NPs affect occludin and zonula occludens 1 distributions, suggesting the opening of tight junctions. Ag(+), corresponding to the release from Ag-NPs, demonstrated a partial contribution in the toxic parameters, induced by Ag-NPs. Two PCs, quercetin and kaempferol, partially protected the Caco-2 cells from Ag-NP-induced toxicity and maintained the epithelial barrier integrity, disrupted by NPs. No protective effect was observed for resveratrol. The protective effect could be beneficial and decrease the potential toxicity of ingested Ag-NPs. However, the precise mechanisms of barrier-integrity-destabilising action of Ag-NPs/Ag(+) and protective effect of PCs still require further elucidation. PMID- 23738888 TI - A Phase II clinical trial of a mixture of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors: haemostatic efficacy, safety and pharmacokinetics/pharmacodynamics. AB - MC710, a mixture of plasma-derived activated factor VII and factor X at a protein weight ratio of 1:10, is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. In a Phase II trial, we evaluated the haemostatic efficacy and safety of single doses of MC710, and investigated pharmacokinetic and pharmacodynamic parameters in nine joint bleeding episodes in six male haemophilia patients with inhibitors. This trial was a multi-centre, open-label, non-randomized study of two doses (60 and 120 MUg kg(-1) as FVIIa dose), allowing the re-administration of different MC710 dosages to the same subjects. Haemostatic efficacy was assessed by evaluating reduction in pain and swelling, as well as increase in range of motion in a bleeding joint. The results of the study showed that in nine bleeding episodes, seven treatments were rated as 'excellent' or 'effective' according to investigator's rating system of efficacy at 8 h after administration. No serious or severe adverse events were observed after administration; furthermore, measurement of several diagnostic markers revealed no signs or symptoms of disseminated intravascular coagulation (DIC). The haemostatic potential of MC710 was confirmed at doses of 60 and 120 MUg kg( 1) in this trial. MC710 is thus expected to be a safe and efficacious novel bypassing agent for controlling bleeding in haemophilia patients with inhibitors. PMID- 23738889 TI - NK cells improve control of friend virus infection in mice persistently infected with murine cytomegalovirus. AB - BACKGROUND: Co-infection of HIV patients with cytomegalovirus (CMV) is associated with enhanced AIDS progression and CMV end-organ diseases. On the other hand, persistent CMV infection has recently been shown to decrease tumor relapse and protect against lethal bacterial infection. The influence of persistent CMV on the outcome of an acute retroviral superinfection is still unknown. RESULTS: Here we show that a persistent murine CMV (mCMV) infection surprisingly confers higher resistance to a primary Friend retrovirus infection (FV) of mice. Decreased FV titers and augmented FV-specific CD8 T-cell responses were found in mCMV infected mice during primary FV superinfection. NK cells produced higher amounts of IFNgamma after FV infection of persistently mCMV infected mice suggesting that these cells were involved in the 'protective' effect. Depletion of NK1.1+ cells or neutralization of IFNgamma during FV superinfection abrogated the mCMV mediated effect. CONCLUSION: Our data demonstrate for the first time that a persistent CMV infection induces long-lasting NK cell responses that can enhance immunity to primary retroviral infections. To our knowledge, studies investigating primary HIV infection have not analyzed the role of the CMV seropositivity in these patients. Our observations suggest that NK cells in CMV seropositive individuals might contribute to the control of primary HIV infection. PMID- 23738890 TI - Acute osteomyelitis of the humerus mimicking malignancy: Streptococcus pneumoniae as exceptional pathogen in an immunocompetent adult. AB - BACKGROUND: Chronic osteomyelitis due to direct bone trauma or vascular insufficiency is a frequent problem in orthopaedic surgery. In contrast, acute haematogenous osteomyelitis represents a rare entity that almost exclusively affects prepubescent children or immunodeficient adults. CASE PRESENTATION: In this article, we report the case of acute pneumococcal osteomyelitis of the humerus in an immunocompetent and otherwise healthy 44-year-old male patient presenting with minor inflammation signs and misleading clinical features. CONCLUSIONS: The diagnosis had to be confirmed by open biopsy which allowed the initiation of a targeted therapy. A case of pneumococcal osteomyelitis of a long bone, lacking predisposing factors or trauma, is unique in adults and has not been reported previously. PMID- 23738892 TI - CO2 mitigation potential of mineral carbonation with industrial alkalinity sources in the United States. AB - The availability of industrial alkalinity sources is investigated to determine their potential for the simultaneous capture and sequestration of CO2 from point source emissions in the United States. Industrial alkalinity sources investigated include fly ash, cement kiln dust, and iron and steel slag. Their feasibility for mineral carbonation is determined by their relative abundance for CO2 reactivity and their proximity to point-source CO2 emissions. In addition, the available aggregate markets are investigated as possible sinks for mineral carbonation products. We show that in the U.S., industrial alkaline byproducts have the potential to mitigate approximately 7.6 Mt CO2/yr, of which 7.0 Mt CO2/yr are CO2 captured through mineral carbonation and 0.6 Mt CO2/yr are CO2 emissions avoided through reuse as synthetic aggregate (replacing sand and gravel). The emission reductions represent a small share (i.e., 0.1%) of total U.S. CO2 emissions; however, industrial byproducts may represent comparatively low-cost methods for the advancement of mineral carbonation technologies, which may be extended to more abundant yet expensive natural alkalinity sources. PMID- 23738891 TI - Proteasome dysfunction in Drosophila signals to an Nrf2-dependent regulatory circuit aiming to restore proteostasis and prevent premature aging. AB - The ubiquitin-proteasome system is central to the regulation of cellular proteostasis. Nevertheless, the impact of in vivo proteasome dysfunction on the proteostasis networks and the aging processes remains poorly understood. We found that RNAi-mediated knockdown of 20S proteasome subunits in Drosophila melanogaster resulted in larval lethality. We therefore studied the molecular effects of proteasome dysfunction in adult flies by developing a model of dose dependent pharmacological proteasome inhibition. Impaired proteasome function promoted several 'old-age' phenotypes and markedly reduced flies' lifespan. In young somatic tissues and in gonads of all ages, loss of proteasome activity induced higher expression levels and assembly rates of proteasome subunits. Proteasome dysfunction was signaled to the proteostasis network by reactive oxygen species that originated from malfunctioning mitochondria and triggered an Nrf2-dependent upregulation of the proteasome subunits. RNAi-mediated Nrf2 knockdown reduced proteasome activities, flies' resistance to stress, as well as longevity. Conversely, inducible activation of Nrf2 in transgenic flies upregulated basal proteasome expression and activity independently of age and conferred resistance to proteotoxic stress. Interestingly, prolonged Nrf2 overexpression reduced longevity, indicating that excessive activation of the proteostasis pathways can be detrimental. Our in vivo studies add new knowledge on the proteotoxic stress-related regulation of the proteostasis networks in higher metazoans. Proteasome dysfunction triggers the activation of an Nrf2 dependent tissue- and age-specific regulatory circuit aiming to adjust the cellular proteasome activity according to temporal and/or spatial proteolytic demands. Prolonged deregulation of this proteostasis circuit accelerates aging. PMID- 23738893 TI - Adverse effects associated with the clinical use of 4% TiF4 on teeth enamel: case report. AB - Titanium tetrafluoride (TiF4) has been studied in dentistry as a promissory alternative for prevention and treatment of carious lesions. However, there are few in vivo studies concerning the consequences of its use on tooth enamel. The goal of this study was to report the effects of a 4% TiF4 application on the remineralization of an incipient carious lesion of a permanent tooth. This research found an unexpected clinical outcome. A patient with active white spots had two of these lesions treated with 4% TiF4 associated with fluoridated dentifrice and another lesion treated with fluoridated dentifrice only, thus the remineralization of the two kinds of treatment administered could be observed and compared. An extrinsic pigment appeared in the regions that received the TiF4 treatment, which was partially removed by professional prophylaxis. Also, regular recidivists of this pigmentation in the review consultations were noted. The authors concluded that although the use of 4% TiF4 was effective in treating incipient carious lesions on enamel, it was also responsible for an undesired pigmented layer on the tooth to which it was applied. Beyond the varied fluoridated materials used in dentistry, titanium tetrafluoride (TiF4) deserves attention. This compound has the common properties of fluorides, and researchers are exploring its role in carious lesion prevention, fissure sealing, and tooth erosion prevention in in vitro and in situ studies. Research is also exploring its use for microinfiltration prevention in tooth restoration and hypersensitivity treatment. However, when compared to other fluoridated products TiF4 demonstrates additional, specific particularities, such as the formation of a titanium dioxide (TiO2) layer, which is tough, hydrophobic, and resistant in acidic environments. Nevertheless, there are insufficient in vivo studies concerning the consequences of TiF4-containing products affecting tooth enamel. Thus, the goals of this study were to report the effects of a 4% TiF4 application on the remineralization of an incipient carious lesion of a permanent tooth and to show the results of a backscattered scanning electron (BSE) analysis that was performed on the primary tooth. The clinical outcome was unexpected. PMID- 23738894 TI - Plaque formation and marginal gingivitis associated with restorative materials. AB - The presence of restorative materials on tooth surfaces is perceived to be a contributing factor to periodontal disease. This observation is a result of the increased accumulation of plaque on restorations adjacent to the gingiva, which may lead to gingivitis. Plaque is believed to adhere better to restorations than to enamel. This may be due to the surface characteristics of restorative materials such as surface roughness and surface-free energy inherent in the materials. This article reviews the experimental studies of plaque formation on different restorative materials. In addition, clinical studies analyzing and comparing restorative materials and the consequent formation of gingivitis are reviewed. While in vitro and in vivo studies show variations in plaque formation among restorative materials and enamel, clinical studies demonstrate that the progression of gingivitis can be prevented if patients maintain adequate oral hygiene and home care. Therefore, instructing the patient to maintain proper oral hygiene and home care is more important than the choice of restorative material. PMID- 23738895 TI - Is gingival recession a consequence of an orthodontic tooth size and/or tooth position discrepancy? "A paradigm shift". AB - BACKGROUND: Gingival recession (GR) is a commonly observed dental lesion. The underlying etiology has not been clearly identified, although several theories have been suggested. Tooth crowding or tooth malalignment is also frequently observed, with both conditions appearing to be more prevalent in developed countries with heterogeneous populations. MATERIALS AND METHODS: A total of 25 consecutively treated patients representing 72 teeth and demonstrating facial clinical GR of > 3 mm were examined clinically, photographically, and with 3 dimensional radiology using cone-beam computed tomography. All examined teeth presented with normal interproximal probing depths and attachment levels (less than 4 mm). Tooth position or tooth volume plus the associated adjacent alveolar bone volume and GR were analyzed. This group was further evaluated during periodontal surgery for associated alveolar bone fenestrations or dehiscences. RESULTS: All teeth demonstrating > 3 mm of GR presented with significantly prominent facial tooth contours and associated alveolar bone dehiscences. Most involved teeth presented with their root structures extending beyond the facial alveolar bony housing (fenestrations). This represents a discrepancy between tooth size and alveolar bone dimensions in the buccolingual, axial, and sagittal orientation. Fewer involved teeth were malpositioned toward the buccal aspect. Both conditions were associated with facial alveolar bone dehiscences and associated GR. CONCLUSIONS: This study suggests tooth volume and/or tooth position within the alveolar bony housing strongly correlate with GR. All nonperiodontitis-involved teeth with GR were associated with either wider teeth or facially aligned teeth. However, it is emphasized that all facially aligned teeth, or "larger" teeth, do not necessarily present with GR. Based on these findings, the radiographic-supporting bone index is proposed. This index should facilitate appropriate evaluation of the alveolar bone supporting the mucogingival complex, both on the facial and lingual aspect of teeth. Further investigations are needed to support these preliminary data. PMID- 23738896 TI - Imaging diagnosis: cranial cervical intraspinal schwannoma in a dog. AB - A 3-year-old, intact female Golden Retriever was presented with acute tetraplegia. Neurologic examination was consistent with a C1-C5 myelopathy. On magnetic resonance (MR) imaging a well-defined, extradural mass was detected within the spinal canal at the level of C1-C2. The mass was isointense to normal spinal cord gray matter on T1-weighted (T1W) images, hyperintense on T2-weighted (T2W), and gradient-echo (GE) images, and enhanced homogeneously after intravenous contrast administration. MR imaging features were mainly consistent with a meningioma. Surgical treatment was refused by the owners, and the dog was euthanized. Postmortem examination demonstrated that the intraspinal mass was a schwannoma. PMID- 23738897 TI - Molecular simulations illuminate the role of regulatory components of the RNA polymerase from the hepatitis C virus in influencing protein structure and dynamics. AB - The RNA polymerase (gene product NS5B) from the hepatitis C virus is responsible for replication of the viral genome and is a validated drug target for new therapeutic agents. NS5B has a structure resembling an open right hand (containing the fingers, palm, and thumb subdomains), a hydrophobic C-terminal region, and two magnesium ions coordinated in the palm domain. Biochemical data suggest that the magnesium ions provide structural stability and are directly involved in catalysis, while the C-terminus plays a regulatory role in NS5B function. Nevertheless, the molecular mechanisms by which these two features regulate polymerase activity remain unclear. To answer this question, we performed molecular dynamics simulations of NS5B variants with different C terminal lengths in the presence or absence of magnesium ions to determine the impact on enzyme properties. We observed that metal binding increases both the magnitude and the degree of correlated enzyme motions. In contrast, we observed that the C-terminus restricts enzyme dynamics. Under certain conditions, our simulations revealed a fully closed conformation of NS5B that may facilitate de novo initiation of RNA replication. This knowledge is important because it fosters the development of a comprehensive description of RNA replication by NS5B and is relevant to understanding the functional properties of a broad class of related RNA polymerases such as 3D-pol from poliovirus. Ultimately, this information may also be pertinent to designing novel NS5B therapeutics. PMID- 23738898 TI - A thioannulation approach to substituted thiophenes from Morita-Baylis-Hillman acetates of acetylenic aldehydes. AB - A new protocol has been developed for the synthesis of substituted thiophenes under mild and metal-free reaction conditions via the base-promoted thioannulation of Morita-Baylis-Hillman acetates of acetylenic aldehydes with potassium thioacetate involving a tandem allylic substitution/deacetylative 5-exo dig-thiocycloisomerization. The obtained products provide an entry to 4H thieno[3,2-c]chromene and thieno[3,2-c]dihydroquinoline. PMID- 23738899 TI - Relapsed angioimmunoblastic T-cell lymphoma with acquired expression of CD20: a case report and review of the literature. AB - BACKGROUND: Angioimmunoblastic T-cell lymphoma is one of the most common types of peripheral T-cell lymphomas, usually presenting at an older age with an aggressive clinical course. Its characteristic morphological presentation and follicular helper T-cell phenotype help to distinguish it from other T-cell lymphomas. CASE PRESENTATION: We recently encountered the unique case of a 63 year old patient with relapsed tumour-cell rich angioimmunoblastic T-cell lymphoma, presenting with a "classical" phenotype and, in addition, an acquired, strong, aberrant expression of CD20."Lineage infidelity" of phenotypic markers is a well-documented phenomenon in lymphomas and leukemias, a circumstance currently still poorly understood and with the potential to bring about erroneous interpretations, causing diagnostic havoc. This case represents one of the few documented angioimmunoblastic T-cell lymphomas with strong CD20 expression. Of interest, CD20 expression was only detected in the recurrent lymphoma and not upon initial diagnosis. The clinical importance of this finding lies in the potential for treatment with an anti-CD20 antibody, for instance Rituximab, in addition to standard chemotherapy protocols for angioimmunoblastic T-cell lymphoma. CONCLUSION: Diagnostic work-up of lymphomas to determine their lineage should therefore consider morphology, pheno- as well as genotypic characteristics, where appropriate, and in particular signs of progression and change in marker profile in relapsed cases e.g. acquisition of "non-lineage" markers such as CD20 in T-cell lymphoma. PMID- 23738900 TI - Surface-induced diastereomeric complex formation of a nucleoside at the liquid/solid interface: stereoselective recognition and preferential adsorption. AB - With the aim of achieving surface-mediated enantioselective adsorption, the self assembly of chiral oligo(p-phenylenevinylene) (OPV3T) with nucleosides is investigated at the liquid/solid interface by means of scanning tunneling microscopy and molecular modeling. OPV3T enantiomers form mirror related hexameric rosette patterns. The DNA nucleoside, thymidine, does not self-assemble into stable adlayers but coadsorbs with OPV3T on the surface, leading to a pattern transformation of OPV3T from rosettes to dimers, and a change in chiral expression as well. Diastereoselective recognition between OPV3T and thymidine enantiomers can be used to resolve thymidine enantiomers at an achiral surface with an OPV3T enantiomer as the resolving agent. The impact of molar ratio and concentration on the self-assembly and chiral resolution is systematically investigated. Because there is no interaction between OPV3T and thymidine in solution, the liquid/solid interface acts as the platform for the chiral resolution of thymidine enantiomers. PMID- 23738901 TI - Screening of feature genes of the ovarian cancer epithelia with DNA microarray. AB - OBJECTIVE: We aimed to screen differentially expressed genes (DEGs) of ovarian surface epithelia in order to provide beneficial help for early diagnosis and treatment of ovarian cancer with DNA microarrays. METHODS: We extracted the microarray expression profile GSE14407 from Gene Expression Omnibus database which conducted gene expression profiling analysis of 12 ovarian surface epithelia (OSE) and 12 laser capture microdissected serous ovarian cancer epithelia (CEPI) samples. The DEGs between OSE and CEPI were identified by Limma package of R language. Cluster analysis was employed to compare the differences of gene expression patterns between OSE and CEPI. Furthermore, DEGs were analyzed with Functional classification tool, GenMAPP software and GENECODIS. RESULTS: We identified 1229 DEGs including 592 down-regulated genes and 637 up-regulated genes. Pathway analysis showed that cell cycle was the most significant pathway and the DEGs related with cell cycle were almost up-regulated. Module mining analysis showed that the up-regulated DEGs were related with signal transduction while the down-regulated DEGs were related with lipid metabolism pathway and cytoskeletal structure. CONCLUSION: The genes related with cell cycle, lipid metabolism and cytoskeletal structure may be the treatment targets for ovarian cancer. PMID- 23738902 TI - Three-dimensional nanolithography using light scattering from colloidal particles. AB - The interaction between light and colloidal elements can result in a wealth of interesting near-field optical patterns. By examining the optical and colloidal properties, the intensity distribution can be tailored and harnessed for three dimensional nanolithography. Here, we examine the use of light scattering from colloidal particles to fabricate complex hollow nanostructures. In this approach, a single colloidal sphere is illuminated to create a scattering pattern, which is captured by a photoresist in close proximity. No external optical elements are required, and the colloidal elements alone provide the modulation of the optical intensity pattern. The fabricated nanostructures can be designed to have multiple shells, confined volumes, and single top openings, resembling "nano-volcanoes." The geometry of such structures is dependent on the scattered light distribution and can be accurately modeled by examining the light-particle interaction. The hollow nanostructures can be used to trap nanomaterial, and we demonstrate their ability to trap 50 nm silica nanoparticles. These well-defined surface hollow structures can be further functionalized for applications in controlled drug delivery and biotrapping. Colloidal elements with different geometries and material compositions can also be incorporated to examine other light-colloid interactions. PMID- 23738903 TI - Surgical intervention for feeding and nutrition difficulties in cerebral palsy: a systematic review. AB - AIM: The aim of the study was to systematically review surgical intervention for feeding difficulties in cerebral palsy. METHOD: We searched databases including MEDLINE from 1980 to July 2012. Two reviewers independently assessed studies and rated the overall quality and strength of the evidence. RESULTS: Thirteen publications (11 unique studies) met the inclusion criteria and addressed gastrostomy outcomes or treatment of reflux via fundoplication. In nine studies, gastrostomy-fed children gained weight. Relative to typically developing populations, baseline weight z-scores ranged from -3.56 to -0.39 and follow-up z scores ranged from -2.63 to -0.33. Other growth measures were mixed. Two studies assessed fundoplication: in one, both Nissen fundoplication and vertical gastric plication reduced reflux (by 57% and 43% respectively), while in one case series, reflux recurred within 12 months in 30% of children. The highest rates of adverse events across studies were site infection (59%), granulation tissue (42%), and recurrent reflux (30%). Death rates ranged from 7 to 29%; however, the underlying cause was probably not surgery. INTERPRETATION: Evidence for the effectiveness of surgical interventions is insufficient to low. Studies of gastrostomy typically demonstrated significant weight gain. Results for other measures were mixed. Many children remained underweight, although, given a lack of appropriate reference standards, these results should be interpreted cautiously. PMID- 23738904 TI - Circadian-clock system in mouse liver affected by insulin resistance. AB - Circadian rhythms are exhibited in the physiological and behavioral processes of all mammals; they are generated by intracellular levels of circadian oscillators, which are named as a set of circadian-clock genes. These genes compose the transcriptional/translational feedback loops to regulate not only circadian rhythmicity, but also energy metabolism. Previous studies have shown that obesity and diabetes cause the dysregulation of the circadian-clock system, and vice versa. However, some diabetes subjects are lean with insulin resistance and the mechanisms of insulin resistance without obesity are much less well known. Therefore, whether insulin resistance alone is enough to influence the expression of circadian-clock genes is uncertain. This study employs a neonatal streptozotocin (STZ)-treated paradigm in mice to model the molecular and physiological progress of nonobese insulin resistance. A single injection of STZ into 2-d-old male C57BL/6 mice induces nonobese, hyperglycemic and hyperinsulinemic conditions, and the levels of gene expression in the liver by a real-time quantitative polymerase chain reaction are then measured. Although the levels of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2), and Cry1 (cryptochrome 1) mRNA expression in the liver change during the progress of insulin resistance conditions, the gene expression patterns still show circadian rhythmicity. This study suggests that changes in the hepatic circadian-clock gene expression mark an early event in the metabolic disruption associated with insulin resistance. Furthermore, 2 wks of treatment with the thiazolidinedione, pioglitazone, fully resolve the dysfunction in metabolic parameters and the changes in circadian-clock gene expression from early insulin resistance conditions. These results indicate that the circadian-clock system is sensitive to insulin resistance, and that treatment with thiazolidinediones can resolve changes in the circadian-clock system in a timely manner. Thus, strengthening the peripheral circadian-clock system may counteract the adverse physiological consequences in the metabolic syndrome. PMID- 23738905 TI - Seasonal variation of activity patterns in roe deer in a temperate forested area. AB - We investigated the activity patterns of a European roe deer (Capreolus capreolus) population living in a forested Apennine area in central Italy, in order to shed light on the environmental and biological factors that were expected to account for the observed activity patterns on daily and yearly bases. Daily and seasonal activity patterns of 31 radio-collared roe deer were assessed through sessions of radio tracking for a total period of 18 consecutive months. Roe deer showed bimodal activity patterns throughout the year, with the two highest peaks of activity recorded at dawn and dusk. Activity patterns of males and females differed during the territorial period (from early spring to late summer), whereas they did not during the nonterritorial period. Most likely, behavioral thermoregulation can be held responsible for variation of daily activity patterns in different seasons. In winter, for instance, activity during the dawn period was significantly higher than in other seasons and daylight activity was significantly higher than at night. Nocturnal activity was highest in summer and lowest in winter. During the hunting season, moreover, roe deer showed lower activity levels than during the rest of the year. The prediction that roe deer would show lower activity levels during full moon nights, when the predation risk was assumed to be higher, was not confirmed by our data. Activity rhythms in roe deer were thus subjected to both endogenous and environmental factors, the latter working as exogenous synchronization cues. Accordingly, in changing environmental and ecological conditions, a circadian cycle of activity could be seen as the result of complex interactions among daily behavioral rhythm, digestive physiology, and external modifying factors. PMID- 23738906 TI - Effect of sleep deprivation on rhythms of clock gene expression and melatonin in humans. AB - This study investigated the impact of sleep deprivation on the human circadian system. Plasma melatonin and cortisol levels and leukocyte expression levels of 12 genes were examined over 48 h (sleep vs. no-sleep nights) in 12 young males (mean+/-SD: 23+/-5 yrs). During one night of total sleep deprivation, BMAL1 expression was suppressed, the heat shock gene HSPA1B expression was induced, and the amplitude of the melatonin rhythm increased, whereas other high-amplitude clock gene rhythms (e.g., PER1-3, REV-ERBalpha) remained unaffected. These data suggest that the core clock mechanism in peripheral oscillators is compromised during acute sleep deprivation. PMID- 23738907 TI - Dexamethasone induces high-amplitude rhythms in preadipocytes, but hinders circadian expression in differentiated adipocytes. AB - Glucocorticoids induce circadian gene expression in cultured cells and change the phase of circadian gene expression in vivo. In addition, glucocorticoids induce differentiation of preadipocyte to adipocytes. We set out to test the effect of dexamethasone, a glucocorticoid receptor agonist, on circadian rhythms in 3T3-L1 differentiated adipocytes. Our results show that differentiated adipocytes exhibit robust circadian rhythms without dexamethasone. Dexamethasone induces phase changes and increases the amplitude of circadian gene expression in nondifferentiated 3T3-L1 preadipocytes. However, dexamethasone had an opposite effect on differentiated adipocytes, leading to low-amplitude circadian expression. In conclusion, although glucocorticoids reset circadian rhythms, once rhythms are reset, glucocorticoid administration hinders circadian expression. PMID- 23738908 TI - Lidocaine-prilocaine (EMLA((r)) ) cream as analgesia in hysteroscopy practice: a prospective, randomized, non-blinded, controlled study. AB - We investigated the efficacy of 5% lidocaine 25 mg-prilocaine 25 mg/g cream (EMLA((r)) ) applied to the uterine cervix for reducing pain during diagnostic or operative hysteroscopy, using a visual analogue scale (VAS) for pain in a prospective randomized, non-blinded, controlled study in 92 successive patients. Patients were randomized to either 3 mL of EMLA cream or 3 mL of ultrasound gel (placebo), placed endocervically and exocervically, 10 min before hysteroscopy. Intensity of pain was evaluated immediately after the procedure using a 10-cm VAS. No differences were found between the two groups (p = 0.07). The number of women who wished to stop the procedure was significantly lower in the EMLA group compared with the control group (p = 0.013). We concluded that topical instillation of EMLA does not decrease pain during hysteroscopy, but does reduce a desire to abandon the procedure. PMID- 23738909 TI - Role of lysines in cytochrome c-cardiolipin interaction. AB - Cytochrome c undergoes structural variations during the apoptotic process; such changes have been related to modifications occurring in the protein when it forms a complex with cardiolipin, one of the phospholipids constituting the mitochondrial membrane. Although several studies have been performed to identify the site(s) of the protein involved in the cytochrome c-cardiolipin interaction, to date the location of this hosting region(s) remains unidentified and is a matter of debate. To gain deeper insight into the reaction mechanism, we investigate the role that the Lys72, Lys73, and Lys79 residues play in the cytochrome c-cardiolipin interaction, as these side chains appear to be critical for cytochrome c-cardiolipin recognition. The Lys72Asn, Lys73Asn, Lys79Asn, Lys72/73Asn, and Lys72/73/79Asn mutants of horse heart cytochrome c were produced and characterized by circular dichroism, ultraviolet-visible, and resonance Raman spectroscopies, and the effects of the mutations on the interaction of the variants with cardiolipin have been investigated. The mutants are characterized by a subpopulation with non-native axial coordination and are less stable than the wild-type protein. Furthermore, the mutants lacking Lys72 and/or Lys79 do not bind cardiolipin, and those lacking Lys73, although they form a complex with the phospholipid, do not show any peroxidase activity. These observations indicate that the Lys72, Lys73, and Lys79 residues stabilize the native axial Met80 Fe(III) coordination as well as the tertiary structure of cytochrome c. Moreover, while Lys72 and Lys79 are critical for cytochrome c-cardiolipin recognition, the simultaneous presence of Lys72, Lys73, and Lys79 is necessary for the peroxidase activity of cardiolipin-bound cytochrome c. PMID- 23738910 TI - Evaluation of insulin initiation on resource utilization and direct costs of treatment over 12 months in patients with type 2 diabetes in Europe: results from INSTIGATE and TREAT observational studies. AB - OBJECTIVES: To describe the changes in resource utilization in seven European countries (Germany, Greece, Portugal, Romania, Sweden, Spain, and Turkey) and direct costs in four European countries (Germany, Spain, Sweden, and Greece) over the first 12 months of insulin treatment in patients with type 2 diabetes mellitus (T2DM). METHODS: INSTIGATE and TREAT (2005-2010) were non interventional, prospective, observational studies in patients with T2DM and initiating insulin for the first time. A 6-month retrospective data capture was conducted at baseline (insulin initiation) followed by prospective data collections at ~3, 6, and 12 months. Statistical analyses were descriptive; estimated costs are presented as nominal values. RESULTS: This study presents data for 1450 patients. Overall, in the first 6 months after insulin initiation, the use and cost of blood glucose monitoring and insulin increased, while the cost of oral diabetic medication decreased. Contributors to total direct costs differed between countries. Ranges of total mean direct costs over the 6-month period before insulin initiation were ?489.10-?658.50 (Greece-Spain); 0-6 months after insulin initiation, ?573.40-?1084.70 (Greece-Spain); and 6-12 months after insulin initiation, ?495.80-?859.30 (Greece-Germany). Thus, the mean cost of treatment increased in all countries in the first 6 months after insulin initiation and then returned to baseline except in Germany. LIMITATIONS: Overall, 15% of patients were lost to follow-up over 12 months. Costs were not pro-rated to account for variation of visits. Participating centres may not have been fully representative of all levels of care. CONCLUSIONS: Contributors to total cost differed between countries, potentially reflecting local clinical practice patterns and insulin regimens. In each country, mean direct total costs of T2DM care increased during the first 6 months after insulin initiation and decreased thereafter. PMID- 23738911 TI - Disturbed protein-protein interaction networks in metastatic melanoma are associated with worse prognosis and increased functional mutation burden. AB - For disseminated melanoma, new prognostic biomarkers and therapeutic targets are urgently needed. The organization of protein-protein interaction networks was assessed via the transcriptomes of four independent studies of metastatic melanoma and related to clinical outcome and MAP-kinase pathway mutations (BRAF/NRAS). We also examined patient outcome-related differences in a predicted network of microRNAs and their targets. The 32 hub genes with the most reproducible survival-related disturbances in co-expression with their protein partner genes included oncogenes and tumor suppressors, previously known correlates of prognosis, and other proteins not previously associated with melanoma outcome. Notably, this network-based gene set could classify patients according to clinical outcomes with 67-80% accuracy among cohorts. Reproducibly disturbed networks were also more likely to have a higher functional mutation burden than would be expected by chance. The disturbed regions of networks are therefore markers of clinically relevant, selectable tumor evolution in melanoma which may carry driver mutations. PMID- 23738912 TI - Spatial risk assessment of alien invasive plants in China. AB - The large-scale distribution patterns of alien invasive plants (AIP) can provide key information and a theoretical basis for management strategies, including the prevention of invasions, the control and eradication of established AIPs, and the identification of areas at high risk of invasion. This study aims to quantify distribution patterns of AIP in China, to develop approaches that measure the social, economic, and ecological impacts, and to identify areas that are at higher risk of plant invasion. Based on published literature, there were 384 AIPs in China, representing 233 genera from 66 families. Climatic factors were among the primary factors determining AIPs' overall distribution patterns. The majority of AIPs were tropically distributed in China, meaning that they were mainly restricted to southern China. Temperate-distributed AIPs, those distributed only or predominantly in northern China, were fewer but had higher average rates of spread than tropically distributed AIPs. Average ecological and economic impact per AIP was negatively correlated with AIP richness, meaning that areas with relatively few AIPs nevertheless have some of the most detrimental ones. Our comparative evaluation showed that the risk of invasion differed among regions of China, with high-risk areas in southern China (Yunnan, Guangxi, and Guangdong) and central coastal areas of eastern China (Shandong, Hebei, and Jiangsu). In the context of climate change, areas around latitudes of 33 degrees N, including Hebei, Shandong, Henan, and Jiangsu, should be given more attention for the control and prevention of plant invasions. Predictions of high-risk areas for future invasions differed depending on the scale of aggregation and the evaluation index, indicating that invasive risk assessments should be based on multiple factors. PMID- 23738913 TI - Effect of variable dose rate on biologically effective dose. AB - PURPOSE: To investigate the effect of variable dose rate on biologically effective dose (BED). MATERIALS AND METHODS: By using the linear-quadratic (LQ) model with bi-exponential repair, we analytically determine the time-dependent dose rate [Formula: see text] which minimizes the effective protraction factor (Geff) and BED under the condition of fixed fraction time and dose per fraction. Because normal tissue complication probability (NTCP) monotonically decreases with decreasing BED, the dose rate [Formula: see text] also minimizes NTCP. RESULTS: The dependences of Geff , BED and NTCP on fraction time were determined for different radiobiological parameters and two different dose rates: constant dose rate R0 and varying dose rate [R]. CONCLUSION: The results of this study indicate that under certain conditions the reduction in BED for late-responding tissues due to increased fraction time can be significantly greater than the reduction in BED for tumors. Our analysis also indicates that dose rate optimization can be radiobiologically beneficial because of the resulting decrease in NTCP. PMID- 23738914 TI - Streptomyces cytochromes P450: applications in drug metabolism. AB - INTRODUCTION: The biotransformation of drugs is critical in assessing safety and efficacy prior to human use. Cytochrome P450 (CYP; P450) enzymes are major enzymes involved in drug metabolism and bioactivation. In general, animal model systems are widely used to evaluate drug candidate toxicity and metabolism. Streptomyces strains have also been used for the metabolism of drugs screening prior to use in human medicine. AREAS COVERED: Utilizing Streptomyces P450s uncovered by genomics to generate drug metabolites represents an additional practical means of new drug screening approach. Now, in the first such review since the advent of the post-genomic era, the authors provide an update on the present knowledge concerning the application of the Streptomyces species and associated P450s with their role(s) in drug metabolism. EXPERT OPINION: Currently traditional biochemical methodology, such as chemical screening to identify substrates using purified enzymes, is still required for successful drug development. Nevertheless, the ability of the Streptomyces species, and their associated P450 enzymes, has shown promise for drug development because of their ability to mimic human drug-metabolizing P450. Furthermore, it should be pointed out that the metabolism of drug candidates with Streptomyces P450 may present a generation of novel products with totally different pharmacology with improved efficacy and pharmacokinetic profile. PMID- 23738915 TI - Positron emission tomography imaging of angiogenesis in a murine hindlimb ischemia model with 64Cu-labeled TRC105. AB - The goal of this study was to assess ischemia-induced angiogenesis with (64)Cu NOTA-TRC105 positron emission tomography (PET) in a murine hindlimb ischemia model of peripheral artery disease (PAD). CD105 binding affinity/specificity of NOTA-conjugated TRC105 (an anti-CD105 antibody) was evaluated by flow cytometry, which exhibited no difference from unconjugated TRC105. BALB/c mice were anesthetized, and the right femoral artery was ligated to induce hindlimb ischemia, with the left hindlimb serving as an internal control. Laser Doppler imaging showed that perfusion in the ischemic hindlimb plummeted to ~ 20% of the normal level after surgery and gradually recovered to near normal level on day 24. Ischemia-induced angiogenesis was noninvasively monitored and quantified with (64)Cu-NOTA-TRC105 PET on postoperative days 1, 3, 10, 17, and 24. (64)Cu-NOTA TRC105 uptake in the ischemic hindlimb increased significantly from the control level of 1.6 +/- 0.2 %ID/g to 14.1 +/- 1.9 %ID/g at day 3 (n = 3) and gradually decreased with time (3.4 +/- 1.9 %ID/g at day 24), which correlated well with biodistribution studies performed on days 3 and 24. Blocking studies confirmed the CD105 specificity of tracer uptake in the ischemic hindlimb. Increased CD105 expression on days 3 and 10 following ischemia was confirmed by histology and reverse transcription polymerase chain reaction (RT-PCR). This is the first report of PET imaging of CD105 expression during ischemia-induced angiogenesis. (64)Cu-NOTA-TRC105 PET may play multiple roles in future PAD-related research and improve PAD patient management by identifying the optimal timing of treatment and monitoring the efficacy of therapy. PMID- 23738917 TI - Challenges posed to the European pharmaceutical regulatory system by highly personalized medicines. AB - The European pharmaceutical regulatory system has not yet been challenged by issues related to highly personalized medicines such as those to be found with active substances that affect RNA biochemistry. We review the current status of RNA-based pharmacology and present three possible case histories. The implications for the European pharmaceutical regulatory system are discussed. PMID- 23738918 TI - Oxidation of gold clusters by thiols. AB - The formation of gold-thiolate nanoparticles via oxidation of gold clusters by thiols is examined in this work. Using the BP86 density functional with a triple zeta basis set, the adsorption of methylthiol onto various gold clusters Aun(Z) (n = 1-8, 12, 13, 20; Z = 0, -1, +1) and Au38(4+) is investigated. The rate limiting step for the reaction of one thiol with the gold cluster is the dissociation of the thiol proton; the resulting hydrogen atom can move around the gold cluster relatively freely. The addition of a second thiol can lead to H2 formation and the generation of a gold-thiolate staple motif. PMID- 23738916 TI - Aging results in copper accumulations in glial fibrillary acidic protein-positive cells in the subventricular zone. AB - Analysis of rodent brains with X-ray fluorescence (XRF) microscopy combined with immunohistochemistry allowed us to demonstrate that local Cu concentrations are thousands of times higher in the glia of the subventricular zone (SVZ) than in other cells. Using XRF microscopy with subcellular resolution and intracellular X ray absorption spectroscopy we determined the copper (I) oxidation state and the sulfur ligand environment. Cu K-edge X-ray absorption near edge spectroscopy is consistent with Cu being bound as a multimetallic Cu-S cluster similar to one present in Cu-metallothionein. Analysis of age-related changes show that Cu content in astrocytes of the SVZ increases fourfold from 3 weeks to 9 months, while Cu concentration in other brain areas remain essentially constant. This increase in Cu correlates with a decrease in adult neurogenesis assessed using the Ki67 marker (both, however, can be age-related effects). We demonstrate that the Cu distribution and age-related concentration changes in the brain are highly cell specific. PMID- 23738919 TI - Noninvasive determination of atrial fibrillation cycle length by atrial colour tissue Doppler imaging in horses. AB - REASONS FOR PERFORMING STUDY: Atrial fibrillation cycle length (AFCL) is an indicator of atrial electrical remodelling during atrial fibrillation (AF). OBJECTIVES: To compare AFCL measured invasively from an intra-atrial electrogram (AFCLEGM ) with AFCL measured noninvasively by atrial colour tissue Doppler imaging (AFCLTDI ). STUDY DESIGN: Prospective descriptive clinical study. METHODS: Measurements were performed in 31 episodes of AF or flutter in 29 horses (588 +/- 61 kg bwt, 9 +/- 3 years old) admitted for transvenous electrical cardioversion. The AFCLEGM was measured from an intracardiac electrogram using a bipolar sensing/pacing electrode inserted into the right atrium. The AFCLTDI was measured from atrial colour tissue velocity curves in the following 5 regions: 1) left atrial free wall from a right parasternal 4-chamber view, 2) left atrial free wall from a short-axis view, 3) left atrial free wall from a left parasternal long-axis view, 4) interatrial septum, and 5) right atrial dorsal wall near the tuberculum intervenosum. The AFCLEGM and AFCLTDI from the 5 regions were compared using a one-way repeated-measures ANOVA with Bonferroni correction for multiple comparisons and calculation of the Bland-Altman mean bias and limits of agreement of AFCLEGM and AFCLTDI . RESULTS: The AFCLEGM was 161 +/- 18 ms in 29 AF episodes. Two horses showed atrial flutter and had an AFCLEGM of 244 and 324 ms. The mean bias between AFCLTDI and AFCLEGM ranged from -18 to +9 ms depending on the atrial wall region. The AFCLTDI was significantly shorter in the left atrial free wall from the right parasternal 4-chamber view and short-axis view than in the other regions (P<0.001). CONCLUSIONS: Tissue Doppler imaging allows noninvasive measurement of AFCL in horses with AF and is able to identify spatial differences within the equine atria. Atrial fibrillation cycle length is an indicator of atrial electrical remodelling and is an important parameter to study AF pathophysiology or the effect of antiarrhythmic drugs. PMID- 23738920 TI - Phthalates suppress type I interferon in human plasmacytoid dendritic cells via epigenetic regulation. AB - BACKGROUND: Exposure to environmental endocrine-disrupting chemicals (EDCs) is associated with allergy, chronic inflammation, and immunodeficiency. Phthalates, the common EDCs used in plastic industry, may act as adjuvants to disrupt immune system and enhance allergy. Plasmacytoid DCs (pDCs) are predominant cells secreting type I interferon (IFN) against infection and are professional antigen presenting cells in regulating adaptive immunity. However, the effects of phthalates on the function of pDCs are unknown. METHODS: Circulating pDCs were isolated from healthy subjects, were pretreated with diethylhexyl phthalate (DEHP) and butyl benzyl phthalate (BBP), and were stimulated with Toll-like receptor (TLR)-9 agonist CpG. IFN-alpha/IFN-beta levels, surface markers, and T cell stimulatory function were investigated using ELISA, flow cytometry, and pDC/T-cell coculture assay. Mechanisms were investigated using receptor antagonists, pathway inhibitors, Western blotting, and chromatin immunoprecipitation. RESULTS: Diethylhexyl phthalate and butyl benzyl phthalate suppressed CpG-induced IFN-alpha/IFN-beta expression in pDCs, and the effect was reversed by aryl hydrocarbon receptor (AHR) antagonist. Diethylhexyl phthalate suppressed CpG-activated mitogen-activated protein kinase (MAPK)-MEK1/2-ERK-ELK1 and NFkappaB signaling pathways. Diethylhexyl phthalate suppressed CpG-induced interferon regulatory factor (IRF)-7 expression by suppressing histone H3K4 trimethylation at IRF7 gene promoter region through inhibiting translocation of H3K4-specific trimethyltransferase WDR5 from cytoplasm into nucleus. Butyl benzyl phthalate or diethylhexyl phthalate-treated pDCs suppressed IFN-gamma but enhanced IL-13 production by CD4+ T cells. CONCLUSION: Phthalates may interfere with immunity against infection and promote the deviation of Th2 response to increase allergy by acting on human pDCs via suppressing IFN-alpha/IFN-beta expression and modulating the ability to stimulate T-cell responses. PMID- 23738921 TI - Overexpression of Escherichia coli phytase in Pichia pastoris and its biochemical properties. AB - To obtain a Pichia pastoris mutant with an Escherichia coli phytase gene, which was synthesized according to P. pastoris codon preference, a mature phytase cDNA of E. coli being altered according to the codons usage preference of P. pastoris was artificially synthesized and cloned into an expression vector of pGAPZalphaC. The final extracellular phytase activity was 112.5 U/mL after 72 h of cultivation. The phytase, with a molecular mass of 46 kDa, was purified to electrophoretical homogeneity after Ni Sepharose 6 Fast Flow chromatography. The yield, purification fold, and specific activity were 63.97%, 26.17, and 1.57 kU/mg, respectively. It had an optimal pH and temperature of 4.0-6.0 and 50 degrees C, respectively, and was stable at pH 3.0-8.0 and 25-40 degrees C. The purified recombinant phytase was resistant to trypsin, highly inhibited by Cu(2+), Zn(2+), Hg(2+), Fe(2+), Fe(3+), phenylmethylsulfonyl fluoride, and N tosyl-l-lysine chloromethyl ketone, but activated by Mg(2+), Ca(2+), Sr(2+), Ba(2+), glutathione, ethylenediaminetetraacetic acid, and N-ethylmaleimide. It revealed higher affinity to calcium phytate than to other phosphate conjugates. PMID- 23738923 TI - Association between molecular monitoring and long-term outcomes in chronic myelogenous leukemia patients treated with first line imatinib. AB - OBJECTIVE: Molecular monitoring using quantitative polymerase chain reaction (qPCR) of BCR-ABL mRNA transcripts using the international scale (IS) is recommended by the National Comprehensive Cancer Network and the European LeukemiaNet for patients with chronic myelogenous leukemia in chronic phase (CML CP). This study assessed the impact of the frequency of qPCR testing on progression-free survival (PFS). RESEARCH DESIGN AND METHODS: This retrospective chart review of 402 CML-CP patients on first line imatinib therapy, performed by 38 community-based US physicians, analyzed the impact of the frequency of molecular monitoring on the risk of progression and PFS. MAIN OUTCOME MEASURES: Time to progression and progression-free survival. RESULTS: Over the 3 year study, 13.2% of patients did not have any qPCR monitoring and 46.3% had 3-4 qPCR tests per year; 5.7% of CML-CP patients progressed to accelerated/blast phase or died. Compared to patients with no qPCR monitoring, those with 3-4 qPCR tests per year had a lower risk of progression (HR = 0.085; p = 0.001) and longer PFS (HR = 0.088; p = 0.001) after adjusting for potential confounders, as did those patients with 1-2 qPCR tests per year (both p < 0.02). Results were consistent after adjusting for Sokal score when available. CONCLUSION: This is the first study to document the clinical impact of frequent molecular monitoring, and the findings underscore the importance of regular molecular monitoring in delivering quality care for CML. These findings could be subject to unobserved confounders. PMID- 23738922 TI - Therapy of intracellular Staphylococcus aureus by tigecyclin. AB - BACKGROUND: In the fields of traumatology and orthopaedics staphylococci are the most frequently isolated pathogens. Staphylococcus aureus and Staphylococcus epidermidis are known to be the major causative agents of osteomyelitis. The increasing number of multiresistant Staphylococcus aureus and resistant coagulase negative staphylococci as a trigger of complicated osteomyelitis and implant associated infections is a major problem. Antibiotic therapy fails in 20% of cases. Therefore the development of novel antibiotics becomes necessary. METHODS: This study analyses tigecyclin, the first antibiotic of the glycylines, as a potential therapy for osteomyelitis caused by multiresistant Staphylococcus aureus. Therefore its intracellular activity and the potential use in polymethylmetacrylate-bone cement are examined. The intracellular activity of tigecyclin is determined by a human osteoblast infection model. The investigation of the biomechanical characteristics is conducted concerning the ISO 5833 guidelines. RESULTS: Tigecyclin shows in vitro an intracellular activity that ranges between the antimicrobial activity of gentamicin and rifampicin. A significant negative effect on the biomechanical characteristics with an impaired stability is detected after adding tigecyclin to polymethylmetacrylate-bone cement with a percentage of 1.225% per weight. CONCLUSIONS: This study shows that tigecyclin might be a potent alternative for the systemic therapy of osteomyelitis and implant-associated infections whereas the local application has to be reconsidered individually. PMID- 23738924 TI - High frequency MoS2 nanomechanical resonators. AB - Molybdenum disulfide (MoS2), a layered semiconducting material in transition metal dichalcogenides (TMDCs), as thin as a monolayer (consisting of a hexagonal plane of Mo atoms covalently bonded and sandwiched between two planes of S atoms, in a trigonal prismatic structure), has demonstrated unique properties and strong promises for emerging two-dimensional (2D) nanodevices. Here we report on the demonstration of movable and vibrating MoS2 nanodevices, where MoS2 diaphragms as thin as 6 nm (a stack of 9 monolayers) exhibit fundamental-mode nanomechanical resonances up to f0 ~ 60 MHz in the very high frequency (VHF) band, and frequency quality (Q) factor products up to f0 * Q ~ 2 * 10(10)Hz, all at room temperature. The experimental results from many devices with a wide range of thicknesses and lateral sizes, in combination with theoretical analysis, quantitatively elucidate the elastic transition regimes in these ultrathin MoS2 nanomechanical resonators. We further delineate a roadmap for scaling MoS2 2D resonators and transducers toward microwave frequencies. This study also opens up possibilities for new classes of vibratory devices to exploit strain- and dynamics-engineered ultrathin semiconducting 2D crystals. PMID- 23738925 TI - Clinicopathological findings of canine seborrhoeic keratosis with comparison to pigmented viral plaques. AB - BACKGROUND: Seborrhoeic keratoses (SKs) are common benign epidermal neoplasms in humans and are rarely diagnosed in the dog. These circumscribed, raised, variably pigmented plaques arise in middle aged to older humans, with a focal or multicentric distribution; although common, the underlying cause of these lesions is not known. Although less common in the dog, the lesions are similar and have features that overlap with papillomavirus-associated pigmented viral plaques. HYPOTHESIS/OBJECTIVES: Seborrhoeic keratoses in the dog are negative for canine papillomavirus. ANIMALS: Eleven cases of SK from a 12 year period were reviewed. METHODS: This was a retrospective study of the histopathological findings and case histories. Complete clinical records following collection of the skin biopsy were available in five of 11 cases. Immunohistochemistry was performed for all cases; PCR analysis was carried out for papillomavirus in six cases. RESULTS: Histologically, SKs had an exophytic to mildly endophytic epidermal proliferation, creating a papillomatous to acanthotic, hyperkeratotic, frequently pigmented plaque. There was an absence of hypergranulosis or viral cytopathic effect; PCRs for canine papillomavirus within the formalin-fixed paraffin embedded skin biopsies were negative. No breed, sex or site predilection was recognized. The mean age at biopsy of the lesions was 8.8 years (range 5-14 years). CONCLUSIONS AND CLINICAL IMPORTANCE: Histopathological features and negative papillomavirus status distinguish SK as an important differential diagnosis for pigmented viral plaques in dogs. PMID- 23738927 TI - Catalysts or initiators? Beckmann rearrangement revisited. AB - The catalytic mechanism of the organo-mediated Beckmann rearrangement has been modeled using DFT calculations. Five representative promoters were shown to be initiators rather than catalysts. A self-propagating mechanism is shown to be energetically much more favored than the previously proposed mechanisms involving a Meisenheimer complex. PMID- 23738928 TI - RODIN and the pitfalls of observational studies. PMID- 23738926 TI - Conditionally-live attenuated SIV upregulates global T effector memory cell frequency under replication permissive conditions. AB - BACKGROUND: Live attenuated SIV induces potent protection against superinfection with virulent virus; however the mechanism of this vaccine effect is poorly understood. Such knowledge is important for the development of clinically acceptable vaccine modalities against HIV. RESULTS: Using a novel, doxycycline dependent, replication-competent live-attenuated SIVmac239Deltanef (SIV rtTADeltanef), we show that under replication-permissive conditions SIV rtTADeltanef is fully viable. Twelve rhesus macaques were infected with a peak plasma vRNA on average two log10 lower than in 6 macaques infected with unconditionally replication-competent SIVDeltanef. Consistent with the attenuated phenotype of the viruses the majority of animals displayed low or undetectable levels of viraemia by 42-84 days after infection. Next, comparison of circulating T cells before and after chronic infection with parental SIVDeltanef revealed a profound global polarisation toward CD28-CCR7- T-effector memory 2 (TEM2) cells within CD95+CD4+ and CD95+CD8+ populations. Critically, a similar effect was seen in the CD95+ CD4+ population and to somewhat lesser extent in the CD95+ CD8+ population of SIV-rtTADeltanef chronically infected macaques that were maintained on doxycycline, but was not seen in animals from which doxycycline had been withdrawn. The proportions of gut-homing T-central memory (TCM) and TEM defined by the expression of alpha4beta7 and CD95 and differential expression of CD28 were increased in CD4 and CD8 cells under replication competent conditions and gut-homing CD4 TCM were also significantly increased under non-permissive conditions. TEM2 polarisation was seen in the small intestines of animals under replication permissive conditions but the effect was less pronounced than in the circulation. Intracellular cytokine staining of circulating SIV-specific T cells for IL-2, IFN-gamma, TNF-alpha and IL-17 showed that the extent of polyfunctionality in CD4 and CD8 T cells was associated with replication permissivity; however, signature patterns of cytokine combinations were not distinguishable between groups of macaques. CONCLUSION: Taken together our results show that the global T memory cell compartment is profoundly skewed towards a mature effector phenotype by attenuated SIV. Results with the replication-conditional mutant suggest that maintenance of this effect, that may be important in vaccine design, might require persistence of replicating virus. PMID- 23738929 TI - Commentary: Hidradenitis suppurativa: surgical and other management techniques. PMID- 23738930 TI - Commentary: A randomized controlled trial of fractional laser therapy and dermabrasion for scar resurfacing. PMID- 23738931 TI - Commentary: Use of nonscalpel instruments for obtaining Mohs layers. PMID- 23738932 TI - Commentary: Commentary on The use of a biosynthetic skin substitute in slow Mohs micrographic surgery. PMID- 23738933 TI - Commentary: New concept in reconstruction after nail unit excision for melanoma in situ. PMID- 23738934 TI - Commentary: Commentary for Secondary intention healing of nasal alar defects. PMID- 23738935 TI - Letter to the editor: Involvement of the epidermal grafting area in the recurrence of segmental vitiligo. PMID- 23738936 TI - Letters to the editor: Lack of adequate evidence to recommend sentinel lymph node biopsy in thin melanoma. PMID- 23738937 TI - Orthodontic and prosthetic treatment of a patient with cystic fibrosis and agenesis of maxillary lateral incisors. AB - The young dental patient with maxillary lateral incisor agenesis, maxillary canine impaction, and cystic fibrosis presents considerable challenges to the dentist. An interdisciplinary approach is described here for the orthodontist and restorative dentist to plan and work together with the patient's and parents' cooperation and consent. Despite some compromises, a successful outcome was achieved, as demonstrated in this case report. The use of conservative yet esthetic and durable fixed replacement prostheses is highlighted. Congenitally absent maxillary lateral incisors, impacted maxillary canines, and cystic fibrosis are clinical conditions that can significantly complicate and compromise dental treatment for any young patient. All three can be present simultaneously, as described in this case report. PMID- 23738938 TI - Peripheral ossifying fibroma: a clincal report. AB - Peripheral ossifying fibroma (POF) is a common solitary gingival overgrowth thought to arise from the gingival corium, periosteum, and periodontal ligament. Commonly used synonyms for POF include calcifying fibroblastic granuloma, peripheral fibroma with calcification, peripheral cementifying fibroma, and calcifying or ossifying fibrous epulis. Because it is possible to misdiagnose POF as pyogenic granuloma, peripheral giant cell granuloma, or odontogenic tumors, histopathological examination is, therefore, essential for accurate diagnosis, and differential diagnosis is important because of POF's tendency to recur. This article presents a case of peripheral ossifying fibroma in a 15-year-old female along with the clinical, histopathologic, and radiographic features and treatment details. PMID- 23738939 TI - Portable INR analysis prior to dental procedures: technique instruction outcomes for senior dental students. AB - OBJECTIVES: This study aimed to teach dental students to use an INRatio(r) (HemoSense) device, to apply the results to patients, and to evaluate the outcomes. DESIGN: This was a retrospective convenience data study that used student surveys. SETTING: The research was conducted at The Ohio State University College of Dentistry Geriatric Dental Program in Columbus, Ohio. PARTICIPANTS: A total of 105 senior dental students participated in an INRatio training program. METHODS: The instructions involved the following: 1) a table showing INRatio protocol and dental procedures versus international normalized ratio (INR) guidelines; 2) an online technique training course, 3) a trial INRatio test on another senior dental student; and 4) INRatio for a dental patient. MAIN OUTCOMES: The clinical outcomes including INR values were a retrospective convenience data study. Instructional outcomes were obtained from student surveys. RESULTS: A total of 79% of students indicated they would use portable INR testing in their future practices; however, 73% of students had difficulty obtaining an adequate blood sample. All patient surgical procedures were completed successfully without serious complications. CONCLUSIONS: This study indicates the INRatio analysis can be included in dental student training, providing safe, efficient, and successful patient care. Difficulty obtaining blood samples suggests the need for extra training, additional clinical experience, and INR devices requiring smaller blood samples. PMID- 23738940 TI - Bone-added osteotome sinus floor elevation for the deficient maxillary posterior implant site: case series. AB - Implant placement in the posterior maxillary region is often compromised due to anatomic limitations. Often, factors like inadequate vertical dimension, poor bone quality, and undercuts result in placement of shorter and/or angled implants. The bone-added osteotome sinus floor elevation technique can be employed in many clinical situations that involve minimal bone height, resulting in increased bone height and placement of longer implants. This article will briefly review the literature and provide a detailed description of the technique as well as present multiple cases in which this procedure was used. PMID- 23738942 TI - Infectious risk factors and clinical indicators for tracheal mucus in British National Hunt racehorses. AB - REASONS FOR PERFORMING STUDY: Many studies of respiratory disease in racehorses have focused on a combination of increased tracheal mucus and airway neutrophilia. Examination of each component separately should provide further insight into this condition. OBJECTIVES: To identify infectious risk factors for endoscopically visible tracheal mucus in National Hunt racehorses. STUDY DESIGN: A 2 year prospective longitudinal study. METHODS: Monthly quantitative bacteriological examinations of tracheal wash samples and viral serological examinations were conducted. Risk factors for 'small amounts of mucus' (mucus score = 1/3) and 'increased mucus' (score >=2/3) were identified. RESULTS: There were increased odds of small amounts of mucus when both Streptococcus zooepidemicus and nonhaemolytic streptococci (NHS) were isolated (odds ratio [OR] 2.6; 95% confidence interval [CI] 1.5-4.6; P<0.001) but not when either species was isolated in the absence of the other. Increased odds of increased mucus were associated with the isolation of either S. zooepidemicus (OR 5.6; 95% CI 1.2 25.9; P = 0.03) or NHS (OR 3.7; 95% CI 1.2-11.6; P = 0.02), with an increased effect when both were isolated together (OR 12.5; 95% CI 3.7-41.6; P<0.001). Approximately 6-fold increased odds of small amounts of mucus were associated with the first 3 months in training (OR 6.3; 95% CI 2.0-19.4; P<0.001) and 3-fold increased odds of increased mucus associated with the first 6 months in training (OR 2.9; 95% CI 1.3-6.4; P = 0.01). Coughing at exercise and increased serous nasal discharge were specific but insensitive indicators of increased mucus. CONCLUSIONS: Associations with S. zooepidemicus corroborate previous research, but an independent effect of NHS has not previously been reported. The possibility that there are individual pathogenic species within this group should be considered. Further work is required to identify S. zooepidemicus subtypes and NHS species associated with disease. Closer monitoring of the respiratory health of horses entering training for the first time is likely to be valuable. PMID- 23738941 TI - Nuclear group I introns in self-splicing and beyond. AB - Group I introns are a distinct class of RNA self-splicing introns with an ancient origin. All known group I introns present in eukaryote nuclei interrupt functional ribosomal RNA genes located in ribosomal DNA loci. The discovery of the Tetrahymena intron more than 30 years ago has been essential to our understanding of group I intron catalysis, higher-order RNA structure, and RNA folding, but other intron models have provided information about the biological role. Nuclear group I introns appear widespread among eukaryotic microorganisms, and the plasmodial slime molds (myxomycetes) contain an abundance of self splicing introns. Here, we summarize the main conclusions from previous work on the Tetrahymena intron on RNA self-splicing catalysis as well as more recent work on myxomycete intron biology. Group I introns in myxomycetes that represent different evolutionary stages, biological roles, and functional settings are discussed. PMID- 23738943 TI - EphA4 is a prognostic factor in gastric cancer. AB - BACKGROUND: Erythropoietin-producing hepatocellular (Eph) receptor, consisting of a family of receptor tyrosine kinases, plays critical roles in tumour development and is considered an attractive target for cancer therapy. METHODS: Tumour samples were obtained from 222 patients with gastric adenocarcinoma who underwent gastrectomy. The expressions of EphA2, EphA4, and ephrinA1 were evaluated immunohistochemically. RESULTS: High expressions of EphA2, EphA4, and ephrinA1 significantly correlated with variables related to tumour progression, including the depth of invasion, metastatic lymph nodes, pathological stage, and distant metastasis or recurrent disease. High expressions of EphA2, EphA4, and ephrinA1 were significantly associated with poorer disease-specific survival (DSS; p < 0.001, p < 0.001, p = 0.026). On multivariate analysis, EphA4 was an independent prognostic factor of DSS (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.1-4.8; p = 0.028), and EphA2 tended to be a prognostic factor (HR, 2.4; 95% CI, 1.0-5.8; p = 0.050). In stage II and III cancer, EphA4 and EphA2 were both significantly associated with shorter survival (p = 0.007 and 0.019), but only EphA2 was an independent prognostic factor (HR, 2.6; 95% CI, 1.1-6.3; p = 0.039). CONCLUSION: EphA4 may play important roles in tumor progression and outcomes in patients with gastric cancer. PMID- 23738944 TI - Copper-catalyzed Huisgen 1,3-dipolar cycloaddition under oxidative conditions: polymer-assisted assembly of 4-acyl-1-substituted-1,2,3-triazoles. AB - We herein document the first example of a reliable copper-catalyzed Huisgen 1,3 dipolar cycloaddition under oxidative conditions. The combined use of two polymer supported reagents (polystyrene-1,5,7-triazabicyclo[4,4,0]dec-5-ene/Cu and polystyrene-2-iodoxybenzamide) overcomes the thermodynamic instability of copper(I) species toward oxidation, enabling the reliable Cu-catalyzed Huisgen 1,3-dipolar cycloadditions in the presence of an oxidant agent. This polymer assisted pathway, not feasible under conventional homogeneous conditions, provides a direct assembly of 4-acyl-1-substituted-1,2,3-triazoles, contributing to expand the reliability and scope of Cu(I)-catalyzed alkyne-azide cycloaddition. PMID- 23738945 TI - Oxidative stress induced by inorganic nanoparticles in bacteria and aquatic microalgae--state of the art and knowledge gaps. AB - Nanotechnology has revolutionised many areas of modern life, technology and research, which is reflected in the steadily increasing global demand for and consumption of engineered nanomaterials and the inevitable increase of their release into the environment by human activity. The overall long-term impact of engineered nanomaterials on ecosystems is still unknown. Various inorganic nanoparticles have been found to exhibit bactericidal properties and cause growth inhibition in model aquatic microalgae, but the mechanisms of toxicity are not yet fully understood. The causal link between particle properties and biological effects or reactive oxygen species generation is not well established and represents the most eminent quest of nanoecotoxicological investigation. In this review, the current mechanistic understanding of the toxicity of inorganic metal and metal oxide engineered nanomaterials towards bacterial and aquatic microalgal model organisms based on the paradigm of oxidative stress is presented along with a detailed compilation of available literature on the major toxicity factors and research methods. PMID- 23738946 TI - In vitro and ex vivo evaluation of polymeric nanoparticles for vaginal and rectal delivery of the anti-HIV drug dapivirine. AB - Prevention strategies such as the development of microbicides are thought to be valuable in the fight against HIV/AIDS. Despite recent achievements, there is still a long road ahead in the field, particularly at the level of drug formulation. Drug nanocarriers based on polymers may be useful in enhancing local drug delivery while limiting systemic exposure. We prepared differently surface engineered poly(epsilon-caprolactone) (PCL) nanoparticles (NPs) and tested their ability to modulate the permeability and retention of dapivirine in cell monolayers and pig vaginal and rectal mucosa. NPs coated with poly(ethylene oxide) (PEO) were shown able to reduce permeability across monolayers/tissues, while modification of nanosystems with cetyl trimethylammonium bromide (CTAB) enhanced transport. In the case of coating NPs with sodium lauryl sulfate (SLS), dapivirine permeability was unchanged. All NPs increased monolayer/tissue drug retention as compared to unformulated dapivirine. This fact was associated, at least partially, to the ability of NPs to be taken up by cells or penetrate mucosal tissue. Cell and tissue toxicity was also affected differently by NPs: PEO modification decreased the in vitro (but not ex vivo) toxicity of dapivirine, while higher toxicity was generally observed for NPs coated with SLS or CTAB. Overall, presented results support that PCL nanoparticles are capable of modulating drug permeability and retention in cell monolayers and mucosal tissues relevant for vaginal and rectal delivery of microbicides. In particular, PEO modified dapivirine-loaded PCL NPs may be advantageous in increasing drug residence at epithelial cell lines/mucosal tissues, which may potentially increase the efficacy of microbicide drugs. PMID- 23738948 TI - CO dimer: new potential energy surface and rovibrational calculations. AB - The spectrum of CO dimer was investigated by solving the rovibrational Schrodinger equation on a new potential energy surface constructed from coupled cluster ab initio points. The Schrodinger equation was solved with a Lanczos algorithm. Several 4D (rigid monomer) global ab initio potential energy surfaces (PESs) were made using a previously reported interpolating moving least-squares (IMLS) fitting procedure specialized to describe the interaction of two linear fragments. The potential has two nonpolar minima giving rise to a complicated set of energy level stacks, which are very sensitive to the shapes and relative depths of the two wells. Although the CO dimer has defied previous attempts at an accurate purely ab initio description our best surface yields results in good agreement with experiment. Root-mean-square (rms) fitting errors of less than 0.1 cm(-1) were obtained for each of the fits using 2226 ab initio data at different levels. This allowed direct assessment of the quality of various levels of ab initio theory for prediction of spectra. Our tests indicate that standard CCSD(T) is slow to converge the interaction energy even when sextuple zeta bases as large as ACV6Z are used. The explicitly correlated CCSD(T)-F12b method was found to recover significantly more correlation energy (from singles and doubles) at the CBS limit. Correlation of the core-electrons was found to be important for this system. The best PES was obtained by extrapolation of calculations at the CCSD(T)(AE)-F12b/CVnZ-F12 (n = 3,4) levels. The calculated energy levels were compared to 105 J <= 10 levels from experiment. The rms error for 68 levels with J <= 6 is only 0.29 cm(-1). The calculated energy levels were assigned stack labels using several tools. New stacks were found. One of them, stack y1, has an energy lower than many previously known stacks and may be observable. PMID- 23738947 TI - Use of partial least squares regression to impute SNP genotypes in Italian cattle breeds. AB - BACKGROUND: The objective of the present study was to test the ability of the partial least squares regression technique to impute genotypes from low density single nucleotide polymorphisms (SNP) panels i.e. 3K or 7K to a high density panel with 50K SNP. No pedigree information was used. METHODS: Data consisted of 2093 Holstein, 749 Brown Swiss and 479 Simmental bulls genotyped with the Illumina 50K Beadchip. First, a single-breed approach was applied by using only data from Holstein animals. Then, to enlarge the training population, data from the three breeds were combined and a multi-breed analysis was performed. Accuracies of genotypes imputed using the partial least squares regression method were compared with those obtained by using the Beagle software. The impact of genotype imputation on breeding value prediction was evaluated for milk yield, fat content and protein content. RESULTS: In the single-breed approach, the accuracy of imputation using partial least squares regression was around 90 and 94% for the 3K and 7K platforms, respectively; corresponding accuracies obtained with Beagle were around 85% and 90%. Moreover, computing time required by the partial least squares regression method was on average around 10 times lower than computing time required by Beagle. Using the partial least squares regression method in the multi-breed resulted in lower imputation accuracies than using single-breed data. The impact of the SNP-genotype imputation on the accuracy of direct genomic breeding values was small. The correlation between estimates of genetic merit obtained by using imputed versus actual genotypes was around 0.96 for the 7K chip. CONCLUSIONS: Results of the present work suggested that the partial least squares regression imputation method could be useful to impute SNP genotypes when pedigree information is not available. PMID- 23738949 TI - Impact of gait analysis on correction of excessive hip internal rotation in ambulatory children with cerebral palsy: a randomized controlled trial. AB - AIM: The aim of this study was to determine if gait analysis improves correction of excessive hip internal rotation in ambulatory children with spastic cerebral palsy (CP). METHOD: Children undergoing orthopedic surgery were randomized to receive or not receive a preoperative gait analysis report. This secondary analysis included all participants whose gait report recommended external femoral derotation osteotomy (FDRO). One-year postoperative, and pre- to postoperative change in femoral anteversion, mean hip rotation in stance, and mean foot progression in stance were compared between groups and in subgroups based on whether the recommendation for FDRO was followed. RESULTS: Outcomes did not differ between the group which received a gait report (n=39; 19 males, 20 females; mean age 10y 4mo [SD 3y]; hemiplegia, 3; di/triplegia, 28; quadriplegia, 8; Gross Motor Function Classification System [GMFCS]: level I, 5; level II, 12; level III 19; level IV, 3) and the control group (n=26; 14 males, 12 females; mean age 9y 5mo [SD 2y 10mo]; hemiplegia, 1; di/triplegia, 21; quadriplegia, 4; GMFCS: level I, 4; level II, 1; level III, 9; level IV, 2; all p values >0.29), but improved more in the gait report subgroup in which the FDRO recommendation was followed (seven limbs; change in anteversion -32.9 degrees , hip rotation 25.5 degrees , foot progression -36.2 degrees ) than in the control group (anteversion -12.2 degrees , hip rotation -7.6 degrees , foot progression -12.4 degrees ; all p values <=0.02) and the gait report subgroup in which FDRO was not performed (32 limbs; anteversion -1.0 degrees , hip rotation 0.5 degrees , foot progression -8.0 degrees ; all p values <=0.003). Postoperative measures became normal only in the gait report subgroup in which the recommended FDRO was performed. INTERPRETATION: Gait analysis can improve outcomes when its recommendations are incorporated in the treatment plan. PMID- 23738950 TI - New spiroindolinones bearing 5-chlorobenzothiazole moiety. AB - In this study, 5-chloro-3H-spiro-[1,3-benzothiazole-2,3'-indole]-2'(1'H)-one derivatives 3a-l were synthesized by the reaction of 1H-indole-2,3-diones 1a-l with 2-amino-4-chlorothiophenol 2 in ethanol. 3a-l were tested for their abilities to inhibit lipid peroxidation (LP), scavenge DPPH(*) and ABTS(*+) radicals, and to reduce Fe(3+) to Fe(2+). Most of the tested compounds exhibited potent scavenging activities against ABTS(*+) radical, reducing powers and strong inhibitory capacity on LP. 3 a, 3 d, 3 e, 3h, 3 j and 3 k chosen as prototypes were evaluated in the National Cancer Institute's in vitro primary anticancer assay. The greatest growth inhibitions were observed against a non-small cell lung cancer cell line HOP-92 for R1-fluoro substituted 3 d and a renal cancer cell line RXF-393 for R-chloro substituted 3 e in the primary screen. PMID- 23738952 TI - Heteroleptic metallosupramolecular racks, rectangles, and trigonal prisms: stoichiometry-controlled reversible interconversion. AB - A simple approach toward preparation of heteroleptic two-dimensional (2D) rectangles and three-dimensional (3D) triangular prisms is described utilizing the HETPYP (HETeroleptic PYridyl and Phenanthroline metal complexes) concept. By mixing metal-loaded linear bisphenanthrolines of varying lengths with diverse (multi)pyridine (py) ligands in a proper ratio, six different self-assembled architectures arise cleanly and spontaneously in the absence of any template. They are characterized by (1)H and DOSY NMR, ESI-FT-ICR mass spectrometry as well as by Job plots and UV-vis titrations. Density functional theory (DFT) computations provide information about each structure. A stoichiometry-controlled supramolecule-to-supramolecule interconversion based on the relative amounts of metal bisphenanthroline and bipyridine forces the rectangular assembly to reorganize to a rack architecture and back to the rectangle, as clearly supported by variable temperature and DOSY NMR as well as dynamic light scattering data. The highly dynamic nature of the assemblies represents a promising starting point for constitutional dynamic materials. PMID- 23738951 TI - Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients. AB - AIMS: To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation. METHODS: The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates. RESULTS: The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation: TVCL = 12.9 x (Weight/13.2)(0.75) x EXP(-0.00158 x TPT) x EXP(0.428 x CYP3A5) where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where *1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h(-1) kg(-1) (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%. CONCLUSION: Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time related changes in tacrolimus clearance. PMID- 23738953 TI - Mutation of Arabidopsis CATALASE2 results in hyponastic leaves by changes of auxin levels. AB - Auxin and H2 O2 play vital roles in plant development and environmental responses; however, it is unclear whether and how H2 O2 modulates auxin levels. Here, we investigate this question using cat2-1 mutant, which exhibits reduced catalase activity and accumulates high levels of H2 O2 under photorespiratory conditions. At a light intensity of 150 MUmol m(-2) s(-1) , the mutant exhibited up-curled leaves that have increased H2 O2 contents and decreased auxin levels. At low light intensities (30 MUmol m(-2) s(-1)), the leaves of the mutant were normal, but exhibited reduced H2 O2 contents and elevated auxin levels. These findings suggest that H2 O2 modulates auxin levels. When auxin was directly applied to cat2-1 leaves, the up-curled leaves curled downwards. In addition, transformation of cat2-1 plants with pCAT2:iaaM, which increases auxin levels, rescued the hyponastic leaf phenotype. Using qRT-PCR, we demonstrated that the transcription of auxin synthesis-related genes and of genes that regulate leaf curvature is suppressed in cat2-1. Furthermore, application of glutathione rescued the up-curled leaves of cat2-1 and increased auxin levels, but did not change H2 O2 levels. Thus, the hyponastic leaves of cat2-1 reveal crosstalk between H2 O2 and auxin signalling that is mediated by changes in glutathione redox status. PMID- 23738954 TI - Bioaccessibility of Cd, Cu, Fe, Mn, Pb, and Zn in hazelnut and walnut kernels investigated by an enzymolysis approach. AB - Bioaccessibility of four essential (Fe, Cu, Mn, Zn) and two toxic (Cd, Pb) elements in kernels of four walnut and four hazelnut cultivars was investigated using sequential enzymolysis approach and atomic absorption spectrometry. It was found that the assimilable part of elements was not dependent on nut cultivar. The bioaccessible fraction of Cu, Mn, and Zn was definitely higher for hazelnuts (62% Cu, 39% Mn, 58% Zn) than for walnuts (14% Cu, 21% Mn, 15% Zn). Bioaccessible Fe was 20-24% from its total content for both nut types. Solubility in the simulated intestinal juice is affected by both formation of stable soluble complexes and back sorption of dissolved elements on nut solid residues. Lead shows strong insolubility due to the high sorption affinity of lead ions to the insoluble fraction of nuts. Thus, walnuts and hazelnuts could act as effective biosorbents for lead detoxication. PMID- 23738956 TI - Commentary on frequency of malignant neoplasms in 257 chronic leg ulcers. PMID- 23738955 TI - Oxidative stress and anti-oxidant enzyme activities in the trophocytes and fat cells of queen honeybees (Apis mellifera). AB - Trophocytes and fat cells of queen honeybees have been used for delayed cellular senescence studies, but their oxidative stress and anti-oxidant enzyme activities with advancing age are unknown. In this study, we assayed reactive oxygen species (ROS) and anti-oxidant enzymes in the trophocytes and fat cells of young and old queens. Young queens had lower ROS levels, lower superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, and higher thioredoxin reductase (TR) activity compared to old queens. These results show that oxidative stress and anti-oxidant enzyme activities in trophocytes and fat cells increase with advancing age in queens and suggest that an increase in oxidative stress and a consequent increase in stress defense mechanisms are associated with the longevity of queen honeybees. PMID- 23738957 TI - Commentary: A split-face study using the 1,927-nm thulium fiber fractional laser for photoaging and melasma in Asian skin. PMID- 23738958 TI - Commentary on preliminary experience with intraoperative near-infrared fluorescence imaging in percutaneous sclerotherapy of soft-tissue venous malformations. PMID- 23738959 TI - Commentary: Use of porcine xenografts on partial-thickness vermilion border and mucosal lower lip Mohs defects. PMID- 23738960 TI - Neonatal seizures therapy: we are still looking for the efficacious drug. AB - Therapeutic options currently available for neonatal seizures are still unsatisfactory both in terms of efficacy and of risk for long-term neurotoxicity, even if there is growing recognition of their potential to worsen neurodevelopmental outcome. A recent paper by Slaughter and colleagues entitled "Pharmacological treatment of neonatal seizures: a systematic review" has been published with the aim to provide a treatment algorithm, but, due to the relative paucity of clinical studies, it relies mainly on traditional antiepileptic drugs and does not distinguish between different neonatal populations, especially preterm and hypothermic neonates, who might require a dedicated approach in order to improve seizure control and reduce side effects. PMID- 23738962 TI - Reconstruction of the premaxilla by segmental distraction osteogenesis for maxillary retrusion in cleft lip and palate. AB - We present a strategy to target one of the main areas causing retruded maxilla, the premaxillary region for patients with cleft lip and palate (CLP). Advancement of the premaxilla by distraction osteogenesis is attempted, and the retruded anterior maxilla, the collapsed dental space, and the arch shape are sufficiently improved. This strategy also prevents deterioration of the velopharyngeal incompetency function. The procedure seems to be a good option for the treatment of maxillary retrusion and malocclusion for CLP. PMID- 23738961 TI - A seroepidemiological survey of Crimean Congo hemorrhagic fever among cattle in North Kordufan State, Sudan. AB - BACKGROUND: Crimean Congo hemorrhagic fever (CCHF), caused by CCHF virus (CCFV), may cause a fatal hemorrhagic illness in humans with mortality rate of approximately 30%. However, in animals the disease is typically asymptomatic and no clinical hemorrhagic infections appears to be associated with CCHFV. Recently, CCHF activity has been detected in western and southern Kordufan region, Sudan. Currently, no information is available in regard to previous exposure of livestock to CCHFV infection in the region. AIMS: In the present study, a seroepidemiological survey was conducted to determine the prevalence of CCHF and to identify the potential risk factors associated with the disease among cattle in North Kordufan State, Sudan. METHODS: In this survey, 299 blood samples were collected randomly from six localities in North Kordufan State and were tested by enzyme-linked immunosorbent assay (ELISA) for detection of CCHFV-specific immunoglobulin G (IgG) antibodies. RESULTS: The result of the study indicated that the prevalence rate of CCHF was relatively high among cattle, where serological evidence of the infection was observed in 21 (7.0%) of 299 animals. Older cattle were eight times more likely to be infected with the virus (OR=8.0824, CI=1.174-66.317, p-value=0.034). Cross breeds were at 37 time higher at risk compared to endogenous breed (OR=37.06, CI=1.455-944, p-value=0.029). Highly tick-infested cattle are 6 times higher at risk for CCHF when compared to tick-free animals (OR=6.532, CI=1.042-10.852, p-value=0.030). CONCLUSION: It is recommended that surveillance of CCHF should be extended to include other ruminant animals and to study the distribution of ticks in the region to better predict and respond to CCHF outbreak in the State of North Kordufan, Sudan. PMID- 23738963 TI - MTTP polymorphisms and susceptibility to non-alcoholic fatty liver disease in a Han Chinese population. AB - BACKGROUND: The microsomal triglyceride transfer protein (MTP) is required for the assembly and secretion of apolipoprotein B (ApoB)-containing lipoproteins from the liver and intestine. Previous studies showed that functional polymorphisms in the MTTP gene correspond to lower LDL levels and protect against other traits of the metabolic syndrome. AIMS: Here, we aimed to investigate whether MTTP single nucleotide polymorphisms (SNPs) and their predicted haplotypes of linkage disequilibrium blocks contribute to non-alcoholic fatty liver disease (NAFLD) susceptibility in a Han Chinese population. METHODS: Seven tag SNPs in the MTTP gene were selected and genotyped in a frequency-matched case control study in a population from Fuzhou City, China. We enrolled 580 patients with NAFLD and 580 healthy controls. RESULTS: In the multivariate logistic regression analysis, the rs1800804 (-164 T/C) was associated with an increased risk of NAFLD, while the rs1057613 A/G and rs3805335 C/T SNPs were associated with a decreased risk of NAFLD. The cumulative effect of the rs1800804 (-164 T/C), rs1057613 and rs3805335 was estimated, and a significant increased trend in the risk of NAFLD with increasing genetic risk score was observed (adjusted P(trend) = 0.014). Furthermore, the results of haplotype analysis suggested that the haplotype GC in block 1 containing the -164 C allele was associated with an increased risk of NAFLD, while haplotype TGTTC in block 2 was associated with a decreased risk of NAFLD. CONCLUSIONS: Our data show that MTTP genetic polymorphisms influence the susceptibility to developing NAFLD independently or jointly in the Han Chinese population. PMID- 23738964 TI - Immunoprofiling of oral squamous cell carcinomas reveals high p63 and survivin expression. AB - BACKGROUND: Cancer is a multifactorial disease composed of cells that show somatic mutations and epigenetic changes. The aim of this study was to investigate the expression of proteins involved in the development and maintenance of epithelia, cell cycle regulation, and apoptosis in human oral squamous cell carcinoma (OSCC) tissue samples. METHODS: A tissue microarray containing 65 primary human OSCC specimens was immunolabeled for bcl-2, survivin, epidermal growth factor receptor (EGFR), p21, p53, p63, and cleaved caspase-3. RESULTS: Samples were scored for percentage of positively stained tumor cells and staining intensity. A total immunostaining score was also calculated, using the product of percentage and intensity scores. All specimens showed high scores, > 75%, for p63 and survivin, and 75.4% of the specimens also presented high EGFR expression. All cases showed p53-positive cells. p21 showed a diffuse staining pattern. The percentage of cells positive for cleaved caspase-3 and bcl-2 was low. CONCLUSIONS: The high frequency of tumor cells expressing p63 and survivin highlights the role of these proteins in the malignant transformation of oral epithelium. Collectively, our results suggest that p63 and survivin may constitute attractive targets for cancer therapy in patients with OSCC. PMID- 23738965 TI - Evaluation of biofilm production by Pseudomonas aeruginosa from canine ears and the impact of biofilm on antimicrobial susceptibility in vitro. AB - BACKGROUND: Pseudomonas aeruginosa is a common cause of canine otitis; P. aeruginosa biofilm formation has been documented in human medicine, but the role of biofilms in canine disease is not well documented. Bacteria within biofilms can be more resistant to antibiotics compared with their planktonic form; therefore, understanding the biofilm-forming capacity of isolates and their susceptibility to antimicrobials is important when developing treatment regimens. HYPOTHESIS/OBJECTIVES: To evaluate the biofilm-forming capacity of canine otic isolates of P. aeruginosa and to compare the minimal inhibitory concentration (MIC) of the planktonic versus biofilm-embedded bacteria. METHODS: Biofilm forming ability was assessed using a microtitre plate assay. Broth microdilution was used to assess the MICs of neomycin, polymyxin B, enrofloxacin and gentamicin for the planktonic and biofilm-embedded bacteria. RESULTS: Eighty-three isolates from dogs with otitis were tested; 33 (40%) were classified as biofilm producers. Biofilm MICs for polymyxin B, neomycin, gentamicin and enrofloxacin were significantly higher than for the planktonic form (P < 0.05). CONCLUSIONS AND CLINICAL IMPORTANCE: Biofilm production by otitis isolates of P. aeruginosa is common and may play a role in the pathogenesis of disease. The MICs for biofilm embedded bacteria differ from their planktonic counterparts, potentially leading to a lack of response to treatment. If polymyxin B, gentamicin, neomycin or enrofloxacin is to be used for topical treatment of a Pseudomonas otitis, the concentration of the medication should be increased, in particular if addressing chronic otitis, because biofilms may have developed. PMID- 23738966 TI - Treatment of traumatic dental intrusion by surgical repositioning. AB - The prevalence of dental trauma and its consequences are challenging. This article presents a clinical case of a 9-year-old female who was in a bicycling accident and had a dental intrusion of the left maxillary lateral incisor with extensive dislocation. In the emergency department, surgical repositioning of the intruded tooth and a splinting with steel wire and composite resin was performed and the soft-tissue lesions were sutured. Two weeks after the first visit, pulp necrosis was found and endodontic treatment of the intruded tooth was started with a calcium hydroxide dressing. Despite the traumatic nature of the dental injury, the result of treatment was favorable. After 3 years of follow-up, repair of the resorptions and no signs of ankylosis of the teeth involved were evident. Considering the patient's age and the extent of intrusion, it was concluded that surgical repositioning associated with adequate endodontic therapy was an effective alternative treatment for this case. PMID- 23738967 TI - Fiber-reinforced composites as a fixed space maintainer in case of primary tooth loss. AB - Restorative dentistry is continually changing, with ground-breaking treatments developing based on new materials, techniques, and technologies. Composite materials are a leading example, and the introduction of fiber reinforcement has further increased the possible uses of composites in restorative dentistry. Maintaining arch length during primary, mixed, and early permanent dentition is essential for the development of occlusion. In an effort to prevent future problems, appliances may be placed to retain space resulting from early loss of teeth. In case of primary teeth loss, fixed space maintainers are being used, but these are time consuming to fabricate, and incorporated wires may lead to soft tissue trauma. This clinical case uses fiber-reinforced composite as a space maintainer, thus reducing the time required to complete treatment. In spite of best efforts of practicing dentists, there still remains a large percentage of the population who do not present for treatment, except with pain or other condition. Unfortunately some of those individuals are children, who are not in a position to make the difficult decision to visit the dentist independently. Often by the time they are examined, there is no chance of saving the involved tooth, necessitating extraction and space maintenance. To prevent closure of space and arch length deficiency, appliances may be placed to retain space. Different appliances may be used for space maintenance, such as the removable and fixed space maintainers, but they are difficult and time consuming to construct. Also, the attention span of a child patient is insufficient for this treatment protocol. Considering these difficulties, the clinician could choose the option of a space maintainer, which is less time consuming to fabricate, and for which patient acceptance is optimal. PMID- 23738968 TI - Survival of dental implants among post-menopausal female dental school patients taking oral bisphosphonates: a retrospective study. AB - HYPOTHESIS: Osteoporotic patients who take oral bisphosphonates have a higher chance of developing osteonecrosis of the jaw if they receive dental implants. INTRODUCTION: Bisphosphonate treatment was first identified by Marx in 2003 as a possible contributor to osteonecrosis of the jaw, a serious dental-medical complication that is seen among individuals undergoing invasive dental procedures such as extractions and implant placement. Bisphosphonate-associated osteonecrosis of the jaw (BONJ) is defined as bone exposed for more than 8 weeks in the maxillofacial region with a negative history for radiation therapy. PATIENTS AND METHODS: A retrospective review of patient electronic health records (EHRs) at the University of Pittsburgh School of Dental Medicine identified 211 women who received 592 dental implants between January 2008 and August 2010. Each woman's EHR was searched for notation in the clinical record of evidence of osteonecrosis of the jaw. Only women taking oral bisphosphonates were included. RESULTS: Among the total 211 women, 120 exceeded age 50 and had received 347 implants. Twenty-two reported taking oral bisphosphonates as treatment for osteoporosis, one as treatment for osteoarthritis. Five additional women reported taking alternative medications instead of bisphosphonates as treatment for diagnosed osteoporosis. Seventy-five implants were placed in women self-reporting a history of oral bisphosphonates; seven implants were placed in osteoporotic women who did not self-report oral bisphosphonate treatment. There was no evidence of osteonecrosis of the jaw in the follow-up medical record of any patient. Only one implant did not osseointegrate and was replaced within 1 year. This 98.7% success rate is consistent with standard implant success rates. CONCLUSIONS: Oral bisphosphonate therapy did not appear to significantly affect implant success. Implant placement in osteoporotic women taking oral bisphosphonates in treatment for osteoporosis did not result in reported clinical evidence of osteonecrosis of the jaw. Nevertheless, because of the increasing number of osteoporotic patients being treated with bisphosphonates, a better understanding of the risks of implant placement in such patients would benefit both the clinician and patient. PMID- 23738969 TI - Characterization of a rare case of Ullrich congenital muscular dystrophy due to truncating mutations within the COL6A1 gene C-terminal domain: a case report. AB - BACKGROUND: Mutations within the C-terminal region of the COL6A1 gene are only detected in Ullrich/Bethlem patients on extremely rare occasions. CASE PRESENTATION: Herein we report two Brazilian brothers with a classic Ullrich phenotype and compound heterozygous for two truncating mutations in COL6A1 gene, expected to result in the loss of the alpha1(VI) chain C2 subdomain. Despite the reduction in COL6A1 RNA level due to nonsense RNA decay, three truncated alpha1 (VI) chains were produced as protein variants encoded by different out-of-frame transcripts. Collagen VI matrix was severely decreased and intracellular protein retention evident. CONCLUSION: The altered deposition of the fibronectin network highlighted abnormal interactions of the mutated collagen VI, lacking the alpha1(VI) C2 domain, within the extracellular matrix, focusing further studies on the possible role played by collagen VI in fibronectin deposition and organization. PMID- 23738970 TI - Tensile properties in collagen-rich tissues of Quarter Horses with hereditary equine regional dermal asthenia (HERDA). AB - REASONS FOR PERFORMING STUDY: Hereditary equine regional dermal asthenia (HERDA) is an autosomal recessive disorder of Quarter Horses characterised by skin fragility. Horses with HERDA have a missense mutation in peptidyl-prolyl cis trans isomerase B (PPIB), which encodes cyclophilin B and alters folding and post translational modifications of fibrillar collagen. OBJECTIVES: The study aimed to test the hypothesis that tendons, ligaments and great vessels, which, like skin, are rich in fibrillar collagen, will also have abnormal biomechanical properties in horses with HERDA. STUDY DESIGN: Ex vivo biomechanical study comparing horses with and without a diagnosis of HERDA. METHODS: Forelimb suspensory ligament, superficial and deep digital flexor tendons; withers, forelimb and abdominal skin; the main pulmonary artery and the aortic arch were harvested from 6 horses with HERDA and 6 control horses without the HERDA allele. Tissues were distracted to failure. Tensile strength (TS), elastic modulus (EM) and energy to failure (ETF) were compared. RESULTS: Horses with HERDA had significantly lower TS and EM in tendinoligamentous tissues and great vessels, respectively. The TS, EM and ETF were significantly lower in skin from horses with HERDA. Differences in TS and ETF were more extreme at the withers than at the forelimb or abdomen. CONCLUSIONS: Tendinoligamentous tissue, great vessels and skin are significantly weaker in horses with HERDA than in horses lacking the PPIB mutation, substantiating that diverse tissues with high fibrillar collagen content are abnormal in HERDA and that the HERDA phenotype is not limited to the integument. PMID- 23738971 TI - Research site monitoring for compliance with ethics regulatory standards: review of experience from Uganda. AB - BACKGROUND: On site monitoring of research is one of the most effective ways to ensure compliance during research conduct. However, it is least carried out primarily for two reasons: presumed high costs both in terms of human resources and finances; and the lack of a clear framework for undertaking site monitoring. In this paper we discuss a model for research site monitoring that may be cost effective and feasible in low resource settings. METHODS: This was a retrospective review of research site monitoring reports covering a period of four years. RESULTS: The monitoring was conducted by the Uganda National Council for Science and Technology, the National Drug Authority and the National HIV/AIDS Research and Ethics Committee over the period 2007 to 2010.The monitoring team was usually three members comprising of two experts in research ethics and an assistant. A total of 28 site monitoring visits covering 40 research projects were reviewed. 25% of the site monitoring reports revealed violation of the regulatory requirement for valid ethical approval. 36% of the site reports showed some instances of informed consent violation, 28% showed violation of the rights and welfare of research participants, 38% revealed that sites did not report SAEs to regulatory authorities and many sites lacked adequate GCP and GCLP. However, most of the sites monitored had adequate facilities to conduct the respective studies and good working practices. CONCLUSION: This model employed by the monitoring teams to evaluate research compliance is effective in auditing ethical practice. Compliance monitoring is feasible and affordable in a resource limited setting. Research protocol non compliance is still a major problem in Uganda, and there is need for a pro-active approach to this vice by all stake holders if ethical conduct of research is to be achieved. PMID- 23738972 TI - Characteristics and prognostic factors for head and neck non-Hodgkin's lymphoma in Chinese patients. AB - BACKGROUND AND OBJECTIVES: The head and neck region is the second most frequent anatomical site of extranodal lymphomas. These tumours affect many individuals worldwide, justifying epidemiological studies in different countries. This study evaluated the characteristics, treatments and prognostic factors for non Hodgkin's lymphoma of the head and neck in Chinese patients. METHOD: The clinical manifestations, clinicopathological characteristics, multidisciplinary treatment and prognostic factors for 102 patients with extranodal non-Hodgkin's lymphoma of the head and neck were analysed retrospectively. RESULT: The tonsil was the most commonly involved primary site, followed by the nasal cavity. The most common histological subtype was diffuse large B-cell lymphoma, followed by natural killer T-cell lymphoma. Patients receiving a combination of rituximab and chemotherapy did better than those receiving chemotherapy alone. Prognosis was significantly associated with both International Prognostic Index and histological subtype; the former was especially strongly associated with poor survival. CONCLUSION: In this group of Chinese patients, diffuse large B-cell lymphoma was the most common pathological subtype, but the incidence of T-cell lymphomas was higher than that reported in the USA. Combined rituximab and chemotherapy led to better outcomes than chemotherapy alone. Prognosis depended on both International Prognostic Index and histological subtype. PMID- 23738973 TI - Current treatment options for hyperprolactinemia. AB - INTRODUCTION: Hyperprolactinemia is a prevalent cause of oligo-amenorrhea, and prolactinomas are the most common type of functional pituitary tumor. Untreated hyperprolactinemia can lead to bone loss and impair gonadal function and fertility. Normalization of prolactin improves bone mass and restores gonadal function in a majority of patients. AREAS COVERED: This article contains an overview of hyperprolactinemia with an emphasis on pharmacologic, surgical and radiation treatment options. Discussion focuses on the efficacy and safety of available treatments and comments on new and emerging therapies. EXPERT OPINION: Dopamine agonists, usually cabergoline, remain the primary choice for initial treatment of hyperprolactinemia. Surgery may also be an appropriate alternative in certain circumstances. Monotherapy with dopamine agonists is often successful at controlling prolactin levels and tumor size, but adjunctive treatments may be necessary for resistant or aggressive prolactinomas. PMID- 23738974 TI - Cardiopulmonary toxicity of pulmonary exposure to occupationally relevant zinc oxide nanoparticles. AB - Exposure to zinc oxide (ZnO) metal fumes is linked to adverse human health effects; however, the hazards of ZnO nanoparticles (ZnONPs) remain unclear. To determine pulmonary exposure to occupationally relevant ZnONPs cause cardiopulmonary injury, Sprague-Dawley rats were exposed to ZnONPs via intratracheal (IT) instillation and inhalation. The relationship between intrapulmonary zinc levels and pulmonary oxidative-inflammatory responses 72 h after ZnONP instillation was determined in bronchoalveolar lavage fluid (BALF). Instilled ZnONPs altered zinc balance and increased the levels of total cells, neutrophils, lactate dehydrogenase (LDH) and total protein in BALF and 8-hydroxy 2'-deoxyguanosine (8-OHdG) in blood after 72 h. The ZnONPs accumulated predominantly in the lungs over 24 h, and trivial amounts of zinc were determined in the heart, liver, kidneys and blood. Furthermore, the inflammatory-oxidative responses induced by occupationally relevant levels of 1.1 and 4.9 mg/m(3) of ZnONP inhalation for 2 weeks were determined in BALF and blood at 1, 7 and 30 days post-exposure. Histopathological examinations of the rat lungs and hearts were performed. Inhalation of ZnONP caused an inflammatory cytological profile. The total cell, neutrophil, LDH and total protein levels were acutely increased in the BALF, and there was an inflammatory pathology in the lungs. There were subchronic levels of white blood cells, granulocytes and 8-OHdG in the blood. Cardiac inflammation and the development of fibrosis were detected 7 days after exposure. Degeneration and necrosis of the myocardium were detected 30 days after exposure. The results demonstrate that ZnONPs cause cardiopulmonary impairments. These findings highlight the occupational health effects for ZnONP-exposed workers. PMID- 23738976 TI - Structure and bonding in ionized water clusters. AB - The structure and bonding in ionized water clusters, (H2O)(n)(+) (n = 3-9), has been studied using the basin hopping search algorithm in combination with quantum chemical calculations. Initially candidate low energy isomers were generated using basin hopping in conjunction with density functional theory. Subsequently, the structures and energies were refined using second order Moller-Plesset perturbation theory and coupled cluster theory, respectively. The lowest energy isomers are found to involve proton transfer to give H(3)O(+) and a OH radical, which are more stable than isomers containing the hemibonded hydrazine-like fragment (H(2)O-OH(2)), with the calculated infrared spectra consistent with experimental data. For (H(2)O)(9)(+) the observation of a new structural motif comprising proton transfer to form H(3)O(+) and OH, but with the OH radical involved in hemibonding to another water molecule is discussed. PMID- 23738975 TI - Development of quinic acid-conjugated nanoparticles as a drug carrier to solid tumors. AB - Nanometer-sized drug carriers including polymeric nanoparticles (NPs) have been used to increase biodistribution of a drug in tumors, thereby reducing the effective dose of chemotherapy. NPs increase drug delivery to tumors to a certain extent, but the amount reaching tumors is only a small fraction of the total administered NPs because they depend on passive accumulation via the leaky vasculature surrounding tumors. In an attempt to further increase the drug delivery to tumors, we develop a polymeric NP system that interacts with an endothelial tumor marker. The NPs are decorated with quinic acid, a synthetic mimic of sialyl Lewis-x, which binds to E-selectin, overexpressed on the surface of endothelial cells surrounding solid tumors. The NPs selectively bind to endothelial cells activated with tumor necrosis factor-alpha, with weak affinity at a relatively high shear stress. These properties may help NPs reach tumors by increasing the encounter of NPs with the peritumoral endothelium without hindering subsequent transport of the NPs. PMID- 23738977 TI - Prospects for emerging infections in East and southeast Asia 10 years after severe acute respiratory syndrome. AB - It is 10 years since severe acute respiratory syndrome (SARS) emerged, and East and Southeast Asia retain a reputation as a hot spot of emerging infectious diseases. The region is certainly a hot spot of socioeconomic and environmental change, and although some changes (e.g., urbanization and agricultural intensification) may reduce the probability of emerging infectious diseases, the effect of any individual emergence event may be increased by the greater concentration and connectivity of livestock, persons, and products. The region is now better able to detect and respond to emerging infectious diseases than it was a decade ago, but the tools and methods to produce sufficiently refined assessments of the risks of disease emergence are still lacking. Given the continued scale and pace of change in East and Southeast Asia, it is vital that capabilities for predicting, identifying, and controlling biologic threats do not stagnate as the memory of SARS fades. PMID- 23738978 TI - Microbial short-chain fatty acid production and extracellular enzymes activities during in vitro fermentation of polysaccharides from the seeds of Plantago asiatica L. treated with microwave irradiation. AB - Effects of microwave irradiation on microbial short-chain fatty acid production and the activites of extracellular enzymes during in vitro fermentation of the polysaccharide from Plantago asiatica L. were investigated in this study. It was found that the apparent viscosity, average molecular weight, and particle size of the polysaccharide decreased after microwave irradiation. Reducing sugar amount increased with molecular weight decrease, suggesting the degradation may derive from glycosidic bond rupture. The polysaccharide surface topography was changed from large flakelike structure to smaller chips. FT-IR showed that microwave irradiation did not alter the primary functional groups in the polysaccharide. However, short-chain fatty acid productions of the polysaccharide during in vitro fermentation significantly increased after microwave irradiation. Activities of microbial extracellular enzymes xylanase, arabinofuranosidase, xylosidase, and glucuronidase in fermentation cultures supplemented with microwave irradiation treated polysaccharide were also generally higher than those of untreated polysaccharide. This showed that microwave irradiation could be a promising degradation method for the production of value-added polysaccharides. PMID- 23738980 TI - Intracellular localization and induction of a dynamic RNA-editing event of macro algal V-ATPase subunit A (VHA-A) in response to copper. AB - A V-ATPase subunit A protein (VHA-A) transcript together with a variant (C793 to U), which introduces a stop codon truncating the subunit immediately downstream of its ATP binding site, was identified within a Fucus vesiculosus cDNA from a heavy metal contaminated site. This is intriguing because the VHA-A subunit is the crucial catalytic subunit responsible for the hydrolysis of ATP that drives ion transport underlying heavy metal detoxification pathways. We employed a chemiluminescent hybridization protection assay to quantify the proportion of both variants directly from mRNA while performing quantification of total transcript using Q-PCR. Polyclonal antisera raised against recombinant VHA-A facilitated simultaneous detection of parent and truncated VHA-A and revealed its cellular and subcellular localization. By exploiting laboratory exposures and samples from an environmental copper gradient, we showed that total VHA-A transcript and protein, together with levels of the truncated variant, were induced by copper. The absence of a genomic sequence representing the truncated variant suggests a RNA editing event causing the production of the truncated VHA A. Based on these observations, we propose RNA editing as a novel molecular process underpinning VHA trafficking and intracellular sequestration of heavy metals under stress. PMID- 23738981 TI - Necrolytic migratory erythema associated with a glucagon-producing primary hepatic neuroendocrine carcinoma in a cat. AB - BACKGROUND: In humans, necrolytic migratory erythema (NME) is a syndrome with a characteristic skin rash that is associated most often with a pancreatic glucagonoma and is recognized as part of the glucagonoma syndrome. In veterinary medicine, NME (also called as superficial necrolytic dermatitis, hepatocutaneous syndrome or metabolic epidermal necrosis) has been described in dogs in association with chronic liver diseases or, less frequently, glucagonoma, but NME associated with glucagonoma has not previously been reported in cats. CASE REPORT: A 6-year-old male neutered domestic short hair cat was diagnosed with NME associated with a glucagon-producing primary hepatic neuroendocrine carcinoma (hepatic carcinoid). The cat presented with a 2 week history of vomiting and anorexia, and a 5-cm-diameter liver mass was detected by abdominal ultrasound. The cat exhibited general weakness, crusted skin lesions and pain in all four limbs. It was euthanized 11 months after the initial presentation. Histopathological review of the paw pads revealed the classic 'red, white and blue' lesion composed of parakeratotic hyperkeratosis, epidermal hydropic change and hyperbasophilia of the deep epidermis. The liver mass was diagnosed as a neuroendocrine carcinoma (hepatic carcinoid). Neoplastic cells were strongly immunoreactive for glucagon. CONCLUSION AND CLINICAL IMPORTANCE: This is the first case report of NME associated with a glucagon-producing primary hepatic neuroendocrine carcinoma in a cat. PMID- 23738983 TI - Problem severity, technology adoption, and intent to seek online counseling among overseas Filipino workers. AB - This study examined the factors that influence the intent to seek online counseling among overseas Filipino workers (OFWs). A survey among 365 OFWs revealed that problem severity and technology adoption predict intent to use online counseling. Among the three factors of technology adoption, perceived ease in the use of technology and perceived presence of organization and technological infrastructure to support use predicted intent to use online counseling. Our hypothesis about the presence of interaction between problem severity and facilitating conditions was supported. Among individuals with low problem severity, those who perceive the presence of organization and technological infrastructure to support use have a higher intent to use online counseling. However, at higher levels of problem severity, the effect of facilitating conditions seems to disappear. These findings highlight the crucial role of preventive online mental health services. The study contributes to theory by integrating the stage model of help-seeking behaviors and technology adoption theory in predicting intent to use online counseling. Specifically, that intent to seek online counseling is affected by the existence and perceived gravity of a problem, moderated by technology adoption factors, particularly facilitating conditions. These have implications on the need to educate potential users on the advantages of counseling and ensure that migrant workers have access to technology and that the technology is easy to use. PMID- 23738982 TI - Abdominal aortic calcification is not superior over other vascular calcification in predicting mortality in hemodialysis patients: a retrospective observational study. AB - BACKGROUND: KDIGO (Kidney Disease: Improving Global Outcomes) guidelines recommend that a lateral abdominal radiograph should be performed to assess vascular calcification (VC) in dialysis patients. However, abdominal aortic calcification is a prevalent finding, and it remains unclear whether other anatomical areas of VC can predict mortality more accurately. METHODS: A total of 217 maintenance hemodialysis patients were enrolled at the Sichuan Provincial People's Hospital between July 2010 and March 2011. Radiographs of the abdomen, pelvis and hands were evaluated by a radiologist to evaluate the presence of VC. The correlation between different areas of VC and all-cause or cardiovascular mortality was analyzed using univariate and multivariate models. RESULTS: The prevalence of VC was 70.0% (152 patients), and most had abdominal aortic calcification (90.1%). During 26 +/- 7 months of follow-up, 37 patients died. The VC score was independently associated with patient mortality. VC observed on abdominal radiographs (abdominal aortic calcification) was associated with all cause mortality in models adjusted for cardiovascular risk factors (HR, 4.69; 95%CI, 1.60-13.69) and dialysis factors (HR, 3.38; 95%CI, 1.18-9.69). VC in the pelvis or hands was associated with all-cause mortality in the model adjusted for dialysis factors. When three combinations of VC in different radiographs were included in models, the presence of abdominal VC was only significantly associated with all-cause mortality in the integrated model. VC in the abdomen and pelvis was associated with all-cause mortality in the model adjusted for cardiovascular factors and the integrated model, but neither was significantly associated with cardiovascular mortality. VC in all radiographs was significantly associated with a more than 6-fold risk of all-cause mortality and a more than 5 fold risk of cardiovascular mortality compared to patients without VC. CONCLUSIONS: VC in different arteries as shown on radiographs is associated with different levels of risk for mortality. The lateral abdominal radiograph may not be superior to other radiographs for predicting patient outcomes. Further research is needed to elucidate the effects of difference burdens of VC on patient outcomes. PMID- 23738984 TI - Pollution of surface waters by metalaxyl and nitrate from non-point sources. AB - The mobility of contaminants in soil is highly dependent upon the characteristics of the contaminant chemical and the properties of the soil. In order to explore these relationships, the district of A Limia (Galicia, NW Spain) was selected as the study area--a cropland devoted to growing potatoes, where the soil had been managed intensively over the last 50 years. The soil was characterised by low slopes with the water table located very close to the soil surface. Our aim was to study the influence of high and intensive crop production on the water bodies and non-point source contamination, with a particular focus on metalaxyl and nitrate. The highest concentrations of metalaxyl occurred when rainfalls were low and in zones of the study area where natural hydrology was significantly altered by numerous drainage canals. The spatial and temporal distributions of the nitrate also showed a high variability, with the interaction between seasons and sampling area being the most significant factor in explaining the levels found. PMID- 23738985 TI - Occupational exposures of airborne trichloramine at indoor swimming pools in Taipei. AB - Ten indoor swimming pools in Taipei, Taiwan were included in the study to assess the exposure of people to airborne trichloramine (NCl3) and also to discover the factors that might affect the associated concentrations. An active air sampling method was performed to determine the levels of NCl3, while questionnaires were administered to swimming pool workers, including lifeguards, swimming instructors, and management employees. The results show that the concentrations of trichloramine ranged from 0.017 to 0.15 mg m(-3), which were generally lower than what have been reported from other studies. Symptoms of sore throat and phlegm were more frequent among lifeguards and swimming instructors (exposure group) than management employees (reference group) (odds ratios were 11.28 and 4.22 for sore throat and phlegm, respectively). It seems that the current exposure limit for airborne NCl3, which was recommended by WHO, was not lower enough to protect the health of pool attendants. Regulated level of free available chlorine in Taipei (i.e., 0.3-0.7 ppm) is lower than what is required in other countries (e.g., 1-3 ppm in the UK). This might be the main reason why the concentrations of NCl3 reported elsewhere were higher than what were found in this research. Further international comparisons will help to elucidate if low free chlorine concentration should be adopted as an operating standard. For the indoor swimming pools in Taipei, the air quality is suggested to be improved, since even with the low concentrations of NCl3, higher respiratory ailments among pool workers were observed. PMID- 23738986 TI - Application of green zero-valent iron nanoparticles to the remediation of soils contaminated with ibuprofen. AB - Zero-valent iron nanoparticles (nZVIs) are often used in environmental remediation. Their high surface area that is associated with their high reactivity makes them an excellent agent capable of transforming/degrading contaminants in soils and waters. Due to the recent development of green methods for the production of nZVIs, the use of this material became even more attractive. However, the knowledge of its capacity to degrade distinct types of contaminants is still scarce. The present work describes the study of the application of green nZVIs to the remediation of soils contaminated with a common anti-inflammatory drug, ibuprofen. The main objectives of this work were to produce nZVIs using extracts of grape marc, black tea and vine leaves, to verify the degradation of ibuprofen in aqueous solutions by the nZVIs, to study the remediation process of a sandy soil contaminated with ibuprofen using the nZVIs, and to compare the experiments with other common chemical oxidants. The produced nZVIs had nanometric sizes and were able to degrade ibuprofen (54 to 66% of the initial amount) in aqueous solutions. Similar remediation efficiencies were obtained in sandy soils. In this case the remediation could be enhanced (achieving degradation efficiencies above 95%) through the complementation of the process with a catalyzed nZVI Fenton-like reaction. These results indicate that this remediation technology represents a good alternative to traditional and more aggressive technologies. PMID- 23738987 TI - An artificial sweetener and pharmaceutical compounds as co-tracers of urban wastewater in groundwater. AB - Groundwater in urban areas can be affected by numerous wastewater sources. Distinguishing these sources can facilitate better management of urban water resources and wastewater, and protection of urban aquatic environments. A single wastewater tracer, even if ideal (i.e. low background levels, non-reactive, low detection limits, etc.), would be unable to accomplish this task. Here, we investigated the potential advantages of using a suite of anthropogenic chemicals as co-tracers to distinguish wastewater sources that contribute to groundwater contamination at two urban sites. We considered both relatively ubiquitous and non-ubiquitous tracers in wastewater. At the Jasper (Alberta, Canada) site, concentrations of an artificial sweetener, two pharmaceutical compounds, and a degradate of nicotine in groundwater were strongly correlated as co-tracers. This evidence, along with the similar spatial distributions of these co-tracers could be used to delineate and distinguish a single municipal wastewater plume. At the Barrie (Ontario, Canada) site, there was moderate to strong correlation of the wastewater co-tracers, but local differences in their distributions and in the ratios of their concentrations could be used to infer that mixtures of two or more domestic septic plumes were present in the groundwater at this site. This study demonstrates the benefit of applying a suite of tracers to urban groundwater affected by wastewater contamination. This approach should be applicable at other urban sites. PMID- 23738988 TI - Evaluation of chemical parameters and ecotoxicity of a soil developed on gossan following application of polyacrylates and growth of Spergularia purpurea. AB - The aim of this study was to evaluate the chemical characteristics and ecotoxicity of a mine soil developed on gossan materials and amended with hydrophilic polyacrylate polymers after a growth cycle of Spergularia purpurea. Different acute bioassays (Daphnia magna immobilization; microalgae growth inhibition; germination and growth of lettuce and oat) were carried out with simulated leachates, pore water and soil samples. The germination and growth of native shrubs (Cistus ladanifer and Lavandula sampaioana) were also evaluated in the lysimeters where S. purpurea had grown. The soil had high total concentrations (g/kg) of Al (3.50-8.60), As (2.55-2.73), Cu (0.13-0.91) and Pb (4.48-6.16). However, the percentages of elements in aqueous extracts (simulating leachates, pore water, and the conditions of the rhizosphere soil) were small when compared to their total soil concentrations (less than 9% except for Na in leachates). Growth of S. purpurea and other natural colonization of plant species (Poaceae, Fabaceae and Asteraceae families) improved chemical characteristics but the application of the polyacrylate polymers contributed to a further improvement of soil quality. However, this was not sufficient to ensure the growth of a large number of shrubs despite a great germination rate. Among the several species used on the ecotoxicological assessment, the D. magna test was the only bioassay that showed a clear toxicity of soil leachates, suggesting the importance of using several ecotoxicological tests to assess the environmental risk of soil contamination and its rehabilitation. Although the studied soil can be considered contaminated taking into account the total soil concentrations of Al, As, Cu and Pb, the low concentrations of the same chemical elements in extractable solutions, that simulated the fractions really available for organisms, did not demonstrate a substantial toxic effects in the organisms and, consequently, negative impact on the environment. PMID- 23738990 TI - Bacterial endophthalmitis caused by an intraocular cilium in a patient under treatment with infliximab. AB - BACKGROUND: We report a case of bacterial endophthalmitis caused by an intraocular cilium in a patient without any history of trauma or ocular surgery. FINDINGS: A 32-year-old Caucasian male showed symptoms of orbital myositis and scleritis, with no intraocular inflammation in the right eye. The patient had been treated with infliximab for Crohn's disease. Three weeks after initiation of oral prednisolone therapy, he developed bacterial endophthalmitis. During pars plana vitrectomy, a cilium in the massive vitreous opacity was found. A focal scleral necrosis was detected just outside where the cilium was intraoperatively observed. Vitreous culture showed the presence of Staphylococcus aureus. CONCLUSIONS: The intraocular cilium seemed to be the aetiology of the endophthalmitis in this case, which suggests that anti-tumour necrosis factor alpha therapy may play a role in the migration of cilia into the globe and the occurrence of endophthalmitis. PMID- 23738989 TI - The willingness of informal caregivers to assist their care-recipient to use Home Medicines Review. AB - OBJECTIVES: Informal caregivers experience daily hassles - a form of persistent stress, as a consequence of caregiving. This study aimed to develop and test a new theoretical model of health information-seeking behaviour, the Knowledge Hassles Information Seeking Model (KHISM). KHISM hypothesized that the knowledge hassles of caregivers - daily stressors experienced while dealing with tasks which require knowledge about the safety and effectiveness of the care recipients' medicines - would influence caregivers' willingness to assist their care-recipient to use an Australian medication management service, Home Medicines Review (HMR). METHODS: A cross-sectional postal survey was conducted among 2350 members of Carers (NSW, Australia). Respondents were included in the study if they were involved in medication-related tasks for their care-recipient and were not paid as caregivers. Also, their care-recipient needed to be taking more than five medicines daily or more than 12 doses daily and had not yet experienced HMR. Structural equation modelling was used to test the model. RESULTS: A total of 324 useable surveys were returned yielding a response rate of 14%. Respondents were quite willing to assist their care-recipient to use HMR (willingness). The model predicted 51% of the variation in willingness. Knowledge hassles increased positive outcome expectancy (beta = 0.40, P < 0.05) and indirectly increased willingness. CONCLUSIONS: The more caregivers experience hassles with medication knowledge, the more they perceive HMR to be a helpful information source and the more willing they are to use it. Targeted marketing centred on HMR as an information source may increase caregivers' demand for HMR. Further exploration of the phenomenon of knowledge hassles is warranted. PMID- 23738991 TI - HIV-related stigma: Impact on healthcare workers in Vietnam. AB - Stigma has been identified as a major barrier to HIV response. While much is known about stigma directed towards people living with HIV (PLHIV), less is known about stigma experienced by health workers who treat PLHIV. This study aims to explore the perceptions and experiences of health workers regarding how stigma influences their work with HIV-positive patients. The study employed a qualitative design involving individual semi-structured in-depth interviews with 14 health workers, purposively selected from hospitals and detention centres for people who use drugs and sex workers in Hanoi, Vietnam. Findings showed that the stigma experienced by health workers may be organised around several themes: (1) lack of social prestige associated with HIV work; (2) fear of infection expressed by family members; (3) feelings of being devalued within the healthcare field; and (4) work-related stress and burnout, especially for staff working in detention centres for drug users and female sex workers. Efforts are needed to improve the public image of HIV work, scale up stigma reduction, enhance stress management and create a safe and supportive working environment for health workers. PMID- 23738993 TI - Direct restorative treatment of dental erosion caused by gastroesophageal reflux disease associated with bruxism: a case report. AB - Gastroesophageal reflux disease (GERD) is a gastrointestinal disorder in which stomach acids are chronically regurgitated into the esophagus and oral cavity. Continual exposure of the teeth to these acids can cause severe tooth wear. Dentists are often the first healthcare professionals to diagnose dental erosion in patients with GERD. This article presents a case report of a 27-year-old male smoker with tooth wear and dentin sensitivity caused by GERD associated with bruxism. After diagnosis, a multidisciplinary treatment plan was established. The initial treatment approach consisted of medical follow-up with counseling on dietary and smoking habits, as well as management of the gastric disorders with medication. GERD management and the dental treatment performed for the eroded dentition are described, including diagnosis, treatment planning, and restorative therapy. PMID- 23738994 TI - Additional diagnostic value of digital bitewing radiographs in detecting proximal caries in primary molars. AB - OBJECTIVE: The objective of this clinical epidemiologic study was to determine the additional yield of bitewing radiographs compared to clinical examinations in the estimation of proximal caries in primary molars. METHODS: Clinical data (N = 238) of 5- to 6-year-old children were collected by a calibrated examiner, and digital bitewing radiographs were taken after obtaining informed written consent from the parents. The radiographic examination of proximal surfaces was based on criteria derived from the clinical protocol. A single calibrated examiner recorded the data, and intra-examiner agreement was assessed using kappa statistics. Statistical analysis of data was performed using Chi-square test. RESULTS: Kappa values for intra-examiner agreement were 0.91 and 0.89 for clinical and radiographic examinations, respectively. Based on clinical judgment alone, the number of carious proximal surfaces was 62.7% (632 surfaces) in males and 58.9% (528 surfaces) in females. When bitewing radiographic judgment was included, this number increased to 80.6% (812 surfaces) in males and 71.9% (644 surfaces) in females. CONCLUSIONS: The overall value of bitewing radiographs in the present study was 18% and 13% in males and females, respectively. The benefits of digital bitewing radiographs can be used in epidemiologic studies and clinical practice to avoid underestimation of proximal caries. PMID- 23738992 TI - Long term effect of depression care management on mortality in older adults: follow-up of cluster randomized clinical trial in primary care. AB - OBJECTIVE: To investigate whether an intervention to improve treatment of depression in older adults in primary care modified the increased risk of death associated with depression. DESIGN: Long term follow-up of multi-site practice randomized controlled trial (PROSPECT-Prevention of Suicide in Primary Care Elderly: Collaborative Trial). SETTING: 20 primary care practices in New York City, Philadelphia, and Pittsburgh, USA, randomized to intervention or usual care. PARTICIPANTS: 1226 participants identified between May 1999 and August 2001 through a two stage, age stratified (60-74; >= 75 years) depression screening of randomly sampled patients; enrollment included patients who screened positive and a random sample of patients who screened negative. INTERVENTION: For two years, a depression care manager worked with primary care physicians in intervention practices to provide algorithm based care for depression, offering psychotherapy, increasing antidepressant dose if indicated, and monitoring symptoms, adverse effects of drugs, and adherence to treatment. This paper reports the long term follow-up. MAIN OUTCOME MEASURE: Mortality risk based on a median follow-up of 98 (range 0.8-116.4) months through 2008. RESULTS: In baseline clinical interviews, 396 people were classified as having major depression, 203 had clinically significant minor depression, and 627 did not meet criteria for depression. At follow-up, 405 patients had died. Patients with major depression in usual care were more likely to die than were those without depression (hazard ratio 1.90, 95% confidence interval 1.57 to 2.31). In contrast, patients with major depression in intervention practices were at no greater risk than were people without depression (hazard ratio 1.09, 0.83 to 1.44). Patients with major depression in intervention practices, relative to usual care, were 24% less likely to have died (hazard ratio 0.76, 0.57 to 1.00; P=0.05). Preliminary data on cause of death are provided. No significant effect on mortality was found for minor depression. CONCLUSIONS: Older adults with major depression in practices provided with additional resources to intensively manage depression had a mortality risk lower than that observed in usual care and similar to older adults without depression. TRIAL REGISTRATION: Clinical trials NCT00000367. PMID- 23738995 TI - Nonmotor symptoms in Parkinson's disease. PMID- 23738997 TI - Fingolimod for the treatment of relapsing multiple sclerosis. AB - Fingolimod 0.5 mg (Gilenya(TM), Novartis Pharmaceuticals Corporation, FL, USA) is the first once-daily oral therapy approved for relapsing forms of multiple sclerosis (MS) in the USA and for rapidly evolving severe MS or highly active disease despite IFN-beta treatment in Europe. An extensive clinical development program has established fingolimod as an effective therapy that reduces relapses by approximately half compared with placebo or intramuscular IFN-beta1a. Over 2 years of postmarketing experience in >63,000 MS patients (with >73,000 patient years of exposure) across the world has contributed to a well-characterized safety profile for fingolimod, and its side effects are manageable through patient monitoring. This article discusses the unique mechanisms of action of fingolimod in the immune and nervous systems, the key data underlying its efficacy and safety profile and perspectives on the role of fingolimod in current and future treatment strategies for MS. PMID- 23738998 TI - Ginsenoside Rd for acute ischemic stroke: translating from bench to bedside. AB - Numerous studies have identified pathophysiological mechanisms of acute ischemic stroke and have provided proof-of-principle evidence that strategies designed to impede the ischemic cascade, namely neuroprotection, can protect the ischemic brain. However, the translation of these therapeutic agents to the clinic has not been successful. Ginsenoside Rd, a dammarane-type steroid glycoside extracted from ginseng plants, has exhibited an encouraging neuroprotective efficacy in both laboratory and clinical studies. This article attempts to provide a synopsis of the physiochemical profile, pharmacokinetics, pharmacodynamics, clinical efficacy, safety and putative therapeutic mechanisms of Rd. Finally, the authors discuss the validity of Rd as a neuroprotective agent for acute ischemic stroke. PMID- 23739000 TI - mTOR inhibitors as a new therapeutic option for epilepsy. AB - Dysregulation of the mTOR signaling pathway is associated with highly epileptogenic conditions such as tuberous sclerosis, focal cortical dysplasia, hemimegalencephaly and ganglioglioma, grouped under the term of 'mTORopathies'. Brain abnormalities associated with mTOR overactivation include enlarged and dysplastic neurons, abnormal cortical organization and astrogliosis. mTOR signaling intervenes in several molecular/biochemical processes leading to epileptogenesis. Animal models demonstrated that mTOR inhibitors could exert both an anticonvulsant action and an antiepileptogenic effect in models of genetic and acquired epilepsy. Preliminary studies in patients affected by tuberous sclerosis and treated with rapamycin or everolimus demonstrated potential benefits in seizure frequency reduction, suggesting that mTOR inhibition could be a promising treatment option for mTORopathies-related epilepsy. The authors reviewed the current knowledge of mTOR overactivation in different forms of epilepsy, and discuss the potential clinical use of mTOR inhibitors. PMID- 23739001 TI - Investigating psychotropic properties of antiepileptic drugs. AB - Antiepileptic drugs (AEDs) are currently used in both neurology and in psychiatry. It is generally accepted that GABA-ergic compounds have sedative and anxiolytic properties, whereas channel blockers are mood stabilizers. However, this paradigm is often challenged. This is related to the variety of mechanisms of action of individual AEDs on biological systems, only some of which are related to the desired CNS effect. At present, just a few AEDs are licensed for psychiatric indications, namely carbamazepine, valproate, lamotrigine and pregabalin. Data on other AEDs show potential benefits, but are still inconclusive in some cases. This article discusses molecular targets of AEDs relevant for their psychotropic properties with special attention to newest compounds. Current knowledge gaps are also highlighted. PMID- 23739002 TI - AMPA receptor inhibitors for the treatment of epilepsy: the role of perampanel. AB - alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the postsynaptic membrane are involved in fast excitatory signaling in the brain and their activation may lead to the firing of action potentials. Talampanel and perampanel were the first noncompetitive AMPA receptor antagonists to be tested as add-on drugs in patients with refractory partial seizures, and were found to be effective in improving seizure control. Due to an unfavorable kinetic and tolerability profile, talampanel clinical development in the field of epilepsy was discontinued early while perampanel has been recently approved in Europe and the USA as adjunctive therapy for adults with partial seizures with or without secondary generalization. The recommended perampanel starting dose is 2 mg/day once daily, which can be increased up to the recommended maintenance dose of 4-8 mg/day. Increments should be of 2 mg/day and based on clinical response and tolerability. Titration should be performed at 1-week intervals or at lower speed and a 12-mg daily dose should be considered after careful evaluation. To date, no serious and/or idiosyncratic adverse effects have been associated with this agent. Most frequently reported adverse effects are dizziness, ataxia, aggression, irritability, vertigo, somnolence, fatigue, headache and gait disturbance. Weight increase is the only non-neurological adverse effects associated with perampanel. PMID- 23738999 TI - Novel frontiers in epilepsy treatments: preventing epileptogenesis by targeting inflammation. AB - Currently available epilepsy drugs only affect the symptoms (seizures), and there is a need for innovative treatments that target the underlying disease. Increasing evidence points to inflammation as a potentially important mechanism in epileptogenesis. In the last decade, a new generation of etiologically realistic syndrome-specific experimental models have been developed, which are expected to capture the epileptogenic mechanisms operating in corresponding patient populations, and to exhibit similar treatment responsiveness. Recently, an intervention known to have broad-ranging anti-inflammatory effects (selective brain cooling) has been found to prevent the development of spontaneously occurring seizures in an etiologically realistic rat model of post-traumatic epilepsy. Several drugs used clinically for other indications also have the potential for inhibiting inflammation, and should be investigated for antiepileptogenic activity in these models. If results of such studies are positive, these compounds could rapidly enter Phase III trials in patients at high risk of developing epilepsy. PMID- 23739004 TI - Revelation in the neuroprotective functions of rasagiline and selegiline: the induction of distinct genes by different mechanisms. AB - In Parkinson's disease, cell death of dopamine neurons in the substantia nigra progresses and neuroprotective therapy is required to halt neuronal loss. In cellular and animal models, selegiline [(-)deprenyl] and rasagiline, inhibitors of type B monoamine oxidase (MAO)-B, protect neuronal cells from programmed cell death. In this paper, the authors review their recent results on the molecular mechanisms by which MAO inhibitors prevent the cell death through the induction of antiapoptotic, prosurvival genes. MAO-A mediates the induction of antiapoptotic bcl-2 and mao-a itself by rasagiline, whereas a different mechanism is associated with selegiline. Rasagiline and selegiline preferentially increase GDNF and BDNF in nonhuman primates and Parkinsonian patients, respectively. Enhanced neurotrophic factors might be applicable to monitor the neurorescuing activity of neuroprotection. PMID- 23739005 TI - Network modeling to identify new mechanisms and therapeutic targets for Parkinson's disease. AB - Biomolecules in subnetworks are the focus of a new strategy to develop drugs that halt complex diseases. In this article, the authors use genome-wide association study and linkage data derived from Parkinson's disease studies to illustrate how algorithms that use gene and protein interaction databases reveal subnetworks in biological systems that suggest mechanisms for disease progression. Network modeling may help develop testable hypotheses for neurodegenerative diseases and open up new avenues for therapeutic development. PMID- 23739003 TI - A critical review of mTOR inhibitors and epilepsy: from basic science to clinical trials. AB - Present medications for epilepsy have substantial limitations, such as medical intractability in many patients and lack of antiepileptogenic properties to prevent epilepsy. Drugs with novel mechanisms of action are needed to overcome these limitations. The mTOR signaling pathway has emerged as a possible therapeutic target for epilepsy. Preliminary clinical trials suggest that mTOR inhibitors reduce seizures in tuberous sclerosis complex (TSC) patients with intractable epilepsy. Furthermore, mTOR inhibitors have antiepileptogenic properties in preventing epilepsy in animal models of TSC. Besides TSC, accumulating preclinical data suggest that mTOR inhibitors may have antiseizure or antiepileptogenic actions in other types of epilepsy, including infantile spasms, neonatal hypoxic seizures, absence epilepsy and acquired temporal lobe epilepsy following brain injury, but these effects depend on a number of conditions. Future clinical and basic research is needed to establish whether mTOR inhibitors are an effective treatment for epilepsy. PMID- 23739006 TI - Gene therapy for Parkinson's disease: state-of-the-art treatments for neurodegenerative disease. AB - Pharmacological and surgical treatments offer symptomatic benefits to patients with Parkinson's disease; however, as the condition progresses, patients experience gradual worsening in symptom control, with the development of a range of disabling complications. In addition, none of the currently available therapies have convincingly shown disease-modifying effects - either in slowing or reversing the disease. These problems have led to extensive research into the possible use of gene therapy as a treatment for Parkinson's disease. Several treatments have reached human clinical trial stages, providing important information on the risks and benefits of this novel therapeutic approach, and the tantalizing promise of improved control of this currently incurable neurodegenerative disorder. PMID- 23739007 TI - Detoxification and antioxidative therapy for levodopa-induced neurodegeneration in Parkinson's disease. AB - Levodopa is the most efficacious drug treatment option for Parkinson's disease. However, in particular, high levodopa dosing may contribute to disease progression. Chronic levodopa metabolism reduces the methylation capacity and the antioxidant defense. Thus, this levodopa-induced free radical production complements the disease process, which considerably depends on free radical induced, apoptotic neuronal cell death. Accordingly, clinical long-term studies with in the laboratory neuroprotective compounds failed in clinical investigations, as these studies were performed in levodopa-naive patients with Parkinson's disease over a relative short interval. Therefore, the likelihood for a positive outcome was rather low, since trials only focused on the disease process in levodopa-naive patients. However, studies on antioxidant therapeutic strategies were positive in levodopa-treated Parkinson's disease patients. To counteract these metabolic long-term levodopa-associated effects, chronic levodopa therapy should be combined with supplemental application of free radical scavengers and methyl group donating vitamins. PMID- 23739008 TI - Continuous dopaminergic delivery to minimize motor complications in Parkinson's disease. AB - Motor fluctuations and dyskinesias are common sequelae of Parkinson's disease (PD) that may limit function and quality of life. With disease progression, striatal dopamine concentration becomes closely linked to plasma levodopa levels, which vary considerably with standard oral regimens. Exposure of striatal dopamine receptors to wildly fluctuating transmitter levels is thought to contribute to the development of dyskinesias and motor fluctuations. Continuous dopaminergic delivery has been shown to reduce motor complications in advanced PD patients, and has been hypothesized to prevent their incidence when given as early therapy in mild PD. In this article, the authors outline the rationale for continuous dopaminergic delivery and review clinical strategies implementing the concept, including transdermal rotigotine, subcutaneous apomorphine infusion, intraduodenal infusion of levodopa gel and the investigational oral levodopa formulation IPX066. PMID- 23739011 TI - The effect of data cleaning on record linkage quality. AB - BACKGROUND: Within the field of record linkage, numerous data cleaning and standardisation techniques are employed to ensure the highest quality of links. While these facilities are common in record linkage software packages and are regularly deployed across record linkage units, little work has been published demonstrating the impact of data cleaning on linkage quality. METHODS: A range of cleaning techniques was applied to both a synthetically generated dataset and a large administrative dataset previously linked to a high standard. The effect of these changes on linkage quality was investigated using pairwise F-measure to determine quality. RESULTS: Data cleaning made little difference to the overall linkage quality, with heavy cleaning leading to a decrease in quality. Further examination showed that decreases in linkage quality were due to cleaning techniques typically reducing the variability - although correct records were now more likely to match, incorrect records were also more likely to match, and these incorrect matches outweighed the correct matches, reducing quality overall. CONCLUSIONS: Data cleaning techniques have minimal effect on linkage quality. Care should be taken during the data cleaning process. PMID- 23739012 TI - Soil pH effects on the comparative toxicity of dissolved zinc, non-nano and nano ZnO to the earthworm Eisenia fetida. AB - To determine how soil properties influence nanoparticle (NP) fate, bioavailability and toxicity, this study compared the toxicity of nano zinc oxide (ZnO NPs), non-nano ZnO and ionic ZnCl2 to the earthworm Eisenia fetida in a natural soil at three pH levels. NP characterisation indicated that reaction with the soil media greatly controls ZnO properties. Three main conclusions were drawn. First that Zn toxicity, especially for reproduction, was influenced by pH for all Zn forms. This can be linked to the influence of pH on Zn dissolution. Secondly, that ZnO fate, toxicity and bioaccumulation were similar (including relationships with pH) for both ZnO forms, indicating the absence of NP-specific effects. Finally, earthworm Zn concentrations were higher in worms exposed to ZnO compared to ZnCl2, despite the greater toxicity of the ionic form. This observation suggests the importance of considering the relationship between uptake and toxicity in nanotoxicology studies. PMID- 23739013 TI - Breath alcohol concentrations of designated drivers. AB - OBJECTIVE: This study established breath alcohol concentrations (BrACs) and alcohol-related behaviors of designated drivers (DDs) to determine (a) whether DDs are abstaining from drinking, (b) whether alcohol-related behaviors of non DDs and DDs were different, and (c) whether the alcohol consumption of DDs resulted in BrAC levels that affected driving performance or caused psychomotor impairment. METHOD: We conducted six anonymous field studies during a 3-month period in a southeastern college community restaurant and bar district. Intercept interviews were conducted with 1,071 bar patrons. Alcohol-related behaviors, BrAC, and whether one was serving as a DD were measured. The sample was primarily White (72.7%), male (62.4%) college students (64.7%). Descriptive statistics and an independent sample t test compared the BrACs of DDs versus non-DDs. A one-way analysis of variance examined the differences in the alcohol-related behaviors (Alcohol Use Disorders Identification Test-consumption [AUDIT-C] score) across DDs abstaining from drinking (BrAC = .00 g/210 L), drinking DDs (BrACs >= .02 and < .05 g/210 L), and impaired DDs (BrACs >= .05 g/210 L). A logistic regression assessed the impact of alcohol-related behaviors (AUDIT-C) on whether one was serving as a DD. RESULTS: Of the 165 DDs, approximately 40% did not abstain from drinking. Approximately 17% of DDs had BrACs between .02 g/210 L and .049 g/210 L, whereas 18% recorded BrACs at .05 g/210 L or greater. The mean AUDIT-C score for impaired DDs significantly differed from both abstaining DDs and drinking DDs. Participants with greater AUDIT-C scores were more likely to serve as a DD and have a BrAC that significantly inhibited driving ability and psychomotor function. CONCLUSIONS: These findings identify the need for consensus across researcher, layperson, and communication campaigns that a DD must be someone who has abstained from drinking entirely. PMID- 23739014 TI - Longitudinal study of urban American Indian 12-step attendance, attrition, and outcome. AB - OBJECTIVE: Strong opinions have been voiced about the "fit" between 12-step treatment, community-based 12-step practices, and American Indian beliefs and values. Little is known, however, about the relative benefit of 12-step programs for urban American Indians, although they are the most widely accessed type of treatment by American Indians. This study investigated rates of 12-step attendance, attrition, and substance use outcomes for American Indians for 9 months relative to non-Hispanic White participants. METHOD: This study compared urban American Indian (n = 63) and non-Hispanic White (n = 133) 12-step attendance, attrition, and substance use over 9 months. The sample was formed by merging data from two prospective single-group longitudinal studies investigating behavior change in community-based 12-step programs. Participants were interviewed at baseline and at 3-, 6-, and 9-month follow-ups. No intervention was provided. Participants were recruited from Alcoholics Anonymous meetings in the community and as they presented for outpatient substance use disorder treatment. Substance use and patterns of 12-step attendance were measured using the Form 90 calendar-based interview, and the General Alcoholics Anonymous Tools of Recovery was administered to assess the adoption of prescribed 12-step practices and beliefs. RESULTS: Trajectories in 12-step meeting attendance over 9 months did not differ between American Indian and non-Hispanic White participants. However, American Indian participants discontinued 12-step attendance significantly less often than non-Hispanic White participants. Higher rates of 12-step attendance predicted increased alcohol abstinence and decreased drinking intensity for both American Indian and non-Hispanic White participants. Twelve-step attendance was unrelated to later illicit drug use for both American Indian and non-Hispanic White participants. CONCLUSIONS: Community-based 12-step program attendance is associated with drinking reductions among urban American Indians. PMID- 23739015 TI - Associations between alcohol use and alcohol-related negative consequences among black and white college men and women. AB - OBJECTIVE: The gender gap in alcohol use has been narrowing among young adults, while race differences in alcohol problems change throughout the life course, with Whites experiencing more problems before middle adulthood and Blacks experiencing more after. Yet, there is a paucity of research on the intricate relationship among gender, race, alcohol use, and alcohol problems in emerging adults. The present study addressed this gap in the literature. METHOD: The sample included White (n = 14,772) and Black (n = 458) college students from multiple colleges across the United States (59% female; 51% freshmen; Mage = 20 years). RESULTS: With alcohol use levels adjusted for, women were more likely to report consequences related to damage to self and dependence-like symptoms than men. There were no significant race differences in either the type or the number of alcohol problems. Further, there was no Race * Alcohol Use interaction in relation to alcohol problems. We found a statistically significant interaction between gender and alcohol use in predicting alcohol problems, suggesting that, at higher levels of drinking, the risk for women to experience alcohol problems was significantly greater than that for men. CONCLUSIONS: The reverse race gap in alcohol use and problems may not surface until young adulthood or may not be relevant for those who attend college. College interventions should help both Black and White students reduce problems associated with drinking and focus on limiting harm among female students. PMID- 23739018 TI - Alcohol as an acute risk factor for recent suicide attempts: a case-crossover analysis. AB - OBJECTIVE: The extent to which acute alcohol use is a unique risk factor for suicide attempts is unknown. The aims of the current study were to quantify the unique effect of acute alcohol use on suicide attempts when adjusting for other acute exposures (other drug use and negative life events). METHOD: The current study used a case-crossover design and participants included 192 (62% female) recent suicide attempters presenting to a Level 1 trauma hospital. A timeline followback methodology was used to assess acute exposures within the 48 hours before the suicide attempt. RESULTS: Results indicated that individuals were at increased odds of attempting suicide soon after drinking (odds ratio [OR] = 6.34), adjusting for acute drug use and negative life events. Furthermore, higher levels of drinking uniquely posed greater risk for a suicide attempt than lower levels of drinking (OR = 6.13) and no drinking (OR = 16.19) before the attempt. CONCLUSIONS: Findings suggest the importance of considering acute alcohol use when evaluating short-term risk for suicide attempts. PMID- 23739017 TI - Are certain college students prone to experiencing excessive alcohol-related consequences? Predicting membership in a high-risk subgroup using pre-college profiles. AB - OBJECTIVE: Previous research identified a high-risk subgroup of students who experience high levels of multiple and repeated alcohol-related consequences (MRC group). Although they consist of 20% of the population and account for nearly 50% of the consequences, the MRC group has not been the focus of etiological or prevention research. The present study identified pre-college profiles of psychosocial and behavioral characteristics and examined the association between these profiles and membership in the MRC group. METHOD: The sample consisted of 370 first-year college students (57% female) recruited in the summer before college. Participants reported on typical drinking, alcohol-related risky and protective drinking behaviors, alcohol beliefs, descriptive and injunctive norms, and alcohol-related consequences at three time points over 15 months. RESULTS: Latent profile analysis identified four baseline student profiles: extreme consequence drinkers, high-risk drinkers, protective drinkers, and nondrinkers. Logistic regression revealed that, when the high-risk drinkers were used as the reference group, both the protective drinkers and the nondrinkers were significantly less likely to be members of the MRC group, whereas the extreme consequence drinkers were at increased odds of being in the MRC group, even after first-year drinking was controlled for. Student profiles and previously identified parental profiles both had unique main effects on MRC group membership, but there was no significant interaction between parental and student profiles. CONCLUSIONS: Findings suggest ways that brief interventions can be tailored for students and parents in relation to the MRC group. PMID- 23739016 TI - Who's at risk? Ethnic drinking cultures, foreign nativity, and problem drinking among Asian American young adults. AB - OBJECTIVE: Despite the low overall prevalence of alcohol use among Asian Americans, rates of alcohol use disorder are high among Asian American young adults. The influence of ethnic drinking cultures on immigrants and their descendants has been overlooked in past research. We took an integrative approach to examine the influence of ethnic drinking culture, acculturation, and socioeconomic disparities on problem drinking among Asian American young adults. METHOD: This study was a nationally representative sample of 854 Asian American young adults extracted from the Wave 4 National Longitudinal Study of Adolescent Health data. About 48% of the sample was female and 52% male. Several multiple logistic regression models were fitted. RESULTS: Controlling for other covariates, two dimensions of ethnic drinking culture were associated with alcohol outcomes only for the foreign born: (a) detrimental drinking pattern with frequent drunkenness and alcohol-abuse symptoms and (b) drinking prevalence with alcohol-dependence symptoms. Financial hardship was a significant predictor of symptoms of alcohol abuse and dependence only for the U.S. born. Asian language use was protective against alcohol-abuse symptoms and alcohol-dependence symptoms for the foreign born. CONCLUSIONS: Cultural and socioeconomic factors of problem drinking may be different for U.S.-and foreign-born Asian American young adults. Ethnic drinking cultures may significantly influence problem drinking of foreign born Asian American young adults, independent of their acculturation into U.S. cultures. To inform effective interventions targeted at immigrants and their descendants, future research might further investigate the cultural and socioeconomic processes in immigrant communities that might significantly influence drinking. PMID- 23739019 TI - Association between childhood adversities and suicide attempts among alcoholic inpatients in Taiwan. AB - OBJECTIVE: Alcohol dependence is frequently associated with suicide attempts. A history of adverse childhood experiences (ACEs) increases the risk of emotional and behavioral problems in adulthood. Child abuse is reported to increase suicide risk among alcohol-dependent patients. However, other types of ACEs, including ACEs related to family dysfunction that may have exceptional impact among the Chinese, are rarely explored. METHOD: The contribution of a broad spectrum of ACEs to lifetime risk of suicide attempts among alcoholic inpatients in Taiwan was examined. Family Health History Questionnaires were used to assess ACEs among 194 male alcohol-dependent inpatients admitted for alcohol detoxification. Logistic regression analysis was applied to examine the prediction of ACEs for lifetime risk of suicide attempts. RESULTS: The rate of attempted suicide in this cohort was 27.4%. The prevalence of ACEs was high, with around 90% of participants reporting at least one type of ACE. In the regression analysis, after adjusting for lifetime depression, illicit drug use, and severity of alcohol dependence, having had a battered mother (odds ratio [OR] = 3.99, 95% CI [1.40, 11.34]) and having parents who were separated/divorced (OR = 7.35, 95% CI [1.56, 34.72]) were associated with the risk of suicide attempts, but having experienced physical and sexual abuse were not. A 1-unit increase in childhood adversity raised the likelihood of a suicide attempt by 61% (OR = 1.61, 95% CI [1.16, 2.25]). CONCLUSIONS: There is a direct and graded relationship between childhood adversities and lifetime risk of suicide attempts among male alcoholic patients. In Chinese societies, adversities related to parental separation, divorce, and interparental violence may have a specific effect in aggravating suicide risk. PMID- 23739021 TI - Drinking to dampen affect variability: findings from a college student sample. AB - OBJECTIVE: We hypothesized that individuals who are unable to effectively regulate emotional reactivity, which we operationalized as variability in self reported affect throughout the day, would use alcohol more frequently and would report higher levels of drinking to cope. Further, we hypothesized that affect variation would be a stronger predictor of alcohol use or drinking to cope than level of negative affect. METHOD: A total of 86 college-age students (53% female, 77% White) participated in an intensive longitudinal study for 28 days. Participants reported positive and negative affect thrice daily and reported alcohol use once daily. Participant coping motives were assessed at study initiation. RESULTS: Affect variability predicted increased drinking frequency and higher levels of self-reported drinking to cope. Mean level of negative affect was not related to an increased probability of drinking, nor was it related to self-reported drinking to cope. Both individual differences in affect variation and intra-individual daily fluctuations in affect were associated with an increased likelihood of drinking. CONCLUSIONS: Our results imply that individuals with higher-than-average levels of affect variation are at risk for high levels of alcohol involvement and that people are more likely to drink on days characterized by higher-than-normal levels of fluctuation in affect. Future studies on self-medication should consider negative affect variability in addition to-or instead of-level of negative affect. PMID- 23739020 TI - Hazardous drinking, depression, and anxiety among sexual-minority women: self medication or impaired functioning? AB - OBJECTIVE: Sexual-minority women are at heightened risk for a number of mental health problems, including hazardous alcohol consumption, depression, and anxiety. We examined self-medication and impaired-functioning models of the associations among these variables and interpreted results within a life course framework that considered the unique social stressors experienced by sexual minority women. METHOD: Data were from a sample of 384 women interviewed during the first two waves of the Chicago Health and Life Experiences of Women (CHLEW) study. RESULTS: Covariance structure modeling revealed that (a) consistent with a self-medication process, anxiety was prospectively associated with hazardous drinking and (b) consistent with an impaired-functioning process, hazardous drinking was prospectively associated with depression. CONCLUSIONS: Our findings support a life course perspective that interprets the mental health of adult sexual-minority women as influenced by adverse childhood experiences, age at drinking onset, first heterosexual intercourse, and first sexual identity disclosure, as well as by processes associated with self-medication and impaired functioning during adulthood. PMID- 23739022 TI - State, but not trait, measures of persistence are related to negative affect. AB - OBJECTIVE: Task persistence describes the act of persisting with a difficult or effortful task. Although there are likely individual differences in persistence, the same person may also display different levels of persistence under different circumstances. This study sought to examine whether task persistence can be conceptualized as both a state and as a trait, and to examine the self-control strength model with negative affect as a drain on limited resources necessary for persisting. METHOD: Smokers with schizophrenia (n = 43), schizoaffective disorder (n = 28), and nonpsychiatric smokers (n = 78) seeking treatment at state-funded tobacco-dependence treatment clinics completed two behavioral measures and two self-report measures of task persistence along with a measure of negative affect before their target quit date. RESULTS: Analyses of covariance suggest that behavioral measures of persistence were significantly related to negative affect while two self-report measures of persistence were not. CONCLUSIONS: These findings suggest that behavioral, but not self-report, measures of persistence are related to negative affect. We argue that these behavioral measures capture "state" persistence whereas the self-report measures capture "trait" persistence. These data also lend support to the self-control strength model by suggesting that negative affect can drain the limited resources necessary for persisting with difficult behavioral tasks. PMID- 23739023 TI - National study of the role of recent illicit substance use on the relationship between depressive symptoms and sexual risk behavior among child welfare-involved adolescents. AB - OBJECTIVE: The present study examined the association between early-adolescent depressive symptoms and lifetime sexual risk behavior and whether that association was moderated by recent illicit substance use among adolescents reported for maltreatment. METHOD: Data came from Waves 1 (baseline) and 4 (36 month follow-up) of the National Survey of Child and Adolescent Well-Being, a national probability study of youths undergoing investigation for abuse or neglect (n = 861). Multivariate logistic regression was used to explore main effects and moderation models among baseline depressive symptoms, lifetime sexual risk behavior, and recent illicit substance use. RESULTS: Baseline depressive symptoms and recent illicit drug use played little role in predicting ever having intercourse, age at first intercourse, or pregnancy. Recent use of illicit substances moderated the relationship between early-adolescent depressive symptoms and condom use behavior (odds ratio = 0.85, p < .001) such that individuals who were more depressed at baseline and who used illicit drugs within the last 30 days were less likely to have often/always used condoms. Conversely, individuals with higher levels of depressive symptoms at baseline who had not engaged in illicit substance use in the last 30 days were more likely to often use condoms during sexual activity. CONCLUSIONS: Results suggest that among adolescents reported for maltreatment, use of illicit substances may moderate the relationship between elevated levels of depressive symptoms during early adolescence and condom use as children age thorough adolescence. Interventions for child welfare-engaged youths should focus on prevention and treatment of depression and substance use. PMID- 23739024 TI - Integration and sustainability of alcohol screening, brief intervention, and pharmacotherapy in primary care settings. AB - OBJECTIVE: At-risk drinking and alcohol use disorders are common in primary care and may adversely affect the treatment of patients with diabetes and/or hypertension. The purpose of this article is to report the impact of dissemination of a practice-based quality improvement approach (Practice Partner Research Network-Translating Research into Practice [PPRNet-TRIP]) on alcohol screening, brief intervention for at-risk drinking and alcohol use disorders, and medications for alcohol use disorders in primary care practices. METHOD: Nineteen primary care practices from 15 states representing 26,005 patients with diabetes and/or hypertension participated in a group-randomized trial (early intervention vs. delayed intervention). The 12-month intervention consisted of practice site visits for academic detailing and participatory planning and network meetings for "best practice" dissemination. RESULTS: At the end of Phase 1, eligible patients in early-intervention practices were significantly more likely than patients in delayed-intervention practices to have been screened (odds ratio [OR] = 3.30, 95% CI [1.15, 9.50]) and more likely to have been provided a brief intervention (OR = 6.58, 95% CI [1.69, 25.7]. At the end of Phase 2, patients in delayed intervention practices were more likely than at the end of Phase 1 to have been screened (OR = 5.18, 95% CI [4.65, 5.76]) and provided a brief intervention (OR = 1.80, 95% CI [1.31, 2.47]). Early-intervention practices maintained their screening and brief intervention performance during Phase 2. Medication for alcohol use disorders was prescribed infrequently. CONCLUSIONS: PPRNet-TRIP is effective in improving and maintaining improvement in alcohol screening and brief intervention for patients with diabetes and/or hypertension in primary care settings. PMID- 23739026 TI - An evaluation of the proposed DSM-5 cannabis use disorder criteria using Australian national survey data. AB - OBJECTIVE: The aim of the current study was to evaluate the proposed cannabis use disorder criteria for the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) using epidemiological data. METHOD: Data came from the 2007 Australian National Survey of Mental Health and Wellbeing. Lifetime DSM IV and DSM-5 cannabis use disorder diagnoses were assessed using a modified version of the World Mental Health Composite International Diagnostic Interview among those respondents who had used cannabis more than five times (n = 1,639; 37% female). RESULTS: The prevalence of cannabis use disorder decreased from DSM IV (6.2%) to DSM-5 (5.4%). Two fifths of those with DSM-IV cannabis abuse would fall below the threshold for DSM-5 cannabis use disorder. More than a third of those classified as DSM-IV "diagnostic orphans" would meet criteria for a DSM-5 mild, moderate, or severe cannabis use disorder. In terms of demographic and clinical characteristics, those who converted from no disorder in DSM-IV to a disorder under DSM-5 were similar to those diagnosed with a disorder according to both systems. Those who converted to no disorder under DSM-5 tended to be young men with cross-substance involvement and high levels of cannabis consumption. CONCLUSIONS: Although a previous study of the Australian population found that alcohol use disorders increase considerably under DSM-5, the current study found a reduction in cannabis use disorders in the transition from DSM-IV to DSM-5. This is likely the result of the high ratio of cannabis abuse to dependence when compared with other substances. Given the implications the proposed changes have on the epidemiology of substance use disorders, further research is needed to determine whether the proposed criteria are optimal. PMID- 23739025 TI - Buprenorphine/naloxone and methadone maintenance treatment outcomes for opioid analgesic, heroin, and combined users: findings from starting treatment with agonist replacement therapies (START). AB - OBJECTIVE: The objective of this secondary analysis was to explore differences in baseline clinical characteristics and opioid replacement therapy treatment outcomes by type (heroin, opioid analgesic [OA], or combined [heroin and OA]) and route (injector or non-injector) of opioid use. METHOD: A total of 1,269 participants (32.2% female) were randomized to receive one of two study medications (methadone or buprenorphine/naloxone [BUP]). Of these, 731 participants completed the 24-week active medication phase. Treatment outcomes were opioid use during the final 30 days of treatment (among treatment completers) and treatment attrition. RESULTS: Non-opioid substance dependence diagnoses and injecting differentiated heroin and combined users from OA users. Non-opioid substance dependence diagnoses and greater heroin use differentiated injectors from non-injectors. Further, injectors were more likely to be using at end of treatment compared with non-injectors. OA users were more likely to complete treatment compared with heroin users and combined users. Non-injectors were more likely than injectors to complete treatment. There were no interactions between type of opioid used or injection status and treatment assignment (methadone or BUP) on either opioid use or treatment attrition. CONCLUSIONS: Findings indicate that substance use severity differentiates heroin users from OA users and injectors from non-injectors. Irrespective of medication, heroin use and injecting are associated with treatment attrition and opioid misuse during treatment. These results have particular clinical interest, as there is no evidence of superiority of BUP over methadone for treating OA users versus heroin users. PMID- 23739027 TI - Exome-wide association study of replicable nonsynonymous variants conferring risk for alcohol dependence. AB - OBJECTIVE: In the present study, we scanned the whole exome in three independent samples to search for replicable risk nonsynonymous (ns) variants (ns single nucleotide polymorphisms [nsSNPs]) for alcohol dependence. METHOD: A total of 10,554 subjects in three independent samples were analyzed for association with alcohol dependence, including one European American sample (1,409 cases with alcohol dependence and 1,518 controls), one African American sample (681 cases and 508 controls), and one European Australian sample (a total of 6,438 family subjects with 1,645 alcohol-dependent probands). RNA expression of the risk genes in human, mouse, and rat brains was also explored. RESULTS: We identified a total of 70 nsSNPs at 65 genes with nominally replicable associations; 22 nsSNPs at 21 genes among them survived corrections for multiple testing in meta-analysis (alpha = .0007). By incorporating the information from bioinformatics and RNA expression analyses, we identified at least two of the most promising risk genes for alcohol dependence: APOER2 and UBAP2. CONCLUSIONS: The gene coding for apolipoprotein E receptor 2 (APOER2) and the gene coding for ubiquitin-associated protein-2 (UBAP2) are among the most appropriate for follow-up in human and nonhuman species as contributors to risk for alcohol dependence. PMID- 23739028 TI - Smokers report greater demand for alcohol on a behavioral economic purchase task. AB - OBJECTIVE: Cigarette smokers have higher levels of alcohol consumption than nonsmokers and poorer response to alcohol treatment. It is possible that the greater severity of alcohol problems observed in smokers reflects a greater susceptibility to alcohol-related reinforcement. The present study used a behavioral economic purchase task to investigate whether heavy drinking smokers would have greater demand for alcohol than heavy drinking nonsmokers. METHOD: Participants were 207 college students who reported at least one heavy drinking episode in the past month. Of the 207 participants, 33.2% (n = 67) reported smoking cigarettes at least 1 day in the past month. Participants completed the hypothetical alcohol purchase task, a simulation task that asked them to report how many drinks they would purchase at varying price increments. RESULTS: After the participants' reported alcohol consumption, gender, alcohol problems, and depression were controlled for, analyses of covariance revealed that heavy drinking smokers had significantly greater reported maximum alcohol expenditures (Omax), greater maximum inelastic price (Pmax), and higher breakpoint values (first price suppressing consumption to zero). CONCLUSIONS: College student heavy drinkers who also smoke cigarettes exhibit increased demand for alcohol. Smokers in this high-risk developmental stage may thus be less sensitive to price and other contingencies that would otherwise serve to modulate drinking and may require more intensive intervention approaches. PMID- 23739029 TI - Acute and chronic effects of alcohol on trail making test performance among underage drinkers in a field setting. AB - OBJECTIVE: Alcohol's effects on executive functioning are well documented. Research in this area has provided much information on both the acute and chronic effects of alcohol on processes such as working memory and mental flexibility. However, most research on the acute effects of alcohol is conducted with individuals older than 21 years of age. Using field recruitment methods can provide unique empirical data on the acute effects of alcohol on an underage population. METHOD: The current study examined the independent effects of acute alcohol intoxication (measured by breath alcohol content) and chronic alcohol use (measured by years drinking) on a test of visuomotor performance and mental flexibility (Trail Making Test) among 91 drinkers ages 18-20 years recruited from a field setting. RESULTS: Results show that breath alcohol predicts performance on Trails B, but not on Trails A, and that years drinking, above and beyond acute intoxication, predicts poorer performance on both Trails A and B. CONCLUSIONS: These data suggest that, independent of the acute effects of alcohol, chronic alcohol consumption has deleterious effects on executive functioning processes among underage drinkers. Our discussion focuses on the importance of these data in describing the effect of alcohol on adolescents and the potential for engaging in risky behavior while intoxicated. PMID- 23739030 TI - Enhanced continuing care provided in parallel to intensive outpatient treatment does not improve outcomes for patients with cocaine dependence. AB - OBJECTIVE: This study tested whether the addition of an enhanced continuing care (ECC) intervention that combined in-person and telephone sessions and began in the first week of treatment improved outcomes for cocaine-dependent patients entering an intensive outpatient program (IOP). METHOD: Participants (N = 152) were randomized to IOP treatment as usual (TAU) or IOP plus 12 months of ECC. ECC included cognitive-behavioral therapy elements to increase coping skills, as well as monetary incentives for attendance. It was provided by counselors situated at a separate clinical research facility who did not provide IOP. The primary outcomes measured were (a) cocaine urine toxicology and (b) good clinical outcome, as indicated by abstinence from all drugs and from heavy alcohol use. Secondary outcomes were frequency of abstinent days, cocaine use days, and heavy drinking days. Follow-ups were conducted at 3, 6, 9, and 12 months after baseline. RESULTS: Patients in ECC completed a mean of 18 sessions. Contrary to the hypotheses, patients in TAU had better scores on both the cocaine urine toxicology and the good clinical outcome measures than those in ECC, as indicated by significant Group * Time interactions (cocaine urine toxicology, p = .0025; abstinence composite, p = .017). These results were not moderated by substance use before or early in treatment or by IOP attendance. Results with the secondary outcomes also did not favor ECC over TAU. CONCLUSIONS: Continuing care that is not well integrated with the primary treatment program may interfere in some way with the therapeutic process, particularly when it is implemented shortly after intake. PMID- 23739031 TI - Hyperbaric oxygen therapy for sudden sensorineural hearing loss in large vestibular aqueduct syndrome. AB - INTRODUCTION: We report the first use in Australia of hyperbaric oxygen therapy for sudden hearing loss following head trauma in a child with large vestibular aqueduct syndrome. CASE REPORT: A 12-year-old boy with large vestibular aqueduct syndrome presented with significant hearing loss following head trauma. He was treated with steroids and hyperbaric oxygen therapy, with good improvement of hearing thresholds on audiography. This case represents the first reported use of hyperbaric oxygen therapy for this indication in Australia, following a few previous reports of patients in Japan. We review the literature on management of acute sensorineural hearing loss in large vestibular aqueduct syndrome. The reported case demonstrates a potentially beneficial therapy for a rare condition that usually results in an inevitable decline in hearing. CONCLUSION: Hyperbaric oxygen therapy can be tolerated well by children, and may represent a potential treatment for sudden sensorineural hearing loss in patients with large vestibular aqueduct syndrome. PMID- 23739032 TI - Hemoglobin and red blood cells catalyze atom transfer radical polymerization. AB - Hemoglobin (Hb) is a promiscuous protein that not only transports oxygen, but also catalyzes several biotransformations. A novel in vitro catalytic activity of Hb is described. Bovine Hb and human erythrocytes were found to display ATRPase activity, i.e., they catalyzed the polymerization of vinyl monomers under conditions typical for atom transfer radical polymerization (ATRP). N isopropylacrylamide (NIPAAm), poly(ethylene glycol) methyl ether acrylate (PEGA), and poly(ethylene glycol) methyl ether methacrylate (PEGMA) were polymerized using organobromine initiators and the reducing agent ascorbic acid in acidic aqueous solution. In order to avoid chain transfer from polymer radicals to Hb's cysteine residues, the accessible cysteines were blocked by a reaction with a maleimide. The formation of polymers with bromine chain ends, relatively low polydispersity indices (PDI), first order kinetics and an increase in the molecular weight of poly(PEGA) and poly(PEGMA) upon conversion indicate that control of the polymerization by Hb occurred via reversible atom transfer between the protein and the growing polymer chain. For poly(PEGA) and poly(PEGMA), the reactions proceeded with a good to moderate degree of control. Sodium dodecyl sulfate (SDS) gel electrophoresis, circular dichroism spectroscopy, and time resolved ultraviolet-visible (UV-vis) spectroscopy revealed that the protein was stable during polymerization, and only underwent minor conformational changes. As Hb and erythrocytes are readily available, environmentally friendly, and nontoxic, their ATRPase activity is a useful tool for synthetic polymer chemistry. Moreover, this novel activity enhances the understanding of Hb's redox chemistry in the presence of organobromine compounds. PMID- 23739034 TI - Neuro-Behcet's disease, its mimickers and anti-TNF therapy: a case-based review. AB - When the central nervous system is the primary affected site in an initial attack of Behcet's disease (BD), the differential diagnosis is particularly challenging. Because the specificity of immunobiologic therapy is growing, the specific diagnosis may impact the chosen therapy. For instance, anti-tumour necrosis factor agents are efficacious in BD but may be harmful in multiple sclerosis or systemic lupus erythematosus. We present two cases with similar neurological features but different diagnosis (BD and systemic lupus erythematosus) as a starting point to review diagnostic and therapeutic approaches for neuro-BD and its differential diagnoses. PMID- 23739035 TI - Modulation of electron carrier density at the n-type LaAlO3/SrTiO3 interface by water adsorption. AB - We investigate the energetic stability and dissociation dynamics of water adsorption at the LaAlO3 surface of the n-type LaAlO3/SrTiO3 (LAO/STO) interface and its effect on the electronic properties of the interface by carrying out first-principles electronic structure calculations. In an ambient atmosphere at room temperature the configuration of 1 monolayer (ML) of water molecules including 3/4 ML of dissociated water molecules adsorbed at the surface is found to be most stable, whereas the configuration of 1 ML of dissociated water molecules is metastable. Water molecule dissociation induces an up-shift of the valence band maximum (VBM) of the LAO surface, reducing the gap between the VBM of the LAO surface and the conduction band minimum of the STO. For the LAO/STO interface with three LAO unit-cell layers, once the coverage of dissociated water molecules reaches 1/2 ML the gap is closed, the interface becomes metallic and the carrier density at the LAO/STO interface increases with increasing coverage of dissociated water molecules. Our findings suggest two ways to control the conductivity at the LAO/STO interface: (I) an insulator-metal transition by adsorbing an amount of water at the bare surface; (II) a carrier density change by the transition between the most stable and the metastable adsorption configurations for 1 ML coverage in an ambient atmosphere at room temperature. PMID- 23739036 TI - A door-to-door prevalence study of feline immunodeficiency virus in an Australian suburb. AB - A door-to-door survey was conducted within the limits of the suburb of Douglas in northern Queensland, Australia, to determine the prevalence of feline immunodeficiency virus (FIV) infection in the overall population of domestic cats. Previous FIV prevalence studies have relied on convenience sampling strategies, leaving out an important group of pet cats that do not receive regular veterinary attention. Saliva was selected for testing because collection was non-invasive and was likely to achieve a high rate of participation. Ninety six cats were surveyed and tested for salivary antibodies against FIV and with real-time polymerase chain reaction (PCR). PCR was considered to be the gold standard and a cat was considered to be FIV-positive if sequencing results on a PCR product of appropriate size matched previously published FIV genome sequences available in GenBank. Results showed 10/96 cats to be infected with FIV subtype A, indicating a prevalence of 10.4% (95% confidence interval: 4.4-16.4) in the area studied. High risk associations were established with the roaming lifestyle of the cat (P <0.002), presence of abscesses (P <0.03) and occurrence of bite wounds (P <0.10). This is the first known cross-sectional study of a population of urban northern Australian cats living in an affluent suburb and presenting saliva as a potential non-invasive sample for large-scale epidemiological surveys on FIV. PMID- 23739037 TI - Impact of neuroradiologist second opinion on staging and management of head and neck cancer. AB - OBJECTIVE: Patients with head and neck cancer frequently present to academic tertiary referral centers with imaging studies that have been performed and interpreted elsewhere. At our institution, these outside head and neck imaging studies undergo formal second opinion reporting by a fellowship-trained academic neuroradiologist with expertise in head and neck imaging. The purpose of this study was to determine the impact of this practice on cancer staging and patient management. METHODS: Our institutional review board approved the retrospective review of randomized original and second opinion reports for 94 consecutive cases of biopsy proven or clinically suspected head and neck cancer in calendar year 2010. Discrepancy rates for staging and recommended patient management were calculated and, for the 32% (30/94) of cases that subsequently went to surgery, the accuracies of the reports were determined relative to the pathologic staging gold standard. RESULTS: Following neuroradiologist second opinion review, the cancer stage changed in 56% (53/94) of cases and the recommended management changed in 38% (36/94) of patients with head and neck cancer. When compared to the pathologic staging gold standard, the second opinion was correct 93% (28/30) of the time. CONCLUSION: In a majority of patients with head and neck cancer, neuroradiologist second opinion review of their outside imaging studies resulted in an accurate change in their cancer stage and this frequently led to a change in their management plan. PMID- 23739038 TI - Occlusal Disharmony Transiently Impairs Learning and Memory in the Mouse by Increasing Dynorphin A Levels in the Amygdala. AB - Occlusal disharmony sometimes causes not only stiffness of neck but also psychiatric depression, suggesting that the condition of oral cavity may affect the central nervous system. Dynorphin A is an endogenous opioid peptide that specifically binds the kappa-opioid receptor and has a protective role against stress. Dynorphinergic nervous system is intensely distributed in the amygdala and hippocampus that are coping areas with stress. As a model of malocclusion, we placed dental resin on the molars to increase the occlusal vertical dimension (bite-raise). After various survival times, we analyzed the amygdala and hippocampus by immunohistochemistry and immunosorbent assay (ELISA). Furthermore, the effects on learning and memory were assessed by Morris water maze test. In the amygdala, the levels of dynorphin A were increased on the 1st day after increasing the vertical dimension as indicated by immunohistochemical and ELISA assessments. The levels of dynorphin A returned to control levels on the 5th day. In the hippocampus, there were no noticeable changes in dynorphin A levels. The water maze test indicated that increasing the vertical dimension caused longer escape latency times on the 3rd day compared to those of sham-operated group. However, the bite-raised mice treated with a dynorphin antagonist, nor binaltorphimine, showed similar escape latency times to the times of sham operated group, even on the 3rd day. These results suggest that occlusal disharmony causes stress resulting in a transient increase of dynorphin A levels at least in the amygdala and that the increased dynorphin A levels transiently impair learning and memory. PMID- 23739039 TI - Myofascial pain syndrome may be the most difficult disorder that is differentiated from fibromyalgia. PMID- 23739041 TI - Antiperiodic oscillations. AB - The investigation of regular and irregular patterns in nonlinear oscillators is an outstanding problem in physics and in all natural sciences. In general, regularity is understood as tantamount to periodicity. However, there is now a flurry of works proving the existence of "antiperiodicity", an unfamiliar type of regularity. Here we report the experimental observation and numerical corroboration of antiperiodic oscillations. In contrast to the isolated solutions presently known, we report infinite hierarchies of antiperiodic waveforms that can be tuned continuously and that form wide spiral-shaped stability phases in the control parameter plane. The waveform complexity increases towards the focal point common to all spirals, a key hub interconnecting them all. PMID- 23739040 TI - Integral analysis of p53 and its value as prognostic factor in sporadic colon cancer. AB - BACKGROUND: p53 (encoded by TP53) is involved in DNA damage repair, cell cycle regulation, apoptosis, aging and cellular senescence. TP53 is mutated in around 50% of human cancers. Nevertheless, the consequences of p53 inactivation in colon cancer outcome remain unclear. Recently, a new role of p53 together with CSNK1A1 in colon cancer invasiveness has been described in mice. METHODS: By combining data on different levels of p53 inactivation, we aimed to predict p53 functionality and to determine its effects on colon cancer outcome. Moreover, survival effects of CSNK1A1 together with p53 were also studied.Eighty-three formalin fixed paraffin embedded colon tumors were enriched for tumor cells using flow sorting, the extracted DNA was used in a custom SNP array to determine chr17p13-11 allelic state; p53 immunostaining, TP53 exons 5, 6, 7 and 8 mutations were determined in combination with mRNA expression analysis on frozen tissue. RESULTS: Patients with a predicted functional p53 had a better prognosis than patients with non functional p53 (Log Rank p=0.009). Expression of CSNK1A1 modified p53 survival effects. Patients with low CSNK1A1 expression and non functional p53 had a very poor survival both in the univariate (Log Rank p<0.001) and in the multivariate survival analysis (HR=4.74 95% CI 1.45 - 15.3 p=0.009). CONCLUSION: The combination of mutational, genomic, protein and downstream transcriptional activity data predicted p53 functionality which is shown to have a prognostic effect on colon cancer patients. This effect was specifically modified by CSKN1A1 expression. PMID- 23739042 TI - Perna canaliculus lipid complex PCSO-524TM demonstrated pain relief for osteoarthritis patients benchmarked against fish oil, a randomized trial, without placebo control. AB - Osteoarthritis (OA) typically generates pain, reduced mobility and reduced quality of life. Most conventional treatments for osteoarthritis, such as non steroidal anti-inflammatory drugs (NSAIDs) and simple analgesics, have side effects. PCSO-524TM, a non polar lipid extract from the New Zealand Green Lipped Mussel, is rich in omega-3 fatty acids and has been shown to reduce inflammation in both animal studies and patient trials. This OA trial examined pain relief changes in relation to quality of life and safety of use for OA patients who took PCSO-524TM compared with patients who took fish oil (containing an industry standard EPA-18% and DHA-12% blend). PCSO-524TM patients showed a statistically significant improvement compared with patients who took fish oil. There was an 89% decrease in their pain symptoms and 91% reported an improved quality of life. Patients treated with fish oil showed significantly less improvement and a greater level of physical discomfort during the study. These results suggest that PCSO-524TM might offer a potential alternative complementary therapy with no side effects for OA patients. PMID- 23739043 TI - New invertebrate vectors for PST, spirolides and okadaic acid in the North Atlantic. AB - The prevalence of poisoning events due to harmful algal blooms (HABs) has declined during the last two decades through monitoring programs and legislation, implemented mainly for bivalves. However, new toxin vectors and emergent toxins pose a challenge to public health. Several locations on the Portuguese coast were surveyed between 2009 and 2010 for three distinct biotoxin groups [saxitoxin (PST), spirolide (SPX) and okadaic acid (OA)], in 14 benthic species of mollusks and echinoderms. Our main goals were to detect new vectors and unravel the seasonal and geographical patterns of these toxins. PSTs were analyzed by the Lawrence method, SPXs by LC-MS/MS, and OA by LC-MS/MS and UPLC-MS/MS. We report 16 new vectors for these toxins in the North Atlantic. There were differences in toxin contents among species, but no significant geographical or seasonal patterns were found. Our results suggest that legislation should be adjusted to extend the monitoring of marine toxins to a wider range of species besides edible bivalves. PMID- 23739044 TI - Cardiovascular fitness in early adulthood and future suicidal behaviour in men followed for up to 42 years. AB - BACKGROUND: Cardiovascular fitness influences many aspects of brain function. However, the relationship between cardiovascular fitness and suicidal behaviour is unknown. Therefore, we aimed to determine whether cardiovascular fitness at age 18 years is associated with future risk of suicide attempt/death. METHOD: We performed a population-based Swedish longitudinal cohort study of male conscripts with no previous or ongoing mental illness (n = 1,136,527). The conscription examination, which took place during 1968-2005, included the cycle ergonometric test and tests of cognitive performance. Future risk of suicide attempt/death over a 5- to 42-year follow-up period was calculated with Cox proportional hazards models controlling for several confounders including familial factors. RESULTS: At least one suicide attempt was recorded for 12,563 men. Death by suicide without a prior attempt was recorded in 4814 additional individuals. In fully adjusted models low cardiovascular fitness was associated with increased risk for future attempt/death by suicide [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.64-1.94]. The HR changed only marginally after exclusion of persons who received in-patient care for depression (HR 1.76, 95% CI 1.61-1.94). Poor performance on both the cardiovascular fitness and cognitive tests was associated with a fivefold increased risk of suicide attempt or suicide death (HR 5.46, 95% CI 4.78-6.24). CONCLUSIONS: Lower cardiovascular fitness at age 18 years was, after adjustment for a number of potential confounders, associated with an increased risk of attempt/death by suicide in adulthood. It remains to be clarified whether interventions designed to improve fitness in teens can influence the risk of suicidal behaviour later in life. PMID- 23739045 TI - SUMOylation, Arc and the regulation homeostatic synaptic scaling: Implications in health and disease. AB - Neurons compensate for changes in network activity by altering the sensitivity of transmission across collections of synapses by up- or downregulating the number of synaptic AMPA receptors. We recently reported that, in parallel to increasing AMPA receptor surface expression, suppression of network activity with TTX increases protein SUMOylation by decreasing levels of the deSUMOylating enzyme SENP1. SUMOylation of the immediate early gene product Arc is required for synaptic scaling. These results reveal a previously unsuspected role for protein SUMOylation in activity-dependent AMPA receptor trafficking and the regulation of neuronal network activity, processes which play important roles in neurodegenerative disease. PMID- 23739046 TI - Plasmon enhanced fluoro-immunoassay using egg yolk antibodies for ultra-sensitive detection of herbicide diuron. AB - Plasmon enhanced fluorescence immunoassay (PEFI) format has been reported in developing a sensitive heterogeneous fluoroimmunoassay for monitoring the phenylurea herbicide diuron. Computer-assisted molecular modeling was carried out to study the conformational and electrostatic effects of synthesized hapten for producing highly specific egg yolk antibody against a phenyl urea herbicide diuron. The generated antibodies were labeled with fluorescein isothiocyanate at different molar ratios and used as tracer in the developed fluorescence based immunoassay. The sensitivity of the assay format was enhanced by using silver nanoparticles tagged with bovine serum albumin as a new blocking reagent in the developed PEFI format. Enhancer treatment on the developed immunoassay showed a significant improvement of fluorescence signal intensity with approximately 10 fold increase in assay sensitivity. The immunoassay has a detection limit of 0.01 ng mL(-1) with good signal precision (~2%) in the optimum working concentration range between 1 pg mL(-1) to 10 MUg mL(-1) of diuron. These findings facilitate high throughput fluorescence-based processes that could be useful in biology, drug discovery and compound screening applications. PMID- 23739047 TI - New horizons in frailty: ageing and the deficit-scaling problem. AB - All the current frailty measures count deficits. They differ chiefly in which items, and how many, they consider. These differences are related: if a measure considers only a few items, to define broad risks those items need to integrate across several systems (e.g. mobility or function). If many items are included, the cumulative effect of small deficits can be considered. Even so, it is not clear just how small deficits can be. To better understand how the scale of deficit accumulation might impact frailty measurement, we consider how age related, subcellular deficits might become macroscopically visible and so give rise to frailty. Cellular deficits occur when subcellular damage has neither been repaired nor cleared. With greater cellular deficit accumulation, detection becomes more likely. Deficit detection can be done by either subclinical (e.g. laboratory, imaging, electrodiagnostic) or clinical methods. Not all clinically evident deficits need cross a disease threshold. The extent to which cellular deficit accumulation compromises organ function can reflect not just what is happening in that organ system, but deficit accumulation in other organ systems too. In general, frailty arises in relation to the number of organ systems in which deficits accumulate. This understanding of how subcellular deficits might scale has implications for understanding frailty as a vulnerability state. Considering the cumulative effects of many small deficits appears to allow important aspects of the behaviour of systems close to failure to be observed. It also suggests the potential to detect frailty with less reliance on clinical observation than current methods employ. PMID- 23739048 TI - A framework for the assessment of community exercise programmes: a tool to assist in modifying programmes to help reduce falls risk factors. AB - BACKGROUND: falls in older adults is a significant global public health challenge. Exercise interventions which incorporate the physiological components of balance and strength can reduce falls risk. However, the optimum qualities, such as type, duration and frequency of engagement in these exercise programmes, are yet to be established. OBJECTIVE: the overall research project aimed to develop and test a tool for the assessment of physiological criteria in community exercise programmes and to determine which community exercise programmes may be modified to help reduce falls risk factors. This initial phase of the research and the aim of this paper are to describe the development of the Community Exercise Program Assessment Matrix (the Matrix). METHODS: a review of the falls literature identified an existing classification system, which guided the development of the Matrix. An expert panel assisted in reviewing, testing and ongoing refinement of the Matrix. RESULTS: the Matrix contains a range of physiological and cognitive components as well as other items which capture non physiological components. After testing some modifications were made to the Matrix to aid usage. CONCLUSION: this paper has outlined the development of the Matrix, which is intended to be used for the recording of physiological components (related to falls prevention) of an exercise programme in terms of type, duration and frequency. The next step is to use the Matrix in conjunction with pre- and post-physiological testing of participants to assess a range of exercise programmes and changes in participant physiological functioning. PMID- 23739049 TI - Metabolism: Taking it all in. PMID- 23739050 TI - Comparative genomics of pathogenic lineages of Vibrio nigripulchritudo identifies virulence-associated traits. AB - Vibrio nigripulchritudo is an emerging pathogen of farmed shrimp in New Caledonia and other regions in the Indo-Pacific. The molecular determinants of V. nigripulchritudo pathogenicity are unknown; however, molecular epidemiological studies have suggested that pathogenicity is linked to particular lineages. Here, we performed high-throughput sequencing-based comparative genome analysis of 16 V. nigripulchritudo strains to explore the genomic diversity and evolutionary history of pathogen-containing lineages and to identify pathogen-specific genetic elements. Our phylogenetic analysis revealed three pathogen-containing V. nigripulchritudo clades, including two clades previously identified from New Caledonia and one novel clade comprising putatively pathogenic isolates from septicemic shrimp in Madagascar. The similar genetic distance between the three clades indicates that they have diverged from an ancestral population roughly at the same time and recombination analysis indicates that these genomes have, in the past, shared a common gene pool and exchanged genes. As each contemporary lineage is comprised of nearly identical strains, comparative genomics allowed differentiation of genetic elements specific to shrimp pathogenesis of varying severity. Notably, only a large plasmid present in all highly pathogenic (HP) strains encodes a toxin. Although less/non-pathogenic strains contain related plasmids, these are differentiated by a putative toxin locus. Expression of this gene by a non-pathogenic V. nigripulchritudo strain resulted in production of toxic culture supernatant, normally an exclusive feature of HP strains. Thus, this protein, here termed 'nigritoxin', is implicated to an extent that remains to be precisely determined in the toxicity of V. nigripulchritudo. PMID- 23739051 TI - Dynamic cyanobacterial response to hydration and dehydration in a desert biological soil crust. AB - Biological soil crusts (BSCs) cover extensive portions of the earth's deserts. In order to survive desiccation cycles and utilize short periods of activity during infrequent precipitation, crust microorganisms must rely on the unique capabilities of vegetative cells to enter a dormant state and be poised for rapid resuscitation upon wetting. To elucidate the key events involved in the exit from dormancy, we performed a wetting experiment of a BSC and followed the response of the dominant cyanobacterium, Microcoleus vaginatus, in situ using a whole-genome transcriptional time course that included two diel cycles. Immediate, but transient, induction of DNA repair and regulatory genes signaled the hydration event. Recovery of photosynthesis occurred within 1 h, accompanied by upregulation of anabolic pathways. Onset of desiccation was characterized by the induction of genes for oxidative and photo-oxidative stress responses, osmotic stress response and the synthesis of C and N storage polymers. Early expression of genes for the production of exopolysaccharides, additional storage molecules and genes for membrane unsaturation occurred before drying and hints at preparedness for desiccation. We also observed signatures of preparation for future precipitation, notably the expression of genes for anaplerotic reactions in drying crusts, and the stable maintenance of mRNA through dormancy. These data shed light on possible synchronization between this cyanobacterium and its environment, and provides key mechanistic insights into its metabolism in situ that may be used to predict its response to climate, and or, land-use driven perturbations. PMID- 23739052 TI - A metabolomic view of how the human gut microbiota impacts the host metabolome using humanized and gnotobiotic mice. AB - Defining the functional status of host-associated microbial ecosystems has proven challenging owing to the vast number of predicted genes within the microbiome and relatively poor understanding of community dynamics and community-host interaction. Metabolomic approaches, in which a large number of small molecule metabolites can be defined in a biological sample, offer a promising avenue to 'fingerprint' microbiota functional status. Here, we examined the effects of the human gut microbiota on the fecal and urinary metabolome of a humanized (HUM) mouse using an optimized ultra performance liquid chromatography-mass spectrometry-based method. Differences between HUM and conventional mouse urine and fecal metabolomic profiles support host-specific aspects of the microbiota's metabolomic contribution, consistent with distinct microbial compositions. Comparison of microbiota composition and metabolome of mice humanized with different human donors revealed that the vast majority of metabolomic features observed in donor samples are produced in the corresponding HUM mice, and individual-specific features suggest 'personalized' aspects of functionality can be reconstituted in mice. Feeding the mice a defined, custom diet resulted in modification of the metabolite signatures, illustrating that host diet provides an avenue for altering gut microbiota functionality, which in turn can be monitored via metabolomics. Using a defined model microbiota consisting of one or two species, we show that simplified communities can drive major changes in the host metabolomic profile. Our results demonstrate that metabolomics constitutes a powerful avenue for functional characterization of the intestinal microbiota and its interaction with the host. PMID- 23739054 TI - Research in audiology education. PMID- 23739053 TI - Quantifying community assembly processes and identifying features that impose them. AB - Spatial turnover in the composition of biological communities is governed by (ecological) Drift, Selection and Dispersal. Commonly applied statistical tools cannot quantitatively estimate these processes, nor identify abiotic features that impose these processes. For interrogation of subsurface microbial communities distributed across two geologically distinct formations of the unconfined aquifer underlying the Hanford Site in southeastern Washington State, we developed an analytical framework that advances ecological understanding in two primary ways. First, we quantitatively estimate influences of Drift, Selection and Dispersal. Second, ecological patterns are used to characterize measured and unmeasured abiotic variables that impose Selection or that result in low levels of Dispersal. We find that (i) Drift alone consistently governs ~25% of spatial turnover in community composition; (ii) in deeper, finer-grained sediments, Selection is strong (governing ~60% of turnover), being imposed by an unmeasured but spatially structured environmental variable; (iii) in shallower, coarser-grained sediments, Selection is weaker (governing ~30% of turnover), being imposed by vertically and horizontally structured hydrological factors;(iv) low levels of Dispersal can govern nearly 30% of turnover and be caused primarily by spatial isolation resulting from limited exchange between finer and coarser grain sediments; and (v) highly permeable sediments are associated with high levels of Dispersal that homogenize community composition and govern over 20% of turnover. We further show that our framework provides inferences that cannot be achieved using preexisting approaches, and suggest that their broad application will facilitate a unified understanding of microbial communities. PMID- 23739055 TI - Theory and research in audiology education: understanding and representing complexity through informed methodological decisions. AB - BACKGROUND: The discipline of audiology has the opportunity to embark on research in education from an informed perspective, learning from professions that began this journey decades ago. The goal of this article is to position our discipline as a new member in the academic field of health professional education (HPE), with much to learn and contribute. PURPOSE: In this article, I discuss the need for theory in informing HPE research. I also stress the importance of balancing our research goals by selecting appropriate methodologies for relevant research questions, to ensure that we respect the complexity of social processes inherent in HPE. DATA COLLECTION AND ANALYSIS: Examples of relevant research questions are used to illustrate the need to consider alternative methodologies and to rethink the traditional hierarchy of evidence. I also provide an example of the thought processes and decisions that informed the design of an educational research study using a constructivist grounded theory methodology. CONCLUSIONS: As audiology enters the scholarly field of HPE, we need to arm ourselves with some of the knowledge and perspective that informs the field. Thus, we need to broaden our conceptions of what we consider to be appropriate styles of academic writing, relevant research questions, and valid evidence. Also, if we are to embark on qualitative inquiry into audiology education (or other audiology topics), we need to ensure that we conduct this research with an adequate understanding of the theories and methodologies informing such approaches. We must strive to conduct high quality, rigorous qualitative research more often than uninformed, generic qualitative research. These goals are imperative to the advancement of the theoretical landscape of audiology education and evolving the place of audiology in the field of HPE. PMID- 23739056 TI - Exploring the utility of measures of critical thinking dispositions and professional behavior development in an audiology education program. AB - BACKGROUND: Discussions about professional behaviors are growing increasingly prevalent across health professions, especially as a central component to education programs. A strong critical thinking disposition, paired with critical consciousness, may provide future health professionals with a foundation for solving challenging practice problems through the application of sound technical skill and scientific knowledge without sacrificing sensitive, empathic, client centered practice. In this article, we describe an approach to monitoring student development of critical thinking dispositions and key professional behaviors as a way to inform faculty members' and clinical supervisors' support of students and ongoing curriculum development. PURPOSE: We designed this exploratory study to describe the trajectory of change for a cohort of audiology students' critical thinking dispositions (measured by the California Critical Thinking Disposition Inventory: [CCTDI]) and professional behaviors (using the Comprehensive Professional Behaviors Development Log-Audiology [CPBDL-A]) in an audiology program. Implications for the CCTDI and CPBDL-A in audiology entry-to-practice curricula and professional development will be discussed. RESEARCH DESIGN: This exploratory study involved a cohort of audiology students, studied over a two year period, using a one-group repeated measures design. STUDY SAMPLE: Eighteen audiology students (two male and 16 female), began the study. At the third and final data collection point, 15 students completed the CCTDI, and nine students completed the CPBDL-A. DATA COLLECTION AND ANALYSIS: The CCTDI and CPBDL-A were each completed at three time points: at the beginning, at the middle, and near the end of the audiology education program. Data are presented descriptively in box plots to examine the trends of development for each critical thinking disposition dimension and each key professional behavior as well as for an overall critical thinking disposition score. RESULTS: For the CCTDI, there was a general downward trend from time point 1 to time point 2 and a general upward trend from time point 2 to time point 3. Students demonstrated upward trends from the initial to final time point for their self-assessed development of professional behaviors as indicated on the CPBDL-A. CONCLUSIONS: The CCTDI and CPBDL-A can be used by audiology education programs as mechanisms for inspiring, fostering, and monitoring the development of critical thinking dispositions and key professional behaviors in students. Feedback and mentoring about dispositions and behaviors in conjunction with completion of these measures is recommended for inspiring and fostering these key professional attributes. PMID- 23739057 TI - Applying experiential learning to audiology curricula. AB - In my quest to become a better professor, I have been searching for the instructional paradigms that best facilitate the educational process between me and my students. To support this endeavor, I opted to study learning diversity. The results of my investigation led me to reflect upon whether my teaching strategies inadvertently engaged only a subset of my students. I believe that was the case. In this article, I will describe the experiential learning model, how I used it to measure my students' learning styles, and how I used the model to make my teaching more holistic. PMID- 23739058 TI - Standardized patients in audiology: a proposal for a new method of evaluating clinical competence. AB - BACKGROUND: While accrediting organizations require AuD programs to provide evidence that their students are able to demonstrate knowledge and competencies in specific content areas, there are no generally accepted mechanisms for the assessment and the measurement of these proficiencies. We propose that AuD programs consider developing standardized patient (SP) cases in order to develop consistent summative assessment programs within and across universities. PURPOSE: The purpose of this article is to provide a framework for establishing SP programs to evaluate competencies in AuD students by detailing the history of SP cases and their use, developing a rationale for this method of assessment, and outlining the steps for writing and implementing SP cases. RESEARCH DESIGN: Literature review. RESULTS: SPs have been used to assess clinical competence in medical students for over 50 yr. The prevalence of SP assessment in allied health professions (e.g., dentistry, psychology, pharmacy) has increased over the last two decades but has only gained a limited following in audiology. SP assessment has been implemented in medical education using the Objective Structured Clinical Examination, a multistation, timed exam that uses fictional cases to assess students' clinical abilities. To date, only one published report has been completed that evaluates the use of SPs to assess clinical abilities in audiology students. This article expands upon the work of English et al (2007) and their efforts to use SPs to evaluate counseling abilities. To this end, we describe the steps necessary to write a case, procedures to determine performance requirements, and the need to develop remediation plans. As an example, we include a case that we have developed in order to evaluate vestibular assessment and patient communication skills. CONCLUSIONS: Utilizing SP assessment in audiology education would provide useful means to evaluate competence in a uniform way. Future research is necessary to develop reliable and valid cases that may be implemented across programs. This article aims to serve as a call to audiology programs to begin developing and reporting these cases. Once these are established we can begin to use SP cases for summative assessment. PMID- 23739059 TI - An evidence-based guide to clinical instruction in audiology. AB - BACKGROUND: A significant portion of the AuD curriculum occurs in clinical settings outside the classroom. Expert clinicians, employed within and outside of the university, are called upon to provide this clinical education. Most have had little or no formal training in clinical teaching yet face pedagogical and logistical challenges when simultaneously providing clinical service and teaching. Training to provide optimal methods and approaches to clinical instruction should be based on research evidence; however, there is a paucity of research in this area within the audiology discipline. PURPOSE: This article provides a review of literature supplying evidence for important concepts, elements, and approaches to the clinical instruction process. Additionally, we provide readers with some practical tools with which to facilitate application of optimal clinical teaching principles. RESEARCH DESIGN: We conducted a systematic review of literature on clinical education in audiology and across a wide array of health professions. Through the use of content analysis we identified four elements of the clinical teaching process most critical in examining optimal practices. RESULTS: The elements identified as critical to positive clinical learning outcomes include the establishment of mutual expectations and goals; structured content and delivery of feedback; establishment of a positive instructor/student relationship; and questioning strategies that lead to the development of critical thinking skills. CONCLUSIONS: Many disciplines outside of audiology demonstrate robust research activity related to understanding and optimizing the clinical education process. The application of a number of evidence-based clinical teaching principles should allow us to improve student outcomes in audiology. Researchers in our field might consider if and how we should develop our own research literature in clinical education. PMID- 23739060 TI - Demand for audiology services: 30-yr projections and impact on academic programs. AB - BACKGROUND: Significant growth in the U.S. population over the next 30 yr will likely increase the demand for hearing-care services. In addition, increased accessibility to hearing-care services may be realized due to increased insurance coverage associated with health-care reform efforts. In order to meet this demand, the supply of audiologists will have to keep pace. The U.S. Department of Health and Human Services has developed a Physician Supply Model to predict the necessary number of physicians needed in the future to meet demand. This model is adopted for predicting whether the supply of audiologists will be adequate over the next 30 yr. PURPOSE: To apply the Physician Supply Model to the audiology profession and then determine if the predicted supply of audiologists will meet the demand for audiologists over the next 30 yr. DATA COLLECTION AND ANALYSIS: The Physician Supply Model was modified to account for variables unique to the profession of audiology, and the future supply of audiologists is predicted. The predicted demand for audiology was developed based on changes in population demographics over the next 30 yr. The results of the demand calculations and the supply calculations were compared. RESULTS: The current growth rate for audiologists was determined by examining the difference between the number of graduates entering the field and the number leaving. One of the unexpected variables is that the past attrition of graduates, that is, the number of persons who voluntarily leave audiology at some point after graduation, is approximately 40%. The attrition rate combined with the retirement rate results in more persons exiting the profession than entering. Lowering the attrition rate to 20% will result in a positive growth rate. However, even with an attrition rate of 0%, the supply of audiologists will not meet demand. CONCLUSIONS: To meet demand, the number of persons entering the field will have to increase by 50% beginning immediately. In addition, the attrition rate will have to be lowered to 20%. Any combination of increased graduation rate and lowered attrition will improve the opportunities to meet demand. Additional strategies could include increasing the capacity of current practitioners or allowing internationally trained audiologists to practice in the United States. PMID- 23739061 TI - Academic programs, class sizes, and obstacles to growth in audiology. AB - BACKGROUND: Over the past 25 yr, the number of academic programs in audiology has been cut by half, yet there continue to be calls for further reductions in the number of programs. Reducing the number of programs potentially affects the number of graduates and therefore could impact the availability of audiologists in the future. There is a question as to whether academic programs in audiology could accommodate more students. PURPOSE: To examine the impact of closure of programs on the number of graduates and to identify obstacles to programs growing class sizes. DATA COLLECTION AND ANALYSIS: An analysis of audiology class sizes over time based on data available from the Council of Academic Programs in Communication Sciences and Disorders, and a comparison of audiology class sizes with other health professions, to identify trends that affect growth in program size. RESULTS: The key obstacles to growth of academic programs are (1) the availability of sufficient clinical experiences to meet the licensure and certification requirements and (2) financial resources to expand didactic and clinical teaching needs associated with larger class sizes. CONCLUSIONS: (1) Certification regulations and licensure laws should be revised to eliminate requirements that directly impact on academic programs or students prior to graduation. (2) The profession should undertake the effort designed to change Medicare regulations to allow alternative supervision models. (3) Academic programs need freedom to be creative in their approaches to teaching and financing programs. (4) A concerted and coordinated effort needs to be undertaken to increase the number of persons interested in audiology as a career. PMID- 23739062 TI - AuD-degree holders in tenure-track positions: survey of program chairpersons and AuD-degree holders. AB - BACKGROUND: The doctor of audiology (AuD) degree is now the entry-level degree for the profession of audiology. Typically, AuD programs train professionals for clinical careers, while those offering PhDs educate students for university teaching and research positions. Some in the communication sciences and disorders have predicted that there could be a shortage of PhDs in academic institutions over the next decade as senior faculty members with PhDs retire, AuD programs expand, and likely fewer students complete PhD degrees or elect to pursue careers in academia. If a PhD shortage becomes a reality, then one solution might be to include AuDs as candidates for vacant academic tenure-track positions. PURPOSE: To survey AuD-degree holders' (AuDs') and program chairpersons' (chairs') views about AuDs in academic tenure-track positions. RESEARCH DESIGN: National Internet survey Data Collection and Analysis: Two questionnaires were designed for this study. One was e-mailed to 1575 "AuDs in general" (randomly sampled from the American Academy of Audiology Membership Directory) and 132 "AuDs in academia." The other was e-mailed to 64 chairs from programs offering the AuD. The two surveys included similar questions so that comparisons could be made across groups. Potential respondents were e-mailed an informational letter inviting them to participate by completing a survey on SurveyMonkey within a 2 wk period in March and April 2010. This process resulted in three data sets: (1) AuDs in general, (2) AuDs in academia, and (3) program chairs. RESULTS: Return rates were 25, 26, and 45% for the three sampling methods for recruiting AuDs in general, AuDs in academia, and program chairs, respectively. Of the respondents, few AuDs held academic tenure-track positions or had achieved rank and tenure success in them. Those AuDs in academia usually had to meet the same or similarly rigorous criteria (with heavier emphasis on teaching than on research) for advancement as did PhD faculty. Overall, AuDs tended to believe that AuDs could be appointed to and succeed at tenure-track positions; chairs reported that such appointments were not permitted in most programs, did not personally believe that AuDs should hold these positions, and felt that AuDs would have more difficulty than PhDs in achieving success in them. Obstacles to AuDs' success in tenure-track positions reported by all three groups included lack of research skills and mentors, biases from faculty within and outside of audiology departments, and poorer pay than could be earned in the private sector. CONCLUSIONS: Considerable variability existed in the types of and titles for faculty positions held by AuDs in academia. Few AuDs were employed in tenure-track positions. Contrary to many of the chairs' responses, most AuDs felt they would be successful in such positions. Many of the AuDs suggested that universities with AuD programs should add more research and mentorship opportunities and tenure tracks for clinicians. Most respondents believed there is a need for both AuDs and PhDs in academic programs. These findings should be of interest to AuDs, chairs, and other stakeholders in academia, and the survey responses identified some areas warranting future investigation. PMID- 23739063 TI - Somatic mutation profiling and associations with prognosis and trastuzumab benefit in early breast cancer. AB - BACKGROUND: Certain somatic alterations in breast cancer can define prognosis and response to therapy. This study investigated the frequencies, prognostic effects, and predictive effects of known cancer somatic mutations using a randomized, adjuvant, phase III clinical trial dataset. METHODS: The FinHER trial was a phase III, randomized adjuvant breast cancer trial involving 1010 women. Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer were further randomized to 9 weeks of trastuzumab or no trastuzumab. Seven hundred five of 1010 tumors had sufficient DNA for genotyping of 70 somatic hotspot mutations in 20 genes using mass spectrometry. Distant disease-free survival (DDFS), overall survival (OS), and interactions with trastuzumab were explored with Kaplan-Meier and Cox regression analyses. All statistical tests were two sided. RESULTS: Median follow-up was 62 months. Of 705 tumors, 687 were successfully genotyped. PIK3CA mutations (exons 1, 2, 4, 9, 13, 18, and 20) were present in 25.3% (174 of 687) and TP53 mutations in 10.2% (70 of 687). Few other mutations were found: three ERBB2 and single cases of KRAS, ALK, STK11/LKB1, and AKT2. PIK3CA mutations were associated with estrogen receptor positivity (P < .001) and the luminal-A phenotype (P = .04) but were not statistically significantly associated with prognosis (DDFS: hazard ratio [HR] = 0.88, 95% confidence [CI] = 0.58 to 1.34, P = .56; OS: HR = 0.603, 95% CI = .32 to 1.13, P = .11), although a statistically significant nonproportional prognostic effect was observed for DDFS (P = .002). PIK3CA mutations were not statistically significantly associated with trastuzumab benefit (P(interaction): DDFS P = .14; OS P = .24). CONCLUSIONS: In this dataset, targeted genotyping revealed only two alterations at a frequency greater than 10%, with other mutations observed infrequently. PIK3CA mutations were associated with a better outcome, however this effect disappeared after 3 years. There were no statistically significant associations with trastuzumab benefit. PMID- 23739064 TI - Selective tropism of Seneca Valley virus for variant subtype small cell lung cancer. AB - We assessed the efficacy of Seneca Valley virus (SVV-001), a neuroendocrine cancer-selective oncolytic picornavirus, in primary heterotransplant mouse models of small cell lung cancer (SCLC), including three lines each of classic and variant SCLC. Half-maximal effective concentrations for cell lines derived from three variant heterotransplants ranged from 1.6*10(-3) (95% confidence interval [CI] = 1*10(-3) to 2.5*10(-3)) to 3.9*10(-3) (95% CI = 2.8*10(-3) to 5.5*10(-3)). Sustained tumor growth inhibition in vivo was only observed in variant lines (two sided Student t test, P < .005 for each). Doses of 10(14) vp/kg were able to completely and durably eradicate tumors in a variant SCLC heterotransplant model in two of six mice. Gene expression profiling revealed that permissive lines are typified by lower expression of the early neurogenic transcription factor ASCL1 and, conversely, by higher expression of the late neurogenic transcription factor NEUROD1. This classifier demonstrates a sensitivity of .89, specificity of .92, and accuracy of .91. The NEUROD1 to ASCL1 ratio may serve as a predictive biomarker of SVV-001 efficacy. PMID- 23739066 TI - Synthesis and characterization of rice straw/Fe3O4 nanocomposites by a quick precipitation method. AB - Small sized magnetite iron oxide nanoparticles (Fe3O4-NPs) with were successfully synthesized on the surface of rice straw using the quick precipitation method in the absence of any heat treatment. Ferric chloride (FeCl3.6H2O), ferrous chloride (FeCl2.4H2O), sodium hydroxide (NaOH) and urea (CH4N2O) were used as Fe3O4-NPs precursors, reducing agent and stabilizer, respectively. The rice straw fibers were dispersed in deionized water, and then urea was added to the suspension, after that ferric and ferrous chloride were added to this mixture and stirred. After the absorption of iron ions on the surface layer of the fibers, the ions were reduced with NaOH by a quick precipitation method. The reaction was carried out under N2 gas. The mean diameter and standard deviation of metal oxide NPs synthesized in rice straw/Fe3O4 nanocomposites (NCs) were 9.93 +/- 2.42 nm. The prepared rice straw/Fe3O4-NCS were characterized using powder X-ray diffraction (PXRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive X-ray fluorescence (EDXF) and Fourier transforms infrared spectroscopy (FT-IR). The rice straw/Fe3O4-NCs prepared by this method have magnetic properties. PMID- 23739065 TI - Polymorphic alleles in exon 1 of the CTLA4 gene do not predict the response to abatacept. PMID- 23739067 TI - Synthesis and structural exploration of disulfide bridged [2(n)] pillararene-like molecules. AB - Disulfide bridged pillararene-like macrocycles were synthesized starting from 1,4 dialkoxybenzene and sulfur monochloride. The structure was determined using X-ray diffraction analysis. PMID- 23739068 TI - The epidemiology of ventilator-associated pneumonia in a network of community hospitals: a prospective multicenter study. AB - OBJECTIVE: To describe the epidemiology of ventilator-associated pneumonia (VAP) in community hospitals. DESIGN AND SETTING: Prospective study in 31 community hospitals from 2007 to 2011. METHODS: VAP surveillance was performed by infection preventionists using the National Healthcare Safety Network protocol. VAP incidence was reported as number of events per 1,000 ventilator-days. We categorized hospitals into small (<30,000 patient-days/year), medium (30,000 60,000 patient-days/year), and large (>60,000 patient-days/year) groups and compared VAP incidence by hospital size. RESULTS: he median VAP incidence was 1.4 (interquartile range, 0.4-2.4), and ventilator utilization ratio (VUR) was 0.33 (0.25-0.47). VAP incidence was higher in small hospitals (2.1) than medium (0.85) or large (0.69) hospitals ([Formula: see text]) despite a lower VUR in small hospitals (0.29 vs 0.31 vs 0.44, respectively; [Formula: see text]). The median age of 247 VAP cases was 64 (53-73); 136 (55.1%) were female; 142 (57.5%) were Caucasian; 170 (68.8%) were admitted from home. The length of stay and duration of ventilation were 26 (14-42) and 12 (4-21) days, respectively. The pre- and postinfection hospital stays were 8 (3-13) days and 14 (8-30) days, respectively. Data on outcomes were available in 214 cases (86.6%), and 75 (35.0%) cases died during hospitalization. The top 3 pathogens were methicillin-resistant Staphylococcus aureus (MRSA; [Formula: see text], 27.9%), Pseudomonas species ([Formula: see text], 16.3%), and Klebsiella species ([Formula: see text], 13.3%). CONCLUSIONS: VAP incidence was inversely associated with size of hospital. VAP in community hospitals was frequently caused by MRSA. Importantly, predictors of VAP incidence in tertiary care hospitals such as VUR may not be predictive in community hospitals with few ventilated patients. PMID- 23739069 TI - Evaluating application of the National Healthcare Safety Network central line associated bloodstream infection surveillance definition: a survey of pediatric intensive care and hematology/oncology units. AB - OBJECTIVE: To evaluate the application of the National Healthcare Safety Network (NHSN) central line-associated bloodstream infection (CLABSI) definition in pediatric intensive care units (PICUs) and pediatric hematology/oncology units (PHOUs) participating in a multicenter quality improvement collaborative to reduce CLABSIs; to identify sources of variability in the application of the definition. DESIGN: Online survey using 18 standardized case scenarios. Each described a positive blood culture in a patient and required a yes- or-no answer to the question "Is this a CLABSI?" NHSN staff responses were the reference standard. SETTING: Sixty-five US PICUs and PHOUs. PARTICIPANTS: Staff who routinely adjudicate CLABSIs using NHSN definitions. RESULTS: Sixty responses were received from 58 (89%) of 65 institutions; 78% of respondents were infection preventionists, infection control officers, or infectious disease physicians. Responses matched those of NHSN staff for 78% of questions. The mean (SE) percentage of concurring answers did not differ for scenarios evaluating application of 1 of the 3 criteria ("known pathogen," 78% [1.7%]; "skin contaminant, >1 year of age," 76% [SE, 2.5%]; "skin contaminant, <=1 year of age," 81% [3.8%]; [Formula: see text]). The mean percentage of concurring answers was lower for scenarios requiring respondents to determine whether a CLABSI was present or incubating on admission (64% [4.6%]; [Formula: see text]) or to distinguish between primary and secondary bacteremia (65% [2.5%]; [Formula: see text]). CONCLUSIONS: The accuracy of application of the CLABSI definition was suboptimal. Efforts to reduce variability in identifying CLABSIs that are present or incubating on admission and in distinguishing primary from secondary bloodstream infection are needed. PMID- 23739070 TI - Infection related to implantable central venous access devices in cancer patients: epidemiology and risk factors. AB - OBJECTIVE: To describe the epidemiology of infections related to the use of implantable central venous access devices (CVADs) in cancer patients and to evaluate measures aimed at reducing the rates of such infections. DESIGN: Prospective cohort study. SETTING: Referral hospital for cancer in Sao Paulo, Brazil. PATIENTS: We prospectively evaluated all implantable CVADs employed between January 2009 and December 2011. Inpatients and outpatients were followed until catheter removal, transfer to another facility, or death. METHODS: Outcome measures were bloodstream infection and pocket infection. We also evaluated the effects that the creation of a multidisciplinary team for CVAD care, avoiding in hospital implantation of CVADs, and limiting CVAD insertion in neutropenic patients have on the rates of such infections. RESULTS: During the study period, 966 CVADs (mostly venous ports) were implanted in 933 patients, for a combined total of 243,792 catheter-days. We identified 184 episodes of infection: 154 (84%) were bloodstream infections, 21 (11%) were pocket infections, and 9 (5%) were surgical site infections. During the study period, the rate of CVAD-related infection dropped from 2.2 to 0.24 per 1,000 catheter-days ([Formula: see text]). Multivariate analysis revealed that relevant risk factors for such infection include surgical reintervention, implantation in a neutropenic patient, in hospital implantation, use of a cuffed catheter, and nonchemotherapy indication for catheter use. CONCLUSIONS: Establishing a multidisciplinary team specifically focused on CVAD care, together with systematic reporting of infections, appears to reduce the rates of infection related to the use of these devices. PMID- 23739071 TI - Variations in identification of healthcare-associated infections. AB - OBJECTIVE: Little is known about whether those performing healthcare-associated infection (HAI) surveillance vary in their interpretations of HAI definitions developed by the Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN). Our primary objective was to characterize variations in these interpretations using clinical vignettes. We also describe predictors of variation in responses. DESIGN: Cross-sectional study. SETTING: United States. PARTICIPANTS: A sample of US-based members of the Society for Healthcare Epidemiology of America (SHEA) Research Network. METHODS: Respondents assessed whether each of 6 clinical vignettes met criteria for an NHSN-defined HAI. Individual- and institutional-level data were also gathered. RESULTS: Surveys were distributed to 143 SHEA Research Network members from 126 hospitals. In total, 113 responses were obtained, representing at least 61 unique hospitals (30 respondents did not identify a hospital); 79.2% (84 of 106 nonmissing responses) were infection preventionists, and 79.4% (81 of 102 nonmissing responses) worked at academic hospitals. Among the 6 vignettes, the proportion of respondents correctly characterizing the vignettes was as low as 27.3%. Combining all 6 vignettes, the mean percentage of correct responses was 61.1% (95% confidence interval, 57.7%-63.8%). Percentage of correct responses was associated with presence of a clinical background (ie, nursing or physician degrees) but not with hospital size or infection prevention and control department characteristics. CONCLUSIONS: Substantial heterogeneity exists in the application of HAI definitions in this survey of infection preventionists and hospital epidemiologists. Our data suggest a need to better clarify these definitions, especially when comparing HAI rates across institutions. PMID- 23739072 TI - Prevalence of colonization and infection with methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus and of Clostridium difficile infection in Canadian hospitals. AB - OBJECTIVE: To determine the prevalence of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and Clostridium difficile infection (CDI) in Canadian hospitals. DESIGN: National point prevalence survey in November 2010. SETTING: Canadian acute care hospitals with at least 50 beds. PATIENTS: Adult inpatients colonized or infected with MRSA or VRE or with CDI. METHODS: The prevalence (per 100 inpatients) of MRSA, VRE, and CDI was determined. Associations between prevalence and institutional characteristics and infection control policies were evaluated. RESULTS: One hundred seventy-six hospitals (65% of those eligible) participated. The median (range) prevalence rates for MRSA and VRE colonization or infection and CDI were 4.2% (0%-22.1%), 0.5% (0%-13.1%), and 0.9% (0%-8.6%), respectively. Median MRSA and VRE infection rates were low (0.3% and 0%, respectively). MRSA, VRE, and CDI were thought to have been healthcare associated in 79%, 96%, and 84% of cases, respectively. In multivariable analysis, routine use of a private room for colonized/infected patients was associated with lower median MRSA infection rate (prevalence ratio [PR], 0.44 [95% confidence interval (CI), 0.22-0.88]) and VRE prevalence (PR, 0.26 [95% CI, 0.12-0.57]). Lower VRE rates were also associated with enhanced environmental cleaning (PR, 0.52 [95% CI, 0.36-0.75]). Higher bed occupancy rates were associated with higher rates of CDI (PR, 1.02 [95% CI, 1.01-1.03]). CONCLUSIONS: These data provide the first national prevalence estimates for MRSA, VRE, and CDI in Canadian hospitals. Certain infection prevention and control policies were found to be associated with prevalence and deserve further investigation. PMID- 23739073 TI - Impact of electronic surveillance on isolation practices. AB - OBJECTIVE: To assess the impact of an electronic surveillance system on isolation practices and rates of methicillin-resistant Staphylococcus aureus (MRSA). DESIGN: A pre-post test intervention. SETTING: Inpatient units (except psychiatry and labor and delivery) in 4 New York City hospitals. PATIENTS: All patients for whom isolation precautions were indicated, May 2009-December 2011. METHODS: Trained observers assessed isolation sign postings, availability of isolation carts, and staff use of personal protective equipment (PPE). Infection rates were obtained from the infection control department. Regression analyses were used to examine the association between the surveillance system, infection prevention practices, and MRSA infection rates. RESULTS: A total of 54,159 isolation days and 7,628 staff opportunities for donning PPE were observed over a 31-month period. Odds of having an appropriate sign posted were significantly higher after intervention than before intervention (odds ratio [OR], 1.10 [95% confidence interval {CI}, 1.01-1.20]). Relative to baseline, postintervention sign posting improved significantly for airborne and droplet precautions but not for contact precautions. Sign posting improved for vancomycin-resistant enterococci (OR, 1.51 [95% CI, 1.23-1.86]; [Formula: see text]), Clostridium difficile (OR, 1.59 [95% CI, 1.27-2.02]; [Formula: see text]), and Acinetobacter baumannii (OR, 1.41 [95% CI, 1.21-1.64]; [Formula: see text]) precautions but not for MRSA precautions (OR, 1.11 [95% CI, 0.89-1.39]; [Formula: see text]). Staff and visitor adherence to PPE remained low throughout the study but improved from 29.1% to 37.0% after the intervention (OR, 1.14 [95% CI, 1.01-1.29]). MRSA infection rates were not significantly different after the intervention. CONCLUSIONS: An electronic surveillance system resulted in small but statistically significant improvements in isolation practices but no reductions in infection rates over the short term. Such innovations likely require considerable uptake time. PMID- 23739074 TI - Burden of hospital-onset Clostridium difficile infection in patients discharged from Rhode Island hospitals, 2010-2011: application of present on admission indicators. AB - OBJECTIVE: The year 2010 is the first time that the Rhode Island hospital discharge database included present on admission (POA) indicators, which give us the opportunity to distinguish cases of hospital-onset Clostridium difficile infection (CDI) from cases of community-onset CDI and to assess the burden of hospital-onset CDI in patients discharged from Rhode Island hospitals during 2010 and 2011. DESIGN: Observational study. PATIENTS: Patients 18 years of age or older discharged from one of Rhode Island's 11 acute-care hospitals between January 1, 2010, and December 31, 2011. METHODS: Using the newly available POA indicators in the Rhode Island 2010 and 2011 hospital discharge database, we identified patients with hospital-onset CDI and without CDI. Adjusting for patient demographic and clinical characteristics using propensity score matching, we measured between-group differences in mortality, length of stay, and cost for patients with hospital-onset CDI and without CDI. RESULTS: In 2010 and 2011, the 11 acute-care hospitals in Rhode Island had 225,999 discharges. Of 4,531 discharged patients with CDI (2.0% of all discharges), 1,211 (26.7%) had hospital onset CDI. After adjusting for patient demographic and clinical characteristics, discharged patients with hospital-onset CDI were found to have higher mortality rates, longer lengths of stay, and higher costs than those without CDI. CONCLUSIONS: Our results highlight the burden of hospital-onset CDI in Rhode Island. These findings emphasize the need to track longitudinal trends to tailor and target population-health and quality-improvement initiatives. PMID- 23739075 TI - Acute hepatitis B outbreaks in 2 skilled nursing facilities and possible sources of transmission: North Carolina, 2009-2010. AB - OBJECTIVE: Acute hepatitis B virus (HBV) infections have been reported in long term care facilities (LTCFs), primarily associated with infection control breaks during assisted blood glucose monitoring. We investigated HBV outbreaks that occurred in separate skilled nursing facilities (SNFs) to determine factors associated with transmission. DESIGN: Outbreak investigation with case-control studies. SETTING: Two SNFs (facilities A and B) in Durham, North Carolina, during 2009-2010. PATIENTS: Residents with acute HBV infection and controls randomly selected from HBV-susceptible residents during the outbreak period. METHODS: After initial cases were identified, screening was offered to all residents, with repeat testing 3 months later for HBV-susceptible residents. Molecular testing was performed to assess viral relatedness. Infection control practices were observed. Case-control studies were conducted to evaluate associations between exposures and acute HBV infection in each facility. RESULTS: Six acute HBV cases were identified in each SNF. Viral phylogenetic analysis revealed a high degree of HBV relatedness within, but not between, facilities. No evaluated exposures were significantly associated with acute HBV infection in facility A; those associated with infection in facility B (all odds ratios >20) included injections, hospital or emergency room visits, and daily blood glucose monitoring. Observations revealed absence of trained infection control staff at facility A and suboptimal hand hygiene practices during blood glucose monitoring and insulin injections at facility B. CONCLUSIONS: These outbreaks underscore the vulnerability of LTCF residents to acute HBV infection, the importance of surveillance and prompt investigation of incident cases, and the need for improved infection control education to prevent transmission. PMID- 23739077 TI - Correlates of improved influenza vaccination of healthcare personnel: a survey of hospitals in Louisiana. AB - OBJECTIVE: To describe practices for influenza vaccination of healthcare personnel (HCP) with emphasis on correlates of increased vaccination rates. DESIGN: Survey. PARTICIPANTS: Volunteer sample of hospitals in Louisiana. METHODS: All hospitals in Louisiana were invited to participate. A 17-item questionnaire inquired about the hospital type, patients served, characteristics of the vaccination campaign, and the resulting vaccination rate. RESULTS: Of 254 hospitals, 153 (60%) participated and were included in the 124 responses that were received. Most programs (64%) required that HCP either receive the vaccine or sign a declination form, and the rest were exclusively voluntary (36%); no program made vaccination a condition of employment. The median vaccination rate was 67%, and the vaccination rate was higher among hospitals that were accredited by the Joint Commission; provided acute care; served children, pregnant women, oncology patients, or intensive care unit patients; required a signed declination form; or imposed consequences for unvaccinated HCP (the most common of which was to require that a mask be worn on patient contact). Hospitals that provided free vaccine, made vaccine widely available, advertised the program extensively, required a declination form, and imposed consequences had the highest vaccination rates (median, 86%; range, 81%-91%). CONCLUSIONS: The rate of influenza vaccination of HCP remains low among the hospitals surveyed. Recommended practices may not be enough to reach 90% vaccination rates unless a signed declination requirement and consequences are implemented. Wearing a mask is a strong consequence. Demanding influenza vaccination as a condition of employment was not reported as a practice by the participating hospitals. PMID- 23739078 TI - The challenges of carbapenemase-producing Enterobacteriaceae and infection prevention: protecting patients in the chaos. PMID- 23739076 TI - Infection control assessment after an influenza outbreak in a residential care facility for children and young adults with neurologic and neurodevelopmental conditions. AB - OBJECTIVE: To assess the knowledge, attitudes, and practices of infection control among staff in a residential care facility for children and young adults with neurologic and neurodevelopmental conditions. DESIGN: Self-administered survey. SETTING: Residential care facility (facility A). PARTICIPANTS: Facility A staff ([Formula: see text]). METHODS: We distributed a survey to staff at facility A. We classified staff with direct care responsibilities as clinical (ie, physicians, nurses, and therapists) or nonclinical (ie, habilitation assistants, volunteers, and teachers) and used chi(2) tests to measure differences between staff agreement to questions. RESULTS: Of 248 surveys distributed, 200 (81%) were completed; median respondent age was 36 years; 85% were female; and 151 were direct care staff (50 clinical, 101 nonclinical). Among direct care staff respondents, 86% agreed they could identify residents with respiratory symptoms, 70% stayed home from work when ill with respiratory infection, 64% agreed that facility administration encouraged them to stay home when ill with respiratory infection, and 72% reported that ill residents with respiratory infections were separated from well residents. Clinical and nonclinical staff differed in agreement about using waterless hand gel as a substitute for handwashing (96% vs 78%; [Formula: see text]) and whether handwashing was done after touching residents (92% vs 75%; [Formula: see text]). CONCLUSIONS: Respondents' knowledge, attitudes, and practices regarding infection control could be improved, especially among nonclinical staff. Facilities caring for children and young adults with neurologic and neurodevelopmental conditions should encourage adherence to infection control best practices among all staff having direct contact with residents. PMID- 23739079 TI - Achieving and sustaining ventilator-associated pneumonia-free time among intensive care units (ICUs): evidence from the Keystone ICU Quality Improvement Collaborative. AB - Our retrospective analysis of the Michigan Keystone intensive care unit (ICU) collaborative demonstrated that adult ICUs could achieve and sustain a zero rate of ventilator-associated pneumonia (VAP) for a considerable number of ventilator and calendar months. Moreover, the results highlight the importance of adjustment for ventilator-days before comparing VAP-free time among ICUs. PMID- 23739080 TI - Comparison of non-intensive care unit (ICU) versus ICU rates of catheter associated urinary tract infection in community hospitals. AB - We describe and compare the epidemiology of catheter-associated urinary tract infection (CAUTI) occurring in non-intensive care unit (ICU) versus ICU wards in a network of community hospitals over a 2-year period. Overall, 72% of cases of CAUTI occurred in non-ICU patients, which indicates that this population is an important target for dedicated surveillance and prevention efforts. PMID- 23739081 TI - Risk factors for persistent methicillin-resistant Staphylococcus aureus colonization in children with multiple intensive care unit admissions. AB - We studied methicillin-resistant Staphylococcus aureus (MRSA)-colonized children with multiple intensive care unit (ICU) admissions to assess the persistence of MRSA colonization. Our data found that children with more than 1 year between ICU admissions had a higher prevalence of MRSA colonization than the overall ICU population, which supports empirical contact precautions for children with previous MRSA colonization. PMID- 23739082 TI - Sustained improvement in hand hygiene at a children's hospital. AB - A quality improvement project was conducted to improve hand hygiene at a children's hospital. Interventions included education, performance feedback, an incentive program, and a marketing campaign. There were 9,322 observations performed over a 5-year period. Hospital-wide adherence increased from 39.9% to 97.9%. Adherence of 95% or greater was sustained for over 3 years. PMID- 23739083 TI - Nosocomial pulmonary tuberculosis contact investigation in a neonatal intensive care unit. AB - The diagnosis of smear-positive pulmonary tuberculosis in a medical officer working in a metropolitan Australian neonatal intensive care unit led to a contact investigation involving 125 neonates, 165 relatives, and 122 healthcare workers with varying degrees of exposure. There was no evidence of nosocomial tuberculosis transmission from the index case. PMID- 23739084 TI - Colonization of high-risk children with carbapenemase-producing Enterobacteriaceae in Greece. PMID- 23739085 TI - Risk of hepatitis C virus transmission from patients to healthcare workers: a prospective observational study. PMID- 23739086 TI - Enterococcus species and the central line-associated bloodstream infection surveillance definition: evaluating the importance of blood culture contamination. PMID- 23739087 TI - Reply to Freeman et al. PMID- 23739088 TI - Epidemic keratoconjunctivitis outbreak in a closed psychiatric ward. PMID- 23739089 TI - Catheter-related bacteremia caused by Aeromonas hydrophila in a hemodialysis patient. PMID- 23739092 TI - Cullin-3 and the endocytic system: New functions of ubiquitination for endosome maturation. AB - Cullin-RING-ligases (CRLs) comprise the largest class of multisubunit E3 ubiquitin ligases, which regulate a broad range of cellular processes. Cullin3 (Cul3) recently emerged as an important regulator of intracellular trafficking, in particular secretion and endosome maturation. Here we summarize and discuss possible functions and substrates of Cul3 in the endocytic system. PMID- 23739098 TI - The continued evolution of epilepsy. PMID- 23739093 TI - Morphology, spatial distribution, and concentration of flame retardants in consumer products and environmental dusts using scanning electron microscopy and Raman micro-spectroscopy. AB - We characterized flame retardant (FR) morphologies and spatial distributions in 7 consumer products and 7 environmental dusts to determine their implications for transfer mechanisms, human exposure, and the reproducibility of gas chromatography-mass spectrometry (GC-MS) dust measurements. We characterized individual particles using scanning electron microscopy/energy dispersive x-ray spectroscopy (SEM/EDS) and Raman micro-spectroscopy (RMS). Samples were screened for the presence of 3 FR constituents (bromine, phosphorous, non-salt chlorine) and 2 metal synergists (antimony and bismuth). Subsequent analyses of select samples by RMS enabled molecular identification of the FR compounds and matrix materials. The consumer products and dust samples possessed FR elemental weight percents of up to 36% and 31%, respectively. We identified 24 FR-containing particles in the dust samples and classified them into 9 types based on morphology and composition. We observed a broad range of morphologies for these FR-containing particles, suggesting FR transfer to dust via multiple mechanisms. We developed an equation to describe the heterogeneity of FR-containing particles in environmental dust samples. The number of individual FR-containing particles expected in a 1-mg dust sample with a FR concentration of 100ppm ranged from <1 to >1000 particles. The presence of rare, high-concentration bromine particles was correlated with decabromodiphenyl ether concentrations obtained via GC-MS. When FRs are distributed heterogeneously in highly concentrated dust particles, human exposure to FRs may be characterized by high transient exposures interspersed by periods of low exposure, and GC-MS FR concentrations may exhibit large variability in replicate subsamples. Current limitations of this SEM/EDS technique include potential false negatives for volatile and chlorinated FRs and greater quantitation uncertainty for brominated FR in aluminum-rich matrices. PMID- 23739099 TI - The 2010 revised classification of seizures and epilepsy. AB - PURPOSE OF REVIEW: Classifications of epilepsies (1989) and seizures (1981) took a central role in epilepsy care and research. Based on nearly century-old concepts, they were abandoned in 2010, and recommendations for new concepts and terminology were made in accordance with a vision of what a future classification would entail. This review outlines the major changes, the ways these changes relate to the earlier systems, the implications for the practicing health care provider, and some of the recommendations for future classification systems. RECENT FINDINGS: New terminology for underlying causes (genetic, structural metabolic, and unknown) was introduced to replace the old (idiopathic, symptomatic, and cryptogenic) in 2010. The use of generalized and focal to refer to the underlying epilepsy was largely abandoned, but the terms were retained in reference to mode of seizure initiation and presentation. The terms "complex" and "simple partial" for focal seizures were abandoned in favor of more descriptive terms. Electroclinical syndromes were highlighted as specific epilepsy diagnoses and distinguished from nonsyndromic-nonspecific diagnoses. The importance of diagnosis (a clinical goal focused on the individual patient) over classification (an intellectual system for organizing information) was emphasized. SUMMARY: Accurate description and diagnosis of the seizures, causes, and specific type of epilepsy remain the goal in clinical epilepsy care. While terminology and concepts are being revised, the implications for patient care currently are minimal; however, the gains in the future of clear, accurate terminology and a multidomain classification system could potentially be considerable. PMID- 23739100 TI - EEG and epilepsy monitoring. AB - PURPOSE OF REVIEW: This article reviews the utility of EEG and prolonged video EEG telemetry in the diagnosis and management of a patient with epilepsy. RECENT FINDINGS: The EEG can be the most helpful test to determine a diagnosis of epilepsy; it can also distinguish focal and generalized neurophysiologic correlates of epilepsy. Furthermore, when paired with video monitoring, EEG can not only define epileptic and nonepileptic events but also aid in localization of seizures in patients with epilepsy. Finally, when history and other imaging modalities are considered with the EEG, the epileptic syndrome can usually be defined and the treatment can be focused. In critically ill patients, continuous EEG monitoring can define subclinical seizures, although a variety of periodic patterns may also be identified. SUMMARY: EEG is an invaluable tool in the diagnosis and management of a patient with epilepsy, and continuous EEG monitoring is useful in identifying subclinical seizures and nonconvulsive status epilepticus in critically ill patients. PMID- 23739101 TI - Neuroimaging in investigation of patients with epilepsy. AB - PURPOSE OF REVIEW: This review discusses the MRI and functional imaging findings in patients with focal seizures, practical ways to improve the detection of subtle lesions, and limitations and pitfalls of the various imaging techniques in this context. RECENT FINDINGS: A proper MRI investigation of patients with focal epilepsy requires the use of specific protocols, selected based on identification of the region of onset by clinical and EEG information. For practical purposes, the focal epilepsies are divided here into mesial temporal lobe epilepsies and neocortical epilepsies. The majority of patients with mesial temporal lobe epilepsies associated with hippocampal sclerosis undergoing presurgical evaluation will have a clear-cut unilateral atrophic hippocampus with increased T2 signal and a normal-appearing contralateral hippocampus. Among the several types of neocortical lesions, focal cortical dysplasias deserve especial attention because these lesions are often missed on routine MRIs. The focal cortical dysplasias include a gradient of morphologic changes from dysplastic lesions that can be easily identified by conventional MRI techniques to minor structural abnormalities with small areas of discrete cortical thickening and blurring of the gray/white matter interface that often go unrecognized. SUMMARY: The use of MRI protocols targeted for the study of patients with epilepsy allows the diagnosis of the etiology of epilepsy in most patients with focal seizures. However, in a considerable number of patients with epilepsy, MRI results are considered normal. Although the etiology remains unclear in these cases, the malformations of cortical development (mainly focal cortical dysplasias) have been identified as most likely pathologic substrates. The effort involved in trying to increase the detection of these "invisible" lesions involves the improvement of structural imaging techniques and the combination of metabolic and functional studies, including 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET), ictal single-photon emission computed tomography (SPECT), diffusion MRI, and magnetic resonance spectroscopy (MRS). The methods used to enhance the detection of subtle cortical abnormalities by improving the structural images have addressed two basic aspects of the examination by MRI: signal acquisition and imaging postprocessing. PMID- 23739102 TI - Antiepileptic drug treatment: new drugs and new strategies. AB - PURPOSE OF REVIEW: Selection of the ideal antiepileptic drug (AED) for an individual patient can be a daunting process. Choice of treatment should be based on several factors, including but not limited to epilepsy classification, AED mechanism of action, AED side-effect profile, and drug interactions. Special consideration must be given to populations such as women, older adults, patients with other medical comorbidities, and patients who are newly diagnosed. RECENT FINDINGS: Head-to-head trials between AEDs in newly diagnosed patients rarely demonstrate that one AED is more or less effective. The second-generation drugs, lamotrigine, topiramate, oxcarbazepine, zonisamide, and levetiracetam, have undergone head-to-head trials confirming similar efficacy and equal or better tolerability than standard drugs in focal epilepsy. SUMMARY: A thoughtful approach to the AED selection process must factor in data from clinical AED trials as well as a variety of patient characteristics and confounding factors. When neurologists apply an individualized approach to AED drug selection for their patients, they can find an effective and well-tolerated drug for most patients. PMID- 23739103 TI - Management of childhood epilepsy. AB - PURPOSE OF REVIEW: This article outlines a diagnostic and management approach to pediatric seizures and epilepsy syndromes, and delineates pharmacologic and nonpharmacologic treatment options. RECENT FINDINGS: Progress in tracking of seizures, identifying and addressing medication nonadherence, treatment with novel devices, and clinical decision support algorithms will provide additional management options in the future. SUMMARY: The management of pediatric seizures and epilepsies presents multiple challenges to the clinician because of nonepileptic imitators, evolving classification approaches, clinical presentations, limited clinical trial data for medications, and the toxicities of therapies. While certain pediatric seizures and epilepsy syndromes respond best to certain medications, early identification of pharmacologically resistant patients who may be candidates for epilepsy surgery is important. Alternative treatment options may include ketogenic diet or vagus nerve stimulation. PMID- 23739104 TI - Epilepsy and neuropsychological comorbidities. AB - PURPOSE OF REVIEW: Epilepsy is a chronic disorder with several associated comorbidities requiring timely recognition and treatment. This article discusses aspects of cognitive impairment; psychiatric disorders including depression, anxiety, and psychosis; and health-related quality-of-life issues pertaining to patients with epilepsy. RECENT FINDINGS: Cognitive problems in epilepsy may be present early in the disease course. Advances in imaging techniques are allowing correlation of structure and function as they relate to cognitive impairment in epilepsy. The relationship between epilepsy, depression, and anxiety is increasingly recognized, and these psychiatric comorbidities may affect suicide risk, patient-reported adverse antiepileptic drug effects, and quality of life. Psychiatric disorders are underrecognized and undertreated in patients with epilepsy. SUMMARY: Physicians who treat patients with epilepsy should be aware of the major impact that cognitive impairment and psychiatric comorbidities have on these patients. Identifying and treating these comorbidities in epilepsy patients is just as important as seizure treatment. PMID- 23739105 TI - Pregnancy, epilepsy, and women's issues. AB - PURPOSE OF REVIEW: Optimal treatment of women with epilepsy includes consideration of the complex interactions of sex steroid hormones with epilepsy and antiepileptic drugs, and of the potential risks of any antiepileptic drug prescribed during a pregnancy. RECENT FINDINGS: Clinical studies in women with epilepsy have provided a better foundation of knowledge about the complex relationships between cycling sex steroid hormones, seizure frequency, antiepileptic drugs, contraception, and neuroendocrine abnormalities. Pregnancy registries and observational studies have provided key data that allow for a better estimation of risks to the developing fetus. SUMMARY: Understanding these key factors should enable informed treatment recommendations that can reduce adverse health effects in women with epilepsy and improve both seizure control and maternal and fetal outcomes. PMID- 23739106 TI - Nonepileptic behavioral disorders: diagnosis and treatment. AB - PURPOSE OF REVIEW: This article will review the important steps in making an accurate diagnosis of psychogenic nonepileptic events or episodes (PNEE), and recent developments in diagnosis and treatment. RECENT FINDINGS: Several clues can be obtained from the history to help the clinician suspect the diagnosis of PNEE. While none of these clues are diagnostic on their own, each is valuable, and there are often multiple clues in a given patient. Clinical clues have limitations, and once PNEE is suspected, video-EEG monitoring remains the gold standard and the only way to make a definite diagnosis of PNEE. Like most tests, video EEG has its limitations, but in most cases the diagnosis can be made and is not difficult. Regarding treatment, growing evidence exists that psychotherapy, especially cognitive behavior therapy, is effective, and a recent finding is that pharmacotherapy may have a role. SUMMARY: The diagnosis of PNEE can be made reliably, but the management of PNEE remains problematic, in large part because of the insufficient involvement of mental health professionals. PMID- 23739107 TI - Surgical treatment of epilepsy. AB - PURPOSE OF REVIEW: This article outlines indications for neurosurgical treatment of epilepsy, describes the presurgical workup, summarizes surgical approaches, and details expected risks and benefits. RECENT FINDINGS: There is class I evidence for the efficacy of temporal lobectomy in treating intractable seizures, and accumulating documentation that successful surgical treatment reverses much of the disability, morbidity, and excess mortality of chronic epilepsy. SUMMARY: Chronic, uncontrolled focal epilepsy causes progressive disability and increased mortality, but these can be reversed with seizure control. Vigorous efforts to stop seizures are warranted. If two well-chosen and tolerated medication trials do not achieve seizure control, an early workup for epilepsy surgery should be arranged. If this workup definitively identifies the brain region from which the seizures arise, and this region can be removed with a low risk of disabling neurologic deficits, neurosurgery will have a much better chance of stopping seizures than further medication trials. PMID- 23739108 TI - Neurostimulation for drug-resistant epilepsy. AB - PURPOSE OF REVIEW: The purpose of this review is to provide an evidence-based update on the neurostimulation options available for patients with drug-resistant epilepsy in the United States and in European countries. RECENT FINDINGS: The field of neurostimulation for epilepsy has grown dramatically since 1997, when vagus nerve stimulation became the first device to be approved for epilepsy by the US Food and Drug Administration (FDA). New data from recently completed randomized controlled trials are available for deep brain stimulation of the anterior thalamus, responsive neurostimulation, and trigeminal nerve stimulation. Although vagus nerve stimulation is the only device currently approved in the United States, deep brain stimulation and responsive neurostimulation devices are awaiting FDA approval. Deep brain stimulation, trigeminal nerve stimulation, and transcutaneous vagus nerve stimulation are now approved for epilepsy in the European Union. In this article, the mechanisms of action, safety, and efficacy of new neurostimulation devices are reviewed, and the key advantages and disadvantages of each are discussed. SUMMARY: The exponential growth of the field of neuromodulation for epilepsy is an exciting development; these new devices provide physicians with new options for patients with drug-resistant epilepsy. PMID- 23739109 TI - Dietary treatment of intractable epilepsy. AB - PURPOSE OF REVIEW: Dietary therapies for seizure management date back further than pharmacologic interventions, but many neurologists are not familiar with these treatment options. This introduction to dietary therapies will discuss administration of ketogenic diets, comparisons between diet types, evidence-based efficacy of diet therapies in epilepsy treatment, and management of side effects. This review will provide the general neurologist with the skills to identify appropriate candidates for these treatments and to offer comprehensive ongoing care. RECENT FINDINGS: In adults and children with medically resistant epilepsy, studies have consistently shown a greater than 50% reduction in seizure frequency in approximately one-half of patients within days to months after starting dietary therapy. SUMMARY: Dietary treatment options for epilepsy include the classic ketogenic diet, the medium-chain triglyceride diet, the modified Atkins diet, and the low glycemic index treatment. These were first used to control seizures in children with intractable epilepsy, but in recent years have also been demonstrated to be safe and effective in children and adults with a broad range of seizure types and are being used with increased frequency worldwide. PMID- 23739110 TI - Status epilepticus. AB - PURPOSE OF REVIEW: This review presents the state of the art in the diagnosis and management of status epilepticus. RECENT FINDINGS: In addition to general background, this article presents the most recent findings regarding the diagnosis and treatment of status epilepticus, including the results of the Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) and the available data on the use of newer antiepileptic and anesthetic drugs in the treatment of refractory status epilepticus. It also presents available guidelines such as those from the Neurocritical Care Society. SUMMARY: Despite recent advances, the management of status epilepticus remains a challenge. Rapid treatment, a written treatment protocol, early consideration of nonconvulsive seizures, and avoiding overtreatment and medical complications are the keys to successful management. This article summarizes the current evidence and guidelines. PMID- 23739111 TI - Genetic testing in children with epilepsy. AB - Genetic testing is now available clinically for several epilepsies. Neurologists increasingly face decisions about diagnostic testing in affected patients and should carefully deliberate the ethical considerations associated with genetic testing. The merits of ordering a genetic test are largely based on the utility for guiding clinical care, providing a prognosis, estimating recurrence risk, and identifying comorbidities. At the same time, a decision to pursue any genetic testing also requires evaluation of associated ethical concerns. This case illustrates ethical challenges that arise when considering genetic testing for a pediatric patient with epilepsy. PMID- 23739112 TI - Monitoring and antiepileptic drug safety. AB - Treatment of patients with epilepsy strives for complete seizure control without intolerable drug side effects. Independent of blood drug levels, toxic effects allow titration to efficacy; however, allergic reactions, metabolically or genetically determined drug-induced illnesses, and idiosyncratic effects of drugs, while rare, may be life-threatening.Monitoring is an attempt to detect serious systemic toxic reactions of antiepileptic drugs in time to intervene and protect patients. The process begins with the disclosure to patients and family members of all information required for an informed decision delivered within the framework of risks and benefits. This review provides guidance regarding designing a monitoring strategy for patients requiring chronic treatment with antiepileptic drugs. PMID- 23739113 TI - Diagnostic coding for epilepsy. PMID- 23739117 TI - Patient management problem. PMID- 23739120 TI - Living longer, living better: preview of CIHR Institute of Aging 2013-2018 strategic plan. PMID- 23739121 TI - DNA methylation of the BDNF gene and its relevance to psychiatric disorders. AB - Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor, which is important for neuronal survival, development and synaptic plasticity. Accumulating evidence suggests that epigenetic modifications of BDNF are associated with the pathophysiology of psychiatric disorders, such as schizophrenia and mood disorders. Patients with psychiatric disorders generally show decreased neural BDNF levels, which are often associated with increased DNA methylation at the specific BDNF promoters. Importantly, observed DNA methylation changes are consistent across tissues including brain and peripheral blood, which suggests potential usefulness of these findings as a biomarker of psychiatric disorders. Here we review DNA methylation characteristics of BDNF promoters of cellular, animal and clinical samples and discuss future perspectives. PMID- 23739122 TI - Histone modifications for human epigenome analysis. AB - Histones function both positively and negatively in the regulation of gene expression, mainly governed by post-translational modifications on specific amino acid residues. Although histone modifications are not necessarily prerequisite codes, they may still serve as good epigenetic indicators of chromatin state associated with gene activation or repression. In particular, six emerging classes of histone H3 modifications are subjected for epigenome profiling by the International Human Epigenome Consortium. In general, transcription start sites of actively transcribed genes are marked by trimethylated H3K4 (H3K4me3) and acetylated H3K27 (H3K27ac), and active enhancers can be identified by enrichments of both monomethylated H3K4 (H3K4me1) and H3K27ac. Gene bodies of actively transcribed genes are associated with trimethylated H3K36 (H3K36me3). Gene repression can be mediated through two distinct mechanisms involving trimethylated H3K9 (H3K9me3) and trimethylated H3K27 (H3K27me3). Enrichments of these histone modifications on specific loci, or in genome wide, in given cells can be analyzed by chromatin immunoprecipitation (ChIP)-based methods using an antibody directed against the site-specific modification. When performing ChIP experiments, one should be careful about the specificity of antibody, as this affects the data interpretation. If cell samples with preserved histone-DNA contacts are available, evaluation of histone modifications, in addition to DNA methylaion, at specific gene loci would be useful for deciphering the epigenome state for human genetics studies. PMID- 23739123 TI - Effects of embryonic manipulation and epigenetics. AB - Embryonic manipulation techniques, such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), are widely used in assisted reproductive technology (ART), livestock propagation and application in other fields. Fertilization with IVF and ICSI have been shown to be highly effective, and the mice produced by these techniques develop healthily and with a normal appearance. However, there remains a possibility of epigenetic changes being induced by these techniques. The early stage of mammalian development from fertilization to implantation is a period in which global changes in the epigenetic landscape take place. The sperm and oocyte epigenetic profiles are very different from each other, and the epigenetic remodeling process after fertilization exhibits allelic differences. It is during this period that embryonic manipulation is performed. In this review, I discuss the effects of embryonic manipulation procedures in relation to the epigenetic asymmetry that is present in mammalian early development. Such regulation in the preimplantation embryo provides an important insight into epigenetics. PMID- 23739124 TI - Transmission of an FMR1 premutation allele in a large family identified through newborn screening: the role of AGG interruptions. AB - The CGG repeat within the premutation range in the fragile X mental retardation 1 (FMR1) gene can lead to neurodegenerative disorders and intellectual disabilities. An increase in size upon the transmission from parent to child is more likely to occur for larger alleles and without AGG interruptions. We describe the molecular structure and the transmission of an FMR1 premutation allele in a multigenerational family, identified through newborn screening for fragile X syndrome. Transmission of the premutation allele was traced through five generations in 14 of the 23 individuals who were genotyped through cascade testing. Allele size instability during transmission was observed, but no expansions to a full mutation were detected. Clinical and molecular characterizations of the participants lead to the diagnosis of fragile X associated tremor ataxia syndrome in one subject identified as a premutation carrier. A gradual small increase in the size of the premutation allele was observed during transmission through five generations. The relative stability is likely due to the presence of two AGGs within the allele. The detection of AGG interruptions within the premutation alleles is important in genetic counseling, to better predict the risk of expansion during transmission from a premutation to a full-mutation allele. PMID- 23739125 TI - A large cohort of myotonia congenita probands: novel mutations and a high frequency mutation region in exons 4 and 5 of the CLCN1 gene. AB - Myotonia congenita is a genetic disease characterized by impaired muscle relaxation after forceful contraction (myotonia) and caused by mutations in the chloride channel voltage-sensitive 1 (CLCN1) gene, encoding the voltage-gated chloride channel of skeletal muscle (ClC-1). In a large cohort of clinically diagnosed unrelated probands, we identified 75 different CLCN1 mutations in 106 individuals, among which 29 were novel mutations and 46 had already been reported. Despite the newly described mutations being scattered throughout the gene, in our patients, mutations were mostly found in exons 4 and 5. Most of the novel mutations located in the region comprising the intramembrane helices are involved in the ion-conducting pathway and predicted to affect channel function. We report for the first time that two mutations, inherited on the same allele as a heterozygous trait, abrogate disease expression, although when inherited singularly they were pathogenic. Such a mode of inheritance might explain the incomplete penetrance reported for autosomal dominant mutations in particular families. PMID- 23739126 TI - Three novel ZBTB24 mutations identified in Japanese and Cape Verdean type 2 ICF syndrome patients. AB - Immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder that shows DNA hypomethylation at pericentromeric satellite-2 and -3 repeats in chromosomes 1, 9 and 16. ICF syndrome is classified into two groups: type 1 (ICF1) patients have mutations in the DNMT3B gene and about half of type 2 (ICF2) patients have mutations in the ZBTB24 gene. Besides satellite-2 and -3 repeats, alpha-satellite repeats are also hypomethylated in ICF2. In this study, we report three novel ZBTB24 mutations in ICF2. A Japanese patient was homozygous for a missense mutation (C383Y), and a Cape Verdean patient was compound heterozygous for a nonsense mutation (K263X) and a frame-shift mutation (C327W fsX54). In addition, the second Japanese patient was homozygous for a previously reported nonsense mutation (R320X). The C383Y mutation abolished a C2H2 motif in one of the eight zinc-finger domains, and the other three mutations caused a complete or large loss of the zinc-finger domains. Our immunofluorescence analysis revealed that mouse Zbtb24 proteins possessing a mutation corresponding to either C383Y or R320X are mislocalized from pericentrometic heterochromatin, suggesting the importance of the zinc finger domains in proper intranuclear localization of this protein. We further revealed that the proper localization of wild-type Zbtb24 protein does not require DNA methylation. PMID- 23739127 TI - Regional DNA methylation differences between humans and chimpanzees are associated with genetic changes, transcriptional divergence and disease genes. AB - Changes in gene expression have been proposed to have an important role in the evolutionary changes in phenotypes. Interspecific changes in gene expression can result not only from genetic changes in regulatory regions but also from epigenetic changes in such regions. Here we report the identification of genomic regions showing differences in DNA methylation between humans and chimpanzees (termed S-DMRs for species-specific differentially methylated regions) on chromosomes 21 and 22. These regional methylation differences are frequently associated with genes, including those relevant to a disease, such as Alzheimer's disease, diabetes mellitus or cancer. Methylation differences are often correlated with changes in promoter activity or alternative splicing. Comparative studies including other great ape species provide evidence for the contribution of genetic changes to some of these S-DMRs. Genetic changes responsible for the S DMRs include gain or loss of CTCF-binding site and changes in CpG density in microsatellite repeats. Our results suggest that DNA methylation changes, often caused by small sequence changes, contribute to transcriptional and phenotypic diversification in hominid evolution. PMID- 23739128 TI - Clinical application of the CpG island methylator phenotype to prognostic diagnosis in neuroblastomas. AB - Clinical applications of aberrant DNA methylation to cancer diagnostics and therapeutics are accelerating. Especially, the CpG island methylator phenotype (CIMP), simultaneous methylation of multiple genes, provides information that cannot be obtained by other diagnostic methods and therapeutic opportunities. CIMP is known to be associated with poor or good prognosis depending upon cancer types. We identified that CIMP in neuroblastomas (NBLs) is strongly associated with poor prognosis in Japanese NBL cases (hazard ratio (HR)=22). Almost all NBLs with MYCN amplification displayed CIMP, and even among NBLs without MYCN amplification, NBLs with CIMP had worse prognosis (HR=12). The prognostic power was faithfully reproduced in German NBL cases by the same methods, and also in Italian and Swedish NBL cases with different analytical methods. Mechanistically, methylation silencing of different sets of tumor-suppressor genes is involved in poor prognosis of NBLs with CIMP, and the presence of CIMP is most sensitively detected by methylation of the PCDHB family. For therapeutic purposes, a combination of 5-aza-2'-deoxycytidine, a DNA-demethylating drug, with 13-cis retinoic acid, a differentiating drug, has been shown to be effective for NBLs in vitro, and further development of a better combination(s) is awaited. Now, epigenetic diagnosis and therapeutics are becoming or have become an important choice for cancer patients. PMID- 23739129 TI - Forearm injury in a 5 year old boy. PMID- 23739130 TI - From clinician to faculty: 10 tips. PMID- 23739131 TI - Incorporating office procedure skills into a family nurse practitioner program. PMID- 23739132 TI - Neuropilin-1 biases dendrite polarization in the retina. AB - The majority of neurons in the nervous system exhibit a polarized morphology, with multiple short dendrites and a single long axon. It is clear that multiple factors govern polarization in developing neurons, and the biased accumulation of intrinsic determinants to one side of the cell, coupled with responses to asymmetrically localized extrinsic factors, appears to be crucial. A number of intrinsic factors have been identified, but surprisingly little is known about the identity of the extrinsic signals. Here, we show in vivo that neuropilin-1 (Nrp1) and its co-receptor plexinA1 (Plxna1) are necessary to bias the extension of the dendrites of retinal ganglion cells to the apical side of the cell, and ectopically expressed class III semaphorins (Sema3s) disrupt this process. Importantly, the requirement for Nrp1 and Plxna1 in dendrite polarization occurs at a developmental time point after the cells have already extended their basally directed axon. Thus, we propose a novel mechanism whereby an extrinsic factor, probably a Sema3, acts through Nrp1 and Plxna1 to promote the asymmetric outgrowth of dendrites independently of axon polarization. PMID- 23739133 TI - Defining skeletal muscle resident progenitors and their cell fate potentials. AB - The satellite cell is the major tissue-resident stem cell underlying muscle regeneration; however, multiple non-satellite myogenic progenitors as well as non myogenic populations that support the muscle regenerative process have been identified. PW1 is expressed in satellite cells as well as in a subset of interstitial cells with myogenic potential termed PICs (PW1+ interstitial cells). Microarray profiling revealed that PICs express a broad range of genes common to mesenchymal stem cells, whereas satellite cells express genes consistent with a committed myogenic progenitor. Isolated PICs from both young and adult muscles can differentiate into smooth and skeletal muscle and fat whereas satellite cells are restricted to a skeletal muscle fate. We demonstrate that the adipogenic potential of PICs corresponds to a subpopulation that expresses platelet derived growth factor receptor alpha (PDGFRalpha) and overlaps with the recently described interstitial adipogenic progenitors. By contrast, PICs with myogenic potential do not express PDGFRalpha. Moreover, we observe a discrete and transient population of juvenile PICs based upon SCA1 expression that disappears by 3 weeks of postnatal development coincident with a switch in the cellular and genetic mechanisms underlying postnatal muscle growth. PMID- 23739134 TI - An exclusively mesodermal origin of fin mesenchyme demonstrates that zebrafish trunk neural crest does not generate ectomesenchyme. AB - The neural crest is a multipotent stem cell population that arises from the dorsal aspect of the neural tube and generates both non-ectomesenchymal (melanocytes, peripheral neurons and glia) and ectomesenchymal (skeletogenic, odontogenic, cartilaginous and connective tissue) derivatives. In amniotes, only cranial neural crest generates both classes, with trunk neural crest restricted to non-ectomesenchyme. By contrast, it has been suggested that anamniotes might generate derivatives of both classes at all axial levels, with trunk neural crest generating fin osteoblasts, scale mineral-forming cells and connective tissue cells; however, this has not been fully tested. The cause and evolutionary significance of this cranial/trunk dichotomy, and its absence in anamniotes, are debated. Recent experiments have disputed the contribution of fish trunk neural crest to fin osteoblasts and scale mineral-forming cells. This prompted us to test the contribution of anamniote trunk neural crest to fin connective tissue cells. Using genetics-based lineage tracing in zebrafish, we find that these fin mesenchyme cells derive entirely from the mesoderm and that neural crest makes no contribution. Furthermore, contrary to previous suggestions, larval fin mesenchyme cells do not generate the skeletogenic cells of the adult fin, but persist to form fibroblasts associated with adult fin rays. Our data demonstrate that zebrafish trunk neural crest does not generate ectomesenchymal derivatives and challenge long-held ideas about trunk neural crest fate. These findings have important implications for the ontogeny and evolution of the neural crest. PMID- 23739136 TI - An initiative offering free pneumococcal vaccination to victims of the Great East Japan earthquake. PMID- 23739135 TI - Polycomb repressive complex PRC2 regulates Xenopus retina development downstream of Wnt/beta-catenin signaling. AB - The histone methyltransferase complex PRC2 controls key steps in developmental transitions and cell fate choices; however, its roles in vertebrate eye development remain unknown. Here, we report that in Xenopus, PRC2 regulates the progression of retinal progenitors from proliferation to differentiation. We show that the PRC2 core components are enriched in retinal progenitors and downregulated in differentiated cells. Knockdown of the PRC2 core component Ezh2 leads to reduced retinal progenitor proliferation, in part due to upregulation of the Cdk inhibitor p15(Ink4b). In addition, although PRC2 knockdown does not alter eye patterning, retinal progenitor gene expression or expression of the neural competence factor Sox2, it does cause suppression of proneural bHLH gene expression, indicating that PRC2 is crucial for the initiation of neural differentiation in the retina. Consistent with this, knocking down or blocking PRC2 function constrains the generation of most retinal neural cell types and promotes a Muller glial cell fate decision. We also show that Wnt/beta-catenin signaling acting through the receptor Frizzled 5, but independent of Sox2, regulates expression of key PRC2 subunits in the developing retina. This is consistent with a role for this pathway in coordinating proliferation and the transition to neurogenesis in the Xenopus retina. Our data establish PRC2 as a regulator of proliferation and differentiation during eye development. PMID- 23739137 TI - Role of tetrahydrobiopterin in pulmonary vascular remodelling associated with pulmonary fibrosis. AB - BACKGROUND: Pulmonary hypertension in idiopathic pulmonary fibrosis (IPF) is indicative of a poor prognosis. Recent evidence suggests that tetrahydrobiopterin (BH4), the cofactor of nitric oxide synthase (NOS), is involved in pulmonary hypertension and that pulmonary artery endothelial-to-mesenchymal transition (EnMT) may contribute to pulmonary fibrosis. However, the role of BH4 in pulmonary remodelling secondary to pulmonary fibrosis is unknown. This study examined the BH4 system in plasma and pulmonary arteries from patients with IPF as well as the antiremodelling and antifibrotic effects of the BH4 precursor sepiapterin in rat bleomycin-induced pulmonary fibrosis and in vitro EnMT models. METHODS: BH4 and nitrotyrosine were measured by high-performance liquid chromatography and ELISA, respectively. Expression of sepiapterin reductase (SPR), GTP cyclohydrolase 1 (GCH-1), endothelial NOS (eNOS) and inducible NOS (iNOS) were measured by quantitative PCR and immunohistochemistry. RESULTS: BH4 plasma levels were downregulated in patients with IPF compared with controls while nitrites, nitrates and nitrotyrosine were upregulated. GCH-1 and eNOS were absent in pulmonary arteries of patients with IPF; however, iNOS expression increased while SPR expression was unchanged. In rats, oral sepiapterin (10 mg/kg twice daily) attenuated bleomycin-induced pulmonary fibrosis, mortality, vascular remodelling and pulmonary hypertension by increasing rat plasma BH4, decreasing plasma nitrotyrosine and increasing vascular eNOS and GCH-1 expression. Both transforming growth factor beta1 and endothelin-1 induced EnMT by decreasing BH4 and eNOS expression. In vitro administration of sepiapterin increased endothelial BH4 and inhibited EnMT in human pulmonary artery endothelial cells. CONCLUSIONS: Targeting the BH4 synthesis 'salvage pathway' with sepiapterin may be a new therapeutic strategy to attenuate pulmonary hypertension in IPF. PMID- 23739138 TI - Expression of vascular remodelling markers in relation to bradykinin receptors in asthma and COPD. AB - BACKGROUND: Vascular remodelling plays a central role in asthma and chronic obstructive pulmonary disease (COPD). Bradykinin (BK) is a vasoactive proinflammatory peptide mediating acute responses in asthma. We investigated the role of angiogenic factors in relation to BK receptors in asthma and COPD. METHODS: Bronchial biopsies from 33 patients with COPD, 24 old (>=50 years) patients with (>=50 years) asthma, 18 old control smokers, 11 old control non smokers, 15 young (<=40yrs) patients with (<=40 years) asthma and 10 young control non-smokers were immunostained for CD31, vascular endothelial growth factor-A (VEGF-A), angiogenin and BK receptors (B2R and B1R). Fibroblast and endothelial co-localisation of relevant molecules were performed by immunofluorescence. BK-induced VEGF-A and angiogenin release was studied (ELISA) in bronchial fibroblasts from subjects with asthma and COPD. RESULTS: In bronchial lamina propria of old patients with asthma, CD31 and VEGF-A(+) cell numbers were higher than old control non-smokers (p<0.05). Angiogenin(+), B2R(+) and B1R(+) cell numbers in old patients with asthma were higher than in old control non-smokers, control smokers and patients with COPD (p<0.01). Angiogenin(+) cell numbers were higher in patients with COPD than both old control groups (p<0.05). In all patients with asthma the number of B2R(+) cells was positively related to the numbers of B1R(+) (rs=0.43), angiogenin(+) (rs=0.42) and CD31 cells (rs=0.46) (p<0.01). Angiogenin(+) cell numbers were negatively related to forced expiratory volume in 1 s (rs=-0.415, p=0.008). Double immunofluorescence revealed that CD31 cells of capillary vessels coexpressed B2R and that fibroblasts coexpressed B2R, VEGF-A and angiogenin. BK (10(-6)M) induced significant angiogenin release in fibroblasts from asthma and to a lesser extent in COPD. CONCLUSIONS: Unlike COPD, this study suggests the involvement of BK receptors in bronchial vascular remodelling in asthma. PMID- 23739139 TI - In situ pH measurement during the formation of conversion coatings on an aluminum alloy (AA2024). AB - The measurement of interfacial pH change is important for understanding the formation mechanism of conversion coatings that are used to protect metals from corrosion. In this work, we used a tungsten microelectrode to measure the interfacial pH change near the surface of an aluminium alloy (AA2024) during the formation of two conversion coatings: (i) a trivalent chromium pretreatment (TCP) and (ii) a Ti-based, non-chromium-containing coating. The tungsten microelectrode exhibited an open circuit potential (OCP) that changed linearly as a function of the solution pH with a slope of -64 mV per pH. The microelectrode was positioned near the AA2024-T3 surface and its potential was measured as a function of time along with the OCP of the alloy sample during formation of the two coatings. The microelectrode exhibited a negative shift in potential immediately upon initiation of the coating formation, consistent with a significant increase in the interfacial pH of 2-6 units depending on the coating system. The pH increase is attributed to proton-consuming cathodic reactions that occur on the alloy surface once the passivating oxide layer is dissolved: hydrogen evolution and oxygen reduction. The increased pH causes the hydrolysis of the soluble fluorometalate precursor species in the baths, which precipitate forming a hydrated metal oxide coating (e.g., ZrO2.nH2O). PMID- 23739140 TI - Should we be taking B vitamins to prevent age-related macular degeneration? Not yet, but worth doing more research. PMID- 23739142 TI - Developing and implementing all-in-one standard paediatric parenteral nutrition. AB - Parenteral nutrition (PN) is a feeding mode suitable for children that do not achieve requirements via the enteral route. For this intervention to be successful, healthcare professionals require: knowledge on nutrient requirements; access to an aseptic compounding facility; and a system that ensures adequate and safe delivery of PN. Previously, it was thought that individualised PN was the "gold standard" for delivering nutrients to children; however, studies have highlighted concerns regarding inadequate delivery of nutrients, prescribing and compounding errors. We, therefore, set out to develop and implement all-in-one (AIO) paediatric PN solutions. Through a systematic approach, four AIO PN solutions were developed: birth-two months of age (Ped 1); two months-10 kg (Ped 2); 11-15 kg (Ped 3); and 16-30 kg (Ped 4). We implemented them with the help of a teaching pack, over a one month time period, and reviewed usage at six months. At that time, five children initially received standard PN without electrolyte changes; but after a few days, electrolytes needed amendments, and three required individualised PN. A change to AIO PN is feasible and safe; however, some may require electrolyte changes, and there will always be those that will require individualised PN. PMID- 23739143 TI - Body fat distribution and insulin resistance. AB - The burden of obesity has increased globally over the last few decades and its association with insulin resistance and related cardio-metabolic problems have adversely affected our ability to reduce population morbidity and mortality. Traditionally, adipose tissue in the visceral fat depot has been considered a major culprit in the development of insulin resistance. However, there is a growing body of evidence supporting the role of subcutaneous truncal/abdominal adipose tissue in the development of insulin resistance. There are significant differences in the functional characteristics of subcutaneous abdominal/truncal vs. intraabdominal vs. gluteo-femoral fat depots. More recently, mounting evidence has been supporting the role of adipose tissue function in the development of metabolic complications independent of adipose tissue volume or distribution. Decreased capacity for adipocyte differentiation and angiogenesis along with adipocyte hypertrophy can trigger a vicious cycle of inflammation leading to subcutaneous adipose tissue dysfunction and ectopic fat deposition. Therapeutic lifestyle change continues to be the most important intervention in clinical practice to improve adipose tissue function and avoid development of insulin resistance and related cardio-metabolic complications. PMID- 23739141 TI - In HIV/hepatitis C virus co-infected patients, higher 25-hydroxyvitamin D concentrations were not related to hepatitis C virus treatment responses but were associated with ritonavir use. AB - BACKGROUND: Among patients with hepatitis C virus (HCV) monoinfection, 25 hydroxyvitamin D [25(OH)D] concentrations are positively associated with a response to peg-interferon/ribavirin. Data on the relation between 25(OH)D concentrations and HCV treatment response in HIV-infected patients are limited. OBJECTIVE: The objective was to determine whether baseline 25(OH)D concentrations predict virologic response in HIV/HCV co-infected patients and to examine variables associated with 25(OH)D concentrations >=30 ng/mL. DESIGN: Data and samples from 144 HCV genotype 1, treatment-naive patients from a completed HCV treatment trial were examined in this retrospective study. Early virologic response (EVR) was defined as >=2 log10 reduction in HCV RNA and/or HCV RNA <600 IU/mL at week 12 of peg-interferon/ribavirin treatment. Baseline 25(OH)D was measured by liquid chromatography/tandem mass spectrometry. RESULTS: Compared with the non-EVR control group (n = 68), the EVR group (n = 76) was younger, had fewer cirrhotic subjects, had a higher proportion with the IL28B CC genotype, had a higher albumin concentration, and had a lower HCV viral load at baseline (P <= 0.05). The difference in baseline 25(OH)D concentrations between EVR and non-EVR patients was not statistically significant (median: 25 ng/mL compared with 20 ng/mL; P = 0.23). Similar results were found for sustained virologic response (SVR). In multivariable analysis, white and Hispanic race-ethnicity (OR: 6.26; 95% CI: 2.47, 15.88; P = 0.0001) and ritonavir use (OR: 2.68; 95% CI: 1.08, 6.65; P = 0.033) were associated with higher 25(OH)D concentrations (>=30 ng/mL). CONCLUSION: Baseline 25(OH)D concentrations did not predict EVR or SVR. Because ritonavir impairs the conversion of 25(OH)D to the active metabolite, utilization of 25(OH)D may have been impaired in subjects taking ritonavir. This trial was registered at www.clinicaltrials.gov as NCT00078403. PMID- 23739145 TI - Three-dimensional analysis of the palmar plate and collateral ligaments at the proximal interphalangeal joint. AB - The purpose of this study was to analyze the palmar plate complex at the proximal interphalangeal joint using a three-dimensional (3D) technique, which makes it easier to understand the dimensions of structures and their relationship to the adjacent components. This method allows individual elements to be removed virtually, facilitating clearer observation of each component. Sixteen cadaveric specimens were dissected and reconstructed in a 3D virtual environment. The palmar plate is made up of a distal, fibrous portion and a proximal, membranous portion, which anchors distally on the base of the middle phalanx and is continuous with the bilateral check-rein ligaments proximally. The accessory collateral ligaments and the A3 pulley suspend the palmar plate laterally. PMID- 23739144 TI - Heated allergens and induction of tolerance in food allergic children. AB - Food allergies are one of the first manifestations of allergic disease and have been shown to significantly impact on general health perception, parental emotional distress and family activities. It is estimated that in the Western world, almost one in ten children have an IgE-mediated allergy. Cow's milk and egg allergy are common childhood allergies. Until recently, children with food allergy were advised to avoid all dietary exposure to the allergen to which they were sensitive, in the thought that consumption would exacerbate their allergy. However, recent publications indicate that up to 70% of children with egg allergy can tolerate egg baked in a cake or muffin without apparent reaction. Likewise, up to 75% of children can tolerate baked goods containing cow's milk, and these children demonstrate IgE and IgG4 profiles indicative of tolerance development. This article will review the current literature regarding the use of heated food allergens as immunotherapy for children with cow's milk and egg allergy. PMID- 23739146 TI - Re-operation after open fasciotomy for Dupuytren's disease in a series of 1,077 consecutive operations. PMID- 23739148 TI - Reply. Alterations of corneal nerve density do not translate into clinically evident corneal hyposensitivity. PMID- 23739147 TI - Lumbar interspinous bursitis in active polymyalgia rheumatica. AB - OBJECTIVES: To evaluate the inflammatory involvement of lumbar interspinous bursae in patients with polymyalgia rheumatica (PMR) using magnetic resonance imaging (MRI). METHODS: Ten consecutive, untreated new patients with PMR and pain in the shoulder and pelvic girdles were investigated. Seven patients with spondyloarthritis (4 with psoriatic spondyloarthrits, one with entheropatic spondyloarthritis, and 2 with ankylosing spondylitis) as well as 2 patients with spinal osteoarthritis and 2 patients with rheumatoid arthritis with lumbar pain served as controls. MRI of lumbar spine was performed in all PMR patients and controls. Nine patients (5 PMR patients and 4 controls) also had MRI of the thoracic spine. RESULTS: MRI evidence of interspinous lumbar bursitis was found in 9/10 patients with PMR and in 5/11 controls. A moderate to marked (grade >=2 on a semiquantitative 0-3 scale) lumbar bursitis occurred significantly more frequently in patients with PMR than in control patients (60% vs. 9%, p=0.020). In most of the patients and controls lumbar bursitis was found at the L3-L5 interspaces. Only 2 patients had bursitis at a different level (one patient had widespread lumbar bursitis, and one control at L2-L4). No interspinous bursitis was demonstrated by MRI of the thoracic spine in patients and controls. CONCLUSIONS: Inflammation of lumbar bursae may be responsible for the low back pain reported by patients with PMR. The prominent inflammatory involvement of bursae including those of the lumbar spine supports the hypothesis that PMR may be a disorder affecting predominantly extra-articular synovial structures. PMID- 23739149 TI - The inhibitory effect of thalidomide analogue on corneal neovascularization in rabbits. AB - PURPOSE: To evaluate the effect of thalidomide analogue CC-3052 on corneal neovascularization in the rabbit model. METHODS: Corneal neovascularization was induced in 15 rabbits by a silk suture in the corneal stroma. At 1 week after suturing, 30 eyes were divided into 5 groups of 6 eyes each. Three groups were treated with topical CC-3052 at 3 different concentrations: 0.25% (group 1), 0.5% (group 2), and 1.0% (group 3). All treatments were performed twice a day for a week. A 0.5% concentration of CC-3052 was injected subconjunctivally once in group 4. In group 5, a topical balanced salt solution was added twice a day for a week as the experimental control group. Rabbit corneas were photographed by a digital camera and examined by the operating microscope. Half of the corneal specimens were analyzed histopathologically, and the other half were used to measure the concentration of tumor necrosis factor alpha and vascular endothelial growth factor (VEGF) messenger RNA by reverse transcriptase-polymerase chain reaction. RESULTS: The neovascularized area was decreased in all treatment groups compared with the control group. There was a significant difference in the percentage and score of corneal neovascularization between the control and all treatment groups. Inflammation, fibroblast, neovascularization, and anti-VEGF antibody intensities were significantly lower in the control group. The concentration of VEGF and tumor necrosis factor alpha was significantly lower in the control group. There was no difference between the treatment groups. CONCLUSIONS: Topical and subconjunctival administration of thalidomide analogue CC-3052 was found to be effective for the inhibition of corneal neovascularization. PMID- 23739150 TI - The significance of antiretroviral-associated acute kidney injury in a cohort of ambulatory human immunodeficiency virus-infected patients. AB - BACKGROUND: To determine the incidence and significance of acute kidney injury (AKI) after initiating highly active antiretroviral therapy (HAART). METHODS: A prospective cohort study of 271 consecutively treated HIV-infected patients, initiating first (75) or sequential HAART (196) from January 2008 to June 2011. AKI was diagnosed according to the Risk, Injury, Failure, Loss of kidney function, End-stage renal disease (RIFLE)/Acute Kidney Injury Network (AKIN) criteria, and the risk of progression to chronic kidney disease (CKD) was evaluated. RESULTS: A greater estimated glomerular filtration rate (eGFR) decrease after 1 year was observed for patients initiating a tenofovir disoproxil fumarate (TDF)-based regimen (-6.45 versus +0.98 mL/min/1.73 m(2) when compared with patients without TDF; P < 0.01), both in the case of the first (-8.5 versus 2.27; P = 0.04) or successive regimens (-5.3 versus + 1.18 mL/min/1.73 m(2); P < 0.01). AKI, as defined, was observed in 10% (28 cases, 6.98 episodes/100 patients year), mostly stage I (27 cases), in a median time of 6 (3-16.5) months. Four cases (14%), having a worse baseline renal function progressed to CKD, whereas four recovered completely. In the multivariate analysis, AKI was associated with the concomitant use of cotrimoxazole prophylaxis and to low CD4+ count. CKD was diagnosed in 2% (six cases) of patients. Therefore, the overall rate of HAART associated renal disorders was 11% (30 cases, 7.46 episodes/100 patients-year (95% confidence interval, 6.09-8.83). CONCLUSIONS: The initiation of a tenofovir based regimen is followed by a significant decline in eGFR, although it could be misinterpreted by the concomitant use of cotrimoxazole. A substantial proportion of patients develop AKI, but only a minority progress to CKD. Patients initiating HAART and developing AKI should be carefully monitored for progression of renal disease. PMID- 23739151 TI - Metabolites associate with kidney function decline and incident chronic kidney disease in the general population. AB - BACKGROUND: Serum metabolites are associated cross-sectionally with kidney function in population-based studies. METHODS: Using flow injection and liquid chromatography tandem mass spectrometry methods, we examined longitudinal associations of baseline concentrations of 140 metabolites and their 19 460 ratios with kidney function decline and chronic kidney disease (CKD) incidence over 7 years in 1104 participants of the Cooperative Health Research in the Region of Augsburg S4/F4 study. RESULTS: Corrected for multiple testing, a significant association with annual change in the estimated glomerular filtration rate was observed for spermidine (P = 5.8 * 10(-7)) and two metabolite ratios, the phosphatidylcholine diacyl C42:5-to-phosphatidylcholine acyl-alkyl C36:0 ratio (P = 1.5 * 10(-6)) and the kynurenine-to-tryptophan ratio (P = 1.9 * 10( 6)). The kynurenine-to-tryptophan ratio was also associated with significantly higher incidence of CKD at the follow-up visit with an odds ratio of 1.36 per standard deviation increase; 95% confidence interval 1.11-1.66, P = 2.7 * 10( 3)). In separate analyses, the predictive ability of the metabolites was assessed: both the three significantly associated metabolite (ratios) as well as a panel of 35 metabolites selected from all metabolites in an unbiased fashion provided as much but not significantly more prognostic information than selected clinical predictors as judged by the area under the curve. CONCLUSIONS: Baseline serum concentrations of spermidine and two metabolite ratios were associated with kidney function change over subsequent years in the general population. In separate analyses, baseline serum metabolites were able to predict incident CKD to a similar but not better extent than selected clinical parameters. Our longitudinal findings provide a basis for targeted studies of certain metabolic pathways, e.g. tryptophan metabolism, and their relation to kidney function decline. PMID- 23739152 TI - Community preferences for the allocation of deceased donor organs for transplantation: a focus group study. AB - BACKGROUND: Solid organ transplantation is the treatment of choice for those with organ failure, but suitable organs are a limited community resource. Little is known about community preferences for the allocation of those organs. We aimed to determine community preferences for organ allocation and reasons for their choices. METHODS: Participants were recruited from the community in four states in Australia. In focus groups, they identified and discussed attributes that they believed were important for allocating organs to potential recipients. Transcripts were analysed thematically. RESULTS: Thirteen focus groups with 114 participants were conducted. Four major themes emerged: (i) saving and improving the lives; (ii) lowering the risk of lost opportunities; (iii) fairness and (iv) accountability. While happy to discuss general principles, many were not comfortable making organ allocation decisions and were happy to defer to health professionals; this reticence tended to disappear when discussing the use of their own organs. CONCLUSIONS: Participants wanted to save as many lives as possible as well as lower the risk of lost opportunities for those on the waiting list by maximizing the chances of success of every donation. A rational utilitarian ethical model of organ allocation, therefore, appeared to be the dominant framework adopted by the community. Key considerations were compatibility, high chance of peri-operative survival and favouring those with positive lifestyle and self-management choices. Communication between the transplant community and general community about organ allocation could be undertaken to create trust and shared understanding, which may ultimately increase organ donation rates in the future. PMID- 23739153 TI - Catheter-based renal denervation as a novel treatment for loin pain haematuria syndrome. PMID- 23739154 TI - Molecular markers of rejection and tolerance: lessons from clinical research. AB - In terms of finding specific molecular markers associated with graft outcome, attempts have been made to study whole genome transcripts using microarray assays or to study the effect of number of genes of interest using quantitative real time polymerase chain reaction. Using these techniques, molecular phenotypes of rejection have been characterized, and the variability of the clinical outcome besides similar morphology explained in part. Recently, several specific transcripts including naive B cell regulation have been identified in the peripheral blood of operationally tolerant kidney transplant recipients. The decrease in immature B cell-related transcripts in the peripheral blood in patients with immunosuppression was shown to be associated with acute rejection. Similarly, tolerance-associated antigen 1 transcripts were identified in biopsies and regulatory T cell transcripts in urine and biopsies in patients without rejection. Better understanding of molecular processes associated with allograft rejection or alloantigen hyporesponsiveness/tolerance may help to improve our knowledge about graft pathology and identify novel markers suitable for future monitoring and guided therapy and finally improve the outcome of kidney transplantation. PMID- 23739155 TI - Exosomes go with the Wnt. AB - Exosomes, small secreted microvesicles, are implicated in intercellular communication in diverse cell types, transporting protein, lipid and nucleic acid cargo that impact the physiology of recipient cells. Besides the signaling function of exosomes they also serve as a mechanism to dispose obsolete cellular material.1 Particularly exciting is the involvement of exosomal communication in the nervous system, as this has important implications for brain development and function. The properties of exosomes are also beginning to entice the biomedical community since they represent potentially novel avenues for the targeted delivery of customized exosome cargo, such as miRNAs, during disease. Our findings implicating exosomes in trans-synaptic communication emerged from the serendipitous observation that at the Drosophila larval neuromuscular junction (NMJ) the release of a signaling molecule, Wnt1/Wingless (Wg) and its binding partner Evenness Interrupted (Evi)/Wntless (Wls)/Sprint (Srt), were released by motorneurons in association with vesicles, which we postulated to be exosomes.2 In our most recent paper3 using in vivo analysis at the Drosophila NMJ as well as in cultured insect cells we formally demonstrate that Evi rides in exosomes that are released to the extracellular space and identify some of the players involved in their release. In addition, a proteomic analysis of exosomes highlights novel potential function of exosomes. PMID- 23739157 TI - Receiver bias and the acoustic ecology of aye-ayes (Daubentonia madagascariensis). AB - The aye-aye is a rare lemur from Madagascar that uses its highly specialized middle digit for percussive foraging. This acoustic behavior, also termed tap scanning, produces dominant frequencies between 6 and 15 kHz. An enhanced auditory sensitivity to these frequencies raises the possibility that the acoustic and auditory specializations of aye-ayes have imposed constraints on the evolution of their vocal signals, especially their primary long-distance vocalization, the screech. Here we explore this concept, termed receiver bias, and suggest that the dominant frequency of the screech call (~2.7 kHz) represents an evolutionary compromise between the opposing adaptive advantages of long distance sound propagation and enhanced detection by conspecific receivers. PMID- 23739158 TI - Blood pressure variability and multiple organ damage in primary hypertension. AB - Organ damage (OD) is an indicator of increased cardiovascular risk. Blood pressure variability (BPV) is related to greater incidence of events, regardless of the severity of hypertension. We investigated the relationship between ambulatory blood pressure monitoring (ABPM)-derived indices of BPV and the presence of multiple OD in primary hypertension (PH). One hundred and sixty-nine untreated patients with PH were evaluated. Systolic (SBP) and diastolic blood pressure (DBP) variability were assessed as the crude and weighted (w.) standard deviation (s.d.), and average real variability (ARV) of the mean value of 24-h, awake and asleep ABPM recordings. Left ventricular mass index, intima-media thickness, estimated-glomerular filtration rate and urinary albumin excretion were assessed as indices of cardiac, vascular and renal damage, respectively. Risk profile progressively increased starting from patients without OD to patients with only one sign of OD, and then to those with multiple OD. In addition to greater severity of the organ involvement, the only variables that were found to significantly differ between subjects with multiple and single OD were office SBP (160 +/- 14 vs 154 +/- 11 mm Hg, P=0.0423) and DBP (101 +/- 7 vs 97 +/- 8 mm Hg, P=0.0291), ambulatory arterial stiffness index (AASI) (0.60 +/- 0.10 vs 0.50 +/- 0.17, P=0.0158) and indices of BPV (24-h SBP s.d., 23 +/- 5 vs 20 +/- 6 mm Hg, P=0.0300; awake SBP s.d., 22 +/- 6 vs 19 +/- 6 mm Hg, P=0.0366; 24-h SBP w.s.d., 20 +/- 5 vs 17 +/- 5 mm Hg, P=0.0385; and 24-h SBP ARV, 18 +/- 4 vs 15 +/- 5 mm Hg, P=0.0420). All the above mentioned BPV parameters turned out to be determinants of multiple OD, regardless of several confounding variables, including BP levels. Therefore, in hypertensive patients increased SBP variability is associated with multiple signs of OD, regardless of BP values. PMID- 23739159 TI - Calcium channel blocker-induced gingival enlargement. AB - Despite the popularity and wide acceptance of the calcium channel blockers (CCBs) by the medical community, their oral impact is rarely recognized or discussed. CCBs, as a group, have been frequently implicated as an etiologic factor for a common oral condition seen among patients seeking dental care: drug-induced gingival enlargement or overgrowth. This enlargement can be localized or generalized, and can range from mild to extremely severe, affecting patient's appearance and function. Treatment options for these patients include cessation of the offending drug and substitution with another class of antihypertensive medication to prevent recurrence of the lesions. In addition, depending on the severity of the gingival overgrowth, nonsurgical and surgical periodontal therapy may be required. The overall objective of this article is to review the etiology and known risk factors of these lesions, their clinical manifestations and periodontal management. PMID- 23739160 TI - Trends of hypertension prevalence, awareness, treatment and control in rural areas of northern China during 1991-2011. AB - This study aims to investigate the trends in prevalence, awareness, treatment and control of hypertension among rural residents aged 35-74 years in northern China during the country's rapid economic development from 1991 to 2011. Two surveys, conducted in 1991 and 2011, included 2196 and 1939 participants aged 35-74 years from same villages in Ji County, Tianjin of China, respectively. The prevalence of hypertension, adjusted by age and gender using the world standard population in 2000, increased 30% (39.9% vs 51.7%) between 1991 and 2011. The increase was greatest (68%) in women aged 35-44 years. Meanwhile, the prevalence of stage II hypertension increased by 75% overall, with a 4-fold increase in men aged 45-54 years. Although the awareness, treatment and control of hypertension increased significantly during the same period, they remained unacceptably poor. In conclusion, the community-based surveys showed that the prevalence of hypertension in rural residents of northern China aged 35-74 years increased rapidly over the past 20 years, and most dramatically in young women. Efforts in the primary prevention of hypertension, particularly for young women, and promoting education for hypertension awareness, treatment and control are of paramount importance in rural China. PMID- 23739161 TI - Resistant hypertension-complex mix of secondary causes and comorbidities. PMID- 23739162 TI - Selective solid-phase extraction of naproxen drug from human urine samples using molecularly imprinted polymer-coated magnetic multi-walled carbon nanotubes prior to its spectrofluorometric determination. AB - A drug imprinted polymer based on suspension polymerization on magnetic multi walled carbon nanotubes (MIPMCNTs) was prepared with a synthesized amidoamine as the functional monomer, ethylene glycol dimethacrylate as the cross-linker, naproxen (NAP) as the template and ammonium persulfate as the initiator. The MIPMCNTs were characterized by TEM, FT-IR and XRD measurements. The prepared magnetic adsorbent can be well dispersed in aqueous media and can be easily separated magnetically from the medium after loading with NAP. All the aspects influencing the adsorption (extraction time, adsorbent dosage and pH) and desorption (desorption time and desorption solvent) of the analyte on the MIPMCNTs have been investigated. The extracted NAP could be easily desorbed with a mixture of methanol/sodium hydroxide aqueous solution and determined spectrofluorometrically at lambdaem = 353 nm (lambdaex = 271 nm). A linear dynamic range was established from 4.0 to 40.0 ng mL-1 of NAP and the limit of detection (LOD) was found to be 2.0 ng mL-1. In addition, the equilibrium adsorption data of NAP by imprinted polymer were analyzed by Langmuir and Freundlich isotherm models. The developed method was utilized for the determination of NAP in human urine samples with satisfactory results. PMID- 23739163 TI - An optical fiber bundle sensor for tip clearance and tip timing measurements in a turbine rig. AB - When it comes to measuring blade-tip clearance or blade-tip timing in turbines, reflective intensity-modulated optical fiber sensors overcome several traditional limitations of capacitive, inductive or discharging probe sensors. This paper presents the signals and results corresponding to the third stage of a multistage turbine rig, obtained from a transonic wind-tunnel test. The probe is based on a trifurcated bundle of optical fibers that is mounted on the turbine casing. To eliminate the influence of light source intensity variations and blade surface reflectivity, the sensing principle is based on the quotient of the voltages obtained from the two receiving bundle legs. A discrepancy lower than 3% with respect to a commercial sensor was observed in tip clearance measurements. Regarding tip timing measurements, the travel wave spectrum was obtained, which provides the average vibration amplitude for all blades at a particular nodal diameter. With this approach, both blade-tip timing and tip clearance measurements can be carried out simultaneously. The results obtained on the test turbine rig demonstrate the suitability and reliability of the type of sensor used, and suggest the possibility of performing these measurements in real turbines under real working conditions. PMID- 23739164 TI - Toggling in the spliceosome. PMID- 23739165 TI - Solo or doppio: how many CENP-As make a centromeric nucleosome? PMID- 23739166 TI - Making sense of nonsense. PMID- 23739167 TI - This is about the in and the out. PMID- 23739170 TI - Scratching the (lateral) surface of chromatin regulation by histone modifications. AB - Histones have two structurally and functionally distinct domains: globular domains forming the nucleosomal core around which DNA is wrapped and unstructured tails protruding from the nucleosomal core. Whereas post-translational modifications (PTMs) in histone tails are well studied, much less is currently known about histone-core PTMs. Many core PTMs map to residues located on the lateral surface of the histone octamer, close to the DNA, and they have the potential to alter intranucleosomal histone-DNA interactions. Here we discuss recent advances in understanding the function of lateral-surface PTMs. Whereas modifications in the histone tails might have limited structural impact on the nucleosome itself and function as signals to recruit specific binding proteins, PTMs in the lateral surface can have a direct structural effect on nucleosome and chromatin dynamics, even in the absence of specific binding proteins, which adds a twist to the debate on the functionality and causality of PTMs. PMID- 23739171 TI - Indan-1,3-dione electron-acceptor small molecules for solution-processable solar cells: a structure-property correlation. AB - A structure-device performance correlation in bulk heterojunction solar cells for new indandione-derived small molecule electron acceptors, FEHIDT and F8IDT, is presented. Devices based on the former exhibit higher power conversion efficiency (2.4%) and higher open circuit voltage, a finding consistent with reduced intermolecular interactions. PMID- 23739172 TI - Reply: The cerebellum in Parkinson's disease and parkinsonism in cerebellar disorders. PMID- 23739173 TI - The cerebellum in Parkinson's disease and Parkinsonism in cerebellar disorders. PMID- 23739174 TI - Application and experimental validation of an integral method for simulation of gradient-induced eddy currents on conducting surfaces during magnetic resonance imaging. AB - The time-varying magnetic fields created by the gradient coils in magnetic resonance imaging can produce negative effects on image quality and the system itself. Additionally, they can be a limiting factor to the introduction of non-MR devices such as cardiac pacemakers, orthopedic implants, and surgical robotics. The ability to model the induced currents produced by the switching gradient fields is key to developing methods for reducing these unwanted interactions. In this work, a framework for the calculation of induced currents on conducting surface geometries is summarized. This procedure is then compared to two separate experiments: (1) the analysis of the decay of currents induced upon a conducting cylinder by an insert gradient set within a head only 7 T MR scanner; and (2) analysis of the heat deposited into a small conductor by a uniform switching magnetic field at multiple frequencies and two distinct conductor thicknesses. The method was shown to allow the accurate modeling of the induced time-varying field decay in the first case, and was able to provide accurate estimation of the rise in temperature in the second experiment to within 30% when the skin depth was greater than or equal to the thickness of the conductor. PMID- 23739175 TI - Attack on Australia: tobacco industry challenges to plain packaging. AB - In 2011, the Australian Government passed landmark legislation requiring tobacco manufacturers to adopt 'plain packaging', a government-mandated design standardized across all brands of tobacco products. In response, plain packaging policy in Australia has faced multiple, simultaneous challenges from a global, well-resourced industry able to use all available fora to seek redress. Generalizing from the Australian experience, we analyze four types of challenges to plain packaging from the tobacco industry. We characterize three ways in which industry questions public health policies through international trade and investment law, on: (i) the intent or purpose of the policy; (ii) the economic consequences of it; and (iii) the regulatory authority behind it. We make recommendations and suggest that public health policymakers can know with some precision what attacks will be launched on tobacco control policies, and prepare their strategies and legislation accordingly. PMID- 23739176 TI - alpha-catenin, vinculin, and F-actin in strengthening E-cadherin cell-cell adhesions and mechanosensing. AB - Classical cadherins play a crucial role in establishing intercellular adhesion, regulating cortical tension, and maintaining mechanical coupling between cells. The mechanosensitive regulation of intercellular adhesion strengthening depends on the recruitment of adhesion complexes at adhesion sites and their anchoring to the actin cytoskeleton. Thus, the molecular mechanisms coupling cadherin associated complexes to the actin cytoskeleton are actively being studied, with a particular focus on alpha-catenin and vinculin. We have recently addressed the role of these proteins by analyzing the consequences of their depletion and the expression of alpha-catenin mutants in the formation and strengthening of cadherin-mediated adhesions. We have used the dual pipette assay to measure the forces required to separate cell doublets formed in suspension. In this commentary, we briefly summarize the current knowledge on the role of alpha catenin and vinculin in cadherin-actin cytoskeletal interactions. These data shed light on the tension-dependent contribution of alpha-catenin and vinculin in a mechanoresponsive complex that promotes the connection between cadherin and the actin cytoskeleton and their requirement in the development of adhesion strengthening. PMID- 23739178 TI - High levels of intravenous mephedrone (4-methylmethcathinone) self-administration in rats: neural consequences and comparison with methamphetamine. AB - Mephedrone (MMC) is a relatively new recreational drug that has rapidly increased in popularity in recent years. This study explored the characteristics of intravenous MMC self-administration in the rat, with methamphetamine (METH) used as a comparator drug. Male Sprague-Dawley rats were trained to nose poke for intravenous MMC or METH in daily 2 h sessions over a 10 d acquisition period. Dose-response functions were then established under fixed- and progressive-ratio (FR and PR) schedules over three subsequent weeks of testing. Brains were analyzed ex vivo for striatal serotonin (5-HT) and dopamine (DA) levels and metabolites, while autoradiography assessed changes in the regional density of 5 HT and serotonin transporter (SERT) and DA transporter (DAT) and induction of the inflammation marker translocator protein (TSPO). Results showed that MMC was readily and vigorously self-administered via the intravenous route. Under a FR1 schedule, peak responding for MMC was obtained at 0.1 mg/kg/infusion, versus 0.01 mg/kg/infusion for METH. Break points under a PR schedule peaked at 1 mg/kg/infusion MMC versus 0.3 mg/kg/infusion for METH. Final intakes of MMC were 31.3 mg/kg/d compared to 4 mg/kg/d for METH. Rats self-administering MMC, but not METH, gained weight at a slower rate than control rats. METH, but not MMC, self administration elevated TSPO receptor density in the nucleus accumbens and hippocampus, while MMC, but not METH, self-administration decreased striatal 5 hydroxyindolacetic acid (5-HIAA) concentrations. In summary, MMC supported high levels of self-administration, matching or exceeding those previously reported with other drugs of abuse. PMID- 23739179 TI - The new psychoactive substances regime in New Zealand: a different approach to regulation. AB - The New Zealand government has proposed a new psychoactive substances regime, which will place the onus onto manufacturers to prove that their products pose a low risk of harm, prior to receiving approval which allows the products to be legally manufactured and sold. This is an innovative and unique development in the regulation of emerging psychoactive substances, and offers an alternative response to prohibition. The details of the new regime and how it will operate are now emerging, and this offers an opportunity to critically explore some of the issues related to the proposed new regime and to speculate on some of the outcomes. This paper brings together a group of New Zealand based researchers from a range of disciplines with experience of 'legal high' research to discuss this innovative new regime. PMID- 23739181 TI - Effect of NSAIDs on Na+/H+ exchanger activity in rat colonic crypts. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs; 1) are widely recommended for several acute and chronic conditions. For example, both indomethacin and aspirin are taken for pain relief. Aspirin is also used for prevention of myocardial infarction, and indomethacin can be administered orally or as a suppository for patients with rheumatoid disease and other chronic inflammatory states. However, use of NSAIDs can cause damage to the mucosal barrier surrounding the gastrointestinal (GI) tract, increasing the risk of ulcer formation. While microencapsulation of NSAIDs has been shown to reduce upper GI injury, sustained release in the lower GI tract and colon may cause epithelial erosion due to increased acidification. The use of suppositories has also been linked to rectal and lower GI bleeding. In this study, we investigated the role of NSAIDs aspirin and indomethacin on Na+/H+ exchanger (NHE) activity in rat colonic crypts. By comparing average rates of pH recovery between control and NSAID perfusion runs, we were able to determine that both aspirin and indomethacin increase hydrogen extrusion into the colonic lumen. Through treatment with 5-ethylisopropyl amiloride (EIPA), amiloride, and zoniporide dihydrochloride, we further demonstrated that indomethacin specifically enhances proton excretion through regulation of apical NHE-3 and NHE-2 and to a lesser extent on basolateral NHE-1 and NHE-4. Our results suggest that clinical exposure to NSAIDs may affect colonic tissue at the site of selected NHE isoforms, resulting in modulation of transport and barrier function. PMID- 23739182 TI - Differential expression of proteins with heparin affinity in patients with rheumatoid and psoriatic arthritis: a preliminary study. AB - OBJECTIVES: Using proteomic approach in this study, we sought to identify proteins with heparin affinity associated with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and non-inflammatory arthritis (NIA). METHODS: Plasma samples from adult RA, PsA and NIA patients, 20 of each, were collected. After enrichment of proteins with heparin affinity, SDS-PAGE and in-gel digestion with trypsin were performed. Peptides were concentrated, micro-purified, separated and measured by nano-scale HPLC system coupled to a mass spectrometer. Peak lists were generated from raw spectra and searched against human complete proteome set by MaxQuant software. Statistical analysis of protein relative expression levels was done in IPython interactive Python shell using NumPy and Matplotlib libraries. Individual protein impact on the whole dataset correlation was done by excluding one protein at a time and calculating the correlation coefficient of remaining data points. RESULTS: Three hundred and eighty-four different proteins were identified keeping false discovery rate to 1%, from which 163 were identified in all three conditions. The plasma proteome showed a good correlation between rheumatoid (RA) and psoriatic arthritis (PsA). Out of 10 proteins whose impact on the correlation coefficient fell outside of two standard deviations from the mean, four were up-regulated (complement factor I, complement component C8 beta, glyceraldehyde-3-phosphate dehydrogenase and inter-alpha-trypsin inhibitor heavy chain H1), and two were down-regulated (immunoglobulin heavy chain V-III region BRO, and immunoglobulin J chain), both in PsA and RA by a similar ratio when compared to NIA. The remaining four proteins (Serpin A11, complement factor H-related protein 5, cartilage acidic protein 1 and coagulation factor IX) were down-regulated in PsA and up-regulated in RA when compared to NIA. CONCLUSIONS: We found differently expressed proteins in patients with inflammatory and non-inflammatory rheumatic conditions. Out of 384 proteins with heparin affinity four proteins should be further validated as potential diagnostic biomarkers in patients with RA and PsA. PMID- 23739180 TI - TRPV4 channel contributes to serotonin-induced pulmonary vasoconstriction and the enhanced vascular reactivity in chronic hypoxic pulmonary hypertension. AB - Transient receptor potential vanilloid 4 (TRPV4) is a mechanosensitive channel in pulmonary arterial smooth muscle cells (PASMCs). Its upregulation by chronic hypoxia is associated with enhanced myogenic tone, and genetic deletion of trpv4 suppresses the development of chronic hypoxic pulmonary hypertension (CHPH). Here we further examine the roles of TRPV4 in agonist-induced pulmonary vasoconstriction and in the enhanced vasoreactivity in CHPH. Initial evaluation of TRPV4-selective antagonists HC-067047 and RN-1734 in KCl-contracted pulmonary arteries (PAs) of trpv4(-/-) mice found that submicromolar HC-067047 was devoid of off-target effect on pulmonary vasoconstriction. Inhibition of TRPV4 with 0.5 MUM HC-067047 significantly reduced the sensitivity of serotonin (5-HT)-induced contraction in wild-type (WT) PAs but had no effect on endothelin-1 or phenylephrine-activated response. Similar shift in the concentration-response curve of 5-HT was observed in trpv4(-/-) PAs, confirming specific TRPV4 contribution to 5-HT-induced vasoconstriction. 5-HT-induced Ca(2+) response was attenuated by HC-067047 in WT PASMCs but not in trpv4(-/-) PASMCs, suggesting TRPV4 is a major Ca(2+) pathway for 5-HT-induced Ca(2+) mobilization. Nifedipine also attenuated 5-HT-induced Ca(2+) response in WT PASMCs but did not cause further reduction in the presence of HC-067047, suggesting interdependence of TRPV4 and voltage-gated Ca(2+) channels in the 5-HT response. Chronic exposure (3 4 wk) of WT mice to 10% O2 caused significant increase in 5-HT-induced maximal contraction, which was partially reversed by HC-067047. In concordance, the enhancement of 5-HT-induced contraction was significantly reduced in PAs of CH trpv4(-/-) mice and HC-067047 had no further effect on the 5-HT induced response. These results suggest unequivocally that TRPV4 contributes to 5-HT-dependent pharmaco-mechanical coupling and plays a major role in the enhanced pulmonary vasoreactivity to 5-HT in CHPH. PMID- 23739183 TI - Psychopharmacology and psychotherapy for the treatment of adults with ADHD-a systematic review of available meta-analyses. AB - OBJECTIVE/INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) in adult life is a prevalent condition. We systematically reviewed the literature available by searching for meta-analyses assessing pharmacological and psychosocial interventions for adults with ADHD. METHODS: Using wide-ranging search terms, we retrieved 191 titles from the PubMed and Cochrane databases. Two independent evaluators judged all abstracts. Only meta-analyses about the treatment of adults with ADHD were included. Information from meta-analyses found was systematically extracted by 3 independent evaluators. RESULTS: Eight meta analyses were identified. Results from those meta-analyses suggest that stimulants are effective in decreasing ADHD symptoms on a short-term basis with a medium to large effect size (ES). Short-acting stimulants might be superior to long-acting stimulants, but no data on difference in adherence are available for the comparison of these two types of formulation. Bupropion is superior to placebo but less effective than stimulants. No conclusions about the impact of psychosocial interventions can be drawn based on meta-analyses so far. Discussion The efficacy of stimulants in reducing ADHD symptoms for adults is well documented in meta-analyses, but there is a concerning lack of meta-analysis about other treatment interventions. CONCLUSION: The available meta-analytic literature does not cover questions of essential clinical relevance for adults with ADHD. PMID- 23739184 TI - Anal transitional zone neoplasia in patients with familial adenomatous polyposis coli syndrome. PMID- 23739185 TI - Emphasizing surgery for colon cancer. PMID- 23739186 TI - Anal transitional zone neoplasia in patients with familial adenomatous polyposis after restorative proctocolectomy and IPAA: incidence, management, and oncologic and functional outcomes. AB - BACKGROUND: Restorative proctocolectomy and IPAA in patients with familial adenomatous polyposis may leave residual anal transitional zone mucosa that is prone to neoplasia. OBJECTIVE: The aim of this study was to evaluate the long term control of neoplasia at the IPAA, the functional outcomes, and the influence of anastomotic technique on these results. DESIGN: : This research is a retrospective cohort study from a prospective database. SETTING: The investigation took place in a high-volume specialized colorectal surgery department. PATIENTS: Patients with familial adenomatous polyposis who underwent IPAA between 1983 and 2010 were included. MAIN OUTCOME MEASURES: The primary outcomes measured were functional outcomes, quality of life, and the incidence of neoplasia in the anal transitional zone. RESULTS: Eighty-six patients underwent mucosectomy and 174 underwent stapled anastomosis with mean 155 +/- 99 and 95 +/- 70 months follow-up. Eighteen patients (20.9%) in the mucosectomy group and 59 patients (33.9%) in the stapled group developed anal transitional zone adenomas (p = 0.03). One of 86 (1.2%) patients undergoing mucosectomy and 3 of 174 (1.7%) patients undergoing stapled anastomosis developed cancer in the anal transitional zone (p > 0.05). Three of these patients underwent an abdominoperineal resection, but one who refused abdominoperineal resection underwent transanal excision with neoileoanal anastomosis. Patients undergoing a mucosectomy had a significantly higher rate of anastomotic stricture, but other complications were similar. Incontinence, seepage, and pad usage were higher in the mucosectomy group. Cleveland global quality-of-life score was 0.8 +/- 0.2 in patients with handsewn anastomoses and 0.8 +/- 0.3 in patients with a stapled anastomoses (p > 0.05). LIMITATIONS: This study was limited by its nonrandomized retrospective design. CONCLUSIONS: Risk for the development of adenomas in the anal transitional zone is higher after a stapled IPAA than after a mucosectomy with handsewn anastomosis. However, control of anal transitional zone neoplasia results in a similar risk of cancer development. Because the stapled procedure is associated with better long-term functional outcomes than a mucosectomy, stapled IPAA is the preferable procedure for most patients with familial adenomatous polyposis. PMID- 23739187 TI - D3 Lymph Node Dissection in Right Hemicolectomy with a No-touch Isolation Technique in Patients With Colon Cancer. AB - BACKGROUND: The role of lymph node dissection in the management of right-sided colon cancer remains controversial. OBJECTIVE: The aim of this study was to investigate the surgical treatment of curable right-sided colon cancer by using D3 lymphadenectomy with a no-touch isolation technique and to determine the extent of lymph node dissection optimal for the prognosis of right-sided colon cancer. DESIGN: This research is a retrospective cohort study from a prospectively collected database. SETTING: The investigation took place in a specialized colorectal surgery department. PATIENTS: : Data on 370 consecutive patients who underwent D3 lymph node dissection for right-sided colon cancer with a no-touch isolation technique were identified. MAIN OUTCOME MEASURES: The survival of patients with involvement of main nodes at the roots of colonic arterial trunks along superior mesenteric vessels through intermediate nodes in the right mesocolon was determined. RESULTS: The 5-year overall survival of patients with stage I (n = 73, 19.7%), II (n = 155, 41.9%), and III (n = 142, 38.4%) cancer were 94.5%, 87.6%, and 79.2%. The 5-year disease-specific survival of patients with stages I, II, and III cancer were 100.0%, 94.5%, and 85.0%. Eleven patients (3.0%) had metastatic involvement of main lymph nodes, whereas 49 (13.2%) had metastases to intermediate lymph nodes. The 5-year overall survival and disease-specific survival of patients with metastases to main lymph nodes were 36.4% for both, and 5-year overall survival and disease-specific survival of patients with metastases to intermediate lymph nodes were 77.6% and 83.5%. LIMITATIONS: This study was limited by its nonrandomized retrospective design. CONCLUSIONS: D3 lymphadenectomy with a no-touch isolation technique allows curative resection and long-term survival in a cohort of patients with cancer of the right colon. PMID- 23739188 TI - Adherence to microsatellite instability testing in young-onset colorectal cancer patients. AB - BACKGROUND: In 1997, the Bethesda guidelines recommended microsatellite instability testing for colorectal cancer in patients younger than 45 years to screen for Lynch syndrome. In 2004, these guidelines were revised to set the screening age at younger than 50 years. OBJECTIVE: The aim of this study was to investigate to what extent these guidelines were followed in young patients with colorectal cancer in the Mid-Netherlands and to identify the predictors of nonadherence. DESIGN: This is a retrospective cohort study. SETTINGS: This study was conducted in 1 academic and 5 nonacademic hospitals. PATIENTS: All patients diagnosed with colorectal cancer younger than 45 years in the period 1999 to 2004 and younger than 50 years in the period 2005 to 2008 were included. Patients known to be affected by or at risk for Lynch syndrome before diagnosis were excluded. MAIN OUTCOME MEASURES: Patient and tumor characteristics, including microsatellite instability testing results, were collected from the database of the Comprehensive Cancer Center, the National Pathological Archive, participating hospitals, and the regional institute of clinical genetics. Logistic regression analysis was performed to detect a trend in adherence over the years and to identify the predictors of nonadherence. RESULTS: A total of 335 patients were identified. Microsatellite instability testing was performed in 130/335 (39%) patients. Adherence did not improve in the period 1999 to 2008. We found that older age at diagnosis (OR 0.96, 95% CI 0.92-1.00), male sex (OR 0.60, 95% CI 0.38-0.95), and stage IV colorectal cancer (OR 0.45, 95% CI 0.24-0.84) were independent predictors of nonadherence, whereas proximal tumor localization, poor differentiation, and mucinous histology were not. LIMITATIONS: This study was limited by its retrospective design. CONCLUSIONS: Adherence to the Bethesda guidelines in young-onset colorectal cancer is low, particularly in older and male patients and in patients with metastatic disease, which suggests that efforts to improve adherence are needed. PMID- 23739189 TI - Management and outcomes of bowel obstruction in patients with stage IV colon cancer: a population-based cohort study. AB - BACKGROUND: Bowel obstruction is a common complication of late-stage abdominal cancer, especially colon cancer, which has been investigated predominantly in small, single-institution studies. OBJECTIVE: We used a large, population-based data set to explore the surgical treatment of bowel obstruction and its outcomes after hospitalization for obstruction among patients with stage IV colon cancer. DESIGN: This was a retrospective cohort study. SETTING AND PATIENTS: We identified 1004 patients aged 65 years or older in the Surveillance, Epidemiology and End Results-Medicare database diagnosed with stage IV colon cancer January 1, 1991 to December 31, 2005, who were later hospitalized for bowel obstruction. MAIN OUTCOME MEASURES: We describe outcomes after hospitalization and analyzed the associations between surgical treatment of obstruction and outcomes. RESULTS: Hospitalization for bowel obstruction occurred a median of 7.4 months after colon cancer diagnosis, and median survival after obstruction was approximately 2.5 months. Median hospitalization for obstruction was about 1 week and in-hospital mortality was 12.7%. Between discharge and death, 25% of patients were readmitted to the hospital at least once for obstruction, and, on average, patients lived 5 days out of the hospital for every day in the hospital between obstruction diagnosis and death. Survival was 3 times longer in those whose obstruction claims suggested an adhesive obstruction origin. In multivariable models, surgical compared with nonsurgical management was not associated with prolonged survival (p = 0.134). LIMITATIONS: Use of an administrative database did not allow determination of quality of life or relief of obstruction as an outcome, nor could nonsurgical interventions, eg, endoscopic stenting or octreotide, be assessed. CONCLUSIONS: In this population-based study of patients with stage IV colon cancer who had bowel obstruction, overall survival following obstruction was poor irrespective of treatment. Universally poor outcomes suggest that a diagnosis of obstruction in the setting of advanced colon cancer should be considered a preterminal event. PMID- 23739190 TI - Recalibration and validation of a preoperative risk prediction model for mortality in major colorectal surgery. AB - BACKGROUND: In 2009, Barwon Health designed a risk stratification model for mortality in major colorectal surgery with the use of only preoperative risk factors. The Barwon Health 2009 model was shown to predict mortality reliably, and it was comparable to other models, such as the original, POSSUM. However, the Barwon Health 2009 model was never validated with data other than those used to develop the model. OBJECTIVE: The aim of this study was to perform temporal and external validation of the Barwon Health 2009 model and to compare it with other published models. DESIGN: : The temporal validation was a prospective observational study, whereas the external validation was a retrospective observational study. The discrimination and calibration of the models were assessed by using the area under receiver operator characteristic and chi test of Hosmer-Lemeshow goodness-of-fi technique. SETTINGS: This is a multi-institutional study. Data were collected from 2008 to 2010. RESULTS: There were 474 major colorectal cases at Geelong Hospital (temporal validation) and 389 cases at Western Hospital (external validation). The overall mortality rate was 5.10% and 1.03%. In the comparison of the 2 demographics, Geelong Hospital had a higher proportion of patients who were older and had higher ASA scores and comorbidity counts, whereas Western Hospital surgeons were operating on a higher number of urgent cases. Despite the differences, the Barwon Health 2009 model was able to discriminate mortality reliably (area under receiver operator characteristic = 0.753) but had poor model calibration (p < 0.001) on temporal validation. Hence, the model was recalibrated to predict mortality accurately(area under receiver operator characteristic = 0.772; p = 0.83), and this was successfully validated at Western Hospital (area under receiver operator characteristic = 0.788; p = 0.24). CONCLUSIONS: We have developed a model that can accurately predict mortality after major colorectal surgery by using only data that are available preoperatively. After recalibration, the model was successfully validated in a second hospital. PMID- 23739191 TI - Geographical disparities of rectal cancer local recurrence and outcomes: a population-based analysis. AB - BACKGROUND: Challenges exist in providing high-quality cancer treatments to populations spread over large geographical areas. Local recurrence of rectal cancer is a complicated clinical problem associated with high morbidity and mortality. OBJECTIVES: objectives of this study were to evaluate population-based rates and predictors of local recurrence of rectal cancer in the Province of Manitoba, Canada, with emphasis on the effects of geography. DESIGN: : This was a population-based retrospective analysis. Administrative data from the Manitoba Cancer Registry and individual patient charts were reviewed. SETTINGS: Patients with stages I to III rectal cancer who underwent surgery with curative intent in Manitoba between 2004 and 2006 were included. MAIN OUTCOME MEASURES: The primary outcome was the development of local recurrence after surgical resection. RESULTS: Three hundred seventy patients with a mean age of 67 years were identified. The 5-year local recurrence rate was 17.4%. In multivariate analysis, relative to Winnipeg residents, rural residents, regardless of where they underwent surgery, had an increased risk of local recurrence (HR, 3.47; 95% CI, 1.74-6.92 for surgery in Winnipeg; HR, 2.98; 95% CI, 1.59-5.57 for surgery in rural Manitoba). The absence of both neoadjuvant radiotherapy and adjuvant chemotherapy was associated with a higher risk of local recurrence. Higher risk of mortality was noted for rural patients (HR, 1.90; 95% CI, 1.24-2.89) and for those who developed local recurrence (HR, 2.01; 95% CI, 1.27-3.19). CONCLUSION: Local recurrence rates for rectal cancer are high in Manitoba. Geography is an important variable, because rural status is associated with higher local recurrence rates and decreased survival. The use of neoadjuvant radiotherapy was an important predictor of lower local recurrence rates. Further initiatives are imperative to identify why rural patients experience differences in outcomes in Manitoba. PMID- 23739192 TI - CEA - a predictor for pathologic complete response after neoadjuvant therapy for rectal cancer. AB - BACKGROUND: Preoperative chemoradiation therapy in patients with rectal cancer results in pathologic complete response in approximately 10% to 30% of patients. Accurate predictive factors for obtaining pathologic complete response would likely influence the selection of patients best treated by chemoradiation therapy as the primary treatment without radical surgery. OBJECTIVE: The aim of this study was to evaluate the impact of tumor size, stage, location, circumferential extent, patient characteristics, and pretreatment CEA levels on the development of pathologic complete response after chemoradiation therapy. DESIGN: This study is a retrospective review. SETTINGS AND PATIENTS: Five hundred thirty patients treated with preoperative chemoradiation therapy and radical surgery for rectal adenocarcinoma between 1998 and 2011 were identified. A total of 469 patients remained after excluding patients with a history of pelvic radiation (n = 2), previous transanal endoscopic microsurgery or polypectomy of the primary lesion (n = 15), concurrent malignant tumor (n = 14), and no information about pre- or posttreatment T stage in the chart (n = 30). Preoperative CEA levels were available for 267 patients (57%). INTERVENTIONS: Preoperative chemoradiation therapy and total mesorectal excision were performed in patients with rectal cancer. MAIN OUTCOME: The primary outcome measured was pathologic complete response. RESULTS: : Ninety-six patients (20%) were found to have a pathologic complete response in the operative specimen. Low pretreatment CEA (3.4 vs 9.6 ng/mL; p = 0.008) and smaller mean tumor size (4.2 vs 4.7 cm; p = 0.02) were significantly associated with pathologic complete response. Low CEA levels and interruption in chemoradiation therapy were significant predictors of pathologic complete response in the multivariate analysis. When stratifying for smoking status, low CEA level was significantly associated with pathologic complete response only in the group of nonsmokers (p = 0.02). LIMITATIONS: This study was limited by its retrospective design, missing CEA values, and lack of tumor regression grade assessment. CONCLUSIONS: We demonstrated an association between low pretreatment CEA levels, interruption in chemoradiation therapy, and pathologic complete response in patients treated with neoadjuvant chemoradiation therapy for locally advanced rectal cancer. The predictive value of CEA in smokers can be limited, and further studies are needed to evaluate the impact of smoking on the predictive value of CEA levels for pathologic complete response in rectal cancer. PMID- 23739193 TI - Dynamic article: long-term outcomes of patients undergoing combined endolaparoscopic surgery for benign colon polyps. AB - BACKGROUND: Patients with large benign colon polyps not amenable to endoscopic removal commonly undergo resections. Polyp removal using combined endolaparoscopic surgery may be an effective alternative to bowel resection in select patients. OBJECTIVE: The aim of this study was to evaluate short-term and long-term outcomes of patients who underwent endolaparoscopy at our institution. DATA SOURCES: Medical records and a prospectively maintained database were reviewed. STUDY SELECTION: This study constituted a retrospective review of consecutive patients who underwent endolaparoscopy for benign polyps from 2003 to 2012. INTERVENTIONS: Combined endolaparoscopic surgery was performed. MAIN OUTCOME MEASURES: The primary outcomes measured were success rate, rate of recurrence, rate of malignancy, length of stay, and complication rate. RESULTS: A total of 75 patients were taken to the operating room with the intention of endolaparoscopy. The most common indications were large polyp size and difficult location. Based on intraoperative findings, 10 patients were suspected of having cancer and underwent immediate laparoscopic colectomy. Of 65 attempted cases, 48 patients (74%) underwent successful combined endolaparoscopic surgery. Median follow-up time was 65 (8-87) months. Patients in whom combined endolaparoscopic surgery was unsuccessful were converted to colectomy (2 open, 15 laparoscopic). Two patients were converted because of concerns of cancer and 15 because of technical difficulties. Median operative time for successful endolaparoscopy was 145 (50-249) minutes. The complication rate was 4.4% (2/48). Median length of stay was 1 (0-6) day for endolaparoscopy vs 5 (3-19) days for those converted to colectomy. Median polyp size was 3 (1.0-7.0) cm. One patient was found to have cancer on final pathology, but refused to have further surgery. Sensitivity and specificity of predicting malignancy based on clinical findings were 33% (4/12) and 98.5% (64/65). Four of 5 patients who had recurrence (10%) after endolaparoscopy had complete endoscopic polypectomy. One patient required delayed laparoscopic colectomy for a second recurrence. LIMITATIONS: This study was limited by its retrospective nature. CONCLUSIONS: Combined endolaparoscopic surgery appears to be a safe and effective alternative to colectomy in all parts of the colon in patients who have benign polyps not removable with colonoscopy alone. PMID- 23739194 TI - En bloc pancreaticoduodenectomy and right colectomy in the treatment of locally advanced colon cancer. AB - BACKGROUND: Carcinoma of the right colon invading the pancreas or duodenum is rare. Evidence of the indication, operative morbidity, and survival of en bloc pancreaticoduodenectomy and right colectomy for right colon cancer invading adjacent organs is limited. OBJECTIVE: : The goal of this study was to investigate the feasibility, safety, indication, and long-term results of en bloc pancreaticoduodenectomy and right colectomy in the treatment of locally advanced right-sided colon cancer. DESIGN: : This was a retrospective analysis of all inpatients undergoing en bloc pancreaticoduodenectomy and right colectomy. Detailed data of these patients were assessed by a thorough review of medical charts. SETTINGS: The study was conducted using a hospital database. PATIENTS: Fourteen patients who underwent en bloc pancreaticoduodenectomy and right colectomy from January 1989 through December 2011 were included in the study. MAIN OUTCOME MEASURES: In-hospital complications, mortality, and survival were the primary outcomes measured. RESULTS: Major postoperative complications included delayed gastric empting (n = 7), class B pancreatic fistula (n = 3), and bile leakage (n = 1). Postoperative death occurred in 2 patients. The median hospital stay was 22.5 days (range, 17.0-57.0 days). Inflammatory adhesion was confirmed by pathologic examination in only 1 patient. Eight patients (57%) did not have lymph node metastasis. The median follow-up time was 21 months (range, 4 276 months). Ten patients were alive at the time of their last scheduled follow up. The overall survival rates were 72% at 1 year and 60% at 2 years. No patient was lost to follow-up. Three patients developed tumor recurrence. The outcomes are no worse than those of the stage-matched patients without adjacent organ involvement and are much better than those of the stage-matched patients who underwent bypass surgery and chemotherapy. LIMITATIONS: The number of patients in current studies is limited. CONCLUSIONS: En bloc pancreaticoduodenectomy and right colectomy can be performed safely with an acceptable morbidity and mortality rate in selected patients with locally advanced right-side colon cancer. The long-term results are promising. PMID- 23739195 TI - Repeat intestinal resections increase the risk of recurrence of Crohn's disease. AB - BACKGROUND: Which factors predict recurrence in patients with Crohn's disease in the era of immunosuppressive medications is still under debate. OBJECTIVE: The current study was conducted to assess long-term outcome after ileocolic resection for Crohn's disease and to define predictive factors for surgical relapse. DESIGN: This is a retrospective study. SETTINGS: The study was conducted in a tertiary referral center. PATIENTS: A consecutive cohort of patients (n = 203) with Crohn's disease who underwent ileocolic resection between 1997 and 2006 were analyzed. The mean follow-up time was 8.4 (+/-2.4) years. MAIN OUTCOME MEASURES: The cumulative probability for repeated intestinal resection for recurrent Crohn's disease was described by Kaplan-Meier curves. Predictors of surgical recurrence were analyzed by univariate tests. RESULTS: One hundred five patients (51.7%) were exposed to azathioprine/6-mercaptopurine, and 28 patients (13.8%) were exposed to tumor necrosis factor-alpha blockers after operation. During the follow-up period, 32 patients (15.8%) were reoperated on for disease recurrence. At 5 and 10 years after index surgery, 95.5% and 81.3% of the patients had reoperation-free survival. Previous resections for Crohn's disease (HR, 2.981; 95% CI, 1.411-6.29; p = 0.003) and urgent indication for surgery (HR, 2.729; 95% CI, 1.047-7.116; p = 0.03) were significant risk factors for reoperation. In addition, patients with postoperative complications following ileocolonic resection were more likely to require reoperation (HR, 1.712; 95% CI, 041-2.817; p = 0.03). In a multiple Cox regression model, previous intestinal resection for Crohn's disease remained significant (p = 0.0114) with a HR of 2.654 (95% CI, 1.246-5.654). LIMITATIONS: The limitation is the retrospective design of the study, with its potential selection bias. CONCLUSION: In the present analysis, previous intestinal resection for Crohn's disease was found to be an independent risk factor for surgical recurrence. Consequently, shorter surveillance intervals in this group of patients should be considered. PMID- 23739196 TI - Safety and efficacy of ulimorelin administered postoperatively to accelerate recovery of gastrointestinal motility following partial bowel resection: results of two randomized, placebo-controlled phase 3 trials. AB - BACKGROUND: Gastrointestinal recovery is a critical milestone after bowel resection with postoperative ileus resulting in increased risk of complications and prolonged hospitalization. OBJECTIVE: The aim of this study is to evaluate the efficacy and safety of ulimorelin, a ghrelin receptor agonist given postoperatively in 2 identically designed phase 3 studies (ClinicalTrials.gov NCT01285570 and NCT01296620). DESIGN: This investigation is designed as a multicenter, double-blind, randomized, parallel-group study. SETTINGS: This study involves hospital inpatients. PATIENTS: Adult patients undergoing partial bowel resection were included. INTERVENTION: Thirty-minute intravenous infusions (160 ug/kg, 480 ug/kg ulimorelin, or placebo) once daily were started within 60 minutes after the end of surgery and ended at the first of the following: primary efficacy end point fulfilled (defined below), hospital discharge, or 7 days treatment. MAIN OUTCOME MEASURES: The primary efficacy end point was the time from the end of surgery to the composite end point of the later of first bowel movement and tolerance of solid food. Safety was assessed with the use of standard assessments including adverse events and laboratory tests. RESULTS: Ulimorelin Study of Efficacy and Safety 007, n = 332 patients; Ulimorelin Study of Efficacy and Safety 008, n = 330 patients: in both studies, the primary efficacy end point and the secondary efficacy outcomes, which included postsurgical time to first bowel movement, tolerance of solid food, and discharge eligibility, did not differ significantly among patients treated with either dose of ulimorelin versus placebo. Rates of serious adverse events were comparable across all treatment groups. There was no statistically significant difference from placebo in regard to events of interest, namely nausea, vomiting, ileus as an adverse event, nasogastric tube reinsertion, anastomotic complications, and infections. LIMITATIONS: A possible limitation is the variance inherent in surgery and comorbidities. CONCLUSIONS: Although the efficacy of ulimorelin in reducing the duration of postoperative ileus was not demonstrated in these studies, intravenous ulimorelin at doses of 160 ug/kg and 480 ug/kg was generally well tolerated in postcolectomy patients. Similar to other promotility agents, ulimorelin may find an application in other indications better suited to its attributes. PMID- 23739197 TI - Anal function after ligation of the intersphincteric fistula tract. AB - BACKGROUND: Although the ligation of the intersphincteric fistula tract is a promising anal sphincter-saving procedure for fistula-in-ano, the objective assessment of the sphincter preservation remains unknown. OBJECTIVE: The primary end point was to measure the anal function before and after this procedure. The secondary end point measured was cure of the disease. DESIGN: This study is a prospective observational study. SETTING: This study was conducted at the Department of Surgery, Kameda Medical Center, Japan, from March 2010 to August 2012. PATIENTS: Twenty patients with transsphincteric or complex fistulas were evaluated. INTERVENTIONS: All patients underwent the ligation of the intersphincteric fistula tract with a loose seton for anal fistulas. MAIN OUTCOME MEASURES: Anal manometric study was performed before and 3 months after the procedure. Fecal incontinence was evaluated by using the fecal incontinence severity index. Failure was defined as nonhealing of the surgical wound or fistula. RESULTS: The median operation time was 42 minutes. No intraoperative complications were documented. The median follow-up duration was 18 (3-32) months. No patients reported any incontinence postoperatively. The median score of the fecal incontinence severity index before and 3 months after the procedure was 0. The median maximum resting pressure measured before and after operation were 125 (71-175) cm H2O and 133 (95-169) cm H2O. The median maximum squeeze pressure measured before and after operation were 390 (170-815) cm H2O and 432 (200-902) cm H2O. There were no significant postoperative changes in either the resting pressure or the squeeze pressure. Primary healing was observed in 19 (95%) patients, and the median healing time was 7 weeks; 1 wound remained incompletely healed. LIMITATIONS: Short-term follow-up may not justify the use of the term definitive cure. CONCLUSION: The ligation of the intersphincteric fistula tract with a loose seton showed no postoperative deterioration on anal sphincter function with favorable healing rates. PMID- 23739198 TI - Functional and structural abnormalities after milligan hemorrhoidectomy: a comparison with healthy subjects. AB - BACKGROUND: Fecal incontinence is a rare but well-known adverse effect of hemorrhoidectomy. OBJECTIVE: The objective of this study was to identify possible reasons for incontinence after hemorrhoidectomy. DESIGN: We conducted a retrospective comparative study. SETTINGS: The study was performed in 1 university hospital and 1 general district hospital serving 2 counties in central Sweden. PATIENTS: In a cohort of 418 patients with consecutive Milligan hemorrhoidectomies, 40 reported fecal incontinence that was attributed to surgery. Of these, 19 patients agreed to participate. Fifteen age- and sex matched patients from the same cohort who were operated on, but without symptoms of incontinence, were also studied, as was a third reference group of 19 age- and sex-matched persons serving as a population-based control group. INTERVENTION: All of the participants answered a bowel function questionnaire and underwent clinical evaluation, including rectoscopy, anal manometry, saline infusion test, and endoanal ultrasound. MAIN OUTCOME MEASURES: We evaluated anal resting and squeeze pressures, sphincter defects, and continence function. RESULTS: The symptomatic patients had higher incontinence scores than the control groups (p = 0.00002). The mean resting pressure at the high-pressure zone was also reduced in this group (p = 0.047). External sphincter injuries were detected in 4 (20%) of 19 subjects compared with none in the control group (p = 0.11). Saline infusion test in the patients reporting incontinence showed reduced ability to hold liquids compared with healthy controls (p = 0.004). LIMITATIONS: This study was limited by selection bias and limited numbers in the groups. CONCLUSIONS: In the group of patients reporting incontinence after hemorrhoidectomy, there was a proportion with sphincter defects and impaired sphincter function. These results indicate a need for cautious patient selection and improved or alternative surgical techniques. PMID- 23739199 TI - Long-term outcomes of robot-assisted laparoscopic rectopexy for rectal prolapse. AB - BACKGROUND: Robot-assisted laparoscopic rectopexy for total rectal prolapse is safe and feasible. Small series proved clinical and functional short-term results comparable with conventional laparoscopy. No long-term results have been reported yet. OBJECTIVE: The primary objective of the study was to evaluate long-term functional and anatomic results of robot-assisted laparoscopic rectopexy. The secondary objective was to evaluate the learning curve of this procedure. DESIGN: Monocentric study data, both preoperative and perioperative, were collected prospectively, and follow-up data were assessed by a telephone questionnaire. SETTINGS: The study was performed in an academic center by 3 different surgeons. PATIENTS: We evaluated all of the consecutive patients who underwent a robot assisted laparoscopic rectopexy between June 2002 and August 2010. INTERVENTION: Rectopexy was performed with 2 anterolateral meshes or with 1 ventral mesh, and in 9 patients a sigmoidectomy was associated with rectopexy. MAIN OUTCOME MEASURES: The actuarial recurrence rate was evaluated using the Kaplan-Meier method. RESULTS: During the study period, 77 patients underwent a robot-assisted laparoscopic rectopexy, and the mean age was 59.9 years (range, 23-90 y). Average operating time was 223 minutes (range, 100-390 min); the learning curve was completed after 18 patients were seen. Two patients died of causes unrelated to surgery at 5 and 24 months. There were 5 conversions (6%) to open procedure. Overall morbidity was low and concerned only 8 patients (10.4%). Mean follow-up time was 52.5 months (range, 12-115 mo). Recurrences have been observed in 9 patients (12.8%). Preoperatively, 24 (34%) of the patients had constipation. Postoperatively, constipation disappeared for 12 (50%) of 24 and constipation appeared for 11 (24%) of 46 patients. Fecal incontinence decreased after surgery from Wexner score 10.5 to 5.1 of 20. LIMITATIONS: There was a lack of standardization of the surgical procedure. The study was monocentric. Seven patients (9%) were lost to follow-up. CONCLUSIONS: Long-term results of robot assisted laparoscopic rectopexy are satisfying. Further studies comparing robot assisted and conventional laparoscopy, including cost-effectiveness, are needed. PMID- 23739200 TI - Outcome of sacral nerve stimulation for fecal incontinence in patients refractory to percutaneous tibial nerve stimulation. AB - BACKGROUND: Percutaneous tibial nerve stimulation and sacral nerve stimulation are both second-line treatments for fecal incontinence, but the comparative efficacy of the 2 therapies is unknown. In our institution, patients with refractory fecal incontinence are generally treated with percutaneous tibial nerve stimulation before being considered for sacral nerve stimulation. OBJECTIVE: The aim of this study was to assess the outcome associated with this treatment algorithm in order to guide future management strategies. DESIGN: All patients with fecal incontinence treated over a 3-year period with tibial nerve stimulation before receiving sacral nerve stimulation were identified from a prospectively recorded database. Demographics and pretreatment anorectal physiological data were available for all patients. SETTINGS: This study was conducted at an academic colorectal unit in a tertiary center. PATIENTS: Twenty patients (17 female:3 male, median age 55 (33-79) years) were identified to be refractory to percutaneous tibial nerve stimulation. MAIN OUTCOME MEASURES: Clinical outcome data were collected prospectively before and after treatment, including 1) Cleveland Clinic Florida-Fecal Incontinence scores and 2) number of incontinence episodes per week. RESULTS: The mean (+/-SD) pretreatment incontinence score (11.7 +/- 3.5) did not differ from the mean incontinence score after 12 sessions of tibial nerve stimulation (10.9 +/- 3.6, p = 0.42). All patients were subsequently counseled for sacral nerve stimulation, and 68.4% of them reported a significant therapeutic benefit with an improved incontinence score (7.7 +/- 4.1, p = 0.014). LIMITATIONS: This was a nonrandomized study with a relatively small number of patients CONCLUSION: Sacral nerve stimulation appears to be an effective treatment for patients who do not gain an adequate therapeutic benefit from percutaneous tibial nerve stimulation and, thus, should be routinely considered for this patient cohort. PMID- 23739201 TI - Timing of surgery after long-course neoadjuvant chemoradiotherapy for rectal cancer: a systematic review of the literature. AB - BACKGROUND: Neoadjuvant long-course chemoradiotherapy is commonly used to improve the local control and resectability of locally advanced rectal cancer, with surgery performed after an interval of a number of weeks. OBJECTIVE: We report an evidence-based systematic review of published data supporting the optimal time to perform surgical resection after long-course neoadjuvant therapy. DATA SOURCES: A systematic literature search was undertaken of the MEDLINE and Embase electronic databases from 1995 to 2012. STUDY SELECTION: English language articles were included that compared outcomes following rectal cancer surgery performed at different times after a long course of neoadjuvant radiation-based therapy. INTERVENTIONS: : Patients received a long course of neoadjuvant therapy followed by radical surgical resection after an interval period. MAIN OUTCOME MEASURES: The rates of tumor response, R0 resection, sphincter preservation, surgical complications, and disease recurrence were the primary outcomes measured. RESULTS: Fifteen studies were identified: 1 randomized controlled trial, 1 prospective nonrandomized interventional study, and 13 observational studies. Studies compared time intervals that varied between <5 days and >12 weeks, with a large degree of variation in what the standard interval length was considered to be. Four of the 7 studies that reported rates of pathological complete response identified significantly higher rates with an extended interval between chemoradiotherapy and surgery; 3 of 8 studies demonstrated increased primary tumor downstaging with a longer interval. No significant differences have been consistently demonstrated in rates of surgical complications, sphincter preservation, or long-term recurrence and survival. LIMITATIONS: Neoadjuvant regimes, indications for neoadjuvant therapy, and time intervals after chemoradiotherapy were heterogeneous between studies; consequently, meta-analysis could not be performed. CONCLUSIONS: There is limited evidence to support decisions regarding when to resect rectal cancer following chemoradiotherapy. There may be benefits in prolonging the interval between chemoradiotherapy and surgery beyond the 6 to 8 weeks that is commonly practiced. However, outcomes need to be studied further in robust randomized studies. PMID- 23739202 TI - Transanal minimally invasive surgery (TAMIS): a technique that can be used for retrograde proctectomy. PMID- 23739203 TI - Comments on nonsteroidal anti-inflammatory drugs and anastomotic dehiscence. PMID- 23739204 TI - Comments on nonsteroidal anti-inflammatory drugs and anastomotic dehiscence. Author reply. PMID- 23739205 TI - What actually constitutes a safe margin? PMID- 23739206 TI - What actually constitutes a safe margin? Author reply. PMID- 23739207 TI - Surgical treatment of acquired rectourethral fistulas: our experience with posterior transrectal transsphincteric approach. PMID- 23739208 TI - Surgical treatment of acquired rectourethral fistulas: our experience with posterior transrectal transsphincteric approach. Author reply. PMID- 23739212 TI - Effect of nutrition and atherogenic index on the occurrence and intensity of insulin resistance. AB - INTRODUCTION: Diet is one of the factors that can stimulate genetic predisposition and, in consequence, lead to insulin resistance. An adequate supply of nutrients and energy-rich diet as well as increased physical activity are the most effective methods to prevent metabolic disorders. OBJECTIVES: The objective of this study was to determine whether there are any associations between nutrition and the occurrence of insulin resistance. PATIENTS AND METHODS: The study included 143 individuals. Fasting glucose and insulin levels were measured and the HOMA-IR index was calculated for each patient. Nondiabetic patients were divided into the study and control groups. We conducted anthropometric measurements (body mass, height, and waist circumference), biochemical analysis (fasting glucose and insulin), and dietary interview. RESULTS: We observed a negative correlation between the percentage of sucrose in the diet and the HOMA-IR value, and a positive correlation between the percentage of protein intake and the HOMA-IR value. Moreover, there was a significantly higher intake of lactose in men without insulin resistance compared with those with insulin resistance. CONCLUSIONS: The results encourage to conduct further, more detailed research involving a larger group of patients to better understand associations between dietary content and insulin resistance. PMID- 23739213 TI - Translation regulation in sleep: Making experience last. AB - Sleep improves cognition and is necessary for normal brain plasticity, but the precise cellular and molecular mechanisms mediating these effects are unknown. At the molecular level, experience-dependent synaptic plasticity triggers new gene and protein expression necessary for long-lasting changes in synaptic strength.(1) In particular, translation of mRNAs at remodeling synapses is emerging as an important mechanism in persistent forms of synaptic plasticity in vitro and certain forms of memory consolidation.(2) We have previously shown that sleep is required for the consolidation of a canonical model of in vivo plasticity (i.e., ocular dominance plasticity [ODP] in the developing cat).(3) Using this model, we recently showed that protein synthesis during sleep participates in the consolidation process. We demonstrate that activation of the mammalian target of rapamycin [mTOR] pathway, an important regulator of translation initiation,(4) is necessary for sleep-dependent ODP consolidation and that sleep promotes translation (but not transcription) of proteins essential for synaptic plasticity (i.e., ARC and BDNF). Our study thus reveals a previously unknown mechanism operating during sleep that consolidates cortical plasticity in vivo. PMID- 23739214 TI - Lowe syndrome: Between primary cilia assembly and Rac1-mediated membrane remodeling. AB - Lowe syndrome (LS) is a lethal X-linked genetic disease caused by functional deficiencies of the phosphatidlyinositol 5-phosphatase, Ocrl1. In the past four years, our lab described the first Ocrl1-specific cellular phenotypes using dermal fibroblasts from LS patients. These phenotypes, validated in an ocrl1 morphant zebrafish model, included membrane remodeling (cell migration/spreading, fluid-phase uptake) defects and primary cilia assembly abnormalities. On one hand, our findings unraveled cellular phenotypes likely to be involved in the observed developmental defects; on the other hand, these discoveries established LS as a ciliopathy-associated disease. This article discusses the possible mechanisms by which loss of Ocrl1 function may affect RhoGTPase signaling pathways leading to actin cytoskeleton rearrangements that underlie the observed cellular phenotypes. PMID- 23739215 TI - Endometriosis in adolescents is a hidden, progressive and severe disease that deserves attention, not just compassion. AB - Endometriosis in the adolescent has, in recent years, been discovered to be a challenging problem in gynaecology. Although the pain may start at a young age, even before the onset of menstruation, the diagnosis by laparoscopy is almost always postponed for several years, by which time destructive lesions have affected the tubo-ovarian structures and severely compromised fecundability. Several factors may play a role, but one important reason for this disease progression is likely to be the delay in diagnosis. Therefore, transvaginal ultrasounds and transvaginal access with a less invasive needle endoscopy are recommended for exploration of the pelvis, diagnosis of endometriosis and treatment at an early stage before severe lesions develop. PMID- 23739216 TI - Ambient temperature and congenital heart defects. AB - STUDY QUESTION: Does maternal exposure during pregnancy to higher ambient temperature increase the risk of congenital heart defects (CHDs)? SUMMARY ANSWER: Significant associations were found between maternal exposure during pregnancy to higher ambient temperature and CHDs risk especially during the cold season. WHAT IS KNOWN ALREADY: From rodents to non-human primates, a teratogenic effect of hyperthermic insult has been demonstrated. There are fewer data regarding the effect on the human fetus and specifically the association between maternal exposures during pregnancy to higher ambient temperature and CHDs. STUDY DESIGN, SIZE, DURATION: This population registry-based cohort study included 135 527 live and stillbirths in the Tel-Aviv region of Israel in 2000-2006. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two clinical diagnostic groups of isolated cardiac defects (atrial septal defects and ventricular septal defects: n = 542 and 481, respectively) and one group of multiple cardiac defects (defined by the presence of two or more cardiac malformations, n = 607) were studied. Temperature measurements were constructed from ambient stations and used to assess the impact of maternal exposure to average ambient temperature and extreme heat events (daily average temperature above the 90th percentile) during Weeks 3 8 of pregnancy on risk of CHDs. Logistic models, adjusted for sociodemographic covariates, were used to evaluate the associations between temperature and CHDs. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, we found no significant associations between ambient temperature and CHDs throughout the year, with one exception for multiple CHDs. After stratifying by season of conception, continuous exposure to average ambient temperature and maximum peak temperature (1 degrees C increase) during the cold season increased the risk for multiple CHDs [odds ratio (OR) 1.05, 95% confidence interval (CI): 1.00, 1.10 and OR 1.03, 95% CI: 1.01, 1.05, respectively]. A 1-day increase in extreme heat events increased the risk for multiple CHDs (OR 1.13, 95% CI: 1.06, 1.21) and also for isolated atrial septal defects (OR 1.10, 95% CI: 1.02, 1.19). LIMITATIONS, REASONS FOR CAUTION: Information both on CHD cases and on ambient temperature was based on registries and it is possible that this may cause some misclassification. In urban areas, pregnant women may be exposed to higher temperatures than recorded by ambient monitors because of the 'heat island effect'. Furthermore, data for the amount of time spent indoors were unavailable and this could have resulted in exposure misclassification. WIDER IMPLICATIONS OF THE FINDINGS: The findings are important within the context of global climate change, which may have implications for public health in countries with mild winters and hot summers. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Israeli Ministry of Environmental Protection (research grant-7-2 7) and by the Environment and Health Fund (PhD Fellowship Program). There are no competing interests. PMID- 23739217 TI - BAY 1002670: a novel, highly potent and selective progesterone receptor modulator for gynaecological therapies. AB - STUDY QUESTION: Does the novel progesterone receptor (PR) modulator BAY 1002670, based on its preclinical pharmacological profile, offer a potential novel treatment option for uterine fibroids? SUMMARY ANSWER: The newly synthesized BAY1002670 has proved to be a very potent, highly selective PR modulator in all in vitro and in vivo pharmacodynamics assays performed: it exhibits marked efficacy in an innovative humanized fibroid disease model, suggesting BAY 1002670 to be a very promising treatment option for uterine fibroids. WHAT IS KNOWN ALREADY: PR inhibiting ligands have shown clinical utility in a range of potential indications and applications. Despite the emergence of the first PR antagonist >30 years ago, no agent of this compound class has been authorized in any indication for long-term application. Among other reasons, suboptimal selectivity and safety profiles of previous candidates have led to discontinuation and modification of development programmes. STUDY, DESIGN, SIZE, DURATION: The preclinical studies include relevant in vitro and in vivo assays to clarify the properties of the PR modulator BAY 1002670 as well as a fibroid xenograft study to show directly the efficacy of BAY 1002670 on the human target tissue. PARTICIPANTS/MATERIAL, SETTING, METHODS: BAY 1002670 was tested for binding and transactivational activity towards different human steroid receptors. Activity of the compound in the corresponding in vivo models (rat, rabbit) was assessed. Furthermore, BAY 1002670 was tested in a disease model for uterine fibroids utilizing primary human tumour tissues as xenograft in immunodeficient mice treated with estradiol (E2) and progesterone (P). MAIN RESULT AND THE ROLE OF CHANCE: BAY1002670 in subnanomolar concentrations exhibits a highly selective binding profile and antagonistic activity for the PR. These properties are also reflected in its action in two progesterone-dependent animal models that assess the termination of pregnancy and endometrial transformation. Favourable selectivity towards other nuclear hormone receptors was demonstrated. No in vivo activity was found at the glucocorticoid, estrogenic and mineralocorticoid receptors with only weak anti-androgenic activity. In a human fibroid xenograft model BAY 1002670 showed a marked dose-dependent reduction of fibroid tumour weight gain of 95% at a dose of 3 mg/kg/day (P < 0.005). LIMITATIONS AND REASON FOR CAUTION: Selectivity and potency of BAY 1002670 have only been determined in vitro and in animal models so far. WIDER IMPLICATIONS OF THE FINDING: The PR modulator BAY 1002670 might offer a treatment option not only for uterine fibroids but also for other gynaecological indications. STUDY FUNDING/COMPETING INTEREST: The studies took place at Bayer Pharma AG. All authors are employees of Bayer Pharma AG. No external funding declared. PMID- 23739218 TI - Fasting glucose measurement as a potential first step screening for glucose metabolism abnormalities in women with anovulatory polycystic ovary syndrome. AB - STUDY QUESTION: Is routine screening by oral glucose tolerance test (OGTT) needed for all women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Screening for glucose metabolism abnormalities of PCOS patients by an OGTT could potentially be limited to patients who present with a fasting glucose concentration between 6.1 and 7.0 mmol/l only. WHAT IS KNOWN ALREADY: Women with PCOS are at increased risk of developing diabetes. This study proposes a stepwise screening strategy for (pre)diabetes for PCOS patients based on risk stratification by fasting plasma glucose. STUDY DESIGN, SIZE, DURATION: A cross sectional study of 226 women diagnosed with anovulatory PCOS. PARTICIPANTS AND SETTING: A consecutive series of 226 patients, diagnosed with PCOS at the University Medical Centre Utrecht, the Netherlands, were screened for glucose metabolism abnormalities by OGTT (75 g glucose load). MAIN RESULTS AND ROLE OF CHANCE: The majority of the 226 women (mean age: 29.6 +/- 4.3 years; BMI: 27.3 +/ 6.7 kg/m(2); 81% Caucasian) presented with a normal OGTT (169 women (75%)). Of the 57 (25%) women presenting with mild to moderate glucose abnormalities, 53 (93%) could be identified by fasting glucose concentrations only. Diabetes was diagnosed in a total of eight women (3.5%). In six women, the diagnosis was based on fasting glucose >7.0 mmol/l. The other two cases of diabetes initially presented with fasting glucose between 6.1 and 7.0 mmol/l and were diagnosed by OGTT assessment. No women diagnosed with diabetes presented with fasting glucose levels below 6.1 mmol/l. We therefore conclude that all diabetes patients could potentially be found by initial fasting glucose assessment followed by OGTT only in patients with fasting glucose between 6.1 and 7.0 mmol/l. LIMITATIONS, REASONS FOR CAUTION: Before general implementation can be advised, this screening algorithm should be validated in a prospective study of a similar or greater number of PCOS women. WIDER IMPLICATIONS OF THE FINDINGS: Our study comprised of a mostly Caucasian (81%) population, therefore generalization to other ethnic populations should be done with caution. STUDY FUNDING/COMPETING INTEREST(S): No external finance was involved in this study. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order); Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. A.J.G. has received fees from Abbott, Bayer Schering and IBSA. T.W.H. has received fees from Merck, Sharpe & Dohme, GlaxoSmithKline, NovoNordisk and Eli Lilly. The authors declare complete independence from funders. CLINICAL TRIAL REGISTRATION NUMBER: NCT00821379. PMID- 23739219 TI - Misoprostol prior to inserting an intrauterine device in nulligravidas: a randomized clinical trial. AB - STUDY QUESTION: How effective is the vaginal administration of misoprostol in dilating the cervix prior to inserting an intrauterine device (IUD) in nulligravidas? SUMMARY ANSWER: The use of misoprostol at a dose of 400 ug administered vaginally 4 h prior to IUD insertion increased the ease of insertion and reduced the incidence of pain during the procedure, although the frequency of cramps increased following misoprostol use. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Misoprostol has been widely used in Obstetrics and Gynecology; however, its usefulness and efficacy in facilitating IUD insertion in nulligravidas have yet to be established. The present study shows that the benefits of misoprostol use prior to IUD insertion include facilitating insertion and reducing pain during the procedure; therefore, weighing up the benefits encountered against the only negative side effect (cramps prior to insertion), these results suggest that misoprostol use should become standard practice to facilitate IUD insertion in nulligravidas. STUDY DESIGN, SIZE DURATION: A randomized, double-blind clinical trial was conducted. PARTICIPANTS/MATERIALS, SETTING METHODS: Nulligravid women of reproductive age were submitted to IUD insertion between July 2009 and November 2011 at the Instituto de Medicina Integral Prof. Fernando Figueira in Recife, Pernambuco, Brazil. A total of 179 women were randomly allocated to two groups: 86 to receive 400 ug of misoprostol vaginally 4 h prior to IUD insertion and 93 to receive placebo. Risk ratios (RRs) were calculated as measures of relative risk, together with their 95% confidence intervals (95% CI). The number needed to treat (NNT) and the number needed to harm (NNH) were also calculated. MAIN RESULTS AND THE ROLE OF CHANCE: Significant differences were found between the groups for all the immediate end points studied, with less difficulty in inserting the IUD [RR = 0.49 (23/86 versus 51/93); 95% CI: 0.33-0.72; P = 0.00005], a lower risk of dilatation <4 mm [RR = 0.48 (24/86 versus 54/93); 95% CI: 0.33-0.70; P = 0.0001], a reduction in moderate-to-severe pain at IUD insertion [RR = 0.56 (32/86 versus 62/93]; 95% CI: 0.41-0.76; P = 0.00008), as well as a lesser likelihood of experiencing a disagreeable or very disagreeable sensation [RR = 0.49(29/86 versus 64/93); 95% CI: 0.35-0.68; P = 0.000004] in the group that was given misoprostol compared with the group that received placebo. There was no significant difference between the groups in relation to complications during IUD insertion. There were no cases of uterine perforation in either group. The frequency of cramps was 40% higher in the misoprostol group. LIMITATIONS, REASONS FOR CAUTION: The present study showed a positive balance between the benefits and risks of the use of misoprostol; however, it is not feasible to conclude that its use is imperative prior to IUD insertion in nulligravidas and IUD insertion should not be canceled when the medication is unavailable. WINDER IMPLICATIONS OF THE FINDINGS: In view of its effect in promoting cervical dilatation, misoprostol may be used prior to IUD insertion both in nulligravidas and in any women with cervical stenosis irrespective of parity. STUDY FUNDING: This study was funded by the Instituto de Medicina Integral Prof Fernando Figueira. COMPETING INTERESTS: None. PMID- 23739221 TI - FISH reanalysis of inner cell mass and trophectoderm samples of previously array CGH screened blastocysts shows high accuracy of diagnosis and no major diagnostic impact of mosaicism at the blastocyst stage. AB - STUDY QUESTION: Does comprehensive chromosome screening (CCS) of cells sampled from the blastocyst trophectoderm (TE) accurately predict the chromosome complement of the inner cell mass (ICM)? SUMMARY ANSWER: Comprehensive chromosome screening of a TE sample is unlikely to be confounded by mosaicism and has the potential for high diagnostic accuracy. WHAT IS KNOWN ALREADY: The effectiveness of chromosome aneuploidy screening is limited by the technologies available and chromosome mosaicism in the embryo. Combined with improving methods for cryopreservation and blastocyst culture, TE biopsy and CCS is considered to be a promising approach to select diploid embryos for transfer. STUDY DESIGN, SIZE, DURATION: The study was performed between January 2011 and August 2011. In the first part, a new ICM isolation method was developed and tested on 20 good morphology blastocysts. In the main phase of the study, fluorescence in situ hybridization (FISH) was used to reanalyse the ICMs and TEs separated from 70 embryos obtained from 26 patients undergoing blastocyst stage array comparative genome hybridization (aCGH) PGS cycles. MATERIALS, SETTING, METHODS: The isolated ICM and TE fractions were characterized by immunostaining for KRT18. Then, non transferrable cryopreserved embryos were selected for the FISH reanalysis based on previous genetic diagnosis obtained by TE aCGH analysis. Blastocysts either diploid for chromosome copy number (20) or diagnosed as single- (40) or double aneuploid (10) were included after preparing the embryo into one ICM and three equal-sized TE sections. Accuracy of the aCGH was measured based on FISH reanalysis. Chromosomal segregations resulting in diploid/aneuploid mosaicism were classified as 'low-', 'medium-' and 'high-' grade and categorized with respect to their distribution (1TE, 2TE, 3TE, ICM or ALL embryo). Linear regression model was used to test the relationship between the distributions and the proportion of aneuploid cells across the four embryo sections. Fisher's exact test was used to test for random allocation of aneuploid cells between TE and ICM. MAIN RESULTS AND THE ROLE OF CHANCE: All ICM biopsy procedures displayed ICM cells in the recovered fraction with a mean number of ICM cells of 26.2 and a mean TE cell contamination rate of 2%. By FISH reanalysis of previously aCGH screened blastocysts, a total of 66 aneuploidies were scored, 52 (78.8%) observed in all cells and 14 (21.2%) mosaic. Overall, mosaic chromosomal errors were observed only in 11 out of 70 blastocysts (15.7%) but only 2 cases were classified as mosaic diploid/aneuploid (2.9%). Sensitivity and specificity of aCGH on TE clinical biopsies were 98.0 and 100% per embryo and 95.2 and 99.8% per chromosome, respectively. Linear regression analysis performed on the 11 mosaic diploid/aneuploid chromosomal segregations showed a significant positive correlation between the distribution and the proportion of aneuploid cells across the four-blastocyst sections (P < 0.01). In addition, regression analysis revealed that both the grade and the distribution of mosaic abnormal cells were significantly correlated with the likelihood of being diagnosed by aCGH performed on clinical TE biopsies (P = 0.019 and P < 0.01, respectively). Fisher's exact test for the 66 aneuploidies recorded showed no preferential allocation of abnormal cells between ICM and TE (P = 0.33). LIMITATIONS, REASONS FOR CAUTION: The study is limited to non-transferable embryos, reanalyzed for only nine chromosomes and excludes segmental imbalance and uniparental disomy. The prevalence of aneuploidy in the study group is likely to be higher than in the general population of clinical PGD embryos. WIDER IMPLICATIONS OF THE FINDINGS: This study showed high accuracy of diagnosis achievable during blastocyst stage PGS cycles coupled with 24-chromosomes molecular karyotyping analysis. The new ICM isolation strategy developed may open new possibilities for basic research in embryology and for clinical grade derivation of human embryonic stem cells. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was sought or obtained for this study. PMID- 23739220 TI - Profibrotic interleukin-33 is correlated with uterine leiomyoma tumour burden. AB - STUDY QUESTION: Are interleukin-33 (IL-33) serum levels higher in women with uterine leiomyoma compared with controls without leiomyoma? SUMMARY ANSWER: Serum IL-33 is elevated in women with uterine leiomyoma and correlated with features of uterine leiomyoma tumour burden, namely fibroid number, size and weight. WHAT IS KNOWN ALREADY: Uterine leiomyomas are the most common benign tumours in premenopausal women associated with major tissue fibrosis. IL-33 is a cytokine involved in fibrotic disorders. The potential role of IL-33 in leiomyoma has not been reported before. STUDY DESIGN, SIZE, DURATION: This is a prospective laboratory study conducted in a tertiary-care university hospital between January 2005 and December 2010. We investigated non-pregnant, 42-year-old patients (n = 151) during surgery for a benign gynaecological condition. PARTICIPANTS/MATERIALS, SETTING, METHODS: After complete surgical exploration of the abdominopelvic cavity, 59 women with histologically proved uterine leiomyoma and 92 leiomyoma-free control women were enrolled. Women with endometriosis or past history of ovarian malignancy and borderline tumours were not included. The control group included women with benign ovarian cysts, paratubal cysts or tubal defects without any evidence of uterine leiomyoma. For each patient, a structured questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding surgery. Serum samples were obtained in the month preceding the surgical procedures according to the menstrual phase or hormonal therapy. IL-33 was measured in sera by enzyme-linked immunosorbent assay, and correlation of IL-33 concentration with the extent and severity of the disease was investigated. MAIN RESULTS AND THE ROLE OF CHANCE: IL-33 was detected in 32 (54.2%) women with leiomyoma and 18 (19.6%) controls (P < 0.001). Serum IL 33 was higher in women with leiomyoma (median, 140.1 pg/ml; range, 7.5-2247.7) than in controls (median, 27.8 pg/ml; range, 7.5-71.6; P = 0.002). We found positive correlations between serum IL-33 concentration and leiomyoma features, such as fibroid weight (r = 0.630; P = 0.001) and size (r = 0.511; P = 0.018) and the number of fibroids (r = 0.503; P = 0.003). LIMITATIONS, REASONS FOR CAUTION: There was a possible selection bias due to inclusion of only surgical patients. Therefore our control group consisted of women who underwent surgery for benign gynaecological conditions. This may lead to biases stemming from the fact that certain of these conditions, such as tubal infertility or ovarian cysts, might be associated with altered serum IL-33 levels. WIDER IMPLICATIONS OF THE FINDINGS: We demonstrate for the first time that elevated serum IL-33 levels are associated with the existence of uterine leiomyoma. However, even if an association does not constitute proof of cause and effect, investigating the mechanisms that underlie fibrogenesis associated with leiomyomas is a step towards understanding this enigmatic disease. This study opens the doors to future, more mechanistics studies to establish the exact role of IL-33 in uterine leiomyomas pathogenesis. STUDY FUNDING/COMPETING INTEREST(S): No funding, no conflict of interest. PMID- 23739222 TI - Altered expression of interleukin-6, interleukin-8 and their receptors in decidua of women with sporadic miscarriage. AB - STUDY QUESTION: Are alterations in decidual expression of interleukin (IL)-6 and IL-8 associated with sporadic miscarriage? SUMMARY ANSWER: IL-6 and IL-8 secretion from decidual uterine natural killer (uNK) cells and macrophages isolated from women with spontaneous miscarriage was reduced compared with normal controls. WHAT IS KNOWN ALREADY: Miscarriage is a common gynaecological problem with huge financial and personal implications. Eleven to twenty per cent of all clinically recognized pregnancies are lost before the 20th week of gestation, with miscarriages often being divided into early (<= 12 completed weeks from last menstrual period) and late (>= 13 weeks). Spiral artery remodelling is a key feature of early pregnancy; failure of this process has been implicated in sporadic miscarriage. The molecular triggers that initiate spiral artery remodelling are not clear, although cytokines such as IL-6 and IL-8 may play a role. STUDY DESIGN, SIZE, DURATION: This was a laboratory-based study using decidual and placental bed biopsy samples from women with sporadic miscarriage (n = 30) and termination of pregnancy controls (n = 30). PARTICIPANTS/MATERIALS, SETTING, METHODS: Total adherent decidual cells, CD10(+) stromal cells, CD14(+) macrophages and CD56(+) uNK cells were isolated from decidua from apparently normal pregnancies that were terminated at either 8-10 or 12-14 weeks' gestation. In addition, CD14(+) macrophages and CD56(+) uNK cells were isolated from decidua from sporadic miscarriage at 8-10 weeks' gestation. Secreted IL-8 was measured in all isolated cell populations, while IL-6 was measured in CD14(+) macrophages and CD56(+) uNK cells from both sporadic miscarriage and normal controls. Placental bed biopsies were taken from women after sporadic miscarriage or termination of pregnancy at <= 12 completed weeks' or >13 weeks' gestational age, formalin fixed, paraffin-embedded and immunostained for IL-6, IL-6Ralpha, GP130, IL-8, CXCR1, CXCR2 and CD13 (aminopeptidase N). Staining intensity for each factor was assessed in extravillous trophoblast cell populations, myometrial and decidual stroma, myometrial and decidual spiral arteries and decidual glandular epithelium. A CPA model was used to assess the potential role of IL-6 and IL-8 in spiral artery remodelling. MAIN RESULTS AND THE ROLE OF CHANCE: IL-8 was secreted by total adherent decidual cells, CD10(+) stromal cells and CD14(+) macrophages at both 8-10 and 12-14 weeks' gestation, with CD14(+) cells secreting the highest levels. Both CD14(+) and CD56(+) cells isolated from decidua of early sporadic miscarriage produced lower IL-6 (P = 0.04, P = 0.01, respectively) and IL-8 levels (P = 0.0007, P = 0.002, respectively) compared with normal cases. In addition, altered expression of IL-6, IL-8 and their receptors was observed in various cell types in placental bed (myometrial stroma, glandular epithelium, interstitial extravillous trophoblast cells, vascular smooth muscle cells and endothelial cells) in sporadic miscarriage, particularly from later gestational ages. IL-6 and IL-8 disrupted vascular smooth muscle morphology and organization in an in vitro model of spiral artery remodelling. LIMITATIONS, REASONS FOR CAUTION: By the nature of sampling at the time of miscarriage, it was not possible to ascertain the cause or effect in the observed alterations of levels of IL-6 and IL-8 in sporadic miscarriage. WIDER IMPLICATIONS OF THE FINDINGS: Alterations in the expression of IL-6, IL-8 and their receptors may be associated with the aetiology of sporadic miscarriage, especially given the potential role of these cytokines in the regulation of trophoblast invasion and spiral artery remodelling. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by funding from Wellbeing of Women (RG1000). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 23739223 TI - Screening for glycaemic abnormalities in PCOS: an ongoing controversy. PMID- 23739224 TI - A novel SPE-HPLC method for simultaneous determination of selected sulfonated phthalocyanine zinc complexes in mouse plasma following cassette dosing. AB - Sulfonated phthalocyanine zinc complexes (ZnPcSn) are a mixture of polymolecules with different number of the sulfonic groups. They are typical photosensitizers for photodynamic therapy (PDT). Analysis of the sulfonic phthalocyanine complexes in blood is a global technical challenge to developing this kind of photosensitizers into clinics. To circumvent the problem, we aimed at developing a novel solid-phase extraction (SPE)-HPLC method, which was primarily composed of (1) the SPE material that has both the aliphatic benzene group and hydrophilic ethylenediamino group bonded to the silica surface typically for retaining those hydrophobic compounds with some degree of hydrophilic anionic (negatively charged) functionality; and (2) the RP-Amide C16 HPLC column packed with palmitamidopropylsilane for both reversed-phase and anion exchange separation. The method was validated in terms of recovery, precision and accuracy for pharmacokinetic study with the photosensitizer following its intravenous cassette dosing to mice. The present study is the first report on using an SPE-HPLC mode to simultaneously determine the phthalocyanine-based polymolecule photosensitizer in blood. The study will aid in clinical development of photosensitizers. PMID- 23739225 TI - Surface plasmon resonance enhanced upconversion luminescence in aqueous media for TNT selective detection. AB - We present a novel report on a surface plasmon resonance enhanced upconversion luminescence strategy in aqueous media for highly sensitive and selective detection of 2,4,6-trinitrotoluene (TNT). PMID- 23739226 TI - Low risk of liver toxicity using the most recently approved antiretroviral agents but still increased in HIV-hepatitis C virus coinfected patients. AB - Liver enzyme elevations (LEE) were investigated in 2717 episodes of initiation of antiretroviral therapy since January 2010 in 1982 HIV patients. Serum hepatitis C virus (HCV)-RNA was positive in 24%. Any grade of LEE was recognized in 9% of episodes, being 6% in HCV-negative and 17% in HCV-positive patients (P < 0.001). Grades 3-4 LEE only occurred in 0.4% of patients. Overall, LEE were more frequent with ritonavir-boosted darunavir and atazanavir than with raltegravir and etravirine. PMID- 23739227 TI - Surveillance neuroimaging and neurologic examinations affect care for intracerebral hemorrhage. AB - OBJECTIVE: We tested the hypothesis that surveillance neuroimaging and neurologic examinations identified changes requiring emergent surgical interventions in patients with intracerebral hemorrhage (ICH). METHODS: Patients with primary ICH were enrolled into a prospective registry between December 2006 and July 2012. Patients were managed in a neuroscience intensive care unit with a protocol that included serial neuroimaging at 6, 24, and 48 hours, and hourly neurologic examinations using the Glasgow Coma Scale and NIH Stroke Scale. We evaluated all cases of craniotomy and ventriculostomy to determine whether the procedure was part of the initial management plan or occurred subsequently. For those that occurred subsequently, we determined whether worsening on neurologic examination or worsened neuroimaging findings initiated the process leading to intervention. RESULTS: There were 88 surgical interventions in 84 (35%) of the 239 patients studied, including ventriculostomy in 52 (59%), craniotomy in 21 (24%), and both in 11 (13%). Of the 88 interventions, 24 (27%) occurred subsequently and distinctly from initial management, a median of 15.9 hours (8.9-27.0 hours) after symptom onset. Thirteen (54%) were instigated by findings on neurologic examination and 11 (46%) by neuroimaging. Demographics, severity of hemorrhage, and hemorrhage location were not associated with delayed intervention. CONCLUSIONS: More than 25% of surgical interventions performed after ICH were prompted by delayed imaging or clinical findings. Serial neurologic examinations and neuroimaging are important and effective surveillance techniques for monitoring patients with ICH. PMID- 23739228 TI - Clinicoradiologic acute monitoring after intracerebral hemorrhage: Toward standards? PMID- 23739229 TI - Atrial fibrillation and cognitive decline: a longitudinal cohort study. AB - OBJECTIVE: We sought to determine whether in the absence of clinical stroke, people with atrial fibrillation experience faster cognitive decline than people without atrial fibrillation. METHODS: We conducted a longitudinal analysis in the Cardiovascular Health Study, a community-based study of 5,888 men and women aged 65 years and older, enrolled in 1989/1990 or 1992/1993. Participants did not have atrial fibrillation or a history of stroke at baseline. Participants were censored when they experienced incident clinical stroke. Incident atrial fibrillation was identified by hospital discharge diagnosis codes and annual study ECGs. The main outcome was rate of decline in mean scores on the 100-point Modified Mini-Mental State Examination (3MSE), administered annually up to 9 times. RESULTS: Analyses included 5,150 participants, of whom 552 (10.7%) developed incident atrial fibrillation during a mean of 7 years of follow-up. Mean 3MSE scores declined faster after incident atrial fibrillation compared with no prior atrial fibrillation. For example, the predicted 5-year decline in mean 3MSE score from age 80 to age 85 was -6.4 points (95% confidence interval [CI]: 7.0, -5.9) for participants without a history of atrial fibrillation, but was 10.3 points (95% CI: -11.8, -8.9) for participants experiencing incident atrial fibrillation at age 80, a 5-year difference of -3.9 points (95% CI: -5.3, -2.5). CONCLUSIONS: In the absence of clinical stroke, people with incident atrial fibrillation are likely to reach thresholds of cognitive impairment or dementia at earlier ages than people with no history of atrial fibrillation. PMID- 23739230 TI - A novel technique for measuring the low-dose envelope of pencil-beam scanning spot profiles. AB - To investigate the profile measurement capabilities of an IBA-Dosimetry scintillation detector and to assess its feasibility for determining the low intensity tails of pencil-beam scanning spots, the responses of the scintillation detector and Gafchromic EBT2 film to a 115 MeV proton spot were measured in-air at the isocenter. Pairs of irradiations were made: one lower-level irradiation insufficient to cause saturation, and one higher-level irradiation which deliberately saturated the central region of the spot, but provided magnification of the tails. By employing the pair/magnification technique, agreement between the film and scintillation detector measurements of the spot profile can be extended from 4% of the central spot dose down to 0.01%. Gamma analysis between these measurements shows 95% and 99% agreement within a +/-9 cm bound using criteria of 3 mm/3% and 5 mm/5%, respectively. Above 4%, our 115 MeV proton spot can be well-described by Gaussian function; below 4%, non-Gaussian, diamond shaped tails predominate. PMID- 23739231 TI - Subcutaneous interstitial pressure and volume characteristics in renal impairment associated with edema. AB - The kidneys and the interstitial compartment play a vital role in body fluid regulation. The latter may be significantly altered in renal dysfunction, but experimental studies are lacking. To help define this we measured the subcutaneous interstitial pressure, bioimpedance volumes, and edema characteristics in 10 healthy subjects and 21 patients with obvious edema and chronic kidney disease (CKD). Interstitial edema was quantified by the time taken for a medial malleolar thumb pit to refill and termed the edema refill time. Interstitial pressure was significantly raised in CKD compared to healthy subjects. Total body water (TBW), extracellular fluid volume (ECFV), interstitial fluid volume, the ratio of the ECFV to the TBW, and segmental extracellular fluid volume were raised in CKD. The ratio of the ECFV to the TBW and the interstitial fluid volume were the best predictors of interstitial pressure. Significantly higher interstitial pressures were noted in edema of 2 weeks or less duration. A significant nonlinear relationship defined interstitial pressure and interstitial fluid volume. Edema refill time was significantly inversely related to interstitial pressure, interstitial compartment volumes, and edema vintage. Elevated interstitial pressure in CKD with obvious edema is a combined function of accumulated interstitial compartment fluid volumes, edema vintage, and tissue mechanical properties. The edema refill time may represent an important parameter in the clinical assessment of edema, providing additional information about interstitial pathophysiology in patients with CKD and fluid retention. PMID- 23739233 TI - Individuals of Pacific Asian origin with IgA nephropathy have an increased risk of progression to end-stage renal disease. AB - IgA nephropathy (IgAN) accounts for a far higher proportion of end-stage renal disease (ESRD) in Asia compared with North America. It is not known whether this is entirely because of differences in disease prevalence or a higher risk of disease progression. The lack of a racially diverse population cohort followed longitudinally has previously precluded the ability to address this question. To determine whether Asians in North America with IgAN are at higher risk for ESRD, we analyzed a cohort of 202 patients of self-reported Pacific Asian origin and 467 of other origin from the Toronto GN Registry followed up for a median of 46.4 months. The primary outcome of ESRD (dialysis, transplantation, or eGFR below 15) was analyzed using Cox regression analysis. Baseline eGFR was 59.6 ml/min/1.73 m(2), and median proteinuria was 1.8 g/day. ESRD occurred in 213 patients. By univariable analysis, the risk of ESRD was similar between the two groups (hazard ratio 0.98, 95% CI 0.73, 1.31); however, after adjusting for age, gender, eGFR, medication use, blood pressure, and proteinuria, the risk of ESRD was significantly higher in Pacific Asian individuals (hazard ratio 1.56, 95% CI 1.10, 2.22). This was supported by a significant 1.62 ml/min/1.73 m(2)/year faster rate of eGFR decline (95% CI -3.19, -0.5) and an increased risk of a reduction in eGFR by half (hazard ratio 1.81, 95% CI 1.25, 2.62). Thus, in a large multiracial cohort of patients with IgAN, individuals of Pacific Asian origin have a higher risk of progression to ESRD. PMID- 23739232 TI - Serum aminoacylase-1 is a novel biomarker with potential prognostic utility for long-term outcome in patients with delayed graft function following renal transplantation. AB - Early identification and prognostic stratification of delayed graft function following renal transplantation has significant potential to improve outcome. Mass spectrometry analysis of serum samples, before and on day 2 post transplant from five patients with delayed graft function and five with an uncomplicated transplant, identified aminoacylase-1 (ACY-1) as a potential outcome biomarker. Following assay development, analysis of longitudinal samples from an initial validation cohort of 55 patients confirmed that the ACY-1 level on day 1 or 2 was a moderate predictor of delayed graft function, similar to serum creatinine, complementing the strongest predictor cystatin C. A further validation cohort of 194 patients confirmed this association with area under ROC curves (95% CI) for day 1 serum (138 patients) of 0.74 (0.67-0.85) for ACY-1, 0.9 (0.84-0.95) for cystatin C, and 0.93 (0.88-0.97) for both combined. Significant differences in serum ACY-1 levels were apparent between delayed, slow, and immediate graft function. Analysis of long-term follow-up for 54 patients with delayed graft function showed a highly significant association between day 1 or 3 serum ACY-1 and dialysis-free survival, mainly associated with the donor-brain-dead transplant type. Thus, proteomic analysis provides novel insights into the potential clinical utility of serum ACY-1 levels immediately post transplantation, enabling subdivision of patients with delayed graft function in terms of long-term outcome. Our study requires independent confirmation. PMID- 23739234 TI - NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy. AB - Oxalate nephropathy with renal failure is caused by multiple disorders leading to hyperoxaluria due to either overproduction of oxalate (primary hyperoxaluria) or excessive absorption of dietary oxalate (enteric hyperoxaluria). To study the etiology of renal failure in crystal-induced kidney disease, we created a model of progressive oxalate nephropathy by feeding mice a diet high in soluble oxalate (high oxalate in the absence of dietary calcium). Renal histology was characterized by intratubular calcium-oxalate crystal deposition with an inflammatory response in the surrounding interstitium. Oxalate nephropathy was not found in mice fed a high oxalate diet that also contained calcium. NALP3, also known as cryopyrin, has been implicated in crystal-associated diseases such as gout and silicosis. Mice fed the diet high in soluble oxalate demonstrated increased NALP3 expression in the kidney. Nalp3-null mice were completely protected from the progressive renal failure and death that occurred in wild-type mice fed the diet high in soluble oxalate. NALP3 deficiency did not affect oxalate homeostasis, thereby excluding differences in intestinal oxalate handling to explain the observed phenotype. Thus, progressive renal failure in oxalate nephropathy results primarily from NALP3-mediated inflammation. PMID- 23739236 TI - The Terminator mouse is a diphtheria toxin-receptor knock-in mouse strain for rapid and efficient enrichment of desired cell lineages. AB - Biomedical research often requires primary cultures of specific cell types, which are challenging to obtain at high purity in a reproducible manner. Here we engineered the murine Rosa26 locus by introducing the diphtheria toxin receptor flanked by loxP sites. The resultant strain was nicknamed the Terminator mouse. This approach results in diphtheria toxin-receptor expression in all non-Cre expressing cell types, making these cells susceptible to diphtheria toxin exposure. In primary cultures of kidney cells derived from the Terminator mouse, over 99.99% of cells were dead within 72 h of diphtheria toxin treatment. After crossing the Terminator with the podocin-Cre (podocyte specific) mouse or the Ggt Cre (proximal tubule specific) mouse, diphtheria toxin treatment killed non-Cre expressing cells but spared podocytes and proximal tubule cells, respectively, enriching the primary cultures to over 99% purity, based on both western blotting and immunostaining of marker proteins. Thus, the Terminator mouse can be a useful tool to selectively and reproducibly obtain even low-abundant cell types at high quantity and purity. PMID- 23739235 TI - Thymosin beta4 and its degradation product, Ac-SDKP, are novel reparative factors in renal fibrosis. AB - Previously, we found thymosin beta4 (Tbeta4) is upregulated in glomerulosclerosis and required for angiotensin II-induced expression of plasminogen activator inhibitor-1 (PAI-1) in glomerular endothelial cells. Tbeta4 has beneficial effects in dermal and corneal wound healing and heart disease, yet its effects in kidney disease are unknown. Here we studied renal fibrosis in wild-type and PAI-1 knockout mice following unilateral ureteral obstruction to explore the impact of Tbeta4 and its prolyl oligopeptidase tetrapeptide degradation product, N-acetyl seryl-aspartyl-lysyl-proline (Ac-SDKP), in renal fibrosis. Additionally, we explored interactions of Tbeta4 with PAI-1. Treatment with Ac-SDKP significantly decreased fibrosis in both wild-type and PAI-1 knockout mice, as observed by decreased collagen and fibronectin deposition, fewer myofibroblasts and macrophages, and suppressed profibrotic factors. In contrast, Tbeta4 plus a prolyl oligopeptidase inhibitor significantly increased fibrosis in wild-type mice. Tbeta4 alone also promoted repair and reduced late fibrosis in wild-type mice. Importantly, both profibrotic effects of Tbeta4 plus the prolyl oligopeptidase inhibitor, and late reparative effects of Tbeta4 alone, were absent in PAI-1 knockout mice. Thus, Tbeta4 combined with prolyl oligopeptidase inhibition is consistently profibrotic, but by itself has antifibrotic effects in late-stage fibrosis, while Ac-SDKP has consistent antifibrotic effects in both early and late stages of kidney injury. These effects of Tbeta4 are dependent on PAI-1. PMID- 23739237 TI - Post-transplant Pneumocystis jirovecii pneumonia--a re-emerged public health problem? AB - Pneumocystis jirovecii is a unicellular organism that in individuals with impaired immunity may cause pneumonia that can progress from minor illness to severe inflammatory pneumonia (PCP) with respiratory failure and death. Despite antimicrobial prophylaxis, which has reduced the incidence of PCP, clusters of late infections have been reported among kidney transplant recipients worldwide. A nosocomial PCP cluster was first recognized in 2010 at a Sydney hospital, but PCP clusters have since occurred in almost half of the renal transplant units on the eastern Australian seaboard, refocussing attention on optimal prophylaxis regimens and the likelihood of patient-to-patient transmission. A consensus meeting was conducted to derive the lessons from this experience for responding to PCP outbreaks. These included: (1) acting quickly--clusters of PCP in kidney transplant recipients with patient-to-patient transmission required transplant programs to act quickly to institute prophylactic and treatment measures; (2) instituting universal prophylaxis for all patients seen in the affected unit; (3) reducing patient-to-patient transmission via airborne droplets in the outpatient waiting areas; (4) examining the P. jirovecii genotypes. The meeting also considered recommendations for the duration of prophylaxis following de novo transplant and, for the individuals in whom long term prophylaxis is required, separating units with and without clusters of PCP. PMID- 23739239 TI - Pulmonary hypertension in patients with chronic and end-stage kidney disease. AB - Pulmonary hypertension is defined as a mean pulmonary artery pressure >=25 mm Hg and is a recently recognized complication of chronic kidney disease and end-stage renal disease. There is significant epidemiological overlap with kidney disease and the underlying causes of World Health Organization group 1-4 pulmonary hypertension (pulmonary arteriopathy, left heart disease, chronic pulmonary disease, and chronic thromboembolic disease, respectively). In addition, an entity of 'unexplained pulmonary hypertension,' group 5, in patients with chronic kidney disease and end-stage renal disease has emerged, with prevalence estimates of 30-50%. The pathogenesis of pulmonary hypertension in this population is due to alterations in endothelial function, increased cardiac output, and myocardial dysfunction leading to elevated left heart filling pressure, with recent data suggesting that left heart dysfunction may account for the vast majority of pulmonary hypertension in patients with kidney disease. Pulmonary hypertension is an independent predictor of increased mortality in patients on dialysis and those undergoing kidney transplantation. This review summarizes what is known about the epidemiology, pathogenesis, transplantation outcomes, mortality, and treatment of pulmonary hypertension in patients with chronic kidney disease and end-stage renal disease. PMID- 23739238 TI - Rituximab is a safe and effective long-term treatment for children with steroid and calcineurin inhibitor-dependent idiopathic nephrotic syndrome. AB - In children with idiopathic nephrotic syndrome, rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin inhibitors. Long-term effects including the number of repeated infusions to maintain remission are unknown. To test this, we treated 46 consecutive children with idiopathic nephrotic syndrome lasting for at least 1 year (mean 6.3 years), maintained in remission with oral prednisone and calcineurin inhibitors. They received 1-5 rituximab courses during a median follow-up of 3 years. Oral agents were tapered after each infusion, and completely withdrawn within 45 days. Rituximab was well tolerated. Six-month probabilities of remission were 48% after the first infusion and 37% after subsequent infusions. One- and 2-year-remission probabilities were, respectively, 20 and 10%. Median time intervals between complete oral-agent withdrawal and relapse were 5.6 and 8.5 months, respectively, following the first and subsequent courses. The time to reconstitution of CD20 cells correlated with the duration of remission, but was not associated with variation in FcyR, CD20, or SMPDL-3B polymorphisms. Podocyte Src phosphorylation was normal. Thus, rituximab can be safely and repeatedly used as a prednisone and calcineurin inhibitor-sparing therapy in a considerable proportion of children with dependent forms of idiopathic nephrotic syndrome. Further study is needed to identify patients who will benefit most from rituximab therapy. PMID- 23739240 TI - Investigations of the pediatric hospice care in Taiwan: 2005 to 2010. AB - BACKGROUND: The utilization of pediatric hospice care remains unclear in Taiwan. METHODS: Data were analyzed from the claims of hospice admissions in patients aged 18 years or younger using the National Health Insurance Research Database from 2005 to 2010. RESULTS: A total of 91 patients and 136 admissions were enrolled (male-female = 50:41; mean 11.6 years old). In all, 62 patients were admitted once, including 47 patients who died. All the patients had cancer, with brain cancer (40.7%) accounting the most . Among acute comorbidities, neurological complications (16.2%) were mostly accounted. Family physicians provided most (64.7%) of the hospice services. Hospice stay <=3 days correlated positively with death in hospices (odds ratio = 2.922, 95% confidence interval = 1.268-6.730). CONCLUSIONS: Pediatric hospice care revealed characteristics different from adults. Underlying late referrals were prevalent. There is space to promote the utilization of hospices for terminally ill pediatric patients. PMID- 23739241 TI - The human coronary collateral circulation: development and clinical importance. AB - Coronary collaterals are an alternative source of blood supply to myocardium jeopardized by ischaemia. In comparison with other species, the human coronary collateral circulation is very well developed. Among individuals without coronary artery disease (CAD), there are preformed collateral arteries preventing myocardial ischaemia during a brief vascular occlusion in 20-25%. Determinants of such anastomoses are low heart rate and the absence of systemic arterial hypertension. In patients with CAD, collateral arteries preventing myocardial ischaemia during a brief occlusion are present in every third individual. Collateral flow sufficient to prevent myocardial ischaemia during coronary occlusion amounts to one-fifth to one-fourth the normal flow through the open vessel. Myocardial infarct size, the most important prognostic determinant after such an event, is the product of coronary artery occlusion time, area at risk for infarction, and the inverse of collateral supply. Well-developed coronary collateral arteries in patients with CAD mitigate myocardial infarcts and improve survival. Approximately one-fifth of patients with CAD cannot be revascularized by percutaneous coronary intervention or coronary artery bypass grafting. Therapeutic promotion of collateral growth is a valuable treatment strategy in those patients. It should aim at growth of large conductive collateral arteries (arteriogenesis). Potential arteriogenic approaches include the treatment with granulocyte colony-stimulating factor, physical exercise training, and external counterpulsation. PMID- 23739242 TI - Management of refractory angina in the contemporary era. PMID- 23739243 TI - Sick leave and a smoking ban. PMID- 23739244 TI - Repeatability of click-evoked otoacoustic emission-based medial olivocochlear efferent assay. AB - OBJECTIVES: Otoacoustic emissions-based efferent assays are evolving to become a part of auditory diagnostics. The wide range of clinical applications, such as assessment of auditory neuropathy, auditory processing disorders, learning disability, monitoring success in auditory intervention and others illustrate the significance of this measurement. Defining the procedure's test-retest repeatability is of critical importance, to allow for distinction between measurement deviations and true physiological or pathological changes. The purpose of this study was to assess the repeatability of a click-evoked otoacoustic emission-based (CEOAE) test of the medial olivocochlear (MOC) reflex in normal-hearing (NH) adults. DESIGN: Test-retest data were collected from 35 NH young adults in two distinct test sessions separated by 1 to 4 days. CEOAEs were recorded without and with contralateral acoustic stimulation (CAS; 35 dB SL). Three indices of the MOC reflex were computed: CAS-induced (a) absolute changes in CEOAE amplitude, (b) normalized changes in CEOAE amplitude, and (c) changes in CEOAE input-output functions. Repeatability of these indices was assessed by a three-layered approach, which consisted of Bland-Altman plots, coefficient of reliability (Cronbach's alpha), and analysis of variance. RESULTS: Analyses indicated good repeatability of three CEOAE-based MOC reflex indices. A two-way analysis of variance of the indices demonstrated no significant difference between test and retest. Normalized index showed similar repeatability as other indices. CEOAE signal to noise ratio did not seem to vary between test sessions. Notably, CAS caused a decrease in CEOAE input-output functions slope in a majority of participants (n = 29). CONCLUSIONS: The present study is the first to elucidate the intrasubject variability of absolute and normalized indices of the MOC inhibitory effect. Although the measurements were conducted under realistic conditions resembling the clinical setting, repeatability was generally good in NH adults. For MOC reflex test, the signal to noise ratio of 6 dB for recording CEOAEs seems to be a recommendable criterion when considering practicability and measurement quality in clinical conditions. The present findings exemplify the suitability of CEOAE-based MOC assay as a monitoring tool of medial efferent status over time. The data are intended to assist clinicians and scientists alike in the accurate interpretation of CAS-induced CEOAE changes in the test-retest situation. PMID- 23739245 TI - Histiocytoid Sweet syndrome with haloed myeloid cells masquerading as a cryptococcal infection. AB - : Histiocytoid Sweet syndrome is a histopathologic variant of Sweet syndrome characterized by an infiltrate of mononuclear cells that have a histiocytic appearance and represent immature granulocytes. The primary histopathologic differential diagnosis for histiocytoid Sweet syndrome includes leukemia cutis and true histiocytic dermatoses. However, it does not usually include a deep mycotic infection. Herein, we describe a case of histiocytoid Sweet syndrome in a 75-year-old man in which histopathologic examination showed a dense dermal infiltrate composed of mature neutrophils and numerous yeast-like mononuclear cells with a surrounding halo, suspicious for cryptococcal organisms. Immunohistochemical and histochemical studies demonstrated expression of myeloperoxidase by the yeast-like forms and an absence of periodic acid-Schiff and mucicarmine staining. Microbiologic culture studies were negative for fungal organisms. The case met all the criteria for Sweet syndrome and, given the cytomorphology of the mononuclear cells with vesicular irregularly rounded nuclei and myeloperoxidase expression, the case was most consistent with histiocytoid Sweet syndrome. The perinuclear haloes in this case most likely represent cytoplasmic vacuolization of the immature, histiocytoid appearing neutrophils secondary to a novel nonapoptotic caspase-independent death pathway. This case highlights the histopathologic similarities that may be present between cryptococcal infection and histiocytoid Sweet syndrome, and the utility of immunohistochemical markers and histochemical staining to differentiate between the two entities. PMID- 23739246 TI - Low incidence of oncogenic EGFR, HRAS, and KRAS mutations in seborrheic keratosis. AB - Seborrheic keratosis (SK) represents a frequent epidermal skin tumor. Although lacking a malignant potential, these tumors reveal multiple oncogenic mutations. A previous study identified activating mutations in 89% of SK, particularly in FGFR3 and PIK3CA genes. The aim of this study was to identify further oncogenic mutations in human SK. Therefore, we screened for mutations in EGFR, FGFR2, PIK3R1, HRAS, KRAS, and NRAS genes using both Sanger sequencing of selected exons and a multiplex SNaPshot assay in 58 SK of 14 patients. We identified a somatic EGFR p.L858R mutation in 1 SK. Furthermore, the HRAS mutations p.G13R (2/58 SK) and p.Q61L (2/58 SK) were found. These mutations have not been described in human SK yet. In addition, 1 SK revealed the KRAS p.G12V mutation, which has already been reported in SK. No mutations were detected in FGFR2, PIK3R1, and NRAS genes. The results of this study suggest that activating mutations of EGFR, HRAS, and KRAS contribute to the pathogenesis of human SK, although at a lower frequency than FGFR3 and PIK3CA mutations. FGFR2, PIK3R1, and NRAS mutations obviously do not have a significant role in the development of SK. PMID- 23739247 TI - Unilateral annular elastolytic giant cell granuloma in a hemiplegic stroke patient. PMID- 23739248 TI - Giant keratoacanthoma: case report and review of the English literature. AB - The giant keratoacanthoma (KA) is a rare variant of KA with a maximum size exceeding 2-3 cm. Like other forms of KA, it has a tendency to spontaneously regress but can cause significant anatomic damage. A 69-year-old male presented to our hospital with a giant KA of the nose that showed complete pathological regression by the time of surgery. Pathology showed dermal scar with keratin granulomas extending through the nasal wall to the respiratory mucosa. A total of 57 similar cases from the English literature were reviewed for comparison. Few provide similar details of histological regression. Literature cases occurred predominately in males (74.1%) with a mean age of 59 years. Head tumors were most common (70.7%) and most were treated by surgery (34.5%) or a combination of surgery and radiotherapy (24.1%). Other treatment modalities reported include methotrexate, 5-fluorouracil, and interferon. PMID- 23739249 TI - Epithelioid leiomyosarcoma arising in the subcutis--a new case report of a rare variant. PMID- 23739250 TI - Craniomaxillofacial battle injuries: injury patterns, conventional treatment limitations and direction of future research. AB - This study analyses the US Army Joint Theatre Trauma Registry database for craniomaxillofacial (CMF) battle injuries (BI) experienced by US Service Members in Iraq/Afghanistan conflict to describe type, distribution and mechanism of injury. METHODS AND MATERIALS: Joint Theatre Trauma Registry was queried from 19 October 2001 to 12 December 2007 for CMF BI entered in the database using ICD-9 codes; the data was compiled for BI soldiers. RESULTS: We have identified 7770 BI. About 26% had CMF BI. There were 4783 CMF BI among the 2014 BI (2.4 injuries per soldier). Majority of CMF BI were male (98%). Average age was 26 years. CMF BI by branch of service was Army 72%, Marines 24%, Navy 2% and Air Force 1%. Penetrating soft tissue injuries and fractures were 58% and 27%, respectively; 76% of fractures were open and 24% of soft tissue injuries were noted as complicated. Frequency of facial fractures was mandible 36%, maxilla/zygoma 19%, nose 14%, and orbit 11%. Remaining 20% not otherwise specified. Primary mechanism of injury was explosive devices (84%). CONCLUSIONS: Twenty-six per cent of all BI were to CMF area. CMF BI account for a disproportionate number of injuries observed in Iraq and Afghanistan compared with the previous American Wars. Mechanism of CMF BI involves explosive devices 84%. PMID- 23739251 TI - Ectodermal dysplasia treated with one-step surgical rehabilitation: a case report. AB - Ectodermal dysplasia (ED) comprises a large heterogeneous group of inherited disorders that are characterized by primary defects in the skin, hair, nails, eccrine glands and teeth. The most characteristic findings are the reduced number of teeth. All rehabilitative programmes involve proper evaluation of skeletal relationships. Prosthetic-implantological treatment at the end of bony growth can be used. In this article a case of ED treated with Le Fort I for maxillary advancement, femur homografts, implants' insertion and immediate loading is described. In December 2007, a 38-year-old female was referred to the Maxillofacial Department of Galeazzi Hospital (Milan, Italy) who had a diagnosis of ED. Twelve implants were inserted in one-step surgical procedure. No implant was lost and all are stable. The occlusion is stable after 15 months of follow up. The results indicate that the one-step oral rehabilitation can be performed in adults who are affected by ED. Also, this significantly reduces the time of oral and facial rehabilitation. PMID- 23739252 TI - Effect of ageing towards location and visibility of mental foramen on panoramic radiographs. AB - Mental foramen is an opening of the mental canal onto the lateral surface of the mandible. In this pilot radiographical study, in Malay population the effects of ageing towards the location and visibility of the mental foramen were determined. Most of the mental foramina were found to be located inferior to the apex of the second premolar. Non-visibility of the foramen was greatly increased in patients aged 50 years and above (Pearson Chi-square; p = 0.00). This finding may provide a guide to dental surgeries in Malay patients of different age groups. PMID- 23739253 TI - Outpatient endoscopic removal of gutta-percha from the maxillary sinus using a sublabial antroscopy: a rare entity. AB - Any foreign body in the paranasal sinuses can cause chronic complications. It is therefore important to remove these foreign bodies meticulously. Various approaches are available to accomplish this. This article is a case report of a patient who had gutta-percha as a foreign body in left maxillary sinus, after a gutta-percha point had been used to trace a sinus to confirm that it was an oroantral fistula. Traditional surgical approaches to the maxillary sinus require invasive techniques, such as radical antrostomy and the Caldwell-Luc approach. These may result in further complications and morbidity. The gutta-percha point in this case report was removed endoscopically in an otolaryngology clinic with local anaesthesia using a sublabial antroscopy. There is only one case reported in the dental literature regarding the endoscopically-assisted technique for removal of displaced gutta-percha using the sublabial antroscopy approach (Yura S, Ohga N, Ooi K, Izumiyama Y. Procedure of endoscopic removal of a gutta-percha point in maxillary sinus mucosa by ultrathin arthroscope. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004;104:e58-60). PMID- 23739254 TI - Adenomatoid odontogenic tumour mimicking a periapical cyst in pregnant woman. AB - Adenomatoid odontogenic tumours (AOT) are uncommon odontogenic lesions characterized histologi-cally by duct-like structures derived from the epithelial component of the lesion and can be distinctly classified into follicular, extrafollicular and extraosseous variants (Neville BW, Damm DD, Allen CM, et al. Adenomatoid Odontogenic Tumor. A Text Book for Oral and Maxillofacial Pathology, 2(nd) edition, 621-3). Most of these tumours develop in the second or third decade of life and have a distinct predilection for women. The follicular variant accounts for 75% of reported cases (Curran AE, Miller EJ, Murrah VA. Adenomatoid odontogenic tumor presenting as periapical disease. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:557-60) and is associated with the crown of an impacted tooth, commonly the maxillary canine. We present a rare case of extrafollicular AOT mimicking a periapical cyst that originated in a woman in her first trimester of pregnancy and enlarged rapidly thereafter. The lesion was enucleated and sent for histopathology and immunohistochemistry, which revealed AOT with a cystic component with no dependence on oestrogen or progestrone for its growth. This case of AOT introduces us to the unique variation in its presentation and the difficulty in differentiation from periapical disease of inflammatory origin. PMID- 23739255 TI - Management of Severe Class II Malocclusion With Sequential Fixed Functional and Orthodontic Appliances: A Case for MOrthRCSEd Examination. AB - Fixed functional appliance is an effective way of treating skeletal Class II malocclusion in children and adolescents. The following case report documented a 13-year-old boy with 15 mm overjet treated by a phase I 12-month growth modification therapy using Herbst appliance with Hyrax palatal expander and high pull headgear in a stepwise mandibular advancement protocol followed by a phase II pre-adjusted edgewise appliance therapy. It is one of the cases submitted for the Membership of Orthodontics Examination of the Royal College of Surgeons of Edinburgh. PMID- 23739256 TI - Three-Dimensional Comparison in Palatal Forms Between Modified Presurgical Nasoalveolar Molding Plate and Hotz's Plate Applied to the Infants With Unilateral Cleft Lip and Palate. AB - The presurgical nasoalveolar molding plate appliance with stent (PNAM) extended from the palatal molding plate; to correct the nostril shape of infants with cleft lip and palate is well known. The PNAM appliance is based on the finding that a high degree of plasticity is maintained in the cartilage of infants during the first 6 weeks after birth. However, on the current PNAM protocol described by Grayson et al. the nasal stent is supposed to be an adjunct to the palatal molding plate after reducing the severity of the alveolar cleft width. We have used the modified Hotz's plate from the setup model and built up the nasal stent even before reducing the severity of the alveolar deformity. In this study we assess the effects of the modified Hotz's plate and the modified PNAM appliance for the alveolar and palatal form. The lateral deviation of the incisal point, the width of the palatal cleft, and the degree of curvature of the palatal vault were first evaluated on plaster models. The PNAM group is smaller on the lateral deviation of the incisal point than the modified Hotz's group. The decreased average width of the palatal cleft and curvature of the palate, was almost the same in both the modified Hotz's and PNAM groups. In comparison with the modified Hotz's plate, the modified PNAM appliance also improves the molding of the alveolar segments and reduces cleft width. PMID- 23739257 TI - The faces of war. PMID- 23739258 TI - Proteomic analysis of synovial fibroblast-like synoviocytes from rheumatoid arthritis. AB - OBJECTIVES: The purpose of this study was to identity protein expression patterns of fibroblast-like synoviocytes (FLSs) derived from the synovial tissue of patients with rheumatoid arthritis (RA) and osteoarthritis. METHODS: Two dimensional gel electrophoresis (2-DE) in combination with matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF-MS) was used to visualise and identify differential cellular protein expression profiles in FLSs between RA and control groups. Western-blot analysis was performed to further verify selected differentially-expressed proteins. RESULTS: A total of 1633 and 1603 protein spots were examined in synovial FLSs of RA patients and controls, respectively. Ninety-two spots in the RA group were statistically over- or under expressed compared with controls. Among them, 33 proteins over-expressed by more than 3-fold were then identified by MALDI-TOF-MS analysis. These proteins included enzymatic and structural proteins (e.g. PKM1/M2, alpha-enolase, ERp60, lamin-A/C), signal transduction proteins (e.g. annexin 11, peroxiredoxin 1, TrpRS), heat-shock/chaperone proteins (e.g. TCP-1, GRP75, HspB5, Bip) and some unknown protein species. Three proteins, namely alpha-enolase, GRP75 and PKM2, were verified by Western blot and the results were found to be consistent with proteomic analysis. CONCLUSIONS: The differentially expressed proteins identified in RA synovial FLSs might be candidate RA-associated proteins and may prove to be promising diagnostic indicators or new therapeutic targets for RA. PMID- 23739259 TI - Is there an association between cortical thickness, age of onset, and duration of illness in schizophrenia? AB - OBJECTIVE: Several studies have shown cortical volume loss in frontotemporal regions in schizophrenia patients, and it is known that these reductions may be associated with disease symptoms and cognitive deficits. The aim of this study was to investigate possible cortical thickness correlations in frontotemporal regions in relation to age at onset and duration of illness. METHODS: One hundred forty-eight schizophrenia patients (97 males; age and SD 36.30 +/- 10.06) and 87 (57 males; age and SD 36.48 +/- 10.10) age-matched healthy subjects underwent a brain MRI scan. Cortical segmentation and surface statistical analysis were performed using the FreeSurfer software package. Results were corrected for multiple comparisons using the Monte Carlo method considering a cluster-corrected Type I Error of 5%. RESULTS: Compared to controls, schizophrenia patients presented significant cortical thinning in the frontotemporal, parietal, and occipital cortices. No correlation between prefrontal cortex thickness and duration of illness in patients with schizophrenia or between frontotemporal cortical thickness and age at onset was found. However, a significant interaction between age and diagnosis was observed on frontal cortical thickness with patients presenting a thinner cortex than expected for age. CONCLUSION: Although there was no correlation between age of onset and duration of illness with brain volume, our findings suggest that there is an accelerated cortical loss in schizophrenia, thus reinforcing the progressive processes of the disease. PMID- 23739260 TI - Myelofibrosis, JAK2 inhibitors and erythropoiesis. PMID- 23739262 TI - Reliability of different radioisotopic techniques in diagnosing solitary hot spots in the spine of patients with malignant neoplasm. AB - INTRODUCTION: Early diagnosis of spinal metastases is of key importance in further therapeutic management. OBJECTIVES: The aim of the study was to assess the reliability of single-photon emission computed tomography (SPECT) or SPECT and computed tomography (SPECT/CT) in the diagnosis of solitary hot nodules in the spine identified by scintigraphy. PATIENTS AND METHODS: In this retrospective study, 70 patients with neoplastic disease and a solitary nodule detected in the spine were analyzed. Using a SPECT/CT gamma-camera, the type and site of the foci in the vertebra were analyzed. Bone scintigraphy, SPECT, and CT were performed. Reliability of the results was assessed depending on the applied technique. RESULTS: In malignant lesions, increased isotope uptake was observed in the vertebral body with the posterior arch (89%), the body and both arches (67%), and the body alone (14%). In benign lesions, increased uptake was observed in the body area or in the joint area. Using SPECT, 25 of 27 cases (93%) of foci were properly classified as malignant. Using SPECT/CT, malignant lesions were observed in 26 of 27 cases (96%). Using SPECT, 19 of 43 cases were identified as benign (44%), and using SPECT/CT, 31 of 43 were identified as benign (72%). The agreement between SPECT and SPECT/CT was higher for malignant lesions (89%) than for benign lesions (67%). The use of CT in SPECT/CT examinations allowed to change the SPECT diagnosis of malignant lesions to that of benign lesions in 50% of the cases. CONCLUSIONS: The criteria used in the diagnosis of solitary nodules in the spine direct the diagnosis largely towards noncancerous lesions. Reliability of positive assessment was significantly lower than that of negative one - 51% in SPECT and 68% in SPECT/CT. A hybrid SPECT/CT camera is more reliable than SPECT alone in the assessment of spinal lesions. PMID- 23739263 TI - Whole-chain traceability, is it possible to trace your hamburger to a particular steer, a U. S. perspective. AB - Traceability through the entire food supply chain from conception to consumption is a pressing need for the food industry, consumers and government regulators. A robust, whole-chain traceability system is needed that will effectively address food quality, food safety and food defense issues by providing real-time, transparent and reliable information from beef production through slaughter and distribution to the consumer. Traceability is an expanding part of the food safety continuum that minimizes the risk of foodborne diseases, assures quality and cold-chain integrity. Traceability can be a positive competitive marketing edge for beef producers who can verify specific quality attributes such as humane production or grass fed or Certified Organic. In this review we address the benefits as well as the remaining issues for whole-chain traceability in the beef industry, with particular focus on ground beef for the markets in the United States. PMID- 23739264 TI - Effect of sage (Salvia officinalis) on the oxidative stability of Chinese-style sausage during refrigerated storage. AB - The objective of this study was to assess the effect of sage, at levels of 0.05%, 0.1% and 0.15% (w/w), on the oxidative stability of Chinese-style sausage stored at 4 degrees C for 21 days. The results showed that inclusion of sage in sausages resulted in lower L* values (P<0.05) and higher a* values (P<0.05) compared to the control. During refrigerated storage, sausages containing sage showed significantly retarded increases in TBARS values, and in the formation of protein carbonyls (P<0.05), but showed accelerated losses of thiol groups (P<0.05). Addition of sage to the sausages at levels of 0.1% and 0.15% reduced textural deterioration during refrigerated storage (P<0.05). Sage used in this study had no negative effects on the sensory properties of sausages. PMID- 23739261 TI - Modelling the physics in the iterative reconstruction for transmission computed tomography. AB - There is an increasing interest in iterative reconstruction (IR) as a key tool to improve quality and increase applicability of x-ray CT imaging. IR has the ability to significantly reduce patient dose; it provides the flexibility to reconstruct images from arbitrary x-ray system geometries and allows one to include detailed models of photon transport and detection physics to accurately correct for a wide variety of image degrading effects. This paper reviews discretization issues and modelling of finite spatial resolution, Compton scatter in the scanned object, data noise and the energy spectrum. The widespread implementation of IR with a highly accurate model-based correction, however, still requires significant effort. In addition, new hardware will provide new opportunities and challenges to improve CT with new modelling. PMID- 23739265 TI - Effect of lipid type on growth performance, meat quality and the content of long chain n-3 fatty acids in pork meat. AB - The aim of the present study was to produce pork with enhanced nutritive value for humans, both in terms of fatty acid profile (mainly long chain n-3 fatty acids by feeding fish oil) and selenium. Forty-eight female pigs were allocated to one of six treatment groups: animal by-products and plant feedstuffs with tallow, plant feedstuffs with a blend of soybean oil and linseed oil with or without a supplement (CLA, selenium, vitamin E and vitamin C), plant feedstuffs with tallow and supplement, plant feedstuffs with fish oil and supplement. The diets containing the fish oil were fed up to either 49 days or 28 days before slaughter. The dietary treatments had no significant effects on growth performance, carcass characteristics and meat quality. When fish oil was included in the diet, higher levels of EPA, DPA and DHA were measured in the subcutaneous fat (up to 3.74%). PMID- 23739266 TI - Effectiveness of a polyamide film releasing lactic acid on the growth of E. coli O157:H7, Enterobacteriaceae and Total Aerobic Count on vacuum-packed beef. AB - The suitability of a polyamide 6 monolayer film containing lactic acid for use as an antimicrobial package for fresh beef cuts was studied. The release of lactic acid in an aqueous environment was immediate (within 1h) and was from approx. 55 MUg lactic acid/cm(2) film at 0-8 degrees C to approx. 67 MUg lactic acid/cm(2) film at 12-20 degrees C. Beef was contaminated with an Escherichia coli O157:H7 isolate with known minimum inhibitory concentration against lactic acid (0.09% v/v), then wrapped with the lactic-acid polyamide film and vacuum packaged. During storage at 12 degrees C, the numbers of E. coli were 1 log unit lower than that of a control (untreated polyamide film) and decreased by an additional 1 log during storage for 14 days. PMID- 23739267 TI - Deciphering the molecular rules governing synaptic targeting of the memory related protein Arc. AB - Neurons express new gene transcripts and proteins upon receiving synaptic inputs, and these events are essential for achieving proper neuronal wiring, adequate synaptic plasticity, and updatable memory. However, the biological impact of new gene expression on input-specific synaptic potentiation remains largely elusive, in part because the cell biological and biochemical mechanisms for synaptic targeting of newly synthesized proteins has remained obscure. A new study investigating the targeting of the memory related protein Arc from the soma to the synapses teases apart a novel "inverse" synaptic tagging mechanism that enables Arc to specifically target the un-potentiated synapses, thereby helping to maintain the contrast of synaptic weight between strengthened and weak synapses. PMID- 23739268 TI - The moron comes of age. AB - Prophage-encoded genes can provide a variety of benefits for their bacterial hosts. These beneficial genes are often contained within "moron" elements. Morons, thus termed as the insertion of the DNA encoding them adds "more on" the genome in which they are found, are independent transcriptional units disseminated among phage genomes through horizontal gene transfer. Morons have been identified in the majority of phage genomes and they have been found to play diverse roles in bacterial physiology. At present, we are only beginning to ascribe functions to the many proteins encoded within these ubiquitous genetic elements. Recently, we discovered that the first described moron-encoded protein, gp15 of phage HK97, is expressed from the HK97 prophage and functions as a superinfection exclusion protein, protecting its host from genome injection by other phages. This work and the growing body of data pertaining to other morons challenges the traditional view of phages as purely parasites of bacteria and emphasizes the symbiotic relationship between bacteria and prophages. PMID- 23739270 TI - Acute achilles tendinopathy diagnosed with ultrasound. PMID- 23739272 TI - Re: Simultaneous and spontaneous bilateral quadriceps tendons rupture. PMID- 23739271 TI - Characteristics of dysphagia in children with cerebral palsy, related to gross motor function. AB - OBJECTIVE: The aim of this study was to report the characteristics of dysphagia in children with cerebral palsy (CP), related to gross motor function. DESIGN: Videofluoroscopic swallow study was performed in 29 children with CP, according to the manual of Logemann. Five questions about oromotor dysfunction were answered. Gross motor function level was classified by the Gross Motor Function Classification System Expanded and Revised. RESULTS: The results of the videofluoroscopic swallowing studies showed that reduced lip closure, inadequate bolus formation, residue in the oral cavity, delayed triggering of pharyngeal swallow, reduced larynx elevation, coating on the pharyngeal wall, delayed pharyngeal transit time, multiple swallow, and aspiration were significantly more common in the severe group (Gross Motor Function Classification System Expanded and Revised IV or V). As for aspiration, 50% of the children with severe CP had problems, but only 14.3% of them with moderate (Gross Motor Function Classification System Expanded and Revised III) CP and none of them with mild CP had abnormalities. In addition, five of the seven aspiration cases occurred silently. CONCLUSIONS: This study shows that dysphagia is closely related to gross motor function in children with CP. Silent aspiration was observed in the moderate to severe CP groups. Aspiration is an important cause of medical problems such as acute and chronic lung disease, and associated respiratory complications contribute significantly in increasing morbidity and mortality in these patient groups. Therefore, the authors suggest that early dysphagia evaluation including videofluoroscopic swallow study is necessary in managing feeding problems and may prevent chronic aspiration, malnutrition, and infections. PMID- 23739273 TI - Isolated deltoid atrophy. PMID- 23739274 TI - Day vs. day-night use of ankle-foot orthoses in young children with spastic diplegia: a randomized controlled study. AB - OBJECTIVE: The aim of this study was to compare the effectiveness of treatment with hinged ankle-foot orthoses (AFOs) during the day vs. during both the day and the night in young ambulant children with spastic diplegia. DESIGN: In this prospective randomized controlled trial, 112 ambulatory children (70 boys and 42 girls; mean age, 2 yrs 6.93 mos; range, 1 yr 1 mo to 4 yrs 0 mo) with spastic diplegia participated. Forty-eight were classified at level I of the Gross Motor Function Classification System; the remaining 64 were at level II. Using stratified randomization, all children were assigned to either the day AFO wearing group (n = 56, wearing AFOs all day) or the day-night AFO-wearing group (n = 56, wearing AFOs all day and all night). The two groups underwent conventional rehabilitative treatments five times a week for 8 wks. The primary outcomes measured were passive ankle dorsiflexion angle and sections D and E of the 66-item Gross Motor Function Measure; the root mean square of surface electromyography in the ventral and dorsal lower limb muscles was compared in a subgroup (ten from each group). RESULTS: Seven children did not complete the full intervention: three in the day AFO-wearing group and four in the day-night AFO wearing group. Significant baseline-postintervention improvements were found for passive ankle dorsiflexion angle and the 66-item Gross Motor Function Measure in both groups (P < 0.05). On the basis of the score changes, there was no significant difference between these two groups with respect to passive ankle dorsiflexion angle; however, the improvements in the 66-item Gross Motor Function Measure were significantly better in the day AFO-wearing group (P < 0.01). A significant root mean square decrease in gastrocnemius (P < 0.05) was present after the intervention in the day AFO-wearing group, whereas the muscles affected in the day-night AFO-wearing group were the gastrocnemius (P < 0.05) and the tibialis anterior (P < 0.001). CONCLUSIONS: The results demonstrate that the daytime use of AFOs was more effective in improving Gross Motor Function Measure scores than the day-night use. In addition, the prolonged wearing of AFOs may influence muscle activity, which should be monitored in the clinic. PMID- 23739275 TI - Minimizing preoperative and postoperative limping in patients after total hip arthroplasty: relevance of hip muscle strength and endurance. AB - OBJECTIVE: The aim of this study was to test the hypothesis that hip muscle function (strength and endurance) improves after total hip arthroplasty and is important for minimizing limping gait. DESIGN: Fifty-two patients who underwent total hip arthroplasty were assessed before and 6 mos after receiving a unilateral total hip endoprosthesis (Adaptiva stem with a Harris-Galante acetabular component). Severity of limping was assessed using a 4-point ordinal scale. Pain was assessed using a standardized ordinal scale. Eccentric, concentric, and isometric muscle strength and endurance of the hip extensors, flexors, adductors, and abductors were measured using a dynamometer. RESULTS: Postoperative limping severity and pain were significantly lower and postoperative muscle strength and endurance were significantly higher than the preoperative values (P < 0.05). The association between impaired muscle strength and endurance and limping severity was stronger postoperatively than preoperatively. This association was stronger for the hip extensor and flexor muscles than for the hip adductor and abductor muscles. Pain level was not associated with postoperative limping severity. CONCLUSIONS: Hip extensor and flexor muscle strength and endurance seem to be relevant for minimizing postoperative limping in patients after total hip arthroplasty. Rehabilitation programs should include exercises aimed at improving hip extensor and flexor strength and endurance to improve gait function. PMID- 23739276 TI - The utility of musculoskeletal ultrasound in rehabilitation settings. AB - Aside from its prompt use in musculoskeletal injuries (sports lesions, degenerative/inflammatory joint disorders, and peripheral nerve pathologies), ultrasonographic imaging can be used quite conveniently in various types of rehabilitation conditions as well. If used in a rehabilitation setting, ultrasound can significantly contribute to the diagnostic/therapeutic algorithm of rehabilitation patients. Accordingly, in this article, the authors focus on the diagnostic/interventional utility of ultrasound particularly for shoulder problems, overuse injuries of wheelchair users, heterotopic ossification, amputee follow-up, peripheral nerve and botulinum toxin injections, and diaphragm imaging/electromyography. PMID- 23739277 TI - Improving treadmill performance in patients with lumbar stenosis: evaluation of a custom angle load reduction device. AB - OBJECTIVE: The aim of this study was to evaluate a custom angle load reduction rolling walker to determine the relationship between flexion and load reduction on walking performance in patients with lumbar spinal stenosis.The hypothesis was that walking performance in patients with lumbar spinal stenosis would be significantly improved using the Oliver Static Measuring Apparatus device compared with unaided treadmill walking. DESIGN: Fifteen patients with symptomatic neurogenic intermittent claudication caused by lumbar spinal stenosis were recruited at a Veterans Affairs Medical Center. This study used a cross sectional design with two random-order treadmill conditions: (1) spinal flexion and unloading and (2) level walking. Primary outcome measures included initiation time of first symptoms, total walking time, spinal flexion angle, and unloading force. Secondary measures included baseline pain, fatigue, and disability severity. RESULTS: The participants' initiation time of symptoms and total walking time were significantly greater with the use of the Oliver Static Measuring Apparatus compared with the unaided walking trial. The participants with increased baseline pain, fatigue, and disability severity had decreased walking performance for the unaided condition but not for the Oliver Static Measuring Apparatus condition. CONCLUSIONS: The results show that spinal flexion is important for pain reduction in lumbar spinal stenosis. The Oliver Static Measuring Apparatus device used in this study was shown to be effective and immediate in significantly increasing total walking time and prolonging the onset of neurogenic intermittent claudication symptoms while ambulating. PMID- 23739278 TI - Independent cough flow augmentation by glossopharyngeal breathing plus table thrust in muscular dystrophy. AB - OBJECTIVE: The purpose of the present study was to compare the unassisted cough peak flow (CPF) of patients affected by muscular dystrophy with CPF augmented by various techniques, including maximal depth glossopharyngeal breathing (GPB) combined with a subsequent self-induced thoracic or abdominal thrust. DESIGN: All of the motorized wheelchair-dependent patients with muscular dystrophy who had previously mastered GPB were trained at home to increase their cough efficacy. This training involved maneuvering their wheelchair against the edge of a specially built table to autonomously produce a thoracic and/or abdominal thrust timed to the opening of the glottis for an independently assisted cough. Both unassisted and variously assisted CPFs were compared. RESULTS: The 18 patients (17 men/1 woman) with muscular dystrophy, aged 21.1 +/- 5.4 yrs, achieved variously assisted CPFs that were significantly higher than the spontaneous CPF (P < 0.001), with assisted CPFs but not unassisted CPFs that significantly exceeded a reported efficacious cough threshold value of 160 liters/min (P < 0.001). Moreover, increases in the CPFs by personal assistance including air stacking by manual resuscitator and thoracoabdominal thrust (326.4 +/- 79.5 liters/min) or by GPB and thoracoabdominal thrust (326.4 +/- 87.5 liters/min) were not significantly different (P = 0.07) from the CPFs independently attained by GPB plus independently maneuvering a wheelchair for a table thrust (310.3 +/- 74.7 liters/min). CONCLUSIONS: The independently assisted (GPB plus table thrust) CPF was comparable to the CPFs that required personal assistance for air stacking and abdominal thrusts. Therefore, for patients with muscular dystrophy, this physical medicine technique and cough-assisted techniques that require personal intervention are strongly recommended. PMID- 23739279 TI - Premedication with N-acetylcysteine and simethicone improves mucosal visualization during gastroscopy: a randomized, controlled, endoscopist-blinded study. AB - OBJECTIVES: Diagnostic gastroscopy provides a unique opportunity to diagnose early oesophagogastric neoplasia; however, intraluminal mucus and bile can obscure mucosal visualization. The aim of this study was to determine whether the use of a premedication solution containing the mucolytic agent N-acetylcysteine and the surfactant simethicone improves mucosal visualization within a UK diagnostic gastroscopy service. MATERIALS AND METHODS: A total of 75 consecutive patients were recruited from a single (S.J.) endoscopist's diagnostic gastroscopy list. They were randomized into three treatment groups: (a) standard control=clear fluids only for 6 h, nil by mouth for 2 h; (b) water control=standard control+100 ml sterile water (given 20 min before gastroscopy); and (c) solution=standard control+100 ml investigated solution (20 min before gastroscopy). The endoscopist was blinded to patient preparation. Inadequate mucosal visualization was defined as fluid/mucus during gastroscopy that could not be suctioned and required flushing with water. The volume of flush, the site at which it was used and the total procedure times were recorded. RESULTS: All three groups showed no statistical difference for age, sex ratio, procedure priority or indication. The mean volume of flush required to obtain clear mucosa was significantly less in the solution group compared with the other groups. The mean overall procedure time was also less in the solution group compared with the other groups. DISCUSSION: Premedication with N-acetylcysteine and simethicone markedly improves mucosal visibility during gastroscopy. It also reduces the time taken for the procedure. This low-cost and well-tolerated intervention may improve detection of early neoplasia. PMID- 23739280 TI - Association study of the platelet collagen receptor glycoprotein VI gene with rheumatoid arthritis. AB - OBJECTIVES: Beyond their role in haemostasis, platelets can actively contribute to immunity. The activation of the platelet collagen receptor glycoprotein VI (GPVI) promotes the release of small extracellular vesicles called microparticles. These microparticles are found in the joint bathing fluid of patients with rheumatoid arthritis (RA) and are thought to amplify inflammation. The gene coding for GPVI is localised on chromosome 19q13.4 and contains different single nucleotide polymorphisms (SNPs). Five non-synonymous SNPs define the major and minor haplotypes of GPVI. The minor haplotype is associated with higher risk of cardiovascular incidents. In this study, we examined whether this minor haplotype is also associated with RA. METHODS: Allelic discrimination of the SNPs reported to define these haplotypes encoding SKTQH and PEALN protein isoforms, ie rs1613662, rs1654416, rs2304167, rs1654413 and rs1671152, was performed in 399 RA patients and their two parents, all of Western European ethnicity. Statistical analysis relied on the transmission disequilibrium test by the use of the FBAT programme. Haplotypes were also estimated by the FBAT programme. RESULTS: We observed no statistically significant transmission disequilibrium for the SNPs tested. The major haplotype TAAC, which encodes the SKTQH isoform, was identified in 78% of our cohort individuals, and the CGGA haplotype which encodes the PEALN isoform was identified in 8% of our individuals. We observed no association of these haplotypes of the GPVI gene with RA. CONCLUSIONS: This demonstrates that the SNPs tested within the GPVI gene are not associated with RA susceptibility and/or severity, suggesting that platelet GPVI may contribute to arthritis independently of its gene polymorphism. PMID- 23739281 TI - A rational approach to dental management of patients on bisphosphonates. AB - There has been a lot of focus on osteonecrosis of the jaws associated with the usage of bisphosphonates both in dental and medical literature in recent years. However, the exact pathogenesis of bisphosphonate-related osteonecrosis of the jaws remains unclear. Against the background of emerging evidence of an evolving condition, it is not surprising that there is a lack of robust evidence-based recommendations on dental treatment of patients on bisphosphonates. This paper seeks to provide a rational approach to the dental management of patients on bisphosphonates based on current literature. PMID- 23739282 TI - A review of the uses of fluoride and outcomes of dental caries control in singapore. AB - In 1958, Singapore was the first country in Asia to implement a community water fluoridation program covering 100% of its population. There were no reports of anti-fluoridation activities or calls for referenda then; and at present, there is only mild opposition to water fluoridation. The water was initially fluoridated at 0.7 ppm but was gradually adjusted downwards to 0.6 ppm in January 1992, with a further reduction to 0.5 ppm in January 2008 where it has since remained unchanged. Fluoride varnishes and gels are also available for use by the professional for judicious application in individuals who are at high-risk of dental caries. In addition, fluoridated dentifrices and mouth rinses are also readily available over the counter for home use. In addition to the use of fluorides, the following factors also contribute to the high level of oral health in Singapore: (i) a highly educated populace; (ii) public health education to increase awareness and literacy is routinely carried out by the Health Promotion Board; (iii) the School Dental Service provides 'free' dental care to school children up to 18 years of age; and (iv) primary dental care is also readily accessible by the general public by an extensive network of private and public sector dental clinics. PMID- 23739283 TI - The accuracy of demirjian method in dental age estimation of malay children. AB - This study is aimed to evaluate the accuracy of Demirjian method in estimating the chronological age of male and female Kelantanese Malay children between 6 and 16 years of age and to establish a new dental age (DA) curve if the Demirjian method was not found to be accurate. About 905 panoramic radiographs of healthy Malay children between 6 and 16 years of age were collected from the radiographic unit in the Hospital Universiti Sains Malaysia (HUSM) and the orthodontic clinic in Hospital Kota Bharu (HKB). Children who had any disease affecting the dental development, or have agenesis in the lower arch and poor quality radiographic images were excluded. The results showed that Demirjian method overestimated the chronological age (CA) by 1.23 years for boys and 1.20 years for girls and it was less accurate for the Kelantanese Malay children. Thus new standard curve were produced and tested on external samples. Results showed that the mean difference between the chronological age and DA is about 0.17 years for boys and 0.11 years for girls. DA was more advanced in the Kelantanese Malay boys and girls as compared to French-Canadian children in all age groups. It is concluded that the Demirjian method tends to be less accurate in estimating the chronological age in Malay children. The new curve that was produced is more applicable to the Kelantanese Malay children. PMID- 23739284 TI - Prosthodontic management of an edentulous patient with an acquired maxillary defect reconstructed with an abdominus free flap: a clinical report. AB - Functional rehabilitation of fully edentulous maxillary defects is always regarded as a prosthodontic challenge. Surgical augmentation does not always offer value addition in the functional treatment outcome. This article describes the maxillofacial prosthodontic treatment of an edentulous patient who received an abdominus microvascular free flap surgical augmentation of a large acquired maxillary defect. PMID- 23739285 TI - Maxillofacial prosthetic management of an auricular defect for a young patient with hemifacial microsomia: a clinical report. AB - Facial anomalies in hemifacial microsomia patients may have significant psychosocial impact even from a very young age. The management and fabrication of an auricular prosthesis replacement supported by endosseous craniofacial implants for a young patient with Goldenhar-Gorlin Syndrome has been reported. It is beneficial for the defects of a hemifacial microsomia patient to be managed as early as possible, consistent with the patient's ability to manage the prosthesis. PMID- 23739286 TI - A land untouched by dentistry - singapore brings dental care to afghanistan. AB - In 2007, the Singapore Armed Forces deployed a Dental Project Team (DPT) to the capital city of the Bamiyan Province in Afghanistan. The team set up the province's first modern dental facility. Besides providing primary dental care to the 60,000 population there, the Singaporeans also trained and prepared a team of Afghan dentist and dental assistants. The Afghan dental team took over the dental clinic and continued to provide care when it was time for the DPT to depart for home. Braving challenging security and austere living conditions, the DPT completed its mission successfully. PMID- 23739287 TI - Letter from the editor. PMID- 23739288 TI - Granulocyte colony-stimulating factor receptor T595I (T618I) mutation confers ligand independence and enhanced signaling. PMID- 23739289 TI - Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. AB - Under the auspices of an International Working Group, seven centers submitted diagnostic and follow-up information on 1545 patients with World Health Organization-defined polycythemia vera (PV). At diagnosis, median age was 61 years (51% females); thrombocytosis and venous thrombosis were more frequent in women and arterial thrombosis and abnormal karyotype in men. Considering patients from the center with the most mature follow-up information (n=337 with 44% of patients followed to death), median survival (14.1 years) was significantly worse than that of the age- and sex-matched US population (P<0.001). In multivariable analysis, survival for the entire study cohort (n=1545) was adversely affected by older age, leukocytosis, venous thrombosis and abnormal karyotype; a prognostic model that included the first three parameters delineated risk groups with median survivals of 10.9-27.8 years (hazard ratio (HR), 10.7; 95% confidence interval (CI): 7.7-15.0). Pruritus was identified as a favorable risk factor for survival. Cumulative hazard of leukemic transformation, with death as a competing risk, was 2.3% at 10 years and 5.5% at 15 years; risk factors included older age, abnormal karyotype and leukocytes >=15 * 10(9)/l. Leukemic transformation was associated with treatment exposure to pipobroman or P32/chlorambucil. We found no association between leukemic transformation and hydroxyurea or busulfan use. PMID- 23739290 TI - Monitoring salt and iodine intakes in Dutch adults between 2006 and 2010 using 24 h urinary sodium and iodine excretions. AB - OBJECTIVE: To monitor the effectiveness of salt-reduction initiatives in processed foods and changes in Dutch iodine policy on Na and iodine intakes in Dutch adults between 2006 and 2010. DESIGN: Two cross-sectional studies among adults, conducted in 2006 and 2010, using identical protocols. Participants collected single 24 h urine samples and completed two short questionnaires on food consumption and urine collection procedures. Daily intakes of salt, iodine, K and Na:K were estimated, based on the analysis of Na, K and iodine excreted in urine. SETTING: Doetinchem, the Netherlands. SUBJECTS: Men and women aged 19 to 70 years were recruited through random sampling of the Doetinchem population and among participants of the Doetinchem Cohort Study (2006: n 317, mean age 48.9 years, 43 % men; 2010: n 342, mean age 46.2 years, 45 % men). RESULTS: While median iodine intake was lower in 2010 (179 MUg/d) compared with 2006 (257 MUg/d; P < 0.0001), no difference in median salt intake was observed (8.7 g/d in 2006 v. 8.5 g/d in 2010, P = 0.70). In 2006, median K intake was 2.6 g/d v. 2.8 g/d in 2010 (P < 0.01). In this 4-year period, median Na:K improved from 2.4 in 2006 to 2.2 in 2010 (P < 0.001). CONCLUSIONS: Despite initiatives to lower salt in processed foods, dietary salt intake in this population remains well above the recommended intake of 6 g/d. Iodine intake is still adequate, although a decline was observed between 2006 and 2010. This reduction is probably due to changes in iodine policy. PMID- 23739291 TI - Immunoglobulin G4-related sclerosing disease invading the trachea and superior vena cava in mediastinum. AB - It is well known that immunoglobulin G4 (IgG4)-related sclerosing disease usually occurs in the pancreas, bile duct and gall bladder, but not in the mediastinum, trachea or superior vena cava (SVC). In this case, a patient underwent mediastinal mass excision and trachea resection and repair for a mediastinal and intratracheal mass 15 years ago. This mass was diagnosed postoperatively as an inflammatory pseudotumour (plasma cell granuloma). Subsequently, a mass was found to have recurred in the SVC. We performed a mass excision and innominate vein to the right atrium auricle bypass operation. The mass was diagnosed as IgG4-related sclerosing disease. This patient is now disease and recurrence free. PMID- 23739292 TI - Which repair technique for which aortic root anatomo-pathology? Still a lack of evidence. PMID- 23739293 TI - Durability of epicardial ventricular restoration without ventriculotomy. AB - OBJECTIVES: We previously presented early results employing a technique designed for beating heart, ventricular volume reduction (surgical ventricular restoration, SVR) without ventriculotomy for patients with antero-septal scar and dilated ischaemic cardiomyopathy. Significant volume reduction and clinical improvement were achieved. We now report durability in the first 11 patients available for assessment at 6 and 12 months after operation. METHODS: After the Ethics Committee approval, 31 symptomatic patients with left ventricular (LV) dilatation and antero-septal scars underwent operation. The scarred lateral LV wall was apposed to the septal scar with serial paired anchors placed through epicardial transmural catheters, excluding non-viable portions of the chamber. Patients were followed at 1, 3, 6 and 12 months postoperatively with echocardiograms. Data are presented for the first 11 patients for whom core lab echocardiographic data were available at 12 months of follow-up. RESULTS: LV end systolic index (LVESVI), percent decreases from baseline at 6 and 12 months were 36.2 +/- 18.3 (P < 0.001) and 39.6 +/- 14.8 (P < 0.001). LV end-diastolic volume index (LVEDVI) percent decreases from baseline at 6 and 12 months were 28.6 +/- 18.8 (P < 0.001) at 6 months and 32.2 +/- 14.9 (P < 0.005) at 12 months. All comparisons were by one-tailed t-tests using paired data. CONCLUSIONS: These results demonstrate the persistence of volume reduction employing a technique designed to be used on beating hearts without ventriculotomy or cardiopulmonary bypass. The extent of volume reduction was consistent with results of conventional SVR in experienced centres. These early data validate the further development of technical iterations leading to a clinical study employing a closed chest endovascular platform. PMID- 23739294 TI - A comparison of maternal serum levels of endothelial nitric oxide synthase, asymmetric dimethylarginine, and homocysteine in normal and preeclamptic pregnancies. AB - BACKGROUND: The aim of this study was to determine the maternal serum concentrations of eNOS, ADMA, and homocysteine in preeclamptic pregnancies. MATERIAL AND METHODS: The study was carried out on 62 patients with pregnancy complicated by early onset and 53 patients with late onset preeclampsia. The control group consisted of 65 healthy normotensive pregnant patients. The serum eNOS, ADMA and homocysteine concentrations were determined using ELISA assays. RESULTS: Our study revealed elevated levels of homocysteine and ADMA in the serum of women with preeclampsia. The highest levels were observed in patients with early onset preeclampsia, but the differences between both groups of preeclamptic patients with early and late onset of preeclampsia were not statistically significant. Both groups of preeclamptic women had slightly lower levels of maternal serum endothelial nitric oxide synthase than in normotensive pregnant women, but these differences were not statistically significant. CONCLUSIONS: The higher levels of homocysteine and ADMA observed in patients with early onset preeclampsia may suggest that higher levels of maternal serum homocysteine and ADMA correlate with the severity, and may determine the earlier clinical onset of the disease. The elevated levels of ADMA and the unchanged levels of eNOS in preeclamptic pregnancies suggest that NO deficiency in this pregnancy disorder results not from a reduced level or activity of eNOS, but from elevated levels of ADMA, an endogenous eNOS inhibitor. The lowering of increased levels of homocysteine and ADMA may be helpful in therapy of vascular disturbances occurring in preeclampsia. PMID- 23739295 TI - Placenta-derived gp96 as a multivalent prophylactic cancer vaccine. AB - A major challenge for designing prophylactic cancer vaccines is to define immunogenic and safe cancer antigens. Given the striking similarity of antigen expression patterns between cancer and embryonic tissues, we defined a prototype strategy of using placenta-derived heat shock protein gp96, which induces prophylactic anti-tumor T cell responses. Immunization with placental gp96 provided partial protection and long-term (at least 3 months) anti-tumor immunity against growth of transplantable melanoma or breast tumors in mice, elicited total protection against 7, 12-dimethylbenz(a)-anthracene (DMBA)-induced mammary tumors in rats, and significantly reduced the occurrence and growth of autochthonous breast tumors in HER2 transgenic mice. Placental gp96 activated HER2- and MUC1-specific T cell responses through binding to tumor-associated antigens. Our results reveal the novel immunogenicity of placental gp96 and its potential use as a multivalent cancer vaccine. PMID- 23739297 TI - Factors affecting dementia screening by general practitioners in community dwelling elderly populations: a large cross-sectional study in 2 areas of France. AB - In patients aged 75 years and above, dementia is associated with increased expenditure and high morbimortality. Although the incidence of dementia is well known, it is often underrecognized in primary care. We conducted a cross sectional study in 2 areas in the southeast of France to identify the factors affecting dementia-screening implementation by the French general practitioners (GPs). In May 2008, an anonymized survey was sent by e-mail and/or post to all GPs with a large clinic practice. Two months later, reminder letters were sent. Overall, 493 GPs answered (26.8%) to self-reported behavior. Of these, 73.2% felt that annual screening was useful, although only 24.5% implemented it each year and 17.5% implemented it every 2 to 5 years. Factors that favorably influenced screening practices were: the older age of the GPs; belief in the usefulness of annual dementia screening; increased frequency of follow-up visits by elderly patients; and the proportion of dementia in the GP's practice. The main barrier to annual screening was the social problems encountered in the medical care of 75 year-old patients. Regardless of the differences in European national health policies or health care systems, all GPs encounter the same difficulties when dealing with elderly dementia patients. PMID- 23739296 TI - Physical activity and cognitive trajectories in cognitively normal adults: the adult children study. AB - Increased physical activity may protect against cognitive decline, the primary symptom of Alzheimer disease. In this study, we examined the relationship between physical activity and trajectories of cognitive functioning over serial assessments. Cognitively normal (Clinical Dementia Rating 0) middle-aged and older adults (N=173; mean age, 60.7 +/- 7.8 y) completed a self-report measure of physical activity and a battery of standard neuropsychological tests assessing processing speed, attention, executive functioning, and verbal memory. At baseline, individuals with higher physical activity levels performed better on tests of episodic memory and visuospatial functioning. Over subsequent follow-up visits, higher physical activity was associated with small performance gains on executive functioning and working memory tasks in participants with one or more copies of the apolipoprotein epsilon4 allele (APOE4). In APOE4 noncarriers, slopes of cognitive performance over time were not related to baseline physical activity. Our results suggest that cognitively normal older adults who report higher levels of physical activity may have slightly better cognitive performance, but the potential cognitive benefits of higher levels of physical activity over time may be most evident in individuals at genetic risk for Alzheimer disease. PMID- 23739298 TI - Rapid screening and structural elucidation of a novel sibutramine analogue in a weight loss supplement: 11-desisobutyl-11-benzylsibutramine. AB - A novel analogue of sibutramine, 11-desisobutyl-11-benzylsibutramine, has been discovered. During routine ion mobility spectrometry (IMS) screening of a weight loss supplement collected at an US FDA import operation facility an unknown peak was observed. Further analysis of the supplement by liquid chromatography-mass spectrometry (LC-MS) and high resolution mass spectrometry revealed an unknown peak with a relative retention time of 1.04 with respect to sibutramine and a predicted formula of C20H24NCl. In order to elucidate the analogue's structure, it was isolated from the supplement and characterized by tandem mass spectrometry and nuclear magnetic resonance (NMR), which revealed the analogue possessed a benzyl moiety at the 11 position in place of the isobutyl group associated with sibutramine. PMID- 23739299 TI - An on-bacterium flow cytometric immunoassay for protein quantification. AB - The polystyrene bead-based flow cytometric immunoassay has been widely reported. However, the preparation of functional polystyrene bead is still inconvenient. This study describes a simple and easy on-bacterium flow cytometric immunoassay for protein quantification, in which Staphylococcus aureus (SAC) is used as an antibody-antigen carrier to replace the polystyrene bead. The SAC beads were prepared by carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling, paraformaldehyde fixation and antibody binding. Carcinoembryonic antigen (CEA) and cytokeratin-19 fragment (CYFRA 21-1) proteins were used as models in the test system. Using prepared SAC beads, biotinylated proteins, and streptavidin phycoerythrin (SA-PE), the on-bacterium flow cytometric immunoassay was validated by quantifying CEA and CYFRA 21-1 in sample. Obtained data demonstrated a concordant result between the logarithm of the protein concentration and the logarithm of the PE mean fluorescence intensity (MFI). The limit of detection (LOD) in this immunoassay was at least 0.25 ng/ml. Precision and accuracy assessments appeared that either the relative standard deviation (R.S.D.) or the relative error (R.E.) was <10%. The comparison between this immunoassay and a polystyrene bead-based flow cytometric immunoassay showed a correlation coefficient of 0.998 for serum CEA or 0.996 for serum CYFRA 21-1. In conclusion, the on-bacterium flow cytometric immunoassay may be of use in the quantification of serum protein. PMID- 23739300 TI - Keeping your curriculum vitae up to date. PMID- 23739306 TI - Orville A. Levander, PhD: 1940-2011. PMID- 23739307 TI - Age, dietary fiber, breath methane, and fecal short chain fatty acids are interrelated in Archaea-positive humans. AB - Recent attention has focused on the significance of colonic Archaea in human health and energy metabolism. The main objectives of this study were to determine the associations among the number of fecal Archaea, body mass index (BMI), fecal short chain fatty acid (SCFA) concentrations, and dietary intakes of healthy humans. We collected demographic information, 3-d diet records, and breath and fecal samples from 95 healthy participants who were divided into 2 groups: detectable Archaea (>10(6) copies/g; Arch+ve) and undetectable Archaea. Dietary intakes, BMI, and fecal SCFAs were similar in both groups. The mean number of Archaea 16S rRNA gene copies detected in Arch+ve participants' feces was 8.9 +/- 0.2 log/g wet weight. In Arch+ve participants, there were positive correlations between breath methane and age (r = 0.52; P = 0.001), total dietary fiber (TDF) intake (r = 0.57; P = 0.0003), and log number of fecal Archaea 16S rRNA gene copies (r = 0.35; P = 0.03). In the Arch+ve group, negative correlations were observed between TDF/1000 kcal and fecal total SCFA (r = -0.46; P <= 0.01) and between breath methane and fecal total SCFA (r = -0.42; P = 0.01). Principal component analysis identified a distinct Archaea factor with positive loadings of age, breath methane, TDF, TDF/1000 kcal, and number of log Archaea 16S rRNA gene copies. The results suggest that colonic Archaea is not associated with obesity in healthy humans. The presence of Archaea in humans may influence colonic fermentation by altering SCFA metabolism and fecal SCFA profile. PMID- 23739308 TI - Fruit and vegetable intakes are associated with lower risk of bladder cancer among women in the Multiethnic Cohort Study. AB - Fruits and vegetables have been examined for their possible effects on the risk of bladder cancer, as they contain numerous nutrients, phytochemicals, and antioxidants with potentially anticarcinogenic properties. In a prospective analysis of 185,885 older adults participating in the Multiethnic Cohort Study, we examined whether the consumption of fruits and vegetables, or of nutrients concentrated in fruits and vegetables, was associated with bladder cancer risk. Cox proportional hazards models were used to calculate HRs and 95% CIs for bladder cancer in relation to dietary intakes. A total of 581 invasive bladder cancer cases (429 men and 152 women) were diagnosed over a mean follow-up period of 12.5 y. In women, total fruits and vegetables [HR = 0.35 (95% CI: 0.22, 0.56); highest vs. lowest quartile], total vegetables [HR = 0.49 (95% CI: 0.29, 0.83)], yellow-orange vegetables [HR = 0.48 (95% CI: 0.30, 0.77)], total fruits [HR = 0.54 (95% CI: 0.34, 0.85)], and citrus fruits [HR = 0.56 (95% CI: 0.34, 0.90)] were inversely associated with the risk of invasive bladder cancer in risk factor adjusted models. In addition, women with the highest intakes of vitamins A, C, and E; the carotenoids alpha-carotene, beta-carotene, and beta-cryptoxanthin; and folate had a lower risk of bladder cancer. For men, no associations for fruits, vegetables, or nutrients were found overall, although inverse associations were observed for vegetable intake among current smokers, and in ethnic-specific analyses, for fruit and vegetable intake among Latinos specifically. Our findings suggest that greater consumption of fruits and vegetables may lower the risk of invasive bladder cancer among women and highlight the need for specific subgroup analyses in future studies. PMID- 23739309 TI - Fish oil increases muscle protein mass and modulates Akt/FOXO, TLR4, and NOD signaling in weanling piglets after lipopolysaccharide challenge. AB - Proinflammatory cytokines play a key role in the pathophysiology of muscle atrophy. In addition, n3 polyunsaturated fatty acids (PUFAs) exert an inhibitory effect on proinflammatory cytokines affecting many inflammatory diseases. We hypothesized that dietary supplementation of fish oil could attenuate lipopolysaccharide (LPS)-induced muscle atrophy. Weanling pigs were used in a 2 * 2 factorial design and the main factors included diet (5% corn oil or 5% fish oil) and immunological challenge (LPS or saline). After 21 d of treatment with either fish oil or corn oil, pigs received an i.p. injection of either saline or LPS. At 4 h postinjection, blood and muscle samples were obtained. Fish oil led to enrichment of eicosapentaenoic acid, docosahexaenoic acid, and total n3 PUFAs in muscles. Fish oil increased muscle protein mass, indicated by a higher protein:DNA ratio in gastrocnemius and longissimus dorsi (LD) muscles. In addition, fish oil increased Akt1 mRNA abundance and decreased Forkhead Box O (FOXO) 1 and FOXO4 mRNA abundance. Fish oil also increased phosphorylation of Akt and FOXO1 in gastrocnemius and LD muscles. Fish oil decreased the mRNA abundance of muscle atrophy F-box (MAFbx) and muscle RING finger 1 in gastrocnemius and LD muscles. Moreover, fish oil reduced the plasma tumor necrosis factor (TNF) alpha, muscle TNFalpha, and prostaglandin E2 concentrations, and muscle TNFalpha and cyclooxygenase 2 (COX2) mRNA abundance. Finally, fish oil downregulated the mRNA abundance of muscle toll-like receptor (TLR4) and its downstream signaling molecules [myeloid differentiation factor 88 (MyD88), TNFalpha receptor associated factor 6 (TRAF6), and NF-kappaB p65], and nucleotide-binding oligomerization domain protein (NOD1), NOD2, and their adaptor molecule [receptor interacting serine/threonine-protein kinase 2 (RIPK2)]. These results indicate fish oil may suppress muscle proinflammatory cytokine production via regulation of TLR and NOD signaling pathways and therefore improve muscle protein mass, possibly through maintenance of Akt/FOXO signaling. PMID- 23739311 TI - Parent-child relationship quality and adolescent alcohol use. PMID- 23739310 TI - Oral branched-chain amino acids have a beneficial effect on manifestations of hepatic encephalopathy in a systematic review with meta-analyses of randomized controlled trials. AB - Supplements with branched-chain amino acid (BCAA) have cerebral, metabolic, and nutritional effects that may benefit patients with hepatic encephalopathy (HE). We therefore conducted a systematic review on the effects of oral BCAAs compared with control supplements or placebo for patients with cirrhosis and recurrent overt or minimal HE. The quantitative analyses included data from 8 trials (n = 382 patients). Individual patient data were retrieved from 4 trials to recalculate outcomes (n = 255 patients). The mean dose of the oral BCAA supplements was 0.25 g/(kg body weight . d). Random effects meta-analysis showed that improvements in HE manifestations were registered for 87 of 172 patients in the BCAA group compared with 56 of 210 controls [risk ratio = 1.71 (95% CI: 1.17, 2.51) number needed to treat = 5 patients]. The effect of BCAAs differed (P = 0.04) for patients with overt [risk ratio = 3.26 (95% CI: 1.47, 7.22)] and minimal HE [risk ratio = 1.32 (95% CI: 0.97, 1.79)]. Subgroup, sensitivity, regression, and sequential analyses found no other sources of heterogeneity or bias. BCAA supplements had no effect on mortality or markers of nutritional status and did not induce adverse events. In conclusion, oral BCAA supplements improve manifestations of HE but have no effect on survival. PMID- 23739312 TI - Effectiveness of psychoeducation for depression: a systematic review. AB - OBJECTIVE: Pharmacological treatment is considered indispensable to major depressive disorder. In spite of this, a significant number of patients do not respond adequately to treatment based only on medication, presenting high relapse and recurrence rates. Therefore, psychosocial interventions, such as psychoeducation, have been increasingly recognized as an essential component in the treatment of depression, associated with pharmacological strategies. Thus, the aim of the present systematic review was to evaluate the effectiveness of psychoeducation for patients with unipolar depression, analyzing the evidence from the literature. METHOD: Searches were undertaken from April to October 2012 in LILACS, PsycINFO, PubMed, SCOPUS and ISI Web of Knowledge with keywords including 'psychoeducation', 'psychoeducational intervention' and 'depression', with no restriction regarding publishing dates. RESULTS: Fifteen studies were included in the review, 13 of which evaluated the effectiveness of psychoeducation for patients with depression: 10 papers evaluated in-person psychoeducation approaches and three papers evaluated long-distance approaches. In addition to these 13 papers, one evaluated psychoeducational interventions for patients' families and patients' responses and another evaluated psychoeducational interventions for patients' families and families' responses. Findings suggest that increased knowledge about depression and its treatment is associated with better prognosis in depression, as well as with the reduction of the psychosocial burden for the family. CONCLUSIONS: Psychoeducation is a psychosocial treatment that has been well documented as an adjunct to pharmacological therapy. However, there are only a few studies regarding its effectiveness on adult patients with major depressive disorder. Although the publications in this area are still very limited, the articles selected in this review suggest that psychoeducation is effective in improving the clinical course, treatment adherence, and psychosocial functioning of depressive patients. PMID- 23739313 TI - Determinants of high rates of smoking among people with psychosis living in a socially disadvantaged region in South Australia. AB - OBJECTIVE: This study aimed to identify factors associated with the high rates of smoking amongst people with psychosis living in a disadvantaged region in Adelaide, South Australia. METHODS: Data were collected from 402 people with psychosis, aged 18-64 years, who lived in the northern suburbs of Adelaide. This area is disadvantaged on many measures of socioeconomic well-being and people living in this region have higher rates of smoking compared to the general Australian population. We hypothesised that whilst tobacco use by people with psychosis living in this region was primarily associated with mental illness, factors related to social disadvantage also contributed to the high rates of smoking. RESULTS: Approximately 74% of men and 71% of women with psychotic disorders living in the northern suburbs of Adelaide were current smokers. Factors such as unemployment, lower levels of education and receiving government welfare, factors known to be associated with smoking in the general population, were more prevalent in the northern region. Smokers with psychosis were less likely to participate in recreational programs and physical activity, and more likely to use illicit substances and be a victim of crime. They had poorer health and financial outcomes than non-smokers. There were some gender differences: for men with psychosis, employment and having a post-school qualification decreased the risk of smoking while cannabis use increased the risk; for women with psychosis, a diagnosis of alcohol abuse/dependence, using cannabis and being sedentary were risk factors for smoking, while attending recreational programs reduced this risk. CONCLUSION: Smoking rates were strikingly high in both men and women, and particularly high in women when compared with previous research. Our study shows that the risk of smoking is increased by factors related to the social disadvantage of living in the northern Adelaide region. Smoking cessation interventions for people with mental illness should take into account the social context, and also address relevant comorbidities such as drug and alcohol disorders. PMID- 23739314 TI - Mental illness and psychiatric treatment amongst firesetters, other offenders and the general community. AB - OBJECTIVE: Firesetting is often reported to be associated with psychopathology, but frequently these conclusions are based on studies reliant on selective forensic psychiatric samples without the use of comparison groups. The aim of the study was to examine the rates of mental illness, substance use disorders, personality pathology and psychiatric service usage in a population of convicted firesetters compared with other offenders and community controls. METHOD: Using a data-linkage design, the study examined the psychiatric histories and usage of public mental health services by 1328 arsonists convicted between 2000 and 2009 in Victoria, Australia. These were compared with 1328 matched community controls and 421 non-firesetting offenders. RESULTS: Firesetters were significantly more likely to have been registered with psychiatric services (37%) compared with other offenders (29.3%) and community controls (8.7%). The firesetters were also more likely to have utilised a diverse range of public mental health services. Firesetters attracted psychiatric diagnoses more often than community controls and other offenders, particularly affective, substance use, and personality disorders. CONCLUSIONS: This study confirms that there is a link between firesetting and psychopathology, suggesting that there is a role for the psychiatric screening of known firesetters, and a need to consider psychopathology in formulating the risk for further firesetting. PMID- 23739315 TI - Life-threatening vasculo-Behcet following discontinuation of infliximab after three years of complete remission. AB - Behcet's disease (BD) is a chronic, complex multisystem vasculitis of unknown cause characterised for its ability to involve blood vessels of all sizes on both the arterial and venous sides of the circulation. It has been suggested that TNF alpha plays a main role in the pathogenesis of BD. This hypothesis is supported by the efficacy of TNF-blocking antibodies in these patients, which have been shown to be very powerful in the induction of remission and as maintenance treatment on different BD manifestations, including severe vascular involvement. However, little is known about when and how to stop IFX after long-standing complete remission of these patients to avoid relapses. We describe a case of BD without previous vascular involvement that developed myocardial infarction and severe venous thromboses only four months after discontinuation of infliximab (IFX) after more than three years of complete remission. The patient did not respond to corticosteroids and intravenous cyclophosphamide and only recovered completely after reintroducing IFX. PMID- 23739316 TI - Incidental maxillary sinus findings in patients referred for head and neck CT angiography. AB - BACKGROUND: Maxillary sinus pathology is a common finding on routine CT scans of the head and neck. The purpose of this study was to assess the incidental findings in the maxillary sinus on CT scans in patients who presented for head and neck CT angiography. STUDY DESIGN: Images of patients referred for head and neck CT angiography were reviewed over a 5-month period. All maxillary sinus incidental findings were recorded and categorised into mucosal thickening, polypoid mucosal thickening, partial and total opacification. The age and gender of the patients and the side of mucosal pathology was also recorded. RESULTS: A total of 262 CT scans were reviewed (524 maxillary sinuses). Seventy-two patients had pathological changes (27.5%), 44 (16.8%) had mucosal thickening, 20 (8.0%) had polypoid thickening, 6 (2.3%) had partial and another 7 (2.7%) had complete opacification. CONCLUSIONS: There is a high rate of undiagnosed maxillary sinus pathology incidentally found on CT scans. Clinicians reviewing head and neck CT scans such as dentists, general medical practitioners, maxillofacial and ENT surgeons should be vigilant and aware of maxillary sinus disease when interpreting CT scans of the maxilla and patients should be followed up appropriately. PMID- 23739317 TI - Clinical effectiveness of autologous platelet rich fibrin in the management of infrabony periodontal defects. AB - BACKGROUND: This interventional controlled clinical trial with split mouth design compares the clinical effectiveness of autologous platelet rich fibrin with open flap debridement in the management of infrabony periodontal defects. METHODS: Fifteen patients with paired contralateral infrabony defects were treated with open flap debridement and autologous platelet rich fibrin (experimental group) or open flap debridement alone (control group). The changes in probing pocket depth, clinical attachment level, and radiographic defect depth were evaluated. Patient perception regarding pain and discomfort following the procedures and early soft tissue healing responses were assessed by visual analog scales, scored 7 days after the surgical procedures. Final reevaluation was done 1 year after surgery. RESULTS: Baseline clinical and radiographic measurements were comparable between the groups. Reevaluation at 1 year revealed that both treatment modalities resulted in a significant decrease in probing pocket depth, gain in clinical attachment and radiographic bone fill of the defects compared to baseline. Postoperative differences observed between the two groups were 2.27+/-0.29mm (P<0.001) for probing pocket depth, 3.33+/-0.35mm (P<0.001) for clinical attachment level and 1.29+/-0.32mm (P<0.001) for radiographic infrabony defect depth reduction, all in favor of the experimental group. Patient preference was greater and early healing response better for the experimental group as assessed by the visual analog scores. CONCLUSION: Within the limitations of this study it can be concluded that use of platelet rich fibrin is more effective than open flap debridement alone in the management of infrabony periodontal defects. PMID- 23739318 TI - Maxillofacial prosthodontic management of an ablative maxillary surgical defect using a combination of conventional obturator prosthesis and an early loading implant supported high-strength full ceramic fixed dental prosthesis. AB - Prosthodontic rehabilitation of maxillary defects and early loading of endosseous implants has been widely published. The combination of the aforementioned treatment modalities are seldom reported in peer reviewed journals. This article describes the clinical presentation, management and prosthodontic rehabilitation of the maxillary defect of a patient. Clinical and scientific concerns are discussed. PMID- 23739319 TI - Cytotoxicity of accelerated white MTA and Malaysian white Portland cement on stem cells from human exfoliated deciduous teeth (SHED): An in vitro study. AB - The aim of this study was to compare the cytotoxicity of accelerated-set white MTA (AWMTA) and accelerated-set Malaysian white PC (AMWPC) on stem cells from human exfoliated deciduous teeth (SHED). The test materials were introduced into paraffin wax moulds after mixing with calcium chloride dihydrate and sterile distilled water. Subsequently, the set cement specimens were sterilized, incubated in a prepared Dulbecco's modified Eagle medium (DMEM) for seven days. The biomarker CD166 was used for characterization of SHED using flow cytometry. The material extracts were diluted at five different concentrations and incubated for 72h with SHED. The cell viability was evaluated using Dimethylthiazol diphenyltetrazolium bromide (MTT) assay, and the data was analysed using Mann Whitney test (P<0.05). The results showed that AWMTA revealed significantly greater cell viability at 25 and 12.5mg/ml concentrations (P<0.05). Concomitantly, AMWPC exhibited greater cell viability at concentrations <12.5mg/ml and the results were significant at 1.563mg/ml (P<0.05). Both materials demonstrated moderate cytotoxicity at 25mg/ml and slight cytotoxicity at 6.25 and 3.125mg/ml. At 1.563mg/ml, no cytotoxic activity was merely observed with AMWPC. In conclusion, AMWPC exhibited favourable and comparable cell viability to that of AWMTA, and has the potential to be used as an alternative and less costly material in dental applications. PMID- 23739320 TI - Jean-Anthelme Brillat-Savarin's 1825 treatise on the mouth and ingestion. AB - This article quotes and discusses Jean-Anthelme Brillat-Savarin's musings on the mouth and ingestion as described in his book The Physiology of Taste. The book was first published in France in December 1825, and is still widely read as a key work in Gastronomy today. The mouth is intimately related to the acts of chewing, swallowing and eating and it would be interesting to report an early 19th century epicurean's views on the mouth. Passages from Brillat-Savarin's book describing the functions of the teeth and tongue and the acts of tasting, chewing, and swallowing are quoted in full. Anecdotes also include one on the horrifying punishment of having one's tongue removed and another illustrating the poor oral health found among Europeans of that era. His work offers a unique glimpse into how a 19th century gastronome viewed the oral cavity and its gastronomical functions. While some of his writings may appear archaic and antediluvian to the modern reader; others relating to, for example chewing and swallowing, are surprisingly accurate by contemporary standards. Nonetheless, the gastronomic savant seemed to know a lot right about modern stomatology! PMID- 23739321 TI - Letter from the editor. PMID- 23739322 TI - Surgical management of an aneurysm of the left atrial appendage to prevent potential sequelae. AB - An aneurysm of the left atrial appendage is an extremely rare anomaly that is commonly associated with supraventricular arrhythmia, compression of the coronary arteries, intracardiac thrombus and pulmonary venous stenosis. This condition may be caused by congenital dysplasia of the musculi pectinati and is usually diagnosed in the second to fourth decades of life. We report the surgical management of an asymptomatic 9-year old girl with this anomaly. She was referred to us because of abnormal chest X-ray findings, and investigation revealed an aneurysm of the left atrial appendage. As this condition may have potentially fatal complications, the aneurysm was completely resected under cardiac arrest with cardiopulmonary bypass to prevent recurrence and thrombus formation. We suggest that resection of an aneurysm of the left atrial appendage under cardiac arrest with cardiopulmonary bypass is a reasonable treatment option to prevent potential complications, particularly in children. PMID- 23739323 TI - Structural and biomechanical effects of photooxidative collagen cross-linking with photosensitizer riboflavin and 370 nm UVA light on human corneoscleral tissues. AB - This study quantitatively investigated the immediate effects of a photooxidative collagen cross-linking treatment with photosensitizer riboflavin (RF) and 370 nm UVA light in in vitro human corneoscleral collagen fibrils using histology, thickness, scanning electron microscopy, and atomic force microscopy analyses. Twenty 8 x 2 mm corneoscleral strips were dissected sagittally from donor tissue using a scalpel. Four parameters were investigated, including the density, thickness, adhesion force, and stiffness of corneoscleral tissues before and after the collagen cross-linking treatment. The RFUVA-catalyzed collagen cross linking treatment led to an increase in the density of both corneal (8%) and scleral (23%) stromal collagens. However, there was no difference in corneoscleral thickness. Furthermore, RFUVA-catalyzed collagen cross-linking treatment led to an increased biomechanical response of corneosclera: 25 and 8% increases in corneoscleral stiffness, and 24 and 22% increases in corneoscleral adhesion force. The collagen cross-linking treatment through RF-sensitized photoreaction may cause structural and biomechanical changes in the collagen fibril network of the cornea and the sclera. This is due to narrowing of the interfibrillar spacing and the stromal edema. PMID- 23739324 TI - Glutathione-complexed iron-sulfur clusters. Reaction intermediates and evidence for a template effect promoting assembly and stability. AB - Assembly and stabilization of a glutathione-complexed [2Fe-2S] cluster is promoted by aggregation of glutathione. The cluster core selects the tetramer species from a collection of equilibrating solution aggregate species, and in turn the core is stabilized toward hydrolytic degradation. Studies of glutathione derivatives, in combination with mass spectrometric and Mossbauer investigations provide insight on reaction intermediates during formation of [2Fe-2S](GS)4(2-). PMID- 23739325 TI - Severe malaria is associated with parasite binding to endothelial protein C receptor. AB - Sequestration of Plasmodium falciparum-infected erythrocytes in host blood vessels is a key triggering event in the pathogenesis of severe childhood malaria, which is responsible for about one million deaths every year. Sequestration is mediated by specific interactions between members of the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family and receptors on the endothelial lining. Severe childhood malaria is associated with expression of specific PfEMP1 subtypes containing domain cassettes (DCs) 8 and 13 (ref. 3), but the endothelial receptor for parasites expressing these proteins was unknown. Here we identify endothelial protein C receptor (EPCR), which mediates the cytoprotective effects of activated protein C, as the endothelial receptor for DC8 and DC13 PfEMP1. We show that EPCR binding is mediated through the amino terminal cysteine-rich interdomain region (CIDRalpha1) of DC8 and group A PfEMP1 subfamilies, and that CIDRalpha1 interferes with protein C binding to EPCR. This PfEMP1 adhesive property links P. falciparum cytoadhesion to a host receptor involved in anticoagulation and endothelial cytoprotective pathways, and has implications for understanding malaria pathology and the development of new malaria interventions. PMID- 23739326 TI - MBNL proteins repress ES-cell-specific alternative splicing and reprogramming. AB - Previous investigations of the core gene regulatory circuitry that controls the pluripotency of embryonic stem (ES) cells have largely focused on the roles of transcription, chromatin and non-coding RNA regulators. Alternative splicing represents a widely acting mode of gene regulation, yet its role in regulating ES cell pluripotency and differentiation is poorly understood. Here we identify the muscleblind-like RNA binding proteins, MBNL1 and MBNL2, as conserved and direct negative regulators of a large program of cassette exon alternative splicing events that are differentially regulated between ES cells and other cell types. Knockdown of MBNL proteins in differentiated cells causes switching to an ES-cell like alternative splicing pattern for approximately half of these events, whereas overexpression of MBNL proteins in ES cells promotes differentiated-cell-like alternative splicing patterns. Among the MBNL-regulated events is an ES-cell specific alternative splicing switch in the forkhead family transcription factor FOXP1 that controls pluripotency. Consistent with a central and negative regulatory role for MBNL proteins in pluripotency, their knockdown significantly enhances the expression of key pluripotency genes and the formation of induced pluripotent stem cells during somatic cell reprogramming. PMID- 23739327 TI - A temporal cloak at telecommunication data rate. AB - Through advances in metamaterials--artificially engineered media with exotic properties, including negative refractive index--the once fanciful invisibility cloak has now assumed a prominent place in scientific research. By extending these concepts to the temporal domain, investigators have recently described a cloak which hides events in time by creating a temporal gap in a probe beam that is subsequently closed up; any interaction which takes place during this hole in time is not detected. However, these results are limited to isolated events that fill a tiny portion of the temporal period, giving a fractional cloaking window of only about 10(-4) per cent at a repetition rate of 41 kilohertz (ref. 15)- which is much too low for applications such as optical communications. Here we demonstrate another technique for temporal cloaking, which operates at telecommunication data rates and, by exploiting temporal self-imaging through the Talbot effect, hides optical data from a receiver. We succeed in cloaking 46 per cent of the entire time axis and conceal pseudorandom digital data at a rate of 12.7 gigabits per second. This potential to cloak real-world messages introduces temporal cloaking into the sphere of practical application, with immediate ramifications in secure communications. PMID- 23739329 TI - The spin Hall effect in a quantum gas. AB - Electronic properties such as current flow are generally independent of the electron's spin angular momentum, an internal degree of freedom possessed by quantum particles. The spin Hall effect, first proposed 40 years ago, is an unusual class of phenomena in which flowing particles experience orthogonally directed, spin-dependent forces--analogous to the conventional Lorentz force that gives the Hall effect, but opposite in sign for two spin states. Spin Hall effects have been observed for electrons flowing in spin-orbit-coupled materials such as GaAs and InGaAs (refs 2, 3) and for laser light traversing dielectric junctions. Here we observe the spin Hall effect in a quantum-degenerate Bose gas, and use the resulting spin-dependent Lorentz forces to realize a cold-atom spin transistor. By engineering a spatially inhomogeneous spin-orbit coupling field for our quantum gas, we explicitly introduce and measure the requisite spin dependent Lorentz forces, finding them to be in excellent agreement with our calculations. This 'atomtronic' transistor behaves as a type of velocity insensitive adiabatic spin selector, with potential application in devices such as magnetic or inertial sensors. In addition, such techniques for creating and measuring the spin Hall effect are clear prerequisites for engineering topological insulators and detecting their associated quantized spin Hall effects in quantum gases. As implemented, our system realizes a laser-actuated analogue to the archetypal semiconductor spintronic device, the Datta-Das spin transistor. PMID- 23739328 TI - HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration. AB - Human immunodeficiency virus-1 (HIV-1) has infected more than 60 million people and caused nearly 30 million deaths worldwide, ultimately the consequence of cytolytic infection of CD4(+) T cells. In humans and in macaque models, most of these cells contain viral DNA and are rapidly eliminated at the peak of viraemia, yet the mechanism by which HIV-1 induces helper T-cell death has not been defined. Here we show that virus-induced cell killing is triggered by viral integration. Infection by wild-type HIV-1, but not an integrase-deficient mutant, induced the death of activated primary CD4 lymphocytes. Similarly, raltegravir, a pharmacologic integrase inhibitor, abolished HIV-1-induced cell killing both in cell culture and in CD4(+) T cells from acutely infected subjects. The mechanism of killing during viral integration involved the activation of DNA-dependent protein kinase (DNA-PK), a central integrator of the DNA damage response, which caused phosphorylation of p53 and histone H2AX. Pharmacological inhibition of DNA PK abolished cell death during HIV-1 infection in vitro, suggesting that processes which reduce DNA-PK activation in CD4 cells could facilitate the formation of latently infected cells that give rise to reservoirs in vivo. We propose that activation of DNA-PK during viral integration has a central role in CD4(+) T-cell depletion, raising the possibility that integrase inhibitors and interventions directed towards DNA-PK may improve T-cell survival and immune function in infected individuals. PMID- 23739330 TI - Stem cells: Regulation by alternative splicing. PMID- 23739332 TI - Structural biology: Ion channel twists to open. PMID- 23739333 TI - X-ray structure of the mammalian GIRK2-betagamma G-protein complex. AB - G-protein-gated inward rectifier K(+) (GIRK) channels allow neurotransmitters, through G-protein-coupled receptor stimulation, to control cellular electrical excitability. In cardiac and neuronal cells this control regulates heart rate and neural circuit activity, respectively. Here we present the 3.5 A resolution crystal structure of the mammalian GIRK2 channel in complex with betagamma G protein subunits, the central signalling complex that links G-protein-coupled receptor stimulation to K(+) channel activity. Short-range atomic and long-range electrostatic interactions stabilize four betagamma G-protein subunits at the interfaces between four K(+) channel subunits, inducing a pre-open state of the channel. The pre-open state exhibits a conformation that is intermediate between the closed conformation and the open conformation of the constitutively active mutant. The resultant structural picture is compatible with 'membrane delimited' activation of GIRK channels by G proteins and the characteristic burst kinetics of channel gating. The structures also permit a conceptual understanding of how the signalling lipid phosphatidylinositol-4,5-bisphosphate (PIP2) and intracellular Na(+) ions participate in multi-ligand regulation of GIRK channels. PMID- 23739334 TI - HIV: Integration triggers death. PMID- 23739336 TI - Heat-related deaths after an extreme heat event--four states, 2012, and United States, 1999-2009. AB - On June 29, 2012, a rapidly moving line of intense thunderstorms with high winds swept across the midwestern and eastern United States, causing widespread damage and power outages. Afterward, the area experienced extreme heat, with maximum temperatures exceeding 100 degrees F (37.8 degrees C). This report describes 32 heat-related deaths in Maryland, Ohio, Virginia, and West Virginia that occurred during the 2 weeks following the storms and power outages. Median age of the decedents was 65 years, and most of the excessive heat exposures occurred within homes. During 1999-2009, an annual average of 658 heat-related deaths occurred in the United States. Heat-related deaths are preventable, and heat response plans should be in place before an extreme heat event (EHE). Interventions should focus on identifying and limiting heat exposure among vulnerable populations. PMID- 23739335 TI - Unusual architecture of the p7 channel from hepatitis C virus. AB - The hepatitis C virus (HCV) has developed a small membrane protein, p7, which remarkably can self-assemble into a large channel complex that selectively conducts cations. We wanted to examine the structural solution that the viroporin adopts in order to achieve selective cation conduction, because p7 has no homology with any of the known prokaryotic or eukaryotic channel proteins. The activity of p7 can be inhibited by amantadine and rimantadine, which are potent blockers of the influenza M2 channel and licensed drugs against influenza infections. The adamantane derivatives have been used in HCV clinical trials, but large variation in drug efficacy among the various HCV genotypes has been difficult to explain without detailed molecular structures. Here we determine the structures of this HCV viroporin as well as its drug-binding site using the latest nuclear magnetic resonance (NMR) technologies. The structure exhibits an unusual mode of hexameric assembly, where the individual p7 monomers, i, not only interact with their immediate neighbours, but also reach farther to associate with the i+2 and i+3 monomers, forming a sophisticated, funnel-like architecture. The structure also points to a mechanism of cation selection: an asparagine/histidine ring that constricts the narrow end of the funnel serves as a broad cation selectivity filter, whereas an arginine/lysine ring that defines the wide end of the funnel may selectively allow cation diffusion into the channel. Our functional investigation using whole-cell channel recording shows that these residues are critical for channel activity. NMR measurements of the channel-drug complex revealed six equivalent hydrophobic pockets between the peripheral and pore-forming helices to which amantadine or rimantadine binds, and compound binding specifically to this position may allosterically inhibit cation conduction by preventing the channel from opening. Our data provide a molecular explanation for p7-mediated cation conductance and its inhibition by adamantane derivatives. PMID- 23739337 TI - Workers' compensation claims for musculoskeletal disorders among wholesale and retail trade industry workers--Ohio, 2005-2009. AB - Work-related musculoskeletal disorders (WMSDs) resulting from ergonomic hazards are common in the United States. Recent data from the Bureau of Labor Statistics (BLS) indicate that in 2011, one third of occupational injuries and illnesses resulting in lost time from work were WMSDs. Based on data from the 2010 BLS Survey of Occupational Injuries and Illnesses, a higher rate of WMSDs resulting in lost time from work occurred in the Wholesale and Retail Trade (WRT) industry compared with most other industries. To assess trends and identify WRT subsectors and subgroups associated with high rates of WMSD workers' compensation claims, the Ohio Bureau of Workers' Compensation (OBWC) and CDC analyzed OBWC claims data for single-location WRT employers in Ohio for the period 2005-2009. From 2005 to 2009, the rate of WMSD claims declined from 86.3 to 52.8 per 10,000 employees. The three WRT industry subsectors with the highest rates of WMSD claims were Merchant Wholesalers, Nondurable Goods; Furniture and Home Furnishings Stores; and Merchant Wholesalers, Durable Goods. Within those three WRT subsectors, the highest rates of WMSD claims were noted in five subgroups: furniture stores and wholesalers of alcoholic beverages, groceries and related products, metal and minerals, and motor vehicle parts. Providing recommendations for WMSD prevention is particularly important for these WRT subgroups. PMID- 23739338 TI - Progress toward measles elimination--Western Pacific Region, 2009-2012. AB - In 2005, the World Health Organization (WHO) Regional Committee for the Western Pacific Region (WPR) resolved that WPR should aim to eliminate measles by 2012. The recommended measles elimination strategies in WPR include 1) achieving and maintaining high (>=95%) coverage with 2 doses of measles-containing vaccine (MCV) through routine immunization services and by implementing supplementary immunization activities (SIAs), when required; 2) conducting high-quality, case based measles surveillance; 3) ensuring high-quality laboratory surveillance, with timely and accurate testing of specimens to confirm or discard suspected cases and detect measles virus for genotyping and molecular analysis; and 4) establishing and maintaining measles outbreak preparedness for rapid response and ensuring appropriate case management. This report updates the previous report and describes progress toward eliminating measles in WPR during 2009-2012. During this period, measles incidence reached a historic low, decreasing by 83%, from 34.0 to 5.9 cases per million population. However, to achieve measles elimination in WPR, additional efforts are needed to strengthen routine immunization services in countries and areas with <95% coverage with the routine first (MCV1) or second dose of MCV (MCV2), to introduce a MCV2 dose in the four remaining countries and areas that do not yet have a routine 2-dose MCV schedule, and to use SIAs to close immunity gaps among measles-susceptible populations in countries and areas that have ongoing measles virus transmission. PMID- 23739339 TI - Vital signs: Listeria illnesses, deaths, and outbreaks--United States, 2009-2011. AB - BACKGROUND: Older adults, pregnant women, and persons with immunocompromising conditions are at higher risk than others for invasive Listeria monocytogenes infection (listeriosis), a rare and preventable foodborne illness that can cause bacteremia, meningitis, fetal loss, and death. METHODS: This report summarizes data on 2009-2011 listeriosis cases and outbreaks reported to U.S. surveillance systems. The Listeria Initiative and PulseNet conduct nationwide surveillance to rapidly detect and respond to outbreaks, the Foodborne Diseases Active Surveillance Network (FoodNet) conducts active, sentinel population-based surveillance to track incidence trends, and the Foodborne Disease Outbreak Surveillance System (FDOSS) receives reports of investigated outbreaks to track foods and settings associated with outbreaks. RESULTS: Nationwide, 1,651 cases of listeriosis occurring during 2009-2011 were reported. The case-fatality rate was 21%. Most cases occurred among adults aged >=65 years (950 [58%]), and 14% (227) were pregnancy-associated. At least 74% of nonpregnant patients aged <65 years had an immunocompromising condition, most commonly immunosuppressive therapy or malignancy. The average annual incidence was 0.29 cases per 100,000 population. Compared with the overall population, incidence was markedly higher among adults aged >=65 years (1.3; relative rate [RR]: 4.4) and pregnant women (3.0; RR: 10.1). Twelve reported outbreaks affected 224 patients in 38 states. Five outbreak investigations implicated soft cheeses made from pasteurized milk that were likely contaminated during cheese-making (four implicated Mexican-style cheese, and one implicated two other types of cheese). Two outbreaks were linked to raw produce. CONCLUSIONS: Almost all listeriosis occurs in persons in higher risk groups. Soft cheeses were prominent vehicles, but other foods also caused recent outbreaks. Prevention targeting higher-risk groups and control of Listeria monocytogenes contamination in foods implicated by outbreak investigations will have the greatest impact on reducing the burden of listeriosis. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Careful attention to food safety is especially important to protect vulnerable populations. Surveillance for foodborne infections like listeriosis identifies food safety gaps that can be addressed by industry, regulatory authorities, food preparers, and consumers. PMID- 23739340 TI - Notes from the field: Investigation of high HIV prevalence in Western Equatoria State--South Sudan, 2012. AB - Data are limited on the human immunodeficiency virus (HIV) epidemic in South Sudan, which became an independent country on July 9, 2011, after decades of civil war. In 2009, estimated HIV prevalence in antenatal clinics across the 10 states that now make up South Sudan was 3.0%, ranging from zero in Northern Bahr el Ghazal to 7.2% in Western Equatoria State (WES). A review of HIV programmatic data in February 2012 suggested consistently higher HIV prevalence in WES than in other states. Because of concerns about the high HIV prevalence and the threat of a worsening epidemic among postconflict communities, the Ministry of Health requested assistance from CDC to investigate the high HIV prevalence in WES and provide recommendations for the public health response. PMID- 23739341 TI - Physiological and molecular mechanisms of salt and water homeostasis in the nematode Caenorhabditis elegans. AB - Intracellular salt and water homeostasis is essential for all cellular life. Extracellular salt and water homeostasis is also important for multicellular organisms. Many fundamental mechanisms of compensation for osmotic perturbations are well defined and conserved. Alternatively, molecular mechanisms of detecting salt and water imbalances and regulating compensatory responses are generally poorly defined for animals. Throughout the last century, researchers studying vertebrates and vertebrate cells made critical contributions to our understanding of osmoregulation, especially mechanisms of salt and water transport and organic osmolyte accumulation. Researchers have more recently started using invertebrate model organisms with defined genomes and well-established methods of genetic manipulation to begin defining the genes and integrated regulatory networks that respond to osmotic stress. The nematode Caenorhabditis elegans is well suited to these studies. Here, I introduce osmoregulatory mechanisms in this model, discuss experimental advantages and limitations, and review important findings. Key discoveries include defining genetic mechanisms of osmolarity sensing in neurons, identifying protein damage as a sensor and principle determinant of hypertonic stress resistance, and identification of a putative sensor for hypertonic stress associated with the extracellular matrix. Many of these processes and pathways are conserved and, therefore, provide new insights into salt and water homeostasis in other animals, including mammals. PMID- 23739342 TI - Seawater acclimation and inositol monophosphatase isoform expression in the European eel (Anguilla anguilla) and Nile tilapia (Orechromis niloticus). AB - Inositol monophosphatase (IMPA) is responsible for the synthesis of inositol, a polyol that can function as an intracellular osmolyte helping re-establish cell volume when exposed to hypertonic environments. Some epithelial tissues in euryhaline teleosts such as the eel and tilapia encounter considerable hyperosmotic challenge when fish move from freshwater (FW) to seawater (SW) environments; however, the roles played by organic osmolytes, such as inositol, have yet to be determined. Syntenic analysis has indicated that, as a result of whole genome- and tandem-duplication events, up to six IMPA isoforms can exist within teleost genomes. Four isoforms are homologs of the mammalian IMPA1 gene, and two isoforms are homologs of the mammalian IMPA2 gene. Although the tissue dependent isoform expression profiles of the teleost isoforms appear to be species-specific, it was primarily mRNA for the IMPA1.1 isoform that was upregulated in epithelial tissues after fish were transferred to SW (up to 16 fold in eel and 90-fold in tilapia). Although up-regulation of IMPA1.1 expression was evident in many tissues in the eel, more substantial increases in IMPA1.1 expression were found in tilapia tissues, where SW acclimation resulted in up to 2,000-fold increases in protein expression, 16-fold increases in enzyme activity and 15-fold increases in tissue inositol contents. Immunohistochemical studies indicated that the tissue and cellular distribution of IMPA1.1 protein differed slightly between eels and tilapia; however, in both species the basal epithelial cell layers within the skin and fin, and the branchial epithelium and interstitial cells within the kidney, exhibited high levels of IMPA1.1 protein expression. PMID- 23739343 TI - Cannabinoid 1 receptors are critical for the innate immune response to TLR4 stimulation. AB - Sickness behaviors are host defense adaptations that arise from integrated autonomic outputs in response to activation of the innate immune system. These behaviors include fever, anorexia, and hyperalgesia intended to promote survival of the host when encountering pathogens. Cannabinoid (CB) receptor activation can induce hypothermia and attenuate LPS-evoked fever. The aim of the present study was to examine the role of CB1 receptors in the LPS-evoked febrile response. CB1 receptor-deficient (CB1(-/-)) mice did not display LPS-evoked fever; likewise, pharmacological blockade of CB1 receptors in wild-type mice blocked LPS-evoked fever. This unresponsiveness is not limited to thermogenesis, as the animals were not hyperalgesic after LPS administration. A Toll-like receptor (TLR)3 agonist and viral mimetic polyinosinic:polycytidylic acid evoked a robust fever in CB1(-/ ) mice, suggesting TLR3-mediated responses are functional. LPS-evoked c-Fos activation in areas of the brain associated with the febrile response was evident in wild-type mice but not in CB1(-/-) mice. Liver and spleen TLR4 mRNA were significantly lower in CB1(-/-) mice compared with wild-type mice, and peritoneal macrophages from CB1(-/-) mice did not release proinflammatory cytokines in response to LPS. These data indicate that CB1 receptors play a critical role in LPS-induced febrile responses through inhibiting TLR4-mediated cytokine production. PMID- 23739344 TI - A high-grain diet causes massive disruption of ruminal epithelial tight junctions in goats. AB - Alterations in rumen epithelial tight junctions (TJs) at the tissue and molecular levels during high-grain (HG) diet feeding are unknown. Here, 10 male goats were randomly assigned to either a hay diet (0% grain; n = 5) or HG diet group (65% grain; n = 5) to characterize the changes in ruminal epithelial structure and TJ protein expression and localization using scanning and transmission electron microscopy, quantitative real-time PCR, Western blot analysis, and immunofluorescence. After 7 wk of feeding, ruminal free LPS in HG group increased significantly (P < 0.001) compared with the hay group, and free LPS in the peripheral blood was detectable with concentrations of 0.8 +/- 0.20 EU/ml, while not detectable in the control, suggesting a leakage of LPS into the blood in the HG group. Correspondingly, the HG-fed goats showed profound alterations in ruminal epithelial structure and TJ proteins, depicted by marked epithelial cellular damage and intercellular junction erosion, down-regulation of TJ proteins claudin-4, occludin, and zonula occludens-1 mRNA and protein expression, as well as redistribution of claudin-1, claudin-4, and occludin. Furthermore, these changes in TJ proteins in the HG group were coupled with the upregulation of mRNA levels for the cytokines TNF-alpha and IFN-gamma in the ruminal epithelia. These results demonstrated for the first time that the HG diet feeding caused disruption of ruminal epithelial TJs that was associated with a local inflammatory response in the rumen epithelium. These findings may provide new insights into understanding the role of TJ proteins in the ruminal epithelial immune homeostasis of ruminants. PMID- 23739345 TI - Angiotensin-converting enzyme and the tumor microenvironment: mechanisms beyond angiogenesis. AB - The renin angiotensin system (RAS) is a network of enzymes and peptides that coalesce primarily on the angiotensin II type 1 receptor (AT1R) to induce cell proliferation, angiogenesis, fibrosis, and blood pressure control. Angiotensin converting enzyme (ACE), the key peptidase of the RAS, is promiscuous in that it cleaves other substrates such as substance P and bradykinin. Accumulating evidence implicates ACE in the pathophysiology of carcinogenesis. While the role of ACE and its peptide network in modulating angiogenesis via the AT1R is well documented, its involvement in shaping other aspects of the tumor microenvironment remains largely unknown. Here, we review the role of ACE in modulating the immune compartment of the tumor microenvironment, which encompasses the immunosuppressive, cancer-promoting myeloid-derived suppressor cells, alternatively activated tumor-associated macrophages, and T regulatory cells. We also discuss the potential roles of peptides that accumulate in the setting of chronic ACE inhibitor use, such as bradykinin, substance P, and N acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), and how they may undercut the gains of anti-angiogenesis from ACE inhibition. These emerging mechanisms may harmonize the often-conflicting results on the role of ACE inhibitors and ACE polymorphisms in various cancers and call for further investigations into the potential benefit of ACE inhibitors in some neoplasms. PMID- 23739346 TI - Editorial Focus: the brain renin-angiotensin system and hypertension. Focus on: hypertension in mice with transgenic activation of the brain renin-angiotensin system is vasopressin dependent. PMID- 23739347 TI - Parallel fabrication of magnetic tunnel junction nanopillars by nanosphere lithography. AB - We present a new method for fabricating magnetic tunnel junction nanopillars that uses polystyrene nanospheres as a lithographic template. Unlike the common approaches, which depend on electron beam lithography to sequentially fabricate each nanopillar, this method is capable of patterning a large number of nanopillars simultaneously. Both random and ordered nanosphere patterns have been explored for fabricating high quality tunneling junctions with magnetoresistance in excess of 100%, employing ferromagnetic layers with both out-of-plane and in plane easy axis. Novel voltage induced switching has been observed in these structures. This method provides a cost-effective way of rapidly fabricating a large number of tunnel junction nanopillars in parallel. PMID- 23739349 TI - Wearable and micro and nano technologies for pHealth: R&D achievements to enable future innovation. AB - The fast developments in information and communication technology as well as R&D work on micro and nano systems in biology and biomedical engineering are stimulating the explosive growth in life sciences, which is leading to an ever increasing understanding of life at sub-cellular and molecular level and so revolutionizing and personalizing diagnosis and therapy. By bringing these parallel developments to biomedicine and health, ultrafast and sensitive systems can be developed to prevention & lifestyle support, to early diagnose or treat diseases with high accuracy and less invasiveness, and to support body functions or to replace lost functionality. Such pHealth systems will enable the delivery of individualized health services with better access & outcomes at lower costs than previously deemed possible, making a substantial contribution to bring healthcare expenditures under control and increase its productivity. PMID- 23739350 TI - Translational medicine meets new technologies for enabling personalized care. AB - For improving quality, safety and efficiency of care processes, health care systems perform two paradigm changes: the organizational transformation of the health care system from organization-centric to person-centric structures and the methodological transformation from the traditional phenomenological approach to individualized health care based on translational medicine. Both paradigm changes are interrelated and require advanced interoperability between different organizations and multiple disciplines. The paper presents a system-theoretical, architecture-centric approach to analyze, design and develop the systems of health care and medicine for enabling personalized health services. According to the translational medicine paradigm, the considered model must be able to describe the subject of care at all levels of granularity from elements to population including the technologies applied at those levels to perform diagnosis and therapy. The system components reflected through different domains, their concepts and interrelations must be consistently described based on the domain ontologies representing those system perspectives. The medical and technological instances of the personalized health system are exemplified, thereby especially focusing on nano and micro levels and discussing biological and technical sensors and actuators, but also addressing profiling, bridging between genotyping and phenotyping and thereby combining molecular and epidemiological studies. PMID- 23739352 TI - Personal portable devices as enablers for advanced pHealth decision support and decision making services. AB - Mobile devices are becoming more and more important for services offered either directly to individuals, or indirectly as part of a therapeutic or rehabilitation procedure. Representing the work of the EFMI WG "Personal Portable Devices", this paper offers an introduction to some of the most important technical and privacy related challenges that arise when introducing mobile sensor or actuator devices (and networks) into health care, wellness, and fitness processes in order to exploit their capability to collect, record and process personal health data. Data processing can be viewed in three classes of application, namely processes for recommendations, decision support and decision making in personalized health and wellbeing service provision. This paper therefore briefly addresses aspects such as the Medical Device Directive for certifying devices in that respect. But regardless whether being MDD-compliant or not, each class of devices may have its own benefits and weaknesses in terms of enabling health-related personalized decisions. PMID- 23739353 TI - Virtual physiological human and its role for advanced pHealth service provision. AB - This paper provides an introduction to some of the most important challenges that may occur when introducing the principle of Personal Portable Devices for providing information in terms of Big Data on the one hand, and the concept of the Virtual Physiological Human on the other. Both concepts can be applied to exploit their specific capability to collect and record personal health data of different levels of granularity into processes of personalized health service provision. The paper thus analyzes Big Data approaches and their capability to provide information for personalized service provision, and the same goes for the Virtual Physiological Human as such. But it is not only devices, concepts, models, and strategies that are involved in personalized health care as well as welfare and wellness service provision to human beings - it is the human being himself, too. This paper addresses technological and methodological aspects of using large amounts of data whereas another paper submitted to this conference will bring forward the aspects of applied sensor and device technology in relation to decision support and decision making for pHealth services. PMID- 23739354 TI - Towards large-scale data analysis: challenges in the design of portable systems and use of Cloud computing. AB - Portable systems and global communications open a broad spectrum for new health applications. In the framework of electrophysiological applications, several challenges are faced when developing portable systems embedded in Cloud computing services. In order to facilitate new developers in this area based on our experience, five areas of interest are presented in this paper where strategies can be applied for improving the performance of portable systems: transducer and conditioning, processing, wireless communications, battery and power management. Likewise, for Cloud services, scalability, portability, privacy and security guidelines have been highlighted. PMID- 23739355 TI - Case-based reasoning in Intelligent Health Decision Support Systems. AB - Decision-making is a crucial task for decision makers in healthcare, especially because decisions have to be made quickly, accurately and under uncertainty. Taking into account the importance of providing quality decisions, offering assistance in this complex process has been one of the main challenges of Artificial Intelligence throughout history. Decision Support Systems (DSS) have gained popularity in the medical field for their efficacy to assist decision making. In this sense, many DSS have been developed, but only few of them consider processing and analysis of information contained in electronic health records, in order to identify individual or population health risk factors. This paper deals with Intelligent Decision Support Systems that are integrated into Electronic Health Records Systems (EHRS) or Public Health Information Systems (PHIS). It provides comprehensive support for a wide range of decisions with the purpose of improving quality of care delivered to patients or public health planning, respectively. PMID- 23739356 TI - Ethicted (evaluation process model to improve personalised ICT services for independent living and active ageing)--future scenario. AB - ICT innovations are constantly developed, and there is no lack of elderly customers, as the number of the elderly is dramatically increasing. Elderly are willing to use ICT to increase their own safety and social activity, but they need trust on the reliability, accessibility and other ethical aspects of ICT including the maintenance of privacy and self-determination. Ethical standards for ICT are usually not considered. "Ethicted" characterizes an ICT service or product as ethically evaluated. As a standardized procedure, it will not only increase the acceptability of ICT, but also provide services for ICT developers. In the future scenario, ICT under development should be evaluated by using a process model that is specifically built to find the lacks in ethical aspects. The model would then be tested by end-users, the formal and informal care givers, to receive direct feedback for redeveloping solutions. As final outcomes, there should be standards for ICT in elderly care and a service for ICT developers to utilize the evaluation model. This future scenario work included partners from 6 EU member countries. The combination of academic research and industrial/commercial interest of ICT developers should and can bring new value to assistive ICT for elderly care. PMID- 23739358 TI - A wireless multi-channel bioimpedance measurement system for personalized healthcare and lifestyle. AB - Miniaturized, noninvasive, wearable sensors constitute a fundamental prerequisite for pervasive, predictive, and preventive healthcare systems. In this sense, this paper presents the design, realization, and evaluation of a wireless multi channel measurement system based on a cost-effective high-performance integrated circuit for electrical bioimpedance (EBI) measurements in the frequency range from 1 kHz to 1 MHz. The resulting on-chip spectrometer provides high measuring EBI capabilities and together with a low-cost, commercially available radio frequency transceiver device. It provides reliable wireless communication, constitutes the basic node to build EBI wireless sensor networks (EBI-WSNs). The proposed EBI-WSN behaves as a high-performance wireless multi-channel EBI spectrometer, where the number of channels is completely scalable and independently configurable to satisfy specific measurement requirements of each individual. A prototype of the EBI node leads to a very small printed circuit board of approximately 8 cm2 including chip-antenna, which can operate several years on one 3-V coin cell battery and make it suitable for long-term preventive healthcare monitoring. PMID- 23739359 TI - Unsupervised abnormal human behaviour detection using acceleration data. AB - Abnormal human behavior detection under free-living conditions is a reliable technique to detect activity disorders and diseases. This work proposes an acceleration-based algorithm to detect abnormal behavior as an abnormal increase or decrease in physical activity (PA). The algorithm is based on statistical features of human physical activity. Using a period of observed physical activity as a reference, the algorithm is able to detect abnormal behavior in other periods of time. The approach is unsupervised as the modeling of the reference behavior is not required. It has been validated with a group of 12 users under free-living conditions for two days. Results show a precision greater than 75% and a recall of 92%. PMID- 23739360 TI - Using sensors and facial expression recognition to personalize emotion learning for autistic children. AB - This paper describes CaptureMyEmotion, an app for smartphones and tablets which uses wireless sensors to capture physiological data together with facial expression recognition to provide a very personalized way to help autistic children identify and understand their emotions. Many apps are targeting autistic children and their carer, but none of the existing apps uses the full potential offered by mobile technology and sensors to overcome one of autistic children's main difficulty: the identification and expression of emotions. CaptureMyEmotion enables autistic children to capture photos, videos or sounds, and identify the emotion they felt while taking the picture. Simultaneously, a self-portrait of the child is taken, and the app measures the arousal and stress levels using wireless sensors. The app uses the self-portrait to provide a better estimate of the emotion felt by the child. The app has the potential to help autistic children understand their emotions and it gives the carer insight into the child's emotions and offers a means to discuss the child's feelings. PMID- 23739361 TI - A MATLAB toolbox for classification and visualization of heterogenous multi-scale human data using the Disease State Fingerprint method. AB - As the amount of data acquired from humans is constantly increasing, efficient tools are needed for extracting relevant information from this data. This paper presents a Matlab implementation of a method to classify and visually explore (highly) multi-variate patient data. The method uses the so-called Disease State Index (DSI) which measures the fit of a test subject's data to two classes present in the data (e.g. 'controls' and 'positives'). DSI values of the different variables measured from a patient can be combined and visualized in a tree-like form using the Disease State Fingerprint (DSF) method. This allows a researcher to explore and understand the relevance of the different variables in classification problems. Moreover, the method is robust with respect to missing data. After giving an introduction to the DSF and DSI methods, the paper describes the steps required to use the methods and presents a MATLAB toolbox to perform these steps. To demonstrate the methods' versatility, the paper illustrates the usage of the toolbox in a few different contexts in which personal health data is to be classified. With this implementation, a powerful and flexible tool is made available to the biomedical research community. PMID- 23739362 TI - EEG sensor based classification for assessing psychological stress. AB - Electroencephalogram (EEG) reflects the brain activity and is widely used in biomedical research. However, analysis of this signal is still a challenging issue. This paper presents a hybrid approach for assessing stress using the EEG signal. It applies Multivariate Multi-scale Entropy Analysis (MMSE) for the data level fusion. Case-based reasoning is used for the classification tasks. Our preliminary result indicates that EEG sensor based classification could be an efficient technique for evaluation of the psychological state of individuals. Thus, the system can be used for personal health monitoring in order to improve users health. PMID- 23739364 TI - Wearable textile-based phototherapy systems. AB - In this paper, we discuss the phototherapy concepts developed by Philips in the EU FP7 PLACE-it project. These concepts demonstrate the use of e-textiles for medical applications in a meaningful way. By introducing a comfortable, wearable technology, Philips has enabled a new world of devices which provide comfortable home treatment of different diseases and complaints. Here, we show concepts and clinical validation, and give insight in the development steps to be taken to build this kind of devices. PMID- 23739365 TI - Implantable medical devices MRI safe. AB - Pacemakers, ICDs, neurostimulators like deep brain stimulator electrodes, spiral cord stimulators, insulin pumps, cochlear implants, retinal implants, hearing aids, electro cardio gram (ECG) leads, or devices in interventional MRI such as vascular guide wires or catheters are affected by MRI magnetic and electromagnetic fields. Design of MRI Safe medical devices requires computer modeling, bench testing, phantom testing, and animal studies. Implanted medical devices can be MRI unsafe, MRI conditional or MRI safe (see glossary). In the following paragraphs we will investigate how to design implanted medical devices MRI safe. PMID- 23739366 TI - Wearable system for non-invasive and continuous monitoring central aortic pressure curve and augmentation index. AB - The paper presents a non-invasive method and system for a long-term and continuous monitoring of the central aortic pressure (CAP) waveform and the augmentation index (AI). The CAP curve is estimated from the measured radial electrical bio-impedance (EBI) using spectral domain transfer functions (TF), which are established on the basis of data analysis during clinical experiments. Experiments were carried out on 3 volunteers by now. During the experiment, a 0.5 mg sublingual nitroglycerin tablet was administrated to each volunteer. Both, the reconstructed CAP curve and the AI have very good correlation with the results obtained by the SphygmoCor system. But, in opposite to the traditional tonometry based CAP curve and AI estimation methods, the proposed one is more convenient to use and allows continuous and long-term personalized monitoring of the CAP curve and of the AI. PMID- 23739367 TI - Wearable data acquisition system of multimodal physiological signals for personal health care. AB - The paper proposes a wearable multimodal data acquisition system for biological signals. The system enables logging of electrical bioimpedance signals from multiple electrodes, electrocardiographic signals (ECG), acceleration signals from multiple locations, and spirometric data from a moving object. Later it will be used to conduct field measurements for characterizing health of the object under investigation. Main goal is to acquire enough data for development, refinement, and simplification of signal processing algorithms. The system is center part of the new wearable compact data acquisition modules ZCardio. Those modules enable multichannel impedance spectroscopy by logging ECG signals and data from the spirometric sensor. Initial reference measurements were conducted. Alternatively, tests were performed using Plessey Semiconductors capacitive sensors. Acceleration signals are gathered. PMID- 23739368 TI - Hand-arm vibration exposure monitoring with wearable sensor module. AB - Vibration exposure is a serious risk within work physiology for several work groups. Combined with cold artic climate, the risk for permanent harm is even higher. Equipment that can monitor the vibration exposure and warn the user when at risk will provide a safer work environment for these work groups. This study evaluates whether data from a wearable wireless multi-parameter sensor module can be used to estimate vibration exposure and exposure time. This work has been focused on the characterization of the response from the accelerometer in the sensor module and the optimal location of the module in the hand-arm configuration. PMID- 23739369 TI - State-of-the-art of wearable EEG for personalized health applications. AB - Despite the proliferation of low-cost wearable sensors, until recently we have not been able to monitor our brain activity in our daily lives with affordable and wearable devices. In this paper we provide an overview of the state-of-the art of wearable electroencephalographic (EEG) devices after determining the key characteristics that enable wider adoption. Furthermore, we explore their potential applications, which suggest that wearable EEG devices can become a major enabler for personalized health. This review can serve as a reference on the state-of-the-art at the beginning of 2013. PMID- 23739370 TI - User acquaintance with mobile interfaces. AB - Handheld technology finds slowly its place in the healthcare world. Some clinicians already use intensively dedicated mobile applications to consult clinical references. However, handheld technology hasn't still broadly embraced to the core of the healthcare business, the hospitals. The weak penetration of handheld technology in the hospitals can be partly explained by the caution of stakeholders that must be convinced about the efficiency of these tools before going forward. In a domain where temporal constraints are increasingly strong, caregivers cannot loose time on playing with gadgets. All users are not comfortable with tactile manipulations and the lack of dedicated peripheral complicates entering data for novices. Stakeholders must be convinced that caregivers will be able to master handheld devices. In this paper, we make the assumption that the proper design of an interface may influence users' performances to record information. We are also interested to find out whether users increase their efficiency when using handheld tools repeatedly. To answer these questions, we have set up a field study to compare users' performances on three different user interfaces while recording vital signs. Some user interfaces were familiar to users, and others were totally innovative. Results showed that users' familiarity with smartphone influences their performances and that users improve their performances by repeating a task. PMID- 23739372 TI - Senior-driven design and development of tablet-based cognitive games. AB - This paper describes the design and development of a tablet-based gaming platform targeting the senior population, aiming at improving their overall wellbeing by stimulating their cognitive capabilities and promoting social interaction between players. To achieve these goals, we started by performing a study of the specific characteristics of the senior user as well as what makes a game appealing to the player. Furthermore we investigated why the tablet proves to be an advantageous device to our target audience. Based on the results of our research, we developed a solution that incorporates cognitive and social mechanisms into its games, while performing iterative evaluations together with the final user by adopting a user-centered design methodology. In each design phase, a pre-selected group of senior participants experimented with the game platform and provided feedback to improve its features and usability. Through a series of short-term and a long term evaluation, the game platform proved to be appealing to its intended users, providing an enjoyable gaming experience. PMID- 23739373 TI - Augmented reality & gesture-based architecture in games for the elderly. AB - Serious games for health and, more specifically, for elderly people have developed rapidly in recent years. The recent popularization of novel interaction methods of consoles, such as the Nintendo Wii and Microsoft Kinect, has provided an opportunity for the elderly to engage in computer and video games. These interaction methods, however, still present various challenges for elderly users. To address these challenges, we propose an architecture consisted of Augmented Reality (as an output mechanism) combined with gestured-based devices (as an input method). The intention of this work is to provide a theoretical justification for using these technologies and to integrate them into an architecture, acting as a basis for potentially creating suitable interaction techniques for the elderly players. PMID- 23739374 TI - Home rehabilitation system supported by the safety model. AB - The paper describes a tele-rehabilitation system for simultaneous motor rehabilitation (post-stroke and post-arthroscopy) and continuous patient's condition assessment with the focus on patient safety observations. Micro-electro mechanical accelerometer and gyroscope sensors attached to the patient gather information about the performed therapeutic exercises. The measurement data processing of the vital sign sensors and accelerometers is done in the health hub device in real time with the patient feedback. Model verification is used for providing that the specified requirements have been actually fulfilled. By the safety model validation, we supplement clinical evaluation, which means the efficacy of the system is proven by the rules given by the physician for the particular patient. PMID- 23739375 TI - Physical activity classification for elderly based on pulse rate. AB - Physical activity is one of the key components for elderly in order to be actively ageing. However, it is difficult to differentiate and identify the body movement and actual physical activity using only accelerometer measurements. Therefore, this paper presents an application of a case-based retrieval classification scheme to classify the physical activity of elderly based on pulse rate measurements. Here, a case-based retrieval approach used the features extracted from both time and frequency domain. The evaluation result shows the best accuracy performance while considering the combination of time and frequency domain features. According to the evaluation result while considering the control measurements, the sensitivity, specificity and overall accuracy are achieved as 95%, 96% and 96%, respectively. Considering the test dataset, the system succeeded to identify 13 physical activities out of 16, i.e,. the percentage of the correctness was 81%. PMID- 23739376 TI - Neuro-physical rehabilitation by means of novel touch technologies. AB - In this work, we present the results of collaboration between an engineering department and a rehabilitation hospital in using innovative touch interfaces properly designed for both neurocognitive and physical rehabilitation. The novel touch interface also measures force, thereby enabling dexterity training through 'direct' manipulation of virtual objects in 3D. Two dimensions are recorded via touch screen, the third by the force channel. We believe that this tool could increase the degree of effectiveness of traditional rehabilitation treatments thanks to its capability to merge physical and cognitive rehabilitation. Furthermore, the exergames implemented allow an easy personalization of the exercise structure and difficulty level. The effectiveness of the FP technology compared with more traditional methods of rehabilitation is measured according to specific parameters observed in an experimental group in comparison with a control group. PMID- 23739378 TI - Exploitation and commercialization within the EU FP7 project PASCA. AB - Within recent years, the analysis of single biological cells has emerged as key topic in cell-biology research. Studying cells and cellular functions within large cell populations is still common practice in the life-sciences, but is hampered by several limitations. True access to a cell's physiology, phenotype and genotype can often only be achieved on a single cell level. The European research project "Platform for Advanced Single Cell Analysis" (PASCA) focuses on developing an approach towards inkjet-like printing of single cells. A fully automated prototype instrument for printing of single living cells has been developed, and its potential use is currently being investigated in various biological applications. The various elements of project design, management, and implementation developed within this project to support the commercial exploitation and dissemination of the project results will be discussed. Based on the dedicated project structure of involving external non-funded participants from the beginning of the project and extending it to the preparation of a prototype related market study, various activities aimed at commercializing the project results are presented. We present the lessons learned from those activities alongside the technical results achieved with the PASCA prototype instruments and the perspectives for future commercialization. PMID- 23739379 TI - AsTeRICS. AB - AsTeRICS - "The Assistive Technology Rapid Integration & Construction Set" is a construction set for assistive technologies which can be adapted to the motor abilities of end-users. AsTeRICS allows access to different devices such as PCs, cell phones and smart home devices, with all of them integrated in a platform adapted as much as possible to each user. People with motor disabilities in the upper limbs, with no cognitive impairment, no perceptual limitations (neither visual nor auditory) and with basic skills in using technologies such as PCs, cell phones, electronic agendas, etc. have available a flexible and adaptable technology which enables them to access the Human-Machine-Interfaces (HMI) on the standard desktop and beyond. AsTeRICS provides graphical model design tools, a middleware and hardware support for the creation of tailored AT-solutions involving bioelectric signal acquisition, Brain-/Neural Computer Interfaces, Computer-Vision techniques and standardized actuator and device controls and allows combining several off-the-shelf AT-devices in every desired combination. Novel, end-user ready solutions can be created and adapted via a graphical editor without additional programming efforts. The AsTeRICS open-source framework provides resources for utilization and extension of the system to developers and researches. AsTeRICS was developed by the AsTeRICS project and was partially funded by EC. PMID- 23739380 TI - universAAL: towards the assisting technologies market breakthrough. AB - The universAAL initiative aims at fulfilling EU objectives to promote open platforms in the Ambient Assisted Living domain by: (1) producing a platform providing the necessary technical support; (2) carrying out support activities promoting widespread acceptance and adoption of the platform. Coordinated exploitation models to ensure the sustainability of project results are being developed by a partnership of committed partners in order to deliver the evidence of usefulness, usability, and reliability of the universAAL platform while assuring its maintenance, thus making universAAL a unique candidate for re-use under real-life conditions. PMID- 23739381 TI - European research on wireless endoscopy--the VECTOR project. AB - Within the European VECTOR project, various technologies to enhance the current field of capsule endoscopy towards screening of colorectal cancers and its precursors, and enhanced diagnostic and therapeutic functionalities have been developed. Among others, this includes technologies for active locomotion, wireless therapy and detection of gastrointestinal bleeding. The VECTOR project has contributed to the trend to develop novel procedures for improved diagnosis and treatment of gastrointestinal diseases. PMID- 23739385 TI - Studies in Health Technology and Informatics. pHealth 2013. Preface. PMID- 23739382 TI - Criteria for successful uptake of AAL technologies: lessons learned from Norwegian pilot projects. AB - Implementation of AAL-technology as an integrated part of public health and care services requires a systematic and multidisciplinary approach. There are several challenges that need to be handled in parallel and with sustained effort over time, to tackle the multidimensional problem of building the value chain that is required for widespread uptake of AAL technology. Several pilot projects are on going in Norway, involving municipalities, technology providers and research partners. Examples are "Home Safety" (NO: Trygghetspakken) and "Safe Tracks" (NO: Trygge spor). This paper will elaborate on our lessons learned with focus on five main points: 1) User-friendly and robust technology 2) Technology adapted organization 3) Service oriented technology providers 4) Care service organizations as demanding customer and 5) Sustainable financial model. PMID- 23739386 TI - On the interactions between virulent bacteriophages and bacteria in the gut. AB - We recently described the targeting of O104:H4 Escherichia coli in mouse gut by several virulent bacteriophages, highlighting several issues relating to virus host interactions, which we discuss further in this addendum to the original publication. PMID- 23739387 TI - Teaching psychoanalytic concepts, skills, and attitudes to medical students. AB - In recent decades the psychoanalytic perspective has been increasingly marginalized in medical school education. This has been driven by political tides, competition with neuroscience education, shifting practice models, and the dominance of an evidence-based perspective. The costs both to medical trainees and to the field of psychoanalysis are considerable. Reasons are presented for why academic psychiatry departments might be motivated to integrate more psychodynamic training into basic medical education and for why organized psychoanalysis might have an interest in developing a greater presence in medical schools. Various formats are discussed in which psychoanalytic theory and technique might effectively be introduced. Finally, broader strategies are proposed for addressing students and their developmental needs such that resistances to learning psychodynamics are reduced. PMID- 23739388 TI - US clinical-research system in need of review. PMID- 23739400 TI - 'Plastic wood' is no green guarantee. PMID- 23739401 TI - Tensions grow as data-mining discussions fall apart. PMID- 23739402 TI - Glowing plants spark debate. PMID- 23739403 TI - Geneticists push for global data-sharing. PMID- 23739404 TI - Europe reforms its fisheries. PMID- 23739405 TI - Agency gets a grip on budget. PMID- 23739406 TI - Quantum physics: The quantum atom. PMID- 23739407 TI - Bohr's model: Extreme atoms. PMID- 23739408 TI - History: The path to the quantum atom. PMID- 23739409 TI - Physics: The enigmatic electron. PMID- 23739414 TI - Alien species: Monster fern makes IUCN invader list. PMID- 23739415 TI - Satellites: Make data freely accessible. PMID- 23739416 TI - Satellites: Ambition for forest initiative. PMID- 23739417 TI - Germany: Avoid more organ transplant scandals. PMID- 23739418 TI - Theoretical physics: Sizing up atoms. PMID- 23739419 TI - High-temperature superconductivity: The sound of a hidden order. PMID- 23739420 TI - Immunology: An innate regulatory cell. PMID- 23739421 TI - Techniques: Optical spectroscopy goes intramolecular. PMID- 23739422 TI - Climate science: Plant a tree, but tend it well. PMID- 23739423 TI - Ice-sheet mass balance and climate change. AB - Since the 2007 Intergovernmental Panel on Climate Change Fourth Assessment Report, new observations of ice-sheet mass balance and improved computer simulations of ice-sheet response to continuing climate change have been published. Whereas Greenland is losing ice mass at an increasing pace, current Antarctic ice loss is likely to be less than some recently published estimates. It remains unclear whether East Antarctica has been gaining or losing ice mass over the past 20 years, and uncertainties in ice-mass change for West Antarctica and the Antarctic Peninsula remain large. We discuss the past six years of progress and examine the key problems that remain. PMID- 23739424 TI - The oldest known primate skeleton and early haplorhine evolution. AB - Reconstructing the earliest phases of primate evolution has been impeded by gaps in the fossil record, so that disagreements persist regarding the palaeobiology and phylogenetic relationships of the earliest primates. Here we report the discovery of a nearly complete and partly articulated skeleton of a primitive haplorhine primate from the early Eocene of China, about 55 million years ago, the oldest fossil primate of this quality ever recovered. Coupled with detailed morphological examination using propagation phase contrast X-ray synchrotron microtomography, our phylogenetic analysis based on total available evidence indicates that this fossil is the most basal known member of the tarsiiform clade. In addition to providing further support for an early dichotomy between the strepsirrhine and haplorhine clades, this new primate further constrains the age of divergence between tarsiiforms and anthropoids. It also strengthens the hypothesis that the earliest primates were probably diurnal, arboreal and primarily insectivorous mammals the size of modern pygmy mouse lemurs. PMID- 23739425 TI - Bounding the pseudogap with a line of phase transitions in YBa2Cu3O6+delta. AB - Close to optimal doping, the copper oxide superconductors show 'strange metal' behaviour, suggestive of strong fluctuations associated with a quantum critical point. Such a critical point requires a line of classical phase transitions terminating at zero temperature near optimal doping inside the superconducting 'dome'. The underdoped region of the temperature-doping phase diagram from which superconductivity emerges is referred to as the 'pseudogap' because evidence exists for partial gapping of the conduction electrons, but so far there is no compelling thermodynamic evidence as to whether the pseudogap is a distinct phase or a continuous evolution of physical properties on cooling. Here we report that the pseudogap in YBa2Cu3O6+delta is a distinct phase, bounded by a line of phase transitions. The doping dependence of this line is such that it terminates at zero temperature inside the superconducting dome. From this we conclude that quantum criticality drives the strange metallic behaviour and therefore superconductivity in the copper oxide superconductors. PMID- 23739426 TI - Chemical mapping of a single molecule by plasmon-enhanced Raman scattering. AB - Visualizing individual molecules with chemical recognition is a longstanding target in catalysis, molecular nanotechnology and biotechnology. Molecular vibrations provide a valuable 'fingerprint' for such identification. Vibrational spectroscopy based on tip-enhanced Raman scattering allows us to access the spectral signals of molecular species very efficiently via the strong localized plasmonic fields produced at the tip apex. However, the best spatial resolution of the tip-enhanced Raman scattering imaging is still limited to 3-15 nanometres, which is not adequate for resolving a single molecule chemically. Here we demonstrate Raman spectral imaging with spatial resolution below one nanometre, resolving the inner structure and surface configuration of a single molecule. This is achieved by spectrally matching the resonance of the nanocavity plasmon to the molecular vibronic transitions, particularly the downward transition responsible for the emission of Raman photons. This matching is made possible by the extremely precise tuning capability provided by scanning tunnelling microscopy. Experimental evidence suggests that the highly confined and broadband nature of the nanocavity plasmon field in the tunnelling gap is essential for ultrahigh-resolution imaging through the generation of an efficient double resonance enhancement for both Raman excitation and Raman emission. Our technique not only allows for chemical imaging at the single-molecule level, but also offers a new way to study the optical processes and photochemistry of a single molecule. PMID- 23739427 TI - Argon isotopic composition of Archaean atmosphere probes early Earth geodynamics. AB - Understanding the growth rate of the continental crust through time is a fundamental issue in Earth sciences. The isotopic signatures of noble gases in the silicate Earth (mantle, crust) and in the atmosphere afford exceptional insight into the evolution through time of these geochemical reservoirs. However, no data for the compositions of these reservoirs exists for the distant past, and temporal exchange rates between Earth's interior and its surface are severely under-constrained owing to a lack of samples preserving the original signature of the atmosphere at the time of their formation. Here, we report the analysis of argon in Archaean (3.5-billion-year-old) hydrothermal quartz. Noble gases are hosted in primary fluid inclusions containing a mixture of Archaean freshwater and hydrothermal fluid. Our analysis reveals Archaean atmospheric argon with a (40)Ar/(36)Ar value of 143 +/- 24, lower than the present-day value of 298.6 (for which (40)Ar has been produced by the radioactive decay of the potassium isotope (40)K, with a half-life of 1.25 billion years; (36)Ar is primordial in origin). This ratio is consistent with an early development of the felsic crust, which might have had an important role in climate variability during the first half of Earth's history. PMID- 23739429 TI - Intuition and cooperation reconsidered. PMID- 23739431 TI - Scurvy mimicking spondyloarthritis in a young man. PMID- 23739432 TI - A M-MLV reverse transcriptase with reduced RNaseH activity allows greater sensitivity of gene expression detection in formalin fixed and paraffin embedded prostate cancer samples. AB - Formalin fixed and paraffin embedded (FFPE) human tissue collections are an invaluable resource for retrospective gene expression studies. However formalin fixation results in chemical modification of RNA and increased RNA degradation. This can affect RNA yield and quality. A critical step when analysing gene expression is the conversion of RNA to complementary DNA (cDNA) using a reverse transcriptase (RT) enzyme. FFPE derived RNA may affect the performance and efficiency of the RT enzyme and cDNA synthesis. We directly compared three commonly used FFPE RNA isolation methods and measured RNA yield, purity and integrity. We also assessed the effectiveness of three commercially available Moloney Murine Leukemia Virus (M-MLV) RTs on cDNA synthesis and gene expression sensitivity when using FFPE RNA as a template. Our results show that gene detection sensitivity is dependent on the isolation method, RT and length of the PCR amplicon (<200bp) when using FFPE RNA. The use of an M-MLV RT enzyme with reduced RNaseH activity gave significantly increased qRT-PCR sensitivity when using FFPE RNA derived from prostate tissue. The choice of RT can also affect perceived changes in target gene expression and thus the same RT should be used when attempting to reproduce results from different studies. This study highlights the need to optimise and evaluate RNA isolation methods and RTs when using FFPE RNA as a template in order to maximise a successful outcome in PCR applications. PMID- 23739433 TI - [Diagnosis of mixed tick-borne encephalitis and tick-borne borreliosis in the early stages of the disease]. AB - The paper describes a method of prognosis for the possible development of mixed tick-borne encephalitis and borreliosis based on a comparison of clinical manifestations of the disease and results of laboratory tests. PMID- 23739434 TI - [Affective disorders in women with reproductive cancer (to the problem of somatoreactive cyclothymia)]. AB - Based on the observation of 26 female patients, authors present a specific subtype of bipolar disorder - a somatoreactive cyclothymia which develops concomitantly with cancer. The affective disorder manifests itself as an acceptor of the clinical rhythm of cancer: the first and recurrent affective episodes coincide with the key stages of the disease. PMID- 23739435 TI - [Cognitive functions and treatment of their impairment in elderly patients with the vertebrobasilar issufficiensy]. AB - Authors studied impairment of cognitive functions in 180 patients, aged 56-74 years, with chronic blood flow deficiency in the vertebrobasilar territory. Along with neurological examination, we used MRI of the brain and the cervical spine, MRI-angiography, ultrasound Doppler method, EEG, ECG, clinical and biochemical blood testing. Cognitive functions were assessed using standard neuropsychological tests (a word retrieval test, the Mini-Mental State Examination, the Frontal Assessment battery, the Schulte test, the Landolt test, Wechsler tests, the Wisconsin Card Sorting Test and others). Neuropsychological performance was assessed before and after treatment with cavinton (25 mg intravenous during 10 days and then 10 mg 3 times daily during 3 months). The treatment improved cognitive function and the effect remained for more than 3 months. PMID- 23739436 TI - [Neurophysiological monitoring of the efficacy of the complex therapy of vascular and posttraumatic encephalopathy]. AB - Authors have studied the efficacy of adaptol and neyromidin in the combined treatment of patients with chronic cerebral circulation insufficiency and consequences of closed head injury using neurophysiological monitoring which included dynamic evaluation of central conductivity, neuropsychological tests and analysis of blood BDNF levels. Severe autonomic disorders, anxiety and low level of learning observed in all patients are correlated with neurophysiological (increased central conductivity time) and neurotrophic (decreased blood BDNF levels) profiles. These indicators may change throughout the treatment. The combination of adaptol and neyromidin enhanced greatly the efficacy of combined treatment. The received data allow recommending neurophysiological monitoring for treatment optimization of numerous neurological diseases that demand neuroplasticity stimulation. PMID- 23739437 TI - [The dynamics of the state of higher mental functions after surgical reconstruction of carotid stenosis using different types of anesthesia]. AB - It was studied 238 patients after the reconstructive surgeries of atherosclerotic stenosing lesions of carotid arteries using different types of anesthesia. Neuropsychological testing included MMSE, the Frontal Assessment battery and the Clock drawing test. Regional anesthesia in the combination with reduced general anesthesia caused the less pronounced cognitive deficits in patients with symptomatic or asymptomatic stenoses. Inhalation anesthesia with sevofluorane led to the more pronounced cognitive impairment compared to total intravenous anesthesia with propofol. Ceraxon was used for the correction of cognitive impairments. This treatment increased the recovery of brain functions and quality of life of patients. PMID- 23739438 TI - [Evaluation of efficacy and safety of mydocalm in the early rehabilitation of stroke]. AB - An effect of mydocalm on muscle tone and functional rehabilitation in 1700 stroke patients (mean age 63,4 years) has been studied. Patients have been divided into two standardized groups: the basic group (850 persons who received mydocalm) and control one (850 persons who didn't receive mydocalm). The muscle tone was followed up using the Ashworth Scale, pain syndrome was assessed with the Huskisson visual analog scale and a multidimensional verbal-color pain test. The functional rehabilitation was evaluated using Barthel, Lindmark, Scandinavian and Merton & Sutton scales. Psychoemotional condition was assessed with the Beck Depression Questionnaire and the Wakefield Depression Scale, quality of life was measured by the Sickness Impact Profile. The results of the study have revealed that the use of mydocalm result in the improvement of muscle tone, decrease of pain syndrome, increase of functional rehabilitation and improvement of psychoemotional condition and the quality of life of post stroke patients. The findings of the study have demonstrated the good tolerability of mydocalm. Adverse events in the mydocalm group have been identified more rarely than in the control group. PMID- 23739439 TI - [Antibodies to endogenous bioregulators and their association with age and sex in chronic pain syndrome]. AB - Authors studied changes in the levels of antibodies to endogenous bioregulators (Ab) to Beta-endorphin, orphanin, serotonin, dopamine and angiotensin in 36 healthy people and 109 patients with dorsopathy with chronic pain syndrome. The association of these immunological indicators with age and sex was found. It has been concluded that the levels of Ab to endogenous bioregulators may be considered as a marker of algic system pathology that does not depend on age and is sex-related. PMID- 23739440 TI - [Guillain-Barre syndrome: an analysis of diagnostic and treatment care]. PMID- 23739441 TI - [Social anxiety and suicidal behaviour in students]. PMID- 23739442 TI - [A role of the level of the nervous system lesion in the development of spasticity]. PMID- 23739443 TI - [A study of neuroregenerative action of cerebrolysin in brain trauma]. PMID- 23739444 TI - [Creutzfeldt-Jakob disease: a new view on an old problem (clinics, diagnosis, prognosis, treatment)]. PMID- 23739446 TI - [Approaches to treatment optimization of depression in patients with Parkinson's disease]. PMID- 23739445 TI - [Neurological presentations of Allgrove (AAA) syndrome]. PMID- 23739447 TI - [Electroencephalographic characteristics of the deja vu phenomenon]. AB - Deja vu (DV, from French "already seen") is an aberration of psychic activity associated with transitory erroneous perception of novel circumstances, objects, or people as already known. An aim of the study was to investigate EEG characteristics of DV in patients with epilepsy. We studied 166 people (63.2% women, mean age 25.17+/-9.19 years). The DV phenomenon was studied in patients (27 people) and in a control group (139 healthy people). Patients were interviewed for DV characteristics and underwent a long (12-16 h) ambulatory EEG monitoring study. In EEG, DV episodes in patients began with polyspike activity in the right temporal lobe and, in some cases, ended with the slow-wave theta delta activity in the right hemisphere. PMID- 23739448 TI - [Cryptogenic epilepsy in adults: "hidden problems of structural well-being"]. AB - Cryptogenic epilepsy (epilepsy with no obvious cause) is the most common form of the disease in adults. The author discuss clinical- electroencephalographic, neuroimaging (magnetic resonance tomography, positron emission tomography, proton magnetic resonance spectroscopy, diffusion tensor magnetic resonance tomography) and treatment aspects of 70 patients with cryptogenic epilepsy. A dynamic study of patients using neuroimaging methods allowed to single out two groups of patients differed by the course, outcome and treatment. The author suggests hypotheses on the explanation of processes underlying epilepsy with no obvious cause. PMID- 23739449 TI - [A modern approach to a definition of cryptogenic epilepsy]. PMID- 23739450 TI - [A comparative study of the prevalence and risk factors of focal epilepsy in adults in the Republic of Kazakhstan and the Russian Federation]. AB - The results of the comparative study of the prevalence and risk factors of epilepsy in adults in the Republic of Kazakhstan and the Russian Federation revealed that the consequences of perinatal pathology was the main risk factor in young patients while the consequences of brain injury or cerebrovascular disease predicted epilepsy in middle age and elderly people, respectively. These data may be used for prediction of course of epilepsy provided that long-term and careful studies on the dynamics of above-mentioned indicators will be carried out. PMID- 23739451 TI - [Risk factors for posttraumatic epilepsy in adults]. PMID- 23739452 TI - [Clinical features of epileptic seizures in acute and chronic cerebral blood circulation disorders]. AB - We present the results of the study of 422 patients with acute and chronic brain ischemia and epileptic seizures. The features of seizures in relation to sex of patients, pathogenetic subtypes of stroke, timing of seizures after stroke as well as EEG and MRI characteristics are described. PMID- 23739453 TI - [Modern approaches to the encephalographic diagnosis of non-convulsive status epilepticus]. AB - The article presents modern conceptions on instrumental diagnosis, using electroencephalography, of non-convulsive status epilepticus (NCSE) based on a traditional classification and recommendations of the American Clinical Neurophysiology Society (2012). The descriptive diagnostic parameters for the recognition of different changes in the brain electrical activity in NCSE and their correlations in the structure of traditional and new classifications are presented. PMID- 23739454 TI - [Anxiety in epileptic patients]. AB - We examined 182 patients with epilepsy using the evaluation of anamnesis, clinical and neurological examination, routine EEG and/or video-EEG-monitoring, MRI of the brain. The period of observation was 1-11 years (on average 2 years). Anxiety and depression symptoms were screened with the Hospital anxiety and depression scale (HADS). Health-related quality of life was examined with the Quality of Life in Epilepsy Inventory (QOLIE-31, version 1). The diagnosis was confirmed in 166 cases and nonepileptic seizures were diagnosed in 16 cases. Subclinical anxiety (8-10 HADS scores) was identified in 23 (12.6%), clinical anxiety (>10 scores) - in 47 (25.8%), subclinical depression (8-10 scores) - in 25 (13.7%) and clinical depression (>10 scores) - in 23 (12.6%) cases. Comorbidity of anxiety and depression was noted in 33 (18.1%) patients. The high level of anxiety was correlated with the young age and short duration of epilepsy. Anxiety (r=0.7; p<0.05) and depression (r=0.63; p<0.05) were significantly correlated with the poor quality of life. PMID- 23739455 TI - [Efficacy and safety of topiramate depending on patient's age and forms of epilepsy]. AB - Seven hundreds and twenty-two epileptic patients receiving topiramate (374 males, 348 females), aged from 3 month to 57 years, were followed with video-EEG control during the period of 2002-2012. Topiramate was effective in 465 (64.4%) patients, and among them the efficacy of monotherapy (72.2%) was higher compared to combined therapy (61.9%). The low efficacy was seen in 198 (27.4%) patients. The aggravation effect was noted in 59 (8.2%) of patients. Drug compliance (for >1 year) was 60.7%. In the group <1 year, the high efficacy was observed in 55.2%, low efficacy - in 34.5%, aggravation - in 10.3%. In the group 1-3 years, these indicators were 54.8%, 31.8% and 13.4%, respectively. In the pediatric population (>3 years), they were 67.3%, 26.2% and 6.5% as well as in the adult population (>18 years) - 82.1%, 16.6% and 1.3%, respectively. Thus, topiramate is a highly effective medication in the therapy of idiopathic generalized epilepsies without absences and in symptomatic/cryptogenic focal forms of epilepsy. The efficacy of topiramate raised with increasing of age while the aggravation risk decreased significantly. PMID- 23739456 TI - [Principles of treatment of epilepsy in elderly patients]. PMID- 23739457 TI - [Antiepileptic drugs: over than epilepsy (anticonvulsants drugs use in different pain syndromes)]. PMID- 23739458 TI - [A paradoxical reaction on valproates in a female patient with juvenile absence epilepsy]. AB - A case of a female patient with juvenile absence epilepsy who developed generalized seizures after the treatment with valproic acid preparations is described. The further choice of antiepileptic treatment for this patient revealed that carbamazepine (finlepsin retard) and lamotrigine were effective for stopping generalized seizures and absences, respectively. PMID- 23739459 TI - [A pharmacoeconomical analysis of idiopathic epilepsy]. AB - We have analyzed pharmacoeconomical indicators in the treatment of idiopathic (generalized and focal) epilepsy in children and adolescence in an ambulatory treatment/diagnostic center of a big industrial city. In the total structure, focal epilepsy made up 41.73% (255 patients, 128 boys (50.2%) and 128 girls (49.8%)). Generalized forms were diagnosed in 61.96% (n=158) and partial forms - in 37.6% (n=97%) patients. Minimal direct and indirect costs for one patient were calculated for patients in remission and did not depend on the form of epilepsy. The costs increased by a magnitude of two or more for treatment efficiency 50% and by 3 times for insufficient efficiency of treatment of different forms of epilepsy. In case of a loss of control of seizures, indirect costs exceeded the economy of direct costs. Adequate treatment of idiopathic epilepsy in children is economically profitable because it allows to improve quality of life of a child and maintain manpower resources in the nearest future. PMID- 23739460 TI - Ultra-widefield imaging for the management of pediatric retinal diseases. AB - PURPOSE: To describe the utility of using ultra-widefield digital fundus photography and ultra-widefield fluorescein angiography (UWFA) in the pediatric patient population to evaluate peripheral retinal pathology and to manage Coats' disease and familial exudative vitreoretinopathy (FEVR). METHODS: Retrospective review of pediatric retinal patients with FEVR or Coats' disease who underwent ultra-widefield fundus photography and UWFA. RESULTS: Eight patients were included in this case series. Five patients had the clinical diagnosis of FEVR, and two eyes of two patients with FEVR received UWFA-guided laser photocoagulation. Three patients were diagnosed as having Coats' disease and received UWFA-guided laser photocoagulation. CONCLUSIONS: Ultra-widefield fundus photography and UWFA can be used successfully as an outpatient procedure in the pediatric patient population without the necessity of examination under anesthesia and can aid the physician in the documentation and evaluation of peripheral retinal pathology. UWFA can also assist in directing laser photocoagulation in the treatment of pediatric retinal diseases. PMID- 23739461 TI - Versatile self-assembled molecular capsule formation of a resorcin[4]arene-based benzamidoiminocavitand. AB - The facile synthesis of a resorcin[4]arene-based imino-cavitand with benzamido moieties and its self-assembly into molecular capsules are reported. Benzamido iminocavitand efficiently self-assembled into thermally inert molecular capsules in the presence of suitable guests via the eight intermolecular N-H...O=C hydrogen bonds. PMID- 23739462 TI - Editorial: Greenhouse Gases and Animal Agriculture Conference, Dublin, 2013. PMID- 23739463 TI - Agriculture in the climate change negotiations; ensuring that food production is not threatened. AB - With the human population predicted to reach nine billion by 2050, demand for food is predicted to more than double over this time period, a trend which will lead to increased greenhouse gas (GHG) emissions from agriculture. Furthermore, expansion in food production is predicted to occur primarily in the developing world, where adaptation to climate change may be more difficult and opportunities to mitigate emissions limited. In the establishment of the United Nations Framework Convention on Climate Change (UNFCCC), 'ensuring that food production is not threatened' is explicitly mentioned in the objective of the Convention. However, the focus of negotiations under the Convention has largely been on reducing GHG emissions from energy, and industrial activities and realizing the potential of forestry as a carbon sink. There has been little attention by the UNFCCC to address the challenges and opportunities for the agriculture sector. Since 2006, concerted efforts have been made to raise the prominence of agriculture within the negotiations. The most recent The Intergovernmental Panel on Climate Change report and 'The Emissions Gap Report' by the UNEP highlighted the significant mitigation potential of agriculture, which can help contribute towards keeping global temperature rises below the 2 degrees C limit agreed in Cancun. Agriculture has to be a part of the solution to address climate change, but this will also require a focus on how agriculture systems can adapt to climate change in order to continue to increase food output. However, to effectively realize this potential, systematic and dedicated discussion and decisions within the UNFCCC are needed. UNFCCC discussions on a specific agriculture agenda item started in 2012, but are currently inconclusive. However, Parties are generally in agreement on the importance of agriculture in contributing to food security and employment as well as the need to improve understanding of agriculture and how it can contribute to realizing climate objectives. Discussions on agriculture are continuing with a view to finding an acceptable approach to address the climate change related challenges faced by agriculture worldwide and to ensure that 'food production is not threatened'. PMID- 23739464 TI - An LCA researcher's wish list--data and emission models needed to improve LCA studies of animal production. AB - The last decade has seen an increase in environmental systems analysis of livestock production, resulting in a significant number of studies with a holistic approach often based on life-cycle assessment (LCA) methodology. The growing public interest in global warming has added to this development; guidelines for carbon footprint (CF) accounting have been developed, including for greenhouse gas (GHG) accounting of animal products. Here we give an overview of methods for estimating GHG emissions, with emphasis on nitrous oxide, methane and carbon from land use change, presently used in LCA/CF studies of animal products. We discuss where methods and data availability for GHGs and nitrogen (N) compounds most urgently need to be improved in order to produce more accurate environmental assessments of livestock production. We conclude that the top priority is to improve models for N fluxes and emissions from soils and to implement soil carbon change models in LCA/CF studies of animal products. We also point at the need for more farm data and studies measuring emissions from soils, manure and livestock in developing countries. PMID- 23739465 TI - Technical options for the mitigation of direct methane and nitrous oxide emissions from livestock: a review. AB - Although livestock production accounts for a sizeable share of global greenhouse gas emissions, numerous technical options have been identified to mitigate these emissions. In this review, a subset of these options, which have proven to be effective, are discussed. These include measures to reduce CH4 emissions from enteric fermentation by ruminants, the largest single emission source from the global livestock sector, and for reducing CH4 and N2O emissions from manure. A unique feature of this review is the high level of attention given to interactions between mitigation options and productivity. Among the feed supplement options for lowering enteric emissions, dietary lipids, nitrates and ionophores are identified as the most effective. Forage quality, feed processing and precision feeding have the best prospects among the various available feed and feed management measures. With regard to manure, dietary measures that reduce the amount of N excreted (e.g. better matching of dietary protein to animal needs), shift N excretion from urine to faeces (e.g. tannin inclusion at low levels) and reduce the amount of fermentable organic matter excreted are recommended. Among the many 'end-of-pipe' measures available for manure management, approaches that capture and/or process CH4 emissions during storage (e.g. anaerobic digestion, biofiltration, composting), as well as subsurface injection of manure, are among the most encouraging options flagged in this section of the review. The importance of a multiple gas perspective is critical when assessing mitigation potentials, because most of the options reviewed show strong interactions among sources of greenhouse gas (GHG) emissions. The paper reviews current knowledge on potential pollution swapping, whereby the reduction of one GHG or emission source leads to unintended increases in another. PMID- 23739466 TI - Genome sequencing of rumen bacteria and archaea and its application to methane mitigation strategies. AB - Ruminant-derived methane (CH4), a potent greenhouse gas, is a consequence of microbial fermentation in the digestive tract of livestock. Development of mitigation strategies to reduce CH4 emissions from farmed animals is currently the subject of both scientific and environmental interest. Methanogens are the sole producers of ruminant CH4, and therefore CH4 abatement strategies can either target the methanogens themselves or target the other members of the rumen microbial community that produce substrates necessary for methanogenesis. Understanding the relationship that methanogens have with other rumen microbes is crucial when considering CH4 mitigation strategies for ruminant livestock. Genome sequencing of rumen microbes is an important tool to improve our knowledge of the processes that underpin those relationships. Currently, several rumen bacterial and archaeal genome projects are either complete or underway. Genome sequencing is providing information directly applicable to CH4 mitigation strategies based on vaccine and small molecule inhibitor approaches. In addition, genome sequencing is contributing information relevant to other CH4 mitigation strategies. These include the selection and breeding of low CH4-emitting animals through the interpretation of large-scale DNA and RNA sequencing studies and the modification of other microbial groups within the rumen, thereby changing the dynamics of microbial fermentation. PMID- 23739467 TI - Progress in the development of vaccines against rumen methanogens. AB - Vaccination against rumen methanogens offers a practical approach to reduce methane emissions in livestock, particularly ruminants grazing on pasture. Although successful vaccination strategies have been reported for reducing the activity of the rumen-dwelling organism Streptococcus bovis in sheep and S. bovis and Lactobacillus spp. in cattle, earlier approaches using vaccines based on whole methanogen cells to reduce methane production in sheep have produced less promising results. An anti-methanogen vaccine will need to have broad specificity against methanogens commonly found in the rumen and induce antibody in saliva resulting in delivery of sufficiently high levels of antibodies to the rumen to reduce methanogen activity. Our approach has focussed on identifying surface and membrane-associated proteins that are conserved across a range of rumen methanogens. The identification of potential vaccine antigens has been assisted by recent advances in the knowledge of rumen methanogen genomes. Methanogen surface proteins have been shown to be immunogenic in ruminants and vaccination of sheep with these proteins induced specific antibody responses in saliva and rumen contents. Current studies are directed towards identifying key candidate antigens and investigating the level and types of salivary antibodies produced in sheep and cattle vaccinated with methanogen proteins, stability of antibodies in the rumen and their impact on rumen microbial populations. In addition, there is a need to identify adjuvants that stimulate high levels of salivary antibody and are suitable for formulating with protein antigens to produce a low-cost and effective vaccine. PMID- 23739468 TI - Plant components with specific activities against rumen methanogens. AB - A wide range of plant bioactive components (phytochemicals) have been identified as having potential to modulate the processes of fermentation in the rumen. The use of plants or plant extracts as natural feed additives has become a subject of interest not only among nutritionists but also other scientists. Although a large number of phytochemicals (e.g. saponins, tannins and essential oils) have recently been investigated for their methane reduction potential, there have not yet been major breakthroughs that could be applied in practice. A key tenet of this paper is the need for studies on the influence of plant components on methane production to be performed with standardized samples. Where there are consistent effects, the literature suggests that saponins mitigate methanogenesis mainly by reducing the number of protozoa, condensed tannins both by reducing the number of protozoa and by a direct toxic effect on methanogens, whereas essential oils act mostly by a direct toxic effect on methanogens. However, because the rumen is a complex ecosystem, analysis of the influence of plant components on the populations of methanogens should take into account not only the total population of methanogens but also individual orders or species. Although a number of plants and plant extracts have shown potential in studies in vitro, these effects must be confirmed in vivo. PMID- 23739469 TI - Manure management for greenhouse gas mitigation. AB - Ongoing intensification and specialisation of livestock production lead to increasing volumes of manure to be managed, which are a source of the greenhouse gases (GHGs) methane (CH4) and nitrous oxide (N2O). Net emissions of CH4 and N2O result from a multitude of microbial activities in the manure environment. Their relative importance depends not only on manure composition and local management practices with respect to treatment, storage and field application, but also on ambient climatic conditions. The diversity of livestock production systems, and their associated manure management, is discussed on the basis of four regional cases (Sub-Saharan Africa, Southeast Asia, China and Europe) with increasing levels of intensification and priorities with respect to nutrient management and environmental regulation. GHG mitigation options for production systems based on solid and liquid manure management are then presented, and potentials for positive and negative interactions between pollutants, and between management practices, are discussed. The diversity of manure properties and environmental conditions necessitate a modelling approach for improving estimates of GHG emissions, and for predicting effects of management changes for GHG mitigation, and requirements for such a model are discussed. Finally, we briefly discuss drivers for, and barriers against, introduction of GHG mitigation measures for livestock production. There is no conflict between efforts to improve food and feed production, and efforts to reduce GHG emissions from manure management. Growth in livestock populations are projected to occur mainly in intensive production systems where, for this and other reasons, the largest potentials for GHG mitigation may be found. PMID- 23739470 TI - Anaerobic digestion of agricultural and other substrates--implications for greenhouse gas emissions. AB - The greenhouse gas (GHG) emissions, expressed in carbon dioxide equivalents (CO2 eq), of different Austrian biogas systems were analyzed and evaluated using life cycle assessment (LCA) as part of a national project. Six commercial biogas plants were investigated and the analysis included the complete process chain: viz., the production and collection of substrates, the fermentation of the substrates in the biogas plant, the upgrading of biogas to biomethane (if applicable) and the use of the biogas or biomethane for heat and electricity or as transportation fuel. Furthermore, the LCA included the GHG emissions of construction, operation and dismantling of the major components involved in the process chain, as well as the use of by-products (e.g. fermentation residues used as fertilizers). All of the biogas systems reduced GHG emissions (in CO2-eq) compared with fossil reference systems. The potential for GHG reduction of the individual biogas systems varied between 60% and 100%. Type of feedstock and its reference use, agricultural practices, coverage of storage tanks for fermentation residues, methane leakage at the combined heat and power plant unit and the proportion of energy used as heat were identified as key factors influencing the GHG emissions of anaerobic digestion processes. PMID- 23739471 TI - Diet effects on urine composition of cattle and N2O emissions. AB - Ruminant production contributes to emissions of nitrogen (N) to the environment, principally ammonia (NH3), nitrous oxide (N2O) and di-nitrogen (N2) to air, nitrate (NO3 -) to groundwater and particulate N to surface waters. Variation in dietary N intake will particularly affect excretion of urinary N, which is much more vulnerable to losses than is faecal N. Our objective is to review dietary effects on the level and form of N excreted in cattle urine, as well as its consequences for emissions of N2O. The quantity of N excreted in urine varies widely. Urinary N excretion, in particular that of urea N, is decreased upon reduction of dietary N intake or an increase in the supply of energy to the rumen microorganisms and to the host animal itself. Most of the N in urine (from 50% to well over 90%) is present in the form of urea. Other nitrogenous components include purine derivatives (PD), hippuric acid, creatine and creatinine. Excretion of PD is related to rumen microbial protein synthesis, and that of hippuric acid to dietary concentration of degradable phenolic acids. The N concentration of cattle urine ranges from 3 to 20 g/l. High-dietary mineral levels increase urine volume and lead to reduced urinary N concentration as well as reduced urea concentration in plasma and milk. In lactating dairy cattle, variation in urine volume affects the relationship between milk urea and urinary N excretion, which hampers the use of milk urea as an accurate indicator of urinary N excretion. Following its deposition in pastures or in animal houses, ubiquitous microorganisms in soil and waters transform urinary N components into ammonium (NH4 +), and thereafter into NO3 - and ultimately in N2 accompanied with the release of N2O. Urinary hippuric acid, creatine and creatinine decompose more slowly than urea. Hippuric acid may act as a natural inhibitor of N2O emissions, but inhibition conditions have not been defined properly yet. Environmental and soil conditions at the site of urine deposition or manure application strongly influence N2O release. Major dietary strategies to mitigating N2O emission from cattle operations include reducing dietary N content or increasing energy content, and increasing dietary mineral content to increase urine volume. For further reduction of N2O emission, an integrated animal nutrition and excreta management approach is required. PMID- 23739472 TI - Reducing GHG emissions through genetic improvement for feed efficiency: effects on economically important traits and enteric methane production. AB - Genetic selection for residual feed intake (RFI) is an indirect approach for reducing enteric methane (CH4) emissions in beef and dairy cattle. RFI is moderately heritable (0.26 to 0.43), moderately repeatable across diets (0.33 to 0.67) and independent of body size and production, and when adjusted for off-test ultrasound backfat thickness (RFI fat) is also independent of body fatness in growing animals. It is highly dependent on accurate measurement of individual animal feed intake. Within-animal repeatability of feed intake is moderate (0.29 to 0.49) with distinctive diurnal patterns associated with cattle type, diet and genotype, necessitating the recording of feed intake for at least 35 days. In addition, direct measurement of enteric CH4 production will likely be more variable and expensive than measuring feed intake and if conducted should be expressed as CH4 production (g/animal per day) adjusted for body size, growth, body composition and dry matter intake (DMI) or as residual CH4 production. A further disadvantage of a direct CH4 phenotype is that the relationships of enteric CH4 production on other economically important traits are largely unknown. Selection for low RFI fat (efficient, -RFI fat) will result in cattle that consume less dry matter (DMI) and have an improved feed conversion ratio (FCR) compared with high RFI fat cattle (inefficient; +RFI fat). Few antagonistic effects have been reported for the relationships of RFI fat on carcass and meat quality, fertility, cow lifetime productivity and adaptability to stress or extensive grazing conditions. Low RFI fat cattle also produce 15% to 25% less enteric CH4 than +RFI fat cattle, since DMI is positively related to enteric methane (CH4) production. In addition, lower DMI and feeding duration and frequency, and a different rumen bacterial profile that improves rumen fermentation in -RFI fat cattle may favor a 1% to 2% improvement in dry matter and CP digestibility compared with +RFI fat cattle. Rate of genetic change using this approach is expected to improve feed efficiency and reduce enteric CH4 emissions from cattle by 0.75% to 1.0% per year at equal levels of body size, growth and body fatness compared with cattle not selected for RFI fat. PMID- 23739473 TI - Heritability estimates of methane emissions from sheep. AB - The objective of this study was to determine the genetic parameters of methane (CH4) emissions and their genetic correlations with key production traits. The trial measured the CH4 emissions, at 5-min intervals, from 1225 sheep placed in respiration chambers for 2 days, with repeat measurements 2 weeks later for another 2 days. They were fed in the chambers, based on live weight, a pelleted lucerne ration at 2.0 times estimated maintenance requirements. Methane outputs were calculated for g CH4/day and g CH4/kg dry matter intake (DMI) for each of the 4 days. Single trait models were used to obtain estimates of heritability and repeatability. Heritability of g CH4/day was 0.29 +/- 0.05, and for g CH4/kg DMI 0.13 +/- 0.03. Repeatability between measurements 14 days apart were 0.55 +/- 0.02 and 0.26 +/- 0.02, for the two traits. The genetic and phenotypic correlations of CH4 outputs with various production traits (weaning weight, live weight at 8 months of age, dag score, muscle depth and fleece weight at 12 months of age) measured in the first year of life, were estimated using bivariate models. With the exception of fleece weight, correlations were weak and not significantly different from zero for the g CH4/kg DMI trait. For fleece weight the phenotypic and genetic correlation estimates were -0.08 +/- 0.03 and -0.32 +/ 0.11 suggesting a low economically favourable relationship. These results indicate that there is genetic variation between animals for CH4 emission traits even after adjustment for feed intake and that these traits are repeatable. Current work includes the establishment of selection lines from these animals to investigate the physiological, microbial and anatomical changes, coupled with investigations into shorter and alternative CH4 emission measurement and breeding value estimation techniques; including genomic selection. PMID- 23739474 TI - Potential for biological nitrification inhibition to reduce nitrification and N2O emissions in pasture crop-livestock systems. AB - Agriculture and livestock production systems are two major emitters of greenhouse gases. Methane with a GWP (global warming potential) of 21, and nitrous oxide (N2O) with a GWP of 300, are largely emitted from animal production agriculture, where livestock production is based on pasture and feed grains. The principal biological processes involved in N2O emissions are nitrification and denitrification. Biological nitrification inhibition (BNI) is the natural ability of certain plant species to release nitrification inhibitors from their roots that suppress nitrifier activity, thus reducing soil nitrification and N2O emission. Recent methodological developments (e.g. bioluminescence assay to detect BNIs in plant root systems) have led to significant advances in our ability to quantify and characterize the BNI function. Synthesis and release of BNIs from plants is a highly regulated process triggered by the presence of NH4 + in the rhizosphere, which results in the inhibitor being released precisely where the majority of the soil-nitrifier population resides. Among the tropical pasture grasses, the BNI function is strongest (i.e. BNI capacity) in Brachiaria sp. Some feed-grain crops such as sorghum also have significant BNI capacity present in their root systems. The chemical identity of some of these BNIs has now been established, and their mode of inhibitory action on Nitrosomonas has been characterized. The ability of the BNI function in Brachiaria pastures to suppress N2O emissions and soil nitrification potential has been demonstrated; however, its potential role in controlling N2O emissions in agro-pastoral systems is under investigation. Here we present the current status of our understanding on how the BNI functions in Brachiaria pastures and feed-grain crops such as sorghum can be exploited both genetically and, from a production system's perspective, to develop low-nitrifying and low N2O-emitting production systems that would be economically profitable and ecologically sustainable. PMID- 23739475 TI - Animal health aspects of adaptation to climate change: beating the heat and parasites in a warming Europe. AB - Weather patterns in northern European regions have changed noticeably over the past several decades, featuring warmer, wetter weather with more extreme events. The climate is projected to continue on this trajectory for the foreseeable future, even under the most modest warming scenarios. Such changes will have a significant impact on livestock farming, both directly through effects on the animals themselves, and indirectly through changing exposure to pests and pathogens. Adaptation options aimed at taking advantage of new opportunities and/or minimising the risks of negative impacts will, in themselves, have implications for animal health and welfare. In this review, we consider the potential consequences of future intensification of animal production, challenges associated with indoor and outdoor rearing of animals and aspects of animal transportation as key examples. We investigate the direct and indirect effects of climate change on the epidemiology of important livestock pathogens, with a particular focus on parasitic infections, and the likely animal health consequences associated with selected adaptation options. Finally, we attempt to identify key gaps in our knowledge and suggest future research priorities. PMID- 23739476 TI - Adaptation to climate change--exploring the potential of locally adapted breeds. AB - The livestock sector and agriculture as a whole face unprecedented challenges to increase production while improving the environment. On the basis of a literature review, the paper first discusses challenges related to climate change, food security and other drivers of change in livestock production. On the basis of a recent discourse in ecology, a framework for assessing livestock species' and breeds' vulnerability to climate change is presented. The second part of the paper draws on an analysis of data on breed qualities obtained from the Food and Agriculture Organization's Domestic Animal Diversity Information System (DAD-IS) to explore the range of adaptation traits present in today's breed diversity. The analysis produced a first mapping of a range of ascribed adaptation traits of national breed populations. It allowed to explore what National Coordinators understand by 'locally adapted' and other terms that describe general adaptation, to better understand the habitat, fodder and temperature range of each species and to shed light on the environments in which targeted search for adaptation traits could focus. PMID- 23739477 TI - Measurement and mitigation of methane emissions from beef cattle in tropical grazing systems: a perspective from Australia and Brazil. AB - The growing global demand for food of animal origin will be the incentive for countries such as Australia and Brazil to increase their beef production and international exports. This increased supply of beef is expected to occur primarily through on-farm productivity increases. The strategies for reducing resultant greenhouse gas (GHG) emissions should be evaluated in the context of the production system and should encompass a broader analysis, which would include the emissions of methane (CH4) and nitrous oxide (N2O) and carbon sequestration. This paper provides an insight into CH4 measurement techniques applicable to grazing environments and proposed mitigation strategies, with relevance to the production systems that are predominant in grazing systems of Australia and Brazil. Research and technology investment in both Australia and Brazil is aimed at developing measurement techniques and increasing the efficiency of cattle production by improving herd genetics, utilization of the seasonal feed-base and reducing the proportion of metabolizable energy lost as CH4. Concerted efforts in these areas can be expected to reduce the number of unproductive animals, reduce age at slaughter and inevitably reduce emission intensity (EI) from beef production systems. Improving efficiency of livestock production systems in tropical grazing systems for Australia and Brazil will be based on cultivated and existing native pastures and the use of additives and by products from other agricultural sectors. This approach spares grain-based feed reserves typically used for human consumption, but potentially incurs a heavier EI than current intensive feeding systems. The determination of GHG emissions and the value of mitigation outcomes for entire beef production systems in the extensive grazing systems is complex and require a multidisciplinary approach. It is fortunate that governments in both Australia and Brazil are supporting ongoing research activities. Nevertheless, to achieve an outcome that feeds a growing population while reducing emissions on a global scale continues to be a monumental challenge for ruminant nutritionists. PMID- 23739478 TI - Whole-farm models to quantify greenhouse gas emissions and their potential use for linking climate change mitigation and adaptation in temperate grassland ruminant-based farming systems. AB - The farm level is the most appropriate scale for evaluating options for mitigating greenhouse gas (GHG) emissions, because the farm represents the unit at which management decisions in livestock production are made. To date, a number of whole farm modelling approaches have been developed to quantify GHG emissions and explore climate change mitigation strategies for livestock systems. This paper analyses the limitations and strengths of the different existing approaches for modelling GHG mitigation by considering basic model structures, approaches for simulating GHG emissions from various farm components and the sensitivity of GHG outputs and mitigation measures to different approaches. Potential challenges for linking existing models with the simulation of impacts and adaptation measures under climate change are explored along with a brief discussion of the effects on other ecosystem services. PMID- 23739479 TI - Developments in micrometeorological methods for methane measurements. AB - Micrometeorological techniques can be applied to estimate methane (CH4) emissions from ruminants and livestock manure using CH4 concentration measured within the internal surface boundary layer. The main advantage of these techniques is that they are non-intrusive, thereby eliminating the impact of the measurement set-up on the calculated CH4 emission. This review focuses on four micrometeorological techniques, namely, the integrated horizontal flux (IHF), flux gradient (FG), eddy covariance (EC) and the dispersion modelling using the backward Lagrangian stochastic method (BLS). Each technique has unique advantages and limitations when used for estimating enteric (ruminant) and manure CH4 emissions. The IHF technique may be theoretically simpler then the FG, EC or BLS techniques, but all require high-resolution instruments to measure concentration. The EC and BLS techniques also require a measurement of the wind statistics. This review discusses the appropriate use of these four micrometeorological techniques for estimating CH4 emissions in animal agriculture and the recent advances in measurement technology. PMID- 23739480 TI - Opportunities and challenges in the use of the Laser Methane Detector to monitor enteric methane emissions from ruminants. AB - The objective of this review was to examine the application and relative efficiency of the proprietary hand-held Laser Methane Detector (LMD) in livestock production, with a focus on opportunities and challenges in different production systems. The LMD is based on IR absorption spectroscopy, uses a semiconductor laser as a collimated excitation source and uses the second harmonic detection of wavelength modulation spectroscopy to establish a methane (CH4) concentration measurement. The use of the LMD for CH4 detection in dairy cows is relatively recent. Although developed for entirely different purposes, the LMD provides an opportunity for non-invasive and non-contact scan sampling of enteric CH4. With the possibility for real-time CH4 measurements, the LMD offers a molecular sensitive technique for enteric CH4 detection in ruminants. Initial studies have demonstrated a relatively strong agreement between CH4 measurements from the LMD with those recorded in the indirect open-circuit respiration calorimetric chamber (correlation coefficient, r = 0.8, P < 0.001). The LMD has also demonstrated a strong ability to detect periods of high-enteric CH4 concentration (sensitivity = 95%) and the ability to avoid misclassifying periods of low-enteric CH4 concentration (specificity = 79%). Being portable, the LMD enables spot sampling of methane in different locations and production systems. Two challenges are discussed in the present review. First is on extracting a representation of a point measurement from breath cycle concentrations. The other is on using the LMD in grazing environment. Work so far has shown the need to integrate ambient condition statistics in the flux values. Despite the challenges that have been associated with the use of the LMD, with further validation, the technique has the potential to be utilised as an alternative method in enteric CH4 measurements in ruminants. PMID- 23739481 TI - Applicability of short-term emission measurements for on-farm quantification of enteric methane. AB - A short term enteric methane emission measurement is not identical to a measure of daily methane production (DMP) made in a respiration chamber (RC). While RC curtail most variation except that from quantity and composition of feed supplied, all short-term measurements contain additional sources of variation. The points of difference can include measurement time(s) relative to feeding, feed intake before measurement, animal behaviour in selection of diet and level of activity before measurement. For systems where a short-term emission measurement is made at the same time in the daily feeding cycle (e.g. during twice-daily milking) scaling up of short-term emission rates to estimate DMP is feasible but the scaling coefficient(s) will be diet dependent. For systems such as GreenFeed where direct emission rates are measured on occasion throughout day and night, no scaling up may be required to estimate DMP. For systems where small numbers of emission measures are made, and there is no knowledge of prior feed intake, such as for portable accumulation chambers, scaling to DMP is not currently possible. Even without scaling up to DMP, short-term measured emission rates are adequate for identifying relative emission changes induced by mitigation strategies and could provide the data to support genetic selection of ruminants for reduced enteric emissions. PMID- 23739482 TI - Chemical markers for rumen methanogens and methanogenesis. AB - The targeting of mcrA or 16S rRNA genes by quantitative PCR (qPCR) has become the dominant method for quantifying methanogens in rumen. There are considerable discrepancies between estimates based on different primer sets, and the literature is equivocal about the relationship with methane production. There are a number of problems with qPCR, including low primer specificity, multiple copies of genes and multiple genomes per cell. Accordingly, we have investigated alternative markers for methanogens, on the basis of the distinctive ether lipids of archaeal cell membranes. The membranes of Archaea contain dialkyl glycerol ethers such as 2,3-diphytanayl-O-sn-glycerol (archaeol), and glycerol dialkyl glycerol tetraethers (GDGTs) such as caldarchaeol (GDGT-0) in different proportions. The relationships between estimates of methanogen abundance using qPCR and archaeol measurements varied across primers. Studies in other ecosystems have identified environmental effects on the profile of ether lipids in Archaea. There is a long history of analysing easily accessible samples, such as faeces, urine and milk, to provide information about digestion and metabolism in livestock without the need for intrusive procedures. Purine derivatives in urine and odd-chain fatty acids in milk have been used to study rumen function. The association between volatile fatty acid proportions and methane production is probably the basis for empirical relationships between milk fatty acid profiles and methane production. However, these studies have not yet identified consistent predictors. We have evaluated the relationship between faecal archaeol concentration and methane production across a range of diets in studies on beef and dairy cattle. Faecal archaeol is diagnostic for ruminant faeces being below the limit of detection in faeces from non-ruminant herbivores. The relationship between faecal archaeol and methane production was significant when comparing treatment means across diets, but appears to be subject to considerable between animal variation. This variation was also evident in the weak relationship between archaeol concentrations in rumen digesta and faeces. We speculate that variation in the distribution and kinetics of methanogens in the rumen may affect the survival and functioning of Archaea in the rumen and therefore contribute to genetic variation in methane production. Indeed, variation in the relationship between the numbers of micro-organisms present in the rumen and those leaving the rumen may explain variation in relationships between methane production and both milk fatty acid profiles and faecal archaeol. As a result, microbial markers in the faeces and milk are unlikely to relate well back to methanogenesis in the rumen. This work has also highlighted the need to describe methanogen abundance in all rumen fractions and this may explain the difficulty interpreting results on the basis of samples taken using stomach tubes or rumenocentesis. PMID- 23739483 TI - Using stable isotopes to follow excreta N dynamics and N2O emissions in animal production systems. AB - Nitrous oxide (N2O) is a potent greenhouse gas and the dominant anthropogenic stratospheric ozone-depleting emission. The tropospheric concentration of N2O continues to increase, with animal production systems constituting the largest anthropogenic source. Stable isotopes of nitrogen (N) provide tools for constraining emission sources and, following the temporal dynamics of N2O, providing additional insight and unequivocal proof of N2O source, production pathways and consumption. The potential for using stable isotopes of N is underutilised. The intent of this article is to provide an overview of what these tools are and demonstrate where and how these tools could be applied to advance the mitigation of N2O emissions from animal production systems. Nitrogen inputs and outputs are dominated by fertiliser and excreta, respectively, both of which are substrates for N2O production. These substrates can be labelled with 15N to enable the substrate-N to be traced and linked to N2O emissions. Thus, the effects of changes to animal production systems to reduce feed-N wastage by animals and fertiliser wastage, aimed at N2O mitigation and/or improved animal or economic performance, can be traced. Further 15N-tracer studies are required to fully understand the dynamics and N2O fluxes associated with excreta, and the biological contribution to these fluxes. These data are also essential for the new generation of 15N models. Recent technique developments in isotopomer science along with stable isotope probing using multiple isotopes also offer exciting capability for addressing the N2O mitigation quest. PMID- 23739484 TI - The Carbon Navigator: a decision support tool to reduce greenhouse gas emissions from livestock production systems. AB - The Carbon Navigator has been developed to support the objective of reducing the carbon intensity of the dairy and beef sectors of Irish agriculture. The system is designed as a knowledge transfer (KT) tool aimed at supporting the realisation at farm level of the mitigation potential. The objective of this paper is to outline the potential role of KT in reducing greenhouse gas emissions in the context of a growing body of science, which identifies potential mitigation. The EU policy framework for agriculture and the environment is examined in terms of its effectiveness in supporting the reduction in emission intensity of agriculture. The important role for KT in reducing agricultural emissions is highlighted. The Carbon Navigator is introduced as a potential aid to achieving improved adoption of emission-reducing technologies and practices at farm level. The paper outlines the criteria guiding the selection of mitigation technologies in Irish ruminant agriculture, describes the technologies and practices included in the system and outlines the basis for their inclusion. The approach of developing the Carbon Navigator to integrate into existing infrastructure and data systems as well as into the existing KT systems is outlined. PMID- 23739485 TI - Farm-specific carbon footprinting to the farm gate for agricultural co-products using the OVERSEER(r) model. AB - The user inputs to OVERSEER(r) Nutrient Budgets (Overseer) allow farm-specific greenhouse gas (GHG) emissions to be estimated. Since the development of the original model, life cycle assessment standards (e.g. PAS 2050) have been proposed and adopted for determining GHG or carbon footprints, which are usually reported as emissions per unit of product, for example, per kg milk, meat or wool. New Zealand pastoral farms frequently generate a range of products with different management practices. A robust system is required to allocate the individual sources of GHGs (e.g. methane, nitrous oxide, direct carbon dioxide and embodied carbon dioxide emissions for inputs used on the farm) to each product from a farm. This paper describes a method for allocating emissions to co products from New Zealand farms. The method requires allocating the emissions, first, to an animal enterprise, separating the emissions between breeding and trading animals, and then allocating to a specific product to give product (e.g. milk, meat, wool, velvet) footprints from the 'cradle-to-farm-gate'. The meat product was based on live-weight gain. Procedures were adopted so that emissions associated with rearing of young stock used in live-weight gain systems, both as a by-product or a primary product could be estimated. This allows the possibility of total emissions for a meat product to be built up from contributing farms along the production chain. PMID- 23739486 TI - Association between adiponectin levels and coronary heart disease and mortality: a systematic review and meta-analysis. AB - BACKGROUND: Our aim was to systematically review prospective studies of the association of plasma adiponectin levels with the risk of coronary heart disease (CHD) events, cardiovascular mortality and all-cause mortality. METHODS: We searched Medline, EMBASE, the Cochrane Library and CINAHL for reports published through October 2011. Search terms included 'adiponectin' AND 'cardiovascular disease' OR 'mortality'. We included prospective studies lasting more than 1 year with plasma adiponectin levels at baseline and all-cause mortality and/or major cardiovascular morbidity and mortality as outcomes. We used a random-effects model to pool the data and conducted additional subgroup meta-analyses according to the pre-existence of CHD. Pooled relative risk (RR) was estimated by a 1-SD increase in the logarithmically transformed circulating adiponectin levels. RESULTS: A total of 24 prospective studies were included in the meta-analysis. The pooled RR of adiponectin for CHD events (23 studies) was 1.03 [95% confidence interval (CI): 1.00, 1.06]. In subgroup analyses, the RR of adiponectin was 0.99 (95% CI: 0.94, 1.03) for new-onset CHD (17 studies), but there was an increased risk (RR = 1.12, 95% CI: 1.04, 1.22) for CHD recurrence (seven studies). A 10% increased risk (RR = 1.10, 95% CI: 1.04, 1.16) of all-cause mortality (six studies) and a 14% increased risk (RR = 1.14, 95% CI: 1.05, 1.23) of cardiovascular disease mortality (five studies) were observed. CONCLUSIONS: No association was observed between adiponectin levels and CHD events. Our results suggest that higher circulating adiponectin levels may be associated with an increased risk of CHD recurrence and all-cause/CVD mortality. PMID- 23739487 TI - Micronutrients after burn injury: a review. AB - Supplementation of micronutrients after burn injury is common practice in order to fight oxidative stress, support the immune system, and optimize wound healing. Assessing micronutrient status after burn injury is difficult because of hemodilution in the resuscitation phase, redistribution of nutrients from the serum to other organs, and decreases in carrier proteins such as albumin. Although there are many preclinical data, there are limited studies in burn patients. Promising research is being conducted on combinations of micronutrients, especially via the intravenous route. PMID- 23739488 TI - Rhamnetin attenuates melanogenesis by suppressing oxidative stress and pro inflammatory mediators. AB - Rhamnetin is a naturally occurring polyphenolic compound. In this report, experimental evidence is presented on the suppression of melanogenesis by rhamnetin using B16 murine melanoma cells (B16 cells). To document the underlying anti-melanogenic action of rhamnetin, several key biochemical mediators were quantified: superoxide (O2(*-)), nitric oxide (.NO) and peroxynitrite (ONOO(-)) in vitro, and total reactive species (RS) generation, O2(*-), .NO and ONOO(-), reduced glutathione (GSH)/GSH-to-oxidized glutathione (GSSG) ratio, prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) in B16 cells. Results revealed that rhamnetin inhibited murine tyrosinase activity, suppressed melanin content and oxidative stress, reducing O2(*-),.NO and ONOO(-) in vitro and total RS generation, O2(*-), .NO and ONOO(-) in B16 cells, while maintaining a well-balanced GSH/GSSG ratio in B16 cells. Results further revealed that rhamnetin suppressed key pro inflammatory mediators such as PGE2 and TXB2. Thus, these results strongly indicate that rhamnetin has powerful anti-melanogenic properties through its anti oxidative and anti-inflammatory actions. PMID- 23739490 TI - Obliterative bronchiolitis in workers laying up fiberglass-reinforced plastics with polyester resin and methylethyl ketone peroxide catalyst. PMID- 23739489 TI - Defined lipid analogues induce transient channels to facilitate drug-membrane traversal and circumvent cancer therapy resistance. AB - Design and efficacy of bioactive drugs is restricted by their (in)ability to traverse cellular membranes. Therapy resistance, a major cause of ineffective cancer treatment, is frequently due to suboptimal intracellular accumulation of the drug. We report a molecular mechanism that promotes trans-membrane movement of a stereotypical, widely used anti-cancer agent to counteract resistance. Well defined lipid analogues adapt to the amphiphilic drug doxorubicin, when co inserted into the cell membrane, and assemble a transient channel that rapidly facilitates the translocation of the drug onto the intracellular membrane leaflet. Molecular dynamic simulations unveiled the structure and dynamics of membrane channel assembly. We demonstrate that this principle successfully addresses multi-drug resistance of genetically engineered mouse breast cancer models. Our results illuminate the role of the plasma membrane in restricting the efficacy of established therapies and drug resistance - and provide a mechanism to overcome ineffectiveness of existing and candidate drugs. PMID- 23739491 TI - Occupational risk factors for sinonasal inverted papilloma: a case-control study. AB - OBJECTIVES: Sinonasal inverted papilloma (IP) is an uncommon benign tumour characterised by frequent recurrence and, in approximately 10% of cases, by neoplastic transformation. IP aetiology is unknown but human papillomavirus is detectable in about one quarter of tumours. As some occupational hazards have been reported to be possible risk factors for IP, the aim of this study was to assess risk for sinonasal IP associated with prior exposure to suspected occupational risk factors for sinonasal malignancies. METHODS: Between 1996 and 2007, data on incident cases were collected from hospitals throughout the Piedmont region of Italy by the regional sinonasal cancer registry. A questionnaire on occupational history, completed by 127 cases and 337 hospital controls, was used to assign previous exposure to a list of 17 occupational hazards. The relationship between IP and cumulative exposure to these hazards was explored using unconditional logistic regression to statistically adjust for age, sex, area of residence, smoking and co-exposures. RESULTS: The risk of IP was significantly increased for ever exposure to welding fumes (OR 2.14) and organic solvents (OR 2.11) after controlling for potential confounders. For organic solvents only, a significant association with continuous cumulative exposure and a significant trend in risk across ordered cumulative exposure categories was found. CONCLUSIONS: The present study revealed a significant association and a significant dose-response relationship between occupational exposure to organic solvents and IP. The lack of a dose-response relationship for welding fumes suggests that the observed association with ever exposure should be interpreted with caution. PMID- 23739492 TI - Work characteristics, socioeconomic position and health: a systematic review of mediation and moderation effects in prospective studies. AB - Social inequalities in health persist in modern societies. The contribution of adverse work and employment conditions towards their explanation is analysed by two approaches, mediation and moderation. Yet the relative significance of each approach remains unclear in respective research. We set out to study this question by conducting a systematic literature review. We included all original papers based on prospective observational studies of employed cohorts that were published between January 1980 and October 2012 meeting our search criteria, by using major databases and by observing established quality criteria. 26 reports were included after quality assessment. 17 studies examined the mediation hypothesis and nine studies tested the moderation hypothesis. Moderate support was found for the mediation hypothesis where OR or HR of health according to socioeconomic position (SEP) were reduced in a majority of analyses after introducing work characteristics in multivariate models. Evidence in favour of the moderation hypothesis was found in some studies, demonstrating stronger effects of adverse work on health among people with low SEP. Despite some support in favour of the two hypotheses future research should aim at reducing the heterogeneity in defining and measuring core variables and at applying advanced statistical analyses. Policy recommendations would benefit from a higher degree of consistency of respective research evidence. PMID- 23739493 TI - Prenatal exposure to psychostimulants increases impulsivity, compulsivity, and motivation for rewards in adult mice. AB - Given the widespread use and misuse of methamphetamine (METH) and methylphenidate (MPD), especially in relation to women of childbearing age, it is important to consider the long-lasting effects of these drugs on the brain of the developing fetus. Male and female C57Bl/6J mice were prenatally exposed to METH (5mg/kg), MPD (10mg/kg), or saline. Following a 3-month washout, behavioral analysis using the 5-Choice Serial Reaction Time Task (5CSRTT) was performed on adult mice. After reaching training criteria, performance on a pseudo-random intertrial interval test session revealed decrements in 5CSRTT behavior. Prenatally-treated METH and MPD mice demonstrated significant increases in impulsivity, compulsivity, and motivation for reward compared to their saline controls. There were sex by drug interactions indicating a possible sexually dimorphic response to these prenatal drug exposures. Of particular clinical interest, we find that mice prenatally exposed to METH or MPD express characteristics of both inhibitory control decrements and heightened motivation for rewards, which represent core symptoms of addiction and other impulse control disorders. PMID- 23739494 TI - [Epidemiology of stroke in the Russian Federation: results of territory's population registry (2009-2010)]. AB - An epidemiological study of stroke based on a territory's population registry, which is, according to WHO recommendations, a scientific basis of treatment organization and medical-social rehabilitation of stroke patients as well as stroke prevention, has been launched in the Russian Federation in 2009. Duration of the project is 5 years. Main epidemiological indices of stroke (morbidity, mortality and lethality) for 2009-2010 are presented. Morbidity of stroke was 3.52 and 3.27 cases per 1000 population in 2009 and 2010, respectively. Mortality was 1.19 and 0.96 per 1000. Significant differences in morbidity, mortality and lethality between different regions of the country were identified. The maximal morbidity was recorded in Chistopol (Tartar Republic) - 6.14 per 1000 and the minimal one in the Altai krai (1.39 per 1000). The decrease in the number of hemorrhagic stroke (HS) in 2009 was noted. The ratio of ischemic strokes to HS was 5:1 compared to 3.5:1 in the registry of 2001-2003. Neuroimaging methods (computed tomography and magnetic-resonance tomography) were used for differential diagnosis of stroke character in 63.1% of cases in 2009 and in 74.2% in 2010. There was 91.1% of stroke patients who received treatment in a hospital in 2010. PMID- 23739495 TI - [Analysis of efficacy and safety in patients with post-stroke spasticity of the lower limbs using botulinotoxin]. PMID- 23739496 TI - [Psychophysiological characteristics of panic disorder and generalized anxiety disorder]. AB - We studied 34 patients with panic disorder, 32 patients with generalized anxiety disorder and 29 healthy controls using clinical-neurological, psychometric, neuropsychological and neurophysiological (auditory event-related potentials) methods. Patients were characterized by pronounced autonomic dysfunctions, a higher level of anxiety and depression as well as cognitive function disturbances in the form of impairment of short-term memory and directed attention in comparison with healthy controls. Patients with generalized anxiety disorder differed from patients with panic disorder by the higher level of anxiety, greater degree of depression and more expressed disturbances of short-term memory and directed attention. Compared to controls, patients with generalized anxiety disorder had lower P300 amplitudes while the latter was higher in patients with panic disorders. It is concluded that recording of event-related potentials may be used as an additional method of differential diagnosis of these types of anxiety disorders. PMID- 23739497 TI - [A clinical and dynamic profile of somatoform depressive disorders of the patients in a general hospital]. AB - It was compared clinical characteristics of somatoform depressive disorders in patients of somatic and psychiatric in-patient departments (110 and 50 people, respectively). The somatic patients were divided into three groups: 1-st group - patients with masked depression (43.6%), 2-nd group - patients with somatic depression (30.9%), 3-rd group - patients with comorbid depression with a somatic disease (25.5%). The clinical presentations of the disease in the 1-st group are characterized by frontal somatic and autonomic disorders, with the presentations of depression corresponding to the term "depression without depression". In the clinical presentations of somatic depression (the 2-nd group) in addition to somatic and autonomic disorders, which mimic the therapeutic pathology, the affective disorders are presented by its reduced variants. In the clinical presentations of disease of the 3-rd group of patients, the symptoms of the somatic disorder are "reproduced" at the level of subjective complaints and symptoms of disease ("psychosomatic imitation"). Such distinction optimizes treatment due to the right choice of the priority clinical model within the framework of unitary psychosomatic disorder. PMID- 23739499 TI - [Therapeutic correction of mild cognitive impairment in patients with chronic cerebral ischemia]. AB - Neurodegenerative and cerebrovascular diseases are the most significant among the main reasons leading to the cognitive impairment of the elderly. Vascular cognitive impairment is not limited to only dementia, representing a heterogeneous group both in pathogenic and clinical terms. The article dwells upon new principles of vascular cognitive impairment's classification and the review of their possible therapeutic correction that was conducted. The article includes the results of the 12-week open therapeutic (randomized with the control group) study of efficiency and safety of vitrum memory for patients with mild vascular cognitive impairment. It is shown that the therapy significantly improved the state of neurodynamic and regulatory functions of the patients with I--II stage dyscirculatory encephalopathy. PMID- 23739498 TI - [Clinical characteristics and treatment of polyneuropathy developed after chemotherapy]. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is one of the main problem of modern cytotoxic therapy. Drug dose reduction, delay or even complete stopping of chemotherapy until the regression of CIPN symptoms impair treatment effectiveness and patients' survival. We studied 44 cancer patients with CIPN developed after polychemotherapy. We suggested a treatment regimen that included a complex of allopathic, homeopathic drugs and hydrotherapy. The treatment resulted in a subjective and objective regression of neuropathy symptoms and improving of quality of life in all patients. Patients who had to delay chemotherapy were able to restart it. PMID- 23739500 TI - [Asthenic disorders and cognitive dysfunction in patients with tension headache]. AB - The article is devoted to the study of cognitive dysfunction in patients suffering from tension headaches. Patients had attention and memory dysfunction, higher levels of anxiety, asthenia and subclinical symptoms of depression. The high efficacy of cerebrolysin in the restoration of cognitive dysfunction confirmed by the data of clinical, psychological and neuropsychological studies was shown. PMID- 23739501 TI - [Efficacy of thiolepta in diabetic polyneuropathy: results of the study ETIKA]. AB - Thiolepta (alpha-lipoic acid preparation) was used in treatment of 205 patients, 134 women and 71 men, mean age 59.3+/-10.1 years; 196 patients with diabetes mellitus (DM) type II and 9 patients with DM type I. Treatment duration was 4 weeks. Dosage of the drug was 600 mg daily. Patients were assessed neurologically and with psychometric scales. Special attention was drawn to the severity of positive and negative symptoms of neuropathy and sleep disorders. The results demonstrated the efficacy of thiolepta in diabetic polyneuropathy assessed by all parameters. The effect remained during 3 months after the end of treatment. Good tolerability and safety of the drug are highlighted. PMID- 23739502 TI - [Effectiveness of the medical-psychological rehabilitation of combatants]. AB - To analyze treatment effectiveness, authors examined 199 combatants during the first days and in 1.5 month after their return from combat zones. Stages and content of medical-psychological rehabilitation, including psychopharmacotherapy and psychotherapy, are described. The significant improvement in clinical and social-psychological characteristics of patients was revealed. The reduction of main psychopathological symptoms was identified in patients with adaptation disorders as well as with post-traumatic-stress disorders. The necessity of rehabilitation for all combatants after their return from combat zones has been grounded. PMID- 23739503 TI - [L-carnitine treatment patients with chronic cerebral ischemia]. AB - The purpose of this study is to investigate the effectiveness of L-carnitine treatment in patients with dodementia stage chronic cerebral ischemia. In parallel comparative clinical study included 60 patients (22 men and 38 women aged 42 to 74 years), the average age of the patients was 61.2+/-8.2 years. All patients received basic treatment, including antihypertensive and antiplatelet drugs. The first group consisted of 20 patients who received 1000 mg of L carnitine per day (bilology supplement karniton). In the second group (20 patients), the drug was administered to 2000 mg per day. In the third (the control group) was carried out only basic therapy. The course of treatment was 60 days. After treatment significantly reduced the frequency of complaints of weakness, decreased performance, memory loss, headache, dizziness, unsteadiness of gait. Statistically significant differences after treatment revealed in the MMSE total score and subtests "focus" and "memory", compared to the baseline reduced the running time with all 5-tables in the test Schulte. According to questionnaire fatigue MFI-20 the main group level decreased overall, physical and mental asthenia, increased activity and the level of motivation. Revealed a dose dependent effect of the drug. PMID- 23739504 TI - [Testing of skin sympathetic reactions in patients with distal diabetic polyneuropathy]. AB - Possibilities of a dynamic segmental diagnostic (DSD-testing) method as a way of testing of autonomic fibers of peripheral nerves in the process of complex examination of patients with diabetes mellitus are considered. Changes in the intensity of skin sympathetic reactions' in patients with diabetic foot syndrome, distal symmetrical sensorimotor polyneuropathy of the lower limbs differed from those in healthy people. A method of DSD-testing is suggested to be used for diagnosis of lesions of autonomic fibers of peripheral nerves in complex examination of patients with diabetes mellitus to predict complications of the disease. PMID- 23739505 TI - [Association of (N251S)-PIP5K2A with schizophrenic disorders: a study of the Russian population of Siberia]. AB - The phosphatidylinositol-4-phosphate-5-kinase type IIa (PIP5K2A) gene has been proposed as a putative susceptibility gene for schizophrenia on both positional and functional grounds. The association between the (N251S)-PIP5K2A (rs10828317) variant and schizophrenia was found in German and Dutch populations but was not replicated in several other populations. The purpose of the study was to examine whether the previously implicated (N251S)-PIP5K2A variant influences susceptibility to schizophrenia in the Russian population of Siberia. Authors studied 355 patients with schizophrenic disorders from the Russian population of Siberia. The control group consisted of 100 healthy. Results confirm the association of the (N251S)-PIP5K2A (rs10828317) polymorphism with schizophrenia (p=0.04, OR=2.48, 95%CI=1.19--5.17 for the CC genotype). The association can be explained by the inability of mutant kinase to activate the phosphatidylinositol 4,5-biphosphate dependent proteins, including neuronal KCNQ channels and glutamate EAAT3 transporters, which leads to the lack of dopaminergic and glutamatergic control in schizophrenic patients carriers of this mutation. PMID- 23739506 TI - [EEG changes in patients with eating disorder]. PMID- 23739507 TI - [The use of topamax in monotherapy of posttraumatic epilepsy]. PMID- 23739508 TI - [Classification system CASCADE for childhood arterial ischemic stroke]. AB - In this review, a new consensus-based classification system for childhood arterial ischemic stroke CASCADE (2012) is described. The CASCADE is an anatomically based classification system which offers the specific diagnostic interventions and suggests the unified terminology. So, it can be used both in clinical practice and in any research in childhood arterial ischemic stroke. PMID- 23739509 TI - [Children mental health and influencing factors]. AB - According to Russian and world publications, there is a growing prevalence of mental disorders among children and adolescences with the domination of mental retardation and nonpsychotic mental disorders. In this review, several main causes of growing prevalence of mental and behavioral disorders in these populations are specified. PMID- 23739510 TI - [Mental pathology in general pediatric practice: a problem of psychovegetative diathesis]. AB - An examination of patients of a pediatric inpatient clinic revealed a variety of psychopathological disorders concomitant to functional autonomic/somatic pathology in children and adolescents as well as the variants of personality deviations and features of the patient's family. Based on this study, we suggest a concept of psychoautonomic diathesis and describe features of its symptoms and course as well as its relation to psychopathological diathesis. Main problems that should be solved to treat effectively functional autonomic/somatic disorders in the frames of psychoautonomic syndrome are presented. PMID- 23739511 TI - [An ontogenic conception of complex multilevel treatment of psychosomatic disorders in children]. AB - The author suggests a conception that considers the etiopathogenesis of psychogenic psychosomatic disorders as a chain of interacting factors. The main patterns of it are stressful life events, personality, psychotype, somatotype, systemic/organic deficit. Mechanisms of stable pathological state join this chain into a "vicious circle" of psychosomatosis. Based on the ontogenetic approach, the author suggests a 5-level system of the complex (psychosomatic) treatment of these disorders. The system integrates pharmacological treatment, neuropsychological correction, syndromal psychological correction of alexithymia and emotional sphere, modification of behavior and personality-oriented psychotherapy. PMID- 23739512 TI - [A multidiscipline clinical and biological approach to the study of psychotic types of autistic spectrum disorders in children]. AB - The current problem of heterogeneity of psychotic types of autistic spectrum disorders (ASD) is reviewed. The authors present results of a multidiscipline psychopathological, pathopsychological, neurophysiological and immunological examination of 87 patients, aged from 3 to 14 years, with psychotic types of ASD: childhood psychosis (CP) and atypical childhood psychosis (ACP). Significant differences in clinical presentations of CP and ACP that were correlated with pathopsychological, neurophysiological and immunological disorders were found. These findings support different nosological entities of these types of ASD. PMID- 23739513 TI - [Developmental dysphasia in children: perspectives of neurotrophic therapy]. AB - Developmental dysphasia (alalia) represents a severe speech and language disorder in children. To assess the efficacy of treatment with cerebrolysin, we have examined 60 children with developmental dysphasia, aged from 3 to 4 years. Group 1 (30 patients) received cerebrolysin (monotherapy, daily dosage 0.1 ml/kg, in the morning hours, on each other day, i.m., 30 injections in total) during 2 months. Group 2 (controls, 30 patients) did not receive pharmacotherapy. A significant improvement of expressive, impressive speech and speech attention was observed in group 1 after the treatment. The active vocabulary increased by a factor of 3.5 and phrases number in colloquial speech by a factor of 5, versus 1.5 in the control group. According to parents' questionnaires, the treatment resulted in the decrease of psychasthenic, psychosomatic problems, motor clumsiness and hyperactivity along with the improvement of attention, emotional control and behavioral measures. The positive effect of cerebrolysin on the motor development was demonstrated by the assessment of motor milestones. PMID- 23739514 TI - [Dynamics of cognitive and emotional-volitional disorders in children and adolescents with refractory epilepsy during the treatment with levetiracetam]. AB - We examined 76 children and adolescents (45 boys (59.2%), 31 girls (40.8%), aged from 6 to 17 years (mean age 14.31 +/- 0.3), with the diagnosis of refractory epilepsy using a clinical/psychopathological method and psychometric scales. Marked non-psychotic mental disorders of varying severity were observed in all patients. The patients were treated with levetiracetam in a dose of 60 mg/kg/day during one year. The reduction in the frequency of epileptic seizures was achieved in 77.6% of patients. The significant (p<0.01) improvement in cognitive functions and speech were found in 81.6% cases. The treatment reduced stress and improved mood in 63.1% of patients. PMID- 23739515 TI - [An electromyographic study on the development of optimal tactics of botulinum toxin type A injections in children with spastic forms of cerebral palsy]. AB - We studied 67 children, aged 2-9 years, with cerebral palsy including 56 children with a spastic form. An electromyographic method was used for the development of optimal tactics of botulinum toxin type A injections in different clinical presentations of spasticity. The best clinical results were obtained in children with the following changes on EMG: 1) the tonic muscle activity in resting state was minimal (<10 microvolts) and had local or regional distribution; 2) the pathological synkinetic activity during voluntary movements was minimal (synergetic activity coefficient for shin muscles was less than 0.45); 3) the disturbance of interactions between synergistic and antagonistic muscles was moderate (reciprocity coefficient was not less than 0.4); 4) EMG amplitude in voluntary muscle contraction should not be less than 150 microvolts. This approach to the treatment allowed to reach higher levels on The Gross Motor Function Classification System in part of children. PMID- 23739516 TI - [Family burden as a target of psychosocial rehabilitation of children and adolescents with mental disorders]. AB - Correlations between indices of family burden and changes in children's social functioning during psychosocial group therapy with parents of children and adolescents with schizophrenia spectrum disorders have been studied. A sample included 140 children and their mothers. Family burden was considered as a separate "target" of psychosocial rehabilitation of children and adolescents with mental disorders. The authors recommend to use this dynamic characteristic of family burden in the development of individualized treatment/prevention programs (modules) and corresponding measures with assessment of their effectiveness in the implementation of psychosocial support to the family. A significant positive effect of this psychosocial group therapy was confirmed by a set of specific scales and questionnaires. PMID- 23739517 TI - [Affective pathology in the premanifesting period of anorexia nervosa in adolescents]. AB - Objective of the study were: to specify the features of clinical presentations and dynamics of anorexia nervosa (AN) developed in adolescence during the current depression; to study affective disorders preceding the onset of AN and to analyze comorbidity of these two pathologies. We examined 21 female patients, aged from 15 to 17 years old (mean age 16.7 +/- 0.8 years). It was shown that depressive symptoms developed 4-11 months (mean 7.9 +/- 2.5 months) before the onset of AN. The development of AN was associated with depression and might be considered as one of mechanisms of formation of eating disorders that might be termed as affective mechanism. Thus, we can specify a variant of adolescent/juvenile depression, or depression with eating disorders. The variant represents a protracted depressive state with overvalued ideas to improve body image and to restrict calories which is combined with adynamic affect associated with anxiety, melancholy and dysphoria. PMID- 23739518 TI - [The possibility of the use of neuroprotective drugs in rehabilitation treatment of infants with perinatal hypoxic damage of central nervous system]. PMID- 23739519 TI - Limited communication capacity unveils strategies for human interaction. AB - Connectivity is the key process that characterizes the structural and functional properties of social networks. However, the bursty activity of dyadic interactions may hinder the discrimination of inactive ties from large interevent times in active ones. We develop a principled method to detect tie de-activation and apply it to a large longitudinal, cross-sectional communication dataset (~19 months, ~20 million people). Contrary to the perception of ever-growing connectivity, we observe that individuals exhibit a finite communication capacity, which limits the number of ties they can maintain active in time. On average men display higher capacity than women, and this capacity decreases for both genders over their lifespan. Separating communication capacity from activity reveals a diverse range of tie activation strategies, from stable to exploratory. This allows us to draw novel relationships between individual strategies for human interaction and the evolution of social networks at global scale. PMID- 23739521 TI - Oronasopharyngeal suction versus wiping of the mouth and nose at birth: a randomised equivalency trial. AB - BACKGROUND: Wiping of the mouth and nose at birth is an alternative method to oronasopharyngeal suction in delivery-room management of neonates, but whether these methods have equivalent effectiveness is unclear. METHODS: For this randomised equivalency trial, neonates delivered at 35 weeks' gestation or later at the University of Alabama at Birmingham Hospital, Birmingham, AL, USA, between October, 2010, and November, 2011, were eligible. Before birth, neonates were randomly assigned gentle wiping of the face, mouth (implemented by the paediatric or obstetric resident), and nose with a towel (wipe group) or suction with a bulb syringe of the mouth and nostrils (suction group). The primary outcome was the respiratory rate in the first 24 h after birth. We hypothesised that respiratory rates would differ by fewer than 4 breaths per min between groups. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01197807. FINDINGS: 506 neonates born at a median of 39 weeks' gestation (IQR 38-40) were randomised. Three parents withdrew consent and 15 non-vigorous neonates with meconium-stained amniotic fluid were excluded. Among the 488 treated neonates, the mean respiratory rates in the first 24 h were 51 (SD 8) breaths per min in the wipe group and 50 (6) breaths per min in the suction group (difference of means 1 breath per min, 95% CI -2 to 0, p<0.001). INTERPRETATION: Wiping the nose and mouth has equivalent efficacy to routine use of oronasopharyngeal suction in neonates born at or beyond 35 weeks' gestation. FUNDING: None. PMID- 23739522 TI - Viral molecular mimicry circumvents abortive infection and suppresses bacterial suicide to make hosts permissive for replication. AB - The global interplay between bacteria and bacteriophages has generated many macromolecules useful in biotechnology, through the co-evolutionary see-saw of bacterial defense and viral counter-attack measures. Bacteria can protect themselves using abortive infection systems, which induce altruistic suicide in an infected cell and therefore protect the clonal population at the expense of the infected individual. Our recent paper describes how bacteriophage PhiTE successfully subverted the activity of a plasmid-borne abortive infection system. PhiTE evolved mimics of the small RNA antitoxin that naturally inhibits the active toxin component of this anti-viral mechanism. These mutant phages further manipulated the behavior of the host population, through transduction of the plasmid encoding the abortive infection system. Transductants thereby became enslaved by the abortive infection system, committing suicide in response to infection by the original phage population. In effect, the new host was infected by an "addictive altruism," to the advantage of the resistant bacteriophage. PMID- 23739523 TI - Cochrane review summary: psychological interventions for parents of children and adolescents with chronic illness. PMID- 23739524 TI - Diet and physical activity in the self-management of type 2 diabetes: barriers and facilitators identified by patients and health professionals. AB - Aim To explore the views of individuals recently diagnosed with type 2 diabetes in relation to self-management of dietary intake and physical activity, and to compare these with the views of health professionals (HPs). BACKGROUND: Diabetes education has become a priority area in primary and secondary care, and many education programmes are now embedded within a patient's care package. There are few contemporaneous explorations of patients' views about lifestyle self management. Such research is vital in order to identify areas that require further support, refinement or enhancement in terms of patient education. METHODS: Focus groups were held with patients recently diagnosed with type 2 diabetes (n = 16, 38% female, aged 45-73 years). In-depth semi-structured interviews were conducted with HPs (n = 7). Discussions focussed on self management specifically in relation to making dietary and physical activity changes. All discussions were tape recorded, transcribed and analysed by emergent themes analysis using NVivo to manage the coded data. Findings Barriers were divided into six main categories: difficulty changing well-established habits, negative perception of the 'new' or recommended regimen, barriers relating to social circumstances, lack of knowledge and understanding, lack of motivation and barriers relating to the practicalities of making lifestyle changes. HPs generally echoed the views of patients. In conclusion, even against a background of diabetes education, recently diagnosed patients with type 2 diabetes discussed a wide range of barriers to self-management of diet and physical activity. The findings could help to provide HPs with a deeper understanding of the needs of recently diagnosed patients and may help refine current diabetes education activities and inform the development of educational resources. PMID- 23739525 TI - SAPC hot topic: increasing the visibility of academic primary care. PMID- 23739527 TI - Autonomic cardiovascular control in Paralympic athletes with spinal cord injury. AB - INTRODUCTION: Disruption of autonomic control after spinal cord injury (SCI) results in life-threatening cardiovascular dysfunctions and impaired endurance performance; hence, an improved ability to recognize those at risk of autonomic disturbances is of critical clinical and sporting importance. PURPOSE: The objective of this study is to assess the effect of neurological level, along with motor, sensory, and autonomic completeness of injury, on cardiovascular control in Paralympic athletes with SCI. METHODS: Fifty-two highly trained male Paralympic athletes (age, 34.8 +/- 7.1 yr) from 14 countries with chronic SCI (C2 L2) completed three experimental trials. During trial 1, motor and sensory functions were assessed according to the American Spinal Injury Association Impairment Scale. During trial 2, autonomic function was assessed via sympathetic skin responses (SSR). During trial 3, cardiovascular control was assessed via the beat-by-beat blood pressure response to orthostatic challenge. RESULTS: Athletes with cervical SCI exhibited the lowest seated blood pressure and the most severe orthostatic hypotension (P < 0.025). There were no differences in cardiovascular function between athletes with different American Spinal Injury Association Impairment Scale grades (P > 0.96). Conversely, those with the lowest SSR scores exhibited the lowest seated blood pressure and the most severe orthostatic hypotension (P < 0.002). Linear regression demonstrated that the combined model of neurological level and autonomic completeness of SCI explained the most variance in all blood pressure indices. CONCLUSION: We demonstrate for the first time that neurological level and SSR score provide the optimal combination of assessments to identify those at risk of abnormal cardiovascular control. We advocate the use of autonomic testing in the clinical and sporting classification of SCI athletes. PMID- 23739526 TI - Detection of the inflammatory process in a Behcet's disease-like mouse model using 18F-fluorodeoxyglucose positron emission tomography. AB - OBJECTIVES: The major role of herpes simplex virus (HSV) type 1 infection in Behcet's disease (BD) immunopathogenesis has been demonstrated and inoculating the earlobes of ICR mice with HSV produced a BD-like mouse model. (18)Ffluorodeoxyglucose positron emission tomography (FDG PET) is widely used for diagnosing numerous human diseases other than malignancies. The aim of our study was to evaluate the inflammatory activities of BD-like symptoms in a HSV type 1 induced BD-like mouse model by small-animal FDG PET. METHODS: Five HSV-infected ICR mice with BD-like lesions, two asymptomatic HSV-infected mice, and two untreated mice were scanned with microPET, and autopsy specimens were histopathologically assessed to evaluate for infiltration by mixed inflammatory cells. RESULTS: The histopathological evaluation of the inflammatory process in knee and elbow joints significantly correlated with the quantitative assessment of FDG accumulation in the same joints in BD-like ICR mice, HSV-infected asymptomatic mice, and untreated control mice. Small-animal FDG PET clearly detected asymptomatic joint inflammatory processes in both BD-like mice and HSV infected asymptomatic mice. In addition, genital ulcers and skin ulcers with associated perilesional lymphadenopathies in BD-like models were detected by microPET. However, biodistributed PET-positive images from the stasis of secreted FDG into the bowel lumen could not be distinguished from the inflammatory bowel lesions of BD when compared to FDG uptake in control mice. CONCLUSIONS: Our data indicate that FDG PET can non-invasively and quantitatively detect the inflammatory process in an HSV-induced BD-like mouse model. PMID- 23739528 TI - Task-oriented control of muscle coordination during cycling. AB - PURPOSE: This study investigated the effects of different biomechanical constraints on the variability of muscle activation during cycling. METHODS: Fifteen male athletes cycled at a power of 150 and 300 W. Surface EMG was recorded from seven lower limb muscles. Wavelet transformed EMG signals of all muscles were subjected to a principal component analysis to study the variability of the EMG. The full vector space was reduced to the first principal components that explained 90% of the variance. The input data of each cycle revolution were projected onto these principal component vectors. Means and SD of the projections were calculated across all cycles and summed across all time points. The relative variability (RV) was expressed as the ratio between the SD and the mean of the summed projections. The principal angle was calculated between the principal components used for the 150-W condition and those used for the 300-W condition. RESULTS: The RV could be split into low- and high-variability components. The variability was smaller for the lower ordered eigenvectors compared with the higher ordered ones (P < 0.001) independent of the loading condition. Overall, the 300-W condition showed lower RV compared with the 150-W condition (P < 0.01). The average principal angle between the 150- and 300-W subspaces was 0.4, respectively. CONCLUSIONS: Structured aspects of variability were found in the muscle activation of lower leg muscles during cycling. In the context of the minimum intervention principal, this might be interpreted as a transition into a regime that requires specific necessary muscles where the increased constraints of the task specify the muscle coordination pattern in a more precise way. PMID- 23739529 TI - Temporal relationships between physical activity and sleep in older women. AB - PURPOSE: The objective of this study is to examine the temporal and bidirectional relationships between accelerometer-derived physical activity estimates and actigraphy-assessed sleep characteristics among older women. METHODS: A subgroup of participants (N = 143, mean age = 73 yr) enrolled in the Healthy Women Study wore an ActiGraph accelerometer on their waist and an Actiwatch sleep monitor on their wrist concurrently for seven consecutive days. Multilevel models examined whether ActiGraph-assessed daily activity counts (ct.min-1.d-1) and moderate- to vigorous-intensity physical activity (MVPA; min.d-1) predicted Actiwatch-assessed sleep onset latency, total sleep time, sleep efficiency, and sleep fragmentation. Similar models were used to determine whether nighttime sleep characteristics predicted physical activity the following day. RESULTS: In unadjusted models, greater daily activity counts (B = -0.05, P = 0.005) and more minutes of MVPA (B = -0.03, P = 0.01) were temporally associated with less total sleep time across the week. Greater sleep efficiency was associated with greater daily activity counts (B = 0.37, P = 0.01) and more minutes of MVPA (B = 0.64, P = 0.009) the following day. Less sleep fragmentation was also associated with greater daily activity counts and more MVPA the following day. Findings were similar after adjustment for age, education, body mass index, depressive symptoms, arthritis, and accelerometer wear time. CONCLUSIONS: Few studies have used objective measures to examine the temporal relationships between physical activity and sleep. Notably, these findings suggest that nightly variations in sleep efficiency influence physical activity the following day. Thus, improving overall sleep quality in addition to reducing nightly fluctuations in sleep may be important for encouraging a physically active lifestyle in older women. PMID- 23739531 TI - Angiopoietin-like protein 2 is associated with chronic kidney disease in a general Japanese population: the Hisayama Study. AB - BACKGROUND: Angiopoietin-like protein 2 (Angptl2) is an adipokine that promotes inflammation and endothelial dysfunction of the vessels. The aim of this study was to investigate the relationship between serum Angptl2 level and chronic kidney disease (CKD). METHODS AND RESULTS: A total of 3,169 community-dwelling subjects aged >=40 years were divided into quintiles by Angptl2 level. CKD was defined as the presence of albuminuria (urine albumin-creatinine ratio >=30.0mg/g) or decreased estimated glomerular filtration rate (eGFR <60ml.min( 1).1.73m(-2)). The odds ratio (OR) for the presence of CKD was calculated using a logistic regression model. The overall prevalence of CKD was 37.5%. The age- and sex-adjusted ORs for the presence of CKD increased with higher serum Angptl2 level. This trend remained significant after adjusting for known cardiovascular risk factors (<2.01ng/ml: OR, 1.00 (reference); 2.01-2.48ng/ml: OR, 1.67, 95% confidence interval [CI]: 1.24-2.24; 2.49-2.99ng/ml: OR, 1.70, 95% CI: 1.27-2.28; 3.00-3.65ng/ml: OR, 1.78, 95% CI: 1.32-2.39; >=3.66ng/ml: OR, 1.79, 95% CI: 1.32 2.43; P-value for trend=0.001). Multivariate-adjusted ORs for the presence of albuminuria increased significantly with elevated serum Angptl2 (P-value for trend=0.004), while there was no evidence of a significant relationship between serum Angptl2 level and decreased eGFR (P-value for trend=0.08). CONCLUSIONS: Elevated serum Angptl2 is associated with the likelihood of CKD in the general population. PMID- 23739532 TI - Chronic amiodarone therapy impairs the function of the superior sinoatrial node in patients with atrial fibrillation. AB - BACKGROUND: The mechanisms underlying amiodarone-induced sinoatrial node (SAN) dysfunction remain unclear, so we used 3-dimensional endocardial mapping of the right atrium (RA) to investigate. METHODS AND RESULTS: In a matched-cohort design, 18 patients taking amiodarone before atrial fibrillation (AF) ablation (amiodarone group) were matched for age, sex and type of AF with 18 patients who had undergone AF ablation without taking amiodarone (no-amiodarone group). The amiodarone group had a slower heart rate than the no-amiodarone group at baseline and during isoproterenol infusion. Only the amiodarone group had sick sinus syndrome (n=4, 22%, P=0.03) and abnormal (>550ms) corrected SAN recovery time (n=5, 29%; P=0.02). The median distance from the junction of the superior vena cava (SVC) and RA to the most cranial earliest activation site (EAS) was longer in the amiodarone group than in the no-amiodarone group at baseline (20.5 vs. 10.6mm, P=0.04) and during isoproterenol infusion (12.8 vs. 6.3mm, P=0.03). The distance from the SVC-RA junction to the EAS negatively correlated with the P wave amplitudes of leads II (r=-0.47), III (r=-0.60) and aVF (r=-0.56) (P<0.001 for all). CONCLUSIONS: In a quarter of the AF patients, amiodarone causes superior SAN dysfunction, which results in a downward shift of the EAS and reduced P-wave amplitude in leads II, III and aVF at baseline and during isoproterenol infusion. PMID- 23739533 TI - The role of pain coping and kinesiophobia in patients with complex regional pain syndrome type 1 of the legs. AB - OBJECTIVES: The aim of this cross-sectional study was to evaluate to what extent pain coping and kinesiophobia contribute to limitations in activity and participation in patients with complex regional pain syndrome type 1 (CRPS-1) of the lower limbs. METHODS: A total of 238 patients with CRPS-1 of the legs from 4 pain clinics and 1 Department of Neurology of University Hospitals participated in this study. Pain and CRPS severity were assessed with the pain rating index of the McGill Pain Questionnaire and the CRPS Severity Score, respectively. Activity was measured with the Rising & Walking scale, and participation with the Social Functioning scale of the SF-36. In addition, the Tampa Scale for Kinesiophobia and Pain Coping Inventory were administered. Hierarchical linear regression was used to evaluate to what extent kinesiophobia and pain coping contributed to difficulties with Rising & Walking and Social Functioning. RESULTS: The analyses showed that the "resting" subscale of the Pain Coping Inventory-that is, 1 of the 3 scales evaluating passive pain coping strategies-contributed significantly to difficulties in rising and walking (explaining 12.5% of the variance) and to difficulties in social functioning (explaining 6.5%), whereas kinesiophobia was not associated with either of these measures. DISCUSSION: These findings indicate that making use of "resting" as a pain coping strategy contributes significantly to limitations in activity and participation in patients with CRPS-1 of the legs. Indications for a negative influence of kinesiophobia or a positive influence of an active pain coping style were not found. PMID- 23739534 TI - Central sensitization and altered central pain processing in chronic low back pain: fact or myth? AB - OBJECTIVE: The purpose of this narrative review is to analyze the available literature concerning central sensitization and altered central pain processing in patients with chronic low back pain (LBP). METHODS: Literature was screened using several electronic search databases. Additional literature was obtained by reference tracking and expert consultation. Studies evaluating central pain processing in conservatively treated patients with chronic LBP were included. RESULTS: Results of studies examining the responsiveness to various stimuli in patients with chronic LBP are conflicting. Some studies in patients with chronic LBP have demonstrated exaggerated pain responses after sensory stimulation of locations outside the painful region, while other studies report no differences between patients and healthy subjects. Studies examining the integrity of the endogenous pain inhibitory systems report unaltered activity of this descending inhibitory system. In contrast, studies analyzing brain structure and function in relation to (experimentally induced) pain provide preliminary evidence for altered central nociceptive processing in patients with chronic LBP. Finally, also psychosocial characteristics, such as inappropriate beliefs about pain, pain catastrophizing, and/or depression may contribute to the mechanisms of central sensitization. CONCLUSIONS: It tempting to speculate that ongoing nociception is associated with cortical and subcortical reorganization and may play an important role in the process of the chronification of LBP. Future prospective research should explore to what extent these changes are reversible and if this reversibility is associated with improved functioning of patients. PMID- 23739536 TI - Clinical approval success rates for investigational cancer drugs. AB - We examined development risks for new cancer drugs. For the full study period, the estimated clinical approval success rate for cancer compounds was 13.4% (9.9% for the first half of the study period, 19.8% for the second half). Small molecules had a somewhat higher clinical approval success rate than did large molecules (14.3 vs. 11.5%). Compounds studied solely in hematologic indications had markedly higher estimated clinical approval success rates than did compounds studied only in solid tumor indications (36.0 vs. 9.8%). The first, second, and third cancer indications pursued had estimated clinical approval success rates of 9.0, 8.2, and 6.9%, respectively. Success rates of second and third indications were found to be highly dependent on the success or failure of the first indication pursued (54.9 and 42.4%, respectively, for second and third indications if the first indication is a success, but 2.5 and 1.8%, respectively, if the first indication is a failure). PMID- 23739535 TI - A morphine conjugate vaccine attenuates the behavioral effects of morphine in rats. AB - Vaccines for opioid dependence may provide a treatment that would reduce or slow the distribution of the drug to brain, thus reducing the drug's reinforcing effects. We tested whether a conjugate vaccine against morphine (keyhole limpet hemocyanin-6-succinylmorphine; KLH-6-SM) administered to rats would produce antibodies and show specificity for morphine or other heroin metabolites. The functional effects of the vaccine were tested with antinociceptive and conditioned place preference (CPP) tests. Rats were either vaccinated with KLH-6 SM and received two boosts 3 and 16 weeks later or served as controls and received KLH alone. Anti-morphine antibodies were produced in vaccinated rats; levels increased and were sustained at moderate levels through 24 weeks. Antibody binding was inhibited by free morphine and other heroin metabolites as demonstrated by competitive inhibition ELISA. Vaccinated rats showed reduced morphine CPP, tested during weeks 4 to 6, and decreased antinociceptive responses to morphine, tested at week 7. Brain morphine levels, assessed using gas chromatography coupled to mass spectrometry (GC-MS) on samples obtained at 26 weeks, were significantly lower in vaccinated rats. This suggests that morphine entry into the brain was reduced or slowed. These results provide support for KLH 6-SM as a candidate vaccine for opioid dependence. PMID- 23739537 TI - The future of population-based postmarket drug risk assessment: a regulator's perspective. AB - The US Food and Drug Administration emphasizes the role of regulatory science in the fulfillment of its mission to promote and protect public health and foster innovation. With respect to the evaluation of drug effects in the real world, regulatory science plays an important role in drug risk assessment and management. This article discusses opportunities and challenges with population based drug risk assessment as well as related regulatory science knowledge gaps in the following areas: (i) population-based data sources and methods to evaluate drug safety issues; (ii) evidence-based thresholds to account for uncertainty in postmarket data; (iii) approaches to optimize the integration and interpretation of evidence from different sources; and (iv) approaches to evaluate the real world impact of regulatory decisions. Regulators should continue the ongoing dialogue with multiple stakeholders to strengthen regulatory safety science and address these and other critical knowledge gaps. PMID- 23739538 TI - Recently introduced qacA/B genes in Staphylococcus epidermidis do not increase chlorhexidine MIC/MBC. AB - OBJECTIVES: Chlorhexidine is used as a disinfectant to prevent surgical infections. Recently, studies have indicated that chlorhexidine usage has selected methicillin-resistant Staphylococcus aureus strains that are tolerant to chlorhexidine and that this may be related to the presence of the qacA/B-encoded efflux pumps. Here, we evaluated if high-level exposure to chlorhexidine selects for tolerant colonizing Staphylococcus epidermidis and we addressed the consequences of long-term exposure to chlorhexidine. METHODS: Chlorhexidine susceptibility and carriage of qacA/B was determined for colonizing S. epidermidis isolated from scrub nurses heavily exposed to chlorhexidine and were compared with isolates from non-users of chlorhexidine hand rubs. S. epidermidis blood isolates from the 1960s, before the wider introduction of chlorhexidine to the market, were also tested and compared with recently collected S. epidermidis blood isolates. RESULTS: There was no correlation between the use of chlorhexidine in scrub nurses and the presence of qacA/B genes in S. epidermidis isolates or increased MICs/MBCs of chlorhexidine for S. epidermidis isolates. While 55% of current blood isolates harboured the qacA/B genes, none of the 33 historical S. epidermidis isolates did, although their MICs and MBCs of chlorhexidine were comparable to those for current isolates. CONCLUSIONS: Chlorhexidine used as a hand rub does not select for S. epidermidis isolates with increased MICs or MBCs of chlorhexidine. However, the absence of qacA/B genes in S. epidermidis isolates obtained in the 1960s suggests that long-term use of biocides like chlorhexidine or related compounds may select for the presence of qacA/B genes. PMID- 23739539 TI - A comparison of actual versus predicted emergency ambulance journey times using generic Geographic Information System software. AB - STUDY OBJECTIVE: The planning of regional emergency medical services is aided by accurate prediction of urgent ambulance journey times, but it is unclear whether it is appropriate to use Geographical Information System (GIS) products designed for general traffic. We examined the accuracy of a commercially available generic GIS package when predicting emergency ambulance journey times under different population and temporal conditions. METHODS: We undertook a retrospective cohort study of emergency ambulance admissions to three emergency departments (ED) serving differing population distributions in northeast England (urban/suburban/rural). The transport time from scene to ED for all the highest priority dispatches between 1 October 2009 and 30 September 2010 was compared with predictions made by generic GIS software. RESULTS: For 10,156 emergency ambulance journeys, the mean prediction discrepancy between actual and predicted journey times across all EDs was an underprediction of 1.6 min (SD 4.9). Underprediction was statistically significant at all population densities, but unlikely to be of clinical significance. Ambulances in urban areas were able to exceed general traffic speed, whereas, the opposite effect was seen in suburban and rural road networks. There were minor effects due to travel outside the busiest traffic times (mean overprediction 0.8 min) and during winter months (mean underprediction 0.4 min). CONCLUSIONS: It is reasonable to estimate emergency ambulance journey times using generic GIS software, but in order to avoid insufficient regional ambulance provision it would be necessary to make small adjustments because of the tendency towards systematic underprediction. PMID- 23739541 TI - Does a claims diagnosis of autism mean a true case? AB - The purpose of this study was to validate autism spectrum disorder cases identified through claims-based case identification algorithms against a clinical review of medical charts. Charts were reviewed for 432 children who fell into one of the three following groups: (a) more than or equal to two claims with an autism spectrum disorder diagnosis code (n = 182), (b) one claim with an autism spectrum disorder diagnosis code (n = 190), and (c) those who had no claims for autism spectrum disorder but had claims for other developmental or neurological conditions (n = 60). The algorithm-based diagnoses were compared with documented autism spectrum disorders in the medical charts. The algorithm requiring more than or equal to two claims for autism spectrum disorder generated a positive predictive value of 87.4%, which suggests that such an algorithm is a valid means to identify true autism spectrum disorder cases in claims data. PMID- 23739542 TI - Association between severity of behavioral phenotype and comorbid attention deficit hyperactivity disorder symptoms in children with autism spectrum disorders. AB - Autism spectrum disorder and attention deficit hyperactivity disorder are neurodevelopmental disorders that cannot be codiagnosed under existing diagnostic guidelines (Diagnostic and Statistical Manual of the American Psychiatric Association, 4th ed., text rev.). However, reports are emerging that attention deficit hyperactivity disorder is sometimes comorbid with autism spectrum disorder. In the current study, we examined rates of parent-reported clinically significant symptoms of attention deficit hyperactivity disorder in school-aged children (4-8 years) with autism spectrum disorder, most of whom were first enrolled in our research protocols as toddlers. Results revealed that children with autism spectrum disorder and attention deficit hyperactivity disorder had lower cognitive functioning, more severe social impairment, and greater delays in adaptive functioning than children with autism spectrum disorder only. Implications for clinical practice include the need to assess for attention deficit hyperactivity disorder symptoms at an early age in children diagnosed with autism spectrum disorder. Research is needed to determine efficacious interventions for young children with autism spectrum disorder with comorbid attention deficit hyperactivity disorder to optimize outcomes. PMID- 23739543 TI - Tumor necrosis factor-alpha, a good biomarker and novel potential therapeutic target for atrial fibrosis. PMID- 23739544 TI - Role of mutations in L-type calcium channel genes in Brugada syndrome, early repolarization syndrome, and idiopathic ventricular fibrillation associated with right bundle branch block. PMID- 23739545 TI - Tumor Necrosis Factor-alpha, a Good Biomarker and Novel Potential Therapeutic Target for Atrial Fibrosis. Reply. PMID- 23739546 TI - Under-utilization of donor hearts in the initial era of the heart transplant program in Korea- review of 13 years' experience from the Korea national registry. AB - BACKGROUND: Heart transplantation (HTPL) is the effective treatment option to improve quality of life as well as survival of terminal heart failure patients. Shortage of donors, however, limits HTPL to all indicated cases. The temporal trend and clinical characteristics of HTPL donors in Korea were therefore investigated. METHODS AND RESULTS: Among 2,001 brain-death donors registered in Korean Network for Organ Sharing from February 2000 to May 2012, a total of 28% of hearts (n=552) were utilized for HTPL. The mean age of Korean heart donors was 10 years younger than that of heart recipients (33.2 +/- 12 years vs. 43.2 +/- 17 years, respectively). The oldest was 56 years old, and donors aged over 50 accounted for only 6.2% (n=34) of total cases. Female donors were utilized less than male donors (23.6% vs. 29.6%, respectively). To determine characteristics of declined donor heart candidates, subgroup analysis of echocardiographic data was done, and 74.6% had normal ventricular function and structure, although only 42.3% were actually transplanted. The utilization rate of donor hearts with minor echocardiography abnormalities was only 15.2%. Clinical outcomes of marginal heart donors were not different from non-marginal donors. CONCLUSIONS: Although shortage of donor organs is an emerging issue, most donor hearts have been under utilized in the past in Korea. In particular, aged and female donor hearts with minor echocardiographic abnormalities had a low rate of utilization. PMID- 23739547 TI - Tertiary-butylhydroquinone upregulates expression of ATP-binding cassette transporter A1 via nuclear factor E2-related factor 2/heme oxygenase-1 signaling in THP-1 macrophage-derived foam cells. AB - BACKGROUND: Tert-butylhydroquinone (tBHQ), a synthetic phenolic antioxidant, is commonly used as a food preservative because of its potent antilipid peroxidation activity. Several lines of evidence have demonstrated that dietary supplementation with antioxidants has an antiatherogenic function through reducing cholesterol uptake or promoting reverse cholesterol transport. In this study, we investigated whether tBHQ affects expression of ATP-binding cassette transporter A1 (ABCA1) and the potential subsequent effect on cellular cholesterol homeostasis. METHODS AND RESULTS: tBHQ increased ABCA1 protein levels and markedly enhanced cholesterol efflux from THP-1 macrophage-derived foam cells. Furthermore, tBHQ reduced calpain-mediated ABCA1 proteolysis via activation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO 1). Inhibition of HO-1 with a pharmacological inhibitor or siRNA and knockdown of Nrf2 suppressed the stimulatory effects of tBHQ on ABCA1 expression and calpain activity. CONCLUSIONS: Nrf2/HO-1 signaling is required for the regulation by tBHQ of ABCA1 expression and cholesterol efflux in macrophage-derived foam cells and an antiatherogenic role of tBHQ is suggested. PMID- 23739548 TI - Serum adiponectin in non-cachectic heart failure patients. PMID- 23739549 TI - Contractility of myofibrils from the heart and diaphragm muscles measured with atomic force cantilevers: effects of heart-specific deletion of arginyl-tRNA protein transferase. AB - BACKGROUND: Contractile properties of myofibrils from the myocardium and diaphragm in chronic heart failure are not well understood. We investigated myofibrils in a knockout (KO) mouse model with cardiac-specific deletion of arginyl-tRNA-protein transferase (alpha-MHCAte1), which presents dilated cardiomyopathy and heart failure. OBJECTIVE: The aim of this study was to test the hypothesis that chronic heart failure in alpha-MHCAte1 mice is associated with abnormal contractile properties of the heart and diaphragm. METHODS: We used a newly developed system of atomic force cantilevers (AFC) to compare myofibrils from alpha-MHCAte1 and age-matched wild type mice (WT). Myofibrils from the myocardium and the diaphragm were attached to the AFC used for force measurements during activation/deactivation cycles at different sarcomere lengths. RESULTS: In the heart, alpha-MHCAte1 myofibrils presented a reduced force during full activation (89+/-9 nN/MUm(2)) when compared to WT (132+/-11 nN/MUm(2)), and the decrease was not influenced by sarcomere length. These myofibrils presented similar kinetics of force development (K(act)), redevelopment (K(tr)), and relaxation (K(rel)). In the diaphragm, alpha-MHCAte1 myofibrils presented an increased force during full activation (209+/-31 nN/MUm(2)) when compared to WT (123+/-20 nN/MUm(2)). Diaphragm myofibrils of alpha-MHCAte1 and WT presented similar K(act), but alpha-MHCAte1 myofibrils presented a faster K(rel) (6.11+/ 0.41s(-1) vs 4.63+/-0.41 s(-1)). CONCLUSION: Contrary to our working hypothesis, diaphragm myofibrils from alpha-MHCAte1 mice produced an increased force compared to myofibrils from WT. These results suggest a potential compensatory mechanism by which the diaphragm works under loading conditions in the alpha-MHCAte1 chronic heart failure model. PMID- 23739550 TI - Coronary spasm and acute myocardial infarction due to a mutation (V734I) in the nucleotide binding domain 1 of ABCC9. AB - BACKGROUND: Alterations in coronary vasomotor tone may participate in the pathogenesis of acute myocardial infarction (AMI). Vascular ATP-sensitive K(+) (KATP) channels, formed by Kir6.x/SUR2B, are key regulators of coronary tone and mutations in cardiac (Kir6.2/SUR2A) KATP channels result in heart disease. Here we explore the pathophysiological mechanism of a rare mutation (V734I) found in exon 17 of the ABCC9 gene, estimated to cause a 6.4-fold higher risk of AMI before the age of 60. METHODS AND RESULTS: Eleven patients carrying the mutation were identified; they presented AMI of vasospastic origin associated with increased plasma levels of endothelin-1 and increased leukocyte ROCK activity. The effects of the mutation on the functional properties of the two splice variants of ABCC9 (SUR2A and SUR2B) were studied using patch-clamp electrophysiology. The mutation reduced the sensitivity to MgATP inhibition of Kir6.2/SUR2B channels but not of Kir6.2/SUR2A and Kir6.1/SUR2B channels. Furthermore, the stimulatory effects of MgNDP (MgADP, MgGDP and MgUDP) were unaltered in mutant Kir6.2/SUR2A and Kir6.1/SUR2B channels. In contrast, mutant channels composed of Kir6.2 and SUR2B were less sensitive to MgNDP activation, assessed in the presence of MgATP. The antianginal drug nicorandil activated Kir6.2/SUR2B-V734I channels, thus substituting for the loss of MgNDP stimulation, suggesting that this drug could be of therapeutic use in the treatment of AMI associated with V734I. CONCLUSIONS: The 734I allele in ABCC9 may influence susceptibility to AMI by impairing the response of vascular, but not cardiac, KATP channels to intracellular nucleotides. This is the first human mutation in an ion channel gene to be implicated in AMI. PMID- 23739551 TI - The incudostapedial articulation in Down's syndrome (trisomy 21): a temporal bone study. AB - HYPOTHESIS: Anomaly in the incudostapedial articulation (IS) may be responsible for persistent conductive hearing loss (HL) in Down's syndrome (DS) patients. Our goal was to perform a detailed histopathologic assessment of the role of the IS joint in the conductive HL. BACKGROUND: In addition to other disabilities, 38% to 78% of patients with Down's syndrome (Trisomy 21) have CHL, some of which are persistent despite maximum treatment. The cause of the persistent conductive HL remains unclear. METHODS: Retrospective analysis of temporal bone histopathology. Analyses of the midsection through the IS joint of 21 temporal bones (13 subjects) patients with DS and 31 temporal bones (18 subjects) from healthy subjects, performed by 2 blinded authors. The length of 7 different parameters of the width of the IS joint was measured and compared between the 2 groups. RESULTS: The IS joint of patients with DS was significantly wider than the normal control. As opposed to the control, it did not decrease because of age. CONCLUSION: The persistent conductive HL in some patients with DS might be caused by anomaly of the IS joint. In severe cases, corrective surgery should be considered. PMID- 23739552 TI - Radiologic examinations in human temporal bone specimens using digital volume tomography and high-resolution computed tomography after implantation of middle ear prosthesis and cochlear implant electrode array. AB - INTRODUCTION: Adequate imaging of the middle ear and its surrounding structures is an essential preoperative part in ear surgery. In the past, the main disadvantage of computed tomography (CT) scanners was the decreased diagnostic quality due to metallic artifacts. Furthermore, these scanners showed mostly an inferior image quality compared to digital volume tomography (DVT) in the temporal bone. It was the aim of this experimental study to compare the image quality of a state-of-the-art dual-source 2 * 128-slice CT scanner to DVT in temporal bone specimen. MATERIALS AND METHODS: Metallic prosthesis (PORP, TORP, stapes piston, cochlear implant electrode array) and an autologous incus were implanted in temporal bone specimen to analyze the diagnostic quality concerning the characterization of anatomic structures. Three further temporal bones were scanned without any preparation. Independently, 2 otologists and 2 radiologists scored the image quality of defined anatomic structures, using a range from 4 (excellent) to 0 (no diagnostic value). RESULTS: The general score for DVT was 2.67, whereas CT reached a score of 2.76. The diagnostic value for hard contrast objects was 3.0 for DVT and 2.9 for CT, whereas the score for soft tissue was 1.1 for DVT and 2.3 for CT. Almost no quality reduction of the display of anatomic structures caused by metallic artifacts could be detected in both diagnostic modalities. DISCUSSION: Both DVT and high-resolution CT allow good overall image quality in temporal bones, with discrete advantages for digital volume tomographic scans in terms of the image quality of hard contrast objects like bony structures or metallic implants. PMID- 23739553 TI - Comparison of 3 procedures for hypoglossal-facial anastomosis. AB - OBJECTIVE: We aimed to evaluate rehabilitation of complete facial palsy with 3 procedures for hypoglossal-facial anastomosis: end-to-end ("original"), partial end-to-end with interpositional jump grafting ("jump") and the new partial end to end without grafting ("modified"). METHODS: A medical jury reviewed videos of 36 patients with complete facial palsy who underwent surgery from 1998 to 2008 by original (n = 13), jump (n = 13), and modified (n = 10) procedures. The jury of 5 ear, nose, and throat surgeons who were blinded to the procedure evaluated rehabilitation by 3 facial nerve grading systems-House and Brackman (HB), Sunnybrook, and Freyss scales-and 3 subjective scores for the face at rest and during voluntary and emotional motions. RESULTS: Recovery time was shorter with the modified and original procedures than jump procedure (5, 6, and 8 mo, respectively). All patients achieved at least good results. Scores on the HB scale (I-VI) were mainly III. HB and Sunnybrook scores did not differ by procedure. Freyss score was better for the modified procedure than original and jump procedures. Scores for the face at rest did not differ by procedure, but those during voluntary and emotional movements were worse for the jump procedure than for other procedures. Synkinesis was more severe with the original procedure than other procedures. CONCLUSION: The 3 procedures give satisfactory results for rehabilitation after surgery for facial palsy. The original procedure should be performed in patients with strong mimic or long-standing facial palsy. The jump procedure is delicate and entails risk of weak reinnervation. The modified procedure is a good compromise in terms of muscle tone and side effects. PMID- 23739554 TI - Idiopathic pachymeningitis presenting with progressive sensorineural hearing loss, tinnitus and confusion. PMID- 23739555 TI - A meta-analysis of the complications associated with osseointegrated hearing aids. AB - OBJECTIVE: To summarize available peer-reviewed literature to describe the range and rate of complications related to osseointegrated hearing aids in adult and pediatric patients. METHODS: We searched PubMed using the terms bone-anchored hearing aid for articles published in English between 2000 and 2011. We included all articles reporting complications rates, except those that were case reports, general review (not systematic review), or commentary, as well as those that did not include patient outcomes, that reported outcomes associated with nonstandard implantation (e.g., 8.5-mm abutment) or were of poor study or reporting quality. RESULTS: After excluding articles that did not meet criteria, 20 articles were identified, comprising 2,134 patients who underwent a total of 2,310 osseoimplants. Complications reported in the literature were typically minor in nature. Skin reactions from Holgers Grade 2 to 4 ranged from 2.4% to 38.1%. Failure of osseointegration ranged from 0% to 18% in adult and mixed populations, and 0% to 14.3% in pediatric populations. The rate of revision surgery ranges from 1.7% to 34.5% in adult and mixed populations and 0.0% to 44.4% in pediatric patients, whereas the total rate of implant loss ranged from 1.6% to 17.4% in adult and mixed populations and from 0.0% to 25% in pediatric patients. CONCLUSION: Overall, the quality of large scale and/or prospective studies reporting the incidence of complications after osseointegrated hearing aid surgery is poor and lacks uniformity. However, based on available data, which shows a lack of major complications, osseointegrated implantation is a safe procedure in both adult and pediatric populations. Well-designed, prospective studies with uniform reporting standards would allow greater comparison between techniques and more reliable analysis of complications of osseointegration surgery of the temporal bone for cochlear stimulation. PMID- 23739556 TI - Increased risk of erectile dysfunction in patients with sudden sensorineural hearing loss: a nationwide, population-based cohort study. AB - OBJECTIVES: Previous studies have proposed that impaired cochlear blood perfusion and microvascular damage are important etiopathogenetic events in the development of sudden sensorineural hearing loss (SSHL). The purpose of this study was to test the hypothesis that SSHL is a risk factor for the development of erectile dysfunction (ED). STUDY DESIGN: A retrospective cohort study. SETTING: Population based study of Taiwan National Health Insurance Research Database. METHODS: We compared male patients newly diagnosed with SSHL between January 1, 2001, and December 31, 2006 (N = 23,212), with age-matched controls (1:2) (N = 46,424). MAIN OUTCOME MEASURES: The incidence of ED at the end of 2009 was determined. RESULTS: After adjusting for potential confounding factors, we found an adjusted hazard ratio (HR) of 1.942 (95% confidence interval, 1.688-2.233, p < 0.05), showing that patients with SSHL were more likely to experience ED than the control population. When stratified by patients' age, the incidence of ED was 1.90-, 2.25-, and 1.84-fold higher for SSHL-diagnosed patients 16 to 34 years old (p = 0.0408), 35 to 49 years old (p < 0.0001), and 50 to 64 years old (p < 0.0001), respectively, than in the non-SSHL group. Hypertension and chronic renal disease comorbidities in patients with SSHL seemed to be associated with an increased risk of developing ED. CONCLUSION: SSHL may confer an independent risk of ED. This observation supports the assumption of the underlying vascular mechanism regarding the development of SSHL. Thus, clinicians managing SSHL patients should be aware of the potential of the development of ED. EVIDENCE LEVEL: 2B. PMID- 23739557 TI - Masking effects in patients with auditory neuropathy-possible involvement of suppression mechanism caused by normal outer hair cell function. AB - OBJECTIVE: Variations in the effects of masking noise were evaluated in different pathologies of sensorineural hearing loss. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. PATIENTS: Fifty-five ears of 30 patients with sensorineural hearing loss who underwent noise audiometry in the Department of Otolaryngology-Head and Neck Surgery, Tohoku University Hospital, since 2010, because of complaints of hearing difficulty in noisy environments. MAIN OUTCOME MEASURES: Masked threshold for narrow band and white noise. RESULTS AND DISCUSSION: Masking effects in patients with auditory neuropathy were significantly larger than those in patients with other types of hearing losses. Masking effects of broad band white noise were greater than those of narrow band noise. Masking effects could be observed for white noise even in the elevated unmasked threshold region, where little contribution of excitatory masking effect would be expected. The present findings support the idea that the suppression mechanism caused by normal outer hair cell function is important in the masking phenomenon in patients with auditory neuropathy. PMID- 23739558 TI - Minimal inhibitory concentration of natural vinegar and of aluminium acetate tartrate solution. AB - HYPOTHESIS: Vinegar and aluminium acetate preparations are used for treatment of ear infections. It is instrumental to know the minimal inhibitory concentration to get effective remedies. This study was performed to assess the lowest dilution of vinegar (specified content, 6% acetic acid) and aluminium acetate-tartrate solution (specified content, 1.4% aluminium and 6% acetic acid) to determine the minimum inhibitory concentration against bacteria commonly found in chronic ear infections. BACKGROUND: Laboratory study on 2 samples of aluminium acetate tartrate and on 1 sample of natural white wine vinegar on antibacterial effects against Staphylococcus aureus, Staphylococcus epidermidis, Proteus vulgaris, Pseudomonas aeruginosa, and Escherichia coli. METHODS: Performing of a susceptibility testing-determination of the minimum inhibitory concentration (MIC) with the method of microbouillon dilution (DIN 58940 part 7). RESULTS: Acetic acid was found to be effective in vitro in concentrations of 0.1% to 0.2% against the tested bacteria; aluminium acetate-tartrate solution was found to be effective in vitro in concentrations of 1.25% to 2.5% against the tested bacteria. CONCLUSION: Vinegar respectively acetic acid diluted with water and aqueous aluminium acetate-tartrate solution could be effective ototopic preparations caused by one of the tested bacteria. For its effectiveness, an acid pH not higher than 4.5 is essential. Experiments with aluminium acetate-tartrate preparations on animals and clinical trials are required to obtain information about the response rates in ear infections and about any adverse effects. PMID- 23739559 TI - Familial aggregation of pure tone hearing thresholds in an aging European population. AB - OBJECTIVE: To investigate the familial correlations and intraclass correlation of age-related hearing impairment (ARHI) in specific frequencies. In addition, heritability estimates were calculated. STUDY DESIGN: Multicenter survey in 8 European centers. SUBJECTS: One hundred ninety-eight families consisting of 952 family members, screened by otologic examination and structured interviews. Subjects with general conditions, known to affect hearing thresholds or known otologic cause were excluded from the study. RESULTS: We detected familial correlation coefficients of 0.36, 0.37, 0.36, and 0.30 for 0.25, 0.5, 1, and 2 kHz, respectively, and correlation coefficients of 0.20 and 0.18 for 4 and 8 kHz, respectively. Variance components analyses showed that the proportion of the total variance attributable to family differences was between 0.32 and 0.40 for 0.25, 0.5, 1, and 2 kHz and below 0.20 for 4 and 8 kHz. When testing for homogeneity between sib pair types, we observed a larger familial correlation between female than male subjects. Heritability estimates ranged between 0.79 and 0.36 across the frequencies. DISCUSSION: Our results indicate that there is a substantial shared familial effect in ARHI. We found that familial aggregation of ARHI is markedly higher in the low frequencies and that there is a trend toward higher familial aggregation in female compared with male subjects. PMID- 23739560 TI - Active middle ear implantation for patients with sensorineural hearing loss and external otitis: long-term outcome in patient satisfaction. AB - OBJECTIVE: To study long-term subjective benefit of patients with sensorineural hearing loss and chronic external otitis who use active middle ear implants. DESIGN: Single-subject repeated measures in a preintervention and postintervention design with multiple postintervention measurements (questionnaires). SETTING: Tertiary academic center. PATIENTS: Moderate-to-severe sensorineural hearing loss (n = 56) with severe chronic external otitis who use the Vibrant Soundbridge (VSB) or Otologics MET middle ear implant systems. MAIN OUTCOME MEASURE: Changes in hearing disability and handicap as evaluated using the Abbreviated Profile of Hearing Aid Benefit (APHAB), the Nijmegen Cochlear Implant Questionnaire (NCIQ), and the Glasgow Benefit Inventory (GBI). RESULTS: Data of 33 patients (mean postoperative duration of 7.5 yr) were available. No difference in subjective results was found between the VSB and Otologics MET patient groups. Total percentage of nonuse was 13%. Long-term APHAB results show a significant decrease in disability for 43% of the patients compared with 54% at 1-year postoperative. NCIQ results show a significant benefit for all subdomains with a negative trend over time. The GBI results show a significant long-term increase in quality of life with positive scores for 82% of the assessed patients. CONCLUSION: Long-term postoperative patient satisfaction and quality of life results show a significant difference compared with preoperative measurements, with conventional hearing aids. A negative trend over time is found on all questionnaires, which might reflect patient aging (increase of hearing loss) or habituation to a situation with fewer concerns regarding a patient's external otitis. PMID- 23739561 TI - Development of cholesterol granuloma in a temporal bone petrous apex previously containing marrow exposed to air cells. AB - OBJECTIVE: There is ongoing debate on the pathogenic mechanisms of cholesterol granuloma formation in the temporal bone. The purpose of this report is to provide evidence in support of the exposed marrow hypothesis in explaining the pathogenesis of petrous apex cholesterol granuloma. STUDY DESIGN: Retrospective single case study. MAIN OUTCOME MEASUREMENT: The primary outcome evaluated was the diagnosis of a new cholesterol granuloma in a petrous apex that previously demonstrated radiologic evidence of bone marrow exposed to petrous apex air cells. RESULTS: A patient with a unilateral petrous apex cholesterol granuloma develops a new, contralateral cholesterol granuloma in a hyperpneumatized temporal bone petrous apex shown previously to have medullary bone exposed to air cells. CONCLUSION: This report implicates the medullary-air cell interface in a hyperaerated temporal bone petrous apex in the development and growth of a petrous apex cholesterol granuloma. PMID- 23739563 TI - [Screening for genes associated with natural killer cell mediated cytotoxicity in pneumonia mice infected with influenza virus and regulation of two herbal anti virus formulas]. AB - OBJECTIVE: To investigate the regulation of two herbal anti-virus formulas on gene expression profile associated with natural killer cell (NK cell) mediated cytotoxicity in pneumonia mice infected with influenza virus. METHODS: According to random number table, 90 ICR mice were divided into nine groups with 10 mice in each group: normal group (N), model group (M), oseltamivir group (control group, C), low-dose, medium-dose and high-dose Shufeng Xuanfei formula groups (SL, SM, SH groups), and low-dose, medium-dose and high-dose Jiebiao Qingli formula groups (JL, JM, JH groups). The model of pneumonia was reproduced by nasal dropping influenza virus A (FM1) in mice. N group was given isotonic saline 0.05 ml in nasal drops. After 2 hours of model-building, C group was received 11.375 mg*kg 1*d-1 oseltamivir phosphate. Shufeng Xuanfei formula (mainly honeysuckle, forsythia and radix isatidis, etc.) with 3.76, 1.88 and 0.94 g*kg-1*d were administrated to SH, SM and SL groups by gastric irrigation respectively. Jiebiao Qingli formula (mainly ephedra, gypsum, glycyrrhiza glabra, etc.) with 4.36, 2.18 and 1.09 g*kg-1*d-1 were administrated to JH, JM and JL groups by gastric irrigation respectively. In N and M groups, normal saline was administrated with gastric perfusion. Each group was in equal dose of 0.2 ml daily over a 4-day period. Total RNA in lung tissue of mice were extracted in each group, then gene chips were used to screen these RNA samples. Some genes involved NK cell mediated cytotoxicity were selected, with "I" representing of signal intensity. These candidate genes were verified by real-time fluorescent quantitation polymerase chain reaction (PCR) and Western blotting. RESULTS: In the pathway of NK cell mediated cytotoxicity, M group up-regulated 43 genes expression, and 36, 29, 22, 21, 20 and 10 genes showed down-regulation in SM, JM, SL, JH, SH and JL groups, respectively. Apart from gene co-expression network in SH, SL, JH, JM and JL, SM also expressed other differential genes which SH, SL, JH, JM and JL did not. So medium-does Shufeng Xuanfei formula had the most significant regulation in gene expression of NK cell mediated cytotoxicity. By real-time PCR and Western blotting experiments showed that compared with the M group, mRNA and protein expression of tumor necrosis factor-alpha (TNF-alpha) in these two formula groups were significantly down-regulated, especially prominent in SM group and JM group (TNF-alpha mRNA: 1.07 +/- 0.19, 1.19 +/- 0.14 vs. 3.20 +/- 0.56, both P<0.01). CONCLUSIONS: Influenza viral replication in host cell, which means influenza antigens exposure in infected cells as target cells. NK cells recognize and exert cell mediated cytotoxic function against influenza antigens. Genes associated with NK cell mediated cytotoxicity in influenza infection were up-regulated. Shufeng Xuanfei and Jiebiao Qingli formulas could down-regulate these genes. The mechanism of down-regulated genes is that the number of influenza infected cells and NK cells activation decreases in treatment with two formulas. PMID- 23739564 TI - [The study of AutoFlow role in volume controlled ventilation]. AB - OBJECTIVE: To evaluate the efficacy and safety of automatic variable flow rate (AutoFlow) for volume control ventilation through monitoring the number of ventilator alarm. METHODS: Forty-eight adult patients receiving the Drager Evita 4 ventilator with an expectation of more than 2 days duration were divided into two groups by randomly digital methods, each n=24. The patients in control group were received routinely mode with synchronized intermittent mandatory ventilation (SIMV), and the others in observation group were given SIMV and assist with AutoFlow. The midazolam and fentanyl was given to retain the Ramsay score 2-3 by continuous micro-pump. The ventilator alarm, blood gas analysis and respiratory function were recorded. RESULTS: There were no significant differences in respiratory rate (RR), tidal volume (VT), positive end-expiratory pressure (PEEP), fraction of inspired oxygen (FiO2), pH, arterial partial pressure of carbon dioxide (PaCO2), arterial partial pressure of oxygen (PaO2), oxygenation index (PaO2/FiO2), as well as sedative dose and time between two groups within 5 days of mechanical ventilation. Duration of mechanical ventilation in all patients was 164 days (3756 hours), and 78 days (1812 hours) in control group, 86 days (1944 hours) in observation group. The duration of mechanical ventilation in observation group was longer than that in control group [3 (1-15) days vs. 2 (1 28) days, P>0.05]. A total of 23 843 alarms were recorded, approximately 6 times/h, and 17 386 alarms in control group, averagely 9.6 times/h, 6457 alarms in the observation group, averagely 3.3 times/h. The number of ventilator alarm in observation group was less than that in control group (P<0.01). The number of airway pressure alarm in observation group was less than that in the control group [122 (8-1068) vs. 565 (13-1898), P<0.01]. There was no significant difference in sequential organ failure assessment (SOFA) score within 5 days between the two sets of mechanical ventilation. In the observation group ventilator-associated pneumonia (VAP) was occurred in 4 cases, and no pneumothorax happened, while in the control group there were 8 cases and 2 cases respectively. The mortality rate in intensive care unit (ICU) in observation group was lower than that in control group, but there was no statistical difference (25.0% vs. 37.5%, P>0.05). CONCLUSIONS: AutoFlow is confirmed be safe for volume control ventilation mode, and could significantly reduce the alarm of ventilator. PMID- 23739565 TI - [The relationship of endoplasmic reticulum stress with paraquat induced lung fibrosis in rats]. AB - OBJECTIVE: To investigate the relationship between pulmonary fibrosis and endoplasmic reticulum stress (ERS) in rats with paraquat poisoning. METHODS: One hundred male Sprague-Dawley (SD) rats were randomly divided into control group (n=10) and paraquat poisoning group (n=90). The animals were sacrificed by exsanguination at 2, 6, 12, 24, 48, 72, 96, 168, 336 hours after administration with 20% parquat solution. The paraffin sections of lung tissue were stained with hematoxylin-eosin (HE) and Masson trichrome to observe the pathological changes. Glucose-regulated protein 78 (GRP78) was determined by immunohistochemistry, and malondialdehyde (MDA) of lung tissue was measured. The total protein of tissue was abstracted, and the alpha-smooth muscle actin (alpha-SMA) and GRP78 was detected by Western blotting. RESULTS: HE and Masson staining demonstrated inflammatory infiltration and collagen deposition in the lung after paraquat administration with a tendency of exaggeration with time, and finally resulted in fibrosis. The expressions of MDA, alpha-SMA and GRP78 in the lung tissue were significantly increased 2 hours after paraquat administration compared with those of control group (MDA: 1.38 +/- 0.18 nmol/mg vs. 0.85 +/- 0.05 nmol/mg, alpha SMA: 0.23 +/- 0.01 vs. 0.14 +/- 0.03, GRP78: 0.72 +/- 0.02 vs. 0.37 +/- 0.06, P<0.05 or P<0.01), and the expressions of MDA and alpha-SMA were gradually increased with time. GRP78 protein expression was decreased at 72 hours after paraquat administration. CONCLUSIONS: The results reveal that the expressions of alpha-SMA and GRP78 in paraquat poisoning group are up-regulated, suggesting ERS plays an important role in paraquat induced-pulmonary fibrosis. PMID- 23739566 TI - [A multicenter study of respiratory multiple index in predicting weaning from mechanical ventilation in patients with acute exacerbation of chronic obstructive pulmonary disease]. AB - OBJECTIVE: To study the result of respiratory multiple index(compliance, respiratory rate, oxygenation, pressure, CROP) in predicting weaning from mechanical ventilation in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). METHODS: A prospective study was conducted. Two hundred and fifteen patients weaning from mechanical ventilation with AECOPD in intensive care unit (ICU) of five tertiary hospitals from September 2010 to October 2012 were enrolled. All of the AECOPD patients were troubled with respiratory failure and received non-invasive mechanical ventilation for more than 24 hours. They were conscious and cooperative at the time of extubation, and passed the spontaneous breathing trial (SBT) for 30 minutes. Before weaning, the maximal inspiratory pressure (PImax), the peak airway pressure (Ppeak), the total positive end expiratory pressure (PEEPtot), tidal volume (VT) and respiratory frequency (f) were recorded; the arterial partial pressure of oxygen (PaO2) and arterial partial pressure of carbon dioxide (PaCO2) were detected; the effective compliance of the respiratory system (Crs) and alveolar oxygen pressure(PAO2) were calculated. The above indexes were substituted into the formula: CROP= Crs * 1/f * PaO2/PAO2* PImax to get the value of CROP. Successful weaning from mechanical ventilation was defined if there was no indication for intubation within 72 hours. The receiver operating characteristic curve (ROC curve) was drawn to analyze the predict value of CROP on result of weaning from mechanical ventilation in patients with AECOPD. RESULTS: In 215 patients, 182 patients successfully weaned from mechanical ventilation, and 33 failed. There were no significant differences in gender, age and the acute physiology and chronic health evaluation II (APACHEII) score between the successfully weaned patients and the failed. Before weaning from mechanical ventilation, PaCO2 in failed group was significantly higher than that in successful group (60.69 +/- 10.47 mm Hg vs. 51.24 +/- 8.81 mm Hg, P<0.05), the CROP was significantly lowered (10.286 +/- 1.392 ml * breath-1 *min-1 vs. 58.746 +/- 7.283 ml*breath-1*min-1, P<0.01), and the duration of mechanical ventilation was prolonged (10.28 +/- 3.94 days vs. 6.21 +/- 2.87 days, P<0.05). The best critical value of CROP which could predict the result of weaning from mechanical ventilation was 13.521 ml*breath-1*min-1. CROP>= 13.521 ml*breath-1*min-1 had a specificity of 91.9% and sensitivity of 87.9% in predicting extubation succeed. The positive predicted value was 0.97, and the negative predicted value was 0.58; Odds ratio (OR)<1, which confirmed that CROP was a strong and independent predictor of extubation. CONCLUSIONS: For the AECOPD patients received mechanical ventilation, most extubation parameter was limited. Complex parameter of CROP has higher specificity and sensitivity, and has important value in predicting extubation outcome. When CROP >= 13.521 ml*breath-1*min-1, the successful rate is high, otherwise the rate is low. PMID- 23739567 TI - [A comparative study of inflammatory factor expression of phlegm-heat syndrome and phlegm-dampness syndrome model with acute exacerbation of chronic obstructive pulmonary disease]. AB - OBJECTIVE: To reveal characteristic of phlegm-heat syndrome and phlegm-dampness syndrome of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) from expression of inflammatory factor. METHODS: Forty-eight Wistar rats were randomly divided into four groups (each n=12): normal control group, AECOPD group, phlegm-heat syndrome of AECOPD group (PHs group) and phlegm-dampness syndrome of AECOPD group (PDs group). The expressions of interleukins (IL-1beta, IL-6, IL-10), tumor necrosis factor-alpha (TNF-alpha) proteins in lung tissue were detected by immunohistochemical staining method. IL-1beta mRNA and IL-10 mRNA expressions were measured by reverse transcription- polymerase chain reaction (RT-PCR). RESULTS: The mRNA and protein expressions of inflammatory factors in lung tissue in AECOPD group, PHs group and PDs group were remarkably enhanced compared with those in normal control group. Compared with AECOPD group, the protein expressions of IL-1beta, TNF-alpha and IL-6 and the mRNA expression of IL-1beta in lung tissue in PHs group and PDs group were markedly enhanced (IL 1beta protein: 6.26 +/- 2.43, 8.20 +/- 2.61 vs. 4.30 +/- 2.38, TNF-alpha protein: 10.28 +/- 2.64, 10.67 +/- 2.68 vs. 7.47 +/- 2.90, IL-6 protein: 8.13 +/- 3.03, 10.45 +/- 3.37 vs. 5.66 +/- 3.18, IL-1beta mRNA: 0.41 +/- 0.03, 0.48 +/- 0.05 vs. 0.35 +/- 0.04, all P<0.01), and the expressions of IL-10 protein and IL-10 mRNA were obviously weakened (IL-10 protein: 7.00 +/- 1.89, 4.70 +/- 2.31 vs. 9.33 +/- 2.58, IL-10 mRNA: 0.43 +/- 0.05, 0.35 +/- 0.03 vs. 0.52 +/- 0.06, P<0.05 or P<0.01). The protein expressions of IL-1beta and IL-6 proteins and the mRNA expression of IL-1beta in PDs group were significantly higher than those in PHs group, while the expressions of IL-10 protein and IL-10 mRNA were evidently lowered (all P<0.05). CONCLUSIONS: There were more strong expressions of IL-1beta and IL-6 and more weaken expressions of IL-10 in phlegm-dampness syndrome than in phlegm-heat syndrome, which may be one of the main reason of serious damage in lung tissue and delayed recovery of the patient with phlegm-dampness syndrome of AECOPD. All the above findings need further investigation. PMID- 23739568 TI - [The effect of hydrogen on hemorrhagic shock induced acute lung injury in rats]. AB - OBJECTIVE: To investigate the effect of hydrogen inhalation on acute lung injury after hemorrhagic shock in rats. METHODS: Twenty-four adult male Sprague-Dawley (SD) rats were equally randomized into three groups: sham operation group, model group and hydrogen-treatment group. Pressure-controlled hemorrhagic shock and resuscitation model was reproduced by blood-letting for 1 hour followed by fluid replacement for 2 hours. The rats in model group received a mixture of 50% oxygen 50% nitrogen during the process. The rats in hydrogen-treatment group received inhalation of a mixture of 2% hydrogen-48% nitrogen-50% oxygen 10 minutes before fluid replacement till the end of resuscitation. The arterial blood samples were collected for the measurement of arterial partial pressure of oxygen (PaO2) before exsanguination, 1 hour after shock, 1 hour and 2 hours after fluid replacement. Blood and lung tissues were collected at the end of experiment, and tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels in plasma, lung wet/dry weight ratio (W/D), malondialdehyde (MDA) content, superoxide dismutase (SOD) and myeloperoxidase (MPO) activity in the lung tissue were determined. The lung tissue was subjected to pathological examination. RESULTS: At the end of fluid replacement, compared with model group, hydrogen could significantly reduce pulmonary edema (lung W/D ratio: 4.72 +/- 0.12 vs. 4.94 +/- 0.14, P<0.05), inhibit oxidative stress (MDA: 0.55 +/- 0.09 nmol/mg vs. 0.72 +/- 0.08 nmol/mg, P<0.05), enhance antioxidant activity (SOD activity: 79.53 +/- 14.33 U/mg vs. 59.55 +/- 9.07 U/mg, P<0.05), reduce the release of pro inflammatory cytokines (TNF-alpha: 55.58 +/- 10.06 ng/L vs. 66.58 +/- 5.17 ng/L; IL-6: 23.00 +/- 2.77 ng/L vs. 27.09 +/- 2.46 ng/L, both P<0.05) and inhibit neutrophil infiltration (MPO: 1.05 +/- 0.18 U/g vs. 1.40 +/- 0.14 U/g, P<0.05). It alleviated the damage to lung tissue, and then improved the lung function (PaO2: 146.3 +/- 22.1 mm Hg vs. 123.6 +/- 16.0 mm Hg, P<0.05). CONCLUSIONS: Hydrogen treatment can alleviate acute lung injury as a result of hemorrhagic shock and resuscitation. PMID- 23739569 TI - [The effect of heme oxygenase-1 on apoptosis and aquaporin-1 expression in type II primary alveolar epithelial cells in rat]. AB - OBJECTIVE: To explore the effect of heme oxygenase-1 (HO-1) on apoptosis and expression of aquaporin-1 (AQP-1) in primary type II alveolar epithelial cells (AECII) in rats with hydrogen peroxide (H2O2) induced oxidative damage. METHODS: Lung tissue of male Sprague-Dawley (SD) rats was collected. Primary AECII were isolated, purified, and cultured for 24 hours, then they were divided into four groups: (1) normal group (treated with normal saline); (2) H2O2 injury group (treated with H2O2 0.5 mmol/L); (3) HO-1 control group (treated with HO-1 1 MUmol/L); (4) HO-1 protection group (treated with HO-1 1 MUmol/L and H2O2 0.5 mmol/L). Cells of each group were cultured for 12 hours after various treatment. The cell suspension was collected before and 1, 3, 6, 12 hours after treatment, the expression of AQP-1 was determined by Western blotting and the apoptosis rate was assessed with flow cytometer. RESULTS: The expression of AQP-1 in H2O2 injury group was significantly declined with time, and was lower than that in normal group at each time point after treatment. The expression of AQP-1 in HO-1 control group and HO-1 protection group was significantly increased with time, and was higher than that of other groups at each time point after treatment. The expression of AQP-1 in HO-1 protection group was significantly up-regulated compared with that in H2O2 injury group (1 hour: 60.81 +/- 5.78 vs. 46.21 +/- 4.81, 3 hours: 63.05 +/- 9.61 vs. 39.32 +/- 4.96, 6 hours: 92.59 +/- 8.21 vs. 36.82 +/- 4.32, 12 hours: 86.16 +/- 14.84 vs. 34.88 +/- 2.66, all P<0.05). No significant difference in apoptosis rate was found between normal group and HO-1 control group. The apoptosis rate in H2O2 injury group was increased with time, and was significantly higher than that of normal group at each time point. The apoptosis rate in HO-1 protection group was gradually increased within 3 hours after treatment, then decreased and remained stable after 6 hours, while it was significantly lower than that of H2O2 injury group at each time point [1 hour: (9.04 +/- 2.17)% vs. (15.14 +/- 2.47)%, 3 hours: (12.90 +/- 2.04)% vs. (22.37 +/- 4.84)%, 6 hours: (10.42 +/- 1.68)% vs. (27.83 +/- 3.93)%, 12 hours: (11.97 +/- 1.91)% vs. (33.63 +/- 6.61)%, all P<0.05]. A negative correlation was found between AQP-1 and apoptosis rate in H2O2 injury group (r=-0.723, P<0.001), and a regression correlation was found [y=672.548(0.914) (x), R2=0.597]. AQP-1 was not correlated with apoptosis rate in HO-1 protection group (r=0.210, P=0.193), but a regression correlation was found [y=e((3.130 - 59.654/x )), R2=0.225]. CONCLUSIONS: HO-1 could increase the expression of AQP-1 in H2O2 injured AECII of rat, and lower its apoptosis rate. Increase in the expression of AQP-1 may be the underlying mechanism of anti-oxygenation property of HO-1. PMID- 23739570 TI - [Comparison of sedative effects of propofol and midazolam on emergency critical patients on mechanical ventilation]. AB - OBJECTIVE: To compare the sedative effects of propofol and midazolam, or combination of them on emergency critically ill patients on mechanical ventilation. METHODS: Medical records of 68 patients treated in emergency intensive care unit (EICU) receiving mechanical ventilation and sedation care from August 2007 to July 2011 were reviewed retrospectively. According to the type of sedatives used, patients were assigned to propofol group (n=28), midazolam group (n=20), combination of propofol and midazolam group (combination group, n=20). Patients in the former two groups were given a loading dose of propofol or midazolam and followed by continuous infusion of the same drugs. Those in the combination group were given a loading dose of propofol and followed by continuous infusion of propofol together with midazolam. In this study, Ramsay anesthesia score was used to evaluate the effectiveness of sedation. The patients in three groups were maintained at depth of sedation level 2-4 according to the Ramsay score, and reassessed every 1-2 hours after the initiation. The change in vital signs and respirator related parameters were observed before and after administration in three groups, and the treatment information of sedative and mechanical ventilation were recorded. RESULTS: Heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), diastolic blood pressure (DBP), tidal volume (VT) were decreased at 1 hour after treatment compared with those before treatment in all the three groups, while the blood oxygen saturation (SpO2) was increased. There were no significant differences in RR and SpO2 at 1 hour after treatment among three groups. HR, SBP, DBP at 1 hour after treatment in propofol group were significantly decreased compared with those in midazolam group and combination group (HR: 20.43 +/- 13.52 bpm vs. 15.27 +/- 13.71 bpm, 18.54 +/- 10.07 bpm; SBP: 39.26 +/- 16.64 mm Hg vs. 25.80 +/- 21.09 mm Hg, 31.50 +/- 28.20 mm Hg; DBP: 21.35 +/- 12.91 mm Hg vs. 14.07 +/- 10.53 mm Hg, 16.42 +/- 13.55 mm Hg, P<0.05 or P<0.01). VT at 1 hour after beginning of the treatment in combination group was decreased significantly compared with propofol group and midazolam group (121.06 +/- 96.50 ml vs. 33.36 +/- 28.49 ml, 39.94 +/- 33.24 ml, both P<0.01). The drug dosage in combination group was decreased significantly compared with propofol group and midazolam group (total dosage of propofol: 25.21 +/- 15.33 mg/kg vs. 90.83 +/- 17.42 mg/kg, total dosage of midazolam: 2.37 +/- 1.87 mg/kg vs. 4.02 +/- 3.62 mg/kg, both P<0.01), but there was no significant difference in sedation time among groups. EICU stay days in combination group was shortened significantly compared with propofol group and midazolam group (7.75 +/ 5.20 days vs. 12.53 +/- 8.24 days, 15.20 +/- 8.33 days, both P<0.05), but there was no significant difference in mechanical ventilation duration among groups. CONCLUSIONS: A combination of propofol with midazolam for emergency critically ill patients on mechanical ventilation not only can achieve a good sedative effect, reduce total amount of the drug, but also alleviate the inhibitory effect of propofol on the circulation, improve the symptoms of asynchronous ventilation, and reduce stay time in EICU. PMID- 23739571 TI - [Relationship between antacid therapy and hospital acquired pneumonia in critically ill patients: a meta-analysis]. AB - OBJECTIVE: To systematically review the effect of antacid medication on stress related mucosal disease (SRMD) bleeding, hospital acquired pneumonia (HAP), and hospital mortality in critically ill patients admitted to intensive care unit (ICU). METHODS: Related articles were retrieved from Medline Database (from January 1980 to December 2012). Randomized control trials (RCTs) focused on comparison between antacid and sucralfate were collected, and then a meta analysis was performed. RESULTS: Twelve studies including a total of 2537 patients admitted to ICU were qualified for analysis. Antacid medication significantly increased the incidence of HAP when compared with sucralfate in 11 trials [19.36% (249/1286) vs. 15.23% (184/1208), odds ratio (OR)=1.27, 95% confidence interval (95%CI): 1.03-1.57, P=0.02]. Subgroup analyses showed that antacid therapy significantly reduce the incidence of clinically significant bleeding compared with sucralfate [1.80% (12/667) vs. 3.86% (26/673), OR=0.46, 95%CI: 0.23-0.91, P=0.03], however, it did not lower the incidence of overt bleeding [7.09% (40/564) vs. 7.35% (36/490), OR=1.00, 95%CI: 0.62-1.62, P=0.99]. There was no significant difference between antacid group and sucralfate group on neither ICU mortality nor hospitalization mortality in 11 studies [25.58% (288/1126) vs. 23.65% (268/1133), OR=1.11, 95%CI: 0.92-1.35, P=0.28]. CONCLUSIONS: Antacid therapy used in critically ill patients may increase the incidence of HAP while reduce the rate of upper gastrointestinal bleeding, while it exerts no influence on mortality rate when compared with sucralfate treatment in this meta-analysis. It is imperative to restrict the overuse of such medication, and further RCTs focused on indication and withdrawal should be encouraged. PMID- 23739572 TI - [The timing of infusion of hypertonic saline to exert protective effect on intestinal barrier function in the rabbit with intestinal ischemia/reperfusion injury]. AB - OBJECTIVE: To study the timing of infusion of hypertonic saline solution (HTS) to exert its protective effect on intestinal barrier function in rabbits with intestinal ischemia/reperfusion (I/R) injury. METHODS: Seventy-two rabbits were randomly divided into four groups (each n=18): sham operation group, I/R group, HTS pretreatment group and HTS delayed treatment group. The intestinal I/R models were produced by blocking the superior mesenteric artery (SMA) for 1 hour followed by release of the SMA. 7.5% HTS (6 ml/kg) was infused in HTS pretreatment group 5 minutes before release of SMA, and HTS was infused in delayed treatment group 2 hours after reperfusion and finished in 5 minutes. Levels of D-lactic acid (D-Lac), lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-alpha), interleukin-10 (IL-10) were determined before ischemia and 2, 4, 6 hours after reperfusion. The levels of malonaldehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO) in intestinal tissues of 8 rabbits in each group were measured at 6 hours after reperfusion. Meanwhile the intestinal morphological changes were observed, and the Chin score, which reflected the degree of injury to intestinal mucosa was calculated. RESULTS: Compared with sham operation group, D-Lac, LPS, TNF-alpha and IL-10 in I/R group were significantly increased from 2 hours after reperfusion (D-Lac: 18.91 +/- 3.46 mg/L vs. 3.92 +/- 0.61 mg/L, LPS: 869 +/- 85 EU/L vs. 422 +/- 27 EU/L, TNF-alpha: 23.80 +/- 4.22 MUg/L vs. 3.65 +/- 0.51MUg/L, IL-10: 8.90 +/- 2.75 MUg/L vs. 2.53 +/- 0.80 MUg/L, all P<0.05); MDA, MPO and Chiu score were significantly increased (MDA: 398 +/- 28 nmol/mg vs. 173 +/- 20 nmol/mg, MPO: 465 +/- 52 mU/mg vs. 183 +/- 25 mU/mg, Chiu score: 4.36 +/- 0.52 vs. 0.38 +/- 0.22, all P<0.05), while SOD decreased significantly (35 +/- 9 U/mg vs. 52 +/- 8 U/mg, P<0.05). Compared with I/R group, the levels of D-Lac, LPS, TNF-alpha, MDA, MPO and Chiu score in HTS pretreatment group were lower (D-Lac: 11.45 +/- 0.92 mg/L vs. 18.91 +/- 3.46 mg/L, LPS: 455 +/ 114 EU/L vs. 869 +/- 85 EU/L, TNF-alpha: 10.32 +/- 2.11 MUg/L vs. 23.80 +/- 4.22 MUg/L, MDA: 221 +/- 21 nmol/mg vs. 398 +/- 28 nmol/mg, MPO: 271 +/- 20 mU/mg vs. 465 +/- 52 mU/mg, Chiu score: 1.69 +/- 0.24 vs. 4.36 +/- 0.52, all P<0.05), while IL-10 and SOD were significantly increased (IL-10: 14.54 +/- 2.02 MUg/L vs. 8.90 +/- 2.75 MUg/L, SOD: 90 +/- 14 U/mg vs. 35 +/- 9 U/mg, both P<0.05). The levels of the above indexes in HTS delayed treatment group were similar to I/R group, and the effect was lower than that in HTS pretreatment group. CONCLUSIONS: HTS had the protective effect on intestine suffering from I/R injury. But the protective effect was time dependent, and early treatment shows protective effect. PMID- 23739573 TI - [Drug resistance analysis of pan-drug-resistant Acinetobacter baumannii in hospital]. AB - OBJECTIVE: To investigate current situation of pan-drug-resistant Acinetobacter baumannii in hospital and its drug-resistance , then provide reference for rational use of antibiotics in clinic. METHODS: All kinds of microbial test specimens from January 2009 to December 2012 of hospitalized patients were cultured and separated. VITEK 2-Compact fully automatic microorganism analyzer was used to identify and analyze drug sensitivity. RESULTS: Three hundred and seven strains pan-drug-resistant Acinetobacter baumannii were isolated in 4 years, the primarily source were sputum, accounted for 69.4%, followed by the wound secretion 14.7%. The highest three places of samples separation of extensive drug-resistant Acinetobacter baumannii positive was intensive care unit (ICU, accounted for 26.4%), department of respiratory medicine (accounted for 26.1%) and department of geriatrics (accounted for 23.1%). Extensive drug resistant Acinetobacter baumannii almost completely resisted to clinical commonly used antimicrobial agents, drug resistant rate could be as high as 100% such as cefotaxime, meropenem, piperacillin, imipenem, ciprofloxacin, and tetracycline except for cefoperazone-sulbactam and polymyxin, and the rate of other drugs were all above 90%. Drug-resistant of cefoperazone-sulbactam was nearly 30% in our hospital, and sensitive rate was 100% to polymyxin. CONCLUSIONS: Pan-drug resistant Acinetobacter baumannii is resistant for most clinical commonly used antimicrobial drug, antimicrobial agents were chosen according to drug susceptibility testing. Antibacterial drugs such as polymyxin and cefoperazone sulbactam or sulbactam contained drugs can be selected for pan-drug-resistant. PMID- 23739574 TI - [Effects of dexmedetomidine on sedation and beta-endorphin in traumatic brain injury: a comparative study with propofol]. AB - OBJECTIVE: To compare the efficacy of dextraldexmede (DEX) and propofol on sedation and beta-endorphin (beta-EP) in patients with moderate and severe traumatic brain injury (TBI). METHODS: Ninety patients with moderate and severe TBI with Glasgow coma score (GCS) 6-13 were randomly divided into three groups according to the order of admission of odd and even numbers. In group A (DEX/+morphine), DEX load 0.5-1.0 MUg/kg was injected within 30 minutes, and maintaining at 0.2-0.6 MUg*kg-1 * h-1 for 24 hours; and in group B (propofol/+ morphine), propofol load 0.5-2.0 mg/kg was injected within 10 minutes, and maintaining at 1-3 mg*kg-1*h-1 for 72 hours. Patients with poor efficacy were added with morphine intravenously. In group C, intramuscular injection of pethidine and other temporary medication was injected. The comprehensive assessment was conducted according to the Riker sedation and agitation score, combined with the physiological body reaction positive indicator elimination. The vital signs was monitored, and blood white blood cell (WBC) count, blood sugar, cortisol and beta-EP before and after administration were determined. RESULTS: (1) The sedation efficiency rate of the group A, B, C were 84.38% (27/32), 80.64% (25/31), 77.78% (21/27), respectively. The booster dose of morphine in group A was less than that in group B (24 h dosage: 16.23 +/- 3.45 mg vs. 21.34 +/- 5.55 mg). (2) Blood pressure and heart rate were significantly affected in the group A. The mean arterial pressure (MAP) in 0.5 hour of reaching loading dose in group A was significantly lower than that in group B and C (75.50 +/- 9.35 mm Hg vs. 87.90 +/- 8.05 mm Hg, 85.70 +/- 7.10 mm Hg, both P<0.05). (3) WBC and cortisol levels showed downwards trends after treatment in group A and group B; WBC fell more in the group A compared with group B, cortisol level fell more in group B compared with group A, and the WBC and cortisol level began to decline after 24 hours in group C. (4) There were no significant differences in blood sugar and beta-EP levels before and after treatment in group B, but beta-EP had an increasing tendency in group A and group C, and the amplification in group C was more obvious than that in group A. CONCLUSIONS: The sedation efficacy of DEX was superior to propofol in moderate and severe TBI, and was able to control excessive stress response after TBI better, and with more effect on blood pressure. Plasma beta-EP was elevated during the early phase of brain injury by DEX, which was considered as its positive role in the regulation of early stress. PMID- 23739575 TI - [Safety and efficacy of percutaneous dilatational tracheostomy in intensive care unit]. PMID- 23739576 TI - [Nursing experience for patients with severe H7N9 bird flu virus in critical care unit]. PMID- 23739577 TI - [Preventive effect of extracorporeal membrane oxygenation on complication during treatment of human infections with highly pathogenic avian influenza]. PMID- 23739578 TI - [Melatonin and delirium]. PMID- 23739579 TI - Does retrieval-induced forgetting affect future social behavior? AB - The current paper presents an experiment examining the impact of retrieval induced forgetting on a behavioral test. Participants first studied neutral and positive, or neutral and negative traits about a target and then practiced the neutral traits either via retrieval practice or re-presentation. Participants then were asked to take a seat outside the laboratory before recalling all the traits. Retrieval-induced forgetting was found in the retrieval practice but not the re-presentation condition for the valenced traits and also on the behavioral task with participants who suppressed positive traits choosing to sit further away from the target and participants who suppressed negative traits choosing to sit closer to the target. The findings indicate that retrieval-induced forgetting extends to behavioral tasks and affects the likely execution of a behavior. The findings are discussed in terms of the inhibitory theory of retrieval-induced forgetting. PMID- 23739580 TI - More equal than others: Equity norms as an integration of cognitive heuristics and contextual cues in bargaining games. AB - Behavior in one-shot bargaining games, like the Ultimatum Game (UG), has been interpreted as an expression of social preferences, such as inequity aversion and negative reciprocity; however, the traditional UG design limits the range of possible psychological interpretation of the results. Here, we employed three different designs for ultimatum games, finding support for a more comprehensive theory: behavior is driven by cognitive factors implementing rules such as equal splitting, speaking up for the idea that equity works as a cognitive heuristic, applicable when the environment provides no reason to behave otherwise. Instead subjects deviate from this rule when environment changes, as, for instance, when personal interest is at stake. Results show that behavior varies systematically with contextual cues, balancing the self-interest with the automatic application of the equity heuristic. Thus, the context suggests the rule to be applied in a specific situation. PMID- 23739581 TI - Reply to: myofascial pain syndrome may be the most difficult disorder that is differentiated from fibromyalgia. PMID- 23739582 TI - Amphioxus makes the cut-Again. AB - The cephalochordate amphioxus is now established as an important model system for understanding the evolution of vertebrate novelties from an invertebrate chordate ancestor. It is also emerging as a serious candidate for studies of organ regeneration. We extend here our previous observations on the European amphioxus' extensive adult regenerative capacity. The expression of Wnt5 and the presence of beta-catenin protein in the early bud-stage blastema support a role for Wnt signaling during tail regeneration in amphioxus. We also present data showing that Branchiostoma lanceolatum continues to regenerate well after repeated amputation of the post-anal tail. These results are discussed in relation to vertebrate regeneration and other stem cell systems, and in the context of regeneration decline with aging. PMID- 23739583 TI - Committed changes in tropical tree cover under the projected 21st century climate change. AB - Warming and drought pose a serious threat to tropical forest. Yet the extent of this threat is uncertain, given the lack of methods to evaluate the forest tree cover changes under future climate predicted by complex dynamic vegetation models. Here we develop an empirical approach based on the observed climate space of tropical trees to estimate the maximum potential tropical tree cover (MPTC) in equilibrium with a given climate. We show that compared to present-day (2000 2009) conditions, MPTC will be reduced by 1 to 15% in the tropical band under equilibrium future (2090-2099) climate conditions predicted by 19 IPCC climate models. Tropical forests are found to regress or disappear mainly in the current transition zones between forest and savanna ecosystems. This climate pressure on tropical forests, added to human-caused land use pressure, poses a grand challenge to the sustainability of the world's largest biomass carbon pool. PMID- 23739584 TI - Bent thorocene complexes with the cyanide, azide and hydride ligands. AB - Reaction of the linear thorocene with NC(-), N3(-) and H(-) led to the bent derivatives [(Cot)2Th(X)](-) (X = CN, N3) and the bimetallic [{(Cot)2Th}2(MU-H)]( ), whereas only [(Cot)2U(CN)](-) could be formed from (Cot)2U. PMID- 23739585 TI - Morbid obesity-the new pandemic: medical and surgical management, and implications for the practicing gastroenterologist. AB - The gastroenterologist, whether in academic or clinical practice, must face the reality that an increasingly large percentage of adult patients are morbidly obese. Morbid obesity is associated with significant morbidity and mortality including enhanced morbidity from cardiovascular, cerebrovascular, hepatobiliary and colonic diseases. Most of these associated diseases are actually preventable. Based on the 1991 NIH consensus conference criteria, for most patients with a body mass index (BMI=weight in kilograms divided by the height in meters squared) of 40 or more, or for patients with a BMI of 35 or more and significant health complications, surgery may be the only reliable option. Currently in the United States, over 250,000 bariatric surgical procedures are being performed annually. The practicing gastroenterologist in every community, large and small, must be familiar with the various surgical procedures together with their associated anatomic changes. These changes may dramatically increase the prevalence of nutritional deficiencies and profoundly alter the clinical and endoscopic approaches to diagnosis and management. PMID- 23739586 TI - Tailorable stimulated Brillouin scattering in nanoscale silicon waveguides. AB - Nanoscale modal confinement is known to radically enhance the effect of intrinsic Kerr and Raman nonlinearities within nanophotonic silicon waveguides. By contrast, stimulated Brillouin-scattering nonlinearities, which involve coherent coupling between guided photon and phonon modes, are stifled in conventional nanophotonics, preventing the realization of a host of Brillouin-based signal processing technologies in silicon. Here we demonstrate stimulated Brillouin scattering in silicon waveguides, for the first time, through a new class of hybrid photonic-phononic waveguides. Tailorable travelling-wave forward stimulated Brillouin scattering is realized-with over 1,000 times larger nonlinearity than reported in previous systems-yielding strong Brillouin coupling to phonons from 1 to 18 GHz. Experiments show that radiation pressures, produced by subwavelength modal confinement, yield enhancement of Brillouin nonlinearity beyond those of material nonlinearity alone. In addition, such enhanced and wideband coherent phonon emission paves the way towards the hybridization of silicon photonics, microelectromechanical systems and CMOS signal-processing technologies on chip. PMID- 23739587 TI - Can intraoperative use of limbal stay suture in strabismus surgery cause epithelial ingrowth? AB - Epithelial ingrowth has been reported extensively as a result of some corneal procedures and secondary to trauma. The authors describe a case of epithelial ingrowth most likely caused by a limbal stay suture used during strabismus surgery. The pathophysiology of epithelial ingrowth and its differential diagnosis of fibrous downgrowth are discussed. PMID- 23739588 TI - Congenital optic nerve pit in trisomy 18. AB - The authors report the first case of trisomy 18 associated with a clinically detectable optic nerve pit. A female infant with a birth weight of 2,150 g was born by cesarean section to a healthy 40-year-old woman at 38 weeks of gestation. Trisomy 18 had been diagnosed by prenatal genetic testing. Ophthalmologic examination was remarkable for bilateral narrowed palpebral fissures with punctal agenesis, corectopic pupils without reaction to light, bilateral inferior peripapillary retinochoroidal hypopigmentation, and significant optic nerve cupping in the left eye with associated temporal optic nerve pit. It has generally been accepted that optic nerve pits are a congenital anomaly. However, the pathophysiological background of optic nerve pits remains unclear and controversial. This is the first clinical and photographic documentation of an optic nerve pit in a neonate and in Edwards syndrome. PMID- 23739589 TI - Dramatic regression of persistent tunica vasculosa lentis associated with retinopathy of prematurity following treatment with intravitreal bevacizumab. AB - The authors describe a preterm infant who developed advanced retinopathy of prematurity bilaterally with a prominent tunica vasculosa lentis. Treatment with intravitreal bevacizumab resulted in regression of the tunica vasculosa lentis and posterior manifestations of the retinopathy of prematurity. RetCam imaging (Clarity Medical Systems, Pleasanton, CA) of the anterior segment was used to document the dramatic tunica vasculosa lentis resolution. PMID- 23739590 TI - Pre-conditioned mesenchymal stem cells: a better way for cell-based therapy. AB - Ischemic heart disease is the major cause of death globally, and a recently developed stem cell transplantation is a promising therapy for myocardial infarction. Mesenchymal stem cells (MSCs) exist in a wide range of tissues, and their differentiation potential and immunoregulatory capacity make them a more optimal candidate for regenerative medicine. However, the poor survival and low differentiation efficiency of the donor cells in the infarcted myocardium challenged therapeutic efficacy of MSC transplantation. To this end, many researchers have focused on improving the microenvironments of MSCs before and after transplantation and on trying to figure out the mechanisms. A recent study by Boopathy and colleagues reported the pro-cardiovascular differentiation effect of oxidative stress on cultured MSCs and the underlying signal pathways, leading to the notion that MSCs pre-conditioned with oxidative reagents promote cardiac differentiation efficiency of MSCs and may result in better clinical effect for ischemic heart diseases. PMID- 23739591 TI - Activation of the sympathetic nervous system, is it key to the developmental origins of enhanced cardiovascular risk? PMID- 23739592 TI - Attenuation of lithium-induced natriuresis and kaliuresis in P2Y2 receptor knockout mice. AB - Whole body knockout (KO) of the P2Y2 receptor (P2Y2R) results in enhanced vasopressin V2 receptor activity and increased renal Na+ conservation. We hypothesized that P2Y2R KO mice would be less sensitive to lithium-induced natriuresis and kaliuresis due to attenuated downregulation of one or more of the major renal Na+ or K+ transporter/channel proteins. KO and wild-type (WT) mice were fed a control or lithium-added diet (40 mmol/kg food) for 14 days. Lithium induced natriuresis and kaliuresis were significantly (~25%) attenuated in KO mice. The subunits of the epithelial Na+ channel (ENaC) were variably affected by lithium and genotype, but, overall, medullary levels were decreased substantially by lithium (15-60%) in both genotypes. In contrast, cortical, beta-, and gamma ENaC were increased by lithium (~50%), but only in WT mice. Moreover, an assessment of ENaC activity by benzamil sensitivity suggested that lithium increased ENaC activity in WT mice but in not KO mice. In contrast, medullary levels of Na+-K+-2Cl- cotransporter 2 and cortical levels of the renal outer medullary K+ channel were not downregulated by lithium and were significantly (15 76%) higher in KO mice under both dietary conditions. In addition, under control conditions, tissue osmolality of the inner medulla as well as furosemide sensitivity were significantly higher in KO mice versus WT mice. Therefore, we suggest that increased expression of these proteins, particularly in the control state, reduces Na+ delivery to the distal nephron and provides a buffer to attenuate collecting duct-mediated natriuresis and kaliuresis. Additional studies are warranted to explore the potential therapeutic benefits of purinergic antagonism. PMID- 23739594 TI - Influence of novel supramolecular substance, [2] rotaxane, on the caspase signaling pathway in melanoma and colon cancer cells in vitro. AB - We studied the influence of novel supramolecular substance, [2] rotaxane (TRO A0001), on caspase signaling and cell viability in cancer cell lines. TRO-A0001 suppressed concentration-dependently cell proliferation. Expression of the cleaved-form caspase-3 and PARP was significantly increased in cells exposed to TRO-A0001. The expression of Bax was increased by TRO-A0001. Furthermore, the down-regulation of Bax by siRNA resulted in growth activation significantly. The morphological analysis demonstrated that TRO-A0001 increased the levels of apoptotic cells in human cancer cell lines. These results suggest that TRO-A0001 induces apoptosis in cancer cells and holds potential as a new anti-tumor medicine. PMID- 23739593 TI - Aldosterone acutely stimulates NCC activity via a SPAK-mediated pathway. AB - Hypertension is a leading cause of morbidity and mortality worldwide, and disordered sodium balance has long been implicated in its pathogenesis. Aldosterone is perhaps the key regulator of sodium balance and thus blood pressure. The sodium chloride cotransporter (NCC) in the distal convoluted tubule of the kidney is a major site of sodium reabsorption and plays a key role in blood pressure regulation. Chronic exposure to aldosterone increases NCC protein expression and function. However, more acute effects of aldosterone on NCC are unknown. In our salt-abundant modern society where chronic salt deprivation is rare, understanding the acute effects of aldosterone is critical. Here, we examined the acute effects (12-36 h) of aldosterone on NCC in the rodent kidney and in a mouse distal convoluted tubule cell line. Studies demonstrated that aldosterone acutely stimulated NCC activity and phosphorylation without affecting total NCC abundance or surface expression. This effect was dependent upon the presence of the mineralocorticoid receptor and serum- and glucocorticoid regulated kinase 1 (SGK1). Furthermore, STE20/SPS-1-related proline/alanine-rich kinase (SPAK) phosphorylation also increased, and gene silencing of SPAK eliminated the effect of aldosterone on NCC activity. Aldosterone administration via a minipump in adrenalectomized rodents confirmed an increase in NCC phosphorylation without a change in NCC total protein. These data indicate that acute aldosterone-induced SPAK-dependent phosphorylation of NCC increases individual transporter activity. PMID- 23739596 TI - Differential effect of schisandrin B stereoisomers on ATR-mediated DNA damage checkpoint signaling. AB - We have previously reported that schisandrin B (SchB) is a specific inhibitor of ATR (ataxia telangiectasia and Rad-3-related) protein kinase. Since SchB consists of a mixture of its diastereomers gomisin N (GN) and gamma-schisandrin (gamma Sch), the inhibitory action of SchB might result from a stereospecific interaction between one of the stereoisomers of SchB and ATR. Therefore, we investigated the effect of GN and gamma-Sch on UV (UVC at 254 nm)-induced activation of DNA damage checkpoint signaling in A549 cells. UV-induced cell death (25 - 75 J/m(2)) was amplified by the presence of the diastereomers, especially GN. At the same time, GN, but not gamma-Sch, inhibited the phosphorylation of checkpoint proteins such as p53, structural maintenance of chromosomes 1, and checkpoint kinase 1 in UV-irradiated cells. Moreover, GN inhibited the G2/M checkpoint during UV-induced DNA damage. The in vitro kinase activity of immunoaffinity-purified ATR was dose-dependently inhibited by GN (IC50: 7.28 MUM) but not by gamma-Sch. These results indicate that GN is the active component of SchB and suggest that GN inhibits the DNA damage checkpoint signaling by stereospecifically interacting with ATR. PMID- 23739595 TI - Pharmacokinetic and pharmacodynamic studies of four major phytochemical components of Da-Cheng-Qi decoction to treat acute pancreatitis. AB - The medicinal herb formulation Da-Cheng-Qi decoction (DCQD) has been shown to ameliorate the severity of acute pancreatitis by regulating an apoptosis-necrosis switch in cells. The active components responsible for this effect and their detailed mechanism of action remain unclear. Here we determine the pharmacokinetic characteristics of the four most abundant compounds in DCQD using a rat model of severe acute pancreatitis. Acute pancreatitis-like symptoms were first induced in rats and then they were given DCQD orally. Rhein was found in rat serum at much higher levels than magnolol, hesperidin, or naringin, even though it was the least abundant of the four compounds in the DCQD. We also examined pharmacodynamics in AR42J cells stimulated with 10(-8) M cerulein as a cellular model of acute pancreatitis. After pretreating AR42J cells with individual compounds and then exposing them to cerulein, we determined cell viability, levels of apoptosis and necrosis, and numbers of cells positive for reactive oxygen species (ROS). Pretreatment with any of the four DCQD compounds increased cell viability and the apoptosis index, while also reducing necrosis and ROS generation. The compounds showed maximal effect in AR42J cells around the same time that they showed maximum serum concentration in rats. Although all four components appear to play a role in an apoptosis-necrosis cellular switch in vitro, rhein may be the most bioactive DCQD ingredient. PMID- 23739597 TI - Iatrogenic blood-borne viral infections in refugee children from war and transition zones. AB - Pediatric infectious disease clinicians in industrialized countries may encounter iatrogenically transmitted HIV, hepatitis B virus, and hepatitis C virus infections in refugee children from Central Asia, Southeast Asia, and sub-Saharan Africa. The consequences of political collapse and/or civil war-work migration, prostitution, intravenous drug use, defective public health resources, and poor access to good medical care-all contribute to the spread of blood-borne viruses. Inadequate infection control practices by medical establishments can lead to iatrogenic infection of children. Summaries of 4 cases in refugee children in Australia are a salient reminder of this problem. PMID- 23739598 TI - [Carbohydrate deficient transferrin and ethyl glucuronide: markers for alcohol use]. AB - In this article, we report on the usefulness of physicians testing for carbohydrate deficient transferrin (CDT) and ethyl glucuronide (EtG) when there are doubts about alcohol use by their patients. A 44-year-old male consulted his general practitioner with depressive symptoms and denied using alcohol. Laboratory examination revealed an elevated CDT value. The latter was caused by chronic alcohol use. The second patient, a 32-year-old female with known alcohol dependence and receiving inpatient treatment at an addiction clinic, came back from leave. She denied having consumed alcohol and her blood alcohol concentration was zero. Examination of her urine showed an elevated EtG/creatinine ratio. This was caused by having had a few drinks during her leave and could not have been caused by using mouthwash or disinfection soap. We describe how to use the results of CDT and EtG testing in the therapeutic process and give recommendations for patient communication before performing these two tests. PMID- 23739599 TI - [Addicted colleagues: a blind spot amongst physicians?]. AB - Physician impairment due to substance abuse or dependence is at least as prevalent as amongst non-physicians and is a real challenge. Not only for the impaired physicians themselves, but also for their colleagues, family members and patients. A 68-year-old physician describes her experiences of being an alcoholic as well as a patient with concomitant psychiatric disorders, including the hurdles she had to get over to deal with her disease and remain abstinent. Although colleagues knew what was going on, some of them took no action. The initial treatment by her general practitioner proved compromised. Addressing addiction amongst fellow physicians can be challenging and for this reason the Royal Dutch Medical Association (KNMG) has started the ABS Programme. On prompt and adequate intervention, treatment in specialised facilities has proved to be highly and durably effective. Addicted physicians who have been successfully treated should be monitored and supported, thus enabling their safe return to practice. PMID- 23739600 TI - [Pharmacogenetics and the treatment of addiction]. AB - This article describes the current scientific knowledge regarding pharmacogenetic predictors of treatment outcome for substance-dependent patients. PubMed was searched for articles on pharmacogenetics and addiction. This search yielded 53 articles, of which 27 were selected. The most promising pharmacogenetic findings are related to the treatment of alcohol dependence. Genetic variation in the u opioid receptor (OPRM1) and the serotonin transporter (5-HTTLPR) appear to be associated with treatment outcomes for naltrexone and ondansetron, respectively. Genetic variation in CYP2D6 is related to efficacy of methadone treatment for opiate dependence. Pharmacogenetics may help explain the great inter-individual variation in treatment response. In the future, treatment matching, based on genetic characteristics of individual patients, could lead to a 'personalized medicine' approach. Pharmacogenetic matching of naltrexone in alcohol-dependent carriers of the OPRM1 G-allele currently seems most promising. PMID- 23739601 TI - [Gastrointestinal tuberculosis: a deceptive disease]. AB - Incidence of tuberculosis has increased in the Netherlands in recent years, especially among immigrants. Nearly half of all patients with tuberculosis have extrapulmonary disease; in 5% of these patients it is localized in the gastrointestinal tract. Despite the low incidence of gastrointestinal tuberculosis we recently established this diagnosis in three of our patients, who demonstrated tuberculosis within the oesophagus, colon and pancreas, respectively. They were successfully treated, but only after a long diagnostic process. PMID- 23739602 TI - [The Morel-Lavallee-lesion: delayed symptoms after trauma]. AB - BACKGROUND: The Morel-Lavallee lesion is a post-traumatic collection of fluid arising after a 'closed degloving injury' has caused the separation of the skin and subcutis from the underlying muscular fascia. It usually occurs in the trochanteric region or proximal thigh. CASE DESCRIPTION: A 36-year-old obese man was referred to the emergency department by his general practitioner for fever and pain in the right lower abdominal quadrant. Blood testing revealed elevated infection parameters. As appendicitis was suspected, a CT scan of the abdomen was performed. This revealed a Morel-Lavallee lesion, which he had sustained 9 months earlier when he had been hit by a car while riding his bicycle. A rapid recovery ensued after ultrasound-guided percutaneous drainage and treatment with antibiotics. CONCLUSION: A Morel-Lavallee lesion, which could manifest even months later, should be considered after any traumatic injury. Ultrasound, CT and MRI are useful tools for proper diagnosis. There is no consensus about treatment in either the acute or the chronic phase to date. PMID- 23739603 TI - [Group counselling for the second trimester ultrasound: can group counselling be an alternative for individual counselling?]. AB - OBJECTIVE: To compare group counselling to individual counselling with respect to the second trimester ultrasound. DESIGN: A prospective cohort study at two hospitals. METHOD: At one hospital, 100 pregnant women were counselled on the risks and benefits of the second trimester ultrasound in groups of up to 15 patients. Shortly before the ultrasound they were asked to fill out a questionnaire. Results were compared to 100 women who were counselled individually at another hospital. The primary outcome was the level of informed choice whether or not to undergo the ultrasound, defined as sufficient knowledge and a value-consistent decision. The secondary outcome measures were level of understanding of the second trimester ultrasound and the degree of satisfaction with the counselling. RESULTS: The resulting level of informed choice was 87.0% after group counselling compared to 79.4% after individual counselling (p = 0.47). The mean knowledge score was 8.8 for the women who attended group counselling; women who were individually counselled had a mean score of 7.4 (p < 0.001). Satisfaction with counselling was 7.0 for group counselling and 6.2 for individual counselling (p < 0.001). CONCLUSION: Although there was no statistically significant difference in the level of informed choice, group counselling was associated with higher post-counselling knowledge and satisfaction scores. Group counselling should therefore be considered as an alternative counselling method. PMID- 23739604 TI - [A man with a 'galaxy sign']. AB - This brief report describes the radiographic images of a 29-year-old man with asymptomatic sarcoidosis. On a CT-scan a coalescent granuloma with a central core and peripheral nodules mimics a globular cluster galaxy; therefore it is called 'galaxy sign'. This is a classic finding in a granulomatous disease like sarcoidosis. PMID- 23739605 TI - [Neisser and the clap]. AB - In 1879, during his specialization in dermatology, Albert Ludwig Sigesmund Neisser (1855-1916) discovered the bacterial cause of gonorrhoea. The gonococcus Neisseria gonorrhoea - would, however, not bear his name until 1933. Neisser's early research focused primarily on venereal diseases, syphilis in particular, and on leprosy. Later, as a hygienist, he became a passionate advocate of public clinics for venereal diseases, regulated prostitution, and health education. In 1916, Neisser died of sepsis after lithotripsy for nephrolithiasis. His scientific inheritance includes many publications on a variety of venereal and skin diseases and public health-related topics, and textbooks such as Ikonographia dermatologica and Stereoskopischer Medizinischer Atlas. PMID- 23739606 TI - [Gluten tolerance as a result of earlier exposure?]. AB - In a recently published article in Pediatrics on the Swedish coeliac disease 'epidemic', it is suggested that the gradual introduction of gluten-containing foods from 4 months of age, preferably while breastfeeding is still ongoing, is favourable for the prevention of coeliac disease. This stirred up the discussion about the timing of introduction of gluten to the diet of infants in the Netherlands, where gluten-containing foods are mostly introduced from 6 months of age onwards. The retrospective character of data collection, however, has to be taken into account when interpreting the Swedish study. Future results of prospective studies on gluten introduction and coeliac disease, such as the PreventCD family study (www.preventcd.com), should provide the information necessary for deciding on a change in the Dutch guidelines for the introduction of gluten to the diet of young children. PMID- 23739607 TI - [Non-heart-beating kidney donors: first improve ischemic times, then allocation]. AB - A study recently published in The Lancet investigated the 3-year graft survival of heart-beating (HB) and non-heart-beating (NHB) kidney donors. This was done utilizing the UK registry. The study concluded that donor age affects graft survival. It also demonstrated that NHB kidneys tolerate cold ischemia less well than kidneys from HB donors. Based on these conclusions, it is suggested that a different allocation algorithm should be designed in order to reduce ischemic time for NHB donor kidneys. These findings are relevant to the Dutch situation in which more than 50% of postmortal kidney donors are now NHB. Despite past efforts, ischemic times in the Netherlands can still be improved compared to neighbouring countries. It is proposed that this matter be dealt with prior to changes in the allocation algorithm. PMID- 23739608 TI - [Feedback during laparoscopic training]. AB - A recent Danish study showed that instructor feedback significantly reduced the duration of training time needed for acquiring laparoscopic skills. While there is a clear advantage to trainees reaching a predetermined expert level of performance more rapidly, this does not necessarily imply that the skills were also acquired more efficiently. Experiencing continual feedback while undergoing a training task could reduce the level of difficulty in performing it; the presence of an instructor can also heighten emotional tension. Both of these factors can impair the learning process. For this reason, we recommend self directed feedback during training on complex laparoscopic skills. PMID- 23739609 TI - Are collapse models testable with quantum oscillating systems? The case of neutrinos, kaons, chiral molecules. AB - Collapse models provide a theoretical framework for understanding how classical world emerges from quantum mechanics. Their dynamics preserves (practically) quantum linearity for microscopic systems, while it becomes strongly nonlinear when moving towards macroscopic scale. The conventional approach to test collapse models is to create spatial superpositions of mesoscopic systems and then examine the loss of interference, while environmental noises are engineered carefully. Here we investigate a different approach: We study systems that naturally oscillate-creating quantum superpositions-and thus represent a natural case-study for testing quantum linearity: neutrinos, neutral mesons, and chiral molecules. We will show how spontaneous collapses affect their oscillatory behavior, and will compare them with environmental decoherence effects. We will show that, contrary to what previously predicted, collapse models cannot be tested with neutrinos. The effect is stronger for neutral mesons, but still beyond experimental reach. Instead, chiral molecules can offer promising candidates for testing collapse models. PMID- 23739612 TI - Crossbite cause TMD: a good hypothesis does not make it always true. PMID- 23739613 TI - Reply: To PMID 21896884. PMID- 23739610 TI - Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes. AB - The dilute plasma cytokine milieu associated with type 1 diabetes (T1D), while difficult to measure directly, is sufficient to drive transcription in a bioassay that uses healthy leukocytes as reporters. Previously, we reported disease associated, partially IL-1 dependent, transcriptional signatures in both T1D patients and the BioBreeding (BB) rat model. Here, we examine temporal signatures in congenic BBDR.lyp/lyp rats that develop spontaneous T1D, and BBDR rats where T1D progresses only after immunological perturbation in young animals. After weaning, the BBDR temporal signature showed early coincident induction of transcription related to innate inflammation as well as IL-10- and TGF-beta mediated regulation. BBDR plasma cytokine levels mirrored the signatures showing early inflammation, followed by induction of a regulated state that correlated with failure of virus to induce T1D in older rats. In contrast, the BBDR.lyp/lyp temporal signature exhibited asynchronous dynamics, with delayed induction of inflammatory transcription and later, weaker induction of regulatory transcription, consistent with their deficiency in regulatory T cells. Through longitudinal analyses of plasma-induced signatures in BB rats and a human T1D progressor, we have identified changes in immunoregulatory processes that attenuate a preexisting innate inflammatory state in BBDR rats, suggesting a mechanism underlying the decline in T1D susceptibility with age. PMID- 23739615 TI - Multicenter cross-sectional analysis of values of glycated haemoglobin (HbA1c) in Polish children and adolescents with long-term type 1 diabetes in Poland: PolPeDiab study group. AB - INTRODUCTION: Glycated haemoglobin is currently a golden standard of evaluation of metabolic control of diabetes. According to the Evidence based Medicine data, better metabolic control of diabetes decreases the prevalence of chronic complications. AIM OF THE STUDY: to analyse HbA1c in children with a longer duration of type 1 diabetes mellitus (t1DM). MATERIAL AND METHODS: We analysed an epidemiological database (2006-2009) of 7783 HbA1c values of 996 children (465 girls) with t1DM treated at three academic centres (Gdansk, Lodz, Katowice) in Poland. the mean age was 13.04+/-3.43 years and the mean duration of diabetes was 6.93+/-2.33 years. RESULTS: the overall mean HbA1c was 7.6+/-1.5% (by age groups: 7.0+/-0.8%, 2-5 yrs; 7.1+/-1.0%, 6-10 yrs; 7.8+/-1.7%, 11-19 yrs) without gender related differences. HbA1c increased significantly with increasing age and t1DM duration. HbA1c values differed significantly between the centres. A group of 455 (55.7%) children reached a stable course of diabetes with HbA1c <7.5%, and 110 (13.5%) had HbA1c levels >9%. The mean HbA1c ?6.5% was found in 150 children (18.4%). CONCLUSIONS: In more than 50% of Polish children with longer t1DM duration, the international target of glycaemic control (HbA1c) is achieved; however, only 18% of them reached Polish national target. Age, t1DM duration and centre-specific factors influence the HbA1c values. PMID- 23739614 TI - Imaging informatics for consumer health: towards a radiology patient portal. AB - OBJECTIVE: With the increased routine use of advanced imaging in clinical diagnosis and treatment, it has become imperative to provide patients with a means to view and understand their imaging studies. We illustrate the feasibility of a patient portal that automatically structures and integrates radiology reports with corresponding imaging studies according to several information orientations tailored for the layperson. METHODS: The imaging patient portal is composed of an image processing module for the creation of a timeline that illustrates the progression of disease, a natural language processing module to extract salient concepts from radiology reports (73% accuracy, F1 score of 0.67), and an interactive user interface navigable by an imaging findings list. The portal was developed as a Java-based web application and is demonstrated for patients with brain cancer. RESULTS AND DISCUSSION: The system was exhibited at an international radiology conference to solicit feedback from a diverse group of healthcare professionals. There was wide support for educating patients about their imaging studies, and an appreciation for the informatics tools used to simplify images and reports for consumer interpretation. Primary concerns included the possibility of patients misunderstanding their results, as well as worries regarding accidental improper disclosure of medical information. CONCLUSIONS: Radiologic imaging composes a significant amount of the evidence used to make diagnostic and treatment decisions, yet there are few tools for explaining this information to patients. The proposed radiology patient portal provides a framework for organizing radiologic results into several information orientations to support patient education. PMID- 23739616 TI - Unequal contribution of familial factors to autoimmunity and clinical course of childhood diabetes. AB - INTRODUCTION: collection of family history of diabetes mellitus (DM) is commonly performed when this illness is diagnosed in children. However the significance of gleaned information may differ depending on the affected family members. AIM OF THE STUDY: this study was performed in order to describe detailed familial history of DM in patients and to evaluate the impact of it on the natural course of childhood DM. MATERIAL AND METHODS: After exclusion of patients with confirmed monogenic basis of the disease or type 2 diabetes, the study group numbered 989 diabetic children. The data on detailed family history of DM among the first- and second- degree relatives, age at the onset of DM, recent percentage of glycated hemoglobin (HbA1c), presence of diabetes-related antibodies and the highest observed fasting c-peptide level were collected. RESULTS: Having siblings with DM was linked to early onset of diabetes in the study group (mean difference -2.83 95% confidence interval [cI] -4.24 to -1.42). Dominant mode of inheritance, particularly from the maternal side was significantly associated with diabetes onset at an older age. Children of diabetic mothers developed diabetes at a mean age of 10.83 in comparison to those without family history of DM - 8.75 years (p=0.0228). However, children whose mothers had any type of DM, had a significantly higher level of glycated hemoglobin than the others (8.34 vs 7.56%, p=0.0315). Additionally, a rising number of units of the family tree affected by any type of diabetes was associated with later onset of diabetes in children (p for trend = 0.0452). CONCLUSION: Familial factors influence the natural course of childhood diabetes, but their contribution is not equal, showing more pronounced effects of maternal factors. PMID- 23739617 TI - [Nutritional status and pulmonary function in children and adolescents with cystic fibrosis]. AB - INTRODUCTION: Somatic development and respiratory function are the most important prognostic factors for the course of the disease and the expected lifespan of patients suffering from cystic fibrosis (cF). Aim of the study was to evaluate nutritional status and pulmonary function in children and adolescents suffering from cystic fibrosis. Pulmonary function was evaluated in relation to several factors connected to the course of the disease. MATERIAL AND METHODS: Anthropometric and spirometric data were extracted from the medical histories of 89 children diagnosed and treated at the institute of Mother and child in Warsaw. Molecular DnA was analyzed in all the patients in order to determine the type of CFTR gene mutation. Anthropometric parameters were expressed in terms of standard deviations away from age-specific and sex-specific reference for the population of Warsaw. RESULTS: the studied children were significantly shorter than healthy children. Ten of the children (11.2%) had severe growth disturbances. nutritional status was also adversely affected. Almost 50% of the children were mal nourished. the children suffered from a deficit in muscularity and adiposity. The percent of predicted FeV1 was highest in those children who were well-nourished, and lowest in the severely malnourished patients. the effect of the nutritional status on pulmonary function was observed. CONCLUSIONS: chronic infection by P. aeruginosa had a marked adverse effect on pulmonary function. PMID- 23739618 TI - Allometric assessment of somatic specificities. AB - The clinical assessment of body build and proportions is usually based on relating anthropometric measurements to the respective mean values found for population of a given age. The other common method is relating the measurements of body parts directly to body height or body mass, i.e. as simple ratios. The first approach is inaccurate because it implies that various body parts develop independently from each other while the second one may be erroneous when the respective relationship is non-linear. The paper presents an alternative, allometric approach to anthropometric measurements and highlights the principal questions associated with points of reference used in an anthropometric assessment of body proportions. As indicated, allometry enables an accurate assessment of body proportions and is practically free from false positive or false negative results, which is of great importance in various areas, e.g. in clinical practice. PMID- 23739619 TI - [Primary prevention of type 1 diabetes. Actual situation and perspectives]. AB - The authors presented a review of the actual literature of primary prevention of type 1 diabetes. They stressed a dramatic increase of patients with newly diagnosed diabetes, which was called an epidemic of the XXI century. According to the recently published data, the increase of newly diagnosed cases was more rapid/faster than it was expected/anticipated, and the dramatic increase in the occurrence/prevalence of type 1 diabetes was observed particularly in children up to 5 years of age. Therefore, like it was mentioned by the authors of recently published reports, the necessity of an effective primary prevention of type 1 diabetes also increased. Many clinical trials of primary prevention of type 1 diabetes, in different clinical stages/phases, are currently being conducted. Scientific investigations about an effective primary prevention are now very important, seen as priority problems. Investigations in Poland, which started in the year 2002 and the end of them was established for the year 2017, are also performed as part of an international scientific program. The identification of subjects with a genetic risk of type 1 diabetes is now possible. Very interesting data of a therapy with t-regulatory cells (tregs), especially those received from the umbilical cord blood of newborns are worth emphasizing. PMID- 23739620 TI - Complex glycerol kinase deficiency - X-linked contiguous gene syndrome involving congenital adrenal hypoplasia, glycerol kinase deficiency, muscular Duchenne dystrophy and intellectual disability (IL1RAPL gene deletion). AB - Contiguous gene syndromes are disorders caused by deletions of genes that are adjacent to one another. One of them is complex glycerol kinase deficiency. It is caused by partial deletion of Xp21, which includes the genes responsible for glycerol kinase deficiency, congenital adrenal hypoplasia, Duchenne muscular dystrophy and intellectual disability. There are no definite dysmorphic features for this syndrome. The diagnosis is based on clinical and laboratory findings. Symptoms depend on the size of deletion and appear almost exclusively in the male gender. Usually the first and most severe are the signs of adrenal hypoplasia, which, if not cured, may lead to death in a short time. The symptoms of glycerol kinase deficiency occur also early in life, but they may be masked by the deficiency of mineralocorticoids. Duchenne muscular dystrophy appears in childhood and is always accompanied by certain symptoms. Developmental retardation and intellectual disability occur often with complex glycerol kinase deficiency. The reasons for it are heterogeneous, but usually, there is a connection with the deletion of DMD or I L1R A P L genes. Due to the fact that loci of all genes responsible for complex glycerol kinase deficiency were determined, it is possible to carry out molecular examination, confirm clinical diagnosis and determine female carriers of the disorder. PMID- 23739621 TI - [Pathological daytime sleepiness in an 11-year old girl receiving growth hormone treatment previously cured from craniopharyngioma]. AB - An 11-year old girl with multihormonal pituitary deficiency previously cured from craniopharyngioma was admitted to the endocrinology Department because of pathological daytime sleepiness. At the age of 7 she had undergone brain tumor surgery with adjuvant radiotherapy (complete dose of 5400 cGy). She had been given replacement therapy of thyroid hormone, cortisol and adiuretin. At the age of 10 years she had started growth hormone (rGH) treatment. After a period of four months of rGH replacement therapy the girl's mother had observed symptoms of excessive daytime sleepiness with a tendency to escalation. MRI of the brain had been performed; no progression has been shown. After 10 months from the start of rGH replacement therapy was referred to the endocrinology department. On the basis of laboratory findings electrolyte and hormonal abnormalities were excluded. On physical examination, the girl manifested massive tonsillar hypertrophy. It was disclosed that she developed obstructive sleep apnea with the drop of oxygen saturation to 60%. The patient was qualified to adenotonsillectomy. There was a spectacular postoperative improvement observed with no future episodes of night apnea and daytime sleepiness. In our opinion, the rGH treatment in our patient induced hypertrophy of the tonsils and adenoid, which led to obstructive sleep apnea syndrome with compensatory daytime sleepiness. CONCLUSIONS: Obstructive sleep apnea syndrome with compensatory daytime sleepiness may occur in children on rGH replacement therapy. During rGH therapy children should be regularly examined by a laryngologist. PMID- 23739622 TI - [Thyroid ectopy - the presentation of four patients]. AB - Ectopy of the thyroid gland means its incorrect location most often along the midline of the body from the foramen cecum to the mediastinum, usually in the dorsum of the tongue. In 75% of patients, the lingual thyroid is the only active thyroid tissue. ectopic thyroid is frequently incidentally diagnosed in patients without symptoms of hypothyroidism. The authors present four patients with lingual location of the thyroid treated due to congenital hypothyroidism. in two of them, an ultrasound examination revealed thyroid tissue in a proper location in front of the trachea, however, the tissue did not show jodine-131 uptake on scintigraphy performed after four week-cessation of thyroxin treatment. The ectopic tissue can undergo the same pathological alterations as in the properly located gland (single or multiple nodules, inflammation, neoplasms), therefore, the monitoring by imaging techniques seems crucial. PMID- 23739623 TI - Rates of speciation and morphological evolution are correlated across the largest vertebrate radiation. AB - Several evolutionary theories predict that rates of morphological change should be positively associated with the rate at which new species arise. For example, the theory of punctuated equilibrium proposes that phenotypic change typically occurs in rapid bursts associated with speciation events. However, recent phylogenetic studies have found little evidence linking these processes in nature. Here we demonstrate that rates of species diversification are highly correlated with the rate of body size evolution across the 30,000+ living species of ray-finned fishes that comprise the majority of vertebrate biological diversity. This coupling is a general feature of fish evolution and transcends vast differences in ecology and body-plan organization. Our results may reflect a widespread speciational mode of character change in living fishes. Alternatively, these findings are consistent with the hypothesis that phenotypic 'evolvability' the capacity of organisms to evolve-shapes the dynamics of speciation through time at the largest phylogenetic scales. PMID- 23739624 TI - Differential impact of inflammation on six laboratory assays measuring residual arachidonic acid-inducible platelet reactivity during dual antiplatelet therapy. AB - AIMS: Inflammation has been postulated to modify the platelet response to aspirin treatment, thereby causing high on-treatment residual platelet reactivity (HRPR). Both high levels of inflammatory markers and HRPR have been linked to adverse cardiovascular events. We aimed to study the impact of inflammation on residual arachidonic acid (AA)-inducible platelet reactivity. METHODS: In 288 patients receiving dual antiplatelet therapy, residual AA-inducible platelet reactivity was assessed using light transmission aggregometry (LTA), the VerifyNow assay, multiple electrode aggregometry (MEA) and the Impact-R. The levels of urinary 11 dehydro-thromboxane B2 (D-TXB2), serum thromboxane B2 (TXB2), interleukin-6 (IL 6) and high-sensitivity C-reactive protein (hsCRP) were determined using immunoassays. RESULTS: The IL-6 level was found to be an independent predictor of platelet reactivity as determined according to LTA and D-TXB2 using a multiple linear regression analysis. Accordingly, patients with supramedian IL-6 levels exhibited significantly higher platelet reactivity than patients with inframedian IL-6 levels when determined according to LTA and D-TXB2 (both p <=0.02). High IL 6 levels were associated with a 3.6-fold (95%CI 2.1-6.4) increased risk of HRPR, as defined according to D-TXB2, and a 3.4-fold (95%CI 1.4-8.3) increased risk of HRPR, as defined according to MEA. The HsCRP level was found to be an independent predictor of platelet reactivity when determined according to LTA, D-TXB2, the Impact-R and TXB2 using a multiple linear regression analysis. High hsCRP levels were associated with a 3.6-fold (95%CI 1.3-10) increased risk of HRPR, as defined according to LTA, and a 2.5-fold (95%CI 1.3-4.6) increased risk of HRPR, as defined according to TXB2. CONCLUSIONS: Increased levels of inflammatory markers are independently associated with residual AA-inducible platelet reactivity in patients receiving dual antiplatelet treatment. PMID- 23739625 TI - Septin filament organization in Saccharomyces cerevisiae. AB - Septins are a family of GTP-binding, membrane-interacting cytoskeletal proteins, highly conserved and essential in all eukaryotes (with the exception of plants). Septins play important roles in a number of cellular events that involve membrane remodeling and compartmentalization. One such event is cytokinesis, the last stage of cell division. While cytokinesis is ultimately achieved via the mechanical contraction of an actomyosin ring at the septum, determination of the location where cytokinesis will take place, and recruitment of factors involved in signaling events leading to septation requires the activity of septins. We are working towards dissecting the properties of septins from the budding yeast Saccharomyces cerevisiae, where they were first discovered as cell cycle mutants. In our studies we have employed several complementary electron microscopy techniques to describe the organization and structure of septins both in vitro and in situ. PMID- 23739626 TI - Epigenetic regulation in obesity. AB - PURPOSE OF REVIEW: Research suggests that 65% of variation in obesity is genetic. However, much of the known genetic associations have little known function and their effect size small, thus the gene-environment interaction, including epigenetic influences on gene expression, is suggested to be an important factor in the susceptibilty to obesity. This review will explore the potential of epigenetic markers to influence expression of genes associated with obesity. RECENT FINDINGS: Epigenetic changes in utero are known to have direct implications on the phenotype of the offspring. More recently work has focused on how such epigenetic changes continue to regulate risk of obesity from infancy through to adulthood. Work has shown that, for example, hypomethylation of the MC4 gene causes an increase in expression, and has a direct impact on appetite and intake, and thus influences risk of obesity. Similar influences are also seen in other aspects of obesity including inflammation and adiposity. SUMMARY: Maternal diet during foetal development has many epigenetic implications, which affect the offspring's risk factors for obesity during childhood and adulthood, and even in subsequent generations. Genes associated with risk of obesity, are susceptible to epigenetic mutations, which have subsequent effects on disease mechanisms, such as appetite and impaired glucose and insulin tolerance. PMID- 23739627 TI - Monocyte gene expression and coronary artery disease. AB - PURPOSE OF REVIEW: Despite current therapy, coronary artery disease (CAD) remains the major cause of morbidity and mortality worldwide. CAD is the consequence of a complex array of deranged metabolic processes including the immune system. In this context, monocytes and macrophages are indisputable players. Thus, monocyte gene expression analysis could be a powerful tool to provide new insights in the pathophysiology of CAD and improve identification of individuals at risk. We discuss current literature assessing monocyte gene expression and its association with CAD. RECENT FINDINGS: Monocyte surface markers CD14 ++and CD16+ have been established as biomarkers for increased cardiovascular disease risk in a large number of studies. More in-depth gene expression analysis identified several interesting genes, such as ABCA1, CD36 and MSR1 with an increased expression in circulating monocytes from patients with CAD. The results for CD36 were replicated in one other study. For ABCA1 and MSR1 conflicting data are published. SUMMARY: Recent findings indicate that genetic differences exist in circulating monocytes of patients suffering from CAD, giving us more insights into the underlying mechanisms. However, larger studies are required to prove that monocytes' expression signature could serve as a marker for diagnostic purposes in the future. PMID- 23739628 TI - Fatty acids regulation of inflammatory and metabolic genes. AB - PURPOSE OF REVIEW: Fatty acids influence human health and diseases in various ways. In recent years, much work has been carried out to elucidate the mechanisms by which dietary fatty acids control short-term and long-term cellular functions. We have reviewed herein the most recent studies on modulation of gene expression by fatty acids. A number of genes respond to transcription factors and present a transcription factor response element in their promoter regions. Fatty acids may exert their effects on metabolism by regulating gene transcription via transcription factors. Understanding how fatty acids control expression of metabolic genes is a promising strategy to be investigated by aiming to treat metabolic diseases such as insulin resistance, obesity, and type 2 diabetes mellitus. RECENT FINDINGS: Fatty acids exert many of their biological effects through the modulation of the activity of transcription factors, such as sterol regulatory element-binding proteins, peroxisome proliferator-activated receptors, and liver X receptors. SUMMARY: Fatty acid action through transcription factors controls the expression of several inflammatory and metabolic genes. PMID- 23739629 TI - Monitoring states of altered carbohydrate metabolism via breath analysis: are times ripe for transition from potential to reality? AB - PURPOSE OF REVIEW: To introduce the potential of breath analysis as a diagnostic or monitoring tool in diabetes. RECENT FINDINGS: Blood testing for plasma glucose and other metabolic variables is the base for the diagnosis and management of diabetes, whose two main types (type 1 and type 2, T1DM, T2DM) are projected to affect 450 million by 2030. As blood testing is often uncomfortable, painful, costly, and in some situations unreliable, the quest for alternative, noninvasive methods has been ongoing for decades. Breath analysis has emerged as an ideal alternative as sample collection is easy, painless, flexible, noninvasive, practical, and inexpensive. No single exhaled gas can reflect systemic glucose concentrations. Multiple gases, however, have been linked to various aspects of glucose metabolism, and integrated analysis of their simultaneous profiles during prolonged glycemic fluctuations has yielded accurate predictions of plasma values, building expectation that a clinically usable breath-based glucometer may be developed within a few years. SUMMARY: While prototypes of hand-held breath testing glucometers may still be several years away, current research shows the imminent promise of this methodology and the widening support for its development. PMID- 23739630 TI - Fructose malabsorption syndrome. AB - PURPOSE OF REVIEW: Fructose malabsorption is associated with gastrointestinal symptoms. This review examines new findings on the physiology, assessment and therapy of fructose malabsorption in functional gastrointestinal disorders. RECENT FINDINGS: Additional GLUT transport mechanisms that regulate fructose absorption might be involved in symptom adaptation to high-fructose diets. Although glucose is known to facilitate fructose absorption, erythritol promotes malabsorption. The methodologies of fructose breath testing and its clinical utility have been questioned by findings of unrealistic testing dose and poor reproducibility. Although fructose restriction appears to benefit children with functional abdominal pain, fructose restriction itself may not be the key player. In irritable bowel syndrome, fructose restriction within a diet low in other fermentable carbohydrates fermentable, oligosaccharide, disaccharide monosaccharide and polyols produced good symptom control compared with habitual diet, but such therapy resulted in significantly reduced bifidobacteria. Fructose absorption and subsequently, abdominal pain and nausea are improved by a novel enzyme therapy that converts fructose to glucose for absorption. SUMMARY: New insights into factors affecting fructose absorption may have therapeutic applications. Doubts surrounding clinical utility of fructose breath testing are emerging. Although restriction of fructose and other fermentable, oligosaccharide, disaccharide monosaccharide and polyols have efficacy for functional gastrointestinal symptoms, potentially negative effects on microbiota deserve attention. PMID- 23739631 TI - Current world literature. Genes and cell metabolism. PMID- 23739634 TI - Public health lessons from severe acute respiratory syndrome a decade later. AB - The outbreak of severe acute respiratory syndrome in 2002-2003 exacted considerable human and economic costs from countries involved. It also exposed major weaknesses in several of these countries in coping with an outbreak of a newly emerged infectious disease. In the 10 years since the outbreak, in addition to the increase in knowledge of the biology and epidemiology of this disease, a major lesson learned is the value of having a national public health institute that is prepared to control disease outbreaks and designed to coordinate a national response and assist localities in their responses. PMID- 23739636 TI - Quetiapine and norquetiapine serum concentrations and clinical effects in depressed patients under augmentation therapy with quetiapine. AB - BACKGROUND: Quetiapine has been recently approved as an add-on therapy in the treatment of major depressive disorders in the case of inadequate response to antidepressant monotherapy. Thereby the antidepressant potential is attributed to the N-demethylated metabolite norquetiapine (NQ). The aim of this cross-sectional analysis was to relate quetiapine (Q) doses to serum concentrations of Q and its active metabolite and clinical effects. METHODS: Data were obtained from patients who had been treated with different antidepressants and augmented under naturalistic conditions with Q for whom blood level measurements were requested. RESULTS: For this analysis, 105 depressed patients were included who had been augmented with Q. The mean daily doses of Q were 222 +/- 125 mg. Doses correlated significantly (P < 0.001) with the highly variable serum concentrations of both Q and NQ. Median serum concentrations of Q and NQ were 46 ng/mL (25th to 75th percentile 20-91 ng/mL) and 59 ng/mL (25th to 75th percentile 26-133 ng/mL), respectively. Concentrations per dose ranged from 0.10 to 0.58 ng.ml.mg for Q and from 0.17 to 0.59 ng.ml.mg for NQ. Most patients (55%) received comedications in addition to the antidepressant drug and Q. According to the clinical global impressions scale, 60% of the patients were either much (36%) or very much improved (24%). Receiver-operating characteristic analysis revealed no significant differences of serum concentrations between responders and nonresponders for NQ (P = 0.835) but a trend for Q (P = 0.056). CONCLUSIONS: Due to marked variability of Q and NQ concentrations in the blood, therapeutic drug monitoring may be helpful to identify pharmacokinetic peculiarities. The lack of correlation between serum concentrations of NQ and clinical improvement casts doubts on the concept that NQ is the pharmacologically active principle for the augmentation therapy. PMID- 23739633 TI - High-flow oxygen and bilevel positive airway pressure for persistent dyspnea in patients with advanced cancer: a phase II randomized trial. AB - CONTEXT: Dyspnea is one of the most distressing symptoms for cancer patients. The role of high-flow oxygen (HFO) and bilevel positive airway pressure (BiPAP) in the palliation of dyspnea has not been well characterized. OBJECTIVES: To determine the feasibility of conducting a randomized trial of HFO and BiPAP in cancer patients and examine the changes in dyspnea, physiologic parameters, and adverse effects with these modalities. METHODS: In this randomized study (ClinicalTrials.gov Identifier: NCT01518140), we assigned hospitalized patients with advanced cancer and persistent dyspnea to either HFO or BiPAP for two hours. We assessed dyspnea with a numeric rating scale (NRS) and modified Borg scale (MBS) before and after the intervention. We also documented vital signs, transcutaneous carbon dioxide, and adverse effects. RESULTS: Thirty patients were enrolled (1:1 ratio) and 23 (77%) completed the assigned intervention. HFO was associated with improvements in both NRS (mean 1.9; 95% CI 0.4-3.4; P = 0.02) and MBS (mean 2.1; 95% CI 0.6-3.5; P = 0.007). BiPAP also was associated with improvements in NRS (mean 3.2; 95% CI 1.3-5.1; P = 0.004) and MBS (mean 1.5; 95% CI -0.3, 3.2; P = 0.13). There were no significant differences between HFO and BiPAP in dyspnea NRS (P = 0.14) and MBS (P = 0.47). Oxygen saturation improved with HFO (93% vs. 99%; P = 0.003), and respiratory rate had a nonstatistically significant decrease with both interventions (HFO -3, P = 0.11; BiPAP -2, P = 0.11). No significant adverse effects were observed. CONCLUSION: HFO and BiPAP alleviated dyspnea, improved physiologic parameters, and were safe. Our results justify larger randomized controlled trials to confirm these findings. PMID- 23739637 TI - A novel hydrazino-substituted naphthalimide-based fluorogenic probe for tert butoxy radicals. AB - A novel fluorogenic probe for tert-butoxy radicals based on the hydrazino naphthalimide system is reported. Interestingly, different regioisomers exhibited significantly different optical properties toward ROS, which suggested 4 hydrazinyl naphthalimide as a potential new platform for the in vitro and in cellulo detection of alkoxyl radicals. PMID- 23739638 TI - Papillary thyroid carcinoma in a lateral neck cyst: primary of ectopic thyroid tissue versus cystic metastasis. AB - OBJECTIVE: To review the diagnosis of primary papillary carcinoma of ectopic thyroid tissue within branchial cleft cysts, and to discuss the diagnostic challenge of differentiating this condition from metastatic disease when an occult microcarcinoma is found in the thyroid gland. METHODS: These comprise a case report and a literature review. We present the case of a 75-year-old woman with papillary thyroid carcinoma within the wall of a recurrent, 15 cm, lateral neck cyst. RESULTS: Histological examination of the patient's thyroid gland found a 0.5 mm papillary thyroid microcarcinoma. CONCLUSION: Our differential diagnosis was primary papillary carcinoma arising from ectopic thyroid tissue, or metastatic cystic degeneration of a lateral lymph node. We make an argument for the former. PMID- 23739640 TI - Influence of C-H...pi interactions on the solid-state [2+2] cycloaddition reaction of a Ag(I) coordination complex in an inorganic co-crystal. AB - The C-H...pi interaction plays a vital role in directing a single-crystal to single-crystal [2+2] cycloaddition reaction to form an intramolecular head-to head photodimer compared to an intermolecular head-to-tail photoproduct of 4 styrylpyridine of a Ag(I) coordination complex in an inorganic co-crystal. PMID- 23739639 TI - HSV-1 exploits the innate immune scavenger receptor MARCO to enhance epithelial adsorption and infection. AB - Herpes simplex virus type 1 is an important epithelial pathogen and has the potential for significant morbidity in humans. Here we demonstrate that a cell surface scavenger receptor, macrophage receptor with collagenous structure (MARCO), previously thought to enhance antiviral defense by enabling nucleic acid recognition, is usurped by herpes simplex virus type 1 and functions together with heparan sulphate proteoglycans to mediate adsorption to epithelial cells. Ligands of MARCO dramatically inhibit herpes simplex virus type 1 adsorption and infection of human keratinocytes and protect mice against infection. Herpes simplex virus type 1 glycoprotein C closely co-localizes with MARCO at the cell surface, and glycoprotein C binds directly to purified MARCO with high affinity. Increasing MARCO expression enhances herpes simplex virus type 1 infection while MARCO(-/-) mice have reduced susceptibility to infection by herpes simplex virus type 1. These findings demonstrate that herpes simplex virus type 1 binds to MARCO to enhance its capacity for disease, and suggests a new therapeutic target to alter pathogenicity of herpes simplex virus type 1 in skin infection. PMID- 23739641 TI - Partition of Myc into immobile vs. mobile complexes within nuclei. AB - Myc levels are highly regulated and usually low in vivo. Dimerized with Max, it regulates most expressed genes and so directly and indirectly controls most cellular processes. Intranuclear diffusion of a functional c-Myc-eGFP, expressed from its native locus in murine fibroblasts and 3T3 cells or by transient transfection, was monitored using Two Photon Fluorescence Correlation Spectroscopy, revealing concentration and size (mobility) of complexes. With increased c-Myc-eGFP, a very immobile pool saturates as a 'mobile' pool increases. Both pools diffuse too slowly to be free Myc-Max dimers. Following serum stimulation, eGFP-c-Myc accumulated in the presence of the proteasome inhbitor MG132. Stimulating without MG132, Myc peaked at 2.5 hrs, and at steady was ~8 +/- 1.3 nM. Inhbiting Myc-Max dimerization by Max-knockdown or drug treatment increased the 'mobile' c-Myc pool size. These results indicate that Myc populates macromolecular complexes of widely heterogenous size and mobility in vivo. PMID- 23739642 TI - Pitavastatin increases HDL particles functionally preserved with cholesterol efflux capacity and antioxidative actions in dyslipidemic patients. AB - AIM: Although statins increase the plasma concentration of high-density lipoprotein cholesterol (HDL-C), it has not been elucidated whether the increased HDL particles possess normal antiatherosclerotic properties. Pitavastatin functions to increase the plasma HDL-C level and decrease the lowdensity lipoprotein cholesterol (LDL-C) level. In the present study, we sought to examine the qualitative changes in HDL during pitavastatin treatment. METHODS: A total of 30 patients with dyslipidemia were treated with 2 mg of pitavastatin for four weeks. The cholesterol efflux capacity and activities of the antioxidative enzymes paraoxonase-1 (PON-1) and platelet-activating factor acetylhydrolase (PAF AH) were evaluated using polyethethylene glycol-treated HDL fractions before and after pitavastatin treatment. RESULTS: Pitavastatin treatment decreased the serum LDL-C level by 39% and increased the serum HDL-C level by 9% (p<0.05). In addition, pitavastatin increased the phospholipid content of HDL by 7.8% (p<0.05). The pitavastatin-induced increase in the HDL-C level coincided with an increase in the cholesterol efflux capacity of the isolated HDL fraction of 8.6% (p<0.05). The post-pitavastatin treatment activity of HDL-associated PON-1 (paraoxonase and arylesterase) was increased by 9% (p<0.05) and 11% (p<0.05), respectively, while the HDL-associated PAF-AH activity was not affected by pitavastatin. CONCLUSIONS: In addition to its LDL-C-lowering effects, pitavastatin elevates the HDL-C level and enhances the cholesterol efflux capacity and antioxidative properties of HDL. Pitavastatin therefore increases the amount of functional HDL without attenuating HDL quality. PMID- 23739643 TI - [Analysis of serum levels of nesfatin-1 in children and adolescents with autoimmune thyroid diseases]. AB - INTRODUCTION: Overweight and diseases connected with it are an increasing problem in children and adolescents. Thyroid disease leads to a change of weight - in hyperthyroidism body mass is reduced whereas in hypothyroidism it is increased. It is emphasized that changes in hormones such as peptide levels are in close relationship with the regulation of body mass. Nesfatin-1 is a recently described anorexigenic peptide produced by the brain. Nesfatin-1 also reduces body weight gain, suggesting a role as a new modulator of energy balance. Excess nesfatin in the brain leads to a loss of appetite, less frequent hunger, a 'sense of fullness', and a drop in body fat and weight. A lack of nesfatin-1 in the brain leads to an increase of appetite, more frequent episodes of hunger, an increase of body fat and weight, and the inability to 'feel full'. Aim of the study was to evaluate nesfatin-1 levels in young patients with untreated Graves' disease, subclinical Hashimoto' thyroiditis, and in healthy children. MATERIAL AND METHODS: The study group formed 78 patients of the Outpatient Endocrinology Clinic of Pediatrics, Endocrinology, Diabetology with Cardiology Division. In all the patients, nesfatin level was analyzed by the ELISA's method. RESULTS: In the group with hyperthyroidism in Graves' disease lower levels of nesfatin-1 were found compared to the group of healthy children (19.37 vs 32.96 ng/ml; p<0.02); after appropriate treatment in that group the levels of nesfatin-1 were higher compared to the group with hyperthyroidism, but lower compared to the group of healthy children (20.35 vs 32.96 ng/ml; NS). On the other hand, nesfatin-1 levels were lower in children with untreated subclinical hypothyroidism in Hashimoto's thyroiditis compared to the group of healthy children (17.2 vs32.96 ng/ml; p<0.002). After treatment of L-thyroxine lower levels of nesfatin-1 were found compared to the control group (14.5 vs 32.96 ng/ml; NS). No relationship between nesfatin-1 and thyroid hormones was observed. CONCLUSIONS: It might be that disturbances in thyroid hormones in thyroid diseases do not have an essential effect on changes of nesfatin-1 - an appetite-controlling hormone/peptide. Secondly, nesfatin-1 levels were lower in children with untreated autoimmune thyroid diseases, however, the mechanism is also unknown. PMID- 23739644 TI - Underweight, overweight and obesity in girls at the age of 7-19 years from the Lubelskie Province in the years 1986-2006. AB - INTRODUCTION: Increasing disproportions in the economic status of the Polish population are tangibly reflected in differences in the nutritional status of children and adolescents. AIM OF THE STUDY: The objective of this study was to determine changes in the population size of girls with proper BMI values and their peers with underweight, overweight and obesity in a twenty-year time span. MATERIAL AND METHODS: The survey conducted in 1986 covered 17 586 girls, whereas that conducted twenty years later covered 9540 girls. Measurements were taken of body height and body mass of the girls, which enabled calculating values of their Body Mass Index (BMI). Pursuant to guidelines of the International Obesity Task Force, girls with the 3rd degree underweight (gr. I), with the 2nd degree underweight (gr. II), with the 1st degree under-weight (gr. III), with proper BMI values (gr. IV), with overweight (gr. V), and with obesity (gr. VI) were selected from the biological material. The statistical significance of differences between mean values achieved in the year 1986 and 2006 was verified with the Student's t test for independent variables. The statistical significance of differences between the number of girls classified to each group in respect of the whole population surveyed in the year 1986 and 2006 was determined with the ?2 test. RESULTS: In the investigated twenty-year period, analyses demonstrated an increased incidence of body mass deficiency and excess in the surveyed girls. Greater differences between the generations in the incidence of underweight, overweight and obesity were observed in the urban girls, compared to their rural peers. In addition, more significant differences in body mass deficiency and excess were noted in the youngest girls from schools of the Lubelskie Province. CONCLUSIONS: It may, therefore, be speculated that the differences in the economic status of Lubelskie Province inhabitants influenced a lower number of girls with appropriate BMI values as well as increased percentages of girls with body mass deficiency and excess. PMID- 23739645 TI - [Selected endo- and exogenous factors and somatic development in children with deafness]. AB - INTRODUCTION: Three major trends in the literature devoted to somatic development of deaf children can be identified. Those various conclusions create a need for further research in the quest for identifying the factors of differentiation in somatic development of deaf children. That is why, the purpose of the presented study was to determine whether selected and classified endo- and exogenous factors (i.e. etiology and location of damage to hearing, educational environment) affect the somatic development of deaf children. MATERIALS AND METHODS: A group of 56 pupils from special care schools in three centers for persons with impaired hearing at the age of 10-16 years was selected. All the subjects were intellectually healthy and no dysfunctions of motor organs were observed among them. Measurements of body height were taken by means of anthropometer. Body weight and fat percentage were measured with impedance analyzer, using the phenomenon of conduction of electricity of low intensity in body tissues. Somatic development profiles were created separately for the groups with different cause, type (location) of hearing loss and educational environment on the basis of the standardization. RESULTS: A varied course of somatic development profiles by type of hearing loss, etiology, and environmental education was found. However, the analysis of variance and Student's t-test did not confirm that components of somatic profiles differ substantially from the selected endo- and exogenous factors. CONCLUSION: 1. In the study group reviewed a factor of educational environment was not dominant for the somatic development in deaf children. The hypothesis that the educational environment factor affects the somatic development was not proved. 2. There has been no significant relationship between the somatic development and deafness i.e. etiology and location of hearing damage. PMID- 23739646 TI - Hyperinsulinism as a common cause of hypoglycemia in children - pathogenesis, diagnosis and treatment. AB - Hypoglycemia is a heterogenic metabolic syndrome with the complicated pathogenesis, diagnosis and treatment. It comprises a broad spectrum of disorders and requires multidisciplinary assessment including pediatrics, endocrinology and diabetology, metabolic medicine and genetics. There are various classifications of hypoglycemia. Commonly it is divided into fasting and postprandial hypoglycemia with or without hyperinsulinemia. Congenital hyperinsulinism (HI) is the commonest cause of severe hypoglycemia in a newborn period. There are many different genetic mutations causing inappropriate insulin secretion. The type of genetic mutation determines diagnostic pathway and management of hyperinsulinemic hypoglycemia. Since recurrent hypoglycemia may cause a serious brain damage in children, it is essential to properly diagnose affected children in order to prevent further attacks of hypoglycemia. PMID- 23739647 TI - [Thyroid gland dysfunction, disorders of somatic and sexual development, disturbances of fertility after hematopoietic stem cell transplantation]. AB - Since the 1980s, hematopoietic stem cell transplantation (HSCT) has been performed for malignant and non-malignant disorders leading to increasing numbers of long-term survivors. Some of them develop long-term posttransplantation complications, among them endocrine complications that arise many years after HSCT and demand to be treated till the end of patients' life. In the paper "classical", observed several years after HSCT had been used as a treatment procedure, endocrine complications are discussed and the review of literature regarding this problem is presented. Thyroid dysfunction, disorders of somatic and sexual development are presented in details. Gonad dysfunction with the problem of fertility disturbances is reported. The paper presents the etiopathogenesis, methods of prevention, as well as treatment and the results of the treatment of these endocrine complications after HSCT. Moreover actual recommendations for screening and prevention of endocrine complications in long term HCT survivors are presented. PMID- 23739648 TI - [Disorders of carbohydrate metabolism, dyslipidemia, and bone metabolic disease after hematopoietic stem cell transplantation]. AB - Among long-term survivors after hematopoietic stem cell transplantation (HSCT) late endocrine complications are observed in 20-50%. Very often these complications influence significantly the patient's life and have to be treated till the end of life. Their proper prevention and monitoring are extremely important in patients who underwent HSCT during childhood. Since the 90s of the last millennium/century, thyroid dysfunction, disorders of somatic and sexual development, and disturbances of fertility have been presented in several publications. In the paper, less known endocrine complications after HSCT published in the last years are discussed. Disorders of carbohydrate metabolism, post-transplant diabetes and insulin resistance are presented. Moreover, dyslipidemia, hypertension, and post-transplant bone metabolic disease are demonstrated/shown. The paper describes the etiopathogenesis, methods of prevention as well as treatment and the results of the treatment of these endocrine complications after HSCT. Moreover, actual recommendations for screening and prevention of endocrine complications in long-term HCT survivors are presented. PMID- 23739650 TI - Increasing doses of simvastatin versus combined ezetimibe/simvastatin: effect on circulating endothelial progenitor cells. AB - BACKGROUND: Patients with coronary artery disease (CAD) should be treated with statins to attain very low cholesterol levels, in order to reduce cardiovascular adverse events. More than 70% of these patients do not reach the appropriate cholesterol goal despite moderate statin doses. However, it is not known whether therapeutic uptitration with different lipid-lowering strategies has a similar "pleiotropic" effect on atherosclerotic endothelial dysfunction evaluated by measurement of endothelial progenitor cells (EPCs). OBJECTIVE: We sought to compare, in patients with stable CAD and with a low-density lipoprotein cholesterol (LDL-C) >70 mg/dL on treatment with simvastatin 20 mg, the effects on EPCs by increasing simvastatin to 80 mg versus adding ezetimibe 10 mg. METHODS: Patients (n = 68, 63 +/- 9 years, 39% men) were randomly allocated to receive ezetimibe 10/simvastatin 20 mg or simvastatin 80 mg for 6 weeks. Circulating EPCs were measured by flow cytometry before and after the treatment. RESULTS: Both strategies presented similar effects on metabolic parameters. The LDLs were equally reduced by ezetimibe 10/simvastatin 20 mg and simvastatin 80 mg (28.9% +/ 13% vs 21.1% +/- 33%; P = .46, respectively). The levels of EPCs were unaffected by ezetimibe 10/simvastatin 20 mg (median [25th, 75th]: pre- vs posttreatment, 7.0 [2.3; 13.3] vs 3.1 [0.1; 13.2] EPCs/10(4) mononuclear cells; P = .43) or simvastatin 80 mg (pre- vs posttreatment, 6.1 [2.9; 15.2] vs 4.0 [1.4; 10.7] EPCs/10(4) mononuclear cells; P = .5), and there were no differences between the groups on treatment effects (P = .9). CONCLUSIONS: Among stable patients with CAD and with an LDL-C >70 mg/dL on simvastatin 20 mg, increasing simvastatin dose to 80 mg or adding ezetimibe 10 mg promoted similar further cholesterol reduction but did not have incremental effects on circulating EPCs. These data suggest that the effects of simvastatin moderate doses on EPCs are not increased by intensive lipid-lowering strategies (clinicaltrials.gov: NCT00474123). PMID- 23739651 TI - Effects of recombinant adenovirus hepatocyte growth factor gene on myocardial remodeling in spontaneously hypertensive rats. AB - BACKGROUND AND OBJECTIVES: Myocardial hypertrophy and fibrosis are important determinants of congestive heart failure. Previous work has shown that hepatocyte growth factor (HGF) can reduce acute myocardial injury and tissue fibrosis. This study was designed to examine the effects of HGF on myocardial remodeling following sustained hypertension. METHODS AND RESULTS: There were 4 experimental groups (n = 6) that included spontaneously hypertensive rats (SHRs) injected with 0.1 mL of adenovirus (Ad)-null into the left ventricular (LV) free wall, SHR injected with 0.1 mL of Ad-HGF gene (5 * 10(9) pfu/mL), and SHR injected with 0.1 mL of normal saline, and Wistar Kyoto rats injected with 0.1 mL of Ad-null served as control. At 4 weeks after injection, rats were sacrificed, and HGF expression, myocardial fibrosis, and LV function were determined. We observed that HGF protein expression was reduced in the hearts of SHR (P < .05 vs normal control) and it was markedly increased in SHR injected with Ad-HGF (P < .01 vs SHR injected with Ad-null). Myocardial fibrosis, collagen I, LV mass index (LVMI), and LV end-diastolic pressure (LVEDP) were increased and -dP/dtmax was decreased in SHR injected with Ad-null or normal saline (P < .01 vs normal control). Upregulation of myocardial HGF expression in SHR significantly suppressed myocardial fibrosis, collagen I content, LVMI, LVEDP, and increased -dP/dtmax (all P < .05 vs SHR-Ad-null, n = 6). CONCLUSIONS: These findings indicate that HGF expression is attenuated in hypertrophic and fibrotic myocardium of SHR. The forced increase in HGF exerts a salutary effect on myocardial fibrosis, collagen I expression, and hemodynamic parameters. PMID- 23739652 TI - Chronic nitrate therapy reduces positivity rate of tilt testing potentiated with sublingual nitroglycerin in patients with unexplained syncope. PMID- 23739653 TI - Atypical hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: clinically differentiating the thrombotic microangiopathies. AB - The increased understanding of the pathophysiology of both atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP) in recent years has led to significant therapeutic advances for both conditions. These advances have placed an increased emphasis on a more rapid differentiation of both disorders which remain clinical diagnoses. In particular, recent data demonstrating the effectiveness of complement inhibition in patients with aHUS have increased the need for a more rapid and accurate differentiation of aHUS and TTP. Previously utilized criteria have used the presence or absence of neurologic or renal injury and the pretreatment ADAMTS13 activity to differentiate aHUS from TTP. The use of presenting clinical symptoms and findings alone to differentiate these conditions is problematic given their overlapping clinical presentations. Similarly, the use of the pretreatment ADAMTS13 activity alone to differentiate aHUS from TTP is also problematic, and could lead to the inappropriate witholding of plasma exchange (PEX) therapy. However, when used collectively, the pretreatment clinical findings (symptoms and laboratory data) and ADAMTS13 activity in the context of the patient's response to PEX therapy can allow for a more effective differentiation of these two disorders in a timely fashion that will allow for the prompt initiation of the most appropriate therapy. PMID- 23739654 TI - Effects of high-protein diets on fat-free mass and muscle protein synthesis following weight loss: a randomized controlled trial. AB - The purpose of this work was to determine the effects of varying levels of dietary protein on body composition and muscle protein synthesis during energy deficit (ED). A randomized controlled trial of 39 adults assigned the subjects diets providing protein at 0.8 (recommended dietary allowance; RDA), 1.6 (2* RDA), and 2.4 (3*-RDA) g kg(-1) d(-1) for 31 d. A 10-d weight-maintenance (WM) period was followed by a 21 d, 40% ED. Body composition and postabsorptive and postprandial muscle protein synthesis were assessed during WM (d 9-10) and ED (d 30-31). Volunteers lost (P<0.05) 3.2 +/- 0.2 kg body weight during ED regardless of dietary protein. The proportion of weight loss due to reductions in fat-free mass was lower (P<0.05) and the loss of fat mass was higher (P<0.05) in those receiving 2*-RDA and 3*-RDA compared to RDA. The anabolic muscle response to a protein-rich meal during ED was not different (P>0.05) from WM for 2*-RDA and 3* RDA, but was lower during ED than WM for those consuming RDA levels of protein (energy * protein interaction, P<0.05). To assess muscle protein metabolic responses to varied protein intakes during ED, RDA served as the study control. In summary, we determined that consuming dietary protein at levels exceeding the RDA may protect fat-free mass during short-term weight loss. PMID- 23739655 TI - Longitudinal muscle of the esophagus: its role in esophageal health and disease. AB - PURPOSE OF REVIEW: The muscularis propria of the esophagus is organized into circular and longitudinal muscle layers. The function of the longitudinal muscle and its role in bolus propulsion are not clear. The goal of this review is to summarize what is known of the role of the longitudinal muscle in health, as well as in sensory and motor disorders of the esophagus. RECENT FINDINGS: Simultaneous manometry and ultrasound imaging reveal that, during peristalsis, the two muscle layers of the esophagus contract in perfect synchrony. On the contrary, during transient lower esophageal sphincter (LES) relaxation, longitudinal muscle contracts independent of the circular muscle. Recent studies have provided novel insights into the role of the longitudinal muscle in LES relaxation and descending relaxation of the esophagus. In certain diseases (e.g. some motility disorders of the esophagus), there is discoordination between the two muscle layers, which likely plays an important role in the genesis of dysphagia and delayed esophageal emptying. There is close temporal correlation between prolonged contractions of the longitudinal muscles of the esophagus and esophageal 'angina-like' pain. Novel techniques to record longitudinal muscle contraction are reviewed. SUMMARY: Longitudinal muscles of the esophagus play a key role in the physiology and pathophysiology of esophageal sensory and motor function. Neuro-pharmacologic controls of circular and longitudinal muscle are different, which provides an opportunity for the development of novel pharmacological therapies in the treatment of esophageal sensory and motor disorders. PMID- 23739656 TI - Current world literature. Inflammatory bowel disease. PMID- 23739649 TI - The social determinants of infant mortality and birth outcomes in Western developed nations: a cross-country systematic review. AB - Infant mortality (IM) and birth outcomes, key population health indicators, have lifelong implications for individuals, and are unequally distributed globally. Even among western industrialized nations, striking cross-country and within country patterns are evident. We sought to better understand these variations across and within the United States of America (USA) and Western Europe (WE), by conceptualizing a social determinants of IM/birth outcomes framework, and systematically reviewing the empirical literature on hypothesized social determinants (e.g., social policies, neighbourhood deprivation, individual socioeconomic status (SES)) and intermediary determinants (e.g., health behaviours). To date, the evidence suggests that income inequality and social policies (e.g., maternal leave policies) may help to explain cross-country variations in IM/birth outcomes. Within countries, the evidence also supports neighbourhood SES (USA, WE) and income inequality (USA) as social determinants. By contrast, within-country social cohesion/social capital has been underexplored. At the individual level, mixed associations have been found between individual SES, race/ethnicity, and selected intermediary factors (e.g., psychosocial factors) with IM/birth outcomes. Meanwhile, this review identifies several methodological gaps, including the underuse of prospective designs and the presence of residual confounding in a number of studies. Ultimately, addressing such gaps including through novel approaches to strengthen causal inference and implementing both health and non-health policies may reduce inequities in IM/birth outcomes across the western developed world. PMID- 23739658 TI - Novel SARS-like betacoronaviruses in bats, China, 2011. AB - To clarify the evolutionary relationships among betavoronaviruses that infect bats, we analyzed samples collected during 2010-2011 from 14 insectivorous bat species in China. We identified complete genomes of 2 novel betacoronaviruses in Rhinolophus pusillus and Chaerephon plicata bats, which showed close genetic relationships with severe acute respiratory syndrome coronaviruses. PMID- 23739659 TI - Cyclometalated cinchophen ligands on iridium(III): towards water-soluble complexes with visible luminescence. AB - Eight cationic heteroleptic iridium(III) complexes, [Ir(epqc)2(N^N)](+), were prepared in high yield from a cyclometalated iridium bridged-chloride dimer bearing two ethyl-2-phenylquinoline-4-carboxylate (epqc) ligands. Two X-ray crystallographic studies were undertaken on selected complexes (where the ancillary ligand N^N = 4,4'-dimethyl-2,2'-bipyridine and 4,7-diphenyl-1,10 phenanthroline) each confirming the proposed formulations, showing an octahedral coordination at Ir(III). In general, the complexes are luminescent (620-630 nm) with moderately long lifetimes indicative of phosphorescence. Hydrolysis of the ethyl ester moieties of the epqc ligands gave the analogous cinchophen-based complexes, which were water-soluble and visibly luminescent (568-631 nm). The spectroscopic and redox characterisation of the complexes was complemented by DFT and TD-DFT calculations, supporting the assignment of dominant (3)MLCT to the emissive character. PMID- 23739660 TI - Seasonal variation in critical limb ischemia requiring endovascular therapy: an analysis of a multicenter database of Japanese patients with critical limb ischemia undergoing endovascular therapy. AB - AIM: We investigated whether any seasonal variation is observed in the incidence, severity and prognosis of critical limb ischemia (CLI) requiring endovascular therapy. METHODS: We analyzed a multicenter database of 1,568 consecutive CLI cases undergoing primary endovascular therapy for infrainguinal lesions between July 2004 and June 2011. The monthly incidence was assessed according to the cumulative number of cases in each month, using a simple moving average. The data were fitted to a nonlinear regression model with a cosine function. The monthly proportion of cases in each Rutherford classification among the overall CLI population was assessed using a multinomial logistic regression model. The monthly risk of major amputation was evaluated using a Cox proportional hazard regression model. RESULTS: Significant seasonal variation was observed in the incidence of CLI (p<0.01). It was higher in the period from winter to spring, with a peak in March, and lower in the period from summer to autumn, with a trough in September; the fold difference between the peak and trough was 2.2. The seasonal variation was more markedly observed in the cases with a more severe Rutherford class. The proportion of cases in each Rutherford class among the overall CLI population also exhibited significant seasonal variation (p<0.01). In addition, the risk of major amputation demonstrated significant seasonal variation (p=0.03); however, the statistical significance was lost following adjustment for the Rutherford classification (p=0.10). CONCLUSIONS: Seasonal variation is observed in the incidence and severity of CLI. The seasonality of the limb prognosis is likely explained by that of the CLI severity. PMID- 23739661 TI - Impact of molecular solvophobicity vs. solvophilicity on device performances of dimeric perylene diimide based solution-processed non-fullerene organic solar cells. AB - Because of their outstanding molecular optoelectronic properties, perylene diimides (PDIs) are promising alternatives to the commonly used PCBM. However, the overly strong aggregation ability, poor solution-processability and compatibility of PDIs severely limit their photovoltaic applications. We turned to borrowing the amphiphile concept to improve these supramolecular properties. Practically, we fine-tuned the molecular solvophobicity with respect to the molecular solvophilicity, e.g. F(solvophob/solvophil), by changing the number of the weakly solvophobic 2-methoxyethoxyl (EG) groups in the bay-region of the thienyl-bridged dimeric PDI backbone, forming three PDI dimers of Bis-PDI-T (0 EG), Bis-PDI-T-EG (2 EG) and Bis-PDI-T-di-EG (4 EG) (Scheme 1). The photovoltaic properties using these dimers as the solution-processed non-fullerene electron acceptor and P3HT as the electron-donor were investigated via the device configuration of ITO/PEDOT:PSS/P3HT:PDI dimer/Ca/Al. Bis-PDI-T exhibited overly strong aggregation ability and very poor solution-processability, which severely limited compatibility, giving a very poor power conversion efficiency (PCE) of 0.007%. When two EG groups were attached at the 1,1'-positions, the resulted Bis PDI-T-EG showed dramatically reduced aggregation ability, improved solution processability, compatibility and proper phase separation. Small sized phases (~20 nm) dominated in the active layer and the best PCE was increased to 0.39%. When four solvophobic EG functions were introduced, affording Bis-PDI-T-di-EG with excellent supramolecular properties, particularly, the improvement of the phase separation with an increased phase size of 24 nm and the enhanced electron and hole mobilities, by 2-4 times, with respect to that of Bis-PDI-T-EG. The best PCE was further enhanced to 0.88%. After using 1-chloronaphthalene as the co solvent of 1,2-dichlorobenzene to further improve the compatibility, the PCE was improved further up to 0.41% for Bis-PDI-T, 0.76% for Bis-PDI-T-EG and 1.54% for Bis-PDI-T-di-EG. PMID- 23739663 TI - End of life care in Canada: a report from the Canadian Academy of Health Sciences Forum. PMID- 23739662 TI - Zscan4 restores the developmental potency of embryonic stem cells. AB - The developmental potency of mouse embryonic stem (ES) cells, which is the ability to contribute to a whole embryo, is known to deteriorate during long-term cell culture. Previously, we have shown that ES cells oscillate between Zscan4(-) and Zscan4(+) states, and the transient activation of Zscan4 is required for the maintenance of telomeres and genome stability of ES cells. Here we show that increasing the frequency of Zscan4 activation in mouse ES cells restores and maintains their developmental potency in long-term cell culture. Injection of a single ES cell with such increased potency into a tetraploid blastocyst gives rise to an entire embryo with a higher success rate. These results not only provide a means to rejuvenate ES cells by manipulating Zscan4 expression, but also indicate the active roles of Zscan4 in the long-term maintenance of ES cell potency. PMID- 23739664 TI - 'INSPIRED' approaches to better care for patients with advanced COPD. AB - Chronic Obstructive Pulmonary Disease (COPD) is the most common cause of admission to acute care facilities in Canada. The burden of illness for patients, caregivers and the health care system is profound. Dyspnea in advanced COPD pervades all aspects of patients' lives. When increasing symptom burden limits patients to their homes, crucial primary care services become less accessible, and care of end-stage COPD becomes increasingly fragmented and reactive. Given the considerable physical and psychosocial consequences of advanced COPD, this phase can be devastating for patients and families. In this article we outline the need for clinical interventions and re-organized models of care designed for better continuity to achieve more favorable outcomes for these patients and their families. Outreach programs and use of personalized action plans that include advice on careful use of opioids can be remarkably effective. The move toward an integrated approach to COPD management with more effective advance care planning will help patients and their families make informed decisions throughout the illness trajectory. Intensive medical treatment focused on increasing survival can coexist with both holistic and palliative approaches to improve the quality of life of patients with severe end-stage COPD. PMID- 23739665 TI - Burdens of family caregiving at the end of life. AB - A patient's ability to be cared for and to die at home is heavily dependent upon the efforts of family caregivers. Considerable stresses are associated with such caregiving, including physical, psychosocial and financial burdens. Research has shown that unmet needs and dissatisfaction with care can lead to negative outcomes for caregivers. While many family caregivers also report caregiving as life-enriching, some report that they would prefer alternatives to care at home, primarily because of these associated burdens. Little is known about which interventions are most effective to support family caregivers ministering palliative care at home. Well-designed studies to test promising interventions are needed, followed by studies of the best ways to implement the most effective interventions. Clinically effective practice support tools in palliative home care are warranted to identify family caregiver needs and to ensure that patients and their family caregivers have a choice about where care is provided. PMID- 23739666 TI - End-of-life care in Canada. AB - End-of-life care and planning is critically important to the next decades of health care in Canada. In our country, between 2005 and 2036, the number of seniors 65 years and older is projected to increase by up to 25%, and the number of deaths by 65%. The majority of patients are currently admitted to hospital and intensive care units at the end of life; however, up to 70% of elderly patients say they would prefer a less aggressive treatment plan focusing on providing comfort rather than a technologically supported, institutionalized death. Herein we provide a brief overview of the end-of-life care in the Canadian context, and highlight challenges and opportunities for health care system change in the coming decades. PMID- 23739667 TI - The biodistribution and pharmacokinetic evaluation of choline-bound gold nanoparticles in a human prostate tumor xenograft model. AB - PURPOSE: Gold nanoparticles (GNPs) have attracted significant attention in the treatment of cancer due to their potential as novel radiation enhancers, particularly when functionalized with various targeting ligands. The aim of this study was to assess the biodistribution and pharmacokinetic characteristics of a novel choline-bound GNP (choline-GNP) stabilized with polyethelenimine (PEI). METHODS: Choline bound to 27 nm diameter GNPs was characterized using transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). Toxicity of choline-GNPs was examined on DU-145 prostate cancer cells using an MTT assay. Using balb/c mice bearing flank DU-145 prostate tumors, choline-GNPs bio-distribution was measured using inductively coupled mass spectroscopy (ICP-MS). Blood, heart, lung, liver, spleen, brain, kidney and tumor gold content were examined at multiple time points over a 24-hour period after tail vein injection. RESULTS: An MTT assay using DU-145 prostate cancer cells yielded a 95% cell viability 72 hours after choline-GNP administration. The tumor GNP area under the concentration-time curve during the first 4 hours (AUC0-4) was 2.2 ug/ml h, representing 13% of the circulating blood GNP concentration over the same time period. The maximum intra tumor GNP concentration observed was 1.4% of the injected dose per gram of tumor tissue (%ID/g) one hour post injection. CONCLUSIONS: GNPs functionalized with choline demonstrates a viable future nanoparticle platform with increased intra tumor uptake as compared to unconjugated GNPs. Decreased intra-hepatic accumulation appears to be the reason for the improved systemic bioavailability. The next logical translational investigation will incorporate external beam radiation with the observed maximum intra-tumor uptake. PMID- 23739668 TI - Association of pericardial adipose tissue volume with presence and severity of coronary atherosclerosis. AB - PURPOSE: This study was to investigate whether high pericardial adipose tissue (PAT) volume is related to the presence and severity of coronary artery disease (CAD). METHODS: Consecutive patients (310 patients) who underwent both dual source 64-slice CT and percutaneous coronary angiography were recruited into this study. Waist circumference (WC), body mass index (BMI), blood biochemical variables, coronary artery calcium (CAC) score and Gensini score were measured. Pericardial adipose tissue (PAT) volume was determined by dual-source CT. RESULTS: PAT volume was positively correlated with BMI, WC, gender (male), hypertension, diabetes, age, total cholesterol and low-density lipoprotein cholesterol. PAT volume in CAD patients was significantly higher than that in patients without CAD (238.36 +/- 81.21 cm3 vs. 200.13+/-72.34 cm3). PAT volumes in patients with multi-vessel lesions were significantly higher than those with one-vessel lesions (P < 0.001). A significant correlation between PAT volume and CAC score (r=0.305, P < 0.001) was found. PAT volume was an independent factor affecting Gensini score. CONCLUSION: PAT volume was significantly correlated with traditional cardiovascular risk factors, the severity of coronary atherosclerosis and the number of stenotic coronary vessels. Thus, PAT volume may be a reliable marker to evaluate the presence and severity of CAD. PMID- 23739669 TI - A non-tracheal intubation (tubeless) anesthetic technique with spontaneous respiration for upper airway surgery. AB - BACKGROUND: The most important consideration for administration of anesthesia in upper airway surgery is maintenance of a patient's airway for optimal surgical exposure, adequate ventilation and sufficient depth of anesthesia. The tubeless anesthetic techniques, including total intravenous anesthesia with a combination of propofol and remifentanil or inhalation anesthesia with the insufflation of anesthetic gas, are considered experimental in many countries. METHODS: Fifteen pediatric (8 to 60 months) and 16 adult (23 to 55 years) patients were included in the study. Anesthesia (gas insufflation) was induced into the pediatric patients by inhalation of 8% sevoflurane in 8 L/min oxygen flow. An endotracheal tube, inserted through the nasal or oral cavity with its tip in the laryngopharynx, was used to maintain anesthesia with 3%-6% sevoflurane in 4 L/min oxygen flow. Total intravenous anesthesia was induced in adult patients by inhalation, 8% sevoflurane in 8 L/min oxygen flow, combined with intravenous injections of propofol (1.5-2 mg/kg) and fentanyl (1.5-2 MUg/kg). Assisted ventilation was maintained by use of a face or laryngeal mask. Propofol infusion at 200-300 MUg/kg/min, combined with remifentanil infusion at 0.06-0.2 MUg/kg/min, was used for maintaining anesthesia. RESULTS: All patients had surgery under tubeless anesthesia with steady spontaneous respiration. The mean time from induction of anesthesia to unconsciousness was 16+/-3 s and 36+/-14 s in pediatric and adult groups, respectively. The average times from induction of anesthesia to the attainment of necessary anesthetic level for surgery while keeping steady spontaneous respiration was 4.17+/-0.96 min and 8.69+/-3.17 min in pediatric and adult groups, respectively. The frequency and extent of respiration and heart rate were maintained within the normal range; SpO2 was > 98%. None of the patients developed complications. CONCLUSION: Tubeless anesthesia with spontaneous ventilation induced in patients can provide both an interference-free operative field and continuous observation of airway activity, which may provide an effective approach in excellent surgical conditions for the actual airway operation. PMID- 23739670 TI - Probing without irrigation in children with congenital nasolacrimal duct obstruction. AB - PURPOSE: The purpose of this study was to evaluate the results of probing, without fluorescein irrigation, as a primary treatment for epiphora and/or mucous discharge, secondary to congenital nasolacrimal duct obstruction (CNLDO) METHODS: The medical records of nine-two children (127 eyes) with CNLDO who underwent a single probing without the use of fluorescein irrigation between January 2006 and December 2011 were reviewed retrospectively. Inclusion criteria were no prior nasolacrimal surgical procedure, history of epiphora and/or discharge since birth or shortly after birth in one or both eyes and at least one of the following clinical signs: epiphora, muco-purulent discharge and increased tear meniscus height. Children were investigated in two sub-groups based on age at time of probing; group 1 (51 eyes/40 children) included children who underwent probing at age <= 2 years and group 2 (76 eyes/52 children) included children who underwent probing at age > 2years. The primary outcome was the complete disappearance of symptoms and signs in the affected eye(s), assessed at 3 months after surgery. RESULTS: The success rate for the overall sample was 83.5 % (106/127 eyes), in group 1 was 90.2% (46/51) and in group 2 was 78.9% (60/76). There was no significant difference in success rate between groups (p=0.094). Gender (p=0.292), affected eye (p=0.647) and bilateral cases (p=0.739) were not associated with successful elimination of symptoms. CONCLUSION: Probing without fluorescein irrigation for CNLDO beyond 1 year of age is highly successful and comparable to the published efficacy rates of the traditional probing with fluorescein irrigation. PMID- 23739673 TI - Return of results to the families of children in genomic sequencing: tallying risks and benefits. PMID- 23739674 TI - Simple and effective graphene laser processing for neuron patterning application. AB - A straightforward fabrication technique to obtain patterned substrates promoting ordered neuron growth is presented. Chemical vapor deposition (CVD) single layer graphene (SLG) was machined by means of single pulse UV laser ablation technique at the lowest effective laser fluence in order to minimize laser damage effects. Patterned substrates were then coated with poly-D-lysine by means of a simple immersion in solution. Primary embryonic hippocampal neurons were cultured on our substrate, demonstrating an ordered interconnected neuron pattern mimicking the pattern design. Surprisingly, the functionalization is more effective on the SLG, resulting in notably higher alignment for neuron adhesion and growth. Therefore the proposed technique should be considered a valuable candidate to realize a new generation of highly specialized biosensors. PMID- 23739675 TI - In vitro and in vivo models of non-alcoholic fatty liver disease (NAFLD). AB - By now, non-alcoholic fatty liver disease (NAFLD) is considered to be among the most common liver diseases world-wide. NAFLD encompasses a broad spectrum of pathological conditions ranging from simple steatosis to steatohepatitis, fibrosis and finally even cirrhosis; however, only a minority of patients progress to end-stages of the disease, and the course of the disease progression to the later stages seems to be slow, developing progressively over several years. Key risk factors including overweight, insulin resistance, a sedentary life-style and an altered dietary pattern, as well as genetic factors and disturbances of the intestinal barrier function have been identified in recent years. Despite intense research efforts that lead to the identification of these risk factors, knowledge about disease initiation and molecular mechanisms involved in progression is still limited. This review summarizes diet-induced and genetic animal models, as well as cell culture models commonly used in recent years to add to the understanding of the mechanisms involved in NAFLD, also referring to their advantages and disadvantages. PMID- 23739676 TI - Role of EZH2 in the growth of prostate cancer stem cells isolated from LNCaP cells. AB - Enhancer of zeste homolog 2 (EZH2) plays a crucial role in embryonic and somatic stem cells for their proliferation and differentiation. However, the roles and underlying mechanisms of EZH2 in prostate cancer stem cells (PCSCs) remain unknown. This study aimed to investigate the effects of EZH2 on PCSCs. PCSCs were isolated from the human prostate cancer cell line LNcap by fluorescence activated cell sorting (FACS). EZH2 expression was compared between PCSCs and non-PCSCs. The association between EZH2 function and PCSC growth was investigated using siRNA-mediated knock-down of EZH2. Cell growth was investigated by MTT, cell cycle and apoptosis of PCSCs were explored by flow cytometric analysis. Finally, the upstream pathway miRNA level was determined via a luciferase reporter assay, and the downstream pathway cycle regulators were examined via reverse transcriptase-polymerase chain reaction. The results showed that LNcap cell line comprised a greater proportion of CD44+/CD133+ cells by comparison to the PC-3 cell line. EZH2 was up-regulated in PCSCs compared with non-PCSCs. Silence of EZH2 inhibited cell growth and the cell cycle and promoted the progression of apoptosis. Furthermore, EZH2 was a direct target of miR-101 in PCSCs and EZH2's mRNA levels were inversely correlated with miR-101 expression and cyclin E2 (a cell-cycle regulator) was suppressed by siEZH2. In conclusion, EZH2 is essential for PCSC growth, partly through a negative regulation by miR-101 and positively regulating cyclin E2. PMID- 23739677 TI - Cloning and polymorphisms of yak lactate dehydrogenase B gene. AB - The main objective of this work was to study the unique polymorphisms of the lactate dehydrogenase-1 (LDH1) gene in yak (Bos grunniens). Native polyacrylamide gel electrophoresis revealed three phenotypes of LDH1 (a tetramer of H subunit) in yak heart and longissimus muscle extracts. The corresponding gene, ldhb, encoding H subunits of three LDH1 phenotypes was obtained by RT-PCR. A total of six nucleotide differences were detected in yak ldhb compared with that of cattle, of which five mutations cause amino acid substitutions. Sequence analysis shows that the G896A and C689A, mutations of ldhb gene, result in alterations of differently charged amino acids, and create the three phenotypes (F, M, and S) of yak LDH1. Molecular modeling of the H subunit of LDH indicates that the substituted amino acids are not located within NAD+ or substrate binding sites. PCR-RFLP examination of G896A mutation demonstrated that most LDH1-F samples are actually heterozygote at this site. These results help to elucidate the molecular basis and genetic characteristic of the three unique LDH1 phenotypes in yak. PMID- 23739678 TI - Interactions between Lactobacillus crispatus and bacterial vaginosis (BV) associated bacterial species in initial attachment and biofilm formation. AB - Certain anaerobic bacterial species tend to predominate the vaginal flora during bacterial vaginosis (BV), with Gardnerella vaginalis being the most common. However, the exact role of G. vaginalis in BV has not yet been determined. The main goal of this study was to test the hypothesis that G. vaginalis is an early colonizer, paving the way for intermediate (e.g., Fusobacterium nucleatum) and late colonizers (e.g., Prevotella bivia). Theoretically, in order to function as an early colonizer, species would need to be able to adhere to vaginal epithelium, even in the presence of vaginal lactobacilli. Therefore, we quantified adherence of G. vaginalis and other BV-associated bacteria to an inert surface pre-coated with Lactobacillus crispatus using a new Peptide Nucleic Acid (PNA) Fluorescence In Situ Hybridization (FISH) methodology. We found that G. vaginalis had the greatest capacity to adhere in the presence of L. crispatus. Theoretically, an early colonizer would contribute to the adherence and/or growth of additional species, so we next quantified the effect of G. vaginalis biofilms on the adherence and growth of other BV-associated species by quantitative Polymerase Chain Reaction (qPCR) technique. Interestingly, G. vaginalis derived a growth benefit from the addition of a second species, regardless of the species. Conversely, G. vaginalis biofilms enhanced the growth of P. bivia, and to a minor extent of F. nucleatum. These results contribute to our understanding of BV biofilm formation and the progression of the disorder. PMID- 23739679 TI - Dose-dependent protective effect of bisperoxovanadium against acute cerebral ischemia in a rat model of ischemia/reperfusion injury. AB - PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a dual specificity lipid and protein phosphatase. The loss of PTEN was originally discovered in numerous human cancers. PTEN inhibition by bisperoxovanadium (bpV) reduces neurological damage after ischemic brain injury. The purpose of this study was to identify the optimal neuroprotective dose of bpV when administrated after focal ischemia/reperfusion (I/R) injury in rats. Focal I/R injury was induced using the middle cerebral artery occlusion method. bpV at doses of 0.25, 0.50 and 1.0 mg/kg were injected intraperitoneally just after reperfusion, with saline serving as a vehicle control. A maximal reduction in brain injury was observed with 1.0 mg/kg bpV. This dose of bpV also significantly blocked apoptosis in the penumbral cortex of rats. This beneficial effect was associated with the increasing levels of Akt phosphorylation in the penumbral cortex. These results demonstrate that the pharmacological inhibition of PTEN protects against I/R injury in a dose-dependent manner and the protective effect might be induced through upregulation of the phosphoinositide-3 kinase/Akt pro-survival pathway, suggesting a new therapeutic strategy to combat ischemic brain injury. PMID- 23739680 TI - Combination of low concentration of (-)-epigallocatechin gallate (EGCG) and curcumin strongly suppresses the growth of non-small cell lung cancer in vitro and in vivo through causing cell cycle arrest. AB - (-)-Epigallocatechin gallate (EGCG) and curcumin are two naturally derived agents that have been widely investigated worldwide. They exhibit their anti-tumor effects in many types of cancers. In the current study, the effect of the combination of the two agents on non-small cell lung cancer (NSCLC) cells was investigated. The results revealed that at low concentrations, the combination of the EGCG and curcumin strongly enhanced cell cycle arrest. Flow cytometry analysis showed that the cells were arrested at G1 and S/G2 phases. Two main cell cycle related proteins cyclin D1 and cyclin B1 were significantly inhibited at the present of EGCG and curcumin. EdU (5-ethynyl-2'-deoxyuridine) fluorescence staining showed that the DNA replication was significantly blocked. A clonal growth assay also confirmed a marked repression of cell growth. In a lung cancer xenograft node mice model, combination of EGCG and curcumin exhibited protective effect against weight loss due to tumor burden. Tumor growth was strongly repressed by the combination of the two agents, without causing any serious side effect. Overall, these results strongly suggest that EGCG in combination with curcumin could be a candidate for chemoprevention agent of NSCLC. PMID- 23739681 TI - Three dimensional quantitative structure-activity relationship of 5H-Pyrido[4,3 b]indol-4-carboxamide JAK2 inhibitors. AB - Janus kinase 2 (JAK2) is an intracellular nonreceptor tyrosine kinase that belongs to the JAK family of kinases, which play an important role in survival, proliferation, and differentiation of a variety of cells. JAK2 inhibitors are potential drugs for the treatment of myeloproliferative neoplasms. The three dimensional quantitative structure-activity relationships have been studied on a series of JAK2 inhibitors by comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA). The CoMFA model had a cross-validated coefficient q2 of 0.633, and the relation non-cross-validated coefficient r2 of 0.976. The F value is 225.030. The contributions of steric and electrostatic fields to the activity are 55.2% and 44.8%, respectively. For the CoMSIA study, the q2, r2, and F values of the model are 0.614, 0.929, and 88.771, respectively. The contributions of steric, electrostatic, hydrophobic, hydrogen bond donor, and hydrogen bond donor fields to the activity are 27.3%, 23.9%, 16.4%, 21.7%, and 10.7%, respectively. The CoMFA and CoMSIA models showed strong predictive ability, and the 3D contour plots give the basis on the structure modification of JAK2 inhibitors. PMID- 23739683 TI - Molecular mechanism of the "feedback loop" model of carcinogenesis. AB - It is commonly accepted that cancer is a genetic disease. The current prevailing theory of carcinogenesis is the somatic mutation theory of carcinogenesis and metastasis (SMT). This theory postulates that mutations in epithelial cells lead to uncontrolled proliferation of tumor cells in a cell-autonomous fashion. This cell-autonomy is increasingly criticized. Current data suggest that the tumor microenvironment is also strongly involved in carcinogenesis. Recently, we published a hypothesis that considers the important contribution of the tumor microenvironment in carcinogenesis and complements the classical clonal evolution model. Essentially, this "feedback loop model" (FBM) postulates that the physiological communication between cancer cells and stromal cells in inflammatory or proliferative conditions is altered by anomalous signal processing within the parenchymal cells. The inability of parenchymal cells to correctly finalize the intercellular communication might result in a perpetuation of the activated state of cells and the tumor micromilieu. The FBM is unique among the tissue-based models because in this model tumor and stromal cells interact together in a reciprocal manner to form the cancer phenotype. Contrary to the SMT, the FBM postulates that mutated genes act in a cell-heteronomous fashion, not in a cell-autonomously fashion. PMID- 23739682 TI - (+)-Dehydroabietic acid, an abietane-type diterpene, inhibits Staphylococcus aureus biofilms in vitro. AB - Potent drugs are desperately needed to counteract bacterial biofilm infections, especially those caused by gram-positive organisms, such as Staphylococcus aureus. Moreover, anti-biofilm compounds/agents that can be used as chemical tools are also needed for basic in vitro or in vivo studies aimed at exploring biofilms behavior and functionability. In this contribution, a collection of naturally-occurring abietane-type diterpenes and their derivatives was tested against S. aureus biofilms using a platform consisting of two phenotypic assays that have been previously published by our group. Three active compounds were identified: nordehydroabietylamine (1), (+)-dehydroabietic acid (2) and (+) dehydroabietylamine (3) that prevented biofilm formation in the low micromolar range, and unlike typical antibiotics, only 2 to 4-fold higher concentrations were needed to significantly reduce viability and biomass of existing biofilms. Compound 2, (+)-dehydroabietic acid, was the most selective towards biofilm bacteria, achieving high killing efficacy (based on log Reduction values) and it was best tolerated by three different mammalian cell lines. Since (+) dehydroabietic acid is an easily available compound, it holds great potential to be used as a molecular probe in biofilms-related studies as well as to serve as inspirational chemical model for the development of potent drug candidates. PMID- 23739684 TI - Pediatric sports injuries: an age comparison of children versus adolescents. AB - BACKGROUND: Significant knowledge deficits exist regarding sports injuries in the young child. Children continue to engage in physically demanding, organized sports to a greater extent despite the lack of physical readiness, predisposing themselves to injury. PURPOSE: To evaluate sports injuries sustained in very young children (5-12 years) versus their older counterparts (13-17 years) with regard to the type and location of injuries, severity, and diagnosis. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A retrospective chart review was performed on a 5% random probability sample (final N = 2133) of 5- to 17-year-old patients treated for sports injuries in the Division of Sports Medicine at a large, academic pediatric medical center between 2000 and 2009. Using descriptive statistics, correlates of injuries by age group, injury type, and body area are shown. RESULTS: Five- to 12-year-old patients differed in key ways from older patients. Children in this category sustained injuries that were more often traumatic in nature and more commonly of the upper extremity. Older patients (13-17 years) were more likely to be treated for injuries to the chest, hip/pelvis, and spine. A greater proportion of the older children were treated for overuse injuries, as compared with their younger counterparts (54.4% vs. 49.2%, respectively), and a much larger proportion of these injuries were classified as soft tissue injuries as opposed to bony injuries (37.9% vs. 26.1%, respectively). Injury diagnosis differed between the 2 age groups. The 13- to 17 year age group sustained more anterior cruciate ligament injuries, meniscal tears, and spondylolysis, while younger children were diagnosed with fractures, including physeal fractures, apophysitis, and osteochondritis dissecans. The 5- to 12-year-old patients treated for spine injuries were disproportionately female (75.8%); most of these injuries were overuse (78.8%) and bony (60.6%); over one third of the youngest children were diagnosed with spondylolysis. Surgery was required in 40% of the injuries in the full sample. CONCLUSION: Sports injuries to children differ by age in injury diagnosis, type, and body area. Older children sustain a greater proportion of overuse injuries classified as soft tissue in nature. Children of all ages are sustaining significant sports injuries that require surgical intervention. PMID- 23739686 TI - Effects of air-pulsed cryotherapy on neuromuscular recovery subsequent to exercise-induced muscle damage. AB - BACKGROUND: Localized cooling has been proposed as an effective strategy to limit the deleterious effects of exercise-induced muscle damage on neuromuscular function. However, the literature reports conflicting results. PURPOSE: This randomized controlled trial aimed to determine the effects of a new treatment, localized air-pulsed cryotherapy (-30 degrees C), on the recovery time-course of neuromuscular function following a strenuous eccentric exercise. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 24 participants were included in either a control group (CONT) or a cryotherapy group (CRYO). Immediately after 3 sets of 20 maximal isokinetic eccentric contractions of elbow flexors, and then 1, 2, and 3 days after exercise, the CRYO group received a cryotherapy treatment (3 * 4 minutes at -30 degrees C separated by 1 minute). The day before and 1, 2, 3, 7, and 14 days after exercise, several parameters were quantified: maximal isometric torque and its associated maximal electromyographic activity recorded by a 64-channel electrode, delayed-onset muscle soreness (DOMS), biceps brachii transverse relaxation time (T2) measured using magnetic resonance imaging, creatine kinase activity, interleukin-6, and C-reactive protein. RESULTS: Maximal isometric torque decreased similarly for the CONT (-33% +/- 4%) and CRYO groups ( 31% +/- 6%). No intergroup differences were found for DOMS, electromyographic activity, creatine kinase activity, and T2 level averaged across the whole biceps brachii. C-reactive protein significantly increased for CONT (+93% at 72 hours, P < .05) but not for CRYO. Spatial analysis showed that cryotherapy delayed the significant increase of T2 and the decrease of electromyographic activity level for CRYO compared with CONT (between day 1 and day 3) in the medio-distal part of the biceps brachii. CONCLUSION: Although some indicators of muscle damage after severe eccentric exercise were delayed (ie, local formation of edema and decrease of muscle activity) by repeated air-pulsed cryotherapy, we provide evidence that this cooling procedure failed to improve long-term recovery of muscle performance. CLINICAL RELEVANCE: Four applications of air-pulsed cryotherapy in the 3 days after a strenuous eccentric exercise are ineffective overall in promoting long-term muscle recovery. Further studies taking into account the amount of exercise-induced muscle damage would allow investigators to make stronger conclusions regarding the inefficiency of this recovery modality. PMID- 23739685 TI - Changes in circulating biomarkers of muscle atrophy, inflammation, and cartilage turnover in patients undergoing anterior cruciate ligament reconstruction and rehabilitation. AB - BACKGROUND: After anterior cruciate ligament (ACL) reconstruction, there is significant atrophy of the quadriceps muscles that can limit full recovery and place athletes at risk for recurrent injuries with return to play. The cause of this muscle atrophy is not fully understood. HYPOTHESIS: Circulating levels of proatrophy, proinflammatory, and cartilage turnover cytokines and biomarkers would increase after ACL reconstruction. STUDY DESIGN: Descriptive laboratory study. METHODS: Patients (N = 18; mean age, 28 +/- 2.4 years) underwent surgical reconstruction of the ACL after a noncontact athletic injury. Circulating levels of biomarkers were measured along with Short Form-12, International Knee Documentation Committee, and objective knee strength measures preoperatively and at 6 postoperative visits. Differences were tested using repeated-measures 1-way analysis of variance. RESULTS: Myostatin, TGF-beta, and C-reactive protein levels were significantly increased in the early postoperative period and returned to baseline. Cartilage oligomeric matrix protein levels decreased immediately after surgery and then returned to baseline. CCL2, CCL3, CCL4, CCL5, EGF, FGF-2, IGF-1, IL-10, IL-1alpha, IL-1beta, IL-1ra, IL-6, myoglobin, and TNF-alpha were not different over the course of the study. CONCLUSION: An increase in potent atrophy inducing cytokines and corresponding changes in knee strength and functional scores were observed after ACL reconstruction. CLINICAL RELEVANCE: Although further studies are necessary, the therapeutic inhibition of myostatin may help prevent the muscle atrophy that occurs after ACL reconstruction and provide an accelerated return of patients to sport. PMID- 23739687 TI - Measuring Arabidopsis chromatin accessibility using DNase I-polymerase chain reaction and DNase I-chip assays. AB - DNA accessibility is an important layer of regulation of DNA-dependent processes. Methods that measure DNA accessibility at local and genome-wide scales have facilitated a rapid increase in the knowledge of chromatin architecture in animal and yeast systems. In contrast, much less is known about chromatin organization in plants. We developed a robust DNase I-polymerase chain reaction (PCR) protocol for the model plant Arabidopsis (Arabidopsis thaliana). DNA accessibility is probed by digesting nuclei with a gradient of DNase I followed by locus-specific PCR. The reduction in PCR product formation along the gradient of increasing DNase I concentrations is used to determine the accessibility of the chromatin DNA. We explain a strategy to calculate the decay constant of such signal reduction as a function of increasing DNase I concentration. This allows describing DNA accessibility using a single variable: the decay constant. We also used the protocol together with AGRONOMICS1 DNA tiling microarrays to establish genome-wide DNase I sensitivity landscapes. PMID- 23739688 TI - Cross-repressive interactions between SOC1 and the GATAs GNC and GNL/CGA1 in the control of greening, cold tolerance, and flowering time in Arabidopsis. AB - The paralogous and functionally redundant GATA transcription factors GNC (for GATA, NITRATE-INDUCIBLE, CARBON-METABOLISM INVOLVED) and GNL/CGA1 (for GNC LIKE/CYTOKININ-RESPONSIVE GATA FACTOR1) from Arabidopsis (Arabidopsis thaliana) promote greening and repress flowering downstream from the phytohormone gibberellin. The target genes of GNC and GNL with regard to flowering time control have not been identified as yet. Here, we show by genetic and molecular analysis that the two GATA factors act upstream from the flowering time regulator SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1) to directly repress SOC1 expression and thereby repress flowering. Interestingly, this analysis inversely also reveals that the MADS box transcription factor SOC1 directly represses GNC and GNL expression to control cold tolerance and greening, two further physiological processes that are under the control of SOC1. In summary, these findings support the case of a cross-repressive interaction between the GATA factors GNC and GNL and the MADS box transcription factor SOC1 in flowering time control on the one side and greening and cold tolerance on the other that may be governed by the various signaling inputs that are integrated at the level of SOC1 expression. PMID- 23739689 TI - Immunohistochemical detection of the latent nuclear antigen-1 of the human herpesvirus type 8 to differentiate cutaneous epidemic Kaposi sarcoma and its histological simulators. AB - Kaposi's sarcoma is the most common neoplasia diagnosed in AIDS patients and the expression of the human herpesvirus-8 (HHV-8) latent nuclear antigen-1 has been useful for its histological diagnosis. The aim of this study is to confirm that immunohistochemistry is a valuable tool for differentiating KS from its simulators in skin biopsies of HIV patients. Immunohistochemical and histological analyses were performed in 49 Kaposi's sarcoma skin biopsies and 60 of its histological simulators. Positivity was present in the 49 Kaposi's sarcoma skin biopsies and no staining was observed in the 60 simulators analyzed, resulting in sensibility and specificity of 100%. HHV-8 immunohistochemical detection is an effective tool for diagnosing Kaposi's sarcoma, especially in early lesions in which neoplastic features are not evident. It also contributes to its histological differential diagnosis. PMID- 23739690 TI - Do you know this syndrome? AB - The Bourneville-Pringle syndrome is an autosomal dominant neurocutaneous disorder characterized by the development of multiple hamartomas in various systems, especially brain, skin, retina, kidney, heart and lung. The case of a patient with brownish plaques on the forehead and temporal region, pink malar and chin papules, and hypopigmented macules on the back and trunk is described. The diagnosis of the Bourneville-Pringle syndrome is based on clinical criteria. Presence of two major criteria, such as facial angiofibromas, forehead fibrous plaques, three or more hypomelanotic macules establish the definitive diagnosis. The diagnosis should be made as early as possible in order to assess and treat the associated complications. PMID- 23739691 TI - American tegumentary leishmaniasis: an uncommon clinical and histopathological presentation. AB - We report a case of an unusual presentation of American Tegumentary Leishmaniasis involving a male patient with a solitary lesion on the ear lobe, persisting with minimal increase for at least six months without ulceration or related symptoms. The histological sections showed epithelial atrophy and a large number of structures consistent with Leishmania sp. amastigotes within macrophages. Treatment commenced with meglumine antimoniate resulting in regression of the condition. This report is of importance given the unusual clinical manifestation and histopathological findings in this case and the fact that there was low correlation with the extended duration of the disease. PMID- 23739692 TI - Inherited epidermolysis bullosa: clinical and therapeutic aspects. AB - Inherited epidermolysis bullosa (EB) is a heterogeneous group of genetic disorders that present with skin and, in some cases, mucosal fragility, predisposing patients to the development of blisters and/or erosions after minimal trauma or friction. Children with a recurrent history of these kinds of lesions or neonates that present them in the absence of another reasonable explanation should be investigated. Diagnosis must be based on clinical and histopathological findings. To date, management of inherited EB basically consists in avoiding traumas that trigger lesions, as well as preventing infection and facilitating healing of the wounds with the systematic use of bandages. PMID- 23739693 TI - Polarized dermoscopy of mammary Paget disease. AB - Mammary Paget's disease is a rare intraepithelial adenocarcinoma, located on the nipple/areola complex, highly associated with breast cancer. Although the international literature emphasizes the dermatoscopic pattern of mammary Paget's disease pigmented variant, the authors describe the dermoscopic findings of classical Paget's disease and demonstrate the presence of chrysalis-like structures, criteria recently described in the literature and not yet reported in Paget's disease. PMID- 23739694 TI - A melanoma risk score in a Brazilian population. AB - BACKGROUND: Important risk factors for cutaneous melanoma (CM) are recognized, but standardized scores for individual assessment must still be developed. OBJECTIVES: The objective of this study was to develop a risk score of CM for a Brazilian sample. METHODS: To verify the estimates of the main risk factors for melanoma, derived from a meta-analysis (Italian-based study), and externally validate them in a population in southern Brazil by means of a case-control study. A total of 117 individuals were evaluated. Different models were constructed combining the summary coefficients of different risk factors, derived from the meta-analysis, multiplied by the corresponding category of each variable for each participant according to a mathematical expression. RESULTS: the variable that best predicted the risk of CM in the studied population was hair color (AUC: 0.71; 95% CI: 0.62-0.79). Other important factors were freckles, sunburn episodes, and skin and eye color. Consideration of other variables such as common nevi, elastosis, family history, and premalignant lesions did not improve the predictive ability of the models. CONCLUSION: The discriminating capacity of the proposed model proved to be superior or comparable to that of previous risk models proposed for CM. PMID- 23739695 TI - Pityriasis versicolor: clinical-epidemiological characterization of patients in the urban area of Buerarema-BA , Brazil. AB - BACKGROUND: Pityriasis versicolor (PV) is a cutaneous pigmentation disorder caused by a lipophilic yeast of the genus Malassezia sp. It is a superficial mycosis characterized by well-defined, slightly scaly skin lesions of variable color. In Brazil, the number of reported cases is small, and there are few epidemiological studies. OBJECTIVES: to assess incidence, characteristics of the lesions, effectiveness of the Zileri's Sign procedure, and the epidemiological profile of PV in the urban area of Buerarema - Bahia. METHODS: Biological samples were collected on pre-established days at Basic Health Care Units from July to September 2010. Sample collection was followed by laboratory diagnosis using Porto's Method. RESULTS: Of the 158 patients with suspected PV participating in the study, 105 (66.5%) were positive; 72 (68.6%) were female and 33 (31.4%) were male. Sex and location of lesions showed statistically significant differences (p<0.05). The region with the highest rate of cases of PV was found to be the center of the city, with 40.9% of diagnosed cases. The most affected age group was between 10 and 19 years. There was a significant association between the results produced through Zileri's Sign and Porto's Method in relation to positive and negative results (p<0.05). CONCLUSIONS: The results showed a higher prevalence of PV among individuals at puberty. The Zileri's Sign method proved to be counterproductive, because it showed low efficacy as a method for clinical diagnosis, yielding negative results for 36 (34.3%) patients who had been diagnosed with PV through laboratory examination. PMID- 23739696 TI - Cutaneous blastomycosis: a clue to a systemic disease. AB - A 55-year-old male presented with back pain and slightly tender annular plaques with central ulceration on his face. A skin biopsy revealed scattered yeast with broad based buds. A CT scan of the abdomen revealed a pathologic T12 fracture. Tissue obtained from the spine confirmed budding yeasts. The patient was diagnosed with disseminated blastomycosis. The patient was treated with amphotericin and itraconazole and completely recovered. PMID- 23739697 TI - Risk factors and predictors of psoriatic arthritis in patients with psoriasis. AB - Given the potential consequences of joint damage for patients with psoriatic arthritis, we believe that the optimization of screening methods and the investigation of arthritis in patients with psoriasis are a medical priority. It is very useful to identify predictors of arthritis in patients with psoriasis. In fact, there is a consensus among doctors that the large gap between the diagnosis of psoriasis and that of psoriatic arthritis should be narrowed. In order to better manage patients with psoriasis, the authors review and discuss recent publications on the evidence of current predictors of arthritis in patients with psoriasis. PMID- 23739698 TI - Prevalence study of dermatoses referred to the phototherapy unit at the Dermatology Service of the Clinics Hospital of Porto Alegre, RS, Brazil. AB - BACKGROUND: Phototherapy consists of exposure to ultraviolet radiation for therapeutic reasons. Radiation is already used in dermatological practice, and many studies have already proved the beneficial effect of UV light treatment for chronic inflammatory or lymphoproliferative skin diseases. The Dermatology Service of the Clinics Hospital of Porto Alegre (Hospital de Clinicas de Porto Alegre) has been using phototherapy for a long time, and no official data have been described so far. OBJECTIVES: To study the prevalence of dermatoses referred to the phototherapy unit at the Clinics Hospital of Porto Alegre and describe the total number of patients who have already been referred to this sector and their phototype. METHODS: This is a descriptive cross-sectional study. Data were collected through a review of the phototherapy patients' records (secondary data), which are available on a database of the Dermatology Service of the Clinics Hospital of Porto Alegre, from August 1997 to July 2011. RESULTS: A total of 653 records were analyzed. Phototype 3 was the most prevalent (n=313). Distribution of the prevalence of dermatoses referred to the phototherapy unit was as follows: vitiligo (279), psoriasis (255), cutaneous T-cell lymphoma/mycosis fungoides (29), graftversus-host disease (15), scleroderma (11), atopic dermatitis (10), alopecia areata (6), parapsoriasis (5), eczema (4), granuloma annulare (4), and others (35). As vitiligo and psoriasis were the two most prevalent dermatoses, they were analyzed separately, with no statistical difference in prevalence between them (P=0,177). CONCLUSIONS: Our findings are in accordance with the literature, showing that although phototherapy is still mostly indicated to treat psoriasis, it has been used to treat other dermatoses, since the results are promising. PMID- 23739699 TI - Consensus on melanonychia nail plate dermoscopy. AB - This statement, focused on melanonychia and nail plate dermoscopy, is intended to guide medical professionals working with melanonychia and to assist choosing appropriate management for melanonychia patients. The International Study Group on Melanonychia was founded in 2007 and currently has 30 members, including nail experts and dermatopathologists with special expertise in nails. The need for common definitions of nail plate dermoscopy was addressed during the Second Meeting of this Group held in February 2008. Prior to this meeting and to date (2010) there have been no evidence-based guidelines on the use of dermoscopy in the management of nail pigmentation. PMID- 23739700 TI - Lymphangiectatic Kaposi's sarcoma in a patient with AIDS. AB - Kaposi's sarcoma is a malignant disease that originates in the lymphatic endothelium. It has a broad spectrum of clinical manifestations. Its four distinct clinical forms are: classic, endemic, iatrogenic and epidemic Kaposi's sarcoma. In non-HIV-associated Kaposi's sarcoma, the disease is typically limited to the lower extremities, but in immunodeficient patients, it is a multifocal systemic disease. The clinical course of the disease differs among patients, ranging from a single or a few indolent lesions to an aggressive diffuse disease. Advanced Kaposi's sarcoma lesions, typically those on the lower extremities, are often associated with lymphedema. In this paper, we report a case of a patient with a rare form of AIDS-associated Kaposi sarcoma called lymphangiectatic Kaposis's sarcoma. PMID- 23739701 TI - Lobomycosis and squamous cell carcinoma. AB - The occurence of squamous cell carcinoma on long-lasting ulcers is classic. Malignant transformation may occur on burn scars and chronic ulcers of varying etiology, including infectious agents. Transformation of old lobomycosis lesion scars into squamous cell carcinoma has been rarely reported. Careful and long term follow-up of such patients is important to avoid carcinomatous transformation. PMID- 23739702 TI - The risk of cutaneous melanoma in melanocytic nevi. AB - The data on melanoma associaed with melanocytic nevus are controversial. A longitudinal prospective study of 107 cases of cutaneous melanoma revealed that 9 (8.4%) cases were presumed to be linked to a precursor lesion, but only in 1 (0.9%) out of these cases the histopathological examination showed an associated melanocytic nevus. The vague information of a preexisting lesion of cutaneous melanoma is not sufficient to consider it a tumour precursor and it requires histopathological evidence to confirm the diagnosis. PMID- 23739703 TI - Rosai-Dorfman disease presenting with extensive cutaneous manifestation - case report. AB - Rosai-Dorfman disease is a benign, self-limited, idiopathic proliferative histiocytic disorder. It was first described in 1969 by Rosai and Dorfman. In its typical form the disease is characterized by extensive cervical lymphadenopathy associated with fever, polyclonal gammopathy and leukocytosis with neutrophilia. The skin is the most common site affected. Extranodal manifestations have been reported in 43% of cases. In this study, we report an atypical case of Rosai Dorfman disease in a female with massive cutaneous manifestation on the thigh, associated with a minimal lymphadenopathy limited to the regional inguinal lymph nodes. PMID- 23739704 TI - The use of ablative lasers in the treatment of facial melasma. AB - Melasma represents a pigmentary disorder that is difficult to treat. This study aims to broadly review the use of ablative lasers (Er:YAG and CO2) in the treatment of melasma, presenting the level of evidence of studies published to date. A total of 75 patients were enrolled in four case series studies (n=39), one controlled clinical trial (n=6) and one randomized controlled clinical trial (n=30). Studies on the Er:YAG laser showed better results with the use of short square-shaped pulses, which determined low rates of post-inflammatory hyperpigmentation and long-lasting maintenance of results. Likewise, studies on the CO2 laser proved the benefits of short pulse duration along with low-density energy. Post-treatment maintenance with the use of antipigmenting creams was necessary and effective to sustain long-term results. Ablative lasers may represent another useful and effective tool against melasma. Postinflammatory hyperpigmentation and difficulty in sustaining long-term results still represent the main limitations to a broader use of ablative lasers. Based on actual evidence, the use of this technology should be restricted to patients with recalcitrant disease. Further studies will help establish optimal laser parameters and treatment regimens. PMID- 23739705 TI - Earlobe reconstruction by the Gavello technique and bilobed flap. AB - The earlobe is an anatomical structure that has a significant aesthetic role. Its surgical repair places a challenge due to the difficulty of obtaining a natural appearing and durable outcome. The authors present two options: the Gavello technique and the bilobed flap, after the excision of malign neoplasms of the earlobe. The Gavello technique makes use of a bilobed flap with an anterior base to mold the new earlobe. D'Hooghe's bilobed flap with a pre and post-auricular lobe allows the reconstruction of small earlobes. Both techniques, although old, acquire an important and current interest in earlobe reconstruction, by reason of the moderate degree of difficulty, the use of a single time surgical act and under local anesthesia, with a proper aesthetic result. PMID- 23739706 TI - Dermoscopy of lichen aureus. AB - Lichen aureus (also called "lichen purpuricus") is an uncommon subtype of pigmented purpuric dermatosis. Clinically characterized by rust macules, papules or plaques, it is a chronic disease which more often affects young adults and is localized mainly on the lower extremities. The diagnosis is made on the basis of clinical and histopathological features. Dermoscopy findings are useful to confirm clinical diagnosis. PMID- 23739707 TI - Scanning electron microscopy of lichen sclerosus. AB - Lichen sclerosus is an acquired inflammatory condition characterized by whitish fibrotic plaques, with a predilection for the genital skin. We performed scanning electron microscopy of the dermis from a lesion of lichen sclerosus. Normal collagen fibers could be easily found in deeper layers of the specimen, as well as the transition to pathologic area, which seems homogenized. With higher magnifications in this transitional area collagen fibers are adherent to each other, and with very high magnifications a pearl chain aspect became evident along the collagen fibers. In the superficial dermis this homogenization is even more evident, collagen fibers are packed together and round structures are also observed. Rupture of collagen fibers and inflammatory cells were not found. These autoimmune changes of the extracellular matrix lead to the aggregation of immune complexes and/or changed matrix proteins along the collagen fibers, the reason why they seem hyalinized when examined by light microscopy. PMID- 23739708 TI - Case for diagnosis. AB - Lichen sclerosus is a chronic inflammatory mucocutaneous disorder of unknown etiology that most commonly affects the female genitalia. Cutaneous involvement with nonhaemorrhagic bullous is very unusual. We describe a case of bullous lichen sclerosus. PMID- 23739709 TI - Correlation between dermoscopic and histopathological diagnoses of atypical nevi in a dermatology outpatient clinic of the Medical School of Sao Jose do Rio Preto, SP, Brazil. AB - BACKGROUND: The incidence of cutaneous melanoma is increasing worldwide. Since it is an aggressive neoplasm, it is difficult to treat in advanced stages; early diagnosis is important to heal the patient. Melanocytic nevi are benign pigmented skin lesions while atypical nevi are associated with the risk of developing melanoma because they have a different histological pattern than common nevi. Thus, the clinical diagnosis of pigmented lesions is of great importance to differentiate benign, atypical and malignant lesions. Dermoscopy appeared as an auxiliary test in vivo, playing an important role in the diagnosis of pigmented lesions, because it allows the visualization of structures located below the stratum corneum. It shows a new morphological dimension of these lesions to the dermatologist and allows greater diagnostic accuracy. However, histopathology is considered the gold standard for the diagnosis. OBJECTIVES: To establish the sensitivity and specificity of dermoscopy in the diagnosis of pigmented lesions suspected of malignancy (atypical nevi), comparing both the dermatoscopic with the histopathological diagnosis, at the Dermatology Service of the outpatient clinic of Hospital de Base, Sao Jose do Rio Preto, SP. METHODS: Analysis of melanocytic nevi by dermoscopy and subsequent biopsy on suspicion of atypia or if the patient so desires, for subsequent histopathological diagnosis. RESULTS: Sensitivity: 93%. Specificity: 42%. CONCLUSIONS: Dermoscopy is a highly sensitive method for the diagnosis of atypical melanocytic nevi. Despite the low specificity with many false positive diagnoses, the method is effective for scanning lesions with suspected features of malignancy. PMID- 23739710 TI - An evaluation of the treatment of parapsoriasis with phototherapy. AB - Whether parapsoriasis represents an early stage of T-cell cutaneous lymphoma is still the subject of controversy. We evaluated the efficacy of phototherapy in the treatment of parapsoriasis and its relation with TCCL. Patients diagnosed with parapsoriasis and treated with phototherapy PUVA or UVB-NB were selected. Between 1 to 8 years following treatment the evolution of their disease was evaluated. In 62 patients the cure rate was 79.3% and 17.2% showed improvement of the lesions. Only two patients developed full blown T-cell cutaneous lymphoma. Phototherapy is an excellent treatment for parapsoriasis, with high cure rates, regardless of the type of phototherapy employed. Of the 62 patients under study, parapsoriasis showed no general tendency to progress to T-cell cutaneous lymphoma. PMID- 23739711 TI - Non Hodgkin T cell lymphoma: an atypical clinical presentation. AB - Cytotoxic lymphomas comprise a spectrum of peripheral T-cell lymphomas that can have a initial or late cutaneous presentation. We describe a 46-year-old man from Cape Verde, with a dermatosis involving his face and trunk, consisting of monomorphic papules with a smooth surface and both motor and sensory polyneuropathy.The hypothesis of leprosy was supported by the clinical and initial hystopathological findings and the patient was referred to our hospital with suspected Hansen's disease. In the new skin and lymph node biopsies a lymphocyte population was identified whose immunohystochemistry study allowed the diagnosis of T-cell lymphoma with expression of cytotoxic markers. The patient was started on chemotherapy with initial remission of the skin lesions but, subsequently, progression of systemic disease. PMID- 23739713 TI - Epidermoid carcinoma of the skin mimicking breast cancer. AB - Nonmelanoma skin cancer is the most frequent cancer in the world. Squamous cell cancer often occurs in sun-exposed areas, such as the head and neck. When it involves the breast and ulce-rates, invading the glandular parenchyma, it may mimic breast cancer. Confirmation by means of histopathological examination, combined with clinical examination, is a critical instrument for the accuracy of the diagnosis. We report a case of an epidermoid carcinoma located on the breast skin, initially diagnosed as breast cancer. PMID- 23739714 TI - Nail apparatus melanoma: a diagnostic opportunity. AB - Malignant Melanoma is a high mortality neoplasm. The involvement of the nail apparatus is rare, with only 2 out of 3 patients seeking medical attention as the result of recent nail melanocytic lesions. This results in late diagnosis and a prognosis worse than cutaneous melanoma. We report a female, presenting with ulcerative lesions with clinical and laboratory features compatible with leishmaniasis. On return after treatment initiation a longitudinal melanonychia was observed on her first right finger. Biopsy of the nail matrix was performed. Histopathology was compatible with melanoma in situ. Longitudinal melanonychia is not a specific sign for melanoma and it is important that the dermatologist should identify the suspect lesions correctly. The incidental diagnosis of nail melanoma in situ in our case significantly impacted the patient's survival. PMID- 23739715 TI - Marshall's syndrome. AB - Marshall's syndrome is a form of acquired cutis laxa without systemic involvement, which is preceded by an inflammatory dermatitis with a neutrophilic component. We report a case of a 6-year-old boy with clinical and histopathological features of this syndrome. The etiology remains unknown and there is no definitive treatment. PMID- 23739716 TI - Case for diagnosis. AB - A 27 year-old-man, with no known personal or familial history of disease, mentioned a 10-year history of asymptomatic groups of telangiectasias, with a Blaschko lines distribution on the right lateral aspect of the neck and asymptomatic. He denied any episodes of disease or drug intake that could be associated with the disease. Blood work had no changes, namely of liver enzymes or infectious serologies. The clinical diagnosis of Idiopathic Acquired Unilateral Nevoid Telangiectasia was made, an uncommon, benign vascular malformation. The patient declined doing a cutaneous biopsy or treatment with a cosmetic intent. PMID- 23739717 TI - Oral Candida spp carriers: its prevalence in patients with type 2 diabetes mellitus. AB - BACKGROUND: Prevalence of oral candidiasis in diabetic patients is 13.7-64%. Candida albicans was the most frequently isolated species (75-86.5%). OBJECTIVE: To obtain the prevalence of Candida carriers among patients with type 2 diabetes mellitus to identify the species of the yeast. STUDY DESIGN: It is an open, observational, descriptive, cross-sectional, and prospective study. METHODS: We included voluntary patients from the National Diabetes Marathon and performed a blood glucose measurement, sialometry test, Gram-stained exfoliative cytology, and culture on Sabouraud dextrose agar and CHROMagar Candida TM. Results were analyzed using descriptive statistics. RESULTS: We examined 141 patients (mean age 57 years): 103 women (73%) and 38 men (26.9%). Exfoliative cytology was positive in 32 cases (23 with oral lesions); 78 had oral lesions but no Candida (93.9%). Candida was isolated in 58 patients (41.1%), 21 (45.6 %) had blood glucose greater than 126 mg/dl, and 37 (38.9%) had less than 126 mg/dl. The most frequent species was C. albicans (82.7%). Forty-two Candida carriers had salivary flow greater than 20 mm (72.4%), and 16 (27.5%) had hyposalivation. Candida was isolated in 25 of 79 patients with dental prosthesis (31.6%), 9 of 15 were smokers (60%), and 22 of 71 had symptoms (30.9%). CONCLUSIONS: Prevalence of oral Candida carriers in patients with type 2 diabetes mellitus in Mexico was similar to that found in other countries; exfoliative cytology was effective in finding Candida; salivary flow rate, use of prosthesis, and presence of oral lesions and symptoms were similar in oral Candida carriers and negative patients. Most smokers were Candida carriers. PMID- 23739718 TI - Cutaneous leukocytoclastic vasculitis in the presence of methimazole therapy. AB - Treatment with antithyroid drugs may be accompanied by side effects. We present a patient diagnosed with Grave's Disease who developed extensive vasculitis in the lower limbs during methimazole use. After suspension of the methimazole and the introduction of prednisone in immunesupressor doses the cutaneous lesions started to involute. PMID- 23739719 TI - Adverse effects of alternative therapy (minocycline, ofloxacin, and clofazimine) in multibacillary leprosy patients in a recognized health care unit in Manaus, Amazonas, Brazil. AB - BACKGROUND: After the introduction of the multidrug therapy, there was a decline in the coefficients of prevalence and detection of new cases of leprosy. However, the records of drug resistance and relapses are threatening factors in leprosy control. Hence, new alternative schemes and monitoring of adverse effects to avoid treatment abandonment are important considerations. OBJECTIVE: Describe the side effects of a multidrug regimen containing minocycline, ofloxacin, and clofazimine in multibacillary leprosy patients. METHODS: We conducted a prospective, descriptive, and observational study with multibacillary patients, including cases of intolerance to standard MDT and relapses. The study was carried out at Fundacao Alfredo da Matta (Alfredo da Matta Foundation), in Manaus, Amazonas, from April 2010 to January 2012. The patients received alternative therapy, which consisted of daily self-administered doses of 100mg of minocycline, 400 mg of ofloxacin, and 50mg of clofazimine and a supervised monthly dose of 300mg of clofazimine for six months, followed by eighteen months of daily doses of ofloxacin 400mg, clofazimine 50mg, and a supervised monthly dose of clofazimine 300mg. RESULTS: Twenty-one cases were included. Mild and transitory side effects occurred in 33.3% of patients. Of the total episodes, 45.9% were attributed to ofloxacin and they included abdominal pain, nausea, vomiting, headache, and insomnia; 21.6% were due to clofazimine, with 100% of patients presenting skin pigmentation. The mean time for the development of adverse effects after beginning the therapy was 15.2 days. CONCLUSION: All patients tolerated the drugs well, and compliance was satisfactory, with no serious events. Unlike other standard MDT studies had shown, no treatment was stopped due to side effects. Nevertheless, patient follow-up and studies with bigger samples are necessary to guarantee the efficacy and safety of the alternative regimen as a second-line scheme in multi-drug therapy. PMID- 23739720 TI - Manganese-catalyzed aerobic dehydrogenative cyclization toward ring-fused indole skeletons. AB - We describe the first example of manganese(III)-catalyzed aerobic dehydrogenative cyclization producing ring-fused indole skeletons. This catalytic system converts from two C-H bonds of indole and malonate to a C-C bond and produces water as the sole side product. This operationally easy method was extended to an intermolecular cross-dehydrogenative coupling of indole and alpha-substituted malonate with complete C2-selectivity. PMID- 23739722 TI - Current world literature. Hematopoiesis. PMID- 23739721 TI - Aging of the hematopoietic system. AB - PURPOSE OF REVIEW: Aging of the hematopoietic system is associated with myeloid malignancies, anemia and immune dysfunction. As hematopoietic stem cells (HSCs) generate all cells of the hematopoietic system, age-associated changes in HSCs may underlie many features of the aged hematopoietic system. Recent findings on age-associated changes in HSCs are reviewed here. RECENT FINDINGS: Aged HSCs are myeloid biased, have acquired DNA damage and are functionally compromised. However, overall function of the HSC compartment is well maintained through age associated expansion of HSCs. Many age-related changes in the hematopoietic system, in particular the clonal myeloid bias of HSCs and the decrease in B and T cell development, in fact begin during development. Furthermore, HSCs possess specific protective mechanisms aimed at maintaining their number, even at the expense of accumulating damaged cells. SUMMARY: We argue that age-related changes in HSCs and in the hematopoietic system may not entirely be due to a degenerative aging process, but are the result of developmental and stem cell-protective mechanisms aimed at maximizing fitness during reproductive life. These mechanisms may be disadvantageous later in life as damaged HSCs accumulate and establishment of responses to neoantigens becomes compromised because of the reduced generation of naive T and B cells. PMID- 23739724 TI - Engineering three-dimensional topological insulators in Rashba-type spin-orbit coupled heterostructures. AB - Topological insulators represent a new class of quantum phase defined by invariant symmetries and spin-orbit coupling that guarantees metallic Dirac excitations at its surface. The discoveries of these states have sparked the hope of realizing non-trivial excitations and novel effects such as a magnetoelectric effect and topological Majorana excitations. Here we develop a theoretical formalism to show that a three-dimensional topological insulator can be designed artificially via stacking bilayers of two-dimensional Fermi gases with opposite Rashba-type spin-orbit coupling on adjacent layers, and with interlayer quantum tunneling. We demonstrate that in the stack of bilayers grown along a (001) direction, a non-trivial topological phase transition occurs above a critical number of Rashba bilayers. In the topological phase, we find the formation of a single spin-polarized Dirac cone at the -point. This approach offers an accessible way to design artificial topological insulators in a set up that takes full advantage of the atomic layer deposition approach. This design principle is tunable and also allows us to bypass limitations imposed by bulk crystal geometry. PMID- 23739726 TI - Homo- and heterometallic planes, chains and cubanes. AB - The synthesis, structural and magnetic characterisation of a family of homo- and heterometallic complexes constructed with the Schiff base ligands 2-iminomethyl-6 methoxy-phenol (L1H) and 2-imino-6-methoxy-phenol (L2H), are discussed. Members include the heterometallic tetranuclear complexes of general formula [Na2M2(X)2(L1)4(Y)2] (where M = Fe(III), X = (-)OMe, Y = NO3(-) (1) and M = Ni(II), X = N3(-) and Y = MeCN (2)), each possessing a butterfly-like topology. We also report the formation of the heterometallic molecular cage [Na3Ni2(L1)6](ClO4) (3) whose metallic skeleton describes a [rare] trigonal bipyramid, the homometallic 1-D coordination polymer [Mn(L1)2(Cl)]n (4), and the tetranuclear cubane clusters [Mn(III)3Mn(IV)(O)3(OEt)(OAc)3(L1)3] (5) and [Ni4(MU3-OMe)4(L2)4(MeOH)4] (6). Dc and ac magnetic susceptibility studies on complexes 5 and 6 reveal S = 9/2 and S = 4 spin ground states. PMID- 23739725 TI - The effects of teacher fidelity of implementation of pathways to health on student outcomes. AB - Previous research has demonstrated the importance of ensuring that programs are implemented as intended by program developers in order to achieve desired program effects. The current study examined implementation fidelity of Pathways to Health (Pathways), a newly developed obesity prevention program for fourth- through sixth-grade children. We explored the associations between self-reported and observed implementation fidelity scores and whether implementation fidelity differed across the first 2 years of program implementation. Additionally, we examined whether implementation fidelity affected program outcomes and whether teacher beliefs were associated with implementation fidelity. The program was better received, and implementation fidelity had more effects on program outcomes in fifth grade than in fourth grade. Findings suggest that implementation in school-based obesity programs may affect junk food intake and intentions to eat healthfully and exercise. School support was associated with implementation fidelity, suggesting that prevention programs may benefit from including a component that boosts school-wide support. PMID- 23739727 TI - [Diagnosis and treatment of eosinophilic gastrointestinal disorders]. PMID- 23739728 TI - [The association between nighttime reflux and sleep]. PMID- 23739729 TI - [Association between nocturnal acid reflux and sleep disturbance]. PMID- 23739730 TI - [Effective therapy for nocturnal gastroesophageal acid reflux]. PMID- 23739731 TI - [Clinical comparison of endoscopic naso-gallbladder drainage versus percutaneous transhepatic gallbladder drainage for acute cholecystitis]. AB - Early cholecystectomy has become the standard treatment for acute cholecystitis. However, gallbladder drainage is often performed before surgery. In the present study, we compared the clinical outcomes between patients who underwent endoscopic naso-gallbladder drainage (ENGBD) and those who underwent percutaneous transhepatic gallbladder drainage (PTGBD). PTGBD was superior to ENGBD in terms of success rate and procedure time. However, there was no significant difference in the rate of complications, improvement effect on inflammation, the length of hospitalization, the duration from drainage to operation, and operation time. Although PTGBD has become the first choice for cases requiring gallbladder drainage, ENGBD should be considered the most appropriate therapy in cases with a contraindication for PTGBD due to antithrombotic treatment, those associated with choledocholithiasis, and those suspected of gallbladder cancer. The importance of ENGBD is expected to increase in the future. PMID- 23739732 TI - [Whipple's disease]. AB - A 36-year-old woman presented with fever, diarrhea, and weight loss in April 2011. Upper GI endoscopy and colonoscopy showed a diffuse yellow-white shaggy mucosa in the second part of the duodenum and the ileum end, respectively. These lesions in these 2 locations were biopsied, and both specimens showed distended epithelial villi and massive infiltration of foamy macrophages in the lamina propria. PCR was performed to identify causative bacilli. DNA extracted from the duodenal mucosa showed a specific PCR product, confirming the diagnosis of Whipple's disease. The patient was treated with a 2-week course of ceftriaxone, followed by sulfamethoxazole/trimethoprim. After we started the treatment, the patient developed complications of infective endocarditis and meningitis. The patient was relieved of her symptoms using a combination of gentamicin, penicillin G, ampicillin, meropenem, and vancomycin. PMID- 23739733 TI - [A case of paralytic ileus associated with varicella zoster virus infection]. AB - A 79-year-old woman with a history of pyothorax was admitted with a 4-day history of abdominal distension. Physical examination revealed marked abdominal distention, absent bowel sounds, and a vesicular rash over the left Th8-10 dermatome. Abdominal radiography showed gaseous distension of the colon and ileum. Colonoscopy excluded any obstructive process of the colon. Laboratory findings yielded positive results for serum IgM and IgG against the varicella zoster virus (VZV) . Paralytic ileus associated with the VZV was therefore diagnosed. The ileus improved after conservative treatment with intravenous acyclovir. Although shingles is frequently encountered, it is a rare cause of paralytic ileus. In the future, the VZV should be considered as one of the causes of paralytic ileus, and complete resolution can be achieved with conservative management. PMID- 23739734 TI - [A case of Peutz-Jeghers syndrome with repeated small intestinal intussusception successfully treated by intraoperative endoscopic polypectomy]. AB - Intestinal polyps are a distinctive feature of Peutz-Jeghers syndrome (PJS). These hamartomas can lead to significant complications such as intussusception or gastrointestinal bleeding which necessitate multiple laparotomies and bowel resections. In an operation for intestinal intussusception, it is preferable to simultaneously resect as many polyps as possible to prevent recurrence of complications caused by intestinal polyps. We report a case of a woman in her twenties with PJS, diagnosed as small intestinal intussusception caused by an intestinal polyp. We performed not only repair of the intussusception but also endoscopic polypectomy without resection of the small intestine. We successfully resected all polyps larger than 10mm from the duodenum to the ascending colon during the operation. PMID- 23739735 TI - [Juvenile gastric polyposis in a patient with antiphospholipid syndrome]. AB - We report a case of juvenile gastric polyposis associated with antiphospholipid syndrome. A 42-year-old woman was admitted with a chief complain of fatigue. Six years earlier, antiphospholipid syndrome was diagnosed and treated with aspirin. Two years earlier, gastric polyps were endoscopically observed, the number and size of which subsequently increased. Juvenile gastric polyposis was diagnosed on the basis of the pathological features of the biopsy specimens. Bleeding was repeatedly identified from the polyposis. Total gastrectomy was performed because of worsening anemia and hypoalbuminemia. PMID- 23739736 TI - [A case of systemic amyloidosis with cholangiectasis diagnosed by liver biopsy]. AB - A 60-year-old man presented with fever and fatigue in a medical clinic and was given a diagnosis of cholangitis with mild cholangiectasis. The cholangiectasis remained even after treatment with an appropriate antibiotic agent. When the patient was transferred to our hospital for further examination, he was newly suffering from orthostatic hypotension and peripheral facial nerve palsy. Computed tomography (CT) scan revealed multiple low-density areas in the liver and intrahepatic bile duct dilatation. We performed percutaneous liver biopsy, and histopathological findings showed amyloid deposition around the portal vein. We diagnosed his condition as AL amyloidosis. Oral administration of melphalan and dexamethasone improved his clinical features and CT findings. We consider this case as rare in that the deposition of amyloid protein caused cholangiectasis. PMID- 23739737 TI - [A case of a patient with splenic arteriovenous fistula associated with portal hypertension who developed refractory ascites and diarrhea as initial symptom]. AB - A 55-year-old woman was admitted to our hospital because of diverse symptoms of portal hypertension, such as refractory ascites, diarrhea, and general malaise. Blood test revealed liver and renal dysfunction and glucose tolerance. Contrast enhancement computed tomography revealed splenic arteriovenous fistula with dilated splenic artery and vein, causing portal hypertension. The splenic arteriovenous fistula was successfully treated by percutaneous transarterial embolization, resulting in the complete recovery of the patient. Herein, we report a case of arteriovenous fistula which was successfully treated with the aid of interventional radiology. PMID- 23739738 TI - [Pancreatic cancer in a patient with congenital agenesis of the dorsal pancreas]. AB - A 65-year-old man with back pain showed a hypovascular lesion of the head of the pancreas on dynamic computed tomography and abdominal ultrasonography. The distal portion of the pancreas was not visible. Endoscopic retrograde cholangiopancreatography revealed pancreatic duct obstruction, and the duodenal minor papilla was not visible. Therefore, we diagnosed the patient's condition as stage IVa pancreatic cancer with congenital agenesis of the dorsal pancreas. The patient underwent successful chemotherapy with 3 courses of gemcitabine and S-1, which was followed by pancreaticoduodenectomy. Pathological staging revealed invasive ductal carcinoma, pT3, pN0, pM0, stage III. We report a rare case of pancreatic cancer with congenital agenesis of the dorsal pancreas. PMID- 23739739 TI - Clustering acinetobacter strains by optical mapping. AB - Optical mapping is a technique that produces an ordered restriction map of a bacterial or eukaryotic chromosome. We have developed a new method, the BOP method, to compare experimental optical maps with in silico optical maps of complete genomes to infer the presence/absence of short DNA sequences (bops) in each genome. The BOP method, as implemented by the Optical Mapping suite of four programs, circumvents the necessity of whole-genome multiple alignments and permits reliable strain typing and clustering on the basis of optical maps. We have applied the Optical Mapping Suite to 125 strains of Acinetobacter sp., including 11 completely sequenced genomes and 114 Acinetobacter complex from three US military hospitals. We found that optical mapping completely resolves all 125 strains. Signal to noise analysis showed that when the 125 strains were considered together almost 1/3 of the experimental fragments were misidentified. We found that the set of 125 genomes could be divided into three clusters, two of which included sequenced genomes. Signal to noise analysis after clustering showed that only 3.5% of the experimental restriction fragments were misidentified. Minimum spanning trees of the two clusters that included sequenced genomes are presented. The programs we have developed provide a more rigorous approach for analyzing optical map data than previously existed. PMID- 23739741 TI - Insights into functional bacterial diversity and its effects on Alpine bog ecosystem functioning. AB - Plant-associated bacteria are important for the growth and health of their host, but little is known about its functional diversity and impact on ecosystem functioning. We studied bacterial nitrogen fixation and methane oxidation from indicator Sphagnum mosses in Alpine bogs to test a hypothesis that the plant microbiome contained different functional patterns depending on their functions within the ecosystem. A high abundance and diversity of nitrogenase genes were detected, mostly specific for each Sphagnum. In contrast, methanotrophs formed highly similar patterns despite a high abundance and diversity of methane monooxygenase genes. Our hypothesis was supported by these contrasting functional patterns together with the result that the Sphagnum sporophyte contained a high proportion of specific diazotrophs (45.5%) but no potential methanotrophs. While essential for plant growth under nutrient-limited conditions, nitrogen-fixing bacteria were highly specific and transferred with the sporophyte unlike the ubiquitous methanotrophs which are important for the climate-relevant ecosystem itself. PMID- 23739740 TI - Induction of apoptosis and the regulation of ErbB signaling by laminarin in HT-29 human colon cancer cells. AB - Laminarin, found in marine brown algae, is used as a carbohydrate reserve for phytoplankton; however, it is also used in traditional Chinese medicine, and has been shown to have several biological activities, including anticancer activities. In this study, we examined the mechanisms through which laminarin from Laminaria digitata induces apoptosis in HT-29 colon cancer cells, as well as the involvement of the ErbB signaling pathway. Cell viability assay revealed that laminarin induced cell death in a dose-dependent manner. Cell cycle analysis revealed that laminarin increased the percentage of cells in the sub-G1 and G2-M phase. Western blot analysis demonstrated that laminarin inhibited the heregulin stimulated phosphorylation of ErbB2. A decrease in cellular proliferation was also observed; this was found to be dependent on ErbB, which activates c-Jun N terminal kinase. These findings demonstrate the important role of the epidermal growth factor receptor in colon cancer tumorigenesis, and suggest the potential of laminarin as a bio-functional food with anticancer effects on human colon cancer. PMID- 23739742 TI - Polymorphisms of warfarin metabolizing enzymes in an Indian population. PMID- 23739743 TI - Pigmented basal cell carcinoma: uncommon presentation in blue-eyed patients. PMID- 23739744 TI - Effects of sciatic nerve transection on ultrastructure, NADPH-diaphorase reaction and serotonin-, tyrosine hydroxylase-, c-Fos-, glucose transporter 1- and 3-like immunoreactivities in frog dorsal root ganglion. AB - Frogs have been used as an alternative model to study pain mechanisms. Since we did not find any reports on the effects of sciatic nerve transection (SNT) on the ultrastructure and pattern of metabolic substances in frog dorsal root ganglion (DRG) cells, in the present study, 18 adult male frogs (Rana catesbeiana) were divided into three experimental groups: naive (frogs not subjected to surgical manipulation), sham (frogs in which all surgical procedures to expose the sciatic nerve were used except transection of the nerve), and SNT (frogs in which the sciatic nerve was exposed and transected). After 3 days, the bilateral DRG of the sciatic nerve was collected and used for transmission electron microscopy. Immunohistochemistry was used to detect reactivity for glucose transporter (Glut) types 1 and 3, tyrosine hydroxylase, serotonin and c-Fos, as well as nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-diaphorase). SNT induced more mitochondria with vacuolation in neurons, satellite glial cells (SGCs) with more cytoplasmic extensions emerging from cell bodies, as well as more ribosomes, rough endoplasmic reticulum, intermediate filaments and mitochondria. c-Fos immunoreactivity was found in neuronal nuclei. More neurons and SGCs surrounded by tyrosine hydroxylase-like immunoreactivity were found. No change occurred in serotonin- and Glut1- and Glut3-like immunoreactivity. NADPH-diaphorase occurred in more neurons and SGCs. No sign of SGC proliferation was observed. Since the changes of frog DRG in response to nerve injury are similar to those of mammals, frogs should be a valid experimental model for the study of the effects of SNT, a condition that still has many unanswered questions. PMID- 23739745 TI - Human papillomavirus infection among sexual partners attending a Sexually Transmitted Disease Clinic in Rio de Janeiro, Brazil. AB - Cervical cancer is a major source of illness and death among women worldwide and genital infection with oncogenic human papillomavirus (HPV) its principal cause. There is evidence of the influence of the male factor in the development of cervical neoplasia. Nevertheless, the pathogenic processes of HPV in men are still poorly understood. It has been observed that different HPV types can be found among couples. The objective of the present study was to investigate HPV infections in female patients (n = 60 females/group) as well as in their sexual partners and to identify the concordance of HPV genotypes among them. By using the polymerase chain reaction, we detected a 95% prevalence of HPV DNA in women with cervical intraepithelial neoplasia (CIN) compared to 18.3% in women with normal cervical epithelium, with a statistically significant difference (P < 0.001). The HPV DNA prevalence was 50% in male partners of women with CIN and 16.6% in partners of healthy women. In the control group (healthy women), only 9 couples were simultaneously infected with HPV, and only 22.2% of them had the same virus type, showing a weak agreement rate (kappa index = 0.2). Finally, we observed that HPV DNA was present in both partners in 30 couples if the women had CIN, and among them, 53.3% shared the same HPV type, showing moderate agreement, with a kappa index of 0.5. This finding supports the idea of circulation and recirculation of HPV among couples, perpetuating HPV in the sexually active population, rather than true recurrences of latent infections. PMID- 23739746 TI - Brief daily postpartum separations from the litter alter dam response to psychostimulants and to stress. AB - Neonatal handling induces several behavioral and neurochemical alterations in pups, including decreased responses to stress and reduced fear in new environments. However, there are few reports in the literature concerning the behavioral effects of this neonatal intervention on the dams during the postpartum period. Therefore, the aim of the current study was to determine if brief postpartum separation from pups has a persistent impact on the dam's stress response and behavior. Litters were divided into two neonatal groups: 1) non handled and 2) handled [10 min/day, from postnatal day (PND) 1 to 10]. Weaning occurred at PND 21 when behavioral tasks started to be applied to the dams, including sweet food ingestion (PND 21), forced swimming test (PND 28), and locomotor response to a psychostimulant (PND 28). On postpartum day 40, plasma was collected at baseline for leptin assays and after 1 h of restraint for corticosterone assay. Regarding sweet food consumption, behavior during the forced swimming test or plasma leptin levels did not differ between dams briefly separated and non-separated from their pups during the postpartum period. On the other hand, both increased locomotion in response to diethylpropion and increased corticosterone secretion in response to acute stress were detected in dams briefly separated from their pups during the first 10 postnatal days. Taken together, these findings suggest that brief, repeated separations from the pups during the neonatal period persistently impact the behavior and induce signs of dopaminergic sensitization in the dam. PMID- 23739747 TI - Correlation between interleukin-18 promoter -607C/A polymorphism and susceptibility to ischemic stroke. AB - Single nucleotide polymorphisms in the promoter region of interleukin-18 (IL-18), an inflammatory cytokine, have been linked to susceptibility to many diseases, including cancer and immune dysfunction. Here, we explored the potential association between the IL-18 -607C/A (rs1946518) promoter region polymorphism and susceptibility to ischemic stroke (IS). This locus was amplified from peripheral blood samples of 386 IS patients (cases) and 364 healthy individuals (controls) by the polymerase chain reaction with sequence-specific primers. Significant differences were observed by the chi2 test in the -607C/A (rs1946518) genotype and allele frequencies between cases and controls (P < 0.05). Furthermore, after excluding for age, gender, smoking status, and hypertension, logistic regression indicated that IS susceptibility of -607C carriers increased 1.6 times (OR = 1.601, 95%CI = 1.148-2.233, P = 0.006) compared to -607A carriers. Additionally, similar increases in IS risk were noted for male patients or patients less than 65 years old. In conclusion, IL-18 -607C/A (rs1946518) promoter polymorphism is associated with IS susceptibility, and the C allele may confer increased IS risk. PMID- 23739748 TI - Pleiotropic effects of simvastatin in physically trained ovariectomized rats. AB - This study tested the hypothesis that simvastatin treatment can improve cardiovascular and autonomic functions and membrane lipoperoxidation, with an increased effect when applied to physically trained ovariectomized rats. Ovariectomized rats were divided into sedentary, sedentary+simvastatin and trained+simvastatin groups (n = 8 each). Exercise training was performed on a treadmill for 8 weeks and simvastatin (5 mg/kg) was administered in the last 2 weeks. Blood pressure (BP) was recorded in conscious animals. Baroreflex sensitivity was evaluated by the tachycardic and bradycardic responses to BP changes. Cardiac vagal and sympathetic effects were determined using methylatropine and propranolol. Oxidative stress was evaluated based on heart and liver lipoperoxidation using the chemiluminescence method. The simvastatin treated groups presented reduced body weight and mean BP (trained+simvastatin = 99 +/- 2 and sedentary+simvastatin = 107 +/- 2 mmHg) compared to the sedentary group (122 +/- 1 mmHg). Furthermore, the trained group showed lower BP and heart rate compared to the other groups. Tachycardic and bradycardic responses were enhanced in both simvastatin-treated groups. The vagal effect was increased in the trained+simvastatin group and the sympathetic effect was decreased in the sedentary+simvastatin group. Hepatic lipoperoxidation was reduced in sedentary+simvastatin (~21%) and trained+simvastatin groups (~57%) compared to the sedentary group. Correlation analysis involving all animals demonstrated that cardiac lipoperoxidation was negatively related to the vagal effect (r = -0.7) and positively correlated to the sympathetic effect (r = 0.7). In conclusion, improvement in cardiovascular and autonomic functions associated with a reduction of lipoperoxidation with simvastatin treatment was increased in trained ovariectomized rats. PMID- 23739749 TI - Field-deployable whole-cell bioluminescent biosensors: so near and yet so far. AB - The use of smart supports and bioinspired materials to confine living cells and use them for field-deployable biosensors has recently attracted much attention. In particular, bioluminescent whole-cell biosensors designed to respond to different analytes or classes of analyte have been successfully implemented in portable and cost-effective analytical devices. Significant advances in detection technology, biomaterial science, and genetic engineering of cells have recently been reported. Now the challenge is to move from benchtop traditional cell-based assays to portable biosensing devices. Improvement of the analytical performance of these biosensors depends on the availability of optimized bioluminescent reporters, and promising approaches that go beyond reporter gene technology are emerging. To enable handling of cells as ready-to-use reagents, nature-inspired strategies have been used, with the objective of keeping cells in a dormant state until use. Several issues must still be investigated, for example long-term viability of cells, the possibility of performing real-time analysis, and multiplexing capability. PMID- 23739750 TI - Solving chromatographic challenges in comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry using multivariate curve resolution-alternating least squares. AB - Multivariate curve resolution-alternating least squares (MCR-ALS) analysis is proposed to solve chromatographic challenges during two-dimensional gas chromatography-time-of-flight mass spectrometry (GC * GC-TOFMS) analysis of complex samples, such as crude oil extract. In view of the fact that the MCR-ALS method is based on the fulfillment of the bilinear model assumption, three-way and four-way GC * GC-TOFMS data are preferably arranged in a column-wise superaugmented data matrix in which mass-to-charge ratios (m/z) are in its columns and the elution times in the second and first chromatographic columns are in its rows. Since m/z values are common for all measured spectra in all second column modulations, unavoidable chromatographic challenges such as retention time shifts within and between GC * GC-TOFMS experiments are properly handled. In addition, baseline/background contributions can be modeled by adding extra components to the MCR-ALS model. Another outstanding aspect of MCR-ALS analysis is its extreme flexibility to consider all samples (standards, unknowns, and replicates) in a single superaugmented data matrix, allowing joint analysis. In this way, resolution, identification, and quantification results can be simultaneously obtained in a very fast and reliable way. The potential of MCR-ALS analysis is demonstrated in GC * GC-TOFMS analysis of a North Sea crude oil extract sample with relative errors in estimated concentrations of target compounds below 6.0 % and relative standard deviations lower than 7.0 %. The results obtained, along with reasonable values for the lack of fit of the MCR-ALS model and high values of the reversed match factor in mass spectra similarity searches, confirm the reliability of the proposed strategy for GC * GC-TOFMS data analysis. PMID- 23739751 TI - Preparation of monodisperse curcumin-imprinted polymer by precipitation polymerization and its application for the extraction of curcuminoids from Curcuma longa L. AB - A monodisperse molecularly imprinted polymer (MIP) for curcumin was first prepared by precipitation polymerization using methacrylamide (MAM) and 4 vinylpyridine as functional co-monomers, divinylbenzene as a crosslinker, and a mixture of acetonitrile and toluene as a porogen. The use of MAM as the co monomer resulted in the formation of a monodisperse MIP and non-imprinted polymer (NIP). MIP and NIP, respectively, were monodispersed with a narrow particle size distribution (3.3 +/- 0.09 and 3.5 +/- 0.10 MUm). In addition to shape recognition, hydrophobic and hydrogen-bonding interactions affected the retention and molecular-recognition of curcumin on the MIP. The MIP for curcumin could extract curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin) in Curcuma longa L. PMID- 23739752 TI - Photophysical properties of 5-substituted 2-thiopyrimidines. AB - The aim of the present work is to determine the influence of C5 substitution on the photophysical properties of 2-thiopyrimidines (2-TPyr). For this purpose, 2 thiouracil, 5-t-butyl-2-thiouracil and 2-thiothymine (TU, BTU and TT, respectively) have been selected as target thionucleobases for the experimental studies and, in parallel, for DFT theoretical calculations. The UV spectra displayed by TU, BTU and TT in EtOH were very similar to each other. They showed a maximum around 275 nm and a shoulder at ca. 290 nm. The three 2-TPyr exhibited a strong phosphorescence emission; from the recorded spectra, triplet excited state energies of ca. 307, 304 and 294 kJ mol(-1) were determined for TU, BTU and TT, respectively. Laser excitation at 308 nm gave rise to a broad transient absorption band from 500 nm to 700 nm, which was in principle assigned to triplet triplet absorption. This assignment was confirmed by energy transfer experiments using biphenyl (ET = 274 kJ mol(-1)) as an acceptor. The triplet lifetimes were 70 ns, 1.1 MUs and 2.3 MUs, for TU, BTU and TT, respectively. The obtained photophysical data, both in phosphorescence and transient absorption measurements, point to significantly different properties of the TT triplet excited state in spite of the structural similarities. Theoretical calculations at the B3LYP/aug-cc-pVDZ/PCM level agree well with the experimental range of excited state energies and support the pipi* nature of the lowest triplet states. PMID- 23739753 TI - Updated recommendations for diagnosis and management of the US population for hepatitis C. PMID- 23739754 TI - International health electives: strengthening graduate medical education. PMID- 23739757 TI - Osteopathic evaluation of somatic dysfunction and craniosacral strain pattern among preterm and term newborns. AB - CONTEXT: Palpatory skills are a central part of osteopathic manipulative treatment and palpatory diagnosis. The aim of osteopathic structural examination is to locate somatic dysfunction and cranial strain pattern, which are the hallmarks that form the basis for treatment decisions and strategy. In the osteopathic literature, there is a lack of studies evaluating preterm or term newborns during hospitalization. OBJECTIVE: To determine the prevalence of somatic dysfunction and cranial strain pattern in a population of preterm and term newborns who were treated in a neonatal intensive care unit (NICU). METHODS: During a period of 6 months--November 2009 through April 2010--the authors performed a retrospective review of data on consecutive preterm and term newborns who were admitted to the NICU of the Spirito Santo Public Hospital. Osteo pathic evaluation was performed once on each newborn, and somatic dysfunction and cranial strain pattern were identified. Descriptive analysis and test of association based on the chi(2) test were performed. RESULTS: One hundred fifty five preterm and term newborns met the study's eligibility criteria. The highest rate of somatic dysfunction was found in the pelvic area of 63 newborns (40.7%). The sacroiliac joints were compressed unilaterally or bilaterally in 82 newborns (52.9%); the lumbosacral junction was restricted in 61 newborns (39.4%), and intraosseous lesions of the sacral bone were diagnosed in 57 newborns (36.8%). The spine accounted for somatic dysfunction in 38 newborns (24.5%), with the middle thoracic and lower thoracic areas restricted in 29 (18.7%) and 21 (16.8%) newborns, respectively. Sphenobasilar synchondrosis compression and lateral vertical strain were diagnosed in 57 newborns (36.8%), with the sagittal and the coronal sutures found restricted in 35 (22.6%) and 30 (19.4%) newborns, respectively. The occipital bone presented the highest rate of intraosseous lesions, with the left condyle compressed in 48 newborns (31%), the right condyle in 46 newborns (29.7%), and the squama in 38 newborns (24.5%). CONCLUSION: Results showed that osteopathic findings are not secondary to gestational age and weight at birth. PMID- 23739758 TI - Osteopathic manual treatment in patients with diabetes mellitus and comorbid chronic low back pain: subgroup results from the OSTEOPATHIC Trial. AB - CONTEXT: Chronic pain is often present in patients with diabetes mellitus. OBJECTIVE: To assess the effects of osteopathic manual treatment (OMT) in patients with diabetes mellitus and comorbid chronic low back pain (LBP). DESIGN: Randomized, double-blind, sham-controlled, 2*2 factorial trial, including OMT and ultrasound therapy (UST) interventions. SETTING: University-based study in Dallas Fort Worth, Texas. PATIENTS: A subgroup of 34 patients (7%) with diabetes mellitus within 455 adult patients with nonspecific chronic LBP enrolled in the OSTEOPAThic Health outcomes In Chronic low back pain (OSTEOPATHIC) Trial. MAIN STUDY MEASURES: The Outpatient Osteopathic SOAP Note Form was used to measure somatic dysfunction at baseline. A 100-mm visual analog scale was used to measure LBP severity over 12 weeks from randomization to study exit. Paired serum concentrations of tumor-necrosis factor (TNF)-alpha obtained at baseline and study exit were available for 6 subgroup patients. RESULTS: Key osteopathic lesions were observed in 27 patients (79%) with diabetes mellitus vs 243 patients (58%) without diabetes mellitus (P=.01). The reduction in LBP severity over 12 weeks was significantly greater in 19 patients with diabetes mellitus who received OMT than in 15 patients with diabetes mellitus who received sham OMT (mean between-group difference in changes in the visual analog scale pain score, 17 mm; 95% confidence interval [CI], -32 mm to -1 mm; P=.04). This difference was clinically relevant (Cohen d=0.7). A corresponding significantly greater reduction in TNF-alpha serum concentration was noted in patients with diabetes mellitus who received OMT, compared with those who received sham OMT (mean between-group difference, -6.6 pg/mL; 95% CI, -12.4 to -0.8 pg/mL; P=.03). This reduction was also clinically relevant (Cohen d=2.7). No significant changes in LBP severity or TNF-alpha serum concentration were associated with UST during the 12-week period. CONCLUSION: Severe somatic dysfunction was present significantly more often in patients with diabetes mellitus than in patients without diabetes mellitus. Patients with diabetes mellitus who received OMT had significant reductions in LBP severity during the 12-week period. Decreased circulating levels of TNF-alpha may represent a possible mechanism for OMT effects in patients with diabetes mellitus. A larger clinical trial of patients with diabetes mellitus and comorbid chronic LBP is warranted to more definitively assess the efficacy and mechanisms of action of OMT in this population. PMID- 23739759 TI - Osteopathic Continuous Certification: it's here--are you prepared? AB - The authors explain Osteopathic Continuous Certification (OCC) as mandated by the American Osteopathic Association Board of Trustees. Implemented on January 1, 2013, OCC is the process wherein osteopathic physicians certify their training and expertise in their chosen specialty and maintain the standard of excellence begun with the initial American Osteopathic Association certification. In contrast to one-time examinations, OCC is intended to be an ongoing, lifelong process for osteopathic physicians. PMID- 23739760 TI - An international health elective in Haiti: a case for osteopathic medicine. AB - As global health education becomes increasingly important, more physicians are participating in international health electives (IHEs). Haiti is a favorable site for an IHE because of its substantial health care needs and rich culture. Although both osteopathic and allopathic physicians can provide effective health care to Haitians, osteopathic physicians may be particularly well suited to serve in Haiti because of their training in osteopathic manipulative treatment (OMT). Because OMT's laying of the hands (high touch) is similar to the touch inherent to Haiti's traditional ethnomedical practices, osteopathic physicians' use of OMT can enhance trust among Haitians and increase Haitians' willingness to work with westernized medical practitioners. In addition, an IHE in a low-resource country such as Haiti can provide osteopathic physicians with a global outlook on medicine and a range of critical communication and clinical skills. The authors advocate for the development of an IHE in Haiti for osteopathic physicians. PMID- 23739761 TI - A challenging case of hypercalcemia. AB - The authors report a case of hypercalcemia in a 79-year-old woman that led to multiple hospitalizations. The case was challenging because the hypercalcemia was ultimately found to have 2 distinct causes. The patient initially presented with an elevated parathyroid hormone (PTH) level, consistent with primary hyperparathyroidism. She underwent parathyroidectomy and her hypercalcemia resolved in the immediate postoperative period. Four days after the operation, she was found to have recurrent hypercalcemia with a suppressed PTH level, raising suspicion for hypercalcemia of malignancy. After an extensive workup, the patient was found to have lymphoma, which was causing hypercalcemia and suppressing PTH. The authors also review the literature on hypercalcemia of malignancy. PMID- 23739762 TI - Barium sulfate aspiration. PMID- 23739764 TI - Biweekly docetaxel, fluorouracil, leucovorin, oxaliplatin (TEF) as first-line treatment for advanced gastric cancer and adenocarcinoma of the gastroesophageal junction: safety and efficacy in a multicenter cohort. AB - BACKGROUND: Docetaxel-cisplatin-5-FU chemotherapy is superior to 5-FU-cisplatin in terms of response rate and survival in advanced gastric cancer (AGC), but is more toxic. Oxaliplatin is better tolerated than cisplatin, which it can effectively replace in this setting. We hypothesize that incorporating docetaxel into a simplified FOLFOX regimen should be a tolerable and effective option in first-line treatment of AGC. METHODS: Data were collected at six French centers from patients with metastatic or local AGC who received docetaxel, fluorouracil, leucovorin, or oxaliplatin (TEF) as first-line treatment. TEF was administered as follows: docetaxel (50 mg/m(2)), oxaliplatin (85 mg/m(2)), and leucovorin (40 mg/m(2)) on day 1, and 5-FU continuous infusion for 48 h (2400 mg/m(2)) every 2 weeks. RESULTS: Forty-one patients were enrolled. Performance status was grade 0 and 1 in respectively 27 and 58 % of patients; 17 patients had adenocarcinoma of the gastroesophageal junction; 37 patients had metastatic disease, 22 had a poorly differentiated or diffuse type. Objective response rate was 66 %, with a complete response in two patients (5 %). Median progression-free survival and overall survival were respectively 6.3 and 12.1 months. Tolerability was acceptable with no treatment-related deaths. The most frequent grade 3-4 toxicities were neutropenia (30 %) and neuropathy (12.5 %). Curative intent surgery after response to TEF was performed in seven patients (17 %). CONCLUSION: TEF is an effective first-line treatment with an acceptable toxicity profile for patients with AGC. It may allow curative resection in initially unresectable patients. TEF should now be evaluated in prospective randomized trials. PMID- 23739765 TI - Vitamin D and kidney stone disease. AB - PURPOSE OF REVIEW: Vitamin D is important in maintaining calcium homeostasis, but its role in kidney stone disease and its effect on stone formation are still not clear. RECENT FINDINGS: Kidney stone formers tend to experience enhanced intestinal calcium absorption, increased urinary calcium excretion, and excessive bone mineral loss. Although direct actions of active vitamin D have been implicated in all these processes, the effect of nutritional vitamin D (vitamin D2 or vitamin D3) use on calcium balance among stone formers is still not clear. In addition, the safety of nutritional vitamin D use in the stone forming population is also not established, considering the potential effect of its use on raising urinary calcium. However, most of the observational studies do not support a significant association between higher nutritional vitamin D store and increased risk of stone formation. Short-term nutritional vitamin D repletion in stone formers with vitamin D deficiency also does not appear to increase urinary calcium excretion. SUMMARY: The effect of nutritional vitamin D use in stone formers is still not clear. As vitamin D deficiency is highly prevalent among stone formers, future prospective studies are needed to establish the biological effect, as well as the safety and efficacy of nutritional vitamin D therapy in this unique patient population. PMID- 23739766 TI - An overview of heavy metal challenge in plants: from roots to shoots. AB - Heavy metals are often present naturally in soils, but many human activities (e.g. mining, agriculture, sewage processing, the metal industry and automobiles) increase their prevalence in the environment resulting in concentrations that are toxic to animals and plants. Excess heavy metals affect plant physiology by inducing stress symptoms, but many plants have adapted to avoid the damaging effects of metal toxicity, using strategies such as metal chelation, transport and compartmentalization. Understanding the molecular basis of heavy metal tolerance in plants will facilitate the development of new strategies to create metal-tolerant crops, biofortified foods and plants suitable for the phytoremediation of contaminated sites. PMID- 23739768 TI - Declining snow cover may affect spring phenological trend on the Tibetan Plateau. PMID- 23739767 TI - Integrated platform for genome-wide screening and construction of high-density genetic interaction maps in mammalian cells. AB - A major challenge of the postgenomic era is to understand how human genes function together in normal and disease states. In microorganisms, high-density genetic interaction (GI) maps are a powerful tool to elucidate gene functions and pathways. We have developed an integrated methodology based on pooled shRNA screening in mammalian cells for genome-wide identification of genes with relevant phenotypes and systematic mapping of all GIs among them. We recently demonstrated the potential of this approach in an application to pathways controlling the susceptibility of human cells to the toxin ricin. Here we present the complete quantitative framework underlying our strategy, including experimental design, derivation of quantitative phenotypes from pooled screens, robust identification of hit genes using ultra-complex shRNA libraries, parallel measurement of tens of thousands of GIs from a single double-shRNA experiment, and construction of GI maps. We describe the general applicability of our strategy. Our pooled approach enables rapid screening of the same shRNA library in different cell lines and under different conditions to determine a range of different phenotypes. We illustrate this strategy here for single- and double shRNA libraries. We compare the roles of genes for susceptibility to ricin and Shiga toxin in different human cell lines and reveal both toxin-specific and cell line-specific pathways. We also present GI maps based on growth and ricin resistance phenotypes, and we demonstrate how such a comparative GI mapping strategy enables functional dissection of physical complexes and context dependent pathways. PMID- 23739769 TI - Molecular roles of Myo1c function in lipid raft exocytosis. AB - Lipid rafts are highly dynamic membrane subdomains enriched in specific protein and lipid components that create specialized 'organizing' platforms essential for an array of important cellular functions. The role of lipid rafts in membrane trafficking involves the constant remodelling of the plasma membrane through membrane uptake and balanced exocytosis of intracellular membranes. Our lab has identified the first motor protein, myosin 1c (Myo1c) involved in driving the recycling of lipid-raft enriched membranes from the perinuclear recycling compartment to the cell surface. This newly discovered role for Myo1c in lipid raft exocytosis is crucial for cell spreading, migration and pathogen entry; key cellular processes that require cell surface expansion and plasticity. Here we present a model suggesting Myo1c's possible molecular functions in lipid raft recycling and discuss its wider implications for important cellular functions. PMID- 23739770 TI - Effects of a Rho kinase inhibitor on the sequential expression of ICAM-1, HIF 1alpha, Bcl-2 and caspase-3 in the retina of rats with oxygen-induced retinopathy. AB - The aim of the present study was to evaluate the effects of blocking the Rho kinase pathway on non-perfused regions and angiogenesis in the retina of rats using a rat model of oxygen-induced retinopathy (OIR) by observing the sequential expression of intercellular adhesion molecule-1 (ICAM-1), hypoxia-inducible factor-1 (HIF-1), B-cell lymphoma/leukemia-2 gene (Bcl-2) and caspase-3 mRNA following the administration of the Rho kinase inhibitor, fasudil (FSD). A total of 240 newborn rats were randomly divided into a normoxia control (N) group, a hyperoxia (H) group and a H + FSD (HF) group. The rats were sacrificed, and the eyes were enucleated from postnatal day (P)12 to P21. Samples were prepared for retinal flat mounts, mRNA and protein quantification. On P14, a higher number of circuitous retinal veins was observed in the H group compared with the HF group. In the HF group, the avascular area was significantly reduced compared with the H group on P18 (P<0.01). In the HF group, the mRNA expression of Bcl-2 was significantly increased on P15 compared with the N and H group (P<0.01). On P15 and P17 in the H group and on P13 in the HF group, the mRNA expression of ICAM-1 was significantly increased compared with the other groups (P<0.05). In the H and HF group, the expression of HIF-1alpha was significantly increased on P12 compared with the N group (P<0.05). On P19 and P21, HIF-1alpha expression was significantly increased to a maximum level in the HF group compared with the H and N group (P<0.01). In conclusion, these results suggest that FSD inhibits the expression of ICAM-1, assisting in the release of Bcl-2, suppressing caspase-3. In the HF group, the retinal flat mounts revealed that FSD had a vasorelaxant effect. On P18, a double-layered retinal vascular network was formed, and the number of non-perfused regions was significantly reduced. However, the late-phase peak expression of HIF-1alpha resulted in an inevitable increase in vascular endothelial growth factor expression and further accelerated neovascularization and vascular reconstruction in the immature retinal model. PMID- 23739771 TI - Breakup and then makeup: a predictive model of how cilia self-regulate hardness for posture control. AB - Functioning as sensors and propulsors, cilia are evolutionarily conserved organelles having a highly organized internal structure. How a paramecium's cilium produces off-propulsion-plane curvature during its return stroke for symmetry breaking and drag reduction is not known. We explain these cilium deformations by developing a torsional pendulum model of beat frequency dependence on viscosity and an olivo-cerebellar model of self-regulation of posture control. The phase dependence of cilia torsion is determined, and a bio physical model of hardness control with predictive features is offered. Crossbridge links between the central microtubule pair harden the cilium during the power stroke; this stroke's end is a critical phase during which ATP molecules soften the crossbridge-microtubule attachment at the cilium inflection point where torsion is at its maximum. A precipitous reduction in hardness ensues, signaling the start of ATP hydrolysis that re-hardens the cilium. The cilium attractor basin could be used as reference for perturbation sensing. PMID- 23739772 TI - Long-term follow-up of a group at ultra high risk ("prodromal") for psychosis: the PACE 400 study. AB - IMPORTANCE: The ultra high-risk (UHR) criteria were introduced to prospectively identify patients at high risk of psychotic disorder. Although the short-term outcome of UHR patients has been well researched, the long-term outcome is not known. OBJECTIVE: To assess the rate and baseline predictors of transition to psychotic disorder in UHR patients up to 15 years after study entry. DESIGN: Follow-up study of a cohort of UHR patients recruited to participate in research studies between 1993 and 2006. SETTING: The Personal Assessment and Crisis Evaluation (PACE) clinic, a specialized service for UHR patients in Melbourne, Australia. PARTICIPANTS: Four hundred sixteen UHR patients previously seen at the PACE clinic. MAIN OUTCOMES AND MEASURES: Transition to psychotic disorder, as measured using the Comprehensive Assessment of At-Risk Mental States, Brief Psychiatric Rating Scale/Comprehensive Assessment of Symptoms and History, or state public mental health records. RESULTS: During the time to follow-up (2.4 14.9 years after presentation), 114 of the 416 participants were known to have developed a psychotic disorder. The highest risk for transition was within the first 2 years of entry into the service, but individuals continued to be at risk up to 10 years after initial referral. The overall rate of transition was estimated to be 34.9% over a 10-year period (95% CI, 28.7%-40.6%). Factors associated with transition included year of entry into the clinic, duration of symptoms before clinic entry, baseline functioning, negative symptoms, and disorders of thought content. CONCLUSIONS AND RELEVANCE: The UHR patients are at long-term risk for psychotic disorder, with the highest risk in the first 2 years. Services should aim to follow up patients for at least this period, with the possibility to return for care after this time. Individuals with a long duration of symptoms and poor functioning at the time of referral may need closer monitoring. Interventions to improve functioning and detect help-seeking UHR patients earlier also may be indicated. PMID- 23739773 TI - 'DSM-V is taking away our identity': the reaction of the online community to the proposed changes in the diagnosis of Asperger's disorder. AB - This article considers the fate of Asperger's disorder in the light of proposals for the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) to collapse Asperger's disorder along with other pervasive developmental disorders into a general spectrum of autism. It is argued that a powerful lay and scientific culture has evolved around the concept of Asperger's disorder, which has found a particularly compelling voice over the last decade in the online Asperger community, with websites such as Wrong Planet recruiting tens of thousands of members. In order to assess the impact of these proposed changes on the online Asperger community, 19 threads on the topic of Diagnostic and Statistical Manual of Mental Disorders (5th ed.) are analysed according to the arguments that community members put forward in favour of, or in opposition to, the proposals. Many members embrace the notion of the spectrum and have already coined a new identity - 'spectrumite' - to adapt to the diagnostic shift. Others, however, are suspicious of the motives behind the absorption of Asperger's disorder, and potential threats to the provision of services as well as the strong 'aspie' identity that reflects the large literature and the online public sphere around Asperger's disorder. To what extent this culture poses a challenge to the authority of the Diagnostic and Statistical Manual of Mental Disorders is uncertain at present. PMID- 23739774 TI - 'Men give in to chips and beer too easily': how working-class men make sense of gender differences in health. AB - This article, based on qualitative research with working-class men, explores men's perceptions and experiences regarding gender differences in health. It demonstrates how men put forward a range of behavioural/cultural, materialist/structural and psychosocial factors, which were believed to differently impact men's health compared to women. A common theme underpinning their explanations was the ways in which men and women were located within two distinct gender categories. These characterisations were used to explain why health-damaging beliefs and behaviours were more prevalent among men and also why men were better suited for certain kinds of jobs, albeit with potential costs to their health. Men also believed that women were protected from the damaging physical and emotional impact of manual employment because of their primary role within the home and because they were less emotionally robust, which required men to shield women from the stresses they experienced. However, men's emotional withdrawal can also be viewed as another example of how men use whatever resources are available to achieve and maintain dominance over women. Finally, the article demonstrates how a gender- and class-based approach can capture the impact of men's health-related practices alongside the broader cultural and structural influences on men's health. PMID- 23739775 TI - The natural course and complications of alpha-mannosidosis--a retrospective and descriptive study. AB - Most alpha-mannosidosis patients described have been children and information on the natural course of the disorder has been based on a very limited number of observations. In order to assess the disease presentation in detail and to study disease characteristics, a study was started in 1991 and has been ongoing for over 20 years. Patients with confirmed alpha-mannosidosis were recruited through The International Society for Mannosidosis and Related Diseases (ISMRD) where families affected with alpha-mannosidosis received a questionnaire on general clinical information to be filled out by the responsible physician. The questionnaire was returned by 125 patients (64%). Of these, 45 patients were 15 years old or older at the time of evaluation. The questionnaire allowed us to assess the following features: Facial dysmorphism, columnar disease, arthritis, myopathy, hearing impairment, mental impairment, psychosis, bone disease and motor function as well as general health. This study describes the progression of alpha-mannosidosis and may be helpful in determining the clinical characteristics for assessments of prognosis. PMID- 23739776 TI - An Electroplating-Free and Minimal Noise Polyimide Microelectrode for Recording Auditory Evoked Potentials From the Epicranius. AB - In this paper, we introduce an electrode for measuring auditory evoked potentials by employing the advantages of polyimide (PI), which is a well-known substrate material for producing flexible electrodes using MEMS technology. The PI multimicroelectrode array has four fingers that include 16 electrodes in order to achieve sufficient adhesion to the curved surface of the animal skull. For high quality signal acquisition, we optimized the device to decrease crosstalk and improve contact impedance by adding ground channels and fabricating a raised electrode structure. In addition, implantation of the device was facilitated by the addition of an alignment site to ensure optimal positioning and enable signal measurement from the specific part of the cerebral cortex in charge of auditory sensing. After the implantation of the PI electrode on the skull surface, electrical signals were measured following stimulation at different stimulus frequencies (5 or 10 kHz). Unlike other techniques, administration of this PI electrode is less invasive, reducing patient recovery time dramatically in comparison with other electrocorticographic operations. Furthermore, as the exterior of the brain would not be exposed at any point, the chance of infection is minimized. PMID- 23739777 TI - Point process modeling of interbreath interval: a new approach for the assessment of instability of breathing in neonates. AB - Interbreath interval (IBI), the time interval between breaths, is an important measure used to analyze irregular breathing patterns in neonates. The discrete bursts of neural activity generate the IBI time series, which exhibits stochastic as well as deterministic dynamics. To quantify the irregularity of breathing, we propose a point process model of IBI using a comprehensive stochastic dynamic modeling framework. The IBIs of immature breathing patterns exhibit a long tail distribution and within a point process model, we have considered the lognormal distribution to represent the stochastic IBI characteristics. An autoregressive (AR) function is embedded within the model to capture the short-term IBI dynamics including abrupt IBI prolongations related to sporadic and periodic apneas that are common in neonates. We tested the utility of our paradigm for depicting the respiratory dynamics in neonatal rats and in preterm infants. Kolmogorov-Smirnov (KS) and independence tests reveal that the model accurately tracks the dynamic characteristics of the signals. In preterm infants, our model-derived indices of IBI instability strongly correlate with clinically derived indices of maturation. Our results validate a new class of algorithms, based on the point process theory, for defining instantaneous measures of breathing irregularity in neonates. PMID- 23739778 TI - Epidermal impedance sensing sheets for precision hydration assessment and spatial mapping. AB - This paper presents a class of hydration monitor that uses ultrathin, stretchable sheets with arrays of embedded impedance sensors for precise measurement and spatially multiplexed mapping. The devices contain miniaturized capacitive electrodes arranged in a matrix format, capable of integration with skin in a conformal, intimate manner due to the overall skin-like physical properties. These "epidermal" systems noninvasively quantify regional variations in skin hydration, at uniform or variable skin depths. Experimental results demonstrate that the devices possess excellent uniformity, with favorable precision and accuracy. Theoretical models capture the underlying physics of the measurement and enable quantitative interpretation of the experimental results. These devices are appealing for applications ranging from skin care and dermatology, to cosmetology and health/wellness monitoring, with the additional potential for combined use with other classes of sensors for comprehensive, quantitative physiological assessment via the skin. PMID- 23739779 TI - A two-level predictive event-related potential-based brain-computer interface. AB - Increasing the freedom of communication using conventional row/column (RC) P300 paradigm by naive way (increasing matrix size) may deteriorate inherent distraction effect and interaction speed. In this paper, we propose a two-level predictive (TLP) paradigm by integrating a 3*3 two-level matrix paradigm with a statistical language model. The TLP paradigm is evaluated using offline and online data from ten healthy subjects. Significantly larger event-related potentials (ERPs) are evoked by the TLP paradigm compared with the classical 6*6 RC. During an online task (correctly spell an English sentence with 57 characters), accuracy and information transfer rate for the TLP are increased by 14.45% and 29.29%, respectively, when compared with the 6*6 RC. Time to complete the task is also decreased by 24.61% using TLP. In sharp contrast, an 8*8 RC (naive extension of the 6*6 RC) consumed 19.18% more time than the classical 6*6 RC. Furthermore, the statistical language model is also exploited to improve classification accuracy in a Bayesian approach. The proposed Bayesian fusion method is tested offline on data from the online spelling tasks. The results show its potential improvement on single-trial ERP classification. PMID- 23739780 TI - SSVEP-based brain-computer interfaces using FSK-modulated visual stimuli. AB - A brain-computer interface (BCI) based on steady-state visual-evoked potentials (SSVEP) has two difficulties: limitation of the number of commands and uneven probabilities of command execution. To address these problems, the present paper proposes a paradigm of BCI using frequency-modulated visual stimuli. The commands are translated into code words consisting of binary digits, to which visual stimuli with distinct frequencies are assigned. Frequencies of SSVEP are recognized to detect bits, and a command to be executed is determined from the sequence of detected bits. Experimental results show that the proposed paradigm achieves a reliable BCI with higher accuracies and balanced command executing probabilities. PMID- 23739781 TI - Simulation and Feasibility Study of Flow Sensor on Flexible Polymer for Healthcare Application. AB - Development of microfabrication technology, along with an ever-increasing demand for reliable, low-cost clinical healthcare has led to the realization of various BioMEMS devices. Present study aims at developing a flexible flow sensor on polymer substrate to monitor real-time blood flow and determine plague formation satisfying sensitivity, biocompatibility, and reliability requirements. Transient simulation of temperature and velocity profile of the thermal-anemometer-based sensor wrapped around the catheter has been studied. Initial fabrication of the sensor over polydimethylsiloxane (PDMS) polymer along with thermal coefficient of resistance (TCR) measurement and flow sensing over straight heater has also been performed. The simulation and fabrication works show promising results toward successful development of a flow sensor for effective healthcare delivery. PMID- 23739782 TI - Radiodensitometric and DXA analyses for the measurement of bone mineral density after systemic alendronate therapy. AB - Precise techniques for the measurement of maxillary bone mineral density (BMD) are useful for the early diagnosis of systemic diseases. The aim of this study was to compare in vivo the efficacy of dual-energy x-ray absorptiometry (DXA) and radiographic densitometry for the measurement of BMD after systemic administration of sodium alendronate. Wistar rats were randomly allocated to a control group (n = 5), which received distilled water, and a sodium alendronate group (n = 8), which received two doses of chemically pure sodium alendronate (1 mg/kg) per week. After 8 weeks, the animals were euthanized, the tibias were removed, and the BMD of the proximal tibial metaphysis was analyzed radiographically and by DXA. The data were subjected to statistical analysis by the Kruskal-Wallis test at a significance level of 5%. Both of the techniques revealed that the alendronate-treated group had a significantly higher BMD (p < 0.05) than the control group after 8 weeks of treatment. Comparing the groups with and without alendronate therapy revealed increases of 14.9% and 29.6% in BMD, as detected radiographically and by DXA, respectively. In conclusion, both of the methods were able to detect an increase in BMD of the proximal tibial metaphysis after alendronate therapy. PMID- 23739783 TI - Reflection on the teaching of cariology in Brazil. PMID- 23739784 TI - Performance of digital radiography with enhancement filters for the diagnosis of proximal caries. AB - Enhancement filters are potentially supposed to improve the diagnostic performance of digital images. Thus, the aim of this study was to compare the performance of digital radiography with and without enhancement filters for the detection of induced proximal caries lesions. The total sample consisted of 120 sound human teeth (40 premolars, 80 molars). Enamel subsurface demineralization was induced in one of the proximal surfaces of 60 teeth. Standardized radiographs of all teeth were acquired after the demineralization phase using the Digora Optime(r) system. Four radiologists examined the digital radiographs and applied the following filters provided by the Digora(r) for Windows 2.6 package: Negative, Sharpen and both (Negative plus Sharpen). Validation of radiographic diagnosis was carried out by Knoop cross-sectional micro-hardness profiling on the proximal surfaces. Intraobserver agreement was estimated using Kappa statistics (k). Sensitivity, specificity and over-all accuracy were compared using ANOVA/Tukey test (alpha = 5%). Intraobserver agreement ranged from good to very good/optimal (k: 0.65-0.83). Although not statistically significant, the highest sensitivity (0.68 +/- 0.22) and accuracy (0.76 +/- 0.16) values were observed using the Sharpen filter as opposed to the Negative filter, which presented the lowest performance indices (0.57 +/- 0.13 and 0.70 +/- 0.10, respectively). Specificity ranged from 0.84 to 0.85, considering all imaging modalities (p > 0.05). Insofar as the Sharpen filter had the highest performance indices, it may be considered a useful adjunct for detecting subtle proximal caries lesions. PMID- 23739785 TI - Efficacy of 1.23% APF gel applications on incipient carious lesions: a double blind randomized clinical trial. AB - The aim of this double-blind randomized clinical trial was to evaluate the efficacy of 1.23% APF gel application on the arrest of active incipient carious lesions in children. Sixty 7- to 12-year-old children, with active incipient lesions were included in the study. Children were divided randomly into 2 groups: 1.23% APF gel and placebo gel applications. Each group received 8 weekly applications of treatment. The lesions were re-evaluated at the 4th and 8th appointments. Poisson regression analysis was used to estimate relative risks of the presence of active white spot lesions. Groups showed similar results (PR = 1.67; CI 95% 0.69-3.98). The persistence of at least 1 active lesion was associated with a higher number of lesions in the baseline (PR = 2.67; CI 95% 1.19-6.03), but not with sugar intake (PR = 1.06; CI 95% 0.56-2.86) and previous exposure to fluoride dentifrice (PR = 1.26; CI 95% 0.49-2.29). The trial demonstrates the equivalence of the treatments. The use of the APF gel showed no additional benefits in this sample of children exposed to fluoridated water and dentifrice. The professional dental plaque removal in both groups may also account for the resulting equivalence of the treatments. PMID- 23739786 TI - Relationship among oral habits, orofacial function and oral health-related quality of life in children. AB - The objective was to evaluate the relationship among oral habits, oral function and oral health-related quality of life (OHRQoL) in children. Three hundred and twenty-eight subjects (8-14 years old) were assessed for orofacial function using the Brazilian version of the Nordic Orofacial Test-Screening (NOT-S). OHRQoL was assessed using the Child Perceptions Questionnaires (Brazilian versions) for the 8-10 (CPQ(8-10)) and 11-14 (CPQ(11-14)) year age groups. The subjects were distributed into a Habit group and a Habit-free group according to domain III (Habits) of the NOT-S. Oral habits were present in 71.3% of the sample (p = .0001), with a higher prevalence in females (62.8%, p = .001). The NOT-S, CPQ(8 10) and CPQ(11-14) scores were higher in the Habit group (P = .0001, P = .009 and p = .001, respectively). Domain I (Sensory Function) was significantly more affected in Habit group subjects (p = .001). The NOT-S scores were positively correlated with the CPQ(8-10) and CPQ(11-14) scores only in the Habit group (r = .32, p = .0003 and r = .30, p = .001, respectively). These results indicate that oral habits can impact OHRQoL. Moreover, orofacial dysfunctions were associated with worse OHRQoL in subjects with oral habits. PMID- 23739787 TI - Marginal microleakage of class V resin-based composite restorations bonded with six one-step self-etch systems. AB - This study compared the microleakage of class V restorations bonded with various one-step self-etching adhesives. Seventy class V resin-based composite restorations were prepared on the buccal and lingual surfaces of 35 premolars, by using: Clearfil S3 Bond, G-Bond, iBond, One Coat 7.0, OptiBond All-In-One, or Xeno IV. The Adper Single Bond etch-and-rinse two-step adhesive was employed as a control. Specimens were thermocycled for 500 cycles in separate water baths at 5 degrees C and 55 degrees C and loaded under 40 to 70 N for 50,000 cycles. Marginal microleakage was measured based on the penetration of a tracer agent. Although the control showed no microleakage at the enamel margins, there were no differences between groups (p = 0.06). None of the adhesives avoided microleakage at the dentin margins, and they displayed similar performances (p = 0.76). When both margins were compared, iBond(r) presented higher microleakage (p < 0.05) at the enamel margins (median, 1.00; Q3-Q1, 1.25-0.00) compared to the dentin margins (median, 0.00; Q3-Q1, 0.25-0.00). The study adhesives showed similar abilities to seal the margins of class V restorations, except for iBond(r), which presented lower performance at the enamel margin. PMID- 23739789 TI - Silanization effect on the photoluminescence characteristics of crystalline and amorphous silicon nanoparticles. AB - Silicon nanoparticles synthesized by two different methods were surface modified with 3-mercaptopropyltrimethoxysilane. The particles of ~2 nm size exhibit photoluminescence (PL) in the UV-Vis range of the spectrum. The most intense PL band at 430 nm with an emission lifetime of 1-2 ns is attributed to the presence of the surface defects Si-O-Si, generated after anchoring the organic molecule onto the interface. The excitation-emission matrix of this band is essentially independent of the technique of synthesis, crystalline structure, and size of the silicon nanoparticles. PMID- 23739788 TI - Effect of a cordless retraction paste on titanium surface: a topographic, chemical and biocompatibility evaluation. AB - Good exposure of the preparation margins and haemostasis in the sulcular gingiva are necessary for accurate impressions to produce precise restorations. The use of cordless retraction paste material in implant dentistry is a relatively novel application. However, few studies have been conducted on the use of retraction pastes and their possible interaction with implant surfaces. Recent literature has described remnants on titanium implant surfaces and expressed the need for an assessment of the biocompatibility of the exposed surface (Chang et al.). This in vitro study evaluated the effect of a cordless gingival retraction paste on sterile titanium disks. Surface chemistry was determined using energy-dispersive X-ray spectroscopy (EDS), and further investigated using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). After exposure to retraction paste, surface chemistry alterations were identified. A fibroblast cell line (L929) was exposed to the disks and the live/dead viability/cytotoxicity assay was used to determine any effects on the proliferation and health of cells. The disks exposed to the retraction paste showed fewer dead cells compared to the unexposed disks. This was statistically significant. PMID- 23739790 TI - Evidence of decreased muscle protein turnover in gilts selected for low residual feed intake. AB - The objective of this study was to evaluate the contribution of muscle protein turnover (synthesis and degradation) to the biological basis for genetic differences in finisher pigs selected for residual feed intake (RFI). Residual feed intake is defined as the difference between expected feed intake (based on the achieved rate of BW gain and backfat depth of individual pigs) and the observed feed intake of the individual pig. We hypothesized that protein turnover would be reduced in pigs selected for low RFI. Twelve gilts from a line selected for 7 generations for low RFI and 12 from a contemporary line selected for 2 generations for high RFI were paired by age and BW and fed a standard corn soybean diet for 6 wk. Pigs were euthanized, muscle and liver samples were collected, and insulin signaling, protein synthesis, and protein degradation proteins were analyzed for expression and activities. Muscle from low RFI pigs tended to have less MU- and m-calpain activities (P = 0.10 and 0.09, respectively) and had significantly greater calpastatin activity and a decreased MU-calpain:calpastatin activity ratio (P < 0.05). Muscle from low RFI pigs had less 20S proteasome activity compared with their high RFI counterparts (P < 0.05). No differences in insulin signaling intermediates and translation initiation signaling proteins [mammalian target of rapamycin (mTOR) pathway] were observed (P > 0.05). Postmortem proteolysis was determined in the LM from the eighth generation of the low RFI pigs versus their high RFI counterparts (n = 9 per line). Autolysis of MU-calpain was decreased in the low RFI pigs and less troponin-T degradation product was observed at 3 d postmortem (P < 0.05), indicating slowed postmortem proteolysis during aging in the low RFI pigs. These data provide significant evidence that less protein degradation occurs in pigs selected for reduced RFI, and this may account for a significant portion of the increased efficiency observed in these animals. PMID- 23739791 TI - Effects of fescue toxicosis on bull growth, semen characteristics, and breeding soundness evaluation. AB - Tall fescue possesses heat, drought, and pest resistance conferred to the plant by its mutualistic relationship with the ergot alkaloid producing fungal endophyte, Neotyphodium coenophialum. The objective of this study was to evaluate the impact of ergot alkaloid consumption on growth, scrotal circumference (SC), and semen quality. The SC measurement and percentage of motile and normal sperm were used to determine if a bull passed the breeding soundness exam (BSE) requirements. Bulls (n = 14) between 13 and 16 mo of age exhibiting >=32 cm SC and having passed a BSE were assigned to 1 of 2 dietary treatments accounting for BCS and BW. Bulls were fed the treatment diet containing toxic tall fescue seed (E+; 0.8 MUg of ergovaline and ergovalanine/g DM) or the control diet containing endophyte-free nontoxic tall fescue seed (E-) for 126 d. Blood samples were collected and BSE and BCS accessed at the start of the test (d 0) and every 21 d to the end of test (d 126). Weights were obtained on d 0 and d 126. Serum prolactin (PRL) concentrations were affected by treatment * day interactions (P = 0.04) verifying the effectiveness of the E+ diet. Bulls consuming the E+ diet exhibited declining PRL concentrations from 250 +/- 52.1 ng/mL on d 0 to 30.6 +/- 46.9 ng/mL by d 126 whereas bulls receiving the E- ration maintained serum PRL concentrations greater than or equal to 226.7 +/- 50.4 ng/mL across the 126-d study. Body condition score (P = 0.4) and BW (P = 0.4) were not different between treatments. No difference due to treatment was observed for the percentage of bulls passing a standard BSE exam (P = 0.6) and no treatment effect was observed for any semen characteristic measured by computer-assisted semen analysis (CASA; P >= 0.2). The SC was negatively affected by treatment * day interaction (P = 0.04) with E- bulls exhibiting a larger SC at d 126 compared with E+ bulls of 36.7 +/- 0.8 versus 34.3 +/- 0.8 cm, respectively. Within treatment, E+ bulls exhibited a decrease in SC (P = 0.0001) with a d 0 SC of 37.3 +/- 0.8 cm and dropping to 34.3 +/- 0.8 by d 126. Theoretically, reduced SC would negatively impact semen quality, but this was not observed. However, CASA and BSE evaluation data are consistent with recent reports indicating that bulls grazing E+ tall fescue exhibited only subtle, if any, differences on semen characteristics. PMID- 23739792 TI - The effect of different feed delivery methods on time to consume feed and the resulting changes in postprandial metabolite concentrations in horses. AB - Management techniques that reduce the insulin response to feeding in horses have application in preventing insulin resistance (IR) and potential associations (e.g., laminitis). Eight mature idle horses of BCS between 5 and 6.5 and with no previous indication of IR were fed a meal of concentrate under 4 feed delivery treatments in a repeated Latin Square design. Treatments were all based on a bucket of equal dimensions. The treatments included a control (CON) and 3 treatments hypothesized to increase time to consume feed (TCF): mobile obstacles above the feed (BALL), stationary obstacles below the feed (WAFF), and feed with water added (WTR). Jugular venous blood samples were taken at feed delivery, every 10 min for the first hour, and then every 30 min until 300 min after feed delivery. The TCF was different across treatment and was greater (P < 0.05) for BALL and WAFF when compared with CON and WTR. Glucose and insulin concentrations increased after feeding (P < 0.05) and tended to differ among treatments (P < 0.10). Peak insulin and glucose concentrations were affected by treatment as were the time to peak insulin and the area under the curve of insulin (P < 0.05). Therefore, feed delivery methods that include obstacles effectively increase TCF and attenuate postprandial glucose and insulin concentrations. A second experiment was designed to determine if the TCF changes associated with BALL and WAFF in Exp. 1 remain effective over a 4-d period. Four horses with no recent or regular history of consuming concentrates were fed concentrate meals for 4 consecutive d using the same treatments described in Exp. 1 and a Latin square design. Horses were subject to a 4-d adaptation period and were randomly assigned to 4-d treatment periods using the 4 previously described treatments. During adaptation, TCF decreased over time (P = 0.02). After adaptation, WAFF had greater TCF when compared with CON and WTR (P < 0.05) whereas WTR had the lowest TCF overall. Using obstacles to increase TCF on a daily basis may be an effective method to reduce postprandial glucose and insulin concentrations, thereby decreasing the risk of IR development in horses. PMID- 23739793 TI - Locomotor activity and body temperature in selected mouse lines differing greatly in feed intake. AB - Locomotor activity, body temperature, feed intake, and BW were measured on 382 mature male mice sampled from lines previously selected (25 generations) for either high (MH) or low (ML) heat loss and an unselected control (MC). Animals were from all 3 independent replicates of the 3 lines and across 4 generations (68 through 71). Locomotor activity and body temperatures were obtained using implanted transmitters with data collection over 4 d following a 3-d postsurgery recovery period. Data were collected every minute and then averaged into 30-min periods, thus providing 192 data points for each mouse. Least-squares means for feed intake adjusted for BW (Feed/BW, feed.BW(-1).d(-1), g/g) were 0.1586, 0.1234, and 0.1125 (+/-0.0022) for MH, MC, and ML, respectively, with line being a highly significant source of variation (P < 0.0003). Line effects for locomotor activity counts, transformed to the 0.25 power for analysis, were significantly different, with MH mice being 2.1 times more active than ML mice (P < 0.003); MC mice were intermediate. Differences in body temperature were significant for both line (P < 0.03) and day effects (P < 0.001), with a 0.32 degrees C difference between the MH and ML lines. Fourier series analysis used the combined significant periodicities of 24, 18, 12, 9, 6, and 3 h to describe circadian cycles for activity and body temperature. All 3 lines expressed daily peaks in body temperature and locomotor activity ~3 h into darkness and ~2 h after lights were turned on. There was a stronger relationship between locomotor activity and Feed/BW (P < 0.0001) than between body temperature and Feed/BW (P < 0.01); differences between lines in locomotor activity and body temperature explained 17% and 3%, respectively, of differences between lines in Feed/BW. Thus, line differences in locomotor activity contribute to line differences in maintenance, but approximately 80% of the differences between the MH and ML selection lines in Feed/BW remains independent of differences in locomotor activity. PMID- 23739794 TI - Prostate histopathology: learning tissue component histograms for cancer detection and classification. AB - Radical prostatectomy is performed on approximately 40% of men with organ confined prostate cancer. Pathologic information obtained from the prostatectomy specimen provides important prognostic information and guides recommendations for adjuvant treatment. The current pathology protocol in most centers involves primarily qualitative assessment. In this paper, we describe and evaluate our system for automatic prostate cancer detection and grading on hematoxylin & eosin stained tissue images. Our approach is intended to address the dual challenges of large data size and the need for high-level tissue information about the locations and grades of tumors. Our system uses two stages of AdaBoost-based classification. The first provides high-level tissue component labeling of a superpixel image partitioning. The second uses the tissue component labeling to provide a classification of cancer versus noncancer, and low-grade versus high grade cancer. We evaluated our system using 991 sub-images extracted from digital pathology images of 50 whole-mount tissue sections from 15 prostatectomy patients. We measured accuracies of 90% and 85% for the cancer versus noncancer and high-grade versus low-grade classification tasks, respectively. This system represents a first step toward automated cancer quantification on prostate digital histopathology imaging, which could pave the way for more accurately informed postprostatectomy patient care. PMID- 23739796 TI - Preoperative ambulatory measurement of asymmetric leg loading during sit-to-stand in hip arthroplasty patients. AB - Total hip arthroplasty (TGA) is a successful surgical procedure to treat patients with hip osteoarthritis. Clinicians use different questionnaires to evaluate these patients. Gait velocity and these questionnaires; usually show significant improvement after TGA . This clinical evaluation does, however, not provide objective, quantifiable information about the movement patterns underlying the functional capacity, which is clinically important and can currently only be obtained in a gait laboratory. There is a need to improve patient instructions and to quantify the rehabilitation process. The sit-to-stand (STS) movement is an objective performance-based task, whose assessment is related with the evaluation of functional recovery. Twenty two patients with hip osteoarthritis participated in this study. For each patient, validated questionnaires were administered and gait velocity was measured. Time, ground reaction forces, and lower limb asymmetry parameters were calculated using the instrumented force shoes (IFS) during STS movement with and without armrest. Significant inter-limb asymmetry was observed. No correlation was found between any parameter and gait velocity and questionnaires outcomes. Significant differences in time and force parameters between with/without armrest were found. Concluding, inter-limb asymmetry can be evaluated with the IFS supplying important additional information not represented by gait velocity and questionnaires usually used. PMID- 23739797 TI - Evaluating blunt pancreatic trauma at whole body CT: current practices and future directions. AB - Blunt pancreatic trauma almost always occurs in the setting of multiple severe injuries, and is usually diagnosed within the context of whole-body trauma CT. Associated injuries may flag the pancreas for greater scrutiny. Main duct laceration is the primary determinant of the need for surgical intervention. Characterization is improved with advanced post-processing techniques. We present useful diagnostic pearls, describe key pitfalls, and review advancements in the evaluation of pancreatic trauma at whole-body MDCT. PMID- 23739798 TI - Musculoskeletal: what is different in children? Fell off tricycle and does not want to move the right arm. PMID- 23739795 TI - Deformable medical image registration: a survey. AB - Deformable image registration is a fundamental task in medical image processing. Among its most important applications, one may cite: 1) multi-modality fusion, where information acquired by different imaging devices or protocols is fused to facilitate diagnosis and treatment planning; 2) longitudinal studies, where temporal structural or anatomical changes are investigated; and 3) population modeling and statistical atlases used to study normal anatomical variability. In this paper, we attempt to give an overview of deformable registration methods, putting emphasis on the most recent advances in the domain. Additional emphasis has been given to techniques applied to medical images. In order to study image registration methods in depth, their main components are identified and studied independently. The most recent techniques are presented in a systematic fashion. The contribution of this paper is to provide an extensive account of registration techniques in a systematic manner. PMID- 23739799 TI - Role of noncontrast head CT in the assessment of vascular abnormalities in the emergency room. AB - Noncontrast CT of the head is a widely used noninvasive investigation for a variety of acute and chronic neurological conditions. Since CT head without contrast is usually the first and often the only investigation in the emergency room for many neurological symptoms, it is imperative to detect subtle vascular changes, which in many patients can be life-saving. The vascular abnormalities may present with increased density and/or size of the vessels, filling defects, and be associated with parenchymal and bony changes. In this article, we present examples of several vascular pathologies which can be identified on the noncontrast CT of the head, and learn imaging and interpretation techniques to help recognize what often are nebulous changes. While some of the findings are diagnostic by themselves and others subtle, any suspicious abnormality should be followed with dedicated vascular imaging such as CT/MR angiogram, venogram, or catheter angiogram for confirmation and better characterization. PMID- 23739800 TI - Characterization of Edenia gomezpompae isolated from a patient with keratitis. AB - Edenia gomezpompae, isolated from a patient suffering from keratitis, who was an agricultural worker with a 4-year history of diabetes mellitus, is described. Fungal hyphae were detected in corneal scrapings after microscopic examination and repeated culture. Isolates were identified by morphology and by sequencing the internal transcribed spacer region of ribosomal DNA. Chlamydospore characteristics of E. gomezpompae are described for the first time. The in vitro antifungal susceptibilities of the isolate were tested using five antifungal agents. With the exception of fluconazole, the other drugs (natamycin, amphotericin B, itraconazole, and voriconazole) assayed were highly effective against this fungus. The keratitis was cured after debridement of the corneal ulcer and treatment with 5 % natamycin. After 3 months, when the patient was reexamined, the corneal ulcer showed signs of healing, with no recurrence. To our knowledge, this is the first reported case of keratitis caused by E. gomezpompae, as well as being the first known case of disease in humans caused by this species. PMID- 23739803 TI - [Pharmacology in the twentieth century: the science of drugs through the analysis of Goodman and Gilman's textbook]. AB - This article analyzes the presentation of pharmacology as a science in the textbook by Louis Goodman and Alfred Gilman, updated and reprinted many times between 1941 and 2006. In the first editions, pharmacology was characterized as the science of drugs and related to other areas of knowledge; the history of drug development, the role of this science in its social context and its relationship with industry were stressed. In the following editions, these aspects were minimized, almost disappearing in the 11th (2006). The treatment of historical aspects may contribute to understanding the development of pharmacology, as well as the material on relationships with industry and society is important when reflecting on the criteria for using drugs. PMID- 23739804 TI - [Teaching science: realism, anti-realism and the construction of the concept of oxygen]. AB - Research on science education has indicated the importance of discussing the nature of science. One way to encourage a more realistic view of the nature of science would be for teachers to adopt a philosophical attitude with respect to unobservable concepts. Concepts already abandoned by scientific theory - such as phlogiston - are normally described as having been discarded because they did not represent empirical knowledge. However, at the time the concept of phlogiston was used, it was part of a theoretical framework that explained and justified it. This article defends the idea that the adoption of philosophical approaches to scientific concepts needs to be supplemented by knowledge of the history of the concept. PMID- 23739805 TI - [Science fiction and the Brave New World: predictions fulfilled in our century and bioethical considerations]. AB - The speed with which science generates results in modern society requires reflection on the limits of scientific progress. This is the foundation of Brave New World, a book published by Aldous Huxley in 1932 that portrays a future technological society along the lines of Fordism. This article establishes a relationship between our current technocratic society and that described by Huxley, discussing the viability of the technical and biological aspects of the manipulations narrated in the book in light of current knowledge. Some bioethical considerations with respect to the procedures 'invented' by the author - and which are already or could be developed in modern society - will also be addressed. PMID- 23739801 TI - Immunostimulatory properties and antitumor activities of glucans (Review). AB - New foods and natural biological modulators have recently become of scientific interest in the investigation of the value of traditional medical therapeutics. Glucans have an important part in this renewed interest. These fungal wall components are claimed to be useful for various medical purposes and they are obtained from medicinal mushrooms commonly used in traditional Oriental medicine. The immunotherapeutic properties of fungi extracts have been reported, including the enhancement of anticancer immunity responses. These properties are principally related to the stimulation of cells of the innate immune system. The discovery of specific receptors for glucans on dendritic cells (dectin-1), as well as interactions with other receptors, mainly expressed by innate immune cells (e.g., Toll-like receptors, complement receptor-3), have raised new attention toward these products as suitable therapeutic agents. We briefly review the characteristics of the glucans from mycelial walls as modulators of the immunity and their possible use as antitumor treatments. PMID- 23739806 TI - [A nosology for supernatural phenomena and the construction of the 'possessed' brain in the nineteenth century]. AB - At the end of the twentieth century, supernatural phenomena such as so called trances and possession by spirits received a scientific classification, which includes the numerous diagnoses of the dominant psychiatry. At the end of the nineteenth century we can observe a process of scientific categorization of phenomena considered to have originated in superstition or popular imagination. In this work we show how trances and spiritual possession were studied by Franz Anton Mesmer and his followers when developing the concept of magnetism; by James Braid during the creation of his theory of hypnosis; and by Jean Martin Charcot, which marked the entry of hysteria into nosological classification. Despite the differences between these schools, we identify the use of the brain and cerebral metaphors as the foundation of theories of the mind. PMID- 23739807 TI - Transition metals in plant photosynthesis. AB - Transition metals are involved in essential biological processes in plants since they are cofactors of metalloproteins and also act as regulator elements. Particularly, plant chloroplasts are organelles with high transition metal ion demand because metalloproteins are involved in the photosynthetic electron transport chain. The transition metal requirement of photosynthetic organisms greatly exceeds that of non-photosynthetic organisms, and either metal deficiency or metal excess strongly impacts photosynthetic functions. In chloroplasts, the transition metal ion requirement needs a homeostasis network that strictly regulates metal uptake, chelation, trafficking and storage since under some conditions metals cause toxicity. This review gives an overview of the current understanding of main features concerning the role of copper (Cu), iron (Fe), manganese (Mn) and zinc (Zn) in plant photosynthesis as well as the mechanisms involved in their homeostasis within chloroplasts. The metalloproteins functioning in photosynthetic proteins of plants as well as those proteins participating in the metal transport and metal binding assembly are reviewed. Furthermore, the role of nickel (Ni) in artificial photosynthesis will be discussed. PMID- 23739808 TI - Effect of lipopolysaccharide (LPS) from Ochrobactrum intermedium on sheep experimentally infected with Fasciola hepatica. AB - The effects of the lipopolysaccharide (LPS) from Ochrobactrum intermedium was evaluated in sheep experimentally infected with Fasciola hepatica. Animals were divided into four groups: two treated with the LPS (T1/T2) and two controls (C1/C2). T1/C1 were slaughtered at 30 days postinfection (dpi) and T2/C2 at 85 dpi. Body weight and body condition were found higher in T1 and T2 than in controls, although differences were not significant. Treated sheep showed lower cumulative fecal egg count than controls (p < 0.01). Levels of red blood cells (RBC), white blood cells, hemoglobin, and hematocrit (HCT) were higher in T1 and T2. Significant differences (p < 0.05) in RBC and HCT were found between groups at 84 dpi. More severe macrocytic and hypochromic anemia was observed in C1 and C2 than in treated groups. Total protein and albumin values were higher in T1 and T2 (p < 0.01) until 29 dpi. At the end of the trial, no significant differences were observed in hepatic enzymes, although gamma-glutamyl transferase and aspartate aminotransferase values were higher in C2, and alanine aminotransferase was higher in T2. At necropsy, the mean weight of liver, fibrosis in portal triads, and ganglion size were similar in all groups. The number and size of flukes was greater in C2 than in T2 (p < 0.05). The histological examinations revealed a higher degree of parenchymatous fibrosis in T2 compared to C2 (p < 0.05). The administration of LPS from O. intermedium increased the nonspecific resistance against F. hepatica in experimentally infected sheep. PMID- 23739809 TI - Influence of site, season, silvering stage, and length on the parasites of the European eel Anguilla anguilla in two Mediterranean coastal lagoons of the island of Corsica, France using indicator species method. AB - The parasites of 425 European eels, Anguilla anguilla, were studied between 2009 and 2012 in two Mediterranean coastal lagoons of the island of Corsica, France. An indicator value (IndVal) method was used for analysis, which combines measures of fidelity and specificity. Because of its resilience to detect changes in abundance, IndVal is an effective ecological bioindicator. The IndVal method demonstrated that site, season, silvering stage, and length could influence the occurrence of parasite species in European eel. A randomization test identified ten parasite species as having a significant indicator value for site (lagoons differed principally in salinity: oligohaline to polyhaline for the Biguglia lagoon and polyhaline to euhaline for the Urbino lagoon; the digeneans Bucephalus anguillae and Lecithochirium musculus, the cestodes Bothriocephalus claviceps, Proteocephalus macrocephalus, and larvae of Myzophyllobothrium sp., the nematodes Anguillicoloides crassus, and encysted larvae of Contracaecum sp., the acanthocephalan Acanthocephaloides incrassatus, the monogenean Pseudodactyogyrus anguillae, and the copepod Ergasilus gibbus); one parasite species for the spring season (the acanthocephalan A. incrassatus); six parasite species for silvering stage (yellow, pre-silver, silver; the trematodes B. anguillae and Deropristis inflata, encysted larvae of the nematode Contracaecum sp., the acanthocephalan A. incrassatus, the monogenean P. anguillae, and the copepod E. gibbus); and three parasite species for some of the five length classes (the cestode P. macrocephalus, encysted larvae of the nematode Contracaecum sp., and the monogenean P. anguillae). Data for species composition and infection levels should help to improve the management of parasitism in the populations of European eels. PMID- 23739810 TI - Revolutionizing volunteer interpreter services: an evaluation of an innovative medical interpreter education program. AB - BACKGROUND: In our ever-increasingly multicultural, multilingual society, medical interpreters serve an important role in the provision of care. Though it is known that using untrained interpreters leads to decreased quality of care for limited English proficiency patients, because of a short supply of professionals and a lack of formalized, feasible education programs for volunteers, community health centers and internal medicine practices continue to rely on untrained interpreters. OBJECTIVE: To develop and formally evaluate a novel medical interpreter education program that encompasses major tenets of interpretation, tailored to the needs of volunteer medical interpreters. DESIGN: One-armed, quasi experimental retro-pre-post study using survey ratings and feedback correlated by assessment scores to determine educational intervention effects. PARTICIPANTS: Thirty-eight students; 24 Spanish, nine Mandarin, and five Vietnamese. The majority had prior interpreting experience but no formal medical interpreter training. OUTCOME MEASURES: Students completed retrospective pre-test and post test surveys measuring confidence in and perceived knowledge of key skills of interpretation. Primary outcome measures were a 10-point Likert scale for survey questions of knowledge, skills, and confidence, written and oral assessments of interpreter skills, and qualitative evidence of newfound knowledge in written reflections. RESULTS: Analyses showed a statistically significant (P <0.001) change of about two points in mean self-ratings on knowledge, skills, and confidence, with large effect sizes (d > 0.8). The second half of the program was also quantitatively and qualitatively shown to be a vital learning experience, resulting in 18 % more students passing the oral assessments; a 19 % increase in mean scores for written assessments; and a newfound understanding of interpreter roles and ways to navigate them. CONCLUSIONS: This innovative program was successful in increasing volunteer interpreters' skills and knowledge of interpretation, as well as confidence in own abilities. Additionally, the program effectively taught how to navigate the roles of the interpreter to maintain clear communication. PMID- 23739811 TI - Capsule commentary on Katz et al., Implementing smoking cessation guidelines for hospitalized veterans: effects on nurse attitudes and performance. PMID- 23739812 TI - Capsule commentary on Ritzwoller et al., Economic analyses of the Be Fit Be Well program: a weight loss program for community health centers. PMID- 23739814 TI - Are we slaves to DSM? A South African perspective. PMID- 23739813 TI - Dose response of the intravascular contrast agent gadofosveset trisodium in MR perfusion imaging of the myocardium using a quantitative evaluation. AB - This study was performed to determine the best concentration of gadofosveset at 1.5 and 3 T MRI for quantitative myocardial perfusion analysis. 18 healthy volunteers have been examined at a 1.5 and a 3 T MRI system assigned to one of three dose groups: low dose (0.00375 mmol/kg), medium dose (0.0075 mmol/kg), high dose (0.0150 mmol/kg). A T1-weighted saturation recovery turboFLASH sequence with parallel imaging was used. Two perfusion scans were performed for each field strength and volunteer. Peak signal-to-noise-ratio, maximum contrast-enhancement ratio and myocardial blood flow (MBF) were calculated. MBF values were significantly higher at 1.5 T in the medium and the high dose groups than in the low dose group (p < 0.001). Higher MBF values could be found at 3 T for the second perfusion scan in the medium and both perfusion scans in the high dose group compared to the low dose group. Optimal dose of gadofosveset for quantitative perfusion analysis at 1.5 T is 0.00375 mmol/kg as higher doses caused overestimation of the MBF. At 3 T 0.0075 mmol/kg seems to be the best dose for a single perfusion scan, while for a second perfusion scan MBF may be overestimated. PMID- 23739815 TI - Conflict of interest: the elephant in your practice. PMID- 23739816 TI - High-intent suicide and the Beck's Suicide Intent Scale: a case report. PMID- 23739817 TI - Stabbing nails into the neck: an unusual self-damaging behaviour mandating neurosurgery. PMID- 23739818 TI - Autonomic nervous system status and responsiveness and the levels of anxiety in a normal population. PMID- 23739819 TI - Neurosurgery for mental disorders: a review. AB - Neurosurgical interventions date back to ancient civilization, 5100 BC through a practice known as trephination. Due to past abuse and ethical considerations, neurosurgical interventions in psychiatry remain a controversial issue. This article aims to review the different surgical techniques and their current application in the treatment of psychiatric disorders. The U.S Food and Drug Administration (FDA) gave its approval for vagal nerve stimulation (VNS) for the management of treatment-resistant depression in 2005 and deep brain stimulation (DBS) for refractory obsessive-compulsive disorders (OCD) in 2009. These invasive but non destructive techniques represent the future of neurosurgery for mental disorder. PMID- 23739820 TI - Attitude towards psychiatric treatment and referral pattern in the University of Maiduguri Teaching Hospital - a preliminary report. AB - OBJECTIVE: There is a paucity of literature on consultation-liaison psychiatry, in northern Nigeria. This study aimed to determine both the pattern of psychiatric referrals, and the attitudes of doctors toward the treatment of mental disorders in a teaching hospital, in northeast Nigeria. METHOD: In this cross-sectional survey, we used a modified version of the self-rated Kumar 12 item questionnaire and a basic socio-demographic questionnaire to assess a non random convenient sample of 100 postgraduate resident doctors (with a response rate of 70%) from the University of Maiduguri Teaching Hospital (UMTH). We subjected the data obtained to descriptive statistical analysis, using EPI info (2003), to report averages. RESULTS: A relatively low percentage (57.1%) of doctors acknowledged treating patients with mental disorders in their practice, with a higher proportion acknowledging referral (75%). Nearly one in five (17.6%) of the respondents were unaware that patients with functional illness could have psychological disorders. We found more awareness for psychotherapy (44.1%) than other non-pharmacological treatment interventions, while 10.3% were ignorant of non-pharmacological forms of treatment for psychological problems. CONCLUSION: Although this is a preliminary report, the research reported here demonstrated that doctors in the teaching hospital concerned recognized the need for psychiatric consultation and referral. It is difficult to draw further conclusions because of the limitations of this study. PMID- 23739821 TI - Organising for self-advocacy in mental health: experiences from seven African countries. AB - OBJECTIVE: This paper reports on overarching strategies which supported the establishment and sustainability of 9 mental health self-help organisations in seven African countries. METHOD: Eleven key informants were identified through snowballing and interviewed regarding their experience in the organisations. Thematic analysis of the interview data and other documentary evidence was guided by a coding scheme derived using a framework analysis approach to defining, categorising, mapping and interpreting textual data. RESULTS: Sustainability strategies include: commitment to members' advocating for their rights and rebuilding their lives within their communities; independent decision-making, user-led membership and leadership; financial self sufficiency, alliances with donor organisations, non-governmental organisations (NGOs), disabled people's organisations (DPOs) and ministries which support self-determination and promote control over agenda-setting and responsiveness to members' needs. Organisations' work include advocacy to destigmatise mental disorders and promote the protection of users rights, activities to improve access to health care and to income generation and social support, participation in legislative and policy reform, and capacity building of members. CONCLUSION: Self-help organisations can provide crucial support to users' recovery in resource-poor settings in Africa. Support of Ministries, NGOs, DPOs, development agencies and professionals can assist to build organisations' capacity for sustainable support to members' recovery. PMID- 23739822 TI - The attitudes of clergy in Benin City, Nigeria towards persons with mental illness. AB - OBJECTIVE: The clergy in sub-Saharan Africa play a major role in the care and pathways to orthodox mental health services of the mentally ill. Their attitudes concerning mental illnesses would influence community mental health intervention efforts. This study aimed to determine the attitudes of clergy towards persons with mental illness. METHOD: A cross-sectional survey of clergy (n = 107) of the Christian and Muslim faiths was conducted, using a socio-demographic questionnaire and the 40- item Community Attitudes towards Mental Illness (CAMI) scale. RESULTS: Stigmatizing attitudes were evident among members of the clergy surveyed. Most (71.1%) believed the mentally ill were different from other persons, while 68.2% were of the opinion that the mentally ill should be controlled like children. Over 80% of respondents were not comfortable with the idea of the mentally ill living in their vicinity and wanted mental health hospitals situated out of residential areas. Almost half of respondents (45.8%) were uncomfortable with women who were once mentally ill baby-sitting and 63.2% agreed that our mental hospitals seem more like prisons than where the mentally ill can be cared for. CONCLUSION: Negative attitudes towards the mentally ill were widespread among the clergy sampled. Mental health professionals need to take proactive steps to improve the mental health knowledge of the clergy which may facilitate their roles in the pathway to mental health care. PMID- 23739823 TI - Differences in the association between childhood trauma and BMI in black and white South African women. AB - OBJECTIVE: Childhood trauma has previously been associated with adult obesity. The aim of this study was to determine if ethnicity altered the relationship between childhood trauma and obesity in South African women. METHODS: Forty-four normal-weight (BMI < 25kg/m(2)) and obese (BMI > 30kg/m(2)), black and white premenopausal women completed the Childhood Trauma Questionnaire (CTQ), which retrospectively assessed emotional and physical neglect, and emotional, physical and sexual abuse in childhood. RESULTS: Body composition did not differ by ethnicity in the normal-weight and obese groups. However,independent of BMI group, there were significant differences in socioeconomic status (SES) between black and white women (P < 0.01). Total CTQ score, as well as the sub-scales, physical and emotional neglect, and physical and sexual abuse were higher in black than white women (all P < 0.05), but these scores did not differ between BMI groups. Apart from the sexual abuse score, the differences in physical and emotional neglect and physical abuse scores were no longer significant after adjusting for ethnic differences in age and SES. For sexual abuse, there was a significant interaction between ethnicity and BMI group(P = 0.04), with scores in normal weight women being higher in black than white women, but scores in obese women not differing by ethnicity. CONCLUSION: Ethnicity alters the association between childhood sexual abuse and BMI status. Larger studies are required to verify this finding, including measures of body image and body size satisfaction that may explain these findings. PMID- 23739824 TI - The correlates of stress, coping styles and psychiatric morbidity in the first year of medical education at a Nigerian University. AB - OBJECTIVES: This study was prompted by the heightened concerns about the stress inherent in medical education evident from the incessant requests for suspension of studies due to psychological problems. The objectives of the study were to: (i) survey the students for possible psychological problems at admission, and follow them up till exit for possible changes in morbidity, and (ii) ascertain possible risk factors, and coping strategies. METHOD: This is a preliminary 2 stage cross-sectional report, which is part of a longitudinal survey. It involves first year medical students of the College of Health Sciences of University of Ilorin between March and April, 2011. Questionnaires used included socio demographic, sources of stress, the general health questionnaire-12 (GHQ-12), Maslach's burnout inventory (MBI), and Brief COPE. Data were analysed using SPSS version 15 at 5% significance level. Chi-square, frequency distributions, Pearson's correlation, Odd ratios, and Confidence Intervals were calculated to determine the levels of risk. RESULTS: 79 students returned completed questionnaires. 12 (15.2%) were ghq-12 cases (i.e., scored >= 3). Students who had morbidity were 9 times at risk of being stressed consequent upon 'competing with their peers' and 4 times at risk due to 'inadequate learning materials'. Morbidity was significantly more likely to engender use of 'religion', 4 times less likely to engender use of 'positive reframing' with a trend in the use of 'self blame' as coping strategies. CONCLUSION: Aside from psychosocial/personal issues in this cohort, academic demand was an additional source of psychological problems thereby causing those who had morbidity to utilize 'religion' and 'positive reframing' to cope. There is therefore an apparent need to incorporate the principle of mental health promotion in medical education. PMID- 23739825 TI - A piece of me died too...... when the ones we love are taken from us. PMID- 23739826 TI - Large-scale synthesis of highly dispersed layered double hydroxide powders containing delaminated single layer nanosheets. AB - A facile method for the synthesis of Zn2Al-borate and Mg3Al-borate layered double hydroxides (LDHs) with extremely high specific surface areas of 458.6 and 263 m(2) g(-1) and containing delaminated nanosheets is reported. To the best of our knowledge, this is the first report of LDH powders that still remain exfoliated on drying. PMID- 23739828 TI - High fluence iontophoretic corneal collagen cross-linking: in vivo OCT imaging of riboflavin penetration. PMID- 23739829 TI - Treatment of postoperative keratoplasty astigmatism using femtosecond laser assisted intrastromal relaxing incisions. AB - PURPOSE: To investigate the effectiveness of femtosecond laser-assisted intrastromal relaxing incisions for astigmatism management and establish laser treatment parameters. METHODS: Sixteen eyes of 16 patients had regular astigmatism after penetrating keratoplasty. All sutures had been removed and the refraction was stabilized. Paired arcuate intrastromal incisions were made 180 degrees apart within the graft stroma with a femtosecond laser preserving the epithelium. Follow-up examinations were performed at 1 week, 2 weeks, 1 month, and 3 months. RESULTS: The logMAR corrected distance visual acuity (CDVA) improved from 0.50 +/- 0.29 to 0.32 +/- 0.23 (Snellen 20/63 to 20/40). Refractive and topographic anterior cylinders decreased from 6.8 +/- 2.2 diopters (D) to 3.7 +/- 1.7 D and from 9.5 +/- 4.8 D to 4.4 +/- 2.1 D, respectively. Stabilization of topographic cylinder was observed 1 month postoperatively. The worse the preoperative CDVA was and the higher the preoperative values for the refractive and topographic cylinders were, the higher the surgically induced changes were. Anterior side cut angles at 90 degrees and 120 degrees produced similar results. A bulge of incision occurred in one eye requiring compression sutures. CONCLUSIONS: Significant improvement in CDVA and refractive and topographic cylinders indicated a good effect of femtosecond laser-assisted intrastromal relaxing incisions in reducing astigmatism. No advantage between 90 degrees and 120 degrees anterior side cut angles was found. No infections were recorded and no patient expressed discomfort. PMID- 23739830 TI - Visual acuity outcomes in eyes with flat corneas after PRK. AB - PURPOSE: To evaluate the impact of corneal curvatures less than 35 diopters (D) after photorefractive keratectomy (PRK) on visual acuity outcomes. METHODS: Visual acuity outcomes of 5,410 eyes that underwent PRK from January 2006 to November 2010 were retrospectively analyzed for the impact of postoperative corneal curvatures on visual outcomes. All procedures were performed on a single platform (Allegretto 200Hz excimer laser; Alcon Laboratories, Inc., Irvine, CA). Main outcome measures were postoperative corrected distance visual acuity (CDVA) and loss of CDVA. RESULTS: Corneas with a measured or a calculated postoperative flat meridian less than 35 D and those with a measured postoperative steep meridian less than 35 D had worse postoperative CDVA than corneas with meridians of either 35 D or more (P <= .021). However, the preoperative CDVA was worse in the flatter curvatures in all comparisons performed (P <= .024). Consequently, the measured or calculated meridian curvature had no effect on CDVA loss (P >= .074). CONCLUSION: Postoperative corneal keratometry values (flat and steep meridians) less than 35 D did not have a predictive effect on the risk of losing visual acuity following myopic PRK performed on the Allegretto 200Hz excimer laser. PMID- 23739831 TI - Rotation stability of the cachet angle-supported phakic intraocular lens. AB - PURPOSE: To evaluate the rotational stability of an acrylic angle-supported phakic intraocular lens (PIOL) 12 months after implantation in myopic eyes. METHODS: Patients with a history of moderate to high myopia underwent unilateral or bilateral implantation of an acrylic angle-supported PIOL (AcrySof Cachet; Alcon Laboratories, Inc., Fort Worth, TX). All were followed up for 12 months. IOL rotation was assessed using digital overlay of ocular photographs captured within 2 weeks of implantation and at postoperative month 12. The secondary outcomes of refractive power (spherical equivalent, refractive sphere, and cylinder) and uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) were assessed preoperatively and again at 3 months after implantation. RESULTS: Fifty eyes of 28 patients with a mean age of 32 years were included in this retrospective cohort study. All underwent successful IOL implantation and follow-up. A mean 12-month rotation of 11 degrees was observed (standard deviation: 15.1 degrees , range: 0 to 60 degrees ). All preoperative measures (mean) of refractive power improved by 3 months postoperatively (spherical equivalent = -0.35 +/- 0.79 diopters [D], spherical refraction = 0.04 +/- 0.82 D, and cylindrical refraction = -0.77 +/- 0.91 D). Two percent of eyes requiring additional laser adjustment by postoperative month 12, primarily due to corneal astigmatism. CONCLUSION: The study findings suggest that AcrySof Cachet angle-supported PIOLs offer moderate 1-year rotational stability. Because this type of IOL also corrects myopia effectively, it appears to be a good treatment option for myopic eyes. However, the rotation that occurs makes it unsuitable for cylinder corrections. PMID- 23739832 TI - A ray tracing approach to calculate toric intraocular lenses. AB - PURPOSE: To quantify the precision of astigmatic correction in routine cataract surgery with toric intraocular lenses (IOLs) and to evaluate the predictability of keratometric and anterior/posterior topographic measurement for the improvement of the overall accuracy. METHODS: Seventy-eight eyes of 56 patients were implanted with toric IOLs. Data acquired by the Lenstar optical biometer (Haag-Streit, Bern, Switzerland) and TMS5 topography (Tomey, Nagoya, Japan) were processed with the ray tracing software Okulix (Tedics, Dortmund, Germany) to predict the residual refraction. Four different inputs were examined: keratometry only, anterior topography, anterior and posterior topography/ tomography, and combination of keratometry only and anterior and posterior topography/tomography. Four weeks postoperatively, the spherical prediction error and the cylindrical prediction error (difference vector between predicted and achieved cylindrical refraction) were determined. RESULTS: Mean absolute error of spherical prediction error was 0.27 diopter (D). Cylindrical prediction errors were 0.57 D (keratometry only), 0.56 D (anterior topography), 0.56 D (anterior and posterior topography/ tomography), and 0.50 D (combination of keratometry only and anterior and posterior topography/tomography). Differences between intraocular lens groups were statistically significant (Friedman test, P < .05). CONCLUSION: The combination of keratometry and anterior and posterior topography/tomography of anterior and posterior surface yielded the best results for toric IOL power calculations. PMID- 23739833 TI - Moderate keratoconus with thick corneas. AB - PURPOSE: To describe two patients with moderate keratoconus and a corneal thickness exceeding 600 MUm at the thinnest point. METHODS: Case report. RESULTS: In the first case, the steepest keratometric power was 51.50 diopters (D) in the right eye and 53.4 in the left eye and the thickness at the thinnest point was 658 and 625 MUm, respectively. In the second case, the steepest keratometric power was 46.70 D in the right eye and 49.60 D in the left eye and the thickness at the thinnest point was 618 and 608 MUm, respectively. CONCLUSIONS: Keratoconus may develop despite a very thick cornea, reinforcing the idea that biomechanical changes can signify an important factor in the development and progression of this pathology. PMID- 23739834 TI - Possible role of IRTKS in Tks5-driven osteoclast fusion. AB - Podosomes and invadopodia seen in osteoclasts and cancer cells, respectively, are actin-rich membrane protrusions. We recently demonstrated that an adaptor protein, Tks5, which is an established regulator of invadopodia in cancer cells, drives osteoclast-osteoclast fusion as well as osteoclast-cancer cell fusion by generating circumferential podosomes/invadopodia. This finding revealed an unexpected potential of podosomes/invadopodia to act as fusion-competent protrusions. Fusion of biological membranes involves the intricate orchestration of various proteins and lipids. Recent literature suggests the importance of membrane curvature formation in lipid bilayer fusion. In this study, we investigated the expression of Bin-Amphiphysin-Rvs161/167 (BAR) domain superfamily proteins, which have membrane deforming activity, during osteoclastogenesis. We found that IRTKS was specifically induced during osteoclast fusion and interacted with Tks5, suggesting the role of IRTKS in the formation of fusion-competent protrusions via its BAR domain. PMID- 23739835 TI - Abnormal rich club organization and functional brain dynamics in schizophrenia. AB - IMPORTANCE: The human brain forms a large-scale structural network of regions and interregional pathways. Recent studies have reported the existence of a selective set of highly central and interconnected hub regions that may play a crucial role in the brain's integrative processes, together forming a central backbone for global brain communication. Abnormal brain connectivity may have a key role in the pathophysiology of schizophrenia. OBJECTIVE: To examine the structure of the rich club in schizophrenia and its role in global functional brain dynamics. DESIGN: Structural diffusion tensor imaging and resting-state functional magnetic resonance imaging were performed in patients with schizophrenia and matched healthy controls. SETTING: Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands. PARTICIPANTS: Forty-eight patients and 45 healthy controls participated in the study. An independent replication data set of 41 patients and 51 healthy controls was included to replicate and validate significant findings. MAIN OUTCOME(S) AND MEASURES: Measures of rich club organization, connectivity density of rich club connections and connections linking peripheral regions to brain hubs, measures of global brain network efficiency, and measures of coupling between brain structure and functional dynamics. RESULTS: Rich club organization between high-degree hub nodes was significantly affected in patients, together with a reduced density of rich club connections predominantly comprising the white matter pathways that link the midline frontal, parietal, and insular hub regions. This reduction in rich club density was found to be associated with lower levels of global communication capacity, a relationship that was absent for other white matter pathways. In addition, patients had an increase in the strength of structural connectivity-functional connectivity coupling. CONCLUSIONS: Our findings provide novel biological evidence that schizophrenia is characterized by a selective disruption of brain connectivity among central hub regions of the brain, potentially leading to reduced communication capacity and altered functional brain dynamics. PMID- 23739836 TI - B chromosomes of rye are highly conserved and accompanied the development of early agriculture. AB - BACKGROUND AND AIMS: Supernumerary B chromosomes (Bs) represent a specific type of selfish genetic element. As Bs are dispensable for normal growth, it is expected to observe B polymorphisms among populations. To address whether Bs maintained in geographically distinct populations of cultivated and weedy rye are polymorphic, the distribution patterns and the transcriptional activity of different B-located repeats were analysed. METHODS: Bs of cultivated and weedy rye from seven origins were analysed by fluorescence in situ hybridization (FISH) with probes specific for the pericentromeric and interstitial regions as well as the B-specific non-disjunction control region. The DNA replication, chromatin composition and transcription behaviour of the non-disjunction regions were determined. To address whether the B-marker repeats E3900 and D1100 have diverged genotypes of different origin at the sequence level, the genomic sequences of both repeats were compared between cultivated rye and weedy rye from five different origins. KEY RESULTS: B chromosomes in cultivated and weedy rye have maintained a similar molecular structure at the level of subspecies. The high degree of conservation of the non-disjunction control region regarding its transcription activity, histone composition and replication underlines the functional importance of this chromosome region for the maintenance of Bs. The conserved chromosome structure suggests a monophyletic origin of the rye B. As Bs were found in different countries, it is likely that Bs were frequently present in the seed material used in early agriculture. CONCLUSIONS: The surprisingly conserved chromosome structure suggests that although the rye Bs experienced rapid evolution including multiple rearrangements at the early evolutionary stages, this process has slowed significantly and may have even ceased during its recent evolution. PMID- 23739837 TI - Dendritic spine dynamics in synaptogenesis after repeated LTP inductions: dependence on pre-existing spine density. AB - Not only from our daily experience but from learning experiments in animals, we know that the establishment of long-lasting memory requires repeated practice. However, cellular backgrounds underlying this repetition-dependent consolidation of memory remain largely unclear. We reported previously using organotypic slice cultures of rodent hippocampus that the repeated inductions of LTP (long-term potentiation) lead to a slowly developing long-lasting synaptic enhancement accompanied by synaptogenesis distinct from LTP itself, and proposed this phenomenon as a model system suitable for the analysis of the repetition dependent consolidation of memory. Here we examined the dynamics of individual dendritic spines after repeated LTP-inductions and found the existence of two phases in the spines' stochastic behavior that eventually lead to the increase in spine density. This spine dynamics occurred preferentially in the dendritic segments having low pre-existing spine density. Our results may provide clues for understanding the cellular bases underlying the repetition-dependent consolidation of memory. PMID- 23739838 TI - Approximation of sojourn-times via maximal couplings: motif frequency distributions. AB - Sojourn-times provide a versatile framework to assess the statistical significance of motifs in genome-wide searches even under non-Markovian background models. However, the large state spaces encountered in genomic sequence analyses make the exact calculation of sojourn-time distributions computationally intractable in long sequences. Here, we use coupling and analytic combinatoric techniques to approximate these distributions in the general setting of Polish state spaces, which encompass discrete state spaces. Our approximations are accompanied with explicit, easy to compute, error bounds for total variation distance. Broadly speaking, if Tn is the random number of times a Markov chain visits a certain subset T of states in its first n transitions, then we can usually approximate the distribution of Tn for n of order (1 - alpha)(-m), where m is the largest integer for which the exact distribution of Tm is accessible and 0 <= alpha <= 1 is an ergodicity coefficient associated with the probability transition kernel of the chain. This gives access to approximations of sojourn times in the intermediate regime where n is perhaps too large for exact calculations, but too small to rely on Normal approximations or stationarity assumptions underlying Poisson and compound Poisson approximations. As proof of concept, we approximate the distribution of the number of matches with a motif in promoter regions of C. PMID- 23739839 TI - Interdependency and hierarchy of exact and approximate epidemic models on networks. AB - Over the years numerous models of S I S (susceptible --> infected --> susceptible) disease dynamics unfolding on networks have been proposed. Here, we discuss the links between many of these models and how they can be viewed as more general motif-based models. We illustrate how the different models can be derived from one another and, where this is not possible, discuss extensions to established models that enables this derivation. We also derive a general result for the exact differential equations for the expected number of an arbitrary motif directly from the Kolmogorov/master equations and conclude with a comparison of the performance of the different closed systems of equations on networks of varying structure. PMID- 23739840 TI - Less invasive transjugular approach with Fallopian bridge technique for facial nerve protection and hearing preservation in surgery of glomus jugulare tumors. AB - For the past three decades, surgery of glomus jugulare tumors (GJTs) has been characterized by extensive combined head and neck, neuro-otologic, and neurosurgical approaches. In recent years, the authors have modified the operative technique to a less invasive approach for preservation of cranial nerves while achieving satisfactory tumor resection. We evaluated and compared the clinical outcomes of our current less invasive approach with our previous more extensive procedures. The clinical records of 39 cases of GJT surgically treated between 1992 and 2011 were retrospectively reviewed. The less invasive transjugular approach with Fallopian bridge technique (LI-TJ) was used for the most recent five cases. The combined transmastoid-transjugular and high cervical (TM-HC) approach was performed in 30 cases, while four cases were treated with a transmastoid-transsigmoid approach with facial nerve translocation. Operative technique, extent of tumor resection, operating time, hospital stay, and morbidity were examined through the operative records, and a comparison was made between the LI-TJ cases and the more invasive cases. No facial nerve palsy was seen in the LI-TJ group while the TM-HC group demonstrated six cases (17.6%) of facial palsy (House-Brackmann facial nerve function grading scale grade II and III). The complication rate was 0 % in the LI-TJ group and 16.7% in the more invasive group. The mean operative time and hospital stay were shorter in the LI TJ group (6.4 h and 4.3 days, respectively) compared with the more invasive group (10.7 h and 8.0 days, respectively). The LI-TJ approach with Fallopian bridge technique provided adequate tumor resection with cranial preservation and definitive advantage over the more extensive approach. PMID- 23739841 TI - Anticoagulation beyond direct thrombin and factor Xa inhibitors: indications for targeting the intrinsic pathway? AB - Antithrombotic drugs like vitamin K antagonists and heparin have been the gold standard for the treatment and prevention of thromboembolic disease for many years. Unfortunately, there are several disadvantages of these antithrombotic drugs: they are accompanied by serious bleeding problems, it is necessary to monitor the therapeutic window, and there are various interactions with food and other drugs. This has led to the development of new oral anticoagulants, specifically inhibiting either thrombin or factor Xa. In terms of effectiveness, these drugs are comparable to the currently available anticoagulants; however, they are still associated with issues such as bleeding, reversal of the drug and complicated laboratory monitoring. Vitamin K antagonists, heparin, direct thrombin and factor Xa inhibitors have in common that they target key proteins of the haemostatic system. In an attempt to overcome these difficulties we investigated whether the intrinsic coagulation factors (VIII, IX, XI, XII, prekallikrein and high-molecular-weight kininogen) are superior targets for anticoagulation. We analysed epidemiological data concerning thrombosis and bleeding in patients deficient in one of the intrinsic pathway proteins. Furthermore, we discuss several thrombotic models in intrinsic coagulation factor deficient animals. The combined results suggest that intrinsic coagulation factors could be suitable targets for anticoagulant drugs. PMID- 23739842 TI - Mass spectrometry and NMR spectroscopy: modern high-end detectors for high resolution separation techniques--state of the art in natural product HPLC-MS, HPLC-NMR, and CE-MS hyphenations. AB - Current natural product research is unthinkable without the use of high resolution separation techniques as high performance liquid chromatography or capillary electrophoresis (HPLC or CE respectively) combined with mass spectrometers (MS) or nuclear magnetic resonance (NMR) spectrometers. These hyphenated instrumental analysis platforms (CE-MS, HPLC-MS or HPLC-NMR) are valuable tools for natural product de novo identification, as well as the authentication, distribution, and quantification of constituents in biogenic raw materials, natural medicines and biological materials obtained from model organisms, animals and humans. Moreover, metabolic profiling and metabolic fingerprinting applications can be addressed as well as pharmacodynamic and pharmacokinetic issues. This review provides an overview of latest technological developments, discusses the assets and drawbacks of the available hyphenation techniques, and describes typical analytical workflows. PMID- 23739843 TI - Over-sulfated glycosaminoglycans are alternative selectin ligands: insights into molecular interactions and possible role in breast cancer metastasis. AB - Distant metastasis account for about 90 % of cancer associated deaths, and yet the oncology field is cruelly lacking tools to accurately predict and/or prevent metastasis. Distant metastasis occurs when circulating tumor cells interact with the endothelium of distant organs and extravasate from the blood vessel into the surrounding tissue. Selectins are a family of carbohydrate receptors well depicted for their role in tumor cells extravasation. They mediate primary interactions of cancer cells with endothelial cells, as well as secondary interactions with leucocytes and platelets, which are also promoting metastasis. The cancer associated carbohydrate antigen sialyl-Lewis x (sLe(x)) has been repeatedly shown to be involved, as selectin ligand, in these interactions. However, recent studies have highlighted that glycosaminoglycans (GAGs), another class of glycans, may also serve as ligands for selectins. We report herein that cancer-associated GAGs are differentially recognized by selectins according to their density of sulfation and the pH conditions of the binding. We also show that these parameters regulate platelets-cancer cells heterotypic aggregation, supporting the idea that GAGs may have pro-metastatic function. Combining our experimental results with in depth analyses of molecular dockings, we propose a model of GAG/selectin interactions robust enough to recapitulate the differential binding of selectins to GAGs, the competition between GAGs and sLe(x) for selectin binding and the effect of sub-physiological pH on GAGs affinities towards selectins. Altogether, our data suggest GAGs to be good ligands for selectins, potentially promoting distant metastasis in a complementary way to sLe(x). PMID- 23739844 TI - eEF1A2 promotes cell migration, invasion and metastasis in pancreatic cancer by upregulating MMP-9 expression through Akt activation. AB - eEF1A2 is a protein translation factor involved in protein synthesis that is overexpressed in various cancers, with important functions in tumor genesis and progression. We have previously showed that the ectopic expression of eEF1A2 is correlated with lymph node metastasis and perineural invasion in pancreatic cancer. In this study, we investigated the functional role of eEF1A2 in the regulation of cell migration, invasion, and metastasis in pancreatic cancer. Furthermore, we investigated the potential molecular mechanisms involved. By evaluating the invasive ability of a panel of pancreatic cancer cell lines with different metastatic potentials, eEF1A2 expression in cells was positively associated with their invasive ability. The knockdown of eEF1A2 by siRNA decreased the migration and invasion of PANC-1 cells. By contrast, the ectopic expression of exogenous eEF1A2 significantly promoted the migration and invasion of SW1990 cells. Stable eEF1A2 overexpression in a nude mouse model of peritoneal metastasis likewise dramatically enhanced the intraperitoneal metastatic ability of SW1990 cells. In addition, eEF1A2 overexpression could upregulate MMP-9 expression and activity. A significant positive correlation between the overexpression of both eEF1A2 and MMP-9 was observed in pancreatic cancer tissues. The inhibition of MMP-9 activity reduced the promoting effect of eEF1A2 on cell migration and invasion. Furthermore, eEF1A2-mediated cell migration and invasion, as well as MMP-9 expression and upregulation, were largely dependent on the eEF1A2-induced Akt activation. The findings suggested the potentially important role of eEF1A2 in pancreatic cancer migration, invasion, and metastasis. Thus, the results provide evidence of eEF1A2 as a potential therapeutic target in the treatment of aggressive pancreatic cancer. PMID- 23739845 TI - Oxidative stress and DNA damage in utero and embryo implantation of mice exposed to carbon disulfide at peri-implantation. AB - Carbon disulfide (CS2) has reproductive toxicity but the mechanism remains unclear. The aim of the present study was to investigate the effect of oxidative stress and DNA damage on embryo implantation of mice exposed to CS2 at peri implantation. CS2 exposure was on gestational day 3 (GD3), GD4, GD5 and GD6, separately, and the number of embryonic day 9 (E9) mouse embryos was obtained. DNA damage of endometrial cells, oxidative stress and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) level in uterus tissues were tested with time series at different end points after exposure. The number of E9 mouse embryos significantly decreased in all CS2 exposure groups, especially on GD4 exposure. The rates of embryo implantation decreased by 43.05%, 63.74%, 60.45% and 47.26% for CS2 exposure on GD3, GD4, GD5 and GD6, respectively. Oxidative stress significantly increased within 24 h and reached the top level at 18 h after exposure. The same time dependent trend was observed no matter when the exposure happened at peri implantation. 8-OH-dG significantly increased at 18 h and 24 h after exposure by 893.8% and 647.4%, respectively, when compared with the control. The indexes of DNA damage significantly increased at 6 h after exposure, which appeared earlier than the changes of oxidative stress and 8-OH-dG. Besides, both oxidative stress and DNA damage showed a strong negative correlation with the number of E9 mouse embryos. The present study illustrated that CS2 directly induced DNA damage in endometrial cells and enhanced the action through oxidative stress, both of which were responsible for CS2-induced embryo loss. PMID- 23739846 TI - An evidence-based analysis of epidemiologic associations between lymphatic and hematopoietic cancers and occupational exposure to gasoline. AB - The presence of benzene in motor gasoline has been a health concern for potential increased risk of acute myelogenous leukemia and perhaps other lymphatic/hematopoietic cancers for approximately 40 years. Because of the widespread and increasing use of gasoline by consumers and the high exposure potential of occupational cohorts, a thorough understanding of this issue is important. The current study utilizes an evidence-based approach to examine whether or not the available epidemiologic studies demonstrate a strong and consistent association between occupational exposure to gasoline and lymphatic/hematopoietic cancers. Among 67 epidemiologic studies initially identified, 54 were ranked according to specific criteria relating to the relevance and robustness of each study for answering the research question. The 30 highest-ranked studies were sorted into three tiers of evidence and were analyzed for strength, specificity, consistency, temporality, dose-response trends and coherence. Meta statistics were also calculated for each general and specific lymphatic/hematopoietic cancer category with adequate data. The evidence based analysis did not confirm any strong and consistent association between occupational exposure to gasoline and lymphatic/hematopoietic cancers based on the epidemiologic studies available to date. These epidemiologic findings, combined with the evidence showing relatively low occupational benzene vapor exposures associated with gasoline formulations during the last three decades, suggest that current motor gasoline formulations are not associated with increased lymphatic/hematopoietic cancer risks related to benzene. PMID- 23739847 TI - Virtual autopsy. PMID- 23739848 TI - Comparison of manual, digital and lateral CBCT cephalometric analyses. AB - OBJECTIVE: The aim of this study was to compare the reliability of three different methods of cephalometric analysis. MATERIAL AND METHODS: Conventional pretreatment lateral cephalograms and cone beam computed tomography (CBCT) scans from 50 subjects from a radiological clinic were selected in order to test the three methods: manual tracings (MT), digitized lateral cephalograms (DLC), and lateral cephalograms from CBCT (LC-CBCT). The lateral cephalograms were manually analyzed through the Dolphin Imaging 11.0TM software. Twenty measurements were performed under the same conditions, and retraced after a 30-day period. Paired t tests and the Dahlberg formula were used to evaluate the intra-examiner errors. The Pearson's correlation coefficient and one-way analysis of variance (ANOVA) tests were used to compare the differences between the methods. RESULTS: Intra examiner reliability occurred for all methods for most of the measurements. Only six measurements were different between the methods and an agreement was observed in the analyses among the 3 methods. CONCLUSIONS: The results demonstrated that all evaluated methodologies are reliable and valid for scientific research, however, the method used in the lateral cephalograms from the CBCT proved the most reliable. PMID- 23739849 TI - In vitro antimicrobial activity of auxiliary chemical substances and natural extracts on Candida albicans and Enterococcus faecalis in root canals. AB - OBJECTIVE: The aim of this study was to evaluate the antimicrobial activity of auxiliary chemical substances and natural extracts on Candida albicans and Enterococcus faecalis inoculated in root canals. MATERIAL AND METHODS: Seventy two human tooth roots were contaminated with C. albicans and E. faecalis for 21 days. The groups were divided according to the auxiliary chemical substance into: G1) 2.5% sodium hypochlorite (NaOCl), G2) 2% chlorhexidine gel (CHX), G3) castor oil, G4) glycolic Aloe vera extract, G5) glycolic ginger extract, and G6) sterile saline (control). The samples of the root canal were collected at different intervals: confirmation collection, at 21 days after contamination; 1st collection, after instrumentation; and 2nd collection, seven days after instrumentation. Microbiological samples were grown in culture medium and incubated at 37 degrees C for 48 hours. RESULTS: The results were submitted to the Kruskal-Wallis and Dunn (5%) statistical tests. NaOCl and CHX completely eliminated the microorganisms of the root canals. Castor oil and ginger significantly reduced the number of CFU of the tested bacteria. Reduction of CFU/mL at the 1st and 2nd collections for groups G1, G2, G3 and G4 was greater in comparison to groups G5 and G6. CONCLUSION: It was concluded that 2.5% sodium hypochlorite and 2% chlorhexidine gel were more effective in eliminating C. albicans and E. faecalis, followed by the castor oil and glycolic ginger extract. The Aloe vera extract showed no antimicrobial activity. PMID- 23739850 TI - Surface hardness evaluation of different composite resin materials: influence of sports and energy drinks immersion after a short-term period. AB - OBJECTIVES: This study evaluated the effect of sports and energy drinks on the surface hardness of different composite resin restorative materials over a 1 month period. MATERIAL AND METHODS: A total of 168 specimens: Compoglass F, Filtek Z250, Filtek Supreme, and Premise were prepared using a customized cylindrical metal mould and they were divided into six groups (N=42; n=7 per group). For the control groups, the specimens were stored in distilled water for 24 hours at 37 degrees C and the water was renewed daily. For the experimental groups, the specimens were immersed in 5 mL of one of the following test solutions: Powerade, Gatorade, X-IR, Burn, and Red Bull, for two minutes daily for up to a 1-month test period and all the solutions were refreshed daily. Surface hardness was measured using a Vickers hardness measuring instrument at baseline, after 1-week and 1-month. Data were statistically analyzed using Multivariate repeated measure ANOVA and Bonferroni's multiple comparison tests (alpha=0.05). RESULTS: Multivariate repeated measures ANOVA revealed that there were statistically significant differences in the hardness of the restorative materials in different immersion times (p<0.001) in different solutions (p<0.001). The effect of different solutions on the surface hardness values of the restorative materials was tested using Bonferroni's multiple comparison tests, and it was observed that specimens stored in distilled water demonstrated statistically significant lower mean surface hardness reductions when compared to the specimens immersed in sports and energy drinks after a 1-month evaluation period (p<0.001). The compomer was the most affected by an acidic environment, whereas the composite resin materials were the least affected materials. CONCLUSIONS: The effect of sports and energy drinks on the surface hardness of a restorative material depends on the duration of exposure time, and the composition of the material. PMID- 23739851 TI - CCL3 and CXCL12 production in vitro by dental pulp fibroblasts from permanent and deciduous teeth stimulated by Porphyromonas gingivalis LPS. AB - OBJECTIVE: The aim of this study was to compare the production of the chemokines CCL3 and CXCL12 by cultured dental pulp fibroblasts from permanent (PDPF) and deciduous (DDPF) teeth under stimulation by Porphyromonas gingivalis LPS (PgLPS). MATERIAL AND METHODS: Primary culture of fibroblasts from permanent (n=3) and deciduous (n=2) teeth were established using an explant technique. After the fourth passage, fibroblasts were stimulated by increasing concentrations of PgLPS (0-10 ug/mL) at 1, 6 and 24 h. The cells were tested for viability through MTT assay, and production of the chemokines CCL3 and CXCL12 was determined through ELISA. Comparisons among samples were performed using One-way ANOVA for MTT assay and Two-way ANOVA for ELISA results. RESULTS: Cell viability was not affected by the antigen after 24 h of stimulation. PgLPS induced the production of CCL3 by dental pulp fibroblasts at similar levels for both permanent and deciduous pulp fibroblasts. Production of CXCL12, however, was significantly higher for PDPF than DDPF at 1 and 6 h. PgLPS, in turn, downregulated the production of CXCL12 by PDPF but not by DDPF. CONCLUSION: These data suggest that dental pulp fibroblasts from permanent and deciduous teeth may present a differential behavior under PgLPS stimulation. PMID- 23739852 TI - Accuracy of five electronic foramen locators with different operating systems: an ex vivo study. AB - OBJECTIVE: The aim of this study was to evaluate, ex vivo, the precision of five electronic root canal length measurement devices (ERCLMDs) with different operating systems: the Root ZX, Mini Apex Locator, Propex II, iPex, and RomiApex A-15, and the possible influence of the positioning of the instrument tips short of the apical foramen. MATERIAL AND METHODS: Forty-two mandibular bicuspids had their real canal lengths (RL) previously determined. Electronic measurements were performed 1.0 mm short of the apical foramen (-1.0), followed by measurements at the apical foramen (0.0). The data resulting from the comparison of the ERCLMD measurements and the RL were evaluated by the Wilcoxon and Friedman tests at a significance level of 5%. RESULTS: Considering the measurements performed at 0.0 and -1.0, the precision rates for the ERCLMDs were: 73.5% and 47.1% (Root ZX), 73.5% and 55.9% (Mini Apex Locator), 67.6% and 41.1% (Propex II), 61.7% and 44.1% (iPex), and 79.4% and 44.1% (RomiApex A-15), respectively, considering +/-0.5 mm of tolerance. Regarding the mean discrepancies, no differences were observed at 0.0; however, in the measurements at -1.0, the iPex, a multi-frequency ERCLMD, had significantly more discrepant readings short of the apical foramen than the other devices, except for the Propex II, which had intermediate results. When the ERCLMDs measurements at -1.0 were compared with those at 0.0, the Propex II, iPex and RomiApex A-15 presented significantly higher discrepancies in their readings. CONCLUSIONS: Under the conditions of the present study, all the ERCLMDs provided acceptable measurements at the 0.0 position. However, at the -1.0 position, the ERCLMDs had a lower precision, with statistically significant differences for the Propex II, iPex, and RomiApex A-15. PMID- 23739853 TI - Temperature and curing time affect composite sorption and solubility. AB - OBJECTIVE: This study evaluated the effect of temperature and curing time on composite sorption and solubility. MATERIAL AND METHODS: Seventy five specimens (8*2 mm) were prepared using a commercial composite resin (ICE, SDI). Three temperatures (10 degrees C, 25 degrees C and 60 degrees C) and five curing times (5 s, 10 s, 20 s, 40 s and 60 s) were evaluated. The specimens were weighed on an analytical balance three times: A: before storage (M1); B: 7 days after storage (M2); C: 7 days after storage plus 1 day of drying (M3). The storage solution consisted of 75% alcohol/25% water. Sorption and solubility were calculated using these three weights and specimen dimensions. The data were analyzed using the Kruskal-Wallis and Mann-Whitney U Tests (alpha=5%). RESULTS: The results showed that time, temperature and their interaction influenced the sorption and solubility of the composite (p<0.05). At 60 degrees C, the composite sorption showed an inverse relationship with the curing time (p<0.05). The composite cured for 5 s showed higher sorption for the 40 s or 60 s curing times when compared with all temperatures (p<0.05). Curing times of 20 s and 40 s showed similar sorption data for all temperatures (p>0.05). The 60 degrees C composite temperature led to lower values of sorption for all curing times when compared with the 10 degrees C temperature (p<0.05). The same results were found when comparing 10 degrees C and 25 degrees C (p<0.05), except that the 20 s and 40 s curing times behaved similarly (p>0.05). Solubility was similar at 40 s and 60 s for all temperatures (p>0.05), but was higher at 10 degrees C than at 60 degrees C for all curing times (p<0.05). When the composite was cured at 25 degrees C, similar solubility values were found when comparing the 5 s and 10 s or 20 s and 40 s curing times (p>0.05). CONCLUSION: In conclusion, higher temperatures or longer curing times led to lower sorption and solubility values for the composite tested; however, this trend was only significant in specific combinations of temperature and curing times. PMID- 23739854 TI - Spectrophotometric analysis of crown discoloration induced by MTA- and ZnOE-based sealers. AB - Crown discoloration can be induced by root canal sealer remnants following root canal treatment. OBJECTIVE: The aim of this study was to evaluate chromatic alterations in human tooth crowns induced by a Mineral Trioxide Aggregate-based sealer (MTA Fillapex(r)) and a commonly used ZnOE-based sealer (Roth-811). The tested null hypothesis was that the application of the materials did not induce clinically perceptible crown discoloration (Ho: CIE color difference DeltaE<3.7). MATERIAL AND METHODS: Forty five fully developed, intact, mandibular third molars were sectioned 1 mm below the cemento-enamel junction. The pulp chambers were chemomechanically debrided via the cervical access. The specimens were randomly assigned into three groups Group 1: MTA Fillapex, Group 2: Roth 811, Group 3: Negative control (unfilled) and immersed in individually marked vials containing distilled water up to the cervix (37+/-1 degrees C). The spectral reflectance lines were recorded by utilizing a UV-VIS spectrophotometer equipped with integration sphere in the visual spectrum at baseline, 1 week, 1 and 3 months after material placement. Data were transformed into values of the CIE L*a*b* color system and the corresponding DeltaE values were calculated. Statistical analysis was performed using two-way mixed ANOVA models, at p=0.05 level of significance. RESULTS: A statistically significant increase in a* and b* chromatic parameters of the MTA Fillapex Group was measured. However, DeltaE values did not exceed the human eye perceptibility threshold (set at DeltaE<3.7) during the experimental period (DeltaEt3=2.88). In Roth-811 Group, a statistically significant decrease in L* and a statistically significant increase in a* and b* chromatic parameters was measured, during all observation periods. Resultant DeltaE values exceeded the human eye perceptibility threshold after 1 week (DeltaEt1=5.65). CONCLUSIONS: Application of MTA Fillapex in tooth crowns resulted in minimal color alterations, while Roth 811 induced severe discoloration, in vitro. It could be suggested that, in terms of aesthetics, the use of MTA Fillapex appears to be favorable. PMID- 23739855 TI - Catechin-incorporated dental copolymers inhibit growth of Streptococcus mutans. AB - OBJECTIVE: To test the inhibitory growth activity of green tea catechin incorporated into dental resins compared to resins containing the broad-spectrum antimicrobial compound chlorhexidine against Streptococcus mutans in vitro. MATERIAL AND METHODS: The minimum inhibitory concentrations (MICs) of epigallocatechin-gallate (EGCg) and chlorhexidine (CHX) were determined according to the microdilution method. Resin discs (5 mm * 3 mm) were prepared from Bis GMA/TEGDMA (R1) and Bis-GMA/CH3Bis-GMA (R2) comonomers (n=9) containing: a) no drug, b) EGCg, c) CHX. Two concentrations of each drug (0.5* MIC and 1* MIC) were incorporated into the resin discs. Samples were individually immersed in a bacterial culture and incubated for 24 h at 37 degrees C under constant agitation. Cell viability was assessed by counting the number of colonies on replica agar plates. Statistical analysis was performed using one-way ANOVA, Tukey and Student t-tests (alpha=0.05). RESULTS: Both resins containing EGCg and CHX showed a significant inhibition of bacterial growth at both concentrations tested (p<0.05). A significantly higher inhibition was observed in response to resins containing CHX at 0.5* MIC and 1* MIC, and EGCg at 1* MIC when compared to EGCg at 0.5* MIC. Also, EGCg at 0.5* MIC in R1 had a significantly higher growth inhibition than in R2. CONCLUSIONS: Both EGCg and CHX retained their antibacterial activity when incorporated into the resin matrix. EGCg at 1* MIC in R1 and R2 resins significantly reduced S. mutans survival at a level similar to CHX. The data generated from this study will provide advances in the field of bioactive dental materials with the potential of improving the lifespan of resin based restorations. PMID- 23739856 TI - Effect of the application time of phosphoric acid and self-etch adhesive systems to sclerotic dentin. AB - OBJECTIVES: To evaluate the effect of application time on the resin-dentin bond strength (uTBS) and etching pattern of adhesive systems applied on sclerotic dentine. MATERIAL AND METHODS: A total of forty-two bovine incisors had their roots removed. The 1-step self-etch GO (SDI), the 2-step self-etch Adper SE Bond (3MESPE) and the 35% phosphoric acid (3MESPE) from the 2-step etch-and-rinse Adper Single Bond 2 (3MESPE) were applied on the bovine incisal surfaces according to the manufacturer's instructions or duplicating the recommended conditioning time. After adhesive application, thirty teeth were restored with composite resin, stored for 24 h in distilled water at 37 degrees C, and sectioned into resin-dentin bonded sticks (0.8 mm2) and tested according to the uTBS at 0.5 mm/min. The etching pattern of the remaining twelve teeth (n=4 for each material) was examined under scanning electron microscopy. Each tooth was divided into a buccal-to-lingual direction into three thirds, and each third randomly assigned to the groups: control (no treatment), according to the manufacturers' instructions and duplicating the recommended application time. The uTBS and the relative percentage of the tubule area opening were evaluated by two way repeated measures ANOVA and Tukey's tests (alpha=0.05). RESULTS: The duplication of the conditioning time favored only the GO adhesive (p<0.05). Both application methods significantly increased the tubule area opening (p<0.05) compared to the controls. CONCLUSIONS: The efficacy of duplicating the conditioning time was only effective for the 1-step self-etch adhesive system tested. PMID- 23739857 TI - Photodynamic therapy associated with full-mouth ultrasonic debridement in the treatment of severe chronic periodontitis: a randomized-controlled clinical trial. AB - BACKGROUND: Photodynamic therapy (PDT) is a method of microbial reduction which can benefit periodontal treatment in areas of difficult access, such as deep pockets and furcations. The aim of this randomized controlled clinical trial was to evaluate the effects of PDT as an adjunct to full-mouth ultrasonic debridement in the treatment of severe chronic periodontitis. MATERIAL AND METHODS: Twenty two patients with at least one pocket with a probing depth (PD) of >=7 mm and one pocket with a PD of >=5 mm and bleeding on probing (BOP) on each side of the mouth were included, characterizing a split mouth design. The control group underwent full-mouth ultrasonic debridement and the test group received the same treatment associated with PDT. The PDT was performed on only one side of the mouth and the initial step consisted of subgingival irrigation with 0.005% methylene blue dye. Two minutes after applying the photosensitizer, the low power laser - AsGaAl (Photon Lase III - PL7336, DMC, Sao Carlos - Sao Paulo, Brazil) was applied (660 nm, 100 mW, 9 J, 90 seconds per site, 320 J/cm2, diameter tip 600 um). The following clinical parameters were evaluated: plaque index, gingival index, BOP, gingival recession (GR), PD, and clinical attachment level (CAL). All parameters were collected before, 1, 3 and 6 months after treatment. RESULTS: An improvement in BOP, PD and CAL was observed after treatment, in both groups, but without any difference between them. After 6 months, the PD decreased from 5.11+/ 0.56 mm to 2.83+/-0.47 mm in the test group (p<0.05) and from 5.15+/-0.46 mm to 2.83+/-0.40 mm in the control group (p<0.05). The CAL changed, after 6 months, from 5.49+/-0.76 mm to 3.41+/-0.84 mm in the test group (p<0.05) and from 5.53+/ 0.54 to 3.39+/-0.51 mm in the control group (p<0.05). CONCLUSION: Both approaches resulted in significant clinical improvements in the treatment of severe chronic periodontits, however, the PDT did not provide any additional benefit to those obtained with full-mouth ultrasonic debridement used alone. PMID- 23739858 TI - Cellular proliferation markers in peripheral and central fibromas: a comparative study. AB - OBJECTIVE: To perform a comparative study of the cellular proliferation in the peripheral and central fibromas. MATERIAL AND METHODS: Immunohistochemistry for PCNA and the AgNOR technique were performed in 9 cases of peripheral odontogenic fibroma (POF), in 4 cases of odontogenic fibroma (OdF), in 8 cases of peripheral ossifying fibroma (PEOF) and 7 cases of ossifying fibroma (OsF). The Kruskal Wallis and Mann-Whitney tests were used for the statistical analyses. RESULTS: Mesenchymal component of the central lesions presented a higher mean number of AgNOR per nucleus and PCNA index than did the peripheral lesions (P<=0.05). The mean number of AgNOR per nucleus in the epithelial component proved to be higher in the OdF than in the POF (P<=0.05). The mesenchymal and epithelial components presented similar mean numbers of AgNOR per nucleus and PCNA index in the OdF, as well as a similar mean number of AgNOR per nucleus in the POF. CONCLUSIONS: The mesenchymal component may well play a role in the differences between the biological behaviour of the central lesions as compared to the peripheral lesions. Moreover, considering that the epithelial and mesenchymal components in odontogenic fibromas presented a similar proliferation index, more research is warranted to understand the true role of the epithelial components, which are believed to be inactive in nature, as well as in the development and biological behaviour of these lesions. PMID- 23739859 TI - Effect of ozone gas on the shear bond strength to enamel. AB - Ozone is an important disinfecting agent, however its influence on enamel adhesion has not yet been clarified. OBJECTIVE: Evaluate the influence of ozone pretreatment on the shear strength of an etch-and-rinse and a self-etch system to enamel and analyze the respective failure modes. MATERIAL AND METHODS: Sixty sound bovine incisors were used. Specimens were randomly assigned to four experimental groups (n=15): Group G1 (Excite(r) with ozone) and group G3 (AdheSE(r) with ozone) were prepared with ozone gas from the HealOzone unit (Kavo(r)) for 20 s prior to adhesion, and groups G2 (Excite(r)) and G4 (AdheSE(r)) were used as control. Teeth were bisected and polished to simulate a smear layer just before the application of the adhesive systems. The adhesives were applied according to the manufacturer's instructions to a standardized 3 mm diameter surface, and a composite (Synergy D6, Coltene Whaledent) cylinder with 2 mm increments was build. Specimens were stored in 100% humidity for 24 h at 37 degrees C and then subjected to a thermal cycling regimen of 500 cycles. Shear bond tests were performed with a Watanabe device in a universal testing machine at 5 mm/min. The failure mode was analyzed under scanning electron microscope. Means and standard deviation of shear bond strength (SBS) were calculated and difference between the groups was analyzed using ANOVA, Kolmogorov-Smirnov, Levene and Bonferroni. Chi-squared statistical tests were used to evaluate the failure modes. RESULTS: Mean bond strength values and failure modes were as follows: G1--26.85+/-6.18 MPa (33.3% of adhesive cohesive failure); G2--27.95+/ 5.58 MPa (53.8% of adhesive failures between enamel and adhesive); G3--15.0+/ 3.84 MPa (77.8% of adhesive failures between enamel and adhesive) and G4--13.1+/ 3.68 MPa (36.4% of adhesive failures between enamel and adhesive). CONCLUSIONS: Shear bond strength values of both adhesives tested on enamel were not influenced by the previous application of ozone gas. PMID- 23739860 TI - Efficacy of HPA Lanolin(r) in treatment of lip alterations related to chemotherapy. AB - The side effects of chemotherapy on the lips may cause esthetic and functional impact and increase the risk of infection. HPA Lanolin(r) is an option for supportive therapy because it has anti-inflammatory, antimicrobial and moisturizing properties. OBJECTIVE: To evaluate the efficacy of this product in the prevention of lip alterations in a population of patients undergoing chemotherapy. MATERIAL AND METHODS: Patients undergoing chemotherapy (n = 57) were examined and distributed into two groups: study (used HPA Lanolin(r)) and control (without supportive therapy on the lips). We evaluated the patients two weeks after chemotherapy, registering oral alterations, symptoms of pain, discomfort, limitation of mouth opening and dehydration, classified according to a visual analogue scale. RESULTS: Patients who used HPA Lanolin(r) had lower dehydration and experienced improvement of lip dryness (p<0.001). The main symptoms were dehydration, discomfort, limitation of mouth opening, pain. The main clinical signs were dry lips, mucositis, cheilitis, hematoma, swelling and cracking. We found no difference concerning the variables of pain, discomfort, and limitation of mouth opening between the study and control group. CONCLUSIONS: We suggest that HPA Lanolin(r) is effective in reducing the symptoms of dehydration and the signs of lip dryness resulting from toxicity of chemotherapy, proving to be an interesting alternative supportive therapy for cancer patients. PMID- 23739861 TI - Post-curing conversion kinetics as functions of the irradiation time and increment thickness. AB - OBJECTIVE: This study evaluated the variation of conversion degree (DC) in the 12 hours following initial photoactivation of a low-shrinkage composite resin (Venus Diamond). MATERIAL AND METHODS: The conversion degree was monitored for 12 hours using Attenuated Total Reflection (ATR) F-TIR Spectroscopy. The composite was placed in 1 or 2 mm rings and cured for 10 or 20 seconds with a LED lamp. ATR spectra were acquired from the bottom surface of each sample immediately after the initial photoactivation (P=0), 30 minutes (P=0.5) and 12 hours after photoactivation (P=12) in order to obtain the DC progression during the post curing period. Interactions between thickness (T), irradiation time (I) and post curing (P) on the DC were calculated through ANOVA testing. RESULTS: All the first order interactions were statistically significant, with the exception of the T-P interaction. Furthermore, the shift from P=0 to P=0.5 had a statistically higher influence than the shift from P=0.5 to P=12. The post-curing period played a fundamental role in reaching higher DC values with the low-shrinkage composite resin tested in this study. Moreover, both the irradiation time and the composite thickness strongly influenced the DC. CONCLUSIONS: Increased irradiation time may be useful in obtaining a high conversion degree (DC) with a low-shrinkage nano hybrid composite resin, particularly with 2 mm composite layers. PMID- 23739862 TI - Influence of different beverages on the force degradation of intermaxillary elastics: an in vitro study. AB - OBJECTIVE: The aim of this study was to evaluate in vitro the effects of frequently ingested beverages on force degradation of intermaxillary elastics. MATERIAL AND METHODS: One hundred and eighty 1/4-inch intermaxillary elastics (TP Orthodontics) were immersed into six different beverages: (1) Coca-Cola(r); (2) Beer; (3) Orange juice; (4) Red wine; (5) Coffee and (6) artificial saliva (control). The period of immersion was 15 min for the first and second cycles and 30 min for the third to fifth cycles. Tensile forces were read in a tensile testing machine before and after the five immersion cycles. One-way repeated measures ANOVA was used to identify significant differences. RESULTS: Force degradation was seen in all evaluated groups and at all observation periods (p<0.05). A greater degree of degradation was present at the initial periods, decreasing gradually over time. However, no statistically significant differences were seen among groups at the same periods, showing that different groups behaved similarly. CONCLUSION: The chemical nature of the evaluated beverages was not able to influence the degree of force degradation at all observation periods. PMID- 23739863 TI - Minimal alterations on the enamel surface by micro-abrasion: in vitro roughness and wear assessments. AB - OBJECTIVE: To evaluate the in vitro changes on the enamel surface after a micro abrasion treatment promoted by different products. MATERIAL AND METHODS: Fifty (50) fragments of bovine enamel (15 mm * 5 mm) were randomly assigned to five groups (n=10) according to the product utilized: G1 (control)= silicone polisher (TDV), G2= 37% phosphoric acid (3M/ESPE) + pumice stone (SS White), G3= Micropol (DMC Equipment), G4= Opalustre (Ultradent) and G5= Whiteness RM (FGM Dental Products). Roughness and wear were the responsible variables used to analyze these surfaces in four stages: baseline, 60 s and 120 s after the micro-abrasion and after polishing, using a Hommel Tester T1000 device. After the tests, a normal distribution of data was verified, with repeated ANOVA analyses (p<=0.05) which were used to compare each product in different stages. One-way ANOVA and Tukey tests were applied for individual comparisons between the products in each stage (p<=0.05). RESULTS: Means and standard deviations of roughness and wear (um) after all the promoted stages were: G1=7.26(1.81)/13.16(2.67), G2=2.02(0.62)/37.44(3.33), G3=1.81(0.91)/34.93(6.92), G4=1.92(0.29)/38.42(0.65) and G5=1.98(0.53)/33.45(2.66). At 60 seconds, all products tended to produce less surface roughness with a variable gradual decrease over time. After polishing, there were no statistically significant differences between the groups, except for G1. Independent of the product utilized, the enamel wear occurred after the micro-abrasion. CONCLUSIONS: In this in vitro study, enamel micro-abrasion presented itself as a conservative approach, regardless of the type of the paste compound utilized. These products promoted minor roughness alterations and minimal wear. The use of phosphoric acid and pumice stone showed similar results to commercial products for the micro-abrasion with regard to the surface roughness and wear. PMID- 23739864 TI - Alteration of the oral environment in patients undergoing esophagectomy during the perioperative period. AB - OBJECTIVE: During the perioperative period, oral ingestion is changed considerably in esophagectomy patients. The aim of this study was to investigate oral environment modifications in patients undergoing esophageal cancer treatments due to changes in dietary intake and swallowing functions. MATERIAL AND METHODS: Thirty patients who underwent operation for removal of esophageal cancer in Tokushima University Hospital were enrolled in this study. RESULTS: It was found that 1) the flow rate of resting saliva decreased significantly at postoperative period by deprived feeding for one week, although it did not recover several days after oral ingestion began, 2) the accumulation of dental plaque and the number of mutans streptococci in saliva decreased significantly after operation, while both increased relatively quick when oral ingestion began, and 3) the swallowing function decreased significantly in the postoperative period. CONCLUSIONS: These results suggest that dental professionals should emphasize the importance of oral health care and provide instructions on plaque control to patients during the perioperative period of esophageal cancer treatment. PMID- 23739865 TI - Prevalence of long face pattern in Brazilian individuals of different ethnic backgrounds. AB - OBJECTIVE: The long face pattern is a facial deformity with increased anterior total facial height due to vertical excess of the lower facial third. Individuals with long face may present different degrees of severity in vertical excess, as well as malocclusions that are difficult to manage. The categorization of vertical excess is useful to determine the treatment prognosis. This survey assessed the distribution of ethnically different individuals with vertical excess according to three levels of severity and determined the prevalence of long face pattern. MATERIAL AND METHODS: The survey was comprised of 5,020 individuals of Brazilian ethnicity (2,480 females and 2,540 males) enrolled in middle schools in Bauru-SP, Brazil. The criterion for inclusion of individuals with vertically impaired facial relationships was based on lip incompetence, evaluated under natural light, in standing natural head position with the lips at rest. Once identified, the individuals were classified into three subtypes according to the severity: mild, moderate, and severe. Then the pooled sample was distributed according to ethnical background as White (Caucasoid), Black (African descent), Brown (mixed descent), Yellow (Asian descent) and Brazilian Indian (Brazilian native descent). The Chi-square (chi2) test was used (p<0.05) to compare the frequency ratios of individuals with vertically impaired facial relationships in the total sample and among different ethnicities, according to the three levels of severity. RESULTS: The severe subtype was rare, except in Black individuals (7.32%), who also presented the highest relative frequency (45.53%) of moderate subtype, followed by Brown individuals (43.40%). In the mild subtype, Yellow (68.08%) and White individuals (62.21%) showed similar and higher relative frequency values. CONCLUSIONS: Black individuals had greater prevalence of long face pattern, followed by Brown, White and Yellow individuals. The prevalence of long face pattern was 14.06% in which 13.39% and 0.68% belonged to moderate and severe subtypes, respectively. PMID- 23739866 TI - To heal or not to heal? Chemokines as determinants of constructive or destructive inflammatory microenvironments. PMID- 23739867 TI - Expression profiles of vault components MVP, TEP1 and vPARP and their correlation to other multidrug resistance proteins in ovarian cancer. AB - Vaults are cytoplasmic ribonucleoprotein particles composed of three proteins (MVP, TEP1, vPARP) and vault-associated RNAs (vRNAs). Although the cellular functions of vaults remain unclear, vaults are strongly linked to the development of multidrug resistance (MDR), the major obstacle to the efficient treatment of cancers. Available published data suggest that vaults and their components are frequently upregulated in broad variety of multidrug-resistant cancer cell lines and tumors of different histological origin. Here, we provide detailed analysis of vault protein expression in post-surgery ovarian cancer samples from patients that were not exposed to chemotherapy. Our analysis suggests that vault proteins are expressed in the ovaries of healthy individuals but their expression in cancer patients is changed. Specifically, MVP, TEP1 and vPARP mRNA levels are significantly decreased in cancer samples with tendency of lower expression in higher-grade tumors. The pattern of vault protein mRNA expression is strongly correlated with the expression of other MDR-associated proteins such as MDR1, MRP1 and BCRP. Surprisingly, the protein levels of MVP, TEP1 and vPARP are actually increased in the higher-grade tumors suggesting existence of post transcriptional regulation of vault component production. PMID- 23739868 TI - From Lichtheim to rich club: brain networks and psychiatry. PMID- 23739869 TI - Reply to Letter to the Editor: The proper blood pressure may impaire cardiovascular risk factors. PMID- 23739870 TI - Responses to booster hepatitis B vaccination are significantly correlated with genotypes of human leukocyte antigen (HLA)-DPB1 in neonatally vaccinated adolescents. AB - Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the human leukocyte antigen (HLA)-DP loci that were significantly correlated with outcomes of hepatitis B virus (HBV) infection. We performed a case-control study nested in a well-characterized cohort of booster recipients to assess whether genetic variants of HLA-DPB1 are also associated with response to hepatitis B (HB) vaccination. The cases and controls were 171 and 510 booster recipients whose post-booster titers of antibodies against HBV surface antigen (anti-HBs) were undetectable and detectable, respectively. The HLA-DPB1 genotype was determined using sequence-based techniques. The frequencies of HLA-DPB1 alleles were significantly different between cases and controls (p = 1.7 * 10( 8)). The HLA-DPB1 05:01 and 09:01 alleles were significantly more frequent in the cases, and 02:01:02, 02:02, 03:01:01, 04:01:01, and 14:01, were significantly more frequent in the controls. The adjusted odds ratio (OR) of undetectable post booster anti-HBs titers was significantly correlated with the number of risk alleles (p for trend = 3.8 * 10(-5)). For the number of protective alleles, the trend was significantly inversed (p for trend = 1.3 * 10(-5)). As compared with subjects with two risk alleles, adjusted OR were 0.34 (95 % confidence interval [CI] 0.21-0.55) and 0.20 (95 % CI 0.08-0.48) for subjects with 1 and 2 protective alleles, respectively. The HLA-DPB1 02:02, 04:01:01, 05:01 and 09:01 alleles were also significantly correlated with the likelihoods of undetectable pre-booster anti-HBs titers. Our results indicated that HLA-DPB1 is significantly correlated with response to booster HB vaccination in adolescent who had received postnatal active HB vaccination. HLA-DBP1 may also determine the long-term persistence of response to HB vaccination. PMID- 23739871 TI - Understanding super-resolution nanoscopy and its biological applications in cell imaging. AB - Optical microscopy has been an ideal tool for studying phenomena in live cells because visible light at reasonable intensity does not perturb much of the normal biological functions. However, optical resolution using visible light is significantly limited by the wavelength. Overcoming this diffraction-limit barrier will reveal biological mechanisms, cellular structures, and physiological processes at a nanometer scale, orders of magnitude lower than current optical microscopy. Although this appears to be a daunting task, recently developed photoswitchable probes enable reconstruction of individual images into a super resolution image, thus the emergence of nanoscopy. Harnessing the resolution power of nanoscopy, we report here nano-resolution fluorescence imaging of microtubules and their network structures in biological cells. The super resolution nanoscopy successfully resolved nanostructures of a microtubule network-a daunting task that cannot be completed using conventional wide-field microscopy. PMID- 23739872 TI - An alternate protocol for establishment of primary caprine fetal myoblast cell culture: an in vitro model for muscle growth study. AB - Cultured myoblasts have been used extensively as an in vitro model in understanding the underlying mechanisms of myogenesis. Various protocols for establishing a pure myoblast culture have been reported which involve the use of special procedures like flow cytometry and density gradient centrifugation. In goat, only a few protocols for establishing a myogenic cell culture are available and these protocols use adult muscle tissues which often does not yield sufficient numbers of precursor cells with adequate proliferative capacity. Considering the disadvantages of adult myoblasts, we are proposing an alternate protocol using caprine fetus which does not require any special procedures. In the present study, more than 90-95% fetal-derived cell populations had the typical spindle to polyhedral shape of myoblast cell and stained positive for desmin, hence confirming their myogenic origin. These cells attained the maximum confluency as early as 3-4 d against 3 wk by adult myoblasts indicating a better growth potential. Further, quantitative real-time PCR analysis revealed a higher expression (p < 0.01) of myogenic regulatory factors (i.e., myogenic determination factor 1, myogenic factor 5, and myogenin) and myostatin (MSTN) in the fetal as compared to the adult myoblasts. Consequently, higher proliferation and differentiation ability along with higher abundance of myogenic markers and MSTN make the fetal myoblasts a better in vitro model. PMID- 23739873 TI - Survivability of parthenogenetic embryos following in vivo transfer in naturally synchronized Capra hircus. AB - The present study was conducted to see the in vivo developmental potency of caprine parthenogenetic embryos generated in a modified way. The good quality caprine oocytes were matured in presence of cytochalasin B (CCB) and then activated by 7% ethanol followed by 2 mM 6-dimethyl amino purine (6-DMAP) and embryo development was recorded. Early stage parthenogenetic embryos (two to four cells) were surgically transferred in recipients (10). The pregnancy diagnosis was done by nonreturn to oestrus, ultrasonography (USG), and progesterone estimation. The levels of progesterone were above normal values (1 ng/ml) of pregnancy and fall below the level of pregnancy just before retuned to oestrus. Progesterone profile revealed that out of ten recipients (G1-G10), four goats (G1, G2, G3, and G5) returned to oestrus after 43 +/- 7.29 (Mean +/- SE) d of embryo transfer and six goats (G4, G6, G7, G8, G9, and G10) did not return to cycle even after 70 d of embryo transfer. In three recipients (G4, G5, and G6), the USG on day 40 revealed that there was fluid filled uterine body with solid fetus-like structure. These might be dead fetus and had started resorption. The progesterone profile also corroborated the assumption of pregnancy in these animals. Authors believe that this may be the first report on in vivo diploid parthenogenetic embryo development in caprine species. PMID- 23739874 TI - Hypoxia affects in vitro proliferation and differentiation of mouse corneal epithelial progenitor cell. AB - This study was to investigate the proliferation and differentiation of mouse corneal epithelial progenitor cell in hypoxic airlift culture. Mouse corneal epithelial progenitor cell line progenitor cells were cultured under airlift with normoxic and hypoxic conditions for various durations up to 2 wk. Under normoxic conditions when exposed to air, the hyperproliferation and abnormal epidermal like differentiation of mouse corneal epithelium was induced, whereas when exposed to air under hypoxic conditions, although we observed augmented proliferation, the abnormal differentiation was inhibited. The mechanism by which hypoxia prevents abnormal differentiation may involve downregulation of Wnt signaling pathways, which were inhibited in cells cultured with hypoxic airlift technique. In conclusion, hypoxia can prevent abnormal differentiation while enhancing the proliferation of corneal epithelial cells by blocking Wnt/beta catenin signaling pathway. PMID- 23739875 TI - Understanding the external pressure and behavior of commercial banks' environmental risk management: an empirical study undertaken in the Yangtze River delta of China. AB - The present study employed a quantitative survey to ascertain whether the external pressure of environmental risk management (ERM) on commercial banks was a contributing factor to their ERM behavior. Data was obtained using questionnaires from 204 branches of commercial banks located in the Yangtze River Delta of China. The relationship between external pressure and behavior was tested using a linear structural relations model through path analysis. The results revealed that external pressure of ERM was significantly and positively related to the behavior and that pressure from governmental regulations was the most important contributing factor in the passive feedback behavior and preventive behavior of commercial banks. The pressure from markets was the most important contributing factor in banks' active participation behavior; the pressure from community and NGOs was the most important contributing factor in their enthusiastic behavior. PMID- 23739876 TI - Progress and transition: so how are we doing? PMID- 23739877 TI - NYSCHP presidential address. PMID- 23739882 TI - Risk factors associated with malnutrition in older adults living in Italian nursing homes: a cross-sectional study. AB - Malnutrition is a significant problem among older adults living in nursing homes: Malnourished residents are at increased risk of hospitalization and mortality. Multiple factors determine malnutrition, and the extant literature has focused attention on individual factors such as aging, sex, and dependence in activities of daily living. However, little evidence is available on factors influenced by nursing care. Exploring the relationship between the nutritional status of nursing home residents and certain individual factors, including those potentially influenced by nursing care, was the aim of this cross-sectional study. A total of 186 nursing home residents was enrolled in the study; in addition, 18 nurses were involved in the data collection process. Twenty-one percent of the residents had an adequate nutritional status, 43% were at risk of malnutrition, and 36% were malnourished. Multivariate analysis revealed that those independent factors associated with malnutrition, once adjusted for age, sex, and dependence in activities of daily living, were: having had a stroke, being dependent in activities of daily living, eating half or less of food provided at mealtimes, and having their weight checked only every 3 months or longer. Nursing care projects may be effective in reducing the risk of malnutrition among nursing home residents. However, further research is needed to develop knowledge of the factors associated with malnutrition and those influenced by care delivered in nursing homes. PMID- 23739883 TI - Carbon nanotubes exert basic excitatory enhancement in rat brain slices. AB - Carbon nanotubes are promising new tools in biomedicine but they may have yet some unknown influences on the organism. In the present study, the acute effect of solubilized, multi-walled carbon nanotubes (MWCNTs) on basic neuronal functions was examined. Rat brain slices were treated in vitro with nanotube containing colloid solutions at concentrations of 100-800 MUg/ml and evoked field potentials were recorded from the somatosensory cortex and hippocampus. Basic excitability of the treated slices was characterized by the amplitude of field excitatory postsynaptic potentials (fEPSPs) and population spikes. Experimental results indicated significantly higher excitability of treated samples than that of controls. Multiple components in evoked potentials were observed, which is in accordance with the increased excitability of investigated brain areas. Tests of short- and long-term plasticity were also performed, which revealed no difference between control and treated slices. Experimental results suggest an interaction between nanotubes and brain tissue. MWCNTs seem to act on the basic membrane potential of neurons by changing membrane properties or via a mechanism linked to voltage-gated ion channels, rather than influencing specific synaptic transmission. Further investigation is needed to clarify the nature of interactions between nanotubes and brain tissue. PMID- 23739884 TI - A comparative study of hepatic mitochondrial oxygen consumption in four vertebrates by using Clark-type electrode. AB - The present study was undertaken to establish a comparative account on hepatic mitochondrial oxygen consumption of Clarias gariepinus (fish), Bufo melanostictus (amphibian), Gallus gallus (bird) and Rattus norvegicus (mammal) and to correlate it with their specific metabolic rate (SMR). Mitochondrial oxygen consumption was measured with a Clarke-type electrode with succinate and pyruvate/malate as substrates. ADP was used to start state-III respiration. The results show that rats and chickens have higher oxygen consumption rate than that of fish and toads. Similarly, a species and substrate specific difference was also noticed in P/O (phosphate utilized per oxygen atom) ratio and respiratory control index. In case of rat, a significant negative correlation was noticed between P/O ratio and SMR with succinate as substrate. It is surmised that the observed difference in the mitochondrial respiration and P/O ratio in the above vertebrates is due to the difference in their metabolic activities. PMID- 23739885 TI - Temporospatial expression of Dmrt1 in chicken urogenital system (Gallus gallus) using whole mount in situ hybridization. AB - Doublesex and mab-3-related transcription factor 1 (Dmrt1) is a Z-linked gene that putatively determines the phenotype of gonads in birds. The sex differential expression of Dmrt1 was examined using wholemount in situ hybridization (WISH) in the urogenital systems during embryogenesis. The results revealed that Dmrt1 showed dimorphic expression in chicken gonads, which increased from day 6.5 to day 10.5. The expression of Dmrt1 in male (ZZ) gonads was not twice as much as in female (ZW) gonads, suggesting the existence of other regulatory mechanisms in addition to Z chromosome dosage effect. PMID- 23739886 TI - Quantitative trait loci for morphometric body measurements of the hybrids of silver carp (Hypophthalmichthys molitrix) and bighead carp (H. nobilis). AB - Quantitative trait loci (QTL) for 11 morphometric body measurements of the hybrids of silver (Hypophthalmichthys molitrix) and bighead carp (H. nobilis) including body weight (BW), standard length (SL), body depth (BD), body thickness (BT), head length (HL), head depth (HD), length of ventral keel (LVK), length of pectoral fin (Lpec), length of pelvic fin (Lpel), length of caudal fin (Lcau) and space between pectoral and pelvic fins (SPP) were located on the sex average microsatellite linkage map constructed using the hybrids of a female bighead and a male silver carp, on which 15 microsatellites were newly mapped. One locus was found to be responsible for BW, LV K and SPP, respectively. As many as 6 loci were found to be responsible for HD. The variances of remaining traits were partitioned by different numbers of loci varying between 2 and 5. The variance explained each locus ranged from 9.1% to 23.8% of the total. The variance explained by all loci responsible for each measurement ranged from 17.7% to 75.1%. It was noted that multiple measurements were mapped on the same locus. For example, a region bounded by Hym435 and Hym145 was found to be responsible for all the measurements analyzed. PMID- 23739887 TI - Optimization of DNA isolation and PCR protocol for analysis and evaluation of genetic diversity of the medicinal plant, Anemopsis californica using RAPD. AB - Anemopsis californica is a perennial herbaceous plant that has been utilized as a medicinal plant for the treatment of various diseases. The present work was carried out with the objective of optimizing a method of extraction of the genomic DNA of A. californica and a PCR protocol and later to evaluate the existing genetic diversity among the genotypes deriving from different origins. For DNA extraction, we tested four procedures: with the CTA B-2 protocol, we obtained the highest yield (61.5+/-2.2 MUg DNA/g of leaf tissues) and the best quality (A260/280 1.83+/-0.022). To estimate genetic variability, we utilized the randomly amplified polymorphism DNA (RAPD) technique, employing 20 oligonucleotides, of which only 18 generated reproducible banding patterns, producing 123 polymorphic bands generated, thus obtaining a polymorphism rate of 93.93% among the genotypes analyzed. The Jaccard similarity coefficient generated a variation ranging from 0.325-0.921, indicating a high level of genetic variation among the studied genotypes. An Unweighted pair-group method with arithmetic mean (UPGMA) group analysis indicated six distinct groups. The present optimized method for DNA isolation and RAPD protocol may serve as an efficient tool for further molecular studies. PMID- 23739888 TI - Phenolics metabolism in boron-deficient tea [Camellia sinensis (L.) O. Kuntze] plants. AB - Modification in the metabolism of phenolic compounds under boron (B) deficiency conditions was studied in tea plants. Plants were grown from seed, treated with low B in hydroponic medium under environmentally controlled conditions for six weeks. Dry matter production and B content of plants were significantly declined under B deficiency conditions. Boron starvation resulted in rising phenylalanine ammonia lyase activity in the young leaves and declining polyphenol oxidase activity in the roots. Soluble phenolics fraction was increased up to 3.4-fold in the young leaves while did not influence by B nutrition in the old leaves and roots. Cell wall (CW) bound phenolics and lignin content was lower in B-deficient plants compared with B-sufficient ones. Boron deficiency increased significantly activity of soluble peroxidase (POD) only in the leaves. Activity of ionically bound POD was decreased in the old leaf and roots while it increased in the young leaves upon B deprivation. Activity of covalently bound POD decreased in the roots and leaves of different age in low B plants. Our results suggested that tea plant is highly tolerant species to B deficiency and CW tightening and accumulation of oxidized phenolics are not mechanisms for growth inhibition under B deficiency conditions. PMID- 23739889 TI - Enzymatic and non-enzymatic antioxidant responses of alfalfa leaves and roots under different salinity levels. AB - The effect of increasing NaCl concentrations on biomass, hydrogen peroxide (H2O2), ascorbic acid (ASC), proline and total thiol, and the activity of some antioxidant enzymes in alfalfa (Medicago sativa L. cv. Gara-Yonjeh) were investigated. The dry weights of roots and shoots with increasing NaCl concentrations decreased progressively, and the strongest toxicity was detected at NaCl treatment of 200 mM. Superoxide dismutase (SOD) activity in the leaves increased gradually up to NaCl concentrations of 100, while the higher concentration of NaCl reduced SOD activity in both leaves and roots. The maximum levels of ascorbate peroxidase (APX) activity were increased at 150 mM and 100 mM NaCl in leaves and roots of Gara-Yonjeh, respectively. Peroxidase (POD) activity in roots of Gara-Yonjeh increased (82% at 200 mM) by salinity, while it decreased (43% at 200 mM) in leaves. In contrast, catalase (CAT) activity increased (84% at 200 mM) in leaves, and decreased (57% at 200 mM) in the roots of Gara-Yonjeh. Electrophoresis analysis suggested that different patterns in SOD, CAT and POD isoenzymes depend on NaCl concentrations, and the staining intensities of these isoforms are supported the results obtained from the spectrophotometric determinations. In POD and CAT, activity of isoform III was detected at all concentrations, by a "low-high-low" pattern, with the maximum activity at 50 mM of NaCl. Results imply that the function of antioxidant systems in higher NaCl concentration is responsible for the salt tolerance observed in Gara-Yonjeh. PMID- 23739890 TI - Efficient plant regeneration of yellow loosestrife (Lysimachia vulgaris L.), a medicinal plant. AB - Lysimachia vulgaris L. (yellow loosestrife) is a medicinal plant that has been used in the treatment of fever, ulcer, diarrhea and wounds in traditional medicine. A reliable in vitro culture protocol for yellow loosestrife was established. Explants (leaf lamina, stem internode and root segments) were cultured on Murashige and Skoog minimal organics (MSMO) medium supplemented with various plant growth regulator combinations. Of the tested combinations, those involving benzyladenine (BA) with either indole-3-acetic acid (IAA) or indole-3 butyric acid (IBA) were the most effective for all used explants in shoot production. Best shoot proliferation was obtained from leaf lamina explant cultured on media containing 0.5 mg/l BA and 0.1, 0.5 or 1 mg/l IBA, from stem internode explant cultured on media containing 1 mg/l BA and 0.5 mg/l IBA or 0.01 mg/l thidiazuron (TDZ) and 0.5 mg/l IAA, and from root explant cultured on media containing 0.5 mg/l BA and 0.5 mg/l IAA. Regenerated shoots were rooted on MSMO medium containing different concentrations of IAA, IBA, 2,4-dichlorophenoxyacetic acid (2,4-D) and naphthalene acetic acid (NAA). IBA was determined as the most effective auxin for rooting. Most shoots developed roots on medium with 0.5 mg/l IBA. PMID- 23739891 TI - Assessment of morphological and molecular similarity of Hungarian white grape varieties. AB - The aim of this paper was to find possible link between molecular and morphological similarities of 38 Hungarian white grape varieties. Three aspects of morphological and molecular similarity were assessed in the study: comparison of the ordered variety pairs, assessment of molecular and morphological mean similarity differences and separation of varieties into similar groups by divisive cluster analysis to define (DIANA). Molecular similarity was calculated from binary data based on allele sizes obtained in DNA analysis. DNA fingerprints were determined at 9 SSR loci recommended by the European GrapeGen06 project. Morphological similarity was calculated on the basis of quantitative morphological descriptors. Morphological and molecular similarity values were ordered and categorized after pairwise comparison. Overall correlation was found to be weak but case by case assessment of the variety pairs confirmed some coincidence of molecular and morphological similarity. General similarity position of each variety was characterized by Mean Similarity Index (MSI). It was calculated as the mean of n-1 pair similarity values of the variety concerned. Varieties were ordered and compared by the difference of the index. Five varieties had low morphological and high molecular MSI meaning that they share several SSR marker alleles with the others but seems relatively distinct according to the expression of their morphological traits. Divisive cluster analysis was carried out to find similar groups. Eight and twelve cluster solutions proved to be sufficient to distinct varieties. Morphological and molecular similarity groups partly coincided according to the results. Several clusters reflected parent offspring relations but molecular clustering gave more realistic results concerning pedigree. PMID- 23739892 TI - Synthesis and different biological activities of novel benzoxazoles. AB - A series of 2-[4-(4-substitutedbenzamido/phenylacetamido/butanamido)phenyl]-5 ethylsulphonyl-benzoxazole derivatives were synthesized and biologically evaluated as possible antimicrobial agents and inhibitors of tyrosinase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). The results demonstrated that the synthesized compounds exhibited a broad spectrum of activity with minimum inhibitory concentration (MIC) values of 128-16 MUg/ml against some Gram-positive, Gram-negative bacteria as well as Candida albicans and C. krusei. The compound 10 displayed higher activity in this series against methicilline resistant Staphylococcus aureus (MRSA) with a MIC value of 16 MUg/ml than the compared control drugs ampicillin and ceftriaxone. Compound 14 showed moderate tyrosinase inhibition, however, none of the compounds showed effect as inhibitor of AChE and BChE. PMID- 23739893 TI - Rapid genotyping of genetically modified laboratory animals from whole blood samples without DNA preparation. AB - A new, rapid method is described which permits the genotyping of genetically modified animals from a microlitre volume of whole blood samples via one step polymerase chain reaction amplification. The major advantage of the presented method is the exclusion of a DNA preparation step, which significantly reduces the time expenditure and work load of the genetic testing. Pilot studies indicate, that this method is efficient and applicable also on tissue biopsies and larger amount of blood providing a rapid and reliable new technique over conventional genotyping approaches. PMID- 23739896 TI - The new metabolic treatments for sarcopenia. AB - In terms of managing sarcopenia, many studies have shown that physical activity (in particular resistance exercise) and specific nutrition interventions such as protein and amino acids supplementation can improve muscle mass and strength in older adults. Moreover, several drugs have been suggested to have an impact on muscle outcomes, with various levels of scientific evidence. In the present paper we have reviewed the evidence regarding the effect of some new metabolic agents (vitamin D, leucine, beta-hydroxy beta-methylbutyrate, citrulline malate, ornithine, isoflavones) on sarcopenia and muscular outcomes in older adults. For each metabolic agent, we have also discussed the biological plausibility of the described effect. PMID- 23739894 TI - Epigenome-wide inheritance of cytosine methylation variants in a recombinant inbred population. AB - Cytosine DNA methylation is one avenue for passing information through cell divisions. Here, we present epigenomic analyses of soybean recombinant inbred lines (RILs) and their parents. Identification of differentially methylated regions (DMRs) revealed that DMRs mostly cosegregated with the genotype from which they were derived, but examples of the uncoupling of genotype and epigenotype were identified. Linkage mapping of methylation states assessed from whole-genome bisulfite sequencing of 83 RILs uncovered widespread evidence for local methylQTL. This epigenomics approach provides a comprehensive study of the patterns and heritability of methylation variants in a complex genetic population over multiple generations, paving the way for understanding how methylation variants contribute to phenotypic variation. PMID- 23739895 TI - The maize methylome influences mRNA splice sites and reveals widespread paramutation-like switches guided by small RNA. AB - The maize genome, with its large complement of transposons and repeats, is a paradigm for the study of epigenetic mechanisms such as paramutation and imprinting. Here, we present the genome-wide map of cytosine methylation for two maize inbred lines, B73 and Mo17. CG (65%) and CHG (50%) methylation (where H = A, C, or T) is highest in transposons, while CHH (5%) methylation is likely guided by 24-nt, but not 21-nt, small interfering RNAs (siRNAs). Correlations with methylation patterns suggest that CG methylation in exons (8%) may deter insertion of Mutator transposon insertion, while CHG methylation at splice acceptor sites may inhibit RNA splicing. Using the methylation map as a guide, we used low-coverage sequencing to show that parental methylation differences are inherited by recombinant inbred lines. However, frequent methylation switches, guided by siRNA, persist for up to eight generations, suggesting that epigenetic inheritance resembling paramutation is much more common than previously supposed. The methylation map will provide an invaluable resource for epigenetic studies in maize. PMID- 23739897 TI - Chronic gout in the elderly. AB - Gout is the most common cause of inflammatory arthritis in men over 40 years old; it is a debilitating disease and, if untreated, can result in a chronic progressive disease, including tophaceous gout. In the elderly it represents a special issue, with notable clinical and therapeutic differences from the classical form with a systemic involvement. The burden of the disease increases particularly in the very old people, in whom arthritis, impaired gait and eyesight problems may enhance the related disability. Chronic gout moreover could aggravate heart and kidney disease and increase overall mortality and organ related damage. Early diagnosis and appropriate treatment are important goals for the clinician that should to rely on the cooperation of specialists working together through the methodology of comprehensive geriatric assessment. The aim of the present review was to analyze chronic gout in old people in terms of epidemiology, pathophysiology, risk factors, clinical approach, and current treatment. PMID- 23739898 TI - Telomere, aging and age-related diseases. AB - Aging is an inevitable biological process that affects most living organisms. The process of aging is regulated at the level of the organism, as well as at the level of tissues and cells. Despite the enormous consequences associated with the aging process, relatively little systematic effort has been expended on the scientific understanding of this important life process. Many theories have been proposed to explain the aging process, the centerpiece of which is molecular damage. Located at the ends of eukaryotic chromosomes and synthesized by telomerase, telomeres maintain the stabilization of chromosomes. Thus, the loss of telomeres may lead to DNA damage. The relationship between cellular senescence and telomere shortening is well established. Furthermore, telomere attrition occurs with age, and is proposed to be a fundamental factor in the aging process. Here, we review the contemporary literatures to explore the current views on the correlation of telomere loss and telomerase action with aging and age-related diseases. PMID- 23739899 TI - Unstimulated whole saliva 25-hydroxycholecalciferol in patients with xerostomia in menopausal women. AB - BACKGROUND AND AIM: The aim of this study was to compare unstimulated whole saliva 25-hydroxycholecalciferol (25(OH)D) in menopausal women with and without oral dryness (OD) feeling, and evaluate the relationship between saliva 25(OH)D and severity of OD feeling. METHODS: A case-control study was carried out on 70 selected menopausal women aged 41-77 years with or without OD feeling (35 as case and 35 as control) conducted at the Clinic of Oral Medicine, Tehran University of Medical Sciences. Unstimulated saliva samples were obtained by expectoration. Xerostomia inventory (XI) score was used as an index of OD feeling severity. The saliva 25(OH)D concentration was measured by ELISA. Statistical analysis of Student's t test and Spearman correlation was used. RESULTS: The mean saliva 25(OH)D level was significantly higher in the case group (897.1 +/- 128.9 pg/ml), compared with control (156.7 +/- 43.4 pg/ml; P < 0.05). XI score correlated significantly with saliva 25(OH)D concentration (r = 0.457, P < 0.001). CONCLUSIONS: It seems that the level of salivary 25(OH)D concentration may be higher in menopausal women with OD feeling than in the control group, and there is a positive correlation between OD feeling severity and unstimulated whole saliva 25(OH)D. PMID- 23739900 TI - Circadian rhythm of TSH levels in subjects with Alzheimer's disease (AD). AB - OBJECTIVES: The circadian rhythm of serum thyroid stimulating hormone (TSH) levels in patients with Alzheimer's disease was measured by means of a case control study. METHODS: Serum samples from cases and controls were collected continuously for 2 days, and then once every 2 h (even number time-point during the first day and odd number time-point in the second). TSH was detected by radioimmunoassay. RESULTS: AD patients had no significant circadian rhythm in serum TSH levels, whereas normal controls did. In normal controls, serum TSH levels from 19:00 to 20:00 were the lowest (19:00, 3.89 +/- 0.97 mIU/L; 20:00, 3.76 +/- 0.84 mIU/L) and those in the period 2:00-4:00 were the highest (2:00, 6.15 +/- 0.94 mIU/L; 3:00, 6.32 +/- 1.04 mIU/L; 4:00, 6.39 +/- 1.13 mIU/L; F = 6.762, df = 23, P = 0.002). However, in AD patients, 24-h serum TSH levels were 3.80-4.03 mIU/L (F = 0.897, df = 23, P = 0.996). At the 24 time-points, except for the four time-points from 16:00 to 19:00, TSH levels in AD patients were significantly lower than those in normal controls. CONCLUSIONS: The circadian rhythm of serum TSH levels in AD patients did not appear, and their serum TSH levels were significantly lower than those in normal controls. SIGNIFICANCE: The circadian rhythm in serum TSH levels in AD patients differs greatly from that of the general population. PMID- 23739901 TI - Multiple joint muscle function with ageing: the force-velocity and power-velocity relationships in young and older men. AB - BACKGROUND AND AIMS: Whilst extensive research has detailed the loss of muscle strength with ageing for isolated single joint actions, there has been little attention to power production during more functionally relevant multiple joint movements. The extent to which force or velocity are responsible for the loss in power with ageing is also equivocal. The aim of this study was to evaluate the contribution of force and velocity to the differences in power with age by comparing the force-velocity and power-velocity relationships in young and older men during a multiple joint leg press movement. METHODS: Twenty-one older men (66 +/- 3 years) and twenty-three young men (24 +/- 2 years) completed a series of isometric (maximum and explosive) and dynamic contractions on a leg press dynamometer instrumented to record force and displacement. RESULTS: The force velocity relationship was lower for the older men as reflected by their 19 % lower maximum isometric strength (p < 0.001). Explosive isometric strength (peak rate of force development) was 21 % lower for the older men (p < 0.05) but was similar between groups when normalised to maximum strength (p = 0.58). The power velocity relationship was lower for the older men as shown by reduced maximum power (-28 %, p < 0.001) and lower force (-20 %, p < 0.001) and velocity (-11 %, p < 0.05). CONCLUSIONS: Whilst force and velocity were lower in older men, the decrement in force was greater and therefore the major explanation for the attenuation of power during a functionally relevant multiple joint movement. PMID- 23739902 TI - Body composition, fitness level, anabolic hormones, and inflammatory cytokines in the elderly: a randomized controlled trial. AB - BACKGROUND AND AIMS: Elastic band exercise is considered as an effective and safe resistance type of exercise. However, there is a paucity of knowledge of the physiological effect of long-term elastic band exercise in the elderly. The purpose of this study was to examine the effects of a 12-week elastic band exercise program on body composition, physical fitness, anabolic hormones, and inflammatory cytokines in the elderly. METHODS: The subjects (aged 65-82 years) were randomly assigned into the exercise group (n = 18) or the control group (n = 22). Elastic band exercise session was performed for 60 min, three times per week for 12 weeks, during which various types of resistance exercises were assigned to the exercise group using red-colored bands. Body composition was analyzed using the biolelectrical impedance measurement. Senior fitness test was adopted to determine the level of physical fitness. RESULTS: After 12 weeks of band exercise program, body composition and all fitness components of senior fitness test were significantly improved in the exercise group compared to the control group. In contrast, blood lipid profiles (TC, TG, and HDL), anabolic hormones (GH, IGF-1 and IGFBP-3), and inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, and CRP) were not significantly changed in the exercise group compared to the control group. CONCLUSIONS: Our results showed that elastic band exercise did not appear to positively impact on blood lipids, anabolic hormones, and inflammatory cytokines, but significantly improved body composition and overall physical fitness level in the elderly. PMID- 23739903 TI - Sleep/wake patterns and physical performance in older adults. AB - BACKGROUND AND AIMS: Sleep problems are common in older adults. They have been associated with reduced physical functionality affecting their health, well being, and consequently their overall quality of life. We conducted this study to examine the association between sleep/wake patterns and functional capacity in hypertensive older adults. METHODS: Participants were recruited from the study "Effect of the angiotensin-converting enzyme inhibitors over grip strength and functionality of older adults" and accepted to be part of this cross-sectional study. Subjects were 97 older adults with a mean age of 74.8 +/- 3.3 years and 77 % were women. Sleep/wake patterns were determined through actigraphic data and the following variables were determined: total sleep time, number of awakenings and wake after sleep onset within the nocturnal period, and number of naps and total sleep time during the diurnal period. Functional performance measurements included short physical performance battery and grip strength. Differences in physical performance according to sleep/wake patterns were explored, and the association between the sleep/wake patterns and functionality adjusting by sex, age, body mass index, use of angiotensin-converting enzyme, number of diseases, and hypnotic intake was studied using logistic regression analysis. RESULTS: Subjects sleeping <7.0 h or having fragmented sleep with >2.0 awakenings/night had a slightly but significant higher odds ratio of having functional performance impairment (p < 0.05). CONCLUSION: Our results suggest that a better nighttime sleep consolidation might help improve daytime physical performance of older people. PMID- 23739904 TI - Alcohol consumption and body composition in a population-based sample of elderly Australian men. AB - BACKGROUND: Alcohol is calorie dense, and impacts activity, appetite and lipid processing. The aim of this study was to therefore investigate the association between alcohol consumption and components of body composition including bone, fat and lean tissue. METHODS: Participants were recruited from a randomly selected, population-based sample of 534 men aged 65 years and older enrolled in the Geelong Osteoporosis Study. Alcohol intake was ascertained using a food frequency questionnaire and the sample categorised as non-drinkers or alcohol users who consumed <=2, 3-4 or >=5 standard drinks on a usual drinking day. Bone mineral density (BMD), lean body mass and body fat mass were measured using dual energy X-ray absorptiometry; overall adiposity (%body fat), central adiposity (%truncal fat) and body mass index (BMI) were calculated. Bone quality was determined by quantitative heel ultrasound (QUS). RESULTS: There were 90 current non-drinkers (16.9 %), 266 (49.8 %) consumed 1-2 drinks/day, 104 (19.5 %) 3-4 drinks/day and 74 (13.8 %) >=5 drinks/day. Those consuming >=5 drinks/day had greater BMI (+4.8 %), fat mass index (+20.1 %), waist circumference (+5.0 %), %body fat (+15.2 %) and proportion of trunk fat (+5.3 %) and lower lean mass ( 5.0 %) than non-drinkers after adjustment for demographic and lifestyle factors. Furthermore, they were more likely to be obese than non-drinkers according to criteria based on BMI (OR = 2.83, 95 %CI 1.10-7.29) or waist circumference (OR = 3.36, 95 %CI 1.32-8.54). There was an inverse relationship between alcohol consumption and QUS parameters and BMD at the mid forearm site; no differences were detected for BMD at other skeletal sites. CONCLUSION: Higher alcohol intake was associated with greater total and central adiposity and reduced bone quality. PMID- 23739905 TI - Activities of daily living dependency and disease-specific mortality during 12 year follow-up in an 80-year-old population. AB - BACKGROUND AND AIMS: Although total mortality is likely to be higher in elderly individuals with frailty or impaired activities of daily living (ADL), little is known about the relationships between disease-specific mortality and ADL dependency in the elderly. Therefore, we examined whether 12-year disease specific mortality may be associated with ADL dependency in an 80-year-old population. METHODS: In 1998, of 1,282 community-dwelling residents of Japan's Fukuoka Prefecture, 824 (64.3 %) (309 males and 515 females) participated, the remaining 458 subjects did not participate, and their deaths and causes of death were followed up for 12 years after the baseline examination. ADL dependency was determined according to the guidelines for disabled elderly from the Health, Labor, and Welfare Ministry of Japan, and ADL dependency was measured only at baseline. RESULTS: During the 12-year follow-up, 506 died, 276 did not die, and 42 were lost. Of the 506 who died, 128 died due to cardiovascular disease, 96 to respiratory tract disease, 87 to cancer, and 51 to senility. The subjects were classified into three groups as follows: ADL-1 (independent group, n = 600), ADL 2 (almost-independent group, n = 113), and ADL-3 (dependent group, n = 93).Total cause mortality was 2.8 times higher in ADL-3 subjects, respiratory disease mortality was 4.1 times higher in ADL-3 subjects, and senility mortality was 5.7 times higher in ADL-3 subjects than in ADL-1 subjects, after adjusting for various confounding factors. There was no association between mortality due to cancer or cardiovascular disease and ADL dependency. CONCLUSIONS: We found an independent association between ADL dependency and mortality due to all causes, respiratory disease or senility, but no association with mortality due to cancer or cardiovascular disease. These findings suggest that improving ADL dependency may reduce all mortality and mortality due to respiratory disease or senility. PMID- 23739906 TI - The ability to point to well-known places in young and older adults. AB - BACKGROUND AND AIMS: A mental map of well-known places is organized according to a specific orientation where spatial information located in front of a person is more accessible than information located at the back (front-back effect). This study investigated age-related differences between young and older adults in building a mental map of well-known places when front and back pointing were required. METHODS: Thirty young (20-30 year olds) and 29 older (60-72 year olds) adults living in the same Italian town were compared in their ability to point to places inside their own town, and surrounding villages located in the front and back of their physical position in the city. A series of visuo-spatial tasks were also administered. RESULTS: Our results showed that young and older adults' performance in pointing to well-known places did not differ significantly, and that participants were affected by the pointing direction (i.e. forwards vs. backwards) and the type of place (i.e. in town vs. surrounding villages). It was easier for both young and older adults to point to places in town that were in front of them rather than behind them; there were no differences between pointing forwards or backwards in the surrounding villages. The influence of visuo-spatial abilities on pointing performance changed as a function of age: it was only in the older adults (not in the younger) that a spatial visualization task correlated with pointing performance. CONCLUSIONS: This study showed that older adults, despite their spatial cognitive decline shown by visuo-spatial tasks, retained the ability to build a mental representation of well-known places and were specifically sustained by spatial visualization ability. PMID- 23739907 TI - Merkel cell carcinoma in elderly: case report and review of the literature. AB - Merkel cell carcinoma (MCC) is a rare neuroendocrine tumour of the skin, characterised by an aggressive clinical course. The incidence of this rare neoplasia is rapidly increasing. Herein we report our experience with a patient who developed a MCC of the inguinal region. PMID- 23739908 TI - Cytomegalovirus esophagitis precipitated with immunosuppression in elderly giant cell arteritis patients. AB - Cytomegalovirus (CMV) infection is generally associated with significant immunosuppression. Cellular immunity is particularly important and corticosteroid treatment increases the risk of CMV infection substantially. Immunocompetence generally decreases with age, older patients are at higher risk for developing CMV disease than are younger patients. CMV infection in the immunocompetent adults is quite rare. Esophagitis is the second most common gastrointestinal manifestation of CMV infection after colitis. Herein, we present three cases of giant cell arteritis who developed CMV esophagitis after various periods of corticosteroid treatment. CMV infection should be included in the differential diagnosis of GI disease in immunocompromised patients, and the clinician should pursue appropriate diagnostic and therapeutic interventions aggressively. PMID- 23739910 TI - Myopathy as paraneoplastic syndrome of colon malignancy in an elderly patient. AB - Neoplastic diseases may be complicated by rheumatic diseases or may be occur with them. Dermatomyositis/polymyositis and polymyalgia rheumatica are described as paraneoplastic syndromes. We report a case with proximal muscular weakness as only symptom of colon cancer in the absence of other symptoms and laboratory abnormalities, and we discuss the nosological classification as a possible atypical form of polymyositis. PMID- 23739911 TI - Percutaneous transluminal angioplasty for critical limb ischemia in very elderly diabetic patients. AB - In diabetic subjects, new less invasive therapies for critical limb ischemia (CLI) are available to obtain limb salvage. One of these is the percutaneous transluminal angioplasty (PTA), a minor surgical intervention which allows obtaining an effective revascularization, avoiding the traditional major surgery and its post-operative complications. Our case report regards a 94-year-old woman with CLI due to critical obstruction (stage IV according to Leriche's classification) of superficial femoral and popliteal arteries and infrapopliteal arteries that should have been treated by the left limb amputation considering her age, severe co-morbidities, and poor compliance. Instead of this quite common approach, our team treated the patient with PTA. This led to very good outcomes, above all in terms of pain control. PTA is able to avoid major surgery, lower intra and post-operative risks, reduce length of hospital stay, and preserve functional autonomy. Therefore, this procedure should be taken into account also for frail very elderly diabetic patients with peripheral artery disease (PAD). PMID- 23739912 TI - The risk of venous thromboembolism in older patients with advanced stages of Parkinson's disease. PMID- 23739913 TI - Brain. Editorial. PMID- 23739914 TI - Imaging neuronal loss and recovery in compromised but viable brain tissue. PMID- 23739915 TI - MANBA, CXCR5, SOX8, RPS6KB1 and ZBTB46 are genetic risk loci for multiple sclerosis. AB - A recent genome-wide association study reported five loci for which there was strong, but sub-genome-wide significant evidence for association with multiple sclerosis risk. The aim of this study was to evaluate the role of these potential risk loci in a large and independent data set of ~ 20,000 subjects. We tested five single nucleotide polymorphisms rs228614 (MANBA), rs630923 (CXCR5), rs2744148 (SOX8), rs180515 (RPS6KB1), and rs6062314 (ZBTB46) for association with multiple sclerosis risk in a total of 8499 cases with multiple sclerosis, 8765 unrelated control subjects and 958 trios of European descent. In addition, we assessed the overall evidence for association by combining these newly generated data with the results from the original genome-wide association study by meta analysis. All five tested single nucleotide polymorphisms showed consistent and statistically significant evidence for association with multiple sclerosis in our validation data sets (rs228614: odds ratio = 0.91, P = 2.4 * 10(-6); rs630923: odds ratio = 0.89, P = 1.2 * 10(-4); rs2744148: odds ratio = 1.14, P = 1.8 * 10( 6); rs180515: odds ratio = 1.12, P = 5.2 * 10(-7); rs6062314: odds ratio = 0.90, P = 4.3 * 10(-3)). Combining our data with results from the previous genome-wide association study by meta-analysis, the evidence for association was strengthened further, surpassing the threshold for genome-wide significance (P < 5 * 10(-8)) in each case. Our study provides compelling evidence that these five loci are genuine multiple sclerosis susceptibility loci. These results may eventually lead to a better understanding of the underlying disease pathophysiology. PMID- 23739916 TI - HLA-DR15-derived self-peptides are involved in increased autologous T cell proliferation in multiple sclerosis. AB - The HLA-DR15 haplotype confers the largest part of the genetic risk to develop multiple sclerosis, a prototypic CD4+ T cell-mediated autoimmune disease. The mechanisms how certain HLA-class II molecules functionally contribute to autoimmune diseases are still poorly understood, but probably involve shaping an autoimmune-prone T cell repertoire during central tolerance in the thymus and subsequently maintaining or even expanding it in the peripheral immune system. Self-peptides that are presented by disease-associated HLA-class II molecules most likely play important roles during both processes. Here, we examined the functional involvement of the HLA-DR15 haplotype in autologous proliferation in multiple sclerosis and the contribution of HLA-DR15 haplotype-derived self peptides in an in vitro system. We observe increased autologous T cell proliferation in patients with multiple sclerosis in relation to the multiple sclerosis risk-associated HLA-DR15 haplotype. Assuming that the spectrum of self peptides that is presented by the two HLA-DR15 allelic products is important for sustaining autologous proliferation we performed peptide elution and identification experiments from the multiple sclerosis-associated DR15 molecules and a systematic analysis of a DR15 haplotype-derived self-peptide library. We identify HLA-derived self-peptides as potential mediators of altered autologous proliferation. Our data provide novel insights about perturbed T cell repertoire dynamics and the functional involvement of the major genetic risk factor, the HLA DR15 haplotype, in multiple sclerosis. PMID- 23739918 TI - Addendum. PMID- 23739917 TI - Impaired thalamocortical connectivity in autism spectrum disorder: a study of functional and anatomical connectivity. AB - The thalamus plays crucial roles in the development and mature functioning of numerous sensorimotor, cognitive and attentional circuits. Currently limited evidence suggests that autism spectrum disorder may be associated with thalamic abnormalities, potentially related to sociocommunicative and other impairments in this disorder. We used functional connectivity magnetic resonance imaging and diffusion tensor imaging probabilistic tractography to study the functional and anatomical integrity of thalamo-cortical connectivity in children and adolescents with autism spectrum disorder and matched typically developing children. For connectivity with five cortical seeds (prefontal, parieto-occipital, motor, somatosensory and temporal), we found evidence of both anatomical and functional underconnectivity. The only exception was functional connectivity with the temporal lobe, which was increased in the autism spectrum disorders group, especially in the right hemisphere. However, this effect was robust only in partial correlation analyses (partialling out time series from other cortical seeds), whereas findings from total correlation analyses suggest that temporo thalamic overconnectivity in the autism group was only relative to the underconnectivity found for other cortical seeds. We also found evidence of microstructural compromise within the thalamic motor parcel, associated with compromise in tracts between thalamus and motor cortex, suggesting that the thalamus may play a role in motor abnormalities reported in previous autism studies. More generally, a number of correlations of diffusion tensor imaging and functional connectivity magnetic resonance imaging measures with diagnostic and neuropsychological scores indicate involvement of abnormal thalamocortical connectivity in sociocommunicative and cognitive impairments in autism spectrum disorder. PMID- 23739919 TI - Neuroprotective evaluation of Tilia americana and Annona diversifolia in the neuronal damage induced by intestinal ischemia. AB - Tilia americana and Annona diversifolia are plants widely distributed in Mexico and sold in markets for their medicinal properties on the central nervous system (CNS) including possible neuroprotection. Pharmacological studies have corroborated CNS activities due to flavonoid constituents, but evidence of their neuroprotector effects are lacking. This study was conducted to test aqueous and organic extracts of these two plants for neuroprotective effects in a novel experimental model of intestinal ischemia in situ. T. americana and A. diversifolia aqueous and organic extracts were administrated to guinea pigs at an oral dose of 100 and 300 mg/kg for 15 days. Twenty four hours after the last administration, the animals were anesthetized and intestinal ischemia in situ was induced by clamping for 80 min selected branches of the superior mesenteric artery. Ischemic segments placed in an in vitro organ bath were stimulated electrically (0.3 Hz frequency, 3.0 ms duration, 14 V intensity) and chemically (ACh; 1 * 10(-9) to 1*10(-5) M). Neuroprotection was considered present when the depressed contractile response of the ischemic tissue to electrical stimulation was normalized in the treated animals. Results showed that pretreatment with the T. americana hexane and aqueous extracts, but not with those from A. diversifolia, significantly improved responses of the ischemic tissue. These results suggest that T. americana possesses neuroprotective effects against neuronal damage induced by ischemia, and that flavonoids as well as non-polar constituents are involved. Our study supports the use of this plant in folk medicine and suggests its possible effectiveness for stroke prevention. PMID- 23739920 TI - Effect of exercise on the plasma BDNF levels in elderly women with knee osteoarthritis. AB - Knee osteoarthritis is a common disease in the elderly population worldwide. The alleviation of the symptoms associated with this disease can be achieved with physical exercise that induces a cascade of molecular and cellular processes. Of the neurotrophins, brain-derived neurotrophic factor (BDNF) appears to be the most affected by physical activity. Moreover, BDNF seems to have a negative modulatory role in inflammation, and its production by skeletal muscle cells or by cells of the immune system drives the immunoprotective role of physical activity in situations of chronic inflammation. Therefore, the aim of this study was to evaluate plasma BDNF concentrations in elderly individuals presenting with knee osteoarthritis. To accomplish this, sixteen volunteers (mean age 67 +/- 4.41 years) presenting with clinically and radiographically diagnosed knee osteoarthritis were evaluated during acute exercise (1 session of 20 min on a treadmill) and after chronic exercise (12 weeks of aerobic training, consisting of a 50-min walk 3 times per week). Additionally, both a functional assessment (during a 6-min walk) and a pain perception assessment were performed at the start and at the end of physical exercises (training). The plasma BDNF concentrations were measured by ELISA. For the population studied, acute exercise increased the levels of BDNF only before the 12-week training period (p < 0.001). Moreover, the training augmented the plasma concentrations of BDNF (p < 0.0001) and improved clinical parameters (functional p < 0.001; pain perception p < 0.01). PMID- 23739921 TI - Effects of isotonic and isometric hand exercises on pain, hand functions, dexterity and quality of life in women with rheumatoid arthritis. AB - The primary objective of our study was to evaluate the effect of 6-week-long isotonic and isometric hand exercises on pain, hand functions, dexterity and quality of life in women diagnosed as rheumatoid arthritis (RA). Our secondary objective was to assess the changes in handgrip strength and disease activity. This randomized, parallel, single-blinded 6-week intervention study enrolled 52 female patients between 40 and 70 years of age, who were diagnosed with RA according to American College of Rheumatology criteria, had disease duration of at least 1 year and had a stage 1-3 disease according to Steinbrocker's functional evaluation scale. Patients were randomized into isotonics and isometrics groups. Exercises were performed on sixth week. All patients were applied wax therapy in the first 2 weeks. Their pain was assessed with visual analog scale (VAS), their hand functions with Duruoz Hand Index (DHI), dexterity with nine hole peg test (NHPT) and quality of life with Rheumatoid Arthritis Quality of Life questionnaire (RAQoL). Dominant and non-dominant handgrip strengths (HS) were measured. Disease activity was determined by disease activity score (DAS 28). We evaluated the difference in the above parameters between baseline and 6 weeks by Wilcoxon paired t test. The study was completed with 47 patients (isotonics n = 23; isometrics n = 24). VAS, DHI, NHPT, and RAQoL scores significantly improved in both groups by the end of 6th week compared to the baseline scores of the study (for isotonics p = 0.036, p = 0.002; p = 0.0001, p = 0.003; for isometrics p = 0.021, p = 0.002, p = 0.005, p = 0.01, respectively). DAS 28 scores decreased in both exercise groups (p = 0.002; p = 0.0001, respectively), while isometrics showed a significant increase in dominant HS (p = 0.029), and isotonics showed a significant increase in non-dominant HS (p = 0.013). This study showed that isometric and isotonic hand exercises decrease pain and disease activity and improve hand functions, dexterity and quality of life as well as mildly increasing muscle strength in patients diagnosed as RA. PMID- 23739922 TI - Protease-activated receptors (PAR)-1 and -3 drive epithelial-mesenchymal transition of alveolar epithelial cells - potential role in lung fibrosis. AB - Extravascular activation of the coagulation cascade in the lung is commonly observed in pulmonary fibrosis. Coagulation proteases may exert profibrotic cellular effects via protease-activated receptors (PARs)-1 and -2. Here, we investigated the potential role of two other members of the PAR family, namely PAR-3 and PAR-4, in the pathobiology of lung fibrosis. Elevated expression of PAR 3, but not PAR-4, was detected in the lungs of idiopathic pulmonary fibrosis (IPF) patients and in bleomycin-induced lung fibrosis in mice. Increased PAR-3 expression in fibrotic lungs was mainly attributable to alveolar type II (ATII) cells. Stimulation of primary mouse ATII, MLE15 and A549 cells with thrombin (FIIa) - that may activate PAR-1, PAR-3 and PAR-4 - induced epithelial mesenchymal transition (EMT), a process that has been suggested to be a possible mechanism underlying the expanded (myo)fibroblast pool in lung fibrosis. EMT was evidenced by morphological alterations, expression changes of epithelial and mesenchymal phenotype markers, and functional changes. Single knockdown of FIIa receptors, PAR-1, PAR-3, or PAR-4, had no major impact on FIIa-induced EMT. Simultaneous depletion of PAR-1 and PAR-3, however, almost completely inhibited this process, whereas only a partial effect on FIIa-mediated EMT was observed when PAR-1 and PAR-4, or PAR-3 and PAR-4 were knocked down. PAR-1 and PAR-3 co localise within ATII cells with both being predominantely plasma membrane associated. In conclusion, our study indicates that PARs synergise to mediate FIIa-induced EMT and provides first evidence that PAR-3 via its ability to potentiate FIIa-triggered EMT could potentially contribute to the pathogenesis of pulmonary fibrosis. PMID- 23739923 TI - Development of a novel interferon-alpha2b gene construct with a repetitive hypoxia-inducible factor binding site and its suppressive effects on human renal cell carcinoma cell lines in vitro. AB - BACKGROUND: Despite the advent of targeted therapies, interferon-alpha (IFN alpha) remains a therapeutic option for advanced renal cell carcinoma (RCC), especially in Japan, with a treatment response rate of 15-20 %. To improve the efficacy of IFN-alpha-based therapies, we evaluated a novel treatment strategy for RCC using an IFN-alpha2b gene construct with a repetitive hypoxia-inducible factor binding site. METHODS: We constructed an expression plasmid designated 5HREp-IFN-alpha2b containing the coding region of the IFN-alpha2b gene. Five copies of the hypoxia-response element (HRE) sequences were inserted upstream of the IFN-alpha2b gene, and the construct was transfected into human RCC cell lines ACHN, 786-O and KU19-20. The concentrations of IFN-alpha2b in the conditioned media were measured by enzyme-linked immunosorbent assay. Cell viabilities were determined by MTS assays. RESULTS: Construct-induced IFN-alpha secretion was confirmed in all three cell lines. IFN-alpha production was significantly enhanced by the hypoxia-mimicking agent deferoxamine mesylate in cell lines expressing the wild-type von Hippel-Lindau (VHL) gene (KU19-20 and ACHN) compared with cells expressing the mutant VHL gene (786-O). The construct exerted significant suppressive effects on the viabilities of all RCC cell lines. CONCLUSION: This is the first study to report on the construction of a cytokine gene with a repetitive hypoxia-inducible factor binding site and its application in the suppression of human cancer cells. Gene therapy using this IFN-alpha2b gene construct with HREs may represent a novel treatment modality for advanced RCC. PMID- 23739924 TI - Orally administered S-1 suppresses circulating endothelial cell counts in metastatic breast cancer patients. AB - BACKGROUND: S-1 is an oral cytotoxic preparation that contains tegafur. Gamma butyrolactone (GBL) is a metabolite of tegafur that is known to suppress vascular endothelial growth factor (VEGF)-mediated angiogenic activity. The aim of this study was to determine the change in circulating endothelial cell (CEC) counts, GBL levels, and angiogenesis-related factors during S-1 administration in metastatic breast cancer (MBC) patients. METHODS: Patients with HER2-negative MBC were eligible. S-1 was administered orally twice daily in a 4 week on/2 week off cycle until disease progression or unacceptable toxicity occurred. Blood was collected on the following: days 1, 43, 85 (before each cycle of S-1 administration), days 15, 57 (1 h after S-1 administration), and day 29. The CellSearch((r)) system was used to count the CECs. The gas chromatographic-mass spectrometric method was used to measure plasma GBL and 5-FU levels. Levels of VEGF were assayed by enzyme-linked immunosorbent assay. RESULTS: A total of 18 patients were enrolled. The plasma GBL levels on days 15 and 57 were 41.3 +/- 15.8 and 41.0 +/- 11.2 ng/mL, respectively. The CEC levels decreased on day 15, and significantly low levels were maintained until day 85 (P = 0.002 vs day 1). The plasma VEGF levels significantly decreased on day 15 (P = 0.012 vs day 1) and had a tendency to decrease until day 57. CONCLUSIONS: This exploratory study showed that GBL levels increased, VEGF levels decreased, and CEC levels were suppressed during S-1 administration. S-1 appears to have anti-angiogenic activity. PMID- 23739925 TI - NRAS mutations in primary and metastatic melanomas of Japanese patients. AB - BACKGROUND: Characterization of the MAPK signaling pathway in melanoma has led to the development of MEK inhibitors for the treatment of NRAS-mutated melanoma. The success of molecular-targeted therapies underscores the need to identify mutations in target genes. Most of the current data on genetic mutations have been obtained from Caucasian melanoma patients, and screenings of Asian populations are limited. OBJECTIVE: The aim of the present study was to examine NRAS mutations in primary and metastatic lesions of Japanese melanoma patients. METHODS: Clinical melanoma specimens were collected from 127 Japanese patients, including primary (n = 67), metastatic (n = 25) and paired primary and metastatic lesions (n = 35). NRAS mutations in exons 1 and 2 were assessed by polymerase chain reaction and Sanger sequencing. RESULTS: The incidence of NRAS mutations was 7.1 %. NRAS (Q61) was the predominant genetic alteration (77.8 %). NRAS mutations were most frequently detected in acral melanomas (9.3 %), followed by melanomas without chronic sun-induced damage (7.0 %) and mucosal melanomas (4.8 %), and were not detected in melanomas with chronic sun-induced damage. In addition, NRAS mutations were more prevalent in the extremities than in other sites. The NRAS sequence in metastatic lesions did not match that of the primary tumor in one case. CONCLUSION: The frequency of NRAS mutations is lower in the Asian population than in Caucasian patients. The observed heterogeneity of melanoma suggests that genotyping of both primary and metastatic lesions is important to identify candidate patients for molecular-targeted therapies. PMID- 23739926 TI - Lumbar drainage for the treatment of severe bacterial meningitis. AB - OBJECTIVE: To assess the safety and effectiveness of lumbar drains as adjuvant therapy in severe bacterial meningitis, and compare it to standard treatment. DESIGN: A retrospective cohort study of all patients above the age of 18 years with bacterial meningitis and altered mental status admitted to the Montreal Neurological Hospital Intensive Care Unit from January 2000 to December 2010. PATIENTS: Thirty-seven patients were identified using clinical and cerebrospinal fluid criteria. Patients were divided into lumbar drain (LD) (n = 11) and conventional therapy (no LD) (n = 26) groups. MEASUREMENTS: Outcomes were assessed using meningitis-related mortality and the Glasgow Outcome Scale (GOS) at 1 and 3 months. OUTCOMES: All patients received broad-spectrum antibiotic therapy, 84% received steroids. There was no significant difference in mean age, type of bacteria, or time from arrival in ER to initiation of therapy. There was significantly less co-morbidity (24% healthy vs. 18.1%) and coma (GCS < 8 34.6 vs. 54.5%) in the conventional therapy group, as well as a longer duration of symptoms prior to admission (mean 1.34 +/- 1.24 vs. 2.19 +/- 2.34 days). The mean opening pressure was high in all patients (20-55 cm H2O in the LD and 12-60 cm H2O in the no LD). Mean time from arrival in ER to insertion of the lumbar drain was 37 h. Lumbar drains were set for a maximum drainage of 10 cc/h and an ICP below 10 mmHg. Despite greater clinical severity, the LD group had 0% mortality and 91% of the patients achieved a GOS of 4-5. The non-LD group had 15.4% mortality and only 60% achieved a GOS of 4-5. No adverse events were associated with LD therapy. CONCLUSIONS: In this study, the use of lumbar drainage in adult patients with severe bacterial meningitis was safe, and likely contributed to the low mortality and morbidity. PMID- 23739927 TI - Impact on early and late mortality after blood transfusion in coronary artery bypass graft surgery. AB - OBJECTIVE: To assess the 30-day and 1-year mortality associated to the red blood cell transfusion after coronary artery bypass grafting surgery. This procedure has been questioned by the international medical community, but it is still widely used in cardiac surgery. Therefore, it is needed more evidence of this medical practice in our country. METHODS: We retrospectively analyzed 3,004 patients who underwent coronary artery bypass grafting surgery between June 2009 and July 2010. Patients were divided into two groups: non-transfused and transfused. RESULTS: The transfused group totaled 1,888 (63%) and non-transfused 1,116 (37%). There were 129 deaths in 30 days, with 108 (84%) in the transfused group and 21 (16%) in the non-transfused (P<0.001). One year mortality totaled 249 distributed in 212 (85%) among transfused patients and 37 (15%) in non transfused (P<0.001). The adjusted odds ratio for mortality in patients transfused was 2.00 (P=0.007) in 30 days and 2.31 (P=0.003) in 1 year. Even in low risk patients (age < 60 years and EuroSCORE < 2 points), and so with fewer comorbidities, both outcomes, 30 day and 1 year mortality were significantly higher in the transfused patients (7.0% vs. 0.0%, P< 0.001) and (10.0% vs. 0.0%, P< 0.001), respectively. CONCLUSION: The perioperative red blood cell transfusions after coronary artery bypass grafting surgery increased significantly the 30-day and 1-year mortality, even after the adjustments for comorbidities and other factors. So, new therapeutic options and autologous blood management and conservation strategies should be encouraged to reduce blood products transfusions. PMID- 23739928 TI - Risk factors for pre, intra, and postoperative hospital mortality in patients undergoing aortic surgery. AB - OBJECTIVES: The primary objective was to identify predictors of hospital mortality in patients undergoing aortic surgery. The secondary objective was to identify factors associated with clinical outcome composed hospital (death, bleeding, neurologic complications or ventricular dysfunction). METHODS: A cross sectional design with longitudinal component. Through chart review, 257 patients were included. Inclusion criteria were: aortic dissection Stanford type A and ascending aortic aneurysm. Exclusion criteria were acute aortic dissection, of any kind, and no aortic aneurysm involving the ascending segment. Variables assessed: demographics, preoperative factors, intraoperative and postoperative. RESULTS: Variables with increased risk of hospital mortality (OR, 95% CI, P value): black ethnicity (6.8, 1.54-30.2; 0.04), cerebrovascular disease (10.5, 1.12-98.7; 0.04), hemopericardium (35.1, 3.73-330.2; 0.002), Cabrol operation (9.9, 1.47-66.36; 0.019), CABG simultaneous (4.4; 1.31 to 15.06; 0.017), bleeding (5.72, 1.29-25.29; 0.021) and cardiopulmonary bypass (CPB) time [min] (1.016; 1.0071.026; 0.001). Thoracic pain was associated with reduced risk of hospital death (0.27, 0.08-0.94, 0.04). Variables with increased risk of hospital clinical outcome compound were: use of antifibrinolytic (3.2, 1.65-6.27; 0.0006), renal complications (7.4, 1.52-36.0; 0.013), pulmonary complications (3.7, 1.58.8, 0.004), EuroScore (1.23; 1.08-1.41; 0.003) and CPB time [min] (1.01; 1.00 to 1.02; 0.027). CONCLUSION: Ethnicity black, cerebrovascular disease, hemopericardium, Cabrol operation, CABG simultaneous, hemostasis review and CPB time was associated with increased risk of hospital death. Chest pain was associated with reduced risk of hospital death. Use of antifibrinolytic, renal complications, pulmonary complications, EuroScore and CPB time were associated with clinical outcome hospital compound. PMID- 23739929 TI - Impact of coronary artery bypass grafting in elderly patients. AB - OBJECTIVE: To analyze the results of isolated on-pump coronary artery bypass graft surgery (CABG) in patients > 65 years-old. METHODS: Patients undergoing isolated on-pump CABG from December 1st 2010 to July 31th 2012 were divided in two groups: GE (elderly > 65 years-old, n=103) and GA (adults < 65 years-old, n=150). Preoperative data, intraoperative (as cardiopulmonar bypass time, aortic clamping time, time length of stay in mechanical ventilation--MV--and number of grafts), and postoperative variable (as morbidity, mortality and time length of stay in hospital) were analyzed during hospitalization. RESULTS: In GE, the morbidity rate was greater than in GA (30% vs. 14%, P=0.004), but there was no difference in the mortality rate (5.8% vs. 2.0%, P=0.165). In GA, there was higher prevalence DM (39.6% vs. 27%, P=0.043) and smoking (32.2% versus 19.8%, P=0.042); and in GE, higher prevalence of stroke (17% vs. 6.7%, P=0.013). There was no difference between the groups regarding intraoperative variables. After multivariate analysis, age > 65-year-old was associated with greater morbidity, but it was not independent predictive factor for in-hospital mortality. Considering in-hospital mortality, stay in ward time length (P=0.006), cardiac (P=0.011) and respiratory complications (P=0.026) were independent predictive factors. CONCLUSION: This study suggests that patients > 65-year old were at increased risk of postoperative complications when submitted to isolated on-pump CABG in comparison to patients < 65-year-old, but not under increased risk of death. PMID- 23739930 TI - Surgical treatment for infective endocarditis and hospital mortality in a Brazilian single-center. AB - OBJECTIVE: We evaluated patients underwent cardiac valve surgery in the presence of infective endocarditis in an attempt to identify independent predictors of 30 day mortality. METHODS: We evaluated 837 consecutive patients underwent cardiac valve surgery from January 2003 to May 2010 in a tertiary hospital in Sao Jose do Rio Preto, Sao Paulo (SP), Brazil. The study group comprised patients who underwent intervention in the presence of infective endocarditis and was compared to the control group (without infective endocarditis), evaluating perioperative clinical outcomes and 30-day all cause mortality. RESULTS: In our series, 64 patients (8%) underwent cardiac valve surgery in the presence of infective endocarditis, and 37.5% of them had surgical intervention in multiple valves. The study group had prolonged ICU length of stay (16%), greater need for dialysis (9%) and higher 30-day mortality (17%) compared to the control group (7%, P=0.020; 2%, P=0.002 and 9%, P=0.038; respectively). In a Cox regression analysis, age (P = 0.007), acute kidney injury (P = 0.004), dialysis (P = 0.026), redo surgery (P = 0.026), re-exploration for bleeding (P = 0.013), tracheal reintubation (P <0.001) and type I neurological injury (P <0.001) were identified as independent predictors for death. Although the manifestation of infective endocarditis influenced on mortality in univariate analysis, multivariate Cox regression analysis did not confirm such variable as an independent predictor of death. CONCLUSION: Age and perioperative complications stand out as predictors of hospital mortality in Brazilian population. Cardiac valve surgery in the presence of active infective endocarditis was not confirmed itself as an independent predictor of 30-day mortality. PMID- 23739931 TI - Surgical repair of chordae tendineae rupture after degenerative valvular regurgitation using standardized bovine pericardium. AB - OBJECTIVE: To evaluate clinically and by Doppler Echocardiography 22 patients submitted to mitral valve repair after valvular regurgitation using standardized bovine pericardium chordae. METHODS: The patients had degenerative mitral regurgitation. Fourteen (63.6%) patients were male and the age ranged from 19 to 76 years (mean 56.8 +/- 13.8 years). The strings of bovine pericardium treated with glutaraldehyde were reinforced in its transverse ends forming a trapezoid. RESULTS: One patient (4.5%) died in the immediate postoperative period with in low cardiac output syndrome and three (13.6%) in the late postoperative period. One patient (4.5%) was reoperated. The actuarial curves for survival free of death from cardiovascular causes and free from reoperation for patients who left the hospital (21), showed rates of 82.0 +/- 9.8% and 83.9 +/- 10.4% at 70 months postoperatively, respectively. Seventeen patients (77.3%) are alive with native valves. Of the 17 patients alive with native valves 16 (94.1%) were in functional class I. The Doppler Echocardiography postoperatively (mean 41 months, 4-70 months), showed no mitral regurgitation in 11 (64.7%) patients and mild regurgitation in five (29.4%). CONCLUSION: The technique of standard cords of bovine pericardium implantation to replace chordae tendineae of the mitral valve in patients with degenerative mitral regurgitation showed satisfactory results. PMID- 23739932 TI - Correlation between quality of life, functional class and age in patients with cardiac pacemaker. AB - OBJECTIVE: To evaluate whether there is a correlation between quality of life and functional class in early heart pacemaker in patients, and its relationship with age. METHODS: 107 patients of both sexes (49.5% female/50.5% male) were investigated, average implant time of 6.36 months (+/-2.99), and average age of 69.3 years (+/-12.6). To assess the FC, a scale suggested by Goldman was used; for QoL the AQUAREL questionnaire was used, associated with SF-36. Statistical analysis was conducted using Spearman's correlation with 5% significance. RESULTS: Negative correlations were observed between QoL and FC: AQUAREL in the three domains, chest discomfort (r=-0.197, P=0.042), dyspnea (r=-0.508, P=0.000), arrhythmia (r=-0.271, P=0.005), and the SF-36 in the eight domains. Regarding age, there was a negative correlation with the SF36 Functional Capacity (r= 0.338, P=0.000) and no correlation was found with AQUAREL. Positive correlation (r=0.237, P=0.014) was observed between age and FC. CONCLUSION: In this study we found a significant negative correlation between QoL and FC, indicating that patients in this sample who belong to a better FC demonstrated better QoL. The older the patient, QoL is worse in functional capacity and FC. It is suggested that age and FC influence QoL, and the functional classification scales may be established as one of the assessment tools and reflect QoL in patients with pacemakers. PMID- 23739933 TI - Beneficial effects of hyperosmotic perfusion in the myocardium after ischemia/reperfusion injury in isolated rat hearts. AB - OBJECTIVE: A simple method to reduce the ischemia/reperfusion injury that can accompany cardiac surgery would have great clinical value. This study was to investigate the effect of hyperosmotic perfusion on ischemia/reperfusion injury in isolated perfused rat hearts. METHOD: Forty male Sprague-Dawley rats were randomly divided either to have their isolated hearts perfused with normal osmotic buffer or buffer made hyperosmotic by addition of glucose. Hearts were then subjected to 30 min ischemia followed by 30 min reperfusion. Coronary flow, time to ischemic arrest, reperfusion arrhythmia, and ventricular function were recorded. Creatine phosphokinase leakage into the coronary artery, and myocardial content and activity of superoxide dismutase and catalase were also examined. RESULTS: Rat hearts with hyperosmotic perfusion showed higher coronary flow, a prolonged time to ischemic arrest (10.60 vs. 5.63 min, P<0.005), a lower reperfusion arrthythmia score (3.2 vs. 5.3, P<0.001), better ventricular function, and less creatine phosphokinase leakage (340.1 vs. 861.9, P<0.001) than normal osmotic controls. Myocardial catalase content and activity were increased significantly (1435 vs. 917 U/g wet weight, P<0.001) in hearts perfused with hyperosmotic solution in comparison to the normal osmotic controls. CONCLUSION: Pretreatment with hyperosmotic perfusion in normal rat hearts, which is attributed partly to the increased antioxidative activity, could provide beneficial effects from ischemia and reperfusion-induced injury by increasing coronary flow, and decreasing reperfusion arrhythmia. PMID- 23739934 TI - Coping strategies after heart transplantation: psychological implications. AB - OBJECTIVES: To investigate coping strategies used by patients submitted to heart transplantation and whether they are related to the perception of the disease and transplantation. METHODS: Cross-sectional study with quantitative and qualitative analysis. The sample of 32 patients was assessed by the Ways of Coping Scale and socio-demographic questionnaire, and five of them were selected for interviews. The internal consistency of the scale was assessed, the variables and strategies involved were crossed and content analysis of interviews, investigating the existence of a relationship with the speech of the participants. RESULTS: The individuals have used all coping styles, with a predominance of the problem focused strategy. Psychologically prepared patients showed a statistically significant increase in the use of problem-focused coping and seek for social support. However, a significant increase in the use of emotion-focused coping was observed in patients who were not prepared. Analysis through the method of Bardin showed as categories: disease; reaction to call; transplantation; fantasies; postoperative; team and coping. CONCLUSION: Patients with a transplanted heart make use of all coping strategies, with a predominance of the problem-focused strategy. Psychologically prepared individuals used more active coping strategies, which highlights the importance of psychological support during the process. PMID- 23739935 TI - Analysis of left ventricular function in patients with heart failure undergoing cardiac resynchronization. AB - BACKGROUND: The gold standard surgical treatment for heart failure is cardiac transplantation, however, due to difficulties of this treatment, other surgical proposals have been reported, including the implantation of cardiac resynchronizer. OBJECTIVE: To analyze the left ventricular function by echocardiography in patients with advanced heart failure with interventricular dyssynchrony undergone implantation of cardiac resynchronizer. METHODS: Between June 2006 and June 2012, 24 patients with average age of 61.5 +/- 11 years were evaluated, carriers of advanced congestive heart failure functional class III and IV (NYHA), interventricular dyssynchrony and optimal drug therapy, and submitted implantation of cardiac resynchronizer and postoperative echocardiographically evaluated in six months. RESULTS: There was significant improvement of the analyzed echocardiography parameters. The average left ventricular diastolic diameter decreased from 69.6 +/- 9.8 mm to 66.8 +/- 8.8 mm, systolic diameters from 58.6 +/- 8.8 mm to 52.7 +/- 8.8 mm, and ejection fraction, average of 31 +/- 8% to 40 +/- 7% with level of significance, respectively, of 0.019, 0.0004 and 0.0002, statistically significant with a significance level of 0.05. CONCLUSION: There was a significant improvement of left ventricular function analyzed by echocardiography at six months, in patients with advanced heart failure undergone implantation of cardiac resynchronizer. PMID- 23739936 TI - The use of cell saver system in cardiac surgery with cardiopulmonary bypass. AB - INTRODUCTION: The use of cell saver (CS) in cardiac surgery is proposed to reduce the use of units of packed red blood cells stored (URBC), which increases morbidity, mortality and causes inflammatory reactions. OBJECTIVE: The objective is to evaluate whether the use of CS decreases the use URBC, is cost /effective and beneficial to the patient. METHODS: In a prospective study, between November 2009 and October 2011, 100 consecutive patients who underwent cardiovascular surgery with CPB, hemodilution and hemofiltration, were enrolled. Patients were divided into group 1 (no CS) and 2 (CS). The criteria for the replacement of RBC were hemodynamic instability and hemoglobin (Hb) <7-8g/dl. Demographic data, as well as Hb and hematocrit, mediastinal drainage, number of URBC and CPB, ICU and hospital time, were analysed. RESULTS: In groups 1 and 2 the average age was 64.1 and 60.6 years; predominantly male; the logistic EuroSCORE 10.3 and 9.4; mortality 2% and 4%. Group 2 had a higher incidence of reoperations (12% versus 6%), but the average of URBC used (4.31 versus 1.25) and mean length of hospital stay (10.8 versus 7.4 days) was lower. Univariate and multivariate analysis, were performed, which showed no statistically significant values, except in the use of URBC. The relationship between the CS and the cost of RBC was not cost /effective and length of stay was shorter. CONCLUSION: The use of CS decreases the number of used URBC, is not cost /effective but has shown benefits for patients. PMID- 23739937 TI - Five-year outcomes following PCI with DES versus CABG for unprotected LM coronary lesions: meta-analysis and meta-regression of 2914 patients. AB - OBJECTIVE: To compare the safety and efficacy at long-term follow-up of coronary artery bypass grafting (CABG) with percutaneous coronary intervention (PCI) using drug-eluting stents (DES) in patients with unprotected left main coronary artery (ULMCA) disease. METHODS: MEDLINE, EMBASE, CENTRAL/CCTR, SciELO, LILACS, Google Scholar and reference lists of relevant articles were searched for clinical studies that reported outcomes at 5-year follow-up after PCI with DES and CABG for the treatment of ULMCA stenosis. Five studies (1 randomized controlled trial and 4 observational studies) were identified and included a total of 2914 patients (1300 for CABG and 1614 for PCI with DES). RESULTS: At 5-year follow-up, there was no significant difference between the CABG and PCI-DES groups in the risk for death (odds ratio [OR] 1.159, P=0.168 for random effect) or the composite endpoint of death, myocardial infarction, or stroke (OR 1.214, P=0.083). The risk for target vessel revascularization (TVR) was significantly lower in the CABG group compared to the PCI-DES group (OR 0.212, P<0.001). The risk of major adverse cardiac and cerebrovascular events (MACCE) was significantly lower in the CABG group compared to the PCI-DES group (OR 0.526, P<0.001). It was observed no publication bias about outcomes and considerably heterogeneity effect about MACCE. CONCLUSION: CABG surgery remains the best option of treatment for patients with ULMCA disease, with less need of TVR and MACCE rates at long-term follow-up. PMID- 23739938 TI - Criss-cross heart: report of two cases, anatomic and surgical description and literature review. AB - Criss-cross heart is an extremely rare anomaly, characterized by an abnormal rotation of the ventricular mass along its major axis. It may be associated with any malformation of the heart segments and connections. Due to the complex structural changes and rarity of the anomaly, the rotation of ventricular axis is often misdiagnosed. In this paper, two cases of criss-cross heart are reported, with emphasis on diagnostic and surgical techniques used to corrected the main defects. A literature review on the subject is also presented which, although sparse, emphasized on the morphologic, diagnostic and surgical aspects of the anomaly. PMID- 23739939 TI - Religion, spirituality and cardiovascular disease: research, clinical implications, and opportunities in Brazil. AB - In this paper we comprehensively review published quantitative research on the relationship between religion, spirituality (R/S), and cardiovascular (CV) disease, discuss mechanisms that help explain the associations reported, examine the clinical implications of those findings, and explore future research needed in Brazil on this topic. First, we define the terms religion, spirituality, and secular humanism. Next, we review research examining the relationships between R/S and CV risk factors (smoking, alcohol/drug use, physical inactivity, poor diet, cholesterol, obesity, diabetes, blood pressure, and psychosocial stress). We then review research on R/S, cardiovascular functions (CV reactivity, heart rate variability, etc.), and inflammatory markers (IL-6, IFN-gamma, CRP, fibrinogen, IL-4, IL-10). Next we examine research on R/S and coronary artery disease, hypertension, stroke, dementia, cardiac surgery outcomes, and mortality (CV mortality in particular). We then discuss mechanisms that help explain these relationships (focusing on psychological, social, and behavioral pathways) and present a theoretical causal model based on a Western religious perspective. Next we discuss the clinical applications of the research, and make practical suggestions on how cardiologists and cardiac surgeons can sensitively and sensibly address spiritual issues in clinical practice. Finally, we explore opportunities for future research. No research on R/S and cardiovascular disease has yet been published from Brazil, despite the tremendous interest and involvement of the population in R/S, making this an area of almost unlimited possibilities for researchers in Brazil. PMID- 23739940 TI - Cardiac surgery: the infinite quest. Part II. PMID- 23739941 TI - Myocardial revascularization in the XXI century. PMID- 23739942 TI - Endovascular repair of ascending aortic dissection. AB - Woman, 84 years-old, with Stanford type A thoracic aortic dissection committing aortic arch and descending aorta. Proposed and accepted endovascular treatment according to the severity of the clinical picture. Common femoral artery dissection bilaterally was done. Aortography confirmed the exclusion of the false lumen and patency of the coronary ostia. PMID- 23739943 TI - Mistakes in Brazilian papers are more from concepts than of expression. PMID- 23739944 TI - Impact on early and late mortality after blood transfusion in CABG surgery. PMID- 23739947 TI - Fetal cardiac evaluation by 3D/4D ultrasonography (STIC): what is its real applicability in the diagnosis of congenital heart disease? PMID- 23739948 TI - The effectiveness of lifestyle interventions to reduce cardiovascular risk in patients with severe mental disorders: meta-analysis of intervention studies. AB - Patients with severe mental illness have higher prevalences of cardiovascular risk factors (CRF). The objective is to determine whether interventions to modify lifestyles in these patients reduce anthropometric and analytical parameters related to CRF in comparison to routine clinical practice. Systematic review of controlled clinical trials with lifestyle intervention in Medline, Cochrane Library, Embase, PsycINFO and CINALH. Change in body mass index, waist circumference, cholesterol, triglycerides and blood sugar. Meta-analyses were performed using random effects models to estimate the weighted mean difference. Heterogeneity was determined using i(2) statistical and subgroups analyses. 26 studies were selected. Lifestyle interventions decrease anthropometric and analytical parameters at 3 months follow up. At 6 and 12 months, the differences between the intervention and control groups were maintained, although with less precision. More studies with larger samples and long-term follow-up are needed. PMID- 23739949 TI - Paleoproteomic study of the Iceman's brain tissue. AB - The Tyrolean Iceman, a Copper-age ice mummy, is one of the best-studied human individuals. While the genome of the Iceman has largely been decoded, tissue specific proteomes have not yet been investigated. We studied the proteome of two distinct brain samples using gel-based and liquid chromatography-mass spectrometry-based proteomics technologies together with a multiple-databases and -search algorithms-driven data-analysis approach. Thereby, we identified a total of 502 different proteins. Of these, 41 proteins are known to be highly abundant in brain tissue and 9 are even specifically expressed in the brain. Furthermore, we found 10 proteins related to blood and coagulation. An enrichment analysis revealed a significant accumulation of proteins related to stress response and wound healing. Together with atomic force microscope scans, indicating clustered blood cells, our data reopens former discussions about a possible injury of the Iceman's head near the site where the tissue samples have been extracted. PMID- 23739952 TI - Effect of chronic hypoxic hypoxia on oxidation and glucuronidation of carvedilol in rats. AB - Heart failure is accompanied with tissue (circulatory) hypoxia, and the metabolism of several drugs has been reported to be reduced in heart failure. The aim of this study was to investigate the effect of another type of respiratory hypoxia, hypoxic hypoxia (FiO2 15 % for 24 h followed by FiO2 10 % for 9 days) on the metabolism of carvedilol enantiomers in rats. Oxidation of carvedilol in rat liver microsomes was evaluated in the presence of reduced nicotinamide adenine dinucleotide phosphate, whereas glucuronidation was evaluated in the presence of UDP-glucuronic acid. Both oxidation and glucuronidation activities for two carvedilol enantiomers in hypoxic rat liver microsomes were similar to those in control rat liver microsomes. We also performed pharmacokinetic analysis of carvedilol enantiomers following intraportal infusion in control and hypoxic rats. The mean (+/-S.E.) portal clearance value of R- and S-carvedilol in control rats was 72 +/- 16 and 156 +/- 31 ml/min/kg, respectively, whereas that of the R- and S-enantiomers in hypoxic rats was 68 +/- 8 and 113 +/- 14 ml/min/kg, respectively. These findings indicated that the metabolism of carvedilol enantiomers was not significantly diminished in rats with chronic hypoxic hypoxia, and that other factor(s) besides hypoxia may be responsible for the reduced drug metabolism in heart failure. PMID- 23739953 TI - Stimuli-responsive self-assembling peptides made from antibacterial peptides. AB - How to use bioactive peptide sequences as fundamental building blocks to make hydrogel materials which are stimuli-responsive? In this article, we provide a novel designed peptide comprising two antibacterial peptide sequences (KIGAKI)3 NH2 and a central tetrapeptide linker. Results show that balancing the forces of the electrostatic repulsion of the charged lysine residues against the hydrophobic collapse of the isoleucine and alanine residues and backbone beta sheet hydrogen bonding allows the structural transition and formation of individually dispersed nanofibers. Circular Dichroism (CD) and rheology analysis demonstrated that the designed peptide can undergo an abrupt structural transition from a random coil to a stable unimolecular beta-hairpin conformation and subsequently form an elastic hydrogel when exposed to external stimuli such as pH, ionic strength and heat. The assembly kinetics of the obtained antibacterial sequence comprising peptide (ASCP) was studied by time-lapse Atomic Force Microscopy (AFM) and Thioflavin T (ThT) binding assay. In addition, the inherent antibacterial activity of the peptide hydrogel was confirmed by the antibacterial assay against Escherichia coli. This example described epitomizes the use of bioactive peptide sequences in the design of finite self-assembled structures with potential inherent activity. These hydrogel materials may find applications in drug delivery, tissue engineering and regenerative medicine. PMID- 23739954 TI - Matching recall and storage in sequence learning with spiking neural networks. AB - Storing and recalling spiking sequences is a general problem the brain needs to solve. It is, however, unclear what type of biologically plausible learning rule is suited to learn a wide class of spatiotemporal activity patterns in a robust way. Here we consider a recurrent network of stochastic spiking neurons composed of both visible and hidden neurons. We derive a generic learning rule that is matched to the neural dynamics by minimizing an upper bound on the Kullback Leibler divergence from the target distribution to the model distribution. The derived learning rule is consistent with spike-timing dependent plasticity in that a presynaptic spike preceding a postsynaptic spike elicits potentiation while otherwise depression emerges. Furthermore, the learning rule for synapses that target visible neurons can be matched to the recently proposed voltage triplet rule. The learning rule for synapses that target hidden neurons is modulated by a global factor, which shares properties with astrocytes and gives rise to testable predictions. PMID- 23739951 TI - MicroRNAs in pulmonary arterial remodeling. AB - Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH. PMID- 23739955 TI - Whisker dynamics underlying tactile exploration. AB - Rodents explore the world by palpating objects with their whiskers. Whiskers interact with objects, causing stresses in whisker follicles and spikes in sensory neurons, which are interpreted by the brain to produce tactile perception. The mechanics of the whisker thus couple self-movement and the structure of the world to sensation. Whiskers are elastic thin rods; hence, they tend to vibrate. Whisker vibrations could be a key ingredient of rodent somatosensation. However, the specific conditions under which vibrations contribute appreciably to the stresses in the follicle remain unclear. We present an analytical solution for the deformation of individual whiskers in response to a time-varying force. We tracked the deformation of mouse whiskers during a pole localization task to extract the whisker Young's modulus and damping coefficient. We further extracted the time course and amplitude of steady-state forces during whisker-object contact. We use our model to calculate the relative contribution of steady-state and vibrational forces to stresses in the follicle in a variety of active sensation tasks and during the passive whisker stimuli typically used for sensory physiology. Vibrational stresses are relatively more prominent compared with steady-state forces for short contacts and for contacts close to the whisker tip. Vibrational stresses are large for texture discrimination, and under some conditions, object localization tasks. Vibrational stresses are negligible for typical ramp-and-hold stimuli. Our calculation provides a general framework, applicable to most experimental situations. PMID- 23739957 TI - Intact learning of new relations in amnesia as achieved through unitization. AB - Hippocampal amnesia is defined by deficits in the binding of relations among items--a deficit captured by the transverse patterning (TP) task. Unitization is a processing mechanism that may allow amnesic patients to compensate for relational memory deficits. Amnesic patient D.A. demonstrated intact TP, and performance was maintained 1 month following training. Successful acquisition of relations occurred only when D.A. fused or integrated objects into a unified representation. D.A. did not acquire relations when he did not generate such integrated scenarios, and acquisition of relations was slowed when integration had to occur for novel stimuli. Amnesic patients K.C. and R.F.R. were tested to provide comparative data; K.C. and R.F.R. did not benefit from unitization, perhaps due to additional cortical damage. We propose that unitization requires visual imagery of multiple items that are fused/integrated; through the benefit of extended on-line maintenance, this fused representation is anchored to existing representations in semantic memory. PMID- 23739956 TI - MHCII is required for alpha-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. AB - Accumulation of alpha-synuclein (alpha-syn) in the brain is a core feature of Parkinson disease (PD) and leads to microglial activation, production of inflammatory cytokines and chemokines, T-cell infiltration, and neurodegeneration. Here, we have used both an in vivo mouse model induced by viral overexpression of alpha-syn as well as in vitro systems to study the role of the MHCII complex in alpha-syn-induced neuroinflammation and neurodegeneration. We find that in vivo, expression of full-length human alpha syn causes striking induction of MHCII expression by microglia, while knock-out of MHCII prevents alpha-syn-induced microglial activation, antigen presentation, IgG deposition, and the degeneration of dopaminergic neurons. In vitro, treatment of microglia with aggregated alpha-syn leads to activation of antigen processing and presentation of antigen sufficient to drive CD4 T-cell proliferation and to trigger cytokine release. These results indicate a central role for microglial MHCII in the activation of both the innate and adaptive immune responses to alpha syn in PD and suggest that the MHCII signaling complex may be a target of neuroprotective therapies for the disease. PMID- 23739958 TI - Spinal commissural connections to motoneurons controlling the primate hand and wrist. AB - Left-right coordination is essential for locomotor movements and is partly mediated by spinal commissural systems. Such coordination is also essential for reaching and manipulation in primates, but the role of spinal commissural systems here has not been studied. We investigated commissural connectivity to motoneurons innervating forelimb muscles using intracellular recordings in acutely anesthetized macaque monkeys. In 57 of 81 motoneurons, synaptic responses (52 of 57 excitatory) were evoked after contralateral intraspinal microstimulation in the gray matter (cISMS; 300 MUA maximum current intensity). Some responses (15 of 57) occurred at latencies compatible with a monosynaptic linkage, including in motoneurons projecting to intrinsic hand muscles (9 cells). Three pieces of evidence suggest that these effects reflected the action of commissural interneurons. In two cells, preceding cISMS with stimulation of the contralateral medial brainstem descending pathways facilitated the motoneuron responses, suggesting that cISMS acted on cell bodies whose excitability was increased by descending inputs. Pairing cISMS with stimulation of the contralateral corticospinal tract yielded no evidence of response occlusion in 16 cells tested, suggesting that the effects were not merely axon reflexes generated by stimulation of corticospinal axon branches, which cross the midline. Finally, stimulation of contralateral peripheral nerves evoked responses in 28 of 52 motoneurons (7 of 9 projecting to the hand). Our results demonstrate the existence of commissural neurons with access to spinal motoneurons in primate cervical spinal cord that receive inputs from the periphery as well as descending pathways. Most importantly, commissural neurons also innervate motoneurons of intrinsic hand muscles. PMID- 23739959 TI - Memantine rescues transient cognitive impairment caused by high-molecular-weight abeta oligomers but not the persistent impairment induced by low-molecular-weight oligomers. AB - Brain accumulation of soluble amyloid-beta oligomers (AbetaOs) has been implicated in synapse failure and cognitive impairment in Alzheimer's disease (AD). However, whether and how oligomers of different sizes induce synapse dysfunction is a matter of controversy. Here, we report that low-molecular-weight (LMW) and high-molecular-weight (HMW) Abeta oligomers differentially impact synapses and memory. A single intracerebroventricular injection of LMW AbetaOs (10 pmol) induced rapid and persistent cognitive impairment in mice. On the other hand, memory deficit induced by HMW AbetaOs (10 pmol) was found to be reversible. While memory impairment in LMW oligomer-injected mice was associated with decreased hippocampal synaptophysin and GluN2B immunoreactivities, synaptic pathology was not detected in the hippocampi of HMW oligomer-injected mice. On the other hand, HMW oligomers, but not LMW oligomers, induced oxidative stress in hippocampal neurons. Memantine rescued both neuronal oxidative stress and the transient memory impairment caused by HMW oligomers, but did not prevent the persistent cognitive deficit induced by LMW oligomers. Results establish that different Abeta oligomer assemblies act in an orchestrated manner, inducing different pathologies and leading to synapse dysfunction. Furthermore, results suggest a mechanistic explanation for the limited efficacy of memantine in preventing memory loss in AD. PMID- 23739960 TI - Continuous flash suppression modulates cortical activity in early visual cortex. AB - A salient visual stimulus can be rendered invisible by presenting it to one eye while flashing a mask to the other eye. This procedure, called continuous flash suppression (CFS), has been proposed as an ideal way of studying awareness as it can make a stimulus imperceptible for extended periods of time. Previous studies have reported robust suppression of cortical activity in higher visual areas during CFS, but the role of primary visual cortex (V1) is still controversial. In this study, we resolve this controversy on the role of V1 in CFS and also begin characterizing the computational processes underlying CFS. Early visual cortical activity was measured with functional magnetic resonance imaging while human subjects viewed stimuli composed of target and mask, presented to the same or different eyes. Functional MRI responses in early visual cortex were smaller when target and mask were in different eyes compared with the same eye, not only for the lowest contrast target rendered invisible by CFS, but also for higher contrast targets, which were visible even when presented to the eye opposite the mask. We infer that CFS is based on modulating the gain of neural responses, akin to reducing target contrast. PMID- 23739961 TI - Pumilio-2 regulates translation of Nav1.6 to mediate homeostasis of membrane excitability. AB - The ability to regulate intrinsic membrane excitability, to maintain consistency of action potential firing, is critical for stable neural circuit activity. Without such mechanisms, Hebbian-based synaptic plasticity could push circuits toward activity saturation or, alternatively, quiescence. Although now well documented, the underlying molecular components of these homeostatic mechanisms remain poorly understood. Recent work in the fruit fly, Drosophila melanogaster, has identified Pumilio (Pum), a translational repressor, as an essential component of one such mechanism. In response to changing synaptic excitation, Pum regulates the translation of the voltage-gated sodium conductance, leading to a concomitant adjustment in action potential firing. Although similar homeostatic mechanisms are operational in mammalian neurons, it is unknown whether Pum is similarly involved. In this study, we report that Pum2 is indeed central to the homeostatic mechanism regulating membrane excitability in rat visual cortical pyramidal neurons. Using RNA interference, we observed that loss of Pum2 leads to increased sodium current (I(Na)) and action potential firing, mimicking the response by these neurons to being deprived of synaptic depolarization. In contrast, increased synaptic depolarization results in increased Pum2 expression and subsequent reduction in INa and membrane excitability. We further show that Pum2 is able to directly bind the predominant voltage-gated sodium channel transcript (NaV1.6) expressed in these neurons and, through doing so, regulates translation of this key determinant of membrane excitability. Together, our results show that Pum2 forms part of a homeostatic mechanism that matches membrane excitability to synaptic depolarization in mammalian neurons. PMID- 23739962 TI - Type III neuregulin 1 is required for multiple forms of excitatory synaptic plasticity of mouse cortico-amygdala circuits. AB - The amygdala plays an important role in the formation and storage of memories associated with emotional events. The cortical glutamatergic inputs onto pyramidal neurons in the basolateral nucleus of the amygdala (BLA) contribute to this process. As the interaction between neuregulin 1 (Nrg1) and its ErbB receptors has been implicated in the pathological mechanisms of schizophrenia, loss of Nrg1 may disrupt cortical-amygdala neural circuits, resulting in altered processing of salient memories. Here we show that Nrg1 is critical in multiple forms of plasticity of cortical projections to pyramidal neurons of the BLA. The miniature EPSCs in Nrg1 heterozygous animals have a faster time constant of decay and evoked synaptic currents have a smaller NMDA/AMPA ratio than those recorded in wild-type (WT) littermates. Both high-frequency electrical stimulation of cortical inputs and theta burst stimulation combined with nicotine exposure results in long-lasting potentiation in WT animals. However, the same manipulations have little to no effect on glutamatergic synaptic plasticity in the BLA from Nrg1 heterozygous mice. Comparison of WT, Nrg1 heterozygous animals and alpha7 nicotinic receptor heterozygous mice reveals that the sustained phase of potentiation of glutamatergic transmission after theta burst stimulation with or without nicotine only occurs in the WT mice. Together, these findings support the idea that type III Nrg1 is essential to multiple aspects of the modulation of excitatory plasticity at cortical-BLA synapses. PMID- 23739963 TI - Prefrontal-temporal disconnection impairs recognition memory but not familiarity discrimination. AB - Neural mechanisms in the temporal lobe are essential for recognition memory. Evidence from human functional imaging and neuropsychology, and monkey neurophysiology and neuropsychology also suggests a role for prefrontal cortex in recognition memory. To examine the interaction of these cortical regions in support of recognition memory we tested rhesus monkeys with prefrontal inferotemporal (PFC-IT) cortical disconnection on two recognition memory tasks, a "constant negative" task, and delayed nonmatching-to-sample (DNMS). In the constant negative task monkeys were presented with sets of 100 discrimination problems. In each problem one unrewarded object was presented once every day, and became familiar over the course of several days testing. The other, rewarded object was always novel. In this task monkeys learned to avoid the familiar constant negatives and choose the novel objects, so performance on this task is guided by a sense of familiarity for the constant negatives. Following PFC-IT disconnection monkeys were severely impaired at reacquiring the rule (to avoid familiar items) but were subsequently unimpaired at acquiring new constant negative problems, thus displaying intact familiarity recognition. The same monkeys were impaired in the acquisition of the DNMS task, as well as memory for lists of objects. This dissociation between two tests of recognition memory is best explained in terms of our general hypothesis that PFC-IT interactions support the representation of temporally complex events, which is necessary in DNMS but not in constant negative. These findings, furthermore, indicate that stimulus familiarity can be represented in temporal cortex without input from prefrontal cortex. PMID- 23739964 TI - O2-sensing neurons control CO2 response in C. elegans. AB - Sensory behaviors are often flexible, allowing animals to generate context appropriate responses to changing environmental conditions. To investigate the neural basis of behavioral flexibility, we examined the regulation of carbon dioxide (CO2) response in the nematode Caenorhabditis elegans. CO2 is a critical sensory cue for many animals, mediating responses to food, conspecifics, predators, and hosts (Scott, 2011; Buehlmann et al., 2012; Chaisson and Hallem, 2012). In C. elegans, CO2 response is regulated by the polymorphic neuropeptide receptor NPR-1: animals with the N2 allele of npr-1 avoid CO2, whereas animals with the Hawaiian (HW) allele or an npr-1 loss-of-function (lf) mutation appear virtually insensitive to CO2 (Hallem and Sternberg, 2008; McGrath et al., 2009). Here we show that ablating the oxygen (O2)-sensing URX neurons in npr-1(lf) mutants restores CO2 avoidance, suggesting that NPR-1 enables CO2 avoidance by inhibiting URX neurons. URX was previously shown to be activated by increases in ambient O2 (Persson et al., 2009; Zimmer et al., 2009; Busch et al., 2012). We find that, in npr-1(lf) mutants, O2-induced activation of URX inhibits CO2 avoidance. Moreover, both HW and npr-1(lf) animals avoid CO2 under low O2 conditions, when URX is inactive. Our results demonstrate that CO2 response is determined by the activity of O2-sensing neurons and suggest that O2-dependent regulation of CO2 avoidance is likely to be an ecologically relevant mechanism by which nematodes navigate gas gradients. PMID- 23739965 TI - Intracranial injection of Gammagard, a human IVIg, modulates the inflammatory response of the brain and lowers Abeta in APP/PS1 mice along a different time course than anti-Abeta antibodies. AB - Gammagard IVIg is a therapeutic approach to treat Alzheimer's disease currently in phase 3 clinical trials. Despite the reported efficacy of the approach the mechanism of action is poorly understood. We have previously shown that intracranial injection of anti-Abeta antibodies into the frontal cortex and hippocampus reveals important information regarding the time course of events once the agent is in the brain. In the current study we compared IVIg, mouse pooled IgG, and the anti-Abeta antibody 6E10 injected intracranially into the frontal cortex and hippocampus of 7-month-old APP/PS1 mice. We established a time course of events ranging from 1 to 21 d postinjection. IVIg and pooled mouse IgG both significantly reduced Abeta deposition to the same degree as the 6E10 anti Abeta antibody; however, the clearance was much slower to occur, happening between the 3 and 7 d time points. In contrast, as we have previously shown, Abeta reductions were apparent with the 6E10 anti-Abeta group at the 1 d time point. Also, neuroinflammatory profiles were significantly altered by the antibody treatments. APP/PS1 transgenic mice at 7 months of age typically exhibit an M2a inflammatory phenotype. All antibody treatments stimulated an M2b response, yet anti-Abeta antibody was a more rapid change. Because the neuroinflammatory switch occurs before the detectable reductions in amyloid deposition, we hypothesize that the IVIg and pooled mouse IgG act as immune modulators and this immune modulation is responsible for the reductions in amyloid pathology. PMID- 23739966 TI - Refining cortical representation of sound azimuths by auditory discrimination training. AB - Although training-based auditory cortical plasticity in the adult brain has been previously demonstrated in multiparametric sound domains, neurochemical mechanisms responsible for this form of plasticity are not well understood. In this study, we trained adult rats to identify a target sound stimulus at a specific azimuth angle by using a reward-contingent auditory discrimination task. We found that auditory spatial discrimination training significantly enhanced representation of sound azimuths in the primary auditory cortex, as shown by sharper azimuth-selective curves and more evenly distributed best angles of cortical neurons. Training also facilitated long-term potentiation of field potentials in the primary auditory cortex induced by theta burst stimulation of the white matter. In parallel, there were significant alterations in expression levels of certain cortical GABA(A) and NMDA receptor subunits, resulting in a marked decrease in the level of GABA(A) relative to NMDA receptors. These changes in the expression profile of inhibitory and excitatory neurotransmitter receptor subunits might enhance synaptic transmission, thereby facilitating training induced cortical plasticity in the spatial domain. PMID- 23739967 TI - Shank3-Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation. AB - Synaptic long-term potentiation (LTP) is a key mechanism involved in learning and memory, and its alteration is associated with mental disorders. Shank3 is a major postsynaptic scaffolding protein that orchestrates dendritic spine morphogenesis, and mutations of this protein lead to mental retardation and autism spectrum disorders. In the present study we investigated the role of a new Shank3 associated protein in LTP. We identified the Rho-GAP interacting CIP4 homolog 2 (Rich2) as a new Shank3 partner by proteomic screen. Using single-cell bioluminescence resonance energy transfer microscopy, we found that Rich2-Shank3 interaction is increased in dendritic spines of mouse cultured hippocampal neurons during LTP. We further characterized Rich2 as an endosomal recycling protein that controls AMPA receptor GluA1 subunit exocytosis and spine morphology. Knock-down of Rich2 with siRNA, or disruption of the Rich2-Shank3 complex using an interfering mimetic peptide, inhibited the dendritic spine enlargement and the increase in GluA1 subunit exocytosis typical of LTP. These results identify Rich2-Shank3 as a new postsynaptic protein complex involved in synaptic plasticity. PMID- 23739968 TI - ASI regulates satiety quiescence in C. elegans. AB - In Caenorhabditis elegans, satiety quiescence mimics behavioral aspects of satiety and postprandial sleep in mammals. On the basis of calcium-imaging, genetics, and behavioral studies, here we report that a pair of amphid neurons, ASI, is activated by nutrition and regulates worms' behavioral states specifically promoting satiety quiescence; ASI inhibits the switch from quiescence to dwelling (a browsing state) and accelerates the switch from dwelling to quiescence. The canonical TGFbeta pathway, whose ligand is released from ASI, regulates satiety quiescence. The mutants of a ligand, a receptor and SMADs in the TGFbeta pathway all eat more and show less quiescence than wild type. The TGFbeta receptor in downstream neurons RIM and RIC is sufficient for worms to exhibit satiety quiescence, suggesting neuronal connection from ASI to RIM and RIC is essential for feeding regulation through the TGFbeta pathway. ASI also regulates satiety quiescence partly through cGMP signaling; restoring cGMP signaling in ASI rescues the satiety quiescence defect of cGMP signaling mutants. From these results, we propose that TGFbeta and cGMP pathways in ASI connect nutritional status to promotion of satiety quiescence, a sleep-like behavioral state. PMID- 23739969 TI - Hebbian and anti-Hebbian spike-timing-dependent plasticity of human cortico cortical connections. AB - Learning of new skills may occur through Hebbian associative changes in the synaptic strength of cortical connections [spike-timing-dependent plasticity (STDP)], but how the precise temporal relationship of the presynaptic and postsynaptic inputs determines the STDP effects in humans is poorly understood. We used a novel paired associative stimulation protocol to repeatedly activate the short-latency connection between the posterior parietal cortex and the primary motor cortex (M1) of the left-dominant hemisphere. In different experiments, we systematically varied the temporal relationships between the stimuli and the preferential activation of different M1 neuronal populations by applying transcranial magnetic stimulation over M1 with different coil orientations and in different states of cortical excitability (rest vs muscular contraction). We found evidence for the existence of both Hebbian and anti Hebbian STDP in human long-range connections. The induction of bidirectional long term potentiation or depression in M1 depended not only on the relative timing between the stimuli but, crucially, on the stimulation of specific neuronal populations and the activity state of the cortex. Our findings demonstrate that these mechanisms are not fixed but susceptible to rapid adaptations. This sudden transition from anti-Hebbian to Hebbian plasticity likely involves local dynamics of interaction with different populations of postsynaptic neurons. PMID- 23739970 TI - Amygdala lesions reduce cataplexy in orexin knock-out mice. AB - Narcolepsy is characterized by excessive sleepiness and cataplexy, sudden episodes of muscle weakness during waking that are thought to be an intrusion of rapid eye movement sleep muscle atonia into wakefulness. One of the most striking aspects of cataplexy is that it is often triggered by strong, generally positive emotions, but little is known about the neural pathways through which positive emotions trigger muscle atonia. We hypothesized that the amygdala is functionally important for cataplexy because the amygdala has a role in processing emotional stimuli and it contains neurons that are active during cataplexy. Using anterograde and retrograde tracing in mice, we found that GABAergic neurons in the central nucleus of the amygdala heavily innervate neurons that maintain waking muscle tone such as those in the ventrolateral periaqueductal gray, lateral pontine tegmentum, locus ceruleus, and dorsal raphe. We then found that bilateral, excitotoxic lesions of the amygdala markedly reduced cataplexy in orexin knock-out mice, a model of narcolepsy. These lesions did not alter basic sleep-wake behavior but substantially reduced the triggering of cataplexy. Lesions also reduced the cataplexy events triggered by conditions associated with high arousal and positive emotions (i.e., wheel running and chocolate). These observations demonstrate that the amygdala is a functionally important part of the circuitry underlying cataplexy and suggest that increased amygdala activity in response to emotional stimuli could directly trigger cataplexy by inhibiting brainstem regions that suppress muscle atonia. PMID- 23739971 TI - Role of the medial prefrontal cortex in cataplexy. AB - Narcolepsy is characterized by chronic sleepiness and cataplexy, episodes of profound muscle weakness that are often triggered by strong, positive emotions. Narcolepsy with cataplexy is caused by a loss of orexin (also known as hypocretin) signaling, but almost nothing is known about the neural mechanisms through which positive emotions trigger cataplexy. Using orexin knock-out mice as a model of narcolepsy, we found that palatable foods, especially chocolate, markedly increased cataplexy and activated neurons in the medial prefrontal cortex (mPFC). Reversible suppression of mPFC activity using an engineered chloride channel substantially reduced cataplexy induced by chocolate but did not affect spontaneous cataplexy. In addition, neurons in the mPFC innervated parts of the amygdala and lateral hypothalamus that contain neurons active during cataplexy and that innervate brainstem regions known to regulate motor tone. These observations indicate that the mPFC is a critical site through which positive emotions trigger cataplexy. PMID- 23739972 TI - Ascl1/Mash1 promotes brain oligodendrogenesis during myelination and remyelination. AB - Oligodendrocytes are the myelin-forming cells of the CNS. They differentiate from oligodendrocyte precursor cells (OPCs) that are produced from progenitors throughout life but more actively during the neonatal period and in response to demyelinating insults. An accurate regulation of oligodendrogenesis is required to generate oligodendrocytes during these developmental or repair processes. We hypothesized that this regulation implicates transcription factors, which are expressed by OPCs and/or their progenitors. Ascl1/Mash1 is a proneural transcription factor previously implicated in embryonic oligodendrogenesis and operating in genetic interaction with Olig2, an essential transcriptional regulator in oligodendrocyte development. Herein, we have investigated the contribution of Ascl1 to oligodendrocyte development and remyelination in the postnatal cortex. During the neonatal period, Ascl1 expression was detected in progenitors of the cortical subventricular zone and in cortical OPCs. Different genetic approaches to delete Ascl1 in cortical progenitors or OPCs reduced neonatal oligodendrogenesis, showing that Ascl1 positively regulated both OPC specification from subventricular zone progenitors as well as the balance between OPC differentiation and proliferation. Examination of remyelination processes, both in the mouse model for focal demyelination of the corpus callosum and in multiple sclerosis lesions in humans, indicated that Ascl1 activity was upregulated along with increased oligodendrogenesis observed in remyelinating lesions. Additional genetic evidence indicated that remyelinating oligodendrocytes derived from Ascl1(+) progenitors/OPCs and that Ascl1 was required for proper remyelination. Together, our results show that Ascl1 function modulates multiple steps of OPC development in the postnatal brain and in response to demyelinating insults. PMID- 23739973 TI - Synaptotagmin-12 phosphorylation by cAMP-dependent protein kinase is essential for hippocampal mossy fiber LTP. AB - Synaptotagmin-12 (Syt12) is an abundant synaptic vesicle protein that--different from other synaptic vesicle-associated synaptotagmins--does not bind Ca(2+). Syt12 is phosphorylated by cAMP-dependent protein kinase-A at serine-97 in an activity-dependent manner, suggesting a function for Syt12 in cAMP-dependent synaptic plasticity. To test this hypothesis, we here generated (1) Syt12 knock out mice and (2) Syt12 knockin mice carrying a single amino-acid substitution [the serine-97-to-alanine- (S97A)-substitution]. Both Syt12 knock-out mice and Syt12 S97A-knockin mice were viable and fertile, and exhibited no measurable change in basal synaptic strength or short-term plasticity as analyzed in cultured cortical neurons or in acute hippocampal slices. However, both Syt12 knock-out and Syt12 S97A-knockin mice displayed a major impairment in cAMP dependent mossy-fiber long-term potentiation (LTP) in the CA3 region of the hippocampus. This impairment was observed using different experimental configurations for inducing and monitoring mossy-fiber LTP. Moreover, although the Syt12 knock-out had no effect on the short-term potentiation of synaptic transmission induced by the adenylate-cyclase activator forskolin in cultured cortical neurons and in the CA1 region of the hippocampus, both the Syt12 knock out and the Syt12 S97A-knockin impaired the long-term increase in mossy-fiber synaptic transmission induced by forskolin. Thus, Syt12 is essential for cAMP dependent presynaptic LTP at mossy-fiber synapses, and a single amino-acid substitution that blocks the cAMP-dependent phosphorylation of Syt12 is sufficient to impair the function of Syt12 in mossy-fiber LTP, suggesting that cAMP-dependent phosphorylation of Syt12 on serine-97 contributes to the induction of mossy-fiber LTP. PMID- 23739974 TI - Integrin-linked kinase regulates process extension in oligodendrocytes via control of actin cytoskeletal dynamics. AB - Integrin-linked kinase (ILK) is a major structural adaptor protein governing signaling complex formation and cytoskeletal dynamics. Here, through the use of conditional knock-out mice, we demonstrate a requirement for ILK in oligodendrocyte differentiation and axonal myelination in vivo. In conjunction, ILK-deficient primary oligodendrocytes are defined by a failure in process extension and an inability to form myelin membrane upon axonal contact. Surprisingly, phosphorylation of the canonical downstream targets Akt and GSK3beta is unaffected following ILK loss. Rather, the defects are due in part to actin cytoskeleton dysregulation with a correspondent increase in active RhoA levels. Morphological rescue is possible following Rho kinase inhibition in an oligodendrocyte subset. Furthermore, phenotypic severity correlates with environmental complexity; oligodendrocytes are severely malformed in vitro (a relatively simple environment), but undergo phenotypic recovery in the context of the whole animal. Together, our work demonstrates ILK as necessary for normal oligodendrocyte development, reinforces its role as a bridge between the actin cytoskeleton and cell membrane, and highlights the overarching compensatory capacity of oligodendrocytes in response to cellular milieu. PMID- 23739975 TI - Motor skill training induces coordinated strengthening and weakening between neighboring synapses. AB - Motor skill training promotes the formation of parallel fiber multiple-synapse boutons (MSBs) contacting dendritic spine pairs of Purkinje cells in the rat cerebellum. However, the dendritic origin of such spine pairs is unknown. Here, we used three-dimensional electron microscopy reconstruction of synaptic connectivity to demonstrate that motor skill training selectively induced MSBs contacting two spines arising from the same dendrite, consistent with strengthening of local synaptic efficacy. However, excitatory synapses near MSBs were smaller in motor-trained animals, suggesting compensatory depression of MSB neighbor synapses. Concerted strengthening and weakening of adjacent synapses may enhance synaptic weight differences for information encoding while maintaining stable overall activity levels within local dendritic segments. PMID- 23739976 TI - 5-HT2C receptor agonist anorectic efficacy potentiated by 5-HT1B receptor agonist coapplication: an effect mediated via increased proportion of pro opiomelanocortin neurons activated. AB - An essential component of the neural network regulating ingestive behavior is the brain 5-hydroxytryptamine2C receptor (5-HT2CR), agonists of which suppress food intake and were recently approved for obesity treatment by the US Food and Drug Administration. 5-HT2CR-regulated appetite is mediated primarily through activation of hypothalamic arcuate nucleus (ARC) pro-opiomelanocortin (POMC) neurons, which are also disinhibited through a 5-HT1BR-mediated suppression of local inhibitory inputs. Here we investigated whether 5-HT2CR agonist anorectic potency could be significantly enhanced by coadministration of a 5-HT1BR agonist and whether this was associated with augmented POMC neuron activation on the population and/or single-cell level. The combined administration of subanorectic concentrations of 5-HT2CR and 5-HT1BR agonists produced a 45% reduction in food intake and significantly greater in vivo ARC neuron activation in mice. The chemical phenotype of activated ARC neurons was assessed by monitoring agonist induced cellular activity via calcium imaging in mouse POMC-EGFP brain slices, which revealed that combined agonists activated significantly more POMC neurons (46%) compared with either drug alone (~25% each). Single-cell electrophysiological analysis demonstrated that 5-HT2CR/5-HT1BR agonist coadministration did not significantly potentiate the firing frequency of individual ARC POMC-EGFP cells compared with agonists alone. These data indicate a functional heterogeneity of ARC POMC neurons by revealing distinct subpopulations of POMC cells activated by 5-HT2CRs and disinhibited by 5-HT1BRs. Therefore, coadministration of a 5-HT1BR agonist potentiates the anorectic efficacy of 5-HT2CR compounds by increasing the number, but not the magnitude, of activated ARC POMC neurons and is of therapeutic relevance to obesity treatment. PMID- 23739977 TI - Repetition probability does not affect fMRI repetition suppression for objects. AB - Previously several functional magnetic resonance imaging (fMRI) studies point toward the role of perceptual expectations in determining adaptation or repetition suppression (RS) in humans. These studies showed that the probability of repetitions of faces within a block influences the magnitude of adaptation in face-related areas of the human brain (Summerfield et al., 2008). However, a current macaque single-cell/local field potential (LFP) recording study using objects as stimuli found no evidence for the modulation of the neural response by the repetition probability in the inferior temporal cortex (Kaliukhovich and Vogels, 2010). Here we examined whether stimulus repetition probability affects fMRI repetition suppression for nonface object stimuli in the human brain. Subjects were exposed to either two identical [repetition trials (RTs)] or two different [alternation trials (ATs)] object stimuli. Both types of trials were presented blocks consisting of either 75% [repetition blocks (RBs)] or 25% [alternation blocks (ABs)] of RTs. We found strong RS, i.e., a lower signal for RTs compared to ATs, in the object sensitive lateral occipital cortex as well as in the face-sensitive occipital and fusiform face areas. More importantly, however, there was no significant difference in the magnitude of RS between RBs and ABs in each of the areas. This is in agreement with the previous monkey single-unit/LFP findings and suggests that RS in the case of nonface visual objects is not modulated by the repetition probability in humans. Our results imply that perceptual expectation effects vary for different visual stimulus categories. PMID- 23739978 TI - Decorrelating action of inhibition in neocortical networks. AB - Inhibitory GABAergic interneurons have been extensively studied but their contribution to circuit dynamics remain poorly understood. Although it has been suggested that interneurons, especially those belonging to the same subclass, synchronize their activity and impart this synchrony onto their local network, recent theoretical and experimental work have challenged this view. To better understand the activity of interneurons during cortical activity, we combined molecular identification, two-photon imaging, and electrophysiological recordings in thalamocortical slices from mouse somatosensory cortex. Using calcium imaging to monitor cortical activity, we found low spiking correlations among parvalbumin or somatostatin interneurons during cortical UP states, indicating that interneurons do not synchronize their firing. Intracellular recordings confirmed that nearby interneurons do not display more synchronous spiking than excitatory cells. The lack of interneuron synchrony was also evident during slow oscillations, even among interneurons that were electrically coupled via gap junctions, suggesting that their coupling does not function to synchronize their activity. Using voltage-clamp recordings from nearby pyramidal cells, we found that inhibitory currents (IPSCs) are more correlated than excitatory ones, but that correlated IPSCs arise from the activation of common presynaptic inhibitory cells, rather than from synchronization of interneuron activity. Finally, we demonstrate that pharmacologically reducing inhibitory currents increases correlated excitatory activity. We conclude that inhibitory interneurons do not have synchronous activity during UP states, and that their function may be to decorrelate rather than to synchronize the firing of neurons within the local network. PMID- 23739979 TI - Activation of guanylate cyclase-C attenuates stretch responses and sensitization of mouse colorectal afferents. AB - Irritable bowel syndrome (IBS) is characterized by altered bowel habits, persistent pain and discomfort, and typically colorectal hypersensitivity. Linaclotide, a peripherally restricted 14 aa peptide approved for the treatment of IBS with constipation, relieves constipation and reduces IBS-associated pain in these patients presumably by activation of guanylate cyclase-C (GC-C), which stimulates production and release of cyclic guanosine monophosphate (cGMP) from intestinal epithelial cells. We investigated whether activation of GC-C by the endogenous agonist uroguanylin or the primary downstream effector of that activation, cGMP, directly modulates responses and sensitization of mechanosensitive colorectal primary afferents. The distal 2 cm of mouse colorectum with attached pelvic nerve was harvested and pinned flat mucosal side up for in vitro single-fiber recordings, and the encoding properties of mechanosensitive afferents (serosal, mucosal, muscular, and muscular-mucosal; M/M) to probing and circumferential stretch studied. Both cGMP (10-300 MUM) and uroguanylin (1-1000 nM) applied directly to colorectal receptive endings significantly reduced responses of muscular and M/M afferents to stretch; serosal and mucosal afferents were not affected. Sensitized responses (i.e., increased responses to stretch) of muscular and M/M afferents were reversed by cGMP, returning responses to stretch to control. Blocking the transport of cGMP from colorectal epithelia by probenecid, a mechanism validated by studies in cultured intestinal T84 cells, abolished the inhibitory effect of uroguanylin on M/M afferents. These results suggest that GC-C agonists like linaclotide alleviate colorectal pain and hypersensitivity by dampening stretch-sensitive afferent mechanosensitivity and normalizing afferent sensitization. PMID- 23739980 TI - A eukaryotic specific transmembrane segment is required for tetramerization in AMPA receptors. AB - Most fast excitatory synaptic transmission in the nervous system is mediated by glutamate acting through ionotropic glutamate receptors (iGluRs). iGluRs (AMPA, kainate, and NMDA receptor subtypes) are tetrameric assemblies, formed as a dimer of dimers. Still, the mechanism underlying tetramerization--the necessary step for the formation of functional receptors that can be inserted into the plasma membrane--is unknown. All eukaryotic compared to prokaryotic iGluR subunits have an additional transmembrane segment, the M4 segment, which positions the physiologically critical C-terminal domain on the cytoplasmic side of the membrane. AMPA receptor (AMPAR) subunits lacking M4 do not express on the plasma membrane. Here, we show that these constructs are retained in the endoplasmic reticulum, the major cellular compartment mediating protein oligomerization. Using approaches to assay the native oligomeric state of AMPAR subunits, we find that subunits lacking M4 or containing single amino acid substitutions along an "interacting" face of the M4 helix that block surface expression no longer tetramerize in either homomeric or heteromeric assemblies. In contrast, subunit dimerization appears to be largely intact. These experiments define the M4 segment as a unique functional unit in AMPARs that is required for the critical dimer-to-tetramer transition. PMID- 23739981 TI - System-like consolidation of olfactory memories in Drosophila. AB - System consolidation, as opposed to cellular consolidation, is defined as the relatively slow process of reorganizing the brain circuits that maintain long term memory. This concept is founded in part on observations made in mammals that recently formed memories become progressively independent of brain regions initially involved in their acquisition and retrieval and dependent on other brain regions for their long-term storage. Here we present evidence that olfactory appetitive and aversive memories in Drosophila evolve using a system like consolidation process. We show that all three classes of mushroom body neurons (MBNs) are involved in the retrieval of short- and intermediate-term memory. With the passage of time, memory retrieval becomes independent of alpha'/beta' and gamma MBNs, and long-term memory becomes completely dependent on alpha/beta MBNs. This shift in neuronal dependency for behavioral performance is paralleled by shifts in the activity of the relevant neurons during the retrieval of short-term versus long-term memories. Moreover, transient neuron inactivation experiments using flies trained to have both early and remote memories showed that the alpha'/beta' MBNs have a time-limited role in memory processing. These results argue that system consolidation is not a unique feature of the mammalian brain and memory systems, but rather a general and conserved feature of how different temporal memories are encoded from relatively simple to complex brains. PMID- 23739982 TI - Characterizing functional integrity: intraindividual brain signal variability predicts memory performance in patients with medial temporal lobe epilepsy. AB - Computational modeling suggests that variability in brain signals provides important information regarding the system's capacity to adopt different network configurations that may promote optimal responding to stimuli. Although there is limited empirical work on this construct, a recent study indicates that age related decreases in variability across the adult lifespan correlate with less efficient and less accurate performance. Here, we extend this construct to the assessment of cerebral integrity by comparing fMRI BOLD variability and fMRI BOLD amplitude in their ability to account for differences in functional capacity in patients with focal unilateral medial temporal dysfunction. We were specifically interested in whether either of these BOLD measures could identify a link between the affected medial temporal region and memory performance (as measured by a clinical test of verbal memory retention). Using partial least-squares analyses, we found that variability in a set of regions including the left hippocampus predicted verbal retention and, furthermore, this relationship was similar across a range of cognitive tasks measured during scanning (i.e., the same pattern was seen in fixation, autobiographical recall, and word generation). In contrast, signal amplitude in the hippocampus did not predict memory performance, even for a task that reliably activates the medial temporal lobes (i.e., autobiographical recall). These findings provide a powerful validation of the concept that variability in brain signals reflects functional integrity. Furthermore, this measure can be characterized as a robust biomarker in this clinical setting because it reveals the same pattern regardless of cognitive challenge or task engagement during scanning. PMID- 23739983 TI - Foraging under competition: the neural basis of input-matching in humans. AB - Input-matching is a key mechanism by which animals optimally distribute themselves across habitats to maximize net gains based on the changing input values of food supply rate and competition. To examine the neural systems that underlie this rule in humans, we created a continuous-input foraging task where subjects had to decide to stay or switch between two habitats presented on the left and right of the screen. The subject's decision to stay or switch was based on changing input values of reward-token supply rate and competition density. High density of competition or low-reward token rate was associated with decreased chance of winning. Therefore, subjects attempted to maximize their gains by switching to habitats that possessed low competition density and higher token rate. When it was increasingly disadvantageous to be in a habitat, we observed increased activity in brain regions that underlie preparatory motor actions, including the dorsal anterior cingulate cortex and the supplementary motor area, as well as the insula, which we speculate may be involved in the conscious urge to switch habitats. Conversely, being in an advantageous habitat is associated with activity in the reward systems, namely the striatum and medial prefrontal cortex. Moreover, amygdala and dorsal putamen activity steered interindividual preferences in competition avoidance and pursuing reward. Our results suggest that input-matching decisions are made as a net function of activity in a distributed set of neural systems. Furthermore, we speculate that switching behaviors are related to individual differences in competition avoidance and reward drive. PMID- 23739984 TI - Blend mode reduces unintended thermal injury by laparoscopic monopolar instruments: a randomized controlled trial. AB - BACKGROUND: The purpose of this study was to compare histologic evidence of thermal injury at the epigastric and umbilical incisions after elective laparoscopic cholecystectomy performed using the monopolar "Bovie" instrument set on the higher voltage coag mode versus the lower voltage blend mode. We hypothesized that the higher voltage coag mode would create more unintended thermal tissue injury at the epigastric trocar's incision. METHODS: A prospective blinded randomized controlled trial of patients undergoing elective laparoscopic cholecystectomy was performed. Patients were randomized to have their operation performed with the monopolar instrument set at 30 W on either the coag mode or the blend mode. Immediately at the end of the operation, a biopsy sample of skin was obtained from the lower edge of the epigastric incision (through which the monopolar instrument was inserted) and the umbilical incision (through which the camera/telescope was inserted). The outcomes measured were histologic evidence of thermal injury at the epigastric and umbilical incisions (determined by a blinded pathologist). RESULTS: Forty patients were randomized (20 per group). Baseline demographics in the two groups were similar for age, gender, body mass index, preoperative diagnosis, operative time, and blood loss. Unintentional thermal injury was found at 20 % of epigastric incisions and 35 % of umbilical incisions in the total group. The incidence of thermal injury was higher after operations using the coag mode compared to the blend mode at both the epigastric (35 vs. 5 %; p = 0.044) and umbilical (55 vs. 15 %; p = 0.019) trocar incisions. CONCLUSIONS: Radiofrequency energy from the monopolar Bovie instrument causes unintentional thermal injury to skin adjacent to the epigastric and umbilical trocar incisions. The incidence of thermal injury was reduced by using the lower voltage blend mode compared to the coag mode at both the epigastric and umbilical trocar incisions. REGISTRATION NUMBER: NCT016648060 ( www.clinicaltrials.gov ). PMID- 23739985 TI - "INTEGRINating" the connexin hemichannel function in bone osteocytes through the action of integrin alpha5. AB - Mechanical loading influences skeletal structural integrity and bone remodeling. Application of a mechanical stimulus such as fluid flow shear stress to the bone osteocytes activates the cascade of mechanotransduction mediated by multiple signaling molecules. Hemichannels formed by connexin molecules are emerging as a candidate mechanosensor. Connexin 43 (Cx43) hemichannels open in response to mechanical stimulation to release bone modulators which influence bone remodeling. Our study identified a direct interaction between integrin alpha5 and Cx43 which was essential for hemichannels to open. Uncoupling the interaction blocked the hemichannels and shear stress enhanced the interaction between the two proteins to promote channel opening. More importantly, integrin alpha5, independent of its association with fibronectin, was activated upon shear stress through a PI3K signaling pathway. These results suggest a critical regulatory mechanism for Cx43 hemichannel opening through the association of integrin alpha5, resulting in release of bone anabolic factors required for bone development. PMID- 23739986 TI - The neuropsychiatric translational revolution: still very early and still very challenging. PMID- 23739987 TI - Brain disposition and catalepsy after intranasal delivery of loxapine: role of metabolism in PK/PD of intranasal CNS drugs. AB - PURPOSE: To elucidate the role of metabolism in the pharmacokinetics and pharmacodynamics of intranasal loxapine in conscious animals. METHODS: At pre determined time points after intranasal or oral loxapine administration, levels of loxapine, loxapine metabolites, and neurotransmitters in rat brain were quantified after catalepsy assessments (block test and paw test). Cataleptogenicity of loxapine was also compared with its metabolites. RESULTS: Intranasally administered loxapine was efficiently absorbed into systemic circulation followed by entering brain, with tmax <=15 min in all brain regions. Oral route delivered minimal amounts of loxapine to plasma and brain. Brain AUC0 240min values of 7-hydroxy-loxapine were similar after intranasal and oral administration. Intranasal loxapine tended to induce less catalepsy than oral loxapine, although statistical significance was not reached. The catalepsy score was positively and significantly correlated with the striatal concentration of 7 hydroxy-loxapine, but not with loxapine. 7-hydroxy-loxapine was more cataleptogenic than loxapine, while the presence of loxapine tended to reduce rather than intensify 7-hydroxy-loxapine-induced catalepsy. The increases in striatal dopamine turnover were comparable after intranasal and oral loxapine administration. CONCLUSIONS: The metabolite 7-hydroxy-loxapine, but not loxapine, was the main contributor to the catalepsy observed after intranasal and oral loxapine treatment. Intranasal route could effectively deliver loxapine to brain. PMID- 23739989 TI - Micellar delivery of flutamide via milk protein nanovehicles enhances its anti tumor efficacy in androgen-dependent prostate cancer rat model. AB - PURPOSE: This article describes the preparation, physicochemical characterization and in vivo assessment of parenteral colloidal formulation of flutamide (FLT) based on biocompatible casein (CAS) self-assembled micelles in order to control drug release, enhance its antitumor efficacy and reduce its hepatotoxicity. METHODS: Spray-drying technique was successfully utilized to obtain solidified redispersible drug-loaded micelles. RESULTS: Spherical core-shell micelles were obtained with a particle size below 100 nm and a negative zeta potential above 30 mV exhibiting a sustained drug release up to 5 days. After intravenous administration into prostate cancer bearing rats for 28 days, FLT-loaded CAS micelles showed a higher antitumor efficacy as revealed by significantly higher reduction in PSA serum level (65.95%) compared to free FLT (55.43%). Moreover, micellar FLT demonstrated a marked decrease in relative weights of both prostate tumor and seminal vesicle (34.62 and 24.59%) compared to free FLT (11.86 and 17.74%), respectively. These antitumor responses were associated with notable reduction of cell proliferation, intratumoral angiogenesis and marked increase of tumor apoptosis. A significantly lower risk of hepatotoxicity was observed by micellar FLT as evidenced by lower alanine aminotransferase (ALT) serum level compared to free FLT. CONCLUSIONS: Overall this approach suggested that CAS micelles might be an ideal candidate for intravenous delivery of hydrophobic anticancer drugs. PMID- 23739990 TI - In vitro lipolysis and intestinal transport of beta-arteether-loaded lipid-based drug delivery systems. AB - PURPOSE: We aimed to assess the fate of beta-arteether lipid-based drug delivery systems (AE-LBDDS) in terms of resistance to lipolysis and permeation across intestinal cells. METHODS: AE-LBDDS contained Tween 80 or Cremophor EL as surfactants, ethanol, Maisine 35-1 and vegetable oil. The solubilization behavior of AE was investigated during dynamic in vitro lipolysis. The permeation of AE LBDDS was evaluated using Caco-2, HT29-MTX and M cell monolayers. RESULTS: A higher level of AE precipitation was observed for formulations containing Cremophor EL (~30%) compared to formulations containing Tween 80 (~10%) after lipolysis. However, rapid re-dissolution of the precipitated AE from LBDDS containing Cremophor EL in the intestinal biorelevant media was observed. The transport of AE loaded in LBDDS was enhanced in comparison to that of free drug due to the increased AE solubility. The apparent permeability of all AE-LBDDS across Caco-2 cell monolayers was approximately 3.10(-6) cm/s. A decrease in the permeability was observed at 4 degrees C. M cells did not influence the transport of AE-LBDDS, and mucus decreased AE permeability when formulated with Tween 80. Furthermore, AE is not a P-glycoprotein substrate. CONCLUSION: LBDDS that are partly resistant to in vitro lipolysis significantly increased the transport of AE across intestinal cell monolayers. PMID- 23739991 TI - Drug delivery using platelet cancer cell interaction. AB - PURPOSE: To develop an efficient biocompatible and targeted drug delivery system in which platelets, an essential blood component having a natural affinity for cancer cells, are used as carrier of anticancer drug as delivery of drug to the targeted site is crucial for cancer treatment. METHODS: Doxorubicin hydrochloride, a potent anti cancer drug, was delivered in lung adenocarcinoma cell line (A549) using platelet as a delivery agent. This delivery mode was also tested in Ehrlich ascites carcinoma (EAC) bearing mice in presence and absence of platelets. RESULTS: The results show that platelets can uptake the drug and release the same upon activation. The efficiency of drug loaded platelets in inducing cytotoxicity was significantly higher in both in vitro and in vivo model, as compared to the free drug. CONCLUSIONS: The proposed drug delivery strategy may lead to clinical improvement in the management of cancer treatment as lower drug concentration can be used in a targeted mode. Additionally the method can be personalized as patient's own platelet can be used for deliver various drugs. PMID- 23739993 TI - Acupuncture therapy related cardiac injury. AB - Cardiac injury is the most serious adverse event in acupuncture therapy. The causes include needling chest points near the heart, the cardiac enlargement and pericardial effusion that will enlarge the projected area on the body surface and make the proper depth of needling shorter, and the incorrect needling method of the points. Therefore, acupuncture practitioners must be familiar with the points of the heart projected area on the chest and the correct needling methods in order to reduce the risk of acupuncture therapy related cardiac injury. PMID- 23739994 TI - Thrombocytopenia as a mortality risk factor in acute respiratory failure in H1N1 influenza. AB - BACKGROUND: A small proportion of patients with influenza H1N1 rapidly develop acute respiratory failure and are a problem for intensive care units (ICUs). Although certain clinical risk factors have been identified, few measurable biochemical/haematological markers able to predict poor outcome have been reported. The aims of the present report are to show which variables on and during admission are associated with increased in-hospital mortality in patients admitted to the ICU with acute respiratory failure due to H1N1 influenza. METHODS: A prospective observational study at two ICUs was carried out between August 2009 and March 2011. The study period covered two waves of pandemic influenza A H1N1 in Spain. Clinical and laboratory data on and during ICU admission were recorded for the purpose of analysis. RESULTS: Sixty patients with acute respiratory failure due to H1N1 influenza were admitted during the period described above; 63.3% (n = 38) were male and the mean age was 49.2 +/- 14 years. Regarding comorbidities, 46.7% (n = 28) were smokers, 38% (n = 23) had hypertension, 30% (n = 18) had a body mass index (BMI) >30 kg/m2, 30% (n = 18) had chronic obstructive pulmonary disease and 26% (n = 16) had cardiac insufficiency; 16.6% (n = 10) had bacterial co-infection, 70% (n = 42) required invasive mechanical ventilation and 48.3% (n = 29) non-invasive mechanical ventilation. Mortality was 20% (n = 12). Comparing survivors with non-survivors, univariate analysis revealed significant differences in BMI, creatinine, haemoglobin, platelets, arterial pH, pCO2, and the rate of bacterial co infection. In the multivariate analysis, only the presence of lower platelet count was statistically significant (214 +/- 101 vs 113 +/- 82 *109/L; p = 0.009). Patients with thrombocytopenia showed a lower in-hospital survival rate (55%vs92.5%; Log Rank = 0.008). CONCLUSIONS: Thrombocytopenia could be valuable marker of in-hospital mortality in patients with respiratory failure due to H1N1 influenza in the ICU scenario. PMID- 23739995 TI - Two new meal- and web-based interactive food frequency questionnaires: validation of energy and macronutrient intake. AB - BACKGROUND: Meal-Q and its shorter version, MiniMeal-Q, are 2 new Web-based food frequency questionnaires. Their meal-based and interactive format was designed to promote ease of use and to minimize answering time, desirable improvements in large epidemiological studies. OBJECTIVE: We evaluated the validity of energy and macronutrient intake assessed with Meal-Q and MiniMeal-Q as well as the reproducibility of Meal-Q. METHODS: Healthy volunteers aged 20-63 years recruited from Stockholm County filled out the 174-item Meal-Q. The questionnaire was compared to 7-day weighed food records (WFR; n=163), for energy and macronutrient intake, and to doubly labeled water (DLW; n=39), for total energy expenditure. In addition, the 126-item MiniMeal-Q was evaluated in a simulated validation using truncated Meal-Q data. We also assessed the answering time and ease of use of both questionnaires. RESULTS: Bland-Altman plots showed a varying bias within the intake range for all validity comparisons. Cross-classification of quartiles placed 70%-86% in the same/adjacent quartile with WFR and 77% with DLW. Deattenuated and energy-adjusted Pearson correlation coefficients with the WFR ranged from r=0.33-0.74 for macronutrients and was r=0.18 for energy. Correlations with DLW were r=0.42 for Meal-Q and r=0.38 for MiniMeal-Q. Intraclass correlations for Meal-Q ranged from r=0.57-0.90. Median answering time was 17 minutes for Meal-Q and 7 minutes for MiniMeal-Q, and participants rated both questionnaires as easy to use. CONCLUSIONS: Meal-Q and MiniMeal-Q are easy to use and have short answering times. The ranking agreement is good for most of the nutrients for both questionnaires and Meal-Q shows fair reproducibility. PMID- 23739996 TI - Long-term assessment of systemic inflammation and the cumulative incidence of age related hearing impairment in the epidemiology of hearing loss study. AB - BACKGROUND: Although research has linked systemic inflammation to various diseases of aging, few studies have examined the potential role it may play in the development of age-related hearing impairment. METHODS: Among 1,073 participants free of hearing impairment (pure-tone average 0.5, 1, 2, 4kHz <= 25 dB HL) in the population-based Epidemiology of Hearing Loss Study (1998-2000), serum C-reactive protein, and interleukin-6 were measured at three time points (1988-1990, 1998-2000, and 2009-2010), and tumor necrosis factor-alpha was measured at one time point (1998-2000), whereas hearing impairment was measured again in 2003-2005 and 2009-2010 to determine the 10-year cumulative incidence. RESULTS: Inflammatory marker levels from a single time point (1998-2000) were not associated with an increased risk of developing hearing impairment. Associations between long-term serum C-reactive protein levels and incident hearing impairment differed by age (p = .031). Participants less than 60 years with consistently high (>3 mg/L) or increasing levels of serum C-reactive protein over 10 years were nearly two times (hazard ratio: 1.96, 95% confidence interval: 1.19, 3.23) as likely to develop hearing impairment over the subsequent 10-year period, an association not seen in participants more than or equal to 60 years. A statistically significant association (p-trend = .041) was also observed between number of markers in the highest group at baseline and incident hearing impairment in this younger age group. CONCLUSIONS: Associations between long-term serum C-reactive protein levels and incident hearing impairment were observed in the cohort as a whole, but differed significantly by age group, with statistically significant associations observed in adults less than 60 years, participants moving through the peak risk period for hearing impairment over the course of the study. PMID- 23739997 TI - A microdose study of 14C-AR-709 in healthy men: pharmacokinetics, absolute bioavailability and concentrations in key compartments of the lung. AB - PURPOSE: To explore, in a microdose (phase-0) study, the pharmacokinetics, bioavailability and concentrations in key compartments of the lung, of AR-709, a novel diaminopyrimidine antibiotic for the treatment of respiratory infection. METHODS: Four healthy men each received two single, 100 MUg microdoses of 14C-AR 709, 7 days apart: the first was administered intravenously (IV), the second orally. Plasma pharmacokinetics of 14C and unchanged AR-709 were obtained by high performance liquid chromatography and accelerator mass spectrometry (AMS). Next, 15 healthy men received a single, 100 MUg microdose of 14C-AR-709 IV. Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS. RESULTS: After IV administration, clearance of AR 709 was 496 mL/min, volume of distribution was 1,700 L and the absolute oral bioavailability was 2.5 %. Excretion in urine was negligible. At 8-12 h after IV dosing, 14C concentrations in lung samples were 15- (bronchial mucosa) to 200- (alveolar macrophages) fold higher than in plasma. In alveolar macrophages, 14C was still mostly associated with AR-709 at 12 h after dosing. CONCLUSIONS: The results of this microdose study indicate that AR-709 attains concentrations appreciably higher within the lung than in plasma. Its low oral bioavailability however, precludes oral administration. Although IV administration would appear to be an effective route of administration, this would limit the use of AR-709 to a clinical setting and would therefore be economically unsustainable. If further clinical development were to be undertaken, therefore, an alternative route of administration would be necessary. PMID- 23739998 TI - Actual drug-drug interactions in elderly patients discharged from internal medicine clinic: a prospective observational study. AB - PURPOSE: The aim of the study was to evaluate the incidence and type of actual drug-drug interactions (DDIs) that result in adverse drug reactions (ADRs) or diminished therapeutic effect in elderly patients within 30 days of discharge from an internal medicine clinic. METHODS: A prospective observational study was conducted at the Internal Medicine Clinic of University Hospital Dubrava, Zagreb, Croatia, between October and December 2011. Patients aged >= 65 years discharged from the Internal Medicine Clinic during the study period with a prescription for two or more medications were eligible for inclusion in the study. A total of 222 patients were ultimately enrolled in the study. For each patient, potential DDIs were identified using Lexi-Interact software. The follow-up visit was scheduled approximately 30 days after discharge. Causality between DDIs and ADRs or diminished therapeutic effect of drugs was assessed by two independent clinicians. RESULTS: Potential DDIs were identified in 190 (85.6 %) patients. Actual DDIs were detected in 21 (9.5 %) patients. In 19 patients, DDIs resulted in an ADR. Diminished therapeutic effect resulting from DDIs was detected in two patients. Angiotensin-converting enzyme inhibitors were the drug class most frequently associated with DDI-related ADRs. CONCLUSIONS: A significant incidence of actual DDIs suggests that DDIs play an important role in patient safety. Drug therapy should be initiated if absolutely necessary, and the number of drugs used to treat elderly patients should be minimized to reduce the incidence of DDI related adverse patient outcomes. PMID- 23739999 TI - Less glucuronidation of morphine in the presence of ethanol in vivo. AB - PURPOSE: Ethanol and morphine are both substrates of uridine diphosphate glucuronosyl transferases (UGTs). A pharmacokinetic interaction between ethanol and morphine is suggested from in vitro studies, but to our knowledge not documented in vivo. The aim of this study was to compare the ratios between M6G and morphine and between M3G and morphine in blood samples from suspected drunk and drugged drivers, with and without presence of ethanol. METHODS: The data in the present study constitute all cases of suspected drunk and drugged driving positive for morphine, collected in Norway, in the period November 1st 2009 to December 1st 2012, during which all morphine positive cases were also routinely analysed for M6G and M3G. The cases were divided into two groups; one where morphine was present together with ethanol (group 1) and one where morphine was present in the absence of ethanol (group 2). RESULTS: The ratios between M3G and morphine was lower in the ethanol positive cases, i.e. mean 4.9 (95 % CI 4.03 5.79) in group 1 and mean 6.7 (95 % CI 6.35-7.00) in group 2 (p < 0.001). The ratios between M6G and morphine was also lower in the ethanol positive cases, i.e. mean 0.62 (95 % CI 0.42-0.81) in group 1 and mean 0.96 (95 % CI 0.89-1.02) in group 2 (p = 0.001). CONCLUSIONS: This study indicated that the metabolism of morphine may be changed in the presence of ethanol, resulting in less formation of the metabolites. This could lead to increased terminal half-life for morphine and also possibly more accumulation after repeated dosing. PMID- 23740000 TI - Comments on Duran et al.'s systematic review of anticholinergic risk scales (EJCP 2DOI 10.1007/s00228-013-1499-3). PMID- 23740001 TI - Systematic review of anticholinergic risk scales in older adults. Response to letter of the editor. PMID- 23740002 TI - The use of allelic imbalance to ascertain cis-regulation for human UGT2B7 in vivo. PMID- 23740003 TI - Effects of legumain as a potential prognostic factor on gastric cancers. AB - Although legumain has been found to be a prognostic factor in both breast cancer and colorectal cancer, its effects on gastric cancer are unknown. In this study, we investigated effects of legumain on gastric cancer and the correlation between legumain expression and prognosis of gastric cancer patients. SGC7901 cells were transduced with legumain cDNA (SGC7901-hLeg) for overexpression of legumain or with legumain shRNA to knock down legumain. In vitro tumor migration was examined by wound healing assay. Furthermore, a tumorigenicity and metastasis mouse model was used to examine legumain function in vivo; asparaginyl endopeptidase inhibitor (AEPI, an inhibitor of legumain) was injected to the mice (i.p.) to evaluate its therapeutic effect. Tissue microarray analysis from 112 gastric cancer patients was performed to evaluate the association between legumain expression and the cumulative survival time. Legumain was highly expressed in gastric cancer patients and some gastric cancer cell lines. Legumain promoted gastric cell migration in vitro and promoted gastric tumor growth and metastasis in vivo, and these effects were reversed by knockdown of legumain with shRNA or treated with AEPI. In gastric cancer clinical samples, legumain expression in tumor was significantly higher than in non-tumor and was negatively associated with the cumulative survival rate. In conclusion, legumain was highly expressed in gastric adenocarcinoma; legumain promoted gastric cancer tumorigenesis and metastasis in vitro and in vivo. Legumain expression in tumor was a poor prognostic factor for gastric cancer patients, and legumain could be a potential target molecule for gastric cancer therapy in clinic. PMID- 23740005 TI - Evaluation of WGA and Concanavalin A (Con A) lectin as biomarkers of hepatosplenic schistosomiasis in human biopsies with no evidence of egg-granuloma system. AB - INTRODUCTION: Colonic lesions are predominant in patients with schistosomiasis. However, carbohydrate alterations in colonic schistosomiasis remain unclear. Lectin-ligands allow us to identify changes in the saccharide patterns of cells. METHODS: Biopsies of descending and rectosigmoid colon of patients were submitted to WGA and Con A lectin histochemistry. RESULTS: WGA stained stroma and gland cells of descending colon and rectosigmoid tissues in a granular strong cytoplasmatic pattern in schistosomiasis specimens differing from normal control and Con A failing to recognize all samples analyzed. CONCLUSIONS: WGA ligands are expressed differently in patients with hepatosplenic schistosomiasis and no evidence of egg-granuloma system. PMID- 23740004 TI - Clinical characteristics and outcomes of patients with small cell lung cancer detected by CT screening. AB - The present study was performed to evaluate the clinical characteristics and survival outcomes in patients with small cell lung cancer (SCLC) detected by low dose computed tomography (CT). We retrospectively reviewed clinical records of patients with SCLC treated at our hospital between 1997 and 2011 and selected patients with SCLC detected by CT screening. We identified 12 patients (male/female 11/1; mean age 67.8 years old. Nine patients had limited disease (LD), and 3 had extensive disease (ED). Five LD patients underwent thoracic surgery, and the pathological staging information included stage IA (n = 1), IB (n = 1), IIA (n = 1), and IIIB (n = 2). Although 2 patients with pathological stages IA and IB had >10-year survival, the median survival times (MST) in LD and ED were 25 months (95 % CI 17.0-32.9) and 16 months (95 % CI; not evaluated), respectively. In addition, MST in 12 patients was not significantly different from that in SCLC patients in general care in our hospital. This analysis suggested that CT screening contributes to the detection of early-stage SCLC in patients that are potentially suitable for surgery, but it remains unclear how to improve clinical outcome in patients with SCLC. PMID- 23740007 TI - Thermotherapy effective and safer than miltefosine in the treatment of cutaneous leishmaniasis in Colombia. AB - In Colombia, pentavalent antimonials and miltefosine are the drugs of choice for the treatment of cutaneous leishmaniasis; however, their toxicity, treatment duration, (treatment adherence problems), cost, and decreased parasite sensitivity make the search for alternative treatments of American cutaneous leishmaniasis necessary. Based on the results found in a controlled, open, randomized, phase III clinical trial, the efficacy and safety of miltefosine was compared to that of thermotherapy for the treatment of cutaneous leishmaniasis in Colombia. Adult patients from the Colombian army participated in the study; they received either 50 mg of miltefosine three times per day for 28 days by the oral route (n = 145) or a thermotherapy (Thermomed(r)) application of 50 degrees C for 30 seconds over the lesion and surrounding area (n = 149). Both groups were comparable with respect to their sociodemographic, clinical, and parasitological characteristics. The efficacy of miltefosine by protocol and by intention to treat was 70% (85/122 patients) and 69% (85/145 patients), respectively. The adverse effects were primarily gastrointestinal for miltefosine and pain at the lesion site after treatment for thermotherapy. No statistically significant difference was found in the efficacy analysis (intention to treat and protocol) between the two treatments. PMID- 23740008 TI - Intestinal parasites in a quilombola community of the Northern State of Espirito Santo, Brazil. AB - The aim of this study was to determine the occurrence of intestinal parasites in a quilombola community from the northern Espirito Santo, Brazil. Descendants of slaves who arrived in Brazil in the sixteenth century, this population settled in the municipality of Sao Mateus in 1858. Fresh fecal samples from 82 individuals who agreed to participate in the study were collected between August 2009 and July 2010, and immediately sent to the Clinical Laboratory of the Centro Universitario Norte do Espirito Santo of the Universidade Federal do Espirito Santo for analysis. Out of all the participants, 36 (43.9%) were male and 46 (56.1%) were female, whose ages ranged from six to 85 years. The study of the occurrence of intestinal parasites indicated that 35 individuals (42.7%) were infected with at least one intestinal parasite. Among helminths, the most frequent were hookworms, with a rate of 14.6%. With regard to protozoa, Entamoeba coli, Entamoeba histolytica/Entamoeba dispar and Endolimax nana stood out, with frequencies of 23.2%, 8.5% and 4.9%, respectively. The occurrence of biparasitism was observed in 13 of the 82 subjects, accounting for 15.8%, and no cases of multiple parasitic infections were observed. It was concluded that the reduction of cases of intestinal diseases due to parasites will only be achieved with the improvement of basic sanitation and quality of life of quilombola populations. PMID- 23740009 TI - Active search for leprosy cases in Midwestern Brazil: a serological evaluation of asymptomatic household contacts before and after prophylaxis with bacillus Calmette-Guerin. AB - Leprosy is a disease caused by Mycobacterium leprae that carries a high risk of disability, making early diagnosis mandatory. This study aimed to determine the applicability of anti-PGL-1 IgM antibody detection, using the ML FLOW technique, as an assistant tool for the detection of leprosy infection in asymptomatic household contacts (AHHC) of multibacillary leprosy index cases from Midwest Brazil. Serological changes induced by the prophylaxis of these household contacts with Bacillus Calmette-Guerin (BCG) were also verified. A total of 91 AHHC were assessed, among which, 18.68% (n = 17) presented both positive bacilloscopy and positive anti-PGL-1 IgM serology. Positivity concordance between these two laboratorial exams (Kappa Index = 1; p < 0.001) was indicated, however, one case did not demonstrate concordance between the semiquantitative assessment of anti-PGL-1 IgM and the bacilloscopy index (Kappa Index = 0.96; p < 0.001). Among the 17 AHHC with positive bacilloscopy, eight were reassessed after prophylaxis with BCG and two of them presented negative anti-PGL-1 IgM serology, being these patients who had presented a bacilloscopy index of < 2[+] in the initial assessment. This study shows that anti-PGL-1 IgM detection may be used as a tool to determine the bacillary load in AHHC and to detect immune changes related to prophylaxis by nonspecific vaccination. PMID- 23740010 TI - Analogies in medicine: spaghetti and meatballs. PMID- 23740011 TI - Varicella emergency vaccination seemed instrumental in declining chickenpox incident in Guangzhou, Southern China. PMID- 23740012 TI - High occurrence of giardiasis in children living on a 'landless farm workers' settlement in Araras, Sao Paulo, Brazil. AB - Enteric parasitosis remains an important public health problem in many areas around the world including in Brazil, and it is frequently associated with poverty and lack of sanitation facilities. Research carried out over the course of a year revealed that 96.6% (28/29) of children randomly selected from a 'landless farm workers' settlement in Araras, Sao Paulo, aged 4 - 15 years, presented Giardia intestinalis cysts. After referral to the neighborhood Health Office, all the children received tinidazole, given as a single dose of 50 mg/kg and 12 months later, new fecal samples were collected and analyzed. Despite the low adherence to the study, a high percentage (64.3% - 9/14) of the children remained positive for the parasite. This study showed a high positivity of giardiasis in child residents of the settlement, even after treatment; adults were not sensitized to the study and did not collected and/or deliver children fecal samples. The precarious living conditions are consistent with a high susceptibility to parasitic diseases, suggesting that the treatment of the infected individuals without identifying and eradicating the means of contamination is simply a palliative measure. PMID- 23740013 TI - Evaluation of the ELISA-F29 test as an early marker of therapeutic efficacy in adults with chronic Chagas disease. AB - This work compared the time at which negative seroconversion was detected by conventional serology (CS) and by the ELISA-F29 test on a cohort of chronic chagasic patients treated with nifurtimox or benznidazole. A retrospective study was performed using preserved serum from 66 asymptomatic chagasic adults under clinical supervision, and bi-annual serological examinations over a mean follow up of 23 years. Twenty nine patients received trypanocide treatment and 37 remained untreated. The ELISA-F29 test used a recombinant antigen which was obtained by expressing the Trypanosoma cruzi flagellar calcium-binding protein gene in Escherichia coli. Among the untreated patients, 36 maintained CS titers. One patient showed a doubtful serology in some check-ups. ELISA-F29 showed constant reactivity in 35 out of 37 patients and was negative for the patient with fluctuating CS. The treated patients were divided into three groups according to the CS titers: in 13 they became negative; in 12 they decreased and in four they remained unchanged. ELISA-F29 was negative for the first two groups. The time at which negativization was detected was significantly lower for the ELISA-F29 test than for CS, 14.5 +/- 5.7 and 22 +/- 4.9 years respectively. Negative seroconversion was observed in treated patients only. The results obtained confirm that the ELISA-F29 test is useful as an early indicator of negative seroconversion in treated chronic patients. PMID- 23740014 TI - Histoplasmosis presenting with multiple pulmonary nodules. A case mimicking radiological features of pulmonary metastasis. AB - We present a case of histoplasmosis with multiple pulmonary nodules in a patient with a history of melanoma. This case closely simulated malignancy, including the presence of feeding vessel sign, which occurs in pulmonary metastasis. We emphasize the need to be aware of this infection in areas where histoplasmosis is endemic. PMID- 23740015 TI - Do Brazilian scientific journals promote the adherence of Chagas disease researchers to international ethical principles? AB - The ethical aspects of the Brazilian publications about human Chagas disease (CD) developed between 1996 and 2010 and the policy adopted by Brazilian medical journals were analyzed. Articles were selected on the SciELO Brazil data basis, and the evaluation of ethical aspects was based on the normative contents about ethics in research involving human experimentation according to the Brazilian resolution of the National Health Council no. 196/1996. The editorial policies of the section "Instructions to authors" were analyzed. In the period of 1996-2012, 58.9% of articles involving human Chagas disease did not refer to the fulfillment of the ethical aspects concerning research with human beings. In 80% of the journals, the requirements and confirmation of the information about ethical aspects in the studies of human CD were not observed. Although a failure in this type of service is still observed, awareness has been raised in federal agencies, educational institutions/research and publishing groups to standardize the procedures and ethical requirements for the Brazilian journals, reinforcing the fulfillment of the ethical parameters, according to the resolution of NHC no. 196/1996. PMID- 23740016 TI - Variability in Galactomannan detection by Platelia Aspergillus EIATM according to the Aspergillus species. AB - Here we investigate the extent to which different Aspergillus species release galactomannan (GM) in vitro. Marked variability was observed in GM reactivity between and within Aspergillus species, with A. terreus strains showing the highest GM indexes. The in vivo significance of these findings remains to be determined. PMID- 23740017 TI - Toxocariasis in children attending a Public Health Service Pneumology Unit in Parana State, Brazil. AB - The enzyme-linked immunosorbent assay (ELISA) is the most widely used tool to detect anti-Toxocara IgG antibodies for both serodiagnostic and seroepidemiological surveys on human toxocariasis. In the last eight years a high prevalence of toxocariasis (32.2-56.0%) has been reported in children attending public health units from municipalities in the state of Parana, Brazil. Therefore, the aim of this work was to compare the frequency found among the general child population with that of children attending a public pneumology service in Maringa, Parana, Brazil and describe the laboratorial, clinical and epidemiological findings. The research was conducted at the Consorcio Publico Intermunicipal de Saude do Setentriao Paranaense (CISAMUSEP) from July 2009 to July 2010 among children aged between one and 15 years. From a total of 167 children studied, only 4.2% (7/167) tested positive for anti-Toxocara spp. IgG antibodies and presented mild eosinophilia (2/7), increased serum IgE levels (6/7) and a positive allergy test for mites (5/7). The presence of pets (dogs or cats) at home did not correlate with the seroprevalence. In conclusion, cases of toxocariasis involving the respiratory tract are rare in children attending a public health pneumology unit in the northwestern region of Parana State, despite the high prevalence of this type of toxocariasis among the infantile population attending Basic Health Units in the same geographical area. PMID- 23740018 TI - Serological survey of hantavirus in rodents in Uberlandia, Minas Gerais, Brazil. AB - We conducted a serological survey to determine the presence of hantavirus infection in rodents in Uberlandia, Minas Gerais as well as to identify and characterize associated factors. Rodents were captured using Sherman live-capture traps set in rural and peri-urban environments. A total of 611 rodents were captured. There was a higher trap success in peri-urban areas (26.3%) and a higher prevalence of antibodies among rodents captured in rural areas (2.9%). Necromys lasiurus was the most common species (42.2%) and the more frequently infected (4.6%). One Calomys tener (1/141; 0.7%) and one Calomys sp. (1/14; 7.1%) were also positive for the hantavirus infection. In N. lasiurus, antibody prevalence correlated with population density (p < 0.01), age class (p = 0.003) and presence of scars (p = 0.02). The data confirm that horizontal transmission is the main mechanism that maintains the virus in nature. The higher seropositivity in N. lasiurus is consistent with genetic studies that associate this species with an Araraquara virus reservoir; the seropositivity of C. tener and Calomys sp. may indicate the occurrence of spillover infection or the presence of other circulating hantaviruses. PMID- 23740019 TI - High occurrence of Entamoeba histolytica in the municipalities of Ariquemes and Monte Negro, State of Rondonia, Western Amazonia, Brazil. AB - INTRODUCTION: Entamoeba histolytica infections were investigated in residents of the Ariquemes and Monte Negro municipalities in Rondonia State, Brazil. METHODS: Stool samples of 216 individuals were processed by the spontaneous sedimentation method and analyzed by microscopy for detection of the E. histolytica/E. dispar complex, followed by the immunoassay method using an enzyme-linked immunosorbent assay-based kit for the E. histolytica stool antigen. RESULTS: E. histolytica/E. dispar cysts were present in 61% (50/82) and 44% (59/134) of the samples from Ariquemes and Monte Negro respectively, with a significant difference in the occurrence of infection between the two populations [p < 0.05; chi2 = 5.2; odds ratio = 2.0 (1.1 - 3.6)]. The E. histolytica antigen detection rate was 36.6% (30/82) for stool samples from Ariquemes, and 19.4% (26/134) for stool taken from the residents of Monte Negro. The rate of the occurrence of amoebiasis was significantly higher in the population from Ariquemes [p < 0.05; chi2 = 7.8; odds ratio = 2.4 (1.2 - 4.7)]. DISCUSSION: Due to the high occurrence of E. histolytica infected residents diagnosed in the region and the unavailability in local clinics of a test to distinguish between the two Entamoeba species, physicians should consider treating E. histolytica/E.dispar infections. CONCLUSION: The results indicate that E. histolytica infection is highly endemic in the studied areas. PMID- 23740020 TI - Prevalence and genetic characterization of Cryptosporidium spp. and Cystoisospora belli in HIV-infected patients. AB - Cryptosporidium spp. and Cystoisospora belli are monoxenic protozoa that have been recognized as the causative agents of chronic diarrhea in immunocompromised individuals, especially HIV-infected subjects. The objective of this study was to evaluate the frequency of these intestinal protozoa in HIV-positive patients in the Triangulo Mineiro region of Brazil and to correlate the presence of these infections with clinical, epidemiological and laboratory data of the patients. Oocysts were detected in stool samples of 10 (16.9%) of the 59 patients studied, while Cryptosporidium spp. were present in 10.1% (6/59) and C. belli in 6.7% (4/59). The frequency of these parasites was higher among patients with diarrheic syndrome and CD4+ T lymphocyte counts < 200 cells/mm 3 , demonstrating the opportunistic characteristic of these infections. A significant association was observed between the lack of adherence to antiretroviral therapy and the presence of Cryptosporidium spp. and/or C. belli. Parasitism with Cryptosporidium spp. was more frequent in February and April, the months following the period of high rainfall. The same was not observed for C. belli. Genetic characterization of two isolates led to the identification of Cryptosporidium parvum, one of the main species associated with the zoonotic transmission of cryptosporidiosis. PMID- 23740021 TI - Evaluation of three different DNA extraction methods from blood samples collected in dried filter paper in Plasmodium subpatent infections from the Amazon region in Brazil. AB - Asymptomatic Plasmodium infection is a new challenge for public health in the American region. The polymerase chain reaction (PCR) is the best method for diagnosing subpatent parasitemias. In endemic areas, blood collection is hampered by geographical distances and deficient transport and storage conditions of the samples. Because DNA extraction from blood collected on filter paper is an efficient method for molecular studies in high parasitemic individuals, we investigated whether the technique could be an alternative for Plasmodium diagnosis among asymptomatic and pauciparasitemic subjects. In this report we compared three different methods (Chelex(r)-saponin, methanol and TRIS-EDTA) of DNA extraction from blood collected on filter paper from asymptomatic Plasmodium infected individuals. Polymerase chain reaction assays for detection of Plasmodium species showed the best results when the Chelex(r)-saponin method was used. Even though the sensitivity of detection was approximately 66% and 31% for P. falciparum and P. vivax, respectively, this method did not show the effectiveness in DNA extraction required for molecular diagnosis of Plasmodium. The development of better methods for extracting DNA from blood collected on filter paper is important for the diagnosis of subpatent malarial infections in remote areas and would contribute to establishing the epidemiology of this form of infection. PMID- 23740022 TI - Health problems awareness during travel among faculty members. PMID- 23740023 TI - Erratum to: Comparative Proteomic Analysis of Mesenchymal Stem Cells Derived from Human Bone Marrow, Umbilical Cord and Placenta: Implication in the Migration. PMID- 23740024 TI - Preliminary observations and clinical value of lipid peak in high-grade uterine sarcomas using in vivo proton MR spectroscopy. AB - OBJECTIVE: To retrospectively evaluate the clinical significance of the lipid peak in in vivo proton magnetic resonance spectroscopy (MRS) for the diagnosis of high-grade uterine sarcomas. METHODS: MRS was performed in patients with 38 pathologically diagnosed uterine corpus tumours (26 leiomyomas and 12 sarcomas) at 3 T. Single-voxel MRS data were collected from a single square volume of interest that encompassed the tumours. The concentrations of lipid and total choline compounds (tCho) were classified as high, low or none. RESULTS: High lipid peaks were observed in all 12 sarcomas and not in benign leiomyomas except for 1 lipoleiomyoma. All 26 leiomyomas and 10 of the 12 sarcomas showed tCho peaks, whereas 2 sarcomas with massive necrosis showed no tCho peak. The presence of a high lipid peak for the diagnosis of sarcoma had a sensitivity of 100 %, specificity of 96 %, positive predictive value of 92 % and negative predictive value of 100 %. CONCLUSIONS: The high lipid peaks in high-grade malignant tumours may be observed in both viable and necrotic areas, and may be useful in distinguishing uterine sarcomas from benign leiomyomas. KEY POINTS: * High lipid peak on MR spectroscopy is suggestive of uterine sarcomas. * Lipid peak is observed in both viable and necrotic areas in sarcomas. * MR spectroscopy may be useful in distinguishing uterine sarcomas from benign leiomyomas. PMID- 23740026 TI - Sacral neuromodulation for bowel dysfunction. PMID- 23740025 TI - A prospective feasibility study of sub-millisievert abdominopelvic CT using iterative reconstruction in Crohn's disease. AB - OBJECTIVE: Iterative reconstruction (IR) allows diagnostic CT imaging with less radiation exposure than filtered back projection (FBP). We studied an IR low-dose CT abdomen/pelvis (LDCTAP) protocol, designed to image at an effective dose (ED) approximating 1 mSv in patients with Crohn's disease (CD). METHODS: Forty patients, mean age 37 +/- 13.4 years (range 17-69), with CD underwent two synchronous CT protocols (conventional-dose (CDCTAP) and LDCTAP). CDCTAP and LDCTAP images were compared for diagnostic acceptability, yield, image quality and ED (in millisieverts). The optimal level of IR for LDCTAP was also studied. RESULTS: LDCTAP yielded a mean ED of 1.3 +/- 0.8 mSv compared with 4.7 +/- 2.9 mSv for CDCTAP, reducing ED by 73.7 +/- 3.3 % (mean dose reduction, 3.5 +/- 2.1 mSv; P < 0.001) and dose length product by 73.6 +/- 2.6 % (P < 0.001). Sub millisievert (0.84 mSv) imaging was performed for patients with a body mass index (BMI) less than 25 (i.e. 63 % of our cohort). LDCTAP resulted in increased image noise and reduced diagnostic acceptability compared with CDCTAP despite use of IR, but detection of extra-luminal complications was comparable. CONCLUSION: Patients with suspected active CD can be adequately imaged using LDCTAP, yielding comparable information regarding extent, activity and complications of CD compared with CDCTAP, but with 74 % less dose. LDCTAP at doses equivalent to that of two abdominal radiographs represents a feasible alternative to CDCTAP. KEY POINTS: * Radiation dose is a concern when imaging patients with Crohn's disease. * New techniques allow low-dose abdominopelvic CT with acceptable image quality. * Using hybrid iterative reconstruction, its diagnostic yield compares well with that of conventional CT. * Sub-millisievert CT of patients with Crohn's disease appears technically and clinically feasible. PMID- 23740027 TI - The American Society of Colon and Rectal Surgeons 2013 annual meeting. PMID- 23740028 TI - Isolated ischemic colitis may mimic occluding cancer in elderly patients. PMID- 23740029 TI - Transanal minimally invasive surgery (TAMIS) using a new disposable device: our initial experience. AB - Disposable single-port surgery devices have been used for transanal minimally invasive surgery (TAMIS). Their advantage, compared to transanal endoscopic microsurgery, is that they do not require special equipment or training. The aim of this study was to assess our initial experience using the single-site laparoscopic (SSLTM) access system (Ethicon Endo-Surgery, Cincinnati, OH, USA) for TAMIS. Five patients eligible for local excision of rectal tumors, four males and one female, mean age 58 years (range 50-78), underwent surgery using the SSLTM device. The average distance from anal verge was 4 cm (range 1-6). Four patients had an initial diagnosis of adenoma, and one had a previous endoscopic excision of a T1 adenocarcinoma with positive margins. In one patient, due to the lack of exposure, the procedure was converted to a low anterior resection. In the remaining four patients, average setup time was 7 minutes (range 4-15) and average operative time was 52 minutes (range 38-72). All resection margins were tumor free. There were no postoperative complications. Two of the presumed adenomas were intramucosal adenocarcinomas, while one patient had a T2 tumor and underwent radical surgery. Although at the present time the appropriate use of local excision is still under debate, TAMIS is a technique with great potential. Because of its simplicity and similarity with conventional laparoscopic surgery, it can be learned easily by surgeons not trained in transanal endoscopic microsurgery. PMID- 23740030 TI - The control of defecation in humans: an evolutionary advantage? PMID- 23740031 TI - Rituximab therapy for recurrent thromboembolic disease in antiphospholipid syndrome. PMID- 23740032 TI - Design and application of an easy to use oligonucleotide mass calculation program. AB - With the development of new synthesis procedures, an ever increasing number of chemical modifications can now be incorporated into synthetic oligonucleotides, representing new challenges for analytical chemists to efficiently identify and characterize such molecules. While conventional mass spectrometry (MS) has proven to be a powerful tool to study nucleic acids, new and improved methods and software are now needed to address this emerging challenge. In this report, we describe a simple yet powerful program that affords great flexibility in the calculation of theoretical masses for conventional as well as modified oligonucleotide molecules. This easy to use program can accept input oligonucleotide sequences and then calculate the theoretical mass values for full length products, process impurities, potential metabolites, and gas phase fragments. We intentionally designed this software so that modified nucleotide residues can be incorporated into oligonucleotide sequences, and corresponding mass values can be rapidly calculated. To test the utility of this program, two oligonucleotides that contain a large number of chemical modifications were synthesized. We have analyzed these samples using a Q-TOF mass spectrometer and compared the calculated masses to the observed ones. We found that all of the data matched very well with less than 30 ppm mass errors, well within the expectation for our instrument operated in its current mode. These data confirmed the validity of calculations performed with this new software. PMID- 23740033 TI - Is the renin-angiotensin system actually hypertensive? AB - The historical view of the renin-angiotensin system (RAS) is that of an endocrine hypertensive system that is controlled by renin and mediated via the action of angiotensin II on its type 1 receptor. Numerous new angiotensins (Ang) and receptors have been described, the majority being hypotensive and natriuretic, namely Ang-(1-7) and its receptor rMas. Renin and its precursor (pro-renin) can bind their common receptor. In addition to the production of Ang II, this receptor triggers intracellular effects. Given the control of renin production by intracellular calcium, calcium homeostasis is of particular importance. Ang-(1 12), which is not controlled by renin, is converted to several different angiotensin peptides and is a new pathway of the RAS. Local RAS enzymes produce or transform the different hyper- or hypotensive angiotensin within vessels and organs, but also in blood through circulating forms of the enzymes. In the kidney, a powerful local vascular RAS allows for the independence of renal vascularization from systemic control. Moreover, the kidney also contains an independent urinary RAS, which counterbalances the systemic RAS and coordinates proximal and distal sodium reabsorption. The systemic and local effects of renal RAS cannot be analyzed without taking into account the antagonistic effect of renalase. Our concept of RAS needs to evolve to take into account its dual potentiality (hyper- or hypotensive). PMID- 23740035 TI - Left ventricular diastolic dysfunction by tissue Doppler echocardiography in pediatric chronic kidney disease. AB - BACKGROUND: Myocardial dysfunction is common in chronic kidney disease (CKD) and related to poor outcomes. New non-invasive methods to assess cardiac function have been introduced, but comparative studies evaluating their clinical usefulness in pediatric CKD are lacking. We studied left ventricular (LV) function in pediatric CKD and renal transplant patients, comparing conventional pulse-wave Doppler echocardiography (cPWD) with newer tissue Doppler imaging (TDI) and relating the results to known cardiovascular risk factors. METHODS: The study included 34 children/adolescents with CKD stages 2-5, 44 renal transplant patients and 19 patients with a normal renal function. The mean age was 11.4 (range 0.8-18.8) years. RESULTS: Both patient groups had significantly lower LV diastolic function than those with a normal renal function. The most sensitive determinants were TDI E'/A' and cPWD E/TDI E' ratios. In a stepwise linear regression analysis, high blood pressure, young age and the presence of albuminuria all independently predicted LV diastolic function. CONCLUSIONS: Our study confirms the high prevalence of LV diastolic dysfunction in pediatric CKD patients and following renal transplantation, where TDI appears to be more sensitive than cPWD in assessing early myocardial dysfunction. Our results also underline the importance of preventive measures, such as rigorous blood pressure control, in pediatric CKD. PMID- 23740036 TI - mTOR inhibitors in pediatric kidney transplantation. AB - The mammalian target of the rapamycin (mTOR) inhibitors sirolimus and everolimus are increasingly being used in pediatric kidney transplantation in different combinations and doses. Several studies have shown beneficial effects of using mTOR inhibitors in children after pediatric renal transplantation. A switch to a low-dose calcineurin inhibitor (CNI) and mTOR inhibitor has been proven to stabilize the glomerular filtration rate. Additionally, de novo studies using a low-dose CNI and an mTOR inhibitor have shown good graft survival and a low number of rejections. Side effects of mTOR inhibitors, such as hyperlipidemia, wound healing problems, and proteinuria, mainly occur if high doses are given and if treatment is not combined with a CNI. Lower doses of mTOR inhibitors do not result in growth impairment or reduced testosterone levels. Treatment with mTOR inhibitors is also associated with a lower number of viral infections, especially cytomegalovirus. Due to their antiproliferative effect, mTOR inhibitors could theoretically reduce the risk of post-transplant lymphoproliferative disease. mTOR inhibitors, especially in combination with low-dose CNIs, can safely be used in children after kidney transplantation as de novo therapy or for conversion from CNI- and mycophenolate mofetil-based regimens. PMID- 23740038 TI - A graphene-based smart catalytic system with superior catalytic performances and temperature responsive catalytic behaviors. AB - We have successfully developed a unique graphene-based smart catalytic system which consists of the graphene supported Au-Pt bimetallic nanocatalyst with a well-defined core-shell structure and a dextran-based temperature-responsive polymer. The unique catalytic system possesses excellent catalytic performances and the catalytic activities could be readily switched on or off at different temperature windows. PMID- 23740037 TI - Associations between fibroblast growth factor 23 and cardiac characteristics in pediatric heart failure. AB - BACKGROUND: In adults with heart failure, elevated levels of fibroblast growth factor 23 (FGF23) are associated with mortality. Data on FGF23 levels in pediatric heart failure are lacking. PATIENTS AND METHODS: We conducted a cross sectional study of 17 healthy children (mean age 13 years) and 20 pediatric patients with heart failure (mean age 12 years) who underwent echocardiography and for whom the following measurements were taken: plasma FGF23 and parathyroid hormone (PTH) and serum phosphate, creatinine and N-terminal prohormone brain natriuretic peptide (NT-proBNP). Symptom severity was assessed with the New York Heart Association and the Ross classification systems. RESULTS: Of the 20 patients, 11 had dilated cardiomyopathy, four had congenital heart disease, three had hypertrophic cardiomyopathy, one had a failing heart transplant and one had pulmonary hypertension. Mean phosphate levels in these patients were within the reported reference range for healthy children. Median PTH levels were in the normal range in patients and controls. The median FGF23 level was higher in patients versus controls (110.9 vs. 66.4 RU/ml; P = 0.03) and higher in patients on diuretics versus other patients (222.4 vs. 82.1 RU/ml; P = 0.01). Levels of FGF23 and NT-proBNP were directly correlated (r = 0.47, P = 0.04), and patients with greater physical functional impairment had higher FGF23 levels (142.5 in those with moderate-severe limitation vs. 92.8 RU/ml in those with no limitation; P = 0.05). Among patients with dilated cardiomyopathy, higher FGF23 levels were associated with a greater left ventricular end-diastolic diameter (r = 0.63, P = 0.04). CONCLUSION: FGF23 levels are elevated in children with heart failure and are associated with diuretic use, severity of heart failure and left ventricular dilation. PMID- 23740039 TI - Lipid profile is associated with risk of thrombotic complications. PMID- 23740040 TI - Reduction of radiocesium load - reply. PMID- 23740041 TI - International guidelines on biobank research leave researchers in ambiguity: why is this so? PMID- 23740042 TI - Ultrasound compared with nerve stimulation guidance for peripheral nerve catheter placement: a meta-analysis of randomized controlled trials. AB - BACKGROUND: The aim of this meta-analysis was to compare the efficacy and safety of ultrasound (US) vs nerve stimulation (NS) guidance for peripheral nerve catheter placement. METHODS: This meta-analysis was performed according to the PRISMA statement and the recommendations of the Cochrane Collaboration. For dichotomous outcomes relative risks [RRs; 95% confidence intervals (CIs)] were calculated, while for continuous outcomes, mean differences (MDs; 95% CI) were calculated. All statistical analyses were performed using the Revman(r) statistical software (Version 5.1). RESULTS: Fifteen randomized controlled trials including 977 patients satisfied the inclusion criteria. Peripheral nerve catheters placed under US guidance showed a higher RR of 1.14 (95% CI: 1.02-1.27; P=0.02) for an overall successful block in comparison with NS. However, postoperative pain scales at movement (numeric rating scale: 0-10) were comparable between US- vs NS-guided peripheral nerve catheters 24 (MD: 0.08; 95% CI: -0.77 to 0.94; P=0.85) and 48 (MD: 1.0; 95% CI: -0.3 to 2.3; P=0.13) h after surgery. Patients receiving a US-guided peripheral nerve catheter had a lower RR of 0.13 (95% CI: 0.04-0.38; P=0.0002) for an accidental vascular puncture. CONCLUSIONS: There is evidence that US-guided peripheral nerve catheters show a higher success rate and a lower risk for an accidental vascular puncture compared with NS guidance. However, this difference resulted only in marginally lower postoperative pain scores at rest. Nevertheless, these results were influenced by heterogeneity and should be interpreted with caution. PMID- 23740043 TI - Influence of variations in systemic blood flow and pressure on cerebral and systemic oxygen saturation in cardiopulmonary bypass patients. AB - BACKGROUND: Although both pressure and flow are considered important determinants of regional organ perfusion, the relative importance of each is less established. The aim of the present study was to evaluate the impact of variations in flow, pressure, or both on cerebral and whole-body oxygen saturation. METHODS: Thirty four consenting patients undergoing elective cardiac surgery on cardiopulmonary bypass were included. Using a randomized cross-over design, four different haemodynamic states were simulated: (i) 20% flow decrease, (ii) 20% flow decrease with phenylephrine to restore baseline pressure, (iii) 20% pressure decrease with sodium nitroprusside (SNP) under baseline flow, and (iv) increased flow with baseline pressure. The effect of these changes was evaluated on cerebral (Sc(O2)) and systemic (Sv(O2)) oxygen saturation, and on systemic oxygen extraction ratio (OER). Data were assessed by within- and between-group comparisons. RESULTS: Decrease in flow was associated with a decrease in [from 63.5 (7.4) to 62.0 (8.5) %, P<0.001]. When arterial pressure was restored with phenylephrine during low flow, Sc(O2) further decreased from 61.0 (9.7) to 59.2 (10.2) %, P<0.001. Increase in flow was associated with an increase in Sc(O2) from 62.6 (7.7) to 63.6 (8.9) %, P=0.03, while decreases in pressure with the use of SNP did not affect Sc(O2). Sv(O2) was significantly lower (P<0.001) and OER was significantly higher (P<0.001) in the low flow arms. CONCLUSIONS: In the present elective cardiac surgery population, Sc(O2) and Sv(O2) were significantly lower with lower flow, regardless of systemic arterial pressure. Moreover, phenylephrine administration was associated with a reduced cerebral and systemic oxygen saturation. PMID- 23740046 TI - Leonardo da Vinci's Mona Lisa. PMID- 23740044 TI - Implications of aberrant temperature-sensitive glucose transport via the glucose transporter deficiency mutant (GLUT1DS) T295M for the alternate-access and fixed site transport models. AB - In silico glucose docking to the transporter GLUT1 templated to the crystal structure of Escherichia coli XylE, a bacterial homolog of GLUT1-4 (4GBZ.pdb), reveals multiple docking sites. One site in the external vestibule in the exofacial linker between TM7 and -8 is adjacent to a missense T295M and a 4-mer insertion mutation. Glucose docking to the adjacent site is occluded in these mutants. These mutants cause an atypical form of glucose transport deficiency syndrome (GLUT1DS), where transport into the brain is deficient, although unusually transport into erythrocytes at 4 degrees C appears normal. A model in which glucose traverses the transporter via a network of saturable fixed sites simulates the temperature sensitivity of normal and mutant glucose influx and the mutation-dependent alterations of influx and efflux asymmetry when expressed in Xenopus oocytes at 37 degrees C. The explanation for the temperature sensitivity is that at 4 degrees C glucose influx between the external and internal vestibules is slow and causes glucose to accumulate in the external vestibule. This retards net glucose uptake from the external solution via two parallel sites into the external vestibule, consequently masking any transport defect at either one of these sites. At 37 degrees C glucose transit between the external and internal vestibules is rapid, with no significant glucose buildup in the external vestibule, and thereby unmasks any transport defect at one of the parallel input sites. Monitoring glucose transport in patients' erythrocytes at higher temperatures may improve the diagnostic accuracy of the functional test of GLUT1DS. PMID- 23740048 TI - Evidence for multiple genetic factors underlying DSM-IV criteria for major depression. AB - IMPORTANCE: We do not know whether the clinical criteria for major depression (MD) reflect a single or multiple dimensions of genetic risk. OBJECTIVE: To determine the structure of genetic and environmental risk factors for the 9 DSM IV symptomatic MD criteria. DESIGN: Population-based twin registry. SETTING: Virginia. PARTICIPANTS: Seven thousand five hundred members of adult twin pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. MAIN OUTCOME MEASURE: Symptoms of lifetime MD as assessed at personal interview. RESULTS: The best-fit twin model was multidimensional, requiring 3 genetic, 1 common environmental and 3 unique environmental common factors, and criterion specific unique environmental factors. The first genetic factor was characterized by high loadings on cognitive and psychomotor depressive symptoms. The second and third genetic factors had strong loadings for mood and neurovegetative depressive symptoms, respectively. Genetic factor scores derived from these 3 factors differentially predicted patterns of comorbidity, other historical/clinical features of MD, and demographic variables. These results suggested that the first genetic factor reflected a general liability to internalizing disorders, while the third genetic factor was more specific for melancholic MD. The 3 unique environmental common factors reflected, respectively, global depressive, core mood, and cognitive depressive symptoms. CONCLUSIONS AND RELEVANCE: The DSM-IV syndrome of MD does not reflect a single dimension of genetic liability. Rather, these criteria reflect 3 underlying dimensions that index genetic risk for cognitive/psychomotor, mood, and neurovegetative symptoms. While in need of replication, these results, validated by predictions using estimated genetic factor scores, have implications for gene-finding efforts for MD. PMID- 23740049 TI - Deficits in conditioned fear extinction in obsessive-compulsive disorder and neurobiological changes in the fear circuit. AB - IMPORTANCE: Obsessive-compulsive disorder (OCD) may be characterized by impaired self-regulation and behavioral inhibition. Elevated fear and anxiety are common characteristics of this disorder. The neurobiology of fear regulation and consolidation of safety memories have not been examined in this patient population. OBJECTIVE: To examine the psychophysiological and neurobiological correlates of conditioned fear extinction in patients with OCD. DESIGN: Cross sectional, case-control, functional magnetic resonance imaging study. SETTING: Academic medical center. PARTICIPANTS: Twenty-one patients with OCD and 21 healthy participants. MAIN OUTCOMES AND MEASURES: Skin conductance responses and blood oxygenation level-dependent responses. RESULTS: The between-group difference noted in our psychophysiological measure (skin conductance responses) was during extinction recall: patients with OCD showed impaired extinction recall relative to control subjects. Regarding the functional magnetic resonance imaging data, patients with OCD showed significantly reduced activation in the ventromedial prefrontal cortex across training phases. Moreover, reduced activation in the patients with OCD was noted in the caudate and hippocampus during fear conditioning, as well as in the cerebellum, posterior cingulate cortex, and putamen during extinction recall. Contrary to our prediction, OCD symptom severity was positively correlated with the magnitude of extinction memory recall. Also contrary to our prediction, functional responses of the ventromedial prefrontal cortex were positively correlated with symptom severity, and functional responses of the dorsal anterior cingulate cortex were inversely correlated with symptom severity. CONCLUSIONS AND RELEVANCE: As expected, our study showed that fear extinction and its neural substrates are impaired in patients with OCD. However, this study also yielded some surprising and unexpected results regarding the correlates between extinction capacity and its neural substrates and the severity of symptoms expressed in this disorder. Thus, our data report neural correlates of deficient fear extinction in patients with OCD. The negative correlations between fear extinction deficits and Yale-Brown Obsessive-Compulsive Scale symptoms in OCD suggest that there may be other factors, in addition to fear extinction deficiency, that contribute to the psychopathology of OCD. PMID- 23740050 TI - Abnormally high degree connectivity of the orbitofrontal cortex in obsessive compulsive disorder. AB - IMPORTANCE: Neurobiological models of obsessive-compulsive disorder (OCD) predict hyperactivity in brain circuits involving the orbitofrontal cortex and the basal ganglia, but it is unclear whether these areas are also characterized by altered brain network properties. OBJECTIVES: To determine regions of abnormal degree connectivity in patients with OCD and to investigate whether connectivity measures are affected by antidepressant medication in OCD. DESIGN: Case-control cross-sectional study using resting-state functional magnetic resonance imaging and a data-driven, model-free method to test for alterations in the degree of whole-brain, distant, and local connectivity in unmedicated patients with OCD compared with healthy controls. SETTING: Outpatient clinic for OCD. PARTICIPANTS: Twenty-three patients with OCD (12 women, 11 men) receiving no medication, 23 patients with OCD (14 women, 9 men) treated with antidepressant medication, and 2 equally sized control samples matched for age, sex, handedness, educational level, and IQ. MAIN OUTCOME MEASURES: Statistical parametric maps testing the degree of distant and local functional connectivity of each voxel (hub analysis at voxel level) and OCD symptom severity. RESULTS: Unmedicated patients with OCD showed greater distant connectivity in the orbitofrontal cortex and subthalamic nucleus and greater local connectivity in the orbitofrontal cortex and the putamen. Furthermore, distant connectivity of the orbitofrontal cortex and the putamen positively correlated with global OCD symptom severity. Medicated patients with OCD showed reduced local connectivity of the ventral striatum compared with the unmedicated patients. CONCLUSIONS AND RELEVANCE: Consistent with neurobiological models of OCD, the orbitofrontal cortex and the basal ganglia are hyperconnected in unmedicated patients. The finding of distant connectivity alterations of the orbitofrontal cortex and the basal ganglia represents initial evidence of greater connections with distant cortical areas outside of corticostriatal circuitry. Furthermore, these data suggest that antidepressant medication may reduce connectivity within corticobasal ganglia thalamo-cortical circuits in OCD. PMID- 23740051 TI - APOE epsilon 4, aging, and effects on white matter across the adult life span. PMID- 23740052 TI - Pandemic influenza A (H1N1) 2009: epidemiological analysis of cases in a tropical/semi-arid region of Brazil. AB - INTRODUCTION: The year 2009 marked the beginning of a pandemic caused by a new variant of influenza A (H1N1). After spreading through North America, the pandemic influenza virus (H1N1) 2009 spread rapidly throughout the world. The aim of this study was to describe the clinical and epidemiological characteristics of cases of pandemic influenza in a tropical/semi-arid region of Brazil. METHODS: A retrospective study analyzed all suspected cases of pandemic influenza (H1N1) 2009 reported in the Ceara State through the National Information System for Notifiable Diseases during the pandemic period between 28 April, 2009 and November 25, 2010. RESULTS: A total of 616 suspected cases were notified, 58 (9.4%) in the containment phase and 558 (90.6%) in the mitigation phase. Most cases were of affected young people resident in the City of Fortaleza, the largest urban center in the State of Ceara. The most frequent symptoms presented by the cases with confirmed infection were fever, cough, myalgia, arthralgia, and nasal congestion. Mortality rate was 0.0009/1,000 inhabitants and lethality was 5.6%. Deaths were observed only in the mitigation phase. Mortality rates were similar for both sexes but were higher in the age group under 5 years. CONCLUSIONS: The study suggests that the influenza A (H1N1) pandemic in this tropical/semi-arid region had a lower magnitude when compared to states in the Southern and Southeastern regions of Brazil. PMID- 23740053 TI - Occurrence of strongyloidiasis among patients with HTLV-1/2 seen at the outpatient clinic of the Nucleo de Medicina Tropical, Belem, State of Para, Brazil. AB - INTRODUCTION: This study investigated the occurrence of Strongyloides stercoralis infestation and coinfection with HTLV-1/2 in Belem, Brazil. METHODS: S. stercoralis was investigated in stool samples obtained from individuals infected with HTLV-1/2 and their uninfected relatives. RESULTS: The frequency of S. stercoralis was 9% (9/100), including six patients infected with HTLV-1 (14.3%), two patients infected with HTLV-2 (11.1%), and one uninfected relative. Two cases of hyperinfestation by S. stercoralis were characterized as HTLV-1. CONCLUSIONS: These results support the need for the routine investigation of S. stercoralis in patients with HTLV-1, in an attempt to prevent the development of severe forms of strongyloidiasis. PMID- 23740054 TI - Survey of sandfly vectors of leishmaniasis in Marambaia Island, municipality of Mangaratiba, State of Rio de Janeiro, Brazil. AB - INTRODUCTION: The influx and efflux of military personnel in the possible endemic areas of leishmaniasis provided the impetus for research on the sandflies on Marambaia Island. METHODS: Sandflies were collected with light traps installed in the 3 ecotypes of 3 areas chosen for their particular landscape aspects. RESULTS: In 2009, were collected 32,006 specimens of sandflies belonging to 13 species. The species that showed highest density were Nyssomyia intermedia and Migoneimyia migonei. CONCLUSIONS: N. intermedia and M. migonei are the principal vectors of American tegumentary leishmaniasis (ATL) in Brazil; thus, extension studies related to the eco-epidemiology of these species of Marambaia Island are essential. PMID- 23740056 TI - Atrial flutter complicating severe leptospirosis: a case report. AB - Cardiac disturbances are relatively common and electrocardiographic abnormalities may be found in more than 70% of patients with leptospirosis. We report the case of a 68 year-old male with severe leptospirosis who developed atrial flutter. Effective treatment was done with amiodarone. The patient became clinical stable, with complete recovery. Rigorous clinical observation and continuous electrocardiogram (ECG) monitoring may facilitate the identification of rhythm disorders, and thus prevent a probable fatal outcome, in severe cases of leptospirosis. PMID- 23740057 TI - Survey of Bancroftian filariasis infection in humans and Culex mosquitoes in the western Brazilian Amazon region: implications for transmission and control. AB - INTRODUCTION: The aim of this work was to identify possible lymphatic filariasis foci in the western Brazilian Amazonian that could be established from the reports of Rachou in the 1950s. The study was conducted in three cities of the western Brazilian Amazon region - Porto Velho and Guajara-Mirim (State of Rondonia) and Humaita (State of Amazonas). METHODS: For human infection evaluation thick blood smear stained with Giemsa was used to analyze samples collected from 10pm to 1am. Polymerase chain reaction (PCR) was used to examine mosquito vectors for the presence of Wuchereria bancrofti DNA. Humans were randomly sampled from night schools students and from inhabitants in neighborhoods lacking sanitation. Mosquitoes were collected from residences only. RESULTS: A total 2,709 night students enrolled in the Program for Education of Young Adults (EJA), and 935 people registered in the residences near the schools were examined, being 641 from Porto Velho, 214 from Guajara-Mirim and 80 from Humaita. No individual examined was positive for the presence of microfilariae in the blood stream. A total of 7,860 female Culex quinquefasciatus specimens examined were negative by PCR. CONCLUSIONS: This survey including human and mosquito examinations indicates that the western Amazon region of Brazil is not a focus of Bancroftian filariasis infection or transmission. Therefore, there is no need to be included in the Brazilian lymphatic filariasis control program. PMID- 23740058 TI - Rotavirus G2P[4] and G2P[4]+[6] infections during norovirus gastroenteritis outbreak: summer season 2010, Brazil. AB - INTRODUCTION: This study aimed to monitor the seasonality of rotavirus infection, and gain insight into the variability of Brazilian strains. METHODS: A total of 28 stool samples were analyzed from 698 revised cases of gastroenteritis during a norovirus outbreak in the summer of 2010 in Guaruja, Brazil. Diagnosis was performed using enzyme-linked immunosorbent assay (ELISA), reverse transcription polymerase chain reaction (RT-PCR), and sequencing. RESULTS: Rotavirus infection was detected in 17.9% (5/28) of samples; 4 samples were G2P[4] genotype, and one G2P[4]+P[6] genotype. G2 and P[4] sequences showed a genetic relationship to strains from India and Russia, respectively. CONCLUSIONS: The seasonal pattern of rotavirus may be a consequence of human activity apart from climate factors. PMID- 23740059 TI - Bilateral posterior circulation stroke secondary to a crotalid envenomation: case report. AB - Snake bite envenoming is a disease with potential serious neurological complications. We report a case of an adolescent who was bitten by a rattlesnake and developed bilateral posterior circulation stroke. The rattlesnake was later identified as being Crotalus durissus terrificus. Stroke was probably due to toxic vasculitis or toxin-induced vascular spasm and endothelial damage. PMID- 23740060 TI - Epidemiological profile of Trypanosoma cruzi-infected mothers and live birth conditions in the state of Minas Gerais, Brazil. AB - INTRODUCTION: The aim of this study was to assess the epidemiological characteristics of Trypanosoma cruzi-infected mothers and the live birth conditions of neonates. METHODS: A serological survey with IgG-specific tests was conducted using dried blood samples from newborn infants in the State of Minas Gerais. T. cruzi infection was confirmed in mothers through positive serology in two different tests, and infected mothers were required to have their infants serologically tested after the age of 6 months. The birth conditions of the neonates were obtained from the System of Information on Live Births database. RESULTS: The study included 407 children born to T. cruzi-infected mothers and 407 children born to uninfected mothers. The average age of seropositive mothers was 32 years (CI95% 31.3-32.6), which was greater than the average age of seronegative mothers - 25 years (CI95% 24.8-25.2). The mothers' level of education was higher among uninfected mothers (41% had 8 or more years of education, versus 22% between the infected mothers). Vaginal delivery was more frequent among infected mothers. There was no evidence of inter-group differences with respect to the child's sex, gestational age, birth weight or Appearance, pulse, grimace, activity and respiration (APGAR) scores at 1 and 5 minutes. CONCLUSIONS: The level of education and the greater number of previous pregnancies and cases of vaginal delivery reflect the lower socioeconomical conditions of the infected mothers. In the absence of vertical transmission, neonates had similar health status irrespective of the infection status of their mothers. PMID- 23740061 TI - Author recognition, impact factor, relevance, and the meaning of publishing. PMID- 23740062 TI - Susceptibility to amphotericin B of Candida spp. strains isolated in Ceara, Northeastern Brazil. AB - INTRODUCTION: Amphotericin B (AMB) is an antifungal agent used extensively in clinical medicine, yet resistance remains low. This study aims to evaluate the susceptibility of Candida spp. against AMB. METHODS: For broth microdilution susceptibility testing, 77 strains of Candida spp. were selected (32 C. albicans, 33 C. tropicalis, and 12 C. parapsilosis). The strains were considered susceptible when they exhibited MIC<=1.0ug/ml. RESULTS: None of the strains showed an MIC greater than 0.25ug/ml. CONCLUSIONS: Further works are necessary, with a higher number of strains, to assess the validity of the results used in this study. PMID- 23740063 TI - Autoantibody profile in individuals with chronic hepatitis C. AB - INTRODUCTION: Autoantibodies are often produced during infection with chronic hepatitis C virus (HCV), but it remains controversial whether they influence the biochemical profile and histological features of this disease. Therefore, this current study sought to describe these autoantibodies and evaluate their impact on the clinical and histological presentation of hepatitis C. METHODS: This cross sectional analytical study assessed patients with HCV (RNA+) from October 2011 to July 2012. RESULTS: This study included 66 patients, with a mean age of 53.2+/ 10.5 years. Of these patients, 60.6% were male, and 54.3% presented with genotype 1. Non-organ-specific autoantibodies (NOSA) were detected in 24% of the patients; of these, 7.6% were anti-mitochondrial antibodies (AMA+), 26.7% were anti-smooth muscle antibodies (SMA+) and 6.8% were liver kidney microsomal type 1 antibodies (LKM1+). With respect to the thyroid autoantibodies, 7.4% were anti-peroxidase (ATPO+) antibodies, and none were anti-thyroglobulin (ATG+) antibodies. Regarding celiac disease autoantibodies, 5.8% were endomysial antibodies (EMA+), and no transglutaminase (TTG+) antibodies were detected. Cryoglobulins were found in 2.1% of patients. When NOSA+ individuals were compared to patients without the presence of NOSAs, they exhibited higher median alkaline phosphatase (0.7 vs. 0.6 xULN; p=0.041), lower median platelet counts (141,500.0 vs. 180,500.0/mm 3 ; p=0.036), lower mean prothrombin activity (72.6+/-11.5% vs. 82.2+/-16.0%; p=0.012) and an increased prevalence of significant fibrosis (E>=2) (45.5% vs. 18.2%; p=0.012). There was also a tendency for a greater proportion of NOSA+ cases to have marked periportal activity (APP>=3) (44.5% vs. 15.6%; p=0.087). CONCLUSIONS: In addition to the high prevalence of autoantibodies associated with HCV infection, it was observed that NOSA positivity was associated with a more severe histological and biochemical profile of hepatitis C infection. PMID- 23740064 TI - Identification of dengue viruses in naturally infected Aedes aegypti females captured with BioGents (BG)-Sentinel traps in Manaus, Amazonas, Brazil. AB - INTRODUCTION: In Manaus, the first autochthonous cases of dengue fever were registered in 1998. Since then, dengue cases were diagnosed by the isolation of viruses 1, 2, 3, and 4. METHODS: One hundred eighty-seven mosquitoes were collected with BioGents (BG)-Sentinel traps in 15 urban residential areas in the Northern Zone of Manaus and processed by molecular tests. RESULTS: Infections with dengue viruses 1, 2, 3, and 4 and a case of co-infection with dengue viruses 2 and 3 were identified. CONCLUSIONS: These findings corroborate the detection of dengue in clinical samples and reinforce the need for epidemiological surveillance by the Health authorities. PMID- 23740065 TI - Historical analysis of the records of sylvan yellow fever in the State of Amazonas, Brazil, from 1996 to 2009. AB - INTRODUCTION: Yellow fever is a non-contagious infectious disease, highly lethal, transmitted by the Aedes, Haemagogus and Sabethes. METHODS: Descriptive retrospective study of the yellow fever cases in Amazonas, between 1996 and 2009. RESULTS: Forty two cases of yellow fever were confirmed, with 30 deaths, 10% of which were foreigners. CONCLUSIONS: The presence of Aedes aegypti and Aedes albopictus in both rural Amazonas and its capital demonstrates the dispersion of these vectors and underscores the need for better and continuous epidemiological and entomological control. PMID- 23740066 TI - Serologic assessment of yellow fever immunity in the rural population of a yellow fever-endemic area in Central Brazil. AB - INTRODUCTION: The yellow fever epidemic that occurred in 1972/73 in Central Brazil surprised the majority of the population unprotected. A clinical epidemiological survey conducted at that time in the rural area of 19 municipalities found that the highest (13.8%) number of disease cases were present in the municipality of Luziania, State of Goias. METHODS: Thirty-eight years later, a new seroepidemiological survey was conducted with the aim of assessing the degree of immune protection of the rural population of Luziania, following the continuous attempts of public health services to obtain vaccination coverage in the region. A total of 383 volunteers, aged between 5 and 89 years and with predominant rural labor activities (75.5%), were interviewed. The presence of antibodies against the yellow fever was also investigated in these individuals, by using plaque reduction neutralization test, and correlated to information regarding residency, occupation, epidemiological data and immunity against the yellow fever virus. RESULTS: We found a high (97.6%) frequency of protective titers (>1:10) of neutralizing antibodies against the yellow fever virus; the frequency of titers of 1:640 or higher was 23.2%, indicating wide immune protection against the disease in the study population. The presence of protective immunity was correlated to increasing age. CONCLUSIONS: This study reinforces the importance of surveys to address the immune state of a population at risk for yellow fever infection and to the surveillance of actions to control the disease in endemic areas. PMID- 23740067 TI - Haemoglobin and red cell counts in leptospirosis patients infected with different serovars. AB - INTRODUCTION: The aim of the study was to compare haemoglobin and red cell counts between patients known to be infected with a range of leptospiral serovars. METHODS: The study retrospectively compared the haemoglobin and red cell count results from the first blood samples taken from 207 patients at presentation to a Queensland Health hospital. RESULTS: Significant differences were observed in haemoglobin and red cell counts in those infected with Leptospira interrogans serovars Szwajizak and Canicola when compared with most of the other serovars. CONCLUSIONS: These findings suggest that haemoglobin and red cell counts may be useful in differentiating leptospiral serovars in leptospirosis patients. PMID- 23740068 TI - cagE as a biomarker of the pathogenicity of Helicobacter pylori. AB - INTRODUCTION: Helicobacter pylori infection is associated with gastro-duodenal diseases. Genes related to pathogenicity have been described for H. pylori and some of them appear to be associated with more severe clinical outcomes of the infection. The present study investigates the role of cagE as a pathogenicity biomarker of H. pylori compare it to cagA, vacA, iceA and babA2 genes and correlate with endoscopic diagnoses. METHODS: Were collected biopsy samples of 144 dyspeptic patients at the Hospital of the Federal University of Rio Grande, Rio Grande do Sul, Brazil. After collection, the samples were sent for histological examination, DNA extraction and detection of all putative pathogenicity genes by PCR. RESULTS: Of the 144 patients undergoing endoscopy, 57 (39.6%) presented H. pylori by histological examination and PCR by detection of the ureA gene. Based on the endoscopic diagnoses, 45.6% (26/57) of the patients had erosive gastritis, while 54.4% (31/57) had enanthematous gastritis. The genes cagA, cagE, vacAs1/m1, vacAs1/m2 and iceA1 were related to erosive gastritis, while the genes vacAs2/m2, iceA2 and babA2 were associated to enanthematous gastritis. We found a statistically significant association between the presence of cagE and the endoscopic diagnosis. However, we detect no statistically significant association between the endoscopic diagnosis and the presence of cagA, vacA, iceA and babA2, although a biological association has been suggested. Conclusions Thus, cagE could be a risk biomarker for gastric lesions and may contribute to a better evaluation of the H. pylori pathogenic potential and to the prognosis of infection evolution in the gastric mucosa. PMID- 23740069 TI - The characteristics, clinical manifestations and outcomes of pandemic influenza A (H1N1) 2009 in the elderly. AB - INTRODUCTION: The objective of this study was to evaluate the 2009 Pandemic Influenza A (H1N1) in the elderly and identify the clinical characteristics, mortality and prognostic factors of the infection in these patients. METHODS: This was an observational, retrospective study. Data were collected from the National Notifiable Diseases (SINAN), from the Brazilian Ministry of Health. Only patients 60 years old or more that had laboratory confirmed infections were included. The socio-demographic and clinical variables and outcomes were evaluated to compare mortality rates in the presence or absence of these factors. RESULTS: We included 93 patients in the study, 16.1% of whom died. The symptoms of cough and dyspnea, the use of the antiviral oseltamivir, influenza vaccine and comorbidities influenced the outcomes of cure or death. Chest radiography can aid in diagnosis. CONCLUSIONS: Although relatively few elderly people were infected, this population presented high lethality that can be justified by the sum of clinical, physical and immunological factors in this population. Treatment with oseltamivir and vaccination against seasonal influenza have significantly reduced rates of hospitalization and mortality. PMID- 23740070 TI - Bone tuberculosis: a case report on child. AB - The authors report a case of a 12-year-old child with a complaint of pain and deformity in the lower thoracic region that had lasted for two years. Clinical, epidemiological and laboratory characteristics associated with images of apparent damage in the T9-T10 and T11-T12 vertebrae taken by radiography of the thoracic spine and nuclear magnetic resonance in addition to the positivity of the molecular test based on the polymerase chain reaction, led to tuberculous spondylitis being diagnosed and specific therapy was started. Culture of vertebral biopsy was positive for Mycobacterium tuberculosis after thirty days. PMID- 23740071 TI - Anal polyp caused by Schistosoma mansoni. AB - We describe a schistosomal polyp in the anus of a 24-year-old patient, born in Vicosa, State of Minas Gerais, and living in Belo Horizonte, State of Minas Gerais. From 8 to 13 years of age, he swam in the rivers that bathe Vicosa. The histopathological examination has shown a lesion, lined by a keratinized squamous epithelium, ulcerated, with granulomas, centered or not by Schistosoma mansoni egg, laid, in loco, by the female present in the vascular lumen of a vein of the hemorrhoidal plexus. There was also a diffuse, nonspecific inflammation in the dermis. The patient was treated with praziquantel. Four months after the treatment, sigmoidoscopy showed a normal rectal mucosa, and negative oogram and stool tests. Ultrasound of abdomen was normal. PMID- 23740072 TI - Spatial distribution and esterase activity in populations of Aedes (Stegomyia) aegypti (Linnaeus) (Diptera: Culicidae) resistant to temephos. AB - INTRODUCTION: The need for studies that describe the resistance patterns in populations of Aedes aegypti (Linnaeus) in function of their region of origin justified this research, which aimed to characterize the resistance to temephos and to obtain information on esterase activity in populations of Aedes aegypti collected in municipalities of the State of Paraiba. METHODS: Resistance to temephos was evaluated and characterized from the diagnostic dose of 0.352mg i.a./L and multiple concentrations that caused mortalities between 5% and 99%. Electrophoresis of isoenzymes was used to verify the patterns of esterase activity among populations of the vector. RESULTS: All populations of Aedes aegypti were resistant to temephos, presenting a resistance rate (RR) greater than 20. The greatest lethal dose 50% of the sample (CL50) was found for the municipality of Lagoa Seca, approximately forty-one times the value of CL50 for the Rockefeller population. The populations characterized as resistant showed two to six regions of alpha and beta-esterase, called EST-1 to EST-6, while the susceptible population was only seen in one region of activity. CONCLUSIONS: Aedes aegypti is widely distributed and shows a high degree of resistance to temephos in all municipalities studied. In all cases, esterases are involved in the metabolism and, consequently, in the resistance to temephos. PMID- 23740073 TI - Pseudo-tumoral spinal cord schistosomiasis. PMID- 23740074 TI - Larval control of Anopheles (Nyssorhinchus) darlingi using granular formulation of Bacillus sphaericus in abandoned gold-miners excavation pools in the Brazilian Amazon rainforest. AB - INTRODUCTION: Use of a Bacillus sphaericus based mosquito larvicide was evaluated as an intervention for malaria vector control at a mining site in Amapa, Brazil. Impacts on larval and adult densities of the primary vector Anopheles darlingi were measured over the course of a 52 week study period. METHODS: In Calcoene, State of Amapa, gold mining activity occurs in 19 mining sites in gold-miners of Lourenco. Large pools are formed in mining sites and naturally colonized by Anopheles darlingi. During one year, the impact of applications of VectoLex(r) CG to these larval sources was evaluated. Applications of 20kg/ha were made as needed, based on 10 immature (3rd, 4th instars and pupae) surveillance of health and established thresholds. RESULTS: One hundred percent initial control was observed 48h after each treatment. The pools received from 2-10 (5.3+/-1.6) treatments during the year. The average re-treatment interval in productive pools was 9.4+/-4.3 weeks. During weeks 3-52 of the study, mean density of late stage larvae was 78% and pupae were 93% lower in the treated pools than in untreated pools (p< 0.0001, n=51) while reduction of adult mosquitoes was 53% in comparison to the untreated area during the last five months of the study, which were the rainy season (p<0.001). CONCLUSIONS: VectoLex(r) CG reduced immature Anopheles darlingi infestation levels during the entire study period, and reduced adult mosquito populations during the rainy season. PMID- 23740075 TI - Non-biting flying insects as carriers of pathogenic bacteria in a Brazilian hospital. AB - INTRODUCTION: Insects have been described as mechanical vectors of nosocomial infections. METHODS: Non-biting flying insects were collected inside a pediatric ward and neonatal-intensive care unit (ICU) of a Brazilian tertiary hospital. RESULTS: Most (86.4%) of them were found to carry one or more species of bacteria on their external surfaces. The bacteria isolated were Gram-positive bacilli (68.2%) or cocci (40.9%), and Gram-negative bacilli (18.2%). CONCLUSIONS: Insects collected inside a hospital were carrying pathogenic bacteria; therefore, one must consider the possibility they may act as mechanical vectors of infections, in especially for debilitated or immune-compromised patients in the hospital environments where the insects were collected. PMID- 23740076 TI - The potential role of vitamins in the management of Chagas disease. PMID- 23740077 TI - Acute schistosomiasis diagnosis: a new tool for the diagnosis of schistosomiasis in a group of travelers recently infected in a new focus of Schistosoma mansoni. AB - INTRODUCTION: The diagnosis of schistosomiasis mansoni on early stages of infection is important to prevent late morbidity. A simple, cheap, sensitive and specific assay for routine diagnosis of schistosome infection based on the detection of specific IgG for schistosomula tegument antigens (ELISA-SmTeg) was developed by our group. METHODS: We describe here an acute outbreak involving a travel group of 80 individuals from a non-endemic area of the State of Minas Gerais, Brazil. These individuals were in contact with a freshwater pool where Biomphalaria glabrata was found. Results obtained from our new methodology were compared to IgG antibody titers against soluble worm antigenic preparation (SWAP) by ELISA and, also to parasitological examination, nuclear magnetic resonance and clinical findings. RESULTS: ELISA-SmTeg was capable of detecting 64 positive cases among the 80 individuals participating at the survey with a positivity ratio of 80% and a higher sensitivity than ELISA-SWAP that was only sensitive for 56% of positive cases. Besides, a significant correlation was found for the severity of the infection and the specific IgG titers against SmTeg. CONCLUSIONS: Our data showed that ELISA-SmTeg might serve as the initial diagnostic tool for acute stages of the infection in community-based helminth control programs or for the surveillance of individuals from non-endemic areas. PMID- 23740078 TI - Paediatric ventricular assist devices: current achievements. AB - In chronic cardiomyopathy, mechanical circulatory support plays an increasingly important role for children as the shortage of suitable donor hearts increases times on the transplant waiting list. Ventricular assist devices (VADs) for adults have evolved dramatically over the last decade, both as a bridge to transplantation and for permanent support. In contrast, VADs designed for children, especially for all age groups, are still in their infancy. The Medos HIA and the Berlin Heart Excor are specially designed for children with a body surface area <1.2 m2. Increased experience with existing paediatric VADs and the introduction of third-generation VADs for the paediatric age group offer new possibilities for children suffering from end-stage heart failure. We review the literature on this topic, summarise the indications and contraindications for long-term support VADs and describe the decision-making algorithm used at our institution for use of long-term VADs in children. PMID- 23740079 TI - Aberrant methylation of multiple imprinted genes in embryos of tamoxifen-treated male rats. AB - Genomic imprinting is an epigenetic phenomenon known to regulate fetal growth and development. Studies from our laboratory have demonstrated that treatment of adult male rats with tamoxifen increased postimplantation loss around mid gestation. Further studies demonstrated the aberrant expression of transcripts of several imprinted genes in the resorbing embryos at days 11 and 13 of gestation including IGF2. In addition, decreased methylation at the Igf2-H19 imprint control region was observed in spermatozoa and in resorbing embryos sired by tamoxifen-treated males. In this study, methylation analysis of the imprinted genes, which were found to be differentially expressed, was done using EpiTYPER in the spermatozoa of tamoxifen-treated rats and in postimplantation embryos sired by tamoxifen-treated rats. Differentially methylated regions (DMRs) for most imprinted genes have not been identified in the rats. Hence, initial experiments were performed to identify the putative DMRs in the genes selected for the study. Increased methylation at CpG islands present in the putative DMRs of a number of imprinted genes was observed in the resorbing embryos sired by tamoxifen-treated male rats. This increase in methylation is associated with the downregulation of most of these genes at the transcript level in resorbing embryos. No change in the methylation status of these genes was observed in spermatozoa. These observations suggest that a deregulation of mechanisms protecting unmethylated alleles from a wave of de novo methylation occurs following implantation. PMID- 23740080 TI - Differential gene expression of granulosa cells after ovarian superstimulation in beef cattle. AB - Microarray analysis was used to compare the gene expression of granulosa cells from dominant follicles with that of those after superstimulatory treatment. Cows were allocated randomly to two groups (superstimulation and control, n=6/group). A new follicular wave was induced by ablation of follicles >=5 mm in diameter, and a progesterone-releasing device controlled internal drug release (CIDR) was placed in the vagina. The superstimulation group was given eight doses of 25 mg FSH at 12-h intervals starting from the day of wave emergence (day 0), whereas the control group was not given FSH treatment. Both groups were given prostaglandin F2alpha twice, 12 h apart, on day 3 and the CIDR was removed at the second injection; 25 mg porcine luteinizing hormone (pLH) was given 24 h after CIDR removal, and cows were ovariectomized 24 h later. Granulosa cells were collected for RNA extraction, amplification, and microarray hybridization. A total of 190 genes were downregulated and 280 genes were upregulated. To validate the microarray results, five genes were selected for real-time PCR (NTS, FOS, THBS1, FN1, and IGF2). Expression of four genes increased significantly in the three different animals tested (NTS, FOS, THBS1, and FN1). The upregulated genes are related to matrix remodeling (i.e. tissue proliferation), disturbance of angiogenesis, apoptosis, and oxidative stress response. We conclude that superstimulation treatment i) results in granulosa cells that lag behind in maturation and differentiation (most of the upregulated genes are markers of the follicular growth stage), ii) activates genes involved with the NFE2L2 oxidative stress response and endoplasmic reticulum stress response, and iii) disturbs angiogenesis. PMID- 23740081 TI - Cryopreservation increases coating of bull sperm by seminal plasma binder of sperm proteins BSP1, BSP3, and BSP5. AB - Artificial insemination with frozen semen allows affordable, worldwide dissemination of gametes with superior genetics. Nevertheless, sperm are damaged by the cryopreservation process. Elucidating the molecular effects of cryopreservation on sperm could suggest methods for improving fertility of frozen/thawed semen. This study was undertaken to examine the effect of cryopreservation on the coating of sperm by binder of sperm (BSP) proteins in seminal plasma. BSP proteins are secreted by the seminal vesicles and coat the surface of sperm by partially intercalating into the outer leaflet of the sperm plasma membrane. The BSP proteins are known to play roles in the formation of the oviductal sperm storage reservoir and in sperm capacitation. We investigated the effects of cryopreservation on the sperm BSP protein coat using Bovipure to separate live sperm from extended semen and then assaying the amounts of BSP proteins on sperm using quantitative western blotting with custom-made antibodies against unique sequences of each BSP protein. Greater amounts of all three BSP proteins (BSP1, BSP3, and BSP5) were detected on frozen/thawed sperm than on fresh sperm. Furthermore, the reduction of BSP3 from 15 to 13 kDa in mass, which occurs during incubation of sperm under mild capacitating conditions, was enhanced by cryopreservation. We concluded that freezing alters the BSP protein coating on sperm, which could account in part for reduced fertility of cryopreserved semen samples. PMID- 23740082 TI - The role of prion protein in stem cell regulation. AB - Cellular prion protein (PrP(C)) has been well described as an essential partner of prion diseases due to the existence of a pathological conformation (PrP(Sc)). Recently, it has also been demonstrated that PrP(C) is an important element of the pluripotency and self-renewal matrix, with an increasing amount of evidence pointing in this direction. Here, we review the data that demonstrate its role in the transcriptional regulation of pluripotency, in the differentiation of stem cells into different lineages (e.g. muscle and neurons), in embryonic development, and its involvement in reproductive cells. Also highlighted are recent results from our laboratory that describe an important regulation by PrP(C) of the major pluripotency gene Nanog. Together, these data support the appearance of new strategies to control stemness, which could represent an important advance in the field of regenerative medicine. PMID- 23740083 TI - Bactericidal/permeability-increasing protein in the reproductive system of male mice may be involved in the sperm-oocyte fusion. AB - Bactericidal/permeability-increasing protein (BPI) is a 455-residue (~55 kDa) protein found mainly in the primary (azurophilic) granules of human neutrophils. BPI is an endogenous antibiotic protein that belongs to the family of mammalian lipopolysaccharide (LPS)-binding and lipid transport proteins. Its major function is to kill Gram-negative bacteria, thereby protecting the host from infection. In addition, BPI can inhibit angiogenesis, suppress LPS-mediated platelet activation, increase DNA synthesis, and activate ERK/Akt signaling. In this study, we found that Bpi was expressed in the testis and epididymis but not in the seminal vesicles, prostate, and solidification glands. BPI expression in the epididymis increased upon upregulation of testosterone, caused by injection of GNRH. In orchidectomized mice, BPI expression was significantly reduced, but its expression was restored to 30% of control levels in orchidectomized mice that received supplementary testosterone. The number of sperm fused per egg significantly decreased after incubation with anti-BPI antiserum. These results suggest that BPI may take part in the process of sperm-oocyte fusion and play a unique and significant role in reproduction. PMID- 23740084 TI - Right ventricular longitudinal deformation parameters and exercise capacity : prognosis of patients with chronic thromboembolic pulmonary hypertension. AB - OBJECTIVE: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease characterized by increased pulmonary vascular resistance resulting in pulmonary hypertension and right heart failure. The six-minute walk test (6MWT) distance is associated with the prognosis of CTEPH patients. Speckle tracking echocardiography (STE) is a reliable method for determining ventricular function. The aim of this study was to assess and compare the right ventricular (RV) function of CTEPH patients according to their 6MWT distances. METHODS: Forty-nine consecutive CTEPH patients (mean age, 50 +/- 16 years; 22 male) who were referred to our center for pulmonary thromboendarterectomy (PTE) were included in the study. All patients underwent the 6MWT and right heart catheterization (RHC). Standard echocardiography and STE were performed on all patients before PTE. Patients were divided into two groups based on their 6MWT distance being less or more than 300 m. RESULTS: Patients with a shorter 6MWT distance had a significantly larger RV, while they had a significantly lower RV fractional area change and higher myocardial performance index suggesting impaired RV function. Both RV basal-lateral strain and strain rate measures were significantly lower in patients with shorter 6MWT distances than those with longer 6MWT distances. Similarly, they had lower RV basal-septal, mid-lateral, and global strain measures. 6MWT distances were correlated with RV basal-lateral and mid-lateral strain measures (r = 0.349, p = 0.025 and r = 0.415, p = 0.008, respectively). CONCLUSION: Our data suggest that RV myocardial deformation parameters are associated with 6MWT distances. Determination of RV dysfunction by STE may be helpful in identifying patients with a poor prognosis. PMID- 23740085 TI - [Cardiorenal syndrome: limits of heart failure therapy]. AB - The cardiorenal syndrome is an interdisciplinary challenge with increasing health economic relevance. Renal failure is a strong predictor for mortality in patients with severe congestive heart failure (CHF) and CHF is one of the fastest increasing morbidities in western countries. For successful therapy a close cooperation between cardiology und nephrology is required. Moreover, a good compliance of the patient is needed to improve symptoms and to reduce the frequency of cardiac decompensation. A broad cardiological and nephrological evaluation and consideration of optimal conservative options according to national and international guidelines are essential. However, a renal replacement therapy might be helpful in patients with refractory heart failure even if they are not dialysis-dependent. In cases of acute heart and renal failure an intensive care management might be necessary to reduce volume overload with the help of extracorporeal ultrafiltration or a dialysis modality. Nevertheless, in cases of chronic refractory CHF peritoneal dialysis should be preferred. The first analysis of the registry of the German Society of Nephrology (http://www.herz-niere.de) confirmed that there is a benefit for health-related quality of life in chronic CHF patients treated with peritoneal dialysis. PMID- 23740086 TI - Use of administrative data for national surveillance of osteoporosis and related fractures in Canada: results from a feasibility study. AB - Using administrative data healthcare databases from five Canadian provinces, we compared prevalence estimates of diagnosed osteoporosis and incidence rates for related fractures in Canada. The algorithms adopted showed consistent age and sex patterns across all provinces and will be suitable for national surveillance and monitoring. PURPOSE: This study aims to evaluate the feasibility of using provincial population-based administrative data to develop a national surveillance system of diagnosed osteoporosis and related fractures (forearm, humerus, vertebra, pelvis, and hip) in Canada. METHODS: Linked healthcare databases from five provinces representing approximately 85 % of the Canadian population were used. Multiple algorithms combining hospitalizations, physician visits, and osteoporosis prescription drug dispensations were evaluated in each province. The adopted algorithms for diagnosed osteoporosis and incident fractures combined hospitalizations and physician visits based on 3 years and 1 year of data, respectively. Sex-specific age-standardized osteoporosis prevalence and fracture incidence rates were estimated for each province from 1995/1996 to 2007/2008. RESULTS: Age-standardized prevalence of diagnosed osteoporosis in those >=50 years increased over the study period but stabilized in the most recent years. Using the adopted algorithm produced provincial estimates ranging from 5.6 to 10.5 % for 2007/2008, with consistent age and sex patterns across provinces. The use of osteoporosis drug data resulted in higher osteoporosis estimates compared with estimates without drug data. Age-standardized incidence of fractures in those >=40 years showed similar age and sex patterns across all provinces. The highest level of agreement among provinces was for hip and humerus fracture rates, with wider provincial variation for forearm, vertebra, and pelvis fractures. CONCLUSIONS: Our results are consistent with previous validation works and confirm that the algorithms adopted will be suitable for the national monitoring of diagnosed osteoporosis and related fractures. A similar approach may be applicable to other countries with high-quality administrative data. PMID- 23740089 TI - Priming effects of tumor necrosis factor-alpha on production of reactive oxygen species during Toxoplasma gondii stimulation and receptor gene expression in differentiated HL-60 cells. AB - Neutrophils are among the principal effector cells that protect against infectious agents, in part by producing reactive oxygen species (ROS) via the actions of tumor necrosis factor-alpha (TNF-alpha). In this study, we investigated whether HL-60 cells that had been differentiated into neutrophil like cells by all-trans retinoic acid could be primed with TNF-alpha similar to human neutrophils. Our results showed that when differentiated HL-60 (dHL-60) cells were primed with TNF-alpha for 10 min, ROS production induced by zymosan A or phorbol myristate acetate (PMA) was enhanced in a TNF-alpha-dose-dependent manner. In addition, when dHL-60 cells were stimulated with live tachyzoites of Toxoplasma gondii after TNF-alpha priming, ROS production was also enhanced. Thus, dHL-60, similar to neutrophils, produced ROS after PMA, zymosan A, or T. gondii stimulation. Furthermore, we examined gene expression in dHL-60 cells after TNF-alpha treatment. The pro-inflammatory cytokine IL-6 was up-regulated more than 1.6-fold by 0.1 ng/mL TNF-alpha. Endogenous TNF-alpha was down regulated by priming. IL-8 receptors genes were not affected by priming with 0.1 ng/mL or 1 ng/mL TNF-alpha. Complement receptor (CR) 1 and CR3 gene expression was not affected by TNF-alpha priming for 10 min. However, when the priming period was extended to 1 h, CR1 and CR3 genes were up-regulated 1.3 and 1.4-fold, respectively. Expression of the cell-surface CR3 (CD11b) was not significantly affected by TNF-alpha for 15 min but was slightly enhanced after priming for 2 h. These results suggest that dHL-60 cells may be used as a substitute for neutrophils when evaluating the effects of cytokines or immunomodulator agents. PMID- 23740088 TI - Cysteine-rich protein 61 (CCN1) and connective tissue growth factor (CCN2) at the crosshairs of ocular neovascular and fibrovascular disease therapy. AB - The vasculature forms a highly branched network investing every organ of vertebrate organisms. The retinal circulation, in particular, is supported by a central retinal artery branching into superficial arteries, which dive into the retina to form a dense network of capillaries in the deeper retinal layers. The function of the retina is highly dependent on the integrity and proper functioning of its vascular network and numerous ocular diseases including diabetic retinopathy, age-related macular degeneration and retinopathy of prematurity are caused by vascular abnormalities culminating in total and sometimes irreversible loss of vision. CCN1 and CCN2 are inducible extracellular matrix (ECM) proteins which play a major role in normal and aberrant formation of blood vessels as their expression is associated with developmental and pathological angiogenesis. Both CCN1 and CCN2 achieve disparate cell-type and context-dependent activities through modulation of the angiogenic and synthetic phenotype of vascular and mesenchymal cells respectively. At the molecular level, CCN1 and CCN2 may control capillary growth and vascular cell differentiation by altering the composition or function of the constitutive ECM proteins, potentiating or interfering with the activity of various ligands and/or their receptors, physically interfering with the ECM-cell surface interconnections, and/or reprogramming gene expression driving cells toward new phenotypes. As such, these proteins emerged as important prognostic markers and potential therapeutic targets in neovascular and fibrovascular diseases of the eye. The purpose of this review is to highlight our current knowledge and understanding of the most recent data linking CCN1 and CCN2 signaling to ocular neovascularization bolstering the potential value of targeting these proteins in a therapeutic context. PMID- 23740090 TI - A case of sepsis caused by Streptococcus canis in a dog owner: a first case report of sepsis without dog bite in Japan. AB - A 91-year-old dog-owning woman with a history of hypertension and femoral neck fracture consulted our hospital with fever and femur pain with redness. Laboratory test results showed leukocytosis with 85% neutrophils and high values of C-reactive protein and procalcitonin. In addition, growth of Gram-positive streptococcus was observed in two independent blood culture sets. The isolated bacterium was identified as Streptococcus canis on the basis of biochemical properties and sequencing analyses of the 16S rRNA gene. The patient recovered completely without critical illness following prompt antimicrobial treatment with ceftriaxone. S. canis, a beta-hemolytic Lancefield group G streptococcus, is in general isolated from various animal sources, but its isolation from a human clinical sample is extremely rare. Since beta-hemolytic streptococci can cause severe infectious diseases such as necrotizing fasciitis, it is absolutely necessary to start antimicrobial treatment immediately. It is necessary to identify pathogenic bacteria carefully and to obtain information on a patient's background, including history of contact with an animal, when S. canis is isolated. PMID- 23740091 TI - Promoter hypermethylation contributes to the frequent suppression of the CDK10 gene in human nasopharyngeal carcinomas. AB - BACKGROUND: Previous studies have shown a down-regulation of the gene encoding cyclin-dependent kinase 10 (CDK10) in hepatocellular carcinomas. Here we provide evidence that down-regulation of the CDK10 gene is mediated by promoter hypermethylation in primary human nasopharyngeal carcinomas (NPC) and NPC-derived cell lines. METHODS: RT-PCR, Western blotting, methylation-specific PCR and bisulfite sequencing were performed to assess the expression and methylation status of the CDK10 gene in primary NPC samples, NPC-derived cell lines and patient-derived peripheral blood samples. The NPC-derived cell line CNE-2 was selected for treatment with a methylation inhibitor to restore CDK10 expression. In addition, cell proliferation, invasion and colony formation assays were performed to assess the inhibitory effects of ectopic CDK10 expression in CNE-2 cells. RESULTS: Down-regulation of CDK10 expression in primary NPC samples (23/40, 57.5%) was found to be significantly correlated with the methylation status of its promoter CpG island (21/40, 52.5%). Demethylation by 5-aza-dC treatment led to reactivation of the CDK10 gene in the CNE-2 cell line. Additionally, exogenous expression of CDK10 in CNE-2 cells strongly suppressed its growth, invasion and colony formation capacities. The high sensitivity (15/40, 37.5%) and specificity (0% false positives) of detecting CDK10 promoter hypermethylation in NPC patient-derived peripheral blood samples suggest that it could be employed as an epigenetic marker for noninvasive cancer diagnosis and recurrence screening. CONCLUSION: Our findings implicate that aberrant methylation of the CDK10 gene promoter occurs frequently in NPC, and that reactivation of CDK10 might be utilized as a novel epigenetic strategy for the treatment of NPC patients. PMID- 23740092 TI - Head-to-head comparison of fee-for-service and diagnosis related groups in two tertiary referral hospitals in Switzerland: an observational study. AB - BACKGROUND: Reimbursement for inpatients in Switzerland differed among states until 2012. Some hospitals used diagnosis related groups (DRG) and others used fee-for-service (FFS). We compared length of hospital stay (LOS), patient satisfaction and quality of life between the two systems before a nation-wide implementation of DRG. METHODS: In a prospective, two-centre observational cohort study, we identified all patients with a main diagnosis of either community acquired pneumonia, exacerbation of chronic pulmonary obstructive disease, acute heart failure or hip fracture from January to June 2011 and performed a systematic questionnaire survey 2-4 months after hospital discharge. RESULTS: Of 1,093 inpatients, 450 were included. Mean age was 71.1 (+/-SD 19.5) years (48% male). Patients in the FFS hospital were older (mean age 74.8 vs. 65.2 years; p <0.001) and suffered from more co-morbidities. Mean LOS was 9 days and shorter in the all-patient DRG (AP-DRG) hospital (unadjusted mean 8.2 vs. 9.5 days, p = 0.04). After multivariate adjustment, no significant difference in LOS was found (p = 0.24). More patients from the FFS hospital were re-hospitalised for any reason (35% vs. 17.5%; p = 0.01), re-admitted to acute-care institutions (11.7% vs. 5.2%; p = 0.014), not satisfied with the discharge process (15.3% vs. 9.7%; p = 0.02), showed problems with self-care (93.8% vs. 88%; p = 0.03) and usual activities (79.3% vs. 76%; p = 0.02). DISCUSSION: This study suggested that the AP-DRG hospital showed higher patient satisfaction regarding discharge, lower re hospitalisation rates and shorter LOS partly explained by a lower burden of co morbidities and disease severity. This study needs validation in a larger cohort of patients and at multiple time points. PMID- 23740093 TI - The prediction of subjective wellness among the old-old: implications for the "fourth-age" conception. AB - OBJECTIVES: As the "fourth-age" conception suggests that the adaptability of psychosocial capabilities is disrupted at old-old age due to failures in maintaining balanced functions, this study examines the predictability of subjective wellness outcomes by factual dysfunction markers of health among old old people across 12 years. METHOD: Participants were self-respondents in a 3 wave survey that sampled the older (age 75-94) Jewish population in Israel. Wave 1 (N = 1,369, mean age = 83.5) preceded Wave 2 (N = 687, mean age = 85.4) by 4 years and Wave 3 (N = 164, mean age = 91.6) by 12 years. RESULTS: The dysfunction markers (comorbidity, medication consumption, doctor's visits, and difficulties in activities of daily living [ADL]) predicted subjective wellness by relating to an increase in depressive symptoms, as well as to a decrease in life evaluation and self-rated health, beyond adjustment for sociodemographics. However, in most cases, an interaction finding indicated that dysfunction markers were weaker predictors of age-related change in subjective wellness among older participants. DISCUSSION: At old-old age, the results point to reduced predictability of subjective wellness by factual dysfunction. This finding supports the fourth-age model. Still, researchers should consider an alternative interpretation, by which increasing independence between factual and subjective indicators is protective, rather than debilitating, among old-old people. PMID- 23740094 TI - The unique impact of late-life bereavement and prolonged grief on diurnal cortisol. AB - OBJECTIVES: This study expands on previous research by examining the effects of prolonged grief disorder (PGD) symptoms and bereavement on diurnal cortisol patterns above and beyond depressive symptomatology. METHODS: Drawing on information from 56 depressed older adults, 3 groups were compared: (1) a depressed nonbereaved group, (2) a depressed bereaved without elevated PGD symptoms group, and (3) a depressed bereaved with elevated PGD symptoms group. Multilevel modeling was used to examine differences in diurnal cortisol profiles between these 3 groups, controlling for demographic factors and depressive symptoms. RESULTS: Results revealed that those who were bereaved had more dysregulated cortisol patterns, but PGD symptomatology seemed to have little effect. Subsidiary analysis with just the bereaved participants suggests that those who were recently widowed may have had greater cortisol dysregulation compared with other bereaved individuals in the sample. DISCUSSION: These findings suggest that the circumstance of being bereaved may be associated with more dysregulated cortisol, regardless of PGD symptomatology. This pattern of results might reflect greater disturbance in daily routines among bereaved individuals and acute stress in the case of those experiencing the recent loss of a spouse, which leads to disruption in circadian rhythms and the diurnal cycle of cortisol. PMID- 23740095 TI - A novel fibrinogen B beta chain frameshift mutation causes congenital afibrinogenaemia. AB - Congenital afibrinogenaemia is a rare autosomal recessive disorder caused by various mutations within the fibrinogen genes FGA, FGB and FGG. Ins/del mutations in FGB are extremely rare. We report a patient with afibrinogenaemia who suffered from umbilical cord bleeding and repeated bleeding episodes. His plasma fibrinogen levels could not be detected using the Clauss method and immunological methods. Molecular analyses revealed homozygosity in a novel four bases insertion in codon 40 of FGB exon 2 (g. 2833_2834 ins GTTT), which resulted in a truncated 50-residue polypeptide that contained 11 exceptional abnormal residues. In the transient expression experiments, mutant fibrinogen could be detected at higher level than wild-type fibrinogen in COS-7 cell lysates but not in culture media. These results suggest that the homozygous mutation in FGB could be responsible for congenital afibrinogenaemia in this patient. This frameshift mutation could impair fibrinogen assembly and secretion without influencing the protein synthesis. PMID- 23740096 TI - SorLA is a molecular link for retromer-dependent sorting of the Amyloid precursor protein. AB - Deficiency in the retromer sorting pathway is known to be associated with the onset of Alzheimer disease (AD), and has been suggested to involve regulation of Amyloid precursor protein (APP) trafficking. Absence of the APP sorting receptor sorLA is also associated to AD, as amyloidogenic processing of APP is increased due to missorting. Reduced activity of either retromer or sorLA thus both lead to enhanced amyloidogenic APP processing, and these pathways are therefore important factors for understanding the development of AD. It is therefore key to outline the neuronal APP trafficking in order to determine the mechanisms that influence AD onset. PMID- 23740098 TI - Thermal and photic stimuli-responsive polydiacetylene liposomes with reversible fluorescence. AB - A novel reversible fluorescent switch of a polydiacetylene liposome (PDA liposome) was realized by alternating heating and UV irradiation processes. The reversible fluorescence switching of the PDA liposome was mainly caused by the microstructural changes of the PDA backbone in the PDA liposomes under the alternating conditions of heating and UV irradiation. PMID- 23740097 TI - Extension MRI is clinically useful in cervical myelopathy. AB - INTRODUCTION: Cervical spine MRI with the neck in extension has been well described over the last 10 years, but its clinical value remains unknown. METHODS: We performed extension imaging in 60 patients in whom the initial neutral study showed borderline cord compression. Images were assessed using a previously validated grading system for cord compression. Multiple linear and area measurements were also obtained. Images were scored blindly and randomly. Inter- and intra-rater variability were determined in a subset of 20 cases. Independent clinical assessment utilised the Ranwat criteria. RESULTS: For most parameters inter/intra-observer variance of kappa/ICC > 0.6 was highly satisfactory. Standard MR was poor at discriminating between patients with and without myelopathy (ROC analysis, area under the curve (AUC), 0.52). This was considerably improved with extension imaging (AUC, 0.60), or by using the change in compression score between neutral and extension studies. Most measurements were not helpful; however, the ratio of cord area/CSF area at the level of maximum compression on extended images was the best discriminator (AUC, 0.71), as well as the presence of T2 change in cord substance (AUC, 0.68). CONCLUSION: This is the first study to demonstrate added clinical value utilising extension MRI. In this cohort of difficult patients, when there was no T2 signal change in the cord, the presence of clinical myelopathy could only be predicted by utilising the data from extension imaging. PMID- 23740100 TI - Domain composition of rhamnose-binding lectin from shishamo smelt eggs and its carbohydrate-binding profiles. AB - Osmerus (Spirinchus) lanceolatus egg lectin (OLL) is a member of the rhamnose binding lectin (RBL) family which is mainly found in aqueous beings. cDNA of OLL was cloned, and its genomic architecture was revealed. The deduced amino acid (aa) sequence indicated that OLL was composed of 213 aa including 95 aa of domain N and 97 aa of domain C. N and C showed 73 % sequence identity and contained both -ANYGR- and -DPC-KYL-peptide motifs which are conserved in most of the RBL carbohydrate recognition domains. The calculated molecular mass of mature OLL was 20,852, consistent with the result, and 20,677.716, from mass spectrometry. OLL was encoded by eight exons: exons 1 and 2 for a signal peptide; exons 3-5 and 6-8 for N- and C-domains, respectively. Surface plasmon resonance spectrometric analyses revealed that OLL showed comparable affinity for Galalpha- and beta linkages, whereas Silurus asotus lectin (SAL), a catfish RBL, bound preferentially to alpha-linkages of neoglycoproteins. The Kd values of OLL and SAL against globotriaosylceramide (Gb3) were 1.69 * 10-5 M for and 2.81 * 10-6 M, respectively. Thus, the carbohydrate recognition property of OLL is slightly different from that of SAL. On the other hand, frontal affinity chromatography revealed that both OLL and SAL interacted with only glycolipid-type oligosaccharides such as Gb3 trisaccharides, not with N-linked oligosaccharides. The domain composition of these RBLs and an analytical environment such as the "cluster effect" of a ligand might influence the binding between RBL and sugar chains. PMID- 23740101 TI - Assessment of pharmacist's recommendation of non-prescription medicines in Brazil: a simulated patient study. AB - BACKGROUND: The number of medicines available without a prescription has increased in Brazil as elsewhere. The Brazilian National Health Surveillance Agency recently passed a resolution emphasizing the role of Brazilian pharmacists in promoting rational use of medicines. However, evidence that Brazilian pharmacists monitor the use of non-prescription medicines in the community promoting rational use of medicines is lacking. OBJECTIVE: To assess practice behavior of pharmacists in Brazil when providing nonprescription medicines in the community pharmacy setting. SETTING: The study was conducted in 25 community pharmacies from a city of Aracaju in Brazil. METHODS: Simulated patients visited a convenience sample of 25 pharmacies twice from March to July 2010. During the visits, simulated patients enacted two standardized scenarios: treatment for a persistent headache and childhood diarrhea accompanied by fever. The interactions with the pharmacists were audiovisually recorded using a hidden micro camera. Recordings were later used to fill out a questionnaire designed to evaluate practice behavior of community pharmacists. MAIN OUTCOME MEASURE: The communication and counseling skills of pharmacists in the recommendation of non prescription medicines, aiming at the rational use of medicines. RESULTS: Pharmacists in the study spent on average 1.5 min counseling the simulated patient. At least one question was asked to assess signs and symptoms in 50.0 % of the simulated patient visits in the headache scenario and in 56.0 % of visits in the childhood diarrhea scenario. Non-pharmacological treatment was suggested in 25 % of visits in the childhood diarrhea scenario. During the counseling process, no pharmacist advised the simulated patient about possible drug interactions, adverse reactions and what to do if the patient forgot to take the medicine. The pharmacists had low scores in measures of non-verbal communication. The sample of this study presented poor communication skills, compromising the treatment of the patients. CONCLUSION: This study showed that the pharmacists' counseling in the simulated patient assessment was insufficient, indicating a need for substantial improvement in practice behavior. PMID- 23740102 TI - Profiles of drug users in Switzerland and effects of early-onset intensive use of alcohol, tobacco and cannabis on other illicit drug use. AB - QUESTIONS UNDER STUDY / PRINCIPLES: The main aim of this study was to investigate profiles of drug users, with a particular focus on illicit drugs other than cannabis, and to explore the effect of early-onset intensive use (drunkenness, daily smoking, high on cannabis) on profiles of illicit drug use. METHODS: Baseline data from a representative sample of 5,831 young Swiss men in the ongoing Cohort Study on Substance Use Risk Factors were used. Substance use (alcohol, tobacco, cannabis and 15 types of other illicit drug) and age of onset of intensive use were assessed. The Item Response Theory (IRT) and prevalence rates at different ages of onset were used to reveal different profiles of illicit drug use. RESULTS: In addition to cannabis, there were two profiles of other illicit drug use: (a) "softer" drug users (uppers, hallucinogens and inhaled drugs), among which ecstasy had the highest discriminatory potential (IRT slope = 4.68, standard error (SE) = 0.48; p <0.001); and (b) "harder" drug users (heroin, ketamine, gamma-hydroxybutyrate/gamma-hydroxylactone, research chemicals, crystal meth and spice), among which ketamine had the highest discriminatory potential (slope = 4.05; SE = 0.63; p <0.001). Onset of intensive use at the age of 12 years or younger also discriminated between these two profiles. CONCLUSION: Both the IRT model and the effect of onset of intensive use enabled two groups of illicit drugs to be identified. In particular, very early onset (at 12 years or younger) intensive use of any substance was a marker for later use of the second group of drugs. PMID- 23740103 TI - In vivo kinetic and steady-state quantification of 18F-CPFPX binding to rat cerebral A1 adenosine receptors: validation by displacement and autoradiographic experiments. AB - In vivo imaging of the A1 adenosine receptor (A1AR) using (18)F-8-cyclopentyl-3 (3-fluoropropyl)-1-propylxanthine ((18)F-CPFPX) and PET has become an important tool for studying physiologic and pathologic states of the human brain. However, dedicated experimental settings for small-animal studies are still lacking. The aim of the present study was therefore to develop and evaluate suitable pharmacokinetic models for the quantification of the cerebral A1AR in high resolution PET. METHODS: On a dedicated animal PET scanner, 15 rats underwent (18)F-CPFPX PET scans of 120-min duration. In all animals, arterial blood samples were drawn and corrected for metabolites. The radioligand was injected either as a bolus or as a bolus plus constant infusion. For the definition of unspecific binding, the A1AR selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) was applied. After PET, the brains of 9 animals were dissected and in vitro saturation binding was performed using high-resolution (3)H-DPCPX autoradiography. RESULTS: The kinetics of (18)F-CPFPX were well described by either compartmental or noncompartmental models based on arterial input function. The resulting distribution volume ratio correlated with a low bias toward identity with the binding potential derived from a reference region (olfactory bulb) approach. Furthermore, PET quantification correlated significantly with autoradiographic in vitro data. Blockade of the A1AR with DPCPX identified specific binding of about 45% in the reference region olfactory bulb. CONCLUSION: The present study provides evidence that (18)F-CPFPX PET based on a reference tissue approach can be performed quantitatively in rodents in selected applications. Specific binding in the reference region needs careful consideration for quantitative investigations. PMID- 23740104 TI - Implementation and validation of an adaptive template registration method for 18F flutemetamol imaging data. AB - The spatial normalization of PET amyloid imaging data is challenging because different white and gray matter patterns of negative (Abeta-) and positive (Abeta+) uptake could lead to systematic bias if a standard method is used. In this study, we propose the use of an adaptive template registration method to overcome this problem. METHODS: Data from a phase II study (n = 72) were used to model amyloid deposition with the investigational PET imaging agent (18)F flutemetamol. Linear regression of voxel intensities on the standardized uptake value ratio (SUVR) in a neocortical composite region for all scans gave an intercept image and a slope image. We devised a method where an adaptive template image spanning the uptake range (the most Abeta- to the most Abeta+ image) can be generated through a linear combination of these 2 images and where the optimal template is selected as part of the registration process. We applied the method to the (18)F-flutemetamol phase II data using a fixed volume of interest atlas to compute SUVRs. Validation was performed in several steps. The PET-only adaptive template registration method and the MR imaging-based method used in statistical parametric mapping were applied to spatially normalize PET and MR scans, respectively. Resulting transformations were applied to coregistered gray matter probability maps, and the quality of the registrations was assessed visually and quantitatively. For comparison of quantification results with an independent patient-space method, FreeSurfer was used to segment each subject's MR scan and the parcellations were applied to the coregistered PET scans. We then correlated SUVRs for a composite neocortical region obtained with both methods. Furthermore, to investigate whether the (18)F-flutemetamol model could be generalized to (11)C Pittsburgh compound B ((11)C-PIB), we applied the method to Australian Imaging, Biomarkers and Lifestyle (AIBL) (11)C-PIB scans (n = 285) and compared the PET only neocortical composite score with the corresponding score obtained with a semimanual method that made use of the subject's MR images for the positioning of regions. RESULTS: Spatial normalization was successful on all scans. Visual and quantitative comparison of the new PET-only method with the MR imaging-based method of statistical parametric mapping indicated that performance was similar in the cortical regions although the new PET-only method showed better registration in the cerebellum and pons reference region area. For the (18)F flutemetamol quantification, there was a strong correlation between the PET-only and FreeSurfer SUVRs (Pearson r = 0.96). We obtained a similar correlation for the AIBL (11)C-PIB data (Pearson r = 0.94). CONCLUSION: The derived adaptive template registration method allows for robust, accurate, and fully automated quantification of uptake for (18)F-flutemetamol and (11)C-PIB scans without the use of MR imaging data. PMID- 23740105 TI - 18F-EF5 PET imaging as an early response biomarker for the hypoxia-activated prodrug SN30000 combined with radiation treatment in a non-small cell lung cancer xenograft model. AB - Hypoxia is a significant therapeutic problem for solid tumors because hypoxic cells are treatment-resistant and more aggressive. Hypoxia-activated prodrugs such as SN30000 use a mechanism of activation in hypoxic cells similar to that of 2-nitroimidazole hypoxia PET tracers. Therefore, we have evaluated the usefulness of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-(18)F-pentafluoropropyl)-acetamide ((18)F-EF5) PET to monitor and predict tumor response to SN30000 plus radiation treatment (RT). METHODS: Human non-small cell lung cancer xenografts (H460) in athymic rats were imaged with (18)F-EF5 PET before and after treatment with SN30000 (90 mg/kg), with or without 15-Gy RT. The feasibility of imaging early changes in hypoxia in response to SN30000 was examined 24 h after treatment, followed by ex vivo gamma-counting and immunohistochemical examination to study drug-induced apoptosis. Subsequently, the therapeutic effects of SN30000 with or without RT were evaluated in tumor growth delay studies and compared with early treatment-induced changes observed by (18)F-EF5 PET. Changes in tumor hemoglobin oxygen saturation as a function of time after treatment measured by optical spectroscopy were compared with PET data. RESULTS: The uptake of (18)F-EF5 was significantly lower in SN30000-treated tumors than in saline controls 24 h after treatment (mean standardized uptake value, 0.44 +/- 0.08 vs. 0.56 +/- 0.08 for control group; P < 0.05). Apoptosis was significantly higher in SN30000-treated tumors than in controls. Early treatment-induced changes in (18)F-EF5 uptake were indicative of tumor response in growth delay studies at the group level. SN30000 plus RT significantly decreased (18)F-EF5 uptake relative to baseline and resulted in complete tumor remission in 5 of 7 animals. SN30000 alone decreased (18)F-EF5 uptake, generally in tumors with high initial standardized uptake values, and showed a minor tumor growth delay effect. The changes induced by SN30000 with or without RT in (18)F-EF5 uptake correlated with baseline hypoxia levels. RT caused significant increases in tumor oxygen concentration and hemoglobin oxygen saturation. CONCLUSION: A hypoxia PET imaging agent can measure changes in tumor hypoxic fraction in response to SN30000. These results suggest the utility of (18)F-EF5 PET for monitoring early response to tumor treatment with SN30000 plus RT in the clinical development of this novel hypoxia-activated prodrug. PMID- 23740106 TI - [Nutrition and gastrointestinal intolerance]. AB - The functional integrity of the gastrointestinal tract is an essential prerequisite in intensive care patients for the sufficient administration of enteral nutrition. Up to 65% of patients in intensive care units develop symptoms of gastrointestinal dysfunction with high residual gastric volume, vomiting and abdominal distension. The pathophysiological alterations of gastrointestinal intolerance and the subsequent effect on the tolerance of enteral nutrition can affect the whole gastrointestinal tract. Gastroduodenal motility disorders in particular, with increased gastroesophageal reflux lead to intolerance. In more than 90% of intensive care patients with gastrointestinal motility disorders an adequate postpyloric enteral nutrition can be carried out using a jejunal tube. In addition to improved tolerance of enteral nutrition this leads to a reduction of gastroesophageal reflux and the incidence of ventilation-associated pneumonia. Apart from the possibility of endoscopic application of the jejunal tube, alternative techniques were developed which allow a faster positioning of the jejunal tube with less complications. Furthermore, there are therapeutic options for improvement of gastrointestinal motility disorders and apart from general measures, also medicinal options for treatment of gastrointestinal intolerance which allow a sufficient enteral nutrition for intensive care patients. PMID- 23740107 TI - [Taking over a patient with preclinical laryngeal tube]. AB - Endotracheal intubation (ETI) is the most effective method for securing the airway. However, the practice and theory of ETI differ considerably. There is a wide gap between reality and the optimum of quality and quantity required by many specialist organizations, e.g., the European Resuscitation Council. Alternative airway devices, such as a laryngeal tube, can be useful provided the hospital staff know how the device functions and how to avoid or control complications. PMID- 23740108 TI - [Coronary computed tomography angiography for acute thoracic pain]. PMID- 23740110 TI - Nanoscale biosensor for detection of reactive oxygen species. AB - Noninvasive detection of biological responses to reactive oxygen species (ROS) in vivo could shed light on mechanisms at work in diverse areas like developmental dynamics, therapeutic effectiveness, drug discovery, pathogenic processes, and disease prevention. Research on ROS is usually dependent on in vitro models without translational relevance. Nanoscale (<100 nm) particulates are attractive carriers and platforms for biosensor technology due to their small size, flexible assembly, and favorable toxicity profiles. Intracellular signalling pathways activated in response to ROS have been well documented and mechanisms elaborated. Likewise, there is a wealth of genetic reporter systems that utilize fluorescent proteins capable of being monitored noninvasively. We combined these elements into a platform technology that utilizes nanoparticle-tethered synthetic genetic elements that respond to cellular response elements to report endogenous responses to oxidative insult through fluorescent gene expression. We envision the future of this technology to play a research role quantifying oxidative stress in vivo and a future clinical role as an automated theragnostic for ROS related diseases. The production of this nanobiosensor technology utilizes off the-shelf components and can be carried out in a molecular biology laboratory. Assessment of fluorescent protein expression can be done with noninvasive imaging and quantitative protein expression analysis. This is a flexible nanoparticle based reporter system for monitoring in vivo responses to ROS. PMID- 23740109 TI - A modified chronic ocular hypertension rat model for retinal ganglion cell neuroprotection. AB - This study aimed to modify a chronic ocular hypertension (OHT) rat model to screen for potential compounds to protect retinal ganglion cells (RGCs) from responding to increased intraocular pressure (IOP). A total of 266 rats were prepared and randomly grouped according to different time-points, namely, weeks 3, 8, 16, and 24. Rats were sedated and eye examination was performed to score as the corneal damage on a scale of 1 to 4. The OHT rat model was created via the injection of a hypertonic saline solution into the episcleral veins once weekly for two weeks. OHT was identified when the IOP at week 0 was [Symbol: see text] 6 mmHg than that at week -2 for the same eye. Viable RGCs were labeled by injecting 4% FluoroGold. Rats were sacrificed, and the eyes were enucleated and fixed. The fixed retinas were dissected to prepare flat whole-mounts. The viable RGCs were visualized and imaged. The IOP (mean +/- SD) was calculated, and data were analyzed by the paired t-test and one-way ANOVA. The OHT model was created in 234 of 266 rats (87.97%), whereas 32 rats (12.03%) were removed from the study because of the absence of IOP elevation (11.28%) and/or corneal damage scores over 4 (0.75%). IOP was elevated by as much as 81.35% for 24 weeks. The average IOP was (16.68 +/- 0.98) mmHg in non-OHT eyes (n = 234), but was (27.95 +/- 0.97) mmHg in OHTeyes (n = 234). Viable RGCs in the OHT eyes were significantly decreased in a time-dependent manner by 29.41%, 38.24%, 55.32%, and 59.30% at weeks 3, 8, 16, and 24, respectively, as compared to viable RGCs in the non-OHT eyes (P < 0.05). The OHT model was successfully created in 88% of the rats. The IOP in the OHT eyes was elevated by approximately 81% for 24 weeks. The number of viable RGCs was decreased by 59% of the rats in a time-dependent manner. The modified OHT model may provide an effective and reliable method for screening drugs to protect RGCs from glaucoma. PMID- 23740111 TI - Nanoparticles: toxicity, radicals, electron transfer, and antioxidants. AB - In recent years, nanoparticles have received increasing attention in research and technology, including a variety of practical applications. The bioactivity appears to be related to the small particle size, in addition to inherent chemical activity as electron transfer (ET) agents, generators of reactive oxygen species (ROS) with subsequent oxidative stress (OS), and as antioxidants (AOs). The mechanism of toxicity, therapeutic action, and AO property is addressed based on the ET-ROS-OS approach. There are several main classes of ET functionalities, namely, quinones (or phenolic precursors), metal compounds, aromatic nitro compounds (or reduction products), and imine or iminium species. Most of the nanospecies fall within the metal category. Cell signaling is also discussed. This review discusses recent developments based on ET-ROS-OS-AO framework. PMID- 23740112 TI - Encapsulation of antioxidants in gastrointestinal-resistant nanoparticulate carriers. AB - Reactive oxygen species (ROS) are known to cause several human pathologies. For this reason, antioxidants have gained utmost importance because of their potential as prophylactic and therapeutic agents in many diseases. Examples of their application include their use in diabetic patients, as aging drugs, in cancer diseases, Parkinson's, Alzheimer's, autoimmune disorders, and also in inflammation. Antioxidants have limited absorption profiles, therefore low bioavailability and low concentrations at the target site. Efforts have been done towards loading antioxidant molecules in advanced nanoparticulate carriers, e.g., liposomes, polymeric nanoparticles, solid lipid nanoparticles, self-emulsifying drug delivery system. Examples of -successful achievements include the encapsulation of drugs and other active ingredients, e.g., coenzyme Q10, vitamin E and vitamin A, resveratrol and polyphenols, curcumin, lycopene, silymarin, and superoxide dismutase. This review focuses on the comprehensive analysis of using nanoparticulate carriers for loading these molecules for oral administration. PMID- 23740113 TI - Toxicity of novel nanosized formulations used in medicine. AB - Nanotechnology involves the creation and manipulation of materials at nanoscale levels (1-100 nm) to create products that exhibit novel properties. While this motivation has driven nanoscience and technology in physics and engineering, it is not the main reason that nanoparticles are useful for systemic applications in the human body. The application of nanotechnology to medicine, known as nanomedicine, concerns the use of precisely engineered materials at this length scale to develop novel therapeutic and diagnostic modalities. A number of nanotherapeutic formulations are already approved for medical use and more are in the approval pipeline currently. This chapter is intended to provide an overview of the toxicity of these therapeutic nanoparticles and to summarize the current state of the field. We begin with background on the sources of exposure to nanoparticles, followed by reviewing different forms of nanosized therapeutic tools as quantum dots, nanoshells, nanocapsules, echogenic bubble, and "nanoshuttles." Moreover, cytotoxic effects of nanoparticles on cell membrane, mitochondrial function, prooxidant/antioxidant status, enzyme leakage, DNA, and other biochemical endpoints were elucidated. We highlight the need for caution during the use and disposal of such manufactured nanomaterials to prevent unintended environmental impacts. Moreover, different strategies which could be used to minimize or eliminate nanotoxicity were also discussed in detail. Understanding of how to tune size and surface properties to provide safety will permit the creation of new, more effective nanomedicines for systemic use. PMID- 23740114 TI - Fullerenol nanoparticles: toxicity and antioxidant activity. AB - Fullerenes are a relatively new group of compounds and represent a class of sphere-shaped molecules made exclusively of carbon atoms. Since their discovery in 1985, many aspects of both fullerene and its analogues have been intensively studied to reveal their physical and chemical reactivity, as well as potential use in biological systems. Both in vitro and in vivo studies have shown that polyhydroxylated fullerene derivatives, fullerenol nanoform (C60(OH) n , n = 2 72), can be potential antioxidative agents in biological systems. This chapter represents a review of published studies of fullerenes' biological activities with special accent on the most tested fullerenol nanoform C60(OH)24. PMID- 23740115 TI - Hydrogen peroxide (H2O2) detection with nanoprobes for biological applications: a mini-review. AB - Hydrogen peroxide (H2O2) is an important member of the reactive oxygen species, playing various roles in biology and medicine. The conventional detection methods for H2O2 are often restricted by their limited sensitivity, poor selectivity towards H2O2, inappropriate physicochemical properties for detection in biological environments, long response time, etc. We briefly review here some recent nanotechnology--based approaches for H2O2 detection, which present an effective improvement, overcoming some of the limitations of the conventional H2O2 sensing techniques. PMID- 23740116 TI - Studying the oxidative stress paradigm in vitro: a theoretical and practical perspective. AB - Since the early 1990s, interest into the biological interaction of nanosized particles of various compositions has increased. Following the initial findings that nanoscaled particles can elicit an adverse biological response when compared to their larger (micron-scale) material counterparts, interest into how nanosized materials may elicit potentially adverse effects upon any biological system has been intensively investigated. Over the past 20 years, hundreds to thousands of research studies have been published highlighting the biological effects and interaction of the plethora of nanoparticles (NPs) that are being either accidentally or intentionally (engineered) produced. While a definitive knowledge of many aspects is required prior to investigating the biological interaction of NPs, such as the relevant exposure route to the biological system, the specific characteristics of the NPs being studied, and the realistic dose (concentration) that would interact with the biological system, understanding how the NPs affect the biological system is not based upon any defined theory. In fact, there is no specific understanding as to why particles show different effects when occurring within a certain nanosize range compared to their larger counterpart (micron size range). Despite this, certain paradigms and theories have been proposed and are studied, such as the fiber paradigm and theory of genotoxicity, in order to try and understand such nanoscale effects. The most studied and widely accepted paradigm, however, is the oxidative stress paradigm. This chapter will provide an insight into this paradigm, how it is perceived, how it is studied, why investigating this paradigm in vitro is advantageous, and how the findings associated with this paradigm can provide an insight into the (potentially adverse) biological interaction of nanoscale objects. PMID- 23740117 TI - Evaluation of the effect of acute and subacute exposure to TiO2 nanoparticles on oxidative stress. AB - The nanosized titanium dioxide (nano-TiO2) is produced abundantly and used widely in the chemical, electrical/electronic, and energy industries because of its special photovoltaic and photocatalytic activities. Past reports have shown that the nano-TiO2 can enter into the human body through different routes such as inhalation, ingestion, dermal penetration, and injection. The effects of nano TiO2 on different organs are currently being investigated. Oxidative stress is considered to play an important role in the oxidative potential of nanoparticles. Here we discuss the association between oxidative stress and the toxicity caused by exposure to nano-TiO2 in different organs. PMID- 23740118 TI - Biomedical applications of nano-antioxidant. AB - For centuries now, antioxidants have been known to provide better health by neutralizing the free radicals which are continuously produced in the human body. In normal circumstances, self-antioxidant defense system of the human body is capable of quantitatively managing the free radicals. However, in certain cases, which are at the threshold of developing diseases like diabetes and Alzheimer's, the human body calls for an external source of antioxidants. Since orally delivered antioxidants are easily destroyed by acids and enzymes present in the human system, only a small portion of what is consumed actually gets absorbed. Hence, there is a recognized and urgent need to develop effective methods for efficiently delivering antioxidants to the required sites. This chapter provides an in-depth overview and analysis of two such methods and processes-nano encapsulation and nano-dendrimers. Among the various nanoscale delivery mechanisms, nano-encapsulation has emerged as a key and efficient delivery process. Designed as a spongelike polymer, nano-encapsulated antioxidants provide a protective vehicle which keeps antioxidants from being destroyed in the human gut and ensures their better absorption in the digestive tract. In fact, the nano capsules bind themselves to the intestinal walls and pour antioxidants directly into the intestinal cells, which allow them to be absorbed directly into the blood stream. Another distinguished and popular mode for delivering antioxidants is that of nano-polymers known as dendrimers. Dendrimers involve multiple branches and sub-branches of atoms radiating out from a central core. Dendrimers afford a high level of control over their architectural design, including their size, shape, branching length or density, and surface functionality. Such flexibility makes these nanostructures ideal carriers in biomedical applications such as drug delivery, gene transfection, and imaging. Antioxidant dendrimers, made out of numerous units of antioxidants connected with each other in a branched fashion, provide numerous possible sites to couple with an active species and have enhanced free radicals scavenging potency. These dendrimer chains are biocompatible, biodegradable with nontoxic degradation products, and well suited for targeted drug delivery and other biomedical applications. Recent successes in simplifying and optimizing the synthesis of dendrimers, such as the "lego" and "click" approaches, provide a large variety of structures while at the same time reducing the cost of their production. The use of these highly branched, nanometer-sized, polymeric materials as nano-antioxidants for prevention and treatment of human diseases, associated with oxidative stress, is of immense public health relevance globally. PMID- 23740119 TI - Lipid peroxidation due to in vitro and in vivo exposure of biological samples to nanoparticles. AB - The increasing use of nanomaterials in biological applications raises numerous concerns about the dangers they might pose to living organisms. The rise in oxidative stress is usually the most readily observed effect induced by nanoparticles, with the measurement of lipid peroxidation levels being one of the most frequently used biological markers for its evaluation. Here, we describe the spectrophotometric and fluorimetric methods for determining the modifications of the malondialdehyde (MDA) level induced by many types of nanoparticles in in vitro and in vivo biological systems. PMID- 23740120 TI - Testing nanomaterial toxicity in unicellular eukaryotic algae and fish cell lines. AB - Nanoecotoxicology as a sub-discipline of ecotoxicology aims to identify and predict effects elicited on ecosystems by nano-sized materials (NM). Two key groups of model organisms in this context are algae and fish. In this chapter, we present considerations for testing NM with respect to their impact on unicellular algae and cell lines derived from various organs of fish.Based on currently available literature on NM effects in unicellular algae and fish cell lines, and our own experience, we provide guidance on test design, including principle test considerations, materials, NM presentation to cells, exposure, bioavailability, and effect assessment. Assessment needs to be based on a meaningful choice of exposure scenario(s) related to the research question. As a first step, one needs to address whether effects of NMs are to be investigated under environmentally relevant or probable conditions, which may include processes such as agglomeration, or whether NM effects from mono-dispersed particles are of interest, which may require special steps to ensure stable NM suspension. Moreover, whether effects on cells are to be studied in the short- or long-term is important with regard to experimental design. Preparation of NM suspensions, which can be done in aqueous media different from the exposure medium, is addressed with regard to energy input, sterility (as required for algae and fish cell exposure) and particle purity.Specified for the two model systems, algae and fish cell lines, availability and choice of culture media are presented and discussed with regard to impact on NM behavior. Light, temperature, and agitation, which are variables during exposure, are discussed. We further provide guidance on the characterization of the NM in the chosen aqueous exposure media regarding size, zeta potential and electrophoretic mobility. The state of NM in exposure media is decisive for their bioavailability and therefore for potential particle effects. Therefore, we present ways of deriving a mass balance and quantitative/qualitative information on the uptake and distribution of NM in cells.As NM have a high surface-to-volume ratio and possess specific physical chemical properties, which make them prone to interfere with various compounds and certain types of toxicity tests, potential interferences and appropriate controls are introduced. Furthermore, different types of dose metrics, which is still a strongly debated issue in nanotoxicology, are highlighted. We also consider laboratory safety regarding NM handling and disposal. PMID- 23740121 TI - Gold nanoparticles and oxidative stress in the blue mussel, Mytilus edulis. AB - Relatively little is known about how gold nanoparticles (GNP) might interact in vivo with aquatic organisms. Gold nanoparticles (GNP) of defined average diameter may be synthesized and used to challenge test organisms held in aquaria. The blue mussel, Mytilus edulis, is a popular sentinel species in environmental toxicology. This chapter describes how mussels exposed to GNP (average diameter ~5 nm) may be dissected and extracts of digestive gland can be analyzed for oxidative stress. Protein thiols are labeled with 5'-iodoacetamide-fluorescein (IAF), and proteins are separated in one-dimensional electrophoresis. After scanning for IAF-associated fluorescence, gels are stained with colloidal coomassie. A ratio of fluorescence to protein stain is calculated revealing that thiol oxidation increases with GNP treatment. PMID- 23740122 TI - Oxidative biomarkers to assess the nanoparticle-induced oxidative stress. AB - Nanotechnology involves the creation and manipulation of materials at nanoscale levels to create products that exhibit novel properties. Engineered nanomaterials either metals (like carbon and silver) or metal oxides (like zinc oxide, magnesium oxide, and titanium oxide) induce toxicity and oxidative stress by generating free radicals. Various in vitro and in vivo models are available to estimate the oxidative stress induced by the nanoparticles. In this chapter, we describe the methods for the estimation of oxidative stress markers like reactive oxygen species (ROS), DNA damage estimation, and lipid peroxidation products; total antioxidant capacity (TAC) was mentioned. PMID- 23740123 TI - Vesicular antioxidants: role in age-related cerebral oxidative injury. AB - Oxidative stress, due to the generation of reactive oxygen species, is a major factor in cerebral ischemic damage and changes the activities of antioxidant enzymes and substantially influences the aging process. Free chemical antioxidant is almost ineffective to treat brain ischemia as blood-brain barrier exists in between blood and brain interstitial fluid, limiting component to pass from the circulation into cerebral region. Different compounds have been tested in vivo in different vesiculated forms to prevent cerebral ischemia. Nanoparticle encapsulated drug treatment resulted in a significant protection of the antioxidant enzymes in both young and old rats. Nanocapsulated drug treatment causes a substantial protection against cerebral ischemia-reperfusion-induced oxidative damage to all parts of brain specifically hippocampal regions of all age groups of rat brain. PMID- 23740124 TI - Methods for detection of oxidative stress and genotoxicity of engineered nanoparticles. AB - The distinctive characteristics of engineered nanoparticles (ENPs) such as higher surface-to-volume ratio find immense applications in personal care products, food packaging, drug delivery systems, therapeutics & biosensors and others. The exponential increase in the ENP containing consumer products in the last 5 years has also increased their inadvertent release in the environment and a debate towards their adverse effects to the human and environment health. A variety of ENPs with different size, shape, and surface properties have been shown to induce genotoxicity, cytotoxicity, and oxidative stress in different cellular models. Here we describe the techniques and protocols used in the assessment of the genotoxicity (single-cell gel electrophoresis (comet) assay, cytokinesis block micronucleus assay) and oxidative stress parameters (reactive oxygen species, lipid peroxidation, and glutathione depletion) induced by the ENPs in the cells. PMID- 23740125 TI - Size-dependent study of pulmonary responses to nano-sized iron and copper oxide nanoparticles. AB - The application of nanotechnology in various fields has resulted in a tremendous increase in the synthesis of variety of engineered nanoparticles (NPs). These applications are possible only due to the small size and large surface area of the NPs which imparts them unique properties. Inorganic oxide NPs as iron and copper oxide NPs are widely used in several biomedical and synthetic applications. The beneficial aspects of these NPs are concurrently associated with several drastic and deleterious effects as well. Size of the NPs plays a critical role in systemic clearance from the body. Initial studies have confirmed inflammatory responses in mice associated with non-biodegradable oxide NPs. The associated oxidative stress varied from mild effects to reactive oxygen species generation which can potentiate DNA damage or even induced carcinogenesis. Copper oxide NPs, in particular, induced acute toxicity and inflict neutrophil infiltration. This chapter focuses on the applicability of various in vivo techniques for studying the effect of these NPs, especially on the pulmonary system. These in vivo techniques would certainly provide a better understanding and insight into the mechanistic pathways by which these NPs interact with various organ systems in human body. PMID- 23740126 TI - In vitro techniques to investigate the oxidative effects of quantum dots. AB - Quantum dots are semiconductor nanoparticles with unique, size-tunable optical properties. Owing to these properties, these nanoparticles are fast emerging as versatile and multimodal agents in diagnostic imaging and drug delivery applications. In the past decade, their interaction with various biological models, ranging from isolated cells and tissues to small animals, has been extensively investigated. However, along with the various beneficial effects, the presence of heavy metals in most quantum dots has led the scientific community to view the biomedical applications of quantum dots in a more cautious manner. One potential deleterious effect of quantum dots is triggering or exacerbating the process of oxidative stress, which can interfere with or destroy key biomolecular components or processes in the body. This can lead to premature ageing or diseases such as dementia and cancer. In this chapter, we describe various in vitro techniques which are fundamental in investigating the oxidative effects of quantum dots following their internalization within cells in culture. PMID- 23740127 TI - Hybrid polymeric nanoparticles: potential candidate for ophthalmic delivery. AB - Nanotechnology that deals with submicron particles has the potential to deeply impact ophthalmic delivery owing to its ability to transport incorporated active ingredient/drugs to the different compartments of the eye while protecting them from any external assault. Polymeric nanoparticles, in particular hybrid nanoparticles made up of different biodegradable and biocompatible polymers, has the potential to revolutionize ocular delivery carrier systems by taking advantage of their highly tunable physicochemical properties. Here we report a synthesis method of hybrid nanoparticles made up of chitosan-poly(lactide-co glycolide) (PLGA, as a building block of the nanocarrier) as a carrier for ophthalmic delivery. The synthesis method, characterization, and uptake study in retinal epithelial cells by confocal imaging is described herein. PMID- 23740128 TI - Relevance of nanotechnology in modulating oxidative stress: an overview. AB - The emergence of nanotechnology has already had a groundbreaking impact in biomedical research. In recent years, there has been significant interest by researchers to use nanotechnology to treat various oxidative stress-related ailments. We have seen a paradigm change in delivery methods of natural antioxidants for the treatment and prevention of various diseases. The use of nanotechnology to deliver natural antioxidants is highlighted, and current and future prospects of nanotechnology are briefly discussed. PMID- 23740129 TI - Alternative therapies in the management of chronic prostatitis/chronic pelvic pain syndrome. AB - PURPOSE: Standard medical therapy for Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) including such agents as nonsteriodal anti-inflammatories, alpha-blockers, antimicrobial therapy, and 5a-reductase inhibitors has not been uniformly effective. The purpose of this review is to focus on the role of alternative therapies available for the management of CP/CPPS. METHODS: We performed a systematic review of the literature for articles published in PubMed up to 2012 pertaining to commonly employed alternative therapies. RESULTS: The evidence for alternative therapies such as diet and lifestyle modifications, phytotherapy, acupuncture, myofascial physical therapy, and stress management/cognitive behavioral therapy is reviewed. CONCLUSION: CP/CPPS often requires a multimodal approach and alternative therapies should be considered as adjuncts in the treatment of refractory CP/CPPS patients. PMID- 23740130 TI - Incidence and predictors of bowel obstruction in elderly patients with stage IV colon cancer: a population-based cohort study. AB - IMPORTANCE: Research has been limited on the incidence, mechanisms, etiology, and treatment of symptoms that require palliation in patients with terminal cancer. Bowel obstruction (BO) is a common complication of advanced abdominal cancer, including colon cancer, for which small, single-institution studies have suggested an incidence rate of 15% to 29%. Large population-based studies examining the incidence or risk factors associated with BO in cancer are lacking. OBJECTIVE: To investigate the incidence and risk factors associated with BO in patients with stage IV colon cancer. DESIGN AND SETTING: Retrospective cohort, population-based study of patients in the Surveillance, Epidemiology, and End Results and Medicare claims linked databases who were diagnosed as having stage IV colon cancer from January 1, 1991, through December 31, 2005. PATIENTS: Patients 65 years or older with stage IV colon cancer (n = 12 553). MAIN OUTCOMES AND MEASURES: Time to BO, defined by inpatient hospitalization for BO. We used Cox proportional hazards regression models to determine associations between BO and patient, prior treatment, and tumor features. RESULTS: We identified 1004 patients with stage IV colon cancer subsequently hospitalized with BO (8.0%). In multivariable analysis, proximal tumor site (hazard ratio, 1.22 [95% CI, 1.07 1.40]), high tumor grade (1.34 [1.16-1.55]), mucinous histological type (1.27 [1.08-1.50]), and nodal stage N2 (1.52 [1.26-1.84]) were associated with increased risk of BO, as was the presence of obstruction at cancer diagnosis (1.75 [1.47-2.04]). A more recent diagnosis was associated with decreased risk of subsequent obstruction (hazard ratio, 0.84 [95% CI, 0.72-0.98]). CONCLUSIONS AND RELEVANCE: In this large population of patients with stage IV colon cancer, BO after diagnosis was less common (8.0%) than previously reported. Risk was associated with site and histological type of the primary tumor. Future studies will explore management and outcomes in this serious, common complication. PMID- 23740131 TI - Correction of hyperphosphatemia suppresses cardiac remodeling in uremic rats. AB - BACKGROUND: Hyperphosphatemia is associated with cardiovascular disease in patients with chronic kidney disease. To examine the effects of correction of hyperphosphatemia, we investigated the association between phosphate metabolism and cardiac remodeling in uremic rats. METHODS: Four groups were studied for 8 weeks: (1) control (sham), (2) 5/6 nephrectomized (Nx) rats fed a normal phosphate regular diet (Nx + NP), (3) Nx rats fed a high phosphate (1.2 %) diet (Nx + HP), and (4) Nx rats fed a high phosphate diet containing 2 % lanthanum carbonate (Nx + HP + La). The relationship between phosphate metabolism and cardiac remodeling was analyzed. RESULTS: Nx + HP rats showed a significant increase in serum phosphate and PTH compared with Nx + NP rats, while Nx + HP + La rats showed slight decreases in these levels. Both Nx + HP and Nx + HP + La rats showed a significant increase in fibroblast growth factor-23 (FGF23) compared with Nx + NP rats. Urinary phosphate excretion showed a similar trend to that of FGF23. Nx + HP rats showed a significant increase in LV weight and matrix deposition compared with Nx + NP rats, and this increase was also significantly suppressed in Nx + HP + La rats. Serum phosphate levels and PTH were significantly correlated with LV weight and matrix deposition, but FGF23 levels did not show the correlation. FGF23 had a high correlation with urinary phosphate excretion. CONCLUSIONS: These results suggest that correction of hyperphosphatemia by lanthanum carbonate could suppress cardiac remodeling independently of changes in FGF23. PMID- 23740132 TI - Should be NICE have a Spanish NICE? PMID- 23740134 TI - Role of XRCC3, XRCC1 and XPD single-nucleotide polymorphisms in survival outcomes following adjuvant chemotherapy in early stage breast cancer patients. AB - INTRODUCTION: Anthracyclines have various mechanisms of action that in the end lead to DNA double-strand breaks. Single-nucleotide polymorphisms (SNPs) in DNA repair genes may alter the protein function, affecting DNA repair proficiency and, therefore, the efficiency of DNA damaging chemotherapy. We have analysed whether SNPs in DNA repair genes (XRCC1, XRCC3 and XPD) could be useful to predict the response to anthracyclines in patients with early-stage breast cancer (EBC). METHODS: Peripheral blood samples from 150 patients with EBC were used for genotyping XRCC3Thr241Met, XRCC1Arg399Gln and XPDLys751Gln. Genotypes were correlated with survival outcomes. RESULTS: Eighty-four patients received treatment with chemotherapy regimens containing anthracyclines. In this group, patients with XRCC1Arg399Arg had a significant improvement in 5-year Disease Free Survival (DFS) compared with those with the Arg/Gln and Gln/Gln variants (84 vs 46 %, p = 0.026). In the multivariate analysis, XRCC1Arg399Arg was reported as an independent prognostic factor for DFS (HR 0.4, CI-95 % 0.2-0.9, p = 0.035). Patients with the XRCC3 Met241Met genotype presented better 5-year OS than those carrying the Thr/Thr and Met/Thr variants (100 vs 70 %, p = 0.030). A multivariate analysis for OS confirmed the independent prognostic value of XRCC3 Met241Met (HR 0.15, CI-95 % 0.02-0.90, p = 0.048). These differences were not significant when patients receiving other chemotherapy treatments, different from anthracyclines, were also considered (n = 150). XPDLys751Lys was associated with older age at diagnosis than the Lys/Gln and Gln/Gln genotypes (65 vs 58 years, p < 0.0001). CONCLUSIONS: XRCC3Thr241Met and XRCC1Arg399Gln may be predictive of survival outcome in EBC patients treated with anthracycline-based chemotherapy regimens. PMID- 23740133 TI - Cytoreductive surgery and intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis from colorectal origin. AB - Peritoneal carcinomatosis (PC) is a common form of tumour metastasis stemming from gastrointestinal and colorectal cancers. For a long time, PC has been considered a terminal clinical condition treated only with palliative systemic chemotherapy and associated with very limited results. During the last decade, the treatment of advanced colorectal disease has greatly improved with the emergence of new chemotherapy drugs and biological agents. However, the median survival rates still do not surpass 24 months, even though most of these studies correspond to groups of patients with metastatic disease to the liver and/or lung. The approach and development of cytoreductive radical surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) are based on performing radical surgery of the entire visible tumour within the abdomen/peritoneum, followed immediately by HIPEC, which acts upon microscopic tumour that remains present after surgery and which is responsible for the persistence or relapse of peritoneal disease. Peritonectomy procedures are demanding surgical techniques that permit elimination of the tumour present in the peritoneal lining and any other organs and/or structures that are infiltrated. The synergistic effect of hyperthermia and chemotherapy has been well documented. Hyperthermia increases the cytotoxicity of some cytostatic agents and increases the penetration of certain drugs into the neoplastic cells. The prognosis for patients with PC who undergo combined treatment correlates with the volume of PC (tumour burden) measured as the Peritoneal Cancer Index (PCI) and the ability to perform a CRS, to completely eliminate the gross tumour. At least one phase III study and an important number of phase II studies have shown that CRS + HIPEC provides important survival benefits for patients with PC of colorectal origin. The combination of CRS + HIPEC is indicated for patients with good general health, a low PCI, absence of extra-abdominal metastasis and who can, technically, undergo CRS. The early identification of this group of patients, rapid referral to centres specialised in CRS + HIPEC, together with the correct application of this treatment, are key in achieving the best results. PMID- 23740135 TI - The adiponectin gene single-nucleotide polymorphism rs1501299 is associated with hepatocellular carcinoma risk. AB - PURPOSE: Increasing lines of evidence have suggested that adiponectin, an adipocyte-derived hormone, plays an important role in the development of hepatocellular carcinoma (HCC). However, the relationship between genetic variants of the adiponectin gene (ADIPOQ) and HCC has not been previously explored. Therefore, we performed a case-control study to examine the association of haplotype-tagging single-nucleotide polymorphisms (SNPs) in ADIPOQ with HCC risk. METHODS: Five haplotype-tagging SNPs of ADIPOQ (rs266729, rs822395, rs822396, rs2241766 and rs1501299) were genotyped in 200 HCC patients and 200 non HCC controls by PCR amplification and direct sequencing. Logistic regression was used to estimate the risk of HCC associated with each individual SNP and we adjusted for multiple testing by the Bonferroni correction. RESULTS: Of the five tested SNPs, rs1501299 showed a strong and significant association with HCC risk even after the Bonferroni correction. After adjusting for the serological status of the hepatitis virus B core antibody and for other SNPs, the odds ratios were 4.33 [95 % confidence interval (CI) 2.07-9.05; corrected P < 0.005] and 3.71 (95 % CI 1.84-7.48; corrected P < 0.005) for the GG genotype and GG/GT combined genotype, respectively, versus the TT genotype. CONCLUSIONS: This is the first report, demonstrating an association of ADIPOQ polymorphisms with HCC risk. Our results implicate the ADIPOQ SNP rs1501299 as a susceptibility locus for HCC. PMID- 23740136 TI - The immunohistochemical expression of c-Met is an independent predictor of survival in patients with glioblastoma multiforme. AB - BACKGROUND AND AIMS: Because the outcome of glioblastoma multiforme (GBM) remains dismal, there is an urgent need for a better molecular characterization of this malignancy. The aim of this prospective study was to investigate the prognostic impact of the expression of c-mesenchymal-epithelial transition (c-Met) a receptor tyrosine kinase implicated in expression growth, survival, motility/migration, and invasion in GMB patients managed according to the established diagnostic and therapeutic protocols. METHODS: Between May 2003 and March 2011, a total of 69 patients (33 males and 36 females; mean age: 52.2 +/- 12.9 years, age range: 23-81 years) referred to our Department for the surgical removal of GBM were evaluated immunohistochemically for c-Met expression. Progression-free survival (PFS) and overall survival (OS) served as the main outcome measures. RESULTS: Compared with c-Met- subjects (n = 38), c-Met+ subjects (n = 31) had both a significantly lower OS (15.3 +/- 2.3 vs. 22.6 +/- 2.5 months, respectively, p < 0.01) and PFS (12.3 +/- 2.1 vs. 19.1 +/- 2.6 months, respectively, p < 0.05). After allowance for potential confounders, multivariate Cox regression analysis identified c-Met+ as an independent predictor of both OS (hazard ratio = 1.7; 95 % confidence interval = 1.2-1.9, p < 0.01) and PFS (hazard ratio = 1.6; 95 % confidence interval = 1.1-2.3, p < 0.05). CONCLUSIONS: Our findings suggest that c-Met immunohistochemical expression is an independent predictor of outcomes in patients with GBM treated by standard of care. PMID- 23740137 TI - Time trends of cancer incidence and mortality in Catalonia during 1993-2007. AB - PURPOSE: To describe time trends of cancer in Catalonia, Spain, during the period 1993-2007. METHODS/PATIENTS: Data have been provided by two population-based cancer registries, Girona and Tarragona, and the Catalan mortality registry. Cancer incidence in Catalonia has been estimated through modeling methods using data from these health structures. RESULTS: During 2003-2007, there were 20,042 cancer cases and 9,842 deaths per year among men and 13,673 new cancer cases and 5,882 deaths among women. The most frequent incident cancers among men were prostate (N = 4,258), lung (N = 3,021), colorectal (N = 3,007) and bladder (N = 2,238), whereas among women they were breast (N = 3,907), colorectal (N = 2,088), corpus uteri (N = 734) and lung (N = 527). During 1993-2007, age-standardized incidence rates (ASIRs) rose 1.2 % per year among men [prostate (6.3 %), testis (5.7 %), kidney (2.9 %), liver (2.2 %) and colorectal (2.1 %)]. ASIRs decreased for stomach (-2.9 %), oral cavity and pharynx (-2.8 %), larynx (-2.7 %) and esophagus (-2 %). Among women, ASIRs only rose for lung (5.2 %), kidney (3.1 %), oral cavity and pharynx (2.6 %) and thyroid (1.6 %). ASIRs decreased for corpus uteri (-2.3 %), stomach (-1.7 %) and ovary (-1.6 %). Cancer mortality decreased 1.3 % per year among men and -2.1 % among women during the same period. CONCLUSION: Among men, the decrease of incidence/mortality of tobacco-related tumors was related to a reduction of smoking prevalence. Among women, the stabilization of breast cancer incidence and the rise of lung cancer incidence are similar to that observed in most European regions. These results allow assessing the effectiveness of public health strategies and they pose new frontiers for cancer control in Catalonia. PMID- 23740138 TI - Prognostic factors for survival in lymphoma patients after autologous stem cell transplantation. PMID- 23740139 TI - The RACHS-1 risk category can be a predictor of perioperative recovery in Asian pediatric cardiac surgery patients. AB - PURPOSE: The Risk Adjustment for Congenital Heart Surgery (RACHS-1) classification was originally designed to facilitate the prediction of in hospital mortality for pediatric cardiac surgery patients. However, there have been few reports on clinical outcomes predicted by the RACHS-1 category, especially in an Asian population. The aim of this study was to determine whether RACHS-1 classification can predict patient outcomes. METHODS: A total of 580 pediatric cardiac surgery procedures performed from January 2005 to December 2009 were retrospectively classified into the six RACHS-1 categories. The association between RACHS-1 category and clinical outcomes, including length of catecholamine requirement, mechanical ventilation time, intensive care unit stay, and in hospital mortality, were examined. RESULTS: The frequencies of RACHS-1 categories in the study population were: category 1, 10.7 %; category 2, 36.7 %; category 3, 42.8 %; category 4, 6.6 %; category 5, 0.0 %; category 6, 3.3 %. There was a significant linear correlation between RACHS-1 category and in-hospital mortality (r = 0.96, p < 0.001). Kaplan-Meier analysis demonstrated that length of catecholamine infusion, mechanical ventilation time, and ICU stay were significantly different (p < 0.05) in the different RACHS-1 categories, except for those between category 4 and 6 (p = 0.09). CONCLUSIONS: Based on the results of our analysis, we conclude that the RACHS-1 stratification system can predict in-hospital mortality and patient outcomes in patients undergoing pediatric cardiac surgery. PMID- 23740140 TI - The effect of monthly ibandronate on bone mineral density and bone turnover markers in patients with haemophilia A and B and increased risk for fracture. AB - Haemophilia A and B have been associated with increased prevalence of low bone mineral density (BMD). However, no study has so far evaluated the effects of anti osteoporotic therapy on BMD in haemophilia.The primary endpoint of this prospective study was to estimate the effect of 12-month therapy of oral ibandronate 150 mg/month on BMD in patients with haemophilia A and B. Secondary endpoint was its effect on turnover markers (BTM) of bone resorption [serum C terminal telopeptide of type 1 collagen (sCTX), tartrate-resistant acid phosphatase band 5b] and bone formation (osteocalcin and bone-specific alkaline phosphatase. Ten adult patients with T-score < -2.5 SD or Z-score < -2 and/or increased risk of fracture according to FRAX model were included. All received 1,000 mg/day calcium carbonate with 800 IU/d cholecalciferol. Males with haemophilia A (n=7) or B (n=3) (mean age 43.5 +/- 13.5 years) were studied. Ibandronate resulted in an increase in lumbar BMD (from 0.886 +/- 0.169 to 0.927 +/- 0.176 g/cm2, 4.7%, p=0.004). No change in BMD of total hip (from 0.717 +/- 0.128 to 0.729 +/- 0.153 g/cm2, p=0.963) or femoral neck (0.741 +/- 0.135 to 0.761 +/- 0.146 g/cm2, p=0.952) was noticed. Ibandronate led to a decrease in sCTX (from 0.520 +/- 0.243 to 0.347 +/- 0.230 ng/ml, -29.9%, p=0.042). No change was observed in other BTM. Ibandronate was generally well-tolerated. In conclusion, ibandronate significantly improved BMD in lumbar spine and reduced bone resorption in adults with haemophilia at increased risk of fracture. Its effect on hip BMD and bone formation markers was not significant. PMID- 23740141 TI - Competency in interpretation of 12-lead electrocardiogram among Swiss doctors. PMID- 23740142 TI - An unusual case of intraorbital foreign body and its management. AB - A 36-year-old aboriginal female presented following an assault with a wooden fence paling. Examination revealed a wooden object protruding lateral to the left eyebrow. CT scan showed a blow-in fracture of lateral orbital wall and a hypodense foreign body causing indentation of the globe and stretching of the optic nerve. The case was managed successfully with complete recovery of the visual acuity on day 1 post-surgery. This case highlights the importance of prompt removal of large lateral wooden intraorbital foreign body to achieve an excellent visual outcome. PMID- 23740143 TI - Identification and localization of multiple intrastromal foreign bodies with anterior segment optical coherence tomography and ocular Pentacam. AB - To report the clinical aspects and the imaging of a patient with intrastromal glass foreign bodies after a road traffic accident using both anterior segment optical coherence tomography (OCT) and ocular Pentacam. A detailed case report was made of the use of anterior segment OCT (AS-OCT) and ocular Pentacam to evaluate intrastromal foreign bodies. AS-OCT and Pentacam were valuable non invasive tools in identification, localization and monitoring patients with intrastromal foreign bodies. This report demonstrates that AS-OCT and ocular Pentacam are effective and necessary procedures for both the diagnosis and follow up of intracorneal foreign bodies. PMID- 23740144 TI - Management of post-goniopuncture iris herniation: a two-step procedure. AB - A 38-year-old male presented to the emergency room suffering acute pain in his left eye. Two months before he had been submitted to uneventful non-penetrating deep sclerectomy and one month before to YAG-laser goniopuncture. Examination showed iris herniation into the trabeculo-descemet's window. Surgical reduction was carried out through a peripheral corneal incision, and a large air bubble was injected into the anterior chamber. Four days later a wide laser peripheral iridotomy was performed. This technique can transform a non-penetrating technique into a full-trabeculectomy, without reopening the superficial flap. PMID- 23740145 TI - Pseudocontingencies derived from categorically organized memory representations. AB - Pseudocontingencies (PCs) allow for inferences about the contingency between two variables X and Y when the conditions for genuine contingency assessment are not met. Even when joint observations X i and Y i about the same reference objects i are not available or are detached in time or space, the correlation r(X i ,Y i ) is readily inferred from base rates. Inferred correlations are positive (negative) if X and Y base rates are skewed in the same (different) directions. Such PC inferences afford useful proxies for actually existing contingencies. While previous studies have focused on PCs due to environmental base rates, the present research highlights memory organization as a natural source of PC effects. When information about two attributes X and Y is represented in a hierarchically organized categorical memory code, as category-wise base rates p(X) and p(Y), the reconstruction of item-level information from category base rates will naturally produce PC effects. Three experiments support this contention. When the yes base rates of two respondents in four questionnaire subscales (categories) were correlated, recalled and predicted item-level responses were correlated in the same direction, even when the original responses to specific items within categories were correlated in the opposite direction. PMID- 23740146 TI - Peptide receptor radionuclide therapy in a patient with disabling non-functioning pituitary adenoma. AB - Non-functioning pituitary adenoma (NFPA) with higher proliferation index (WHO II) are often a therapeutical challenge. Low somatostatin receptor expression in these tumors usually prevents a treatment with somatostatin analogs. In 1996, a 55-year-old patient was referred due to right-sided headache. A pituitary macroadenoma with infiltration into the right cavernous sinus was diagnosed. There was no visual field deficit and the clinical and biochemical work up was consistent with a NFPA. The patient underwent transsphenoidal surgery. Residual adenoma remained in the right cavernous sinus. Histologically, a null-cell adenoma with a high proliferation index was documented (MIB-1: 11.6%, WHO II). Somatostatin receptor autoradiography was performed in the surgical specimen showing a homogenous expression of sst2 receptors. Radiosurgery was completed with stable disease for 8 years. In 2004, the patient was diagnosed with an incomplete palsy of the right oculomotorius nerve and a significant increase in the volume of the adenoma in the right cavernous sinus. After a positive Octreoscan((r)) the patient consented to an experimental therapy approach using Lutetium DOTATOC (3 * 200 mCi). The palsy of the oculomotorius nerve improved and remained stable until today (March 2013), the follow-up MRI scans demonstrated stable disease. This is the first case of a patient with a NFPA (WHO II) in whom PRRT successfully improved the local complications of the tumor for more than 8 years after ineffective surgery and gamma knife therapy. The determination of sst2 in vitro using autoradiography and in vivo by Octreoscan was instrumental to administer this therapy in a challenging situation. PMID- 23740147 TI - The effect of the ANKK1/DRD2 Taq1A polymorphism on weight changes of dopaminergic treatment in prolactinomas. AB - Treatment with dopamine agonists in patients with prolactinomas has been associated with weight loss in short term studies. However, long-term studies on weight changes are lacking. Taq1A is a restriction fragment length polymorphism considered as a gene marker for the DRD2 gene. The presence of at least one A1 allele is linked to reduced brain dopaminergic activity due to reduced receptor binding and lower density of the dopamine 2 receptor. We aimed at testing the hypothesis that the dopaminergic treatment in prolactinoma patients leads to sustained weight loss and that the presence of diminished weight loss response under dopamine agonists is associated with the minor A1 allele of Taq1A.We included n = 44 patients (17 male and 27 female, 26 macroadenomas and 18 microadenomas) with prolactinomas treated with dopamine agonists. Outcome measures were weight and body mass index (BMI) change under dopaminergic treatment after 2 years with regard to Taq1A status and sex. We observed that the dopaminergic treatment leads to a significant mean weight loss of 3.1 +/- 6.25 kg after 2 years. Regarding Taq1A polymorphisms, 21 patients were carriers of at least one A1 allele and 23 patients had a genotype of A2/A2. However, the presence of the A1 allele was neither associated with the mean BMI at baseline nor with an altered weight loss response under dopamine agonist therapy. Our results implicate that the dopaminergic treatment leads to a sustained weight loss in patients with prolactinomas after 2 years. However, there was no association to the A1 allele of Taq1A, observation that needs to be analysed in larger cohorts. PMID- 23740148 TI - Whole blood lactate kinetics in patients undergoing quantitative resuscitation for severe sepsis and septic shock. AB - BACKGROUND: We sought to compare the association of whole-blood lactate kinetics with survival in patients with septic shock undergoing early quantitative resuscitation. METHODS: This was a preplanned analysis of a multicenter, ED based, randomized, controlled trial of early sepsis resuscitation. Inclusion criteria were suspected infection, two or more systemic inflammation criteria, either systolic BP< 90 mm Hg after a fluid bolus or lactate level > 4 mM, two serial lactate measurements, and an initial lactate level > 2.0 mM. We calculated the relative lactate clearance, rate of lactate clearance, and occurrence of early lactate normalization (decline to < 2.0 mM in the first 6 h). Area under the receiver operating characteristic curve (AUC) and multivariate logistic regression were used to determine the lactate kinetic parameters that were the strongest predictors of survival. RESULTS: The analysis included 187 patients, of whom 36% (n = 68) normalized their lactate level. Overall survival was 76.5% (143 of 187 patients), and the AUC of initial lactate to predict survival was 0.64. The AUCs for relative lactate clearance and lactate clearance rate were 0.67 and 0.58, respectively. Lactate normalization was the strongest predictor of survival (adjusted OR, 5.2; 95% CI, 1.7-15.8), followed by lactate clearance >= 50% (OR, 4.0; 95% CI, 1.6-10.0). Lactate clearance >= 10% (OR, 1.6; 95% CI, 0.6-4.4) was not a significant independent predictor in this cohort. CONCLUSIONS: In patients in the ED with a sepsis diagnosis, early lactate normalization during the first 6 h of resuscitation was the strongest independent predictor of survival and was superior to other measures of lactate kinetics. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00372502; URL: clinicaltrials.gov. PMID- 23740149 TI - A proposal for combination of total number and anatomical location of involved lymph nodes for nodal classification in non-small cell lung cancer. AB - BACKGROUND: We previously reported the prognostic impact of the number of involved lymph nodes (LNs) on survival in non-small cell lung cancer (NSCLC). However, it remains unknown whether the total number or anatomic location of involved LNs is a superior prognostic factor. METHODS: A total of 689 patients with NSCLC who underwent complete resection involving dissection of the hilar and mediastinal LNs with curative intent of >= 10 LNs were enrolled. The association between the total number of LNs (nN) involved and survival was assessed by comparison with the anatomic location of LN involvement (pathologic lymph node [pN]), the present nodal category. RESULTS: We classified the patients into five categories according to the combined pN and nN status as follows: pN0-nN0, pN1 nN1-3, pN1-nN4-, pN2-nN1-3, and pN2-nN4. Although there was no statistically significant difference between the pN1-nN4- and pN2-nN1-3 categories, pN2-nN1-3 had better prognoses than pN1-nN4-. On multivariate analysis, the nN category was an independent prognostic factor for overall survival and disease-free survival (vs nN4-; the hazard ratios of nN0 and nN1-3 for overall survival were 0.223 and 0.369, respectively, P < .0001 for all), similar to the pN category. We propose a new classification based on a combination of the pN and nN categories: namely, N0 becomes pN0-nN0, the N1 category becomes pN1-nN1-3, the N2a category becomes pN2 nN1-3 + pN1-nN4-, and the N2b category becomes pN2-nN4. Each survival curve was proportional and was well distributed among the curves. CONCLUSIONS: A combined anatomically based pN stage classification and numerically based nN stage classification is a more accurate prognostic determinant in patients with NSCLC, especially in the prognostically heterogeneous pN1 and pN2 cases. Further large scale international cohort validation analyses are warranted. PMID- 23740151 TI - Facile synthesis of novel Si nanoparticles-graphene composites as high performance anode materials for Li-ion batteries. AB - Improving the Li storage properties of a Si negative electrode is of great significance for Li-ion batteries. A major challenge is to fabricate Si-based active materials with good electronic conduction and structural integrity in the process of discharging and charging. In this study, novel Si nanoparticles graphene composites have been synthesized by hybrid electrostatic assembly between positively charged aminopropyltriethoxysilane modified Si nanoparticles and negatively charged graphene oxide, followed by thermal reduction. Commercially available Si nanoparticles are well embedded and uniformly dispersed into the graphene sheets, and the typically wrinkled graphene sheets form a network and cover the highly dispersed Si nanoparticles well. No any obvious aggregation of the Si nanoparticles can be found and many nanospaces exist around the Si nanoparticles, which provide buffering spaces needed for volume changes of Si nanoparticles during insertion/extraction of Li. High capacity and long cycle life (822 mA h g(-1) after 100 cycles at a current density of 0.1 A g(-1)) have been realized in the novel Si nanoparticles-graphene composites for Li-ion batteries. The excellent electrochemical performance is ascribed to the uniform distribution of Si nanoparticles and graphene, which effectively prevents aggregation and pulverization of Si nanoparticles, keeps the overall electrode highly conductive, and maintains the stability of the structure. PMID- 23740152 TI - Using the Langmuir-Schaefer technique to fabricate large-area dense SERS-active Au nanoprism monolayer films. AB - Interfacial self-assembly of nanoparticles is capable of creating large-area close-packed structures for a variety of applications. However, monolayers of hydrophilic cetyltrimethylammonium bromide (CTAB)-coated Au nanoparticles are challenging to assemble via interfacial self-assembly. This report presents a facile and scalable process to fabricate large-area monolayer films of ultrathin CTAB-coated Au nanoprisms at the air-water interface using the Langmuir-Schaefer technique. This is first achieved by a one-step functionalization of Au nanoprisms with poly(vinylpyrrolidone) (PVP). PVP functionalization is completed within a short time without loss of nanoprisms due to aggregation. Uniform and near close-packed monolayers of the Au nanoprisms formed over large areas (~1 cm(2)) at the air-water interface can be transferred to substrates with different wettabilities. The inter-prism gaps are tuned qualitatively through the introduction of dodecanethiol and oleylamine. The morphological integrity of the nanoprisms is maintained throughout the entire assembly process, without truncation of the nanoprism tips. The near close-packed arrangement of the nanoprism monolayers generates large numbers of hot spots in the 2D arrays in the tip-to-tip and edge-to-edge inter-particle regions, giving rise to strong surface enhanced Raman scattering (SERS) signals. When deposited on an Au mirror film, additional hotspots are created in the 3(rd) dimension in the gaps between the 2D nanoprism monolayers and the Au film. SERS enhancement factors reaching 10(4) for non-resonant probe molecules are achieved. PMID- 23740153 TI - Obstructive sleep apnea is associated with fatty liver and abnormal liver enzymes: a meta-analysis. AB - BACKGROUND: Obstructive sleep apnea (OSA) is associated with the cluster of clinical conditions that comprise the metabolic syndrome, including nonalcoholic fatty liver disease (NAFLD). Our primary purpose was to estimate the effect of OSA on serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Our secondary purpose was to investigate the potential influence of OSA on histological severity of NAFLD to explore whether chronic intermittent hypoxia is associated with inflammation and fibrosis. METHODS: Our literature search identified 11 studies, from which we extracted information about numbers of control subjects and OSA patients, and ALT, AST, and NAFLD. RESULTS: From a total of 668 OSA patients and 404 controls, we found that the standardized difference in mean values of ALT and AST levels in patients with OSA was significantly different from that in the controls. Meta-regression showed that the association was independent of body mass index and type 2 diabetes. Fatty liver was associated with OSA in five studies with 400 subjects. OSA was significantly associated with liver fibrosis in 208 subjects, but not with lobular inflammation. CONCLUSIONS: Routine assessment of liver enzymes and liver damage should be implemented in OSA patients because they have an increase of 13.3% of ALT and 4.4% of AST levels, and a 2.6-fold higher risk of liver fibrosis when they have NAFLD, which is 2.6 times more frequent in OSA patients. PMID- 23740154 TI - Determination of the molecular subtypes of diffuse large B-cell lymphomas using immunohistochemistry: a case series from the Inselspital, Bern, and a critical appraisal of this determination in Switzerland. AB - The two major subtypes of diffuse large B-cell lymphoma (DLBCL) (germinal centre B-cell - like (GCB-DLBCL) and activated B-cell - like (ABC-DLBCL)) are defined by means of gene expression profiling (GEP). Patients with GCB-DLBCL survive longer with the current standard regimen R-CHOP than patients with ABC-DLBCL. As GEP is not part of the current routine diagnostic work-up, efforts have been made to find a substitute than involves immunohistochemistry (IHC). Various algorithms achieved this with 80-90% accuracy. However, conflicting results on the appropriateness of IHC have been reported. Because it is likely that the molecular subtypes will play a role in future clinical practice, we assessed the determination of the molecular DLBCL subtypes by means of IHC at our University Hospital, and some aspects of this determination elsewhere in Switzerland. The most frequently used Hans algorithm includes three antibodies (against CD10, bcl 6 and MUM1). From records of the routine diagnostic work-up, we identified 51 of 172 (29.7%) newly diagnosed and treated DLBCL cases from 2005 until 2010 with an assigned DLBCL subtype. DLBCL subtype information was expanded by means of tissue microarray analysis. The outcome for patients with the GCB subtype was significantly better compared with those with the non-GC subtype, independent of the age-adjusted International Prognostic Index. We found a lack of standardisation in the subtype determination by means of IHC in Switzerland and significant problems of reproducibility. We conclude that the Hans algorithm performs well in our hands and that awareness of this important matter is increasing. However, outside clinical trials, vigorous efforts to standardise IHC determination are needed as DLBCL subtype-specific therapies emerge. PMID- 23740155 TI - Three-dimensional surface scanning for accurate patient positioning and monitoring during breast cancer radiotherapy. AB - PURPOSE: Clinical evaluation of an optical three-dimensional surface scanning (3D SS) system for patient positioning and monitoring during radiotherapy (RT) for breast cancer. MATERIALS AND METHODS: A ceiling-mounted scanner was developed to acquire multiple 3D body surface images and tested in 14 conservatively operated breast cancer patients. A reference skin surface was derived from the planning computed tomography (CT) scan as basis for rigid registration with the surface scans. In addition to electronic portal images (EPIs), optical scans were acquired at three defined time points before and during daily RT. Patient setup was guided by laser alignments and corrected according to EPI findings. The accuracy of the 3D-SS system was validated by comparison of the optical scans to EPIs generated in parallel. Interfraction shifts were investigated by comparison of the first 3D-SS image with the reference body outline. Intrafractional motions were analysed by comparing the three daily surface scans with the first EPI. RESULTS: Comparison of EPIs and 3D-SS images revealed good accordance (- 0.05+/ 0.94 mm). Analysis of daily patient positions revealed average deviations of 0.4+/-2.4 mm laterally, 0.3+/-1.9 mm longitudinally and 0.2+/-3.3 mm vertically. After 2 weeks, a systematic interfraction shift in patient positioning was noted, particularly in the vertical direction (4.9+/-0.56 mm), which was attributed to patients progressively relaxing. 3D-SS images showed intrafractional shifts of 1.2+/-0.7 mm over a time course of 2 min. CONCLUSION: Optical surface scanning is a simple, fast and reproducible method for breast cancer patient alignment. Particularly for more sophisticated irradiation techniques, it helps to improve accuracy in patient positioning during radiotherapy without the exposure to additional ionizing radiation. PMID- 23740156 TI - A new survival score for patients with brain metastases from non-small cell lung cancer. AB - BACKGROUND AND PURPOSE: Non-small cell lung cancer (NSCLC) is the most common primary tumor in patients developing brain metastasis. This study was performed to develop and validate a survival score particularly for this group of patients. PATIENTS AND METHODS: In this study, the data of 514 patients treated with whole brain radiotherapy (WBRT) alone for brain metastasis from NSCLC were retrospectively analyzed. The patients were divided into a test group (n = 257) and a validation group (n = 257). In the multivariate analysis of the test group, gender, performance status, and extracranial metastases were independent predictors of survival and, therefore, included in the scoring system. The score for each of the three factors was obtained from the 6-month survival rate (in %) divided by 10. The total scores that represented the sum of the three scores were 5, 8, 9, 11, 12, or 15 points. Three prognostic groups were formed according to the total scores. RESULTS: The 6-month survival rates in the test group were 9 % for 5-9 points (group A), 54 % for 11-12 points (group B), and 79 % for 15 points (group C). In the validation group the 6-month survival rates were 14, 56, and 78 %, respectively. The comparisons between the prognostic groups A, B, and C of the test and the validation group did not reveal any significant differences. CONCLUSION: This new score appears valid and reproducible. It can help predict the survival of patients with brain metastasis from NSCLC. PMID- 23740157 TI - A simple survival score for patients with brain metastases from breast cancer. AB - BACKGROUND AND PURPOSE: Personalized cancer treatment considers the patient's survival prognosis. Therefore, it is important to be able to estimate the patient's survival time, particularly in a palliative situation such as brain metastasis. This study aimed to create and validate a survival score for patients with brain metastasis from breast cancer, which is the second most common primary tumor in these patients. PATIENTS AND METHODS: Data of 230 patients treated with whole-brain radiotherapy (WBRT) alone for brain metastasis from breast cancer were retrospectively analyzed. Patients were assigned to a test (n = 115) or a validation group (n = 115). According to the results of the multivariate analysis of the test group, Karnofsky Performance Score and extracranial metastases were included in the scoring system. The score for each factor was obtained from the 6 month survival rate (in %) divided by 10. Total scores represented the sum of these scores and were 4, 7, 9, or 12 points. Three prognostic groups were formed. RESULTS: The 6-month survival rates in the test group were 10 % for 4-7 points, 55 % for 9 points, and 78 % for 15 points (p < 0.001). In the validation group the corresponding 6-month survival rates were 11, 54, and 75 %, respectively (p < 0.001). The comparisons between the prognostic groups of the test and the validation group did not show significant differences. CONCLUSION: This simple survival score appears valid and reproducible. It can be used to estimate the survival time of patients with brain metastasis from breast cancer receiving WBRT alone. PMID- 23740158 TI - [Prevention and management of complications in Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping automated endothelial keratoplasty (DSAEK)]. AB - BACKGROUND: Posterior lamellar keratoplasty, in the form of Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping automated endothelial keratoplasty (DSAEK), has become a standard procedure for therapy of endothelial diseases of the cornea. The aim of this article is to describe strategies to prevent and manage complications in DMEK and DSAEK surgery. METHODS: The article is based on a PubMed literature search and own clinical data. Key words used were "DMEK", "DSAEK", "Descemet membrane endothelial keratoplasty" and "Descemet stripping automated endothelial keratoplasty". RESULTS: The DMEK and DSAEK procedures are safe surgical strategies for treating endothelial corneal diseases if the indications are made correctly. CONCLUSIONS: The DMEK procedure is the standard procedure for improvement of visual acuity especially for younger patients with Fuchs' dystrophy and DSAEK is particularly suitable for eyes with complicated anterior chamber situations. PMID- 23740159 TI - [Peripheral fine granular retinal pigmentation in combination with macular gliosis]. PMID- 23740160 TI - Computational identification and evolutionary relationships of the microRNA gene cluster miR-71/2 in protostomes. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules which are processed into ~20 24 nt molecules that can regulate the gene expression post-transcriptionally. MiRNA gene clusters have been identified in a range of species, where in miRNAs are often processed from polycistronic transcripts. In this study, a computational approach is used to investigate the extent of evolutionary conservation of the miR-71/2 cluster in animals, and to identify novel miRNAs in the miRNA cluster miR-71/2. The miR-71/2 cluster, consisting of copies of the miR 71 and miR-2 (including miR-13) families, was found to be Protostome-specific. Although, this cluster is highly conserved across the Protostomia, the miR-2 family is completely absent from the Deuterostomia species, while miR-71 is absent from the Vertebrata and Urochordata. The evolutionary conservation and clustering propensity of the miR-71/2 family across the Protostomes could indicate the common functional roles across the member species of the Protostomia. PMID- 23740161 TI - Dermoscopy and confocal microscopy of nested melanoma of the elderly: recognizing a newly defined entity. AB - IMPORTANCE: Nested melanoma of the elderly is a newly identified histopathologic variant of superficial spreading melanoma, characterized by intraepidermal large nests. However, the clinical, dermoscopic, and confocal aspects have been depicted only partially. OBSERVATIONS: In our cases series, nested melanoma was a flat, irregularly shaped lesion with variably pigmented and irregularly distributed globules on dermoscopic examination. Confocal microscopy revealed the presence of a "clod" pattern made of large compact nests with variable atypia. These findings correlated well with histopathologic features. CONCLUSIONS AND RELEVANCE: Nested melanoma of the elderly should be included in the differential diagnosis when a flat pigmented lesion, showing dermoscopically an irregular globular pattern, is seen in a patient older than 60 years. PMID- 23740162 TI - Delayed metastasis to the mandible of esophageal adenocarcinoma. AB - Around 1 % of oral cancers are metastases from distant sites. Tumor metastases to the jaw bones are uncommon and are most likely to arise from primary lung, breast, prostate or kidney tumors. Jaw bone metastases from a primary esophageal adenocarcinoma are especially rare, with only 7 reports published in the literature. Here, we describe a case of a 69 year-old male patient where 7 years elapsed between the diagnosis and successful treatment of a poorly differentiated, stage pT2N0 primary esophageal adenocarcinoma and re-presentation with jaw pain due to a metastatic mandibular deposit. The morphological appearance of the metastasis and immunohistochemical positivity with CK20, CK7 and CDX2 strongly supported an adenocarcinoma of upper gastrointestinal tract origin. This case is of particular interest as there is an unusually long time between the detection of the primary esophageal adenocarcinoma and diagnosis of metastatic disease. The longest period of time we have found for this in the literature is 9 months, although it is also reported that some oral metastases may appear more than 10 years following the primary tumor diagnosis. PMID- 23740163 TI - Apocrine hidrocystoma of the lower lip: a case report and literature review. AB - The hidrocystomas (HCs) are cystic forms of sweat gland resulting from proliferation of the apocrine secretory coil or eccrine duct. Apocrine -HCs are cystic lesions that arise from the apocrine secretory coil, while eccrine -HCs represent retention cysts of the eccrine duct. The commonest site for such lesions is around the eye, and they may also occur on the ears, scalp, chest, shoulders, or feet. However, HCs of the perioral region are uncommon. The differential diagnosis with minor salivary gland cyst or cystic neoplasms often poses a problem in this site. Here we report a rare case of apocrine -HC of the right lower lip for which excisional biopsy of the lesion was performed. Histopathologically, the lesion was a unilocular cyst lined by a double-layered epithelium of the apocrine secretory type. Immunohistochemically, the secretory epithelium was positive for mammaglobin, gross cystic disease fluid protein 15 (GCDFP-15), cytokeratin 7 (CK 7) and CK18, and the myoepithelium was positive for alpha-smooth muscle actin (alpha-SMA) and weakly positive for S100 protein. Here we present this very rare case of apocrine -HC of the lower lip, and discussed regarding differential diagnosis with minor salivary gland cystic lesion in the lip. PMID- 23740164 TI - Preliminary evidence that obese patients with obstructive sleep apnea/hypopnea syndrome are refractory to the acute beneficial metabolic effects of a very low calorie diet. AB - Since obesity seems to play a causal role in both obstructive sleep apnea/hypopnea syndrome (OSAHS) and type 2 diabetes, the question arises whether diet-induced weight loss is equally efficacious in type 2 diabetic patients with and without OSAHS. The present study was aimed to investigate the effect of 1 week very low calorie diet (VLCD) on oxygen desaturation index (ODI) and on glucose regulation in OSAHS versus non-OSAHS patients. Fourteen patients with type 2 diabetes mellitus and morbid obesity were enrolled. According to ODI, patients were divided into 2 groups (with and without OSAHS) and evaluated by a hyperglycemic clamp study, before and after a 7 day-VLCD. After a VLCD, a significant reduction of anthropometric parameters, in the overall group and in subgroups, was observed. M-value and acute insulin response increased significantly only in patients without obstructive sleep apnea (990.10 +/- 170.19 vs. 1,205.22 +/- 145.73 MUmol min(-1) m(-2), p = 0.046; -1.05 +/- 8.40 vs. 48.26 +/- 11. 90 pmol/L, p = 0.028, respectively). The average 24-h heart rate (24-h HR) fell significantly (p = 0.05), primarily because of a decrease during daytime (p = 0.041), in the whole group. In conclusion, we observed that morbidly obese patients with type 2 diabetes and OSAHS are specifically resistant to the acute beneficial effects of VLCD on metabolic parameters. Our preliminary observation deserves further investigation to clarify the pathogenetic mechanisms involved. PMID- 23740165 TI - Suicide attempts in the county of Basel: results from the WHO/EURO Multicentre Study on Suicidal Behaviour. AB - BACKGROUND: This article presents epidemiological and clinical findings from the Basel research centre parti-cipating in the WHO/EURO Multicentre Study on Suicidal Behaviour. METHODS: Between January 2003 and December 2006, 984 suicide attempts were documented for patients presenting at medical institutions with a suicide attempt. RESULTS: The mean suicide attempt rate was 164/100,000 inhabitants. Women attempted suicide nearly twice as often as men. The highest suicide attempt rates were found for women aged 20-24 years, for men aged 30-34 years, and for people who were unmarried, of foreign nationality, and of low education or low employment status. 'Soft methods' were used significantly more often than 'hard methods'. Of the suicide attempt methods employed, a relatively high proportion was accounted for by self-poisoning with drugs (X60-64), especially with non-steroidal anti-inflammatory drugs, benzodiazepines and antidepressants. Significant gender differences were found in the various methods and in the frequency of psychiatric diagnoses. A total of 98.7% of the attempters were diagnosed with a psychiatric disorder according to ICD-10; 35% suffered from an affective disorder. Men were significantly more frequently affected by substance abuse disorder or psychosis, whereas in women adjustment disorders and personality disorders were diagnosed significantly more often. CONCLUSIONS: This study offers the first published representative data of an entire Swiss county. Established sociodemographic and clinical risk factors for suicide attempts were reproduced. The identification of risk factors contributes to developing local targeted prevention strategies, for example education of risk groups and caregivers, and pharmacolegal consequences for package sizes. Gender- and age specific prevention and aftercare programmes are indicated. PMID- 23740166 TI - Neuronal synaptobrevin promotes longevity in Drosophila photoreceptors. AB - Neurons have unique challenges relative to other cell types. Unlike most other cells, neurons must remain healthy and functional throughout the lifespan of an animal. Premature neuronal loss underlies many age-related neurodegenerative diseases, including Alzheimer and Parkinson Diseases. Despite previous research aimed at understanding the mechanisms of age-related neurodegenerative diseases, little is known about the mechanisms that allow neurons to remain functional for the lifetime of a healthy animal. Understanding these cellular and biochemical processes is essential to promote healthful aging and reduce the severity of neurodegenerative disease. Here we discuss our recent identification of neuron specific proteins that regulate endosome fusion events and the role of endosomes in maintaining healthy neurons. PMID- 23740167 TI - PROMIS(r) Parent Proxy Report Scales for children ages 5-7 years: an item response theory analysis of differential item functioning across age groups. AB - OBJECTIVE: The objective of the present study is to describe the extension of the National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS((r))) pediatric parent proxy-report item banks for parents of children ages 5-7 years, and to investigate differential item functioning (DIF) between the data obtained from parents of 5-7-year-old children with the data obtained from parents of 8-17 year-old children in the original construction of the scales. METHODS: Item response theory (IRT) analyses of DIF were conducted comparing data from the 5-7 age group with data from the established scales for ages 8-17 across 5 generic health domains (physical functioning, pain, fatigue, emotional health, and social health) and asthma. RESULTS: IRT DIF analyses revealed that the majority of the items functioned similarly with responses from parents of younger and older children. A small number of items were removed from the item bank for younger children, and a few items that exhibited statistical DIF were retained in the pools with the caveat that they should not be used in studies that involve comparisons of younger children with older children. CONCLUSIONS: The study confirms that most of the items in the PROMIS parent proxy report item banks can be used with parents of children ages 5-7. It is anticipated that these new scales will have application for younger pediatric populations when pediatric self-report is not feasible. PMID- 23740168 TI - The association between motor vehicle injuries and health-related quality of life: a longitudinal study of a population-based sample in the United States. AB - PURPOSE: As many as 3 million US residents are injured in traffic-related incidents every year leaving many victims with disabling conditions. To date, limited numbers of studies have examined the effects of traffic-related injuries on self-reported health. This study aims to examine the association between health-related quality of life (HRQOL) and traffic-related injuries longitudinally in a nationally representative sample of US adult population. METHODS/APPROACH: This is a longitudinal study of adult participants (age >=18) from seven panels (2000-2007) of the Medical Expenditure Panel Survey. The dependent variables included the physical and mental components of the SF-12, a measure of self-reported health. The outcome was assessed twice during the follow up period: round 2 (~4-5 months into the study) and round 4 (~18 months into the study) for 62,298 individuals. Two methods estimate the association between traffic-related injuries and HRQOL: a within person change using paired tests and a between person change using multivariable regression adjusting for age, sex, income and educational level. RESULTS: Nine hundred and ninety-three participants reported traffic-related injuries during the follow-up period. Compared to their pre-crash HRQOL, these participants lost 2.7 of the physical component score while their mental component did not change. Adjusted results showed significant deficits in the physical component (-2.84, p value = <.001) but not the mental component (-0.07, p value = .83) of HRQOL after controlling for potential confounders. CONCLUSION: Traffic injuries were significantly associated with the physical component of HRQOL. These findings highlight the individual and societal burden associated with motor vehicle crash-related disability in the United States. PMID- 23740169 TI - The relevance of relevance in research. AB - A new Swiss law requires that any research involving humans must aim to answer "a relevant research question". This paper explains the relevance of the relevance criterion in research, analyses the Swiss and British guidelines on relevance, and proposes a framework for researchers and research ethics committee (REC) members that enables a clearer conception of the role of relevance in research. We conclude that research must be either scientifically or societally beneficial in order to qualify as relevant, and RECs therefore cannot avoid reviewing the scientific aspects of proposed studies. Normally only scientifically relevant studies can be of benefit to society, but research of low scientific relevance can nonetheless be relevant to society if it forms part of the education of new doctors and scientists. PMID- 23740170 TI - Continuities and changes in the friendships of children with and without ADHD: a longitudinal, observational study. AB - We examined how the real-life dyadic friendships of 87 children with ADHD and 46 comparison children (76 % boys) aged 7-13 years evolved during a 6-month follow up period. The methods included friendship quality self-report measures and direct observation of friends' dyadic behaviors in three structured analogue tasks. At Time 2, the friends of the participants with ADHD reported less positive friendship quality and more conflict with their friends than at Time 1. They were also considerably less satisfied with their friendship than 6 months prior. In contrast, the friends of comparison children reported fewer negative friendship features, more positive friendship features and a slightly greater friendship satisfaction than at Time 1. In sharp contrast with the invited friends' reports, referred children with ADHD did not report deterioration in their friendship quality over time. Unlike comparison children who significantly reduced violations of game rules between Time 1 and Time 2, children with ADHD broke more game rules during the same period. In negotiating with friends, comparison children, but not children with ADHD, reduced the number of self centered and insensitive proposals at Time 2. Controlling for Time 1 variance, violations of game rules and a self-centered, insensitive negotiation approach predicted deterioration in friendship quality for children with and without ADHD over time. PMID- 23740171 TI - Cognitive vulnerability to depressive symptoms in children: the protective role of self-efficacy beliefs in a multi-wave longitudinal study. AB - The current multi-wave longitudinal study on childhood examined the role that social and academic self-efficacy beliefs and cognitive vulnerabilities play in predicting depressive symptoms in response to elevations in idiographic stressors. Children (N = 554; males: 51.4 %) attending second and third grade completed measures of depressive symptoms, negative cognitive styles, negative life events, and academic and social self-efficacy beliefs at four time-points over 6 months. Results showed that high levels of academic and social self efficacy beliefs predicted lower levels of depressive symptoms, whereas negative cognitive styles about consequences predicted higher depression. Furthermore, children reporting higher social self-efficacy beliefs showed a smaller elevation in levels of depressive symptoms when reporting an increases in stress than children with lower social self-efficacy beliefs. Findings point to the role of multiple factors in predicting children's depression in the long term and commend the promotion of self-efficacy beliefs and the modification of cognitive dysfunctional styles as relevant protective factors. PMID- 23740172 TI - The Arnold Berliner Award 2013. PMID- 23740173 TI - Standards of evidence for bioluminescence in cockroaches. PMID- 23740174 TI - Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy. AB - IMPORTANCE: The role of interval appendectomy after conservative management of perforated appendicitis remains controversial. Determining the etiology of perforated appendicitis is one reason to perform interval appendectomies. OBJECTIVE: To determine whether adult patients undergoing interval appendectomy experience an increased rate of neoplasms. DESIGN: Retrospective study. SETTING: A single tertiary care institution. PARTICIPANTS: All patients 18 years or older who underwent appendectomy for presumed appendicitis from January 1, 2006, through December 31, 2010. EXPOSURES Appendectomy for presumed appendicitis. MAIN OUTCOMES AND MEASURES: Underlying neoplasm as the cause of presentation for presumed appendicitis. Demographic data, clinicopathologic characteristics, interval resection rate, and complication data were collected and analyzed. RESULTS: During the study period, 376 patients underwent appendectomies. Interval appendectomy was performed in 17 patients (4.5%). Neoplasms were identified in 14 patients (3.7%); 5 of those tumors occurred in patients who had undergone interval appendectomy (29.4%). Nine neoplasms were mucinous tumors (64.3%), including all neoplasms associated with interval appendectomies. The mean age of all patients with appendiceal tumors was 49 years (range, 35-74 years). CONCLUSIONS AND RELEVANCE: Mucinous neoplasms of the appendix were found in 5 of 17 patients (29.4%) undergoing interval appendectomy. Interval appendectomies should be considered in all adult patients, especially those 40 years or older, to determine the underlying cause of appendicitis. A multi-institutional study to determine the generalizability of these findings is warranted. PMID- 23740175 TI - [Medical tourism and travel - an interdisciplinary approach]. AB - BACKGROUND: Medical tourism (or medical travel, international patient service, cross-border or global health care) is a new current phenomenon with increasing relevance for the two disciplines of medicine and tourism. Both sides hope to improve their reputation and image, as well as to increase their revenues and rate of employment; furthermore, they want to provide better care and service for patients and tourists: Medical tourism can close the gap of the health care system at home, providing better quality, quicker access and cheaper procedures abroad, also with treatments, not - legally - available in the sending country. For the tourism sector it broadens the variety of tourism products and supply of the host country and combines medical treatments and recovery with an attractive stay in a tourism destination for patients and their companions. But in spite of all popularity of this new type of tourism and treatment, there is quite a lack of theory and academic analysis. METHODS: This article outlines the status quo of scientific research both from a medical and tourism point of view. This interdisciplinary method of approach is based mainly on a state-of-the art review of the current literature. CONCLUSIONS: There is a great need for more scientific research in the field of medical tourism, based on the common knowledge of both disciplines tourism and medicine. First there is neither an internationally agreed definition nor a common methodology for data collection. So the real impact of touristic and medical services both for the source and for the receiving countries is un-known and imprecise. Second the internal processes of the health system have to be adapted to the needs of international patients, e. g., medical fee schedule, billing, language, inter-cultural qualifications of the staff. Moreover the whole service chain has to be taken into account, especially the pre- and post-processes, which mostly start or end abroad. Here quality standards as well as accreditations are current issues. Furthermore, several sociocultural impacts need to be analysed, such as making health care less affordable for local patients and/or moral and ethical concerns about certain treatment methods. Another area concerns the legal questions of risk, liability and malpractice. PMID- 23740176 TI - Scleroderma-like hands in a 16-year-old boy. Congenital erythropoetic porphyria (CEP). PMID- 23740177 TI - Increased expression of cell adhesion molecule receptors on monocyte subsets in ischaemic heart failure. AB - The objective of this study was to evaluate the expression of cell adhesion molecule (CAM) receptors (integrins) on monocyte subsets in heart failure (HF) and examine their prognostic implication.Increased levels of soluble CAMs have been observed in patients with HF, but the precise mechanism of monocyte adhesion to the vascular endothelium remains unknown. Patients with acute HF (AHF, n=51) were compared to those with stable HF (SHF, n=42) and stable coronary artery disease (CAD, n=44) without HF. Expression of integrins-receptors to intercellular adhesion molecule-1 (ICAM-1R) and vascular CAM-1 (VCAM-1R) on monocyte subsets was assessed by flow cytometry. Monocyte subsets were defined as CD14++CD16-CCR2+ ('classical', Mon1), CD14++CD16+CCR2+ ('intermediate', Mon2), and CD14+CD16++CCR2- ('non-classical', Mon3). Compared to patients with SHF, those with AHF had significantly higher expression of ICAM-1R on Mon2 (p=0.01). Compared to those with stable CAD, patients with SHF had a significantly higher expression of ICAM-1R on Mon2 (p=0.025).Compared to SHF, patients with AHF had a similar expression of VCAM-1R on both Mon1 and Mon3 but significantly higher expression on Mon2 (p=0.019). There were no significant differences between SHF and CAD in monocyte expression of VCAM-1R. In multivariate Cox regression analysis, VCAM-1R expression on Mon2 was associated with adverse clinical outcome (death or rehospitalisation) in AHF [HR 1.07 (1.01-1.14), p=0.029]. In conclusion, HF is associated with increased monocyte expression of integrins receptors to both ICAM-1 and VCAM-1, being particularly linked to Mon2 subset. Expression of VCAM-1R on Mon2 may have prognostic value in patients with AHF. PMID- 23740178 TI - Parental allografts in the management of Adams-Oliver syndrome. PMID- 23740179 TI - A versatile strategy to the selective synthesis of Cu nanocrystals and the in situ conversion to CuRu nanotubes. AB - Compared with Ag, Au, Pt and Pd, the synthesis of Cu nanocrystals that exhibit well-defined structures and surface properties has achieved limited success. Herein, we report an etching and protecting strategy to prepare Cu nanostructures with controllable shapes, crystalline nature and surface properties. In the developed strategy, the selective use of different additives is critical to the successful synthesis of the Cu nanocrystals: while NH4Cl (or hexadecyltrimethylammonium chloride (CTAC)) functions as an etchant by a Cl(-)-O2 pair that can selectively remove twinned nuclei and induce the formation of single nanocrystals with a cubic morphology, the addition of RuCl3 (or FeCl3, FeCl2) can protect the multiply twinned seeds from being etched, and leads to the formation of 5-fold twined nanowires. The controlling strategy reported herein is highlighted by its simplicity and versatility. By further increasing the reaction temperature and prolonging the reaction time, bimetallic CuRu nanotubes can be readily prepared. The applications of these well-defined nanostructures and the developed strategy in controlling other metals are currently under investigation. PMID- 23740180 TI - Sensitivity and specificity of Ankara University Cerebral Dominance Inventory in comparison with the Wada test. AB - We aimed to examine the sensitivity and specificity of the Ankara University Cerebral Dominance Inventory (AUCDI) in determining left cerebral dominance compared with the Wada test. The AUCDI and Wada test were applied to 49 patients referred to Ankara University for epilepsy surgery. Hand, foot and 'total' preference scores were specified according to the results of the inventory. Thirty-eight of the patients had left cerebral dominance and 11 had atypical cerebral dominance for language. 86 % of the patients were right-handed and 43 % were right-footed. When compared with the results of the Wada test, the sensitivity of the AUCDI for each 'total preference', and hand and foot preference was 90, 95 and 50 % and specificity was 46, 46 and 82 %, respectively. The percentage of right-footed patients was low when compared with the other studies. This difference might result from the method used for assessing foot preference by the actual demonstration of the task rather than just asking about the performance. The AUCDI was found to be sensitive in terms of 'total preference' and hand preference, and specific in terms of foot preference for determining the left hemisphere dominance in patients preferring the right side. It was a cheap and noninvasive alternative to the Wada test, appropriate for clinical bedside evaluation. PMID- 23740181 TI - Anomalous posterior inferior cerebellar artery crossing the C1-2 facet in patient with atlanto-axial dislocation associated with down's syndrome. PMID- 23740182 TI - Treatment of distal radial fractures with antegrade intra-medullary Kirschner wires. AB - The treatment of unstable Colles-type distal radial fractures remains a challenge. A prospective study was conducted to evaluate the outcomes of the treatment of unstable distal radial fractures using antegrade intra-medullary K wires. Twenty-eight Colles-type distal radial fractures were selected excluding comminuted intra-articular and Barton's fractures. The blunt tips of intra medullary K-wires were introduced in an antegrade direction to support the subchondral bone of the distal fragment. The scoring system of Green and O'Brien modified by Cooney et al. was used for the final clinical evaluation. The radiological outcomes were evaluated using the scale proposed by Stewart et al. After a mean follow-up of 34 months (range 14-46), 17 patients were rated clinically excellent, seven good, three fair and one poor. The mean loss of radial height, radial inclination, volar tilt and ulnar variance was 0.9 mm, 1.9 degrees , 0.5 degrees and 0.4 mm, respectively. These results were comparable with the values reported in other pinning studies. Only one patient complained of skin irritation and painful bursitis in the forearm; otherwise, no complications related to tendon or nerve injury were encountered. One patient had protrusion of K-wire into the wrist joint. The technique proved to be effective in maintaining reduction in distal radial fracture with low rate of soft tissue complications. PMID- 23740185 TI - Progestin as an alternative treatment option for multi-treated recurrent triple negative breast cancer. AB - OBJECTIVE: Patients with recurrent triple-negative breast cancer (TNBC) currently have no established treatment option other than chemotherapy. However, long-term chemotherapy is often difficult due to adverse effects. A previous study documented a 10%-30% response rate of progestins in oestrogen receptor-negative breast cancer. The aim of this study was to investigate the effect of medroxyprogesterone/megestrol acetate (MPA/MA) in patients with recurrent TNBC. METHODS: This retrospective observational analysis included 51 patients with recurrent TNBC; 17 were treated with MPA/MA and 34 underwent chemotherapy. The two groups were matched at a 1:2 ratio according to age, metastatic sites, and salvage treatment lines. Efficacy was compared using the chi2 and rank-sum tests. Progression-free survival (PFS) was calculated using the Kaplan-Meier method, and the two groups were compared using the log-rank test. RESULTS: The two groups were well balanced in terms of age, disease-free survival, number of metastases, and salvage therapy lines. Clinical benefit rates in the MPA/MA and chemotherapy groups were 52.94% and 73.53%, respectively (chi2 test, p = 0.208), and median PFS was comparable between groups (log-rank test, p = 0.135). Median PFS of 1st 6th-line salvage treatments was shorter in the MPA/MA group than in the chemotherapy group (log-rank test, p = 0.036), but median PFS of >=7th-line salvage treatments was comparable (log-rank test, p = 0.139). Eight patients discontinued chemotherapy due to adverse effects, and one patient withdrew from MPA treatment because of weight gain. CONCLUSIONS: Progestins (MPA/MA) are an alternative treatment option for multi-treated recurrent TNBC. PMID- 23740184 TI - Classifying human audiometric phenotypes of age-related hearing loss from animal models. AB - Age-related hearing loss (presbyacusis) has a complex etiology. Results from animal models detailing the effects of specific cochlear injuries on audiometric profiles may be used to understand the mechanisms underlying hearing loss in older humans and predict cochlear pathologies associated with certain audiometric configurations ("audiometric phenotypes"). Patterns of hearing loss associated with cochlear pathology in animal models were used to define schematic boundaries of human audiograms. Pathologies included evidence for metabolic, sensory, and a mixed metabolic + sensory phenotype; an older normal phenotype without threshold elevation was also defined. Audiograms from a large sample of older adults were then searched by a human expert for "exemplars" (best examples) of these phenotypes, without knowledge of the human subject demographic information. Mean thresholds and slopes of higher frequency thresholds of the audiograms assigned to the four phenotypes were consistent with the predefined schematic boundaries and differed significantly from each other. Significant differences in age, gender, and noise exposure history provided external validity for the four phenotypes. Three supervised machine learning classifiers were then used to assess reliability of the exemplar training set to estimate the probability that newly obtained audiograms exhibited one of the four phenotypes. These procedures classified the exemplars with a high degree of accuracy; classifications of the remaining cases were consistent with the exemplars with respect to average thresholds and demographic information. These results suggest that animal models of age-related hearing loss can be used to predict human cochlear pathology by classifying audiograms into phenotypic classifications that reflect probable etiologies for hearing loss in older humans. PMID- 23740186 TI - Explaining fatigue in ANCA-associated vasculitis. AB - OBJECTIVES: To identify the determinants of fatigue among patients with ANCA associated vasculitis (AAV). METHODS: A multicentre cross-sectional study was conducted. Subjects fulfilling the European Medicines Agency criteria for granulomatosis with polyangiitis (Wegener's), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) were approached according to consecutive clinic attendance and invited to complete a questionnaire assessing fatigue and putative biopsychosocial determinants of this symptom. Concurrently, potential clinical determinants were recorded. Independent associations of fatigue were identified using forward stepwise logistic regression modelling and their overall impact expressed as population attributable risk (PAR). RESULTS: The majority (74.8%) of participants (n = 410) reported high levels of fatigue that were found to be significantly associated with numerous biopsychosocial and clinical factors. Sleep disturbance [odds ratio (OR) 5.3, 95% CI 2.7, 10.5] and pain (OR 3.8, 95% CI 2.0, 7.3) were the strongest independent associations of fatigue and, on a population level, each was more than twice as important as any other putative determinant (PAR 18.1% and 16.5%, respectively). Female gender (OR 2.1, 95% 1.1, 4.0), elevated CRP (OR 3.7, 95% CI 1.7, 8.1) and the dysfunctional coping strategies of behavioural disengagement (OR 2.4, 95% CI 1.04, 5.6) and denial (OR 2.4, 95% CI 0.9, 6.7) were also independently associated with fatigue. CONCLUSION: The data suggest that AAV related fatigue is multifactorial in origin. Sleep disturbance and pain were found to be most important, although inflammation, as measured by CRP, was also associated. This study has identified potentially modifiable determinants that will inform future interventions aimed at alleviating fatigue. PMID- 23740187 TI - Treatment choices of paediatric rheumatologists for juvenile idiopathic arthritis: etanercept or adalimumab? AB - OBJECTIVES: To evaluate differences in baseline characteristics between etanercept- and adalimumab-treated JIA patients and to reveal factors that influence the choice between these TNF inhibitors, which are considered equally effective in the recent ACR recommendations for JIA treatment. METHODS: Biologic naive JIA patients with active arthritis who started treatment with adalimumab or etanercept between March 2008 and December 2011 were selected from the Dutch Arthritis and Biologicals in Children register. Baseline characteristics were compared. Focus group interviews with paediatric rheumatologists were performed to evaluate factors determining treatment choices. RESULTS: A total of 193 patients started treatment with etanercept and 21 with adalimumab. Adalimumab treated patients had longer disease duration prior to the start of biologics (median 5.7 vs 2.0 years) and more often a history of uveitis (71% vs 4%). Etanercept-treated patients had more disability at baseline (median Childhood Health Assessment Questionnaire score 1.1 vs 0.4) and more active arthritis (median number of active joints 6 vs 4). The presence of uveitis was the most important factor directing the choice towards adalimumab. Factors specific for the paediatric population-such as painful adalimumab injections-as well as the physician's familiarity with the drug accounted for the preference for etanercept. CONCLUSION: Although the two TNF inhibitors are considered equally effective, in daily practice etanercept is most often prescribed; adalimumab is mainly preferred when uveitis is present. In choosing the most suitable biologic treatment, paediatric rheumatologists take into account drug and patient factors, considering newly published data and cautiously implementing this into daily care. PMID- 23740188 TI - Evidence that two distinct crypt cell types secrete chloride and potassium in human colon. AB - BACKGROUND: Human colon may secrete substantial amounts of water secondary to chloride (Cl(-)) and/or potassium (K(+)) secretion in a variety of diarrhoeal diseases. Ion secretion occurs via Cl(-) and K(+) channels, which are generally assumed to be co-located in the colonocyte apical membrane, although their exact cellular sites remain unclear. OBJECTIVE: To investigate the location of apical Cl(-) (CFTR) and apical K(+) (large conductance; BK) channels within human colonic epithelium. DESIGN: Whole-cell patch clamp recordings were obtained from intact human colonic crypts. Specific blockers of K(+) channels and CFTR identified different types of K(+) channel and CFTR under resting conditions and after stimulating intracellular cAMP with forskolin. The BK channel beta3-subunit was localised by immunostaining. RESULTS: Two types of crypt cells were identified. One (73% of cells) had whole-cell currents dominated by intermediate conductance (IK) K(+) channels under resting conditions, which developed large CFTR-mediated currents in response to increasing intracellular cAMP. The other (27% of cells) had resting currents dominated by BK channels inhibited by the BK channel blocker penitrem A, but insensitive to both forskolin and the IK channel blocker clotrimazole. Immunostaining showed co-localisation of the BK channel beta3-subunit and the goblet cell marker, MUC2. CONCLUSIONS: In human colon, Cl( ) secretion originates from the dominant population of colonocytes expressing apical CFTR, whereas K(+) secretion is derived from a smaller population of goblet cells expressing apical BK channels. These findings provide new insights into the pathophysiology of secretory diarrhoea and should be taken into account during the development of anti-diarrhoeal drugs. PMID- 23740189 TI - Western lifestyle: a 'master' manipulator of the intestinal microbiota? PMID- 23740190 TI - Perforated tuberculosis lymphadenitis. AB - A 26-year-old man (human immunodeficiency virus-positive and not taking highly active antiretroviral treatment [HAART]) presented to the emergency room with 2 months of malaise, 20 kg weight loss, high spiking fevers, generalized lymph nodes, night sweats, dry cough, and chest pain when swallowing. On physical examination, he had multiple cervical lymphadenopathies. Suspecting a systemic opportunistic infection, a contrasted chest computed tomography (CT) was done, showing an esophageal to mediastinum fistulae. Two days after admission, a fluoroscopic contrasted endoscopy was done that showed two esophageal fistulae from scrofula to esophagus and then, to mediastinum. A bronchoalveolar lavage and a cervical lymphadenopathy biopsy were done, both showing multiple acid-fast bacillae, where cultures grew Mycobacterium tuberculosis. PMID- 23740193 TI - Hepatitis B and C in Switzerland - healthcare provider initiated testing for chronic hepatitis B and C infection. AB - Hepatitis B and hepatitis C are contagious liver diseases caused by the hepatitis B virus (HBV) and the hepatitis C virus (HCV), respectively. In particular, chronic infection with HBV or HCV is a major public health problem throughout Europe. The majority of persons chronically infected (65%-75%) are not aware of their infection status until symptoms of advanced liver disease appear. In addition, the peak in the number of patients suffering from advanced stages of the disease, such as cirrhosis and hepatocellular carcinoma, has not yet been reached. In order to reduce the current and future morbidity and mortality associated with chronic HBV or HCV infection, the timely detection of chronically infected persons, with follow-up and case management, is crucial. However, the current screening strategies in Europe and Switzerland have to be considered as inadequate to detect the majority of chronically infected persons. Hence, we emphasise the importance of an alternative approach: the healthcare provider initiated identification of HBV or HCV infection in defined risk groups. This entails determining whether a person is not only at risk of being chronically infected, but also at risk of becoming infected with HBV or HCV and, if necessary, testing for HBV or HCV infection. PMID- 23740194 TI - Effects of triple antioxidant therapy on measures of cardiovascular autonomic neuropathy and on myocardial blood flow in type 1 diabetes: a randomised controlled trial. AB - AIMS/HYPOTHESIS: We evaluated the effects of a combination triple antioxidant therapy on measures of cardiovascular autonomic neuropathy (CAN) and myocardial blood flow (MBF) in patients with type 1 diabetes. METHODS: This was a randomised, parallel, placebo-controlled trial. Participants were allocated to interventions by sequentially numbered, opaque, sealed envelopes provided to the research pharmacist. All participants and examiners were masked to treatment allocation. Participants were evaluated by cardiovascular autonomic reflex testing, positron emission tomography with [(11)C]meta-hydroxyephedrine ([(11)C]HED) and [(13)N]ammonia, and adenosine stress testing. Markers of oxidative stress included 24 h urinary F2-isoprostanes. Diabetic peripheral neuropathy (DPN) was evaluated by symptoms, signs, electrophysiology and intra epidermal nerve fibre density. Randomised participants included 44 eligible adults with type 1 diabetes and mild-to-moderate CAN, who were aged 46 +/- 11 years and had HbA1c 58 +/- 5 mmol/mol (7.5 +/- 1.0%), with no evidence of ischaemic heart disease. Participants underwent a 24-month intervention, consisting of antioxidant treatment with allopurinol, alpha-lipoic acid and nicotinamide, or placebo. The main outcome was change in the global [(11)C]HED retention index (RI) at 24 months in participants on the active drug compared with those on placebo. RESULTS: We analysed data from 44 participants (22 per group). After adjusting for age, sex and in-trial HbA1c, the antioxidant regimen was associated with a slight, but significant worsening of the global [(11)C]HED left ventricle RI (-0.010 [95% CI -0.020, -0.001] p = 0.045) compared with placebo. There were no significant differences at follow-up between antioxidant treatment and placebo in the global MBF, coronary flow reserve, or in measures of DPN and markers of oxidative stress. The majority of adverse events were of mild to-moderate severity and did not differ between groups CONCLUSIONS/INTERPRETATION: In this cohort of type 1 diabetes patients with mild to-moderate CAN, a combination antioxidant treatment regimen did not prevent progression of CAN, had no beneficial effects on myocardial perfusion or DPN, and may have been detrimental. However, a larger study is necessary to assess the underlying causes of these findings. PMID- 23740195 TI - Setting the record straight on TIDE: a lost opportunity for patients with diabetes. AB - Much has been written regarding the recently discontinued Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE) trial (ClinicalTrials.gov NCT00879970; Diabetologia 55: 36-45) and a variety of opinions have been advanced regarding its purpose, context and design (N Engl J Med 397: 959-964). As such, we deemed it appropriate to clarify TIDE's objectives, research questions and design and the clinical equipoise regarding its research questions. PMID- 23740196 TI - Predictors of 1-year mortality in patients with contemporary guideline-adherent therapy after acute myocardial infarction: results from the OMEGA study. AB - BACKGROUND: Predictors of long-term mortality after discharge after acute myocardial infarction (AMI) are well characterized. However, these established risk factors are based on data almost exclusively derived from older studies without consistent use of revascularization therapy and adjunctive therapy with statins, platelet inhibitors, beta-blockers and ACE inhibitors/ARBs. We therefore sought to investigate predictors of 1-year mortality in survivors of AMI treated with contemporary guideline-adherent therapy. METHODS AND RESULTS: We performed a retrospective analysis of 3,782 patients surviving acute ST-elevation and non ST elevation myocardial infarction who were enrolled in the prospective, randomized, double-blind, controlled OMEGA trial with 104 German centers. The primary objective of the OMEGA study was to determine the effect of highly purified omega 3 fatty acid ethyl esters-90 on the rate of sudden cardiac death in patients surviving AMI and receiving current guideline-adherent treatment within the 1 year of follow-up. 80.8 % of the patients received early revascularization therapy. At discharge, 94.2 % of the patients received beta-blocker, 90.4 % ACE inhibitor/angiotensin receptor blocker, 94.3 % statin, 95.4 % aspirin and 88.4 % clopidogrel. During the 1-year follow-up 139 patients (3.7 %) died. Multivariate logistic regression analysis revealed the following independent predictors of 1 year mortality in decreasing order of importance: ejection fraction <45 % [odds ratio (OR) 2.28, 95 % confidence interval (CI) 1.53-3.41], age >=70 years (OR 2.17, 95 % CI 1.42-3.32), no acute revascularization (OR 2.02, 95 % CI 1.33 3.08), prior stroke/transient ischemic attack (OR 1.90, 95 % CI 1.09-3.30), peripheral arterial disease (OR 1.86, 95 % CI 1.12-3.10), heart rate >85/min (OR 1.82, 95 % CI 1.23-2.71), chronic obstructive lung disease (OR 1.77, 95 % CI 1.01 3.10) and HDL cholesterol <40 mg/dl (OR 1.75, 95 % CI 1.15-2.67). CONCLUSIONS: In patients surviving AMI and treated with contemporary guideline-adherent therapy, 1-year mortality was low. Nevertheless, traditional risk factors such as ejection fraction <45 %, older age, no acute revascularization and comorbidities were the strongest predictors of long-term mortality supporting the findings from previous studies. PMID- 23740197 TI - Severity of cardiac impairment in the early stage of community-acquired sepsis determines worse prognosis. AB - INTRODUCTION: In sepsis, the reduced systemic vascular resistance (SVR) can lead to a compensatory increase in cardiac output (CO). This may mimic a normal cardiac function although there is already a sepsis-induced myocardial depression. On a cohort of patients with septic multi-organ dysfunction syndrome, we have recently developed a method to correlate the actual CO to the afterload (estimated by SVR) and introduced the parameter "afterload-related cardiac performance" (ACP), which indicates if the rise of CO is adequate for the particular SVR. In this present study it was to be investigated, if ACP can reveal septic cardiomyopathy in patients with community-acquired sepsis in the early state soon after admission to the emergency department (ED), and if there is a prognostic relevance of septic cardiomyopathy defined by ACP. Results were compared to cardiac index (CI) and cardiac power index (CPI). METHODS: Adults presenting at the ED with sepsis were included. ACP, CI and CPI were calculated at the time of admission, after 24, and 72 h. They were correlated to severity of disease and the prognostic values were analyzed. RESULTS: A total of 141 patients were included. Only ACP was significantly influenced by severity of sepsis, whereas CI and CPI were not. ACP was the only hemodynamic parameter predicting mortality: nonsurvivors had lower ACP values at the time of admission to the ED (66.9 vs. 88.9 %, p < 0.05) and ACP predicted non-survival with an AUC value of 0.72, p = 0.003. Cardiac impairment defined by an ACP value of 80 % or below determined worse prognosis. CONCLUSIONS: Septic cardiomyopathy occurs already at the early stage of disease and is of prognostic relevance. It might be recognized best, if cardiac function is correlated to afterload. PMID- 23740199 TI - Biofilms on tuff stones at historical sites: identification and removal by nonthermal effects of radiofrequencies. AB - A methodology aiming at identifying and removing biofilms from cultural heritage was applied to stones from tuff walls in historical sites. Identification of phototrophic encrusting microorganisms was carried out by optical and electron microscopy, as well as by molecular techniques (DNA analyses and denaturing gradient gel electrophoresis (DGGE)). In all sites, the examination of microbial components of biofilms resulted in the identification of 17 species belonging to Cyanobacteria, Rhodophyta, Bacillariophyta and Chlorophyta, with Cyanobacteria being the dominant components in all biofilms. In order to remove the biofilms, an innovative technique based on the use of nonthermal effects of radiofrequencies was adopted. The source of the electromagnetic fields was a signal generator connected to a horn antenna through an amplifier to provide the power boost required to generate the target field amplitude. Seven days after exposure to radiofrequency electromagnetic field, about 50 % reduction of biofilm was observed; after 14 days, biofilm extension was reduced by about 90 %. DGGE analyses performed after 14 days confirmed these visual inspections. Also, DGGE analyses carried out before and 14 days after treatments showed that 12 out of 17 identified species disappeared. A complete visual disappearance of biofilms was observed a month after the beginning of treatments. DGGE repeated at this time confirmed the total disappearance of biofilm-forming species. Treated stones, when transferred back to their original sites, did not show any microorganism re growing after 6 months. No alteration in the color and structural consistency of tuff substrata was observed after radiofrequency treatments. PMID- 23740200 TI - Effectiveness of using the Modified Checklist for Autism in Toddlers in two-stage screening of autism spectrum disorder at the 18-month health check-up in Japan. AB - To determine whether the Modified Checklist for Autism in Toddlers (M-CHAT) in conjunction with the routine 18-month health check-up identifies Japanese toddlers with autism spectrum disorder (ASD). Two-stage screening using the M CHAT was conducted with 1,851 children attending the check-up. Final ASD diagnosis was confirmed at age >=3 years. Screening identified 20/51 children with ASD: 12/20 true positives were developmentally delayed, whereas 16/22 false negatives were high-functioning. Sensitivity was 0.476, specificity 0.986, positive predictive value 0.455, and likelihood ratio 33.4 for children with ASD. With a few modifications, M-CHAT screening successfully detected toddlers with ASD with and without developmental delay and is a promising screening tool to complement existing community surveillance. PMID- 23740201 TI - Antibodies against thrombin in dengue patients contain both anti-thrombotic and pro-fibrinolytic activities. AB - Dengue virus (DENV) infection may result in severe life-threatening Dengue haemorrhagic fever (DHF). The mechanisms causing haemorrhage in those with DHF are unclear. In this study, we demonstrated that antibodies against human thrombin were increased in the sera of Dengue patients but not in that of patients infected with other viruses. To further characterise the properties of these antibodies, affinity-purified anti-thrombin antibodies (ATAs) were collected from Dengue patient sera by thrombin and protein A/L affinity columns. Most of the ATAs belonged to the IgG class and recognized DENV nonstructural protein 1 (NS1). In addition, we found that dengue patient ATAs also cross reacted with human plasminogen (Plg). Functional studies in vitro indicated that Dengue patient ATAs could inhibit thrombin activity and enhance Plg activation. Taken together, these results suggest that DENV NS1-induced thrombin and Plg cross-reactive antibodies may contribute to the development of haemorrhage in patients with DHF by interfering with coagulation and fibrinolysis. PMID- 23740202 TI - Obstructions to understanding malignant bowel obstruction. PMID- 23740203 TI - Importance of leadership in cardiac arrest situations: from simulation to real life and back. AB - The 2010 American Heart Association guidelines now recommend leadership training in Advanced Cardiac Life Support courses. In this review we provide a comprehensive summary of data derived from clinical studies that investigated the importance of leadership in cardiopulmonary resuscitation (CPR). Only a few, mostly observational, studies have been conducted under real-life conditions because of the high heterogeneity of the situations, difficulties in capturing the initial phase of CPR, and ethical issues. Well-controlled studies in the human simulator can fill existing gaps and provide important insights. High fidelity video-assisted simulator studies from different research groups have shown that a prolonged process of teambuilding is associated with significant shortcomings in CPR, whereas effective leadership improves team performance. In addition, randomised controlled studies have provided evidence that medical students receiving leadership training subsequently showed improved CPR performance, which was sustained after a follow up of 4 months. In addition, leadership is influenced by gender and other factors such as emotional stress. Future studies are needed to investigate cultural differences and how findings from the simulator can be transferred to real-life situations. PMID- 23740204 TI - Fertility preservation in young females with non-gynaecologic malignancy: an emerging speciality. AB - BACKGROUND: As new treatment and research advances continue to improve the prognosis of cancer patients, oncologists and surgeons are increasingly faced with the issue of fertility protection and preservation. Cancer patients are frequently exposed to gonadotoxic chemotherapy and radiation therapy as a component of their treatment regimens. There are currently various anticipatory techniques available to women who wish to retain future reproductive ability, the most successful of which involves oocyte retrieval followed by in vitro fertilisation and embryo cryopreservation. Innovative methods include oocyte cryopreservation, ovarian follicle cryopreservation and oophoropexy. AIM: The aim of this study was to examine our combined experiences at Mayo General Hospital of treating female patients (<30 years) with non-gynaecologic malignancy and requiring referral to the HARI Unit during a 6-year period (2007-2012). Emphasis was placed on reviewing the fertility-preservation options available. METHODS: The hospital inpatient enquiry system was inspected for all cases of non gynaecologic malignancy referred for fertility preservation from 2007 to 2012. RESULTS: Three cases of non-gynaecologic malignancy in young females, with an intention to protect and preserve future fertility were identified. The primary treatment plan did not initially incorporate input from a gynaecology or fertility specialist. It was after concerted inquiry and reflection by both physician and patient that oncofertility consultation was sought. CONCLUSION: The responsibility is on both physicians and surgeons to consider a more holistic approach to cancer care in young female patients, which focuses not only on the elimination of malignancy but also on preservation of fertility and quality of life. PMID- 23740205 TI - Multigene engineering of starch biosynthesis in maize endosperm increases the total starch content and the proportion of amylose. AB - Maize (Zea mays spp. mays) is a staple crop for more than 900 million people. The seeds or kernels provide a rich source of calories because ~70% of the weight is carbohydrate, mostly in the form of starch. The content and composition of starch are complex traits controlled by many genes, offering multiple potential targets for intervention. We used a multigene engineering approach combining the overexpression of Bt2, Sh2, Sh1 and GbssIIa (to enhance the activity of sucrose synthase, AGPase and granule-bound starch synthase) with the suppression of SbeI and SbeIIb by RNA interference (to reduce the activity of starch branching enzyme). Maize plants expressing all six genes plus the selectable marker showed a 2.8-7.7% increase in the endosperm starch content and a 37.8-43.7% increase in the proportion of amylose, which was significant compared to untransformed control plants. We also observed improvements in other agronomic traits, such as a 20.1-34.7% increase in 100-grain weight, a 13.9-19.0% increase in ear weight, and larger kernels with a better appearance, presumably reflecting the modified starch structure within the kernels. Our results confirm that multigene engineering applied to the starch biosynthesis pathway can not only modulate the quality and quantity of starch but can also improve starch-dependent agronomic traits. PMID- 23740207 TI - Optically isotropic responses induced by discrete rotational symmetry of nanoparticle clusters. AB - Fostered by the recent progress of the fields of plasmonics and metamaterials, the seminal topic of light scattering by clusters of nanoparticles is attracting enormous renewed interest gaining more attention than ever before. Related studies have not only found various new applications in different branches of physics and chemistry, but also spread rapidly into other fields such as biology and medicine. Despite the significant achievements, there still exists unsolved but vitally important challenges of how to obtain robust polarisation-invariant responses of different types of scattering systems. In this paper, we demonstrate polarisation-independent responses of any scattering system with a rotational symmetry with respect to an axis parallel to the propagation direction of the incident wave. We demonstrate that the optical responses such as extinction, scattering, and absorption, can be made independent of the polarisation of the incident wave for all wavelengths. Such polarisation-independent responses are proven to be a robust and generic feature that is purely due to the rotational symmetry of the whole structure. We anticipate our finding will play a significant role in various applications involving light scattering such as sensing, nanoantennas, optical switches, and photovoltaic devices. PMID- 23740206 TI - Genomic stability and long-term transgene expression in poplar. AB - Stable expression of foreign genes over the entire life span of a plant is important for long-lived organisms such as trees. For transgenic forest trees, very little information is available on long-term transgene expression and genomic stability. Independent transgenic lines obtained directly after transformation are initially screened in respect to T-DNA integration and transgene expression. However, very little consideration has been given to long term transgene stability in long-lived forest trees. We have investigated possible genome wide changes following T-DNA integration as well as long-term stability of transgene expression in different transgenic lines of hybrid aspen (Populus tremula * Populus tremuloides) that are up to 19 years old. For studies on possible genome wide changes following T-DNA integration, four different independent rolC-transgenic lines were subjected to an extensive AFLP study and compared to the non-transgenic control line. Only minor genomic changes following T-DNA integration could be detected. To study long-term transgene expression, six different independent rolC-transgenic lines produced in 1993 and since that time have been kept continuously under in vitro conditions. In addition, 18 transgenic plants belonging to eight independent rolC-transgenic lines transferred to glasshouse between 1994 and 2004 were chosen to determine the presence and expression of the rolC gene. In all transgenic lines examined, the rolC gene could successfully be amplified by PCR tests. Both, the 19 years old tissue cultures and the up to 18 years old glasshouse-grown trees revealed expression of the rolC transgene, as demonstrated by the rolC-phenotype and/or northern blot experiments confirming long-term transgene expression. PMID- 23740208 TI - Variants in the promoter region of CYP7A1 are associated with neuromyelitis optica but not with multiple sclerosis in the Han Chinese population. AB - Multiple sclerosis (MS) and neuromyelitis optica (NMO) are common autoimmune demyelinating disorders of the central nervous system. The exact etiology of each remains unclear. CYP7A1 was reported to be associated with NMO in Korean patients, but this is yet to be confirmed in other populations. In this study, we used Sanger sequencing to detect SNPs in the promoter region of CYP7A1 in a population consisting of unrelated patients and controls from the Han Chinese population (129 MS; 89 NMO; 325 controls). Two known SNPs, -204A>C (rs3808607) and -469T>C (rs3824260), and a novel SNP (-208G>C) were identified in the 5'-UTR of CYP7A1. The -204A>C was in complete linkage with -469T>C and both were associated with NMO but not with MS. Results suggest that the CYP7A1 allele was associated with NMO. NMO and MS have different genetic risk factors. This further supports the emerging evidence that MS and NMO are distinct disorders. PMID- 23740209 TI - MicroRNA-98 induces an Alzheimer's disease-like disturbance by targeting insulin like growth factor 1. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by extracellular senile plaques and intracellular neurofibrillary tangles. Many microRNAs (miRs) participate in regulating amyloid beta (Abeta) formation and the metabolism of tau protein in the process of AD, and some are up regulated in AD patients or transgenic models of AD. However, the role of miR-98 in AD remains unclear. Here, we showed that the expression of miR-98 was negatively correlated with the insulin-like growth factor 1 (IGF-1) protein level in APP/PS1 mice. MiR-98 target sites in IGF-1 were confirmed by luciferase assay in HEK293 cells. Overexpression of miR-98 in N2a/APP cells down-regulated the IGF 1 protein level and promoted Abeta production, whereas inhibition of miR-98 in N2a/APP cells up-regulated the IGF-1 protein level and suppressed Abeta production. Furthermore, overexpression of miR-98 in N2a/WT cells increased the phosphorylation of tau, whereas inhibition of miR-98 reduced it. These results suggest that miR-98 increases Abeta formation and tau phosphorylation by inhibiting the translation of IGF-1, which might provide a therapeutic strategy for AD. PMID- 23740210 TI - [Strategies in revision shoulder arthroplasty]. AB - The increasing number of primary shoulder arthroplasty operations is correlated to an increasing revision rate of up to 11.2% for anatomical shoulder arthroplasty and 13.4% for reverse shoulder arthroplasty. To reduce the risk of implant revision the surgeon has to take the possibility of late complications into account for the index operation and to choose a modular implant system. Indications for revision arthroplasty are secondary glenoid wear, aseptic loosening, infections, rotator cuff deficiency, instability, implant malpositioning, mechanical complications and periprosthetic fractures. Due to the high rate of humeral fractures during revision surgery of anatomical stemmed implants (12%) and reverse implants (30%) osteotomy of the humerus is of particular importance. Osteotomy of the humeral shaft with a distal window or transhumeral shaft osteotomy as described by Gohlke can be used. The most demanding step during implantation of the revision implant is the accurate reconstruction of the prosthetic height because the stability, strength of the deltoid muscle and in unfavourable situations the degree of stiffness in the glenohumeral joint all depend on the prosthetic height. The result of anatomical glenoid revision surgery totally depends on the bony defect. Revision glenoid components showed better results compared to glenoid reconstruction using a corticocancellous bone graft but resulted in a higher rate of secondary loosening of the glenoid implant. Cementless glenoid revision implants seem to achieve a higher stability of bony fixation than cemented implants. Due to a better form closure with the reverse humeral implant and a mechanically more favorable loading of the glenoid bone stock, the glenosphere should be implanted with an inferior tilt in revision surgery. PMID- 23740211 TI - Efficacy, tolerability and consumer acceptability of terbinafine topical spray versus terbinafine topical solution: a phase IIa, randomised, observer-blind, comparative study. AB - INTRODUCTION: Tinea pedis is one of the world's most prevalent dermatophyte infections. MedSprayTM tinea pedis 1 % w/w (topical spray) is a novel, easy-to use propellant-based spray formulation containing 1 % w/w terbinafine, requiring no manipulation at the site of infection. This is in contrast to the only formulation currently approved in Europe for single application (none are approved in the USA for single use), which is Lamisil((r)) Once 1 % w/w (topical solution), containing 1 % w/w terbinafine hydrochloride, which requires manipulation on the affected area. OBJECTIVE: The aim of this study was to evaluate the efficacy, tolerability and consumer acceptability of a topical spray versus a topical solution in the treatment of tinea pedis. METHODS: This study is a phase IIa, randomised, observer-blind, non-inferiority comparative study of the topical spray compared with the topical solution over a 12-week study period. The study was conducted at Bioskin GmbH, Hamburg and Berlin. Patients (n = 120) who presented with the presence of interdigital tinea pedis caused by dermatophytes on one or both feet were enrolled in the study. Patients were randomly assigned between the two treatment groups. Either the topical spray or the topical solution was administered by the study nurse and consisted of a single application (equivalent to 20 mg of terbinafine per foot) on day 1 of the study. No further applications were made for the duration of the study. The hypothesis formulated before commencement of the study was that the topical spray would prove to be non-inferior to the topical solution. Efficacy assessments, including clinical signs and symptoms, mycology and microscopy were performed at baseline and 1, 6 and 12 weeks after treatment. RESULTS: The rate of mycological cure at week 1 was statistically equivalent for both treatments. There was a significant reduction in the overall clinical score as assessed by the Physician's Global Assessment of signs and symptoms for both treatment groups. CONCLUSION: The topical spray and the topical solution showed comparable anti-fungal activity. Furthermore, the non-inferiority of topical spray to the topical solution was confirmed as determined by the proportion of patients categorised as successfully treated at week 1. This confirms that a topical spray product, which can be applied once without touching the affected skin, is equally as effective in the treatment of tinea pedis and removes the risk of organism transfer associated with touching infected areas. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT-No. 2008-002399-92. PMID- 23740212 TI - Complementary and alternative medicine in paediatrics: a systematic overview/synthesis of Cochrane Collaboration reviews. AB - BACKGROUND: A high prevalence of complementary and alternative medicine (CAM) use has been documented in children with chronic illnesses. Conversely, evidence based medicine is considered an important contributor in providing the best quality of care. METHODS: We performed a systematic overview/synthesis of all Cochrane reviews published between 1995 and 2012 in paediatrics that assessed the efficacy, and clinical implications and limitations of CAM use in children. Main outcome variables were: percentage of reviews that concluded that a certain intervention provides a benefit, percentage of reviews that concluded that a certain intervention should not be performed, and percentage of studies that concluded that the current level of evidence is inconclusive. RESULTS: A total of 135 reviews were included - most from the United Kingdom (29/135), Australia (24/135) and China (24/135). Only 5/135 (3.7%) reviews gave a recommendation in favour of a certain intervention; 26/135 (19.4%) issued a conditional positive recommendation, and 9/135 (6.6%) reviews concluded that certain interventions should not be performed. Ninety-five reviews (70.3%) were inconclusive. The proportion of inconclusive reviews increased during three, a priori-defined, time intervals (1995-2000: 15/27 [55.6%]; 2001-2006: 33/44 [75%]; and 2007-2012: 47/64 [73.4%]). The three most common criticisms of the quality of the studies included were: more research needed (82/135), low methodological quality (57/135) and small number of study participants (48/135). CONCLUSIONS: Given the disproportionate number of inconclusive reviews, there is an ongoing need for high quality research to assess the potential role of CAM in children. Unless the study of CAM is performed to the same science-based standards as conventional therapies, CAM therapies risk being perpetually marginalised by mainstream medicine. PMID- 23740213 TI - Special issue "Novel perspectives on heart failure". PMID- 23740215 TI - Contributions of cardiomyocyte-cardiac fibroblast-immune cell interactions in heart failure development. AB - The heart contains various types of cells, including cardiomyocytes, cardiac fibroblasts, many kinds of immune cells and vascular cells. Initial studies mainly focused on cardiomyocytes, which directly reflect the contractile function of the heart. Recently, pivotal functions of cardiac fibroblasts have been revealed in the maintenance of cardiac function, physiological cardiac remodeling after heart stress and pathological remodeling using genetically engineered mouse models, like the fibroblast-specific gene knockout mouse, bone marrow transplantation and immune cell-specific gene knockout. Moreover, chronic inflammation is considered to be a basic pathological mechanism that underlies various diseases, including heart failure. In the development of heart failure, the contributions of immune cells like T lymphocytes and monocyte/macrophage lineage cells have been also reported. Immune cells have diverse and multiple functions in regulating both pro-inflammatory effects and the resolution of heart failure. On the one hand, immune cells have protective effects to compensate for and overcome heart stresses. On the other hand, they also contribute to sustained inflammation and result in the development of heart failure. These observations prompted a shift in the heart-related studies to include the complex communications between cardiomyocytes and other kinds of cardiac cells, including inflammatory cells residing in or recruited to the heart. This review will summarize the current knowledge regarding cell-cell interactions during cardiac remodeling and the development of heart failure. We will especially focus on the interactions among cardiomyocytes, cardiac fibroblasts and immune cells. PMID- 23740214 TI - How can we cure a heart "in flame"? A translational view on inflammation in heart failure. AB - The prevalence of chronic heart failure is still increasing making it a major health issue in the 21st century. Tremendous evidence has emerged over the past decades that heart failure is associated with a wide array of mechanisms subsumed under the term "inflammation". Based on the great success of immuno-suppressive treatments in auto-immunity and transplantation, clinical trials were launched targeting inflammatory mediators in patients with chronic heart failure. However, they widely lacked positive outcomes. The failure of the initial study program directed against tumor necrosis factor-alpha led to the search for alternative therapeutic targets involving a broader spectrum of mechanisms besides cytokines. We here provide an overview of the current knowledge on immune activation in chronic heart failure of different etiologies, summarize clinical studies in the field, address unresolved key questions, and highlight some promising novel therapeutic targets for clinical trials from a translational basic science and clinical perspective. PMID- 23740216 TI - Myocardial energetics in heart failure. AB - It has become common sense that the failing heart is an "engine out of fuel". However, undisputable evidence that, indeed, the failing heart is limited by insufficient ATP supply is currently lacking. Over the last couple of years, an increasingly complex picture of mechanisms evolved that suggests that potentially metabolic intermediates and redox state could play the more dominant roles for signaling that eventually results in left ventricular remodeling and contractile dysfunction. In the pathophysiology of heart failure, mitochondria emerge in the crossfire of defective excitation-contraction coupling and increased energetic demand, which may provoke oxidative stress as an important upstream mediator of cardiac remodeling and cell death. Thus, future therapies may be guided towards restoring defective ion homeostasis and mitochondrial redox shifts rather than aiming solely at improving the generation of ATP. PMID- 23740217 TI - Novel aspects of ROS signalling in heart failure. AB - Heart failure and many of the conditions that predispose to heart failure are associated with oxidative stress. This is considered to be important in the pathophysiology of the condition but clinical trials of antioxidant approaches to prevent cardiovascular morbidity and mortality have been unsuccessful. Part of the reason for this may be the failure to appreciate the complexity of the effects of reactive oxygen species. At one extreme, excessive oxidative stress damages membranes, proteins and DNA but lower levels of reactive oxygen species may exert much more subtle and specific regulatory effects (termed redox signalling), even on physiological signalling pathways. In this article, we review our current understanding of the roles of such redox signalling pathways in the pathophysiology of heart failure, including effects on cardiomyocyte hypertrophy signalling, excitation-contraction coupling, arrhythmia, cell viability and energetics. Reactive oxygen species generated by NADPH oxidase proteins appear to be especially important in redox signalling. The delineation of specific redox-sensitive pathways and mechanisms that contribute to different components of the failing heart phenotype may facilitate the development of newer targeted therapies as opposed to the failed general antioxidant approaches of the past. PMID- 23740218 TI - Novel aspects of excitation-contraction coupling in heart failure. AB - Excitation-contraction coupling is the process by which electrical activation is translated into contraction of a cardiac myocyte and thus the heart. In heart failure, expression, phosphorylation, and function of several intracellular proteins that are involved in excitation-contraction coupling are altered. The present review article summarizes central principles and highlights novel aspects of alterations in heart failure, focusing especially on recent findings regarding altered sarcoplasmic reticulum Ca2+ -leak and late Na+ -current without being able to cover all changes in full detail. These two pathomechanisms seem to play interesting roles with respect to systolic and diastolic dysfunction and may also be important for cardiac arrhythmias. Furthermore, the article outlines the translation of these novel findings into potential therapeutic approaches. PMID- 23740219 TI - Epigenetics: a new mechanism of regulation of heart failure? AB - Heart failure is a syndrome resulting from a complex genetic predisposition and multiple environmental factors, and is a leading cause of morbidity and mortality. It is frequently accompanied by changes in heart mass, size, and shape, a process known as pathological cardiac remodeling. At the molecular level, these changes are preceded and accompanied by a specific gene expression program characterized by expression of certain 'fetal' genes. This re-expression of fetal genes in the adult heart contributes to the development of the syndrome. Therefore, counteracting the gene expression changes occurring in heart failure could be a therapeutic approach for this pathology. One mechanism of gene expression regulation that has gained importance is epigenetics. This review gives an overview of the roles of some epigenetic mechanisms, such as DNA methylation, histone modifications, ATP-dependent chromatin remodeling, and microRNA-dependent mechanisms, in heart failure. PMID- 23740221 TI - Death or secretion? The demise of a plausible assumption about CSF-tau in Alzheimer Disease? AB - Our recent identification of an exosomal route for tau protein secretion(1) marks a key similarity between tau and other aggregation-prone proteins implicated in neurodegenerative disease pathogenesis and is to some extent congruent with the popular idea that tau pathology spreads between neurons via a "prionlike" template-mediated protein misfolding mechanism in AD and other tauopathies. However, the observation that much of the phosphotau in CSF samples from early AD patients is exosomal (and thus likely to have been secreted) calls into question a very widely held and plausible assumption - the idea that the elevated CSF-tau in AD is due to the passive release and accumulation of tau in the CSF as a consequence of widespread neuronal death. Here we examine this issue directly and explore some of the broader implications of this study for our understanding of AD pathogenesis and the prospects for improving its diagnosis and treatment. PMID- 23740222 TI - Perinatal depression: a review of US legislation and law. AB - Accumulating research documenting the prevalence and negative effects of perinatal depression, together with highly publicized tragic critical incidents of suicide and filicide by mothers with postpartum psychosis, have fueled a continuum of legislation. Specialists in perinatal mental health should recognize how their work influences legislative initiatives and penal codes, and take this into consideration when developing perinatal services and research. Yet, without legal expertise, the status of legislative initiatives can be confusing. To address this shortfall, we assembled an interdisciplinary team of academics specializing in law, as well as perinatal mental health, to summarize these issues. This review presents the relevant federal and state legislation and summarizes the criminal codes that governed the court decisions on cases in which a mother committed filicide because of postpartum psychosis. Moreover, the review aims to help researchers and providers who specialize in perinatal depression understand their role in this legal landscape. PMID- 23740223 TI - Association between vitiligo and atopic disorders: a pilot study. PMID- 23740224 TI - Dabigatran versus warfarin anticoagulation before and after catheter ablation for the treatment of atrial fibrillation. AB - BACKGROUND: Systemic thromboembolism and bleeding remain the two most common and serious complications of catheter ablation of atrial fibrillation. A variety of periprocedure anticoagulation strategies have been proposed to mitigate these risks. Although operators are now routinely administering dabigatran for anticoagulation in this setting, its relative safety and effectiveness compared to warfarin are unknown. METHODS AND RESULTS: A total of 202 patients received dabigatran as part of their periprocedural anticoagulation regimen at the time of initial or redo catheter ablation for symptomatic atrial fibrillation. A comparison group of 202 patients treated with warfarin was randomly selected from patients undergoing atrial fibrillation (AF) ablation during the same time period. AF types were paroxysmal in 223 patients, persistent in 158 patients, and longstanding persistent in 13 patients. Mean age was 60.0 +/- 10.5 years, 55 % had a history of hypertension, and mean CHADS-VASc score was 1.7 +/- 1.3. "Continuous" warfarin or dabigatran was administered in 80 and 32 % of patients, respectively. Time to first dose of dabigatran post-procedure was 12.2 +/- 10.3 h. Two dabigatran and no warfarin-treated patients had systemic thromboembolism (p = NS); five dabigatran and three warfarin-treated patients had bleeding complications (p = NS, combined endpoint p = 0.116). One dabigatran patient had severe pericardial bleeding (3 L blood loss). CONCLUSIONS: In a retrospective pilot trial comparing the risks of systemic thromboembolism or bleeding complications in patients treated with warfarin or dabigatran anticoagulation, the outcomes were similar. A prospective trial is warranted. PMID- 23740225 TI - Luminescence spectroscopy of singlet oxygen enables monitoring of oxygen consumption in biological systems consisting of fatty acids. AB - The interaction of singlet oxygen ((1)O2) generated in a photosensitized process with well-known reference photosensitizers Perinaphthenone (PN) and TMPyP is investigated in a model system consisting of fatty acids and the respective exogenous photosensitizer (PS) in solution by direct detection of the luminescence photons of (1)O2 at 1270 nm. Such a model system is a first approach to mimic the complex environment of (1)O2 in a biological cell which consists mainly of water, proteins, sugars and lipids. Firstly, the important issue of oxygen consumption is evaluated which has to be considered during luminescence detection of (1)O2. It is known that the luminescence signal of (1)O2 is dependent on the oxygen concentration of the environment. Cellular components such as lipids represent oxygen consumers due to peroxidation of their unsaturated double bonds. Secondly, the experimental conditions for this model system regarding oxygen consumption are optimized to estimate the rates and rate constants of the coupled system. Thirdly, the triplet decay of the PS can provide more precise information about the actual oxygen concentration close to the PS and can be used, therefore, as a more precise method to determine the oxygen concentration in more complex systems such as a biological cell. The aim is to get a better understanding of photosensitized reactions of (1)O2 with cellular components to further improve methodologies, in particular at a cellular level using luminescence spectroscopy. In conclusion, luminescence detection might be a helpful tool to monitor precisely and promptly changes in oxygen concentration in a complex environment. PMID- 23740227 TI - Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. AB - OBJECTIVES: Lupus nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE). All current treatment regimens include oral steroids, which are associated with severe adverse events and long-term damage. We have piloted a steroid-avoiding protocol (rituxilup) for the treatment of biopsy-proven active International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III, IV, or class V LN. METHODS: We report the findings from the first 50 consecutive patients, treated with 2 doses of rituximab (1 g) and methyl prednisolone (500 mg) on days 1 and 15, and maintenance treatment of mycophenolate mofetil. Patients on maintenance steroids or with life-threatening SLE or requiring dialysis were excluded. Renal remission was defined as serum creatinine no greater than 15% above baseline; complete biochemical remission (CR) was defined as urine protein : creatinine ratio (PCR)<50 mg/mmol or partial remission (PR) if PCR>50 mg/mmol but non-nephrotic and >50% reduction. RESULTS: A total of 45 (90%) patients achieved CR or PR by a median time of 37 weeks (range 4-200). Overall, 72% (n=36) achieved CR (median time 36 weeks (11-58)) and a further 18% (n=9) achieved persistent PR (median time 32 weeks (19-58)). By 52 weeks, CR and PR had been achieved in 52% (n=26) and 34% (n=17) respectively. In all, 12 relapses occurred in 11 patients, at a median time of 65.1 weeks (20-112) from remission. A total of 6/50 patients had systemic flares. Of the 45 responders, only 2 required >2 weeks of oral steroids. Adverse events were infrequent; 18% were admitted, 10% for an infective episode. CONCLUSIONS: The rituxilup cohort demonstrates that oral steroids can be safely avoided in the treatment of LN. If findings are confirmed, it could mark a step change in the approach to the treatment of LN. PMID- 23740226 TI - Efficacy and safety of golimumab as add-on therapy to disease-modifying antirheumatic drugs: results of the GO-MORE study. AB - OBJECTIVES: To evaluate the efficacy and safety of subcutaneous golimumab as add on therapy in patients with active rheumatoid arthritis (RA) despite disease modifying antirheumatic drug (DMARD) treatment. To evaluate an intravenous plus subcutaneous (IV+SC) golimumab strategy in patients who had not attained remission. METHODS: GO-MORE was an open-label, multinational, prospective study in patients with active RA in typical clinical practice settings. In part 1, patients received add-on monthly 50-mg subcutaneous golimumab for 6 months. The percentage of patients with good/moderate European League Against Rheumatism (EULAR) 28-joint disease activity score (DAS28)-erythrocyte sedimentation rate (ESR) response was compared in patient subgroups with various concurrent or previous DMARD treatments. In part 2, patients with EULAR responses but not remission were randomly assigned to receive IV+SC or subcutaneous golimumab to month 12; DAS28-ESR remission was measured. RESULTS: 3366 patients were enrolled. At baseline of part 1, 3280 efficacy-evaluable patients had mean disease duration of 7.6 years and mean DAS28-ESR of 5.97 (SD=1.095). At month 6, 82.1% achieved good/moderate EULAR responses and 23.9% attained remission. When EULAR responses were analysed by the number of previously failed DMARD or the concomitant methotrexate dose, DMARD type, or corticosteroid use, no statistically significant differences were observed. Part 2 patients (N=490) who received IV+SC or subcutaneous golimumab achieved similar remission rates (~25%). Adverse events were consistent with previous reports of golimumab and other tumour necrosis antagonists in this population. CONCLUSIONS: Add-on monthly subcutaneous golimumab resulted in good/moderate EULAR response in most patients; 25% achieved remission after 6 more months of golimumab, but an IV+SC regimen provided no additional efficacy over the subcutaneous regimen. PMID- 23740228 TI - Disparity between ultrasound and clinical findings in psoriatic arthritis. AB - OBJECTIVE: To investigate the association between psoriatic arthritis (PsA) specific clinical composite scores and ultrasound-verified pathology as well as comparison of clinical and ultrasound definitions of remission. METHODS: We performed a prospective study on 70 consecutive PsA patients. Clinical assessments included components of Disease Activity Index for Psoriatic Arthritis (DAPSA) and the Composite Psoriatic Disease Activity Index (CPDAI). Minimal disease activity (MDA) and the following remission criteria were applied: CPDAI joint, entheses and dactylitis domains (CPDAI-JED)=0, DAPSA<=3.3, Boolean's remission definition and physician-judged remission (rem-phys). B-mode and power Doppler (PD-) ultrasound findings were semiquantitatively scored at 68 joints (evaluating synovia, peritendinous tissue, tendons and bony changes) and 14 entheses. Ultrasound remission and minimal ultrasound disease activity (MUDA) were defined as PD-score=0 and PD-score <=1, respectively, at joints, peritendinous tissue, tendons and entheses. RESULTS: DAPSA but not CPDAI correlated with B-mode and PD-synovitis. Ultrasound signs of enthesitis, dactylitis, tenosynovitis and perisynovitis were not linked with clinical composites. Clinical remission or MDA was observed in 15.7% to 47.1% of PsA patients. Ultrasound remission and MUDA were present in 4.3% and 20.0% of patients, respectively. Joint and tendon-related PD-scores were higher in patients with active versus inactive disease according to CPDAI-JED, DAPSA, Boolean's and rem-phys, whereas no difference was observed regarding enthesitis and perisynovitis. DAPSA<=3.3 (OR 3.9, p=0.049) and Boolean's definition (OR 4.6, p=0.03) were more useful to predict MUDA than other remission criteria. CONCLUSIONS: PsA-specific composite scores partially reflect ultrasound findings. DAPSA and Boolean's remission definitions better identify MUDA patients than other clinical criteria. PMID- 23740230 TI - Relationship between the functional exon 3 deleted growth hormone receptor polymorphism and symptomatic osteoarthritis in women. AB - BACKGROUND: Several studies suggest a role of the growth hormone (GH)/insulin like growth factor-1 (IGF-1) axis in the pathophysiology of primary osteoarthritis (OA). A common polymorphism of the GH receptor (exon 3 deletion, d3-GHR) is associated with increased GH/IGF-1 activity. OBJECTIVE: To study associations between the d3-GHR polymorphism and symptomatic OA. METHODS: In the GARP (Genetics, osteoARthritis and Progression) study, we compared the d3-GHR polymorphism between OA patients and controls. GARP patients were genotyped for seven single nucleotide polymorphisms encompassing the d3-GHR gene, using rs4590183 as proxy for d3-GHR (pairwise r(2)=1). Binary logistic regression models with robust SEs were performed, stratified by sex. For replication, rs4590183 was tested in three additional cohorts. Fixed- and random-effects combined analyses were performed. RESULTS: In female GARP patients with severe familial OA, d3-GHR was associated with OA (adjusted OR 1.36 (95% CI 1.01 to 1.83), p=0.043), independently of age and body mass index. Combined analysis of all studies showed suggestive evidence for association between d3-GHR and OA (OR=1.17 (95% CI 1.04 to 1.30), p=0.008). Evidence was strongest in hip OA cases, without any evidence for heterogeneity. CONCLUSIONS: In women, the d3-GHR polymorphism was associated with symptomatic OA, especially at the hip site. PMID- 23740229 TI - Evidence that autophagy, but not the unfolded protein response, regulates the expression of IL-23 in the gut of patients with ankylosing spondylitis and subclinical gut inflammation. AB - OBJECTIVES: Interleukin (IL)-23 has been implicated in the pathogenesis of ankylosing spondylitis (AS). The aim of the study was to clarify the mechanisms underlying the increased IL-23 expression in the gut of AS patients. METHODS: Consecutive gut biopsies from 30 HLA-B27(+) AS patients, 15 Crohn's disease (CD) patients and 10 normal subjects were obtained. Evidence for HLA-B27 misfolding was studied. Unfolded protein response (UPR) and autophagy were assessed by RT PCR and immunohistochemistry. The contribution of UPR and autophagy in the regulation of IL-23 expression was evaluated in in vitro experiments on isolated lamina propria mononuclear cells (LPMCs). RESULTS: Intracellular colocalisation of SYVN1 and FHCs but not a significant overexpression of UPR genes was observed in the gut of AS patients. Conversely, upregulation of the genes involved in the autophagy pathway was observed in the gut of AS and CD patients. Immunohistochemistry showed an increased expression of LC3II, ATG5 and ATG12 but not of SQSTM1 in the ileum of AS and CD patients. LC3II was expressed among infiltrating mononuclear cells and epithelial cells resembling Paneth cells (PC) and colocalised with ATG5 in AS and CD. Autophagy but not UPR was required to modulate the expression of IL-23 in isolated LPMCs of AS patients with chronic gut inflammation, CD patients and controls. CONCLUSIONS: Our data suggest that HLA-B27 misfolding occurs in the gut of AS patients and is accompanied by activation of autophagy rather than a UPR. Autophagy appears to be associated with intestinal modulation of IL-23 in AS. PMID- 23740231 TI - Maintenance of biologic-free remission with naproxen or no treatment in patients with early, active axial spondyloarthritis: results from a 6-month, randomised, open-label follow-up study, INFAST Part 2. AB - OBJECTIVE: To investigate whether biologic-free remission can be achieved in patients with early, active axial spondyloarthritis (SpA) who were in partial remission after 28 weeks of infliximab (IFX)+naproxen (NPX) or placebo (PBO)+NPX treatment and whether treatment with NPX was superior to no treatment to maintain disease control. METHOD: Infliximab as First-Line Therapy in Patients with Early Active Axial Spondyloarthritis Trial (INFAST) Part 1 was a double-blind, randomised, controlled trial in biologic-naive patients with early, active, moderate-to-severe axial SpA treated with either IFX 5 mg/kg+NPX 1000 mg/d or PBO+NPX 1000 mg/d for 28 weeks. Patients achieving Assessment of SpondyloArthritis international Society (ASAS) partial remission at week 28 continued to Part 2 and were randomised (1:1) to NPX or no treatment until week 52. Treatment group differences in ASAS partial remission and other efficacy variables were assessed through week 52 with Fisher exact tests. RESULTS: At week 52, similar percentages of patients in the NPX group (47.5%, 19/40) and the no treatment group (40.0%, 16/40) maintained partial remission, p=0.65. Median duration of partial remission was 23 weeks in the NPX group and 12.6 weeks in the no-treatment group (p=0.38). Mean Bath Ankylosing Spondylitis Disease Activity Index scores were low at week 28, the start of follow-up treatment (NPX, 0.7; no treatment, 0.6), and remained low at week 52 (NPX, 1.2; no treatment, 1.7). CONCLUSIONS: In axial SpA patients who reached partial remission after treatment with either IFX+NPX or NPX alone, disease activity remained low, and about half of patients remained in remission during 6 months in which NPX was continued or all treatments were stopped. PMID- 23740232 TI - Adverse outcomes after major surgery in patients with systemic lupus erythematosus: a nationwide population-based study. AB - OBJECTIVES: To investigate the postoperative adverse outcomes among surgical patients with preoperative systemic lupus erythematosus (SLE) in a nationwide population-based study. METHODS: We used Taiwan's National Health Insurance Research Database to identify 4321 surgical inpatients with SLE and 17 284 sex- and age-matched controls receiving major surgery. Sociodemographic characteristics, preoperative comorbidities, postoperative 30-day in-hospital major complications and mortality were analysed among surgical patients with and without SLE. RESULTS: Surgical patients with SLE had a higher prevalence of preoperative coexisting medical conditions and postoperative major complications. The OR of 30-day postoperative mortality for surgical patients with SLE was 1.71 (95% CI 1.09 to 2.67) after adjustment. Surgical patients who had received more recent (within 6 months) preoperative SLE-related inpatient care had higher risks of 30-day postoperative acute renal failure (OR=7.23, 95% CI 4.52 to 11.6), pneumonia (OR=2.60, 95% CI 1.82 to 3.72), pulmonary embolism (OR=4.86, 95% CI 1.20 to 19.7), septicaemia (OR=3.43, 95% CI 2.48 to 4.74), stroke (OR=2.01, 95% CI 1.38 to 2.92), overall complications (OR=2.30, 95% CI 1.89 to 2.80) and 30-day postoperative mortality (OR=2.39, 95% CI 1.28 to 4.45) than surgical patients without SLE. SLE-related preoperative steroid injections showed a dose-dependent relationship with postoperative complications and mortality. CONCLUSIONS: SLE significantly increased the risks of surgical patients for overall major complications and mortality after major surgery. Our findings demonstrated the need for integrated care and revised protocols for perioperative management to improve outcomes for surgical patients with SLE. PMID- 23740233 TI - Senescence marker killer cell lectin-like receptor G1 (KLRG1) contributes to TNF alpha production by interaction with its soluble E-cadherin ligand in chronically inflamed joints. AB - OBJECTIVES: Killer cell lectin-like receptor G1 (KLRG1) is an NK cell marker also expressed on T cells showing an immunosenescent phenotype. KLRG1 binding to its ligand E-cadherin inhibits functional responses. It was recently shown that soluble E-cadherin (sE-cadherin) also influences KLRG1 signalling, although its involvement in arthritis is unknown. Our goal was to evaluate the contribution of KLRG1(+) T cells to synovitis. METHODS: Paired peripheral blood (PB) and synovial fluid (SF) mononuclear cells from 21 patients with spondyloarthritis (SpA) or rheumatoid arthritis (RA), eight with crystal-induced arthritis and 10 controls were obtained. T cells were characterised for KLRG1 expression directly ex vivo, while TNF-alpha/IFN-gamma production was assessed after polyclonal stimulation. Assays of chemotaxis response towards SF were conducted. Additionally, sE cadherin levels in our paired samples were determined. Moreover, TNF-alpha/IFN gamma production by antigen-specific T cells was evaluated in the presence of sE cadherin. RESULTS: KLRG1(+) T cells were enriched in SF as opposed to PB of SpA and RA patients, which contrasts with results obtained in crystal-induced arthritides. KLRG1(+) T cells were more functionally active as opposed to KLRG1( ) T cells and migrated preferentially towards SpA and RA SF. sE-cadherin levels were higher in SF versus plasma. The presence of sE-cadherin enhanced the number of KLRG1(+) CD4(+) T cells able to produce TNF-alpha but not IFN-gamma. CONCLUSIONS: sE-cadherin contributes to the local proinflammatory environment in the joint by favouring TNF-alpha production by KLRG1(+) CD4(+) T cells. This pathway seems to be operational in both SpA and RA, but not in crystal-induced arthritis. PMID- 23740234 TI - Treating axial and peripheral spondyloarthritis, including psoriatic arthritis, to target: results of a systematic literature search to support an international treat-to-target recommendation in spondyloarthritis. AB - BACKGROUND: Current recommendations for the management of axial spondyloarthritis (SpA) and psoriatic arthritis are to monitor disease activity and adjust therapy accordingly. However, treatment targets and timeframes of change have not been defined. An international expert panel has been convened to develop 'treat-to target' recommendations, based on published evidence and expert opinion. OBJECTIVE: To review evidence on targeted treatment for axial and peripheral SpA, as well as for psoriatic skin disease. METHODS: We performed a systematic literature search covering Medline, Embase and Cochrane, conference abstracts and studies in http://www.clinicaltrials.gov. RESULTS: Randomised comparisons of targeted versus routine treatment are lacking. Some studies implemented treatment targets before escalating therapy: in ankylosing spondylitis, most trials used a decrease in Bath Ankylosing Spondylitis Disease Activity Index; in psoriatic arthritis, protocols primarily considered a reduction in swollen and tender joints; in psoriasis, the Modified Psoriasis Severity Score and the Psoriasis Area and Severity Index were used. Complementary evidence correlating these factors with function and radiographic damage at follow-up is sparse and equivocal. CONCLUSIONS: There is a need for randomised trials that investigate the value of treat-to-target recommendations in SpA and psoriasis. Several trials have used thresholds of disease activity measures to guide treatment decisions. However, evidence on the effect of these data on long-term outcome is scarce. The search data informed the expert committee regarding the formulation of recommendations and a research agenda. PMID- 23740235 TI - Antibodies to modified citrullinated vimentin are associated with severe extra articular manifestations in rheumatoid arthritis. PMID- 23740236 TI - Evaluation of the RABBIT Risk Score for serious infections. AB - OBJECTIVE: To evaluate the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) Risk Score for serious infections in patients with rheumatoid arthritis (RA). METHODS: The RABBIT Risk Score for serious infections was developed in 2011 on a cohort of RA patients enrolled in the German biologics register RABBIT between 2001 and 2007. To evaluate this score, we used data from patients enrolled in RABBIT after 1 January 2009. Expected numbers of serious infections and expected numbers of patients with at least one serious infection per year were calculated by means of the RABBIT Risk Score and compared with observed numbers in the evaluation sample. RESULTS: The evaluation of the score in an independent cohort of 1522 RA patients treated with tumour necrosis factor alpha (TNFalpha) inhibitors and 1468 patients treated with non-biological disease modifying antirheumatic drugs (DMARDs) showed excellent agreement between observed and expected rates of serious infections. For patients exposed to TNF inhibitors, expected as well as observed numbers of serious infections were 3.0 per 100 patient-years (PY). For patients on non-biological DMARDs the expected and observed numbers were 1.5/100 PY and 1.8/100 PY, respectively. The score was highly predictive in groups of patients with low as well as with high infection risk. CONCLUSIONS: The RABBIT Risk Score is a reliable instrument which determines the risk of serious infection in individual patients based on clinical and treatment information. It helps the rheumatologist to balance benefits and risks of treatment, to avoid high-risk treatment combinations and thus to make informed clinical decisions. PMID- 23740237 TI - The timing of serum infliximab loss, or the appearance of antibodies to infliximab (ATI), is related with the clinical activity in ATI-positive patients with rheumatoid arthritis treated with infliximab. PMID- 23740238 TI - Ethnic specificity of lupus-associated loci identified in a genome-wide association study in Korean women. AB - OBJECTIVES: To identify novel genetic candidates for systemic lupus erythematosus (SLE) in the Korean population, and to validate the risk loci for SLE identified in previous genome-wide association studies (GWAS). METHODS: We performed a GWAS in 400 Korean female SLE patients and 445 controls. Selected single-nucleotide polymorphisms (SNP) were then replicated in an independent cohort of 385 SLE patients and 583 controls (replication cohort 1), and in a further 811 SLE patients and 1502 controls (replication cohort 2). RESULTS: In the GWAS phase, rs9275428 located near HLA-DQB1 showed the strongest association with SLE (OR 0.50, false discovery rate (FDR) p=3.07*10(-6)). Although no loci reached genome wide significance outside major histocompatibility complex (MHC), C8orf13-BLK, STAT4, CSMD1, DIAPH3, GLDC and TNFSF4 showed FDR p < 0.05. Our results suggest that STAT4, BLK, IRF5, PTTG1-miR-146a, UBE2L3 and TNFAIP3 are shared susceptibility loci among Caucasians and Asians, while ETS1, IKZF1, SLC15A4 are likely to be Asian-specific loci. In a combined analysis of 1596 SLE patients and 2540 controls for selected 22 candidate SNP, STAT4 and BLK as positive controls showed a strong association with SLE (FDR p=9.85*10(-13) and 2.28*10(-8), respectively). Of these, 16 candidates (PEX5L, TRAJ50, MYO18B, SOS1, ARHGAP26, SMURF1, CADPS, HAND1, FAM78B, DIAPH3, TBL1XR1, CSMD1, ZBTB20, C3orf21, HIPK1 and AP001042.1) showed only nominal significance (7.05*10(-4)<=FDR p<=4.38*10(-2)). CONCLUSIONS: There are similarities and differences in genetic susceptibility for SLE between Caucasian and Asian ethnic groups. Although 16 putative novel loci for SLE have been suggested in the Korean population, further research on a larger sample is required to discriminate truth from error. PMID- 23740239 TI - Pathophysiological role of neutrophils in acute myocardial infarction. AB - The pathogenesis of acute myocardial infarction is known to be mediated by systemic, intraplaque and myocardial inflammatory processes. Among different immune cell subsets, compelling evidence now indicates a pivotal role for neutrophils in acute coronary syndromes. Neutrophils infiltrate coronary plaques and the infarcted myocardium and mediate tissue damage by releasing matrix degrading enzymes and reactive oxygen species. In addition, neutrophils are also involved in post-infarction adverse cardiac remodelling and neointima formation after angioplasty. The promising results obtained in preclinical modelswith pharmacological approaches interfering with neutrophil recruitment or function have confirmed the pathophysiological relevance of these immune cells in acute coronary syndromes and prompted further studies of these therapeutic interventions. This narrative review will provide an update on the role of neutrophils in acute myocardial infarction and on the pharmacological means that were devised to prevent neutrophil-mediated tissue damage and to reduce post ischaemic outcomes. PMID- 23740240 TI - I COUGH: reducing postoperative pulmonary complications with a multidisciplinary patient care program. AB - IMPORTANCE: Postoperative pulmonary complications can be a devastating consequence of surgery. Validated strategies to reduce these adverse outcomes are needed. OBJECTIVES: To design, implement, and determine the efficacy of a suite of interventions for reducing postoperative pulmonary complications. DESIGN: A before-after trial comparing our National Surgical Quality Improvement Program (NSQIP) pulmonary outcomes before and after implementing I COUGH, a multidisciplinary pulmonary care program. SETTING: An urban, academic, safety-net hospital. PARTICIPANTS: All patients who underwent general or vascular surgery at our institution during a 1-year period before and after implementation of I COUGH. INTERVENTIONS: A multidisciplinary team developed a strategy to reduce pulmonary complications based on comprehensive patient and family education and a set of standardized electronic physician orders to specify early postoperative mobilization and pulmonary care. Designated by the acronym I COUGH, the program emphasizes incentive spirometry, coughing and deep breathing, oral care (brushing teeth and using mouthwash twice daily), understanding (patient and family education), getting out of bed at least 3 times daily, and head-of-bed elevation. Nursing and physician education promoted a culture of mobilization and I COUGH interventions. I COUGH was implemented for all general surgery and vascular surgery patients at our institution in August 2010. MAIN OUTCOMES AND MEASURES: The NSQIP-reported incidence and risk-adjusted ratios of postoperative pneumonia and unplanned intubation, which NSQIP reports as observed-expected (OE) ratios for the 1-year period before implementing I COUGH and as odds ratios (ORs, statistically comparable to OE ratios) for the period after its implementation. RESULTS: Before implementation of I COUGH, our incidence of postoperative pneumonia was 2.6%, falling to 1.6% after its implementation, and risk-adjusted outcomes fell from an OE ratio of 2.13 to an OR of 1.58. The incidence of unplanned intubations was 2.0% before I COUGH and 1.2% after I COUGH, with risk adjusted outcomes decreasing from an OE ratio of 2.10 to an OR of 1.31. CONCLUSIONS AND RELEVANCE: I COUGH, a standardized postoperative care program emphasizing patient education, early mobilization, and pulmonary interventions, reduced the incidence of postoperative pneumonia and unplanned intubation among our patients. PMID- 23740241 TI - Effect of large-scale installation of deltamethrin-impregnated screens and curtains in Bam, a major focus of anthroponotic cutaneous leishmaniasis in Iran. AB - INTRODUCTION: Installation of deltamethrin-impregnated screens and curtains was assessed as a preventive measure against transmission of anthroponotic cutaneous leishmaniasis (ACL) by Phlebotomus sergenti in Bam, a well-known focus of ACL in Iran with a population of nearly 100,000. METHODS: This was a quasi-experiment based on official data from an ACL control program in which one section of the city with about one-quarter of the population received the intervention. In the analysis, the rest of the city was used as control. Data covered June 2007 through October 2010. RESULTS: Comparison of cumulative incidence between the intervention and control areas before and after installation indicate a significant differential reduction in the cumulative ACL incidence in the intervention area and a reversal of the relative risk, beginning four months after the completion of installation, from RR = 1.14 (95% CI:1.05-1.23) to RR = 0.84 (95% CI:0.72-0.98). Results also indicate a return to a higher cumulative relative risk, RR = 1.51 (95% CI:1.30-1.77), several months after the loss of the preventive effect. CONCLUSIONS: Findings indicate the short-term effectiveness of such preventive measures but highlight the necessity of long-term, sustainable strategies. Results also suggest that shrinkage in the human reservoir pool in response to the intervention may play a significant role in prolongation of the preventive effect beyond the insecticidal life of impregnated materials in foci of anthroponotic cutaneous leishmaniasis and possibly anthroponotic visceral leishmaniasis due to L. donovani. PMID- 23740242 TI - Repellent activity screening of 11 kinds of essential oils against Aedes albopictus Skuse: microcapsule preparation of Herba Schizonepetae oil and repellent bioassay on hand skin. AB - BACKGROUND: The main ingredient of most repellents on the market is DEET, an effective compound that has the disadvantages of toxic reactions as well as damaging effects on plastic and synthetic fabric. DEET alternatives are urgently needed. METHODS: The repellent activities of 11 kinds of essential oils were tested against Aedes albopictus Skuse by a Y-tube olfactometer. Using essential oils with high repellent activity as core material and gelatin and gum arabic as wall materials, we prepared microcapsules of essential oils and optimized the preparation process. The microcapsule formulation was then subjected to repellent bioassay on hand skin. RESULTS: when the dosage of essential oils was 5 uL, the cinnamon oil repellent rate was 87.5% within 10 min and the Herba Schizonepetae oil (HSO) repellent rate was 98.0% within 3 min. Up to 1.5% (w/v) gelatin and 1.5% (w/v) gum arabic (as wall materials), and HSO (as core material) were used to form microcapsules with a 1:1 ratio of core material to wall material. CONCLUSION: The ointment preparations effectively protected hand skin exposed to a high-density A. albopictus Skuse rearing cage for 4-5 h. The HSO microcapsule repellent has broad application and development prospects. PMID- 23740243 TI - Activation of the transcription factor GLI1 by WNT signaling underlies the role of SULFATASE 2 as a regulator of tissue regeneration. AB - Tissue regeneration requires the activation of a set of specific growth signaling pathways. The identity of these cascades and their biological roles are known; however, the molecular mechanisms regulating the interplay between these pathways remain poorly understood. Here, we define a new role for SULFATASE 2 (SULF2) in regulating tissue regeneration and define the WNT-GLI1 axis as a novel downstream effector for this sulfatase in a liver model of tissue regeneration. SULF2 is a heparan sulfate 6-O-endosulfatase, which releases growth factors from extracellular storage sites turning active multiple signaling pathways. We demonstrate that SULF2-KO mice display delayed regeneration after partial hepatectomy (PH). Mechanistic analysis of the SULF2-KO phenotype showed a decrease in WNT signaling pathway activity in vivo. In isolated hepatocytes, SULF2 deficiency blocked WNT-induced beta-CATENIN nuclear translocation, TCF activation, and proliferation. Furthermore, we identified the transcription factor GLI1 as a novel target of the SULF2-WNT cascade. WNT induces GLI1 expression in a SULF2- and beta-CATENIN-dependent manner. GLI1-KO mice phenocopied the SULF2-KO, showing delayed regeneration and decreased hepatocyte proliferation. Moreover, we identified CYCLIN D1, a key mediator of cell growth during tissue regeneration, as a GLI1 transcriptional target. GLI1 binds to the cyclin d1 promoter and regulates its activity and expression. Finally, restoring GLI1 expression in the liver of SULF2-KO mice after PH rescues CYCLIN D1 expression and hepatocyte proliferation to wild-type levels. Thus, together these findings define a novel pathway in which SULF2 regulates tissue regeneration in part via the activation of a novel WNT-GLI1-CYCLIN D1 pathway. PMID- 23740244 TI - An undesired effect of chemotherapy: gemcitabine promotes pancreatic cancer cell invasiveness through reactive oxygen species-dependent, nuclear factor kappaB- and hypoxia-inducible factor 1alpha-mediated up-regulation of CXCR4. AB - Recently, we have shown that CXCL12/CXCR4 signaling plays an important role in gemcitabine resistance of pancreatic cancer (PC) cells. Here, we explored the effect of gemcitabine on this resistance mechanism. Our data demonstrate that gemcitabine induces CXCR4 expression in two PC cell lines (MiaPaCa and Colo357) in a dose- and time-dependent manner. Gemcitabine-induced CXCR4 expression is dependent on reactive oxygen species (ROS) generation because it is abrogated by pretreatment of PC cells with the free radical scavenger N-acetyl-L-cysteine. CXCR4 up-regulation by gemcitabine correlates with time-dependent accumulation of NF-kappaB and HIF-1alpha in the nucleus. Enhanced binding of NF-kappaB and HIF 1alpha to the CXCR4 promoter is observed in gemcitabine-treated PC cells, whereas their silencing by RNA interference causes suppression of gemcitabine-induced CXCR4 expression. ROS induction upon gemcitabine treatment precedes the nuclear accumulation of NF-kappaB and HIF-1alpha, and suppression of ROS diminishes these effects. The effect of ROS on NF-kappaB and HIF-1alpha is mediated through activation of ERK1/2 and Akt, and their pharmacological inhibition also suppresses gemcitabine-induced CXCR4 up-regulation. Interestingly, our data demonstrate that nuclear accumulation of NF-kappaB results from phosphorylation induced degradation of IkappaBalpha, whereas HIF-1alpha up-regulation is NF kappaB-dependent. Lastly, our data demonstrate that gemcitabine-treated PC cells are more motile and exhibit significantly greater invasiveness against a CXCL12 gradient. Together, these findings reinforce the role of CXCL12/CXCR4 signaling in gemcitabine resistance and point toward an unintended and undesired effect of chemotherapy. PMID- 23740246 TI - Role of the adapter protein Abi1 in actin-associated signaling and smooth muscle contraction. AB - Actin filament polymerization plays a critical role in the regulation of smooth muscle contraction. However, our knowledge regarding modulation of the actin cytoskeleton in smooth muscle just begins to accumulate. In this study, stimulation with acetylcholine (ACh) induced an increase in the association of the adapter protein c-Abl interactor 1 (Abi1) with neuronal Wiskott-Aldrich syndrome protein (N-WASP) (an actin-regulatory protein) in smooth muscle cells/tissues. Furthermore, contractile stimulation activated N-WASP in live smooth muscle cells as evidenced by changes in fluorescence resonance energy transfer efficiency of an N-WASP sensor. Abi1 knockdown by lentivirus-mediated RNAi inhibited N-WASP activation, actin polymerization, and contraction in smooth muscle. However, Abi1 silencing did not affect myosin regulatory light chain phosphorylation at Ser-19 in smooth muscle. In addition, c-Abl tyrosine kinase and Crk-associated substrate (CAS) have been shown to regulate smooth muscle contraction. The interaction of Abi1 with c-Abl and CAS has not been investigated. Here, contractile activation induced formation of a multiprotein complex including c-Abl, CAS, and Abi1. Knockdown of c-Abl and CAS attenuated the activation of Abi1 during contractile activation. More importantly, Abi1 knockdown inhibited c-Abl phosphorylation at Tyr-412 and the interaction of c-Abl with CAS. These results suggest that Abi1 is an important component of the cellular process that regulates N-WASP activation, actin dynamics, and contraction in smooth muscle. Abi1 is activated by the c-Abl-CAS pathway, and Abi1 reciprocally controls the activation of its upstream regulator c-Abl. PMID- 23740245 TI - EB1 levels are elevated in ascorbic Acid (AA)-stimulated osteoblasts and mediate cell-cell adhesion-induced osteoblast differentiation. AB - Osteoblasts are differentiated mesenchymal cells that function as the major bone producing cells of the body. Differentiation cues including ascorbic acid (AA) stimulation provoke intracellular changes in osteoblasts leading to the synthesis of the organic portion of the bone, which includes collagen type I alpha1, proteoglycans, and matrix proteins, such as osteocalcin. During our microarray analysis of AA-stimulated osteoblasts, we observed a significant up-regulation of the microtubule (MT) plus-end binding protein, EB1, compared with undifferentiated osteoblasts. EB1 knockdown significantly impaired AA-induced osteoblast differentiation, as detected by reduced expression of osteoblast differentiation marker genes. Intracellular examination of AA-stimulated osteoblasts treated with EB1 siRNA revealed a reduction in MT stability with a concomitant loss of beta-catenin distribution at the cell cortex and within the nucleus. Diminished beta-catenin levels in EB1 siRNA-treated osteoblasts paralleled an increase in phospho-beta-catenin and active glycogen synthase kinase 3beta, a kinase known to target beta-catenin to the proteasome. EB1 siRNA treatment also reduced the expression of the beta-catenin gene targets, cyclin D1 and Runx2. Live immunofluorescent imaging of differentiated osteoblasts revealed a cortical association of EB1-mcherry with beta-catenin-GFP. Immunoprecipitation analysis confirmed an interaction between EB1 and beta-catenin. We also determined that cell-cell contacts and cortically associated EB1/beta-catenin interactions are necessary for osteoblast differentiation. Finally, using functional blocking antibodies, we identified E-cadherin as a major contributor to the cell-cell contact-induced osteoblast differentiation. PMID- 23740247 TI - The MID1 E3 ligase catalyzes the polyubiquitination of Alpha4 (alpha4), a regulatory subunit of protein phosphatase 2A (PP2A): novel insights into MID1 mediated regulation of PP2A. AB - Alpha4 (alpha4) is a key regulator of protein phosphatase 2A (PP2A) and mTOR in steps essential for cell-cycle progression. alpha4 forms a complex with PP2A and MID1, a microtubule-associated ubiquitin E3 ligase that facilitates MID1 dependent regulation of PP2A and the dephosphorylation of MID1 by PP2A. Ectopic overexpression of alpha4 is associated with hepatocellular carcinomas, breast cancer, and invasive adenocarcinomas. Here, we provide data suggesting that alpha4 is regulated by ubiquitin-dependent degradation mediated by MID1. In cells stably expressing a dominant-negative form of MID1, significantly elevated levels of alpha4 were observed. Treatment of cells with the specific proteasome inhibitor, lactacystin, resulted in a 3-fold increase in alpha4 in control cells and a similar level in mutant cells. Using in vitro assays, individual MID1 E3 domains facilitated monoubiquitination of alpha4, whereas full-length MID1 as well as RING-Bbox1 and RING-Bbox1-Bbox2 constructs catalyzed its polyubiquitination. In a novel non-biased functional screen, we identified a leucine to glutamine substitution at position 146 within Bbox1 that abolished MID1-alpha4 interaction and the subsequent polyubiquitination of alpha4, indicating that direct binding to Bbox1 was necessary for the polyubiquitination of alpha4. The mutant had little impact on the RING E3 ligase functionality of MID1. Mass spectrometry data confirmed Western blot analysis that ubiquitination of alpha4 occurs only within the last 105 amino acids. These novel findings identify a new role for MID1 and a mechanism of regulation of alpha4 that is likely to impact the stability and activity level of PP2Ac. PMID- 23740248 TI - SLLISWD sequence in the 10FNIII domain initiates fibronectin fibrillogenesis. AB - Fibronectin (FN) assembly into extracellular matrix is tightly regulated and essential to embryogenesis and wound healing. FN fibrillogenesis is initiated by cytoskeleton-derived tensional forces transmitted across transmembrane integrins onto RGD binding sequences within the tenth FN type III (10FNIII) domains. These forces unfold 10FNIII to expose cryptic FN assembly sites; however, a specific sequence has not been identified in 10FNIII. Our past steered molecular dynamics simulations modeling 10FNIII unfolding by force at its RGD loop predicted a mechanical intermediate with a solvent-exposed N terminus spanning the A and B beta-strands. Here, we experimentally confirm that the predicted 23-residue cryptic peptide 1 (CP1) initiates FN multimerization, which is mediated by interactions with 10FNIII that expose hydrophobic surfaces that support 8-anilino 1-napthalenesulfonic acid binding. Localization of multimerization activity to the C terminus led to the discovery of a minimal 7-amino acid "multimerization sequence" (SLLISWD), which induces polymerization of FN and the clotting protein fibrinogen in addition to enhancing FN fibrillogenesis in fibroblasts. A point mutation at Trp-6 that reduces exposure of hydrophobic sites for 8-anilino-1 napthalenesulfonic acid binding and beta-structure formation inhibits FN multimerization and prevents physiological cell-based FN assembly in culture. We propose a model for cell-mediated fibrillogenesis whereby cell traction force initiates a cascade of intermolecular exchange starting with the unfolding of 10FNIII to expose the multimerization sequence, which interacts with strand B of another 10FNIII domain via a Trp-mediated beta-strand exchange to stabilize a partially unfolded intermediate that propagates FN self-assembly. PMID- 23740249 TI - The minimum M3-M4 loop length of neurotransmitter-activated pentameric receptors is critical for the structural integrity of cytoplasmic portals. AB - The 5-HT3A receptor homology model, based on the partial structure of the nicotinic acetylcholine receptor from Torpedo marmorata, reveals an asymmetric ion channel with five portals framed by adjacent helical amphipathic (HA) stretches within the 114-residue loop between the M3 and M4 membrane-spanning domains. The positive charge of Arg-436, located within the HA stretch, is a rate limiting determinant of single channel conductance (gamma). Further analysis reveals that positive charge and volume of residue 436 are determinants of 5-HT3A receptor inward rectification, exposing an additional role for portals. A structurally unresolved stretch of 85 residues constitutes the bulk of the M3-M4 loop, leaving a >45-A gap in the model between M3 and the HA stretch. There are no additional structural data for this loop, which is vestigial in bacterial pentameric ligand-gated ion channels and was largely removed for crystallization of the Caenorhabditis elegans glutamate-activated pentameric ligand-gated ion channels. We created 5-HT3A subunit loop truncation mutants, in which sequences framing the putative portals were retained, to determine the minimum number of residues required to maintain their functional integrity. Truncation to between 90 and 75 amino acids produced 5-HT3A receptors with unaltered rectification. Truncation to 70 residues abolished rectification and increased gamma. These findings reveal a critical M3-M4 loop length required for functions attributable to cytoplasmic portals. Examination of all 44 subunits of the human neurotransmitter-activated Cys-loop receptors reveals that, despite considerable variability in their sequences and lengths, all M3-M4 loops exceed 70 residues, suggesting a fundamental requirement for portal integrity. PMID- 23740250 TI - The amyloid precursor protein (APP) triplicated gene impairs neuronal precursor differentiation and neurite development through two different domains in the Ts65Dn mouse model for Down syndrome. AB - Intellectual disability in Down syndrome (DS) appears to be related to severe proliferation impairment during brain development. Recent evidence shows that it is not only cellular proliferation that is heavily compromised in DS, but also cell fate specification and dendritic maturation. The amyloid precursor protein (APP), a gene that is triplicated in DS, plays a key role in normal brain development by influencing neural precursor cell proliferation, cell fate specification, and neuronal maturation. APP influences these processes via two separate domains, the APP intracellular domain (AICD) and the soluble secreted APP. We recently found that the proliferation impairment of neuronal precursors (NPCs) from the Ts65Dn mouse model for DS was caused by derangement of the Shh pathway due to overexpression of patched1(Ptch1), its inhibitory regulator. Ptch1 overexpression was related to increased levels within the APP/AICD system. The overall goal of this study was to determine whether APP contributes to neurogenesis impairment in DS by influencing in addition to proliferation, cell fate specification, and neurite development. We found that normalization of APP expression restored the reduced neuronogenesis, the increased astrogliogenesis, and the reduced neurite length of trisomic NPCs, indicating that APP overexpression underpins all aspects of neurogenesis impairment. Moreover, we found that two different domains of APP impair neuronal differentiation and maturation in trisomic NPCs. The APP/AICD system regulates neuronogenesis and neurite length through the Shh pathway, whereas the APP/secreted AP system promotes astrogliogenesis through an IL-6-associated signaling cascade. These results provide novel insight into the mechanisms underlying brain development alterations in DS. PMID- 23740251 TI - P2X receptor chimeras highlight roles of the amino terminus to partial agonist efficacy, the carboxyl terminus to recovery from desensitization, and independent regulation of channel transitions. AB - P2X receptor subtypes can be distinguished by their sensitivity to ATP analogues and selective antagonists. We have used chimeras between human P2X1 and P2X2 receptors to address the contribution of the extracellular ligand binding loop, transmembrane segments (TM1 and TM2), and intracellular amino and carboxyl termini to the action of partial agonists (higher potency and efficacy of BzATP and Ap5A at P2X1 receptors) and antagonists. Sensitivity to the antagonists NF449, suramin, and PPADS was conferred by the nature of the extracellular loop (e.g. nanomolar for NF449 at P2X1 and P2X2-1EXT and micromolar at P2X2 and P2X1 2EXT). In contrast, the effectiveness of partial agonists was similar to P2X1 levels for both of the loop transfers, suggesting that interactions with the rest of the receptor played an important role. Swapping TM2 had reciprocal effects on partial agonist efficacy. However, TM1 swaps increased partial agonist efficacy at both chimeras, and this was similar for swaps of both TM1 and 2. Changing the amino terminus had no effect on agonist potency but increased partial agonist efficacy at P2X2-1N and decreased it at P2X1-2N chimeras, demonstrating that potency and efficacy can be independently regulated. Chimeras and point mutations also identified residues in the carboxyl terminus that regulated recovery from channel desensitization. These results show that interactions among the intracellular, transmembrane, and extracellular portions of the receptor regulate channel properties and suggest that transitions to channel opening, the behavior of the open channel, and recovery from the desensitized state can be controlled independently. PMID- 23740252 TI - Functional properties of five Dictyostelium discoideum P2X receptors. AB - The Dictyostelium discoideum genome encodes five proteins that share weak sequence similarity with vertebrate P2X receptors. Unlike vertebrate P2X receptors, these proteins are not expressed on the surface of cells, but populate the tubules and bladders of the contractile vacuole. In this study, we expressed humanized cDNAs of P2XA, P2XB, P2XC, P2XD, and P2XE in human embryonic kidney cells and altered the ionic and proton environment in an attempt to reflect the situation in amoeba. Recording of whole-cell membrane currents showed that four receptors operated as ATP-gated channels (P2XA, P2XB, P2XD, and P2XE). At P2XA receptors, ATP was the only effective agonist of 17 structurally related putative ligands that were tested. Extracellular sodium, compared with potassium, strongly inhibited ATP responses in P2XB, P2XD, and P2XE receptors. Increasing the proton concentration (pH 6.2) accelerated desensitization at P2XA receptors and decreased currents at P2XD receptors, but increased the currents at P2XB and P2XE receptors. Dictyostelium lacking P2XA receptors showed impaired regulatory volume decrease in hypotonic solution. This phenotype was readily rescued by overexpression of P2XA and P2XD receptors, partially rescued by P2XB and P2XE receptors, and not rescued by P2XC receptors. The failure of the nonfunctional receptor P2XC to restore the regulatory volume decrease highlights the importance of ATP activation of P2X receptors for a normal response to hypo-osmotic shock, and the weak rescue by P2XB and P2XE receptors indicates that there is limited functional redundancy among Dictyostelium P2X receptors. PMID- 23740253 TI - alpha-Synuclein senses lipid packing defects and induces lateral expansion of lipids leading to membrane remodeling. AB - There is increasing evidence for the involvement of lipid membranes in both the functional and pathological properties of alpha-synuclein (alpha-Syn). Despite many investigations to characterize the binding of alpha-Syn to membranes, there is still a lack of understanding of the binding mode linking the properties of lipid membranes to alpha-Syn insertion into these dynamic structures. Using a combination of an optical biosensing technique and in situ atomic force microscopy, we show that the binding strength of alpha-Syn is related to the specificity of the lipid environment (the lipid chemistry and steric properties within a bilayer structure) and to the ability of the membranes to accommodate and remodel upon the interaction of alpha-Syn with lipid membranes. We show that this interaction results in the insertion of alpha-Syn into the region of the headgroups, inducing a lateral expansion of lipid molecules that can progress to further bilayer remodeling, such as membrane thinning and expansion of lipids out of the membrane plane. We provide new insights into the affinity of alpha-Syn for lipid packing defects found in vesicles of high curvature and in planar membranes with cone-shaped lipids and suggest a comprehensive model of the interaction between alpha-Syn and lipid bilayers. The ability of alpha-Syn to sense lipid packing defects and to remodel membrane structure supports its proposed role in vesicle trafficking. PMID- 23740254 TI - Structural analysis of the N-terminal domain of subunit a of the yeast vacuolar ATPase (V-ATPase) using accessibility of single cysteine substitutions to chemical modification. AB - The vacuolar ATPase (V-ATPase) is a multisubunit complex that carries out ATP driven proton transport. It is composed of a peripheral V1 domain that hydrolyzes ATP and an integral V0 domain that translocates protons. Subunit a is a 100-kDa integral membrane protein (part of V0) that possesses an N-terminal cytoplasmic domain and a C-terminal hydrophobic domain. Although the C-terminal domain functions in proton transport, the N-terminal domain is critical for intracellular targeting and regulation of V-ATPase assembly. Despite its importance, there is currently no high resolution structure for subunit a of the V-ATPase. Recently, the crystal structure of the N-terminal domain of the related subunit I from the archaebacterium Meiothermus ruber was reported. We have used homology modeling to construct a model of the N-terminal domain of Vph1p, one of two isoforms of subunit a expressed in yeast. To test this model, unique cysteine residues were introduced into a Cys-less form of Vph1p and their accessibility to modification by the sulfhydryl reagent 3-(N-maleimido-propionyl) biocytin (MPB) was determined. In addition, accessibility of introduced cysteine residues to MPB modification was compared in the V1V0 complex and the free V0 domain to identify residues protected from modification by the presence of V1. The results provide an experimental test of the proposed model and have identified regions of the N terminal domain of subunit a that likely serve as interfacial contact sites with the peripheral V1 domain. The possible significance of these results for in vivo regulation of V-ATPase assembly is discussed. PMID- 23740255 TI - Thermal and spectroscopic characterization of a proton pumping rhodopsin from an extreme thermophile. AB - So far retinylidene proteins (~rhodopsin) have not been discovered in thermophilic organisms. In this study we investigated and characterized a microbial rhodopsin derived from the extreme thermophilic bacterium Thermus thermophilus, which lives in a hot spring at around 75 degrees C. The gene for the retinylidene protein, named thermophilic rhodopsin (TR), was chemically synthesized with codon optimization. The codon optimized TR protein was functionally expressed in the cell membranes of Escherichia coli cells and showed active proton transport upon photoillumination. Spectroscopic measurements revealed that the purified TR bound only all-trans-retinal as a chromophore and showed an absorption maximum at 530 nm. In addition, TR exhibited both photocycle kinetics and pH-dependent absorption changes, which are characteristic of rhodopsins. Of note, time-dependent thermal denaturation experiments revealed that TR maintained its absorption even at 75 degrees C, and the denaturation rate constant of TR was much lower than those of other proton pumping rhodopsins such as archaerhodopsin-3 (200 *), Haloquadratum walsbyi bacteriorhodopsin (by 10 times), and Gloeobacter rhodopsin (100 *). Thus, these results suggest that microbial rhodopsins are also distributed among thermophilic organisms and have high stability. TR should allow the investigation of the molecular mechanisms of ion transport and protein folding. PMID- 23740257 TI - Sustainable capacity building among immigrant communities: the raising sexually healthy children program in Canada. AB - The Raising Sexually Healthy Children (RSHC) program is a peer-to-peer leadership training program for immigrant parents in Toronto, Canada. It was established in 1998 with the goal of promoting family sex education and parent-child communication. This evaluative study examined the developmental processes and outcomes of the RSHC program to identify the strengths, challenges and insights that can be used to improve the program. It employed a multi-case study approach to compare the RSHC programs delivered in the Chinese, Portuguese and Tamil communities. Data collection methods included focus groups, individual interviews and document analysis. The cross-case analysis identified both common and unique capacity building processes and outcomes in the three communities. In this paper, we report factors that have enhanced and hindered sustainable capacity building at the individual, group/organizational and community levels, and the strategies used by these communities to address challenges common to immigrant families. We will discuss the ecological and synergetic, but time-consuming processes of capacity building, which contributed to the sustainability of RSHC as an empowering health promotion program for immigrant communities. We conclude the paper by noting the implications of using a capacity building approach to promote family health in ethno-racial-linguistic minority communities. PMID- 23740258 TI - Weight status and depression: moderating role of fat talk between female friends. AB - This study examined whether engagement in fat talk would moderate the association between weight status (body mass index) and depression between female friends. Individuals' body mass index was significantly related to their own (actor effect) and friend's (partner effect) depression. For low-fat-talk friends, higher actor's body mass index was associated with higher actor's depression, but not for high-fat-talk friends. For high-fat-talk friends, higher actor's body mass index was associated with higher partner's depression, but not for low-fat talk friends. Theoretical and practical implications are discussed. PMID- 23740256 TI - In the beginning, Escherichia coli assembled the proto-ring: an initial phase of division. AB - Cell division in Escherichia coli begins by assembling three proteins, FtsZ, FtsA, and ZipA, to form a proto-ring at midcell. These proteins nucleate an assembly of at least 35 components, the divisome. The structuring of FtsZ to form a ring and the processes that effect constriction have been explained by alternative but not mutually exclusive mechanisms. We discuss how FtsA and ZipA provide anchoring of the cytoplasmic FtsZ to the membrane and how a temporal sequence of alternative protein interactions may operate in the maturation and stability of the proto-ring. How the force needed for constriction is generated and how the proto-ring proteins relate to peptidoglycan synthesis remain as the main challenges for future research. PMID- 23740259 TI - Fluency of pharmaceutical drug names predicts perceived hazardousness, assumed side effects and willingness to buy. AB - The impact of pharmaceutical drug names on people's evaluations and behavioural intentions is still uncertain. According to the representativeness heuristic, evaluations should be more positive for complex drug names; in contrast, fluency theory suggests that evaluations should be more positive for simple drug names. Results of three experimental studies showed that complex drug names were perceived as more hazardous than simple drug names and negatively influenced willingness to buy. The results are of particular importance given the fact that there is a worldwide trend to make more drugs available for self-medication. PMID- 23740260 TI - The relationship between perfectionism and engagement in preventive health behaviours: the mediating role of self-concealment. AB - If perfectionists avoid engaging in preventive health behaviours, they may be putting their long-term health and well-being at risk. Correlational analyses based on a sample of 370 university students identified maladaptive perfectionism to be associated with decreased levels of engagement in preventive health behaviours, life satisfaction and well-being and increased levels of self concealment and psychological distress. Adaptive perfectionism was associated with higher levels of engagement in preventive health behaviours. Self concealment was identified as a partial mediator in the relationship between maladaptive perfectionism and both engagement in preventive health behaviours and psychological distress. Implications of the findings are discussed. PMID- 23740261 TI - Materialism and well-being among Chinese college students: the mediating role of basic psychological need satisfaction. AB - Based on self-determination theory, this study explored the potential mediating role of basic psychological need satisfaction in the relationship between materialism and well-being among Chinese college students. The results showed that basic psychological need satisfaction partially mediated the relationship between materialism and life satisfaction and fully mediated the relationships among materialism and emotional well-being, subjective vitality, and self actualization. The findings indicated the importance of considering both subjective and psychological well-being and the interpretative power of basic psychological need satisfaction and Chinese culture in the flow from materialism to well-being. PMID- 23740262 TI - The psychological well-being of couples experiencing a chronic illness: a matter of personal and partner illness cognitions and the role of marital quality. AB - This study aimed to examine the effects of 75 cardiac patients' and their spouses' illness cognitions of acceptance and helplessness on their own and their partner's psychological symptoms, as well as the impact of marital quality. Dyadic responses were examined with the Actor-Partner Interdependence Model, while PROCESS was used to examine possible conditional indirect effects. Patients' and spouses' cognitions were related to their partners' symptoms through the partners' cognitions. These relationships were not statistically significant at the higher levels of marital quality. Thus, there seems to be a flow of information between partners, while marital quality may impact self regulation processes. PMID- 23740263 TI - A confirmatory factor analysis of the General Health Questionnaire-28 in a Black South African sample. AB - This study examined the latent factor structure of the General Health Questionnaire-28 (GHQ-28) in a Black South African sample (N = 523). Results of the single-group confirmatory factor analysis support the universal four-factor structure of general psychological health observed in Western samples. However, multigroup confirmatory factor analyses (i.e. split-sample cross-validation approach, conducted with invariance analyses) for a three-factor structure suggest that psychological health could have a less differentiated dimensional structure in some African populations. Theoretical and practical implications of the study results are discussed. PMID- 23740264 TI - Weekly variability in outcome expectations: examining associations with related physical activity experiences during physical activity initiation. AB - Little is known about how outcome expectations change after physical activity initiation and whether changes are associated with physical activity experiences. In a diary study, physically inactive adults (N = 102) initiated an exercise regimen and reported their experiences daily (e.g. progress toward goals) and corresponding outcome expectations weekly (e.g. how much progress they expect this week). Average levels (between-person effects) for eight experiences (ps < .01) and deviations from the average levels (within-person effects) for three experiences (ps < .05) were associated with changes in outcome expectations. The findings demonstrate that outcome expectations for exercise vary over time and are associated with people's subjective experiences. PMID- 23740265 TI - Assessing modern health worries: dimensionality and factorial invariance across age and sex of the Modern Health Worries Scale in a general population sample. AB - Previous work suggests a four-factor structure of the Modern Health Worries Scale. This study is the first to investigate its dimensionality and factorial invariance across age and sex in a representative population sample (N = 2524) using confirmatory factor analysis. The proposed four-factor model failed to achieve good model fit. Model fit was optimized by allowing correlating error terms resulting in acceptable model fit. Multi-group analysis revealed invariance across age and sex. Our study proved the proposed four-factor structure across age and sex. Consequently, the Modern Health Worries Scale can be applied in general population surveys using subscale scores. PMID- 23740266 TI - Gender-related personality traits, self-efficacy, and social support: how do they relate to women's waist circumference change? AB - This study investigated whether gender-role related traits agency and communion contribute to successful health behavior change, in an interplay with domain specific psychosocial factors, namely, agency, mediated by health-related self efficacy, and communion, moderated by social support. Data from women (N = 282) participating in the GOAL Lifestyle Implementation Trial were analyzed using structural equation modeling. Agency and increase in self-efficacy both independently predicted waist circumference reduction in the 1-year follow-up. Individuals high in communion succeeded in waist reduction only if they received social support. Initial self-efficacy increase predicted 3-year waist reduction. Gender-role orientation, together with social environment, influences behavior change intervention outcomes. PMID- 23740267 TI - Do affective attitudes predict organ donor registration? A prospective study. AB - This study assessed whether people's affective attitudes predicted organ donor registration at a later time. People who were not registered as an organ donor prior to completing the study (N = 150) first rated their affective attitudes towards organ donation. We then measured whether they clicked on a hyperlink to register as an organ donor. Believing that the body should be kept whole for burial (bodily integrity) was the only affective attitude to predict this organ donation behaviour. Future campaigns should target this concern in order to increase organ donor registration and the availability of donor organs. PMID- 23740268 TI - From men to the media and back again: help-seeking in popular men's magazines. AB - Men's help-seeking behaviour for health issues is apparent in advice columns in men's magazines. This study discursively analysed men's help-seeking letters and expert replies within two international and popular men's magazines, Men's Health and For Him Magazine or FHM. Findings showed that the texts reinforced hegemonic ideals. Letters positioning men as self-reliant, independently knowledgeable, stoic and avoiding associations with femininity were positively reinforced in expert replies, while other types of positioning were responded to with condescension or ridicule. Results suggest the policing of boundaries by 'experts' around unacceptable/acceptable enactments of masculinity, which may have implications for if, how and when men seek help from experts. PMID- 23740269 TI - Reflects the coat protein variability of apple mosaic virus host preference? AB - Apple mosaic virus (ApMV) is a widespread ssRNA virus which infects diverse species of Rosales. The phylogenetic analysis of complete capsid protein gene of the largest set of ApMV isolates discriminated two main clusters of isolates: one cluster correlates with Maloideae hosts and Trebouxia lichen algae hosts; a second with hop, Prunus, and other woody tree hosts. No correlation was found between clusters and geographic origin of virus isolates, and positive selection hypothesis in distinct hosts was not confirmed: in all virus populations, purifying selection had occurred. GGT->AAT substitution resulted in Gly->Asn change inside the zinc-finger motif in the capsid protein was revealed specific for discrimination of the clusters and we hypothesise that could influence the host preference. PMID- 23740271 TI - Electrogenerated chemiluminescence of BODIPY, Ru(bpy)3(2+), and 9,10 diphenylanthracene using interdigitated array electrodes. AB - Interdigitated array electrodes (IDAs) were used to produce steady-state electrogenerated chemiluminescence (ECL) by annihilation of oxidized and reduced forms of a substituted boron dipyrromethene (BODIPY) dye, 9,10-diphenylanthracene (DPA), and ruthenium(II) tris(bypiridine) (Ru(bpy)3(2+)). Digital simulations were in good agreement with the experimentally obtained currents and light outputs. Coreactant experiments, using tri-n-propylamine and benzoyl peroxide as a sacrificial homogeneous reductant or oxidant, show currents corresponding to electrode reactions of the dyes and not the oxidation or reduction of the coreactants. The results show that interdigitated arrays can produce stable ECL where the light intensity is magnified due to the larger currents as a consequence of feedback between generator and collector electrodes in the IDA. The light output for ECL is around 100 times higher than that obtained with regular planar electrodes with similar area. PMID- 23740270 TI - Genetic characterization of Thai swine influenza viruses after the introduction of pandemic H1N1 2009. AB - Pandemic H1N1 2009 (pH1N1), influenza virus containing triple reassortant internal genes (TRIG) from avian, human, and swine influenza viruses emerged in 2009 as a highly infectious virus that was able to be transmitted from humans to pigs. During June 2010-May 2012, influenza virus surveillance was conducted in Thai pig population. Twenty-three samples (1.75%) were successfully isolated from total of 1,335 samples. Interestingly, pH1N1 (7 isolates, 30.34%), reassortant pH1N1 (rH1N1) (1 isolate, 4.35%), Thai endemic H1N1 (enH1N1) (3 isolates, 13.04%), reassortant H3N2 with pH1N1 internal genes (rH3N2) (9 isolates, 39.13%), and reassortant H1N2 with pH1N1 internal genes (rH1N2) (3 isolates, 13.04%) were found. It should be noted that rH1N1, rH1N2, and rH3N2 viruses contained the internal genes of pH1N1 virus having a TRIG cassette descendant from the North American swine lineage. Although all isolates in this study were obtained from mild clinically sick pigs, the viruses were still highly infective and possibly may play an important role in human-animal interfacing transmission. In addition, the TRIG cassette may have an influence on antigenic shift resulting in emergence of novel viruses, as seen in this study. Continuing surveillance of influenza A natural hosts, particularly in pigs is necessary. PMID- 23740272 TI - Cancer, meta-analysis and reporting biases: the case of erythropoiesis stimulating agents. AB - Reporting and publication bias is a well-known problem in meta-analysis and healthcare research. In 2002 we conducted a meta-analysis on the effects of erythropoiesis-stimulating agents (ESAs) on overall survival in cancer patients, which suggested some evidence for improved survival in patients receiving ESAs compared with controls. However, a meta-analysis of individual patient data conducted several years later showed the opposite of our first meta-analysis, that is, evidence for increased on-study mortality and reduced overall survival in cancer patients receiving ESAs. We aimed to determine whether the results of our first meta-analysis could have been affected by publication and reporting biases and, if so, whether timely access to clinical study reports and individual patient data could have prevented this. We conducted a hypothetical meta-analysis for overall survival including all studies and study data that could have been available in 2002, at the time when we conducted our first meta-analysis. Compared with our original meta-analysis, which suggested an overall survival benefit for cancer patients receiving ESAs [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.67-0.99], our hypothetical meta-analysis based on the results of all studies conducted at the time of the first analysis did not show evidence for a beneficial effect of ESAs on overall survival (HR 0.97, 95% CI 0.83-1.12). Thus we have to conclude that our first meta-analysis showed misleading overall survival benefits due to publication and reporting biases, which could have been prevented by timely access to clinical study reports and individual patient data. Unrestricted access to clinical study protocols including amendments, clinical study reports and individual patient data is needed to ensure timely detection of both beneficial and harmful effects of healthcare interventions. PMID- 23740273 TI - Purulent vomica from subdiaphragmatic origin. PMID- 23740274 TI - Epidemiology and outcome of thrombocytopenic patients in the intensive care unit: results of a prospective multicenter study. AB - PURPOSE: To assess the epidemiology of intensive care unit (ICU) patients with thrombocytopenia (TP). METHODS: All consecutive ICU-admitted patients with TP either on admission or acquired during ICU stay were included. TP was defined as either absolute (platelet count <100 * 10(9)/L) or relative (decrease in the platelet count >30 %). Extensive diagnostic workup of TP including bone marrow aspiration was performed. RESULTS: Absolute TP was diagnosed in 208 patients and relative TP in 93. In six patients (2 %), no cause of TP was identified. The median number of TP etiologies per patient was two, with sepsis being the leading cause. Bone marrow aspirates were analyzed in 238 patients. They showed a normal megakaryocyte number in 221 (93 %) and provided novel information for diagnosis in 52 (22 %). Results were susceptible to having an impact on patient management in 22 cases (11 %). The frequency of bone marrow aspiration with results susceptible to having an impact on management did not differ between patients with and without disseminated intravascular coagulation (P = 0.22) and with and without sepsis/septic shock (P = 0.7) but was significantly lower in patients with relative TP than in those with absolute TP (P < 0.01). A serious bleeding event was observed in 30 patients (14.9 %) and a nadir platelet count below 50 * 10(9)/L was an independent risk factor (P < 0.05). CONCLUSIONS: In thrombocytopenic patients, sepsis is the leading cause of TP. Bone marrow aspirates may yield significant information on TP mechanisms and contribute to the subsequent management of patients, especially those with absolute TP. PMID- 23740275 TI - Innovative continuous non-invasive cuffless blood pressure monitoring based on photoplethysmography technology. AB - PURPOSE: To develop and validate a continuous non-invasive blood pressure (BP) monitoring system using photoplethysmography (PPG) technology through pulse oximetry (PO). METHODS: This prospective study was conducted at a critical care department and post-anesthesia care unit of a university teaching hospital. Inclusion criteria were critically ill adult patients undergoing invasive BP measurement with an arterial catheter and PO monitoring. Exclusion criteria were arrhythmia, imminent death condition, and disturbances in the arterial or the PPG curve morphology. Arterial BP and finger PO waves were recorded simultaneously for 30 min. Systolic arterial pressure (SAP), mean arterial pressure (MAP), and diastolic arterial pressure (DAP) were extracted from computer-assisted arterial pulse wave analysis. Inherent traits of both waves were used to construct a regression model with a Deep Belief Network-Restricted Boltzmann Machine (DBN RBM) from a training cohort of patients and in order to infer BP values from the PO wave. Bland-Altman analysis was performed. RESULTS: A total of 707 patients were enrolled, of whom 135 were excluded. Of the 572 studied, 525 were assigned to the training cohort (TC) and 47 to the validation cohort (VC). After data processing, 53,708 frames were obtained from the TC and 7,715 frames from the VC. The mean prediction biases were -2.98 +/- 19.35, -3.38 +/- 10.35, and -3.65 +/- 8.69 mmHg for SAP, MAP, and DAP respectively. CONCLUSIONS: BP can be inferred from PPG using DBN-RBM modeling techniques. The results obtained with this technology are promising, but its intrinsic variability and its wide limits of agreement do not allow clinical application at this time. PMID- 23740276 TI - Is it time to measure lung water by ultrasound? PMID- 23740277 TI - Effect of intensive care environment on family and patient satisfaction: a before after study. AB - PURPOSE: To determine to what extent intensive care unit environment affects family and patient satisfaction. METHODS: A before-after study was performed in one university hospital in The Netherlands, 2 months before and 2 months after the migration of an intensive care unit (ICU) with multiple beds on a ward to a newly built ICU with all single rooms. Family and patient satisfaction were determined by two surveys: family satisfaction with care in the ICU and patient satisfaction with care in the ICU, respectively. RESULTS: From 387 of 617 (63 %) discharged patients at least one survey (patient and/or family) was returned. Both family and patients were more satisfied with their overall ICU experience in the new ICU as compared with the old ICU. Mean scores for family satisfaction increased from 69.5 [standard deviation (SD) 16.6] to 74.1 (SD 15.2) for old and new ICU, respectively (p = 0.02). For patients, satisfaction rates increased from 63.6 (SD 18.9) to 69.6 (SD 18.3) for old and new ICU, respectively (p = 0.02). The largest differences on single items of the surveys were noted on environmental aspects. CONCLUSIONS: This is the first study to quantify the effect of ICU environment on family and patient satisfaction. Family and patient satisfaction with ICU experience increased by 6 % in the new ICU environment with noise-reduced, single rooms with daylight, adapted colouring and improved family facilities. PMID- 23740278 TI - High-volume versus standard-volume haemofiltration for septic shock patients with acute kidney injury (IVOIRE study): a multicentre randomized controlled trial. AB - PURPOSE: Septic shock is a leading cause of death among critically ill patients, in particular when complicated by acute kidney injury (AKI). Small experimental and human clinical studies have suggested that high-volume haemofiltration (HVHF) may improve haemodynamic profile and mortality. We sought to determine the impact of HVHF on 28-day mortality in critically ill patients with septic shock and AKI. METHODS: This was a prospective, randomized, open, multicentre clinical trial conducted at 18 intensive care units in France, Belgium and the Netherlands. A total of 140 critically ill patients with septic shock and AKI for less than 24 h were enrolled from October 2005 through March 2010. Patients were randomized to either HVHF at 70 mL/kg/h or standard-volume haemofiltration (SVHF) at 35 mL/kg/h, for a 96-h period. RESULTS: Primary endpoint was 28-day mortality. The trial was stopped prematurely after enrolment of 140 patients because of slow patient accrual and resources no longer being available. A total of 137 patients were analysed (two withdrew consent, one was excluded); 66 patients in the HVHF group and 71 in the SVHF group. Mortality at 28 days was lower than expected but not different between groups (HVHF 37.9 % vs. SVHF 40.8 %, log-rank test p = 0.94). There were no statistically significant differences in any of the secondary endpoints between treatment groups. CONCLUSIONS: In the IVOIRE trial, there was no evidence that HVHF at 70 mL/kg/h, when compared with contemporary SVHF at 35 mL/kg/h, leads to a reduction of 28-day mortality or contributes to early improvements in haemodynamic profile or organ function. HVHF, as applied in this trial, cannot be recommended for treatment of septic shock complicated by AKI. PMID- 23740279 TI - Time to reach a new steady state after changes of positive end expiratory pressure. AB - PURPOSE: To assess the time interval required to reach a new steady state of oxygenation-, ventilation-, respiratory mechanics- and hemodynamics-related variables after decreasing/increasing positive end expiratory pressure (PEEP). METHODS: In 23 patients (group 1) with acute respiratory distress syndrome (ARDS), PEEP was decreased from 10 to 5 cmH2O and, after 60', it was increased from 5 to 15 cmH2O. In 21 other ARDS patients (group 2), PEEP was increased from 10 to 15 cmH2O and, after 60', decreased from 15 to 5 cmH2O. Oxygenation, ventilation, respiratory mechanics and hemodynamic variables were recorded at time 5', 15', 30' and 60' after each PEEP change. RESULTS: When PEEP was decreased, PaO2, PaO2/FiO2, venous admixture and arterial oxygen saturation reached their equilibrium after 5'. In contrast, when PEEP was increased, the equilibrium was not reached even after 60'. The ventilation-related variables did not change significantly with PEEP. The respiratory system compliance, when PEEP was decreased, significantly worsened only after 60'. Hemodynamics did not change significantly with PEEP. In the individual patients the change of oxygenation related variables and of respiratory system compliance observed after 5' could predict the changes recorded after 60'. This was not possible for PaCO2. CONCLUSIONS: We could not find a unique equilibration time for all the considered variables. However, in general, a decremental PEEP test requires far lower equilibrium time than an incremental PEEP test, suggesting a different time course for derecruitment and recruitment patterns. PMID- 23740280 TI - Neurodevelopmental, educational and behavioral outcome at 8 years after neonatal ECMO: a nationwide multicenter study. AB - PURPOSE: Reporting neurodevelopmental outcome of 8-year-old children treated with neonatal extracorporeal membrane oxygenation (ECMO). METHODS: In a follow-up study in 135 8-year-old children who received neonatal ECMO between 1996 and 2001 we assessed intelligence (Revised Amsterdam Intelligence Test), concentration (Bourdon-Vos test), eye-hand coordination (Developmental Test of Visual-Motor Integration) and behavior (Child Behavior Checklist and Teacher Report Form). RESULTS: Intelligence fell within normal range (mean IQ 99.9, SD 17.7, n = 125) with 91 % of the children following regular education. Significantly more children attended special education (9 %) or received extra support in regular education (39 %) compared with normative data. Slower working speed (chi(2) = 132.36, p < 0.001) and less accuracy (chi(2) = 12.90, p < 0.001) were found on the Bourdon-Vos test (n = 123) compared with normative data. Eye-hand coordination fell within the normal range (mean 97.6, SD 14.3, n = 126); children with congenital diaphragmatic hernia scored lowest but still normally (mean 91.0, SD 16.4, n = 28). Mothers (n = 117) indicated more somatic and attention behavior problems; teachers (n = 115) indicated more somatic, social, thought, aggression and total problems compared with normative data. Mothers indicated more somatic problems than teachers (p = 0.003); teachers reported more attention problems than mothers (p = 0.036; n = 111). CONCLUSIONS: Eight-year-old children treated with neonatal ECMO fall in the normal range of intelligence with problems with concentration and behavior. Long-term follow-up for children treated with neonatal ECMO should focus on early detection of (subtle) learning deficits. PMID- 23740281 TI - Is early implementation of extracorporeal life support in severely colchicine poisoned patients lifesaving? Definitive evidence is still lacking. PMID- 23740282 TI - Mean systemic pressure: we can now estimate it, but for what? PMID- 23740283 TI - On being an intensivist. PMID- 23740284 TI - Effects of dobutamine on systemic, regional and microcirculatory perfusion parameters in septic shock: a randomized, placebo-controlled, double-blind, crossover study. AB - PURPOSE: The role of dobutamine during septic shock resuscitation is still controversial since most clinical studies have been uncontrolled and no physiological study has unequivocally demonstrated a beneficial effect on tissue perfusion. Our objective was to determine the potential benefits of dobutamine on hemodynamic, metabolic, peripheral, hepatosplanchnic and microcirculatory perfusion parameters during early septic shock resuscitation. METHODS: We designed a randomized, controlled, double-blind, crossover study comparing the effects of 2.5-h infusion of dobutamine (5 mcg/kg/min fixed-dose) or placebo in 20 septic shock patients with cardiac index >=2.5 l/min/m(2) and hyperlactatemia. Primary outcome was sublingual perfused microvascular density. RESULTS: Despite an increasing cardiac index, heart rate and left ventricular ejection fraction, dobutamine had no effect on sublingual perfused vessel density [9.0 (7.9-10.1) vs. 9.1 n/mm (7.9-9.9); p = 0.24] or microvascular flow index [2.1 (1.8-2.5) vs. 2.1 (1.9-2.5); p = 0.73] compared to placebo. No differences between dobutamine and placebo were found for the lactate levels, mixed venous-arterial pCO2 gradient, thenar muscle oxygen saturation, capillary refill time or gastric-to arterial pCO2 gradient. The indocyanine green plasma disappearance rate [14.4 (9.5-25.6) vs. 18.8 %/min (11.7-24.6); p = 0.03] and the recovery slope of thenar muscle oxygen saturation after a vascular occlusion test [2.1 (1.1-3.1) vs. 2.5 %/s (1.2-3.4); p = 0.01] were worse with dobutamine compared to placebo. CONCLUSIONS: Dobutamine failed to improve sublingual microcirculatory, metabolic, hepatosplanchnic or peripheral perfusion parameters despite inducing a significant increase in systemic hemodynamic variables in septic shock patients without low cardiac output but with persistent hypoperfusion. PMID- 23740286 TI - Electrical observation of sub-band formation in SnO2 nanobelts. AB - The electrical observation of energy sub-band formation in the electronic structure, that gives rise to the phenomenon of quantized transport is reported in tin oxide (SnO2) nanobelt back-gate field-effect transistors, at low temperatures. Sub-band formation was observed as current oscillations in the drain current vs. gate voltage characteristics, and was analyzed considering the nanobelt as a "quantum wire" with a rectangular cross-section and hard walls. The lateral quantum confinement in the nanowires created conditions for the successive filling of the first twelve electron energy sub-bands, as the gate voltage increases. When the source-drain voltage is changed, the oscillations are not dislocated with respect to the gate voltage indicating flat-band energies, and that the observations are incompatible with the phenomena of Coulomb blockade and tunnelling oscillations. The separation of the energy sub-bands was found to be in good agreement with the measured cross-section dimensions of the nanobelt and with the threshold temperature, since for T > 60 K the oscillations tend to vanish. PMID- 23740285 TI - Long-term results of treatment with diquafosol ophthalmic solution for aqueous deficient dry eye. AB - PURPOSE: To evaluate the preliminary long-term efficacy of diquafosol ophthalmic solution for aqueous-deficient dry eye. METHODS: Fifteen patients with mild-to moderate aqueous-deficient dry eye were enrolled. After a washout period, the patients were treated with 3 % diquafosol ophthalmic solution for 6 months. We assessed 12 subjective dry eye symptoms, corneal and conjunctival staining with fluorescein, tear film break-up time (BUT), lower tear meniscus height measured with anterior-segment optical coherence tomography, Schirmer's testing, and adverse reactions at baseline and 1, 3, and 6 months after the start of treatment. RESULTS: Treatment with diquafosol ophthalmic solution significantly improved dry eye symptoms, corneal staining, BUT, and tear meniscus height at 1 month and maintained the effectiveness for 6 months. Conjunctival staining significantly improved 3 and 6 months after treatment. No significant adverse reactions developed. CONCLUSIONS: Prolonged use of diquafosol ophthalmic solution for 6 months produced significant improvement both subjectively (dry eye symptom score) and objectively (ocular staining score and tear function tests) for aqueous-deficient dry eye. PMID- 23740287 TI - Recombinant allergen immunotherapy: clinical evidence of efficacy--a review. AB - Recombinant allergens for immunotherapy aim to overcome the problems of natural extracts as they can be produced in unlimited amounts with exact physiochemical and immunological properties. These can be modified to have more favourable characteristics including reduced IgE reactivity or enhanced immunogenicity. Different types of recombinant allergens have been evaluated in clinical phase II and III trials whilst others are currently under development. In this review, we identified double-blind, placebo-controlled randomised clinical trials assessing the efficacy and safety of various recombinant allergen preparations. The majority of studies have up to now focused on cat, grass, birch, ragweed and bee venom allergens. Some studies have shown some of these preparations to be effective and well tolerated. However, there are still outstanding issues regarding optimum doses, minimising side effects and long-term effects. PMID- 23740290 TI - Tobacco and alcohol during pregnancy: prevalence and determinants in Geneva in 2008. AB - OBJECTIVES: To describe alcohol and tobacco consumption during pregnancy in women giving birth in a public hospital in Geneva, to evaluate risk factors related to these consumptions and to explore the influence of close relatives on the consumption habits of pregnant women. METHODS: A cross-sectional questionnaire survey after delivery in 207 women in the maternity ward of the Geneva University Hospitals in 2008. We used retrospective self-reports of smoking during pregnancy (including temporary smoking), smoking during the entire pregnancy and alcohol drinking during pregnancy (even a single glass). RESULTS: The proportion of smokers decreased from 31.2% before pregnancy to 21.7% during pregnancy (temporary smoking included), and 9.2% of women smoked continuously until delivery. Major factors associated with tobacco use were living alone, living with a smoker and tobacco consumption of the husband/partner in the presence of the pregnant woman. Regarding alcohol consumption, 62.7% of the participants reported drinking (even occasionally) before pregnancy, and 36.3% of the women drank at least one glass of alcohol during pregnancy. The alcohol consumption of the husband/partner and invitations to drink from other people were associated with alcohol consumption during pregnancy. CONCLUSIONS: Among women delivering in a public hospital, tobacco and alcohol consumption during pregnancy was important and significantly influenced by the habits and attitude of close relatives. The involvement of relatives in health promotion interventions should be addressed. PMID- 23740289 TI - Anti-cancer IAP antagonists promote bone metastasis: a cautionary tale. AB - The bone microenvironment is complex, containing bone-forming osteoblasts, bone resorbing osteoclasts, bone-maintaining osteocytes, hematopoietic lineage cells, as well as blood vessels, nerves, and stromal cells. Release of embedded growth factors from the bone matrix via osteoclast resorption has been shown to participate in the alteration of bone microenvironment to facilitate tumor metastasis to this organ. Many types of malignancies including solid tumors and leukemias are associated with elevated levels of inhibitor of apoptosis (IAP) proteins, and IAP antagonists represent an important emerging class of anti cancer agents. IAPs exert anti-apoptotic roles by inhibiting caspases and upregulating pro-survival proteins, at least in part by activating classical NF kappaB signaling. In addition, IAPs act as negative regulators in the alternative NF-kappaB pathway, so that IAP antagonists stimulate this pathway. The role of the classical NF-kappaB pathway in IAP antagonist-induced apoptosis has been extensively studied, whereas much less attention has been paid to the role of these agents in the alternative pathway. Thus far, several IAP antagonists have been tested in preclinical and early stage clinical trials, and have shown promise in sensitizing tumor cells to apoptosis without significant side effects. However, recent preclinical evidence suggests an increased risk of bone metastasis caused by IAP antagonists, along with potential for promoting osteoporosis. In this review, the connection between IAP antagonists, the alternative NF-kappaB pathway, osteoclasts, and bone metastasis are discussed. In light of these effects of IAP antagonists on the bone microenvironment, more attention should be paid to this and other host tissues as these drugs are developed further. PMID- 23740292 TI - A randomized, double-blinded, placebo-controlled trial of oral Polypodium leucotomos extract as an adjunct to sunscreen in the treatment of melasma. PMID- 23740288 TI - IL-34 and CSF-1: similarities and differences. AB - Colony-stimulating factor-1 (CSF-1) is widely expressed and considered to regulate the development, maintenance, and function of mononuclear phagocyte lineage cells such as monocytes, macrophages, dendritic cells (DCs), Langerhans cells (LCs), microglia, and osteoclasts. Interleukin-34 (IL-34) was recently identified as an alternative ligand for the CSF-1 receptor (CSF-1R) through functional proteomics experiments. It is well established that the phenotype of CSF-1R-deficient (CSF-1R-/-) mice is more severe than that of mice bearing a spontaneous null mutation in CSF-1 (CSF-1(op/op)). CSF-1R-/- mice are severely depleted of macrophages and completely lack LCs, microglia, and osteoclasts during their lifetime. In contrast, CSF-1(op/op) mice exhibit late-onset macrophage development and osteoclastogenesis, whereas they show modestly reduced numbers of microglia and a relatively normal LC development. In contrast, IL-34 deficient (IL-34-/-) mice show a marked reduction of LCs and a decrease in microglia. IL-34 and CSF-1 display different spatiotemporal expression patterns and have distinct biological functions. In this review, we focus on the functional similarities and differences between IL-34 and CSF-1 in vivo. PMID- 23740293 TI - Biomolecular ligands screening using radiation damping difference WaterLOGSY spectroscopy. AB - Water-ligand observed via gradient spectroscopy (WaterLOGSY) is a widely used nuclear magnetic resonance method for ligand screening. The crucial procedure for the effectiveness of WaterLOGSY is selective excitation of the water resonance. The selective excitation is conventionally achieved by using long selective pulse, which causes partial saturation of the water magnetization leading to reduction of sensitivity, in addition to time consuming and error prone. Therefore, many improvements have been made to enhance the sensitivity and robustness of the method. Here we propose an alternative selective excitation scheme for WaterLOGSY by utilizing radiation damping effect. The pulse scheme starts simply with a hard inversion pulse, instead of selective pulse or pulse train, followed by a pulse field gradient to control the radiation damping effect. The rest parts of the pulse scheme are similar to conventional WaterLOGSY. When the gradient pulse is applied immediately after the inversion pulse, the radiation damping effect is suppressed, and all of the magnetization is inversed. When the gradient pulse and the inversion pulse are about 10-20 ms apart, the radiation damping effect remains active and drives the water magnetization toward +z-axis, resulting in selective non-inversion of the water magnetization. By taking the differences of the spectra obtained under these two conditions, one should get the result of WaterLOGSY. The method is demonstrated to be simple, robust and sensitive for ligand screening. PMID- 23740294 TI - Environmental transmission of a personality trait: foster parent exploration behaviour predicts offspring exploration behaviour in zebra finches. AB - Consistent behavioural differences among individuals are common in many species and can have important effects on offspring fitness. To understand such 'personality' variation, it is important to determine the mode of inheritance, but this has been quantified for only a few species. Here, we report results from a breeding experiment in captive zebra finches, Taeniopygia guttata, in which we cross-fostered offspring to disentangle the importance of genetic and non-genetic transmission of behaviour. Genetic and foster-parents' exploratory type was measured in a novel environment pre-breeding and offspring exploratory type was assessed at adulthood. Offspring exploratory type was predicted by the exploratory behaviour of the foster but not the genetic parents, whereas offspring size was predicted by genetic but not foster-parents' size. Other aspects of the social environment, such as rearing regime (uni- versus biparental), hatching position, brood size or an individual's sex did not influence offspring exploration. Our results therefore indicate that non-genetic transmission of behaviour can play an important role in shaping animal personality variation. PMID- 23740295 TI - Spermatophore consumption in a cephalopod. AB - An individual's gametes can represent a nourishing food source for a manipulative mate. Here, we provide evidence of ejaculate and sperm consumption in a cephalopod. Through labelling male spermatophores with (14)C radiolabel, we found that female squid, Sepiadarium austrinum, consumed the spermatophores of their partners and directed the nutrients received into both somatic maintenance and egg production. We further show that in this species-where fertilization occurs externally in the female's buccal cavity-sperm storage is short-term (less than 21 days). The combination of female spermatophore consumption and short-term external sperm storage has the potential to exert strong selection on male ejaculates and reproductive strategies. PMID- 23740296 TI - Genome-wide evolutionary response to a heat wave in Drosophila. AB - Extreme climatic events can substantially affect organismal performance and Darwinian fitness. In April 2011, a strong heat wave struck extensive geographical areas of the world, including Western Europe. At that time, we happened to resume and extend a long-term time series of seasonal genetic data in the widespread fly Drosophila subobscura, which provided a unique opportunity to quantify the intensity of the genetic perturbation caused by the heat wave. We show that the spring 2011 genetic constitution of the populations transiently shifted to summer-like frequencies, and that the magnitude of the genetic anomaly quantitatively matched the temperature anomaly. The results provide compelling evidence that direct effects of rising temperature are driving adaptive evolutionary shifts, and also suggest a strong genetic resilience in this species. PMID- 23740298 TI - Mechanism of septal bounce in constrictive pericarditis: a simultaneous cardiac catheterisation and echocardiographic study. PMID- 23740297 TI - Lack of fidelity revealed in an insect-fungal mutualism after invasion. AB - Symbiont fidelity is an important mechanism in the evolution and stability of mutualisms. Strict fidelity has been assumed for the obligate mutualism between Sirex woodwasps and their mutualistic Amylostereum fungi. This assumption has been challenged in North America where the European woodwasp, Sirex noctilio, and its fungal mutualist, Amylostereum areolatum, have recently been introduced. We investigate the specificity of the mutualism between Sirex and Amylostereum species in Canada, where S. noctilio co-infests Pinus with native Sirex nigricornis and its mutualist, Amylostereum chailletii. Using phylogenetic and culture methods, we show that extensive, reciprocal exchange of fungal species and strains is occurring, with 75.3 per cent of S. nigricornis carrying A. areolatum and 3.5 per cent of S. noctilio carrying A. chailletii. These findings show that the apparent specificity of the mutualism between Sirex spp. and their associated Amylostereum spp. is not the result of specific biological mechanisms that maintain symbiont fidelity. Rather, partner switching may be common when shifting geographical distributions driven by ecological or anthropogenic forces bring host and mutualist pairs into sympatry. Such novel associations have potentially profound consequences for fitness and virulence. Symbiont sharing, if it occurs commonly, may represent an important but overlooked mechanism of community change linked to biological invasions. PMID- 23740299 TI - Lipid-lowering therapy with statins reduces microparticle shedding from endothelium, platelets and inflammatory cells. AB - Hyperlipidaemia is a causal factor in the ethiopathogenesis of atherosclerosis. Statins are the cornerstone drug therapy for LDL-cholesterol (LDL-c) lowering, that exert beneficial effects beyond lipid lowering. Circulating microparticles (cMPs), microvesicles released by activated cells into the bloodstream, are markers of vascular and inflammatory cell activation with tentative role in disease progression. However, the role of statins on cMPs seems controversial. We aimed at the evaluation of the effects of lipid-lowering treatment (LLT) on cMP generation in patients in primary prevention of atherosclerosis. A case-control study was conducted in hypercholesterolaemic patients receiving LLT with statins and normocholesterolaemic controls (LLT+ and LLT-, respectively, n=37/group), matched by age, gender and LDL-c levels. cMPs were characterised by flow cytometry using annexin-V and cell-specific antibodies. In LLT+-patients overall numbers of cMPs (p<0.005) were lower than in controls. Levels of cMPs carrying parental cell markers from vascular and circulating cell origin (platelet, endothelial cell, pan-leukocyte and specific-leukocyte subsets) were significantly lower in blood of LLT+ compared to LLT--patients. Moreover, MPs from LLT+-patients had reduced markers of activated platelets (alphaIIbbeta3 integrin), activated inflammatory cells (alphaM-integrin) and tissue factor. The effect of LLT on cMP shedding was found to be accumulative in years. cMP shedding associated to cardiovascular risk in LLT+-patients. In summary, at similar plasma cholesterol levels patients on statin treatment had a significant lower number of cMPs carrying markers of activated cells. These findings indicate that statins protect against vascular cell activation. PMID- 23740300 TI - Particulate copper in soils and surface runoff from contaminated sandy soils under citrus production. AB - Soil contamination by copper (Cu) is a worldwide concern. Laboratory incubation and soil Cu characterization were conducted to examine the effects of external Cu loading and liming on Cu speciation in both bulk soil and particulates of an Alfisol and Spodosol under citrus production. Also, drainage water from the sites was evaluated for dissolved and particulate forms of Cu. Soil available Cu estimated by CaCl2, NH4OAc, or Mehlich-3 extraction significantly increased with external Cu loads and decreased with soil pH. Most increases in soil Cu occurred in the exchangeable and oxide-bound fractions. Organically bound Cu was the dominant fraction in both bulk soil and particulates, but more in particulates than bulk soil (P <= 0.001). Organically bound Cu was highly correlated with total recoverable Cu (P <= 0.01), increased significantly with external Cu loads (P <= 0.001), and decreased with soil pH (P <= 0.05). Lime addition converted part of Cu from available pools to more stable forms. Organically bound Cu complexes were found to dominate in soil solution or surface runoff. These results indicate that most Cu accumulated in the contaminated soils is highly mobile, and thus may impact citrus production and the environment. PMID- 23740301 TI - Neutralization/prevention of acid rock drainage using mixtures of alkaline by products and sulfidic mine wastes. AB - Backfilling of open pit with sulfidic waste rock followed by inundation is a common method for reducing sulfide oxidation after mine closure. This approach can be complemented by mixing the waste rock with alkaline materials from pulp and steel mills to increase the system's neutralization potential. Leachates from 1 m3 tanks containing sulfide-rich (ca.30 wt %) waste rock formed under dry and water saturated conditions under laboratory conditions were characterized and compared to those formed from mixtures. The waste rock leachate produced an acidic leachate (pH<2) with high concentrations of As (65 mg/L), Cu (6 mg/L), and Zn (150 mg/L) after 258 days. The leachate from water-saturated waste rock had lower concentrations of As and Cu (<2 MUg/L), Pb and Zn (20 MUg/L and 5 mg/L), respectively, and its pH was around 6. Crushed (<6 mm) waste rock mixed with different fractions (1-5 wt %) of green liquid dregs, fly ash, mesa lime, and argon oxygen decarburization (AOD) slag was leached on a small scale for 65 day, and showed near-neutral pH values, except for mixtures of waste rock with AOD slag and fly ash (5% w/w) which were more basic (pH>9). The decrease of elemental concentration in the leachate was most pronounced for Pb and Zn, while Al and S were relatively high. Overall, the results obtained were promising and suggest that alkaline by-products could be useful additives for minimizing ARD formation. PMID- 23740302 TI - Concentrations and distribution of organochlorine pesticides in pine needles of typical regions in Northern Xinjiang. AB - The residues of organochlorine pesticides (OCPs) in 29 pine needle samples of typical regions (including Shihezi, Beitun, and Kanas) in Northern Xinjiang was determined with a gas chromatograph equipped with an electron capture detector. Total OCPs concentrations in pine needles ranged from 2.94 to 186 ng/g dry weight, with a mean concentration of 39.63 ng/g. The results indicated that Beitun was the most polluted region while Kanas was the least polluted one. Hexachlorocyclohexanes (HCHs) and dichlorodiphenyltrichloroethanes (DDTs) were the predominant species in samples. Analysis of the sources of contamination showed that HCHs in the needles were derived from an old mixed source of technical HCHs or lindane. For DDTs, it was suspected to have recent application at some sites, which were derived mainly from a mixture of technical DDTs and dicofol containing DDT impurities. Categorical principal component analysis was performed in finding out more about the degradation behavior of DDTs and HCHs, which was identical with the results of source analysis. PMID- 23740303 TI - A comparative analysis of the characteristics of a range of real and synthetic wastewaters. AB - Synthetic wastewaters are widely used in many fields of wastewater research and operational management. However, few comparative studies have been conducted on the large number of published formulations. Eleven synthetic formulations simulating municipal wastewaters were selected based on their frequency of use, relative complexity, ease of formulation and cost and compared to two real municipal wastewaters. Synthetic wastewaters vary significantly in their compositions and characteristics, especially in terms of alkalinity, BOD K 1, SOUR, BODU, COD/BOD and C/N/P ratio, although they are portrayed as 'typical' in terms of characteristics and suitability for use. The pH, alkalinity and the presence of Ca and Mg should be considered in combination with the diluent used. Where the diluent is tap water, then the presence of treatment chemicals should also be considered. The effects of the micronutrients present are also an important factor. The study found that no single formulation is appropriate for all situations. Both the Syntho and Synthes formulations attempt to simulate real wastewater, whereas other formulations primarily act as readily biodegradable vectors for toxicity analyses, characterisation studies and treatment process evaluations. The criteria for choosing a particular synthetic wastewater very much depend on its intended application and require careful selection. PMID- 23740305 TI - [Spectral tomosynthesis - galactography with photon counting detector]. PMID- 23740304 TI - Activated sludge systems removal efficiency of veterinary pharmaceuticals from slaughterhouse wastewater. AB - The knowledge on the efficiency of wastewater treatment plants (WWTPs) from animal food production industry for the removal of both hormones and antibiotics of veterinary application is still very limited. These compounds have already been reported in different environmental compartments at levels that could have potential impacts on the ecosystems. This work aimed to evaluate the role of activated sludge in the removal of commonly used veterinary drugs, enrofloxacin (ENR), tetracycline (TET), and ceftiofur, from wastewater during a conventional treatment process. For that, a series of laboratory-controlled experiments using activated sludge were carried out in batch reactors. Sludge reactors with 100 MUg/L initial drug charge presented removal rates of 68 % for ENR and 77 % for TET from the aqueous phase. Results indicated that sorption to sludge and to the wastewater organic matter was responsible for a significant percentage of drugs removal. Nevertheless, these removal rates still result in considerable concentrations in the aqueous phase that will pass through the WWTP to the receiving environment. Measuring only the dissolved fraction of pharmaceuticals in the WWTP effluents may underestimate the loading and risks to the aquatic environment. PMID- 23740306 TI - [Asystole in endovascular procedure for juvenile nasopharyngeal fibroma]. PMID- 23740307 TI - [Delayed but nonetheless characteristic: the clinical manifestation of hypertrophic degeneration of the olivary nucleus]. PMID- 23740308 TI - [Splenic torsion in situs inversus abdominalis with polysplenia]. PMID- 23740309 TI - [Brown tumors: a pitfall in PET-CT diagnosis]. PMID- 23740310 TI - A rare cause of abdominal pain: emphysematous cystitis. PMID- 23740311 TI - Comparison of noninvasive imaging modalities for stenosis grading in mesenteric arteries. AB - OBJECTIVE: To prospectively analyze duplex sonography, CTA, and MRA with respect to stenosis grading of the celiac trunk (TC) and the superior mesenteric artery (SMA), with DSA as the reference. MATERIALS AND METHODS: 52 subjects were enrolled (mean age: 71). The image quality was graded: 1-insufficient, 2-bad, 3 moderate, 4-good or 5-excellent. Stenosis was graded: 1 (< 25 %), 2 (25 - < 50 %), 3 (50 - 75 %) or 4 (75 %). Two-sided chi-square tests were used to check for correlation of stenosis grading between modalities. The weighted Cohen's kappa was calculated to assess the strength of correlation. With a threshold of 50 % for non-relevant stenosis vs. relevant stenosis, the sensitivity, specificity, PPV, NPV, and accuracy were calculated. RESULTS: The mean image quality was 3.8 +/- 0.7, 3.1 +/- 1.0, 4.4 +/- 0.7, and 3.8 +/- 0.9 for DSA, duplex sonography, CTA, and MRA, respectively. For both TC and SMA, stenosis grading reached a significant level of correlation between each noninvasive modality with DSA (p < 0.001, each). The weighted Cohen's kappa for duplex sonography/CTA/MRA was 0.94/0.93/0.74, respectively, for the TC and 0.64/0.91/0.56, respectively, for the SMA. Highest sensitivity/specificity/NPV/PPV/accuracy were found for CTA with 100 %/95 %/85 %/100 %/96 % for the TC and with na/98 %/na/100 %/98 %, respectively, for the SMA. CONCLUSION: CTA provided the best image quality, reached the highest level of agreement and significance in correlation in stenosis grading, and offered the best diagnostic accuracy. PMID- 23740312 TI - MRI of the breast as part of the assessment in population-based mammography screening. AB - PURPOSE: To evaluate the indications and impact of MRI of the breast as an assessment modality in population-based mammography screening. MATERIALS AND METHODS: 135 consecutive contrast-enhanced MRI exams of the breast, which were performed between April 2007 and October 2012 as part of the assessment at one mammography screening unit before issuance of a final management recommendation (e. g. definitely benign or malignant), were retrospectively reviewed. Overall, the cases with an MRI exam of the breast during assessment represent less than 2 % of all assessment cases at this screening unit. All MRI exams were performed as part of the routine clinical care on a 1.5 T or 3 T whole-body magnet using a standard dynamic breast MRI protocol. RESULTS: In the 135 study patients, a total of 30 malignancies in 28 patients were found, including two bilateral cancers. One patient was diagnosed with a non-Hodgkin lymphoma, and of the remaining 29 malignant lesions, 3 (10 %) were in-situ cancers (DCIS) and 26 (90 %) were invasive breast cancers including 3 multifocal or multicentric cancers. All 26 detected invasive cancers were lymph-node negative and 25/29 (86 %) of the detected breast cancer were early stage cancers (stage 0 or 1). 53 of the 135 MRI exams (39.3 %) were suspicious for malignancy (BIRADS 4 or 5) with no cancer missed by MRI. The sensitivity, specificity, positive predictive value, and negative predictive value of the MRI on a per patient basis were 100 %, 77 %, 0.53, and 1, respectively. CONCLUSION: MRI is a useful problem-solving tool in mammography screening assessment with a high sensitivity and an acceptable positive predictive value. PMID- 23740313 TI - Enhancement of succinate production by metabolically engineered Escherichia coli with co-expression of nicotinic acid phosphoribosyltransferase and pyruvate carboxylase. AB - Escherichia coli BA002, in which the ldhA and pflB genes are deleted, cannot utilize glucose anaerobically due to the inability to regenerate NAD(+). To restore glucose utilization, overexpression of nicotinic acid phosphoribosyltransferase (NAPRTase) encoded by the pncB gene, a rate-limiting enzyme of NAD(H) synthesis pathway, resulted in a significant increase in cell mass and succinate production under anaerobic conditions. However, a high concentration of pyruvate accumulated. Thus, co-expression of NAPRTase and the heterologous pyruvate carboxylase (PYC) of Lactococcus lactis subsp. cremoris NZ9000 in recombinant E. coli BA016 was investigated. The total concentration of NAD(H) was 9.8-fold higher in BA016 than in BA002, and the NADH/NAD(+) ratio decreased from 0.60 to 0.04. Under anaerobic conditions, BA016 consumed 17.50 g l(-1) glucose and produced 14.08 g l(-1) succinate with a small quantity of pyruvate. Furthermore, when the reducing agent dithiothreitol or reduced carbon source sorbitol was added, the cell growth and carbon source consumption rate of BA016 was reasonably enhanced and succinate productivity increased. PMID- 23740314 TI - Flavipin in Chaetomium globosum CDW7, an endophytic fungus from Ginkgo biloba, contributes to antioxidant activity. AB - 1,2-Benzenedicarboxaldehyde-3,4,5-trihydroxy-6-methyl (flavipin) was found to be antagonistic against nematodes and fungi. Here we demonstrated that flavipin is a potent antioxidant in vitro and in vivo, which has great potential in the therapy for free radical-associated diseases. Therefore, flavipin-producing bio-source was screened from 80 endophytes in Ginkgo biloba. Seven endophytic fungi were able to synthesize antioxidant substances and identified by ITS rDNA sequences. Among them, Chaetomium globosum CDW7 was a remarkable producer of flavipin. The fermentation parameters of CDW7 were then optimized for high flavipin production. Cultured under the optimal condition (25 degrees C, 100/250 mL flask, 12 discs/flask, 150 rpm, pH 6.5) for 14 days, CDW7 was able to synthesize flavipin at a production of 315.5 mg/L. In addition, flavipin output was positively correlated to antioxidant activities of crude extracts with a correlation coefficient of 0.8235, indicating that flavipin was the major antioxidant component of CDW7's metabolites. These data demonstrated that CDW7 was a highly yielded bio-source of antioxidant flavipin. PMID- 23740315 TI - The nonattending physician. PMID- 23740316 TI - Frequency of isolation and antibiotic resistance of staphylococcal flora from external otitis of dogs. PMID- 23740317 TI - Similar challenges, different approaches: a review of student support systems in UK veterinary schools. PMID- 23740318 TI - The ECG in cardiovascular-relevant animal models of electrophysiology. AB - The most frequently used animal species in experimental cardiac electrophysiology are mice, rabbits, and dogs. Murine and human electrocardiograms (ECGs) show salient differences, including the occurrence of a pronounced J-wave and a less distinctive T-wave in the murine ECG. Mouse models can resemble human cardiac arrhythmias, although mice differ from human in cardiac electrophysiology. Thus, arrhythmia mechanisms in mice may differ from those in humans and should be transferred to the human situation with caution. Further relevant cardiovascular animal models are rabbits, dogs, and minipigs, as they show similarities of cardiac ion channel distribution with the human heart and are suitable to study ventricular repolarization or pro- and antiarrhythmic drug effects. ECG recordings in large animals like goats and horses are feasible. Both goats and horses are a suitable animal model to study atrial fibrillation (AF) mechanisms. Horses frequently show spontaneous AF due to their high vagal tone and large atria. The zebrafish has become an important animal model. Models in "exotic" animals such as kangaroos may be suitable for particular studies. PMID- 23740319 TI - Effect of heat application on the mechanical behaviour of glass ionomer cements. AB - OBJECTIVES: The aim of this study was to examine the long-term effect of heat on the mechanical behaviour of conventional highly viscous glass ionomer cements. Besides, the effect of storage time was evaluated. MATERIALS AND METHODS: Five cements (ChemFil Rock, Riva Self Cure, Fuji IX GP Fast, Equia and Ketac Molar Aplicap) were evaluated using three different preparation methods: no heat application, application of heat by means of a LED curing unit for 20 and 60 s. Four hundred fifty bar-shaped specimens were produced, maintained in distilled water at 37 degrees C and tested after 1 week, 1 month and 3 months (n = 10). The Vickers hardness, indentation modulus and creep were measured. In addition, the amount and size of the glass fillers and voids were examined using a light and a scanning electron microscope. RESULTS: Fuji IX GP Fast showed the highest Vickers hardness, Ketac Molar Aplicap showed the highest indentation modulus and the best value of creep was measured for Riva Self Cure. Vickers hardness, modulus of elasticity and creep resistance increased most for ChemFil Rock and Equia up to 1-month storage. CONCLUSIONS: Heat application showed no effect on the mechanical behaviour of ChemFil Rock, Fuji IX GP Fast and Equia at all ageing time. The impact of storage duration was low. CLINICAL RELEVANCE: Considering the measured mechanical properties, there is no need of using heat when restoring teeth with glass ionomer cements. PMID- 23740320 TI - Investigation of the prevalence, clinical features, and risk factors of dentin hypersensitivity in a selected Brazilian population. AB - OBJECTIVES: To evaluate the prevalence, clinical features, and risk factors of dentin hypersensitivity (DH) in a Brazilian population. MATERIALS AND METHODS: 300 patients at the Dentistry Clinic of the University of Sao Paulo participated in this study. The subjects completed a questionnaire regarding their personal information, the presence of DH, and some of its risk factors. Following completion of the questionnaire, a clinical examination was undertaken. To confirm the presence of DH, the subjects were evaluated with the use of a probe and cold air from a triple syringe. Statistical analysis was performed with the chi-square test and odds ratio, with the critical level p <0.05. RESULTS: The prevalence of DH was 46%. Females presented a higher prevalence than males (p <0.05). The left posterior region was affected by DH the most (maxilla = 41% and mandible = 36%). Cold was reported as the most common pain-inducing stimulus (88%). The pain was described as "discomfort" by 51% of the subjects with DH. Toothbrushing four times a day (p <0.05), toothbrushing with excessive force (p <0.05), bruxism (p <0.05), and gastroesophageal reflux (p <0.05) were strongly correlated with DH. CONCLUSIONS: The prevalence of DH was particularly high. The risk factors for DH were gender (female), toothbrushing four times a day, toothbrushing with excessive force, bruxism, and gastroesophageal reflux. CLINICAL RELEVANCE: DH was a common finding in this population suggesting that preventive measures considering its risk factors must be implemented in order to reduce or control the symptoms. PMID- 23740321 TI - Comparative clinical evaluation of different epinephrine concentrations in 4% articaine for dental local infiltration anesthesia. AB - OBJECTIVES: The aims of this study were to compare and evaluate the clinical anesthetic efficacy of five 4% articaine solutions with and without epinephrine in pulpal anesthesia after infiltration. MATERIALS AND METHODS: In a randomized, double-blinded, crossover study, ten volunteers received local anesthesia infiltration in the maxillary right central incisor with five different solutions (4% articaine + epinephrine 1:100,000, + epinephrine 1:200,000, + epinephrine 1:300,000, + epinephrine 1:400,000, without epinephrine). Electronic pulp tester was used to calculate the onset, utilization time, time to recede, and the surface integral under the time-effect curve. Additionally, cardiovascular parameters and post-experimental soft tissue anesthesia were examined. RESULTS: Onset as well as time to recede was not influenced by the epinephrine concentration. When using the epinephrine-free agent, time to recede was significantly shorter. Upon decreasing epinephrine concentration, duration of pulpal anesthesia and total anesthetic efficacy declined. The shortest time of anesthesia and lowest anesthetic efficacy were seen for the solution without epinephrine. No association was found between the local anesthetic drug and cardiovascular parameters. Soft tissue anesthesia was significantly shorter without epinephrine. CONCLUSIONS: This study shows the substantial benefits of vasoconstrictors in dental infiltration anesthesia. These findings were reflected by means of prolonged and deeper therapeutic effect in a dose-dependent manner. CLINICAL RELEVANCE: Even when utilizing agents with reduced amount of epinephrine, a safe anesthesia is possible. The epinephrine-free solutions resulted in a distinct limitation of utilization time and efficacy. PMID- 23740322 TI - Variation in joint stressing magnitudes during knee arthroscopy. AB - PURPOSE: When performing knee arthroscopy, joint stressing is essential to increase the operative joint space. Adequate training of joint stressing is important, since high stressing forces can damage knee ligaments, and low stressing might not give sufficient operative space. As forces are difficult to transfer since they cannot be seen, simulators might be suited to train joint stressing as they can visualise the amount of applied stress. This requires the joint stressing thresholds to be validated. The purpose of this study was to measure the variation in the maximum joint stressing forces applied by various surgeons in vivo in a human population and based on that derive thresholds for safe stressing. METHODS: From studies on ligament failure properties, we inferred a theoretical maximum stressing force of 78 N. Twenty-one patients were included, and knee arthroscopies were performed by five experienced surgeons. Forces solely performed in the varus and in valgus direction were measured. A load sensor was mounted on a belt, which was rotated along the hip to measure both varus and valgus stressing. The measurements started as soon as the interior of the knee joint was visualised using joint stressing. RESULTS: The average maximum stressing force was 60 N (SD = 28 N). The mean first frame force was 47 N (SD = 34 N). No significant differences were found between varus and valgus stressing. CONCLUSION: Since variation in stressing forces is high, offering training cases on simulators where the complete range of stressing forces can be experienced is recommended. Abiding to safety levels is essential to increase patient safety. PMID- 23740323 TI - Intra-articular injection of hyaluronic acid for the reduction in joint adhesion formation in a rabbit model of knee injury. AB - PURPOSE: Our purpose was to evaluate the effectiveness of intra-articular injections of hyaluronic acid (HA) into immobilized joints for reducing rigidity and formation of joint adhesions following surgery and prolonged joint immobilization. METHODS: Twenty-four New Zealand white rabbits were randomly divided into experimental (n = 12) and control groups (n = 12). A model of knee injury was created in the right hind leg, and external plaster fixation was performed for 8 weeks. The experimental and control groups received weekly intra articular injections of 0.3 mL HA solution or normal saline, respectively, in the knee joint. The degree of adhesions, range of motion (ROM), and collagen content of the synovium of the knee joint were observed after 8 weeks. RESULTS: At the end of 8 weeks, the experimental compared with control group had significantly higher mean ROM (70.3 degrees +/- 11.1 degrees vs. 54.6 degrees +/- 11.2 degrees , respectively; P = 0.002) and mean adhesion score. The experimental group compared with the control group had significantly lower mean adhesion score (2.2 +/- 0.9 vs. 3.1 +/- 0.7, respectively; P = 0.012) and collagen content (32.4 +/- 4.7 vs. 39.0 +/- 4.2 MUg/mg, P = 0.001). CONCLUSIONS: In a rabbit model of knee injury, intra-articular injection of HA decreased adhesion formation and collagen content and increased ROM after prolonged immobilization. These results indicate that HA may be clinically useful to prevent adhesions and improve joint mobility in patients who require joint immobilization for up to 8 weeks. PMID- 23740324 TI - Long-term outcomes of all-inside meniscal repair. AB - PURPOSE: The mean reported healing rate after meniscal repair is 60% of complete healing, 25% of partial healing and 15% of failure. However, partially or incompletely healed menisci are often asymptomatic in the short term. It is unknown whether the function of the knee with a partially or incompletely healed meniscus is disturbed in the long term. The purpose of this study was to assess the long-term outcomes of meniscal repairs according to the initial rate of healing. METHODS: Forty-one consecutive meniscal repairs were performed between 2002 and 2003. The median age at the time of surgery was 22 years (9-40). There were 25 medial and 16 lateral menisci. When present, all ACL lesions underwent reconstruction (61.3% of cases). According to Henning's criteria, by Arthro-CT at 6 months, twenty cases had healed completely, seven partially healed and four cases healed incompletely. RESULTS: At a mean follow-up of 114 +/- 10 months, 31 patients were retrospectively followed for clinical and imaging assessments. Objective IKDC score was good in 92% of the cases (17 IKDC A, 8 B and 2 C). The mean KOOS distribution was as follows: pain 94.3 +/- 9; symptoms 90.9 +/- 15; daily activities 98.7 +/- 2; sports activities 91.1 +/- 14; and quality of life 91.5 +/- 15. Twenty-three patients displayed no signs of osteoarthritis when compared to the non-injured knee, six patients had grade 1 osteoarthritis and two grade 2. The subjective IKDC score did not decrease with time (ns). Moreover, there were no differences between lateral and medial menisci (ns), in stable or stabilised knees (ns). The initial meniscal healing rate did not significantly influence clinical or imaging outcomes (ns). Four patients with no healing underwent a meniscectomy (12.9%). CONCLUSION: Arthroscopic all-inside meniscal repair with hybrid devices may provide long-term protective effects, even if the initial healing is incomplete. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 23740325 TI - Epidemiology of acute knee injuries seen at the Emergency Department at Umea University Hospital, Sweden, during 15 years. AB - PURPOSE: To describe the incidence and injury distribution of knee injuries in the general population of a European setting. METHODS: Retrospective study of all knee injuries registered at the Emergency Department at Umea University Hospital, Sweden, during 1995-2009 in relation to age, sex, diagnosis, location and activity at the time of injury, mechanism of injury, and treatment and/or follow up plan. RESULTS: During 1995-2009, 12,663 knee injuries were registered, 8% of all injuries. The incidence of knee injuries resulting in a visit to the Emergency Department was six cases per 1,000 person years. One-third of all injuries occurred during sports. And 30% were 15-24 years. More men than women were injured during sporting activities and women were mostly injured during transportation. CONCLUSION: Knee injuries in a general population are common and the injury distribution varies with age and sex. Sports activities and young age were prominent features of the injured population. LEVEL OF EVIDENCE: IV. PMID- 23740326 TI - Medial tibial pain pressure threshold algometry in runners. AB - PURPOSE: Pressure algometry (PA) may provide an objective and standardised tool in assessing palpation pain over the tibia. The purpose of this study was to analyse the intra-rater repeatability of PA and to determine whether tibial tenderness in healthy runners differ from runners with medial tibial stress syndrome (MTSS). METHODS: Pressure algometry was performed on 20 asymptomatic runners (40 legs) and 9 MTSS patients (14 symptomatic legs) at standardised locations along the medial border of the tibia. Intra-rater reliability was assessed in 10 randomly selected asymptomatic runners through repeated measurements 2 weeks later. RESULTS: Intra-rater reliability was moderate to excellent (ICC 0.53-0.90) in asymptomatic runners. Pain pressure threshold (PPT) was significantly reduced at 2/9-5/9 of the distance from the medial malleolus to the medial tibial condyle (p = 0.002-0.022). There was evidence of a statistically significant association between both height and weight, and PPT from the 3/9 (r = 0.416, p = 0.008) to 7/9 (r = 0.334, p = 0.035) and 3/9 (r = 0.448, p = 0.004) to 6/9 (r = 0.337, p = 0.034) area, respectively. In both MTSS patients and healthy runners, there was evidence of lower PPT in females compared to males (p = 0.0001-0.049) and a negative association between age and PPT (p = 0.001-0.033). MTSS patients had significantly lower PPT at the 3/9 site (p = 0.048) compared to asymptomatic runners. CONCLUSION: Pain pressure threshold algometry can be incorporated into MTSS clinical assessment to objectively assess pain and monitor progress. The presence of reduced medial tibial PPT in asymptomatic runners suggests that clinicians may not need to await resolution of medial tibia tenderness before allowing return to sport in MTSS patients. PMID- 23740327 TI - Tibial rotational osteotomy and distal tuberosity transfer for patella subluxation secondary to excessive external tibial torsion: surgical technique and clinical outcome. AB - PURPOSE: Recurrent patella subluxation may be secondary to excessive external tibial torsion. The purpose of this study is to evaluate the clinical and radiographic outcome of patients undergoing tibial derotation osteotomy and tibial tuberosity transfer for recurrent patella subluxation in association with excessive external tibial torsion. METHODS: A combined tibial derotation osteotomy and tibial tuberosity transfer was performed in 15 knees (12 patients) with recurrent patella subluxation secondary to excessive external tibial torsion. Clinical evaluation was carried out using preoperative and post operative Knee Society Score (KSS), Kujala Patellofemoral score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, the short form-12 (SF-12) and a visual analogue score (VAS) pain scale. RESULTS: The median follow-up period was 84 months (range 15-156) and median patient age was 34 years (range 19-57 years). The median preoperative external tibial torsion was 62 degrees (range 55 degrees -70 degrees ), with a median rotational correction of 36 degrees (range 30 degrees -45 degrees ) after surgery. Significant improvement (p < 0.05) was found in the KSS part I (37 +/- 14 to 89 +/- 11 points), KSS part II (25 +/- 26 to 85 +/- 14 points), Kujala score, the SF-12 outcome, WOMAC score and VAS score (8.8 +/- 1.9 to 2.4 +/- 1.5). Two patients had a nonunion of the tibial osteotomy site; one patient required bone grafting, while another patient required revision to total knee arthroplasty. CONCLUSION: Patients presenting with recurrent patella subluxation secondary to excessive external tibial torsion >45 degrees who underwent tibial derotation osteotomy and tibial tuberosity transfer achieved a satisfactory outcome in terms of pain relief and improved function. A significant complication was seen in 2/15 patients. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 23740328 TI - The concept of individualized anatomic anterior cruciate ligament (ACL) reconstruction. AB - PURPOSE: To describe the concept of individualized anatomic anterior cruciate ligament (ACL) reconstruction. METHODS: The PubMed/Medline database was searched using keywords pertaining to ACL reconstruction. Relevant articles were reviewed in order to summarize important concepts of individualized surgery in ACL reconstruction. Surgical experiences with case examples are also highlighted. RESULTS: Individualized ACL surgery allows for the customization of surgery to each individual patient. Accounting for graft selection and other characteristics such as anatomy, lifestyle and activity preferences may provide the patient with the best potential for a successful outcome. The surgeon should be comfortable with a variety of graft harvests and surgical techniques when practicing individualized surgery. CONCLUSION: Individualized anatomic ACL reconstruction is founded on the objective evaluation of functional anatomy and individual characteristics, thereby restoring the ACL as closely as possible to the native anatomy and function. The adoption and subsequent use of individualized surgery may facilitate improved clinical as well as objective outcomes, particularly in the long term. LEVEL OF EVIDENCE: V. PMID- 23740329 TI - C-Peptide and its career from innocent bystander to active player in diabetic atherogenesis. AB - The incidence and prevalence of diabetes are increasing worldwide. According to the International Diabetes Federation, more than 55 million people in the European region have diabetes, and this number is expected to rise to 64 million in 2030, with most of the cases being due to type 2 diabetes. Diabetes is associated with potentially serious microvascular and macrovascular complications such as nephropathy, neuropathy, and retinopathy as well as coronary artery disease. The pathophysiological mechanism behind this phenomenon is complex. In recent years the impact of proinsulin C-peptide in the development of vascular disease has been highlighted, but it displays differential function in type 1 and type 2 diabetes. In type 1 diabetes, which is characterized by a lack of insulin and C-peptide, supplementation of C-peptide has been shown to improve microvascular complications. In type 2 diabetes, however, C-peptide levels are increased above normal levels and correlate with the occurrence of macrovascular complications and cardiovascular deaths. This review focuses on the impact of C peptide in the atherogenic process. PMID- 23740330 TI - Renewed interest in basic and applied research involving monoclonal antibodies against an oncofetal Tn-antigen. AB - Tn-antigen (GalNAcalpha-Ser/Thr) is one of the most common aberrations associated with cancer progression and metastasis, and thus is an excellent target for development of cancer diagnostics and therapeutics. MLS128 monoclonal antibody (mAb), derived from a mouse immunized with human colon carcinoma cells, was reported to bind to two or three consecutive Tn-antigens (Tn2 or Tn3) with one order higher affinity for Tn3 than for Tn2. Our recent studies demonstrated that MLS128 significantly inhibits breast and colon cancer cell growth. Molecular cloning of the variable regions of heavy (VH) and light (VL) chains revealed that the VH sequence of MLS128 shared 97% nucleotide sequence identity with the VH of 83D4 mAb, derived from breast cancer-immunized mice, which has a similar affinity for Tn2/Tn3. MLS128 single-chain antibodies (scFv) and scFv-Fc were constructed to confirm the affinity for synthetic Tn2/Tn3 peptides. Thermodynamic studies on MLS128 binding to Tn2/Tn3 revealed its unique nature of temperature-dependent binding. PMID- 23740331 TI - Stereotactic body radiation therapy in stage I inoperable lung cancer: from palliative to curative options. AB - Surgery has historically been the standard of care for operable stage I non-small cell lung cancer (NSCLC). However, nearly one-quarter of patients with stage I NSCLC will not undergo surgery because of medical comorbidity or other factors. Stereotactic ablative radiotherapy (SABR) is the new standard of care for these patients. SABR offers high local tumour control rates rivalling the historical results of surgery and is generally well tolerated by patients with both peripheral and centrally located tumours. This article reviews the history of SABR for stage I NSCLC, summarises the currently available data on efficacy and toxicity, and describes some of the currently controversial aspects of this treatment. PMID- 23740333 TI - Nested melanoma, a newly defined entity. PMID- 23740332 TI - Reduction of urinary catheter use and prescription of antibiotics for asymptomatic bacteriuria in hospitalised patients in internal medicine: before and-after intervention study. AB - PRINCIPLES: Unnecessary treatment of asymptomatic bacteriuria and overuse of urinary catheters in hospitals are of concern regarding antimicrobial resistance and patient safety, respectively. We investigated the effectiveness of a multifaceted intervention in reducing urinary catheter use and unnecessary prescription of antibiotics for asymptomatic bacteriuria in hospitalised patients in a clinic for internal medicine. METHODS: Data were collected retrospectively from all inpatients during a 3-month period both before and after a multifaceted intervention from the Clinic for Internal Medicine of our secondary care hospital. The intervention consisted of implementation of guidelines, establishment of a standard for urinary catheter management, introduction of restricted orders and a reminder of indwelling catheters, as well as lectures and internet-based learning focusing on asymptomatic bacteriuria. RESULTS: The incidence rate of urinary catheter days decreased significantly from 27 to 17 catheter days per 100 patient days (incidence rate ratio 0.61, 95% confidence interval 0.57-0.67). The incidence rate of unnecessary antibiotic treatment days for asymptomatic bacteriuria dropped significantly from 22 to 10 treatment days per 1,000 patient days (incidence rate ratio 0.46, 95% confidence interval 0.33 0.63). CONCLUSIONS: A multifaceted intervention was effective in reducing both urinary catheter days and inappropriate antibiotic use for asymptomatic bacteriuria. PMID- 23740334 TI - Catalytic templating approaches for three-dimensional hollow carbon/graphene oxide nano-architectures. AB - We report a catalytic templating method to synthesize well-controlled three dimensional carbon nano-architectures. Depending on graphene oxide content, the morphology can be systematically tuned from layered composites to 3D hollow structures to microporous materials. The composites with high surface area and high porosity induce a significant enhancement to its capacitance at high current density. PMID- 23740335 TI - Mechanically induced deformation and strain dynamics in actin stress fibers. AB - It is becoming evident that physical forces in the microenvironment play a key role in regulating many important aspects of cell biology. However, although mechanical cues are known to have clear effects over the long-term (days), the short-term (seconds to minutes) cellular responses to mechanical stimuli are less well characterized. In our recent study, we exposed committed fibroblast cells to well controlled nanoscale forces while simultaneously imaging force transduction through the actin cytoskeleton. One of the earliest responses of a cell to physical force is rapid deformation of the cytoskeleton, taking place over the course of seconds. We were able to directly visualize deformation, force propagation and strain dynamics in actin stress fibers in response to a relatively simple mechanical stimulus. Moreover, these dynamics were also dependent on myosin-driven contractility and the presence of an intact microtubule cytoskeleton. Interestingly, although stem cells are sensitive to mechanical cues, they do not display the same degree of stress fiber organization as observed in committed cells indicating the possibility of alternative sensing and mechanotransduction mechanisms. PMID- 23740336 TI - Current topics in opioid therapy for pain management: addressing the problem of abuse. AB - Opioids are an established therapy for cancer pain and have become an accepted therapy for chronic noncancer pain. However, increased prescribing of opioids in recent years has been accompanied by an increase in prescription opioid abuse. All opioids have inherent potential for abuse, but gaps in healthcare provider understanding of or adherence to best prescribing practices may facilitate the misdirection of opioids for abuse. To address these concerns, the US Food and Drug Administration has required pharmaceutical manufacturers to develop Risk Evaluation and Mitigation Strategies (REMS) for prescribers of extended release/long-acting (ER/LA) opioids and has encouraged research to develop opioid formulations that are less easily abused or less attractive for abuse. The ER/LA opioid REMS require a partnership between the pharmaceutical industry, regulators, and healthcare providers to develop educational materials for physicians and patients that are not promotional. This article addresses challenges associated with improving the quality of pain care through support of prescriber education, developing formulations that combine efficacy with tamper resistant properties, and encouraging collaborative efforts by regulatory bodies, legislators, healthcare providers, and patient advocacy groups to achieve these ends. PMID- 23740339 TI - Efficacy of surgery for internal snapping hip. AB - Our purpose was to evaluate evidence regarding the effectiveness of open iliopsoas release and lengthening with arthroscopic approaches, which combine iliopsoas release with the treatment of intra-articular pathology as treatments for internal snapping hip syndrome. Searches were performed of 4 databases and 12 reports on the surgical treatment of internal snapping hip were reviewed. The authors tabulated data according to year of study, journal, study type, level of evidence, patient demographics, procedure, and outcomes. We found that surgical treatment of internal snapping hip improves patient symptoms in the majority of patients. Endoscopic release is associated with fewer reported complications compared with open release. All studies of endoscopic treatment of internal snapping hip syndrome also performed intra-articular examination and treatment of intra-articular pathology. The incidence of associated intra-articular pathology was reported in 5 of 6 studies. These results suggest that a painful snapping iliopsoas tendon in many cases may be a result of intra-articular hip pathology rather than an independent entity. Early studies suggest no difference in efficacy or associated complications rate when comparing extracapsular to transcapsular iliopsoas tendon release. Further studies are needed comparing operative to nonoperative treatment and methods of determining patients likely to benefit from operative intervention. PMID- 23740338 TI - Brain activity in predictive sensorimotor control for landings: an EEG pilot study. AB - Landing from a jump is related to predictive sensorimotor control. Frontal, central and parietal brain areas are known to play a role in this process based on online sensory feedback. This can be measured by EEG. However, there is only limited knowledge about brain activity during predictive preparation for drop landings (DL). The purpose is to demonstrate changes in brain activity in preparation for DL in different conditions. After resting, 10 athletes performed a series of DLs and were asked to concentrate on the landing preparation for 10 s before an auditory signal required them to drop land from a 30 cm platform. This task was executed before and after a standardized fatigue protocol. EEG spectral power was calculated during DL preparation. Frontal Theta power was increased during preparation compared to rest. Parietal Alpha-2 power demonstrated higher values in preparation after fatigue condition while lower limb kinematics remained unchanged. Cortical activity in frontal and parietal brain areas is sensitive for predictive sensorimotor control of drop landings. Frontal Theta power demonstrates an increase and is related to higher attentional control. In a fatigued condition the parietal Alpha-2 power increase might be related to a deactivation in the somatosensory brain areas. PMID- 23740337 TI - Treatment of Morton neuroma with botulinum toxin A: a pilot study. AB - BACKGROUND AND OBJECTIVE: Morton neuroma is a common cause of metatarsalgia of neuropathic origin. Systematic reviews suggest that insufficient studies have been performed on the efficacy of the different treatments available. OnabotulinumtoxinA has shown a degree of usefulness in other conditions associated with neuropathic pain. The aim of this study was to investigate the therapeutic potential of onabotulinumtoxinA in Morton neuroma. PATIENTS AND METHODS: We present an open-label, pilot study with 17 consecutive patients with Morton neuroma and pain of more than 3 months' duration that had not responded to conservative treatment with physical measures or corticosteroid injection. Patients received one onabotulinumtoxinA injection in the area of the neuroma. The main outcome measure was the variation in the pain on walking evaluated using a visual analogue scale (VAS) before treatment and at 1 and 3 months after treatment. The secondary outcome was the change in foot function, which was assessed using the Foot Health Status Questionnaire. RESULTS: In the overall group, the mean initial VAS score on walking was 7. This mean score had fallen to 4.8 at 1 month after treatment and to 3.7 at 3 months. Twelve patients (70.6 %) reported an improvement in their pain and five patients (29.4 %) reported no change; exacerbation of the pain did not occur in any patient. Improvements were also observed in two of the dimensions of the Foot Health Status Questionnaire: foot pain, which improved from a mean of 38.88 before treatment to 57 at 3 months, and foot function, which improved from a mean of 42.27 before treatment to 59.9 at 3 months. Clinical variables including age, sex, site and size of the lesion, standing activity, weekly duration of walking, footwear, foot type and footprint had no influence on the outcome. No adverse effects were reported. CONCLUSIONS: In this pilot study, injection with onabotulinumtoxinA was shown to be of possible usefulness to relieve the pain and improve function in Morton neuroma. This finding opens the door to further clinical research. PMID- 23740340 TI - Biomechanical and structural parameters of tendons in rats subjected to swimming exercise. AB - The aim of this study was to evaluate the effect of swimming exercise, without overloading, on the biomechanical parameters of the calcaneal tendon of rats. 27 male Wistar rats (70 days) were distributed randomly into 2 groups, Control Group (CG; n=15) with restricted movements inside the cage and Swimming Group (SG; n=12), subjected to exercise training in a tank with a water temperature of 30+/ 1 degrees C, for 1 h/day, 5 days/week for 8 weeks. All animals were kept in a reversed light/dark cycle of 12 h with access to food and water ad libitum. After that, they were anesthetized and had their calcaneus tendons collected from their left rear paws. The tendon was submitted to a mechanical test on a conventional test machine. From the stress vs. strain curve, the biomechanical data were analyzed. For the statistical analysis, the Student-T test was used (p<0.05). Of the variables examined, the maximum tension (p=0.009), maximum force (p=0.03), energy of deformation/tendon cross sectional area (p=0.017) and elastic modulus of the tendon (p=0.013) showed positive outcomes in SG. There was no difference in the other parameters. The results indicate that the swimming exercise training, without overloading, was an important stimulus for improving the biomechanical parameters and structural properties of the calcaneal tendon. PMID- 23740341 TI - Effect of a training week on heart rate variability in elite youth rugby league players. AB - The aim of this study was to examine the influence of weekly training including a competitive game on heart rate (HR) variability (HRV). Youth players (n=9, age 17 20 years) were monitored during daily supine rest (10 min) and standing (8 min), 5 times over 8 days. Heart rate recordings were analysed for time domain, frequency (e. g. low frequency [LF], high frequency [HF]) domain and non-linear measures of HRV and compared using ANOVA or Friedman's tests. Relationships between HRV and training workloads were examined via Spearman rank rho (rho) correlation coefficients. Prior to a game, mean HR was significantly increased and remained elevated until 2 days post-game while parasympathetic modulations (HF) were significantly reduced (p<0.05). The supine to standing change in HRV was significantly reduced for up to 4 days post-game (LF/HF ratio, - 1.0+/-2.9 vs. - 3.0+/-1.9, p<0.05). These results confirm that prior to a game, players exhibited reduced parasympathetic and/or predominant sympathetic modulation with the game significantly reducing autonomic responses to standing for up to the following 4 days. Identification of day to day fluctuations in HRV may provide a helpful tool for monitoring player workload to maximise training and game performance. PMID- 23740342 TI - Analysis of square-wave bouts to verify VO2max. AB - Submaximal and supramaximal square-wave bouts have been reported to consistently verify 'true' VO2max. Although a direct comparison between both protocols exists, knowledge on the statistical consistency between the protocols using the same group of participants is lacking. The purpose of this study was to conduct an analysis of the submaximal and supramaximal verification bout performed shortly subsequent to a graded exercise test (GXT). On 2 separate occasions, 6 males and 7 females (age: 29+/-9 years) completed a GXT protocol and an exhaustive, square wave bout at either end-GXT power minus 2-stages or 105% end-GXT power. No differences (p>0.05) in VO2max were observed between the GXT and square-wave bouts. The typical error (ml/kg/min) for submaximal (1.09) and supramaximal (1.04) trials was similar. Likewise, similar relative measures of consistency were observed for the submaximal (ICC alpha=0.97, CV=2.4%) and supramaximal trials (ICC alpha=0.95, CV=2.3%). For a GXT lasting ~10-12 min, the submaximal or supramaximal protocols appear to be equally effective. PMID- 23740343 TI - Repeated-sprint performance, locomotor profile and muscle oxygen uptake recovery: effect of training background. AB - The aim of the present study was to examine the respective importance of locomotor profile and muscle oxygen uptake (mV()O2) recovery on repeated-sprint ability (RSA) and overall repeated-sprint performance. 11 sprint- (STR) and 10 middle-distance-trained (MDTR) athletes (20.8+/-4.0 yr) performed an incremental test and a 40-to-50-m sprint to estimate their maximal aerobic (MAS) and sprinting (MSS) speeds. They also performed 6*30-m sprints, departing every 30 s, where mean (RS(mean)) sprint time was calculated. Muscle oxygenation (Near infrared spectroscopy, NIRS, [Hb(diff)]) was measured for ~ 4 min post test. The mean response time of [Hb(diff)]-mV()O2 recovery (monoexponential curve fitting, MRT[Hb(diff)]-mV()O2) was calculated. Compared with MDTR, STR presented faster MSS (+11.4+/-6.7%, with 99% chances to observe a substantially greater value) and RS(mean) (-3.7+/-5.4%, 78%), but slower MAS (-15.8+/-8.0%, 100%) and MRT[Hb(diff)]-mV()O2 (+46.2+/-31.7%, 96%). RS(mean) was largely correlated with MSS [r=-0.83 (90%CL, -0.92;-0.67)], but neither with MAS [r=-0.12 (-0.47;0.25)] nor MRT[Hb(diff)]-mV()O2 [r=-0.27(-0.58;0.11)]. RS(mean) adjusted for MSS (which indirectly reflects RSA) was largely correlated with both MAS [r=0.51(0.18;0.74)] and MRT[Hb(diff)]-mV()O2 [r=0.53(0.20;0.75)]. While a fast mV()O2 recovery is associated with an improved RSA, MSS remains of primary importance for overall repeated-sprint performance (i.e., RS(mean)). PMID- 23740345 TI - Surgical prevention of reflux after esophagectomy for cancer. AB - BACKGROUND: Reflux frequently occurs after a gastric conduit has replaced the resected esophagus. In this Swedish population-based cohort study, the potential antireflux effects of using cervical anastomosis, intrathoracic antireflux anastomosis, or pyloric drainage, and a risk of dysphagia due to cervical anastomosis and intrathoracic antireflux anastomosis were studied. METHODS: Patients undergoing esophagectomy with gastric conduit reconstruction in 2001 2005 were included. Reflux symptoms and dysphagia were assessed 6 months and 3 years postoperatively using a validated questionnaire (EORTC QLQ-OES18). The study exposures were cervical anastomosis, antireflux anastomosis, and pyloric drainage procedure. Multivariable logistic regression and propensity-adjusted analyses based on multinomial logistic regression estimated odds ratios (OR) with 95 % confidence intervals (CI), adjusted for potential confounding. RESULTS: A total of 304 patients were included in the study. Adjusted ORs for reflux symptoms were 0.9 (95 % CI 0.3-2.2) for patients with a cervical anastomosis compared to patients with an intrathoracic anastomosis, 0.9 (95 % CI 0.4-2.0) for patients with an antireflux anastomosis versus patients with a conventional anastomosis, and 1.5 (95 % CI 0.9-2.6) for patients after pyloric drainage versus patients without such a pyloric drainage procedure. Dysphagia was not statistically significantly increased after cervical anastomosis or antireflux anastomosis. ORs were virtually similar 3 years after surgery. No interactions were identified. The propensity analyses rendered similar results as the logistic regression models, except for a possibly increased dysphagia with a cervical anastomosis. CONCLUSIONS: Cervical anastomosis, antireflux anastomosis, and pyloric drainage do not seem to prevent reflux symptoms 6 months or 3 years after esophagectomy for cancer with a gastric conduit. PMID- 23740344 TI - International rates of breast reconstruction after prophylactic mastectomy in BRCA1 and BRCA2 mutation carriers. AB - BACKGROUND: Breast reconstruction is an option for women with BRCA1 or BRCA2 mutations who elect to undergo prophylactic mastectomy to prevent breast cancer. We report on the uptake of breast reconstruction after prophylactic mastectomy in women with BRCA mutations from eight countries. METHODS: Women with a BRCA1 or BRCA2 mutation were questioned regarding their cancer preventive practices. Information was recorded on prophylactic mastectomy and breast reconstruction. RESULTS: A total of 1,635 women with a BRCA1 or BRCA2 mutation who elected to undergo prophylactic mastectomy from eight countries were included. A total of 1,137 women (69.5%) had breast reconstruction after prophylactic mastectomy. A total of 58.7% of women over the age of 45 years at the time of prophylactic mastectomy had breast reconstruction compared to 77.6% of women 35 years of age or younger [odds ratio (OR) 0.36, 95% confidence interval (CI) 0.26-0.50, p < 0.001]. In addition, 62.9% of women with a breast cancer diagnosis (contralateral prophylactic mastectomy) had breast reconstruction after prophylactic mastectomy compared to 79.7% of women without a previous breast cancer diagnosis (OR 0.48, 95% CI 0.38-0.61, p < 0.001). A total of 66.9% of women from Canada had breast reconstruction after mastectomy compared to 71.9% of American women (OR 0.75, 95% CI 0.59-0.96, p = 0.02). CONCLUSIONS: The majority of women elect for breast reconstruction after prophylactic mastectomy. However, younger women and those without a previous diagnosis of breast cancer are more likely to have breast reconstruction than older women or those with a previous diagnosis of cancer. PMID- 23740346 TI - Italian Adolescent Gambling Behaviour: Psychometric Evaluation of the South Oaks Gambling Screen: Revised for Adolescents (SOGS-RA) among a sample of Italian students. AB - Since no Italian validated instrument focuses specifically on the measurement of pathological gambling in very young people, with this study, we aim to adapt an international instrument (SOGS-RA) and assess its psychometric properties in a sample (n = 14.910) of young Italian students aged between 15 and 19 years. Cross cultural adaptation of the instrument was performed through translation, synthesis of translation, back-translation, expert committee review, and pre testing. The kappa statistic for test-retest concordance ranged from 0.53 to 0.80. Internal validity was assessed by the MCA that identified one principal component with eigenvalue equal to 3,875: the Divgi index and very simple structure analysis also pointed out one common factor, so uni-dimensionality of the SOGS-RA was accepted. Moreover the SOGS-RA was found to have acceptable internal consistency (alpha = 0.780). Cronbach's alpha was also assessed separately among males and females (respectively 0.786 and 0.707). The SOGS-RA was assessed in relation to gambling frequency, alcohol and drug use: Chi squared test revealed a strong association both for males and females with gambling frequency (p value <= 0.0001), frequent use of illicit drugs (for each drug p value <= 0.0001) and having had 3 or more occasions of binge drinking in the last month (p value <= 0.0001). At the end we can say that, the results of our study suggest that the SOGS-RA screen may be useful to assess at-risk or problem gambling for both genders in comprehensive youth surveys. PMID- 23740347 TI - Show me the money: incorporating financial motives into the gambling motives questionnaire. AB - Although research has only recently begun to measure what motivates all levels of gambling involvement, motives could offer a theoretically interesting and practical way to subtype gamblers in research and for responsible gambling initiatives. The Gambling Motives Questionnaire (GMQ) is one measure that weaves together much of the gambling motives literature, but it has been criticized for neglecting financial reasons for gambling. This study uses a series of factor analyses to explore the effect of adding nine financial motives to the GMQ in a heterogeneous sample of 1,014 adult past-year gamblers. After trimming trivial financial motives, the penultimate factor analysis of the 15 GMQ items and four financial motives led to a four-factor solution, with factors tapping enhancement, social, coping and financial motives, as predicted. A final factor analysis performed on a modified GMQ-F (i.e., 16 items, including a financial subscale) revealed the same four factors, and hierarchical regression showed that the financial motives improve the GMQ-F's prediction of gambling frequency. This study provides evidence that omitting financial motives is a clear gap in the GMQ, yet suggests that the GMQ is a promising tool that can be conceptually and empirically strengthened with the simple addition of financial items. PMID- 23740348 TI - Gambling harms and gambling help-seeking amongst indigenous Australians. AB - This paper aimed to analyze the harms arising from gambling and gambling-related help-seeking behaviour within a large sample of Indigenous Australians. A self selected sample of 1,259 Indigenous Australian adults completed a gambling survey at three Indigenous sports and cultural events, in several communities and online. Based on responses to the problem gambling severity index (PGSI), the proportions of the sample in the moderate risk and problem gambler groups were higher than those for the population of New South Wales. Many in our sample appeared to face higher risks with their gambling and experience severe gambling harms. From PGSI responses, notable harms include financial difficulties and feelings of guilt and regret about gambling. Further harms, including personal, relationship, family, community, legal and housing impacts, were shown to be significantly higher for problem gamblers than for the other PGSI groups. Most problem gamblers relied on family, extended family and friends for financial help or went without due to gambling losses. Nearly half the sample did not think they had a problem with gambling but the results show that the majority (57.7 %) faced some risk with their gambling. Of those who sought gambling help, family, extended family, friends and respected community members were consulted, demonstrating the reciprocal obligations underpinning traditional Aboriginal culture. The strength of this finding is that these people are potentially the greatest source of gambling help, but need knowledge and resources to provide that help effectively. Local Aboriginal services were preferred as the main sources of professional help for gambling-related problems. PMID- 23740349 TI - An examination of factors driving chinese gamblers' fallacy bias. AB - Gambling is a leisure activity, which is enjoyed by many people around the world. Among these people, Chinese are known for their high propensity to gamble and are highly sought after by many casinos. In this exploratory study, the effect of two types of fallacy bias-positive recency and negative recency-on the betting behavior of Chinese gamblers is investigated. Although the influence of fallacy bias on a betting decision is well documented, little is known about the interaction of the factors that dictate fallacy bias. Drawing from an analysis of 2,645 betting decisions, the results show that Chinese gamblers primarily endorse positive recency, especially when the latest outcome is more frequent. This is contrary to most findings on Western subjects in which negative recency is more common. Current findings have meaningful implications to casino gaming entertainment businesses and public policymakers. PMID- 23740350 TI - Examining gambling-related crime reports in the National Finnish Police Register. AB - The aim of this study is to examine the connection between gambling and criminal activity in the National Finnish Police Register. First, a method was created that enabled the search for gambling-related police reports in the National Finnish Police Register. The method is based on finding gambling-related police reports by using gambling-related headwords. Second, all police reports from 2011 that included any mention of gambling were read through (n = 2,233). Suspected gambling-related of crimes (n = 737) were selected from these reports. Those suspected gambling-related crimes were then described and categorized into six different categories: suspected online-related crimes; suspected crimes that were related to lifestyle-gaming; suspected crimes that involved a gambler as a victim of a crime; criminal activity related to problem gambling; casino-connected crimes, and intimate partnership violence resulting from gambling problems. This study, being the first in Finland, generated information on the connection between gambling and criminal activity from the perspective of police reports. Moreover, the study highlights methodological issues that are involved in studying police reports. PMID- 23740352 TI - [Gastroenterology in Germany today: development, achievements, challenges]. PMID- 23740351 TI - On being attracted to the possibility of a win: reward sensitivity (via gambling motives) undermines treatment seeking among pathological gamblers. AB - Unfortunately, only a small percent of pathological gamblers seek the professional help they need. In the current study, we test the idea that individual differences in reward sensitivity should predict whether a pathological gambler has sought treatment-the odds of treatment seeking should decrease as reward sensitivity increases. This hypothesis rests on the proposition that reward sensitive pathological gamblers should find treatment seeking aversive because doing so would remove a route to reward. We also tested those motivations to gamble that are positively reinforcing (social affliction and self-enhancement) as a possible mechanism by which reward sensitivity undermines treatment seeking-we did not anticipate negatively reinforcing motivations (e.g., coping) to be a mechanistic variable. Ninety-two pathological gamblers completed a large-scale survey that contained the variables of interest. As predicted, pathological gamblers were less likely to have sought treatment as reward sensitivity increased. Moreover, this relationship was mediated by social affiliation motivations to gamble, but not self-enhancement or coping motives. Reward sensitive gamblers did not wish to seek treatment to the extent that they were motivated to gamble for the social interactions it provides-seeking treatment would cut this avenue of affiliation with others. In light of these results, we suggest health care professionals take reward sensitivity into account when trying to promote treatment seeking, to say nothing of the social affiliation motives that underlie the reward sensitivity-treatment seeking link. PMID- 23740354 TI - Self-expandable metal stent for malignant colonic obstruction: outcome in proximal vs. left sided tumor localization. AB - INTRODUCTION: The aim of this study was to evaluate the outcome of through-the scope (TTS) implanted self-expanding metal stent (SEMS) comparing left-sided vs. proximal placement with regard to complications and outcome in palliation of malignant colorectal obstruction. MATERIAL AND METHODS: All patients were consecutively retrospectively enrolled to this study between January 2009 and February 2012 due to impending or prevalent complete malignant colorectal obstruction. TTS applicable uncovered nitinol SEMS with unique flexible properties were used (Taewoong Medical, South Korea). Left-sided obstruction (aboral from the left flexure) was compared to proximal (from the ileo-cecal valve to the left flexure) localization. All patients have been discussed in the interdisciplinary tumor conference and the recommendation to treat by endoscopic stent placement was given in consensus. RESULTS: A total of 15 patients was enrolled to this study (10 male and 5 female; mean age 68.3 +/- 15.4 years, range 48 - 94), five patients with obstructions located in the proximal hemicolon whereas ten patients had a left-sided malignancy. Technical success was achieved in all cases and there was no early complication noticed. Three late complications included tumor overgrowth (n = 1), stent occlusion (1), and dislocation (1). Stent-in-stent insertion achieved, again, clinical success. The site of SEMS implantation (proximal vs. left colon) had no impact on patient outcome or complication rate. SEMS patency duration was 269.8 +/- 175.2 days (range 30 - 570) and mean survival of the patients was 305.1 +/- 279.3 days (range 16 - 990). CONCLUSION: TTS application of flexible, non-covered SEMS seems to be safe and effective for palliation of malignant colorectal obstruction independent of localization of the tumor in the colon. PMID- 23740355 TI - [Focal liver lesions in patients with malignant haematological disease: value of B-mode ultrasound in comparison to contrast-enhanced ultrasound--a retrospective study with N = 61 patients]. AB - PURPOSE: The aim of the retrospective study is to illustrate the role of contrast enhanced ultrasound (CEUS) in the dignity assessment of focal liver lesions compared to B-mode ultrasound (US) in patients with malignant haematological diseases (MHD). PATIENTS AND METHODS: Focal liver lesions were diagnosed in n = 61 patients (24 female, 37 male) with MHD via US within the period from November 2005 to February 2009. After the presentation of a not clearly cystic liver lesion (n = 48), CEUS was performed and documented in addition to US. The underlying diagnoses were stem cell diseases (n = 31) and malignant lymphomas (n = 30). The detection of a lesion was documented in n = 17 patients with at this time point primary diagnosed haematological disease, n = 13 patients were in relapse and n = 31 in complete remission (CR). The diagnoses of the liver pathology were confirmed through sonographic follow-up studies and clinical courses (n = 22), CT/MRI (n = 18) and histology (n = 21). RESULTS: In total 67 % of the cases were diagnosed as benign and 33 % as malignant liver lesions. Regarding the therapeutic state, the numbers of benign lesions differ from those of malignant lesions: primary diagnosis 53 vs. 47 %, relapse 69 vs. 31 %, CR 90 vs. 10 %. The frequency distributions of benign versus malignant lesions were 94 vs. 6 % in patients with stem cell diseases and 40 vs. 60 % in patients with malignant lymphomas. Regarding dignity assessment of focal liver lesions, CEUS showed a sensitivity of 90 vs. 45 % and specificity of 96 vs. 18 % (p < 0.0001) compared to US. CONCLUSION: CEUS possesses a significant diagnostic value in the characterization of focal liver lesions and should be used in the context of staging procedures in patients with MHD. PMID- 23740356 TI - Sedation-associated complications in endoscopy--prospective multicentre survey of 191142 patients. AB - BACKGROUND/AIMS: Propofol sedation is applied as moderate sedation for almost all diagnostic and interventional endoscopies. Propofol sedation bears the risk of complications such as respiratory as well as cardiopulmonary insufficiency including sedation-induced death. According to recent guidelines, non anesthesiologist-administered propofol (NAAP) should be performed by an additional person who has NAAP as their sole task. METHODS: In a prospective multicentre survey involving 191,142 patients, clinically relevant endoscopy associated complications were registered from 02/2010 to 01/2012. RESULTS: The majority of propofol sedations were applied without additional persons for NAAP. Overall endoscopy-related complication rate was 0.0022 % (n = 424) and sedation related complications 0.00 042 % (n = 82). Variability over time and between the clinics was low and not influenced by the number of endoscopies performed during the investigation period. Sedation-related death occurred in 6 patients (0.00 003 %), 50 % during emergency endoscopies. In all sedation-associated deaths the patients had ASA class 3 before endoscopy. All fatal complications occurred in the presence of an additional trained person for NAAP. CONCLUSION: This large prospective survey shows that propofol sedation in gastrointestinal endoscopy is a safe procedure with a low potential of risk in daily routine. However, high risk patients (ASA >= 3) should be identified, especially before emergency endoscopies and managed by additional persons for NAAP and under intensive care surveillance. PMID- 23740357 TI - Multiplanar reconstruction computed tomography for diagnosis of scaphoid waist fracture union: a prospective cohort analysis of accuracy and precision. AB - OBJECTIVE: To examine reliability and validity concerning union of scaphoid fractures determined by multiplanar reconstruction computed tomography randomized at 6, 12, and 24 weeks after injury. MATERIALS AND METHODS: We used Fleiss' kappa to measure the opinions of three observers reviewing 44 sets of computed tomographic scans of 44 conservatively treated scaphoid waist fractures. We calculated kappa for the extent of consolidation (0-24 %, 25-49 %, 50-74 %, or 75 100 %) on the transverse, sagittal and coronal views. We also calculated kappa for no union, partial union, and union, and grouped the results for 6, 12, and 24 weeks after injury. As the reference standard for union, CT scans were performed at a minimum of 6 months after injury to determine validity. RESULTS: Overall inter-observer agreement was found to be moderate (kappa = 0.576). No union (kappa = 0.791), partial union (kappa = 0.502), and union (kappa = 0.683) showed substantial, moderate, and substantial agreement, respectively. The average sensitivity of multiplanar reconstruction CT for diagnosing union of scaphoid waist fractures was 73 %. The average specificity was 80 %. CONCLUSIONS: Our results suggest that multiplanar reconstruction computed tomography is a reliable and accurate method for diagnosing union or nonunion of scaphoid fractures. However, inter-observer agreement was lower with respect to partial union. PMID- 23740353 TI - [Determinant-based classification of acute pancreatitis severity. International multidisciplinary classification of acute pancreatitis severity: the 2013 German edition]. AB - OBJECTIVE: The aim of this study was to develop a new international classification of acute pancreatitis severity on the basis of a sound conceptual framework, comprehensive review of published evidence, and worldwide consultation. BACKGROUND: The Atlanta definitions of acute pancreatitis severity are ingrained in the lexicon of pancreatologists but suboptimal because these definitions are based on empiric descriptions of occurrences that are merely associated with severity. METHODS: A personal invitation to contribute to the development of a new international classification of acute pancreatitis severity was sent to all surgeons, gastroenterologists, internists, intensive medicine specialists, and radiologists who are currently active in clinical research on acute pancreatitis. The invitation was not limited to members of certain associations or residents of certain countries. A global Web-based survey was conducted and a dedicated international symposium was organised to bring contributors from different disciplines together and discuss the concept and definitions. RESULT: The new international classification is based on the actual local and systemic determinants of severity, rather than descriptions of events that are correlated with severity. The local determinant relates to whether there is (peri)pancreatic necrosis or not, and if present, whether it is sterile or infected. The systemic determinant relates to whether there is organ failure or not, and if present, whether it is transient or persistent. The presence of one determinant can modify the effect of another such that the presence of both infected (peri)pancreatic necrosis and persistent organ failure have a greater effect on severity than either determinant alone. The derivation of a classification based on the above principles results in 4 categories of severity mild, moderate, severe, and critical. CONCLUSIONS: This classification is the result of a consultative process amongst pancreatologists from 49 countries spanning North America, South America, Europe, Asia, Oceania, and Africa. It provides a set of concise up-to-date definitions of all the main entities pertinent to classifying the severity of acute pancreatitis in clinical practice and research. This ensures that the determinant-based classification can be used in a uniform manner throughout the world. PMID- 23740360 TI - Self-assembly and chemical processing of block copolymers: a roadmap towards a diverse array of block copolymer nanostructures. AB - Block copolymers can yield a diverse array of nanostructures. Their assembly structures are influenced by their inherent structures, and the wide variety of structures that can be prepared especially becomes apparent when one considers the number of routes available to prepare block copolymer assemblies. Some examples include self-assembly, directed assembly, coupling, as well as hierarchical assembly, which can yield assemblies having even higher structural order. These assembly routes can also be complemented by processing techniques such as selective crosslinking and etching, the former technique leading to permanent structures, the latter towards sculpted and the combination of the two towards permanent sculpted structures. The combination of these pathways provides extremely versatile routes towards an exciting variety of architectures. This review will attempt to highlight destinations reached by LIU Guojun and coworkers following these pathways. PMID- 23740359 TI - Tumor necrosis factor-blocker dose escalation in rheumatoid arthritis patients in a pharmacy benefit management setting. AB - INTRODUCTION: Dose escalation with tumor necrosis factor (TNF)-blockers is poorly characterized in pharmacy benefit management (PBM) settings. METHODS: This retrospective study used integrated pharmacy and medical claims from the PBM Medco to characterize dose escalation among rheumatoid arthritis (RA) patients treated with etanercept and adalimumab. Data from adults with RA with pharmacy claims for etanercept or adalimumab between 1/1/2007 and 12/31/2009 and continuous enrollment for >= 6 months before and >= 12 months after first (index) pharmacy claim were analyzed. "New" patients had no claim for TNF-blocker in the 6 months prior to receipt of their index TNF-blocker; otherwise, they were classified as "continuing" patients. Endpoints included 12-month persistence and duration on index medication and dose escalation. Dose escalation (allowed per adalimumab label but not for etanercept) in patients' persistent >= 12 months was estimated using five methods: (1) average weekly dose >= 110% of recommended label dose; (2) average subsequent dose >= 130% of starting dose; (3) last dose >= 110% of starting dose; (4) >= 2 consecutive instances of dose >= 130% of starting dose; and (5) any instance where dose increase connoted an additional syringe/vial use. RESULTS: Data from 1,260 patients on etanercept and 852 patients on adalimumab were analyzed; 45.3 and 45.9% of new patients on etanercept and adalimumab, respectively, and 60.5 and 60.8% of continuing patients had >= 12 months persistence on index medication. Across all five methods used to estimate dose escalation, patients receiving etanercept had significantly lower rates of dose escalation (P < 0.001) than patients receiving adalimumab. For new patients, rates of dose escalation were 0.4-1.2% for etanercept and 8.3-14.1% for adalimumab. For continuing patients, rates ranged from 1.1 to 2.9% for etanercept and 7.0-28.3% for adalimumab. CONCLUSIONS: New and continuing patients from this PBM database on etanercept had significantly lower rates of dose escalation than patients on adalimumab. PMID- 23740361 TI - Quantitative assessment of acute kidney injury by noninvasive arterial spin labeling perfusion MRI: a pilot study. AB - The kidneys are essential for maintaining homeostasis, are responsible for the reabsorption of water, glucose and amino acids, and filter the blood by removing waste. Acute kidney injury (AKI) is a syndrome characterized by the rapid loss of renal excretory function and the accumulation of end metabolic products of urea and creatinine. AKI is associated with the later development of chronic kidney disease and end-stage kidney disease, and may eventually be fatal. Early diagnosis of AKI and assessments of the effects of treatment, however, are challenging. The pathophysiological mechanism of AKI is thought to be the imbalance between oxygen supply and demand in the kidneys. We have assessed the ability of arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI), without the administration of contrast media, to quantify renal blood flow (RBF) non-invasively. We found that RBF was significantly lower in AKI patients than in healthy volunteers. These results suggest that ASL perfusion MRI, a noninvasive measurement of RBF, may be useful in the early diagnosis of AKI. PMID- 23740362 TI - Renal denervation in the treatment of hypertension. AB - Despite advances in nonpharmacologic and pharmacologic therapy, blood pressure control rates in hypertension are low. About 10 % of patients with hypertension fulfill the criteria of therapy resistance, which is defined as noncontrolled blood pressure despite treatment with >=3 antihypertensive drugs of different classes, including a diuretic, at optimal or maximal tolerated doses. Although the pathogenesis of resistant hypertension is multifactorial, an interaction between renal afferent and efferent sympathetic nerves and the central nervous system plays a key role, leading to increased renal and central sympathetic activity. Catheter-based renal sympathetic denervation (RDN) is a novel therapeutic technique for the treatment of resistant hypertension. Clinical trials of RDN have shown a significant and sustained reduction of blood pressure as well as renal and central sympathetic activity. In clinical practice, appropriate patient selection is crucial to ensure successful and safe treatment. Beyond hypertension, RDN was associated with reduction of heart rate, regression of left ventricular mass, and improvements in glucose metabolism and severity of sleep apnea. Further studies addressing open questions in the treatment of resistant hypertension and evaluating potential new indications such as metabolic syndrome or heart failure (RE-ADAPT-HF) are necessary to prove effectiveness and safety of RDN in these patients. By modulating sympathetic activity, RDN has the potential to provide benefit in a variety of diseases, but these concepts have to be evaluated in well-designed prospective controlled clinical trials. PMID- 23740363 TI - Out of bed with a good COUGH, just what the doctor ordered. PMID- 23740364 TI - Acute pulmonary embolism during warfarin therapy and long-term risk of recurrent fatal pulmonary embolism. AB - The clinical characteristics and long-term outcomes of patients presenting with acute pulmonary embolism (PE) during treatment with warfarin have not been described. Clinical details of all patients admitted to a tertiary institution from 2000-2007 with acute PE were retrieved retrospectively, baseline warfarin status and the international normalised ratio (INR) were recorded, and their outcomes tracked using a statewide death registry. Of 923 patients with clearly documented warfarin status included in this study, 83 (9%) were taking warfarin. Mean (+/- standard deviation) day-1 INR of those taking warfarin was 2.3 +/- 0.9, with 67% of patients therapeutically anti-coagulated (INR >=2.0) at presentation (49 patients with INR <2.5 and 34 with INR >=2.5). Patients taking warfarin on admission were more likely to have heart failure, atrial fibrillation and valvular heart disease, with similar prevalence of malignancy and ischaemic heart disease, compared to patients not on warfarin. Total mortality of the cohort (mean follow-up 4.0 +/- 2.5 years) was 31.6% (in-hospital mortality 1.5%), and was similar between warfarin and no warfarin groups. There was however a greater than four-fold increased risk of post-discharge death due to recurrent PE for the patients taking warfarin on admission (hazard ratio [HR] 4.43, 95% confidence interval [CI] 1.36-14.42, p=0.01). Among patients taking warfarin on admission, day-1 INR <2.5 significantly increased long-term all-cause mortality compared to INR >=2.5 (adjusted HR 2.51, 95% CI 1.08-5.86, p=0.03). In conclusion, patients presenting with PE during treatment with warfarin have an increased risk of death from recurrent PE. Admission INR appears to have independent long-term prognostic importance in these patients. PMID- 23740365 TI - Lanthanide-doped NaScF4 nanoprobes: crystal structure, optical spectroscopy and biodetection. AB - Trivalent lanthanide ions (Ln(3+))-doped inorganic nanoparticles (NPs) as potential luminescent bioprobes have been attracting tremendous interest because of their unique upconversion (UC) and downconversion (DC) luminescence properties. NaScF4, as an important host material, has been rarely reported and its crystal structure remains unclear. Herein, based on the single crystal X-ray diffraction, the space group of NaScF4 crystals was determined to be P31 containing multiple sites of Sc(3+) with crystallographic site symmetry of C1, which was verified by high-resolution photoluminescence spectroscopy of Eu(3+) at low temperature (10 K). Furthermore, monodisperse and size-controllable NaScF4:Ln(3+) NPs were synthesized via a facile thermal decomposition method. The biotinylated NaScF4:Er(3+)/Yb(3+) NPs were demonstrated for their applications as a heterogeneous UC luminescence bioprobe to detect avidin with a detection limit of 180 pM. After bioconjugation with amino-terminal fragment (ATF) of urokinase plasminogen activator (uPA), NaScF4:Ln(3+) NPs also exhibited specific recognition of cancer cells overexpressed with uPA receptor (uPAR, an important marker of tumor biology and metastasis), showing great potentials in tumor targeted bioimaging. PMID- 23740366 TI - Assessment of urinary incontinence in the women in eastern Turkey. AB - INTRODUCTION AND HYPOTHESIS: The aims of the present study were to determine the types of UI among women visiting the urology department, to identify the potential risk factors associated with each type of UI, and to identify healthcare-seeking behaviors of affected women in our region. METHODS: The data of 617 community-dwelling women, who were at least 18 years of age or older and who presented with a complaint of UI ongoing over a year, and those without UI, who were admitted for any other reason, from June 2010 to April 2012, were evaluated. RESULTS: Mean age was 51.29 years (range 18-110 years); median parity was 3.54 (range 0-11) and 88.2% of the women were married. Mean BMI was 28.01 kg/m(2). Very few women (18.5%) accepted UI as a disease and searched for medical help by themselves; however, the remaining women (81.5%) were brought or directed for evaluation by someone else. Stress UI was reported by 43 women (10.5%), urge UI and mixed UI were noted by 153 (37.5%) and 212 (52%) women respectively. CONCLUSIONS: The most frequent type of UI was mixed UI in our region. Age, BMI, multiparity, and hypertension were identified to have a different importance for each type of UI, but diabetes mellitus, birth trauma, gynecological surgery, lumbar disc hernia (LDH), and multiple sclerosis (MS) were the other important related factors. However, a small number of patients accepted UI as a disease and searched for therapy. This reveals that the public should be informed in detail about female UI in developing countries. PMID- 23740367 TI - Synchronous EMG activity in the piper frequency band reveals the corticospinal demand of walking tasks. AB - Evidence indicates that the frequency-domain characteristics of surface electromyogram (EMG) signals are modulated according to the contributing sources of neural drive. Modulation of inter-muscular EMG synchrony within the Piper frequency band (30-60 Hz) during movement tasks has been linked to drive from the corticospinal tract. However, it is not known whether EMG synchrony is sufficiently sensitive to detect task-dependent differences in the corticospinal contribution to leg muscle activation during walking. We investigated this question in seventeen healthy older men and women. It was hypothesized that, relative to typical steady state walking, Piper band EMG synchrony of the triceps surae muscle group would be reduced for dual-task walking (because of competition for cortical resources), similar for fast walking (because walking speed is directed by an indirect locomotor pathway rather than by the corticospinal tract), and increased when taking a long step (because voluntary gait pattern modifications are directed by the corticospinal tract). Each of these hypotheses was confirmed. These findings support the use of frequency-domain analysis of EMG in future investigations into the corticospinal contribution to control of healthy and disordered human walking. PMID- 23740368 TI - The impact of inflammation on metabolomic profiles in patients with arthritis. AB - OBJECTIVE: Inflammatory arthritis is associated with systemic manifestations including alterations in metabolism. We used nuclear magnetic resonance (NMR) spectroscopy-based metabolomics to assess metabolic fingerprints in serum from patients with established rheumatoid arthritis (RA) and those with early arthritis. METHODS: Serum samples were collected from newly presenting patients with established RA who were naive for disease-modifying antirheumatic drugs, matched healthy controls, and 2 groups of patients with synovitis of <=3 months' duration whose outcomes were determined at clinical followup. Serum metabolomic profiles were assessed using 1-dimensional (1) H-NMR spectroscopy. Discriminating metabolites were identified, and the relationships between metabolomic profiles and clinical variables including outcomes were examined. RESULTS: The serum metabolic fingerprint in established RA was clearly distinct from that of healthy controls. In early arthritis, we were able to stratify the patients according to the level of current inflammation, with C-reactive protein correlating with metabolic differences in 2 separate groups (P < 0.001). Lactate and lipids were important discriminators of inflammatory burden in both early arthritis patient groups. The sensitivities and specificities of models to predict the development of either RA or persistent arthritis in patients with early arthritis were low. CONCLUSION: The metabolic fingerprint reflects inflammatory disease activity in patients with synovitis, demonstrating that underlying inflammatory processes drive significant changes in metabolism that can be measured in the peripheral blood. The identification of metabolic alterations may provide insights into disease mechanisms operating in patients with inflammatory arthritis. PMID- 23740369 TI - Stress and melanoma: increasing the evidence towards a causal basis. AB - Melanoma is a multifactorial disease with a strong genetic component and known risk factors such as excessive ultraviolet exposure, intermittent sunburns and fair skin type. The prognosis is poor if diagnosis is delayed, in spite of recent treatment advances. Evidence is mounting that the incidence of melanoma is higher in the immunosuppressed and individuals with highly stressful occupations. We present a case series of individuals diagnosed with multiple cutaneous melanomas over a few months to 1 year. All had encountered psychological stressors in their lives, and the melanomas were diagnosed briefly after encountering these stressors. No known causes of immunosuppression were detected to explain the sporadic occurrence of melanomas in these individuals. There is evidence in the current literature that stress can lead to immune disregulation, predisposing an individual to various disease states including melanoma. Stress hormones such as norepinephrine have been shown to cause upregulation of cytokines such as Interleukin 6 and 8, which are proangiogenic and support tumour progression. Coupled with genetic and environmental factors, stress appears to play a role in melanoma formation and progression. Large prospective studies are required to study the link between stress and melanoma and gain further insight into the etiology of melanoma. PMID- 23740370 TI - Patient-specific dosimetry for intracavitary 32P-chromic phosphate colloid therapy of cystic brain tumours. AB - PURPOSE: (32)P-chromic phosphate colloid treatments of astrocytoma and craniopharyngioma cystic brain tumours in paediatric patients are conventionally based on a sphere model under the assumption of uniform uptake. The aims of this study were to determine the distribution of the absorbed dose delivered by (32)P on a patient-specific basis and to evaluate the accuracy with which this can be predicted from a pretherapy administration of (99m)Tc-Sn colloid. METHODS: Three patients were treated with (32)P-chromic phosphate colloid following (99m)Tc-Sn colloid administrations. Convolution dosimetry was performed using pretherapy and posttherapy sequential SPECT imaging, and verified with EGSnrc Monte Carlo radiation transport simulations. Mean absorbed doses to the cyst wall and dose volume histograms were also calculated and compared with those obtained by the sphere model approach. RESULTS: Highly nonuniform uptake distributions of both the (99m)Tc and (32)P colloids were observed and characterized by dose-volume histograms to the cyst wall. Mean absorbed doses delivered to the cyst wall, obtained with the convolution method, were on average 21 % (SD 18 %) and 50 % (SD 30 %) lower than those predicted by the (99m)Tc distribution and the uniform assumption of the sphere model, respectively. CONCLUSION: Absorbed doses delivered to the cyst wall by (32)P are more accurately predicted from image based patient-specific convolution dosimetry than from simple sphere models. These results indicate the necessity to perform personalized treatment planning and verification for intracavitary irradiation of cystic brain tumours treated with radiocolloids. Patient-specific dosimetry can be used to guide the frequency and levels of repeated administrations and would facilitate data collection and comparison to support the multicentre trials necessary to progress this therapy. PMID- 23740371 TI - The role of 131I-metaiodobenzylguanidine (MIBG) therapy in unresectable and compromising localised neuroblastoma. AB - PURPOSE: In patients with localised neuroblastoma without adverse genetic aberrations, observational treatment is justified. Therapy is required when organ or respiratory functions have become compromised. As the outcome is good, side effects of treatment should be prevented. The aim of this retrospective study was to evaluate response and outcome in patients treated with (131)I metaiodobenzylguanidine (MIBG) for unresectable localised neuroblastoma, with compromised organ functions. METHODS: Patients with localised neuroblastoma [median age 1.6 years (0-5.5 years)] diagnosed between 1989 and 2008 were included in this retrospective study (n = 21). Primary tumours were unresectable and there was a compromised organ or respiratory function. Diagnosis and staging were performed according to the International Neuroblastoma Staging System. Fixed doses of (131)I-MIBG therapy (50-200 mCi) were given. The median number of infusions was two (range one to seven). Response was graded according to the International Neuroblastoma Response Criteria. RESULTS: Of the 21 patients, 14 did not need any chemotherapy. Patients were treated with (131)I-MIBG therapy and, in most cases, with additional surgery and/or chemotherapy. Sixteen achieved complete response (CR), three very good partial response (VGPR), one partial response (PR) and one progressive disease (PD). Two patients died of PD after having achieved CR initially and due to surgical complications a few months after resection. Ten-year overall survival and event-free survival were 90.5 %. The median follow-up was 8.5 years (range 0.4-19.6 years). CONCLUSION: (131)I-MIBG therapy is an effective treatment modality for unresectable localised neuroblastoma with compromised organ functions. However, this was a small and heterogeneous cohort and further studies are needed. PMID- 23740373 TI - Observer reproducibility of results from a low-dose 123I-metaiodobenzylguanidine cardiac imaging protocol in patients with heart failure. AB - PURPOSE: Imaging of the cardiac autonomic system with (123)I metaiodobenzylguanidine (MIBG) is useful in the evaluation of patients with a variety of cardiac conditions, including heart failure (HF), but few data are available about the reproducibility of this technique. We assessed the observer reproducibility of the results from a low-dose (123)I-MIBG cardiac imaging protocol in patients with HF. METHODS: A total of 74 patients (62 men, age 67 +/- 10 years) with HF and left ventricular systolic dysfunction (ejection fraction 31 +/- 7 %) underwent low-dose (111 MBq) planar and single-photon emission computed tomography (SPECT) (123)I-MIBG cardiac sympathetic imaging. The intraclass coefficient of correlation (ICC), Lin's concordance correlation coefficient, and Bland-Altman analysis were used to evaluate the intraobserver and interobserver reproducibility of early and late heart-to-mediastinum (H/M) ratios and of defect scores on SPECT images. The kappa statistic was used to evaluate the concordance rates for the identification of patients with a low H/M ratio (<1.60) on late planar imaging. RESULTS: The differences between measurements obtained twice by the same examiner and by two examiners were negligible for both early and late H/M ratios and for SPECT defect scores. These findings were confirmed by the results of Bland-Altman analysis, and ICC and Lin's coefficient values were excellent (>0.90) for all measurements. For the identification of patients with a low H/M ratio, the kappa values were 0.90 for intraobserver concordance and 0.83 for interobserver concordance. CONCLUSION: The present study showed a high observer reproducibility of planar H/M ratios and SPECT defect scores using a low dose (123)I-MIBG cardiac imaging protocol in patients with HF. PMID- 23740372 TI - Transient changes in the endocannabinoid system after acute and chronic ethanol exposure and abstinence in the rat: a combined PET and microdialysis study. AB - PURPOSE: Recent biochemical and post-mortem evidence suggests involvement of the endocannabinoid system in alcohol drinking behaviour and dependence. Using [(18)F]MK-9470 small-animal PET imaging, our primary objective was to evaluate in vivo type 1 cannabinoid receptor (CB1R) binding changes in rats subjected to several ethanol conditions: (1) at baseline, (2) after acute intraperitoneal administration of ethanol (4 g/kg) or saline, (3) after 7 days of forced chronic ethanol consumption, and (4) after abstinence for 7 and 14 days. Secondly, levels of anandamide (AEA) in the nucleus accumbens (NAcc) were investigated in the same animals using in vivo microdialysis and correlated with the changes in CB1R binding. METHODS: In total, 28 male Wistar rats were investigated. Small-animal PET was done on a FOCUS-220 tomograph with [(18)F]MK-9470. Parametric images of [(18)F]MK-9470 binding based on standard uptake values (SUV, as a measure of CB1R binding) were generated. Images were normalized to Paxinos space and analysed voxel-wise using SPM8 (p(height) = 0.005; k(ext) = 200). The AEA content was quantified using HPLC with tandem mass spectrometry detection. RESULTS: Acute ethanol administration increased relative CB1R binding in the NAcc that was positively correlated with the change in AEA levels of that region. In contrast, compared to rats at baseline, AEA levels in the NAcc were not significantly different in rats after chronic ethanol consumption or after a 14-day abstinence period. Chronic ethanol consumption decreased relative CB1R binding in the hippocampus and caudate-putamen, whereas same regions showed increased relative CB1R binding after 7 and 14 days of abstinence compared to the baseline condition. After 7 and 14 days of abstinence, relative CB1R binding additionally decreased in the orbitofrontal cortex. The magnitude of the hippocampal and frontal changes was highly correlated with daily ethanol intake. CONCLUSION: This study provides in vivo evidence that acute ethanol consumption is associated with enhanced endocannabinoid signalling in the NAcc, indicated by an increased CB1R binding and AEA content. In addition, chronic ethanol exposure leads to regional dysfunctions in CB1R levels, involving the hippocampus and caudate-putamen that are reversible within 2 weeks in this animal model. PMID- 23740374 TI - Pharmacokinetic analysis of [18F]FAZA in non-small cell lung cancer patients. AB - PURPOSE: [(18)F]Fluoroazomycin arabinoside (FAZA) is a positron emission tomography (PET) tracer developed to enable identification of hypoxic regions within a tumour. The aims of this study were to determine the optimal kinetic model along with validation of using alternatives to arterial blood sampling for analysing [(18)F]FAZA studies and to assess the validity of simplified analytical methods. METHODS: Dynamic 70-min [(18)F]FAZA PET/CT scans were obtained from nine non-small cell lung cancer patients. Continuous arterial blood sampling, together with manual arterial and venous sampling, was performed to derive metabolite corrected plasma input functions. Volumes of interest (VOIs) were defined for tumour, healthy lung muscle and adipose tissue generating [(18)F]FAZA time activity curves (TACs). TACs were analysed using one- and two-tissue compartment models using both metabolite-corrected blood sampler plasma input functions (BSIF) and image-derived plasma input functions (IDIF). RESULTS: The reversible two-tissue compartment model with blood volume parameter (2T4k+VB) best described kinetics of [(18)F]FAZA in tumours. Volumes of distribution (VT) obtained using IDIF correlated well with those derived using BSIF (R(2) = 0.82). Venous samples yielded the same radioactivity concentrations as arterial samples for times >50 min post-injection (p.i.). In addition, both plasma to whole blood ratios and parent fractions were essentially the same for venous and arterial samples. Both standardised uptake value (SUV), normalised to lean body mass, and tumour to blood ratio correlated well with VT (R(2) = 0.77 and R(2) = 0.87, respectively, at 50-60 min p.i.), although a bias was observed at low VT. CONCLUSION: The 2T4k+VB model provided the best fit to the dynamic [(18)F]FAZA data. IDIF with venous blood samples can be used as input function. Further data are needed to validate the use of simplified methods. PMID- 23740376 TI - Recycling rate of bile acids in the enterohepatic recirculation as a major determinant of whole body 75SeHCAT retention. AB - Measurement of the whole body retention of orally administered (75)SeHCAT is used to investigate patients with unexplained diarrhoea. Retention values of <15 % at 7 days post-administration are taken to indicate bile acid malabsorption (BAM). Whilst idiopathic BAM is frequently diagnosed with (75)SeHCAT, functional and morphological studies of the terminal ileum rarely show any abnormality, so the disorder may be more appropriately termed bile acid diarrhoea (BAD). In addition to malabsorption, excess bile acid may reach the colon, where the events leading to diarrhoea take place, as a result firstly of increased bile acid synthesis and secondly of an increased recycling rate of bile acids. Increased recycling has been largely ignored as a cause of BAD, but, as shown in this study, can readily result in excess bile acids reaching the colon even when ileal absorption efficiency is normal (i.e. 95-97 %). There needs to be a re-evaluation of the causes of BAD in patients without a history of previous intestinal resection or evidence of ileal pathology, such as Crohn's disease. PMID- 23740377 TI - What happened to a thrombus during apical ballooning syndrome: a case report. PMID- 23740375 TI - Detection of misery perfusion in the cerebral hemisphere with chronic unilateral major cerebral artery steno-occlusive disease using crossed cerebellar hypoperfusion: comparison of brain SPECT and PET imaging. AB - PURPOSE: In patients with unilateral internal carotid or middle cerebral artery (ICA or MCA) occlusive disease, the degree of crossed cerebellar hypoperfusion that is evident within a few months after the onset of stroke may reflect cerebral metabolic rate of oxygen in the affected cerebral hemisphere relative to that in the contralateral cerebral hemisphere. The aim of the present study was to determine whether the ratio of blood flow asymmetry in the cerebellar hemisphere to blood flow asymmetry in the cerebral hemisphere on positron emission tomography (PET) and single photon emission computed tomography (SPECT) correlates with oxygen extraction fraction (OEF) asymmetry in the cerebral hemisphere on PET in patients with chronic unilateral ICA or MCA occlusive disease and whether this blood flow ratio on SPECT detects misery perfusion in the affected cerebral hemisphere in such patients. METHODS: Brain blood flow and OEF were assessed using (15)O-PET and N-isopropyl-p-[(123)I]iodoamphetamine ((123)I-IMP) SPECT, respectively. All images were anatomically standardized using SPM2. A region of interest (ROI) was automatically placed in the bilateral MCA territories and in the bilateral cerebellar hemispheres using a three-dimensional stereotaxic ROI template, and affected-to-contralateral asymmetry in the MCA territory or contralateral-to-affected asymmetry in the cerebellar hemisphere was calculated. Sixty-three patients with reduced blood flow in the affected cerebral hemisphere on (123)I-IMP SPECT were enrolled in this study. RESULTS: A significant correlation was observed between MCA ROI asymmetry of PET OEF and the ratio of cerebellar hemisphere asymmetry of blood flow to MCA ROI asymmetry of blood flow on PET (r = 0.381, p = 0.0019) or SPECT (r = 0.459, p = 0.0001). The correlation coefficient was higher when reanalyzed in a subgroup of 43 patients undergoing a PET study within 3 months after the last ischemic event (r = 0.541, p = 0.0001 for PET; r = 0.609, p < 0.0001 for SPECT). The blood flow ratio on brain perfusion SPECT in all patients provided 100 % sensitivity and 58 % specificity, with 43 % positive and 100 % negative predictive values for detecting abnormally elevated MCA ROI asymmetry of PET OEF. CONCLUSION: The ratio of blood flow asymmetry in the cerebellar hemisphere to blood flow asymmetry in the cerebral hemisphere on PET and SPECT correlates with PET OEF asymmetry in the cerebral hemisphere, and this blood flow ratio on SPECT detects misery perfusion in the affected cerebral hemisphere. PMID- 23740378 TI - Hypersensitivity reactions to etoposide phosphate. AB - Etoposide phosphate is a prodrug of intravenous etoposide recommended for use in patients with demonstrated allergy to etoposide. We have previously published a case series comprising six patients who were successfully treated with etoposide phosphate following preceding etoposide hypersensitivity. In this new paper we now present the cases of two patients who had allergic reactions to both etoposide and etoposide phosphate. As such, we suggest that whilst most patients with etoposide hypersensitivity can safely be treated with etoposide phosphate, a small number are at risk of an additional allergic reaction to etoposide phosphate. Patients being treated for the first time with etoposide phosphate after etoposide allergy should receive their first dose under medical supervision. PMID- 23740379 TI - Subcutaneous panniculitis-like T-cell lymphoma in a patient with history of B cell lymphoma treated successfully with chemotherapy 15 years prior. PMID- 23740380 TI - Loxapine inhalation powder: a review of its use in the acute treatment of agitation in patients with bipolar disorder or schizophrenia. AB - Loxapine is a well-established, first-generation antipsychotic agent. Loxapine inhalation powder (Adasuve((r))) was recently approved in the USA and the EU for use in the acute treatment of agitation in patients with bipolar disorder or schizophrenia. Inhaled loxapine is delivered by a hand-held, single-dose, single use device that uses the Staccato((r)) drug delivery system. With Adasuve((r)), maximum plasma loxapine concentrations are reached in a median of 2 min. In two randomized, double-blind, placebo-controlled, multicentre trials, inhaled loxapine 5 or 10 mg significantly reduced agitation (assessed using Positive and Negative Syndrome Scale-Excited Component scores) in patients with bipolar I disorder or schizophrenia, with the onset of effect seen within 10 min of administration. Inhaled loxapine was generally well tolerated in phase III trials (which excluded patients with clinically significant acute or chronic pulmonary disease), with the most commonly occurring adverse events including dysgeusia and sedation. Inhaled loxapine is contraindicated in patients with airways disease associated with bronchospasm or acute respiratory signs or symptoms. In conclusion, inhaled loxapine provides a novel new option for use in the acute treatment of agitation in patients with bipolar disorder or schizophrenia, combining a rapid onset of effect with a noninvasive route of administration. PMID- 23740381 TI - Robotic-assisted laparoscopic reconstructive surgery in the lower urinary tract. AB - Open surgery has long been the most common surgical approach for the correction of congenital anomalies of the lower urinary tract in children. With the continued development of minimally invasive surgery in adult urology, including endoscopic, conventional, and robot-assisted laparoscopic approaches, the indications for minimally invasive surgery have similarly expanded in the pediatric population. The most commonly performed robotic procedure in children has been pyeloplasty for ureteropelvic junction obstruction; the use of robotics in complex reconstructive surgery in the lower urinary tract has also been acceptable. In this review, we summarize recent viewpoints regarding robotic assisted laparoscopic reconstructive surgeries in the lower urinary tract, such as ureteral reimplantation, appendicovesicostomy, and augmentation enterocystoplasty in the pediatric population, and critically summarize the current knowledge on outcomes in the literature. We also discuss our technique and the outcomes of robotic ureteral reimplantation. This review demonstrates that robotic-assisted laparoscopic reconstructive surgeries in the lower urinary tract are technically feasible and may achieve outcomes that are equalto those of open surgery, with reduced morbidity. PMID- 23740382 TI - Laparoendoscopic single-site surgery in kidney surgery: clinical experience and future perspectives. AB - Laparoscopic surgery of the upper urinary tract has reduced the morbidity related to large abdominal incisions and has resulted in significant advantages over open surgery. Nevertheless, the pursuit for even more minimally invasive alternatives to laparoscopy has led to the concept of scarless surgery and the approach of laparoendoscopic single-site surgery (LESS). LESS is currently a feasible approach for the majority of kidney surgical procedures, and there is intense debate regarding its efficiency and advantages. In the present review of the literature, the current status of upper urinary LESS and its advantages and disadvantages, as well the technological and technical evolution, are presented. PMID- 23740383 TI - Simultaneous treatment with azelnidipine and olmesartan inhibits apoptosis of Hl 1 cardiac myocytes expressing E334k cMyBPC. AB - BACKGROUND: Apoptosis appears to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM). We have previously reported 3 HCM patients carrying the E334K MYBPC3, and that heterologous expression of E334K cMyBPC in cultured cells induced apoptosis. The purpose of this study was to identify pharmacological agents that would inhibit apoptosis in HL-1 cardiomyocytes expressing E334K cMyBPC. METHODS AND RESULTS: E334K cMyBPC expression in cells increased levels of pro-apoptosis (p53, Bax and cytochrome c) and decreased levels of anti-apoptosis (Bcl-2 and Bcl-XL). While the beta blocker carvedilol (1 MUM) normalized the level of p53 and Bcl-2 and the calcium channel blocker (CCB) bepridil (0.5 MUM) normalized that of Bcl-2, both the CCB azelnidipine (1 MUM) and the angiotensin receptor blocker (ARB) olmesartan (10 MUM) normalized those of p53, Bax, cytochrome c, and Bcl-XL. Among those proteins, cytochrome c was the one which showed the highest degree of change. Both azelnidipine (0.1 MUM) and olmesartan (1 MUM) reduced the level of cytochrome c by 40.2 +/- 4.3% and 31.3 +/ 5.1%, respectively. The CCB amlodipine and the ARB valsartan reduced it only by 19.1 +/- 2.1% and 20.1 +/- 5.2%, respectively. Flow cytometric analysis and annexin V staining showed that treatment of cells with azelnidipine (0.1 MUM) plus olmesartan (0.3 MUM) or that with amlodipine (0.1 MUM) plus valsartan (0.3 MUM) reduced the number of apoptotic cells by 35.8 +/- 10.5% and 18.4 +/- 3.2%, respectively. CONCLUSION: Azelnidipine plus olmesartan or amlodipine plus valsartan inhibited apoptosis of HL-1 cells expressing E334K cMyBPC, and the former combination was more effective than the latter. PMID- 23740384 TI - Pharmacokinetics and relative bioavailability evaluation of linezolid suspension and tablet formulations. AB - The oral liquid formulations poses an alternative way in providing medications to pediatric patients, geriatric patients, patients with feeding tubes, and patients who cannot swallow solid dosage forms. This study was conducted to evaluate the pharmacokinetics (PKs) and relative bioavailability of suspension (reference) and tablet (test) formulations of Linezolid (LZD). In vivo study was established according to a single-center, randomized, single-dose, laboratory-blinded, 2 Way, Cross-Over Study with a washout period of 1-week. Under fasting conditions, 28 healthy Egyptian male volunteers were randomly allocated to receive a single oral dose of either 30 ml LZD or 1 tablet (600 mg LZD) of marketed suspension and tablet formulations. Plasma samples were obtained over a 48-h interval and analyzed for LZD by reversed phase liquid chromatography with ultraviolet detection. The 90% confidence intervals for the ratio of log transformed values of Cmax, AUC0-t, and AUCt-infinity of the two treatments were within the acceptable range (0.8-1.25) for bioequivalence. From PK perspectives, in this small study in healthy Egyptian adult male volunteers, a single 600 mg dose of the tablet formulation demonstrated comparable rate and extent of absorption to a single 600 mg dose of the suspension formulation based on the US FDA's regulatory definition. No adverse events occurred or were reported after a single 600 mg LZD and both formulations were well tolerated. PMID- 23740385 TI - An ultrasensitive, non-enzymatic glucose assay via gold nanorod-assisted generation of silver nanoparticles. AB - This report demonstrates a colorimetric, non-enzymatic glucose assay with a low detection limit of 0.07 MUM based on negatively charged gold nanorod-enhanced redox reaction. This glucose assay could generate silver nanoparticles as the readout that can be visualized by the naked eye, and only 4 femtomoles of nanorods are needed for glucose determination in one human plasma sample. PMID- 23740387 TI - Pro- or anti-inflammatory role of apolipoprotein A-1 in high-density lipoproteins? AB - Apolipoprotein A-1 (apoA-1) is the principal protein fraction of high-density lipoprotein (HDL), conferring to the latter many of its pleiotropic atheroprotective functions. After its effect on cholesterol efflux, the second most studied feature of apoA-1 is its anti-inflammatory property. In addition, it interferes with lipid peroxidation and innate immune receptors. These anti inflammatory effects are due to various properties, in particular the ability to inhibit the transendothelial migration of immune cells by reducing integrin expression, to inhibit monocyte activation and cytokine production induced by T cell contact, to inhibit lipid peroxidation and to interfere with innate immune receptors. Recent studies have demonstrated that during chronic systemic inflammation HDL could lose some of its atheroprotective functions and become dysfunctional or even proinflammatory. Recent evidence suggests that specific post-translational modifications of apoA-1 transform this genuine anti inflammatory molecule into a proinflammatory one. The structural changes include chlorination, nitration and carbamylation of amino acids by myeloperoxidase, oxidation by reactive carbonyls, as well as glycation. Humoral autoimmunity to apoA-1 and HDL has been reported in populations at high cardiovascular risk and constitutes another emerging mechanism contributing to the loss of functions of apoA-1 and HDL. The fact that in recent trials cholesteryl ester transfer protein inhibitors (torcerapib and dalcetrapib) have unfortunately failed to prevent cardiovascular disease despite increasing cholesterol efflux in vitro and HDL levels in vivo, further highlights the clinical importance of understanding the mechanisms driving apoA-1 and HDL towards pro- or anti-inflammatory molecules. These findings should not affect current dyslipidaemia management guidelines. PMID- 23740386 TI - The blood-brain barrier. AB - The concept of a blood-brain barrier (BBB) dates back to experiments performed by Paul Ehrlich. Using "intravital tracers" which change their color depending on their oxidative state, he intended to estimate the oxygen consumption of the bodily organs. An important prerequisite of this approach, however, would have been an equal distribution of these tracers at the beginning of the experiment, but this was not what he found: Hydrophilic dyes uniformly did not reach the parenchyma, which led his student, the Berlin physician Lewandowski to claim that the capillary wall provides a barrier for certain molecules in the brain, but it was not before the golden era of electron microscopy that Reese and Karnovsky detected what they called "morphological barriers" of the BBB. In this article, we provide an overview of what maintains barrier function for blood-molecules, clarify that a BBB for solutes is neither mechanistically equal to a barrier for immune cells nor in regard to the sites of entry (capillaries versus post capillary venules), formulate areas of lack of knowledge and consequently, raise open questions to be addressed in the future. PMID- 23740388 TI - Nanomaterials with enzyme-like characteristics (nanozymes): next-generation artificial enzymes. AB - Over the past few decades, researchers have established artificial enzymes as highly stable and low-cost alternatives to natural enzymes in a wide range of applications. A variety of materials including cyclodextrins, metal complexes, porphyrins, polymers, dendrimers and biomolecules have been extensively explored to mimic the structures and functions of naturally occurring enzymes. Recently, some nanomaterials have been found to exhibit unexpected enzyme-like activities, and great advances have been made in this area due to the tremendous progress in nano-research and the unique characteristics of nanomaterials. To highlight the progress in the field of nanomaterial-based artificial enzymes (nanozymes), this review discusses various nanomaterials that have been explored to mimic different kinds of enzymes. We cover their kinetics, mechanisms and applications in numerous fields, from biosensing and immunoassays, to stem cell growth and pollutant removal. We also summarize several approaches to tune the activities of nanozymes. Finally, we make comparisons between nanozymes and other catalytic materials (other artificial enzymes, natural enzymes, organic catalysts and nanomaterial-based catalysts) and address the current challenges and future directions (302 references). PMID- 23740389 TI - Network nonlinearities in drug treatment. AB - Despite major achievements in the understanding of human disease, there is a general perception that the drug development industry has failed to meet the expectations that recent advances in biotechnology should drive. One of the potential sources of failure of many next generation drugs is that their targets are embedded in highly nonlinear signaling pathways and gene networks with multiple negative and positive feedback loops of regulation. There is increasing evidence that this complex network shapes the response to external perturbations in the form of drug treatment, originating bistability, hypersensitivity, robustness, complex dose-response curves or schedule dependent activity. This review focuses on the effect of nonlinearities on signaling and gene networks involved in human disease, using tools from Nonlinear Dynamics to discuss the implications and to overcome the effects of the nonlinearities on regulatory networks. PMID- 23740390 TI - Can we predict blood brain barrier permeability of ligands using computational approaches? AB - An ideal neurotherapeutics agent for central nervous system (CNS) molecular targets should cross Blood Brain Barrier (BBB) whereas peripherally acting agent should not cross BBB to avoid CNS related side effects. Hence prediction of BBB permeability index has been proved to be an efficient tool for drug discovery and development. Various experimental and computational approaches are being used in recent past for the prediction of BBB permeability and they have been successful up to some extent. However the accuracy and authenticity of these methods have been under question. The current review article attempts to answer a vital question that is, can we predict BBB permeability using computational approaches. PMID- 23740391 TI - Evolution driven structural changes in CENP-E motor domain. AB - Genetic evolution corresponds to various biochemical changes that are vital development of new functional traits. Phylogenetic analysis has provided an important insight into the genetic closeness among species and their evolutionary relationships. Centromere-associated protein-E (CENP-E) protein is vital for maintaining cell cycle and checkpoint signal mechanisms are vital for recruitment process of other essential kinetochore proteins. In this study we have focussed on the evolution driven structural changes in CENP-E motor domain among primate lineage. Through molecular dynamics simulation and computational chemistry approaches we examined the changes in ATP binding affinity and conformational deviations in human CENP-E motor domain as compared to the other primates. Root mean square deviation (RMSD), Root mean square fluctuation (RMSF), Radius of gyration (Rg) and principle component analysis (PCA) results together suggested a gain in stability level as we move from tarsier towards human. This study provides a significant insight into how the cell cycle proteins and their corresponding biochemical activities are evolving and illustrates the potency of a theoretical approach for assessing, in a single study, the structural, functional, and dynamical aspects of protein evolution. PMID- 23740392 TI - Human papilloma virus 16 E6 protein as a target for curcuminoids, curcumin conjugates and congeners for chemoprevention of oral and cervical cancers. AB - Curcumin (diferuloyl methane) and its naturally occurring analogs viz. demethoxy, bisdemethoxy and cyclocurcumin, present in rhizomes of curcuma species turmeric, have been shown to inhibit the proliferation of a wide variety of tumor cells. Target nuclear protein HPV 16 E6 (PDB ID: 2fk4) is the major protein actively participating in oral and cervical cancers. In silico studies indicate that curcumin and its natural analogs have effective binding with different active sites on HPV 16 E6 protein, ideal target for restoring the tumor suppressor function of p53 and thus allowing the apoptosis of infected cells. The main limitation in the use of curcuminoids as therapeutic agents is their low bioavailability. Since piperine is known to enhance curcumin bioavailability to more than two thousand times by inhibiting its efflux, a conjugate of curcumin piperic acid was also used. Although curcumin has been found to have strongest binding with this target and the two curcuminoids, demethoxy and bisdemethoxy curcumin have lower but comparable affinity, chlorogenic acid amongst the naturally occurring analogs has been found to have best binding affinity amongst all the analogs. Although curcumin-piperoyl conjugate does not show very encouraging results, it is likely to have potential activity in vitro and in vivo. These results throw light on the SAR of curcuminoids, leading to future designing of potent, non-toxic drugs for oral and cervical cancers. PMID- 23740393 TI - High throughput virtual screening and E-pharmacophore filtering in the discovery of new BACE-1 inhibitors. AB - Alzheimer's disease is a progressive neurodegenerative disorder, which is characterized by amyloid beta peptide deposition in the brain. Abeta peptide, the major component of amyloid plaques is generated by the sequential processing of a larger protein called amyloid Precursor Protein by beta-amyloid cleaving enzyme (BACE-1). In this study, we appllied computer assisted methodology unifying molecular docking and pharmacophore filtering to identify potent inhibitors against BACE-1. In order to inspect the pharmacophore region and binding mode of BACE-1 135 reported co-crystallized ligands of BACE-1 were docked into the active site using Glide XP. The present molecular docking studies provided critical information on protein ligand interactions that revealed imminent information on chemical features essential to inhibiting BACE-1. Based on the docking results we proposed structure based pharmacophore features that hold well as potent BACE-1 inhibitors. A huge set of compounds was docked into the active site of BACE-1 and the hits from the docking were filtered to match the chemical features of the pharmacophore model. The compounds resulting from the pharmacophore filtering were again re-docked into the active site of BACE-1 and the three hits bound well into the active sites and matched the pharmacophore models which were identified as possible potential inhibitors of BACE-1. Molecular dynamics simulation reveals that lead 3 shows constant RMSD and the number of hydrogen bonding with the protein among the identified three lead molecules. PMID- 23740394 TI - Characterization of Bacillus thuringiensis Cry1 class proteins in relation to their insecticidal action. AB - Thirty nine Bt Cry1 subgroup protein sequences were retrieved from NCBI and analyzed for physicochemical properties, active site and relationship in relation to their variations in toxicity. Cry1 proteins were found to be hydrophilic and stable. SOSUI server predicted presence of two transmembrane regions in Ag and a single transmembrane region from Aa to Ae. EMBOSS PepWheel tool analysis of the transmembrane regions showed that there were 23 highly conserved residues towards the N terminal which are hydrophobic and more than half of the residues were neutrally charged. No signal peptide was detected which classifies the Cry1 group proteins as non-secretory proteins. Cry1 proteins have very high composition of neutral amino acids and might transform into negative charge after solubilization in alkaline environment (insect midgut). The negatively charged protein might misfold causing difficultly to digest and thereby be toxic to lepidopteran. Active sites of Cry1 proteins with more than 50% neutral amino acids showed wide insecticidal spectrum and further positive correlation (r = 0.7731) was observed between neutral amino acids and insect species affected (Y = -138.21 + 2.907X). Similarity of sequences was found between Cry1 proteins based on their high or low spectrum of insecticidal activity. PMID- 23740395 TI - Homology modeling of LmxMPK4 of Leishmania mexicana and virtual screening of potent inhibitors against it. AB - Leishmaniasis is one of the most important diseases of mankind. In the life cycle of Leishmania mexicana, two most important developmental stages are observed. In insect vector it is in promastigote form and in mammalian macrophages is the amastigote form. The family of protein kinases are extremely important regulators of many different cellular processes such as transcriptional control, cell cycle development and differentiation, and also draw much attention as possible drug targets for protozaon parasites. Leishmania mexicana mitogen activated protein kinase 4 (LmxMPK4) is essential for proliferation and survival of the parasite promastigote and amastigote forms and is a potential drug target for leishmaniasis. The existing therapy for leishmaniasis is not enough due to host toxicity and drug resistance. The experimental 3D structure of this protein has not yet been determined. In this study, we have used homology modelling techniques to generate the 3D structure of LmxMPK4 and selected effective inhibitors by ZINC database on the basis of structure of berberine alkaloid for molecular docking studies with LmxMPK4. The inhibitors ZINC05999210, ZINC40402312 and ZINC40977377 were found to be more potent for inhibition of leishmaniasis due to the robust binding affinity and strong inhibition constant (Ki) of the protein ligand interactions. This finding may help to understand the nature of MAP kinase and development of specific anti-leishmanial therapies. PMID- 23740396 TI - Interaction of Streptomyces sp. VITSTK7 compounds with selected antifungal drug target enzymes by in silico molecular docking studies. AB - Antifungal drugs are inhibitors either of fungal cell wall biosynthesis or essential reaction steps of fungal metabolic pathways. In silico studies have proved to be very effective on screening small molecules to be used as drugs and identifying essential reactions and pathways as targets. The aim of the present study was to predict the interactions of compounds present in the ethyl acetate extract of Streptomyces sp. VITSTK7 against selected fungal drug target enzymes. The ethyl acetate extract of the isolate showed significant anti-Aspergillus activity against the selected Aspergillus pathogens. Presence of the three compounds (C22H37NO7, C17H24N4O6 and C24H28N2O5) in the extract was identified by GC-MS spectra and matched with reference compounds available in the MS spectra library, NIST (National Institute for Standards and Technology). These compounds were analysed for the interaction with five selected fungal target proteins 1AFR, 1EA1, 1LKP, 1ZHX and 3PD73i3E. Docking was done using Patch dock beta 1.3 version and analysed by pymol 1.3 version. The tested compounds C22H37NO7, C17H24N4O6 and C24H28N2O5 showed least binding energy of -254.64 kcal/mol, -248.71 kcal/mol and 338.57 kcal/mol respectively with 1ZHX. The result of this study revealed that all the three compounds from the strain had higher interaction with 1ZHX protein than with the other proteins. It shows that this strain could be the promising source for the antifungal drug. PMID- 23740397 TI - Global QSAR modeling of logP values of phenethylamines acting as adrenergic alpha 1 receptor agonists. AB - Global QSAR models predict biological response of molecular structures which are generic in particular class. A global QSAR dataset admits structural features derived from larger chemical space, intricate to model but more applicable in medicinal chemistry. The present work is global in either sense of structural diversity in QSAR dataset or large number of descriptor input. Forty phenethylamine structure derivatives were selected from a large pool (904) of similar phenethylamines available in Pubchem database. LogP values of selected candidates were collected from physical properties database (PHYSPROP) determined in identical set of conditions. Attempts to model logP value have produced significant QSAR models. MLR aided linear one-variable and two-variable QSAR models with their respective R(2) (0.866, 0.937), R(2)A (0.862, 0.932), F-stat (181.936, 199.812) and Standard Error (0.365, 0.255) are statistically fit and found predictive after internal validation and external validation. The descriptors chosen after improvisation and optimization reveal mechanistic part of work in terms of Verhaar model of Fish base-line toxicity from MLOGP, i.e. (BLTF96) and 3D-MoRSE -signal 15 /unweighted molecular descriptor calculated by summing atom weights viewed by a different angular scattering function (Mor15u) are crucial in regulation of logP values of phenethylamines. PMID- 23740398 TI - Computational approaches to identify common subunit vaccine candidates against bacterial meningitis. AB - Bacterial meningitis, an infection of the membranes (meninges) and cerebrospinal fluid (CSF) surrounding the brain and spinal cord, is a major cause of death and disability all over the world. From perinatal period to adult, four common organisms responsible for most of the bacterial meningitis are Streptococcus pneumonia, Neisseria meningitidis, Haemophilus influenza and Staphylococcus aureus. As the disease is caused by more organisms, currently available vaccines for bacterial meningitis are specific and restricted to some of the serogroups or serotypes of each bacterium. In an effort to design common vaccine against bacterial meningitis, proteomes of the four pathogens were compared to extract seven common surface exposed ABC transporter proteins. Pro-Pred server was used to investigate the seven surface exposed proteins for promiscuous T-cell epitopes prediction. Predicted 22 T-cell epitopes were validated through published positive control, SYFPEITHI and immune epitope database to reduce the epitope dataset into seven. T-cell epitope 162-FMILPIFNV-170 of spermidine/putrescine ABC transporter permease (potH) protein was conserved across the four selected pathogens of bacterial meningitis. Hence, structural analysis was extended for epitope 162-FMILPIFNV-170. Crystal structures of HLA-DRB alleles were retrieved and structure of potH was modeled using Prime v3.0 for structural analysis. Computational docking of HLA-DRB alleles and epitope 162-FMILPIFNV-170 of potH was performed using Glide v5.7. RMSD and RMSF of simulation studies were analyzed by Desmond v3.2. The docking and simulation results revealed that the HLA-DRB epitope complex was stable with interaction repressive function of HLA. Thus, the epitope would be ideal candidate for T-cell driven subunit vaccine design against bacterial meningitis. PMID- 23740399 TI - Combating inadequate anesthesia in periapical infections, with sodium bicarbonate: a clinical double blind study. AB - INTRODUCTION: Local anesthetics are generally much less effective when administered in inflamed tissues. PURPOSE: This study was conducted to validate the addition of sodium bicarbonate in local anesthetics to increase its effectiveness as local infiltrations in teeth associated with periapical infections. METHODS: Two hundred subjects requiring extraction of maxillary teeth with periapical infections were enrolled. These subjects were divided in two groups of 100 subjects each. One group received local infiltration with 2 % lignocaine and 1:80,000 adrenaline, and the other group received local infiltration with sodium bicarbonate as an adjunct to the above mentioned local anesthetic solution. All extractions were performed using a consistent intra alveolar technique by a single operator. Both the patient and the operator were blinded to the contents of local anesthetic solution. Data related to the onset of action of local anesthesia, pain experienced by the patient while undergoing extraction on two scales-"the visual analog scale and the verbal response scale", and any requirement of repeated injections during the procedure was recorded. RESULTS: Clinical and statistical data confirmed that the addition of sodium bicarbonate in local anesthetics did increase the efficacy of local anesthesia in inflamed tissues. CONCLUSION: It has been observed in this study that the action of sodium bicarbonate in local anesthetics increases the pH levels of these solutions, thus possibly making them more effective in an acidic environment. PMID- 23740400 TI - Association between birth weight and cardiovascular risk factors in adolescents. AB - BACKGROUND: Birth weight (BW) is a medium- and long-term risk determinant of cardiovascular risk factors. OBJECTIVE: To assess the association between BW and cardiovascular risk factors in adolescents of the city of Salvador, Bahia state. METHODS: Cross-sectional study with comparison of BW groups. Sample comprising 250 adolescents classified according to the BMI as follows: high-normal (> 50th percentile and < 85th percentile); overweight (> 85th percentile and < 95th percentile); and obesity (> 95th percentile). The risk variables compared were as follows: waist circumference (WC); arterial blood pressure; lipid profile; glycemia; serum insulin; HOMA-IR; and metabolic syndrome. The BW was informed by parents and classified as follows: low (BW < 2,500g); normal (BW > 2,500g and < 4,000g); and high (BW > 4,000g). RESULTS: One hundred and fifty-three (61.2%) girls, age 13.74 +/- 2.03 years, normal BW 80.8%, low BW 8.0%, and high BW 11.2%. The high BW group as compared with the normal BW group showed a higher frequency of obesity (42.9%, p=0.005), elevated SBP and DBP (42.9%, p=0.000 and 35.7%, p=0.007, respectively), and metabolic syndrome (46.4%, p=0.002). High BW adolescents as compared with normal BW adolescents had a prevalence ratio for high SBP 3.3 (95% CI: 1.7-6.4) and obesity 2.6 (95% CI: 1.3-5.2). The WC of high BW adolescents was 83.3 +/- 10.1 (p=0.038). The lipid profile showed no statistically significant differences. CONCLUSION: Our findings suggest that obesity, elevated SBP and DBP, and metabolic syndrome during adolescence might be associated with high BW. PMID- 23740401 TI - 3D Echo pilot study of geometric left ventricular changes after acute myocardial infarction. AB - BACKGROUND: Left ventricular remodeling (LVR) after AMI characterizes a factor of poor prognosis. There is little information in the literature on the LVR analyzed with three-dimensional echocardiography (3D ECHO). OBJECTIVE: To analyze, with 3D ECHO, the geometric and volumetric modifications of the left ventricle (VE) six months after AMI in patients subjected to percutaneous primary treatment. METHODS: Prospective study with 3D ECHO of 21 subjects (16 men, 56 +/- 12 years old), affected by AMI with ST segment elevation. The morphological and functional analysis (LV) with 3D ECHO (volumes, LVEF, 3D sphericity index) was carried out up to seven days and six months after the AMI. The LVR was considered for increase > 15% of the end diastolic volume of the LV (LVEDV) six months after the AMI, compared to the LVEDV up to seven days from the event. RESULTS: Eight (38%) patients have presented LVR. Echocardiographic measurements (n = 21 patients): I- up to seven days after the AMI: 1- LVEDV: 92.3 +/- 22.3 mL; 2- LVEF: 0.51 +/- 0.01; 3- sphericity index: 0.38 +/- 0.05; II- after six months: 1- LVEDV: 107.3 +/- 26.8 mL; 2- LVEF: 0.59 +/- 0.01; 3- sphericity index: 0.31 +/- 0.05. Correlation coefficient (r) between the sphericity index up to seven days after the AMI and the LVEDV at six months (n = 8) after the AMI: r: 0.74, p = 0.0007; (r) between the sphericity index six months after the AMI and the LVEDV at six months after the AMI: r: 0.85, p < 0.0001. CONCLUSION: In this series, LVR has been observed in 38% of the patients six months after the AMI. The three dimensional sphericity index has been associated to the occurrence of LVR. PMID- 23740402 TI - LIN7-IRSp53: A novel pathway for filopodia and neurite formation? AB - Filopodia are dynamic, actin-rich finger-like structures that protrude from the cell membrane and play important roles in cell migration and neurite initiation and outgrowth. The insulin receptor substrate protein of 53 kDa (IRSp53) and the mammalian Diaphanous members of the formin family of proteins (mDia) are two key players in the formation of filopodia and neurites. IRSp53 is an adaptor protein that acts at the membrane:actin interface, coupling membrane deformation with F actin polymerization. mDia formin proteins, instead, can nucleate and polymerize linear actin filaments. Emerging genetic and biochemical evidence indicate that there are multiple and independent pathways leading to filopodium and neurite formation, but the precise molecular components of these pathways remain ill defined. We recently identified the PDZ domain-containing protein LIN7 as a novel regulator of IRSp53. We further showed that the association between these two proteins is required to promote the formation of filopodia and neurites independently from mDia formin proteins, highlighting novel mechanisms of filopodia and neurite formation. PMID- 23740403 TI - A novel system enhancing the endosomal escapes of peptides promotes Bak BH3 peptide inducing apoptosis in lung cancer A549 cells. AB - Therapeutic peptides have been proven useful for treating various diseases. However, it is difficult for therapeutic peptides to reach their target sites with an effective concentration due to inefficient intracellular delivery. Although Tat transduction peptide is a promising tool to deliver therapeutic peptides into cells, the entrapment within endosomes and the nuclear localization of Tat transduction peptide severely limited the biological effects of Tat-linked cargos. In this study, we designed a novel peptide delivering system, Tat-INF7 ubiquitin (TIU), which consisted of Tat transduction peptide, endosomal escape enhancer peptide INF7, and ubiquitin protein. We found that the TIU system was able to efficiently deliver the mCherry fluorescent proteins and the apoptosis inducing Bak BH3 peptide into the cytosol. The Bak BH3 peptide transported into the cells by the TIU system increased the apoptotic rate to 46.15 +/- 4.86% (p < 0.001) in A549 cells, while Tat-BH3 could result in only 20.45 +/- 2.89%. These results demonstrated that the TIU system could enhance the effects of therapeutic peptides by facilitating the transmembrane delivery of peptides into the cells and the escape of target proteins from the endosome efficiently. PMID- 23740404 TI - Three-dimensional conducting oxide nanoarchitectures: morphology-controllable synthesis, characterization, and applications in lithium-ion batteries. AB - We report the synthesis, characterization and applications in Li-ion batteries of a set of 3-dimensional (3-D) nanostructured conducting oxides including fluorinated tin oxide (FTO) and aluminum zinc oxide (AZO). The morphology of these 3-D conducting oxide nanoarchitectures can be directed towards either mono dispersed hollow nanobead matrix or mono-dispersed sponge-like nanoporous matrix by controlling the surface charge of the templating polystyrene (PS) nanobeads, the steric hindrance and hydrolysis rates of the precursors, pH of the solvents etc. during the evaporative co-assembly of the PS beads. These 3-D nanostructured conducting oxide matrices possess high surface area (over 100 m(2) g(-1)) and accessible interconnected pores extending in all three spatial dimensions. By optimizing the temperature profile during calcination, we can obtain large area (of a few cm(2)) and crack-free nanoarchitectured films with thickness over 60 MUm. As such, the sheet resistance of these nanoarchitectured films on FTO glass can reach below 20 Omega per square. The nanoarchitectured FTO electrodes were used as anodes in Li-ion batteries, and they showed an enhanced cycling performance and stability over pure SnO2. PMID- 23740406 TI - Renal hybrid oncocytic/chromophobe tumors - a review. AB - Hybrid oncocytic/chromophobe tumors (HOCT) occur in three clinico-pathologic situations; (1) sporadically, (2) in association with renal oncocytomatosis and (3) in patients with Birt-Hogg-Dube syndrome (BHD). There are no specific clinical symptoms in patients with sporadic or HOCT associated with oncocytosis/oncocytomatosis. HOCT in patients with BHD are usually encountered on characteristic BHD clinicopathologic background. Sporadic HOCT are composed of neoplastic cells with eosinophilic oncocytic cytoplasm. Tumors are usually arranged in a solid-alveolar pattern. Some neoplastic cells may have a perinuclear halo, no raisinoid nuclei are present. HOCT occurring in patients with oncocytomatosis are morphologically identical to sporadic HOCT. HOCT in BHD frequently display 3 morphologic patterns, either in isolation or in combination; (1) An admixture of areas typical of RO and CHRCC, respectively, (2) Scattered chromophobe cells in the background of a typical RO, (3) Large eosinophilic cells with intracytoplasmic vacuoles. The immunohistochemical profiles of HOCT in all clinicopathologic and morphologic groups differ slightly. The majority of tumors express parvalbumin, antimitochondrial antigen and CK 7. CD117 is invariably positive. HOCT show significant molecular genetic heterogeneity. The highest degree of variability in numerical chromosomal changes is present in sporadic HOCT. HOCT in the setting of oncocytomatosis have revealed a lesser degree of variability in the chromosomal numerical aberrations. HOCT in patients with BHD display FLCN gene mutations, which are absent in the other groups. HOCT (all three clinicopathologic groups) seem to behave indolently, as no evidence of aggressive behavior has been documented. However, no report with follow up longer than 10 years has been published. PMID- 23740407 TI - Lipopolysaccharide (LPS) promotes osteoclast differentiation and activation by enhancing the MAPK pathway and COX-2 expression in RAW264.7 cells. AB - Bone degradation is a serious complication of chronic inflammatory diseases such as septic arthritis, osteomyelitis and infected orthopedic implant failure. At present, effective therapeutic treatments for lipopolysaccharide (LPS)-induced bone destruction are limited to antibiotics and surgical repair in chronic inflammatory diseases. The present study aimed to evaluate the mechanism of LPS on osteoclast differentiation and activation. RAW264.7 cells were non-induced, or induced by the receptor activator of nuclear factor-kappaB (RANK) ligand (RANKL) and macrophage-colony stimulating factor (M-CSF), and then treated with LPS. Following treatment, the number of osteoclasts and cell viability were measured. The expression of osteoclast-related genes including tartrate-resistant acid phosphatase (TRAP), matrix metalloproteinase-9 (MMP-9), cathepsin K (CK), carbonic anhydrase II (CAII) and cyclooxygenase-2 (COX-2) was determined by RT PCR. Protein levels of RANK, tumor necrosis factor receptor-associated factor 6 (TRAF6), COX-2 and mitogen-activated protein kinases (MAPK) were measured using western blotting assays. LPS promoted osteoclast differentiation of RAW264.7 cells and differentiated osteoclasts. LPS significantly increased mRNA expression of osteoclast-related genes in RAW264.7 cells. Differentiated osteoclasts were treated with LPS (100 ng/ml) and the results showed a significantly increased mRNA expression of osteoclast-related genes and protein levels of RANK, TRAF6 and COX-2. Furthermore, LPS at 100 ng/ml significantly promoted the MAPK pathway including increasing the phosphorylation of c-Jun N-terminal kinases (JNK) and the phosphorylation of the extracellular signal-regulated kinase (ERK1/2). In conclusion, LPS promoted osteoclast differentiation and activation by enhancing RANK signaling and COX-2 expression. LPS also promoted osteoclast differentiation via activation of the JNK and ERK1/2 cell proliferation pathways. PMID- 23740408 TI - Potentially harmful side-effects: medically unexplained symptoms, somatization, and the insufficient illness narrative for viewers of mystery diagnosis. AB - Illness narrative has often been found to play a positive role in both patients' and providers' efforts to find meaning in the illness experience. However, illness narrative can sometimes become counterproductive, even pathological, particularly in cases of medical mystery--cases wherein biopsychosocial factors blur the distinction between bodily dysfunction and somatizing behavior. In this article, the author draws attention to two examples of medical mystery, the clinical presentation of medically unexplained symptoms, and the popular reality television program Mystery Diagnosis, to demonstrate the potentially harmful effects of illness narrative. The medical mystery's complex narrative structure reflects and tends to reinforce providers' and patients' mistaken assumptions, anxieties, and conflicts in ways which obstruct, rather than facilitate, healing. PMID- 23740409 TI - Whether reactive oxygen species plays a critical role in intrinsic (mitochondrial) pathway-mediated apoptosis in notochordal cells under high glucose concentrations? PMID- 23740410 TI - Safety in surgery: the role for registries. PMID- 23740411 TI - Loteprednol etabonate ophthalmic gel 0.5%: a review of its use in post-operative inflammation and pain following ocular surgery. AB - Loteprednol etabonate ophthalmic gel 0.5% (Lotemax((r))) is approved in the USA for the treatment of post-operative inflammation and pain in patients who have undergone ocular surgery. The new gel formulation of loteprednol etabonate offers some potential advantages over the previously available ophthalmic suspension and ointment formulations of the drug. Because the gel is non-settling, a uniform dose of loteprednol etabonate is delivered without the need to vigorously shake the product. The pH of the gel formulation is close to that of physiological tears and the concentration of preservative is low. In clinical trials, loteprednol etabonate ophthalmic gel 0.5% for 14 days was effective, very well tolerated and safe when used for the treatment of post-operative inflammation and pain following cataract surgery. Relative to vehicle, loteprednol etabonate ophthalmic gel 0.5% effectively reduced postoperative ocular inflammation and ocular pain and had a similar overall tolerability, comfort and safety profile. It is associated with a low risk of inducing clinically significant increases in intraocular pressure. In conclusion, loteprednol etabonate ophthalmic gel 0.5% is an additional formulation option for the short-term treatment of post-operative inflammation and pain in patients who have undergone ocular surgery. It provides uniform dosing of a topical ophthalmic corticosteroid that has been demonstrated to be effective and well-tolerated in the treatment of ocular inflammation. PMID- 23740412 TI - Metreleptin: first global approval. AB - Metreleptin is an analogue of the human hormone leptin being developed by Amylin Pharmaceuticals (a subsidiary of Bristol-Myers Squibb) for the subcutaneous treatment of metabolic disorders including lipodystrophy. The compound is expected to improve insulin sensitivity, hypertriglyceridaemia and hyperglycaemia in patients with lipodystrophy who are unresponsive to conventional treatment. Metreleptin has been approved in Japan as a leptin therapy for the treatment of lipodystrophy. Amylin has also completed a submission for regulatory approval to the US FDA for metreleptin in the treatment of diabetes mellitus and/or hypertriglyceridaemia in patients with rare forms of lipodystrophy. Clinical development of the drug is also underway in the USA for the treatment of type 1 diabetes. Amgen was previously assessing the use of metreleptin as a treatment for amenorrhoea; however, it appears that development in this indication has been discontinued. This article summarizes the milestones in the development of metreleptin leading to this first approval for lipodystrophy. PMID- 23740413 TI - Coexistence of peripheral myelin protein 22 and dystrophin mutations in a chinese boy. AB - INTRODUCTION: We describe a 10-year-old Chinese boy with features of Charcot Marie-Tooth disease (CMT) and Duchenne muscular dystrophy (DMD). METHODS: Case report. RESULTS: Weakness and mild sensory loss in the distal extremities, pes cavus, and nerve conduction findings suggested demyelinating neuropathy, while moderate calf pseudohypertrophy, proximal muscle weakness, a myopathic pattern on electromyography, and deficiency of dystrophin immunohistochemical staining on muscle biopsy indicated DMD. Genetic testing revealed a large deletion spanning exon 50 in the gene coding for dystrophin and duplications in the gene coding for peripheral myelin protein 22. CONCLUSIONS: This is an interesting and very rare case of CMT type 1A comorbid with DMD. This results in an unusual phenotype and rapid deterioration of motor function. Usage of both target region capture and next generation sequencing is a powerful tool for predicting precisely the range of the large DNA fragment deletion in DMD. PMID- 23740416 TI - [Malignant lymphoma in the larynx]. AB - Malignant haematological diseases such as the highly malignant diffuse large B cell lymphoma, the MALT-lymphoma and the extramedullary plasmocytoma are seldom located in the larynx. In this review, clinical symptoms, laryngoscopic findings, further diagnostics as well as therapy concepts are presented. Diagnosis is complicated and delayed due to the absence of classical pathognomic findings. Biopsy of the affected tissue can secure a correct diagnosis and malignant haematological disease can be ruled out. PMID- 23740414 TI - A minimally invasive technique for the implantation of bone-anchored hearing devices. AB - OBJECTIVE: To describe and evaluate a novel technique for the implantation of bone conduction hearing devices as compared with a common, conventional technique. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral otology and neurotology practice. METHODS: Individuals who underwent the implantation of bone-anchored hearing devices between January 1, 2004, and December 31, 2011, were identified. Demographic data, surgical indications, surgical technique used, surgical time, and complications were recorded. Soft tissue complications were graded on the Holgers classification scheme. Group 1 was defined as those undergoing a traditional technique using a dermatome with subcutaneous tissue reduction. Group 2 was defined as those undergoing the described technique for implantation of the coupling hardware with minimal subcutaneous soft tissue reduction. RESULTS: Forty patients underwent the procedure, with 11 patients comprising group 1 and 29 patients comprising group 2. Group 2 required a shorter operative time (32.3 vs 56.1 minutes, P < .0001). Of patients in group 1, 2 of 11 developed soft tissue complications, whereas 5 of 29 in group 2 developed soft tissue complications (P = 1.000). Most soft tissue complications were reversed with conservative wound care. CONCLUSION: Surgery was performed faster with similar postoperative outcomes in individuals undergoing implantation of bone-anchored hearing devices using the described technique that necessitated minimal soft tissue reduction. PMID- 23740417 TI - [BGH: no criminal judgment against established contract physicians for bribery]. PMID- 23740418 TI - [Inflammations and emergencies in otorhinolaryngology]. PMID- 23740419 TI - [Interventions for implantation of hearing aids]. PMID- 23740421 TI - Note of clarification concerning our article: controversies in the determination of death: perspectives from Switzerland. PMID- 23740424 TI - A ferrocenyl-substituted 1,2,4-triazole ligand and its Fe(II), Ni(II) and Cu(II) 1D-chain complexes. AB - As part of a program aimed at making bifunctional iron(II) spin-crossover (SCO) materials, particularly those having redox/electron transfer as the second function, we have made the new ferrocene-triazole ligand ATF ([(4H-1,2,4-triazol 4-yl)amino]methylferrocene), (1), and a series of M(II) complexes of this ligand with emphasis on iron(II). Polynuclear 1D-chain complexes [Fe(ATF)3](Br)2.0.5(H2O) (2), [Fe(ATF)3](ClO4)2.0.5(H2O) (3), [Ni(ATF)3](ClO4)2.0.5(H2O) (4) and an analogous complex formed with a positively charged ATF ligand [Fe(ATF(+))3](ClO4)5 (6) were formed as polycrystalline powders. Crystals of a mixed ATF/NCS-bridged copper(II) polymer [Cu(ATF)2(NCS)](ClO4).(Et2O)0.5(MeCN) (5) were formed and structurally characterised. Magnetic and Mossbauer spectral measurements on 2, 3 and 6 indicated that SCO has not been achieved though the Mossbauer data show interesting temperature dependence for doublets of the two iron sites for complexes 2 and 3. Solid state cyclic voltammetric data on the iron(II) complexes 3 and 4 showed well defined, reversible ATF-based electrochemistry, similar to those shown by ATF in solution. PMID- 23740423 TI - Non-pharmacological strategies used by patients at high risk for future fracture to manage fracture risk--a qualitative study. AB - We examined patients' self-management of bone health and fracture risk, particularly behaviors other than medication use and seeking diagnostic testing. Awareness of fracture risk was accompanied by positive lifestyle changes in participants' lives such as being careful. Future research should evaluate how lifestyle changes mitigate fracture risk. INTRODUCTION: We examined patients' understanding of bone health and self-management decisions regarding bone health and fracture risk, particularly behaviors other than medication use and seeking diagnostic testing. METHODS: A phenomenological (qualitative) study was conducted. English-speaking patients, 65+ years old, who were "high risk" for future fracture and prescribed pharmacotherapy after being screened through a post-fracture osteoporosis initiative were eligible. Patients were interviewed for 1-2 h and were asked to discuss perceptions of bone health status (bone densitometry results and perceived fracture risk), recommendations received for bone health, and lifestyle changes since their most recent fracture. We analyzed the data guided by Giorgi's methodology. RESULTS: We interviewed 21 fracture patients (6 males and 15 females), aged 65 to 88 years old. With the exception of one participant, all participants appeared to understand that they had low bone mass and were at risk of sustaining another fracture. Most participants (n = 20) were predominantly concerned about being careful, and they focused their responses on personal and environmental factors that they perceived to be modifiable. Participants also spoke about strategies to manage their bone health such as exercise, having a healthy diet and taking supplements, and using aids and devices. Non-pharmacological strategies used by patients appeared to be independent of current use of pharmacotherapy. CONCLUSIONS: Awareness of fracture risk was accompanied by a number of positive lifestyle changes in participants' lives such as being careful and engaging in exercise. Future research needs to evaluate how lifestyle changes such as being careful mitigate fracture risk. PMID- 23740422 TI - Early changes in biochemical markers of bone formation during teriparatide therapy correlate with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis. AB - Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. INTRODUCTION: To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. METHODS: A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 MUg/day, n = 45) and risedronate (35 mg/week, n = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. RESULTS: PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. CONCLUSIONS: Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients. PMID- 23740425 TI - The importance of multimodality therapy in the treatment of sinonasal neuroendocrine carcinoma. AB - Sinonasal carcinoma with neuroendocrine differentiation (SCND) is a rare group of tumors known for their aggressive behavior and poor response to treatment. The data in the literature are sparse and cover a wide range of therapeutic approaches over a protracted timeline. Therefore, it is important that institutions report on their experience with these rare neoplasms. Clinical data, such as age at diagnosis, gender, tumor subtype and stage, treatment intention and modality, recurrence, salvage treatment, and survival of patients with a SCND, diagnosed at our department between 1980 and 2010, were retrospectively analyzed. Fifteen patients were available for analysis; eight with sinonasal undifferentiated carcinoma (SNUC), five with sinonasal neuroendocrine carcinoma (SNEC), and two with small cell neuroendocrine carcinoma (SmCC). The median age at the time of diagnosis was 68 years (range 28-87). Treatment consisted of surgery (2), radiotherapy (4), a combination of these modalities (6) and palliation (3). The estimated 5-year overall survival was 60 % for SNEC, 44 % for SNUC and 0 % for SmCC. According to our institutional experience an aggressive multi-modality approach incorporating (neoadjuvant) chemoradiotherapy, radical surgery and elective treatment of the neck is the best treatment strategy for SCND. The high propensity for distant metastasis and poor prognosis of SmCC warrants consideration of the impact of treatment on the remaining quality of life in these patients. PMID- 23740426 TI - A speech nasoendoscopy-based surgeon's decision for correction of velopharyngeal insufficiency following adenotonsillectomy. AB - Both sphincter pharyngoplasty (SP) and pharyngeal flap (PF) procedures have gained popularity among surgeons as effective surgical management for velopharyngeal insufficiency (VPI). Different centers prefer either SP or PF and have published their results to support this preference. But is one technique superior to the other? To answer this question, we have adopted the concept of differential therapeutic management, based on detailed assessment of velopharyngeal function. According to this assessment either SP or PF was performed for management of VPI (secondary to adenotonsillectomy). The aim of this work is to evaluate and compare the surgical results after SP and PF (based on the preoperative nasoendoscopy and phoniatrics' evaluation). This study was conducted on 31 patients with persistent hypernasality after adenotonsillectomy. All patients were subjected to perceptual speech evaluation and nasoendoscopic examination. According to this evaluation and data analysis, 18 patients were operated by SP and 13 patients underwent PF. Statistically, highly significant improvements were found when comparing pre- versus postoperative perceptual speech evaluation following both SP and PF (P < 0.001). When comparing the postoperative perceptual speech evaluation following both techniques, statistically non-significant differences were reported (P > 0.05). Preoperative differential diagnosis of VPI using perceptual speech assessment and nasoendoscopy of the velopharynx allows for tailored surgical management with either SP or PF. Both SP and PF procedures could yield good surgical outcomes, when patients are properly selected and the technique is chosen according to preoperative assessment. PMID- 23740427 TI - Endoscopic laser-assisted diverticulotomy without versus with wound closure in the treatment of Zenker's diverticulum. AB - The aim of the present study was to compare the modifications of endoscopic laser assisted diverticulotomy regarding closure of mucosal wound at the cricopharyngeal bridge. The results of 62 cases after endoscopic laser-assisted diverticulotomy without and with wound closure were retrospectively compared. After laser-assisted transection of the cricopharyngeal bridge, the mucosa wound was left open (OW) in 35 cases (56%), whereas a closure of the mucosa wound (CW) with sutures and fibrin glue was performed in 27 patients (44%). Duration of hospitalization, residual diverticular sac rate and occurrence of complications did not differ significantly between the two groups. Mean surgical time was significantly less in the OW cases. According to these results, it can be assumed that readapting and sealing the wound after transecting the cricopharyngeal bridge does not significantly reduce the complication rate. It does, however, extend the length of surgery and increases the cost of the procedure. PMID- 23740428 TI - Evaluation of a novel mouse model of intracisternal strychnine-induced trigeminal allodynia. AB - PURPOSE: Intractable neuropathic dynamic allodynia remains one of the major symptoms of human trigeminal neuropathy and is commonly accepted to be the most excruciatingly painful condition known to humankind. At present, a validated animal model of this disorder is necessary for efficient and effective development of novel drug treatments. Intracisternal strychnine in rats has been shown to result in localized trigeminal dynamic allodynia, thus representing a possible model of trigeminal neuralgia. The purpose of this study was to validate a mouse model of trigeminal glycinergic inhibitory dysfunction using established positive (carbamazepine epoxide) and negative (morphine) controls. METHODS: The actions of conventional first-line treatment (carbamazepine epoxide [CBZe]) and clinically ineffective morphine were tested for trigeminal dynamic mechanical allodynia produced by intracisternal strychnine. In mice under halothane anesthesia, we injected either strychnine (0.3 MUg), strychnine with CBZe (4 ng), or artificial cerebrospinal fluid (aCSF) intracisternally (i.c.). In a separate set of experiments, subcutaneous morphine (3 mg.kg(-1) sc) was injected with intracisternal strychnine. Dynamic mechanical allodynia was induced by stroking the fur with polyethylene (PE-10) tubing. The response of each mouse was rated to determine its allodynia score, and scores of each group were compared. In addition, in a separate dichotomous disequilibrium study, pairs of mice were injected with strychnine/saline, strychnine/strychnine-CBZe, or strychnine/strychnine-morphine. A blinded observer recorded which mouse of each pair had the greater global pain behaviour. RESULTS: Strychnine (i.c.) produced higher quantitative allodynia scores in the trigeminal distribution (mean 81.5%; 95% confidence interval [CI] 76.4 to 86.6) vs the aCSF group (mean 11.3%; 95% CI 8.1 to 14.4) (P < 0.0001). Carbamazepine epoxide (i.c.) completely abolished allodynia when co-injected with strychnine (mean 83.2%; 95% CI 78.1 to 88.4) vs strychnine alone (mean 3.2%; 95% CI -0.9 to 7.2) (P < 0.0001). Morphine co injected with strychnine did not result in reduced allodynia (mean 65.7%; 95% CI 42.0 to 89.4) compared with strychnine alone (mean 87.6%; 95% CI 77.6 to 97.6) (P = 0.16). In a further global allodynia assessment, strychnine (i.c.) produced greater allodynia than both aCSF and strychnine administered with CBZe (P = 0.03). Morphine (ip) administered with strychnine did not result in reduced global allodynia compared with strychnine administered alone (P = 1.0). CONCLUSION: In this study, we have developed and validated a novel murine model of trigeminal dynamic allodynia induced by intracisternal strychnine. The use of mice to study trigeminal allodynia has many benefits, including access to a vast repository of transgenic mouse variants, ease of handling, low cost, and minimal variance of results. The present model may have utility in screening drug treatments for dynamic mechanical allodynia resulting from trigeminal neuropathies. PMID- 23740429 TI - NMDA receptor as a newly identified member of the metabotropic glutamate receptor family: clinical implications for neurodegenerative diseases. AB - Recent reports have proposed a novel function for the N-methyl-D-aspartate (NMDA) receptor (NMDAR), a well-known excitatory, ionotropic receptor. A series of observations employing pharmacological techniques has proposed that upon ligand binding, this ionotropic receptor can actually function via signaling cascades independent of traditional ionotropic action. Moreover, the "metabotropic" action of NMDARs is suggested to mediate a form of synaptic plasticity, namely long-term synaptic depression (LTD), which shares cellular mechanisms with the synaptic deficits observed in Alzheimer's disease. Given that a growing body of clinical and preclinical evidence strongly recommends NMDAR antagonists for their therapeutic potentials and advantages in a variety of diseases, further investigation into their molecular and cellular mechanisms is required to better understand the "metabotropic" action of NMDARs. PMID- 23740430 TI - Rescue of deleterious mutations by the compensatory Y30F mutation in ketosteroid isomerase. AB - Proteins have evolved to compensate for detrimental mutations. However, compensatory mechanisms for protein defects are not well understood. Using ketosteroid isomerase (KSI), we investigated how second-site mutations could recover defective mutant function and stability. Previous results revealed that the Y30F mutation rescued the Y14F, Y55F and Y14F/Y55F mutants by increasing the catalytic activity by 23-, 3- and 1.3-fold, respectively, and the Y55F mutant by increasing the stability by 3.3 kcal/mol. To better understand these observations, we systematically investigated detailed structural and thermodynamic effects of the Y30F mutation on these mutants. Crystal structures of the Y14F/Y30F and Y14F/Y55F mutants were solved at 2.0 and 1.8 previoulsy solved structures of wild-type and other mutant KSIs. Structural analyses revealed that the Y30F mutation partially restored the active-site cleft of these mutant KSIs. The Y30F mutation also increased Y14F and Y14F/Y55F mutant stability by 3.2 and 4.3 kcal/mol, respectively, and the melting temperatures of the Y14F, Y55F and Y14F/Y55F mutants by 6.4 degrees C, 5.1 degrees C and 10.0 degrees C, respectively. Compensatory effects of the Y30F mutation on stability might be due to improved hydrophobic interactions because removal of a hydroxyl group from Tyr30 induced local compaction by neighboring residue movement and enhanced interactions with surrounding hydrophobic residues in the active site. Taken together, our results suggest that perturbed active-site geometry recovery and favorable hydrophobic interactions mediate the role of Y30F as a secondsite suppressor. PMID- 23740431 TI - Genetic identification of a second site modifier of ctr1-1 that controls ethylene responsive and gravitropic root growth in Arabidopsis thaliana. AB - Ethylene controls myriad aspects of plant growth throughout developmental stages in higher plants. It has been well established that ethylene-responsive growth entails extensive crosstalk with other plant hormones, particularly auxin. Here, we report a genetic mutation, named 1-aminocyclopropane carboxylic acid (ACC) resistant root1-1 (are1-1) in Arabidopsis thaliana (L.) Heynh. The CONSTITUTIVE TRIPLE RESPONSE1 (CTR1) encodes a Raf-related protein, functioning as an upstream negative regulator of ethylene signaling in Arabidopsis thaliana. We found that the ctr1-1, a kinase-inactive allele exhibited slightly, but significantly, longer root length, compared to ACC-treated wild-type or ctr1-3, a null allele. Our genetic studies unveiled the existence of are1-1 mutation in the ctr1-1 mutant, as a second-site modifier which confers root-specific ethylene resistance. Based on well-characterized crosstalk between ethylene and auxin during ethylene-responsive root growth, we performed various physiological analyses. Whereas are1-1 displayed normal sensitivity to synthetic auxins, it showed modest resistance to an auxin transport inhibitor, 1-Nnaphthylphthalamic acid. In addition, are1-1 mutant exhibited ectopically altered DR5:GUS activity upon ethylenetreatment. The results implicated the involvement of are1-1 in auxin distribution, but not in auxin-biosynthesis, -uptake, or -sensitivity. In agreement, are1-1 mutant exhibited reduced gravitropic root growth and defective redistribution of DR5:GUS activity upon gravi-stimulation. Taken together with genetic and molecular analysis, our results suggest that ARE1 defines a novel locus to control ethylene-responsive root growth as well as gravitropic root growth presumably through auxin distribution in Arabidopsis thaliana. PMID- 23740432 TI - Rationale and design: BREATHE registry--I Brazilian Registry of Heart Failure. AB - BACKGROUND: Several local registries have sought to individually depict clinical characteristics of patients hospitalized with heart failure (HF) in Brazilian hospitals and communities. Overall, the analysis of these data suggests that there are important differences in etiology, decompensation factors, treatment and prognosis of patients with HF in different Brazilian regions. OBJECTIVES: To evaluate the demographic, clinical and prognostic characteristics of 1,200 patients admitted with a clinical diagnosis of decompensated HF in a group of 60 hospitals representative of the different Brazilian regions. METHODS: Transversal observational study (registry) with a longitudinal twelve-month follow-up (admission consultations, hospital discharge, three months, six months and twelve months after inclusion), in which patients admitted to public and private hospitals clinical with a primarily defined HF diagnosis will be studied. RESULTS: The results will be shown soon after data collection completion, quality assessment and statistical analysis. CONCLUSIONS: The results of this multicenter registry will allow for a more appropriate planning of financial, technological and personal resource supply for the health care area, as well as the planning of more effective preventive measures in decompensated HF. PMID- 23740433 TI - Stratification of cardiovascular risk by cardiac computerized tomography: shall we keep on ignoring? PMID- 23740434 TI - Development of regionalized STEMI care networks in Brazil. PMID- 23740435 TI - Case 2: sudden death after coronary artery bypass surgery in a 49-year-old female, diabetic, dyslipidemic, hypertensive, obese patient. PMID- 23740436 TI - Stent Thrombosis eight years past drug-eluting stent placement: a case report. PMID- 23740437 TI - Transapical mitral valve implant for the treatment of degenerated bioprosthesis. PMID- 23740438 TI - Warfarin in valvulopathy: how important is seniority? PMID- 23740439 TI - Land surface phenology and land surface temperature changes along an urban-rural gradient in Yangtze River Delta, china. AB - Using SPOT/VGT NDVI time series images (2002-2009) and MODIS/LST images (2002 2009) smoothed by a Savitzky-Golay filter, the land surface phenology (LSP) and land surface temperature (LST), respectively, are extracted for six cities in the Yangtze River Delta, China, including Shanghai, Hangzhou, Nanjing, Changzhou, Wuxi, and Suzhou. The trends of the averaged LSP and LST are analyzed, and the relationship between these values is revealed along the urban-rural gradient. The results show that urbanization advances the start of the growing season, postpones the end of the growing season, prolongs the growing season length (GSL), and reduces the difference between maximal NDVI and minimal NDVI in a year (NDVIamp). More obvious changes occur in surface vegetation phenology as the urbanized area is approached. The LST drops monotonously and logarithmically along the urban-rural gradient. Urbanization generally affects the LSP of the surrounding vegetation within 6 km to the urban edge. Except for GSL, the difference in the LSP between urban and rural areas has a significant logarithmic relationship with the distance to the urban edge. In addition, there is a very strong linear relationship between the LSP and the LST along the urban-rural gradient, especially within 6 km to the urban edge. The correlations between LSP and gross domestic product and population density reveal that human activities have considerable influence on the land surface vegetation growth. PMID- 23740440 TI - Can we prevent, reduce or reverse intestinal fibrosis in IBD? AB - Intestinal fibrosis is a common complication of in inflammatory bowel disease (IBD) and can occur in both ulcerative colitis (UC) and Crohn's disease (CD), but is much more prevalent in CD. Fibrosis is a consequence of local chronic inflammation and is characterized by abnormal deposition of extracellular matrix (ECM) proteins producted by activated myofibroblasts. Current anti-inflammatory therapies used in IBD do not prevent nor they reverse established fibrosis and strictures. Despite the therapeutic advance in the treatment of IBD in the last two decades, the incidence of intestinal strictures in CD has not significantly changed. This implies that control of intestinal inflammation does not necessarily affect the associated fibrotic process. The conventional view that intestinal fibrosis is an inevitable and irreversible process in patients with IBD is progressively changing in light of improved understanding of the cellular and molecular mechanisms that underline the pathogenesis of fibrosis. Comprehension of the mechanisms of intestinal fibrosis may pave the way for the developments of anti-fibrotic agents and of new possible therapeutic approches in IBD. Nevertheless, there are important clinical issues that need further investigations, in particular the identification of factors relevant for the development of the intestinal fibrosis in IBD and the need of accurate and effective monitoring of the fibrotic progression and of effectiveness of the new proposed treatments. PMID- 23740441 TI - Lipoic acid prevents hepatic and intestinal damage induced by obstruction of the common bile duct in rats. AB - INTRODUCTION: Cholestatic liver diseases are characterized by impaired hepatocellular secretion of bile, resulting in intracellular accumulation of bile acids which result in a shift in the oxidant/prooxidant balance in favor of increased free radical activity and injury of different tissues including liver and intestine. The aim of this research was to study protective effect of lipoic acid (LA) as a potent antioxidant in cholestsis induced hepatic and intestinal injury in rats. MATERIALS AND METHODS: Forty five adult male Wistar rats were randomly assigned to four groups each containing fifteen rats as follows: sham operation (SO) (control), bile duct ligating (BDL), and BDL+LA (25 mg/kg). After fourteen days hepatic and intestinal tissue sampled and blood serum sampled for pathologic and biochemical studies. RESULTS: Levels of SOD and GPx antioxidant enzymes were higher in BDL+LA group comparing to BDL group, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma glutamyltranspeptidase (GGT), and pathologic scores in liver and intestine were lower in BDL+LA group comparing to BDL group significantly, but there is no significant difference in concentrations of total bilirubin between groups. CONCLUSIONS: Our results showed the protective potential of LA with liver and intestine damage. Despite improvements in operative technique and the development of potent, broad-spectrum antibiotics, biliary tract surgery in patients with obstructive jaundice is still associated with high morbidity and mortality rates In summary, our results show that BDL induced hepatic and intestinal injury were significantly attenuated by LA administration and the administration of LA could effectively diminish this damage. PMID- 23740442 TI - Procalcitonin as a diagnostic and prognostic marker for sepsis caused by intestinal infection: a case report. AB - BACKGROUND: In recent years, procalcitonin has emerged as a promising marker for bacterial infection, with the high sensitivity and specificity. CASE PRESENTATION: This report presents a 76-year-old woman with fever, vomiting and diarrhea. The clinical and laboratory examination revealed that the patient had a suspected serious intestinal infection and sepsis. The extremely high level of procalcitonin and positive blood culture result confirmed our diagnosis. CONCLUSIONS: Early identification of severe sepsis sometimes is very difficult. Procalcitonin is a useful tool in the early diagnosis of sepsis, differentiating from other inflammatory syndrome. The high PCT level (10 ng/ml) in this case could suggest serious bacterial infection and sepsis, and also predicts mortality and worse outcome. PMID- 23740443 TI - Rifaximin treatment for small intestinal bacterial overgrowth in children with irritable bowel syndrome. AB - OBJECTIVES: Aims of the study were to assess the effects of rifaximin treatment on small intestinal bacterial overgrowth (SIBO) prevalence and gastrointestinal symptoms. STUDY DESIGN: Fifty (50) irritable bowel syndrome (IBS) children were consecutively enrolled. All subjects underwent lactulose hydrogen/methane breath test (LBT) to assess SIBO before and one month after the treatment with rifaximin 600 mg daily for one week. All IBS patients filled out a Visual Analogic Scale (VAS) to assess and score gastrointestinal symptoms (abdominal pain, constipation, diarrhoea, bloating, flatulence) at baseline and one month after treatment. RESULTS: The prevalence of abnormal LBT in patients with IBS was 66% (33/50). LBT normalization rate was 64% (21/33). Compliance was excellent, and no relevant side-effects were observed during treatment. VAS score was significantly higher in IBS patients with abnormal LBT than SIBO negatives, and strongly improved after successful treatment. CONCLUSIONS: Rifaximin was effective and safe in SIBO treatment and IBS symptoms improvement in childhood. Double blind placebo-controlled interventional studies are warranted to verify the real impact of SIBO on gastrointestinal symptoms in children with IBS. PMID- 23740444 TI - Association of anthropometric and biochemical markers with length of stay and mortality in the hospital. AB - INTRODUCTION: Malnutrition is associated with patient outcome, hospital stay and costs. The objective of our study was evaluated the relationship of different anthropometric and biochemical nutritional markers with hospital stance (days) and mortality. PATIENTS AND METHODS: A sample of 3087 hospitalized patients in a Universitary Hospital was enrolled. Nutritional status was assessed from anthropometric variables; body mass index (BMI), weight, weight loss in previous three months, tricipital skin fold thickness, midarm muscle circumference and midarm muscle area. Biochemical evaluation was assessed with albumin, prealbumin, transferrin and lymphocytes. Length of hospital stance and mortality were recorded. RESULTS: A total of 3087 patients were enrolled, mean age was 67.7+/ 18.3 years, weight 63.3+/-15,7 kg and BMI 23.7+/-6.8, with a weight loss (3 months) of 6.3+/-4.6 kg. Length of stay was 24.7+/-22.1 days. A total of 2583 patients were discharged. Hospital discharge data showed 87.8% of patients went home, and a 12.2% of patients were discharged to a secondary Hospital. A (n=504) 16.3% of patients died. In the multivariate analysis with a dependent variable [length of stay (days)], only albumin levels remained as an independent predictor in the model (F=2.9; p < 0.05), with an increase of 3.1 days in hospital stay (CI 95%: 0.4-5.8) with each decrease of 1 g/dl of albumin. In multivariate analysis, an independent factor that decrease mortality was high albumin levels (hazard ratio: 0.41; 95% CI: 0.22-0.80), adjusted by age and sex. CONCLUSIONS: Our study shows a significant association among serum albumin levels with length of stay in hospital and mortality. PMID- 23740445 TI - Pharmacological interference with 123I-metaiodobenzylguanidine: a limitation to developing cardiac innervation imaging in clinical practice? AB - BACKGROUND: (123)I-metaiodo-benzylguanidine (MIBG) scintigraphy is considered a valid imaging test to evaluate the cardiac sympathetic nervous system. However, scientific literature showed that some drugs are able to or are expected to interfere with MIBG uptake. Thirty years after introduction of the method and over 15 years since the appearance of the first document on pharmacological interference with MIBG, an update on this issue has become necessary. AIM: The aims of this review paper are: (1) to identify the pharmacological basis of interference of a variety of substances with MIBG uptake; and (2) to update the list of drugs that definitely interfere with MIBG on the grounds of evidence in the literature. MATERIALS AND METHODS: A MEDLINE search was conducted. Scientific studies, case report and review articles were collected. Papers published demonstrating drugs interfering with MIBG uptake were evaluated. RESULTS: Drugs may interact with MIBG uptake by 5 mechanism: (1) type-1 uptake inhibition; (2) inhibition of active transport to vesicles; (3) competition in transport to vesicles; (4) depletion of neurosecretory vesicle content; (5) calcium-mediated mechanism. We find that drugs like cocaine, antidepressants, some antipsychotic, tramadol, labetalol, sympatho-mimetics, reserpine and some calcium antagonists (as diltiazem, verapamil and nifedipine) do interfere with MIBG uptake. On the other hand, we find that controversial data are available on scientific literature regarding digoxin and amiodarone. CONCLUSIONS: A compiled statement of MIBG interfering medicines is now recommended to help nuclear medicine physicians in clinical practice to avoid potential pitfalls and improve the efficacy of (123)I-MIBG scintigraphy as a diagnostic tool. PMID- 23740446 TI - Elderly man with rapidly enlarging axillary mass. AB - Melanoma has long been known to be a malignancy that can present in a plethora of forms. This often makes diagnosing it a challenge, but lends support to the concept of frequently keeping it in the clinician's differential. We present the unique case of a rapidly enlarging axillary mass in an elderly man that initially did not appear concerning for malignancy. Pathologic diagnosis was particularly difficult due to the cystic nature of the mass, and the uncommon histo-chemical staining pattern of this malignant melanoma. We discuss the variety of therapies directed at symptom relief and control when discovered in advanced stages. This was a rare presentation of a malignant melanoma that highlights the need to maintain a suspicion for the disease in uncertain clinical situations. PMID- 23740447 TI - Secretory clusterin (sCLU) overexpression is associated with resistance to preoperative neoadjuvant chemotherapy in primary breast cancer. AB - OBJECTIVES: Preoperative chemotherapy is often used in patients with locally advanced breast cancer. However, commonly used clinical and pathological parameters are poor predictors of response to this type of therapy. The secreted form of the CLU protein (sCLU) is a glycosylated protein of 76-80 kDa. It has become increasingly clear that in most cells sCLU is a stress-associated cytoprotective protein that is upregulated by various apoptotic triggers. Furthermore, sCLU confers resistance by some unknown mechanism when overexpressed. The purpose of the present study was to examine the sCLU proteins as predictors of clinical outcome and response to chemotherapy in locally advanced breast cancer. PATIENTS AND METHODS: The expression levels of sCLU was determined by immunohistochemistry before preoperative chemotherapy in 72 patients with locally advanced breast cancer. All patients were treated with cyclophosphamide/doxorubicin/5-FU(CAF) and some patients received additional treatment with docetaxel. Expression data were compared with patients' clinical and pathological features, clinical outcome, and response to chemotherapy. RESULTS: The results showed sCLU expression before preoperative chemotherapy was inversely related to the tumor size, expression of estrogen and progesterone receptors. High preoperative expression of sCLU was associated with resistance to CAF therapy, but not with resistance to docetaxel. CONCLUSIONS: We, therefore, suggested sCLU expression may be a useful marker for predicting response to preoperative chemotherapy and clinical outcome in patients with locally advanced breast cancer. PMID- 23740448 TI - Relaxin promotes in vitro tumour growth, invasion and angiogenesis of human Saos 2 osteosarcoma cells by AKT/VEGF pathway. AB - OBJECTIVES: In the present study, we determine the role of relaxin on cellular growth, invasion and angiogenesis of osteosarcoma Saos-2 cells in vitro, and discuss the molecular mechanisms of this action. MATERIALS AND METHODS: Saos-2 cells were transfected with Akt1/2 siRNA or VEGF siRNA for 24 hours then treated with 10-100 ng/mL recombinant human relaxin-2 (rh-RLN) for 48 h. MTT, matrigel and bone marrow-derived endothelial cells (BMDECs) was used for cell proliferation, invasion and angiogenesis assay. Western blot was used for relaxin 2, pAKT and VEGF protein assay. RESULTS: The results showed treatment with 10-100 ng/mL rh-RLN resulted in 18%, 48%, 107%, 212% increase in cell proliferation, respectively (vs control, *p < 0.05;**p < 0.01), the relative invasive cells was 1.4;1.9;2.6;4.8 (control was defined to 1) (vs control, #p < 0.01; ##p < 0.001) and the relative anglogenic branch points in Saos-2 cells was 1.04;1.36;1.69;2.10 (control was defined to 1.00) (vs control, *p < 0.05; **p < 0.01). Furthermore, treatment with rh-RLN exhibited a significant increase in the expression level of pAKT and VEGF proterin in dose-dependent manner. Saos-2 cells were transfected with AKT1/2 siRNA for 24 h. No significant increase of VEGF protein expression was shown after rh-RLN treatment. CONCLUSIONS: These results suggested that rh RLN could promoted proliferation, invasion and angiogenesis by upregulation pAKT dependent VEGF expression. PMID- 23740449 TI - The effect of Amifostine (Ethyol) on intestinal anastomosis in rats with radiation enteritis. AB - BACKGROUND: Preoperative radiotherapy in colorectal cancers is being used as an adjuvant therapy with increasing frequency. Postoperative complications in early and late periods in various ratios are reported. It has also been shown that radiation has a delaying effect on wound healing and this effect is dose dependent. AIM: This study investigated the effects of the Amifostine on healing of the irradiated colonic anastomosis. MATERIALS AND METHODS: 30 female Wistar rats were divided randomly into three groups equally (n=10). Colonic anastomosis were performed to all rats. Group I served as a control. 800 rad abdominopelvic irradiation on the 5th day of preoperation was given to group II and III. Rats in the group III, prior to radiation, were given Amifostine at a dose of 200 mg/kg. On the 5th postoperative day all the rats were sacrificed and the healing of anastomosis was measured with bursting pressure, hydroxyproline levels and histopathological evaluations. Statistical analyses were expressed by analysis of variance (ANOVA) test and p < 0.05 was regarded as significant. RESULTS: In group II, all parameters were found lower compared with control group and Amifostine+Radiation group. As compared with hydroxyproline values and the anastomotic wound healing scores, except group II, no significantly difference were determined between the two other groups. In bursting pressure levels, Group I and III were higher than group II, but not statistically significant (p > 0.05). In group III (Amifostine+Radiation group), the hydroxyproline levels and anastomotic wound healing scores were found significantly higher than group II (p < 0.05), and no significant difference were found between the control group. CONCLUSIONS: It is determined that radiation given on the 5th preoperative day has a negative effect on anastomotic wound healing and administered Amifostine prevent this negative effect. In the light of these data, the Amifostine may have a positive effect on preoperative irradiated colonic anastomosis and may play an important role in future on the supporting of the colonic anastomosis. PMID- 23740450 TI - Ameliorating effects of curcumin on 6-OHDA-induced dopaminergic denervation, glial response, and SOD1 reduction in the striatum of hemiparkinsonian mice. AB - BACKGROUND: Inflammation and oxidative stress are believed to contribute to neuronal degeneration of the nigrostriatal dopaminergic (DA) pathway in Parkinson's disease. Curcumin, a component of the yellow curry spice, has been reported possessing anti-inflammatory and anti-oxidative effects. AIM: The present study investigated the effects of curcumin on the extent of DA innervation, glial response, and Cu/Zn superoxide dismutase (SOD1) expression in the striatum of 6-hydroxydopamine (6-OHDA)-lesioned mice. MATERIALS AND METHODS: 6-OHDA was unilaterally injected into the right striatum of ICR male mice. Curcumin (200 mg/kg) was administered daily for 7 days starting instantaneously after 6-OHDA injection. Seven days after 6-OHDA insult, mice were euthanized and striatal sections were collected, immunohistochemically stained, and quantitated for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), ionized calcium binding adapter molecule 1 (Iba1), and SOD1 immunoreactivity. RESULTS: 6 OHDA injection triggered a significant loss of TH-immunoreactive (-IR) axons, induced reaction of GFAP-IR astrocytes and Iba1-IR microglia, and decreased SOD1 expression in the 6-OHDA-lesioned striatum. Curcumin attenuated loss of TH-IR fibers, diminished activation of astrocytes and microglia, and sustained SOD1 level in the lesioned striatum. CONCLUSIONS: These results suggest that curcumin counteracts the neurotoxicity of 6-OHDA through its anti-inflammatory properties (inhibition of glial response) and preservation of SOD1 expression. PMID- 23740451 TI - Potential involvement of mineralocorticoid receptor activation in the pathogenesis of central serous chorioretinopathy: case report. AB - BACKGROUND: Recently it has been suggested that excessive glucocorticoid dependent choroidal mineralocorticoid receptor (MR) activation may be involved in the pathogenesis of central serous chorioretinopathy (CSCR). AIM: To present a 38 year-old woman with an impressive improvement of CSCR following MR antagonist eplerenone administration. CASE REPORT: At presentation, visual acuity (VA) was 0.2 in the left eye and 1.0 in the right eye. Optical coherence tomography (OCT) of the left eye showed extended serous retinal detachment including the macular area. RESULTS: After six weeks of treatment with eplerenone (25 mg/day) total resorption of subretinal fluid with an increase in VA to 0.8 was observed. At that point the therapy with eplerenone was discontinued, with no recurrence in the left eye during five months follow-up. Two months after the discontinuation of eplerenone, subretinal fluid accumulation in the right eye was revealed by OCT. Four weeks after reintroducing the treatment with eplerenone (25 mg/day) almost total resorption of subretinal fluid in the right eye was observed. CONCLUSIONS: The effectiveness of MR antagonism in unresolved CSCR supports the hypothesis that excessive choroidal MR activation may be a potential pathological pathway leading to CSCR, and MR blockage may be an effective treatment option for CSCR. Controlled clinical trials are necessary to evaluate this therapeutic approach. PMID- 23740452 TI - Gene expression analysis of ruptured and un-ruptured saccular intracranial aneurysm. AB - BACKGROUND: Although Saccular intracranial aneurysm (sIA) is the most common type abnormality of all intracranial aneurysms, the biological mechanisms of sIA are not fully understood. METHODS: We downloaded microarray datasets from Gene Expression Omnibus (GEO) database which includes 11 ruptured intracranial aneurysm samples and 8 unruptured intracranial aneurysm samples. Significant Analysis of Microarray (SAM) was employed to identify the differentially expressed genes (DEGs) between ruptured and unruptured intracranial aneurysms. RESULTS: We found 2129 genes differentially expressed in rupture sIA, of which 1062 genes up-regulated and 1057 genes down-regulated. Functional analysis demonstrated these genes were significantly associated with inflammatory response, wounding response and defense response. Protein-protein interaction (PPI) analysis revealed that these genes may play important roles in the pathogenesis of sIAs. Results suggested that four transcription factors (TFs) could cooperated with each other, together with several microRNAs play roles in the pathonegensis of ruptured sIAs. CONCLUSIONS: All of above results indicate the existence of DEGs between ruptured and unruptured sIAs, which regulating the pathogenesis of ruptured sIAs. TFs and microRNAs may also play key roles in ruptured sIAs. This research hints a new thought to the therapy of ruptured sIAs. PMID- 23740453 TI - A new parameter in the diagnosis of vascular erectile dysfunction with penile Doppler ultrasound: cavernous artery ondulation index. AB - AIM: Our aim is to introduce the cavernous artery ondulation index (CA-OI) as a new parameter that could be accepted as an indirect indicator of vascular hemodynamics and also gives us information about the efficiency of erection. PATIENTS AND METHODS: A total of 27 patients with erectile dysfunction were evaluated with penile Doppler ultrasonography (PDUS). After injection of papaverine intracavernously, arterial diameter and peak-systolic and end diastolic velocities were measured. For measuring at a standart time, five minutes after injection, bilateral cavernosal arteries were examined and gray scale and color Doppler US images through the long axis were recorded at the mentioned phases. Cavernosal artery ondulation index (CA-OI) showing the amount of ondulation was calculated for each subject using these images. RESULTS: In 9 of total 27 patients, erection could not pass the tumescence phase with 3 flaccid phases, while the remaining 18 had full erection. Mean CA-OI values were measured as 2.51+/-0.37 mm, 3.15+/-0.38 mm, and 2.68+/-0.09 mm in normal, arterial insufficiency and venous insufficiency groups, respectively. CONCLUSIONS: It is possible to differentiate the arterial insufficiency by using the cut-off value of CA-OI >= 2.5 values as a criteria. PMID- 23740454 TI - Comparison of the right and left laparoscopic live donor nephrectomies: a clinical case load. AB - BACKGROUND: The aim of the present study was to retrospectively compare the results of right- and left-laparoscopic donor nephrectomy (LDN) performed in our Center. PATIENTS AND METHODS: Two hundred and eight patients who were operated on between October 2010 and October 2011 were included. Of the patients, 65 underwent right-LDN and 143 underwent left-LDN. The groups were compared in terms of duration of surgery, warm ischemia time, postoperative complications, length of hospital stay, and donor outcomes. RESULTS: The mean duration of surgery was 144+/-19.7 min and 147.8+/-20.2 min in the right- and left-LDN groups, respectively. The mean warm ischemia times were 139.1+/-54.1 s and 141.5+/-37.9 in the right- and left-LDN groups, respectively. The mean length of hospital stay was 2.4+/-1.0 days for both groups. No major complications were observed in the groups. There was no significant difference between the groups in terms of donor outcomes. CONCLUSIONS: The right-LDN is approached cautiously because of short length of vein and the risk for thrombosis. The results of the present study demonstrated that the right-LDN is as safe and effective as the left-LDN. PMID- 23740455 TI - The effects of water birth on neonatal outcomes: a five-year result of a referral tertiary centre. AB - OBJECTIVE: As scant information is present about the effect of water birth on newborns, we aimed to detect the fetal outcomes of water birth. MATERIALS AND METHODS: A hundred and ninety one among totally 220 newborns who were born by water birth were enrolled. The demographic and clinical features of the patients, birth complications, infection rates and rates of neonatal intensive care unit attendance were evaluated. RESULTS: The mean gestational week and birth weight were 39.2+/-1.3 weeks and 3326+/-409 g. 26% of the mothers was primiparous. Birth trauma was observed in three patients (1.6%) as one brachial nerve paralysis, one cord rupture and one cephal hematoma. Six of the patients (3.1%) were admitted to neonatal intensive care unit (NICU); four of whom had respiratory tract problems. CONCLUSIONS: Water birth is a safe method of delivery for the neonates when certain criteria are met. PMID- 23740456 TI - The role of vaginal Lactobacillus Rhamnosus (Normogin(r)) in preventing Bacterial Vaginosis in women with history of recurrences, undergoing surgical menopause: a prospective pilot study. AB - BACKGROUND: Bacterial vaginosis (BV), a poly-microbial clinical syndrome, is the most common cause of vaginal symptoms among women. The recurrence rate of BV is up to 30% after traditional antimicrobial therapy. Lactobacillus rhamnosus vaginal tablets have demonstrated to be a reliable topical effective and safe treatment to reduce the BV recurrence rate. AIM: to assess topical long-lasting (6 months) Lactobacillus rhamnosus effectiveness in decreasing recurrences in women with positive anamnesis of recurrent BV and concomitant hypo-estrogenism as consequence of surgical menopause. PATIENTS AND METHODS: A total of 22 consecutive patients affected by recurrent BV and treated for surgical menopause for benign pathology were enrolled. All women were treated with Lactobacillus rhamnosus vaginal tablets (Normogin((r))) according to the following protocol: 1 tablet/day for 6 days, than two tablets per week for 2 months and then one tablet once a week till 6 months. RESULTS: Of the 22 women enrolled only one has been lost after the first visit. A total of 21 cases were reported; 7 out of 21 had only one case of recurrence, while 2 out of 21 had two episodes of BV during the year successive to menopause. No side effects have been reported. CONCLUSIONS: Considering the low recurrence rate of BV during follow-up it seems that long lasting treatment with vaginal tablets of Lactobacillus rhamnosus could reduce the BV recurrence also in women at high risk with positive history of pathology and undergoing surgical menopause with a safe profile. This study supports the use of vaginal Lactobacillus rhamnosus administration in high risk population without side effects. PMID- 23740457 TI - Larvicidal activity of Saponin isolated from Gymnema sylvestre R. Br. (Asclepiadaceae) against Japanese Encephalitis vector, Culex tritaeniorhynchus Giles (Diptera: Culicidae). AB - AIM: To determine the larvicidal activity of various extracts of Gymnema (G.) sylvestre against the Japanese Encephalitis vector, Culex tritaeniorynchus in Tamilnadu, India. To identify the active principle present in the promising fraction obtained in Chlorofom:Methanol extract of Fraction 2. MATERIALS AND METHODS: The G. Sylvestre leaf extracts were tested, employing WHO procedure against fourth instar larvae of C. tritaeniorhynchus and the larval mortalities were recorded at various concentrations (6.25 microg/ml); the 24h LC(50) values of the G. Sylvestre leaf extracts were determined following Probit analysis. It was noteworthy, that treatment level 100 ppm exhibited highest mortality rates for the three different crude extracts and was significantly different from the mean mortalities recorded for the other concentrations. RESULTS: The LC(50) values of 34.756 microg/ml (24.475-51.41), 31.351 microg/ml (20.634-47.043) and 28.577 microg/ml (25.159-32.308) were calculated in acetone, chloroform and methanol extract with the chi-square values of 10.301, 31.351 and 4.093 respectively. CONCLUSIONS: The present investigation proved that G. Sylvestre could be possibly utilized as an important component in the Vector control Programme. PMID- 23740458 TI - Reconstruction of severe atrophic jaws with Fresh Frized Bone Allografts: clinical histologic and histomorphometric evaluation. AB - OBJECTIVES: Rehabilitation of maxillary edentulism with implant-supported prostheses has come into common clinical practice. Although autologous bone has osteoinductive, osteoconductive and osteogenetic properties, its use is subject to certain disadvantages such as: Increased morbidity Limited amount of bone harvested from each donor site. AIM: The aim of this study is to analyze clinical, histological and histomorphometric results of homologous bone for implantoprosthetic rehabilitation in severe atrophic jaws. PATIENTS AND METHODS: Twenty consecutive patients, 14 female and 6 males, were treated with homologous bone bank. Treatment protocol consist of: first surgycal step, trasversal and vertical volume restore, second surgycal step: screw remove, specimen biopsy and insert implant fixtures. RESULTS: Data show that Fresh Frozen Bone Allografts (FFBA) could be a valuable substitute for autologous bone, in as much as histological and histomorphometric results are widely overlapping. CONCLUSIONS: Homologous bone is a valuable option for its large availability with a low cost, good versatility, no morbidity at the donor site, shorter surgical time and hospital stay. PMID- 23740459 TI - Vernal keratoconjunctivitis: atopy and autoimmunity. AB - BACKGROUND: Vernal Keratoconjunctivitis (VKC) is a rare chronic ocular inflammatory disease and it mainly affects boys in the first decade of life. Although it is a self-limiting disease, patients may present many phases characterized by an exacerbation of inflammatory symptoms with a consequent decline of the quality of life. PURPOSE: define the clinical and immunological profile of patients affected by VKC and investigate their familiar history of autoimmune disorders and their autoimmunity pattern. PATIENTS AND METHODS: 28 children were enrolled (20 males, 71%) aged between 4 and 14 years of life affected by VKC. Family history of allergic and immunological diseases was collected for each patient. In particular, it was asked whether some components of their families were affected by Hashimoto's thyroiditis, type I diabetes, psoriasis or rheumatoid arthritis and Systemic Lupus Erythematosus (SLE). All VKC children underwent a serological evaluation of anti-nuclear antibodies (ANA). RESULTS: A family history of immunological disorders was found in 46% of patients, 28% of Hashimoto's thyroiditis, 14% of type I diabetes, 14% of psoriasis, and 1 of Systemic Lupus Erythematosus. Furthermore, 35% of patients was ANA positive and they corresponded to patients with a higher ocular score and with the most important clinical symptoms. CONCLUSIONS: the detection of ANA positivity and of a familiar history of autoimmune disorders in a high percentage of children with VKC may help us to better understand the association of this ocular inflammatory disease with systemic autoimmune disorders and atopic condition. PMID- 23740460 TI - CCL19, a B cell chemokine, is related to the decrease of blood memory B cells and predicts the clinical response to rituximab in patients with rheumatoid arthritis. AB - OBJECTIVE: Migration of B cells from peripheral blood to the synovium in patients with rheumatoid arthritis (RA) may predict clinical response to rituximab (RTX). We undertook this study to investigate whether serum levels of chemokines involved in B cell trafficking are correlated with blood levels of memory B cells or serum levels of B cell activation biomarkers before B cell depletion and whether chemokine levels predict RTX responsiveness. METHODS: Blood B cell subsets were analyzed by flow cytometry (CD27, IgD), and serum B cell activation biomarkers (rheumatoid factor, anti-cyclic citrullinated peptide, free light chains, IgG, IgA, IgM, and BAFF) were measured in 208 RA patients and 70 control subjects. Serum CCL19, CXCL12, and CXCL13 chemokine levels in patients and controls were determined by enzyme-linked immunosorbent assay. The first course of RTX was administered to RA patients, and the response was evaluated at week 24 according to European League Against Rheumatism (EULAR) criteria. Results were expressed as the odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: Levels of all chemokines were increased in RA patients compared with controls, and levels were inversely correlated with CD27+ memory B cell frequency. CCL19 and CXCL13 levels correlated with levels of 6 serum B cell biomarkers and 4 serum B cell biomarkers, respectively. By univariate analysis, the CCL19 level was positively associated with EULAR response (OR 1.43 [95% CI 1.08-1.90], P = 0.01). By multivariate analysis, the CCL19 level was predictive of a response to RTX (OR 1.48 [95% CI 1.06-2.06], P = 0.02), but this did not persist after adjustment for autoantibody status. CONCLUSION: CXCL13 and CCL19 reflect blood B cell disturbances and their levels correlate with those of other serum B cell biomarkers. CXCL13 and CCL19 are, therefore, surrogate measures for serum B cell biomarkers in RA. Serum CCL19 measurement is a new hallmark of the B cell mediated RA subtype and may predict clinical response to RTX. PMID- 23740462 TI - Inflammatory hypertrophic cauda equina following intrathecal neural stem cell injection. AB - INTRODUCTION: Potential benefit from stem cell treatments has more patients seeking treatment without understanding possible risks. METHODS: We describe a woman who presented with progressive bilateral leg pain, numbness, and gait difficulties. A prior stroke, macular degeneration, osteoarthritis, and depression, led her to receive intrathecal neural stem cell therapy overseas 1 year before onset of symptoms. RESULTS: Imaging showed marked enlargement of lumbosacral roots of the cauda equina, which was not seen before stem cell treatment. Electrodiagnostic studies confirmed chronic multiple lumbosacral radiculopathies. Biopsy of a lumbar dorsal sensory root showed myelinated fiber degeneration and loss, with endoneurial inflammation. The hypertrophic inflammatory cauda equina syndrome was potentially triggered by the prior intrathecal neural stem cell injection. CONCLUSIONS: Safety of intrathecal stem cell treatments is not routinely regulated in overseas stem cell facilities. We wish to bring this potential complication to the attention of health care providers. PMID- 23740463 TI - DNA methylation analysis. AB - DNA methylation, the addition of a methyl group to cytosines and adenosines, regulates gene expression on a level that is usually referred to as epigenetic, that is, stably maintained during cell divisions. In humans, aberrant DNA methylation is associated with several malignancies, including cancer and so called imprinting disorders, making it an attractive target for diagnostic purposes. Here we give a brief introduction to the biology of DNA methylation and present the use of methylation biomarkers in laboratory medicine. DNA methylation assays have become the standard procedure in the diagnosis of imprinting disorders, and they are about to shift cancer diagnostics and prognostics to the next level of molecular medicine. However, there is evidence of problems associated with the introduction of such cancer assays in routine diagnostics. We review several assays that have been proposed for DNA methylation analysis. The assays presented analyse the methylation status of single loci and are based either on a bisulphite-treatment or on methylation-sensitive restriction of the DNA under investigation. PMID- 23740464 TI - Tolerance of intravenous methylprednisolone for relapse treatment in demyelinating CNS disease. AB - BACKGROUND: In Switzerland, the first course of intravenous steroids for treatment of episodes of demyelinating CNS disease is usually administered in an inpatient setting. We prospectively evaluated short term tolerance of treatment with special emphasis on sleep quality. METHODS: Patients with a first event of presumed demyelinating disease (CIS), multiple sclerosis relapses (MS) or sub acute disease progression were treated with a 5-day regimen of intravenous methylprednisolone (IVMP) in our inpatient clinic. Patients' experience was documented by self-report questionnaires including a standardised depression scale (ADSL). Laboratory tests were performed on a routine basis. Fasting glucose, blood pressure and pulse were measured before every infusion. Activity and sleep patterns were analysed by wrist actigraphs during the 5 day infusion period and at follow-up after 1-2 months. RESULTS: A total of 66 patients participated in the study. Of these, 55 were steroid treatment naive, and 11 patients, who had received intravenous steroid relapse treatment before, were admitted because of disabling symptoms. Mood disturbances were reported before steroid treatment, however significantly less often at the end of the steroid pulse and during follow-up. Sleep efficiency as measured by wrist actimetry was high before, during and after steroid treatment. CONCLUSION: Therapy was well tolerated without severe side effects in CIS and MS patients. Sleep efficiency was not disturbed. In conclusion there are no obstacles to change from an inpatient to an outpatient setting for the steroid treatment of relapses in MS and CIS, but rare psychotic reactions to steroid treatment are not predictable. PMID- 23740465 TI - Confluent hepatic fibrosis in liver cirrhosis: possible relation with middle hepatic venous drainage. AB - PURPOSE: Our aim was to retrospectively analyze the location of confluent hepatic fibrosis in relation to the portal and hepatic venous anatomy using multidetector computed tomography (CT) and to clarify the influence of the hepatic venous drainage on confluent fibrosis. MATERIALS AND METHODS: The study population consisted of 879 patients diagnosed with cirrhosis: 539 men and 340 women (65.9 +/- 10.6 years) and 633 with Child-Pugh class A, 161 with class B, and 85 with class C. The cause of cirrhosis was hepatitis C (n = 528) and hepatitis B (n = 122) virus infection, alcoholism (n = 114), and others (n = 115). The confluent fibrosis was diagnosed using CT images according to previous reports and statistically analyzed (p < 0.05). RESULTS: Thirty-five confluent fibrosis lesions in 30 patients (3.4 %) were identified. The predictive factors were alcoholic cirrhosis [odds ratio (OR), 7.25; p < 0.0001], Child-Pugh class C (OR, 6.95; p < 0.0001), and Child-Pugh class B (OR, 2.91; p < 0.0023). Confluent fibrosis was most frequently seen in the middle hepatic venous drainage area (n = 21) or at the boundary between the medial and anterior segments (n = 17), and each distribution of the location of confluent fibrosis was significantly unequal (p < 0.0001). CONCLUSION: Confluent fibrosis was most commonly located in the middle hepatic venous drainage area. PMID- 23740466 TI - Self-appraisals of arousal-oriented online sexual activities in university and community samples. AB - Arousal-oriented online sexual activities (OSAs) are any activities on the Internet that involve sexually explicit and/or sexually arousing stimuli. These can be solitary-arousal activities, requiring only one person be involved. They can also be partnered-arousal activities that involve at least two people interacting (Shaughnessy, Byers, & Walsh, 2011). Most researchers have focused on the negative outcomes of arousal-oriented OSAs on users' sexual life and life in general. Yet, these activities can also have positive outcomes. In two separate studies, we examined men's and women's perceptions of the positive and negative outcomes of their solitary- and partnered-arousal OSA experience. Study 1 included heterosexual university students (N = 191); Study 2 consisted of heterosexual and sexual minority individuals from the community (N = 316). Participants completed a background questionnaire and measures of their solitary- and partnered-arousal OSA experience and outcomes of these experiences. Overall, solitary- and partnered-arousal OSA was common among study participants. In both studies, participants reported significantly greater positive than negative outcomes of their solitary- and partnered-arousal OSAs, albeit the overall impact was small. We did not find significant gender differences or differences by sexual orientation in positive or negative outcomes of arousal-oriented OSAs. Our results suggest that, for most people, participating in solitary- and partnered arousal OSAs has little impact on them. PMID- 23740467 TI - Sex differences in attraction to familiar and unfamiliar opposite-sex faces: men prefer novelty and women prefer familiarity. AB - Familiarity is attractive in many types of stimuli and exposure generally increases feelings of liking. However, men desire a greater number of sexual partners than women, suggesting a preference for novelty. We examined sex differences in preferences for familiarity. In Study 1 (N = 83 women, 63 men), we exposed individuals to faces twice and found that faces were judged as more attractive on the second rating, reflecting attraction to familiar faces, with the exception that men's ratings of female faces decreased on the second rating, demonstrating attraction to novelty. In Studies 2 (N = 42 women, 28 men) and 3 (N = 51 women, 25 men), exposure particularly decreased men's ratings of women's attractiveness for short-term relationships and their sexiness. In Study 4 (N = 64 women, 50 men), women's attraction to faces was positively related to self rated similarity to their current partner's face, while the effect was significantly weaker for men. Potentially, men's attraction to novelty may reflect an adaptation promoting the acquisition of a high number of sexual partners. PMID- 23740468 TI - The potential of alcohol "heat-of-the-moment" scenarios in HIV prevention: A qualitative study exploring intervention implications. AB - Scenarios simulating real-world risk situations have proven effective for substance use intervention methods and could potentially prove useful as an HIV prevention method. This study explored qualitatively the development and use of such "in-the-moment" methods. We interviewed 97 moderate-drinking women (50 % Caucasian) after participation in an experiment requiring that they project themselves into a risky-sex scenario. Most participants (58 %) reported experiencing the scenario as a reflective tool characterized by two primary themes: (1) increased awareness of risk and (2) contemplation of behavior change. Findings suggest that "in-the-moment" methods depicting real-world risk situations and providing opportunities to reflect about behavioral choices and subsequent outcomes could prove a useful adjunct to HIV/AIDS-prevention interventions. Such methods could potentially augment existing prevention protocols. PMID- 23740469 TI - Suspect aggression and victim resistance in multiple perpetrator rapes. AB - Several research studies have reported an elevated level of aggression in rapes committed by multiple perpetrators compared to rapes committed by lone suspects. Several factors that have been linked to elevated aggression in generic samples of rape were examined for the first time with a sample of multiple perpetrator rapes. Factors that might be associated with victim resistance were also investigated. Victim and offender characteristics, as well as the behaviors displayed by victims and offenders, were extracted from the police files of 89 multiple perpetrator stranger rapes perpetrated against female victims in the United Kingdom. These behaviors were rated for their level of suspect (non sexual) aggression and victim resistance, respectively. Degree of victim resistance was significantly and positively associated with suspect aggression. Older victims were the recipients of significantly higher levels of suspect aggression. Victims who were incapacitated from drugs and/or alcohol were less likely to be the recipients of suspect aggression. Group leaders displayed more aggression towards the victim than the followers in the groups. The number of perpetrators was significantly related to the degree of resistance displayed by the victim with offences perpetrated by fewer suspects being characterized by more victim resistance. Research regarding cognitive appraisal during criminal interactions and the respective roles of offenders is referred to in considering these relationships. PMID- 23740470 TI - Sociosexuality in mainland China. AB - The construct of sociosexuality or sociosexual orientation describes the extent to which people will have casual, uncommitted sexual relationships. The Sociosexual Orientation Inventory (SOI) has been used to measure sociosexuality in many countries, but not in China. The aims of this study were to explore sociosexuality in a cross-section of the Chinese adult population, to quantify sex differences in sociosexuality, and to examine the sociodemographic correlates and the impact of the high sex ratio. The study consisted of a cross-sectional survey using a self-completion questionnaire. It was administered to adults of reproductive age in three provinces: Zhejiang, Guizhou, and Yunnan. While questionnaires were received from 7,424 participants, total SOI scores could be computed only for the 4,645 (63 %) who completed all seven items of the SOI. The mean score for men and women combined was 21.0, very low compared with most other countries, indicating restricted sociosexuality. The men (n = 2,048) had a mean of 27, showing more restricted sociosexuality than in all other countries where the SOI has been used. Wealth was the strongest independent correlate of high (unrestricted) sociosexuality in men and women. The effect size for the difference between the sexes was moderate (Cohen's d = .64), and comparable to more developed countries, perhaps reflecting relative gender equality in contemporary China. Despite the very high sex ratio, which is theorized to lead to restricted sexuality, its influence was difficult to determine, since differences in sociosexuality between high and low sex ratio areas within this population were inconsistent. PMID- 23740471 TI - Working and reference memory of pigs (Sus scrofa domesticus) in a holeboard spatial discrimination task: the influence of environmental enrichment. AB - Interest in cognitive research in pigs is increasing, but little is known about the impact of environmental conditions on pigs' cognitive capabilities. The present study investigated the effect of environmental enrichment on cognitive performance of pigs in a holeboard spatial task, in which they had to discriminate four baited buckets out of 16. Pigs (n = 32) were either housed in stimulus-poor, barren pens, or in larger pens enriched with rooting substrates. Pigs were subjected to 30 holeboard trials. Both working memory (WM), that is, the ratio (baited visits/total number of (re)visits to baited buckets), and reference memory (RM), that is, the ratio ((re)visits to baited buckets/total number of visits to all buckets), improved over trials. WM scores were higher in pigs from enriched pens than in pigs from barren pens. Housing did not affect RM scores. Personality type of the pigs, as assessed early in life using a backtest, did not affect WM or RM. In conclusion, housing conditions of pigs did not affect reference memory, but environmental enrichment improved working memory of pigs in a spatial discrimination task. Based on the findings of this study, we suggest that cognitive functioning of pigs may be impaired under commonly used housing conditions. PMID- 23740472 TI - An exploratory study of zoo visitors' exhibit experiences and reactions. AB - Visiting a zoo or aquarium is not only fun, but can also have a positive impact on visitors' knowledge and attitudes regarding animals and the environment. The biggest challenge, however, is for these institutions to strategically provide opportunities for cognitive and affective learning while simultaneously facilitating enjoyment and fun. Recent studies in zoos and aquaria have examined various factors that can influence learning such as engaging visitors' emotions or connecting with visitors' prior knowledge and interests. The intent of the current study was to further this line of investigation and explore the relationship between visitors' predispositions and their cognitive and affective experiences and reactions as they walked through an animal exhibit. We selected three indoor immersion exhibits and one outdoor naturalistic exhibit for the study to obtain a wide range of different animals and exhibit settings. Research assistants randomly intercepted visitors leaving the exhibits and asked, among other things, the extent they experienced certain thoughts and feelings while they were walking through the exhibits. Results revealed that visitors' emotional responses to viewing animals were key experiences along with opportunities for introspection and reflection during their time in the exhibits. Implications of the study are discussed in reference to providing both fun and meaningful learning experiences for visitors. PMID- 23740473 TI - Acid-catalyzed liquefaction of bagasse in the presence of polyhydric alcohol. AB - Bagasse was subjected to a liquefaction process with polyethylene glycol/glycerol using sulfuric acid as catalyst. The effects of various liquefaction conditions, such as reaction time, liquefaction temperature, catalyst content, and liquid ratio (liquefaction solvents/bagasse), on the liquefied residue (LR) content and hydroxyl and acid numbers of liquefied products were investigated. The preferred liquefaction condition of bagasse was determined through orthogonal experiments. The results showed that the catalyst content and reaction time have a greater influence than liquid ratio and liquefaction temperature on the percentage of LR. The hydroxyl and acid numbers of the liquefied products were influenced by many factors, including liquefaction temperature, reaction time, acid content, and liquid ratio. The hydroxyl number of liquefied products decreased as the liquefaction reaction progressed, but the acid number of liquefied products increased. Based on the obtained data, the kinetics for liquefaction was modeled using the first-order reaction rate law and the apparent activation energy for the liquefaction of bagasse was estimated to be 38.30 kJ mol(-1). PMID- 23740474 TI - Quantified high-throughput screening of Escherichia coli producing poly(3 hydroxybutyrate) based on FACS. AB - Here, we report on a highly sensitive method for the detection of P(3HB) accumulation in Escherichia coli cells based on the automated flow cytometry system using fluorescent dyes. E. coli containing P(3HB) were stained with either BODIPY or Nile red fluorescent dye, and their staining properties were analyzed under a variety of conditions. Compared with Nile red, BODIPY was much more sensitive in staining P(3HB) and overall demonstrated a more rapid staining of cells, a greater resistance to photobleaching, and greater cell viability. In addition, we also successfully monitored heterogeneity in P(3HB) accumulation within a cell population using BODIPY staining and flow cytometry. We believe this optimized staining method using BODIPY in combination with screening by high speed flow cytometer will be helpful in the engineering of host cells toward an enhanced production of bioplastics. PMID- 23740475 TI - Identifying the source of bullet wipe: a randomised blind trial. AB - OBJECTIVE: To assess the usefulness of scanning electron microscopy and energy dispersive x-ray spectroscopy in matching bullet wipe to the bullet. HYPOTHESIS: Bullet wipe can be used to match a bullet type to a crime scene. PMID- 23740476 TI - Adaptive response to hydrogen peroxide in yeast: induction, time course, and relationship to dose-response models. AB - The assay for trp5 gene conversion and ilv1-92 reversion in Saccharomyces cerevisiae strain D7 was used to characterize the induction of an adaptive response by hydrogen peroxide (H(2)O(2)). Effects of a small priming dose on the genotoxic effects of a larger challenge dose were measured in exponential cultures and in early stationary phase. An adaptive response, indicated by smaller convertant and revertant frequencies after the priming dose, occurred at lower priming and challenge doses in young, well-aerated cultures. Closely spaced priming doses from 0.000975 to 2 mM, followed by a 1 mM challenge, showed that the induction of the adaptive response is biphasic. In exponential cultures it was maximal with a priming dose of 0.125-0.25 mM. Very small priming doses were insufficient to induce the adaptive response, whereas higher doses contributed to damage. A significant adaptive response was detected when the challenge dose was administered 10-20 min after the priming exposure. It was fully expressed within 45 min, and the yeast began to return to the nonadapted state after 4-6 hr. Because of the similarity of the biphasic induction to hormetic curves and the proposal that adaptive responses are a manifestation of hormesis, we evaluated whether the low doses of H(2)O(2) that induce the adaptive response show a clear hormetic response without a subsequent challenge dose. Hormesis was not evident, but there was an apparent threshold for genotoxicity at or slightly below 0.125 mM. The results are discussed with respect to linear, threshold, and hormesis dose-response models. PMID- 23740477 TI - No benefit adding eleutherococcus senticosus to stress management training in stress-related fatigue/weakness, impaired work or concentration, a randomized controlled study. AB - INTRODUCTION: Plant adaptogens are traditionally used for stress-related symptoms, but clinical evidence is inconsistent. This trial explored the effects of 120 mg/day Eleutherococcus senticosus root extract (ES), 2-day professional stress management training (SMT) and a combination of both (COM). METHODS: 144 participants suffering from asthenia and reduced working capacity related to chronic stress were randomized to the treatments. Validated scales and tests were used to investigate cognitive performance; feeling stressed; fatigue and exhaustion; alertness, restlessness and mood; quality of life and sleep; physical complaints and activities; and physiological stress parameters including cortisol awakening response (CAR), at baseline, after 2 and 8 weeks of treatment (German Clinical Trials Register DRKS00000692). RESULTS: Almost all parameters improved significantly over time without group differences. Significant differences were found in mental fatigue and restlessness, both in favor of COM vs. ES. COM was not superior to SMT in any parameter at week 8. An attenuation of the CAR was seen at week 2 without group differences. All treatments were well tolerated. DISCUSSION: Effects of adding ES to SMT are, if any, negligible. PMID- 23740479 TI - Enhancing in vitro selection techniques to assist the discovery, understanding and use of inorganic binding peptides. AB - Reflecting the increasing interest in combinatorial approaches, peptide phage display has seen an unprecedented expansion in a wide range of research areas. Its application to the discovery and analysis of metal binding peptides has opened up new research directions and largely contributed to the nanotechnology field. The rationale behind the need to identify such peptides varies depending on the final aim of the research and its application. Therefore, the possibility to modify the selection technique according to the different requirements would allow for a more systematic approach to be adopted and would ultimately provide substantial benefits. Although the standard panning method can be virtually applied to any target, its use for the identification of metal binding peptides does not provide the characteristics and the flexibility required for an efficient and tailored selection. Here we report on the development of a new panning method that can contribute to a faster, versatile and more informative analysis. Through the use of rolling-circle amplification, polymerase reaction and wild type phage, we have converted the standard selection technique into a more dynamic process in which adjustments can be evaluated and made consistently with the need of the experiment. The successfulness of the improved method is demonstrated in a number of panning experiments with different inorganic targets. The modifications applied to each selection are described and comparisons between the results obtained are made in order to extensively assess and evaluate the impact of the new process. The importance of tailoring the screening method to the specific objectives of a study is also considered. New binder sequences for the materials included in the investigation are identified; their sequences and distinctive characteristics are reported and their ability to act as templates for the nucleation of inorganic material is demonstrated and discussed. PMID- 23740478 TI - Improving efficiency of human pluripotent stem cell differentiation platforms using an integrated experimental and computational approach. AB - Human pluripotent stem cells (hPSCs) have an unparalleled potential for tissue engineering applications including regenerative therapies and in vitro cell-based models for studying normal and diseased tissue morphogenesis, or drug and toxicological screens. While numerous hPSC differentiation methods have been developed to generate various somatic cell types, the potential of hPSC-based technologies is hinged on the ability to translate these established lab-scale differentiation systems to large-scale processes to meet the industrial and clinical demands for these somatic cell types. Here, we demonstrate a strategy for investigating the efficiency and scalability of hPSC differentiation platforms. Using two previously reported epithelial differentiation systems as models, we fit an ODE-based kinetic model to data representing dynamics of various cell subpopulations present in our culture. This fit was performed by estimating rate constants of each cell subpopulation's cell fate decisions (self renewal, differentiation, death). Sensitivity analyses on predicted rate constants indicated which cell fate decisions had the greatest impact on overall epithelial cell yield in each differentiation process. In addition, we found that the final cell yield was limited by the self-renewal rate of either the progenitor state or the final differentiated state, depending on the differentiation protocol. Also, the relative impact of these cell fate decision rates was highly dependent on the maximum capacity of the cell culture system. Overall, we outline a novel approach for quantitative analysis of established laboratory-scale hPSC differentiation systems and this approach may ease development to produce large quantities of cells for tissue engineering applications. PMID- 23740480 TI - Assembly and characterization of foot-and-mouth disease virus empty capsid particles expressed within mammalian cells. AB - The foot-and-mouth disease virus (FMDV) structural protein precursor, P1-2A, is cleaved by the virus-encoded 3C protease (3C(pro)) into the capsid proteins VP0, VP1 and VP3 (and 2A). In some systems, it is difficult to produce large amounts of these processed capsid proteins since 3C(pro) can be toxic for cells. The expression level of 3C(pro) activity has now been reduced relative to the P1-2A, and the effect on the yield of processed capsid proteins and their assembly into empty capsid particles within mammalian cells has been determined. Using a vaccinia-virus-based transient expression system, P1-2A (from serotypes O and A) and 3C(pro) were expressed from monocistronic cDNA cassettes as P1-2A-3C, or from dicistronic cassettes with the 3C(pro) expression dependent on a mutant FMDV internal ribosome entry site (IRES) (designated P1-2A-mIRES-3C). The effects of using a mutant 3C(pro) with reduced catalytic activity or using two different mutant IRES elements (the wt GNRA tetraloop sequence GCGA converted, in the cDNA, to GAGA or GTTA) were analysed. For both serotypes, the P1-2A-mIRES-3C construct containing the inefficient GTTA mutant IRES produced the highest amount of processed capsid proteins. These products self-assembled to form FMDV empty capsid particles, which have a related, but distinct, morphology (as determined by electron microscopy and reconstruction) from that determined previously by X ray crystallography. The assembled empty capsids bind, in a divalent cation dependent manner, to the RGD-dependent integrin alphavbeta6, a cellular receptor for FMDV, and are recognized appropriately in serotype-specific antigen ELISAs. PMID- 23740481 TI - An interaction between the methyltransferase and RNA dependent RNA polymerase domains of the West Nile virus NS5 protein. AB - The flavivirus nonstructural protein 5 (NS5) is a large protein that is structurally conserved among members of the genus, making it an attractive target for antiviral drug development. The protein contains a methyltransferase (MTase) domain and an RNA dependent RNA polymerase (POL) domain. Previous studies with dengue viruses have identified a genetic interaction between residues 46-49 in the alphaA3-motif in the MTase and residue 512 in POL. These genetic interactions are consistent with structural modelling of these domains in West Nile virus (WNV) NS5 that predict close proximity of these regions of the two domains, and potentially a functional interaction mediated via the alphaA3-motif. To demonstrate an interaction between the MTase and POL domains of the WNV NS5 protein, we co-expressed affinity-tagged recombinant MTase and POL proteins in human embryonic kidney cells with simian virus 40 large T antigen (HEK293T cells) and performed pulldown assays using an antibody to the flag tag on POL. Western blot analysis with an anti-MTase mAb revealed that the MTase protein was specifically co-immunoprecipitated with POL, providing the first evidence of a specific interaction between these domains. To further assess the role of the alphaA3 helix in this interaction, selected residues in this motif were mutated in the recombinant MTase and the effect on POL interaction determined by the pulldown assay. These mutations were also introduced into a WNV infectious clone (FLSDX) and the replication properties of these mutant viruses assessed. While none of the alphaA3 mutations had a significant effect on the MTase-POL association in pulldown assays, suggesting that these residues were not specific to the interaction, an E46L mutation completely abolished virus viability indicating a critical requirement of this residue in replication. Failure to generate compensatory mutations in POL to rescue replication, even after several passages of the transfection supernatant in Vero cells, precluded further conclusion of the role of this residue in the context of MTase-POL interactions. PMID- 23740482 TI - Porcine, murine and human sialoadhesin (Sn/Siglec-1/CD169): portals for porcine reproductive and respiratory syndrome virus entry into target cells. AB - Porcine sialoadhesin (pSn; a sialic acid-binding lectin) and porcine CD163 (pCD163) are molecules that facilitate infectious entry of porcine reproductive and respiratory syndrome virus (PRRSV) into alveolar macrophages. In this study, it was shown that murine Sn (mSn) and human Sn (hSn), like pSn, can promote PRRSV infection of pCD163-expressing cells. Intact sialic acid-binding domains are crucial, since non-sialic acid-binding mutants of pSn, mSn and hSn did not promote infection. Endodomain-deletion mutants of pSn, mSn and hSn promoted PRRSV infection less efficiently, but also showed markedly reduced expression levels, making further research into the potential role of the Sn endodomain in PRRSV receptor activity necessary. These data further complement our knowledge on Sn as an important PRRSV receptor, and suggest - in combination with other published data - that species differences in the main PRRSV entry mediators Sn and CD163 do not account for the strict host species specificity displayed by the virus. PMID- 23740483 TI - The cytomegalovirus egress proteins pUL50 and pUL53 are translocated to the nuclear envelope through two distinct modes of nuclear import. AB - The nucleocytoplasmic export of cytomegaloviral capsids is regulated by formation of a multi-component nuclear egress complex (NEC), essentially based on viral proteins pUL50 and pUL53. In this study, the generation of recombinant human cytomegaloviruses, expressing tagged versions of pUL50 and pUL53, enabled the investigation of NEC formation in infected primary fibroblasts. For these recombinant viruses, a wild-type-like mode of pUL50-pUL53 interaction and recruitment of both proteins to the nuclear envelope could be demonstrated. Importantly, pUL50 was translocated from an initial cytoplasmic distribution to the nuclear rim, whereas pUL53 accumulated in the nucleus before attaining overall rim colocalization with pUL50. Specified experimental settings illustrated that pUL50 and pUL53 were subject to different pathways of intracellular trafficking. Importantly, a novel nuclear localization signal (NLS) could be identified and functionally verified for pUL53 (amino acids 18-27), whereas no NLS was present in pUL50. Analysis of amino acid replacement mutants further illustrated the differential modes of nuclear import of the two essential viral egress proteins. Taken together, our findings suggest a combination of classical nuclear import (pUL53) and interaction-mediated recruitment (pUL50) as the driving forces for core NEC formation and viral nuclear egress. PMID- 23740484 TI - The effect of sampling rate on observed statistics in a correlated random walk. AB - Tracking the movement of individual cells or animals can provide important information about their motile behaviour, with key examples including migrating birds, foraging mammals and bacterial chemotaxis. In many experimental protocols, observations are recorded with a fixed sampling interval and the continuous underlying motion is approximated as a series of discrete steps. The size of the sampling interval significantly affects the tracking measurements, the statistics computed from observed trajectories, and the inferences drawn. Despite the widespread use of tracking data to investigate motile behaviour, many open questions remain about these effects. We use a correlated random walk model to study the variation with sampling interval of two key quantities of interest: apparent speed and angle change. Two variants of the model are considered, in which reorientations occur instantaneously and with a stationary pause, respectively. We employ stochastic simulations to study the effect of sampling on the distributions of apparent speeds and angle changes, and present novel mathematical analysis in the case of rapid sampling. Our investigation elucidates the complex nature of sampling effects for sampling intervals ranging over many orders of magnitude. Results show that inclusion of a stationary phase significantly alters the observed distributions of both quantities. PMID- 23740486 TI - Improvement of the aerodynamic performance by wing flexibility and elytra--hind wing interaction of a beetle during forward flight. AB - In this work, the aerodynamic performance of beetle wing in free-forward flight was explored by a three-dimensional computational fluid dynamics (CFDs) simulation with measured wing kinematics. It is shown from the CFD results that twist and camber variation, which represent the wing flexibility, are most important when determining the aerodynamic performance. Twisting wing significantly increased the mean lift and camber variation enhanced the mean thrust while the required power was lower than the case when neither was considered. Thus, in a comparison of the power economy among rigid, twisting and flexible models, the flexible model showed the best performance. When the positive effect of wing interaction was added to that of wing flexibility, we found that the elytron created enough lift to support its weight, and the total lift (48.4 mN) generated from the simulation exceeded the gravity force of the beetle (47.5 mN) during forward flight. PMID- 23740485 TI - Predator confusion is sufficient to evolve swarming behaviour. AB - Swarming behaviours in animals have been extensively studied owing to their implications for the evolution of cooperation, social cognition and predator-prey dynamics. An important goal of these studies is discerning which evolutionary pressures favour the formation of swarms. One hypothesis is that swarms arise because the presence of multiple moving prey in swarms causes confusion for attacking predators, but it remains unclear how important this selective force is. Using an evolutionary model of a predator-prey system, we show that predator confusion provides a sufficient selection pressure to evolve swarming behaviour in prey. Furthermore, we demonstrate that the evolutionary effect of predator confusion on prey could in turn exert pressure on the structure of the predator's visual field, favouring the frontally oriented, high-resolution visual systems commonly observed in predators that feed on swarming animals. Finally, we provide evidence that when prey evolve swarming in response to predator confusion, there is a change in the shape of the functional response curve describing the predator's consumption rate as prey density increases. Thus, we show that a relatively simple perceptual constraint--predator confusion--could have pervasive evolutionary effects on prey behaviour, predator sensory mechanisms and the ecological interactions between predators and prey. PMID- 23740487 TI - Epidemiological mechanisms of genetic resistance to kuru. AB - Transmissible spongiform encephalopathies (TSEs), such as kuru, are invariably fatal neurodegenerative conditions caused by a malformation of the prion protein. Heterozygosity of codon 129 of the prion protein gene has been associated with increased host resistance to TSEs, although the mechanism by which this resistance is achieved has not been determined. To evaluate the epidemiological mechanism of human resistance to kuru, we developed a model that combines the dynamics of kuru transmission and the population genetics of human resistance. We fitted our model to kuru data from the epidemic that occurred in Papua New Guinea over the last hundred years. To elucidate the epidemiological mechanism of human resistance, we estimated the incubation period and transmission rate of kuru for codon 129 heterozygotes and homozygotes using kuru incidence data and human genotype frequency data from 1957 to 2004. Our results indicate that human resistance arises from a combination of both a longer incubation period and reduced susceptibility to infection. This work provides evidence for balancing selection acting on a human population and the mechanistic basis for the heterozygote resistance to kuru. PMID- 23740489 TI - Optical parameters of the tunable Bragg reflectors in squid. AB - Cephalopods (e.g. octopus, squid and cuttlefish) dynamically tune the colour and brightness of their skin for camouflage and communication using specialized skin cells called iridocytes. We use high-resolution microspectrophotometry to investigate individual tunable Bragg structures (consisting of alternating reflectin protein-containing, high-refractive index lamellae and low-refractive index inter-lamellar spaces) in live and chemically fixed iridocytes of the California market squid, Doryteuthis opalescens. This subcellular, single-stack microspectrophotometry allows for spectral normalization, permitting use of a transfer-matrix model of Bragg reflectance to calculate all the parameters of the Bragg stack-the refractive indices, dimensions and numbers of the lamellae and inter-lamellar spaces. Results of the fitting analyses show that eight or nine pairs of low- and high-index layers typically contribute to the observed reflectivity in live cells, whereas six or seven pairs of low- and high-index layers typically contribute to the reflectivity in chemically fixed cells. The reflectin-containing, high-index lamellae of live cells have a refractive index proportional to the peak reflectivity, with an average of 1.405 +/- 0.012 and a maximum around 1.44, while the reflectin-containing lamellae in fixed tissue have a refractive index of 1.413 +/- 0.015 suggesting a slight increase of refractive index in the process of fixation. As expected, incremental changes in refractive index contribute to the greatest incremental changes in reflectivity for those Bragg stacks with the most layers. The excursions in dimensions required to tune the measured reflected wavelength from 675 (red) to 425 nm (blue) are a decrease from ca 150 to 80 nm for the high-index lamellae and from ca 120 to 50 nm for the low-index inter-lamellar spaces. Fixation-induced dimensional changes also are quantified, leading us to suggest that further microspectrophotometric analyses of this iridocyte system can be used as a model system to quantify the effects of various methods of tissue fixation. The microspectrophotometry technique described can be expected to provide deeper insights into the molecular and physical mechanisms governing other biophotonically active cells and structures. PMID- 23740488 TI - A deterministic model for the occurrence and dynamics of multiple mutations in hierarchically organized tissues. AB - Cancers are rarely caused by single mutations, but often develop as a result of the combined effects of multiple mutations. For most cells, the number of possible cell divisions is limited because of various biological constraints, such as progressive telomere shortening, cell senescence cascades or a hierarchically organized tissue structure. Thus, the risk of accumulating cells carrying multiple mutations is low. Nonetheless, many diseases are based on the accumulation of such multiple mutations. We model a general, hierarchically organized tissue by a multi-compartment approach, allowing any number of mutations within a cell. We derive closed solutions for the deterministic clonal dynamics and the reproductive capacity of single clones. Our results hold for the average dynamics in a hierarchical tissue characterized by an arbitrary combination of proliferation parameters. We show that hierarchically organized tissues strongly suppress cells carrying multiple mutations and derive closed solutions for the expected size and diversity of clonal populations founded by a single mutant within the hierarchy. We discuss the example of childhood acute lymphoblastic leukaemia in detail and find good agreement between our predicted results and recently observed clonal diversities in patients. This result can contribute to the explanation of very diverse mutation profiles observed by whole genome sequencing of many different cancers. PMID- 23740490 TI - Buckling morphology of an elastic beam between two parallel lateral constraints: implication for a snake crawling between walls. AB - A snake crawling on horizontal surfaces between two parallel walls exhibits a unique wave-like shape, which is different from the normal shape of a snake crawling without constraints. We propose that this intriguing system is analogous to a buckled beam under two lateral constraints. A new theoretical model of beam buckling, which is verified by numerical simulation, is firstly developed to account for the special boundary conditions. Under this theoretical model, the effect of geometrical parameters on the deformation shape, such as the distance between walls, length of the snake and radius of the snake, is examined. The buckling beam model is then applied to explain qualitatively the wave-like shape of the snake. PMID- 23740491 TI - Supramolecular immobilization of laccase on carbon nanotube electrodes functionalized with (methylpyrenylaminomethyl)anthraquinone for direct electron reduction of oxygen. AB - An efficient way of immobilizing and wiring a large amount of laccase on non covalently-functionalized multi-walled carbon nanotube (MWCNT) electrodes is reported. 1-(2-anthraquinonylaminomethyl)pyrene and 1-[bis(2 anthraquinonyl)aminomethyl]pyrene were synthesized and studied for their capability to non-covalently functionalize MWCNT electrodes and immobilize and orientate laccase on the nanostructured electrodes. This led to high-performance biocathodes for oxygen reduction by direct electron transfer with maximum current densities of (1+/-0.2) mA cm(-2). The performance of the resulting bioelectrodes could be doubled simply by using the bis-anthraquinone compound. The bioelectrodes show excellent stability over weeks and can thus be envisioned in enzymatic biofuel cells. PMID- 23740492 TI - Prognostic impact of the number of methylated genes in myelodysplastic syndromes and acute myeloid leukemias treated with azacytidine. AB - The prognostic impact of the aberrant hypermethylation in response to azacytidine (AZA) remains to be determined. Therefore, we have analyzed the influence of the methylation status prior to AZA treatment on the overall survival and clinical response of myeloid malignancies. DNA methylation status of 24 tumor suppressor genes was analyzed by methylation-specific multiplex ligation-dependent probe amplification in 63 patients with myelodysplastic syndromes and acute myeloid leukemia treated with azacytidine. Most patients (73 %) showed methylation of at least one gene, but only 12 % of patients displayed >=3 methylated genes. The multivariate analysis demonstrated that the presence of a high number (>=2) of methylated genes (P = 0.022), a high WBC count (P = 0.033), or anemia (P = 0.029) were independent prognostic factors associated with shorter overall survival. The aberrant methylation status did not correlate with the response to AZA, although four of the five patients with >=3 methylated genes did not respond. By contrast, favorable cytogenetics independently influenced the clinical response to AZA as 64.7 % of patients with good-risk cytogenetic abnormalities responded (P = 0.03). Aberrant methylation status influences the survival of patients treated with AZA, being shorter in those patients with a high number of methylated genes. PMID- 23740493 TI - The significance of macroautophagy in health and disease. AB - During the past decade there has been a substantial increase in macroautophagy (herein simply referred to as autophagy) research due to a growing understanding of this process, coupled with improved new techniques for its detection. Autophagy (auto - self, phagy - eating) is defined as a fundamental lysosomal catabolic pathway responsible for degrading long-lived proteins, protein aggregates, oxidised lipids, damaged organelles, and even microbial invaders. Although autophagy occurs at basal levels in normal conditions, many different forms of metabolic stress, including starvation, hypoxia, high temperature, high culture density, hormones, and growth factor deprivation can dramatically stimulate an autophagic response. Autophagy plays a critical role in maintaining cellular homeostasis and genomic integrity and therefore has been implicated in many physiological activities such development, differentiation, and tissue remodelling.Consequently, defects in autophagy have been linked to various human diseases such as neurodegenerative and muscle disorders, cancers, cardiac failure, and inflammatory disorders. This mini-review summarises current knowledge in a field of mammalian autophagy and considers the significance of autophagy in human physiology and pathology. PMID- 23740494 TI - Extra- and intracerebral course of the recurrent artery of Heubner. AB - BACKGROUND: The aim of the current study was to analyse the extra- and intracerebral course of the recurrent artery of Heubner (RAH) to provide detailed information for neurosurgeons operating in this area. MATERIALS AND METHODS: The material for this study was obtained from cadavers (ages 31-75 years) during routine autopsies. A total of 70 human brains (39 male and 31 female) were examined. The material was collected not later than 48 h post-mortem. People who died due to neurological disorders were not included into the study. Right after dissection the arteries were perfused with either acrylicpaint emulsion, polyvinyl chloride or Mercox CL-2R resin, through the Circle of Willis or electively through the RAH. The obtained material was analysed using a stereoscopic light microscope, magnification 2-40'. RESULTS: The RAH was present in 138 hemispheres with a mean of 1.99 RAH per hemisphere (275 RAH in total). The mean RAH length was 25.2 mm and the mean RAH diameter, in its place of origin, was 1 mm. In 168 (61%) cases the RAH ran superiorly, in 88 (32%) cases anteriorly, in 11 (4%) cases inferiorly and in 8 (3%) cases posteriorly to the A1 segment. In 70.2% of the cases the course of the RAH was parallel to the anterior communicating artery A1 segment, and in 29.8% of the cases the RAH arched towards the olfactory tract. As the extracerebral course of the RAH was always tortuous,its length was 1 to 5 times the distance between its place of origin and the most lateral point of anterior perforated substance (APS) penetration. The intracerebral course of the RAH was almost always univectorial - towards the head of the caudate nucleus.The course of RAH branches depended on their number. When the number of RAH sand their branches was low, they separated immediately after penetrating the APS and formed multiple small branches. When the number of RAHs and branches was high,post-APS branching was less frequent and occurred in distal segments. CONCLUSIONS: The origin and course of the RAH is highly variable. The RAH, in its extra- and intracerebral course, may join with the middle group of the lenticulostriate arteries or directly with the middle cerebral artery. This artery should be routinely identified during anterior communicating artery aneurysm clipping to prevent postoperative neurological deficits. PMID- 23740495 TI - The pneumatisation of anterior clinoid process is not associated with any predictors that might be recognised preoperatively. AB - The anterior clinoid process (ACP) is usually removed during surgeries of proximal internal carotid artery (ICA) aneurysms. However, some ACPs present with air cells originating from the sphenoid or/and ethmoid sinus. In surgeries containing a clinoidectomy of a pneumatised process, up to 40% of patients experience cerebrospinal fluid (CSF) rhinorrhoea. The aim of this study was to explore the potential predictors of pneumatisation of the ACP, as well as to compare the occurrence of CSF rhinorrhoea between total and partial anterior clinoidectomies. This study comprised 2 different groups, with 2 different analyses. Firstly, the pneumatisation of the ACP was evaluated in 496 ACPs and was based on 248 computer tomography exams (CT). The c2 test and ROC curve comparisons were utilised in conjunction, to explore possible predictors of air cell accumulation in the ACP. The overall pneumatisation rate was 9.7%, unilateral and bilateral aerial ACP was found in 4.4% and 2.6% of all patients respectively, while at least one pneumatised ACP was found in 14.1% of examined patients. The route of pneumatisation was established in 87.5% of cases. The side of the ACP, gender, and patient age were not significantly associated with both pneumatisation of ACP or route of pneumatisation.Secondly, a clinical group of 23 patients after operative securing of an ICA aneurysm were retrospectively assessed with regards to the extent of anterior clinoidectomy and the occurrence of CSF rhinorrhoea. A total of 23 ACPs were removed, 17 ACPs were totally resected, and 6 underwent partial resection. CSF rhinorrhoea was not noted in any patients, thus the comparison between clinical groups was not valid. Moreover, we described a novel method of partial removal of the lateral aspect of ACP, which was applied in 6 patients treated for an ICA - ophthalmic artery junction aneurysm. PMID- 23740496 TI - Volumetric reconstruction of the right ventricle improves reproducibility of interventricular septum bowing in patients with pulmonary embolism. AB - Bowing of the interventricular septum (IVS) is a sign of severe pulmonary embolism(PE); however, it is affected by high interobserver variability. The aim of the study was to evaluate the application of volumetric reconstructions of the right ventricle for assessment of IVS position regarding its accuracy in identifying right ventricular dysfunction, as well as interobserver agreement in evaluating this sign.IVS bowing was evaluated with multiplanar reformations (MPR) and volumetric reconstruction (VR, volume rendering) by 2 observers. The accuracy of IVS bowing sign was better for VR-based assessment; however, it was not significantly better than the MPR-based evaluation. Interobserver agreement was found to be fair (kappa = 0.381) for the MPR-based grading of IVS position as normal orabnormal, while it was significantly better for the VR method (kappa = 0.629,p < 0.001). The VR-based method may improve utilisation of IVS bowing sign inpatients with PE. PMID- 23740497 TI - Anatomy and radiology of the variations of aortic arch branches in 1,266 patients. AB - BACKGROUND: The most reliable data about arterial variations, which are very important in surgery and radiology, can be obtained from a large series of patients. MATERIALS AND METHODS: We examined angiographic and multislice computerised tomography (MSCT) images in a group of 1,265 patients and in 1 dissected specimen. RESULTS: While in 946 (74.72%) of the patients a normal vascular pattern (type I) was noticed, in the remaining 320 (25.28%) patients variations of the branches of the aortic arch were found, which were classified into types II through VIII and a few subtypes. Type II (2.84%) comprised a common origin of the left commoncarotid and subclavian arteries. Type III (15.56%) was related to an origin of the left subclavian artery from the brachiocephalic trunk. Type IV (0.55%) included the aortic origin of both common carotid and subclavian arteries, with the right subclavian artery having a retroesophageal course. Type V (0.24%) included the same 4 supra-aortic branches, which, however, arose from a double or a right--sided aortic arch. Type VI (3.63%) comprised the aortic origin of the left vertebral artery, type VII (0.24%) the same origin of the right vertebral artery, and type VIII(2.22%) the aortic origin of the thyroideaima artery. A corresponding embryological background and clinical implications of the described aberrant vessels were presented. CONCLUSIONS: In more than one quarter of the cases, the branching pattern of the examined arteries did not follow the classical pattern. Detailed knowledge of aortic branch variations is of great significance in anatomy, embryology, and clinical medicine, especially in radiology and thoracic surgery. PMID- 23740498 TI - Coronary arterial anomalies in a large group of patients undergoing coronary angiography in southeast Turkey. AB - BACKGROUND: The prevalence of coronary artery anomalies (CAA) are reported between 0.6-1.3% in the literature. CAA are usually asymptomatic incidental findings, but they may deteriorate coronary circulation, cause symptoms and lead to sudden cardiac death; especially in young athletes. Since interventional procedures are increasing rapidly for treatment of coronary artery disease (CAD) in the modern era, comprehensive understanding of CAA is becoming progressively critical element in dealing with CAD. MATERIALS AND METHODS: We reviewed the database of the Cardiac Catheterisation Laboratory of Sani Konukoglu University Hospital in Gaziantep, Turkey. All patients who were subjected to coronary angiography from 1998 to 2006 were included. RESULTS: Among 53,655 coronary angiographies performed, CAA were found in 653 patients (incidence of 1.21%); 590 (90.3%) patients had anomalies of origin and distribution and 63 (11.7%) had coronary fistulae. Separate origins of left anterior descending (LAD) and left circumflex (LCX) coronary artery from the left sinus of Valsalva was the most common anomaly (64.1%). Coronary arteries branching from anomalous aortic origin was the second most common anomaly(16.5%). Right coronary artery (RCA) originating from left sinus of Valsalva or left main coronary artery (LMCA) was observed in 55 (8.4%) patients, LCX arising from RCA or right sinus of Valsalva (RSV) was seen in 52 (7.9%) patients and LMCA orLAD originating from RSV was seen in 14 (0.2%) patients. There were 16 (2.45%) patients with single coronary artery and 1 (0.15%) patient with LMCA originating from pulmonary artery. CONCLUSIONS: The incidence and the pattern of CAA in our patient population were similar with previous studies. Angiographic recognition of these vessels is important because of their clinical significance and importance in patients undergoing coronary angioplasty or cardiac surgery. PMID- 23740499 TI - The prevalence and clinical importance of an "additional" terminal branch of the left coronary artery. AB - The left coronary artery (LCA) usually divides into two (anterior interventricular artery [AIA] and left circumflex [LCx] artery) or less frequently into the AIA, LCx,and one or more "additional" terminal branch/es (ATBs). These ATBs of the LCA have no unanimity regarding their anatomical nomenclature. There is a lack of common consensus on the criteria used for their definition, and they are also absent from the current Terminologia Anatomica (1998). This study, therefore,aimed to document the prevalence of the ATBs of the LCA, discuss their clinical importance, and propose an anatomical nomenclature. This study was conducted by reviewing 367 coronary angiograms. The termination patterns of the LCA were classified into 3 categories based on the number of their branches, viz. (a) bifurcation78.2%, (b) trifurcation 20.4%, and (c) quadrifurcation 1.4%, respectively. The presence of an ATB was recorded in 21.8% of the angiograms. The identification of this vessel may be of clinical importance because the extent of its supply may decrease the effect of occlusion of the LCx artery and AIA on the myocardium.The term "left ramus medianus artery" is proposed as the nomenclature for the ATB of the LCA. PMID- 23740500 TI - Microvascularisation of the scrotal integument of Holstein-Friesian bulls. AB - Based on standard histological methods and specific injection technique, the study demonstrates for the first time the blood vessel system of the scrotal integument.The latter is relatively thin and shows a thick underlying fascia, the tunica dartos. The vessel networks found in both structures are somewhat different from each other, i.e., the former displays the typical integumental vessel scheme, which, because of its thinness, shows a higher vessel density. The tunica dartos displayed a blood vessel system with specific characteristics, i.e. horizontal networks are present, which are on the one hand directly connected to the rete dermidis and on the other hand, with the ascending (arteries) or descending (venes) vessels of the dartos, so that a rather uniform distribution and nutrition of the latter, including its muscle layers, is assured.The findings support the idea that the functions of the scrotal integument and the dartos are based on a dependable energy supply, but with regard to vessel type, particularly arteries, may also be involved in the regulation of blood flow. Thus, the scrotal integument as well as the dartos can be used for thermoregulation. PMID- 23740501 TI - Normative dimensions and symmetry of the lacrimal drainage system on dacryocystography: statistical analysis of morphometric characteristics. AB - BACKGROUND: Asymmetric lacrimal flow occurs in females more than males. We hypothesised that the normal lacrimal drainage system (LDS) may show subtle left right asymmetry in morphometry when imaged on dacryocystography (DCG). MATERIALS AND METHODS: We retrospectively reviewed 60 normal bilateral LDSs.Images were analysed for 7 parameters: (1) combined length of either the superior or inferior canaliculus plus common canaliculus, (2) angle of insertion of common canaliculus into lacrimal sac (LS), (3, 4) length and width of the LS, (5) length of the naso lacrimal duct (NLD), and (6, 7) width of proximal and distal NLD. We tested the effect of independent variables (age, gender, and side) on each dependent variable (length, width, or angle) using regression analysis. We used a Studentt test for independent samples to statistically compare bilateral LDSs. RESULTS: Patient median age was 62 years, and male:female ratio was 27:73. Mean dimensions and angles for all LDSs were: (1) 14.5 mm, (2) 57 degrees ,(3) 11.6 mm, (4) 2.1 mm, (5) 20.7 mm, (6) 1.4 mm, and (7) 1.8 mm. No independent variable affected variation in length, width, or angle. No significant difference emerged between dimensions of right and left LDSs in both sexes. CONCLUSIONS: A degree of affective lateralisation in the brain is known to result in lacrimal flow asymmetry after mood manipulation. We show that this is not reflected in LDS anatomy. Moreover, our detailed morphometric data can aid in therapeutic planning of LDS luminal procedures, especially when DCG images of one LDS are used as a road map for contralateral interventions. PMID- 23740502 TI - A novel index in healthy infants and children - subarachnoid space: ventricle ratio. AB - BACKGROUND: The subarachnoid space (SAS) and ventricular width (VW) in normal infants and children were studied with ultrasonography to provide the objective measurement and define a normal range for these measurements. The additional aim was to determine the stable ratio as a SAS/VW. MATERIALS AND METHODS: A total of 100 healthy subjects, including 48 males and 52 females, were studied. The cases were divided into 3 age groups: 0-6 months(n = 65), 7-12 months (n = 24) and > 13 months (n = 11). Transfontanel ultrasonography was performed in all the cases. SAS, VW and the SAS/VW ratios were calculated. The study was approved by the ethical committee. All parents were informed about the sonographic examination and their approvals were taken. RESULTS: SAS was calculated as 3.1 (0.5-6) mm and VW was calculated as 3.6(1.3-5) mm. SAS/VW ratio was 0.9 +/- 0.3. There was no statistically significant difference among SAS, VW and SAS/VW ratios in 3-97 percentile group (p > 0.05). CONCLUSIONS: Ultrasonography can be used as a practicable and reproducible modality in the measurement of SAS and VW in healthy children. It is a non-invasive method and allows for serial follow-up. SAS/VW ratio can be used as an index in healthy children. PMID- 23740503 TI - Reappraisal of the ligament of Henle (ligamentum inguinale internum mediale; Henle, 1871): a topohistological study using Korean foetuses. AB - Ligament of Henle is one of muscle-associated connective tissues of the rectus abdominis muscle, but it has been confused with the conjoint tendon (a common aponeurosis for insertion of the inferomedial end of the obliquus internus and transversus abdominis muscles). To reconsider the inguinal connective tissue structures, we examined 20 mid-term foetuses (10 males and 10 females) at approximately 14-20 weeks of gestation (crown rump length 100-170 mm). In female horizontal sections, we consistently found the ligament of Henle asa wing-like aponeurosis extending from the lateral margin of the rectus tendon behind the superficial inguinal ring. The ligament was separated from and located behind the conjoint tendon. In all male foetuses, instead of the ligament, the conjoint tendon was evident behind the superficial ring and it winded around the posterior aspect of the spermatic cord. Therefore, although a limited number of specimens were examined, the ligament of Henle was likely to be a female-specific structure. The ligament of Henle, if developed well, may provide an arch-like structure suitable for a name "falx inguinalis" instead of the inferomedial end ofthe conjoint tendon. In addition, a covering fascia of the iliopsoas muscle joined the posterior wall of the inguinal canal in male, but not in female, specimens. PMID- 23740504 TI - Evaluation of upper airways depth among patients with skeletal Class I and III. AB - BACKGROUND: The aim of this study was to determine the value of upper and lower pharyngeal depth among patients with skeletal Class III malocclusion on lateral cephalograms, as well as to examine the relationship between SNA, SNB, and ANB angles, along with Wits appraisal and the cross-sectional value of upper airway space at the level of the soft palate and tongue base among patients with skeletal Class I and III. MATERIALS AND METHODS: The material consisted of lateral cephalograms taken from 80 patients living in the Lubelskie voivodeship. The study group consisted of cephalograms of 50 patients with skeletal Class III malocclusion (17 male and 33 female), whereas the control group consisted of 30 roentgenograms of patients with Class I malocclusion with proper jaw to mandible relation (14 maleand 16 female). The study and the control group shared no statistically significant differences considering basic sociographic data such as gender (chi = 1.267, p = 0.26)and age (U = 727.5, p = 0.82). The upper and lower pharyngeal depths were assessed with the use of McNamara's method. Spearman's rho test, Mann--Whitney's U test, and chi test were used for statistical analysis. RESULTS: Among both males and females the pharyngeal depths were greater considering patients with skeletal Class III in comparison to patients with Class Imalocclusion (p < 0.001). Furthermore, it was determined that the lower as well as the upper pharyngeal width is statistically significantly dependent on ANB and SNB angles and Wits appraisal (p < 0.001). CONCLUSIONS: Pharyngeal width at the level of the soft palate and tongue base depends on skeletal class, namely ANB angle and Wits appraisal; it increases with the increase of SNB angle (forward movement of the mandible). The SNA angle (position of the maxilla) does not influence the anterior-posterior nasopharyngeal dimension. PMID- 23740505 TI - Variations of the abductor pollicis longus tendon: an anatomic study. AB - This study was performed to investigate the variations, dimensions and attachment of the abductor pollicis longus (APL) tendon. Fifty upper limbs of adult cadavers were dissected in the Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia. Variations of APL tendon and its way of insertion were observed;its length, width and thickness were also measured and statistically analysed. No single-tendon-APL was found in all the examined upper limbs. The APL exhibited 2 6 tendons in all the cases. Tendons of APL were classified into medial and lateral. The lateral was considered as the main APL tendon, which was inserted into the base of the first metacarpal bone. The medial tendons were regarded as accessory slips and were inserted most commonly into the base of the first metacarpalbone; 80% on its anterolateral surface vs. 20% on the lateral one. The rest of the medial slips extended to trapezium, abductor pollicis brevis, thenar fascia, capsule of first carpometacarpal joint and opponens pollicis, with a frequency of 80%,60%, 40%, 30% and 20%, respectively. Transverse tendinous fibres were noted connecting the various slips of the APL tendons. No significant difference was recorded between the length of the main APL tendon and its accessory tendons, however, a highly significant difference was found between their thicknesses as well as their widths. Thus it is verified that the lateral tendon of APL is the main,whereas the medial tendons are accessory. The observations regarding dimensions and variations of the APL and their accessory tendons may prove useful to surgeons as a source of grafting material. PMID- 23740506 TI - Anatomical and genetic study of an ancient animal tooth showing brachyodont and hypsodont mixed taxonomical characteristics. AB - A non-human dental piece was found in a Roman Empire tomb dated the 3rd century A.C. in Zaragoza (Spain). The morphology of this piece showed mixed brachyodont (carnivores) and hypsodont (herbivores) characteristics. As a result, the taxonomical assignation of the piece was impossible. Therefore, a protocol based on the DNA sequence of the cytochrome c oxidase subunit 1 mitochondrial region (COI) was applied. For this purpose, a pair of primers able to amplify this region in a large variety of animals was designed. The results point to a species of the Genus Bos (Family Bovidae). This assignation was later confirmed by these quencing of a short fragment of the mitochondrial D-loop region. A complete morphological description of the tooth is presented together with the DNA sequence study and comparison protocol. PMID- 23740507 TI - Celiomesenteric trunk demonstrated by multi-detector computed tomography angiography: two cases of a rare vascular variation. AB - We present two cases of patients with celiomesenteric trunk in whom the celiac trunk and the superior mesenteric artery arise off a common vessel from the ventral part of the aorta, which was demonstrated by multi-detector (16 slices) computed tomography angiography (MDCTA) and confirmed by digital subtraction angiography (DSA). This is a very rare congenital vascular anomaly and its imaging demonstration is of great importance in several interventional procedures. These cases demonstrate the capability of MDCTA in the evaluation of abdominal aorta and its branches and shows that this method might replace diagnostic DSA. PMID- 23740508 TI - A new anatomical variation of the musculocutaneous and the median nerve anastomosis. AB - Variations of the brachial plexus and its terminal branches are not uncommon.Therein, the anatomical variations of the musculocutaneous and the median nerve are classified into 5 types, while the communicating branches between the musculocutaneous and the median nerve are classified into 3 types, depending on their position related to the coracobrachial muscle. The case reviewed in this paper presents a variation similar to that of the second variety, but is significantly different due to the appearance of the proximal musculocutaneous nerve and its communicating branching, the site rising from the communicating branch (through the coracobrachial), and important clinical implications of this new variation. Despite the communicating branch being located in the upper third of the upper arm, it should not be considered as being a double lateral root of the median nerve. PMID- 23740510 TI - Forty years after Abramson: beliefs about the criminalization of people with serious mental illnesses. PMID- 23740509 TI - Cancer stage knowledge and desire for information: mismatch in Latino cancer patients? AB - Having more health knowledge has a crucial and positive impact on cancer outcomes. Patients' cancer knowledge influences their ability to participate actively in decision-making processes for medical care and in treatment choices. The purpose of this study was to determine the demographic and medical correlates of lack of cancer stage knowledge and desire for information among Latino cancer patients. The sample included 271 underserved Latino cancer patients recruited from four cancer clinics in New York City. Participants completed a needs assessment survey in their preferred language, which included sociodemographic and health-related questions. Close to two-thirds of the sample (65%) had no knowledge of their stage, and 38% were unaware of the metastatic state of their tumor. Only 15% of the patients expressed that they would like additional information about their diagnosis and/or treatment. After controlling for sociodemographic characteristics, being an immigrant with limited English proficiency and monolingual in Spanish were predictors of stage unawareness and less desire/need for cancer information. Patients needing interpretation for health care were less likely to know whether their tumor had metastasized and their cancer stage and to desire information about their cancer diagnosis and/or treatment. This study shows considerably low levels of stage awareness among Latinos diagnosed with cancer. This lack of knowledge might adversely impact their treatment decisions and disease management. Future studies should focus on identifying barriers to acquisition of disease information and other disease specific informational deficits. PMID- 23740511 TI - The proper blood pressure may impair cardiovascular risk factors. PMID- 23740512 TI - Patellofemoral joint loading during stair ambulation in people with patellofemoral osteoarthritis. AB - OBJECTIVE: To determine whether people with patellofemoral (PF) joint osteoarthritis (OA) ascend and descend stairs with different PF joint loading, knee joint moments, lower limb kinematics, and muscle forces compared to healthy people. METHODS: We recruited 17 participants with isolated PF joint OA, 13 participants with concurrent PF joint OA and tibiofemoral (TF) joint OA, and 21 age-matched controls. Joint kinematics and ground reaction forces were measured while participants ascended and descended stairs at a self-selected speed. Musculoskeletal computer modeling was used to determine lower limb muscle forces and the PF joint reaction force, and these parameters were compared between groups by analysis of variance. RESULTS: Compared to their healthy counterparts, participants with isolated PF joint OA and participants with concurrent PF and TF joint OA ascended and descended stairs with lower knee extension moments, lower quadriceps muscle forces, lower PF joint reaction forces, and increased anterior pelvic tilt. Participants with OA also ascended stairs with increased hip flexion angles and descended stairs with smaller knee flexion angles and smaller hip abductor muscle forces. No differences were evident between the two groups with OA. CONCLUSION: Compared to their healthy counterparts, people with PF joint OA (with or without concurrent TF joint OA) exhibit lower PF joint reaction forces during stair ascent and descent, in conjunction with lower knee extension moments and lower quadriceps muscle forces. PMID- 23740513 TI - Critical evaluation of mixed treatment comparison meta-analyses using examples assessing antidepressants and opioid detoxification treatments. AB - Comparing multiple treatment options using meta-analytical methods requires complex statistical methods called mixed treatment comparisons (MTCs). Such methods offer the possibility to summarize data from many clinical trials comparing the different available options. However, those methods are based on a number of assumptions and inherent difficulties that are discussed and illustrated with examples from the psychiatric literature to help readers to understand the strengths and weaknesses of these methods. This review will help enable readers to critically appraise the methodology and results of publications that use MTCs. PMID- 23740514 TI - Comprehensive review in current developments of imidazole-based medicinal chemistry. AB - Imidazole ring is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron-rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole-based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes. PMID- 23740515 TI - Expression of Hsp27 correlated with rat detrusor contraction after acute urinary retention. AB - Heat shock protein 27 (Hsp27) can regulate actin cytoskeleton dynamics and contractile protein activation. This study investigates whether Hsp27 expression is related to bladder contractile dysfunction after acute urinary retention (AUR). Female rats were randomized either to AUR by urethral ligation or to normal control group. Bladder and smooth muscle strip contraction at time points from 0 h to 7 days after AUR were estimated by cystometric and organ bath studies. Hsp27 expression in bladder tissue at each time point was detected with immunofluorescence, Western blots, and real-time PCR. Expression of the three phosphorylated forms of Hsp27 was detected by Western blots. Smooth muscle ultrastructure was observed by transmission electron microscopy. Data suggest that maximum detrusor pressure and both carbachol-induced and spontaneous detrusor strip contraction amplitude decreased gradually for the duration from 0 to 6 h, and then increased gradually to near-normal values at 24 h. Treatment of muscle strips with the p38MAK inhibitor, SB203580, inhibited carbachol-induced contractions. Smooth muscle ultrastructure damage was the highest at 6 h after AUR, and then lessened gradually during next 7 days, and ultrastructure was close to normal. Expressions of Hsp27 mRNA and protein and the proteins of the three phosphorylated forms were higher at 0 h, decreased to lower levels up to 6 h, and then gradually increased. Therefore, we conclude that rat bladder contractile function after AUR worsens during 0-6 h, and then gradually recovers. The findings of the current study suggest that Hsp27 modulates bladder smooth muscle contraction after AUR, and that phosphorylation of Hsp27 may be an important pathway modulating actin cytoskeleton dynamics in bladder smooth muscle contraction and reconstruction after injury. PMID- 23740516 TI - Cryptotanshinone inhibits human glioma cell proliferation by suppressing STAT3 signaling. AB - Malignant gliomas (MGs) are among the most aggressive types of cancers in the human brain. Frequent tumor recurrence caused by a lack of effective therapeutic approaches results in a poor prognosis. Signal transducer and activator of transcription 3 (STAT3), an oncogenic protein, is constitutively activated in MGs and predicts a poor clinical outcome. STAT3 therefore is considered to be a promising target for the treatment of MGs. Cryptotanshinone (CTS), the main bioactive compound from the root of Salvia miltiorrhiza Bunge, has been reported to have various pharmacological effects. However, little is known about its function in MG cells. In this study, we evaluated the effect of CTS on the proliferation of human glioma cell lines (T98G and U87). Our results revealed that CTS significantly suppresses glioma cell proliferation. The phosphorylation of STAT3 Tyr705, but not Ser727, was inhibited by CTS, and STAT3 nuclear translocation was attenuated. Overexpression of constitutively active mutant STAT3C reversed the inhibitory effect of CTS, while knockdown STAT3 showed a similar inhibitory effect as CTS treatment. Following the downregulation of STAT3 regulated proteins cyclinD1 and survivin, cell cycle progression significantly arrested in G1/G0 phase. These results indicate that CTS may be a potential antiproliferation agent for the treatment of MGs and that its mechanism may be related to the inhibition of STAT3 signaling. PMID- 23740517 TI - Preliminary study of retinal pathological features in preterm birth pups exposed to an animal model of oxygen-induced retinopathy in mice. AB - BACKGROUND: The main risk factors of retinopathy of prematurity (ROP) are low gestational age and low birth weight, which are mainly caused by preterm birth. Currently, the animal model of oxygen-induced retinopathy (OIR) in mice is the most widely used model in ROP-associated studies. However, the experimental mice are normal-term pups, and may not mimic the pathogenic status of human ROP patients. In this study, we investigated the retinal pathological features in preterm birth pups exposed to an animal model of oxygen-induced retinopathy in mice. METHODS: Preterm-birth mice were obtained from pregnant C57BL/6J mice that were induced by an intraperitoneal injection of lipopolysaccharide (LPS). The preterm and control mice were treated with high oxygen (75%) from postnatal day 7 (P7) to P12. The mice were perfused with high-molecular-weight FITC-dextran on P12, P15 and P17, and the retinas were whole-mounted and imaged. Vascular endothelial growth factor (VEGF) mRNA was also detected. Cross-sections of the retina were stained with hematoxylin and eosin (H&E) to identify preretinal neovascular tufts. For general observation, whole retinal images were also obtained using a microscope. RESULTS: Leakage of the retinal blood vessels was aggravated in the preterm mice, particularly on P12 and P15. The non-perfused areas of the retina (pixel value, 183,673 +/- 28,148 vs 132,110 +/- 23,732, P = 0.009) and the number of preretinal endothelial cell nuclei were smaller (30.17 +/- 8.33 vs 22.17 +/- 6.74, P < 0.0001) on P17. The VEGF mRNA levels in the retinas were higher on P12 and P15 but lower on P17, compared with the control mice. Retinal hemorrhage was observed in the preterm mouse group (five out of six examined eyes). CONCLUSIONS: Preterm-birth mice that were subject to OIR exhibited several pathological features, such as retinal hemorrhage, severe retinal leakage and moderate retinal neovascularization, which were similar to the clinical manifestations in ROP patients. PMID- 23740518 TI - Response to: position-dependent accommodative shift of retropupillary fixated iris-claw lenses. PMID- 23740519 TI - Enzymes of urea synthesis are expressed at the ocular surface, and decreased urea in the tear fluid is associated with dry-eye syndrome. AB - PURPOSE: The present study aims at determining whether enzymes of urea synthesis are expressed in the human lacrimal gland and in tissues of ocular surface (conjunctiva, cornea), to give evidence for the hypothesis that urea can be locally formed from ocular tissues and is important for the composition of the tear fluid. METHODS: The presences of enzymes (arginase 1, 2 and agmatinase) that directly contribute to the formation of urea were investigated in the lacrimal gland and tissues of ocular surface by RT-PCR and immunohistochemistry. We collected tear fluid, aqueous humour, and blood samples from a total of 38 subjects, and tear fluid samples from a total of 78 subjects, with and without dry-eye syndrome (DES, keratoconjunctivitis sicca), and determined the urea concentration. RESULTS: The enzymes arginase 1, 2 and agmatinase were expressed in all tissues examined except for arginase 1, which was not expressed in the cornea. There was no correlation of urea concentration in tear fluid with aqueous humour and blood plasma (r = 0.13, p = 0.58 and r = 0.45, p = 0.05 respectively). However, correlation of urea concentration between aqueous humour and blood plasma was highly significant (r = 0.7, p = 0.0001). The concentration of urea in the tear fluid of patients with DES compared to healthy control group was significantly reduced (p < 0.0001). CONCLUSION: Enzymes that are directly involved in the formation of urea are expressed in ocular tissues. This may imply that in the ocular surface is a well-coordinated system of enzymes that can produce urea which might be independent of external urea supply. PMID- 23740520 TI - Anti-angiogenic effect of KH902 on retinal neovascularization. AB - PURPOSE: KH902 is a fusion protein derived from the extracellular domains of vascular endothelial growth factor (VEGF) receptors 1 and 2 and the Fc portion of immunoglobulin G1 (IgG1). Retinopathy of prematurity (ROP) is an eye disease that affects premature babies who have received intensive neonatal care, and the disorganization of retinal blood vessels may result in scarring and retinal detachment. This study was designed to examine the inhibitory effects of KH902 on mice with oxygen-induced retinopathy (OIR), one of the animal models of ROP. METHODS: Human umbilical vein endothelial cells (HUVECs) were used for an in vitro study, and the C57BL/6 J OIR mouse model was used for an in vivo study. HUVECs were incubated with KH902 or a VEGF- and KH902-containing medium. Cell proliferation, migration, apoptosis, and tube formation were measured with BrdU incorporation, Transwell, flow cytometry, and Matrigel assays. C57BL/6 J mice were exposed to 75 % oxygen from postnatal day 7 (P7) to P12, after which the mice were brought to room air and intravitreously injected with KH902. At P18, the mice were perfused with fluorescein isothiocyanate (FITC)-dextran and Evans Blue, and flat-mounted retinas were used to measure the non-perfused and leakage areas. The data were analyzed with GraphPad Prism 5.0 software. RESULTS: In vitro, KH902 dose-dependently inhibited HUVEC proliferation in general culture medium and in VEGF165-containing medium at different time points. Moreover, KH902 inhibited HUVEC migration and tube formation and induced HUVEC apoptosis. In vivo, an intravitreous injection of KH902 reduced the retinal non-perfused area from 34 % in the control group to 19 % in the treatment group and significantly reduced the retinal leakage area from 18 % to 9 %. CONCLUSION: KH902 had marked inhibitory effects on angiogenesis both in vitro and in vivo. These data suggest that KH902 could serve as an innovative pharmaceutical agent to prevent retinal neovascularization (NV) and as a strategy for the treatment of ROP. PMID- 23740521 TI - Outcomes of phacoemulsification in eyes with congenital choroidal coloboma. PMID- 23740522 TI - Dental disease in slender lorises (Loris tardigradus). AB - Necropsies were performed in 25 slender lorises (Loris tardigradus) from a colony at Bochum University. In seven adult individuals, teeth were missing, loose, or severely affected by dental calculus. In one of these cases, a severe periodontal disease was seen without abscess formation. In another four lorises purulent/gangrenous inflammation was found next to the teeth either in the maxillary or the mandibular region. PMID- 23740524 TI - Cerium oxide nanoparticles protect endothelial cells from apoptosis induced by oxidative stress. AB - Oxidative stress is well documented to cause injury to endothelial cells (ECs), which in turn trigger cardiovascular diseases. Previous studies revealed that cerium oxide nanoparticles (nanoceria) had antioxidant property, but the protective effect of nanoceria on ROS injury to ECs and cardiovascular diseases has not been reported. In the current study, we investigated the protective effect and underlying mechanisms of nanoceria on oxidative injury to ECs. The cell viability, lactate dehydrogenase release, cellular uptake, intracellular localization and reactive oxygen species (ROS) levels, endocytosis mechanism, cell apoptosis, and mitochondrial membrane potential were performed. The results indicated that nanoceria had no cytotoxicity on ECs but had the ability to prevent injury by H2O2. Nanoceria could be uptaken into ECs through caveolae- and clathrin-mediated endocytosis and distributed throughout the cytoplasma. The internalized nanoceria effectively attenuated ROS overproduction induced by H2O2. Apoptosis was also alleviated greatly by nanoceria pretreatment. These results may be helpful for more rational application of nanoceria in biomedical fields in the future. PMID- 23740525 TI - Intestinal IgA+ cell numbers as well as IgA, IgG, and IgM contents correlate with mucosal humoral immunity of broilers during supplementation with high fluorine in the diets. AB - Fluoride (F), a well-recognized harmful substance, is easily absorbed by the intestinal mucosa. The intestinal mucosal immune system is equipped with unique innate and adaptive defense mechanisms that provide a first line of protection against infectious agents. Meanwhile, immunoglobulins are the major secretory products of the adaptive immune system and their levels can be a strong indicator of a disease or condition. In this study, therefore, we investigated the effects of high dietary fluorine on the numbers of immunoglobulin A-positive (IgA(+)) cells in the lamina propria of intestines (duodenum, jejunum and ileum) by immunohistochemistry as well as on the contents of immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM) in the mucosa of intestines (duodenum, jejunum, and ileum) by enzyme-linked immunosorbent assay (ELISA). A total of 280 1-day-old healthy avian broilers were randomly divided into four groups and fed on a corn-soybean basal diet as control diet (fluorine 22.6 mg/kg) or the same basal diet supplemented with 400, 800, and 1,200 mg/kg fluorine (high fluorine groups I, II, and III) in the form of sodium fluoride (NaF) for 42 days. The experimental data showed that the numbers of IgA(+) cells as well as the IgA, IgG, and IgM contents were significantly decreased (P < 0.01 or P < 0.05) in the high fluorine groups II and III when compared with those of the control group. It was concluded that dietary fluorine in the range of 800-1,200 mg/kg significantly reduced the numbers of the IgA(+) cells and the contents of aforementioned immunoglobulins in the intestines (duodenum, jejunum, and ileum) of broilers, which could finally impact the mucosal humoral immune function in the intestines by a way that reduces the lymphocyte population and/or lymphocyte activation. PMID- 23740523 TI - The next therapeutic challenge in HIV: polypharmacy. AB - With the adoption of combination antiretroviral therapy (ART), most HIV-infected individuals in care are on five or more medications and at risk of harm from polypharmacy, a risk that likely increases with number of medications, age, and physiologic frailty. Established harms of polypharmacy include decreased medication adherence and increased serious adverse drug events, including organ system injury, hospitalization, geriatric syndromes (falls, fractures, and cognitive decline) and mortality. The literature on polypharmacy among those with HIV infection is limited, and the literature on polypharmacy among non-HIV patients requires adaptation to the special issues facing those on chronic ART. First, those aging with HIV infection often initiate ART in their 3rd or 4th decade of life and are expected to remain on ART for the rest of their lives. Second, those with HIV may be at higher risk for age-associated comorbid disease, further increasing their risk of polypharmacy. Third, those with HIV may have an enhanced susceptibility to harm from polypharmacy due to decreased organ system reserve, chronic inflammation, and ongoing immune dysfunction. Finally, because ART is life-extending, nonadherence to ART is particularly concerning. After reviewing the relevant literature, we propose an adapted framework with which to address polypharmacy among those on lifelong ART and suggest areas for future work. PMID- 23740526 TI - Impact of diabetes on platelet activation in different manifestations of atherosclerosis. AB - BACKGROUND: Atherosclerosis affects many patients with type 2 diabetes. Both are associated with platelet activation, but it remains unclear how diabetes contributes to, or even enhances, platelet activation in patients with atherosclerosis. We therefore investigated the impact of diabetes on platelet activation and protease activated receptor-1 (PAR-1) mediated platelet response in patients with symptomatic coronary artery disease (CAD), as compared with other manifestations of atherosclerosis. METHODS: Baseline P-selectin expression, thrombin receptor activating peptide-6 (TRAP-6) inducible P-selectin, and relative increase of platelet P-selectin after activation with TRAP-6 were measured using flow cytometry in platelets from 317 patients after angioplasty and stenting for symptomatic atherosclerotic disease, and from 50 healthy controls. RESULTS: Patients with symptomatic atherosclerosis exhibited significantly higher levels of baseline P-selectin expression, TRAP-6-inducible P selectin and relative increase of platelet P-selectin after stimulation with TRAP 6 than healthy controls. Patients with symptomatic peripheral artery disease or cerebrovascular disease (PAD/CVD) had higher levels of platelet activation and PAR-1-mediated platelet reactivity than patients with symptomatic CAD. Of interest, CAD patients with diabetes responded more strongly to TRAP-6 than those without diabetes, and their platelet activation and PAR-1-mediated platelet reactivity resembled those from PAD/CVD patients. CONCLUSION: Compared with healthy controls, platelets from patients with symptomatic atherosclerotic disease are activated and susceptible to PAR-1-mediated activation. Diabetes affects platelet reactivity only in patients with symptomatic CAD, while other manifestations of atherosclerosis may have an overwhelming effect on platelet reactivity that is not further enhanced by diabetes. PMID- 23740527 TI - Selective inhibition of PCAF suppresses microglial-mediated beta-amyloid neurotoxicity. AB - Recent studies have emphasized the functional role of the P300/CBP-associated factor (PCAF) enzyme in resistance to beta-amyloid (Abeta)-mediated neurotoxicity; however, the underlying mechanisms through which PCAF regulates inflammation and neurotoxicity have not yet been elucidated. In this study, we used computer-based molecular docking simulations to perform structure-based artificial screening for PCAF-specific inhibitors. Our results revealed that one of the compounds from the screened library, compound C-11, selectively inhibited PCAF, but not p300 or GCN5, with a half-maximal inhibitory concentration (IC50) of approximately 0.25 uM. Furthermore, C-11 had no effects on the activities of other epigenetic enzymes. Western blot analysis using an antibody against acetyl nuclear factor-kappaB (NF-kappaB) demonstrated that PCAF mediated the Abeta induced activation of NF-kappaB by acetylation at Lys-122. We also found that the knockdown of PCAF completely inhibited Abeta-induced cytokine production in BV-2 cells in a similar manner to C-11 treatment. Finally, PCAF inhibition suppressed both Abeta-induced cytokine production and Abeta-mediated neuronal cell death. Therefore, our results suggest that in neuronal cells, PCAF is a promising therapeutic target for alleviating the inflammatory progression of Alzheimer's disease. PMID- 23740528 TI - Growth or longevity: the TOR's decision on lifespan regulation. AB - TOR (target of rapamycin) pathway has been well known for its central role in growth control. Interestingly, recent studies also implicate the TOR pathway in lifespan regulation in various organisms ranging from budding yeast to mammals. TOR gains momentum in a study showing that rapamycin administration later in life significantly extends lifespan in mice. How the TOR kinase controls these two seemingly distinct biological processes is an especially intriguing question yet to be answered. Here, we summarize the literatures concerning TOR's role in growth control, stress response and lifespan regulation, hoping to obtain a better understanding of how cell growth and maintenance are balanced by TOR and how TOR-mediated shift in metabolisms or energy allocations may translate into lifespan extension at the organismal level. We also evaluate the undergoing efforts to target the TOR pathway for health in human, with focus on looking for new drugs that can bypass the unwanted side effects of rapamycin derivatives. PMID- 23740529 TI - C-H functionalization logic enables synthesis of (+)-hongoquercin A and related compounds. PMID- 23740531 TI - Synthesis of paclitaxel-conjugated beta-cyclodextrin polyrotaxane and its antitumor activity. PMID- 23740530 TI - Development of a multi-institutional cohort to facilitate cardiovascular disease biomarker validation using existing biorepository samples linked to electronic health records. AB - BACKGROUND: Emerging biomarkers for acute myocardial infarction (AMI) may enhance conventional risk-prediction algorithms if they are informative and associated with risk independently of established predictors. In this study, we constructed a cohort for testing emerging biomarkers for AMI in managed-care populations using existing biospecimen repositories linked to electronic health records (EHR). HYPOTHESIS: Electronic health record-based biorepositories collected by healthcare systems can be federated to provide large, methodologically sound testing sets for biomarker validation. METHODS: Subjects ages 40 to 80 years were selected from 2 existing population-based biospecimen repositories. Incident AMI status and covariates were ascertained from the EHR. An ad hoc model for AMI risk was parameterized and validated. Simulation was used to test incremental gains in performance due to the inclusion of biomarkers in this model. Gains in performance were assessed in terms of area under the receiver operating characteristic curve (ROC-AUC) and case reclassification. RESULTS: A total of 18 329 individuals (57% female) contributed 108 400 person-years of EHR follow-up. The crude AMI incidence was 10.8 and 5.0 per 1000 person-years among males and females, respectively. Compared with the model with risk factors alone, inclusion of a simulated biomarker yielded substantial gains in sensitivity without loss of specificity. Furthermore, a net ROC-AUC gain of 13.3% was observed, as well as correct reclassification of 9.8% of incident cases (79 of 806) that were otherwise not considered statin-indicated at baseline under the National Cholesterol Education Program Adult Treatment Panel III criteria. CONCLUSIONS: More research is needed to assess incremental contribution of emerging biomarkers for AMI prediction in managed-care populations. PMID- 23740532 TI - "On-site" prevention and education to improve cardiac pre-competition screening in competitive amateur athletes. AB - STUDY/PRINCIPLES: To assess the effects of an "on-site" prevention and education programme to improve the cardiac screening in competitive amateur athletes. METHODS: We integrated an "on-site prevention and education programme" at the 2012 edition of the Swiss Alpine Marathon in Davos, Switzerland. After a specific lecture, the athletes could visit a "Sports-Cardiology-Section" at the official "medical-park". On an anonymised questionnaire, they could state their intention for a screening programme in general and after our "on-site" intervention. RESULTS: Among the 150 athletes who attended the medical day (3.3% of 4,500 finishers) the response rate was 82%. While 39 (31.7%) athletes were aware of "exercise related SCD", more than twice as many (64.2%) were not. 72.4% of the participants (n = 89) reported that they never had taken part in cardiac screening examinations. 70.7% (n = 87) runners were convinced that they would benefit from such a screening. 65.9% (n = 81) of the runners stated that our "on site" prevention concept influenced their decision to consider a cardiac screening in the future. CONCLUSION: An "on-site prevention and education" concept for the prevention of SCD in competitive amateur athletes is feasible and successfully increased the athletes' awareness of the issue. The vast majority of athletes felt to have benefited from such a programme. The current study confirms that there is an alarming lack of preventive measures in the very large group of ambitious, competitive, amateur athletes that are frequently underprepared for challenging sports events. PMID- 23740533 TI - Development of a novel and efficient cell culture flocculation process using a stimulus responsive polymer to streamline antibody purification processes. AB - Recent advances in mammalian cell culture processes have significantly increased product titers, but have also resulted in substantial increases in cell density and cellular debris as well as process and product related impurities. As such, with improvements in titer, corresponding improvements in downstream processing are essential. In this study we have developed an alternative antibody harvest process that incorporates flocculation using a novel stimulus responsive polymer, benzylated poly(allylamine), followed by depth filtration. As tested on multiple antibodies, this process demonstrates high process yield, improved clearance of cells and cell debris, and efficient reduction of aggregates, host cell proteins (HCP) and DNA. A wide operating window was established for this novel flocculation process through design of experiments condition screening and optimization. Residual levels of impurities in the Protein A eluate were achieved that potentially meet requirements of drug substance and thus alleviate the burden for further impurities removal in subsequent chromatography steps. In addition, efficient clearance of residual polymer was demonstrated using a fluorescence tagged polymer in the presence of a stimulus reagent. The mechanism of HCP and aggregates removal during flocculation was also explored. This novel and efficient process can be easily integrated into current mAb purification platforms, and may overcome downstream processing challenges. PMID- 23740534 TI - Treatment of infantile spasms. AB - BACKGROUND: Infantile spasms (West's Syndrome) is a syndrome that includes a peculiar type of epileptic seizure-the spasms-and an electroencephalographic (EEG) abnormality often called hypsarrhythmia. Psychomotor retardation is frequently found at follow-up. Approximately two-thirds of affected infants will have a detectable underlying neurological abnormality, but still little is known about the pathophysiological basis for infantile spasms, and treatment remains problematic. OBJECTIVES: To compare the effects of single pharmaceutical therapies used to treat infantile spasms in terms of control of the spasms, resolution of the EEG, relapse rates, psychomotor development, subsequent epilepsy, side effects, and mortality. SEARCH METHODS: To identify published data, we searched the Cochrane Epilepsy Group Specialised Register (October 2012), CENTRAL (The Cochrane Library 2012, Issue 9), MEDLINE (1946 to September Week 4, 2012), EMBASE (1980 to March 2003), and the reference lists of all retrieved articles.To identify unpublished data, we searched the ISRCTN Register (www.controlled-trials.com), corresponded with colleagues and drug companies, and made requests at international conferences. SELECTION CRITERIA: All randomised controlled trials (RCTs) of the administration of drug therapy to patients with infantile spasms. DATA COLLECTION AND ANALYSIS: Data collection from all relevant publications was independently undertaken by three review authors (before 2010) or by two review authors using a standard proforma. Analysis included assessment of study quality and a search for sources of heterogeneity. MAIN RESULTS: We found 16 small RCTs (fewer than 100 patients enrolled) and 2 larger RCTs (more than 100 patients enrolled). These 18 studies looked at a total of 916 patients treated with a total of 12 different pharmaceutical agents. Overall methodology of the studies was poor, in part because of ethical dilemmas such as giving placebo injections to children. Two studies showed that placebo was not as good as active treatment in resolving the spasms. The strongest evidence suggested that hormonal treatment (prednisolone or tetracosactide depot) leads to resolution of spasms faster and in more infants than does vigabatrin. Responses without subsequent relapse may be no different. The same study suggests that hormonal treatments might improve the long-term developmental outcome compared with vigabatrin in infants not found to have an underlying cause for their infantile spasms. AUTHORS' CONCLUSIONS: To date, few well-designed RCTs have considered the treatment of infantile spasms, and the numbers of patients enrolled have been small. In the majority, methodology has been poor, hence it is not clear which treatment is optimal in the treatment of this epilepsy syndrome. Hormonal treatment resolves spasms in more infants than vigabatrin, but this may or may not translate into better long-term outcomes. If prednisolone or vigabatrin is used, high dosage is recommended. Vigabatrin may be the treatment of choice in tuberous sclerosis. Resolution of the EEG features may be important, but this has not been proven. Further research using large studies with robust methodology is required. PMID- 23740535 TI - Cognitive training and cognitive rehabilitation for mild to moderate Alzheimer's disease and vascular dementia. AB - BACKGROUND: Cognitive impairments, particularly memory problems, are a defining feature of the early stages of Alzheimer's disease (AD) and vascular dementia. Cognitive training and cognitive rehabilitation are specific interventional approaches designed to address difficulties with memory and other aspects of cognitive functioning. The present review is an update of previous versions of this review. OBJECTIVES: The main aim of the current review was to evaluate the effectiveness and impact of cognitive training and cognitive rehabilitation for people with mild Alzheimer's disease or vascular dementia in relation to important cognitive and non-cognitive outcomes for the person with dementia and the primary caregiver in the short, medium and long term. SEARCH METHODS: The CDCIG Specialized Register, ALOIS, which contains records from MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS and many other clinical trial databases and grey literature sources, was most recently searched on 2 November 2012. SELECTION CRITERIA: Randomised controlled trials (RCTs), published in English, comparing cognitive rehabilitation or cognitive training interventions with control conditions, and reporting relevant outcomes for the person with dementia and/or the family caregiver, were considered for inclusion. DATA COLLECTION AND ANALYSIS: Eleven RCTs reporting cognitive training interventions were included in the review. A large number of measures were used in the different studies, and meta-analysis could be conducted for 11 of the primary and secondary outcomes of interest. Several outcomes were not measured in any of the studies. The unit of analysis in the meta-analysis was the change from baseline score. Overall estimates of treatment effect were calculated using a fixed-effect model, and statistical heterogeneity was measured using a standard Chi(2) statistic. One RCT of cognitive rehabilitation was identified, allowing examination of effect sizes, but no meta-analysis could be conducted. MAIN RESULTS: Cognitive training was not associated with positive or negative effects in relation to any reported outcomes. The overall quality of the trials was low to moderate. The single RCT of cognitive rehabilitation found promising results in relation to a number of participant and caregiver outcomes, and was generally of high quality. AUTHORS' CONCLUSIONS: Available evidence regarding cognitive training remains limited, and the quality of the evidence needs to improve. However, there is still no indication of any significant benefit derived from cognitive training. Trial reports indicate that some gains resulting from intervention may not be captured adequately by available standardised outcome measures. The results of the single RCT of cognitive rehabilitation show promise but are preliminary in nature. Further, well-designed studies of cognitive training and cognitive rehabilitation are required to obtain more definitive evidence. Researchers should describe and classify their interventions appropriately using available terminology. PMID- 23740536 TI - Magnesium for alcohol withdrawal. AB - BACKGROUND: Patients have been given magnesium to treat or prevent alcohol withdrawal syndrome (AWS). Evidence to support this practice is limited, and is often based on the controversial link between hypomagnesaemia and AWS. OBJECTIVES: To assess the effects of magnesium for the prevention or treatment of AWS in hospitalised adults. SEARCH METHODS: We searched the Cochrane Drugs and Alcohol Group Register of Controlled Trials (August 2012), PubMed (from 1966 to August 2012 ), EMBASE (from 1988 to August 2012), CINAHL (from 1982 to March 2010), Web of Science (1965 to August 2012). We also carried out Internet searches. SELECTION CRITERIA: Randomised or quasi-randomised trials of magnesium for hospitalised adults with, or at risk for, acute alcohol withdrawal. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data with a standardised data extraction form, contacting the correspondence investigator if the necessary information was not available in the reports. Dichotomous outcomes were analysed by calculating the risk ratio (RR) for each trial, with the uncertainty in each result expressed with a 95% confidence interval (CI). Continuous outcomes were to be analysed by calculating the standardised mean difference (SMD) with 95% CI. For outcomes assessed by scales we compared and pooled the mean score differences from the end of treatment to baseline (post minus pre) in the experimental and control groups. MAIN RESULTS: Four trials involving 317 people met the inclusion criteria. Three trials studied oral magnesium, with doses ranging from 12.5 mmol/day to 20 mmol/day. One trial studied parenteral magnesium (16.24 mEq q6h for 24 hours). Each trial demonstrated a high risk of bias in at least one domain. There was significant clinical and methodological variation between trials.We found no study that measured all of the identified primary outcomes and met the objectives of this review. Only one trial measured clinical symptoms of seizure, delirium tremens or components of the Clinical Institute Withdrawal Assessment for Alcohol (CIWA) score. A single outcome (handgrip strength) in three trials (113 people), was amenable to meta-analysis. There was no significant increase in handgrip strength in the magnesium group (SMD 0.04; 95% CI -0.22 to 0.30). No clinically important changes in adverse events were reported. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether magnesium is beneficial or harmful for the treatment or prevention of alcohol withdrawal syndrome. PMID- 23740537 TI - Antiepileptic drugs for the primary and secondary prevention of seizures after subarachnoid haemorrhage. AB - BACKGROUND: Subarachnoid haemorrhage may result in seizures both acutely and in the longer term. The use of antiepileptic drugs (AEDs) in the primary and secondary prevention of seizures after subarachnoid haemorrhage is uncertain, and there is currently no consensus on treatment. OBJECTIVES: To assess the effects of AEDs for the primary and secondary prevention of seizures after subarachnoid haemorrhage. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 1) in The Cochrane Library, and MEDLINE (1946 to 12th March 2013). We checked the reference lists of articles retrieved from these searches. SELECTION CRITERIA: We considered all randomised and quasi-randomised controlled trials in which patients were assigned to a treatment (one or more AEDs) or placebo. DATA COLLECTION AND ANALYSIS: Two review authors (RM and JK) independently screened and assessed the methodological quality of the studies. If studies were included, one author extracted the data and the other checked it. MAIN RESULTS: No relevant studies were found. AUTHORS' CONCLUSIONS: There was no evidence to support or refute the use of antiepileptic drugs for the primary or secondary prevention of seizures related to subarachnoid haemorrhage. Well-designed randomised controlled trials are urgently needed to guide clinical practice. PMID- 23740538 TI - Media campaigns for the prevention of illicit drug use in young people. AB - BACKGROUND: Substance-specific mass media campaigns which address young people are widely used to prevent illicit drug use. They aim to reduce use and raise awareness of the problem. OBJECTIVES: To assess the effectiveness of mass media campaigns in preventing or reducing the use of or intention to use illicit drugs amongst young people. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2013, Issue 1), including the Cochrane Drugs and Alcohol Group's Specialised Register; MEDLINE through PubMed (from 1966 to 29 January 2013); EMBASE (from 1974 to 30 January 2013) and ProQuest Dissertations & Theses A&I (from 1861 to 3 February 2013). SELECTION CRITERIA: Cluster-randomised controlled trials, prospective and retrospective cohort studies, interrupted time series and controlled before and after studies evaluating the effectiveness of mass media campaigns in influencing drug use, intention to use or the attitude of young people under the age of 26 towards illicit drugs. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures of The Cochrane Collaboration. MAIN RESULTS: We included 23 studies involving 188,934 young people, conducted in the USA, Canada and Australia between 1991 and 2012. Twelve studies were randomised controlled trials (RCT), two were prospective cohort studies (PCS), one study was both a RCT and a PCS, six were interrupted time series and two were controlled before and after (CBA) studies. The RCTs had an overall low risk of bias, along with the ITS (apart from the dimension 'formal test of trend'), and the PCS had overall good quality, apart from the description of loss to follow-up by exposure.Self reported or biomarker-assessed illicit drug use was measured with an array of published and unpublished scales making comparisons difficult. Pooled results of five RCTs (N = 5470) show no effect of media campaign intervention (standardised mean difference (SMD) -0.02; 95% confidence interval (CI) -0.15 to 0.12).We also pooled five ITS studies (N = 26,405) focusing specifically on methamphetamine use. Out of four pooled estimates (two endpoints measured in two age groups), there was evidence of a reduction only in past-year prevalence of methamphetamine use among 12 to 17 years old.A further five studies (designs = one RCT with PCS, two PCS, two ITS, one CBA, N = 151,508), which could not be included in meta-analyses, reported a drug use outcome with varied results including a clear iatrogenic effect in one case and reduction of use in another. AUTHORS' CONCLUSIONS: Overall the available evidence does not allow conclusions about the effect of media campaigns on illicit drug use among young people. We conclude that further studies are needed. PMID- 23740539 TI - Multidisciplinary rehabilitation following botulinum toxin and other focal intramuscular treatment for post-stroke spasticity. AB - BACKGROUND: Spasticity may affect stroke survivors by contributing to activity limitations, caregiver burden, pain and reduced quality of life (QoL). Spasticity management guidelines recommend multidisciplinary (MD) rehabilitation programmes following botulinum toxin (BoNT) treatment for post-stroke spasticity. However, the evidence base for the effectiveness of MD rehabilitation is unclear. OBJECTIVES: To assess the effectiveness of MD rehabilitation, following BoNT and other focal intramuscular treatments such as phenol, in improving activity limitations and other outcomes in adults and children with post-stroke spasticity. To explore what settings, types and intensities of rehabilitation programmes are effective. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (February 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 12), MEDLINE (1948 to December 2011), EMBASE (1980 to January 2012), CINAHL (1982 to January 2012), AMED (1985 to January 2012), LILACS (1982 to September 2012), PEDro, REHABDATA and OpenGrey (September 2012). In an effort to identify further published, unpublished and ongoing trials we searched trials registries and reference lists, handsearched journals and contacted authors. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared MD rehabilitation (delivered by two or more disciplines in conjunction with medical input) following BoNT and other focal intramuscular treatments for post-stroke spasticity with placebo, routinely available local services, or lower levels of intervention; or studies that compared MD rehabilitation in different settings, of different types, or at different levels of intensity. We excluded RCTs that assessed the effectiveness of unidisciplinary therapy (for example physiotherapy only) or a single modality (for example stretching, casting, electrical stimulation or splinting only). The primary outcomes were validated measures of activity level (active and passive function) according to the World Health Organization's International Classification of Functioning, Disability and Health. Secondary outcomes included measures of symptoms, impairments, participation, QoL, impact on caregivers and adverse events. DATA COLLECTION AND ANALYSIS: We independently selected the trials, extracted data, and assessed methodological quality using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE). Due to the limited number of included studies, with clinical, methodological and statistical heterogeneity, quantitative meta-analysis was not possible. Therefore, GRADE provided qualitative synthesis of 'best evidence'. MAIN RESULTS: We included three RCTs involving 91 participants. All three studies scored 'low quality' on the methodological quality assessment, implying high risk of bias. All studies investigated various types and intensities of outpatient rehabilitation programmes following BoNT for upper limb spasticity in adults with chronic stroke. Rehabilitation programmes included: modified constraint-induced movement therapy (mCIMT) compared with a neurodevelopmental therapy programme; task practice therapy with cyclic functional electrical stimulation (FES) compared with task practice therapy only; and occupational, manual therapy with dynamic elbow extension splinting compared with occupational therapy only. There was 'low quality' evidence for mCIMT improving upper limb motor function and spasticity in chronic stroke survivors with residual voluntary upper limb activity, up to six months, and 'very low quality' evidence for dynamic elbow splinting and occupational therapy reducing elbow range of movement at 14 weeks. Task practice therapy with cyclic FES did not improve upper limb function more than task practice therapy alone, only at 12 weeks. No studies addressed interventions in children and those with lower limb spasticity, or after other focal intramuscular treatments for spasticity. AUTHORS' CONCLUSIONS: At best there was 'low level' evidence for the effectiveness of outpatient MD rehabilitation in improving active function and impairments following BoNT for upper limb spasticity in adults with chronic stroke. No trials explored the effect of MD rehabilitation on 'passive function' (caring for the affected limb), caregiver burden, or the individual's priority goals for treatment. The optimal types (modalities, therapy approaches, settings) and intensities of therapy for improving activity (active and passive function) in adults and children with post-stroke spasticity, in the short and longer term, are unclear. Further research is required to build evidence in this area. PMID- 23740540 TI - Slow-release oral morphine as maintenance therapy for opioid dependence. AB - BACKGROUND: Opioid substitution treatments are effective in retaining people in treatment and suppressing heroin use. An open question remains whether slow release oral morphine (SROM) could represent a possible alternative for opioid dependent people who respond poorly to other available maintenance treatments. OBJECTIVES: To evaluate the efficacy of SROM as an alternative maintenance pharmacotherapy for the treatment of opioid dependence. SEARCH METHODS: We searched Cochrane Drugs and Alcohol Group's Register of Trials, Cochrane Central Register of Controlled Trials (CENTRAL - The Cochrane Library Issue 3, 2013), MEDLINE (January 1966 to April 2013), EMBASE (January 1980 to April 2013) and reference lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-randomised trials assessing efficacy of SROM compared with other maintenance treatment or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently selected articles for inclusion, extracted data and assessed risk of bias of included studies. MAIN RESULTS: Three studies with 195 participants were included in the review. Two were cross-over trials and one was a parallel group RCT. The retention in treatment appeared superior to 80% in all the three studies (without significant difference with controls). Nevertheless, it has to be underlined that the studies had different durations. One lasted six months, and the other two lasted six and seven weeks. The use of opioids during SROM provision varied from lower to non-statistically or clinically different from comparison interventions, whereas there were no differences as far as the use of other substances was concerned.SROM seemed to be equal to comparison interventions for severity of dependence, or mental health/social functioning, but there was a trend for less severe opiate withdrawal symptoms in comparison with methadone (withdrawal score 2.2 vs. 4.8, P value = 0.06). Morphine was generally well tolerated and was preferred by a proportion of participants (seven of nine people in one study). Morphine appeared to reduce cravings, depressive symptoms (measured using the Beck Depression Inventory; P value < 0.001), physical complaints (measured using the Beschwerde-Liste (BL); P value < 0.001) and anxiety symptoms (P value = 0.008). Quality of life in people treated with SROM resulted in no significant difference or a worst outcome than in those taking methadone and buprenorphine. Other social functioning measures, such as finances, family and overall satisfaction, scored better in people maintained with the comparison substances than in those maintained with SROM. In particular, people taking methadone showed more favourable values for leisure time (5.4 vs. 3.7, P value < 0.001), housing (6.1 vs. 4.7, P value < 0.023), partnerships (5.7 vs. 4.2, P value = 0.034), friend and acquaintances (5.6 vs. 4.4, P value = 0.003), mental health (5.0 vs. 3.4, P value = 0.002) and self esteem (8.2 vs. 5.7, P value = 0.002) compared to people taking SROM; while people taking buprenorphine obtained better scores for physical health.Medical adverse events were consistently higher in people in SROM than in the comparison groups. None of the studies included people with a documented poor response to other maintenance treatment. AUTHORS' CONCLUSIONS: The present review did not identify sufficient evidence to assess the effectiveness of SROM for opioid maintenance because only three studies meeting our inclusion criteria have been identified. Two studies suggested a possible reduction of opioid use in people taking SROM. In another study, the use of SROM was associated with fewer depressive symptoms. Retention in treatment was not significantly different among compared interventions while the adverse effects were more frequent with the people given SROM. PMID- 23740541 TI - Occupational therapy for care home residents with stroke. AB - BACKGROUND: Stroke is a worldwide problem and is a leading cause of adult disability, resulting in dependency in activities of daily living (ADL) for around half of stroke survivors. It is estimated that up to 25% of all care home residents in the USA and in the UK have had a stroke. Stroke survivors who reside in care homes are likely to be more physically and cognitively impaired and therefore more dependent than those able to remain in their own home. Overall, 75% of care home residents are classified as severely disabled, and those with stroke are likely to have high levels of immobility, incontinence and confusion, as well as additional co-morbidities. It is not known whether this clinically complex population could benefit from occupational therapy in the same way as community-dwelling stroke survivors. The care home population with stroke differs from the general stroke population living at home, and a review was needed to examine the benefits of occupational therapy provided to this specific group. This review therefore focused on occupational therapy interventions for ADL for stroke survivors residing in care homes. OBJECTIVES: To measure the effects of occupational therapy interventions (provided directly by an occupational therapist or under the supervision of an occupational therapist) targeted at improving, restoring and maintaining independence in ADL among stroke survivors residing in long-term institutional care, termed collectively as 'care homes'. As a secondary objective, we aimed to evaluate occupational therapy interventions for reducing complications such as depression and low mood. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (August 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, September 2012), MEDLINE (1948 to September 2012), EMBASE (1980 to September 2012), CINAHL (1982 to September 2012) and 10 additional bibliographic databases and six trials registers. We also handsearched seven journals, checked reference lists and obtained further information from individual trialists. SELECTION CRITERIA: Randomised controlled trials investigating the impact of an occupational therapy intervention for care home residents with stroke versus standard care. DATA COLLECTION AND ANALYSIS: The lead review author performed all searches. Two review authors then independently assessed all titles and abstracts of studies and selected trials for inclusion, with a third review author resolving any discrepancies. The same two review authors independently extracted data from all included published sources to ensure reliability. Primary outcomes were performance in ADL at the end of scheduled follow-up and death or a poor outcome. Secondary outcomes aimed to reflect the domains targeted by an occupational therapy intervention. MAIN RESULTS: We included in the review one study involving 118 participants. We found one ongoing study that also met the inclusion criteria for the review, but the data were not yet available. AUTHORS' CONCLUSIONS: We found insufficient evidence to support or refute the efficacy of occupational therapy interventions for improving, restoring or maintaining independence in ADL for stroke survivors residing in care homes. The effectiveness of occupational therapy for the population of stroke survivors residing in care homes remains unclear, and further research in this area is warranted. PMID- 23740543 TI - N-hexane inhalation during pregnancy alters DNA promoter methylation in the ovarian granulosa cells of rat offspring. AB - The N-hexane-induced impact on the reproductive system of the offspring of animals exposed to n-hexane has caused great concern. Pregnant Wistar rats inhaled 500, 2 500 or 12 500 ppm n-hexane during gestational days 1-20. Clinical characteristics and developmental indices were observed. Ovarian granulosa cells were extracted from F1 rats, the number of follicles was determined in ovarian slices and promoter methylation was assessed using MeDIP-Chip. Several methods were used to analyze the scanned genes, including the Gene Ontology Consortium tools, the DAVID Functional Annotation Clustering Tool, hierarchical clustering and KEGG pathway analysis. The results indicated that the live pups/litter ratio was significantly lowest in the 12 500 ppm group. A significant decrease in secondary follicles and an increase in atresic follicles were observed in the 12 500 ppm group. The number of shared demethylated genes was higher than that of the methylated genes, and the differentially methylated genes were enriched in cell death and apoptosis, cell growth and hormone regulation. The methylation profiles of the offspring from the 500 ppm and control groups were different from those of the 2500 and 12 500 ppm groups. Furthermore, the methylation status of genes in the PI3K-Akt and NF-kappa B signaling pathways was changed after n hexane exposure. The Cyp11a1, Cyp17a1, Hsd3b1, Cyp1a1 and Srd5a1 promoters were hypermethylated in the n-hexane-exposed groups. These results indicate that the developmental toxicity of n-hexane in F1 ovaries is accompanied by the altered methylation of promoters of genes associated with apoptotic processes and steroid hormone biosynthesis. PMID- 23740545 TI - Enantioseparation of Troger's base derivatives by capillary electrophoresis using cyclodextrins as chiral selectors. AB - The enantioseparation of seven Troger's base derivatives (TBs) was carried out by capillary electrophoresis using alpha-, beta-, and gamma-cyclodextrins as chiral selectors and phosphate at 20 mmol/l concentration, pH 2.5, as background electrolyte. The method was optimized with respect to the concentration of chosen chiral selectors (0-50 mmol/l) and the amount of organic solvent (acetonitrile, 0 25 % (v/v)) in the electrolyte. The results indicate that all the studied variables, i.e., type of chiral selector, its concentration, and the amount of the added organic solvent, have a significant impact on the enantioseparation of the studied TBs. The best results for the majority of the separated TBs were obtained utilizing beta-cyclodextrin at 5 mmol/l concentration and with various amounts of acetonitrile added ranging from 5 to 15% (v/v) in the background electrolyte. For the two smallest studied TBs, gamma-cyclodextrin with 10% (v/v) acetonitrile also provided good resolution. PMID- 23740546 TI - Demetalation of metal porphyrins via magnesium porphyrins by reaction with Grignard reagents. PMID- 23740547 TI - Doxycycline-induced expression of transgenic human tumor necrosis factor alpha in adult mice results in psoriasis-like arthritis. AB - OBJECTIVE: To generate doxycycline-inducible human tumor necrosis factor alpha (TNFalpha)-transgenic mice to overcome a major disadvantage of existing transgenic mice with constitutive expression of TNFalpha, which is the limitation in crossing them with various knockout or transgenic mice. METHODS: A transgenic mouse line that expresses the human TNFalpha cytokine exclusively after doxycycline administration was generated and analyzed for the onset of diseases. RESULTS: Doxycycline-inducible human TNFalpha-transgenic mice developed an inflammatory arthritis- and psoriasis-like phenotype, with fore and hind paws being prominently affected. The formation of "sausage digits" with characteristic involvement of the distal interphalangeal joints and nail malformation was observed. Synovial hyperplasia, enthesitis, cartilage and bone alterations, formation of pannus tissue, and inflammation of the skin epidermis and nail matrix appeared as early as 1 week after the treatment of mice with doxycycline and became aggravated over time. The abrogation of human TNFalpha expression by the removal of doxycycline 6 weeks after beginning stimulation resulted in fast resolution of the most advanced macroscopic and histologic disorders, and 3-6 weeks later, only minimal signs of disease were visible. CONCLUSION: Upon doxycycline administration, the doxycycline-inducible human TNFalpha-transgenic mouse displays the major features of inflammatory arthritis. It represents a unique animal model for studying the molecular mechanisms of arthritis, especially the early phases of disease genesis and tissue remodeling steps upon abrogation of TNFalpha expression. Furthermore, unlimited crossing of doxycycline inducible human TNFalpha-transgenic mice with various knockout or transgenic mice opens new possibilities for unraveling the role of various signaling molecules acting in concert with TNFalpha. PMID- 23740548 TI - In vivo loading model to examine bone adaptation in humans: a pilot study. AB - Bone is typically well suited for its habitual loading environment because of its ability to adapt. Although characteristics of the mechanical loading environment predict the bone adaptive response in animals, this has not been prospectively validated in humans. Here, we describe an in vivo loading model in which women apply forces to the radius by leaning onto their hand. We characterized the strain environment imposed on the radius using cadaveric experimentation and conducted a prospective study in which 19 adult women loaded their distal radii 50 cycles/day, 3 days/week, for 28 weeks and seven additional adult women served as controls. In four cadaveric specimens, loading caused compressive principal strains of -1,695 +/- 396 MUepsilon with radial bending dorsally and towards the ulna. Prospective in vivo loading produced measurable improvements to bone and appeared to protect against bone loss associated with seasonal fluctuations in physical activity and sun exposure. Experimental subjects had significant gains to bone volume (BV) and moments of inertia, while, control subjects had significant losses in BMC and moments of inertia. The loading model is thus suitable as a model system for exploring bone adaptation in humans, and may eventually be clinically useful for strengthening the radius of women. PMID- 23740549 TI - Perceiving social inequity: when subordinate-group positioning on one dimension of social hierarchy enhances privilege recognition on another. AB - Researchers have suggested that viewing social inequity as dominant-group privilege (rather than subordinate-group disadvantage) enhances dominant-group members' support for social policies aimed at lessening such inequity. However, because viewing inequity as dominant-group privilege can be damaging to dominant group members' self-images, this perspective is frequently resisted. In the research reported here, we explored the circumstances that enhance the likelihood of dominant-group members' viewing inequity as privilege. Because social hierarchies have multiple vertical dimensions, individuals may have high status on one dimension but low status on another. We predicted that occupying a subordinate position on one dimension of social hierarchy could enhance perceptions of one's own privilege on a different dimension of hierarchy, but that this tendency would be diminished among individuals who felt they had achieved a particularly high level of success. Results from three studies that considered gender-based and race-based hierarchies in organizational settings supported our hypothesis. PMID- 23740550 TI - Extreme rituals promote prosociality. PMID- 23740551 TI - Lay theories of obesity predict actual body mass. AB - Obesity is a major public health problem, but despite much research into its causes, scientists have largely neglected to examine laypeople's personal beliefs about it. Such naive beliefs are important because they guide actual goal directed behaviors. In a series of studies across five countries on three continents, we found that people mainly believed either that obesity is caused by a lack of exercise or that it is caused by a poor diet. Moreover, laypeople who indicted a lack of exercise were more likely to actually be overweight than were those who implicated a poor diet. This effect held even after controlling for several known correlates of body mass index (BMI), thereby explaining previously unexplained variance. We also experimentally demonstrated the mechanism underlying this effect: People who implicated insufficient exercise tended to consume more food than did those who indicted a poor diet. These results suggest that obesity has an important, pervasive, and hitherto overlooked psychological antecedent. PMID- 23740552 TI - Individual differences in eye movements during face identification reflect observer-specific optimal points of fixation. AB - In general, humans tend to first look just below the eyes when identifying another person. Does everybody look at the same place on a face during identification, and, if not, does this variability in fixation behavior lead to functional consequences? In two conditions, observers had their free eye movements recorded while they performed a face-identification task. In another condition, the same observers identified faces while their gaze was restricted to specific locations on each face. We found substantial differences, which persisted over time, in where individuals chose to first move their eyes. Observers' systematic departure from a canonical, theoretically optimal fixation point did not correlate with performance degradation. Instead, each individual's looking preference corresponded to an idiosyncratic performance-maximizing point of fixation: Those who looked lower on the face performed better when forced to fixate the lower part of the face. The results suggest an observer-specific synergy between the face-recognition and eye movement systems that optimizes face identification performance. PMID- 23740554 TI - Circular dichroism spectroscopy study of crystalline-to-amorphous transformation in chiral platinum(II) complexes. AB - Two couples of enantiomeric platinum(II) complexes: Pt(L1a )Cl (1a), Pt(L1b )Cl (1b) and Pt(L1a )(C = C - Ph) (2a), Pt(L1b )(C = C - Ph) (2b) (L1a = (+)-1,3-di (2-(4,5-pinene)pyridyl)benzene, L1b = (-)-1,3-di-(2-(4,5-pinene)pyridyl)benzene) were synthesized and characterized. Their absolute configurations were determined by single crystal X-ray diffraction and further verified by circular dichroism (CD) spectra (including electronic circular dichroism [ECD] and vibrational circular dichroism [VCD]). These complexes show interesting mechanoluminescence and/or vapoluminescence due to crystalline-to-amorphous transformation. The crystalline solids, grinding-induced amorphous powders, and vapor-induced amorphous powders of complexes 2a and 2b were comparatively investigated by solid state ECD and VCD spectra. The transformation from crystalline solids to amorphous powders was accompanied by significant variances of the spectral feature in both ECD and VCD spectra. PMID- 23740553 TI - Axonal regeneration and remyelination evaluation of chitosan/gelatin-based nerve guide combined with transforming growth factor-beta1 and Schwann cells. AB - Despite efforts in peripheral nerve injury and regeneration, it is difficult to achieve a functional recovery following extended peripheral nerve lesions. Even if artificial nerve conduit, cell components and growth factors can enhance nerve regeneration, integration in peripheral nerve repair and regeneration remains yet to be explored. For this study, we used chitosan/gelatin nerve graft constructed with collagenous matrices as a vehicle for Schwann cells and transforming growth factor-beta1 to bridge a 10-mm gap of the sciatic nerve and explored the feasibility of improving regeneration and reinnervation in rats. The nerve regeneration was assessed with functional recovery, electrophysiological test, retrograde labeling, and immunohistochemistry analysis during the post-operative period of 16 weeks. The results showed that the internal sides of the conduits were compact enough to prevent the connective tissues from ingrowth. Nerve conduction velocity, average regenerated myelin area, and myelinated axon count were similar to those treated with autograft (p > 0.05) but significantly higher than those bridged with chitosan/gelatin nerve graft alone (p < 0.05). Evidences from retrograde labeling and immunohistochemistry analysis are further provided in support of improving axonal regeneration and remyelination. A designed graft incorporating all of the tissue-engineering strategies for peripheral nerve regeneration may provide great progress in tissue engineering for nerve repair. PMID- 23740555 TI - A bipodal dicyano anchor unit for single-molecule spintronic devices. AB - The conductance through single 7,7,8,8-tetracyanoquinodimethane (TCNQ) connected to gold electrodes is studied with the nonequilibrium Green's function method combined with density functional theory. The aim of the study is to derive the effect of a dicyano anchor group, =C(CN)2, on energy level alignment between the electrode Fermi level and a molecular energy level. The strong electron withdrawing nature of the dicyano anchor group lowers the LUMO level of TCNQ, resulting in an extremely small energy barrier for electron injection. At zero bias, electron transfer from electrodes easily occurs and, as a consequence, the anion radical state of TCNQ with a magnetic moment is formed. The unpaired electron in the TCNQ anion radical causes an exchange splitting between the spin alpha and spin-beta transmission spectra, allowing the single TCNQ junction to act as a spin-filtering device. PMID- 23740556 TI - Moderate physical exercise attenuates the alterations of feeding behaviour induced by social stress in female rats. AB - Epidemiological studies have demonstrated that stress-related disorders, such as the increase on the caloric intake, are twice as common in women as in men, but surprisingly, very few studies have been tested this subject on female experimental animals. Additionally, it has been proposed that regular physical exercise can improve the deleterious effects of stress. Therefore, the present longitudinal study, performed in female rats, aimed to test the influence of chronic stress (ST) imposed by social isolation on the animals' caloric intake and to assess the effect of regular physical exercise of low intensity on this behaviour. In 4 groups of Wistars rats (control sedentary, n = 6; control exercised, n = 6; ST sedentary, n = 6; ST exercised, n = 6), body weight, food intake, abdominal fat weight, adrenal weight, corticosterone metabolites in faeces and plasma insulin levels were measured during the experimental protocol and/or at its end. The results showed that social isolation was not able to modify the amount of abdominal fat and the body weight; however, it promoted significant increases in the corticosterone metabolites and in the amount of caloric intake, which were attenuated in exercised rats. Additionally, exercised groups presented lower levels of fasting insulin than sedentary groups. Therefore, the present study demonstrated that regular physical exercise of low intensity attenuates the corticosterone metabolites and overeating behaviour triggered by social stress. PMID- 23740557 TI - Antioxidants in organophosphorus compounds poisoning. AB - Oxidative stress has recently been implicated as a factor in the mortality and morbidity induced by organophosphorus (OP) compound poisoning. An overwhelming number of research papers are based on studying at the cellular and organ level. Such studies have concluded that antioxidants can be used as an adjunct compound in the treatment of both chronic as well as acute OP poisoning. Still, the role of antioxidants in reducing the mortality and morbidity induced by OP compounds has scarcely been verified, as well as their role as adjunct treatment compounds for both structurally and functionally different OP compounds. The present review of the literature was undertaken to establish the role of antioxidants in survival studies following acute exposure to OP compounds. The review found no substantial evidence that antioxidants demonstrate any positive effect following extremely toxic poisoning. However, for a more comprehensive and rational conclusion, further research needs to be conducted. PMID- 23740558 TI - Premature adrenarche: not always benign? PMID- 23740559 TI - Children at risk of diabetes type 1. Treatment with acetyl-L-carnitine plus nicotinamide - case reports. AB - Abstract Objectives: The aim was to evaluate the treatment with acetyl-L carnitine (50 mg/kg/day) and nicotinamide (25 mg/kg/day) in children at risk of type 1 diabetes. This treatment was effective and harmless in experimental type 1 diabetes in mice. PATIENTS: Nine out of seventy healthy participants of the type 1 diabetes risk study were treated. They were typified for diabetes with HLA-DQB1 and positive autoantibodies. Children with a first peak of insulin response <=48 uU were randomly distributed in control and treated patients. Children evolution was followed with an intravenous glucose tolerance test. Control children were treated when was another risk parameter was added. During their evolution all children were treated. RESULTS: Treatment periods differ (range: 120-16 months) because children began treatment at different times. During the treatment 4 patients recovered their parameters and the medication was suspended; 2 patients continued the treatment with favorable evolution. Two children evolved slowly with normal growth and development. One girl became diabetic because she was treated late. CONCLUSIONS: In children at risk, this treatment delays the development or remits the evolution of type 1 diabetes. PMID- 23740560 TI - Allosteric regulation of the calcium-sensing receptor in obese individuals. AB - We have previously reported that the calcium-sensing receptor (CaSR) plays an important role in modulating lipid metabolism under low calcium conditions. The aim of this study was to identify possible regulators of CaSR and the mechanisms of action of CaSR in obese individuals. Subcutaneous fat samples were obtained from 10 obese and 10 non-obese males undergoing elective abdominal surgery. Visceral fat pads were obtained from 12 obese and 12 non-obese male rats. Serum lipid, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) concentrations, as well as the gene and protein expression of CaSR in the white adipose tissue of obese subjects and rats were determined. Serum total calcium, vitamin D, parathyroid hormone (PTH) and amino acid levels in human subjects were measured. Intracellular calcium and cyclic adenosine monophosphate (cAMP) levels in rat adipocytes were measured by laser scanning confocal microscopy and ELISA, respectively. The results revealed that serum triglyceride (TG), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), TNF-alpha, IL-6 and PTH levels were significantly higher in the obese individuals versus the controls. By contrast, serum vitamin D and amino acid concentrations were lower in the obese individuals versus the controls. In addition, intracellular calcium levels were higher, while cAMP levels were lower in the obese rat adipocytes compared with the control group. However, the gene and protein expression of CaSR in white adipose tissue did not differ between the obese groups and the controls. Thus, these results suggest that CaSR functions not through its expression, but rather through allosteric regulation in obese individuals. PMID- 23740561 TI - [Congenital disorders of the lungs and airways--survey of cases at the Paediatric Hospital Erlangen in the period 2000 to 2011]. AB - BACKGROUND: Congenital malformations of the lungs are rare, but might limit the quality of life of the patient. With the increased possibilities of diagnostic and therapeutic procedures during the last decades, these diseases can be recognised and successfully treated earlier than before. The aim of this article is to give an overview about the congenital malformations of the lungs in children who have been treated at the Kinderklinik Erlangen during the years 2000 and 2011. Clinical symptoms of the disease and associated malformations, diagnostic and therapeutic procedures were discussed. METHODS: The analysis was done retrospectively (January 1st 2000-April 15th 2011) on the basis of the patients records. Patients who had been treated only at the outpatient clinic were not considered. All patients' data were listed according to the ICD code. RESULTS: 121 children were treated because of a congenital malformation of the lungs in the years between 2000 and 2011 in Erlangen. 68.6 % (n = 83) were males and 31.45 % (n = 38) were females. Nearly all of the malformations of the lungs were associated with other abnormalities. Most of the children also suffered from at least one cardiac defect. 28 of the 121 children had more than one malformation of the lungs. The diagnostic and therapeutic interventions correlated with the published recommendations. CONCLUSIONS: The analysis of the patients' data used in this study indicate the importance of the early diagnosis and treatment. The cooperation of different medical disciplines is mandatory for a good outcome of those children. PMID- 23740562 TI - The impact of emotion on perception, attention, memory, and decision-making. AB - Reason and emotion have long been considered opposing forces. However, recent psychological and neuroscientific research has revealed that emotion and cognition are closely intertwined. Cognitive processing is needed to elicit emotional responses. At the same time, emotional responses modulate and guide cognition to enable adaptive responses to the environment. Emotion determines how we perceive our world, organise our memory, and make important decisions. In this review, we provide an overview of current theorising and research in the Affective Sciences. We describe how psychological theories of emotion conceptualise the interactions of cognitive and emotional processes. We then review recent research investigating how emotion impacts our perception, attention, memory, and decision-making. Drawing on studies with both healthy participants and clinical populations, we illustrate the mechanisms and neural substrates underlying the interactions of cognition and emotion. PMID- 23740563 TI - High-throughput screening for transglutaminase activities using recombinant fluorescent proteins. AB - Since detailed evaluation of specific transglutaminases (TGs) from various species requires identification of their substrate specificities, rapid substrate screening method by measurement of their relative activities is in great demand. Here, a novel evaluation method of TG activity was developed using two recombinant fluorescent proteins (FPs), that is, eYFP and DsRed, tagged with TG substrate peptides. By cross-linking the two FPs based on the tagged target peptide sequences at their C-terminus, the expression of co-transformed TG allows quenching of the yellow fluorescence intensities. It was shown that the degree of in vivo fluorescent quenching by the TG activity agrees well with its in vitro reaction data, suggesting that this system can be used to identify relative substrate specificity of TGs for target peptide sequences. Using this method, the lysine substrates of TGs from Bacillus species (BTG) were evaluated, and the newly selected pentapeptide, KTKTN showed almost the same reactivity with the well-known hexa-lysine (K6) substrate for BTG reaction. PMID- 23740564 TI - Subtyping non-small cell lung cancer: relevant issues and operative recommendations for the best pathology practice. AB - Morphology still remains the cornerstone in lung cancer classification and cytology and small biopsy samples should be interpreted by morphology, whenever feasible, according to shared and widely agreed-upon diagnostic schemes. However, as novel therapy strategies are being offered on the basis of the diverse tumor characteristics, pathologists are now challenged by the need to offer clinicians more detailed typing of non-small cell lung cancer, not otherwise specified (NSCLC-NOS), especially when dealing with limited diagnostic material or poorly differentiated tumors. Close integration of morphology, immunohistochemistry, and clinical data is highly warranted according to a multidisciplinary approach to limit the category of NSCLC-NOS as much as possible or exclude unsuspected metastases, so rendering more definite and clinically useful diagnoses. Among the many proposed immunohistochemical markers, which as a whole are more practical and diagnostically useful than cumbersome and expensive molecular assays, a 2-hit model including thyroid transcription factor-1 (TTF-1) and p40 (the latter more specific for squamous differentiation than p63) seems to be the most effective to basically highlight adenocarcinoma (positivity for TTF-1 regardless of p63) and squamous (always strongly and diffusely positive for p40 or p63 and negative for TTF-1) differentiation. This minimalist 2-hit diagnostic approach paves the way to novel perspectives in clinical trials on lung cancer, and it is also in keeping with the need of strategically preserving diagnostic material for molecular assays that are essential for personalizing therapies. PMID- 23740565 TI - 125 years of liquid crystals--a scientific revolution in the home. PMID- 23740566 TI - Furosemide for transient tachypnoea of the newborn. AB - BACKGROUND: Transient tachypnoea of the newborn (TTN) results from delayed clearance of lung liquid and is a common cause of admission of full term infants to neonatal intensive care units. The condition is particularly common after elective caesarean section. Conventional treatment involves appropriate oxygen administration and continuous positive airway pressure in some cases. Most infants receive antibiotic therapy. Hastening the clearance of lung liquid may shorten the duration of the symptoms and reduce complications. OBJECTIVES: To determine whether furosemide administration reduces the duration of oxygen therapy and respiratory symptoms and shortens hospital stay in term infants with transient tachypnoea of the newborn. SEARCH METHODS: An updated search was carried out in January 2013 of the following databases: The Cochrane Library issue 1, 2013 (CENTRAL, The Cochrane Central Register of Controlled Trials), PubMed, MEDLINE via Ovid, CINAHL via OVID and EMBASE. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials that compared the effect of furosemide administration versus placebo or no treatment in infants of less than seven days of age, born at 37 or more weeks of gestation with the clinical picture of transient tachypnoea of the newborn. DATA COLLECTION AND ANALYSIS: We extracted and analysed data according to the methods outlined in the latest Cochrane Handbook for Systematic Reviews of Interventions. Two review authors assessed trial quality in each potentially eligible manuscript and two review authors extracted data. MAIN RESULTS: Our updated review includes two completed trials. Wiswell 1985 and Karabayir 2006 investigated 100 infants with transient tachypnoea of the newborn. Wiswell 1985 randomised 50 infants to receive either oral furosemide (2 mg/kg body weight at time of diagnosis followed by a 1 mg/kg dose 12 hours later if the tachypnoea persisted) or placebo. Karabayir 2006 randomised 50 infants to receive either intravenous furosemide (2 mg/kg body weight) or an equal volume of normal saline placebo. Neither trial reported on the need for respiratory support. Neither trial demonstrated a statistically significant impact of furosemide on transient tachypnoea of the newborn regarding duration of symptoms or length of hospitalisation. AUTHORS' CONCLUSIONS: Oral or intravenous furosemide cannot be recommended as treatment for transient tachypnoea of the newborn and it should not be used unless additional data become available. This finding suggests that either furosemide is not effective in promoting resorption of lung fluid, or factors other than delayed resorption of this fluid contribute to the pathogenesis of transient tachypnoea of the newborn. The question remains as to whether furosemide given to the infant (or even to the mother before caesarean section) might shorten the duration of the illness. As elective caesarean section continues at a high level, these two interventions might be worthy of trials. PMID- 23740567 TI - Chinese herbal medicine Huangqi type formulations for nephrotic syndrome. AB - BACKGROUND: Patients with primary nephrotic syndrome mostly need immunosuppression to achieve remission, but many of them either relapse after immunosuppression therapy or resistant to it. On the other hand, immunosuppression therapy could increase the adverse effect. Huangqi and Huangqi type formulations have been used to treat nephrotic syndrome for years in China, however the effects and safety of these formulations have not been systematically reviewed. This is an update of a review first published in 2008. OBJECTIVES: To assess the benefits and harms of Huangqi and Huangqi type formulations in treating nephrotic syndrome in any age group, either as sole agents or in addition to other drug therapies. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Chinese Biomedicine Database (CBM), CNKI, VIP and reference lists of articles. There was no language restriction.Date of search: April 2011. SELECTION CRITERIA: All randomised controlled trials (RCTs) assessing the use of Huangqi or Huangqi type formulations in treating nephrotic syndrome in adults and children, either as sole agents or in addition to other drug therapies. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. For dichotomous outcomes results were expressed as relative risk (RR) and 95% confidence intervals (CI). Continuous outcomes were expressed as mean difference (MD) with 95% CI. MAIN RESULTS: Nine studies were identified. One was judged to be at high risk of bias for random sequence, the rest were judged to be at low risk of bias. All studies had high risk of bias for allocation concealment and performance bias; unclear risk for detection bias and low risk for attrition bias. Two studies had unclear risk reporting bias and the rest had low risk. No other potential threats to validity were found. Compared to control interventions, Huangqi type formulations had a positive effect on plasma albumin (MD 6.41 g/dL, 95% Cl 4.24 to 8.59), urine albumin excretion (-0.57 g/24 h, 95% CI -1.04 to -0.10), cholesterol (MD -1.70 mmol/L, 95% Cl -2.60 to -1.13) and triglycerides (-0.33 mmol/L, 95% CI -0.63 to -0.03); and more patients showed improvement at three months (RR 0.41, 95% CI 0.20 to 0.84). There was no significant difference between Huangqi type formulations and control interventions for complete (RR 1.59, 95% CI 0.29 to 8.65) or partial remission (RR 1.22, 95% CI 0.57 to 2.58). While some formulations showed improvement in the number of patients achieving complete or partial remission, the number of studies (usually one per formulation), and the number patients (ranging from 38 to 78) were small. Relapse was reported at varying time points, ranging from three months to three years, and therefore these results were not pooled. Complications of nephrotic syndrome and adverse events were only reported by two studies; Only one study reported complications of nephrotic syndrome (infection) and another reported adverse reactions to treatment (Cushing's syndrome, steroid withdrawal syndrome, respiratory tract infection, and upper gastrointestinal haemorrhage). Both studies reported those treated with Huangqi type formulations had significantly less complications or adverse reactions. AUTHORS' CONCLUSIONS: Huangqi and Huangqi type formulations may have some positive effects in treating nephrotic syndrome by increasing plasma albumin and reducing urine albumin excretion, blood cholesterol and triglycerides, and decreasing the number who don't show improvement at three months. Some formulations showed an increase in the number of patients achieving complete or partial remission, however study and participant numbers were small. PMID- 23740568 TI - Calcium mobilization in HeLa cells induced by nitric oxide. AB - Nitric oxide (NO) has been proposed to be involved in tumor growth and metastasis. However, the mechanism by which nitric oxide modulates cancer cell growth and metastasis on cellular and molecular level is still not fully understood. This work utilized confocal microscopy and fluorescence microplate reader to investigate the effects of exogenous NO on the mobilization of calcium, which is one of the regulators of cell migration, in HeLa cells. The results show that NO elevates calcium in concentration-dependent manner in HeLa cells. And the elevation of calcium induced by NO is due to calcium influx and calcium release from intracellular calcium stores. Moreover, calcium release from intracellular stores is dominant. Furthermore, calcium release from mitochondria is one of the modulation pathways of NO. These findings would contribute to recognizing the significance of NO in cancer cell proliferation and metastasis. PMID- 23740569 TI - Visual outcomes after pituitary surgery. PMID- 23740570 TI - SAR and temperature distribution in the rat head model exposed to electromagnetic field radiation by 900 MHz dipole antenna. AB - Rats are often used in the electromagnetic field (EMF) exposure experiments. In the study for the effect of 900 MHz EMF exposure on learning and memory in SD rats, the specific absorption rate (SAR) and the temperature rise in the rat head are numerically evaluated. The digital anatomical model of a SD rat is reconstructed with the MRI images. Numerical method as finite difference time domain has been applied to assess the SAR and the temperature rise during the exposure. Measurements and simulations are conducted to characterize the net radiated power of the dipole to provide a precise dosimetric result. The whole body average SAR and the localized SAR averaging over 1, 0.5 and 0.05 g mass for different organs/tissues are given. It reveals that during the given exposure experiment setup, no significant temperature rise occurs. The reconstructed anatomical rat model could be used in the EMF simulation and the dosimetric result provides useful information for the biological effect studies. PMID- 23740571 TI - Redox-selective generation of aldehydes and H2 from alcohols under visible light. PMID- 23740572 TI - Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. AB - OBJECTIVE: Pulmonary hypertension (PH) is a frequent and life-limiting complication of systemic sclerosis (SSc). However, data on survival rates and their evolution over time, as well as prognostic factors in SSc complicated by PH, are still conflicting. The aim of this study was to conduct a systematic review and meta-analysis of cohort studies to assess pooled survival and prognostic factors for survival in patients with SSc-associated PH. METHODS: For this systematic review and meta-analysis, we searched the Medline and EMBase databases (January 1960 to January 2012). All cohort studies in which survival and/or prognostic factors for SSc-associated PH were reported were included in the analysis. We calculated the pooled survival rates and analyzed their evolution over time and identified prognostic factors for survival. RESULTS: Twenty-two studies were included, representing a total of 2,244 patients with SSc associated PH. The pooled 1-, 2-, and 3-year survival rates were 81% (95% confidence interval [95% CI] 79-84%), 64% (95% CI 59-69%), and 52% (95% CI 47 58%), respectively. Meta-regression did not reveal a significant change in survival over time, while baseline hemodynamic measures of PH severity were significantly correlated with survival. In patients with SSc complicated by pulmonary arterial hypertension (PAH), age, male sex, diffusing capacity for carbon monoxide (DLCO), pericardial effusion, and the parameters classically associated with the severity of idiopathic PAH, including the 6-minute walk distance, mean pulmonary artery pressure, cardiac index, and right atrial pressure, were significant prognostic factors. DLCO and pericardial effusion were the only prognostic factors in patients with interstitial lung disease-related PH. CONCLUSION: Our meta-analysis revealed a poor pooled 3-year survival rate of 52% in patients with SSc-associated PH. Baseline hemodynamic measures of PAH severity, but not the period of time during which patients were included in the studies, correlated significantly with survival in patients with SSc-associated PAH. All of the prognostic factors typically observed in idiopathic PAH, including the 6-minute walk distance and right atrial pressure, were also prognostic factors in SSc-associated PAH. PMID- 23740573 TI - Ca2+/calmodulin-dependent protein kinase II in the cockroach Periplaneta americana: identification of five isoforms and their tissues distribution. AB - Calcium/calmodulin-dependent protein kinase II (CaMKII) is a key kinase that transduces Ca2+ signals into downstream effects acting on a range of cellular processes in nervous system and muscular tissues. In insects, different CaMKII isoforms have been reported in Drosophila melanogaster, Apis florae, Bombus terrestris, and Bombus impatiens but little is known on the organization and tissue-specific expression of these isoforms with the exception of Drosophila. The present study reports the cloning of five CaMKII splice variants issued from a single gene and their tissue-specific expression in the cockroach Periplaneta americana. Each CaMKII isoform shared 82-90% identity with Drosophila CaMKII isoforms and accordingly were named PaCaMKII-A, PaCaMKII-B,PaCaMKII-C,PaCaMKII-D, and PaCaMKII-E. PaCaMKII-A and PaCaMKII-D isoforms are ubiquitously expressed in all tissues, but some such as PaCaMKII-B andPaCaMKII-C are preferentially expressed in the nerve cord and muscle. In addition, using single-cell reverse transcriptase-polymerase chain reaction (RT-PCR), we found a tissue-specific expression of PaCaMKII-E in the dorsal unpaired median neurons. Alternative splicing of PaCaMKII transcripts is likely a common mechanism in insects to control the pattern of isoform expression in the different tissues. PMID- 23740574 TI - Functional screening of enzymes and bacteria for the dechlorination of hexachlorocyclohexane by a high-throughput colorimetric assay. AB - Two distinct microbial dehalogenases are involved in the first steps of degradation of hexachlorocyclohexane (HCH) isomers. The enzymes, LinA and LinB, catalyze dehydrochlorination and dechlorination reactions of HCH respectively, each with distinct isomer specificities. The two enzymes hold great promise for use in the bioremediation of HCH residues in contaminated soils, although their kinetics and isomer specificities are currently limiting. Here we report the functional screening of a library of 700 LinA and LinB clones generated from soil DNA for improved dechlorination activity by means of a high throughput colorimetric assay. The assay relies upon visual colour change of phenol red in an aqueous medium, due to the pH drop associated with the dechlorination reactions. The assay is performed in a microplate format using intact cells, making it quick and simple to perform and it has high sensitivity, dynamic range and reproducibility. The method has been validated with quantitative gas chromatographic analysis of promising clones, revealing some novel variants of both enzymes with superior HCH degrading activities. Some sphingomonad isolates with potentially superior activities were also identified. PMID- 23740575 TI - Hypoxia-induced invadopodia formation: a role for beta-PIX. AB - During tumour progression, oxygen tension in the microenvironment surrounding tumour cells is reduced, resulting in hypoxia. It is well established that cancer cells resist the negative effects of hypoxia by inducing angiogenesis predominantly via the activity of transcription factor hypoxia-inducible factor-1 (HIF-1). However, more recently HIF-1alpha has also been linked to increased invasive potential, although the molecular mechanisms remain to be defined. Invasive cancer cells are thought to employ membrane protrusions, termed invadopodia, to achieve matrix degradation. While many invadopodia components have been identified, signalling pathways that link extracellular stimuli to invadopodia formation remain largely unknown. Indeed, the relationship between invadopodia formation and HIF-1alpha has not been explored. We now report that HIF-1alpha is a driver of invadopodia formation. Furthermore, we have identified an important, direct and novel link between the Rho family activator beta-PIX, HIF-1alpha and invadopodia formation. Indeed, we find that beta-PIX expression is essential for invadopodia formation. In conclusion, we identify a new HIF-1alpha mechanistic pathway and suggest that beta-PIX is a novel downstream signalling mediator during invadopodia formation. PMID- 23740576 TI - Identification of the YfgF MASE1 domain as a modulator of bacterial responses to aspartate. AB - Complex 3'-5'-cyclic diguanylic acid (c-di-GMP) responsive regulatory networks that are modulated by the action of multiple diguanylate cyclases (DGC; GGDEF domain proteins) and phosphodiesterases (PDE; EAL domain proteins) have evolved in many bacteria. YfgF proteins possess a membrane-anchoring domain (MASE1), a catalytically inactive GGDEF domain and a catalytically active EAL domain. Here, sustained expression of the Salmonella enterica spp. Enterica ser. Enteritidis YfgF protein is shown to mediate inhibition of the formation of the aspartate chemotactic ring on motility agar under aerobic conditions. This phenomenon was c di-GMP-independent because it occurred in a Salmonella strain that lacked the ability to synthesize c-di-GMP and also when PDE activity was abolished by site directed mutagenesis of the EAL domain. YfgF-mediated inhibition of aspartate chemotactic ring formation was impaired in the altered redox environment generated by exogenous p-benzoquinone. This ability of YfgF to inhibit the response to aspartate required a motif, (213)Lys-Lys-Glu(215), in the predicted cytoplasmic loop between trans-membrane regions 5 and 6 of the MASE1 domain. Thus, for the first time the function of a MASE1 domain as a redox-responsive regulator of bacterial responses to aspartate has been shown. PMID- 23740577 TI - Mass spectrometry study and infrared spectroscopy of the complex between camphor and the two enantiomers of protonated alanine: the role of higher-energy conformers in the enantioselectivity of the dissociation rate constants. AB - The properties of the protonated complexes built from S camphor and R or S alanine were studied in a Paul ion trap at room temperature by collision-induced dissociation (CID) and infrared multiple-photon dissociation spectroscopy (IRMPD), as well as molecular dynamics and ab initio calculations. While the two diastereomer complexes display very similar vibrational spectra in the fingerprint region, in line with similar structures, and almost identical calculated binding energies, their collision-induced dissociation rates are different. Comparison of the IRMPD results to computed spectra shows that the SS and SR complexes both contain protonated alanine strongly hydrogen-bonded to the keto group of camphor. The floppiness of this structure around the NH+...O=C hydrogen bond results in a complex potential energy surface showing multiple minima. Calculating the dissociation rate constant within the frame of the transition state theory shows that the fragmentation rate larger for the heterochiral SR complex than the homochiral SS complex can be explained in terms of two almost isoenergetic low-energy conformers in the latter that are not present for the former. PMID- 23740580 TI - Step adjustments among young and elderly when walking toward a raised surface. AB - BACKGROUND: Falls among the elderly are often associated with walking on uneven ground. Obstacle negotiation requires both postural reaction strategies and anticipatory strategies which may be impaired with age. Anticipatory strategies are necessary in many daily living situations such as crossing the street and negotiating a kerb. The aim of this study was to evaluate whether elderly and young people use different step adjustment strategies during the approach to a raised surface. METHODS: Eleven community-dwelling elderly adults and 14 young adults participated in the study. Characteristics in the gait pattern leading to the negotiation of a raised surface were examined by the use of an electronic gait mat in a laboratory setting. RESULTS: Both groups changed their gait pattern to adjust the placement of the last step leading to negotiation of the obstacle. The young participants had a tendency to gradually increase their step velocity and step length while the elderly participants slowed their velocity and shortened their step length. Major step length adjustments began four steps prior to ascending the platform among the young participants, but one step later among the elderly. CONCLUSION: Elderly people use more cautious anticipatory strategies. These strategies allow more time for postural adjustments, but they also result in a loss of forward momentum which may influence the negotiation of a raised surface negatively. PMID- 23740581 TI - Aging and airway inflammation. AB - BACKGROUND: Since little is known of airways inflammation in the elderly, we have carried out a study to explore the presence of some inflammatory markers in the airways of healthy subjects of different ages using a non-invasive method which is particularly suitable for aged people. OBJECTIVE: The aim of this work was to investigate whether parameters, including (1) pH, IL-8 and TNF-alpha in exhaled breath condensate (EBC), (2) exhaled nitric oxide levels (NO), and (3) inflammatory cell profile in induced sputum, are age-related. MATERIALS AND METHODS: Thirty healthy adults (10 subjects below the age of 30 [A], 10 subjects between 30 and 60 years [B], and 10 subjects over 60 years of age [C]), were enrolled in the study. IL-8 and TNF-alpha levels were measured in breath condensate. Exhaled pH was measured after deaeration/decarbonation by means of a pH-meter. A rapid-response chemiluminescence NO analyzer was used to quantify NO. Induced sputum was collected, homogenized with dithiothreitol, and cytospins for differential cell were produced. RESULTS: The levels of IL-8 and TNF-alpha in EBC, the levels of exhaled NO, and the percentage of neutrophils in induced sputum were significantly elevated in C and B compared with A; the EBC pH level was significantly reduced in C and B compared with A. The EBC levels of IL-8, TNF alpha, pH, the level of exhaled NO, and the percentage of neutrophils correlated significantly with age. CONCLUSION: This study has shown the presence of age related airways inflammation in healthy subjects. PMID- 23740582 TI - The influence of chair seat height on the performance of community-dwelling older adults' 30-second chair stand test. AB - BACKGROUND AND AIMS: Although chair seat height affects the performance of sit-to stand movement, no previous study has examined the influence of chair seat height on the 30-second chair stand test (CST). METHODS: Fifty-five community-dwelling older adults (age 70.0 +/- 6.3 years) performed the test from the standard height of 43 cm and then from five randomly ordered seat heights from 80 to 120 % of each participant's lower leg length. RESULTS: Chair seat height significantly influences the performance of community-dwelling older adults' 30-s CST (F = 57.50, p < 0.001). The mean score for standard conditions was significantly lower from those at 120, 110, and 100 % conditions (p < 0.05). No significant difference was observed between the standard and 80 % conditions (p > 0.95) and between the standard and 90 % conditions (p = 0.353). When comparing the scores between the randomly ordered chair seat heights, all comparisons were significantly different (p < 0.001) except for the difference between the 120 and 110 % conditions (p = 0.104). CONCLUSION: Chair seat height's relation to the lower leg length should be considered when interpreting 30-s CST scores. Additionally, it is necessary to optimize the chair seat height when using the 30 s CST as an outcome measure for exercise intervention or to screen for people with weaker lower extremities. PMID- 23740583 TI - A novel infrared laser device that measures multilateral parameters of stepping performance for assessment of fall risk in elderly individuals [corrected]. AB - BACKGROUND AND AIMS: Avoiding falls requires fast and appropriate step responses in real-life situations. We developed a step-tracking device that uses an infrared laser sensor for convenient assessment of stepping performance, including concurrent assessment of temporal and spatial parameters. In the present study, we created a new index for assessment of fall risk that uses step speed and accuracy measurements. The purpose of this study was to determine whether the new index could discriminate between elderly individuals with different risks of falling. METHODS: One hundred and fifty-two community-dwelling elderly individuals (73.9 +/- 4.6 years) participated and performed stepping tasks as quickly as possible on a plus-shaped mat in response to optical cues. The step-tracking device with the infrared sensor detected the motion and position of both legs in the step field. The device recorded temporal and spatial parameters, foot-off and foot-contact time, step length, and the percentage of correctly executed steps. We used the coefficients of a logistic regression model to develop "stepping-response score" based on the weighted sum of these temporal and spatial parameters. RESULTS: The faller group had significantly worse stepping-response score than the non-faller group (p < 0.001). A stepwise logistic regression analysis demonstrated that stepping-response score was independently associated with falling (odds ratio = 0.15; p < 0.001). The ROC curve had a moderate AUC (0.73) for stepping-response score (sensitivity 73.0 %; specificity 69.7 %). CONCLUSIONS: This study indicates that the stepping-response score calculated from measurements obtained using the new step-tracking device can identify elderly individuals who are at a risk of falling. PMID- 23740584 TI - Endothelial dysfunction associated with mild cognitive impairment in elderly population. AB - BACKGROUND AND AIMS: According to the original Petersen criteria, we investigated the association between endothelial dysfunction and mild cognitive impairment (MCI) by flow-mediated dilation (FMD). We aimed to verify if endothelial dysfunction occurs in MCI and whether vascular factors are implicated in the MCI pathogenesis. METHODS: This is a cross-sectional study performed on 34 subjects with clinical diagnosis of MCI and 37 controls, older than 60 years. Patients were enrolled from a geriatric outpatient clinic. All the recognized cardiovascular risk factors and an objective state of cognitive impairment were used as exclusion criteria. Cognitive function was evaluated using a scientific validated neuropsychological battery, whereas MCI was recognized according to the Petersen criteria. Endothelial function was evaluated according to FMD from the brachial artery. The association between FMD and MCI was evaluated both by using a multivariate analysis and a correlation test. Finally, using the ANOVA analysis of variance, we tested the differences in flow-mediated dilation among MCI subgroups. RESULTS: Brachial FMD was significantly associated with MCI (p < 0.01). The multivariate analysis showed that age, years of education and MMSE independently predicted the FMD variation (r (2) = 0.73; p < 0.0001). In addition, MCI patients with prevalent amnestic multiple domain impairment showed the worst brachial FMD. CONCLUSIONS: This finding suggests that vascular dysfunction may play a role in the pathogenesis of cognitive impairment and underlines the lack of therapeutic strategies targeted to such dysfunctions. PMID- 23740585 TI - Executive function moderates the role of muscular fitness in determining functional mobility in older adults. AB - BACKGROUND AND AIMS: Both physical and cognitive factors are known to independently predict functional mobility in older people. However, the combined predictive value of both physical fitness and cognitive factors on functional mobility has been less investigated. The aim of the present study was to assess if cognitive executive functions moderate the role of physical fitness in determining functional mobility of older individuals. METHODS: Fifty-seven 65- to 75-year-old healthy participants performed tests of functional mobility (habitual and maximal walking speed, maximal walking speed while picking up objects/stepping over obstacles), physical fitness (peak power, knee extensors torque, back/lower limb flexibility, aerobic fitness), and executive function (inhibition and cognitive flexibility). RESULTS: Maximal walking speeds were predicted by physical fitness parameters and their interaction with cognitive factors. Knee extensor torque emerged as the main predictor of all tested locomotor performances at maximal speed. The effect of peak power and back/lower limb flexibility was moderated by executive functions. In particular, inhibition and cognitive flexibility differed in the way in which they moderate the role of fitness. High levels of cognitive flexibility seem necessary to take advantage of leg power for walking at maximal speed. In contrast, high levels of inhibitory capacity seem to compensate for low levels of back/lower limb flexibility when picking up movements are added to a locomotor task. CONCLUSIONS: These findings may have important practical implications for the design and implementation of multi-component training programs aimed at optimizing functional abilities in older adults. PMID- 23740586 TI - Alterations in the telomere length distribution and the subtelomeric methylation status in human vascular endothelial cells under elevated temperature in culture condition. AB - Temperature-associated alteration in the telomere lengths of vascular endothelial cells has not been well investigated. Telomere length of human umbilical vein endothelial cells (HUVECs) cultured at a high temperature (42 degrees C) was analyzed. Here described are heat-associated phenotypical alterations of human vascular endothelial cell under prolonged heat stress in terms of telomere length, telomerase activity, and the expression of telomere associated proteins and heat shock proteins. The genomic DNA extracted from HUVECs cultured for 3 days under 42 degrees C was digested with methylation-sensitive and -insensitive isoschizomers and was subjected to genomic Southern blot probed with a telomere DNA fragment. Their telomere lengths and telomere length distributions were analyzed. Telomerase activity and the expressions of telomere-associated RNA, telomere-associated proteins (TERC, TERT, TRF1, and TRF2), and heat shock proteins (Hsp60, Hsp70, and Hsp90) were also analyzed. At 42 degrees C, cell growth was suppressed and the cell senescence rate was transiently elevated. A proportional decrease in the number of long telomeres was observed transiently at 42 degrees C. A trend of subtelomeric hypomethylation and lowered telomerase activity were observed at 42 degrees C after 3-day culture. The altered phenotypes on day 1 seemed reactive responses for cell protection to heat, and those on day 3 seemed exhausted reactions after 3-day culture. Maintained expression was observed in Hsps, TRF2, and TERC. These altered phenotypes might contribute to cell-survival under prolonged heat stress. PMID- 23740587 TI - Association between dual task-related decrease in walking speed and real versus imagined Timed Up and Go test performance. AB - BACKGROUND AND AIMS: To examine whether older people with markedly dual task related decreases in walking speed - a marker of disturbed higher-level gait control and falls - have a larger discrepancy between real and imagined Timed Up and Go (TUG) test times than those with less dual task-related decreases in walking speed. METHODS: Based on a prospective cross-sectional study, 193 older adults (mean age 77.4 +/- 5.9 years; 44.0 % women) referred to and consecutively assessed at a Swiss university clinic for a gait analysis to assess either gait disorders, fall risk or memory disorders were included. For all participants, walking speed was measured using a GAITRite((r)) electronic walkway system during usual walking at self-selected pace and while dual tasking (i.e., usual walking and simultaneously counting backwards out loud). In addition, real Timed Up and Go (TUGr) and imagined Timed Up and Go (TUGi) (i.e., the time needed to imagine performing the TUGr) times were measured with a stopwatch. Differences between both walking conditions for walking speed (delta of walking speed) and both TUG conditions (delta of TUG time) were calculated. Age, gender, height, total number drugs taken per day, daily use of psychoactive drugs, use of walking aid, history of falls, Mini-Mental State Examination score, near vision and education level were used as covariables in this analysis. RESULTS: Participants were categorized into two groups based on being in the lowest tertian (i.e., <33 %: group A corresponding to participants undisturbed by dual task) or not (i.e., >=33 %: group B corresponding to participants disturbed by dual task) of the delta of walking speed. In both groups, TUGr and TUGi times were similar (P = .169 and P = .839). In both groups, TUGi was faster than TUGr (P < .001). Delta of TUG time was significantly greater in group B compared to group A (P < .001). After adjustment for all covariables, only the delta of walking speed was significantly associated with the delta of TUG time (P = <.001). Stepwise backward regression showed that polypharmacy (P = .017) and delta of walking speed (P = <.001) were associated with an increase in delta of TUG time, whereas an increased MMSE score (P = .030) was associated with a decrease in delta of TUG time. CONCLUSION: These findings show that a large discrepancy between real and imagined TUG performances is significantly correlated with a decrease in walking speed while dual tasking, and thus may also be a surrogate marker of disturbed higher-level gait control. The quickly and easily performed TUG tests may represent a feasible, practical screening tool for early detection of higher-level gait disorders in older adults. PMID- 23740588 TI - Intermediate care as a means of improving mental status in post-acute elderly patients. AB - AIM OF THE STUDY: To evaluate the impact of residential intermediate care (IC) on the cognitive status of post-acute older patients and its correlation with the improvement in physical independence. METHODS: This prospective observational study involved 299 subjects (116 males and 183 females; mean age 80.1 +/- 8.3 years) transferred to IC. The Mini Mental State Examination (MMSE) and a panel of laboratory and functional parameters were evaluated upon admission to IC (T0) and at the time of discharge (T1). The functional evaluations included the Cumulative Illness Rating Scale, the Barthel Index (BI) and the Morse Fall Scale (MFS). Afterwards, the patients were grouped on the basis of their MMSE score at T1: those with an unchanged or worse MMSE score (group A) and those with a better MMSE score (group B). The laboratory and functional parameters of the two groups were then compared. RESULTS: There was a significant improvement between T0 and T1 in the MMSE score (18.1 +/- 7.5 vs 19.6 +/- 7.3, P < 0.001) and the BI (42.1 +/- 27.7 vs 53.6 +/- 30.0, P < 0.001), as well as brain natriuretic peptide, C reactive protein and blood glucose levels. Group B had a significantly better BI (57.7 +/- 29.1 vs 47.2 +/- 31.5, P = 0.003) and a slightly better MFS. There was a close relation between the MMSE scores and BI. CONCLUSIONS: Residential IC is a type of rehabilitation that favourably affects the cognitive status and physical independence of older post-acute patients. PMID- 23740589 TI - The effect of functional circuit training on self-reported fear of falling and health status in a group of physically frail older individuals: a randomized controlled trial. AB - BACKGROUND AND AIM: Physical frailty has been regarded as a precursor state to disability and dependence on others for daily activities. Frail individuals are considered to be the group of patients that presents the most complex and challenging problems to health care professionals. The purpose of this study was to evaluate whether a 12-week functional circuit training program (FCT) could reduce self-reported fear of falling and improve health status in a group of physically frail community-dwelling older individuals. METHODS: Fifty-one individuals (31 F, 20 M), mean age (SD) 84 (2.9) years old, were considered frail and tested at week 0 and randomly assigned into two groups (intervention group, FCT = 26; control group, CG = 25). FCT underwent a structured 12-week FCT program, which focused on a combination of functional balance and lower-body strength-based exercises. CG met once a week for health education meetings. Measures of self-reported fear of falling (Activities-specific Balance Confidence scale) and health status (SF-12) were assessed at week 0, 12 and 36. All longitudinal analyses for continuous variables that were measured at the three time points (week 0, 12 and 36) were performed using linear mixed modeling. RESULTS: FCT participants had greater improvements than those in the CG in fear of falling and self-reported physical function, physical composite score and mental composite score; these improvements were maintained in the week 36 follow up, with significant group-by-time interactions by the end of the study. CONCLUSIONS: These data indicate that a FCT program is effective in improving self-reported measures of fear of falling and health status in a group of physically frail individuals. PMID- 23740590 TI - Testosterone effect on brain metabolism in elderly patients with Alzheimer's disease: comparing two cases at different disease stages. AB - OBJECTIVE: To describe the effect of testosterone replacement therapy (TRT) on the brain activity of two demented, hypogonadal male patients with early and late stage Alzheimer's disease (AD), respectively. METHODS: We describe the clinical and positron emission tomography (PET) findings for two individuals, one with early stage and the other with late-stage Alzheimer's disease, before and after treatment with a topical testosterone gel. Both patients were hypogonadal at baseline. We assessed cerebral glucose metabolism (CGM) via (18)F fluorodeoxyglucose (FDG)-positron emission tomography (PET). We investigated whether there are testosterone-susceptible areas within cerebral structures in patients with Alzheimer's disease. RESULTS: Under testosterone replacement therapy, changes in cerebral glucose metabolism were observed in both patients. Improvement in glucose uptake was observed most consistently in the parietal lobe and brainstem; decreased glucose metabolism was observed in the temporal lobe, the limbic system and the insula for these two subjects. DISCUSSION: These case reports demonstrate the potential for PET scanning to detect changes in cerebral glucose metabolism in hypogonadal men with Alzheimer's disease who are treated with testosterone. Further study will be needed to investigate the consistency and significance of these changes in terms of magnitude and brain region, and the correlation with functional changes. PMID- 23740591 TI - Aspects of housing and perceived health among ADL independent and ADL dependent groups of older people in three national samples. AB - AIMS: Good housing solutions are important for the ageing population in order to promote health and maintain functional ability. The objective of this study was to investigate whether and how objective and perceived aspects of housing were related to perceived health among ADL independent and ADL dependent groups of older, single-living people within three national samples. METHODS: The current study was based on national samples (German, n = 450; Latvian, n = 303; Swedish, n = 397) from the European ENABLE-AGE Project, using data on ADL dependence, perceived health, objective and perceived aspects of housing. Descriptive statistics, correlations and multivariate ordinal regression models were used to analyze the data. RESULTS: The participants in the ADL dependent groups generally were older, had more functional limitations and perceived their health as poorer compared to ADL independent groups. With regard to perceived housing, usability as well as meaning of home indicators was often lower in the ADL dependent groups, housing satisfaction was at the same level while housing-related external control beliefs were higher. The differences among the national samples were highly significant for both ADL groups, for all variables except number of outdoor environmental barriers in the ADL independent groups. The relations between perceived health on one hand and objective and perceived aspects of housing on the other show great diversities among the ADL groups and the national samples. CONCLUSIONS: The results serve to alert health care practitioners that it is important to draw attention to how older people perceive their housing situation and to the fact that different levels of functional independence demand different interventions. PMID- 23740592 TI - Health behavior of hypertensive elderly patients and influencing factors. AB - AIM: This study aimed to investigate the factors associated with the health behavior of hypertensive elderly patients. METHODS: This cross-sectional survey used a general data scale, a health conception scale, a scale for self-rated abilities for health practice, and health-promoting lifestyle profiles to investigate the health behavior of hypertensive elderly patients from clinical check-up to hospitalization. RESULTS: The health behavior score of hypertensive patients was 72.25 +/- 16.66, and 23.8 % of the patients had high scores. The health-promotion score was positively correlated with those of health conception, self-efficacy, and education level, but negatively correlated with that of unhealthy habits (P < 0.05). CONCLUSIONS: Health practitioners should promote the health conception, enhance the self-efficacy, and improve the health behavior of hypertensive elderly patients. PMID- 23740593 TI - Behavioral correlates of depressive symptoms in older unlike-sex twin pairs. AB - BACKGROUND AND AIMS: This study examines gender-specific behavioral correlates of depressive symptoms using a secondary data analysis of a cross-sectional, population-based sample of older unlike-sex twins. METHODS: Unlike-sex twins aged 69-88 were identified through a national Swedish registry and sent a survey about health, including depressive symptoms (CES-D) and the frequency of engaging in physical, social and mental activities. A total of 605 complete twin pairs responded. RESULTS: Depressive symptom scores were associated with frequency of engagement in physical and mental activities, but only in men. No statistically significant associations with depressive symptom scores for any of the three types of activities were found in women. CONCLUSIONS: The results suggest that engaging in physical and mental activities may protect older men from developing depressive symptoms, but longitudinal data are needed to offer more conclusive findings on the role that physical, mental, and social activities play in the maintenance of psychological health in older men and women. PMID- 23740594 TI - Chronic myelomonocytic leukemia presenting as relapsing thrombotic thrombocytopenic purpura. AB - A 67-year-old woman presented with fever, purpura, and confusion. A preliminary diagnosis of thrombotic thrombocytopenic purpura (TTP) was made on the basis of clinical presentation and lab findings, such as reduced platelet count, increased bilirubin, and so on. She was treated with therapeutic plasma exchange (TPE) and methylprednisolone. During the treatment, peripheral blood monocytosis (monocyte 4 * 10(9)/L) was noticed. The monocytes were CD56 positive. A putative diagnosis of chronic myelomonocytic leukemia (CMML) was proposed. Three months later, the diagnosis of CMML was established on the basis of persistent monocytosis. All other potential causes were considered (e.g., quinine exposure, diarrhea) and excluded. This case highlights the needs to consider hematological malignancy such as CMML in patients with TTP. PMID- 23740595 TI - Prevalence of metabolic syndrome in cognitive impairment: the possible role of malnutrition. PMID- 23740597 TI - Sex- and age-dependent activity of glutathione peroxidase in reproductive organs in pre- and post-pubertal cattle in relation to total antioxidant capacity. AB - Antioxidative/oxidative balance is crucial for proper functioning of cells and tissues. It is suggested that this balance can be partly controlled by sex steroid hormones and in consequence can exhibit age- and sex-related dependency. The aim of present study was to describe sex- and age-related changes in the activity of glutathione peroxidase (GSH-Px) with respect to total antioxidant activity (TAC) in reproductive organs of cattle. Biological samples were collected from slaughterhouse and comprised of ovaries, uterus, testes as well as livers as reference tissue. Animals were divided into group of bulls (aged between 13 and 24 months; n = 12), cows (aged between 14 and 27 months; n = 12) and female calves (aged between 2 weeks and 2 months; n = 12). Examined parameters were determined spectrophotometrically and the presence of GSH-Px isoform was confirmed by Western blotting technique. Activity of GSH-Px in genital tissues regardless of sex was significantly higher than in livers, while TAC showed opposite relationship. The differences in antioxidative parameters between testes and mature ovaries (e.g. GSH-Px-1.42 +/- 0.47 nkat/mg prot vs. 1.08 +/- 0.24 and 1.15 +/- 0.23) were noticed as well as in chosen values between cows and female calves. Western blotting allowed the detection of cytosolic GSH Px in all examined tissues with molecular weight around 21 kDa as monomer and around 84 kDa as tetramer depending on conditions of electrophoresis. The results may confirm the influence and regulatory role of sex steroid hormones on GSH-Px activity because the alterations were sex and age dependent. PMID- 23740598 TI - Parathyroid hormone is significantly associated with body fat compartment in men but not in women following a hip fracture. AB - BACKGROUND AND AIMS: Parathyroid hormone (PTH) exerts several actions beyond mineral metabolism and may affect body composition. The aim of our study was to assess the association between serum PTH and body fat compartment in hip fracture patients. METHODS: We studied 575 of 630 inpatients with hip fracture consecutively admitted to our Rehabilitation ward. Dual-energy X-ray absorptiometry (DXA) was used to measure body composition. DXA scan was performed 18.5 +/- 8.6 (mean +/- SD) days after hip fracture occurrence. A blood sample was collected within 4 days after DXA scan. In each subject, we evaluated PTH, 25 hydroxyvitamin D, calcium, phosphate, albumin, magnesium, and creatinine. Glomerular filtration rate was estimated by a conventional formula. RESULTS: In the 57 men, we found a significant correlation between PTH and both body mass index (BMI) (rho = 0.37; p = 0.020) and trunk fat percentage (rho = 0.62; p < 0.001). After multiple adjustments, we confirmed a significant association between PTH and BMI (r = 0.38; p = 0.004) or trunk fat percentage (r = 0.51; p < 0.001). In the 518 women, we found a slightly significant correlation between PTH and BMI (rho = 0.09; p = 0.047), but after adjustments the correlation coefficient dropped to 0.02 (p = 0.69). We found no significant relationships between PTH and trunk fat percentage at bivariate correlation (rho = 0.04; p = 0.35) or after adjustments (r = 0.04; p = 0.38). CONCLUSIONS: PTH serum levels were robustly associated with body fat compartment in men, but not in women following a fracture of the hip. A role of PTH in affecting body composition in hip fracture men is suggested. Its potential role in male prognostic disadvantage needs further investigation. PMID- 23740599 TI - Prevalence of cardiovascular disorders and risk factors in two 75-year-old birth cohorts examined in 1976-1977 and 2005-2006. AB - BACKGROUND AND AIMS: The number of older people are increasing worldwide, and cardiovascular diseases are the major causes of death in western societies. This study examines birth cohort differences in cardiovascular disorders and risk factors in Swedish elderly. METHODS: Representative samples of 75-year-olds living in Gothenburg, Sweden, examined in 1976-1977 and in 2005-2006. Blood pressure, s-cholesterol, s-triglycerides, height, body weight, body mass index, history of myocardial infarction, angina pectoris and stroke/TIA, and diabetes mellitus were measured. RESULTS: The prevalence of total cardiovascular disorders, hypertension and hypercholesterolemia decreased, and the prevalence of stroke increased in both genders. The prevalence of cardiovascular disorders was higher in women than in men in 1976-1977, and higher in men than in women in 2005 2006. The decrease in blood pressure occurred independently of antihypertensive treatment. The prevalence of current smokers decreased in men and increased in women. The prevalence of life-time smokers and diabetes mellitus increased only in women. The proportion on antihypertensive treatment and overweight and obesity increased only in men. Hypertension, overweight and obesity were more common in women in 1976-1977. These sex differences were not observed in 2005-2006. CONCLUSIONS: The overall prevalence of cardiovascular disorders decreased, and sex differences reversed between the 1970s and 2000s among Swedish septuagenarians. Our findings emphasize the importance of environmental factors, not only for the prevalence of cardiovascular disorders, but also as explanations for sex differences. Reasons for changes could be increased survival in those with disorders and risk factors, changes in lifestyle and diet, and better preventive strategies, such as treatment of hypercholesterolemia and hypertension. PMID- 23740600 TI - Establishment and serial passage of cell cultures derived from LuCaP xenografts. AB - BACKGROUND: LuCaP serially transplantable xenografts derived from primary and metastatic human prostate cancer encompass the molecular and cellular heterogeneity of the disease and are an invaluable resource for in vivo preclinical studies. A limitation of this model, however, has been the inability to establish and passage cell cultures derived from the xenografts. Here, we describe a novel spheroid culture system that supports long-term growth of LuCaP cells in vitro. METHODS: Xenografts were minced and digested with collagenase. Tissue dissociation was terminated while the majority of cells remained as clusters rather than single cells. The cell clusters were suspended in StemPro medium supplemented with R1881 and Y-27632, a Rho kinase inhibitor, and placed in ultralow attachment dishes for spheroid culture. Serial passage was achieved by partial digestion to small clusters with trypsin/EDTA in the presence of Y-27632. Cell viability, growth and phenotype were monitored with LIVE/DEAD(r), MTS, qRT PCR, and immunocytochemical assays. RESULTS: Cells from six LuCaP xenografts formed proliferating spheroids that were serially passaged a minimum of three times and cryopreserved. Two of the cell lines, LuCaP 136 and LuCaP 147, were further passaged and characterized. Both expressed biomarkers characteristic of the xenografts of origin, were determined to be of independent origin by STR fingerprinting, and were free of mycoplasma. LuCaP 147 formed tumors similar to the original xenograft when injected into mice. CONCLUSIONS: The ability to culture LuCaP cells affords new opportunities for fast, cheap, and efficient preclinical studies and extends the value of the LuCaP xenograft models. PMID- 23740601 TI - Ozone-induced band bending on metal-oxide surfaces studied under environmental conditions. AB - Ozone adsorption and decomposition on metal oxides is of wide interest in technology and in atmospheric chemistry. Here, ozone-adsorption-induced band bending is observed on Ti- and Fe-oxide model surfaces under dry and humid conditions. Photoelectron spectroscopic studies indicate the effect of charge transfer to O3, which limits the surface coverage of the precursor to decomposition reactions. This is also consistent with the negative pressure dependence observed in previous studies. These results contribute to our fundamental understanding of ozone adsorption and decomposition mechanisms on metal oxides of environmental and technological relevance. PMID- 23740603 TI - Endothelin-1-induced endoplasmic reticulum stress in disease. AB - The accumulation of unfolded proteins in the endoplasmic reticulum (ER) represents a cellular stress induced by multiple stimuli and pathologic conditions. Recent evidence implicates endothelin-1 (ET-1) in the induction of placental ER stress in pregnancy disorders. ER stress has previously also been implicated in various other disease states, including neurodegenerative disorders, diabetes, and cardiovascular diseases, as has ET-1 in the pathophysiology of these conditions. However, to date, there has been no investigation of the link between ET-1 and the induction of ER stress in these disease states. Based on recent evidence and mechanistic insight into the role of ET-1 in the induction of placental ER stress, the following review attempts to outline the broader implications of ET-1-induced ER stress, as well as strategies for therapeutic intervention based around ET-1. PMID- 23740602 TI - Survivin inhibitor YM-155 sensitizes tumor necrosis factor- related apoptosis inducing ligand-resistant glioma cells to apoptosis through Mcl-1 downregulation and by engaging the mitochondrial death pathway. AB - Induction of apoptosis by the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising antitumor therapy. However, not all tumor cells are sensitive to TRAIL, highlighting the need for strategies to overcome TRAIL resistance. Inhibitor of apoptosis family member survivin is constitutively activated in various cancers and blocks apoptotic signaling. Recently, we demonstrated that YM-155 [3-(2-methoxyethyl)-2-methyl-4,9-dioxo-1 (pyrazin-2-ylmethyl)-4,9-dihydro-3H-naphtho[2,3-d]imidazol-1-ium bromide], a small molecule inhibitor, downregulates not only survivin in gliomas but also myeloid cell leukemia sequence 1 (Mcl-1), and it upregulates proapoptotic Noxa levels. Because Mcl-1 and survivin are critical mediators of resistance to various anticancer therapies, we questioned whether YM-155 could sensitize resistant glioma cells to TRAIL. To address this hypothesis, we combined YM-155 with TRAIL and examined the effects on cell survival and apoptotic signaling. TRAIL or YM-155 individually induced minimal killing in highly resistant U373 and LNZ308 cell lines, but combining TRAIL with YM-155 triggered a synergistic proapoptotic response, mediated through mitochondrial dysfunction via activation of caspases-8, -9, -7, -3, poly-ADP-ribose polymerase, and Bid. Apoptosis induced by combination treatments was blocked by caspase-8 and pan-caspase inhibitors. In addition, knockdown of Mcl-1 by RNA interference overcame apoptotic resistance to TRAIL. Conversely, silencing Noxa by RNA interference reduced the combined effects of YM-155 and TRAIL on apoptosis. Mechanistically, these findings indicate that YM-155 plays a role in counteracting glioma cell resistance to TRAIL-induced apoptosis by downregulating Mcl-1 and survivin and amplifying mitochondrial signaling through intrinsic and extrinsic apoptotic pathways. The significantly enhanced antitumor activity of the combination of YM-155 and TRAIL may have applications for therapy of malignant glioma. PMID- 23740604 TI - Gene expression analysis in Merkel cell polyomavirus-positive non-small cell lung cancer from Japanese patients. PMID- 23740605 TI - Rehabilitation following carpal tunnel release. AB - BACKGROUND: Various rehabilitation treatments may be offered following carpal tunnel syndrome (CTS) surgery. The effectiveness of these interventions remains unclear. OBJECTIVES: To review the effectiveness of rehabilitation following CTS surgery compared with no treatment, placebo, or another intervention. SEARCH METHODS: On 3 April 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register (3 April 2012), CENTRAL (2012, Issue 3), MEDLINE (January 1966 to March 2012), EMBASE (January 1980 to March 2012), CINAHL Plus (January 1937 to March 2012), AMED (January 1985 to April 2012), LILACS (January 1982 to March 2012), PsycINFO (January 1806 to March 2012), PEDRO (29 January 2013) and clinical trials registers (29 January 2013). SELECTION CRITERIA: Randomised or quasi-randomised clinical trials that compared any postoperative rehabilitation intervention with either no intervention, placebo or another postoperative rehabilitation intervention in individuals who had undergone CTS surgery. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion, extracted data and assessed the risk of bias according to standard Cochrane methodology. MAIN RESULTS: In this review we included 20 trials with a total of 1445 participants. We studied different rehabilitation treatments including: immobilisation using a wrist orthosis, dressings, exercise, controlled cold therapy, ice therapy, multimodal hand rehabilitation, laser therapy, electrical modalities, scar desensitisation, and arnica. Three trials compared a rehabilitation treatment to a placebo comparison; three trials compared rehabilitation to a no treatment control; three trials compared rehabilitation to standard care; and 14 trials compared various rehabilitation treatments to one another.Overall, the included studies were very low in quality. Eleven trials explicitly reported random sequence generation and, of these, three adequately concealed the allocation sequence. Four trials achieved blinding of both participants and outcome assessors. Five studies were at high risk of bias from incompleteness of outcome data at one or more time intervals. Eight trials had a high risk of selective reporting bias.The trials were heterogenous in terms of the treatments provided, the duration of interventions, the nature and timing of outcomes measured and setting. Therefore, we were not able to pool results across trials.Four trials reported our primary outcome, change in self reported functional ability at three months or longer. Of these, three trials provided sufficient outcome data for inclusion in this review. One small high quality trial studied a desensitisation program compared to standard treatment and revealed no statistically significant functional benefit based on the Boston Carpal Tunnel Questionnaire (BCTQ) (MD -0.03; 95% CI -0.39 to 0.33). One moderate quality trial assessed participants six months post surgery using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire and found no significant difference between a no formal therapy group and a two-week course of multimodal therapy commenced at five to seven days post surgery (MD 1.00; 95% CI 4.44 to 6.44). One very low quality quasi-randomised trial found no statistically significant difference in function on the BCTQ at three months post surgery with early immobilisation (plaster wrist orthosis worn until suture removal) compared with a splint and late mobilisation (MD 0.39; 95% CI -0.45 to 1.23).The differences between the treatments for the secondary outcome measures (change in self reported functional ability measured at less than three months; change in CTS symptoms; change in CTS-related impairment measures; presence of iatrogenic symptoms from surgery; return to work or occupation; and change in neurophysiological parameters) were generally small and not statistically significant. Few studies reported adverse events. AUTHORS' CONCLUSIONS: There is limited and, in general, low quality evidence for the benefit of the reviewed interventions. People who have had CTS surgery should be informed about the limited evidence of the effectiveness of postoperative rehabilitation interventions. Until the results of more high quality trials that assess the effectiveness and safety of various rehabilitation treatments have been reported, the decision to provide rehabilitation following CTS surgery should be based on the clinician's expertise, the patient's preferences and the context of the rehabilitation environment. It is important for researchers to identify patients who respond to a certain treatment and those who do not, and to undertake high quality studies that evaluate the severity of iatrogenic symptoms from the surgery, measure function and return-to-work rates, and control for confounding variables. PMID- 23740606 TI - Creatine for treating muscle disorders. AB - BACKGROUND: Progressive muscle weakness is a main symptom of most hereditary and acquired muscle diseases. Creatine improves muscle performance in healthy individuals. This is an update of our 2007 Cochrane review that evaluated creatine treatment in muscle disorders. Previous updates were in 2009 and 2011. OBJECTIVES: To evaluate the efficacy of creatine compared to placebo for the treatment of muscle weakness in muscle diseases. SEARCH METHODS: On 11 September 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2012, Issue 9 in The Cochrane Library), MEDLINE (January 1966 to September 2012) and EMBASE (January 1980 to September 2012) for randomised controlled trials (RCTs) of creatine used to treat muscle diseases. SELECTION CRITERIA: RCTs or quasi-RCTs of creatine treatment compared to placebo in hereditary muscle diseases or idiopathic inflammatory myopathies. DATA COLLECTION AND ANALYSIS: Two authors independently applied the selection criteria, assessed trial quality and extracted data. We obtained missing data from investigators. MAIN RESULTS: A total of 14 trials, including 364 randomised participants, met the selection criteria. The risk of bias was low in most studies. Only one trial had a high risk of selection, performance and detection bias. No new studies were identified at this update.Meta-analysis of six trials in muscular dystrophies including 192 participants revealed a significant increase in muscle strength in the creatine group compared to placebo, with a mean difference of 8.47%; (95% confidence intervals (CI) 3.55 to 13.38). Pooled data of four trials including 115 participants showed that a significantly higher number of participants felt better during creatine treatment compared to placebo with a risk ratio of 4.51 (95% CI 2.33 to 8.74). One trial in 37 participants with idiopathic inflammatory myopathies also showed a significant improvement in functional performance. No trial reported any clinically relevant adverse event.In metabolic myopathies, meta-analyses of three cross-over trials including 33 participants revealed no significant difference in muscle strength. One trial reported a significant deterioration of activities of daily living (mean difference 0.54 on a 1 to 10 scale; 95% CI 0.14 to 0.93) and an increase in muscle pain during high-dose creatine treatment in McArdle disease. AUTHORS' CONCLUSIONS: High quality evidence from RCTs shows that short- and medium-term creatine treatment increases muscle strength in muscular dystrophies. There is also evidence that creatine improves functional performance in muscular dystrophy and idiopathic inflammatory myopathy. Creatine is well tolerated in these people. High quality but limited evidence from RCTs does not show significant improvement in muscle strength in metabolic myopathies. High-dose creatine treatment impaired activities of daily living and increased muscle pain in McArdle disease. PMID- 23740607 TI - Drug therapy for pain in amyotrophic lateral sclerosis or motor neuron disease. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is the most common neurodegenerative disorder of the motor system in adults. Pain in ALS is a frequent symptom especially in the later stages of disease and can have a pronounced influence on quality of life and suffering. Treatment of pain therefore should be recognised as an important aspect of palliative care in ALS. This is an update of a review first published in 2008. OBJECTIVES: To systematically review the evidence for the efficacy of drug therapy in relieving pain in ALS. We also aimed to evaluate possible adverse effects associated with the different drugs and their influence on survival and quality of life. SEARCH METHODS: On 2 July 2012, we searched the following databases: the Cochrane Neuromuscular Disease Group Specialized Register (2 July 2012), CENTRAL (2012, Issue 6 in The Cochrane Library), MEDLINE (January 1966 to June 2012), EMBASE (January 1980 to June 2012), CINAHL (January 1982 to June 2012), AMED (January 1985 to June 2012) and LILACS (January 1982 to June 2012). We checked the bibliographies of trials identified and contacted other disease experts to identify further published and unpublished trials. SELECTION CRITERIA: We searched for randomised or quasi-randomised controlled trials on drug therapy for pain in amyotrophic lateral sclerosis. DATA COLLECTION AND ANALYSIS: We collected data using a specially designed form and analysed them using the Cochrane Review Manager software. MAIN RESULTS: We found no randomised or quasi randomised controlled trials on drug therapy for pain in ALS or MND. AUTHORS' CONCLUSIONS: There is no evidence from randomised controlled trials about the management of pain in ALS. Further research on this important aspect of palliative care in ALS is needed. Randomised controlled trials should be initiated to determine the effectiveness of different analgesics for treatment of pain in ALS. PMID- 23740608 TI - Abacavir-based triple nucleoside regimens for maintenance therapy in patients with HIV. AB - BACKGROUND: Regimen simplification can be defined as a change in established effective therapy to reduce pill burden and dosing frequency, to enhance tolerability, or to decrease specific food and fluid requirements. Many patients on suppressive antiretroviral therapy may be considered candidates for a simplification strategy and, among them, those who have achieved virologic suppression. Several clinical trials have evaluated the efficacy of triple nucleoside combination as a simplification therapy in patients who achieved virologic suppression OBJECTIVES: The aim of this review is to combine randomised, controlled trials to examine whether in patients with undetectable viraemia on a Protease inhibitor (PI) based regimen simplification treatment with abacavir (ABC)-based triple-nucleoside combinations has similar rates of efficacy and tolerability compared with a PI regimen or simplification with a NNRTIs (efavirenz-EFV- or nevirapine-NVP) containing regimen. Studies were included if they had at least two of the three interventions, including one 3NRTI arm. SEARCH METHODS: Electronic databases and conference proceedings were searched (1996 2012) with relevant search terms without limits to language. SELECTION CRITERIA: Randomised controlled trials (RCTs) only are included in this review. Patients population is represented by HIV-infected adult patients treated with a PI containing regimen (PI or boosted PI), with undetectable viral load. Patients on a PI-containing regimen had three possibilities: continue the PI regimen or switch to a simplification maintenance regimen, including switch to a NNRTI (EFV or NVP) containing regimen, or switch to a triple-NRTI regimen (ABC-zidovudine lamivudine) DATA COLLECTION AND ANALYSIS: The primary outcomes were: proportion of patients discontinuing or switching antiretroviral therapy due to virologic failure or to adverse events; death (all cause) and AIDS defining illness; occurrence of myocardial infarction and cardiovascular disease. Secondary outcomes were: proportion of patients maintaining an undetectable viral load (e.g. HIV-RNA <50 or <400 copies/mm(3)); change in mean CD4+ cell count; occurrence of lipodystrophy. We applied Cochrane Collaboration tools to assess each individual study for risk for bias. MAIN RESULTS: We included eight RCT, for a total of 1,610 patients. All the studies included HIV-1 infected patients virologically suppressed after a successful treatment with PI containing ART. Articles included in the analysis were published between 2001 and 2010, and could be classified as low risk of bias trials in most of the domains considered. Overall, there was no significant difference between the participants on triple nucleoside combination and controls, either PI-based or NNRTI based in terms of overall failures, death and AIDS related events, and rates of patients with viral load below the detectability cut-off. For the outcomes discontinuation for adverse events and virologic failures, the RRs were not significant , albeit being not far from the alpha level of 0.05, thus suggesting a weak evidence of lower incidence of side effects and an higher incidence of virologic failure in the 3NRTI group compared to controls . Change in lipids and in CD4 cells from baselines were reported in 7 studies, but inconsistency in reporting these data did not allow quantitative analysis. However, all agreed that simplification with ABC had a favourable and significant impact on lipid metabolism compared to control group. An increase in CD4 cells count from baseline was evident in all analysed studies, without significant differences between ABC and controls in individual studies. AUTHORS' CONCLUSIONS: The strategy of switching to triple nucleoside regimens shows weak evidence of lower incidence of side effects and a higher incidence of virologic failure in the 3NRTI group compared to controls. Simplification with 3NRTI holds the advantages of preserving other classes of antiretroviral drugs, to lower blood lipids, and to be cost effective and simple to administer.Thus, simplification with triple nucleoside regimens AZT + 3TC + ABC should be still considered for individuals who are unable to tolerate or have contraindications to NNRTI or PI based regimens. Additional data are needed on longer-term efficacy of triple NRTI regimens, particularly on the development of antiretroviral resistance. Though studies in the current review were conducted between 2001 and 2010, the large majority of patients from studies analysed received old PI regimens (e.g., indinavir, ritonavir, nelfinavir, saquinavir) not longer recommended by International Guidelines. Since current guidelines recommend new "lipid -friendly" PI, future studies should compare regimens containing these news PIs to triple NRTI regimens. More realistically, however, there are opportunities to examine these issues in existing cohorts. PMID- 23740609 TI - Cryotherapy for liver metastases. AB - BACKGROUND: Primary liver tumours and liver metastases from colorectal carcinoma are the two most common malignant tumours to affect the liver. The liver is second only to the lymph nodes as the most common site for metastatic disease. More than half of the patients with metastatic liver disease will die from metastatic complications. In cryoablation, liquid nitrogen or argon gas is delivered to the liver tumour, guided by ultrasound using a specially designed probe. Ice crystal formation during the rapid freezing process causes destruction of cellular structure and kills the tumour cells. OBJECTIVES: To study the beneficial and harmful effects of cryotherapy compared with no intervention, other ablation methods, or systemic treatments in patients with liver metastases. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, and CINAHL up to December 2012. SELECTION CRITERIA: We included all randomised clinical trials assessing the beneficial and harmful effects of cryotherapy and its comparators, irrespective of the location of the primary tumour. DATA COLLECTION AND ANALYSIS: We extracted relevant information on participant characteristics, interventions, study outcomes, and data on the outcomes for our review, as well as information on the design and methodology of the trials. Bias risk assessment of and data extraction from the trials fulfilling the inclusion criteria were done by one author and checked by a second author. MAIN RESULTS: One randomised clinical trial fulfilled the inclusion criteria of the review. The trial was judged as a trial with high risk of bias due to the unclear report on the generation of the allocation sequence and allocation concealment, blinding, incomplete outcome data and the selective outcome reporting domain. The trial included 123 consecutive patients with solitary or multiple unilobar or bilobar liver metastases who were randomised into two groups, 63 received cryotherapy and 60 received conventional surgery. There were 36 females and 87 males. The primary sites for the metastases were colorectal (66.6%), stomach (7.3%), breast (6.5%), melanoma (4.9%), ovarian adenocarcinoma (4.1%), uterus (3.3%), kidney (3.3%), intestinal (1.6%), pancreatic (1.6%), and unknown (0.8%). The tumours were resectable and non-resectable.The patients were followed for up to 10 years (minimum five months). Mortality at the last follow-up was 81% (51/63) in the cryotherapy group and 92% (55/60) in the conventional surgery group (RR 0.88; 95% CI 0.77 to 1.02); that is, no statistically significant difference was observed. In the cryotherapy group, 60%, 44%, and 19% of the participants survived 3, 5, and 10 years respectively, while in the conventional surgery group the percentages were 51%, 36%, and 8%. The hazard ratio calculated using the Parmar method was 0.71 (95% confidence interval (CI) 0.47 to 1.09). Recurrence in the liver was observed in 86% (54/63) of the patients in the cryotherapy group and 95% (57/60) of the patients in the conventional surgery group (relative risk (RR) 0.9; 95% CI 0.8 to 1.01); that is, no statistically significant difference was observed. Frequency of reported complications was similar between the cryotherapy group and the conventional surgery group except for postoperative pain. Both insignificant and pronounced pain were reported to be more common in the cryotherapy group while intense pain was reported to be more common in the control group. However, it was not reported by the authors whether the differences were significant. No intervention-related mortality and no bile leakage were observed. AUTHORS' CONCLUSIONS: On the basis of one randomised clinical trial with high risk of bias, there is insufficient evidence to conclude if in patients with liver metastases from various primary sites cryotherapy brings any significant benefit in terms of survival or recurrence compared with conventional surgery. In addition, there is no evidence for the effectiveness of cryotherapy when compared with no intervention. At present, cryotherapy cannot be recommended outside randomised clinical trials. PMID- 23740610 TI - Environmental and behavioural interventions for reducing physical activity limitation in community-dwelling visually impaired older people. AB - BACKGROUND: Impairment of vision is associated with a loss of function in activities of daily living. Avoidance of physical activity and consequent reduced functional capacity is common in older people with visual impairment and an important risk factor for falls. Indeed, the rate of falls and fractures is higher in older people with visual impairment than age-matched visually normal older people. Depression and anxiety is common in older people with vision impairment and leads to further restriction of activity, reduced social contact and reduced quality of life. Possible mechanisms to reduce activity restriction and therefore improve mobility and activity include environmental and behavioural interventions delivered by a number of health professionals, including occupational therapists. OBJECTIVES: The objective of this review was to assess the effectiveness of environmental and behavioural interventions in reducing activity limitation and improving quality of life amongst visually impaired older people. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 10), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to November 2012), EMBASE (January 1980 to November 2012), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 1937 to November 2012), Allied and Complementary Medicine Database (AMED) (January 1985 to November 2012), OT Seeker (inception to November 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 9 November 2012. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-randomised controlled trials (Q RCTs) that compared environmental interventions, behavioural interventions or both, versus control (placebo control or no intervention or usual care), and trials comparing different types of environmental or behavioural interventions, in older people (aged 60 and over) with irreversible visual impairment living independently or in residential settings. To be eligible for inclusion the primary aim of studies must be reducing physical activity limitation and must include a measure of physical activity. Secondary outcome measures included falls, fear of falling, quality of life. DATA COLLECTION AND ANALYSIS: Two authors independently read abstracts retrieved by the search to identify eligibility and study quality. We contacted study authors for additional information. MAIN RESULTS: Our searches found no RCTs or Q-RCTs that met the eligibility criteria for this review. AUTHORS' CONCLUSIONS: We are unable to reach any conclusion about the effectiveness of environmental or behavioural interventions for reducing physical activity limitation in community-dwelling visually impaired older people, as no eligible studies were found. However a number of studies reviewed included only the secondary outcome measures of this review. Although behavioural interventions delivered by occupational therapists have been shown to reduce the rate of falls, we are unable to conclude if this is due to reduced activity restriction (increased mobility) or reduced activity (lessening exposure to risk). There are inconclusive and conflicting results from trials evaluating the effectiveness of behavioural and environmental interventions aimed at improving quality of life. Further research is necessary (such as ongoing Dutch and UK trials considering the effectiveness of orientation and mobility training on activity restriction, physical activity, falls, fear of falling and quality of life in older adults with low vision, and the effect of an occupational therapist delivering home safety modification, coping strategies and exercise with older people with low vision) before any conclusions can be reached. PMID- 23740611 TI - Vitrectomy with internal limiting membrane (ILM) peeling versus vitrectomy with no peeling for idiopathic full-thickness macular hole (FTMH). AB - BACKGROUND: Several observational studies have suggested the potential benefit of internal limiting membrane (ILM) peeling to treat idiopathic full-thickness macular hole (FTMH). However, no strong evidence is available on the potential benefit(s) of this surgical manoeuvre and uncertainty remains among vitreoretinal surgeons about the indication for peeling the ILM, whether to use it in all cases or in long-standing and/or larger holes. OBJECTIVES: To determine whether ILM peeling improves anatomical and functional outcomes of macular hole surgery compared with the no-peeling technique and to investigate the impact of different parameters such as presenting vision, stage/size of the hole and duration of symptoms in the success of the surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) which contains the Cochrane Eyes and Vision Group Trials Register (The Cochrane Library 2013, Issue 2), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, (January 1950 to February 2013), EMBASE (January 1980 to February 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to February 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We searched the reference lists of included studies for any additional studies not identified by the electronic searches. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 February 2013.We searched reference lists of the studies included in the review for information about other studies on ILM peeling in macular hole surgery. We searched Proceedings for the following conferences up to February 2013: American Academy of Ophthalmology (AAO), Annual Meeting of the American Society of Retina Specialists (ASRS), Annual Meeting of the Retina Society, Congress of the Asia-Pacific Academy of Ophthalmology (APAO), European Association for Vision and Eye Research (EVER) Annual Congress, European Vitreoretinal Society (EVRS) Annual Meeting, Association for Research in Vision and Ophthalmology (ARVO) Meeting, International Vitreoretinal Meeting, and World Ophthalmology Congress. SELECTION CRITERIA: Only randomised controlled trials (RCTs) comparing ILM peeling with the no-peeling counterpart were included. DATA COLLECTION AND ANALYSIS: Two review authors (KSC and NL) independently assessed the titles and abstracts of all RCTs identified by electronic and manual searches.We obtained Individual patient data (IPD) from three of the four identified eligible trials. The fourth identified RCT had only been published in abstract form and no IPD were available; we included data from this published abstract for one outcome (macular hole closure).The primary outcome was distance visual acuity at six months. Secondary outcomes included distance and near visual acuity at three and 12 months postoperatively, near visual acuity at six months postoperatively, primary (after a single surgery) and final (following more than one surgery) macular hole closure, need for additional surgical interventions, vision-related quality of life and intraoperative and postoperative complications.We performed meta analysis using standard techniques (the Mantel-Haenszel odds ratio (OR) for binary outcomes, mean difference (MD) for continuous outcomes) using a fixed effect model. For two outcomes we also used the IPD to perform adjusted analyses using regression methods. MAIN RESULTS: We identified and included four RCTs; these were conducted in Denmark, France, Hong Kong and the United Kingdom/Republic of Ireland and randomised 47, 80, 49 and 141 participants respectively.There was no evidence of a difference in the primary outcome (distance visual acuity at six months), nor in distance visual acuity at 12 months between randomised groups. However, there was evidence of improved best corrected distance visual acuity in the ILM peeling group at three months (WMD 0.09, 95% CI -0.17 to -0.02). We found no evidence for a difference in near vision between groups at any of the time points investigated.Overall, more participants in the ILM peeling group than in the no-peeling group had primary macular hole closure (OR 9.27, 95% CI 4.98 to 17.24); this held true when results were stratified by the stage of the macular hole. There was also evidence that those in the ILM peeling group were more likely to have final macular hole closure (OR 3.99, 95% CI 1.63 to 9.75). Fewer participants required further surgery in the ILM peeling group than in the no-peeling group (OR 0.11, 95% CI: 0.05 to 0.23).Rates of intraoperative and postoperative complications were similar in both groups.Based on the results of one study, there was no evidence that total VFQ-25 or EQ-5D scores differed between the groups at six months. Based on this same study, ILM peeling is highly likely to be cost-effective. AUTHORS' CONCLUSIONS: Although we found no evidence of a benefit of ILM peeling in terms of the primary outcome (visual acuity at six months), ILM peeling appears to be superior to its no-peeling counterpart as it offers more favourable cost effectiveness by increasing the likelihood of primary anatomical closure and subsequently decreasing the likelihood of further surgery, with no differences in unwanted side-effects compared with no peeling. PMID- 23740613 TI - Study on effects of scan parameters on the image quality and tip wear in AFM tapping mode. AB - Due to the tip-sample interaction which is the measurement principle of Atomic Force Microscope (AFM), tip wear constantly occurs during scanning. The blunt tip caused by the wear process makes more tip geometry information involved in the image, and correspondingly it increases the measurement error. In the present study, the scan parameters of AFM in tapping mode which affect the wear of single crystal silicon tips, such as the approaching rate, the scan rate, the scan amplitude, and the integral gain are investigated. By proposing a parameter reflecting the imaging quality, the tip state tracing the sample surface is evaluated quantitatively. The influences of scan parameters on this imaging quality parameter are obtained by experiments. Finally, in order to achieve the perfect images with little tip wear influence, tip wear experiments are carried out and then the optimal parameter settings which can lighten the tip wear are obtained. PMID- 23740612 TI - High-resolution magnetic resonance imaging of ankle joints in murine arthritis discriminates inflammation and bone destruction in a quantifiable manner. AB - OBJECTIVE: The ability to noninvasively monitor the development of inflammatory arthritis longitudinally has become increasingly important in experimental rheumatology. Magnetic resonance imaging (MRI) allows for detailed examination of anatomic structures, as well as the assessment of joint and soft tissue inflammation. The aim of this study was to extend the use of MRI to include quantitative measurements of bone destruction in murine ankle joints. METHODS: Joint disease was measured serially using clinical, histologic, in vivo imaging system (IVIS), micro-computed tomography (micro-CT), and MRI techniques in mouse ankle joints, using the K/BxN serum transfer-induced acute arthritis and K/BxA(g7) chronic arthritis models. Ankle joint MRI was performed using a gradient-echo pulse sequence to evaluate bone destruction and a spin-echo sequence to evaluate inflammation (long T2 signal). RESULTS: Arthritic mice, as compared to control mice, demonstrated increased disease severity according to clinical, histologic, IVIS, and MRI measures. Following induction of arthritis, the majority of volume expansion of the long T2 signal occurred in a juxtaarticular, rather than intrarticular, manner within the ankle joints. Bone destruction in K/BxA(g7) mouse ankle joints was readily detectible by MRI. Linear regression analyses demonstrated significant correlations between the clinical score and joint radiance intensity assessed by IVIS, between the ankle joint width and increased long T2 signal on MRI, and between the bone volume obtained by micro-CT and bone volume obtained by MRI. CONCLUSION: MRI is an optimal technology for anatomic localization of articular and soft tissue changes during the development and progression of inflammatory arthritis. Future studies may combine MRI with in vivo labeling agents to investigate joint disease in a cell type-specific manner. PMID- 23740614 TI - Effect of miR-335 upregulation on the apoptosis and invasion of lung cancer cell A549 and H1299. AB - MicroRNAs are small non-coding RNAs that may also function as oncogenes and tumor suppressor genes, as the abnormal expression of microRNAs is associated with various human tumors. However, the effect of miR-335 on the lung cancer cells remains unclear. The aim of the paper was to study the expression of miR335 in non-small cell lung cancer (NSCLC) and miR335's relation to the metastasis, invasion, and apoptosis in lung cancer cells A549 and H1299. qRT-PCR was used to identify the miR-335 expression. The effects of miR-335 on cell proliferation, apoptosis, and invasion were further analyzed. Luciferase reporter assay and Western blot were to verify Bcl-w and SP1 as potential major target genes of miR 335. Finally, the effect of Bcl-w on miR-335-induced cell survival was determined. Our results showed that miR-335 expression was significantly lower in NSCLC tissue, which was significantly associated with lymph node metastasis. In contrast to cells in blank and negative control groups, incidence of apoptosis was significantly higher (P < 0.05) and the number of cells migrating through matrigel was significantly lower (P < 0.05) in miR-335 mimics transfected group. Western blot and luciferase reporter assay demonstrated that miR-335 could bind to the putative binding sites in Bcl-w (or SP1) mRNA 3'-untranslated region to visibly lower the expression of Bcl-w (or SP1). The introduction of Bcl-w cDNA without 3'-untranslated region abrogated miR-335-induced cell survival. These results indicated that upregulation of miR-335 can simultaneously suppress the invasiveness and promote apoptosis of lung cancer cell A549 and H1299 by targeting Bcl-w and SP1. Therefore, miR-335 may be a potential therapeutic target in NSCLC treatment. PMID- 23740615 TI - MicroRNA 181a improves proliferation and invasion, suppresses apoptosis of osteosarcoma cell. AB - MicroRNA 181a (miR-181a) was found dysregulated in a variety of human cancers and significantly associated with clinical outcome of cancer patients. However, the direct role of miR-181a has not yet been characterized in osteosarcoma progression. This study was aimed at investigating the effects of miR-181a on osteosarcoma cell biological behavior. First, the expression of miR-181a in osteosarcoma cell lines (MG63, HOS, SaOS-2, and U2OS) and a human osteoblastic cell line (hFOB1.19) was detected by qRT-PCR. Results showed that miR-181a was overexpressed in osteosarcoma cell lines compared to human osteoblastic cell line (hFOB1.19). To investigate the effects of miR-181a on proliferation, apoptosis, and invasion of osteosarcoma cells, we generated human osteosarcoma MG63 cells in which miR-181a was either overexpressed or depleted. The MG63 cell viability, cycle, apoptosis, and invasive ability were analyzed by 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide staining, propidium iodide (PI) staining, Annexin V-FITC/PI double staining, and Transwell invasion experiment, respectively. The results showed that MG63 cell viability, proliferation, and invasive abilities were suppressed, and the apoptosis was enhanced in the group with underexpression of miR-181a. The viability, proliferation, and invasive abilities were improved, and the apoptosis was inhibited in the group with overexpression of miR-181a. The results from Western blotting indicated that miR 181a might be associated with the up-regulation of bcl-2 and matrix metalloproteinase 9 and the down-regulation of tissue inhibitor of metalloproteinases-3 and p21 in MG63 cells. Taken together, our results suggested that miR-181a might facilitate proliferation and invasion and suppress apoptosis of osteosarcoma cells, which might be a potential target for the treatment of osteosarcoma. PMID- 23740616 TI - Enantioselective aza-Morita-Baylis-Hillman reaction with ketimines and acrolein catalyzed by organic assemblies. PMID- 23740617 TI - Photoinduced relaxation dynamics in iron(II) spin-crossover nanoparticles: the significance of crystallinity. PMID- 23740618 TI - Visual outcomes after pituitary surgery. Reply. PMID- 23740620 TI - Impact of migrant workers on the Human Development Index. PMID- 23740619 TI - Short-term weight loss patterns, baseline predictors, and longer-term follow-up within a randomized controlled trial. AB - OBJECTIVE: To examine weight loss patterns and predictors among participants in a primary care-based translation study of the Diabetes Prevention Program lifestyle intervention. DESIGN AND METHODS: Cluster analysis identified short-term (12 week) weight loss patterns among 72 intervention participants. Analysis of variance assessed cluster differences in weight loss maintenance at 15-month follow-up. Discriminant analysis identified baseline characteristics that best differentiated between clusters. RESULTS: Participants had baseline mean (SD) age of 55.0 (10.8) years and BMI of 31.9 (5.2) kg/m(2) . Cluster analysis identified three short-term weight loss patterns: modest (n = 15; 21%), moderate-and-steady (n = 43; 60%), and substantial-and-early (n = 14; 19%). Only participants with the latter two patterns achieved clinically significant (>=5%) short-term weight loss and maintained it at 15 months. On discriminant analysis, the modest cluster was most differentiated from other clusters by high friend encouragement for dietary change, high obesity-related problems, and low physical well-being. The moderate-and-steady cluster was differentiated by lower physical activity, family encouragement, and depression symptoms. CONCLUSION: Results provided insight into the heterogeneity of response to an effective lifestyle intervention by identifying short-term weight loss patterns and their baseline predictors and relationship to 15-month success. If replicated, results may help tailor strategies for participant subgroups in weight loss programs. PMID- 23740621 TI - An entomopathogenic bacterium, Xenorhabdus nematophila, suppresses expression of antimicrobial peptides controlled by Toll and Imd pathways by blocking eicosanoid biosynthesis. AB - Immune-associated genes of the beet armyworm, Spodoptera exigua, were predicted from 454 pyrosequencing transcripts of hemocytes collected from fifth instar larvae challenged with bacteria. Out of 22,551 contigs and singletons, 36% of the transcripts had at least one significant hit (E-value cutoff of 1e-20) and used to predict immune-associated genes implicated in pattern recognition, prophenoloxidase activation, intracellular signaling, and antimicrobial peptides (AMPs). Immune signaling and AMP genes were further confirmed in their expression patterns in response to different types of microbial challenge. To discriminate the AMP expression signaling between Toll and Imd pathways, RNA interference was applied to specifically knockdown each signal pathway; the separate silencing treatments resulted in differential suppression of AMP genes. An entomopathogenic bacterium, Xenorhabdus nematophila, suppressed expression of most AMP genes controlled by Toll and Imd pathways, while challenge with heat-killed X. nematophila induced expression of all AMPs in experimental larvae. Benzylideneacetone (BZA), a metabolite of X. nematophila, suppressed the AMP gene inductions when it was co-injected with the heat-killed X. nematophila. However, arachidonic acid, a catalytic product of PLA2 , significantly reversed the inhibitory effect of BZA on the AMP gene expression. This study suggests that X. nematophila suppresses AMP production controlled by Toll and Imd pathways by inhibiting eicosanoid biosynthesis in S. exigua. PMID- 23740622 TI - Is there a need for a universal benefit-risk assessment framework for medicines? Regulatory and industry perspectives. AB - PURPOSE: To explore the current status and need for a universal benefit-risk framework for medicines in regulatory agencies and pharmaceutical companies. METHODS: A questionnaire was developed and sent to 14 mature regulatory agencies and 24 major companies. The data were analysed using descriptive statistics, for a minority of questions preceded by manual grouping of the responses. RESULTS: Overall response rate was 82%, and study participants included key decision makers from agencies and companies. None used a fully quantitative system, most companies preferring a qualitative method. The major reasons for this group not using semi-quantitative or quantitative systems were lack of a universal and scientifically validated framework. The main advantages of a benefit-risk framework were that it provided a systematic standardised approach to decision making and that it acted as a tool to enhance quality of communication. It was also reported that a framework should be of value to both agencies and companies throughout the life cycle of a product. They believed that it is possible to develop an overarching benefit-risk framework that should involve relevant stakeholders in the development, validation and application of a universal framework. The entire cohort indicated common barriers to implementing a framework were resource limitations, a lack of knowledge and a scientifically validated and acceptable framework. CONCLUSIONS: Stakeholders prefer a semi quantitative, overarching framework that incorporates a toolbox of different methodologies. A coordinating committee of relevant stakeholders should be formed to guide its development and implementation. Through engaging the stakeholders, these outcomes confirm sentiments and need for developing a universal benefit risk assessment framework. PMID- 23740623 TI - Combined use of ionic liquid and hydroxypropyl-beta-cyclodextrin for the enantioseparation of ten drugs by capillary electrophoresis. AB - In the present study, hydroxypropyl-beta-cyclodextrin and an ionic liquid (1 ethyl-3-methylimidazolium-l-lactate) were used as additives in capillary electrophoresis for the enantioseparation of 10 analytes, including ofloxacin, propranolol hydrochloride, dioxopromethazine hydrochloride, isoprenaline hydrochloride, chlorpheniramine maleate, liarozole, tropicamide, amlodipine benzenesulfonate, brompheniramine maleate, and homatropine methylbromide. The effects of ionic liquid concentrations, salt effect, cations, and anions of ionic liquids on enantioseparation were investigated and the results proved that there was a synergistic effect between hydroxypropyl-beta-cyclodextrin and the ionic liquid, and the cationic part of the ionic liquid played an important role in the increased resolution. With the developed dual system, all the enantiomers of 10 analytes were well separated in resolutions of 5.35, 1.76, 1.85, 2.48, 2.88, 1.43, 5.45, 4.35, 2.76, and 2.98, respectively. In addition, the proposed method was applied to the determination of the enantiomeric purity of S-ofloxacin after validation of the method in terms of selectivity, repeatability, linearity range, accuracy, precision, limit of detection (LOD), and limit of quality (LOQ). PMID- 23740624 TI - Pseudorotaxanes with self-sorted sequence and stereochemical orientation. AB - Partner preferences in pseudorotaxane formation were exploited to establish an integrative self-sorting system able to discriminate simultaneously at the sequence and stereochemical level (see picture). It was found that calix[6]arenes were threaded selectively with a preferred orientation onto bisammonium axles, even when the structural differences between the possible building blocks were small and located remote from the binding sites. PMID- 23740625 TI - Validation of a generic quantitative (1)H NMR method for natural products analysis. AB - INTRODUCTION: Nuclear magnetic resonance (NMR) spectroscopy is increasingly employed in the quantitative analysis and quality control (QC) of natural products (NP) including botanical dietary supplements (BDS). The establishment of QC protocols based on quantitative (1) H NMR (qHNMR) requires method validation. OBJECTIVE: Develop and validate a generic qHNMR method. Optimize acquisition and processing parameters, with specific attention to the requirements for the analysis of complex NP samples, including botanicals and purity assessment of NP isolates. METHODS: In order to establish the validated qHNMR method, samples containing two highly pure reference materials were used. The influence of acquisition and processing parameters on the method validation was examined, and general aspects of method validation of qHNMR methods discussed. Subsequently, the method established was applied to the analysis of two NP samples: a purified reference compound and a crude mixture. RESULTS: The accuracy and precision of qHNMR using internal or external calibration were compared, using a validated method suitable for complex samples. The impact of post-acquisition processing on method validation was examined using three software packages: TopSpin, Mnova and NUTS. The dynamic range of the qHNMR method developed was 5000:1 with a limit of detection (LOD) of better than 10 um. The limit of quantification (LOQ) depends on the desired level of accuracy and experiment time spent. CONCLUSION: This study revealed that acquisition parameters, processing parameters and processing software all contribute to qHNMR method validation. A validated method with a high dynamic range and general workflow for qHNMR analysis of NP is proposed. PMID- 23740627 TI - Susceptibility of older adults to health effects induced by ambient air pollutants regulated by the European Union and the United States. AB - Air pollution is a health concern for the general population, but a few subpopulations (e.g., children, individuals with preexisting cardiovascular or respiratory diseases, etc.) are considered more susceptible to the adverse health effects attributed to air pollution. There is sufficient evidence to suggest that older adults (>=65 years old) are more susceptible to air pollution-induced health effects compared to younger adults due to decreased physiological, metabolic and compensatory processes, and a greater incidence of cardiovascular and respiratory disease. This review examines health effects induced by exposures to common ambient air pollutants regulated by the European Union and the United States. Studies were evaluated that examined the potential susceptibility of older adults to air pollutant-induced health effects. This review focuses on epidemiologic studies that directly compared the health effects of older adults to younger adults and/or the general population in order to compare populations within the same study design. Supplementary information is used from controlled human exposure studies, which examined only older adults, and animal toxicological studies, which utilized animal models of senescence, to provide coherence and biological plausibility for the health effects observed in epidemiologic studies. Overall, evidence from available published studies demonstrates that older adults may be more susceptible to air pollution-induced health effects than younger adults and/or the general population. Clinicians and other health professionals should consider advising older adults on pollution avoiding behaviors in order to decrease the risk of adverse air pollution-related health effects. PMID- 23740628 TI - The quality of reporting in clinical research: the CONSORT and STROBE initiatives. AB - Inaccurate reporting of data hampers the generalizability and the correct interpretation of results of scientific medical papers. The Consolidated Standards of Reporting Trials (CONSORT) and Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiatives, both included in the Enhancing the Quality and Transparency of Health Research (EQUATOR) international network, have elaborated appropriate guidelines in order to improve the transparence, clearness and completeness of scientific literature. The CONSORT statement consists of a 25 items checklist and a flow-chart diagram which provide guidance to Authors on how to report randomized clinical trials. The STROBE is a checklist of 22 items which should be addressed when observational studies (case control, cohort and cross-sectional) are made up. Many editorial committees and prestigious international journals have now embraced these guidelines to improve the quality and methodology of their scientific reports. PMID- 23740629 TI - Analysis of telomere length and subtelomeric methylation of circulating leukocytes in women with Alzheimer's disease. AB - BACKGROUNDS AND AIMS: Telomere attrition proceeds with the aging process, and is also associated with aging disease conditions, such as Alzheimer's disease (AD). The aging process also affects subtelomeric methylation status. In the present study, the telomere length and the subtelomeric methylation status in female AD patients were analyzed to see how AD affects telomere structure. METHODS: Terminal restriction fragment length of 23 AD patients' peripheral leukocytes was analyzed with methylation sensitive- and insensitive-isoschizomer by Southern blot. RESULTS: AD patients were found to have normal mean telomere lengths (controls; 6.4 +/- 0.9 kb, AD; 6.1 +/- 0.8 kb, p = 0.131), a proportionally decreased number of the longest telomeres (>9.4 kb) (controls; 30.3 +/- 7.9%, AD; 24.4 +/- 8.3%, p = 0.013), increased medium-sized telomeres (controls; 51.7 +/- 3.3%, AD 55.5 +/- 6.4%, p = 0.015) and unchanged numbers of the shortest telomeres (<4.4 kb) (controls; 18.0 +/- 7.8, AD; 20.2 +/- 8.9%, p = 0.371) in their peripheral leukocytes. The subtelomeres of telomeres in the shortest range (<4.4 kb) were more methylated in AD subjects than in controls (controls; 0.21 +/ 0.23, AD; 0.41 +/- 0.26, p = 0.016). CONCLUSIONS: These results may indicate that AD contributes to the loss of cells bearing the shortest telomeres, with hypomethylation of subtelomeres occurring in addition to telomere attrition, resulting in an apparent normal mean telomere length in AD patients. The relatively high subtelomeric methylation status of the shortest telomeres in peripheral blood leukocytes may be a characteristic of AD. This report demonstrates that the epigenetic status of the telomeric region is affected by disease conditions. PMID- 23740630 TI - Cell biology of normal brain aging: synaptic plasticity-cell death. AB - Senescence of the brain seems to be related to increased levels of free oxygen radical (FOR). FOR may damage macromolecular compounds such as: proteins, lipids, and DNA. In the aging brain, increased FOR levels damage DNA, mitochondrial DNA (mtDNA), and nuclear DNA (nDNA). In DNA they damage single and double strands, leading to mutations in mtDNA and nDNA. Damage to mtDNA seems to result in decay of mitochondria, decreased production of ATP, and in the activation of the apoptotic process. In the aging brain, apoptosis does not seem to be activated in wild-type p53-expressing cells because the elevated levels of the p53 protein are no longer accompanied by decreased levels of the Bcl-2 protein and increased levels of the Bax protein. It seems that, in the aging brain, changes in the metabolism of neurons may lead to their decreased numbers in the cerebral and cerebellar cortex, hippocampus, basal nucleus of Meynert, locus ceruleus, and substantia nigra, as well as to decreased numbers of synapses and disturbed stimulation of synaptic plasticity in the senescent brain. Simultaneously, a decrease in neurogenesis in the aging brain may lead to a decline in the maintenance of tissue integrity, function, and regenerative response. Environmental enrichment and physical activity may improve hippocampal neurogenesis and induce neuronal plasticity. The morphological lesions in the senescent brain are undoubtedly followed by a disturbed balance between various types of neurons in the CNS. Nevertheless, the high plasticity of the CNS in humans most probably does not allow for the development of abnormalities in higher functions. PMID- 23740631 TI - Cognitive plasticity, cognitive functioning and quality of life (QoL) in a sample of young-old and old-old adults in southern Spain. AB - BACKGROUND AND AIMS: The present study was designed to assess the differences in cognitive plasticity, cognitive functioning and quality of life (QoL) in young old and old-old adults, and to determine whether variables related to QoL can predict cognitive plasticity in old age. METHODS: The study population consisted of 215 people living in sheltered accommodation for elderly people in southern Spain. Participants were divided into two groups according to age: young-old aged (between 65 and 80 years) and old-old (81 and above). Participants were assessed by means of cognitive performance tests, a QoL questionnaire, and the auditory verbal learning test-learning potential (AVLT-LP) as a measure of cognitive plasticity. RESULTS: No significant differences were found in cognitive plasticity between the young-old and old-old adults, although the former performed better on immediate and sustained verbal recall. Likewise, no significant inter-group differences arose in most of the QoL variables. However, differences in cognitive plasticity did appear as a function of the level of cognitive functioning of the old adults, and cognitive functioning has been shown to be the best predictor of cognitive plasticity in old age. CONCLUSIONS: Differences in cognitive plasticity between young-old and old-old adults only appear when the cognitive functioning of individuals is taken into account, rather than their age group. The variables cognitive functioning, social integration and education level appear to be the best predictors of cognitive plasticity in old age. PMID- 23740632 TI - Exercise intensity modulates nitric oxide and blood pressure responses in hypertensive older women. AB - BACKGROUND AND AIMS: Whether intensity or other characteristics of physical activity can better promote the release of nitric oxide (NO) and reduction of blood pressure in hypertensive older-adults is still unknown. In this study, the post-exercise blood pressure (BP) response and NO release after different intensities of aerobic exercise in elderly women were analyzed. METHODS: Blood pressure response and NO were analyzed in 23 elderly mildly hypertensive women. Participants underwent (1) high-intensity incremental exercise (IT); (2) moderate intensity 20 min exercise at 90% of the anaerobic threshold (AT), and (3) control (CONT) session. BP was measured before and after interventions; volunteers remained seated for 1 h. NO estimates were made through NO2- analyses. RESULTS: After CONT session, both diastolic BP and mean arterial pressure (MAP) were significantly higher than during pre-exercise resting. Post-exercise hypotension (PEH) was observed after exercise at IT and 90% of AT. Although exercise in both sessions lowered SBP and MAP compared with CONT, exercise at the highest intensity (IT) was more effective on lowering systolic BP after exercise. In comparison with pre-exercise resting, NO2- increased significantly only after IT, but both exercise sessions caused NO2- to increase compared with CONT. CONCLUSION: Exercise intensity and NO release may exert a role in eliciting PEH in mildly hypertensive elderly women. PMID- 23740633 TI - Effects of exercise on the prevention of conditions leading to the need for long term care. AB - BACKGROUND: Intervention strategies for 'prevention of conditions leading to the need for long-term care' (prevention of long-term care status) that have physically and mentally proven effects are needed. OBJECTIVE: The aim of this randomized controlled trial was to clarify the physical and psycho-social effects of an exercise program, easily performed at home and in communities using inexpensive equipments for prevention of long-term care status. METHODS: A cluster of 196 participants was randomly assigned to the intervention group that performed the exercise for 8 weeks and the control group. Both groups received tests for physical strength and endurance and interview surveys at baseline and 9 weeks later. The exercise consisted of six types of stretching exercises, six types of muscle strength training, two types of balance training and toe stretching in order to improve ambulatory, balance and stability ability of elderly. The physical aspects of the subjects were assessed by balance assessment, activities of daily living (ADL), timed up-and-go test (TUG), functional reach test (FRT), sit and reach. The psycho-social aspects were assessed by the fall prevention self-efficacy scale (FPSE), instrumental activities of daily living (IADL), degree of houseboundness, and assessment at the end of intervention. RESULTS: The intervention and control groups consisted of 101 and 81 persons at the baseline and 92 and 74 after intervention, respectively. The intervention group showed significantly higher values than the control group after exercise in the FRT, the FPSE and degree of houseboundness. CONCLUSION: This exercise program can promote physical and psycho-social aspects of the health in the elderly, and may reduce the amount of care that the elderly require. PMID- 23740634 TI - Falls in elderly people: a multifactorial analysis of risk markers using data from the Swedish general population study 'Good ageing in Skane'. AB - BACKGROUND AND AIMS: The aim of this study was to describe the prevalence of falls in a general older population, especially among the most elderly, and the risk markers associated with falls. METHODS: This is a cross-sectional study in which 38 fall risk markers were analysed in non-, occasional- and frequent fallers. The population was 2,865 individuals (aged 60-93), randomly selected from the general population register. The risk of falling was calculated as age adjusted odds ratios. The relation between the number of risk markers for an individual and falls was also analysed. RESULTS: About one in ten reported falling during the past 6 months, 35% of which were over 90 years old. Twenty-one risk markers were significantly related to falls confirming falling as a multifactorial problem. These included a variety of diseases, symptoms, medical and physical functions, life-style factors and the taking of certain drugs. The five risk markers with the highest odds ratio in frequent fallers were 'tendency to fall' (37.9), 'low walking speed' (12.8), consumption of 'neuroleptics' (10.9), 'impaired mobility' (10.0) and 'dementia' (5.4). Subjects with more than four and seven risk markers showed a 9- respectively 28-fold increase in the risk of falling, especially among frequent fallers and those aged over 90 years. CONCLUSION: Falls are common in the elderly population and the risk is multifactorial. The results imply that there is an overrepresentation of fallers in a distinct subgroup of the very elderly and those with multiple risk markers. The self-perceived clinical sign 'tendency to fall' seems highly sensitive as indicator of individuals at risk. Several risk markers may be treatable. Fall risk seems to increase in a non-linear, almost exponential way with increasing number of risk markers. PMID- 23740635 TI - Correlates associated with the desire for PEG tube placement at the end of life among community-dwelling older Mexican Americans: a pilot study. AB - BACKGROUND AND AIMS: Use of percutaneous endoscopic gastrostomy (PEG) tubes in older adults remains controversial. This cross-sectional study examines community dwelling Mexican American older adults' attitudes toward PEG tube placement in the hypothetical event of a terminal illness. METHODS: Interviews were conducted with 100 community-dwelling Mexican American (MA's) adults, age 60 and over, in San Antonio, Texas. Subjects were screened for cognitive competence using Folstein's mini-mental examination. This was followed by an evaluation of socioeconomic status, depressive symptoms, religiosity, health status and attitudes toward end-of-life care, including PEG tube feeding. RESULTS: Higher income MA's, professionals, those without a living will, those who saw religious belief as not important and those who attended church less than once a month were more likely to agree with PEG placement (all P < 0.05). Logistic regression analysis revealed that higher income (OR = 3.16, CI = 1.13-8.83), lack of a living will (OR = 3.34, CI = 1.03-20.87) and low importance of religious beliefs (OR = 7.14, CI = 1.25-41.67) were all independently associated with the desire for insertion of a PEG tube at the end of life. CONCLUSIONS: This is the first community-based study to describe older Mexican American's attitudes toward PEG tube placement at the end of life. Older community-dwelling Mexican Americans with higher incomes, lack of a living will or low religious involvement might be more likely to choose PEG tube placement even in the context of a terminal condition. PMID- 23740636 TI - Factors associated with adverse outcome following urologic surgery in patients aged 80 years and older. AB - BACKGROUND AND AIMS: This study was designed to find predictors for adverse post operative outcomes in elderly patients aged 80 years and older, who underwent urologic surgery. METHODS: In this prospective observational study, we analysed data, including age, gender, American Society of Anesthesiologists (ASA) class, co-morbidities, number of regular medications, type and extent of surgery, type of anesthesia, duration of surgery and hospitalization, post-operative morbidity and mortality. We studied the correlations between each pre- and intra-operative parameter to the consequence, to find predictors for adverse outcome. RESULTS: During a 12-month period, 217 patients underwent 294 urologic procedures in our institution. Ninety-eight procedures (33%) were followed by complications and 11 patients (5%) died. Patients who had uneventful surgery and hospitalization were significantly younger than those who experienced morbidity or mortality. There was a significantly higher complication rate among patients with a higher ASA class or with ischemic heart disease, following higher graded or longer operations, and after emergency surgery. CONCLUSIONS: Older age is a significant risk factor. Patients with higher ASA class or ischemic heart disease are at higher risk for post-operative complications and thus, require careful follow-up. In this age population, extensive or prolonged surgery should be carefully considered. PMID- 23740637 TI - Mobility limitation as a predictor of inpatient care in the last year of life among community-living older people. AB - BACKGROUND AND AIMS: Need for inpatient care increases toward the end of life. We studied whether mobility limitation assessed approximately 5.8 years prior to death predicts the number of days in care during the last year of life. METHODS: A population-based, prospective study with interviews conducted, on average, 5.8 years prior to death. Data on vital status and health care use were register based. Participants consisted of 846 persons who had died between 1989 and 2004 at the age of 66-98 years. Participants were categorized as having mobility limitation if, at baseline, they reported difficulties in walking 2 km or climbing one flight of stairs. RESULTS: Mean +/- standard deviation of age at death for men was 81.6 +/- 6.2 years and the median number of days in inpatient care in the last year of life was 38.5 days. For women, the corresponding figures were 84.1 +/- 6.1 years and 66.0 days. Only 11% of men and 7% of women had no inpatient care in the last year of life. The adjusted incidence rate ratio for all-cause inpatient care in the last year of life was 1.53 (95% CI 1.09-2.16) among men with mobility limitation compared to those with intact mobility. Among women, mobility limitation did not increase the risk for all-cause inpatient care. CONCLUSION: Mobility limitation (vs. intact mobility) at 5.8 years prior to death markedly increases the need of inpatient care in the last year of life among men. PMID- 23740638 TI - Remembering the past and imagining the future: age-related differences between young, young-old and old-old. AB - BACKGROUND AND AIMS: Few studies have analyzed the ability to remember past events and imagine future events in older adults. The present study examines age related differences between young, young-old, and old-old adults in creating mental images of autobiographic episodes from the past and from the future. METHODS: Cue words were presented, and for each of these, participants had to remember an autobiographic past event or imagine a future event. Performance was analyzed in terms of type of autobiographical images created (specific or general) and their vividness. Moreover, individual differences in temporal perspective were analyzed as a mediator of performance. RESULTS: Old-old adults produced less specific, but more general events compared to young adults and young-old in the future condition. Moreover, only old-old produced more general images in the future than in the past. In contrast, young-old showed intermediate performance, more similar to that of young adults for both specific and autobiographical images. A similar pattern was found with regard to vividness of images produced. Regression analyses showed that the proportion of images produced in the past and the future was interdependent and was accounted by age and individual differences in temporal perspective. CONCLUSIONS: Taken together, these results indicate that the ability to recall specific autobiographical past events and imagined future events is maintained in young-old, but is impaired when old-old adults are considered. Results are discussed in terms of the more accentuated cognitive decline that occurs in late adulthood. PMID- 23740639 TI - Motor dual-task effect on gait and task of upper limbs in older adults under specific task prioritization: pilot study. AB - BACKGROUND AND AIMS: Performing multiple tasks simultaneously may result in reduced performance of subtasks (dual-task cost) particularly among old individuals. Subtask performance during dual tasking is also known to be affected by task prioritization. However, it has not been well studied how the performance of subtasks is affected during motor dual task in old adults compared to young when instructed to prioritize one task over the other. This study aims to investigate the dual-task effect on subtasks during motor dual tasking under specific instruction of task prioritization in old compared to young adults. METHODS: Sixteen independent old and 18 young adults performed two single tasks (usual walking, holding a tray as steady as possible while standing) and two dual tasks (walking while holding a tray focusing attention on keeping tray as steady as possible-WTAT, and walking while holding tray focusing attention on walking WTAW). Gait parameters [velocity and variability (coefficient of variation, CV) of stride length] and the pitch (forward-backward) and roll (side-to-side) angles of the tray were measured during the four conditions. RESULTS: During the WTAT compared to single tasks, both young and old groups showed reduced gait velocity (beta = -14.0 for old, -34.3 for young), increased gait variability (beta = 0.19 for old, 0.51 for young), and increased tray tilt (beta = 9.4 for old, 7.9 for young in pitch; beta = 8.8 for old, 5.9 for young in roll). Higher proportion of older individuals showed higher dual-task effect on tray stability, but lower dual-task effect on gait compared to young individuals. During WTAW, there was no difference in dual-task effect between age groups in tray stability or gait performance. CONCLUSIONS: Compared to young, older adults tend to compromise the task involving upper limbs during motor dual tasking even when instructed to prioritize this task over gait. These findings may have ramifications on developing training strategies to learn or relearn complex motor activities in seniors. PMID- 23740640 TI - Association between vitamin D deficiency and long hospital stay in geriatric acute care unit: results from a pilot cohort study. AB - Finding a biomarker of long length-of-stay (LOS) would provide a simple solution to target frail older inpatients at such risk. The aim of this study was to determine whether serum 25-hydroxyvitamin D (25OHD) deficiency, defined as serum concentration <25 nmol/L, was associated with long LOS among inpatients admitted to a geriatric acute care unit. Three hundred and six older inpatients (mean age 84.6 +/- 6.4 years, 61.8% women) were consecutively included in this longitudinal prospective cohort study. Patients were separated into two groups according to LOS tertiles: highest tertile (>=14 days; n = 120) versus the other two tertiles combined (<14 days; n = 186). Serum 25OHD deficiency (58.3 vs. 38.7%, P = 0.001) and the prevalence of male gender (58.3 vs. 28.5%, P < 0.001) were higher among inpatients with the highest LOS compared with those with lower LOS. Serum 25OHD deficiency [odds ratio (OR) = 2.22, P = 0.001 for unadjusted model; OR = 1.87, P = 0.012 for fully adjusted model) and male gender (OR = 2.87, P < 0.001 for unadjusted model; OR = 2.64, P = 0.001 for full model) were associated with a high LOS. Vitamin D deficiency and male gender were risk factors for a long LOS in this pilot study. Using these risk factors to identify inpatients at risk of long LOS may be helpful in adapting early care plans, and thus improving inpatients' health and shortening LOS. PMID- 23740641 TI - Encephalopathy induced by levetiracetam in an elderly woman. AB - Levetiracetam is frequently used in the elderly considering its favorable pharmacological profile, efficacy, and good tolerance. We reported an encephalopathy with levetiracetam in an elderly subject who had no renal failure, no concomitant valproate medication, and no other additional co-morbidities. Levetiracetam should be discontinued when this condition is suspected. PMID- 23740642 TI - Olanzapine as a cause of peripheric edema in an elderly man. AB - Edema can be observed as side-effect of many medications, of which calcium channel blockers are the best known. Elderly people use many more medications than their younger counterparts and are usually more prone to developing medication-induced side-effects. Atypical antipsychotics have occasionally been shown to induce peripheric edema. Age is put forward as a risk factor for olanzapine-induced edema. We present here the case of an elderly man who developed upper- and lower-limb edema during use of olanzapine to emphasize its relatively frequent association with edema in the elderly. PMID- 23740643 TI - Tubulin cofactor A functions as a novel positive regulator of ccRCC progression, invasion and metastasis. AB - Microtubules (Mts), which consist of alpha/beta-tubulin heterodimers, are involved in cancer development and metastasis. Tubulin cofactor A (TBCA) plays crucial roles in modulating tubulin folding and alpha/beta-tubulin heterodimer polymerization. Here, we identified the aberrant expression of TBCA in clear cell renal cell carcinoma (ccRCC) specimens as well as cell lines and revealed the function of TBCA as a novel positive regulator in ccRCC progression, invasion and metastasis. qRT-PCR, Western blot and immunohistochemistry assays confirmed that TBCA was significantly highly expressed in ccRCC specimens and cell lines compared to their corresponding normal kidney tissues and HKC. Accordingly, the influence of TBCA on cell proliferation, apoptosis and invasion/migration was detected through overexpression and knockdown of endogenous TBCA protein level in ccRCC cells via plasmids. Silencing of TBCA expression inhibited the proliferation of 786-O cells and Caki-1 cells and promoted the apoptosis of 786-O cells. Down-regulation of TBCA expression also reduced the invasion and migration ability of 786-O cells. Interestingly, overexpression of TBCA did not induce biocharacteristics that directly contrasted to those of TBCA knockdown. Importantly, exploration of the mechanism showed that TBCA could function via modulating cytoskeleton integration and influencing cell cycle progress. Furthermore, down-regulation of TBCA expression in 786-O and Caki-1 cells affected cytoskeleton integration and cell size, induced S/G2 cell cycle arrest and led to cyclineA/E and CDK2 aberrant expression. By investigating novel roles of TBCA in regulation of ccRCC cell progression, invasion and metastasis, our study identified that TBCA may be a potential molecular target for ccRCC therapy. PMID- 23740646 TI - Direct observation of unstable reaction intermediates by acid-base complex formation. AB - The structures of several unstable or metastable reaction intermediates that were photoproduced in crystals were analyzed by using X-ray techniques. The presence of enough void space around the reactive group(s) is an essential factor for the reaction to occur with retention of the single-crystal form. To expand the void space, an acid group (COOH) was substituted onto the reactant molecule and acid base complex crystals were prepared with several amines, such as dibenzylamine and dicyclohexylamine. Following the formation of such acid-base complexes in crystals, the metastable structures of nitrenes and red species of photochromic salicylideneanilines have been successfully analyzed by using X-ray techniques. Moreover, the structure of a Pt complex anion in the excited state has been analyzed, which formed acid-base complex crystals with various alkylammonium cations. The formation of acid-base complexes will be a powerful tool for directly observing the structure of unstable or metastable reaction intermediates by using X-ray techniques. PMID- 23740645 TI - Neurotoxicology of bis(n)-tacrines on Blattella germanica and Drosophila melanogaster acetylcholinesterase. AB - A series of bis(n)-tacrines were used as pharmacological probes of the acetylcholinesterase (AChE) catalytic and peripheral sites of Blattella germanica and Drosophila melanogaster, which express AChE-1 and AChE-2 isoforms, respectively. In general, the potency of bis(n)-tacrines was greater in D. melanogaster AChE (DmAChE) than in B. germanica AChE (BgAChE). The change in potency with tether length was high in DmAChE and low in BgAChE, associated with 90-fold and 5.2-fold maximal potency gain, respectively, compared to the tacrine monomer. The optimal tether length for Blattella was 8 carbons and for Drosophila was 10 carbons. The two species differed by only about twofold in their sensitivity to tacrine monomer, indicating that differential potency occurred among dimeric bis(n)-tacrines due to structural differences in the peripheral site. Multiple sequence alignment and in silico homology modeling suggest that aromatic residues of DmAChE confer higher affinity binding, and the lack of same at the BgAChE peripheral site may account, at least in part, to the greater overall sensitivity of DmAChE to bis(n)-tacrines, as reflected by in vitro assay data. Topical and injection assays in cockroaches found minimal toxicity of bis(n)-tacrines. Electrophysiological studies on D. melanogaster central nervous system showed that dimeric tacrines do not readily cross the blood brain barrier, explaining the observed nonlethality to insects. Although the bis(n)-tacrines were not good insecticide candidates, the information obtained in this study should aid in the design of selective bivalent ligands targeting insect, pests, and disease vectors. PMID- 23740647 TI - A parallel finite element simulator for ion transport through three-dimensional ion channel systems. AB - A parallel finite element simulator, ichannel, is developed for ion transport through three-dimensional ion channel systems that consist of protein and membrane. The coordinates of heavy atoms of the protein are taken from the Protein Data Bank and the membrane is represented as a slab. The simulator contains two components: a parallel adaptive finite element solver for a set of Poisson-Nernst-Planck (PNP) equations that describe the electrodiffusion process of ion transport, and a mesh generation tool chain for ion channel systems, which is an essential component for the finite element computations. The finite element method has advantages in modeling irregular geometries and complex boundary conditions. We have built a tool chain to get the surface and volume mesh for ion channel systems, which consists of a set of mesh generation tools. The adaptive finite element solver in our simulator is implemented using the parallel adaptive finite element package Parallel Hierarchical Grid (PHG) developed by one of the authors, which provides the capability of doing large scale parallel computations with high parallel efficiency and the flexibility of choosing high order elements to achieve high order accuracy. The simulator is applied to a real transmembrane protein, the gramicidin A (gA) channel protein, to calculate the electrostatic potential, ion concentrations and I - V curve, with which both primitive and transformed PNP equations are studied and their numerical performances are compared. To further validate the method, we also apply the simulator to two other ion channel systems, the voltage dependent anion channel (VDAC) and alpha Hemolysin (alpha-HL). The simulation results agree well with Brownian dynamics (BD) simulation results and experimental results. Moreover, because ionic finite size effects can be included in PNP model now, we also perform simulations using a size-modified PNP (SMPNP) model on VDAC and alpha-HL. It is shown that the size effects in SMPNP can effectively lead to reduced current in the channel, and the results are closer to BD simulation results. PMID- 23740649 TI - Tackling the challenges of systemic sclerosis-associated pulmonary hypertension: one step forward. PMID- 23740648 TI - Weight loss after bariatric surgery in morbidly obese adolescents with MC4R mutations. AB - OBJECTIVE: To determine the frequency of Melanocortin 4 Receptor (MC4R) mutations in morbidly obese adolescents undergoing bariatric surgery and compare weight loss outcomes in patients with and without mutations. DESIGN AND METHODS: In this prospective cohort study, 135 adolescent patients evaluated for bariatric surgery were screened for MC4R mutations; 56 had 12-month postoperative data available for analysis. RESULTS: MC4R mutations were detected in five of the 135 patients (3.7%); four underwent restrictive bariatric surgery. For the three patients with gastric banding, percent excess weight loss (%EWL) postoperatively was 36.0% at 5 years in one, 47% at 4 years in the second, and 85% at 1 year in the third. For the patient with gastric sleeve resection, %EWL of 96% was attained at 1 year postoperatively. The four MC4R cases had a higher, although nonsignificant, %EWL compared to 52 nonmatched controls at 12 months postoperatively (48.6% vs. 23.4%; P < 0.37). When matched by age, sex, and race to 14 controls, there was no significant difference in %EWL (P < 0.31), BMI change (P < 0.27), or absolute weight loss (P < 0.20). CONCLUSION: The frequency of MC4R mutations is similar to prior studies, with affected patients showing beneficial weight loss outcomes. PMID- 23740650 TI - Top-down chemoenzymatic approach to a high-mannose-type glycan library: synthesis of a common precursor and its enzymatic trimming. AB - From the stacks: A novel method for construction of a high-mannose-type glycan library by systematic enzymatic trimming of a single synthetic Man9-based precursor was developed. Efficient chemical synthesis of the tetradecasaccharide common precursor and orthogonal enzymatic trimming to obtain all M(8-9) and G(1)M(8-9) derivatives was demonstrated. G = glucose, M = mannose. PMID- 23740651 TI - Supply-side response to declining heroin purity: fentanyl overdose episode in New Jersey. AB - The inelastic price demand observations characteristic of illegal drug markets have led to the conclusion that the burden of a negative supply shock would be completely reflected to consumers. This paper argues that the increasing availability of prescription opioids may threaten heroin sellers' profit margin and force them to find alternative methods to compensate buyers in the event of a supply shock. We investigate the 2006 fentanyl overdose episode in New Jersey and argue that the introduction of non-pharmaceutical fentanyl, its spatial distribution, and the timing of overdose deaths may have been related to trends in heroin purity. Using medical examiner data, as well as data from the Drug Enforcement Administration, Office of Diversion Control on retail sales of prescription opioids in a negative binomial specification, we show that month-to month fluctuations in heroin purity have a significant effect on fentanyl-related overdoses, particularly in those areas where prescription opioids are highly available. PMID- 23740652 TI - Intraoperative optical imaging in neurosurgery. PMID- 23740653 TI - SEP-induced activity and its thermographic cortical representation in a murine model. AB - This article is a methodical report on the generation of reproducible changes in brain activity in a murine model. Somatosensory evoked potentials (SEP) are used to generate synchronized cortical activity. After electrical stimulation of mice forelimbs, the potentials were recorded with a flexible thin-film polyimide electrode structure directly from the cortex. Every registration included a simultaneous recording from both hemispheres that repeated four times to reproduce and compare the results. The SEPs in the murine model were shown to generate a very stable signal. The latency of the second positive wave (P2 wave) ranged between 16 and 19 ms, and the N1-P2 amplitude ranged between 39 and 48 uV. In addition, the temperature distribution of the cortex was acquired using infrared thermography. Surface cortical temperature changed during electrical stimulation without a clear hemispheric correlation. These initial results could be a step toward a better understanding of the different synchronized cortical activities and basic methods of evaluation of various mathematical algorithms to detect them. PMID- 23740654 TI - Evaluation of the clinical practicability of intraoperative optical imaging comparing three different camera setups. AB - Intraoperative optical imaging (IOI) is a method to visualize functional activated brain areas during brain surgery using a camera system connected to a standard operating microscope. Three different high-resolution camera systems (Hamamatsu EB-CCD C7190-13W, Hamamatsu C4742-96-12G04, and Zeiss AxioCam MRm) have been evaluated for suitability to detect activated brain areas by detecting stimulation-dependent blood volume changes in the somatosensory cerebral cortex after median nerve stimulation. The image quality of the camera systems was evaluated in 14 patients with tumors around the somatosensory cortex. The intraoperative images of the brain surface were continuously recorded over 9 min. With all three camera systems, the activity maps of the median nerve area could be visualized. The image quality of a highly sensitive electron-bombarded camera was up to 10-fold lower compared with two less sensitive standard cameras. In each IOI-positive case, the activated area was in accordance with the anatomical and neurophysiological location of the corresponding cortex. The technique was found to be very sensitive, and several negative influencing factors were identified. However, all possible artifacts seem to be controllable in the majority of the cases, and the IOI method could be well adapted for routine clinical use. Nevertheless, further systematic studies are needed to demonstrate the reliability and validity of the method. PMID- 23740655 TI - Quantitative fluorescence angiography for neurosurgical interventions. AB - Present methods for quantitative measurement of cerebral perfusion during neurosurgical operations require additional technology for measurement, data acquisition, and processing. This study used conventional fluorescence video angiography--as an established method to visualize blood flow in brain vessels- enhanced by a quantifying perfusion software tool. For these purposes, the fluorescence dye indocyanine green is given intravenously, and after activation by a near-infrared light source the fluorescence signal is recorded. Video data are analyzed by software algorithms to allow quantification of the blood flow. Additionally, perfusion is measured intraoperatively by a reference system. Furthermore, comparing reference measurements using a flow phantom were performed to verify the quantitative blood flow results of the software and to validate the software algorithm. Analysis of intraoperative video data provides characteristic biological parameters. These parameters were implemented in the special flow phantom for experimental validation of the developed software algorithms. Furthermore, various factors that influence the determination of perfusion parameters were analyzed by means of mathematical simulation. Comparing patient measurement, phantom experiment, and computer simulation under certain conditions (variable frame rate, vessel diameter, etc.), the results of the software algorithms are within the range of parameter accuracy of the reference methods. Therefore, the software algorithm for calculating cortical perfusion parameters from video data presents a helpful intraoperative tool without complex additional measurement technology. PMID- 23740657 TI - Unintentional death in childhood and adolescence. PMID- 23740656 TI - Autostereoscopic 3D visualization and image processing system for neurosurgery. AB - A demonstrator system for planning neurosurgical procedures was developed based on commercial hardware and software. The system combines an easy-to-use environment for surgical planning with high-end visualization and the opportunity to analyze data sets for research purposes. The demonstrator system is based on the software AMIRA. Specific algorithms for segmentation, elastic registration, and visualization have been implemented and adapted to the clinical workflow. Modules from AMIRA and the image processing library Insight Segmentation and Registration Toolkit (ITK) can be combined to solve various image processing tasks. Customized modules tailored to specific clinical problems can easily be implemented using the AMIRA application programming interface and a self developed framework for ITK filters. Visualization is done via autostereoscopic displays, which provide a 3D impression without viewing aids. A Spaceball device allows a comfortable, intuitive way of navigation in the data sets. Via an interface to a neurosurgical navigation system, the demonstrator system can be used intraoperatively. The precision, applicability, and benefit of the demonstrator system for planning of neurosurgical interventions and for neurosurgical research were successfully evaluated by neurosurgeons using phantom and patient data sets. PMID- 23740658 TI - Perception of transition readiness and preferences for use of technology in transition programs: teens' ideas for the future. AB - BACKGROUND: Efforts to facilitate transition of care to adult providers for adolescents with chronic disease are not uniformly successful and many patients encounter challenges. The goal of this study was to assess transition readiness and preferences for tools to aid in the transition process with an emphasis on technology and social media. METHODS: We surveyed and performed focus groups on patients aged 13-21 years from a pediatric university-based rheumatology and general pediatric practice. Demographics and transition readiness were assessed using a questionnaire. Transition readiness was assessed by examining patient knowledge and independence with care. Focus groups were conducted to elicit perspectives about desirable features of a transition program and useful tools. RESULTS: Thirty-five patients completed surveys; and 20 patients and 13 of their parents participated in a focus group. The median patient age was 17 years and 74.3% were female. A Likert scale (0-10, 10=most) was used to evaluate concern over changing to an adult medical provider, (mean=6.4, SD=2.6), preparedness for disease self-management (mean=6.0, SD=2.8), and perceived importance of self managing their condition (mean=7.1, SD=3.1). Themes that emerged from focus groups included a desire for support groups with other teens, a preference for using text messaging for communication and a desire for an online health management program. CONCLUSIONS: Teens with chronic disease are able to identify health maintenance tasks and strategies that will aid in developing independence with healthcare management. These findings support the idea that developing engaging applications and support groups will assist teens in the transitioning. PMID- 23740659 TI - Interleukin-6 and interleukin-11: same same but different. AB - The pleiotropic physiological functions of interleukin (IL-)6 type cytokines range from embryonic development and tissue homoeostasis to neuronal development and T cell differentiation. In contrast, imbalance of the well-controlled cytokine signaling network leads to chronic inflammatory diseases and cancer. IL 6 and IL-11 both signal through a homodimer of the ubiquitously expressed beta receptor glycoprotein 130 (gp130). Specificity is gained through an individual IL 6/IL-11 alpha-receptor, which does not directly participate in signal transduction, although the initial cytokine binding event to the alpha-receptor leads to the final complex formation with the beta-receptors. Both cytokines activate the same downstream signaling pathways, which are predominantly the mitogen-activated protein kinase (MAPK)-cascade and the Janus kinase/signal transducer and activator of transcription (Jak/STAT) pathway. However, recent studies have highlighted divergent roles of the two related cytokines. Here, we will discuss how the biochemical similarities are translated into unique and non redundant functions of IL-6 and IL-11 in vivo and illustrate strategies for cytokine-specific therapeutic intervention. PMID- 23740660 TI - In memoriam, Andrew Marston, November 16, 1953 - March 26, 2013. PMID- 23740661 TI - Spinel/layered heterostructured cathode material for high-capacity and high-rate Li-ion batteries. AB - Best of both worlds: A heterostructured material is synthesized that comprises a core of layered lithium-rich material and an outer layer of nanospinel material. This spinel/layered heterostructured material maximizes the inherent advantages of the 3D Li(+) insertion/extraction framework of the spinel structure and the high Li(+) storage capacity of the layered structure. The material exhibits super high reversible capacities, outstanding rate capability and excellent cycling ability. PMID- 23740662 TI - The impact of morbidity trajectories on identifying high-cost cases: using Taiwan's National Health Insurance as an example. AB - BACKGROUND: Incorporating longitudinal information into risk-adjustment models has been considered important. This study aimed to evaluate how morbidity trajectories impact risk-adjustment models in identifying high-cost cases. METHODS: Claims-based risk adjusters, with or without morbidity trajectories derived from 3-year claims from Taiwan's National Insurance System, were used to predict being a prospective high-cost user. A random sample of Taiwanese National Health Insurance enrollees continuously enrolled from 2002 to 2005 (n = 147,892) was the study sample. A logistic regression model was employed. The performance measures, based on the split analysis, included statistical indicators (c statistics, sensitivity and predictive positive value), proportions of true cases identified by models and medical utilization of predicted cases. RESULTS: As the comprehensiveness of risk adjustment models increased, the performance of the models generally increased. The effect of adding trajectories on the model performance decreased as the comprehensiveness of the model increased. Such impact was most apparent in statistical indicators and medical utilization of the predicted groups. CONCLUSIONS: In identifying high-cost cases, adding morbidity trajectories might be necessary only for less comprehensive risk adjustment models, and its contributions came from higher c-statistics and increasing medical utilization of predicted groups. PMID- 23740663 TI - The Spodoptera frugiperda effector caspase Sf-caspase-1 becomes unstable following its activation. AB - Sf-caspase-1 is the principal effector caspase in Spodoptera frugiperda cells. Like the caspases in other organisms, Sf-caspase-1 is processed by upstream caspases to form an active heterotetramer composed of the p19 and p12 subunits. The regulation of active caspases is crucial for cellular viability. In mammal cells, the subunits and the active form of caspase-3 were rapidly degraded relative to its proenzyme form. In the present study, the S. frugiperda Sf9 cells were transiently transfected with plasmids encoding different fragments of Sf caspase-1: the pro-Sf-caspase-1 (p37), a prodomain deleted fragment (p31), a fragment containing the large subunit and the prodomain (p25), the large subunit (p19), and the small subunit (p12). Flow cytometry and Western blot analysis revealed that p12, p19, and p25 were unstable in the transfected cells, in contrast to p37 and p31. Lactacystin, a proteasome inhibitor, increased the accumulation of the p19 and p12 subunits, suggesting that the degradation is performed by the ubiquitin-proteasome system. During the activation, the Sf caspase-1 produces an intermediate form and then undergoes proteolytic processing to form active Sf-caspase-1. We found that both the active and the intermediate form were unstable, indicating that once activated or during its activation, the Sf-caspase-1 was unstable. PMID- 23740664 TI - A prospective pilot study to evaluate combined topical photodynamic therapy and surgery for extramammary paget's disease. AB - BACKGROUND AND OBJECTIVE: Extramammary Paget's disease (EMPD) is a rare intra epithelial neoplasm. Surgical excision is the treatment of choice. The usefulness of topical photodynamic therapy (PDT) in the treatment of EMPD has been reported. The objective of this prospective pilot study was to investigate the feasibility of combined PDT and surgery in the treatment of EMPD. SUBJECTS AND METHODS: A total of 13 patients with 19 large EMPD lesions were recruited and assigned to surgery (n = 5) or PDT + surgery (n = 8) group. For the PDT + surgery group, four sessions of topical PDT mediated with 20% 5-aminolevulinic acid (ALA-PDT) were applied prior to surgery. Patients were followed up for 12 months. Treatment outcomes, adverse reactions and recurrence were compared. RESULTS: In the surgery group, recurrence was seen in 2 out of 8 lesions (25%). In the combination group, over 58% reduction in lesion size was achieved after 4-sessions of PDT and recurrence was seen in 1 out of 11 lesions (9.1%) after surgery. CONCLUSIONS: Multiple ALA-PDT could be applied to reduce the severity of EMPD lesion and improve the success of surgery. PMID- 23740665 TI - Interleukin-6 as an inflammatory mediator and target of therapy in chronic periaortitis. AB - OBJECTIVE: Chronic periaortitis (CP) usually responds to glucocorticoids, but some patients have glucocorticoid-refractory disease or contraindications to glucocorticoid therapy. This study was undertaken to evaluate treatment with the anti-interleukin-6 receptor (anti-IL-6R) antibody tocilizumab in 2 patients with CP, one with refractory disease and the other with contraindications to glucocorticoids, and to assess IL-6 levels in an additional cohort of patients with CP. METHODS: Both patients were given intravenous tocilizumab (8 mg/kg) once every 4 weeks for 6 months. Serum IL-6 was measured in 22 patients with active CP and 16 healthy controls. Tissue IL-6 expression was assessed by confocal microscopy in biopsy specimens obtained from 6 patients with CP. RESULTS: In the first patient, whose disease was refractory to various immunosuppressive treatments, tocilizumab added to ongoing therapy with prednisone and methotrexate allowed prednisone withdrawal and induced resolution of symptoms, acute-phase reactant normalization, and reduction in (18) F-fluorodeoxyglucose ((18) F-FDG) uptake on positron emission tomography. The patient experienced a relapse 7 months later and was successfully retreated with tocilizumab. In the second patient, who was unable to tolerate glucocorticoids because of psychiatric side effects, tocilizumab monotherapy induced sustained clinical and laboratory remission, (18) F-FDG uptake disappearance, and CP shrinkage. Serum IL-6 levels were significantly higher in patients with active CP than in controls (P < 0.0001), and IL-6 was abundantly expressed in biopsy specimens from CP patients, particularly by T cells, B cells, histiocytes, fibroblasts, and vascular smooth muscle cells. CONCLUSION: Tocilizumab may be a therapeutic option for CP. The systemic and tissue up-regulation of IL-6 in CP, together with the clinical benefit of IL-6R blockade observed in our 2 patients, suggest that IL-6 may contribute to CP pathogenesis. PMID- 23740666 TI - The synthesis of size- and color-controlled silver nanoparticles by using microwave heating and their enhanced catalytic activity by localized surface plasmon resonance. AB - Silver nanoparticles (Ag NPs) of various colors were synthesized within the mesopore structure of SBA-15 by using microwave-assisted alcohol reduction. The charge density is partially localized on the surface of these Ag NPs owing to localized surface plasmon resonance. This charge localization results in them having enhanced catalytic activity under visible light irradiation compared to Ag NPs obtained by thermal processes. PMID- 23740667 TI - Novel point mutations and mutational complexes in the enhancer II, core promoter and precore regions of hepatitis B virus genotype D1 associated with hepatocellular carcinoma in Saudi Arabia. AB - In this study, a cohort of 182 patients [55 hepatocellular carcinoma (HCC) and 127 non-HCC] infected with hepatitis B virus (HBV) in Saudi Arabia was investigated to study the relationship between sequence variation in the enhancer II (EnhII), basal core promoter (BCP) and precore regions of HBV genotype D (HBV/D) and the risk of HCC. HBV genotypes were determined by sequencing analysis and/or enzyme-linked immunosorbent assay. Variations in the EnhII, BCP and precore regions were compared between 107 non-HCC and 45 HCC patients infected with HBV/D, followed by age-matched analysis of 40 cases versus equal number of controls. Age and male gender were significantly associated with HCC (p = 0.0001 and p = 0.03, respectively). Serological markers such as aspartate aminotransferase, albumin and anti-HBe were significantly associated with HCC (p = 0.0001 for all), whereas HBeAg positivity was associated with non-HCC (p = 0.0001). The most prevalent HBV genotype was HBV/D (94%), followed by HBV/E (4%), HBV/A (1.6%) and HBV/C (0.5%). For HBV/D1, genomic mutations associated with HCC were T1673/G1679, G1727, C1741, C1761, A1757/T1764/G1766, T1773, T1773/G1775 and C1909. Age- and gender-adjusted stepwise logistic regression analysis indicated that mutations G1727 [odds ratio (OR) = 18.3; 95% confidence interval (CI) = 2.8 118.4; p = 0.002], A1757/T1764/G1766 (OR = 4.7; 95% CI = 1.3-17.2; p = 0.01) and T1773 (OR = 14.06; 95% CI = 2.3-84.8; p = 0.004) are independent predictors of HCC development. These results implicate novel individual and combination patterns of mutations in the X/precore region of HBV/D1 as predictors of HCC. Risk stratification based on these mutation complexes would be useful in determining high-risk patients and improving diagnostic and treatment strategies for HBV/D1. PMID- 23740668 TI - The angiogenic peptide vascular endothelial growth factor-basic fibroblast growth factor signaling is up-regulated in a rat pressure ulcer model. AB - The purpose of this study is to investigate the mRNA and protein expression levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in pressure ulcers, and to elucidate the molecular mechanism by which VEGF and bFGF are involved in pressure ulcer formation. A rat model of ischemia-reperfusion pressure ulcer was established by magnetic disk circulating compression method. Real-time fluorescence quantitative PCR and Western blot assays were conducted to detect the mRNA and protein expression of VEGF and bFGF in the tissues of rat I-, II-, and III-degree pressure ulcers, the surrounding tissues, and normal skin. Our study confirmed that the mRNA and protein expression levels of VEGF and bFGF in the tissues of rat I-degree pressure ulcer were significantly higher than that in the II- and III-degree pressure ulcer tissues (P < 0.05). The expression of VEGF and bFGF in the tissues surrounding I- and II-degree pressure ulcers were higher than the rats with normal skin. The expression of VEGF and bFGF in the tissues of rat III-degree pressure ulcer was lower than that in the surrounding tissues and normal skin (P < 0.05). There was a significant positive correlation between change in the VEGF and bFGF. The results showed that with an increase in the degree of pressure ulcers, the expression of VEGF and bFGF in pressure ulcers tissue are decreased. This leads to a reduction in angiogenesis and may be a crucial factor in the formation of pressure ulcers. PMID- 23740669 TI - Surgical versus non-surgical treatment for thoracolumbar burst fractures without neurological deficit. AB - BACKGROUND: Spinal burst fractures result from the failure of both the anterior and the middle columns of the spine under axial compression loads. Conservative management is through bed rest and immobilisation once the acute symptoms have settled. Surgical treatment involves either anterior or posterior stabilisation of the fracture, sometimes with decompression involving the removal of bone fragments that have intruded into the vertebral canal. This is an update of a review first published in 2006. OBJECTIVES: To compare the outcomes of surgical with non-surgical treatment for thoracolumbar burst fractures without neurological deficit. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (October 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 8), MEDLINE (1946 to October 2012), EMBASE (1980 to October 2012) and the Chinese Biomedical Literature Database (1978 to October 2012). We also searched trial registers and reference lists of articles. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials comparing surgical with non-surgical treatment of thoracolumbar burst fractures without neurological deficit. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted data independently. Only limited pooling of data was done. MAIN RESULTS: We included two trials that compared surgical with non-surgical treatment for patients with thoracolumbar burst fractures without neurological deficit. These recruited a total of 87 participants and reported outcomes for 79 participants at follow-up of two years or more. Both trials were judged at unclear risk of selection bias and at high risk of performance and detection biases, resulting from lack of blinding.The two trials reported contrasting results for pain and function-related outcomes at final follow-up, and numbers returning to work. One trial found less pain (mean difference (MD) -15.09 mm, 95% CI -27.81 to -2.37; 100 mm visual analogue scale), and better function based on the Roland and Morris disability questionnaire results (MD -5.87, 95% CI -10.10 to -1.64; 24 points = maximum disability) in the surgical group. Based on the same outcome measures, the other trial found the surgical group had more pain (MD 13.60 mm, 95% CI -0.31 to 27.51) and worse function (MD 4.31, 95% CI 0.54 to 8.08). Neither trial reported a statistically significant difference in return to work. There were greater numbers of participants with complications in the surgical group of both trials (21/41 versus 6/38; RR 2.85, 95% CI 0.83 to 9.75; 2 trials), and only participants of this group had subsequent surgery, involving implant removal either for complications or as a matter of course. One trial reported that surgery was over four times more costly than non-surgical treatment. AUTHORS' CONCLUSIONS: The contradictory evidence provided by two small and potentially biased randomised controlled trials is insufficient to conclude whether surgical or non-surgical treatment yields superior pain and functional outcomes for people with thoracolumbar burst fractures without neurological deficit. It is likely, however, that surgery is associated with more early complications and the need for subsequent surgery, as well as greater initial healthcare costs. PMID- 23740670 TI - Surgical versus conservative interventions for treating fractures of the middle third of the clavicle. AB - BACKGROUND: Clavicle fractures are common, accounting for 2.6% to 4% of all fractures. Eighty per cent of clavicle fractures are located in the middle third of the clavicle. Although treatment of these fractures is usually non-surgical, displaced clavicle fractures may be considered for surgical treatment because of their greater risk of non-union. OBJECTIVES: To assess the effects (benefits and harms) of surgical versus conservative interventions for treating middle third clavicle fractures. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (to December 2012), Cochrane Central Register of Controlled Trials (CENTRAL; in The Cochrane Library 2012, Issue 11), MEDLINE (1966 to December 2012), EMBASE (1980 to 2012 Week 40), LILACS (1982 to December 2012), and trial registries (December 2012). No language or publication restrictions were applied. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials evaluating surgical versus conservative interventions for treating middle third of the clavicle fractures were considered. The primary outcomes were shoulder function or disability, pain and treatment failure (defined as the number of participants who had been given a non-routine secondary surgical intervention (excluding hardware removal) for symptomatic non-union, malunion or other complications). DATA COLLECTION AND ANALYSIS: At least two review authors selected eligible trials, independently assessed risk of bias and cross-checked data. Where appropriate, results of comparable trials were pooled. MAIN RESULTS: We included eight trials involving 555 participants with middle third clavicle fractures. Four studies compared plate fixation with wearing a sling and four studies compared intramedullary fixation with wearing either a sling or a figure-of-eight bandage. Almost all trials had design features that carry a high risk of bias, thus limiting the strength of their findings.Low quality evidence from seven trials (429 participants) showed that, compared with conservative treatment, surgical treatment of acute middle third clavicle fractures may not result in a significant improvement in upper arm function at one year of more follow-up: standardised mean difference 0.46, 95% confidence interval (CI) CI -0.06 to 0.98. This corresponds to an absolute mean improvement of 3.2 points in favour of surgery (0.4 points worse to 7 points improvement) on the 100-point Constant score; this is neither clinically nor statistically significant. Low-quality evidence from seven trials (437 participants) indicates a marginal difference in the incidence of treatment failure between surgery (9/232, 3.9%) and conservative treatment (24/205, 11.7%) (risk ratio 0.38, 95% CI 0.15 to 0.99). However, this was dominated by the results of the largest trial, which had an unusually high number of symptomatic malunions in the conservative treatment group. One trial providing pain results at one-year follow-up found no difference between the two groups. No trials reported on quality of life.No significant difference between groups was noted in the pooled results for adverse events but separate analyses by type of adverse events showed that wound infection and/or dehiscence (data from three trials) and secondary surgery due to hardware complications (data from five trials) occurred only in the surgical group. Skin and nerve problems were also more common after surgical treatment, although the difference between the two groups was not statistically significant (data from four trials). Conversely, stiffness or restriction of shoulder movement was more common after conservative treatment (data from three trials). AUTHORS' CONCLUSIONS: Limited evidence is available from randomised controlled trials on the relative effectiveness of surgical versus conservative treatment for acute middle third clavicle fractures. Treatment options must be chosen on an individual patient basis, after careful consideration of the relative benefits and harms of each intervention and of patient preferences. PMID- 23740671 TI - Conservative interventions for treating exercise-related musculotendinous, ligamentous and osseous groin pain. AB - BACKGROUND: Musculoskeletal, ligamentous and osseous groin injuries are common in athletes and may result in a delay of several months to resume sports. Even then, this may not be at the former level of sport activity. The treatment of exercise related groin pain is mainly conservative (non-surgical), using interventions such as exercises, electrotherapy, manual therapy and steroid injections. OBJECTIVES: To assess the effects (benefits and harms) of conservative interventions for treating exercise-related musculotendinous, ligamentous and osseous groin pain. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (December 2011); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4); MEDLINE (1948 to November week 3 2011); EMBASE (1980 to Week 49 2011); CINAHL (1982 to December 2011); LILACS (1982 to December 2011); PEDro (1929 to December 2011), SPORTDiscus (1985 to December 2011), OTseeker (to December 2011), reference lists of papers and conference proceedings (2000 to 2011). SELECTION CRITERIA: Randomized controlled trials and quasi-randomized controlled trials evaluating conservative interventions for treating exercise-related musculotendinous, ligamentous and osseous groin pain were included. Studies comparing conservative with surgical treatments were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and conducted risk of bias assessments. There was no pooling of data. MAIN RESULTS: Two studies, involving a total of 122 participants who had experienced adductor-related groin pain for at least two months, were included in this review. All but one of the participants were male athletes aged between 18 and 50 years old. Both studies were assessed as 'high risk of bias' for at least one source of bias domain. The 'successful treatment' outcome reported in both studies was based primarily on pain measures.One study, based on an intention-to-treat analysis, found a significant difference favouring exercise therapy (strengthening with an emphasis on the adductor and abdominal muscles and training muscular co-ordination) compared with 'conventional' physiotherapy (stretching exercises, electrotherapy and transverse friction massage) in successful treatment at 16-week follow-up (25/34 (74%) versus 10/34 (29%); risk ratio (RR) 2.50, 95% CI 1.43 to 4.37, P = 0.001). Similarly, of those followed-up significantly more athletes treated by exercise therapy returned to sport at the same level (23/29 (79%) versus 4/30 (13%); RR 5.95, 95% CI 2.34 to 15.09, P = 0.0002). Although still favouring the exercise group, the differences between the two groups in patients' subjective global assessment at 16 weeks and successful treatment at 8 to 12 years follow-up were not statistically significant.The second study (54 participants) found no significant differences at 16-week follow-up between a multi-modal treatment (heat, manual therapy and stretching) and exercise therapy (the same intervention as in the above study) for the outcomes of successful treatment (14/26 (54%) versus 12/22 (55%); RR 0.99, 95% CI 0.59 to 1.66, P = 0.96) and return to full sports participation (13/26 (50%) versus 12/22 (55%); RR 0.92, 95% CI 0.53 to 1.58, P = 0.75). Those returning to full sports participation returned on average 4.5 weeks earlier after receiving multi-modal therapy (mean difference -4.50 weeks, 95% CI -8.60 to -0.40, P = 0.03) than those in the exercise therapy group. This study reported that there were no complications or side effects found in either intervention group. AUTHORS' CONCLUSIONS: The available evidence from the randomized trials is insufficient to advise on any specific conservative modality for treating exercise-related groin pain. While still low quality, the best evidence is from one trial which found that exercise therapy (strengthening of hip and abdominal muscles) in athletes improves short-term outcomes (based primarily on pain measures) and return to sports compared with physiotherapy consisting of passive modalities. Given the low quality of the available evidence from both included trials, further randomized trials are necessary to reinforce their findings. PMID- 23740672 TI - Partial duplication of the PARK2 gene in a child with developmental delay and her normal mother: a second report. PMID- 23740675 TI - Tumor redox heterogeneity-responsive prodrug nanocapsules for cancer chemotherapy. AB - A prodrug forms nanocapsules responsive to tumor GSH/ROS heterogeneity releasing the parent drug SN38 via thiolysis in the presence of GSH (glutathione) or via enhanced hydrolysis due to ROS (reactive oxygen species)-oxidation of the linker, giving rise to high in vitro cytotoxicity and in vivo anticancer therapeutic activity. The nanocapsules are a suitable size for tumor targeting by means of the EPR effect and have a fixed SN38 loading content of 35 wt%, ideal for translational nanomedicine. PMID- 23740676 TI - Observational study of diabetes management in type 1 diabetic school-age children during holiday versus school days. AB - BACKGROUND: Type 1 diabetes (T1D) management requires year-round adherence to treatment regimen. Holidays may present a challenge towards achieving good metabolic control. OBJECTIVES: Our aim was to investigate the effect of holidays on diabetes management of schoolchildren with T1D. METHODS: Observational, case crossover study of 45 schoolchildren, age range 7-19 years, mean 13.2 +/- 3.4 years, followed in a pediatric diabetes clinic. Subjects were stratified by age [<12 years (n=21), >12 years (n=24)] and treatment modality [insulin pump (n=29) or multiple daily injections (n=16)]. Data were downloaded from glucometers and insulin pumps during five non-weekend holidays and five subsequent school days. RESULTS: The mean number of blood glucose (BG) readings was significantly lower (4.4 +/- 1.9 vs. 4.8 +/- 1.9, p<0.01) and mean BG marginally higher (11.4 +/- 2.7 vs. 10.7 +/- 3.1 mmol/L, p=0.1) during holidays than during school days in the entire cohort. Children were significantly more adherent to diabetes management than adolescents as expressed by lower mean glycated hemoglobin level (7.7 +/- 0.8% vs. 8.6 +/- 1.4%, p<0.05), more BG readings per day (p<0.001) and lower mean BG on holidays (p<0.05) and on school days (p<0.01). In pump users, no difference in the mean number of boluses per day and mean insulin units per kilogram per day was observed between holidays and school days. CONCLUSIONS: The management of school-aged children with T1D during holidays was worse than during school days; these finding were more pronounced in adolescents. The diabetes team should be aware of suboptimal therapy during holidays and should consider intervention programs in attempts to educate patients accordingly. PMID- 23740677 TI - Speech and language delay in two children: an unusual presentation of hyperthyroidism. AB - BACKGROUND: Hyperthyroidism is rare in pre-school children. Untreated, it can have a profound effect on normal growth and development, particularly in the first 2 years of life. Although neurological manifestations of dysthyroid states are well known, specific expressive speech and language disorder as a presentation of hyperthyroidism is rarely documented. METHODS: Case reports of two children with hyperthyroidism presenting with speech and language delay. RESULTS: We report two pre-school children with hyperthyroidism, who presented with expressive speech and language delay, and demonstrated a significant improvement in their language skills following treatment with anti-thyroid medication. CONCLUSIONS: Hyperthyroidism must be considered in all children presenting with speech and language difficulties, particularly expressive speech delay. Prompt recognition and early treatment are likely to improve outcome. PMID- 23740678 TI - Central precocious puberty in a girl with Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) is characterized by infantile lethargy and hypotonia causing poor feeding and failure to thrive, childhood obesity, short stature, and hypogonadism. The complex phenotype is most probably caused by a hypothalamic dysfunction that is responsible for the hormonal dysfunction. The resulting hypogonadism in PWS causes incomplete, delayed, and sometimes disordered pubertal development. Precocious puberty is very rare in PWS. We report the case of a girl with PWS who was diagnosed with idiopathic precocious puberty and was treated with gonadotropin-releasing hormone analog. PMID- 23740679 TI - Evaluation of serum neopterin levels and its relationship with adipokines in pediatric obesity-related nonalcoholic fatty liver disease and healthy adolescents. AB - AIM: Nonalcoholic fatty liver disease (NAFLD) is associated with inflammation and increased risk of atherosclerosis. Neopterin is regarded as a biochemical marker of cell-mediated immunity, which is secreted by monocytes and macrophages, mainly in response to interferon-gamma. The aim of the present study was to investigate the serum neopterin levels in obese adolescents and compare the neopterin levels in patients with and without NAFLD and also with healthy controls. The second aim of the study was to research the possible relationship between neopterin levels and adipokines (leptin, adiponectin, resistin, and ghrelin). METHODS: Ninety three obese adolescents (39 with NAFLD, 54 without NAFLD) and 55 healthy controls were enrolled in the study. Serum levels of neopterin and adipokines were measured with high-performance liquid chromatography and sandwich enzyme-linked immunosorbent assay, respectively. RESULTS: Serum neopterin levels were significantly higher in patients with NAFLD (3.20 +/- 0.09 nmol/L) than in their healthy peers (2.91 +/- 0.08 nmol/L) (p=0.020). Neopterin levels were positively correlated with leptin levels in obese patients (r=0.380, p<0.001) and in the group comprising all individuals (r=0.206, p<0.05). There was no correlation between neopterin concentrations and relative weight, alanin aminotransferase, adiponectin, resistin, and ghrelin levels. CONCLUSION: The serum neopterin levels were significantly higher in obese adolescents with fatty liver disease compared to controls, and this may be related to increased cell-mediated immunity in fatty liver disease. PMID- 23740680 TI - Concept of interactions between consumable substances in Ayurveda with special reference to foods and drugs. AB - Ayurvedic medicines are available in the market as over-the-counter products. Today people use prescription and nonprescription medicines along with Ayurvedic medicines for quick relief from ailments. In the ancient texts of Ayurveda, the concept of interactions with various examples of food interactions and food-drug interactions are mentioned. Recent studies and publications reported drug interactions of Ayurveda medicines and modern drugs. In the present review article, the concept of interactions mentioned in the Ayurvedic texts along with the examples of food interactions, food-drug interactions and the recent research work and publications indicating the interactions of the Ayurvedic drugs and drug interactions of Ayurvedic medicines and modern drugs are compiled. This will help the consumer of the prescription and nonprescription medicines with the Ayurvedic medicines to be cautious about the probable interactions. PMID- 23740681 TI - MDR-1 genotypes and quetiapine pharmacokinetics in healthy volunteers. AB - BACKGROUND: P-glycoprotein is an efflux transporter encoded by the multidrug resistance MDR-1 gene, which influences the absorption and excretion of a variety of drugs. The relation between quetiapine pharmacokinetics and MDR-1 genetic polymorphisms remains controversial. Therefore, the aim of the present study was to analyze the association between quetiapine plasma concentrations and MDR-1 genetic polymorphisms in a bioequivalence trial. METHODS: Quetiapine bioequivalence was studied in 24 unrelated healthy Caucasian adults with an open label, randomized, cross-over, two-sequence and two-period design. Subjects were genotyped for 3435C>T and 1236C>T single-nucleotide polymorphisms. A linear mixed model was performed to compare pharmacokinetic parameters. RESULTS: Subjects with 3435T/T genotype vs. C carriers showed a higher area under the concentration-time curve from 0 to 36 h (p=0.01). Subjects classified according to 1236C>T SNP and haplotypes showed no statistically significant differences. CONCLUSIONS: These results suggest that the polymorphic MDR-1, in particular the 3435C>T allelic variant, might influence plasma levels of quetiapine. PMID- 23740682 TI - Viewing drug action as network perturbation in multiple scale systems. PMID- 23740683 TI - Lexical fields of predictive and personalized medicine. AB - With human genome mapping, the omics revolution and the empowering sequencing technologies developed at the turn of the century, the new goals in medicine are to switch from population medicine to individualized therapies, not only to cure diseases but also to prevent them. The purpose of this review by the pharmacogenetics and predictive medicine working group of the French clinical biology society (SFBC) is to situate in their correct context the notions of personalized medicine, pharmacogenetics, genetics and genomics, emphasizing their interactions and discussing their significance for researchers and clinicians. PMID- 23740684 TI - Inhibition of key enzymes linked to type 2 diabetes and sodium nitroprusside induced lipid peroxidation in rat pancreas by water-extractable phytochemicals from unripe pawpaw fruit (Carica papaya). AB - BACKGROUND: Various parts of unripe pawpaw (Carica papaya Linn) fruit have been reportedly used for the management or treatment of diabetes mellitus in folklore medicine. Therefore, the present study sought to investigate the inhibitory effects of the aqueous extract of different parts of unripe pawpaw fruit on key enzymes linked to type 2 diabetes (alpha-amylase and alpha-glucosidase) and sodium nitroprusside (SNP)-induced lipid peroxidation in rat pancreas in vitro. METHODS: The aqueous extracts of the unripe pawpaw (C. papaya) fruit parts were prepared (1:20 w/v) and the ability of the extracts to inhibit alpha-amylase, alpha-glucosidase and SNP-induced lipid peroxidation in rat pancreas in vitro was investigated. RESULTS: The results revealed that all the extracts inhibited alpha amylase (IC50=0.87-1.11 mg/mL), alpha-glucosidase (IC50=1.76-2.64 mg/mL) and SNP induced lipid peroxidation (IC50=1.99-2.42 mg/mL) in a dose-dependent manner. However, combination of the flesh, seed and peel in equal amounts had the highest inhibitory effect on alpha-amylase and alpha-glucosidase activities. CONCLUSIONS: Strong inhibitory activities of the unripe pawpaw fruit against key enzymes linked to type 2 diabetes and SNP-induced lipid peroxidation in rat pancreas could be part of the mechanism by which unripe pawpaw is used in the management/prevention of diabetes mellitus in folk medicine. However, combining the unripe pawpaw fruit parts in equal amounts exhibited synergistic properties on alpha-amylase and alpha-glucosidase inhibitory activities. PMID- 23740685 TI - Presepsin (sCD14-ST) in preoperative diagnosis of abdominal sepsis. AB - BACKGROUND: The aim of the study was to identify the diagnostic significance of presepsin in acute abdominal conditions and also to examine the correlation between presepsin, procalcitonin (PCT) and other parameters. METHODS: To detect presepsin we used a new rapid method based on a chemiluminescent enzyme immunoassay. The clinical usefulness of presepsin to differentiate bacterial and non-bacterial infection [including systemic inflammation response syndrome (SIRS)] was studied and compared with PCT, C-reactive protein (CRP) and white blood cells (WBC). RESULTS: The presepsin values in different conditions were (mean+/-standard deviation): healthy group (n=70) 258.7+/-92.53 pg/mL; SIRS (n=30) 430.0+/-141.33 pg/mL; sepsis (n=30) 1508.3+/-866.6 pg/mL. The presepsin values were significantly higher in patients with sepsis than the SIRS group (p<0.0001, Mann-Whitney U-test). The area under the receiver operating characteristics (ROC) curve (AUC) for discriminating of the SIRS from the sepsis patients was 0.996 for presepsin and it was greater than the AUC of PCT (0.912), CRP (0.857) or WBC (0.777). CONCLUSIONS: The ROC curve of the SIRS patient without infection and the sepsis patient showed that the presepsin concentration was a significantly sensitive indicator of sepsis and useful marker for the rapid diagnosis of sepsis. PMID- 23740686 TI - Folic acid supplementation does not reduce intracellular homocysteine, and may disturb intracellular one-carbon metabolism. AB - BACKGROUND: In randomized trails, folic acid (FA) lowered plasma homocysteine, but failed to reduce cardiovascular risk. We hypothesize this is due to a discrepancy between plasma and intracellular effects of FA. METHODS: In a double blind trial, 50 volunteers were randomized to received 500 ug FA daily for 8 weeks, or placebo. Plasma and peripheral blood mononuclear cell (PBMC) concentrations of homocysteine, S-adenosylmethionine (SAM), S adenosylhomocysteine, methionine, cystathionine and 5-methyltetrahydrofolate (bioactive folate) were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). PBMCs were used as a cellular model since they display the full spectrum of one-carbon (1C) enzymes and reactions. RESULTS: At baseline, plasma concentrations were a poor reflection of intracellular concentrations for most 1C metabolites, except 5-methyltetrahydrofolate (R=0.33, p=0.02), homocysteine (Hcy) (R=0.35, p=0.01), and cystathionine (R=0.45, p=0.001). FA significantly lowered plasma homocysteine (p=0.00), but failed to lower intracellular homocysteine or change the concentrations of any of the other PBMC 1C metabolites. At baseline, PBMC homocysteine concentrations correlated to PBMC SAM. After FA supplementation, PBMC homocysteine no longer correlated with PBMC SAM, suggesting a loss of SAM's regulatory function. In vitro experiments in lymphoblasts confirmed that at higher folate substrate concentrations, physiological concentrations of SAM no longer effectively inhibit the key regulatory enzyme methylenetetrahydrofolate reductase (MTHFR). CONCLUSIONS: FA supplementation does not reduce intracellular concentrations of Hcy or any of its closely related substances. Rather, FA may disturb physiological regulation of intracellular 1C metabolism by interfering with SAM's inhibitory effect on MTHFR activity. PMID- 23740687 TI - Current and future use of "dried blood spot" analyses in clinical chemistry. AB - The analysis of blood spotted and dried on a matrix (i.e., "dried blood spot" or DBS) has been used since the 1960s in clinical chemistry; mostly for neonatal screening. Since then, many clinical analytes, including nucleic acids, small molecules and lipids, have been successfully measured using DBS. Although this pre-analytical approach represents an interesting alternative to classical venous blood sampling, its routine use is limited. Here, we review the application of DBS technology in clinical chemistry, and evaluate its future role supported by new analytical methods such as mass spectrometry. PMID- 23740688 TI - Evaluation of a hot-wire hair removal device compared to razor shaving. AB - BACKGROUND AND OBJECTIVES: We describe a blinded, controlled, prospective clinical study of a hot-wire device promoted for hair removal and the reduction or delay of hair regrowth (no!no!, Radiancy, Inc., Orangeburg, NY) compared to a shaving control. STUDY DESIGN/MATERIALS AND METHODS: Twenty-two subjects were treated by trained clinical staff with the hot-wire device according to its Instructions for Use on the lower leg two times per week for 8 weeks. An adjacent site was shaved with a razor blade on the same schedule to provide a control. Subjects were followed for 3 months after the last treatment to study the durability of the results. Standardized high-resolution photographs were made at baseline, once a week during treatment, and monthly during the post-treatment follow-up period. Micro-tattoos were used to ensure treatments and photographs were reliably made in the same anatomical location from visit to visit. Both active and control sites were shaved prior to baseline and allowed to regrow for a fixed period of time before first treatment to provide a consistent and well defined baseline hair condition. Quantitative hair counts were made by a third party from the photographs and standard statistical analysis was performed to look for differences between the active and control sites. Visual assessments and quantitative analysis was also performed on the photographs to see if there were any differences in hair thickness (diameter) and hair color between the active and control sites. RESULTS: The results show that shaving and the hot-wire device are indistinguishable in short-term or long-term effect, based on both visual assessment of the photographs and statistical analysis of the hair counts. The control (shaving) had a mean baseline hair count of 79.4, which remained stable (74.8-84.3) during the 8 week-treatment phase and climbed substantially after stopping treatment to 98.8, 100.1, and 104.6 at 1, 2, and 3 months post treatment, respectively. The active (hot-wire device) had a mean baseline hair count of 86.0 which remained fairly stable (81.7-95.1) during the treatment phase and then climbed substantially after stopping treatment to 104.0, 106.4, and 109.0 at 1, 2, and 3 months post-treatment, respectively. The difference in hair counts between the control and shaving showed that (a) in the treatment phase, shaving was slightly more effective at hair removal than the hot-wire device with weak statistical significance (P < 0.05 at 5 of 7 time points) and (b) in the follow-up phase, shaving and the hot-wire device were statistically indistinguishable (P = 0.252, 0.0972, and 0.230 at 1, 2, and 3 months, respectively). Likewise, the difference in percentage change from baseline in hair counts (which normalizes to baseline values) between the shaving control and hot-wire device is close to zero at every time point (-4.9% to +4.9%) and the t test P-values are high (0.154< P < 0.890 over all the time points in the study and 0.360 < P < 0.890 during the 1, 2, and 3 month follow-up period), indicating no detectable difference between shaving and the hot-wire. In terms of hair characteristics, no difference in hair color or hair thickness was seen between the shaving control and the hot-wire sites in the treatment or follow-up period. CONCLUSIONS: Relative to shaving, the hot-wire (no!no!) device does not produce lessened hair density, decreased hair re-growth rate, greater duration of effect, nor induce changes in hair thickness and color. We conclude that the hot-wire device does not offer any benefit as compared to shaving. PMID- 23740689 TI - Molecular pathological findings of Merkel cell polyomavirus in lung cancer: a possible etiopathogenetic link? PMID- 23740692 TI - Asymmetric ruthenium-catalyzed hydrogenation of 2- and 2,9-substituted 1,10 phenanthrolines. PMID- 23740691 TI - Characterization and correction of error in genome-wide IBD estimation for samples with population structure. AB - The proportion of the genome that is shared identical by descent (IBD) between pairs of individuals is often estimated in studies involving genome-wide SNP data. These estimates can be used to check pedigrees, estimate heritability, and adjust association analyses. We focus on the method of moments technique as implemented in PLINK [Purcell et al., 2007] and other software that estimates the proportions of the genome at which two individuals share 0, 1, or 2 alleles IBD. This technique is based on the assumption that the study sample is drawn from a single, homogeneous, randomly mating population. This assumption is violated if pedigree founders are drawn from multiple populations or include admixed individuals. In the presence of population structure, the method of moments estimator has an inflated variance and can be biased because it relies on sample based allele frequency estimates. In the case of the PLINK estimator, which truncates genome-wide sharing estimates at zero and one to generate biologically interpretable results, the bias is most often towards over-estimation of relatedness between ancestrally similar individuals. Using simulated pedigrees, we are able to demonstrate and quantify the behavior of the PLINK method of moments estimator under different population structure conditions. We also propose a simple method based on SNP pruning for improving genome-wide IBD estimates when the assumption of a single, homogeneous population is violated. PMID- 23740690 TI - Balancing the fat: lipid droplets and human disease. AB - Lipid droplets (LDs) are dynamic, cytosolic lipid-storage organelles found in nearly all cell types. Too many or too few LDs during excess or deficient fat storage lead to many different human diseases. Recent insights into LD biology and LD protein functions shed new light on mechanisms underlying those metabolic pathologies. These findings will likely provide opportunities for treatment of diseases associated with too much or too little fat. PMID- 23740693 TI - Deliberate hypotension with propofol under anaesthesia for functional endoscopic sinus surgery (FESS). AB - BACKGROUND: Functional endoscopic sinus surgery (FESS) is a minimally invasive technique that is used to treat chronic sinusitis. Small bleeding areas can reduce operative visibility and result in destruction of surrounding structures. Deliberate hypotension (lowering the mean arterial blood pressure to between 50 and 65 mm Hg in normotensive patients) using a range of pharmacological agents during general anaesthesia reduces blood loss in many operations. OBJECTIVES: We aimed to compare the use of the intravenous anaesthetic agent propofol versus other techniques for deliberate hypotension during FESS with regard to blood loss and operative conditions. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 1), MEDLINE (1950 to April 2012), EMBASE (1980 to April 2012), LILACS (1982 to April 2012) and ISI Web of Science (1946 to April 2012). We also searched the reference lists of relevant articles and conference proceedings and contacted the authors of included trials. SELECTION CRITERIA: We sought all randomized controlled trials (RCTs) conducted to compare propofol with other techniques. Our primary outcome was total blood loss (TBL). Other outcomes included surgical field quality, operation time, mortality within 24 hour, complications and failure to reach target blood pressure. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted details of trial methodology and outcome data from reports of all trials considered eligible for inclusion. All analyses were made on an intention-to-treat basis where possible. When I(2) was < 40% and the P value from the Chi(2) test was > 0.10, we pooled data by using the fixed-effect model. Otherwise we pooled data by using the random-effects model. MAIN RESULTS: We included four studies with 278 participants in the review. Deliberate hypotension with propofol did not decrease TBL (millilitres) when compared with inhalation anaesthetics in either children or adults. Propofol improved the quality of the surgical field by less than one category on a scale from 0 (no bleeding) to 5 (severe bleeding) (mean difference (MD) 0.64 better with propofol, 95% confidence interval (CI) 0.37 to 0.91 better), but no difference in operation time was reported. Failure to lower blood pressure to target was less common in the propofol group (relative risk of failure with propofol (RR) 0.24, 95% CI 0.09 to 0.66). AUTHORS' CONCLUSIONS: Using propofol to achieve deliberate hypotension may improve the surgical field, but the effect is small. Deliberate hypotension with propofol did not decrease TBL and operation time. RCTs with good quality methodology and large sample size are required to investigate the effectiveness of deliberate hypotension with propofol for FESS. PMID- 23740694 TI - Epidural analgesia for cardiac surgery. AB - BACKGROUND: A combination of general anaesthesia (GA) with thoracic epidural analgesia (TEA) may have a beneficial effect on clinical outcomes by reducing the risk of perioperative complications after cardiac surgery. OBJECTIVES: The objective of this review was to determine the impact of perioperative epidural analgesia in cardiac surgery on perioperative mortality and cardiac, pulmonary or neurological morbidity. We performed a meta-analysis to compare the risk of adverse events and mortality in patients undergoing cardiac surgery under general anaesthesia with and without epidural analgesia. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12) in The Cochrane Library; MEDLINE (PubMed) (1966 to November 2012); EMBASE (1989 to November 2012); CINHAL (1982 to November 2012) and the Science Citation Index (1988 to November 2012). SELECTION CRITERIA: We included randomized controlled trials comparing outcomes in adult patients undergoing cardiac surgery with either GA alone or GA in combination with TEA. DATA COLLECTION AND ANALYSIS: All publications found during the search were manually and independently reviewed by the two authors. We identified 5035 titles, of which 4990 studies did not satisfy the selection criteria or were duplicate publications, that were retrieved from the five different databases. We performed a full review on 45 studies, of which 31 publications met all inclusion criteria. These 31 publications reported on a total of 3047 patients, 1578 patients with GA and 1469 patients with GA plus TEA. MAIN RESULTS: Through our search (November 2012) we have identified 5035 titles, of which 31 publications met our inclusion criteria and reported on a total of 3047 patients. Compared with GA alone, the pooled risk ratio (RR) for patients receiving GA with TEA showed an odds ratio (OR) of 0.84 (95% CI 0.33 to 2.13, 31 studies) for mortality; 0.76 (95% CI 0.49 to 1.19, 17 studies) for myocardial infarction; and 0.50 (95% CI 0.21 to 1.18, 10 studies) for stroke. The relative risks (RR) for respiratory complications and supraventricular arrhythmias were 0.68 (95% CI 0.54 to 0.86, 14 studies) and 0.65 (95% CI 0.50 to 0.86, 15 studies) respectively. AUTHORS' CONCLUSIONS: This meta-analysis of studies, identified to 2010, showed that the use of TEA in patients undergoing coronary artery bypass graft surgery may reduce the risk of postoperative supraventricular arrhythmias and respiratory complications. There were no effects of TEA with GA on the risk of mortality, myocardial infarction or neurological complications compared with GA alone. PMID- 23740695 TI - Music interventions for preoperative anxiety. AB - BACKGROUND: Patients awaiting surgical procedures often experience significant anxiety. Such anxiety may result in negative physiological manifestations, slower wound healing, increased risk of infection, and may complicate the induction of anaesthesia and impede postoperative recovery. To reduce patient anxiety, sedatives and anti-anxiety drugs are regularly administered before surgery. However, these often have negative side effects and may prolong patient recovery. Therefore, increasing attention is being paid to a variety of non-pharmacological interventions for reduction of preoperative anxiety such as music therapy and music medicine interventions. Interventions are categorized as 'music medicine' when passive listening to pre-recorded music is offered by medical personnel. In contrast, music therapy requires the implementation of a music intervention by a trained music therapist, the presence of a therapeutic process, and the use of personally tailored music experiences. A systematic review was needed to gauge the efficacy of both music therapy and music medicine interventions for reduction of preoperative anxiety. OBJECTIVES: To examine the effects of music interventions with standard care versus standard care alone on preoperative anxiety in surgical patients. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 7), MEDLINE (1950 to August 2012), CINAHL (1980 to August 2012), AMED (1985 to April 2011; we no longer had access to AMED after this date), EMBASE (1980 to August 2012), PsycINFO (1967 to August 2012), LILACS (1982 to August 2012), Science Citation Index (1980 to August 2012), the specialist music therapy research database (March 1 2008; database is no longer functional), CAIRSS for Music (to August 2012), Proquest Digital Dissertations (1980 to August 2012), ClinicalTrials.gov (2000 to August 2012), Current Controlled Trials (1998 to August 2012), and the National Research Register (2000 to September 2007). We handsearched music therapy journals and reference lists, and contacted relevant experts to identify unpublished manuscripts. There was no language restriction. SELECTION CRITERIA: We included all randomized and quasi-randomized trials that compared music interventions and standard care with standard care alone for reducing preoperative anxiety in surgical patients. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data and assessed the risk of bias. We contacted authors to obtain missing data where needed. Where possible, results were presented in meta analyses using mean differences and standardized mean differences. Post-test scores were used. In cases of significant baseline differences, we used change scores. MAIN RESULTS: We included 26 trials (2051 participants). All studies used listening to pre-recorded music. The results suggested that music listening may have a beneficial effect on preoperative anxiety. Specifically, music listening resulted, on average, in an anxiety reduction that was 5.72 units greater (95% CI -7.27 to -4.17, P < 0.00001) than that in the standard care group as measured by the Stait-Trait Anxiety Inventory (STAI-S), and -0.60 standardized units (95% CI -0.90 to -0.31, P < 0.0001) on other anxiety scales. The results also suggested a small effect on heart rate and diastolic blood pressure, but no support was found for reductions in systolic blood pressure, respiratory rate, and skin temperature. Most trials were assessed to be at high risk of bias because of lack of blinding. Blinding of outcome assessors is often impossible in music therapy and music medicine studies that use subjective outcomes, unless in studies in which the music intervention is compared to another treatment intervention. Because of the high risk of bias, these results need to be interpreted with caution.None of the studies included wound healing, infection rate, time to discharge, or patient satisfaction as outcome variables. One large study found that music listening was more effective than the sedative midazolam in reducing preoperative anxiety and equally effective in reducing physiological responses. No adverse effects were identified. AUTHORS' CONCLUSIONS: This systematic review indicates that music listening may have a beneficial effect on preoperative anxiety. These findings are consistent with the findings of three other Cochrane systematic reviews on the use of music interventions for anxiety reduction in medical patients. Therefore, we conclude that music interventions may provide a viable alternative to sedatives and anti-anxiety drugs for reducing preoperative anxiety. PMID- 23740696 TI - Catheter impregnation, coating or bonding for reducing central venous catheter related infections in adults. AB - BACKGROUND: The central venous catheter (CVC) is a commonly used device in managing acutely ill patients in the hospital. Bloodstream infections are major complications in patients who require a CVC. Several infection control measures have been developed to reduce bloodstream infections, one of which is CVC impregnated with various forms of antimicrobials (either with an antiseptic or with antibiotics). OBJECTIVES: We aimed to assess the effects of antimicrobial CVCs in reducing clinically diagnosed sepsis, established catheter-related bloodstream infection (CRBSI) and mortality. SEARCH METHODS: We used the standard search strategy of the Cochrane Anaesthesia Review Group (CARG). We searched MEDLINE (OVID SP) (1950 to March 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 3, 2012), EMBASE (1980 to March 2012), CINAHL (1982 to March 2012) and other Internet resources using a combination of keywords and MeSH headings. SELECTION CRITERIA: We included randomized controlled trials that assessed any type of impregnated catheter against either non-impregnated catheters or catheters with another impregnation. We excluded cross-over studies. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the CARG. Two authors independently assessed the relevance and risk of bias of the retrieved records. We expressed our results using risk ratio (RR), absolute risk reduction (ARR) and number need to treat to benefit (NNTB) for categorical data and mean difference (MD) for continuous data where appropriate with their 95% confidence intervals (CIs). MAIN RESULTS: We included 56 studies with 16,512 catheters and 11 types of antimicrobial impregnations. The total number of participants enrolled was unclear as some studies did not provide this information. There were low or unclear risks of bias in the included studies, except for blinding, which was impossible in most studies due to different appearances between the catheters assessed. Overall, catheter impregnation significantly reduced CRBSI, with an ARR of 2% (95% CI 3% to 1%), RR of 0.61 (95% CI 0.51 to 0.73) and NNTB of 50. Catheter impregnation also reduced catheter colonization, with an ARR of 10% (95% CI 13% to 7%), RR of 0.66 (95% CI 0.58 to 0.75) and NNTB of 10. However, catheter impregnation made no significant difference to the rates of clinically diagnosed sepsis (RR 1.0 (95% CI 0.88 to 1.13)) and all-cause mortality (RR 0.88 (95% CI 0.75 to 1.05)).In our subgroup analyses, we found that the magnitudes of benefits for impregnated CVCs varied in studies that enrolled different types of participants. For the outcome of catheter colonization, catheter impregnation conferred significant benefit in studies conducted in intensive care units (ICUs) (RR 0.68 (95% CI 0.59 to 0.78)) but not in studies conducted in haematological and oncological units (RR 0.75 (95% CI 0.51 to 1.11)) or studies that assessed predominantly patients who required CVCs for long-term total parenteral nutrition (TPN)(RR 0.99 (95% CI 0.74 to 1.34)). However, there was no such variation for the outcome of CRBSI. The magnitude of the effects was also not affected by the participants' baseline risks.There were no significant differences between the impregnated and non impregnated groups in the rates of adverse effects, including thrombosis/thrombophlebitis, bleeding, erythema and/or tenderness at the insertion site. AUTHORS' CONCLUSIONS: This review confirms the effectiveness of antimicrobial CVCs in improving such outcomes as CRBSI and catheter colonization. However, the magnitude of benefits in catheter colonization varied according to the setting, with significant benefits only in studies conducted in ICUs. Limited evidence suggests that antimicrobial CVCs do not appear to significantly reduce clinically diagnosed sepsis or mortality. Our findings call for caution in routinely recommending the use of antimicrobial-impregnated CVCs across all settings. Further randomized controlled trials assessing antimicrobial CVCs should include important clinical outcomes like the overall rates of sepsis and mortality. PMID- 23740697 TI - High versus low positive end-expiratory pressure (PEEP) levels for mechanically ventilated adult patients with acute lung injury and acute respiratory distress syndrome. AB - BACKGROUND: Mortality in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remains high. These patients require mechanical ventilation, but this modality has been associated with ventilator induced lung injury. High levels of positive end-expiratory pressure (PEEP) could reduce this condition and improve patient survival. OBJECTIVES: To assess the benefits and harms of high versus low levels of PEEP in patients with ALI and ARDS. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2013, Issue 4), MEDLINE (1950 to May 2013), EMBASE (1982 to May 2013), LILACS (1982 to May 2013) and SCI (Science Citation Index). We used the Science Citation Index to find references that have cited the identified trials. We did not specifically conduct manual searches of abstracts of conference proceedings for this review. We also searched for ongoing trials (www.trialscentral.org; www.clinicaltrial.gov and www.controlled trials.com). SELECTION CRITERIA: We included randomized controlled trials that compared the effects of two levels of PEEP in ALI and ARDS participants who were intubated and mechanically ventilated in intensive care for at least 24 hours. DATA COLLECTION AND ANALYSIS: Two review authors assessed the trial quality and extracted data independently. We contacted investigators to identify additional published and unpublished studies. MAIN RESULTS: We included seven studies that compared high versus low levels of PEEP (2565 participants). In five of the studies (2417 participants), a comparison was made between high and low levels of PEEP with the same tidal volume in both groups, but in the remaining two studies (148 participants), the tidal volume was different between high- and low-level groups. We saw evidence of risk of bias in three studies, and the remaining studies fulfilled all criteria for adequate trial quality.In the main analysis, we assessed mortality occurring before hospital discharge only in those studies that compared high versus low PEEP with the same tidal volume in both groups. With the three studies that were included, the meta-analysis revealed no statistically significant differences between the two groups (relative risk (RR) 0.90, 95% confidence interval (CI) 0.81 to 1.01), nor was any statistically significant difference seen in the risk of barotrauma (RR 0.97, 95% CI 0.66 to 1.42). Oxygenation was improved in the high-PEEP group, although data derived from the studies showed a considerable degree of statistical heterogeneity. The number of ventilator-free days showed no significant difference between the two groups. Available data were insufficient to allow pooling of length of stay in the intensive care unit (ICU). The subgroup of participants with ARDS showed decreased mortality in the ICU, although it must be noted that in two of the three included studies, the authors used a protective ventilatory strategy involving a low tidal volume and high levels of PEEP. AUTHORS' CONCLUSIONS: Available evidence indicates that high levels of PEEP, as compared with low levels, did not reduce mortality before hospital discharge. The data also show that high levels of PEEP produced no significant difference in the risk of barotrauma, but rather improved participants' oxygenation to the first, third, and seventh days. This review indicates that the included studies were characterized by clinical heterogeneity. PMID- 23740698 TI - Osteoarthritis: when chondrocytes don't wake up on time. PMID- 23740699 TI - We are family--parents, siblings, and eating disorders in a prospective total population study of 250,000 Swedish males and females. AB - OBJECTIVE: We examined how parental characteristics and other aspects of family background were associated with the development of eating disorders (ED) in males and females. METHOD: We used register data and record linkage to create the prospective, total-population study the Stockholm Youth Cohort. This cohort comprises all children and adolescents who were ever residents in Stockholm County between 2001 and 2007, plus their parents and siblings. Individuals born between 1984 and 1995 (N = 249, 884) were followed up for ED from age 12 to end of 2007. We used Cox regression modeling to investigate how ED incidence was associated with family socioeconomic position, parental age, and family composition. RESULTS: In total, 3,251 cases of ED (2,971 females; 280 males) were recorded. Higher parental education independently predicted a higher rate of ED in females [e.g., adjusted hazard ratio (HR) 1.69 (95% CI: 1.42, 2.02) for degree level vs. elementary-level maternal education], but not in males [HR 0.73 (95% CI: 0.42, 1.28), p < 0.001 for gender interaction]. In females, an increasing number of full-siblings was associated with lower rate of ED [e.g., fully adjusted HR 0.92 (95% CI: 0.88, 0.97) per sibling], whereas an increasing number of half-siblings was associated with a higher rate [HR 1.05 (95% CI: 1.01, 1.09) per sibling]. DISCUSSION: The effect of parental education on ED rate varies between males and females, whereas the effect of number of siblings varies according to whether they are full or half-siblings. A deeper understanding of these associations and their underlying mechanisms may provide etiological insights and inform the design of preventive interventions. PMID- 23740700 TI - [Differential Diagnosis of Intrasellar and Suprasellar Neoplasia ]. PMID- 23740701 TI - [Vague chest pain - fast spiral CT for patients]. PMID- 23740702 TI - [Mammary tumors - MR Spectroscopy for differential diagnosis]. PMID- 23740703 TI - [Acute pancreatitis - abdominal wall edema on MRI as a complementary indicator of severity]. PMID- 23740704 TI - [Breast cancer diagnosis - of what benefit is "second-look" ultrasound with VI RADS 3?]. PMID- 23740705 TI - [MR-mammography - highly variable signal intensities in normal tissue]. PMID- 23740706 TI - [Hepatocellular carcinoma - is there a sequential genesis?]. PMID- 23740707 TI - [Mouth and oropharynx tumors - Gantry-Kippung improved CT diagnosis]. PMID- 23740708 TI - [Silent brain infarcts after coronary angiography - effective inhibition of platelet aggregation is necessary]. PMID- 23740709 TI - [Oligodendrogliomas - MRI can assist grading]. PMID- 23740710 TI - [Axial spondyloarthritis - reduced progression with high-dose NSAIDS]. PMID- 23740712 TI - [Revised requirements planning policy by the G-BA - What changes come from 1.1.2013 to private practitioners?]. PMID- 23740711 TI - [Radiologist for outstanding scientific work with the Gustav Bucky Award 2013]. PMID- 23740715 TI - Comparative and quantitative myology of the forearm and hand of prosimian primates. AB - Associations between the relative development of muscles of the forearm and hand of prosimian primates and locomotor behavior, body size, and grasping specializations have been made on the basis of qualitative observations. These associations are here tested through comparative and quantitative analyses of muscle mass data for a broad sample of prosimian species (i.e., strepsirrhines and tarsiers). The musculature of the forearm and hand of 17 fresh-frozen specimens representing six families and 12 species was dissected and weighed. Muscle weights were scaled relative to body mass of individual specimens using regression and compared by limb compartment and functional group. Forearm and digital flexor muscle masses are highly correlated with body mass (r = 0.97 and r = 0.96, respectively) and scale isometrically. As a general trend within the prosimian sample, the relative mass of the flexor compartment increases with body size. Interspecific comparisons of functional groups of muscles did not identify any association between larger muscle mass and locomotor adaptations or grasping specializations of the hand. However, compared to other prosimians, the adductor pollicis muscle of Nycticebus is more developed (52% of the intrinsic hand musculature sampled) and the flexor digitorum profundus muscle has two well separated heads with more individualized tendons, with the pollex and digit IV receiving tendinous contributions from both muscle heads. These differences that characterize the forearm and hand of Nycticebus correlate with the extreme thumb divergence and pincer-like grips of lorises. PMID- 23740716 TI - FMR1 CGG expansions: prevalence and sex ratios. AB - We have estimated the prevalence of FMR1 premutation and gray zone CGG repeat expansions in a population-based sample of 19,996 male and female adults in Wisconsin and compared the observed sex ratios of the prevalence of FMR1 CGG premutation and gray zone expansions to theoretical sex ratios. The female premutation prevalence was 1 in 148 and comparable to past research, but the male premutation prevalence of 1 in 290 is somewhat higher than most previous estimates. The female:male premutation prevalence ratio is in line with the theoretically predicted sex ratio. The prevalence of CGG repeats in the gray zone (45-54 repeats) was 1 in 33 females and 1 in 62 males. The prevalence of the "expanded" gray zone (defined here as 41-54 CGG repeats) was 1 in 14 females and 1 in 22 males, leading to a female:male ratio of 1.62 (95% confidence interval 1.39-1.90). This female:male ratio was significantly lower than the expected ratio of 2.0. We examined results from three previously published FMR1 prevalence studies and found similar female:male ratios for CGG repeats in this "expanded" gray zone range (pooled female:male ratio across all four studies 1.66, 95% confidence interval 1.51-1.82). Further research is needed to understand the apparent excess prevalence of males with CGG repeats in this range. PMID- 23740717 TI - Implications of HIV drug resistance on first- and second-line therapies in resource-limited settings: report from a workshop organized by the Collaborative HIV and Anti-HIV Drug Resistance Network. AB - Here, we summarize the discussions and conclusions from an expert workshop held in October 2012 to consider the implications of HIV drug resistance in the context of scale-up of access to antiretroviral therapy and prophylaxis in resource-limited settings. Topics considered during the workshop included the implications of drug resistance for the selection of first-line regimens and sequencing of treatments, optimal surveillance strategies and prevention of mother-to-child transmission. PMID- 23740719 TI - Dye-sensitized solar cell with energy storage function through PVDF/ZnO nanocomposite counter electrode. AB - Dye-sensitized solar cells with an energy storage function are demonstrated by modifying its counter electrode with a poly (vinylidene fluoride)/ZnO nanowire array composite. This simplex device could still function as an ordinary solar cell with a steady photocurrent output even after being fully charged. An energy storage density of 2.14 C g(-1) is achieved, while simultaneously a 3.70% photo to-electric conversion efficiency is maintained. PMID- 23740718 TI - Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds. AB - Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the SMN1 gene. SMN2 is a nearly identical copy of SMN1, which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full-length SMN protein from the endogenous SMN2 gene should lessen disease severity. We have developed and implemented a new high-throughput screening assay to identify small molecules that increase the expression of full length SMN from a SMN2 reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA. PMID- 23740720 TI - Genetic association with multiple traits in the presence of population stratification. AB - Testing association between a genetic marker and multiple-dependent traits is a challenging task when both binary and quantitative traits are involved. The inverted regression model is a convenient method, in which the traits are treated as predictors although the genetic marker is an ordinal response. It is known that population stratification (PS) often affects population-based association studies. However, how it would affect the inverted regression for pleiotropic association, especially with the mixed types of traits (binary and quantitative), is not examined and the performance of existing methods to correct for PS using the inverted regression analysis is unknown. In this paper, we focus on the methods based on genomic control and principal component analysis, and investigate type I error of pleiotropic association using the inverted regression model in the presence of PS with allele frequencies and the distributions (or disease prevalences) of multiple traits varying across the subpopulations. We focus on common alleles but simulation results for a rare variant are also reported. An application to the HapMap data is used for illustration. PMID- 23740721 TI - Lagenidium sp. ocular infection mimicking ocular pythiosis. AB - This is a report of a Lagenidium sp. in a Thai patient who was diagnosed with severe keratitis that was unresponsive to antibacterial and antifungal drugs. Examination of a corneal biopsy specimen confirmed the presence of aseptate hyphae. The internal transcribed spacer DNA sequence of the strain isolated showed 97% identity with Lagenidium giganteum and other Lagenidium species. PMID- 23740722 TI - Cell extract-containing medium for culture of intracellular fastidious bacteria. AB - The culture of fastidious microorganisms is a critical step in infectious disease studies. As a proof-of-concept experiment, we evaluated an empirical medium containing eukaryotic cell extracts for its ability to support the growth of Coxiella burnetii. Here, we demonstrate the exponential growth of several bacterial strains, including the C. burnetii Nine Mile phase I and phase II strains, and C. burnetii isolates from humans and animals. Low-oxygen-tension conditions and the presence of small hydrophilic molecules and short peptides were critical for facilitating growth. Moreover, bacterial antigenicity was conserved, revealing the potential for this culture medium to be used in diagnostic tests and in the elaboration of vaccines against C. burnetii. We were also able to grow the majority of previously tested intracellular and fastidious bacterial species, including Tropheryma whipplei, Mycobacterium bovis, Leptospira spp., Borrelia spp., and most putative bioterrorism agents. However, we were unable to culture Rickettsia africae and Legionella spp. in this medium. The versatility of this medium should encourage its use as a replacement for the cell based culture systems currently used for growing several facultative and putative intracellular bacterial species. PMID- 23740723 TI - Cat scratch disease caused by Bartonella grahamii in an immunocompromised patient. AB - Bartonella grahamii colonizes rodents worldwide and has been detected in questing Ixodes ricinus ticks. Here, the first human B. grahamii infection confirmed by multilocus sequence typing is reported. The route of transmission and clinical picture of the patient are similar to those seen in patients with cat scratch disease, which is typically diagnosed as a Bartonella henselae infection. PMID- 23740724 TI - Biographical feature: Melvin P. Weinstein, M.D. PMID- 23740725 TI - First report of carbapenem-resistant Acinetobacter nosocomialis isolates harboring ISAba1-blaOXA-23 genes in Latin America. AB - In recent years, different resistance genes have been found in Acinetobacter spp., especially in the species A. baumannii. We describe two isolates of carbapenem-resistant A. nosocomialis harboring ISAba1-blaOXA-23 and blaOXA-51 found in patients from the city of Porto Alegre, southern Brazil. To the best of the authors' knowledge, this is the first report of carbapenem-resistant A. nosocomialis in Latin America. PMID- 23740726 TI - Surface microbes in the neonatal intensive care unit: changes with routine cleaning and over time. AB - Premature infants in neonatal intensive care units (NICUs) are highly susceptible to infection due to the immaturity of their immune systems, and nosocomial infections are a significant risk factor for death and poor neurodevelopmental outcome in this population. To investigate the impact of cleaning within a NICU, a high-throughput short-amplicon-sequencing approach was used to profile bacterial and fungal surface communities before and after cleaning. Intensive cleaning of surfaces in contact with neonates decreased the total bacterial load and the percentage of Streptococcus species with similar trends for total fungal load and Staphylococcus species; this may have clinical relevance since staphylococci and streptococci are the most common causes of nosocomial NICU infections. Surfaces generally had low levels of other taxa containing species that commonly cause nosocomial infections (e.g., Enterobacteriaceae) that were not significantly altered with cleaning. Several opportunistic yeasts were detected in the NICU environment, demonstrating that these NICU surfaces represent a potential vector for spreading fungal pathogens. These results underline the importance of routine cleaning as a means of managing the microbial ecosystem of NICUs and of future opportunities to minimize exposures of vulnerable neonates to potential pathogens and to use amplicon-sequencing tools for microbial surveillance and hygienic testing in hospital environments. PMID- 23740727 TI - In vitro activities of isavuconazole and comparator antifungal agents tested against a global collection of opportunistic yeasts and molds. AB - Isavuconazole is a new broad-spectrum triazole with a favorable pharmacokinetic and safety profile. We report the MIC distributions for isavuconazole and 111 isolates of Candida (42 Candida albicans, 25 Candida glabrata, 22 Candida parapsilosis, 14 Candida tropicalis, and 8 Candida krusei isolates), as determined by Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) broth microdilution (BMD) methods. Also, the relative activities of isavuconazole, itraconazole, fluconazole, posaconazole, voriconazole, and the three echinocandins were assessed against a recent (2011) global collection of 1,358 isolates of Candida spp., 101 of Aspergillus spp., 54 of non-Candida yeasts, and 21 of non Aspergillus molds using CLSI BMD methods. The overall essential agreement (EA) (+/-2 log2 dilutions) between the CLSI and EUCAST methods was 99.1% (EA at +/-1 log2 dilution, 90.1% [range, 80.0 to 100.0%]). The activities of isavuconazole against the larger collection of Candida spp. and Aspergillus spp. were comparable to those of posaconazole and voriconazole; the MIC90 values for isavuconazole, posaconazole, and voriconazole against Candida spp. were 0.5, 1, and 0.25 MUg/ml and against Aspergillus spp. were 2, 1, and 1 MUg/ml, respectively. Isavuconazole showed good activities against Cryptococcus neoformans (MIC90, 0.12 MUg/ml) and other non-Candida yeasts (MIC90, 1 MUg/ml) but was less potent against non-Aspergillus molds (MIC90, >8 MUg/ml). Isavuconazole MIC values for three mucormycete isolates were 4, 1, and 2 MUg/ml, whereas all three were inhibited by 1 MUg/ml posaconazole. Isavuconazole demonstrates broad-spectrum activity against this global collection of opportunistic fungi, and the CLSI and EUCAST methods can be used to test this agent against Candida, with highly comparable results. PMID- 23740728 TI - Serodiagnosis of Mycobacterium avium complex and Mycobacterium abscessus complex pulmonary disease by use of IgA antibodies to glycopeptidolipid core antigen. AB - An enzyme immunoassay kit that detects serum IgA antibody reacting to glycopeptidolipid core antigen derived from Mycobacterium avium complex (MAC) was not useful for differentiating MAC pulmonary disease (PD) from Mycobacterium abscessus complex PD (MAB-PD). However, this assay could be useful for differentiating MAC- and MAB-PD from pulmonary tuberculosis. (This study has been registered at ClinicalTrials.gov under registration no. NCT00970801.). PMID- 23740729 TI - Presence of antibodies to Schmallenberg virus in a dog in Sweden. PMID- 23740731 TI - PCR-based diagnosis of prosthetic joint infection. AB - We performed a meta-analysis to evaluate use of PCR assays for diagnosis of prosthetic joint infection (PJI). The pooled sensitivity and specificity were 0.86 (95% confidence interval [CI], 0.77 to 0.92) and 0.91 (CI, 0.81 to 0.96), respectively. Subgroup analyses showed that use of tissue samples may improve sensitivity, and quantitative PCR and sonication of prostheses fluid may improve specificity. The results showed that PCR is reliable and accurate for detection of PJI. PMID- 23740732 TI - Emerging Escherichia pathogen. AB - Escherichia hermannii was first identified as a new species in 1982. It has rarely been reported as a human pathogen. We report the first case of E. hermannii as the sole pathogen in a catheter-related bloodstream infection. PMID- 23740730 TI - Multilocus sequence analysis provides insights into molecular epidemiology of Chlamydia pecorum infections in Australian sheep, cattle, and koalas. AB - Chlamydia pecorum is a significant pathogen of domestic livestock and wildlife. We have developed a C. pecorum-specific multilocus sequence analysis (MLSA) scheme to examine the genetic diversity of and relationships between Australian sheep, cattle, and koala isolates. An MLSA of seven concatenated housekeeping gene fragments was performed using 35 isolates, including 18 livestock isolates (11 Australian sheep, one Australian cow, and six U.S. livestock isolates) and 17 Australian koala isolates. Phylogenetic analyses showed that the koala isolates formed a distinct clade, with limited clustering with C. pecorum isolates from Australian sheep. We identified 11 MLSA sequence types (STs) among Australian C. pecorum isolates, 10 of them novel, with koala and sheep sharing at least one identical ST (designated ST2013Aa). ST23, previously identified in global C. pecorum livestock isolates, was observed here in a subset of Australian bovine and sheep isolates. Most notably, ST23 was found in association with multiple disease states and hosts, providing insights into the transmission of this pathogen between livestock hosts. The complexity of the epidemiology of this disease was further highlighted by the observation that at least two examples of sheep were infected with different C. pecorum STs in the eyes and gastrointestinal tract. We have demonstrated the feasibility of our MLSA scheme for understanding the host relationship that exists between Australian C. pecorum strains and provide the first molecular epidemiological data on infections in Australian livestock hosts. PMID- 23740733 TI - Isomerization polymerization of the phosphaalkene MesP=CPh2: an alternative microstructure for poly(methylenephosphine)s. PMID- 23740734 TI - Functional neuroanatomy of body checking in people with anorexia nervosa. AB - OBJECTIVE: The neural correlates of body checking perceptions in eating disorders have not yet been identified. This functional Magnetic Resonance Imaging study examined the neuroanatomy involved in altered perception and identification with body checking in female with anorexia nervosa (AN). METHOD: Brain activation while viewing images depicting normal weight individuals involved in either body checking behavior or a neutral (noneating disorder) body action, was compared between 20 females with AN and 15 matched healthy controls (HC). RESULTS: Females with AN reported higher anxiety compared to HC during the body checking task. The level of anxiety positively correlated with body shape concern scores. People with AN had less activation in the medial prefrontal cortex (PFC) and right fusiform gyrus compared to HC in response to body checking compared to neutral action images. Body shape concern scores correlated negatively with medial PFC activation in AN group. DISCUSSION: This preliminary study with modest power suggests that AN patients have reduced activation in cortical areas associated with self-reference, body action perception, and social cognition in females with AN. PMID- 23740735 TI - Tumor-infiltrating CD14-positive myeloid cells and CD8-positive T-cells prolong survival in patients with cervical carcinoma. AB - One of the hallmarks of cancer is the influx of myeloid cells. In our study, we investigated the constitution of tumor-infiltrating myeloid cells and their relationship to other tumor-infiltrating immune cells, tumor characteristics and the disease-specific survival of patients with cervical cancer (CxCa). Triple color immunofluorescence confocal microscopy was used to locate, identify and quantify macrophages (CD14), their maturation status (CD33) and their polarization (CD163) in a cohort of 86 patients with cervical carcinoma. Quantification of the numbers of myeloid cells revealed that a strong intraepithelial infiltration of CD14+ cells, and more specifically the population of CD14+CD33-CD163- matured M1 macrophages, is associated with a large influx of intraepithelial T lymphocytes (p = 0.008), improved disease-specific survival (p = 0.007) and forms an independent prognostic factor for survival (p = 0.033). The intraepithelial CD8+ T-cell and regulatory T-cell (Treg) ratio also forms an independent prognostic factor (p = 0.010) and combination of these two factors reveals a further increased benefit in survival for patients whose tumor displays a dense infiltration with intraepithelial matured M1 macrophages and a high CD8 T cell/Treg ratio, indicating that both populations of immune cells simultaneously improve survival. Subsequently, we made a heatmap including all known immune parameters for these patients, whereby we were able to identify different immune signatures in CxCa. These results indicate that reinforcement and activation of the intratumoral M1 macrophages may form an attractive immunotherapeutic option in CxCa. PMID- 23740736 TI - Metered dose inhalers versus nebulizers for aerosol bronchodilator delivery for adult patients receiving mechanical ventilation in critical care units. AB - BACKGROUND: Nebulizers and metered dose inhalers (MDI) have both been adapted for delivering aerosol bronchodilation to mechanically ventilated patients, but there is incomplete knowledge as to the most effective method of delivery. OBJECTIVES: To compare the effectiveness of nebulizers and MDIs for bronchodilator delivery in invasively ventilated, critically ill adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5); Ovid MEDLINE (1950 to Week 19 2012); Ovid EMBASE (1980 to Week 19 2012); CINAHL via EBSCOhost (1982 to Week 19 2012) and reference lists of articles. We searched conference proceedings and reference lists of articles. We also contacted manufacturers and researchers in this field. There were no constraints based on language or publication status. SELECTION CRITERIA: Randomized controlled trials (RCTs), including randomized cross-over trials where the order of the intervention was randomized, comparing the nebulizer and MDI for aerosol bronchodilation in mechanically ventilated adult patients in critical care units. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information where required. We collected information about adverse effects from the trials. MAIN RESULTS: This review included three trials, two addressing the primary outcome measure of a reduction of airway resistance (measured as a reduction in interrupter and additional airway resistance) with a total of 28 patients (n =10, n =18) and two addressing adverse changes to haemodynamic observations with a total of 36 patients (n =18, n =18). Limitations in data availability and reporting in the included trials precluded meta-analysis and therefore the present review consisted of a descriptive analysis. Risk of bias in the included trials was judged as low or of unknown risk across the majority of items in the 'Risk of bias' tool.Cautious interpretation of the included study results suggests that nebulizers could be a more effective method of bronchodilator administration than MDI in terms of a change in resistance. No apparent changes to haemodynamic observations (measured as an increase in heart rate) were associated with either mode of delivery. Due to missing data issues, meta analyses were not possible. Additionally, small sample sizes and variability between the studies with regards to patient diagnoses, bronchodilator agent and administration technique mean that it would be speculative to infer definitive recommendations based on these results at this time. This is insufficient evidence to determine which is the most effective delivery system between nebuliser and MDI for aerosol bronchodilation in adult patients receiving mechanical ventilation. AUTHORS' CONCLUSIONS: Existing randomized controlled trials, including randomized cross-over trials where the order of the intervention was randomized, comparing nebulizer and MDI for aerosol bronchodilation in mechanically ventilated adult patients do not provide sufficient evidence to support either delivery method at this time. PMID- 23740737 TI - Automated versus non-automated weaning for reducing the duration of mechanical ventilation for critically ill adults and children. AB - BACKGROUND: Automated closed loop systems may improve adaptation of the mechanical support to a patient's ventilatory needs and facilitate systematic and early recognition of their ability to breathe spontaneously and the potential for discontinuation of ventilation. OBJECTIVES: To compare the duration of weaning from mechanical ventilation for critically ill ventilated adults and children when managed with automated closed loop systems versus non-automated strategies. Secondary objectives were to determine differences in duration of ventilation, intensive care unit (ICU) and hospital length of stay (LOS), mortality, and adverse events. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2); MEDLINE (OvidSP) (1948 to August 2011); EMBASE (OvidSP) (1980 to August 2011); CINAHL (EBSCOhost) (1982 to August 2011); and the Latin American and Caribbean Health Sciences Literature (LILACS). In addition we received and reviewed auto-alerts for our search strategy in MEDLINE, EMBASE, and CINAHL up to August 2012. Relevant published reviews were sought using the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment Database (HTA Database). We also searched the Web of Science Proceedings; conference proceedings; trial registration websites; and reference lists of relevant articles. SELECTION CRITERIA: We included randomized controlled trials comparing automated closed loop ventilator applications to non-automated weaning strategies including non protocolized usual care and protocolized weaning in patients over four weeks of age receiving invasive mechanical ventilation in an intensive care unit (ICU). DATA COLLECTION AND ANALYSIS: Two authors independently extracted study data and assessed risk of bias. We combined data into forest plots using random-effects modelling. Subgroup and sensitivity analyses were conducted according to a priori criteria. MAIN RESULTS: Pooled data from 15 eligible trials (14 adult, one paediatric) totalling 1173 participants (1143 adults, 30 children) indicated that automated closed loop systems reduced the geometric mean duration of weaning by 32% (95% CI 19% to 46%, P = 0.002), however heterogeneity was substantial (I(2) = 89%, P < 0.00001). Reduced weaning duration was found with mixed or medical ICU populations (43%, 95% CI 8% to 65%, P = 0.02) and Smartcare/PSTM (31%, 95% CI 7% to 49%, P = 0.02) but not in surgical populations or using other systems. Automated closed loop systems reduced the duration of ventilation (17%, 95% CI 8% to 26%) and ICU length of stay (LOS) (11%, 95% CI 0% to 21%). There was no difference in mortality rates or hospital LOS. Overall the quality of evidence was high with the majority of trials rated as low risk. AUTHORS' CONCLUSIONS: Automated closed loop systems may result in reduced duration of weaning, ventilation, and ICU stay. Reductions are more likely to occur in mixed or medical ICU populations. Due to the lack of, or limited, evidence on automated systems other than Smartcare/PSTM and Adaptive Support Ventilation no conclusions can be drawn regarding their influence on these outcomes. Due to substantial heterogeneity in trials there is a need for an adequately powered, high quality, multi-centre randomized controlled trial in adults that excludes 'simple to wean' patients. There is a pressing need for further technological development and research in the paediatric population. PMID- 23740738 TI - How effective are geometric morphometric techniques for assessing functional shape variation? An example from the great ape temporomandibular joint. AB - Functional shape analyses have long relied on the use of shape ratios to test biomechanical hypotheses. This method is powerful because of the ease with which results are interpreted, but these techniques fall short in quantifying complex morphologies that may not have a strong biomechanical foundation but may still be functionally informative. In contrast, geometric morphometric methods are continually being adopted for quantifying complex shapes, but they tend to prove inadequate in functional analyses because they have little foundation in an explicit biomechanical framework. The goal of this study was to evaluate the intersection of these two methods using the great ape temporomandibular joint as a case study. Three-dimensional coordinates of glenoid fossa and mandibular condyle shape were collected using a Microscribe digitizer. Linear distances extracted from these landmarks were analyzed using a series of one-way ANOVAs; further, the landmark configurations were analyzed using geometric morphometric techniques. Results suggest that the two methods are broadly similar, although the geometric morphometric data allow for the identification of shape differences among taxa that were not immediately apparent in the univariate analyses. Furthermore, this study suggests several new approaches for translating these shape data into a biomechanical context by adjusting the data using a biomechanically relevant variable. PMID- 23740740 TI - Insights into polypharmacology from drug-domain associations. AB - MOTIVATION: Polypharmacology (the ability of a single drug to affect multiple targets) is a key feature that may explain part of the decreasing success of conventional drug discovery strategies driven by the quest for drugs to act selectively on a single target. Most drug targets are proteins that are composed of domains (their structural and functional building blocks). RESULTS: In this work, we model drug-domain networks to explore the role of protein domains as drug targets and to explain drug polypharmacology in terms of the interactions between drugs and protein domains. We find that drugs are organized around a privileged set of druggable domains. CONCLUSIONS: Protein domains are a good proxy for drug targets, and drug polypharmacology emerges as a consequence of the multi-domain composition of proteins. CONTACT: amoyag@uma.es SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23740739 TI - In vivo laser assisted microvascular repair and end-to-end anastomosis by means of indocyanine green-infused chitosan patches: a pilot study. AB - BACKGROUND AND OBJECTIVES: Laser-based repairing techniques offer several advantages respect to standard suturing in microsurgery. In this work we evaluate the applicability and feasibility of two innovative laser-based approaches for microvascular repair and anastomoses: (1) laser-assisted vascular repair (LAVR); (2) laser-assisted end-to-end vascular anastomosis (LAVA). All these procedures have been executed by the use of diode laser irradiation and chitosan-patches infused with Indocyanine Green (ICG). STUDY DESIGN/MATERIALS AND METHODS: Experiments were performed on 30 rabbits. Twenty animals underwent LAVR and 10 end-to-end LAVA procedures. In the LAVR group, a 5-mm longitudinal cut was performed on the common carotid artery (CCA), then an ICG-infused chitosan patch was topically applied and laser-soldered over the arterial lesion. In the LAVA group the end-to-end anastomosis was executed on CCA by means of application of the three interrupted sutures and subsequent laser soldering of the ICG-infused patch. Animals underwent different follow-up periods (2, 7, 30, and 90 days). At the end of every follow-up, the animals were re-anesthetized and a microdoppler analysis was performed in order to check patency of the treated vessels. Then soldered segments were excised and subjected to histological and ultrastructural evaluations. RESULTS: At the end of surgery no bleeding from the treated segment was observed; all the treated vessels were patent. At the end of follow-up periods, no signs of perivascular haemorrhage were found. An intraoperative microdoppler evaluation assessed the patency of all the treated vessels. Histology showed a good reorganization of the vascular wall structures and an early endothelial regeneration was observed by SEM. CONCLUSIONS: Our study demonstrated the efficacy of laser tissue soldering by means of ICG-infused chitosan patches for the in vivo repairing of microvascular lesions and end-to end anastomoses. This approach offers several advantages over conventional suturing methods and is technically easy to perform, minimizing the surgical trauma to vessels. PMID- 23740741 TI - DIGEP-Pred: web service for in silico prediction of drug-induced gene expression profiles based on structural formula. AB - SUMMARY: Experimentally found gene expression profiles are used to solve different problems in pharmaceutical studies, such as drug repositioning, resistance, toxicity and drug-drug interactions. A special web service, DIGEP Pred, for prediction of drug-induced changes of gene expression profiles based on structural formulae of chemicals has been developed. Structure-activity relationships for prediction of drug-induced gene expression profiles were determined by Prediction of Activity Spectra for Substances (PASS) software. Comparative Toxicogenomics Database with data on the known drug-induced gene expression profiles of chemicals was used to create mRNA- and protein-based training sets. An average prediction accuracy for the training sets (ROC AUC) calculated by leave-one-out cross-validation on the basis of mRNA data (1385 compounds, 952 genes, 500 up- and 475 down-regulations) and protein data (1451 compounds, 139 genes, 93 up- and 55 down-regulations) exceeded 0.85. AVAILABILITY: Freely available on the web at http://www.way2drug.com/GE. PMID- 23740742 TI - WhichCyp: prediction of cytochromes P450 inhibition. AB - SUMMARY: In this work we present WhichCyp, a tool for prediction of which cytochromes P450 isoforms (among 1A2, 2C9, 2C19, 2D6 and 3A4) a given molecule is likely to inhibit. The models are built from experimental high-throughput data using support vector machines and molecular signatures. AVAILABILITY: The WhichCyp server is freely available for use on the web at http://drug.ku.dk/whichcyp, where the WhichCyp Java program and source code is also available for download. PMID- 23740743 TI - Alternative polyadenylation sites reveal distinct chromatin accessibility and histone modification in human cell lines. AB - MOTIVATION: In addition to alternative splicing, alternative polyadenylation has also been identified as a critical and prevalent regulatory mechanism in human gene expression. However, the mechanism of alternative polyadenylation selection and the involved factors is still largely unknown. RESULTS: We use the ENCODE data to scan DNA functional elements, including chromatin accessibility and histone modification, around transcript cleavage sites. Our results demonstrate that polyadenylation sites tend to be less sensitive to DNase I. However, these polyadenylation sites have preference in nucleosome-depleted regions, indicating the involvement of chromatin higher-order structure rather than nucleosomes in the resultant lower chromatin accessibility. More interestingly, for genes using two polyadenylation sites, the distal sites show even lower chromatin accessibility compared with the proximal sites or the unique sites of genes using only one polyadenylation site. We also observe that the histone modification mark, histone H3 lysine 36 tri-methylation (H3K36Me3), exhibits different patterns around the cleavage sites of genes using multiple polyadenylation sites from those of genes using a single polyadenylation site. Surprisingly, the H3K36Me3 levels are comparable among the alternative polyadenylation sites themselves. In summary, polyadenylation and alternative polyadenylation are closely related to functional elements on the DNA level. CONTACT: liang.chen@usc.edu. PMID- 23740744 TI - opm: an R package for analysing OmniLog(R) phenotype microarray data. AB - SUMMARY: opm is an R package designed to analyse multidimensional OmniLog(r) phenotype microarray (PM) data. opm provides management, visualization and statistical analysis of PM data, including curve-parameter estimation and discretization, dedicated and customizable plots, metadata management, automated generation of textual and tabular reports, mapping of substrates to databases, batch conversion of files and export to phylogenetic software in the YAML markup language. AVAILABILITY: opm is distributed under the GPL through the Comprehensive R Archive Network (http://cran.r-project.org/package=opm) along with a comprehensive manual and a user-friendly tutorial. Further information may be found at http://www.dsmz.de/research/microorganisms/projects/. CONTACT: johannes.sikorski@dsmz.de. PMID- 23740745 TI - Triplex-Inspector: an analysis tool for triplex-mediated targeting of genomic loci. AB - SUMMARY: At the heart of many modern biotechnological and therapeutic applications lies the need to target specific genomic loci with pinpoint accuracy. Although landmark experiments demonstrate technological maturity in manufacturing and delivering genetic material, the genomic sequence analysis to find suitable targets lags behind. We provide a computational aid for the sophisticated design of sequence-specific ligands and selection of appropriate targets, taking gene location and genomic architecture into account. AVAILABILITY: Source code and binaries are downloadable from www.bioinformatics.org.au/triplexator/inspector. CONTACT: t.bailey@uq.edu.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23740746 TI - Exploration of conformational transition pathways from coarse-grained simulations. AB - MOTIVATION: A new algorithm to trace conformational transitions in proteins is presented. The method uses discrete molecular dynamics as engine to sample protein conformational space. A multiple minima Go-like potential energy function is used in combination with several enhancing sampling strategies, such as metadynamics, Maxwell Demon molecular dynamics and essential dynamics. The method, which shows an unprecedented computational efficiency, is able to trace a wide range of known experimental transitions. Contrary to simpler methods our strategy does not introduce distortions in the chemical structure of the protein and is able to reproduce well complex non-linear conformational transitions. The method, called GOdMD, can easily introduce additional restraints to the transition (presence of ligand, known intermediate, known maintained contacts, ...) and is freely distributed to the community through the Spanish National Bioinformatics Institute (http://mmb.irbbarcelona.org/GOdMD). AVAILABILITY: Freely available on the web at http://mmb.irbbarcelona.org/GOdMD. PMID- 23740747 TI - Pathway Processor 2.0: a web resource for pathway-based analysis of high throughput data. AB - SUMMARY: Pathway Processor 2.0 is a web application designed to analyze high throughput datasets, including but not limited to microarray and next-generation sequencing, using a pathway centric logic. In addition to well-established methods such as the Fisher's test and impact analysis, Pathway Processor 2.0 offers innovative methods that convert gene expression into pathway expression, leading to the identification of differentially regulated pathways in a dataset of choice. AVAILABILITY AND IMPLEMENTATION: Pathway Processor 2.0 is available as a web service at http://compbiotoolbox.fmach.it/pathwayProcessor/. Sample datasets to test the functionality can be used directly from the application. CONTACT: duccio.cavalieri@fmach.it SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23740748 TI - GSATools: analysis of allosteric communication and functional local motions using a structural alphabet. AB - MOTIVATION: GSATools is a free software package to analyze conformational ensembles and to detect functional motions in proteins by means of a structural alphabet. The software integrates with the widely used GROMACS simulation package and can generate a range of graphical outputs. Three applications can be supported: (i) investigation of the conformational variability of local structures; (ii) detection of allosteric communication; and (iii) identification of local regions that are critical for global functional motions. These analyses provide insights into the dynamics of proteins and allow for targeted design of functional mutants in theoretical and experimental studies. AVAILABILITY: The C source code of the GSATools, along with a set of pre-compiled binaries, is freely available under GNU General Public License from http://mathbio.nimr.mrc.ac.uk/wiki/GSATools. PMID- 23740749 TI - An image-based multi-label human protein subcellular localization predictor (iLocator) reveals protein mislocalizations in cancer tissues. AB - MOTIVATION: Human cells are organized into compartments of different biochemical cellular processes. Having proteins appear at the right time to the correct locations in the cellular compartments is required to conduct their functions in normal cells, whereas mislocalization of proteins can result in pathological diseases, including cancer. RESULTS: To reveal the cancer-related protein mislocalizations, we developed an image-based multi-label subcellular location predictor, iLocator, which covers seven cellular localizations. The iLocator incorporates both global and local image descriptors and generates predictions by using an ensemble multi-label classifier. The algorithm has the ability to treat both single- and multiple-location proteins. We first trained and tested iLocator on 3240 normal human tissue images that have known subcellular location information from the human protein atlas. The iLocator was then used to generate protein localization predictions for 3696 protein images from seven cancer tissues that have no location annotations in the human protein atlas. By comparing the output data from normal and cancer tissues, we detected eight potential cancer biomarker proteins that have significant localization differences with P-value < 0.01. AVAILABILITY: http://www.csbio.sjtu.edu.cn/bioinf/iLocator/ PMID- 23740750 TI - Pathview: an R/Bioconductor package for pathway-based data integration and visualization. AB - SUMMARY: Pathview is a novel tool set for pathway-based data integration and visualization. It maps and renders user data on relevant pathway graphs. Users only need to supply their data and specify the target pathway. Pathview automatically downloads the pathway graph data, parses the data file, maps and integrates user data onto the pathway and renders pathway graphs with the mapped data. Although built as a stand-alone program, Pathview may seamlessly integrate with pathway and functional analysis tools for large-scale and fully automated analysis pipelines. AVAILABILITY: The package is freely available under the GPLv3 license through Bioconductor and R-Forge. It is available at http://bioconductor.org/packages/release/bioc/html/pathview.html and at http://Pathview.r-forge.r-project.org/. CONTACT: luo_weijun@yahoo.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23740751 TI - High-throughput instant quantification of protein expression and purity based on photoactive yellow protein turn off/on label. AB - Quantifying the concentration and purity of a target protein is essential for high-throughput protein expression test and rapid screening of highly soluble proteins. However, conventional methods such as PAGE and dot blot assay generally involve multiple time-consuming tasks requiring hours or do not allow instant quantification. Here, we demonstrate a new method based on the Photoactive yellow protein turn Off/On Label (POOL) system that can instantly quantify the concentration and purity of a target protein. The main idea of POOL is to use Photoactive Yellow Protein (PYP), or its miniaturized version, as a fusion partner of the target protein. The characteristic blue light absorption and the consequent yellow color of PYP is absent when initially expressed without its chromophore, but can be turned on by binding its chromophore, p-coumaric acid. The appearance of yellow color upon adding a precursor of chromophore to the co expressed PYP can be used to check the expression amount of the target protein via visual inspection within a few seconds as well as to quantify its concentration and purity with the aid of a spectrometer within a few minutes. The concentrations measured by the POOL method, which usually takes a few minutes, show excellent agreement with those by the BCA Kit, which usually takes ~1 h. We demonstrate the applicability of POOL in E. coli, insect, and mammalian cells, and for high-throughput protein expression screening. PMID- 23740752 TI - Cross-presentation of malaria antigen by brain microvessels: why CD8(+) T cells are critical for the pathogenesis of experimental cerebral malaria. PMID- 23740753 TI - Nanomaterials for ultrasensitive protein detection. AB - The advances of nanomaterials have provided exciting technologies and novel materials for protein detection, based on the unique properties associated with nanoscale phenomena such as plasmon resonance, catalysis and energy transfer. This article reviews a series of nanomaterials including nanoparticles, nanofibers, nanowires, and nanosheets, and evaluates their performances in the application for protein detection, focusing on approaches that realize ultrasensitive detection. Many of these nanomaterials were used to analyze clinically relevant protein biomarkers. Their detection in the picomolar, femtomolar or even zeptomolar regime has been realized, sometimes even with naked eye readout. We summarize the detection methods and results according to materials and targets, review the current challenges, and discuss the solution in the context of technological integration such as combining nanomaterials with microfluidics, and classical analytical technologies. PMID- 23740754 TI - Encore: Genetic Association Interaction Network centrality pipeline and application to SLE exome data. AB - Open source tools are needed to facilitate the construction, analysis, and visualization of gene-gene interaction networks for sequencing data. To address this need, we present Encore, an open source network analysis pipeline for genome wide association studies and rare variant data. Encore constructs Genetic Association Interaction Networks or epistasis networks using two optional approaches: our previous information-theory method or a generalized linear model approach. Additionally, Encore includes multiple data filtering options, including Random Forest/Random Jungle for main effect enrichment and Evaporative Cooling and Relief-F filters for enrichment of interaction effects. Encore implements SNPrank network centrality for identifying susceptibility hubs (nodes containing a large amount of disease susceptibility information through the combination of multivariate main effects and multiple gene-gene interactions in the network), and it provides appropriate files for interactive visualization of a network using tools from our online Galaxy instance. We implemented these algorithms in C++ using OpenMP for shared-memory parallel analysis on a server or desktop. To demonstrate Encore's utility in analysis of genetic sequencing data, we present an analysis of exome resequencing data from healthy individuals and those with Systemic Lupus Erythematous (SLE). Our results verify the importance of the previously associated SLE genes HLA-DRB and NCF2, and these two genes had the highest gene-gene interaction degrees among the susceptibility hubs. An additional 14 genes previously associated with SLE emerged in our epistasis network model of the exome data, and three novel candidate genes, ST8SIA4, CMTM4, and C2CD4B, were implicated in the model. In summary, we present a comprehensive tool for epistasis network analysis and the first such analysis of exome data from a genetic study of SLE. PMID- 23740756 TI - Fitting and interpreting continuous-time latent Markov models for panel data. AB - Multistate models characterize disease processes within an individual. Clinical studies often observe the disease status of individuals at discrete time points, making exact times of transitions between disease states unknown. Such panel data pose considerable modeling challenges. Assuming the disease process progresses accordingly, a standard continuous-time Markov chain (CTMC) yields tractable likelihoods, but the assumption of exponential sojourn time distributions is typically unrealistic. More flexible semi-Markov models permit generic sojourn distributions yet yield intractable likelihoods for panel data in the presence of reversible transitions. One attractive alternative is to assume that the disease process is characterized by an underlying latent CTMC, with multiple latent states mapping to each disease state. These models retain analytic tractability due to the CTMC framework but allow for flexible, duration-dependent disease state sojourn distributions. We have developed a robust and efficient expectation maximization algorithm in this context. Our complete data state space consists of the observed data and the underlying latent trajectory, yielding computationally efficient expectation and maximization steps. Our algorithm outperforms alternative methods measured in terms of time to convergence and robustness. We also examine the frequentist performance of latent CTMC point and interval estimates of disease process functionals based on simulated data. The performance of estimates depends on time, functional, and data-generating scenario. Finally, we illustrate the interpretive power of latent CTMC models for describing disease processes on a dataset of lung transplant patients. We hope our work will encourage wider use of these models in the biomedical setting. PMID- 23740755 TI - Personalized cytomic assessment of vascular health: Evaluation of the vascular health profile in diabetes mellitus. AB - BACKGROUND: An inexpensive and accurate blood test does not currently exist that can evaluate the cardiovascular health of a patient. This study evaluated a novel high dimensional flow cytometry approach in combination with cytometric fingerprinting (CF), to comprehensively enumerate differentially expressed subsets of pro-angiogenic circulating progenitor cells (CPCs), involved in the repair of vasculature, and microparticles (MPs), frequently involved in inflammation and thrombosis. CF enabled discovery of a unique pattern, involving both MPs and CPCs and generated a personalized signature of vascular health, the vascular health profile (VHP). METHODS: Levels of CPCs and MPs were measured with a broad panel of cell surface markers in a population with atherosclerosis and type 2 diabetes mellitus (DM) and age-similar Healthy controls (HC) using an unbiased computational approach, termed CF. RESULTS: Circulating hematopoietic stem and progenitor cell (CHSPCAng) levels were detected at significantly lower concentrations in DM (P < 0.001), whereas levels of seven phenotypically distinct MPs were present at significantly higher concentrations in DM patients and one MP subset was present at significantly lower concentration in DM patients. Collectively, the combination of CHSPC(Ang) and MP levels was more informative than any one measure alone. CONCLUSIONS: This work provides the basis for a personalized cytomic vascular health profile that may be useful for a variety of applications including drug development, clinical risk assessment and companion diagnostics. PMID- 23740757 TI - Bilateral ulcers on the face as a manifestation of granulomatosis with polyangiitis (Wegener's). PMID- 23740758 TI - Disorder-driven low-temperature anomalies in single-crystalline Ce2Co0.4Rh0.4Si3.2. AB - A single crystal of the cerium-based solid solution Ce2Co0.4Rh0.4Si3.2 was investigated by means of magnetic, resistivity and heat capacity measurements in wide ranges of temperature and external magnetic field. Our results confirmed that the phase remains paramagnetic down to 0.4 K. At low temperatures, some anomalous features due to intrinsic crystallographic disorder in the compound were observed. PMID- 23740759 TI - An aluminum-nitrogen based Lewis pair as an effective catalyst for the oligomerization of cyanamides: formation of acyclic C-N oligomers instead of thermodynamically favored cyclic aromatic trimers. PMID- 23740761 TI - Does flow experience lead to risk? How and for whom. AB - BACKGROUND: Previous research has focused on the positive consequences of flow, an intrinsically rewarding state of deep absorption. In contrast, the present research links flow to impaired risk awareness and to risky behaviour. We expected flow to enhance self-efficacy beliefs, which in turn were hypothesised to result in low risk awareness and risky behaviour in sports. In addition, we predicted that individuals' level of experience in the activity would moderate the expected effects. METHODS: One study with kayakers (Study 1) and two studies with rock climbers (Studies 2 and 3) were conducted. Kayakers completed a survey while still on the river; climbers responded during and upon completion of a climb. RESULTS: In all studies flow was related to risk awareness. Study 2 additionally showed its association with risky behaviour. Studies 2 and 3 revealed that these relationships were mediated by self-efficacy. The mediations were moderated by level of experience (Study 3). CONCLUSIONS: The results indicated that inexperienced but not experienced participants respond to self efficacy beliefs evoked by flow with impaired risk awareness and with risky behaviour. Theoretical implications for flow and risk research as well as practical implications for risk prevention are discussed. PMID- 23740760 TI - Haplotype kernel association test as a powerful method to identify chromosomal regions harboring uncommon causal variants. AB - For most complex diseases, the fraction of heritability that can be explained by the variants discovered from genome-wide association studies is minor. Although the so-called "rare variants" (minor allele frequency [MAF] < 1%) have attracted increasing attention, they are unlikely to account for much of the "missing heritability" because very few people may carry these rare variants. The genetic variants that are likely to fill in the "missing heritability" include uncommon causal variants (MAF < 5%), which are generally untyped in association studies using tagging single-nucleotide polymorphisms (SNPs) or commercial SNP arrays. Developing powerful statistical methods can help to identify chromosomal regions harboring uncommon causal variants, while bypassing the genome-wide or exome-wide next-generation sequencing. In this work, we propose a haplotype kernel association test (HKAT) that is equivalent to testing the variance component of random effects for distinct haplotypes. With an appropriate weighting scheme given to haplotypes, we can further enhance the ability of HKAT to detect uncommon causal variants. With scenarios simulated according to the population genetics theory, HKAT is shown to be a powerful method for detecting chromosomal regions harboring uncommon causal variants. PMID- 23740762 TI - Knockdown of the cochaperone SGTA results in the suppression of androgen and PI3K/Akt signaling and inhibition of prostate cancer cell proliferation. AB - Solid tumors have an increased reliance on Hsp70/Hsp90 molecular chaperones for proliferation, survival and maintenance of intracellular signaling systems. An underinvestigated component of the chaperone system is the tetratricopeptide repeat (TPR)-containing cochaperone, which coordinates Hsp70/Hsp90 involvement on client proteins as well as having diverse individual actions. A potentially important cochaperone in prostate cancer (PCa) is small glutamine-rich TPR containing protein alpha (SGTA), which interacts with the androgen receptor (AR) and other critical cancer-related client proteins. In this study, the authors used small interfering RNA coupled with genome-wide expression profiling to investigate the biological significance of SGTA in PCa and its influence on AR signaling. Knockdown of SGTA for 72 hr in PCa C4-2B cells significantly altered expression of >1,900 genes (58% decreased) and reduced cell proliferation (p < 0.05). The regulation of 35% of 5alpha-dihydrotestosterone (DHT) target genes was affected by SGTA knockdown, with gene-specific effects on basal or DHT-induced expression or both. Pathway analysis revealed a role for SGTA in p53, generic PCa and phosphoinositol kinase (PI3K) signaling pathways; the latter evident by a reduction in PI3K subunit p100beta levels and decreased phosphorylated Akt. Immunohistochemical analysis of 64 primary advanced PCa samples showed a significant increase in the AR:SGTA ratio in cancerous lesions compared to patient-matched benign prostatic hyperplasia tissue (p < 0.02). This study not only provides insight into the biological actions of SGTA and its effect on genome-wide AR transcriptional activity and other therapeutically targeted intracellular signaling pathways but also provides evidence for PCa-specific alterations in SGTA expression. PMID- 23740763 TI - Electrical stimulation with non-implanted electrodes for urinary incontinence in men. AB - BACKGROUND: Electrical stimulation with non-implanted devices is used for patients with different types of urinary incontinence and symptoms of urgency, frequency and nocturia. The current review focused on electrical stimulation with non-implanted devices for the treatment of urinary incontinence in men. OBJECTIVES: To determine the effectiveness of electrical stimulation with non implanted devices for men with stress, urgency or mixed urinary incontinence in comparison with no treatment, placebo treatment, or any other 'single' treatment. Additionally, the effectiveness of electrical stimulation with non-implanted devices in combination with another intervention was compared with the other intervention alone. Finally, the effectiveness of one method of electrical stimulation with non-implanted devices was compared with another method. SEARCH METHODS: We searched the Cochrane Incontinence Group Specialised Trials Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PreMEDLINE, and handsearching of journals and conference proceedings (searched 21 January 2012). We also searched other electronic and non-electronic bibliographic databases and the reference lists of the included studies as well as contacting researchers in the field to identify other relevant trials. SELECTION CRITERIA: Randomized and quasi-randomized controlled trials. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all the identified trials for eligibility. Risk of bias was assessed using the Cochrane tool for determining bias. Disagreements were resolved by discussion, and a third review author was involved in the case of no consensus. Data were analysed using Cochrane methods. MAIN RESULTS: Six randomized controlled trials (five full papers and one abstract) were included. There was considerable variation in the interventions used, study protocols, types of electrical stimulation parameters and devices, study populations and outcome measures. In total 544 men were included, of whom 305 received some form of electrical stimulation, and 239 a control or comparator treatment. The trials were mostly small and generally there was not sufficient information to assess risk of bias; only two trials used secure methods of randomization.There was some evidence that electrical stimulation (ES) had a short-term effect in reducing incontinence compared with sham treatment (for example risk ratio (RR) at six months 0.38, 95% CI 0.16 to 0.87) but not at 12 months. Four trials evaluated the effect of adding PFMT to ES versus pelvic floor muscle training (PFMT) alone or with biofeedback. There was no evidence of a statistically significant difference in the number of men with urinary incontinence at three months (146/239, 61% for combined treatment versus 98/156, 63% with PFMT alone; RR 0.93, 95% CI 0.82 to 1.06). However, there were more adverse effects with combined treatment (23/139, 17% versus 2/99, 2% with PFMT alone; RR 7.04, 95% CI 1.51 to 32.94) and quality of life also seemed better with PFMT alone. One small trial did not detect statistically significant differences between two methods of administration of transcutaneous electrical stimulation (anal versus perineal) but the quality of life score was lower (better) in the anal stimulation group. AUTHORS' CONCLUSIONS: There was some evidence that electrical stimulation enhanced the effect of PFMT in the short term but not after six months. There were, however, more adverse effects (pain or discomfort) with electrical stimulation. PMID- 23740764 TI - Antibiotic prophylaxis for preventing burn wound infection. AB - BACKGROUND: Infection of burn wounds is a serious problem because it can delay healing, increase scarring and invasive infection may result in the death of the patient. Antibiotic prophylaxis is one of several interventions that may prevent burn wound infection and protect the burned patient from invasive infections. OBJECTIVES: To assess the effects of antibiotic prophylaxis on rates of burn wound infection. SEARCH METHODS: In January 2013 we searched the Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid MEDLINE - In-Process & Other Non-Indexed Citations (2013); Ovid EMBASE; EBSCO CINAHL and reference lists of relevant articles. There were no restrictions with respect to language, date of publication or study setting. SELECTION CRITERIA: All randomised controlled trials (RCTs) that evaluated the efficacy and safety of antibiotic prophylaxis for the prevention of BWI. Quasi-randomised studies were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed the risk of bias, and extracted relevant data. Risk ratio (RR) and mean difference (MD) were estimated for dichotomous data and continuous data, respectively. When sufficient numbers of comparable RCTs were available, trials were pooled in a meta-analysis to estimate the combined effect. MAIN RESULTS: This review includes 36 RCTs (2117 participants); twenty six (72%) evaluated topical antibiotics, seven evaluated systemic antibiotics (four of these administered the antibiotic perioperatively and three administered upon hospital admission or during routine treatment), two evaluated prophylaxis with non absorbable antibiotics, and one evaluated local antibiotics administered via the airway.The 11 trials (645 participants) that evaluated topical prophylaxis with silver sulfadiazine were pooled in a meta analysis. There was a statistically significant increase in burn wound infection associated with silver sulfadiazine compared with dressings/skin substitute (OR = 1.87; 95% CI: 1.09 to 3.19, I(2) = 0%). These trials were at high, or unclear, risk of bias. Silver sulfadiazine was also associated with significantly longer length of hospital stay compared with dressings/skin substitute (MD = 2.11 days; 95% CI: 1.93 to 2.28).Systemic antibiotic prophylaxis in non-surgical patients was evaluated in three trials (119 participants) and there was no evidence of an effect on rates of burn wound infection. Systemic antibiotics (trimethoprim sulfamethoxazole) were associated with a significant reduction in pneumonia (only one trial, 40 participants) (RR = 0.18; 95% CI: 0.05 to 0.72) but not sepsis (two trials 59 participants) (RR = 0.43; 95% CI: 0.12 to 1.61).Perioperative systemic antibiotic prophylaxis had no effect on any of the outcomes of this review.Selective decontamination of the digestive tract with non-absorbable antibiotics had no significant effect on rates of all types of infection (2 trials, 140 participants). Moreover, there was a statistically significant increase in rates of MRSA associated with use of non-absorbable antibiotics plus cefotaxime compared with placebo (RR = 2.22; 95% CI: 1.21 to 4.07).There was no evidence of a difference in mortality or rates of sepsis with local airway antibiotic prophylaxis compared with placebo (only one trial, 30 participants). AUTHORS' CONCLUSIONS: The conclusions we are able to draw regarding the effects of prophylactic antibiotics in people with burns are limited by the volume and quality of the existing research (largely small numbers of small studies at unclear or high risk of bias for each comparison). The largest volume of evidence suggests that topical silver sulfadiazine is associated with a significant increase in rates of burn wound infection and increased length of hospital stay compared with dressings or skin substitutes; this evidence is at unclear or high risk of bias. Currently the effects of other forms of antibiotic prophylaxis on burn wound infection are unclear. One small study reported a reduction in incidence of pneumonia associated with a specific systematic antibiotic regimen. PMID- 23740765 TI - Interventions for promoting participation in shared decision-making for children with cancer. AB - BACKGROUND: Children's rights to have their views heard in matters that affect their lives are now well established since the publication of the UN Convention treaty (1989). Children with cancer generally prefer to be involved in decision making and consider it important that they have the opportunity to take part in decision-making concerning their health care, even in end-of-life decisions. There is considerable support for involving children in healthcare decision making at a level commensurate with their experience, age and abilities. Thus healthcare professionals and parents need to know how they should involve children in decision-making and what interventions are most effective in promoting shared decision-making (SDM) for children with cancer. OBJECTIVES: To examine the effects of SDM interventions on the process of SDM for children with cancer who are aged four to 18 years. SEARCH METHODS: We searched the following sources: Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library, Issue 9, 2012); PubMed (1946 to September 2012); EMBASE (1974 to September 2012); CINAHL (1982 to September 2012); PsycINFO (1806 to September 2012); BIOSIS (1980 to December 2009 - subscription ceased at that date); ERIC (1966 to September 2012); ProQuest Dissertations and Theses (1637 to September 2012); and Sociological Abstracts (1952 to September 2012). We searched for information about trials not registered in these resources, either published or unpublished, by searching the reference lists of relevant articles and review articles and the following conference proceedings (2005-2012):American Academy on Communication in Healthcare (AACH), European Society for Medical Oncology (ESMO), European Cancer Conference (ECCO), European Association for Communication in Healthcare (EACH), International Conference on Communication in Healthcare (ICCH), International Shared Decision Making Conference (ISDM 2005-2011 as held every two years), Annual Conference of the International Society for Paediatric Oncology (SIOP) and Annual Scientific Meeting of the Society for Medical Decision Making (SMDM).We searched the International Scientific and Technical Proceedings database (2005 to September 2012). We also searched Dissertation Abstracts (from 1980 to September 2012).We scanned the ISRCTN (International Standard Randomized Controlled Trial Number) register and the National Institute of Health (NIH) Register for ongoing trials at: www.controlled-trials.com and clinicaltrials.gov on the 1 October 2012. We contacted authors for further details. We also contacted experts in this field.We did not impose language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) of SDM interventions for children with cancer aged four to 18 years. The types of decisions included were: treatment, health care, and research participation decisions. The primary outcome was SDM as measured with any validated scale. DATA COLLECTION AND ANALYSIS: Two review authors undertook the searches, and three review authors independently assessed the studies obtained. We contacted study authors for additional information. MAIN RESULTS: No studies met the inclusion criteria, and hence no analysis could be undertaken. AUTHORS' CONCLUSIONS: No conclusions can be made on the effects of interventions to promote SDM for children with cancer aged four to 18 years. This review has highlighted the dearth of high-quality quantitative research on interventions to promote participation in SDM for children with cancer. There are many potential reasons for the lack of SDM intervention studies with children. Attitudes towards children's participation are slowly changing in society and such changes may take time to be translated or adopted in healthcare settings. The priority may be on developing interventions that promote children's participation in communication interactions since information-sharing is a prerequisite for SDM. Restricting this review to RCTs was a limitation and extending the review to non-randomised studies (NRS) may have produced more evidence. We plan to expand the types of studies in future updates. Clearly more research is needed. PMID- 23740766 TI - Foam dressings for healing diabetic foot ulcers. AB - BACKGROUND: Foot ulcers in people with diabetes are a prevalent and serious global health issue. Dressings form a key part of ulcer treatment, with clinicians and patients having many different types to choose from. A clear and current overview of current evidence is required to facilitate decision-making regarding dressing use. OBJECTIVES: The review aimed to evaluate the effects of foam wound dressings on the healing of foot ulcers in people with diabetes. SEARCH METHODS: For this first update we searched the following databases the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL in April 2013. There were no restrictions based on language or date of publication. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) that evaluated the effects on ulcer healing of one or more foam wound dressings in the treatment of foot ulcers in people with diabetes. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: We included six studies (157 participants) in this review. Meta analysis of two studies indicated that foam dressings do not promote the healing of diabetic foot ulcers compared with basic wound contact dressings (RR 2.03, 95%CI 0.91 to 4.55). Pooled data from two studies comparing foam and alginate dressing found no statistically significant difference in ulcer healing (RR 1.50, 95% CI 0.92 to 2.44). There was no statistically significant difference in the number of diabetic foot ulcers healed when foam dressings were compared with hydrocolloid (matrix) dressings. All included studies were small and/or had limited follow-up times. AUTHORS' CONCLUSIONS: Currently there is no research evidence to suggest that foam wound dressings are more effective in healing foot ulcers in people with diabetes than other types of dressing however all trials in this field are very small. Decision makers may wish to consider aspects such as dressing cost and the wound management properties offered by each dressing type e.g. exudate management. PMID- 23740767 TI - High-optical-quality ferroelectric film wet-processed from a ferroelectric columnar liquid crystal as observed by non-linear-optical microscopy. AB - The self-organization of ferroelectric columnar liquid crystals (FCLCs) is demonstrated. Columnar order is spontaneously formed in thin films made by the wet-process due to its liquid crystallinity. Electric-field application results in high optical quality and uniform spontaneous polarization. Such good processability and controllability of the wet-processed FCLC films provide us with potential organic ferroelectric materials for device applications. PMID- 23740768 TI - Imaging and characterization of bioengineered blood vessels within a bioreactor using free-space and catheter-based OCT. AB - BACKGROUND AND OBJECTIVE: Regenerative medicine involves the bioengineering of a functional tissue or organ by seeding living cells on a biodegradable scaffold cultured in a bioreactor. A major barrier to creating functional tissues, however, has been the inability to monitor the dynamic and complex process of scaffold maturation in real time, making control and optimization extremely difficult. Current methods to assess maturation of bioengineered constructs, such as histology or organ bath physiology, are sample-destructive. Optical coherence tomography (OCT) has recently emerged as a key modality for structural assessment of native blood vessels as well as engineered vessel mimics. The objective of this study was to monitor and assess in real time the development of a bioengineered blood vessel using a novel approach of combining both free-space and catheter-based OCT imaging in a new quartz-walled bioreactor. Development of the blood vessel was characterized by changes in thickness and scattering coefficient over a 30-day period. MATERIALS AND METHODS: We constructed a novel blood vessel bioreactor utilizing a rotating cylindrical quartz cuvette permitting free-space OCT imaging of an installed vessel's outer surface. A vascular endoscopic OCT catheter was used to image the lumen of the vessels. The quartz cuvette permits 360 degree, free-space OCT imaging of the blood vessel. Bioengineered blood vessels were fabricated using biodegradable polymers (15% PCL/collagen, ~300 um thick) and seeded with CH3 10t1/2 mesenchymal stem cells. A swept-source OCT imaging system comprised of a 20 kHz tunable laser (Santec HSL2000) with 1,300 nm central wavelength and 110 nm FWHM bandwidth was used to assess the vessels. OCT images were obtained at days 1, 4, 7, 14, 21, and 30. Free-space (exterior surface) OCT images were co-registered with endoscopic OCT images to determine the vessel wall thickness. DAPI-stained histological sections, acquired at same time point, were evaluated to quantify wall thickness and cellular infiltration. Non-linear curve fitting of free-space OCT data to the extended Huygen-Fresnel model was performed to determine optical scattering properties. RESULTS: Vessel wall thickness increased from 435 +/- 15 um to 610 +/ 27 um and Vessel scattering coefficient increased from 3.73 +/- 0.32 cm-1 to 5.74 +/- 0.06 cm-1 over 30 days. Histological studies showed cell migration from the scaffold surface toward the lumen and cell proliferation over the same time course. The imaging procedure did not have any significant impact on scaffold dimensions, cell migration, or cell proliferation. CONCLUSIONS: This study suggests that combination of free-space and catheter-based OCT for blood vessel imaging provides accurate structural information of the developing blood vessel. We determined that free-space OCT images could be co-registered with catheter based OCT images to monitor structural features such as wall thickness or delamination of the developing tissue-engineered blood vessel within a bioreactor. Structural parameters and optical properties obtained from OCT imaging correlate with histological sections of the blood vessel and could potentially be used as markers to non-invasively and non-destructively assess regeneration of engineered tissues in real time. PMID- 23740769 TI - Field- and temperature-induced evolution of the magnetocaloric effect in Ba0.3Sr1.7Co2Fe12O22 single crystals with heliconical magnetism. AB - The magnetocaloric effect (MCE) associated with the spin transitions of alternating longitudinal conical (ALC)-mixed conical (MC) and MC-ferrimagnetic (FIM) states in a Ba0.3Sr1.7Co2Fe12O22 single crystal has been investigated. For magnetic field directions applied along either the [120] or [001] directions, the crystal is found to exhibit the conventional and inverse MCE near the ALC-MC (T(N1) = 235 K) and MC-FIM (T(N2) = 348 K) states, respectively. The dependence of the magnetic entropy on the magnetic field also exhibits such sign change behaviors in the MCE, which is attributed to the magnetic field induced gradual collapse of heliconical magnetic order. PMID- 23740770 TI - The role of tyrosine sulfation in the dimerization of the CXCR4:SDF-1 complex. AB - Oligomerization of G protein-coupled receptors is a recognized mode of regulation of receptor activities, with alternate oligomeric states resulting in different signaling functions. The CXCR4 chemokine receptor is a G protein-coupled receptor that is post-translationally modified by tyrosine sulfation at three sites on its N-terminus (Y7, Y12, Y21), leading to enhanced affinity for its ligand, stromal cell derived factor (SDF-1, also called CXCL12). The complex has been implicated in cancer metastasis and is a therapeutic target in cancer treatment. Using molecular dynamics simulation of NMR-derived structures of the CXCR4 N-terminus in complex with SDF-1, and calculations of electrostatic binding energies for these complexes, we address the role of tyrosine sulfation in this complex. Our results show that sulfation stabilizes the dimeric state of the CXCR4:SDF-1 complex through hydrogen bonding across the dimer interface, conformational changes in residues at the dimer interface, and an enhancement in electrostatic binding energies associated with dimerization. These findings suggest a mechanism through which post-translational modifications such as tyrosine sulfation might regulate downstream function through modulation of the oligomeric state of the modified system. PMID- 23740771 TI - HER2 and breast cancer stem cells: more than meets the eye. AB - The development of HER2 targeting agents has dramatically altered the natural history of HER2-positive breast cancer and is often cited as a prime example of the effectiveness of molecularly targeted therapy. Emerging data suggest that the remarkable clinical efficacy of these agents may be related to their ability to target the breast cancer stem cell (CSC) population. A new study suggests that the regulation of BCSCs by HER2 may extend to breast cancers that do not display HER2 gene amplification. In these tumors, HER2 is selectively expressed in the CSC population, and this expression is regulated by the tumor microenvironment. In mouse models, trastuzumab blocked growth of these HER2-negative tumors when administered in the adjuvant setting but had no effect on established tumors. These studies provide a potential biologic explanation for retrospective analysis of clinical trials, which surprisingly suggest that the clinical benefits of adjuvant trastuzumab may extend to women currently classified as HER2-negative. In addition to having significant implications for breast cancer therapy, these studies suggest the need to reevaluate the role of HER2 in regulating CSCs in other tumor types. Furthermore, these studies suggest that effective adjuvant therapies may need to target the CSC population. PMID- 23740772 TI - From integrative genomics to therapeutic targets. AB - Combinatorial approaches that integrate conventional pathology with genomic profiling and functional genomics have begun to enhance our understanding of the genetic basis of breast cancer. These methods have identified key genotypic phenotypic correlations in different breast cancer subtypes that have led to the discovery of genetic dependencies that drive their behavior. Moreover, this knowledge has been applied to define novel tailored therapies for these groups of patients with cancer. With the current emphasis on characterizing the mutational repertoire of breast cancers by next-generation sequencing, the question remains as to what constitutes a driver event. By focusing efforts on homogenous subgroups of breast cancer and integrating orthogonal data-types combined with functional approaches, we can begin to unravel the heterogeneity and identify aberrations that can be therapeutically targeted. PMID- 23740773 TI - Peripheral G protein-coupled inwardly rectifying potassium channels are involved in delta-opioid receptor-mediated anti-hyperalgesia in rat masseter muscle. AB - BACKGROUND: Although the efficacy of peripherally administered opioid has been demonstrated in preclinical and clinical studies, the underlying mechanisms of its anti-hyperalgesic effects are poorly understood. G protein-coupled inwardly rectifying potassium (GIRK) channels are linked to opioid receptors in the brain. However, the role of peripheral GIRK channels in analgesia induced by peripherally administered opioid, especially in trigeminal system, is not clear. METHODS: Expression of GIRK subunits in rat trigeminal ganglia (TG) was examined with reverse transcription-polymerase chain reaction, Western blot and immunohistochemistry. Chemical profiles of GIRK-expressing neurons in TG were further characterized. Behavioural and Fos experiments were performed to examine the functional involvement of GIRK channels in delta-opioid receptor (DOR) mediated anti-hyperalgesia under an acute myositis condition. RESULTS: TG expressed mRNA and proteins for GIRK1 and GIRK2 subunits. Majority of GIRK1- and GIRK2-expressing neurons were non-peptidergic afferents. Inhibition of peripheral GIRK using Tertiapin-Q (TPQ) attenuated antinociceptive effects of peripherally administered DOR agonist, [D-Pen(2), D-Pen(6) ]-enkephalin (DPDPE), on mechanical hypersensitivity in masseter muscle. Furthermore, TPQ attenuated the suppressive effects of peripheral DPDPE on neuronal activation in the subnucleus caudalis of the trigeminal nucleus (Vc) following masseteric injection of capsaicin. CONCLUSIONS: Our data indicate that peripheral DOR agonist-induced suppression of mechanical hypersensitivity in the masseter muscle involves the activity of peripheral GIRK channels. These results could provide a rationale for developing a novel therapeutic approach using peripheral GIRK channel openers to mimic or supplement the effects of peripheral opioid agonist. PMID- 23740774 TI - Increased coexpression of c-KIT and FLT3 receptors on myeloblasts: independent predictor of poor outcome in pediatric acute myeloid leukemia. AB - BACKGROUND: Significance of mutations in FLT3 and c-KIT genes in AML has been well established, but role of their coexpression has not been evaluated. The aim of this study was to evaluate clinical significance of FLT3 (CD135) and c-KIT (CD117) coexpression on myeloblasts in AML. METHODS: Using flow-cytometry, we prospectively observed in 115 AML patients that CD135, CD117, and CD135+CD117 coexpression was expressed in 95 (82%), 104 (90%), and 81 (70%) patients respectively. Median expression of CD135, CD117, and their co expression was used as cut off for high and low expression. RESULTS: FLT3 ITD (internal tandem duplication) was present in 20 (17%) patients. High coexpression did not correlate with FLT3 ITD (P = 0.432) and cytogenetics (P = 0.244). Out of 115 patients, 86 (74.7%) achieved remission. At median followup of 15.5 months, EFS and OS was 29% and 35%, respectively for the entire cohort. Patients with high coexpression of CD135 and CD117 in comparison to those with low coexpression had significantly inferior EFS (20% vs 38% P < 0.001) and OS (27% vs 44% P = 0.001). In step wise Cox regression multivariable analysis, hazard ratio for high hemoglobin, WBC count, and coexpression of CD135 and CD117 was 0.63, 1.73, and 2.46 respectively for EFS, and for OS only CD135+CD117 coexpression emerged as an independent predictor (hazard ratio 2.25). CONCLUSIONS: This is the first study to show that high coexpression of CD135+CD117 is an independent predictor of poor outcome in AML and is easily measurable by routine diagnostic flow-cytometry. PMID- 23740776 TI - A general framework for robust and efficient association analysis in family-based designs: quantitative and dichotomous phenotypes. AB - Although transmission disequilibrium tests (TDT) and the FBAT statistic are robust against population substructure, they have reduced statistical power, as compared with fully efficient tests that are not guarded against confounding because of population substructure. This has often limited the application of transmission disequilibrium tests/FBATs to candidate gene analysis, because, in a genome-wide association study, population substructure can be adjusted by approaches such as genomic control and EIGENSTRAT. Here, we provide new statistical methods for the analysis of quantitative and dichotomous phenotypes in extended families. Although the approach utilizes the polygenic model to maximize the efficiency, it still preserves the robustness to non-normality and misspecified covariance structures. In addition, the proposed method performs better than the existing methods for dichotomous phenotype, and the new transmission disequilibrium test for candidate gene analysis is more efficient than FBAT statistics. PMID- 23740775 TI - Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: evidence from genome-wide analysis. AB - OBJECTIVE: To identify genetic determinants of granulomatosis with polyangiitis (Wegener's) (GPA). METHODS: We carried out a genome-wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls. RESULTS: Genome-wide significant associations were identified in 32 single-nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA-DPB1 and HLA-DPA1 genes encoding the class II major histocompatibility complex (MHC) DPbeta chain 1 and DPalpha chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPbeta chain 1) and rs9277341 (DPalpha chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 * 10(-50) and 2.18 * 10(-39) , respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA-DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome-wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 * 10(-8) ). CONCLUSION: We identified the SEMA6A and HLA-DP loci as significant contributors to risk for GPA, with the HLA-DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA. PMID- 23740777 TI - Histopathologic parameters in chronic rhinosinusitis with nasal polyposis: impact on quality of life outcomes. AB - BACKGROUND: Chronic rhinosinusitis (CRS) is a common disease with a significant impact on health-related quality of life (QOL) of the patient. Histologic inflammatory markers in CRS are an important marker in determining the severity of the disease. In this study, we evaluated the association of histopathologic parameters with QOL questionnaires in patients with CRS with nasal polyposis after endoscopic sinus surgery (ESS). METHODS: A total of 57 patients were included in this study. Preoperative patient characteristics, clinical findings, and computed tomography scores were recorded. Two QOL measures, the Rhinosinusitis Disability Index (RSDI) and Short Form-36 General Health Survey (SF-36) were analyzed preoperatively and postoperatively. Sinus mucosal specimens were collected at the time of surgery. Presence of the inflammation was evaluated with cellular (eosinophils, neutrophils, lymphocytes, mast cells, macrophages), epithelial (basement membrane thickness [BMT], goblet cell) and stromal markers (subepithelial edema). The histopathological findings were compared statistically with the QOL measures. RESULTS: In comparison of the absolute change of the RSDI and SF-36 scores with mucosal eosinophilia, patients with eosinophilia showed significantly less improvement only in the SF-36 physical functioning subscale (p = 0.004). There was a statistically significant relationship between BMT and RSDI total (p = 0.042), emotional scores (p = 0.003), SF-36 general health (p = 0.032), SF-36 physical function (p = 0.007), SF-36 bodily pain (p = 0.044), and SF-36 mental health (p = 0.022). CONCLUSION: For most patients QOL significantly improved after surgery. Mucosal eosinophilia did not correlate with the absolute change of the RSDI. However, thickening of basal membrane adversely affects symptoms of the patients and correlates with the disease severity. PMID- 23740778 TI - Clocks for the city: circadian differences between forest and city songbirds. AB - To keep pace with progressing urbanization organisms must cope with extensive habitat change. Anthropogenic light and noise have modified differences between day and night, and may thereby interfere with circadian clocks. Urbanized species, such as birds, are known to advance their activity to early morning and night hours. We hypothesized that such modified activity patterns are reflected by properties of the endogenous circadian clock. Using automatic radio-telemetry, we tested this idea by comparing activity patterns of free-living forest and city European blackbirds (Turdus merula). We then recaptured the same individuals and recorded their activity under constant conditions. City birds started their activity earlier and had faster but less robust circadian oscillation of locomotor activity than forest conspecifics. Circadian period length predicted start of activity in the field, and this relationship was mainly explained by fast-paced and early-rising city birds. Although based on only two populations, our findings point to links between city life, chronotype and circadian phenotype in songbirds, and potentially in other organisms that colonize urban habitats, and highlight that urban environments can significantly modify biologically important rhythms in wild organisms. PMID- 23740779 TI - Giant lizards occupied herbivorous mammalian ecospace during the Paleogene greenhouse in Southeast Asia. AB - Mammals dominate modern terrestrial herbivore ecosystems, whereas extant herbivorous reptiles are limited in diversity and body size. The evolution of reptile herbivory and its relationship to mammalian diversification is poorly understood with respect to climate and the roles of predation pressure and competition for food resources. Here, we describe a giant fossil acrodontan lizard recovered with a diverse mammal assemblage from the late middle Eocene Pondaung Formation of Myanmar, which provides a historical test of factors controlling body size in herbivorous squamates. We infer a predominately herbivorous feeding ecology for the new acrodontan based on dental anatomy, phylogenetic relationships and body size. Ranking body masses for Pondaung Formation vertebrates indicates that the lizard occupied a size niche among the larger herbivores and was larger than most carnivorous mammals. Paleotemperature estimates of Pondaung Formation environments based on the body size of the new lizard are approximately 2-5 degrees C higher than modern. These results indicate that competitive exclusion and predation by mammals did not restrict body size evolution in these herbivorous squamates, and elevated temperatures relative to modern climates during the Paleogene greenhouse may have resulted in the evolution of gigantism through elevated poikilothermic metabolic rates and in response to increases in floral productivity. PMID- 23740780 TI - Ecological variation in South American geophagine cichlids arose during an early burst of adaptive morphological and functional evolution. AB - Diversity and disparity are unequally distributed both phylogenetically and geographically. This uneven distribution may be owing to differences in diversification rates between clades resulting from processes such as adaptive radiation. We examined the rate and distribution of evolution in feeding biomechanics in the extremely diverse and continentally distributed South American geophagine cichlids. Evolutionary patterns in multivariate functional morphospace were examined using a phylomorphospace approach, disparity-through time analyses and by comparing Brownian motion (BM) and adaptive peak evolutionary models using maximum likelihood. The most species-rich and functionally disparate clade (CAS) expanded more efficiently in morphospace and evolved more rapidly compared with both BM expectations and its sister clade (GGD). Members of the CAS clade also exhibited an early burst in functional evolution that corresponds to the development of modern ecological roles and may have been related to the colonization of a novel adaptive peak characterized by fast oral jaw mechanics. Furthermore, reduced ecological opportunity following this early burst may have restricted functional evolution in the GGD clade, which is less species-rich and more ecologically specialized. Patterns of evolution in ecologically important functional traits are consistent with a pattern of adaptive radiation within the most diverse clade of Geophagini. PMID- 23740781 TI - Optimal behaviour can violate the principle of regularity. AB - Understanding decisions is a fundamental aim of behavioural ecology, psychology and economics. The regularity axiom of utility theory holds that a preference between options should be maintained when other options are made available. Empirical studies have shown that animals violate regularity but this has not been understood from a theoretical perspective, such decisions have therefore been labelled as irrational. Here, I use models of state-dependent behaviour to demonstrate that choices can violate regularity even when behavioural strategies are optimal. I also show that the range of conditions over which regularity should be violated can be larger when options do not always persist into the future. Consequently, utility theory--based on axioms, including transitivity, regularity and the independence of irrelevant alternatives--is undermined, because even alternatives that are never chosen by an animal (in its current state) can be relevant to a decision. PMID- 23740782 TI - Toxin constraint explains diet choice, survival and population dynamics in a molluscivore shorebird. AB - Recent insights suggest that predators should include (mildly) toxic prey when non-toxic food is scarce. However, the assumption that toxic prey is energetically as profitable as non-toxic prey misses the possibility that non toxic prey have other ways to avoid being eaten, such as the formation of an indigestible armature. In that case, predators face a trade-off between avoiding toxins and minimizing indigestible ballast intake. Here, we report on the trophic interactions between a shorebird (red knot, Calidris canutus canutus) and its two main bivalve prey, one being mildly toxic but easily digestible, and the other being non-toxic but harder to digest. A novel toxin-based optimal diet model is developed and tested against an existing one that ignores toxin constraints on the basis of data on prey abundance, diet choice, local survival and numbers of red knots at Banc d'Arguin (Mauritania) over 8 years. Observed diet and annual survival rates closely fit the predictions of the toxin-based model, with survival and population size being highest in years when the non-toxic prey is abundant. In the 6 of 8 years when the non-toxic prey is not abundant enough to satisfy the energy requirements, red knots must rely on the toxic alternative. PMID- 23740783 TI - Is low pathogenic avian influenza virus virulent for wild waterbirds? AB - Although low pathogenic avian influenza virus (LPAIV) is traditionally considered to have adapted to its wild waterbird host to become avirulent, recent studies have suggested that LPAIV infection might after all have clinical effects. Therefore, I reviewed the literature on LPAIV infections in wild waterbirds. The virulence of LPAIV was assessed in 17 studies on experimental infections and nine studies on natural infections. Reported evidence for virulence were reductions in return rate, feeding rate, body weight, long-range movement and reproductive success, as well as pathological changes in infected organs. However, major caveats in studies of experimental infections were unnatural route of LPAIV inoculation, animal husbandry not simulating natural stressors and low sensitivity of clinical assessment. Major caveats in studies of natural infections were incomplete measurement of LPAIV infection burden, quasi experimental design and potential misclassification of birds. After taking these caveats into account, the only remaining evidence for virulence was that presence and intensity of LPAIV infection were negatively correlated with body weight. Based on this correlation, together with the demonstrated LPAIV tropism for the intestinal tract, I hypothesize that LPAIV reduces digestive tract function, and suggest how future studies could be directed to test this hypothesis. PMID- 23740784 TI - The sense of agency is action-effect causality perception based on cross-modal grouping. AB - Sense of agency, the experience of controlling external events through one's actions, stems from contiguity between action- and effect-related signals. Here we show that human observers link their action- and effect-related signals using a computational principle common to cross-modal sensory grouping. We first report that the detection of a delay between tactile and visual stimuli is enhanced when both stimuli are synchronized with separate auditory stimuli (experiment 1). This occurs because the synchronized auditory stimuli hinder the potential grouping between tactile and visual stimuli. We subsequently demonstrate an analogous effect on observers' key press as an action and a sensory event. This change is associated with a modulation in sense of agency; namely, sense of agency, as evaluated by apparent compressions of action-effect intervals (intentional binding) or subjective causality ratings, is impaired when both participant's action and its putative visual effect events are synchronized with auditory tones (experiments 2 and 3). Moreover, a similar role of action-effect grouping in determining sense of agency is demonstrated when the additional signal is presented in the modality identical to an effect event (experiment 4). These results are consistent with the view that sense of agency is the result of general processes of causal perception and that cross-modal grouping plays a central role in these processes. PMID- 23740785 TI - Calves as social hubs: dynamics of the social network within sperm whale units. AB - It is hypothesized that the primary function of permanent social relationships among female sperm whales (Physeter macrocephalus) is to provide allomothers for calves at the surface while mothers make foraging dives. In order to investigate how reciprocity of allocare within units of sperm whales facilitates group living, we constructed weighted social networks based on yearly matrices of associations (2005-2010) and correlated them across years, through changes in age and social role, to study changes in social relationships within seven sperm whale units. Pairs of association matrices from sequential years showed a greater positive correlation than expected by chance, but as the time lag increased, the correlation coefficients decreased. Over all units considered, calves had high values for all measured network statistics, while mothers had intermediate values for most of the measures, but high values for connectedness and affinity. Mothers showed sharp drops in strength and connectedness in the first year of their new calves' lives. These broad patterns appear to be consistent across units. Calves appeared to be significant nodes in the network of the social unit, and thus provide quantitative support for the theory in which communal care acts as the evolutionary force behind group formation in this species. PMID- 23740786 TI - Beyond lifetime reproductive success: the posthumous reproductive dynamics of male Trinidadian guppies. AB - In semelparous populations, dormant germ banks (e.g. seeds) have been proposed as important in maintaining genotypes that are adaptive at different times in fluctuating environments. Such hidden storage of genetic diversity need not be exclusive to dormant banks. Genotype diversity may be preserved in many iteroparous animals through sperm-storage mechanisms in females. This allows males to reproduce posthumously and increase the effective sizes of seemingly female-biased populations. Although long-term sperm storage has been demonstrated in many organisms, the understanding of its importance in the wild is very poor. We here show the prevalence of male posthumous reproduction in wild Trinidadian guppies, through the combination of mark-recapture and pedigree analyses of a multigenerational individual-based dataset. A significant proportion of the reproductive population consisted of dead males, who could conceive up to 10 months after death (the maximum allowed by the length of the dataset), which is more than twice the estimated generation time. Demographic analysis shows that the fecundity of dead males can play an important role in population growth and selection. PMID- 23740787 TI - Mix to validate: a facile, reversible PEGylation for fast screening of potential therapeutic proteins in vivo. PMID- 23740788 TI - Retinoids for preventing the progression of cervical intra-epithelial neoplasia. AB - BACKGROUND: Invasive cervical carcinoma is preceded by a precancerous phase, cervical intra-epithelial neoplasia (CIN), which can be detected on cervical smears and confirmed by colposcopy and biopsy. Moderate and severe cases of intra epithelial neoplasia (CIN2 and CIN3) are treated mainly with surgery to prevent progression to invasive carcinoma. Medical methods of preventing the progression or inducing the regression of CIN are needed. Retinoids are potent modulators of epithelial cell growth and differentiation that may have potential for the treatment of CIN. OBJECTIVES: To ascertain whether retinoids can cause regression or prevent progression of CIN. SEARCH METHODS: We searched the Cochrane Gynaecological Cancer Review Group's Specialised Register and Non-Trials Database, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3, 2010), and MEDLINE and EMBASE (July 2010).For the 2013 update, the searches were re-run as follows: CENTRAL, Issue 3, 2013; MEDLINE, April, Week 2, 2013; and EMBASE, Week 16, 2013. SELECTION CRITERIA: Randomized controlled trials (RCTs) and non-RCTs of retinoids for treating CIN in women. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data from the trials. Adverse effects information was also collected from the trials. MAIN RESULTS: Five RCTs comparing the efficacy of four different retinoids were identified. Two studies examined the effects on CIN2 and CIN3 of the retinoids N-(4-hydroxyphenyl)retinamide (fenretinide) and 9-cis-retinoic acid (aliretinoin) given orally. Two examined the effect of all-trans-retinoic acid administered topically to the cervix. The fifth study investigated the use of 13 cis-retinoic acid (isotretinoin) given orally to human immunodeficiency virus (HIV)-positive participants with CIN1 and condyloma.Four studies reported no significant effect of retinoids on the progression to higher grades of CIN, and the fifth did not report data on progression. In all studies retinoids had no significant effect on regression of CIN3. Two studies reported that retinoids were associated with regression of CIN2. One reported a greater complete regression of CIN2 over that seen with placebo, which was of borderline statistical significance (odds ratio (OR) 0.5, 95% confidence interval (CI) 0.25 to 1.02). The other study reported a nonsignificant dose-related trend toward increased rates of complete and partial regression compared with placebo. One study reported significantly worse outcomes in women receiving retinoid (OR for regression 6.00, 95% CI 1.00 to 35.91). In general, the retinoid medications were well tolerated.In the 2010 review and in this update, no new studies were identified for inclusion. AUTHORS' CONCLUSIONS: The retinoids studied are not effective in causing regression of CIN3 but may have some effect on CIN2. The data on CIN1 are inadequate. Retinoids are not effective in preventing progression of CIN of any grade. At the doses given for the duration of treatment studied, the retinoids were reasonably well tolerated. PMID- 23740789 TI - Interferon after surgery for women with advanced (Stage II-IV) epithelial ovarian cancer. AB - BACKGROUND: Epithelial ovarian cancer (EOC) is a life-threatening disease. Most often women become symptomatic only in the advanced stages of the disease, increasing the difficulty of treatment. Whilst the disease responds well to surgery and chemotherapy, the relapse rate is high. New treatments to prevent disease recurrence or progression, prolong survival, and increase the quality of life are needed. OBJECTIVES: To assess the effectiveness and safety of interferon after surgery in the treatment of advanced (stage II-IV) EOC. SEARCH METHODS: The Cochrane Gynaecological Cancer Review Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2012, MEDLINE and EMBASE were searched to January 2012. Handsearching of conference proceedings was also undertaken. Reference lists of reviews and included trials were screened and experts in the field were contacted for additional trials. Clinical trials registers were searched for ongoing trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) involving participants with advanced EOC that compared post-operative chemotherapy alone with post-operative interferon therapy in combination with chemotherapy or post-operative chemotherapy followed by interferon or observation alone DATA COLLECTION AND ANALYSIS: Two review authors (AL and AM) independently screened the search results for relevant trials and extracted pre-specified information from each included trial. Data were managed using Review Manager 5.1. Hazard ratios (HR) were calculated for time-to-event outcomes and risk ratios (RR) for dichotomous outcomes, with corresponding 95% confidence intervals (CI). MAIN RESULTS: Five trials, including 1476 participants, were included in the review. Two trials compared interferon with observation alone and three trials compared interferon plus chemotherapy with chemotherapy alone. A meta-analysis of two trials involving 370 participants found no significant difference in both overall survival (HR 1.14, 95% CI 0.84 to 1.55) and progression free survival (HR 0.99, 95% CI 0.79 to 1.24) between the interferon and observation alone groups in post-surgical women who had undergone first-line chemotherapy for advanced EOC. One trial with 293 participants found that while no significant difference was observed in incidence of nausea or vomiting between the two treatment groups, significantly more flu-like symptoms (RR 2.25, 95% CI 1.73 to 2.91) and fatigue (RR 1.54, 95% CI 1.27 to 1.88) were reported in the interferon group. For the second comparison, a meta-analysis of two trials comprising 244 participants found that although there was no significant difference in overall survival between the interferon plus chemotherapy and the chemotherapy alone group (HR 1.14, 95% CI 0.74 to 1.76), women in the interferon plus chemotherapy group had worse progression free survival than those in the chemotherapy alone group (HR 1.43, 95% CI 1.02 to 2.00). Compared to chemotherapy alone, adding interferon to chemotherapy did not alter the incidence of adverse events in post-surgical women with advanced EOC. AUTHORS' CONCLUSIONS: Implications for practice Based on low quality evidence, the addition of interferon to first-line chemotherapy did not alter the overall survival in post-surgical women with advanced EOC compared with chemotherapy alone. There is low quality evidence to suggest that interferon in combination with chemotherapy worsened the progression free survival in post-surgical women with advanced EOC compared with chemotherapy alone. There is not enough evidence that interferon therapy alone alters overall survival or progression free survival compared to observation alone in post-surgical women who have undergone first-line chemotherapy. IMPLICATIONS FOR RESEARCH: Three of the five trials included in this review were stopped early and were, therefore, underpowered to detect any true effect of the intervention. The trials did not report the results of important outcomes in a uniform manner, preventing statistical aggregation of the results. Trial methodology was poorly reported resulting in unclear risk of bias. For clear recommendations to be made regarding the effectiveness of interferon in the treatment of advanced EOC, long-term, well conducted and adequately powered RCTs would be needed. However, the available data do not suggest that interferon has an adequately advantageous effect to warrant further investigation. PMID- 23740790 TI - Preventive interventions for postnatal psychosis. AB - BACKGROUND: Postnatal psychosis is a worldwide life-threatening condition that affects one to two in every 1000 new mothers. It has an abrupt onset within a month of childbirth. Affected new mothers rapidly develop frank psychosis, cognitive impairment, and disorganised behaviours. Factors that increase the risk of postnatal psychosis include primiparous mothers who are single, women who are older, or with a past psychiatric history and family history of affective psychosis, prenatal depression and autoimmune thyroid dysfunction. The risk of a future postnatal recurrence is 25% to 57%. Preventive interventions for postnatal psychosis aim at identifying women with risk factors, early recognition of imminent psychosis through screening, and preventive drug therapy. Mood stabilisers, antipsychotic drugs and hormone therapy may be beneficial in the prevention of postnatal psychotic episodes in women at risk. OBJECTIVES: To investigate the best available evidence for interventions aimed at preventing postnatal psychosis. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register and the Cochrane Central Register of Controlled Trials (CENTRAL) in October 2012 using the search strategy of the Cochrane Schizophrenia Group. SELECTION CRITERIA: All randomised controlled trials relevant to the prevention of postnatal psychosis. DATA COLLECTION AND ANALYSIS: Two review authors inspected all citations to ensure reliable selection. If we had included relevant trials, we planned to assess the methodological quality of identified trials using the criteria recommended in the Cochrane Handbook for Systematic Reviews of Interventions. Two review authors would have independently extracted data. For homogenous dichotomous data, we planned to calculate the risk ratio (RR), 95% confidence interval (CI), and the number needed to treat to benefit/harm (NNTB/NNTH) on an intention-to-treat basis. MAIN RESULTS: There are no included studies in this review. The electronic search produced three relevant references, among which we identified two old planned trials that seem never to have started, and one which we excluded a study because it was a report of a case series. AUTHORS' CONCLUSIONS: This is not an empty review - it is a review full of unanswered questions. Despite growing interest in women's mental health, the literature in the area of postnatal psychosis is still very limited. It seems that clinicians have no choice but to continue with their current practices guided solely by varied clinical judgement. Women at risk of postnatal psychosis and their relatives are justified to be disappointed in the medical/research fraternity. A post hoc PubMed topic (not methodology-specific) search identified mainly case series. Policy makers have no trial-based evidence upon which to base their guidelines. Certainly, preventive interventions for postnatal psychosis are difficult to justify with confidence without well-designed, well-conducted, and well-reported randomised studies. Available publications suggest that such studies are possible and funders of research may wish to make this work a priority. PMID- 23740791 TI - Mechanism of the deprotonation reaction of alkyl benzyl ethers with n butyllithium. AB - Kinetic study of the alpha-lithiation of benzyl methyl ether (BME) by nBuLi has revealed that increasing the concentration of the organolithium compound does not necessarily increase the reactivity, and this is a consequence of the reactivities of the different nBuLi aggregates present in solution. We propose a dimer-based mechanism, in which a pre-complexation step is a key process for substrates bearing a donor oxygen atom that can interact with the lithium cation to form mixed dimers. For these studies, we have developed a system based on UV/Vis spectroscopy that allows kinetic measurements to be conducted at -80 degrees C under argon. PMID- 23740793 TI - Editorial: ESBES - European Society of Biochemical Engineering Sciences. AB - The latest ESBES special issue on "Biochemical Engineering Sciences" is edited by Prof. Guilherme Ferreira (Chairman, ESBES) and Prof. Alois Jungbauer (co-Editor in-Chief, Biotechnology Journal). This special issue comprises the latest research in biochemical engineering science presented at the 9(th) ESBES Conference held in Istanbul, Turkey in 2012. PMID- 23740800 TI - Influence of different modifications of a calcium phosphate cement on resorption and new bone formation: an in vivo study in the minipig. AB - Calcium phosphate cements (CPCs) are established in surgery as temporary bone replacement materials. The most common and important class of CPC, transformed into nanocrystalline hydroxyapatite after setting, is characterized by good biocompatibility and osteoconductivity. However, acceleration of remodelling is in the focus of ongoing research. In the present study, the bone healing efficacy of Biocement D (BioD) modified with mineralized collagen alone (BioD/coll) or in combination with osteocalcin (BioD/coll/OC), O-phospho-L-serine (BioD/coll/PS), sodium citrate (BioD/coll/cit), and polylactide (BioD/coll/PL), respectively, was evaluated in a large animal model. Resorption of the bone substitutes and new bone formation were studied in cyst-like jaw defects of minipigs after filling with the unmodified BioD and the modified BioD variants, respectively. Histomorphometric analysis revealed small differences between the different cement types with respect to resorption. However, new bone formation was improved in case of defects repaired with BioD/coll/OC and BioD/coll/PS and slightly improved in case of BioD/coll and BioD/coll/PL. PMID- 23740801 TI - Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study. AB - OBJECTIVE: To investigate the efficacy and safety of ocrelizumab in patients with class III/IV lupus nephritis (LN). METHODS: Patients were randomized 1:1:1 to receive placebo, 400 mg ocrelizumab, or 1,000 mg ocrelizumab given as an intravenous infusion on days 1 and 15, followed by a single infusion at week 16 and every 16 weeks thereafter, accompanied by background glucocorticoids plus either mycophenolate mofetil (MMF) or the Euro-Lupus Nephritis Trial (ELNT) regimen (cyclophosphamide followed by azathioprine). The study was terminated early due to an imbalance in serious infections in ocrelizumab-treated patients versus placebo-treated patients. We report week 48 efficacy data for patients receiving >=32 weeks of treatment (n = 223) and safety results for all treated patients (n = 378). RESULTS: The overall renal response rate was 54.7%, 66.7%, 67.1%, and 66.9% in the placebo-treated, 400 mg ocrelizumab-treated, 1,000 mg ocrelizumab-treated, and combined ocrelizumab-treated groups, respectively. The associated treatment difference versus placebo for the combined ocrelizumab treated groups was 12.7% (95% confidence interval [95% CI] -0.8, 26.1) (P = 0.065), with similar differences observed for both ocrelizumab-treated groups. Ocrelizumab versus placebo treatment differences were apparent in patients receiving the background ELNT regimen, but not in those receiving background MMF. A numerically greater proportion of ocrelizumab-treated patients had a >=50% reduction in the urinary protein:urinary creatinine ratio at 48 weeks compared with placebo-treated patients (placebo-treated patients, 58.7%; 400 mg ocrelizumab-treated patients, 70.7%; 1,000 mg ocrelizumab-treated patients, 68.5%). Serious adverse events occurred in 27.2% of placebo-treated patients, 35.7% of 400 mg ocrelizumab-treated patients, and 22.0% of 1,000 mg ocrelizumab treated patients. Corresponding serious infection rates (events/100 patient years) were 18.7 (95% CI 12.2, 28.7), 28.8 (95% CI 20.6, 40.3), and 25.1 (95% CI 17.4, 36.1), respectively. The imbalance in serious infections with ocrelizumab occurred with background MMF but not with the background ELNT regimen. CONCLUSION: In patients with active LN, overall renal response rates with ocrelizumab were numerically but not statistically significantly superior to those with placebo. Ocrelizumab treatment was associated with a higher rate of serious infections in the subgroup receiving background MMF. PMID- 23740802 TI - Application of a PEG precipitation method for solubility screening: a tool for developing high protein concentration formulations. AB - Previous publications demonstrated that the extrapolated solubility by polyethylene glycol (PEG) precipitation method (Middaugh et al., J Biol Chem 1979; 254:367-370; Juckes, Biochim Biophys Acta 1971; 229:535-546; Foster et al., Biochim Biophys Acta 1973; 317:505; Mahadevan and Hall, AIChE J 1990; 36:1517 1528; Stevenson and Hageman, Pharm Res 1995; 12:1671-1676) has a strong correlation to experimentally measured solubility of proteins. Here, we explored the utility of extrapolated solubility as a method to compare multiple protein drug candidates when nonideality of a highly soluble protein prohibits accurate quantitative solubility prediction. To achieve high efficiency and reduce the amount of protein required, the method is miniaturized to microwell plate format for high-throughput screening application. In this simplified version of the method, comparative solubility of proteins can be obtained without the need of concentration measurement of the supernatant following the precipitation step in the conventional method. The monoclonal antibodies with the lowest apparent solubilities determined by this method are the most difficult to be concentrated, indicating a good correlation between the prediction and empirical observations. This study also shows that the PEG precipitation method gives results for opalescence prediction that favorably compares to experimentally determined opalescence levels at high concentration. This approach may be useful in detecting proteins with potential solubility and opalescence problems prior to the time-consuming and expensive development process of high concentration formulation. PMID- 23740803 TI - The added value of propensity score matching when using health-related quality of life reference data. AB - Direct comparisons of health-related quality of life (HRQoL) outcomes between non randomized groups might be biased, as outcomes are confounded by imbalance in pre treatment patient characteristics. Such bias can be reduced by adjusting on observed covariates. This is the setting of HRQoL comparisons with reference data, where age and gender adjustment is commonly used for this purpose. However, other observed covariates can be used to lessen this bias and yield more precise estimates. The objective of this study is to show that more accurate HRQoL comparisons with reference data can be obtained, accounting for few covariates in addition to age and gender by a propensity score matching approach. PMID- 23740804 TI - Room-temperature ferromagnetism of all-epitaxial beta-Fe-Ge/diamond-Ge/beta-Fe-Ge trilayers. AB - We report on the first all-epitaxial ferromagnet/inorganic semiconductor/ferromagnet hybrid heterostructure that exhibits (i) a Ge barrier of diamond crystal structure, (ii) room-temperature ferromagnetic electrodes and (iii) very smooth interfaces. Both bottom- and top-Fe-Ge electrodes exhibit tiny in-plane magnetic anisotropies dominated by a magnetocrystalline contribution of six-fold symmetry originating from the hexagonal symmetry of the B82 (Ni2In) beta Fe-Ge phase. A key result is the absence of any magnetic coupling between these soft-magnetic electrodes for Ge barrier thickness as low as ~2.5 nm, which allows us to easily tune the parallel and antiparallel magnetic alignments by applying suitably small magnetic fields. This confirms the beneficial use of H-surfactant in order to drastically reduce the roughness of the Ge barrier, as revealed by our scanning tunneling microscopy and transmission electron microscopy measurements. This new all-epitaxial ferromagnet/semiconductor hybrid system appears, therefore, to be a promising candidate for the realization of magnetic tunnel junctions with a single crystal semiconductor barrier that are fully compatible with Si-based technology. PMID- 23740805 TI - Replication of LIN28B SNP association with age of menarche in young Filipino women. AB - BACKGROUND: Age of menarche, or the timing of first menses in girls, is a physiological trait that shows substantial genetic heritability. Earlier age of menarche is associated with increased childhood adiposity and with adult risk of obesity and cardiovascular disease. OBJECTIVES: We sought to further characterize the single nucleotide polymorphism (SNP) rs7759938 from the menarche locus LIN28B in 827 young Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). METHODS: We tested rs7759938 for additive association with age of menarche and also tested whether childhood adiposity, as measured by body mass index (BMI) at age 8, mediated this relationship. RESULTS: We observed nominal association of rs7759938 with age of menarche (beta = -0.118 years, 95% confidence interval = (-0.216, -0.020), P = 0.019) with an effect direction consistent with the previous report. We also observed suggestive evidence that the effect of the SNP on age of menarche was independent of childhood BMI. CONCLUSIONS: These data confirm the strongest gene reported in Europeans (LIN28B) as a contributor to age of menarche in an Asian population. PMID- 23740806 TI - Placental three-dimensional power Doppler indices in mid-pregnancy and late pregnancy complicated by gestational diabetes mellitus. AB - OBJECTIVES: The aim of our study was to evaluate placental three-dimensional power Doppler indices in diabetic pregnancies in the second and third trimesters and to compare them with those of the normal controls. METHODS: Placental vascularization of pregnant women was determined by three-dimensional power Doppler ultrasound technique. The calculated indices included vascularization index (VI), flow index (FI), and vascularization flow index (VFI). Uncomplicated pregnancies (n = 113) were compared with pregnancies complicated by gestational diabetes mellitus (n = 56) and diabetes mellitus (n = 43). RESULTS: The three dimensional power Doppler indices were not significantly different between the two diabetic subgroups. All the indices in diabetic patients were significantly reduced compared with those in non-diabetic individuals (p < 0.001). Placental three-dimensional power Doppler indices are slightly diminished throughout diabetic pregnancy [regression coefficients: -0.23 (FI), -0.06 (VI), and -0.04 (VFI)] and normal pregnancy [regression coefficients: -0.13 (FI), -0.20 (VI), and -0.11 (VFI)]. The uteroplacental circulation (umbilical and uterine artery) was not correlated significantly to the three-dimensional power Doppler indices. If all placental indices are low during late pregnancy, then the odds of the diabetes are significantly high (adjusted odds ratio: 1.10). CONCLUSIONS: A decreased placental vascularization could be an adjunct sonographic marker in the diagnosis of diabetic pregnancy in mid-gestation and late gestation. PMID- 23740807 TI - Modifying alkylzinc reactivity with 2,2'-dipyridylamide: activation of tBu-Zn bonds for para-alkylation of benzophenone. PMID- 23740808 TI - Vascular changes after stroke in the rat: a longitudinal study using optimized magnetic resonance imaging. AB - During stroke, the reduction of blood flow leads to undersupply of oxygen and nutrients and, finally, to cell death, but also to upregulation of pro-angiogenic molecules and vascular remodeling. However, the temporal profile of vascular changes after stroke is still poorly understood. Here, we optimized steady-state contrast-enhanced magnetic resonance imaging (SSCE MRI) and followed the dynamic changes in vascular architecture for up to 4 weeks after transient middle cerebral artery occlusion (MCAO) in rats. Using MRI diffusion measurements and the changes of transversal relaxation rates DeltaR2 and DeltaR2* after injection of a superparamagnetic contrast agent, SSCE MRI provided several hemodynamic parameters: relative cerebral blood volume (rCBV), rCBV in small vessels, microvascular density, and relative vessel size. Six rats underwent SSCE MRI before MCAO and at 7, 14, 21 and 28 days after surgery. 5-Bromo-2'deoxyuridine (BrdU) was injected between days 2 and 7 to label proliferating cells during this time. SSCE MRI depicted a decrease in microvessel density and an increase in vessel size in the ischemic striatum after stroke. A persistently decreased MRI vessel density was confirmed with histology at 28 days. BrdU + endothelial cells were found in regions close to the infarct indicating endothelial cell proliferation during the first week after MCAO; however, late-stage angiogenesis, as would be reflected by increased vessel density, was not detected. The optimized SSCE MRI protocol was used to follow spatio-temporal changes of important vessel characteristics, which may contribute to a better understanding of the role of angiogenesis at different stages after stroke. PMID- 23740809 TI - PECAM-1-targeted micron-sized particles of iron oxide as MRI contrast agent for detection of vascular remodeling after cerebral ischemia. AB - An increasing amount of studies have provided evidence for vascular remodeling, for example, angiogenesis, after cerebral ischemia, which may play a significant role in post-stroke brain plasticity and recovery. Molecular imaging can provide unique in vivo whole-brain information on alterations in the expression of specific endothelial markers. A possible target for molecular magnetic resonance imaging (MRI) of post-stroke (neo)vascularization is platelet endothelial cell adhesion molecule-1 (PECAM-1). Here we describe significantly increased PECAM-1 mRNA levels in ipsilesional brain tissue at 6 h, 24 h and 3 days after transient middle cerebral artery occlusion in mice, and elevated PECAM-1 staining throughout the lesion at 3, 7 and 21 days post-stroke. The potential of micron sized particles of iron oxide (MPIO) conjugated with PECAM-1-targeted antibodies, that is, alphaPECAM-1-MPIO, to expose stroke-induced PECAM-1 upregulation with molecular MRI was assessed. In vitro studies demonstrated that PECAM-1-expressing brain endothelial cells could be effectively labeled with alphaPECAM-1-MPIO, giving rise to a fourfold increase in MRI relaxation rate R2. Injection of near infrared fluorescent dye-labeled alphaPECAM-1 showed target specificity and dose efficiency of the antibody for detection of brain endothelial cells at 3 days post-stroke. However, in vivo molecular MRI at 3 and 7 days after stroke revealed no alphaPECAM-1-MPIO-based contrast enhancement, which was corroborated by the absence of alphaPECAM-1-MPIO in post mortem brain tissue. This indicates that this molecular MRI approach, which has been proven successful for in vivo detection of other types of cell adhesion molecules, is not invariably effective for MRI-based assessment of stroke-induced alterations in expression of cerebrovascular markers. PMID- 23740810 TI - Antibody-functionalized nanoparticles for imaging cancer: influence of conjugation to gold nanoparticles on the biodistribution of 89Zr-labeled cetuximab in mice. AB - Antibody-labeled gold nanoparticles represent a promising novel tool regarding cancer imaging and therapy. Nevertheless, the characterization of biodistribution of such immunonanocarriers has been poorly documented. In this study, the biodistribution of (89)Zr-labeled cetuximab before and after the coupling reaction to gold nanoparticles (AuNPs) was compared and the quantitative imaging performance of (89)Zr immuno-PET was evaluated. Cetuximab was functionalized with the desferal moiety and labeled with (89)Zr ((89)Zr-Df-Bz-NCS-cetuximab). AuNPs with a mean diameter of 5 nm were synthesized according a new method developed in the laboratory, and conjugated to (89)Zr-Df-Bz-NCS-cetuximab using carbodiimide chemistry (AuNPs-PPAA-cetuximab-(89)Zr). The two tracers were injected in A431 xenograft-bearing mice. Tumor and liver uptakes were assessed at different times after injection using quantitative PET imaging. The in vivo specificity of the binding was investigated using a saturating dose of unlabeled cetuximab. Radiolabeled cetuximab was conjugated to AuNPs with a coupling reaction yield >75%. All conjugates were stable in vitro and to a lesser extent in plasma. In vivo distribution studies revealed no significant difference in tumor uptake for cetuximab conjugated to nanoparticles up to 72 h after injection, compared with unconjugated cetuximab. Immuno-PET studies showed that AuNPs-PPAA-cetuximab (89)Zr provided high tumor-to-background ratio. The liver uptake of AuNPs-PPAA cetuximab-(89)Zr was higher, compared with (89)Zr-Df-Bz-NCS-cetuximab. In vivo blocking experiments demonstrated selective tumor targeting after coupling reaction. This study showed that the conjugation of AuNPs to cetuximab did not affect its tumor accumulation and that the efficacy of EGFR-targeted nanoparticles was unaltered. The (89)Zr-labeled cetuximab-targeted gold nanoparticles could be a valuable tool for theranostic purposes. PMID- 23740811 TI - [18F]-FBEM, a tracer targeting cell-surface protein thiols for cell trafficking imaging. AB - We used [(18)F]-4-fluorobenzamido-N-ethylamino-maleimide ([(18)F]-FBEM) to radiolabel cells ex vivo for in vivo positron emission tomography (PET) in order to assess cell trafficking in mice. In contrast to commonly used imaging agents, [(18)F]-FBEM forms a covalent bond with thiol groups present on the cells surface. The stability of the probe in aqueous medium was tested at different pH values and cross-experiment showed that thiol-labeling efficiency was retained (at least) up to pH 9. The labeling procedure did not affect significantly the cell viability. To illustrate the procedure, PET images of living mice injected intravenously with labeled T lymphocytes were obtained. They showed the expected cell homing in the spleen that was absent in mice injected with free label. PMID- 23740812 TI - 15N-permethylated amino acids as efficient probes for MRI-DNP applications. AB - The synthesis, NMR properties and preliminary polarization tests on protonated and perdeuterated forms of alpha-trimethylglutamine (NMe3Gln), alpha trimethylglutamate (NMe3Glu) and epsilon-trimethyllysine (NMe3Lys) are reported. The (15)N-permethylated, perdeuterated amino acids display very long (15)N-T1 values, ranging between 190 and 330 s, are well polarized by the dynamic nuclear polarization (DNP) procedure, yielding good polarization levels (10%), and appear to be well tolerated by cells and mice. The obtained results make perdeuterated amino acids excellent candidates for innovative DNP (15)N-MRI applications such as perfusion or targeting studies. PMID- 23740814 TI - Evaluation of patient doses and lens radiation doses to interventional cardiologists in a nationwide survey in Chile. AB - The objective of this study was to perform a nationwide survey in Chile to determine dose levels to patients and staff in four risk scenarios during cardiac catheterisation procedures. Different phantom thicknesses of polymethyl methacrylate (PMMA) were used to simulate adult patients. Scenario 1: 10-min fluoroscopy and 800 cine frames for 20 cm of PMMA; Scenario 2: 10-min fluoroscopy and 800 cine frames for 28 cm of PMMA; Scenario 3: 30-min fluoroscopy and 2400 cine frames for 20 cm of PMMA; Scenario 4: 30-min fluoroscopy and 2400 cine frames for 28 cm of PMMA. The average values regarding dose-area product and scattered doses at the cardiologist eye lens achieved for the four scenarios were 94, 249, 281, 747 Gy cm(2) and 0.3, 0.8, 0.9 and 2.5 mSv, respectively. Large variations in radiation doses received by both patients and staff for the same type of procedure suggest that optimising procedure protocols and using the most effective types of protective devices may substantially reduce the dose values found here. PMID- 23740816 TI - Ostwald-ripening-induced growth of parallel face-exposed Ag nanoplates on micro hemispheres for high SERS activity. AB - Ag nanoplates, as two-dimensional plasmonic nanostructures, have attracted intensive attention due to their strong shape-dependent optical properties and related applications. Here parallel face-exposed Ag nanoplates vertically grown on micro-hemisphere surfaces have been achieved by firstly electrodepositing the micro-hemispheres assembled by Ag nanoplates, whose planar surfaces are stuck together, on indium tin oxide substrates, and then Ostwald ripening the as electrodeposited micro-hemispheres in water. The sizes of the nanoplates and the gaps between the neighboring nanoplates have been tailored by tuning the Ostwald ripening duration, so that the SERS activity of the micro-hemispheres has been remarkably improved. The improved SERS activity can be well explained by our systematic finite-element simulation. Therefore, Ostwald ripening offers a route to the synthesis of Ag nanoplates, and the optimization of plasmon coupling and SERS activity of nanostructure-assembled systems. PMID- 23740815 TI - Interferon-alpha induction and detection of anti-ro, anti-la, anti-sm, and anti rnp autoantibodies by autoantigen microarray analysis in juvenile dermatomyositis. AB - OBJECTIVE: To evaluate serum interferon-alpha (IFNalpha) activity in the context of autoantibody profiles in patients with juvenile dermatomyositis (JDM). METHODS: Sera from 36 patients with JDM were analyzed. Autoantibody profiles were determined by probing microarrays, which were fabricated with ~80 distinct autoantigens, with serum and a Cy3-conjugated secondary antibody. Arrays were scanned and analyzed to determine antigen reactivity. Serum IFNalpha activity was measured using a functional reporter cell assay. Sera were assayed alone or in combination with cellular material released from necrotic U937 cells to stimulate peripheral blood mononuclear cells from healthy donors in vitro, and IFNalpha production in culture was measured by a dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA). RESULTS: Reactivity against at least 1 of 41 autoantigens on the microarray, including Ro 52, Ro 60, La, Sm, and RNP, was observed in 75% of the serum samples from patients with JDM. IFNalpha activity was detected in 7 samples by reporter cell assay. The reporter cell assay showed a significant association of reactivity against Ro, La, Sm, and proliferating cell nuclear antigen with serum IFNalpha activity (P = 0.005). Significance Analysis of Microarrays (SAM) identified increased reactivity against Sm, RNP, Ro 52, U1-C, and Mi-2 in these sera. Sixteen samples induced IFNalpha production as measured by DELFIA, and there was a significant association of reactivity against Ro, La, Sm, and RNP with the induction of IFNalpha by serum and necrotic cell material (P = 0.034). SAM identified increased reactivity against Ro 60 in these sera. CONCLUSION: These data support the hypothesis that nucleic acid-associated autoantibodies, including the Ro/La and Sm/RNP complexes, may stimulate the production of active IFNalpha in children with JDM. PMID- 23740817 TI - Rational design of angiotensin-I-converting enzyme inhibitory peptides by integrating in silico modeling and an in vitro assay. AB - Human angiotensin-I-converting enzyme (ACE) is a classic target of antihypertensive drugs and possesses a bulky, amphiphilic active pocket that is physicochemically compatible with a wide spectrum of small peptide ligands. Herein we describe a synthetic pipeline to directly optimize the atomic interactions between ACE in complex with its peptide ligands. By using this pipeline, we were able to derive thousands of peptides with potential ACE inhibitory capacity, from which 15 structurally diverse, theoretically active samples were investigated systematically with respect to the structural, energetic, and dynamic aspects of their interactions with ACE. Subsequently, ACE inhibitory activities of several highly promising candidates were evaluated in vitro using a standard spectrophotometric method. As might be expected, three of these candidates showed high inhibitory activities against ACE and others also significantly inhibited the enzymatic activity at low or moderate doses. Furthermore, one of these peptides, LHGPYP, was chosen for structural modification based on the details of its interaction with ACE using modeled structure data. Consequently, a Gly 3 Leu/Tyr 5 Ala double mutation on the peptide was assessed to obtain a more potent mutant LHLPAP, leading to a considerable increase in ACE-inhibitory activity (IC50 decrease from 75.4 to 4.2 MUM). PMID- 23740818 TI - Optimal combination of number of participants and number of repeated measurements in longitudinal studies with time-varying exposure. AB - In the context of observational longitudinal studies, we explored the values of the number of participants and the number of repeated measurements that maximize the power to detect the hypothesized effect, given the total cost of the study. We considered two different models, one that assumes a transient effect of exposure and one that assumes a cumulative effect. Results were derived for a continuous response variable, whose covariance structure was assumed to be damped exponential, and a binary time-varying exposure. Under certain assumptions, we derived simple formulas for the approximate solution to the problem in the particular case in which the response covariance structure is assumed to be compound symmetry. Results showed the importance of the exposure intraclass correlation in determining the optimal combination of the number of participants and the number of repeated measurements, and therefore the optimized power. Thus, incorrectly assuming a time-invariant exposure leads to inefficient designs. We also analyzed the sensitivity of results to dropout, mis-specification of the response correlation structure, allowing a time-varying exposure prevalence and potential confounding impact. We illustrated some of these results in a real study. In addition, we provide software to perform all the calculations required to explore the combination of the number of participants and the number of repeated measurements. PMID- 23740819 TI - Structural transitions in tau k18 on micelle binding suggest a hierarchy in the efficacy of individual microtubule-binding repeats in filament nucleation. AB - The protein tau is found in an aggregated filamentous state in the intraneuronal paired helical filament deposits characteristic of Alzheimer's disease and other related dementias and mutations in tau protein and mRNA cause frontotemproal dementia. Tau isoforms include a microtubule-binding domain containing either three or four imperfect tandem microtubule binding repeats that also form the core of tau filaments and contain hexapaptide motifs that are critical for tau aggregation. The tau microtubule-binding domain can also engage in direct interactions with detergents, fatty acids, or membranes, which can greatly facilitate tau aggregation and may also mediate some tau functions. Here, we show that the alternatively spliced second microtubule-binding repeat exhibits significantly different structural characteristics compared with the other three repeats in the context of the intact repeat domain. Most notably, the PHF6* hexapeptide motif located at the N-terminus of repeat 2 has a lower propensity to form strand-like structure than the corresponding PHF6 motif in repeat 3, and unlike PHF6 converts to partially helical structure in the micelle-bound state. Interestingly, the behavior of the Module-B motif, located at the beginning of repeat 4, resembles that of PHF6* rather than PHF6. Our observations, combined with previous results showing that PHF6* and Module-B are both less effective than PHF6 in nucleating tau aggregation, suggest a hierarchy in the efficacy of these motifs in nucleating tau aggregation that originates in differences in their intrinsic propensities for extended strand-like structure and the resistance of these propensities to changes in tau's environment. PMID- 23740821 TI - Cobalt(III) as a stable and inert mediator ion between NTA and His6-tagged proteins. AB - Don't let go! The Co(3+)-mediated interaction between nitrilotriacetic acid (NTA) and the His6-tag is so stable and inert towards ligand exchange that it has a half-life of 7 days in the presence of imidazole and survives even under strongly chelating as well as reducing conditions, unlike the commonly used Ni(2+) or Co(2+) complexes. Possible applications include the separation of labeled proteins and the stable immobilization of proteins on surfaces. PMID- 23740822 TI - Online audit and feedback improve fetal second-trimester four-chamber view images: a randomised controlled trial. AB - OBJECTIVES: We aimed to study the impact of online audit and feedback on fetal four-chamber view image quality. METHODS: Ultrasonographers uploaded a set of four-chamber views from 10 consecutive screening examinations and a second set 3 months later. They were randomised to receive (group A) or not (group B) a feedback for their first set. The primary outcome was the difference in image mean score and in percentage of inadequate images between the first set and the second set, comparing the groups with and without feedback. RESULTS: There were 258 ultrasonographers who completed the trial (group A: 122; group B: 136), and 5160 images were audited. In both groups, the mean score increased. In group A, it rose from 17.0 to 18.5 (p < 0.0001), and in group, B from 17.6 to 18.3 (p < 0.0001). The improvement was greater in group A than in group B (1.5 vs. 0.7, p = 0.0007). The mean percentage of inadequate images decreased in both groups. In group A, it dropped from 32% to 19% (p < 0.0001), and in group B, from 26% to 21% (p = 0.012). The decrease was greater in group A than in group B (13% vs. 5%, p = 0.007). CONCLUSIONS: Image quality improved following online audit, the improvement being slightly greater with feedback. PMID- 23740823 TI - GABA transaminases from Saccharomyces cerevisiae and Arabidopsis thaliana complement function in cytosol and mitochondria. AB - GABA transaminase (GABA-T) catalyses the conversion of GABA to succinate semialdehyde (SSA) in the GABA shunt pathway. The GABA-T from Saccharomyces cerevisiae (ScGABA-TKG) is an alpha-ketoglutarate-dependent enzyme encoded by the UGA1 gene, while higher plant GABA-T is a pyruvate/glyoxylate-dependent enzyme encoded by POP2 in Arabidopsis thaliana (AtGABA-T). The GABA-T from A. thaliana is localized in mitochondria and mediated by an 18-amino acid N-terminal mitochondrial targeting peptide predicated by both web-based utilities TargetP 1.1 and PSORT. Yeast UGA1 appears to lack a mitochondrial targeting peptide and is localized in the cytosol. To verify this bioinformatic analysis and examine the significance of ScGABA-TKG and AtGABA-T compartmentation and substrate specificity on physiological function, expression vectors were constructed to modify both ScGABA-TKG and AtGABA-T, so that they express in yeast mitochondria and cytosol. Physiological function was evaluated by complementing yeast ScGABA TKG deletion mutant Deltauga1 with AtGABA-T or ScGABA-TKG targeted to the cytosol or mitochondria for the phenotypes of GABA growth defect, thermosensitivity and heat-induced production of reactive oxygen species (ROS). This study demonstrates that AtGABA-T is functionally interchangeable with ScGABA-TKG for GABA growth, thermotolerance and limiting production of ROS, regardless of location in mitochondria or cytosol of yeast cells, but AtGABA-T is about half as efficient in doing so as ScGABA-TKG. These results are consistent with the hypothesis that pyruvate/glyoxylate-limited production of NADPH mediates the effect of the GABA shunt in moderating heat stress in Saccharomyces. PMID- 23740824 TI - Patient perspectives on achieving treat-to-target goals: a critical examination of patient-reported outcomes. AB - OBJECTIVE: Treat-to-target (T2T) recommendations suggest that rheumatoid arthritis (RA) patients should strive for remission or low disease activity (LDA). However, it is unclear whether patients experiencing a good response to biologic agents might experience further improvement in patient-reported outcomes (PROs) if they subsequently achieve a lower disease activity state, particularly the T2T goals of LDA or remission. METHODS: Using the Consortium of Rheumatology Researchers of North America database, we identified RA patients initiating biologic agents. We restricted the analysis to patients with improvement (Clinical Disease Activity Index [CDAI] improvement of >=10 units) at 3-6 months (baseline visit; n = 1,368) with a followup visit approximately 9 months later (n = 984). Patients in CDAI remission or with a worsened disease activity category were excluded, leaving 562 eligible patients. PROs (global assessment, pain, and fatigue by 0-10 visual analog scales and disability by the modified Health Assessment Questionnaire [M-HAQ]) were examined at these 2 visits. Mean change in PROs compared achievement of a lower disease activity category versus staying in the same disease activity category, adjusting for potential confounders. RESULTS: Patients who achieved a lower disease activity category (40% of the eligible cohort, 86% of these achieving LDA or remission) had significantly better improvement in patient pain (-14.9; 95% confidence interval [95% CI] -18.4, 11.6), patient global (-17.5; 95% CI -20.8, -14.3), fatigue (-8.5; 95% CI -15.8, 1.3), and M-HAQ score (-0.13; 95% CI -0.18, -0.08) compared to patients who stayed in the same disease activity category. However, even for patients improving, fewer than half exceeded the minimum clinically important difference for each PRO. CONCLUSION: Achievement of a lower disease activity disease state, especially T2T goals, was associated with further improvement in PROs, albeit modest in magnitude. PMID- 23740825 TI - Fibroblast growth factor 2 drives changes in gene expression following injury to murine cartilage in vitro and in vivo. AB - OBJECTIVE: The articular cartilage is known to be highly mechanosensitive, and a number of mechanosensing mechanisms have been proposed as mediators of the cellular responses to altered mechanical load. These pathways are likely to be important in tissue homeostasis as well as in the pathogenesis of osteoarthritis. One important injury-activated pathway involves the release of pericellular fibroblast growth factor 2 (FGF-2) from the articular cartilage. Using a novel model of murine cartilage injury and surgically destabilized joints in mice, we examined the extent to which FGF-2 contributes to the cellular gene response to injury. METHODS: Femoral epiphyses from 5-week-old wild-type mice were avulsed and cultured in serum-free medium. Explant lysates were Western blotted for phospho-JNK, phospho-p38, and phospho-ERK or were fixed for immunohistochemical analysis of the nuclear translocation of p65 (indicative of NF-kappaB activation). RNA was extracted from injured explants, rested explants that had been stimulated with recombinant FGF-2 or FGF-18, or whole joints from either wild-type mice or FGF-2(-/-) mice. Reverse transcription-polymerase chain reaction was performed to examine a number of inflammatory response genes that had previously been identified in a microarray analysis. RESULTS: Murine cartilage avulsion injury resulted in rapid activation of the 3 MAP kinase pathways as well as NF-kappaB. Almost all genes identified in murine joints following surgical destabilization were also regulated in cartilage explants upon injury. Many of these genes, including those for activin A (Inhba), tumor necrosis factor-stimulated gene 6 (Tnfaip6), matrix metalloproteinase 19 (Mmp19), tissue inhibitor of metalloproteinases 1 (Timp1), and podoplanin (Pdpn), were significantly FGF-2 dependent following injury to cartilage in vitro and to joint tissues in vivo. CONCLUSION: FGF-2-dependent gene expression occurs in vitro and in vivo in response to cartilage/joint injury in mice. PMID- 23740826 TI - Arginine and nitric oxide synthase: regulatory mechanisms and cardiovascular aspects. AB - L-Arginine (L-Arg) is a conditionally essential amino acid in the human diet. The most common dietary sources of L-Arg are meat, poultry and fish. L-Arg is the precursor for the synthesis of nitric oxide (NO); a key signaling molecule via NO synthase (NOS). Endogenous NOS inhibitors such as asymmetric-dimethyl-L-Arg inhibit NO synthesis in vivo by competing with L-Arg at the active site of NOS. In addition, NOS possesses the ability to be "uncoupled" to produce superoxide anion instead of NO. Reduced NO bioavailability may play an essential role in cardiovascular pathologies and metabolic diseases. L-Arg deficiency syndromes in humans involve endothelial inflammation and immune dysfunctions. Exogenous administration of L-Arg restores NO bioavailability, but it has not been possible to demonstrate, that L-Arg supplementation improved endothelial function in cardiovascular disease such as heart failure or hypertension. L-Arg supplementation may be a novel therapy for obesity and metabolic syndrome. The utility of l-Arg supplementation in the treatment of L-Arg deficiency syndromes remains to be established. Clinical trials need to continue to determine the optimal concentrations and combinations of L-Arg, with other protective compounds such as tetrahydrobiopterin (BH4 ), and antioxidants to combat oxidative stress that drives down NO production in humans. PMID- 23740827 TI - Convenient titanium(III)-catalyzed synthesis of cyclic aminoketones and pyrrolidinones--development of a formal [4+1] cycloaddition. PMID- 23740829 TI - Pyrenoimidazole-based deep-blue-emitting materials: optical, electrochemical, and electroluminescent characteristics. AB - A series of pyrenoimidazoles that contained various functional chromophores, such as anthracene, pyrene, triphenylamine, carbazole, and fluorene, were synthesized and characterized by optical, electrochemical, and theoretical studies. The absorption spectra of the dyes are dominated by electronic transitions that arise from the pyrenoimidazole core and the additional chromophore. All of the dyes exhibited blue-light photoluminescence with moderate-to-high quantum efficiencies. They also displayed high thermal stability and their thermal decomposition temperatures fell within the range 462-512 degrees C; the highest decomposition temperature was recorded for a carbazole-containing dye. The oxidation propensity of the dyes increased on the introduction of electron-rich chromophores, such as triphenylamine or carbazole. The application of selected dyes that featured additional chromophores such as pyrene, carbazole, and triphenylamine as blue-emissive dopants into multilayered organic light-emitting diodes with a 4,4'-bis(9H-carbazol-9-yl)biphenyl (CBP) host was investigated. Devices that were based on triphenylamine- and carbazole-containing dyes exhibited deep-blue emission (CIE 0.157, 0.054 and 0.163, 0.041), whereas a device that was based on a pyrene-containing dye showed a bright-blue emission (CIE 0.156, 0.135). PMID- 23740828 TI - Antioxidant activity of carnosic acid and rosmarinic acid in raw and cooked ground chicken patties. AB - BACKGROUND: Carnosic acid (CA) and rosmarinic acid (RA) are potent antioxidants. The effectiveness of an antioxidant in a food system is dependent on a range of factors such as concentration, phenolic content, physical state of the substrate, processing and storage. However, the antioxidant activity of powder vs liquid and higher vs lower phenols is not clear in different matrices. In this study, OxiKan WS4 (4.0% RA), OxiKan-S10 (10% CA) and OxiKan-R8 (8% CA) were investigated against lipid oxidation in raw and cooked ground chicken patties during refrigerated storage. RESULTS: OxiKan-WS4 had the highest (P < 0.05) total phenolic content, whereas OxiKan-S10 and OxiKan-R8 exhibited higher DPPH radical scavenging activity and reducing power relative to OxiKan-WS4. Lipid oxidation was minimized in meat with added extracts, as indicated by lower (P < 0.05) thiobarbituric acid-reactive substances, peroxide value and free fatty acid. Addition of natural antioxidant extracts at 10 mg equivalent total phenols per 100 g meat did not affect the sensory scores relative to non-treated controls. CONCLUSION: This study demonstrates that the physical state (powder vs liquid) of CA or RA plays an important role in determining their antioxidant efficacy. PMID- 23740830 TI - Multivariate t linear mixed models for irregularly observed multiple repeated measures with missing outcomes. AB - Missing outcomes or irregularly timed multivariate longitudinal data frequently occur in clinical trials or biomedical studies. The multivariate t linear mixed model (MtLMM) has been shown to be a robust approach to modeling multioutcome continuous repeated measures in the presence of outliers or heavy-tailed noises. This paper presents a framework for fitting the MtLMM with an arbitrary missing data pattern embodied within multiple outcome variables recorded at irregular occasions. To address the serial correlation among the within-subject errors, a damped exponential correlation structure is considered in the model. Under the missing at random mechanism, an efficient alternating expectation-conditional maximization (AECM) algorithm is used to carry out estimation of parameters and imputation of missing values. The techniques for the estimation of random effects and the prediction of future responses are also investigated. Applications to an HIV-AIDS study and a pregnancy study involving analysis of multivariate longitudinal data with missing outcomes as well as a simulation study have highlighted the superiority of MtLMMs on the provision of more adequate estimation, imputation and prediction performances. PMID- 23740832 TI - Molecular engineering of organic sensitizers with planar bridging units for efficient dye-sensitized solar cells. PMID- 23740833 TI - Anthracene-containing wide-band-gap conjugated polymers for high-open-circuit voltage polymer solar cells. AB - The synthesis, characterization, and photophysical and photovoltaic properties of two anthracene-containing wide-band-gap donor and acceptor (D-A) alternating conjugated polymers (P1 and P2) are described. These two polymers absorb in the range of 300-600 nm with a band gap of about 2.12 eV. Polymer solar cells with P1:PC71 BM as the active layer demonstrate a power conversion efficiency (PCE) of 2.23% with a high Voc of 0.96 V, a Jsc of 4.4 mA cm(-2) , and a comparable fill factor (FF) of 0.53 under simulated solar illumination of AM 1.5 G (100 mW cm(-2) ). In addition, P2:PC71 BM blend-based solar cells exhibit a PCE of 1.42% with a comparable Voc of 0.89 V, a Jsc of 3.0 mA cm(-2) , and an FF of 0.53. PMID- 23740834 TI - Self-propelled micromotors driven by the magnesium-water reaction and their hemolytic properties. PMID- 23740835 TI - Effects of repeated electroconvulsive shocks on catecholamine systems: electrophysiological studies in the rat brain. AB - Electroconvulsive therapy (ECT) treats depression by repeated administration of seizure-inducing electrical stimuli. To assess the effects of repeated electroconvulsive shocks (ECSs), an animal model of ECT on monoamine transmission, Sprague-Dawley rats were administered 6 ECS over 2 weeks and in vivo single-unit extracellular electrophysiological recordings were obtained 48 h after the final ECS. Overall firing activity of dopamine (DA) neurons in the ventral tegmental area was unchanged following repeated ECS. In the locus coeruleus (LC), the burst activity of norepinephrine (NE) neurons was increased while population activity was decreased after ECS. In the substantia nigra pars compacta (SNc), there were more spontaneously active neurons, suggesting greater DA tone in the nigrostriatal motor pathway, which may contribute to an alleviation of motor retardation. In the facial motor nucleus (FMN), facilitation of electrophysiological activity by serotonin (5-HT), and NE was determined to be through the 5-HT2C receptor and alpha1 -adrenoceptor, respectively. Locally administered NE, but not 5-HT, facilitated glutamate-induced firing following repeated ECS, which may contribute to improved motor function. These results showed that repeated ECS enhance DA activity in the SNc and NE transmission in the FMN, which could be a part of the mechanism behind the alleviation of depressive symptoms, including motor retardation, by ECT. PMID- 23740836 TI - Presenilin 1/gamma-secretase modulates P-cadherin processing and influences cell adhesion in oral squamous cell carcinoma cell lines. AB - P-cadherin belongs to a family of Ca(2+)-dependent homophilic cell-cell adhesion proteins that are important for correct cellular localization and tissue integrity in the oral epithelium. P-cadherin is only expressed in the basal and suprabasal cell layers of the oral epithelium, but in advanced oral squamous cell carcinoma (OSCC), a reduced membranous and an enhanced cytoplasmic truncated P cadherin level is observed. In this study, we investigated the impact of presenilin (PS) 1/gamma-secretase on P-cadherin processing in OSCC. Western blot analyses showed an enhanced PS1 expression in OSCC cell lines and in primary oral keratinocytes (POK) isolated from primary OSCC tissue (OSCC POK) compared with POKs isolated from normal oral mucosa. Immunocytochemical stainings and co immunoprecipitation experiments revealed a cytoplasmic colocalization and a direct interaction of P-cadherin and PS1 in OSCC POKs. Blocking of PS1/gamma secretase activity by the PS1/gamma-secretase inhibitors and N-[N-(3,5 difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, another specific gamma-secretase inhibitor yielded a 100 kDa P-cadherin band on western blots of OSCC cell line extracts. Small interfering RNA knockdown of PS1 equally generated a 100 kDa P-cadherin form in OSCC POKs. Mass spectrometry analyses and experiments with the glycosylation inhibitor tunicamycin characterized the appearing 100 kDa P-cadherin band as the unglycosylated full-length form of P cadherin. On the functional level, cell attachment assays demonstrated an enhanced cell adhesion after PS1/gamma-secretase inhibition only in the transiently P-cadherin expressing OSCC cell line PCI52 but not in the PCI52 control cells. In summary, our results show that PS1/gamma-secretase contributes to P-cadherin processing and to reduced cell adhesion in OSCC. PMID- 23740837 TI - Tumor promotion through the mesenchymal stem cell compartment in human hepatocellular carcinoma. AB - Although the infiltration of mesenchymal stem (stromal) cells (MSCs) into different tumors is widely recognized in animal models, the question whether these MSCs have a positive or negative effect on disease progression remains unanswered. The aim of this study is to investigate whether human hepatocellular carcinoma (HCC) harbors MSCs and whether these MSCs affect tumor growth. We observed that cells capable of differentiation into both adipocyte and osteocyte lineages and expressing MSC markers can be cultured from surgically resected HCC tissues. In situ staining of human HCC tissues with a STRO-1 antibody showed that the tumor and tumor-stromal region are significantly enriched with candidate MSCs compared with adjacent tissue (n = 12, P < 0.01). In mice, coengraftment of a human HCC cell line (Huh7) with MSCs resulted in substantially larger tumors compared with paired engraftment of Huh7 alone (n = 8, P < 0.01). Consistently, coculturing Huh7 with irradiated MSCs significantly increased the number and the size of colonies formed. This enhancement of Huh7 colony formation was also observed by treatment of MSC-conditioned medium (MSC-CM), suggesting that secreted trophic factors contribute to the growth-promoting effects. Genome-wide gene expression array and pathway analysis confirmed the upregulation of cell growth and proliferation-related processes and downregulation of cell death related pathways by treatment of MSC-CM in Huh7 cells. In conclusion, these results show that MSCs are enriched in human HCC tumor compartment and could exert trophic effects on tumor cells. Thus, targeting of HCC tumor MSCs may represent a new avenue for therapeutic intervention. PMID- 23740838 TI - HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression. AB - Hypoxic microenvironments frequently exist in many solid tumours with oxygen levels fluctuating temporally and spatially from normoxia to hypoxia. The response to hypoxia in human cells is mainly regulated by hypoxia-inducible factors (HIFs), a family of transcription factors which orchestrate signalling events leading to angiogenesis and tumorigenesis. Several events conspire together to lead to the stabilization of HIF-alpha, commonly expressed in many cancer cell types. These events can result from low oxygen tensions occurring within the expanding tumour mass to produce hypoxic microenvironments or from mutations whereby the HIFs cause changes in expression of genes involved in several cellular functions. Hypoxia-mediated HIF-alpha regulation has gained significant prominence in tumour biology over recent years, and the hypoxic microenvironments have been shown to facilitate and trigger major molecular and immunological processes necessary to drive the progression of tumours to malignancy. More recently, it has been realized that the hypoxic microenvironments also play significant roles in shielding tumour cells from immune attack by promoting immune suppression. In addition, the hypoxic microenvironment promotes many other oncogenic events, such as the metabolic reconfiguration of tumour cells, neovascularization, epithelial to mesenchymal transition (EMT), and cancer stem cell renewal and accumulation. This article reviews the molecular mechanisms underlying tumour hypoxia and their pro-tumour contributions, such as immune suppression, development of nascent and more permeable tumour vasculature, selective cancer stem cell renewal, accumulation, mobilization and promotion of EMT leading to tumour cell metastasis. PMID- 23740839 TI - Correlating transcriptional networks to breast cancer survival: a large-scale coexpression analysis. AB - Weighted gene coexpression network analysis (WGCNA) is a powerful 'guilt-by association'-based method to extract coexpressed groups of genes from large heterogeneous messenger RNA expression data sets. We have utilized WGCNA to identify 11 coregulated gene clusters across 2342 breast cancer samples from 13 microarray-based gene expression studies. A number of these transcriptional modules were found to be correlated to clinicopathological variables (e.g. tumor grade), survival endpoints for breast cancer as a whole (disease-free survival, distant disease-free survival and overall survival) and also its molecular subtypes (luminal A, luminal B, HER2+ and basal-like). Examples of findings arising from this work include the identification of a cluster of proliferation related genes that when upregulated correlated to increased tumor grade and were associated with poor survival in general. The prognostic potential of novel genes, for example, ubiquitin-conjugating enzyme E2S (UBE2S) within this group was confirmed in an independent data set. In addition, gene clusters were also associated with survival for breast cancer molecular subtypes including a cluster of genes that was found to correlate with prognosis exclusively for basal-like breast cancer. The upregulation of several single genes within this coexpression cluster, for example, the potassium channel, subfamily K, member 5 (KCNK5) was associated with poor outcome for the basal-like molecular subtype. We have developed an online database to allow user-friendly access to the coexpression patterns and the survival analysis outputs uncovered in this study (available at http://glados.ucd.ie/Coexpression/). PMID- 23740840 TI - miR-451 inhibits cell proliferation in human hepatocellular carcinoma through direct suppression of IKK-beta. AB - It has been demonstrated that nuclear factor-kappa B (NF-kappaB), which is overactivated in hepatocellular carcinoma (HCC), plays important roles in the development of HCC. Recently, a group of dysregulated micro RNAs were reported to be involved in HCC progression. Further understanding of micro RNA-mediated regulation of NF-kappaB pathway may provide novel therapeutic targets for HCC. In this study, we found that miR-451 expression was markedly downregulated in HCC cells and tissues compared with immortalized normal liver epithelial cells and adjacent non- cancerous tissues, respectively. Upregulation of miR-451 inhibited, while downregulation of miR-451 promoted, the tumorigenicity of HCC cells both in vitro and in vivo. These changes in the properties of HCC cells were associated with deregulation of two well-known cellular G1/S transitional regulators, cyclin D1 and c-Myc, which are downstream targets of NF-kappaB pathway. Furthermore, we demonstrated that miR-451 upregulation led to downregulation of cyclin D1 and c Myc through inhibition of NF-kappaB pathway initiated by direct targeting of the IKBKB 3'-untranslated region. Therefore, these results suggest that miR-451 downregulation plays an important role in promoting proliferation of HCC cells and may provide the basis for the development of novel anti-HCC therapies. PMID- 23740842 TI - 23(rd) American Peptide Symposium. PMID- 23740841 TI - Radiation pressure on a biconcave human Red Blood Cell and the resulting deformation in a pair of parallel optical traps. AB - We calculated the three-dimensional optical stress distribution and the resulting deformation on a biconcave human red blood cell (RBC) in a pair of parallel optical trap. We assumed a Gaussian intensity distribution with a spherical wavefront for each trapping beam and calculated the optical stress from the momentum transfer associated with the reflection and refraction of the incident photons at each interface. The RBC was modelled as a biconcave thin elastic membrane with uniform elasticity and a uniform thickness of 0.25 MUm. The resulting cell deformation was determined from the optical stress distribution by finite element software, Comsol Structure Mechanics Module, with Young's modulus (E) as a fitting parameter in order to fit the theoretical results for cell elongation to our experimental data. PMID- 23740843 TI - Haloboration of internal alkynes with boronium and borenium cations as a route to tetrasubstituted alkenes. AB - Hail boration! 2-Dimethylaminopyridine-ligated dihaloborocations [X2B(2-DMAP)](+) with a strained four-membered boracycle were used for the haloboration of terminal and dialkyl internal alkynes (see scheme). Esterification then provided vinyl boronate esters as useful precursors to tetrasubstituted alkenes. Following mechanistic studies, the scope of the haloboration was expanded simply by variation of the amine. Pin = 2,3-dimethyl-2,3-butanedioxy. PMID- 23740854 TI - Pregnancy-associated plasma protein A levels and neonatal complications in post date pregnancies. AB - OBJECTIVES: To assess the association between serum pregnancy-associated plasma protein A (PAPP-A) and free beta-human chorionic gonadotropin (free beta-hCG) in the first trimester and perinatal complications in post-date pregnancies. METHODS: A total of 4948 women, who delivered after 40 gestational weeks, were included. Labour was not induced routinely until 42 weeks. Serum levels of PAPP-A and free beta-hCG were determined at the first-trimester screening for Down syndrome. Neonatal complications were obtained from specific registration forms filled out by senior neonatologists. RESULTS: In post-date pregnancies, PAPP-A < 0.4 multiples of the median was associated with Apgar score of less than 7 at 5 min (ORadj 5.4, 95% CI 2.0-14.3), admission to the neonatal intensive care unit (ORadj 1.5, 95% CI 1.0-2.3) and newborn hypoglycaemia (ORadj 3.4, 95% CI 1.8 6.4). In small for gestation (SGA) neonates, the risk of hypoglycaemia was further increased (OR 14.6, 95% CI 3.4-58.0). Similar analyses were made with free beta-hCG, but no statistically significant associations were found. CONCLUSIONS: Low first-trimester serum PAPP-A was associated with increased neonatal morbidity in post-date pregnancies, particularly in newborns with SGA. Thus, PAPP-A may qualify the timing of induction of labour in these pregnancies. PMID- 23740855 TI - Review of recent data on the metabolism, biological effects, and toxicity of resveratrol in humans. AB - Several recently published clinical trials have extended our knowledge on the use of resveratrol (RVT) to treat several human pathological and metabolic disorders. Herein, we present insights into the metabolism, biological effects, and toxicity of RVT in humans. Recent data show that RVT exhibits antioxidant and anti inflammatory activities. It can also improve glucose and lipid metabolism, it acts on cardiovascular parameters, and can modify some pathways involved in carcinogenesis. However, these effects are mostly tiny and the results are sometimes controversial as they depend on the protocols (i.e. dose, form of administration, patients' characteristics, adjuvant therapy, etc.). Toxicological data confirm that RVT is well tolerated. Any adverse effects (mainly concerning the abdomen), at doses of >=0.5 g/day for long periods, remain moderate and reversible. Nevertheless, the efficacy and safety of RVT need to be further investigated. PMID- 23740856 TI - Molecular-level understanding of the carbonisation of polysaccharides. AB - Understanding of both the textural and functionality changes occurring during (mesoporous) polysaccharide carbonisation at the molecular level provides a deeper insight into the whole spectrum of material properties, from chemical activity to pore shape and surface energy, which is crucial for the successful application of carbonaceous materials in adsorption, catalysis and chromatography. Obtained information will help to identify the most appropriate applications of the carbonaceous material generated during torrefaction and different types of pyrolysis processes and therefore will be important for the development of cost- and energy-efficient zero-waste biorefineries. The presented approach is informative and semi-quantitative with the potential to be extended to the formation of other biomass-derived carbonaceous materials. PMID- 23740857 TI - Iron chelation in the treatment of cancer: a new role for deferasirox? AB - Iron plays a crucial role in a number of metabolic pathways including oxygen transport, DNA synthesis, and ATP generation. Although insufficient systemic iron can result in physical impairment, excess iron has also been implicated in a number of diseases including ischemic heart disease, diabetes, and cancer. Iron chelators are agents which bind iron and facilitate its excretion. Experimental iron chelators have demonstrated potent anti-neoplastic properties in a number of cancers in vitro. These agents have yet to be translated into clinical practice, however, largely due to the significant side effects encountered in pre-clinical models. A number of licensed chelators, however, are currently in clinical use for the treatment of iron overload associated with certain non-neoplastic diseases. Deferasirox is one such agent and the drug has shown significant anti tumor effects in a number of in vitro and in vivo studies. Deferasirox is orally administered and has demonstrated a good side effect profile in clinical practice to date. It represents an attractive agent to take forward into clinical trials of iron chelators as anti-cancer agents. PMID- 23740858 TI - Thermoresponsive organic-inorganic hybrid large-compound vesicles. AB - Herein, gelated thermoresponsive large-compound vesicles (LCVs) are reported for the first time. The LCVs are prepared by self-assembly of poly(ethylene oxide) block-poly[N-isopropylacrylamide-random-3-(trimethoxysilyl)propyl methacrylate] [PEO-b-P(NIPAM-r-TMPM)] in DMF-water mixture. Then, sol-gel reaction of the reactive PTMPM block is performed to stabilize the LCVs. LCVs with higher cross linking density keep almost the same size under different temperatures while LCVs with lower cross-linking density display obviously thermoresponsive size transition between 22 and 36 degrees C. The gelated LCVs exhibit enhanced permeability with temperature elevation and their permeabilities at different temperatures all elevate with increasing the cross-linking density. PMID- 23740859 TI - Synthesis, anti-breast cancer activity, and molecular modeling of some benzothiazole and benzoxazole derivatives. AB - A new series of benzothiazoles and benzoxazoles was synthesized using 4 benzothiazol-2-yl-phenylamine and 4-benzoxazol-2-yl-phenylamine as starting materials. All the prepared compounds were evaluated for their antitumor activities against human breast cancer cell lines, MCF-7 and MDA-231, using 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability analysis. Almost all the tested compounds revealed potent antitumor activity, especially the N-methyl piperazinyl substituted derivatives 6f and 6c, which displayed the most potent inhibitory activity with IC50 values ranging from 8 to 17 nM. Docking the synthesized compounds into the epidermal growth factor receptor (EGFR), which is highly expressed in breast cancer, was employed to explore the possible interactions of these compounds with the EGFR. The activity of the reported compounds supports its clinical promise as a component of therapeutic strategies for cancer, for which high concentrations of chemotherapeutic agents are always a major limitation. PMID- 23740860 TI - Assessment of chronic postsurgical pain after knee replacement: a systematic review. AB - OBJECTIVE: Approximately 20% of patients experience chronic pain after total knee replacement (TKR), yet there is no consensus about how best to assess such pain. This systematic review aimed to identify measures used to characterize chronic pain after TKR.Methods. MEDLINE, Embase, PsycINFO, Cochrane Library, and CINAHL databases were searched for research articles published in all languages from January 2002 to November 2011. Articles were eligible for inclusion if they assessed knee pain at a minimum of 3 months after TKR, yielding a total of 1,164 articles. The data extracted included the study design,country, timings of assessments, and outcome measures containing pain items. The outcome measures were compared with domains recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials(IMMPACT) for inclusion in the assessment of chronic pain-related outcomes within clinical trials. Temporal trends were also explored. RESULTS: The review found use of a wide variety of composite and single-item measures, with the American Knee Society Score the most common. Many measures used in published studies did not capture the multidimensional nature of pain recommended by the IMMPACT; of those commonly used, the Western Ontario and McMaster Universities Osteoarthritis Index and Oxford Knee Score were the most comprehensive. Geographic trends were evident, with nation-specific preferences for particular measures. A recent reduction in the use of some clinically administered tools was accompanied by an increased use of patient-reported outcome measures. CONCLUSION: There was wide variation in the methods of pain assessment alongside nation-specific preferences and changing temporal trends in pain assessment after TKR. Standardization and improvements in assessment are needed to enhance the quality of research and facilitate the establishment of a core outcome set. PMID- 23740861 TI - Prenatal diagnosis, clinical outcomes, and associated pathology in pregnancies complicated by massive subchorionic thrombohematoma (Breus' mole). AB - OBJECTIVES: To review the association between ultrasound findings, placental pathology, and prognosis in pregnancies complicated by massive subchorionic thrombohematoma (MTH)/Breus' mole. METHOD: We identified 14 cases of MTH from January 2004 to December 2012. MTH was defined by >1 cm thickness hematoma and extensive (>=50%) involvement of the fetal surface of the placenta. Patient information, details of initial presentation, and perinatal outcome were obtained from the manual and electronic chart records. Ultrasound findings were related to pregnancy outcomes and associated placental pathology. Participants were stratified on the basis of birth outcome into survivors (live births, n = 7) and nonsurvivors (neonatal deaths or intrauterine fetal deaths/termination of pregnancy, n = 7). RESULTS: All 14 cases of MTH were suspected on ultrasound and confirmed by pathology assessment. All cases in the nonsurvivor group had abnormal umbilical artery (UA) Doppler waveforms compared with none in the survivors (p = 0.02). All cases in the nonsurvivor group had extreme preterm deliveries (p = 0.02). Birth weight was significantly reduced in the nonsurvivor group (p = 0.001), and 5/7 cases were diagnosed with severe intrauterine growth restriction, compared with none in the survivor group (p = 0.02). CONCLUSION: Massive subchorionic thrombohematoma/Breus' mole may be diagnosed in the second trimester by ultrasound assessment of the placenta. Normal fetal growth and UA Doppler waveforms are associated with perinatal survival. PMID- 23740862 TI - A perspective on health care for the elderly who lose their only child in China. AB - OBJECTIVES: The 30-plus years of the One Child Policy has brought about a new "childless" elderly phenomenon in China and this group is expanding rapidly. These elderly parents who lose their only child are forced to endure psychological suffering and cope with health problems alone, as they are often ignored by society. The aim of this study is to explore the psychological trauma and living dilemma among older Chinese people who lose their only child and to discuss the support and health care to this newly vulnerable group in China. METHODS: In-depth interviews with 34 childless older people were conducted in three districts in Beijing. RESULTS: The study shows that the death of only child causes an unbearable psychological trauma for elderly parents, who display prominent clusters of symptoms. Moreover, the childless elderly frequently encounter discrimination in their lives and they feel neglected by the government and society. CONCLUSIONS: Although several local governments have launched schemes to support the childless elderly, the gap in assistance is still vast. Support from the government is essential in relieving the difficulties currently faced by the childless elderly, and the difficulties they face in the future. This includes two major aspects: health and life care, and spiritual comfort. PMID- 23740863 TI - Social factors and coping status in asymptomatic middle-aged Danes: association to coronary artery calcification. AB - AIMS: Understanding the determinants of social and coping inequalities in subclinical cardiovascular disease is an important prerequisite in developing and implementing preventive strategies. The aim of this study was to investigate the association between social factors and coping status, respectively, and subclinical coronary artery disease (CAD) in middle-aged Danes. METHODS: This is a DanRisk screening substudy, thus including healthy Danish males and females aged 50 or 60 years. Social measures included grade of education, employment and co-habiting status. The coping status was estimated by the general self-efficacy (GES) scale. Coronary artery calcification (CAC) was assessed by computed tomography using the Agatston score (AS). Conventional clinical risk factors included sex, family history of CAD, BMI > 25, smoking, hypercholesterolaemia and hypertension. RESULTS: In 568 individuals the prevalence of subjects with CAC was 267 (45%). Independent predictors of CAC in males were age (OR = 1.10, 95% CI = 1.04-1.16, p < 0.001), smoking (OR = 1.75, 95% CI = 1.03-2.99, p = 0.038), and low co-habiting status (OR = 3.66, 95% CI = 1.19-11.25, p = 0.023). Independent predictors in females were age (OR = 1.67, 95% CI = 1.02-1.12, p = 0.006), and smoking (OR = 1.71, 95% CI = 1.06-2.78, p = 0.029). Higher AS was associated to lower employment level in females (p = 0.001) but not in males (p = 0.833). CONCLUSIONS: Social factors are associated to the prevalence and severity of CAC in asymptomatic middle-aged individuals with gender differences. The relative value of gender specific social versus conventional clinical risk factors in the risk assessment of subclinical CAC in middle-aged individuals needs further investigation in future prospective studies. PMID- 23740864 TI - Base-catalyzed synthesis of substituted indazoles under mild, transition-metal free conditions. AB - Back to basics: A transition-metal-free method developed for the synthesis of indazoles involves an inexpensive catalytic system composed of a diamine and K2CO3. Various (Z)-2-bromoacetophenone tosylhydrazones were converted into indazoles at room temperature in excellent yields (see example; Ts = p toluenesulfonyl). The yield was improved by photoisomerization with UV light when E/Z isomeric mixtures of the starting material were used. PMID- 23740866 TI - Late brain alterations in sepsis-survivor rats. AB - Central nervous system (CNS) dysfunction secondary to sepsis is characterized by long-term cognitive impairment. It was observed that oxidative damage, energetic metabolism impairment, and cytokine level alteration seen in early times in an animal model of sepsis may persist for up to 10 days and might be associated with cognitive damage. In order to understand these mechanisms, at least in part, we evaluated the effects of sepsis on cytokine levels in the cerebrospinal fluid (CSF), oxidative parameters, and energetic metabolism in the brain of rats at both 30 and 60 days after sepsis induction by cecal ligation and perforation (CLP). To this aim, male Wistar rats underwent CLP with "basic support" or were sham-operated. Both 30 and 60 days after surgery, the CSF was collected and the animals were killed by decapitation. Then, the prefrontal cortex, hippocampus, striatum, and cortex were collected. Thirty days after surgery, an increase of IL 6 level in the CSF; an increase in the thiobarbituric acid-reactive species (TBARS) in prefrontal cortex and a decrease in hippocampus, striatum, and cortex; a decrease of carbonyl protein formation only in prefrontal cortex and an increase in striatum; and an increase in the complex IV activity only in hippocampus were observed. Sixty days after sepsis, an increase of TNF-alpha level in the CSF; a decrease of TBARS only in hippocampus; an increase of carbonyl protein formation in striatum; and a decrease of complex I activity in prefrontal cortex, hippocampus, and striatum were observed. These findings may contribute to understanding the role of late cognitive impairment. Further studies may address how these findings interact during sepsis development and contribute to CNS dysfunction. PMID- 23740867 TI - Arsa-diazonium salts with an arsenic-nitrogen triple bond. PMID- 23740865 TI - Organ specific optical imaging of mitochondrial redox state in a rodent model of hereditary hemorrhagic telangiectasia-1. AB - Hereditary Hemorrhagic Telangiectasia-1 (HHT-1) is a vascular disease caused by mutations in the endoglin (Eng)/CD105 gene. The objective of this study was to quantify the oxidative state of a rodent model of HHT-1 using an optical imaging technique. We used a cryofluorescence imaging instrument to quantitatively assess tissue metabolism in this model. Mitochondrial redox ratio (FAD/NADH), FAD RR, was used as a quantitative marker of the metabolic status and was examined in the kidneys, and eyes of wild-type and Eng +/- mice. Kidneys and eyes from wild-type P21, 6W, and 10M old mice showed, respectively, a 9% (+/-2), 24% (+/-0.4), 15% (+/-1), and 23% (+/-4), 33% (+/-0.6), and 30% (+/-2) change in the mean FAD RR compared to Eng +/- mice at the same age. Thus, endoglin haploinsufficiency is associated with less oxidative stress in various organs and mitigation of angiogenesis. PMID- 23740868 TI - The neural correlates of 'vitality form' recognition: an fMRI study: this work is dedicated to Daniel Stern, whose immeasurable contribution to science has inspired our research. AB - The observation of goal-directed actions performed by another individual allows one to understand what that individual is doing and why he/she is doing it. Important information about others' behaviour is also carried out by the dynamics of the observed action. Action dynamics characterize the 'vitality form' of an action describing the cognitive and affective relation between the performing agent and the action recipient. Here, using the fMRI technique, we assessed the neural correlates of vitality form recognition presenting participants with videos showing two actors executing actions with different vitality forms: energetic and gentle. The participants viewed the actions in two tasks. In one task (what), they had to focus on the goal of the presented action; in the other task (how), they had to focus on the vitality form. For both tasks, activations were found in the action observation/execution circuit. Most interestingly, the contrast how vs what revealed activation in right dorso-central insula, highlighting the involvement, in the recognition of vitality form, of an anatomical region connecting somatosensory areas with the medial temporal region and, in particular, with the hippocampus. This somatosensory-insular-limbic circuit could underlie the observers' capacity to understand the vitality forms conveyed by the observed action. PMID- 23740869 TI - Stereodivergent synthesis of piperidine alkaloids by ring-rearrangement metathesis/reductive lactam alkylation of nitroso Diels-Alder cycloadducts. AB - A general methodology for the stereoselective synthesis of 2-(2 hydroxyalkyl)piperidine alkaloids by ring-rearrangement metathesis of nitroso Diels-Alder cycloadducts is reported. The approach is illustrated by the formal synthesis of porantheridine and the total synthesis of andrachcinidine through a diastereodivergent allylation of an N-alkoxy bicyclic lactam. The asymmetric synthesis of the latter alkaloid provides new insights into the configurational stability of cycloadducts between chloronitroso reagents and cyclopentadiene. PMID- 23740871 TI - Gender bias in the measurement of peer victimization: an application of item response theory. AB - There continues to be great debate regarding the conceptualization and measurement of peer victimization, particularly with respect to gender differences in children's victimization experiences. We employed traditional and modern psychometric methods (e.g., item response theory) to evaluate a 10-item youth-report measure of peer victimization (e.g., threatening, spreading rumors/lies, and cyberbullying) among 17,198 students in Grades 6-12. A two factor model that differentiated between direct and indirect victimization subtypes best characterized students' experiences and substantially reduced the potential for gender-based measurement bias. Implications for the gender sensitive assessment of peer victimization are discussed. PMID- 23740872 TI - Personal distributed exposimeter for radio frequency exposure assessment in real environments. AB - For the first time, a personal distributed exposimeter (PDE) for radio frequency (RF) measurements is presented. This PDE is designed based on numerical simulations and is experimentally evaluated using textile antennas and wearable electronics. A prototype of the PDE is calibrated in an anechoic chamber. Compared to conventional exposimeters, which only measure in one position on the body, an excellent isotropy of 0.5 dB (a factor of 1.1) and a 95% confidence interval of 7 dB (a factor of 5) on power densities are measured. PMID- 23740873 TI - Oxazepine synthesis by copper-catalyzed intermolecular cascade reactions between O-propargylic oximes and dipolarophiles. AB - Three-step cascade: Oxazepine derivatives were efficiently prepared from O propargylic oximes and dipolarophiles through copper-catalyzed cascade reactions which proceed through a 2,3-rearrangement, [3+2] cycloaddition, and subsequent 1,3-oxygen rearrangement. The process involves the cleavage of C?- and N-O bonds. PMID- 23740870 TI - Repulsive guidance molecules (RGMs) and neogenin in bone morphogenetic protein (BMP) signaling. AB - Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-beta (TGFbeta) superfamily. BMPs mediate a highly conserved signal transduction cascade through the type-I and type-II serine/threonine kinase receptors and intracellular Smad proteins, which regulate multiple developmental and homeostatic processes. Mutations in this pathway can cause various diseases in humans, such as skeletal disorders, cardiovascular diseases, and various cancers. Multiple levels of regulation, including extracellular regulation, help to ensure proper spatiotemporal control of BMP signaling in the right cellular context. The family of repulsive guidance molecules (RGMs) and the type-I transmembrane protein neogenin, a paralog of DCC (Deleted in Colorectal Cancer), have been implicated in modulating the BMP pathway. In this review, we discuss the properties and functions of RGM proteins and neogenin, focusing on their roles in the modulation of BMP signal transduction. PMID- 23740874 TI - Plasmonic laser treatment for Morpholino oligomer delivery in antisense applications. AB - Several cell transfection techniques have been developed in the last decades for specific applications and for various types of molecules. In this context, laser based approaches are of great interest due to their minimal invasiveness and spatial selectivity. In particular, laser induced plasmon based delivery of exogenous molecules into cells can have great impact on future applications. This approach allows high-throughput laser transfection by excitation of plasmon resonances at gold nanoparticles non-specifically attached to the cell membrane. In this study, we demonstrate specific gene-knockdown by transfection of Morpholino oligos using this technique with optimized particle size. Furthermore, we evaluated the cytotoxicity of plasmonic laser treatment by various assays, including LDH activity and ROS formation. In summary, this study gives important insights into this new approach and clearly demonstrates its relevance for possible biological applications. PMID- 23740875 TI - Submaximal heart and pulmonary evaluation: a novel noninvasive test to identify pulmonary hypertension in patients with systemic sclerosis. AB - OBJECTIVE: Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc; scleroderma). Although right-sided heart catheterization (RHC) is the gold standard for diagnosing PH, it is an invasive test with associated risks. The submaximal heart and pulmonary evaluation (step test) is a noninvasive, submaximal stress test that could be used to identify patients with PH. The purpose of this study is to assess the correlation between change in end tidal carbon dioxide (DeltaPETCO2 ) from rest to end-exercise on the step test and mean pulmonary artery pressure (mPAP) on RHC in SSc patients. METHODS: This is a retrospective cohort study of patients with limited or diffuse cutaneous SSc who were evaluated in an academic cardiology practice between November 2007 and November 2011 and underwent a step test and RHC. Statistical analysis was performed using Spearman's correlation test and multivariable linear regression. RESULTS: A total of 679 charts were reviewed. Nineteen SSc patients who underwent a step test and RHC were included. DeltaPETCO2 was negatively correlated with mPAP (r = -0.82, P < 0.0001). In a multivariable linear regression model evaluating the relationship between DeltaPETCO2 and mPAP, controlling for age, sex, and time between and order of step test and RHC, DeltaPETCO2 remained the only variable statistically significantly associated with mPAP (P < 0.001). The step test had a sensitivity of 100%, specificity of 75%, positive predictive value of 93.8%, and negative predictive value of 100% for the diagnosis of PH. CONCLUSION: DeltaPETCO2 on the step test has a strong, statistically significant negative correlation with mPAP on RHC. PMID- 23740876 TI - Expectation maximization-based likelihood inference for flexible cure rate models with Weibull lifetimes. AB - Recently, a flexible cure rate survival model has been developed by assuming the number of competing causes of the event of interest to follow the Conway-Maxwell Poisson distribution. This model includes some of the well-known cure rate models discussed in the literature as special cases. Data obtained from cancer clinical trials are often right censored and expectation maximization algorithm can be used in this case to efficiently estimate the model parameters based on right censored data. In this paper, we consider the competing cause scenario and assuming the time-to-event to follow the Weibull distribution, we derive the necessary steps of the expectation maximization algorithm for estimating the parameters of different cure rate survival models. The standard errors of the maximum likelihood estimates are obtained by inverting the observed information matrix. The method of inference developed here is examined by means of an extensive Monte Carlo simulation study. Finally, we illustrate the proposed methodology with a real data on cancer recurrence. PMID- 23740877 TI - Formation of bismuth(V) thiolates: protolysis and oxidation of triphenylbismuth(III) with heterocyclic thiols. PMID- 23740878 TI - alpha-L-fucosidase inhibition by pyrrolidine-ferrocene hybrids: rationalization of ligand-binding properties by structural studies. AB - Enhanced metabolism of fucose through fucosidase overexpression is a signature of some cancer types, thus suggesting that fucosidase-targetted ligands could play the role of drug-delivery vectors. Herein, we describe the synthesis of a new series of pyrrolidine-ferrocene conjugates, consisting of a L-fuco-configured dihydroxypyrrolidine as the fucosidase ligand armed with a cytotoxic ferrocenylamine moeity. Three-dimensional structures of several of these fucosidase inhibitors reveal transition-state-mimicking (3)E conformations. Elaboration with the ferrocenyl moiety results in sub-micromolar inhibitors of both bovine and bacterial fucosidases, with the 3D structure of the latter revealing electron density indicative of highly mobile alkylferrocene compounds. The best compounds show a strong antiproliferative effect, with up to 100% inhibition of the proliferation of MDA-MB-231 cancer cells at 50 MUM. PMID- 23740879 TI - CrossTalk proposal: the human upper airway does behave like a Starling resistor during sleep. PMID- 23740880 TI - CrossTalk opposing view: the human upper airway during sleep does not behave like a Starling resistor. PMID- 23740881 TI - Rebuttal from Alan R. Schwartz and Philip L. Smith. PMID- 23740882 TI - Rebuttal from James P. Butler, Robert L. Owens, Atul Malhotra and Andrew Wellman. PMID- 23740883 TI - Blood pressure regulation in women - differences emerge when challenged by orthostasis. PMID- 23740884 TI - Controversies surrounding the role of CFTR in airway bicarbonate secretion. PMID- 23740885 TI - You get what you give: localized vascular changes are apparent following long term exercise training. PMID- 23740886 TI - Correlation between human clusterin in seminal plasma with sperm protamine deficiency and DNA fragmentation. AB - Seminal proteins can be considered as factors that control fertilization. Clusterin is one such protein that has been implicated in many activities, including apoptosis inhibition, cell cycle control, DNA repair, and sperm maturation. In this study, the relationship between human secretory clusterin (sCLU) in seminal plasma with sperm parameters, protamine deficiency, and DNA fragmentation was investigated. Semen samples were collected from 63 Iranian men, and semen analysis was performed according to World Health Organization criteria and computer aided semen analysis (CASA). The concentration of sCLU in seminal plasma was measured by enzyme-linked immunosorbant assay (ELISA), protamine deficiency was determined by chromomycin A3 staining (CMA3 ), and sperm DNA fragmentation was checked by sperm chromatin dispersion (SCD) assay. The level of sCLU in seminal fluid of fertile patients was 48.3 +/- 38.6 ng/ml and in infertile patients was 15.5 +/- 9.7 ng/ml; this difference was significant (P < 0.001). sCLU correlated negatively with protamine deficiency, sperm DNA fragmentation, and abnormal morphology. In conclusion, seminal clusterin can be considered as a marker for the quick assessment of semen quality in male infertility studies. PMID- 23740887 TI - Irreversible electroporation and apoptosis in human liver cancer cells induced by nanosecond electric pulses. AB - The goal of this study was to assess the effect of nanosecond electric pulses on HepG2 human liver cancer cells. Electric pulses with a high strength of 10 kV/cm, duration of 500 ns and frequency of 1 Hz were applied to the cells. After delivery of electric pulses, apoptosis, intracellular calcium ion concentrations, transmembrane mitochondrial potentials, electropermeabilization and recovery from electropermeabilization in cells were investigated. The results showed that electric pulse treatment for 20 s and more could trigger apoptosis in cells. Real time observation indicated an immediate increase in intracellular calcium ion concentration and a dramatic decrease in mitochondrial membrane potential in cells responding to electric pulses. In subsequent experiments, propidium iodide uptake in cells emerged after exposure to electric pulses, indicating electropermeabilization of the cell membrane. Furthermore, recovery from electropermeabilization was not observed even 4 h after the stimulation, demonstrating that irreversible electropermeabilization was induced by electric pulses. In conclusion, electric pulses with a high strength and nanosecond duration can damage cancer cells, accompanied by a series of intracellular changes, providing strong evidence for the application of electric pulses in cancer treatment. PMID- 23740888 TI - Metal-assisted cyclomerization of N-confused dipyrrins into expanded norroles. PMID- 23740889 TI - Evaluation of histologic, serologic, and clinical changes in response to abatacept treatment of primary Sjogren's syndrome: a pilot study. AB - OBJECTIVE: To prospectively evaluate histopathologic, blood cellular, serologic, and clinical changes in response to abatacept treatment in patients with primary Sjogren's syndrome (SS). METHODS: Blood, saliva, and minor salivary gland biopsy samples were obtained before and after the last of 8 doses of abatacept in 11 primary SS patients. The histologic data evaluated the numbers of lymphocytic foci and B and T cell subtypes (CD20+, CD3+, CD4+, and CD8+). The numbers of FoxP3+ regulatory T cells were measured and the FoxP3:CD3 ratio was calculated. Histologic data were compared with results from peripheral blood and with changes in saliva secretion. RESULTS: The numbers of lymphocytic foci decreased significantly (P = 0.041). Numbers of local FoxP3+ T cells decreased significantly in percentage of total lymphocytic infiltrates (P = 0.037). In the peripheral blood, B cells increased (P = 0.038). This was due to an expansion of the naive B cell pool (P = 0.034). When adjusting for disease duration, an increase was also noted for total lymphocytes (P = 0.044) and for CD4 cells (P = 0.009). Gamma globulins decreased significantly(P = 0.005), but IgG reduction did not reach significance. Adjusted for disease duration, saliva production increased significantly (P = 0.029). CONCLUSION: CTLA-4Ig treatment significantly reduces glandular inflammation in primary SS, induces several cellular changes, and increases saliva production. Remarkably, this increase in saliva production is significantly influenced by disease duration. PMID- 23740890 TI - Regioselective one-step synthesis of pyrazoles from alkynes and N tosylhydrazones: [3+2] dipolar cycloaddition/[1,5] sigmatropic rearrangement cascade. PMID- 23740891 TI - Transient loss of consciousness: summary of NICE guidance. PMID- 23740892 TI - Retraction. Human induced pluripotent stem cell-derived cardiomyocytes serve as in vitro model of cardiac hypertrophy. Heart;2011:97.e7. PMID- 23740893 TI - Insight, psychosis, and depression in Africa: a cross-sectional survey from an inpatient unit in Ghana. AB - Few studies of the relationship of insight to psychopathology have been conducted in non-Western populations. This study examined the relationships between insight and depression, anxiety, and positive and negative symptoms on patients with schizophrenia resident in a psychiatric hospital in Ghana. A sample of 49 participants, (37 men and 12 women), with DSM-IV defined schizophrenia took part in semistructured interviews consisting of the Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A); the Schedule for the Assessment of Insight - Expanded Version (SAI-E) and the Positive and Negative Syndrome Scale (PANSS). Bivariate correlations between variables were examined and those significantly correlated with an insight domain were included in multiple regression models. Variables associated with the total insight score were age, gender, anxiety symptoms, depression symptoms, and treatment compliance. In the final model, HAM-D positively predicted total SAI-E score, whilst PANSS-pos was negatively associated with total SAI-E score. The results are broadly consistent with those found in Western samples regarding insight and depressive symptoms. Implications of these results for competing theories of insight in psychoses are discussed. Patients able to identify themselves as ill may be aware of their affective symptoms. PMID- 23740894 TI - Randomized phase III trial of concurrent chemoradiotherapy vs accelerated hyperfractionation radiotherapy in locally advanced head and neck cancer. AB - The aim of this study was to compare the efficacy and safety of concurrent chemoradiotherapy (CCRT) vs accelerated hyperfractionation with concomitant boost (CCB) as a primary treatment for patients with Stage III-IV squamous cell carcinoma of head and neck (SCCHN). A total of 85 non-metastatic advanced SCCHN patients were accrued from January 2003 to December 2007. Of these, 48 and 37 patients received CCRT and CCB, respectively. The patients were randomized to receive either three cycles of carboplatin and 5-fluorouracil plus conventional radiotherapy (CCRT, 66 Gy in 6.5 weeks) or hybrid accelerated radiotherapy (CCB, 70 Gy in 6 weeks). The primary endpoint was determined by locoregional control rate. The secondary endpoints were overall survival and toxicity. With a median follow-up of 43 months (range, 3-102), the 5-year locoregional control rate was 69.6% in the CCRT arm vs 55.0% in the CCB arm (P = 0.184). The 5-year overall survival rate was marginally significantly different (P = 0.05): 76.1% in the CCRT arm vs 63.5% in the CCB arm. Radiotherapy treatment interruptions of more than three days were 60.4% and 40.5% in the CCRT arm and CCB arm, respectively. The median total treatment time was 55.5 days in the CCRT arm and 49 days in the CCB arm. The rate of Grade 3-4 acute mucositis was significantly higher in the CCB arm (67.6% vs 41.7%, P = 0.01), but no high grade hematologic toxicities were found in the CCB arm (27.2% vs 0%). CCRT has shown a trend of improving outcome over CCB irradiation in locoregionally advanced head and neck cancer. PMID- 23740895 TI - One is better than two: TCR pairing and GVHD. AB - T lymphocytes that express dual TCRs were found more frequently in patients with acute graft-versus-host disease (GVHD) as compared with patients who also underwent allogeneic stem cell transplantation but did not develop acute GVHD (Morris et al., this issue). PMID- 23740896 TI - Preventing the pain of PTSD. AB - A selective opioid receptor agonist prevents fear memory consolidation in the amygdala in a mouse model of posttraumatic stress disorder (Andero et al.). PMID- 23740897 TI - Comment on "Drug screening for ALS using patient-specific induced pluripotent stem cells". AB - Egawa et al. recently showed the value of patient-specific induced pluripotent stem cells (iPSCs) for modeling amyotrophic lateral sclerosis in vitro. Their study and our work highlight the need for complementary assays to detect small, but potentially important, phenotypic differences between control iPSC lines and those carrying disease mutations. PMID- 23740898 TI - Response to comment on "Drug screening for ALS using patient-specific induced pluripotent stem cells". AB - Our work and the study of Bilican et al. highlight the need for complementary assays to detect subtle phenotypic differences between control and mutant induced pluripotent stem cell lines. PMID- 23740899 TI - Amygdala-dependent fear is regulated by Oprl1 in mice and humans with PTSD. AB - The amygdala-dependent molecular mechanisms driving the onset and persistence of posttraumatic stress disorder (PTSD) are poorly understood. Recent observational studies have suggested that opioid analgesia in the aftermath of trauma may decrease the development of PTSD. Using a mouse model of dysregulated fear, we found altered expression within the amygdala of the Oprl1 gene (opioid receptor like 1), which encodes the amygdala nociceptin (NOP)/orphanin FQ receptor (NOP R). Systemic and central amygdala infusion of SR-8993, a new highly selective NOP R agonist, impaired fear memory consolidation. In humans, a single-nucleotide polymorphism (SNP) within OPRL1 is associated with a self-reported history of childhood trauma and PTSD symptoms (n = 1847) after a traumatic event. This SNP is also associated with physiological startle measures of fear discrimination and magnetic resonance imaging analysis of amygdala-insula functional connectivity. Together, these data suggest that Oprl1 is associated with amygdala function, fear processing, and PTSD symptoms. Further, our data suggest that activation of the Oprl1/NOP receptor may interfere with fear memory consolidation, with implications for prevention of PTSD after a traumatic event. PMID- 23740900 TI - Dual receptor T cells mediate pathologic alloreactivity in patients with acute graft-versus-host disease. AB - Acute graft-versus-host disease (aGVHD) results from a robust response of donor T cells transferred during hematopoietic stem cell transplantation (HSCT) to allogeneic peptide-major histocompatibility complex antigens. Previous investigations have not identified T cell subsets that selectively mediate either protective immunity or pathogenic alloreactivity. We demonstrate that the small subset of peripheral T cells that naturally express two T cell receptors (TCRs) on the cell surface contributes disproportionately to aGVHD in patients after allogeneic HSCT. Dual TCR T cells from patients with aGVHD demonstrate an activated phenotype and produce pathogenic cytokines ex vivo. Dual receptor clones from a patient with symptomatic aGVHD responded specifically to mismatched recipient human leukocyte antigens (HLAs), demonstrating pathologic alloreactivity. Human dual TCR T cells are strongly activated and expanded by allogeneic stimulation in vitro, and disproportionately contribute to the repertoire of T cells recognizing both major (HLA) and minor histocompatibility antigens, providing a mechanism for their observed activity in vivo in patients with aGVHD. These results identify dual TCR T cells as a target for focused analysis of a T cell subset mediating GVHD and as a potential prognostic indicator. PMID- 23740902 TI - International dental education. PMID- 23740903 TI - Expanding the global conversation in dental education: guidelines for scholarly research and writing for international authors. PMID- 23740901 TI - Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis. AB - Multiple sclerosis (MS) is a devastating inflammatory disease of the brain and spinal cord that is thought to result from an autoimmune attack directed against antigens in the central nervous system. The aim of this first-in-man trial was to assess the feasibility, safety, and tolerability of a tolerization regimen in MS patients that uses a single infusion of autologous peripheral blood mononuclear cells chemically coupled with seven myelin peptides (MOG1-20, MOG35-55, MBP13-32, MBP83-99, MBP111-129, MBP146-170, and PLP139-154). An open-label, single-center, dose-escalation study was performed in seven relapsing-remitting and two secondary progressive MS patients who were off-treatment for standard therapies. All patients had to show T cell reactivity against at least one of the myelin peptides used in the trial. Neurological, magnetic resonance imaging, laboratory, and immunological examinations were performed to assess the safety, tolerability, and in vivo mechanisms of action of this regimen. Administration of antigen coupled cells was feasible, had a favorable safety profile, and was well tolerated in MS patients. Patients receiving the higher doses (>1 * 10(9)) of peptide-coupled cells had a decrease in antigen-specific T cell responses after peptide-coupled cell therapy. In summary, this first-in-man clinical trial of autologous peptide-coupled cells in MS patients establishes the feasibility and indicates good tolerability and safety of this therapeutic approach. PMID- 23740904 TI - A case study on development of an integrated, multidisciplinary dental curriculum. AB - Calls for fundamental reform of dental education were made twice in the twentieth century. More recently, spurred by the work of the American Dental Education Association's Commission on Change and Innovation in Dental Education (ADEA CCI), North American dental educators have again begun advocating for major curriculum reform in order to develop in students the higher order thinking skills required for the contemporary practice of dentistry. This case study describes the process of curricular reform at one school designed to move from a traditional siloed curriculum to one that uses case-based, integrated multidisciplinary courses to improve teaching and learning. The process was broad-based and comprehensive and included a schoolwide values clarification exercise and agreement on desired characteristics of an ideal graduate. Stakeholders agreed that the reform curriculum should incorporate inter- and multidisciplinary courses, case-based and active learning strategies, and concepts from adult learning theory. The new curriculum model is comprised of five unique but related curriculum "strands," each managed by a small group of interdisciplinary faculty content experts. Challenges in the development and implementation of the reform curriculum are discussed, and an assessment plan is presented. PMID- 23740905 TI - Dental student perceptions of case-based educational effectiveness. AB - This study investigated the effects of a case-based education course on second year dental students. It explored what impact the small-group environment had on the participants professionally, communicatively, and personally and also analyzed their performance evaluations of the facilitators. The study employed a pretest-posttest survey design. Students' professional development consistently showed a positive significant change as a result of the course, especially regarding perceived skills. The course was found to have impacted the students' confidence in their own team contribution, and their ability to discuss and present treatment plans also significantly increased. This study did not find evidence of influence on the students' personal benefit. The students reported perceiving that the facilitators' abilities were stronger at the beginning of the course, but then the ratings decreased over time. Overall, the case-based education course was found to have positively affected students' knowledge and skills acquisition as well as their communication skills. PMID- 23740906 TI - Comprehensive training in suspected child abuse and neglect for dental students: a hybrid curriculum. AB - Child abuse and neglect are tragic realities of American society. However, most U.S. dental schools do not provide students with adequate training to deal with the problem. This article proposes expanding the predoctoral dental curriculum with a problem-based learning model that can effectively stimulate critical thinking skills to assist graduates in screening and reporting suspected child abuse and neglect throughout their careers. The unique multicultural environment of dental school offers students an unprecedented opportunity to develop awareness about child abuse and domestic violence, while increased vigilance can potentially save innocent young lives. Educating students about proper protocol when they suspect child abuse or neglect is imperative, particularly for dental schools involving students in community sealant and other preventive programs in public schools. By expanding their curriculum to include recognition and intervention, dental schools can help break the cycle of violence and transform attitudes towards taking decisive action. Clinical curricula that have moved to private practice preceptor models are well suited to screen for child abuse. The goal is to motivate dental schools to deal with this critical issue, develop reporting protocols and procedures for appropriate response, and provide their students with consummate training. PMID- 23740907 TI - The utility of hybrid promotion and tenure tracks for dental school faculty. AB - The promotion and tenure process for faculty members varies, by design, for different disciplines, departments, and academic institutions. For many faculty members in U.S. dental schools, the process may thus appear nebulous and be difficult to navigate. In this article, we review the history, forces of change, and some of the mechanisms utilized for promotion and tenure of faculty in the health sciences, particularly for clinician-educators. Some institutions have successfully created hybrid tracks for clinician-educators in order to develop and recognize these faculty members' scholarly activity in addition to their clinical teaching. Hybrid tracks empower faculty members to successfully perform scholarly activities that realistically reflect institutional missions. The authors of this article conclude with a number of practical suggestions to enhance development and retention of faculty using the hybrid promotion and tenure mechanism. These include demonstrating the congruence of institutional mission, faculty activities, and promotion and tenure guidelines; developing scholarly activities for clinician-educators that can be measured in the promotion and tenure process; rewarding scholarly achievement for clinician educators utilizing the promotion and tenure mechanism; and developing an evaluation system that accounts for changes in mission and faculty activities. PMID- 23740908 TI - Long-term follow-up of a dental faculty development program. AB - Many, if not most, dental faculty members have not received formal training to be educators. However, the importance of faculty development programs in improving teaching skills, fostering career development, and reinforcing relationships with colleagues and mentors has increasingly been acknowledged. In 2005, the Excellence in Clinical Teaching Program at New York University College of Dentistry (NYUCD) was created to enhance the clinical teaching skills of NYUCD faculty members. As of spring 2009, fifty-nine faculty members had participated in eight separate cohorts. The program consists of five formal group sessions supplemented by readings, reflection papers, and a final project. This study examined the short- and long-term effectiveness of the program. Participants were asked to complete a short pre-program survey to self-assess their teaching abilities and, at the last session, a satisfaction survey. In fall 2011, forty eight faculty members who completed the program from spring 2005 to fall 2009 and were actively teaching at least one session a week at NYUCD were asked to complete a follow-up survey asking about the long-term value of the program and their academic career progression since program completion. Thirty-three faculty members responded for a response rate of 69 percent. Ninety-seven percent of the respondents indicated they would recommend the program to their colleagues, 94 percent said program participation led to a greater likelihood of conferring with peers about teaching issues,79 percent had increased their teaching responsibilities, and 62 percent said that presenting the final project improved their presentation skills. In addition, the retention rate of those still teaching at the school (81 percent) exceeds national retention rate averages for dental faculty. This follow-up study suggests that participation in the Excellence in Clinical Teaching Program is associated with meaningful professional growth. PMID- 23740909 TI - A four-tier problem-solving scaffold to teach pain management in dental school. AB - Pain constitutes a major reason patients pursue dental treatment. This article presents a novel curriculum to provide dental students comprehensive training in the management of pain. The curriculum's four-tier scaffold combines traditional and problem-based learning to improve students' diagnostic, pharmacotherapeutic, and assessment skills to optimize decision making when treating pain. Tier 1 provides underpinning knowledge of pain mechanisms with traditional and contextualized instruction by integrating clinical correlations and studying worked cases that stimulate clinical thinking. Tier 2 develops critical decision making skills through self-directed learning and actively solving problem-based cases. Tier 3 exposes students to management approaches taken in allied health fields and cultivates interdisciplinary communication skills. Tier 4 provides a "knowledge and experience synthesis" by rotating students through community pain clinics to practice their assessment skills. This combined teaching approach aims to increase critical thinking and problem-solving skills to assist dental graduates in better management of pain throughout their careers. Dental curricula that have moved to comprehensive care/private practice models are well-suited for this educational approach. The goal of this article is to encourage dental schools to integrate pain management into their curricula, to develop pain management curriculum resources for dental students, and to provide leadership for change in pain management education. PMID- 23740910 TI - Teaching with technology: learning outcomes for a combined dental and dental hygiene online hybrid oral histology course. AB - Among the challenges leaders in dental and allied dental education have faced in recent years is a shortage of well-qualified faculty members, especially in some specialty areas of dentistry. One proposed solution has been the use of technology. At the University of Missouri-Kansas City School of Dentistry, the departure of a faculty member who taught the highly specialized content in oral histology and embryology provided the opportunity to implement distance delivery of that course. The course is taught once a year to a combined group of dental and dental hygiene students. Previous to spring semester of 2009, the course was taught using traditional face-to-face, in-class lectures and multiple-choice examinations. During the spring semesters of 2009, 2010, and 2011, the course was taught using synchronous and asynchronous distance delivery technology. Outcomes for these courses (including course grades and performance on the National Board Dental Examination Part I) were compared to those from the 2006, 2007, and 2008 courses. Students participating in the online hybrid course were also given an author-designed survey, and the perceptions of the faculty member who made the transition from teaching the course in a traditional face-to-face format to teaching in an online hybrid format were solicited. Overall, student and faculty perceptions and student outcomes and course reviews have been positive. The results of this study can provide guidance to those seeking to use technology as one method of curricular delivery. PMID- 23740911 TI - Embryology and histology education in North American dental schools: the Basic Science Survey Series. AB - As part of the Basic Science Survey Series (BSSS) for Dentistry, members of the American Dental Education Association (ADEA) Anatomical Sciences Section surveyed faculty members teaching embryology and histology courses at North American dental schools. The survey was designed to assess, among other things, curriculum content, utilization of laboratories, use of computer-assisted instruction (CAI), and recent curricular changes. Responses were received from fifty-nine (88.1 percent) of the sixty-seven U.S. and Canadian dental schools. Findings suggest the following: 1) a trend toward combining courses is evident, though the integration was predominantly discipline-based; 2) embryology is rarely taught as a stand-alone course, as content is often covered in gross anatomy, oral histology, and/or in an integrated curriculum; 3) the number of contact hours in histology is decreasing; 4) a trend toward reduction in formal laboratory sessions, particularly in embryology, is ongoing; and 5) use of CAI tools, including virtual microscopy, in both embryology and histology has increased. Additionally, embryology and histology content topic emphasis is identified within this study. Data, derived from this study, may be useful to new instructors, curriculum and test construction committees, and colleagues in the anatomical sciences, especially when determining a foundational knowledge base. PMID- 23740912 TI - Integration of basic sciences and clinical sciences in oral radiology education for dental students. AB - Educational research suggests that cognitive processing in diagnostic radiology requires a solid foundation in the basic sciences and knowledge of the radiological changes associated with disease. Although it is generally assumed that dental students must acquire both sets of knowledge, little is known about the most effective way to teach them. Currently, the basic and clinical sciences are taught separately. This study was conducted to compare the diagnostic accuracy of students when taught basic sciences segregated or integrated with clinical features. Predoctoral dental students (n=51) were taught four confusable intrabony abnormalities using basic science descriptions integrated with the radiographic features or taught segregated from the radiographic features. The students were tested with diagnostic images, and memory tests were performed immediately after learning and one week later. On immediate and delayed testing, participants in the integrated basic science group outperformed those from the segregated group. A main effect of learning condition was found to be significant (p<0.05). The results of this study support the critical role of integrating biomedical knowledge in diagnostic radiology and shows that teaching basic sciences integrated with clinical features produces higher diagnostic accuracy in novices than teaching basic sciences segregated from clinical features. PMID- 23740913 TI - Improving light-curing instruction in dental school. AB - Delivering an inadequate amount of light to a light-cured resin will result in a resin that is inadequately cured. This study measured the radiant exposure that students delivered to a simulated restoration to determine if instruction with immediate feedback increased the amount of light they delivered. The amount of light (radiant exposure in J/cm(2)) delivered to a simulated restoration by sixty three dental students using the same curing light for twenty seconds was recorded. The experiment was repeated after the students had been given detailed light-curing instructions together with immediate feedback using the MARCPS system. Initially, the students delivered between 1.4 and 17.5 J/cm(2) (mean+/ SD: 9.8+/-3.5 J/cm(2)). After receiving instructions and feedback on their light curing technique, they delivered between 6.7 J/cm(2) and 17.8 J/cm(2) (mean+/-SD: 13.2+/-3.3 J/cm(2)). ANOVA and Fisher's post hoc multiple comparison tests showed that providing immediate feedback on the students' light-curing technique made a significant improvement in the radiant exposure they delivered (p<0.05). It was concluded that many dental students in this study were not using the curing light properly. After the students had received one session of additional instruction and immediate feedback using the MARC-PS, they delivered 35 percent more light energy to the same simulated restoration. Students who were closer to graduation showed a greater improvement in their light-curing technique (p=0.0091). PMID- 23740914 TI - Training and use of lasers in postgraduate orthodontic programs in the United States and Canada. AB - This study was designed to determine if orthodontic residents are being trained to use lasers in the postgraduate orthodontic residency programs of the United States and Canada. An anonymous electronic survey was sent to the program director/chair of each of the seventy orthodontic residency programs, and thirty seven (53 percent) of the programs responded. Of these thirty-seven programs, twenty-eight (76 percent) reported providing patient treatment with lasers in the orthodontic graduate program, eight (22 percent) said they do not provide treatment in the orthodontic graduate program, and one program (3 percent) reported providing laser training but not using lasers on patients. Gingivectomy and canine exposure were reported as the most common procedures that residents perform with a laser, while debonding of orthodontic brackets was the least common procedure performed with a laser. A diode laser was the most common type of laser used. Of the eight programs (22 percent) not offering laser training, four indicated having no plans to begin using lasers or training on their use. The other four indicated that they have plans to incorporate laser use in the future. PMID- 23740915 TI - Evaluation of a virtual reality simulation system for porcelain fused to metal crown preparation at Tokyo Medical and Dental University. AB - The use of virtual reality simulation (VRS) is a new teaching modality in dentistry, and there is scope for further research evaluating its use under different educational programs. The purpose of this study was to evaluate how VRS with or without instructor feedback influenced students' learning and skills related to porcelain fused to metal (PFM) crown preparation. In this study, forty three dental students in their fifth year of study at Tokyo Medical and Dental University, Tokyo, Japan, were randomly divided into three groups: the first group used VRS (DentSim) with the instructor's feedback (DSF) (n=15), the second group used VRS without the instructor's feedback (DS) (n=15), and the third group neither used features of VRS (NDS) (n=13) nor received the instructor's feedback. All the students performed PFM crown preparation under the same setup once a week for four weeks. Total scores, preparation time, and twelve evaluation items were compared among the three groups and four experiments. The total scores of students in the DSF and DS groups were significantly higher than those in the NDS group. The presence of the instructor did not result in significant difference when VRS was used for training, while it shortened the preparation time at early stages. The results of this study suggested that the use of the VRS system improved student training for PFM crown preparation. PMID- 23740916 TI - Nigerian dental therapy students' knowledge, attitude, and willingness to care for patients with HIV. AB - The objective of this study was to assess Nigerian dental therapy students' knowledge, attitudes, and willingness to care for patients with HIV. A twenty-six item questionnaire was used to conduct a cross-sectional study of the dental therapy students of Federal School of Dental Therapy and Technology, Enugu State, Nigeria. The level of knowledge of HIV transmission and prevention among the respondents was high. However, misconceptions about the transmission of HIV through blood donation, mosquito bite, and sharing cups and plates were noted. Erroneous descriptions of HIV as harmless, self-limiting, antibiotic sensitive infection, punishment virus, and contagious infection were also reported. More than half (56.2 percent) and 25.2 percent of the respondents, respectively, expressed feelings of empathy and sympathy towards individuals with HIV. About three-quarters (74.3 percent) expressed willingness to treat patients with HIV, and 87.6 percent expressed confidence in their ability to prevent occupational HIV acquisition. This expressed confidence was significantly associated with their willingness to treat patients with HIV. More than half (55.7 percent) of the respondents reported they can adequately deliver HIV-related information to patients. A total of 86.2 percent said there is a need for training dental therapists in the clinical care of patients with HIV, and 89.0 percent said that dental therapists can play a significant role in the dissemination of HIV-related information. The vast majority (90.0 percent) expressed willingness to disseminate HIV-related information, and the majority (70.5 percent) considered the dental therapist the most suitable dental professional to give HIV-related information to patients. PMID- 23740917 TI - Stress and health-promoting attributes in Australian, New Zealand, and Chilean dental students. AB - This study investigated stress levels and health-promoting attributes (sense of coherence, social support, and coping strategies) in dental students using a Salutogenic approach. All dental students (n=2,049) from two Australian universities, two Chilean universities, and one New Zealand university were invited to participate in this cross-sectional study. The questionnaire covered sociodemographic and career choice questions, Perceived Stress Scale, Orientation to Life Questionnaire, Multidimensional Scale of Perceived Social Support, and Brief COPE scale. A total of 897 students participated, for a 44 percent response rate. Students' mean age was 22.1 (SD=2.7). The majority were females (59.3 percent). Students reported moderate stress, moderate sense of coherence (SOC), and high levels of social support. Significant differences in the SOC scores by country were reported. The linear regression model for stress explained 44 percent of the variance, in which SOC and social support are negatively associated with stress and the use of maladaptive coping strategies positively predicts high stress. These findings confirm that health-promoting attributes were negatively related to stress in these dental students. This is an initial approach to guide academics in the creation of Salutogenic programs that optimize students' chances to successfully cope with stress. PMID- 23740918 TI - Women's motivation to become dentists in Brazil. AB - There has been a marked increase of women in dentistry in Brazil and in many countries around the world. The behavioral mechanisms behind the choice of career differ between men and women, and the inclination to care for others is thought by some to be more present in women than it is in men. This article discusses the reasons that lead women to choose dentistry as a profession in Brazil and the impact of feminization on the current and future profile of the profession, based on the ethics of care. The authors' review of the relevant literature published between 2000 and 2011, primarily in Brazil, suggests that whereas men have tended to choose dentistry as a good business opportunity, women have tended to base their decision on relations with other people and the flexibility of practicing the profession. Many women dentists have been found to decide to work fewer hours, report more interruptions in their activities, and have less preference to work in private practice than men dentists. In the view of service users and dental auxiliaries in Brazil, women dentists invest more time in their patients and communicate in a more pleasant, sensitive, and friendly manner. The conclusion suggests that characteristics often associated with women can affect the dental profession in Brazil by introducing greater concern with the promotion of health and other people's well-being in contrast to traditional dentistry based on curative procedures. PMID- 23740919 TI - Does binding of complement factor H to the meningococcal vaccine antigen, factor H binding protein, decrease protective serum antibody responses? AB - Factor H binding protein (fHbp) is a principal antigen in a multicomponent meningococcal vaccine recently licensed in Europe for prevention of serogroup B diseases. The protein recruits the complement downregulator, factor H (fH), to the bacterial surface, which enables the organism to resist complement-mediated bacteriolysis. Binding is specific for human fH. In preclinical studies, mice and rabbits immunized with fHbp vaccines developed serum bactericidal antibody responses, which in humans predict protection against developing meningococcal disease. These studies, however, were in animals whose fH did not bind to the vaccine antigen. Here we review the immunogenicity of fHbp vaccines in human fH transgenic mice. The data suggest that animals with high serum human fH concentrations have impaired protective antibody responses. Further, mutant fHbp vaccines with single amino acid substitutions that decrease fH binding are superior immunogens, possibly by unmasking epitopes in the fH binding site that are important for eliciting serum bactericidal antibody responses. Humans immunized with fHbp vaccines develop serum bactericidal antibody, but achieving broad coverage in infants required incorporation of additional antigens, including outer membrane vesicles, which increased rates of fever and local reactions at the injection site. The experimental results in transgenic mice predict that fHbp immunogenicity can be improved in humans by using mutant fHbp vaccines with decreased fH binding. These results have important public health implications for developing improved fHbp vaccines for control of serogroup B meningococcal disease and for development of vaccines against other microbes that bind host molecules. PMID- 23740920 TI - Comparison of different assays to assess human papillomavirus (HPV) type 16- and 18-specific antibodies after HPV infection and vaccination. AB - We compared the measurement of human papillomavirus (HPV)-specific serum antibody levels with the virus-like-particle multiplex immunoassay (VLP-MIA), competitive Luminex immunoassay (cLIA), and glutathione S-transferase (GST) L1-based MIA. Using a large panel of serum samples, these assays showed mutually good correlations for both naturally induced and vaccine-derived HPV-specific antibody levels. However, an adaptation of the GST L1-based MIA resulted in an improved correlation with both cLIA and VLP-MIA. PMID- 23740921 TI - Development of an enzyme-linked immunosorbent assay for serodiagnosis of ringworm infection in cattle. AB - The aim of this study was to develop an in-house enzyme-linked immunosorbent assay (ELISA) for the serological diagnosis of ringworm infection in cattle. We used available recombinant forms of Trichophyton rubrum dipeptidyl peptidase V (TruDppV) and T. rubrum leucin aminopeptidase 2 (TruLap2), which are 98% identical to Trichophyton verrucosum orthologues. Field serum samples from 135 cattle with ringworm infection, as confirmed by direct microscopy, fluorescence microscopy, and PCR, and from 55 cattle without any apparent skin lesions or history of ringworm infection that served as negative controls were used. Sensitivities, specificities, and positive and negative predictive values were determined to evaluate the diagnostic value of our ELISA. Overall, the ELISAs based on recombinant TruDppV and TruLap2 discriminated well between infected animals and healthy controls. Highly significant differences (P < 0.0001, Mann Whitney U test) were noted between optical density values obtained when sera from infected versus control cattle were tested. The ELISA developed for the detection of specific antibodies against DppV gave 89.6% sensitivity, 92.7% specificity, a 96.8% positive predictive value, and a 78.4% negative predictive value. The recombinant TruLap2-based ELISA displayed 88.1% sensitivity, 90.9% specificity, a 95.9% positive predictive value, and a 75.7% negative predictive value. To the best of our knowledge, this is the first ELISA based on recombinant antigens for assessing immune responses to ringworm infection in cattle; it is particularly suitable for epidemiological studies and also for the evaluation of vaccines and/or vaccination procedures. PMID- 23740922 TI - A single dose of a DNA vaccine encoding apa coencapsulated with 6,6'-trehalose dimycolate in microspheres confers long-term protection against tuberculosis in Mycobacterium bovis BCG-primed mice. AB - Mycobacterium bovis BCG prime DNA (Mycobacterium tuberculosis genes)-booster vaccinations have been shown to induce greater protection against tuberculosis (TB) than BCG alone. This heterologous prime-boost strategy is perhaps the most realistic vaccination for the future of TB infection control, especially in countries where TB is endemic. Moreover, a prime-boost regimen using biodegradable microspheres seems to be a promising immunization to stimulate a long-lasting immune response. The alanine proline antigen (Apa) is a highly immunogenic glycoprotein secreted by M. tuberculosis. This study investigated the immune protection of Apa DNA vaccine against intratracheal M. tuberculosis challenge in mice on the basis of a heterologous prime-boost regimen. BALB/c mice were subcutaneously primed with BCG and intramuscularly boosted with a single dose of plasmid carrying apa and 6,6'-trehalose dimycolate (TDM) adjuvant, coencapsulated in microspheres (BCG-APA), and were evaluated 30 and 70 days after challenge. This prime-boost strategy (BCG-APA) resulted in a significant reduction in the bacterial load in the lungs, thus leading to better preservation of the lung parenchyma, 70 days postinfection compared to BCG vaccinated mice. The profound effect of this heterologous prime-boost regimen in the experimental model supports its development as a feasible strategy for prevention of TB. PMID- 23740923 TI - Rapid Wuchereria bancrofti-specific antigen Wb123-based IgG4 immunoassays as tools for surveillance following mass drug administration programs on lymphatic filariasis. AB - The Global Programme to Eliminate Lymphatic Filariasis has an urgent need for rapid assays to detect ongoing transmission of lymphatic filariasis (LF) following multiple rounds of mass drug administration (MDA). Current WHO guidelines support using the antigen card immunochromatographic test (ICT), which detects active filarial infection but does not detect early exposure to LF. Recent studies found that antibody-based assays better serve this function. In the present study, two tests, a rapid IgG4 enzyme-linked immunosorbent assay (ELISA) and a lateral-flow strip immunoassay, were developed based on the highly sensitive and specific Wuchereria bancrofti antigen Wb123. A comparison of W. bancrofti-infected and -uninfected patients (with or without other helminth infections) demonstrated that both tests had high sensitivities and specificities (93 and 97% [ELISA] and 92 and 96% [strips], respectively). When the W. bancrofti uninfected group was separated into those with other filarial/helminth infections (i.e., onchocerciasis, loiasis, and strongyloidiasis) and those who were parasite uninfected, the specificities of the assays varied between 91 and 100%. In addition, the geometric mean response by ELISA of W. bancrofti-infected patients was significantly higher than the response of those without W. bancrofti infection (P < 0.0001). Furthermore, the Wb123 ELISA and the lateral-flow strips had high positive and negative predictive values, giving valuable information on the size of survey population needed to be reasonably certain whether or not transmission is ongoing. These highly sensitive and specific IgG4 tests to the W. bancrofti Wb123 protein give every indication that they will serve as useful tools for post-MDA monitoring. PMID- 23740924 TI - Oral inoculation of chickens with a candidate fowl adenovirus 9 vector. AB - Fowl adenoviruses (FAdVs) are a potential alternative to human adenovirus-based vaccine vectors. Our previous studies demonstrated that a 2.4-kb region at the left end of the FAdV-9 genome is nonessential for virus replication and is suitable for the insertion or replacement of transgenes. Our in vivo study showed that the virus FAdV-9Delta4, lacking six open reading frames (ORFs) at the left end of its genome, replicates less efficiently than wild-type FAdV-9 (wtFAdV-9) in chickens that were infected intramuscularly. However, the fecal-oral route is the natural route of FAdV infection, and the oral administration of a vaccine confers some advantages compared to administration through other routes, especially when developing an adenovirus as a vaccine vector. Therefore, we sought to investigate the effects of FAdV-9 in orally inoculated chickens. In the present study, we orally inoculated specific-pathogen-free (SPF) chickens with FAdV-9 and FAdV-9Delta4 and assessed virus shedding, antibody response, and viral genome copy number and cytokine gene expression in tissues. Our data showed that FAdV-9Delta4 replicated less efficiently than did wtFAdV-9, as evidenced by reduced virus shedding in feces, lower viral genome copy number in tissues, and lower antibody response, which are consistent with the results of the intramuscular route of immunization. Furthermore, we found that both wtFAdV-9 and FAdV-9Delta4 upregulated the mRNA expression of alpha interferon (IFN-alpha), IFN gamma, and interleukin-12 (IL-12). In addition, there was a trend toward downregulation of IL-10 gene expression caused by both viruses. These findings indicate that one or more of the six deleted ORFs contribute to modulating the host response against virus infection as well as virus replication in vivo. PMID- 23740925 TI - Characterization and protective immunogenicity of the SzM protein of Streptococcus zooepidemicus NC78 from a clonal outbreak of equine respiratory disease. AB - Streptococcus zooepidemicus of Lancefield group C is a highly variable tonsillar and mucosal commensal that usually is associated with opportunistic infections of the respiratory tract of vertebrate hosts. More-virulent clones have caused epizootics of severe respiratory disease in dogs and horses. The virulence factors of these strains are poorly understood. The antiphagocytic protein SeM is a major virulence factor and protective antigen of Streptococcus equi, a clonal biovar of an ancestral S. zooepidemicus strain. Although the genome of S. zooepidemicus strain H70, an equine isolate, contains a partial homolog (szm) of sem, expression of the gene has not been documented. We have identified and characterized SzM from an encapsulated S. zooepidemicus strain from an epizootic of equine respiratory disease in New Caledonia. The SzM protein of strain NC78 (SzM(NC78)) has a predicted predominantly alpha-helical fibrillar structure with an LPSTG cell surface anchor motif and resistance to hot acid. A putative binding site for plasminogen is present in the B repeat region, the sequence of which shares homology with repeats of the plasminogen binding proteins of human group C and G streptococci. Equine plasminogen is activated in a dose-dependent manner by recombinant SzM(NC78). Only 23.20 and 25.46% DNA homology is shared with SeM proteins of S. equi strains CF32 and 4047, respectively, and homology ranges from 19.60 to 54.70% for SzM proteins of other S. zooepidemicus strains. As expected, SzM(NC78) reacted with convalescent-phase sera from horses with respiratory disease associated with strains of S. zooepidemicus. SzM(NC78) resembles SeM in binding equine fibrinogen and eliciting strong protective antibody responses in mice. Sera of vaccinated mice opsonized S. zooepidemicus strains NC78 and W60, the SzM protein of which shared partial amino acid homology with SzM(NC78). We conclude that SzM is a protective antigen of NC78; it was strongly reactive with serum antibodies from horses during recovery from S. zooepidemicus-associated respiratory disease. PMID- 23740926 TI - Acquired antibodies to merozoite antigens in children from Uganda with uncomplicated or severe Plasmodium falciparum malaria. AB - Malaria can present itself as an uncomplicated or severe disease. We have here studied the quantity and quality of antibody responses against merozoite antigens, as well as multiplicity of infection (MOI), in children from Uganda. We found higher levels of IgG antibodies toward erythrocyte-binding antigen EBA181, MSP2 of Plasmodium falciparum 3D7 and FC27 (MSP2-3D7/FC27), and apical membrane antigen 1 (AMA1) in patients with uncomplicated malaria by enzyme-linked immunosorbent assay (ELISA) but no differences against EBA140, EBA175, MSP1, and reticulocyte-binding protein homologues Rh2 and Rh4 or for IgM against MSP2 3D7/FC27.Patients with uncomplicated malaria were also shown to have higher antibody affinities for AMA1 by surface plasmon resonance (SPR). Decreased invasion of two clinical P. falciparum isolates in the presence of patient plasma correlated with lower initial parasitemia in the patients, in contrast to comparisons of parasitemia to ELISA values or antibody affinities, which did not show any correlations. Analysis of the heterogeneity of the infections revealed a higher MOI in patients with uncomplicated disease, with the P. falciparum K1 MSP1 (MSP1-K1) and MSP2-3D7 being the most discriminative allelic markers. Higher MOIs also correlated positively with higher antibody levels in several of the ELISAs. In conclusion, certain antibody responses and MOIs were associated with differences between uncomplicated and severe malaria. When different assays were combined, some antibodies, like those against AMA1, seemed particularly discriminative. However, only decreased invasion correlated with initial parasitemia in the patient, signaling the importance of functional assays in understanding development of immunity against malaria and in evaluating vaccine candidates. PMID- 23740928 TI - Comparison of the Vidas system and two recent fully automated assays for diagnosis and follow-up of toxoplasmosis in pregnant women and newborns. AB - Serological testing to detect toxoplasmosis is of major importance to avoid the possible effects of the disease in newborns. This study assessed anti-Toxoplasma IgG and IgM with the Vidas (bioMerieux), Architect (Abbott), and Liaison (DiaSorin) systems in 631 sera from pregnant women and newborns as well as anti Toxoplasma IgG avidity with these three systems on 54 sera from pregnant women with positive IgG and IgM. The IgG and IgM results were in agreement in, respectively, 95.2% and 98.3% (Vidas versus Architect) and 96.9% and 95.3% (Vidas versus Liaison) of the samples. Specificities were excellent for all the assays, while Vidas sensitivities ranged (depending on the classification of gray zone results) from 93.8 to 98.4% for IgG (Architect, 84.4 to 93.8%; Liaison, 93.8%) and from 81.8 to 90.9% for IgM (Architect, 63.6%; Liaison, 81.8 to 90.9%). In seroconversion sequences, IgMs were generally detected simultaneously by the three assays, while Architect was the earliest assay to detect IgG. In noninfected children, maternally transmitted IgGs were detected for a longer time with Architect than with the other systems. IgMs were positive in only one infected child with the Vidas and Liaison systems. Significantly more sera were classified in the high-avidity category with Vidas than with Architect. This evaluation shows similar performances for Vidas and more recent systems. The Vidas system adequately detects toxoplasmosis in pregnant women and newborns. This system fits the needs of laboratories working on small routine series for first-line testing as well as expert laboratories, due to a high specificity and a powerful avidity test. PMID- 23740927 TI - Dried blood as an alternative to plasma or serum for Trypanosoma cruzi IgG detection in screening programs. AB - Trypanosoma cruzi serological screening is recommended for people potentially exposed to this parasite in countries where Trypanosoma cruzi is endemic and those where it is not endemic. Blood samples on filter paper may be a practical alternative to plasma/serum for antibody detection. Using the Architect Chagas assay, we detected the presence of IgG against T. cruzi in matched serum and dried blood spots (DBS) collected from 147 patients residing in Madrid, Spain, who had potential previous exposure to T. cruzi. The kappa statistic for the DBS/serum proportion of agreement for the detection of antibodies against T. cruzi was 0.803, considering an S/CO (assay result unit; chemiluminescent signal from the sample [S] divided by the mean chemiluminescent signal for the three calibrators used in the test [CO]) cutoff value of >=1.00. The relative sensitivity of the Architect test using DBS increased from 95.2% to 98.8% when the cutoff was lowered from >=1.00 to >=0.88, while the relative specificity decreased from 84.1% to 71.6%. Overall, the median S/CO values for DBS were significantly lower than those for serum (2.6 versus 6.5; P < 0.001). Discrepancies that occurred with the use of DBS included 10 false positives (with low S/CO values in 9 cases [median, 2.13]) and 4 false negatives, with mean S/CO values of 0.905 (gray zone). Using DBS plus a highly sensitive and specific enzyme-linked immunosorbent assay (ELISA) may be a simple and reliable method for detecting IgG against T. cruzi when blood sampling by venipuncture is not feasible. This method may also reduce the false-negative rates observed with some rapid diagnostic tests. The lower relative sensitivity compared to the reference method may be increased by lowering the optical density threshold. PMID- 23740929 TI - Impact of the Yosemite hantavirus outbreak on hantavirus antibody testing at a national reference laboratory. AB - In conjunction with the 2012 Yosemite hantavirus outbreak, the number of sera our facility tested for hantavirus antibodies increased. We tracked test results and used the data set to determine if a more efficient testing algorithm was possible. Sera were screened using laboratory-developed pan-hantavirus IgG and IgM enzyme immunoassays (EIAs), with an index of >1.10 defined as positive. Sera that were IgM positive by screening (screen IgM(+)) were tested for Sin Nombre virus (SNV)-specific IgM using a laboratory-developed EIA; screen IgM(+) IgG(+) sera were also tested for SNV IgG using a laboratory-developed immunoblot assay. SNV antibody-positive samples were sent to state public health laboratories (PHL) or the CDC for confirmation. Of 3,946 sera tested from July through December 2012, 205 were screen IgM(+) IgG negative (IgG(-)); 7/205 were SNV IgM(+), but only 1/5 sent to PHL/CDC was confirmed as SNV IgM(+). Of 61 screen IgM(+) IgG(+) sera, 16 were SNV antibody positive; 13/16 sera (from 11 patients) went to PHL/CDC, where SNV infection was confirmed for all patients. Of 12 confirmed patients, 7 had been exposed at Yosemite. A modified algorithm defining screen indices of >=2.00 as positive identified 11/12 confirmed cases while reducing the number of sera requiring SNV-specific antibody testing by 65%; the patient missed was not tested until 3 months after the onset of symptoms. Hantavirus antibody testing at our facility identified 12 SNV-infected patients, including 7 exposed at Yosemite. Some screen IgM(+) IgG(-) SNV IgM(+) results were false positives, emphasizing the value of PHL/CDC confirmatory testing. We identified a modified algorithm requiring analysis of fewer specimens for SNV-specific antibodies without loss of sensitivity. PMID- 23740930 TI - Mortality differentials 1991-2005 by self-reported ethnicity: findings from the ONS Longitudinal Study. AB - BACKGROUND: Research on ethnic differentials in mortality in England and Wales has focused on immigrants because, until now, studies collecting data on ethnicity have not covered sufficient deaths to investigate the subject. International migrants are selected for good health and tend to have low mortality. METHODS: We investigated all-cause mortality at ages 1-79 in 1991-2005 by self-reported ethnicity and country of birth. The data are from the Office for National Statistics Longitudinal Study of England and Wales for the cohort aged 0 64 in 1991 (n=436 195). Poisson regression was used to adjust the estimates for metropolitan residence and three indicators of socioeconomic status. RESULTS: White, Black Caribbean, Other Asian and Other immigrants all had lower mortality than Whites born in the UK. Indian, Pakistani, Bangladeshi and Chinese immigrants had lower mortality than the UK-born Whites living in similar circumstances to them. By contrast, the UK-born Black Caribbean group had higher mortality (RR=1.38, 95% CI 1.03 to 1.86) than the UK-born Whites. This excess mortality was accounted for by their low socioeconomic status. Within the Black Caribbean population, the UK-born individuals had significantly higher mortality than those born abroad whether or not the estimates were adjusted for socioeconomic status and metropolitan residence. Adjusting exposure time for undocumented emigration made little difference to the estimates. CONCLUSIONS: Immigrants are selected for good health. This has offset the impact of socioeconomic disadvantage on the mortality of minority ethnic groups. As the immigrant population ages and the UK born minority ethnic population grows, ethnic differentials in all-cause mortality are likely to change. PMID- 23740931 TI - Cultures of the internet: identity, community and mental health. PMID- 23740932 TI - Influence of carbon to nitrogen ratios on soybean somatic embryo (cv. Jack) growth and composition. AB - Soybean [Glycine max (L.) Merr.] seed are valued for their protein and oil content. Soybean somatic embryos cultured in Soybean Histodifferentiation and Maturation (SHaM) medium were examined for their suitability as a model system for developing an understanding of assimilate partitioning and metabolic control points for protein and oil biosynthesis in soybean seed. This report describes the growth dynamics and compositional changes of SHaM embryos in response to change in the carbon to nitrogen ratio of the medium. It was postulated that at media compositions that were sufficient to support maximal growth rates, changes in the C:N ratio are likely to influence the partitioning of resources between the various storage products, especially protein and oil. As postulated, at steady-state growth rates, embryo protein content was strongly correlated with decreasing C:N ratios and increasing glutamine consumption rates. However, oil content remained relatively unchanged across the C:N ratio range tested, and resources were instead directed towards the starch and residual biomass (estimated by mass balance) pools in response to increasing C:N ratios. Protein and oil were inversely related only at concentrations of sucrose in the medium <88 mM, where carbon limited growth and no starch was found to accumulate in the tissues. These observations and the high reproducibility in the data indicate that SHaM embryos are an ideal model system for the application of metabolic flux analysis studies designed to test hypotheses regarding assimilate partitioning in developing soybean seeds. PMID- 23740933 TI - Elevated atmospheric CO2 decreases the ammonia compensation point of barley plants. AB - The ammonia compensation point ( ) controls the direction and magnitude of NH3 exchange between plant leaves and the atmosphere. Very limited information is currently available on how responds to anticipated climate changes. Young barley plants were grown for 2 weeks at ambient (400 MUmol mol(-1)) or elevated (800 MUmol mol(-1)) CO2 concentration with or NH4NO3 as the nitrogen source. The concentrations of and H(+) in the leaf apoplastic solution were measured along with different foliar N pools and enzymes involved in N metabolism. Elevated CO2 caused a threefold decrease in the concentration in the apoplastic solution and slightly acidified it. This resulted in a decline of the from 2.25 and 2.95 nmol mol(-1) under ambient CO2 to 0.37 and 0.89 nmol mol(-1) at elevated CO2 in the and NH4NO3 treatments, respectively. The decrease in at elevated CO2 reflected a lower N concentration (-25%) in the shoot dry matter. The activity of nitrate reductase also declined (-45 to -60%), while that of glutamine synthetase was unaffected by elevated CO2. It is concluded that elevated CO2 increases the likelihood of plants being a sink for atmospheric NH3 and reduces episodes of NH3 emission from plants. PMID- 23740935 TI - Phase II trial of neoadjuvant docetaxel and CG1940/CG8711 followed by radical prostatectomy in patients with high-risk clinically localized prostate cancer. AB - BACKGROUND: Prostate cancer (PC) is the most commonly diagnosed noncutaneous malignancy in American men. PC, which exhibits a slow growth rate and multiple potential target epitopes, is an ideal candidate for immunotherapy. GVAX for prostate cancer is a cellular immunotherapy, composed of PC-3 cells (CG1940) and LNCaP cells (CG8711). Each of the components is a prostate adenocarcinoma cell line that has been genetically modified to secrete granulocyte-macrophage colony stimulating factor. Hypothesizing that GVAX for prostate cancer could be effective in a neoadjuvant setting in patients with locally advanced disease, we initiated a phase II trial of neoadjuvant docetaxel and GVAX. For the trial, the clinical effects of GVAX were assessed in patients undergoing radical prostatectomy (RP). METHODS: Patients received docetaxel administered at a dose of 75 mg/m(2) every 3 weeks for 4 cycles. GVAX was administered 2-3 days after chemotherapy preoperatively for four courses of immunotherapy. The first dose of GVAX was a prime immunotherapy of 5*10(8) cells. The subsequent boost immunotherapies consisted of 3*10(8) cells. After RP, patients received an additional six courses of immunotherapy. Pathologic complete response, toxicity, and clinical response were assessed. The primary endpoint of the trial was a pathologic state of pT0, which is defined as no evidence of cancer in the prostate. RESULTS: Six patients completed neoadjuvant docetaxel and GVAX therapy. No serious drug-related adverse events were observed. Median change in prostate specific antigen (PSA) following neoadjuvant therapy was 1.47 ng/ml. One patient did not undergo RP due to the discovery of positive lymph nodes during exploration. Of the five patients completing RP, four had a downstaging of their Gleason score. Undetectable PSA was achieved in three patients at 2 months after RP and in two patients at 3 years after RP. CONCLUSIONS: Neoadjuvant docetaxel/GVAX is safe and well tolerated in patients with high-risk locally advanced PC. No evidence of increased intraoperative hemorrhage or increased length of hospital stay postoperatively was noted. These results justify further study of neoadjuvant immunotherapy. PMID- 23740936 TI - Decreased number of Gemini of coiled bodies and U12 snRNA level in amyotrophic lateral sclerosis. AB - Disappearance of TAR-DNA-binding protein 43 kDa (TDP-43) from the nucleus contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS), but the nuclear function of TDP-43 is not yet fully understood. TDP-43 associates with nuclear bodies including Gemini of coiled bodies (GEMs). GEMs contribute to the biogenesis of uridine-rich small nuclear RNA (U snRNA), a component of splicing machinery. The number of GEMs and a subset of U snRNAs decrease in spinal muscular atrophy, a lower motor neuron disease, suggesting that alteration of U snRNAs may also underlie the molecular pathogenesis of ALS. Here, we investigated the number of GEMs and U11/12-type small nuclear ribonucleoproteins (snRNP) by immunohistochemistry and the level of U snRNAs using real-time quantitative RT PCR in ALS tissues. GEMs decreased in both TDP-43-depleted HeLa cells and spinal motor neurons in ALS patients. Levels of several U snRNAs decreased in TDP-43 depleted SH-SY5Y and U87-MG cells. The level of U12 snRNA was decreased in tissues affected by ALS (spinal cord, motor cortex and thalamus) but not in tissues unaffected by ALS (cerebellum, kidney and muscle). Immunohistochemical analysis revealed the decrease in U11/12-type snRNP in spinal motor neurons of ALS patients. These findings suggest that loss of TDP-43 function decreases the number of GEMs, which is followed by a disturbance of pre-mRNA splicing by the U11/U12 spliceosome in tissues affected by ALS. PMID- 23740934 TI - Progress in the biological understanding and management of breast cancer associated central nervous system metastases. AB - Metastasis to the central nervous system (CNS) is a devastating neurological complication of systemic cancer. Brain metastases from breast cancer have been documented to occur in approximately 10%-16% of cases over the natural course of the disease with leptomeningeal metastases occurring in approximately 2%-5% of cases of breast cancer. CNS metastases among women with breast cancer tend to occur among those who are younger, have larger tumors, and have a more aggressive histological subtype such as the triple negative and HER2-positive subtypes. Treatment of CNS metastases involves various combinations of whole brain radiation therapy, surgery, stereotactic radiosurgery, and chemotherapy. We will discuss the progress made in the treatment and prevention of breast cancer associated CNS metastases and will delve into the biological underpinnings of CNS metastases including evaluating the role of breast tumor subtype on the incidence, natural history, prognostic outcome, and impact of therapeutic efficacy. PMID- 23740938 TI - RD3 gene delivery restores guanylate cyclase localization and rescues photoreceptors in the Rd3 mouse model of Leber congenital amaurosis 12. AB - RD3 is a 23 kDa protein implicated in the stable expression of guanylate cyclase in photoreceptor cells. Truncation mutations are responsible for photoreceptor degeneration and severe early-onset vision loss in Leber congenital amaurosis 12 (LCA12) patients, the rd3 mouse and the rcd2 collie. To further investigate the role of RD3 in photoreceptors and explore gene therapy as a potential treatment for LCA12, we delivered adeno-associated viral vector (AAV8) with a Y733F capsid mutation and containing the mouse Rd3 complementary DNA (cDNA) under the control of the human rhodopsin kinase promoter to photoreceptors of 14-day-old Rb(11.13)4Bnr/J and In (5)30Rk/J strains of rd3 mice by subretinal injections. Strong RD3 transgene expression led to the translocation of guanylate cyclase from the endoplasmic reticulum (ER) to rod and cone outer segments (OSs) as visualized by immunofluorescence microscopy. Guanylate cyclase expression and localization coincided with the survival of rod and cone photoreceptors for at least 7 months. Rod and cone visual function was restored in the In (5)30Rk/J strain of rd3 mice as measured by electroretinography (ERG), but only rod function was recovered in the Rb(11.13)4Bnr/J strain, suggesting that the latter may have another defect in cone phototransduction. These studies indicate that RD3 plays an essential role in the exit of guanylate cyclase from the ER and its trafficking to photoreceptor OSs and provide a 'proof of concept' for AAV mediated gene therapy as a potential therapeutic treatment for LCA12. PMID- 23740937 TI - A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci. AB - Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21,109 (6835 cases and 14,274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 * 10(-11), OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 * 10(-11), OR = 1.20) and JAZF1 (P = 1.11 * 10(-8), OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity. PMID- 23740939 TI - Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines. AB - Bioenergetic dysfunction occurs in Alzheimer's disease (AD) and mild cognitive impairment (MCI), a clinical syndrome that frequently precedes symptomatic AD. In this study, we modeled AD and MCI bioenergetic dysfunction by transferring mitochondria from MCI, AD and control subject platelets to mtDNA-depleted SH-SY5Y cells. Bioenergetic fluxes and bioenergetics-related infrastructures were characterized in the resulting cytoplasmic hybrid (cybrid) cell lines. Relative to control cybrids, AD and MCI cybrids showed changes in oxygen consumption, respiratory coupling and glucose utilization. AD and MCI cybrids had higher ADP/ATP and lower NAD+/NADH ratios. AD and MCI cybrids exhibited differences in proteins that monitor, respond to or regulate cell bioenergetic fluxes including HIF1alpha, PGC1alpha, SIRT1, AMPK, p38 MAPK and mTOR. Several endpoints suggested mitochondrial mass increased in the AD cybrid group and probably to a lesser extent in the MCI cybrid group, and that the mitochondrial fission-fusion balance shifted towards increased fission in the AD and MCI cybrids. As many of the changes we observed in AD and MCI cybrid models are also seen in AD subject brains, we conclude reduced bioenergetic function is present during very early AD, is not brain-limited and induces protean retrograde responses that likely have both adaptive and mal-adaptive consequences. PMID- 23740941 TI - Delayed myelination in a mouse model of fragile X syndrome. AB - Fragile X Syndrome is the most common inherited cause of autism. Fragile X mental retardation protein (FMRP), which is absent in fragile X, is an mRNA binding protein that regulates the translation of hundreds of different mRNA transcripts. In the adult brain, FMRP is expressed primarily in the neurons; however, it is also expressed in developing glial cells, where its function is not well understood. Here, we show that fragile X (Fmr1) knockout mice display abnormalities in the myelination of cerebellar axons as early as the first postnatal week, corresponding roughly to the equivalent time in human brain development when symptoms of the syndrome first become apparent (1-3 years of age). At postnatal day (PND) 7, diffusion tensor magnetic resonance imaging showed reduced volume of the Fmr1 cerebellum compared with wild-type mice, concomitant with an 80-85% reduction in the expression of myelin basic protein, fewer myelinated axons and reduced thickness of myelin sheaths, as measured by electron microscopy. Both the expression of the proteoglycan NG2 and the number of PDGFRalpha+/NG2+ oligodendrocyte precursor cells were reduced in the Fmr1 cerebellum at PND 7. Although myelin proteins were still depressed at PND 15, they regained wild-type levels by PND 30. These findings suggest that impaired maturation or function of oligodendrocyte precursor cells induces delayed myelination in the Fmr1 mouse brain. Our results bolster an emerging recognition that white matter abnormalities in early postnatal brain development represent an underlying neurological deficit in Fragile X syndrome. PMID- 23740940 TI - Loss of cone cyclic nucleotide-gated channel leads to alterations in light response modulating system and cellular stress response pathways: a gene expression profiling study. AB - The cone photoreceptor cyclic nucleotide-gated (CNG) channel is essential for central and color vision and visual acuity. Mutations in the channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophy. We investigated the gene expression profiles in mouse retina with CNG channel deficiency using whole genome expression microarrays. As cones comprise only 2 to 3% of the total photoreceptor population in the wild-type mouse retina, the mouse lines with CNG channel deficiency on a cone-dominant background, i.e. Cnga3-/ /Nrl-/- and Cngb3-/-/Nrl-/- mice, were used in our study. Comparative data analysis revealed a total of 105 genes altered in Cnga3-/-/Nrl-/- and 92 in Cngb3 /-/Nrl-/- retinas, relative to Nrl-/- retinas, with 27 genes changed in both genotypes. The differentially expressed genes primarily encode proteins associated with cell signaling, cellular function maintenance and gene expression. Ingenuity pathway analysis (IPA) identified 26 and 9 canonical pathways in Cnga3-/-/Nrl-/- and Cngb3-/-/Nrl-/- retinas, respectively, with 6 pathways being shared. The shared pathways include phototransduction, cAMP/PKA mediated signaling, endothelin signaling, and EIF2/endoplasmic reticulum (ER) stress, whereas the IL-1, CREB, and purine metabolism signaling were found to specifically associate with Cnga3 deficiency. Thus, CNG channel deficiency differentially regulates genes that affect cell processes such as phototransduction, cellular survival and gene expression, and such regulations play a crucial role(s) in the retinal adaptation to impaired cone phototransduction. Though lack of Cnga3 and Cngb3 shares many common pathways, deficiency of Cnga3 causes more significant alterations in gene expression. This work provides insights into how cones respond to impaired phototransduction at the gene expression levels. PMID- 23740942 TI - New evidence for positive selection helps explain the paternal age effect observed in achondroplasia. AB - There are certain de novo germline mutations associated with genetic disorders whose mutation rates per generation are orders of magnitude higher than the genome average. Moreover, these mutations occur exclusively in the male germ line and older men have a higher probability of having an affected child than younger ones, known as the paternal age effect (PAE). The classic example of a genetic disorder exhibiting a PAE is achondroplasia, caused predominantly by a single nucleotide substitution (c.1138G>A) in FGFR3. To elucidate what mechanisms might be driving the high frequency of this mutation in the male germline, we examined the spatial distribution of the c.1138G>A substitution in a testis from an 80 year-old unaffected man. Using a technology based on bead-emulsion amplification, we were able to measure mutation frequencies in 192 individual pieces of the dissected testis with a false-positive rate lower than 2.7 * 10(-6). We observed that most mutations are clustered in a few pieces with 95% of all mutations occurring in 27% of the total testis. Using computational simulations, we rejected the model proposing an elevated mutation rate per cell division at this nucleotide site. Instead, we determined that the observed mutation distribution fits a germline selection model, where mutant spermatogonial stem cells have a proliferative advantage over unmutated cells. Combined with data on several other PAE mutations, our results support the idea that the PAE, associated with a number of Mendelian disorders, may be explained primarily by a selective mechanism. PMID- 23740943 TI - Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice. AB - microRNAs (miRNAs) are dysregulated in a variety of disease states, suggesting that this newly discovered class of gene expression repressors may be viable therapeutic targets. A microarray of miRNA changes in ALS-model superoxide dismutase 1 (SOD1)(G93A) rodents identified 12 miRNAs as significantly changed. Six miRNAs tested in human ALS tissues were confirmed increased. Specifically, miR-155 was increased 5-fold in mice and 2-fold in human spinal cords. To test miRNA inhibition in the central nervous system (CNS) as a potential novel therapeutic, we developed oligonucleotide-based miRNA inhibitors (anti-miRs) that could inhibit miRNAs throughout the CNS and in the periphery. Anti-miR-155 caused global derepression of targets in peritoneal macrophages and, following intraventricular delivery, demonstrated widespread functional distribution in the brain and spinal cord. After treating SOD1(G93A) mice with anti-miR-155, we significantly extended survival by 10 days and disease duration by 15 days (38%) while a scrambled control anti-miR did not significantly improve survival or disease duration. Therefore, antisense oligonucleotides may be used to successfully inhibit miRNAs throughout the brain and spinal cord, and miR-155 is a promising new therapeutic target for human ALS. PMID- 23740944 TI - NOD1 and NOD2 regulate proinflammatory and prolabor mediators in human fetal membranes and myometrium via nuclear factor-kappa B. AB - Preterm birth remains one of the most important issues facing perinatal medicine today, with chronic inflammation and/or infection being the biggest etiological factor. The nucleotide oligomerization domain (NOD) intracellular molecules recognize a wide range of microbial products as well as other intracellular danger signals, thereby initiating inflammation through activation of nuclear factor KB (NFKB), a central regulator of the terminal processes of human labor and delivery. The aims of this study were to determine the effect of 1) human labor, proinflammatory cytokines, and bacterial endotoxin LPS on NOD1 and NOD2 expression and 2) NOD1 and NOD2 activation on the expression of prolabor mediators in human fetal membranes and myometrium. NOD1 and NOD2 expression was significantly higher in fetal membranes and myometrium after spontaneous labor when compared to nonlaboring tissues. Bacterial endotoxin LPS and the proinflammatory cytokines TNF and IL1B significantly increased NOD2, but not NOD1, expression. Furthermore, LPS-induced NOD2 expression was decreased by the NFKB inhibitor BAY 11-7082. In both fetal membranes and myometrium, the NOD1 ligand bacterial iE-DAP and the NOD2 ligand bacterial MDP significantly increased the expression and secretion of proinflammatory cytokines (IL6 and IL8), cyclooxygenase (PTGS2) expression and subsequent release of prostaglandins PGE2 and PGF2alpha, and the expression and activity of MMP9. The effects of these NOD1 and NOD2 ligands were mediated via NFKB, as 1) both iE-DAP and MDP significantly increased NFKB activation and 2) the NFKB inhibitor BAY 11-7082 attenuated iE-DAP and MDP-induced expression and secretion of prolabor mediators. In conclusion, NOD1 and NOD2 are increased in laboring fetal membranes and myometrium and with bacterial infection. Agonist activation of NOD1 and NOD2 by bacterial products leads to NFKB activation and transcription of NFKB induced prolabor genes. NOD1 and NOD2 may thus represent therapeutic targets for the treatment and/or management of preterm birth. PMID- 23740945 TI - Loss of CDH1 and Pten accelerates cellular invasiveness and angiogenesis in the mouse uterus. AB - E-cadherin (CDH1) is a cell adhesion molecule that coordinates key morphogenetic processes regulating cell growth, cell proliferation, and apoptosis. Loss of CDH1 is a trademark of the cellular event epithelial to mesenchymal transition, which increases the metastatic potential of malignant cells. PTEN is a tumor-suppressor gene commonly mutated in many human cancers, including endometrial cancer. In the mouse uterus, ablation of Pten induces epithelial hyperplasia, leading to endometrial carcinomas. However, loss of Pten alone does not affect longevity until around 5 mo. Similarly, conditional ablation of Cdh1 alone does not predispose mice to cancer. In this study, we characterized the impact of dual Cdh1 and Pten ablation (Cdh1(d/d) Pten(d/d)) in the mouse uterus. We observed that Cdh1(d/d) Pten(d/d) mice died at Postnatal Days 15-19 with massive blood loss. Their uteri were abnormally structured with curly horns, disorganized epithelial structure, and increased cell proliferation. Co-immunostaining of KRT8 and ACTA2 showed invasion of epithelial cells into the myometrium. Further, the uteri of Cdh1(d/d) Pten(d/d) mice had prevalent vascularization in both the endometrium and myometrium. We also observed reduced expression of estrogen and progesterone receptors, loss of cell adherens, and tight junction molecules (CTNNB1 and claudin), as well as activation of AKT in the uteri of Cdh1(d/d) Pten(d/d) mice. However, complex hyperplasia was not found in the uteri of Cdh1(d/d) Pten(d/d) mice. Collectively, these findings suggest that ablation of Pten with Cdh1 in the uterus accelerates cellular invasiveness and angiogenesis and causes early death. PMID- 23740946 TI - Changes in mouse uterine transcriptome in estrus and proestrus. AB - Changes in the CD-1 mouse uterine transcriptome during proestrus and estrus were investigated to help elucidate mechanisms of uterine tissue remodeling during the estrus cycle and their regulation by estrogen and progesterone in preparation of the uterus for pregnancy. Mice were staged beginning at 6 weeks of age, and uterine horns were harvested after monitoring two estrus cycles. Microarray analysis of whole uterine horn RNA identified 2428 genes differentially expressed in estrus compared to proestrus, indicating there is extensive remodeling of mouse uterus during the estrus cycle, affecting ~10% of all protein-encoding genes. Many (~50%) of these genes showed the same differential expression in independent analyses of isolated uterine lumenal epithelial cells. Changes in gene expression associated with structural alterations of the uterus included remodeling of the extracellular matrix, changes in cell keratins and adhesion molecules, activation of mitosis and changes in major histocompatibility complex class II (MHCII) presentation, complement and coagulation cascades, and cytochrome P450 expression. Signaling pathways regulated during the estrus cycle, involving ligand-gated channels, Wnt and hedgehog signaling, and transcription factors with poorly understood roles in reproductive tissues, included several genes and gene networks that have been implicated in pathological states. Many of the molecular pathways and biological functions represented by the genes differentially expressed from proestrus to estrus are also altered during the human menstrual cycle, although not necessarily at the corresponding phases of the cycle. These findings establish a baseline for further studies in the mouse model to dissect mechanisms involved in uterine tissue response to endocrine disruptors and the development of reproductive tract diseases. PMID- 23740948 TI - Unconventional RORgammat+ T cells drive hepatic ischemia reperfusion injury. AB - An emerging body of evidence suggests a pivotal role of CD3(+) T cells in mediating early ischemia reperfusion injury (IRI). However, the precise phenotype of T cells involved and the mechanisms underlying such T cell-mediated immune responses in IRI, as well as their clinical relevance, are poorly understood. In this study, we investigated early immunological events in a model of partial warm hepatic IRI in genetically targeted mice to study the precise pathomechanistic role of RORgammat(+) T cells. We found that unconventional CD27( )gammadeltaTCR(+) and CD4(-)CD8(-) double-negative T cells are the major RORgammat-expressing effector cells in hepatic IRI that play a mechanistic role by being the main source of IRI-mediating IL-17A. We further show that unconventional IRI-mediating T cells are contingent on RORgammat, as highlighted by the fact that a genetic deficiency for RORgammat, or its therapeutic antagonization via digoxin, is protective against hepatic IRI. Therefore, identification of CD27(-)gammadeltaTCR(+) and CD4(-)CD8(-) double-negative T cells as the major source of IL-17A via RORgammat in hepatic IRI opens new therapeutic options to improve liver transplantation outcomes. PMID- 23740947 TI - Mitochondrial hydrogen peroxide and defective cholesterol efflux prevent in vitro fertilization by cryopreserved inbred mouse sperm. AB - Recent advances in the cryopreservation of mouse sperm have resulted in dramatically improved in vitro fertilization (IVF) rates, but the biological mechanisms underlying the techniques remain unclear. Two different classes of compounds have been widely utilized to improve the IVF rates of cryopreserved mouse sperm: antioxidants and cyclodextrins. To determine how cryopreservation reduces mouse sperm IVF and how antioxidants and cyclodextrins mitigate this effect, we examined sperm function and oxidative damage after cryopreservation, with and without treatments, in mouse strains important for biomedical research. Our investigation revealed mouse strain-specific effects on IVF by modulation of oxidative stress and cholesterol efflux of cryopreserved sperm. Antioxidants improved IVF rates of C57Bl6/J cryopreserved mouse sperm by reducing hydrogen peroxide produced by sperm mitochondria and ameliorating peroxidative damage to the sperm acrosome. Enhancing cholesterol efflux with cyclodextrin restored capacitation-dependent sperm function and IVF after cryopreservation of C57Bl/6J, C57Bl/6N, and 129X1 mouse sperm. Our results highlight two accessible pathways for continued development of IVF techniques for mouse sperm and provide novel endpoints prognostic of IVF success. These insights may improve sperm cryopreservation methods of other mouse strains and species. PMID- 23740949 TI - Dendritic cell-dependent in vivo generation of autoregulatory T cells by antidiabetogenic MHC class II. AB - Several mechanisms have been proposed to explain how certain MHC class II molecules afford dominant resistance to autoimmune diseases like type 1 diabetes (T1D). However, it remains unclear how protective MHC types can blunt autoreactive T cell responses directed against a diverse repertoire of autoantigenic epitopes presented by disease-promoting MHCs. In this study, we show that expression of I-E on dendritic cells (DCs) of NOD mice promotes the differentiation of MHC promiscuous autoreactive CD4(+) clonotypes into antidiabetogenic autoregulatory T cells. We expressed an I-Ealpha(kloxP) transgene in NOD mice and used cell type-specific I-E ablation to show that I-E expressing DCs, but not B cells, promote the generation of autoreactive CD4(+)Foxp3(+) regulatory T cells (Tregs) and their accumulation in the pancreas draining lymph nodes. There, these Tregs suppress the presentation of beta cell Ags to naive autoreactive CD4(+) and CD8(+) T cells restricted by diabetogenic MHC molecules in an I-E-independent manner. Whereas selective removal of I-E on DCs abrogated autoregulatory Treg formation and T1D protection, selective removal of I-E on B cells was inconsequential. These results explain how certain MHC class II molecules can completely suppress antigenically complex autoimmune responses in an Ag-nonspecific manner. PMID- 23740950 TI - Independent expansion of epitope-specific plasma cell responses upon HIV-1 envelope glycoprotein immunization. AB - Abs that bind the functional envelope glycoprotein (Env) spike are considered critical for a broadly effective prophylactic HIV-1 vaccine. The difficulty in eliciting such Abs by vaccination is partially attributed to the immunodominance of hydrophilic, surface-exposed variable protein regions of Env. However, little is known about the potential for competition between B cells that recognize distinct and distal epitopes on Env during protein subunit vaccination. In this study, we address this basic question at the level of Ab-secreting cells and serum IgG using a pair of isogenic soluble Env trimers, designated wildtype and gV3, which differ only in their potential to activate B cell responses against the highly immunogenic V3 region of Env. Immunization of mice with gV3 resulted in a markedly lower Ag-specific response compared with that induced by wildtype Env and could be explained by a loss of V3-directed reactivities. There was no redistribution of the response to other regions of Env in gV3-inoculated mice, suggesting that the epitope-specific Ab-secreting cell responses measured after boost are independently regulated rather than dictated by direct or indirect competition between B cells recognizing different structural elements of Env. This information is relevant for ongoing efforts in Env immunogen design to focus responses on conserved neutralizing determinants and for our general understanding of B cell responses to large-protein Ags that display numerous B cell epitopes. PMID- 23740951 TI - Cutting edge: CD1d restriction and Th1/Th2/Th17 cytokine secretion by human Vdelta3 T cells. AB - Human gammadelta T cells expressing the Vdelta3 TCR make up a minor lymphocyte subset in blood but are enriched in liver and in patients with some chronic viral infections and leukemias. We analyzed the frequencies, phenotypes, restriction elements, and functions of fresh and expanded peripheral blood Vdelta3 T cells. Vdelta3 T cells accounted for ~0.2% of circulating T cells, included CD4(+), CD8(+), and CD4(-)CD8(-) subsets, and variably expressed CD56, CD161, HLA-DR, and NKG2D but neither NKG2A nor NKG2C. Vdelta3 T cells were sorted and expanded by mitogen stimulation in the presence of IL-2. Expanded Vdelta3 T cells recognized CD1d but not CD1a, CD1b, or CD1c. Upon activation, they killed CD1d(+) target cells, released Th1, Th2, and Th17 cytokines, and induced maturation of dendritic cells into APCs. Thus, Vdelta3 T cells are glycolipid-reactive T cells with distinct Ag specificities but functional similarities to NKT cells. PMID- 23740952 TI - Synergistic expression of the CXCL10 gene in response to IL-1beta and IFN-gamma involves NF-kappaB, phosphorylation of STAT1 at Tyr701, and acetylation of histones H3 and H4. AB - The CXCL10 gene encodes a peptide that chemoattracts a variety of leukocytes associated with type 1 and type 2 diabetes. The present study was undertaken to determine the molecular mechanisms required for expression of the CXCL10 gene in response to IL-1beta and IFN-gamma using rat islets and beta cell lines. IL-1beta induced the expression of the CXCL10 gene and promoter activity, whereas the combination of IL-1beta plus IFN-gamma was synergistic. Small interfering RNA mediated suppression of NF-kappaB p65 markedly inhibited the ability of cytokines to induce the expression of the CXCL10 gene, whereas targeting STAT1 only diminished the synergy provided by IFN-gamma. Furthermore, we found that a JAK1 inhibitor dose dependently reduced IFN-gamma-controlled CXCL10 gene expression and promoter activity, concomitant with a decrease in STAT1 phosphorylation at Tyr(701). We further discovered that, although the Tyr(701) phosphorylation site is inducible (within 15 min of IFN-gamma exposure), the Ser(727) site within STAT1 is constitutively phosphorylated. Thus, we generated single-mutant STAT1 Y701F and double-mutant STAT1 Y701F/S727A adenoviruses. Using these recombinant adenoviruses, we determined that overexpression of either the single- or double mutant STAT1 decreased the IFN-gamma-mediated potentiation of CXCL10 gene expression, promoter activity, and secretion of protein. Moreover, the Ser(727) phosphorylation was neither contingent on a functional Y701 site in beta cells nor was it required for cytokine-mediated expression of the CXCL10 gene. We conclude that the synergism of IL-1beta and IFN-gamma to induce expression of the CXCL10 gene requires NF-kappaB, STAT1 phosphorylated at Tyr(701), recruitment of coactivators, and acetylation of histones H3 and H4. PMID- 23740953 TI - Amino acid copolymers that alleviate experimental autoimmune encephalomyelitis in vivo interact with heparan sulfates and glycoprotein 96 in APCs. AB - Multiple sclerosis (MS) is an autoimmune disease that affects the CNS. One approved treatment for relapsing forms of MS is YEAK, a random copolymer of the amino acids tyrosine, glutamic acid, alanine, and lysine. YFAK, a second generation copolymer composed of tyrosine, phenylalanine, alanine, and lysine, is more successful in treating experimental autoimmune encephalomyelitis, a mouse model of MS. Although originally designed and optimized based on the autoantigen myelin basic protein (MBP) and the MBP-derived peptide MBP85-99 presented to the MS-associated class II MHC molecule HLA-DR2, YEAK and YFAK also stimulate cytokine and chemokine production in APCs that lack class II MHC products. How YEAK and YFAK copolymers interact with APCs remains enigmatic. We used biotinylated YFAK to affinity-purify YFAK-interacting proteins from RAW264.7 cells and tested APCs from mice deficient in several of the newly identified interactors for their capacity to secrete CCL22 in response to YEAK and YFAK. We propose that initial contact of YFAK with cells is mediated mainly by electrostatic interactions, and find that interaction of YFAK with host proteins is strongly dependent on ionic strength. Cells deficient in enzymes involved in sulfation of proteins and proteoglycans showed strongly reduced binding of biotinylated YFAK. Lastly, cells stimulated with YFAK in the presence of heparin, structurally similar to heparan sulfates, failed to produce CCL22. We conclude that charge-dependent interactions of copolymers that alleviate MS/experimental autoimmune encephalomyelitis are critical for their effects exerted on APCs and may well be the main initial mediators of these therapeutically active copolymers. PMID- 23740954 TI - Intrinsic molecular factors cause aberrant expansion of the splenic marginal zone B cell population in nonobese diabetic mice. AB - Marginal zone (MZ) B cells are an innate-like population that oscillates between MZ and follicular areas of the splenic white pulp. Differentiation of B cells into the MZ subset is governed by BCR signal strength and specificity, NF-kappaB activation through the B cell-activating factor belonging to the TNF family (BAFF) receptor, Notch2 signaling, and migration signals mediated by chemokine, integrin, and sphingosine-1-phosphate receptors. An imbalance in splenic B cell development resulting in expansion of the MZ subset has been associated with autoimmune pathogenesis in various murine models. One example is the NOD inbred mouse strain, in which MZ B cell expansion has been linked to development of type 1 diabetes and Sjogren's syndrome. However, the cause of MZ B cell expansion in this strain remains poorly understood. We have determined that increased MZ B cell development in NOD mice is independent of T cell autoimmunity, BCR specificity, BCR signal strength, and increased exposure to BAFF. Rather, mixed bone marrow chimeras showed that the factor(s) responsible for expansion of the NOD MZ subset is B cell intrinsic. Analysis of microarray expression data indicated that NOD MZ and precursor transitional 2-MZ subsets were particularly dysregulated for genes controlling cellular trafficking, including Apoe, Ccbp2, Cxcr7, Lgals1, Pla2g7, Rgs13, S1pr3, Spn, Bid, Cd55, Prf1, and Tlr3. Furthermore, these B cell subsets exhibited an increased steady state dwell time within splenic MZ areas. Our data therefore reveal that precursors of mature B cells in NOD mice exhibit an altered migration set point, allowing increased occupation of the MZ, a niche favoring MZ B cell differentiation. PMID- 23740955 TI - Staphylococcus aureus formyl peptide receptor-like 1 inhibitor (FLIPr) and its homologue FLIPr-like are potent FcgammaR antagonists that inhibit IgG-mediated effector functions. AB - To evade opsonophagocytosis, Staphylococcus aureus secretes various immunomodulatory molecules that interfere with effective opsonization by complement and/or IgG. Immune-evasion molecules targeting the phagocyte receptors for these opsonins have not been described. In this study, we demonstrate that S. aureus escapes from FcgammaR-mediated immunity by secreting a potent FcgammaR antagonist, FLIPr, or its homolog FLIPr-like. Both proteins were previously reported to function as formyl peptide receptor inhibitors. Binding of FLIPr was mainly restricted to FcgammaRII receptors, whereas FLIPr-like bound to different FcgammaR subclasses, and both competitively blocked IgG-ligand binding. They fully inhibited FcgammaR-mediated effector functions, including opsonophagocytosis and subsequent intracellular killing of S. aureus by neutrophils and Ab-dependent cellular cytotoxicity of tumor cells by both neutrophils and NK cells. In vivo, treatment of mice with FLIPr-like prevented the development of an immune complex-mediated FcgammaR-dependent Arthus reaction. This study reveals a novel immune-escape function for S. aureus-secreted proteins that may lead to the development of new therapeutic agents in FcgammaR-mediated diseases. PMID- 23740956 TI - Cryptococcus gattii is killed by dendritic cells, but evades adaptive immunity by failing to induce dendritic cell maturation. AB - During adaptive immunity to pathogens, dendritic cells (DCs) capture, kill, process, and present microbial Ags to T cells. Ag presentation is accompanied by DC maturation driven by appropriate costimulatory signals. However, current understanding of the intricate regulation of these processes remains limited. Cryptococcus gattii, an emerging fungal pathogen in the Pacific Northwest of Canada and the United States, fails to stimulate an effective immune response in otherwise healthy hosts leading to morbidity or death. Because immunity to fungal pathogens requires intact cell-mediated immunity initiated by DCs, we asked whether C. gattii causes dysregulation of DC functions. C. gattii was efficiently bound and internalized by human monocyte-derived DCs, trafficked to late phagolysosomes, and killed. Yet, even with this degree of DC activation, the organism evaded pathways leading to DC maturation. Despite the ability to recognize and kill C. gattii, immature DCs failed to mature; there was no increased expression of MHC class II, CD86, CD83, CD80, and CCR7, or decrease of CD11c and CD32, which resulted in suboptimal T cell responses. Remarkably, no increase in TNF-alpha was observed in the presence of C. gattii. However, addition of recombinant TNF-alpha or stimulation that led to TNF-alpha production restored DC maturation and restored T cell responses. Thus, despite early killing, C. gattii evades DC maturation, providing a potential explanation for its ability to infect immunocompetent individuals. We have also established that DCs retain the ability to recognize and kill C. gattii without triggering TNF alpha, suggesting independent or divergent activation pathways among essential DC functions. PMID- 23740957 TI - The incidence of retinal haemorrhages and their implications. PMID- 23740958 TI - The long-term psychosocial impact of correction surgery for adults with strabismus. PMID- 23740959 TI - Choroid blood flow measurement with laser speckle flowgraphy in macular disease. PMID- 23740960 TI - Evaluating the risk of extraocular tumour spread following intravitreal injection therapy for retinoblastoma: a systematic review. AB - BACKGROUND: Intravitreal injection therapy (IViT) for retinoblastoma has shown promise in the treatment of vitreous seeds; however, the potential for tumour dissemination following intravitreal penetration has limited its use. This review evaluates the risk of extraocular tumour spread in patients receiving therapeutic intravitreal injections for retinoblastoma. METHODS: PUBMED (1946-present), SCOPUS (all years), Science Citation Index (1900-present) and Conference Proceedings Citation Index--Science (1990-present) electronic databases were searched to identify all published reports of IViT for retinoblastoma in humans. RESULTS: 14 studies with original IViT data were included in this review. A total of 1304 intravitreal injections were given in 315 eyes of 304 patients, with one report of extraocular tumour spread and one patient in whom intravitreal treatment could not be excluded as a contributor to metastatic disease. The proportion of subjects with extraocular tumour spread potentially due to IViT in these combined reports was 0.007 (95% CI 0.0008 to 0.0236), with a mean follow-up of 72.1 months. In a subset of 61 patients receiving IViT via safety enhancing injection techniques (347 injections, 19.6 months mean follow-up), there were no reports of tumour spread. CONCLUSIONS: Local and systemic tumour spread following IViT in cases of retinoblastoma is rare, and this risk is potentially reduced by the use of safety enhancing injection techniques. These results suggest that the risk of tumour spread should not preclude IViT use for carefully selected patients as part of multi-modal globe salvaging therapy. PMID- 23740961 TI - Spectral domain optical coherence tomography in children operated for primary congenital glaucoma. AB - AIM: To evaluate optic nerve head, retinal nerve fibre layer (RNFL) and ganglion cell complex (GCC) thickness measurements in children operated for primary congenital glaucoma (PCG) using spectral domain optical coherence tomography (SDOCT). METHODS: In a case-control study, 45 eyes of 37 children operated for PCG and 72 eyes of 41 normal children underwent optic nerve head, RNFL and GCC imaging with SDOCT. Differences in SDOCT parameters between PCG and control group, correlation between SDOCT parameters and a range of clinical variables, namely preop corneal diameter, intraocular pressure, degree of corneal oedema and age at which surgery was performed in PCG eyes, were evaluated. RESULTS: Mean (+/ SD) age of children in PCG group was 10.1+/-3.6 years and control group was 13.6+/-3.2 years (p<0.001) at the time of SDOCT imaging. Visual fields, whenever possible were unreliable in 20 of 23 PCG and 30 of 46 normal eyes. All SDOCT parameters were significantly different (p<0.001) in PCG compared with control group. All global SDOCT parameters (rim area, average RNFL and GCC thickness) correlated significantly with the clinical cup to disc ratio measurements (correlation coefficients better than -0.70) in children with PCG. Age at which surgery was performed was inversely related to SDOCT parameter thickness but was not statistically significant. CONCLUSIONS: All SDOCT parameters were significantly different in children operated for PCG compared with normal children. Future research should evaluate the test-retest variability of SDOCT and its ability to diagnose progression in children unable to perform reliable visual field tests. PMID- 23740962 TI - Understanding the expectations of patients with inherited retinal dystrophies. AB - BACKGROUND: UK genetic ophthalmology services for patients with retinal dystrophy (RD) are variable. Little research exists to define service requirements, or expectations, of patients and their families. This study aimed to explore the views and perceived benefits of genetic ophthalmology services among members of families with RD. METHODS: Twenty participants with known RD mutations were recruited through UK genetic ophthalmic clinics. Semistructured qualitative interviews explored interviewees' perceptions of the role of these services. Interviews were transcribed verbatim and analysed using inductive thematic analysis. RESULTS: Interviewees' expectations and requirements of genetic ophthalmology services were wide-ranging and often perceived to be unmet. Participant expectations were classified in three groups: (1) Medical expectations included obtaining a diagnosis and information about disease/prognosis, genetic risks and research (2) Psychosocial expectations related to participants' need for support in adjusting to RD (3) Practical expectations included the desire for information about welfare and support. CONCLUSIONS: Expectations of RD families for clinical services are complex, encompassing a range of healthcare specialties. Services that align to these expectations will need to reach beyond the diagnostic arena and provide practical and psychosocial support. The identification of measurable outcomes will facilitate future development and evaluation of service delivery models. Many of the expectations identified here map to an existing, previously validated, outcomes framework for clinical genetic services. However, an additional outcome domain, labelled 'Independence' was also identified; this could either be specific to vision loss or relate generally to disability caused by genetic conditions. PMID- 23740963 TI - Corneal response to canakinumab in cryopyrin associated periodic fever syndrome. PMID- 23740964 TI - A longstanding cystic swelling of the upper eyelid. PMID- 23740965 TI - Age-related macular degeneration: choroidal ischaemia? AB - AIM: Our aim is to use ultrasound to non-invasively detect differences in choroidal microarchitecture possibly related to ischaemia among normal eyes and those with wet and dry age-related macular degeneration (AMD). DESIGN: Prospective case series of subjects with dry AMD, wet AMD and age-matched controls. METHODS: Digitised 20 MHz B-scan radiofrequency ultrasound data of the region of the macula were segmented to extract the signal from the retina and choroid. This signal was processed by a wavelet transform, and statistical modelling was applied to the wavelet coefficients to examine differences among dry, wet and non-AMD eyes. Receiver operating characteristic (ROC) analysis was used to evaluate a multivariate classifier. RESULTS: In the 69 eyes of 52 patients, 18 did not have AMD, 23 had dry AMD and 28 had wet AMD. Multivariate models showed statistically significant differences between groups. Multiclass ROC analysis of the best model showed an excellent volume-under-curve of 0.892+/ 0.17. The classifier is consistent with ischaemia in dry AMD. CONCLUSIONS: Wavelet augmented ultrasound is sensitive to the organisational elements of choroidal microarchitecture relating to scatter and fluid tissue boundaries such as seen in ischaemia and inflammation, allowing statistically significant differentiation of dry, wet and non-AMD eyes. This study further supports the association of ischaemia with dry AMD and provides a rationale for treating dry AMD with pharmacological agents to increase choroidal perfusion. ClinicalTrials.gov registration: NCT00277784. PMID- 23740966 TI - Characterization and biological effects of di-hydroxylated compounds deriving from the lipoxygenation of ALA. AB - We have recently described a di-hydroxylated compound called protectin DX (PDX) which derives from docosahexaenoic acid (DHA) by double lipoxygenation. PDX exhibits anti-aggregatory and anti-inflammatory properties, that are also exhibited by similar molecules, called poxytrins, which possess the same E,Z,E conjugated triene geometry, and are synthesized from other polyunsaturated fatty acids with 22 or 20 carbons. Here we present new biological activities of di hydroxylated metabolites deriving from alpha-linolenic acid (18:3n-3) treated by soybean 15-lipoxygenase (sLOX). We show that 18:3n-3 is converted by sLOX into mainly 13(S)-OH-18:3 after reduction of the hydroperoxide product. But surprisingly, and in contrast to DHA which is metabolized into only one di hydroxylated compound, 18:3n-3 leads to four di-hydroxylated fatty acid isomers. We report here the complete characterization of these compounds using high field NMR and GC-MS techniques, and some of their biological activities. These compounds are: 9(R),16(S)-dihydroxy-10E,12E,14E-octadecatrienoic acid, 9(S),16(S) dihydroxy-10E,12E,14E-octadecatrienoic acid, 9(S),16(S)-dihydroxy-10E,12Z,14E octadecatrienoic acid, and 9(R),16(S)-dihydroxy-10E,12Z,14E-octadecatrienoic acid. They can also be synthesized by the human recombinant 15-lipoxygenase (type 2). Their inhibitory effect on blood platelet and anti-inflammatory properties were compared with those already reported for PDX. PMID- 23740967 TI - The impact of genetic stress by ATGL deficiency on the lipidome of lipid droplets from murine hepatocytes. AB - We showed earlier that nutritional stress like starvation or high-fat diet resulted in phenotypic changes in the lipidomes of hepatocyte lipid droplets (LDs), representative for the pathophysiological status of the mouse model. Here we extend our former study by adding genetic stress due to knockout (KO) of adipocyte triglyceride lipase (ATGL), the rate limiting enzyme in LD lipolysis. An intervention trial for 6 weeks with male wild-type (WT) and ATGL-KO mice was carried out; both genotypes were fed lab chow or were exposed to short-time starvation. Isolated LDs were analyzed by LC-MS/MS. Triacylglycerol, diacylglycerol, and phosphatidylcholine lipidomes, in that order, provided the best phenotypic signatures characteristic for respective stresses applied to the animals. This was evidenced at lipid species level by principal component analysis, calculation of average values for chain-lengths and numbers of double bonds, and by visualization in heat maps. Structural backgrounds for analyses and metabolic relationships were elaborated at lipid molecular species level. Relating our lipidomic data to nonalcoholic fatty liver diseases of nutritional and genetic etiologies with or without accompanying insulin resistance, phenotypic distinction in hepatocyte LDs dependent on insulin status emerged. Taken together, lipidomes of hepatocyte LDs are sensitive responders to nutritional and genetic stress. PMID- 23740968 TI - Distinct populations of adipogenic and myogenic Myf5-lineage progenitors in white adipose tissues. AB - Brown adipose tissues (BAT) are derived from a myogenic factor 5 (Myf5) expressing cell lineage and white adipose tissues (WAT) predominantly arise from non-Myf5 lineages, although a subpopulation of adipocytes in some WAT depots can be derived from the Myf5 lineage. However, the functional implication of the Myf5 and non-Myf5-lineage cells in WAT is unclear. We found that the Myf5-lineage constitution in subcutaneous WAT depots is negatively correlated to the expression of classical BAT and newly defined beige/brite adipocyte-specific genes. Consistently, fluorescent-activated cell sorting (FACS)-purified Myf5 lineage adipo-progenitors give rise to adipocytes expressing lower levels of BAT specific Ucp1, Prdm16, Cidea, and Ppargc1a genes and beige adipocyte-specific CD137, Tmem26, and Tbx1 genes compared with the non-Myf5-lineage adipocytes from the same depots. Ablation of the Myf5-lineage progenitors in WAT stromal vascular cell (SVC) cultures leads to increased expression of BAT and beige cell signature genes. Strikingly, the Myf5-lineage cells in WAT are heterogeneous and contain distinct adipogenic [stem cell antigen 1(Sca1)-positive] and myogenic (Sca1 negative) progenitors. The latter differentiate robustly into myofibers in vitro and in vivo, and they restore dystrophin expression after transplantation into mdx mouse, a model for Duchenne muscular dystrophy. These results demonstrate the heterogeneity and functional differences of the Myf5- and non-Myf5-lineage cells in the white adipose tissue. PMID- 23740969 TI - Mechanistic target of rapamycin controls homeostasis of adipogenesis. AB - Signaling mediated by the mechanistic target of rapamycin (mTOR) is believed to play a critical and positive role in adipogenesis, based on pharmacological evidence and genetic manipulation of mTOR regulators and targets. However, there is no direct genetic evidence for an autonomous role of mTOR itself in preadipocyte differentiation. To seek such evidence, we employed a conditional knockdown approach to deplete mTOR in preadipocytes. Surprisingly, while knockdown of S6K1, a target of mTOR, impairs 3T3-L1 preadipocyte differentiation, reduction of mTOR levels leads to increased differentiation. This enhanced adipogenesis requires the remaining mTOR activity, as mTOR inhibitors abolish differentiation in the mTOR knockdown cells. We also found that mTOR knockdown elevates the levels of CCAAT/enhancer-binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma (PPARgamma). Furthermore, partial reduction of mTOR levels alleviates inhibition of Akt by mTORC1 via IRS1, while at the same time maintaining its positive input through mTORC1 into the adipogenic program. The greater sensitivity of the IRS1-Akt pathway to mTOR levels provides a mechanism that explains the net outcome of enhanced adipogenesis through PPARgamma upon mTOR knockdown. Our observations reveal an unexpected role of mTOR in suppressing adipogenesis and suggest that mTOR governs the homeostasis of the adipogenic process by modulating multiple signaling pathways. PMID- 23740973 TI - Arginine-rich motifs are not required for hepatitis delta virus RNA binding activity of the hepatitis delta antigen. AB - Hepatitis delta virus (HDV) replication and packaging require interactions between the unbranched rodlike structure of HDV RNA and hepatitis delta antigen (HDAg), a basic, disordered, oligomeric protein. The tendency of the protein to bind nonspecifically to nucleic acids has impeded analysis of HDV RNA protein complexes and conclusive determination of the regions of HDAg involved in RNA binding. The most widely cited model suggests that RNA binding involves two proposed arginine-rich motifs (ARMs I and II) in the middle of HDAg. However, other studies have questioned the roles of the ARMs. Here, binding activity was analyzed in vitro using HDAg-160, a C-terminal truncation that binds with high affinity and specificity to HDV RNA segments in vitro. Mutation of the core arginines of ARM I or ARM II in HDAg-160 did not diminish binding to HDV unbranched rodlike RNA. These same mutations did not abolish the ability of full length HDAg to inhibit HDV RNA editing in cells, an activity that involves RNA binding. Moreover, only the N-terminal region of the protein, which does not contain the ARMs, was cross-linked to a bound HDV RNA segment in vitro. These results indicate that the amino-terminal region of HDAg is in close contact with the RNA and that the proposed ARMs are not required for binding HDV RNA. Binding was not reduced by mutation of additional clusters of basic amino acids. This result is consistent with an RNA-protein complex that is formed via numerous contacts between the RNA and each HDAg monomer. PMID- 23740974 TI - Obstruction of dengue virus maturation by Fab fragments of the 2H2 antibody. AB - The 2H2 monoclonal antibody recognizes the precursor peptide on immature dengue virus and might therefore be a useful tool for investigating the conformational change that occurs when the immature virus enters an acidic environment. During dengue virus maturation, spiky, immature, noninfectious virions change their structure to form smooth-surfaced particles in the slightly acidic environment of the trans-Golgi network, thereby allowing cellular furin to cleave the precursor membrane proteins. The dengue virions become fully infectious when they release the cleaved precursor peptide upon reaching the neutral-pH environment of the extracellular space. Here we report on the cryo-electron microscopy structures of the immature virus complexed with the 2H2 antigen binding fragments (Fab) at different concentrations and under various pH conditions. At neutral pH and a high concentration of Fab molecules, three Fab molecules bind to three precursor membrane proteins on each spike of the immature virus. However, at a low concentration of Fab molecules and pH 7.0, only two Fab molecules bind to each spike. Changing to a slightly acidic pH caused no detectable change of structure for the sample with a high Fab concentration but caused severe structural damage to the low-concentration sample. Therefore, the 2H2 Fab inhibits the maturation process of immature dengue virus when Fab molecules are present at a high concentration, because the three Fab molecules on each spike hold the precursor membrane molecules together, thereby inhibiting the normal conformational change that occurs during maturation. PMID- 23740975 TI - Topological analysis of HIV-1 glycoproteins expressed in situ on virus surfaces reveals tighter packing but greater conformational flexibility than for soluble gp120. AB - In natural infection, antibodies interact with HIV-1 primarily through nonfunctional forms of envelope glycoproteins (Env), including uncleaved (UNC) gp160 and gp41 stumps. These antigens are important to fully characterize, as they may be decoys that promote nonneutralizing responses and may also be targets for nonneutralizing effector responses. In this study, we compared the antigenic properties of Env expressed in situ on pseudovirion virus-like particle (VLP) surfaces and soluble gp120 using harmonized enzyme-linked immunosorbent assays (ELISAs) and a panel of 51 monoclonal antibodies (MAbs). Only 32 of 46 soluble gp120-reactive MAbs recognized the primary UNC gp160 antigen of VLPs. Indeed, many epitopes were poorly exposed (C1, V2, C1-C4, C4, C4-V3, CD4 induced [CD4i], and PGT group 3) or obscured (C2, C5, and C1-C5) on VLPs. In further studies, VLP Env exhibited an increased degree of inter-MAb competition, the epicenter of which was the base of the V3 loop, where PGT, 2G12, V3, and CD4 binding site specificities competed. UNC gp160 also underwent more drastic soluble CD4 (sCD4) induced conformational changes than soluble gp120, exposing CD4i, C1-C4, and V2 epitopes. A greater propensity of UNC gp160 to undergo conformational changes was also suggested by the induction of CD4i MAb binding to VLPs by a V3 MAb as well as by soluble CD4. The same effect was not observed for soluble gp120. Taken together, our data suggest that membrane-expressed UNC gp160 exists in a less "triggered" conformational state than soluble gp120 and that MAb binding to UNC gp160 tends to have greater conformational consequences. PMID- 23740977 TI - MicroRNA 181 suppresses porcine reproductive and respiratory syndrome virus (PRRSV) infection by targeting PRRSV receptor CD163. AB - We previously showed that microRNA 181 (miR-181) can inhibit PRRSV replication by directly targeting its genomic RNA. Here, we report that miR-181 can downregulate the PRRSV receptor CD163 in blood monocytes and porcine alveolar macrophages (PAMs) through targeting the 3' untranslated region (UTR) of CD163 mRNA. Downregulation of CD163 leads to the inhibition of PRRSV entry into PAMs and subsequently suppresses PRRSV infection. Our findings indicate that delivery of miR-181 can be used as antiviral therapy against PRRSV infection. PMID- 23740976 TI - Thiouracil cross-linking mass spectrometry: a cell-based method to identify host factors involved in viral amplification. AB - Eukaryotic RNA viruses are known to utilize host factors; however, the identity of these factors and their role in the virus life cycle remain largely undefined. Here, we report a method to identify proteins bound to the viral RNA during amplification in cell culture: thiouracil cross-linking mass spectrometry (TUX MS). TUX-MS relies on incorporation of a zero-distance cross-linker into the viral RNA during infection. Proteins bound to viral RNA are cross-linked prior to cell lysis, purified, and identified using mass spectrometry. Using the TUX-MS method, an unbiased screen for poliovirus (PV) host factors was conducted. All host and viral proteins that are known to interact with the poliovirus RNA were identified. In addition, TUX-MS identified an additional 66 host proteins that have not been previously described in poliovirus amplification. From these candidates, eight were selected and validated. Furthermore, we demonstrate that small interfering RNA (siRNA)-mediated knockdown of two of these uncharacterized host factors results in either a decrease in copy number of positive-stranded RNA or a decrease in PV translation. These data demonstrate that TUX-MS is a robust, unbiased method to identify previously unknown host cell factors that influence virus growth. This method is broadly applicable to a range of RNA viruses, such as flaviviruses, alphaviruses, picornaviruses, bunyaviruses, and coronaviruses. PMID- 23740978 TI - N-linked glycosylation of the hemagglutinin protein influences virulence and antigenicity of the 1918 pandemic and seasonal H1N1 influenza A viruses. AB - The hemagglutinin (HA) protein is a major virulence determinant for the 1918 pandemic influenza virus; however, it encodes no known virulence-associated determinants. In comparison to seasonal influenza viruses of lesser virulence, the 1918 H1N1 virus has fewer glycosylation sequons on the HA globular head region. Using site-directed mutagenesis, we found that a 1918 HA recombinant virus, of high virulence, could be significantly attenuated in mice by adding two additional glycosylation sites (asparagine [Asn] 71 and Asn 286) on the side of the HA head. The 1918 HA recombinant virus was further attenuated by introducing two additional glycosylation sites on the top of the HA head at Asn 142 and Asn 172. In a reciprocal experimental approach, deletion of HA glycosylation sites (Asn 142 and Asn 177, but not Asn 71 and Asn 104) from a seasonal influenza H1N1 virus, A/Solomon Islands/2006 (SI/06), led to increased virulence in mice. The addition of glycosylation sites to 1918 HA and removal of glycosylation sites from SI/06 HA imposed constraints on the theoretical structure surrounding the glycan receptor binding sites, which in turn led to distinct glycan receptor binding properties. The modification of glycosylation sites for the 1918 and SI/06 viruses also caused changes in viral antigenicity based on cross-reactive hemagglutinin inhibition antibody titers with antisera from mice infected with wild-type or glycan mutant viruses. These results demonstrate that glycosylation patterns of the 1918 and seasonal H1N1 viruses directly contribute to differences in virulence and are partially responsible for their distinct antigenicity. PMID- 23740979 TI - Kaposi's sarcoma-associated herpesvirus kaposin B induces unique monophosphorylation of STAT3 at serine 727 and MK2-mediated inactivation of the STAT3 transcriptional repressor TRIM28. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD), and the inflammation-driven neoplasm Kaposi's sarcoma (KS). A triad of processes, including abnormal proliferation of endothelial cells, aberrant angiogenesis, and chronic inflammation, characterize KS lesions. STAT3 is a key transcription factor governing these processes, and deregulation of STAT3 activity is linked to a wide range of cancers, including PEL and KS. Using primary human endothelial cells (ECs), I demonstrate that KSHV infection modulated STAT3 activation in two ways: (i) KSHV induced uncoupling of canonical tyrosine (Y) and serine (S) phosphorylation events while (ii) concomitantly inducing the phosphorylation and inactivation of TRIM28 (also known as KAP-1 or TIF-1beta), a newly identified negative regulator of STAT3 activity. KSHV infection of primary ECs induced chronic STAT3 activation characterized by a shift from the canonical dual P-STAT3 Y705 S727 form to a mono P-STAT3 S727 form. Expression of the latent protein kaposin B promoted the unique phosphorylation of STAT3 at S727, in the absence of Y705, activated the host kinase mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 (MK2), and stimulated increased expression of STAT3 dependent genes, including CCL5, in ECs. TRIM28-mediated repression of STAT3 is relieved by phosphorylation of S473, and in vitro kinase assays identified TRIM28 S473 as a bona fide target of MK2. Together, these data suggest that kaposin B significantly contributes to the chronic inflammatory environment that is a hallmark of KS by unique activation of the proto-oncogene STAT3, coupled with MK2 mediated inactivation of the STAT3 transcriptional repressor TRIM28. PMID- 23740980 TI - Mutational analysis of the Pseudomonas aeruginosa myovirus KZ morphogenetic protease gp175. AB - Pseudomonas aeruginosa myovirus KZ has a 270-kb genome within a T=27 icosahedral capsid that contains a large, unusual, and structurally well-defined protein cylindrical inner body (IB) spanning its interior. Proteolysis forms a pivotal stage in KZ head and IB morphogenesis, with the protease gp175 cleaving at least 19 of 49 different head proteins, including the major capsid protein and five major structural IB proteins. Here we show that the purified mature form of gp175 is active and cleaves purified IB structural proteins gp93 and gp89. Expression vector synthesis and purification of the zymogen/precursor yielded an active, mature-length protease, showing independent C-terminal gp175 self-cleavage autoactivation. Mutation of either the predicted catalytic serine or histidine inactivated mature gp175, supporting its classification as a serine protease and representing the first such direct biochemical demonstration with purified protease and substrate proteins for any phage protease. These mutations also blocked self-cleavage of the precursor while allowing intermolecular gp175 processing. To confirm the cleavage specificity of gp175, we mutated three cleavage sites in gp93, which blocked proteolysis at these sites. The N-terminal propeptide of gp93 was shown to undergo more extensive proteolysis than previously identified. We found that proteolysis in gp93 progressed from the N to C terminus, while blocking cleavage sites slowed but did not eliminate downstream proteolysis. These findings were shown by informatics to be relevant to the head morphogenesis of numbers of other related IB-containing giant phages as well as to T4 and herpesviruses, which have homologous proteases. PMID- 23740981 TI - The kinase activity of ataxia-telangiectasia mutated interferes with adenovirus E4 mutant DNA replication. AB - Adenovirus (Ad) mutants that lack early region 4 (E4) are unable to produce the early regulatory proteins that normally inactivate the Mre11/Rad50/Nbs1 (MRN) sensor complex, which is a critical component for the ability of cells to respond to DNA damage. E4 mutant infection therefore activates a DNA damage response, which in turn interferes with a productive viral infection. MRN complex proteins localize to viral DNA replication centers in E4 mutant-infected cells, and this complex is critical for activating the kinases ataxia-telangiectasia mutated (ATM) and ATM and Rad3-related (ATR), which phosphorylate numerous substrates important for DNA repair, cell cycle checkpoint activation, and apoptosis. E4 mutant growth defects are substantially rescued in cells lacking an intact MRN complex. We have assessed the role of the downstream ATM and ATR kinases in several MRN-dependent E4 mutant phenotypes. We did not identify a role for either ATM or ATR in "repair" of E4 mutant genomes to form concatemers. ATR was also not observed to contribute to E4 mutant defects in late protein production. In contrast, the kinase activity of ATM was important for preventing efficient E4 mutant DNA replication and late gene expression. Our results suggest that the MRN complex interferes with E4 mutant DNA replication at least in part through its ability to activate ATM. PMID- 23740982 TI - Positively charged residues at the five-fold symmetry axis of cell culture adapted foot-and-mouth disease virus permit novel receptor interactions. AB - Field isolates of foot-and-mouth disease virus (FMDV) have a restricted cell tropism which is limited by the need for certain RGD-dependent integrin receptors. In contrast, cell culture-adapted viruses use heparan sulfate (HS) or other unidentified molecules as receptors to initiate infection. Here, we report several novel findings resulting from cell culture adaptation of FMDV. In cell culture, a virus with the capsid of the A/Turkey/2/2006 field isolate gained the ability to infect CHO and HS-deficient CHO cells as a result of a single glutamine (Q)-to-lysine (K) substitution at VP1-110 (VP1-(Q)110(K)). Using site directed mutagenesis, the introduction of lysine at this same site also resulted in an acquired ability to infect CHO cells by type O and Asia-1 FMDV. However, this ability appeared to require a second positively charged residue at VP1-109. CHO cells express two RGD-binding integrins (alpha5beta1 and alphavbeta5) that, although not used by FMDV, have the potential to be used as receptors; however, viruses with the VP1-(Q)110(K) substitution did not use these integrins. In contrast, the VP1-(Q)110(K) substitution appeared to result in enhanced interactions with alphavbeta6, which allowed a virus with KGE in place of the normal RGD integrin-binding motif to use alphavbeta6 as a receptor. Thus, our results confirmed the existence of nonintegrin, non-HS receptors for FMDV on CHO cells and revealed a novel, non-RGD-dependent use of alphavbeta6 as a receptor. The introduction of lysine at VP1-110 may allow for cell culture adaptation of FMDV by design, which may prove useful for vaccine manufacture when cell culture adaptation proves intractable. PMID- 23740983 TI - Echovirus 1 entry into polarized Caco-2 cells depends on dynamin, cholesterol, and cellular factors associated with macropinocytosis. AB - Enteroviruses invade their hosts by crossing the intestinal epithelium. We have examined the mechanism by which echovirus 1 (EV1) enters polarized intestinal epithelial cells (Caco-2). Virus binds to VLA-2 on the apical cell surface and moves rapidly to early endosomes. Using inhibitory drugs, dominant negative mutants, and small interfering RNAs (siRNAs) to block specific endocytic pathways, we found that virus entry requires dynamin GTPase and membrane cholesterol but is independent of both clathrin- and caveolin-mediated endocytosis. Instead, infection requires factors commonly associated with macropinocytosis, including amiloride-sensitive Na(+)/H(+) exchange, protein kinase C, and C-terminal-binding protein-1 (CtBP1); furthermore, EV1 accumulates rapidly in intracellular vesicles with dextran, a fluid-phase marker. These results suggest a role for macropinocytosis in the process by which EV1 enters polarized cells to initiate infection. PMID- 23740984 TI - Landscape of DNA virus associations across human malignant cancers: analysis of 3,775 cases using RNA-Seq. AB - Elucidation of tumor-DNA virus associations in many cancer types has enhanced our knowledge of fundamental oncogenesis mechanisms and provided a basis for cancer prevention initiatives. RNA-Seq is a novel tool to comprehensively assess such associations. We interrogated RNA-Seq data from 3,775 malignant neoplasms in The Cancer Genome Atlas database for the presence of viral sequences. Viral integration sites were also detected in expressed transcripts using a novel approach. The detection capacity of RNA-Seq was compared to available clinical laboratory data. Human papillomavirus (HPV) transcripts were detected using RNA Seq analysis in head-and-neck squamous cell carcinoma, uterine endometrioid carcinoma, and squamous cell carcinoma of the lung. Detection of HPV by RNA-Seq correlated with detection by in situ hybridization and immunohistochemistry in squamous cell carcinoma tumors of the head and neck. Hepatitis B virus and Epstein-Barr virus (EBV) were detected using RNA-Seq in hepatocellular carcinoma and gastric carcinoma tumors, respectively. Integration sites of viral genes and oncogenes were detected in cancers harboring HPV or hepatitis B virus but not in EBV-positive gastric carcinoma. Integration sites of expressed viral transcripts frequently involved known coding areas of the host genome. No DNA virus transcripts were detected in acute myeloid leukemia, cutaneous melanoma, low- and high-grade gliomas of the brain, and adenocarcinomas of the breast, colon and rectum, lung, prostate, ovary, kidney, and thyroid. In conclusion, this study provides a large-scale overview of the landscape of DNA viruses in human malignant cancers. While further validation is necessary for specific cancer types, our findings highlight the utility of RNA-Seq in detecting tumor associated DNA viruses and identifying viral integration sites that may unravel novel mechanisms of cancer pathogenesis. PMID- 23740985 TI - Pyrrolidine dithiocarbamate inhibits herpes simplex virus 1 and 2 replication, and its activity may be mediated through dysregulation of the ubiquitin proteasome system. AB - Pyrrolidine dithiocarbamate (PDTC) is widely used as an antioxidant or an NF kappaB inhibitor. It has been reported to inhibit the replication of human rhinoviruses, poliovirus, coxsackievirus, and influenza virus. In this paper, we report that PDTC could inhibit the replication of herpes simplex virus 1 and 2 (HSV-1 and HSV-2). PDTC suppressed the expression of HSV-1 and HSV-2 viral immediate early (IE) and late (membrane protein gD) genes and the production of viral progeny. This antiviral property was mediated by the dithiocarbamate moiety of PDTC and required the presence of Zn(2+). Although PDTC could potently block reactive oxygen species (ROS) generation, it was found that this property did not contribute to its anti-HSV activity. PDTC showed no activity in disrupting the mitogen-activated protein kinase (MAPK) pathway activation induced by viral infection that was vital for the virus's propagation. We found that PDTC modulated cellular ubiquitination and, furthermore, influenced HSV-2-induced IkappaB-alpha degradation to inhibit NF-kappaB activation and enhanced PML stability in the nucleus, resulting in the inhibition of viral gene expression. These results suggested that the antiviral activity of PDTC might be mediated by its dysregulation of the cellular ubiquitin-proteasome system (UPS). PMID- 23740986 TI - A role for Ifit2 in restricting West Nile virus infection in the brain. AB - Previous studies have demonstrated that type I interferon (IFN-I) restricts West Nile virus (WNV) replication and pathogenesis in peripheral and central nervous system (CNS) tissues. However, the in vivo role of specific antiviral genes that are induced by IFN-I against WNV infection remains less well characterized. Here, using Ifit2(-/-) mice, we defined the antiviral function of the interferon stimulated gene (ISG) Ifit2 in limiting infection and disease in vivo by a virulent North American strain of WNV. Compared to congenic wild-type controls, Ifit2(-/-) mice showed enhanced WNV infection in a tissue-restricted manner, with preferential replication in the CNS of animals lacking Ifit2. Virological analysis of cultured macrophages, dendritic cells, fibroblasts, cerebellar granule cell neurons, and cortical neurons revealed cell type-specific antiviral functions of Ifit2 against WNV. In comparison, small effects of Ifit2 were observed on the induction or magnitude of innate or adaptive immune responses. Our results suggest that Ifit2 restricts WNV infection and pathogenesis in different tissues in a cell type-specific manner. PMID- 23740987 TI - A mutation in the stalk of the newcastle disease virus hemagglutinin neuraminidase (HN) protein prevents triggering of the F protein despite allowing efficient HN-F complex formation. AB - Newcastle disease virus (NDV)-induced membrane fusion requires formation of a complex between the hemagglutinin-neuraminidase (HN) and fusion (F) proteins. Substitutions for NDV HN stalk residues A89, L90, and L94 block fusion by modulating formation of the HN-F complex. Here, we demonstrate that a nearby L97A substitution, though previously shown to block fusion, allows efficient HN-F complex formation and likely acts by preventing changes in the HN stalk required for triggering of the bound F protein. PMID- 23740988 TI - Possible role of a cell surface carbohydrate in evolution of resistance to viral infections in old world primates. AB - Due to inactivation of the alpha1,3-galactosyltransferase gene (GGTA1, or the alpha1,3GT gene) approximately 28 million years ago, the carbohydrate alphaGal (Galalpha1,3Galbeta1,4GlcNAc) is not expressed on the cells of Old World monkeys and apes (including humans) but is expressed in all other mammals. The proposed selective advantage of this mutation for these primates is the ability to produce anti-Gal antibodies, which may be an effective immune component in neutralizing alphaGal-expressing pathogens. However, loss of alpha1,3GT expression may have been advantageous by providing natural resistance against viral pathogens that exploited the alpha1,3GT pathway or cell surface alphaGal for infection. Infections of paired cell lines with differential expression of alpha1,3GT showed that Sindbis viruses (SINV) preferentially replicate in alpha1,3GT-positive cells, whereas herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) preferentially grow in cells lacking alpha1,3GT. Viral growth and spread correlated with the ability of the different viruses to successfully initiate infection in the presence or absence of alpha1,3GT expression. GT knockout (KO) suckling mice infected with SINV strains (AR339 and S.A.AR86) experienced significant delay in onset of disease symptoms and mortality compared to wild type (WT) B6 suckling mice. In contrast, HSV-2-infected GT KO mice had higher viral titers in spleen and liver and exhibited significantly more focal hepatic necrosis than WT B6 mice. This study demonstrates that alpha1,3GT activity plays a role in the course of infections for certain viruses. Furthermore, this study has implications for the evolution of resistance to viral infections in primates. PMID- 23740989 TI - HIV-1 gag cytotoxic T lymphocyte epitopes vary in presentation kinetics relative to HLA class I downregulation. AB - Although CD8(+) cytotoxic T lymphocytes (CTLs) are protective in HIV-1 infection, the factors determining their antiviral efficiency are poorly defined. It is proposed that Gag targeting is superior because of very early Gag epitope presentation, allowing early killing of infected cells before Nef-mediated downregulation of human leukocyte antigen class I (HLA-I). To study Gag epitope presentation kinetics, three epitopes (SL977-85, KF11162-172, and TW10240-249) were genetically translocated from their endogenous location in the Rev-dependent (late) gag gene into the Rev-independent (early) nef gene with concomitant mutation of the corresponding endogenous epitopes to nonrecognized sequences. These viruses were compared to the index virus for CTL-mediated suppression of replication and the susceptibility of this antiviral activity to Nef-mediated HLA I downregulation. SL9-specific CTLs gained activity after SL9 translocation to Nef, going from Nef sensitive to Nef insensitive, indicating that translocation accelerated infected cell recognition from after to before HLA-I downregulation. KF11-specific CTL antiviral activity was unchanged and insensitive to HLA-I downregulation before and after KF11 translocation, suggesting that already rapid recognition of infected cells was not accelerated. However, TW10-specific CTLs that were insensitive to Nef at the baseline became sensitive with reduced antiviral activity after translocation, indicating that translocation retarded epitope expression. Cytosolic peptide processing assays suggested that TW10 was inefficiently generated after translocation to Nef, compared to SL9 and KF11. As a whole, these data demonstrate that epitope presentation kinetics play an important role in CTL antiviral efficiency, that Gag epitopes are not uniformly presented early, and that the epitope context can play a major role in presentation kinetics. PMID- 23740990 TI - Characterization of a discontinuous neutralizing epitope on glycoprotein B of human cytomegalovirus. AB - Human cytomegalovirus (HCMV) is a ubiquitously distributed pathogen that causes severe disease in immunosuppressed patients and newborn infants infected in utero. The viral envelope glycoprotein B (gB) is an attractive molecule for active vaccination and passive immunoprophylaxis and therapy. Using human monoclonal antibodies (MAbs), we have recently identified antigenic region 4 (AD 4) on gB as an important target for neutralizing antibodies. AD-4 is formed by a discontinuous sequence comprising amino acids 121 to 132 and 344 to 438 of gB of HCMV strain AD169. To map epitopes for human antibodies on this protein domain, we used a three-dimensional (3D) model of HCMV gB to identify surface-exposed amino acids on AD-4 and selected juxtaposed residues for alanine scans. A tyrosine (Y) at position 364 and a lysine (K) at position 379 (the YK epitope), which are immediate neighbors on the AD-4 surface, were found to be essential for binding of the human MAbs. Recognition of AD-4 by sera from HCMV-infected individuals also was largely dependent on these two residues, indicating a general importance for the antibody response against AD-4. A panel of AD-4 recombinant viruses harboring mutations at the crucial antibody binding sites was generated. The viruses showed significantly reduced susceptibility to neutralization by AD-4-specific MAbs or polyclonal AD-4-specific antibodies, indicating that the YK epitope is dominant for the AD-4-specific neutralizing antibody response during infection. To our knowledge, this is the first molecular identification of a functional discontinuous epitope on HCMV gB. Induction of antibodies specific for this epitope may be a desirable goal following vaccination with gB. PMID- 23740991 TI - In memoriam:Hilary Koprowski, 1916-2013. PMID- 23740992 TI - Prion replication elicits cytopathic changes in differentiated neurosphere cultures. AB - The molecular mechanisms of prion-induced cytotoxicity remain largely obscure. Currently, only a few cell culture models have exhibited the cytopathic changes associated with prion infection. In this study, we introduced a cell culture model based on differentiated neurosphere cultures isolated from the brains of neonatal prion protein (PrP)-null mice and transgenic mice expressing murine PrP (dNP0 and dNP20 cultures). Upon exposure to mouse Chandler prions, dNP20 cultures supported the de novo formation of abnormal PrP and the resulting infectivity, as assessed by bioassays. Furthermore, this culture was susceptible to various prion strains, including mouse-adapted scrapie, bovine spongiform encephalopathy, and Gerstmann-Straussler-Scheinker syndrome prions. Importantly, a subset of the cells in the infected culture that was mainly composed of astrocyte lineage cells consistently displayed late-occurring, progressive signs of cytotoxicity as evidenced by morphological alterations, decreased cell viability, and increased lactate dehydrogenase release. These signs of cytotoxicity were not observed in infected dNP0 cultures, suggesting the requirement of endogenous PrP expression for prion-induced cytotoxicity. Degenerated cells positive for glial fibrillary acidic protein accumulated abnormal PrP and exhibited features of apoptotic death as assessed by active caspase-3 and terminal deoxynucleotidyltransferase nick-end staining. Furthermore, caspase inhibition provided partial protection from prion mediated cell death. These results suggest that differentiated neurosphere cultures can provide an in vitro bioassay for mouse prions and permit the study of the molecular basis for prion-induced cytotoxicity at the cellular level. PMID- 23740993 TI - Adenovirus E1A oncogene induces rereplication of cellular DNA and alters DNA replication dynamics. AB - The oncogenic property of the adenovirus (Ad) transforming E1A protein is linked to its capacity to induce cellular DNA synthesis which occurs as a result of its interaction with several host proteins, including pRb and p300/CBP. While the proteins that contribute to the forced induction of cellular DNA synthesis have been intensively studied, the nature of the cellular DNA replication that is induced by E1A in quiescent cells is not well understood. Here we show that E1A expression in quiescent cells leads to massive cellular DNA rereplication in late S phase. Using a single-molecule DNA fiber assay, we studied the cellular DNA replication dynamics in E1A-expressing cells. Our studies show that the DNA replication pattern is dramatically altered in E1A-expressing cells, with increased replicon length, fork velocity, and interorigin distance. The interorigin distance increased by about 3-fold, suggesting that fewer DNA replication origins are used in E1A-expressing cells. These aberrant replication events led to replication stress, as evidenced by the activation of the DNA damage response. In earlier studies, we showed that E1A induces c-Myc as a result of E1A binding to p300. Using an antisense c-Myc to block c-Myc expression, our results indicate that induction of c-Myc in E1A-expressing cells contributes to the induction of host DNA replication. Together, our results suggest that the E1A oncogene-induced cellular DNA replication stress is due to dramatically altered cellular replication events and that E1A-induced c-Myc may contribute to these events. PMID- 23740994 TI - Lack of prophylactic efficacy of oral maraviroc in macaques despite high drug concentrations in rectal tissues. AB - Maraviroc (MVC) is a potent CCR5 coreceptor antagonist that is in clinical testing for daily oral pre-exposure prophylaxis (PrEP) for HIV prevention. We used a macaque model consisting of weekly SHIV162p3 exposures to evaluate the efficacy of oral MVC in preventing rectal SHIV transmission. MVC dosing was informed by the pharmacokinetic profile seen in blood and rectal tissues and consisted of a human-equivalent dose given 24 h before virus exposure, followed by a booster postexposure dose. In rectal secretions, MVC peaked at 24 h (10,242 ng/ml) with concentrations at 48 h that were about 40 times those required to block SHIV infection of peripheral blood mononuclear cells (PBMCs) in vitro. Median MVC concentrations in rectal tissues at 24 h (1,404 ng/g) were 30 and 10 times those achieved in vaginal or lymphoid tissues, respectively. MVC significantly reduced macrophage inflammatory protein 1beta-induced CCR5 internalization in rectal mononuclear cells, an indication of efficient binding to CCR5 in rectal lymphocytes. The half-life of CCR5-bound MVC in PBMCs was 2.6 days. Despite this favorable profile, 5/6 treated macaques were infected during five rectal SHIV exposures as were 3/4 controls. MVC treatment was associated with a significant increase in the percentage of CD3(+)/CCR5(+) cells in blood. We show that high and durable MVC concentrations in rectal tissues are not sufficient to prevent SHIV infection in macaques. The increases in CD3(+)/CCR5(+) cells seen during MVC treatment point to unique immunological effects of CCR5 inhibition by MVC. The implications of these immunological effects on PrEP with MVC require further evaluation. PMID- 23740995 TI - Role of immediate early protein ICP27 in the differential sensitivity of herpes simplex viruses 1 and 2 to leptomycin B. AB - Leptomycin B (LMB) is a highly specific inhibitor of CRM1, a cellular karyopherin beta that transports nuclear export signal-containing proteins from the nucleus to the cytoplasm. Previous work has shown that LMB blocks herpes simplex virus 1 (HSV-1) replication in Vero cells and that certain mutations in viral immediate early protein ICP27 can confer LMB resistance. However, little is known of the molecular mechanisms involved. Here we report that HSV-2, a close relative of HSV 1, is naturally resistant to LMB. To see whether the ICP27 gene determines this phenotypic difference, we generated an HSV-1 mutant that expresses the HSV-2 ICP27 instead of the HSV-1 protein. This recombinant was fully sensitive to LMB, indicating that one or more other viral genes must be important in determining HSV-2's LMB-resistant phenotype. In additional work, we report several findings that shed light on how HSV-1 ICP27 mutations can confer LMB resistance. First, we show that LMB treatment of HSV-1-infected cells leads to suppression of late viral protein synthesis and a block to progeny virion release. Second, we identify a novel type of ICP27 mutation that can confer LMB resistance, that being the addition of a 100-residue amino-terminal affinity purification tag. Third, by studying infections where both LMB-sensitive and LMB-resistant forms of ICP27 are present, we show that HSV-1's sensitivity to LMB is dominant to its resistance. Together, our results suggest a model in which the N-terminal portion of ICP27 mediates a nonessential activity that interferes with HSV-1 replication when CRM1 is inactive. We suggest that LMB resistance mutations weaken or abrogate this activity. PMID- 23740996 TI - Role of cell-type-specific endoplasmic reticulum-associated degradation in polyomavirus trafficking. AB - BK polyomavirus (BKPyV) is a widespread human pathogen that establishes a lifelong persistent infection and can cause severe disease in immunosuppressed patients. BKPyV is a nonenveloped DNA virus that must traffic through the endoplasmic reticulum (ER) for productive infection to occur; however, it is unknown how BKPyV exits the ER before nuclear entry. In this study, we elucidated the role of the ER-associated degradation (ERAD) pathway during BKPyV intracellular trafficking in renal proximal tubule epithelial (RPTE) cells, a natural host cell. Using proteasome and ERAD inhibitors, we showed that ERAD is required for productive entry. Altered trafficking and accumulation of uncoated viral intermediates were detected by fluorescence in situ hybridization and indirect immunofluorescence in the presence of an inhibitor. Additionally, we detected a change in localization of partially uncoated virus within the ER during proteasome inhibition, from a BiP-rich area to a calnexin-rich subregion, indicating that BKPyV accumulated in an ER subcompartment. Furthermore, inhibiting ERAD did not prevent entry of capsid protein VP1 into the cytosol from the ER. By comparing the cytosolic entry of the related polyomavirus simian virus 40 (SV40), we found that dependence on the ERAD pathway for cytosolic entry varied between the polyomaviruses and between different cell types, namely, immortalized CV-1 cells and primary RPTE cells. PMID- 23740997 TI - Quantitative comparison of human parainfluenza virus hemagglutinin-neuraminidase receptor binding and receptor cleavage. AB - The human parainfluenza virus (hPIV) hemagglutinin-neuraminidase (HN) protein binds (H) oligosaccharide receptors that contain N-acetylneuraminic acid (Neu5Ac) and cleaves (N) Neu5Ac from these oligosaccharides. In order to determine if one of HN's two functions is predominant, we measured the affinity of H for its ligands by a solid-phase binding assay with two glycoprotein substrates and by surface plasmon resonance with three monovalent glycans. We compared the dissociation constant (Kd) values from these experiments with previously determined Michaelis-Menten constants (Kms) for the enzyme activity. We found that glycoprotein substrates and monovalent glycans containing Neu5Acalpha2 3Galbeta1-4GlcNAc bind HN with Kd values in the 10 to 100 MUM range. Km values for HN were previously determined to be on the order of 1 mM (M. M. Tappert, D. F. Smith, and G. M. Air, J. Virol. 85:12146-12159, 2011). A Km value greater than the Kd value indicates that cleavage occurs faster than the dissociation of binding and will dominate under N-permissive conditions. We propose, therefore, that HN is a neuraminidase that can hold its substrate long enough to act as a binding protein. The N activity can therefore regulate binding by reducing virus receptor interactions when the concentration of receptor is high. PMID- 23740998 TI - A novel hepacivirus with an unusually long and intrinsically disordered NS5A protein in a wild Old World primate. AB - GB virus B (GBV-B; family Flaviviridae, genus Hepacivirus) has been studied in New World primates as a model for human hepatitis C virus infection, but the distribution of GBV-B and its relatives in nature has remained obscure. Here, we report the discovery of a novel and highly divergent GBV-B-like virus in an Old World monkey, the black-and-white colobus (Colobus guereza), in Uganda. The new virus, guereza hepacivirus (GHV), clusters phylogenetically with GBV-B and recently described hepaciviruses infecting African bats and North American rodents, and it shows evidence of ancient recombination with these other hepaciviruses. Direct sequencing of reverse-transcribed RNA from blood plasma from three of nine colobus monkeys yielded near-complete GHV genomes, comprising two distinct viral variants. The viruses contain an exceptionally long nonstructural 5A (NS5A) gene, approximately half of which codes for a protein with no discernible homology to known proteins. Computational structure-based analyses indicate that the amino terminus of the GHV NS5A protein may serve a zinc-binding function, similar to the NS5A of other viruses within the family Flaviviridae. However, the 521-amino-acid carboxy terminus is intrinsically disordered, reflecting an unusual degree of structural plasticity and polyfunctionality. These findings shed new light on the natural history and evolution of the hepaciviruses and on the extent of structural variation within the Flaviviridae. PMID- 23740999 TI - Integrated analyses of genome-wide DNA occupancy and expression profiling identify key genes and pathways involved in cellular transformation by a Marek's disease virus oncoprotein, Meq. AB - Marek's disease (MD) is an economically significant disease in chickens that is caused by the highly oncogenic Marek's disease virus (MDV). A major unanswered question is the mechanism of MDV-induced tumor formation. Meq, a bZIP transcription factor discovered in the 1990s, is critically involved in viral oncogenicity, but only a few of its host target genes have been described, impeding our understanding of MDV-induced tumorigenesis. Using chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray analysis, a high confidence list of Meq binding sites in the chicken genome and a global transcriptome of Meq-responsive genes were generated. Meq binding sites were found to be enriched in the promoter regions of upregulated genes but not in those of downregulated genes. ChIP-seq was also performed for c-Jun, a known heterodimeric partner of Meq. The close location of binding sites of Meq and c Jun was noted, suggesting cooperativity between these two factors in modulating transcription. Pathway analysis indicated that Meq transcriptionally regulates many genes that are part of several signaling pathways including the extracellular signal-regulated kinase /mitogen-activated protein kinase (ERK/MAPK), Jak-STAT, and ErbB pathways, which are critical for oncogenesis and/or include signaling mediators involved in apoptosis. Meq activates oncogenic signaling cascades by transcriptionally activating major kinases in the ERK/MAPK pathway and simultaneously repressing phosphatases, as verified using inhibitors of MEK and ERK1/2 in a cell proliferation assay. This study provides significant insights into the mechanistic basis of Meq-dependent cell transformation. PMID- 23741000 TI - The endosomal pathway and the Golgi complex are involved in the infectious bursal disease virus life cycle. AB - Infectious bursal disease virus (IBDV), a double-stranded RNA virus belonging to the Birnaviridae family, causes immunosuppression in chickens. In this study, we defined the localization of IBDV replication complexes based on colocalization analysis of VP3, the major protein component of IBDV ribonucleoproteins (RNPs). Our results indicate that VP3 localizes to vesicular structures bearing features of early and late endocytic compartments located in the juxtanuclear region. Interfering with the endocytic pathway with a dominant negative version of Rab5 after the internalization step leads to a reduction in virus titer. Triple immunostaining studies between VP3, the viral RNA-dependent RNA polymerase VP1, and viral double-stranded RNA (dsRNA) showed a well-defined colocalization, indicating that the three critical components of the RNPs colocalize in the same structure, likely representing replication complexes. Interestingly, recombinant expressed VP3 also localizes to endosomes. Employing Golgi markers, we found that VP3-containing vesicles were closely associated with this organelle. Depolymerization of microtubules with nocodazole caused a profound change in VP3 localization, showing a punctate distribution scattered throughout the cytoplasm. However, these VP3-positive structures remained associated with Golgi ministacks. Similarly, brefeldin A (BFA) treatment led to a punctate distribution of VP3, scattered throughout the cytoplasm of infected cells. In addition, analysis of intra- and extracellular viral infective particles after BFA treatment of avian cells suggested a role for the Golgi complex in viral assembly. These results constitute the first study elucidating the localization of IBDV replication complexes (i.e., in endocytic compartments) and establishing a role for the Golgi apparatus in the assembly step of a birnavirus. PMID- 23741001 TI - Role of RNA interference (RNAi) in dengue virus replication and identification of NS4B as an RNAi suppressor. AB - RNA interference (RNAi) is an important antiviral defense response in plants and invertebrates; however, evidences for its contribution to mammalian antiviral defense are few. In the present study, we demonstrate the anti-dengue virus role of RNAi in mammalian cells. Dengue virus infection of Huh 7 cells decreased the mRNA levels of host RNAi factors, namely, Dicer, Drosha, Ago1, and Ago2, and in corollary, silencing of these genes in virus-infected cells enhanced dengue virus replication. In addition, we observed downregulation of many known human microRNAs (miRNAs) in response to viral infection. Using reversion-of-silencing assays, we further showed that NS4B of all four dengue virus serotypes is a potent RNAi suppressor. We generated a series of deletion mutants and demonstrated that NS4B mediates RNAi suppression via its middle and C-terminal domains, namely, transmembrane domain 3 (TMD3) and TMD5. Importantly, the NS4B N terminal region, including the signal sequence 2K, which has been implicated in interferon (IFN)-antagonistic properties, was not involved in mediating RNAi suppressor activity. Site-directed mutagenesis of conserved residues revealed that a Phe-to-Ala (F112A) mutation in the TMD3 region resulted in a significant reduction of the RNAi suppression activity. The green fluorescent protein (GFP) small interfering RNA (siRNA) biogenesis of the GFP-silenced line was considerably reduced by wild-type NS4B, while the F112A mutant abrogated this reduction. These results were further confirmed by in vitro dicer assays. Together, our results suggest the involvement of miRNA/RNAi pathways in dengue virus establishment and that dengue virus NS4B protein plays an important role in the modulation of the host RNAi/miRNA pathway to favor dengue virus replication. PMID- 23741002 TI - Susceptibility and pathogenesis of little brown bats (Myotis lucifugus) to heterologous and homologous rabies viruses. AB - Rabies virus (RABV) maintenance in bats is not well understood. Big brown bats (Eptesicus fuscus), little brown bats (Myotis lucifugus), and Mexican free-tailed bats (Tadarida brasiliensis) are the most common bats species in the United States. These colonial bat species also have the most frequent contact with humans and domestic animals. However, the silver-haired bat (Lasionycteris noctivagans) RABV is associated with the majority of human rabies virus infections in the United States and Canada. This is of interest because silver haired bats are more solitary bats with infrequent human interaction. Our goal was to determine the likelihood of a colonial bat species becoming infected with and transmitting a heterologous RABV. To ascertain the potential of heterologous RABV infection in colonial bat species, little brown bats were inoculated with a homologous RABV or one of two heterologous RABVs. Additionally, to determine if the route of exposure influenced the disease process, bats were inoculated either intramuscularly (i.m.) or subcutaneously (s.c.) with a homologous or heterologous RABV. Our results demonstrate that intramuscular inoculation results in a more rapid progression of disease onset, whereas the incubation time in bats inoculated s.c. is significantly longer. Additionally, cross protection was not consistently achieved in bats previously inoculated with a heterologous RABV following a challenge with a homologous RABV 6 months later. Finally, bats that developed rabies following s.c. inoculation were significantly more likely to shed virus in their saliva and demonstrated increased viral dissemination. In summary, bats inoculated via the s.c. route are more likely to shed virus, thus increasing the likelihood of transmission. PMID- 23741003 TI - Mutations in the capsid protein of Brome mosaic virus affecting encapsidation eliminate vesicle induction in planta: implications for virus cell-to-cell spread. AB - Positive-strand RNA viruses are known to rearrange the endomembrane network to make it more conducive for replication, maturation, or egress. Our previous transmission electron microscopic (TEM) analysis showed that ectopic expression of wild-type (wt) capsid protein (CP) of Brome mosaic virus (BMV) has an intrinsic property of modifying the endoplasmic reticulum (ER) to induce vesicles similar to those present in wt BMV infection. In this study, we evaluated the functional significance of CP-mediated vesicle induction to the BMV infection cycle in planta. Consequently, the cytopathologic changes induced by wt CP or its mutants defective in virion assembly due to mutations engineered in either N- or C-proximal domains were comparatively analyzed by TEM in two susceptible (Nicotiana benthamiana and Chenopodium quinoa) and one nonhost (N. clevelandii) plant species. The results showed that in susceptible hosts, CP-mediated ER derived vesicle induction is contingent on the expression of encapsidation competent CP. In contrast, unlike in N. benthamiana and C. quinoa, transient expression of wt CP in nonhost N. clevelandii plants eliminated vesicle induction. Additionally, comparative source-to-sink analysis of virus spread in leaves of N. benthamiana and N. clevelandii coexpressing wt BMV and Cucumber mosaic virus (CMV) showed that despite trans-encapsidation, CMV failed to complement the defective cell-to-cell movement of BMV. The significance and relation of CP-mediated vesicle induction to virus cell-to-cell movement are discussed. PMID- 23741004 TI - Language proficiency among hospitalized immigrant psychiatric patients in Italy. AB - BACKGROUND: and aim: Lack of cultural adaptation may risk or worsen mental illness among immigrants, and interfere with assessment and treatment. Language proficiency (LP) seems essential for access to foreign environments, and the limited research concerning its effects on mental health care encouraged this preliminary study. METHODS: We reviewed clinical records of all immigrant psychiatric patients hospitalized at the University of Foggia in 2004-09 (N = 85), and compared characteristics of patients with adequate versus inadequate LP. RESULTS: Subjects (44 men, 41 women; aged 35.7+/-10.0 years) represented 3.62+/ 0.94% of all hospitalizations in six years. (2004-09). Most (60.0%) had emigrated from other European countries. Many were diagnosed with a DSM-IV unspecified psychosis (40.0%) or adjustment disorder (18.8%), and 45.9% were in first lifetime episodes. Average comprehension and spoken LP was considered adequate in 62.4% and inadequate in 37.6%. In multivariate modelling, adequate LP was more prevalent among women, emigration from another European country, receiving more psychotropic drugs at hospitalization, and having entered Italy legally. CONCLUSION: Findings support an expected importance of LP among immigrant psychiatric inpatients, and encourage language assessment and training as part of the comprehensive support of such patients, especially men. PMID- 23741005 TI - How perceived social support relates to suicidal ideation: a Japanese social resident survey. AB - BACKGROUND: The loss of social support is one of the major risk factors for suicide. However, there are few empirical studies that have examined how a person's suicide ideation relates to their social support. AIMS: To examine the relationship between social support and suicidal ideation. METHODS: Self-report questionnaires were sent to 2,200 randomly selected adults in Japan. The questionnaire inquired the participants about the severity of suicidal ideation, the details of current perceived social support and their degree of satisfaction with this social support. Social support and related indicators were compared among three groups of participants that varied in severity of suicidal ideation. RESULTS: People in the group that had suicide ideation during their lives reported receiving significantly less support from their family and had greater feelings of dissatisfaction with that support than those in the other groups. Furthermore, people who had suicide ideation during the month immediately preceding the survey reported providing less support to their family, relatives or friends, as well as receiving less support from family than other groups, and having stronger feelings of dissatisfaction with social support. CONCLUSION: Our study identified a strong relationship between the severity of suicidal ideation and perceived social support. PMID- 23741006 TI - Connective tissue growth factor regulates adipocyte differentiation of mesenchymal stromal cells and facilitates leukemia bone marrow engraftment. AB - Mesenchymal stromal cells (MSCs) are a major component of the leukemia bone marrow (BM) microenvironment. Connective tissue growth factor (CTGF) is highly expressed in MSCs, but its role in the BM stroma is unknown. Therefore, we knocked down (KD) CTGF expression in human BM-derived MSCs by CTGF short hairpin RNA. CTGF KD MSCs exhibited fivefold lower proliferation compared with control MSCs and had markedly fewer S-phase cells. CTGF KD MSCs differentiated into adipocytes at a sixfold higher rate than controls in vitro and in vivo. To study the effect of CTGF on engraftment of leukemia cells into BM, an in vivo model of humanized extramedullary BM (EXM-BM) was developed in NOD/SCID/IL-2rg(null) mice. Transplanted Nalm-6 or Molm-13 human leukemia cells engrafted at a threefold higher rate in adipocyte-rich CTGF KD MSC-derived EXM-BM than in control EXM-BM. Leptin was found to be highly expressed in CTGF KD EXM-BM and in BM samples of patients with acute myeloid and acute lymphoblastic leukemia, whereas it was not expressed in normal controls. Given the established role of the leptin receptor in leukemia cells, the data suggest an important role of CTGF in MSC differentiation into adipocytes and of leptin in homing and progression of leukemia. PMID- 23741007 TI - Loss of endothelial protein C receptors links coagulation and inflammation to parasite sequestration in cerebral malaria in African children. AB - Cerebral malaria (CM) is a major cause of mortality in African children and the mechanisms underlying its development, namely how malaria-infected erythrocytes (IEs) cause disease and why the brain is preferentially affected, remain unclear. Brain microhemorrhages in CM suggest a clotting disorder, but whether this phenomenon is important in pathogenesis is debated. We hypothesized that localized cerebral microvascular thrombosis in CM is caused by a decreased expression of the anticoagulant and protective receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR) and that low constitutive expression of these regulatory molecules in the brain make it particularly vulnerable. Autopsies from Malawian children with CM showed cerebral fibrin clots and loss of EPCR, colocalized with sequestered IEs. Using a novel assay to examine endothelial phenotype ex vivo using subcutaneous microvessels, we demonstrated that loss of EPCR and TM at sites of IE cytoadherence is detectible in nonfatal CM. In contrast, although clotting factor activation was seen in the blood of CM patients, this was compensated and did not disseminate. Because of the pleiotropic nature of EPCR and TM, these data implicate disruption of the endothelial protective properties at vulnerable sites and particularly in the brain, linking coagulation and inflammation with IE sequestration. PMID- 23741008 TI - A far downstream enhancer for murine Bcl11b controls its T-cell specific expression. AB - Bcl11b is a T-cell specific gene in hematopoiesis that begins expression during T lineage commitment and is required for this process. Aberrant expression of BCL11B or proto-oncogene translocation to the vicinity of BCL11B can be a contributing factor in human T-ALL. To identify the mechanism that controls its distinctive T-lineage expression, we corrected the identified Bcl11b transcription start site and mapped a cell-type-specific differentially methylated region bracketing the Bcl11b promoter. We identified a 1.9-kb region 850 kb downstream of Bcl11b, "Major Peak," distinguished by its dynamic histone marking pattern in development that mirrors the pattern at the Bcl11b promoter. Looping interactions between promoter-proximal elements including the differentially methylated region and downstream elements in the Major Peak are required to recapitulate the T-cell specific expression of Bcl11b in stable reporter assays. Functional dissection of the Major Peak sequence showed distinct subregions, in which TCF-1 sites and a conserved element were required for T lineage-specific activation and silencing in non-T cells. A bacterial artificial chromosome encompassing the full Bcl11b gene still required the addition of the Major Peak to exhibit T-cell specific expression. Thus, promoter-proximal and Major Peak sequences are cis-regulatory elements that interact over 850 kb to control expression of Bcl11b in hematopoietic cells. PMID- 23741009 TI - Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. AB - Long-term engraftment of allogeneic cells necessitates eluding immune-mediated rejection, which is currently achieved by matching for human leukocyte antigen (HLA) expression, immunosuppression, and/or delivery of donor-derived cells to sanctuary sites. Genetic engineering provides an alternative approach to avoid clearance of cells that are recognized as "non-self" by the recipient. To this end, we developed designer zinc finger nucleases and employed a "hit-and-run" approach to genetic editing for selective elimination of HLA expression. Electro transfer of mRNA species coding for these engineered nucleases completely disrupted expression of HLA-A on human T cells, including CD19-specific T cells. The HLA-A(neg) T-cell pools can be enriched and evade lysis by HLA-restricted cytotoxic T-cell clones. Recognition by natural killer cells of cells that had lost HLA expression was circumvented by enforced expression of nonclassical HLA molecules. Furthermore, we demonstrate that zinc finger nucleases can eliminate HLA-A expression from embryonic stem cells, which broadens the applicability of this strategy beyond infusing HLA-disparate immune cells. These findings establish that clinically appealing cell types derived from donors with disparate HLA expression can be genetically edited to evade an immune response and provide a foundation whereby cells from a single donor can be administered to multiple recipients. PMID- 23741011 TI - Runx3 deficiency results in myeloproliferative disorder in aged mice. AB - The RUNX family genes encode transcription factors that are involved in development and human diseases. RUNX1 is one of the most frequently mutated genes in human hematological malignancies and is a critical factor for the generation and maintenance of hematopoietic stem cells. Another Runx family gene, Runx3, is known to be expressed in hematopoietic cells. However, its involvement in hematopoiesis remains unclear. Here we show the hematopoietic phenotypes in Runx3 conditional knockout (KO) mice (Runx3(fl/fl);Mx1-Cre(+)): whereas young Runx3 KO mice did not exhibit any significant hematopoietic defects, aged Runx3 KO mice developed a myeloproliferative disorder characterized by myeloid-dominant leukocytosis, splenomegaly, and an increase of hematopoietic stem/progenitor cells (HSPCs). Notably, Runx3-deficient cells showed hypersensitivity to granulocyte-colony stimulating factor, suggesting enhanced proliferative and mobilization capability of Runx3-deficient HSPCs when stimulated. These results suggest that, besides Runx1, Runx3 also plays a role in hematopoiesis. PMID- 23741010 TI - Erwinia asparaginase achieves therapeutic activity after pegaspargase allergy: a report from the Children's Oncology Group. AB - AALL07P2 evaluated whether substitution of Erwinia asparaginase 25000 IU/m(2) for 6 doses given intramuscularly Monday/Wednesday/Friday (M/W/F) to children and young adults with acute lymphoblastic leukemia and clinical allergy to pegaspargase would provide a 48-hour nadir serum asparaginase activity (NSAA) >= 0.10 IU/mL. AALL07P2 enrolled 55 eligible/evaluable patients. NSAA >= 0.1 IU/mL was achieved in 38 of 41 patients (92.7%) with acceptable samples 48 hours and in 38 of 43 patients (88.4%) 72 hours after dosing during course 1. Among samples obtained during all courses, 95.8% (252 of 263) of 48-hour samples and 84.5% (125 of 148) of 72-hour samples had NSAA >= 0.10-IU/mL. Pharmacokinetic parameters were estimated by fitting the serum asparaginase activity-time course for all 6 doses given during course 1 to a 1-compartment open model with first order absorption. Erwinia asparaginase administered with this schedule achieved therapeutic NSAA at both 48 and 72 hours and was well tolerated with no reports of hemorrhage, thrombosis, or death, and few cases of grade 2 to 3 allergic reaction (n = 6), grade 1 to 3 hyperglycemia (n = 6), or grade 1 pancreatitis (n = 1). Following allergy to pegaspargase, Erwinia asparaginase 25000 IU/m(2) * 6 intramuscularly M/W/F can be substituted for a single dose of pegaspargase. PMID- 23741012 TI - STAT3 mediates oncogenic addiction to TEL-AML1 in t(12;21) acute lymphoblastic leukemia. AB - The t(12;21)(p13;q22) translocation is the most common chromosomal abnormality in pediatric leukemia. Although this rearrangement involves 2 well-characterized transcription factors, TEL and AML1, the molecular pathways affected by the result of the translocation remain largely unknown. Also in light of recent studies showing genetic and functional heterogeneities in cells responsible for cancer clone maintenance and propagation, targeting a single common deregulated pathway may be critical for the success of novel therapies. Here we describe a novel signaling pathway that is essential for oncogenic addiction in TEL-AML1 leukemia. Our data indicate a direct role for TEL-AML1, via increasing the activity of RAC1, in regulating the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which results in transcriptional induction of MYC. We demonstrate that human leukemic cell lines carrying this translocation are highly sensitive to treatment with S3I-201, a specific STAT3 inhibitor, and, more interestingly, that primary human leukemic samples are also responsive to the drug in the same concentration range. Thus, STAT3 inhibition represents a promising possible therapeutic strategy for the treatment of TEL-AML1 leukemia. PMID- 23741013 TI - Bone morphogenetic protein 9 (BMP9) controls lymphatic vessel maturation and valve formation. AB - Lymphatic vessels are critical for the maintenance of tissue fluid homeostasis and their dysfunction contributes to several human diseases. The activin receptor like kinase 1 (ALK1) is a transforming growth factor-beta family type 1 receptor that is expressed on both blood and lymphatic endothelial cells (LECs). Its high affinity ligand, bone morphogenetic protein 9 (BMP9), has been shown to be critical for retinal angiogenesis. The aim of this work was to investigate whether BMP9 could play a role in lymphatic development. We found that Bmp9 deficiency in mice causes abnormal lymphatic development. Bmp9-knockout (KO) pups presented hyperplastic mesenteric collecting vessels that maintained LYVE-1 expression. In accordance with this result, we found that BMP9 inhibited LYVE-1 expression in LECs in an ALK1-dependent manner. Bmp9-KO pups also presented a significant reduction in the number and in the maturation of mesenteric lymphatic valves at embryonic day 18.5 and at postnatal days 0 and 4. Interestingly, the expression of several genes known to be involved in valve formation (Foxc2, Connexin37, EphrinB2, and Neuropilin1) was upregulated by BMP9 in LECS. Finally, we demonstrated that Bmp9-KO neonates and adult mice had decreased lymphatic draining efficiency. These data identify BMP9 as an important extracellular regulator in the maturation of the lymphatic vascular network affecting valve development and lymphatic vessel function. PMID- 23741014 TI - Two-colored fluorescence correlation spectroscopy screening for LC3-P62 interaction inhibitors. AB - The fluorescence correlation spectroscopy (FCS)-based competitive binding assay to screen for protein-protein interaction inhibitors is a highly sensitive method as compared with the fluorescent polarization assay used conventionally. However, the FCS assay identifies many false-positive compounds, which requires specifically designed orthogonal screenings. A two-colored application of the FCS based screening was newly developed, and inhibitors of a protein-protein interaction, involving selective autophagy, were selected. We focused on the interaction of LC3 with the adaptor protein p62, because the interaction is crucial to degrade the specific target proteins recruited by p62. First, about 10,000 compounds were subjected to the FCS-based competitive assay using a TAMRA labeled p62-derived probe, and 29 hit compounds were selected. Next, the obtained hits were evaluated by the second FCS assay, using an Alexa647-labeled p62 derived probe to remove the false-positive compounds, and six hit compounds inhibited the interaction. Finally, we tested all 29 compounds by surface plasmon resonance-based competitive binding assay to evaluate their inhibition of the LC3 p62 interaction and selected two inhibitors with IC50 values less than 2 uM. The two-colored FCS-based screening was shown to be effective to screen for protein protein interaction inhibitors. PMID- 23741020 TI - Detection of clonal KPC-2-producing Klebsiella pneumoniae ST258 in Korea during nationwide surveillance in 2011. AB - This study analysed the characteristics and genetic similarity of recent Klebsiella pneumoniae carbapenemase (KPC-2)-producing Klebsiella pneumoniae isolates from Korea. Recent laboratory surveillance detected an increase in carbapenemase-producing Enterobacteriaceae in Korea. A total of 6 KPC-2-producing K. pneumoniae were identified from 277 Enterobacteriaceae clinical isolates. All were sequence type (ST) 258 and they had the same pulsotype. They had high MICs for carbapenems and multi-drug resistance. TEM-1, SHV-11 and OXA type beta lactamases were detected in all isolates, whereas CTX-M type beta-lactamases and plasmid-mediated AmpC beta-lactamase (PABL) were not present. A conjugation experiment failed, but blaKPC-2-harbouring plasmids from the six isolates were used to transform Escherichia coli DH5-alpha by electroporation. Each of the transformants harboured a blaKPC-2-positive approximately 95 kb plasmid, which was typed in the IncFII incompatibility group and co-harboured TEM-1 and OXA-9 beta-lactamases. They shared the same restriction profile. This study confirms the emergence of clonal ST258 KPC-2-producing K. pneumoniae in some regions of Korea. PMID- 23741021 TI - Molecular genotyping of Acinetobacter spp. isolated in Arizona, USA, using multilocus PCR and mass spectrometry. AB - Acinetobacter spp. are a diverse group of Gram-negative bacteria frequently implicated in nosocomial infections. Genotypic methods have been instrumental in studying Acinetobacter, but few offer high resolution, rapid turnaround time, technical ease and high inter-laboratory reproducibility, which has hampered understanding of disease incidence, transmission patterns and diversity within this genus. Here, we further evaluated multilocus PCR electrospray ionization/mass spectrometry (PCR/ESI-MS), a method that is simple and robust, and provides both species characterization and strain-level resolution of Acinetobacter spp. on a single platform. We examined 125 Acinetobacter isolates from 21 hospitals, laboratories and medical centres spanning four counties in Arizona, USA, using PCR/ESI-MS. We compared PCR/ESI-MS with an in-house amplified fragment length polymorphism (AFLP) genotyping scheme. PCR/ESI-MS demonstrated that Acinetobacter spp. from Arizonan hospitals had similar species and strain distributions to other US civilian hospitals. Furthermore, we showed that the PCR/ESI-MS and AFLP genotypes were highly congruent, with the former having the advantages of robust inter-laboratory reproducibility, rapid turnaround time and simple experimental set-up and data analysis. PCR/ESI-MS is an effective and high throughput platform for strain typing of Acinetobacter baumannii and for identification of other Acinetobacter spp., including the emerging nosocomial pathogens Acinetobacter pittii and Acinetobacter nosocomialis. PMID- 23741022 TI - A 10 year surveillance for antimicrobial susceptibility of Escherichia coli and Klebsiella pneumoniae in community- and hospital-associated intra-abdominal infections in China. AB - The objective of this study was to investigate the susceptibility of hospital associated (HA) and community-associated (CA) Escherichia coli and Klebsiella pneumoniae isolated from patients with intra-abdominal infections (IAIs) in China. From 2002 to 2011, the minimum inhibitory concentrations (MICs) of 12 antibiotics against 3074 E. coli and 1025 K. pneumoniae from 23 centres located in 16 cities were determined by the broth microdilution method. During the 10 year study period, ertapenem, imipenem, amikacin and piperacillin-tazobactam retained high and stable activity against E. coli and K. pneumoniae isolates regardless of whether their source was HA or CA and regardless of their extended spectrum beta-lactamase (ESBL) production. However, the susceptibility of E. coli to cephalosporins and ampicillin-sulbactam decreased dramatically during the 10 years, especially for the CA isolates. Fluoroquinolones showed low activity against E. coli. During the whole study period, the ESBL rates for E. coli isolates from IAIs increased from 36.1 % in 2002-2003 to 68.1 % in 2010-2011 (P<0.001). Correspondingly, the ESBL rates in HA isolates increased from 52.2 % in 2002-2003 to 70.0 % in 2010-2011 (P = 0.001), and in CA isolates from 19.1 % in 2002-2003 to 61.6 % in 2010-2011 (P<0.001). The ESBL-positive rate in K. pneumoniae remained between 30.1 and 39.3 % of the total isolates with no significant change during the 10 years. In conclusion, carbapenems retained the highest susceptibility rates against HA and CA E. coli and K. pneumoniae. High prevalence of ESBL in HA E. coli and fast-growing resistance in CA E. coli severely limit the empirical use of the third- and fourth-generation cephalosporins in the therapy of IAIs. PMID- 23741023 TI - Clostridium difficile erm(B)-containing elements and the burden on the in vitro fitness. AB - In Clostridium difficile, resistance to the macrolide-lincosamide-streptogramin B group of antibiotics generally relies on erm(B) genes. In this study, we investigated elements with a genetic organization different from Tn5398, the mobilizable non-conjugative element identified in C. difficile strain 630. Our results suggested that the elements most frequently found in strains isolated during the European surveillance study in 2005 were related to Tn6194, the conjugative transposon recently detected in different C. difficile types, including PCR-ribotype 027. We characterized a Tn6194-like and a novel element rarely found in clinical isolates. A burden on the in vitro fitness of C. difficile was observed after the acquisition of these elements as well as of Tn5398. PMID- 23741024 TI - Extended-spectrum beta-lactamases in Enterobacteriaceae isolated in Brazil carry distinct types of plasmid-mediated quinolone resistance genes. AB - One hundred and six nalidixic acid-resistant Enterobacteriaceae isolates from two Brazilian hospitals isolated from June to October 2010 were evaluated to characterize the co-existence of plasmid-mediated quinolone resistant (PMQR) and extended-spectrum beta-lactamase (ESBL) determinants. The qnr genetic environment was determined by PCR and sequencing. Conjugation and hybridization experiments determined whether qnr-carrying plasmids were self-transferable. The aac(6')-Ib cr and qepA genes were also screened. Thirteen qnr-like genes (12.3 %) were identified, with qnrB1 the most common, followed by qnrS1, qnrB2 and qnrB19. No qnrA, qnrC, qnrD or qepA determinant was detected. All qnr-positive strains possessed chromosomal substitutions in gyrase- and topoisomerase-encoding genes and four harboured a aac(6')-Ib-cr gene. The co-production of blaCTX-M was observed in ten qnr-positive strains. These results indicate the dissemination of PMQR genes shown in clinical isolates from Brazil, and their co-existence with ESBL genes emphasizes the complexity of plasmid-mediated resistance determinants among Enterobacteriaceae. PMID- 23741025 TI - Genetic characteristics of blaNDM-1-positive plasmid in Citrobacter freundii isolate separated from a clinical infectious patient. AB - This study reports an infectious case involving an (NDM-1)-producing Citrobacter freundii and further explored the potential threat of the bla(NDM-1) gene by analysing the characteristics of the (NDM-1)-encoding plasmid sequence. A bla(NDM 1)-positive C. freundii with high resistance to carbapenems was separated from a clinical patient suffering from a urinary tract infection. S1 nuclease-based plasmid analysis followed by Southern blot hybridization, a conjugation experiment and electrotransformation confirmed that the bla(NDM-1) gene was located on a plasmid. High-throughput sequencing of the bla(NDM-1)-positive plasmid (pCFNDM-CN) showed that it was a 54 kb IncX-type plasmid and contained a backbone region and a variable region with two beta-lactamase genes (bla(NDM-1) and bla(SHV-12)). The NDM-1 composite transposon in the variable region was surrounded by IS26 and IS5-truncated ISAba125, and shared a high sequence similarity to the bla(NDM-1) surrounding structure in Acinetobacter spp. Our research suggested that the NDM-1 composite transposon might play an essential role in mobilization of the bla(NDM-1) gene from Acinetobacter spp. to Enterobacteriaceae. PMID- 23741026 TI - Diagnostic microRNA markers to screen for sporadic human colon cancer in stool: I. Proof of principle. AB - To present proof-of-principle application for employing micro(mi)RNAs as diagnostic markers for colon cancer, we carried out global microarray expression studies on stool samples obtained from fifteen individuals (three controls, and three each with TNM stage 0-1, stage 2, stage 3, and stage 4 colon cancer), using Affymetrix GeneChip miRNA 3.0 Array, to select for a panel of miRNA genes for subsequent focused semi-quantitative polymerase chain reaction (PCR) analysis studies. Microarray results showed 202 preferentially expressed miRNA genes that were either increased (141 miRNAs), or reduced (61 miRNAs) in expression. We then conducted a stem-loop reverse transcriptase (RT)-TaqMan(r) minor groove binding (MGB) probes, followed by a modified qPCR expression study on 20 selected miRNAs. Twelve of the miRNAs exhibited increased and 8 decreased expression in stool from 60 individuals (20 controls, 20 with tumor-lymph node-metastatic (TNM) stage 0-1, 10 with stage 2, five with stage 3, and 5 with stage 4 colon cancer) to quantitatively monitor miRNA changes at various TNM stages of colon cancer progression. We also used laser-capture microdissection (LCM) of colon mucosal epithelial tissue samples (three control samples, and three samples from each of the four stages of colon cancer, for a total of 15 samples) to find concordance or lack thereof with stool findings. The reference housekeeping pseudogene-free ribosomal gene (18S rRNA), which shows little variation in expression, was employed as a normalization standard for relative PCR quantification. Results of the PCR analyses confirmed that twelve miRNAs (miR-7, miR-17, miR-20a, miR-21, miR-92a, miR-96, miR-106a, miR-134, miR-183, miR-196a, miR-199a-3p and miR214) had an increased expression in the stool of patients with colon cancer, and that later TNM carcinoma stages exhibited a more pronounced expression than did adenomas. On the other hand, eight miRNAs (miR-9, miR-29b, miR-127-5p, miR-138, miR-143, miR-146a, miR-222 and miR-938) had decreased expression in the stool of patients with colon cancer, which was also more pronounced from early to later TNM stages. Results from colon mucosal tissues were similar to those from stool samples, although with more apparent changes in expression. Cytological studies on purified stool colonocytes that employed Giemsa staining showed 80% sensitivity for detecting tumor cells in stool smears. The performance characteristics of the test confirmed that stool is a medium well-suited for colon cancer screening, and that the quantitative changes in the expression of few mature miRNA molecules in stool associated with colon cancer progression provided for more sensitive and specific non-invasive diagnostic markers than tests currently available on the market. Thus, a larger prospective and properly randomized validation study of control individuals and patients exhibiting various stages of colon cancer progression (TNM stages 0-IV) is now needed in order to standardize test conditions, and provide a means for determining the true sensitivity and specificity of a miRNA screening approach in stool for the non-invasive detection of colon cancer, particularly at an early stage (0-I). Eventually, we will develop a chip to enhance molecular screening for colon cancer, as has been accomplished for the detection of genetically-modified organisms (GMOs) in foods. PMID- 23741027 TI - Mutational analysis of gastrointestinal stromal tumors (GISTs): procedural approach for diagnostic purposes. AB - BACKGROUND: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract characterized, in the majority of cases, by activating mutations in the KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) or PDGFRA (platelet-derived growth factor receptor, alpha polypeptide) genes. Mutations affecting these tyrosine kinase receptors are also responsible for the mechanisms of primary and secondary drug resistance during the treatment with tyrosine kinase inhibitors. We performed mutational analysis to evaluate the pharmacotherapy susceptibility of GISTs, adopting a comprehensive procedural approach, in order to optimize the identification of mutations that may result in cellular resistance to conventional therapy. MATERIALS AND METHODS: DNA from paraffin-embedded tumor sections from 40 GISTs were analyzed using microdissection, direct sequencing analysis and allelic separation by cloning. RESULTS: KIT mutations were found in 55.0% of the tumor samples. PDGFRA mutations were present in 5.0% of cases. Allelic cloning assay allowed for better definition of the extent of the mutations and clarification of the exact nucleotidic position of complex mutations. CONCLUSION: Our experience suggests that sequential microdissection, direct sequencing and allelic separation by PCR cloning of large variants may improve the approach to mutational analysis and interpretation of sequence data of KIT and PDGFRA in patients with GIST. PMID- 23741028 TI - Proteomic analysis of normal murine brain parts. AB - Murine brain is an excellent tool for studying protein expression and brain function in mammals. Although mice are an extensively used model to recapitulate various pathological conditions, the proteome of the normal mouse brain has not been yet reported. In the present study, we identified the total proteins of different parts of the brain of CB7BL/6 mice, a widely used strain, by applying proteomic methodologies. The adult mouse brain was dissected anatomically into the following regions: frontal cortex, olfactory bulb, hippocampus, midbrain, cerebellum, hypothalamus and medulla. Total protein extracts of these regions were separated by two-dimensional gel electrophoresis and analyzed by matrix assisted laser desorption ionisation time-of-flight mass spectrometry, following in-gel digestion with trypsin. Protein identification was carried out by peptide mass fingerprint. Thus, 515 different single-gene products were identified in total, 54 expressed specifically in the olfactory bulb, 62 in the hippocampus, 36 in the frontal cortex, five in the cerebellum, nine in the midbrain, eight in the hypothamamus and 10 in the medulla. The majority of the proteins were enzymes, structural proteins and transporters. Moreover, the distribution of these molecules appears to exhibit direct correlation with the function of the brain regions where they were expressed. This study leads to the complete characterization of the normal mouse brain proteome as well as the protein expression profile of the different brain regions. These results will aid in addressing unmet scientific needs regarding physiological and pathological brain functions. PMID- 23741029 TI - Axial T1 weighted magnetic resonance imaging of the female pelvis. PMID- 23741030 TI - Trade secrets: will an EU-US treaty enable US big business to gain a foothold? PMID- 23741031 TI - Arsenic: the largest mass poisoning of a population in history. PMID- 23741032 TI - The government's drug pricing policy is falling apart messily. PMID- 23741033 TI - Study links drugs for Alzheimer's disease with reduced risk of heart attack and death. PMID- 23741034 TI - General practice is just as pressured as emergency departments, MPs hear. PMID- 23741035 TI - Turkish doctors accuse police of deliberately injuring protesters. PMID- 23741036 TI - Evidence for a role of Nav1.6 in facilitating increases in neuronal hyperexcitability during epileptogenesis. AB - During epileptogenesis a series of molecular and cellular events occur, culminating in an increase in neuronal excitability, leading to seizure initiation. The entorhinal cortex has been implicated in the generation of epileptic seizures in both humans and animal models of temporal lobe epilepsy. This hyperexcitability is due, in part, to proexcitatory changes in ion channel activity. Sodium channels play an important role in controlling neuronal excitability, and alterations in their activity could facilitate seizure initiation. We sought to investigate whether medial entorhinal cortex (mEC) layer II neurons become hyperexcitable and display proexcitatory behavior of Na channels during epileptogenesis. Experiments were conducted 7 days after electrical induction of status epilepticus (SE), a time point during the latent period of epileptogenesis and before the onset of seizures. mEC layer II stellate neurons from post-SE animals were hyperexcitable, eliciting action potentials at higher frequencies compared with control neurons. Na channel currents recorded from post-SE neurons revealed increases in Na current amplitudes, particularly persistent and resurgent currents, as well as depolarized shifts in inactivation parameters. Immunocytochemical studies revealed increases in voltage-gated Na (Nav) 1.6 isoform levels. The toxin 4,9-anhydro-tetrodotoxin, which has greater selectivity for Nav1.6 over other Na channel isoforms, suppressed neuronal hyperexcitability, reduced macroscopic Na currents, persistent and resurgent Na current densities, and abolished depolarized shifts in inactivation parameters in post-SE neurons. These studies support a potential role for Nav1.6 in facilitating the hyperexcitability of mEC layer II neurons during epileptogenesis. PMID- 23741037 TI - Experience-dependent overrepresentation of ultrasonic vocalization frequencies in the rat primary auditory cortex. AB - Cortical sensory representation is highly adaptive to the environment, and prevalent or behaviorally important stimuli are often overrepresented. One class of such stimuli is species-specific vocalizations. Rats vocalize in the ultrasonic range >30 kHz, but cortical representation of this frequency range has not been systematically examined. We recorded in vivo cortical electrophysiological responses to ultrasonic pure-tone pips, natural ultrasonic vocalizations, and pitch-shifted vocalizations to assess how rats represent this ethologically relevant frequency range. We find that nearly 40% of the primary auditory cortex (AI) represents an octave-wide band of ultrasonic vocalization frequencies (UVFs; 32-64 kHz) compared with <20% for other octave bands <32 kHz. These UVF neurons respond preferentially and reliably to ultrasonic vocalizations. The UVF overrepresentation matures in the cortex before it develops in the central nucleus of inferior colliculus, suggesting a cortical origin and corticofugal influences. Furthermore, the development of cortical UVF overrepresentation depends on early acoustic experience. These results indicate that natural sensory experience causes large-scale cortical map reorganization and improves representations of species-specific vocalizations. PMID- 23741038 TI - A locomotor adaptation including explicit knowledge and removal of postadaptation errors induces complete 24-hour retention. AB - Locomotor patterns are generally very consistent but also contain a high degree of adaptability. Motor adaptation is a short-term type of learning that utilizes this plasticity to alter locomotor behaviors quickly and transiently. In this study, we used a variation of an adaptation paradigm in order to test whether explicit information as well as the removal of the visual error signal after adaptation could improve retention of a newly learned walking pattern 24 h later. On two consecutive days of testing, participants walked on a treadmill while viewing a visual display that showed erroneous feedback of swing times for each leg. Participants were instructed to use this feedback to monitor and adjust swing times so they appeared symmetric within the display. This was achieved by producing a novel interlimb asymmetry between legs. For both legs, we measured adaptation magnitudes and rates and immediate and 24-h retention magnitudes. Participants showed similar adaptation on both days but a faster rate of readaptation on day 2. There was complete retention of adapted swing times on the increasing leg (i.e., no evidence of performance decay over 24 h). Overall, these findings suggest that the inclusion of explicit information and the removal of the visual error signal are effective in inducing full retention of adapted increases in swing time over a moderate (24 h) interval of time. PMID- 23741039 TI - A neurophysiological basis for the coordination between hand and foot movement. AB - Hand and foot movements are made more reliably when both limbs move in the same direction at the same time (isodirectional) compared with when they are made in opposite directions (anisodirectional). We hypothesized that M1 intracortical facilitation may subserve hand-foot coordination and reveal correlates that explain the preference for hand-foot movements to be performed in an isodirectional pattern. To test our hypothesis we investigated behavioral kinematics of hand-foot coordination (experiment 1) and neurophysiological measures of corticomotor excitability and intracortical facilitation (experiment 2) in 17 healthy young adults. As expected, coordination became unstable in the anisodirectional pattern but not the isodirectional pattern, as confirmed in measures of wrist and ankle relative phase error and stability (both P < 0.001). Short-latency paired-pulse TMS was used to elicit motor evoked potentials (MEPs) and produce short-latency intracortical facilitation (sICF) in right extensor carpi radialis (ECR) and flexor carpi radialis (FCR) in the presence and absence of right ankle plantarflexion/dorsiflexion (P < 0.015). An isodirectional preference was confirmed by facilitation of FCR MEPs and TMS-induced wrist flexion during ankle plantarflexion (both P < 0.025) but no evidence of modulation of any particular "I wave" during foot movement compared with rest. A novel finding was the association between loss of stability of the anisodirectional pattern (experiment 1) and the modulation of corticomotor excitability in support of the isodirectional pattern (experiment 2) (P < 0.05). The preference for isodirectional hand-foot movements appears not to depend on M1 intracortical facilitation. PMID- 23741041 TI - Bilateral transient changes in thalamic nucleus ventroposterior lateralis after thoracic hemisection in the rat. AB - We made simultaneous bilateral recordings of unit activity in the nucleus ventroposterior lateralis (VPL) in intact rats and after acute and chronic left thoracic hemisection. We observed an immediate bilateral decline in multireceptive units, reflecting a loss of nociceptive input on the lesion side and a loss of low-threshold inputs contralaterally. Unit properties were restored to normal by 6 wk. Mean spontaneous discharge frequency remained unchanged in left VPL at all intervals. Right VPL displayed a substantial increase in spontaneous discharge frequency at 2 and 4 wk, returning to normal by 6 wk. Activity in left VPL driven by Pinch or Brush of the right limb was unchanged except for an immediate decrease in the response to Pinch, which was reversed by 2 wk despite persistent left hemisection. In right VPL, the response to Pinch or Brush of the left hindlimb was enhanced at 2 and 4 wk but returned to normal by 6 wk. Behaviorally, the same rats displayed increased sensitivity to mechanical stimulation of the left hindlimb, but, unlike VPL activity, there was no significant behavioral recovery. Bursting cells were also observed bilaterally in VPL, but this did not match the restriction of scratches to the hindlimb contralateral to the hemisection considered to be evidence for neuropathic pain. The novel findings include recovery of responsiveness to Pinch on the side ipsilateral to the hemisection despite the lack of spinothalamic input as well as failure for the thalamus contralateral to hemisection to maintain its elevated responsiveness. PMID- 23741042 TI - Pre- and postsynaptic mechanisms underlying inhibition of hypoglossal motor neuron excitability by riluzole. AB - Riluzole is the sole treatment for amyotrophic lateral sclerosis (ALS), but its therapeutically relevant actions on motor neurons are not well defined. Whole cell patch-clamp recordings were made from hypoglossal motor neurons (HMs, n = 25) in brain stem slices from 10- to 23-day-old rats anesthetized with pentobarbital sodium to investigate the hypothesis that riluzole inhibits HMs by multiple mechanisms. Riluzole (20 MUM) hyperpolarized HMs by decreasing an inward current, inhibited voltage-gated persistent Na(+) and Ca(2+) currents activated by slow voltage ramps, and negatively shifted activation of the hyperpolarization activated cationic current (IH). Repetitive firing of HMs was strongly inhibited by riluzole, which also increased action potential threshold voltage and rheobase and decreased amplitude and maximum rise slope but did not alter the maximal afterhyperpolarization amplitude or decay time constant. HM rheobase was inversely correlated with persistent Na(+) current density. Glutamatergic synaptic transmission was inhibited by riluzole by both pre- and postsynaptic effects. Riluzole decreased activity-dependent glutamate release, as shown by decreased amplitude of evoked and spontaneous excitatory postsynaptic currents (EPSCs), decreased paired-pulse ratio, and decreased spontaneous, but not miniature, EPSC frequency. However, riluzole also decreased miniature EPSC amplitude and the inward current evoked by local application of glutamate onto HMs, suggesting a reduction of postsynaptic glutamate receptor sensitivity. Riluzole thus has a marked inhibitory effect on HM activity by membrane hyperpolarization, decreasing firing and inhibiting glutamatergic excitation by both pre- and postsynaptic mechanisms. These results broaden the range of mechanisms controlling motor neuron inhibition by riluzole and are relevant to researchers and clinicians interested in understanding ALS pathogenesis and treatment. PMID- 23741040 TI - Many hats: intratrial and reward level-dependent BOLD activity in the striatum and premotor cortex. AB - Human functional magnetic resonance imaging (fMRI) studies, as well as lesion, drug, and single-cell recording studies in animals, suggest that the striatum plays a key role in associating sensory events with rewarding actions, both by facilitating reward processing and prediction (i.e., reinforcement learning) and by biasing and later updating action selection. Previous human neuroimaging research has failed to dissociate striatal activity associated with reward, stimulus, and response processing, and previous electrophysiological research in nonhuman animals has typically only examined single striatal subregions. Overcoming both these limitations, we isolated blood oxygen level-dependent (BOLD) signal associated with four intratrial processes (stimulus, preparation of response, response, and feedback) in a visuomotor learning task and examined activity associated with each within four striatal subregions (ventral striatum, putamen, head of the caudate nucleus, and body of the caudate) and the lateral premotor cortex. Overall, the striatum and lateral premotor cortex were recruited during all trial components, confirming their importance in all aspects of visuomotor learning. However, the caudate was most active at stimulus and feedback, whereas the putamen peaked in activity at response. Activation in the lateral premotor cortex was, surprisingly, strongest during stimulus and following response as feedback approached. Activity was additionally examined at three reward magnitudes. Reward magnitude affected neural activity only during stimulus in the caudate, putamen, and premotor cortex, whereas the ventral striatum showed reward sensitivity during both stimulus and feedback. Collectively, these results indicate that each striatal region makes a unique contribution to visuomotor learning through functions performed at different points within single trials. PMID- 23741043 TI - Vasoactive intestinal peptide produces long-lasting changes in neural activity in the suprachiasmatic nucleus. AB - The neuropeptide vasoactive intestinal peptide (VIP) is expressed at high levels in the neurons of the suprachiasmatic nucleus (SCN). While VIP is known to be important to the input and output pathways from the SCN, the physiological effects of VIP on electrical activity of SCN neurons are not well known. Here the impact of VIP on firing rate of SCN neurons was investigated in mouse slice cultures recorded during the night. The application of VIP produced an increase in electrical activity in SCN slices that lasted several hours after treatment. This is a novel mechanism by which this peptide can produce long-term changes in central nervous system physiology. The increase in action potential frequency was blocked by a VIP receptor antagonist and lost in a VIP receptor knockout mouse. In addition, inhibitors of both the Epac family of cAMP binding proteins and cAMP dependent protein kinase (PKA) blocked the induction by VIP. The persistent increase in spike rate following VIP application was not seen in SCN neurons from mice deficient in Kv3 channel proteins and was dependent on the clock protein PER1. These findings suggest that VIP regulates the long-term firing rate of SCN neurons through a VIPR2-mediated increase in the cAMP pathway and implicate the fast delayed rectifier (FDR) potassium currents as one of the targets of this regulation. PMID- 23741044 TI - Effective intracortical microstimulation parameters applied to primary motor cortex for evoking forelimb movements to stable spatial end points. AB - High-frequency, long-duration intracortical microstimulation (HFLD-ICMS) applied to motor cortex is recognized as a useful and informative method for corticomotor mapping by evoking natural-appearing movements of the limb to consistent stable end-point positions. An important feature of these movements is that stimulation of a specific site in motor cortex evokes movement to the same spatial end point regardless of the starting position of the limb. The goal of this study was to delineate effective stimulus parameters for evoking forelimb movements to stable spatial end points from HFLD-ICMS applied to primary motor cortex (M1) in awake monkeys. We investigated stimulation of M1 as combinations of frequency (30-400 Hz), amplitude (30-200 MUA), and duration (0.5-2 s) while concurrently recording electromyographic (EMG) activity from 24 forelimb muscles and movement kinematics with a motion capture system. Our results suggest a range of parameters (80-140 Hz, 80-140 MUA, and 1,000-ms train duration) that are effective and safe for evoking forelimb translocation with subsequent stabilization at a spatial end point. The mean time for stimulation to elicit successful movement of the forelimb to a stable spatial end point was 475.8 +/- 170.9 ms. Median successful frequency and amplitude were 110 Hz and 110 MUA, respectively. Attenuated parameters resulted in inconsistent, truncated, or undetectable movements, while intensified parameters yielded no change to movement end points and increased potential for large-scale physiological spread and adverse focal motor effects. Establishing cortical stimulation parameters yielding consistent forelimb movements to stable spatial end points forms the basis for a systematic and comprehensive mapping of M1 in terms of evoked movements and associated muscle synergies. Additionally, the results increase our understanding of how the central nervous system may encode movement. PMID- 23741045 TI - Physiological and anatomical properties of intramedullary projection neurons in rat rostral nucleus of the solitary tract. AB - The rostral nucleus of the solitary tract (rNTS), the first-order relay of gustatory information, not only transmits sensory information to more rostral brain areas but also connects to various brain stem sites responsible for orofacial reflex activities. While much is known regarding ascending projections to the parabrachial nucleus, intramedullary projections to the reticular formation (which regulate oromotor reflexive behaviors) remain relatively unstudied. The present study examined the intrinsic firing properties of these neurons as well as their morphological properties and synaptic connectivity with primary sensory afferents. Using in vitro whole cell patch-clamp recording, we found that intramedullary projection neurons respond to depolarizing current injection with either tonic or bursting action potential trains and subsets of these groups of neurons express A-type potassium, H-like, and postinhibitory rebound currents. Approximately half of the intramedullary projection neurons tested received monosynaptic innervation from primary afferents, while the rest received polysynaptic innervation, indicating that at least a subpopulation of these neurons can be directly activated by incoming sensory information. Neuron morphological reconstructions revealed that many of these neurons possessed numerous dendritic spines and that neurons receiving monosynaptic primary afferent input have a greater spine density than those receiving polysynaptic primary afferent input. These results reveal that intramedullary projection neurons represent a heterogeneous class of rNTS neurons and, through both intrinsic voltage-gated ion channels and local circuit interactions, transform incoming gustatory information into signals governing oromotor reflexive behaviors. PMID- 23741046 TI - Skill learning involves optimizing the linking of action phases. AB - Many manual tasks involve object manipulation and are achieved by an evolving series of actions, or action phases, recruited to achieve task subgoals. The ability to effectively link action phases is an important component of manual dexterity. However, our understanding of how the effective linking of sequential action phases develops with skill learning is limited. Here, we addressed this issue using a task in which participants applied forces to a handle to move a cursor on a computer screen to successively acquire visual targets. Target acquisition required actively holding the cursor within the target zone (hold phase) for a required duration before moving to the next target (transport phase). If the transport phase was initiated prematurely, before the end of the required hold duration, participants had to return to the target to acquire it. The goal was to acquire targets as quickly as possible. Distinct visual and auditory sensory events marked goal completion of each action phase. During initial task performance, the transport phase was reactively triggered by sensory events signaling hold phase completion. However, with practice, participants learned to initiate the transport phase based on a prediction of the time of hold phase completion. Simulations revealed that participants learned to near optimally compensate for temporal uncertainty, presumably related to estimation of time intervals and execution of motor commands, so as to reduce the average latency between the end of the required hold phase duration and the start of the transport phase, while avoiding an excess of premature exits. PMID- 23741047 TI - Competition driven by retinal waves promotes morphological and functional synaptic development of neurons in the superior colliculus. AB - Prior to eye opening, waves of spontaneous activity sweep across the developing retina. These "retinal waves," together with genetically encoded molecular mechanisms, mediate the formation of visual maps in the brain. However, the specific role of wave activity in synapse development in retino-recipient brain regions is unclear. Here we compare the functional development of synapses and the morphological development of neurons in the superior colliculus (SC) of wild type (WT) and transgenic (beta2-TG) mice in which retinal wave propagation is spatially truncated (Xu HP, Furman M, Mineur YS, Chen H, King SL, Zenisek D, Zhou ZJ, Butts DA, Tian N, Picciotto MR, Crair MC. Neuron 70: 1115-1127, 2011). We use two recently developed brain slice preparations to examine neurons and synapses in the binocular vs. mainly monocular SC. We find that retinocollicular synaptic strength is reduced whereas the number of retinal inputs is increased in the binocular SC of beta2-TG mice compared with WT mice. In contrast, in the mainly monocular SC the number of retinal inputs is normal in beta2-TG mice, but, transiently, synapses are abnormally strong, possibly because of enhanced activity-dependent competition between local, "small" retinal wave domains. These findings demonstrate that retinal wave size plays an instructive role in the synaptic and morphological development of SC neurons, possibly through a competitive process among retinofugal axons. PMID- 23741048 TI - Simultaneous determination of 11 major components in Palmul-tang by HPLC-DAD and LC-MS-MS. AB - Palmul-tang, a traditional herbal medicine, is composed of eight herbs (Ginseng radix, Glycyrrhizae radix, Hoelen, Atractylodis rhizoma, Angelicae gigantis radix, Cnidii rhizoma, Paeoniae radix and Rehmanniae radix) and exhibits various bioactivities, including antiallergic and antitumor effects. In this study, an effective, reliable and accurate high-performance liquid chromatography method has been developed for the simultaneous determination of 11 marker components in Palmul-tang: hydroxymethylfurfural, albiflorin, paeoniflorin, ferulic acid, nodakenin, ginsenoside Rg1, decursinol, glycyrrhizin, 6-gingerol, ginsenoside Rg3 and decursin. All calibration curves of the 11 components indicated excellent linearity (correlation coefficient > 0.9997) within the test range. The limits of detection and quantification of each component were in the ranges of 0.08-1.03 and 0.23-3.11 ug/mL, respectively. The intra-day and inter-day relative standard deviation values were within 1.65 and 2.71%, respectively. The mean recovery values were 94.49 to 101.10%. The established method was successfully applied to the simultaneous determination of 11 major components in 12 commercial samples of Palmul-tang. The developed analytical method is simple and suitable for the quality control of Palmul-tang. PMID- 23741049 TI - Sorting of GLUT4 into its insulin-sensitive store requires the Sec1/Munc18 protein mVps45. AB - Insulin stimulates glucose transport in fat and muscle cells by regulating delivery of the facilitative glucose transporter, glucose transporter isoform 4 (GLUT4), to the plasma membrane. In the absence of insulin, GLUT4 is sequestered away from the general recycling endosomal pathway into specialized vesicles, referred to as GLUT4-storage vesicles. Understanding the sorting of GLUT4 into this store is a major challenge. Here we examine the role of the Sec1/Munc18 protein mVps45 in GLUT4 trafficking. We show that mVps45 is up-regulated upon differentiation of 3T3-L1 fibroblasts into adipocytes and is expressed at stoichiometric levels with its cognate target-soluble N-ethylmaleimide-sensitive factor attachment protein receptor, syntaxin 16. Depletion of mVps45 in 3T3-L1 adipocytes results in decreased GLUT4 levels and impaired insulin-stimulated glucose transport. Using sub-cellular fractionation and an in vitro assay for GLUT4-storage vesicle formation, we show that mVps45 is required to correctly traffic GLUT4 into this compartment. Collectively our data reveal a crucial role for mVps45 in the delivery of GLUT4 into its specialized, insulin-regulated compartment. PMID- 23741050 TI - Multivalent immune complexes divert FcRn to lysosomes by exclusion from recycling sorting tubules. AB - The neonatal receptor for immunoglobulin G (IgG; FcRn) prevents IgG degradation by efficiently sorting IgG into recycling endosomes and away from lysosomes. When bound to IgG-opsonized antigen complexes, however, FcRn traffics cargo into lysosomes, where antigen processing can occur. Here we address the mechanism of sorting when FcRn is bound to multivalent IgG-opsonized antigens. We find that only the unbound receptor or FcRn bound to monomeric IgG is sorted into recycling tubules emerging from early endosomes. Cross-linked FcRn is never visualized in tubules containing the unbound receptor. Similar results are found for transferrin receptor, suggesting a general mechanism of action. Deletion or replacement of the FcRn cytoplasmic tail does not prevent diversion of trafficking to lysosomes upon cross-linking. Thus physical properties of the lumenal ligand-receptor complex appear to act as key determinants for sorting between the recycling and lysosomal pathways by regulating FcRn entry into recycling tubules. PMID- 23741051 TI - Hsp90 cochaperones p23 and FKBP4 physically interact with hAgo2 and activate RNA interference-mediated silencing in mammalian cells. AB - Argonaute proteins and small RNAs together form the RNA-induced silencing complex (RISC), the central effector of RNA interference (RNAi). The molecular chaperone Hsp90 is required for the critical step of loading small RNAs onto Argonaute proteins. Here we show that the Hsp90 cochaperones Cdc37, Aha1, FKBP4, and p23 are required for efficient RNAi. Whereas FKBP4 and p23 form a stable complex with hAgo2, the function of Cdc37 in RNAi appears to be indirect and may indicate that two or more Hsp90 complexes are involved. Our data also suggest that p23 and FKBP4 interact with hAgo2 before small RNA loading and that RISC loading takes place in the cytoplasm rather than in association with RNA granules. Given the requirement for p23 and FKBP4 for efficient RNAi and that these cochaperones bind to hAgo2, we predict that loading of hAgo2 is analogous to Hsp90-mediated steroid hormone receptor activation. To this end, we outline a model in which FKBP4, p23, and Aha1 cooperatively regulate the progression of hAgo2 through the chaperone cycle. Finally, we propose that hAgo2 and RNAi can serve as a robust model system for continued investigation into the Hsp90 chaperone cycle. PMID- 23741052 TI - Local, cell-nonautonomous feedback regulation of myosin dynamics patterns transitions in cell behavior: a role for tension and geometry? AB - How robust patterns of tissue dynamics emerge from heterogeneities, stochasticities, and asynchronies in cell behavior is an outstanding question in morphogenesis. A clear understanding of this requires examining the influence of the behavior of single cells on tissue patterning. Here we develop single-cell manipulation strategies to uncover the origin of patterned cell behavior in the amnioserosa during Drosophila dorsal closure. We show that the formation and dissolution of contractile, medial actomyosin networks previously shown to underlie pulsed apical constrictions in the amnioserosa are apparently asynchronous in adjacent cells. We demonstrate for the first time that mechanical stresses and Rho1 GTPase control myosin dynamics qualitatively and quantitatively, in amplitude and direction, both cell autonomously and nonautonomously. We then demonstrate that interfering with myosin-dependent contractility in single cells also influences pulsed constrictions cell nonautonomously. Our results suggest that signals and stresses can feedback regulate the amplitude and spatial propagation of pulsed constrictions through their influence on tension and geometry. We establish the relevance of these findings to native closure by showing that cell delamination represents a locally patterned and collective transition from pulsed to unpulsed constriction that also relies on the nonautonomous feedback control of myosin dynamics. PMID- 23741053 TI - Influence of pacing site characteristics on response to cardiac resynchronization therapy. AB - BACKGROUND: Transmural scar occupying left ventricular (LV) pacing regions has been associated with reduced response to cardiac resynchronization therapy (CRT). However, spatial influences of lead tip delivery relative to scar at both pacing sites remain poorly explored. This study evaluated scar distribution relative to LV and right ventricular (RV) lead tip placement through coregistration of late gadolinium enhancement MRI and cardiac computed tomographic (CT) findings. Influences on CRT response were assessed by serial echocardiography. METHODS AND RESULTS: Sixty patients receiving CRT underwent preimplant late gadolinium enhancement MRI, postimplant cardiac CT, and serial echocardiography. Blinded segmental evaluations of mechanical delay, percentage scar burden, and lead tip location were performed. Response to CRT was defined as a reduction in LV end systolic volume >=15% at 6 months. The mean age and LV ejection fraction were 64+/-9 years and 25+/-7%, respectively. Mean scar volume was higher among CRT nonresponders for both the LV (23+/-23% versus 8+/-14% [P=0.01]) and RV pacing regions (40+/-32% versus 24+/-30% [P=0.04]). Significant pacing region scar was identified in 13% of LV pacing regions and 37% of RV pacing regions. Absence of scar in both regions was associated with an 81% response rate compared with 55%, 25%, and 0%, respectively, when the RV, LV, or both pacing regions contained scar. LV pacing region dyssynchrony was not predictive of response. CONCLUSIONS: Myocardial scar occupying the LV pacing region is associated with nonresponse to CRT. Scar occupying the RV pacing region is encountered at higher frequency and seems to provide a more intermediate influence on CRT response. PMID- 23741054 TI - Contrasting patterns of evolution of 45S and 5S rDNA families uncover new aspects in the genome constitution of the agronomically important grass Thinopyrum intermedium (Triticeae). AB - We employed sequencing of clones and in situ hybridization (genomic and fluorescent in situ hybridization [GISH and rDNA-FISH]) to characterize both the sequence variation and genomic organization of 45S (herein ITS1-5.8S-ITS2 region) and 5S (5S gene + nontranscribed spacer) ribosomal DNA (rDNA) families in the allohexaploid grass Thinopyrum intermedium. Both rDNA families are organized within several rDNA loci within all three subgenomes of the allohexaploid species. Both families have undergone different patterns of evolution. The 45S rDNA family has evolved in a concerted manner: internal transcribed spacer (ITS) sequences residing within the arrays of two subgenomes out of three got homogenized toward one major ribotype, whereas the third subgenome contained a minor proportion of distinct unhomogenized copies. Homogenization mechanisms such as unequal crossover and/or gene conversion were coupled with the loss of certain 45S rDNA loci. Unlike in the 45S family, the data suggest that neither interlocus homogenization among homeologous chromosomes nor locus loss occurred in 5S rDNA. Consistently with other Triticeae, the 5S rDNA family in intermediate wheatgrass comprised two distinct array types-the long- and short-spacer unit classes. Within the long and short units, we distinguished five and three different types, respectively, likely representing homeologous unit classes donated by putative parental species. Although the major ITS ribotype corresponds in our phylogenetic analysis to the E-genome species, the minor ribotype corresponds to Dasypyrum. 5S sequences suggested the contributions from Pseudoroegneria, Dasypyrum, and Aegilops. The contribution from Aegilops to the intermediate wheatgrass' genome is a new finding with implications in wheat improvement. We discuss rDNA evolution and potential origin of intermediate wheatgrass. PMID- 23741055 TI - Putting the vascular back into cardiovascular research: ST-segment-elevation myocardial infarction as a blueprint for improving care in patients with acute limb ischemia. PMID- 23741056 TI - Twenty-year analysis of trends in the incidence and in-hospital mortality for lower-extremity arterial thromboembolism. AB - BACKGROUND: Epidemiology data for lower-extremity arterial thromboembolism (LET) are limited and may result from either acute limb ischemia or an acute exacerbation of critical limb ischemia. Given marked changes in both diagnosis and therapy over the last 2 decades, we hypothesized that this time period would have witnessed reductions in both the incidence and in-hospital mortality of LET. METHODS AND RESULTS: Data from 1988 through 2007 from the National Hospital Discharge Survey were analyzed. All admissions for patients with LET were extracted, and the respective International Classification of Diseases, Ninth Revision, Clinical Modification codes were internally validated for both LET and acute limb ischemia. Descriptive statistics were used. The validity of the codes was good for identifying LET cases but poor for identifying acute limb ischemia cases because many of these acute presentations were attributable to critical limb ischemia. Over the 20-year span, there were 1.76 million cases of LET. The incidence of LET decreased significantly from 42.4 per 100 000 persons between 1988 and 1997 to 23.3 per 100 000 persons between 1998 and 2007. The in-hospital mortality for LET decreased significantly from 8.28% between 1988 and 1997 to 6.34% between 1998 and 2007, and male patients achieved greater mortality reduction compared with female patients. Treatments for acute limb ischemia showed decreasing use of surgical bypass and amputation and increasing rates of catheter-based thrombolysis. CONCLUSIONS: Over the 20-year study period, there have been significant reductions in both LET incidence and in-hospital mortality. Unfortunately, LET admissions extracted from an administrative database comprise a diverse group of individuals, including those with acute and chronic forms of limb ischemia and iatrogenic arterial injury, limiting the true assessment of ALI incidence. PMID- 23741057 TI - 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. PMID- 23741058 TI - 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. PMID- 23741060 TI - Energy management by enhanced glycolysis in G1-phase in human colon cancer cells in vitro and in vivo. AB - Activation of aerobic glycolysis in cancer cells is well known as the Warburg effect, although its relation to cell- cycle progression remains unknown. In this study, human colon cancer cells were labeled with a cell-cycle phase-dependent fluorescent marker Fucci to distinguish cells in G1-phase and those in S + G2/M phases. Fucci-labeled cells served as splenic xenograft transplants in super immunodeficient NOG mice and exhibited multiple metastases in the livers, frozen sections of which were analyzed by semiquantitative microscopic imaging mass spectrometry. Results showed that cells in G1-phase exhibited higher concentrations of ATP, NADH, and UDP-N-acetylglucosamine than those in S and G2-M phases, suggesting accelerated glycolysis in G1-phase cells in vivo. Quantitative determination of metabolites in cells synchronized in S, G2-M, and G1 phases suggested that efflux of lactate was elevated significantly in G1-phase. By contrast, ATP production in G2-M was highly dependent on mitochondrial respiration, whereas cells in S-phase mostly exhibited an intermediary energy metabolism between G1 and G2-M phases. Isogenic cells carrying a p53-null mutation appeared more active in glycolysis throughout the cell cycle than wild type cells. Thus, as the cell cycle progressed from G2-M to G1 phases, the dependency of energy production on glycolysis was increased while the mitochondrial energy production was reciprocally decreased. IMPLICATIONS: These results shed light on distinct features of the phase-specific phenotypes of metabolic systems in cancer cells. PMID- 23741059 TI - Epithelial-specific deletion of 11beta-HSD2 hinders Apcmin/+ mouse tumorigenesis. AB - Cyclooxygenase-2 (COX-2)-derived prostaglandin E2 (PGE2) promotes colorectal tumorigenesis. Glucocorticoids are endogenous and potent COX-2 inhibitors, and their local actions are downregulated by 11beta-hydroxysteroid dehydrogenase type II (11beta-HSD2)-mediated metabolism. Previously, it was reported that 11beta HSD2 is increased in human colonic and Apc(min/+) mouse intestinal adenomas and correlated with increased COX-2, and 11beta-HSD2 inhibition suppressed the COX-2 pathway and decreased tumorigenesis. Because 11beta-HSD2 is expressed in Apc(min/+) mouse intestinal adenoma stromal and epithelial cells, Apc(min/+) mice were generated with selective deletion of 11beta-HSD2 in intestinal epithelial cells (Vil-Cre-HSD2(-/-) Apc(min/+)). Deletion of 11beta-HSD2 in intestinal epithelia led to marked inhibition of Apc(min/+) mouse intestinal tumorigenesis. Immunostaining indicated decreased 11beta-HSD2 and COX-2 expression in adenoma epithelia, whereas stromal COX-2 expression was intact in Vil-Cre-HSD2(-/-) Apc(min/+) mice. In Vil-Cre-HSD2(-/-) Apc(min/+) mouse intestinal adenomas, both p53 and p21 mRNA and protein were increased, with a concomitant decrease in pRb, indicating glucocorticoid-mediated G1-arrest. Further study revealed that REDD1 (regulated in development and DNA damage responses 1), a novel stress-induced gene that inhibits mTOR signaling, was increased, whereas the mTOR signaling pathway was inhibited. Therefore, in Vil-Cre-HSD2(-/-) Apc(min/+) mice, epithelial cell 11beta-HSD2 deficiency leads to inhibition of adenoma initiation and growth by attenuation of COX-2 expression, increased cell-cycle arrest, and inhibition of mTOR signaling as a result of increased tumor intracellular active glucocorticoids. IMPLICATIONS: Inhibition of 11beta-HSD2 may represent a novel approach for colorectal cancer chemoprevention by increasing tumor glucocorticoid activity, which in turn inhibits tumor growth by multiple pathways. PMID- 23741061 TI - Metformin blocks melanoma invasion and metastasis development in AMPK/p53 dependent manner. AB - Metformin was reported to inhibit the proliferation of many cancer cells, including melanoma cells. In this report, we investigated the effect of metformin on melanoma invasion and metastasis development. Using different in vitro approaches, we found that metformin inhibits cell invasion without affecting cell migration and independently of antiproliferation action. This inhibition is correlated with modulation of expression of proteins involved in epithelial mesenchymal transition such as Slug, Snail, SPARC, fibronectin, and N-cadherin and with inhibition of MMP-2 and MMP-9 activation. Furthermore, our data indicate that this process is dependent on activation of AMPK and tumor suppressor protein p53. Finally, we showed that metformin inhibits melanoma metastasis development in mice using extravasation and metastasis models. The presented data reinforce the fact that metformin might be a good candidate for clinical trial in melanoma treatment. PMID- 23741062 TI - Telling sperm to sort themselves out. PMID- 23741063 TI - LlSR28 is involved in pollen germination by affecting filamentous actin dynamics. AB - Alternative splicing plays important roles in gene regulation and contributes to protein complexity. Previous studies suggest that alternative splicing exists in members of the villin/gelsolin/fragmin superfamily. In this study, a serine/argine-rich (SR) protein cDNA with 28 kDa protein (LlSR28) was isolated from a lily (Lilium longiflorum) expression library. Protein domain analysis showed that LlSR28 had similar structures to Arabidopsis SR45 (AtSR45), and LlSR28 could complement the phenotype of loss of AtSR45 function. Therefore, overexpression of LlSR28 and AtSR45 mutant (atsr45-1) were used in the following experiments. Overexpression of LlSR28 in Arabidopsis completely inhibited pollen germination. In contrast, the pollen germination of atsr45-1 was earlier than that of wild-type. In addition, pollen of atsr45-1 contained less F-actin at the corresponding hydration stage during pollen germination compared to that of wild type. Alternative splicing analysis showed that Arabidopsis villin1 (AtVLN1) transcript encoding the full-length protein was increased, and that encoding the truncated protein was decreased in atst45-1. Moreover, the mRNA expression level of other actin-binding proteins (ABPs) abundant in Arabidopsis pollen was also changed in atsr45-1. In conclusion, we hypothesize that LlSR28 alters F-actin dynamics probably through its alternative splicing activities to affect directly or indirectly the alternative splicing of AtVLN1 and the expression of different ABPs, which then affects the pollen germination. PMID- 23741065 TI - Is conflict of interest becoming a challenge for institution-based institutional review boards? AB - Expansion of business relationships between academic institutions and their leaders and industry have become a reality, whereas media attention regarding conflict of interest (COI) at academic institutions has raised concerns about possible erosion of public trust. The Institutional Review Board (IRB) should collaborate with institutional COI committees to ensure that research with human subjects is in compliance with various applicable federal regulations. The IRB and COI committee should take additional independent action as necessary under their separate mandates to protect the welfare, safety, and rights of human subjects and to include limits on protocols affected by significant financial interests of the institution or its decision makers. If unable to review research due to an intrainstitutional conflict, the local IRB should consider transferring the study review and oversight to an external unaffiliated institutional or central IRB. A process for involvement of an executive institutional IRB is proposed. PMID- 23741064 TI - The calcineurin B-like Ca2+ sensors CBL1 and CBL9 function in pollen germination and pollen tube growth in Arabidopsis. AB - Ca(2+) has been established as an important second messenger regulating pollen germination and tube growth. However, to date, only a few signaling components have been identified to decode and relay Ca(2+) signals in growing pollen tubes. Here, we report a function for the calcineurin B-like (CBL) Ca(2+) sensor proteins CBL1 and CBL9 from Arabidopsis in pollen germination and tube growth. Both proteins are expressed in mature pollen and pollen tubes and impair pollen tube growth and morphology if transiently overexpressed in tobacco pollen. The induction of these phenotypes requires efficient plasma membrane targeting of CBL1 and is independent of Ca(2+) binding to the fourth EF-hand of CBL1. Overexpression of CBL1 or its closest homolog CBL9 in Arabidopsis renders pollen germination and tube growth hypersensitive towards high external K(+) concentrations while disruption of CBL1 and CBL9 reduces pollen tube growth under low K(+) conditions. Together, our data identify a crucial function for CBL1 and CBL9 in pollen germination and tube growth and suggest a model in which both proteins act at the plasma membrane through regulation of K(+) homeostasis. PMID- 23741066 TI - A phase I study of quisinostat (JNJ-26481585), an oral hydroxamate histone deacetylase inhibitor with evidence of target modulation and antitumor activity, in patients with advanced solid tumors. AB - PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic and pharmacodynamic profile of quisinostat, a novel hydroxamate, pan-histone deacetylase inhibitor (HDACi). EXPERIMENTAL DESIGN: In this first-in-human phase I study, quisinostat was administered orally, once daily in three weekly cycles to patients with advanced malignancies, using a two stage accelerated titration design. Three intermittent schedules were subsequently explored: four days on/three days off; every Monday, Wednesday, Friday (MWF); and every Monday and Thursday (M-Th). Toxicity, pharmacokinetics, pharmacodynamics, and clinical efficacy were evaluated at each schedule. RESULTS: Ninety-two patients were treated in continuous daily (2-12 mg) and three intermittent dosing schedules (6-19 mg). Treatment-emergent adverse events included: fatigue, nausea, decreased appetite, lethargy, and vomiting. DLTs observed were predominantly cardiovascular, including nonsustained ventricular tachycardia, ST/T-wave abnormalities, and other tachyarhythmias. Noncardiac DLTs were fatigue and abnormal liver function tests. The maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of quisinostat increased proportionally with dose. Pharmacodynamic evaluation showed increased acetylated histone 3 in hair follicles, skin and tumor biopsies, and in peripheral blood mononuclear cells as well as decreased Ki67 in skin and tumor biopsies. A partial response lasting five months was seen in one patient with melanoma. Stable disease was seen in eight patients (duration 4-10.5 months). CONCLUSIONS: The adverse event profile of quisinostat was comparable with that of other HDACi. Intermittent schedules were better tolerated than continuous schedules. On the basis of tolerability, pharmacokinetic predictions, and pharmacodynamic effects, the recommended dose for phase II studies is 12 mg on the MWF schedule. PMID- 23741068 TI - Dual PI3K/mTOR inhibitors: does p53 modulate response? AB - Head and neck squamous cell carcinomas have multiple genetic alterations that can influence clinical response to treatment. It is important to evaluate how distinct alterations affect response to targeted agents to identify a subset of patients who can benefit from therapy, improving survival and decreasing toxicity. PMID- 23741067 TI - Somatic profiling of the epidermal growth factor receptor pathway in tumors from patients with advanced colorectal cancer treated with chemotherapy +/- cetuximab. AB - PURPOSE: To study the somatic molecular profile of the EGF receptor (EGFR) pathway in advanced colorectal cancer, its relationship to prognosis, the site of the primary and metastases, and response to cetuximab. EXPERIMENTAL DESIGN: We used Sequenom and Pyrosequencing for high-throughput somatic profiling of the EGFR pathway in 1,976 tumors from patients with advanced colorectal cancer from the COIN trial (oxaliplatin and fluoropyrimidine chemotherapy +/- cetuximab). Correlations between mutations, clinicopathologic, response, and survival data were carried out. RESULTS: Sequenom and Pyrosequencing had 99.0% (9,961/10,063) genotype concordance. We identified 13 different KRAS mutations in 42.3% of advanced colorectal cancers, 2 BRAF mutations in 9.0%, 4 NRAS mutations in 3.6%, and 5 PIK3CA mutations in 12.7%. 4.2% of advanced colorectal cancers had microsatellite instability (MSI). KRAS and PIK3CA exon 9, but not exon 20, mutations cooccurred (P = 8.9 * 10(-4)) as did MSI and BRAF mutations (P = 5.3 * 10(-10)). KRAS mutations were associated with right colon cancers (P = 5.2 * 10( 5)) and BRAF mutations with right (P = 7.2 * 10(-5)) and transverse colon (P = 9.8 * 10(-6)) cancers. KRAS mutations were associated with lung-only metastases (P = 2.3 * 10(-4)), BRAF mutations with peritoneal (P = 9.2 * 10(-4)) and nodal only (P = 3.7 * 10(-5)) metastases, and MSI (BRAF(WT)) with nodal-only metastases (P = 2.9 * 10(-4)). MSI (BRAF(WT)) was associated with worse survival (HR = 1.89, 95% CI 1.30-2.76, P = 8.5 * 10(-4)). No mutations, subsets of mutations, or MSI status were associated with response to cetuximab. CONCLUSIONS: Our data support a functional cooperation between KRAS and PIK3CA in colorectal tumorigenesis and link somatic profiles to the sites of metastases. MSI was associated with poor prognosis in advanced disease, and no individual somatic profile was associated with response to cetuximab in COIN. PMID- 23741069 TI - Targeting treatment-resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway. AB - PURPOSE: FK506-binding protein like (FKBPL) and its peptide derivative, AD-01, have already shown tumor growth inhibition and CD44-dependent antiangiogenic activity. Here, we explore the ability of AD-01 to target CD44-positive breast cancer stem cells (BCSC). EXPERIMENTAL DESIGN: Mammosphere assays and flow cytometry were used to analyze the effect of FKBPL overexpression/knockdown and AD-01 treatment +/- other anticancer agents on BCSCs using breast cancer cell lines (MCF-7/MDA-231/ZR-75), primary patient samples, and xenografts. Delays in tumor initiation were evaluated in vivo. The anti-stem cell mechanisms were determined using clonogenic assays, quantitative PCR (qPCR), and immunofluorescence. RESULTS: AD-01 treatment was highly effective at inhibiting the BCSC population by reducing mammosphere-forming efficiency and ESA(+)/CD44(+)/CD24(-) or aldehyde dehydrogenase (ALDH)(+) cell subpopulations in vitro and tumor initiation in vivo. The ability of AD-01 to inhibit the self renewal capacity of BCSCs was confirmed; mammospheres were completely eradicated by the third generation. The mechanism seems to be due to AD-01-mediated BCSC differentiation shown by a significant decrease in the number of holoclones and an associated increase in meroclones/paraclones; the stem cell markers, Nanog, Oct4, and Sox2, were also significantly reduced. Furthermore, we showed additive inhibitory effects when AD-01 was combined with the Notch inhibitor, DAPT. AD-01 was also able to abrogate a chemo- and radiotherapy-induced enrichment in BCSCs. Finally, FKBPL knockdown led to an increase in Nanog/Oct4/Sox2 and an increase in BCSCs, highlighting a role for endogenous FKBPL in stem cell signaling. CONCLUSIONS: AD-01 has dual antiangiogenic and anti-BCSC activity, which will be advantageous as this agent enters clinical trial. PMID- 23741070 TI - Exposure-response relationships of the efficacy and safety of ipilimumab in patients with advanced melanoma. AB - PURPOSE: This retrospective analysis was conducted to characterize ipilimumab exposure-response relationships for measures of efficacy and safety in patients with advanced melanoma. EXPERIMENTAL DESIGN: Data were pooled from 498 patients who received ipilimumab monotherapy at 0.3, 3, or 10 mg/kg in 1 of 4 completed phase II clinical trials. The relationships between steady-state ipilimumab trough concentration (Cminss), complete or partial tumor response (CR or PR), and safety [immune-related adverse events (irAEs)] were described by logistic regression models. The relationship between exposure and overall survival was characterized using a Cox proportional-hazards model. RESULTS: The steady-state trough concentration of ipilimumab was found to be a significant predictor of a CR or PR (P < 0.001). Model-based estimates indicate that the probabilities of a CR or PR at median Cminss for the 0.3, 3, and 10 mg/kg groups were 0.6%, 4.9%, and 11.6%, respectively. Overall survival at the median Cminss for ipilimumab at 0.3 mg/kg was estimated to be 0.85- and 0.58-fold lower relative to that at the median Cminss for 3 and 10 mg/kg, respectively. Model-based estimates indicate that the probabilities of a grade 3 or more irAE at the median Cminss for the 0.3, 3, and 10 mg/kg doses were 3%, 13%, and 24%, respectively. CONCLUSIONS: Higher doses of ipilimumab produce greater Cminss that may be associated with increased tumor responses, longer survival, and higher rates of irAEs. The efficacy and safety of ipilimumab at 3 versus 10 mg/kg in patients with advanced melanoma is being evaluated in an ongoing phase III trial. PMID- 23741073 TI - Writing an effective manuscript review: The 6 "Be's" to success. PMID- 23741072 TI - Glioma grade is associated with the accumulation and activity of cells bearing M2 monocyte markers. AB - PURPOSE: This study is directed at identifying the cell source(s) of immunomodulatory cytokines in high-grade gliomas and establishing whether the analysis of associated markers has implications for tumor grading. EXPERIMENTAL DESIGN: Glioma specimens classified as WHO grade II-IV by histopathology were assessed by gene expression analysis and immunohistochemistry to identify the cells producing interleukin (IL)-10, which was confirmed by flow cytometry and factor secretion in culture. Finally, principal component analysis (PCA) and mixture discriminant analysis (MDA) were used to investigate associations between expressed genes and glioma grade. RESULTS: The principle source of glioma associated IL-10 is a cell type that bears phenotype markers consistent with M2 monocytes but does not express all M2-associated genes. Measures of expression of the M2 cell markers CD14, CD68, CD163, and CD204, which are elevated in high grade gliomas, and the neutrophil/myeloid-derived suppressor cell (MDSC) subset marker CD15, which is reduced, provide the best index of glioma grade. CONCLUSIONS: Grade II and IV astrocytomas can be clearly differentiated on the basis of the expression of certain M2 markers in tumor tissues, whereas grade III astrocytomas exhibit a range of expression between the lower and higher grade specimens. The content of CD163(+) cells distinguishes grade III astrocytoma subsets with different prognosis. PMID- 23741071 TI - Putative predictive biomarkers of survival in patients with metastatic pancreatic adenocarcinoma treated with gemcitabine and ganitumab, an IGF1R inhibitor. AB - PURPOSE: This planned exploratory analysis assessed the predictive nature of baseline circulating factors of the insulin-like growth factor (IGF) axis on the treatment effect of ganitumab (monoclonal antibody inhibitor of IGF-1 receptor) plus gemcitabine in a randomized phase II study in metastatic pancreatic adenocarcinoma. EXPERIMENTAL DESIGN: Baseline levels of IGFs/IGF binding proteins (IGFBP) were analyzed in serum or plasma. Mutations and gene expression were analyzed in archival samples. Treatment effects between biomarker subgroups were compared for overall survival (OS). Associations of tumor markers with OS were evaluated. RESULTS: For patients with evaluable samples, ganitumab was associated with improved OS versus placebo (HR, 0.49; 95% CI: 0.28-0.87). The treatment effect on improved OS was strong in the patient subset with higher levels of IGF 1, IGF-2, or IGFBP-3, or lower levels of IGFBP-2, but not so on the other corresponding subset. Median OS of ganitumab versus placebo in patients with higher levels of IGF-1, IGF-2, and IGFBP-3 was 16 versus 6.8 months (HR, 0.25; 95% CI: 0.09-0.67), 16 versus 5.9 months (HR, 0.24; 95% CI: 0.09-0.68), and 16 versus 6.8 months (HR, 0.28; 95% CI: 0.11-0.73), and in patients with lower IGFBP 2 levels was 12.7 versus 6.6 months (HR, 0.19; 95% CI: 0.07-0.55). Interaction between treatment and IGFs/IGFBPs in multivariate analyses suggested predictive potential for IGF-2 (P = 0.002) and IGFBP-2 (P = 0.02). KRAS mutation status and PTEN expression were not associated with OS. CONCLUSIONS: Baseline circulating factors of the IGF axis may predict OS benefit from ganitumab plus gemcitabine in metastatic pancreatic adenocarcinoma. PMID- 23741074 TI - American Sign Language/English bilingual model: a longitudinal study of academic growth. AB - This study examines reading and mathematics academic growth of deaf and hard-of hearing students instructed through an American Sign Language (ASL)/English bilingual model. The study participants were exposed to the model for a minimum of 4 years. The study participants' academic growth rates were measured using the Northwest Evaluation Association's Measure of Academic Progress assessment and compared with a national-normed group of grade-level peers that consisted primarily of hearing students. The study also compared academic growth for participants by various characteristics such as gender, parents' hearing status, and secondary disability status and examined the academic outcomes for students after a minimum of 4 years of instruction in an ASL/English bilingual model. The findings support the efficacy of the ASL/English bilingual model. PMID- 23741075 TI - Age, stage and senescence in plants. AB - 1. Senescence (an increase in the mortality rate or force of mortality, or a decrease in fertility, with increasing age) is a widespread phenomenon. Theories about the evolution of senescence have long focused on the age trajectories of the selection gradients on mortality and fertility. In purely age-classified models, these selection gradients are non-increasing with age, implying that traits expressed early in life have a greater impact on fitness than traits expressed later in life. This pattern leads inevitably to the evolution of senescence if there are trade-offs between early and late performance. 2. It has long been suspected that the stage- or size-dependent demography typical of plants might change these conclusions. In this paper, we develop a model that includes both stage- and age-dependence and derive the age-dependent, stage dependent and age*stage-dependent selection gradients on mortality and fertility. 3. We applied this model to stage-classified population projection matrices for 36 species of plants, from a wide variety of growth forms (from mosses to trees) and habitats. 4. We found that the age-specific selection gradients within a life cycle stage can exhibit increases with age (we call these contra-senescent selection gradients). In later stages, often large size classes in plant demography, the duration of these contra-senescent gradients can exceed the life expectancy by several fold. 5.Synthesis. The interaction of age- and stage dependence in plants leads to selection pressures on senescence fundamentally different from those found in previous, age-classified theories. This result may explain the observation that large plants seem less subject to senescence than most kinds of animals. The methods presented here can lead to improved analysis of both age-dependent and stage-dependent demographic properties of plant populations. PMID- 23741076 TI - Partisan Joiners: Associational Membership and Political Polarization in the United States (1974-2004)* AB - OBJECTIVES: Associational life may foster political integration or amplify division, depending on how individuals partition themselves into groups and whether their multiple affiliations embed them into concentric or cross-cutting social circles. Starting from this premise, I relate trends in associational membership to political partisanship, and ask if there is any evidence of increased political polarization in the associative patterns of Americans. METHODS: Using GSS data (1974-2004) on affiliations to 16 types of groups, I plot trends and run multilevel models to examine changes over time in the partisan allegiances of group members and patterns of overlapping memberships. RESULTS: The often-lamented decline in group membership affects primarily the category of single-group members and is limited to a few types of groups. The density of the network of overlapping memberships has remained stable over time and there are no real changes in the patterns of shared memberships between group types, nor do Republicans and Democrats differ in their patterns of preferential affiliation. Although political partisanship does not drive patterns of group affiliation, group members, especially those affiliated with multiple groups, are more radical in their partisan identification than nonmembers, and most types of groups have become politically more heterogeneous over time. CONCLUSION: The puzzling finding that group types are not becoming more partisan, while group members are, leads to the hypothesis (to be tested in future research) that civil society polarization is occurring at the level of actual groups, and not group types. PMID- 23741077 TI - A new strategy for the synthesis of beta-benzylmercaptoethylamine derivatives. AB - Here we describe a new experimental approach to the synthesis of the beta benzylmercaptoethylamine functionality and illustrate its synthetic utility in multi-component reactions. Although prevalent in modern organic synthesis, no general methods have been described for this functionality. Using a carefully developed LiOH-water-ethanol reaction mixture we were able to produce a diverse collection of beta-benzylmercaptoethylamines containing a range of sensitive functional groups in excellent yields. To further illustrate their utility in molecular library synthesis, we also report the use of beta benzylmercaptoethylamines in five different multi-component reactions. PMID- 23741078 TI - Coupled hydromechanical and electromagnetic disturbances in unsaturated porous materials. AB - A theory of cross-coupled flow equations in unsaturated soils is necessary to predict (1) electroosmotic flow with application to electroremediation and agriculture, (2) the electroseismic and the seismoelectric effects to develop new geophysical methods to characterize the vadose zone, and (3) the streaming current, which can be used to investigate remotely ground water flow in unsaturated conditions in the capillary water regime. To develop such a theory, the cross-coupled generalized Darcy and Ohm constitutive equations of transport are extended to unsaturated conditions. This model accounts for inertial effects and for the polarization of porous materials. Rather than using the zeta potential, like in conventional theories for the saturated case, the key parameter used here is the quasi-static volumetric charge density of the pore space, which can be directly computed from the quasi-static permeability. The apparent permeability entering Darcy's law is also frequency dependent with a critical relaxation time that is, in turn, dependent on saturation. A decrease of saturation increases the associated relaxation frequency. The final form of the equations couples the Maxwell equations and a simplified form of two-fluid phases Biot theory accounting for water saturation. A generalized expression of the Richard equation is derived, accounting for the effect of the vibration of the skeleton during the passage of seismic waves and the electrical field. A new expression is obtained for the effective stress tensor. The model is tested against experimental data regarding the saturation and frequency dependence of the streaming potential coupling coefficient. The model is also adapted for two phase flow conditions and a numerical application is shown for water flooding of a nonaqueous phase liquid (NAPL, oil) contaminated aquifer. Seismoelectric conversions are mostly taking place at the NAPL (oil)/water encroachment front and can be therefore used to remotely track the position of this front. This is not the case for other geophysical methods. PMID- 23741079 TI - Comment on "Adaptive Confidence Intervals for the Test Error in Classification" AB - Inspired by the non-regular framework studied in Laber and Murphy (2011), we propose a family of adaptive classifiers. We discuss briefly their asymptotic properties and show that under the non-regular framework these classifiers have an "oracle property," and consequently have smaller asymptotic variance and smaller asymptotic test error variance than those of the original classifier. We also show that confidence intervals for the test error of the adaptive classifiers, based on either normal approximation or centered percentile bootstrap, are consistent. PMID- 23741080 TI - The role of parallelism in the real-time processing of anaphora. AB - Parallelism effects refer to the facilitated processing of a target structure when it follows a similar, parallel structure. In coordination, a parallelism related conjunction triggers the expectation that a second conjunct with the same structure as the first conjunct should occur. It has been proposed that parallelism effects reflect the use of the first structure as a template that guides the processing of the second. In this study, we examined the role of parallelism in real-time anaphora resolution by charting activation patterns in coordinated constructions containing anaphora, Verb-Phrase Ellipsis (VPE) and Noun-Phrase Traces (NP-traces). Specifically, we hypothesised that an expectation of parallelism would incite the parser to assume a structure similar to the first conjunct in the second, anaphora-containing conjunct. The speculation of a similar structure would result in early postulation of covert anaphora. Experiment 1 confirms that following a parallelism-related conjunction, first conjunct material is activated in the second conjunct. Experiment 2 reveals that an NP-trace in the second conjunct is posited immediately where licensed, which is earlier than previously reported in the literature. In light of our findings, we propose an intricate relation between structural expectations and anaphor resolution. PMID- 23741081 TI - Elucidation of the structure of poly(gamma-benzyl-l-glutamate) nanofibers and gel networks in a helicogenic solvent. AB - The synthesis, characterization, self-assembly, and gel formation of poly(gamma benzyl-l-glutamate) (PBLG) in a molecular weight range from ca. 7,000-100,000 g/mol and with narrow molecular weight distribution are described. The PBLG is synthesized by the nickel-mediated ring-opening polymerization and is characterized by size-exclusion chromatography coupled with multiple-angle laser light scattering, NMR, and Fourier transform infrared spectroscopy. The self assembly and thermoreversible gel formation in the helicogenic solvent toluene is investigated by transmission electron microscopy, atomic force microscopy, small angle X-ray scattering, and synchrotron powder X-ray diffraction. At concentrations significantly below the minimum gelation concentration, spherical aggregates are observed. At higher concentrations, gels are formed, which show a 3D network structure composed of nanofibers. The proposed self-assembly mechanism is based on a distorted hexagonal packing of PBLG helices parallel to the axis of the nanofiber. The gel network forms due to branching and rejoining of bundles of PBLG nanofibers. The network exhibits uniform domains with a length of 200 +/- 42 nm composed of densely packed PBLG helices. PMID- 23741082 TI - Nanostructured polymer-titanium composites and titanium oxide through polymer swelling in titania precursor. AB - Polymer (XAD7HP)/Ti4+ nanocomposites were prepared through the swelling of polymer in titanium (IV) ethoxide as a titanium dioxide precursor. The nanocomposite beads exhibit relatively high porosity different than the porosity of the initial polymer. Thermal treatment of composite particles up to 200 degrees C in vacuum causes the change of their internal structure. At higher temperature, the components of composite become more tightly packed. Calcination at 600 degrees C and total removal of polymer produce spherically shaped TiO2 condensed phase as determined by XRD. Thermally treated composites show the substantial change of pore dimensions within micro- and mesopores. The presence of micropores and their transformation during thermal processing was studied successfully by positron annihilation lifetime spectroscopy (PALS). The results derived from PALS experiment were compared with those obtaining from low temperature nitrogen adsorption data. PMID- 23741083 TI - A New Perspective on Job Lock. AB - This paper analyses the situation when employees fail to adapt to overall job dissatisfaction. By combining the existing knowledge in economics on job lock and in psychology on employees' feeling of being 'stuck' at work, the paper explains why some employees fail to adapt when dissatisfied with their job. Thus, the paper aims to expand our understanding of why some employees are job locked or are 'stuck' at their work even though dissatisfied. Using the British household panel survey, the possibility of falling in a job-lock state is analyzed to outline a set of factors that explain why employees differ in the way they adjust to job dissatisfaction. We divide these factors into socio-demographic features, personality attributes, type of occupation, employment conditions, type of sector, and work-related contextual features. Based on results of probit regression analysis, we provide evidence that all these group of factors can jointly predict the state of job dissatisfaction, the absence of job turnover and job lock (being 'stuck' at job). Moreover, our results suggest that the adaptation to job dissatisfaction could be better understood if personality attributes (such as self-esteem) are included in the analysis. Thus, this study expands our understanding of how and why employees might feel 'stuck' at work and fall in a state of job lock. PMID- 23741084 TI - Family Therapy in Poland: Development and Current Perspectives. AB - The authors of the present article describe the historical context of family therapy in Poland and current issues in the field. They highlight the fact that Polish therapists first began to develop the field after coming into contact with family therapy leaders from the United States and Western Europe. With the political breakthrough of 1989, there were new opportunities for multilateral cooperation, attendance at international conferences, and the exchange of experiences. Currently, the work of Polish family therapists, the place of family therapy among other forms of psychotherapy, and the related problems and challenges do not differ from other European nations. PMID- 23741085 TI - Mono- and bimetallic Rh and Pt NSR-catalysts prepared by controlled deposition of noble metals on support or storage component. AB - Mono- and bimetallic Rh and Pt based NOx storage-reduction (NSR) catalysts, where the noble metals were deposited on the Al2O3 support or BaCO3 storage component, have been prepared using a twin flame spray pyrolysis setup. The catalysts were characterized by nitrogen adsorption, CO chemisorption combined with diffuse reflectance infrared Fourier transform spectroscopy, X-ray diffraction, and scanning transmission electron microscopy combined with energy dispersive X-ray spectroscopy. The NSR performance of the catalysts was investigated by fuel lean/rich cycling in the absence and presence of SO2 (25 ppm) as well as after H2 desulfation at 750 degrees C. The performance increased when Rh was located on BaCO3 enabling good catalyst regeneration during the fuel rich phase. Best performance was observed for bimetallic catalysts where the noble metals were separated, with Pt on Al2O3 and Rh on BaCO3. The Rh-containing catalysts generally showed much higher tolerance to SO2 during fuel rich conditions and lost only little activity during thermal aging at 750 degrees C. PMID- 23741086 TI - Making the cut: The production of 'self-harm' in post-1945 Anglo-Saxon psychiatry. AB - 'Deliberate self-harm', 'self-mutilation' and 'self-injury' are just some of the terms used to describe one of the most prominent issues in British mental health policy in recent years. This article demonstrates that contemporary literature on 'self-harm' produces this phenomenon (to varying extents) around two key characteristics. First, this behaviour is predominantly performed by those identified as female. Second, this behaviour primarily involves cutting the skin. These constitutive characteristics are traced back to a corpus of literature produced in the 1960s and 1970s in North American psychiatric inpatient institutions; analysis shows how pre-1960 works were substantially different. Finally, these gendered and behavioural assertions are shown to be the result of historically specific processes of exclusion and emphasis. PMID- 23741087 TI - Flu and pulmonary fibrosis. PMID- 23741088 TI - Fat embolism syndrome in long bone trauma following vehicular accidents: Experience from a tertiary care hospital in north India. AB - BACKGROUND: Fat embolism syndrome (FES) is a clinical problem arising mainly due to fractures particularly of long bones and pelvis. Not much literature is available about FES from the Indian subcontinent. MATERIALS AND METHODS: Thirty five patients referred/admitted prospectively over a 3-year period for suspected FES to a north Indian tertiary care center and satisfying the clinical criteria proposed by Gurd and Wilson, and Schonfeld were included in the study. Clinical features, risk factors, complications, response to treatment and any sequelae were recorded. RESULTS: The patients (all male) presented with acute onset breathlessness, 36-120 hours following major bone trauma due to vehicular accidents. Associated features included features of cerebral dysfunction (n = 24, 69%), petechial rash (14%), tachycardia (94%) and fever (46%). Hypoxemia was demonstrable in 80% cases, thrombocytopenia in 91%, anemia in 94% and hypoalbuminemia in 59%. Bilateral alveolar infiltrates were seen on chest radiography in 28 patients and there was evidence of bilateral ground glass appearance in 5 patients on CT. Eleven patients required ventilatory assistance whereas others were treated with supportive management. Three patients expired due to associated sepsis and respiratory failure, whereas others recovered with a mean hospital stay of 9 days. No long term sequelae were observed. CONCLUSION: FES remains a clinical challenge and is a diagnosis of exclusion based only on clinical grounds because of the absence of any specific laboratory test. A high index of suspicion is required for diagnosis and initiating supportive management in patients with traumatic fractures, especially in those having undergone an invasive orthopedic procedure. PMID- 23741089 TI - Annual change in spirometric parameters among patients affected in Bhopal gas disaster: A retrospective observational study. AB - BACKGROUND: The involvement of respiratory system due to inhalation of methyl isocyanate (MIC) during Bhopal gas disaster was particularly severe. We retrospectively evaluated the annual changes in spirometric parameters among those who were affected in this disaster (exposed survivors) and had respiratory symptoms. MATERIALS AND METHODS: Spirometry reports of exposed survivors that were carried out in our institution were retrospectively reviewed and we identified 252 subjects who had performed spirometry at least twice with interval of more than one year. The annual changes in spirometric indices of them were calculated. RESULTS: The average age of study population was 55.7 years and 72% were male. Annual decline of FEV1 >= 40 ml/yr was observed among 48% exposed survivors. The mean annual decline of FEV1 among symptomatic exposed survivors with initial normal spirometry was 91 ml (95% CI: 52 ml to 130 ml) and this was more than the patients with initial obstructive pattern. Among fifty four patients with initial normal spirometry, ten patients (18.5%) developed obstructive and two patients (5%) developed restrictive lung function abnormalities during follow up spirometry. CONCLUSION: The exposed survivors with chronic respiratory symptoms had accelerated decline in lung function and they are at higher risk of developing obstructive lung function. PMID- 23741090 TI - Pulmonary function tests in type 2 diabetes mellitus and their association with glycemic control and duration of the disease. AB - BACKGROUND: Pulmonary complications of diabetes mellitus (DM) have been poorly characterized. Some authors have reported normal pulmonary functions and even concluded that spirometry is not at all necessary in diabetic patients. Some studies have shown abnormal respiratory parameters in patients of DM. Moreover, the duration of DM and glycemic control have varied impact on the pulmonary functions. AIMS AND OBJECTIVES: The study was undertaken to analyze the pulmonary function parameters in diabetic patients and compare them with age and gender matched healthy subjects. We correlated forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) in diabetic patients with duration of the disease and glycosylated hemoglobin (HbA1c). MATERIALS AND METHODS: Pulmonary function tests (PFTs) were recorded in 60 type 2 diabetic male patients and 60 normal healthy male controls aged 40-60 years by using Helios 702 spirometer. The PFTs recorded were - FVC, FEV1, FEV1/FVC, FEF25, FEF50, FEF75, FEF25-75, FEF0.2 1.2, and peak expiratory flow rate (PEFR). HbA1c of all the patients was estimated by ion exchange resin method, which is a very standard method of estimation. PFTs of diabetic patients and controls were compared by applying Student's unpaired t test. Associations between FVC and FEV1 and HbA1c and duration of illness in diabetic patients were analyzed by applying Pearson's coefficient. RESULTS: The PFTs were significantly decreased in diabetic patients compared with the healthy controls except FEV1/FVC. There was no correlation found between FVC and FEV1 and duration of illness as well as HbA1c. CONCLUSION: DM being a systemic disease, which also affects lungs causing restrictive type of ventilatory changes probably because of glycosylation of connective tissues, reduced pulmonary elastic recoil and inflammatory changes in lungs. We found glycemic levels and duration of disease are probably not the major determinants of lung pathology, which requires further research. PMID- 23741091 TI - Evaluation of cariogenic potential of dry powder inhalers: A case-control study. AB - OBJECTIVE: Dry powder inhalers (DPIs) are commonly employed in the management of asthma and other diseases with airway obstruction. A causal relationship of DPI use and occurrence of dental caries has been speculated. The present case-control study was therefore designed to examine the potential link between dental caries and specific use of dry powder inhalers in patients with bronchial asthma. MATERIALS AND METHODS: The present study was conducted on 100 asthmatic patients aged between 10 and 45 years who were using DPIs for at least one year. The control group (n = 100) was selected from non-asthmatic individuals and were matched with the study group with respect to age, gender, and socio-economic status. RESULTS: The results revealed that asthmatic subjects exhibited higher occurrence of dental caries in comparison to control group, but the difference was statistically non-significant. The mean decayed, missing, and filled teeth (DMFT) indices scores in asthmatic and control group were found to be 1.71 +/- 2.34 SD and 1.46 +/- 1.89 SD (P = 0.408), respectively. Likewise, the mean decayed, missing, and filled surfaces (DMFS) indices scores in both the groups were 2.41 +/- 3.84 SD and 2.34 +/- 4.48 SD (P = 0.90). However, increased frequency of DPI use was associated with significant risk of caries (P = 0.01). It has been observed that oral rinsing after an inhaler use limited the occurrence of dental caries to a certain extent although was non significant. CONCLUSIONS: Dry powder inhaler use in patients with bronchial asthma was not associated with significant risk of dental caries. PMID- 23741092 TI - Usefulness of induced sputum eosinophil count to assess severity and treatment outcome in asthma patients. AB - CONTEXT: Currently treatment decisions in asthma are governed by clinical assessment and spirometry. Sputum eosinophil, being a marker of airway inflammation, can serve as a tool for assessing severity and response to treatment in asthma patients. AIMS: To establish correlation between change in sputum eosinophil count and forced expiratory volume in one second (FEV1)% predicted value of asthma patients in response to treatment. In this study, we also predicted prognosis and treatment outcome of asthma patients from baseline sputum eosinophil count. SETTINGS AND DESIGN: A longitudinal study was conducted to determine the treatment outcome among newly diagnosed asthma patients who were classified into A (n = 80) and B (n = 80) groups on the basis of initial sputum eosinophil count (A >= 3% and B < 3%). MATERIALS AND METHODS: After starting treatment according to Global Initiative for Asthma Guideline, both A and B groups were evaluated every 15 days interval for the 1(st) month and monthly thereafter for a total duration of 12 months. In each follow-up visit detailed history, induced sputum eosinophil count and spirometry were done to evaluate severity and treatment outcome. RESULTS: FEV1% predicted of group A asthma patients gradually increased and sputum eosinophil count gradually decreased on treatment. Longer time was required to achieve satisfactory improvement (FEV1% predicted) in asthma patients with sputum eosinophil count >=3%. There was statistically significant negative correlation between FEV1% predicted and sputum eosinophil count (%) in of group A patients in each follow-up visit, with most significant negative correlation found in 8(th) visit (r = -0.9237 and P = < 0.001). Change in mean FEV1% (predicted) from baseline showed strong positive correlation (r = 0.976) with change in reduction of mean sputum eosinophil count at each follow-up visits in group A patients. CONCLUSIONS: Sputum eosinophil count, being an excellent biomarker of airway inflammation, can serve as a useful marker to assess disease severity, treatment outcome, and prognosis in asthma patients. PMID- 23741093 TI - Role of HRCT in detection and characterization of pulmonary abnormalities in patients with febrile neutropenia. AB - BACKGROUND: Fever is of grave concern in the management of patients with neutropenia with early detection of a focus of infection being the major goal. As lungs are the most common focus, chest imaging is of vital importance. This Institute Review Board approved prospective study was undertaken to assess the usefulness of high resolution computed tomography (HRCT) in early detection and characterization of pulmonary abnormalities in febrile neutropenia. MATERIALS AND METHODS: A total of 104 consecutive patients (M:F:75:29, age range 11-66 years) with fever of 38.2 degrees C or more with an absolute neutrophil count <500/MUl underwent HRCT chest. HRCT diagnosis was compared with final diagnosis based on ancillary investigations. RESULTS: HRCT could detect pulmonary abnormalities in 93 patients (89.4%) with air space consolidation being the predominant finding (n = 57), followed by ground-glass opacities (Ground glass opacity (GGO), n = 49) and nodules (n = 39). HRCT could correctly characterize the infective lesions in 76 patients (81.7%). Presence of random or pleural-based nodules >10 mm with or without surrounding GGO or cavitations was sensitive (95.23%) and specific (96.7%) for fungal infection, while small (1-4 mm) random or centrilobular nodules with tree-in-bud appearance was sensitive (90%) and highly specific (97.02%) for tuberculosis. Diagnosis of pyogenic infection based on presence of air-space consolidation, pleural effusion, GGO or centrilobular nodules showed a sensitivity of 84.78% and specificity of 93.84%, whereas patchy or diffuse GGO, interstitial thickening and/or air-space consolidation showed high sensitivity (86.7%) and specificity (96.8%) for Pneumocystis jiroveci pneumonia. CONCLUSION: HRCT chest is an excellent modality in the diagnostic work-up of patients with febrile neutropenia allowing early detection and characterization of pulmonary abnormalities. PMID- 23741094 TI - Clinical management practices adopted by physiotherapists in India for chronic obstructive pulmonary disease: A national survey. AB - BACKGROUND AND OBJECTIVE: Evidence supports the use of pulmonary rehabilitation in the treatment of chronic obstructive pulmonary disease (COPD) patients both during acute exacerbation and at later stages. It is used in India; but, to date, there has been no study that has investigated the structure of pulmonary rehabilitation programs for COPD patients in India. The recent study aims to determine the current practice patterns of Indian Physiotherapists for COPD patients admitted in Intensive Care Units (ICUs) and wards in terms of assessment and treatment. MATERIALS AND METHODS: A questionnaire-based survey was conducted across India. Questionnaires were distributed to around 800 physiotherapists via E-mail. Physiotherapists with a Master Degree and a specialization in cardiopulmonary science or a minimum of 1 year of experience in treating cardiopulmonary patients were included. The questionnaires addressed assessment measures and treatment techniques given to COPD patients. RESULTS: A total of 342 completed questionnaires were received, yielding a response rate of 43.8%, with a majority of responses from Karnataka, Maharashtra and Gujarat. The assessment and treatment techniques used were almost similar between ICUs and wards. More than 80% of the responders carried out the assessment of certain respiratory impairments in both ICUs and wards. An objective measure of dyspnea was taken by less than 40% of the responders, with little attention given to functional exercise capacity and health-related quality of life. Eighty-five percent of the responders used Dyspnea-relieving strategies and traditional airway clearance techniques in both ICUs and wards. Eighty-three percent of the responders were giving patients in the wards training for upper and lower extremity. Fifty percent were giving strength training in the wards. CONCLUSION: Whether patients are admitted in ICUs or Wards, the practice pattern adopted by Physiotherapists to treat them vary very little with respect to certain measures taken. Assessment predominantly focused on respiratory impairment measures, followed by dyspnea quantifying measures, with little attention given to functional exercise capacity and health-related quality of life measures. Treatment techniques given were concentrated on dyspnea-relieving strategies, airway clearance techniques and upper and lower extremity exercises, with little attention given to strength training. PMID- 23741095 TI - Level of awareness about tuberculosis in urban slums: Implications for advocacy and communication strategy planning in the National program. AB - BACKGROUND: Tuberculosis (TB) remains as an important public health problem in India. Awareness about the disease, its diagnosis, and treatment among public will help in controlling the killer disease. This study aims at arriving at an educational diagnosis about TB in an urban poor community. MATERIALS AND METHODS: A cross-sectional study was conducted in an urban slum in South India using a structured, pretested questionnaire. Domains identified were knowledge about TB, symptoms, spread, diagnosis, treatment, and prevention of TB. RESULTS: A total of 395 households were interviewed. Of them, 370 (94%) respondents had heard about TB. Regarding the symptoms of TB, 82% were aware that cough is a symptom of TB. Among the 79% of study subjects who reported any test to diagnose TB, sputum examination as a method of diagnosis was known to only 40%. However, 84% of the subjects were aware of the free treatment available for TB under National program. CONCLUSION: Level of awareness about TB among urban poor in a slum area is good. Knowledge about "free treatment" and "duration of treatment" has to be stressed during health education activities. PMID- 23741096 TI - Pulmonary alveolar microlithiasis. AB - Pulmonary alveolar microlithiasis (PAM) is a rare, chronic lung disease with bilateral intra-alveolar calcium and phosphate deposition throughout the lung parenchyma with predominance to lower and midzone. Although, etiology and pathogenesis of PAM is not fully understood, the mutation in SLC34A2 gene that encodes a sodium-phosphate co-transporter in alveolar type II cells resulting in the accumulation and forming of microliths rich in calcium phosphate (due to impaired clearance) are considered to be the cause of the disease. Chest radiograph and high-resolution CT of thorax are nearly pathognomonic for diagnosing PAM. HRCT demonstrates diffuse micronodules showing slight perilobular predominance resulting in calcification of interlobular septa. Patients with PAM are asymptomatic till development of hypoxemia and cor-pulmonale. No therapy has been proven to be beneficial except lung transplantation. PMID- 23741097 TI - Spontaneous pneumopericardium an unusual complication in a patient of HIV and pulmonary tuberculosis. AB - Pneumopericardium is defined as a collection of air or gas in the pericardial cavity. It is a rare entity and spontaneous pneumopericardium is even rarer. It is a rare complication of tuberculosis and human immunodeficiency virus and just three cases have been reported so far. PMID- 23741098 TI - Alveolar hemorrhage in a case of fat embolism syndrome: A case report with short systemic review. AB - Fat embolism and fat embolism syndrome (FES) are well-known complications of long bone fracture and surgery involving manipulation of skeletal elements. Many non traumatic causes of FES have been suggested but they constitute only a small portion. FES presents with classical symptoms of petechiae, hypoxemia, central nervous system symptoms along with other features such as tachycardia and pyrexia. Diagnosis of FES relies on clinical judgment rather than objective findings such as emboli present in the retinal vessels on fundoscopy, fat globules present in urine and sputum, a sudden inexplicable drop in hematocrit or platelet values, increasing erythrocyte sedimentation rate. PMID- 23741099 TI - Recurrent hemoptysis in a 62-year-old smoker. AB - Tracheal papillary adenoma is a rare benign tumor. We report a case of papillary adenoma in a 62-year-old male smoker who presented with recurrent hemoptysis. The tumor was located in the upper third of trachea and forceps biopsy through flexible bronchoscopy was uncomplicated and diagnostic. PMID- 23741101 TI - Progressive dyspnea with a classic radiological sign. PMID- 23741100 TI - Pleural effusion: An unusual cause and association. AB - Filaria has a wide spectrum of presentation. We hereby present a case of Filarial pleural effusion that is a rarity in itself. Filarial lung involvement is usually in the form of tropical pulmonary eosinophilia with pulmonary infiltrates and peripheral eosinophilia, unlike our case where isolated pleural effusion of Filarial etiology was detected. Microfilaria has been isolated from Pleural fluid in very few cases, and ours was one such. Of late, there have been many incidental detections of Filarial parasites from varied anatomical sites in association with malignancy. Even in our case, we had one such unusual association. PMID- 23741102 TI - Sudden onset of dyspnea in a woman with skin lesions and lung cysts. PMID- 23741103 TI - Flow volume loop as a diagnostic marker. PMID- 23741104 TI - Cognitive functions in nonhypoxemic chronic obstructive pulmonary disease (COPD). PMID- 23741105 TI - Authors' reply. PMID- 23741106 TI - Organizing pneumonia as a pulmonary sequela of swine flu. PMID- 23741107 TI - Status of LEPR Gene in PCB-exposed Population: A Quick Look. AB - Earlier, we have reported that Polychlorinated Biphenyls (PCBs) exposure in Slovak population has made differential gene expression that has linked to the possibilities of some diseases and disorder development in the studied population. Here we report that down-regulation of LEPR (Leptin receptor) gene in the 45-month children may have been following consequences in developing obesity later in life. A pilot high-throughput qRT-PCR [Taqman Low Density Array (TLDA)] study in a small population also corroborated the gene-expression results, and their pathways underlying the consequences of the diseases, amid further detailed large-scale population validation. The study shows the opportunity of predicting long-term effects of chemical exposures using selected genomic classifiers may reflect exposure effect and risk from environmental toxicants. PMID- 23741108 TI - Laparoscopic gastrectomy: Quo vadis? PMID- 23741109 TI - Laparoscopic appendectomy in complicated appendicitis: Is it safe? AB - BACKGROUND: Because of lack of good evidence supporting laparoscopic approach for complicated appendicitis, we carried out this study to evaluate efficacy of laparoscopic appendectomy (LA) in management of patients with complicated appendicitis. MATERIALS AND METHODS: This study was carried out in Surgical Department, Minia University, Egypt involving 214 patients underwent appendectomy for complicated appendicitis over three years. 132 patients underwent LA and remaining 82 patients underwent OA. Parameters studied included operating time, return to oral feeding, postoperative pain, wound infection, intra-abdominal abscess, duration of abdominal drainage and hospital stay. RESULTS: There were four conversions, two due to extensive cecal adhesions and two due to friable appendix. LA took longer time to perform (p = 0.0002) but with less use of analgesics (p < 0.0001), shorter hospital stay (p < 0.0001), shorter duration of abdominal drainage (p < 0.0001) and lower incidence of wound infection (p = 0.0005). Nine patients in LA and seven patients in OA group developed intra abdominal abscess treated successfully with sonographic guided percutaneous drainage. Postoperative ileus was recorded in two patients in LA group and three patients in OA group, chest infection in one patient in OA group, hernia in one patient in LA and fecal fistula was present in one patient in OA. Overall complications were significantly lower in laparoscopy group and managed conservatively with no mortality in either group. CONCLUSIONS: LA in complicated appendicitis is feasible and safe with lower incidence of complications than OA and should be the initial choice for all patients with complicated appendicitis. PMID- 23741110 TI - Analysis of laparoscopic port site complications: A descriptive study. AB - CONTEXT: The rate of port site complications following conventional laparoscopic surgery is about 21 per 100,000 cases. It has shown a proportional rise with increase in the size of the port site incision and trocar. Although rare, complications that occur at the port site include infection, bleeding, and port site hernia. AIMS: To determine the morbidity associated with ports at the site of their insertion in laparoscopic surgery and to identify risk factors for complications. SETTINGS AND DESIGN: Prospective descriptive study. MATERIALS AND METHODS: In the present descriptive study, a total of 570 patients who underwent laparoscopic surgeries for various ailments between August 2009 and July 2011 at our institute were observed for port site complications prospectively and the complications were reviewed. STATISTICAL ANALYSIS USED: Descriptive statistical analysis was carried out in the present study. The statistical software, namely, SPSS 15.0 was used for the analysis of the data. RESULTS: Of the 570 patients undergoing laparoscopic surgery, 17 (3%) had developed complications specifically related to the port site during a minimum follow-up of three months; port site infection (PSI) was the most frequent (n = 10, 1.8%), followed by port site bleeding (n = 4, 0.7%), omentum-related complications (n = 2; 0.35%), and port site metastasis (n = 1, 0.175%). CONCLUSIONS: Laparoscopic surgeries are associated with minimal port site complications. Complications are related to the increased number of ports. Umbilical port involvement is the commonest. Most complications are manageable with minimal morbidity, and can be further minimized with meticulous surgical technique during entry and exit. PMID- 23741111 TI - Laparoscopic cholecystectomy under spinal anaesthesia: A prospective, randomised study. AB - CONTEXT: Spinal anaesthesia has been reported as an alternative to general anaesthesia for performing laparoscopic cholecystectomy (LC). AIMS: Study aimed to evaluate efficacy, safety and cost benefit of conducting laparoscopic cholecystectomy under spinal anaesthesia (SA) in comparison to general anaesthesia(GA). SETTINGS AND DESIGN: A prospective, randomised study conducted over a two year period at an urban, non teaching hospital. MATERIALS AND METHODS: Patients meeting inclusion criteria e randomised into two groups. Group A and Group B received general and spinal anaesthesia by standardised techniques. Both groups underwent standard four port laparoscopic cholecystectomy. Mean anaesthesia time, pneumoperitoneum time and surgery time defined primary outcome measures. Intraoperative events and post operative pain score were secondary outcome measure. STATISTICAL ANALYSIS USED: The Student t test, Pearson's chi square test and Fisher exact test. RESULTS: Out of 235 cases enrolled in the study, 114 cases in Group A and 110 in Group B analysed. Mean anaesthesia time appeared to be more in the GA group (49.45 vs. 40.64, P = 0.02) while pneumoperitoneum time and corresponding the total surgery time was slightly longer in the SA group. 27/117 cases who received SA experienced intraoperative events, four significant enough to convert to GA. No postoperative complications noted in either group. Pain relief significantly more in SA group in immediate post operative period (06 and 12 hours) but same as GA group at time of discharge (24 hours). No late postoperative complication or readmission noted in either group. CONCLUSION: Laparoscopic cholecystectomy done under spinal anaesthesia as a routine anaesthesia of choice is feasible and safe. Spinal anaesthesia can be recommended to be the anaesthesia technique of choice for conducting laparoscopic cholecystectomy in hospital setups in developing countries where cost factor is a major factor. PMID- 23741112 TI - Incise, dissect, excise and suture technique of laparoscopic repair of paediatric male inguinal hernia. AB - BACKGROUND: Authors report incise, dissect, excise and suture (IDES) technique of laparoscopic repair of paediatric male inguinal hernia (LRPMIH). This series retrospectively evaluates a consecutive personal series of children undergoing laparoscopic hernia repair by this new technique. MATERIALS AND METHODS: It is a retrospective review of the LRPMIH done by single surgeon from January 2001 to December 2007. All male patients who were referred to the first author for management of inguinal hernia were given the option of laparoscopic repair. Parents who gave consent for their child to undergo LRPMIH were retrospectively reviewed. RESULTS: A total of 155 patients were operated. Age group was 2 months to 13 years (average-5 years). Follow-up period ranges from 1 to 7 years. Average operating time was 29 min for unilateral and 40 min for bilateral inguinal hernia. Maximum time required was 50 min which was for bilateral inguinal hernia. Bilateral inguinal hernia was present in 10 (6.4%) patients. There were no intraoperative complications. Contralateral processus vaginalis was patent in 25 (16.12%) patients. In the immediate post-operative period 8 patients had port site surgical emphysema which resolved on its own. There are no recurrences so far. One patient developed port site hernia, which was repaired with the standard surgery. There is no incidence of clinical testicular atrophy. CONCLUSION: LRPMIH can be done as routine procedure and also has fewer complications. It has advantage of diagnosing and repairing contra lateral patent processus vaginalis. However a double-blind controlled study is required to establish the results. PMID- 23741113 TI - SILACIG: A novel technique of single-incision laparoscopic appendicectomy based on institutional experience of 29 cases. AB - INTRODUCTION: More reports of single-incision laparoscopic appendectomy are appearing in literature as it is an improvement over multiport laparoscopy in further reducing the trauma to abdomen. But, most of techniques require expensive gadgets like commercial ports and manoeuverable instruments, which are not available at many centres. In this context, a feasibility study of our own operative technique of single-incision laparoscopic appendectomy with less expensive conventional instrumentation was conducted at a single centre. MATERIALS AND METHODS: This prospective study was carried out in tertiary care teaching institute of a semi-urban area in South India over a period of 1 year from March 2011 to February 2012. Twenty-nine patients of appendicitis were included in this study. Based on the principles of single-incision laparoscopy, we developed a glove port utilizing readily available operation theatre equipment. RESULTS: Mean operative time was 56+/-12 minutes. Mean age of subjects was 34+/-15 years. M: F ratio was 2:1. There was no significant perioperative morbidity or mortality. Mean follow-up period was 8 months. CONCLUSION: Our initial experience with this technique of single-incision laparoscopic appendectomy demonstrates its feasibility, safety at a very low cost. PMID- 23741114 TI - Laparoscopic removal of a needle from the pancreas. AB - Foreign bodies inside the pancreas are rare and usually occur after the ingestion of sharp objects like fish bone, sewing needle and toothpick. Most of the ingested foreign bodies pass spontaneously through the anus without being noticed but about 1% of them can perforate through the wall of stomach or duodenum to reach solid organs like pancreas or liver. Once inside the pancreas they can produce complications like abscess, pseudoaneurysm or pancreatits. Foreign bodies of pancreas should be removed by endoscopic or surgical methods. We hereby report our experience of successful removal one a sewing needle from pancreas. PMID- 23741115 TI - Retrograde intussusception seven years after a laparoscopic Roux-en-Y gastric bypass. AB - Intussusception after Roux-en-Y gastric bypass is more common than previously believed. It usually occurs between one and three years post-operatively, though we present a case that presented with a retrograde intussusception necessitating bowel resection seven years after a laparoscpic Roux-en-Y gastric bypass. The diagnosis and etiological theories are discussed based on findings from the literature. PMID- 23741116 TI - VATS therapy of chylothorax caused by leiomyomatosis complicated with tuberous sclerosis complex. AB - Lymphangioleiomyomatosis with tuberous sclerosis complex is a rare disease. One of the most frequent complications of lymphangioleiomyomatosis is pleural effusion (chylothorax) wich can be treated with the use of VATS. Authors report a case of pulmonary lymphangioleiomyomatosis in a 56-year-old female patient with tuberous sclerosis complex with an 8-week history of recurrent chylothorax, dyspnea and debilitating weakness. By CT scan a flat tissue proliferation was seen in the site of the thoracic duct and it was supposed to be the reason for the pleural effusion. A VATS resection of this laesion and ligation of the thoracic duct was performed successfully. Chylothorax is often associated with pulmonary lymphangioleiomyomatosis. Lymphangioleiomyomatosis combined with tuberous sclerosis complex is extremely rare. In case of chylothorax VATS treatment is successful and may be the first choice. PMID- 23741117 TI - Single port Billroth I gastrectomy. AB - INTRODUCTION: Experience has allowed increasingly complex procedures to be undertaken by single port surgery. We describe a technique for single port Billroth I gastrectomy with a hand-sewn intracorporeal anastomosis in the resection of a benign tumour diagnosed incidentally on a background of cholelithiasis. MATERIALS AND METHODS: Single port Billroth I gastrectomy and cholecystectomy was performed using a transumbilical quadport. Flexible tipped camera and straight conventional instruments were used throughout the procedure. The stomach was mobilised including a limited lymph node dissection and resection margins in the proximal antrum and duodenum were divided with a flexible tipped laparoscopic stapler. The lesser curve was reconstructed and an intracorporal hand sewn two layer end-to-end anastomosis was performed using unidirectional barbed sutures. Intraoperative endoscopy confirmed the anastomosis to be patent without leak. RESULTS: Enteral feed was started on the day of surgery, increasing to a full diet by day 6. Analgesic requirements were a patient-controlled analgesia morphine pump for 4 postoperative days and paracetamol for 6 days. There were no postoperative complications and the patient was discharged on the eighth day. Histology confirmed gastric submucosal lipoma. DISCUSSION: As technology improves more complex procedures are possible by single port laparoscopic surgery. In this case, flexible tipped cameras and unidirectional barbed sutures have facilitated an intracorporal hand-sewn two layer end-to-end anastomosis. Experience will allow such techniques to become mainstream. PMID- 23741118 TI - Single incision multi-trocar hepatic cyst excision with partial splenectomy. AB - INTRODUCTION: Surgery has the potential to remove the entire hydatid cyst and can lead to complete cure. Presence of hydatid cysts in multiple abdominal organs imposes special challenges for laparoscopic management. The patient position and port placement for one organ may not be adequate for other and proper exposure in hydatid cyst is of paramount importance to prevent spillage and complete removal of the cyst. Single incision multi-trocar technique has a unique advantage of allowing surgeon to work in different quadrants of abdomen using the same incision and ports. We report in this paper the first Laparo-endoscopic single site hepatic cyst excision with partial splenectomy for hydatid cyst in liver and spleen using conventional laparoscopic instruments. PATIENT AND TECHNIQUE: The procedure was performed on a 64 year old female diagnosed to have Hydatid cyst in segment VIII of liver and another cyst in lower pole of spleen a transverse 3 cm incision was made 6 cm above umbilicus and was deepened up to fascia. Two 10mm and one 5mm ports were inserted. Procedure was completed in 160 minutes without any intra-operative complication. There were no post-operative complication and patient was discharged on day 5. CONCLUSION: Single incision multi-trocar surgery has cosmetic advantage over standard laparoscopic approach. It is even more marked when two procedures are combined in different quadrants of abdomen. As this is a rare combination procedure so it remains to be determined if this technique offers additional advantages of decreased analgesia, decreased hospital stay or cost effectiveness. PMID- 23741119 TI - Double rolling and center hitch technique for laparoscopic ventral hernia repair. AB - BACKGROUND: Intraperitoneal onlay mesh repair is an established modality to treat large ventral hernias. Various techniques of laying the mesh are utilized. We present the Double Rolling and Center Hitch technique to lay a large intraperitoneal onlay mesh. OBJECTIVE: The aim of the study is to devise and adopt a method to reduce the difficulty in manoeuvring a large mesh inside the peritoneal cavity. It should also help in correct placement of mesh and decrease the operative time. MATERIALS AND METHODS: The DRACH technique was used in eighteen patients with large ventral hernias between May 2010 and September 2011. The Mesh size used was 15x20cm and more (considered to be large mesh). RESULTS: All the procedures were completed successfully. Mesh handling was significantly easier with the DRACH technique. The average mesh deployment time (MDT) was 15mins. In all cases the mesh was adequately centred with a margin of 3-5cm from the defect. CONCLUSION: The DRACH technique can be employed to lay large intraperitoneal meshes in order to reduce the handling difficulties associated with large meshes, and to aid in better placement of meshes so as to centered over the defect. PMID- 23741120 TI - Instability and basilar invagination. PMID- 23741121 TI - Keraunoparalysis: What a neurosurgeon should know about it? AB - Keraunoparalysis or transient weakness in limbs following a lightning strike has been well described in literature. Many times, neurosurgeons encounter patients with paraparesis secondary to trauma in the setting of a lightning strike. In these cases, it becomes imperative to find out the true cause behind such weakness in lower limbs because the prognosis differs significantly depending on the etiology. We report a case of keraunoparalysis affecting both lower limbs in a 50-year-old male, where he recovered within 48 hours of the impact. As far as our knowledge is concerned, this is the first case of keraunoparalysis reported from India. We also review the available literature and discuss the physics of lightning, its mechanism, other clinical presentations, and management strategy in the light of our case. These patients must be investigated for other possible causes of paraparesis secondary to trauma and keraunoparalysis should rather be a diagnosis of exclusion, only to be confirmed on imageology. Awareness regarding similar cases will make neurosurgeons notice this entity early, avoiding unnecessary investigation, and hence they will be able to prognosticate in the most efficient manner. PMID- 23741122 TI - Management of low back pain in computer users: A multidisciplinary approach. AB - BACKGROUND: Low back pain is a very common phenomenon in computer users. More than 80% people using computers for more than 4 h complain of back pain. OBJECTIVE: To compare the effectiveness of multidisciplinary treatment approach and conventional treatment approach amongst computer users. MATERIALS AND METHODS: A prospective interventional study was carried out at a private spine clinic amongst the computer users with the complaint of low back pain. The study participants were randomly distributed in two groups. The first group comprised the study participants treated by conventional approach and the second group was treated by multidisciplinary approach. Primary outcomes analyzed were pain intensity, sick leave availed, and quality of life. Statistical analysis was done using proportions, unpaired "t" test, and Wilcoxon signed-rank test. RESULTS: Totally 44 study participants were randomly assigned to groups I and II, and each group had 22 study participants. Intensity of pain was reduced significantly in the group treated by multidisciplinary approach (t = 5.718; P = 0.0001). Similarly only 4 (19.19%) of the study participants of the group treated by multidisciplinary approach availed sick leave due to low back pain, while 14 (63.63%) study participants availed sick leave in the other group (P = 0.02). The quality of life amongst the study participants treated by multidisciplinary approach was significantly improved compared to the group treated by conventional approach (t = 7.037; P = 0.0001). CONCLUSION AND RECOMMENDATION: The multidisciplinary treatment approach was better than the conventional treatment approach in low back pain cases when some factors like pain and quality of life were assessed. The multidisciplinary approach for treatment of low back pain should be promoted over conventional approach. Larger studies are required to confirm the findings in different settings. PMID- 23741123 TI - Mechanism and patterns of cervical spine fractures-dislocations in vertebral artery injury. AB - PURPOSE: To identify the fracture patterns and mechanism of injury, based on subaxial cervical spine injury classification system (SLIC), on non-contrast computed tomography (NCCT) of cervical spine predictive of vertebral artery injury (VAI). PATIENTS AND METHODS: We retrospectively analyzed cervical spine magnetic resonance imaging (MRI) of 320 patients who were admitted with cervical spine injury in our level I regional trauma center over a period of two years (April 2010 to April 2012). Diagnosis of VAI was based on hyperintensity replacing the flow void on a T2-weighted axial image. NCCT images of the selected 43 patients with MRI diagnosis of VAI were then assessed for the pattern of injury. The cervical spinal injuries were classified into those involving the C1 and C2 and subaxial spine. For the latter, SLIC was used. RESULTS: A total of 47 VAI were analyzed in 43 patients. Only one patient with VAI on MRI had no detectable abnormality on NCCT. C1 and C2 injuries were found in one and six patients respectively. In subaxial injuries, the most common mechanism of injury was distraction (37.5%) with facet dislocation with or without fracture representing the most common pattern of injury (55%). C5 was the single most common affected vertebral level. Extension to foramen transversarium was present in 20 (42.5%) cases. CONCLUSION: CT represents a robust screening tool for patients with VAI. VAI should be suspected in patients with facet dislocation with or without fractures, foramina transversarium fractures and C1-C3 fractures, especially type III odontoid fractures and distraction mechanism of injury. PMID- 23741124 TI - Large intradural craniospinal arachnoid cyst: A case report and review of literature. AB - Presence of an arachnoid cyst at craniospinal junction is not very common. This is a very rare anatomic site, with only seven other cases reported in the literature. We report a case of large intradural craniospinal arachnoid cyst presenting with obstructive hydrocephalus and cranial nerve palsy. A 39-year-old male presented with 8-month history of neck pain, headache, vomiting, visual disturbances, diminished taste sensation, and numbness of face. He had bilateral papilledema on ophthalmoscopy. Magnetic resonance imaging (MRI) revealed a posterior fossa arachnoid cyst extending down to the lower border of C5 vertebra. Posterior decompression was done through C5 laminectomy. He made a full recovery and was asymptomatic at 6-month follow-up examination. The clinical features, diagnosis, and management of these rare craniospinal arachnoid cysts are discussed. PMID- 23741125 TI - Delayed anterior cervical plate dislodgement with pharyngeal wall perforation and oral extrusion of cervical plate screw after 8 years: A very rare complication. AB - We report a patient with congenital anomaly of cervical spine, who presented with clinical features suggestive of cervical compressive spondylotic myelopathy. He underwent C3 median corpectomy, graft placement, and stabilization from C2 to C4 vertebral bodies. Postoperative period was uneventful and he improved in his symptoms. Eight years later, he presented with a difficulty in swallowing and occasional regurgitation of feeds of 2 months duration and oral extrusion of screw while having food. On oral examination, there was a defect in the posterior pharyngeal wall through which the upper end of plate with intact self-locking screw and socket of missed fixation screw was seen. This was confirmed on X-ray cervical spine. He underwent removal of the plate system and was fed through nasogastric tube and managed with appropriate antibiotics. This case is presented to report a very rare complication of anterior cervical plate fixation in the form of very late-onset dislodgement, migration of anterior cervical plate, and oral extrusion of screw through perforated posterior pharyngeal wall. PMID- 23741126 TI - Pediatric intervertebral disc calcification: A no touch lesion. AB - Intervertebral disc calcification (IVDC), though rare, remains an important differential of pediatric spinal pain. A 7-year-old boy presented with sudden onset severe neck pain and restricted movements. There was no definite history of trauma or infection. Imaging of the cervical spine showed calcification of the intervertebral disc at C2-3 level, with significant posterior protrusion into the spinal canal causing compression of the cervical spinal cord. The child was kept on conservative management. The calcification and posterior protrusion showed near-complete resolution on 3-month follow-up. This case report emphasizes that childhood IVDC is a benign condition which commonly resolves spontaneously, without any surgical intervention and neurological sequelae. PMID- 23741127 TI - Syringomyelia as a presenting feature of shunt dysfunction: Implications for the pathogenesis of syringomyelia. AB - The pathogenesis of syringomyelia continues to be an enigma. The patency of the central canal and its role in the pathogenesis of communicating syringomyelia continues to elicit controversy. The case reported here provides an opportunity to retest some of the hypotheses of syringomyelia. A 33 year old female presented with sensory disturbances over the left upper extremity and trunk and was diagnosed to have panventriculomegaly with communicating syringomyelia. She was initially treated with ventriculoperitoneal shunting. As there was no change in her neurological status following shunt, this was followed by foramen magnum decompression with excision of an arachnoid veil covering the fourth ventricular outlet. She had clinical and radiological improvement after foramen magnum decompression. Five months later she had reappearance of the symptoms of syringomyelia and was found to have shunt dysfunction and holocord syrinx. She improved following shunt revision. This case is being reported to highlight the following points: 1. In patients with communicating syringomyelia and hydrocephalus, shunt dysfunction can present with symptoms of syringomyelia without the classical clinical features of shunt dysfunction, 2. In patients with communicating syringomyelia, the central canal of the spinal cord acts as an "exhaust valve" for the ventricular system, and, 3. studies about the patency of the central canal are reviewed in the context of this case and the role of the central canal in the pathogenesis of communicating syringomyelia is reviewed. PMID- 23741128 TI - Primary calcified rhabdoid meningioma of the cranio-cervical junction: A case report and review of literature. AB - Rhabdoid meningioma (RM) is a relatively new, rare, and aggressive subtype of meningioma, classified as Grade III malignancy in 2000, 2007 versions of WHO classification of the central nervous system. We reviewed the data available from all published cases of RMs. To the best of our knowledge, there are more than 100 published cases of RMs; none have documented extensive calcification or origin from the cranio cervical junction. We report the first case of a totally calcified (stony mass), primary RM, at the cranio cervical junction. Also, we highlighted the role of the transcondylar approach to achieve microscopic total removal of such a challenging lesion. A 37 year old female, allergic to erythromycin, presented with 5 years of progressive right upper extremity numbness and weakness, right facial numbness, and occipital pain. Imaging demonstrated a large calcified mass at the right posterior-lateral margin of the cranio cervical junction, encasing the right vertebral artery and right PICA loop. Patient underwent microscopic total resection of the lesion. Pathological diagnosis was confirmed as RM with atypical features. Subsequently, the patient received postoperative intensity modulated radiotherapy (IMRT) on the tumor bed, and close follow up imaging showed no recurrence 2 years after surgery. We report the first case of a primary RM originating from the cranial cervical junction; also, it is the first case to present with extensive calcification in this morphological subtype. We also conclude that RM has now become a feature of newly diagnosed cases and not only a disease of recurrent cases as it was thought in the past. Since RMs are typically considered aggressive, total surgical resection with close follow up and postoperative adjuvant radiation should be considered. However, the adjuvant therapy of each separate case of RM should be tailored according to its particular histopathologic profile. PMID- 23741129 TI - Strengthening institutional capacity for glaucoma care in sub-Saharan Africa. PMID- 23741131 TI - Glaucoma drainage implant surgery--an evidence-based update with relevance to sub Saharan Africa. AB - Glaucoma represents a leading cause of preventable vision loss in Sub-Saharan Africa. Recent studies evaluating outcomes of glaucoma drainage implant (GDI) surgery suggest an important role for this approach in the African patient population. The Tube Versus Trabeculectomy study demonstrated a higher success rate with non-valved GDI surgery compared to trabeculectomy with mitomycin C after five years. The Ahmed Baerveldt Comparison study showed no difference in surgical failure rates between the Ahmed Glaucoma Valve and the Baerveldt Glaucoma Implant (BGI) but better intraocular pressure outcomes with the BGI at one year. The Ahmed Versus Baerveldt study demonstrated a lower failure rate for the BGI, but also a requirement for more post-operative interventions. Further study of GDI surgery in the Sub-Saharan Africa is necessary to determine its optimal place in the treatment paradigm for glaucoma patients in the region. PMID- 23741130 TI - Epidemiology of glaucoma in sub-saharan Africa: prevalence, incidence and risk factors. AB - PURPOSE: The purpose of this study is to review the epidemiology of different types of glaucoma relevant to Sub-Saharan Africa (SSA) and to discuss the evidence regarding the risk factors for onset and progression of glaucoma, including risk factors for glaucoma blindness. METHODS: Electronic databases (PubMed, MedLine, African Journals Online- AJOL) were searched using the full text, Medical Subject Headings (MeSH) terms, author(s) and title to identify publications since 1982 in the following areas: population-based glaucoma prevalence and incidence studies in SSA and in African-derived black populations outside Africa; population-based prevalence and incidence of blindness and visual impairment studies in SSA including rapid assessment methods, which elucidate the glaucoma-specific blindness prevalence; studies of risk factors for glaucoma; and publications that discussed public health approaches for the control of glaucoma in Africa. RESULTS: Studies highlighted that glaucoma in SSA is a public health problem and predominantly open-angle glaucoma. It is the second-leading cause of blindness, has a high prevalence, an early onset and progresses more rapidly than in Caucasians. These factors are further compounded by poor awareness and low knowledge about glaucoma even by persons affected by the condition. CONCLUSION: Glaucoma care needs to be given high priority in Vision 2020 programs in Africa. Many questions remain unanswered and there is a need for further research in glaucoma in SSA in all aspects especially epidemiology and clinical care and outcomes involving randomized controlled trials. Genetic and genome-wide association studies may aid identification of high-risk groups. Social sciences and qualitative studies, health economics and health systems research will also enhance public health approaches for the prevention of blindness due to glaucoma. PMID- 23741132 TI - Advanced glaucoma: management pearls. AB - A significant proportion of glaucoma patients present late, particularly in the developing world, and unfortunately, in an advanced stage of the disease. They are at imminent danger of losing remaining vision, and may also be afflicted with various socioeconomic and health challenges. The encounter with such a patient is typically characterized by anxiety/fear and sometimes hopelessness from the patient's perspective. The physician may also feel that they are in a difficult position managing the patient's disease. When dealing with such cases, we suggest a holistic, individualized approach taking into account the 'biopsychosociospiritual' (BPSS) profile of each patient. The BPSS model takes into account relevant ocular as well as systemic biology (factors such as the mechanism of glaucoma, level of intraocular pressure [IOP], rate of progression, life expectancy, general health), psychological considerations (e.g., fear, depression), socio-economic factors and spiritual/cultural values and beliefs before being able to decide with the patient and their care partner(s) what treatment goals should be and how they can best be approached. Treatment for advanced glaucoma can be highly effective, and patients and their care partners should be informed that aggressive IOP lowering to the low teens or even single digits offers the best chance of protecting remaining vision. This can be achieved safely and effectively in most cases with trabeculectomy (including an antimetabolite), and in some cases with medical and/or laser therapy. Vision rehabilitation and psychosocial support should also be considered in order to optimize remaining vision, replace fear with hope as appropriate, and thus improve the overall quality of life. PMID- 23741133 TI - Teleglaucoma: improving access and efficiency for glaucoma care. AB - Teleglaucoma is the application of telemedicine for glaucoma. We review and present the current literature on teleglaucoma; present our experience with teleglaucoma programs in Alberta, Canada and Western Australia; and discuss the challenges and opportunities in this emerging field. Teleglaucoma is a novel area that was first explored a little over a decade ago and early studies highlighted the technical challenges of delivering glaucoma care remotely. Advanced technologies have since emerged that show great promise in providing access to underserviced populations. Additionally, these technologies can improve the efficiency of healthcare systems burdened with an increasing number of patients with glaucoma, and a limited supply of ophthalmologists. Additional benefits of teleglaucoma systems include e-learning and e-research. Further work is needed to fully validate and study the cost and comparative effectiveness of this approach relative to traditional models of healthcare. PMID- 23741134 TI - The Muranga Teleophthalmology Study: Comparison of Virtual (Teleglaucoma) with in Person Clinical Assessment to Diagnose Glaucoma. AB - PURPOSE: While the effectiveness of teleophthalmology is generally accepted, its ability to diagnose glaucomatous eye disease remains relatively unknown. This study aimed to compare a web-based teleophthalmology assessment with clinical slit lamp examination to screen for glaucoma among diabetics in a rural African district. MATERIALS AND METHODS: Three hundred and nine diabetic patients underwent both the clinical slit lamp examination by a comprehensive ophthalmologist and teleglaucoma (TG) assessment by a glaucoma subspecialist. Both assessments were compared for any focal glaucoma damage; for TG, the quality of photographs was assessed, and vertical cup-to-disk ratio (VCDR) was calculated in a semi-automated manner. In patients with VCDR > 0.7, the diagnostic precision of the Frequency Doubling Technology (FDT) C-20 screening program was assessed. RESULTS: Of 309 TG assessment photos, 74 (24%) were deemed unreadable due to media opacities, patient cooperation, and unsatisfactory photographic technique. While the identification of individual optic nerve factors showed either fair or moderate agreement, the ability to diagnose glaucoma based on the overall assessment showed moderate agreement (Kappa [kappa] statistic 0.55% and 95% confidence interval [CI]: 0.48-0.62). The use of FDT to detect glaucoma in the presence of disc damage (VCDR > 0.7) showed substantial agreement (kappa statistic of 0.84 and 95% CI 0.79-0.90). A positive TG diagnosis of glaucoma carried a 77.5% positive predictive value, and a negative TG diagnosis carried an 82.2% negative predicative value relative to the clinical slit lamp examination. CONCLUSION: There was moderate agreement between the ability to diagnose glaucoma using TG relative to clinical slit lamp examination. Poor quality photographs can severely limit the ability of TG assessment to diagnose optic nerve damage and glaucoma. Although further work and validation is needed, the TG approach provides a novel, and promising method to diagnose glaucoma, a major cause of ocular morbidity throughout the world. PMID- 23741135 TI - Dynamic contour tonometry in primary open angle glaucoma and pseudoexfoliation glaucoma: factors associated with intraocular pressure and ocular pulse amplitude. AB - PURPOSE: To compare the intraocular pressures (IOP) and ocular pulse amplitudes (OPAs) in patients with primary open-angle glaucoma (POAG) and pseudoexfoliation glaucoma (PXG), and to evaluate ocular and systemic factors associated with the OPA. MATERIALS AND METHODS: In this prospective study, on 28 POAG and 30 PXG patients, IOP was measured with the Goldmann applanation tonometry (GAT) and the Pascal dynamic contour tonometry (DCT). Other measurements included central corneal thickness (CCT), vertical cup-to-disc ratio (CDR), and systolic and diastolic blood pressure. Statistical significance was defined as P < 0.05. RESULTS: In each of the POAG and PXG groups, GAT IOP was correlated with CCT (r = 0.40, P = 0.03 and r = 0.35, P = 0.05, respectively), whereas DCT IOP and CCT were not correlated. In all patients and in the POAG group, OPA was positively correlated with DCT IOP (r = 0.39, P = 0.002). OPA was not correlated with CCT in the POAG (P = 0.80), nor in the PXG (P = 0.20) group, after adjusting for DCT IOP. When corrected for DCT IOP and CCT, there was a significant negative correlation between OPA and vertical CDR in all patients (r = -0.41, P = 0.002). There was no significant difference in OPA between groups (P = 0.55), even when OPA was adjusted for IOP and systolic and diastolic pressure (P = 0.40), in a linear regression model. CONCLUSION: DCT IOP and OPA are not correlated with CCT. There is no significant difference between the OPA of PXG and POAG eyes. OPA is correlated with DCT IOP, and is lower in eyes with more advanced glaucomatous cupping. PMID- 23741136 TI - Awareness and knowledge of glaucoma among workers in a Nigerian tertiary health care institution. AB - PURPOSE: The aim of this study reports the level of awareness and knowledge of glaucoma among selected health care personnel at a health institution in southwestern Nigeria. MATERIALS AND METHODS: Health personnel at the Federal Medical Centre, Owo, Nigeria, a tertiary health care institution were stratified into a clinical and an administrative directorate. One-hundred twenty participants were selected from each directorate by a random sampling technique. A structured questionnaire was used to collect sociodemographic data and data on the level of knowledge and awareness of glaucoma. Statistical analyses included the independent t-test and Pearson's chi-square test for categorical variables. Statistical significance was indicated by P < 0.05. RESULTS: From the target population of 240 participants, 216 (98 males; 118 females) completed the questionnaire. The mean age of the participants was 35.07 +/- 07 years. A total of 148 (68.6%) participants had heard of glaucoma comprising all participants from the clinical directorate and 28 participants from the administrative directorate. There was no statistically significant difference between the clinical and administrative directorates about the knowledge of the aspect of vision that is first affected by glaucoma, the painless nature of glaucoma among most Africans and the irreversible nature of glaucoma-related blindness (P > 0.05, all comparisons). CONCLUSION: There is the need to update the knowledge base of these workers if they are to be useful in propagating information of the irreversible blindness that could arise from delay in glaucoma diagnosis and treatment. PMID- 23741137 TI - Patient refusal of glaucoma surgery and associated factors in Lagos, Nigeria. AB - PURPOSE: To determine the prevalence of patient refusal of glaucoma surgery (GSR) and the associated factors in Lagos, Nigeria. MATERIALS AND METHODS: A multicenter cross-sectional survey was conducted in Lagos state, Nigeria. Twelve centres were invited to participate, but data collection was completed in 10. Newly diagnosed glaucoma patients were recruited and interviewed from these sites over a four week period on prior awareness of glaucoma, surgery refusal, and reason(s) for the refusal. Presenting visual acuity was recorded from the patient files. The odds ratio and 95% confidence intervals (CI) were calculated. RESULTS: A total of 208 newly diagnosed glaucoma patients were recruited. Sixty-five (31.2%) patients refused surgery. Fear of surgery (31 (47.7%) patients), and fear of going blind (19 (29.2%) patients) were the most common reasons. The odds ratio of surgery refusal were marital status - not married versus married (2.0; 95% CI, 1.02-3.94), use of traditional medication - users versus non users (2.4; 95% CI, 1.1-5.2), perception of glaucoma causing blindness - no versus yes (3.7; 95% CI, 1.3-10.5), type of institution - government versus private (5.7; 95% CI, 1.3 25.1), and visual acuity in the better eye - normal vision versus visual impairment (2.3; 95% CI, 1.1-4.9). Age, gender, level of education, family history of glaucoma, and prior awareness of the diagnosis of glaucoma, were not significantly associated with surgery refusal. Perception of patients concerning glaucoma blindness was the strongest factor on multivariate analysis. CONCLUSION: GSR was relatively low in this study. Unmarried status, use of traditional medications, perception that glaucoma cannot cause blindness, government hospital patients, and good vision in the better eye were associated with GSR. These factors might help in the clinical setting in identifying appropriate individuals for targeted counseling, as well as the need for increased public awareness about glaucoma. PMID- 23741138 TI - Ocular blood flow velocity in primary open angle glaucoma--a tropical African population study. AB - PURPOSE: To assess blood flow velocity in newly diagnosed indigenous black skinned Africans with primary open angle glaucoma (POAG). MATERIALS AND METHODS: Prospective case-control study at Obafemi Awolowo University Teaching Hospital, Ile-Ife, Nigeria on 50 newly diagnosed POAG patients (POAG group) and 50 control patients (control group). Ocular Doppler Color Imaging was performed on subjects in the supine position using 9 MHz linear array transducer of a Fukuda Denshi Ultrasound. The Peak Systolic Velocity (PSV) and End Diastolic Velocity (EDV) values were obtained by finding the average of two readings each for the ophthalmic artery (OA) and central retinal artery (CRA). Resistive Index (RI) was calculated as (PSV - EDV)/PSV. Data were analyzed and statistical significance was defined at P < 0.05. RESULTS: The mean intraocular pressure (IOP) for the POAG group and control group was 28.1 +/- 7.4 mmHg and 16.6 +/- 2.0 mmHg, respectively (P < 0.001). The mean PSV for OA was 31.35 cm/s in POAG group and 37.61 cm/s for the control group (P < 0.001). The EDV for both OA and CRA were significantly lower in glaucoma patients as compared with the corresponding values in the control group (P < 0.001, both comparisons). The mean RI in the OA was 0.71 +/- 0.05 and 0.63 +/- 0.03 for the POAG and control group groups, respectively (P < 0.001). The increase in IOP in the POAG group was statistically significantly negatively correlated with PSV and EDV and positively correlated with RI for both OA and CRA. CONCLUSION: The outcomes of this study indicate that ocular blood flow alterations including reductions in PSV and EDV and increase in RI of the OA and CRA are present in black-skinned Africans with POAG. PMID- 23741139 TI - Postoperative suprachoroidal hemorrhage in a glaucoma patient on low molecular weight heparin. AB - Suprachoroidal hemorrhage is a complication associated with intraocular surgery that can occur both intraoperatively and postoperatively. Several intraoperative or postoperative risk factors have been identified. The use of low-molecular weight heparin (LMWH) is considered one of the risk factors in surgical cases (ocular or non ocular) and non-surgical cases. Here we present a case of suprachoroidal hemorrhage in a glaucoma patient that occurred after preoperative prophylactic LMWH for deep venous thrombosis. The use of LMWH has been reported to cause suprachoroidal hemorrhage even in patients without any risk factors. The use of LMWH continues to increase, hence it is important to be aware of the possibility of suprachoroidal hemorrhage and to determine the risk/benefit ratio, especially in patients with other risk factors. PMID- 23741141 TI - Status of forensic odontology in India. PMID- 23741140 TI - Glycopyrrolate induced bilateral angle closure glaucoma after cervical spine surgery. AB - To report a case of bilateral acute angle closure glaucoma (AACG) that occurred after cervical spine surgery with the use of glycopyrolate. A 59-year-old male who presented with severe bilateral bifrontal headache and eye pain that started 12 h postextubation from a cervical spine surgery. Neostigmine 0.05 mg/kg (4.5 mg) and glycopyrrolate 0.01 mg/kg (0.9 mg) were used as muscle relaxant reversals at the end of the surgery. Ophthalmic examination revealed he had bilateral AACG with plateau iris syndrome that was treated medically along with laser iridotomies. Thorough examination of anterior chamber should be performed preoperatively on all patients undergoing surgeries in the prone position and receiving mydriatic agents under general anesthesia. PMID- 23741142 TI - Mandibular ramus: An indicator for sex determination - A digital radiographic study. AB - BACKGROUND: The identification of skeletal remains is of paramount importance in medico-legal investigations. The skeletal components most often investigated for gender determination are the pelvis and skull, with the mandible being a practical element to analyze sexual dimorphism in the fragmented bones. Presence of a dense layer of compact bone makes it very durable and well preserved than many other bones. Mandibular ramus can be used to differentiate between sexes and it also expresses strong univariate sexual dimorphism. When skeleton sex determination is considered, metric analyses on the radiographs are often found to be of superior value owing to their objectivity, accuracy, and reproducibility. AIMS AND OBJECTIVES: (1) To measure, compare, and evaluate the various measurements of mandibular ramus as observed on orthopantomographs. (2) To assess the usefulness of mandibular ramus as an aid in sex determination. MATERIALS AND METHODS: A retrospective study was conducted using orthopantomographs of 50 males and 50 females, which were taken using Kodak 8000C Digital Panoramic and Cephalometric System (73 kVp, 12 mA, 13.9 s). Mandibular ramus measurements were carried out using Master View 3.0 software. The measurements of the mandibular ramus were subjected to discriminant function analysis. RESULTS: We observed each variable of the mandibular ramus to be a significant predictor in classifying a given sample (P < 0.001). CONCLUSION: This study on mandibular ramus measurements using orthopantomograph shows strong evidence suggesting that the ramus can be used for gender determination for forensic analysis. PMID- 23741143 TI - Age estimation using third molar teeth: A study on southern Saudi population. AB - OBJECTIVE: To estimate the age of an individual between 13 and 23 years, using Demirjian method in Saudi male patients in the southern region of the Kingdom of Saudi Arabia. MATERIALS AND METHODS: A total of 360 male patient's digital panoramic radiographs were used to evaluate the morphology of mandibular 3rd molar teeth roots according to the Demirjian method. Using descriptive statistical method, age was calculated. RESULTS: Result showed a strong relation of age with stages of root development of 3rd molar teeth. The standard deviation of mean of root development stages is 1.47 years of age. CONCLUSION: This study suggests that age can be predicted with a statistical significant result for ages between 13 and 23. Further studies with large population are needed for better statistical results and for female age assessment. PMID- 23741144 TI - Determination of sex by exfoliative cytology using acridine orange confocal microscopy: A short study. AB - CONTEXT: Establishing individuality is an imperative aspect in any investigation procedure. Sometimes, in identifying an individual, it becomes necessary to determine the sex of that particular individual. Combining rapidity with reliability, an innovative idea has been put forward using a confocal microscope in exfoliative cytology. In the present study, we have determined the sex of the individual from buccal mucosal scrapings. The exfoliative cells were observed for Barr bodies under a confocal microscope, and the percentage of Barr-body-positive cells was determined. AIMS: The main objective of this study is to assess confocal microscopy for the determination of sex by observing Barr bodies in the exfoliative cells of both men and women. SETTINGS AND DESIGN: Samples of buccal mucosa smears were made followed by acridine orange staining. The stained slides were observed under a confocal microscope and the data obtained was subjected for statistical analysis, especially for mean and standard deviation. MATERIALS AND METHODS: Samples of buccal mucosa smears from 20 men and 20 women were obtained by scraping with flat wooden sticks (exfoliative cytology). The smears were fixed in 100% alcohol for 15 min, followed by acridine orange (AO) staining as described by Von Bertalanffy et al. Smears stained with AO were examined under a confocal microscope and the percentage of Barr-body-positive cells was determined. STATISTICAL ANALYSIS USED: Data obtained was subjected for statistical analysis, especially for mean and standard deviation. RESULTS: Two non-overlapping ranges for the percentage of Barr-body-positive cells have been obtained for men and women. It was observed that in the male samples, the percentage of Barr-body-positive cells ranged from 0-3%. In the female samples, the percentage of Barr-body-positive cells ranged from 18-72%, and all the females showed the presence of Barr bodies. CONCLUSION: The study showed that the presence of Barr body in buccal mucosal cells can be demonstrated with a fair degree of accuracy using acridine orange confocal microscopy. The sex of the individual can be determined accurately with other advantages offered, such as the rapidity of processing and screening a specimen that results in saving of time. PMID- 23741145 TI - Sex determination using cheiloscopy and mandibular canine index as a tool in forensic dentistry. AB - INTRODUCTION: Establishment of a person's individuality is important for legal as well as humanitarian purpose and gender determination is an essential step in identifying an individual. In forensic odontology the sum total of all the characteristics of teeth and their associated structures provide a unique totality and forms the basis for personal identification. AIMS AND OBJECTIVES: To investigate the accuracy of various methods employed in sex determination such as cheiloscopy and mandibular canine index (MCI). MATERIALS AND METHODS: The study group comprises adults between 20 and 25 years of age, who were assessed for gender identification using lip prints and MCI. The results were subjected to statistical analysis. RESULTS: MCI and lip prints were found to be accurate and specific for sex determination. CONCLUSION: There is scope for use of these methods in criminal investigations, personal identification, and genetic studies. Thus, dental tissues make good witnesses although they speak softly, they never lie and they never forget. PMID- 23741146 TI - Palatal rugae in population differentiation between South and North Indians: A discriminant function analysis. AB - AIM: The present study is aimed at delineation of different types of rugae in two different populations and developing a discriminant function for the same. MATERIALS AND METHODS: A total of 940 subjects were included in the present study. The sample consisted of 466 subjects from South Indian population and 474 from North Indian population in the age group of 18-23 years. Neo colloid Easy flow((TM)) alginate impressions of maxillary arch were made and casts were immediately poured with Type IV dental stone. A sharp graphite pencil was used to delineate the rugae and patterns were recorded according to the classification given by Kapali et al. The association between different population and different sexes was analyzed with chi-square test and a stepwise discriminant function analysis was also performed to develop a discriminant formula. RESULTS: Wavy, curved and straight rugae were the most common forms in both groups. Chi-square analysis for association between rugae shape and population groups showed significant differences among all the rugae patterns at the P < 5%. Chi-square analysis for assessing sex differences in the rugae shapes showed significant difference in straight, unification and circular type. Five rugae shapes - curved, wavy, nonspecific, unification and circular - were selected for discriminant function. CONCLUSION: The discriminant function equation obtained from the different rugae shapes in the present study was highly accurate enough to distinguish the Southern and Northern Indian population with the classification accuracy of 87.8%. Thus to identify a specific population, separate discriminant function formulae have to be developed. Hence, the study of palatal rugae is one of the simple and reliable tools for population identification in forensic science. PMID- 23741147 TI - Canine tooth dimorphism: An adjunct for establishing sex identity. AB - BACKGROUND: Teeth are an excellent material for genetic, odontological and forensic investigations and research purpose. From all the teeth, the mandibular canines are found to exhibit sexual dimorphism. However, very few studies have been published on maxillary canine's measurements. AIMS: 1. To find out utility of maxillary and mandibular canine width as a tool for sex determination in Central Indian population. 2. To find out the average size of canines in males and females of Central Indian population. 3. To compare the findings with National and International studies. MATERIALS AND METHODS: The present study was conducted in 100 cases in the age group of 17-21 years. Mesiodistal width of right and left mandibular and maxillary canines were measured on the casts with digital calliper and subjected to statistical analysis. STATISTICAL ANALYSIS: Statistical analysis was done to assess sex difference using Students "t" test (paired). RESULTS AND CONCLUSIONS: It was seen that a definite statistically significant sexual dimorphism exists when mandibular and maxillary canine measurements were compared. Thus, it can be suggested that canine width measurements can be used as an adjunct for sex identification purpose in Central Indian Population. PMID- 23741148 TI - A study of lip prints among Pondicherry population. AB - BACKGROUND: Cheiloscopy is a forensic investigation that deals with the examination of the system of furrows on the red part of human lips. Like fingerprint, lip print is also unique for every individual. But most of the crime detecting agencies are unaware of the importance of lip print and it is not commonly attempted in identification of the suspects. AIM: The aim of the present study is to determine the predominant lip print pattern among Pondicherry population, India, and also to determine its uniqueness. MATERIALS AND METHODS: The study comprised of 60 students (30 males and 30 females), aged from 17 to 25 years, from Pondicherry population, India. A dark-colored lipstick was applied with a single stroke and the students were asked to rub both the lips to spread the applied lipstick, after which a lip print was made on butter paper. The lip print was visualized with magnifying lens. STATISTICAL ANALYSIS: Percentage calculation method was used to identify the predominant lip pattern. One-sample T test was done to identify the statistical significance within the different types of lip pattern with P value <0.05. RESULTS AND CONCLUSION: The present study concludes that every individual has unique lip print and Type III appears to be the most predominant pattern in males, followed by the Type II, Type IV, Type I and Type V patterns. In females, Type II appears to be the most predominant pattern followed by the Type IV, Type I, Type III and Type V patterns. PMID- 23741149 TI - A cephalometric study of skulls from the Bahriyah oasis. AB - OBJECTIVES: To determine the craniofacial characteristics of crania from the Bahariyah oasis dating from the Greco-Roman period and to compare their cephalometric traits with other ancient Egyptian samples from various time periods and to evaluate sexual dimorphism. MATERIALS AND METHODS: The sample comprised 149 skulls (90 males and 59 females), belonging to the Greco-Roman (332 B.C. - 395 A.D.). Lateral and postero-anterior cephalograms were taken. Sixteen linear measurements were analyzed and six indices were calculated. RESULTS: Significant differences were found between males and females almost in all measurements. All male measurements were greater than those of the females. The study shows notable differences in the craniofacial parameters of the present sample as compared to other ancient Egyptians from various periods and from various geographical areas. CONCLUSION: The present study suggests that the studied crania from Bahriyah oasis had a specific craniometric phenotype, which is distinguished from other Egyptian samples from different periods, suggesting some migration could have occurred along the Egyptian Nile Valley over various times. PMID- 23741150 TI - Assessment of palatal rugae patterns in Manipuri and Kerala population. AB - BACKGROUND: Palatal rugae comprises three to seven ridges radiating out tangentially from the incisive papilla on the anterior part of the palate. These rugae patterns are studied for various reasons, mainly in the fields of anthropology, genetics, orthodontics, prosthodontics, and forensic science. OBJECTIVE: To compare the palatal rugae pattern in two different populations (Manipuri and Kerala), and to assess the predominant pattern if any in the selected groups. MATERIALS AND METHODS: Sixty maxillary study models (30 from each group including males and females) were examined in the age group ranging from 17 to 23 years. Palatal rugae pattern were analyzed on the right and left sides of the palate for total number, length, shape, direction, and unification. RESULTS: After analyzing the rugae patterns in both the groups and between the two sides of the palate, the wavy pattern was found to be predominant followed by curved, straight, and circular in overall population. Manipuri population showed predominant curved shape than the Kerala population and was statistically significant. Females in general had slightly more rugae than males and the left side of the palate showed comparatively more number of rugae than on the right side. CONCLUSION: A statistically significant association between the shape of the rugae and population exists although, subtle. Parameters like direction and unification need more attention for better understanding. PMID- 23741151 TI - Age estimation using maxillary central incisors: A radiographic study. AB - BACKGROUND: In the field of forensic dentistry, secondary changes in teeth with advancing age have been used as reliable predictors of age in various studies. AIM: The purpose of the present study was to present a method for assessing the chronological age based on the relationship between age and morphological parameters of maxillary central incisors. MATERIALS AND METHODS: Fifty subjects between 20-70 years of age were included in the study. Intraoral periapical radiographs were taken in relation to maxillary central incisors using paralleling technique. The following measurements were recorded: lengths of tooth, pulp, root and width of root and pulp at three different points. Regression formulas were used to calculate the dental age. RESULTS: The mean estimated age showed no statistically significant difference from the actual mean age (P > 0.05). Also, maximum difference was seen for root length variable ( 1.035 +/- 1.86 years). PMID- 23741152 TI - Permanent maxillary first molars: Role in gender determination (Morphometric analysis). PMID- 23741153 TI - Traditional knowledge patents: New guidelines or deterrents? PMID- 23741154 TI - Approaches to pre-formulation R and D for phytopharmaceuticals emanating from herb based traditional Ayurvedic processes. AB - Botanicals constitute a large part of the drugs from the traditional medicine (TM) and ethno medicine (EM) known for their history of safe use (HOSU). Phytopharmaceuticals having a base of such origin offer high advantages as they come with safety profiles, and often allow extrapolation of the HOSU data, under certain circumstances. However, while current pharmaceutical technologies are being adopted by the industry to make phytopharmaceuticals with such origin, there is a need for preformulation research and development (R and D) during formulation. Some suggestions for R and D studies in case of aqueous extracts known in Ayurveda, converted on an industrial scale to obtain a phytopharmaceutical, and formulated as a solid dosage form (granules, tablets, or capsules) are discussed. PMID- 23741155 TI - Basti: Does the equipment and method of administration matter? AB - Basti is one of the five procedures of panchakarma in Ayurveda. Classically, it is advocated in the diseases of vata. It is mainly of two types viz. asthapana and anuvasana. According to the classical texts basti administration is done with the help of animal bladder (bastiputaka) and specially prepared metal/wooden nozzle/catheter (bastinetra), the whole assembly is called as bastiyantra. Nowadays, except in some of the Vaidya traditions in Kerala, basti administration is often done using enema-can or douche-set. In the aforesaid classical procedure active pressure is expected to be given on the bastiputaka whereas, in conventionally used enema-can only passive or gravitational force plays a role. This is important in the context of 'basti danakala or pidanakala i.e. time for basti administration'. PMID- 23741156 TI - Anti-granuloma activity of Coriandrum sativum in experimental models. AB - BACKGROUND: Coriandrum sativum has been used in the traditional systems of medicine for management of arthritis and other inflammatory disorders. OBJECTIVES: In this study, we have evaluated the anti-inflammatory and anti granuloma activities of Coriandrum sativum hydroalcoholic extract (CSHE) in experimental models. MATERIALS AND METHODS: The anti-inflammatory activity of CSHE was evaluated using carrageenan-induced paw edema model and the anti granuloma activity of CSHE was evaluated using the subcutaneous cotton pellet implantation-induced granuloma formation and stimulation of peritoneal macrophages with complete Freund's adjuvant. Serum tumor necrosis factor-alpha (TNF-alpha), IL-6, IL-1 beta levels, and peritoneal macrophage expression of TNF R1 were evaluated as markers of global inflammation. RESULTS: CSHE at the highest dose tested (32 mg/kg) produced a significant reduction (P < 0.05) in paw edema after carrageenan administration. CSHE treatment also reduced dry granuloma weight in all treated animals. Serum IL-6 and IL-1 beta levels were significantly (P < 0.05) lower in the CSHE (32 mg/kg)-treated group as compared to control. Although there was an increase in serum TNF-alpha level in the CSHE-treated group as compared to control, TNF-R1 expression on peritoneal macrophages was found to be reduced. CONCLUSION: Thus, the result of this study demonstrates the anti inflammatory and anti-granuloma activities of CSHE in experimental models, and validates its traditional use for the management of arthritis and other inflammatory disorders. PMID- 23741157 TI - Fate of beta-asarone in Ayurvedic Sodhana process of Vacha. AB - BACKGROUND: Calamus (Acorus calamus Linn., Araceae) rhizome synonymously called sweet flag or Vacha is an aromatic herb indigenous to Central Asia and Eastern Europe. It has been used by the Ayurvedic practitioners since time immemorial for diseases ranging from weakness of memory to being used as an anthelminthic. Reports of its use have been found in books like Charak Samhita, Sushruta Samhita, etc., The major constituent of the oil of Vacha is a phenyl propanoid called beta-asarone, which is reported to show carcinogenic properties. Due to the toxic effects of beta-asarone, sodhana prakriya (detoxification process) has been prescribed for Vacha before its inclusion in the Ayurvedic medicines. Shodhanaprakriya (S. prakriya) of Vacha has been mentioned in the Ayurvedic texts. OBJECTIVES: This study was undertaken with an aim to find out the mechanism involved in the S. prakriya of Vacha and also to suggest an alternate method for the conventional one. MATERIALS AND METHODS: The conventional method was studied in the laboratory and equivalent alternate methods were designed based on the mechanism involved. Vacha samples were subjected to the conventional method as well as the alternate methods and the content of beta-asarone in the different samples was monitored using Gas Chromatography technique. RESULTS: Various alternate methods have been devised based on the mechanism involved in the S. prakriya which have given results comparable with those of the conventional method. CONCLUSION: The scientific mechanism involved in the S. prakriya of Vacha has been established and alternate methods have been proposed. PMID- 23741158 TI - Anti-inflammatory activity of two classical formulations of Laghupanchamula in rats. AB - BACKGROUND: Laghupanchamula denotes combinations of roots of five herbs. However, in Ayurvedic classics besides four common herbs viz. Kantakari, Brihati, Shaliparni, and Prinshniparni, the fifth one is either Gokshura (Laghupanchamula with Gokshura LPG) or Eranda (Laghupanchamula with Eranda LPE), and both formulations have been documented to have shothahara (anti-inflammatory) action. OBJECTIVES: The present study was undertaken to compare the anti-inflammatory activity of 50% ethanolic extract of LPG (LPGE) and LPE (LPEE) in rats and safety in mice. MATERIALS AND METHODS: LPGE and LPEE were given orally, administered either just before or 60 min before experiment on mice and for 7 days to rats. Paw edema was induced by carrageenan (acute) and formalin (sub-acute), whereas granuloma pouch (sub-acute) was induced by turpentine in rats. RESULTS: Both LPGE and LPEE (1.0 g/kg) at 3 h after their administration showed inhibition of formalin-induced paw edema by 46.2% and 44.3% (P < 0.001) and carrageenan-induced paw edema by 53.9% and 60.4% (P < 0.001), respectively. After 7 days of treatment, both LPGE and LPEE showed 26.3% (P < 0.01) and 32.5% (P < 0.05) inhibition, respectively, against formalin-induced paw edema, and reduced weight of turpentine-induced granuloma pouch by 42.8% and 36.1% (P < 0.001), and volume of exudates by 31.2% and 36.2% (P < 0.001), respectively. No acute toxicity was observed in mice even with a 10.0-g/kg dose of both extracts. CONCLUSION: LPGE and LPEE significantly reduced acute and sub-acute inflammation, and showed effective and similar anti-inflammatory activity. They seemed to be safe, and use of both formulations in the Laghupanchamula for their anti-inflammatory activity is, thus, authenticated. PMID- 23741159 TI - Impact of long term Yoga practice on sleep quality and quality of life in the elderly. AB - BACKGROUND: Sleep disturbances and decline in the physical functionality are common conditions associated with aging. Pharmacological treatment of sleep disturbances can be associated with various adverse effects. Short term trials of Yoga on sleep have shown beneficial effects. OBJECTIVES: To evaluate the effect of long-term Yoga exercises on sleep quality and quality of life (QOL) in the elderly. MATERIALS AND METHODS: This was a cross-sectional study in which data were collected from elderly people aged 60 years or more living in Nagpur city. We employed two types of survey questionnaires: Pittsburgh sleep quality index (PSQI) and QOL Leiden-Padua (LEIPAD) Questionnaire. A total of 65 elderly men and women who signed an informed consent and completed questionnaires were included in the study. Sleep quality score PSQI and QOL (LEIPAD Questionnaire) score of the study group were evaluated and compared with the control group using Mann Whitney U test. RESULTS: Total PSQI score in Yoga group was lower than that of the control group. Also various QOL scores of the Yoga groups were higher than the control group. CONCLUSION: Addition of regular Yoga exercises in the daily routine of elderly people can help to achieve good sleep quality as well as improve the QOL. PMID- 23741160 TI - An open label, prospective, clinical study on a polyherbal formulation in osteoarthritis of knee. AB - BACKGROUND: Currently, though pharmacological, mechanical, and surgical interventions are used, there is no known cure for osteoarthritis (OA). OBJECTIVES: The main aim of the study was to assess the efficacy and safety of "TLPL/AY/03/2008", a polyherbal formulation on knee joint pain assessed on visual analogue scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). MATERIALS AND METHODS: It was an open label, single center, prospective, clinical study conducted in 36 patients of OA Knee. Two capsules of 'TLPL/AY/03/2008' were given to all patients twice daily orally after meals for 180 days. RESULTS: Data describing quantitative measures are expressed as mean +/ SD. Comparison of variables representing categorical data was performed using Chi-square test. The mean joint pain (as assessed on VAS) reduced significantly (59.85%; P < 0.05) and the mean WOMAC combined score, WOMAC pain sub-score, WOMAC stiffness sub-score, and WOMAC difficulty sub-score also reduced significantly at the end of the study. The mean time taken by the patients to walk 50 feet too, was reduced significantly (25.26%) at the end of the study. At the end of 4 months of the treatment, no patient needed paracetamol as rescue medicine to control pain. Most of the patients had shown good overall improvement assessed by the physician and by the patients. Majority of the patients showed excellent tolerability to the study drug. No significant change in most of the safety laboratory parameters was observed at the end of the study. CONCLUSION: The study provides good evidence in support of the efficacy and safety of the 'TLPL/AY/03/2008' in OA of knee. PMID- 23741161 TI - Shirodhara: A psycho-physiological profile in healthy volunteers. AB - BACKGROUND: Shirodhara is a classical and a well-established ayurvedic procedure of slowly and steadily dripping medicated oil or other liquids on the forehead. This procedure induces a relaxed state of awareness that results in a dynamic psycho-somatic balance. OBJECTIVES: The objective of the study is to evaluate the psychological and physiological effects of Shirodhara in healthy volunteers by monitoring the rating of mood and levels of stress, electrocardiogram (ECG), electroencephalogram (EEG), and selected biochemical markers of stress. MATERIALS AND METHODS: The study was conducted in the human pharmacology laboratory. The study design was open labeled, comparing the baseline variables with values after Shirodhara. The subjects (n = 16) chosen were healthy human volunteers who gave an informed consent. Shirodhara was preceded by Abhyanga - whole body massage. The Shirodhara method was standardized for rate of dripping with peristaltic pump and temperature was controlled with a thermostat. Mood and stress levels were assessed by validated rating scales. The pre- and post-Shirodhara ECG and EEG records were evaluated. RESULTS: Student's paired "t" test was applied to the means + SE of the variables to calculate statistical significance at P <0.05. There was a significant improvement in mood scores and the level of stress (P <0.001). These changes were accompanied by significant decrease in rate of breathing and reduction in diastolic blood pressure along with reduction in heart rate. The relaxed alert state, after Shirodhara, was co-related with an increase in alfa rhythm in EEG. CONCLUSION: A standardized Shirodhara leads to a state of alert calmness similar to the relaxation response observed in meditation. The clinical benefits observed with Shirodhara in anxiety neurosis, hypertension, and stress aggravation due to chronic degenerative diseases could be mediated through these adaptive physiological effects. PMID- 23741162 TI - Management of tennis elbow by Agnikarma. AB - Tennis elbow is a painful condition and causes restricted movement of forearm which requires treatment for long period. Till date only symptomatic treatments are available like use of anti-inflammatory analgesic drugs, steroids injection, physiotherapy, exercise etc. But none of these provide satisfactory result. Long term use of anti-inflammatory, analgesic drugs and steroids injection is also not free from the adverse effects. Usually, 'wait-and-see policy' of treatment guideline is recommended in most of medical texts. According to Ayurveda, snayugata vata can be correlated with the condition of tennis elbow. Sushruta has advised Agnikarma for disorders of snayu (ligaments and tendons), asthi (bone), siddhi (joints) etc. Hence, in this study a case of tennis elbow (snayugata vata) was treated by Agnikarma, along with administration of powder of Ashwagandha and Navajivana Rasa orally, for a period of 03 weeks. This combination therapy provided considerable relief in pain and movement of the elbow joint. PMID- 23741163 TI - A case discussion on presbyacusis. AB - Presbyacusis is one among the many socio-medical problems, which is considered as a hidden disability. The hearing impairment in elderly people is described as presbyacusis. Hearing problem among elderly people is a major issue and a person with hearing loss may be unable to hear doorbells and alarms, to respond while talking with anyone, etc. All this can make them feel frustrated, lonely, and depressed. It is the third most common chronic condition after arthritis and hypertensive diseases among elders. Hearing loss can be improved by using the hearing aids. Hearing aids work well for some while for others; it may not be a perfect solution due to many reasons such as some people do not buy aids that meet their needs, incorrect amplification adjustments, low custom design, etc. In classics of Ayurveda this ailment has been described as karnabaadhirya under the heading of ear diseases. Karnapurana (Instillation of medicated oil into the external auditory canal) is one of the major treatments for ear diseases explained in classics. Clinical observation has shown its effectiveness in the management of presbyacusis. A case report of 75-year-old male who presented with complaints of reduced hearing and tinnitus in both ears has been presented here. PMID- 23741164 TI - Medical education in India: Time to encourage cross-talk between different streams. AB - Currently, India recognizes five different healthcare systems, collectively known as AYUSH (Ayurveda, Yoga, Unani, Siddha, Homeopathy), along with the conventional biomedicine. These systems have their own institutionalized structure for monitoring medical education and practice. However, because of the 'parallel' kind of policy model that is followed in India, there is no formal provision for any cross-talk between the professionals belonging to these different streams. This situation has not only given rise to mutual misgivings among these professionals regarding the strengths and weaknesses of each other, but also has led to a poor appreciation of the historical and socio-cultural connections these streams share with the community at large. To tackle these issues and to promote adequate participation of biomedicine experts in AYUSH-related research projects, 'introduction of an AYUSH module in the current curriculum of MBBS (Bachelor of Medicine and Bachelor of Surgery) program' has been proposed in this communication along with a possible roadmap for its implementation. It is also suggested that the experts in biomedicine be engaged for training AYUSH graduates in their respective specialties so that quality AYUSH education may be ensured. PMID- 23741165 TI - The menopausal age and associated factors in Gorgan, Iran. AB - BACKGROUND: Considering the physical, emotional and psychological complications of early or delayed menopause on women's life, it is necessary to determine associated factors of menopause age. This study designed to determine menopausal age and associated factors in women of Gorgan, i.e. the capital of Golestan province in the north-east of Iran. METHODS: In this cross-sectional study, 804 menopausal women in Gorgan were selected via two-stage sampling method in 2009. The study included only women who had undergone natural menopause and had their last menstrual bleeding at least one year before. Data were gathered through structured questionnaire that included individual characteristics, socioeconomic characteristics, menstrual and fertility characteristics and climacteric complaints. Socioeconomic status was defined using principal component analysis. Data were analyzed with T-student's and ANOVA tests using SPSS version 16 (SPSS Inc, Chicago, IL, USA) for Windows. RESULTS: The mean menopause age was 47.6+/ 4.45 years with the median age of 48 years. The mean menopause age in women with first pregnancy before 30 years (47.58+/-4.47years), without pregnancy (46.26+/ 4.90years) and without delivery (46.30+/-4.47 years) was significantly lower than others (p<0.01). The mean menopause age was lower in single women (46.6+/-2.80 years), with low income level (47.7+/-4.39 years) and smokers (47.6+/-4.45 years) compared to others; but these differences were not statistically significant (p>0.05). Socioeconomic status was not associated significantly with menopause age (p>0.05). CONCLUSION: This study illustrated that menstrual and fertility factors have influence on menopausal age while socioeconomic factors were not effective. PMID- 23741166 TI - Effect of Zafirlukast on improving lung function in patients with chronic obstructive pulmonary diseases. AB - BACKGROUND: There is little evidence about the role of Zafirlukast (a highly selective LTD4 antagonist) in Chronic Obstructive Pulmonary Disease (COPD). The Zafirlukast can reduce the need for short-acting rescue beta2 agonists, produce fewer exacerbations of asthma and increased quality of life as possible benefits treatment for asthma. The aim of our study was to evaluate the effects of Zafirlukast improvement of lung function in patients with COPD. METHODS: Twenty five patients with moderate to severe COPD, in stable phase of the disease, participated in this interventional, quasi-experimental study. All patients were received 40mg oral Zafirlukast per day for 2 weeks. Pulmonary function Test was performed both at the baseline and at the end of the study. Data were analyzed with paired t-test using SPSS v.16. RESULTS: The mean age of the patients was 67.29 (SD=5.56) years with the mean baseline for forced expiratory volume in first second (FEV1) equal to 41.79% (SD=14.96) of predicted value. After 2 weeks, the mean improvements in forced vital capacity (FVC), FEV1 and FEV1/FVC were 4.75% (SD=13.18), 3.71% (SD=9.19) and 9.33(SD=27.08), respectively. Zafirlukast produced a non-significant (p>0.05) bronchodilation, with maximum mean increase in FEV1 of 0.04 lit (3%) above baseline. CONCLUSION: Results showed that Zafirlukast has no considerable bronchodilatory effect in COPD. Present study consisted of a very short treatment period and it is possible that the extension of this period could possibly have more effects. Additional larger studies are needed to verify the impact of leukoterien receptor antagonists on improving the lung function in COPD patients. PMID- 23741167 TI - Osteoid osteoma of the hand and wrist: a report of 25 cases. AB - BACKGROUND: The hand and wrist bones are infrequent sites for osteoid osteoma, and its diagnosis can be difficult. This paper reports 25 cases of osteoid osteoma in the hand and wrist. METHODS: Records of the 25 patients who had pathological conditions of osteoid osteoma of the hand and wrist were reviewed and analyzed. RESULTS: Twenty-five cases of osteoid osteoma of the hand and wrist were treated in 20 years period. The average age was 25.2+/-7.6 years (range, 16 to 46 years) with men to women and right to left side ratio of 5.25 and 4 respectively. The most common site was in the proximal phalanx (ten cases). The diagnosis was made using x-rays, three- phase Technetium bone scans, CT, and MRI and all the diagnoses were confirmed by histological examination. The average time from the onset of symptom to successful treatment was 16.3+/-11.1 months, and at a mean follow-up of 36.6+/-46.9 mouths. Five recurrences of disease took place in which three of them were operated elsewhere. All five patients subsequently were treated and cured by reoperation. CONCLUSION: Osteoid osteoma is relatively rare lesions in the hand and wrist that can be a persistent source of hand and wrist pain. Patients under age of 40 who have otherwise unexplained pain should be evaluated. PMID- 23741168 TI - Ankle rotation changes and its influences in knee osteoarthritis. AB - BACKGROUND: Biomechanical factors are known to be important in knee osteoarthritis (OA) development and progression. This study was designed to determine changes of hamstrings muscle activation, knee adduction moment and ankle rotation angle in two knee osteoarthritis (mild and moderate) and a healthy control group. METHODS: 16 females (10 with mild and 6 with moderate medial knee osteoarthritis) and 10 control matched females were recruited. A 3D gait analysis was performed on the subjects while they walked along the walkway. Electromyography data was also collected during gait from lateral and medial hamstrings. Post Hoc Tukey HSD (multi comparison) was performed to compare knee adduction moment, ankle rotation angle and medial and lateral hamstrings activity at early and late stance, between three groups. RESULTS: Ankle rotation angle, knee adduction moment and lateral hamstrings activation showed no significant difference between three groups. Interestingly, medial hamstrings activity was significantly higher at late stance in moderate group compared with asymptomatic and mild groups (p=0.03, 0.02 respectively). Also knee adduction moment at late stance was significantly and directly correlated with ankle rotation angle, and lateral hamstrings activity at early stance was significantly and inversely correlated with this angle. CONCLUSIONS: It can be concluded that, increased lateral hamstrings activity can increase external ankle rotation and consequently decrease knee adduction moment. PMID- 23741169 TI - Searching the H. pylori; serology & PCR in children with adenoid hypertrophy and rhino sinusitis: a cross sectional study, Tehran, Iran. AB - OBJECTIVE: Searching the H. pylori -DNAs in adenoid and IgA, IgG antibodies in serum of children. METHODS: A cross- sectional study had done upon 53 children (Mean age 8 +/-1.9 years) with adenoid surgery in ENT and Pediatric Department of Rasul Akram Hospital (2008-2010). Of 53 cases with adenoid surgery, 40 cases had rhino sinusitis (in sinus CT scan). The resected adenoid tissues (n=40) centrifuged and homogenized and its DNAs extracted and searched for H. pylori- DNAs by qualitative PCR. Serum H. pylori antibodies (IgG &IgA ELISA) calculated quantitatively. Chi square values (p < 0.05) calculated for all categorical variables. The agreement between serologic test and PCR was assessed by the calculation of kappa statistic. RESULTS: Positive PCR for H. pylori detected in 15%of cases; regardless of sex and age of cases. Positive IgA: 17.5% (7/40) and IgG: 20% (8/40) respectively. All cases with positive H. pylori- IgG were female; p=0.003 and meaningful differences in mean age of cases observed for positive IgA (p=0.001) and IgG (p=0.01). Poor agreement observed between positive PCR and serum IgG&IgA (Fisher's Exact test=0.3; 0.5). CONCLUSION: Positive PCR in adenoid tissue (15%) was very close to positive serum IgA (15%) but without any agreement for each case. The H. pylori infection may have a relative role at least in 15% of children with adenoid surgery. Chronic sinusitis and ear infection might be added to infected adenoid tissue as a reservoir for bacteria. The search by specific culture may elucidate better the role of H. pylori infections in both gastric and adenoid tissues. The decision for use of antibiotics to eradicate the H. pylori infection in recurrent or chronic adenotonsillar infections (with rhinosinusitis) before adenoid surgery needs Randomized Control Trial (RCT) studies. Drug of choice for eradication of H. pylori dependent to antibiotic sensitivity test in each country. PMID- 23741170 TI - Preventive measures against the mustard gas: a review. AB - The main aim in this study was to collect the experiences of Iranian researchers about sulfur mustard (SM) and provide a guideline for the prevention of abuse for this dangerous agent. We searched valid national and international databases using related key words in the two languages. We found 193 articles which had been published in medical journals. Among them, 25 articles had some implications about prevention measures. In this study, we have mentioned 8 preventive points before the attacks, 10 points during and 2 points afterwards, we also found 12 points for the prevention of people who were exposed with SM and suffering from respiratory, ocular, dermatologic and psychological complications. In conclusion, most of the published studies on chemical war victims in Iran are focused on diagnosis and treatment of late SM-induced complications. Hence, a research should be conducted separately in relation to the prevention. PMID- 23741171 TI - An unusual case of preaxial polydactyly of the hand (triplication of the thumbs). AB - Preaxial polydactyly is the most common duplication pattern in white and Asian populations (1). It is a congenital anomaly with a wide range of manifestations. Current classification do not have the capacity to classify all different types of radial polydactyly. We describe here a very rare and unusual case of bilateral preaxial polydactyly (triplication) in a woman and report the operations results. We have not found similar case in the literature. Our case is unique and did not fit into the classification systems described for thumb polydactyly. PMID- 23741172 TI - Non-Hodgekin's lymphoma of female genital tract: a case report. AB - Non-Hodgkin lymphoma (NHL) causes many deaths worldwide with increasing incidence. Non-Hodgkin's lymphoma (NHL) may involve the gynecologic tract, and the ovary to be one of the commoner anatomic sites as reported. Ovarian involvement by NHL is usually secondary, occurring as a part of systemic disease. The diagnosis is often made incidentally while investigating for gynecological symptoms. We report an interesting case of NHL in a 35 year old female, who primarily presented with acute abdomen disease with secondary ovarian and cervical involvement and occult extra-ovarian disease. PMID- 23741173 TI - Brucella meningitis. PMID- 23741174 TI - Males' Reactions to Participating in Research on Dating Violence Victimization and Childhood Abuse. AB - Childhood abuse and dating violence victimization are prevalent and devastating problems. While there has been an abundance of research on these topics in recent years, researchers and Institutional Review Boards (IRBs) often struggle with determining whether asking respondents questions on previous violence will result in increased emotional distress or other negative research outcomes. Empirical data is therefore needed that examines the research reactions of individuals who participate in research on childhood abuse and dating violence. The current study examined this topic among a sample of male college students (N = 193). Results showed that victims of childhood sexual abuse had more negative emotional reactions and victims of physical dating violence had more negative perceived drawbacks to research participation than non-victims. However, victims and non victims did not differ on positive research reactions. These findings suggest that there are few differences between victims and non-victims on research reactions. PMID- 23741175 TI - Arsenic speciation in food chains from mid-Atlantic hydrothermal vents. AB - Arsenic concentration and speciation were determined in benthic fauna collected from the Mid-Atlantic Ridge hydrothermal vents. The shrimp species, Rimicaris exoculata, the vent chimney-dwelling mussel, Bathymodiolus azoricus, Branchipolynoe seepensis, a commensal worm of B. azoricus, and the gastropod Peltospira smaragdina showed variations in As concentration and in stable isotope (delta13C and delta15N) signature between species, suggesting different sources of As uptake. Arsenic speciation showed arsenobetaine to be the dominant species in R. exoculata, whereas in B. azoricus and B. seepensis arsenosugars were most abundant, although arsenobetaine, dimethylarsinate, and inorganic arsenic were also observed, along with several unidentified species. Scrape samples from outside the vent chimneys, covered with microbial mat, which is a presumed food source for many vent organisms, contained high levels of total As, but organic species were not detectable. The formation of arsenosugars in pelagic environments is typically attributed to marine algae, and the pathway to arsenobetaine is still unknown. The occurrence of arsenosugars and arsenobetaine in these deep sea organisms, where primary production is chemolithoautotrophic and stable isotope analyses indicate food sources are of vent origin, suggests that organic arsenicals can occur in a food web without algae or other photosynthetic life. PMID- 23741176 TI - Bayesian latent structure models with space-time-dependent covariates. AB - Spatial-temporal data requires flexible regression models which can model the dependence of responses on space- and time-dependent covariates. In this paper, we describe a semiparametric space-time model from a Bayesian perspective. Nonlinear time dependence of covariates and the interactions among the covariates are constructed by local linear and piecewise linear models, allowing for more flexible orientation and position of the covariate plane by using time-varying basis functions. Space-varying covariate linkage coefficients are also incorporated to allow for the variation of space structures across the geographical location. The formulation accommodates uncertainty in the number and locations of the piecewise basis functions to characterize the global effects, spatially structured and unstructured random effects in relation to covariates. The proposed approach relies on variable selection-type mixture priors for uncertainty in the number and locations of basis functions and in the space varying linkage coefficients. A simulation example is presented to evaluate the performance of the proposed approach with the competing models. A real data example is used for illustration. PMID- 23741177 TI - Reviews and guidelines: Evidence of progress and a starting point for standardization and changes. PMID- 23741178 TI - Sexuality and sickle cell disease. PMID- 23741179 TI - Neutropenic diet and quality of food: a critical analysis. PMID- 23741180 TI - Molecular assays as tools to facilitate new discoveries and to enhance immunohematology in daily transfusion practice. PMID- 23741181 TI - Comment on: Determination of serum levels of imatinib mesylate in patients with chronic myeloid leukemia: validation and application of a new analytical method to monitor treatment compliance. PMID- 23741182 TI - alpha-chain hemoglobin variants with electrophoretic mobility similar to that of hemoglobin S in newborn screening programs. PMID- 23741183 TI - Anemia in the elderly: an important clinical problem. PMID- 23741184 TI - Sexuality and sickle cell anemia. AB - BACKGROUND: Sickle cell disease, the most common hereditary blood disease in the world, is the result of an atypical hemoglobin called S (Hb S) which, when homozygous (Hb SS) is the cause of sickle cell anemia. Changes of puberty, correlated with a delayed growth spurt, begin late in both male and female sickle cell anemia individuals with repercussions on sexuality and reproduction. The objectives of this exploratory and descriptive study were to characterize the development of sexuality in adults with sickle cell anemia by investigating the patient's perception of their sex life, as well as the information they had and needed on this subject. METHODS: Twenty male and female sickle cell anemia patients treated at the Hemocentro Regional de Uberaba (UFTM) with ages between 19 and 47 years old were enrolled. A socioeconomic questionnaire and a semi structured interview on sexuality, reproduction and genetic counseling were applied. RESULTS: This study shows that the sickle cell anemia patients lacked information on sexuality especially about the risks of pregnancy and the possible inheritance of the disease by their children. Moreover, the sexual life of the patients was impaired due to pain as well as discrimination and negative feelings experienced in close relationships. CONCLUSION: The health care of sickle cell anemia patients should take into account not only the clinical aspects of the disease, but also psychosocial aspects by providing counseling on sexuality, reproduction and genetics, in order to give this population the possibility of a better quality of life. PMID- 23741185 TI - Microbiological profile and nutritional quality of raw foods for neutropenic patients under hospital care. AB - OBJECTIVE: This study aimed to analyze and compare the microbiological profile and vitamin C content of raw and cooked foods destined for neutropenic inpatients. METHODS: Three vegetables and nine fruits, raw and boiled, washed and sanitized were examined. Heat-tolerant coliforms and coagulase-positive staphylococci were counted and the presence of Salmonella spp was investigated. The vitamin C content was analyzed by a colorimetric reaction. The Statistical Package for Social Sciences (SPSS) software was used for statistical analysis and the nonparametric Wilcoxon test was used to compare the mean vitamin C values of the cooked and raw foods. The Spearman correlation test was applied to determine the associations between the parameters evaluated. RESULTS: Salmonella spp was absent in all samples and the populations of coagulase-positive staphylococci and heat-tolerant coliforms were below the minimum detectable limits of the methods employed (< 100 colony forming units (CFU)/g and < 3 most probable number (MPN)/g, respectively). There was a significant loss of vitamin C in the cooked foods, 38.9% on average, compared to the raw foods, a loss that was positively correlated with cooking time. CONCLUSION: The fresh fruits and vegetables properly sanitized in this study had a microbiological profile consistent with that required by Brazilian law. Furthermore, the nutritional value of the neutropenic diet is diminished, at least in terms of the vitamin C content. PMID- 23741186 TI - An easy and efficient strategy for KEL genotyping in a multiethnic population. AB - BACKGROUND: The Kell blood group system expresses high and low frequency antigens with the most important in relation to transfusion including the antithetic KEL1 and KEL2; KEL3 and KEL4; KEL6 and KEL7 antigens. Kell is a clinically relevant system, as it is highly immunogenic and anti-KEL antibodies are associated with hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. Although required in some situations, Kell antigen phenotyping is restricted due to technical limitations. In these cases, molecular approaches maybe a solution. This study proposes three polymerase chain reaction genotyping protocols to analyze the single nucleotide polymorphisms responsible for six Kell antithetic antigens expressed in a Brazilian population. METHODS: DNA was extracted from 800 blood donor samples and three polymerase chain reaction-restriction fragment length polymorphism protocols were used to genotype the KEL*1/KEL*2, KEL*3/KEL*4 and KEL*6/KEL*7 alleles. KEL*3/KEL*4 and KEL*6/KEL*7 genotyping was standardized using the NlaIII and MnlI restriction enzymes and validated using sequencing. KEL*1/KEL*2 genotyping was performed using a previously reported assay. RESULTS: KEL genotyping was successfully implemented in the service; the following distribution of KEL alleles was obtained for a population from southeastern Brazil: KEL*1 (2.2%), KEL*2 (97.8%), KEL*3 (0.69%), KEL*4 (99.31%), KEL*6 (2.69%) and KEL*7 (97.31%). Additionally, two individuals with rare genotypes, KEL*1/KEL*1 and KEL*3/KEL*3, were identified. CONCLUSION: KEL allele genotyping using these methods proved to be reliable and applicable to predict Kell antigen expressions in a Brazilian cohort. This easy and efficient strategy can be employed to provide safer transfusions and to help in rare donor screening. PMID- 23741187 TI - Determination of serum levels of imatinib mesylate in patients with chronic myeloid leukemia: validation and application of a new analytical method to monitor treatment compliance. AB - OBJECTIVE: The goal of this study was to monitor imatinib mesylate therapeutically in the Tumor Biology Laboratory, Department of Hematology and Hemotherapy, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo (USP). A simple and sensitive method to quantify imatinib and its metabolite (CGP74588) in human serum was developed and fully validated in order to monitor treatment compliance. METHODS: The method used to quantify these compounds in serum included protein precipitation extraction followed by instrumental analysis using high performance liquid chromatography coupled with mass spectrometry. The method was validated for several parameters, including selectivity, precision, accuracy, recovery and linearity. RESULTS: The parameters evaluated during the validation stage exhibited satisfactory results based on the Food and Drug Administration and the Brazilian Health Surveillance Agency (ANVISA) guidelines for validating bioanalytical methods. These parameters also showed a linear correlation greater than 0.99 for the concentration range between 0.500 ug/mL and 10.0 ug/mL and a total analysis time of 13 minutes per sample. This study includes results (imatinib serum concentrations) for 308 samples from patients being treated with imatinib mesylate. CONCLUSION: The method developed in this study was successfully validated and is being efficiently used to measure imatinib concentrations in samples from chronic myeloid leukemia patients to check treatment compliance. The imatinib serum levels of patients achieving a major molecular response were significantly higher than those of patients who did not achieve this result. These results are thus consistent with published reports concerning other populations. PMID- 23741188 TI - Alpha chain hemoglobins with electrophoretic mobility similar to that of hemoglobin S in a newborn screening program. AB - OBJECTIVE: To characterize alpha-chain variant hemoglobins with electric mobility similar to that of hemoglobin S in a newborn screening program. METHODS: beta(S) allele and alpha-thalassemia deletions were investigated in 14 children who had undefined hemoglobin at birth and an electrophoretic profile similar to that of hemoglobin S when they were six months old. Gene sequencing and restriction enzymes (DdeI, BsaJI, NlaIV, Bsu36I and TaqI) were used to identify hemoglobins. Clinical and hematological data were obtained from children who attended scheduled medical visits. RESULTS: THE FOLLOWING ALPHA CHAIN VARIANTS WERE FOUND: seven children with hemoglobin Hasharon [alpha2 47(CE5) Asp>His, HbA2:c.142G>C], all associated with alpha-thalassemia, five with hemoglobin Ottawa [alpha1 15(A13) Gly>Arg, HBA1:c.46G>C], one with hemoglobin St Luke's [alpha1 95(G2) Pro>Arg, HBA1:c.287C>G] and another one with hemoglobin Etobicoke [alpha212 84(F5) Ser>Arg, HBA212:c.255C>G]. Two associations with hemoglobin S were found: one with hemoglobin Ottawa and one with hemoglobin St Luke's. The mutation underlying hemoglobin Etobicoke was located in a hybrid alpha212 allele in one child. There was no evidence of clinically relevant hemoglobins detected in this study. CONCLUSION: Apparently these are the first cases of hemoglobin Ottawa, St Luke's, Etobicoke and the alpha212 gene described in Brazil. The hemoglobins detected in this study may lead to false diagnosis of sickle cell trait or sickle cell disease when only isoelectric focusing is used in neonatal screening. Additional tests are necessary for the correct identification of hemoglobin variants. PMID- 23741189 TI - Hematological parameters and prevalence of anemia among free-living elderly in south Brazil. AB - OBJECTIVE: The aims of this study were to analyze the hematological parameters, the prevalence of anemia and the association between anemia and socioeconomic conditions in an elderly community-based population. METHODS: A population-based study was performed as part of the Multidimensional Study of the Elderly in Porto Alegre, Brazil (EMIPOA). An initial total of 1058 community residents aged 60 years and older were interviewed. Of these, 392 agreed to have a physical evaluation and a blood sample was taken from each. The hematological parameters analyzed in the blood samples included the hemoglobin concentration, mean cell volume (MCV), mean corpuscular hemoglobin concentration (MCHC) and red cell distribution width (RDW). The association between the variables and the diagnosis of anemia was assessed using the chi-squared test and a multiple logistic regression model. RESULTS: The overall prevalence of anemia was 12.8%. Anemia was present in 13.7% of women and in 10.4% of men. Normocytic normochromic anemia without anisocytosis was the most common type of anemia (46%). The assessment of erythrocyte morphology showed significant differences between anemic and non anemic individuals (microcytosis = 12% vs. 1.5%, hypochromia = 40% vs. 8.8%, and anisocytosis = 26% vs. 7%). In the analysis of socioeconomic conditions, significant differences were found in respect to age and race. CONCLUSION: The prevalence of anemia increases with age and is associated with race, microcytosis, hypochromia and anisocytosis. Anemia is not a condition that should be associated only with the aging process, as it may be due to pathological conditions that occur most frequently in this age group. As a result, a diagnosis of anemia warrants adequate clinical attention. PMID- 23741190 TI - Effects of omega-3 fatty acids on regulatory T cells in hematologic neoplasms. AB - The development of leukemia and lymphomas is related to the increase in inflammatory process modulators. These, in turn, have divergent actions on the neoplastic process. Populations of T cells have different roles in the neoplastic environment; while interferon-gamma positive T cells have antitumor activity, the FoxP3+interleukin-10 positive population present a pro-tumor activity. Simultaneously, the inflammatory process promotes the mobilization of fatty acids from the cell membrane to produce lipid mediators, which also participate of the inflammatory response. Eicosapentaenoic (EPA) and docosahexaenoic (DHA) omega-3 fatty acids, when incorporated in the plasmatic membrane, decrease the arachidonic acid (AA) metabolism and the production of eicosanoids derived from it. Thus, an alternative family of lipid mediators are produced that are often less inflammatory than those produced from arachidonic acid. Fatty acids can also influence the production of peptide mediators such as cytokines, and the expression of transcription factors, which can determine the production patterns of eicosanoids and cytokines as well as cell differentiation. Due to these properties, the objective of this literature review was to investigate studies published over the last 15 years on the effects of using omega-3 fatty acids on inflammatory markers in leukemia and lymphomas. PMID- 23741193 TI - Compassionate use of cell products. PMID- 23741191 TI - Epigenetic therapy in allogeneic hematopoietic stem cell transplantation. AB - DNA methylation and other epigenetic phenomena appear to be relevant in the pathogenesis of several malignant disorders. DNA methyltransferases add methyl groups to cytosine-phosphate-guanine (CpG) islandsleading to gene promoter silencing. The DNA methyltransferases inhibitors azacitidine and decitabine have anti-tumor activity against a broad range of malignancies, but have been investigated mostly in myelodysplastic syndrome. In addition, these agents have immunomodulatory effects that are under investigation in the allogeneic stem cell transplantation scenario. Both drugs have been used in the perioperative period of allogeneic transplantations with varying degrees of success. It has been hypothesized that low dose azacitidine may increase the graft-versus-leukemia effect and have a role in the maintenance of remission after allogeneic transplantation for myeloid leukemias. It is also intriguing that this favorable effect might occur while mitigating graft-versus-host disease. Here we present a review of the rapidly growing field of epigenetic manipulation using hypomethylating agents in allogeneic transplantation. PMID- 23741192 TI - Guidelines of the Brazilian society of bone Marrow transplantation on hematopoietic stem cell transplantation as a treatment for the autoimmune diseases systemic sclerosis and multiple sclerosis. PMID- 23741194 TI - Hb Southampton [B106(G8)Leu->PRO, CTG->CCG] in a Uruguayan woman. AB - Hemoglobin Southampton (also known as hemoglobin Casper) is a rare hemoglobin structural variant resulting from a substitution of a leucine residue for proline at codon beta106 [beta106(G8)Leu->Pro, CTG->CCG]. It is very unstable and associated with severe hemolytic anemia. We detected this mutation in a 37-year old Uruguayan woman with a history of severe chronic hemolytic anemia since her childhood. According to our knowledge this is the first time that this variant has been found in the Uruguayan population. PMID- 23741195 TI - Autologous stem cell transplantation as first line treatment after incomplete excision of pancreatoblastoma. AB - Pancreatoblastoma is a rare tumor and surgery with complete resection is the main treatment approach. Prognosis for patients with residual disease after surgery is usually dismal. A 14-year-old girl with pancreatoblastoma in the pancreatic body and tail was submitted to preoperative chemotherapy. She underwent surgery and the tumor was resected with microscopic margins. Postoperative chemotherapy was followed by high dose chemotherapy and autologous hematopoietic stem cell transplantation. After four years she remains very well with no evidence of disease. This is the first case reported of pancreatoblastoma that was treated with autologous hematopoietic stem cell transplantation as first line treatment without radiotherapy at the site of the microscopic disease. PMID- 23741196 TI - Response to Comment on "Towards identification of the reaction coordinate directly from the transition state ensemble using the kernel PCA method" by D. Antoniou and S. Schwartz, J. Phys. Chem. B. 115, 2465-2469 (2011). PMID- 23741197 TI - Linear Fitted-Q Iteration with Multiple Reward Functions. AB - We present a general and detailed development of an algorithm for finite-horizon fitted-Q iteration with an arbitrary number of reward signals and linear value function approximation using an arbitrary number of state features. This includes a detailed treatment of the 3-reward function case using triangulation primitives from computational geometry and a method for identifying globally dominated actions. We also present an example of how our methods can be used to construct a real-world decision aid by considering symptom reduction, weight gain, and quality of life in sequential treatments for schizophrenia. Finally, we discuss future directions in which to take this work that will further enable our methods to make a positive impact on the field of evidence-based clinical decision support. PMID- 23741198 TI - Mentoring undergraduate students in neuroscience research: a model system at baldwin-wallace college. AB - As neuroscience research and discovery undergoes phenomenal growth worldwide, undergraduate students are seeking complete laboratory experiences that go beyond the classic classroom curriculum and provide mentoring in all aspects of science. Stock, in-class, laboratory experiences with known outcomes are less desirable than discovery-based projects in which students become full partners with faculty in the design, conduct and documentation of experiments that find their way into the peer-reviewed literature. The challenges of providing such experiences in the context of a primarily undergraduate institution (PUI) can be daunting. Faculty teaching loads are high, and student time is spread over a variety of courses and co-curricular activities. In this context, undergraduates are often reluctant, or ill equipped, to take individual initiative to generate and perform empirical studies. They are more likely to become involved in a sustained, faculty initiated research program. This paper describes such a program at Baldwin Wallace College. Students frequently start their laboratory activities in the freshman or sophomore year and enter into a system of faculty and peer mentoring that leads them to experience all aspects of the research enterprise. Students begin with learning basic laboratory tasks and may eventually achieve the status of "Senior Laboratory Associate" (SLA). SLAs become involved in laboratory management, training of less-experienced students, manuscript preparation, and grant proposal writing. The system described here provides a structured, but encouraging, community in which talented undergraduates can develop and mature as they are mentored in the context of a modern neuroscience laboratory. Retention is very good - as most students continue their work in the laboratory for 2-3 years. Student self-reports regarding their growth and satisfaction with the experiences in the laboratory have been excellent and our neuroscience students' acceptance rate in graduate, medical and veterinary schools has been well above the College average. The system also fosters faculty productivity and satisfaction in the context of the typical challenges of conducting research at a PUI. PMID- 23741199 TI - Teaching neuroscience at a religious institution: pedagogical models for handling neuroscience and theology. AB - The interdisciplinary nature of neuroscience makes it one of the most fascinating and complex subjects to address in the classroom. This can be compounded, however, by the addition of theology or a faith-related context at a religious institution (RI). The addition of theology and faith can enrich student appreciation and understanding of neuroscience and stimulate discussion in the classroom. This provides a practical way to make the course content relevant to students who may see neuroscience as antagonistic towards their faith. Over the past century questions of human experience and personhood that were long held to be under the authority of religion now can be addressed from findings in neuroscience. While there has been debate on a variety of topics which range from positions on origins to ethical questions about the nature of research (i.e. stem cells, cloning), it is important that teaching faculty at RIs be prepared to deal with the hard questions faced by students of faith. Recommendations for faculty are given including: self assessment of personal position on matters of faith and science, framing a number of models for the integration of neuroscience and theology, 'Worldviews', and mentoring students who are struggling with reconciling their faith with neuroscience. While this paper is designed for teachers at RIs, it may also aid teaching faculty at other institutions who may benefit from an awareness of this framework and aid in teaching students of faith in a secular setting. PMID- 23741200 TI - Testing the relationship between levels of endogenous testosterone and physiological responses to facial expressions in men: an experiment conducted by students in an undergraduate behavioral neuroscience class. AB - To determine if endogenous testosterone (T) is related to physiological responses to aggressive stimuli in human males, students in a behavioral neuroscience laboratory class conducted an experiment that determined if levels of salivary T in adult males are correlated with autonomic and/or somatic responses to angry facial expressions. Each student collected a saliva sample from one subject and, within 30 minutes of collecting the sample, measured heart rate (HR), skin conductance (SC), and corrugator supercilii electromyographic (EMG) responses to emotionally neutral, happy, and angry male facial expressions. Salivary T levels were analyzed by an enzyme-linked immunoassay. A significant, positive correlation was found between levels of salivary T and HR responses to angry and happy, but not neutral, male facial expressions. This laboratory experience not only provided students with the opportunity to design and conduct a scientific experiment, but it also generated preliminary data suggesting that levels of salivary T collected within 30 minutes of testing are related to autonomic responses to emotional social stimuli in humans. If verified by future experiments, this finding would be consistent with the hypothesis that fluctuations in circulating T might influence ongoing social behavior in human males by rapidly modulating autonomic responses to emotional social stimuli. The potential significance of such a general mechanism for the regulation of aggressive behavior is discussed. PMID- 23741201 TI - Integrated undergraduate research experience for the study of brain injury. AB - We developed a series of hands-on laboratory exercises on "Brain Injury" designed around several pedagogical goals that included the development of: 1) knowledge of the scientific method, 2) student problem solving skills by testing cause and effect relationships, 3) student analytical and critical thinking skills by evaluating and interpreting data, identifying alternative explanations for data, and identifying confounding variables, and 4) student writing skills by reporting their findings in manuscript form. Students, facilitated by the instructor, developed a testable hypothesis on short-term effects of brain injury by analyzing lesion size and astrocytic activity. Four sequential laboratory exercises were used to present and practice ablation techniques, histological processing, microscopic visualization and image-capture, and computer aided image analysis. This exercise culminated in a laboratory report that mimicked a research article. The effectiveness of the laboratory sequence was assessed by measuring the acquisition of 1) content on anatomical, physiological, and cellular responses of the brain to traumatic brain injury, and 2) laboratory skills and methods of data-collection and analysis using surgical procedures, histology, microscopy, and image analysis. Post-course test scores, significantly greater than pre-course test scores and greater than scores from a similar but unstructured laboratory class, indicated that this hands-on approach to teaching an undergraduate research laboratory was successful. Potential variations in the integrated laboratory exercise, including multidisciplinary collaborations, are also noted. PMID- 23741202 TI - Introductory neuroscience-courses in an evolving concept, teaching that which is yet to be truly defined. PMID- 23741203 TI - Research jobs for recent college graduates: A comparison between traditional lab technician positions and NIH's postbaccalaureate IRTA fellowship. AB - The features that distinguish the Postbaccalaureate IRTA experience from a normal lab tech job are the enhanced educational opportunities, greater independence, more organized social outlets and networking opportunities, life in the DC Metro area, and the NIH itself. Also, research experience looks great on a CV when applying for research jobs or graduate schools, and the NIH name and Postbaccalaureate IRTA fellowship are impressive to potential employers and admissions committees. On the other hand, lab tech jobs often require fewer commitments outside of a normal 9-to-5 work day and usually have better pay and benefits than the Postbaccalaureate IRTA fellowship. In addition, working at a specific university often carries the benefit of being closer to one's family, friends, and/or significant others. Someone who does not like cities can choose to work at a university that has ready access to the beach, mountains, or regions of the country that are more personally appealing than the Washington, DC, area. Lab tech jobs also usually require at least a two year commitment, whereas the Postbac IRTA fellowship is generally a one year commitment (possibly two). Regardless of which option you choose, you should be active in searching for a job that lets you fulfill the goals you set for yourself in the years between graduating and starting graduate or medical school. Whether those goals are to publish, get experience, save money, or just enjoy yourself, with careful questioning and circumspection, you should be able to maximize the possibility that you will meet your goals. PMID- 23741204 TI - Synaptic transmission: a four step process by betty zimmerberg. PMID- 23741205 TI - The Effect of Multiple Vectors on Arbovirus Transmission. AB - Many mosquito-borne arboviruses have more than one competent vector. These vectors may or may not overlap in space and time, and may interact differently with vertebrate hosts. The presence of multiple vectors for a particular virus at one location over time will influence the epidemiology of the system, and could be important in the design of intervention strategies to protect particular hosts. A simulation model previously developed for West Nile and St. Louis encephalitis viruses and Culex nigripalpus was expanded to consider two vector species. These vectors differed in their abundance through the year, but were otherwise similar. The model was used to examine the consequences of different combinations of abundance patterns on the transmission dynamics of the virus. The abundance pattern based on Cx. nigripalpus dominated the system and was a key factor in generating epidemics in the wild bird population. The presence of two vectors often resulted in multiple epidemic peaks of transmission. A species which was active in the winter could enable virus persistence until another vector became active in the spring, summer, or fall. The day the virus was introduced into the system was critical in determining how many epidemic peaks were observed and when the first peak occurred. The number of epidemic peaks influenced the overall proportion of birds infected. The implications of these results for assessing the relative importance of different vector species are discussed. PMID- 23741206 TI - Substituent Effect on the Formation and Their Reactivity of Platinum Carbenoids. AB - A propargylic ester containing a propargylic alkoxy group has been observed to preferentially undergo [1,2]-acyl shift over [1,3]-shift. In addition, the complementary and contrasting reactivity of vinyl vs. alkynyl platinum carbenoids has been discovered. Vinyl Pt-carbenoids are more prone to undergo [1,2]-H shift over addition to pi-bonds whereas alkynyl Pt-carbenoids preferentially add to pi bonds. PMID- 23741207 TI - Mirizzi syndrome with endoscopic ultrasound image. AB - We describe a 66-year-old Caucasian man with type 1 Mirizzi syndrome diagnosed on endoscopic ultrasound. He presented with acute onset of jaundice, malaise, dark urine over 3-4 days, and was found to have obstructive jaundice on lab testing. CT scan of the abdomen showed intrahepatic biliary ductal dilation, a 1.5 cm common bile duct (CBD) above the pancreas, and possible stones in the CBD, but no masses. Endoscopic retrograde cholangiopancreatography (ERCP) by a community gastroenterologist failed to cannulate the CBD. At the University Center, type 1 Mirizzi syndrome was noted on endoscopic ultrasound with narrowing of the CBD with extrinsic compression from cystic duct stone. During repeat ERCP, the CBD could be cannulated over the pancreatic duct wire. A mid CBD narrowing, distal CBD stones, proximal CBD and extrahepatic duct dilation were noted, and biliary sphincterotomy was performed. A small stone in the distal CBD was removed with an extraction balloon. The cystic duct stone was moved with the biliary balloon into the CBD, mechanical basket lithotripsy was performed and stone fragments were delivered out with an extraction balloon. The patient was seen 7 weeks later in the clinic. Skin and scleral icterus had cleared up and he is scheduled for an elective cholecystectomy. Mirizzi syndrome refers to biliary obstruction resulting from impacted stone in the cystic duct or neck of the gallbladder and commonly presents with obstructive jaundice. Type 1 does not have cholecystocholedochal fistulas, but they present in types 2, 3 and 4. Surgery is the mainstay of therapy. Endoscopic treatment is effective and can also be used as a temporizing measure or definitive treatment in poor surgical risk candidates. PMID- 23741208 TI - Brain abscess after transanal hemorrhoidal dearterialization: a case report. AB - A relatively new therapy in the treatment of hemorrhoids is transanal hemorrhoidal dearterialization (THD). We report a case of brain abscess caused by Streptococcus milleri following THD. Although a brain abscess after drainage of a perianal abscess has been described in the literature, no report exists of a brain abscess following treatment of hemorrhoids. A healthy 51-year-old man with hemorrhoids underwent THD. Two weeks later he presented with a headache, bradyphrenia, flattened behavior and a left hemiplegia. No perianal complaint and/or perianal abscess was present. A contrast CT scan of the cerebrum showed a right temporoparieto-occipital abscess, with edema and compression of the surrounding tissue and lateral ventricles. MRI showed an abscess with leakage in the right lateral ventricle. Treatment with dexamethasone and intravenous antibiotics was started. Because of progression of symptoms, 3 weeks later ventriculoscopy was performed and the abscess was drained. Culture of the punctuate showed S. milleri. Because of developing hydrocephalus 3 days after ventriculoscopy, first an external ventricle drain and later a ventriculoperitoneal drain was placed. Hereafter the hemiplegia and cognitive disorders improved. This case report describes a severe complication following treatment of hemorrhoids with THD which until now, to our knowledge, has never been described in the literature. PMID- 23741209 TI - Successful Self-Expandable Metallic Stent Placement for a Case of Distal Rectal Stenosis due to Gastric Cancer Metastasis. AB - A 47-year-old woman was diagnosed as having advanced gastric cancer with malignant ascites. Despite chemotherapy, recurrent peritoneal dissemination was seen 1.5 years after operation. A computed tomography scan revealed rectal stenosis due to Schnitzler's metastasis. When the distance from the distal end of the obstruction to the anal verge is less than 5 cm, stent replacement has been said to be contraindicated due to the development of anal pain and foreign body sensation. Although the distance from the distal end of the obstruction to the anal verge was 4 cm in this case, a WallFlex(TM) colonic stent could be placed. She stayed home, and luminal patency remained until she died 270 days after stent insertion. This report demonstrates that rectal obstruction located less than 5 cm from the anal verge due to Schnitzler's metastasis could be treated by stenting without any symptomatic or technical complications. PMID- 23741210 TI - A case of perianal mucinous adenocarcinoma arising from an anorectal fistula successfully resected after preoperative radiotherapy. AB - A case of mucinous adenocarcinoma arising on a long-standing anorectal fistula is described. A 60-year-old man with a long history of mucinous discharge, pain and perianal induration underwent a biopsy of the external opening of the fistula that showed a mucinous infiltrating adenocarcinoma. Due to the large size of the tumor and the fact that it had extended into the surrounding tissue, preoperative radiotherapy was performed. Radiotherapy was given with 40 Gy in 25 fractions for 5 weeks through posterior and bilateral portals. After radiotherapy the tumor was markedly shrunk and the serum level of carcinoembryonic antigen was also improved. Abdominoperineal resection was performed 8 weeks after the termination of radiotherapy. Histological examination of the resected specimen revealed that the invasion of the tumor remained within the sphincter muscle and that no cancer cells were present on the surgical margin. The histological effect of radiotherapy was judged as grade 1b. This treatment can result in downstaging and R0 resection, which also has a possibility to prevent local recurrence. This case suggests that preoperative radiotherapy may play an important role in the definitive treatment of locally advanced perianal mucinous adenocarcinoma. PMID- 23741211 TI - Adult intestinal intussusception caused by an inflammatory myofibroblastic tumor. AB - Inflammatory myofibroblastic tumor (IMT), which usually affects young adults and children, is a solid neoplastic mesenchymal proliferation composed of myofibroblastic spindle cells admixed with inflammatory infiltrates. Numerous extrapulmonary sites of these tumors have been found, but intestinal IMT is rare, especially in elderly patient. Its diagnosis is recognized as difficult because the patients usually do not have a specific symptom. Here, we present the case of a 79-year-old man with an IMT that caused small intestinal intussusception, which was diagnosed by abdominal ultrasonography. We review the literature on IMT and specially focus on the diagnostic modalities for this disease. PMID- 23741212 TI - Eczematous Dermatitis Occurring on a Cafe-au-Lait Spot Long after Laser Radiation. AB - A 40-year-old woman presented with an itchy erythematosquamous change of a cafe au-lait spot in her face. The onset of this change occurred just after her relocation. The cafe-au-lait spot had been irradiated by laser approximately 20 years ago. Clinically, there was a coin-sized erythema with a slight scale on the pigmented lesion in the left lateral orbital region. Histopathologically, the lesion demonstrated both spongiotic dermatitis and interface dermatitis together with lymphohistiocytic cell infiltration, in addition to moderate acanthosis and elongation of rete ridges with slight basal hyperpigmentation. From these clinical and histopathological findings, the lesion was diagnosed as eczematous dermatitis occurring on the cafe-au-lait spot after laser radiation. Another interesting histopathological finding was that some parts of a lobule of the sebaceous gland were occupied exclusively by degenerative atrophic sebocytes. From the viewpoint of pathogenesis, the eczematous dermatitis of this patient could have been an accompanying feature of a neurogenic inflammation occurring on the cafe-au-lait spot after laser radiation, and the atrophic change of a part of the sebaceous lobule might have been induced by a morphogenetic alteration of certain germinative cells of the sebaceous lobule due to laser radiation. PMID- 23741213 TI - Polymorphic eruption of pregnancy presented with targetoid lesions: a report of two cases. AB - BACKGROUND: Skin lesions in pregnant women could be caused by physiologic or pathologic changes. Polymorphic eruption of pregnancy (PEP), which manifests as various types of skin lesions, is the most common pregnancy dermatosis. Thus, PEP could mimic other skin diseases related to unfavorable maternal and fetal outcomes. MAIN OBSERVATIONS: Two PEP patients with targetoid lesions are presented here. One of them was a primigravida, whereas the other was a secundigravida. Both patients had singleton pregnancies and skin rash which started during the third trimester. The lesions began on the abdomen and then spread to the trunk and extremities. The face, palms, soles, and mucosa were not affected. Pruritus was observed but no other systemic symptoms were reported. Both patients delivered healthy, term infants without complications. CONCLUSION: Targetoid lesions in PEP are an uncommon presentation, and the differential diagnosis of PEP along with other dermatoses should be considered. However, the prognosis for this type of PEP is not different from that for classic PEP. PMID- 23741214 TI - Evaluation of the Effectiveness of Antibiotics against Eosinophilic Pustular Folliculitis. AB - Eosinophilic pustular folliculitis (EPF) is a chronic intractable pruritic dermatosis. Although indomethacin is generally effective against EPF and considered as a first-line therapy, quite a few patients with indomethacin still suffer from the symptoms. Among other therapeutic options, some antibiotics have been reported to be effective; however, there has been no epidemiological description regarding oral antibiotics use in patients with EPF. In this study, we investigated the frequency of antibiotics use and the effectiveness in patients with EPF. PMID- 23741215 TI - Successful treatment of diffuse normolipemic plane xanthoma with probucol. AB - We report on a 70-year-old woman with diffuse normolipemic plane xanthoma (DNPX) who developed macular yellowish patches on the eyelids, both cheeks, and the nose. Histology revealed the accumulation of CD68-positive foam cells and Touton giant cells in the superficial dermis. Plasma lipid levels were within normal limits. The patient had no underlying hematological diseases. Her extensive lesions precluded surgical excision. The patient was given oral probucol instead, which resulted in a significant reduction of the lesions after 2 weeks. The lesions almost disappeared within 8 months. Plane xanthoma is primarily treated with excisional or abrasive therapies; however, probucol can be a safe and effective alternative therapy for DNPX. PMID- 23741216 TI - Multiple low-grade fibromyxoid sarcoma on the upper arms with atypical histological presentation. AB - Low-grade fibromyxoid sarcoma (LGFMS) is a rare variant of spindle cell tumor that is composed of collagen-rich and myxoid parts. We describe the case of a 61 year-old Japanese patient with multiple, recurrent LGFMS on the upper arms with atypical histological presentation. In the present case, we resected the tumor several times with a minimal surgical margin, as in Moh's microsurgery. However, this can frequently lead to local recurrence of the tumor. Our case suggested that, regarding mesenchymal tumors with potential of malignancy in the skin, an initial wide excision is indispensable for complete remission of the tumor, even for low-grade malignancy such as LGFMS. PMID- 23741217 TI - Asphyxiation with a fentanyl patch. AB - Narcotics are frequently prescribed to alleviate pain in patients with serious medical illnesses such as cancer. Because of their nonoral route of administration, fentanyl patches are now being frequently prescribed. However, the widespread use of fentanyl patches has been associated with medication errors and misuse [Butts and Jatoi: J Opioid Manag 2011;7:35-45]. The transdermal delivery of fentanyl may lead to unusual, unanticipated complications. Herein, we describe a fentanyl patch complication, which, to our knowledge, has not been previously reported. PMID- 23741218 TI - Matrix-producing carcinoma of the breast: a case report. AB - Matrix-producing breast cancer (MPC) is a subtype of metaplastic carcinoma of the breast. It is a very rare tumor, which constitutes less than 1% of all malignant mammary tumors. The origin of this tumor is still unclear: there are molecular studies that suggest an origin from myoepithelial cells, whereas other studies underline the neoplastic transformation of a multipotent stem cell. Even the differential diagnosis of MPC and other breast neoplasms (phyllodes tumors and real sarcomas of the breast) is not always easy. In the literature, a certain chemoresistance has been demonstrated, and a standard treatment of this tumor does not exist at this time. We report the case of a 44-year-old, premenopausal, female patient with a 6-cm breast lump. Neither imaging nor fine needle aspiration biopsy was crucial in achieving a diagnosis. The patient underwent a simple mastectomy. In consideration of the negative lymph node status, the patient was not subjected to radiotherapy or adjuvant chemotherapy. Moreover, since the receptor status was negative, hormone therapy was not necessary. The patient has been disease free for 4 years now. PMID- 23741219 TI - Postradiation osteosarcoma in an older prostate cancer survivor: case study and literature review with emphasis on geriatric principles. AB - The aging population and the increasing number of cancer survivors will likely be associated with more second primary malignancies due to prior cancer treatment. Since the incidence of most cancers increases with age, these treatment associated second malignancies will likely disproportionately impact older adults. Here, we present the case of a 78-year-old man with a history of localized prostate cancer treated with external beam radiation therapy 11 years prior, who developed osteosarcoma of the ilium. Geriatric screening showed a fit older male with few comorbidities, functional independence and no other geriatric syndromes. Given the patient's preference for a limb-sparing operation, neoadjuvant chemotherapy was undertaken. With the paucity of clinical trial data on osteosarcoma in older adults, the patient was given a regimen of carboplatin (substituted for cisplatin), doxorubicin and methotrexate. Unfortunately, he developed methotrexate-induced acute kidney injury. Chemotherapy was discontinued, and he proceeded to hemipelvectomy. His postoperative course was marked by numerous complications, including delirium, depression and recurrent hospitalizations. He ultimately developed a local recurrence and elected for hospice care. This case highlights the challenges of managing older adults with treatment-associated malignancies. Clinicians face a lack of clinical trial data from which to extrapolate limitations of therapeutic options because of prior therapy and a limited ability to precisely predict which elders will experience adverse outcomes. Better approaches are needed to help older patients make decisions which fulfill their goals of care and to improve the care of older adults with treatment-associated malignancies. PMID- 23741220 TI - Pancreatic metastasis from mixed adenoneuroendocrine carcinoma of the uterine cervix: a case report. AB - Metastatic cancers of the pancreas are rare, accounting for approximately 2-4% of all pancreatic malignancies. Renal cell carcinoma is the most common solid tumor that metastasizes to the pancreas. Here, we present a case of uterine cervical carcinoma metastasizing to the pancreas and review the literature regarding this rare event. A 44-year-old woman with a uterine cervical tumor had undergone radical hysterectomy and had been diagnosed pathologically with stage Ib mixed adenoneuroendocrine carcinoma in 2004. She underwent concurrent radiotherapy and chemotherapy postoperatively. Pulmonary metastases subsequently appeared in 2008 and 2011, and she underwent complete resection of the lung tumors by video assisted thoracic surgery. Although she was followed up without any treatment and with no other recurrences, positron emission tomography revealed an area of abnormal uptake within the pancreatic body in 2012. Enhanced computed tomography demonstrated a 20-mm lesion in the pancreatic body and upstream pancreatic duct dilatation. Endoscopic ultrasonography-guided fine needle aspiration was performed and pathological examination suggested neuroendocrine carcinoma (NEC). On the basis of these results and the patient's oncological background, lesions in the pancreatic body were diagnosed as secondary metastasis from the cervical carcinoma that had been treated 8 years earlier. No other distant metastases were visualized, and the patient subsequently underwent middle pancreatectomy. Pathological examination showed NEC consistent with pancreatic metastasis from the uterine cervical carcinoma. The patient has survived 7 months since the middle pancreatectomy without any signs of local recurrence or other metastatic lesions. PMID- 23741221 TI - Epidermal growth factor receptor mutation in a patient with squamous cell carcinoma of the lung: who should be tested? AB - We report the case of a 64-year-old ex-smoker with metastatic poorly differentiated squamous cell carcinoma (SCC) of the lung and an epidermal growth factor receptor (EGFR) mutation in exon 21 (p.L858R) who achieved prolonged clinical benefit from treatment with an EGFR tyrosine kinase inhibitor (TKI). The initial diagnosis of SCC of the lung obtained by bronchoscopic biopsy was based on immunohistochemical staining only with positivity for cytokeratin (CK) 5/6 and p63 because morphological diagnosis was not possible. Patients with non-small cell lung cancer (NSCLC), not otherwise specified (NOS) favouring SCC are usually not tested for the presence of EGFR mutations, and therefore may not receive EGFR TKI therapy. A bronchoscopic rebiopsy showed small nests of undifferentiated tumour cells with weak immunoreactivity of some tumour cells for CK5/6, p63 and no positivity of some tumour cells for thyroid transcription factor-1. These findings suggested a mixed squamous/glandular immunophenotype that has been missed at the initial biopsy. Our clinical case illustrates the problem of tumour heterogeneity encountered in small bronchoscopic biopsies and the difficulties of evaluating the histological subtype in poorly differentiated carcinomas. Initial bronchoscopy should be performed by an experienced pulmonologist who attempts to obtain sufficient material from different areas of the tumour. In the era of targeted therapy, a remote smoking history in a patient with NOS favouring SCC should also lead to EGFR mutation testing to allow highly effective therapy to be offered to mutation-positive patients. PMID- 23741222 TI - Spontaneous remission of epstein-barr virus-positive diffuse large B-cell lymphoma of the elderly. AB - A 94-year-old female patient presented with anorexia and left axillar lymphadenopathy on admission. Her past history was angina pectoris at 83 years of age and total gastrectomy due to gastric cancer at 87 years. The family history revealed that her son had had a malignant lymphoma, the histopathological diagnosis of which was diffuse large B-cell lymphoma. A physical examination showed both cervical, axillar, and inguinal lymphadenopathy without tenderness. She had elevated lactate dehydrogenase, ferritin, and soluble interleukin-2 receptor (sIL-2R). Whole-body computed tomography confirmed the cervical, axillary, and inguinal lymphadenopathy. Gallium-68 imaging revealed positive accumulation in these superficial lymph nodes. A right inguinal lymph node biopsy showed features of Epstein-Barr virus-associated lymphoproliferative disorder. Immunohistological studies on this lymph node biopsy showed CD20-positive large cells, CD3-positive small cells, and CD30-partly-positive large cells. In situ hybridization showed Epstein-Barr virus-positive, LMP-partly-positive, and EBNA2 negative cells. She refused chemotherapy as her son had died from hematemesis during chemotherapy. She received intravenous hyperalimentation for 1 month after admission. No palpable lymph nodes were identified by physical examination or computed tomography 3 months after admission, and regression of lactate dehydrogenase, ferritin, and sIL-2R was observed. She recovered from anorexia and was discharged. She died from pneumonia 10 months later after initial symptoms of anorexia. The autopsy showed no superficial lymphadenopathy. PMID- 23741223 TI - Chemotherapy for liver metastasis originating from colorectal cancer with portal vein tumor thrombosis: a case report. AB - The patient was a male in his 70s with a history of chronic renal failure and dilated cardiomyopathy. In January 2011, he underwent abdominoperineal resection of the rectum, right hepatic lobectomy, and resection of a portal vein tumor thrombus with a diagnosis of rectal cancer and metastatic liver cancer accompanied by portal vein tumor thrombosis. Although 5-fluorouracil + l leucovorin therapy (RPMI regimen) was carried out as postoperative adjuvant chemotherapy, the tumor marker (CEA and VA19-9) levels increased 8 months after surgery. Since the functions of major organs were impaired, UFT((r)) + UZEL((r)) therapy was started. The tumor marker levels decreased temporarily, but increased again 12 months after surgery, and so intravenous instillation of panitumumab was initiated. Nine administrations have been performed to date, with no increase in tumor marker levels or exacerbation of the condition. Also, no grade 2 or severer adverse event has been noted according to CTCAE v.4.0. The experience with this patient suggests the possibility that exacerbation of the condition of patients with liver metastasis of colorectal cancer accompanied by portal vein tumor thrombosis with abnormalities in the functions of major organs can be controlled temporarily by the administration of panitumumab alone. PMID- 23741224 TI - Tracheal adenocarcinoma treated with adjuvant radiation: a case report and literature review. AB - Primary adenocarcinoma of the trachea is extremely rare and a standard treatment does not exist due to nonavailability of evidence-based randomized control studies. This paper reports the case of a 60-year-old male, who presented with cough and occasional respiratory distress. Bronchoscopic examination and a computed tomography scan revealed a soft tissue mass in the trachea arising from the posterior tracheal wall. Cytological examination and immunochemistry confirmed primary adenocarcinoma of the trachea. Excision of the tumor followed by three-dimensional conformal radiation therapy was performed, and a dose of 56 Gy was delivered to the primary site. Two and a half years after treatment, the patient has no clinical or radiological evidence of the disease, and no late complication has occurred. PMID- 23741225 TI - Mood disorder as the presenting manifestation of demyelination. AB - OBJECTIVE: To report an unusual presenting manifestation of multiple sclerosis in a teenager. CASE REPORT: We report the case of a 16-year-old male who was diagnosed with schizoaffective disorder a year prior to his neurological consultation. Neurological examination showed evidence of mild lower extremity spasticity with ataxia and dysarthria. Imaging revealed lesions suggestive of multiple sclerosis. CONCLUSION: An organic basis for psychiatric disorders is often overlooked. Children presenting with symptoms suggestive of a mood disorder, decline in cognition or psychosis deserve a detailed neurological examination and appropriate imaging if indicated, before starting them on antidepressant or neuroleptic medication. PMID- 23741226 TI - Recurrent stereotyped episodes in cerebral amyloid angiopathy: response to migraine prophylaxis in two patients. AB - BACKGROUND: Cerebral amyloid angiopathy (CAA) typically presents with cognitive decline or symptomatic intracerebral hemorrhage, but episodes of recurrent stereotyped limb attacks have also been reported. METHODS: Retrospective review of the medical records of 4 patients referred to the general neurology services and a specialist stroke center with clinically probable CAA. RESULTS: Four subjects, all Caucasian, mean age 74 years, were followed up over a mean duration of 20 months. They all experienced recurrent prolonged stereotyped attacks of sensory symptoms, lasting 5-30 min, that resolved completely between attacks. Three subjects developed intracerebral hemorrhage, and 2 had an irreversible rapid cognitive decline. Two patients experienced symptomatic improvement with migraine prophylaxis (verapamil or topiramate). CONCLUSIONS: Recurrent stereotyped prolonged attacks with sensory and motor elements can predate the development of intracerebral hemorrhage in individuals with clinically probable CAA. When evaluating patients with such attacks, neurologists need to consider CAA as a possible mimic of transient ischemic attacks. We suggest a trial of migraine prophylaxis for symptomatic management. PMID- 23741227 TI - Prevalence and clinical implication of microbleeds in dementia with lewy bodies in comparison with microbleeds in Alzheimer's disease. AB - BACKGROUND: Cerebral microbleeds (MBs) have been well investigated in Alzheimer's disease (AD), but not very extensively in non-AD dementias or in dementia with Lewy bodies (DLB). AIMS: To elucidate the clinical significance of MBs in DLB. METHODS: We compared the prevalence, locations and risk factors for MBs in 59 DLB and 81 AD patients. We visually counted MBs in each of the cortical and subjacent areas (frontal, temporal, parietal and occipital), the basal ganglia and the thalamus, and the brainstem and the cerebellar hemispheres on 1.5-tesla T2* weighted gradient-recalled-echo MRI images. White matter lesions were semiquantified in fluid-attenuated inversion recovery images according to the Fazekas rating scale. RESULTS: While the prevalence of MBs was comparable, MBs tended to be more abundant in DLB than in AD in all brain areas with the exception of the occipital lobes. The number of MBs was positively associated with the severity of white matter lesions but not with other vascular risk factors in either AD or DLB. The presence of MBs could be associated with cognitive impairment at onset. MB-positive DLB patients showed less impairment on (123)I-metaiodobenzylguanidine myocardial scintigraphy (MIBG scintigraphy) images, supporting the notion of an inverse relationship between vascular lesions and Lewy body pathology. CONCLUSION: It was suggested that an intricate association between Lewy body pathology, AD-type pathologies and vascular lesions seems to be related to the initial symptoms and results of MIBG scintigraphy in DLB. PMID- 23741228 TI - Lack of Genetic Associations of PPAR-gamma and PGC-1alpha with Alzheimer's Disease and Parkinson's Disease with Dementia. AB - BACKGROUND AND AIMS: Similar clinical and pathological features have been observed in Alzheimer's disease (AD) and Parkinson's disease with dementia (PDD). Both the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) gene and the peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC 1alpha) gene are candidates modifying the risk for both diseases. The aim of this study was to clarify whether common single nucleotide polymorphisms (SNPs) of the PPAR-gamma gene and the PGC-1alpha gene affect the onset of AD and PDD genetically. METHODS: Four exonic SNPs of both genes (rs1801282 and rs3856806 of the PPAR-gamma gene, rs3736265 and rs8192678 of the PGC-1alpha gene) were genotyped in 171 AD patients, 136 age-matched controls and 53 PDD patients. Haplotype analysis and logistic regression analysis with apolipoprotein E (APO E) status were performed for AD. RESULTS: There was no statistical difference between AD cases and controls for the 4 SNPs, nor was there any statistical difference between PDD cases and controls for the 4 SNPs. We could not find any synergetic associations between these SNPs, APO E4 and AD. CONCLUSIONS: The 4 SNPs studied here did not influence the risk for AD in a Japanese population. As the number of PDD cases was small, comprehensive genetic studies considering diabetes would be needed. PMID- 23741229 TI - Predictors of mild cognitive impairment in early-stage Parkinson's disease. AB - AIM: The aim of this study was to identify mild cognitive deficits in Parkinson's disease (PD) prior to extensive neurodegeneration and to evaluate the extent to which dopamine depletion and other disease-related predictors can explain cognitive profiles. METHODS: Neuropsychological performances of 40 nondemented early-stage PD patients and 42 healthy controls were compared across on or off dopaminergic medications. Stepwise regression evaluated cognitive predictors of early-stage PD and disease-related predictors of PD cognition (levodopa dose, disease duration, Unified Parkinson's Disease Rating Scale score, sleep, quality of life, and mood) across on and off states. RESULTS: Neuropsychological performance was lower in PD patients across cognitive domains with significant memory, naming, visuomotor, and complex attention/executive deficits, but with intact visuospatial, simple attention, and phonemic fluency functions. However, medication effects were absent except for simple attention. Regression analyses revealed age, working memory, and memory recall to be the best cognitive predictors of PD, while age, quality of life, disease duration, and anxiety predicted PD cognition in the off state. CONCLUSION: Nondemented early-stage PD patients presented with extensive mild cognitive deficits including prominent memory impairment. The profile was inconsistent with expected isolated frontostriatal dysfunction previously attributed to dopamine depletion and this highlights the need to further characterize extranigral sources of mild cognitive impairment in PD. PMID- 23741231 TI - Phenotypes and endotypes of severe asthma in children. AB - Severe childhood asthma is a complicated and heterogeneous disorder with distinct phenotypes. Children with severe asthma have more persistent symptoms despite receiving treatment, more atopy, greater airway obstruction, and more air trapping than those with mild-to-moderate asthma. They also have higher morbidity and substantial airflow limitations that persist throughout adulthood. Identification of the phenotype clusters and endotypes of severe asthma can allow further modulation of the natural history of severe asthma and may provide the pathophysiologic rationale for appropriate management strategies. PMID- 23741232 TI - Systemic use of fluoroquinolone in children. AB - Fluoroquinolones are an important class of antibiotics that are widely used in adult patients because of their broad spectrum of activity, good tissue penetration, and oral bioavailability. However, fluoroquinolone use in children is limited because juvenile animals developed arthropathy in previous experiments on fluoroquinolone use. Indications for fluoroquinolone use in patients younger than 18 years, as stated by the U.S. Food and Drug Administration, include treatment of complicated urinary tract infections and postexposure treatment for inhalation anthrax. In Korea, the systemic use of fluoroquinolones has not been approved in children younger than 18 years. Although concerns remain regarding the adverse musculoskeletal effects of fluoroquinolones in children, their use in the pediatric population has increased in many circumstances. While pediatricians should be aware of the indications and adverse effects of fluoroquinolones, recent studies have shown that the risk for musculoskeletal complications in children did not significantly increase following fluoroquinolone treatment. In addition, fluoroquinolones may be particularly helpful in treating multidrug resistant infections that have not responded to standard antibiotic therapy in immunocompromised patients. In the present article, we provide an updated review on the safety and current recommendations for using fluoroquinolones in children. PMID- 23741233 TI - Comparison of the serum vitamin D level between breastfed and formula-fed infants: several factors which can affect serum vitamin D concentration. PMID- 23741234 TI - Vitamin D deficiency in infants aged 1 to 6 months. AB - PURPOSE: The aim of this study was to recognize the state of vitamin D among healthy infants aged 1 to 6 months in South Korea, and also to identify the risk factors affecting the level of vitamin D. METHODS: A total of 117 infants were enrolled in this study for 12 months, from March 1, 2011 to February 29, 2012. Serum levels of 25-hydroxyvitamin D (25[OH]D), calcium, phosphorus, and alkaline phosphatase were measured and data including birth weight, body weight, sex, feeding pattern, delivery mode, siblings and maternal age and occupation were collected. Data was mainly analyzed with independent t-test model. RESULTS: We determined that the prevalence of vitamin D deficiency (serum 25[OH]D<20 ng/mL [50 mmol/L]) was 48.7% in the population investigated. Particularly in breastfed infants, the prevalence of vitamin D deficiency was strikingly high (90.4%). The mean serum level of 25(OH)D in breastfed infants was lower than that of formula fed infants (9.35 ng/mL vs. 28.79 ng/mL). Also female infants showed lower mean serum level of 25(OH)D than male. Mean serum values of calcium and phosphorus had positive correlation with vitamin D state (P<0.001). CONCLUSION: Vitamin D deficiency was found to be very common in infants aged 1 to 6 months in South Korea, and breast feeding was the most critical risk factor of vitamin D deficiency. Therefore we suggest to start vitamin D supplementation in South Korea, as soon as possible, to all infants, including breastfed and female infants. PMID- 23741235 TI - Depression and marital intimacy level in parents of infants with sleep onset association disorder: a preliminary study on the effect of sleep education. AB - PURPOSE: Sleep onset association disorder (SOAD) is a form of behavioral insomnia observed in children that is caused by inappropriate sleep training. SOAD typically disturbs the sleep of not only infants and children but also their parents. We investigated levels of depression and marital intimacy among parents of infants with typical SOAD, to understand the influence of SOAD on family dynamics, as well as examine ways for improving depression and marital intimacy through behavioral training. METHODS: Depression and marital intimacy were assessed using the Beck Depression Inventory (BDI) and Waring Intimacy Questionnaire (WIQ). These measures were administered to 65 parents of infants (n=50) diagnosed with SOAD. We conducted sleep education and behavioral training for the parents and compared levels of depression and marital intimacy after 2-6 weeks of training. RESULTS: The 65 parents consisted of 50 mothers and 15 fathers. Depressive symptoms were higher among mothers than fathers (P =0.007). Marital intimacy was negatively correlated with depressive symptoms. Twenty-six parents were assessed again after sleep training. We found that mothers' depressive symptoms and marital intimacy improved post training. CONCLUSION: SOAD can be detrimental to both infants and parents, especially for parents who sleep with their infants. For instance, disruption of sleep patterns in such parents can reduce marital intimacy. However, behavioral modification is an effective treatment for infants with frequent nighttime waking, as well as for diminishing the depressive symptoms of sleep-deprived parents. PMID- 23741237 TI - Liver transplantation in a child with acute liver failure resulting from drug rash with eosinophilia and systemic symptoms syndrome. AB - Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is characterized by a severe idiosyncratic reaction including rash and fever, often with associated hepatitis, arthralgias, lymph node enlargement, or hematologic abnormalities. The mortality rate is approximately 10%, primarily owing to liver failure with massive or multiple disseminated focal necrosis. Here, we report a case of a 14-year-old girl treated with vancomycin because of a wound infection by methicillin-resistant Staphylococcus aureus, who presented with non-specific symptoms, which progressed to acute liver failure, displaying the hallmarks of DRESS syndrome. With the presence of aggravated hepatic encephalopathy and azotemia, the patient was refractory to medical treatments, she received a living donor liver transplantation, and a cure was achieved without any sign of recurrence. Vancomycin can be a cause of DRESS syndrome. A high index of suspicion and rapid diagnosis are necessary not to miss this potentially lethal disease. PMID- 23741236 TI - Serum levels of interleukin-6 and interleukin-8 as diagnostic markers of acute pyelonephritis in children. AB - PURPOSE: Early diagnosis and treatment of acute pyelonephritis in children is of special importance in order to prevent serious complications. This study was conducted to determine the diagnostic value of serum interleukin (IL)-6 and IL-8 in children with acute pyelonephritis. METHODS: Eighty-seven patients between 1 month to 12 years old with urinary tract infection (UTI) were divided into 2 groups based on the result of 99m-technetium dimercapto-succinic acid renal scan: acute pyelonephritis (n=37) and lower UTI (n=50) groups. White blood cell (WBC) count, neutrophil (Neutl) count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) concentration, platelet count, and serum IL-6 and IL-8 concentrations of both groups were measured and compared. RESULTS: There was a significant difference between two groups regarding WBC count, Neutl count, ESR, and CRP concentration (P<0.05). In addition, the difference between the two groups regarding serum IL-6 and IL-8 concentrations was not significant (IL-6, 60 and 35.4 pg/mL and IL-8, 404 and 617 pg/mL, respectively). The sensitivity and specificity of serum IL-6 and IL-8 for diagnosis of acute pyelonephritis were 73%, 42% and 78%, 32%, respectively. Sensitivity, specificity, negative and positive predictive values of serum IL-6 and IL-8 were less than those of acute phase serum reactants such as CRP. CONCLUSION: This study showed that there was no significant difference between acute pyelonephritis and lower UTI groups regarding serum IL-6 and IL-8 levels. Therefore, despite confirming results of previous studies, it seems that IL-6 and IL-8 are not suitable markers for differentiating between acute pyelonephritis and lower UTI. PMID- 23741238 TI - Two cases of chronic pancreatitis associated with anomalous pancreaticobiliary ductal union and SPINK1 mutation. AB - Chronic pancreatitis is a progressive inflammatory disease resulting from repeated episodes of acute pancreatitis that impair exocrine function and eventually produce endocrine insufficiency. Some causes of chronic pancreatitis appear to be associated with alterations in the serine-protease inhibitor, Kazal type 1 (SPINK1), cationic trypsinogen (PRSS1), and cystic fibrosis-transmembrane conductance regulator (CFTR) genes, or with structural disorders in the pancreaticobiliary ductal system, such as pancreatic divisum or anomalous pancreaticobiliary ductal union (APBDU). However, it is unusual to observe both genetic alteration and structural anomaly. Here, we report 2 cases with both APBDU and a mutation in the SPINK1 genes, and we discuss the implications of these findings in clinical practice. PMID- 23741239 TI - Systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood: Report of a case with review of the literature. AB - Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease (LPD) of childhood is an extremely rare and distinct clinicopathological entity. The majority of these cases occur with an apparent primary EBV infection. In this study, we describe a case of systemic EBV-positive T-cell LPD of childhood in a 23-year-old female with primary EBV infection, and review the clinicopathological features of this disease. A 23-year-old previously healthy female without an immunocompromized status presented with an acute onset of high fever. Laboratory examinations revealed a markedly elevated white blood cell count and liver and renal function. Peripheral blood smears identified a number of atypical lymphocytes with small azurophilic granules in the cytoplasm. Bone marrow aspiration revealed marked proliferation of small-sized lymphocytes with convoluted nuclei, which expressed EBER1, CD3, CD8 and cytotoxic granules. Monoclonal rearrangements of T-cell receptors were also detected. The patient underwent chemotherapy, but succumbed to multiorgan failure 20 weeks after administration. Upon review of 17 cases of this disease, including the one in the present study, we identified that the major clinicopathological features of systemic EBV-positive T-cell LPD of childhood are as follows: i) clonal systemic proliferation of EBV-infected T-cells that appear morphologically innocuous with an activated cytotoxic phenotype; ii) a high prevalence in the Asian population, commonly affecting children and young adults; iii) a predilection for males; iv) most commonly involved sites are the liver, spleen, lymph node and bone marrow, and the main clinical presentations are hepatosplenomegaly, fever and pancytopenia; v) almost all cases have an aggressive clinical course, which results in mortality. Cytological atypia of the neoplastic cells in this disease, as observed in the present case, is minimal. This study revealed that the cytomorphological features of atypical lymphocytes in the peripheral blood are indistinguishable from those of infectious mononucleosis. PMID- 23741240 TI - Fibrosarcomatous pigmented dermatofibrosarcoma protuberans: A case report with review of the literature. AB - Dermatofibrosarcoma protuberans (DFSP) is a relatively rare low-grade sarcoma that occasionally exhibits melanin-containing spindle cells within the tumor. Fibrosarcomatous DFSP (FS-DFSP) is a variant that is characterized by areas which are histopathologically indistinguishable from fibrosarcoma. In the present study, we describe a case of fibrosarcomatous pigmented DFSP and review the clinicopathological features of this extremely rare lesion. A 51-year-old male presented with a slow-growing nodular cutaneous mass in his left upper arm. Histopathologically, the resected tumor was comprised of pigmented DFSP in approximately 20% of the tumor, with the remaining area further covered by a fibrosarcomatous component. A review of the clinicopathological features of the five previously reported cases as well as the present case indicated that this lesion mainly affects middle-aged males and occurs mostly in the extremities. Melanin-containing spindle cells are present only in the conventional DFSP component. The prognosis appears to be poor; in the six cases reviewed, four demonstrated multiple metastases and three succumbed to the disease. Our analyses revealed that the presence of a fibrosarcomatous component in pigmented DFSP is associated with aggressive behavior; therefore, careful assessment for the presence of a fibrosarcomatous component is necessary in the diagnosis of this disease. PMID- 23741241 TI - A case of poorly differentiated hepatocellular carcinoma with intriguing ultrasonography findings. AB - A 60-year-old female was referred to the Toho University Omori Medical Center due to ultrasonography findings revealing a notable hepatic mass. The 44*32 mm isoechoic mass had a high-echo band along the margin in the liver. Contrast enhanced ultrasonography (CEUS) with Sonazoid detected an enhancement pattern extending from the outer periphery to the inside of the mass in the vascular phase and a pattern similar to that of surrounding hepatic tissue in the post vascular phase. High-flow hepatic hemangioma was suspected due to the hyperechoic rim-like high-echo band, the oval shape and the CEUS findings. However, computed tomography revealed a hypervascular hepatocellular carcinoma (HCC) pattern and the patient underwent surgery. Histopathological findings revealed poorly differentiated HCC. As poorly and moderately differentiated HCC types are conventionally classified as 'hypervascular HCC', few detailed ultrasonography (US) studies of poorly differentiated HCC are available. US characteristics of hypervascular HCC include the presence of a halo (hypoechoic band) around the lesion and reduced signal intensity in the post-vascular phase of CEUS. US in the patient revealed a mass with a hyperechoic band and a signal intensity in the post-vascular phase of CEUS that was almost identical to that of the surrounding liver parenchyma. These findings suggest poorly differentiated HCC and indicate that further research on hypervascular HCC is required. PMID- 23741242 TI - Antitumor activity of placenta-derived mesenchymal stem cells producing pigment epithelium-derived factor in a mouse melanoma model. AB - Mesenchymal stem cells (MSCs) are a new tool that can be used for the delivery of therapeutic agents to tumor cells. Among the various types of MSCs, placenta derived MSCs (PDMSCs) have emerged as one of the most attractive vehicles for gene therapy due to their high throughput, lack of ethical concerns, non-invasive procedure for their harvesting and ease of isolation. In this study, we evaluated the antitumor activity of human PDMSCs loaded with recombinant adenoviruses expressing pigment epithelium-derived factor (PEDF). PDMSCs were transduced with adenovirus PEDF and the expression of PEDF was confirmed by western blotting and ELISA. The inhibition of angiogenesis mediated by PEDF-expressing PDMSCs (PDMSC PEDF) was determined using human umbilical vein endothelial cell (HUVEC) proliferation inhibition assay and migration inhibition assay in vitro. In in vivo experiments, C57BL/6 mice bearing B16-F10 melanoma were treated with intratumoral injection of PDMSC-PEDF twice at a 4-day interval. The tumor volume and weight were recorded. The results demonstrated that the administration of PDMSC-PEDF resulted in marked suppression of tumor growth in an established melanoma model, which was associated with a decreased number of microvessels and increased apoptosis of tumor cells compared with the controls. The results suggest that human PDMSCs have potential use as effective delivery vehicles for cancer gene therapy. PMID- 23741243 TI - Overexpression of the hydatidiform mole-related gene F10 inhibits apoptosis in A549 cells through downregulation of BCL2-associated X protein and caspase-3. AB - The aim of this study was to investigate how the overexpression of the hydatidiform mole-related gene F10 affects apoptosis in human lung cancer A549 cells. A549 cells were transfected with pEGFP-N1-F10 (A549-F10) or pEGFP-N1 empty vector (A549-empty). Untransfected A549, A549-F10 or A549-empty cells were examined using the MTT cell proliferation assay and the TUNEL-FITC/Hoechst 33258 apoptosis assay. Western blotting was used to examine the expression levels of the pro-apoptotic genes, BCL2-associated X protein (BAX) and caspase-3. F10 was stably expressed in A549 cells. From 12 h, A549-F10 cells proliferated markedly faster than the untransfected and A549-empty cells. F10 overexpression also significantly inhibited apoptosis, as shown by the reduced number of TUNEL and Hoechst 33258 double-positive cells. This inhibition was likely due to an F10 induced reduction in the BAX and caspase-3 levels. The results of this study indicate that F10 overexpression inhibits apoptosis in A549 cells through the downregulation of the pro-apoptotic genes BAX and caspase-3. PMID- 23741244 TI - Clinicopathological investigation of four cases of desmoplastic small round cell tumor. AB - The purpose of this study was to perform clinicopathological and immunohistochemical analysis and to investigate the Ewing sarcoma gene (EWS) Wilms' tumor suppressor gene (WT1) fusion within desmoplastic small round cell tumors (DSRCTs). Histology slides and clinical data were reviewed for four patients with DSRCT. A variety of immunohistochemical staining was performed. Fluorescence in situ hybridization (FISH) was performed to detect the EWS-WT1 fusion transcripts resulting from the chromosomal translocation t(11;22)(p13;q12). The patients consisted of four males aged from 26 to 52 years old (mean, 33.5). In three of these patients, the tumors were situated in the abdominal cavity and the tumor from the other patient was located in the pelvic cavity. The tumors were 8-15 cm in diameter (mean tumor diameter, 13), solid and gray-white, with an appearance of nodosity or sublobes, and hemorrhage or necrosis was observed. Microscopically, the tumors consisted of small round cell nests of unequal size. Hyperplastic and thick fibrous connective tissue surrounding the neoplastic cell nests was present in all cases. The tumor nuclei were hyperchromatic and contained inconspicuous nucleoli with a high level of karyokinesis. Immunohistochemical staining revealed diffuse and strong staining for CK, vimentin, desmin and CAM5.2 in all cases. Certain cases also expressed WT 1, EMA, NSE, CD56, CD99 and CK5/6. Staining was negative for myogenin, MyoD1, calretinin, CD117, CD34, HMB45 and CEA. EWS-WT1 fusion transcripts were detected in 3 out of 4 cases, but not in any other tumor types studied as controls using paraffin-embedded tissue by FISH. DSRCT is a highly maligant tumor occuring predominantly in the abdominal or pelvic cavity of young males with multiphenotypic differentiation. Basic morphological features, clinical manifestations and the detection of the EWS-WT1 fusion transcript within the tumor aid the recognition and diagnosis of the tumor. PMID- 23741245 TI - EphA2 silencing in nasopharyngeal carcinoma leads to decreased proliferation, invasion and increased sensitization to paclitaxel. AB - EphA2 is frequently overexpressed and functionally altered in a variety of human cancers. However, its roles in human nasopharyngeal carcinoma (NPC) remain unclear. To investigate the roles of EphA2 in the development and progression of NPC, we initially evaluated the expression pattern of EphA2 protein in NPC tissues using western blotting and CCK-8 assay. Fluorescence-activated cell sorting analysis and invasion assay were conducted to observe the effects of EphA2 inhibition in vivo. Our results demonstrated that EphA2 was overexpressed in NPC specimens and the expression of EphA2 was significantly associated with T classification, advanced clinical stage and lymph node metastasis. Moreover, human NPC 5-8F cells were infected with lentiviral vector-mediated EphA2-specific shRNA, which resulted in the significant inhibition of cell growth, invasion of 5 8F cells and markedly enhanced the sensitivity of 5-8F cells to the chemotherapeutic agent paclitaxel in vitro. Collectively, our results demonstrate that EphA2 is involved in malignant cell behavior and is a potential therapeutic target in human NPC. PMID- 23741246 TI - Chemotherapy for non-small cell lung cancer complicated by idiopathic interstitial pneumonia. AB - Idiopathic interstitial pneumonia (IIP) is considered to be one of the risk factors for lung cancer (LC). However, therapeutic options for patients with LC complicated by IIP are not well established. In this study, we investigated the feasibility and efficacy of chemotherapy for patients with non-small cell lung cancer (NSCLC) complicated by IIP (NSCLC-IIP). We retrospectively analyzed 22 NSCLC-IIP patients who received chemotherapy. To determine how IIP affected the clinical outcomes in NSCLC, they were compared with 276 NSCLC patients without IIP, who were treated with chemotherapy alone. The response rate (partial response + stable disease) was 72.3% (17/22), whereas the incidence of acute exacerbation (AE) was 13.6% (3/22) in NSCLC-IIP patients treated with chemotherapy. NSCLC-IIP patients had significantly shorter survival compared with NSCLC patients without IIP (P<0.001) following chemotherapy, although the response rates to chemotherapy were not significantly different between the two groups. Multivariate analysis demonstrated that, in NSCLC patients receiving chemotherapy, IIP was a significantly unfavorable factor for progression-free and overall survival. Despite similar response rates to chemotherapy, NSCLC-IIP patients showed poorer prognosis than NSCLC patients without IIP, possibly due to the natural course of IIP. Chemotherapy may be a feasible option for NSCLC-IIP, if the risks of adverse effects are acceptable. PMID- 23741247 TI - miR-224 functions as an onco-miRNA in hepatocellular carcinoma cells by activating AKT signaling. AB - microRNAs (miRNAs) are a class of small non-coding RNAs that post transcriptionally regulate gene expression. Increasing evidence has shown that the deregulation of miRNAs is linked to cancer. The overexpression of miR-224 has been reported in several human cancers. The aim of the present study was to investigate the function of miR-224 in the pathogenetic process of hepatocellular carcinoma (HCC), and the precise mechanism underlying its function. Both gain-of function and loss-of function assays were conducted through transfection with miR 224 mimics and miR-224 inhibitors in the HepG2 liver carcinoma cell line. The data revealed that miR-224 exerts a significant role in promoting cell proliferation, migration and invasion. Western blot analysis showed that the phosphorylation levels of AKT positively correlated with endogenous levels of miR 224. In addition, results from a dual luciferase reporter assay showed that the expression of the serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B) is inhibited by miR-224; thus, it appears that PPP2R1B is a candidate target of miR-224 in HCC. These data suggest that miR-224 plays a significant role in HCC, possibly through the activation of the AKT signaling pathway by targeting PPP2R1B. PMID- 23741248 TI - Apoptotic effect of hot water extract of Sanguisorba officinalis L. in human oral cancer cells. AB - Sanguisorba officinalis L. has been used in traditional Asian medicine to treat diseases including diarrhea, chronic intestinal infections, duodenal ulcers and bleeding. This study examined the antiproliferative effects and apoptotic activity of hot water extract of S. officinalis L. (HESO) on HSC4 and HN22 human oral cancer cells. The effects of HESO were evaluated by the 3-(4,5 dimethylthiazol-20yl)-(3-carboxymethoxyphenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS) assay, 4'-6-diamidino-2-phenylindole (DAPI) staining and western blot analysis. HESO was found to inhibit cell growth and induce apoptosis in HSC4 and HN22 oral cancer cells. HESO downregulated myeloid cell leukemia-1 (Mcl-1) in HSC4 cells and was associated with the activation of Bak, resulting in Bak oligomerization on the mitochondrial outer membrane. HESO did not alter Mcl-1 expression in HN22 cells, but it decreased Sp1 expression. The downregulation of Sp1 by HESO in HN22 cells resulted in a decrease in survivin, a downstream target protein of Sp1. These results suggested that HESO inhibited the growth of oral cancer through either Mcl-1 or Sp1, indicating that HESO may serve as a potential drug candidate against oral cancer. PMID- 23741249 TI - RhoA regulates invasion of glioma cells via the c-Jun NH2-terminal kinase pathway under hypoxia. AB - The purpose of this study was to investigate the mechanism of glioma cell invasion in hypoxic conditions. We demonstrated that hypoxia increased cell invasion, matrix metalloproteinase-2 (MMP2) activity and time-dependent expression of hypoxia inducible factor-1alpha (HIF-1alpha) in human glioma cells. These data suggest that MMP2 may play a significant role in tumor invasion in hypoxic conditions. We investigated the mechanisms involved in the increased MMP2 activity and cell invasion in hypoxic conditions. Increased expression of phospho Jun NH2-terminal kinase (p-JNK) and phospho-c-Jun (p-c-Jun) in glioma cells induced by hypoxia was detected. Furthermore, this effect may be reduced by inhibiting the JNK signaling pathway. We found that inhibition of RhoA geranylgeranylation by geranylgeranyltransferase inhibitor-2147 (GGTI-2147) or knockdown of RhoA by siRNA against RhoA reduced the expression of p-JNK and p-c Jun, and decreased MMP2 activity and glioma cell invasion in hypoxic conditions. These data suggest a link among RhoA, JNK, c-Jun and MMP2 activity that is functionally involved in the increased glioma cell invasion induced by hypoxia. PMID- 23741250 TI - Multiple cervical ganglioneuroma: A case report and review of the literature. AB - Ganglioneuromas (GNs) arising from neural crest sympathogonia are rare benign neurogenic tumors. The most commonly affected sites are the posterior mediastinum, the retroperitoneum and the adrenal gland. GNs often present as a solitary, painless and slow-growing mass, and multiple occurrences in the cervical region are extremely rare. Here, we report a case of massive multiple cervical GN in a 4-year-old girl, and review cases of cervical GN that have been reported in the past 10 years. The results demonstrated that cervical GN, compared to other sites, is seldom secretory. The signs and symptoms of cervical GN are unspecific; the ultimate diagnosis of GN depends on pathological examination. Fine-needle aspiration biopsy has limited value in diagnosis. Surgical excision is the treatment of choice and the prognosis is excellent even in cases where complete excision cannot be achieved. Furthermore, GNs should be considered in patients with multiple masses in the neck. PMID- 23741251 TI - Intramedullary nailing for fibrous dysplasia of lower limbs. AB - Fibrous dysplasia (FD) of the bone is rare and self-limiting. However, lesion expansion may occur, causing pain, deformity and pathological fracture, in which case surgery is occasionally required. Indicators of FD have not been previously described, although there are several surgical procedures reported (curettage, curettage and graft, and internal fixation). In this study we discuss whether intramedullary nailing of these lesions could result in more favorable outcomes in correcting deformities, including the prevention of secondary fractures and maintenance of the bone, compared to other internal fixation methods. A total of 39 patients with FD of the bone treated with intramedullary nailing were retrospectively analyzed. The surgical procedures involved curettage, grafting and intramedullary nailing. No infection, thromboembolism or other notable complications occurred. The patients resumed full activities of daily living. At the last follow-up, 33 patients presented no pain and seven patients had occasional mild pain. The clinical score according to the modified criteria of Guille improved from an average of 4.4 points prior to surgery to an average of 8 points following surgery. The neck shaft angle of the femur improved from an average of 90 prior to surgery to 125 following surgery. Intramedullary nailing may be used to correct deformity and prevent pain and refracture in FD of the bone of the lower limbs with large lesions, pathological fracture or deformities. All patients were allowed full athletic recovery following surgery. PMID- 23741252 TI - (-)-Epigallocatechin gallate inhibits the expression of indoleamine 2,3 dioxygenase in human colorectal cancer cells. AB - Immune escape, the ability of tumor cells to avoid tumor-specific immune responses, occurs during the development and progression of several types of human malignancies, including colorectal cancer (CRC). Indoleamine 2,3 dioxygenase (IDO), the tryptophan catabolic enzyme, plays a significant role in regulating the immune response and provides tumor cells with a potent tool to evade the immune system. In the present study, we examined the effects of (-) epigallocatechin gallate (EGCG), the major catechin in green tea, on the inhibition of IDO expression induced by interferon (IFN)-gamma in human CRC cells. We found that IFN-gamma increased the expression levels of IDO protein and mRNA in HT29 and SW837 CRC cell lines. Treatment of SW837 cells with EGCG significantly decreased IFN-gamma-induced expression of IDO protein and mRNA in a dose-dependent manner. Enzymatic activity of IDO, determined by the concentration of L-kynurenine in the culture medium, was also significantly inhibited by EGCG treatment. Phosphorylation of signal transducer and activator of transcription 1 (STAT1) induced by IFN-gamma was also significantly inhibited by EGCG. Reporter assays indicated that EGCG inhibited the transcriptional activities of IDO promoters, IFN-stimulated response element and IFN-gamma activation sequence, activated by STAT1 phosphorylation. These findings suggest that EGCG may exert antitumor effects on CRC, at least in part, by inhibiting the expression and function of IDO through the suppression of STAT1 activation. EGCG may, thus, serve as a potential agent for antitumor immunotherapy and be useful in the chemoprevention and/or treatment of CRC. PMID- 23741253 TI - miR-96 regulates FOXO1-mediated cell apoptosis in bladder cancer. AB - Transitional cell carcinoma (TCC) is one of the most common types of malignancies and a leading cause of genitourinary system cancer mortality worldwide. The tumor suppressor gene FOXO1, a member of the forkhead box O (FOXO) subfamily of transcription factors, is downregulated in a number of cancers, including TCC; however, the underlying mechanisms are poorly understood. In the present study, we used microRNA (miRNA) target prediction algorithms to identify a conserved potential miR-96 binding site in the 3'-untranslated region (3'-UTR) of FOXO1. Using quantitative real-time PCR (qRT-PCR) and northern blot analysis, we identified that miR-96 was downregulated in TCC tissues compared to normal bladder tissues (NB), suggesting that the loss of FOXO1 expression in TCC may be mediated by miR-96. To confirm this, we transfected pre-miR-96/anti-miR-96 into the T24 TCC cell line and revealed that miR-96 expression was sufficient to significantly reduce FOXO1 expression. Conversely, FOXO1 expression was not completely restored by the inhibition of miR-96 in T24 cells. Moreover, RNA silencing of FOXO1 significantly reduced miR-96 inhibitor-mediated T24 cell apoptosis. In conclusion, our study demonstrates that the miR-96 targeting of FOXO1 is upregulated in TCC; in addition, TCC tumorigenesis may be partly due to the ability of miR-96 to promote FOXO1 repression, thereby bypassing cell apoptosis controls. PMID- 23741254 TI - Inhibition of Grb2-mediated activation of MAPK signal transduction suppresses NOR1/CB1954-induced cytotoxicity in the HepG2 cell line. AB - The nitroreductase oxidored-nitro domain containing protein 1 (NOR1) gene may be involved in the chemical carcinogenesis of hepatic cancer and nasopharyngeal carcinoma (NPC). We have previously demonstrated that NOR1 overexpression is capable of converting the monofunctional alkylating agent 5-(aziridin-1-yl)-2,4 dinitrobenzamide (CB1954) into a toxic form by reducing the 4-nitro group of CB1954. Toxic CB1954 is able to enhance cell killing in the NPC cell line CNE1; however, the underlying mechanisms remain unknown. Using cDNA microarrays and quantitative real-time PCR, we previously discovered that NOR1 increases the expression of growth factor receptor-bound protein 2 (Grb2) mRNA by 4.8-fold in the human hepatocellular carcinoma cell line HepG2. In the present study, we revealed that NOR1 increased Grb2 protein expression by 3-fold in HepG2 cells. Additionally, we demonstrated that NOR1 enhanced CB1954-induced cell killing in HepG2 cells, and cell cytotoxicity was inhibited with the tyrosine kinase inhibitor genistein, or by stable transfection of Grb2 small hairpin RNA (shRNA) pU6+27-shGrb2 to silence the expression of Grb2. Western blot analysis revealed that Grb2 downregulation may reduce the activity of the mitogen-activated protein kinase (MAPK). Inhibiting the activation of MAPK using the methyl ethyl ketone (MEK) inhibtor PD98059 suppressed CB1954-induced cell killing. These results suggested that the NOR1 gene enhances CB1954-mediated cell cytotoxicity through the upregulation of Grb2 expression and the activation of MAPK signal transduction in the HepG2 cell line. PMID- 23741255 TI - Education in neurosurgery in the web era. PMID- 23741256 TI - Improving on-time start for iMRI neurosurgeries. AB - BACKGROUND: In the Singapore General Hospital, intraoperative MRI (iMRI) neurosurgery is a multi-disciplinary process that involves staff from multiple departments. However, a baseline analysis showed that only 10.5% of iMRI neurosurgeries start on time, resulting in unnecessary waste of resources. The project aimed to improve the percentage of on-time start iMRI neurosurgeries to 100% within nine months. MATERIALS AND METHODS: Clinical Practice Improvement methodology was used. The project involves four phases: Diagnostic, in which a baseline analysis is conducted; Intervention, in which problem areas are identified; Implementation, in which potential solutions are implemented; and sustaining, in which strategies to sustain gains are discussed. RESULTS: The percentage of on-time start cases gradually increased to 100% in eight months, and was sustained above 85% in the following five months. CONCLUSION: This project serves as a successful demonstration of how quality improvement can be effected in a complex, multidisciplinary workflow, which is the norm for many hospital procedures. PMID- 23741257 TI - Protective effect on normal brain tissue during a combinational therapy of 2 deoxy-d-glucose and hypofractionated irradiation in malignant gliomas. AB - PURPOSE: To investigate the effect of 2-deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolysis, on glioblastoma and the normal brain tissue during combined treatment with hypofractionated radiotherapy. MATERIALS AND METHODS: Twenty patients with malignant gliomas (18 Glioblastoma Multiformae, 2 Anasplastic Astrocytoma grade III) following surgery were treated weekly (once) with 2-DG, (250 mg/kg body weight), followed by 5 Gy of radiation to the tumor bed per fraction for 7 weeks. Clinical evaluation, complete hemogram, and random blood sugar levels were carried out in each cycle. Follow-up computed tomography (CT)/magnetic resonance imaging (MRI) was done to evaluate radiation-induced changes. Kernofsky Performance scale (KPS) was recorded preoperatively; postoperatively, and post-therapy till the last follow-up. RESULTS: Twenty patients were recruited for this trail; 19 of them completed the treatment and 1 discontinued. The survival period ranged between 6 and 36 months after the treatment, with a median survival of 14 months. CT and MRI revealed significant tumor necrosis. Histological evidence from the tissue during reexploration confirms the hypothesis of protective effect of 2-DG on normal brain. KPS was above 80% in majority of the patients, 6 months after the surgery. CONCLUSION: Radiotherapy coupled with 2-DG enhances tumor necrosis selectively and significantly while the normal brain gets relatively protected. This has been reflected in our study both clinically by preservation of quality-of-life and pathologically by retaining the integrity of normal brain architecture. PMID- 23741258 TI - Decompressive craniectomy with multi-dural stabs - A combined (SKIMS) technique to evacuate acute subdural hematoma with underlying severe traumatic brain edema. AB - CONTEXT: The decompressive craniotomy alone or with dural flap opening to evacuate acute subdural hematoma with underlying brain edema in severe traumatic brain injury has proved either insufficient in the first place or has fatal complications secondly. AIMS: To reduce the fatality of conventional procedures and to evacuate acute subdural hematoma with severe brain edema by a combination of decompressive craniotomy and multi-dural stabs (SKIMS-Technique) without brain pouting and lacerations in low Glasgow coma scale (GCS) score patients. SETTINGS AND DESIGN: The prospective study was conducted in the Department of Neurosurgery, from June, 2006 to June 2011, under a uniform protocol. MATERIALS AND METHODS: A total of 225 patients of severe brain trauma were admitted to the accident and emergency unit of Neurosurgery and after initial resuscitation a CT brain was performed. All patients had a GCS score of 8 and below. All patients were ventilated postoperatively and ICP was monitored. STATISTICAL ANALYSIS USED: The data was analyzed and evaluated by the statistical methods like student's T test. The analysis of Variance was used where-ever applicable. RESULTS: The survival of multi-dural stab group was 77.31% (92/119) with good recovery in 42.02% (50/119) and a mortality of 22.69% (27/119) as compared with 46.23% (49/106) survival in open dural flap (control) group with 15.09% (16/106) good recovery and mortality of 53.77% (57/106). CONCLUSIONS: This new approach, known as SKIMS-Technique or Combined Technique i.e., "decompressive craniectomy with multi-dural stabs", proved much effective in increasing survival of low GCS and severe traumatic brain edema patients with acute subdural hematoma. PMID- 23741259 TI - Intracranial epidermoid tumor; microneurosurgical management: An experience of 23 cases. AB - OBJECTIVES: An intracranial epidermoid tumor is relatively a rare tumor, accounting for approximately 0.1% of all intracranial space occupying lesions. These are also known as pearly tumor due to their pearl like appearance. In this series, the localization of the tumor, presenting age and symptoms, imaging criteria for diagnosis, surgical management strategy with completeness of excision and overall outcome were studied prospectively. Here, we report our short experience of intracranial epidermoid as a whole. MATERIALS AND METHODS: Between January 2006 to December 2010, 23 cases of intracranial epidermoid were diagnosed preoperatively with almost certainty by computed tomography (CT) and magnetic resonance imaging (MRI) of brain in plain, contrast and other relevant studies. All of them underwent operation in Dhaka Medical College Hospital and in some Private Hospital in Dhaka, Bangladesh. All patients were followed-up routinely by clinical examination and neuroimaging. Average follow-up was 39 (range-71-11months) months. Patients of the series were prospectively studied. RESULTS: Supratentorial epidermoids were 04 cases and infratemporal epidermoids were 19 cases. Clinical features and surgical strategy varies according to the location and extension of the tumors. Age range was 19-71 years (37.46 years). Common clinical features were headache, cerebellar features, seizure, vertigo, hearing impairment and features of raised intracranial pressure (ICP). Investigation was CT scan or/+ MRI of brain in all cases. Pre-operative complete excision was 20 cases, but post-operative images showed complete excision in 17 cases. Content of tumor was pearly white/white material in all cases except one, where content was putty material. Re-operation for residual/recurrent tumor was nil. Complications included pre-operative mortality one case, persisted sixth nerve palsy in one case, transient memory disturbance one case, and extra dural hematoma one case. One senior patient expired three months after the operation from spontaneous intracerebral hemorrhage. Rest of the patients were stable and symptom/s free till last follow-up. CONCLUSION: In the management of such tumors, one should keep in mind that an aggressive radical surgery carrying a high morbidity and mortality and a conservative subtotal tumor excision is associated with a higher rate of recurrence, but earlier diagnosis and complete excision or near total excision of this benign tumor can cure the patient with the expectation of normal life. PMID- 23741260 TI - Choroid plexus tumors: A clinico-pathological and neuro-radiological study of 23 cases. AB - BACKGROUND: Choroid plexus tumors are intraventricular tumors derived from choroid plexus epithelium. AIM: To study the choroid plexus tumors with reference to their clinical, radiological, and pathological features. MATERIALS AND METHODS: The study was performed by the retrospectively reviewing the clinical, radiological, and pathological records of patients of choroid plexus tumors. RESULTS: A total of 23 cases (11 males, 13 females) of choroid plexus tumor were diagnosed from 1997 to 2009. Fourteen patients were below 15 years of age. Raised intracranial pressure was the main presenting feature in all the cases. Tumor was located in lateral ventricle (n = 14; in 3 cases tumor was going into third ventricle), fourth ventricle (n = 7), and cerebellopontine angle (n = 2). Total tumor excision was achieved in 21 cases. The histopathology was suggestive of choroid plexus papilloma (n = 19), atypical choroid plexus papilloma (n = 1), and choroid plexus carcinoma (n = 2). Clears cell areas were noted in three cases. Other histopathological features observed were foci of calcification (n = 5), Psammoma bodies (n = 2), hemorrhage (n = 5), hyalinization (n = 2), and oncocytic changes (n = 1). CONCLUSIONS: Choroid plexus tumors are intraventricular tumors arising from choroid plexus epithelium. The predominant clinical presentation is raised intracranial pressure. Surgery is the mainstay of treatment; histopathologically, they include choroid plexus papilloma, atypical choroid plexus papilloma, and choroid plexus carcinoma. PMID- 23741261 TI - Post-craniotomy blindness in the supine position: Unlikely or ignored? AB - Immediate visual loss following craniotomy in the supine position is a disastrous complication in neurosurgical patients. The incidence is unknown and little is known on the definite pathogenesis. Also, preventive or restorative interventions are unclear. We describe the rare case of post-craniotomy optic neuropathy and sudden visual loss after craniotomy in the supine position for an olfactory groove meningioma, discuss the possible pathophysiology and review the literature on the pathogenesis, risk factors, and outcome. Although rare, neurosurgeons, as well as neuroanesthesiologists should be aware of the possibility of this devastating complication in the high-risk group of patients. PMID- 23741262 TI - Intracranial metastasis from primary spinal primitive neuroectodermal tumor. AB - Primary spinal primitive neuroectodermal tumors (PNET) are rare tumors, with only 94 cases reported till date. Metastasis to brain from a spinal PNET is even rarer. In the present report, we evaluate the pathology and treatment of solitary intracranial metastasis from spinal PNET in a 22-year-old female who presented with headache and left hemiparesis and was diagnosed to have right parietal parasagittal tumor. She has been previously diagnosed to have cervicothoracic primary spinal PNET, and was treated by surgery, radiotherapy, and chemotherapy seven years back. The intracranial tumor has been removed and pathological examination confirmed as PNET. She received radiotherapy and chemotherapy with ifosfamide and etoposide, following surgery for the right parietal PNET. At 20 months follow-up, patient is stable and has no recurrence of the disease. Critical review of reported cases of primary spinal PNET metastsising to brain was done. PMID- 23741263 TI - Intracerebral hemorrhage cause by a ruptured oncotic aneurysm from choriocarcinoma metastasis. AB - Ruptured oncotic aneurysms from choriocarcioma metastasis are very rare. One rare case of metastatic cerebral choriocarcioma with an initial presentation of intracerebral hemorrhage is reported. A 25-year-old woman initially presented with sudden onset of alteration of consciousness. The computed tomography scan showed left parietal hematoma and CT angiography showed a small aneurysm of the left middle cerebral arteries territories. Her chest X-ray showed two lung masses. A craniectomy was performed to remove the hematoma and decompression following the aneurysm excision. After surgery the patient regained consciousness and had no neurological deficit. The pathology reported metastatic choriocarcioma and her beta - HCG was 73,656 units. After recovery she received chemotherapy with an etoposide, methotrexate, actinomycin D, cyclophosphamide, and vincristine/oncovine (EMA-CO) regimen. PMID- 23741264 TI - Neglected primary Ewing's sarcoma of ethmoid presenting as surgical emergency. AB - We present a male child with primary Ewing's sarcoma arising from ethmoid sinuses with intradural and extracranial extension (bilateral nasal cavities, orbits, and maxillary sinuses). This is a rare condition. He presented with recurrent episodes of epistaxis for 2 years, sudden onset rapidly progressive bilateral proptosis, with painful restriction of extraocular movements, and decreased visual acuity for 4 days. Sudden complete loss of vision following admission demanded emergency tumor decompression. PMID- 23741265 TI - Migration of intraventricular neurocysticercus after ventriculostomy. AB - Intraventricular neurocysticerci are an uncommon occurrence and are often difficult to diagnose. They are often a cause of obstructive hydrocephalus and inflammatory reactions, which can be life threatening. Intraventricular neurocysticerci are most common in the fourth ventricle and surgical decompression of obstructive hydrocephalus is an important step in their management. However, these cysticerci are also known to migrate within the ventricular system and may cause confusion during surgery. It thus becomes very important for radiologists and neurosurgeons to be aware of this phenomenon. PMID- 23741266 TI - Pulmonary hypertension: Another light in the dark tunnel. Learning the lesson from cancer. PMID- 23741267 TI - Approach to acute exacerbation of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia with a median survival of 3 years after diagnosis. Acute exacerbation of IPF (AE-IPF) is now identified as a life-threatening complication. It presents as worsening dyspnea with new ground glass opacities superimposed upon a radiographic usual interstitial pneumonia (UIP) pattern. It is a diagnosis of exclusion. The prognosis of AE-IPF is poor and treatment strategies lack standardization. In order to rule out any reversible etiology for an acute decompensation of a previously stable IPF patient diagnostic modalities include computerized tomographic angiogram (CTA) coupled with high-resolution computerized tomography (HRCT) imaging of the chest, bronchoalveolar lavage (BAL) and echocardiogram with bubble study. Avoiding risk factors, identifying underlying causes and supportive care are the mainstays of treatment. Anti-inflammatory and immunosuppressant medications have not shown to improve survival in AE-IPF. Most of the patients are managed in a critical care setting with mechanical ventilation. Lung transplantation is a promising option but most institutions are not equipped and not every patient is a candidate. PMID- 23741268 TI - Pulmonary hypertension in Saudi Arabia: A single center experience. AB - CONTEXT: Several international studies have described the epidemiology of pulmonary hypertension (PH). However, information about the incidence and prevalence of PH in Saudi Arabia is unknown. AIMS: To report cases of PH and compare the demographic and clinical characteristics of PH due to various causes in a Saudi population. METHODS: Newly diagnosed cases of PH [defined as mean pulmonary artery pressure >25 mmHg at right heart cauterization (RHC)] were prospectively collected at a single tertiary care hospital from January 2009 and June 2012. Detailed demographic and clinical data were collected at the time of diagnosis, along with hemodynamic parameters. RESULTS: Of the total 264 patients who underwent RHC, 112 were identified as having PH. The mean age at diagnosis was 55.8 +/- 15.8 years, and there was a female preponderance of 72.3%. About 88 (78.6%) of the PH patients were native Saudis and 24 (21.4%) had other origins. Twelve PH patients (10.7%) were classified in group 1 (pulmonary arterial hypertension), 7 (6.2%) in group 2 (PH due to left heart disease), 73 (65.2%) in group 3 (PH due to lung disease), 4 (3.6%) in group 4 (chronic thromboembolic PH), and 16 (14.3%) in group 5 (PH due to multifactorial mechanisms). PH associated with diastolic dysfunction was noted in 28.6% of group 2 patients, 31.5% of group 3 patients, and 25% of group 5 patients. CONCLUSIONS: These results offer the first report of incident cases of PH across five groups in Saudi Arabia. PMID- 23741270 TI - Prognostic factors for bronchoscopic intervention in advanced lung or esophageal cancer patients with malignant airway obstruction. AB - CONTEXT: Bronchoscopic intervention can provide immediate relief from suffocation and an opportunity for additional treatment in patients with malignant airway obstruction. However, few studies have specifically identified prognostic factors affecting the survival of advanced lung or esophageal cancer patients receiving bronchoscopic intervention. AIMS: We aimed to investigate prognostic factors influencing survival in these patients. STUDY DESIGN: We conducted retrospective study. METHODS: The clinical parameters were retrospectively reviewed in 51 patients (lung cancer: n = 35; esophageal cancer: n = 16) who underwent palliative bronchoscopic interventions due to malignant airway. RESULTS: Bronchoscopic interventions, such as mechanical removal (n = 26), stenting (n = 31), laser cauterization (n = 19), and ballooning (n = 16), were performed on intraluminal (n = 21, 41%), extrinsic (n = 8, 16%), and combined lesions (n = 22, 43%). Tracheal invasion was found in 24 patients (47%). Successful palliation was achieved in 49 patients (96%). After the intervention, additional anti-cancer treatment was followed in 24 patients (47%). The median survival time and overall survival rate were 3.4 months and 4%. Survival was increased with selected conditions, including a treatment-naive status (hazard ratio [HR], 0.359; confidence interval [CI], 0.158-0.815; P = 0.01), an intact proximal airway (HR, 0.265; CI, 0.095-0.738; P = 0.01), and post-procedural additional treatment (HR, 0.330; CI, 0.166-0.657; P < 0.01). CONCLUSIONS: Brochoscopic intervention could provide immediate relief and survival improvement in advanced lung or esophageal cancer patients with selected conditions such as a treatment-naive status, an intact proximal airway, and available post-procedural additional treatment. PMID- 23741271 TI - Detection of premalignant bronchial lesions can be significantly improved by combination of advanced bronchoscopic imaging techniques. AB - BACKGROUND: The search for the most efficient bronchoscopic imaging tool in detection of early lung cancer is still active. The major aim of this study was to determine sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each bronchoscopic technique and their combination in detection of premalignant bronchial lesions. METHODS: This was a prospective trial that enrolled 96 patients with indication for bronchoscopy. Lesions were classified as visually positive if pathological fluorescence was observed under autofluorescence imaging (AFI) videobronchoscopy or dotted, tortuous, and abrupt-ending blood vessels were identified under narrow band imaging (NBI) videobronchoscopy. Squamous metaplasia, mild, moderate, or severe dysplasia, and carcinoma in situ (CIS) were regarded as histologically positive lesions. RESULTS: Sensitivity, specificity, PPV, and NPV of white light videobronchoscopy (WLB) in detection of premalignant lesions were 26.5%, 63.9%, 34.4%, and 54.9%, respectively; the corresponding values for AFI were 52%, 79.6%, 64.6%, and 69.9% respectively, for NBI were 66%, 84.6%, 75.4%, 77.7%, respectively, while the values for combination of NBI and AFI were 86.1%, 86.6%, 84.6%, and 88%, respectively. Combination of NBI and AFI significantly improves sensitivity when compared to each individual technique (P < 0.001). When specificity is of concern, combination of techniques improves specificity of WLB (P < 0.001) and specificity of AFI (P = 0.03), but it does not have significant influence on specificity of NBI (P = 0.53). CONCLUSION: Combination of NBI and AFI in detection of premalignant bronchial lesions increases both sensitivity and specificity of each technique. However, it seems that NBI is most sufficient and effective in detection of these lesions. PMID- 23741272 TI - The role of thoracic ultrasonography in the diagnosis of pulmonary embolism. AB - OBJECTIVES: The diagnosis of pulmonary embolism (PE) is still a problem especially at emergency units. The purpose of study was to determine the diagnostic accuracy of thoracic ultrasonography (TUS) in patients with PE. METHODS: In this prospective study, 50 patients with suspected PE were evaluated in Department of Pulmonary Diseases of a Training and Reasearch Hospital between January 2010 and July 2011. At the begining, TUS was performed by a chest physician, subsequently for definitive diagnosis computed tomography pulmonary angiography were performed in all cases as a reference method. Other diagnostic procedures were examination of serum d-dimer levels, echocardiography, and venous doppler ultrasonography of the legs. Both chest physician and radiologist were blinded to the results of other diagnostic method. Diagnosis of PE was suggested if at least one typical pleural-based/subpleural wedge-shaped or round hypoechoic lesion with or without pleural effusion was reported by TUS. Presence of pure pleural effusion or normal sonographic findings were accepted as negative TUS for PE. RESULTS: PE was diagnosed in 30 patients. It was shown that TUS was true positive in 27 patients and false positive in eight and true negative in 12 and false negative in three. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of TUS in diagnosis of PE for clinically suspected patients were 90%, 60%, 77.1%, 80%, and 78%, respectively. CONCLUSIONS: TUS with a high sensitivity and diagnostic accuracy, is a noninvasive, widely available, cost-effective method which can be rapidly performed. A negative TUS study cannot rule out PE with certainty, but positive TUS findings with moderate/high suspicion for PE may prove a valuable tool in diagnosis of PE at bedside especially at emergency setting, for critically ill and immobile patients, facilitating immediate treatment decision. PMID- 23741273 TI - Does the patients' educational level and previous counseling affect their medication knowledge? AB - AIMS: The direct involvement of clinical pharmacists in patient care is an ever evolving role in the pharmacy profession. Studies have demonstrated that discharge counseling performed by a clinical pharmacist improves patients' knowledge of their medications. The aim of this article is to evaluate the effect of patients' educational level and previous counseling on medication knowledge among patients visiting King Abdulaziz Medical City, a tertiary care center. METHODS: The effect of the education level and previous counseling on medication knowledge was assessed in 90 patients in both inpatient and outpatient settings at King Abdul Aziz Medical City during a 5-week period using a questionnaire that contains items to assess patients' medication knowledge and the pharmacists' performance during counseling. RESULTS: The average age of the participants was 52.9 +/- 17.6 years. The participants' education level was not significantly associated with gender; however, it was significantly associated with age, P < 0.05. A higher educational level was found to positively affect the aspects of medication knowledge that were assessed in this study (P < 0.05): 35.8-56.9% of the non-educated patients showed good to excellent recognition of medications, knowledge of their indications, and knowledge of dosage schedule compared to 76.2 90.5% for the more educated participants. Furthermore, 13.6%, 38.1%, and 70.0% of the non-educated group, the below high school group and high school education or above group, respectively, demonstrated good to excellent knowledge of their medications' side effects. Previous counseling was also positively linked to medication knowledge (P < 0.05). Here, 87.8-97.6% of the patients who received previous counseling showed good to excellent recognition of medications, knowledge of their indications, and better knowledge of dosage schedule compared to 37.2-43.2% for those who did not. Finally, 52.9% of the patients who received previous counseling showed good to excellent knowledge of medication side effects compared to only 12.5% for those who did not. CONCLUSIONS: The education level of the patient and previous counseling are positively linked to medication knowledge. Knowledge of the medications' side effects proved to be the most difficult task for the participants in this study, requiring the highest level of education, and was improved by previous counseling. PMID- 23741274 TI - Concomitant chemoradiotherapy with docetaxel and cisplatin followed by consolidation chemotherapy in locally advanced unresectable non-small cell lung cancer. AB - OBJECTIVES: To evaluate treatment results and toxicities in patients who received concomitant chemoradiotherapy (CRT) followed by consolidation with docetaxel and cisplatin in locally advanced unresectable non-small cell lung cancer (NSCLC). METHODS: Ninety three patients were included in this retrospective study. The patients received 66 Gy radiotherapy and weekly 20 mg/m(2) docetaxel and 20 mg/m(2) cisplatin chemotherapy concomitantly. One month later than the end of CRT, consolidation chemotherapy with four cycles of docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) were administered at each 21 days. RESULTS: Median age of the patients was 57 (range, 30-74). Following concomitant CRT, 14 patients (15%) showed complete and 50 patients (54%) showed partial response (total response rate was 69%). The median follow-up was 13 months (range: 2-51 months). The median overall survival was 18 months (95% confidential interval [CI]: 13.8-22.1 months); local control was 15 months (95% CI: 9.3-20.6 months); progression-free survival was 9 months (95% CI: 6.5-11.4 months). Esophagitis in eight (9%) patients, neutropenia in seven (8%) patients and pneumonitis in eight (9%) patients developed as grade III-IV toxicity due to concomitant CRT. CONCLUSION: Concomitant CRT with docetaxel and cisplatin followed by docetaxel and cisplatin consolidation chemotherapy might be considered as a feasible, and well tolerated treatment modality with high response rates despite the fact that it has not a survival advantage in patients with locally advanced unresectable NSCLC. PMID- 23741275 TI - Broncho-vascular fistulas from self-expanding metallic stents: A retrospective case review. AB - To highlight a potentially fatal complication of broncho-vascular fistula arising from the self expanding metallic stent (SEMS) placement. We retrospectively analyzed five patients with benign and malignant airway diseases, who developed tracheo/broncho-vascular fistulas following SEMS placement in our tertiary care setting. All patients received either Wallstent or Ultraflex((r)) stent (Boston Scientific, Natick, MA) between 1999 and 2007. All patients had received adjunct therapy such as balloon bronchoplasty, laser therapy or electrocautery. Most patients presented with massive hemoptysis. A total of 483 SEMS were placed during this period. SEMS placement can be complicated by Broncho-vascular fistula formation. True incidence and precise time interval between the insertion of stent and onset of this complication is unknown. Additional therapeutic modalities to maintain stent patency may enhance the risk of fistula formation. SEMS should only be used in a select sub-group of patients, after exhaustive evaluation of other treatment options. These cases provide evidence that broncho vascular fistulas can develop at any time following SEMS placement, suggesting the need for a more cautious approach, especially while using them for a long term management. In benign airway disease, the stent should be removed as soon as healing has taken place. PMID- 23741276 TI - A case of primary mediastinal Ewing's sarcoma / primitive neuroectodermal tumor presenting with initial compression of superior vena cava. AB - Ewing's sarcomas and peripheral primitive neuroectodermal tumors (ES/PNETs) are high grade malignant neoplasms. These malignancies are characterized by a chromosome 22 rearrangement, arise from bone or soft tissue, predominantly affect children and young adults, and are grouped in the Ewing family of tumors. Multimodality treatment programs are the treatment of choice. Primary localization of ES/PNET in the mediastinum is extremely rare. We describe a case of ES/PNET presenting as a mediastinal mass with tracheal compression and initial signs of superior vena cava in a 66-year-old woman. PMID- 23741277 TI - Cerebral gas embolism in a case of Influenza A-associated acute respiratory distress syndrome treated with high-frequency oscillatory ventilation. AB - A 22-year-old obese asthmatic woman with Influenza A (H1N1)-associated acute respiratory distress syndrome died from cerebral artery gas emboli with massive cerebral infarction while being treated with High-Frequency Oscillatory Ventilation in the absence of a right to left intracardiac shunt. We review and briefly discuss other causes of systemic gas emboli (SGE). We review proposed mechanisms of SGE, their relation to our case, and how improved understanding of the risk factors may help prevent SGE in positive pressure ventilated patients. PMID- 23741278 TI - Evaluation of right ventricle with echocardiography: Utility of combined techniques. PMID- 23741279 TI - Author's reply. PMID- 23741280 TI - Comments on the utility of endorbonchial ultrasound-guided transbronchial needle aspiration in mediastinal or hilar lymph node evaluation in extrathoracic malignancy: Benign or malignant? PMID- 23741281 TI - Author reply. PMID- 23741282 TI - Regulation of Toll-like receptors in the choroid plexus in the immature brain after systemic inflammatory stimuli. AB - The choroid plexus is the site of the blood-cerebrospinal fluid (CSF) barrier (BCSFB) and has also been considered as a possible route for peripheral immune signals and cells to transfer to the central nervous system. Infection/inflammation stimulates innate and subsequent adaptive immune responses via Toll-like receptors (TLRs). In this study, we have investigated the mRNA expression of TLRs, cytokines, and tight junction proteins in the choroid plexus in the immature brain after systemic inflammation, as well as accumulation of immune cells into the CSF. Specific ligands for TLR-1/2, TLR-3, and TLR-4 were administered to postnatal day 8 mice and mRNA expression for the targeted genes was examined in the choroid plexus. We found that mRNA for all four TLRs was detected in the choroid plexus under control conditions. Following immune stimulation, expression of all the TLRs was upregulated by their respective ligands, except for TLR-4 mRNA, which was downregulated by Pam3CSK4 (PAM; a TLR 1/2 ligand). In addition, we investigated BCSFB regulation after TLR stimulation and found that TLR-1/2 and TLR-4 activation was associated with changes in mRNA expression of the tight junction protein occludin in the choroid plexus. PAM induced choroid plexus transcription of TNF-alpha and resulted in the most dramatic increase in numbers of white blood cells in the CSF. The data suggest a possible mechanism whereby systemic inflammation stimulates TLRs in the choroid plexus, which may lead to disturbances in choroid plexus barrier function, as well as infiltration of immune cells through the plexus. PMID- 23741283 TI - Perinatal Polychlorinated Biphenyl 126 Exposure Alters Offspring Body Composition. AB - Polychlorinated biphenyls (PCBs) are ubiquitous environmental contaminants whose exposure levels are associated with various health hazards. We hypothesized that in utero and lactational exposure to PCBs can cause changes in body composition and obesity in a mouse model. Pregnant mice were exposed biweekly to two concentrations of PCB 126 via oral gavage. Maternal PCB exposure did not result in heavier offspring, however, dose-dependent and sex specific changes in body composition were observed. Female offspring displayed the most susceptibility to PCB-induced alterations in body composition, having less percent lean body mass and increased adiposity compared to females born to control dams, and these effects were largely dose-dependent. In contrast to females, and independent of the exposure level of PCB 126, male offspring had reduced lean body mass but no change in fat mass compared to males born to control dams. In conclusion, perinatal PCB 126 exposure did not affect body weight, but rather modulated body composition in a dose-dependent and gender-specific manner. PMID- 23741284 TI - Nonparametric Bayesian Segmentation of a Multivariate Inhomogeneous Space-Time Poisson Process. AB - A nonparametric Bayesian model is proposed for segmenting time-evolving multivariate spatial point process data. An inhomogeneous Poisson process is assumed, with a logistic stick-breaking process (LSBP) used to encourage piecewise-constant spatial Poisson intensities. The LSBP explicitly favors spatially contiguous segments, and infers the number of segments based on the observed data. The temporal dynamics of the segmentation and of the Poisson intensities are modeled with exponential correlation in time, implemented in the form of a first-order autoregressive model for uniformly sampled discrete data, and via a Gaussian process with an exponential kernel for general temporal sampling. We consider and compare two different inference techniques: a Markov chain Monte Carlo sampler, which has relatively high computational complexity; and an approximate and efficient variational Bayesian analysis. The model is demonstrated with a simulated example and a real example of space-time crime events in Cincinnati, Ohio, USA. PMID- 23741289 TI - Sputum inflammatory cell-based classification of patients with acute exacerbation of chronic obstructive pulmonary disease. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) commonly suffer from acute exacerbations (AECOPD) and display varying disease severity. However, there is no available biomarker for the classification of AECOPD. This study is aimed at investigating the sputum cellular profiles to classify patients with AECOPD. METHODS: A total of 83 patients with AECOPD and 26 healthy controls were recruited. Their demographic and clinical characteristics were recorded, and their lung function was examined. The phenotypes of sputum inflammatory cells were characterised, and the concentrations of sputum and serum amyloid-A (SAA), C reactive protein (CRP), interleukin-6 (IL-6), and matrix metalloproteinase-9 (MMP 9) were measured. Based on the sputum inflammatory cell profiles, individual patients were categorized into one of the four subgroups with inflammatory eosinophilic, neutrophilic, paucigranulocytic, and mixed granulocytic AECOPD. Most AECOPD patients were reevaluated within 12-14 months after discharge. RESULTS: There were 10 (12%) eosinophilic, 36 (43%) neutrophilic, 5 (6%) mixed granulocytic, and 32 (39%) paucigranulocytic AECOPD patients. The patients with mixed granulocytic or neutrophilic AECOPD had a higher BODE score, more sputum inflammatory cells, lower lung function, and longer hospital stay, accompanied by higher concentrations of sputum MMP-9, IL-6 and CRP, and serum SAA, IL-6 and CRP. Notably, 83% of patients with neutrophilic AECOPD displayed evidence of bacterial infection and many of them responded poorly to standard therapies. In addition, patients with mixed granulocytic or neutrophilic stable COPD remained at lower lung functions and higher levels of inflammation. CONCLUSION: Patients with AECOPD display heterogeneous inflammation, and the profiles of sputum inflammatory cells may be used as valuable biomarkers for the classification of AECOPD patients. PMID- 23741290 TI - N-6 and N-3 fatty acid cholesteryl esters in relation to fatal CHD in a Dutch adult population: a nested case-control study and meta-analysis. AB - BACKGROUND: Dietary polyunsaturated fatty acids (PUFA) are inversely related to coronary heart disease (CHD) in epidemiological studies. We examined the associations of plasma n-6 and n-3 PUFA in cholesteryl esters with fatal CHD in a nested case-control study. Additionally, we performed a dose-response meta analysis of similar prospective studies on cholesteryl ester PUFA. METHODS: We used data from two population-based cohort studies in Dutch adults aged 20-65 y. Blood and data collection took place from 1987-1997 and subjects were followed for 8-19 y. We identified 279 incident cases of fatal CHD and randomly selected 279 controls, matched on age, gender, and enrollment date. Odds ratios (OR) were calculated per standard deviation (SD) increase of cholesteryl ester PUFA. RESULTS: After adjustment for confounders, the OR (95%CI) for fatal CHD per SD increase in plasma linoleic acid was 0.89 (0.74-1.06). Additional adjustment for plasma total cholesterol and systolic blood pressure attenuated this association (OR:0.95; 95%CI: 0.78-1.15). Arachidonic acid was not associated with fatal CHD (OR per SD:1.11; 95%CI: 0.92-1.35). The ORs (95%CI) for fatal CHD for an SD increase in n-3 PUFA were 0.92 (0.74-1.15) for alpha-linolenic acid and 1.06 (0.88-1.27) for EPA-DHA. In the meta-analysis, a 5% higher linoleic acid level was associated with a 9% lower risk (relative risk: 0.91; 95% CI: 0.84-0.98) of CHD. The other fatty acids were not associated with CHD. CONCLUSION: In this Dutch population, n-6 and n-3 PUFA in cholesteryl esters were not significantly related to fatal CHD. Our data, together with findings from previous prospective studies, support that linoleic acid in plasma cholesteryl is inversely associated with CHD. PMID- 23741291 TI - Photobacterium profundum under pressure: a MS-based label-free quantitative proteomics study. AB - Photobacterium profundum SS9 is a Gram-negative bacterium, originally collected from the Sulu Sea. Its genome consists of two chromosomes and a 80 kb plasmid. Although it can grow under a wide range of pressures, P. profundum grows optimally at 28 MPa and 15 degrees C. Its ability to grow at atmospheric pressure allows for both easy genetic manipulation and culture, making it a model organism to study piezophily. Here, we report a shotgun proteomic analysis of P. profundum grown at atmospheric compared to high pressure using label-free quantitation and mass spectrometry analysis. We have identified differentially expressed proteins involved in high pressure adaptation, which have been previously reported using other methods. Proteins involved in key metabolic pathways were also identified as being differentially expressed. Proteins involved in the glycolysis/gluconeogenesis pathway were up-regulated at high pressure. Conversely, several proteins involved in the oxidative phosphorylation pathway were up-regulated at atmospheric pressure. Some of the proteins that were differentially identified are regulated directly in response to the physical impact of pressure. The expression of some proteins involved in nutrient transport or assimilation, are likely to be directly regulated by pressure. In a natural environment, different hydrostatic pressures represent distinct ecosystems with their own particular nutrient limitations and abundances. However, the only variable considered in this study was atmospheric pressure. PMID- 23741292 TI - Insulin receptor substrate 2 is required for testicular development. AB - Insulin receptor substrate (IRS) proteins are key mediators of insulin and insulin-like growth factor (IGF) signalling. In mice, deletion of Irs1 is associated with profound growth retardation and increased longevity whereas Irs2 deficiency causes diabetes and female infertility. Clinical studies suggest that diabetes and obesity diminish male fertility. However, the role of IRS proteins in male reproduction is unknown. We observed that testis weight is reduced by 45% in Irs2-deficient mice as compared with control males. The weight of these organs in Irs1(-/-) males was similar to controls; however, since Irs1-deficient mice are 50% smaller, testis weight:body weight was increased in this model. Neonatal Irs2(-/-) mice also exhibited reduced testicular size, suggesting that impairments in this model occur during development. Histological examination of testicular cross sections from Irs2(-/-) mice revealed normal cellular associations without obvious abnormalities in the seminiferous epithelium. Reduced testicular weight was associated with fewer Sertoli cells, spermatogonia, spermatocytes, elongated spermatids, and epididymal spermatozoa. However, Leydig cell number and the concentration of serum testosterone were equivalent between Irs2-deficient and control males. Testicular weight was reduced similarly in non diabetic and diabetic Irs2(-/-) mice, indicating that hyperglycemia does not compound the effects of Irs2 deletion on impaired testis development. Expression of Irs1, Irs3, and Irs4 was comparable between experimental groups. Collectively, our results demonstrate that IRS2 plays a critical role in testicular development, potentially by mediating IGF1 signalling during embryonic and early postnatal development. PMID- 23741293 TI - Assessing methods for assigning SNPs to genes in gene-based tests of association using common variants. AB - Gene-based tests of association are frequently applied to common SNPs (MAF>5%) as an alternative to single-marker tests. In this analysis we conduct a variety of simulation studies applied to five popular gene-based tests investigating general trends related to their performance in realistic situations. In particular, we focus on the impact of non-causal SNPs and a variety of LD structures on the behavior of these tests. Ultimately, we find that non-causal SNPs can significantly impact the power of all gene-based tests. On average, we find that the "noise" from 6-12 non-causal SNPs will cancel out the "signal" of one causal SNP across five popular gene-based tests. Furthermore, we find complex and differing behavior of the methods in the presence of LD within and between non causal and causal SNPs. Ultimately, better approaches for a priori prioritization of potentially causal SNPs (e.g., predicting functionality of non-synonymous SNPs), application of these methods to sequenced or fully imputed datasets, and limited use of window-based methods for assigning inter-genic SNPs to genes will improve power. However, significant power loss from non-causal SNPs may remain unless alternative statistical approaches robust to the inclusion of non-causal SNPs are developed. PMID- 23741295 TI - MHD forced convective laminar boundary layer flow from a convectively heated moving vertical plate with radiation and transpiration effect. AB - A two-dimensional steady forced convective flow of a Newtonian fluid past a convectively heated permeable vertically moving plate in the presence of a variable magnetic field and radiation effect has been investigated numerically. The plate moves either in assisting or opposing direction to the free stream. The plate and free stream velocities are considered to be proportional to x(m) whilst the magnetic field and mass transfer velocity are taken to be proportional to x((m-1)/2) where x is the distance along the plate from the leading edge of the plate. Instead of using existing similarity transformations, we use a linear group of transformations to transform the governing equations into similarity equations with relevant boundary conditions. Numerical solutions of the similarity equations are presented to show the effects of the controlling parameters on the dimensionless velocity, temperature and concentration profiles as well as on the friction factor, rate of heat and mass transfer. It is found that the rate of heat transfer elevates with the mass transfer velocity, convective heat transfer, Prandtl number, velocity ratio and the magnetic field parameters. It is also found that the rate of mass transfer enhances with the mass transfer velocity, velocity ratio, power law index and the Schmidt number, whilst it suppresses with the magnetic field parameter. Our results are compared with the results existing in the open literature. The comparisons are satisfactory. PMID- 23741294 TI - Glutathione S-transferases interact with AMP-activated protein kinase: evidence for S-glutathionylation and activation in vitro. AB - AMP-activated protein kinase (AMPK) is a cellular and whole body energy sensor with manifold functions in regulating energy homeostasis, cell morphology and proliferation in health and disease. Here we apply multiple, complementary in vitro and in vivo interaction assays to identify several isoforms of glutathione S-transferase (GST) as direct AMPK binding partners: Pi-family member rat GSTP1 and Mu-family members rat GSTM1, as well as Schistosoma japonicum GST. GST/AMPK interaction is direct and involves the N-terminal domain of the AMPK beta subunit. Complex formation of the mammalian GSTP1 and -M1 with AMPK leads to their enzymatic activation and in turn facilitates glutathionylation and activation of AMPK in vitro. GST-facilitated S-glutathionylation of AMPK may be involved in rapid, full activation of the kinase under mildly oxidative physiological conditions. PMID- 23741296 TI - Ex-PRESS implantation versus trabeculectomy in uncontrolled glaucoma: a meta analysis. AB - OBJECTIVE: To evaluate the efficacy and tolerability of Ex-PRESS implantation (Ex Press) compared with trabeculectomy (Trab) in the treatment of patients with uncontrolled glaucoma. METHODS: A comprehensive literature meta-analysis was performed according to the Cochrane Collaboration methodology to identify controlled clinical trials comparing Ex-Press with Trab. Efficacy estimates were measured by weight mean difference (WMD) for the percentage intraocular pressure (IOP) reduction from baseline to end-point, odds ratio (OR) for complete success, and qualified success rates. Tolerability estimates were measured by OR for adverse events. All outcomes were reported with a 95% confidence interval (CI). Data were synthesized by Stata 11.0 SE for Windows. RESULTS: Eight controlled clinical trials meeting the predefined criteria were included in the meta analysis. A total of 605 eyes from 559 patients with medically uncontrolled glaucoma were included. The weighted mean difference of the percentage IOP reduction from baseline was 2.33 (95% confidence interval: -2.59-7.24) when comparing Ex-Press with Trab. Ex-Press was associated with numerically greater, but nonsignificant, IOP lowering efficacy than Trab. The pooled odds ratio comparing Ex-Press with Trab were 0.93 (0.39, 2.23) for the complete success rate and 1.00 (0.39, 2.56) for the qualified success rate. Ex-Press was associated with a significantly lower frequency of hypotony and hyphema than Trab, with pooled ORs of 0.29 (0.13, 0.65) and 0.36 (0.13, 0.97), respectively. CONCLUSION: Ex-Press was associated with equivalent efficacy to Trab in lowering IOP. Comparable proportions of patients reached the IOP target with Ex-Press and Trab. Ex-Press was better tolerated than Trab. PMID- 23741297 TI - The role of host gender in the pathogenesis of Cryptococcus neoformans infections. AB - Cryptococcus neoformans (Cn) is a pathogenic yeast and the cause of cryptococcal meningitis. Prevalence of disease between males and females is skewed, with males having an increased incidence of disease. Based on the reported gender susceptibility differences to Cn in the literature, we used clinical isolates from Botswanan HIV-infected patients to test the hypothesis that different gender environments exerted different selective pressures on Cn. When we examined this data set, we found that men had significantly higher risk of death despite having significantly higher CD4(+) T lymphocyte counts upon admittance to the hospital. These observations suggested that Cn strains are uniquely adapted to different host gender environments and that the male immune response may be less efficient in controlling Cn infection. To discriminate between these possibilities, we tested whether there were phenotypic differences between strains isolated from males and females and whether there was an interaction between Cn and the host immune response. Virulence phenotypes showed that Cn isolates from females had longer doubling times and released more capsular glucoronoxylomannan (GXM). The presence of testosterone but not 17-beta estradiol was associated with higher levels of GXM release for a laboratory strain and 28 clinical isolates. We also measured phagocytic efficiency, survival of Cn, and amount of killing of human macrophages by Cn after incubation with four isolates. While macrophages from females phagocytosed more Cn than macrophages from males, male macrophages had a higher fungal burden and showed increased killing by Cn. These data are consistent with the hypothesis that differential interaction between Cn and macrophages within different gender environments contribute to the increased prevalence of cryptococcosis in males. This could be related to differential expression of cryptococcal virulence genes and capsule metabolism, changes in Cn phagocytosis and increased death of Cn-infected macrophages. PMID- 23741298 TI - Adverse effects of ocean acidification on early development of squid (Doryteuthis pealeii). AB - Anthropogenic carbon dioxide (CO2) is being absorbed into the ocean, altering seawater chemistry, with potentially negative impacts on a wide range of marine organisms. The early life stages of invertebrates with internal and external aragonite structures may be particularly vulnerable to this ocean acidification. Impacts to cephalopods, which form aragonite cuttlebones and statoliths, are of concern because of the central role they play in many ocean ecosystems and because of their importance to global fisheries. Atlantic longfin squid (Doryteuthis pealeii), an ecologically and economically valuable taxon, were reared from eggs to hatchlings (paralarvae) under ambient and elevated CO2 concentrations in replicated experimental trials. Animals raised under elevated pCO2 demonstrated significant developmental changes including increased time to hatching and shorter mantle lengths, although differences were small. Aragonite statoliths, critical for balance and detecting movement, had significantly reduced surface area and were abnormally shaped with increased porosity and altered crystal structure in elevated pCO2-reared paralarvae. These developmental and physiological effects could alter squid paralarvae behavior and survival in the wild, directly and indirectly impacting marine food webs and commercial fisheries. PMID- 23741299 TI - World Health Organization guideline development: an evaluation. AB - BACKGROUND: Research in 2007 showed that World Health Organization (WHO) recommendations were largely based on expert opinion, rarely used systematic evidence-based methods, and did not follow the organization's own "Guidelines for Guidelines". In response, the WHO established a "Guidelines Review Committee" (GRC) to implement and oversee internationally recognized standards. We examined the impact of these changes on WHO guideline documents and explored senior staff's perceptions of the new procedures. METHODS AND FINDINGS: We used the AGREE II guideline appraisal tool to appraise ten GRC-approved guidelines from nine WHO departments, and ten pre-GRC guidelines matched by department and topic. We interviewed 20 senior staff across 16 departments and analyzed the transcripts using the framework approach. Average AGREE II scores for GRC-approved guidelines were higher across all six AGREE domains compared with pre-GRC guidelines. The biggest changes were noted for "Rigour of Development" (up 37.6%, from 30.7% to 68.3%) and "Editorial Independence" (up 52.7%, from 20.9% to 73.6%). Four main themes emerged from the interviews: (1) high standards were widely recognized as essential for WHO credibility, particularly with regard to conflicts of interest; (2) views were mixed on whether WHO needed a single quality assurance mechanism, with some departments purposefully bypassing the procedures; (3) staff expressed some uncertainties in applying the GRADE approach, with departmental staff concentrating on technicalities while the GRC remained concerned the underlying principles were not fully institutionalized; (4) the capacity to implement the new standards varied widely, with many departments looking to an overstretched GRC for technical support. CONCLUSIONS: Since 2007, WHO guideline development methods have become more systematic and transparent. However, some departments are bypassing the procedures, and as yet neither the GRC, nor the quality assurance standards they have set, are fully embedded within the organization. PMID- 23741300 TI - The triterpenoid CDDO-Me inhibits bleomycin-induced lung inflammation and fibrosis. AB - Pulmonary Fibrosis (PF) is a devastating progressive disease in which normal lung structure and function is compromised by scarring. Lung fibrosis can be caused by thoracic radiation, injury from chemotherapy and systemic diseases such as rheumatoid arthritis that involve inflammatory responses. CDDO-Me (Methyl 2-cyano 3,12-dioxooleana-1,9(11)dien-28-oate, Bardoxolone methyl) is a novel triterpenoid with anti-fibrotic and anti-inflammatory properties as shown by our in vitro studies. Based on this evidence, we hypothesized that CDDO-Me would reduce lung inflammation, fibrosis and lung function impairment in a bleomycin model of lung injury and fibrosis. To test this hypothesis, mice received bleomycin via oropharyngeal aspiration (OA) on day zero and CDDO-Me during the inflammatory phase from days -1 to 9 every other day. Bronchoalveolar lavage fluid (BALF) and lung tissue were harvested on day 7 to evaluate inflammation, while fibrosis and lung function were evaluated on day 21. On day 7, CDDO-Me reduced total BALF protein by 50%, alveolar macrophage infiltration by 40%, neutrophil infiltration by 90% (p<=0.01), inhibited production of the inflammatory cytokines KC and IL-6 by over 90% (p<=0.001), and excess production of the pro-fibrotic cytokine TGFbeta by 50%. CDDO-Me also inhibited alpha-smooth muscle actin and fibronectin mRNA by 50% (p<=0.05). On day 21, CDDO-Me treatment reduced histological fibrosis, collagen deposition and alphaSMA production. Lung function was significantly improved at day 21 by treatment with CDDO-Me, as demonstrated by respiratory rate and dynamic compliance. These new findings reveal that CDDO-Me exhibits potent anti-fibrotic and anti-inflammatory properties in vivo. CDDO-Me is a potential new class of drugs to arrest inflammation and ameliorate fibrosis in patients who are predisposed to lung injury and fibrosis incited by cancer treatments (e.g. chemotherapy and radiation) and by systemic autoimmune diseases. PMID- 23741301 TI - Compound heterozygous mutations in SLC30A2/ZnT2 results in low milk zinc concentrations: a novel mechanism for zinc deficiency in a breast-fed infant. AB - Zinc concentrations in breast milk are considerably higher than those of the maternal serum, to meet the infant's requirements for normal growth and development. Thus, effective mechanisms ensuring secretion of large amounts of zinc into the milk operate in mammary epithelial cells during lactation. ZnT2 was recently found to play an essential role in the secretion of zinc into milk. Heterozygous mutations of human ZnT2 (hZnT2), including H54R and G87R, in mothers result in low (>75% reduction) secretion of zinc into the breast milk, and infants fed on the milk develop transient neonatal zinc deficiency. We identified two novel missense mutations in the SLC30A2/ZnT2 gene in a Japanese mother with low milk zinc concentrations (>90% reduction) whose infant developed severe zinc deficiency; a T to C transition (c.454T>C) at exon 4, which substitutes a tryptophan residue with an arginine residue (W152R), and a C to T transition (c.887C>T) at exon 7, which substitutes a serine residue with a leucine residue (S296L). Biochemical characterization using zinc-sensitive DT40 cells indicated that the W152R mutation abolished the abilities to transport zinc and to form a dimer complex, indicating a loss-of-function mutation. The S296L mutation retained both abilities but was extremely destabilized. The two mutations were found on different alleles, indicating that the genotype of the mother with low milk zinc was compound heterozygous. These results show novel compound heterozygous mutations in the SLC30A2/ZnT2 gene causing zinc deficiency in a breast-fed infant. PMID- 23741302 TI - Stream hydrological fragmentation drives bacterioplankton community composition. AB - In Mediterranean intermittent streams, the hydrological fragmentation in summer and the successive water flow re-convergence in autumn allow exploring how local processes shape the microbial community within the same habitat. The objectives of this study were to determine how bacterial community composition responded to hydrological fragmentation in summer, and to evaluate whether the seasonal shifts in community composition predominate over the effects of episodic habitat fragmentation. The bacterial community was assessed along the intermittent stream Fuirosos (Spain), at different levels of phylogenetic resolution by in situ hybridization, fingerprinting, and 16S rRNA gene sequencing. The hydrological fragmentation of the stream network strongly altered the biogeochemical conditions with the depletion of oxidized solutes and caused changes in dissolved organic carbon characteristics. In the isolated ponds, beta-Proteobacteria and Actinobacteria increased their abundance with a gradual reduction of the alpha diversity as pond isolation time increased. Moreover, fingerprinting analysis clearly showed a shift in community composition between summer and autumn. In the context of a seasonal shift, the temporary stream fragmentation simultaneously reduced the microbial dispersion and affected local environmental conditions (shift in redox regime and quality of the dissolved organic matter) tightly shaping the bacterioplankton community composition. PMID- 23741303 TI - Cognitive decline in older persons initiating anticholinergic medications. AB - BACKGROUND: This study examines the effect of initiating medications with anticholinergic activity on the cognitive functions of older persons. METHODS: Participants were 896 older community-dwelling, Catholic clergy without baseline dementia. Medication data was collected annually. The Anticholinergic Cognitive Burden Scale was utilized to identify use of a medication with probable or definite anticholinergic activity. Participants had at least two annual cognitive evaluations. RESULTS: Over a mean follow-up of 10 years, the annual rate of global cognitive function decline for never users, prevalent users, and incident users was -0.062 (SE = 0.005), -0.081(SE = 0.011), and -0.096 (SE = 0.007) z score units/year, respectively. Compared to never users, incident users had a more rapid decline (difference = -0.034 z-score units/year, SE = 0.008, p<0.001) while prevalent users did not have a significantly more rapid decline (p = 0.1). CONCLUSIONS: Older persons initiating a medication with anticholinergic activity have a steeper annual decline in cognitive functioning than those who are not taking these medications. PMID- 23741304 TI - Role of the carbohydrate-binding sites of griffithsin in the prevention of DC SIGN-mediated capture and transmission of HIV-1. AB - BACKGROUND: The glycan-targeting C-type DC-SIGN lectin receptor is implicated in the transmission of the human immunodeficiency virus (HIV) by binding the virus and transferring the captured HIV-1 to CD4(+) T lymphocytes. Carbohydrate binding agents (CBAs) have been reported to block HIV-1 infection. We have now investigated the potent mannose-specific anti-HIV CBA griffithsin (GRFT) on its ability to inhibit the capture of HIV-1 to DC-SIGN, its DC-SIGN-directed transmission to CD4(+) T-lymphocytes and the role of the three carbohydrate binding sites (CBS) of GRFT in these processes. FINDINGS: GRFT inhibited HIV 1(IIIB) infection of CEM and HIV-1(NL4.3) infection of C8166 CD4(+) T-lymphocytes at an EC50 of 0.059 and 0.444 nM, respectively. The single mutant CBS variants of GRFT (in which a key Asp in one of the CBS was mutated to Ala) were about ~20 to 60-fold less potent to prevent HIV-1 infection and ~20 to 90-fold less potent to inhibit syncytia formation in co-cultures of persistently HIV-1 infected HuT-78 and uninfected C8166 CD4(+) T-lymphocytes. GRFT prevents DC-SIGN-mediated virus capture and HIV-1 transmission to CD4(+) T-lymphocytes at an EC50 of 1.5 nM and 0.012 nM, respectively. Surface plasmon resonance (SPR) studies revealed that wild-type GRFT efficiently blocked the binding between DC-SIGN and immobilized gp120, whereas the point mutant CBS variants of GRFT were ~10- to 15-fold less efficient. SPR-analysis also demonstrated that wild-type GRFT and its single mutant CBS variants have the capacity to expel bound gp120 from the gp120-DC-SIGN complex in a dose dependent manner, a property that was not observed for HHA, another mannose-specific potent anti-HIV-1 CBA. CONCLUSION: GRFT is inhibitory against HIV gp120 binding to DC-SIGN, efficiently prevents DC-SIGN-mediated transfer of HIV-1 to CD4(+) T-lymphocytes and is able to expel gp120 from the gp120-DC-SIGN complex. Functionally intact CBS of GRFT are important for the optimal action of GRFT. PMID- 23741305 TI - Manufacture of clinical-grade CD19-specific T cells stably expressing chimeric antigen receptor using Sleeping Beauty system and artificial antigen presenting cells. AB - Adoptive transfer of T cells expressing a CD19-specific chimeric antigen receptor (CAR) is being evaluated in multiple clinical trials. Our current approach to adoptive immunotherapy is based on a second generation CAR (designated CD19RCD28) that signals through a CD28 and CD3-zeta endodomain. T cells are electroporated with DNA plasmids from the Sleeping Beauty (SB) transposon/transposase system to express this CAR. Stable integrants of genetically modified T cells can then be retrieved when co-cultured with designer artificial antigen presenting cells (aAPC) in the presence of interleukin (IL)-2 and 21. Here, we reveal how the platform technologies of SB-mediated transposition and CAR-dependent propagation on aAPC were adapted for human application. Indeed, we have initiated clinical trials in patients with high-risk B-lineage malignancies undergoing autologous and allogeneic hematopoietic stem-cell transplantation (HSCT). We describe the process to manufacture clinical grade CD19-specific T cells derived from healthy donors. Three validation runs were completed in compliance with current good manufacturing practice for Phase I/II trials demonstrating that by 28 days of co culture on gamma-irradiated aAPC ~10(10) T cells were produced of which >95% expressed CAR. These genetically modified and propagated T cells met all quality control testing and release criteria in support of infusion. PMID- 23741306 TI - Evaluation of autologous serum skin test and skin prick test reactivity to house dust mite in patients with chronic spontaneous urticaria. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) is a common skin disorder with etiology that is not well understood. METHODS: In this study, we evaluated the prevalence of autologous serum skin test (ASST) and skin prick testing (SPT) to house dust mite (HDM) in 862 CSU cases in China. Clinical features, courses and treatment responses were also recorded. RESULTS: The prevalence of positive ASST was 46.3%, and patients aged 30-39 years had the highest positive rate (52.1%). Positive SPT to HDM was seen in 153 patients (17.7%) with the highest positive rate (34.2%) in patients aged 20 or less. Patients with positive ASST had higher urticaria activity scores (UAS) (4.18+/-0.65 vs. 3.67+/-0.53) but lower positive rates of HDM (24.6% vs. 37.6%), as compared with those with negative ASST (odds ratio (OR) 1.84, 95% CI 1.38-2.47). Patients could be categorized into four groups based on the results of ASST and SPT to HDM and patients with positive ASST and positive SPT to HDM had the highest disease activity scores, experienced higher frequencies of angioedema, diseases duration, and required higher dosage of loratadine every month, compared with other subgroups (P<0.0001). CONCLUSIONS: Patients with CSU showed varied responses of positive ASST and varied sensitivity to HDM, Patients with positive ASST and/or positive SPT had more disease activity compared with patients with negative ASST and/or negative SPT. Further classification can be made based on the result of SPT and ASST. PMID- 23741307 TI - On the validity and phylogenetic position of Eubrachiosaurus browni, a kannemeyeriiform dicynodont (Anomodontia) from Triassic North America. AB - The large dicynodont Eubrachiosaurus browni from the Upper Triassic Popo Agie Formation of Wyoming is redescribed. Eubrachiosaurus is a valid taxon that differs from Placerias hesternus, with which it was previously synonymized, by greater anteroposterior expansion of the scapula dorsally and a very large, nearly rectangular humeral ectepicondyle with a broad supinator process. Inclusion of Eubrachiosaurus in a revised phylogenetic analysis of anomodont therapsids indicates that it is a stahleckeriid closely related to the South American genera Ischigualastia and Jachaleria. The recognition of Eubrachiosaurus as a distinct lineage of North American dicynodonts, combined with other recent discoveries in the eastern USA and Europe, alters our perception of Late Triassic dicynodont diversity in the northern hemisphere. Rather than being isolated relicts in previously therapsid-dominated regions, Late Triassic stahleckeriid dicynodonts were continuing to disperse and diversify, even in areas like western North America that were otherwise uninhabited by coeval therapsids (i.e., cynodonts). PMID- 23741308 TI - Digital quantification of gene expression in sequential breast cancer biopsies reveals activation of an immune response. AB - Advancements in molecular biology have unveiled multiple breast cancer promoting pathways and potential therapeutic targets. Large randomized clinical trials remain the ultimate means of validating therapeutic efficacy, but they require large cohorts of patients and are lengthy and costly. A useful approach is to conduct a window of opportunity study in which patients are exposed to a drug pre surgically during the interval between the core needle biopsy and the definitive surgery. These are non-therapeutic studies and the end point is not clinical or pathological response but rather evaluation of molecular changes in the tumor specimens that can predict response. However, since the end points of the non therapeutic studies are biologic, it is critical to first define the biologic changes that occur in the absence of treatment. In this study, we compared the molecular profiles of breast cancer tumors at the time of the diagnostic biopsy versus the definitive surgery in the absence of any intervention using the Nanostring nCounter platform. We found that while the majority of the transcripts did not vary between the two biopsies, there was evidence of activation of immune related genes in response to the first biopsy and further investigations of the immune changes after a biopsy in early breast cancer seem warranted. PMID- 23741309 TI - Perioperative allogenenic blood transfusion is associated with worse clinical outcomes for hepatocellular carcinoma: a meta-analysis. AB - BACKGROUND AND OBJECTIVE: The impact of perioperative allogenenic blood transfusion (ABT) on clinical outcomes for hepatocellular carcinoma (HCC) is conflicting and unclear. The aim of this meta-analysis is to evaluate the association between ABT and HCC clinical outcomes. Outcomes evaluated were all cause death, tumor recurrence and postoperative complications. METHODS: Relevant articles were identified through MEDLINE search (up to November 2012). Meta analyses were performed by using the fixed or random effect models. Study heterogeneity was assessed by Q-test and I(2) test. Publication bias was evaluated by funnel plots, Egger's and Begg's test. RESULTS: A total of 5635 cases from 22 studies finally met our inclusion criteria. Meta-analysis indicated HCC patients with ABT had an increased risk of all-cause death at 3 and 5 years after surgery (respectively: OR = 1.92, 95% CI, 1.61-2.29,P<0.001; OR = 1.60, 95% CI, 1.47-1.73,P<0.001 ) compared with those without ABT. The risk of tumor recurrence was significantly higher for ABT cases at 1, 3 and 5 years (respectively: OR = 1.70, 95% CI, 1.38-2.10, P<0.001; OR = 1.22, 95% CI, 1.08 1.38, P<0.001; OR = 1.16, 95% CI, 1.08-1.24, P<0.001). The HCC cases with ABT significantly increased postoperative complications occurrence compared with non ABT cases (OR = 1.78,95% CI, 1.34-2.37, P<0.001). CONCLUSIONS: The findings from the current meta-analysis demonstrated that ABT was associated with adverse clinical outcomes for HCC patients undergoing surgery, including increased death, recurrence and complications. Therefore, ABT should not be performed if possible. PMID- 23741310 TI - Maternal dietary restriction alters offspring's sleep homeostasis. AB - Nutritional state in the gestation period influences fetal growth and development. We hypothesized that undernutrition during gestation would affect offspring sleep architecture and/or homeostasis. Pregnant female mice were assigned to either control (fed ad libitum; AD) or 50% dietary restriction (DR) groups from gestation day 12 to parturition. After parturition, dams were fed AD chow. After weaning, the pups were also fed AD into adulthood. At adulthood (aged 8-9 weeks), we carried out sleep recordings. Although offspring mice displayed a significantly reduced body weight at birth, their weights recovered three days after birth. Enhancement of electroencephalogram (EEG) slow wave activity (SWA) during non-rapid eye movement (NREM) sleep was observed in the DR mice over a 24 hour period without changing the diurnal pattern or amounts of wake, NREM, or rapid eye movement (REM) sleep. In addition, DR mice also displayed an enhancement of EEG-SWA rebound after a 6-hour sleep deprivation and a higher threshold for waking in the face of external stimuli. DR adult offspring mice exhibited small but significant increases in the expression of hypothalamic peroxisome proliferator-activated receptor alpha (Pparalpha) and brain-specific carnitine palmitoyltransferase 1 (Cpt1c) mRNA, two genes involved in lipid metabolism. Undernutrition during pregnancy may influence sleep homeostasis, with offspring exhibiting greater sleep pressure. PMID- 23741312 TI - A continuum model of actin waves in Dictyostelium discoideum. AB - Actin waves are complex dynamical patterns of the dendritic network of filamentous actin in eukaryotes. We developed a model of actin waves in PTEN deficient Dictyostelium discoideum by deriving an approximation of the dynamics of discrete actin filaments and combining it with a signaling pathway that controls filament branching. This signaling pathway, together with the actin network, contains a positive feedback loop that drives the actin waves. Our model predicts the structure, composition, and dynamics of waves that are consistent with existing experimental evidence, as well as the biochemical dependence on various protein partners. Simulation suggests that actin waves are initiated when local actin network activity, caused by an independent process, exceeds a certain threshold. Moreover, diffusion of proteins that form a positive feedback loop with the actin network alone is sufficient for propagation of actin waves at the observed speed of * 6 mm/min. Decay of the wave back can be caused by scarcity of network components, and the shape of actin waves is highly dependent on the filament disassembly rate. The model allows retraction of actin waves and captures formation of new wave fronts in broken waves. Our results demonstrate that a delicate balance between a positive feedback, filament disassembly, and local availability of network components is essential for the complex dynamics of actin waves. PMID- 23741311 TI - Increased levels of plasma soluble Sema4D in patients with heart failure. AB - Semaphorin 4D (Sema4D/CD100) is a 150-kDa transmembrane glycoprotein expressed by platelets and T-cells. When these cells are activated, Sema4D is cleaved proteolytically, generating a biologically active 120-kDa fragment (soluble Sema4D) capable of targeting receptors on platelets, B-cells, endothelial cells and tumor cells. However, its plasma levels and significance in heart failure (HF) have not been reported. In this study, we established an ELISA and detected soluble Sema4D in human plasma. In healthy controls, plasma Sema4D levels were higher in men than women (5.15+/-3.30 ng/mL, n = 63, vs. 4.19+/-2.39 ng/mL, n = 63, P<0.05). In HF patients, plasma Sema4D levels were significantly higher than those in healthy controls (8.94+/-5.89 ng/mL, n = 157 vs. 4.67+/-2.99 ng/mL, n = 126, P<0.0001) with the highest levels being in HF patients with diabetes mellitus (DM) (10.45+/-5.76 ng/mL, n = 40). We also found that there was a higher percentage of Sema4D(high) CD3(+) (P<0.01), CD4(+) (P<0.001), and CD8(+) (P<0.01) T-cells in samples from HF patients, but no changes in Sema4D expression levels in B cells and platelets. Therefore, our investigation shows that plasma Sema4D levels are increased in HF patients, especially in those who also have diabetes. There was an accompanying increase in the Sema4D(high) population of T-cells, suggesting a potential role of these T-cells in heart failure. PMID- 23741313 TI - Albumin fusion of interleukin-28B: production and characterization of its biological activities and protein stability. AB - The cytokine interleukin-28B (IL-28B) has potential antiviral properties and regulatory roles in adaptive cellular immunity. A genome-wide association study identified a single nucleotide polymorphism near the IL-28B gene that strongly predicts response to hepatitis C treatment with interferon and ribavirin. In this study, we produced human serum albumin (HSA) fused to interleukin-28B (HSA-IL28B) in an attempt to determine the effects of albumin fusion on anti-Hepatitis C virus (HCV) activity and protein stability. HSA-IL28B was expressed at high levels in the yeast expression system we used and was easily purified. The biological activities of IL-28B were only retained when HSA was fused at the N terminus. Compared with the native IL-28B, HSA-IL28B showed improved protein stability. HSA-IL28B inhibited HCV infection through the membrane receptors IL28R1 and IL10R2. Additionally, we demonstrated that HSA-IL28B was able to induce interferon-stimulated genes, phosphorylate intracellular STAT1, and act in restricted cell types. Our findings highlight the potential clinical applications of the fusion protein during virus infection and for immune regulation. PMID- 23741314 TI - Hydrogen sulfide prevents hydrogen peroxide-induced activation of epithelial sodium channel through a PTEN/PI(3,4,5)P3 dependent pathway. AB - Sodium reabsorption through the epithelial sodium channel (ENaC) at the distal segment of the kidney plays an important role in salt-sensitive hypertension. We reported previously that hydrogen peroxide (H2O2) stimulates ENaC in A6 distal nephron cells via elevation of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) in the apical membrane. Here we report that H2S can antagonize H2O2 induced activation of ENaC in A6 cells. Our cell-attached patch-clamp data show that ENaC open probability (PO ) was significantly increased by exogenous H2O2, which is consistent with our previous finding. The aberrant activation of ENaC induced by exogenous H2O2 was completely abolished by H2S (0.1 mM NaHS). Pre treatment of A6 cells with H2S slightly decreased ENaC P(O); however, in these cells H2O2 failed to elevate ENaC PO . Confocal microscopy data show that application of exogenous H2O2 to A6 cells significantly increased intracellular reactive oxygen species (ROS) level and induced accumulation of PI(3,4,5)P3 in the apical compartment of the cell membrane. These effects of exogenous H2O2 on intracellular ROS levels and on apical PI(3,4,5)P3 levels were almost completely abolished by treatment of A6 cells with H2S. In addition, H2S significantly inhibited H2O2-induced oxidative inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN) which is a negative regulator of PI(3,4,5)P3. Moreover, BPV(pic), a specific inhibitor of PTEN, elevated PI(3,4,5)P3 and ENaC activity in a manner similar to that of H2O2 in A6 cells. Our data show, for the first time, that H2S prevents H2O2-induced activation of ENaC through a PTEN-PI(3,4,5)P3 dependent pathway. PMID- 23741316 TI - Transforming growth factor-beta1 (TGF-beta1) regulates cell junction restructuring via Smad-mediated repression and clathrin-mediated endocytosis of nectin-like molecule 2 (Necl-2). AB - Nectin-like molecule-2 (Necl-2), a junction molecule, is exclusively expressed by spermatogenic cells. It mediates homophilic interaction between germ cells and heterophilic interaction between Sertoli and germ cells. Knockout studies have shown that loss of Necl-2 causes male infertility, suggesting Necl-2-based cell adhesion is crucial for spermatogenesis. Transforming growth factor-betas (TGF betas) are crucial for regulating cell junction restructuring that are required for spermatogenesis. In the present study, we aim to investigate the mechanism on how TGF-beta1 regulates Necl-2 expression to achieve timely junction restructuring in the seminiferous epithelium during spermatogenesis. We have demonstrated that TGF-beta1 reduces Necl-2 mRNA and protein levels at both transcriptional and post-translational levels. Using inhibitor and clathrin shRNA, we have revealed that TGF-beta1 induces Necl-2 protein degradation via clathrin-dependent endocytosis. Endocytosis assays further confirmed that TGF beta1 accelerates the internalization of Necl-2 protein to cytosol. Immunofluorescence staining also revealed that TGF-beta1 effectively removes Necl 2 from cell-cell interface. In addition, TGF-beta1 reduces Necl-2 mRNA via down regulating Necl-2 promoter activity. Mutational studies coupled with knockdown experiments have shown that TGF-beta1-induced Necl-2 repression requires activation of Smad proteins. EMSA and ChIP assays further confirmed that TGF beta1 promotes the binding of Smad proteins onto MyoD and CCAATa motifs in vitro and in vivo. Taken together, TGF-beta1 is a potent cytokine that provides an effective mechanism in controlling Necl-2 expression in the testis via Smad dependent gene repression and clathrin-mediated endocytosis. PMID- 23741315 TI - Assessing phylogenetic relationships among galliformes: a multigene phylogeny with expanded taxon sampling in Phasianidae. AB - Galliform birds (relatives of the chicken and turkey) have attracted substantial attention due to their importance to society and value as model systems. This makes understanding the evolutionary history of Galliformes, especially the species-rich family Phasianidae, particularly interesting and important for comparative studies in this group. Previous studies have differed in their conclusions regarding galliform phylogeny. Some of these studies have suggested that specific clades within this order underwent rapid radiations, potentially leading to the observed difficulty in resolving their phylogenetic relationships. Here we presented analyses of six nuclear intron sequences and two mitochondrial regions, an amount of sequence data larger than many previous studies, and expanded taxon sampling by collecting data from 88 galliform species and four anseriform outgroups. Our results corroborated recent studies describing relationships among the major families, and provided further evidence that the traditional division of the largest family, the Phasianidae into two major groups ("pheasants" and "partridges") is not valid. Within the Phasianidae, relationships among many genera have varied among studies and there has been little consensus for the placement of many taxa. Using this large dataset, with substantial sampling within the Phasianidae, we obtained strong bootstrap support to confirm some previously hypothesized relationships and we were able to exclude others. In addition, we added the first nuclear sequence data for the partridge and quail genera Ammoperdix, Caloperdix, Excalfactoria, and Margaroperdix, placing these taxa in the galliform tree of life with confidence. Despite the novel insights obtained by combining increased sampling of taxa and loci, our results suggest that additional data collection will be necessary to solve the remaining uncertainties. PMID- 23741318 TI - Serum 1,25-dihydroxyvitamin D: an outcome prognosticator in human sepsis. AB - In sepsis, the vitamin D active metabolite 1,25-dihydroxyvitamin D (1,25(OH)2D) may play a crucial role by its action to produce cathelicidin and improve endothelial barrier function, such that a deficiency in 1,25(OH)2D is associated with poor outcome. To test our hypothesis, we performed analysis of stored plasma samples from a prospective observational study in 91 patients with sepsis, age of 59.1+/-2.0 years, 52.7% females, and 11.0% deaths at 30 days. Vitamin D status, including 25-hydroxyvitamin D (25(OH)D), 1,25(OH)2D, 24,25-dihydroxyvitamin D (24,25(OH)2D), and parathyroid hormone (PTH), were measured daily over 3 days after hospital admission. At baseline, 1,25(OH)2D was significantly different between survivors vs. non-survivors. But there was no significant difference in 25(OH)D, 24,25(OH)2D, and PTH. In a multivariable binomial logistic regression model, age, total calcium and 1,25(OH)2D were significant predictors of 30-day mortality. Kaplan Meier analysis showed that patients with mean 1,25(OH)2D measured over 3 days of < = 13.6 pg/mL had 57.1% 30-day survival compared to 91.7% in patients with 1,25 (OH)2D level >13.6 pg/mL (p<0.01). From repeated measures regression analysis, there was significant increase in 1,25(OH)2D for increases in 25(OH)D in both survivors and non-survivors. However, compared to survivors, the low 25(OH)D in non-survivors was insufficient to account for the larger decrease in 1,25(OH)2D, indicating a dysfunctional 1alpha-hydroxylase. Additionally, there was a significant negative correlation between PTH and 1,25(OH)2D in both survivors and non-survivors, suggesting a severe impairment in the effect of PTH to increase renal 1alpha-hydroxylase activity. In conclusion, low 1,25(OH)2D levels are associated with increased 30-day mortality in sepsis patients, likely due to impaired 25(OH)D hydroxylation and PTH insensitivity. Our data also suggest that the active metabolite 1,25(OH)2D may be an important therapeutic target in the design of sepsis clinical trials. PMID- 23741317 TI - Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway. AB - Cadmium (Cd) is an extremely toxic metal, capable of severely damaging several organs, including the brain. Studies have shown that Cd disrupts intracellular free calcium ([Ca(2+)]i) homeostasis, leading to apoptosis in a variety of cells including primary murine neurons. Calcium is a ubiquitous intracellular ion which acts as a signaling mediator in numerous cellular processes including cell proliferation, differentiation, and survival/death. However, little is known about the role of calcium signaling in Cd-induced apoptosis in neuronal cells. Thus we investigated the role of calcium signaling in Cd-induced apoptosis in primary rat cerebral cortical neurons. Consistent with known toxic properties of Cd, exposure of cerebral cortical neurons to Cd caused morphological changes indicative of apoptosis and cell death. It also induced elevation of [Ca(2+)]i and inhibition of Na(+)/K(+)-ATPase and Ca(2+)/Mg(2+)-ATPase activities. This Cd induced elevation of [Ca(2+)]i was suppressed by an IP3R inhibitor, 2-APB, suggesting that ER-regulated Ca(2+) is involved. In addition, we observed elevation of reactive oxygen species (ROS) levels, dysfunction of cytochrome oxidase subunits (COX-I/II/III), depletion of mitochondrial membrane potential (DeltaPsim), and cleavage of caspase-9, caspase-3 and poly (ADP-ribose) polymerase (PARP) during Cd exposure. Z-VAD-fmk, a pan caspase inhibitor, partially prevented Cd-induced apoptosis and cell death. Interestingly, apoptosis, cell death and these cellular events induced by Cd were blocked by BAPTA-AM, a specific intracellular Ca(2+) chelator. Furthermore, western blot analysis revealed an up-regulated expression of Bcl-2 and down-regulated expression of Bax. However, these were not blocked by BAPTA-AM. Thus Cd toxicity is in part due to its disruption of intracellular Ca(2+) homeostasis, by compromising ATPases activities and ER-regulated Ca(2+), and this elevation in Ca(2+) triggers the activation of the Ca(2+)-mitochondria apoptotic signaling pathway. This study clarifies the signaling events underlying Cd neurotoxicity, and suggests that regulation of Cd-disrupted [Ca(2+)]i homeostasis may be a new strategy for prevention of Cd-induced neurodegenerative diseases. PMID- 23741319 TI - Alternative computational protocols for supercharging protein surfaces for reversible unfolding and retention of stability. AB - Reengineering protein surfaces to exhibit high net charge, referred to as "supercharging", can improve reversibility of unfolding by preventing aggregation of partially unfolded states. Incorporation of charged side chains should be optimized while considering structural and energetic consequences, as numerous mutations and accumulation of like-charges can also destabilize the native state. A previously demonstrated approach deterministically mutates flexible polar residues (amino acids DERKNQ) with the fewest average neighboring atoms per side chain atom (AvNAPSA). Our approach uses Rosetta-based energy calculations to choose the surface mutations. Both protocols are available for use through the ROSIE web server. The automated Rosetta and AvNAPSA approaches for supercharging choose dissimilar mutations, raising an interesting division in surface charging strategy. Rosetta-supercharged variants of GFP (RscG) ranging from -11 to -61 and +7 to +58 were experimentally tested, and for comparison, we re-tested the previously developed AvNAPSA-supercharged variants of GFP (AscG) with +36 and -30 net charge. Mid-charge variants demonstrated ~3-fold improvement in refolding with retention of stability. However, as we pushed to higher net charges, expression and soluble yield decreased, indicating that net charge or mutational load may be limiting factors. Interestingly, the two different approaches resulted in GFP variants with similar refolding properties. Our results show that there are multiple sets of residues that can be mutated to successfully supercharge a protein, and combining alternative supercharge protocols with experimental testing can be an effective approach for charge-based improvement to refolding. PMID- 23741320 TI - Cancer associated E17K mutation causes rapid conformational drift in AKT1 pleckstrin homology (PH) domain. AB - BACKGROUND: AKT1 (v-akt murine thymoma viral oncogene homologue 1) kinase is one of the most frequently activated proliferated and survival pathway of cancer. Recently it has been shown that E17K mutation in the Pleckstrin Homology (PH) domain of AKT1 protein leads to cancer by amplifying the phosphorylation and membrane localization of protein. The mutant has shown resistance to AKT1/2 inhibitor VIII drug molecule. In this study we have demonstrated the detailed structural and molecular consequences associated with the activity regulation of mutant protein. METHODS: The docking score exhibited significant loss in the interaction affinity to AKT1/2 inhibitor VIII drug molecule. Furthermore, the molecular dynamics simulation studies presented an evidence of rapid conformational drift observed in mutant structure. RESULTS: There was no stability loss in mutant as compared to native structure and the major cation-pi interactions were also shown to be retained. Moreover, the active residues involved in membrane localization of protein exhibited significant rise in NHbonds formation in mutant. The rise in NHbond formation in active residues accounts for the 4-fold increase in the membrane localization potential of protein. CONCLUSION: The overall result suggested that, although the mutation did not induce any stability loss in structure, the associated pathological consequences might have occurred due to the rapid conformational drifts observed in the mutant AKT1 PH domain. GENERAL SIGNIFICANCE: The methodology implemented and the results obtained in this work will facilitate in determining the core molecular mechanisms of cancer-associated mutations and in designing their potential drug inhibitors. PMID- 23741321 TI - Bounds on the average sensitivity of nested canalizing functions. AB - Nested canalizing Boolean functions (NCF) play an important role in biologically motivated regulatory networks and in signal processing, in particular describing stack filters. It has been conjectured that NCFs have a stabilizing effect on the network dynamics. It is well known that the average sensitivity plays a central role for the stability of (random) Boolean networks. Here we provide a tight upper bound on the average sensitivity of NCFs as a function of the number of relevant input variables. As conjectured in literature this bound is smaller than 4/3. This shows that a large number of functions appearing in biological networks belong to a class that has low average sensitivity, which is even close to a tight lower bound. PMID- 23741322 TI - Obestatin enhances in vitro generation of pancreatic islets through regulation of developmental pathways. AB - Availability of large amounts of in vitro generated beta-cells may support replacement therapy in diabetes. However, methods to obtain beta-cells from stem/progenitor cells are limited by inefficient endocrine differentiation. We have recently shown that the ghrelin gene product obestatin displays beneficial effects on pancreatic beta-cell survival and function. Obestatin prevents beta cell apoptosis, preserves beta-cell mass and stimulates insulin secretion in vitro and in vivo, in both normal and diabetic conditions. In the present study, we investigated whether obestatin may promote in vitro beta-cell generation from mouse pancreatic islet-derived precursor cells. Treatment of cultured islets of Langerhans with obestatin (i) enriched cells expressing the mesenchymal/neuronal marker nestin, which is associated with pancreatic precursors; (ii) increased cell survival and reduced apoptosis during precursor selection; (iii) promoted the generation of islet-like cell clusters (ICCs) with increased insulin gene expression and C-peptide secretion. Furthermore, obestatin modulated the expression of fibroblast growth factor receptors (FGFRs), Notch receptors and neurogenin 3 (Ngn3) during islet-derived precursor cell selection and endocrine differentiation. These results indicate that obestatin improves the generation of functional beta-cells/ICCs in vitro, suggesting implications for cell-based replacement therapy in diabetes. Moreover, obestatin may play a role in regulating pathways involved in pancreas development and regeneration. PMID- 23741323 TI - Effects of different resuscitation fluids on pulmonary expression of aquaporin1 and aquaporin5 in a rat model of uncontrolled hemorrhagic shock and infection. AB - BACKGROUND: To investigate the effects of fluids resuscitation on pulmonary expression of aquaporin1 and aquaporin5 in a rat model of uncontrolled hemorrhagic shock and infection. METHODS: Sixty Sprague-Dawley rats were randomly assigned to five groups, sham operation group (Group C) and four treated groups: no fluid resuscitation group (Group NF), groups resuscitated with Lactated Ringer's (LR),7.5% NaCl (HTS) and Hydroxyl ethyl starch (HES) respectively. Three phased uncontrolled hemorrhagic shock and infection model was used. Phase I: Massive hemorrhage with a mean arterial pressure of 35-40 mmHg for 60 min, and followed by infection of lipopolysaccharide. Then some animals were resuscitated with solutions mentioned above, until 90 min. Phase II: At hemorrhagic shock 90 minutes, phase II of 60 minutes began with hemostasis and returning of all the initial shed blood. Phase III: Observation phase for 3.5 hours. After phase III, arterial blood gas analysis and the survival rates of the rats were recorded, Wet to-dry lung weight ratio, BALF protein, pulmonary permeability index, and expressions of aquaporin1 and aquaporin5 were tested. RESULTS: The expressions of aquaporin1 and aquaporin5 were decreased in treatment groups comparing with sham operation group. Group HES and Group HTS decreased pulmonary vascular permeability and Wet-to-dry lung weight ratio, improved arterial blood gas analysis and survival rates, and attenuated the decreased pulmonary expression of aquaporin1 and aquaporin5 after the "two-hit", comparing with groups NF and LR,but these beneficial effects were blunted in group HTS. CONCLUSION: The expression of aquaporin1 and aquaporin5 may play important roles in formation of pulmonary edema. Resuscitation with HTS and HES, especially HES can reduce lung injury after hemorrhagic shock, partly by up-regulating the expressions of aquaporin1 and aquaporin5. PMID- 23741324 TI - Quantitative analysis of calcium spikes in noisy fluorescent background. AB - Intracellular calcium signals are studied by laser-scanning confocal fluorescence microscopy. The required spatio-temporal resolution makes description of calcium signals difficult because of the low signal-to-noise ratio. We designed a new procedure of calcium spike analysis based on their fitting with a model. The accuracy and precision of calcium spike description were tested on synthetic datasets generated either with randomly varied spike parameters and Gaussian noise of constant amplitude, or with constant spike parameters and Gaussian noise of various amplitudes. Statistical analysis was used to evaluate the performance of spike fitting algorithms. The procedure was optimized for reliable estimation of calcium spike parameters and for dismissal of false events. A new algorithm was introduced that corrects the acquisition time of pixels in line-scan images that is in error due to sequential acquisition of individual pixels along the space coordinate. New software was developed in Matlab and provided for general use. It allows interactive dissection of temporal profiles of calcium spikes from x-t images, their fitting with predefined function(s) and acceptance of results on statistical grounds, thus allowing efficient analysis and reliable description of calcium signaling in cardiac myocytes down to the in situ function of ryanodine receptors. PMID- 23741325 TI - Generation and characterisation of keratin 7 (K7) knockout mice. AB - Keratin 7 (K7) is a Type II member of the keratin superfamily and despite its widespread expression in different types of simple and transitional epithelia, its functional role in vivo remains elusive, in part due to the lack of any appropriate mouse models or any human diseases that are associated with KRT7 gene mutations. Using conventional gene targeting in mouse embryonic stem cells, we report here the generation and characterisation of the first K7 knockout mouse. Loss of K7 led to increased proliferation of the bladder urothelium although this was not associated with hyperplasia. K18, a presumptive type I assembly partner for K7, showed reduced expression in the bladder whereas K20, a marker of the terminally differentiated superficial urothelial cells was transcriptionally up regulated. No other epithelia were seen to be adversely affected by the loss of K7 and western blot and immunofluorescence microscopy analysis revealed that the expression of K8, K18, K19 and K20 were not altered in the absence of K7, with the exception of the kidney where there was reduced K18 expression. PMID- 23741326 TI - Superior control of HIV-1 replication by CD8+ T cells targeting conserved epitopes: implications for HIV vaccine design. AB - A successful HIV vaccine will likely induce both humoral and cell-mediated immunity, however, the enormous diversity of HIV has hampered the development of a vaccine that effectively elicits both arms of the adaptive immune response. To tackle the problem of viral diversity, T cell-based vaccine approaches have focused on two main strategies (i) increasing the breadth of vaccine-induced responses or (ii) increasing vaccine-induced responses targeting only conserved regions of the virus. The relative extent to which set-point viremia is impacted by epitope-conservation of CD8(+) T cell responses elicited during early HIV infection is unknown but has important implications for vaccine design. To address this question, we comprehensively mapped HIV-1 CD8(+) T cell epitope specificities in 23 ART-naive individuals during early infection and computed their conservation score (CS) by three different methods (prevalence, entropy and conseq) on clade-B and group-M sequence alignments. The majority of CD8(+) T cell responses were directed against variable epitopes (p<0.01). Interestingly, increasing breadth of CD8(+) T cell responses specifically recognizing conserved epitopes was associated with lower set-point viremia (r = - 0.65, p = 0.009). Moreover, subjects possessing CD8(+) T cells recognizing at least one conserved epitope had 1.4 log10 lower set-point viremia compared to those recognizing only variable epitopes (p = 0.021). The association between viral control and the breadth of conserved CD8(+) T cell responses may be influenced by the method of CS definition and sequences used to determine conservation levels. Strikingly, targeting variable versus conserved epitopes was independent of HLA type (p = 0.215). The associations with viral control were independent of functional avidity of CD8(+) T cell responses elicited during early infection. Taken together, these data suggest that the next-generation of T-cell based HIV-1 vaccines should focus on strategies that can elicit CD8(+) T cell responses to multiple conserved epitopes of HIV-1. PMID- 23741327 TI - Branched motifs enable long-range interactions in signaling networks through retrograde propagation. AB - Branched structures arise in the intra-cellular signaling network when a molecule is involved in multiple enzyme-substrate reaction cascades. Such branched motifs are involved in key biological processes, e.g., immune response activated by T cell and B-cell receptors. In this paper, we demonstrate long-range communication through retrograde propagation between branches of signaling pathways whose molecules do not directly interact. Our numerical simulations and experiments on a system comprising branches with JNK and p38MAPK as terminal molecules respectively that share a common MAP3K enzyme MEKK3/4 show that perturbing an enzyme in one branch can result in a series of changes in the activity levels of molecules "upstream" to the enzyme that eventually reaches the branch-point and affects other branches. In the absence of any evidence for explicit feedback regulation between the functionally distinct JNK and p38MAPK pathways, the experimentally observed modulation of phosphorylation amplitudes in the two pathways when a terminal kinase is inhibited implies the existence of long-range coordination through retrograde information propagation previously demonstrated in single linear reaction pathways. An important aspect of retrograde propagation in branched pathways that is distinct from previous work on retroactivity focusing exclusively on single chains is that varying the type of perturbation, e.g., between pharmaceutical agent mediated inhibition of phosphorylation or suppression of protein expression, can result in opposing responses in the other branches. This can have potential significance in designing drugs targeting key molecules which regulate multiple pathways implicated in systems-level diseases such as cancer and diabetes. PMID- 23741328 TI - A rapid transcriptome response is associated with desiccation resistance in aerially-exposed killifish embryos. AB - Delayed hatching is a form of dormancy evolved in some amphibian and fish embryos to cope with environmental conditions transiently hostile to the survival of hatchlings or larvae. While diapause and cryptobiosis have been extensively studied in several animals, very little is known concerning the molecular mechanisms involved in the sensing and response of fish embryos to environmental cues. Embryos of the euryhaline killifish Fundulus heteroclitus advance dvelopment when exposed to air but hatching is suspended until flooding with seawater. Here, we investigated how transcriptome regulation underpins this adaptive response by examining changes in gene expression profiles of aerially incubated killifish embryos at ~100% relative humidity, compared to embryos continuously flooded in water. The results confirm that mid-gastrula embryos are able to stimulate development in response to aerial incubation, which is accompanied by the differential expression of at least 806 distinct genes during a 24 h period. Most of these genes (~70%) appear to be differentially expressed within 3 h of aerial exposure, suggesting a broad and rapid transcriptomic response. This response seems to include an early sensing phase, which overlaps with a tissue remodeling and activation of embryonic development phase involving many regulatory and metabolic pathways. Interestingly, we found fast (0.5-1 h) transcriptional differences in representatives of classical "stress" proteins, such as some molecular chaperones, members of signalling pathways typically involved in the transduction of sensor signals to stress response genes, and oxidative stress-related proteins, similar to that described in other animals undergoing dormancy, diapause or desiccation. To our knowledge, these data represent the first transcriptional profiling of molecular processes associated with desiccation resistance during delayed hatching in non-mammalian vertebrates. The exceptional transcriptomic plasticity observed in killifish embryos provides an important insight as to how the embryos are able to rapidly adapt to non lethal desiccation conditions. PMID- 23741329 TI - Circulating mitochondrial DNA as biomarker linking environmental chemical exposure to early preclinical lesions elevation of mtDNA in human serum after exposure to carcinogenic halo-alkane-based pesticides. AB - There is a need for a panel of suitable biomarkers for detection of environmental chemical exposure leading to the initiation or progression of degenerative diseases or potentially, to cancer. As the peripheral blood may contain increased levels of circulating cell-free DNA in diseased individuals, we aimed to evaluate this DNA as effect biomarker recognizing vulnerability after exposure to environmental chemicals. We recruited 164 individuals presumably exposed to halo alkane-based pesticides. Exposure evaluation was based on human biomonitoring analysis; as biomarker of exposure parent halo-methanes, -ethanes and their metabolites, as well as the hemoglobin-adducts methyl valine and hydroxyl ethyl valine in blood were used, complemented by expert evaluation of exposure and clinical intoxication symptoms as well as a questionnaire. Assessment showed exposures to halo alkanes in the concentration range being higher than non-cancer reference doses (RfD) but (mostly) lower than the occupational exposure limits. We quantified circulating DNA in serum from 86 individuals with confirmed exposure to off-gassing halo-alkane pesticides (in storage facilities or in home environment) and 30 non-exposed controls, and found that exposure was significantly associated with elevated serum levels of circulating mitochondrial DNA (in size of 79 bp, mtDNA-79, p = 0.0001). The decreased integrity of mtDNA (mtDNA-230/mtDNA-79) in exposed individuals implicates apoptotic processes (p = 0.015). The relative amounts of mtDNA-79 in serum were positively associated with the lag-time after intoxication to these chemicals (r = 0.99, p<0.0001). Several months of post-exposure the specificity of this biomarker increased from 30% to 97% in patients with intoxication symptoms. Our findings indicate that mitochondrial DNA has a potential to serve as a biomarker recognizing vulnerable risk groups after exposure to toxic/carcinogenic chemicals. PMID- 23741330 TI - Quantifying species diversity with a DNA barcoding-based method: Tibetan moth species (Noctuidae) on the Qinghai-Tibetan Plateau. AB - With the ongoing loss of biodiversity, there is a great need for fast and effective ways to assess species richness and diversity: DNA barcoding provides a powerful new tool for this. We investigated this approach by focusing on the Tibetan plateau, which is one of the world's top biodiversity hotspots. There have been few studies of its invertebrates, although they constitute the vast majority of the region's diversity. Here we investigated species diversity of the lepidopteran family Noctuidae, across different environmental gradients, using measurements based on traditional morphology as well as on DNA barcoding. The COI barcode showed an average interspecific K2P distance of 9.45+/-2.08%, which is about four times larger than the mean intraspecific distance (1.85+/-3.20%). Using six diversity indices, we did not detect any significant differences in estimated species diversity between measurements based on traditional morphology and on DNA barcoding. Furthermore, we found strong positive correlations between them, indicating that barcode-based measures of species diversity can serve as a good surrogate for morphology-based measures in most situations tested. Eastern communities were found to have significantly higher diversity than Western ones. Among 22 environmental factors tested, we found that three (precipitation of driest month, precipitation of driest quarter, and precipitation of coldest quarter) were significantly correlated with species diversity. Our results indicate that these factors could be the key ecological factors influencing the species diversity of the lepidopteran family Noctuidae on the Tibetan plateau. PMID- 23741331 TI - Identification of novel tissue-specific genes by analysis of microarray databases: a human and mouse model. AB - Understanding the tissue-specific pattern of gene expression is critical in elucidating the molecular mechanisms of tissue development, gene function, and transcriptional regulations of biological processes. Although tissue-specific gene expression information is available in several databases, follow-up strategies to integrate and use these data are limited. The objective of the current study was to identify and evaluate novel tissue-specific genes in human and mouse tissues by performing comparative microarray database analysis and semi quantitative PCR analysis. We developed a powerful approach to predict tissue specific genes by analyzing existing microarray data from the NCBI's Gene Expression Omnibus (GEO) public repository. We investigated and confirmed tissue specific gene expression in the human and mouse kidney, liver, lung, heart, muscle, and adipose tissue. Applying our novel comparative microarray approach, we confirmed 10 kidney, 11 liver, 11 lung, 11 heart, 8 muscle, and 8 adipose specific genes. The accuracy of this approach was further verified by employing semi-quantitative PCR reaction and by searching for gene function information in existing publications. Three novel tissue-specific genes were discovered by this approach including AMDHD1 (amidohydrolase domain containing 1) in the liver, PRUNE2 (prune homolog 2) in the heart, and ACVR1C (activin A receptor, type IC) in adipose tissue. We further confirmed the tissue-specific expression of these 3 novel genes by real-time PCR. Among them, ACVR1C is adipose tissue-specific and adipocyte-specific in adipose tissue, and can be used as an adipocyte developmental marker. From GEO profiles, we predicted the processes in which AMDHD1 and PRUNE2 may participate. Our approach provides a novel way to identify new sets of tissue-specific genes and to predict functions in which they may be involved. PMID- 23741332 TI - De novo characterization of Japanese scallop Mizuhopecten yessoensis transcriptome and analysis of its gene expression following cadmium exposure. AB - BACKGROUND: Japanese scallop has been cultured on a large-scale in China for many years. However, serious marine pollution in recent years has resulted in considerable loss to this industry. Moreover, due to the lack of genomic resources, limited research has been carried out on this species. To facilitate the understanding at molecular level immune and stress response mechanism, an extensive transcriptomic profiling and digital gene expression (DGE) database of Japanese scallop upon cadmium exposure was carried out using the Illumina sequencing platform. RESULTS: RNA-seq produced about 112 million sequencing reads from the tissues of adult Japanese scallops. These reads were assembled into 194,839 non-redundant sequences with open reading frame (ORF), of which 14,240 putative amino acid sequences were assigned biological function annotation and were annotated with gene ontology and eukaryotic orthologous group terms. In addition, we identified 720 genes involved in response to stimulus and 302 genes involved in immune-response pathways. Furthermore, we investigated the transcriptomic changes in the gill and digestive gland of Japanese scallops following cadmium exposure using a tag-based DGE system. A total of 7,556 and 3,002 differentially expressed genes were detected, respectively, and functionally annotated with KEGG pathway annotations. CONCLUSION: This study provides a comprehensive transcripts sequence resource for the Japanese scallop and presents a survey of gene expression in response to heavy metal exposure in a non-model marine invertebrate via the Illumina sequencing platform. These results may contribute to the in-depth elucidation of the molecular mechanisms involved in bivalve responses to marine pollutants. PMID- 23741333 TI - Variation in structure of a protein (H2AX) with knowledge-based interactions. AB - The structure of a protein (H2AX) as a function of temperature is examined by three knowledge-based phenomenological interactions, MJ (Miyazawa and Jernigan), BT (Betancourt and Thirumalai), and BFKV (Bastolla et al.) to identify similarities and differences in results. Data from the BT and BFKV residue residue interactions verify finding with the MJ interaction, i.e., the radius of gyration (Rg ) of H2AX depends non-monotonically on temperature. The increase in Rg is followed by a decay on raising the temperature with a maximum at a characteristic value, Tc , which depends on the knowledge-based contact matrix, TcBFKV <= TcMJ <= TcBT . The range (DeltaT) of non-monotonic thermal response and its decay pattern with the temperature are sensitive to interaction. A rather narrow temperature range of DeltaTMJ ~ 0.015-0.022 with the MJ interaction expands and shifts up to DeltaTBT ~ 0.018-0.30 at higher temperatures with the BT interaction and shifts down with the BFKV interaction to DeltaTBFKV ~ 0.011 0.018. The scaling of the structure factor with the wave vector reveals that the structure of the protein undergoes a transformation from a random coil at high temperature to a globular conformation at low temperatures. PMID- 23741334 TI - Effects of adhesion dynamics and substrate compliance on the shape and motility of crawling cells. AB - Computational modeling of eukaryotic cells moving on substrates is an extraordinarily complex task: many physical processes, such as actin polymerization, action of motors, formation of adhesive contacts concomitant with both substrate deformation and recruitment of actin etc., as well as regulatory pathways are intertwined. Moreover, highly nontrivial cell responses emerge when the substrate becomes deformable and/or heterogeneous. Here we extended a computational model for motile cell fragments, based on an earlier developed phase field approach, to account for explicit dynamics of adhesion site formation, as well as for substrate compliance via an effective elastic spring. Our model displays steady motion vs. stick-slip transitions with concomitant shape oscillations as a function of the actin protrusion rate, the substrate stiffness, and the rates of adhesion. Implementing a step in the substrate's elastic modulus, as well as periodic patterned surfaces exemplified by alternating stripes of high and low adhesiveness, we were able to reproduce the correct motility modes and shape phenomenology found experimentally. We also predict the following nontrivial behavior: the direction of motion of cells can switch from parallel to perpendicular to the stripes as a function of both the adhesion strength and the width ratio of adhesive to non-adhesive stripes. PMID- 23741335 TI - Uncoupling the functions of CALM in VAMP sorting and clathrin-coated pit formation. AB - CALM (clathrin assembly lymphoid myeloid leukemia protein) is a cargo-selective adaptor for the post-Golgi R-SNAREs VAMPs 2, 3, and 8, and it also regulates the size of clathrin-coated pits and vesicles at the plasma membrane. The present study has two objectives: to determine whether CALM can sort additional VAMPs, and to investigate whether VAMP sorting contributes to CALM-dependent vesicle size regulation. Using a flow cytometry-based endocytosis efficiency assay, we demonstrate that CALM is also able to sort VAMPs 4 and 7, even though they have sorting signals for other clathrin adaptors. CALM homologues are present in nearly every eukaryote, suggesting that the CALM family may have evolved as adaptors for retrieving all post-Golgi VAMPs from the plasma membrane. Using a knockdown/rescue system, we show that wild-type CALM restores normal VAMP sorting in CALM-depleted cells, but that two non-VAMP-binding mutants do not. However, when we assayed the effect of CALM depletion on coated pit morphology, using a fluorescence microscopy-based assay, we found that the two mutants were as effective as wild-type CALM. Thus, we can uncouple the sorting function of CALM from its structural role. PMID- 23741336 TI - The independent acquisition of plant root nitrogen-fixing symbiosis in Fabids recruited the same genetic pathway for nodule organogenesis. AB - Only species belonging to the Fabid clade, limited to four classes and ten families of Angiosperms, are able to form nitrogen-fixing root nodule symbioses (RNS) with soil bacteria. This concerns plants of the legume family (Fabaceae) and Parasponia (Cannabaceae) associated with the Gram-negative proteobacteria collectively called rhizobia and actinorhizal plants associated with the Gram positive actinomycetes of the genus Frankia. Calcium and calmodulin-dependent protein kinase (CCaMK) is a key component of the common signaling pathway leading to both rhizobial and arbuscular mycorrhizal symbioses (AM) and plays a central role in cross-signaling between root nodule organogenesis and infection processes. Here, we show that CCaMK is also needed for successful actinorhiza formation and interaction with AM fungi in the actinorhizal tree Casuarina glauca and is also able to restore both nodulation and AM symbioses in a Medicago truncatula ccamk mutant. Besides, we expressed auto-active CgCCaMK lacking the auto-inhibitory/CaM domain in two actinorhizal species: C. glauca (Casuarinaceae), which develops an intracellular infection pathway, and Discaria trinervis (Rhamnaceae) which is characterized by an ancestral intercellular infection mechanism. In both species, we found induction of nodulation independent of Frankia similar to response to the activation of CCaMK in the rhizobia-legume symbiosis and conclude that the regulation of actinorhiza organogenesis is conserved regardless of the infection mode. It has been suggested that rhizobial and actinorhizal symbioses originated from a common ancestor with several independent evolutionary origins. Our findings are consistent with the recruitment of a similar genetic pathway governing rhizobial and Frankia nodule organogenesis. PMID- 23741337 TI - Identification of C/EBPbeta target genes in ALK+ anaplastic large cell lymphoma (ALCL) by gene expression profiling and chromatin immunoprecipitation. AB - C/EBPbeta (CCAAT enhancer binding protein) is a transcription factor that plays a crucial role in survival and transformation of ALK+ anaplastic large cell lymphoma (ALCL). The aim of this study was to identify the downstream targets of C/EBPbeta responsible for ALK-mediated oncogenesis. C/EBPbeta was knocked down in ALK+ ALCL cell lines with a C/EBPbeta-shRNA, followed by gene expression profiling (GEP). GEP analysis revealed a reproducible signature of genes that were significantly regulated by C/EBPbeta. Classification into biological categories revealed overrepresentation of genes involved in the immune response, apoptosis and cell proliferation. Transcriptional regulation by C/EBPbeta was found in 6 of 11 (BCL2A1, G0S2, TRIB1, S100A9, DDX21 and DDIT4) genes investigated by chromatin immunoprecipitation. We demonstrated that BCL2A1, G0S2 and DDX21 play a crucial role in survival and proliferation of ALK+ ALCL cells. DDX21, a gene involved in rRNA biogenesis, was found differentially overexpressed in primary ALK+ ALCL cases. All three candidate genes were validated in primary ALCL cases by either immunohistochemistry or RT-qPCR. In conclusion, we identified and validated several key C/EBPbeta-regulated genes with major impact on survival and cell growth in ALK+ ALCL, supporting the central role of C/EBPbeta in ALK-mediated oncogenesis. PMID- 23741339 TI - Doxycycline alters metabolism and proliferation of human cell lines. AB - The tetracycline antibiotics are widely used in biomedical research as mediators of inducible gene expression systems. Despite many known effects of tetracyclines on mammalian cells-including inhibition of the mitochondrial ribosome-there have been few reports on potential off-target effects at concentrations commonly used in inducible systems. Here, we report that in human cell lines, commonly used concentrations of doxycycline change gene expression patterns and concomitantly shift metabolism towards a more glycolytic phenotype, evidenced by increased lactate secretion and reduced oxygen consumption. We also show that these concentrations are sufficient to slow proliferation. These findings suggest that researchers using doxycycline in inducible expression systems should design appropriate controls to account for potential confounding effects of the drug on cellular metabolism. PMID- 23741338 TI - Dissociations in the effects of beta2-adrenergic receptor agonists on cAMP formation and superoxide production in human neutrophils: support for the concept of functional selectivity. AB - In neutrophils, activation of the beta2-adrenergic receptor (beta2AR), a Gs coupled receptor, inhibits inflammatory responses, which could be therapeutically exploited. The aim of this study was to evaluate the effects of various beta2AR ligands on adenosine-3',5'-cyclic monophosphate (cAMP) accumulation and N-formyl L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced superoxide anion (O2(*-)) production in human neutrophils and to probe the concept of ligand-specific receptor conformations (also referred to as functional selectivity or biased signaling) in a native cell system. This is an important question because so far, evidence for functional selectivity has been predominantly obtained with recombinant systems, due to the inherent difficulties to genetically manipulate human native cells. cAMP concentration was determined by HPLC/tandem mass spectrometry, and O2(*-) formation was assessed by superoxide dismutase inhibitable reduction of ferricytochrome c. beta2AR agonists were generally more potent in inhibiting fMLP-induced O2(*-) production than in stimulating cAMP accumulation. (-)-Ephedrine and dichloroisoproterenol were devoid of any agonistic activity in the cAMP assay, but partially inhibited fMLP-induced O2(*-) production. Moreover, (-)-adrenaline was equi-efficacious in both assays whereas the efficacy of salbutamol was more than two-fold higher in the O2(*-) assay. Functional selectivity was visualized by deviations of ligand potencies and efficacies from linear correlations for various parameters. We obtained no evidence for involvement of protein kinase A in the inhibition of fMLP-induced O2(*-) production after beta2AR-stimulation although cAMP-increasing substances inhibited O2(*-) production. Taken together, our data corroborate the concept of ligand-specific receptor conformations with unique signaling capabilities in native human cells and suggest that the beta2AR inhibits O2(*-) production in a cAMP-independent manner. PMID- 23741340 TI - Quality of life of people living with HIV/AIDS under the new epidemic characteristics in China and the associated factors. AB - BACKGROUND: Improvement of quality of life has been one of goals in health care for people living with HIV/AIDS (PLWHA). In China, the epidemic characteristics have changed and transmission is now most commonly sexual contact. However, the assessment of quality of life of PLWHA under new characteristics has limited reporting. This study was designed to assess the quality of life among PLWHA who contracted disease mainly via sexual contact and to clarify the associated factors. METHODS: A cross-sectional study was performed in Liaoning Province. Sample size (800) was calculated based on the fatality rate and enlarged with consideration on the loss of response. Participants were sampled by tables of random numbers among all registered PLWHA. Questionnaires pertaining to quality of life (SF-36) and related factors (demographic characteristics, social support and network, HIV/AIDS awareness, and behavior factors) were distributed during December 2010-April 2011. 783 effective responses were obtained. RESULTS: The average scores of physical component summary (PCS), mental component summary (MCS), and total score (TS) were 66.8+/-21.9 (Mean+/-SD), 62.2+/-20.9, and 64.5+/ 20.2. General linear model analysis revealed that, in standardized estimate (beta) sequence, PCS was significantly associated with monthly income, perceived social support, antiretroviral therapy, transmission, and ethnicity; MCS was associated with perceived social support, antiretroviral therapy, condom use, monthly income, transmission, ethnicity, and alcohol consumption; whereas TS was associated with perceived social support, antiretroviral therapy, monthly income, transmission, condom use, and ethnicity. CONCLUSIONS: Quality of life for PLWHA who contracted HIV mainly via sexual contact was worse and both physical conditions and social integration were impacted. Under current epidemic characteristics, efforts to increase social support and enhance the implementation of supporting policy are necessary to improve the quality of life of PLWHA. PMID- 23741341 TI - Community flux balance analysis for microbial consortia at balanced growth. AB - A central focus in studies of microbial communities is the elucidation of the relationships between genotype, phenotype, and dynamic community structure. Here, we present a new computational method called community flux balance analysis (cFBA) to study the metabolic behavior of microbial communities. cFBA integrates the comprehensive metabolic capacities of individual microorganisms in terms of (genome-scale) stoichiometric models of metabolism, and the metabolic interactions between species in the community and abiotic processes. In addition, cFBA considers constraints deriving from reaction stoichiometry, reaction thermodynamics, and the ecosystem. cFBA predicts for communities at balanced growth the maximal community growth rate, the required rates of metabolic reactions within and between microbes and the relative species abundances. In order to predict species abundances and metabolic activities at the optimal community growth rate, a nonlinear optimization problem needs to be solved. We outline the methodology of cFBA and illustrate the approach with two examples of microbial communities. These examples illustrate two useful applications of cFBA. Firstly, cFBA can be used to study how specific biochemical limitations in reaction capacities cause different types of metabolic limitations that microbial consortia can encounter. In silico variations of those maximal capacities allow for a global view of the consortium responses to various metabolic and environmental constraints. Secondly, cFBA is very useful for comparing the performance of different metabolic cross-feeding strategies to either find one that agrees with experimental data or one that is most efficient for the community of microorganisms. PMID- 23741342 TI - Fatty acid synthase is a key target in multiple essential tumor functions of prostate cancer: uptake of radiolabeled acetate as a predictor of the targeted therapy outcome. AB - Fatty acid synthase (FASN) expression is elevated in several cancers, and this over-expression is associated with poor prognosis. Inhibitors of FASN, such as orlistat, reportedly show antitumor effects against cancers that over-express FASN, making FASN a promising therapeutic target. However, large variations in FASN expression levels in individual tumors have been observed, and methods to predict FASN-targeted therapy outcome before treatment are required to avoid unnecessary treatment. In addition, how FASN inhibition affects tumor progression remains unclear. Here, we showed the method to predict FASN-targeted therapy outcome using radiolabeled acetate uptake and presented mechanisms of FASN inhibition with human prostate cancer cell lines, to provide the treatment strategy of FASN-targeted therapy. We revealed that tumor uptake of radiolabeled acetate reflected the FASN expression levels and sensitivity to FASN-targeted therapy with orlistat in vitro and in vivo. FASN-targeted therapy was noticeably effective against tumors with high FASN expression, which was indicated by high acetate uptake. To examine mechanisms, we established FASN knockdown prostate cancer cells by transduction of short-hairpin RNA against FASN and investigated the characteristics by analyses on morphology and cell behavior and microarray based gene expression profiling. FASN inhibition not only suppressed cell proliferation but prevented pseudopodia formation and suppressed cell adhesion, migration, and invasion. FASN inhibition also suppressed genes involved in production of intracellular second messenger arachidonic acid and androgen hormones, both of which promote tumor progression. Collectively, our data demonstrated that uptake of radiolabeled acetate is a useful predictor of FASN targeted therapy outcome. This suggests that [1-(11)C]acetate positron emission tomography (PET) could be a powerful tool to accomplish personalized FASN targeted therapy by non-invasive visualization of tumor acetate uptake and selection of responsive tumors. FASN-targeted therapy could be an effective treatment to suppress multiple steps related to tumor progression in prostate cancers selected by [1-(11)C]acetate PET. PMID- 23741343 TI - Complete genome phasing of family quartet by combination of genetic, physical and population-based phasing analysis. AB - Phased genome maps are important to understand genetic and epigenetic regulation and disease mechanisms, particularly parental imprinting defects. Phasing is also critical to assess the functional consequences of genetic variants, and to allow precise definition of haplotype blocks which is useful to understand gene-flow and genotype-phenotype association at the population level. Transmission phasing by analysis of a family quartet allows the phasing of 95% of all variants as the uniformly heterozygous positions cannot be phased. Here, we report a phasing method based on a combination of transmission analysis, physical phasing by pair end sequencing of libraries of staggered sizes and population-based analysis. Sequencing of a healthy Caucasians quartet at 120x coverage and combination of physical and transmission phasing yielded the phased genotypes of about 99.8% of the SNPs, indels and structural variants present in the quartet, a phasing rate significantly higher than what can be achieved using any single phasing method. A false positive SNP error rate below 10*E-7 per genome and per base was obtained using a combination of filters. We provide a complete list of SNPs, indels and structural variants, an analysis of haplotype block sizes, and an analysis of the false positive and negative variant calling error rates. Improved genome phasing and family sequencing will increase the power of genome-wide sequencing as a clinical diagnosis tool and has myriad basic science applications. PMID- 23741344 TI - Gut microbiota contributes to the growth of fast-growing transgenic common carp (Cyprinus carpio L.). AB - Gut microbiota has shown tight and coordinated connection with various functions of its host such as metabolism, immunity, energy utilization, and health maintenance. To gain insight into whether gut microbes affect the metabolism of fish, we employed fast-growing transgenic common carp (Cyprinus carpio L.) to study the connections between its large body feature and gut microbes. Metagenome based fingerprinting and high-throughput sequencing on bacterial 16S rRNA genes indicated that fish gut was dominated by Proteobacteria, Fusobacteria, Bacteroidetes and Firmicutes, which displayed significant differences between transgenic fish and wild-type controls. Analyses to study the association of gut microbes with the fish metabolism discovered three major phyla having significant relationships with the host metabolic factors. Biochemical and histological analyses indicated transgenic fish had increased carbohydrate but decreased lipid metabolisms. Additionally, transgenic fish has a significantly lower Bacteroidetes:Firmicutes ratio than that of wild-type controls, which is similar to mammals between obese and lean individuals. These findings suggest that gut microbiotas are associated with the growth of fast growing transgenic fish, and the relative abundance of Firmicutes over Bacteroidetes could be one of the factors contributing to its fast growth. Since the large body size of transgenic fish displays a proportional body growth, which is unlike obesity in human, the results together with the findings from others also suggest that the link between obesity and gut microbiota is likely more complex than a simple Bacteroidetes:Firmicutes ratio change. PMID- 23741345 TI - A trans-hemispheric migratory songbird does not advance spring schedules or increase migration rate in response to record-setting temperatures at breeding sites. AB - The decline of long distance migratory songbirds has been linked to an increasing mismatch between spring arrival date and timing of food availability caused by climate change. It is unclear to what extent individuals can adjust migration timing or en route rate in response to annual variation in temperature at breeding sites. We tracked the ca. 7300 km spring migration of 52 purple martins Progne subis from the Amazon basin to two breeding sites in eastern North America. Spring 2012 was the warmest on record in eastern North America, but contrary to predictions, this did not result in earlier departure, faster migration, or earlier arrival at breeding areas compared with earlier years. Temperatures and rainfall in the Amazon basin at the time of departure were not higher in 2012, and conditions along migration routes did not give consistent signals of a warmer spring at the breeding site. Once in North America, individuals likely had limited opportunity to speed up their migration because this final portion of the journey was already very rapid (570 km/d; 4-5 d in duration). Migration timing over the entire journey was best predicted by breeding latitude and sex and was not sensitive to ecological cues (temperature and rainfall amount) at departure from South American overwintering sites or en route, in contrast to recent studies of other songbirds. Our results provide the first direct evidence for a mismatch between higher spring temperatures at breeding sites and departure schedules of individual songbirds, and suggest phenotypic responses to short-term climatic warming may be limited for some species. Further direct-tracking data with greater geographic and temporal scope is needed to test for individual plasticity in response to temperature and rainfall along migratory routes for this, and other, species. PMID- 23741346 TI - Ecological facilitation between two epiphytes through drought mitigation in a subtropical rainforest. AB - Positive species interactions (facilitation) play an important role in shaping the structures and species diversity of ecological communities, particularly under stressful environmental conditions. Epiphytes in rainforests often grow in multiple-species clumps, suggesting interspecies facilitation. However, little is known about the patterns and mechanisms of epiphyte co-occurrence. We assessed the interactions of two widespread epiphyte species, Asplenium antiquum and Haplopteris zosterifolia, by examining their co-occurrence and size-class association in the field. To elucidate factors controlling their interactions, we conducted reciprocal-removal and greenhouse-drought experiments, and nutrient and isotope analyses. Forty-five percent of H. zosterifolia co-occurred with A. antiquum, whereas only 17% of A. antiquum co-occurred with H. zosterifolia. Removing the fronds plus substrate of A. antiquum reduced the relative frond length and specific leaf area of H. zosterifolia, but removing fronds only had little effect. Removing H. zosterifolia had no significant effects on the growth of A. antiquum. H. zosterifolia co-occurring and not co-occurring with A. antiquum had similar foliar nutrient concentrations and delta(15)N values, suggesting that A. antiquum does not affect the nutrient status of H. zosterifolia. Reduced growth of H. zosterifolia with the removal of A. antiquum substrate, together with higher foliar delta(13)C for H. zosterifolia growing alone than those co-occurring with A. antiquum, suggest that A. antiquum enhances water availability to H. zosterifolia. This enhancement probably resulted from water storage in the substrate of A. antiquum, which could hold water up to 6.2 times its dry weight, and from reduced evapotranspiration due to shading of A. antiquum fronds. Greater water loss occurred in the frond-clipped group than the unclipped group between days 3-13 of the drought treatment. Our results imply that drought mitigation by substrate-forming epiphytes is important for maintaining epiphyte diversity in tropic and subtropic regions with episodic water limitations, especially in the context of anthropogenic climate change. PMID- 23741347 TI - Identification of a novel de novo mutation associated with PRKAG2 cardiac syndrome and early onset of heart failure. AB - INTRODUCTION: The major structure elements of the AMP-activated protein kinase (AMPK) are alpha, beta, and gamma sunbunits. Mutations in gamma2 subunit (PRKAG2) have been associated with a cardiac syndrome including inherited ventricular preexcitation, conduction disorder and hypertrophy mimicking hypertrophic cardiomyopathy. The aim of the present study was to identify PRKAG2 syndrome among patients presenting with left ventricular hypertrophy (LVH). METHODS AND RESULTS: Nineteen unrelated subjects with unexplained LVH were clinically and genetically evaluated. Among 4 patients with bradycardia, manifestations of preexcitation were only found in a 19 year old male who also developed congestive heart failure 3 years later. Electrophysiological study of this case identified the coexistence of an AV accessory pathway and AV conduction defect. Histological analysis of his ventricular tissue isolated by biopsy confirmed excessive glycogen accumulation, prominent myofibrillar disarray and interstitial fibrosis. Direct sequencing of his DNA revealed a heterozygous mutation in PRKAG2 consisting of an A-to-G transition at nucleotide 1453 (c.1453A>G), predicting a substitution of a glutamic acid for lysine at highly-conserved residue 485 (p.Lys485Glu, K485E), which was absent in his unaffected family members and in 215 healthy controls. To assess the role of K485 in the structure and function of the protein, computational modeling calculations and conservation analyses were performed. Electrostatic calculations indicate that K485 forms a salt bridge with the conserved D248 residue in the AMPK beta subunit, which is critical for proper regulation of the enzyme, and the K485E mutant disrupts the connection. CONCLUSIONS: Our study identifies a novel de novo PRKAG2 mutation in a young, in which progression of the disease warrants close medical attention. It also underlines the importance of molecular screening of PRKAG2 gene in patients with unexplained LVH, ventricular preexcitation, conduction defect, and/or early onset of heart failure. PMID- 23741348 TI - Clinical impact and cost-effectiveness of expanded voluntary HIV testing in India. AB - BACKGROUND: Despite expanding access to antiretroviral therapy (ART), most of the estimated 2.3 to 2.5 million HIV-infected individuals in India remain undiagnosed. The questions of whom to test for HIV and at what frequency remain unclear. METHODS: We used a simulation model of HIV testing and treatment to examine alternative HIV screening strategies: 1) current practice, 2) one-time, 3) every five years, and 4) annually; and we applied these strategies to three population scenarios: 1) the general Indian population ("national population"), i.e. base case (HIV prevalence 0.29%; incidence 0.032/100 person-years [PY]); 2) high-prevalence districts (HIV prevalence 0.8%; incidence 0.088/100 PY), and 3) high-risk groups (HIV prevalence 5.0%; incidence 0.552/100 PY). Cohort characteristics reflected Indians reporting for HIV testing, with a median age of 35 years, 66% men, and a mean CD4 count of 305 cells/ul. The cost of a rapid HIV test was $3.33. Outcomes included life expectancy, HIV-related direct medical costs, incremental cost-effectiveness ratios (ICERs), and secondary transmission benefits. The threshold for "cost-effective" was defined as 3x the annual per capita GDP of India ($3,900/year of life saved [YLS]), or for "very cost effective" was <1x the annual per capita GDP ($1,300/YLS). RESULTS: Compared to current practice, one-time screening was very cost-effective in the national population (ICER: $1,100/YLS), high-prevalence districts (ICER: $800/YLS), and high-risk groups (ICER: $800/YLS). Screening every five years in the national population (ICER: $1,900/YLS) and annual screening in high-prevalence districts (ICER: $1,900/YLS) and high-risk groups (ICER: $1,800/YLS) were also cost effective. Results were most sensitive to costs of care and linkage-to-care. CONCLUSIONS: In India, voluntary HIV screening of the national population every five years offers substantial clinical benefit and is cost-effective. Annual screening is cost-effective among high-risk groups and in high-prevalence districts nationally. Routine HIV screening in India should be implemented. PMID- 23741349 TI - Detection of subclinical synovial inflammation by microwave radiometry. AB - OBJECTIVE: Microwave Radiometry is a non-invasive method which determines within seconds the in vivo temperature of internal tissues at a depth of 3-7 cm with an accuracy of +/-0.2 degrees C. In this proof-of-concept study, we tested the hypothesis that, in absence of relevant clinical signs, increased local temperature detected by microwave radiometry reflects subclinical synovial inflammation, using ultrasound as reference method. METHODS: Knees of healthy controls, subjects with recent knee trauma and symptom-free patients with rheumatoid arthritis (RA) or osteoarthritis were examined by placing the microwave radiometry sensor, a) at the upper one third of the anterior surface of the thigh (control-point), and b) over the suprapatellar recess. Ultrasound was performed immediately after and the possible presence of fluid and/or synovitis was correlated with microwave radiometry findings. RESULTS: In 30 healthy and 10 injured knees the temperature was always lower than thigh (32.3+/-1.1 and 31.8+/ 1.4 versus 34.1+/-0.9 and 33.6+/-1.2 degrees C with a difference (DeltaTau) of 1.8+/-0.2 and -1.9+/-0.4 degrees C respectively). Of 40 RA and 20 osteoarthritis knees examined, ultrasound findings indicative of subclinical inflammation (fluid effusion and/or Doppler signal) were found in 24 and 12, respectively, in which the temperature was higher than healthy knees and DeltaTau was lower (-0.9+/-0.7 in RA and -1.0+/-0.5 in osteoarthritis versus -1.8+/-0.2 degrees C, p<0.001). The 5 RA knees with power Doppler findings indicative of grade 2 inflammation had a DeltaTau 3 times lower compared to healthy (-0.6+/-0.6, p = 0.007), whereas the 9 RA and the 7 osteoarthritis knees with additionally fluid effusion, had even lower DeltaTau (-0.4+/-0.7, p<0.001). CONCLUSION: Using a safe, rapid and easy-to perform method, such as microwave radiometry, thermal changes within the knee joint may reflect non-clinically apparent joint inflammation. Refinement of this method, including production of sensors for small joints, could result to the development of the ideal objective tool to detect subclinical synovitis in clinical practice. PMID- 23741350 TI - Does naloxone reinstate secondary hyperalgesia in humans after resolution of a burn injury? A placebo-controlled, double-blind, randomized, cross-over study. AB - INTRODUCTION: Development of secondary hyperalgesia following a cutaneous injury is a centrally mediated, robust phenomenon. The pathophysiological role of endogenous opioid signalling to the development of hyperalgesia is unclear. Recent animal studies, carried out after the resolution of inflammatory pain, have demonstrated reinstatement of tactile hypersensitivity following administration of MU-opioid-receptor-antagonists. In the present study in humans, we analyzed the effect of naloxone when given after the resolution of secondary hyperalgesia following a first-degree burn injury. METHODS: Twenty-two healthy volunteers were included in this placebo-controlled, randomized, double-blind, cross-over study. Following baseline assessment of thermal and mechanical thresholds, a first-degree burn injury (BI; 47 degrees C, 7 minutes, thermode area 12.5 cm(2)) was induced on the lower leg. Secondary hyperalgesia areas around the BI-area, and separately produced by brief thermal sensitization on the contralateral thigh (BTS; 45 degrees C, 3 minutes, area 12.5 cm(2)), were assessed using a polyamide monofilament at pre-BI and 1, 2, and 3 hours post-BI. At 72 hrs, BI and BTS secondary hyperalgesia areas were assessed prior to start of a 30 minutes intravenous infusion of naloxone (total dose 21 microg/kg) or placebo. Fifteen minutes after start of the infusion, BI and BTS secondary hyperalgesia areas were reassessed, along with mechanical and thermal thresholds. RESULTS: Secondary hyperalgesia areas were demonstrable in all volunteers 1-3 hrs post-BI, but were not demonstrable at 72 hrs post-burn in 73-86% of the subjects. Neither magnitude of secondary hyperalgesia areas nor the mechanical and thermal thresholds were associated with naloxone-treated compared to placebo-treated subjects. CONCLUSION: Naloxone (21 microg/kg) did not reinstate secondary hyperalgesia when administered 72 hours after a first-degree burn injury and did not increase BTS-generated hyperalgesia. The negative results may be due to the low dose of naloxone or insufficient tissue injury to generate latent sensitization. PMID- 23741351 TI - TGF-beta enhanced IL-21-induced differentiation of human IL-21-producing CD4+ T cells via Smad3. AB - IL-21 has pleiotropic effects on innate and adaptive immune response, and plays an important role in the development of autoimmune disease and antitumor activity. It has been reported that IL-21 is produced by CD4(+) T cells and NKT cells. However, the differentiation of IL-21-producing CD4(+) T cells in humans remains largely unclear. In the present study, we showed that cytokines of IL 1beta, IL-6 or IL-21 induced differentiation of human IL-21-producing CD4(+) T cells, and TGF-beta enhanced the effect of inflammatory cytokines on the development of IL-21-producing CD4(+) T cells. Furthermore, we found that the majority of IL-21-producing cells were distinct from Th17 cells and Th1 cells since they did not co-express IL-17 and IFN-gamma. TGF-beta significantly inhibited the production of IFN-gamma and enhanced the effect of IL-21 on the development of IL-21-producing CD4(+) T cells. In addition, we found that IL-21 inhibited the differentiation of CD4(+) Foxp3(+) T cells induced by TGF-beta. Further study indicated that IL-21 induced phosphorylation of transcriptional factors of STAT1, STAT3 and STAT5, and TGF-beta induced phosphorylation of Smad3 in CD4(+) T cells. Taken together, our data indicated that TGF-beta enhanced IL 21-induced differentiation of IL-21-producing CD4(+) T cells, and the majority of IL-21-producing cells were different from Th17 and Th1 cells. Our results provide a new sight regarding the differentiation of human CD4(+) T cells. PMID- 23741352 TI - Zoledronic acid sensitizes renal cell carcinoma cells to radiation by downregulating STAT1. AB - Zoledronic acid (ZOL), a third-generation bisphosphonate that strongly inhibits osteoclast activity, is widely used for the treatment of bone metastasis from a variety of malignancies, including renal cell carcinoma (RCC). We previously reported that zoledronic acid (ZOL) clinically potentiates antitumor effects of radiotherapy (RT) on bone metastases from RCC. To date, however, it remains unknown whether ZOL radiosensitizes RCC and if it does, how. Here, we demonstrated that ZOL directly radiosensitizes RCC cells independent of osteoclast activity by potentiating the caspase-3-mediated apoptosis pathway. The radiosensitization by ZOL was observed in 786-O, A-498, and ACHN cells but not in Caki-1 cells. As its underlying molecular mechanism, we found that the signal transducer and activator of transcription 1 (STAT1) plays a key role. The three RCC cell lines, in which ZOL exerted a radiosensitizing effect, expressed STAT1 abundantly but Caki-1 cells did not. ZOL downregulated endogenous STAT1 expression in 786-O, A-498, and ACHN cells by a post-transcriptional modification. We confirmed that knockdown of endogenous STAT1 by siRNA sensitized 786-O cells to RT equivalently to ZOL, and that introduction of exogenous STAT1 rendered Caki-1 cells more RT-resistant. This is the first study to clarify the molecular mechanism by which ZOL directly radiosensitizes tumor cells. Because tumor cells commonly overexpress STAT1 and ZOL reportedly radiosensitizes various types of tumor cells, ZOL warrants further clinical and translational studies as a potent radiosensitizer against RT-resistant tumors overexpressing STAT1. PMID- 23741353 TI - Postnatal leptin promotes organ maturation and development in IUGR piglets. AB - Babies with intra-uterine growth restriction (IUGR) are at increased risk for experiencing negative neonatal outcomes due to their general developmental delay. The present study aimed to investigate the effects of a short postnatal leptin supply on the growth, structure, and functionality of several organs at weaning. IUGR piglets were injected from day 0 to day 5 with either 0.5 mg/kg/d leptin (IUGRLep) or saline (IUGRSal) and euthanized at day 21. Their organs were collected, weighed, and sampled for histological, biochemical, and immunohistochemical analyses. Leptin induced an increase in body weight and the relative weights of the liver, spleen, pancreas, kidneys, and small intestine without any changes in triglycerides, glucose and cholesterol levels. Notable structural and functional changes occurred in the ovaries, pancreas, and secondary lymphoid organs. The ovaries of IUGRLep piglets contained less oogonia but more oocytes enclosed in primordial and growing follicles than the ovaries of IUGRSal piglets, and FOXO3A staining grade was higher in the germ cells of IUGRLep piglets. Within the exocrine parenchyma of the pancreas, IUGRLep piglets presented a high rate of apoptotic cells associated with a higher trypsin activity. In the spleen and the Peyer's patches, B lymphocyte follicles were much larger in IUGRLep piglets than in IUGRSal piglets. Moreover, IUGRLep piglets showed numerous CD79(+) cells in well-differentiated follicle structures, suggesting a more mature immune system. This study highlights a new role for leptin in general developmental processes and may provide new insight into IUGR pathology. PMID- 23741354 TI - Association of galanin and major depressive disorder in the Chinese Han population. AB - OBJECTIVE: This study aimed to investigate the association of galanin (GAL) gene and the development of depression in the Chinese Han population. METHODS: A total of 700 patients with depression who met the diagnostic criteria of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and 673 healthy controls were used in this study. Ligase detection reactions were performed on 10 selected single nucleotide polymorphism (SNP) sites in the GAL gene. A series of statistical methods were carried out to investigate the correlation between the GAL gene SNP and the patient susceptibility to depression. RESULTS: The SNPs of rs694066 in the GAL gene showed a positive correlation with MDD. Compared with the healthy controls, lower frequency of G/G genotype and higher frequency of A/G genotype were observed in rs694066 in MDD patients, a lower frequency of G-allele and higher frequency of A-allele were observed in rs694066. These correlations were more pronounced in the 376 female patients and 360 female control subjects than in the 324 male patients and 313 healthy male subjects. CONCLUSIONS: This study investigated the relationship between the GAL gene SNP and the susceptibility to depression in the Chinese Han population. The findings clearly indicate that the GAL gene polymorphism is closely correlated to the incidence of depression in the Chinese Han female patients. PMID- 23741355 TI - Generalized and improved (G'/G)-expansion method for (3+1)-dimensional modified KdV-Zakharov-Kuznetsev equation. AB - The generalized and improved (G'/G)-expansion method is a powerful and advantageous mathematical tool for establishing abundant new traveling wave solutions of nonlinear partial differential equations. In this article, we investigate the higher dimensional nonlinear evolution equation, namely, the (3+1)-dimensional modified KdV-Zakharov-Kuznetsev equation via this powerful method. The solutions are found in hyperbolic, trigonometric and rational function form involving more parameters and some of our constructed solutions are identical with results obtained by other authors if certain parameters take special values and some are new. The numerical results described in the figures were obtained with the aid of commercial software Maple. PMID- 23741356 TI - Carbon transfer from the host to Tuber melanosporum mycorrhizas and ascocarps followed using a 13C pulse-labeling technique. AB - Truffles ascocarps need carbon to grow, but it is not known whether this carbon comes directly from the tree (heterotrophy) or from soil organic matter (saprotrophy). The objective of this work was to investigate the heterotrophic side of the ascocarp nutrition by assessing the allocation of carbon by the host to Tuber melanosporum mycorrhizas and ascocarps. In 2010, a single hazel tree selected for its high truffle (Tuber melanosporum) production and situated in the west part of the Vosges, France, was labeled with (13)CO2. The transfer of (13)C from the leaves to the fine roots and T. melanosporum mycorrhizas was very slow compared with the results found in the literature for herbaceous plants or other tree species. The fine roots primarily acted as a carbon conduit; they accumulated little (13)C and transferred it slowly to the mycorrhizas. The mycorrhizas first formed a carbon sink and accumulated (13)C prior to ascocarp development. Then, the mycorrhizas transferred (13)C to the ascocarps to provide constitutive carbon (1.7 mg of (13)C per day). The ascocarps accumulated host carbon until reaching complete maturity, 200 days after the first labeling and 150 days after the second labeling event. This role of the Tuber ascocarps as a carbon sink occurred several months after the end of carbon assimilation by the host and at low temperature. This finding suggests that carbon allocated to the ascocarps during winter was provided by reserve compounds stored in the wood and hydrolyzed during a period of frost. Almost all of the constitutive carbon allocated to the truffles (1% of the total carbon assimilated by the tree during the growing season) came from the host. PMID- 23741357 TI - Missense mutation in CAPN1 is associated with spinocerebellar ataxia in the Parson Russell Terrier dog breed. AB - Spinocerebellar ataxia (SCA) in the Parson Russell Terrier (PRT) dog breed is a disease of progressive incoordination of gait and loss of balance. Clinical signs usually become notable between 6 and 12 months of age with affected dogs presenting with symmetric spinocerebellar ataxia particularly evident in the pelvic limbs. The degree of truncal ataxia, pelvic limb hypermetria and impaired balance is progressive, particularly during the initial months of disease. A certain degree of stabilisation as well as intermittent worsening may occur. At the later stages of the disease ambulation often becomes difficult, with owners often electing to euthanise affected dogs on welfare grounds. Using a GWAS approach and target-enriched massively-parallel sequencing, a strongly associated non-synonymous SNP in the CAPN1 gene, encoding the calcium dependent cysteine protease calpain1 (mu-calpain), was identified. The SNP is a missense mutation causing a cysteine to tyrosine substitution at residue 115 of the CAPN1 protein. Cysteine 115 is a highly conserved residue and forms a key part of a catalytic triad of amino acids that are crucial to the enzymatic activity of cysteine proteases. The CAPN1 gene shows high levels of expression in the brain and nervous system and roles for the protein in both neuronal necrosis and maintenance have been suggested. Given the functional implications and high level of conservation observed across species, the CAPN1 variant represents a provocative candidate for the cause of SCA in the PRT and a novel potential cause of ataxia in humans. PMID- 23741358 TI - Altered serum IgG levels to alpha-synuclein in dementia with Lewy bodies and Alzheimer's disease. AB - Natural self-reactive antibodies in the peripheral blood may play a considerable role in the control of potentially toxic proteins that may otherwise accumulate in the aging brain. The significance of serum antibodies reactive against alpha synuclein is not well known. We explored serum IgG levels to monomeric alpha synuclein in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) with a novel and validated highly sensitive ELISA assay. Antibody levels revealed stark differences in patients compared to healthy subjects and were dependent on diagnosis, disease duration and age. Anti-alpha-synuclein IgG levels were increased in both patient groups, but in early DLB to a much greater extent than in AD. Increased antibody levels were most evident in younger patients, while with advanced age relatively low levels were observed, similar to healthy individuals, exhibiting stable antibody levels independent of age. Our data show the presence of differentially altered IgG levels against alpha-synuclein in DLB and AD, which may relate to a disturbed alpha-synuclein homeostasis triggered by the disease process. These observations may foster the development of novel, possibly preclinical biomarkers and immunotherapeutic strategies that target alpha-synuclein in neurodegenerative disease. PMID- 23741359 TI - Endothelial nitric oxide synthase reduces crescentic and necrotic glomerular lesions, reactive oxygen production, and MCP1 production in murine lupus nephritis. AB - Systemic lupus erythematosus, in both animal models and in humans, is characterized by autoantibody production followed by immune complex deposition in target tissues. Ensuing target organ damage is modulated by reactive intermediates, including reactive nitrogen and oxygen species, through as of now incompletely understood mechanisms. Endothelial nitric oxide synthase is known to impact vascular reactivity; however its impact on reactive intermediate production and inflammatory renal disease is less well defined. In this study, we assessed the impact of endothelial nitric oxide synthase (eNOS) on disease in lupus prone MRL/lpr mice. Mice lacking eNOS developed earlier more severe disease with decreased survival. eNOS deficient mice died sooner and developed significantly more glomerular crescents, necrosis, inflammatory infiltrates and vasculitis, indicating a role for eNOS in modulating these renal lesions. Immune complex deposition was similar between groups, indicating the impact of eNOS is distal to antibody/complement glomerular deposition. Urinary nitric oxide production was decreased in the eNOS deficient mice, while proteinuria was increased. Urinary monocyte chemotactic protein-1 was also increased in the knockout mice. CD4+ T cells from MRL/lpr mice demonstrated mitochondrial hyperpolarization, increased nitric oxide and superoxide production and increased calcium flux compared to B6 control mice. Deficiency of eNOS resulted in decreased nitric oxide and mitochondrial calcium levels but had no effect on mitochondrial hyperpolarization. Renal cortices from MRL/lpr mice that are eNOS deficient demonstrated increased superoxide production, which was blocked by both nitric oxide synthase and NADPH oxidase inhibitors. These studies thus demonstrate a key role for eNOS in modulating renal disease in lupus prone MRL/lpr mice. The impact appears to be mediated by effects on superoxide production in the kidney, impacting downstream mediators such as monocyte chemotactic protein-1. These results suggest that modulation of eNOS may be a novel therapeutic approach to treating lupus nephritis. PMID- 23741360 TI - Metagenomic insights into anaerobic metabolism along an Arctic peat soil profile. AB - A metagenomic analysis was performed on a soil profile from a wet tundra site in northern Alaska. The goal was to link existing biogeochemical knowledge of the system with the organisms and genes responsible for the relevant metabolic pathways. We specifically investigated how the importance of iron (Fe) oxides and humic substances (HS) as terminal electron acceptors in this ecosystem is expressed genetically, and how respiratory and fermentative processes varied with soil depth into the active layer and into the upper permafrost. Overall, the metagenomes reflected a microbial community enriched in a diverse range of anaerobic pathways, with a preponderance of known Fe reducing species at all depths in the profile. The abundance of sequences associated with anaerobic metabolic processes generally increased with depth, while aerobic cytochrome c oxidases decreased. Methanogenesis genes and methanogen genomes followed the pattern of CH4 fluxes: they increased steeply with depth into the active layer, but declined somewhat over the transition zone between the lower active layer and the upper permafrost. The latter was relatively enriched in fermentative and anaerobic respiratory pathways. A survey of decaheme cytochromes (MtrA, MtrC and their homologs) revealed that this is a promising approach to identifying potential reducers of Fe(III) or HS, and indicated a possible role for Acidobacteria as Fe reducers in these soils. Methanogens appear to coexist in the same layers, though in lower abundance, with Fe reducing bacteria and other potential competitors, including acetogens. These observations provide a rich set of hypotheses for further targeted study. PMID- 23741361 TI - Inhibition of UBE2D3 expression attenuates radiosensitivity of MCF-7 human breast cancer cells by increasing hTERT expression and activity. AB - The known functions of telomerase in tumor cells include replenishing telomeric DNA and maintaining cell immortality. We have previously shown the existence of a negative correlation between human telomerase reverse transcriptase (hTERT) and radiosensitivity in tumor cells. Here we set out to elucidate the molecular mechanisms underlying regulation by telomerase of radiosensitivity in MCF-7 cells. Toward this aim, yeast two-hybrid (Y2H) screening of a human laryngeal squamous cell carcinoma radioresistant (Hep2R) cDNA library was first performed to search for potential hTERT interacting proteins. We identified ubiquitin conjugating enzyme E2D3 (UBE2D3) as a principle hTERT-interacting protein and validated this association biochemically. ShRNA-mediated inhibition of UBE2D3 expression attenuated MCF-7 radiosensitivity, and induced the accumulation of hTERT and cyclin D1 in these cells. Moreover, down-regulation of UBE2D3 increased hTERT activity and cell proliferation, accelerating G1 to S phase transition in MCF-7 cells. Collectively these findings suggest that UBE2D3 participates in the process of hTERT-mediated radiosensitivity in human breast cancer MCF-7 cells by regulating hTERT and cyclin D1. PMID- 23741362 TI - Isolation and characterization of cDNAs encoding leucoanthocyanidin reductase and anthocyanidin reductase from Populus trichocarpa. AB - Proanthocyanidins (PAs) contribute to poplar defense mechanisms against biotic and abiotic stresses. Transcripts of PA biosynthetic genes accumulated rapidly in response to infection by the fungus Marssonina brunnea f.sp. multigermtubi, treatments of salicylic acid (SA) and wounding, resulting in PA accumulation in poplar leaves. Anthocyanidin reductase (ANR) and leucoanthocyanidin reductase (LAR) are two key enzymes of the PA biosynthesis that produce the main subunits: (+)-catechin and (-)-epicatechin required for formation of PA polymers. In Populus, ANR and LAR are encoded by at least two and three highly related genes, respectively. In this study, we isolated and functionally characterized genes PtrANR1 and PtrLAR1 from P. trichocarpa. Phylogenetic analysis shows that Populus ANR1 and LAR1 occurr in two distinct phylogenetic lineages, but both genes have little difference in their tissue distribution, preferentially expressed in roots. Overexpression of PtrANR1 in poplar resulted in a significant increase in PA levels but no impact on catechin levels. Antisense down-regulation of PtrANR1 showed reduced PA accumulation in transgenic lines, but increased levels of anthocyanin content. Ectopic expression of PtrLAR1 in poplar positively regulated the biosynthesis of PAs, whereas the accumulation of anthocyanin and flavonol was significantly reduced (P<0.05) in all transgenic plants compared to the control plants. These results suggest that both PtrANR1 and PtrLAR1 contribute to PA biosynthesis in Populus. PMID- 23741363 TI - Purification, cloning, characterization and essential amino acid residues analysis of a new iota-carrageenase from Cellulophaga sp. QY3. AB - iota-Carrageenases belong to family 82 of glycoside hydrolases that degrade sulfated galactans in the red algae known as iota-carrageenans. The catalytic mechanism and some substrate-binding residues of family GH82 have been studied but the substrate recognition and binding mechanism of this family have not been fully elucidated. We report here the purification, cloning and characterization of a new iota-carrageenase CgiA_Ce from the marine bacterium Cellulophaga sp. QY3. CgiA_Ce was the most thermostable carrageenase described so far. It was most active at 50 degrees C and pH 7.0 and retained more than 70% of the original activity after incubation at 50 degrees C for 1 h at pH 7.0 or at pH 5.0-10.6 for 24 h. CgiA_Ce was an endo-type iota-carrageenase; it cleaved iota-carrageenan yielding neo-iota-carrabiose and neo-iota-carratetraose as the main end products, and neo-iota-carrahexaose was the minimum substrate. Sequence analysis and structure modeling showed that CgiA_Ce is indeed a new member of family GH82. Moreover, sequence analysis of iota-carrageenases revealed that the amino acid residues at subsites -1 and +1 were more conserved than those at other subsites. Site-directed mutagenesis followed by kinetic analysis identified three strictly conserved residues at subsites -1 and +1 of iota-carrageenases, G228, Y229 and R254 in CgiA_Ce, which played important roles for substrate binding. Furthermore, our results suggested that Y229 and R254 in CgiA_Ce interacted specifically with the sulfate groups of the sugar moieties located at subsites -1 and +1, shedding light on the mechanism of iota-carrageenan recognition in the family GH82. PMID- 23741364 TI - Conditional use of social and private information guides house-hunting ants. AB - Social animals can use both social and private information to guide decision making. While social information can be relatively economical to acquire, it can lead to maladaptive information cascades if attention to environmental cues is supplanted by unconditional copying. Ants frequently employ pheromone trails, a form of social information, to guide collective processes, and this can include consensus decisions made when choosing a place to live. In this study, I examine how house-hunting ants balance social and private information when these information sources conflict to different degrees. Social information, in the form of pre-established pheromone trails, strongly influenced the decision process in choices between equivalent nests, and lead to a reduced relocation time. When trails lead to non-preferred types of nest, however, social information had less influence when this preference was weak and no influence when the preference was strong. These results suggest that social information is vetted against private information during the house-hunting process in this species. Private information is favoured in cases of conflict and this may help insure colonies against costly wrong decisions. PMID- 23741365 TI - REXO2 is an oligoribonuclease active in human mitochondria. AB - The Escherichia coli oligoribonuclease, ORN, has a 3' to 5' exonuclease activity specific for small oligomers that is essential for cell viability. The human homologue, REXO2, has hitherto been incompletely characterized, with only its in vitro ability to degrade small single-stranded RNA and DNA fragments documented. Here we show that the human enzyme has clear dual cellular localization being present both in cytosolic and mitochondrial fractions. Interestingly, the mitochondrial form localizes to both the intermembrane space and the matrix. Depletion of REXO2 by RNA interference causes a strong morphological phenotype in human cells, which show a disorganized network of punctate and granular mitochondria. Lack of REXO2 protein also causes a substantial decrease of mitochondrial nucleic acid content and impaired de novo mitochondrial protein synthesis. Our data constitute the first in vivo evidence for an oligoribonuclease activity in human mitochondria. PMID- 23741366 TI - Coarse-grained/molecular mechanics of the TAS2R38 bitter taste receptor: experimentally-validated detailed structural prediction of agonist binding. AB - Bitter molecules in humans are detected by ~25 G protein-coupled receptors (GPCRs). The lack of atomic resolution structure for any of them is complicating an in depth understanding of the molecular mechanisms underlying bitter taste perception. Here, we investigate the molecular determinants of the interaction of the TAS2R38 bitter taste receptor with its agonists phenylthiocarbamide (PTC) and propylthiouracil (PROP). We use the recently developed hybrid Molecular Mechanics/Coarse Grained (MM/CG) method tailored specifically for GPCRs. The method, through an extensive exploration of the conformational space in the binding pocket, allows the identification of several residues important for agonist binding that would have been very difficult to capture from the standard bioinformatics/docking approach. Our calculations suggest that both agonists bind to Asn103, Phe197, Phe264 and Trp201, whilst they do not interact with the so called extra cellular loop 2, involved in cis-retinal binding in the GPCR rhodopsin. These predictions are consistent with data sets based on more than 20 site-directed mutagenesis and functional calcium imaging experiments of TAS2R38. The method could be readily used for other GPCRs for which experimental information is currently lacking. PMID- 23741367 TI - If cooperation is likely punish mildly: insights from economic experiments based on the snowdrift game. AB - Punishment may deter antisocial behavior. Yet to punish is costly, and the costs often do not offset the gains that are due to elevated levels of cooperation. However, the effectiveness of punishment depends not only on how costly it is, but also on the circumstances defining the social dilemma. Using the snowdrift game as the basis, we have conducted a series of economic experiments to determine whether severe punishment is more effective than mild punishment. We have observed that severe punishment is not necessarily more effective, even if the cost of punishment is identical in both cases. The benefits of severe punishment become evident only under extremely adverse conditions, when to cooperate is highly improbable in the absence of sanctions. If cooperation is likely, mild punishment is not less effective and leads to higher average payoffs, and is thus the much preferred alternative. Presented results suggest that the positive effects of punishment stem not only from imposed fines, but may also have a psychological background. Small fines can do wonders in motivating us to chose cooperation over defection, but without the paralyzing effect that may be brought about by large fines. The later should be utilized only when absolutely necessary. PMID- 23741368 TI - Sustained protection in mice immunized with fractional doses of Salmonella Enteritidis core and O polysaccharide-flagellin glycoconjugates. AB - Non-typhoidal Salmonella (NTS) serovars S. Enteritidis and S. Typhimurium are a major cause of invasive bacterial disease (e.g., bacteremia, meningitis) in infants and young children in sub-Saharan Africa and also occasionally cause invasive disease in highly susceptible hosts (young infants, the elderly, and immunocompromised subjects) in industrialized countries. No licensed vaccines exist against human NTS infections. NTS core and O polysaccharide (COPS) and FliC (Phase 1 flagellin subunits) each constitute protective antigens in murine models. S. Enteritidis COPS conjugated to FliC represents a promising vaccine approach that elicits binding and opsonophagocytic antibodies and protects mice against lethal challenge with virulent S. Enteritidis. We examined the protective efficacy of fractional dosages of S. Enteritidis COPS:FliC conjugate vaccines in mice, and also established that protection can be passively transferred to naive mice by administering sera from mice immunized with conjugate. Mice were immunized with three doses of either 10 ug, 2.5 ug (full dose), 0.25 ug, or 0.025 ug S. Enteritidis COPS:FliC conjugate at 28 day intervals. Antibody titers to COPS and FliC measured by ELISA fell consonant with progressively smaller vaccine dosage levels; anti-FliC IgG responses remained robust at fractional dosages for which anti-COPS serum IgG titers were decreased. Nevertheless, >90% protection against intraperitoneal challenge was observed in mice immunized with fractional dosages of conjugate that elicited diminished titers to both FliC and COPS. Passive transfer of immune sera from mice immunized with the highest dose of COPS:FliC to naive mice was also protective, demonstrating the role of antibodies in mediating protection. These results provide important insights regarding the potency of Salmonella glycoconjugate vaccines that use flagellin as a carrier protein. PMID- 23741369 TI - Simultaneous screening and validation of effective zinc finger nucleases in yeast. AB - Zinc finger nucleases (ZFNs) have been successfully used for genome modification in various cell types and species. However, construction of an effective ZFN remained challenging. Previous studies all focused on obtaining specific zinc finger proteins (ZFPs) first via bacterial 2-hybrid approach, and then fusing selected ZFPs to FokI nuclease domain. These assembled ZFNs have high rate of failing to cleave target sites in vivo. In this study, we developed a simultaneous screening and validation system to obtain effective ZFNs directly in yeast AH109. This system is based on Gal4 reporter system carrying a unique intermediate reporter plasmid with two 30-bp Gal4 homology arms and a ZFN target site. DNA double strand breaks introduced on target sequence by ZFNs were repaired by single strand annealing (SSA) mechanism, and the restored Gal4 drove reporter genes expression. Taking the advantage of OPEN (Oligomerized Pool ENgineering) selection, we constructed 3 randomized ZFNs libraries and 9 reporter strains for each target gene. We tested this system by taking goat alpha s1 casein as target gene following three-step selection. Consequently, 3 efficient pairs of ZFNs were obtained from positive colonies on selective medium. The ZFNs achieved a 15.9% disruption frequency in goat mammary epithelial cells. In conclusion, we created a novel system to obtain effective ZFNs directly with simultaneous screening and validation. PMID- 23741370 TI - Human neutrophil elastase degrades SPLUNC1 and impairs airway epithelial defense against bacteria. AB - BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are a significant cause of mortality of COPD patients, and pose a huge burden on healthcare. One of the major causes of AECOPD is airway bacterial (e.g. nontypeable Haemophilus influenzae [NTHi]) infection. However, the mechanisms underlying bacterial infections during AECOPD remain poorly understood. As neutrophilic inflammation including increased release of human neutrophil elastase (HNE) is a salient feature of AECOPD, we hypothesized that HNE impairs airway epithelial defense against NTHi by degrading airway epithelial host defense proteins such as short palate, lung, and nasal epithelium clone 1 (SPLUNC1). METHODOLOGY/MAIN RESULTS: Recombinant human SPLUNC1 protein was incubated with HNE to confirm SPLUNC1 degradation by HNE. To determine if HNE mediated impairment of host defense against NTHi was SPLUNC1-dependent, SPLUNC1 protein was added to HNE-treated primary normal human airway epithelial cells. The in vivo function of SPLUNC1 in NTHi defense was investigated by infecting SPLUNC1 knockout and wild-type mice intranasally with NTHi. We found that: (1) HNE directly increased NTHi load in human airway epithelial cells; (2) HNE degraded human SPLUNC1 protein; (3) Recombinant SPLUNC1 protein reduced NTHi levels in HNE-treated human airway epithelial cells; (4) NTHi levels in lungs of SPLUNC1 knockout mice were increased compared to wild-type mice; and (5) SPLUNC1 was reduced in lungs of COPD patients. CONCLUSIONS: Our findings suggest that SPLUNC1 degradation by neutrophil elastase may increase airway susceptibility to bacterial infections. SPLUNC1 therapy likely attenuates bacterial infections during AECOPD. PMID- 23741371 TI - Dynamics of nanoparticle-protein corona complex formation: analytical results from population balance equations. AB - BACKGROUND: Nanoparticle-protein corona complex formation involves absorption of protein molecules onto nanoparticle surfaces in a physiological environment. Understanding the corona formation process is crucial in predicting nanoparticle behavior in biological systems, including applications of nanotoxicology and development of nano drug delivery platforms. METHOD: This paper extends the modeling work in to derive a mathematical model describing the dynamics of nanoparticle corona complex formation from population balance equations. We apply nonlinear dynamics techniques to derive analytical results for the composition of nanoparticle-protein corona complex, and validate our results through numerical simulations. RESULTS: The model presented in this paper exhibits two phases of corona complex dynamics. In the first phase, proteins rapidly bind to the free surface of nanoparticles, leading to a metastable composition. During the second phase, continuous association and dissociation of protein molecules with nanoparticles slowly changes the composition of the corona complex. Given sufficient time, composition of the corona complex reaches an equilibrium state of stable composition. We find analytical approximate formulae for metastable and stable compositions of corona complex. Our formulae are very well-structured to clearly identify important parameters determining corona composition. CONCLUSION: The dynamics of biocorona formation constitute vital aspect of interactions between nanoparticles and living organisms. Our results further understanding of these dynamics through quantitation of experimental conditions, modeling results for in vitro systems to better predict behavior for in vivo systems. One potential application would involve a single cell culture medium related to a complex protein medium, such as blood or tissue fluid. PMID- 23741372 TI - A novel high throughput invasion screen identifies host actin regulators required for efficient cell entry by Toxoplasma gondii. AB - Toxoplasma gondii critically relies on cell invasion as a survival strategy to evade immune clearance during infection. Although it was widely thought that Toxoplasma entry is parasite directed and that the host cell is largely a passive victim, recent studies have suggested that host components such as microfilaments and microtubules indeed contribute to entry. Hence to identify additional host factors, we performed a high-throughput siRNA screen of a human siRNA library targeting druggable proteins using a novel inducible luciferase based invasion assay. The top 100 hits from the primary screen that showed the strongest decreases in invasion were subjected to confirmation by secondary screening, revealing 24 proteins that are potentially involved in Toxoplasma entry into host cells. Interestingly, 6 of the hits appear to affect parasite invasion by modifying host cell actin dynamics, resulting in increased deposition of F-actin at the periphery of the cell. These findings support the emerging notion that host actin dynamics are important for Toxoplasma invasion along with identifying several novel host factors that potentially participate in parasite entry. PMID- 23741373 TI - Urinary ATP may be a dynamic biomarker of detrusor overactivity in women with overactive bladder syndrome. AB - BACKGROUND: Nowadays, there is a considerable bulk of evidence showing that ATP has a prominent role in the regulation of human urinary bladder function and in the pathophysiology of detrusor overactivity. ATP mediates nonadrenergic noncholinergic detrusor contractions in overactive bladders. In vitro studies have demonstrated that uroepithelial cells and cholinergic nerves from overactive human bladder samples (OAB) release more ATP than controls. Here, we compared the urinary ATP concentration in samples collected non-invasively from OAB women with detrusor overactivity and age-matched controls. METHODS: Patients with neurologic diseases, history of malignancy, urinary tract infections or renal impairment (creatinine clearance <70 ml/min) were excluded. All patients completed a 3-day voiding diary, a 24 h urine collection and blood sampling to evaluate creatinine clearance. Urine samples collected during voluntary voids were immediately freeze preserved for ATP determination by the luciferin-luciferase bioluminescence assay; for comparison purposes, samples were also tested for urinary nerve growth factor (NGF) by ELISA. RESULTS: The urinary content of ATP, but not of NGF, normalized to patients' urine creatinine levels (ATP/Cr) or urinary volume (ATP.Vol) were significantly (P<0.05) higher in OAB women with detrusor overactivity (n = 34) than in healthy controls (n = 30). Significant differences between the two groups were still observed by boosting urinary ATP/Cr content after water intake, but these were not detected for NGF/Cr. In OAB patients, urinary ATP/Cr levels correlated inversely with mean voided volumes determined in a 3-day voiding diary. CONCLUSION: A high area under the receiver operator characteristics (ROC) curve (0.741; 95% CI 0.62-0.86; P<0.001) is consistent with urinary ATP/Cr being a highly sensitive dynamic biomarker for assessing detrusor overactivity in women with OAB syndrome. PMID- 23741374 TI - High metabolomic microdiversity within co-occurring isolates of the extremely halophilic bacterium Salinibacter ruber. AB - Salinibacter ruber is an extremely halophilic member of the Bacteroidetes that thrives in crystallizer ponds worldwide. Here, we have analyzed two sets of 22 and 35 co-occurring S. ruber strains, newly isolated respectively, from 100 microliters water samples from crystalizer ponds in Santa Pola and Mallorca, located in coastal and inland Mediterranean Spain and 350 km apart from each other. A set of old strains isolated from the same setting were included in the analysis. Genomic and taxonomy relatedness of the strains were analyzed by means of PFGE and MALDI-TOF, respectively, while their metabolomic potential was explored with high resolution ion cyclotron resonance Fourier transform mass spectrometry (ICR-FT/MS). Overall our results show a phylogenetically very homogeneous species expressing a very diverse metabolomic pool. The combination of MALDI-TOF and PFGE provides, for the newly isolated strains, the same scenario presented by the previous studies of intra-specific diversity of S. ruber using a more restricted number of strains: the species seems to be very homogeneous at the ribosomal level while the genomic diversity encountered was rather high since no identical genome patterns could be retrieved from each of the samples. The high analytical mass resolution of ICR-FT/MS enabled the description of thousands of putative metabolites from which to date only few can be annotated in databases. Some metabolomic differences, mainly related to lipid metabolism and antibiotic-related compounds, provided enough specificity to delineate different clusters within the co-occurring strains. In addition, metabolomic differences were found between old and new strains isolated from the same ponds that could be related to extended exposure to laboratory conditions. PMID- 23741375 TI - Effects of DNMT1 and HDAC inhibitors on gene-specific methylation reprogramming during porcine somatic cell nuclear transfer. AB - Somatic cell nuclear transfer (SCNT) in mammalian cloning currently remains inefficient. Incomplete or erroneous epigenetic reprogramming of specialized donor somatic nuclear and resulting aberrant gene expression during development of cloned embryos is commonly believed as the main reason that causes the low efficiency of SCNT. Use of small molecular reprogramming modifiers to assist the somatic nucleus to mimic naturally occurring DNA methylation and chromatin remodeling in nucleus of fertilization-derived zygotes, has been widely attempted to improve cloning efficiency. However, impacts of these small modifiers on gene specific methylation dynamics and their potential effects on methylation of imprinted gene have rarely been traced. Here, we attempted two relatively novel DNMT1 inhibitor (DNMTi) and histone deacetylase inhibitor (HDACi), scriptaid and RG108, and demonstrated their effects on dynamics of gene-specific DNA methylation and transcription of porcine SCNT embryos. We found that scriptaid and RG108 had synergetic effects on rescuing the disrupted methylation imprint of H19 during SCNT at least partially by repression over-expressed MBD3 in eight cell cloned embryos. Furthermore, we firstly identified a differential methylation regions (DMRs) at 5' flanking regions of XIST gene and found that scriptaid alone and its combination with RG108 modify the dynamics of both transcription and DNA methylation levels in cloned embryos, by different manners. Additionally, we found that scriptaid alone and its combination with RG108 can significantly promote the transcription of NANOG in cloned embryos and enhance their pre-implantation developmental capacity. Our results would contribute to uncovering the epigenetic reprogramming mechanisms underlying the effects of assisted small molecules on improvement of mammalian cloning efficiency. PMID- 23741376 TI - Increased beta2-adrenoceptors in doxorubicin-induced cardiomyopathy in rat. AB - BACKGROUND: The toxicity of doxorubicin, leading to an irreversible heart failure, limits its use as chemotherapeutic agent. The beneficial effects of early administration of beta-blocker were reported in patients with heart failure due to doxorubicin, suggesting an important role of beta-adrenoceptors (beta ARs). This study aimed to identify a putative target (beta-AR and/or its effectors) at the early phase of a chronic doxorubicin-induced cardiomyopathy (Dox-CM) in a rat model. METHODOLOGY: Dox-CM was induced by six doxorubicin injections (cumulative dose: 15 mg x kg(-1)) and validated by echocardiography and left ventricle (LV) catheterization. The beta-AR protein expressions in LV were evaluated by western-blot at days 35 (d35) and 70 (d70) after the first doxorubicin injection. Ex vivo cardiac contractility (dP/dtmax, dP/dtmin) was evaluated on isolated heart in response to specific beta-AR stimulations at d35. RESULTS: At d35, Dox-CM hearts were characterized by mild LV systolic and diastolic dysfunctions, which were exacerbated at d70. In Dox-CM hearts, beta3-AR expression was only decreased at d70 (-37+/-8%). At d35, beta1-AR expression was decreased by 68+/-6%, but ex vivo beta1-AR function was preserved due to, at least in part, an increased adenylyl cyclase response assessed by forskolin. beta2-AR expression was increased both at d35 (+58+/-22%) and d70 (+174+/-35%), with an increase of ex vivo beta2-AR response at d35. Inhibition of Gi protein with pertussis toxin did not affect beta2-AR response in Dox-CM hearts, suggesting a decoupling of beta2-AR to Gi protein. CONCLUSION: This study highlights the beta1/beta2-AR imbalance in early Dox-CM and reveals the important role that beta2-AR/Gi coupling could play in this pathology. Our results suggest that beta2-AR could be an interesting target at early stage of Dox-CM. PMID- 23741377 TI - Adult bone marrow neural crest stem cells and mesenchymal stem cells are not able to replace lost neurons in acute MPTP-lesioned mice. AB - Adult bone marrow stroma contains multipotent stem cells (BMSC) that are a mixed population of mesenchymal and neural-crest derived stem cells. Both cells are endowed with in vitro multi-lineage differentiation abilities, then constituting an attractive and easy-available source of material for cell therapy in neurological disorders. Whereas the in vivo integration and differentiation of BMSC in neurons into the central nervous system is currently matter of debate, we report here that once injected into the striatum of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-treated mice, pure populations of either bone marrow neural crest stem cells (NCSC) or mesenchymal stem cells (MSC) survived only transiently into the lesioned brain. Moreover, they do not migrate through the brain tissue, neither modify their initial phenotype, while no recovery of the dopaminergic system integrity was observed. Consequently, we tend to conclude that MSC/NCSC are not able to replace lost neurons in acute MPTP-lesioned dopaminergic system through a suitable integration and/or differentiation process. Altogether with recent data, it appears that neuroprotective, neurotrophic and anti-inflammatory features characterizing BMSC are of greater interest as regards CNS lesions management. PMID- 23741378 TI - Bone plasticity in response to exercise is sex-dependent in rats. AB - PURPOSE: To characterize the potential sexual dimorphism of bone in response to exercise. METHODS: Young male and female Wistar rats were either submitted to 12 weeks of exercise or remained sedentary. The training load was adjusted at the mid-trial (week 6) by the maximal speed test. A mechanical test was performed to measure the maximal force, resilience, stiffness, and fracture load. The bone structure, formation, and resorption were obtained by histomorphometric analyses. Type I collagen (COL I) mRNA expression and tartrate-resistant acid phosphatase (TRAP) mRNA expression were evaluated by quantitative real-time PCR (qPCR). RESULTS: The male and female trained rats significantly improved their maximum speed during the maximal exercise test (main effect of training; p<0.0001). The male rats were significantly heavier than the females, irrespective of training (main effect of sex; p<0.0001). Similarly, both the weight and length of the femur were greater for the male rats when compared with the females (main effect of sex; p<0.0001 and p<0.0001, respectively). The trabecular volume was positively affected by exercise in male and female rats (main effect of training; p = 0.001), whereas the trabecular thickness, resilience, mineral apposition rate, and bone formation rate increased only in the trained males (within-sex comparison; p<0.05 for all parameters), demonstrating the sexual dimorphism in response to exercise. Accordingly, the number of osteocytes increased significantly only in the trained males (within-sex comparison; p<0.05). Pearson's correlation analyses revealed that the COL I mRNA expression and TRAP mRNA expression were positively and negatively, respectively, related to the parameters of bone remodeling obtained from the histomorphometric analysis (r = 0.59 to 0.85; p<0.05). CONCLUSION: Exercise yielded differential adaptations with respect to bone structure, biomechanical proprieties, and molecular signaling in male and female rats. PMID- 23741379 TI - Impact of vacuum-assisted closure (VAC) therapy on clinical outcomes of patients with sternal wound infections: a meta-analysis of non-randomized studies. AB - OBJECTIVE: To examine the impact of VAC therapy on mortality of patients with sternal wound infections after cardiothoracic surgery. SUMMARY BACKGROUND DATA: Controversial results regarding mortality of patients with sternal wound infections were published. METHODS: We performed a systematic search in PubMed and Scopus. Mortality was the primary outcome of the meta-analysis. Recurrences, complications and length of stay were secondary outcomes. RESULTS: Twenty-two retrospective studies including 2467 patients were eligible for inclusion. Patients treated with VAC had significantly lower mortality compared to those treated without VAC [2233 patients, RR = 0.40, (95% CI 0.28, 0.57)]. This finding was consistent regardless of the study design, the exclusion of studies with positive findings, the criteria for establishment of the compared groups, the time of mortality assessment or the type of infections under study, provided that adequate data was available. VAC therapy was associated with fewer recurrences (RR = 0.34, 95% CI: 0.19-0.59). The meta-analysis did not show any difference in the length of stay (RR = -2.25, 95% CI: -7.52-3.02). CONCLUSIONS: VAC therapy was associated with lower mortality than other surgical techniques in retrospective cohorts of patients with DSWIs following cardiothoracic surgery. PMID- 23741381 TI - Population structure of Atlantic mackerel (Scomber scombrus). AB - Atlantic mackerel (Scomber scombrus) occurs on both sides of the north Atlantic and has traditionally been grouped into 5 spawning components, some of which were thought to be isolated natal homing stocks. Previous studies have provided no evidence for cross Atlantic migration and no or weak support for isolated spawning components within either side of the North Atlantic. We question the de facto accepted hypothesis of isolation between spawning components on the basis of spawning and age distribution data. The spawning intensities, proxied by larval abundances, are negatively correlated between the North Sea and Celtic Sea, which indicates that the two spawning components may be connected by straying individuals. This finding is based on unique larvae samples collected before the collapse of North Sea component, thus showing that the exchange is not a recent phenomenon due to the collapse. The analyses of old as well as more recent age distributions show that strong year classes spread into other areas where they spawn as adults ("twinning"). Our findings are in accordance with the lack of solid evidence for stock separation from previous analyses of tagging data, genetics, ectoparasite infections, otolith shapes, and blood phenotypes. Because no method has been able to identify the origin of spawning mackerel unequivocally from any of the traditional spawning components, and in the light of our results, we conclude that straying outweighs spatial segregation. We propose a new model where the population structure of mackerel is described as a dynamic cline, rather than as connected contingents. Temporal changes in hydrography and mackerel behavior may affect the steepness of the cline at various locations. The new interpretation of the population structure of Atlantic mackerel has important implications for research, assessment and management. PMID- 23741380 TI - Postoperative neurocognitive dysfunction in patients undergoing cardiac surgery after remote ischemic preconditioning: a double-blind randomized controlled pilot study. AB - BACKGROUND: Remote ischemic preconditioning (RIPC) has been shown to enhance the tolerance of remote organs to cope with a subsequent ischemic event. We hypothesized that RIPC reduces postoperative neurocognitive dysfunction (POCD) in patients undergoing complex cardiac surgery. METHODS: We conducted a prospective, randomized, double-blind, controlled trial including 180 adult patients undergoing elective cardiac surgery with cardiopulmonary bypass. Patients were randomized either to RIPC or to control group. Primary endpoint was postoperative neurocognitive dysfunction 5-7 days after surgery assessed by a comprehensive test battery. Cognitive change was assumed if the preoperative to postoperative difference in 2 or more tasks assessing different cognitive domains exceeded more than one SD (1 SD criterion) or if the combined Z score was 1.96 or greater (Z score criterion). RESULTS: According to 1 SD criterion, 52% of control and 46% of RIPC patients had cognitive deterioration 5-7 days after surgery (p = 0.753). The summarized Z score showed a trend to more cognitive decline in the control group (2.16+/-5.30) compared to the RIPC group (1.14+/-4.02; p = 0.228). Three months after surgery, incidence and severity of neurocognitive dysfunction did not differ between control and RIPC. RIPC tended to decrease postoperative troponin T release at both 12 hours [0.60 (0.19-1.94) ug/L vs. 0.48 (0.07-1.84) ug/L] and 24 hours after surgery [0.36 (0.14-1.89) ug/L vs. 0.26 (0.07-0.90) ug/L]. CONCLUSIONS: We failed to demonstrate efficacy of a RIPC protocol with respect to incidence and severity of POCD and secondary outcome variables in patients undergoing a wide range of cardiac surgery. Therefore, definitive large-scale multicenter trials are needed. TRIAL REGISTRATION: ClinicalTrials.gov NCT00877305. PMID- 23741382 TI - Molecular epidemiology, drug susceptibility and economic aspects of tuberculosis in Mubende district, Uganda. AB - BACKGROUND: Tuberculosis (TB) remains a global public health problem whose effects have major impact in developing countries like Uganda. This study aimed at investigating genotypic characteristics and drug resistance profiles of Mycobacterium tuberculosis isolated from suspected TB patients. Furthermore, risk factors and economic burdens that could affect the current control strategies were studied. METHODS: TB suspected patients were examined in a cross-sectional study at the Mubende regional referral hospital between February and July 2011. A questionnaire was administered to each patient to obtain information associated with TB prevalence. Isolates of M. tuberculosis recovered during sampling were examined for drug resistance to first line anti-TB drugs using the BACTEC MGIT960(TM) system. All isolates were further characterized using deletion analysis, spoligotyping and MIRU-VNTR analysis. Data were analyzed using different software; MIRU-VNTR plus, SITVITWEB, BioNumerics and multivariable regression models. RESULTS: M. tuberculosis was isolated from 74 out of 344 patients, 48 of these were co-infected with HIV. Results from the questionnaire showed that previously treated TB, co-infection with HIV, cigarette smoking, and overcrowding were risk factors associated with TB, while high medical related transport bills were identified as an economic burden. Out of the 67 isolates that gave interpretable results, 23 different spoligopatterns were detected, nine of which were novel patterns. T2 with the sub types Uganda-I and Uganda-II was the most predominant lineage detected. Antibiotic resistance was detected in 19% and multidrug resistance was detected in 3% of the isolates. CONCLUSION: The study detected M. tuberculosis from 21% of examined TB patients, 62% of whom were also HIV positive. There is a heterogeneous pool of genotypes that circulate in this area, with the T2 lineage being the most predominant. High medical related transport bills and drug resistance could undermine the usefulness of the current TB strategic interventions. PMID- 23741383 TI - CD14 -159 C>T gene polymorphism with increased risk of tuberculosis: evidence from a meta-analysis. AB - Cluster of differentiation 14 (CD14) gene is an important component of the human innate immune system and its role in tuberculosis (TB) has been sparsely documented. The enhanced plasma CD14 levels in TB patients as compared to healthy controls are associated with CD14 gene promoter (C-159T) polymorphism. In the past few years, the relationship between CD14 -159 C>T (rs2569190) polymorphism and risk of TB has been reported in various ethnic populations; however, those studies have yielded contradictory results. In this study systemic assessment was done for the published studies based on the association between CD14 -159 C>T polymorphism and TB risk retrieved from PubMed (Medline) and EMBASE search. A total number of 1389 TB cases and 1421 controls were included in this study and meta-analysis was performed to elucidate the association between CD14 -159 C>T polymorphism and its susceptibility towards TB. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for allele contrast, homozygous comparison, heterozygous comparison, dominant and recessive genetic model. It was found that T allele carrier was significantly associated with increased TB risk (T vs. C: p-value = 0.023; OR = 1.305, 95% CI = 1.038 to 1.640). Similarly, homozygous mutant TT genotype also revealed 1.6 fold increased risk of TB (TT vs. CC; p-value = 0.040; OR = 1.652, 95% CI = 1.023 to 2.667). Additionally, dominant genetic model demonstrated increased risk of developing TB (TT vs. CC+CT: p-value = 0.006; OR = 1.585, 95% CI = 1.142 to 2.201). The study demonstrates that CD14 gene (-159 C>T) polymorphism contributes increased susceptibility for TB. Moreover, this meta-analysis also suggests for future larger studies with stratified case control population and biological characterization for validation studies. PMID- 23741384 TI - Pharmacological administration of the isoflavone daidzein enhances cell proliferation and reduces high fat diet-induced apoptosis and gliosis in the rat hippocampus. AB - Soy extracts have been claimed to be neuroprotective against brain insults, an effect related to the estrogenic properties of isoflavones. However, the effects of individual isoflavones on obesity-induced disruption of adult neurogenesis have not yet been analyzed. In the present study we explore the effects of pharmacological administration of daidzein, a main soy isoflavone, in cell proliferation, cell apoptosis and gliosis in the adult hippocampus of animals exposed to a very high-fat diet. Rats made obese after 12-week exposure to a standard or high-fat (HFD, 60%) diets were treated with daidzein (50 mg kg(-1)) for 13 days. Then, plasma levels of metabolites and metabolic hormones, cell proliferation in the subgranular zone of the dentate gyrus (SGZ), and immunohistochemical markers of hippocampal cell apoptosis (caspase-3), gliosis (GFAP and Iba-1), food reward factor FosB and estrogen receptor alpha (ERalpha) were analyzed. Treatment with daidzein reduced food/caloric intake and body weight gain in obese rats. This was associated with glucose tolerance, low levels of HDL-cholesterol, insulin, adiponectin and testosterone, and high levels of leptin and 17beta-estradiol. Daidzein increased the number of phospho-histone H3 and 5-bromo-2-deoxyuridine (BrdU)-ir cells detected in the SGZ of standard diet and HFD-fed rats. Daidzein reversed the HFD-associated enhanced immunohistochemical expression of caspase-3, FosB, GFAP, Iba-1 and ERalpha in the hippocampus, being more prominent in the dentate gyrus. These results suggest that pharmacological treatment with isoflavones regulates metabolic alterations associated with enhancement of cell proliferation and reduction of apoptosis and gliosis in response to high-fat diet. PMID- 23741385 TI - Characterization of flavin-based fluorescent proteins: an emerging class of fluorescent reporters. AB - Fluorescent reporter proteins based on flavin-binding photosensors were recently developed as a new class of genetically encoded probes characterized by small size and oxygen-independent maturation of fluorescence. Flavin-based fluorescent proteins (FbFPs) address two major limitations associated with existing fluorescent reporters derived from the green fluorescent protein (GFP)-namely, the overall large size and oxygen-dependent maturation of fluorescence of GFP. However, FbFPs are at a nascent stage of development and have been utilized in only a handful of biological studies. Importantly, a full understanding of the performance and properties of FbFPs as a practical set of biological probes is lacking. In this work, we extensively characterize three FbFPs isolated from Pseudomonas putida, Bacillus subtilis, and Arabidopsis thaliana, using in vitro studies to assess probe brightness, oligomeric state, maturation time, fraction of fluorescent holoprotein, pH tolerance, redox sensitivity, and thermal stability. Furthermore, we validate FbFPs as stable molecular tags using in vivo studies by constructing a series of FbFP-based transcriptional constructs to probe promoter activity in Escherichia coli. Overall, FbFPs show key advantages as broad-spectrum biological reporters including robust pH tolerance (4-11), thermal stability (up to 60 degrees C), and rapid maturation of fluorescence (<3 min.). In addition, the FbFP derived from Arabidopsis thaliana (iLOV) emerged as a stable and nonperturbative reporter of promoter activity in Escherichia coli. Our results demonstrate that FbFP-based reporters have the potential to address key limitations associated with the use of GFP, such as pH-sensitive fluorescence and slow kinetics of fluorescence maturation (10-40 minutes for half maximal fluorescence recovery). From this view, FbFPs represent a useful new addition to the fluorescent reporter protein palette, and our results constitute an important framework to enable researchers to implement and further engineer improved FbFP based reporters with enhanced brightness and tighter flavin binding, which will maximize their potential benefits. PMID- 23741386 TI - Plant oils were associated with low prevalence of impaired glucose metabolism in Japanese workers. AB - Fatty acid has been suggested to be involved in development of diabetes. However, its association is unclear among Japanese populations, which consume large amounts of fish rich in n-3 polyunsaturated fatty acids. The present cross sectional study examined the association of individual dietary fatty acids and dietary fatty acid patterns with abnormal glucose metabolism among 1065 Japanese employees, aged 18-69 years. Impaired glucose metabolism is defined if a person has a history of diabetes, current use of anti-diabetic drug, fasting plasma glucose of 110 mg/dl (>=6.1 mmol/L) or greater, or hemoglobin A1C of 6.0% (>=42 mmol/mol) or greater. Dietary intake was assessed with a self-administered diet history questionnaire. Dietary fatty acid patterns were extracted by principal component analysis. Odds ratios of impaired glucose metabolism according to tertile categories of each fatty acids and dietary fatty acid patterns were estimated using logistic regression with adjustment for potential confounding variables. A higher intake of polyunsaturated fatty acid, n-6 fatty acid, linoleic acid, and oleic acid were significantly associated with a decreased prevalence of impaired glucose metabolism (P for trend = 0.03, 0.01, 0.02, and 0.04, respectively). Alpha-linolenic acid was marginally significantly associated with a decreased prevalence of impaired glucose metabolism (P for trend = 0.12). Of three fatty acid patterns identified, a higher plant oil pattern score, which characterized by high intake of alpha-linolenic acid, linoleic acid, and oleic acid, was associated with a decreased prevalence of impaired glucose metabolism (P for trend = 0.03). No association was observed for other patterns. In conclusion, plant source fatty acids might be protectively associated with development of diabetes in Japanese adults. PMID- 23741387 TI - Comparative genomic and phylogenetic analysis of the first Usutu virus isolate from a human patient presenting with neurological symptoms. AB - Usutu virus (USUV) is a mosquito-borne flavivirus, belonging to the Japanese encephalitis antigenic complex, that circulates among mosquitoes and birds. We describe and analyze the complete genome sequence of the first USUV strain isolated from an immunocompromised patient with neuroinvasive disease. This USUV isolate showed an overall nucleotide identity of 99% and 96%, respectively, with the genomes of isolates from Europe and Africa. Comparison of the human USUV complete polyprotein sequence with bird-derived strains, showed two unique amino acid substitutions. In particular, one substitution (S595G) was situated in the DIII domain of the viral Envelope protein that is recognized by flavivirus neutralizing antibodies. An additional amino acid substitution (D3425E) was identified in the RNA-dependent RNA polymerase (RdRp) domain of the NS5 protein. This substitution is remarkable since E3425 is highly conserved among the other USUV isolates that were not associated with human infection. However, a similar substitution was observed in Japanese encephalitis and in West Nile viruses isolated from humans. Phylogenetic analysis of the human USUV strain revealed a close relationship with an Italian strain isolated in 2009. Analysis of synonymous nucleotide substitutions (SNSs) among the different USUV genomes showed a specific evolutionary divergence among different countries. In addition, 15 SNSs were identified as unique in the human isolate. We also identified four specific nucleotide substitutions in the 5' and 3' untranslated regions (UTRs) in the human isolate that were not present in the other USUV sequences. Our analyses provide the basis for further experimental studies aimed at defining the effective role of these mutations in the USUV genome, their potential role in the development of viral variants pathogenic for humans and their evolution and dispersal out of Africa. PMID- 23741389 TI - Ictal modulation of cardiac repolarization, but not of heart rate, is lateralized in mesial temporal lobe epilepsy. AB - OBJECTIVES: Human and animal studies provided controversial data on asymmetric cortical representation of cardiac function, which may partially be due to different study designs and inter-individual variability. Here, we investigated whether seizure-related changes in heart rate (HR) and cardiac repolarization depend on the side of seizure-activity in people with mesial temporal lobe epilepsy (mTLE). METHODS: To account for inter-individual variability, EEG and ECG data were reviewed from patients with medically refractory mTLE undergoing pre-surgical video-EEG telemetry with at least 2 seizures arising from each hippocampus as assessed by bilateral hippocampal depths electrodes. RR and QT intervals were determined at different timepoints using a one-lead ECG. QT intervals were corrected for HR (QTc) using 4 established formulas. RESULTS: Eighty-two seizures of 15 patients were analyzed. HR increased by ~30% during hippocampal activity irrespective of the side (p = 0.411). QTc intervals were lengthened to a significantly greater extent during left hippocampal seizures (e.g. difference of QT intervals between preictal and ictal state using Bazett's formula; left side 32.0+/-5.3 ms, right side 15.6+/-7.7 ms; p = 0.016). Abnormal QTc prolongation occurred in 7 of 41 left hippocampal seizures of 4 patients, and only in 2 of 37 right hippocampal seizures of 2 patients. CONCLUSIONS: Seizure related modulation of cardiac repolarization, but not of HR, appears to depend on the side of ictal activity, strengthening the hypothesis of asymmetric cerebral representation of cardiac function. The clinical relevance of this is unclear, but may indicate an increased risk of abnormal ictal QT prolongation in people with left mTLE. PMID- 23741388 TI - Photooxidation-guided ultrastructural identification and analysis of cells in neuronal tissue labeled with green fluorescent protein. AB - The ultrastructural characterization of neuronal compartments in intact tissue labeled with green fluorescent protein (GFP) remains a frequently encountered challenge, despite work establishing photooxidation of GFP in cultured cells. However, most applications require the detection of GFP or GFP fusion proteins expressed in intact tissue. Here, we report that illumination of GFP variants in oxygen-enriched environment reliably generated electron-dense 3,3' diaminobenzidine (DAB) precipitates in slices from rat brain. The method is applicable to GFP variants tagged to presynaptic proteins as well as to soluble GFP in various brain regions. Serial section scanning electron microscopy was used to examine genetically labeled presynaptic terminals at high resolution and to generate three-dimensional representations of the synapses. Thus, we introduce a generally applicable correlative approach for the identification of presynaptic terminals genetically labeled with green fluorescent proteins in tissue slices and their ultrastructural characterization. PMID- 23741390 TI - Fusing a carbohydrate-binding module into the Aspergillus usamii beta-mannanase to improve its thermostability and cellulose-binding capacity by in silico design. AB - The AuMan5A, an acidophilic glycoside hydrolase (GH) family 5 beta-mannanase derived from Aspergillus usamii YL-01-78, consists of an only catalytic domain (CD). To perfect enzymatic properties of the AuMan5A, a family 1 carbohydrate binding module (CBM) of the Trichoderma reesei cellobiohydrolase I (TrCBH I), having the lowest binding free energy with cellobiose, was selected by in silico design, and fused into its C-terminus forming a fusion beta-mannanase, designated as AuMan5A-CBM. Then, its encoding gene, Auman5A-cbm, was constructed as it was designed theoretically, and expressed in Pichia pastoris GS115. SDS-PAGE analysis displayed that both recombinant AuMan5A-CBM (reAuMan5A-CBM) and AuMan5A (reAuMan5A) were secreted into the cultured media with apparent molecular masses of 57.3 and 49.8 kDa, respectively. The temperature optimum of the reAuMan5A-CBM was 75 degrees C, being 5 degrees C higher than that of the reAuMan5A. They were stable at temperatures of 68 and 60 degrees C, respectively. Compared with reAuMan5A, the reAuMan5A-CBM showed an obvious decrease in K m and a slight alteration in V max. In addition, the fusion of a CBM of the TrCBH I into the AuMan5A contributed to its cellulose-binding capacity. PMID- 23741391 TI - Effects of abortion legalization in Nepal, 2001-2010. AB - BACKGROUND: Abortion was legalized in Nepal in 2002, following advocacy efforts highlighting high maternal mortality from unsafe abortion. We sought to assess whether legalization led to reductions in the most serious maternal health consequences of unsafe abortion. METHODS: We conducted retrospective medical chart review of all gynecological cases presenting at four large public referral hospitals in Nepal. For the years 2001-2010, all cases of spontaneous and induced abortion complications were identified, abstracted, and coded to classify cases of serious infection, injury, and systemic complications. We used segmented Poisson and ordinary logistic regression to test for trend and risks of serious complications for three time periods: before implementation (2001-2003), early implementation (2004-2006), and later implementation (2007-2010). RESULTS: 23,493 cases of abortion complications were identified. A significant downward trend in the proportion of serious infection, injury, and systemic complications was observed for the later implementation period, along with a decline in the risk of serious complications (OR 0.7, 95% CI 0.64, 0.85). Reductions in sepsis occurred sooner, during early implementation (OR 0.6, 95% CI 0.47, 0.75). CONCLUSION: Over the study period, health care use and the population of reproductive aged women increased. Total fertility also declined by nearly half, despite relatively low contraceptive prevalence. Greater numbers of women likely obtained abortions and sought hospital care for complications following legalization, yet we observed a significant decline in the rate of serious abortion morbidity. The liberalization of abortion policy in Nepal has benefited women's health, and likely contributes to falling maternal mortality in the country. The steepest decline was observed after expansion of the safe abortion program to include midlevel providers, second trimester training, and medication abortion, highlighting the importance of concerted efforts to improve access. Other countries contemplating changes to abortion policy can draw on the evidence and implementation strategies observed in Nepal. PMID- 23741392 TI - Genome-wide small RNA sequencing and gene expression analysis reveals a microRNA profile of cancer susceptibility in ATM-deficient human mammary epithelial cells. AB - Deficiencies in the ATM gene are the underlying cause for ataxia telangiectasia, a syndrome characterized by neurological, motor and immunological defects, and a predisposition to cancer. MicroRNAs (miRNAs) are useful tools for cancer profiling and prediction of therapeutic responses to clinical regimens. We investigated the consequences of ATM deficiency on miRNA expression and associated gene expression in normal human mammary epithelial cells (HME-CCs). We identified 81 significantly differentially expressed miRNAs in ATM-deficient HME CCs using small RNA sequencing. Many of these have been implicated in tumorigenesis and proliferation and include down-regulated tumor suppressor miRNAs, such as hsa-miR-29c and hsa-miR-16, as well as over-expressed pro oncogenic miRNAs, such as hsa-miR-93 and hsa-miR-221. MicroRNA changes were integrated with genome wide gene expression profiles to investigate possible miRNA targets. Predicted mRNA targets of the miRNAs significantly regulated after ATM depletion included many genes associated with cancer formation and progression, such as SOCS1 and the proto-oncogene MAF. While a number of miRNAs have been reported as altered in cancerous cells, there is little understanding as to how these small RNAs might be driving cancer formation or how they might be used as biomarkers for cancer susceptibility. This study provides preliminary data for defining miRNA profiles that may be used as prognostic or predictive biomarkers for breast cancer. Our integrated analysis of miRNA and mRNA expression allows us to gain a better understanding of the signaling involved in breast cancer predisposition and suggests a mechanism for the breast cancer-prone phenotype seen in ATM-deficient patients. PMID- 23741393 TI - Simplified large-scale Sanger genome sequencing for influenza A/H3N2 virus. AB - BACKGROUND: The advent of next-generation sequencing technologies and the resultant lower costs of sequencing have enabled production of massive amounts of data, including the generation of full genome sequences of pathogens. However, the small genome size of the influenza virus arguably justifies the use of the more conventional Sanger sequencing technology which is still currently more readily available in most diagnostic laboratories. RESULTS: We present a simplified Sanger-based genome sequencing method for sequencing the influenza A/H3N2 virus in a large-scale format. The entire genome sequencing was completed with 19 reverse transcription-polymerase chain reactions (RT-PCRs) and 39 sequencing reactions. This method was tested on 15 native clinical samples and 15 culture isolates, respectively, collected between 2009 and 2011. The 15 native clinical samples registered quantification cycle values ranging from 21.0 to 30.56, which were equivalent to 2.4*10(3)-1.4*10(6) viral copies/uL of RNA extract. All the PCR-amplified products were sequenced directly without PCR product purification. Notably, high quality sequencing data up to 700 bp were generated for all the samples tested. The completed sequence covered 408,810 nucleotides in total, with 13,627 nucleotides per genome, attaining 100% coding completeness. Of all the bases produced, an average of 89.49% were Phred quality value 40 (QV40) bases (representing an accuracy of circa one miscall for every 10,000 bases) or higher, and an average of 93.46% were QV30 bases (one miscall every 1000 bases) or higher. CONCLUSIONS: This sequencing protocol has been shown to be cost-effective and less labor-intensive in obtaining full influenza genomes. The constant high quality of sequences generated imparts confidence in extending the application of this non-purified amplicon sequencing approach to other gene sequencing assays, with appropriate use of suitably designed primers. PMID- 23741394 TI - Sen1p contributes to genomic integrity by regulating expression of ribonucleotide reductase 1 (RNR1) in Saccharomyces cerevisiae. AB - Gene expression is a multi-step process which requires recruitment of several factors to promoters. One of the factors, Sen1p is an RNA/DNA helicase implicated in transcriptional termination and RNA processing in yeast. In the present study, we have identified a novel function of Sen1p that regulates the expression of ribonucleotide reductase RNR1 gene, which is essential for maintaining genomic integrity. Cells with mutation in the helicase domain or lacking N-terminal domain of Sen1p displayed a drastic decrease in the basal level transcription of RNR1 gene and showed enhanced sensitivity to various DNA damaging agents. Moreover, SEN1 mutants [Sen1-1 (G1747D), Sen1-2 (Delta1-975)] exhibited defects in DNA damage checkpoint activation. Surprisingly, CRT1 deletion in Sen1p mutants (Sen1-1, Sen1-2) was partly able to rescue the slow growth phenotype upon genotoxic stress. Altogether, our observations suggest that Sen1p is required for cell protection against DNA damage by regulating the expression of DNA repair gene RNR1. Thus, the misregulation of Sen1p regulated genes can cause genomic instability that may lead to neurological disorders and premature aging. PMID- 23741396 TI - Rabies virus infection in Eptesicus fuscus bats born in captivity (naive bats). AB - The study of rabies virus infection in bats can be challenging due to quarantine requirements, husbandry concerns, genetic differences among animals, and lack of medical history. To date, all rabies virus (RABV) studies in bats have been performed in wild caught animals. Determining the RABV exposure history of a wild caught bat based on the presence or absence of viral neutralizing antibodies (VNA) may be misleading. Previous studies have demonstrated that the presence of VNA following natural or experimental inoculation is often ephemeral. With this knowledge, it is difficult to determine if a seronegative, wild caught bat has been previously exposed to RABV. The influence of prior rabies exposure in healthy, wild caught bats is unknown. To investigate the pathogenesis of RABV infection in bats born in captivity (naive bats), naive bats were inoculated intramuscularly with one of two Eptesicus fuscus rabies virus variants, EfV1 or EfV2. To determine the host response to a heterologous RABV, a separate group of naive bats were inoculated with a Lasionycteris noctivagans RABV (LnV1). Six months following the first inoculation, all bats were challenged with EfV2. Our results indicate that naive bats may have some level of innate resistance to intramuscular RABV inoculation. Additionally, naive bats inoculated with the LnV demonstrated the lowest clinical infection rate of all groups. However, primary inoculation with EfV1 or LnV did not appear to be protective against a challenge with the more pathogenic EfV2. PMID- 23741395 TI - Bcl11a controls Flt3 expression in early hematopoietic progenitors and is required for pDC development in vivo. AB - Bcl11a is a transcription factor known to regulate lymphoid and erythroid development. Recent bioinformatic analysis of global gene expression patterns has suggested a role for Bcl11a in the development of dendritic cell (DC) lineages. We tested this hypothesis by analyzing the development of DC and other lineages in Bcl11a (-/-) mice. We found that Bcl11a was required for expression of IL-7 receptor (IL-7R) and Flt3 in early hematopoietic progenitor cells. In addition, we found severely decreased numbers of plasmacytoid dendritic cells (pDCs) in Bcl11a (-/-) fetal livers and in the bone marrow of Bcl11a (-/-) fetal liver chimeras. Moreover, Bcl11a (-/-) cells showed severely impaired in vitro development of Flt3L-derived pDCs and classical DCs (cDCs). In contrast, we found normal in vitro development of DCs from Bcl11a (-/-) fetal liver cells treated with GM-CSF. These results suggest that the persistent cDC development observed in Bcl11a (-/-) fetal liver chimeras reflects derivation from a Bcl11a- and Flt3 independent pathway in vivo. PMID- 23741397 TI - A focused ethnographic study of Alberta cattle veterinarians' decision making about diagnostic laboratory submissions and perceptions of surveillance programs. AB - The animal and public health communities need to address the challenge posed by zoonotic emerging infectious diseases. To minimize the impacts of future events, animal disease surveillance will need to enable prompt event detection and response. Diagnostic laboratory-based surveillance systems targeting domestic animals depend in large part on private veterinarians to submit samples from cases to a laboratory. In contexts where pre-diagnostic laboratory surveillance systems have been implemented, this group of veterinarians is often asked to input data. This scenario holds true in Alberta where private cattle veterinarians have been asked to participate in the Alberta Veterinary Surveillance Network-Veterinary Practice Surveillance, a platform to which pre diagnostic disease and non-disease case data are submitted. Consequently, understanding the factors that influence these veterinarians to submit cases to a laboratory and the complex of factors that affect their participation in surveillance programs is foundational to interpreting disease patterns reported by laboratories and engaging veterinarians in surveillance. A focused ethnographic study was conducted with ten cattle veterinarians in Alberta. Individual in-depth interviews with participants were recorded and transcribed to enable thematic analysis. Laboratory submissions were biased toward outbreaks of unknown cause, cases with unusual mortality rates, and issues with potential herd level implications. Decreasing cattle value and government support for laboratory testing have contributed to fewer submissions over time. Participants were willing participants in surveillance, though government support and collaboration were necessary. Changes in the beef industry and veterinary profession, as well as cattle producers themselves, present both challenges and opportunities in surveillance. PMID- 23741398 TI - Genomic copy number variants: evidence for association with antibody response to anthrax vaccine adsorbed. AB - BACKGROUND: Anthrax and its etiologic agent remain a biological threat. Anthrax vaccine is highly effective, but vaccine-induced IgG antibody responses vary widely following required doses of vaccinations. Such variation can be related to genetic factors, especially genomic copy number variants (CNVs) that are known to be enriched among genes with immunologic function. We have tested this hypothesis in two study populations from a clinical trial of anthrax vaccination. METHODS: We performed CNV-based genome-wide association analyses separately on 794 European Americans and 200 African-Americans. Antibodies to protective antigen were measured at week 8 (early response) and week 30 (peak response) using an enzyme-linked immunosorbent assay. We used DNA microarray data (Affymetrix 6.0) and two CNV detection algorithms, hidden markov model (PennCNV) and circular binary segmentation (GeneSpring) to determine CNVs in all individuals. Multivariable regression analyses were used to identify CNV-specific associations after adjusting for relevant non-genetic covariates. RESULTS: Within the 22 autosomal chromosomes, 2,943 non-overlapping CNV regions were detected by both algorithms. Genomic insertions containing HLA-DRB5, DRB1 and DQA1/DRA genes in the major histocompatibility complex (MHC) region (chromosome 6p21.3) were moderately associated with elevated early antibody response (beta = 0.14, p = 1.78*10(-3)) among European Americans, and the strongest association was observed between peak antibody response and a segmental insertion on chromosome 1, containing NBPF4, NBPF5, STXMP3, CLCC1, and GPSM2 genes (beta = 1.66, p = 6.06*10(-5)). For African-Americans, segmental deletions spanning PRR20, PCDH17 and PCH68 genes on chromosome 13 were associated with elevated early antibody production (beta = 0.18, p = 4.47*10(-5)). Population-specific findings aside, one genomic insertion on chromosome 17 (containing NSF, ARL17 and LRRC37A genes) was associated with elevated peak antibody response in both populations. CONCLUSION: Multiple CNV regions, including the one consisting of MHC genes that is consistent with earlier research, can be important to humoral immune responses to anthrax vaccine adsorbed. PMID- 23741399 TI - To bind or not to bind? Different temporal binding effects from voluntary pressing and releasing actions. AB - Binding effect refers to the perceptual attraction between an action and an outcome leading to a subjective compression of time. Most studies investigating binding effects exclusively employ the "pressing" action without exploring other types of actions. The present study addresses this issue by introducing another action, releasing action or the voluntary lifting of the finger/wrist, to investigate the differences between voluntary pressing and releasing actions. Results reveal that releasing actions led to robust yet short-lived temporal binding effects, whereas pressing condition had steady temporal binding effects up to super-seconds. The two actions also differ in sensitivity to changes in temporal contiguity and contingency, which could be attributed to the difference in awareness of action. Extending upon current models of "willed action," our results provide insights from a temporal point of view and support the concept of a dual system consisting of predictive motor control and top-down mechanisms. PMID- 23741400 TI - Evaluation of ALK rearrangement in Chinese non-small cell lung cancer using FISH, immunohistochemistry, and real-time quantitative RT- PCR on paraffin-embedded tissues. AB - Patients with ALK gene rearrangements often manifest dramatic responses to crizotinib, an ALK inhibitor. Accurate identification of patients with ALK positive non-small cell lung cancer (NSCLC) is essential for the clinical application of ALK-targeted therapy. However, assessing EML4-ALK rearrangement in NSCLC remains challenging in routine pathology practice. The aim of this study was to compare the diagnostic accuracy of FISH, immunohistochemistry (IHC), and real-time quantitative RT-PCR (QPCR) methodologies for detection of EML4-ALK rearrangement in NSCLC and to appraise immunohistochemistry as a pre-screening tool. In this study, a total of 473 paraffin-embedded NSCLC samples from surgical resections and biopsies were analyzed by IHC with ALK antibody. ALK rearrangement was further confirmed by FISH and QPCR. ALK protein expression was detected in twenty patients (20/473, 4.2%). Of the 20 ALK-positive cases by IHC, 15 cases were further confirmed as ALK rearrangement by FISH, and 5 cases were not interpretable. Also, we evaluated 13 out of the 20 IHC-positive tissues by QPCR in additional to FISH, and found that 9 cases were positive and 2 cases were equivocal, whereas 2 cases were negative although they were positive by both IHC and FISH. The ALK status was concordant in 5 out of 8 cases that were interpretable by three methods. Additionally, none of the 110 IHC-negative cases with adenocarcinoma histology showed ALK rearrangements by FISH. Histologically, almost all the ALK-rearranged cases were adenocarcinoma, except that one case was sarcomatoid carcinoma. A solid signet-ring cell pattern or mucinous cribriform pattern was presented at least focally in all ALK-positive tumors. In conclusion, our findings suggested that ALK rearrangement was associated with ALK protein expression. The conventional IHC assay is a valuable tool for the pre-screening of patients with ALK rearrangement in clinical practice and a combination of FISH and QPCR is required for further confirmation. PMID- 23741401 TI - Gating of long-term potentiation by nicotinic acetylcholine receptors at the cerebellum input stage. AB - The brain needs mechanisms able to correlate plastic changes with local circuit activity and internal functional states. At the cerebellum input stage, uncontrolled induction of long-term potentiation or depression (LTP or LTD) between mossy fibres and granule cells can saturate synaptic capacity and impair cerebellar functioning, which suggests that neuromodulators are required to gate plasticity processes. Cholinergic systems innervating the cerebellum are thought to enhance procedural learning and memory. Here we show that a specific subtype of acetylcholine receptors, the alpha7-nAChRs, are distributed both in cerebellar mossy fibre terminals and granule cell dendrites and contribute substantially to synaptic regulation. Selective alpha7-nAChR activation enhances the postsynaptic calcium increase, allowing weak mossy fibre bursts, which would otherwise cause LTD, to generate robust LTP. The local microperfusion of alpha7-nAChR agonists could also lead to in vivo switching of LTD to LTP following sensory stimulation of the whisker pad. In the cerebellar flocculus, alpha7-nAChR pharmacological activation impaired vestibulo-ocular-reflex adaptation, probably because LTP was saturated, preventing the fine adjustment of synaptic weights. These results show that gating mechanisms mediated by specific subtypes of nicotinic receptors are required to control the LTD/LTP balance at the mossy fibre-granule cell relay in order to regulate cerebellar plasticity and behavioural adaptation. PMID- 23741402 TI - Passing messages between biological networks to refine predicted interactions. AB - Regulatory network reconstruction is a fundamental problem in computational biology. There are significant limitations to such reconstruction using individual datasets, and increasingly people attempt to construct networks using multiple, independent datasets obtained from complementary sources, but methods for this integration are lacking. We developed PANDA (Passing Attributes between Networks for Data Assimilation), a message-passing model using multiple sources of information to predict regulatory relationships, and used it to integrate protein-protein interaction, gene expression, and sequence motif data to reconstruct genome-wide, condition-specific regulatory networks in yeast as a model. The resulting networks were not only more accurate than those produced using individual data sets and other existing methods, but they also captured information regarding specific biological mechanisms and pathways that were missed using other methodologies. PANDA is scalable to higher eukaryotes, applicable to specific tissue or cell type data and conceptually generalizable to include a variety of regulatory, interaction, expression, and other genome-scale data. An implementation of the PANDA algorithm is available at www.sourceforge.net/projects/panda-net. PMID- 23741403 TI - Comparison of modules of wild type and mutant Huntingtin and TP53 protein interaction networks: implications in biological processes and functions. AB - Disease-causing mutations usually change the interacting partners of mutant proteins. In this article, we propose that the biological consequences of mutation are directly related to the alteration of corresponding protein protein interaction networks (PPIN). Mutation of Huntingtin (HTT) which causes Huntington's disease (HD) and mutations to TP53 which is associated with different cancers are studied as two example cases. We construct the PPIN of wild type and mutant proteins separately and identify the structural modules of each of the networks. The functional role of these modules are then assessed by Gene Ontology (GO) enrichment analysis for biological processes (BPs). We find that a large number of significantly enriched ([Formula: see text]) GO terms in mutant PPIN were absent in the wild type PPIN indicating the gain of BPs due to mutation. Similarly some of the GO terms enriched in wild type PPIN cease to exist in the modules of mutant PPIN, representing the loss. GO terms common in modules of mutant and wild type networks indicate both loss and gain of BPs. We further assign relevant biological function(s) to each module by classifying the enriched GO terms associated with it. It turns out that most of these biological functions in HTT networks are already known to be altered in HD and those of TP53 networks are altered in cancers. We argue that gain of BPs, and the corresponding biological functions, are due to new interacting partners acquired by mutant proteins. The methodology we adopt here could be applied to genetic diseases where mutations alter the ability of the protein to interact with other proteins. PMID- 23741404 TI - Phylogenetically diverse ureC genes and their expression suggest the urea utilization by bacterial symbionts in marine sponge Xestospongia testudinaria. AB - Urea is one of the dominant organic nitrogenous compounds in the oligotrophic oceans. Compared to the knowledge of nitrogen transformation of nitrogen fixation, ammonia oxidization, nitrate and nitrite reduction mediated by sponge associated microbes, our knowledge of urea utilization in sponges and the phylogenetic diversity of sponge-associated microbes with urea utilization potential is very limited. In this study, Marinobacter litoralis isolated from the marine sponge Xestospongia testudinaria and the slurry of X. testudinaria were found to have urease activity. Subsequently, phylogenetically diverse bacterial ureC genes were detected in the total genomic DNA and RNA of sponge X. testudinaria, i.e., 19 operative taxonomic units (OTUs) in genomic DNA library and 8 OTUs in cDNA library at 90% stringency. Particularly, 6 OTUs were common to both the genomic DNA library and the cDNA library, which suggested that some ureC genes were expressed in this sponge. BLAST and phylogenetic analysis showed that most of the ureC sequences were similar with the urease alpha subunit of members from Proteobacteria, which were the predominant component in sponge X. testudinaria, and the remaining ureC sequences were related to those from Magnetococcus, Cyanobacteria, and Actinobacteria. This study is the first assessment of the role of sponge bacterial symbionts in the regenerated utilization of urea by the detection of transcriptional activity of ureC gene, as well as the phylogenetic diversity of ureC gene of sponge bacterial symbionts. The results suggested the urea utilization by bacterial symbionts in marine sponge X. testudinaria, extending our understanding of nitrogen cycling mediated by sponge-associated microbiota. PMID- 23741405 TI - A multi-system approach assessing the interaction of anticonvulsants with P-gp. AB - 30% of epilepsy patients receiving antiepileptic drugs (AEDs) are not fully controlled by therapy. The drug transporter hypothesis for refractory epilepsy proposes that P-gp is over expressed at the epileptic focus with a role of P-gp in extruding AEDs from the brain. However, there is controversy regarding whether all AEDs are substrates for this transporter. Our aim was to investigate transport of phenytoin, lamotrigine and carbamazepine by using seven in-vitro transport models. Uptake assays in CEM/VBL cell lines, oocytes expressing human P gp and an immortalised human brain endothelial cell line (hCMEC/D3) were carried out. Concentration equilibrium transport assays were performed in Caco-2, MDCKII +/-P-gp and LLC-PK1+/-P-gp in the absence or presence of tariquidar, an inhibitor of P-gp. Finally, primary porcine brain endothelial cells were used to determine the apparent permeability (Papp) of the three AEDs in the absence or presence of P-gp inhibitors. We detected weak transport of phenytoin in two of the transport systems (MDCK and LLC-PK1 cells transfected with human P-gp) but not in the remaining five. No P-gp interaction was observed for lamotrigine or carbamazepine in any of the seven validated in-vitro transport models. Neither lamotrigine nor carbamazepine was a substrate for P-gp in any of the model systems tested. Our data suggest that P-gp is unlikely to contribute to the pathogenesis of refractory epilepsy through transport of carbamazepine or lamotrigine. PMID- 23741406 TI - On the brain of a crustacean: a morphological analysis of CaMKII expression and its relation to sensory and motor pathways. AB - Calcium/calmodulin kinase II (CaMKII) is a Ca(2+)-activated enzyme that is abundant in vertebrate and invertebrate brains. However, its characterization is poorly addressed in the nervous system of crustaceans, and, to our knowledge, no studies have determined the microanatomical location of CaMKII in a crustacean species. In this study, we found labeling of CaMKII in the eyestalk and brain of the prawn Macrobrachium acanthurus, by means of immunohistochemistry and Western blotting. Antibodies against neuron (beta tubulin III), glutamate receptor (GluA1), and FMRFamide were used in order to further characterize the CaMKII labeled cells in the brain. In the eyestalk, strong labeling with CaMKII was observed in the photoreceptors. These cells, especially in the rhabdom, were also reactive to anti-beta tubulin III, whereas the pigment cells were labeled with anti-CaMKII. GluA1 co-located with CaMKII in the photoreceptors. Also, CaMKII appeared in the same sites as FMRFamide in the deutocerebrum, including the olfactory lobe, and in the tritocerebrum, specifically in the antennular neuropil, indicating that the synaptic areas in these regions may be related to sensory-motor processing. In the brain, the identification of cells and regions that express CaMKII contributes to the understanding of the processing of neural connections and the modulating role of CaMKII in decapod crustaceans. PMID- 23741408 TI - Structure and possible functions of constant-frequency calls in Ariopsis seemanni (Osteichthyes, Ariidae). AB - In the 1970s, Tavolga conducted a series of experiments in which he found behavioral evidence that the vocalizations of the catfish species Ariopsis felis may play a role in a coarse form of echolocation. Based on his findings, he postulated a similar function for the calls of closely related catfish species. Here, we describe the physical characteristics of the predominant call-type of Ariopsis seemanni. In two behavioral experiments, we further explore whether A. seemanni uses these calls for acoustic obstacle detection by testing the hypothesis that the call-emission rate of individual fish should increase when subjects are confronted with novel objects, as it is known from other vertebrate species that use pulse-type signals to actively probe the environment. Audio video monitoring of the fish under different obstacle conditions did not reveal a systematic increase in the number of emitted calls in the presence of novel objects or in dependence on the proximity between individual fish and different objects. These negative findings in combination with our current understanding of directional hearing in fishes (which is a prerequisite for acoustic obstacle detection) make it highly unlikely that A. seemanni uses its calls for acoustic obstacle detection. We argue that the calls are more likely to play a role in intra- or interspecific communication (e.g. in school formation or predator deterrence) and present results from a preliminary Y-maze experiment that are indicative for a positive phonotaxis of A. seemanni towards the calls of conspecifics. PMID- 23741407 TI - Genome implosion elicits host-confinement in Alcaligenaceae: evidence from the comparative genomics of Tetrathiobacter kashmirensis, a pathogen in the making. AB - This study elucidates the genomic basis of the evolution of pathogens alongside free-living organisms within the family Alcaligenaceae of Betaproteobacteria. Towards that end, the complete genome sequence of the sulfur-chemolithoautotroph Tetrathiobacter kashmirensis WT001(T) was determined and compared with the soil isolate Achromobacter xylosoxidans A8 and the two pathogens Bordetella bronchiseptica RB50 and Taylorella equigenitalis MCE9. All analyses comprehensively indicated that the RB50 and MCE9 genomes were almost the subsets of A8 and WT001(T), respectively. In the immediate evolutionary past Achromobacter and Bordetella shared a common ancestor, which was distinct from the other contemporary stock that gave rise to Tetrathiobacter and Taylorella. The Achromobacter-Bordetella precursor, after diverging from the family ancestor, evolved through extensive genome inflation, subsequent to which the two genera separated via differential gene losses and acquisitions. Tetrathiobacter, meanwhile, retained the core characteristics of the family ancestor, and Taylorella underwent massive genome degeneration to reach an evolutionary dead end. Interestingly, the WT001(T) genome, despite its conserved architecture, had only 85% coding density, besides which 578 out of its 4452 protein-coding sequences were found to be pseudogenized. Translational impairment of several DNA repair-recombination genes in the first place seemed to have ushered the rampant and indiscriminate frame-shift mutations across the WT001(T) genome. Presumably, this strain has just come out of a recent evolutionary bottleneck, representing a unique transition state where genome self-degeneration has started comprehensively but selective host-confinement has not yet set in. In the light of this evolutionary link, host-adaptation of Taylorella clearly appears to be the aftereffect of genome implosion in another member of the same bottleneck. Remarkably again, potent virulence factors were found widespread in Alcaligenaceae, corroborating which hemolytic and mammalian cell-adhering abilities were discovered in WT001(T). So, while WT001(T) relatives/derivatives in nature could be going the Taylorella way, the lineage as such was well prepared for imminent host-confinement. PMID- 23741409 TI - In situ quantification of experimental ice accretion on tree crowns using terrestrial laser scanning. AB - In the eastern hardwood forests of North America ice storms are an important disturbance event. Ice storms strongly influence community dynamics as well as urban infrastructure via catastrophic branch failure; further, the severity and frequency of ice storms are likely to increase with climate change. However, despite a long-standing interest into the effects of freezing rain on forests, the process of ice accretion and thus ice loading on branches remains poorly understood. This is because a number of challenges have prevented in situ measurements of ice on branches, including: 1) accessing and measuring branches in tall canopies, 2) limitations to travel during and immediately after events, and 3) the unpredictability of ice storms. Here, utilizing a novel combination of outdoor experimental icing, manual measurements and terrestrial laser scanning (TLS), we perform the first in situ measurements of ice accretion on branches at differing heights in a tree crown and with increasing duration of exposure. We found that TLS can reproduce both branch and iced branch diameters with high fidelity, but some TLS instruments do not detect ice. Contrary to the expectations of ice accretion models, radial accretion varied sharply within tree crowns. Initially, radial ice accretion was similar throughout the crown, but after 6.5 hours of irrigation (second scanning) radial ice accretion was much greater on upper branches than on lower (~factor of 3). The slope of the change in radial ice accretion along branches increased with duration of exposure and was significantly greater at the second scanning compared to the first. We conclude that outdoor icing experiments coupled with the use of TLS provide a robust basis for evaluation of models of ice accretion and breakage in tree crowns, facilitating estimation of the limiting breaking stress of branches by accurate measurements of ice loads. PMID- 23741410 TI - TRPV2 mediates adrenomedullin stimulation of prostate and urothelial cancer cell adhesion, migration and invasion. AB - Adrenomedullin (AM) is a 52-amino acid peptide initially isolated from human pheochromocytoma. AM is expressed in a variety of malignant tissues and cancer cell lines and was shown to be a mitogenic factor capable of stimulating growth of several cancer cell types. In addition, AM is a survival factor for certain cancer cells. Some data suggest that AM might be involved in the progression cancer metastasis via angiogenesis and cell migration and invasion control. The Transient Receptor Potential channel TRPV2 is known to promote in prostate cancer cell migration and invasive phenotype and is correlated with the stage and grade of bladder cancer. In this work we show that AM induces prostate and urothelial cancer cell migration and invasion through TRPV2 translocation to plasma membrane and the subsequent increase in resting calcium level. PMID- 23741411 TI - Dietary glycemic index during pregnancy is associated with biomarkers of the metabolic syndrome in offspring at age 20 years. AB - OBJECTIVE: Growing evidence indicates that metabolic syndrome is rooted in fetal life with a potential key role of nutrition during pregnancy. The objective of the study was to assess the possible associations between the dietary glycemic index (GI) and glycemic load (GL) during pregnancy and biomarkers of the metabolic syndrome in young adult offspring. METHODS: Dietary GI and GL were assessed by questionnaires and interviews in gestation week 30 and offspring were clinically examined at the age of 20 years. Analyses based on 428 mother offspring dyads were adjusted for maternal smoking during pregnancy, height, pre pregnancy body mass index (BMI), education, energy intake, and the offspring's ambient level of physical activity. In addition, possible confounding by gestational diabetes mellitus was taken into account. OUTCOME MEASURES: Waist circumference, blood pressure, HOMA insulin resistance (HOMA-IR) and plasma levels of fasting glucose, triglycerides, HDL cholesterol, LDL cholesterol, total cholesterol, insulin, and leptin were measured in the offspring. RESULTS: Significant associations were found between dietary GI in pregnancy and HOMA-IR (the relative increase in HOMA-IR per 10 units' GI increase was 1.09 [95% CI: 1.01, 1.16], p = 0.02), insulin (1.09 [95% CI: 1.02, 1.16], p = 0.01) and leptin (1.21 [95% CI: 1.06, 1.38], p = 0.01) in the offspring; whereas no associations were detected for GL. CONCLUSIONS: Our data suggests that high dietary GI in pregnancy may affect levels of markers for the metabolic syndrome in young adult offspring in a potentially harmful direction. PMID- 23741412 TI - Brain-derived neurotrophic factor-dependent cdk1 inhibition prevents G2/M progression in differentiating tetraploid neurons. AB - Neurodegeneration is often associated with DNA synthesis in neurons, the latter usually remaining for a long time as tetraploid cells before dying by apoptosis. The molecular mechanism preventing G2/M transition in these neurons remains unknown, but it may be reminiscent of the mechanism that maintains tetraploid retinal ganglion cells (RGCs) in a G2-like state during normal development, thus preventing their death. Here we show that this latter process, known to depend on brain-derived neurotrophic factor (BDNF), requires the inhibition of cdk1 by TrkB. We demonstrate that a subpopulation of chick RGCs previously shown to become tetraploid co-expresses TrkB and cdk1 in vivo. By using an in vitro system that recapitulates differentiation and cell cycle re-entry of chick retinal neurons we show that BDNF, employed at concentrations specific for the TrkB receptor, reduces the expression of cdk1 in TrkB-positive, differentiating neurons. In this system, BDNF also inhibits the activity of both endogenous cdk1 and exogenously-expressed cdk1/cyclin B1 complex. This inhibition correlates with the phosphorylation of cdk1 at Tyr15, an effect that can be prevented with K252a, a tyrosine kinase inhibitor commonly used to prevent the activity of neurotrophins through their Trk receptors. The effect of BDNF on cdk1 activity is Tyr15-specific since BDNF cannot prevent the activity of a constitutively active form of cdk1 (Tyr15Phe) when expressed in differentiating retinal neurons. We also show that BDNF-dependent phosphorylation of cdk1 at Tyr15 could not be blocked with MK-1775, a Wee1-selective inhibitor, indicating that Tyr15 phosphorylation in cdk1 does not seem to occur through the canonical mechanism observed in proliferating cells. We conclude that the inhibition of both expression and activity of cdk1 through a BDNF-dependent mechanism contributes to the maintenance of tetraploid RGCs in a G2-like state. PMID- 23741413 TI - Fast, non-competitive and reversible inhibition of NMDA-activated currents by 2 BFI confers neuroprotection. AB - Excessive activation of the N-methyl-D-aspartic acid (NMDA) type glutamate receptors (NMDARs) causes excitotoxicity, a process important in stroke-induced neuronal death. Drugs that inhibit NMDA receptor-mediated [Ca(2+)]i influx are potential leads for development to treat excitotoxicity-induced brain damage. Our previous studies showed that 2-(2-benzofu-ranyl)-2-imidazoline (2-BFI), an immidazoline receptor ligand, dose-dependently protects rodent brains from cerebral ischemia injury. However, the molecular mechanisms remain unclear. In this study, we found that 2-BFI transiently and reversibly inhibits NMDA, but not AMPA currents, in a dose-dependent manner in cultured rat cortical neurons. The mechanism of 2-BFI inhibition of NMDAR is through a noncompetitive fashion with a faster on (Kon = 2.19+/-0.33*10(-9) M(-1) sec(-1)) and off rate (Koff = 0.67+/ 0.02 sec(-1)) than those of memantine, a gold standard for therapeutic inhibition NMDAR-induced excitotoxicity. 2-BFI also transiently and reversibly blocked NMDA receptor-mediated calcium entry to cultured neurons and provided long-term neuroprotection against NMDA toxicity in vitro. Collectively, these studies demonstrated a potential mechanism of 2-BFI-mediated neuroprotection and indicated that 2-BFI is an excellent candidate for repositioning as a drug for stroke treatment. PMID- 23741414 TI - Estimation of low quantity genes: a hierarchical model for analyzing censored quantitative real-time PCR data. AB - Analysis of gene quantities measured by quantitative real-time PCR (qPCR) can be complicated by observations that are below the limit of quantification (LOQ) of the assay. A hierarchical model estimated using MCMC methods was developed to analyze qPCR data of genes with observations that fall below the LOQ (censored observations). Simulated datasets with moderate to very high levels of censoring were used to assess the performance of the model; model results were compared to approaches that replace censored observations with a value on the log scale approximating zero or with values ranging from one to the LOQ of ten gene copies. The model was also compared to a Tobit regression model. Finally, all approaches for handling censored observations were evaluated with DNA extracted from samples that were spiked with known quantities of the antibiotic resistance gene tetL. For the simulated datasets, the model outperformed substitution of all values from 1-10 under all censoring scenarios in terms of bias, mean square error, and coverage of 95% confidence intervals for regression parameters. The model performed as well or better than substitution of a value approximating zero under two censoring scenarios (approximately 57% and 79% censored values). The model also performed as well or better than Tobit regression in two of three censoring scenarios (approximately 79% and 93% censored values). Under the levels of censoring present in the three scenarios of this study, substitution of any values greater than 0 produced the least accurate results. When applied to data produced from spiked samples, the model produced the lowest mean square error of the three approaches. This model provides a good alternative for analyzing large amounts of left-censored qPCR data when the goal is estimation of population parameters. The flexibility of this approach can accommodate complex study designs such as longitudinal studies. PMID- 23741415 TI - In vivo visualization of Notch1 proteolysis reveals the heterogeneity of Notch1 signaling activity in the mouse cochlea. AB - Mechanosensory hair cells (HCs) and surrounding supporting cells (SCs) in the mouse cochlea are important for hearing and are derived from the same prosensory progenitors. Notch1 signaling plays dual but contrasting and age-dependent roles in mouse cochlear development: early lateral induction and subsequent lateral inhibition. However, it has been difficult to directly visualize mouse cochlear cells experiencing various levels of Notch1 activity at single cell resolution. Here, we characterized two knock-in mouse lines, Notch1(Cre (Low)/+) and Notch1(Cre (High)/+) , with different Cre recombinase activities, that can detect Notch1 receptor proteolysis or Notch1 activity at high and low thresholds, respectively. Using both lines together with a highly sensitive Cre reporter line, we showed that Notch1 activity is nearly undetectable during lateral induction but increases to medium and high levels during lateral inhibition. Furthermore, we found that within the neonatal organ of Corti, the vast majority of cells that experience Notch1 activity were SCs not HCs, suggesting that HCs kept undetectable Notch1 activity during the entire lineage development. Furthermore, among SC subtypes, ~85-99% of Deiters' and outer pillar cells but only ~19-38% of inner pillar cells experience medium and high levels of Notch1 activity. Our results demonstrate that Notch1 activity is highly heterogeneous: 1) between lateral induction and inhibition; 2) between HC and SC lineages; 3) among different SC subtypes; 4) among different cells within each SC subtype. Such heterogeneity should elucidate how the development of the cochclear sensory epithelium is precisely controlled and how HC regeneration can be best achieved in postnatal cochleae. PMID- 23741416 TI - Mild blast events alter anxiety, memory, and neural activity patterns in the anterior cingulate cortex. AB - There is a general interest in understanding of whether and how exposure to emotionally traumatizing events can alter memory function and anxiety behaviors. Here we have developed a novel laboratory-version of mild blast exposure comprised of high decibel bomb explosion sound coupled with strong air blast to mice. This model allows us to isolate the effects of emotionally fearful components from those of traumatic brain injury or bodily injury typical associated with bomb blasts. We demonstrate that this mild blast exposure is capable of impairing object recognition memory, increasing anxiety in elevated O maze test, and resulting contextual generalization. Our in vivo neural ensemble recording reveal that such mild blast exposures produced diverse firing changes in the anterior cingulate cortex, a region processing emotional memory and inhibitory control. Moreover, we show that these real-time neural ensemble patterns underwent post-event reverberations, indicating rapid consolidation of those fearful experiences. Identification of blast-induced neural activity changes in the frontal brain may allow us to better understand how mild blast experiences result in abnormal changes in memory functions and excessive fear generalization related to post-traumatic stress disorder. PMID- 23741417 TI - Time course of the cross-over effect of fatigue on the contralateral muscle after unilateral exercise. AB - We investigated the cross-over effect of muscle fatigue and its time course on the non-exercising contralateral limb (NEL) after unilateral fatiguing contractions of the ipsilateral exercising limb (EL). For this purpose, 15 males performed two bouts of 100-second maximal isometric knee extensions with the exercising limb, and neuromuscular function of both the EL and NEL was assessed before (PRE), after a first fatiguing exercise (MID) and after a second fatiguing exercise (POST). Maximal voluntary isometric torque production declined in the EL after the first bout of exercise (-9.6%; p<0.001) while in the NEL, the decrease occurred after the second bout of exercise (-10.6%; p<0.001). At MID, torque decline of the EL was strictly associated to an alteration of the mechanical twitch properties evoked by neurostimulation of the femoral nerve (i.e., peak twitch torque, maximal rate of twitch development). According to these markers, we suggest that peripheral fatigue occurred. At POST, after the second bout of exercise, the voluntary activation level of the knee extensor muscles was altered from PRE (-9.1%; p<0.001), indicating an overall central failure in both the EL and NEL. These findings indicate that two bouts of unilateral fatiguing exercise were needed to induce a cross-over effect of muscle fatigue on the non-exercising contralateral limb. Differential adjustments of the motor pathway (peripheral fatigue vs. central fatigue) might contribute to the respective torque decline in the EL and the NEL. Given that our unilateral fatiguing exercise induced immediate maximal torque reduction in the EL and postponed the loss of torque production in the NEL, it is also concluded that the time course of muscle fatigue differed between limbs. PMID- 23741418 TI - 1,25-dihydroxyvitamin D(3) inhibits podocyte uPAR expression and reduces proteinuria. AB - BACKGROUND: Accumulating studies have demonstrated that 1,25-Dihydroxyvitamin D(3) (1,25(OH)2D3) reduces proteinuria and protects podocytes from injury. Recently, urokinase receptor (uPAR) and its soluble form have been shown to cause podocyte injury and focal segmental glomerulosclerosis (FSGS). Here, our findings showed that 1,25(OH)2D3 did inhibit podocyte uPAR expression and attenuate proteinuria and podocyte injury. METHODOLOGY/PRINCIPAL FINDINGS: In this study, the antiproteinuric effect of 1,25(OH)2D3 was examined in the lipopolysaccharide mice model of transient proteinuria (LPS mice) and in the 5/6 nephrectomy rat FSGS model(NTX rats). uPAR protein expression were tested by flow cytometry, immune cytochemistry and western blot analysis, and uPAR mRNA expression by real time quantitative PCR in cultured podocytes and kidney glomeruli isolated from mice and rats. Podocyte motility was observed by transwell migration assay and wound healing assay. Podocyte foot processes effacement was identified by transmission electron microscopy. We found that 1,25(OH)2D3 inhibited podocyte uPAR mRNA and protein synthesis in LPS-treated podocytes, LPS mice and NTX rats, along with 1,25(OH)2D3 reducing proteinuria in NTX rats and LPS mice.1,25(OH)2D3 reduced glomerulosclerosis in NTX rats and alleviated podocyte foot processes effacement in LPS mice. Transwell migration assay and wound healing assay showed that LPS-induced podocyte motility, irrespective of random or directed motility, were substantially reduced by 1,25(OH)2D3. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated that 1,25(OH)2D3 inhibited podocyte uPAR expression in vitro and in vivo, which may be an unanticipated off target effect of 1,25(OH)2D3 and explain its antiproteinuric effect in the 5/6 nephrectomy rat FSGS model and the LPS mouse model of transient proteinuria. PMID- 23741419 TI - Prevalence of TB/HIV co-infection in countries except China: a systematic review and meta-analysis. AB - BACKGROUND: TB and HIV co-epidemic is a major public health problem in many parts of the world. But the prevalence of TB/HIV co-infection was diversified among countries. Exploring the reasons of the diversity of TB/HIV co-infection is important for public policy, planning and development of collaborative TB/HIV activities. We aimed to summarize the prevalence of TB and HIV co-infection worldwide, using meta-analysis based on systematic review of published articles. METHODS: We searched PubMed, Embase, and Web of Science for studies of the prevalence of TB/HIV co-infection. We also searched bibliographic indices, scanned reference lists, and corresponded with authors. We summarized the estimates using meta-analysis and explored potential sources of heterogeneity in the estimates by metaregression analysis. RESULTS: We identified 47 eligible studies with a total population of 272,466. Estimates of TB/HIV co-infection prevalence ranged from 2.93% to 72.34%; the random effects pooled prevalence of TB/HIV co-infection was 23.51% (95% CI 20.91-26.11). We noted substantial heterogeneity (Cochran's chi (2) = 10945.31, p<0.0001; I (2) = 99.58%, 95% CI 99.55-99.61). Prevalence of TB/HIV co-infection was 31.25%(95%CI 19.30-43.17) in African countries, 17.21%(95%CI 9.97-24.46) in Asian countries, 20.11%(95%CI 13.82-26.39) in European countries, 25.06%(95%CI 19.28-30.84) in Latin America countries and 14.84%(95%CI 10.44-19.24) in the USA. Prevalence of TB/HIV co infection was higher in studies in which TB diagnosed by chest radiography and HIV diagnosis based on blood analyses than in those which used other diagnostic methods, and in countries with higher prevalence HIV in the general population than in countries with lower general prevalence. CONCLUSIONS: Our analyses suggest that it is necessary to attach importance to HIV/TB co-infection, especially screening of TB/HIV co-infection using methods with high sensitivity, specificity and predictive values in the countries with high HIV/AIDS prevalence in the general population. PMID- 23741420 TI - Intranasal vaccination with Chlamydia pneumoniae induces cross-species immunity against genital Chlamydia muridarum challenge in mice. AB - Chlamydia trachomatis is the most common bacterial sexually transmitted disease in the world and specifically in the United States, with the highest incidence in age-groups 14-19 years. In a subset of females, the C. trachomatis genital infection leads to serious pathological sequelae including pelvic inflammatory disease, ectopic pregnancy, and infertility. Chlamydia pneumoniae, another member of the same genus, is a common cause of community acquired respiratory infection with significant number of children aged 5-14 yr displaying sero-conversion. Since these bacteriae share several antigenic determinants, we evaluated whether intranasal immunization with live C. pneumoniae (1*10(6) inclusion forming units; IFU) in 5 week old female C57BL/6 mice would induce cross-species protection against subsequent intravaginal challenge with Chlamydia muridarum (5*10(4) IFU), which causes a similar genital infection and pathology in mice as C. trachomatis in humans. Mice vaccinated intranasally with live C. pneumoniae, but not mock (PBS) immunized animals, displayed high levels of splenic cellular antigen specific IFN-gamma production and serum antibody response against C. muridarum and C. trachomatis. Mice vaccinated with C. pneumoniae displayed a significant reduction in the vaginal C. muridarum shedding as early as day 12 after secondary i.vag. challenge compared to PBS (mock) immunized mice. At day 19 after C. muridarum challenge, 100% of C. pneumoniae vaccinated mice had cleared the infection compared to none (0%) of the mock immunized mice, which cleared the infection by day 27. At day 80 after C. muridarum challenge, C. pneumoniae vaccinated mice displayed a significant reduction in the incidence (50%) and degree of hydrosalpinx compared to mock immunized animals (100%). These results suggest that respiratory C. pneumoniae infection induces accelerated chlamydial clearance and reduction of oviduct pathology following genital C. muridarum challenge, and may have important implications to the C. trachomatis-induced reproductive disease in humans. PMID- 23741421 TI - Pretherapeutic plasma pro- and anti- inflammatory mediators are related to high risk of oral mucositis in pediatric patients with acute leukemia: a prospective cohort study. AB - OBJECTIVE: This prospective study evaluated clinical risk indicators as well as pro- and anti- inflammatory mediators at the time of malignancy diagnosis in relation to chemotherapy-related oral mucositis in pediatric population. METHODS: Patients (n = 104) under 18 years of age with primary malignancies and undergoing chemotherapy were included. Potential risk indicators were analyzed using binary logistic regression with oral mucositis as the outcome. In a subgroup (n = 35), plasma samples at the time of malignancy diagnosis were analyzed for inflammatory cytokines and an antimicrobial protein pro-LL-37 (hCAP18). RESULTS: In the multivariable model, type of malignancy diagnosis was significantly associated with oral mucositis, with highest risk of oral mucositis in patients with acute leukemia compared to those with lymphoma or solid tumors. At the time of malignancy diagnosis, plasma from patients with acute leukemia displayed higher concentrations (P<0.05) of IL-6, IL-8, IL-10, and TNF-alpha and lower levels of pro-LL-37 (P<0.001). CONCLUSIONS: The results imply that pretherapeutic high levels of inflammatory cytokines and low levels of pro-LL-37 in plasma might contribute to the high incidence of oral mucositis in patients with acute leukemia. These findings may add to our understanding of the predispositions to oral mucositis in children with malignancies. PMID- 23741422 TI - An iron 13S-lipoxygenase with an alpha-linolenic acid specific hydroperoxidase activity from Fusarium oxysporum. AB - Jasmonates constitute a family of lipid-derived signaling molecules that are abundant in higher plants. The biosynthetic pathway leading to plant jasmonates is initiated by 13-lipoxygenase-catalyzed oxygenation of alpha-linolenic acid into its 13-hydroperoxide derivative. A number of plant pathogenic fungi (e.g. Fusarium oxysporum) are also capable of producing jasmonates, however, by a yet unknown biosynthetic pathway. In a search for lipoxygenase in F. oxysporum, a reverse genetic approach was used and one of two from the genome predicted lipoxygenases (FoxLOX) was cloned. The enzyme was heterologously expressed in E. coli, purified via affinity chromatography, and its reaction mechanism characterized. FoxLOX was found to be a non-heme iron lipoxygenase, which oxidizes C18-polyunsaturated fatty acids to 13S-hydroperoxy derivatives by an antarafacial reaction mechanism where the bis-allylic hydrogen abstraction is the rate-limiting step. With alpha-linolenic acid as substrate FoxLOX was found to exhibit a multifunctional activity, because the hydroperoxy derivatives formed are further converted to dihydroxy-, keto-, and epoxy alcohol derivatives. PMID- 23741424 TI - Education in health research methodology: use of a wiki for knowledge translation. AB - INTRODUCTION: A research-practice gap exists between what is known about conducting methodologically rigorous randomized controlled trials (RCTs) and what is done. Evidence consistently shows that pediatric RCTs are susceptible to high risk of bias; therefore novel methods of influencing the design and conduct of trials are required. The objective of this study was to develop and pilot test a wiki designed to educate pediatric trialists and trainees in the principles involved in minimizing risk of bias in RCTs. The focus was on preliminary usability testing of the wiki. METHODS: The wiki was developed through adaptation of existing knowledge translation strategies and through tailoring the site to the identified needs of the end-users. The wiki was evaluated for usability and user preferences regarding the content and formatting. Semi-structured interviews were conducted with 15 trialists and systematic reviewers, representing varying levels of experience with risk of bias or the conduct of trials. Data were analyzed using content analysis. RESULTS: Participants found the wiki to be well organized, easy to use, and straightforward to navigate. Suggestions for improvement tended to focus on clarification of the text or on esthetics, rather than on the content or format. Participants liked the additional features of the site that were supplementary to the text, such as the interactive examples, and the components that focused on practical applications, adding relevance to the theory presented. While the site could be used by both trialists and systematic reviewers, the lack of a clearly defined target audience caused some confusion among participants. CONCLUSIONS: Participants were supportive of using a wiki as a novel educational tool. The results of this pilot test will be used to refine the risk of bias wiki, which holds promise as a knowledge translation intervention for education in medical research methodology. PMID- 23741423 TI - Cocaine tolerance in honey bees. AB - Increasingly invertebrates are being used to investigate the molecular and cellular effects of drugs of abuse to explore basic mechanisms of addiction. However, in mammals the principle factors contributing to addiction are long-term adaptive responses to repeated drug use. Here we examined whether adaptive responses to cocaine are also seen in invertebrates using the honey bee model system. Repeated topical treatment with a low dose of cocaine rendered bees resistant to the deleterious motor effects of a higher cocaine dose, indicating the development of physiological tolerance to cocaine in bees. Cocaine inhibits biogenic amine reuptake transporters, but neither acute nor repeated cocaine treatments caused measurable changes in levels of biogenic amines measured in whole bee brains. Our data show clear short and long-term behavioural responses of bees to cocaine administration, but caution that, despite the small size of the bee brain, measures of biogenic amines conducted at the whole-brain level may not reveal neurochemical effects of the drug. PMID- 23741426 TI - Age-specific trends in morbidity, mortality and case-fatality from cardiovascular disease, myocardial infarction and stroke in advanced age: evaluation in the Swedish population. AB - BACKGROUND: It is not clear if the downward trend in cardiovascular disease (CVD) observed for ages up to 85 years can be extended to the oldest old, those 85 years and above. METHODS AND FINDINGS: This nationwide cohort study presents age specific trends of CVD as well as for myocardial infarction (MI) and stroke separately for the period 1994 to 2010 for individuals 85 to 99 years old in Sweden. Data were extracted from national registries. All analyses were based on one-year age- and sex- specific figures. The risk for CVD increased with every age above 85 years although the rate of increase leveled off with age. Over time, the risk for CVD and MI decreased for all ages, and for stroke for ages up to 89 years. However, the risk of MI increased until around 2001 in all age groups and both sexes but decreased after that. The overall mortality improved for all outcomes over the period 1994 to 2010, so did the survival within 28 days from an event. The average annual decline in mortality over all ages, 85 and above was 3% for MI, 2% for stroke and for 2% CVD. Corresponding figures for ages 60-84 was 4% for each of MI, stroke and CVD. The results were similar for men and women. CONCLUSIONS: Improvements in CVD risks observed among ages up to 85 years appear to have extended also to ages above 85 years, even if the rate of improvement plateaued with age. The improvements in survival for all ages up to 99 years give no support to the hypothesis that more fragile individuals reach higher ages. Additional research is needed to find out if improvement in survival can be seen also for the second and third event of CVD, stroke and MI. PMID- 23741425 TI - Robust automated detection of microstructural white matter degeneration in Alzheimer's disease using machine learning classification of multicenter DTI data. AB - Diffusion tensor imaging (DTI) based assessment of white matter fiber tract integrity can support the diagnosis of Alzheimer's disease (AD). The use of DTI as a biomarker, however, depends on its applicability in a multicenter setting accounting for effects of different MRI scanners. We applied multivariate machine learning (ML) to a large multicenter sample from the recently created framework of the European DTI study on Dementia (EDSD). We hypothesized that ML approaches may amend effects of multicenter acquisition. We included a sample of 137 patients with clinically probable AD (MMSE 20.6+/-5.3) and 143 healthy elderly controls, scanned in nine different scanners. For diagnostic classification we used the DTI indices fractional anisotropy (FA) and mean diffusivity (MD) and, for comparison, gray matter and white matter density maps from anatomical MRI. Data were classified using a Support Vector Machine (SVM) and a Naive Bayes (NB) classifier. We used two cross-validation approaches, (i) test and training samples randomly drawn from the entire data set (pooled cross-validation) and (ii) data from each scanner as test set, and the data from the remaining scanners as training set (scanner-specific cross-validation). In the pooled cross validation, SVM achieved an accuracy of 80% for FA and 83% for MD. Accuracies for NB were significantly lower, ranging between 68% and 75%. Removing variance components arising from scanners using principal component analysis did not significantly change the classification results for both classifiers. For the scanner-specific cross-validation, the classification accuracy was reduced for both SVM and NB. After mean correction, classification accuracy reached a level comparable to the results obtained from the pooled cross-validation. Our findings support the notion that machine learning classification allows robust classification of DTI data sets arising from multiple scanners, even if a new data set comes from a scanner that was not part of the training sample. PMID- 23741427 TI - IKKepsilon knockout prevents high fat diet induced arterial atherosclerosis and NF-kappaB signaling in mice. AB - AIMS: Atherosclerosis is a public health concern affecting many worldwide, but its pathogenesis remains unclear. In this study we investigated the role of IKKepsilon during the formation of atherosclerosis and its molecular mechanism in the mouse aortic vessel wall. METHODS AND RESULTS: C57BL/6 wild-type or IKKepsilon knockout mice bred into the ApoE knockout genetic background were divided into 4 groups: (1) wild-type (WT), (2) ApoE knockout (AK), (3) IKKepsilon knockout (IK), (4) or both ApoE and IKKepsilon knockout (DK). Each group of mice were fed with a high fat diet (HFD) for 12 weeks from 8 weeks of age. Immunohistochemistry and Western blotting analysis demonstrated obvious increases in the expression of IKKepsilon in the AK group compared with the WT group, especially in the intima. Serum lipid levels were significantly higher in the AK and DK groups than in the other two groups. Staining with hematoxylin-eosin and Oil Red, as well as scanning electron microscopy revealed less severe atherosclerotic lesions in the DK group than in the AK group. Immunofluorescence and Western blot analysis demonstrated obvious increases in the expression of NF kappaB pathway components and downstream factors in the AK group, especially in the intima, while these increases were blocked in the DK group. CONCLUSION: The knockout of IKKepsilon prevented significant atherosclerosis lesions in the mouse aorta from in both wild-type and ApoE knockout mice fed a HFD, suggesting that IKKepsilon may play a vital role in HFD-induced atherosclerosis and would be an important target for the treatment of atherosclerosis. PMID- 23741429 TI - Filling the gap 115 years after Ronald Ross: the distribution of the Anopheles coluzzii and Anopheles gambiae s.s from Freetown and Monrovia, West Africa. AB - It was in Freetown, Sierra Leone, that the malaria mosquito Anopheles coastalis, now known as Anopheles gambiae, was first discovered as the vector of malaria, in 1899. That discovery led to a pioneering vector research in Sierra Leone and neighbouring Liberia, where mosquito species were extensively characterized. Unfortunately, the decade long civil conflicts of the 1990s, in both countries, resulted in a stagnation of the once vibrant research on disease vectors. This paper attempts to fill in some of the gaps on what is now known of the distribution of the sibling species of the An. gambiae complex, and especially the An. coluzzii and An. gambiae s.s, formerly known as the An. gambiae molecular M and S forms respectively, in the cities of Freetown and Monrovia. PMID- 23741428 TI - 2-octynoic acid inhibits hepatitis C virus infection through activation of AMP activated protein kinase. AB - Many chronic hepatitis C virus (HCV)-infected patients with current therapy do not clear the virus. It is necessary to find novel treatments. The effect of 2 octynoic acid (2-OA) on HCV infection in human hepatocytes was examined. The mechanism of 2-OA antiviral activity was explored. Our data showed that 2-OA abrogated lipid accumulation in HCV replicon cells and virus-infected hepatocytes. It suppressed HCV RNA replication and infectious virus production with no cytotoxicity to the host cells. 2-OA did not affect hepatitis B virus replication in HepG2.2.15 cells derived from HepG2 cells transfected with full genome of HBV. Further study demonstrated that 2-OA activated AMP-activated protein kinase (AMPK) and inhibited acetyl-CoA carboxylase in viral-infected cells. Compound C, a specific inhibitor of AMPK, inhibited AMPK activity and reversed the reduction of intracellular lipid accumulation and the antiviral effect of 2-OA. Knockdown of AMPK expression by RNA interference abolished the activation of AMPK by 2-OA and blocked 2-OA antiviral activity. Interestingly, 2 OA induced interferon-stimulated genes (ISGs) and inhibited microRNA-122 (miR 122) expression in virus-infected hepatocytes. MiR-122 overexpression reversed the antiviral effect of 2-OA. Furthermore, knockdown of AMPK expression reversed both the induction of ISGs and suppression of miR-122 by 2-OA, implying that activated AMPK induces the intracellular innate response through the induction of ISGs and inhibiting miR-122 expression. 2-OA inhibits HCV infection through regulation of innate immune response by activated AMPK. These findings reveal a novel mechanism by which active AMPK inhibits HCV infection. 2-OA and its derivatives hold promise for novel drug development for chronic hepatitis C. PMID- 23741430 TI - Metal-macrofauna interactions determine microbial community structure and function in copper contaminated sediments. AB - Copper is essential for healthy cellular functioning, but this heavy metal quickly becomes toxic when supply exceeds demand. Marine sediments receive widespread and increasing levels of copper contamination from antifouling paints owing to the 2008 global ban of organotin-based products. The toxicity of copper will increase in the coming years as seawater pH decreases and temperature increases. We used a factorial mesocosm experiment to investigate how increasing sediment copper concentrations and the presence of a cosmopolitan bioturbating amphipod, Corophium volutator, affected a range of ecosystem functions in a soft sediment microbial community. The effects of copper on benthic nutrient release, bacterial biomass, microbial community structure and the isotopic composition of individual microbial membrane [phospholipid] fatty acids (PLFAs) all differed in the presence of C. volutator. Our data consistently demonstrate that copper contamination of global waterways will have pervasive effects on the metabolic functioning of benthic communities that cannot be predicted from copper concentrations alone; impacts will depend upon the resident macrofauna and their capacity for bioturbation. This finding poses a major challenge for those attempting to manage the impacts of copper contamination on ecosystem services, e.g. carbon and nutrient cycling, across different habitats. Our work also highlights the paucity of information on the processes that result in isotopic fractionation in natural marine microbial communities. We conclude that the assimilative capacity of benthic microbes will become progressively impaired as copper concentrations increase. These effects will, to an extent, be mitigated by the presence of bioturbating animals and possibly other processes that increase the influx of oxygenated seawater into the sediments. Our findings support the move towards an ecosystem approach for environmental management. PMID- 23741431 TI - ApoE4 induces synaptic and ERG impairments in the retina of young targeted replacement apoE4 mice. AB - The vertebrate retina, which is part of the central nervous system, is a window into the brain. The present study investigated the extent to which the retina can be used as a model for studying the pathological effects of apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD). Immunohistochemical studies of retinas from young (4 months old) apoE4-targeted replacement mice and from corresponding mice which express the AD benign apoE3 allele, revealed that the density of the perikarya of the different classes of retinal neurons was not affected by apoE4. In contrast, the synaptic density of the retinal synaptic layers, which was assessed immunohistochemically and by immunoblot experiments, was significantly lower in the apoE4 than in the apoE3 mice. This was associated with reduced levels of the presynaptic vesicular glutamatergic transporter, VGluT1, but not of either the GABAergic vesicular transporter, VGaT, or the cholinergic vesicular transporter, VAChT, suggesting that the glutamatergic nerve terminals are preferentially affected by apoE4. In contrast, the post synaptic scaffold proteins PSD-95 and Gephyrin, which reside in excitatory and inhibitory synapses, respectively, were both elevated, and their ratio was not affected by apoE4. Electroretinogram (ERG) recordings revealed significant attenuation of mixed rod-cone responses in dark-adapted eyes of apoE4 mice. These findings suggest that the reduced ERG response in the apoE4 mice may be related to the observed decrease in the retinal nerve terminals and that the retina could be used as a novel model for non-invasive monitoring of the effects of apoE4 on the CNS. PMID- 23741432 TI - Identification of diverse lipid droplet targeting motifs in the PNPLA family of triglyceride lipases. AB - Members of the Patatin-like Phospholipase Domain containing Protein A (PNPLA) family play key roles in triglyceride hydrolysis, energy metabolism, and lipid droplet (LD) homoeostasis. Here we report the identification of two distinct LD targeting motifs (LTM) for PNPLA family members. Transient transfection of truncated versions of human adipose triglyceride lipase (ATGL, also known as PNPLA2), PNPLA3/adiponutrin, or PNPLA5 (GS2-like) fused to GFP revealed that the C-terminal third of these proteins contains sequences that are sufficient for targeting to LDs. Furthermore, fusing the C-termini of PNPLA3 or PNPLA5 confers LD localization to PNPLA4, which is otherwise cytoplasmic. Analyses of additional mutants in ATGL, PNPLA5, and Brummer Lipase, the Drosophila homolog of mammalian ATGL, identified two different types of LTMs. The first type, in PNPLA5 and Brummer lipase, is a set of loosely conserved basic residues, while the second type, in ATGL, is contained within a stretch of hydrophobic residues. These results show that even closely related members of the PNPLA family employ different molecular motifs to associate with LDs. PMID- 23741433 TI - Altered composition of bone as triggered by irradiation facilitates the rapid erosion of the matrix by both cellular and physicochemical processes. AB - Radiation rapidly undermines trabecular architecture, a destructive process which proceeds despite a devastated cell population. In addition to the 'biologically orchestrated' resorption of the matrix by osteoclasts, physicochemical processes enabled by a damaged matrix may contribute to the rapid erosion of bone quality. 8w male C57BL/6 mice exposed to 5 Gy of Cs(137) gamma-irradiation were compared to age-matched control at 2d, 10d, or 8w following exposure. By 10d, irradiation had led to significant loss of trabecular bone volume fraction. Assessed by reflection-based Fourier transform infrared imaging (FTIRI), chemical composition of the irradiated matrix indicated that mineralization had diminished at 2d by 4.3+/-4.8%, and at 10d by -5.8+/-3.2%. These data suggest that irradiation facilitates the dissolution of the matrix through a change in the material itself, a conclusion supported by a 13.7+/-4.5% increase in the elastic modulus as measured by nanoindentation. The decline in viable cells within the marrow of irradiated mice at 2d implies that the immediate collapse of bone quality and inherent increased risk of fracture is not solely a result of an overly-active biologic process, but one fostered by alterations in the material matrix that predisposes the material to erosion. PMID- 23741434 TI - Sorafenib inhibits epithelial-mesenchymal transition through an epigenetic-based mechanism in human lung epithelial cells. AB - The epithelial to mesenchymal transition (EMT) has been well recognized for many decades as an essential early step in the progression of primary tumors towards metastases. Widespread epigenetic reprogramming of DNA and histone modifications tightly regulates gene expression and cellular activity during carcinogenesis, and epigenetic therapy has been developed to design efficient strategies for cancer treatment. As the first oral agent approved for the clinical treatment of cancer, sorafenib has significant inhibitory effects on tumor growth and EMT. However, a detailed understanding of the underlying epigenetic mechanism remains elusive. In this manuscript, we performed a ChIP-seq assay to evaluate the activity of sorafenib on the genome-wide profiling of histone modifications. We demonstrate that sorafenib largely reverses the changes in histone modifications that occur during EMT in A549 alveolar epithelial cells. Sorafenib also significantly reduces the coordinated epigenetic switching of critical EMT associated genes in accordance with their expression levels. Furthermore, we show that sorafenib potentiates histone acetylation by regulating the expression levels of histone-modifying enzymes. Collectively, these findings provide the first evidence that sorafenib inhibits the EMT process through an epigenetic mechanism, which holds enormous promise for identifying novel epigenetic candidate diagnostic markers and drug targets for the treatment of human malignancies. PMID- 23741435 TI - Age-associated metabolic and morphologic changes in mitochondria of individual mouse and hamster oocytes. AB - BACKGROUND: In human oocytes, as in other mammalian ova, there is a significant variation in the pregnancy potential, with approximately 20% of oocyte-sperm meetings resulting in pregnancies. This frequency of successful fertilization decreases as the oocytes age. This low proportion of fruitful couplings appears to be influenced by changes in mitochondrial structure and function. In this study, we have examined mitochondrial biogenesis in both hamster (Mesocricetus auratus ) and mouse (Mus musculus) ova as models for understanding the effects of aging on mitochondrial structure and energy production within the mammalian oocyte. METHODOLOGY/PRINCIPAL FINDINGS: Individual metaphase II oocytes from a total of 25 young and old mice and hamsters were collected from ovarian follicles after hormone stimulation and prepared for biochemical or structural analysis. Adenosine triphosphate levels and mitochondrial DNA number were determined within individual oocytes from young and old animals. In aged hamsters, oocyte adenosine triphosphate levels and mitochondrial DNA molecules were reduced 35.4% and 51.8%, respectively. Reductions of 38.4% and 44% in adenosine triphosphate and mitochondrial genomes, respectively, were also seen in aged mouse oocytes. Transmission electron microscopic (TEM) analysis showed that aged rodent oocytes had significant alterations in mitochondrial and cytoplasmic lamellae structure. CONCLUSIONS/SIGNIFICANCE: In both mice and hamsters, decreased adenosine triphosphate in aged oocytes is correlated with a similar decrease in mtDNA molecules and number of mitochondria. Mitochondria in mice and hamsters undergo significant morphological change with aging including mitochondrial vacuolization, cristae alterations, and changes in cytoplasmic lamellae. PMID- 23741436 TI - Dominance of orientation over frequency in the perception of 3-D slant and shape. AB - In images of textured three-dimensional surfaces, pattern changes can be characterized as changes in orientation and spatial frequency, features for which neurons in primary visual cortex are classically selective. Previously, we have demonstrated that correct 3-D shape perception is contingent on the visibility of orientation flows that run parallel to the surface curvature. We sought to determine the relative contributions of orientation modulations (OMs) and frequency modulations (FMs) for the detection of slant and shape from 3-D surfaces. Results show that 1) when OM and FM indicate inconsistent degrees of surface slant or curvature, observer responses were consistent with the slant or curvature specified by OM even if the FM indicated a slant or curvature in the opposite direction to the same degree. 2) For slanted surfaces, OM information dictates slant perception at both shallow and steep slants while FM information is effective only for steep slants. Together these results point to a dominant role of OM information in the perception of 3-D slant and shape. PMID- 23741437 TI - Low rates of mother-to-child HIV transmission in a routine programmatic setting in Lilongwe, Malawi. AB - BACKGROUND: The Tingathe program utilizes community health workers to improve prevention of mother-to-child transmission (PMTCT) service delivery. We evaluated the impact of antiretroviral (ARV) regimen and maternal CD4+ count on HIV transmission within the Tingathe program in Lilongwe, Malawi. METHODS: We reviewed clinical records of 1088 mother-infant pairs enrolled from March 2009 to March 2011 who completed follow-up to first DNA PCR. Eligibility for antiretroviral treatment (ART) was determined by CD4+ cell count (CD4+) for women not yet on ART. ART-eligible women initiated stavudine-lamivudine-nevirapine. Early ART was defined as ART for >=14 weeks prior to delivery. For women ineligible for ART, optimal ARV prophylaxis was maternal AZT >=6 weeks+sdNVP, and infant sdNVP+AZT for 1 week. HIV transmission rates were determined for ARV regimens, and factors associated with vertical transmission were identified using bivariate logistic regression. RESULTS: Transmission rate at first PCR was 4.1%. Pairs receiving suboptimal ARV prophylaxis were more likely to transmit HIV (10.3%, 95% CI, 5.5-18.1%). ART was associated with reduced transmission (1.4%, 95% CI, 0.6-3.0%), with early ART associated with decreased transmission (no transmission), compared to all other treatment groups (p = 0.001). No association was detected between transmission and CD4+ categories (p = 0.337), trimester of pregnancy at enrollment (p = 0.100), or maternal age (p = 0.164). CONCLUSION: Low rates of MTCT of HIV are possible in resource-constrained settings under routine programmatic conditions. No transmissions were observed among women on ART for more than 14 weeks prior to delivery. PMID- 23741438 TI - Linguistic grammar learning and DRD2-TAQ-IA polymorphism. AB - As research into the neurobiology of language has focused primarily on the systems level, fewer studies have examined the link between molecular genetics and normal variations in language functions. Because the ability to learn a language varies in adults and our genetic codes also vary, research linking the two provides a unique window into the molecular neurobiology of language. We consider a candidate association between the dopamine receptor D2 gene (DRD2) and linguistic grammar learning. DRD2-TAQ-IA polymorphism (rs1800497) is associated with dopamine receptor D2 distribution and dopamine impact in the human striatum, such that A1 allele carriers show reduction in D2 receptor binding relative to carriers who are homozygous for the A2 allele. The individual differences in grammatical rule learning that are particularly prevalent in adulthood are also associated with striatal function and its role in domain-general procedural memory. Therefore, we reasoned that procedurally-based grammar learning could be associated with DRD2-TAQ-IA polymorphism. Here, English-speaking adults learned artificial concatenative and analogical grammars, which have been respectively associated with procedural and declarative memory. Language learning capabilities were tested while learners' neural hemodynamic responses were simultaneously measured by fMRI. Behavioral learning and brain activation data were subsequently compared with the learners' DRD2 (rs1800497) genotype. Learners who were homozygous for the A2 allele were better at concatenative (but not analogical) grammar learning and had higher striatal responses relative to those who have at least one A1 allele. These results provide preliminary evidence for the neurogenetic basis of normal variations in linguistic grammar learning and its link to domain-general functions. PMID- 23741439 TI - Y-chromosome analysis in Retuertas horses. AB - Several studies based on a variety of genetic markers have attempted to establish the origins of horse domestication. Thus far a discrepancy between the results of mitochondrial DNA analysis, which show high levels of diversity, and results from the Y-chromosome, with almost no genetic variability, has been identified. Most previous work on the horse Y-chromosome has focused on widespread, popular breeds or local Asian breeds. It is possible that these breeds represent a reduced set of the genetic variation present in the species. Additional genetic variation may be present in local breeds and ancient feral populations, such as the Retuertas horse in Spain. In this study we analyzed the Y-chromosome of the Retuertas horse, a feral horse population on the Iberian Peninsula that is at least several hundred years old, and whose genetic diversity and morphology suggests that it has been reproductively isolated for a long time. Data from the Retuertas horse was compared to another 11 breeds from the region (Portugal, Spain and France) or likely of Iberian origin, and then to data from 15 more breeds from around the globe. We sequenced 31 introns, Zinc finger Y-chromosomal protein (ZFY) and anonymous Y-linked fragments and genotyped 6 microsatellite loci found on the Y chromosome. We found no sequence variation among all individuals and all breeds studied. However, fifteen differences were discovered between our data set and reference sequences in GenBank. We show that these likely represent errors within the deposited sequences, and suggest that they should not be used as comparative data for future projects. PMID- 23741440 TI - Left and right ventricle late remodeling following myocardial infarction in rats. AB - BACKGROUND: The mechanisms involved in cardiac remodeling in left (LV) and right ventricles (RV) after myocardial infarction (MI) are still unclear. We assayed factors involved in collagen turnover in both ventricles following MI in rats either presenting signs of heart failure (pulmonary congestion and increased LVEDP) or not (INF-HF or INF, respectively). METHODS: MI was induced in male rats by ligation of the left coronary artery. Four weeks after MI gene expression of collagen I, connective tissue growth factor (CTGF), transforming growth factor beta (TGF-beta) and lysyl oxidase (LOX), metalloproteinase-2 (MMP2) and tissue inhibitor metalloproteinase-2 (TIMP2) as well as cardiac hemodynamic in both ventricles were evaluated. RESULTS: Ventricular dilatation, hypertrophy and an increase in interstitial fibrosis and myocyte size were observed in the RV and LV from INF-HF animals, whereas only LV dilatation and fibrosis in RV was present in INF. The LV fibrosis in INF-HF was associated with higher mRNA of collagen I, CTGF, TGF-beta and LOX expressions than in INF and SHAM animals, while MMP2/TIMP2 mRNA ratio did not change. RV fibrosis in INF and INF-HF groups was associated with an increase in LOX mRNA and a reduction in MMP2/TIMP2 ratio. CTGF mRNA was increased only in the INF-HF group. CONCLUSIONS: INF and INF-HF animals presented different patterns of remodeling in both ventricles. In the INF-HF group, fibrosis seems to be consequence of collagen production in LV, and by reductions in collagen degradation in RV of both INF and INF-HF animals. PMID- 23741442 TI - Comparative demography of skates: life-history correlates of productivity and implications for management. AB - Age-structured demographic models were constructed based on empirical estimates of longevity and maturity for five deepwater Bering Sea skates to investigate how observed differences in life history parameters affect population growth rates. Monte Carlo simulations were used to incorporate parameter uncertainty. Estimated population growth rates ranged from 1.045 to 1.129 yr(-1) and were lower than those reported for other Alaskan skates and most chondrichthyans. Population growth rates of these and other high-latitude skates increased with relative reproductive lifespan, but displayed no significant relationship with body size or depth distribution, suggesting that assemblage shifts may be difficult to predict for data-poor taxa. Elasticity analyses indicated that juvenile and adult survival had greater per-unit effects on population growth rates than did egg case survival or fecundity. Population growth rate was affected more by uncertainty in age at maturity than maximum age. The results of this study indicate that if skates are deemed to be a management concern, gear modifications or depth-specific effort controls may be effective. PMID- 23741441 TI - Expression of the growth factor progranulin in endothelial cells influences growth and development of blood vessels: a novel mouse model. AB - Progranulin is a secreted glycoprotein that regulates cell proliferation, migration and survival. It has roles in development, tumorigenesis, wound healing, neurodegeneration and inflammation. Endothelia in tumors, wounds and placenta express elevated levels of progranulin. In culture, progranulin activates endothelial proliferation and migration. This suggested that progranulin might regulate angiogenesis. It was, however, unclear how elevated endothelial progranulin levels influence vascular growth in vivo. To address this issue, we generated mice with progranulin expression targeted specifically to developing endothelial cells using a Tie2-promoter/enhancer construct. Three Tie2 Grn mouse lines were generated with varying Tie2-Grn copy number, and were called GrnLo, GrnMid, and GrnHi. All three lines showed increased mortality that correlates with Tie2-Grn copy number, with greatest mortality and lowest germline transmission in the GrnHi line. Death of the transgenic animals occurred around birth, and continued for three days after birth. Those that survived beyond day 3 survived into adulthood. Transgenic neonates that died showed vascular abnormalities of varying severity. Some exhibited bleeding into body cavities such as the pericardial space. Smaller localized hemorrhages were seen in many organs. Blood vessels were often dilated and thin-walled. To establish the development of these abnormalities, we examined mice at early (E10.5-14.5) and later (E15.5-17.5) developmental phases. Early events during vasculogenesis appear unaffected by Tie2-Grn as apparently normal primary vasculature had been established at E10.5. The earliest onset of vascular abnormality was at E15.5, with focal cerebral hemorrhage and enlarged vessels in various organs. Aberrant Tie2-Grn positive vessels showed thinning of the basement membrane and reduced investiture with mural cells. We conclude that progranulin promotes exaggerated vessel growth in vivo, with subsequent effects in the formation of the mural cell layer and weakening of vessel integrity. These results demonstrate that overexpression of progranulin in endothelial cells influences normal angiogenesis in vivo. PMID- 23741443 TI - Aspirin minimized the pro-metastasis effect of sorafenib and improved survival by up-regulating HTATIP2 in hepatocellular carcinoma. AB - BACKGROUND AIMS: We previously demonstrated the pro-metastasis effect of sorafenib in hepatocellular carcinoma (HCC), which is mediated by down-regulation of tumor suppressor HTATIP2. The aim of the present study was to determine whether aspirin minimizes this effect and improves survival. METHODS: The effects of sorafenib, aspirin, and combined sorafenib and aspirin were observed in HCCLM3 and HepG2 xenograft nude mice. Tumor growth, intrahepatic metastasis (IHM), lung metastasis, and survival were assessed. Polymerase chain reaction (PCR) array, real-time (RT)-PCR, and Western blotting were used to examine gene expression. The anti-invasion and anti-metastasis effects of aspirin were studied in HTATIP2 knockdown and HTATIP2-overexpressing HCC cell lines. The molecular mechanism of HTATIP2 regulation by aspirin was explored. RESULTS: Aspirin suppressed the pro invasion and pro-metastasis effects of sorafenib in HCC and up-regulated HTATIP2 expression. Aspirin did not inhibit the proliferation of HCC cells, but it decreased the invasiveness of HCC with lower expression of HTATIP2 and increased expression of a set of markers, indicating a mesenchymal-to-epithelial transition in tumor cells. The up-regulation of HTATPI2 expression by aspirin is most likely mediated through inhibition of cyclooxygenase (COX) 2 expression. CONCLUSIONS: Aspirin minimized the pro-metastasis effect of sorafenib by up-regulating the tumor suppressor HTATIP2; this mechanism is mediated through inhibition of COX2. PMID- 23741444 TI - Prospective ECG-triggered coronary CT angiography: clinical value of noise-based tube current reduction method with iterative reconstruction. AB - OBJECTIVES: To evaluate the clinical value of noise-based tube current reduction method with iterative reconstruction for obtaining consistent image quality with dose optimization in prospective electrocardiogram (ECG)-triggered coronary CT angiography (CCTA). MATERIALS AND METHODS: We performed a prospective randomized study evaluating 338 patients undergoing CCTA with prospective ECG-triggering. Patients were randomly assigned to fixed tube current with filtered back projection (Group 1, n = 113), noise-based tube current with filtered back projection (Group 2, n = 109) or with iterative reconstruction (Group 3, n = 116). Tube voltage was fixed at 120 kV. Qualitative image quality was rated on a 5-point scale (1 = impaired, to 5 = excellent, with 3-5 defined as diagnostic). Image noise and signal intensity were measured; signal-to-noise ratio was calculated; radiation dose parameters were recorded. Statistical analyses included one-way analysis of variance, chi-square test, Kruskal-Wallis test and multivariable linear regression. RESULTS: Image noise was maintained at the target value of 35HU with small interquartile range for Group 2 (35.00-35.03HU) and Group 3 (34.99-35.02HU), while from 28.73 to 37.87HU for Group 1. All images in the three groups were acceptable for diagnosis. A relative 20% and 51% reduction in effective dose for Group 2 (2.9 mSv) and Group 3 (1.8 mSv) were achieved compared with Group 1 (3.7 mSv). After adjustment for scan characteristics, iterative reconstruction was associated with 26% reduction in effective dose. CONCLUSION: Noise-based tube current reduction method with iterative reconstruction maintains image noise precisely at the desired level and achieves consistent image quality. Meanwhile, effective dose can be reduced by more than 50%. PMID- 23741445 TI - Biosynthesis of sesquiterpene lactones in pyrethrum (Tanacetum cinerariifolium). AB - The daisy-like flowers of pyrethrum (Tanacetum cinerariifolium) are used to extract pyrethrins, a botanical insecticide with a long history of safe and effective use. Pyrethrum flowers also contain other potential defense compounds, particularly sesquiterpene lactones (STLs), which represent problematic allergenic residues in the extracts that are removed by the pyrethrum industry. The STLs are stored in glandular trichomes present on the pyrethrum achenes, and have been shown to be active against herbivores, micro-organisms and in the below ground competition with other plants. Despite these reported bioactivities and industrial significance, the biosynthetic origin of pyrethrum sesquiterpene lactones remains unknown. In the present study, we show that germacratrien-12-oic acid is most likely the central precursor for all sesquiterpene lactones present in pyrethrum. The formation of the lactone ring depends on the regio- (C6 or C8) and stereo-selective (alpha or beta) hydroxylation of germacratrien-12-oic acid. Candidate genes implicated in three committed steps leading from farnesyl diphosphate to STL and other oxygenated derivatives of germacratrien-12-oic acid were retrieved from a pyrethrum trichome EST library, cloned, and characterized in yeast and in planta. The diversity and distribution of sesquiterpene lactones in different tissues and the correlation with the expression of these genes are shown and discussed. PMID- 23741446 TI - Cholecalciferol (vitamin D3) improves myelination and recovery after nerve injury. AB - Previously, we demonstrated i) that ergocalciferol (vitamin D2) increases axon diameter and potentiates nerve regeneration in a rat model of transected peripheral nerve and ii) that cholecalciferol (vitamin D3) improves breathing and hyper-reflexia in a rat model of paraplegia. However, before bringing this molecule to the clinic, it was of prime importance i) to assess which form - ergocalciferol versus cholecalciferol - and which dose were the most efficient and ii) to identify the molecular pathways activated by this pleiotropic molecule. The rat left peroneal nerve was cut out on a length of 10 mm and autografted in an inverted position. Animals were treated with either cholecalciferol or ergocalciferol, at the dose of 100 or 500 IU/kg/day, or excipient (Vehicle), and compared to unlesioned rats (Control). Functional recovery of hindlimb was measured weekly, during 12 weeks, using the peroneal functional index. Ventilatory, motor and sensitive responses of the regenerated axons were recorded and histological analysis was performed. In parallel, to identify the genes regulated by vitamin D in dorsal root ganglia and/or Schwann cells, we performed an in vitro transcriptome study. We observed that cholecalciferol is more efficient than ergocalciferol and, when delivered at a high dose (500 IU/kg/day), cholecalciferol induces a significant locomotor and electrophysiological recovery. We also demonstrated that cholecalciferol increases i) the number of preserved or newly formed axons in the proximal end, ii) the mean axon diameter in the distal end, and iii) neurite myelination in both distal and proximal ends. Finally, we found a modified expression of several genes involved in axogenesis and myelination, after 24 hours of vitamin supplementation. Our study is the first to demonstrate that vitamin D acts on myelination via the activation of several myelin-associated genes. It paves the way for future randomised controlled clinical trials for peripheral nerve or spinal cord repair. PMID- 23741447 TI - Identifying hypoxia in a newborn piglet model using urinary NMR metabolomic profiling. AB - Establishing the severity of hypoxic insult during the delivery of a neonate is key step in the determining the type of therapy administered. While successful therapy is present, current methods for assessing hypoxic injuries in the neonate are limited. Urine Nuclear Magnetic Resonance (NMR) metabolomics allows for the rapid non-invasive assessment of a multitude breakdown products of physiological processes. In a newborn piglet model of hypoxia, we used NMR spectroscopy to determine the levels of metabolites in urine samples, which were correlated with physiological measurements. Using PLS-DA analysis, we identified 13 urinary metabolites that differentiated hypoxic versus nonhypoxic animals (1 methylnicotinamide, 2-oxoglutarate, alanine, asparagine, betaine, citrate, creatine, fumarate, hippurate, lactate, N-acetylglycine, N-carbamoyl-beta alanine, and valine). Using this metabolomic profile, we then were able to blindly identify hypoxic animals correctly 84% of the time compared to nonhypoxic controls. This was better than using physiologic measures alone. Metabolomic profiling of urine has potential for identifying neonates that have undergone episodes of hypoxia. PMID- 23741448 TI - Meningococcal serogroup A, C, W135 and Y conjugated vaccine: a cost-effectiveness analysis in the Netherlands. AB - BACKGROUND: In 2002, vaccination with a serogroup C meningococcal conjugate vaccine (MenC) was introduced in the Netherlands for all children aged 14 months. Despite its success, herd immunity may wane over time. Recently, a serogroup A,C,W135,Y meningococcal conjugate vaccine (MenACWY) was licensed for use in subjects of 12 months of age and above. OBJECTIVES: To evaluate the cost effectiveness of meningococcal vaccination at 14 months and an additional vaccination at the age of 12 years, both with the MenACWY vaccine. METHODS: A decision analysis cohort model, with 185,000 Dutch newborns, was used to evaluate the cost-effectiveness of different immunization strategies. For strategies including a vaccination at 12 years of age, an additional cohort with adolescents aged 12 years was followed. The incremental cost-effectiveness ratio (ICER) was estimated for the current disease incidence and for a scenario when herd immunity is lost. RESULTS: Vaccination with MenACWY at 14 months is cost-saving. Vaccinating with MenACWY at 14 months and at 12 years would prevent 7 additional cases of meningococcal serogroup A,C,W135,Y disease in the birth cohort and adolescent cohort followed for 99 years compared to the current vaccine schedule of a single vaccination with MenC at 14 months. With the current incidence, this strategy resulted in an ICER of ?635,334 per quality adjusted life year. When serogroup C disease incidence returns to pre-vaccination levels due to a loss of vaccine-induced herd-immunity, vaccination with MenACWY at 14 months and at 12 years would be cost-saving. CONCLUSIONS: Routine vaccination with MenACWY is cost saving. With the current epidemiology, a booster-dose with MenACWY is not likely cost-effective. When herd immunity is lost, a booster-dose has the potential of being cost-effective. A dynamic model should be developed for more precise estimation of the cost-effectiveness of the prevention of disappearance of herd immunity. PMID- 23741450 TI - The global economic impact of manta ray watching tourism. AB - As manta rays face increased threats from targeted and bycatch fisheries, manta ray watching tourism, if managed properly, may present an attractive economic alternative to consumptive use of these species. Both species in the genus Manta (Manta alfredi and Manta birostris) are classified by the International Union for the Conservation of Nature Red List as species Vulnerable to extinction in the wild, and are considered unsustainable as fisheries resources due to their conservative life history characteristics, which considerably reduce their ability to recover population numbers when depleted. Utilising dive operator surveys, Internet research, and a literature review, this study provides the first global estimate of the direct economic impact of manta ray watching tourism and examines the potential socio-economic benefits of non-consumptive manta ray watching operations relative to consumptive use of manta rays as a fishery resource. In the 23 countries in which manta ray watching operations meeting our criteria were identified, we estimated direct revenue to dive operators from manta ray dives and snorkels at over US$73 million annually and direct economic impact, including associated tourism expenditures, of US$140 million annually. Ten countries account for almost 93% of the global revenue estimate, specifically Japan, Indonesia, the Maldives, Mozambique, Thailand, Australia, Mexico, United States, Federated States of Micronesia and Palau. In many of the areas where directed fisheries for manta rays are known to occur, these activities overlap with manta ray tourism sites or the migratory range of the mantas on which these sites depend, and are likely to be unsustainable and detrimental to manta ray watching tourism. PMID- 23741449 TI - DDX5 facilitates HIV-1 replication as a cellular co-factor of Rev. AB - HIV-1 Rev plays an important role in the late phase of HIV-1 replication, which facilitates export of unspliced viral mRNAs from the nucleus to cytoplasm in infected cells. Recent studies have shown that DDX1 and DDX3 are co-factors of Rev for the export of HIV-1 transcripts. In this report, we have demonstrated that DDX5 (p68), which is a multifunctional DEAD-box RNA helicase, functions as a new cellular co-factor of HIV-1 Rev. We found that DDX5 affects Rev function through the Rev-RRE axis and subsequently enhances HIV-1 replication. Confocal microscopy and co-immunoprecipitation analysis indicated that DDX5 binds to Rev and this interaction is largely dependent on RNA. If the DEAD-box motif of DDX5 is mutated, DDX5 loses almost all of its ability to bind to Rev, indicating that the DEAD-box motif of DDX5 is required for the interaction between DDX5 and Rev. Our data indicate that interference of DDX5-Rev interaction could reduce HIV-1 replication and potentially provide a new molecular target for anti-HIV-1 therapeutics. PMID- 23741451 TI - Pharmacological characterization of a 5-HT1-type serotonin receptor in the red flour beetle, Tribolium castaneum. AB - Serotonin (5-hydroxytryptamine, 5-HT) is known for its key role in modulating diverse physiological processes and behaviors by binding various 5-HT receptors. However, a lack of pharmacological knowledge impedes studies on invertebrate 5-HT receptors. Moreover, pharmacological information is urgently needed in order to establish a reliable classification system for invertebrate 5-HT receptors. In this study we report on the molecular cloning and pharmacological characterization of a 5-HT1 receptor from the red flour beetle, Tribolium castaneum (Trica5-HT1). The Trica5-HT1 receptor encoding cDNA shows considerable sequence similarity with members of the 5-HT1 receptor class. Real time PCR showed high expression in the brain (without optic lobes) and the optic lobes, consistent with the role of 5-HT as neurotransmitter. Activation of Trica5-HT1 in mammalian cells decreased NKH-477-stimulated cyclic AMP levels in a dose dependent manner, but did not influence intracellular Ca(2+) signaling. We studied the pharmacological profile of the 5-HT1 receptor and demonstrated that alpha-methylserotonin, 5-methoxytryptamine and 5-carboxamidotryptamine acted as agonists. Prazosin, methiothepin and methysergide were the most potent antagonists and showed competitive inhibition in presence of 5-HT. This study offers important information on a 5-HT1 receptor from T. castaneum facilitating functional research of 5-HT receptors in insects and other invertebrates. The pharmacological profiles may contribute to establish a reliable classification scheme for invertebrate 5-HT receptors. PMID- 23741452 TI - Trophic structure and mercury biomagnification in tropical fish assemblages, Itenez River, Bolivia. AB - We examined mercury concentrations in three fish assemblages to estimate biomagnification rates in the Itenez main river, affected by anthropogenic activities, and two unperturbed rivers from the Itenez basin, Bolivian Amazon. Rivers presented low to moderate water mercury concentrations (from 1.25 ng L(-1) to 2.96 ng L(-1)) and natural differences in terms of sediment load. Mercury biomagnification rates were confronted to trophic structure depicted by carbon and nitrogen stable isotopes composition (delta(15)N; delta(13)C) of primary trophic sources, invertebrates and fishes. Results showed a slight fish contamination in the Itenez River compared to the unperturbed rivers, with higher mercury concentrations in piscivore species (0.15 ug g(-1) vs. 0.11 ug g(-1) in the unperturbed rivers) and a higher biomagnification rate. Trophic structure analysis showed that the higher biomagnification rate in the Itenez River could not be attributed to a longer food chain. Nevertheless, it revealed for the Itenez River a higher contribution of periphyton to the diet of the primary consumers fish species; and more negative delta(13)C values for primary trophic sources, invertebrates and fishes that could indicate a higher contribution of methanotrophic bacteria. These two factors may enhance methylation and methyl mercury transfer in the food web and thus, alternatively or complementarily to the impact of the anthropogenic activities, may explain mercury differences observed in fishes from the Itenez River in comparison to the two other rivers. PMID- 23741453 TI - Retinoic acid-activated Ndrg1a represses Wnt/beta-catenin signaling to allow Xenopus pancreas, oesophagus, stomach, and duodenum specification. AB - How cells integrate multiple patterning signals to achieve early endoderm regionalization remains largely unknown. Between gastrulation and neurulation, retinoic acid (RA) signaling is required, while Wnt/beta-catenin signaling has to be repressed for the specification of the pancreas, oesophagus, stomach, and duodenum primordia in Xenopus embryos. In attempt to screen for RA regulated genes in Xenopus endoderm, we identified a direct RA target gene, N-myc downstream regulated gene 1a (ndrg1a) that showed expression early in the archenteron roof endoderm and late in the developing pancreas, oesophagus, stomach, and duodenum. Both antisense morpholino oligonucleotide mediated knockdown of ndrg1a in Xenopus laevis and the transcription activator-like effector nucleases (TALEN) mediated disruption of ndrg1 in Xenopus tropicalis demonstrate that like RA signaling, Ndrg1a is specifically required for the specification of Xenopus pancreas, oesophagus, stomach, and duodenum primordia. Immunofluorescence data suggest that RA-activated Ndrg1a suppresses Wnt/beta catenin signaling in Xenopus archenteron roof endoderm cells. Blocking Wnt/beta catenin signaling rescued Ndrg1a knockdown phenotype. Furthermore, overexpression of the putative Wnt/beta-catenin target gene Atf3 phenocopied knockdown of Ndrg1a or inhibition of RA signaling, while Atf3 knockdown can rescue Ndrg1a knockdown phenotype. Lastly, the pancreas/stomach/duodenum transcription factor Pdx1 was able to rescue Atf3 overexpression or Ndrg1a knockdown phenotype. Together, we conclude that RA activated Ndrg1a represses Wnt/beta-catenin signaling to allow the specification of pancreas, oesophagus, stomach, and duodenum progenitor cells in Xenopus embryos. PMID- 23741454 TI - Use of a four-tiered graph to parse the factors leading to phenotypic clustering in bacteria: a case study based on samples from the Aletsch Glacier. AB - An understanding of bacterial diversity and evolution in any environment requires knowledge of phenotypic diversity. In this study, the underlying factors leading to phenotypic clustering were analyzed and interpreted using a novel approach based on a four-tiered graph. Bacterial isolates were organized into equivalence classes based on their phenotypic profile. Likewise, phenotypes were organized in equivalence classes based on the bacteria that manifest them. The linking of these equivalence classes in a four-tiered graph allowed for a quick visual identification of the phenotypic measurements leading to the clustering patterns deduced from principal component analyses. For evaluation of the method, we investigated phenotypic variation in enzyme production and carbon assimilation of members of the genera Pseudomonas and Serratia, isolated from the Aletsch Glacier in Switzerland. The analysis indicates that the genera isolated produce at least six common enzymes and can exploit a wide range of carbon resources, though some specialist species within the pseudomonads were also observed. We further found that pairwise distances between enzyme profiles strongly correlate with distances based on carbon profiles. However, phenotypic distances weakly correlate with phylogenetic distances. The method developed in this study facilitates a more comprehensive understanding of phenotypic clustering than what would be deduced from principal component analysis alone. PMID- 23741455 TI - Toll-like receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-fat diet. AB - The purpose of this study was to investigate whether toll-like receptor 4 (TLR4) is implicated in the development of endoplasmic reticulum stress (ER stress) observed after a high-fat diet (HFD) in liver, skeletal muscle and adipose tissue. TLR4(-/-) and C57BL/6J wild-type mice (WT) were fed with chow or HFD (45% calories from fat) during 18 weeks. An oral glucose tolerance-test was performed. The animals were sacrificed in a fasted state and the tissues were removed. TLR4 deletion protected from body weight gain and glucose intolerance induced by HFD whereas energy intake was higher in transgenic mice suggesting larger energy expenditure. HFD induced an ER stress in skeletal muscle, liver and adipose tissue of WT mice as assessed by BiP, CHOP, spliced and unspliced XBP1 and phospho-eIF2alpha. TLR4(-/-) mice were protected against HFD-induced ER stress. Then, we investigated the main signaling downstream of TLR4 namely the NF-kappaB pathway, expecting to identify the mechanism by which TLR4 is able to activate ER stress. The mRNA levels of cytokines regulated by NF-kappaB namely TNFalpha, IL 1beta and IL-6, were not changed after HFD and phospho-IkappaB-alpha (ser 32) was not changed. Our results indicate that TLR4 is essential for the development of ER stress related to HFD. Nevertheless, the NFkappa-B pathway does not seem to be directly implicated. The reduced fat storage in TLR4(-/-) mice could explain the absence of an ER stress after HFD. PMID- 23741456 TI - Degradation of phytate by the 6-phytase from Hafnia alvei: a combined structural and solution study. AB - Phytases hydrolyse phytate (myo-inositol hexakisphosphate), the principal form of phosphate stored in plant seeds to produce phosphate and lower phosphorylated myo inositols. They are used extensively in the feed industry, and have been characterised biochemically and structurally with a number of structures in the PDB. They are divided into four distinct families: histidine acid phosphatases (HAP), beta-propeller phytases, cysteine phosphatases and purple acid phosphatases and also split into three enzyme classes, the 3-, 5- and 6-phytases, depending on the position of the first phosphate in the inositol ring to be removed. We report identification, cloning, purification and 3D structures of 6 phytases from two bacteria, Hafnia alvei and Yersinia kristensenii, together with their pH optima, thermal stability, and degradation profiles for phytate. An important result is the structure of the H. alvei enzyme in complex with the substrate analogue myo-inositol hexakissulphate. In contrast to the only previous structure of a ligand-bound 6-phytase, where the 3-phosphate was unexpectedly in the catalytic site, in the H. alvei complex the expected scissile 6-phosphate (sulphate in the inhibitor) is placed in the catalytic site. PMID- 23741457 TI - Conditional inactivation of p53 in mouse ovarian surface epithelium does not alter MIS driven Smad2-dominant negative epithelium-lined inclusion cysts or teratomas. AB - Epithelial ovarian cancer is the most lethal gynecological malignancy among US women. The etiology of this disease, although poorly understood, may involve the ovarian surface epithelium or the epithelium of the fallopian tube fimbriae as the progenitor cell. Disruptions in the transforming growth factor beta (TGFbeta) pathway and p53 are frequently found in chemotherapy-resistant serous ovarian tumors. Transgenic mice expressing a dominant negative form of Smad2 (Smad2DN), a downstream transcription factor of the TGFbeta signaling pathway, targeted to tissues of the reproductive tract were created on a FVB background. These mice developed epithelium-lined inclusion cysts, a potential precursor lesion to ovarian cancer, which morphologically resembled oviductal epithelium but exhibited protein expression more closely resembling the ovarian surface epithelium. An additional genetic "hit" of p53 deletion was predicted to result in ovarian tumors. Tissue specific deletion of p53 in the ovaries and oviducts alone was attempted through intrabursal or intraoviductal injection of Cre recombinase expressing adenovirus (AdCreGFP) into p53 (flox/flox) mice. Ovarian bursal cysts were detected in some mice 6 months after intrabursal injection. No pathological abnormalities were detected in mice with intraoviductal injections, which may be related to decreased infectivity of the oviductal epithelium with adenovirus as compared to the ovarian surface epithelium. Bitransgenic mice, expressing both the Smad2DN transgene and p53 (flox/flox), were then exposed to AdCreGFP in the bursa and oviductal lumen. These mice did not develop any additional phenotypes. Exposure to AdCreGFP is not an effective methodology for conditional deletion of floxed genes in oviductal epithelium and tissue specific promoters should be employed in future mouse models of the disease. In addition, a novel phenotype was observed in mice with high expression of the Smad2DN transgene as validated through qPCR analysis, characterized by teratoma-like lesions implicating Smad signaling in teratoma development. PMID- 23741459 TI - Severe impact and subsequent recovery of a coral assemblage following the 1997-8 El Nino event: a 17-year study from Bahia, Brazil. AB - The coral reefs of northern Bahia evolved in isolation from other Atlantic systems and under conditions of high environmental stress, particularly high turbidity. We have monitored the scleractinian assemblage of four shallow bank reefs (Praia do Forte, Itacimirim, Guarajuba and Abai) annually for 17 years since 1995, collecting quantitative data on diversity and density of coral colonies. As the sampling period included the 1997-8 El Nino event, the most severe on record, for the first time these results allow a quantitative assessment of the long-term impact of this major environmental stressor on such a coral assemblage. After El Nino, most species showed significantly reduced densities of colonies, this decline occurring for the subsequent two years without evidence of any new settlement until 2001. From 2000 to 2007 the species Porites astreoides went unrecorded. Recovery was slow, and multivariate analysis revealed that assemblages had not returned to the pre-El Nino state until 2011. It therefore took 13 years for full recovery of the coral assemblage to occur, which has consequences for reef systems if such El-Nino events become more frequent in the future. PMID- 23741460 TI - Preclinical evaluation of invariant natural killer T cells in the 5T33 multiple myeloma model. AB - Immunomodulators have been used in recent years to reactivate host anti-tumor immunity in several hematological malignancies. This report describes the effect of activating natural killer T (NKT) cells by alpha-Galactosylceramide (alpha GalCer) in the 5T33MM model of multiple myeloma (MM). NKT cells are T lymphocytes, co-expressing T and NK receptors, while invariant NKT cells (iNKTs) also express a unique semi-invariant TCR alpha-chain. We followed iNKT numbers during the development of the disease in both 5T33MM mice and MM patients and found that their numbers dropped dramatically at the end stage of the disease, leading to a loss of total IFN-gamma secretion. We furthermore observed that alpha-GalCer treatment significantly increased the survival of 5T33MM diseased mice. Taken together, our data demonstrate for the first time the possibility of using a preclinical murine MM model to study the effects of alpha-GalCer and show promising results of alpha-GalCer treatment in a low tumor burden setting. PMID- 23741458 TI - Successful isolation of infectious and high titer human monocyte-derived HIV-1 from two subjects with discontinued therapy. AB - BACKGROUND: HIV-1 DNA in blood monocytes is considered a viral source of various HIV-1 infected tissue macrophages, which is also known as "Trojan horse" hypothesis. However, whether these DNA can produce virions has been an open question for years, due to the inability of isolating high titer and infectious HIV-1 directly from monocytes. RESULTS: In this study, we demonstrated successful isolation of two strains of M-HIV-1 (1690 M and 1175 M) from two out of four study subjects, together with their in vivo controls, HIV-1 isolated from CD4+ T cells (T-HIV-1), 1690 T and 1175 T. All M- and T- HIV-1 isolates were detected CCR5-tropic. Both M- HIV-1 exhibited higher levels of replication in monocyte derived macrophages (MDM) than the two T- HIV-1. Consistent with our previous reports on the subject 1175 with late infection, compartmentalized env C2-V3-C3 sequences were identified between 1175 M and 1175 T. In contrast, 1690 M and 1690 T, which were isolated from subject 1690 with relatively earlier infection, showed homogenous env C2-V3-C3 sequences. However, multiple reverse transcriptase (RT) inhibitor resistance-associated variations were detected in the Gag-Pol region of 1690 M, but not of 1690 T. By further measuring HIV DNA intracellular copy numbers post-MDM infection, 1690 M was found to have significantly higher DNA synthesis efficiency than 1690 T in macrophages, indicating a higher RT activity, which was confirmed by AZT inhibitory assays. CONCLUSIONS: These results suggested that the M- and T- HIV-1 are compartmentalized in the two study subjects, respectively. Therefore, we demonstrated that under in vitro conditions, HIV-1 infected human monocytes can productively release live viruses while differentiating into macrophages. PMID- 23741461 TI - Localised JAK/STAT pathway activation is required for Drosophila wing hinge development. AB - Extensive morphogenetic remodelling takes place during metamorphosis from a larval to an adult insect body plan. These changes are particularly intricate in the generation of the dipteran wing hinge, a complex structure that is derived from an apparently simple region of the wing imaginal disc. Using the characterisation of original outstretched alleles of the unpaired locus as a starting point, we demonstrate the role of JAK/STAT pathway signalling in the process of wing hinge development. We show that differences in JAK/STAT signalling within the proximal most of three lateral folds present in the wing imaginal disc is required for fold morphology and the subsequent differentiation of the first and second auxiliary sclerites as well as the posterior notal wing process. Changes in these domains are consistent with the established fate map of the wing disc. We show that outstretched wing posture phenotypes arise from the loss of a region of Unpaired expression in the proximal wing fold and demonstrate that this results in a decrease in JAK/STAT pathway activity. Finally we show that reduction of JAK/STAT pathway activity within the proximal wing fold is sufficient to phenocopy the outstretched phenotype. Taken together, we suggest that localised Unpaired expression and hence JAK/STAT pathway activity, is required for the morphogenesis of the adult wing hinge, providing new insights into the link between signal transduction pathways, patterning and development. PMID- 23741462 TI - Cytoplasmic and genomic effects on non-meiosis-driven genetic changes in Brassica hybrids and allotetraploids from pairwise crosses of three cultivated diploids. AB - Nuclear-cytoplasmic interactions are predicted to be important in shaping the genetic changes in early stage of allopolyploidization. Our previous study shows the specific role of genome and cytoplasm affecting the chromosome pairing in Brassica hybrids and allotetraploids from pairwise crosses between three cultivated diploids with A, B and C genomes, respectively. Herein, to address how parental genomes and cytoplasm affects genomic, epigenetic and gene expression changes prior to meiosis in these hybrids and allopolyploids, their patterns of AFLP (Amplified fragment length polymorphism), mAFLP (Methylation AFLP) and cDNA AFLP were compared with the progenitors, revealing the major absent bands within each genome. These changes varied under various cytoplasm backgrounds and genome combinations, following the significant order of AFLP> mAFLP> cDNA -AFLP. The frequencies of AFLP bands lost were positively correlated with the divergence degrees of parental genomes, but not obvious for those of mAFLP and cDNA-AFLP absent bands, and methylation change showed least variations among hybrids and within each genome. These changes within each genome followed the A>B>C hierarchy, except the highest rate of cDNA loss in B genome. Among three changes, only overall AFLP bands were significantly correlated with cDNA-AFLP, and their correlations varied within each genome. These changes in allotetraploids were mainly caused by genome merger rather than doubling. Parental genomes altered differently at three levels, responded to the types of cytoplasm and genome and their interaction or divergence. The result provides new clues for instant non meiosis-driven genome restructuring following genome merger and duplication. PMID- 23741463 TI - Diverse strategies for vertical symbiont transmission among subsocial stinkbugs. AB - Sociality may affect symbiosis and vice versa. Many plant-sucking stinkbugs harbor mutualistic bacterial symbionts in the midgut. In the superfamily Pentatomoidea, adult females excrete symbiont-containing materials from the anus, which their offspring ingest orally and establish vertical symbiont transmission. In many stinkbug families whose members are mostly non-social, females excrete symbiont-containing materials onto/beside eggs upon oviposition. However, exceptional cases have been reported from two subsocial species representing the closely related families Cydnidae and Parastrachiidae, wherein females remain nearby eggs for maternal care after oviposition, and provide their offspring with symbiont-containing secretions at later stages, either just before or after hatching. These observations suggested that sociality of the host stinkbugs may be correlated with their symbiont transmission strategies. However, we found that cydnid stinkbugs of the genus Adomerus, which are associated with gammaproteobacterial gut symbionts and exhibit elaborate maternal care over their offspring, smear symbiont-containing secretions onto eggs upon oviposition as many non-social stinkbugs do. Surface sterilization of the eggs resulted in aposymbiotic insects of slower growth, smaller size and abnormal body coloration, indicating vertical symbiont transmission via egg surface contamination and presumable beneficial nature of the symbiosis. The Adomerus symbionts exhibited AT-biased nucleotide compositions, accelerated molecular evolutionary rates and reduced genome size, while these degenerative genomic traits were less severe than those in the symbiont of a subsocial parastrachiid. These results suggest that not only sociality but also other ecological and evolutionary aspects of the host stinkbugs, including the host-symbiont co-evolutionary history, may have substantially affected their symbiont transmission strategies. PMID- 23741465 TI - Pool-type fishways: two different morpho-ecological cyprinid species facing plunging and streaming flows. AB - Fish are particularly sensitive to connectivity loss as their ability to reach spawning grounds is seriously affected. The most common way to circumvent a barrier to longitudinal connectivity, and to mitigate its impacts, is to implement a fish passage device. However, these structures are often non effective for species with different morphological and ecological characteristics so there is a need to determine optimum dimensioning values and hydraulic parameters. The aim of this work is to study the behaviour and performance of two species with different ecological characteristics (Iberian barbel Luciobarbus bocagei-bottom oriented, and Iberian chub Squalius pyrenaicus-water column) in a full-scale experimental pool-type fishway that offers two different flow regimes plunging and streaming. Results showed that both species passed through the surface notch more readily during streaming flow than during plunging flow. The surface oriented species used the surface notch more readily in streaming flow, and both species were more successful in moving upstream in streaming flow than in plunging flow. Streaming flow enhances upstream movement of both species, and seems the most suitable for fishways in river systems where a wide range of fish morpho-ecological traits are found. PMID- 23741464 TI - Rapid and reversible impairments of short- and long-term social recognition memory are caused by acute isolation of adult rats via distinct mechanisms. AB - Mammalian social organizations require the ability to recognize and remember individual conspecifics. This social recognition memory (SRM) can be examined in rodents using their innate tendency to investigate novel conspecifics more persistently than familiar ones. Here we used the SRM paradigm to examine the influence of housing conditions on the social memory of adult rats. We found that acute social isolation caused within few days a significant impairment in acquisition of short-term SRM of male and female rats. Moreover, SRM consolidation into long-term memory was blocked following only one day of social isolation. Both impairments were reversible, but with different time courses. Furthermore, only the impairment in SRM consolidation was reversed by systemic administration of arginine-vasopressin (AVP). In contrast to SRM, object recognition memory was not affected by social isolation. We conclude that acute social isolation rapidly induces reversible changes in the brain neuronal and molecular mechanisms underlying SRM, which hamper its acquisition and completely block its consolidation. These changes occur via distinct, AVP sensitive and insensitive mechanisms. Thus, acute social isolation of rats swiftly causes changes in their brain and interferes with their normal social behavior. PMID- 23741466 TI - Temporal asthma patterns using repeated questionnaires over 13 years in a large French cohort of women. AB - Variable expression is one aspect of the heterogeneity of asthma. We aimed to define a variable pattern, which is relevant in general health epidemiological cohorts. Our objectives were to assess whether: 1) asthma patterns defined using simple asthma questions through repeated measurements could reflect disease variability 2) these patterns may further be classified according to asthma severity/control. Among 70,428 French women, we used seven questionnaires (1992 2005) and a comprehensive reimbursement database (2004-2009) to define three reliable asthma patterns based on repeated positive answers to the ever asthma attack question: "never asthma" (n = 64,061); "inconsistent" ("yes" followed by "no", n = 3,514); "consistent" (fully consistent positive answers, n = 2,853). The "Inconsistent" pattern was related to both long-term (childhood-onset asthma with remission in adulthood) and short-term (reported asthma attack in the last 12 months, associated with asthma medication) asthma variability, showing that repeated questions are relevant markers of the variable expression of asthma. Furthermore, in this pattern, the number of positive responses (1992-2005) predicted asthma drug consumption in subsequent years, a marker of disease severity. The "Inconsistent" pattern is a phenotype that may capture the variable expression of asthma. Repeated answers, even to a simple question, are too often neglected. PMID- 23741467 TI - Attributing variance in supportive care needs during cancer: culture-service, and individual differences, before clinical factors. AB - BACKGROUND: Studies using the Supportive Care Needs Survey (SCNS) report high levels of unmet supportive care needs (SCNs) in psychological and less-so physical & daily living domains, interpreted as reflecting disease/treatment coping deficits. However, service and culture differences may account for unmet SCNs variability. We explored if service and culture differences better account for observed SCNs patterns. METHODS: Hong Kong (n = 180), Taiwanese (n = 263) and Japanese (n = 109) CRC patients' top 10 ranked SCNS-34 items were contrasted. Mean SCNS-34 domain scores were compared by sample and treatment status, then adjusted for sample composition, disease stage and treatment status using multivariate hierarchical regression. RESULTS: All samples were assessed at comparable time-points. SCNs were most prevalent among Japanese and least among Taiwanese patients. Japanese patients emphasized Psychological (domain mean = 40.73) and Health systems and information (HSI) (38.61) SCN domains, whereas Taiwanese and Hong Kong patients emphasized HSI (27.41; 32.92) and Patient care & support (PCS) (19.70; 18.38) SCN domains. Mean Psychological domain scores differed: Hong Kong = 9.72, Taiwan = 17.84 and Japan = 40.73 (p<0.03-0.001, Bonferroni). Other SCN domains differed only between Chinese and Japanese samples (all p<0.001). Treatment status differentiated Taiwanese more starkly than Hong Kong patients. After adjustment, sample origin accounted for most variance in SCN domain scores (p<0.001), followed by age (p = 0.01-0.001) and employment status (p = 0.01-0.001). Treatment status and Disease stage, though retained, accounted for least variance. Overall accounted variance remained low. CONCLUSIONS: Health service and/or cultural influences, age and occupation differences, and less so clinical factors, differentially account for significant variation in published studies of SCNs. PMID- 23741468 TI - Early spatial frequency processing of natural images: an ERP study. AB - The present study examined the role of spatial stimulus frequencies in the early visual processing of natural scenes. The content of initially degraded (low- or high-pass filtered) pictures was progressively revealed in a sequence of steps by adding high or low spatial frequencies. Event Related Potentials (ERPs) were used to track the early stages of visual processing. Picture degradation modulated the topography of the P1, with an occipital midline distribution for the most degraded pictures, which became progressively more laterally distributed as pictures became more complete. Picture degradation also modulated the amplitude of the P2. For both low-passed and high-passed scenes, a linear relationship between the spectral power and the amplitude of the P1 and P2 was observed. These results are likely to reflect the progressive engagement of the lateral occipital complex as the amount of information in both the low and high portions of the frequency spectrum increased. PMID- 23741469 TI - Stronger T cell immunogenicity of ovalbumin expressed intracellularly in Gram negative than in Gram-positive bacteria. AB - This study aimed to clarify whether Gram-positive (G+) and Gram-negative (G-) bacteria affect antigen-presenting cells differently and thereby influence the immunogenicity of proteins they express. Lactobacilli, lactococci and Escherichia coli strains were transformed with plasmids conferring intracellular ovalbumin (OVA) production. Murine splenic antigen presenting cells (APCs) were pulsed with washed and UV-inactivated OVA-producing bacteria, control bacteria, or soluble OVA. The ability of the APCs to activate OVA-specific DO11.10 CD4(+) T cells was assessed by measurments of T cell proliferation and cytokine (IFN-gamma, IL-13, IL-17, IL-10) production. OVA expressed within E. coli was strongly immunogenic, since 500 times higher concentrations of soluble OVA were needed to achieve a similar level of OVA-specific T cell proliferation. Furthermore, T cells responding to soluble OVA produced mainly IL-13, while T cells responding to E. coli-expressed OVA produced high levels of both IFN-gamma and IL-13. Compared to E. coli, G+ lactobacilli and lactococci were poor inducers of OVA-specific T cell proliferation and cytokine production, despite efficient intracellular expression and production of OVA and despite being efficiently phagocytosed. These results demonstrate a pronounced difference in immunogenicity of intracellular antigens in G+ and G- bacteria and may be relevant for the use of bacterial carriers in vaccine development. PMID- 23741470 TI - Neuroprotective efficacy of a new brain-penetrating C-Abl inhibitor in a murine Parkinson's disease model. AB - Experimental evidence suggests that oxidative and nitrative mechanisms account for much of the dopaminergic neuronal injury in Parkinson's disease (PD). The ubiquitously expressed non-receptor tyrosine kinase c-Abl is activated by oxidative stress and thus, may play a role in redox-mediated neurodegeneration. Recently, we reported that c-Abl is activated in PD and that a c-Abl inhibitor mitigated neuronal damage in a PD animal model, suggesting a novel neuroprotective therapeutic approach. In the studies presented here, we evaluated the efficacy of a potent and clinically relevant second-generation irreversible Abl kinase inhibitor, INNO-406, as a therapeutic agent for PD. Our studies reveal that INNO-406 is capable of preventing the progression of dopaminergic neuronal damage in a toxin-induced C57 mouse model of PD. Using bovine brain microvessel endothelium as an in vitro blood-brain barrier (BBB) model, we detected rapid and significant transfer of INNO-406. Additionally, pharmacokinetic analyses demonstrated significant nanomolar concentrations of INNO-406 in brain in the presence or absence of MPTP administration, however, INNO-406 did not alter the brain levels of MPP+ in MPTP-treated mice. Finally, we showed that 10 mg/kg of INNO-406 given to C57 mice for one week before MPTP treatment (4*20 mg/kg i.p., every 2 h) and then for one week after MPTP treatment decreased the loss of dopamine in the striatum by 45% and the loss of TH+ neurons in substantia nigra pars compacts by 40%. This treatment regimen also abrogated activation of c-Abl, tyrosine phosphorylation of the Abl substrate and E3-ubiquitin ligase parkin, and accumulation of the toxic parkin substrate AIMP2. We propose that compounds of the INNO-406 class of Abl inhibitors will be useful new neuroprotective drugs for the treatment of PD-like pathology in preclinical systems that should be easily translated to the clinic. PMID- 23741471 TI - Interactions between the R2R3-MYB transcription factor, AtMYB61, and target DNA binding sites. AB - Despite the prominent roles played by R2R3-MYB transcription factors in the regulation of plant gene expression, little is known about the details of how these proteins interact with their DNA targets. For example, while Arabidopsis thaliana R2R3-MYB protein AtMYB61 is known to alter transcript abundance of a specific set of target genes, little is known about the specific DNA sequences to which AtMYB61 binds. To address this gap in knowledge, DNA sequences bound by AtMYB61 were identified using cyclic amplification and selection of targets (CASTing). The DNA targets identified using this approach corresponded to AC elements, sequences enriched in adenosine and cytosine nucleotides. The preferred target sequence that bound with the greatest affinity to AtMYB61 recombinant protein was ACCTAC, the AC-I element. Mutational analyses based on the AC-I element showed that ACC nucleotides in the AC-I element served as the core recognition motif, critical for AtMYB61 binding. Molecular modelling predicted interactions between AtMYB61 amino acid residues and corresponding nucleotides in the DNA targets. The affinity between AtMYB61 and specific target DNA sequences did not correlate with AtMYB61-driven transcriptional activation with each of the target sequences. CASTing-selected motifs were found in the regulatory regions of genes previously shown to be regulated by AtMYB61. Taken together, these findings are consistent with the hypothesis that AtMYB61 regulates transcription from specific cis-acting AC elements in vivo. The results shed light on the specifics of DNA binding by an important family of plant-specific transcriptional regulators. PMID- 23741472 TI - Source discrimination in adults with attention deficit hyperactivity disorder. AB - OBJECTIVES: The context of memory experiences is referred to as source memory and can be distinguished from the content of episodic item memory. Source memory represents a crucial part of biographic events and elaborate memory experiences. Whereas individuals with attention deficit hyperactivity disorder (ADHD) were shown to have inefficient item memory, little is known about the context of memory experiences. METHODS: The present study compared 37 adult patients with a diagnosed ADHD with 40 matched healthy participants on a word list paradigm. Memory functions of encoding, retention and source discrimination were assessed. Furthermore, standardized measures of memory and executive control were applied in order to explore a qualitative differentiation of memory components. RESULTS: Adult patients with ADHD showed impaired performance in encoding of new information whereas the retention of encoded items was found to be preserved. The most pronounced impairment of patients with ADHD was observed in source discrimination. Regression models of cognitive functions on memory components supported some qualitative differentiation. CONCLUSIONS: Data analysis suggests a differential pattern of memory impairment in adults suffering from ADHD with a particular deficit in source discrimination. Inefficient source discrimination in adults with ADHD can affect daily functioning by limiting biographic awareness and disturbing general cognitive processes. PMID- 23741473 TI - Rice OsGL1-6 is involved in leaf cuticular wax accumulation and drought resistance. AB - Cuticular wax is a class of organic compounds that comprises the outermost layer of plant surfaces. Plant cuticular wax, the last barrier of self-defense, plays an important role in plant growth and development. The OsGL1-6 gene, a member of the fatty aldehyde decarbonylase gene family, is highly homologous to Arabidopsis CER1, which is involved in cuticular wax biosynthesis. However, whether OsGL1-6 participates in cuticular wax biosynthesis remains unknown. In this study, an OsGL1-6 antisense-RNA vector driven by its own promoter was constructed and introduced into the rice variety Zhonghua11 by Agrobacterium-mediated transformation to obtain several independent transgenic plants with decreased OsGL1-6 expression. These OsGL1-6 antisense-RNA transgenic plants showed droopy leaves at the booting stage, significantly decreased leaf cuticular wax deposition, thinner cuticle membrane, increased chlorophyll leaching and water loss rates, and enhanced drought sensitivity. The OsGL1-6 gene was constitutively expressed in all examined organs and was very highly expressed in leaf epidermal cells and vascular bundles. The transient expression of OsGL1-6-GFP fusion indicated that OsGL1-6 is localized in the endoplasmic reticulum. Qualitative and quantitative analysis of the wax composition using gas chromatography-mass spectrometry revealed a significantly reduced total cuticular wax load on the leaf blades of the OsGL1-6 antisense-RNA transgenic plants as well as markedly decreased alkane and aldehyde contents. Their primary alcohol contents increased significantly compared with those in the wild type plants, suggesting that OsGL1 6 is associated with the decarbonylation pathways in wax biosynthesis. We propose that OsGL1-6 is involved in the accumulation of leaf cuticular wax and directly impacts drought resistance in rice. PMID- 23741474 TI - Thiazolidinediones promote axonal growth through the activation of the JNK pathway. AB - The axon is a neuronal process involved in protein transport, synaptic plasticity, and neural regeneration. It has been suggested that their structure and function are profoundly impaired in neurodegenerative diseases. Previous evidence suggest that Peroxisome Proliferator-Activated Receptors-gamma (PPARgamma promote neuronal differentiation on various neuronal cell types. In addition, we demonstrated that activation of PPARgammaby thiazolidinediones (TZDs) drugs that selectively activate PPARgamma prevent neurite loss and axonal damage induced by amyloid-beta (Abeta). However, the potential role of TZDs in axonal elongation and neuronal polarity has not been explored. We report here that the activation of PPARgamma by TZDs promoted axon elongation in primary hippocampal neurons. Treatments with different TZDs significantly increased axonal growth and branching area, but no significant effects were observed in neurite elongation compared to untreated neurons. Treatment with PPARgamma antagonist (GW 9662) prevented TZDs-induced axonal growth. Recently, it has been suggested that the c-Jun N-terminal kinase (JNK) plays an important role regulating axonal growth and neuronal polarity. Interestingly, in our studies, treatment with TZDs induced activation of the JNK pathway, and the pharmacological blockage of this pathway prevented axon elongation induced by TZDs. Altogether, these results indicate that activation of JNK induced by PPARgammaactivators stimulates axonal growth and accelerates neuronal polarity. These novel findings may contribute to the understanding of the effects of PPARgamma on neuronal differentiation and validate the use of PPARgamma activators as therapeutic agents in neurodegenerative diseases. PMID- 23741475 TI - Iron-induced changes in the proteome of Trichomonas vaginalis hydrogenosomes. AB - Iron plays a crucial role in metabolism as a key component of catalytic and redox cofactors, such as heme or iron-sulfur clusters in enzymes and electron transporting or regulatory proteins. Limitation of iron availability by the host is also one of the mechanisms involved in immunity. Pathogens must regulate their protein expression according to the iron concentration in their environment and optimize their metabolic pathways in cases of limitation through the availability of respective cofactors. Trichomonas vaginalis, a sexually transmitted pathogen of humans, requires high iron levels for optimal growth. It is an anaerobe that possesses hydrogenosomes, mitochondrion-related organelles that harbor pathways of energy metabolism and iron-sulfur cluster assembly. We analyzed the proteomes of hydrogenosomes obtained from cells cultivated under iron-rich and iron deficient conditions employing two-dimensional peptide separation combining IEF and nano-HPLC with quantitative MALDI-MS/MS. We identified 179 proteins, of which 58 were differentially expressed. Iron deficiency led to the upregulation of proteins involved in iron-sulfur cluster assembly and the downregulation of enzymes involved in carbohydrate metabolism. Interestingly, iron affected the expression of only some of multiple protein paralogues, whereas the expression of others was iron independent. This finding indicates a stringent regulation of differentially expressed multiple gene copies in response to changes in the availability of exogenous iron. PMID- 23741476 TI - Genetic variation and cerebrospinal fluid levels of mannose binding lectin in pneumococcal meningitis patients. AB - It has been suggested that genetic variants in mannose binding lectin (MBL2) influence susceptibility and outcome of invasive pneumococcal disease. We assessed the influence of genetic variation in MBL2 on susceptibility, outcome and causative serotype of pneumococcal meningitis in a prospective nationwide cohort study including 299 white patients and 216 controls. We assessed functionality of the genetic polymorphisms by measuring levels of MBL, C3a, iC3b, C5a and sC5b-9 in cerebrospinal fluid. We also performed a meta-analysis of studies on MBL2 polymorphisms and susceptibility to invasive pneumococcal disease. The risk of contracting pneumococcal meningitis was substantially increased for white individuals homozygous with the defective MBL2 0/0 genotype (odds ratio [OR] 8.21, 95% confidence interval [CI] 1.05-64.1; p = 0.017). CSF MBL levels were significantly lower in patients with the A/0 and 0/0 genotype compared to homozygotes for the wild-type alleles (A/A; p<0.001). CSF MBL levels were positively correlated with C3a and iC3b levels, indicating complement activation by the lectin pathway. The effect of MBL2 genetic variants on susceptibility remained robust in a meta-analysis including 5 studies with 287 patients (OR 2.33, 99% CI 1.39-3.90). We conclude that MBL2 polymorphisms influence CSF MBL levels and substantially increase the risk of pneumococcal meningitis. PMID- 23741477 TI - Acyl chain-dependent effect of lysophosphatidylcholine on endothelium-dependent vasorelaxation. AB - Previously we identified palmitoyl-, oleoyl-, linoleoyl-, and arachidonoyl lysophosphatidylcholine (LPC 16:0, 18:1, 18:2 and 20:4) as the most prominent LPC species generated by endothelial lipase (EL). In the present study, we examined the impact of those LPC on acetylcholine (ACh)- induced vascular relaxation. All tested LPC attenuated ACh-induced relaxation, measured ex vivo, using mouse aortic rings and wire myography. The rank order of potency was as follows: 18:2>20:4>16:0>18:1. The attenuating effect of LPC 16:0 on relaxation was augmented by indomethacin-mediated cyclooxygenase (COX)-inhibition and CAY10441, a prostacyclin (PGI2)- receptor (IP) antagonist. Relaxation attenuated by LPC 20:4 and 18:2 was improved by indomethacin and SQ29548, a thromboxane A2 (TXA2)- receptor antagonist. The effect of LPC 20:4 could also be improved by TXA2- and PGI2-synthase inhibitors. As determined by EIA assays, the tested LPC promoted secretion of PGI2, TXA2, PGF2alpha, and PGE2, however, with markedly different potencies. LPC 16:0 was the most potent inducer of superoxide anion production by mouse aortic rings, followed by LPC 18:2, 20:4 and 18:1, respectively. The strong antioxidant tempol recovered relaxation impairment caused by LPC 18:2, 18:1 and 20:4, but not by LPC 16:0. The tested LPC attenuate ACh-induced relaxation through induction of proconstricting prostanoids and superoxide anions. The potency of attenuating relaxation and the relative contribution of underlying mechanisms are strongly related to LPC acyl-chain length and degree of saturation. PMID- 23741478 TI - Improved production process for native outer membrane vesicle vaccine against Neisseria meningitidis. AB - An improved detergent-free process has been developed to produce vaccine based on native outer membrane vesicles (NOMV) against Neisseria meningitidis serogroup B. Performance was evaluated with the NonaMen vaccine concept, which provides broad coverage based on nine distinct PorA antigens. Scalable aseptic equipment was implemented, replacing undesirable steps like ultracentrifugation, inactivation with phenol, and the use of preservatives. The resulting process is more consistent and gives a higher yield than published reference processes, enabling NOMV production at commercial scale. Product quality met preliminary specifications for 9 consecutive batches, and an ongoing study confirmed real time stability up to 12 months after production. As the NOMV had low endotoxic activity and induced high bactericidal titres in mice, they are expected to be safe and effective in humans. The production process is not limited to NonaMen and may be applicable for other N. meningitidis serogroups and other gram negative pathogens. The current results therefore facilitate the late-stage development and clinical evaluation of NOMV vaccines. PMID- 23741479 TI - A role of TGFbeta1 dependent 14-3-3sigma phosphorylation at Ser69 and Ser74 in the regulation of gene transcription, stemness and radioresistance. AB - Transforming growth factor-beta (TGFbeta) is a potent regulator of tumorigenesis, although mechanisms defining its tumor suppressing and tumor promoting activities are not understood. Here we describe phosphoproteome profiling of TGFbeta signaling in mammary epithelial cells, and show that 60 identified TGFbeta regulated phosphoproteins form a network with scale-free characteristics. The network highlighted interactions, which may distribute signaling inputs to regulation of cell proliferation, metabolism, differentiation and cell organization. In this report, we identified two novel and TGFbeta-dependent phosphorylation sites of 14-3-3sigma, i.e. Ser69 and Ser74. We observed that 14-3 3sigma phosphorylation is a feed-forward mechanism in TGFbeta/Smad3-dependent transcription. TGFbeta-dependent 14-3-3sigma phosphorylation may provide a scaffold for the formation of the protein complexes which include Smad3 and p53 at the Smad3-specific CAGA element. Furthermore, breast tumor xenograft studies in mice and radiobiological assays showed that phosphorylation of 14-3-3sigma at Ser69 and Ser74 is involved in regulation of cancer progenitor population and radioresistance in breast cancer MCF7 cells. Our data suggest that TGFbeta dependent phosphorylation of 14-3-3sigma orchestrates a functional interaction of TGFbeta/Smad3 with p53, plays a role in the maintenance of cancer stem cells and could provide a new potential target for intervention in breast cancer. PMID- 23741480 TI - Short ROSE-like RNA thermometers control IbpA synthesis in Pseudomonas species. AB - The bacterial small heat shock protein IbpA protects client proteins from aggregation. Due to redundancy in the cellular chaperone network, deletion of the ibpA gene often leads to only a mild or no phenotypic defect. In this study, we show that a Pseudomonas putida ibpA deletion mutant has a severe growth defect under heat stress conditions and reduced survival during recovery revealing a critical role of IbpA in heat tolerance. Transcription of the ibpA gene depends on the alternative heat shock sigma factor sigma(32). Production of IbpA protein only at heat shock temperatures suggested additional translational control. We conducted a comprehensive structural and functional analysis of the 5' untranslated regions of the ibpA genes from P. putida and Pseudomonas aeruginosa. Both contain a ROSE-type RNA thermometer that is substantially shorter and simpler than previously reported ROSE elements. Comprised of two hairpin structures only, they inhibit translation at low temperature and permit translation initiation after a temperature upshift. Both elements regulate reporter gene expression in Escherichia coli and ribosome binding in vitro in a temperature-dependent manner. Structure probing revealed local melting of the second hairpin whereas the first hairpin remained unaffected. High sequence and structure conservation of pseudomonal ibpA untranslated regions and their ability to confer thermoregulation in vivo suggest that short ROSE-like thermometers are commonly used to control IbpA synthesis in Pseudomonas species. PMID- 23741481 TI - Childhood dysglycemia: prevalence and outcome in a referral hospital. AB - INTRODUCTION: Hypoglycemia is a defining feature of severe malaria and several other infectious diseases in children but the prevalence, significance, and prognosis of abnormal blood glucose, including hyperglycemia, have rarely been addressed in severely ill children in non-malaria endemic areas. METHODS: In Madagascar, consecutive children (1 month-15 years) admitted to the pediatric ward of a referral hospital, were categorized using the integrated management of childhood illness (IMCI). Samples were taken once on admission for measuring blood glucose concentration. Glycemia levels (hypoglycemia <2.2 mmol/l; low glycemia: 2.2-4.4 mmol/l; normoglycemia >4.4-8.3 mmol/l; and hyperglycemia >8.3 mmol/l) were related to the IMCI algorithm and case fatality. Factors associated with blood glucose concentration and case fatality were analysed using univariate and multivariate analysis. RESULTS: Of 420 children, 48.1% (n = 202) were severely ill; 3.1% (n = 13) had hypoglycemia; 20.0% (n = 84) low glycemia; 65.9% (n = 277) normoglycemia; and 10.9% (n = 46) hyperglycemia. In univariate analysis, hypoglycemia and hyperglycemia both showed significant increase in the risk of death, as compared to normal blood glucose (RR: 12.2, 95% CI: 6.2-23.7 and RR: 2.5, 95% CI: 1.0-6.2, respectively). Children with low glycemia had no increased risk of death (RR: 1.2, 95% CI: 0.4-3.2) despite a poorer IMCI status on admission. After logistic regression, hypoglycemia (RR: 19.4, 95% CI: 5.0 .74.7, hepatomegaly (RR: 12.2, 95% CI: 3.3-44.9) and coma (RR: 4.8, 95% CI: 1.3 17.6) were the features on admission associated with an increased risk of death. CONCLUSIONS: Dysglycemia in non-neonates is associated with increased mortality. These findings underline the need for the use of rapid screening tests to initiate early treatment. Alternative treatments such as oral or sublingual administration of glucose should be developed in structures with limited resources. PMID- 23741482 TI - Abnormal chloride homeostasis in the substancia nigra pars reticulata contributes to locomotor deficiency in a model of acute liver injury. AB - BACKGROUND: Altered chloride homeostasis has been thought to be a risk factor for several brain disorders, while less attention has been paid to its role in liver disease. We aimed to analyze the involvement and possible mechanisms of altered chloride homeostasis of GABAergic neurons within the substantia nigra pars reticulata (SNr) in the motor deficit observed in a model of encephalopathy caused by acute liver failure, by using glutamic acid decarboxylase 67 - green fluorescent protein knock-in transgenic mice. METHODS: Alterations in intracellular chloride concentration in GABAergic neurons within the SNr and changes in the expression of two dominant chloride homeostasis-regulating genes, KCC2 and NKCC1, were evaluated in mice with hypolocomotion due to hepatic encephalopathy (HE). The effects of pharmacological blockade and/or activation of KCC2 and NKCC1 functions with their specific inhibitors and/or activators on the motor activity were assessed. RESULTS: In our mouse model of acute liver injury, chloride imaging indicated an increase in local intracellular chloride concentration in SNr GABAergic neurons. In addition, the mRNA and protein levels of KCC2 were reduced, particularly on neuronal cell membranes; in contrast, NKCC1 expression remained unaffected. Furthermore, blockage of KCC2 reduced motor activity in the normal mice and led to a further deteriorated hypolocomotion in HE mice. Blockade of NKCC1 was not able to normalize motor activity in mice with liver failure. CONCLUSION: Our data suggest that altered chloride homeostasis is likely involved in the pathophysiology of hypolocomotion following HE. Drugs aimed at restoring normal chloride homeostasis would be a potential treatment for hepatic failure. PMID- 23741483 TI - Elevated incidence of polyp formation in APC(Min/+)Msh2-/- mice is independent of nitric oxide-induced DNA mutations. AB - Gut microbiota has been linked to a number of human diseases including colon cancer. However, the mechanism through which gut bacteria influence colon cancer development and progression remains unclear. Perturbation of the homeostasis between the host immune system and microbiota leads to inflammation and activation of macrophages which produce large amounts of nitric oxide that acts as a genotoxic effector molecule to suppress bacterial growth. However, nitric oxide also has genotoxic effects to host cells by producing mutations that can predispose to colon cancer development. The major DNA lesions caused by nitric oxide are 8oxoG and deamination of deoxycytosine bases. Cellular glycosylases that belong to the base excision repair pathway have been demonstrated to repair these mutations. Recent evidence suggests that the mismatch repair pathway (MMR) might also repair nitric oxide-induced DNA damage. Since deficiency in MMR predisposes to colon cancer, we hypothesized that MMR-deficient colon epithelial cells are incapable of repairing nitric-oxide induced genetic lesions that can promote colon cancer. Indeed, we found that the MMR pathway repairs nitric oxide induced DNA mutations in cell lines. To test whether nitric oxide promotes colon cancer, we genetically ablated the inducible nitric oxide synthase (iNOS) or inhibited iNOS activity in the APC(Min/+)Msh2(-/-) mouse model of colon cancer. However, despite the fact that nitric oxide production was strongly reduced in the colon using both approaches, colon cancer incidence was not affected. These data show that nitric oxide and iNOS do not promote colon cancer in APC(Min/+)Msh2(-/-) mice. PMID- 23741484 TI - The Enterococcus faecium enterococcal biofilm regulator, EbrB, regulates the esp operon and is implicated in biofilm formation and intestinal colonization. AB - Nowadays, Enterococcus faecium is one of the leading nosocomial pathogens worldwide. Strains causing clinical infections or hospital outbreaks are enriched in the enterococcal surface protein (Esp) encoding ICEEfm1 mobile genetic element. Previous studies showed that Esp is involved in biofilm formation, endocarditis and urinary tract infections. In this study, we characterized the role of the putative AraC type of regulator (locus tag EfmE1162_2351), which we renamed ebrB and which is, based on the currently available whole genome sequences, always located upstream of the esp gene, and studied its role in Esp surface exposure during growth. A markerless deletion mutant of ebrB resulted in reduced esp expression and complete abolishment of Esp surface exposure, while Esp cell-surface exposure was restored when this mutant was complemented with an intact copy of ebrB. This demonstrates a role for EbrB in esp expression. However, during growth, ebrB expression levels did not change over time, while an increase in esp expression at both RNA and protein level was observed during mid log and late-log phase. These results indicate the existence of a secondary regulation system for esp, which might be an unknown quorum sensing system as the enhanced esp expression seems to be cell density dependent. Furthermore, we determined that esp is part of an operon of at least 3 genes putatively involved in biofilm formation. A semi-static biofilm model revealed reduced biofilm formation for the EbrB deficient mutant, while dynamics of biofilm formation using a flow cell system revealed delayed biofilm formation in the ebrB mutant. In a mouse intestinal colonization model the ebrB mutant was less able to colonize the gut compared to wild-type strain, especially in the small intestine. These data indicate that EbrB positively regulates the esp operon and is implicated in biofilm formation and intestinal colonization. PMID- 23741485 TI - Quantitative assessment of finger motor impairment in multiple sclerosis. AB - OBJECTIVE: To address the disability impact on fine hand motor functions in patients with Multiple Sclerosis (MS) by quantitatively measuring finger opposition movements, with the aim of providing a new "score" integrating current methods for disability assessment. METHODS: 40 MS patients (Expanded Disability Status Scale (EDSS): 0-7) and 80 healthy controls (HC) performed a repetitive finger-to-thumb opposition sequence with their dominant hand at spontaneous and maximal velocity, and uni- and bi-manually metronome-paced. A sensor-engineered glove was used to measure finger motor performance. Twenty-seven HC were tested twice, one month apart, to assess test-retest reliability. RESULTS: The motor parameters showed a good reproducibility in HC and demonstrated significantly worse performance in MS patients with respect to HC. A multivariate model revealed that rate of movement in the spontaneous velocity condition and inter hand interval (IHI), indicating bimanual coordination, contributed independently to differentiate the two groups. A finger motor impairment score based on these two parameters was able to discriminate HC from MS patients with very low EDSS scores (p<0.001): a significant difference was already evident for patients with EDSS = 0. Further, in the MS group, some motor performance parameters correlated with the clinical scores. In particular, significant correlations were found between IHI and EDSS (r = 0.56; p<0.0001), MS Functional Composite (r = -0.40; p = 0.01), Paced Auditory Serial Addition (r = -0.38; p = 0.02). No motor performance parameter correlated with Timed 25-Foot Walk. CONCLUSIONS: A simple, quantitative, objective method measuring finger motor performance could be used to define a score discriminating healthy controls and MS patients, even with very low disability. This sensitivity might be of crucial importance for monitoring the disease course and the treatment effects in early MS patients, when changes in the EDSS are small or absent. PMID- 23741486 TI - Protected areas in South Asia have not prevented habitat loss: a study using historical models of land-use change. AB - Habitat loss imperils species both locally and globally, so protection of intact habitat is critical for slowing the rate of biodiversity decline. Globally, more than 150,000 protected areas have been designated with a goal of protecting species and ecosystems, but whether they can continue to achieve this goal as human impacts escalate is unknown. Here we show that in South Asia, one of the world's major growth epicentres, the trajectory of habitat conversion rates inside protected areas is indistinguishable from that on unprotected lands, and habitat conversion rates do not decline following gazettement of a protected area. Moreover, a quarter of the land inside South Asia's protected areas is now classified as human modified. If the global community is to make significant progress towards the Convention on Biological Diversity's Aichi Target on protected areas, there is an urgent need both to substantially enhance management of these protected areas and to develop systematic conservation outside the formal protected area system. PMID- 23741487 TI - The noncoding RNA expression profile and the effect of lncRNA AK126698 on cisplatin resistance in non-small-cell lung cancer cell. AB - BACKGROUND: The efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer is limited by the acquired drug resistance. Identification the RNAs related to the cisplatin resistance may help to improve clinical response rates. METHODS: Microarray expression profiling of mRNAs, lncRNA and miRNA was undertaken in A549 cells and cisplatin resistant A549/CDDP cells. Differentially expressed mRNAs, lncRNAs and miRNAs, verified by realtime RT-PCR, were subjected to pathway analysis. Expression of NKD2 and beta-catenin was assessed by realtime RT-PCR and western blot analysis. The effect of lncRNA AK126698 on cisplatin induced apoptosis was investigated by annexin-V/PI flow cytometry. RESULTS: In total, 1471 mRNAs, 1380 lncRNAs and 25 miRNAs differentially expressed in A549/CDDP and A549 cells. Among them, 8 mRNAs, 8 lncRNAs and 5 miRNAs differentially expressed in gene chip analysis were validated. High-enrichment pathway analysis identified that some classical pathways participated in proliferation, differentiation, avoidance of apoptosis, and drug metabolism were differently expressed in these cells lines. Gene co-expression network identified many genes like FN1, CTSB, EGFR, and NKD2; lncRNAs including BX648420, ENST00000366408, and AK126698; and miRNAs such as miR-26a and let-7i potentially played a key role in cisplatin resistance. Among which, the canonical Wnt pathway was investigated because it was demonstrated to be targeted by both lncRNAs and miRNAs including lncRNA AK126698. Knockdown lncRNA AK126698 not only greatly decreased NKD2 which can negatively regulate Wnt/beta-catenin signaling but also increased the accumulation and nuclear translocation of beta-catenin, and significantly depressed apoptosis rate induced by cisplatin in A549 cells. CONCLUSION: Cisplatin resistance in non-small-cell lung cancer cells may relate to the changes in noncoding RNAs. Among these, AK126698 appears to confer cisplatin resistance by targeting the Wnt pathway. PMID- 23741488 TI - The time of maximum post-ischemic hyperperfusion indicates infarct growth following transient experimental ischemia. AB - After recanalization, cerebral blood flow (CBF) can increase above baseline in cerebral ischemia. However, the significance of post-ischemic hyperperfusion for tissue recovery remains unclear. To analyze the course of post-ischemic hyperperfusion and its impact on vascular function, we used magnetic resonance imaging (MRI) with pulsed arterial spin labeling (pASL) and measured CBF quantitatively during and after a 60 minute transient middle cerebral artery occlusion (MCAO) in adult rats. We added a 5% CO2 - challenge to analyze vasoreactivity in the same animals. Results from MRI were compared to histological correlates of angiogenesis. We found that CBF in the ischemic area recovered within one day and reached values significantly above contralateral thereafter. The extent of hyperperfusion changed over time, which was related to final infarct size: early (day 1) maximal hyperperfusion was associated with smaller lesions, whereas a later (day 4) maximum indicated large lesions. Furthermore, after initial vasoparalysis within the ischemic area, vasoreactivity on day 14 was above baseline in a fraction of animals, along with a higher density of blood vessels in the ischemic border zone. These data provide further evidence that late post-ischemic hyperperfusion is a sequel of ischemic damage in regions that are likely to undergo infarction. However, it is transient and its resolution coincides with re-gaining of vascular structure and function. PMID- 23741489 TI - High prevalence of HIV-1 intersubtype B'/C recombinants among injecting drug users in Dehong, China. AB - OBJECTIVE: To examine the distribution of HIV-1 genotypes among injecting drug users (IDUs) from Dehong, Yunnan province. MATERIALS AND METHODS: Blood samples from a total of 95 HIV-positive IDUs were retrospectively analyzed. Samples were collected between 2005 and 2009 from four cities in Dehong prefecture, western Yunnan province, the geographical origin of the HIV epidemic in China. HIV-1 gag, partial pol, vpr-env fragment, half-genome, or near-full-length sequences were analyzed to determine the HIV-1 genotypes of each subject. Results were compared with findings from past studies of IDUs in Dehong and in neighboring Myanmar. RESULTS: We observed a high prevalence of B'/C recombinants (82.4%) among IDUs in Dehong, the structural profiles of which do not match those previously reported in Dehong or in Myanmar. Furthermore, statistically significant differences in geographical and temporal distributions of HIV-1 genotypes were characterized by a predominance of HIV-1 B'/C recombinant forms among older subjects(p = 0.034), subjects from Longchuan district (p = 0.022), and subjects diagnosed between 2000 and 2004 (p = 0.004). CONCLUSIONS: The increasing prevalence of multiple, new B'/C recombinant forms suggest that HIV-1 intersubtype recombination is substantial and ongoing in western Yunnan. This reflects the high-risk behavior of IDUs in this region and argues the need for stronger monitoring and prevention measures in Dehong and other high-prevalence areas around China. PMID- 23741490 TI - Natural history of skeletal muscle mass changes in chronic kidney disease stage 4 and 5 patients: an observational study. AB - Cross-sectional studies in dialysis demonstrate muscle wasting associated with loss of function, increased morbidity and mortality. The relative drivers are poorly understood. There is a paucity of data regarding interval change in muscle in pre-dialysis and dialysis-dependant patients. This study aimed to examine muscle and fat mass change and elucidate associations with muscle wasting in advanced CKD. 134 patients were studied (60 HD, 28 PD, 46 CKD 4-5) and followed up for two years. Groups were similar in age, sex and diabetes prevalence. Soft tissue cross-sectional area (CSA) was measured annually on 3 occasions by a standardised multi-slice CT thigh. Potential determinants of muscle and fat CSA were assessed. Functional ability was assessed by sit-to-stand testing. 88 patients completed follow-up (40 HD, 16 PD, 32 CKD). There was a significant difference in percentage change in muscle CSA (MCSA) over year 1, dependant on treatment modality (chi(2) = 6.46; p = 0.039). Muscle loss was most pronounced in pre-dialysis patients. Muscle loss during year 1 was partially reversed in year 2 in 39%. Incident dialysis patients significantly lost MCSA during the year which they commenced dialysis, but not the subsequent year. Baseline MCSA, change in MCSA during year 1 and dialysis modality predicted year 2 change in MCSA (adjusted R(2) = 0.77, p<0.001). There was no correlation between muscle or fat CSA change and any other factors. MCSA correlated with functional testing, although MCSA change correlated poorly with change in functional ability. These data demonstrate marked variability in MCSA over 2 years. Loss of MCSA in both pre-dialysis and established dialysis patients is reversible. Factors previously cross-sectionally shown to correlate with MCSA did not correlate with wasting progression. The higher rate of muscle loss in undialysed CKD patients, and its reversal after dialysis commencement, suggests that conventional indicators may not result in optimal timing of dialysis initiation. PMID- 23741491 TI - Population-based childhood overweight prevention: outcomes of the 'Be active, eat right' study. AB - OBJECTIVE: An overweight prevention protocol was used in the 'Be active, eat right' study; parents of overweight children (5 years) were offered healthy lifestyle counseling by youth health care professionals. Effects of the protocol on child BMI and waist circumference at age 7 years were evaluated. METHODS: A cluster RCT was conducted among nine youth health care centers in the Netherlands. Parents of overweight, not obese, children received lifestyle counseling and motivational interviewing according to the overweight prevention protocol in the intervention condition (n = 349) and usual care in the control condition (n = 288). Measurements were made of child height, weight and waist circumference at baseline and at a two-year follow-up; parents completed questionnaires regarding demographic characteristics. Linear mixed models were applied; interaction terms were explored. RESULTS: The analyzed population consisted of 38.1% boys; mean age 5.7 [sd: 0.4] years; mean BMI 18.1 [sd: 0.6], the median number of counseling sessions in the intervention condition was 2. The regression model showed no significant difference in BMI increase between the research conditions at follow-up (beta -0.16; 95% CI:-0.60 to 0.27; p = 0.463). There was a significant interaction between baseline BMI and research condition; children with a baseline BMI of 17.25 and 17.50 had a smaller increase in BMI at follow-up when allocated to the intervention condition compared to control condition (estimated adjusted mean difference -0.67 [se: 0.30] and -0.52 [se: 0.36]). CONCLUSION: Mildly overweight children (baseline BMI 17.25 and 17.50) in the intervention condition showed a significantly smaller increase in BMI at follow-up compared to the control condition; there was no overall difference between intervention and control condition. Future research may explore and evaluate improvements of the prevention protocol. TRIAL REGISTRATION: Current Controlled Trials ISRCTN04965410. PMID- 23741492 TI - Experimental evolution reveals genome-wide spectrum and dynamics of mutations in the rice blast fungus, Magnaporthe oryzae. AB - Knowledge on mutation processes is central to interpreting genetic analysis data as well as understanding the underlying nature of almost all evolutionary phenomena. However, studies on genome-wide mutational spectrum and dynamics in fungal pathogens are scarce, hindering our understanding of their evolution and biology. Here, we explored changes in the phenotypes and genome sequences of the rice blast fungus Magnaporthe oryzae during the forced in vitro evolution by weekly transfer of cultures on artificial media. Through combination of experimental evolution with high throughput sequencing technology, we found that mutations accumulate rapidly prior to visible phenotypic changes and that both genetic drift and selection seem to contribute to shaping mutational landscape, suggesting the buffering capacity of fungal genome against mutations. Inference of mutational effects on phenotypes through the use of T-DNA insertion mutants suggested that at least some of the DNA sequence mutations are likely associated with the observed phenotypic changes. Furthermore, our data suggest oxidative damages and UV as major sources of mutation during subcultures. Taken together, our work revealed important properties of original source of variation in the genome of the rice blast fungus. We believe that these results provide not only insights into stability of pathogenicity and genome evolution in plant pathogenic fungi but also a model in which evolution of fungal pathogens in natura can be comparatively investigated. PMID- 23741493 TI - Apolipoprotein A-I glycation by glucose and reactive aldehydes alters phospholipid affinity but not cholesterol export from lipid-laden macrophages. AB - Increased protein glycation in people with diabetes may promote atherosclerosis. This study examined the effects of non-enzymatic glycation on the association of lipid-free apolipoproteinA-I (apoA-I) with phospholipid, and cholesterol efflux from lipid-loaded macrophages to lipid-free and lipid-associated apoA-I. Glycation of lipid-free apoA-I by methylglyoxal and glycolaldehyde resulted in Arg, Lys and Trp loss, advanced glycation end-product formation and protein cross linking. The association of apoA-I glycated by glucose, methylglyoxal or glycolaldehyde with phospholipid multilamellar vesicles was impaired in a glycating agent dose-dependent manner, with exposure of apoA-I to both 30 mM glucose (42% decrease in kslow) and 3 mM glycolaldehyde (50% decrease in kfast, 60% decrease in kslow) resulting is significantly reduced affinity. Cholesterol efflux to control or glycated lipid-free apoA-I, or discoidal reconstituted HDL containing glycated apoA-I (drHDL), was examined using cholesterol-loaded murine (J774A.1) macrophages treated to increase expression of ATP binding cassette transporters A1 (ABCA1) or G1 (ABCG1). Cholesterol efflux from J774A.1 macrophages to glycated lipid-free apoA-I via ABCA1 or glycated drHDL via an ABCG1-dependent mechanism was unaltered, as was efflux to minimally modified apoA I from people with Type 1 diabetes, or controls. Changes to protein structure and function were prevented by the reactive carbonyl scavenger aminoguanidine. Overall these studies demonstrate that glycation of lipid-free apoA-I, particularly late glycation, modifies its structure, its capacity to bind phospholipids and but not ABCA1- or ABCG1-dependent cholesterol efflux from macrophages. PMID- 23741495 TI - Distribution of wild mammal assemblages along an urban-rural-forest landscape gradient in warm-temperate East Asia. AB - Urbanization may alter mammal assemblages via habitat loss, food subsidies, and other factors related to human activities. The general distribution patterns of wild mammal assemblages along urban-rural-forest landscape gradients have not been studied, although many studies have focused on a single species or taxon, such as rodents. We quantitatively evaluated the effects of the urban-rural forest gradient and spatial scale on the distributions of large and mid-sized mammals in the world's largest metropolitan area in warm-temperate Asia using nonspecific camera-trapping along two linear transects spanning from the urban zone in the Tokyo metropolitan area to surrounding rural and forest landscapes. Many large and mid-sized species generally decreased from forest landscapes to urban cores, although some species preferred anthropogenic landscapes. Sika deer (Cervus nippon), Reeves' muntjac (Muntiacus reevesi), Japanese macaque (Macaca fuscata), Japanese squirrel (Sciurus lis), Japanese marten (Martes melampus), Japanese badger (Meles anakuma), and wild boar (Sus scrofa) generally dominated the mammal assemblage of the forest landscape. Raccoon (Procyon lotor), raccoon dog (Nyctereutes procyonoides), and Japanese hare (Lepus brachyurus) dominated the mammal assemblage in the intermediate zone (i.e., rural and suburban landscape). Cats (feral and free-roaming housecats; Felis catus) were common in the urban assemblage. The key spatial scales for forest species were more than 4000-m radius, indicating that conservation and management plans for these mammal assemblages should be considered on large spatial scales. However, small green spaces will also be important for mammal conservation in the urban landscape, because an indigenous omnivore (raccoon dog) had a smaller key spatial scale (500 m radius) than those of forest mammals. Urbanization was generally the most important factor in the distributions of mammals, and it is necessary to consider the spatial scale of management according to the degree of urbanization. PMID- 23741494 TI - Transforming growth factor-beta inhibition reduces progression of early choroidal neovascularization lesions in rats: P17 and P144 peptides. AB - The purpose of this study was to assess the effects of transforming growth factor beta (TGF-beta) inhibitor peptides (P17 & P144) on early laser-induced choroidal neovascularization (LI-CNV) lesions in rats, two weeks after laser CNV induction. Seventy-one Long Evans rats underwent diode laser application in an established LI-CNV model. Baseline fluorescein angiography (FA) was performed 14 days following laser procedure, and treatments were administered 16 days post-laser application via different administration routes. Intravenous groups included control (IV-Control), P17 (IV-17), and P144 (IV-144) groups, whereas intravitreal groups included P17 (IVT-17), P144 (IVT-144), and a mixture of both peptides (IVT 17+144) (with fellow eyes receiving vehicle alone). CNV evolution was assessed using FA performed weekly for four weeks after treatment. Following sacrifice, VEGF, TGF-beta, COX-2, IGF-1, PAI-1, IL-6, MMP-2, MMP-9, and TNF-alpha gene expression was assessed using RT-PCR. VEGF and p-SMAD2 protein levels were also assessed by western-blot, while MMP-2 activity was assessed with gelatin zymography. Regarding the FA analysis, the mean CNV area was lower from the 3(rd) week in IVT-17 and IVT-144 groups, and also from the 2(nd) week in IVT-17+144. Biochemical analysis revealed that gene expression was lower for VEGF and COX-2 genes in IV-17 and IV-144 groups, VEGF gene in IVT-17+144 group and MMP-2 gene in IVT-17 and IVT-144 groups. VEGF protein expression was also decreased in IV-17, IV-144, IVT-17 and IVT-144, whereas pSMAD-2 levels were lower in IV-17, IV-144 and IVT-17+144 groups. Zymogram analysis revealed decreased MMP-2 activity in IV 17, IV-144, IVT-17 and IVT-144 groups. These data suggest that the use of TGF beta inhibitor peptides (P17 & P144) decrease the development of early CNV lesions by targeting different mediators than those typically affected using current anti-angiogenic therapies. Its potential role in the treatment of early CNV appears promising as a single therapy or adjuvant to anti-VEGF drugs. PMID- 23741496 TI - Altered expression of ZnT10 in Alzheimer's disease brain. AB - There is an increasing body of evidence suggesting that metal homeostasis is dysregulated in the pathology of Alzheimer's disease (AD). Although expression levels of several transporters belonging the SLC30 family, which comprises predominantly zinc transporters, have been studied in the AD brain, SLC30A10 (ZnT10) has not been studied in this context. To determine if dysregulated expression of ZnT10, which may transport both Zn and Mn, could be a factor that contributes to AD, we investigated if there were differences in ZnT10 mRNA levels in specimens of frontal cortex from AD patients and controls and also if brain tissue from the APP/PS1 transgenic (Tg) mouse model showed abnormal levels of ZnT10 mRNA expression. Our results show that ZnT10 is significantly (P<0.01) decreased in the frontal cortex in AD. Furthermore, we observed a significant decrease in ZnT10 mRNA levels in the APP/PS1-Tg mice compared with wild-type controls (P<0.01). Our results suggest that this dysregulation in ZnT10 could further contribute to disease progression. PMID- 23741497 TI - Dynamic of livestock-associated methicillin-resistant Staphylococcus aureus CC398 in pig farm households: a pilot study. AB - The aim of this study was to determine the long-term carriage rates and transmission dynamics of methicillin-resistant Staphylococcus aureus (MRSA) in pig farmers and their household members. During a 6-month period in 2009-2010, 4 pig farms in Denmark, Belgium, and the Netherlands, respectively, were studied for the presence of MRSA. The proportion of persistent carriers was significantly higher among farmers than among household members (87% vs. 11%) and significantly higher in household members from Belgium compared to those from Denmark and the Netherlands (29% vs. 0% vs. 6%). Determinant analysis of MRSA carriage revealed that pig contact was the most important determinant for MRSA carriage among household members and that the increased MRSA carriage rate observed among household members from Belgium is linked to country-specific differences in pig exposure. These findings demonstrated that even in pig farms with very high carriage rates of MRSA both in livestock and farmers, the risk for household members to acquire MRSA is limited and still depends strongly on pig exposure. By restricting access to the stables and exposure to pigs, MRSA acquisition by household members could be greatly reduced. PMID- 23741498 TI - Pulsed electromagnetic fields increased the anti-inflammatory effect of A2A and A3 adenosine receptors in human T/C-28a2 chondrocytes and hFOB 1.19 osteoblasts. AB - Adenosine receptors (ARs) have an important role in the regulation of inflammation and their activation is involved in the inhibition of pro inflammatory cytokine release. The effects of pulsed electromagnetic fields (PEMFs) on inflammation have been reported and we have demonstrated that PEMFs increased A2A and A3AR density and functionality in different cell lines. Chondrocytes and osteoblasts are two key cell types in the skeletal system that play important role in cartilage and bone metabolism representing an interesting target to study the effect of PEMFs. The primary aim of the present study was to evaluate if PEMF exposure potentiated the anti-inflammatory effect of A2A and/or A3ARs in T/C-28a2 chondrocytes and hFOB 1.19 osteoblasts. Immunofluorescence, mRNA analysis and saturation binding assays revealed that PEMF exposure up regulated A2A and A3AR expression. A2A and A3ARs were able to modulate cAMP production and cell proliferation. The activation of A2A and A3ARs resulted in the decrease of some of the most relevant pro-inflammatory cytokine release such as interleukin (IL)-6 and IL-8, following the treatment with IL-1beta as an inflammatory stimuli. In human chondrocyte and osteoblast cell lines, the inhibitory effect of A2A and A3AR stimulation on the release of prostaglandin E2 (PGE2), an important lipid inflammatory mediator, was observed. In addition, in T/C-28a2 cells, the activation of A2A or A3ARs elicited an inhibition of vascular endothelial growth factor (VEGF) secretion. In hFOB 1.19 osteoblasts, PEMF exposure determined an increase of osteoprotegerin (OPG) production. The effect of the A2A or A3AR agonists in the examined cells was enhanced in the presence of PEMFs and completely blocked by using well-known selective antagonists. These results demonstrated that PEMF exposure significantly increase the anti inflammatory effect of A2A or A3ARs suggesting their potential therapeutic use in the therapy of inflammatory bone and joint disorders. PMID- 23741499 TI - The development of a universal in silico predictor of protein-protein interactions. AB - Protein-protein interactions (PPIs) are essential for understanding the function of biological systems and have been characterized using a vast array of experimental techniques. These techniques detect only a small proportion of all PPIs and are labor intensive and time consuming. Therefore, the development of computational methods capable of predicting PPIs accelerates the pace of discovery of new interactions. This paper reports a machine learning-based prediction model, the Universal In Silico Predictor of Protein-Protein Interactions (UNISPPI), which is a decision tree model that can reliably predict PPIs for all species (including proteins from parasite-host associations) using only 20 combinations of amino acids frequencies from interacting and non interacting proteins as learning features. UNISPPI was able to correctly classify 79.4% and 72.6% of experimentally supported interactions and non-interacting protein pairs, respectively, from an independent test set. Moreover, UNISPPI suggests that the frequencies of the amino acids asparagine, cysteine and isoleucine are important features for distinguishing between interacting and non interacting protein pairs. We envisage that UNISPPI can be a useful tool for prioritizing interactions for experimental validation. PMID- 23741500 TI - Progesterone receptor-mediated regulation of N-acetylneuraminate pyruvate lyase (NPL) in mouse uterine luminal epithelium and nonessential role of NPL in uterine function. AB - N-acetylneuraminate pyruvate lyase (NPL) catalyzes N-acetylneuraminic acid, the predominant sialic acid. Microarray analysis of the periimplantation mouse uterine luminal epithelium (LE) revealed Npl being the most downregulated (35*) gene in the LE upon embryo implantation. In natural pregnant mouse uterus, Npl expression increased 56* from gestation day 0.5 (D0.5) to D2.5. In ovariectomized mouse uterus, Npl was significantly upregulated by progesterone (P4) but downregulated by 17beta-estradiol (E2). Progesterone receptor (PR) antagonist RU486 blocked the upregulation of Npl in both preimplantation uterus and P4 treated ovariectomized uterus. Npl was specifically localized in the preimplantation D2.5 and D3.5 uterine LE. Since LE is essential for establishing uterine receptivity, it was hypothesized that NPL might play a critical role in uterine function, especially during embryo implantation. This hypothesis was tested in the Npl ((-/-)) mice. No significant differences were observed in the numbers of implantation sites on D4.5, gestation periods, litter sizes, and postnatal offspring growth between wild type (WT) and Npl ((-/-)) females from mating with WT males. Npl ((-/-))xNpl ((-/-)) crosses produced comparable little sizes as that from WTxWT crosses. Comparable mRNA expression levels of several genes involved in sialic acid metabolism were observed in D3.5 uterus and uterine LE between WT and Npl ((-/-)), indicating no compensatory upregulation in the D3.5 Npl ((-/-)) uterus and LE. This study demonstrates PR-mediated dynamic expression of Npl in the periimplantation uterus and dispensable role of Npl in uterine function and embryo development. PMID- 23741501 TI - Latent transforming growth factor beta-binding protein 4 is downregulated in esophageal cancer via promoter methylation. AB - Latent transforming growth factor beta-binding protein 4 (LTBP4) is an extracellular matrix molecule that is a member of important connective tissue networks and is needed for the correct folding and the secretion of TGF-beta1. LTBP4 is downregulated in carcinomas of various tissues. Here we show that LTBP4 is also downregulated in adenocarcinomas and squamous cell carcinomas of the esophagus in vitro and in vivo. Re-expression of LTBP4 in esophageal cancer cell lines reduced cell migration ability, whereas cell viability and cell proliferation remained unchanged. Hypermethylation of the promoter regions of the two main human LTBP4 transcriptional forms, LTBP4L and LTBP4S, was found to be involved in LTBP4 silencing. Detailed investigations of the methylation patterns of the promoter regions of LTBP4L and LTBP4S identified GATA1, SP1, E2F4 and SMAD3 as potential transcription factors involved in LTBP4 expression. In in vitro transcription factor activity studies we discovered E2F4 as novel powerful regulator for LTBP4S expression. PMID- 23741502 TI - Galectin-9 activates and expands human T-helper 1 cells. AB - Galectin-9 (Gal-9) is known for induction of apoptosis in IFN-gamma and IL-17 producing T-cells and amelioration of autoimmunity in murine models. On the other hand, Gal-9 induced IFN-gamma positive T-cells in a sarcoma mouse model and in food allergy, suggesting that Gal-9 can have diametric effects on T-cell immunity. Here, we aimed to delineate the immunomodulatory effect of Gal-9 on human resting and ex vivo activated peripheral blood lymphocytes. Treatment of resting lymphocytes with low concentrations of Gal-9 (5-30 nM) induced apoptosis in ~60% of T-cells after 1 day, but activated the surviving T-cells. These viable T-cells started to expand after 4 days with up to 6 cell divisions by day 7 and an associated shift from naive towards central memory and IFN-gamma producing phenotype. In the presence of T-cell activation signals (anti-CD3/IL-2) Gal-9 did not induce T-cell expansion, but shifted the CD4/CD8 balance towards a CD4 dominated T-cell response. Thus, Gal-9 activates resting T-cells in the absence of typical T-cell activating signals and promotes their transition to a TH1/C1 phenotype. In the presence of T-cell activating signals T-cell immunity is directed towards a CD4-driven response by Gal-9. Thus, Gal-9 may specifically enhance reactive immunological memory. PMID- 23741503 TI - Natural experiment demonstrates that bird loss leads to cessation of dispersal of native seeds from intact to degraded forests. AB - In healthy forests, vertebrate frugivores move seeds from intact to degraded forests, aiding in the passive regeneration of degraded forests. Yet vertebrate frugivores are declining around the world, and little is known about the impact of this loss on regeneration of degraded areas. Here, we use a unique natural experiment to assess how complete vertebrate frugivore loss affects native seed rain in degraded forest. All native vertebrate frugivores (which were primarily avian frugivores) have been functionally extirpated from the island of Guam by the invasive brown tree snake (Boiga irregularis), whereas the nearby island of Saipan has a relatively intact vertebrate frugivore community. We captured seed rain along transects extending from intact into degraded forest and compared the species richness, density and condition of the seed rain from native bird dispersed tree species between the two islands. Considering seeds from native bird-dispersed species, approximately 1.66 seeds landed per 26 days in each square meter of degraded forest on Saipan, whereas zero seeds landed per 26 days per square meter in degraded forest on Guam. Additionally, on Saipan, 69% of native bird-dispersed seeds in intact forest and 77% of seeds in degraded forest lacked fleshy fruit pulp, suggesting ingestion by birds, compared to 0% of all seeds on Guam. Our results show an absence of seed rain in degraded forests on Guam, correlated with the absence of birds, whereas on Saipan, frugivorous birds regularly disperse seeds into degraded forests, providing a mechanism for re colonization by native plants. These results suggest that loss of frugivores will slow regeneration of degraded forests on Guam. PMID- 23741504 TI - SOAP3-dp: fast, accurate and sensitive GPU-based short read aligner. AB - To tackle the exponentially increasing throughput of Next-Generation Sequencing (NGS), most of the existing short-read aligners can be configured to favor speed in trade of accuracy and sensitivity. SOAP3-dp, through leveraging the computational power of both CPU and GPU with optimized algorithms, delivers high speed and sensitivity simultaneously. Compared with widely adopted aligners including BWA, Bowtie2, SeqAlto, CUSHAW2, GEM and GPU-based aligners BarraCUDA and CUSHAW, SOAP3-dp was found to be two to tens of times faster, while maintaining the highest sensitivity and lowest false discovery rate (FDR) on Illumina reads with different lengths. Transcending its predecessor SOAP3, which does not allow gapped alignment, SOAP3-dp by default tolerates alignment similarity as low as 60%. Real data evaluation using human genome demonstrates SOAP3-dp's power to enable more authentic variants and longer Indels to be discovered. Fosmid sequencing shows a 9.1% FDR on newly discovered deletions. SOAP3-dp natively supports BAM file format and provides the same scoring scheme as BWA, which enables it to be integrated into existing analysis pipelines. SOAP3 dp has been deployed on Amazon-EC2, NIH-Biowulf and Tianhe-1A. PMID- 23741505 TI - Candidate genes and genetic architecture of symbiotic and agronomic traits revealed by whole-genome, sequence-based association genetics in Medicago truncatula. AB - Genome-wide association study (GWAS) has revolutionized the search for the genetic basis of complex traits. To date, GWAS have generally relied on relatively sparse sampling of nucleotide diversity, which is likely to bias results by preferentially sampling high-frequency SNPs not in complete linkage disequilibrium (LD) with causative SNPs. To avoid these limitations we conducted GWAS with >6 million SNPs identified by sequencing the genomes of 226 accessions of the model legume Medicago truncatula. We used these data to identify candidate genes and the genetic architecture underlying phenotypic variation in plant height, trichome density, flowering time, and nodulation. The characteristics of candidate SNPs differed among traits, with candidates for flowering time and trichome density in distinct clusters of high linkage disequilibrium (LD) and the minor allele frequencies (MAF) of candidates underlying variation in flowering time and height significantly greater than MAF of candidates underlying variation in other traits. Candidate SNPs tagged several characterized genes including nodulation related genes SERK2, MtnodGRP3, MtMMPL1, NFP, CaML3, MtnodGRP3A and flowering time gene MtFD as well as uncharacterized genes that become candidates for further molecular characterization. By comparing sequence-based candidates to candidates identified by in silico 250K SNP arrays, we provide an empirical example of how reliance on even high-density reduced representation genomic makers can bias GWAS results. Depending on the trait, only 30-70% of the top 20 in silico array candidates were within 1 kb of sequence-based candidates. Moreover, the sequence-based candidates tagged by array candidates were heavily biased towards common variants; these comparisons underscore the need for caution when interpreting results from GWAS conducted with sparsely covered genomes. PMID- 23741506 TI - Pericytes derived from adipose-derived stem cells protect against retinal vasculopathy. AB - BACKGROUND: Retinal vasculopathies, including diabetic retinopathy (DR), threaten the vision of over 100 million people. Retinal pericytes are critical for microvascular control, supporting retinal endothelial cells via direct contact and paracrine mechanisms. With pericyte death or loss, endothelial dysfunction ensues, resulting in hypoxic insult, pathologic angiogenesis, and ultimately blindness. Adipose-derived stem cells (ASCs) differentiate into pericytes, suggesting they may be useful as a protective and regenerative cellular therapy for retinal vascular disease. In this study, we examine the ability of ASCs to differentiate into pericytes that can stabilize retinal vessels in multiple pre clinical models of retinal vasculopathy. METHODOLOGY/PRINCIPAL FINDINGS: We found that ASCs express pericyte-specific markers in vitro. When injected intravitreally into the murine eye subjected to oxygen-induced retinopathy (OIR), ASCs were capable of migrating to and integrating with the retinal vasculature. Integrated ASCs maintained marker expression and pericyte-like morphology in vivo for at least 2 months. ASCs injected after OIR vessel destabilization and ablation enhanced vessel regrowth (16% reduction in avascular area). ASCs injected intravitreally before OIR vessel destabilization prevented retinal capillary dropout (53% reduction). Treatment of ASCs with transforming growth factor beta (TGF-beta1) enhanced hASC pericyte function, in a manner similar to native retinal pericytes, with increased marker expression of smooth muscle actin, cellular contractility, endothelial stabilization, and microvascular protection in OIR. Finally, injected ASCs prevented capillary loss in the diabetic retinopathic Akimba mouse (79% reduction 2 months after injection). CONCLUSIONS/SIGNIFICANCE: ASC-derived pericytes can integrate with retinal vasculature, adopting both pericyte morphology and marker expression, and provide functional vascular protection in multiple murine models of retinal vasculopathy. The pericyte phenotype demonstrated by ASCs is enhanced with TGF-beta1 treatment, as seen with native retinal pericytes. ASCs may represent an innovative cellular therapy for protection against and repair of DR and other retinal vascular diseases. PMID- 23741507 TI - Single nucleotide polymorphisms of the angiotensin-converting enzyme (ACE) gene are associated with essential hypertension and increased ACE enzyme levels in Mexican individuals. AB - AIM: To explore the role of the ACE gene polymorphisms in the risk of essential hypertension in Mexican Mestizo individuals and evaluate the correlation between these polymorphisms and the serum ACE levels. METHODS: Nine ACE gene polymorphisms were genotyped by 5' exonuclease TaqMan genotyping assays and polymerase chain reaction (PCR) in 239 hypertensive and 371 non- hypertensive Mexican individuals. Haplotypes were constructed after linkage disequilibrium analysis. ACE serum levels were determined in selected individuals according to different haplotypes. RESULTS: Under a dominant model, rs4291 rs4335, rs4344, rs4353, rs4362, and rs4363 polymorphisms were associated with an increased risk of hypertension after adjusting for age, gender, BMI, triglycerides, alcohol consumption, and smoking. Five polymorphisms (rs4335, rs4344, rs4353, rs4362 and rs4363) were in strong linkage disequilibrium and were included in four haplotypes: H1 (AAGCA), H2 (GGATG), H3 (AGATG), and H4 (AGACA). Haplotype H1 was associated with decreased risk of hypertension, while haplotype H2 was associated with an increased risk of hypertension (OR = 0.77, P = 0.023 and OR = 1.41, P = 0.004 respectively). According to the codominant model, the H2/H2 and H1/H2 haplotype combinations were significantly associated with risk of hypertension after adjusted by age, gender, BMI, triglycerides, alcohol consumption, and smoking (OR = 2.0; P = 0.002 and OR = 2.09; P = 0.011, respectively). Significant elevations in serum ACE concentrations were found in individuals with the H2 haplotype (H2/H2 and H2/H1) as compared to H1/H1 individuals (P = 0.0048). CONCLUSION: The results suggest that single nucleotide polymorphisms and the "GGATG" haplotype of the ACE gene are associated with the development of hypertension and with increased ACE enzyme levels. PMID- 23741508 TI - Differential expression of secreted phosphoprotein 1 in the motor cortex among primate species and during postnatal development and functional recovery. AB - We previously reported that secreted phosphoprotein 1 (SPP1) mRNA is expressed in neurons whose axons form the corticospinal tract (CST) of the rhesus macaque, but not in the corresponding neurons of the marmoset and rat. This suggests that SPP1 expression is involved in the functional or structural specialization of highly developed corticospinal systems in certain primate species. To further examine this hypothesis, we evaluated the expression of SPP1 mRNA in the motor cortex from three viewpoints: species differences, postnatal development, and functional/structural changes of the CST after a lesion of the lateral CST (l CST) at the mid-cervical level. The density of SPP1-positive neurons in layer V of the primary motor cortex (M1) was much greater in species with highly developed corticospinal systems (i.e., rhesus macaque, capuchin monkey, and humans) than in those with less developed corticospinal systems (i.e., squirrel monkey, marmoset, and rat). SPP1-positive neurons in the macaque monkey M1 increased logarithmically in layer V during postnatal development, following a time course consistent with the increase in conduction velocity of the CST. After an l-CST lesion, SPP1-positive neurons increased in layer V of the ventral premotor cortex, in which compensatory changes in CST function/structure may occur, which positively correlated with the extent of finger dexterity recovery. These results further support the concept that the expression of SPP1 may reflect functional or structural specialization of highly developed corticospinal systems in certain primate species. PMID- 23741509 TI - Atorvastatin enhance efficacy of mesenchymal stem cells treatment for swine myocardial infarction via activation of nitric oxide synthase. AB - BACKGROUND: In a swine model of acute myocardial infarction (AMI), Statins can enhance the therapeutic efficacy of mesenchymal stem cell (MSCs) transplantation. However, the mechanisms remain unclear. This study aims at assessing whether atorvastatin (Ator) facilitates the effects of MSCs through activation of nitric oxide synthase (NOS), especially endothelial nitric oxide synthase (eNOS), which is known to protect against ischemic injury. METHODS AND RESULTS: 42 miniswines were randomized into six groups (n = 7/group): Sham operation; AMI control; Ator only; MSC only, Ator+MSCs and Ator+MSCs+NG-nitrol-L-arginine (L-NNA), an inhibitor of NOS. In an open-heart surgery, swine coronary artery ligation and reperfusion model were established, and autologous bone-marrow MSCs were injected intramyocardium. Four weeks after transplantation, compared with the control group, Ator+MSCs animals exhibited decreased defect areas of both "perfusion" defined by Single-Photon Emission Computed Tomography (-6.2+/-1.8% vs. 2.0+/ 5.1%, P = 0.0001) and "metabolism" defined by Positron Emission Tomography ( 3.00+/-1.41% vs. 4.20+/-4.09%, P = 0.0004); Ejection fraction by Magnetic Resonance Imaging increased substantially (14.22+/-12.8% vs. 1.64+/-2.64%, P = 0.019). In addition, indices of inflammation, fibrosis, and apoptosis were reduced and survivals of MSCs or MSC-derived cells were increased in Ator+MSCs animals. In Ator or MSCs alone group, perfusion, metabolism, inflammation, fibrosis or apoptosis were reduced but there were no benefits in terms of heart function and cell survival. Furthermore, the above benefits of Ator+MSCs treatment could be partially blocked by L-NNA. CONCLUSIONS: Atorvastatin facilitates survival of implanted MSCs, improves function and morphology of infarcted hearts, mediated by activation of eNOS and alleviated by NOS inhibitor. The data reveal the cellular and molecular mechanism for anti-AMI therapy with a combination of statin and stem cells. PMID- 23741510 TI - Determination of olanzapine and N-desmethyl-olanzapine in plasma using a reversed phase HPLC coupled with coulochemical detection: correlation of olanzapine or N desmethyl-olanzapine concentration with metabolic parameters. AB - BACKGROUND: Olanzapine (OLZ) is one of the most prescribed atypical antipsychotic drugs but its use is associated with unfavorable metabolic abnormalities. N desmethyl-olanzapine (DMO), one of the OLZ metabolites by CYP1A2, has been reported to have a normalizing action on metabolic abnormalities, but this remains unclear. Our aim was to explore the correlation between the concentrations of OLZ or DMO with various metabolic parameters in schizophrenic patients. METHODS: The chromatographic analysis was carried out with a solvent delivery system coupled to a Coulochem III coulometric detector to determine OLZ and DMO simultaneously in OLZ-treated patients. The correlation between the concentration of OLZ or DMO and the metabolic parameters was analyzed by the Spearman rank order correlation method (r s). PRINCIPAL FINDINGS: The established analytical method met proper standards for accuracy and reliability and the lower limitation of quantification for each injection of DMO or OLZ was 0.02 ng. The method was successfully used for the analysis of samples from nonsmoking patients (n = 48) treated with OLZ in the dosage range of 5-20 mg per day. There was no correlation between OLZ concentrations and tested metabolic parameters. DMO concentrations were negatively correlated with glucose (r s = -0.45) and DMO concentrations normalized by doses were also negatively correlated with insulin levels (r s = -0.39); however, there was a marginally positive correlation between DMO and homocysteine levels (r s = +0.38). CONCLUSIONS: The observed negative correlations between levels of DMO and glucose or insulin suggest a metabolic normalization role for DMO regardless of its positive correlation with a known cardiovascular risk factor, homocysteine. Additional studies of the mechanisms underlying DMO's metabolic effects are warranted. PMID- 23741511 TI - Impairment of ribosome maturation or function confers salt resistance on Escherichia coli cells. AB - We found that loss of integrity of the ribosome by removal of a putative ribosome maturation factor or a ribosomal protein conferred salt tolerance on Escherichia coli cells. Some protein synthesis inhibitors including kasugamycin and chloramphenicol also had a similar effect, although kasugamycin affected neither 16S rRNA maturation nor subunit association into a 70S ribosome. Thus, salt tolerance is a common feature of cells in which maturation or function of the ribosome is impaired. In these cells, premature induction of an alternative sigma factor, sigma(E), by salt stress was observed. These results suggest the existence of a yet-unknown stress response pathway mediated by the bacterial ribosome. PMID- 23741512 TI - Evidence that transcription factor AP-2gamma is not required for Oct4 repression in mouse blastocysts. AB - In mouse blastocysts segregation of the inner cell mass (ICM) and the trophectoderm (TE) is regulated by the mutually antagonistic effects of the transcription factors Oct4 and Cdx2 expressed in the ICM and TE, respectively. In contrast, in other species such as bovine and human, Oct4 is not restricted to the ICM and continues to be expressed in the Cdx2-positive TE. A recent comparative study of the bovine and mouse Oct4 promoters revealed that additional mechanisms might act in conjunction with Cdx2 to downregulate Oct4 expression in the mouse TE lineage. For instance, the mouse Oct4 distal enhancer contains an AP 2gamma (Tcfap2c) binding motif that is absent in the bovine and human Oct4 distal enhancer. Nonetheless, the functional relevance of Tcfap2c in Oct4 repression during mouse preimplantation development was not tested. To elucidate the role of Tcfap2c in Oct4 expression an RNA interference approach was utilized. Depletion of Tcfap2c triggered a decrease in Oct4 expression at the 8-cell and morula stage. Remarkably, at the blastocyst stage depletion of Tcfap2c and/or its family member Tcfap2a had no effect on Oct4 repression. To test whether Tcfap2c interacts with Oct4 to positively regulate Oct4 expression, chromatin immunoprecipitation and in situ co-immunoprecipitation analyses were performed. These experiments revealed Tcfap2c and Oct4 binding were enriched at the Oct4 distal enhancer in embryonic stem (ES) cells, but were rapidly lost during differentiation into trophoblast-like cells when Oct4 became repressed. Moreover, Tcfap2c and Oct4 interactions were detected at the morula stage, but were lost during blastocyst formation. In summary, these data demonstrate that Tcfap2c is not required for Oct4 silencing in mouse blastocysts, but may be necessary for the maintenance of Oct4 expression during the 8 cell-to-morula transition. These findings support the notion Cdx2 is the predominant negative regulator of Oct4 expression during blastocyst formation in mice. PMID- 23741513 TI - Association of cardiovascular burden with mobility limitation among elderly people: a population-based study. AB - BACKGROUND: Cardiovascular risk factors (CRFs) such as smoking and diabetes have been associated with mobility limitations among older adults. We seek to examine to what extent individual and aggregated CRFs and cardiovascular diseases (CVDs) are associated with mobility limitation. METHODS: The study sample included 2725 participants (age >=60 years, mean age 72.7 years, 62% women) in the Swedish National Study on Aging and Care in the Kungsholmen district of central Stockholm, Sweden, who were living either at their own home or in institutions. Data on demographic features, CRFs, and CVDs were collected through interview, clinical examination, self-reported history, laboratory tests, and inpatient register. Mobility limitation was defined as walking speed <0.8 m/s. Data were analyzed using multiple logistic models controlling for potential confounders. RESULTS: Of the 2725 participants, 581 (21.3%) had mobility limitation. The likelihood of mobility limitation increased linearly with the increasing number of CRFs (i.e., hypertension, high C-reactive protein, obesity, diabetes and smoking) (p for linear trend<0.010) and of CVDs (i.e., ischemic heart disease, atrial fibrillation, heart failure and stroke) (p for linear trend<0.001). There were statistical interactions of aggregated CRFs with age and APOE epsilon4 allele on mobility limitation (p interaction<0.05), such that the association of mobility limitation with aggregated CRFs was statistically evident only among people aged <80 years and among carriers of the APOE epsilon4 allele. CONCLUSION: Aggregations of multiple CRFs and CVDs are associated with an increased likelihood of mobility limitation among older adults; however the associations of CRFs with mobility limitation vary by age and genetic susceptibility. PMID- 23741514 TI - Heterogeneity in the energy cost of posture maintenance during standing relative to sitting: phenotyping according to magnitude and time-course. AB - BACKGROUND: Reducing sitting-time may decrease risk of disease and increase life span. In the search for approaches to reduce sitting-time, research often compares sitting to standing and ambulation, but the energetic cost of standing alone versus sitting is equivocal, with large variation in reported mean values (0% to >20% increase in energy expenditure (EE) during standing). OBJECTIVE: To determine the magnitude and time-course of changes in EE and respiratory quotient (RQ) during steady-state standing versus sitting. DESIGN: Min-by-min monitoring using a posture-adapted ventilated-hood indirect calorimetry system was conducted in 22 young adults with normal BMI during 10 min of steady-state standing versus sitting comfortably. RESULTS: This study reveals three distinct phenotypes based on the magnitude and time-course of the EE response to steady-state standing. One third of participants (8/22) showed little or no change in EE during standing relative to sitting (DeltaEE <5%; below first quartile). Of the 14 responders (DeltaEE 7-21%), 4 showed sustained, elevated EE during standing, while 10 decreased their EE to baseline sitting values during the second half of the standing period. These EE phenotypes were systematically mirrored by alterations in RQ (a proxy of substrate oxidation), with DeltaEE inversely correlated with DeltaRQ (r = 0.6-0.8, p<0.01). CONCLUSION: This study reveals different phenotypes pertaining to both energy cost and fuel utilization during standing, raising questions regarding standing as a strategy to increase EE and thermogenesis for weight control, and opening new avenues of research towards understanding the metabolic and psychomotor basis of variability in the energetics of standing and posture maintenance. PMID- 23741515 TI - A herbivore knows its patch: luderick, Girella tricuspidata, exhibit strong site fidelity on shallow subtidal reefs in a temperate marine park. AB - Understanding movement patterns, habitat use and behaviour of fish is critical to determining how targeted species may respond to protection provided by "no-take" sanctuary zones within marine parks. We assessed the fine and broad scale movement patterns of an exploited herbivore, luderick (Girella tricuspidata), using acoustic telemetry to evaluate how this species may respond to protection within Jervis Bay (New South Wales, Australia). We surgically implanted fourteen fish with acoustic transmitters and actively and passively tracked individuals to determine fine and broad scale movement patterns respectively. Eight fish were actively tracked for 24 h d-(1) for 6 d (May 2011), and then intermittently over the following 30 d. Six fish were passively tracked from December 2011 to March 2012, using a fixed array of receivers deployed across rocky reefs around the perimeter of the bay. Luderick exhibited strong site fidelity on shallow subtidal reefs, tending to remain on or return consistently to the reef where they were caught and released. All eight fish actively tracked used core areas solely on their release reef, with the exception of one fish that used multiple core areas, and four of the six fish passively tracked spent between 75 to 96% of days on release reefs over the entire tracking period. Luderick did move frequently to adjacent reefs, and occasionally to more distant reefs, however consistently returned to their release reef. Luderick also exhibited predictable patterns in movement between spatially distinct daytime and night-time core use areas. Night time core use areas were generally located in sheltered areas behind the edge of reefs. Overall, our data indicate luderick exhibit strong site fidelity on shallow subtidal reefs in Jervis Bay and suggests that this important herbivore may be likely to show a positive response to protection within the marine park. PMID- 23741516 TI - Habitat quality and geometry affect patch occupancy of two Orthopteran species. AB - Impacts of habitat loss and fragmentation on distribution and population size of many taxa are well established. In contrast, less is known about the role of within-patch habitat quality for the spatial dynamics of species, even though within-patch habitat quality may substantially influence the dynamics of population networks. We studied occurrence patterns of two Orthopteran species in relation to size, isolation and quality of habitat patches in an intensively managed agricultural landscape (16.65 km(2)) in the Swiss lowland. Occurrence of field crickets (Gryllus campestris) was positively related to patch size and negatively to the distance to the nearest occupied patch, two measures of patch geometry. Moreover, field crickets were more likely to occur in extensively managed meadows, meadows used at low intensity and meadows dominated by Poa pratensis, three measures of patch quality. Occurrence of the large gold grasshopper (Chrysochraon dispar) was negatively related to two measures of patch geometry, distance to the nearest occupied patch and perimeter index (ratio of perimeter length to patch area). Further, large gold grasshoppers were more likely to occupy patches close to water and patches with vegetation left uncut over winter, two measures of patch quality. Finally, examination of patch occupancy dynamics of field crickets revealed that patches colonized in 2009 and patches occupied in both 2005 and 2009 were larger, better connected and of other quality than patches remaining unoccupied and patches from which the species disappeared. The strong relationships between Orthopteran occurrence and aspects of patch geometry found in this study support the "area-and-isolation paradigm". Additionally, our study reveals the importance of patch quality for occurrence patterns of both species, and for patch occupancy dynamics in the field cricket. An increased understanding of patch occupancy patterns may be gained if inference is based on variables related to both habitat geometry and quality. PMID- 23741517 TI - Mapping the epitopes of a neutralizing antibody fragment directed against the lethal factor of Bacillus anthracis and cross-reacting with the homologous edema factor. AB - The lethal toxin (LT) of Bacillus anthracis, composed of the protective antigen (PA) and the lethal factor (LF), plays an essential role in anthrax pathogenesis. PA also interacts with the edema factor (EF, 20% identity with LF) to form the edema toxin (ET), which has a lesser role in anthrax pathogenesis. The first recombinant antibody fragment directed against LF was scFv 2LF; it neutralizes LT by blocking the interaction between PA and LF. Here, we report that scFv 2LF cross-reacts with EF and cross-neutralizes ET, and we present an in silico method taking advantage of this cross-reactivity to map the epitope of scFv 2LF on both LF and EF. This method identified five epitope candidates on LF, constituted of a total of 32 residues, which were tested experimentally by mutating the residues to alanine. This combined approach precisely identified the epitope of scFv 2LF on LF as five residues (H229, R230, Q234, L235 and Y236), of which three were missed by the consensus epitope candidate identified by pre-existing in silico methods. The homolog of this epitope on EF (H253, R254, E258, L259 and Y260) was experimentally confirmed to constitute the epitope of scFv 2LF on EF. Other inhibitors, including synthetic molecules, could be used to target these epitopes for therapeutic purposes. The in silico method presented here may be of more general interest. PMID- 23741518 TI - Masked priming of conceptual features reveals differential brain activation during unconscious access to conceptual action and sound information. AB - Previous neuroimaging studies suggested an involvement of sensory-motor brain systems during conceptual processing in support of grounded cognition theories of conceptual memory. However, in these studies with visible stimuli, contributions of strategic imagery or semantic elaboration processes to observed sensory-motor activity cannot be entirely excluded. In the present study, we therefore investigated the electrophysiological correlates of unconscious feature-specific priming of action- and sound-related concepts within a novel feature-priming paradigm to specifically probe automatic processing of conceptual features without the contribution of possibly confounding factors such as orthographic similarity or response congruency. Participants were presented with a masked subliminal prime word and a subsequent visible target word. In the feature priming conditions primes as well as targets belonged to the same conceptual feature dimension (action or sound, e.g., typewriter or radio) whereas in the two non-priming conditions, either the primes or the targets consisted of matched control words with low feature relevance (e.g., butterfly or candle). Event related potential analyses revealed unconscious feature-specific priming effects at fronto-central electrodes within 100 to 180 ms after target stimulus onset that differed with regard to topography and underlying neural generators. In congruency with previous findings under visible stimulation conditions, these differential subliminal ERP feature-priming effects demonstrate an unconscious automatic access to action versus sound features of concepts. The present results therefore support grounded cognition theory suggesting that activity in sensory and motor areas during conceptual processing can also occur unconsciously and is not mandatorily accompanied by a vivid conscious experience of the conceptual content such as in imagery. PMID- 23741519 TI - Endolymphatic Na+ and K+ concentrations during cochlear growth and enlargement in mice lacking Slc26a4/pendrin. AB - Slc26a4 (Delta/Delta) mice are deaf, develop an enlarged membranous labyrinth, and thereby largely resemble the human phenotype where mutations of SLC26A4 cause an enlarged vestibular aqueduct and sensorineural hearing loss. The enlargement is likely caused by abnormal ion and fluid transport during the time of embryonic development, however, neither the mechanisms of ion transport nor the ionic composition of the luminal fluid during this time of development are known. Here we determine the ionic composition of inner ear fluids at the time at which the enlargement develops and the onset of expression of selected ion transporters. Concentrations of Na(+) and K(+) were measured with double-barreled ion-selective electrodes in the cochlea and the endolymphatic sac of Slc26a4 (Delta/+), which develop normal hearing, and of Slc26a4 (Delta/Delta) mice, which fail to develop hearing. The expression of specific ion transporters was examined by quantitative RT-PCR and immunohistochemistry. High Na(+) (~141 mM) and low K(+) concentrations (~11 mM) were found at embryonic day (E) 16.5 in cochlear endolymph of Slc26a4 (Delta/+) and Slc26a4 (Delta/Delta) mice. Shortly before birth the K(+) concentration began to rise. Immediately after birth (postnatal day 0), the Na(+) and K(+) concentrations in cochlear endolymph were each ~80 mM. In Slc26a4 (Delta/Delta) mice, the rise in the K(+) concentration occurred with a ~3 day delay. K(+) concentrations were also found to be low (~15 mM) in the embryonic endolymphatic sac. The onset of expression of the K(+) channel KCNQ1 and the Na(+)/2Cl(-)/K(+) cotransporter SLC12A2 occurred in the cochlea at E19.5 in Slc26a4 (Delta/+) and Slc26a4 (Delta/Delta) mice. These data demonstrate that endolymph, at the time at which the enlargement develops, is a Na(+)-rich fluid, which transitions into a K(+)-rich fluid before birth. The data suggest that the endolymphatic enlargement caused by a loss of Slc26a4 is a consequence of disrupted Na(+) transport. PMID- 23741520 TI - A giant pliosaurid skull from the late Jurassic of England. AB - Pliosaurids were a long-lived and cosmopolitan group of marine predators that spanned 110 million years and occupied the upper tiers of marine ecosystems from the Middle Jurassic until the early Late Cretaceous. A well-preserved giant pliosaurid skull from the Late Jurassic Kimmeridge Clay Formation of Dorset, United Kingdom, represents a new species, Pliosaurus kevani. This specimen is described in detail, and the taxonomy and systematics of Late Jurassic pliosaurids is revised. We name two additional new species, Pliosaurus carpenteri and Pliosaurus westburyensis, based on previously described relatively complete, well-preserved remains. Most or all Late Jurassic pliosaurids represent a globally distributed monophyletic group (the genus Pliosaurus, excluding 'Pliosaurus' andrewsi). Despite its high species diversity, and geographically widespread, temporally extensive occurrence, Pliosaurus shows relatively less morphological and ecological variation than is seen in earlier, multi-genus pliosaurid assemblages such as that of the Middle Jurassic Oxford Clay Formation. It also shows less ecological variation than the pliosaurid-like Cretaceous clade Polycotylidae. Species of Pliosaurus had robust skulls, large body sizes (with skull lengths of 1.7-2.1 metres), and trihedral or subtrihedral teeth suggesting macropredaceous habits. Our data support a trend of decreasing length of the mandibular symphysis through Late Jurassic time, as previously suggested. This may be correlated with increasing adaptation to feeding on large prey. Maximum body size of pliosaurids increased from their first appearance in the Early Jurassic until the Early Cretaceous (skull lengths up to 2360 mm). However, some reduction occurred before their final extinction in the early Late Cretaceous (skull lengths up to 1750 mm). PMID- 23741521 TI - Near their thresholds for detection, shapes are discriminated by the angular separation of their corners. AB - Observers make sense of scenes by parsing images on the retina into meaningful objects. This ability is retained for line drawings, demonstrating that critical information is concentrated at object boundaries. Information theoretic studies argue for further concentration at points of maximum curvature, or corners, on such boundaries [1]-[3] suggesting that the relative positions of such corners might be important in defining shape. In this study we use patterns subtly deformed from circular, by a sinusoidal modulation of radius, in order to measure threshold sensitivity to shape change. By examining the ability of observers to discriminate between patterns of different frequency and/or number of cycles of modulation in a 2x2 forced choice task we were able to show, psychophysically, that difference in a single cue, the periodicity of the corners (specifically the polar angle between two points of maximum curvature) was sufficient to allow discrimination of two patterns near their thresholds for detection. We conclude that patterns could be considered as labelled for this measure. These results suggest that a small number of such labels might be sufficient to identify an object. PMID- 23741522 TI - Eye-blink behaviors in 71 species of primates. AB - The present study was performed to investigate the associations between eye-blink behaviors and various other factors in primates. We video-recorded 141 individuals across 71 primate species and analyzed the blink rate, blink duration, and "isolated" blink ratio (i.e., blinks without eye or head movement) in relation to activity rhythms, habitat types, group size, and body size factors. The results showed close relationships between three types of eye-blink measures and body size factors. All of these measures increased as a function of body weight. In addition, diurnal primates showed more blinks than nocturnal species even after controlling for body size factors. The most important findings were the relationships between eye-blink behaviors and social factors, e.g., group size. Among diurnal primates, only the blink rate was significantly correlated even after controlling for body size factors. The blink rate increased as the group size increased. Enlargement of the neocortex is strongly correlated with group size in primate species and considered strong evidence for the social brain hypothesis. Our results suggest that spontaneous eye-blinks have acquired a role in social communication, similar to grooming, to adapt to complex social living during primate evolution. PMID- 23741523 TI - Serum interleukin-18 at commencement of renal replacement therapy predicts short term prognosis in critically ill patients with acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI) requiring renal replacement therapy (RRT) in critically ill patients results in a high hospital mortality. Outcome prediction in this selected high-risk collective is challenging due to the lack of appropriate biomarkers. The aim of this study was to identify outcome-specific biomarkers in this patient population. METHODOLOGY/PRINCIPAL FINDINGS: Serum samples were collected from 101 critically ill patients with AKI at the initiation of RRT in intensive care units (ICUs) of a tertiary care university hospital between August 2008 and March 2011. Measurements of serum levels of cystatin C (CysC), neutrophil gelatinase-associated lipocalin, and interleukin-18 (IL-18) were performed. The primary outcome measure was hospital mortality. The observed overall mortality rate was 56.4% (57/101). Multiple logistic regression analysis indicated that the serum IL-18 and CysC concentrations and Acute Physiology and Chronic Health Evaluation III (ACPACHE III) scores determined on the first day of RRT were independent predictors of hospital mortality. The APACHE III score had the best discriminatory power (0.872 +/- 0.041, p<0.001), whereas serum IL-18 had the best Youden index (0.65) and the highest correctness of prediction (83%). Cumulative survival rates at 6-month follow-up following hospital discharge differed significantly (p<0.001) for serum IL-18 <1786 pg/ml vs. >= 1786 pg/ml in these critically ill patients. CONCLUSIONS: In this study, we confirmed the grave prognosis for critically ill patients at the commencement of RRT and found a strong correlation between serum IL-18 and the hospital mortality of ICU patients with dialysis-dependent AKI. In addition, we demonstrated that the APACHE III score has the best discriminative power for predicting hospital mortality in these critically ill patients. PMID- 23741525 TI - Design optimization of pin fin geometry using particle swarm optimization algorithm. AB - Particle swarm optimization (PSO) is employed to investigate the overall performance of a pin fin.The following study will examine the effect of governing parameters on overall thermal/fluid performance associated with different fin geometries, including, rectangular plate fins as well as square, circular, and elliptical pin fins. The idea of entropy generation minimization, EGM is employed to combine the effects of thermal resistance and pressure drop within the heat sink. A general dimensionless expression for the entropy generation rate is obtained by considering a control volume around the pin fin including base plate and applying the conservations equations for mass and energy with the entropy balance. Selected fin geometries are examined for the heat transfer, fluid friction, and the minimum entropy generation rate corresponding to different parameters including axis ratio, aspect ratio, and Reynolds number. The results clearly indicate that the preferred fin profile is very dependent on these parameters. PMID- 23741524 TI - The proto-oncogene TWIST1 is regulated by microRNAs. AB - Upregulation of the proto-oncogene Twist1 is highly correlated with acquired drug resistance and poor prognosis in human cancers. Altered expression of this multifunctional transcription factor is also associated with inherited skeletal malformations. The mammalian Twist1 3'UTRs are highly conserved and contain a number of potential regulatory elements including miRNA target sites. We analyzed the translational regulation of TWIST1 using luciferase reporter assays in a variety of cell lines. Among several miRNAs tested, miR-145a-5p, miR-151-5p and a combination of miR-145a-5p + miR-151-5p and miR-151-5p + miR-337-3p were able to significantly repress Twist1 translation. This phenomena was confirmed with both exogenous and endogenous miRNAs and was dependent on the presence of the predicted target sites in the 3'UTR. Furthermore, the repression was sensitive to LNA-modified miRNA antagonists and resulted in decreased migratory potential of murine embryonic fibroblast cells. Understanding the in vivo mechanisms of this oncogene's regulation might open up a possibility for therapeutic interference by gene specific cancer therapies. PMID- 23741526 TI - Claims-based definition of death in Japanese claims database: validity and implications. AB - BACKGROUND: For the pending National Claims Database in Japan, researchers will not have access to death information in the enrollment files. We developed and evaluated a claims-based definition of death. METHODOLOGY/PRINCIPAL FINDINGS: We used healthcare claims and enrollment data between January 2005 and August 2009 for 195,193 beneficiaries aged 20 to 74 in 3 private health insurance unions. We developed claims-based definitions of death using discharge or disease status and Charlson comorbidity index (CCI). We calculated sensitivity, specificity and positive predictive values (PPVs) using the enrollment data as a gold standard in the overall population and subgroups divided by demographic and other factors. We also assessed bias and precision in two example studies where an outcome was death. The definition based on the combination of discharge/disease status and CCI provided moderate sensitivity (around 60%) and high specificity (99.99%) and high PPVs (94.8%). In most subgroups, sensitivity of the preferred definition was also around 60% but varied from 28 to 91%. In an example study comparing death rates between two anticancer drug classes, the claims-based definition provided valid and precise hazard ratios (HRs). In another example study comparing two classes of anti-depressants, the HR with the claims-based definition was biased and had lower precision than that with the gold standard definition. CONCLUSIONS/SIGNIFICANCE: The claims-based definitions of death developed in this study had high specificity and PPVs while sensitivity was around 60%. The definitions will be useful in future studies when used with attention to the possible fluctuation of sensitivity in some subpopulations. PMID- 23741527 TI - Identification of a human protein-derived HIV-1 fusion inhibitor targeting the gp41 fusion core structure. AB - The HIV-1 envelope glycoprotein (Env) gp41 plays a crucial role in the viral fusion process. The peptides derived from the C-terminal heptad repeat (CHR) of gp41 are potent HIV fusion inhibitors. However, the activity of these anti-HIV-1 peptides in vivo may be attenuated by their induction of anti-gp41 antibodies. Thus, it is essential to identify antiviral peptides or proteins with low, or no, immunogenicity to humans. Here, we found that the C-terminal fragment (aa 462 521) of the human POB1 (the partner of RalBP1), designated C60, is an HIV-1 fusion inhibitor. It bound to N36, the peptide derived from the N-terminal heptad repeat (NHR) of gp41, and to the six-helix bundle (6-HB) formed by N36 and C34, a CHR-peptide, but it did not bind to C34. Unlike the CHR-peptides, C60 did not block gp41 6-HB formation. Rather, results suggest that C60 inhibits HIV-1 fusion by binding to the 6-HB, in particular, the residues in the gp41 NHR domain that are exposed on the surface of 6-HB. Since 6-HB plays a crucial role in the late stage of fusion between the viral envelope and endosomal membrane during the endocytic process of HIV-1, C60 may serve as a host restriction factor to suppress HIV-1 entry into CD4+ T lymphocytes. Taken together, it can be concluded from these results that C60 can be used as a lead for the development of anti-HIV 1 therapeutics or microbicides for the treatment and prevention of HIV-1 infection, as well as a molecular probe to study the fusogenic mechanism of HIV 1. PMID- 23741528 TI - DGCR8-mediated production of canonical microRNAs is critical for regulatory T cell function and stability. AB - Regulatory T cells (Treg) are integral for immune homeostasis. Here we demonstrate that canonical microRNAs (miRNAs) are required for Treg function because mice with DGCR8-deficient Treg cells spontaneously develop a scurfy-like disease. Using genetic lineage marking we show that absence of miRNAs leads to reduced FoxP3 expression in Treg cells in vivo. In vitro culture of purified DGCR8-deficient Treg leads to a loss of FoxP3 expression. We conclude that canonical miRNAs are essential to maintain stable FoxP3 expression and Treg function. Thus, signals interfering with miRNA homeostasis might contribute to autoimmune diseases. PMID- 23741529 TI - Improving the measurement of semantic similarity between gene ontology terms and gene products: insights from an edge- and IC-based hybrid method. AB - BACKGROUND: Explicit comparisons based on the semantic similarity of Gene Ontology terms provide a quantitative way to measure the functional similarity between gene products and are widely applied in large-scale genomic research via integration with other models. Previously, we presented an edge-based method, Relative Specificity Similarity (RSS), which takes the global position of relevant terms into account. However, edge-based semantic similarity metrics are sensitive to the intrinsic structure of GO and simply consider terms at the same level in the ontology to be equally specific nodes, revealing the weaknesses that could be complemented using information content (IC). RESULTS AND CONCLUSIONS: Here, we used the IC-based nodes to improve RSS and proposed a new method, Hybrid Relative Specificity Similarity (HRSS). HRSS outperformed other methods in distinguishing true protein-protein interactions from false. HRSS values were divided into four different levels of confidence for protein interactions. In addition, HRSS was statistically the best at obtaining the highest average functional similarity among human-mouse orthologs. Both HRSS and the groupwise measure, simGIC, are superior in correlation with sequence and Pfam similarities. Because different measures are best suited for different circumstances, we compared two pairwise strategies, the maximum and the best-match average, in the evaluation. The former was more effective at inferring physical protein-protein interactions, and the latter at estimating the functional conservation of orthologs and analyzing the CESSM datasets. In conclusion, HRSS can be applied to different biological problems by quantifying the functional similarity between gene products. The algorithm HRSS was implemented in the C programming language, which is freely available from http://cmb.bnu.edu.cn/hrss. PMID- 23741530 TI - New Class of Molecular Conductance Switches Based on the [1,3]-Silyl Migration from Silanes to Silenes. AB - On the basis of first-principles density functional theory calculations, we propose a new molecular photoswitch which exploits a photochemical [1,3] silyl(germyl) shift leading from a silane to a silene (a Si=C double bonded compound). The silanes investigated herein act as the OFF state, with tetrahedral saturated silicon atoms disrupting the conjugation through the molecules. The silenes, on the other hand, have conjugated paths spanning over the complete molecules and thus act as the ON state. We calculate ON/OFF conductance ratios in the range of 10-50 at a voltage of +1 V. In the low bias regime, the ON/OFF ratio increases to a range of 200-1150. The reverse reaction could be triggered thermally or photolytically, with the silene being slightly higher in relative energy than the silane. The calculated activation barriers for the thermal back rearrangement of the migrating group can be tuned and are in the range 108-171 kJ/mol for the switches examined herein. The first-principles calculations together with a simple one-level model show that the high ON/OFF ratio in the molecule assembled in a solid state device is due to changes in the energy position of the frontier molecular orbitals compared to the Fermi energy of the electrodes, in combination with an increased effective coupling between the molecule and the electrodes for the ON state. PMID- 23741531 TI - Lessons from the FNIH-NIA-FDA sarcopenia consensus summit. PMID- 23741532 TI - Responses of a Sample of Practicing Psychologists to Questions About Clinical Work With Trauma and Interest in Specialized Training. AB - This study reports on selected findings from a survey conducted by the American Psychological Association Practice Organization, which assessed the number of hours per month that practicing psychologists estimated they spent treating trauma survivors and their interest in additional clinical training on trauma related issues and topics. Respondents reported 14.3 mean number of hours spent working with trauma survivors over the past month. Of the 76% of the sample who treated any trauma patients, the mean was 16.9 hours. Although trauma psychology is not currently an integral component of the standard curricula in graduate level education, generalist psychology practitioners are treating trauma-related concerns in their clinical practices. It is imperative therefore to ascertain if they are adequately trained in specialized trauma recognition, assessment, and treatment. The fact that almost 64% of survey respondents expressed interest in participating in educational endeavors to learn more about trauma-related clinical topics suggests that such a need exists and that more training opportunities, including ongoing continuing education offerings, should be organized. PMID- 23741533 TI - From Nuremberg to bioethics: an educational project for students of dentistry and dental prosthesis. AB - In the lessons of medical-scientific methodologies of the medical faculty at the Sapienza University of Rome, basic notions on the ethical and deontologic aspects characterizing the history of the medical profession are provided, including the formulation and application of bioethical principles to clinics and biomedical research. Within such framework, an educational project has been initiated on the historical origin of the current normative and juridic dispositions in the regulation of experimental biomedical research and the relationship between health operators and patients, with particular attention to the procedure, the meaning the value either professional or deontologic, of ethics and the legality of the informed consensus. Emphasis is put on medical and experimental abuses that occurred in Germany during the nazi regime. PMID- 23741534 TI - Microcomputed tomographic analysis of the furcation grooves of maxillary first premolars. AB - OBJECTIVES: The aims of this study were to conduct a morphometric analysis on the buccal furcation grooves in freshly extracted bifurcated maxillary first premolars (MFPs) and to correlate all anatomical measurements using microcomputed tomography. MATERIALS AND METHODS: Twenty-three human MFPs with bifurcated canals were selected for this study. The specimens were analyzed with microcomputed tomography. The length, the beginning, and the ending of the grooves were measured. The minimum cross-sectional canal wall thickness in the grooves was located, and the width of the dentin thickness was calculated. All measurements were recorded and statistically analyzed. RESULTS: The concavity of the grooves begins before the bifurcation site in 9/23 samples and after the bifurcation in 56.5% of samples. The groove length varied between 1.1-9 mm; the cross-sectional area with minimum palatal dentin thickness was 0.78+/-0.14 mm, which was located at a mean distance of 7.1 mm from the cementoenamel junction (CEJ) and 1.38 mm from the furcation. CONCLUSIONS: The presence of the furcation grooves in the palatal aspects of the buccal roots of the MFPs was 100%. The length, depth, location, and width of the dentin thickness of the grooves varied in relation to tooth length, bifurcation, and CEJ. These parameters should be taken into consideration before any endodontic or restorative procedures are performed. Reducing dentin width too vigorously by intracanal instrumentation can predispose to vertical root fractures or perforations; if a post cannot be avoided, it should not extend 6.5 mm from the CEJ. PMID- 23741535 TI - Influence of file motion on cyclic fatigue of new nickel titanium instruments. AB - AIM: The aim of the present study was to compare the resistance to cyclic fatigue of Hyflex(r) (Coltene-Whaledent, Allstatten, Switzerland) size 40 taper.04 nickel titanium instruments used in continuous rotation versus the use with a reciprocating motion. The null hypothesis was that different file motions had no influence on the lifetime of instruments subjected to a cyclic fatigue test. METHODOLOGY: 24 Hyflex(r) size 40 taper.04 nickel titanium instruments were randomly divided in two groups (n=12 each), and submitted to a cyclic fatigue test. The first group (CR group) were used with a continuous rotation, while the second one (RCP group) with a reciprocating motion. The cyclic fatigue tests were performed by using a stainless steel block containing an artificial canal shaped with a 135 degrees angle. All instruments were rotated or reciprocated until fracture occurred. The time to fracture was recorded visually with a 1/100 second chronometer. Data were recorded and statistically analysed. RESULTS: Results indicated that instruments used with a reciprocating motion showed a significant increase in the meantime to failure when compared to those used in continuous rotation. CONCLUSIONS: The null hypothesis was rejected. Results of the present study showed that reciprocating motion extended resistance to cyclic fatigue of the tested nickel titanium instruments, when compared to continuous rotation. PMID- 23741536 TI - The influence of three different instrumentation techniques on the incidence of postoperative pain after endodontic treatment. AB - AIMS: Apical extrusion of infected debris to the periradicular tissues is one of the principal causes of postoperative pain and discomfort. Recent researches have shown that reciprocating instrumentation techniques seem to significantly increase the amount of debris extruded beyond the apex and, consequently, the risk of postoperative pain. The goal of the present study was to evaluate and compare postoperative pain using three different nickel-titanium instrumentation techniques: a rotary crown-down technique using TF instruments (SybronEndo, Orange, Ca), a reciprocating single-file technique using WaveOne instruments (Maillefer DEntsply, Baillagues, CH), and a novel instrumentation technique (TF Adaptive, SybronEndo, Orange, Ca), using a unique, proprietary movement, combining reciprocation and continuous rotation. METHODS: Ninety patients requiring endodontic treatment on permanent premolar and molar teeth with non vital pulps preoperatively were included in the study. The patients were assigned into three groups of 30 patients each, trying to make the groups very similar, concerning the number of root canals, presence of initial pain and periapical lesions. The teeth in group 1 (n = 30) were instrumented with a crown-down technique using TF instruments, whilst those in group 2 (n = 30) were instrumented with a single-file technique using Waveone 08 25. The third group (n = 30) used the 3-file Tf Adaprtive sequence. All techniques were performed following manufacturers' instructions and all canals were shaped, cleaned and obturated in a single-visit by the same operator. The assessment of postoperative pain was carried out at 3 days by using a visual analogue scale. VAS pain scores were compared using one-way ANOVA post hoc Tukey test. A value of p < 0.05 was required for statistical significance. RESULTS: Results for VAS pain scores showed a statistically significant difference was found between the WaveOne (p=0,021) technique and the other two techniques. No statistical significant differences were found between TF and TF Adaptive (p= 0,087). When evaluating patient experiencing sever pain the incidence of symptoms was significantly higher with the WaveOne technique. CONCLUSIONS: Since the incidence of preoperative pain, the type of tooth and the pulp and periodontal pathology were quite similar between the three tested groups, and all the other variables (operator, irrigation, obturation) were identical, we may conclude that the difference in postoperative pain can be mainly related to the different instrumentation techniques. PMID- 23741537 TI - Ameloblastomatous calcifying ghost cell odontogenic cyst - a rare variant of a rare entity. AB - Calcifying odontogenic cyst (COC) is an uncommon benign cystic neoplasm of odontogenic origin, which shows extensive diversity in its clinico-pathological appearances and biological behavior. It most commonly occurs in broader age group of 1-82 years in anterior part of jaws which is classically described by presence of ghost cells. There are variants of COC according to clinical, histopathological, and radiological characteristics. Therefore a proper categorization of the cases is needed for better understanding of the pathogenesis of each variant. Here we report a rare case of ameloblastomatous calcifying ghost cell odontogenic cyst in 24 year old female with brief review of literature. Presence of ameloblastomatous proliferation and impacted canine presented a diagnostic dilemma and was diagnosed by careful radiographic and histopathogical interpretation. Long follow up and more case report are required to shed light on its behaviour as there scarcity of data of this lesion in literature. PMID- 23741538 TI - Epidemiological analysis on 2375 patients with TMJ disorders: basic statistical aspects. AB - The aim of this work was to present data from a large sample of patients with Temporo-Mandibular Disorders (TMD) in order to clarify some aspects of the development of pathological conditions that affect large parts of the population. This preliminary work put in relation, through an epidemiological evaluation, anamnestic and clinical data collected from a sample of 2375 patients affected by TMD. Personal data were provided by questionnaire (age, sex, status, etc.), while clinical data were collected following a specific medical chart compiled in accordance with international criteria for TMD. An analysis of these data clearly showed that there were large quantities of variables involved in these disorders and which occur with a wide variety possible of clinical signs. This complexity, in accordance with the current knowledge that it is not able to clarify the etiology of these disorders, makes intricate both diagnostic then therapeutic aspects. You would find in front of a multi-factorial systemic disease that, interfering with the individual bioavailability, exposes him to the possibility of perceiving noxious stimuli which otherwise would not able to reach the pain threshold. To support this hypothesis is the data founded in this report that showed how many patients suffered, at the same time, by muscle and spinal pain associated to headache, pain that occur with high frequency from the same side. The presence of these painful conditions tends to underestimate the dysfunctional problems even if they occur with greater clinical prevalence. Further research should be carried out to clarify these controversial issues. PMID- 23741539 TI - Two cases of complete hydatidiform mole and coexistent live fetus. AB - The aim of this study was to report the clinical features, management, and outcome of complete hydatidiform mole with a coexisting viable fetus. Two cases are reported. In both cases ultrasound examination demonstrated a normally growing live fetus alongside a normal placenta and an additional intrauterine echogenic mass with features of hydatidiform mole. The hCG levels were significantly increased and fetal karyotypes were normal. A cesarean section performed at 28 weeks' gestation in the first case and at 26 weeks' gestation in the second one resulted in the delivery of live normal infant and two adjoining placentas in both cases. Microscopic examination of the abnormal placentas confirmed complete hydatidiform mole. The babies did well and serial maternal serum hCG levels showed a declining trend and were undetectable by a few months after delivery. Continuation of a twin pregnancy with complete hydatidiform mole (CHMF) is an acceptable option. There is, although, an increased risk of developing maternal and fetal complications. Close surveillance of an ongoing pregnancy is compulsory to detect potential early signs of complications. PMID- 23741540 TI - Increased nuchal translucency and short femur length as possible early signs of osteogenesis imperfecta type III. AB - OBJECTIVE: this paper reports an association between an increased Nuchal Translucency (NT) and Osteogenesis Imperfecta (OI), a type of skeletal dysplasia. Measurement of fetal NT at 10-14 weeks of gestation is a sensitive and effective screening method for chromosomal abnormalities. METHODS: a 35-year- old Caucasian woman in her fourth pregnancy was referred to our clinic for an ultrasound scan at 12 weeks of gestation, that confirmed increased Nuchal Translucency. Chorionic villi sampling was performed, showing a normal karyotype. The patient was evaluated by a team of experienced ultra sonographers for pregnancy follow-up at our Department, that is a tertiary center. RESULTS: in our case the ultrasound scan at 12 week of gestation revealed only an increased NT (3 mm). Cytogenetic analysis on chorionic villi demonstrated a normal male karyotype. US follow-up, performed every 3-4 weeks, confirmed normal anthropometric parameters except for shortening of both femurs, but at 23 weeks an incorrect attitude of the feet was revealed. A clinical and radiographic diagnosis of OI type III was made only at birth, and through follow-up continuing to date. DISCUSSION: NT screening was successful for chromosomal abnormalities at 11-14 weeks of gestation. An increased NT thickness is also associated with numerous fetal anomalies and genetic syndromes in a chromosomally normal fetus. In our case there were no sonographic signs of imperfect osteogenesis in the first trimester, although there was an increased NT with a normal karyotype. CONCLUSION: currently, in literature, there are not other cases of OI type III associated with an increased NT. Our report is the first to suggest an association between an increased nuchal translucency, short femur length and osteogenesis imperfecta type III. PMID- 23741541 TI - Placental mesenchymal dysplasia, a case of intrauterine sudden death in a normal sized fetus. AB - INTRODUCTION: placental mesenchymal dysplasia (PMD) is a rare placental anomaly characterized by placentomegaly and grape-like vesicles which resemble molar pregnancy. CASE: we report the case of 33-year-old woman (1-gravid) who visited our clinic at 11 weeks of gestation due to a suspected molar pregnancy. Ultrasound examination showed an enlarged placenta with multiple vesicular lesions. Maternal human chorionic gonadotropin level was normal and chorionic villus sampling showed a normal male karyotype (46 XY). The fetus exhibited no specific anomalies and fetal growth was normal during pregnancy with no signs of fetal suffering. At 31 weeks, the pregnancy ended owing to intrauterine fetal death (IUFD). The patient delivered a normal-sized male fetus (1800 g) with no definite anomalies. A pathological examination led to a diagnosis of placental mesenchymal dysplasia. CONCLUSION: in the presence of placental ultrasound anomalies with no other sign of fetal suffering, the pregnancy should be considered at risk and, therefore, should be monitored carefully including the option of hospitalization. PMID- 23741542 TI - Carbetocin versus oxytocin in caesarean section with high risk of post-partum haemorrhage. AB - OBJECTIVES: the aims of the present study were to compare the haemodynamic effects of oxytocin and carbetocin and to assess the efficacy of these two drugs in terms of blood loss and the additional uterotonic needed in caesarean section at high risk of primary post-partum haemorrhage. METHODS: women in the carbetocin group (group A) received a bolus of 100 MUg IV; women in the control group (group B) received 20 IU of oxytocin in 1000 ml of 0,9% Na-Cl solution IV (150 mL/hour). The main parameter evaluated was the haemodynamic effects of drugs and the need for additional uterotonic agents. In addition we compared the drop in haemoglobin level, the uterine tone, the uterine fundal state and the diuresis. RESULTS: regarding the haemodynamic effects, both drugs have a hypotensive effect, but we found a greater reduction in blood pressure within the oxytocin group. Significantly more women needed additional uterotonic agents in the oxytocin group (23,5% vs 0%, p<0.01), though there was no significant difference in estimated blood loss and in the drop haemoglobin level (p>0.05). There was a significant difference in the diuresis, higher in carbetocin group (1300 ml +/- 450 ml vs 1100 ml +/- 250 ml, p=0.01). CONCLUSIONS: a single injection of carbetocin appears to be more effective than a continuous infusion of oxytocin to prevent the PPH, with a similar haemodynamic profile and minor antidiuretic effect. PMID- 23741543 TI - Conservative management of spinal tuberculosis: initial series from pakistan. AB - STUDY DESIGN: A prospective study on spinal tuberculosis (TB) at a tertiary care hospital in an endemic region. PURPOSE: The aim of the study is to reiterate the importance of conservative management of spinal TB. OVERVIEW OF LITERATURE: Spinal tuberculosis can present with wide spectrum of symptoms, with back pain being the most common symptom. It is the leading cause of non-traumatic paraplegia in developing countries. There is an emerging trend to operate on patients early with spinal TB. METHODS: Forty-seven (M=14, F=33) patients were enrolled in the study during the four year study period. Initially, all the patients were subjected to computed tomography guided percutaneous needle aspiration (PCNA) followed by antituberculous therapy (ATT) for 12 months. Indications for surgery included patients with moderate to severe symptoms in which PCNA either failed, was impossible to carry out, or produced minimal improvement within 48 hours. RESULTS: Presenting complaints included pain (95.7%), weakness (85.1%) and sphincter involvement (12.8%). On the magnetic resonance imaging, a paravertebral abscess was seen in 37 (78.7%), disc and body destruction in 29 (61.7%), and an epidural abscess in 12 (25.9%) patients. Of the 47 patients, 9 (19.1%) required surgery, 4 of whom had failed PCNA attempts and 5 demonstrated indications despite successful PCNA. CONCLUSIONS: The results of conservative treatment consisting of PCNA and ATT for at least 12 months in compliant patients are excellent. A combined approach using clinical staging, PCNA, and ATT can minimize surgical intervention in most patients. However, ATT remains to be the cornerstone of management of spinal TB. PMID- 23741544 TI - The efficacy of percutaneous long-segmental posterior fixation of unstable thoracolumbar fracture with partial neurologic deficit. AB - STUDY DESIGN: Retrospective analysis. PURPOSE: The aim of this study was to evaluate the clinical and radiological outcomes of patients with unstable thoracolumbar fracture (UTLF) who were treated by percutaneous long-segmental posterior fixation (PLSPF) by two vertebrae cranial to the fracture with two vertebrae caudal. OVERVIEW OF LITERATURE: To the best of our knowledge, PLSPF for stabilization of UTLF has not been reported. METHODS: The study involved retrospective analysis and investigation from the results of 27 patients who had undergone PLSPF for stabilization of a UTLF with partial neurologic deficit, over a follow-up period of two years. Kyphotic angle (KA), anterior vertebral height percentage (AVHP) and cross-sectional ratio of the displaced fragment within the spinal canal were evaluated with simple radiographs and axial computed tomography scans preoperatively and two years postoperatively. The clinical outcome for pain was assessed by a visual analogue scale (VAS) and Denis' scale, and the degree of neurologic deficit was measured by modified Frankel classification. RESULTS: Five patients had minor complications. The KA, AVHP, and cross-sectional ratio of the displaced fragment improved significantly after surgery (p<0.001, p<0.001, p<0.003, respectively). Neurologic recovery of one or more for the Frankel grade was seen in 19 patients with an average improvement of 1.7. The VAS and Denis' score improved significantly at a two year follow-up (p=0.02, p=0.012, respectively). CONCLUSIONS: The technique of PLSPF is useful for the treatment of UTLF with partial neurologic deficit, and produces decreased morbidity and fewer complications. PMID- 23741545 TI - Reduction of halo pin site morbidity with a new pin care regimen. AB - STUDY DESIGN: A retrospective analysis of halo device associated morbidity over a 4-year period. PURPOSE: To assess the impact of a new pin care regimen on halo pin site related morbidity. OVERVIEW OF LITERATURE: Halo orthosis treatment still has a role in cervical spine pathology, despite increasing possibilities of open surgical treatment. Published figures for pin site infection range from 12% to 22% with pin loosening from 7% to 50%. METHODS: We assessed the outcome of a new pin care regimen on morbidity associated with halo spinal orthoses, using a retrospective cohort study from 2001 to 2004. In the last two years, our pin care regimen was changed. This involved pin site care using chlorhexidene & regular torque checking as part of a standard protocol. Previously, povidone iodine was used as skin preparation in theatre, followed by regular sterile saline cleansing when pin sites became encrusted with blood. RESULTS: There were 37 patients in the series, the median age was 49 (range, 22-83) and 20 patients were male. The overall infection rate prior to the new pin care protocol was 30% (n=6) and after the introduction, it dropped to 5.9% (n=1). This difference was statistically significant (p<0.05). Pin loosening occurred in one patient in the group prior to the formal pin care protocol (3%) and none thereafter. CONCLUSIONS: Reduced morbidity from halo use can be achieved with a modified pin cleansing and tightening regimen. PMID- 23741546 TI - (18)F-FDG PET/CT for Diagnosis of Osteosclerotic and Osteolytic Vertebral Metastatic Lesions: Comparison with Bone Scintigraphy. AB - STUDY DESIGN: A retrospective study. PURPOSE: The aims of this study were to investigate the diagnostic value of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in PET/computed tomography (CT) in the evaluation of spinal metastatic lesions. OVERVIEW OF LITERATURE: Recent studies described limitations regarding how many lesions with abnormal (18)F-FDG PET findings in the bone show corresponding morphologic abnormalities. METHODS: The subjects for this retrospective study were 227 patients with primary malignant tumors, who were suspected of having spinal metastases. They underwent combined whole-body (18)F-FDG PET/CT scanning for evaluation of known neoplasms in the whole spine. (99m)Tc-methylene diphosphonate bone scan was performed within 2 weeks following PET/CT examinations. The final diagnosis of spinal metastasis was established by histopathological examination regarding bone biopsy or magnetic resonance imaging (MRI) findings, and follow-up MRI, CT and (18)F-FDG PET for extensively wide lesions with subsequent progression. RESULTS: From a total of 504 spinal lesions in 227 patients, 224 lesions showed discordant image findings. For 122 metastatic lesions with confirmed diagnosis, the sensitivity/specificity of bone scan and FDG PET were 84%/21% and 89%/76%, respectively. In 102 true-positive metastatic lesions, the bone scan depicted predominantly osteosclerotic changes in 36% and osteolytic changes in 19%. In 109 true-positive lesions of FDG PET, osteolytic changes were depicted predominantly in 38% while osteosclerotic changes were portrayed in 15%. CONCLUSIONS: (18)F-FDG PET in PET/CT could be used as a substitute for bone scan in the evaluation of spinal metastasis, especially for patients with spinal osteolytic lesions on CT. PMID- 23741547 TI - Evaluation of bone mineral density in patients with chronic low back pain. AB - STUDY DESIGN: This was designed as a retrospective study. PURPOSE: We investigated the relationship between bone mineral density (BMD) and chronic lower back pain (LBP). OVERVIEW OF LITERATURE: In spite of a large number of epidemiological surveys on the prevalence of LBP and BMD measurements completed separately in the general population, the relationship between the two has not been well documented. METHODS: The study included 171 patients with chronic LBP who underwent the BMD study. The control group was selected from our database regarding BMD without LBP. RESULTS: A total of 678 subjects, aged 18 to 100 years (mean, 49.9+/-12.9 years) were included in the study, 25% (n=171) of the subjects had LBP. Compared to those patients without LBP, patients exhibiting LBP had statistically significant lower mean weight, hip and spine BMD and T-score. Lower BMD and T-scores were significant regardless of the age group, gender, menopausal status, and obesity classification. CONCLUSIONS: Chronic LBP has a negative correlation with hip and spine bone mineral density. PMID- 23741548 TI - Treatment of irreducible bilateral cervical facet fracture-dislocation with a prolapsed disc using a prefixed polyetheretherketone cage and plate system. AB - When anterior reduction fail in the surgical treatment of cervical bilateral facet fracture-dislocation with concomitant disc extrusion, it is necessary to perform a reduction using a posterior approach and then a third anterior procedure is often necessary to accomplish the anterior reconstruction. This presents difficulties for both patients and surgeons because of the need for frequent position changes (supine-prone-supine). The purpose of this study is to illustrate a modified surgical technique, which is anterior reduction and fixation with a prefixed polyetheretherketone (PEEK) cage to a buttress plate for the treatment of irreducible bilateral cervical facet fracture-dislocation with a prolapsed disc is an enhancing technique for the stability of the interbody graft than a buttress plate alone because the PEEK cage has more fixation power and reduces both the number of position changes and the length of the operation. PMID- 23741549 TI - V-rod technique for direct repair surgery of pediatric lumbar spondylolysis combined with posterior apophyseal ring fracture. AB - We report a pediatric baseball player having both a fracture of the posterior ring apophysis and spondylolysis. He was presented to a primary care physician complaining of back pain and leg pain. Despite conservative treatment for 3 months, the pain did not subside. He was referred to our clinic, and surgical intervention was carried out. First, a bony fragment of the caudal L5 apophyseal ring was removed following fenestration at the L5-S interlaminal space, bilaterally: and decompression of the bilateral S1 nerve roots was confirmed. Next, pseudoarthrosis of the L5 pars was refreshed and pedicle screws were inserted bilaterally. A v-shaped rod was inserted beneath the L5 spinous process, which stabilized the pars defects. After the surgery, back pain and leg pain completely disappeared. In conclusion, the v-rod technique is appropriate for the spondylolysis direct repair surgery, especially, in case the loose lamina would have a partial laminotomy. PMID- 23741550 TI - Anterior cervical arachnoid cyst. AB - This report is composed of two patients with anteriorly located cervical intradural arachnoid cyst and review of 24 cases in Englishlanguage literature. Both of our patients were in the first two decades of life with neck pain and motor weakness. With suspicious diagnosis of anterior arachnoid cyst surgery was carried out in both cases, though laminectomy in one and laminoplasty in the other. The cyst wall was widely fenestrated with subsequent subtotal excision of the cyst. Both cases had good long-term outcome. The review disclosed male predominance. 73% of the patients were diagnosed within the first two decades of life. Neck pain and motor weakness were the dominant signs and symptoms of this pathology. Magnetic resonance imaging showing a cerebrospinal fluid (CSF) containing cyst was the best mode of diagnosis. Wide cyst fenestration with waying CSF into subarachnoid cyst was the most appropriate and applied surgery with optimal outcome. PMID- 23741551 TI - A rare hyperextension injury in thoracic spine presenting with delayed paraplegia. AB - Hyperextension injury in the thoracic spine is uncommon with only a few cases documented in the literature. The mechanism of these injuries is hyperextension combined with axial or shearing force. These types of injuries are associated with a high risk of dural tears and paraplegia. A 91-year-old female presented with acute back pain from a hyperextension injury in thoracic spine with no neurological deficit. Lumbar magnetic resonance imaging showed a intervertebral disc rupture. On day 20 of hospitalization, the herniated intervertebral disc compressed the spinal cord with incomplete paraplegia. Hyperextension injuries involving the three columns are very unstable and we recommend surgical treatment as soon as possible, not only because of the initial trauma, but a ruptured disc herniation can damage the spinal cord. PMID- 23741552 TI - Acute schmorl node in dorsal spine: an unusual cause of a sudden onset of severe back pain in a young female. AB - Schmorl nodes represent displacement of intervertebral disc tissue into the vertebral body and have been considered as an asymptomatic incidental radiological finding on plain radiographs, computed tomography and magnetic resonance imaging (MRI). Although uncommon, acute symptomatic Schmorl nodes causing severe back pain do occur. We report here an unusual case of acute painful Schmorl node in a young healthy woman, with no previous trauma, presenting with a sudden significant localized back pain within hours accompanied by characteristic findings on a MRI scan. We reviewed all reports of symptomatic Schmorl nodes known in the literature, focusing mainly on MRI findings, and recent treatment options. PMID- 23741553 TI - Lumbar epidural varix mimicking perineural cyst. AB - Lumbar epidural varices are rare and usually mimick lumbar disc herniations. Back pain and radiculopathy are the main symptoms of lumbar epidural varices. Perineural cysts are radiologically different lesions and should not be confused with epidural varix. A 36-year-old male patient presented to us with right leg pain. The magnetic resonance imaging revealed a cystic lesion at S1 level that was compressing the right root, and was interpreted as a perineural cyst. The patient underwent surgery via right L5 and S1 hemilaminectomy, and the lesion was coagulated and removed. The histopathological diagnosis was epidural varix. The patient was clinically improved and the follow-up magnetic resonance imaging showed the absence of the lesion. Lumbar epidural varix should be kept in mind in the differential diagnosis of the cystic lesions which compress the spinal roots. PMID- 23741554 TI - Intradural extramedullary spinal ependymoma: a case report of malignant transformation occurring. AB - Intradural extramedullary spinal ependymomas are extremely rare. Herein, we describe a lesion-type spinal ependymoma that followed a malignant course, and discuss its clinical presentation, etiopathogenesis, and treatment. We present a patient who was diagnosed with an intradural extramedullary spinal tumor at T4 T6. The patient underwent gross total resection of the tumor without damage to the spinal cord. Histological examination, classified the lesion as a World Health Organization (WHO)-grade 2 ependymoma. One and a half years later, magnetic resonance imaging detected a recurring tumor at T4-T5. The tumor was removed and classified as a WHO-grade 3 anaplastic ependymoma. The patient was started on a course of regional spinal cord radiotherapy. The patient achieved tumoral control and clinical stabilization after the recurrence. We must consider the differential diagnosis of intradural extramedullary spinal tumors. The best treatment for this lesion is gross total resection and adjunctive radiotherapy is necessary in cases of malignant-change. PMID- 23741555 TI - Minimally invasive surgery for osteoid osteoma of the cervical spine using microendoscopic discectomy system. AB - We report herein the case of an 18-year-old man who underwent endoscopic resection for an osteoid osteoma in the seventh cervical facet joint. The patient had experienced right neck pain for approximately one year, but no neurological abnormalities were noted. Cervical magnetic resonance imaging suggested an osteoid osteoma in the superior articular process of the seventh cervical vertebra. The tumor was resected microendoscopically. Operative time was 1 hour 29 minutes, and blood loss was 5 mL. During the two years since surgery, the patient has remained pain free with no cervical spine instability. We thus propose microendoscopic surgery for osteoid osteoma developing in a posterior element of the cervical spine is a potentially effective operative procedure. PMID- 23741556 TI - Vertebral compression fracture with intravertebral vacuum cleft sign: pathogenesis, image, and surgical intervention. AB - The intravertebral vacuum cleft (IVC) sign in vertebral compression fracture patients has obtained much attention. The pathogenesis, image character and efficacy of surgical intervention were disputed. Many pathogenesis theories were proposed, and its image characters are distinct from malignancy and infection. Percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP) have been the main therapeutic methods for these patients in recent years. Avascular necrosis theory is the most supported; PVP could relieve back pain, restore vertebral body height and correct the kyphotic angulation (KA), and is recommended for these patients. PKP seems to be more effective for the correction of KA and lower cement leakage. The Kummell's disease with IVC sign reported by modern authors was incomplete consistent with syndrome reported by Dr. Hermann Kummell. PMID- 23741557 TI - Neglected Fracture-Dislocation of the Cervical Spine without Neurological Deficits. PMID- 23741558 TI - Erratum: correction of title. Ruptured conus medullaris dermoid cyst with fat droplets in the central canal. PMID- 23741560 TI - Recovery from sedation during regional anesthesia. PMID- 23741559 TI - Bacterial sex in dental plaque. AB - Genes are transferred between bacteria in dental plaque by transduction, conjugation, and transformation. Membrane vesicles can also provide a mechanism for horizontal gene transfer. DNA transfer is considered bacterial sex, but the transfer is not parallel to processes that we associate with sex in higher organisms. Several examples of bacterial gene transfer in the oral cavity are given in this review. How frequently this occurs in dental plaque is not clear, but evidence suggests that it affects a number of the major genera present. It has been estimated that new sequences in genomes established through horizontal gene transfer can constitute up to 30% of bacterial genomes. Gene transfer can be both inter- and intrageneric, and it can also affect transient organisms. The transferred DNA can be integrated or recombined in the recipient's chromosome or remain as an extrachromosomal inheritable element. This can make dental plaque a reservoir for antimicrobial resistance genes. The ability to transfer DNA is important for bacteria, making them better adapted to the harsh environment of the human mouth, and promoting their survival, virulence, and pathogenicity. PMID- 23741561 TI - The prevention and handling of the missing data. AB - Even in a well-designed and controlled study, missing data occurs in almost all research. Missing data can reduce the statistical power of a study and can produce biased estimates, leading to invalid conclusions. This manuscript reviews the problems and types of missing data, along with the techniques for handling missing data. The mechanisms by which missing data occurs are illustrated, and the methods for handling the missing data are discussed. The paper concludes with recommendations for the handling of missing data. PMID- 23741562 TI - Impact of priming the infusion system on the performance of target-controlled infusion of remifentanil. AB - BACKGROUND: The start-up behavior of syringe and syringe pump is known to be one of the causes of inaccurate intravenous infusion. This study evaluated the method of priming the infusion system (PRIMING), and its impact on the target-controlled infusion (TCI) of two remifentanil diluents. METHODS: PRIMING was performed using an evacuation of 2.0 ml to the atmosphere prior to TCI. Forty-eight TCI, using 50 ug/ml (Remi50) or 20 ug/ml (Remi20) of diluents, were performed targeting 4.0 ng/ml of effect-site concentration (Ceff), with PRIMING or not. The gravimetrical measurements of the delivered infusates reproduced actual Ceff. The bolus amount and time to reach 95% target were compared. RESULTS: Without PRIMING, Remi50 infused less bolus (43 +/- 23 %) than Remi20 (19 +/- 9 %) (P = 0.003), and showed more delayed increase of Ceff (11.2 +/- 4.0 min) than Remi20 (7.4 +/- 0.4 min) (P = 0.028). However, PRIMING significantly decreased the deficit of the bolus (2 +/ 1%), as well as the delay of the increase of Ceff in Remi50 (1.2 +/- 0.2 min) (both P < 0.001). In addition, with PRIMING, the start-up bolus showed minimal difference to the nominal bolus (1 and 2%), and Ceff were increased to 4.0 +/- 0.1 ng/ml at the expected time of peak effect, irrespective of the diluents. CONCLUSIONS: Proper operation of the syringe pump used in the priming of the syringe may be helpful in reduction of the inaccuracy of TCI, particularly during the early phase of infusion, or the infusion of a more concentrated diluent. PMID- 23741563 TI - Comparison between monitored anesthesia care with remifentanil under ilioinguinal hypogastric nerve block and spinal anesthesia for herniorrhaphy. AB - BACKGROUND: The use of monitored anesthesia care (MAC) as the technique of choice for a variety of invasive or noninvasive procedures is increasing. The purpose of this study to compare the outcomes of two different methods, spinal anesthesia and ilioinguinal-hypogastric nerve block (IHNB) with target concentrated infusion of remifentanil for inguinal herniorrhaphy. METHODS: Fifty patients were assigned to spinal anesthesia (Group S) or IHNB with MAC group (Group M). In Group M, IHNB was performed and the effect site concentration of remifentanil, starting from 2 ng/ml, was titrated according to the respiratory rate or discomfort, either by increasing or decreasing the dose by 0.3 ng/ml. The groups were compared to assess hemodynamic values, oxygen saturation, bispectral index (BIS), observer assessment alertness/sedation scale (OAA/S), visual analogue scale (VAS) for pain score and patients' and surgeon's satisfaction. RESULTS: BIS and OAA/S were not significantly different between the two groups. Hemodynamic variables were stable in Group M. Thirteen patients in the same group showed decreased respiratory rate without desaturation, and recovered immediately by encouraging taking deep breaths without the use of assist ventilation. Although VAS in the ward was not significantly different between the two groups, interestingly, patients' and surgeon's satisfaction scores (P = 0.0004, P = 0.004) were higher in Group M. The number of the patients who suffered from urinary retention was higher in Group S (P = 0.0021). CONCLUSIONS: IHNB under MAC with remifentanil is a useful method for inguinal herniorrhaphy reflecting hemodynamic stability, fewer side effects and higher satisfaction. This approach can be applied for outpatient surgeries and patients who are unfit for spinal anesthesia or general anesthesia. PMID- 23741564 TI - Effect of a single dose of esmolol on the bispectral index to endotracheal intubation during desflurane anesthesia. AB - BACKGROUND: In this prospective, randomized, double-blind, placebo-controlled trial, we investigated the effect of a single dose of esmolol on the bispectral index (BIS) to endotracheal intubation during desflurane anesthesia. METHODS: After induction of anesthesia, 60 patients were mask-ventilated with desflurane (end-tidal 1 minimum alveolar concentration) for 5 min and then received either normal saline, esmolol 0.5 or 1 mg/kg, 1 min prior to intubation (control, esmolol-0.5 and esmolol-1 groups, n = 20/group). BIS, mean arterial pressure, and heart rate were measured prior to anesthesia induction and esmolol administration, immediately preceding intubation (time point 0), and every minute for 5 min after intubation (time point 1 to 5). At time point 0, 1 and 5, 5 ml of arterial blood was taken to measure plasma concentrations of norepinephrine and epinephrine. RESULTS: BIS increased significantly at 1 min after intubation when compared with pre-intubation values in all groups. Both mean arterial pressure and heart rate increased significantly 1 min after intubation when compared with preintubation values for all groups. Plasma epinephrine concentrations did not increase significantly after tracheal intubation in any of the groups. Norepinephrine increased at 1 min after intubation when compared with the preintubation values in the esmolol groups (P < 0.05). CONCLUSIONS: A single bolus of esmolol was unable to blunt the increase in BIS to endotracheal intubation during desflurane anesthesia. PMID- 23741565 TI - Optimal dose of dexmedetomidine for sedation during spinal anesthesia. AB - BACKGROUND: Sedation in spinal anesthesia can reduce patient's anxiety and discomfort. Dexmedetomidine has a sedative, hypnotic, analgesic, and minimal respiratory depression effect. However, use of the dexmedetomidine is associated with prolonged recovery. This study was designed to investigate the optimal dose of intravenous dexmedetomidine for proper sedation with minimal recovery time in spinal anesthesia. METHODS: One hundred twenty eight patients, aged 20-70 years (58.8 +/- 0.7), were recruited. After performing the spinal anesthesia with hyperbaric bupivacaine (13 mg), a loading dose of dexmedetomidine (1 ug/kg) was administered for 10 min, followed by the maintenance infusion of the following: Group A (n = 33; normal saline), Group B (n = 35; dexmedetomidine 0.2 ug/kg/hr), and Group C (n = 39; dexmedetomidine 0.4 ug/kg/hr). Heart rate, blood pressure, and the bispectral index score (BIS) were recorded during the operation. In the recovery room, modified aldrete score (MAS) was measured. RESULTS: There were no significant differences in mean blood pressure and heart rate among the three groups. BIS was not significantly different among the three groups from baseline to 60 min after the infusion of dexmedetomidine. BIS were significantly increased in Group A after 70 and 80 min, and Group A and B after 90, 100, 110 min of dexmedetomidine infusion (P < 0.05). MAS was higher in Group A as compared to Group B and C, within 30 min after admission in the recovery room (P < 0.05). CONCLUSIONS: The loading dose (1 ug/kg/10 min) of dexmedetomidine was sufficient for surgery of less than 60 min. Dexmedetomidine infusion followed by maintenance dose (0.2 ug/kg/hr) was sufficient for surgery within 90 min. PMID- 23741566 TI - Effect of interscalene brachial plexus block on heart rate variability. AB - BACKGROUND: Interscalene brachial plexus block (ISB) may be followed by cardiovascular instability. Until date, there is no clear picture available about the underlying mechanisms of ISB. In this study, we aimed to determine the changes in heart rate variability (HRV) parameters after ISB and the differences between right- and left-sided ISBs. METHODS: We prospectively studied 24 patients operated for shoulder surgery in sitting position and divided them into two respective groups: R (right-sided block = 14 pts) and L (left-sided block = 10 pts). HRV data were taken before and 30 min after the block. Ropivacaine without ephedrine was used for the ISB through an insulated block needle connected to a nerve stimulator. Statistical analysis implemented chi-square, Student's and t paired tests. Skewed distributions were analyzed after logarithmic transformation. RESULTS: All the studied patients had successful blocks. Horner's syndrome signs were observed in 33.3% of the patients (R = 5/14, L = 3/10; [P = 0.769]). There were no significant differences in pre-block HRV between the groups. The application of ISB had differential effect on HRV variables: R-blocks increased QRS and QTc durations and InPNN50, while a statistical decrease was seen in InLF. L-blocks did not show any significant changes. These changes indicate a reduced sympathetic and an increased parasympathetic influence on the heart's autonomic flow after R-block. CONCLUSIONS: Based on the obtained results we conclude that ISB, possibly through extension of block to the ipsilateral stellate ganglion, alters the autonomic outflow to the central circulatory system in a way depending on the block's side. PMID- 23741567 TI - Effect of stellate ganglion block on laryngopharyngeal reflux disease. AB - BACKGROUND: Laryngopharyngeal reflux (LPR) disease has many symptoms such as globus pharyngeus, excessive throat clearing and hoarseness. The aim of this study was to investigate the effect of stellate ganglion block (SGB) in addition to proton pump inhibitors (PPI) on LPR. METHODS: Fifty patients complaining of more than 3 typical LPR symptoms for over 3 months were enrolled in the study. The P group took PPI for 8 weeks. The SP group took PPI and interwent a series of 8 SGB procedure once a week during the period of treatment. The blocks were performed one at a time unilaterally on the right and left stellate ganglions by injecting 1% mepivacaine 6 ml. We evaluated the reflux symptom index (RSI) before treatment and following 4 weeks and 8 weeks of treatment in both groups. RESULTS: After 4 weeks of treatment, the RSI of the P group decreased, but not significantly, to 16.6 +/- 6.8 compared with the baseline value of 19.2 +/- 2.7 (P = 0.093), whereas the RSI of the SP group decreased significantly to 9.8 +/- 3.3 compared with the baseline value of 19.0 +/- 4.7 (P = 0.000). After 8 weeks of treatment, the RSI of the P group decreased significantly to 13.7 +/- 6.7 (P = 0.001) and the RSI of the SP group also decreased significantly to 7.7 +/- 3.4 (P = 0.000). There were significant differences in the RSI between the two groups after 4 weeks (P = 0.000) and 8 weeks (P = 0.001) of treatment. CONCLUSIONS: The symptoms of LPR improved earlier when PPI therapy was combined with SGB compared with PPI therapy alone. PMID- 23741568 TI - Direction of catheter insertion and the incidence of paresthesia during continuous epidural anesthesia in the elderly patients. AB - BACKGROUND: Continuous epidural anesthesia is useful for endoscopic urologic surgery, as mostly performed in the elderly patients. In such a case, it is necessary to obtain successful sacral anesthesia, and the insertion of epidural catheter in the caudad direction may be needed. However, continuous epidural catherization has been related to paresthesias. This study aimed to evaluate the effects of the direction of the catheter insertion on the incidence of paresthesias in the elderly patients. METHODS: Two hundred elderly patients scheduled for endoscopic urologic surgery were enrolled. The epidural catheter was inserted at L2-3, L3-4, and L4-5 using the Tuohy needle. In Group I (n = 100), the Tuohy needle with the bevel directed the cephalad during the catheter insertion. In Group II (n = 100), it directed the caudad. During the catheter insertion, an anesthesiologist evaluated the presence of paresthesias and the ease or difficulty during the catheter insertion. RESULTS: In Group I (n = 97), 15.5% of the patients had paresthesias versus 18.4% in Group II (n = 98), and there was no significant difference between the two groups. In paresthesia depending on the insertion site and the ease or difficulty during the catheter insertion, there were no significant differences between the two groups. CONCLUSIONS: Our results concluded that the direction of epidural catheter insertion did not significantly influence the incidence of paresthesias in the elderly patients. PMID- 23741569 TI - Right upper lobe tracheal bronchus: anesthetic challenge in one-lung ventilated patients -A report of three cases-. AB - Tracheal bronchus (TB) is an aberrant, accessary or ectopic bronchus arising almost exclusively from the right side of the tracheal wall above the carina. In our center, 673 bronchoscopic examinations were performed from 2009 to 2011 in patients undergoing one lung ventilation (OLV) and 3 TB were found. The incidence of a TB at bronchoscopy was 0.45% in our research, which is consistent with the reported incidence range from 0.1-5%. The clinician should consider the possibility of anomalous right upper lobe bronchus and perform bronchoscopy prior to the right bronchial blocker insertion, when left-sided OLV using bronchial blocker is planned. Also, for the patient with TB, a double lumen tube insertion is recommended than a blocker insertion to achieve OLV completely. PMID- 23741570 TI - Noninvasive estimation of raised intracranial pressure using ocular ultrasonography in liver transplant recipients with acute liver failure -A report of two cases-. AB - Intracranial pressure (ICP) monitoring is an important issue for liver transplant recipients, since increased ICP is associated with advanced hepatic encephalopathy or graft reperfusion during liver transplantation. Invasive monitoring of ICP is known as a gold standard method, but it can provoke bleeding and infection; thus, its use is a controversial issue. Studies have shown that optic nerve sheath diameter > 5 mm by ocular ultrasonography is useful for evaluating ICP > 20 mmHg noninvasively in many clinical settings. In this case report, we present experiences of using ocular ultrasound as a diagnostic tool that could detect changes in ICP noninvasively during liver transplantation. PMID- 23741571 TI - Unexpected tracheal narrowing during general anesthesia in the prone position of Duchenne muscular dystrophy patient -A report of two cases-. AB - Unexpected tracheal narrowing was observed in a patient with Duchenne muscular dystrophy during a corrective operation for thoracolumbar scoliosis. As the operating time progressed, peak airway pressure and end-tidal CO2 increased gradually in the prone position. We found a floppy portion of the trachea using fiberoptic bronchoscopy (FB) in the prone position. We advanced a wire-reinforced tube toward the carina beyond the lesion. This allowed correction of the ventilatory abnormalities. We encountered another patient scheduled for the same operation. We performed FB in advance before the position change and observed a narrowed portion of trachea. We advanced the tracheal tube under FB beyond the pathologic portion and then moved the patient into the prone position. The operation was done successfully without any problems. PMID- 23741572 TI - Anesthesia for cesarean section in a patient with respiratory failure -A case report-. AB - We present successful epidural anesthesia and assisted mechanical ventilation in a parturient woman with respiratory failure. A 41-year-old woman at 35 weeks' of gestation was entering labor. She was pneumonectomized on the left, had bronchiectasis on the remnant lung, and was under assisted mechanical ventilation by continuous positive airway pressure (CPAP) because of severely restricted lung function and superimposed pneumonia. We administered continuous epidural analgesia for vaginal delivery, and extended it for cesarean section after failure of vaginal delivery. During the procedure, her ventilation was continuously assisted by CPAP. The maternal and fetal outcomes were successful. PMID- 23741573 TI - Pyomyositis of the iliacus muscle and pyogenic sacroiliitis after sacroiliac joint block -A case report-. AB - Sacroiliac joint block can be performed for the diagnosis and treatment of sacroiliac joint dysfunction. Although sacroiliac joint block is a common procedure, complications have not been reported in detail. We report a case of iliacus pyomyositis and sacroiliac joint infection following a sacroiliac joint block. A 70-year-old female patient received sacroiliac joint blocks to relieve pelvic pain. The patient was admitted to the emergency room two days after the final sacroiliac joint block (SIJB) with the chief complaints of left pelvic pain corresponding to a visual analogue scale (VAS) score of 9 and fever. A pelvic MRI indicated a diagnosis of myositis. After 1 month of continuous antibiotic therapy, the patient's erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level remained elevated. A (67)Ga SPECT/CT was done. Abnormal uptake was seen at the left sacroiliac joint (SIJ), and septic sacroiliitis was suspected. The CRP normalized to 0.29 mg/dl and the ESR decreased to 60 mm/hr, and the patient had no fever after 57 days of antibiotic therapy. She was directed for follow up at an outpatient clinic. PMID- 23741574 TI - Guidewire malposition during central venous catheterization despite the use of ultrasound guidance. PMID- 23741575 TI - Paresthesia and sensory deficits on the unilateral leg arising from an unrecognized intramedullary tumor after spinal anesthesia. PMID- 23741576 TI - Pulmonary aspiration occurring during the induction of anesthesia in a patient with esophageal dilatation. PMID- 23741577 TI - Massive bleeding despite tourniquet inflation in total knee replacement patient with a femoro-popliteal artery bypass graft. PMID- 23741578 TI - Survey on understanding after anesthetic induction simulation training in medical students' anesthesiology practice. PMID- 23741579 TI - Bioengineering tissue for organ repair, regeneration, and renewal. PMID- 23741580 TI - Diagnosis and management of adnexal masses in pregnancy. AB - Widespread use of ultrasound in early pregnancy has led to the detection of incidental adnexal masses more frequently. This article reviews the diagnosis and management options for adnexal masses in pregnancy. The availability of high resolution ultrasound has made observation to be a viable option in some cases. However, for those masses suspicious of malignancy, at risk of torsion, rupture, or clinically symptomatic, surgical treatment is warranted. Laparoscopy has been successfully used in pregnancy and is safe in experienced and trained hands in properly equipped units. PMID- 23741581 TI - Patient satisfaction following minimally invasive repair of pectus excavatum: single surgeon experience. AB - BACKGROUND: Pectus excavatum (PE) is the most common chest wall deformity in adolescent life. Nuss procedure is a well-established technique for the repair of PE. The indication for correction is mainly medical aesthetic. Advantages of Nuss over conventional methods include reduced length of hospital stay, smaller incisions, and absence of need for osteochondrectomies. Here, we describe our experience with this procedure. MATERIALS AND METHODS: This was a retrospective study of patients who underwent Nuss procedure by a single surgeon between 2006 and 2010 in a regional center. Indications for surgery included the following: Progressive deformity and psychological stress. All patients underwent chest X ray and pulmonary function testing. A standard Nuss procedure was performed using a single bar. Patients' satisfaction was assessed by a questionnaire and follow up clinic letters. Satisfaction with body image was scored on a scale of 1-10. RESULTS: Eleven patients with PE underwent correction by Nuss procedure. Mean age of the patient was 19 years (range: 15-30). The average hospital stay was 7 days (range: 4-23 days). There was no mortality and no episodes of wound infection. In the immediate post-operative period, three patients (12.5%) were noted to have poor pain control. The post-operative course was uneventful in all cases except one patient who developed lung collapse, pleural effusion, and bar dislocation. Hundred percent of patients were satisfied with the scar. Seven patients scored 7 out of 10 on satisfaction with body image and two patients scored 6 or less. None of the patients complained of chronic pain. CONCLUSION: Nuss procedure is an effective method for the correction of PE. Most patients were satisfied with the outcome and none experienced chronic pain. PMID- 23741582 TI - Mesh-free Ventral Rectopexy for Women with Complete Rectal and Uterovaginal Prolapse. AB - BACKGROUND: Mesh rectopexy may be associated with infective complications, erosion into the vagina or rectum, and disintegration or dislodgement. A mesh free rectopexy will avoid these complications. Objective of the study was to perform mesh-free ventral rectopexy and assess its safety and effectiveness. MATERIALS AND METHODS: Nine women with complete rectal and uterovaginal prolapse were treated with total abdominal hysterectomy, closure of the vaginal vault, extirpation of the pouch of Douglas and suture of anterior rectal wall to the posterior vaginal wall (ventral suture rectopexy). The ventral suture rectopexy was achieved by three pairs of interrupted silk sutures, 2.5 cm above each other, and the first pair very close to the pelvic floor. This composite structure (anterior rectal wall and posterior vaginal wall), sits astride the perineal body. Intussusception and subsequent prolapse of the sutured rectum and vaginal wall is prevented. Vaginal vault prolapse was prevented by the suture of each round ligament of the uterus to the corresponding lateral vaginal fornix. No mesh was used. RESULTS: Nine multiparous women aged between 52 and 70 years had the procedure. The mean operative time was 135 minutes (range 110-220). The follow-up period was between 29 months and 7 years. Full continence was restored in all patients within eight weeks of the operation. Bowel habit returned to once daily in four patients and once every other day in the remaining five patients, within thirteen weeks of surgery. One patient had intermittent mucus discharge per rectum for six months. This stopped without a specific treatment. There has been no known recurrence in these nine patients. One patient developed wound infection as a complication. There was no mortality. All the patients are now asymptomatic. CONCLUSION: Ventral suture rectopexy is a safe and effective treatment for complete rectal prolapse in a selected group of patients. PMID- 23741583 TI - "The Dendritic Bonding Technique": A Newly-devised Technique for the Fixation of Mesh Skin Graft. AB - We describe a newly designed technique for the quick, easy, and cost-effective fixation of mesh skin grafts in a range of skin conditions and patients. We fixed the skin graft using octyl-2-cyanoacrylate (Dermabond; Ethicon), which was termed "Dendritic bonding." This technique exhibits several advantages over surgical stapling and suturing with absorbable sutures. PMID- 23741584 TI - Dorsal slit-sleeve technique for male circumcision. AB - Male circumcision is a commonly performed surgical procedure. There are several techniques of circumcision. The device methods are thought to have lower complication rates when compared to the open methods. The devices for circumcision may not be readily available or may be expensive. The open methods are therefore still commonly used in this setting. The dorsal slit-sleeve technique combines strategies from two open methods. The technique is described, together with its merit and demerits. This technique is feasible, safe, and the general outcome is good. PMID- 23741585 TI - Early Weight-bearing Using Percutaneous External Fixator for Calcaneal Fracture. AB - Calcaneal fracture, the most common tarsal bone fracture, occurs predominantly in manual labors and subsequently has got considerable socioeconomic implications. Treatment modality which can offer early weight bearing and early return to work is therefore needed for those patients. We have used a biplanar percutaneous external fixator for treating calcaneal fractures without operative and per operative visualization of the fractures. We have treated 17 calcaneal fractures in 16 patients, 12 intra articular and five extra articular, with our percutaneous external fixator system without preoperative X-ray control or reduction. Functional outcome was measured using the American Orthopaedic Foot and ankle society Hind foot score. All fractures united with a mean of 55 days. Partial weight bearing was possible in a mean of 1.8 days and full bearing was possible in a mean of 11.6 days. All the patients were returned to their original work within six weeks. Minor infectious complications occurred in 17.6 percent of cases. The average AOFAS score at six months follow up was 83.8. We conclude that our percutaneous external fixator technique for fracture calcaneum is an effective alternative to the currently available - surgical and conservative treatment modalities especially in lower socio economic labor population who need to return to their job as early as possible. Level of Evidence - IV Case series. PMID- 23741586 TI - Phlebectasia of internal jugular vein. AB - Internal jugular phlebectasia (IJP) is a rare disease in which there is a fusiform dilatation of internal jugular vein, usually presenting as a neck mass in children. Accurate diagnosis from careful history, physical examination, and radiological study can be made. We report a 12-year-old boy with history of swelling appearing on the right side of the neck only on straining, coughing, or during a Valsalva maneuver. Diagnosis of right IJP was made. Exploration and wrapping the dilated segment in an 8-mm-diameter polytetrafluoroethylene tube graft was done. Because of its rarity, this entity is frequently ignored or misdiagnosed. This case report intends to stress the importance of keeping IJP as differential diagnosis while dealing with such a swelling to avoid invasive investigations and inappropriate treatment. PMID- 23741587 TI - Is aggressive therapy the answer for all cases of emphysematous pyelonephritis: a report of three cases. AB - Emphysematous Pyelonephritis (EPN) is a severe, necrotizing, life threatening infection of the renal parenchyma and management is not standardised due to scarcity of literature. We present 3 patients with this rare entity. All 3 patients were of class III on CECT findings based on Huang's classification and had more than two risk factors. Our first patient underwent percutaneous drainage of his condition upon which he recovered. The second and third patients underwent a laparotomy and nephrectomy. The second patient recovered after a stormy post operative period and the third patient died. Management of the first patient was contrary to that recommended in literature, for the other two it was as per recommendations. On successful management of our first patient without surgery and seeing no discernable benefits of surgery for our other two patients, it is possible that percutaneous drainage alone, coupled with antibiotics may be a viable strategy for managing this condition with nephrectomy being considered as a second tier option. PMID- 23741588 TI - A rare case of spindle cell lipoma of nose. AB - We present a case report of a 45-year-old lady with history of swelling on right side of the nose since two years. On clinical examination, there was a firm swelling, 3 * 2 cm in size, just above the right nasoalar crease, nontender and mobile. Computed tomography revealed fibrous tissue over anterior surface of the right maxilla and nasal bone with mild sclerosis of the right nasal bone. Excision was done through lateral rhinotomy incision. Histopathological examination of the excised specimen revealed spindle cell lipoma which is very rare. Very few cases have been reported in the literature so far. PMID- 23741589 TI - Follicular thyroid carcinoma presenting as massive skull metastasis: a rare case report and literature review. AB - Follicular carcinoma of thyroid is a well differentiated thyroid malignancy. It is slow growing in nature and tends to metastasize to remote organs in advanced stage by hematogenous route. Lung and bone are the two most common sites of metastasis. In most of the reported cases of follicular thyroid carcinoma metastasizing to the skull, metastases occurred long after the diagnosis and institution of treatment for primary cancer. Very few cases have been reported with occult follicular thyroid carcinoma presenting as skull metastasis. A 48 year-old female patient presented with massive swelling in the frontal region of skull associated with swellings in occipital region. Evaluation confirmed that it is multiple metastases to skull bones from follicular thyroid carcinoma. This is a very rare presentation with such a large size of metastasis. We report this case of a metastatic follicular thyroid carcinoma presenting as massive skull tumor at our institution. PMID- 23741590 TI - Melioidosis of chest wall masquerading as a tubercular cold abscess. AB - Melioidosis caused by Burkholderia pseudomallei, an important human pathogen in the tropical regions causes protean and multisystem clinical manifestations. A 50 year-old man on treatment for pulmonary tuberculosis developed a chest wall abscess. With a suspicion of tuberculous cold abscess, pus culture was done and it revealed Burkholderia pseudomallei. He was treated with 10 days of ceftazidime and incision and drainage was done. Wound healed well and he has now completed three months of oral cotrimoxazole eradication therapy and is on follow-up without recurrence. We report this case for the unusual presentation of melioidosis and the diagnostic challenge posed due to clinical similarity with tuberculosis. PMID- 23741591 TI - An Unusual Presentation of Vallecular Cyst with near Fatal Respiratory Distress and Management Using Conventional Laparoscopic Instruments. AB - Vallecular cyst is a rare cause of upper airway obstruction in infants and children and presentation like acute stridor with near fatal respiratory distress is extremely rare. It is one of the rare causes of difficult intubation, during which cyst aspiration can improve the access. Vallecular cyst is commonly managed using microlaryngoscope and specialized instruments. We hereby report a method of endoscopic management of these cysts using conventional laparoscopic instruments. PMID- 23741592 TI - Arthroscopic bullet removal from the acetabulum (hip joint). AB - Hip arthroscopy has been shown to offer minimally invasive access to the hip joint compared with standard open arthrotomy. The use of arthroscopy for diagnosing and treating disorders about the hip continues to evolve. This study describes a case that involves arthroscopic removal of a bullet from a low velocity gunshot wound. The patient sustained a gunshot wound that entered the abdomen and traversed the small bowel, sigmoid colon then penetrated the urinary bladder before ending up in the medial wall of the acetabulum. After surgical repair of the viscus, the bullet was retrieved from the hip joint using standard arthroscopic portals and a fracture table. A number of issues led to the decision to use arthroscopy. Most importantly was the need to minimize soft tissue dissection, which was required to access the bullet, without interfering with previous wound at the suprapubic area. The risks of potential bullet fragmentation and migration, as well as a possible abdominal compartment syndrome were considered before proceeding. Arthroscopy allowed adequate inspection of the articular surface, irrigation of the joint, and removal of the foreign body while avoiding an invasive arthrotomy with its associated morbidity and soft tissue disruption. This surgical technique afforded a very satisfactory outcome for this patient and serves as a model for others when encountering a similar injury pattern in a trauma patient. It is a procedure that can be performed safely, quickly, and with minimal complications for surgeons with experience in arthroscopy of the hip joint. PMID- 23741593 TI - Triorchidism: a rare genitourinary abnormality. AB - Polyorchidism is an extremely rare congenital anomaly which refers to the presence of more than two testicles. There are very few reports of triorchidism in a 2 year old child. Polyorchidism is usually discovered incidentally. The most common anomalies associated with polyorchidism are inguinal hernia (30%), maldescended testis (15% to 30%), testicular torsion (13%) and hydrocele (9%). A 2-year-old child was brought with bilateral undescended testis with normal milestones. Ultrasonography of scrotum and abdomen showed both the testes to be in inguinal canal. Intra-operatively, on left side - there were two testes, which belonged to Leung III class and one testis on right side. Management of polyorchidism is still controversial. The management of polyorchidism will depend upon the location, size and anatomical organisation of the testicular drainage system and the age of the patient. PMID- 23741594 TI - Single Incision Laparoscopic Cholecystectomy in situs Inversus Totalis. AB - Situs inversus totalis (SIT) is a rare genetic anomaly characterized by arrangement of the abdominal and thoracic organs in a perfect mirror image reversal of the normal positioning. Transposition of the organs causes difficulty in diagnosis and treatment of the diseases related to abdomen and thorax. Single incision laparoscopic surgery (SILS) is a new technique and it is increasingly used with better cosmetic results. In this paper, a single incision laparoscopic cholecystectomy (SILC) performed in a patient with SIT is presented. SILC can be performed safely in the patients with SIT with better cosmetic results. PMID- 23741595 TI - Management of chronic subdural haematoma in a case of idiopathic thrombocytopenic purpura. AB - Intracranial hemorrhage is a rare devastating complication of idiopathic thrombocytopenic purpura (ITP), mostly presenting as intraparenchymal or subarachnoid haemorrhage. Isolated chronic subdural haematoma (SDH) is still very rare and the optimal management is unsettled. Spontaneous resolution of chronic SDH in patients with idiopathic thrombocytopenic purpura is possible. We report a case of spontaneous chronic SDH in a patient with ITP with hemiparesis where the haematoma significantly decreased in size with complete resolution of hemiparesis as a result of platelet transfusions and continuing therapy with steroids. Surgical treatment of subdural haematoma with consequent bleeding complications can be avoided in this scenario. PMID- 23741596 TI - Spontaneous epidural haematoma in sickle cell anaemia: case report and literature review. AB - Non traumatic spontaneous epidural Haematoma is a rare and often unmentioned complication of sickle cell disease. It is often associated with skull bone infarction. We report an eighteen year old boy with sickle cell anaemia who developed persistence headache during a vaso-occlusive crisis. Brain computed tomography (CT) revealed a right frontal epidural Haematoma (EDH) compressing on the brain. No other etiologic factor was identified. A right frontal craniotomy and evacuation of the Haematoma was performed and he made good recovery. The possible pathogeneses of this rare condition are discussed. PMID- 23741597 TI - "Bilateral Double J Stent Removal: The way to do it!". AB - There are many urological and non-urological indications which require bilateral double J stenting. We describe a point of technique for simultaneous removal of both the Double J stents. Both the stents are held by stent removing forceps at a point where they cross each other and then removed in one go with the help of cystoscope. Medline search did not reveal any techniques of removing two DJ stents in one go. PMID- 23741598 TI - Portal annular pancreas: an under-reported pancreatic anomaly. PMID- 23741599 TI - Management of maternofetal emergency in shock with fracture of femur. PMID- 23741600 TI - Rita Levi Montalcini and research. PMID- 23741601 TI - Prophylometric and SEM analyses of four different finishing methods. AB - Adhesion is the pivot of the modern restorative dentistry. Inlays, onlays and veneers have become a valid alternative to the traditional prosthetic treatments even in the rehabilitation of extremely damaged teeth, allowing a consistent saving of sound tooth tissues. Composite resins and dental adhesive are continously investigated and improved, nevertheless the optimization of the tooth adhesive interface has to be considered: in fact, the long-term stability of adhesion between tooth and composite material depends on the treatment of the amelo-dentinal surfaces. THIS STUDY INVESTIGATED THE QUALITY OF THE OCCLUSAL WALLS OF A CAVITY PREPARED TO RECEIVE AN INLAY AND FINISHED WITH FOUR DIFFERENT SYSTEMS: thin and extra-thin diamond coated burs, a 12-blades carbide burs and a diamond-coated tip driven by sonic instrument. Consequently, prophylometric and SEM analyses were performed on the samples. The average roughness values recorded by the prophylometer were expressed by the parameters Ra and RZ: there is a correspondence between the numeric values and the pictures of the SEM. The results show a better quality (low roughness values) of the surface treated with multi-blade burs, followed by the this and extra-thin diamond coated burs. The 25 micron diamond-coated tip of the sonic instrument obtains the roughest surface and a sensibly higher amount of smear layer than the other tested systems. PMID- 23741602 TI - Development of patient-based questionnaire about aesthetic and functional differences between overdentures implant-supported and overdentures tooth supported. Study of 43 patients with a follow up of 1 year. AB - Development of patient-based questionnaire about aesthetic and functional differences between overdentures implant-supported and overdentures tooth supported. Study of 43 patients with a follow up of 1 year. OBJECTIVE: The aim of this study is to compare functional efficiency and patients satisfaction between tooth-supported and implant-supported overdenture through a questionnaire that accurately reflects the real concerns of patients with dental prosthesis. METHODS: Forty-three patients were selected from the out patient clinic, Department of Dentistry "Fra G.B. Orsenigo Ospedale San Pietro F.B.F.", Rome, Italy. Their age were ranging from 61 to 83 years. Eighteen patients were rehabilitated with overdentures supported by natural teeth and twenty-five with overdentures implant-supported. DISCUSSION AND RESULT: The questionnaire proposed one year after the insertion of the prosthetis has showed that there isn't difference statistically significant in terms of function, phonetics and aesthetics between overdenture implant-supported and tooth-supported. CONCLUSIONS: The results of the questionnaire showed that the patients generally had a high level of satisfaction concern to the masticatory function, esthetics and phonetics. In addition, on average, they haven't difficulty in removal and insertion of the denture and in oral hygiene. They haven't in both groups problems related to fractures. PMID- 23741603 TI - Plaque retention on elastomeric ligatures. An in vivo study. AB - Fixed orthodontic appliances make it difficult to maintain the oral hygiene, resulting in plaque accumulation. Retention of bacterial plaque, represents a risk for white spot lesions and development of periodontal disease. AIM: Purpose of this study was to determine in vivo the retention of plaque on three different elastic ligatures, in comparison with stainless steel ligature, to determine a possible association between type of ligatures and accumulation of microorganisms. MATERIAL AND METHODS: THREE ELASTIC LIGATION SYSTEMS WERE ANALYZED FOR PLAQUE RETENTION: ring-shape, clear, latex ligatures (Leone(r) Spa), ring-shape, grey, polyurethane ligatures (Micerium(r) Spa) and grey, polyurethane, Slide low-friction ligatures (Leone(r) Spa), compared with stainless steel ligatures (Leone(r) Spa) used as control. Forthy orthodontic patients undergoing fixed orthodontic therapy were selected. A sample for each type of ligature were applied inside the oral cavity of each subject. Samples were kept in the oral cavity for 28 days, ligating 0.16 X 0.22 stainless steel archwire to stainless steel orthodontic premolars brackets. The presence of bacterical slime was quantified by spectrophotometric method (crystal violet Bouin's fixative) and morphological observations was evaluated by Scanning Electron Microscopy (SEM). RESULTS: From analysis of bacterical slime emerges that all the elastics showed a low plaque retention, especially if compared to the group of steinless steel ligatures, that presented a greater plaque adhesion, statistically significant compared to the Slide group (r<0.0002) and the two elastic groups (r<0.0001). This study reported no significant difference between the Slide ligatures and the traditional elastic ligatures as regards the retention of plaque. SEM images showed presence of cocci, rods and few filamentous organisms and an interbacterial matrix in all observed samples. CONCLUSION: Elastomeric ligatures showed a significant lower susceptibility to plaque adhesion, in comparison to the stainless steel of the metallic ligatures. No statistically significant difference was observed among the elastic devices. PMID- 23741604 TI - Four impacted fourth molars in a young patient: a case report. AB - The occurrence of supernumerary teeth is a relatively uncommon dental anomaly and it's rare for patients to have impacted fourth molars in all quadrant. Aim of this work is to describe the presence of bilateral fourth molars in the maxilla and the mandible in a young male patient aged 22 years came to our hospital with acute pericoronal infection around unerupted third inferior molars. Routine radiographic examination revealed impacted inferior third molars but also unerupted bilateral upper and inferior fourth molars. The acute infection was treated by local measures and the patient was subsequently admitted for removal of third and fourth impacted upper and lower molars under general anesthesia. PMID- 23741605 TI - A review of protein adsorption on bioceramics. AB - Bioceramics, because of its excellent biocompatible and mechanical properties, has always been considered as the most promising materials for hard tissue repair. It is well know that an appropriate cellular response to bioceramics surfaces is essential for tissue regeneration and integration. As the in vivo implants, the implanted bioceramics are immediately coated with proteins from blood and body fluids, and it is through this coated layer that cells sense and respond to foreign implants. Hence, the adsorption of proteins is critical within the sequence of biological activities. However, the biological mechanisms of the interactions of bioceramics and proteins are still not well understood. In this review, we will recapitulate the recent studies on the bioceramic-protein interactions. PMID- 23741606 TI - Hyaluronic acid-based scaffold for central neural tissue engineering. AB - Central nervous system (CNS) regeneration with central neuronal connections and restoration of synaptic connections has been a long-standing worldwide problem and, to date, no effective clinical therapies are widely accepted for CNS injuries. The limited regenerative capacity of the CNS results from the growth inhibitory environment that impedes the regrowth of axons. Central neural tissue engineering has attracted extensive attention from multi-disciplinary scientists in recent years, and many studies have been carried out to develop cell- and regeneration-activating biomaterial scaffolds that create an artificial micro environment suitable for axonal regeneration. Among all the biomaterials, hyaluronic acid (HA) is a promising candidate for central neural tissue engineering because of its unique physico-chemical and biological properties. This review attempts to outline current biomaterials-based strategies for CNS regeneration from a tissue engineering point of view and discusses the main progresses in research of HA-based scaffolds for central neural tissue engineering in detail. PMID- 23741607 TI - Mesoporous bioactive glasses: structure characteristics, drug/growth factor delivery and bone regeneration application. AB - The impact of bone diseases and trauma in the whole world has increased significantly in the past decades. Bioactive glasses are regarded as an important bone regeneration material owing to their generally excellent osteoconductivity and osteostimulativity. A new class of bioactive glass, referred to as mesoporous bioglass (MBG), was developed 7 years ago, which possess a highly ordered mesoporous channel structure and a highly specific surface area. The study of MBG for drug/growth factor delivery and bone tissue engineering has grown significantly in the past several years. In this article, we review the recent advances of MBG materials, including the preparation of different forms of MBG, composition-structure relationship, efficient drug/growth factor delivery and bone tissue engineering application. By summarizing our recent research, the interaction of MBG scaffolds with bone-forming cells, the effect of drug/growth factor delivery on proliferation and differentiation of tissue cells and the in vivo osteogenesis of MBG scaffolds are highlighted. The advantages and limitations of MBG for drug delivery and bone tissue engineering have been compared with microsize bioactive glasses and nanosize bioactive glasses. The future perspective of MBG is discussed for bone regeneration application by combining drug delivery with bone tissue engineering and investigating the in vivo osteogenesis mechanism in large animal models. PMID- 23741608 TI - Peptide- and saccharide-conjugated dendrimers for targeted drug delivery: a concise review. AB - Dendrimers comprise a category of branched materials with diverse functions that can be constructed with defined architectural and chemical structures. When decorated with bioactive ligands made of peptides and saccharides through peripheral chemical groups, dendrimer conjugates are turned into nanomaterials possessing attractive binding properties with the cognate receptors. At the cellular level, bioactive dendrimer conjugates can interact with cells with avidity and selectivity, and this function has particularly stimulated interests in investigating the targeting potential of dendrimer materials for the design of drug delivery systems. In addition, bioactive dendrimer conjugates have so far been studied for their versatile capabilities to enhance stability, solubility and absorption of various types of therapeutics. This review presents a brief discussion on three aspects of the recent studies to use peptide- and saccharide conjugated dendrimers for drug delivery: (i) synthesis methods, (ii) cell- and tissue-targeting properties and (iii) applications of conjugated dendrimers in drug delivery nanodevices. With more studies to elucidate the structure-function relationship of ligand-dendrimer conjugates in transporting drugs, the conjugated dendrimers hold promise to facilitate targeted delivery and improve drug efficacy for discovery and development of modern pharmaceutics. PMID- 23741609 TI - Surface modification of biomaterials using plasma immersion ion implantation and deposition. AB - Although remarkable progress has been made on biomaterial research, the ideal biomaterial that satisfies all the technical requirements and biological functions is not available up to now. Surface modification seems to be a more economic and efficient way to adjust existing conventional biomaterials to meet the current and ever-evolving clinical needs. From an industrial perspective, plasma immersion ion implantation and deposition (PIII&D) is an attractive method for biomaterials owing to its capability of treating objects with irregular shapes, as well as the control of coating composition. It is well acknowledged that the physico-chemical characteristics of biomaterials are the decisive factors greatly affecting the biological responses of biomaterials including bioactivity, haemocompatibility and antibacterial activity. Here, we mainly review the recent advances in surface modification of biomaterials via PIII&D technology, especially titanium alloys and polymers used for orthopaedic, dental and cardiovascular implants. Moreover, the variations of biological performances depending on the physico-chemical properties of modified biomaterials will be discussed. PMID- 23741610 TI - Gradient biomaterials and their influences on cell migration. AB - Cell migration participates in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. The cells specifically migrate to destiny sites induced by the gradually varying concentration (gradient) of soluble signal factors and the ligands bound with the extracellular matrix in the body during a wound healing process. Therefore, regulation of the cell migration behaviours is of paramount importance in regenerative medicine. One important way is to create a microenvironment that mimics the in vivo cellular and tissue complexity by incorporating physical, chemical and biological signal gradients into engineered biomaterials. In this review, the gradients existing in vivo and their influences on cell migration are briefly described. Recent developments in the fabrication of gradient biomaterials for controlling cellular behaviours, especially the cell migration, are summarized, highlighting the importance of the intrinsic driving mechanism for tissue regeneration and the design principle of complicated and advanced tissue regenerative materials. The potential uses of the gradient biomaterials in regenerative medicine are introduced. The current and future trends in gradient biomaterials and programmed cell migration in terms of the long-term goals of tissue regeneration are prospected. PMID- 23741611 TI - Biomimetic modification of metallic cardiovascular biomaterials: from function mimicking to endothelialization in vivo. AB - Biosystem-surface interactions play an important role in various biological events and determine the ultimate functionality of implanted devices. Endothelialization or mimicking of endothelium on the surface of cardiovascular materials is a promising way to solve the problems of material-induced thrombosis and restenosis. Meanwhile, a multifunctional surface design is needed as antithrombotic properties should be considered in the period when the implants are not yet completely endothelialized. In this article, we summarize some successful approaches used in our laboratory for constructing multifunctional endothelium-like surfaces on metallic cardiovascular biomaterials through chemical modification of the surface or by the introduction of specific biological molecules to induce self-endothelialization in vivo. Some directions on future research in these areas are also presented. PMID- 23741612 TI - Poly(lactide-co-glycolide) porous scaffolds for tissue engineering and regenerative medicine. AB - Porous scaffolds fabricated from biocompatible and biodegradable polymers play vital roles in tissue engineering and regenerative medicine. Among various scaffold matrix materials, poly(lactide-co-glycolide) (PLGA) is a very popular and an important biodegradable polyester owing to its tunable degradation rates, good mechanical properties and processibility, etc. This review highlights the progress on PLGA scaffolds. In the latest decade, some facile fabrication approaches at room temperature were put forward; more appropriate pore structures were designed and achieved; the mechanical properties were investigated both for dry and wet scaffolds; a long time biodegradation of the PLGA scaffold was observed and a three-stage model was established; even the effects of pore size and porosity on in vitro biodegradation were revealed; the PLGA scaffolds have also been implanted into animals, and some tissues have been regenerated in vivo after loading cells including stem cells. PMID- 23741613 TI - Dual functional selenium-substituted hydroxyapatite. AB - Hydroxyapatite (HA) doped with trace elements has attracted much attention recently owing to its excellent biological functions. Herein, we use a facile co precipitation method to incorporate selenium into HA by adding sodium selenite during synthesis. The obtained selenium-substituted HA products are needle-like nanoparticles which have size and crystallinity that are similar to those of the pure HA nanoparticles (HANs) when the selenium content is low. HANs are found to have the ability to induce the apoptosis of osteosarcoma cells, and the anti tumour effects are enhanced after incorporation of selenium. Meanwhile, the nanoparticles can also support the growth of bone marrow stem cells. Furthermore, the flow cytometric results indicate that the apoptosis induction of osteosarcoma cells is caused by the increased reactive oxygen species and decreased mitochondrial membrane potential. These results show that the selenium substituted HANs are potentially promising bone graft materials in osteosarcoma treatment due to their dual functions of supporting normal cell growth and inducing tumour cell apoptosis. PMID- 23741614 TI - Exploration on the safety assessment of nanomaterials in China. AB - More and more applications of nanomaterials have been achieved in the biomedicine field. Numerous nanomedical devices, such as bone grafts with nano-hydroxyapatite and the silver-based anti-bacteria products, have been developed and have been trying to enter into the Chinese market. The State Food and Drug Administration of China (SFDA) is facing a critical challenge of how to explore and supervise the safety assessment of the nanomedical products. This paper briefly introduces the approval status of nanomedical products and the current advances of the safety assessment of nanomaterials in China. PMID- 23741615 TI - Sequence-dependent base pair stepping dynamics in XPD helicase unwinding. AB - Helicases couple the chemical energy of ATP hydrolysis to directional translocation along nucleic acids and transient duplex separation. Understanding helicase mechanism requires that the basic physicochemical process of base pair separation be understood. This necessitates monitoring helicase activity directly, at high spatio-temporal resolution. Using optical tweezers with single base pair (bp) resolution, we analyzed DNA unwinding by XPD helicase, a Superfamily 2 (SF2) DNA helicase involved in DNA repair and transcription initiation. We show that monomeric XPD unwinds duplex DNA in 1-bp steps, yet exhibits frequent backsteps and undergoes conformational transitions manifested in 5-bp backward and forward steps. Quantifying the sequence dependence of XPD stepping dynamics with near base pair resolution, we provide the strongest and most direct evidence thus far that forward, single-base pair stepping of a helicase utilizes the spontaneous opening of the duplex. The proposed unwinding mechanism may be a universal feature of DNA helicases that move along DNA phosphodiester backbones. DOI:http://dx.doi.org/10.7554/eLife.00334.001. PMID- 23741616 TI - Decoding the neural mechanisms of human tool use. AB - Sophisticated tool use is a defining characteristic of the primate species but how is it supported by the brain, particularly the human brain? Here we show, using functional MRI and pattern classification methods, that tool use is subserved by multiple distributed action-centred neural representations that are both shared with and distinct from those of the hand. In areas of frontoparietal cortex we found a common representation for planned hand- and tool-related actions. In contrast, in parietal and occipitotemporal regions implicated in hand actions and body perception we found that coding remained selectively linked to upcoming actions of the hand whereas in parietal and occipitotemporal regions implicated in tool-related processing the coding remained selectively linked to upcoming actions of the tool. The highly specialized and hierarchical nature of this coding suggests that hand- and tool-related actions are represented separately at earlier levels of sensorimotor processing before becoming integrated in frontoparietal cortex. DOI:http://dx.doi.org/10.7554/eLife.00425.001. PMID- 23741617 TI - Pharmacological brake-release of mRNA translation enhances cognitive memory. AB - Phosphorylation of the alpha-subunit of initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2alpha kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating a unique serine in eIF2alpha. This collection of signaling pathways is termed the 'integrated stress response' (ISR). eIF2alpha phosphorylation diminishes protein synthesis, while allowing preferential translation of some mRNAs. Starting with a cell-based screen for inhibitors of PERK signaling, we identified a small molecule, named ISRIB, that potently (IC50 = 5 nM) reverses the effects of eIF2alpha phosphorylation. ISRIB reduces the viability of cells subjected to PERK-activation by chronic endoplasmic reticulum stress. eIF2alpha phosphorylation is implicated in memory consolidation. Remarkably, ISRIB-treated mice display significant enhancement in spatial and fear-associated learning. Thus, memory consolidation is inherently limited by the ISR, and ISRIB releases this brake. As such, ISRIB promises to contribute to our understanding and treatment of cognitive disorders. DOI:http://dx.doi.org/10.7554/eLife.00498.001. PMID- 23741618 TI - TRPM5-mediated calcium uptake regulates mucin secretion from human colon goblet cells. AB - Mucin 5AC (MUC5AC) is secreted by goblet cells of the respiratory tract and, surprisingly, also expressed de novo in mucus secreting cancer lines. siRNA mediated knockdown of 7343 human gene products in a human colonic cancer goblet cell line (HT29-18N2) revealed new proteins, including a Ca(2+)-activated channel TRPM5, for MUC5AC secretion. TRPM5 was required for PMA and ATP-induced secretion of MUC5AC from the post-Golgi secretory granules. Stable knockdown of TRPM5 reduced a TRPM5-like current and ATP-mediated Ca(2+) signal. ATP-induced MUC5AC secretion depended strongly on Ca(2+) influx, which was markedly reduced in TRPM5 knockdown cells. The difference in ATP-induced Ca(2+) entry between control and TRPM5 knockdown cells was abrogated in the absence of extracellular Ca(2+) and by inhibition of the Na(+)/Ca(2+) exchanger (NCX). Accordingly, MUC5AC secretion was reduced by inhibition of NCX. Thus TRPM5 activation by ATP couples TRPM5-mediated Na(+) entry to promote Ca(2+) uptake via an NCX to trigger MUC5AC secretion. DOI:http://dx.doi.org/10.7554/eLife.00658.001. PMID- 23741620 TI - Building for the future. AB - As the staff of the MRC Laboratory of Molecular Biology settle into their new building in Cambridge, its director Hugh Pelham explains the challenges of living up to its prestigious past. PMID- 23741619 TI - The rise and fall of the Phytophthora infestans lineage that triggered the Irish potato famine. AB - Phytophthora infestans, the cause of potato late blight, is infamous for having triggered the Irish Great Famine in the 1840s. Until the late 1970s, P. infestans diversity outside of its Mexican center of origin was low, and one scenario held that a single strain, US-1, had dominated the global population for 150 years; this was later challenged based on DNA analysis of historical herbarium specimens. We have compared the genomes of 11 herbarium and 15 modern strains. We conclude that the 19th century epidemic was caused by a unique genotype, HERB-1, that persisted for over 50 years. HERB-1 is distinct from all examined modern strains, but it is a close relative of US-1, which replaced it outside of Mexico in the 20th century. We propose that HERB-1 and US-1 emerged from a metapopulation that was established in the early 1800s outside of the species' center of diversity. DOI:http://dx.doi.org/10.7554/eLife.00731.001. PMID- 23741621 TI - Watching the brain in action. AB - Functional magnetic resonance imaging has been used to identify the different networks in the brain that underpin the use of tools by humans. PMID- 23741622 TI - Less translational control, more memory. AB - A small molecule can enhance the memories of rats and mice by blocking the integrated stress response in these animals. PMID- 23741623 TI - Developing a prototype system for integrating pharmacogenomics findings into clinical practice. AB - Findings from pharmacogenomics (PGx) studies have the potential to be applied to individualize drug therapy to improve efficacy and reduce adverse drug events. Researchers have identified factors influencing uptake of genomics in medicine, but little is known about the specific technical barriers to incorporating PGx into existing clinical frameworks. We present the design and development of a prototype PGx clinical decision support (CDS) system that builds on existing clinical infrastructure and incorporates semi-active and active CDS. Informing this work, we updated previous evaluations of PGx knowledge characteristics, and of how the CDS capabilities of three local clinical systems align with data and functional requirements for PGx CDS. We summarize characteristics of PGx knowledge and technical needs for implementing PGx CDS within existing clinical frameworks. PGx decision support rules derived from FDA drug labels primarily involve drug metabolizing genes, vary in maturity, and the majority support the post-analytic phase of genetic testing. Computerized provider order entry capabilities are key functional requirements for PGx CDS and were best supported by one of the three systems we evaluated. We identified two technical needs when building on this system, the need for (1) new or existing standards for data exchange to connect clinical data to PGx knowledge, and (2) a method for implementing semi-active CDS. Our analyses enhance our understanding of principles for designing and implementing CDS for drug therapy individualization and our current understanding of PGx characteristics in a clinical context. Characteristics of PGx knowledge and capabilities of current clinical systems can help govern decisions about CDS implementation, and can help guide decisions made by groups that develop and maintain knowledge resources such that delivery of content for clinical care is supported. PMID- 23741624 TI - Active DNA Abeta42 vaccination as immunotherapy for Alzheimer disease. AB - As a neurodegenerative disorder, Alzheimer disease (AD) is the most common form of dementia found in the aging population. Immunotherapy with passive or active immunizations targeting amyloid beta (Abeta) build-up in the brain may provide a possible treatment option and may help prevent AD from progressing. A number of passive immunizations with anti-Abeta42 antibodies are in different phases of clinical trials. One active immunization approach, AN-1792, was stopped after the development of autoimmune encephalitis in 6% of patients and a second one, CAD106, in which a small Abeta epitope is used, is currently in safety and tolerability studies. Besides active immunizations with proteins or peptides, active immunizations using DNA which codes for the protein against which the immune response will be directed, so called genetic immunizations, provide additional safety as the immune response in DNA immunizations differs quantitatively and qualitatively from the response elicited by peptide immunizations. In this review, we summarize our data using DNA Abeta42 immunizations in mouse models and discuss the results together with the results presented by other groups working on a DNA vaccine as treatment option for AD. PMID- 23741625 TI - Exposure to Maternal Diabetes in Utero and DNA Methylation Patterns in the Offspring. AB - Perturbations in early life environments, including intrauterine exposure to maternal gestational diabetes (GDM), are hypothesized to lead to metabolic imprinting resulting in increased risk of cardiometabolic outcomes later in life. We aimed to 1) identify candidate genes and biological pathways associated with differentially methylated regions (DMRs) in relation to exposure to GDM in utero and, 2) using mediation analysis, more definitively investigate the potential for mediation of the effect of exposure to maternal diabetes in utero on cardiometabolic traits in childhood risk through our identified DMRs. Genome-wide methylation analysis of peripheral blood mononuclear cell's DNA was conducted in 21 healthy children, ages 8-12 years. P-values from multiple linear regression analyses for >27,000 CpG sites were ranked to identify DMRs between the exposure groups. Among the top 10 ranked DMRs, we identified several genes, including NPR1, PANK1, SCAND1, and GJA4, which are known to be associated with cardiometabolic traits. Gene enrichment analysis of the top 84 genes, each with p<=0.005, identified the ubiquitin proteasome system (UPS) as the most enriched biological pathway (p = 0.07). The UPS pathway reflects biological processes known to be associated with endothelial function, inflammation, lipid metabolism, insulin resistance and beta-cell apoptosis, whose derangements are central to the pathogenesis of cardiometabolic diseases. Increased methylation of PYGO1 and CLN8 had the greatest relative mediation effect (RME = 87%, p=0.005 and RME=50%, p=0.01) on the impact of exposure to maternal diabetes in utero on VCAM-1 levels in the offspring. Multiple candidate genes and the UPS were identified for future study as possible links between exposure to maternal gestational diabetes in utero and adverse cardiometabolic traits in the offspring. In particular, increased methylation of PYGO1 and CLN8 may be biological links between intrauterine exposure to maternal diabetes and significantly increased VCAM-1 levels in the offspring. PMID- 23741626 TI - PLGA-polymer encapsulating tumor antigen and CpG DNA administered into the tumor microenvironment elicits a systemic antigen-specific IFN-gamma response and enhances survival. AB - Critical to the generation of an effective therapeutic antitumor immune response is the elicitation of effective antigen presentation coupled with overcoming tumor-immune escape mechanisms. Towards this end, we aimed to understand the therapeutic effectiveness of a polymer based vaccine approach at enhancing the anti-tumor responses in a tumor-bearing mouse model. While we and others have previously demonstrated the effectiveness of PLGA based systems in delivering antigen etc., studies scarcely focus on understanding the immunological mechanisms of polymer based therapies in tumor bearing treatment models. Considering tumors modulate the immune system and consequently the efficacy of therapies, understanding treatment mechanisms in the presence of tumor will help lead to more efficacious treatment options. We demonstrate here that a poly(lactic-co-glycolic acid) (PLGA) based delivery system encapsulating tumor antigen (OVA) and the TLR9 agonist CpG motif DNA administered into the tumor microenvironment initiates an effective type 1 mediated (IFN-gamma producing) anti-tumor response in a syngeneic murine model of T cell lymphoma (E.G7-OVA). Although E.G7-OVA tumors spontaneously generate antigen specific CTLs in draining lymph nodes (LN), tumors progress rapidly. Modulation of the tumor microenvironment via local PLGA based therapy led to the generation of a systemic antigen specific Th1 response, absent in the non-polymer delivery method, subsequently associated with reduced tumor growth and prolongation of survival. These studies provide further insight into the use of a PLGA-based therapeutic approach at modulating the tumor microenvironment and highlight the need for analyzing the treatment effects in a tumor bearing model. PMID- 23741627 TI - A Multiplex Microsphere-Based Immunoassay Increases the Sensitivity of SIV Specific Antibody Detection in Serum Samples and Mucosal Specimens Collected from Rhesus Macaques Infected with SIVmac239. AB - Results from recent HIV-1 vaccine studies have indicated that high serum antibody (Ab) titers may not be necessary for Ab-mediated protection, and that Abs localized to mucosal sites might be critical for preventing infection. Enzyme linked immunosorbent assay (ELISA) has been used for decades as the gold standard for Ab measurement, though recently, highly sensitive microsphere-based assays have become available, with potential utility for improved detection of Abs. In this study, we assessed the Bio-Plex((r)) Suspension Array System for the detection of simian immunodeficiency virus (SIV)-specific Abs in rhesus macaques (RMs) chronically infected with SIV, whose serum or mucosal SIV-specific Ab titers were negative by ELISA. We developed a SIVmac239-specific 4-plex bead array for the simultaneous detection of Abs binding to Env, Gag, Pol, and Nef. The 4-plex assay was used to quantify SIV-specific serum IgG and rectal swab IgA titers from control (SIV-naive) and SIVmac239-infected RMs. The Bio-Plex assay specifically detected anti-SIV Abs in specimens from SIV-infected animals for all four analytes when compared to SIV-naive control samples (p<=0.04). Furthermore, in 70% of Env and 79% of Gag ELISA-negative serum samples, specific Ab was detected using the Bio-Plex assay. Similarly, 71% of Env and 48% of Gag ELISA negative rectal swab samples were identified as positive using the Bio-Plex assay. Importantly, assay specificity (i.e., probability of true positives) was comparable to ELISA (94%-100%). The results reported here indicate that microsphere-based methods provide a substantial improvement over ELISA for the detection of Ab responses, aid in detecting specific Abs when analyzing samples containing low levels of Abs, such as during the early stages of a vaccine trial, and may be valuable in attempts to link protective efficacy of vaccines with induced Ab responses. PMID- 23741628 TI - Extending human hematopoietic stem cell survival in vitro with adipocytes. AB - Human hematopoietic stem cells (hHSCs) cannot be maintained in vitro for extended time periods because they rapidly differentiate or die. To extend in vitro culture time, researchers have made attempts to use human mesenchymal stem cells (hMSCs) to create feeder layers that mimic the stem cell niche. We have conducted an array of experiments including adipocytes in these feeder layers that inhibit hHSC differentiation and by that prolong stem cell survival in vitro. The amount of CD34(+) cells was quantified using flow cytometry. In a first experiment, feeder layers of undifferentiated hMSCs were compared with feeder layers differentiated toward osteoblasts or adipocytes using minimal medium, showing the highest survival rate where adipocytes were included. The same conclusion was drawn in a second experiment in comparing hMSCs with adipogenic feeder cells, using a culture medium supplemented with a cocktail of hHSC growth factors. In a third experiment, it was shown that direct cell-cell contact is necessary for the supportive effect of the feeder layers. In a fourth and fifth experiment the amount of adipocytes in the feeder layers were varied, and in all experiments a higher amount of adipocytes in the feeder layers showed a less rapid decay of CD34(+) cells at later time points. We therefore concluded that adipocytes assist in suppressing hHSC differentiation and aid in prolonging their survival in vitro. PMID- 23741629 TI - Near-infrared optical imaging for monitoring the regeneration of osteogenic tissue-engineered constructs. AB - Millions of cases of bone injury or loss due to trauma, osteoporosis, and cancer occur in the United States each year. Because bone is limited in its ability to regenerate, alternative therapy approaches are needed. Bone tissue engineering has the potential to correct musculoskeletal disorders through the development of cell-based substitutes for osteogenic tissue replacement. Multiple medical imaging techniques such as magnetic resonance microscopy (MRM) were investigated recently; these techniques are able to provide useful information on the anatomical and structural changes of developing bone. However, there is a need for noninvasive approaches to evaluate biochemical constituents and consequent compositional development associated with growing osteogenic constructs. In this study, near-infrared (NIR) optical imaging with a bone-specific NIR-targeted probe, IRDye((r)) 800CW BoneTagTM (800CW BT), was applied in this study to longitudinally visualize regions of mineralization of tissue-engineered bone constructs in vivo. A fluorescent cell-based assay was performed to confirm the preferential binding of 800CW BT to the mineralized matrix of differentiated osteogenically driven human mesenchymal stem cells (hMSCs) in vitro. The hMSCs were seeded onto a biocompatible gelatin scaffold, allowed to develop, and implanted into a mouse model. Engineered constructs were examined in vivo using NIR imaging for bone mineralization, paired with MRM for verification of developing tissue. Results showed that NIR imaging with 800CW BT labeling can effectively assess the calcification of the developing osteogenic constructs, which is consistent with the analysis of excised tissue using NIR microscopy and histology. In conclusion, this study evaluated bone-like function of regenerating bone through tracking calcium deposition via NIR optical imaging with a fluorophore-labeled probe in a noninvasive manner. PMID- 23741630 TI - Mechanical compression and nucleus pulposus application on dorsal root Ganglia differentially modify evoked neuronal activity in the thalamus. AB - A combination of mechanical compression caused by a protruding disc and leakage of nucleus pulposus (NP) from the disc core is presumed to contribute to intervertebral disc hernia-related pain. Experimental models of disc hernia including both components have resulted in changes in neuronal activity at the level of the dorsal root ganglion (DRG) and spinal cord, but changes within the brain have been less well studied. However, acute application of NP to a DRG without mechanical compression rapidly increases neuronal activity in the thalamus, a major brain relay nucleus processing information from sensory pathways including ascending nociceptive tracts. The combination of mechanical compression and NP might therefore result in further increases in central neuronal activity. Using an experimental disc herniation rat model including both mechanical compression and NP the present study aimed to investigate changes in neuronal activity in the contralateral thalamic ventral posterior lateral nucleus in vivo. Measurements were obtained while electrically stimulating the ipsilateral sciatic nerve at Adelta fiber intensities. The L4 DRG was subjected to light mechanical compression and NP exposure, and acute changes in evoked thalamic responses were recorded for up to 40 min. In order to compare effects in naive animals with effects following a longer period of NP exposure, animals that were either disc-punctured or sham-operated 24 h previously were also included. In all animals, light mechanical compression of the DRG depressed the number of evoked neuronal responses. Prior NP exposure resulted in less potent changes following mechanical compression (80% of baseline) than that observed in naive animals (50%). During the subsequent NP application, the number of evoked responses compared to baseline increased in pre-exposed animals (to 87%) as well as in naive animals (72%) in which the removal of the mechanical compression resulted in a further increase (106%). The contribution of acute DRG compression and disc material leakage to changes in transmission in central neuronal networks is likely to be complex and to involve both short-term and long-term effects. Since a light mechanical compression may reduce transmission in nociceptive pathways, it is possible that the presence or absence of NP is crucial for pain development in the acute phase of disc herniation. PMID- 23741631 TI - Low oxygen tension enhances proliferation and maintains stemness of adipose tissue-derived stromal cells. AB - Recent evidence indicates that low oxygen tension or hypoxia alters the characteristics of stem cells. The actions of hypoxia are mediated through the hypoxia-inducible factor, a critical mediator of the cellular response to hypoxia. Adipose tissue-derived stromal cells (ASCs) are one of the most promising cell sources for tissue engineering applications. This study investigated the effect of hypoxia on ASCs in terms of the ability to proliferate and differentiate. ASCs were extracted from mice and maintained under hypoxic atmosphere (2% O2) for up to eight in vitro passages. The proliferation rate was examined as a growth curve, and the potency of differentiation was evaluated. To investigate the cell characteristics, we checked several stem-cell markers and growth factors. Compared with the normoxic state (20% O2), hypoxia enhances proliferation with an approximately six- to sevenfold higher ASC expansion over 6 weeks. The expression of Oct3/4 and Nanog (stem-cell marker) and the amount of secreted growth factors were increased under the hypoxic condition. These results suggest that low oxygen tension enhances proliferation and maintains stemness of ASCs. Thus, this study emphasizes the profitability of hypoxic culture for expansion of ASCs and maintenance of their undifferentiated state for further therapeutic use. PMID- 23741632 TI - An In Silico Evaluation of Deleterious Nonsynonymous Single Nucleotide Polymorphisms in the ErbB3 Oncogene. AB - ErbB3 is a significant oncogenic target that is involved in the development of numerous malignancies. In the present in silico study, we evaluated the structural and functional impact of single nucleotide polymorphisms (SNPs) on the ErbB3 gene. The nonsynonymous SNPs (nsSNPs) are known to be deleterious or disease-causing variations because they alter protein sequence, structure, and function. Out of a total 531 SNPs in ErbB3, we investigated 77 coding nsSNPs and observed that 20 of them could be expected to alter the protein's function based on the predictions of both sequence homology-based (SIFT) and structural homology based (Polyphen) algorithms. Thereafter, we computed the stability of mutants in units of free energy using I-Mutant 3.0, MuStab, and iPTree-STAB programs and identified seven crucial point mutations (V89M, V105G, C290Y, I418N, R669C, I744T, and A1131T) in epidermal growth factor receptor 3 that are manifested as nsSNPs. Furthermore, FASTSNP determined 14 synonymous SNPs that may have a profound impact on splicing regulation. The computational study identified seven novel hotspots predicted to maintain the native structural conformation and functional activity of ErbB3 and may account for cancer if mutated. PMID- 23741633 TI - Inducing neurite outgrowth by mechanical cell stretch. AB - Establishing extracellular milieus to stimulate neuronal regeneration is a critical need in neuronal tissue engineering. Many studies have used a soluble factor (such as nerve growth factor or retinoic acid [RA]), micropatterned substrate, and electrical stimulation to induce enhanced neurogenesis in neuronal precursor cells. However, little attention has been paid to mechanical stimulation because neuronal cells are not generally recognized as being mechanically functional, a characteristic of mechanoresponsive cells such as osteoblasts, chondrocytes, and muscle cells. In this study, we performed proof-of concept experiments to demonstrate the potential anabolic effects of mechanical stretch to enhance cellular neurogenesis. We cultured human neuroblastoma (SH SY5Y) cells on collagen-coated membrane and applied 10% equibiaxial dynamic stretch (0.25 Hz, 120 min/d for 7 days) using a Flexcell device. Interestingly, cell stretch alone, even without a soluble neurogenic stimulatory factor (RA), produced significantly more and longer neurites than the non-RA-treated, static control. Specific neuronal differentiation and cytoskeletal markers (e.g., microtubule-associated protein 2 and neurofilament light chain) displayed compatible variations with respect to stretch stimulation. PMID- 23741634 TI - Human skin keratinocytes can be reprogrammed to express neuronal genes and proteins after a single treatment with decitabine. AB - Patient-specific cell replacement therapy is fast becoming the future of medicine, requiring safe, effective methods for reprogramming a patient's own cells. Previously, we showed that a single transient transfection with a plasmid encoding Oct4 was sufficient to reprogram human skin keratinocytes (HSKs), and that this transfection resulted in a decrease in global DNA methylation. In more recent work we showed that decreasing global DNA methylation using the U.S. Food and Drug Administration-approved cancer treatment drug decitabine was sufficient to induce expression of endogenous Oct4. Here we report that a single treatment with decitabine, followed by 5 days in a defined neuronal transformation medium, then 7 days in a neuronal maintenance medium is sufficient to convert HSKs into cells that change their morphology substantially, gain expression of neuronal markers, and lose expression of keratinocyte markers. Within 1 week of treatment the cells express mRNA for beta3-tubulin and doublecortin, and at the end of 2 weeks express mRNA for NeuN, FOXP2, and NCAM1. Additionally, at the end of this protocol, neurofilament-1, nestin, synapsin, FOXP2, and GluR1 proteins are detectable by immunostaining. Thus, we demonstrate a simple method that begins the process for producing cells for cell replacement therapies without using exogenously introduced DNA. PMID- 23741635 TI - A PCR-Based Method to Genotype Mice Knocked Out for All Four CD3 Subunits, the Standard Recipient Strain for Retrogenic TCR/CD3 Bone Marrow Reconstitution Technology. AB - The novel T-cell receptor (TCR)/CD3-retrogenic-reconstitution system represents a very useful strategy for studying TCR/CD3 signaling. Two retroviral vectors containing genes for all six subunits of the TCR/CD3 complex are used to transduce bone marrow precursors and reconstitute lethally irradiated recipient mice. Mice used in this system as bone marrow donors lack all four CD3 subunits (CD3gammadeltaEzeta(-/-)). These mice are generated by crossing the strains CD3zeta(-/-) and CD3gammadeltaE(-/-), the latter resulting from a knockout construct targeted to CD3E that additionally silences the linked genes, CD3gamma and CD3delta. Lacking mature T-cell function, CD3gammadeltaEzeta(-/-) mice are immunocompromised animals often produced by heterozygous breeding strategies on the C57BL/6 background. As a more rapid and reliable means to identify CD3gammadeltaEzeta(-/-) mice than previously described Northern and Southern blots, we designed polymerase chain reactions to distinguish knockout from wild type CD3E and CD3zeta alleles, facilitating the identification of CD3gammadeltaEzeta(-/-) mice. PMID- 23741636 TI - The effect of pulsatile loading and scaffold structure for the generation of a medial equivalent tissue engineered vascular graft. AB - A reliable and cost-effective scaffold for tissue-engineered vascular graft that would not only support cell proliferation and growth but also maintain cell phenotype has been a long-term challenge. In this study, we propose a biodegradable and biomimetic copolymer of gelatin with vinyl acetate synthesized via a graft copolymerization technique to generate tubular scaffolds for vascular tissue engineering. Two fabrication techniques, freeze drying and electrospinning, were used to generate the differing architectures for the scaffolds and characterized. The electrospun scaffolds were found to have a faster rate of mass loss in physiological saline of 81.72% within 4 months compared with 60% mass loss for the freeze-dried samples, though the materials were more crystalline. Vascular (v) smooth muscle cells (SMCs) were seeded on these tubes, which were then subjected to dynamic pulsatile stimulation on a vascular bioreactor for a week. Gross examination of the tissue-engineered constructs revealed that the cells secreted extensive extracellular matrix, with the dynamically conditioned samples exhibiting well-orientated SMCs and collagenous fibers in comparison with growth in static conditions. In addition, the alignment of cells in the direction of strain was greater in the electrospun constructs. The electrospun scaffolds maintained the characteristic contractile phenotype of SMCs, which was confirmed by higher gene expression rates of contractile protein markers like SM22alpha and calponin. A significant increase in the total matrix components (collagen and elastin) in the electrospun constructs compared with the freeze-dried samples was confirmed by biochemical analysis. The results of this study indicate that a combination approach involving a biomimetic scaffold with the nanofibrillar architecture and good mechanical strength conducive to the growth of SMCs and the use of the pulsatile forces to modulate the cell morphology and phenotypic plasticity of vSMCs helps in the successful engineering of a medial layer of blood vessel. PMID- 23741637 TI - Rhodomycin analogues from Streptomyces purpurascens: isolation, characterization and biological activities. AB - During a screening program for bioactive natural products, a potential Streptomyces sp was isolated from soil. On the basis of biochemical, cultural, physiological and 16S rRNA gene analysis, it was identified as Streptomyces purpurascens. The isolate was grown in liquid medium and the crude antibiotic complex was obtained by ethyl acetate extraction. Seven purified fractions were obtained by preparative Thin Layer Chromatography (TLC). Acid hydrolysis of each fraction and subsequent TLC led to the identification of aglycones and sugars indicating these compounds to be Rhodomycin and its analogues. The identity of these compounds was established on the basis of UV-visible and FT-IR spectra and comparison with published data. The compounds were active against Gram-positive bacteria. Compound E, identified as Rhodomycin B, was found to be the most potent compound with an MIC of 2 MUg/ml against Bacillus subtilis. Compounds A and F identified as alpha2-Rhodomycin II and Obelmycin respectively, and Compound E exhibited an IC50 of 8.8 MUg/ml against HeLa cell line but no cytotoxicity was found against L929. PMID- 23741638 TI - Usefulness of dynamic volume scanning with 320-row CT in detecting recanalization of pulmonary arteriovenous fistula after coil embolization. AB - Pulmonary arteriovenous fistula is a congenital and rarely acquired anomalous direct communications between pulmonary arteries and veins. Transcatheter embolization using metallic coil or detachable balloon is one of the common treatment procedure. However, recanalization after the embolization is one of the concern and its differentiation from the retrograde filling via pulmonary vein is difficult except using invasive angiography. We report a case with recanalized pulmonary arteriovenous fistula non-invasively detected by dynamic CT angiography with 320-rows multi detector CT. A 45-year-old women who had underwent coil embolization for pulmonary arteriovenous fistula was examined with dynamic CT angiography and antegrade contrast enhancement of the fistula was noted. The recanalization through the embolized artery was confirmed by digital subtraction angiography, and the second coil embolization was performed. The follow-up dynamic CT angiography at three months after the second procedure found the retrograde enhancement of aneurysmal sac and no antegrade shunt. The dynamic CT angiography was useful for the detect the recanalization of pulmonary arteriovenous fistula. Delayed pulmonary artery recanalization was reported to be observed in 5- 10% of cases as a complication after the successful occlusion of segmental pulmonary artery. Lack of change in aneurysmal diameter of pulmonary arteriovenous fistula demonstrated by CT was reported as the result of persistent aneurysmal perfusion or aneurysmal thrombosis. However, the retrograde filling of aneurysmal sac via pulmonary vein or remnant collateral pathway to the pulmonary arteriovenous fistula were also considered. Therefore, before the invasive procedure, we performed dynamic CT angiography to detect the flow direction and pathway to the pulmonary arteriovenous fistula. Using dynamic CT angiography, we could obtain hemodynamic information through the aneurysmal sac of pulmonary arteriovenous fistula and decide to proceed to the invasive embolotherapy. Prospective perfusion CT scan could be an alternative to invasive angiography in the initial follow-up after the embolotherapy or in the cases with the recanalization of pulmonary arteriovenous fistula. PMID- 23741639 TI - In -silico molecular docking analysis of prodigiosin and cycloprodigiosin as COX 2 inhibitors. AB - Prodigiosin and cycloprodigiosin are tripyrrole red pigmented compounds with medical importance for their anticancer property. In the present investigation, molecular docking studies were performed for both prodigiosin and cycloprodigiosins to evaluate the in- silico anti-inflammatory activity against Cycloxigenase-2 (COX-2) protein as model compound and the data compared with rofecoxib and celcoxid. Cycloprodigiosin showed higher initial potential, initial RMS gradient and potential energy values compared to prodigiosin. Analysis of COX 2 protein and ligand binding revealed that cyclprodigiosin interacted with COX-2 protein amino acid residues of Tyr(324), Phe(487) and Arg(89) while prodigiosin interaction was observed with two amino acids i.e. Leu(321) and Tyr(324). The computational ligand binding interaction suggested > 45% higher fitness score value for prodigiosin to that of cycloprodigiosin with COX-2 protein while the standard compounds rofecoxib and celecoxid revealed fitness score of 44 and 62, respectively. The prodigiosin ligand revealed the best fitness score compared with the standard drug rofecoxib suggesting the prodigiosin could be effective as the potential inhibitor compound against COX-2 protein and can be evaluated as anti-inflammatory drug molecule using clinical trials. PMID- 23741640 TI - Bioequivalance and pharmacokinetic study of febuxostat in human plasma by using LC-MS/MS with liquid liquid extraction method. AB - A bioequivalence study was proved of generic Febuxostat 80 mg tablets (T) in healthy volunteers.For this purpose, Authors developed a simple, sensitive, selective, rapid, rugged and reproducible liquid chromatography-tandem mass spectrometry method for the quantification of Febuxostat (FB) in human plasma using Febuxostat D7 (FBD7) as an internal standard (IS) was used. Chromatographic separation was performed on Ascentis Express C18 (50x4.6 mm, 3.5 MU) column. Mobile phase composed of 10 mM Ammonium formate: Acetonitrile (20:80 v/v), with 0.8 mL/min flow-rate. Drug and IS were extracted by Liquid- liquid extraction. FB and FBD7 were detected with proton adducts at m/z 317.1->261.1 and 324.2->262.1 in multiple reaction monitoring (MRM) positive mode respectively. The method was validated with the correlation coefficients of (r(2)) >= 0.9850 over a linear concentration range of 1.00-8000.00 ng/mL. This method demonstrated intra and inter-day precision within 2.64 to 3.88 and 2.76 to 8.44% and accuracy within 97.33 to 99.05 and 100.30 to 103.19% for FB. This method is successfully applied in the Bioequivalence study of 9 human volunteers. PMID- 23741641 TI - Is emphysema a risk factor for pneumothorax in CT-guided lung biopsy? AB - INTRODUCTION: Computed tomography (CT)-guided lung biopsy is commonly used to make a histological diagnosis for pulmonary lesions. Its most common complication is pneumothorax. While it is thought that CT-guided lung biopsy should be avoided in patients with emphysema, however, there is no scientific report documenting the relationship the occurrence of pneumothorax and the severity of emphysema. PURPOSE AND METHODS: To investigate the relationship between the severity of emphysema and the frequency of pneumothorax, we retrospectively reviewed all the patients who received CT-guided lung biopsy. Severity of emphysema is evaluated by Goddard classification, a visual scale by which areas of vascular disruption and low attenuation value were scored for each lung field of high resolution CT. Patients' characteristics, prognostic accuracy of this method, size and location of the lesion, length of intrapulmonary biopsy paths, and frequency of complications such as pneumothorax or intrapulmonary hemorrhage were evaluated. RESULTS: One hundred-two patients (69 males and 33 females) received 102 procedures. Diagnostic accuracy was 90.2%. Pneumothorax occurred in 41 of 102 biopsies (40.2%). Chest tube placement was required in 3 out of the 41 cases (7.3%) complicated by pneumothorax (2.9% of all the biopsies). The longer lesion depths from pleura were, the more frequently pneumothorax occurred (6.67 vs 3.66 mm, p=0.019). No correlation was found between location of lesions and frequency of pneumothorax. No significant differences of COPD staging or LAA score were seen between the patients with and without pneumothorax (5.73 vs 4.32 points, p=0.339). CONCLUSION: We suggest that severity of emphysema such as stage I or II COPD may not be related to the frequency of pneumothorax. PMID- 23741642 TI - Effect of beta-glucan on the immune response of early stage of Anabas testudineus (Bloch) challenged with fungus Saprolegnia parasitica. AB - The present study was carried out to study the effect of different dosages of beta-glucan suspension on immune response and disease resistance in Anabas testudineus spawns against a fungal pathogen Saprolegnia parasitica. Eight day old spawns were exposed for 3 h in four different dosages of beta-glucan suspension in phosphate buffered saline at the rate of 0, 5, 10, 15 mg l(-1). The cell suspension of spawn was assayed for total protein, acid phosphate, lysozyme, bactericidal and NBT activity. The spawns were then challenged with 3x10(5) CFU ml(-1) of S. parasitica. The survivability percentage and immunological parameters were assayed upto day 7. Exposure of fish for 3h to all the concentrations of beta-glucan recorded a significant enhancement in the immunological parameters such as lysozyme activity, bactericidal activity and NBT activity by the end of day 7. The challenge study indicated least mortality in the groups exposed to 10 mgl(-1) and 15 mgl(-1) but 15 mgl(-1) gives little higher survivability. Thus 3 h exposure of beta-glucan suspension could reduce the mortality and increase the immunity of A. testudineus spawns against S. parasitica. PMID- 23741643 TI - Long-term, up to 18 months, protective effects of the angiotensin II receptor blocker telmisartan on Epirubin-induced inflammation and oxidative stress assessed by serial strain rate. AB - PURPOSE: The primary objective of the present study was to show the long lasting cardioprotective activity, at different time-points, up to 18 month-follow-up, of telmisartan in preserving the systolic function (assessed as Strain Rate-SR) in cancer patients treated with EPI both in the adjuvant and metastatic setting; the secondary objective was to confirm the correlation of the cardioprotective activity of telmisartan with a reduction of inflammation and oxidative stress induced by EPI. METHODS: Phase II single blind placebo-controlled randomized trial. Sample size 50 patients per arm: based on a pre-planned interim analysis for early stopping rules, the study was discontinued for ethical reasons at 49 patients. Cardiovascular disease-free patients with cancer at different sites eligible for EPI-based treatment randomized to: telmisartan n = 25 or placebo n = 24. Echocardiography Tissue Doppler imaging (TDI) strain and strain rate was performed, serum levels of proinflammatory cytokines (IL-6, TNF-alpha) and oxidative stress (reactive oxygen species, ROS) were assessed at baseline, every 100 mg/m(2) EPI dose and at 6-, 12- and 18-month follow-up (FU). RESULTS: Significant SR peak reduction in both arms was observed at t2 (cumulative dose EPI 200 mg/m(2)) vs t0. Conversely, at t3, t4, 6-, 12- and 18-month FU SR increased towards normal range in the telmisartan arm, while in the placebo arm SR remained significantly lower. Differences between SR changes in the placebo and telmisartan arm were significant from t3 up to 18 month-FU. IL-6 and ROS increased significantly in the placebo arm at t2 but did not change in the telmisartan arm. A significant (p < 0.05) correlation between changes of SR vs IL 6 and ROS was observed. CONCLUSIONS: Our results suggest that the protective effect of telmisartan is long lasting, probably by ensuring a permanent (at least up to 18-month FU) defense against chronic or late-onset types of anthracycline induced cardiotoxicity. PMID- 23741644 TI - A rapid analysis of plasma/serum ethylene and propylene glycol by headspace gas chromatography. AB - A rapid headspace-gas chromatography (HS-GC) method was developed for the analysis of ethylene glycol and propylene glycol in plasma and serum specimens using 1,3-propanediol as the internal standard. The method employed a single-step derivitization using phenylboronic acid, was linear to 200 mg/dL and had a lower limit of quantitation of 1 mg/dL suitable for clinical analyses. The analytical method described allows for laboratories with HS-GC instrumentation to analyze ethanol, methanol, isopropanol, ethylene glycol, and propylene glycol on a single instrument with rapid switch-over from alcohols to glycols analysis. In addition to the novel HS-GC method, a retrospective analysis of patient specimens containing ethylene glycol and propylene glycol was also described. A total of 36 patients ingested ethylene glycol, including 3 patients who presented with two separate admissions for ethylene glycol toxicity. Laboratory studies on presentation to hospital for these patients showed both osmolal and anion gap in 13 patients, osmolal but not anion gap in 13 patients, anion but not osmolal gap in 8 patients, and 1 patient with neither an osmolal nor anion gap. Acidosis on arterial blood gas was present in 13 cases. Only one fatality was seen; this was a patient with initial serum ethylene glycol concentration of 1282 mg/dL who died on third day of hospitalization. Propylene glycol was common in patients being managed for toxic ingestions, and was often attributed to iatrogenic administration of propylene glycol-containing medications such as activated charcoal and intravenous lorazepam. In six patients, propylene glycol contributed to an abnormally high osmolal gap. The common presence of propylene glycol in hospitalized patients emphasizes the importance of being able to identify both ethylene glycol and propylene glycol by chromatographic methods. PMID- 23741645 TI - Purification and identification of trichloroethylene induced proteins from Stenotrophomonas maltophilia PM102 by immuno-affinity-chromatography and MALDI TOF Mass spectrometry. AB - A novel bacterial isolate capable of growth on trichloroethylene as the sole carbon source was identified as Stenotrophomonas maltophilia PM102 by 16S rDNA sequencing (GenBank Acc.no. JQ797560). Serum was obtained from a rabbit immunized with the total protein extracted from the PM102 isolate grown in 0.2% TCE with 0.2% peptone. Antibodies to the common antigens were removed by preadsorbing the serum antibody on total protein extracted from the PM102 strain grown in 0.2% peptone. Western blot with the preadsorbed antibody reacted to a single band in TCE and TCE with peptone lane. No reaction was seen in peptone lane. This preadsorbed antibody specific for TCE inducible antigens was immobilised on epoxy activated sepharose 6B and total protein from PM102 cells grown in minimal medium with TCE as the sole carbon source was purified through the column. The bound protein fraction was eluted and resolved through 12% SDS PAGE. Four prominent bands observed in the protein profile were analysed by matrix-assisted laser desorption/ionization time of flight-mass spectrometry (MS) and tandem mass spectrometry (MS/MS) after in gel digestion with 25 ng/MUl trypsin. A number of mono/di-oxygenases that cometabolise TCE in presence of some other primary carbon source are present in literature but this is the first attempt in identification of TCE induced proteins linked to metabolic activity with oxidoreductase like function, from a bacterial isolate that utilises TCE as the sole carbon source. PMID- 23741646 TI - Investigation of soils affected by burnt hospital wastes in Nigeria using PIXE. AB - Improper management of hospital waste has been reported to be responsible for several acute outbreaks like the severe acute respiratory syndrome (SARS). In spite of these challenges, hospital wastes are sometimes not properly handled in Nigeria. To date, there has not been an adequate study on the effect and fate of burnt hospital waste on agricultural soil. The effect of burnt hospital wastes on the agricultural soil was conducted on soils sampled around farm settlement near Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, South West Nigeria. PIXE technique was employed with a 1.7 MV 5SDH Tandem Pelletron accelerator available at Centre for Energy Research and Development O.A.U Ile Ife, Nigeria. Eleven elements- Si, Cl, K, Ca, Ti, V, Cr, Mn, Fe, Zr and Pb were detected and their concentrations and enrichment factors determined. The presence of Pb and Cl at the elevated concentrations range of (77.8 +/- 3.5 - 279.6 +/- 97.6 and 102.2 +/- 37.4 -167.2+/-17.43) ppm respectively in this study, is of serious health concern because of the agricultural practices in the neighborhoods of the study sites. There is a need for proper handling of hospital and other related hazardous wastes because of the possibility of such posing serious environmental pollution problems. PMID- 23741647 TI - Testosterone-derived estradiol production by male endothelium is robust and dependent on p450 aromatase via estrogen receptor alpha. AB - Vascular endothelium expresses both the estrogen receptors (ERs) alpha and beta, and ERalpha mediates development of early atherosclerosis in male mice. This process is thought to be testosterone-dependent. We hypothesized that male murine aortic endothelium produces robust levels of estradiol by aromatase conversion of testosterone, and that regulation of this process is mediated by the presence of ERs, primarily ERalpha. Aortic endothelium was isolated from ERalpha knockout (ERalpha -/-) and wild-type (ERalpha +/+) male mice and treated with testosterone or the 5alpha reduction product dihydrotestosterone (DHT), with or without the P450 aromatase inhibitor anastrazole, or a non-specific estrogen receptor antagonist. Aromatase gene expression and estradiol production were assayed. Treatment with testosterone, but not DHT, caused increased aromatase expression and estradiol production in ERalpha +/+ endothelium that was attenuated by disruption of ERalpha in the ERalpha -/- group. Anastrazole inhibition of aromatase reduced testosterone-induced aromatase expression and estradiol levels in both ERalpha -/- and ERalpha +/+ endothelium. Antagonism of both ERs decreased testosterone-induced aromatase expression in both wild-type and knockout groups. The effects of the receptor antagonist on estradiol production differed between the two groups, however, with a reduction in estradiol release from the ERalpha +/+ cells and complete abolition of estradiol release from the ERalpha -/- cells. Thus, estradiol production in vascular endothelium from male mice is robust, depends on the aromatic conversion of testosterone and requires functional ERalpha to achieve maximal levels of estradiol generation. Local vascular production of aromatase-mediated estradiol in response to circulating testosterone may affect ERalpha-dependent mechanisms to increase susceptibility to early atheroma formation in male mice. This pathway may have important therapeutic relevance for reducing the risk of atherosclerotic cardiovascular disease in human males. PMID- 23741648 TI - Cardiovascular hemodynamic effects of Red Bull(r) Energy Drink during prolonged, simulated, monotonous driving. AB - PURPOSE: The purpose of this study was to investigate the cardiovascular hemodynamic effects of Red Bull(r) Energy Drink during prolonged, simulated, monotonous driving. METHODS: This was a double-blind, within-subjects-design, crossover study. Twelve healthy volunteers (21.7 +/- 0.8 years old) experienced each of three conditions at various times: 1) consumption of Red Bull(r) Energy Drink; 2) consumption of placebo-controlled drink; and 3) no test drink. All subjects undertook 90-min periods of simulated monotonous driving, during which physiological measurements were made. The variables recorded were cardiovascular indices, i.e., mean blood pressure (MBP), cardiac output (CO), electrocardiogram RR interval (RR), total peripheral-vascular resistance (TPR: = MBP/CO), and normalized pulse volume (NPV). Additional parameters were the standard deviation of lateral position, i.e., the weaving of the car, and subjective rating of sleepiness. RESULTS: CO, RR, and TPR during the monotonous task were significantly different in those consuming the energy drink as compared with those receiving the placebo and as compared with no drink values. The energy drink elicited a cardiac-dominant reaction pattern, while the other conditions demonstrated the vascular-dominant reaction pattern typically observed in monotonous driving tasks. The observed differences indicate the cardiovascular system being more aroused with the energy drink. CONCLUSION: The effects of Red Bull(r) Energy Drink were reflected in cardiovascular hemodynamic phenomena especially to the heart function, and we conclude that consumption of this drink before long-distance driving in non-sleepy drivers could facilitate more physiologically active, and possibly safer, driving. PMID- 23741649 TI - Vehicular emission inventory of criteria pollutants in Delhi. AB - The rapid urbanization in Delhi has resulted in a tremendous increase in the number of motor vehicles with the increase in population and urban mobilization. The vehicular traffic is now recognized as one of the main sources of air pollution in Delhi and has noticeable impact on air quality. The emission of criteria pollutants namely Carbon Monoxide (CO), Nitrogen Oxide (NOx) and Particulate Matter (PM) due to vehicles is estimated through the International Vehicle Emission (IVE) model, which includes the different driving modes of vehicles and meteorological parameters. The estimated emissions of Carbon Monoxide (CO), Nitrogen Oxides (NOx) and Particulate Matter (PM) due to different types of vehicles in the year 2008-09 are found to be 509, 194 and 15 tons/day respectively. The diurnal variation of emissions of air pollutants shows two peaks, which are fortunately matching with the morning and evening office hours. The emissions of CO and NOx due to personal cars (PCs) are found to be about 34% and 50% respectively, and the emission of CO due to 2 W (2- Wheeler) is about 61%. Similarly, the Heavy Commercial Vehicles (HCVs) are contributing PM about 92%. The analysis of fuel-wise emission of pollutants reveals that CO is mainly contributed by petrol, and NOx and PM are contributed by diesel. It is also noticeable that CO, NOx and PM emissions at ITO, one of the busiest traffic intersections of Delhi, are approximately 15, 6 and 0.5 tons/day respectively, which are found to be the maximum followed by Kashmiri Gate (ISBT), Nizamuddin etc. The present vehicular emissions inventory has been compared quantitatively with previous studies of Delhi. The present vehicular emission inventory has also validated using US environmental protection agency's (USEPA's) AERMOD model with observed concentration at different locations in Delhi. However, the present study shows that the air quality of Delhi has been degraded due to high level emissions of criteria pollutants. PMID- 23741650 TI - An audit to determine if vitamin b12 supplementation is necessary after sleeve gastrectomy. AB - ABSTRACT: Sleeve gastrectomy has increased in popularity over the last five years and it is likely to supersede gastric banding. Nevertheless, it is unclear whether vitamin B12 supplementation is required after surgery. The aim of this short report is to identify any vitamin B12 deficiency and highlight the necessity of post laparoscopic sleeve gastrectomy vitamin B12 monitoring. PATIENTS AND METHODS: A review of 66 patients underwent LSG in our institution. 25 patients were excluded as they had no postoperative vitamin B12 screening. 41 patients were included as screened for vitamin B12 and other micronutrients including selenium, serum folate, ferritin, iron, zinc, copper, magnesium and vitamin D. RESULT: There were 5 male (12%) and 36 females (88%), 8/41 patients (20%) had Vitamin B12 deficiency, none of them developed macrocytic anaemia. 17/21 (81%) patient were vitamin D deficient and 9/21 (43%) exhibited low selenium. CONCLUSION: In this small group, a 20% prevalence of vitamin B12 was identified. As a consequence vitamin B12 monitoring and supplementation will be a standard of care in the early postoperative period after LSG at this institution. PMID- 23741651 TI - Usability assessment of an electronic health record in a comprehensive dental clinic. AB - In this paper we present the development and usability of an electronic health record (EHR) system in a comprehensive dental clinic.The graphic user interface of the system was designed to consider the concept of cognitive ergonomics.The cognitive task analysis was used to evaluate the user interface of the EHR by identifying all sub-tasks and classifying them into mental or physical operators, and to predict task execution time required to perform the given task. We randomly selected 30 cases that had oral examinations for routine clinical care in a comprehensive dental clinic. The results were based on the analysis of 4 prototypical tasks performed by ten EHR users. The results showed that on average a user needed to go through 27 steps to complete all tasks for one case. To perform all 4 tasks of 30 cases, they spent about 91 min (independent of system response time) for data entry, of which 51.8 min were spent on more effortful mental operators. In conclusion, the user interface can be improved by reducing the percentage of mental effort required for the tasks. PMID- 23741652 TI - Neurodevelopmental outcomes of moderately preterm birth: precursors of attention deficit hyperactivity disorder at preschool age. AB - Moderately preterm birth seems to be an evolutional risk condition at cognitive, behavioural and socio-relational levels. The study is aimed to investigate the likely occurrence of precursors of Attention Deficit Hyperactivity Disorder (ADHD) in moderately preterm children at preschool age. The research involved an experimental group made up of 50 moderately preterm children (mean: 34.6 weeks' gestational age, standard deviation [SD]: 2) without any medical and neurologic neonatal complications and low birth weight (mean:2100g., SD: 350g.) and a check group of 50 full term born children. Parents and teachers of children were administered specific questionnaires to detect ADHD. The outcomes show a risk of ADHD highlighting statically significant differences related to gender [F(2, 99) = 2.99, p = .04], birth [F(2, 99) = 9.6, p = .03] and interaction [F(2, 99) = 2.2, p = .01]. The moderately preterm children showed deficit in self-regulation [F(2, 99) = 1.14, p = .04] and attention deficit in daily life both in family [F(2, 99) = 7.8, p = .04] and school contexts [F(1, 99) = 3.3, p = .04]. The outcomes hint assessment paths aimed to monitor the aspects of cognitive, motor, behavioural development of moderately preterm children recognised as signs of problematic functioning profiles. Therefore, specific training will have been designed since preschool age in order to control the ADHD risk factors. PMID- 23741653 TI - Composite structure of silken threads and a proteinaceous hydrogel which form the diving bell wall of the water spider Agyroneta aquatica. AB - The unique ability of Argyroneta aquatica to form a diving bell web was re examined using a new approach in a structurally simplified environment. The spiders generated sheet-webs from stiff, anchored threads and bundles of fine threads crossing each other, to which a hydrogel was added in several places. Due to the hydrophilic property of the web, small air bubbles could not pass this composite and remained perfectly spherical at the contact point. As revealed using Coomassie Brilliant Blue, the hydrogel and the silken threads are proteinaceous. The spider uses the web as a diving bell by transporting air bubbles to a small area underneath such a sheet-web, and by additional spinning activities. As revealed by light microscopy, the composite of threads and hydrogel is free of any meshes. In contrast, scanning electron microscopy shows only remnants of the hydrogel. PMID- 23741654 TI - Definition and application of an assurance case development method (d*). AB - Now, information systems are developed as open system that depend on each other. Assurance cases are expected to confirm a dependability of open systems. D*Framework is a method that can make assurance case for open system. In this paper we defined d*Framework formally. Furthermore we apply this method with case study and made discussion. PMID- 23741655 TI - Genetic structure and diversity of indigenous rice (Oryza sativa) varieties in the Eastern Himalayan region of Northeast India. AB - The Eastern Himalayan region of Northeast (NE) India is home to a large number of indigenous rice varieties, which may serve as a valuable genetic resource for future crop improvement to meet the ever-increasing demand for food production. However, these varieties are rapidly being lost due to changes in land-use and agricultural practices, which favor agronomically improved varieties. A detailed understanding of the genetic structure and diversity of indigenous rice varieties is crucial for efficient utilization of rice genetic resources and for developing suitable conservation strategies. To explore the genetic structure and diversity of rice varieties in NE India, we genotyped 300 individuals of 24 indigenous rice varieties representing sali, boro, jum and glutinous types, 5 agronomically improved varieties, and one wild rice species (O. rufipogon) using seven SSR markers. A total of 85 alleles and a very high level of gene diversity (0.776) were detected among the indigenous rice varieties of the region. Considerable level of genetic variation was found within indigenous varieties whereas improved varieties were monoporphic across all loci. The comparison of genetic diversity among different types of rice revealed that sali type possessed the highest gene diversity (0.747) followed by jum (0.627), glutinous (0.602) and boro (0.596) types of indigenous rice varieties, while the lowest diversity was detected in agronomically improved varieties (0.459). The AMOVA results showed that 66% of the variation was distributed among varieties indicating a very high level of genetic differentiation in rice varieties in the region. Two major genetically defined clusters corresponding to indica and japonica groups were detected in rice varieties of the region. Overall, traditionally cultivated indigenous rice varieties in NE India showed high levels of genetic diversity comparable to levels of genetic diversity reported from wild rice populations in various parts of the world. The efforts for conservation of rice germplasm in NE India should consider saving rice varieties representing different types with specific emphasis given to sali and jum types. The protection against the loss of vast genetic diversity found in indigenous rice varieties in NE India is crucial for maintaining future food security in the changing world. PMID- 23741656 TI - Estimating changes in metabolic power from EMG. AB - Metabolic rates can increase 21 times above resting levels during cycling with the majority attributed to muscular contractions. Metabolic estimates attained through gas exchange parameters are limited by the respiration rate and time delay with respect to these contractions. In contrast surface electromyography (EMG) contains instantaneous muscle contraction information at higher temporal resolutions. An adequate metabolic power-EMG relationship has not been established to use EMG as a metabolic estimate during dynamic activities. The purpose of this study was to establish a metabolic power-EMG relationship during non steady-state conditions. Participants cycled at workloads between 25 and 90% O2max while EMG and gas exchange were monitored. The EMG was resolved into intensities and total EMG intensity was calculated as the sum of intensities across all muscles for each pedal cycle. Metabolic power was estimated from gas exchange parameters and the mean total EMG intensity between breaths was calculated and used as breath-by-breath values. Comparisons were made between breath-by-breath resolutions of metabolic power and total EMG intensity. Different weighting coefficients were also applied to the EMG for each muscle to analyze the effects of different muscle weightings on metabolic power estimations. There was a significant correlation (r = 0.91) between estimates of metabolic power from EMG and gas exchange. Muscle weighting had a significant effect on metabolic power determination with the highest and lowest correlated estimates having the largest weightings on muscles proximal and distal to the knee respectively. This study demonstrates that EMG contains important information about the metabolic costs of muscle contractions and provides good predictions of metabolic changes during non steady-state conditions. Also, the importance of each muscle is workload dependent with inappropriate weightings reducing metabolic estimations. These findings have implications for future EMG applications as they provide more immediate, higher temporal resolution predictions of changes in metabolic power. PMID- 23741657 TI - The Chronobra identifies prevailing mammary vascularity as a candidate variable in breast cancer post-operative outcome prediction. AB - We previously described a menstrual heat cycle of the breast in four groups of women (healthy, family history of breast cancer, benign breast disease, 'cancer associated') who wore a thermometric brassiere (Chronobra). We now ask if 'breast minus oral temperature', indicating 'breast-associated vascularity', could be associated with breast cancer cell vascular access around different aspects of the menstrual cycle rhythm and survival. Thirty-six pre-menopausal breast cancer patients (average age: 38.97 y) were enrolled consecutively over 15 y and followed for more than 22 y after surgery in order to compare survival and peri operative vascularity. Each subject wore the Chronobra, which provides an internal bioassay of the vascularity of both breasts, including the operated breast, during 1 h each evening at home for one menstrual cycle, and collected saliva for "free" progesterone to confirm pre-menopausal status and ovulation. Sixty-five healthy age-matched pre-menopausal women served as controls. Both oral and breast temperatures revealed menstrual cycle oscillations, rising just before ovulation until menses onset. Breast-adjusted vascularity also showed menstrual cycle oscillations, with levels differing significantly between the 3 groups during the luteal phase only. At the end of the follow-up span, 18 post-operative breast cancer patients had died from "disseminated" breast cancer and 18 were alive and well. Median follow-up time was 22.6 y for survivors, 6.2 y for non survivors, and 21.0 y for controls (3 died from diseases unrelated to breast cancer). Based on 'during luteal-phase breast-adjusted vascularity', breast cancer survivors (mean +/- SD: -1.65 +/- 0.23 degrees C) were significantly hypo vascular (i.e., -0.23 degrees C cooler) compared with controls (-1.42 +/- 0.09 degrees C), while non-survivors (-1.25 +/- 0.12 degrees C) were highly significantly hyper-vascular compared with survivors (+0.41 degrees C warmer) and controls (+0.23 degrees C warmer). This suggests that in pre-menopausal breast cancer patients, peri-operative mammary vascularity could offer an outcome test of survival and biologically may be on the "final common pathway" of any tumor to metastatic risk and recurrence. PMID- 23741658 TI - Intra-operative radiological margins assessment in conservative treatment for non palpable DCIS: correlation to pathological examination and re-excision rate. AB - What constitutes an adequate surgical margin in partial mastectomy is still controversial: intra-operative specimen radiogram is commonly used during partial mastectomy for nonpalpable lesions in order verify the adequacy of the resection but what margin is to be considered "adequate" is still debatable. An intraoperative specimen mammogram was performed during all consecutive conservative resections for nonpalpable DCIS and a 15-mm radiological margin was considered "adequate". Margins were pathologically assessed and classified as "negative", "close" or "positive" and the rate of margin involvement constitued the main outcome of the study. Among 272 conservative interventions, 80.51% had negative margins at final pathology, 3.31% had close margins and 16.18% had positive margins. An intraoperative "adequate" margin of 15 mm as defined on intraoperative specimen mammogram granted a high rate of histologically negative margin at primary surgery; this finding was paralleled by confirmation of the treatment as conservative in 95% of cases. PMID- 23741659 TI - Theory of Mind and embedding of perspective: A psychological test of a literary "sweet spot" AB - Theory of Mind (ToM) has been proposed to explain social interactions, with real people but also with fictional characters, by interpreting their mind as well as our own. "Perspective embedding" exploits ToM by placing events in characters' minds (e.g., "he remembered she was home"). Three levels of embedment, common in literature, may be a "sweet spot" that provides enough information about a character's motivation, but not a confusing over-abundance. Here, we use short vignettes with 1 or 3 characters and 0-5 levels of perspective embedding in two reading studies to see whether these preferences might be related to processing ease. Self-paced readers were fastest with one level of embedment, increasingly slower as embedment increased; vignettes without embedment were approximately as slow as level 4. With both self-paced and imposed timing, error rates on probe questions increased only at the fifth level. Readers seem to prefer literary texts in which ToM operations are obvious due to embedding of perspectives within the narrative but still somewhat challenging. PMID- 23741661 TI - The scope of teledermatology in India. AB - Telemedicine describes the application of information and communication technologies in the entire range of functions that involve the health sector. Several medical and surgical specialties utilize tele-consultation. Dermatology is the best clinical specialty in the use of communications technology because of its inherently visual nature in both diagnosis and follow-up, which makes it easily applicable to virtual medicine. Teledermatology embraces great potential for revolutionizing the delivery of dermatologic services to remote and distant locations by means of telecommunications and information technology. It encompasses consultations between a patient (and the primary healthcare provider) and a dermatologist for diagnosis and management advice. Teledermatology also covers dermatological education for health professionals and for consumers. Teleconsultations reduce time and increase the chances of access to one or more consultants as the patient or referring doctor desires, irrespective of the distance between the two. Its usefulness in the field of surgery and aesthetic surgery is immeasurable as there are only a few experts in the field of aesthetic surgery available currently in comparison to the dermatology population and the ever growing awareness and demand of the patients towards aesthetics. As the field of teledermatology is advancing in leaps and bounds the day is not far off when an aesthetic surgeon will be able to perform his skill from his own office on a patient in a distant locality with the help of a qualified and trained assistant. By adopting high-tech medical communication, high-performance computers, high-resolution cameras, and fiber-optic equipment's the entire world shrinks! PMID- 23741662 TI - Smokers' hair: Does smoking cause premature hair graying? AB - AIMS: To determine if there is a significant association between premature hair graying and cigarette smoking. MATERIALS AND METHODS: A cross-sectional observational study was conducted in a nonclinical setting on 207 participants on August 24 until 25, 2010. Participants were classified into two groups [premature hair graying (PHG) and normal hair graying]. PHG was defined as the first appearance of gray hair before the age of 30. Data were collected using an interview questionnaire and measurements of body mass index, waist circumference, fasting blood glucose and blood pressure. Collected data were statistically analyzed using SPSS 16, Chicago, IL. RESULTS: Of the 207 subjects, 104 (50.2%) had first appearance of gray hair before the age of 30 (PHG group) while the other 103 (49.8%) were considered normal hair graying group. The prevalence of smokers in the "PHG" group was higher (40.2% vs. 24.7%, P = 0.031). Smokers had earlier onset of hair graying (smokers: 31 (7.4) vs. nonsmokers: 34 (8.6), P = 0.034). Using multiple logistic regression with conditional likelihood, smokers were two and half times (95% CI: 1.5-4.6) more prone to develop PHG. CONCLUSION: This study suggests that there is a significant relation (with adjusted odds ratio of two and half) between onset of gray hair before the age of 30 and cigarette smoking. PMID- 23741660 TI - Achieving hemostasis in dermatology - Part 1: Preoperative, intraoperative, and postoperative management. AB - As dermatological procedures continue to become increasingly complex, improved methods and tools to achieve appropriate hemostasis become necessary. The methods for achieving adequate hemostasis are variable and depend greatly on the type of procedure performed and the unique characteristics of the individual patient. In Part 1 of this review, we discuss the preoperative, intraoperative, and postoperative management of patients undergoing dermatologic surgery. We address oral medications and supplements that affect hemostasis, hemostatic anesthesia, and intraoperative interventions such as suture ligation and heat-generating cautery devices. In Part 2 of this review, we will discuss topical hemostats. The authors conducted an extensive literature review using the following keywords: "hemostasis," "dermatology," "dermatological surgery," "dermatologic sutures," "electrosurgery," "hemostatic anesthesia," and "laser surgery." Sources for this article were identified by searching the English literature in the Pubmed database for the time period from 1940 to March 2012. A thorough bibliography search was also conducted and key references were examined. PMID- 23741663 TI - Outcome of wide local excision in dermatofibrosarcoma protuberans and use of radiotherapy for margin-positive disease. AB - PURPOSE: Wide local excision (WLE) is the preferred treatment of dermatofibrosarcoma protuberans (DFSP). The aim is to achieve negtive margins. We followed the impact of radiotherapy used postoperatively for both margin-negative and margin-positive DFSP tumors. MATERIALS AND METHODS: Outcome of treatment of 36 patients of DFSP treated at our hospital was assessed. Thirty patients received radiotherapy postoperatively and six patients received radiotherapy alone. The maximum dimension of the lesion was 15 cm(2). Patients were followed up for varying periods of time for any recurrence. RESULTS: 10-year actuarial local control rate was determined. Local control was realized in six patients who were treated with radiotherapy alone. 30 patients were treated by radiotherapy and surgery. Out of these 30 patients, there were 6 local failures (failure rate 10%). Actuarial control rate was 82%. The failures were among patients who had positive margins. CONCLUSION: Radiotherapy is effective, and it decreases the recurrence rate in the treatment of DFSP. It is especially helpful in margin positive disease. This appears true for patients treated with radiotherapy alone or radiotherapy used postoperatively. PMID- 23741664 TI - Nerve damage in leprosy: An electrophysiological evaluation of ulnar and median nerves in patients with clinical neural deficits: A pilot study. AB - BACKGROUND: Leprosy involves peripheral nerves sooner or later in the course of the disease leading to gross deformities and disabilities. Sadly, by the time it becomes clinically apparent, the nerve damage is already quite advanced. However, if the preclinical damage is detected early in the course of disease, it can be prevented to a large extent. MATERIALS AND METHODS: We conducted an electrophysiological pilot study on 10 patients with clinically manifest leprosy, in the Dermatology Department of Mahatma Gandhi Institute of Medical Sciences, Sewagram. This study was done to assess the nerve conduction velocity, amplitude and latency of ulnar and median nerves. RESULTS AND CONCLUSION: We found reduced conduction velocities besides changes in latency and amplitude in the affected nerves. Changes in sensory nerve conduction were more pronounced. Also, sensory latencies and amplitude changes were more severe than motor latencies and amplitude in those presenting with muscle palsies. However, further studies are going on to identify parameters to detect early nerve damage in leprosy. PMID- 23741666 TI - Acute hemorrhagic edema of infancy-a rare entity. AB - A patient presenting with fever and purpura often presents a diagnostic challenge for the dermatologist. Acute hemorrhagic edema of infancy (AHEI) is a rare acute cutaneous leukocytoclastic vasculitic syndrome of infants leading to this presentation. We present an 18-month-old girl with AHEI who presented with fever, edema, and purpuric lesions involving the face, ears and extremities with uneventful complete recovery. PMID- 23741665 TI - Impact of hand eczema severity on quality of life. AB - BACKGROUND: Hand eczema is a common disease seen in dermatological practice comprising of a spectrum ranging from mild disease to a severe distressing and chronic course with a negative impact on the quality of life. AIM: To assess the impact of hand eczema severity on quality of life. MATERIALS AND METHODS: Patients with hand eczema were enrolled in a prospective study. Disease severity was assessed by hand eczema severity index (HECSI) score and quality of life by dermatology life quality index (DLQI) questionnaire. RESULTS: Forty-six patients participated of which 22 (47.8%) were males and 24 (52.2%) females. The commonest age group affected among men and women was 50-59 years (31.8%) and 40-49 years (41.7%) respectively. History of atopy was found in 23.9% and 63% had persistent disease. In 28 (60.9%), the trigger was washing soaps and detergents of which 21 (87.5%) were housewives. Of those employed, 27.7% reported loss of work days. The mean HECSI score was 14.46 (S.D = 20.98) and mean DLQI score was 9.54 (S.D = 5.62). Gender, age, occupation and duration of disease did not significantly affect the quality of life or disease severity. Increased episodes of eczema (>4 episodes/year) showed a statistically significant correlation with DLQI (P value = 0.021). There was no significant correlation between HECSI score and DLQI in this study. CONCLUSION: Majority of the patients with hand eczema had a significant impairment of their quality of life. The impairment of quality of life in this study was mainly dependent on increased frequency of the eruptions and not on hand eczema severity. PMID- 23741667 TI - Holocord syrinx presenting as hemi anhidrosis. AB - We present a 41-year-old man with Chiari type 1 malformation and syrinx up to tenth thoracic level who presented with left side hemi anhidrosis. Neurological findings of syrinx were absent in this case. Though Horner's syndrome is reported, this report is probably first. PMID- 23741668 TI - Coexistence of lip-tip vitiligo and disseminated discoid lupus erythematosus with hypothyroidism: Need for careful therapeutic approach. AB - There have been rare published cases of discoid lupus erythematosus (DLE) with other autoimmune cutaneous and systemic disorders. We describe a 36 years old female patient with DLE lesions on the face and hands with coexistence of lip-tip vitiligo and hypothyroidism. We discuss how the treatment has to be modified and innovative in the presence of these three coexisting autoimmune disorders and how the dermatologist should do this to get a successful outcome. PMID- 23741669 TI - Linear IgA disease in an adult with unusual clinical features. AB - A 19-year-old male presented with complaints of fluid-filled lesions on the body of 2 weeks duration. On examination, he was found to have multiple tense bullae distributed on the flexures, face, and genitalia with associated oral ulcers and "cluster of jewels" sign. The diagnosis was confirmed by histopathology and direct immunofluorescence. There are very few reports of linear IgA earlier from India according to the literature available so far, that too from the Southern part of the country. The patient had bullous pemphigoid-like lesions typically seen in adults, but the distribution of lesions was akin to that of the "chronic bullous disease of childhood variant" found in children. This case has been reported for rarity in this region and also because the patient had atypical morphology and distribution of lesions. PMID- 23741670 TI - Melanoacanthoma: Uncommon presentation of an uncommon condition. AB - Melanoacanthoma is very rare variant of seborrheic keratosis presenting as a deeply pigmented benign proliferation of melanocytes and keratinocytes usually presenting over the head, neck and trunk of elderly people. A sixty-two-years-old male was presented with a solitary slow growing asymptomatic hyperpigmented verrucous outgrowth with cerebriform surface measuring 15 cm by 8 cm present over the left inguinal region extending on to the scrotum since past 8 years. There was no associated lymphadenopathy. The histopathology revealed hyperkeratosis, papillomatosis, acanthosis with presence of melanocytes at all levels of epidermis with abundant melanin giving the diagnosis of melanoacanthoma. The patient further underwent surgical excision of the lesion. The case is being reported for its rarity, unusual location, massive size and clinical resemblance to a verrucous carcinoma. PMID- 23741671 TI - Morbihan syndrome. AB - We report a case of severe Morbihan syndrome (chronic erythematous edema of the upper portion of the face) in a 60-year-old man. The syndrome was characterized clinically by erythematous edema involving the forehead, glabella, and both eyelids, because of which the patient was not able to open completely his eyes. Furthermore, erythema and telangiectasiae were visible on the nose and cheeks. Laboratory and instrumental examinations were within normal ranges or negative. Histopathological examination showed dermal edema, perivascular and periadnexal lympho-histiocytic infiltrate, and sebaceous gland hyperplasia. Oral isotretinoin was ineffective despite the relatively long duration of the therapy (26 weeks). PMID- 23741672 TI - A rare case of malignant acanthosis nigricans in a lady with ovarian cancer. AB - "Tripe palms" or pachydermatoglyphy is a descriptive term of acanthosis nigricans of the palms and is associated with internal malignancy. It often precedes the diagnosis of a new or recurrent tumor. Malignant acanthosis nigricans is most commonly associated with intra-abdominal malignancies. In patients with both tripe palms and acanthosis nigricans, gastric carcinoma is the most common followed by lung carcinoma. There are very few reports in the literature of malignant acanthosis nigricans associated with gynecological malignancies. We report this case because of its rarity. A 47-year-old lady presented with lower abdominal swelling and progressive hyperpigmentation which preceded the abdominal swelling by 6 months. On investigations, she was found to have ovarian cancer. The presence of acanthosis nigricans in conjunction with tripe palms in a female patient is highly suggestive of an internal malignancy including an ovarian cancer and demands an extensive search for the hidden ovarian cancer. PMID- 23741673 TI - Dermpath quiz. PMID- 23741674 TI - Transillumination: A simple tool to assess subungual extension in periungual warts. PMID- 23741676 TI - Vitamin C in dermatology. AB - Vitamin C is a potent antioxidant drug that can be used topically in dermatology to treat and prevent changes associated with photoageing. It can also be used for the treatment of hyperpigmentation. Because it is unstable and difficult to deliver into the dermis in the optimum dosage, research is being directed to find stable compounds of Vitamin C and newer methods of delivery of Vitamin C into the dermis. PMID- 23741677 TI - Koebnerization and generalized spread of vitiligo following radiotherapy. PMID- 23741675 TI - Paradoxes in dermatology. AB - Many paradoxical phenomena related to clinical, immunological, and therapeutic dermatology have been described. While some of them can be explained logically, the cause for others can only be speculated. Whenever encountered in clinical practice, background knowledge of such paradoxes may be useful to the clinician. PMID- 23741678 TI - Hyperpigmentary disorders in children: A hospital-based study in a tertiary care center. PMID- 23741679 TI - Nicolau syndrome following intramuscular diclofenac injection. PMID- 23741680 TI - Paederus dermatitis among residents of nursing hostel in central India: An outbreak investigation. PMID- 23741681 TI - Acral steatocystoma multiplex. PMID- 23741682 TI - A rare case of cutaneous actinomycosis. PMID- 23741683 TI - Herpes zoster in pregnancy leading to keloids and post herpetic neuralgia: A double whammy? PMID- 23741684 TI - SkIndia Quiz 9: Solitary cystic nodule with a horn on the thigh of elderly male. PMID- 23741685 TI - Mid-borderline leprosy. PMID- 23741686 TI - Erythematous, firm, papular lesions over the face. PMID- 23741688 TI - Correlation between the molecular subtype of breast cancer and the in vitro adenosine triphosphate-based chemosensitivity assay. AB - PURPOSE: The empirical use of a chemotherapy regimen shows different results in individual breast cancer patient treatment. Recent studies showed the effectiveness of the adenosine triphosphate-based chemotherapy response assay (ATP-CRA). However, little is known about the correlation between chemosensitivity and breast cancer molecular subtypes. Therefore, we investigated whether the result of ATP-CRA is associated with a molecular subtype of breast cancer. METHODS: Two hundred eighty-seven patients diagnosed with breast cancer and receiving ATP-CRA at Mokdong Hospital, Ewha Womans University between September 2007 and December 2010 were enrolled in this study. Hormone receptor status, HER2/neu expression, and results of chemosensitivity tests of the patients was analyzed. RESULTS: In all of four subtypes, the combination of two agents showed significant higher mean cell death rate than a single agent. Within the breast cancer cell lines in this study, the range of chemosensitivity response was very wide and varied for each patient. For this reason, the molecular subtype of breast cancer is inconclusive in choosing an effective chemotherapeutic agent and in vitro chemosensitivity test, prior to therapy, could be a useful method for planning chemotherapy for each patient. CONCLUSION: Chemosensitivity response to anticancer agents was found to vary depending on the individual breast cancer patients. The molecular subtype of breast cancer is inconclusive to choose the effective chemotherapeutic agent and the in vitro chemosensitivity test, prior to therapy, could be more useful for planning chemotherapy for each patient. PMID- 23741689 TI - Antiadhesive effect and safety of oxidized regenerated cellulose after thyroidectomy: a prospective, randomized controlled study. AB - PURPOSE: To evaluate the antiadhesive effects and safety of an oxidized regenerated cellulose (Interceed) after thyroidectomy. METHODS: Seventy-six thyroidectomized patients were prospectively randomized into two groups with regard to the use of Interceed. We evaluated each group for their adhesive symptoms using four subjective and four objective items at the 2nd week, 3rd and 6th month after thyroidectomy. All patients were examined for vocal cord motility by indirect laryngoscope at each period. RESULTS: Total adhesion scores at each postoperative follow-up period decreased with time, but were not significantly different in each group. The median score for swallowing discomfort for liquid was significantly lower in the Interceed group than in the control group 2 weeks after surgery. In addition, the severity of skin adhesion to the trachea was reduced in the Interceed group compared with the control group 6 months after surgery. During the study, there were no adverse effects or significant differences in postoperative complications between the groups. CONCLUSION: Interceed appeared to be safe and effective in improving neck discomfort at early postoperative periods and preventing skin adhesion to the trachea 6 months after thyroidectomy. PMID- 23741690 TI - Early experiences of minimally invasive surgery to treat gastroesophageal reflux disease. AB - PURPOSE: There are fewer patients with gastroesophageal reflux disease (GERD) in Korea compared with Western countries. The incidence of GERD has increased in recent years however, concerning many physicians. Here, we report our early experiences of using a recently introduced method of laparoscopic antireflux surgery for the treatment of GERD in Korean patients. METHODS: Fifteen patients with GERD were treated using antireflux surgery between May 2009 and February 2012 at the University of Ulsan College of Medicine and Asan Medical Center. Laparoscopic Nissen fundoplication with 360 degrees wrapping was performed on all patients. RESULTS: Eleven male and four female patients were evaluated and treated with an average age of 58.1 +/- 14.1 years. The average surgical time was 118.9 +/- 45.1 minutes, and no complications presented during surgery. After surgery, the reflux symptoms of each patient were resolved; only two patients developed transient dysphagia, which resolved within one month. One patient developed a 6-cm hiatal hernia that had to be repaired and reinforced using mesh. CONCLUSION: The use of laparoscopic surgery for the treatment of GERD is safe and feasible. It is also an efficacious method for controlling the symptoms of GERD in Korean patients. However, the use of this surgery still needs to be standardized (e.g., type of surgery, bougienage size, wrap length) and the long term outcomes need to be evaluated. PMID- 23741691 TI - Optimal timing of surgery after neoadjuvant chemoradiation therapy in locally advanced rectal cancer. AB - PURPOSE: The optimal time between neoadjuvant chemoradiotherapy (CRT) and surgery for rectal cancer has been debated. This study evaluated the influence of this interval on oncological outcomes. METHODS: We compared postoperative complications, pathological downstaging, disease recurrence, and survival in patients with locally advanced rectal cancer who underwent surgical resection <8 weeks (group A, n = 105) to those who had surgery >=8 weeks (group B, n = 48) after neoadjuvant CRT. RESULTS: Of 153 patients, 117 (76.5%) were male and 36 (23.5%) were female. Mean age was 57.8 years (range, 28 to 79 years). There was no difference in the rate of sphincter preserving surgery between the two groups (group A, 82.7% vs. group B, 77.6%; P = 0.509). The longer interval group had decreased postoperative complications, although statistical significance was not reached (group A, 28.8% vs. group B, 14.3%; P = 0.068). A total of 111 (group A, 75 [71.4%] and group B, 36 [75%]) patients were downstaged and 26 (group A, 17 [16.2%] and group B, 9 [18%]) achieved pathological complete response (pCR). There was no significant difference in the pCR rate (P = 0.817). The longer interval group experienced significant improvement in the nodal (N) downstaging rate (group A, 46.7% vs. group B, 66.7%; P = 0.024). The local recurrence (P = 0.279), distant recurrence (P = 0.427), disease-free survival (P = 0.967), and overall survival (P = 0.825) rates were not significantly different. CONCLUSION: It is worth delaying surgical resection for 8 weeks or more after completion of CRT as it is safe and is associated with higher nodal downstaging rates. PMID- 23741692 TI - Reconstruction of portal vein and superior mesenteric vein after extensive resection for pancreatic cancer. AB - PURPOSE: Tumor invasion to the portal vein (PV) or superior mesenteric vein (SMV) can be encountered during the surgery for pancreatic cancer. Venous reconstruction is required, but the optimal surgical methods and conduits remain in controversies. METHODS: From January 2007 to July 2012, 16 venous reconstructions were performed during surgery for pancreatic cancer in 14 patients. We analyzed the methods, conduits, graft patency, and patient survival. RESULTS: The involved veins were 14 SMVs and 2 PVs. The operative methods included resection and end-to-end anastomosis in 7 patients, wedge resection with venoplasty in 2 patients, bovine patch repair in 3 patients, and interposition graft with bovine patch in 1 patient. In one patient with a failed interposition graft with great saphenous vein (GSV), the SMV was reconstructed with a prosthetic interposition graft, which was revised with a spiral graft of GSV. Vascular morbidity occurred in 4 cases; occlusion of an interposition graft with GSV or polytetrafluoroethylene, segmental thrombosis and stenosis of the SMV after end-to-end anastomosis. Patency was maintained in patients with bovine patch angioplasty and spiral vein grafts. With mean follow-up of 9.8 months, the 6- and 12-month death-censored graft survival rates were both 81.3%. CONCLUSION: Many of the involved vein segments were repaired primarily. When tension-free anastomosis is impossible, the spiral grafts with GSV or bovine patch grafts are good options to overcome the size mismatch between autologous vein graft and portomesenteric veins. Further follow-up of these patients is needed to demonstrate long-term patency. PMID- 23741693 TI - Role of surgical treatment for peripheral arterial disease in endovascular era. AB - PURPOSE: The purpose of this study is to review the roll changes of surgical treatment for peripheral artery disease in endovascular era. METHODS: One hundred and twelve surgically treated cases of peripheral artery disease at a single institution during the period from 2006 to 2011 were studied retrospectively. The cases were divided into two groups of different time periods, one before 2009 (surgical period group) and the other from 2009 onward (endovascular period group). We analyzed the type and location of surgery as well as clinical characteristics of patients and treatment results. RESULTS: Fifty-three cases were for the surgical period group and 59 cases for the endovascular group. No difference in the demographic characteristics and the distribution of major atherosclerosis risk factors was found between the two groups. Additionally, the technical and functional success rate was similar in both groups. However, it is found that there were more acute cases in the endovascular period group than in the surgical period group. The number of cases in need of suprainguinal or below knee exposure was similar in both groups. In hybrid cases, suprainguinal or below knee exposures were more frequently needed during the former period than the latter period. CONCLUSION: The role of surgical treatment is currently in the process of changing. Surgical treatment seems to be a complementary alternative to endovascular treatment for chronic limb ischemia. However, it still seems to play a major role for acute limb ischemia. PMID- 23741694 TI - Transumbilical scarless surgery with thoracic trocar: easy and low-cost. AB - PURPOSE: Single-site laparoscopic surgery has become increasingly common. We herein report an easy and low-cost thoracic trocar technique (TTT) for these types of procedures and recommend the simpler name "transumbilical scarless surgery" (TUSS) to minimize confusion in nomenclature. METHODS: We retrospectively reviewed patients who underwent TUSS by TTT using a thoracic trocar and surgical glove in our hospital between November 2011 and November 2012. Operating time, postoperative stay, and complications were detailed. RESULTS: A total of 101 TUSS by TTT were successfully performed, comprising appendectomy (n = 63), ovarian cyst excision (n = 7), splenectomy (n = 5), nephroureterectomy (n = 5), orchidopexy (n = 4), pyeloplasty (n = 3), nephrolithotomy (n = 2), orchiectomy (n = 2), varicocelectomy (n = 2), lymphangioma excision (n = 2), ureterectomy (n = 1), Morgagni diaphragmatic hernia repair (n = 1), ovarian detorsion (n = 1), antegrade continence enema (n = 1), intestinal resection anastomosis (n = 1), and intestinal duplication excision (n = 1). Kirschner wires were used for some organ traction. Nine patients required an additional port, but no major complications occurred. The postoperative stay (mean +/- standard deviation) was 3.2 +/- 1.4 days, and operating time was 58.9 +/- 38.3 minutes. CONCLUSION: We recommend the simpler name of TUSS to minimize confusion in nomenclature for all transumbilical single incision laparoendoscopic surgeries. TTT is an easy and low-cost TUSS technique. PMID- 23741695 TI - Adenocarcinoma arising from Meckel's diverticulum in the ileum with malrotation of the midgut. AB - Meckel's diverticulum (MD) is a true congenital diverticulum that is remnant by incomplete obliteration of the omphalomesenteric duct. It is the most common congenital anomaly of the gastrointestinal tract, with an estimated prevalence of 2% (0.3% to 3% in autopsy studies). About 90% of MD occurs within 100 cm of the ileocecal valve. A primary malignant tumor arising within an MD is extremely uncommon. Malignancies are reported to account for only 0.5% to 3.2% of the complications. Carcinoids are the most common malignant tumors occurring in MD. Adenocarcinomas are extremely uncommon and very poor prognosis has been reported. We report a case of radiographically diagnosed chronic inflammatory mass caused by adenocarcinoma arising from MD in the ileum with malrotation of the midgut incidentally discovered at exploration. PMID- 23741696 TI - Laparoscopic repair of parastomal and incisional hernias with a modified Sugarbaker technique. AB - A parastomal hernia is the most common surgical complication following stoma formation. As the field of laparoscopic surgery advances, different laparoscopic approaches to repair of parastomal hernias have been developed. Recently, the Sugarbaker technique has been reported to have lower recurrence rates compared to keyhole techniques. As far as we know, the Sugarbaker technique has not yet been performed in Korea. We herein present a case report of perhaps the first laparoscopic parastomal hernia repair with a modified Sugarbaker technique to be successfully carried out in Korea. A 79-year-old woman, who underwent an abdominoperineal resection for an adenocarcinoma of the rectum 9 years ago, presented with a large parastomal and incisional hernias, and was treated with a laparoscopic repair with a modified Sugarbaker technique. Six months after surgery, follow-up with the patient has shown no evidence of recurrence. PMID- 23741698 TI - Thromboprophylaxis for deep vein thrombosis and pulmonary embolism after total joint arthroplasty in a low incidence population. AB - Postoperative venous thromboembolism is one of the most serious complications following total joint arthroplasty. Pharmacological and mechanical prophylaxis methods are used to reduce the risk of postoperative symptomatic deep vein thrombosis and pulmonary embolism. Use of pharmacological prophylaxis requires a fine balance between the efficacy of the drug in preventing deep vein thrombosis and the adverse effects associated with the use of these drugs. In regions with a low prevalence of deep vein thrombosis such as Korea, there might be a question whether the benefits of using pharmacological prophylaxis outweigh the risks involved. The current article reviews the need for thromboprophylaxis, guidelines, problems with the guidelines, pharmacological prophylaxis use, and the current scenario of deep vein thrombosis, and discusses whether the use of pharmacological prophylaxis should be mandatory in low incidence populations. PMID- 23741699 TI - Effect of posterior femoral condylar offset and posterior tibial slope on maximal flexion angle of the knee in posterior cruciate ligament sacrificing total knee arthroplasty. AB - PURPOSE: To evaluate the effect of femoral condylar offset and posterior tibial slope on maximal flexion angle of the knee in posterior cruciate ligament (PCL) sacrificing total knee arthroplasty (TKA, Medial-Pivot Knee System). MATERIALS AND METHODS: Forty-five knees in 35 patients who could be followed up more than 1 year after PCL-sacrificing TKA were evaluated retrospectively. We measured and analyzed the preoperative and postoperative maximal flexion angle, posterior femoral condylar offset difference, posterior femoral condylar offset ratio difference, and tibial slope. RESULTS: The mean maximal flexion angle after TKA was 118.44 degrees +/-9.8 degrees and significantly related to postoperative tibial slope (11.78 degrees +/-6.2 degrees ) in correlation analysis (R=0.451, p=0.002). There was no statistical relationship between the postoperative maximal flexion angle and the posterior femoral condylar offset difference (3.24+/-3.862 mm, R=0.105, p=0.493) and posterior femoral condylar offset ratio difference (0.039+/-0.029 mm, R=-0.163, p=0.284). CONCLUSIONS: The maximal flexion angle of the knee after PCL-sacrificing TKA was significantly related to the postoperative tibial slope. Therefore, posterior tibial slope can be considered as a factor that affects maximal flexion angle after PCL-sacrificing TKA. PMID- 23741700 TI - Soft Tissue Balancing of Varus Arthritic Knee in Minimally Invasive Surgery Total Knee Arthroplasty: Comparison between Posterior Oblique Ligament Release and Superficial MCL Release. AB - PURPOSE: To assess proper soft tissue balancing of the varus arthritic knee between posterior oblique ligament (POL) release group and superficial medial collateral ligament (SMCL) release group. MATERIALS AND METHODS: This retrospective study was performed on 186 patients who underwent minimally invasive surgery (MIS) total knee arthroplasty (TKA) from January 2011 to December 2011. Eighty-three patients were in the group of SMCL release and 103 patients were in the POL release group. We intended to use a 10 mm polyethylene insert (PE) during TKA, and retrospectively compared the actual thickness of PE between POL release group and SMCL release group. RESULTS: The mean PE thickness was 10.59+/-1.3 mm (range, 8 to 15 mm) in POL group and 11.88+/-1.8 mm (range, 10 to 18 mm) in SMCL group (p=0.001). We found a significant difference in the mean PE thickness between POL release group and SMCL release group. CONCLUSIONS: POL and deep MCL releases in MIS-TKA would be beneficial for varus deformity correction in the osteoarthritic knee. PMID- 23741701 TI - The effect of autotransfusion system in minimally invasive total knee arthroplasty. AB - PURPOSE: To evaluate the effect of autotransfusion system in minimally invasive total knee arthroplasty (TKA). MATERIALS AND METHODS: Seventy-one patients who underwent unilateral minimally invasive TKA between October 2009 and June 2010 were selected. The first group included 36 patients who received standard vacuum drainage and the second group, 35 patients who underwent autologous retransfusion drainage. In the first group, allogeneic blood transfusion was performed if the postoperative hemoglobin level was <7.0 g/dL or 7.0-8.0 g/dL with the presence of a medical complication and an anemic symptom. The second group received autotransfusion and allogeneic transfusion additionally according to the same criteria. Changes in the pre- and postoperative hemoglobin level, amount of auto- or allotransfusion, and frequency of allogeneic transfusion were assessed. RESULTS: Allogeneic transfusion was required in 13 patients (36.1%) in the first group and four patients (11.4%) in the second group. The mean allogeneic transfusion volume was significantly low in the second group compared to the first group (64.4 mL vs. 278.9 mL; p<0.05). The hemoglobin level on the 1st postoperative day compared to the preoperative level decreased by 22.6% in the first group and 11.7% in the second group. The postoperative hemoglobin level was higher in the second group (p<0.05). CONCLUSIONS: Minimally invasive unilateral TKA with an autotransfusion system can be beneficial in patients with no medical complications because of the decreased allogeneic transfusion. PMID- 23741702 TI - Results of microfracture in the osteoarthritic knee with focal full-thickness articular cartilage defects and concomitant medial meniscal tears. AB - PURPOSE: To evaluate the efficacy of arthroscopic microfracture in patients with focal full-thickness cartilage defects in the osteoarthritic knee. MATERIALS AND METHODS: Seventy-six patients were enrolled in this study. They were divided into group I (n=38) who underwent microfracture plus meniscectomy and group II (n=38) who underwent only meniscectomy. Clinical and radiological evaluations were performed. RESULTS: At the time of the three-year follow-up, a total of five failures (6.6%) were reported: four patients in group I and one in group II. The two groups showed no significant difference in the Lysholm score, the Tegner activity score and the visual analog pain scale score at three years after surgery. However, at the time of the three-month follow-up, group II showed significantly more improvement in the Tegner activity and the visual analog pain score compared with group I. CONCLUSIONS: In the osteoarthritic knee, additional microfracture did not confer any additional benefit to meniscectomy. PMID- 23741703 TI - Treatment of Schatzker Type V and VI Tibial Plateau Fractures Using a Midline Longitudinal Incision and Dual Plating. AB - PURPOSE: The purpose of this study was to evaluate the results of the treatment of Schatzker type V and VI tibial plateau fractures using a midline longitudinal incision and dual-plate fixation. MATERIALS AND METHODS: Ten patients with Schatzker type V and VI tibial plateau fractures treated with a midline longitudinal incision and dual plating were analyzed. The patients were followed for a minimum of one year. Clinical outcomes were evaluated using range of motion, visual analogue scale (VAS) and Knee Society Score. Radiological outcomes were evaluated using the bony union time, medial proximal tibial angle (MPTA) and posterior proximal tibial angle (PPTA). RESULTS: The mean VAS score was 2.2 points, and the mean Knee Society function score was 85 points at the final follow-up. The mean flexion contracture was 2.5 degrees and the mean further flexion was 125 degrees . It took an average of 4 months until bony union occurred. The mean MPTA and PPTA were 90.5 degrees and 4.4 degrees , respectively. There was one case of delayed wound healing, but no other complications were observed. CONCLUSIONS: The treatment of Schatzker type V and VI tibial plateau fractures with a midline longitudinal incision and dual-plate fixation resulted in satisfactory clinical and radiological outcomes. This can be an option when treating Schatzker type V and VI tibial plateau fractures. PMID- 23741704 TI - Massive Proximal Extravasation as a Complication during Arthroscopic Anterior Cruciate Ligament Reconstruction. AB - Extra-articular extravasation of irrigation fluid is relatively common around entry incisions and is usually limited to the subcutaneous tissue. Very rarely, extravasation occurs above the knee, in the thigh and even up into the pelvis. We are reporting the second case of irrigation fluid extravasation during a knee arthroscopy, which spread up to the thigh, groin and perineum during anterior cruciate ligament reconstruction, whilst the tourniquet was inflated. In our case, we think that the extravasation was caused by a fault in the pressure sensor due to the fact that the reservoir was over-filled. The irrigation pressure was therefore too high, and the irrigation fluid was able to diffuse, despite the presence of a pneumatic tourniquet, up past the thigh. PMID- 23741705 TI - Bilateral osteochondritis dissecans of the femoral condyles in both knees: a report of two sibling cases. AB - Osteochondritis dissecans (OCD) of both femoral condyles is very rare, with no previously reported cases of bilateral OCD of both knees in two siblings. We report on a brother and sister with both femoral condyle OCD with a description of surgical technique and clinical results. Fixation using headless compressive screws, osteochondral autologous transplantation and autologous chondrocyte implantation were all successful. PMID- 23741706 TI - Restorative Dentistry facing Global Mercury Agreement. PMID- 23741707 TI - Does apical root resection in endodontic microsurgery jeopardize the prosthodontic prognosis? AB - Apical surgery cuts off the apical root and the crown-to-root ratio becomes unfavorable. Crown-to-root ratio has been applied to periodontally compromised teeth. Apical root resection is a different matter from periodontal bone loss. The purpose of this paper is to review the validity of crown-to-root ratio in the apically resected teeth. Most roots have conical shape and the root surface area of coronal part is wider than apical part of the same length. Therefore loss of alveolar bone support from apical resection is much less than its linear length.The maximum stress from mastication concentrates on the cervical area and the minimum stress was found on the apical 1/3 area. Therefore apical root resection is not so harmful as periodontal bone loss. Osteotomy for apical resection reduces longitudinal width of the buccal bone and increases the risk of endo-perio communication which leads to failure. Endodontic microsurgery is able to realize 0 degree or shallow bevel and precise length of root resection, and minimize the longitudinal width of osteotomy. The crown-to-root ratio is not valid in evaluating the prosthodontic prognosis of the apically resected teeth. Accurate execution of endodontic microsurgery to preserve the buccal bone is essential to avoid endo-perio communication. PMID- 23741708 TI - Inhibition of Streptococcus mutans biofilm formation on composite resins containing ursolic acid. AB - OBJECTIVES: To evaluate the inhibitory effect of ursolic acid (UA)-containing composites on Streptococcus mutans (S. mutans) biofilm. MATERIALS AND METHODS: Composite resins with five different concentrations (0.04, 0.1, 0.2, 0.5, and 1.0 wt%) of UA (U6753, Sigma Aldrich) were prepared, and their flexural strengths were measured according to ISO 4049. To evaluate the effect of carbohydrate source on biofilm formation, either glucose or sucrose was used as a nutrient source, and to investigate the effect of saliva treatment, the specimen were treated with either unstimulated whole saliva or phosphate-buffered saline (PBS). For biofilm assay, composite disks were transferred to S. mutans suspension and incubated for 24 hr. Afterwards, the specimens were rinsed with PBS and sonicated. The colony forming units (CFU) of the disrupted biofilm cultures were enumerated. For growth inhibition test, the composites were placed on a polystyrene well cluster, and S. mutans suspension was inoculated. The optical density at 600 nm (OD600) was recorded by Infinite F200 pro apparatus (TECAN). One-way ANOVA and two-way ANOVA followed by Bonferroni correction were used for the data analyses. RESULTS: The flexural strength values did not show significant difference at any concentration (p > 0.01). In biofilm assay, the CFU score decreased as the concentration of UA increased. The influence of saliva pretreatment was conflicting. The sucrose groups exhibited higher CFU score than glucose group (p < 0.05). In bacterial growth inhibition test, all experimental groups containing UA resulted in complete inhibition. CONCLUSIONS: Within the limitations of the experiments, UA included in the composite showed inhibitory effect on S. mutans biofilm formation and growth. PMID- 23741710 TI - Correlation between clinical clerkship achievement and objective structured clinical examination (OSCE) scores of graduating dental students on conservative dentistry. AB - OBJECTIVES: This study aimed to investigate the effect of clinical clerkship associated achievements, such as performance of procedures at the student clinic, observation, and attitude towards a clerkship, on the objective structured clinical examination (OSCE) scores of dental students graduating in restorative dentistry. MATERIALS AND METHODS: The OSCEs consisted of two stations designed to assess students' clinical skills regarding cavity preparation for a class II gold inlay and a class IV composite restoration. The clerkship achievements, consisting of the number of student clinical procedures performed, observation related OSCE, and scores of their attitudes towards a conservative dentistry clerkship, were assessed. Correlation and multiple regression analyses were conducted. RESULTS: The correlation coefficient between the OSCE scores for cavity preparation for a class II gold restoration and clerkship attitude scores was 0.241 (p < 0.05). Regarding a class IV composite restoration, OSCE scores showed statistically significant correlations with the observation (r = 0.344, p < 0.01) and attitude (r = 0.303, p < 0.01) scores. In a multiple regression analysis, attitudes towards a clerkship (p = 0.033) was associated with the cavity preparation for a class II gold inlay OSCE scores, while the number of procedure observations (p = 0.002) was associated with the class IV composite restoration OSCE scores. CONCLUSIONS: The number of clinical procedures performed by students, which is an important requirement for graduation, showed no correlation with either of the OSCEs scores. PMID- 23741709 TI - Effect of different air-drying time on the microleakage of single-step self-etch adhesives. AB - OBJECTIVES: This study evaluated the effect of three different air-drying times on microleakage of three self-etch adhesive systems. MATERIALS AND METHODS: Class I cavities were prepared for 108 extracted sound human premolars. The teeth were divided into three main groups based on three different adhesives: Opti Bond All in One (OBAO), Clearfil S(3) Bond (CSB), Bond Force (BF). Each main group divided into three subgroups regarding the air-drying time: without application of air stream, following the manufacturer's instruction, for 10 sec more than manufacturer's instruction. After completion of restorations, specimens were thermocycled and then connected to a fluid filtration system to evaluate microleakage. The data were statistically analyzed using two-way ANOVA and Tukey test (alpha = 0.05). RESULTS: The microleakage of all adhesives decreased when the air-drying time increased from 0 sec to manufacturer's instruction (p < 0.001). The microleakage of BF reached its lowest values after increasing the drying time to 10 sec more than the manufacturer's instruction (p < 0.001). Microleakage of OBAO and CSB was significantly lower compared to BF in all three drying time (p < 0.001). CONCLUSIONS: Increasing in air-drying time of adhesive layer in one-step self-etch adhesives caused reduction of microleakage, but the amount of this reduction may be dependent on the adhesive components of self-etch adhesives. PMID- 23741711 TI - Use of temporary filling material for index fabrication in Class IV resin composite restoration. AB - When a patient with a fractured anterior tooth visits the clinic, clinician has to restore the tooth esthetically and quickly. For esthetic resin restoration, clinician can use 'Natural Layering technique' and an index for palatal wall may be needed. In this case report, we introduce pre-restoration index technique on a Class IV defect, in which a temporary filling material is used for easy restoration. Chair-side index fabrication for Class IV restoration is convenient and makes a single-visit treatment possible. PMID- 23741712 TI - Necrosis of intact premolar caused by an adjacent apical infection: a case report. AB - Although periapical inflammatory lesions are usually resulted by infection in the root canal system, this rare case showed that a periapical lesion related to an infected tooth may cause pulpal necrosis in adjacent intact tooth, with no history or clinical signs of caries, disease, trauma or developmental anomaly. This case also suggests that the periapical lesion can be treated conservatively, without surgical intervention. Furthermore, this case highlights the importance of prompt treatment of apical periodontitis before the lesion becomes extensive as well as follows up of large lesions. PMID- 23741714 TI - Statistical notes for clinical researchers: Evaluation of measurement error 1: using intraclass correlation coefficients. PMID- 23741713 TI - Retrieval of a separated nickel-titanium instrument using a modified 18-guage needle and cyanoacrylate glue: a case report. AB - During root canal preparation procedures, the potential for instrument breakage is always present. When instrument breakage occurs, it leads to anxiety of the clinician and as well as a metallic obstruction of the canal which hinders further cleaning and shaping. Separated instruments must always be attempted for retrieval and if retrieval is not possible bypass should be tried. With the increased use of nickel-titanium (NiTi) instruments the incidence of separated instruments has increased. A considerable amount of research has been done to understand the various factors related to the fracture of NiTi instruments to minimize its occurrence. This paper presents a review of the literature regarding the fracture of NiTi instruments and also describes a case report showing the use of a modified 18-guage needle and cyanoacrylate glue to retrieve a separated NiTi instrument from the mesiolingual canal of a mandibular first molar. PMID- 23741715 TI - Prepare the pre-heated composite resin. PMID- 23741716 TI - A focus on homocysteine in autism. AB - Homocysteine is an amino acid, which plays several important roles in human physiology. A wide range of disorders, including neuropsychiatric disorders and autism, are associated with increased homocysteine levels in biological fluids. Various B vitamins: B6 (pyridoxine), B12 (cobalamin), and B9 (folic acid) are required as co-factors by the enzymes involved in homocysteine metabolism. Therefore, monitoring of homocysteine levels in body fluids of autistic children can provide information on genetic and physiological diseases, improper lifestyle (including dietary habits), as well as a variety of pathological conditions. This review presents information on homocysteine metabolism, determination of homocysteine in biological fluids, and shows abnormalities in the levels of homocysteine in the body fluids of autistic children. PMID- 23741717 TI - A toy model of prebiotic peptide evolution: the possible role of relative amino acid abundances. AB - This paper presents a mathematical-computational toy model based on the assumed dynamic principles of prebiotic peptide evolution. Starting from a pool of amino acid monomers, the model describes in a generalized manner the generation of peptides and their sequential information. The model integrates the intrinsic and dynamic key elements of the initiation of biopolymerization, such as the relative amino acid abundances and polarities, as well as the oligomer reversibility, i.e. fragmentation and recombination, and peptide self-replication. Our modeling results suggest that the relative amino acid abundances, as indicated by Miller Urey type electric discharge experiments, played a principal role in the early sequential information of peptide profiles. Moreover, the computed profiles display an astonishing similarity to peptide profiles observed in so-called biological common ancestors found in the following three microorganisms; E. coli, M. jannaschii, and S. cereviasiae. The prebiotic peptide fingerprint was obtained by the so-called polarity index method that was earlier reported as a tool for the identification of cationic amphipathic antibacterial short peptides. PMID- 23741718 TI - Detection of selective antibacterial peptides by the Polarity Profile method. AB - Antimicrobial peptides occupy a prominent place in the production of pharmaceuticals, because of their effective contribution to the protection of the immune system against almost all types of pathogens. These peptides are thoroughly studied by computational methods designed to shed light on their main functions. In this paper, we propose a computational approach, named the Polarity Profile method that represents an improvement to the former Polarity Index method. The Polarity Profile method is very effective in detecting the subgroup of antibacterial peptides called selective cationic amphipathic antibacterial peptides (SCAAP) that show high toxicity towards bacterial membranes and exhibit almost zero toxicity towards mammalian cells. Our study was restricted to the peptides listed in the antimicrobial peptides database (APD2) of December 19, 2012. Performance of the Polarity Profile method is demonstrated through a comparison to the former Polarity Index method by using the same sets of peptides. The efficiency of the Polarity Profile method exceeds 85% taking into account the false positive and/or false negative peptides. PMID- 23741719 TI - Development of a new, simple and cost-effective diagnostic tool for genetic screening of hereditary colorectal cancer--the DNA microarray assay. AB - Detection of mutations in families with a hereditary predisposition to colon cancer gives an opportunity to precisely define the high-risk group. 36 patients operated on for colon cancer, with familiar prevalence of this malignancy, were investigated using the DNA microarrays method with the potential detection of 170 mutations in MLH1, MSH2, MSH6, CHEK2, and NOD2 genes. In microarrays analysis of DNA in 9 patients (25% of the investigated group), 6 different mutations were found. The effectiveness of genetic screening using the microarray method is comparable to the effectiveness of other, much more expensive and time-consuming methods. PMID- 23741721 TI - Pilgrimage of an herb named foxglove. PMID- 23741722 TI - 'The doing of medicine, the being of a doctor'. PMID- 23741720 TI - Establishing a legacy: the Aronson Chair for Neurodegenerative Disorders. PMID- 23741723 TI - Orthopedic medical devices: ethical questions, implant recalls and responsibility. AB - The hip replacement is a surgical procedure to replace the femoral head and acetabulum with prosthetic implants to improve function, increase mobility, and relieve pain caused by damage from disorders such as osteoarthritis and fractures. In recent years, we have seen several recalls of poorly functioning implant systems, most recently, the Johnson and Johnson (J&J) Articular Surface Replacement device. Product recalls are often the results of premature failure of implants requiring additional surgery to exchange the failed device. This raises many questions - technical, medical, regulatory, ethical, and legal - that ultimately put patients at risk, compromise confidence in medicine and regulatory agencies, and important relationships including those between the physician patient and physician-industry. Where do the responsibilities lie for the patients' suffering, morbidity, and costs of removing the failed device? This article discusses the current recall of the J&J implant, the responsibilities of the manufacturer, surgeons, and the regulatory agency. PMID- 23741724 TI - The Brown School of Public Health. AB - The nation's newest school of public health boasts research excellence in aging, obesity, addictions, health care services and policy research, and more. The Brown School of Public Health is home to a variety of master's and doctoral programs, in addition to one of the oldest undergraduate concentrations in community health. The School plays a key role in the development of public policy at the state and national level and implements programs that benefits Rhode Island physicians and their patients. PMID- 23741725 TI - Educational opportunities in clinical and translational research. AB - Clinical and translational research extends basic science research into the clinical realm, bringing the latest advances and potential treatments to the patients who need them. The Brown School of Public Health offers a number of educational programs that trains physicians and researchers in these research methods. The goal of these programs is to help students develop an independent research career and make important contributions in clinical and translational sciences. PMID- 23741726 TI - The sum is greater than its parts: the center for evidence-based medicine. AB - The Center for Evidence-Based Medicine in the Brown School of Public Health develops computational tools to help analyze the vast amounts of data generated by medical research. By conducting meta-analyses and systemic reviews of published literature, Center researchers can tease out which treatments are most effective and efficient, helping to guide medical practice. PMID- 23741727 TI - Creating the future: Brown University's Executive Master of Healthcare Leadership. AB - The Affordable Care Act is ushering in a new paradigm for all aspects of the healthcare industry - from hospitals to insurers, from IT companies to physician practice groups. Brown's new executive master's degree in healthcare leadership provides the knowledge healthcare leaders need to navigate this new world. The 16 month program mixes online learning and short campus-based sessions to accommodate the working professional. PMID- 23741728 TI - Joan Teno, MD: leader in crusade for quality hospice, palliative care. PMID- 23741729 TI - Kahler's research bridges behavioral/social sciences and medical care. PMID- 23741730 TI - A case of intracranial hemorrhage causing stress-induced cardiomyopathy. AB - The classic finding of Takotsubo's cardiomyopathy is left ventricular systolic dysfunction with echocardiographic evidence of apical ballooning in the absence of significant coronary disease. Intracranial hemorrhage is a known cause for stress-induced cardiomyopathy with a similar echocardiographic presentation. This diagnostic finding suggests a similar pathophysiologic mechanism between neurogenic cardiac damage and the wide array of medical and psychosocial disorders that are known to cause stress-induced cardiomyopathy (Takotsubo's syndrome). The neurogenic-cardiac variant of stress-induced cardiomyopathy is associated with good cardiovascular prog- nosis; the hallmark feature of the disorder is complete echocardiographic resolution of systolic dysfunction within a short period of time. While malignant presentations are rare, the disorder can present as severe heart failure or ventricular tachyarrhythmias. We report a case of a near life-threatening episode of polymorphic ventricular tachycardia due to a subarachnoid hemorrhage (SAH)-induced stress-cardiomyopathy. PMID- 23741731 TI - Adult suicide and circumstances in Rhode Island, 2004-2010. PMID- 23741732 TI - Alternative SERRS probes for the immunochemical localization of ovalbumin in paintings: an advanced mapping detection approach. AB - In the field of analytical chemistry, many scientific efforts have been devoted to develop experimental procedures for the characterization of organic substances present in heterogeneous artwork samples, due to their challenging identification. In particular, performances of immunochemical techniques have been recently investigated, optimizing ad hoc systems for the identification of proteins. Among all the different immunochemical approaches, the use of metal nanoparticles - for surface enhanced Raman scattering (SERS) detection - remains one of the most powerful methods that has still not been explored enough for the analysis of artistic artefacts. For this reason, the present research work was aimed at proposing a new optimized and highly efficient indirect immunoassay for the detection of ovalbumin. In particular, the study proposed a new SERRS probe composed of gold nanoparticles (AuNPs) functionalised with Nile Blue A and produced with an excellent green and cheap alternative approach to the traditional chemical nanoparticles synthesis: the laser ablation synthesis in solution (LASiS). This procedure allows us to obtain stable nanoparticles which can be easily functionalized without any ligand exchange reaction or extensive purification procedures. Moreover, the present research work also focused on the development of a comprehensive analytical approach, based on the combination of potentialities of immunochemical methods and Raman analysis, for the simultaneous identification of the target protein and the different organic and inorganic substances present in the paint matrix. An advanced mapping detection system was proposed to achieve the exact spatial location of all the components through the creation of false colour chemical maps. PMID- 23741733 TI - Electrochemical study of ricin at glassy carbon electrode. AB - Ricin, Ricinus communis agglutinin 60 - RCA 60, is a deadly phytotoxic protein which inhibits ribosomes (class II), and there is no known effective antidote in living organisms. Ricin is composed of two polypeptide chains, A and B, linked covalently by a single disulfide bond. The analytical methods for the detection of RCA 60 are commonly laborious, expensive, require skilled labor, and involve sophisticated equipment. Aimed at the development of electroanalytical methods for RCA 60 detection, here we studied the electrochemical oxidation of RCA 60 on a glassy carbon (GC) electrode over a wide pH range, using cyclic voltammetry, differential pulse voltammetry (DPV) and square wave voltammetry (SWV). Two quasi reversible electrochemical RCA 60 oxidation peaks were identified on the GC electrode by SWV. For values of 2.2 <= pH <= 10.2, DPV studies revealed that the peak potentials, EP1 and EP2, display a linear dependence with pH and the reaction mechanism involves the transfer of 2H+/2e- (peak 1) and 1H+/1e- (peak 2). The first and second RCA 60 oxidation steps may correspond to the oxidation of cysteine and tyrosine-tryptophan residues, respectively. The oxidation product of the second RCA 60 oxidation step appears at 7.0 <= pH <= 11.8. For pH >= 10.2, both processes are pH independent, resulting in a pKa of ca. 10.2. A third RCA 60 oxidation peak only appears at acidic pH. RCA 60 samples extracted from different castor seed cultivars showed similar electrochemical behavior, enabling the implementation of an analytical voltammetric method. PMID- 23741734 TI - FTIR spectroscopic characterization of differently cultivated food related yeasts. AB - The application of Fourier Transform Infrared Spectroscopy for characterization of yeasts is growing rapidly. Since it is known that the phenotypic expression of yeast cells depends sensitively on the nutrients that are available in the growth medium, one standardized growth medium is usually used for identification and characterization purposes in order to obtain reproducible FTIR signals. Since our recently developed high-throughput micro-cultivation protocol has the capacity to use more than one standardized growth medium, we wanted to investigate if the parallel use of multiple growth media can improve identification results. For this purpose, five different cultivation media (YP, YPD, YMB, SAB and SD) were used. In total 91 food spoilage yeast strains of 12 different genera were cultivated in different cultivation media and subsequently characterized by FTIR spectroscopy. For spectral identifications, Radial Basis Function-Partial Least Squares (RBF-PLS) was used in combination with cross-model validation where an inner cross-validation loop was used to optimize the model, while in an outer loop an independent test set was kept aside to test the optimized model. Sensitivity and specificity were evaluated for each studied genus class. The results show that the YMB selective medium gave the best discrimination results for 9 of the 12 genera with sensitivity above 90%. Only three genera showed better identification results on other media (Clavispora and Metschnikowia on medium SD, Debaryomyces on medium YPD). We therefore suggest to use the media SD, YPD in combination with the YMB medium for the identification of food spoilage yeasts. PMID- 23741735 TI - Green synthesized silver nanoparticles for selective colorimetric sensing of Hg2+ in aqueous solution at wide pH range. AB - In the present study, the syntheses of crystalline silver and gold nanoparticles (NPs) has been demonstrated in a green and environmentally friendly approach using citrus fruit extracts (lemon, Citrus limon (Cl-1) and sweet orange, Citrus limetta (Cl-2)). In addition, potentially hazardous metal ion sensing properties of these NPs in aqueous solution has been explored. Cl-1 and Cl-2 that predominantly contained citric and ascorbic acid, exhibited different reducing abilities towards silver and gold ions into NPs. Cl-1 reduces silver ions into AgNPs only in the presence of sunlight whereas AuNPs from gold ions were formed without exposure to sunlight. In contrast, Cl-2 converts both silver and gold ions into the corresponding NPs in the absence of sunlight. The colorimetric sensor studies of these green synthesized AgNPs (Cl-1-AgNPs) showed selective sensing of the potentially hazardous Hg(2+) ion in water at micromolar concentrations. More importantly, green synthesized Cl-1-AgNPs sensor systems detected Hg(2+) ions in water in a wide pH range (3.2 to 8.5). PMID- 23741736 TI - Potential of capillary electrophoresis with wavelength-resolved fluorescence detection for protein unfolding studies using beta-lactoglobulin B as a test compound. AB - Capillary electrophoresis (CE) with wavelength-resolved fluorescence detection (wrFlu) was evaluated for the study of protein unfolding using non-reduced and reduced beta-lactoglobulin B (beta-LGB) as model compounds. Protein unfolding was achieved by incubation in sodium phosphate (pH 3.0) containing increasing concentrations of urea (0-7.1 M). CE-wrFlu was performed using the incubation media as background electrolytes (BGEs). At low urea concentrations (0-3.1 M), CE wrFlu analysis of non-reduced beta-LGB showed a single peak with a maximum emission wavelength (lambdamax) of 333 nm, indicating the protein was in its folded state. When beta-LGB was exposed to 3.6 and 4.1 M urea, CE-wrFlu revealed an additional peak with a lambdamax of 353 nm and a reduced migration time, suggesting the formation of fully unfolded species. Upon further raising the urea concentration up to 6.5 M, the peak intensity of the unfolded protein increased. At the same time, the later-migrating peak became wider and lower, showing a decrease of migration time and a shift of lambdamax (333-353 nm), indicating gradual unfolding. Construction of a lambdamax-based transition curve for the later-migrating beta-LGB species provided a denaturant-concentration midpoint of unfolding (cm) of 5.39 M, which was similar to the cm determined by plotting the corrected effective electrophoretic mobility (MUeff,c) vs. urea concentration. Stand-alone fluorescence spectroscopy of the same beta-LGB solutions revealed a lower cm (4.97 M), most probably because the respective beta-LGB species were not separated, yielding ensemble average data. For reduced beta-LGB, at all tested urea concentrations one protein peak was observed, whereas lambdamax and MUeff,c indicated protein unfolding at much lower urea concentrations (cm of 1.2 M). We conclude that CE-wrFlu can distinguish protein conformational states and thus may provide useful additional information on unfolding pathways. PMID- 23741737 TI - A novel electrochemical aptasensor for thrombin detection based on the hybridization chain reaction with hemin/G-quadruplex DNAzyme-signal amplification. AB - In this work, a novel signal amplification electrochemical aptasensor for the sensitive and selective detection of thrombin was successfully fabricated. The amplification method was based on the hybridization chain reaction (HCR) and a pseudobienzyme electrocatalytic system. HCR-based double-stranded DNA (dsDNA) polymers not only constructed an effective carrier for anchoring larger amounts of electron mediator methylene blue (MB) into the DNA duplexes to produce a strong differential pulse voltammetry (DPV) signal, but also resulted in the formation of hemin/G-quadruplex DNAzymes nanowires by intercalating hemin into two induced single-stranded DNA (ssDNA). With the addition of NADH into the electrolytic cell, the hemin/G-quadruplex acting as an NADH oxidase and HRP mimicking DNAzyme for the pseudobienzyme amplifying system could in situ biocatalyze the formation of H2O2 with local concentrations and low transfer loss resulting in dramatic signal enhancements. The binding event can be detected by a decrease in the integrated charge of MB which electrostatically absorbed onto dsDNA polymers. In the presence of thrombin, the dsDNA polymers associated with MB and hemin/G-quadruplex structures were removed from the electrode surface, leading to a significant decrease of redox current. DPV signals of MB provided quantitative measures of the concentrations of thrombin, with a linear calibration range of 0.01-50 nM and a detection limit of 2 pM. Moreover, the resulting aptasensor also exhibited good specificity, acceptable reproducibility and stability, indicating that the present strategy was promising for broad potential application in clinic assay and various protein analyses. PMID- 23741738 TI - Response to letter regarding article, "training of future interventional neuroradiologists: the European approach. PMID- 23741739 TI - Response to letter regarding article, "endovascular treatment of intracranial aneurysms with flow-diverters: a meta-analysis. PMID- 23741740 TI - Response to letter regarding article, "cannabis-related stroke: myth or reality?". PMID- 23741741 TI - Response to letter regarding article, "smoking-thrombolysis paradox: recanalization and reperfusion rates after intravenous tissue plasminogen activator in smokers with ischemic stroke". PMID- 23741742 TI - Response. PMID- 23741743 TI - Response. PMID- 23741744 TI - Reflections: neurology and the humanities. I come armed with words. PMID- 23741745 TI - Author response: Di Dong, Cynthia Hung, Andrew Finkelstein, Singapore. PMID- 23741746 TI - Response to letter regarding article, "Implementation of the fifth link of the chain of survival concept for out-of-hospital cardiac arrest". PMID- 23741747 TI - Tudor domain-containing proteins of Drosophila melanogaster. AB - Tudor domain-containing proteins (Tudor proteins), which recognize and bind to methyl-arginine / lysine residues, play important roles in diverse epigenetics, gene expression and the regulation of various small RNAs. Using the complete set of 23 Tudor proteins from Drosophila, together with the available functional information, we propose a putative link for different types of Tudor domains (histone-binding, SMN and SND1) and the four functional groups of Tudor proteins (Group 1, binding the methyl-lysine / arginine of histone tails; Group 2, binding the methyl-RG / RA box of ligand; Group 3, binding the methyl-RG /RA box of microRNPs; and Group 4, binding the methyl-RG /RA box of PIWI proteins). Tudor domain types are distinguished by the nature of the sequence flanking the canonical Tudor domains. Sequence analysis indicates that Tudor domains experienced stepwise transit from one type to another during evolution. Tudor proteins of Group 4, collectively representing the great majority of Tudor proteins in Drosophila, are characterized by multiple Tudor domain repeats, which might be required for associating with several molecules of the same germ granule components. Tudor domain, a segment of approximately 60 amino acid residues, has been found in fungi, protozoa, unicellular eukaryota, plants and metazoa but not in the Guillardia theta nucleomorph. Similar frequencies of Tudor-containing genes (Tudor genes) among vertebrates and the frequent occurrence of orthologues among vertebrates, along with similar observations within arthropods suggest that Tudor genes are inherited largely vertically during evolution within different phylogenetic lineages. PMID- 23741748 TI - piRNA pathway and the potential processing site, the nuage, in the Drosophila germline. AB - The accurate transfer of genetic material in germline cells during the formation of gametes is important for the continuity of the species. However, animal germline cells face challenges from transposons, which seek to spread themselves in the genome. This review focuses on studies in Drosophila melanogaster on how the genome protects itself from such a mutational burden via a class of gonad specific small interfering RNAs, known as piRNAs (Piwi-interacting RNAs). In addition to silencing transposons, piRNAs also regulate other processes, such as chromosome segregation, mRNA degradation and germline differentiation. Recent studies revealed two modes of piRNA processing - primary processing and secondary processing (also known as ping-pong amplification). The primary processing pathway functions in both germline and somatic cells in the Drosophila ovaries by processing precursor piRNAs into 23-29 nt piRNAs. In contrast, the secondary processing pathway functions only in the germline cells where piRNAs are amplified in a feed-forward loop and require the Piwi-family proteins Aubergine and Argonaute3. Aubergine and Argonaute3 localize to a unique structure found in animal germline cells, the nuage, which has been proposed to function as a compartmentalized site for the ping-pong cycle. The nuage and the localized proteins are well-conserved, implying the importance of the piRNA amplification loop in animal germline cells. Nuage components include various types of proteins that are known to interact both physically and genetically, and therefore appear to be assembled in a sequential order to exert their function, resulting in a macromolecular RNA-protein complex dedicated to the silencing of transposons. PMID- 23741749 TI - Addressing the evidence gap-randomized controlled trials for the surgical management of localized genitourinary tract malignancies. PMID- 23741750 TI - miR165/166 and the development of land plants. AB - In the developmental process of plant cells, cell fate is determined by expression of specific genes. Their expressions are directed by specific transcriptional regulators and positional signals that convey the locations of respective cells along various body axes, including proximal-distal, adaxial abaxial and medial-lateral axes. Recently it was reported that some small regulatory RNAs work in a non-cell-autonomous fashion and provide neighboring cells with positional signals. Among such small RNAs, we will review unique biological features of microRNA 165 / 166 widely involved in plant development. PMID- 23741751 TI - Epigenetic regulation of monoallelic gene expression. AB - Monoallelic expression from biallelic genes is frequently observed in diploid eukaryotic organisms. Classic examples of this phenomenon include the well characterized cases of genomic imprinting and X-chromosome inactivation. However, recent studies have shown that monoallelic expression is widespread in autosomal genes. This discovery was met with great interest because it represents another mechanism to generate diversity in gene expression that can affect cell fate and physiology. To date, the molecular mechanisms underlying this phenomenon are largely unknown. In our original study describing the dominant / recessive relationships of pollen- determinant alleles in Brassica self-incompatibility, we found that the recessive allele was specifically methylated and silenced through the action of small RNA derived from the dominant allele. In this review, we focus on recent studies of monoallelic expression in autosomal genes, and discuss the possible mechanisms driving this form of monoallelic gene suppression. PMID- 23741752 TI - The immunology and ecology of co-infection. AB - It's a wormy world. All natural vertebrate populations are subject to infection and re-infection with helminth parasites (Stoll 1947). Even in humans, around one billion people in developing nations are infected by one or several of a range of helminth parasites (Lustigman et al. 2012). Infection by worms is therefore the norm and is reflected in vertebrate immune responses. Thus, there is probably little point in generating an inflammatory response to clear every last worm, with ensuing collateral damage to our own tissue, when rapid re-infection from the environment by another worm is pretty much assured. Instead, the vertebrate immune system modifies its response to worms, controlling (but not always clearing) these infections and at the same time limiting damage to host tissue caused by inflammatory immune responses (Jackson et al. 2009). The immune system, however, has to fight battles on several fronts and, while fighting a prolonged war of attrition against helminth parasites, it also has to protect against periodic invasion by bacteria, where a rapid response to kill invading microbes before they spread is essential. In this issue of Molecular Ecology, Friberg et al. (2013) ask what effect worm infections have on a host's ability to mount antimicrobial responses. PMID- 23741753 TI - World Association for the Advancement of Veterinary Parasitology (W.A.A.V.P.) second edition: guidelines for evaluating the efficacy of parasiticides for the treatment, prevention and control of flea and tick infestations on dogs and cats. AB - These second edition guidelines, updated from the 2007 version (Marchiondo et al., 2007), are intended to assist the planning and conduct of laboratory and clinical studies to assess the efficacy of ectoparasiticides applied to dogs or cats for the purpose of treating, preventing and controlling flea and tick infestations. Major revisions to this second edition include guidelines on the assessment of systemic flea and tick products, an update of the geographical distribution of the common fleas and ticks species on dogs and cats, determination of flea and tick efficacy based on geometric versus arithmetic means with respect to geographic regulatory agencies, modification of tick categorization in the assessment of efficacy, expanded guidelines on repellency and anti-feeding effects, enhanced practical field study guidance, and considerations on the ranges of flea and ticks for infestations in laboratory studies. The term ectoparasiticide includes insecticidal and acaricidal compounds, as well as insect growth regulators. The range of biological activities from animal treatment that are considered include: repellency and anti feeding effects, knockdown, speed of kill, immediate and persistent lethal effects, and interference with egg fertility and subsequent development of off host life cycle stages. Information is provided on the selection of animals, dose determination, dose confirmation and field studies, record keeping, interpretation of results and animal welfare. These guidelines are also intended to assist regulatory authorities involved in the approval and registration of new topical or systemic ectoparasiticides, and to facilitate the worldwide adoption of harmonized procedures. PMID- 23741754 TI - The role of nurse practitioners in pediatric mental health. PMID- 23741755 TI - Personal reflections of a woman scientist growing up in a man's world. PMID- 23741756 TI - Winners and losers. Corporate tax overhaul would have very different effects for various healthcare sectors. AB - Washington is in the mood for a corporate tax overhaul, but not every segment of healthcare will like the result. One proposed change cracks down on opportunities for companies to shift profits on intellectual property to countries with lower tax rates---a tactic frequently deployed by the pharmaceutical industry. Providers and insurers would be winners under the proposals. PMID- 23741757 TI - New rules, responsibilities. Revenue-cycle companies facing more data scrutiny. PMID- 23741787 TI - Hyperthyroidism in Cats. PMID- 23741788 TI - From seat-of-the-pants financial management to a blueprint for success. PMID- 23741789 TI - Biodegradation of benzo[a]pyrene by the mixed culture of Bacillus cereus and Bacillus vireti isolated from the petrochemical industry. AB - Polycyclic aromatic hydrocarbons are a group of compounds that pose threat to humans and animal life. Methods to reduce the amount of PAHs in the environment are continuously being sought. The bacterial consortium capable of utilizing benzo(a)pyrene as the sole source of carbon and energy was isolated from petrochemical soil. The isolates were identified as Bacillus cereus and Bacillus viretibased on morphological characterization, and 16S rDNA gene sequence analysis. About 58.98% of benzo(a)pyrene at concentration of 500 mg l(-1) in mineral salts medium were removed by bacterial consortium. GC mass spectral analysis showed the presence of metabolite cis-4-(7-hydroxypyren-8-yl)-2-oxobut 3enoic acid. The results indicate that the bacterial consortium is a new bacterial resource for biodegrading benzo(a)pyrene and might be used for bioremediation of sites heavily contaminated by benzo[a]pyrene and its derivatives. PMID- 23741790 TI - Utilization of intron-flanking EST-specific markers in the genetic characterization of Artemisia annua genotypes from the trans-Himalayan region of Ladakh, India. AB - Genetic variation was assessed utilizing intron-flanking EST-specific markers among genotypes of Artemesia annua collected from two sampling sites viz. Nubra (9,600 ft) and Leh (11,500 ft) valleys of the trans-Himalayan region, Ladakh, India. The available ESTs (3,60,906) sequences of A. annua were aligned with the genomic sequences of Arabidopsis to developed 'intron-flanking' EST-PCR based primers. These primers anneal with the conserved region of exon (flanking to the intron) and amplified the introns. Out of the 39 primers selected and tested on 20 genotypes of A. annua, we successfully exploited 81 codominant intron length polymorphism (ILP) markers, with an average of 2.08 markers per primer and 92.04% polymorphism detection. Clustering of genotypes revealed distribution of genotypes into 2 distinct clusters with respect to their site of collection. Significantly, this study demonstrates that Arabidopsis genome sequence can be useful in developing gene-specific PCR-based markers for other non-model plant species like A. annua in the absence of genome sequences. PMID- 23741791 TI - Preliminary information on noise pollution in commercial banks of Balasore, India. AB - The environmental noise in some commercial banks of Balasore, in terms of standard noise indices was worked out in the present study. Noise pollution was assessed in twenty different commercial banks of the city on 31st August, 2010 and during first week of September, 2010. The present noise monitoring was conducted with the help of sound level meter, which was calibrated acoustically using an external reference source, and placed over the microphone. It is inferred that the noise levels were more than the permissible limit i.e. 50 dB as prescribed in USA in all the investigated banks of Balasore and the maximum noise levels were around double of the said permissible limit, which is a contradiction with that of developed countries. Analysis of variance was also computed for all the banks during peak hour (10 a.m.-12 noon). The mean values of noise levels in different banks ranged from 75.5 to 90dB; from 69 to 83.6dB and 71.5 to 83.5dB during 10 a.m.-12 noon, 12-2 p.m. and 2-4 p.m., respectively. It was categorically observed that noise levels were more during 10 a.m.-12 noon than other investigated time intervals in all the 20 investigated banks. It is imperative to mention here that such an attemptof assessing noise in banks is first of its kind in India. PMID- 23741792 TI - Copepod population in Vellar estuary, Parangipettai coast in relation to environmental conditions. AB - Distribution and abundance of copepods were studied in relation to environmental conditions at two different ecosystems viz: Neritic (Bay of Bengal) and estuarine (Vellar estuary) of Parangipettai coast from September, 1998 toAugust, 2000. Over the study period, total 85 species of copepods were reported. Among these, the calanoid copepods constituted the major component with 63.52% followed by cyclopoids (29.41%) and harpacticoids (7.05%). The copepods population density was found to be high (2, 53,000 org l(-1)) in estuarine water, while the species diversity was higher (5.47) in neritic water. The observed spatio-temporal variations in the population density and species diversity of copepods were more related to the environmental state of respective study area. PMID- 23741793 TI - Effect of available nutrients on yield and quality of pear fruit Bartlett in Kashmir Valley India. AB - Pear is one of the most important commercial crops grown in the Kashmir valley of India. A study was conducted during 2008 to find out the effect of available nutrients on yield and quality parameters of pear cultivar "Bartlett" which revealed that nitrogen, phosphorus and potassium exhibited significant and positive relationship with fruit length (0.882, 0.856, and 0.482 mm, respectively), diameter (0.869, 0.794 and 0.458 mm, respectively), weight (0.876, 0.825 and 0.439 g, respectively), volume (0.908, 0.806 and 0.404, Cm3 respectively) and yield (0.908, 0.764 and 0.702 kg tree(-1), respectively) however, only nitrogen and phosphorus showed similar relationship with total sugars (0.833 and 0.838% respectively). The calcium indicated significant and negative relationship with fruit diameter (-0.433) and yield (-0.589), while as it showed significant and positive correlation with fruit firmness (0.442) only. The sulphur revealed significant and positive relationship with fruit length (0.440), diameter (0.434), TSS (0.482) and yield (0.729) whereas zinc, copper, iron and manganese exhibited significant and positive relationship with fruit length (0.889, 793, 0.671 and 0.619, respectively), diameter (0.875, 0.807, 0.653 and 0.576, respectively) weight (0.881, 0.784, 0.669 and 0.615, respectively), volume (0.885, 0.832, 0.692 and 0.572, respectively) TSS (0.858, 0.761, 0.735 and 0.609, respectively), total sugars (0.853, 0.890, 0.705 and 0.517, respectively) and yield (0.777, 0.618, 0.789 and 0.701, respectively). It is therefore suggested that nutrients have effect on quality and yield of pear fruits. PMID- 23741794 TI - Zooplankton population in relation to physico-chemical parameters of Lal Diggi pond in Aligarh, India. AB - Physico-chemical parameters and zooplankton were assessed Lal Diggi pond from January to December, 2008. Four groups of zooplankton were recorded. Rotifera constituted the main dominant group in this pond contributing 44.89% of the total zooplankton population followed by Cladocera (30.41%), Copepoda (15.51%) and Ostracoda (4.68%). The highest density of zooplankton was recorded during January and February being 197 and 182 no l(-1) respectively, while the lowest density was recorded during May and June being 64 no l(-1) each could be due to the negative and significant value of correlation between zooplankton and water temperature (r = -0.700). These data is supported by similarity indices which recorded high values during January and February while the lowest values recorded during June and July. PMID- 23741795 TI - Kinetics of fungal extracellular alpha-amylase from Fusarium solani immobilized in calcium alginate beads. AB - Extracellular alpha-amylase mass produced by Fusarium solani using mango kernel as substrate was immobilized in calcium alginate beads through entrapment technique. Maximum enzyme immobilization efficiency was achieved in 2 mm size beads formed by 6.5% (w/v) of sodium alginate in 2% (w/v) calcium chloride. The catalytic properties of the immobilized alpha-amylase were compared with that of free enzyme (soluble). The activity yield of the immobilized enzyme was 81% of the free enzyme. The immobilized enzyme showed optimum activityat pH 4.5-6.0 and temperature 40 degrees C, in contrast to the free enzyme at 5.5 and 30 degrees C, respectively. Thermal stability of the immobilized enzyme was found to be more than the free enzyme over a longer time interval. The immobilized enzyme retained activity upto 20% of optimum even after 180 min. While the free enzyme lost its 80% activity after 60 min and lost total activity down to zero by 120 min. The kinetic constants, viz., K(M) (Michaelis constant), V(max) and activation energy were affected by immobilization. However, the immobilized alpha-amylase in calcium alginate beads supports its long-term storage which has immense industrial applications. PMID- 23741796 TI - Role of nitric oxide in cadmium-induced stress on growth, photosynthetic components and yield of Brassica napus L. AB - Experiments were carried out to study the effect of cadmium (Cd) and exogenous nitric oxide (NO) on growth, photosynthetic attributes, yield components and structural features of Brassica napus L. (cv. GSL 1). Cadmium in the growth medium at different levels (1, 2 and 4 Mm) retarded plant growth viz. shoot (27%) and root (51%) length as compared to control. The accumulation of total dry matter and its partitioning to different plant parts was also reduced by 31% due to Cd toxicity. Photosynthetic parameters viz., leaf area plant(-1) (51%), total Chl (27%), Chl a / Chl b ratio (22%) and Hill reaction activity of chloroplasts (42%) were greatly reduced in Cd-treated plants. Cd treatments adversely affected various yield parameters viz., number of branches (23) and siliquae plant(-1) (246), seed number siliqua(-1) (10.3), 1000-seed weight (2.30g) and seed yield plant(-1) (7.09g). Different Cd treatments also suppressed the differentiation of various tissues like vessels in the root with a maximum inhibition caused by 4mM Cd. Exogenous application of nitric oxide (NO) improved the various morpho physiological and photosynthetic parameters in control as well as Cd-treated plants. PMID- 23741797 TI - Rhizobacterial population density and nitrogen fixation in seagrass community of Gulf of Mannar, India. AB - Seagrass rhizosphere generally supports high bacterial population density which plays a major role in determining the nutrient cycles of the sea. Higher densities of total heterotrphic bacteria (26.3 x 10(6) CFU g(-1)), nitrogen fixing (27.3 x 10(3) CFUg(-1), ammonifying (44.66 x 10(6) MPN g(-1)) and nitrifying bacteria (42.33 X 10(6) MPN g(-1)) have been registered in the seagrass areas than the non seagrass area. In particular, all these rhizosphere microbial population was higher in Thalassia hemprichii. The rates of nitrogen fixation was recorded in the different species of seagrasses such as Enhalus acoroides (1.166 n mol g(-1) d(-1)), Halophila ovalis (0.166 n mol g(-1) d(-1)), Thalassia hemprichii(18.5 n mol g(-1) d(-1)), Cymodocea serrulata (10.5 n mol g( 1) d(-1)), Halodule uninervis (5.375 n mol g(-1) d(-1)) and Syringodium isoetifolium (0.666 n mol g(-1) d(-1)) using gas chromatography. The average nitrogen fixation by the seagrasses of Gulf of Mannar alone was estimated to be 7640.58 n mol m(-2) d(-1) and the contributions from the rhizosphere microbes will increase the quantity to many fold. PMID- 23741798 TI - Some ecological aspects and potential threats to an intertidal gastropod, Umbonium vestiarium. AB - Kalbadevi Bay in Ratgnairi has been identified as potential site for placer mining along the west coast of India. Since, U. vestiarium is a keystone species of the region; study on some ecological aspect was carried. The paper also discusses the possible impact of beach sand mining and other threats to this ecologically important gastropod. Seasonal sampling was carried in 2004-2005 at 13 transects by quadrate method. U. vestiarium was restricted to mid and low tide zone of Station 1-3 and 8-10 located at the north and south ends of the beach. Abundance was highest at Station 10 MT (16 to 12488 ind m(-2)). Based on the size frequency, it may be considered that U. vestiarium like other tropical fauna recruit during monsoon. Eleven different colour patterns of U. vestiarium were observed. However, average individual size was larger in the samples collected from the north (stn. 1-3) end of the beach. The fastidious nature and sporadic distribution of U. vestiarium make them vulnerable to natural and anthropogenic disturbance. PMID- 23741799 TI - Comparative study of heavy metals in selected mangroves of Sundarban ecosystem, India. AB - Accumulation and partitioning of eight heavy metals Cr, Pb, Zn, Cd, Ni, Cu, Co and Fe were studied in the root, stem and leaf of mangrove species (Sonneratia caseolaris, Acanthus ilicifolius and Excoecaria agallocha) for comparison and in mangrove sediments for calculation of bio concentration factor (BFC) in Sundarban India. Magnitude of Fe was found highest in the sediments (35371.71 mg kg(-1)) and plant parts of the three species (a maximum of 11428.0 mg kg(-1) in the root of S. caseolaris). For other heavy metals, plants showed exclusion and selection mainly based on utilization, regardless of their level in the sediments. In most of the cases significant variation of absorption was found between the three species (F = 11.48 to 157.37; p < 0.001) and between their plant parts (F = 10.98 to 338.03; p < 0.001). S. caseolaris was found to be a less potential heavy metal accumulator than the other two species, except for Fe and Zn in the root. Irrespective of the magnitude of the heavy metals, other species showed significant correlations (r = 0.509 to 0.961; p < 0.001) between heavy metal accumulations, exclusively due to chemical reason, whereas S. caseolaris showed significant correlations (r = 0.554 to 0.926; p < 0.001) between each and every heavy metal, which signifies similar mode of absorption pattern regardless of their utilization. This nonbiased manner of heavy metal accumulation pattern may help the species to withstand in the polluted areas. PMID- 23741800 TI - Physiological attributes of lichen, Phaeophyscia hispidula in heavy metal rich sites of Dehra Dun, India. AB - Phaeophyscia hispidula (Ach.) Moberg, foliose lichen is widespread in Garhwal Himalayas and grows luxuriantly on different substratum in polluted as well as non polluted sites, where no other macrolichens are able to colonize. The elemental concentration and biochemical parameters in P. hispidula collected from Dehra Dun city were analyzed to assess its tolerance to heavy metals. The major source of pollution in the city is automobiles. Among the biochemical parameters protein was significantly and negatively correlated with pigment concentrations (r = -0.3838 (Chl.b); -0.5809 (Carotenoid); -0.5034 (OD)) however it is significantly positively correlated with Cd (r = 0.6822: P < 0.01). Among heavy metals, Cd was negatively correlated with Cu (r = -0.4639), Fe (r = -0.2676), and Zn (r = -0.0549). It was observed that the chlorophyll and protein content increased parallel to the level of metallic pollutants indicating the mechanism of stress tolerance in P. hispidula. The study shows that P. hispidula is tolerant to inorganic pollution and a useful tool for biomonitoring of air quality in the Himalayan region. PMID- 23741801 TI - Effects of cadmium chloride on oxygen consumption and gill morphology of Indian flying barb, Esomus danricus. AB - Effects of three sub lethal concentrations of cadmium chloride (0.636, 0.063 and 0.006 mg l(-1)) on oxygen consumption and gill morphology in Indian flying barb, Esomus danricus (Hamilton-Buchanan), a teleost fish, were studied. When compared to control, 0.636 mg l(-1) of cadmium chloride after 7,14, 21 and 28 day exposure showed a significant decline in rates of oxygen consumption at 32.98, 28.40, 23.88 and 21.69 ml hr(1) 100 g(-1) of tissue, respectively; while, 0.063 mg l(-1) of cadmium chloride for the same exposure durations showed a significant decline in rates of oxygen consumption at 34.28, 29.30, 28.05 and 26.47 ml hr(1)100 g(-1) of tissue, respectively. However, significant decline in the rate of oxygen consumption at 0.006 mg l(-1) of cadmium chloride could be observed from 21st day of exposure. Gill tissue showed various histopathological changes including epithelial lifting, hyperplasia, mucous secretion, marked leucocyte infiltration in the epithelium after 28 days of cadmium chloride exposure. PMID- 23741802 TI - Bioaccumulation potential of Aspergillus niger and Aspergillus flavus for removal of heavy metals from paper mill effluent. AB - In the present study Aspergillus niger and Aspergillus flavus isolated from paper mill effluent showed tolerance and accumulation of toxic metals Ni, Zn, Cd, Pb, Cr and Cu from synthetic medium and paper mill effluent. Physico-chemical and heavy metals characterization of industrially treated paper mill effluent showed insignificant reduction in BOD, hardness, TDS and heavy metals as compared to permissible limits of BIS and WHO. A. niger and A. flavus were treated with synthetic medium containing 100-1000 mg l(-1) of six heavy metals. A. niger was able to tolerate and grow in 1000 mg l(-1) Pb, 500 mg l(-1) Cu, 250 mg l(-1) Zn and 100 mg l(-1) Cr, Ni respectively. No growth of A. niger was observed in 100 mg l-(-1) of Cd. A. flavus was capable to tolerate and grow in 1000 mg l(-1) Pb, Zn and Ni, 100mg l(-1) Cu. A. flavus growth was completely inhibited in 100 mg l( 1) of Cd and Cr. The Cd, Zn, Cu and Pb reduction were found significant (p < 0.05) in the paper effluent inoculated with A. niger and A. flavus biomass compared to industrial treated effluent. A. niger and A. flavus accumulated maximum of Pb (75.82%) followed by Zn (49.40%) > Cu (45.34%) > Ni (25.20%), while only 41% Cr was accumulated by A. nigerfrom 100 mg l(-1) of Cr solution. PMID- 23741803 TI - Impact of mine waste dumps on growth and biomass of economically important crops. AB - The present study aimed to investigate the effect of magnesite and bauxite waste dumps on growth and biochemical parameters of some edible and economically important plants such as Vigna radiata, V. mungo, V. unguiculata, Eleusine coracana, Cajanus cajan, Pennisetum glaucum, Macrotyloma uniflorum, Oryza sativa, Sorghum bicolour, Sesamum indicum, Ricinus communis, Brassica juncea, Gossypium hirsutum and Jatropha curcas. The growth rate of all the crops was observed in the range of 75 to 100% in magnesite and 15 to 100% in bauxite mine soil. The moisture content of roots and shoots of all the crops were in the range of 24 to 77, 20 to 88% and 42 to 87, 59 to 88% respectively. The height of the crops was in the range of 2.6 to 48 cm in magnesite soil and 3 to 33 cm in bauxite soil. Thus the study shows that both mine soils reflects some physical and biomolecule impact on selected crops. PMID- 23741804 TI - Impact of dyeing industry effluent on germination and growth of pea (Pisum sativum). AB - Dye industry effluent was analyzed for physico-chemical characteristics and its impact on germination and growth behaviour of Pea (Pisum sativum). The 100% effluent showed high pH (10.3) and TDS (1088 mg l(-1)). The germination parameters included percent germination, delay index, speed of germination, peak value and germination period while growth parameters comprised of root and shoot length, root and shootweight, root-shoot ratio and number of stipules. The study showed the maximum values of positive germination parameters viz. speed of germination (7.85), peak value (3.28), germination index (123.87) and all growth parameters at 20% effluent concentration while the values of negative germination parameters viz. delay index (-0.14) and percent inhibition (-8.34) were found to be minimum at 20% effluent concentration. The study demonstrated that at lower concentrations the dyeing industry effluent caused a positive impact on germination and growth of Pisum sativum. PMID- 23741805 TI - Studies on abundance of zooplanktons in lakes of Mysore, India. AB - This is the first comprehensive ecological study on the abundance of zooplankton in Kalale, Alanahalli and Dalvoy lakes of Mysore. The abundance of zooplankton as well as their relation with physico-chemical parameters was analyzed, every month in these lakes from June 2008-May 2010. The mean abundance of Rotifer (281 Org (l 1)), Cladocerans (27 Org l(-1)) and total abundance of zooplankton (343 Org l( 1)) were more and significantly different in Dalvoy lake; whereas, in Kalale lake the mean abundance of Rotifer (19 Org l(-1)), Cladocerans (3 Org l(-1)) and total abundance of zooplankton (79 Org l(-1)) and in Alanahalli lake the mean abundance of Rotifer (84 Org l(-1)), Cladocerans (9 Org l(-1)) and total abundance of zooplankton (149 Org l(-1)) were significantly less. However, the abundance of Copepods and Ostracods was similar in all the three lakes studied. The water bodies of Kalale lake were less polluted when compared toAlanahalli and Dalvoy lakes. The increases in conductivity, Chl a, turbidity, phosphate, carbon-di oxide and total anions in Alanahalli and Dalvoy lakes may be attributed to the various anthropogenic activities in the catchment areas. Interrelationships between zooplankton variables and physico-chemical parameters were calculated using Pearson's correlation co-efficient (r) which revealed (25) significant (P < 0.05) relationships (More (11) in Dalvoy lake and moderate (7) in Alanahalli and Kalale lakes). The stepwise multiple regression analysis (r2) showed out of 21 physico-chemical parameters studied, as many as 12 were positively controlling the abundance of zooplankton, where as the phosphate and chloride were negatively controlling the total abundance of zooplankton and the abundance of ostracods respectively. The results obtained have been discussed in the light of the present literature available in the field of aquatic microbial ecology. PMID- 23741806 TI - Dynamics of road traffic noise in Bhadrak city, India. AB - Road traffic noise assessed in 13 different squares of major intersection points in Bhadrak city during four different specified times i.e. 7-10 a.m., 11 a.m.-2 p.m., 3-6 p.m. and 7-10 p.m.. Road traffic was found to be the most important source of community noise at the studied sites. The noise levels of all the 13 squares were found to be beyond the permissible limit [70 dB (A)] during day time. Leq (equivalent noise level) values ranged from 93.4 to 100.5; 91.5 to 100.6; 95.1 to 107.3 and 97.3 to 106.3 dB during 7-10 a.m., 11 a.m.-2 p.m., 3-6 p.m. and 7-10 p.m. respectively. LNP values range from 115.7 to 127.7; 114.2 to 129.8; 118.2 to 138.2 and 120.7 to 135 dB, while TNI values range from 134.3 to 154.7; 130.7 to 157.9; 136.7 to 168.2 and 137.2 to 165 dB during 7-10 a.m., 11 a.m.-2 p.m., 3-6 p.m. and 7-10 p.m. respectively. Reprehensibly, even minimum LNP and TNI values are more than 114 and 130 dB respectively. Analysis of variance also computed for investigated squares at the peak hour i.e. 7-10 p.m. to infer the level of significance. The observed value of F (0.47) was less than the tabulated values and was not significant at both 5 and 1% levels of significance. Thus, the noise levels of different squares did not differ significantly at their peak hours. A preliminary public health survey carried out based on questionnaire method amongst 202 local inhabitants reveal the degree of annoyance due to road traffic noise. PMID- 23741807 TI - Influence of temperature and humidity on rumen pH and fatty acids in dairy cows. AB - The aim of this study was to investigate the variations of rumen pH and fatty acids (acetic acid, propionic acid, iso-butyric acid, n-butyric acid, iso valerianic acid, n-valerianic, caproic acid and total fatty acids) in 245 early lactating dairy cows under different temperature and humidity conditions. The animals were divided into six groups and rumen fluid was collected by rumenocentesis on 22 dairy cows in April (Group A), 33 in May (Group B), 43 in June (Group C), 48 in July (Group D), 36 in September (Group E) and 60 in October (Group F). One-way analysis of variance (ANOVA), followed by the Bonferroni's test, showed a significant effect of environmental variations on all studied parameters (P < 0.0001). Changes in studied parameters can be explained in relation to the microbial population and shift in the optima for rumen conditions associated with variations of environmental conditions. We can affirm that the microbial assemblages that underlie energy and protein supply to wild ruminant are evident especially in relation to temperature and humidity conditions. PMID- 23741808 TI - Phytotoxicity of heptachlor and endosulfan sulfate contaminants in soils to economic crops. AB - The intensive use of organochlorine in the past decades has resulted in contamination of soil worldwide. The phytotoxicity of two organochlorine pesticide, endosulfan sulfate and heptachlor, on the early growth stage of sweet corn (Zea mays), waxy corn (Zea mays) cowpea (Vigna sinensis), cucumber (Cucumis sativus) and water morning glory (Ipomoea aquatica) were studied. In the range of concentration found in Thai agricultural soil, 0.4-40 mg kg(-1) of each pesticide, did not affect the percentage of seed germination. Heptachlor seemed to affect the shoot and root length of test plants more than endosulfan sulfate. The combined effect of both pesticides to corn seedling growth was tested. There was no significant effect on combined treatment of both pesticides to corn growth. The 0.4-40 mg kg(-1) concentration of endosulfan sulfate and heptachlor did not produced significant effect on early growth of plants. PMID- 23741809 TI - Studies on Oecophylla smaragdina as a bio-control agent against pentatomid bug infesting on Pongamia tree. AB - Weaver ants, (Oecophylla smaragdina) have been found to predate on pentatomid bug (Cyclopelta siccifolia) infesting Pongamia pinnata tree in mid-western Ghat region of Shimoga district, Karnataka. The present study was undertaken to evaluate the potential of weaver ants, that are abundant on P. pinnata trees, to control the pentatomid bugs. Consistent and systematic field surveillance was carried out for a period of two months, March and July 2010. This showed that the number of pentatomid bugs colony found on branches of tree was significantly lower in tree with abundant weaver ants (11.21-16.84%) than in trees with fewer weaver ants (26.51-38.24%), or in trees without ants (61.42-75.47%) similarly, the branches damaged by pentatomid bug (9.42-11.43%) their in trees with abundant weaver ants which was significantly lower than in trees with fewer weaver ants (16.13-23.24%) and without ants (38.42-51.47%) in March and July. The pentatomid bug colony and their damage was significantly low on trees with abundant weaver ants than with fewer ants, or without the ants. Field observations regarding infestation of pentatomid bugs revealed that weaver ants are effective naturally occurring biological agents help in controlling damage caused by pentatomid bugs on Pongamia trees. PMID- 23741810 TI - Single dose toxicity studies of sulfated water soluble beta-D-glucan in Sprague Dawley rats. AB - The fungal beta-D-glucan is a biological response modifier (BRM), but a major obstacle to the clinical utilization of these BRMs is their relative insolubility in aqueous media. We made soluble sulfated-beta-glucan (SGL) from insoluble beta glucan (IGL) by sulfation method. In single dose toxicity study of SGL for 7 days, no negative effects on body weight or food consumption of rats were evident below a dose rate of 2,000 mg kg(-1) SGL. No clinical pathology, functional/behavioral, or gross observations indicating toxicity were detected. In hematology and biochemistry, statistically significant increases of WBC and neutrophils (P < 0.01) in male and increase of MCV (P < 0.05) in females was observed. However, since the changes were not dose-responsive, the effects were considered to be of no toxicological significance. These results suggest that chemically modified sulfated-beta-D-glucan was lesstoxic than the insoluble b glucan and not considered acutely toxic following peritoneal exposure to 2,000 mg kg(-1) day(-1) in Sprague-Dawley rats. PMID- 23741811 TI - Phytoplankton diversity in the Parangipettai coastal waters, southeast coast of India. AB - An investigation was carried out during June 2005 to May 2007 on hydrography, composition and community structure of phytoplankton including chlorophyll a in Parangipettai coastal waters (southeast coast of India). Air and surface water temperatures varied from 25.5 to 31.2 degrees C and from 25 to 29.3 degrees C, respectively. Salinity values varied from 5 to 33.1 per thousand and the pH ranged between 7.2 and 8.3. Dissolved oxygen content varied from 3.1 to 7.9 mg l( 1) while the light extinction coefficient values (LEC) ranged between 1.8 and 11.0 cm. The range of inorganic nutrients viz., nitrate, nitrite, phosphate and silicate were: 6.5 - 27.0 microM; 1.0 - 8.9 microM; 0.1 - 3.0 microM and 15.0 - 140 microM, respectively. The range of chlorophyll a was: 2.0 - 7.5 microg l(-1). Presently, 117 phytoplankton species representing different classes viz: Bacillariophyceae (66); Dinophyceae (22); Cyanophyceae (19); Chlorophyceae (7) and Chrysophyceae (3) were recorded. The phytoplankton cell abundance varied from 0.14 to 132 cells ml(-1), with peak diversity (3.52 bits ind.(-1)) during summer season. The maximum abundance was found during summer season coinciding with the stable hydrographical conditions. Canonical Correspondence Analysis was applied in this study for discriminating environmental factors effecting on phytoplankton community at species level. PMID- 23741812 TI - Determination of microbial quality and plasmid-mediated multidrug resistant bacteria in fountain drinking water sources in Turkey. AB - The bacterial contamination as the total aerobic bacteria, coliform and fecal coliform numbers were determined and analyzed for temperature, pH, conductivity and dissolved oxygen in seasonally collected water samples from fifteen different stations placed in Adana-Tufanbeyli road line during March 2008 - January 2009. In addition, antibiotic resistance profiles of isolates were examined against frequently used antibiotics, and analyzed plasmid DNAof multiple antibiotic resistant (MAR) isolates. Total aerobic bacteria in fountain water samples was determined as 3 x 10(3) CFU ml(-1) and total and fecal coliforms were determined 460 MPN/100 ml. Results obtained from biochemical analysis showed that 121 of the isolates were Proteus vulgaris, 69 Escherichia coli, 51 Pseudomonas aeruginosa and 28 Citrobacter spp. According to these results, the existence of Vibrio parahaemolyticus in stations 2 and 10, and Streptococcus faecalis in stations 11 and 15 respectively were confirmed. Clostridium perfringens was not detected in water samples. A total of 273 isolates were tested for antimicrobial susceptibility by agar disc diffusion methods. A total of sixteen antibiotics were used for determination of antibiotic resistance of isolates. Resistance to bacitracin, vancomycine, cephalothin and ampicillin was detected in 77, 77, 63 and 50%, respectively. Multiple antibiotic resistance (MAR) value > or = 0.25 was determined in 68.4% of identified 273 isolates and meaning of this percentage were resistant to four and more antibiotics. Plasmid DNA was isolated from 22 isolates with multiple antibiotic resistance index ranged from 0.3 to 0.6 taken randomly by agarose-gel electrophoresis, some of them contain a high-molecular weight plasmid DNA. Highlight of our study that the appearance of potential antibiotic resistances in fountain drinking water requires increased surveillance for risk assessment and prevention strategies to protect public health. PMID- 23741813 TI - Variation in growth, physiology and yield of four chickpea cultivars exposed to cadmium chloride. AB - Cadmium is a highly toxic metallic pollutant which adversely affects plant growth. A green house experiment was conducted to study the variation in growth, yield and proline content of four chickpea (Cicer arietinum L.) cultivars namely ICC1069, ICC12422, ICC7589 and ICC4969 at two plant growth stages (30 and 60 days after sowing), treated with 0, 25, 50 and 100 mg Cd kg(-1) soil. Plant growth, plant fresh weight, plant biomass, leaf area, total photosynthetic area, carbonic anhydrase activity, yield and proline content exhibited a dose-dependent response to Cd on four cultivars of Cicer arietinum L. The shoot and root length showed a reduction of 10.02, 10.63, 12.97, 7.93 and 4.95, 6.09, 7.85, 9.23% in all the four cultivars respectively, whereas shoot and root dry weight showed a reduction of 18.82, 27.61, 11.27, 44.59 and 10.63, 4.89, 3, 11.94% in all the cultivars respectively at 50 mg Cd kg(-1) soil at 30 days of growth stage. It was a general observation from the results that all the parameters of plants were reduced in a concentration-duration dependent manner. However, the proline content of leaf is increased with the increase in Cd concentration. It showed an increase of 15.66, 17.5, 18.42 and 23.61% at 100 mg Cd kg(-1) soil at 30 days of growth stage. Maximal significant reductions in the growth characteristics were observed with 100 mg Cd kg(-1) soil in all the cultivars in both the samplings. Among cultivars, ICC1069 proved tolerant and showed lesser decrease in the growth characteristics, whereas ICC4969 proved as non-tolerant and showed maximum decrease in the growth characteristics. PMID- 23741814 TI - 66th year of independence--are we independent in health? PMID- 23741815 TI - Perinatal complications associated with autism--a case control study in a neurodevelopment and early intervention clinic. AB - Early and intensive intervention can have a profound impact on the quality of life for children at risk for autism. Hence a high degree of suspicion towards babies exposed to known risk factors is warranted. Previous studies have shown that different perinatal factors like antepartum bleeding, postmaturity, birth asphyxia, meconium aspiration syndrome, anaemia in early infancy and exposure to toxins of various origins makes an infant susceptible to development of autism; attention deficit hyperactivity disorder (ADHD) and other neurodevelopmental disorders in later life.This study aims to find out the association of perinatal risk factors in relation to development of autism spectrum disorders. All babies who are at least three years of age, attending the neurodevelopment and early intervention clinic at SSKM Hospital at Kolkata taken as cases. Age matched controls were taken from general paediatric OPD of the same hospital. After history taking, physical and neurological examination, developmental maturity was assessed by the Denver Developmental Screening Test (DDST) and Vineland Social Maturity Scale (VSMS). A semi-structured parent's questionnaire and the modified checklist for autism in toddlers (M-CHAT) was used to screen for autism. Diagnosis was confirmed by DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition, Text Revision) criteria. Significant correlation was found between presence of antepartum haemorrhage, pregnancy induced hypertension, preterm delivery and autism in the baby. Perinatal complications are important risk factor for autism. Knowing the risk factors will help clinicians to be aware of the avoidable complications, and to undertake either preventive steps or intense intervention to reduce the degree of disability. PMID- 23741816 TI - Perception of young doctors towards service to rural population in Bihar. AB - With the launch of National Rural Health Mission (NRHM), rural health is being given more attention than ever before but health of the rural population is still in the hands of handful of qualified doctors. To know the willingness of young doctors to serve rural population and factors associated with their decision, 176 participants (101 students and 75 interns) of a medical college of Bihar were interviewed during the period July 2005 to December 2006. Only 9.1% participants showed their willingness to serve in rural area despite the fact that 38.6% of them had a rural background, parent(s) of 19.9% had rural occupation and 30.1% subjects had their primary schooling in villages. Rural background (X2 = 22.54, df = 1, p < 0.001) and primary schooling in villages (p = 0.004) were found to be associated significantly with those willing to serve rural population. Whereas land and house property in village (87.5%), village located near towns (81.2%), less competition (62.5%) and need for a job (56.2%) were prime factors in willing medicos, poor living conditions in rural area and lack of professional future (96%), priority for postgraduation (90.6%) and tough working conditions (89.4%) were found to be main factors for reluctance. No significant difference (X2 = 0.929, df = 1, p = 0.335) was seen in the perception of students and interns. Willingness in young doctors to serve rural population is dismal in the present situation. To make them work for rural health, effective efforts to redress all the factors are urgently needed. PMID- 23741817 TI - Encapsulated follicular variant papillary thyroid carcinoma: problems in histological diagnosis. AB - Thyroid neoplasms are the commonest endocrine neoplasms and account for the most number of thyroidectomies done. Encapsulated thyroid lesions are being encountered more commonly in thyroidectomy specimens in recent time. The present study was undertaken to analyse the incidence of thyroid malignancies with a changing pattern and to discuss the difficulties encountered in histopathological interpretation of encapsulated neoplastic lesions of follicular cell origin. It is a retrospective study done in the department of pathology, NRS Medical College, Kolkata. Data of all the thyroidectomy specimens examined over last four years (August 2006 to July 2010) were retrieved and slides were reviewed. All slides of thyroid lesion received in the department of pathology, NRS Medical College for review were also included in this study. Frequency distribution study was done with the sample analysed. Follicular variant of papillary carcinoma was the commonest type of thyroid malignancy, on review, with the encapsulated sub variant exceeding the diffuse type. This variant is a diagnostic challenge because it has to be differentiated from other encapsulated follicular thyroid lesions, especially follicular adenoma. The data analysis, results and problems in the diagnostic protocols are discussed in this study along with review of literature. Reclassification of thyroid tumour may be warranted in future with this background. PMID- 23741818 TI - Peripapillary nerve fibre layer thickness and macular thickness in children with anisometropic amblyopia attending a referral centre in Eastern India. AB - To study the macular thickness and peripapillary nerve fibre layer thickness in children with anisometropic amblyopia, a prospective non-randomised case series study was undertaken among 39 children (25 boys and 14 girls) aged between 5 and 16 years. This study was carried out between January 2010 and April 2011. The peripapillary retinal nerve fibre layer (RNFL) thickness and macular layer thickness was measured using optical coherence tomography (OCT), the RNFL thickness and the macular layer thickness of the amblyopic eye was assessed and compared to the normal eye of the same subject. It was found that macular layer thickness in the amblyopic eye was greater than that of the macular thickness in the normal eye. The mean macular layer thickness in the amblyopic eyes was 229.589 microm with a standard deviation of -+/- 31.9149 microm. The mean macular layer thickness in the normal eyes of these children was 206.8717 microm with a standard deviation of +/- 28.490 microm, the p-value was 0.00141 which is much lesser than 0.005 and hence is strongly statistically significant. However the mean RNFL thickness in the amblyopic eye was 104.454 microm with a standard deviation of +/- 22.244 microm. The mean RNFL thickness of the normal eye was 108.2746 microm with a SD of +/- 19.370 microm. The p-value in this case being 0.4246 which is statistically insignificant. It is conducted that macular layer thickness is raised in the amblyopic eye of children with anisometropic amblyopia though the RNFL thickness is not. PMID- 23741819 TI - Prediction of pre-eclampsia: comparative analysis of two screening tests. AB - Pre-eclampsia is a major cause of maternal and perinatal morbidity and mortality. Unfortunately, in spite of extensive research worldwide, still we lack an effective screening test for pre-eclampsia. The aim of the current study is to assess the importance of micro-albuminuria and uterine artery Doppler resistance index as a screening test for pre-eclampsia during antenatal period. The study is a prospective audit. The study population consisted of 160 antenatal mothers attending the outpatient department. Test for micro-albuminuria was done at 14 weeks, 18 weeks, 28 weeks and 34 weeks of gestation. Uterine artery Doppler resistance index (0.58 taken as cut-off) was recorded at 18 weeks of gestation. The subjects were followed up till delivery for development of pre-eclampsia. Sensitivity, specificity, positive and negative predictive value (along with confidence interval and diagnostic odd's ratio) of the tests were calculated. Sensitivity, specificity, positive and negative predictive value of micro albuminuria was recorded as 66.67%, 93.24%, 44.44% and 97.18% respectively. Those of uterine artery Doppler resistance index were 33.33%, 95.96%, 40% and 94.67% respectively. Diagnostic odd's ratio of micro-albuminuria and uterine artery Doppler resistance index were 27.600 and 11.833 respectively. Confidence interval and diagnostic odd's ratios show that uterine artery Doppler study is a better screening test amongst the two. Both the tests being non-invasive in nature and having high specificity and high negative predictive value can be utilised in community-based antenatal care for identifying women who need intensive vigilance. PMID- 23741820 TI - A community based study of health related quality of life of the elderly in urban India. AB - The increasing population of elderly and emergence of chronic diseases, which adversely affects their quality of life, have implications in form of rising burden on the health systems in developing countries like India. A study was conducted to know the common morbidities and their effect on the health related quality of life (HRQOL) of the elderly. A community based cross-sectional study was conducted and 200 subjects, selected by cluster sampling from central Delhi, India, were studied from April 2005-February 2006. A pretested, semi-structured questionnaire along with short form-36 (SF-36) survey was used for data collection. The data was analysed using Chi-square and Student's 't' test on SPSS 12 statistical software. There were 89 males and 111 females, majority (64.5%) between 60 and 69 years of the age, were included in the study; 68.0% men and 37.8% of the women were married at the time of the study. Mean number of morbidities was 2.25 and 71.5% subjects had at least one disability/impairment. Around 2.5% subjects reported their health being poor and, another 50% of worsening of their health in last one year. HRQOL score for people with and without chronic morbidity/disability was 51.8 and 73.5 respectively with mean being at 56.7 (p < 0.05). Most commonly affected HRQOL domains were role physical, physical functioning and general health. Scores decreased as the age increased with females having less mean scores than males (p < 0.05). The quality of life of elderly in urban India is severely affected by the disabilities, impairments and chronic morbidities. There is an immediate need for specific preventive and rehabilitative measures targeted on elderly to maintain their quality of life in this population in Delhi. PMID- 23741821 TI - Bone marrow examination in pancytopenia. AB - Pancytopenia is defined by reduction of all the three formed elements of blood below the normal reference. It may be a manifestation of a wide variety of disorders, which primarily or secondarily affect the bone marrow. Haematological investigation forms the bedrock in the management of patients with pancytopenia and therefore needs detailed study. The total number of cases studied were 100 over a period of two years in the department of pathology, JSS Hospital, Mysore. Megaloblastic anaemia (33%) was the commonest cause of pancytopenia. Other causes were nutritional anaemia (16%), aplastic anaemia (14%), hypersplenism (10%), sepsis (9%) and leukaemia (5%). Less common causes were alcoholic liver disease, haemolytic anaemia, HIV, dengue, systemic lupus erythematosus, viral hepatitis, disseminated TB and multiple myeloma. Most of the patients were in the age group of 11-30 years with a male:female ratio of 1.6:1.Generalised weakness and fatigue (88%) were the commonest presenting complaints. Haemoglobin level varied from 1 10 g/dl with majorIty (70%) of them in the range of 5.1-10 g/dI. TLC was in the range of 500-4000 cells/cmm. Most (34%) of them had 3100-4000 cells/cmm. Platelet count was in the range of 4000-1,40,000 cells/cmm. Reticulocyte count varied from 0.1%-15% with majority (82%) of them ranging from 0.1%-2%. The bone marrow cellularity was hypocellular in 14%, hypercellular in 75%, and normocellular in 11% of the patients. Pancytopenia is a relatively common entity with inadequate attention in Indian subcontinent. A comprehensive clinical and haematological study of patients with pancytopenia will usually help in the identification of the underlying cause. However in view of wide array of aetiologies, pancytopenia continues to be a diagnostic challenge for haematologists. PMID- 23741822 TI - Towards the innovation for microbiology curriculum change: students' perception. AB - For a medical curriculum to be an effective means of learning for today's students, it has to be designed with knowledge of their priorities, needs and abilities. This can be best achieved by inviting students' view-point during curriculum planning. The present study thus elicits opinion of the medical students through a randomly issued set of questionnaires, towards the present microbiology curriculum in order to quantitate from their view-point, the weakness as well as the strengths of the existing curriculum. Their evaluation reveals that they welcome new techniques like problem-based learning but at the same time emphasise the need to integrate what is taught in close association with clinical circumstance. Hence it is important to understand the minds and needs of our students before implementing the syllabus content across to the consumers. PMID- 23741823 TI - Tumours of minor salivary glands--a clinicopathologic study. AB - The salivary gland system comprises 3 pairs of major glands ie, parotid, submandibular and sublingual and also thousands of lobules of minor salivary glands dispersed in oral cavity, nasal cavity, maxillary sinuses and upper airways. Most of the studies on salivary gland tumours included both major and minor salivary glands. Objectives of this study were to see the age, sex and site distribution of minor salivary gland tumours as well as cytohistologic correlation during their diagnosis. The study is a retrospective one and done in the pathology department of Medical College, Kolkata taking the cases referred from ENT and Surgery departments in the period from April 2008 to March 2011. There were 123 cases of salivary gland tumours including both major and minor salivary glands in this study. Out of these, 21 cases of minor salivary gland tumours were selected and further analysed. There were 9 cases of benign and 12 cases of malignant tumours. Most benign cases were pleomorphic adenoma and most of malignant were adenoid cystic carcinoma affecting maximally males above 40 years of age. For malignant cases the cytohistologic correlation was 100% whereas in benign it was 70%. We had no need of using immunohistochemistry as histologic diagnosis were clear-cut. Pathologic staging were done in most of malignant cases thus helping the clinicians to adopt better treatment protocol. PMID- 23741824 TI - Changes in maternal lipid peroxidation before and immediately after delivery. AB - Oxidative damage has been implicated in pathogenesis of many diseases. It is known that various kinds of stresses accelerate the production of free radicals. As pregnancy being a physiological state accompanied by a high energy demand of many bodily functions and an increased oxygen requirement, increased level of oxidative stress would be expected. The present study was to elucidate the degree of oxidative stress during labour and immediately after delivery. Twenty healthy pregnant women and age matched and 20 healthy non-pregnant women were selected as subjects for this longitudinal study. Plasma malondialdehyde concentration was estimated as thiobarbituric acid reacting substances. A significant (p < 0.01) increase in plasma malondialdehyde concentration was noted in pregnant women during labour than in the non-pregnant women. Plasma malondialdehyde concentration was noted to increase with the progression and duration of labour to immediately following delivery. Labour being stressful state results in oxidative stress, which increased with increase in duration and progression of the labour till immediately following delivery. PMID- 23741825 TI - Late onset hypogonadism in type 2 diabetic and nondiabetic male: a comparative study. AB - Sexual dysfunction in diabetic men can result from a variety of causes of which late onset hypogonadism is now a recognised entity. The study described here was conducted to determine this entity by comparing diabetic men with age matched controls. A significant number of diabetic men had low levels of testosterone and free testosterone. Among the patients with low testosterone a large percentage had low pituitary gonadotrophic hormones signifying that the disorder was actually hypogonadotrophic hypogonadism. This finding was then correlated with various risk factors present in the diabetic patients and positive correlations were found for many parameters. PMID- 23741826 TI - Thyrotoxicosis induced liver disease: a case report. AB - Thyroid storm is a severe variety of thyrotoxicosis. It is an uncommon condition but can be fatal. Mildly raised serum bilirubin levels can be seen in up to 5% of patients with thyrotoxicosis, butmarked elevations are rare. The association of severe thyrotoxicosis with severe hepatic dysfunction hasbeen rarely reported. Here an interesting case of thyrotoxicosis induced liver disease which improved following aggressive treatment is reported. PMID- 23741827 TI - Melanotic neuro-ectodermal tumour of infancy. AB - A rare case of melanotic neuro-ectodermal tumour of infancy is presented. A 5 month-old child presented with rapidly progressing large swelling that almost filled up the opening of oral cavity. The vanillyl mandelic acid level was increased in the 24-hour urine sample of the child. Surgical excision was done and recovery was uneventful. PMID- 23741828 TI - Breast mass as a presenting feature of acute lymphoblastic leukaemia. PMID- 23741829 TI - A multicentric, open label, randomised, postmarketing efficacy study comparing multidose of lincomycin hydrochloride capsule 500 mg with multidose cefpodoxime proxetil tablet 200 mg in patients with tonsillitis, sinusitis. AB - Tonsillitis causes considerable short and medium term morbidity, and can be recurrent. Sinusitis can be acute (less than 4 weeks), subacute (4-8 weeks) or chronic (8 weeks or more). To study the comparative efficacy and safety of multidose treatments of lincomycin hydrochloride 500 mg capsules against cefpodoxime proxetil 200 mg tablets on its outcome in the Indian scenario are the aims and objective of the study. A total of 41 tonsillitis, sinusitis cases of either gender aged above 18 years were enrolled in the study. The diagnosis of sonsillitis, sinusitis was made based on examination of symptoms and throat swab. A randomised treatment of either lincomycin hydrochloride 500 mg capsules or cefpodoxime proxetil 200 mg tablets twice daily for five days alongwith other concomitant medications depending on related symptoms was given to 40 patients. At the end of study, all patients were re-evaluated and the response rate was assessed. The most common clinical symptoms were body temperature, headache, throat pain, postnasal discharge, mucopus, odynophagia, sinus tenderness, nasal congestion, pharyngeal congestion and tonsillar congestion. The overall response rate of lincomycin hydrochloride in all the symptoms except headache was more effective than cefpodoxime proxetil. Out of 100% (n = 20) patients in each group, 67.89% in lincomycin and 52.27% in cefpodoxime patients achieved complete relief, in all the clinical symptoms. The study suggests that lincomycin hydrochloride capsules, a conventional antibiotic indicates effective treatment for relief from tonsillitis and sinusitis, as compared to new third generation antibiotic. PMID- 23741830 TI - Neuro-oncology--a difficult problem in modern cancer management. PMID- 23741831 TI - Neuropathic pain and complex regional pain syndrome. PMID- 23741832 TI - Prevalence of diabetic foot ulcers in newly diagnosed diabetes mellitus patients. AB - Foot ulcer is one of the most common and dreadest complication of diabetes mellitus.This is also a frequent cause of hospitalisation and disability. Most of the patients with diabetic foot ulcers living in developing countries present to healthcare facilities fairly late with advanced foot ulcers because of poor economic status, inadequate knowledge of self-care, sociocultural reasons and poor and inadequate diabetes healthcare. To determine the prevalence of diabetic foot ulcers amongst the newly diagnosed diabetes mellitus patients (n = 1674) a cross-sectional study was carried out during the period January 2010 to January 2011 in the department of medicine, NRS Medical College, Kolkata. Diabetic foot ulcers were found in 4.54% newly diagnosed diabetes mellitus patients. Neuropathic type of foot ulcer was present in 46.06% of patients (52.5% in male and 38.88% in female). Ischaemic type of foot ulcer was present in 19.74% of patients (22.5% in male and in 16.66% females). Neuroischaemic type of foot ulcer was present in 34.2% of patients (25% in males and 44.44% in females). Neuropathy occurred most frequently either singly or with peripheral vascular disease. General awareness about the disease, early diagnosis and proper management will prevent this dreaded complication. PMID- 23741833 TI - Screening of hospital patients for HIV: an experience in a tertiary care hospital of West Bengal. AB - The clinical consequences of HIV infection encompass a wide spectrum. Early recognition of persons who have HIV will help in early interventions to halt or slow down the progress of HIV disease and to extend fruitful lives.This cross sectional study was conducted among patients referred to the voluntary counselling and testing centre (VCTC) from various departments in North Bengal Medical College & Hospital, Darjeeling, West Bengal, to find out the pattern of disease/symptoms, high risk behaviour (HRB) for HIV, and HIV serostatus among the hospital patients. Following the guidelines prescribed by the National AIDS Control Organisation (NACO), anonymous data were collected through interview from 407 individuals. Where specific diagnosis of a disease was obtained, it was analysed as mutually exclusive disease; and where specific diagnosis was not obtained, mutually exclusive symptoms were considered for analysis.The major diseases/symptoms observed among those patients were tuberculosis in 32.19%, STD in 29.97%, prolonged unexplained fever in 19.41% of patients. The overall rate of HIV seroreactivity was 17.44%. The HIV serostatus by disease/symptoms showed that 32.91% of patients with prolonged unexplained fever were HIV seroreactive; the rate was 12.90% among patients with skin diseases, 12.29% in STD and 12.21% in tuberculosis patients. Overall, 270 patients (66.34%) had HRB for HIV/AIDS.The rate of HIV seroreactivity was more among patients who had HRB for HIV/ AIDS and who were referred from indoor departments (23.24%) compared to outdoor departments (13.65%).The patients suffering from prolonged unexplained fever need greater attention for HIV screening. Early detection of HIV positive patients makes Intervention possible at a very early stage and this can slow down/block the progress of HIV disease and, as a result, can extend fruitful life. PMID- 23741834 TI - Update in diabetic neuropathy with special reference to Indian scenario. PMID- 23741835 TI - Critical illness neuropathy. PMID- 23741836 TI - Immune-mediated neuropathy. PMID- 23741837 TI - Management options in neuropathic pain. PMID- 23741838 TI - Did you choose the right suture material for skin closure in elective caesarean section? AB - Surgical incision should heal with first intension with minimum deformity. Pain perception during postoperative period (short term) and appreciation of scar (long term) are two key components assessed by patients after a caesarean section. The present study compares these parameters using absorbable and non absorbable material for skin closure using subcuticular stitch. The study shows a significant difference in pain perception on 1st postoperative week along with shorter duration of hospital stay and patients appreciation of scar quality on long term are significantly better in absorbable suture group. PMID- 23741839 TI - Association of diabetes and tuberculosis--a major public health challenge. AB - The burden of tuberculosis and diabetes is remarkably high in India. There is an increased risk for diabetic subjects to have active form of tuberculosis compared to their normal counterparts. The chance of reactivation of past tuberculosis infection is also common among the people with diabetes. In addition to that, few studies had reported that proportion of poor tuberculosis treatment outcomes such as treatment failure and death was higher in people with both tuberculosis and diabetes. A recent report from Tamil Nadu showed a very high prevalence of diabetes and prediabetes among tuberculosis patients. These findings strongly suggest the need of universal screening for diabetes among tuberculosis patients. There are several questions to be answered to assist in the formulation of strategies to address this dual burden in developing countries like India. The main purpose of the article is to summarise and discuss the available evidences and to define the area of future research to identify a cost-effective screening method for diabetes among tuberculosis patients and the best mode of reporting and managing the two diseases for the better control of tuberculosis and diabetes. PMID- 23741840 TI - Unusual presentation of metastasis in adenocarcinoma cervix. AB - Metastatic carcinoma in an abdominal wall incision from carcinoma cervix is an uncommon and often a preterminal event. It has been reported mostly in advanced cases, often previously treated with radiotherapy. Here a case of cervical cancer with subcutaneous and rectus sheath recurrence 4 months after abdominal hysterectomy in a previously unsuspected case of adenocarcinoma cervix is reported. The patient was treated with excision of the metastatic masses followed by chemoradiation and is doing well at 5 months since presentation. PMID- 23741841 TI - Rheumatic valvular insufficiency in Bardet-Biedl syndrome: a case report. AB - Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder with multisystem affection. Cardiac Involvement, when present is usually in the form of congenital heart disease. However, valvular involvement due to acquired heart disease is extremely unusual. Herein, a 10-year-old boy of Bardet-Biedl syndrome is reported who presented with multiple rheumatic valvular regurgitation. PMID- 23741842 TI - Xanthogranulomatous oophoritis: pathologic findings with clinical correlation. AB - Xanthogranulomatous inflammation is an uncommon form of chronic inflammation that destroys the affected organs. It is characterised by the presence of lipid laden macrophages, lymphocytes, plasma cells, neutrophils, multinucleate giant cells and foci of necrosis. Only a few cases of xanthogranulomatous Inflammation exclusively involving the ovary have been reported till date. The case presented here was associated with fever, abdominal mass and Escherichia coli infection. A knowledge of this entity is essential to avoid a misdiagnosis of malignancy and extensive surgery. PMID- 23741843 TI - Strangulated double omental hernia presenting as an epigastric lump. AB - Internal herniations constitute one of the relatively uncommon surgical emergencies. Among them double omental hernia with bowel strangulation is very rare and is a major diagnostic challenge. A case of a strangulated double omental hernia in a 42-year-old female patient is reported. The patient presented with a painful tender epigastric lump.There was a diagnostic dilemma. CT scan was followed by laparotomy which revealed a strangulated double omental hernia. PMID- 23741844 TI - Spindle cell sarcoma of the maxillary antrum. AB - Maxillary antral malignancies are mostly squamous cancers. Sarcomas in this region are rare. The head and neck region houses around 8.9% of all sarcomas and spindle cell sarcomas of the maxillary antrum had rarely been reported.The presentation, pathology, clinical findings, management and short term response to treatment of a left maxillary antral spindle cell sarcoma, in a Muslim, male tobacco chewer is reported here. PMID- 23741845 TI - Dysphagia--an uncommon presentation of unnoticed snakebite. AB - Snakebite cases do not always present with classical features of bite, resulting in delay in diagnosis and treatment with disastrous consequences, especially when bite occurs during sleep at night. Ptosis is the most common early symptom. Dysphagia, though not uncommon in cases of snakebite but presenting solely with this, is very rare. Here a case of a young man with complaints of only severe dysphagia without any history of bite is reported. He was treated as a case of neurotoxic snakebite poisoning and found to have recovered. PMID- 23741846 TI - Prevalence of HIV seropositivity among surgical patients. PMID- 23741847 TI - Let us be a little bit social also. PMID- 23741848 TI - Cancer pain. PMID- 23741849 TI - The final answer to cancer--a new horizon beckons. PMID- 23741850 TI - Cardiac surgery in octogenarians. AB - The incidence of cardiac surgery in elderly patients has been increasing. Recent studies have shown that cardiac surgical procedures performed in octogenarians, in otherwise good physical and mental health, can improve mortality, morbidity, and quality of life. This study aimed to describe the preoperative clinical and demographic characteristics associated with immediate postoperative outcomes and determine whether intra-operative factors related to surgical and cardiopulmonary by-pass techniques impacted upon these. The results of cardiac surgeries performed at BM Birla Heart Research Centre, Kolkata for patients older than 80 years were retrospectively analysed between January 2009 and September 2011. Out of 61 cases, rate of hospital death, prolonged stay (length of stay > 14 days), return to intensive care unit were as follows: 2 (3.2%), 30 (49.1%), 3 (4.9%). Eight patients (13.1%) developed pulmonary, 5 (8.1%) renal and 1 (1.6%) gastro intestinal complications. Two patients (3.2%) developed neurological defecit. Thus, newer techniques in cardiac surgical procedures are successful in most octogenarians with increased hospital morbidity, and longer hospital stay. PMID- 23741851 TI - Effect of organic loading rates and proton exchange membrane surface area on the performance of an up-flow cylindrical microbial fuel cell. AB - The effect of organic loading rates (OLRs) and proton exchange membrane (PEM) surface area on the performance of microbial fuel cells (MFCs) was evaluated. Three MFCs (MFC-1, MFC-2 and MFC-3) having PEM surface area of 10 cm2, 20 cm2 and 40 cm2, respectively, were used in the study. The MFCs were operated at influent chemical oxygen demand (COD) of 500 mg L(-1) and hydraulic retention time (HRT) of 20 h, 17 h, 13 h and 6 h in experimental Run-1 to Run-4. MFC-3, with highest PEM surface area showed highest power generation throughout the study. The optimum performancewas obtained at HRT of 13 h. In Run-5 and Run-6, the influent COD was increased to 1000 mg L(-1) and 1500 mg L(-1), respectively, maintaining the HRT at 13 h. Maximum volumetric powers of 4.26 W m(-3), 9.41 W m(-3) and 17.24 W m(-3) were obtained in MFC-1, MFC-2 and MFC-3, respectively, in Run-5 under the OLR of 1.84 kg COD m(-3) d(-1). These power values are among the higher values reported in literature; MFCs with higher PEM surface area showed better electricity generation, which clearly demonstrates that proton mass transfer is the main constraint in the MFCs which limits the power output. Combined effect of influent COD and HRT was found on electricity generation. PMID- 23741852 TI - Evaluation of methanogenic activity of biogas plant slurry on ossein factory wastes. AB - The objective of the present work was to evaluate the ossein factory wastes, which include primary clarified bone waste (PCBW) and sinews for methane production, by monitoring methanogenic activity of predigested biogas plant slurry. A specific methanogenic activity of biogas plant slurry (anaerobic seed) was measured at 38 degrees C using different proportions of ossein factory wastes in an assay medium. The pH of slurry was intensively maintained until course of digestion. A moderate proportion of both substrates showed a maximum methane production at 20 days of incubation in batch mode. However, a maximum cumulative methane yield achieved by biogas plant slurry on PCBW was low as compared to sinews. The best organic matter degradation was achieved even at a high proportion of ossein factory wastes used in digesters. These substitutes would be useful, without seriously reducing total gas production, for methane production if they partially mixed with cattle dung. As a result of this preliminary study, we suggest that ossein factory wastes are potential alternative sources for biogas production in ossein factory. PMID- 23741853 TI - Discritization of the Gaussian Plume model. AB - In general a plume is more known than a puff for stack emissions. A plume may be regarded as a number of puffs ejected out in quick succession. Conversely a continuous plume can be discritized (dissected) at intervals to form puffs. The main objective of the present study is to establish a relationship between a plume and a puff by dissecting the plume longitudinally and equating the contents of the segmented plume to a spheroidal shaped puff for different distances and stabilities to meet vagaries of weather. PMID- 23741854 TI - Determination of persistent organochlorine residues in a commercial fresh water catfish by GLC and study of their accumulation pattern. AB - Concentrations of various organochlorine pesticides in a commercial fresh water catfish, Heteropneustes fossilis, were measured. This study reveals possible toxicological exposure of human beings by way of consuming such fish containing pesticide and that will amount to possible exposure. Tissue extracts obtained by Soxhlet apparatus were used for analysis and the concentrations of analytes were determined by gas chromatography with electron capture detection. The major organochlorines found in blood sample were Endosulfan, Alpha-HCH, Beta-HCH and Gamma-HCH. However, the organochlorines found in edible portion of fish (i.e.flesh) were mainly--Endosulfan, Delta-HCH, Aldrine, pp-DDE etc. The concentrations of these organochlorines were at or above the theoretical threshold limit and hence are supposed to be effectively toxic to fish eaters, due to biomagnification. PMID- 23741855 TI - Accumulation of few heavy metals in sewage sludges, soils and plants of Coimbatore, Tamil Nadu (India). AB - A study was carried out in Coimbatore district of Tamil Nadu (India) to assess the distribution pattern of heavy metals in the soils and plants irrigated with sewage effluent/sludge. About 69 soil samples (surface and subsurface), 65 plant samples as well as 34-sewage sludge samples were collected from various tehsils of Coimbatore. Six tehsils in Coimbatore have been identified and categorized into two groups--Class I City (densely populated tehsils) and Class II city (thinly populated tehsils). The available micronutrients like Fe, Mn, Zn and Cu; heavy metals: Cr, Cd, Ni, and Pb were within the safe limits. However, the total Cr and Cd concentrations were relatively higher in the sludge samples collected from Coimbatore and Tiruppur tehsils compared to other tehsils, while for Ni, the sequence was in the order Coimbatore > Tiruppur > Palladam > Pollachi > Avinashi > Mettupalayam and for Pb, Coimbatore > Mettupalayam > Palladam > Tiruppur > Avinashi > Pollachi. Soil analysis results indicated that heavy metal concentration recorded higher level in soils of Class I city (densely populated tehsils) compared to Class II city (thinly populated tehsils). The plant samples analyzed had also registered higher concentration of total Cd, Ni and Pb, which were classified under toxic, excessive and below excessive level, respectively. Correlation analysis revealed that iron (Fe), zinc (Zn), copper (Cu), cadmium (Cd) and lead (Pb) were significantly negatively correlated with pH of soil. EC had a significant positive correlation with available iron (Fe), zinc (Zn), cadmium (Cd) and lead (Pb). A significant positive correlation of Fe, Mn, Zn, Cu, Cd and Pb was also registered with OC. Among the plant samples collected, it was evident that heavy metal concentrations were recorded higher in grass spp followed by Amaranthus spp. It was inferred from the study that soils samples had higher levels of heavy metals even though the values recorded were below the critical value/toxic limit. However, long-term and indiscriminate application of untreated (raw) sewage sludge and/or letting of sewage effluent directly to agricultural field without prior treatment may result in accumulation of toxic metals in surface and subsurface soils and subsequent biotransfer (bioaccumlation) into the food chain, it may further lead to toxicity not only to plants and animals but also to consumers of the harvested crops. PMID- 23741856 TI - Detection of heavy metal resistance bioluminescence bacteria using microplate bioassay method. AB - Effects of different heavy metals on Vibrio harveyi, V. fischeri, Photobacterium phosphoreum and P. leiognathi were examined. Checkerboard assay was used for the detection of the natural metal tolerance levels of a large number of marine luminous eubacteria. 57 strains of luminous bacteria were investigated for their natural patterns of heavy metal tolerance. The behaviors of these strains were not homogeneous with respect to all metals tested, even within the strains belonging to the same genus. At least 1 to 4 different MICs were detected for every metal except barium and cobalt. Isolated bacteria were tested for the presence of plasmids using the modified alkaline lysis method, was effective for identification of plasmids of different sizes. This study revealed the frequency of the occurrence of plasmids in heavy metal resistance bacteria and inferred that plasmids are highly ubiquitous and predominant in most heavy metal resistant bacteria. PMID- 23741857 TI - Effect of direct dyes effluent on germination/growth of maize and sorghum plants. AB - The effect of direct dyes effluent used for irrigation of maize and sorghum plants was examined in germination of seeds, shoot length, root length and chlorophyll contents. Studies were also carried out by irrigating these plants with 50% water diluted effluent sample and as such. Here effluent of four different colored direct dyes, i.e. Direct Red 28, Direct Yellow 12, Direct Orange 26 and Direct Blue 1 have been used for irrigation. On comparing the results with water (control), it was found that unexhausted dye and its concentration in the effluent leads to decrease in germination of the seeds, shoot length, root length, chlorophyll contents of the plants up to 44%, 55%, 45% and 48% respectively. PMID- 23741858 TI - Polycyclic aromatic hydrocarbons distribution and related carcinogenic potencies in roadside soil at major traffic intercepts within a developing city of Northern India. AB - The objective of the study was to ascertain contamination levels of soil with Polycyclic Aromatic Hydrocarbons (PAHs), their distribution behavior and human exposure during summer, winter and rainy seasons in one of the developing city of Jalandhar in the state of Punjab, India. PAHs concentration was measured at 10 different locations (within 3 m) in roadside soil, covering all major traffic intercepts of the city. Recovery range was between 30% and 70% with the lower value corresponds to the lower molecular weight PAHs compound. Identification and quantification of PAHs were done by GC-FID. Average PAHs concentrations (city average) were found to be 16.53, 4.04 and 7.82 microg g(-1), during summer, winter and rainy seasons respectively. Average concentrations of low and high carcinogenic PAHs during summer, winter and rainy seasons were found 5.1 and 31.29, 2.1 and 6.4, & 3.97 and 12.77 microg g(-1) respectively. The average ratios of low and high carcinogenic PAHs were found to be 1:6, 1:3 and 1:7.6 during summer, winter and rainy seasons at most intercepts. Dibenzo (ah) Anthracene and Benzo (a) Pyrene were the two individual PAH found in highest concentration during summer, winter and rainy seasons. It was worth also observed that high carcinogenic PAHs concentration was quite higher (around 85%) in comparison to low carcinogenic PAHs (around 15%) at most intercepts round the year. Five ringed PAHs were in highest concentration at all intercepts and seasons. PMID- 23741859 TI - Nitrate pollution in groundwater in some rural areas of Nalgonda district, Andhra Pradesh, India. AB - Intake of water with high concentration of nitrate is a major problem in many countries as it affects health of humans. The present study was carried out with the objective of determining the causes for higher nitrate concentration in groundwater in parts of Nalgonda district, Andhra Pradesh, India. The study area is located at a distance of about 135 km towards ESE direction from Hyderabad. Nitrate concentration in groundwater of this area was analysed by collecting groundwater samples from 46 representative wells. Samples were collected once in two months from March 2008 to January 2009. The nitrate concentration was analysed in the laboratory using Metrohm 861 advanced compact ion chromatograph using appropriate standards. The highest concentration recorded during the sampling period was 879.65 mg/L and the lowest concentration was below detection limit. Taking into consideration 45 mg/L of nitrate as the maximum permissible limit for drinking water set by BIS, it was found that 13.78% of the groundwater samples collected from this study area possessed nitrate concentration beyond the limit. Overall, wells present in agricultural fields had nitrate levels within permissible limits when compared to those groundwater samples from wells present in settlements which are used for domestic purpose. This indicates that the high nitrate concentration in groundwater of this area is due to poor sanitation facilities and leaching from indiscriminate dumping of animal waste. PMID- 23741860 TI - Influence of conjunctive use of coffee effluent and fresh water on performance of robusta coffee and soil properties. AB - A field experiment was conducted to study the influence of treated coffee effluent irrigation on performance of established robusta coffee, nutrient contribution and microbial activities in the soil. The results revealed that the field irrigated with coffee effluent from aerobic tank having COD of 1009 ppm, did not affect the yield of clean coffee (1309 kg/ha) and it was statistically similar (on par) with the plots irrigated with fresh water (1310 kg/ha) with respect to clean coffee yield. Effluent irrigation increased significantly the population bacteria, yeast, fungi, actinomycetes and PSB (122, 52, 12, 34 and 6 x 104/g respectively)) in the soil compared to the soil irrigated with fresh water (87, 22, 5, 24 and 2 x 10(4)/g respectively). The organic carbon (2.60%), available nutrients in the soil like P (57.2 kg/ha), K (401.6 kg/ha, Ca (695.3 ppm), S (5.3 ppm),Cu (4.09 ppm) and Zn(4.78 ppm) were also increased due to effluent irrigation compared to fresh water irrigation. Thus analysis of coffee effluent for major and minor plant nutrients content revealed its potential as source of nutrients and water for plant growth. PMID- 23741861 TI - Assessment of river water quality under urban influence: a case study. AB - In this study, the water quality status of river Solani in India was assessed under the influence of urbanization. Physico-chemical and biological analysis of water reflected maximum adverse impact during summer low flow season. Variation in river flows during monsoon, post monsoon and low flow seasons was found to substantially affect the river water quality regime. Whereas the monsoon season displayed addition of suspended impurities and provided dilution in the dissolved components, the summer low flow season revealed an anaerobic condition in the river as the entire river flow comprised of only drain effluents. All the drains were observed to carry contaminated water with impurities from various point and non-point sources emanating from diverse human activities. The present study indicated that the drain waste water deserves a prior treatment in order to protect the Solani river water from pollution. PMID- 23741862 TI - Morphometric analysis of Kunderu river basin, Kurnool district, A.P, India for watershed management. AB - Morphometric analysis has been carried out to assess the drainage characteristics of Kunderu river basin of India. The basin is mostly dendritic to subdendritic in nature. Bifurcation ratio of successive orders has shown a gradual decrease from one order to next and this is attributed to differences in rock types and stage of development. The high values for lower stream orders indicate that the lower streams are mostly found in mountainous and highly dissected areas and the low bifurcation ratio approaching a value of in higher order streams indicates the flow of these streams in a flat to rolling terrain. The drainage density ranged from 0.54 to 0.76 and stream frequencies ranged from 0.09 to 0.23 in Kunderu river sub-basins. The drainage density and drainage frequency are low, which indicate a higher recharge of groundwater and a higher transmissibity of aquifers. The low drainage density ranged from 0.54 to 0.76 for sub-basins and low stream frequencies ranged from 0.09 to 0.23 in Kunderu river sub-basins, indicating a higher recharge of groundwater. PMID- 23741863 TI - Nitrate contamination of shallow aquifer groundwater in the central districts of Punjab, India. AB - The increasing trend in nitrogenous fertilizer use and extensive irrigation in the agricultural production system in Punjab, India are the reasons of contamination of groundwater, which is the main source of drinking water. A study was conducted to determine the extent of nitrate-nitrogen (NO3-N) contamination of groundwater in the shallow aquifers of Ludhiana district. Pre and post-monsoon groundwater samples from hand pumps of 36 villages, located at or near the nodes of 6-12 km grid, were collected during the years 1998 and 1999 and were analyzed for NO3-N concentration. During the period of study, the NO3-N concentration in 34.7%, 37.5%, 15.3%, 11.1% and 1.4% of the groundwater samples was between 0-5 mg/L, 6-10 mg/L, 11-15 mg/L, 16-20 mg/L and 21-25 mg/L, respectively. Around 72% of the groundwater samples were safe and did not exceed the critical limit of NO3 N concentration (10 mg/L) prescribed for drinking water. Although, statistically no change in the mean NO3-N concentration level has been observed during the study period and is within the safe limit in most of the samples (72%), yet there is every possibility of further contamination of groundwater due to continuous high N-fertilizer use and over irrigation which necessitates judicious and efficient N-fertilizer and irrigation water use in Punjab (India). PMID- 23741864 TI - Microbial desulfurization of diesel by Desulfobacterium indolicum. AB - Recalcitrant organosulfur compounds such as Dibenzothiophene (DBT) and its derivatives in real petroleum fractions such as diesel cannot be removed by convectional hydrodesulfurization (HDS) treatment using metallic catalysts as well as extremes of conditions of high pressure and temperature. Biodesulfurization was identified as one of the possible routes for the removal of sulfur from middle distillate fractions of petroleum. The desulfurizing bacterium Desulfobacterium indolicum was isolated and subsequently identified by the Department of Botany and Microbiology, University of Lagos, Nigeria. The bacterium exhibited very high desulfurizing ability towards diesel at 30 degrees C and normal atmospheric pressure. The biodesulfurization of diesel by Desulfobacterium indolicum resulted in reduction of sulfur from 166.037 ppm to 33.412 ppm over a period of 72 hours. Gas chromatography analysis with a pulsed flame photometric detector revealed that the peaks of benzothiophene and dibenzothiophene significantly decreased after biodesulfurization. Thus, Desulfobacterium indolicum could effectively desulfurize diesel and therefore, may be a promising biocatalyst for practical biodesulfurization of diesel. PMID- 23741865 TI - Study of Ni uptake and its compartmentalization in Ni(r), Pd(r) and Ni(s)/ Pd(s) strain of Nostoc muscorum. AB - A Ni(r)20 and its analog Pd(r)20 mutant strain was obtained from its Ni(s)/Pd(s) (nickel and palladium sensitive) strain of Nostoc muscorum. Ni(r)20 and Pd(r)20 mutant strain of Nostoc muscorum was resistant to 20 microM Ni and Pd. Ni uptake was observed in Ni(s)/Pd(s), Ni(r)20 and Pd(r)20 mutant strain of Nostoc muscorum by treating with 120 microM Ni saturating concentration. Ni uptake was two fold more in Ni(r)20 cells (31.0 nmol microg(-1) protein) than the Ni(s) cells, however Pd(r)20 strain took less Ni (9.31 nmol microg(-1) protein). Phosphate uptake was also investigated to determine the poly phosphate synthesis. The cells of Ni(s)/ Pd(s), Ni(r)20 and Pd(r)20 strain were treated for four hours in 2mM K2HPO4 exposure. Phosphate uptake in Ni(r)20 strain was 1.8 fold more over Ni(s)/Pd(s), and was least in Pd(r)20 strain. Polyphosphate level was determined to better understand the Ni transport in Ni(s), Ni(r)20, Pd(r)20 strain. Polyp level was increased two fold in Ni(r) strain and least in Pd(r) strain followed by Ni(s) strain. Results based on the Ni distribution pattern in Ni(s), Ni(r)20, Pd(r)20 are the evidence that poly p is the main metal sink. PMID- 23741866 TI - Assessing the economic and environmental feasibility of utility scaled PV electricity production in the state of Georgia. AB - Photovoltaic (PV) technology, an increasingly popular source for renewable energy, is being deployed in places with solar insolation that is comparable to that in state of Georgia. This study assesses the feasibility and environmental impact of utility scale photovoltaic (PV) electricity production in Georgia by assessing the economic costs, avoided costs, health benefits, and environmental benefits. The cost of PV used in this study is 3.52 $/kW. The RETScreen model was employed to analyze the impact of incentives on the economic viability of the plants that produce 93 GWh, 371 GWh, and 1,484 GWh, respectively. 57% of the capital cost is required in the form of incentives or subsidies to make the projects economically feasible. The high estimated cost of cleaning the equivalent amount of emissions from a coal-fired power plant is $14.5 million, $58 million, and $232 million for a 50 MW, 200 MW, and 800 MW plant, respectively Avoided costs in health damages are estimated to be $28 million, $112 million, and $449 million and the numbers of jobs to be created are 2,500, 10,000, and 40,000 for 50 MW, 200 MW, and 800 MW plants, respectively. And, the cumulative value of renewable energy credits from a 50 MW, 200 MW, and a 800 MW plant are $59 million, $237 million, and $789 million, respectively. PMID- 23741867 TI - Study of the efficiency of immobilized algal technology for wastewater treatment. AB - The present paper deals with the study of efficiency of immobilized algal technology in wastewater treatment. The acclimatized algal species and wastewater samples were collected from three different sampling sites such as Kham River, Waluj [MIDC], Salim Ali Lake for the study. The encapsulation of collected algal species such as Spirogyra, Cyanobacteria in mixture form and Arthospira from selected sampling sites were made in sodium alginate for wastewater treatment. The percentage efficiency of immobilized algal technology for wastewater treatment was studied with respect to physico-chemical parameters. The physicochemical parameters were analyzed before and after treatment and compared for percentage efficiency study. The results obtained from present investigation reveal that the immobilized algal technology has maximum percentage efficiency in reduction of BOD, COD, Total Hardness, Total Alkalinity, Chloride. TSS, TDS and TSS. Whereas, the minimum fluctuations were found in pH and temperature. However, the immobilized algal technology is also useful to increase the dissolved oxygen concentration in wastewater treatment process. PMID- 23741868 TI - Municipal solid waste stabilisation by leachate recirculation. AB - The purpose of this study is to determine the impact of leachate recirculation on stabilisation of municipal solid wastes. The study was carried out by using two lab-scale landfill bioreactors containing approximately 10 kg of waste each, in order to follow waste degradation over 16 weeks of time period. The main difference between anaerobic recirculated and without recirculation bioreactors options is determined in leachate quality. Leachate quality is regularly measured by the means of pH, electrical conductivity, calcium, magnesium, total kjeldahl nitrogen, phosphate and chemical oxygen demand (COD). It has been observed that leachate recirculation is more effective on anaerobic degradation of solid waste than non-recirculated degradation. The leachate recirculated bioreactor appears to be the more effective option in the removal of COD by 89.93% and stabilisation of pH at 7.5. After 16 weeks of anaerobic degradation, waste stabilization seemed to have reached for the recirculated bioreactor. Therefore, further studies are required to determine the optimum operational conditions for leachate recirculation rates, also with the operational costs of recirculation for solid waste stabilisation. PMID- 23741869 TI - Vermi composting--organic waste management and disposal. AB - Solid waste is an unwanted byproduct of modern civilization. Landfills are the most common means of solid waste disposal. But the increasing amount of solid waste is rapidly filling existing landfills, and new sites are difficult to establish. Alternatives to landfills include the use of source reduction, recycling, composting and incineration, as well as use of landfills. Incineration is most economical if it includes energy recovery from the waste. Energy can be recovered directly from waste by incineration or the waste can be processed to produce storable refuse derived fuel (RDF). Information on the composition of solid wastes is important in evaluating alternative equipment needs, systems, management programs and plans. Pulverization of municipal solid waste is done and the pulverized solid waste is dressed to form a bed and the bed is fed by earthworms which convert the bed into vermi compost. The obtained vermi compost is sent to Ministry of Environment & Forests (MoEF) recognized lab for estimating the major nutrients, i.e. Potassium (K), Phosphorous (P), Nitrogen (N) and Micro nutrient values. It is estimated that 59 - 65 tons of wet waste can be collected in a town per day and if this wet waste is converted to quality compost, around 12.30 tons of vermi compost can be generated. If a Municipal Corporation manages this wet waste an income of over (see text symbol) for 0.8 9 crore per anum can be earned which is a considerable amount for providing of better services to public. PMID- 23741870 TI - Steel slag: a waste industrial by-product as an alternative sustainable green building material in construction applications--an attempt for solid waste management. AB - This investigation explores the possibility of utilizing granular slag as an alternative to fine aggregate (natural sand) in construction applications like masonry and plastering. Construction industry utilizes large volume of fine aggregate in all the applications which has resulted into shortage of good quality naturally available fine aggregate. Use of granular slag serves two fold purposes, i.e. waste utilisation as well as alternative eco-friendly green building material for construction. The investigation highlights comparative study of properties with partial and full replacement of fine aggregate (natural sand) by granular slag in cement mortar applications (masonry and plastering). For this purpose, cement mortar mix proportions from 1:3, 1:4, 1:5 & 1:6 by volume were selected for 0, 25, 50, 75 & 100% replacement levels with w/c ratios of 0.60, 0.65, 0.70 & 0.72 respectively. Based on the study results, it could be inferred that replacement of natural sand with granular slag from 25 to 75% increased the packing density of mortar which resulted into reduced w/c ratio, increased strength properties of all mortar mixes. Hence, it could be recommended that the granular slag could be effectively utilized as fine aggregate in masonry and plastering applications in place of conventional cement mortar mixes using natural sand. PMID- 23741871 TI - Phytostabilisation potential of lemon grass (Cymbopogon flexuosus (Nees ex Stend) Wats) on iron ore tailings. AB - The present pot culture study was carried out for the potential phytostabilisation of iron ore tailings using lemon grass (Cymbopogon flexuosus) a drought tolerant, perennial, aromatic grass. Experiments have been conducted by varying the composition of garden soil (control) with iron ore tailings. The various parameters, viz. growth of plants, number of tillers, biomass and oil content of lemon grass are evaluated. The studies have indicated that growth parameters of lemon grass in 1:1 composition of garden soil and iron ore tailings are significantly more (-5% increase) compared to plants grown in control soil. However, the oil content of lemon grass in both the cases more or less remained same. The results also infer that at higher proportion of tailings the yield of biomass decreases. The studies indicate that lemongrass with its fibrous root system is proved to be an efficient soil binder by preventing soil erosion. PMID- 23741872 TI - Osteo-dental fluorosis in relation to chemical constituents of drinking waters. AB - Study was conducted in 17 fluoride endemic villages to find out association between the prevalence and severity of osteo-dental fluorosis with different chemical constituents of drinking waters. These villages were arranged in 7 sets, each containing 2 to 3 villages with identical mean fluoride (F) concentrations in the range 1.0 to 5.8 mg/L but having different mean values of total hardness, alkalinity and nitrate (NO3) content in drinking water sources. A close association or relationship was found between the prevalence of fluorosis and the total hardness and alkalinity of potable waters. A low prevalence of fluorosis was found at low alkalinity and at high total hardness. But no specific association was observed between the prevalence figures of fluorosis with pH and NO3 levels which is also discussed in the present communication. PMID- 23741873 TI - Analysis of finit in urine sample using thin layer chromatography. AB - Finit is a common insecticide generally used to control a variety of insects in homes. Routinely it is analysed by Gas Liquid Chromatography (GLC) and High Performance Liquid Chromatography (HPLC). An attempt has been made to develop a new method for analysis of finit in urine samples using Thin Layer Chromatography (TLC) technique which is inexpensive, accurate and non-destructive. Finit was extracted from urine using solvent extraction methods and then identified on the TLC plates. For detection on developed plates, palladium chloride, silver nitrate, iodine vapour and bromophenol blue were used which successfully increased the sensitivity without dispensing with the simplicity of the method. The method developed is simple, inexpensive, accurate and non-destructive that allows for sensitive and reproducible analysis of finit. PMID- 23741874 TI - Solid and hazardous waste management practices onboard ocean going vessels: a review. AB - Shipping or carriage of goods play an important role in the development of human societies and international shipping industry, which carries 90% of the world trade, is the life blood of global economy. During ships operational activity a number of solid and hazardous wastes, also referred as garbage are produced from galleys, crew cabins and engine/deck departments stores. This review provides an overview of the current practices onboard and examines the evidence that links waste management plan regulations to shipping trade. With strict compliance to International Maritime Organization's MARPOL regulations, which prevents the pollution of sea from ships various discharges, well documented solid and hazardous waste management practices are being followed onboard ships. All ship board wastes are collected, segregated, stored and disposed of in appropriate locations, in accordance with shipping company's environmental protection policy and solid and hazardous waste management plan. For example, food residues are ground onboard and dropped into the sea as fish food. Cardboard and the like are burned onboard in incinerators. Glass is sorted into dark/light and deposited ashore, as are plastics, metal, tins, batteries, fluorescent tubes, etc. The residue from plastic incineration which is still considered as plastic is brought back to shore for disposal. New targets are being set up to reduce the volume of garbage generated and disposed of to shore facilities, and newer ships are using baling machines which compress cardboard etc into bales to be taken ashore. The garbage management and its control system work as a 'continual improvement' process to achieve new targets. PMID- 23741875 TI - Creating awareness of an evidence-based approach to urban design. AB - Urban Design is a framework of urban studies that helps to understand the behavior of a city and, thus, the reasoning of its formation in a multidisciplinary way. Appropriate design policies help to attain solutions to urban problems by minimizing development impacts and by optimizing socioeconomic values of inner-city environments. However, development impacts and socio economic values of an urban built-environment have a strong relationship with its spatial and organizational characteristics. That is, the pattern of the space organization itself helps to understand how the space is being used, and perhaps, what changes will make the space more interactive, usable, and environment friendly. This study explores the spatial and organizational characteristics of urban morphology in evaluating urban development impacts by using the theory of space syntax. Conclusions suggest that space syntax simulates the likely effects of urban development solutions and, consequently, helps to evaluate urban design policies with data-based evidence before making recommendations for capital investments. PMID- 23741877 TI - Leprosy Review from Professor Diana Lockwood. PMID- 23741876 TI - Children and leprosy. PMID- 23741878 TI - Biomarkers for leprosy: would you prefer T (cells)? AB - The need for rapid diagnostic tests that can be applied in non-expert settings may now be greater than ever before, due to changes in leprosy control programmes and the decrease in special expertise required for (early) diagnosis of leprosy. However, there is no test available that can detect asymptomatic Mycobacterium leprae infection or predict progression of infection to clinical disease. The characteristics of the leprosy disease spectrum, in which both cellular and humoral immunity against M. leprae determine the outcome of infection, are pre eminently suitable for development of tests that simultaneously detect biomarkers specific for both types of immune responses, thereby covering the complete immunological leprosy spectrum. Since publication of the M. leprae genome, many research groups have investigated the potential of M. leprae-unique antigens in serologic as well as T cell assays. Despite the early promise of the genome towards identifying antigens that induce M. leprae-specific T cells, it took more than a decade before promising candidates were identified. This review describes recent studies on M. leprae-specific T cell responses and discusses the application of measuring specific cellular mediated immune responses possibly combined with serologic responses in field-friendly tests for early diagnosis of M. leprae exposure and infection. PMID- 23741879 TI - The concurrent validity of the Amharic version of Screening of Activity Limitation and Safety Awareness (SALSA) in persons affected by leprosy. AB - OBJECTIVES: Leprosy is endemic in many countries and results in activity limitations. There is a need for assessment tools to guide professionals in their evaluation and choice of intervention in order to improve conditions for leprosy affected people. The purpose of our study was to evaluate the concurrent validity of the Amharic version of Screening of Activity Limitation and Safety Awareness (SALSA-am) scale with Amharic version of Disability of the Arm, Shoulder and Hand (DASH-am) questionnaire. DESIGN: Thirty-eight individuals with nerve damage due to leprosy completed the SALSA-am and DASH-am questionnaires. Spearman's rank correlation was used to determine relationships between SALSA and DASH scores. Specificity, sensitivity and accuracy were calculated. RESULTS: There was a good correlation 0.87 (P < 0.001) between SALSA-am and DASH-am scores. Sensitivity, specificity and accuracy were calculated with acceptable results. CONCLUSIONS: SALSA-am is considered a useful questionnaire for determining activity limitations in persons affected by leprosy, and showed good correlation with DASH am. The concurrent validity was considered good. PMID- 23741880 TI - BCG immunotherapy as an adjunct to chemotherapy in BL-lL patients--its effect on clinical regression, reaction severity, nerve function, lepromin conversion, bacterial/antigen clearance and 'persister' M. leprae. AB - BACKGROUND AND OBJECTIVE: Multidrug therapy in leprosy has failed to eliminate the problem of persister bacilli. Clearance of bacterial antigens is extremely slow which could predispose to continued nerve damage even after release from treatment. In the present study the immunomodulatory efficacy of BCG vaccine administered post-MDT in BL-LL leprosy patients was investigated in depth with a view to determining if augmenting chemotherapy with immunotherapy would help in faster clearance of M. leprae/antigens, bring down the level of persisters and minimise the occurrence/severity of reaction and nerve damage. METHODS: This is a placebo-controlled study in treated BL-LL patients. The patients are matched with respect to age, sex, bacteriological index and history of reaction, stratified and allocated to the two groups. One group (Gr A) received two doses of BCG MOSCOW (3-33 x 10(5) cells) and the other (Gr B) normal saline (0.85%), injected intra-dermally at 3 month intervals. The Primary outcomes assessed at the end of 6 months were bacterial/antigen clearance, lepromin conversion, granuloma clearance and the occurrence of persisters. The secondary outcomes were clinical regression, occurrence and severity of reaction and changes in nerve functions. MATERIAL: A total of 107 BL-LL patients comprised of 49 in Gr A and 58 in Gr B; of which 36 and 42 respectively completed the study as per protocol, and are included in the final analysis. FINDINGS: The study findings show that both the primary and the secondary out comes were comparable in the two groups. Two doses of BCG administered post-MDT (Gr A) did not significantly alter the level of persisters or help in hastening the bacterial/antigen clearance, clinical regression of lesions and granuloma clearance. Lepromin conversion rates were also comparable. While the frequency of lepra reaction/neuritis following the intervention was comparable, the severity of reactions was significantly higher in Gr A. On the positive side neural functions assessed by nerve conduction studies showed that deterioration of motor nerve conduction was significantly lower in the BCG arm. Since all patients developing moderate to severe reactions, immediately received a course of corticosteroids, it is possible that timely use of it might have helped. PMID- 23741881 TI - Pure neuritic leprosy in patients from a high endemic region of Colombia. AB - Agua de Dios was a leprosarium for leprosy patients' obligatory isolation (1872 1961). Its leprosy incidence is the highest in Colombia (1.5-7/10000). Relapses are common. Government grant of US$ 200 per month subsidy is available to patients with disabilities. Spontaneous consultation with neural symptoms is frequent and simulation to get the subsidy has to be considered. We studied 36 subjects (2007-2009), with ages from 29-78, 19 of them men, with neural symptoms of 6 months to 20 years evolution. All had clinical examination, bacteriological examination, skin and nerve biopsies, electromyography (EMG), PCR for M. leprae, IgM anti-PGL1, and lepromin A. All but two are household contacts of leprosy patients. Symptoms were hypoesthesia of the hands and feet, and difficulty using hands with loss of muscular strength. None had skin lesions. Three had thickening of ulnar nerve. Lepromin was positive in all; bacteriology and biopsies were negative in all. The speed and amplitude of neural conduction were altered in 34 patients; two women had normal EMG and were considered to be feigning the disease; 21 were diagnosed as PNL by clinical, epidemiological and EMG findings; five of them had a positive PCR and one, high titers for IgM anti PGL1. Nine other subjects had diabetes and six carpal tunnel syndrome (CTS). Slow progression of disease, the lack of neural enlargement and the neural biopsies without inflammation suggest that most of these patients could have spontaneously cured PNL, as happens with other cases of paucibacillary leprosy. Diabetes and CTS are important differential diagnoses of PNL. Patients were treated with MDT and received the state subsidy. PMID- 23741882 TI - A study on histological features of lepra reactions in patients attending the Dermatology Department of the Government Medical College, Calicut, Kerala, India. AB - OBJECTIVES: 1. To study and compare the clinical and histological features of Type 1 and Type 2 lepra reactions. 2. To document the histological patterns of Type 1 and Type 2 lepra reactions observed in the study population. DESIGN: Two year cross sectional study. Patients attending the outpatient department of our tertiary care hospital, during the 2 year study period with clinical evidence of Type 1 (T1R) or Type 2 (T2R) lepra reactions were included in this study after obtaining written informed consent. During this period 34 T1R patients and 14 T2R patients attended our hospital. Biopsies were taken from reacting skin lesions of all patients and histological features were studied. RESULTS: Dermal or intragranuloma oedema was evident in 50% of T1R patients and all of them had clinically severe reactions. The T1R patients showed three different histological patterns--pgrading reactions, downgrading reactions and reactions without upgrading or downgrading. Among T2R patients 8/14 showed neutrophil infiltration histologically, 5/14 showed no histological evidence of neutrophil infiltration and only one patient had features of neutrphilic vasculitis. Dermal oedema was seen in 11/14 cases. CONCLUSIONS: Histology revealing dermal or intragranuloma oedema on a background of leprosy granuloma favours the diagnosis of lepra reaction. A careful analysis of subtle variations in the cells constituting the granuloma may aid in differentiating between upgrading T1R, downgrading T1R or T1R without upgrading or downgrading. Histology can also be useful in distinguishing T2R from T1R, in the absence of typical erythema nodosum leprosum (ENL) lesions. Neutrophils are the major inflammatory cells in the former where as lymphocytes or macrophages predominate in the latter. We recommend that histopathological analysis should form an integral part of the evaluation of all lepra reactions. PMID- 23741883 TI - Clinical characteristics and outcome in multibacillary (MB) leprosy patients treated with 12 months WHO MDT-MBR: a retrospective analysis of 730 patients from a leprosy clinic at a tertiary care hospital of Northern India. AB - BACKGROUND: Shortened (12 months) multidrug multibacillary regimen (MDT MBR) was implemented in India in 1998, however there is yet a paucity of crucial data on its long-term outcome. OBJECTIVE: To assess the efficacy of 12 months MDT MBR in multibacillary (MB) patients at our centre. DESIGN: This was a retrospective study undertaken analysing the clinic records of 1210 patients registered at the leprosy clinic of our institute from 1999 to 2010. RESULTS: 730 MB patients were treated with 12 months MDT MBR over this period. High bacillary index (BI) > or = 3 + was observed in 313 patients at the time of registration. Four hundred and one (54.9%) patients experienced lepra reactions. Recurrent ENL was observed in only 14 patients which manifested even after 5 years of stopping treatment. Clinico-histological correlation was noted in 361 (49.5%) patients. During follow up period ranging from 9 months to 10 years, nearly all patients had clearance of skin lesions including histopathological/bacteriological improvement. Only 13 (1.7%) patients relapsed. CONCLUSIONS: All patients responded well with 12 months MDT MBR without significant side effects. The overall relapse rate was only 1.7%. Thus, the recommendation for 12 months MDT MBR for all MB patients is robust and operationally practical, a decision which seems logical. PMID- 23741885 TI - Bacterial load in the nose and its correlation to the immune response in leprosy patients. AB - INTRODUCTION: Leprosy, whose etiologic agent is M. leprae, has its clinical manifestations correlated with distinct immunologic forms. The mechanism of infectivity and dissemination of the disease are not completely known, although the nasal mucosa is supposed to have an important role in pathogenesis. OBJECTIVE: To correlate the clinical and bacteriological parameters with that of nasal biopsy and immunological tests, such as lepromin and ML-Flow results, in untreated leprosy patients. MATERIAL AND METHOD: Two hundred and twenty-two patients were evaluated, clinically classified and subjected to skin smear, nasal biopsy, ML-Flow, and Mitsuda test. RESULTS: 689% of the cases were borderline cases. Nasal biopsy revealed 91.4% positivity in those who had specific antibodies against M. leprae on blood sample. Lepromatous leprosy cases were 100% positive on ML-flow test, had a large involvement in the nasal mucosa (91%), positive skin smears (100%) and negative Mitsuda test. Nasal bacillary index showed a good correlation with ML-Flow and had similar results when compared to skin smear. The tests agreement was good, revealing that nasal biopsy can be reliable in the diagnosis of multibacillary clinical forms and in the evaluation of the immunological status of leprosy patients. CONCLUSION: The presence of disseminated bacilli in the nasal mucosa was similar to skin involvement, when correlated with Mitsuda test and ML-Flow. As a result, the role of nasal bacillary index may play an important role in the clinical and immunologic characterization of leprosy patients. PMID- 23741884 TI - Health related quality of life amongst people affected by leprosy in South Ghana: a needs assessment. AB - AIM: This study examined Health Related Quality of Life (HRQOL) among leprosy affected elderly people at three leprosoria located in South Ghana. METHODS: Seventy elderly people who have been cured of leprosy but were undergoing socio economic rehabilitation at three selected Leprosaria in the southern part of Ghana, were involved in this study. They comprised 31 female and 39 male adults with leprosy-related residual impairment and disability. The main outcome measure was a standardised HRQOL questionaire which comprised physical functioning, role functioning, social functioning, cognitive functioning, health perception and pain. Descriptive statistics of mean and standard deviation were used to summarize the data whilst relationships and comparisons among and between the variables were evaluated using linear regression analysis and independent t-test respectively. Alpha level was set at P < 0.05. RESULTS: The mean age of the participants was 59.7 +/- 13-5 years. The overall mean score of the subjects (40.9 +/- 7.6) on the six domains of the questionnaire was below average. The highest and lowest mean scores were obtained in social functioning (56.9 +/- 20.1) and physical functioning (15.0 +/- 25.1) domains respectively. All the domains were significantly and positively correlated (P < 0.05) with the overall HRQOL scores. Age had no significant relationship (P > 0.05) on any of the domains and the overall HRQOL scores. Male participants scored signicantly higher (P < 0.05) than their female peer on cognitive functioning and HRQOL. CONCLUSION AND IMPLICATION: This study demonstrated low QOL among the sampled elderly people affected by leprosy at the selected leprosoria, thus stressing the need for measures that could improve their health and socio-economic status within the settlements. PMID- 23741886 TI - A case of stigma in an urban metropolis in India. What new tools should be used? PMID- 23741887 TI - Borderline leprosy masquerading as cheilitis granulomatosa: a case report. PMID- 23741888 TI - Extensive ulnar nerve necrosis: a complication of tuberculoid leprosy. AB - Pure neural leprosy without cutaneous manifestations is a relatively rare manifestation of leprosy. It can present as a mono- or poly-neuritis with sensory and/or motor impairment. Neural leprosy may or may not be associated with thickening of the involved nerve. We report the case of a 14 year old boy with extensive ulnar nerve necrosis who was diagnosed to have tuberculoid leprosy. What makes this case unique is that we have here a case of pure neural leprosy with a single nerve turned 'necrotic'. PMID- 23741889 TI - Using methotrexate to treat patients with ENL unresponsive to steroids and clofazimine: a report on 9 patients. AB - Erythema nodosum leprosum (ENL) is a chronic recurrent systemic complication of multi-bacillary leprosy frequently associated with the development of neuritis, iritis, orchitis, arthritis and dactylitis. It is well managed by thalidomide, but thalidomide is not available in Bangladesh. The World Health Organization recommends high doses of clofazimine and prednisolone. About 19% of patients do not respond completely to this regimen or experience relapse when reducing steroid dosage. OBJECTIVE: We undertook this study to determine whether oral prednisolone combined with methotrexate was an effective and safe treatment regimen for individuals with ENL resistant to clofazimine and prednisolone. METHODOLOGY: Between September, 2006-June, 2011, we treated nine resistant ENL patients with a combination of prednisolone and methotrexate for 24-36 months with a mean duration of 30 months. RESULT: We observed improvement leading to persistent remission of ENL in all our patients. Adverse effects were mild weight gain, weight gain with facial swelling, folliculitis and extensive Pityriasis versicolor infection in one patient and crusted scabies in another. CONCLUSION: A combination of prednisolone and methotrexate was safe and effective in managing ENL not controlled by clofazimine and prednisolone. PMID- 23741890 TI - A cross sectional research on the height, weight and body mass index of children aged 5-6 years in Latvia and its secular changes during the last century. AB - AIM: To determine the main anthropometric parameters and their changes during the 20th and early 21st centuries for children aged 5-6 and to analyze the nutritional level of the population based on percentage. METHODS: 536 healthy Latvian 5 and 6 year old children were randomly selected and a cross sectional survey was carried out. To collect anthropometric data, the height and weight of each child was measured and BMI calculated. The Kolmogorov-Smirnov Goodness-of Fit test was used to assess the distribution of data; it was concluded, that the data for both boys and girls in both analyzed age groups fits a normal distribution. Using a t-test statistical tool, the results were compared to our previous study (1998/1999) and to the most significant national anthropometric investigations of the 20th century. RESULTS: During the last decade, the mean values of height and weight (for both boys and girls) have increased in both age groups. The mean BMI value increase for 6 year old boys and girls was not statistically significant (p > 0.05). The BMI mean values for 5 year old boys and girls have decreased (p < 0.05). In both age groups the highest percentage of children are of normal weight. In the past 10 years the proportion of 5 year old underweight children has increased, but the proportion of overweight children has decreased percentage-wise. In all analyzed age groups a little tendency towards increase of the percentage of obese children can be observed. From 1929 to 2007/2009, the overall mean values of height and weight have increased, but BMI mean values have decreased. CONCLUSION: Positive secular changes were observed in body height and weight during the past decade (p < 0.01) and century. The increase in BMI at the beginning of the 21st century in comparison to the end of the 20th century may possibly be facilitated by the increased occurrence of overweight, obesity and related diseases in Latvian children. However, the number of underweight children has increased in the last decade as well. PMID- 23741891 TI - Effects of supervised vs non-supervised combined aerobic and resistance exercise programme on cardiometabolic risk factors. AB - OBJECTIVE: We examined the effect of a 6-month combined aerobic and resistance training programme on cardiometabolic risk factors in nondiabetic subjects and compared its effectiveness when executed under strict professional supervision or without direct supervision. METHODS: Eighty-five sedentary, non-diabetic subjects (27 men and 58 women), mean age 47.5 +/- 0.6 years, mean body mass index (BMI, 33.8 +/- 0.6 kg/m2) participated in a combined exercise programme assigned to supervised (S, n = 31), non-supervised (NS, n = 24) or control group (C, n = 30). Cardiometabolic risk parameters were assessed at baseline and after the 6-month training. RESULTS: In both the S and NS group there was a significant decrease in BMI (-1.6 +/- 0.3, p < 0.001 and -1.0 +/- 0.3 kg/m2, p = 0.004), waist circumference (-10.1 +/- 1.1 cm, p < 0.001 and -7.8 +/- 0.8 cm, p < 0.001), fat mass (-1.8 +/- 0.4%, p < 0.001 and -2.1 +/- 0.6%, p = 0.003), and a significant increase in fat-free mass (+1.7 +/- 0.4%, p < 0.001 and +2.0 +/- 0.7%, p = 0.008), and aerobic capacity (+6.9 +/- 1.1, p < 0.001 and +6.9 +/- 0.8 ml/kg per min, p = 0.008). Fasting glucose did not change in S and NS, but increased in C (p = 0.048). In the S group a significant decrease in fasting insulin (p < 0.001), homeostasis model assessment of insulin resistance (p < 0.001), highly sensitive C-reactive protein (p = 0.004), leucocytes count (p = 0.04), systolic high (p < 0.001) and diastolic (p = 0.009) blood pressure was found. Comparable significant decreases in total and low-density lipoprotein cholesterol were observed in all study groups. CONCLUSIONS: A 6-month combined exercise programme led to substantial improvement of various cardiometabolic risk factors. This programme was effective even when executed without direct supervision, although the effects were more pronounced in the supervised group. Our findings suggest that non-supervised exercise programmes may be a valuable, cost-effective tool to translate the current physical activity guidelines in a real-life setting. PMID- 23741892 TI - WHO issues new guidance on dietary salt and potassium. PMID- 23741893 TI - Lung cancer trends in Southeastern Serbia. AB - The aim of the study was to assess recent changes in lung cancer incidence and mortality trends in the male and female population in Southeastern Serbia, in the period 1999-2008. Data used for analyses were provided by the Cancer Registry of the Institute for Public Health, Nis. Incidence and mortality trends were based on crude and age-standardized incidence and mortality rates for the period 1999 2008. Standardized rates were calculated by the direct method of standardization (per 100,000), using the world population as the standard. Statistical significance was checked on the basis of correlation coefficient (r) for probability (p) on the level of 0.05. A total of 3,128 new cases and 2,327 deaths from lung cancer were registered (males/females ratio is 4:1). In males, the crude (107.94) and the age-standardized incidence rate (59.88) were four-fold higher than in females (27.10 and 14.21). In males, the crude mortality rate was four-fold higher than in females (80.61 vs. 19.87), while the age-standardized mortality rate was four and a half higher than in females (43.78 vs. 9.54). Lung cancer incidence trend, based on crude and age-standardized incidence rates, in females was increasing while in males was decreasing. Lung cancer mortality trends, based on crude and age-standardized incidence rates, were increasing in both sexes. Registration of unfavourable incidence and mortality trends of lung cancer indicate failure in primary and secondary prevention in the past. It is thus of vital importance to provide much intensive and comprehensive activities for primary and secondary prevention of lung cancer in the future, including education and rigorous tobacco control as well. PMID- 23741895 TI - Protocol to eliminate illicit trade in tobacco products opened for signature. PMID- 23741894 TI - Regional and ethnic aspects of viral hepatitis B among pregnant women. AB - OBJECTIVES: The aim of this study was to determine the prevalence of HBV infection among pregnant women in districts of Eastern Slovakia with a diverse prevalence of Roma population. METHODS: Overall 59,279 serum samples from 9 regional departments of clinical microbiology from Eastern Slovakia were collected in the period from January 2008 till December 2009 and analysed. RESULTS: The number of HBsAg positive samples overall and during pregnancy was 1.74% and 2.12%, respectively. Comparing districts with higher (> 5%) and lower (< 5%) Roma population, there was no significant difference in the prevalence of HBsAg positive samples overall (1.95% vs.1.62%). However, in the subgroup of pregnant women the prevalence of HBsAg positive samples (2.72% vs. 0.95%) differs significantly (p < 0.01). CONCLUSIONS: The prevalence of HBV infection among pregnant women in Eastern Slovakia did not rapidly exceed the estimated nationwide prevalence. However, in districts with higher Roma population the expected higher prevalence of HBV infection was confirmed. This indicates the need to pay special attention to the prevention of hepatitis B in these districts. PMID- 23741896 TI - Prevalence and genotyping of the human papillomavirus in the cervical specimens among women of Southern Croatia (Dalmatia County). AB - AIM: The aim of this study was to evaluate the prevalence of HPV types in the female population with either normal or abnormal Pap smears in Southern Croatia (Dalmatia County) and to evaluate the distribution of HPV types and their association with different cytological findings. METHODS: During one year period, we routinely screened 1,160 women for HR HPV at the Educational Public Health Institute of Split and Dalmatia County, by using Hybrid Capture 2 HPV DNA test. Only HR HPV positive specimens determined by HC2 were further genotyped by polymerase chain reaction (PCR) based assay at the Department of Pathology and Forensic Medicine, Split. RESULTS: Out of the total number of tested women, 406 (35%) of them were positive to HR HPV. The following frequency was observed: HPV 16 in 10.8%, HPV 18 in 7.8%, HPV 31 in 2.3%, HPV 33 in 1.1%, HPV 52 in 0.9%, HPV 45 in 0.6%, and HPV 59 in 0.4% specimens. CONCLUSION: The data obtained from our study indicate that HPV 16 is the most common HPV type found in the cervical specimens among women of Southern Croatia, as in most studies worldwide, followed by HPV 18 and HPV 31. The positivity rates in our study slightly differed for HPV types 18 and 31 from those found in the other studies conducted in Northern Croatia. These suggesting geographic and environmental factors are related to the prevalence of HPV types. We consider it very important to gather information on regional variations in the HPV type spectrum. PMID- 23741897 TI - Influence of gestational exposure on the effects of prenatal exposure to methyl mercury on postnatal development in rats. AB - Fish and other aquatic organisms are important source of dietary proteins for the human population. Fish meat, however, is contaminated with methyl mercury (MeHg), a potent neurotoxin. The well known Minamata and Niigata epidemic outcomes in Japan have raised the awareness of the health risk resulting from consumption of fish (and shellfish) from water basins polluted with industrial wastes containing mercury. In the present study, pregnant rat dams were exposed to environmental toxic elements--methyl mercury, 1000-1200 h, daily from the fifth gestation day (GD5) till parturition. Three groups of animals were given, by gavages, MeHg (0.5, 1.0 and 2.0 mg/kg/day) and control group received 0.9% saline at the same time. All animals were allowed to deliver and wean their offspring. Pups were evaluated for early development effects. There was a significant effect of treatment on somatic growth such as reduction in percentage of maternal weight gain (20.62%) at higher dose level whereas there was no change in percentage of live birth (100.00%) with 0.5 and 1.0 mg/kg dose treatment groups. There was a significant increase in the percentage of resorption (100.00%) per litter with 2.0 mg/kg/day MeHg dose. Average gestation length (days) and percentage resorption per litter or percentage foetuses/malformations per litter were not affected at 0.5 and 1.0 mg/kg/day dose level. The results of the study confirmed the high-teratogenic potential of MeHg and the need of payng increased attention to MeHg concerning its exogenous use during pregnancy. PMID- 23741898 TI - Seasonal folate serum concentrations at different nutrition. AB - Folic acid (vitamin B9) rich sources are leafy green vegetables, legumes, whole grains, egg yolk, liver, and citrus fruit. In winter and early spring, there could be insufficient supply of vegetables and fruit and thus lower intake of folic acid and possible deficient folic acid blood concentrations. The aim of the study was to assess serum vitamin B9 concentrations depending on the season (the last third of winter - March, the last third of spring - May/June and the beginning of autumn - September) and different nutritional habits (apparently healthy adults non-smoking, non-obese 366 subjects; 204 persons of general population on traditional mixed diet; and 162 long-term lacto-ovo vegetarians). In general population group, the mean concentration of folate in March was low (narrowly above lower reference limit) with high incidence of deficient values - 31.5%. In May/ June vs. March was folate concentration significantly higher with deficient values in 13.2% of individuals. The highest serum values were observed in September with 11.1% of deficient values. In vegetarian vs. non-vegetarian group, significantly higher folate concentrations were found in each season with no deficient values. Folate and vitamin B12 are the regulators of homocysteinemia; plant food lacks of vitamin B12. The deficient folate serum values in March caused the mild hyperhomocysteinemia in 12.3% of individuals vs. only 5.9% and 4.8% of subjects in groups investigated in May/June and September. In spite of high folate concentrations in all investigations and no deficient value, 19.6-22.8% of vegetarians suffer from mild hyperhomocysteinemia as a consequence of deficient vitamin B12 concentrations in one quarter of subjects. As far as the general population is concerned, our findings suggest that winter and early spring are critical seasons in regards to optimal serum folate concentrations. PMID- 23741899 TI - Dental caries experience in Croatian school children in Primorsko-Goranska county. AB - BACKGROUND: Dental caries as an infectious disease is still a major oral public health issue. As documented in some recent studies, it has been recognized as the most common chronic childhood disease. AIM: The aim of this study was to evaluate caries prevalence, DMFT and dmft scores, as opposed to caries free children at the age of 6 years from a well developed western region of Primorsko-Goranska county. The purpose was also to evaluate a Significant Caries Index (SiC) and a Restoration Index (RI) in the same study sample of 6 year olds. METHODS: Data for a sample of 1,825 (868 girls and 957 boys) children was collected and analyzed by using Chi-square and Mann-Whitney U Tests. RESULTS: Results showed that the mean dmft was 4.68 +/- 4.19, and the mean DMFT was 0.22 +/- 0.69. D/d component constituted a major part of caries score (DMFT/dmft) in both primary and permanent dentitions in the population of 6 years old children. Caries prevalence was 74.5 in primary dentition and 11.9 in permanent dentition. Significant Caries Index value (SiC) was 0.66 for permanent and 9.6 for primary teeth, respectively. The Restoration Index (RI) was 20.1 for primary and 39.5 for permanent dentition. CONCLUSION: The results obtained in this study revealed that dental caries still appears to be quite a significant problem among 6 year olds. However, collected data, particularly considering the SiC Index, can be used for further planning of preventive and restorative dental treatments as well as setting up future goals for the prevention of dental caries in Croatian school children of Primorsko Goranska county. PMID- 23741900 TI - Caries prevalence in chronic alcoholics and the relationship to salivary flow rate and pH. AB - AIM: The aim of this study was to investigate the dental status of alcoholics; to evaluate the relationship of unstimulated and stimulated saliva pH on their decayed/missing/filled teeth (DMFT); and to evaluate the relationship of unstimulated and stimulated salivary flow rate on their DMFT. METHOD: A cross sectional study was conducted in patients treated for alcohol dependency (n = 70; mean age 41.7 years) and a control group of non-alcoholics (n = 70; mean age 39.1 years). Examinations for dental caries were conducted using the World Health Organization (WHO) criteria and questionnaires. The correlation between nominal variables was determined using chi2 test (alpha = 0.05). The correlation between interval variables was determined using Pearson's correlation coefficient. RESULT: The mean DMFT was similar in alcoholics (14.40) and the control group (13.44) (p > 0.05). There was a statistically significant correlation between alcoholism and unstimulated salivary flow rate (p < 0.05), but no relationship on DMFT was recorded. No statistically significant differences were found between alcoholics and controls in terms of stimulated salivary flow rate (p > 0.05) or stimulated salivary flow on DMFT (p > 0.05). There was a statistically significant correlation between alcoholism and the pH value of stimulated saliva (p < 0.01). There was no correlation between the amount of alcohol consumed and the number of carious lesions (p > 0.05). CONCLUSIONS: No major differences were found with respect to overall DMFT in alcoholics compared to the control group. Alcoholism and stimulated salivary flow rate showed no correlation. Unstimulated salivary flow rate as well as the pH values of both unstimulated and stimulated saliva, were lower in the alcoholic group. PMID- 23741901 TI - The GAy MEn Sex StudieS: design of an online registration of sexual behaviour of men having sex with men and preliminary results (GAMESSS-study). AB - BACKGROUND: There has been limited investigation of the sexuality and sexual dysfunction in homosexuals by the sexual medicine community. The purpose of this article is to describe the methodology of the online GAy MEn Sex StudieS (GAMESSS) on the sexual behaviour and sexual dysfunctions of Belgian men who have sex with men (MSM). AIM: To describe the methodology of an online study that investigate sexual behaviour and sexual function and dysfunction in a sample of Belgian MSM. METHODS: An internet-based survey on sexual behaviour and sexual dysfunctions was administered to MSM between April and December 2008. The questionnaire was a compilation of the Kinsey Scale for Sexual Orientation, the Index of Premature Ejaculation (IPE), the Erection Quality Scale (EQS), the Female Sexual Function Index (FSFI), the Brief (Male) Sexual Function Inventory (BSFI) and the Gay Men Sexual Addiction Screening Test (G-SAST). The analytic sample comprised 1,830 Belgian men aged 18 years or older, who reported having sex with men. CONCLUSION: The use of an online questionnaire is a convenient way to gather information from a hidden population such as MSM. The anonymity of the participants is guaranteed. The collected data can be easily analyzed. With this online study, we aim to detect variables in sexual behaviour (SB) and sexual dysfunction (SD) that can help to improve care for MSM. Belgian MSM have a very active and varied sex life. They are rather promiscuous and do not always practice safe sex. This behaviour poses a high risk of spreading sexually transmitted diseases. Additional research in this MSM population is needed. PMID- 23741903 TI - The public health service in the Czech and Slovak Republics celebrates its 60th anniversary. PMID- 23741902 TI - Knowledge, attitudes and behaviour towards sexually transmitted diseases in Turkish Cypriot adolescents. AB - BACKGROUND: The incidence of sexually transmitted diseases (STDs) is increasing among adolescents all around the world. There may be differences in knowledge and attitudes among different cultures and ethnic populations. The aim of this study is to determine knowledge, attitudes and behaviour of Turkish Cypriot adolescents related to STDs. OBJECTIVES: To assess knowledge of STDs, attitudes towards sexual behaviour and STDs among the secondary school students. METHODS: A cross sectional study, with a sample size of 423 students, was conducted by using a semi-structured questionnaire. Simple random sampling method was applied during the selection of the sample. RESULTS: The mean age of all participants was 15.61 +/- 1.22, 211 (49.88%) of them were male and 212 (50.12%) female. The majority of students (91.25%) stated that they had some knowledge about STDs; hovewer, 8.75% of the participants did not have any knowledge at all. Most of them, 42.32% described school as a source of information on STDs, nonetheless, only 7.57% of the group cited health care professionals as the information source. The majority of students (97.64%) has never been treated for STDs. Among 423 applicants, 93.14% indicated that they would have appreciated information about STDs during the high school years. CONCLUSIONS: There is a general understanding that the students are willing to participate and are in need of seminars that will be held about STDs during high school attendance. Furthermore, awareness raising educational events on this matter should be reviewed and revised in order to come up with more powerful ways of fighting against STDs transmission in this young population group of Turkish Cypriot (TC) community. PMID- 23741904 TI - "Hunt's attack hurt and confused congress". PMID- 23741905 TI - A&E nurses warn growing crisis. PMID- 23741906 TI - "The link between understaffing and neglect must not be ignored". PMID- 23741907 TI - Continence care is every nurse's business. AB - Maintaining continence lies at the heart of a sense of adulthood and is essential to preserving dignity, a core and universal nursing value. This article explores the reasons why poor continence care was found at Mid Staffordshire Foundation Trust, the changes to the culture of the health service that led to it, and why it is so important for nurses to maintain patients' dignity. Recommendations for changing this culture in the future are discussed. PMID- 23741908 TI - Digital removal of faeces. AB - Defecation is essential to enable us to eliminate waste and keep our bowels functioning. In some individuals, defecation is not possible without an intervention. This might be oral medication, such as laxatives to soften the stool and propel the faeces round the colon, or digital removal of faeces (DRF) by a competent health professional on a regular basis. This article considers who needs DRF, who can carry it out, the ethical and legal implications, and the importance of appropriate bowel care being carried out in all care settings. PMID- 23741909 TI - Any qualified provider: facilitating patient choice. AB - When patients are referred to specialist services, it is important they have the opportunity to choose a service that best suits their needs. To make this a reality, the government has introduced. Any Qualified Provider (AQP)--referrers can show their patient a list of appropriate services that meet standard requirements. This article explains how an AQP pack was developed for continence services. PMID- 23741911 TI - Generous gifts of free time. PMID- 23741910 TI - Use of process mapping in service improvement. AB - This article, the last of our three-part series on change management tools, analyses how process mapping can be used to show how processes are currently carried out and identify any changes that may improve the patient experience. The tool takes into account patient opinions so staff are able to see the pathway from patients' perspectives. It offers advice on how to write up the results and how they can be analysed to identify where changes can be made. PMID- 23741912 TI - Transforming trouble into triumph. PMID- 23741913 TI - Dr. Otto U. King: small-town dentist, world-wide impact. PMID- 23741914 TI - Birds. PMID- 23741915 TI - Location, vocation, vacation. PMID- 23741916 TI - How to open a new dental office or relocate your current one: a journey through the dark side of dentistry. PMID- 23741917 TI - Editors picks: top 5 new items for patient swag bags. PMID- 23741918 TI - Through the patients' eyes. PMID- 23741919 TI - Wisdom for running an exceptional dental practice. PMID- 23741920 TI - Join the digital party: what's really holding you back? PMID- 23741921 TI - Emerging trends in dentistry: sleep disordered breathing therapy. PMID- 23741922 TI - Laser periodontal therapy for bone regeneration. PMID- 23741923 TI - Laugh often, long and loud. PMID- 23741924 TI - Let the ball come to you. PMID- 23741925 TI - Pancreatic adenocarcinoma: general histological overview. AB - In Belgium, approximately 1100 new cases of pancreatic ductal adenocarcinoma are diagnosed each year. Although in the last twenty years several advances have been registered in the field of pancreatic pathology, few therapies are efficacious, and it remains one of the deadliest of all cancers. Histological variants with a somewhat different prognosis have been recognised, and precursor lesions identified. This article reviews the histological aspects of ductal adenocarcinoma, its variants and the precursor lesions. Study and knowledge of these precursor lesions offers the best hope for treating pancreatic cancer before an incurable invasive tumour develops. PMID- 23741926 TI - Training models in laparoscopy: a systematic review comparing their effectiveness in learning surgical skills. AB - BACKGROUND: Surgery has traditionally been learned on patients in the operating room, which is time-consuming, can have an impact on the patient outcomes, and is of variable effectiveness. As a result, surgical training models have been developed, which are compared in this systematic review. METHODS: We searched Pubmed, CENTRAL, and Science Citation index expanded for randomised clinical trials and randomised cross-over studies comparing laparoscopic training models. Studies comparing one model with no training were also included. The reference list of identified trials was searched for further relevant studies. RESULTS: Fifty-eight trials evaluating several training forms and involving 1591 participants were included (four studies with a low risk of bias). Training (virtual reality (VR) or video trainer (VT)) versus no training improves surgical skills in the majority of trials. Both VR and VT are as effective in most studies. VR training is superior to traditional laparoscopic training in the operating room. Outcome results for VR robotic simulations versus robot training show no clear difference in effectiveness for either model. Only one trial included human cadavers and observed better results versus VR for one out of four scores. Contrasting results are observed when robotic technology is compared with manual laparoscopy. CONCLUSION: VR training and VT training are valid teaching models. Practicing on these models similarly improves surgical skills. A combination of both methods is recommended in a surgical curriculum. VR training is superior to unstructured traditional training in the operating room. The reciprocal effectiveness of the other models to learn surgical skills has not yet been established. PMID- 23741927 TI - Laparoscopic repair of primary ventral hernias: a series of 118 consecutive patients. AB - BACKGROUND: The aim of that study is to assess the surgical outcomes after laparoscopic repair of primary ventral hernias (PVH). METHODS: The series consisted of 118 consecutive patients presenting with PVH (13 epigastric and 105 umbilical hernias) operated between 2001 and 2010 by laparoscopy. Surgical repair consisted in intraperitoneal placement of a Parietex composite mesh centred on the defect with a minimum overlapping of 3 cm. The mesh was secured to the abdominal wall with a double crown of helical tacks alone or by an association of transfascial sutures and tacks. Patients' data were recorded prospectively. All patients were checked during office visit one month and one year after surgery and thereafter periodically evaluated by phone call. RESULTS: There were 32 women and 86 men with a mean age of 53 +/- 12 years and a body mass index (BMI) of 32 +/- 5. The median width of the defect was 2 cm (range : 1-6 cm). There was no conversion to open surgery. The mean operative time was 44 +/- 18 min. and the hospital stay 2 +/- 1 days. We noted 7 (6%) postoperative complications: 6 seromas and 1 hypodermitis. One month after surgery, no umbilical skin necrosis was observed and 102 patients (84%) considered the cosmetic result as excellent. With a mean follow-up of 66 +/- 37 months, no complication related to the use of the mesh was recorded and the recurrence rate was 3% (4/118). Predictive factors of recurrence were: BMI > or = 35 (14% (4/29), p < 0.001), mesh overlapping < 5 cm (20% (3/15), p < 0.002) and mesh fixation by tacks alone (8% (4/48), p < 0.05). CONCLUSION: Laparoscopic PVH repair is associated with very low morbidity, excellent cosmetic result and a recurrence rate of 3%. Improvement in surgical repair technique with systematic use of transfascial sutures and mesh overlapping > or = 5 cm should decrease the recurrence rate especially in obese patients. PMID- 23741928 TI - Lessons learned after more than 400 laparoscopic ventral rectopexies. AB - BACKGROUND: Laparoscopic ventral recto(colpo)pexy (LVR) is a minimally invasive, autonomic nerve-sparing technique to treat rectal prolapse syndromes. The position of the mesh on the anterior aspect of the rectum in the rectovaginal septum allows correction of concomitant rectocele and enterocele. METHODS: Demographic, perioperative, and follow-up data of consecutive patients were analyzed in order to audit our 10-years' experience with the technique. RESULTS: From January 1999 to December 2008, 405 patients (93% female) underwent LVR for internal rectal prolapse (45.9%, n = 186), total rectal prolapse (43%, n = 174) and rectocele or enterocele (11.1%, n = 45). Mean age was 54.6 years (SD 15). The median hospital stay was 4 days (range 2-21). Conversion rate was 2%. There was no postoperative mortality. At a mean follow-up of 25.3 months, recurrence was observed in 4.6% (19 patients). Most often detachment of the mesh at the sacral promontory was found. Late complications occurred in 18% of patients. In five patients, LVR combined with perineotomy was complicated by mesh erosion into the vagina. Mesh erosion was not observed after LVR without perineotomy. Symptomatic improvement was observed in 85% of patients with total rectal prolapse and in 70% of patients with internal rectal prolapse (p < 0.050). The difference was mainly due to a lesser effect on obstructed defecation symptoms. CONCLUSIONS: LVR, with or without perineotomy, appears to be safe and feasible, with relatively low morbidity. Functional outcome data support its efficacy. The indication for LVR in patients with internal rectal prolapse could be optimised. PMID- 23741929 TI - Comparison of extended hemicolectomy versus transverse colectomy in patients with cancer of the transverse colon. AB - BACKGROUND: Cancer of the transverse colon is rare and postoperative mortality tends to be high. Standard surgical treatment involves either extended hemicolectomy or transverse colectomy, depending on the location of the tumour. The aim of the present study was to compare postoperative mortality and five-year survival between these types of surgery. METHODS: For this observational study, data on patients with a tumour of the transverse colon, treated by open resection in the Dordrecht Hospital from 1989 through 2003, were derived from the database of the regional cancer registry. Information on type of resection, tumour stage, complications, postoperative mortality (30-day) and survival was abstracted from the medical files. Patients with multi-organ surgery, (sub)total colectomy or stage IV disease were excluded from the analysis, leaving a total series of 103 patients. RESULTS: Transverse colectomy comprised one third of operations, predominantly involving partial resections. Postoperative mortality was 6% (2/34) after transverse colectomy and 7% (5/69) after extended hemicolectomy. Five-year survival was slightly higher for the hemicolectomy group (61% versus 50%), but this difference did not reach statistical significance (p = 0.34). CONCLUSION: Our results confirm the high postoperative risk after surgery for cancer of the transverse colon and show that this risk does not depend on the type of surgery. Considering the satisfactory results after partial transverse colectomy, segmental resections may be considered as an option for the treatment of localised tumours of the transverse colon. PMID- 23741931 TI - Levels of Cr, Co, Ni and Mo in erythrocytes, serum and urine after hip resurfacing arthroplasty. AB - BACKGROUND: Hip resurfacing arthroplasty is known to increase the metal ion concentration in the serum, urine and whole blood, with potentially adverse effects on the organism. However, only few data are available about the metal ion concentrations in erythrocytes, although they are directly exposed to the higher concentrations of the serum. METHODS: The ion levels of chromium, cobalt, nickel and molybdenum in erythrocytes of 25 patients with a hip resurfacing implant were analysed with high resolution ICP-sf-MS (inductively-coupled-plasma-sector-field mass-spectrometry). The results were compared to the ion levels in the serum and urine of the patients, and also to the ion levels of 27 control persons without an implant. RESULTS: Compared to the control group, ion levels in the erythrocytes of the hip resurfacing group were markedly increased for cobalt (0.10 vs. 3.26 microg/kg) and slightly for chromium (6.04 vs. 7.38 microg/kg). In contrast, ion levels in the serum of the hip resurfacing group were increased for cobalt (0.21 vs. 1.92 microg/l), chromium (1.48 vs. 5.64 microg/l), nickel (1.53 vs. 4.25 microg/l) and molybdenum (2.17 vs. 3.78 microg/l). CONCLUSION: Ion concentrations of cobalt and chromium are also increased in erythrocytes after hip resurfacing arthroplasty. Further research is required to evaluate the impact of the elevated ion levels on the erythrocytes, and to evaluate if metal ions also accumulate in other tissues of the body. PMID- 23741932 TI - Expression of tissue IGF 1, TGFbeta and EGFR in the sequential steps of intestinal adaptation in a rat model of short bowel syndrome. AB - BACKGROUND: The long-term morphological changes and the expression of tissue growth factors IGF 1, TGFbeta and EGFR in the gut mucosa, during the process of intestinal adaptation were examined. METHODS: Four groups of rats were used: a. Sham rats (n = 10) underwent bowel transection and reanastomosis, b. SBS rats underwent an 80% small bowel resection: group A rats (n = 10) were sacrificed 15 days after surgery, group B (n = 10), 30 days after surgery, and group C (n = 10), 60 days after surgery. Morphological small bowel parameters (villus height, lumen diameter and others) of adaptation were examined sequentially. Tissue samples were studied immunohistochemically for the detection of IGF 1, TGFbeta, and EGFR. RESULTS: There was a significant increase in all morphological parameters at day 15, in the intestinal samples; a further increase followed at day 30 and day 60 (p < 0.0001). Accordingly, an increase in the expression of IGF 1, TGFbeta and EGFR was noted at day 15 (p < 0.05), and at day 30 (NS). CONCLUSION: Intestinal adaptation is an ongoing process lasting more than 2 months after massive small bowel resection. Peptide growth factors are expressed in the intestine continuously during this period, but the first two weeks are the most critical for the mucosal growth. PMID- 23741933 TI - Appendicitis-like clinical image elicited by Enterobius vermicularis: case report and review of the literature. AB - A 17-year-old female patient presented with the clinical features of an acute appendicitis. During laparoscopic exploration a macroscopically normal appendix was found. Since there were no intra-abdominal abnormalities found, the appendix was resected. Anatomopathology demonstrated Enterobius vermicularis, a pinworm infecting only humans, and mostly living in the caecum. This parasite is responsible for possibly the most common helminthic infection in the developed world. Its role in the pathogenesis of acute appendicitis is controversial, but more recent studies indicate a stronger association between enterobiasis and appendicitis. Often, enterobius mimics appendicitis by obstructing the lumen of the appendix, thereby causing appendiceal colic. This case report stresses the importance of microscopic examination of all appendectomy resection specimens. In case of enterobius infestation, systemic therapy of patient and family is necessary. PMID- 23741934 TI - Frostbite injury: a paragliding accident at 5500 meters. AB - Frostbite as a result of mountaineering or arctic expeditions is a well-known problem. In this article a rare case of frostbite injury following a paragliding accident at high altitude is described. A cumulonimbus cloud formation drifted the patient up with a high velocity to approximately 5500 m. He acquired frostbite injuries of the neck, wrists, hands and left leg, affecting 5% of the total body surface area. The frostbite was initially treated by rewarming, with later debridement and local application of silver sulfadiazine and povidone iodine dressings. Within three months all the injuries were healed. PMID- 23741930 TI - The rationale for performing MR imaging before surgery for primary hyperparathyroidism. AB - OBJECTIVE: The purpose of this study was to evaluate prospectively Magnetic Resonance Imaging (MRI) for the preoperative localization of hyperfunctioning parathyroid glands. DESIGN: Prospective study of 58 consecutive patients with biochemically confirmed primary hyperparathyroidism who underwent preoperative MRI. SETTING: The setting is a referral centre. PATIENTS: Fifty-six of the 58 consecutive patients (41 women, 17 men) were studied by both preoperative MRI and 99mTC MIBI scintigraphy, and two by MRI alone. The same surgeon, using the information from both MRI and 99mTC MIBI, performed surgery in 58 patients, including 19 with a history of neck surgery. Initial interpretation of each MR study was done independently by one radiologist and the surgeon and then results were compared. At surgery, the operative duration, the precise anatomical location, weight, and dimensions as well as complete histopathological evaluations of all excised glands were recorded. MAIN OUTCOME MEASURE: In addition to the prospective assessment of MRI, this study compared performance of MRI with double-phase 99mTC MIBI scintigraphy for preoperative localization of hyperfunctioning parathyroid glands. RESULTS: All patients became normocalcaemic after surgery. MRI and 99mTC MIBI imaging revealed 53 of 58 (91%) and 47 of 56 (84%) of abnormal glands, respectively. Sensitivities of MRI and 99mTC MIBI were respectively 94.3 and 88.0. Positive predictive values were 96.15 and 93.60. When MRI and 99mTC MIBI were interpreted together, the sensitivity and positive predictive values both raised to 98.10. Median operative duration was 30 minutes (ranges 20-300 minutes, mean 65). CONCLUSION: MRI has better sensitivity and positive predictive value than 99mTC MIBI scintigraphy for the detection of hyperfunctioning parathyroid glands. The combination of the two studies provides an additional increase in sensitivity and positive predictive value leading to a more precise anatomical localization of the abnormal parathyroid glands reducing both the extent of the surgical dissection and the operative duration. PMID- 23741935 TI - Relapsing emphysematous gastritis: a case report. PMID- 23741936 TI - Retroperitoneal abscess resulting from perforated retrocecal appendicitis:a case report. AB - Retroperitoneal abscess secondary to acute appendicitis is a relatively rare, but serious surgical infection. Adequate drainage and coverage with the appropriate antibiotics has led to improved outcome of retroperitoneal abscesses in recent years. We report the case of a 52 years old patient operated in emergency for perforated retrocecal appendicitis. A retroperitoneal abscess was diagnosed 5 days later, by computed tomography. The drainage of the abscess and the antibiotic therapy have ensured the total recovery of the patient. The alternatives of therapy are discussed. PMID- 23741937 TI - Atypical clinical presentation of internal herniation after laparoscopic Roux-en Y gastric bypass. AB - A 60-years old women with history of Roux-en-Y gastric bypass presented with progressive abdominal pain, mainly at the left loin. Imaging was aspecific. Exploratory laparoscopy showed an internal herniation trough the Petersen space. PMID- 23741938 TI - The fight against tobacco. PMID- 23741939 TI - E-cigarettes, smokers and health policies. PMID- 23741940 TI - A sequential school based smoke prevention program in secondary school adolescents. AB - BACKGROUND AND AIM: The hazardous health effects of smoking and second-hand smoke are well known and have been confirmed in several studies. We wondered whether a school based programme involving media models such as those represented by famous soccer players and TV characters, was effective in prevention of smoking habit in secondary school adolescents. METHODS: Since October 2006 to May 2007 an anonymous survey was submitted to 1382 secondary schools pupils. After completing the questionnaire all students of 42 out of 70 classes selected by the school principals underwent a prevention programme consisting of 1 hour lecture on smoke healthy hazard with educational material (slides, video, leaflets). Furthermore each pupil was given card games with significant pictures. Since October 2007 to May 2008 and Since October 2008 to May 2009 pupils underwent a 1 hour interactive lesson on smoke related health hazards respectively. On December 2007 pupils in study attended a theatre event with show business characters acting to smoke dissuasion. No intervention was performed on the 568 pupils of the other classes along all the same 2 school- year period (controls). RESULTS: Among other results at the end of the 2-year program 4% pupils of study group and 14% of controls reported smoking habit (p = 0.001) whereas 7% and 27% (p = 0.001) of study and control pupils respectively ignored smoking induced dependence. CONCLUSION: A school based programme involving media models such as those represented by famous soccer players, TV characters, was effective in prevention of smoking habit in secondary school adolescents. PMID- 23741941 TI - Electronic cigarette: a possible substitute for cigarette dependence. AB - Cigarette smoking is the leading cause of premature mortality in western countries and it is important for smokers to stop as early as possible. Electronic cigarettes are a popular phenomenon of global proportion. Recent uncontrolled studies, reported that a certain number of smokers have quit using electronic cigarettes. This could hint a role for electronic cigarettes to be used for smoking cessation, and therefore merits further evaluation for this purpose. Besides vaporising nicotine to be inhaled, electronic cigarettes may also provide a coping mechanism for conditioned smoking cues by replacing some of the rituals associated with smoking gestures, and for these reasons cigarette could become a tool--if studied more extensively--in the fight against tobacco related morbidity and mortality. PMID- 23741942 TI - Varenicline and evaluated outcomes in smoking cessation programmes. AB - The morbidity and mortality rates attributed to smoking are substantial and cigarette smoke remains the first preventable cause of premature death worldwide. Despite the knowledge of the adverse consequences of smoking, many smokers struggle to quit. Cigarette smoking is the primary cause of chronic obstructive pulmonary disease, and smoking cessation represents the most effective way of stopping its progression. Varenicline is one of the first-line smoking cessation aids recommended in many Clinical Practice Guidelines and its efficacy and safety have been demonstrated in several clinical trials. Varenicline has a unique mechanism of action and clinical trials support its use as an effective and generally well-tolerated therapy. This article reviews the clinical pharmacological trials on smoking cessation published in recent years on varenicline, with particular attention to the outcomes used in the studies. MedLine, the Cochrane database and Embase were evaluated. Almost all the trials have, as a primary endpoint, the abstinence from cigarettes at 9-12 weeks of treatment. Only one study considers lung function spirometric changes as a secondary endpoint. No study has evaluated lung function. This marker could be very important as a way of evaluating, objectively, an improvement in lung function, which correlates also with subjective parameters, as dyspnea and fatigue. PMID- 23741943 TI - Smoking cessation treatment for COPD smokers: the role of pharmacological interventions. AB - Because stopping smoking is such a pressing necessity for COPD smokers physicians should use smoking cessation treatments aggressively. For optimal efficacy smoking cessation in COPD smokers should combine behavioral and pharmacological treatments. Three types of pharmacological treatments are proven to be safe and effective: Nicotine Replacement Therapy (NRT), Bupropion and Varenicline. Use of NRT, bupropion or varenicline, single or in combination, at standard doses or at high doses, for 8-12 weeks or for more than 6-12 months have proven to help these patients to quit. For optimizing efficacy these medications can also be introduced some weeks before actual quitting. In COPD smoking patients that are not interested in stopping completely or abruptly these medications can be used to aid cessation in a more gradual way. Pharmacotherapy to aid cessation in COPD smokers have proven to be highly cost effective. PMID- 23741944 TI - Smoking cessation treatment for COPD smokers: the role of counselling. AB - Smoking cessation is the only therapeutic intervention that can prevent COPD smokers from the chronic progression of their disorder. The most important intervention for helping these smokers to quit is a combination of counseling plus pharmacological treatment. The characteristics of the counseling should be different depending if this intervention is offered to smokers with a previous diagnosis of COPD or if the intervention is offered to smokers who have been recently diagnoses with COPD. The counseling of patients who have been recently diagnosed should include: a) explanation of the direct relationship between smoking and COPD, b) encouraging these patients to quit and c) using of spirometry and measurements of CO as a motivational tools. The counseling of patients who have been previously diagnosed should include: a) encouragement to make a serious quit attempt, b) an intervention that increases motivation, self efficacy and self-esteem, c) and the intervention should also control depression and be directed to weight gain control. PMID- 23741945 TI - Third-hand smoke exposure and health hazards in children. AB - Smoking still represents a huge public health problem. Millions of children suffer the detrimental effects of passive smoking. An increasing number of countries have recently issued laws to regulate smoking in public places. Instead, homes remain a site where children are dangerously exposed to environmental tobacco smoke (ETS). The combination of tobacco smoke pollutants which remain in an indoor environment, the so-called 'third-hand smoke' (THS), represent a new concept in the field of tobacco control. THS consists of pollutants that remain on surfaces and in dust after tobacco has been smoked, are re-emitted into the gas-phase, or react with other compounds in the environment to form secondary pollutants. Indoor surfaces can represent a hidden reservoir of THS constituents that could be re-emitted long after the cessation of active smoking. Human exposure to THS pollutants has not yet been thoroughly studied. Infants and children are more prone to the risks related to THS exposure than adults because they typically spend more time indoors and have age-specific behaviours that may expose them to potential health hazards from THS. Further investigations are warranted to study the health effects of THS relevant to different exposure pathways and profiles. It would also be very important to evaluate how THS may affect the lung development through the in utero exposure during the pre-natal life. We aimed at reviewing recent findings published about THS, with special reference to the effects on children's health. PMID- 23741946 TI - Severe pneumonia after intravesical BCG instillation in a patient with invasive bladder cancer: case report and literature review. AB - We present here the case of a 66 year old man with a severe bilateral community acquired pneumonia secondary to dissemination after an intravesical instillation of bacilllus Calmette-Guerin (BCG). Diagnosis was based on positive polymerase chain reaction (PCR) for mycobacterium tuberculosis complex in bronchoalveolar lavage and on the finding on transbronchial biopsy of non necrotising granulomas histopathologically similar to the granulomas found in bladder biopsies. These findings were confirmed using a validated real time PCR assay demonstrating the presence of the BCG genome in transbronchial and bladder biopsies. PMID- 23741947 TI - When the chest is clueless, look downstairs. PMID- 23741948 TI - Federal auditors question medical necessity. PMID- 23741949 TI - Relationships matter ... Part 2. PMID- 23741950 TI - Digital camera surveillance: friend or foe? PMID- 23741951 TI - Elopement: assessment safety essentials . PMID- 23741952 TI - Breaking down barriers: school-based oral health care. PMID- 23741953 TI - Dealing with patients you believe shouldn't be driving. PMID- 23741954 TI - ADA working harder to prioritize member needs. PMID- 23741955 TI - Exposure to nitrous oxide during pregnancy is no laughing matter. PMID- 23741956 TI - Search engine optimization and ethical issues. PMID- 23741957 TI - Dealing with refund requests. PMID- 23741958 TI - Mentoring: sharing the wealth. PMID- 23741959 TI - Cariology for the 21st Century: current caries management concepts for dental practice. AB - The objective of this manuscript is to provide an overview of currently accepted, evidence-based and/or expert opinion recommendations for the prevention and management of dental caries in dental practice. Discussions are centered on current concepts for caries lesion detection (e.g., cavitated and non-cavitated lesions) and diagnosis (e.g., active vs. arrested lesions), including thresholds for non-surgical (e.g., fluorides, sealant) and surgical (i.e., restorative) interventions, risk assessment, and a review of caries management interventions for caries disease management. The goal is to prevent and manage the caries disease process using patient-centered, risk-based interventions supported by the best available evidence, taking into account the dentist's clinical expertise and the patient's treatment needs and preferences, in order to maintain or re establish health and preserve tooth structure. PMID- 23741960 TI - Oral health in school-based health care clinics. PMID- 23741961 TI - Selecting a school-based oral health care program. PMID- 23741962 TI - The American Taxpayer Relief Act: what it means for dentists. PMID- 23741963 TI - MR imaging in Crohn's disease: correlation of MR motility measurement with histopathology in the terminal ileum. AB - BACKGROUND: The objective of the study was to correlate MR-detectable motility alterations of the terminal ileum with biopsy-documented active and chronic changes in Crohn's disease. METHODS: This IRB approved retrospective analysis of 43 patients included magnetic resonance enterography (MRE) and terminal ileum biopsies (<2 weeks apart). Motility was measured at the terminal ileum using coronal 2D trueFISP pulse sequences (1.5T MRI,TR 83.8,TE1.89) and dedicated motility assessment software. Motility grading (hypermotility, normal, hypomotility, complete arrest) was agreed by two experienced readers. Motility was compared and correlated with histopathology using two-tailed Kruskal-Wallis test and paired Spearman Rank-Order Correlation tests. KEY RESULTS: Motility abnormalities were present in 27/43 patients: nine hypomotility and 18 complete arrest. Active disease was diagnosed on 15 biopsies: eight moderate and seven severe inflammatory activity. Chronic changes were diagnosed on 17 biopsies: 13 moderate and four severe cases. In four patients with normal motility alterations on histopathology were diagnosed. Histopathology correlated with presence (P = 0.0056 for hypomotility and P = 0.0119 for complete arrest) and grade (P < 0.0001; P = 0.0004) of motility alterations. A significant difference in the motility was observed in patients with active or chronic CD compared with patients without disease (P < 0.001; P = 0.0024). CONCLUSIONS & INFERENCES: MR detectable motility changes of the terminal ileum correlate with histopathological findings both in active and chronic CD. Motility changes may indicate the presence pathology, but do not allow differentiation of active and chronic disease. PMID- 23741964 TI - From one to three dimensions: corrugated infinity(1)[NiGe] ribbons as a building block in alkaline earth metal Ae/Ni/Ge phases with crystal structure and chemical bonding in AeNiGe (Ae = Mg, Sr, Ba). AB - The new equiatomic nickel germanides MgNiGe, SrNiGe, and BaNiGe have been synthesized from the elements in sealed tantalum tubes using a high-frequency furnace. The compounds were investigated by X-ray diffraction both on powders and single crystals. MgNiGe crystallizes with TiNiSi-type structure, space group Pnma, Z = 4, a = 6.4742(2) A, b = 4.0716(1) A, c = 6.9426(2) A, wR2 = 0.033, 305 F(2) values, 20 variable parameters. SrNiGe and BaNiGe are isotypic and crystallize with anti-SnFCl-type structure (Z = 4, Pnma) with a = 5.727(1) A, b = 4.174(1) A, c = 11.400(3) A, wR2 = 0.078, 354 F(2) values, 20 variable parameters for SrNiGe, and a = 5.969(4) A, b = 4.195(1) A, c = 11.993(5) A, wR2 = 0.048, 393 F(2) values, 20 variable parameters for BaNiGe. The increase of the cation size leads to a reduction of the dimensionality of the [NiGe] polyanions. In the MgNiGe structure the nickel and germanium atoms build a infinity(3)[NiGe] network with magnesium atoms in the channels. In SrNiGe and BaNiGe the infinity(1)[NiGe] ribbons are separated by strontium/barium atoms, whereas in the known CaNiGe structure the ribbons are fused to two-dimmensional atom slabs. The crystal chemistry and chemical bonding in AeNiGe (Ae = Mg, Ca, Sr, Ba) are discussed. The experimental results are reconciled with electronic structure calculations performed using the tight-binding linear muffin-tin orbital (TB-LMTO-ASA) method. PMID- 23741965 TI - The effect of cabergoline on folicular microenviroment profile in patients with high risk of OHSS. AB - The aim of this study to evaluate the effect of cabergoline on follicular microenvironment by measuring follicular fluid (FF) insulin like growth hormone I (IGF-I), antimullerian hormone (AMH), inhibin B and hepatocyte growth factor (HGF) levels in women with PCOS and high risk of ovarian hyperstimulation syndrome (OHSS). In this prospective cohort study, 41 women with PCOS undergoing controlled ovarian hyperstimulation for assisted reproduction and having the high risk factors for OHSS are included. The women in the study group (n = 15) received cabergoline for OHSS prevention while the women in the control did not received any medications for OHSS prevention. FF samples were collected during oocyte pick-up procedure for all women were determined using commercially available ELISA kits. Concentrations of FF IGF-I, AMH, inhibin B and HGF were assessed. In the study group FF AMH (2.96 +/- 1.27 versus 1.91 +/- 0.64 ng/mL), Inhibin B (1339.47 +/- 198.56 versus 1200.09 +/- 133.64 pg/mL), HGF (5623.21 +/- 2411.09 versus 3787.42 +/- 2269.89 pg/mL) and IGF-I (298.60 +/- 37.80 versus 219.90 +/- 71.40 pg/mL) concentrations were significantly decreased compared with control group. Cabergolin prevents OHSS in high risk patients by disrupting FF hormone microenvironment. PMID- 23741966 TI - Phytoestrogens and bone health at different reproductive stages. AB - BACKGROUND: Isoflavones are an alternative to hormonal therapy for the relief of menopausal symptoms. Since isoflavones interact with estrogen receptors it has been hypothesized that such substances may have an effect on bone health. OBJECTIVE: To clarify the effect of isoflavones on bone at experimental and clinical level, and to identify areas that require further clarification and research. METHOD: A systematic review of studies involving isoflavones and bone health was performed, and a specific search on isoflavone's mechanism of action and the importance of equol production was made based on Internet search engines, MEDLINE (1966-October 2012) and the Cochrane Controlled Clinical Trials Register. This search was supplemented by a handsearch of reference lists of selected papers. RESULTS: In vitro and animal studies show a positive effect of isoflavones on bone which has not been clearly confirmed by long-term human trials. Equol producers seem to present a more positive response to isoflavone intervention. Isoflavone rich diets could help maintain peak bone mass in premenopausal women. The effect of isoflavones in perimenopausal women is insufficiently studied but it seems to attenuate bone loss in the menopausal transition. In postmenopause, isoflavones may present a modest benefit but its clinical relevance in preventing osteoporotic fractures remains to be determined. CONCLUSIONS: The present review suggests that isoflavone increase bone mineral density and decrease the bone turnover resorption markers. The effect of soy isoflavones on BMD is mediated by equol production, reproductive status, supplement type, isoflavone dose and intervention duration. PMID- 23741967 TI - Adenomyosis within a uterine septum in a patient with secondary infertility. AB - BACKGROUND: Adenomyosis is a benign infiltration of endometrial stroma and glands into the myometrium. Until the advent and advancement of imaging techniques such as transvaginal ultrasound scan (TVUS) and magnetic resonance imaging (MRI), the diagnosis of adenomyosis could only be made with confidence using histology following hysterectomy. CASE: The patient is a 37-year-old woman, with a long history of secondary infertility. A hysterosalpingogram (HSG) and a pelvic MRI showed two separate uterine cavities. The patient underwent laparoscopy and hysteroscopy revealing a bicornuate appearance of the uterus and a uterine septum. Resection of the septum showed adenomyosis on histologic examination. COMMENT: Adenomyosis of uterine septum should be considered if MRI shows features of adenomyosis elsewhere in the uterus with thickened junctional zone. Further research is needed to investigate this association with the pathogenesis of adenomyosis. PMID- 23741968 TI - Thyrotropin receptor autoantibodies and early miscarriages in patients with Hashimoto thyroiditis: a case-control study. AB - We have previously hypothesized that early miscarriage in women with Hashimoto thyroiditis might be the result of a cross-reactivity process, in which blocking autoantibodies against thyrotropin receptor (TSHr-Ab) antagonize hCG action on its receptor on the corpus luteum. To test this hypothesis from the clinical perspective, we investigated the presence of TSHr-Ab in Hashimoto thyroiditis patients with apparently unexplained, first-trimester recurrent miscarriages compared to that in Hashimoto thyroiditis patients with documented normal fertility. A total of 86 subjects (43 cases and 43 age-matched controls) were finally included in a case-control study. No difference in the prevalence of TSHr Ab positivity was detected between cases and controls (Fisher's exact test, p value = 1.00). In patients with recurrent miscarriages, TSHr-Ab concentrations did not predict the number of miscarriages (univariate linear regression, p value = 0.08). These results were robust in sensitivity analyses, including only cases with full investigation or those with three or more miscarriages. We conclude that no role could be advocated for TSHr-Ab in the aetiology of recurrent miscarriages in women with Hashimoto thyroiditis. PMID- 23741969 TI - Polymorphisms of estrogen receptor-alpha gene in Brazilian women with high breast density after menopause. AB - The association of genetic polymorphism in the estrogen receptor alpha (ERalpha) gene and risk for diseases including breast cancer (BC) has been the subject of great interest. OBJECTIVE: Checking on women with high breast density after menopause, the frequency of the Pvull and Xbal polymorphisms of the ERalpha gene and the correlation between them and the known risk factors for breast cancer. METHOD: Observational study with 308 women between 45 and 65 years old with high breast density, without hormonal therapy, menstruation for a year or more, breast and ovarian cancer history. It was characterized in clinical history and physical examination: menarche, menopause, parity, family history of BC, smoking, alcohol intake and body mass index. RESULTS: The allelic and genotypic frequencies for ERalpha-Pvull and Xbal: p = 43.99%; p = 56.01%; pp = 32.14%; Pp = 47.73% and PP = 20.13%; X = 41.56%; x = 58.44%; xx = 33.44%; Xx = 50.00% and XX = 16.56%, respectively. The most frequent risk factors for BC: menarche before 12 years old (35.38%), nulliparity or first child after 28 years old (41.66%), family history of BC (19.16%) and overweight/obesity (62.01%). CONCLUSION: Allelic and genotypic distribution similar to literature. The risk factors for BC were more prevalent in women with high breast density but without significant associations with these polymorphisms. PMID- 23741970 TI - Palladium-catalyzed regio-, diastereo-, and enantioselective allylation of nitroalkanes with monosubstituted allylic substrates. AB - Pd-catalyzed asymmetric allylic alkylation of nitroalkanes and monosubstituted allylic substrates was performed to afford products with two adjacent chiral centers and with excellent regio-, diastereo-, and enantioselectivities. The usefulness of the protocol in organic synthesis was demonstrated by transformation of the product to an optically active homoallylamine, a 2,3 disubstituted tetrahydropyridine, and an alpha,beta-disubstituted amino acid derivative. PMID- 23741971 TI - Single-molecule fluorescence imaging of DNA at a potential-controlled interface. AB - Many interfacial chemical phenomena are governed in part by electrostatic interactions between polyelectrolytes and charged surfaces; these phenomena can influence the performance of biosensors, adsorption of natural polyelectrolytes (humic substances) on soils, and production of polyelectrolyte multilayer films. In order to understand electrostatic interactions that govern these phenomena, we have investigated the behavior of a model polyelectrolyte, 15 kbp fluorescently labeled plasmid DNA, near a polarized indium tin oxide (ITO) electrode surface. The interfacial population of DNA was monitored in situ by imaging individual molecules through the transparent electrode using total-internal-reflection fluorescence microscopy. At applied potentials of +0.8 V versus Ag/AgCl, the DNA interfacial population near the ITO surface can be increased by 2 orders of magnitude relative to bulk solution. The DNA molecules attracted to the interface do not adsorb to ITO, but rather they remain mobile with a diffusion coefficient comparable to free solution. Ionic strength strongly influences the sensitivity of the interfacial population to applied potential, where the increase in the interfacial population over a +300 mV change in potential varies from 20% in 30 mM ionic strength to over 25-fold in 300 MUM electrolyte. The DNA accumulation with applied potential was interpreted using a simple Boltzmann model to predict average ion concentrations in the electrical double layer and the fraction of interfacial detection volume that is influenced by applied potential. A Gouy Chapman model was also applied to the data to account for the dependence of the ion population on distance from the electrode surface, which indicates that the net charge on DNA responsible for interactions with the polarized surface is low, on the order of one excess electron. The results are consistent with a small fraction of the DNA plasmid being resident in the double-layer and with counterions screening much of the DNA excess charge. PMID- 23741972 TI - Emerging role of three-dimensional speckle tracking strain for accurate quantification of left ventricular dyssynchrony. AB - A case was 53-year-old female with dilated-phase hypertrophic cardiomyopathy. She was classified as New York Heart Association functional class III heart failure despite receiving optimal medical therapy. The electrocardiogram taken showed intraventricular conduction delay with a QRS width of 194 msec. The left ventricular (LV) end-diastolic and systolic volumes, and ejection fraction (EF) were 101 mL, 68 mL, and 32%, respectively. The patient showed no significant mechanical LV dyssynchrony as evidenced by two-dimensional (2D) speckle tracking radial strain, which is defined as the time difference between anterior-septum and posterior wall, of 105 msec (<130 msec). Three-dimensional (3D) speckle tracking radial strain was performed for more detailed LV mechanical dyssynchrony analysis. An especially important finding for 3D speckle tracking radial strain analysis was that the average time-to-peak strain of 5 septum segments at 3 different LV levels (basal-anterior-septum, basal-septum, mid-anterior-septum, mid-septum, apical-septum) was significantly shorter than that of 5 posterolateral segments at 3 different LV levels (basal-posterior, basal-lateral, mid-posterior, mid-lateral, apical-lateral). This time difference between septum and posterolateral wall was 216 msec (204 msec vs. 420 msec), which was considered to indicate significant LV mechanical dyssynchrony (>=130 msec). 12 months after cardiac resynchronization therapy (CRT), EF had improved to 47%, while end-systolic and diastolic volumes had decreased to 88 mL and 47 mL, respectively, so that the patient was classified as a responder. In conclusions, a newly developed 3D speckle tracking strain can provide a comprehensive evaluation of "true" LV mechanical dyssynchrony from pyramidal 3D data sets acquired in the same beat, thus yielding more accurate information than previously possible with the 2D speckle tracking system. PMID- 23741973 TI - New mutation L324M in the ABL1 kinase domain: does it confer high resistance to second-generation inhibitors? PMID- 23741974 TI - DNMT3A mutations at R882 hotspot are only found in major clones of acute myeloid leukemia. PMID- 23741975 TI - Rapamycin interacts synergistically with idarubicin to induce T-leukemia cell apoptosis in vitro and in a mesenchymal stem cell simulated drug-resistant microenvironment via Akt/mammalian target of rapamycin and extracellular signal related kinase signaling pathways. AB - T-cell acute lymphoblastic leukemias (T-ALLs) are clonal lymphoid malignancies with a poor prognosis, and still a lack of effective treatment. Here we examined the interactions between the mammalian target of rapamycin (mTOR) inhibitor rapamycin and idarubicin (IDA) in a series of human T-ALL cell lines Molt-4, Jurkat, CCRF-CEM and CEM/C1. Co-exposure of cells to rapamycin and IDA synergistically induced T-ALL cell growth inhibition and apoptosis mediated by caspase activation via the intrinsic mitochondrial pathway and extrinsic pathway. Combined treatment with rapamycin and IDA down-regulated Bcl-2 and Mcl-1, and inhibited the activation of phosphoinositide 3-kinase (PI3K)/mTOR and extracellular signal-related kinase (ERK). They also played synergistic pro apoptotic roles in the drug-resistant microenvironment simulated by mesenchymal stem cells (MSCs) as a feeder layer. In addition, MSCs protected T-ALL cells from IDA cytotoxicity by up-regulating ERK phosphorylation, while rapamycin efficiently reversed this protective effect. Taken together, we confirm the synergistic antitumor effects of rapamycin and IDA, and provide an insight into the potential future clinical applications of combined rapamycin-IDA regimens for treating T-cell malignancies. PMID- 23741976 TI - Extranodal marginal zone lymphoma arising in a patient with chronic myelogenous leukemia on long-term tyrosine kinase inhibitors. PMID- 23741977 TI - Impact of rituximab on incidence of and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: a systematic review and meta-analysis. AB - The impact of rituximab (R) on the incidence of central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is unclear. We performed a meta analysis to explore the risk factors and assess the association between R chemotherapy (R-chemo) and CNS relapse. We searched MEDLINE, PubMed, EMBASE and OVID for eligible studies. Published group statistics were extracted from each study for analysis; individual patient data from each study were not accessed. Fixed- or random-effects models were used to estimate the odds ratio (OR) with a 95% confidence interval (CI). Eight studies were identified. The OR for R-chemo compared with identical chemotherapy was 0.70 (95% CI 0.54-0.91). Stage III/IV (OR 2.25, 95% CI 1.64-3.08), International Prognostic Index (IPI) > 1 (OR 2.62, 95% CI 1.59-4.33), performance status (PS) > 1 (OR 1.67, 95% CI 1.23-2.27), elevated lactate dehydrogenase (LDH) (OR 2.23, 95% CI 1.54-3.22), bone marrow involvement (OR 2.85, 95% CI 1.99-4.07), more than one extranodal involvement (OR 2.61, 95% CI 1.93-3.54), presence of B symptoms (OR 1.87, 95% CI 1.37-2.56) and testicular involvement (OR 3.83, 95% CI 1.84-7.97) were associated with increased risks of CNS relapse. This meta-analysis demonstrated a lower incidence of CNS relapse of DLBCL in the rituximab era. The risk of CNS relapse can be assessed by stage, IPI, PS, LDH, presence of B symptoms, number of extranodal sites, bone marrow and testicular involvement. PMID- 23741978 TI - Favorable conception and pregnancy involving a male patient affected by chronic myeloid leukemia while taking dasatinib. PMID- 23741979 TI - Severe drug-induced anaphylaxis: analysis of 333 cases recorded by the Allergy Vigilance Network from 2002 to 2010. AB - BACKGROUND: A few series of well-documented cases of severe drug-induced anaphylaxis (SDA) are available. METHODS: Cases collected by the Allergy Vigilance Network from 2002 to 2010 were analyzed for clinical signs, causative drugs, and efficacy of a stepwise approach to diagnosis, using skin tests, laboratory tests, and oral challenges. RESULTS: Three hundred and thirty-three cases concerned 300 adults (90.1%) and 33 children (9.9%): 206 females (61.9%) and 127 males (38.1%). Mean age was 42.7 +/- 18 years. Anaphylactic shock (76.6%), severe systemic reactions (10.5%), acute laryngeal edema (9%), severe bronchospasm (2.1%), and six fatal cases (1.8%) were recorded. There were 270 cases (81.1%) of ambulatory anaphylaxis. Sixty-three cases (18.9%) occurred during anesthesia. Hospitalization was required in 94.8% of cases. 23.7% of patients were admitted to an intensive care unit. Epinephrine was used in 57.9% of cases. Eighty-four drugs were incriminated: antibiotics (49.6%), muscle relaxants, latex and anesthetics (15%), nonsteroidal anti-inflammatory drugs (10.2%), acetaminophen (3.9%), iodinated or magnetic resonance imaging contrast media (4.2%), immunotherapy and vaccines (3.9%), and other drugs (13%). Among antibiotics, amoxicillin (97 cases), other penicillins (four cases), cephalosporins (41 cases), quinolones (15 cases), and pristinamycin (seven cases) were the most common. The diagnosis of drug hypersensitivity was obtained by skin tests in 72.9%, laboratory tests only in 2.4% of cases, and oral challenges (OCs) only in 3.9% of cases. CONCLUSIONS: Three hundred and thirty-three case reports provided data on drugs involved in severe anaphylaxis. The efficacy of skin tests and poor use of laboratory tests are underlined. Further progress may depend on OCs. PMID- 23741980 TI - Postpartum culture. PMID- 23741981 TI - Changing our view of minimally invasive gynecologic surgery: a review of laparoendoscopic single-site surgery and a report on new approaches. AB - The recent emergence of laparoendoscopic single-site surgery (LESS) has had a great impact on gynecology. As LESS grows in popularity, attention has been paid to the procedure's cosmetic benefits. Although in theory LESS is an ideal approach that leaves no visible scars and improves patients' quality of life, the outcomes are not always ideal according to recently published data. Therefore, alternative approaches, such as mini-laparoscopy, are also becoming more popular. Herein, we review randomized trials studying the benefits of LESS in gynecology and discuss alternative approaches. Finally, we propose the mimic approach as the next generation for non-visible scar surgery. PMID- 23741983 TI - Structure of Au15(SR)13 and its implication for the origin of the nucleus in thiolated gold nanoclusters. AB - Au15(SR)13 is the smallest stable thiolated gold nanocluster experimentally identified so far, and its elusive structure may hold the key to the origin of the nucleus in the formation of thiolated gold nanoclusters. By an extensive exploration of possible isomers by density functional theory, we arrive at a novel structure for Au15(SR)13 with high stability and whose optical absorption characteristics match those of the experiment. Different from the previous structures and the prevailing working hypothesis about the construction of thiolated gold nanoclusters, the Au15(SR)13 model features a cyclic [Au(I)-SR] pentamer interlocked with one staple trimer motif protecting the tetrahedral Au4 nucleus, together with another trimer motif. This structure suggests that Au15(SR)13 is a transitional composition from an [Au(I)-SR]x polymer such as Au10(SR)10 to larger Aun(SR)m (n > m) clusters that have only the staple motifs and that the nucleation process starts from the Au4 core. PMID- 23741984 TI - Heterogeneous nuclear ribonucleoproteins and their interactors are a major class of deregulated proteins in anaplastic astrocytoma: a grade III malignant glioma. AB - Anaplastic astrocytoma is a high grade malignant glioma (WHO grade III) of the central nervous system which arises from a low grade II tumor and invariably progresses into lethal glioblastoma (WHO grade IV). We have studied differentially expressed proteins from the microsomal fraction of the clinical specimens of these tumors, using iTRAQ and high-resolution mass spectrometry followed by immunohistochemistry for representative proteins on tissue sections. A total of 2642 proteins were identified, 266 of them with minimum 2 peptide signatures and 2-fold change in expression. The major groups of proteins revealed to be differentially expressed were associated with key cellular processes such as post transcriptional processing, protein translation, and acute phase response signaling. A distinct inclusion among these important proteins is 10 heterogeneous nuclear ribonucleoproteins (hnRNPs) and their interacting partners which have regulatory functions in the cell. hnRNP-mediated post transcriptional events are known to play a major role in mRNA processing, stability, and distribution. Their altered levels have also been observed by us in lower (diffused astrocytoma) and higher (glioblastoma) grades of gliomas, and membrane localization of hnRNPs has also been documented in the literature. hnRNPs may thus be major factors underlying global gene expression changes observed in glial tumors while their differential presence in the microsomal fraction suggests yet additional and unknown roles in tumorigenesis. PMID- 23741982 TI - The modulation of apoptosis by oncogenic viruses. AB - Transforming viruses can change a normal cell into a cancer cell during their normal life cycle. Persistent infections with these viruses have been recognized to cause some types of cancer. These viruses have been implicated in the modulation of various biological processes, such as proliferation, differentiation and apoptosis. The study of infections caused by oncogenic viruses had helped in our understanding of several mechanisms that regulate cell growth, as well as the molecular alterations leading to cancer. Therefore, transforming viruses provide models of study that have enabled the advances in cancer research. Viruses with transforming abilities, include different members of the Human Papillomavirus (HPV) family, Hepatitis C virus (HCV), Human T-cell Leukemia virus (HTLV-1), Epstein Barr virus (EBV) and Kaposi's Sarcoma Herpesvirus (KSHV).Apoptosis, or programmed cell death, is a tightly regulated process that plays an important role in development and homeostasis. Additionally, it functions as an antiviral defense mechanism. The deregulation of apoptosis has been implicated in the etiology of diverse diseases, including cancer. Oncogenic viruses employ different mechanisms to inhibit the apoptotic process, allowing the propagation of infected and damaged cells. During this process, some viral proteins are able to evade the immune system, while others can directly interact with the caspases involved in apoptotic signaling. In some instances, viral proteins can also promote apoptosis, which may be necessary for an accurate regulation of the initial stages of infection. PMID- 23741985 TI - Malpractice litigation and nursing home quality of care. AB - OBJECTIVE: To assess the potential deterrent effect of nursing home litigation threat on nursing home quality. DATA SOURCES/STUDY SETTING: We use a panel dataset of litigation claims and Nursing Home Online Survey Certification and Reporting (OSCAR) data from 1995 to 2005 in six states: Florida, Illinois, Wisconsin, New Jersey, Missouri, and Delaware, for a total of 2,245 facilities. Claims data are from Westlaw's Adverse Filings database, a proprietary legal database, on all malpractice, negligence, and personal injury/wrongful death claims filed against nursing facilities. STUDY DESIGN: A lagged 2-year moving average of the county-level number of malpractice claims is used to represent the threat of litigation. We use facility fixed-effects models to examine the relationship between the threat of litigation and nursing home quality. PRINCIPAL FINDINGS: We find significant increases in registered nurse-to-total staffing ratios in response to rising malpractice threat, and a reduction in pressure sores among highly staffed facilities. However, the magnitude of the deterrence effect is small. CONCLUSIONS: Deterrence in response to the threat of malpractice litigation is unlikely to lead to widespread improvements in nursing home quality. This should be weighed against other benefits and costs of litigation to assess the net benefit of tort reform. PMID- 23741986 TI - Physiologic effects of an ambulatory ventilation system in chronic obstructive pulmonary disease. AB - RATIONALE: Exercise intolerance limits the ability of patients with chronic obstructive pulmonary disease (COPD) to perform daily living activities. Noninvasive ventilation reduces dyspnea and improves exercise performance, but current systems are unsuitable for ambulatory use. OBJECTIVES: In patients with COPD experiencing exercise-induced desaturation, we evaluated improvements in exercise tolerance facilitated by a wearable, 1-lb, noninvasive open ventilation (NIOV) system featuring a nasal pillow interface during constant work rate (CWR) cycle ergometer exercise and associated effects on dyspnea, respiratory muscle activation, and pulmonary gas exchange efficiency. METHODS: Fifteen men with COPD (FEV1 = 32.2 +/- 12.0% predicted; FEV1/FVC = 31.6 +/- 7.1%; exercise oxygen saturation as measured by pulse oximetry [Spo2] = 86.5 +/- 2.9%) participated. After incremental testing establishing peak work rate, subjects completed three visits in which they performed CWR exercise to tolerance at 80% peak work rate: (1) unencumbered breathing room air, (2) using NIOV+compressed air, (3) using NIOV+compressed O2, or (4) using O2 via nasal cannula. Assessments included exercise duration, surface inspiratory muscle EMG, Spo2, transcutaneous Pco2, and Borg dyspnea scores. MEASUREMENTS AND MAIN RESULTS: Exercise endurance was 17.6 +/- 5.7 minutes using NIOV+O2, greatly prolonged compared with unencumbered (5.6 +/- 1.9 min), nasal O2 (11.4 +/- 6.8 min), and NIOV+Air (6.3 +/- 4.1 min). Isotime Spo2 was higher and intercostal, scalene, and diaphragmatic EMG activity was reduced using NIOV+O2 compared with unencumbered, nasal O2, and NIOV+Air, signifying respiratory muscle unloading. Isotime dyspnea reduction correlated with isotime EMG reduction (r = 0.42, P = 0.0053). There were no significant differences in isotime VD/VT or transcutaneous Pco2 among treatments. CONCLUSIONS: NIOV+O2 yielded substantial exercise endurance improvements accompanied by respiratory muscle unloading and dyspnea reductions in patients with severe hypoxemic COPD. PMID- 23741987 TI - Social network types and well-being among South Korean older adults. AB - OBJECTIVE: The social networks of older individuals reflect personal life history and cultural factors. Despite these two sources of variation, four similar network types have been identified in Europe, North America, Japan, and China: namely 'restricted', 'family', 'friend', and 'diverse'. This study identified the social network types of Korean older adults and examined differential associations of the network types with well-being. METHOD: The analysis used data from the 2008 wave of the Korean Longitudinal Study of Aging (KLoSA: N = 4251, age range 65-108). We used a two-step cluster analytical approach to identify network types from seven indicators of network structure and function. Regression models determined associations between network types and well-being outcomes, including life satisfaction and depressive symptomatology. RESULTS: Cluster analysis of indicators of network structure and function revealed four types, including the restricted, friend, and diverse types. Instead of a family type, we found a couple-focused type. The young-old (age 65-74) were more likely to be in the couple-focused type and more of the oldest old (age 85+) belonged to the restricted type. Compared with the restricted network, older adults in all other networks were more likely to report higher life satisfaction and lower depressive symptomatology. DISCUSSION: Life course and cohort-related factors contribute to similarities across societies in network types and their associations with well being. Korean-specific life course and socio-historical factors, however, may contribute to our unique findings about network types. PMID- 23741988 TI - Invasive cancers are not necessarily from preformed in situ tumours - an alternative way of carcinogenesis from misplaced stem cells. AB - Cancers are thought to be the result of accumulated gene mutations in cells. Carcinomas, which are cancers arising from epithelial tissues usually go through several stages of development: atypical hyperplasia, carcinoma in situ and then invasive carcinoma, which might further metastasize. However, we think that the present pathological data are enough to prove that there might be an alternative way of carcinogenesis. We propose that majority of invasive cancers arise in the connective tissue stroma de novo, from the misplaced epithelial stem cells which come to the wrong land of connective tissue stroma by accident. The in situ carcinomas, which are mostly curable, should not be considered genuine cancer, but rather as quasi-cancer. We design this new theory of carcinogenesis as the stem cell misplacement theory (SCMT). Our SCMT theory chains together other carcinogenesis theories such as the inflammation-cancer chain, the stem cell theory and the tissue organization field theory. However, we deny the pathway of somatic mutation theory as the major pathway of carcinogenesis. PMID- 23741989 TI - Decrease in survival and fecundity of Glossina palpalis gambiensis vanderplank 1949 (Diptera: Glossinidae) fed on cattle treated with single doses of ivermectin. AB - BACKGROUND: Human and Animal Trypanosomes are major problems for the socio economic growth of developing countries like Burkina Faso. Ivermectin is currently used to treat humans in mass drug administration programs in Africa, and is also commonly used for veterinary purposes. In this study, we tested the effect of ivermectin injected into cattle on the survival and fecundity of Glossina palpalis gambiensis, the main vector of human and animal trypanosomes in West Africa. METHODS: Three cows (local zebu*baoule crossbreds) were used, and received either no ivermectin (for the control), or ivermectin at therapeutic dose (0.2 mg/kg) and 10 times the therapeutic dose (2 mg/kg) respectively. G. palpalis gambiensis were fed on the cattle for their first bloodmeal, and then either on cattle or on membrane for subsequent meals. RESULTS: Our results showed that survival of Glossina palpalis gambiensis was significantly decreased when they were fed on cattle treated with ivermectin. This decrease in survival ranged from 21% to 83.7% for the therapeutic dose (0.2 mg/kg), up to 8 days after treatment. The effects of a dose of 2 mg/kg were higher with a 78.3% to 93.9% decrease in survival, until 14 days after injection. The therapeutic dose of ivermectin also decreased fecundity, and delayed the first larviposition, but there was no significant effect on hatching rate. CONCLUSION: Ivermectin injected into cattle may constitute an additional potential tool for the control of Glossina palpalis gambiensis and possibly other vector species. Further studies will be needed to assess its effect on trypanosome transmission, and to define more precisely the adequate dose to be used for control purposes. PMID- 23741990 TI - Comment on absorption of aminoethyl cysteine ketimine decarboxylated dimer in mice: effect on plasma antioxidant potential. PMID- 23741992 TI - Laser biostimulation. PMID- 23741991 TI - Evaluation of cardiovascular biomarkers in a randomized trial of fosamprenavir/ritonavir vs. efavirenz with abacavir/lamivudine in underrepresented, antiretroviral-naive, HIV-infected patients (SUPPORT): 96-week results. AB - BACKGROUND: Rates of cardiovascular disease are higher among HIV-infected patients as a result of the complex interplay between traditional risk factors, HIV-related inflammatory and immunologic changes, and effects of antiretroviral therapy (ART). This study prospectively evaluated changes in cardiovascular biomarkers in an underrepresented, racially diverse, HIV-1-infected population receiving abacavir/lamivudine as backbone therapy. METHODS: This 96-week, open label, randomized, multicenter study compared once-daily fosamprenavir/ritonavir 1400/100 mg and efavirenz 600 mg, both with ABC/3TC 600 mg/300 mg, in antiretroviral-naive, HLA-B*5701-negative adults without major resistance mutations to study drugs. We evaluated changes from baseline to weeks 4, 12, 24, 48, and 96 in interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), soluble vascular adhesion molecule-1 (sVCAM-1), d-dimer, plasminogen, and fibrinogen. Biomarker data were log-transformed before analysis, and changes from baseline were described using geometric mean ratios. RESULTS: This study enrolled 101 patients (51 receiving fosamprenavir/ritonavir; 50 receiving efavirenz): 32% female, 60% African American, and 38% Hispanic/Latino; 66% (67/101) completed 96 weeks on study. At week 96, levels of IL-6, sVCAM-1, d-dimer, fibrinogen, and plasminogen were lower than baseline in both treatment groups, and the decrease was statistically significant for sVCAM-1 (fosamprenavir/ritonavir and efavirenz), d-dimer (fosamprenavir/ritonavir and efavirenz), fibrinogen (efavirenz), and plasminogen (efavirenz). Values of hs-CRP varied over time in both groups, with a significant increase over baseline at Weeks 4 and 24 in the efavirenz group. At week 96, there was no difference between the groups in the percentage of patients with HIV-1 RNA <50 copies/mL (fosamprenavir/ritonavir 63%; efavirenz 66%) by ITT missing-equals-failure analysis. Treatment-related grade 2 4 adverse events were more common with efavirenz (32%) compared with fosamprenavir/ritonavir (20%), and median lipid concentrations increased in both groups over 96 weeks of treatment. CONCLUSIONS: In this study of underrepresented patients, treatment with abacavir/lamivudine combined with either fosamprenavir/ritonavir or efavirenz over 96 weeks, produced stable or declining biomarker levels except for hs-CRP, including significant and favorable decreases in thrombotic activity (reflected by d-dimer) and endothelial activation (reflected by sVCAM-1). Our study adds to the emerging data that some cardiovascular biomarkers are decreased with initiation of ART and control of HIV viremia. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00727597. PMID- 23741993 TI - Medium-term follow-up findings in imaging manifestation after percutaneous laser disc decompression. AB - OBJECTIVE: The purpose of this study was to observe the midterm follow-up findings of the change in imaging manifestation after percutaneous laser disc decompression (PLDD), and to evaluate the safety and efficacy of this operation. MATERIALS AND METHODS: A retrospective review of the imaging manifestation of the 22 patients with cervical and lumbar vertebra disease who were treated by PLDD was analyzed. RESULTS: There was no significant difference in the anterior, middle, and posterior height of the intervertebral spaces of pathological discs before and after operation in the last follow-up (p>0.05). Preoperative herniation indices of the lesion segments of cervical disc ranged from 0.10 to ~0.54, whereas the indices ranged from 0.06 to ~0.39 at the last follow-up, that is, they diminished distinctly (p<0.05). Preoperative herniation indices of the lesion segments of lumbar disc ranged from 0 to ~0.71, whereas the indices ranged from 0 to ~0.48 at the last follow-up, which had significant statistical difference (p<0.01). CONCLUSIONS: PLDD did not obviously lower the height of the intervertebral space, instead, it could effectively promote the reduction of disc herniation. By analyzing the medical images, we found that PLDD is a safe and effective minimal invasive surgery for cervical and lumbar disc diseases. PMID- 23741994 TI - Effects of biosilicate((r)) scaffolds and low-level laser therapy on the process of bone healing. AB - OBJECTIVE: This study aimed to investigate the in vivo tissue performance of the association of Biosilicate((r)) scaffolds and low-level laser therapy (LLLT) in a tibial bone defects model in rats. BACKGROUND DATA: Many studies have been demonstrating the osteogenic potential of Biosilicate and LLLT. However, there is a need to investigate the effects of both treatments for bone consolidation. METHODS: The animals were divided into control group (CG), Biosilicate scaffold group (BG), and Biosilicate scaffolds plus LLLT group (BLG). Animals were euthanized after 15, 30, and 45 days post-injury. RESULTS: The histological analysis revealed that all the experimental groups showed inflammatory infiltrate and granulation tissue, at the area of the defect at day 15. After 30 days, CG still showed granulation tissue and bone ingrowth. Both Biosilicate groups presented newly formed bone and interconected trabeculae. At 45 days, CG showed immature newly formed bone. A more mature newly formed bone was observed in BG and BLG. On day 15, BG demonstrated a statistically higher expression of cyclooxygenase (COX)-2 compared with CG and BLG. No statistically significant difference was observed in COX-2 immunoexpression among the groups at 30 and 45 days. Similar expression of bone morphogenetic protein (BMP)-9 was demonstrated for all experimental groups at 15 and 30 days. At 45 days, the BMP-9 immunoexpression was statistically upregulated in the BLG compared with the CG and BG. No statistically significant difference was observed in the receptor activator of nuclear factor kappa-B ligand (RANKL) immunoexpression among the groups in all periods evaluated. Biosilicate groups presented a decrease in biomechanical properties compared with CG at 30 and 45 days post-surgery. CONCLUSIONS: Our findings suggest that Biosilicate presented osteogenic activity, accelerating bone repair. However, laser therapy was not able to enhance the bioactive properties of the Biosilicate. PMID- 23741995 TI - Shear bond strength of veneering ceramic to zirconia core after different surface treatments. AB - OBJECTIVE: The aim of this study was to evaluate the effect of different surface treatments: sandblasting, liners, and different laser irradiations on shear bond strength (SBS) of pre-sintered zirconia to veneer ceramic. BACKGROUND DATA: The SBS between veneering porcelain and zirconium oxide (ZrO2) substructure was weak. Various surface treatment methods have been suggested for zirconia to obtain high bond strength to veneering porcelain. There is no study that evaluated the bond strength between veneering porcelain and the different surface treatments on pre sintered ZrO2 substructure. METHODS: Two hundred specimens with 7 mm diameter and 3 mm height pre-sintered zirconia blocks were fabricated. Specimens were randomly divided into 10 groups (n=20) according to surface treatments applied. Group C, untreated (Control); Group E, erbium:yttrium-aluminum-garnet (Er:YAG) laser irradiated; Group N, neodymium:yttrium-aluminum-garnet (Nd:YAG) laser irradiated; Group SB, sandblasted; Group L, liner applied; Group NL, Nd:YAG laser irradiated+liner applied; Group EL, Er:YAG laser irradiated+liner applied; Group SN, sandblasted+Nd:YAG laser irradiated; Group SE, sandblasted+Er:YAG laser irradiated; and Group SL, sandblasted+liner applied. The disks were then veneered with veneering porcelain. Before the experiment, specimens were steeped in 37 degrees C distilled water for 24 h. All specimens were thermocycled for 5000 cycles between 5 degrees C and 55 degrees C with a 30 sec dwell time. Shear bond strength test was performed at a crosshead speed of 1 mm/min. The fractured specimens were examined under a stereomicroscope to evaluate the fracture pattern. RESULTS: Surface treatments significantly changing the topography of the yttrium-stabilized tetragonal zirconia (Y-TZP) ceramic according to scanning electron microscopic (SEM) images. The highest mean bond strength value was obtained in Group SE, and the lowest bond strength value was observed in NL group. Bond strength values of the other groups were similar to each other. CONCLUSIONS: This study shows that sandblasting+Er:YAG, sandblasting, Er:YAG+liner, sandblasting+Nd:YAG, and Er:YAG laser treatment on pre-sintered ZrO2 substructure increased the bond strength to veneering porcelain, compared with other surface treatments. After different surface treatments, there was no difference in surface roughness of pre-sintered zirconia to compare after sintering; sintering enhanced the bond strength within the limitations of present study. PMID- 23741996 TI - The effects of 1064 nm Nd:YAG laser irradiation under the different treatment conditions for skin rejuvenation: quantitative and histologic analyses. AB - OBJECTIVE: The aim of this study was to estimate heat distributions and evaluate degrees of tissue damages histologically after transmitting therapeutic lasers to find optimum ranges for skin rejuvenation. BACKGROUND DATA: To treat skin aging, many researchers attempted to evaluate treatment effects for the different approaches. The noninvasive skin rejuvenation method was mostly employed to optimize the therapeutic effects by quantifying the laser conditions. However, current approaches produced low reliability for predicting tissue damage. METHODS: We transmitted the 1064 nm Nd:YAG laser into a skin-mimicking phantom and pig skin samples according to the different fluences and spot diameters, and analyzed its internal-external temperatures. For histologic analyses, we also stained pig skin samples with hematoxylin and eosin (H&E) and compared degrees of tissue damage. The spot diameter conditions were classified into 5, 8, and 10 mm, and the fluence conditions were divided into 26, 30, and 36 J/cm(2). In addition, the pulse duration was set to 30 ms. RESULTS: In our experiments, the conditions of a spot diameter of 5 mm with a fluence of 36 J/cm(2) and a spot diameter of 10 mm with a fluence of 26 J/cm(2) yielded the maximum surface temperatures>40 degrees C. Regarding histologic evaluations, we also found that the degrees of internal thermal injuries are worsened as spot diameters and fluences increased. CONCLUSIONS: We selected the optimum treatment conditions for skin rejuvenation as being the laser condition of a spot diameter of 5 mm with a fluence of 36 J/cm(2) and a spot diameter of 10 mm with a fluence of 26 J/cm(2). PMID- 23741997 TI - Evaluation of the clinical and antimicrobial effects of the Er:YAG laser or topical gaseous ozone as adjuncts to initial periodontal therapy. AB - OBJECTIVE: The aim of this study was to evaluate the clinical and microbiological results of treatment with the Er:YAG laser and topical gaseous ozone application as adjuncts to initial periodontal therapy in chronic periodontitis (CP) patients. BACKGROUND DATA: Although many studies have evaluated the effectiveness of the Er:YAG laser as an adjunct to initial periodontal therapy, few studies have focused on the use of gaseous ozone as an adjunct. MATERIALS AND METHODS: Thirty patients with CP were randomly divided into three parallel groups, each composed of 10 individuals with at least four teeth having at least one approximal site with a probing depth (PD) of >=5 mm and a sulcus bleeding index (SBI) >=2 in each quadrant. Groups of patients received: (1) Scaling and root planing (SRP)+Er:YAG laser; (2) SRP+topical gaseous ozone; or (3) SRP alone. The microbiological and clinical parameters were monitored at day 0 and day 90. RESULTS: At the end of the observation period, statistically significant improvements in clinical parameters were observed within each group. Parallel to the clinical changes, all treatments reduced the number of total bacteria and the proportion of obligately anaerobic microorganisms. Although intergroup comparisons of microbiological parameters showed no significant differences, clinical findings, including attachment gain and PD reduction, were found to be statistically significant in favor of the SRP+Er:YAG laser group. CONCLUSIONS: Although statistically nonsignificant, the fact that the obligate anaerobic change was mostly observed in the SRP+Er:YAG laser group, and a similar decrease was noted in the SRP+topical gaseous ozone group, shows that ozone has an antimicrobial effect equivalent to that of the Er:YAG laser. PMID- 23741998 TI - Dysfunction of the PI3K-Akt-GSK-3 pathway is a common feature in cell culture and in vivo models of prion disease. AB - AIMS: Transmissible spongiform encephalopathies, also called prion diseases, are characterized by the cerebral accumulation of misfolded prion protein (PrP(SC) ) and subsequent neurodegeneration. However, despite considerable research effort, the molecular mechanisms underlying prion-induced neurodegeneration are poorly understood. Here, we explore the hypothesis that prions induce dysfunction of the PI3K/Akt/GSK-3 signalling pathway. METHODS: We employed two parallel approaches. Using cell cultures derived from mouse primary neurones and from a human neuronal cell line, we identified common elements that were modified by the neurotoxic fragment of PrP(106-126) . These studies were then complemented by comparative analyses in a mouse model of prion infection. RESULTS: The presence of a polymerized fragment of the prion protein (PrP(106-126) ) or of a prion strain altered PI3K-mediated signalling, as evidenced by Akt inhibition and GSK-3 activation. PI3K activation by the addition of insulin or the expression of a constitutively active Akt mutant restored normal levels of Akt and GSK-3 activity. These changes were correlated with a reduction in caspase activity and an increase in neuronal survival. Moreover, we found that activation of caspase 3, Erk and GSK-3 are common features of PrP(106-126) -mediated neurotoxicity in cellular systems and prion infection in the mouse cerebellum, while activation of caspase 12 and JNK was observed in cellular models. CONCLUSIONS: Our findings in cell culture and in vivo models of prion disease demonstrate marked alterations to the PI3K/Akt/GSK-3 pathway and suggest that two additional pathways contribute to PrP-induced neurotoxicity as responsible of JNK and caspase 12 activation. PMID- 23742001 TI - Abstracts of 4th International Hematologic Malignancies Conference held by the Asia-Pacific Consortium, Bridging the Gap 2013 (BTG2013). Hong Kong. February 22 23, 2013. PMID- 23741999 TI - The value of chest CT for prediction of breast tumor size: comparison with pathology measurement. AB - BACKGROUND: Little information is available on the use of chest computed tomography (CT) to predict breast tumor size in breast cancer, despite the fact that chest CT examinations are being increasingly used. The purpose of this study was to evaluate the value of chest CT for predicting breast tumor size using pathology measurements as reference standards. METHODS: Tumor sizes (defined as greatest diameter) were retrospectively measured on the preoperative chest CT images of 285 patients with surgically proven unifocal, invasive breast carcinoma. Greatest tumor diameters as determined by chest CT and pathologic examinations were compared by linear regression and Spearman's rho correlation analysis. Concordance between CT and pathology results was defined as a diameter difference of <5 mm. Subgroup analyses were also performed with respect to tumor size (<20 mm or >=20 mm) and histological subtype (invasive ductal carcinoma(IDC) or non-IDC). RESULTS: CT and pathology measured diameters were found to be linearly related (size at pathology = 1.086 * CT determined tumor size - 1.141; Spearman's rho correlation coefficient = 0.84, P<0.001). Most tumors (n = 228, 80.0%) were concordant by chest CT and pathology, but 36 tumors (12.7%) were underestimated by CT (average underestimation, 11 mm; range, 6-36 mm) and 21 tumors (7.4%) were overestimated (average overestimation by CT, 10 mm; range, 6 19 mm). The concordance rate between the two sets of measurements was greater for tumor of <20 mm and for IDC (P<0.001 and P = 0.011, respectively). CONCLUSIONS: Tumor size by chest CT is well correlated with pathology determined tumor size in breast cancer patients, and the diameters of the majority of tumors by chest CT and pathology differed by <5 mm. In addition, the concordance rate was higher for breast tumors of <20 mm and for tumors of the IDC histologic subtype. PMID- 23742005 TI - Comorbid symptoms of sleep-disordered breathing and behavioral sleep problems from 18-57 months of age: a population-based study by Moore and Bonuck. PMID- 23742006 TI - Caveolin-1 controls airway epithelial barrier function. Implications for asthma. AB - The molecular basis for airway epithelial fragility in asthma has remained unclear. We investigated whether the loss of caveolin-1, the major component of caveolae and a known stabilizer of adherens junctions, contributes to epithelial barrier dysfunction in asthma. We studied the expression of caveolin-1 and adhesion molecules E-cadherin and beta-catenin in airway sections, and we cultured bronchial epithelial cells from patients with asthma and from healthy control subjects. To determine the functional role of caveolin-1, we investigated the effects of caveolin-1 up-regulation and down-regulation on E-cadherin expression, barrier function, and proallergic activity in the human bronchial epithelial cell lines 16HBE and BEAS-2B. The membrane expression of caveolin-1 was significantly lower in airway epithelia from patients with asthma than from subjects without asthma, and this lower expression was maintained in vitro upon air-liquid interface and submerged culturing. Importantly, reduced caveolin-1 expression was accompanied by a loss of junctional E-cadherin and beta-catenin expression, disrupted epithelial barrier function, and increased levels of the proallergic cytokine thymic stromal lymphopoietin (TSLP). Furthermore, E-cadherin redistribution upon exposure to epidermal growth factor or house dust mite was paralleled by the internalization of caveolin-1 in 16HBE cells. These effects appear to be causally related, because the short, interfering RNA down-regulation of caveolin-1 resulted in the delocalization of E-cadherin and barrier dysfunction in 16HBE cells. Moreover, caveolin-1 overexpression improved barrier function and reduced TSLP expression in BEAS-2B cells. Together, our data demonstrate a crucial role for caveolin-1 in epithelial cell-cell adhesion, with important consequences for epithelial barrier function and the promotion of Th2 responses in asthma. PMID- 23742007 TI - Nighttime blood pressure and white matter hyperintensities in patients with Parkinson disease. AB - Increasing evidence indicates that nocturnal blood pressure level and/or loss of nocturnal blood pressure dips are sensitive markers of cardiovascular morbidity and mortality. Several studies have suggested that blunted heart rate variability and nocturnal decline in heart rate are also associated with target organ damage. These phenomena occur relatively commonly in patients with Parkinson disease (PD); however, few studies have assessed the consequences of these abnormalities in patients with PD. We investigated the influence of circadian changes in blood pressure and heart rate on white matter hyperintensities (WMHs) in patients with PD. The presence of nocturnal hypertension was associated with increased WMH score, and nighttime systolic pressure was closely related with white matter changes. Blunted heart rate variability and nocturnal decline in heart rate were also related to increasing WMH scores. The non-dipping phenomenon did not influence WMHs. These findings suggest that white matter changes are related to circadian autonomic dysfunction, particularly nocturnal hypertension in patients with PD. Therefore, it is important to monitor nocturnal blood pressure status, because modifying these circadian regulatory disturbances can be beneficial to protect against vascular brain damage in patients with PD. PMID- 23742008 TI - State-based metacognition: how time of day affects the accuracy of metamemory. AB - Although there is an abundance of research on how stimulus characteristics and encoding conditions affect metamemory, and how those effects either do or do not mirror effects on memory, there is little research on whether and how characteristics of participants' states-like mood, fatigue, or hunger-affect metamemory. The present study examined whether metamemory ability fluctuates with time of day. Specifically, we evaluated whether learners can successfully account for the effects of time of day on their memory, and whether metacognitive monitoring is more accurate at an individual's optimal time of day. Young adults studied and recalled lists of words in both the morning and the afternoon, providing various metamemory judgements during each test session. We replicated the finding that young participants recalled more words in the afternoon than in the morning. Prior to study, participants did not predict superior recall in the afternoon, but they did after they had an opportunity to study the list (but before the test on that material). We also found that item-by-item predictions were more accurate in the afternoon, suggesting that self-regulated learning might benefit from being scheduled during times of day that accord with individuals' peak arousal. PMID- 23742009 TI - Mitochondrial mutations and aging: random drift is insufficient to explain the accumulation of mitochondrial deletion mutants in short-lived animals. AB - Mitochondrial DNA deletions accumulate over the life course in post-mitotic cells of many species and may contribute to aging. Often a single mutant expands clonally and finally replaces the wild-type population of a whole cell. One proposal to explain the driving force behind this accumulation states that random drift alone, without any selection advantage, is sufficient to explain the clonal accumulation of a single mutant. Existing mathematical models show that such a process might indeed work for humans. However, to be a general explanation for the clonal accumulation of mtDNA mutants, it is important to know whether random drift could also explain the accumulation process in short-lived species like rodents. To clarify this issue, we modelled this process mathematically and performed extensive computer simulations to study how different mutation rates affect accumulation time and the resulting degree of heteroplasmy. We show that random drift works for lifespans of around 100 years, but for short-lived animals, the resulting degree of heteroplasmy is incompatible with experimental observations. PMID- 23742010 TI - Impact of continuing or quitting smoking on episodic cluster headache: a pilot survey. AB - BACKGROUND: The majority of patients suffering from cluster headache (CH) are smokers and it has been suggested that smoking may trigger the development of CH. The aim of this pilot survey was to describe: 1. the differences between current, former, and never smokers CH patients; 2. if smoking changed during an active cluster period; 3. if CH changed after quitting. METHODS: All outpatients with episodic CH according to the criteria of ICHD-II who were consecutively seen for the first time from October 2010 to April 2012 at a headache centre were interviewed by phone using a specifically prepared questionnaire. Statistical differences between continuous variables were analysed by the Student's t-test or the one-way analysis of variance (ANOVA), followed by Newman-Keuls post-hoc testing. Comparisons between percentages were made using the Chi-square test or Fisher's exact test. All data were expressed as the mean +/- standard deviation (SD). RESULTS: Among a total of 200 patients surveyed (172 males, 28 females; mean age +/- SD: 48.41 +/- 12 years) there were 60%, 21%, and 19% of current, former, and never smokers, respectively. Current smokers reported longer active periods (12.38 +/- 10 weeks) and a higher maximum number of attacks per day (3.38 +/- 1) compared to never smoker CH patients (5.68 +/- 4 weeks, P <0.05 and 2.47 +/- 1, P <0.05, respectively). During the active period most of the patients stated to decrease (45.7%) or not to change (45.7%) the number of cigarettes smoked. Among those who decreased smoking, most (83.8%) reported that they had less desire to smoke. After quitting, the majority of former smokers stated that their headache had not changed. CONCLUSIONS: Patients with episodic CH who are also smokers appear to have a more severe form of the disorder. However, it is unlikely that between CH and smoking there is a causal relationship, as CH patients rarely improve quitting smoking. PMID- 23742012 TI - Spontaneous echo contrast at a large inter-atrial septal aneurysm. PMID- 23742011 TI - Non-apoptotic function of caspases in a cellular model of hydrogen peroxide associated colitis. AB - Oxidative stress, caused by reactive oxygen species (ROS), is a major contributor to inflammatory bowel disease (IBD)-associated neoplasia. We mimicked ROS exposure of the epithelium in IBD using non-tumour human colonic epithelial cells (HCEC) and hydrogen peroxide (H2 O2 ). A population of HCEC survived H2 O2 induced oxidative stress via JNK-dependent cell cycle arrests. Caspases, p21(WAF1) and gamma-H2AX were identified as JNK-regulated proteins. Up-regulation of caspases was linked to cell survival and not, as expected, to apoptosis. Inhibition using the pan-caspase inhibitor Z-VAD-FMK caused up-regulation of gamma-H2AX, a DNA-damage sensor, indicating its negative regulation via caspases. Cell cycle analysis revealed an accumulation of HCEC in the G1 -phase as first response to oxidative stress and increased S-phase population and then apoptosis as second response following caspase inhibition. Thus, caspases execute a non apoptotic function by promoting cells through G1 - and S-phase by overriding the G1 /S- and intra-S checkpoints despite DNA-damage. This led to the accumulation of cells in the G2 /M-phase and decreased apoptosis. Caspases mediate survival of oxidatively damaged HCEC via gamma-H2AX suppression, although its direct proteolytic inactivation was excluded. Conversely, we found that oxidative stress led to caspase-dependent proteolytic degradation of the DNA-damage checkpoint protein ATM that is upstream of gamma-H2AX. As a consequence, undetected DNA damage and increased proliferation were found in repeatedly H2 O2 -exposed HCEC. Such features have been associated with neoplastic transformation and appear here to be mediated by a non-apoptotic function of caspases. Overexpression of upstream p-JNK in active ulcerative colitis also suggests a potential importance of this pathway in vivo. PMID- 23742013 TI - How Medicare Part D benefit phases affect adherence with evidence-based medications following acute myocardial infarction. AB - OBJECTIVE: Assess impact of Medicare Part D benefit phases on adherence with evidence-based medications after hospitalization for an acute myocardial infarction. DATA SOURCE: Random 5 percent sample of Medicare beneficiaries. STUDY DESIGN: Difference-in-difference analysis of drug adherence by AMI patients stratified by low-income subsidy (LIS) status and benefit phase. DATA COLLECTION/EXTRACTION METHODS: Subjects were identified with an AMI diagnosis in Medicare Part A files between April 2006 and December 2007 and followed until December 2008 or death (N = 8,900). Adherence was measured as percent of days covered (PDC) per month with four drug classes used in AMI treatment: angiotensin converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs), beta blockers, statins, and clopidogrel. Monthly exposure to Part D benefit phases was calculated from flags on each Part D claim. PRINCIPAL FINDINGS: For non-LIS enrollees, transitioning from the initial coverage phase into the Part D coverage gap was associated with statistically significant reductions in mean PDC for all four drug classes: statins (-7.8 percent), clopidogrel (-7.0 percent), beta blockers (-5.9 percent), and ACE inhibitor/ARBs (-5.1 percent). There were no significant changes in adherence associated with transitioning from the gap to the catastrophic coverage phase. CONCLUSIONS: As the Part D doughnut hole is gradually filled in by 2020, Medicare Part D enrollees with critical diseases such as AMI who rely heavily on brand name drugs are likely to exhibit modest increases in adherence. Those reliant on generic drugs are less likely to be affected. PMID- 23742014 TI - ABA and the ubiquitin E3 ligase KEEP ON GOING affect proteolysis of the Arabidopsis thaliana transcription factors ABF1 and ABF3. AB - The ABA Binding Factor/ABA-Responsive Element Binding Proteins (ABF/AREB) subfamily of bZIP-type transcription factors are positive effectors of ABA responses. Here, we examine the proteolytic regulation of two members: Arabidopsis thaliana ABF1 and ABF3. Both transcription factors are unstable in seedlings, and their degradation is sensitive to proteasome inhibition. ABA treatment of seedlings leads to their rapid accumulation, the result of slowed proteolysis. Deletion of the conserved C-terminal region required for 14-3-3 interaction destabilizes the proteins. The degradation of ABF1 and ABF3 are slower in vivo in seedlings lacking the ubiquitin E3 ligase KEEP ON GOING (KEG), and in vitro in extracts from keg seedlings, implicating KEG in their degradation. ABF1 and ABF3 are ubiquitylation substrates of KEG in vitro, and in vitro pull-down assays document their direct interaction. In contrast to ABI5, another KEG substrate, the degradation of ABFs and proteolytic regulation of ABFs by ABA still occurs in keg seedlings, suggesting that additional E3s participate in ABF1 and ABF3 proteolysis. Loss of ABF1 or ABF3 in the keg background has a phenotypic effect similar to the loss of ABI5, and there is no additional rescue of the keg phenotype in abf1 abf3 abi5 keg seedlings. This result suggests that the abundance of other substrates is altered in keg seedlings, affecting growth. In conclusion, ABF1 and ABF3 abundance is affected by ABA and KEG, and the conserved C4 region serves as a stabilizing element. PMID- 23742016 TI - Dietary glycine+serine responses of male broilers given low-protein diets with different concentrations of threonine. AB - 1. The objective of this study was to determine the optimum glycine+serine (Gly+Ser) concentration in low-crude protein (CP) diets that have adequate or high concentrations of dietary threonine (Thr) for broiler chickens in the initial growth phase. 2. Treatments consisted of four concentrations of dietary Gly+Ser (18.4; 19.8; 21.2 and 22.6 g/kg) and two concentrations of dietary Thr (9.3 and 10.7 g/kg, corresponding to 100 and 115% of the required Thr, respectively). 3. At 21d, interactions were observed between dietary Gly+Ser and Thr concentrations for the feed conversion ratio, creatine content in the pectoral muscles and serum concentrations of uric acid. There was a quadratic effect of the concentrations of Gly+Ser in the diets with 9.3 g Thr/kg on the feed conversion ratio and creatine content in the pectoral muscles, with an optimisation concentration of 20.8 and 21.1 g Gly+Ser/kg, respectively. 4. Diets containing 10.7 g Thr/kg negatively affected the feed conversion ratio, relative breast weight, creatine content in the pectoral muscles, serum concentrations of uric acid and ammonia in poultry compared to diets containing 9.3 g Thr/kg. 5. The need for Gly+Ser in diets with low-protein concentration (190 g CP/kg) and adequate concentration of Thr (9.3 g/kg) is 20.8 g/kg for broilers in the 1- to 21-d phase. PMID- 23742015 TI - The consequences of not having eosinophils. AB - Several lines of evidence suggest that deficiency of eosinophils is not associated with any characteristic abnormality. Patients lacking eosinophils, in the setting of immunodeficiency or as a consequence of IgG-mediated eosinophil precursor destruction, do not display any distinguishing abnormalities related to eosinophil reduction. The observation that eosinophil-deficient mice do not display any distinctive syndrome or failure of their health is evidence that, under ordinary laboratory conditions, the eosinophil does not play a critical role in the well-being of mammals. Observations that monoclonal antibodies to interleukin-5 (IL-5) are well tolerated appear unsurprising in light of these findings. For example, patients with the hypereosinophilic syndrome have received mepolizumab, an anti-IL-5 monoclonal antibody, for as long as 6 years and have not developed any characteristic set of adverse events. Safety data for reslizumab, another anti-IL-5 monoclonal antibody, and benralizumab, a monoclonal antibody to the IL-5 receptor alpha-chain, are comparatively limited, especially for benralizumab, although reports of administration of these antibodies to humans suggest that they are well tolerated. Thus, data to the present suggest that reduction of eosinophils appears to have no characteristic ill effects on normal health, and monoclonal antibodies that deplete eosinophils have the potential to be widely employed in the treatment of eosinophil-associated diseases. PMID- 23742017 TI - Arthroscopic anatomy of the equine cervical articular process joints. AB - REASON FOR PERFORMING STUDY: Although arthropathy of the cervical articular process joints (APJs) is common, descriptions of the arthroscopic technique of the cervical APJ have not been reported previously. OBJECTIVES: To develop an arthroscopic approach to the APJ and to describe the arthroscopic anatomy of the APJ. STUDY DESIGN: Descriptive cadaver study and clinical case report. METHODS: The regional anatomy was reviewed and the technique developed on fresh cadaver necks. A series of cadaveric APJ arthroscopies from C2-C3 to C6-C7 were performed to evaluate the procedure, which was then used in 3 clinical cases. A description of the procedure and the potential complications encountered were recorded. RESULTS: The equine APJ consists of cranioventral and caudodorsal recesses; a single entry point at one of these recesses enables almost complete evaluation of cartilage surfaces and the synovial membrane and its villi. Successful entry into both APJ recesses was achieved in 22 cadaveric APJs and 5 APJs in the 3 clinical cases operated upon. An instrument portal was created to assess the feasibility of surgical arthroscopy. Complications were minor, and dissection of the APJs following the arthroscopic exploration revealed that the cartilage and periarticular neurovascular structures were not damaged during the procedure. CONCLUSIONS: This study shows that arthroscopic examination of the APJs of equine cervical vertebra is feasible and can be performed in mature horses. Arthroscopy of the APJs may provide additional diagnostic information compared to conventional diagnostic techniques. PMID- 23742018 TI - Receptors and mechanisms mediating the biphasic response evoked by bradykinin in rat colonic smooth muscle. AB - BACKGROUND: In rat duodenum, bradykinin induces a relaxation followed by a contraction. Different types of ion channels and receptors as well as non-muscle cells have been suggested to be involved in this response. As it is unclear whether these changes are observed also in rat large intestine and the mechanisms which might underlie this response, the effect of bradykinin on rat colonic motility was tested. METHODS: Isometric contractions were measured on full thickness preparations or preparations, from which individual layers had been dissected. The expression of bradykinin receptors was analyzed by immunohistochemistry and RT-PCR. Isolated intestinal muscle cells were investigated with Ca(2+) -imaging techniques. KEY RESULTS: Bradykinin caused a biphasic contractile response (initial relaxation followed by contraction) in rat colon, which was resistant against tetrodotoxin. The kinin-induced relaxation was inhibited by tetrapentylammonium chloride, a blocker of Ca(2+) -activated K(+) channels. Des-arg(9) -bradykinin did not induce any effect on the native colon, although after 5 h in vitro preincubation, a contractile response was evoked by this B1 receptor agonist. The consecutive ablation of adherent layers of the intestinal wall strongly reduced the response to bradykinin in comparison with a control stimulus, i.e., carbachol, suggesting a contribution of non-muscle cells in the mediation of this response. CONCLUSIONS & INFERENCES: Bradykinin induced a biphasic change in contractility in the rat colon. In the native intestine, only the B2 receptor is involved in this effect. Neighboring cell obviously sensitize the smooth muscle to the stimulation of these receptors. PMID- 23742020 TI - Development and psychometric evaluation of the Sexual Intent Scale. AB - Men have been found to attribute more sexual meaning to cross-gender interactions than women do--a finding that has come to be known as the oversexualization effect. Despite the large body of research supporting the notion that men are more biased in their perceptions than women, researchers are moving beyond gender differences and examining personality variables to identify factors that can explain and predict the oversexualization effect. However, results have been mixed. Thus, the goal of this study was to develop a measurement tool, the Sexual Intent Scale, which assesses individual differences in attributing sexual intent. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) of the Sexual Intent Scale revealed the scale has three components we termed Sexual Facility, Friendship Facility, and Sexual Empathy. Temporal reliability and convergent and construct validity as well as norms and subscale correlations are presented. Results are discussed in terms of the scale's utility and directions for future research are explored. PMID- 23742021 TI - IOR effects in a social free-choice task. AB - Social inhibition of return (S-IOR) refers to the finding that reaction times (RTs) are longer for movements to the same location as a partner's previous response. Wilson and Pratt (2007) found that when people acting alone freely chose their responses, they were less likely to choose a response that was spatially-compatible with a recently presented stimulus, suggesting that the processes underlying IOR effects in RT also affect response selection. The current study investigated if a similar response selection bias would occur in a free-choice S-IOR task. It was found that participants were less likely to move to the location that their partner previously contacted. This similarity in responses biases in free-choice tasks is generally consistent with the notion that similar processes underlie individual and S-IOR. PMID- 23742019 TI - Hyperoxia synergizes with mutant bone morphogenic protein receptor 2 to cause metabolic stress, oxidant injury, and pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) has been associated with a number of different but interrelated pathogenic mechanisms. Metabolic and oxidative stresses have been shown to play important pathogenic roles in a variety of model systems. However, many of these relationships remain at the level of association. We sought to establish a direct role for metabolic stress and oxidant injury in the pathogenesis of PAH. Mice that universally express a disease-causing mutation in bone morphogenic protein receptor 2 (Bmpr2) were exposed to room air or to brief daily hyperoxia (95% oxygen for 3 h) for 6 weeks, and were compared with wild-type animals undergoing identical exposures. In both murine tissues and cultured endothelial cells, the expression of mutant Bmpr2 was sufficient to cause oxidant injury that was particularly pronounced in mitochondrial membranes. With the enhancement of mitochondrial generation of reactive oxygen species by hyperoxia, oxidant injury was substantially enhanced in mitochondrial membranes, even in tissues distant from the lung. Hyperoxia, despite its vasodilatory actions in the pulmonary circulation, significantly worsened the PAH phenotype (elevated right ventricular systolic pressure, decreased cardiac output, and increased pulmonary vascular occlusion) in Bmpr2 mutant animals. These experiments demonstrate that oxidant injury and metabolic stress contribute directly to disease development, and provide further evidence for PAH as a systemic disease with life-limiting cardiopulmonary manifestations. PMID- 23742022 TI - Why has research in face recognition progressed so slowly? The importance of variability. AB - Despite many years of research, there has been surprisingly little progress in our understanding of how faces are identified. Here I argue that there are two contributory factors: (a) Our methods have obscured a critical aspect of the problem, within-person variability; and (b) research has tended to conflate familiar and unfamiliar face processing. Examples of procedures for studying variability are given, and a case is made for studying real faces, of the type people recognize every day. I argue that face recognition (specifically identification) may only be understood by adopting new techniques that acknowledge statistical patterns in the visual environment. As a consequence, some of our current methods will need to be abandoned. PMID- 23742023 TI - Synthesizing axial inserting p-n heterojunction nanowire arrays for realizing synergistic performance. AB - Consideration of the material design and components match on structure and energy, the solid-solid combined nanowires of p-type conductive polymer of poly[3 thiophene carboxylic acid methyl ester] (PTCM) and n-type inorganic semiconductor PbS was prepared with a 2.57 MUm(2) heterojunction interface. The axial deeply inserting heterojunction nanowire arrays exhibited excellent rectifying features and diode nature, as well as obvious electrical switching behavior, which are much excelled individual components of PTCM and PbS nanowire arrays for realizing synergistic performance. PMID- 23742024 TI - Catalytic formation of ketones from unactivated esters through rhodium chelation assisted C-O bond activation. AB - A new method for building aryl aryl ketones containing heterocyclic rings through chelation-assisted C-O bond activation catalyzed by a rhodium complex has been developed. In this reaction, methyl quinoline-8-carboxylate, methyl quinoxaline-5 carboxylate, and their derivatives were reacted with an excess amount of a substituted phenyl boronic acid in the presence of a rhodium(I) complex to give substituted phenyl(quinolin-8-yl)methanone, phenylquinoxalin-5-ylmethanone, and their derivatives in medium to high yields. The current method offers a highly favorable synthetic pathway to efficiently build related drugs with an 8 benzoylquinoline core structure. This method may prove especially valuable for medicinal chemists for the late-stage introduction of versatile ketone moieties into complex scaffolds for diversity-oriented synthetic strategies. PMID- 23742025 TI - Global comparators project: international comparison of hospital outcomes using administrative data. AB - OBJECTIVE: To produce comparable risk-adjusted outcome rates for an international sample of hospitals in a collaborative project to share outcomes and learning. DATA SOURCES: Administrative data varying in scope, format, and coding systems were pooled from each participating hospital for the years 2005-2010. STUDY DESIGN: Following reconciliation of the different coding systems in the various countries, in-hospital mortality, unplanned readmission within 30 days, and "prolonged" hospital stay (>75th percentile) were risk-adjusted via logistic regression. A web-based interface was created to facilitate outcomes analysis for individual medical centers and enable peer comparisons. Small groups of clinicians are now exploring the potential reasons for variations in outcomes in their specialty. PRINCIPAL FINDINGS: There were 6,737,211 inpatient records, including 214,622 in-hospital deaths. Although diagnostic coding depth varied appreciably by country, comorbidity weights were broadly comparable. U.S. hospitals generally had the lowest mortality rates, shortest stays, and highest readmission rates. CONCLUSIONS: Intercountry differences in outcomes may result from differences in the quality of care or in practice patterns driven by socio economic factors. Carefully managed administrative data can be an effective resource for initiating dialog between hospitals within and across countries. Inclusion of important outcomes beyond hospital discharge would increase the value of these analyses. PMID- 23742026 TI - Intranasal immunization with a helper-dependent adenoviral vector expressing the codon-optimized fusion glycoprotein of human respiratory syncytial virus elicits protective immunity in BALB/c mice. AB - BACKGROUND: Human respiratory syncytial virus (RSV) is a serious pediatric pathogen of the lower respiratory tract. Currently, there is no clinically approved vaccine against RSV infection. Recent studies have shown that helper dependent adenoviral (HDAd) vectors may represent effective and safe vaccine vectors. However, viral challenge has not been investigated following mucosal vaccination with HDAd vector vaccines. METHODS: To explore the role played by HDAd as an intranasally administered RSV vaccine vector, we constructed a HDAd vector encoding the codon optimized fusion glycoprotein (Fsyn) of RSV, designated HDAd-Fsyn, and delivered intranasally HDAd-Fsyn to mice. RESULTS: RSV-specific humoral and cellular immune responses were generated in BALB/c mice, and serum IgG with neutralizing activity was significantly elevated after a homologous boost with intranasal (i.n.) application of HDAd-Fsyn. Humoral immune responses could be measured even 14 weeks after a single immunization. Immunization with i.n. HDAd-Fsyn led to effective protection against RSV infection on challenge. CONCLUSION: The results indicate that HDAd-Fsyn can induce powerful systemic immunity against subsequent i.n. RSV challenge in a mouse model and is a promising candidate vaccine against RSV infection. PMID- 23742027 TI - Polybrominated diphenyl ethers (PBDEs) and indicator polychlorinated biphenyls (PCBs) in foods from China: levels, dietary intake, and risk assessment. AB - A national survey of polybrominated diphenyl ethers (PBDEs) and indicator polychlorinated biphenyls (PCBs) congeners in various foodstuffs from the Chinese total diet study (TDS) performed in 2007 was conducted for the first time. Meats and aquatic foods had the highest average sum PBDEs (192.5 and 190.6 pg g-1 fresh weight, respectively). For indicator PCBs, the highest average concentration was found in aquatic foods (628.7 pg g-1 fresh weight). On the basis of measured PBDE and indicator PCB levels, the dietary intake estimate was subsequently calculated for the nonoccupationally exposed population in China. For adults, average estimated dietary intakes of PBDEs and indicator PCBs were 0.76 and 2.34 ng kg-1 bw day-1, respectively. Health risk assessment of PBDEs using a MOE approach recommended by EFSA suggested unlikely health concern with respect to current dietary intake of PBDEs in China. PMID- 23742028 TI - Hydrogen therapy may be an effective and specific novel treatment for acute graft versus-host disease (GVHD). AB - Allogeneic haematopoietic stem cell transplantation (HSCT) has been widely used for the treatment of haematological malignant and non-malignant haematologic diseases. However, acute graft-versus-host disease (aGVHD) is a kind of severe complication of HSCT limiting its application. Cytokines such as tumour necrosis factor-alpha (TNF-alpha), IL-6 play an extremely important role in the formation and development of aGVHD. Besides, the oxidation phenomena and/or the formation of free radicals have been suggested to be causally related to various haematological disorders including aGVHD. Reactive oxygen species (ROS), such as hydroxyl radicals, play an important role in the formation and development of aGVHD. Hydrogen has been reported to have the ability to inhibit levels of cytokines such as TNF, IL-6 in vivo. Our recent studies provided evidence that hydrogen inhalation can selectively reduce cytotoxic oxygen radicals and exert antioxidant effects. Therefore, we suggested that hydrogen may have therapeutic effects on aGVHD. This hypothesis entails many experimentally testable predictions. We propose the experimental study by detecting complete blood counts (CBC) and Clinic signs of aGVHD mice. We also propose to detect the levels of TNF alpha, IL-2, IL-1beta, IL-6 which play important roles in the pathogenesis of aGVHD. To discover potential mechanisms of the therapeutic effects of hydrogen on the aGVHD model, we will examine gene-expression profiles. This study will open a new therapeutic avenue combining the field of therapeutic medical gases and aGVHD. This theory is original and probably of importance, because therapeutic medical gases have never been used for aGVHD previously. PMID- 23742029 TI - A highly specific fluorescent probe for hypochlorous acid and its application in imaging microbe-induced HOCl production. AB - Oxidative stress induced by reactive oxygen species (ROS) plays crucial roles in a wide range of physiological processes and is also implicated in various diseases, including cancer, chronic inflammatory diseases, and neurodegenerative disorders. Among the various ROS, hypochlorous acid (HOCl) plays as a powerful microbicidal agent in the innate immune system. The regulated production of microbicidal HOCl is required for the host to control the invading microbes. However, as a result of the highly reactive and diffusible nature of HOCl, its uncontrolled production may lead to an adverse effect on host physiology. Because of its biological importance, many efforts have been focused on developing selective fluorescent probes to image ROS. However, it is still challenging to design a fluorescent probe with exclusive selectivity toward a particular member of ROS. In the current work, we designed FBS as a new fluorescent HOCl probe which has high selectivity, sensitivity, and short response time in a broad range of pH. Compared with other sensors, the "dual-lock" structure of FBS has an advantage of eliminating interferences from other ROS/RNS. Importantly, we further showed that our HOCl probe could be applied for the in vivo imaging of physiological HOCl production in the mucosa of live animals. This probe provides a promising tool for the study of HOCl production. PMID- 23742031 TI - Risky business: Is there an association between casual sex and mental health among emerging adults? AB - A multiethnic sample of single, heterosexual, emerging-adult college students (N = 3,907) ages 18 to 25, from 30 institutions across the United States, participated in a study about identity, culture, psychological well-being, and risky behaviors. Given ongoing debates about the connection between casual sex and psychological adjustment, in the current study we assessed the cross sectional association of participation in casual sex with psychological well being and distress. A greater proportion of men (18.6%) compared to women (7.4%) reported having had casual sex in the month prior to assessment. Structural equation modeling indicated that casual sex was negatively associated with well being (beta = .20, p < .001) and positively associated with psychological distress (beta = .16, p < .001). Gender did not moderate these associations. For emerging-adult college students, engaging in casual sex may elevate risk for negative psychological outcomes. PMID- 23742030 TI - Up-dosing with bilastine results in improved effectiveness in cold contact urticaria. AB - BACKGROUND: Cold contact urticaria (CCU) is characterized by itchy wheal and flare responses due to the release of histamine and other pro-inflammatory mediators after exposure to cold. The treatment of choice is nonsedating antihistamines, dosages of which may be increased up to fourfold if standard doses are ineffective. Here, we assess the effects of a standard 20 mg dose and up-dosing to 40 and 80 mg of bilastine in reducing the symptoms of CCU and inflammatory mediator release following cold challenge. METHODS: Twenty patients with CCU were included in this randomized, crossover, double-blind, placebo controlled 12-week study. They received placebo, 20, 40 or 80 mg of bilastine daily each for 7 days with 14-day washout periods. The primary readout was change in critical temperature thresholds (CTT). Secondary readouts were changes in pruritus, levels of histamine IL-6, IL-8 and TNF-alpha collected by skin microdialysis and safety and tolerability of bilastine. RESULTS: Bilastine 20 mg was highly effective (P < 0.0001) in reducing CTT. Up-dosing to 80 mg significantly (P < 0.04) increased its effectiveness. At this dose, 19 of 20 (95%) patients responded to treatment, with 12 of 20 (60%) becoming symptom free. Only one patient was refractory to treatment. Microdialysis levels of histamine, IL-6 and IL-8 assessed 1-3 h after cold challenge were significantly (P < 0.05) decreased following up-dosing with 80 mg bilastine. Bilastine treatment was well tolerated without evidence of increased sedation with dose escalation. CONCLUSIONS: Bilastine was effective in reducing the symptoms of patients with CCU. Increased efficacy of bilastine with fourfold up-dosing was without sedation and supports urticaria treatment guidelines. PMID- 23742032 TI - Analysis of population genetic structure of Indian Anopheles culicifacies species A using microsatellite markers. AB - BACKGROUND: Anopheles culicifacies sensu lato is an important vector of malaria in Southeast Asia contributing to almost 70% of malaria cases in India. It exists as morphologically similar sibling species A, B, C, D and E with varied geographical distribution patterns. Vector control measures have been difficult for this important vector as the sibling species have developed varying levels of resistance to the currently used insecticides. In view of the importance of this vector, we developed and validated a set of microsatellite markers and the same were used to analyze the population genetic structure of five different geographical populations of An. culicifacies A. METHODS: Anopheles culicifacies A samples were collected from different localities across India, and genotyping was performed using eight microsatellite markers on ABI Prism 310 Genetic Analyzer. Several statistical analyses were performed to ascertain the genetic diversity that exists within and between the populations. RESULTS: The markers were found to be moderately polymorphic in the populations. Genetic analysis indicated significant genetic differentiation between the majority of the population pairs analyzed and was not found to be related to the geographical distances between populations. CONCLUSION: This is the first and successful attempt to test the microsatellite markers developed for population genetic analysis of An. culicifacies A. Host feeding and breeding habits of species A suggest that factors other than ecological and geographical barriers were responsible for the genetic differentiation that has been observed between the populations. PMID- 23742033 TI - Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer--the RAPIDO trial. AB - BACKGROUND: Current standard for most of the locally advanced rectal cancers is preoperative chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy. Short-course preoperative radiation with delayed surgery has been shown to induce tumour down-staging in both randomized and observational studies. The concept of neo-adjuvant chemotherapy has been proven successful in gastric cancer, hepatic metastases from colorectal cancer and is currently tested in primary colon cancer. METHODS AND DESIGN: Patients with rectal cancer with high risk features for local or systemic failure on magnetic resonance imaging are randomized to either a standard arm or an experimental arm. The standard arm consists of chemoradiation (1.8 Gy x 25 or 2 Gy x 25 with capecitabine) preoperatively, followed by selective postoperative adjuvant chemotherapy. Postoperative chemotherapy is optional and may be omitted by participating institutions. The experimental arm includes short-course radiotherapy (5 Gy x 5) followed by full-dose chemotherapy (capecitabine and oxaliplatin) in 6 cycles before surgery. In the experimental arm, no postoperative chemotherapy is prescribed. Surgery is performed according to TME principles in both study arms. The hypothesis is that short-course radiotherapy with neo-adjuvant chemotherapy increases disease-free and overall survival without compromising local control. Primary end-point is disease-free survival at 3 years. Secondary endpoints include overall survival, local control, toxicity profile, and treatment completion rate, rate of pathological complete response and microscopically radical resection, and quality of life. DISCUSSION: Following the advances in rectal cancer management, increased focus on survival rather than only on local control is now justified. In an experimental arm, short-course radiotherapy is combined with full-dose chemotherapy preoperatively, an alternative that offers advantages compared to concomitant chemoradiotherapy with or without postoperative chemotherapy. In a multi-centre setting this regimen is compared to current standard with the aim of improving survival for patients with locally advanced rectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT01558921. PMID- 23742034 TI - Older African American women's lived experiences with depression and coping behaviours. AB - Little is known about older African American women's lived experiences with depression. What does depression mean to this group? What are they doing about their depression? Unfortunately, these questions are unanswered. This study examined older African American women's lived experiences with depression and coping behaviours. The common sense model provided the theoretical framework for present study. Thirteen community-dwelling African American women aged 60 and older (M = 71 years) participated. Using qualitative phenomenological data analysis, results showed the women held beliefs about factors that can cause depression including experiences of trauma, poverty and disempowerment. Results also indicated the women believed that depression is a normal reaction to life circumstances and did not see the need to seek professional treatment for depression. They coped by use of culturally sanctioned behaviours including religious practices and resilience. It appears these women's beliefs about depression and use of culturally sanctioned coping behaviours might potentially be a barrier to seeking professional mental healthcare, which could result in missed opportunities for early diagnosis and treatment of depression among this group. Implications for research, educational and clinical interventions are discussed. PMID- 23742035 TI - Hypertension risk: exercise is medicine* for most but not all. AB - Hypertension is a risk factor for heart disease, and chronic exercise is recognized as a method for reducing resting blood pressure. Recent studies report that while exercise may benefit the majority of the population, the blood pressure adaptation is not always uniform; some individuals have an adverse blood pressure response to chronic aerobic exercise programmes. The purpose of this study was to examine the individual changes in resting blood pressure in response to exercise training regimens aimed at increasing muscle mass and strength. We have also included exercise (resistance and aerobic) in combination with blood flow restriction (BFR). Of 74 individuals, 11% had an increased risk, 16% had a decreased risk and 73% had no change in risk classification following exercise. The statistical analysis found that the group that decreased risk with exercise tended to have higher baseline levels of blood pressure. However, there were little baseline differences between the group that increased risk or the group that had no change in risk, suggesting that starting values may not necessarily determine who will see a beneficial response. In conclusion, the blood pressure adaptation to resistance training and exercise with BFR is not homogeneous with some participants increasing, decreasing or staying in the same risk category following an exercise intervention. These are important findings as they would not have been noted or discussed when looking only at the group means. Future research may identify molecular predictors so that individuals at risk for adverse events can be identified prior to exercise. PMID- 23742036 TI - Postoperative outcomes following pancreaticoduodenectomy: how should age affect clinical practice? AB - BACKGROUND: Pancreaticoduodenectomy is an increasingly common procedure performed for both benign and malignant disease. There are conflicting data regarding the safety of pancreatic resection in older patients. Potentially modifiable perioperative risk factors to improve outcomes in older patients have yet to be determined. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database for 2008 to 2009 was used for this retrospective analysis. Patients undergoing pancreaticoduodenectomy were identified and divided into those above and below the age of 65. Preoperative risk factors and postoperative morbidity and mortality were evaluated. RESULTS: Among 2,045 patients included in this analysis, 994 patients were >65 years (48.6%) while 1,051 were (less than or equal to) 65 years (51.4%). Thirty-day mortality was higher in the older age group compared to the younger age group 3.6% vs. 1.9% respectively, P = 0.017, odds ratio 1.94. Older patients had a higher incidence of unplanned intubation, ventilator support >48 h and septic shock compared with younger patients. On multivariate logistic regression, after adjusting for other 30-day postoperative occurrences (significant at the P <0.1 level) only septic shock was independently associated with a higher odds of mortality, unplanned intubation, and ventilator support >48 h in older patients compared with younger patients. CONCLUSIONS: This report from a population-based database is the first to highlight postoperative sepsis as an independent risk factor for mortality and morbidity in older patients undergoing pancreatic resection. Careful perioperative management addressing this issue is essential for patients over the age of 65. PMID- 23742037 TI - Charge inversion, water splitting, and vortex suppression due to DNA sorption on ion-selective membranes and their ion-current signatures. AB - The physisorption of negatively charged single-stranded DNA (ssDNA) of different lengths onto the surface of anion-exchange membranes is sensitively shown to alter the anion flux through the membrane. At low surface concentrations, the physisorbed DNAs act to suppress an electroconvection vortex instability that drives the anion flux into the membrane and hence reduce the overlimiting current through the membrane. Beyond a critical surface concentration, determined by the total number of phosphate charges on the DNA, the DNA layer becomes a cation selective membrane, and the combined bipolar membrane has a lower net ion flux, at low voltages, than the original membrane as a result of ion depletion at the junction between the cation- (DNA) and anion-selective membranes. However, beyond a critical voltage that is dependent on the ssDNA coverage, water splitting occurs at the junction to produce a larger overlimiting current than that of the original membrane. These two large opposite effects of polyelectrolyte counterion sorption onto membrane surfaces may be used to eliminate limiting current constraints of ion-selective membranes for liquid fuel cells, dialysis, and desalination as well as to suggest a new low-cost membrane surface assay that can detect and quantify the number of large biomolecules captured by probes functionalized on the membrane surface. PMID- 23742039 TI - Selective actuation of arrays of carbon nanotubes using magnetic resonance. AB - We introduce the use of ferromagnetic resonance (FMR) to actuate mechanical resonances in as grown arrays of carbon nanotubes (CNTs) loaded with Ni particles (Ni-CNTs). This contactless method is closely related to the magnetic resonance force microscopy technique and provides spatial selectivity of actuation along the array. The Ni-CNT arrays are grown by chemical vapor deposition and are composed of homogeneous CNTs with uniform length (~600 nm) and almost equal diameter (~20 nm), which are loaded with Ni catalyst particles at their tips due to the tip growth mode. The vibrations of the Ni-CNTs are actuated by relying on the driving force that appears due to the FMR excited at about 2 GHz in the Ni particles (diameter ~100 nm). The Ni-CNT oscillations (frequency ~40 MHz) are detected mechanically by atomic force microscopy. The acquired oscillation images of the Ni-CNT uniform array reveal clear maxima in the spatial distribution of the oscillation amplitudes. We attribute these maxima to the "sensitive slices", i.e., the spatial regions of the Ni-CNT array where the FMR condition is met. Similar to magnetic resonance imaging, the sensitive slice is determined by the magnetic field gradient and moves along the Ni-CNT array as the applied magnetic field is ramped. Our excitation method does not require the presence of any additional microfabricated electrodes or coils near the CNTs and is particularly advantageous in cases where the traditional electrical actuation methods are not effective or cannot be implemented. The remote actuation can be effectively implemented also for arrays of other magnetic nanomechanical resonators. PMID- 23742038 TI - Distinct regulation of dengue virus-induced inflammasome activation in human macrophage subsets. AB - Macrophages (Mphi) are the major source of inflammatory cytokines and are target cells for dengue virus (DV) replication. However, Mphi are heterogeneous and their phenotypic and functional diversities are influenced by cytokines that regulate their differentiation, tissue distribution, and defense against invading pathogens. In vitro, human primary macrophages are derived from peripheral blood CD14+ monocytes in the presence of macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF). These are essential for developing tissue/resting macrophages (M-Mphi) and inflammatory macrophages (GM-Mphi), respectively. While IFN production is similar between M-Mphi and GM Mphi, M-Mphi cannot produce IL-1beta after DV infection. In contrast, GM-Mphi is more susceptible to DV infection and DV triggers CLEC5A in GM-Mphi to activate NLRP3 inflammasomes, which in turn release IL-18 and IL-1beta that are critical for Th17 activation and contribute to disease severity. Thus, GM-Mphi is more representative than M-Mphi for investigating inflammasome activation in dengue infection, and is invaluable for revealing the molecular mechanism of pathogen induced inflammatory reaction. Distinct phenotypes of macrophage subsets under the influence of M-CSF and GM-CSF raise the question of optimal conditions for culturing primary macrophages to study host-pathogen interaction. PMID- 23742040 TI - Distal hindlimb kinematics of galloping Thoroughbred racehorses on dirt and synthetic racetrack surfaces. AB - REASONS FOR PERFORMING STUDY: The effect of racetrack surface (dirt or synthetic) on distal hindlimb kinematics of racehorses running at competition speeds is not known. OBJECTIVES: To compare distal hindlimb and hoof kinematics during stance of breezing (unrestrained gallop) racehorses between dirt and synthetic surfaces. STUDY DESIGN: Two-dimensional kinematic video analysis of 5 Thoroughbred racehorses galloping at high speeds (12-17 m/s) on a dirt racetrack and a synthetic racetrack. METHODS: The positions of kinematic markers applied to the left hindlimb were recorded at 500 Hz. Position, velocity and acceleration of joint angles and hoof translation during stance were calculated in the sagittal plane. Peak translational and angular kinematic values were compared between the dirt and synthetic race surfaces using mixed model analyses of covariance. RESULTS: Maximum and heel-strike metatarsophalangeal (fetlock) angles were greater (P<0.05) on the dirt surface than on the synthetic surface. Maximum fetlock angle occurred earlier during stance on the dirt surface (P<0.05). Greater horizontal displacement of the heel during slide occurred on the dirt surface (P<0.05). CONCLUSIONS: During high-speed gallop, hindlimb fetlock hyperextension and horizontal hoof slide are greater on a dirt surface than on a synthetic surface. Synthetic race surfaces may mitigate risk of injury to hindlimb fetlock structures by reducing fetlock hyperextension and associated strains in fetlock support structures. Differences in hoof slide may contribute to different distal hindlimb kinematics between surfaces. PMID- 23742041 TI - Psychometric properties of the Brazilian Portuguese versions of the 29- and 13 item scales of the Antonovsky's Sense of Coherence (SOC-29 and SOC-13) evaluated in Brazilian cardiac patients. AB - AIM AND OBJECTIVES: To assess the construct validity and reliability of the Brazilian Portuguese versions of the 29- and 13-item scales of the Antonovsky's Sense of Coherence Scale (SOC-29 and SOC-13). BACKGROUND: Antonovsky's Sense of Coherence Questionnaire was developed to measure the main construct of the salutogenic theory, the sense of coherence. The use of the sense of coherence by health professionals might help identifying specific coping strategies used by person with chronic illness. DESIGN: Cross-sectional study. METHODS: The SOC-29 has been culturally adapted to Brazilian Portuguese language. In this study, we assessed its psychometric properties (construct validity and internal reliability) tested on 203 cardiac patients. The SOC-13 was tested on another 100 cardiac patients hospitalised in the same hospital. The construct validity of both versions was investigated through Pearson correlation between the measures of sense of coherence and of correlated constructs (self-esteem, depression and age), analysis of the principal components and comparison of distinct groups (male vs. female). The internal reliability for both versions was evaluated by Cronbach's alpha. RESULTS: For both versions, the construct validity assessments showed strong positive correlations between sense of coherence and self-esteem and strong negative correlations between sense of coherence and depression (convergent validity), and weak correlation between sense of coherence and age (divergent validity). Principal component analysis supported in part the presence of a single component (unidimensionality). Differences in sense of coherence were found by sex with SOC-29, but not with SOC-13. Cronbach's alpha coefficients showed satisfactory internal consistency in both versions. CONCLUSIONS: The Brazilian Portuguese versions of SOC-29 and SOC-13 can be considered valid and reliable for the populations studied. More studies need to be performed to assess these proprieties in other Brazilian populations. RELEVANCE TO CLINICAL PRACTICE: This scale can be used in research and clinical practice in Brazil to assess nursing interventions aimed at decreasing stress during cardiac rehabilitation. PMID- 23742042 TI - Cystic fibrosis transmembrane conductance regulator is expressed in mucin granules from Calu-3 and primary human airway epithelial cells. AB - Cystic fibrosis (CF) is caused by mutations in the tightly regulated anion channel cystic fibrosis transmembrane conductance regulator (CFTR), yet much of the pathology in this disease results from mucus obstruction of the small airways and other organs. Mucus stasis has been attributed to the abnormal luminal environment of CF airways, which results from dehydration of the mucus gel or low bicarbonate concentration. We show here that CFTR and MUC5AC are present in single mucin-containing granules isolated from a human airway epithelial cell line and from highly differentiated airway primary cell cultures. CFTR was not detected in MUC5AC granules from CFTR knockdown cells or CF primary cells. The results suggest a direct link between CFTR and the mucus defect. PMID- 23742043 TI - Leflunomide discontinuation in rheumatoid arthritis and influence of associated disease-modifying anti-rheumatic drugs: a survival analysis. AB - OBJECTIVES: The aims of this study were to describe the rate of leflunomide discontinuation in rheumatoid arthritis (RA) patients, in standard clinical practice, and to analyse which factors could influence this rate, paying particular attention to the concomitant treatment with other disease-modifying anti-rheumatic drugs (DMARDs). METHOD: We selected RA patients, diagnosed according to the 1987 American College of Rheumatology (ACR) criteria, attending the rheumatology outpatient clinic of the San Carlos Clinical Hospital (Madrid, Spain), who had started treatment with leflunomide between 1 January 2006 and 1 January 2011. Clinical records were examined until withdrawal of the drug, loss of follow-up, or 1 October 2011. Kaplan-Meier curves were set to account for leflunomide withdrawal. Cox bivariate and multivariate regression models were conducted to examine risk factors for leflunomide discontinuation. RESULTS: The incident rate (IR) for leflunomide discontinuation, regardless of the cause, was 27 per 100 patient-years [95% confidence interval (CI) 22-31]. We observed, in both the bivariate and multivariate regression analysis, that those aged > 75 years at the start of the leflunomide treatment and undergoing concurrent treatment with methotrexate (MTX) and/or hydroxychloroquine (HC) had a significantly higher risk of leflunomide discontinuation. CONCLUSIONS: An older age at the start of the treatment with leflunomide, or concomitant treatment with MTX and/or HC, could be associated with a higher risk of leflunomide discontinuation, regardless of the cause. Therefore, when taking MTX or HC, patients receiving leflunomide should be closely monitored early to detect the occurrence of adverse reactions, and hence prevent their aggravation. PMID- 23742044 TI - Postural control in quiet standing with a concurrent cognitive task in psychotic conditions. AB - Differences in postural control and performance between psychotic patients and healthy subjects were investigated using a dual task paradigm. Center of pressure (CoP) data and whole-body kinematics of the center of mass (CoM) were recorded during quiet standing with and without a backward counting task. Dual task response was similar in both groups: the magnitude of CoM-migration did not change, while CoP-CoM magnitude, a measure related to ankle joint torque, and CoP frequency both increased. The magnitudes of migration for CoM and CoP-CoM were greater in patients during both conditions, while CoP-frequency was similar to control subjects. Our results suggest that exaggerated ankle joint torque relative to CoP-frequency caused greater postural sway in patients during both conditions. PMID- 23742045 TI - Analysis of fatty acids and phytosterols in ethanol extracts of Nelumbo nucifera seeds and rhizomes by GC-MS. AB - The purpose of this study was to investigate the fatty acid and phytosterol contents in ethanol extracts of lotus seeds and rhizomes. These ethanol extracts were extracted with hexane. The hexane extracts were hydrolyzed in a microwave reactor, and total fatty acids and phytosterols were analyzed. The hexane extracts were also subjected to silica gel column chromatography. Nonpolar components (triglycerides and steryl-fatty acid esters) were hydrolyzed, and then the contents were analyzed. Polar components (diglycerides, monoglycerides, fatty acids, and phytosterols) were analyzed directly. Seeds contained higher concentrations of fatty acids and phytosterols compared to rhizomes. Linoleic acid, palmitic acid, and oleic acid were the main fatty acid components in seeds and rhizomes, and most of them in seeds were in the ester form. In seeds, phytosterols existed mainly in the free form rather than in steryl-fatty acid ester form. beta-Sitosterol was the most abundant phytosterol in seeds and rhizomes. PMID- 23742046 TI - Stress proteins in aging and life span. AB - Heat shock proteins (HSP) are molecular chaperones and have been implicated in longevity and aging in many species. Their major functions include chaperoning misfolded or newly synthesised polypeptides, protecting cells from proteotoxic stress, and processing of immunogenic agents. These proteins are expressed constitutively and can be induced by stresses such as heat, oxidative stress and many more. The induction of HSP in aging could potentially maintain protein homeostasis and longevity by refolding the damaged proteins which accumulate during aging and are toxic to cells. HSP are shown to increase life span in model organisms such as Caenorhabditis elegans and decrease aging-related proteotoxicity. Thus, decrease in HSP in aging is associated with disruption of cellular homeostasis which causes diseases such as cancer, cell senescence and neurodegeneration. HSP levels are decreased with aging in most organs including neurons. Aging also causes attenuation or alteration of many signalling pathways as well as the expression of transcription factors such as heat shock factor (HSF). The alteration in regulation and synthesis of Forkhead box O3a (FoxO3a) family of transcription factors as well as major antioxidant enzymes (manganese superoxide dismutase, catalase) are also seen in aging. Among many signalling mechanisms involved in altering longevity and aging, the insulin/IGF-1 pathway and the Sir2 deacetylase are highly significant. This review enquires into the role of some of these pathways in longevity/aging along with HSP. PMID- 23742048 TI - Albumin administration protects against bilirubin-induced auditory brainstem dysfunction in Gunn rat pups. AB - BACKGROUND: Free bilirubin (Bf), the unbound fraction of unconjugated bilirubin (UCB), can induce neurotoxicity, including impairment of the auditory system, which can be assessed by brainstem auditory evoked potentials (BAEPs). We hypothesized that albumin might reduce the risk of neurotoxicity by decreasing Bf and its translocation into the brain. AIM: To determine the effects of albumin on BAEPs and brain bilirubin content in two Gunn rat pup models of acute hyperbilirubinemia. METHODS: We used Gunn rat pups, which have a deficiency of the bilirubin-conjugating enzyme UGT1A1. We induced haemolysis by injection of phenylhydrazine (phz) into 14-days old pups. Subsequently, pups were treated with either i.p. human serum albumin (HSA; 2.5 g/kg; n = 8) or saline (control, n = 8). We induced acute neurotoxicity by injecting 16-days old pups with sulphadimethoxine (sulpha) and treated them with either HSA (n = 9) or saline (control, n = 10). To assess bilirubin neurotoxicity, we used the validated BAEP method and compared relevant parameters; i.e. peak latency values and interwave interval (IWI) between peak I and peak II, a marker of acute neurotoxicity. RESULTS: Phz and sulpha significantly increased IWI I-II by 26% and 29% (P < 0.05) in the haemolysis and the displacement model, respectively. Albumin completely prevented the increase of IWI I-II in either model. The beneficial effect of albumin in the displacement-model by means of normal BAEPs was in line with less bilirubin in the brain (NS). Interestingly, in the haemolysis model the accumulation of total bilirubin in the brain was unaltered, and BAEPs still appeared normal. This might advocate for a role of brain Bf which was calculated and showed that albumin treatment non-significantly reduces Bf concentrations in brain, compared with saline treatment. CONCLUSIONS: Albumin treatment is neuroprotective in acute hyperbilirubinemia in Gunn rat pups. Our present results underline the importance of functional diagnostic test of neurotoxicity above biochemical concentrations. PMID- 23742047 TI - Structure and mechanism of non-histone protein acetyltransferase enzymes. AB - Post-translational modification of proteins is ubiquitous and mediates many cellular processes, including intracellular localization, protein-protein interactions, enzyme activity, transcriptional regulation and protein stability. While the role of phosphorylation as a key post-translational modification has been well studied, the more evolutionarily conserved post-translational modification acetylation has only recently attracted attention as a key regulator of cellular events. Protein acetylation has been largely studied in the context of its role in histone modification and gene regulation, where histones are modified by histone acetyltransferases to promote transcription. However, more recent acetylomic and biochemical studies have revealed that acetylation is mediated by a broader family of protein acetyltransferases. The recent structure determination of several protein acetyltransferases has provided a wealth of molecular information regarding structural features of protein acetyltransferases, their enzymatic mechanisms, their mode of substrate-specific recognition and their regulatory elements. In this review, we briefly describe what is known about non-histone protein substrates, but mainly focus on a few recent structures of protein acetyltransferases to compare and contrast them with histone acetyltransferases to better understand the molecular basis for protein recognition and modification by this family of protein modification enzymes. PMID- 23742049 TI - Temporal trend analysis of avoidable mortality in Taiwan, 1971-2008: overall progress, with areas for further medical or public health investment. AB - BACKGROUND: Avoidable mortality (AM), or "unnecessary untimely death," is considered an indicator of health care quality. We investigated trends in the age standardized mortality rates (ASMRs) and associated standard expected years of life lost (SEYLL) for deaths amenable to medical care or public health measures in Taiwan from 1971-2008, with an emphasis on identifying areas where additional medical or public health investment may help reduce the burden of AM. METHODS: Taiwan's ASMRs per 100,000 for AM and other causes of death were calculated using data from the National Death Certificate Registry in five-year bins from 1971 to 2008. SEYLL rates per 100,000 were calculated annually from 1971 to 2008 using the same data source. RESULTS: ASMR for almost all AM and other causes of death declined dramatically from 1971 to 2008 except for lung cancer (16.6% and 7.4% increase among men and women, respectively) and breast cancer (109.8% increase among women). In the same period, SEYLL due to lung cancer increased from 269.2 to 555.7 for men and 249.7 to 342.5 for women. For women, SEYLL due to breast cancer increased from 263.5 in 1971 to 659.3 in 2008. There were gender-specific differences in the reduction (or increase) in AM rates, with women showing larger rates of reduction or smaller rates of increase. Among men, AM fell by 65.9% from 1971-1975 to 2006-2008, and deaths from other causes increased by 15.6%. Among women, AM and deaths from other causes fell by 80.8% and 59.8% respectively. SEYLL decreased, respectively among males and females, from 23,147.3 and 24,081.1 in 1971 to 11,261.8 and 5,929.6 in 2008. CONCLUSION: From 1971 to 2008, Taiwan experienced a dramatic reduction in most AM and corresponding SEYLL except for lung cancer (for both males and females) and breast cancer (for females). Additional effort should be devoted to public health measures to combat the rising prevalence of smoking in Taiwan, which may be responsible for the increasing AM from lung cancer. If AM in breast cancer continues unabated in the future, greater policy emphasis on the early detection and treatment of breast cancer may also be warranted. PMID- 23742050 TI - GP73 is down-regulated in gastric cancer and associated with tumor differentiation. AB - BACKGROUND: Golgi protein 73 (GP73) is a type II Golgi transmembrane protein. It is over-expressed in several cancers, including hepatocellular carcinomas, bile duct carcinomas, lung cancer and prostate cancer. However, there are few reports of GP73 in gastric cancer. This study is aimed at investigating the expression of GP73 and its relationship with clinical pathological characters in gastric cancer. METHODS: GP73 mRNA level was determined by quantitative real-time RT-PCR in 41 pairs of matched gastric tumorous tissues and adjacent non-tumorous mucosal tissues. Western blotting was also performed to detect the GP73 protein level. GP73 protein expression was analyzed by immunohistochemistry in 52 clinically characterized gastric cancer patients and 10 non-tumorous gastric mucosal tissue controls. RESULTS: The mRNA and protein level of GP73 were significantly down regulated in gastric tumorous tissues compared with the non-tumorous mucosal tissues. In non-tumorous mucosa, strong diffuse cytoplasmic staining can be seen in cells located at the surface of the glandular and foveolar compartment; while in tumorous tissues, the staining was much weaker or even absent, and mainly in a semi-granular dot-like staining pattern. The expression level of GP73 protein was associated with patients' gender and tumor differentiation. CONCLUSIONS: GP73 was normally expressed in non-tumorous gastric mucosa and down-regulated in gastric cancer. Its expression in gastric cancer was correlated with tumor differentiation. PMID- 23742051 TI - Attention deficit hyperactivity disorder in the European adult population: prevalence, disease awareness, and treatment guidelines. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobiological disorder with childhood onset and persistence into adolescence and adulthood. METHODS: Our literature review reports scientific publications and guidelines on the treatment of adult ADHD, with a particular focus on European countries, identified by literature searches in Medline and Embase. The final literature search was performed in July 2012, incorporating literature from 1974 to 2012. The primary research parameters were 'Europe' (including single European countries), 'ADHD', 'attention deficit disorder', 'attention deficit', 'attention disorder', and 'hyperactivity'. Secondary search parameters were 'comorbid', 'epidemiology' or 'prevalence', 'disease management', 'drug therapy', or 'therapy'. The main searches were also limited to adults and English language publications. The papers identified by this literature review were selected for inclusion by consensus of the authors based on clinical relevance. RESULTS: Appropriate resources for the diagnosis and treatment of adult ADHD in Europe are scarce, and many cases go untreated, particularly because of the frequent presence of psychiatric comorbidities. Apart from atomoxetine, and an extended release form of methylphenidate in Germany, no other medications have been approved for starting treatment in adult ADHD patients in the European Union. However, a variety of stimulant and non-stimulant medications are used off-label, and a number of studies have confirmed that these medications are well tolerated and effective in adult patients with ADHD. CONCLUSIONS: Our results emphasize the need for broader access to effective treatments for adult ADHD patients in Europe. PMID- 23742052 TI - An efficient Rh/O2 catalytic system for oxidative C-H activation/annulation: evidence for Rh(I) to Rh(III) oxidation by molecular oxygen. AB - A novel and efficient Rh/O2 catalytic system has been developed and shown to catalyze highly efficient oxidative C-H activation/annulation reactions, producing a broad range of isoquinolinium salts with high turnover numbers (up to 740). Mechanistic studies provided strong evidence of facile oxidation of Rh(I) to Rh(III) by molecular oxygen facilitated by acid. PMID- 23742054 TI - Alterations in the rate of binge ethanol consumption: implications for preclinical studies in mice. AB - The rate at which alcohol (ethanol) is consumed has direct impact on its behavioral and subjective effects. For this reason, alterations in the pattern of ethanol consumption as a function of drinking history might be critical to the development and maintenance of alcoholism. Furthermore, because pharmacological interventions aimed at disrupting the motivation to consume ethanol are dependent on the brain/plasma concentrations present when an individual is most likely to engage in consumption of this substance, characterizing temporal drinking patterns might be useful to determine the timing of such treatments. The primary goal of the present study was to evaluate alterations in the timecourse of daily binge (drinking-in-the-dark; DID) ethanol consumption. We gave 14 daily 2 hour DID ethanol or water access sessions to male C57BL/6J (B6) mice using a state of the art volumetric drinking monitoring device. We then, primarily as a proof-of principle, used the GABAB allosteric modulator GS39783 (GS) to determine how this compound influenced the timecourse of binge-like ethanol intake. The rate of ethanol consumption increased dramatically over sessions with the majority occurring in the first few minutes of the final session. Additionally, ethanol consumption occurring immediately following access was almost completely abolished in mice pre-treated with GS; an effect which was ethanol-specific only at this early time interval. These data characterize progressive alterations in the rate of ethanol intake using the DID model and suggest that careful consideration of prior ethanol history and timing of drug administration are warranted when interpreting results of pre-clinical drug administration studies. PMID- 23742053 TI - 5-methyl-cytosine and 5-hydroxy-methyl-cytosine in the genome of Biomphalaria glabrata, a snail intermediate host of Schistosoma mansoni. AB - BACKGROUND: Biomphalaria glabrata is the mollusc intermediate host for Schistosoma mansoni, a digenean flatworm parasite that causes human intestinal schistosomiasis. An estimated 200 million people in 74 countries suffer from schistosomiasis, in terms of morbidity this is the most severe tropical disease after malaria. Epigenetic information informs on the status of gene activity that is heritable, for which changes are reversible and that is not based on the DNA sequence. Epigenetic mechanisms generate variability that provides a source for potentially heritable phenotypic variation and therefore could be involved in the adaptation to environmental constraint. Phenotypic variations are particularly important in host-parasite interactions in which both selective pressure and rate of evolution are high. In this context, epigenetic changes are expected to be major drivers of phenotypic plasticity and co-adaptation between host and parasite. Consequently, with characterization of the genomes of invertebrates that are parasite vectors or intermediate hosts, it is also essential to understand how the epigenetic machinery functions to better decipher the interplay between host and parasite. METHODS: The CpGo/e ratios were used as a proxy to investigate the occurrence of CpG methylation in B. glabrata coding regions. The presence of DNA methylation in B. glabrata was also confirmed by several experimental approaches: restriction enzymatic digestion with isoschizomers, bisulfite conversion based techniques and LC-MS/MS analysis. RESULTS: In this work, we report that DNA methylation, which is one of the carriers of epigenetic information, occurs in B. glabrata; approximately 2% of cytosine nucleotides are methylated. We describe the methylation machinery of B. glabrata. Methylation occurs predominantly at CpG sites, present at high ratios in coding regions of genes associated with housekeeping functions. We also demonstrate by bisulfite treatment that methylation occurs in multiple copies of Nimbus, a transposable element. CONCLUSIONS: This study details DNA methylation for the first time, one of the carriers of epigenetic information in B. glabrata. The general characteristics of DNA methylation that we observed in the B. glabrata genome conform to what epigenetic studies have reported from other invertebrate species. PMID- 23742055 TI - Disulfide cross-linked phosphorylcholine micelles for triggered release of camptothecin. AB - A series of block copolymers based on 2-methacryloyloxyethyl phosphorylcholine (MPC) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Incorporation of dihydrolipoic acid (DHLA) into the hydrophobic block led to formation of block copolymer micelles in water. The micelles were between 15 and 30 nm in diameter, as characterized by dynamic light scattering (DLS), with some size control achieved by adjusting the hydrophobic/hydrophilic balance. Cross-linked micelles were prepared by disulfide formation, and observed to be stable in solution for weeks. The micelles proved amenable to disassembly when treated with a reducing agent, such as dithiothreitol (DTT), and represent a potential delivery platform for chemotherapeutic agents. As a proof-of-concept, camptothecin (CPT) was conjugated to the polymer scaffold through a disulfide linkage, and release of the drug from the micelle was monitored by fluorescence spectroscopy. These CPT-loaded prodrug micelles showed a reduction in release rate compared to physically encapsulated CPT. The use of disulfide conjugation facilitated drug release under reducing conditions, with a half-life (t1/2) of 5.5 h in the presence of 3 mM DTT, compared to 28 h in PBS. The toxicity of the micellar prodrugs was evaluated in cell culture against human breast (MCF7) and colorectal (COLO205) cancer cell lines. PMID- 23742056 TI - Implications of metric choice for common applications of readmission metrics. AB - OBJECTIVE: To quantify the differential impact on hospital performance of three readmission metrics: all-cause readmission (ACR), 3M Potential Preventable Readmission (PPR), and Centers for Medicare and Medicaid 30-day readmission (CMS). DATA SOURCES: 2000-2009 California Office of Statewide Health Planning and Development Patient Discharge Data Nonpublic file. STUDY DESIGN: We calculated 30 day readmission rates using three metrics, for three disease groups: heart failure (HF), acute myocardial infarction (AMI), and pneumonia. Using each metric, we calculated the absolute change and correlation between performance; the percent of hospitals remaining in extreme deciles and level of agreement; and differences in longitudinal performance. PRINCIPAL FINDINGS: Average hospital rates for HF patients and the CMS metric were generally higher than for other conditions and metrics. Correlations between the ACR and CMS metrics were highest (r = 0.67-0.84). Rates calculated using the PPR and either ACR or CMS metrics were moderately correlated (r = 0.50-0.67). Between 47 and 75 percent of hospitals in an extreme decile according to one metric remained when using a different metric. Correlations among metrics were modest when measuring hospital longitudinal change. CONCLUSIONS: Different approaches to computing readmissions can produce different hospital rankings and impact pay-for-performance. Careful consideration should be placed on readmission metric choice for these applications. PMID- 23742057 TI - Generation and functional analysis of human TNF-alpha/iNOS-producing dendritic cells (Tip-DC). AB - BACKGROUND: A unique type of CD11c(pos) dendritic cells (DC) is abundant in inflamed tissue, for example, in chronic inflammatory skin diseases. Due to their remarkable production of tumor necrosis factor (TNF)-alpha and inducible NO synthase (iNOS), these cells have been referred to as TNF and iNOS-producing DC (Tip-DC). While Tip-DC have been mainly characterized in murine models of infection, functional data about their human counterpart are lacking. OBJECTIVES: We sought to generate human Tip-DC in vitro und thus provide a new model for the investigation of their phenotype and function. METHODS: We generated human Tip-DC from monocytic precursor cells of healthy individuals, atopic and psoriatic patients using human serum. Resting and stimulated cells were analyzed by flow cytometry, real-time PCR, and by ELISA. INOS activity was measured by fluorometric detection of NO. RESULTS: Tip-DC closely resembled their in vivo counterparts by expressing CD11c, CD86, and CD40 while lacking CD1a, CD1c, or CD207/Langerin. Bacterial stimulation of Tip-DC from healthy donors, atopic dermatitis, or psoriasis patients resulted in a similar increase in iNOS activity and TNF-alpha production. In kinetic experiments, TNF-alpha, a putative activator of Tip-DC, could not induce NOS2. Upon bacterial stimulation, TNFA, IL6, IL12B, and IL23A mRNA appeared in a first wave, while IL12A and NOS2 mRNA were up regulated later on but not blocked by anti-TNF-alpha agents, implying a biphasic pro-inflammatory response. CONCLUSIONS: We developed a new model for the study of human Tip-DC and provide the first evidence of their pro-inflammatory capacity. PMID- 23742058 TI - Exposure to wood smoke increases arterial stiffness and decreases heart rate variability in humans. AB - BACKGROUND: Emissions from biomass combustion are a major source of indoor and outdoor air pollution, and are estimated to cause millions of premature deaths worldwide annually. Whilst adverse respiratory health effects of biomass exposure are well established, less is known about its effects on the cardiovascular system. In this study we assessed the effect of exposure to wood smoke on heart rate, blood pressure, central arterial stiffness and heart rate variability in otherwise healthy persons. METHODS: Fourteen healthy non-smoking subjects participated in a randomized, double-blind crossover study. Subjects were exposed to dilute wood smoke (mean particle concentration of 314+/-38 MUg/m3) or filtered air for three hours during intermittent exercise. Heart rate, blood pressure, central arterial stiffness and heart rate variability were measured at baseline and for one hour post-exposure. RESULTS: Central arterial stiffness, measured as augmentation index, augmentation pressure and pulse wave velocity, was higher after wood smoke exposure as compared to filtered air (p < 0.01 for all), and heart rate was increased (p < 0.01) although there was no effect on blood pressure. Heart rate variability (SDNN, RMSSD and pNN50; p = 0.003, p < 0.001 and p < 0.001 respectively) was decreased one hour following exposure to wood smoke compared to filtered air. CONCLUSIONS: Acute exposure to wood smoke as a model of exposure to biomass combustion is associated with an immediate increase in central arterial stiffness and a simultaneous reduction in heart rate variability. As biomass is used for cooking and heating by a large fraction of the global population and is currently advocated as a sustainable alternative energy source, further studies are required to establish its likely impact on cardiovascular disease. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01488500. PMID- 23742059 TI - Investigation of rhythms of secretion and repeatability of plasma adrenocorticotropic hormone concentrations in healthy horses and horses with pituitary pars intermedia dysfunction. AB - REASONS FOR PERFORMING STUDY: There is little published information on whether measurement of plasma ACTH concentration at a single timepoint is a repeatable indicator of pituitary pars intermedia dysfunction (PPID). OBJECTIVES: To determine whether ultradian or circadian fluctuations in ACTH production influence plasma ACTH concentration in normal horses and horses with PPID. STUDY DESIGN: Prospective observational study. METHODS: Plasma ACTH concentration in 8 non-PPID horses and 8 horses with PPID was measured at 08.00, 11.00, 14.00 and 17.00 h on 5 nonconsecutive days within a 3 week period. In addition, at 08.30 h on one day, 6 samples were collected from each horse at precisely 5 min intervals over a period of 25 min. Descriptive and graphical analysis was performed and a linear mixed effects model was fitted to assess the effect of time of day on ACTH concentration in non-PPID and PPID horses. RESULTS: Evidence of ultradian fluctuation in ACTH production was not identified in either non-PPID or PPID horses. Evidence for circadian fluctuation was identified in non-PPID horses; plasma ACTH concentrations were highest at 08.00 h and decreased through the day. There was no evidence of circadian fluctuation in PPID horses. In non-PPID horses, the magnitude of circadian changes in ACTH concentration was smaller than variations in concentration that occurred at random. Intrahorse variability of ACTH concentration was greater in PPID horses than in non-PPID horses. CONCLUSIONS: Ultradian and circadian fluctuations in ACTH concentration are unlikely to influence clinical decision making; however, variations of potential clinical relevance do occur in individual horses, for reasons that remain to be determined, and increase in magnitude with progression of PPID. Results of the current study indicate that when an ACTH concentration between 19 and 40 pg/ml is measured, further testing should be considered to increase the accuracy of PPID diagnosis. PMID- 23742060 TI - Nucleoside 5'-phosphorothioate derivatives as oxidative stress protectants in PC12 cells. AB - Iron-induced oxidative damage of mitochondria contributes to cellular death seen in neurodegenerative diseases, therefore, there is a demand for nontoxic, biocompatible, and effective Fe-ion chelators. We evaluated the chelation of Fe(II) by phosphate derivatives using ferrozine as an indicator. We studied the effect of phosphate derivatives on inhibiting Fe(II)-induced oxidative stress in PC12 cells, and metabolic stability in PC12 cells was evaluated. Nucleotides containing phosphorothioate moieties inhibited ROS formation better than natural nucleotides and were more metabolically stable in PC12 cells. Finally, we elucidated that these nucleotides activate the MAP-kinase pathway that contributes to protection of PC12 cells under oxidative stress. PMID- 23742061 TI - Cloning, characterization, and promoter analysis of mouse Myo10 gene. AB - Myosin X (Myo10) is an unconventional myosin associated with filopodia motility. Recent studies show that in addition to full-length Myo10, brain expresses a shorter form of Myo10 that lacks a myosin motor domain named headless Myo10. Herein, we analyzed and cloned 2-kb of the 5'-upstream sequences of mouse full length Myo10 (fMyo10) and headless Myo10 (hMyo10) to understand the transcriptional regulation of the Myo10 gene. The putative transcription factor binding sites and CpG island were analyzed by a bioinformatic approach. Luciferase reporter assays showed that the 2-kb of 5'-upstream sequences of both fMyo10 and hMyo10 had promoter activities. PMID- 23742062 TI - Synthesis, characterization, and cytotoxicity studies of a novel palladium(II) complex and evaluation of DNA-binding aspects. AB - A new water-soluble palladium(II) complex, [Pd(bpy)(pyr-Ac]NO3 in which bpy = 2,2'-bipyridine and pyr-Ac is 1-pyrrolacetato, has been synthesized and characterized by spectroscopic methods (1H NMR, FT-IR, and UV-Vis), molar conductivity measurements, and elemental analysis. The results obtained from elemental analysis and conductivity measurements confirmed the stoichiometry of ligand and its complex while the characteristic peaks in UV-Vis and FT-IR and resonance peaks in (1H NMR spectra confirmed the formation of ligand frameworks around the palladium ion. The 50% cytotoxic concentration (Ic50) of new synthesized Pd(II) complex was determined by using MTT assay against human breast cancer cell line, T47D. The interaction between the Pd(II) complex with calf thymus DNA was studied at different temperatures by using absorption spectroscopy, fluorescence titration spectra, ethidium bromide displacement, and gel chromatography studies. The results obtained by absorption spectroscopy revealed that the Pd(II) complex can bind to DNA cooperatively at low concentrations. Several binding parameters in the above interaction were calculated by the fluorescence quenching method. The quenching mechanism was suggested to be the static quenching. The thermodynamic parameters: enthalpy change (DeltaH degrees ), entropy change (DeltaS degrees ), and Gibbs free energy (DeltaG degrees ), showed that van der Waals and hydrogen binding are predominant intermolecular forces between Pd(II) complex and DNA. These results were also consistent with the results obtained from Scatchard's plots. PMID- 23742063 TI - A new route for the synthesis of 4-amino-5-fluoro-7-(2'-deoxy-2'-fluoro-2'-C methyl-beta-D-ribofuranosyl)-1H-pyrrolo[2,3-d]pyrimidine. AB - A new route for the synthesis of 4-amino-5-fluoro-7-(2'-deoxy-2'-fluoro-2'-C methyl-beta-D-ribofuranosyl)-1H-pyrrolo[2,3-d]pyrimidine 1, was developed. PMID- 23742064 TI - Synthesis and evaluation of novel 6',6'-difluoro 5'-deoxycarbocyclic phosphonic acid nucleosides as antiviral agents. AB - The authors describe highly efficient synthetic routes for the preparation of novel 6',6'-difluoro 5'-deoxycarbocyclic phosphonic acid nucleosides from 1,4 dihydroxy-2-butene. The discovery that the 6'-fluorinated carbocyclic nucleoside (2, EC50 = 0.16 MUM) is a potent anti-HSV-1 agent led to the syntheses and biological evaluations of 6'-modified 5'-deoxyversions of carbocyclic phosphonate nucleosides. The synthesized nucleoside analogues 15, 18, 22, and 25 were tested for anti-HIV activity and for cytotoxicity. However, none of them showed significant anti-HIV-1 activity or cytotoxicity at concentrations up to 100 MUM. PMID- 23742065 TI - A loss of social eating: the experience of individuals living with gastroparesis. AB - AIMS AND OBJECTIVES: To report the experience of patients living with gastroparesis. BACKGROUND: The complex illness of gastroparesis is a condition of delayed gastric emptying associated with a range of different symptoms, including nausea, vomiting and depression, resulting in altered eating patterns. Patients are often over-investigated, treatments are not always successful, and quality of life is often impaired. DESIGN: A descriptive phenomenology study was undertaken to examine the experience of living with gastroparesis. Nine gastroparesis patients gave in-depth interviews. The interviews were transcribed, and framework analysis methods applied. METHODS: A descriptive phenomenology study was undertaken. Nine gastroparesis patients gave in-depth interviews. The interviews were transcribed, and framework analysis methods applied. RESULTS: Four main themes emerged: the first described their experiences and opinions of medical professionals, the second their understanding of mental health and mental illness, the third how they managed social settings and the fourth their identity and security. Their behaviour around food and mealtimes was often associated with feelings of loss, isolation and rejection, which influenced their reported quality of life. These factors resulted in their personal struggle to understand how this chronic, stigmatising illness affects their identity and their need for security. CONCLUSIONS: The complex illness of gastroparesis affects every aspect of patients' lives. As treatments for gastroparesis continue to evolve, therapies to help these patients address the psychological impact and the feelings of loss they report must not be overlooked. RELEVANCE TO CLINICAL PRACTICE: A better understanding of these patients' sense of loss of normal eating behaviour and the associated psychological distress needs to inform gastroparesis service provision with a view to developing a more holistic service for this patient group. PMID- 23742066 TI - Suicide commitment with metformin: our experience with five cases. AB - Biguanides can function as oral antihyperglycemic drugs. They were used for diabetes mellitus or prediabetes treatment over the last nine decades, but they lost their popularity in 1970s because of phenformin and regained with metformin. For metformin, the most common side effects are diarrhea and dyspepsia, occurring in up to 30% of patients. The most important and serious side effect is lactic acidosis. Phenformin was removed from the markets before 1970, because it caused lactic acidosis in 40-65 patients in 100,000 patient-years. Metformin causes lactate accumulation only in patients who have hepatic failure, renal failure or in patients who attempt suicide with high dosage of drugs. In this report, we present five patients who used high doses of metformin for suicide attempt. PMID- 23742067 TI - Optimization and variability of motor behavior in multifinger tasks: what variables does the brain use? AB - The neural control of movement has been described using different sets of elemental variables. Two possible sets of elemental variables have been suggested for finger pressing tasks: the forces of individual fingers and the finger commands (also called finger modes or central commands). The authors analyzed which of the 2 sets of the elemental variables is more likely used in the optimization of the finger force sharing and which set is used for the stabilization of performance. They used two recently developed techniques-the analytical inverse optimization (ANIO) and the uncontrolled manifold (UCM) analysis-to evaluate each set of elemental variables with respect to both aspects of performance. The results of the UCM analysis favored the finger commands as the elemental variables used for performance stabilization, while ANIO worked equally well on both sets of elemental variables. A simple scheme is suggested as to how the CNS could optimize a cost function dependent on the finger forces, but for the sake of facilitation of the feed forward control it substitutes the original cost function by a cost function, which is convenient to optimize in the space of finger commands. PMID- 23742068 TI - Women and HIV in a moderate prevalence setting: an integrative review. AB - BACKGROUND: Almost 32,000 people are living with human immunodeficiency virus (HIV) in Papua New Guinea (PNG). The primary route of transmission in this moderate prevalence setting is through heterosexual sex. Thus a gendered understanding of HIV is required to inform HIV prevention, treatment and care options. The aim of this review is to investigate understandings specifically about women and HIV in PNG and to identify gaps in the literature to inform future HIV research. METHODS: An integrative review of literature about women, HIV and PNG was conducted using a systematic search of online databases, including book chapters and grey literature. Prior to inclusion, literature was assessed using inclusion and exclusion criteria, and the Critical Appraisal Skills Programme (CASP) appraisal tool. Selected articles, book chapters and reports were coded and a constant comparative method of analysis used to construct a series of themes. RESULTS: The 26 articles, book chapters and reports included in the review were predominantly descriptive, original research (23/26 pieces of literature). Six themes were identified in the literature: economic, social and cultural factors (including mobility); gender issues (including violence against women); knowledge about HIV (including perception of risk of HIV); religious beliefs about HIV; women perceived as responsible for HIV transmission; and prevention of HIV. Literature about women and HIV in PNG is predominantly focussed upon women who sell sex, women as mothers or young women. Women are usually represented as either victims of HIV or responsible for transmitting HIV. Anthropological and social research has described the economic, social and cultural context along with the lived experience of HIV in PNG, but there is limited operations research or implementation research available. CONCLUSIONS: The literature reviewed has highlighted the importance of a gendered analysis of HIV prevention, care and treatment in PNG. There is an opportunity for operations, implementation and health systems research about HIV in PNG to shift research from description to action. PMID- 23742069 TI - Spectroscopic studies of the mononuclear non-heme Fe(II) enzyme FIH: second sphere contributions to reactivity. AB - Factor inhibiting hypoxia-inducible factor (FIH) is an alpha-ketoglutarate (alphaKG)-dependent enzyme which catalyzes hydroxylation of residue Asn803 in the C-terminal transactivation domain (CAD) of hypoxia-inducible factor 1alpha (HIF 1alpha) and plays an important role in cellular oxygen sensing and hypoxic response. Circular dichroism (CD), magnetic circular dichroism (MCD), and variable-temperature, variable-field (VTVH) MCD spectroscopies are used to determine the geometric and electronic structures of FIH in its (Fe(II)), (Fe(II)/alphaKG), and (Fe(II)/alphaKG/CAD) forms. (Fe(II))FIH and (Fe(II)/alphaKG)FIH are found to be six-coordinate (6C), whereas (Fe(II)/alphaKG/CAD)FIH is found to be a 5C/6C mixture. Thus, FIH follows the general mechanistic strategy of non-heme Fe(II) enzymes. Modeling shows that, when Arg238 of FIH is removed, the facial triad carboxylate binds to Fe(II) in a bidentate mode with concomitant lengthening of the Fe(II)/alphaKG carbonyl bond, which would inhibit the O2 reaction. Correlations over alpha-keto acid-dependent enzymes and with the extradiol dioxygenases show that members of these families (where both the electron source and O2 bind to Fe(II)) have a second-sphere residue H-bonding to the terminal oxygen of the carboxylate, which stays monodentate. Alternatively, structures of the pterin-dependent and Rieske dioxygenases, which do not have substrate binding to Fe(II), lack H-bonds to the carboxylate and thus allow its bidentate coordination which would direct O2 reactivity. Finally, vis-UV MCD spectra show an unusually high-energy Fe(II) -> alphaKG pi* metal-to-ligand charge transfer transition in (Fe(II)/alphaKG)FIH which is red-shifted upon CAD binding. This red shift indicates formation of H bonds to the alphaKG that lower the energy of its carbonyl LUMO, activating it for nucleophilic attack by the Fe-O2 intermediate formed along the reaction coordinate. PMID- 23742070 TI - Exploring the transcription factor activity in high-throughput gene expression data using RLQ analysis. AB - BACKGROUND: Interpretation of gene expression microarray data in the light of external information on both columns and rows (experimental variables and gene annotations) facilitates the extraction of pertinent information hidden in these complex data. Biologists classically interpret genes of interest after retrieving functional information from a subset of genes of interest. Transcription factors play an important role in orchestrating the regulation of gene expression. Their activity can be deduced by examining the presence of putative transcription factors binding sites in the gene promoter regions. RESULTS: In this paper we present the multivariate statistical method RLQ which aims to analyze microarray data where additional information is available on both genes and samples. As an illustrative example, we applied RLQ methodology to analyze transcription factor activity associated with the time-course effect of steroids on the growth of primary human lung fibroblasts. RLQ could successfully predict transcription factor activity, and could integrate various other sources of external information in the main frame of the analysis. The approach was validated by means of alternative statistical methods and biological validation. CONCLUSIONS: RLQ provides an efficient way of extracting and visualizing structures present in a gene expression dataset by directly modeling the link between experimental variables and gene annotations. PMID- 23742072 TI - Simultaneous or delayed placement of surface modified and fluoridated dental implants into autogenous block bone grafts: a histologic and biomechanical study in the rabbit. AB - BACKGROUND: A delayed approach is recommended for reconstruction of the jaws with autogenous bone grafts and dental implants. Experimental studies have shown stronger bone tissue responses to surface modified implants than to nonmodified ones. AIM: The aim of the study was to evaluate bone integration and stability of surface modified and fluoridated implants when placed with fresh or healed autogenous bone grafts. MATERIAL AND METHODS: Six rabbits were used in this study. Each right rabbit tibia (control) received an autogenous bone graft, harvested from the calvarium. Eight weeks later, a second graft was harvested from the other side of the calvarium and placed on the left tibia (test) with an implant. Another implant was installed in the healed graft of the right tibia. TiO2-blasted and fluoridated OsseoSpeed(TM) implants (Astra Tech AB, Molndal, Sweden), 3.5 mm in diameter and 9 mm long, were used. After additional 8 weeks, the rabbits were sacrificed and the implants were removed en bloc for light microscopic analysis. Bone-to-implant contact (BIC) was registered as well as the amount of bone filling a rectangle indicating a region of interest (ROI). Resonance frequency analysis (RFA) was conducted both at the time of surgery and at the end of the experiment. RESULTS: There were no statistically significant differences either in BIC or ROI between the test and control sides. RFA showed higher implant stability for the control side at the time of the surgery, but the difference had leveled out at the time of the sacrifice. CONCLUSION: The present study showed similar bone tissue responses and stability for surface modified and fluoridated implants after 8 weeks of healing in fresh or healed autogenous bone grafts. PMID- 23742071 TI - Engineering RNA-binding proteins for biology. AB - RNA-binding proteins play essential roles in the regulation of gene expression. Many have modular structures and combine relatively few common domains in various arrangements to recognize RNA sequences and/or structures. Recent progress in engineering the specificity of the PUF class RNA-binding proteins has shown that RNA-binding domains may be combined with various effector or functional domains to regulate the metabolism of targeted RNAs. Designer RNA-binding proteins with tailored sequence specificity will provide valuable tools for biochemical research as well as potential therapeutic applications. In this review, we discuss the suitability of various RNA-binding domains for engineering RNA binding specificity, based on the structural basis for their recognition. We also compare various protein engineering and design methods applied to RNA-binding proteins, and discuss future applications of these proteins. PMID- 23742073 TI - Quantitation of recombinant protein in whole cells and cell extracts via solid state NMR spectroscopy. AB - Recombinant proteins (RPs) are commonly expressed in bacteria followed by solubilization and chromatography. Purified RP yield can be diminished by losses at any step with very different changes in methods that can improve the yield. Time and labor can therefore be saved by first identifying the specific reason for the low yield. This study describes a new solid-state nuclear magnetic resonance approach to RP quantitation in whole cells or cell extracts without solubilization or purification. The method is straightforward and inexpensive and requires only ~50 mL culture and a low-field spectrometer. PMID- 23742074 TI - Transplantation of modified human adipose derived stromal cells expressing VEGF165 results in more efficient angiogenic response in ischemic skeletal muscle. AB - BACKGROUND: Modified cell-based angiogenic therapy has become a promising novel strategy for ischemic heart and limb diseases. Most studies focused on myoblast, endothelial cell progenitors or bone marrow mesenchymal stromal cells transplantation. Yet adipose-derived stromal cells (in contrast to bone marrow) are abundantly available and can be easily harvested during surgery or liposuction. Due to high paracrine activity and availability ADSCs appear to be a preferable cell type for cardiovascular therapy. Still neither genetic modification of human ADSC nor in vivo therapeutic potential of modified ADSC have been thoroughly studied. Presented work is sought to evaluate angiogenic efficacy of modified ADSCs transplantation to ischemic tissue. MATERIALS AND METHODS: Human ADSCs were transduced using recombinant adeno-associated virus (rAAV) serotype 2 encoding human VEGF165. The influence of genetic modification on functional properties of ADSCs and their angiogenic potential in animal models were studied. RESULTS: We obtained AAV-modified ADSC with substantially increased secretion of VEGF (VEGF-ADSCs). Transduced ADSCs retained their adipogenic and osteogenic differentiation capacities and adhesion properties. The level of angiopoetin-1 mRNA was significantly increased in VEGF-ADSC compared to unmodified cells yet expression of FGF-2, HGF and urokinase did not change. Using matrigel implant model in mice it was shown that VEGF-ADSC substantially stimulated implant vascularization with paralleling increase of capillaries and arterioles. In murine hind limb ischemia test we found significant reperfusion and revascularization after intramuscular transplantation of VEGF-ADSC compared to controls with no evidence of angioma formation. CONCLUSIONS: Transplantation of AAV-VEGF- gene modified hADSC resulted in stronger therapeutic effects in the ischemic skeletal muscle and may be a promising clinical treatment for therapeutic angiogenesis. PMID- 23742076 TI - Quality assessment of Japanese knotweed (Fallopia japonica) grown on Prince Edward Island as a source of resveratrol. AB - Japanese knotweed (Fallopia japonica , also known as Polygonum cuspidatum) is a common invasive plant species on Prince Edward Island (PEI), Canada, whereas it has been used in Chinese medicine and more recently as a raw material for extracting resveratrol. This paper reports on the quantification of resveratrol, polydatin, emodin, and physcion in roots, stems, and leaves of Japanese knotweed samples from PEI and British Columbia (BC), Canada, and nine provinces of China, by ultraperformance liquid chromatography (UPLC). The results showed that the root contains a much higher level of resveratrol than the stem and leaf, and it is accumulated in its highest level in October. PEI-grown knotweed contains similar levels of resveratrol and polydatin compared to Chinese samples collected in the month of October, but the contents of the other anthraquinones (emodin and physcion) are different. As such, Japanese knotweed grown in PEI could be a commercially viable source of raw material for resveratrol production; however, caution has to be taken in harvesting the right plant species. PMID- 23742075 TI - Loss of basal cells precedes bronchiolitis obliterans-like pathological changes in a murine model of chlorine gas inhalation. AB - Bronchiolitis obliterans (BO) is a major cause of chronic airway dysfunction after toxic chemical inhalation. The pathophysiology of BO is not well understood, but epithelial cell injury has been closely associated with the development of fibrotic lesions in human studies and in animal models of both toxin-induced and transplant-induced BO. However, whereas almost all cases and models of BO include epithelial injury, not all instances of epithelial injury result in BO, suggesting that epithelial damage per se is not the critical event leading to the development of BO. Here, we describe a model of chlorine-induced BO in which mice develop tracheal and large airway obliterative lesions within 10 days of exposure to high (350 parts per million [ppm]), but not low (200 ppm), concentrations of chlorine gas. Importantly, these lesions arise only under conditions and in areas in which basal cells, the resident progenitor cells for large airway epithelium, are eliminated by chlorine exposure. In areas of basal cell loss, epithelial regeneration does not occur, resulting in persistent regions of epithelial denudation. Obliterative airway lesions arise specifically from regions of epithelial denudation in a process that includes inflammatory cell infiltration by Day 2 after exposure, fibroblast infiltration and collagen deposition by Day 5, and the ingrowth of blood vessels by Day 7, ultimately leading to lethal airway obstruction by Days 9-12. We conclude that the loss of epithelial progenitor cells constitutes a critical factor leading to the development of obliterative airway lesions after chemical inhalation. PMID- 23742077 TI - Retinoic acids up-regulate functional eosinophil-driving receptor CCR3. AB - Eotaxins and their receptor CCR3 have a definitive role for tissue accumulation of eosinophils both under homeostatic and pathologic conditions. However, physiological stimuli that can up-regulate CCR3 in blood-derived human eosinophils have not been recognized. As a prior gene microarray study revealed up-regulation of CCR3 in eosinophils stimulated with retinoic acids (RAs), the expression of functional CCR3 was examined. We found that 9-cis RA and all-trans RA (ATRA) significantly induced surface CCR3 expression regardless of the presence of IL-3 or IL-5. Pharmacological manipulations with receptor-specific agonists and antagonists indicated that retinoic acid receptor-alpha activation is critical for CCR3 up-regulation. RA-induced CCR3 was associated with its functional capacity, in terms of the calcium mobilization and chemotactic response to eotaxin-1 (CCL11). Our study suggests an important role of vitamin A derivatives in the tissue accumulation of eosinophils. PMID- 23742078 TI - Seroprevalence of Toxoplasma gondii in horses and donkeys in Yunnan Province, Southwestern China. AB - BACKGROUND: Toxoplasma gondii is an intracellular protozoan parasite that infects almost all warm-blooded animals, including humans, with a worldwide distribution. There have been limited reports about the seroprevalence of T. gondii infection in equids around the world and little is known about the seroprevalence of T. gondii in equids in southwestern China, in particular in Yunnan Province. The objective of the present investigation was to estimate the seroprevalence of T. gondii infection in equids in this area. METHODS: A total of 399 serum samples (266 from horses and 133 from donkeys) were collected in 2012, and assayed for T. gondii antibodies by Indirect Haemagglutination (IHA) test using a commercially available kit. RESULTS: A total of 108 (27.1%) equids, including 81 (30.5%) horses and 27 (20.3%) donkeys were positive for T. gondii antibodies, and the seroprevalence ranged from 18.8% to 37.5% among different sampling areas. The seroprevalence was 27.4% and 26.8% for male and female equids, respectively, and the difference was not statistically significant (P > 0.05). The seroprevalence ranged from 21% to 32.9% among different age groups, and the difference was not statistically significant (P > 0.05). CONCLUSIONS: The results of the present survey indicated the existence of high T. gondii seroprevalence in Yunnan Province, southwestern China, which has significant public health concern. Therefore, it is imperative that improved integrated measures be carried out to prevent and control T. gondii infection in equids in the studied region. PMID- 23742079 TI - Isolation of Treponema and Tannerella spp. from equine odontoclastic tooth resorption and hypercementosis related periodontal disease. AB - REASONS FOR PERFORMING STUDY: Red complex bacteria, i.e. Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia, are involved in the onset and progression of periodontal disease in man, yet seldom inhabit the oral cavity of healthy individuals. Periodontal disease is also encountered in horses, with equine odontoclastic tooth resorption and hypercementosis (EOTRH) constituting a particular form of disease. However, only little is known about the oral microbiome of healthy and periodontitis-affected equids. OBJECTIVE: We aimed to test the hypothesis that red complex bacteria are also associated with EOTRH-related periodontal disease. STUDY DESIGN: Controlled cross-sectional study. METHODS: We screened DNA purified from crevicular fluid derived from 23 EOTRH-affected and 21 disease-free horses for the presence of Treponema spp., Tannerella spp. and Porphyromonas gingivalis DNA by polymerase chain reaction. Subsequently, amplified DNA was bidirectionally sequenced and identified via BLAST analysis. RESULTS: Treponema and/or Tannerella DNA was detected in 100% of periodontitis-related samples and in 52.2% of DNA derived from healthy horses. Twenty-six amplicon sequences were 98-100% homologous to published bacterial sequences, which mostly corresponded to Treponema pectinovorum, oral Treponema clones JU025 and OMZ 840, and Tannerella forsythia. P. gingivalis DNA was only found in 3 EOTRH-related samples. Forty-three amplicon sequences revealed weaker homologies ranging between 80% and 97% to known Treponema or Tannerella strains, partly because of their heterogeneity, partly because they obviously represented so far unknown types. CONCLUSIONS: This is the first report in which known and novel Treponema and Tannerella spp. were isolated in association with EOTRH related periodontal disease. PMID- 23742080 TI - TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia. AB - Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLD-TDP). Recently, a genome-wide association study identified the first FTLD-TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD-TDP risk. Intriguingly, the most significant association was in FTLD-TDP patients carrying progranulin (GRN) mutations. Here, we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and transmembrane protein 106 B (TMEM106B) regulation. First, we confirmed the association of TMEM106B variants with FTLD TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B-specific antibody for investigation of this protein. Enzyme-linked immunoassay analysis of progranulin protein levels showed similar effects upon T185 and S185 TMEM106B over-expression. However, over-expression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N-glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD-TDP risk. We studied the p.T185S TMEM106B genetic variant previously implicated in frontotemporal dementia with TAR DNA binding protein 43 pathology caused by progranulin mutations. Our cell culture studies provide evidence that the protective S185 isoform is degraded more rapidly than T185 TMEM106B, potentially due to differences in glycosylation. These findings suggest that low TMEM106B levels might protect against FTLD-TDP in these patients. PMID- 23742081 TI - Methodologies for the quantitative estimation of toxicant dose to cigarette smokers using physical, chemical and bioanalytical data. AB - Methodologies have been developed, described and demonstrated that convert mouth exposure estimates of cigarette smoke constituents to dose by accounting for smoke spilled from the mouth prior to inhalation (mouth-spill (MS)) and the respiratory retention (RR) during the inhalation cycle. The methodologies are applicable to just about any chemical compound in cigarette smoke that can be measured analytically and can be used with ambulatory population studies. Conversion of exposure to dose improves the relevancy for risk assessment paradigms. Except for urinary nicotine plus metabolites, biomarkers generally do not provide quantitative exposure or dose estimates. In addition, many smoke constituents have no reliable biomarkers. We describe methods to estimate the RR of chemical compounds in smoke based on their vapor pressure (VP) and to estimate the MS for a given subject. Data from two clinical studies were used to demonstrate dose estimation for 13 compounds, of which only 3 have urinary biomarkers. Compounds with VP > 10(-5) Pa generally have RRs of 88% or greater, which do not vary appreciably with inhalation volume (IV). Compounds with VP < 10(-7) Pa generally have RRs dependent on IV and lung exposure time. For MS, mean subject values from both studies were slightly greater than 30%. For constituents with urinary biomarkers, correlations with the calculated dose were significantly improved over correlations with mouth exposure. Of toxicological importance is that the dose correlations provide an estimate of the metabolic conversion of a constituent to its respective biomarker. PMID- 23742082 TI - Protective effect of salicylic acid on Hg(0) intoxication in mice. AB - Elemental mercury (Hg(0)) is a hazardous metal with significant human exposure through diverse sources. In this study, the role of salicylic acid (SA) was assessed against Hg(0)-induced injury in mice, with the aim of screening alternative clinical drugs to prevent or treat Hg(0) poisoning. An exposure to Hg(0) (1.0 mg/m(3) in a glass box) for 2 h per day for successive 15 d significantly increased Hg accumulation in mouse brain and lung, inhibited the animal growth and altered the neurobehavior such as impairing the spatial learning and memory in the Barnes maze test. However, although oral SA (5.5 mg/kg body weight) during the Hg(0) exposure did not reduce the Hg levels in these organs, it effectively counteracted the Hg(0)-induced growth inhibition, and improved the behavioral performance, accompanied by a series of ameliorations in the antioxidative defense and anti-inflammatory response. For instance, when compared with control, Hg(0)-inhaled animals had significant decreases in the activities of superoxide dismutase and peroxidase, and in the levels of reduced form of glutathione and the ratio to its oxidized form, concomitantly with a high accumulation of hydrogen peroxide and malondialdehyde in the brain and lung. However, these values in Hg(0) + SA-exposed animals were comparable with the basal levels in control. Likewise, interleukin-6 in the brain and lung of Hg(0) exposed animals were dramatically elevated, whereas it was maintained to the basal level in Hg(0) + SA-exposed animals. These data suggested that application of SA could protect mice against Hg(0)-induced injury. PMID- 23742083 TI - Biodistribution and toxicity of pegylated single wall carbon nanotubes in pregnant mice. AB - BACKGROUND: Single wall carbon nanotubes (SWCNTs) are considered promising nanoparticles for industrial and biomedical applications; however their potential toxicity in several biological systems, including the feto-placental unit, has been demonstrated. Functionalization of SWCNTs with polyethylene glycol chains (PEG-SWCNTs) dramatically reduces their toxicity, and for this reason PEG-SWCNTs are candidates for biomedical applications. However, no data are available on their safety for the developing embryo, in spite of the clinical and social relevance of this topic. The purpose of this study is therefore to investigate the safety of PEG-SWCNTs for their use as biomedical carriers in pregnancy. METHODS: For toxicological studies, amino-functionalized PEG-SWCNT were intravenously injected in CD1 pregnant mice at different doses (range 0.1-30 MUg/mouse), in single or multiple administrations. For biodistribution studies, fluorescently labeled PEG-SWCNTs were obtained by acylation of terminal PEG amino groups with near infrared emitting fluorochromes (PEG-SWCNT-750) and injected at the dosage of 10 MUg/mouse, at either day 5.5 (when the placenta is still developing) or day 14.5 of gestation (when the maturation of the placenta is complete). RESULTS: We found no adverse effects both on embryos and dams up to the dose of 10 MUg/mouse. At the dose of 30 MUg/mouse, occasional teratogenic effects, associated with placental damage, were detected both when administered as a single bolus (1 out of 10 dams; 1 malformed embryo) or as multiple doses (2 out of 10 dams; 5 malformed embryos). The difference in the prevalence of dams with malformed embryos between the 30 MUg exposed group and controls approached the statistical significance (p = 0.06). Hepatic damage in dams was seen only in the multiple exposure group (4 out of 10; p = 0.04 when compared with the single exposure group or controls). PEG-SWCNT-750 reached the conceptus when administered early in pregnancy. At later stages, PEG-SWCNT-750 were detected in the placenta and the yolk sac, but not in the embryo. CONCLUSIONS: PEG-SWCNTs may cause occasional teratogenic effects in mice beyond a threshold dose. Such effect might depend on their ability to reach the feto-placenta unit. Although not automatically transferable to humans, these data should be considered if exposing women during pregnancy. PMID- 23742084 TI - Comparative study of the hydrolytic metabolism of methyl-, ethyl-, propyl-, butyl , heptyl- and dodecylparaben by microsomes of various rat and human tissues. AB - Hydrolytic metabolism of methyl-, ethyl-, propyl-, butyl-, heptyl- and dodecylparaben by various tissue microsomes and plasma of rats, as well as human liver and small-intestinal microsomes, was investigated and the structure metabolic activity relationship was examined. Rat liver microsomes showed the highest activity toward parabens, followed by small-intestinal and lung microsomes. Butylparaben was most effectively hydrolyzed by the liver microsomes, which showed relatively low hydrolytic activity towards parabens with shorter and longer alkyl side chains. In contrast, small-intestinal microsomes exhibited relatively higher activity toward longer-side-chain parabens, and showed the highest activity towards heptylparaben. Rat lung and skin microsomes showed liver type substrate specificity. Kidney and pancreas microsomes and plasma of rats showed small-intestinal-type substrate specificity. Liver and small-intestinal microsomal hydrolase activity was completely inhibited by bis(4 nitrophenyl)phosphate, and could be extracted with Triton X-100. Ces1e and Ces1d isoforms were identified as carboxylesterase isozymes catalyzing paraben hydrolysis by anion exchange column chromatography of Triton X-100 extract from liver microsomes. Ces1e and Ces1d expressed in COS cells exhibited significant hydrolase activities with the same substrate specificity pattern as that of liver microsomes. Small-intestinal carboxylesterase isozymes Ces2a and Ces2c expressed in COS cells showed the same substrate specificity as small-intestinal microsomes, being more active toward longer-alkyl-side-chain parabens. Human liver microsomes showed the highest hydrolytic activity toward methylparaben, while human small-intestinal microsomes showed a broadly similar substrate specificity to rat small-intestinal microsomes. Human CES1 and CES2 isozymes showed the same substrate specificity patterns as human liver and small intestinal microsomes, respectively. PMID- 23742085 TI - Isolation of high-quality total RNA from leaves of Myrciaria dubia "CAMU CAMU". AB - Myrciaria dubia is a main source of vitamin C for people in the Amazon region. Molecular studies of M. dubia require high-quality total RNA from different tissues. So far, no protocols have been reported for total RNA isolation from leaves of this species. The objective of this research was to develop protocols for extracting high-quality total RNA from leaves of M. dubia. Total RNA was purified following two modified protocols developed for leaves of other species (by Zeng and Yang, and by Reid et al.) and one modified protocol developed for fruits of the studied species (by Silva). Quantity and quality of purified total RNA were assessed by spectrophotometric and electrophoretic analysis. Additionally, quality of total RNA was evaluated with reverse-transcription polymerase chain reaction (RT-PCR). With these three modified protocols we were able to isolate high-quality RNA (A260nm/A280nm >1.9 and A260nm/A230nm >2.0). Highest yield was produced with the Zeng and Yang modified protocol (384+/-46ug ARN/g fresh weight). Furthermore, electrophoretic analysis showed the integrity of isolated RNA and the absence of DNA. Another proof of the high quality of our purified RNA was the successful cDNA synthesis and amplification of a segment of the M. dubia actin 1 gene. We report three modified protocols for isolation total RNA from leaves of M. dubia. The modified protocols are easy, rapid, low in cost, and effective for high-quality and quantity total RNA isolation suitable for cDNA synthesis and polymerase chain reaction. PMID- 23742086 TI - Improvement of microbial strain and fermentation process of rapamycin biosynthesis. AB - The purpose of this investigation is to enhance the production of the immunosuppressant drug rapamycin by subjecting the strain CBS 773.23 to ultraviolet (UV) and N-methyl-N'-nitro-N-nitroso guanidine (NTG) mutations. Among all the mutants tested, MTCC 5681 (NRC-CM03/SH) obtained by NTG mutagenesis of strain CBS 773.72 showed the highest activity, 210 mg/L. The effect of different factors including medium composition, pH, temperature, and intensity of mixing on rapamycin production was studied. Based on the study, the optimal concentrations of soluble starch and dry yeast granules were found to be 50 g/L and 1.5 g/L, respectively. Furthermore, optimal values for pH, temperature, and shaking speed were found to be 6.0, 28 degrees C, and 220 rpm, respectively. The production of rapamycin increased 1.6-fold, to 360 mg/L, in shake-flask culture using the optimal combination of factors observed compared with basal cultivation medium using MTCC 5681 mutant strain. PMID- 23742087 TI - Isolation of acetoin-producing Bacillus strains from Japanese traditional food natto. AB - In this study, Bacillus strains with an ability to produce acetoin were isolated from a Japanese traditional food, natto, on the basis of the Voges-Proskauer (VP) reaction, and strain SF4-3 was shown to be a predominant strain in acetoin production. Based on a variety of morphological, physiological, and biochemical characteristics as well as the nucleotide sequence analysis of 16S rDNA, the strain SF4-3 was identified as Bacillus subtilis. When it was incubated at 37 degrees C with a speed of 180 rpm for 96 hr in the flasks, the maximum acetoin concentration was up to 33.90 g/L. The fermentation broths were determined by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) analyses; the results showed that the major metabolite was acetoin, and the purity could reach more than 95% without butanedione and 2,3-butanediol, which were usually produced together with acetoin in other strains. A novel aqueous two-phase system (ATPS) composed of hydrophilic solvents and inorganic salts was developed for the extraction of acetoin from fermentation broths. The ethanol and dipotassium hydrogen phosphate system could be used to extract acetoin from fermentation broths. The influences of phase composition on partition of acetoin were investigated. The maximum partition coefficient (9.68) and recovery (94.6%) of acetoin were obtained, when 25% (w/w) dipotassium hydrogen phosphate and 24% (w/w) ethanol were used. PMID- 23742088 TI - Production of small antibacterial peptides using silkworm-baculovirus protein expression system. AB - The recombinant proteins with strong antimicrobial activity are known to be very difficult to express using bacterial expression system. Here, human beta-defensin (DEFB) 1, DEFB2, and DEFB3 were successfully produced using a silkworm baculovirus protein expression system. We have generated four baculoviruses for each DEFB protein to compare the effect of different peptide tags in secretion into silkworm larval hemolymph. Interestingly, the best performing peptide tags for the secretion were different among DEFBs: C-terminal GST-H8 tag for DEFB1, N terminal H8 tag for DEFB2, and C-terminal H8 tag for DEFB3, respectively. In addition, the colony count assay demonstrated that the recombinant DEFB2 s showed antimicrobial activities against Escherichia coli, Pseudomonas aeruginosa, and Paenibacillus thiaminolyticus. PMID- 23742089 TI - Engineering a high-yield glutathione strain of Hansenula polymorpha using ion beam implantation. AB - To generate an industrial strain of Hansenula polymorpha capable of yielding greater levels of glutathione (GSH), wild strain H. polymorpha DL-1 cells were mutated using a nitrogen ion beam, a novel mutagen. At an energy level of 20 keV and dose of 2.13 * 10(16) ions/cm(2), H. polymorpha strain 28 (HP28) with a high yield of GSH was screened. HP28 intracellular GSH levels reached 337.16 mg/L by ion beam implantation, 1.56 times greater than that of the wild type strain when the fermentation time was shortened from 48 hr to 42 hr, greatly improving efficiency and reducing the cost of industrial-scale production. The enhanced efficiency of HP28 is promising for GSH production from lignocellulosic materials. Therefore, the ion beam implantation would be a cost-effective alternative to the conventional mutation method for engineering yeast and improving its utility. PMID- 23742090 TI - Production, purification, and chemical stability of recombinant human interferon gamma in low oxygen tension condition: a formulation approach. AB - The low stability of recombinant human interferon-gamma (rhIFN-gamma) therapeutic protein imposes some restrictions in its medical applications. In the current study, the effect of oxygen tension on the stability of purified rhIFN-gamma was investigated. The rhIFN-gamma was purified (>99%) by a two-step chromatographic process. Storage vials were filled by purified formulated product under normal atmospheric oxygen and low oxygen tension conditions. At different time intervals, the amounts of rhIFN-gamma covalent dimers and deamidated forms were analyzed using analytical high-performance liquid chromatography (HPLC; size exclusion and cation exchange) and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) methods. To determine the biological activity of purified rhIFN-gamma, an antiviral activity assay against vesicular stomatitis virus (VSV) was performed. Upon rhIFN-gamma long-term storage in a low oxygen tension condition, the amounts of rhIFN-gamma covalent dimers and deamidated forms and also the biological activity of rhIFN-gamma changed a little. In contrast, by 9 months of storage of rhIFN-gamma preparations under normal atmospheric condition, the amount of covalent dimers and deamidated forms increased with time and reached to approximately 3.5% and 11.5% of the initial amount, respectively. The antiviral specific activity of 9-month-old rhIFN-gamma preparations decreased to 41% of the initial amount at normal storage condition, while no significant reduction was seen at the low oxygen tension condition. In conclusion, oxygen tension during storage could have a significant impact on rhIFN-gamma stability and finally on the quality of pharmaceutical rhIFN-gamma product. PMID- 23742091 TI - Citric acid production by Candida species grown on a soy-based crude glycerol. AB - Citric acid was produced by five species of the yeast Candida after growth on a medium containing soy biodiesel-based crude glycerol. After growth on a medium containing 10 g L(-1) or 60 g L(-1) crude glycerol for 168 hr at 30 degrees C, Candida parapsilosis ATCC 7330 and C. guilliermondii ATCC 9058 produced the highest citric acid levels. On 10 g L(-1) or 60 g L(-1) crude glycerol for 168 hr at 30 degrees C, the citric acid level produced by C. parapsilosis ATCC 7330 was 1.8 g L(-1) or 11.3 g L(-1), respectively, while C. guilliermondii ATCC 9058 produced citric acid concentrations of 3.0 g L(-1) or 10.4 g L(-1), respectively. Biomass production by C. guilliermondii ATCC 9058 on 10 g L(-1) or 60 g L(-1) crude glycerol for 168 hr at 30 degrees C was highest at 1.2 g L(-1) or 6.9 g L( 1), respectively. The citric acid yields observed for C. guilliermondii ATCC 9058 after growth on 10 g L(-1) or 60 g L(-1) crude glycerol (0.35 g g(-1) or 0.21 g g(-1), respectively) were generally higher than for the other Candida species tested. When similar crude glycerol concentrations were present in the culture medium, citric acid yields observed for some of the Candida species utilized in this study were about the same or higher compared to citric acid yields by Yarrowia lipolytica strains. Based on the findings, it appeared that C. guilliermondii ATCC 9058 was the most effective species utilized, with its citric acid production being similar to what has been observed when citric acid producing strains of Y. lipolytica were grown on crude glycerol under batch conditions that could be of significance to biobased citric acid production. PMID- 23742092 TI - Prediction of aortic dilation in Turner syndrome--the use of serial cardiovascular magnetic resonance. AB - BACKGROUND: Identification of the subset females with Turner syndrome who face especially high risk of aortic dissection is difficult, and more optimal risk assessment is pivotal in order to improve outcomes. This study aimed to provide comprehensive, dynamic mathematical models of aortic disease in Turner syndrome by use of cardiovascular magnetic resonance (CMR). METHODS: A prospective framework of long-term aortic follow-up was used, which comprised diameters of the thoracic aorta prospectively assessed at nine positions by CMR at the three points in time (baseline [n = 102, age 38 +/- 11 years], follow-up [after 2.4 +/- 0.4 years, n = 80] and end-of-study [after 4.8 +/- 0.5 years, n = 78]). Mathematical models were created that cohesively integrated all measurements at all positions, from all visits and for all participants, and using these models cohesive risk factor analyses were conducted based on which predictive modeling was performed on which predictive modelling was performed. RESULTS: The cohesive models showed that the variables with effect on aortic diameter were aortic coarctation (P < 0.0001), bicuspid aortic valves (P < 0.0001), age (P < 0.0001), diastolic blood pressure (P = 0.0008), body surface area (P = 0.015) and antihypertensive treatment (P = 0.005). Oestrogen replacement therapy had an effect of borderline significance (P = 0.08). From these data, mathematical models were created that enabled preemption of aortic dilation from CMR derived aortic diameters in scenarios both with and without known risk factors. The fit of the models to the actual data was good. CONCLUSION: The presented cohesive model for prediction of aortic diameter in Turner syndrome could help identifying females with rapid growth of aortic diameter, and may enhance clinical decision making based on serial CMR. PMID- 23742093 TI - Barriers to information exchange during older patients' transfer: nurses' experiences. AB - AIMS AND OBJECTIVES: To describe nurses' experiences of barriers that influence their information exchange during the transfer of older patients between hospital and home care. BACKGROUND: The successful transfer of an older patient across health organisations requires good communication and coordination between providers. Despite an increased focus on the need for cooperation among providers across healthcare organisations, researchers still report problems in the exchange of information between the hospitals and the healthcare systems in the municipalities. DESIGN: A qualitative study using focus group methodology. METHODS: Three focus group interviews using topic guides were conducted and interpreted. The study included registered nurses (n = 14) from hospital and home care. The data were analysed through content analysis. RESULTS: Three main themes were identified: barriers associated with the nurse, barriers associated with interpersonal processes and barriers associated with the organisation. These themes included several subthemes. CONCLUSIONS: The findings highlight the challenges that nurses encounter in ensuring a successful information exchange during older patients' transfer through the healthcare system. The barriers negatively influence the nurses' information exchange and may put the patients in a vulnerable and exposed situation. In order for nurses to conduct a successful exchange of information, it is critical that hospital and home care systems facilitate this through adequate resources, clear missions and responsibilities, and understandable policies. RELEVANCE TO CLINICAL PRACTICE: Recognition of the barriers that affect nurses' exchange of information is important to ensure patient safety and successful transitions. The barriers described here should help both nurses in practice and their leaders to be more attentive to the prerequisites needed to achieve a satisfactory nursing information exchange and enhance informational continuity. PMID- 23742094 TI - Cortisol response to stress in caregivers of offspring with autism spectrum disorder is associated with care recipient characteristics. AB - Providing care for people with autism spectrum disorder (ASD) is particularly stressful and frequently associated with disturbances in the hypothalamic pituitary-adrenal (HPA) axis of the caregiver. This study examined whether the stress response is modulated by factors such as age of the care recipient and number of years spent by the caregiver in providing care for the ASD individual. Caregivers of children (n = 15), adolescents (n = 12), and adults (n = 11) with ASD were exposed to two episodes of acute psychosocial stressor in a 1 day session. Salivary cortisol samples were obtained before, during, and after the stressor episodes. Psychological characteristics (states of anxiety, anger, and mood) were measured before and after the stressor episodes. The characteristics of the ASD individuals (age, degree of autism, global activity, and level of autonomy) were also registered. A difference in stress response was found when caregivers of ASD children were compared with those of ASD adolescents and adults, epsilon = 0.25, F(2.24,53.65) = 5.82, p < 0.004; epsilon = 0.23 and F(2.11,48.43) = 4.88, p < 0.01, respectively. Thus, upon acute-stressor exposure, caregivers of ASD individuals presented a stress response that correlated with the age of the patient (the older the patient, the lower the cortisol response). Additional factors, such as number of years spent providing care and level of autonomy of the recipient, also significantly contributed to the stress response. Together, the results demonstrate that recipient characteristics contribute to the detection of high-risk individuals within a caregiver population. PMID- 23742095 TI - Modelling and visualizing fine-scale linkage disequilibrium structure. AB - BACKGROUND: Detailed study of genetic variation at the population level in humans and other species is now possible due to the availability of large sets of single nucleotide polymorphism data. Alleles at two or more loci are said to be in linkage disequilibrium (LD) when they are correlated or statistically dependent. Current efforts to understand the genetic basis of complex phenotypes are based on the existence of such associations, making study of the extent and distribution of linkage disequilibrium central to this endeavour. The objective of this paper is to develop methods to study fine-scale patterns of allelic association using probabilistic graphical models. RESULTS: An efficient, linear time forward-backward algorithm is developed to estimate chromosome-wide LD models by optimizing a penalized likelihood criterion, and a convenient way to display these models is described. To illustrate the methods they are applied to data obtained by genotyping 8341 pigs. It is found that roughly 20% of the porcine genome exhibits complex LD patterns, forming islands of relatively high genetic diversity. CONCLUSIONS: The proposed algorithm is efficient and makes it feasible to estimate and visualize chromosome-wide LD models on a routine basis. PMID- 23742096 TI - Identification of a hepatoprotective peptide in wheat gluten hydrolysate against D-galactosamine-induced acute hepatitis in rats. AB - A hepatoprotective peptide, pyroglutamyl leucine (pyroGlu-Leu), was identified in wheat gluten hydrolysate through an in vivo activity-guided fractionation approach based on D-galactosamine-induced acute hepatitis in rats and fractionation of peptides with large-scale preparative ampholine-free isoelectric focusing. The active acidic fraction predominantly consisted of pyroglutamyl peptides and free pyroglutamic acid. Pyroglutamyl peptides were derivatized with phenyl isothiocyanate after removal of a pyroglutamyl residue by pyroglutamate aminopeptidase. The derivatives were purified by reversed-phase HPLC and subjected to sequence analysis. The active fraction contained pyroGlu-Ile, pyroGlu-Leu, pyroGlu-Gln, pyroGlu-Gln-Gln, and free pyroGlu. Ingestion of pyroGlu Leu at 20 mg/kg body weight significantly decreased serum aspartate and alanine aminotransferases to approximately 30% and 20% of those values of the vehicle group, respectively, which were near the normal levels. Thirty minutes after ingestion of pyroGlu-Leu at 20 mg/kg, the concentration of pyroGlu-Leu in portal blood plasma increased to approximately 2 MUM. PMID- 23742097 TI - Identification of metabolically active proteobacterial and archaeal communities in the rumen by DNA- and RNA-derived 16S rRNA gene. AB - AIMS: To gain new insights into the metabolic contribution of bacterial group in the rumen. METHODS AND RESULTS: Both DNA- and RNA-derived bacterial 16S ribosomal materials from bovine rumen contents were used as the template for bacterial community and analyse microbiota by three methods namely custom phylogenetic microarray, quantitative real-time PCR and denaturing gradient gel electrophoresis techniques. Bacterial analysis showed that genera affiliating with the Proteobacteria apparently made a greater metabolic contribution to rumen function than their population sizes indicated. Analysis of another rumen microbial group, the methanogens, using clone libraries for the expressed methyl coenzyme reductase subunit A (mcrA) revealed that an uncultivated methanogen clade contributes one-third of RNA-derived mcrA sequences based on a limited number of clones analysed. These uncultivated methanogen species were not observed in the mcrA gene library based on the DNA-derived sequences. CONCLUSIONS: The comparison of results obtained from DNA- and RNA-derived materials suggests that some of the Proteobacteria and novel methanogen species appeared to be low in abundance in the rumen maintained on grain-based diets might play a greater role in rumen metabolism. SIGNIFICANCE AND IMPACT OF THE STUDY: These studies provide the first report to compare high-throughput analysis of bacterial 16S rRNA genes from DNA- and RNA-derived materials to indicate differences that species make to community structure and metabolic activity. PMID- 23742098 TI - Time interval after radiotherapy and dental implant failure: systematic review of observational studies and meta-analysis. AB - BACKGROUND: Typically, dental implants are placed in irradiated bone after a delay that exceeds 6 months, but it is not known whether longer delays are beneficial. PURPOSE: The purpose of the study is to review the literature comparing the failure rate of dental implants placed in irradiated bone between 6 and 12 months and after 12 months from the cessation of radiotherapy. MATERIALS AND METHODS: Four electronic databases were searched for articles published until February 2013 without language restriction: Lilacs, Medline, Scopus, and the Cochrane Central Register of Controlled Trials. Two reviewers independently assessed the eligibility criteria and extracted data. Fixed effect meta-analysis was performed. RESULTS: Overall, 3,749 observational studies were identified. After the screening of titles and abstracts, 236 publications were selected, and 10 were included in the final analysis. The pooled relative risk (RR) of failure was RRpooled = 1.34 (95% confidence interval [CI]: 1.01-1.79), higher in individuals who had dental implants installed between 6 and 12 months after receiving radiotherapy. I(2) indicated nearly 21% heterogeneity (p = .25). Egger's test indicated no evidence of publication bias (p = .62); however, the removal of one study significantly affected the overall RR (RRpooled = 1.08, 95% CI: 0.77-1.52). CONCLUSIONS: Placing implants in bone within a period shorter than 12 months after radiotherapy may result in a higher risk of failure; however, additional evidence from clinical trials is needed to verify this risk. PMID- 23742099 TI - H2O2 stimulates cystic fibrosis transmembrane conductance regulator through an autocrine prostaglandin pathway, using multidrug-resistant protein-4. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) activity is essential for the maintenance of airway surface liquid depth, and therefore mucociliary clearance. Reactive oxygen species, increased during inflammatory airway diseases, alter CFTR activity. Here, H2O2 levels in the surface liquid of normal human bronchial epithelial cultures differentiated at the air-liquid interface were estimated, and H2O2-mediated changes in CFTR activity were examined. In Ussing chambers, H2O2-induced anion currents were sensitive to the CFTR inhibitors CFTRinh172 and GlyH-101. These currents were absent in cells from patients with cystic fibrosis. Responses to greater than 500 MUM H2O2 were transient. Cyclooxygenase inhibitors blocked the H2O2 response, as did EP1 and EP4 receptor antagonists. A multidrug-resistant protein (MRP) inhibitor and short hairpin RNA directed against MRP4 blocked H2O2 responses. EP1 and EP4 agonists mimicked H2O2 in both control and MRP4 knockdown cells. Thus, H2O2 activates the synthesis, export, and binding of prostanoids via EP4 and, interestingly, EP1 receptors in normal, differentiated human airway epithelial cells to activate cyclic adenosine monophosphate pathways that in turn activate CFTR channels in the apical membrane. PMID- 23742100 TI - Socioeconomic disparity in cervical cancer screening among Korean women: 1998 2010. AB - BACKGROUND: Cervical cancer is the sixth most common cause of cancer among Korean women and is one of the most preventable cancers in the world. This study aimed to investigate the change in cervical cancer screening rates, the level of socioeconomic disparities in cervical cancer screening participation, and whether there was a reduction in these disparities between 1998 and 2010. METHODS: Using the Korean Health and Nutrition Examination Survey, women 30 years or older without a history of cervical cancer and who completed a health questionnaire, physical examination, and nutritional survey were included (n = 17,105). Information about participation in cervical cancer screening was collected using a self-administered questionnaire. Multiple logistic regression analysis was performed to investigate the relationship between cervical cancer screening participation and the socioeconomic status of the women. RESULTS: The cervical cancer screening rate increased from 40.5% in 1998 to 52.5% in 2010. Socioeconomic disparities influenced participation, and women with lower educational levels and lower household income were less likely to be screened. Compared with the lowest educational level, the adjusted odds ratios (ORs) for screening in women with the highest educational level were 1.56 (95% confidence interval (CI): 1.05-2.30) in 1998, and 1.44 (95% CI: 1.12-1.87) in 2010. Compared with women with the lowest household income level, the adjusted ORs for screening in women with the highest household income level were 1.80 (95% CI: 1.22-2.68), 2.82 (95% CI: 2.01-3.96), and 1.45 (95% CI: 1.08-1.94) in 2001, 2005, and 2010, respectively. CONCLUSION: Although population-wide progress has been made in participation in cervical cancer screening over the 12-year period, socioeconomic status remained an important factor in reducing compliance with cancer screening. PMID- 23742101 TI - Pharmacokinetics of difloxacin in olive flounder Paralichthys olivaceus at two water temperatures. AB - In this study, the pharmacokinetics profiles of difloxacin in the olive flounder (Paralichthys olivaceus) were investigated following intravenous and oral administration (10 mg/kg BW) at 14 and 22 degrees C water temperatures. Plasma and tissue samples (muscle, liver, and kidney) were analyzed using an HPLC method. The results showed that the plasma concentration-time data for difloxacin were described commendably by two-compartment open model at the two water temperatures. The absorption half-life (t(1/2ka)) of difloxacin after oral administration were 2.08 and 1.10 h at 14 and 22 degrees C, respectively; whereas the elimination half-life (t(1/2beta)) was 4.41 and 2.38 h, respectively. The muscle concentration of 1.35 +/- 0.19 MUg/g was observed at 9 h at 14 degrees C, and 2.11 +/- 0.33 MUg/g at 6 h at 22 degrees C, respectively. For liver, the peak concentration of difloxacin 2.43 +/- 0.30 MUg/g occurred at 6 h at 14 degrees C, which was lower than the 3.34 +/- 0.24 MUg/g peak that occurred at 4 h at 22 degrees C. The calculated bioavailability of difloxacin was 68.07% at 22 degrees C, which was higher than the 53.43% calculated for 14 degrees C. After intravenous administration, the t(1/2beta) were 4.79 and 2.81 h at 14 and 22 degrees C, respectively. The results indicate that the peak concentrations in muscle and liver at 14 degrees C are approximately half of those achieved at 22 degrees C. However, the C(max) in kidney at 14 and 22 degrees C were similar. The Vd values were 1.20 and 1.75 L/kg at 14 and 22 degrees C, respectively. These data indicated that both temperature and drug administration had significant effects on the elimination of difloxacin, and lower temperature or oral administration resulted in lower elimination. PMID- 23742102 TI - A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. AB - Our purpose was to compare healing characteristics of diabetic foot ulcers treated with dehydrated human amniotic membrane allografts (EpiFix(r), MiMedx, Kennesaw, GA) versus standard of care. An IRB-approved, prospective, randomised, single-centre clinical trial was performed. Included were patients with a diabetic foot ulcer of at least 4-week duration without infection having adequate arterial perfusion. Patients were randomised to receive standard care alone or standard care with the addition of EpiFix. Wound size reduction and rates of complete healing after 4 and 6 weeks were evaluated. In the standard care group (n = 12) and the EpiFix group (n = 13) wounds reduced in size by a mean of 32.0% +/- 47.3% versus 97.1% +/- 7.0% (P < 0.001) after 4 weeks, whereas at 6 weeks wounds were reduced by -1.8% +/- 70.3% versus 98.4% +/- 5.8% (P < 0.001), standard care versus EpiFix, respectively. After 4 and 6 weeks of treatment the overall healing rate with application of EpiFix was shown to be 77% and 92%, respectively, whereas standard care healed 0% and 8% of the wounds (P < 0.001), respectively. Patients treated with EpiFix achieved superior healing rates over standard treatment alone. These results show that using EpiFix in addition to standard care is efficacious for wound healing. PMID- 23742103 TI - Impact of intravitreal triamcinolone acetonide versus intravitreal bevacizumab on retrobulbar hemodynamic in patients with diabetic macular edema. AB - PURPOSE: To evaluate and compare retrobulbar hemodynamic changes measured with color Doppler imaging (CDI) in diabetic patients receiving intravitreal triamcinolone acetonide (IVTA) versus bevacizumab. METHODS: Patients with diffuse diabetic macular edema were assessed prospectively by CDI following intravitreal injection of triamcinolone acetonide (group I, 12 eyes) versus bevacizumab (group II, 14 eyes). CDI was used to measure the peak systolic velocity (PSV), end diastolic velocity (EDV) and the resistive index (RI) of the central retinal artery (CRA), ophthalmic artery (OA) and posterior ciliary arteries (PCA) one day preoperatively and one week postoperatively. RESULTS: In group I, EDV of OA and CRA decreased significantly (p = 0.007 and 0.018, respectively). The PSV and RI of PCA decreased significantly (p = 0.035 and 0.002, respectively). In group II, both the PSV and EDV of the CRA decreased significantly (p = 0.000). Comparing the percentage of change in both groups, PSV of the CRA decreased significantly in group II (p = 0.034), while IVTA has more significant effect on the ophthalmic artery hemodynamic parameters as EDV decreased and RI increased significantly (p = 0.045 and 0.043, respectively) CONCLUSION: Intravitreal injections of triamcinolone acetonide and bevacizumab have a significant effect on the ocular hemodynamic. The effect of bevacizumab is statistically significant on the PSV of CRA compared to IVTA. PMID- 23742104 TI - Structural analysis of activated SgrAI-DNA oligomers using ion mobility mass spectrometry. AB - SgrAI is a type IIF restriction endonuclease that cuts an unusually long recognition sequence and exhibits self-modulation of DNA cleavage activity and sequence specificity. Previous studies have shown that SgrAI forms large oligomers when bound to particular DNA sequences and under the same conditions where SgrAI exhibits accelerated DNA cleavage kinetics. However, the detailed structure and stoichiometry of the SgrAI-DNA complex as well as the basic building block of the oligomers have not been fully characterized. Ion mobility mass spectrometry (IM-MS) was employed to analyze SgrAI-DNA complexes and show that the basic building block of the oligomers is the DNA-bound SgrAI dimer (DBD) with one SgrAI dimer bound to two precleaved duplex DNA molecules each containing one-half of the SgrAI primary recognition sequence. The oligomers contain variable numbers of DBDs with as many as 19 DBDs. Observation of the large oligomers shows that nanoelectrospray ionization (nano-ESI) can preserve the proposed activated form of an enzyme. Finally, the collision cross section of the SgrAI-DNA oligomers measured by IM-MS was found to have a linear relationship with the number of DBDs in each oligomer, suggesting a regular, repeating structure. PMID- 23742105 TI - Acanthamoeba castellanii of the T4 genotype is a potential environmental host for Enterobacter aerogenes and Aeromonas hydrophila. AB - BACKGROUND: Acanthamoeba can interact with a wide range of microorganisms such as viruses, algae, yeasts, protists and bacteria including Legionella pneumophila, Pseudomonas aeruginosa, Vibrio cholerae, Helicobacter pylori, Listeria monocytogenes, Mycobacterium spp., and Escherichia coli. In this capacity, Acanthamoeba has been suggested as a vector in the transmission of bacterial pathogens to the susceptible hosts. METHODS: Here, we used a keratitis isolate of A. castellanii of the T4 genotype and studied its interactions with two bacterial genera which have not been tested before, Enterobacter aerogenes, and Aeromonas hydrophila, as well as E. coli. Assays were performed to determine bacterial association with and invasion of A. castellanii. Additionally, bacterial survival intracellular of A. castellanii trophozoites as well as cysts was determined. RESULTS: All three bacterial isolates tested, associated, invaded, and survived inside A. castellanii trophozoites as well as A. castellanii cysts. However, E. aerogenes and E. coli exhibited significantly reduced association with and invasion of A. castellanii as compared with A. hydrophila (P < 0.01 using paired T-test, one tail distribution). In the long term survival assays, all three bacterial isolates tested remained viable inside A. castellanii trophozoites, while amoeba remained intact; however A. hydrophila exhibited higher survival inside amoebae (14.54 +/- 3.3 bacteria:amoeba ratio) compared with E. aerogenes (3.96 +/- 0.7 bacteria:amoeba ratio) and E. coli (5.85 +/- 1.1 bacteria:amoeba ratio). A. hydrophila, E. coli, and E. aerogenes remained viable during the encystment process and exhibited higher levels of recovery from mature cysts (14.13 +/- 0.89 A. hydrophila:amoeba ratio, 10.13 +/- 1.17 E. aerogenes:amoeba ratio, and 11.95 +/- 0.7 E. coli:amoeba ratio). CONCLUSIONS: A. hydrophila and E. aerogenes also joined the ranks of other bacteria that could benefit from A. castellanii. Because cysts can be airborne, these findings suggest that Acanthamoeba is a potential vector in the transmission of A. hydrophila and E. aerogenes to susceptible hosts. PMID- 23742106 TI - Validation of two-dimensional methods for left atrial volume measurement: a comparison of echocardiography with cardiac computed tomography. AB - BACKGROUND: Left atrial volume (LAVol) is an important predictor of cardiovascular outcomes. Different formulas are applied to calculate LAVol using two-dimensional transthoracic echocardiography (2DTTE) with variable reference values. The objective of the study was to evaluate the accuracy of methods to calculate LAVol by 2DTTE or cardiac computed tomography (CT). METHODS AND RESULTS: Overall 177 consecutive patients who underwent both a 2DTTE and retrospective electrocardiogram (ECG)-gated coronary CT angiography (CTA) within 15 days were included for this study. LA volume measurements were calculated by 2DTTE and 2DCT using the biplane area-length, biplane Simpson's, prolate ellipsoid-1 and prolate-ellipsoid-2 methods. These results were compared with those measured by CT using a volumetric method. There was very good correlation between the CT and echocardiographic measures for LAVol, but significant underestimation of the echocardiographic methods when compared to the reference standard (33.5%, 39.1%, 48.1%, and 53.2% for the biplane area-length, biplane Simpson's, prolate-ellipsoid-1, and prolate-ellipsoid-2 methods, respectively). The biplane area-length method using 2DTTE had the closest volume estimation of all echocardiographic methods to the reference standard (67.6 +/- 25.5 mL vs. 106 +/- 35.5 mL, r = 0.712). Similarly, the biplane area-length method using CT most accurately predicted LAVol (103.3 +/- 36.0 mL, r = 0.965). CONCLUSIONS: Compared to CT, 2DTTE provides reasonable assessment of LAVol, although all measurement methods underestimate LAVol. For both 2DTTE and CT, the biplane area-length method appears to provide the most accurate 2D estimate of LAVol. PMID- 23742107 TI - Proteome-wide dysregulation by glucose-6-phosphate dehydrogenase (G6PD) reveals a novel protective role for G6PD in aflatoxin B1-mediated cytotoxicity. AB - Glucose-6-phosphate dehydrogenase (G6PD) is pivotal to reduced nicotinamide adenine dinucleotide phosphate (NADPH) production and cellular redox balance. Cells with G6PD deficiency are susceptible to oxidant-induced death at high oxidative stress. However, it remains unclear what precise biological processes are affected by G6PD deficiency due to altered cellular redox homeostasis, particularly at low oxidative stress. To further explore the biological role of G6PD, we generated G6PD-knockdown cell clones using lung cancer line A549. We identified proteins differentially expressed in the knockdown clones without the addition of exogenous oxidant by means of isobaric tags for relative and absolute quantification (iTRAQ) labeling coupled with multidimensional liquid chromatography-mass spectrometry (LC-MS/MS). We validated a panel of proteins that showed altered expression in G6PD-knockdown clones and were involved in metabolism of xenobiotic and glutathione (GSH) as well as energy metabolism. To determine the physiological relevancy of our findings, we investigated the functional consequence of G6PD depletion in cells treated with a prevalent xenobiotic, aflatoxin B1(AFB1). We found a protective role of G6PD in AFB1 induced cytotoxicity, possibly via providing NADPH for NADPH oxidase to induce epoxide hydrolase 1 (EPHX1), a xenobiotic-metabolizing enzyme. Collectively, our findings reveal for the first time a proteome-wide dysregulation by G6PD depletion under the condition without exogenous oxidant challenge, and we suggest a novel association of G6PD activity with AFB1-related xenobiotic metabolism. PMID- 23742108 TI - Facile B-H bond activation of borane by stable carbenoid species. AB - Stable nucleophilic carbene compounds have recently been shown to be able to mimic in some instances the reactivity of metal fragments in the reaction of unactivated E-H bonds (E = H, R3Si, NH2, R2P). However, the insertion into a B-H bond of the strongly Lewis acidic BH3 molecule has never been observed at a single C atom or even at a metal fragment. Our results show that designed stable, highly electrophilic carbenoid fragments in compounds 4 and 6 can achieve this reactivity in a controlled manner. Density functional theory calculations corroborated the experimental results on the presently designed systems as well as the lack of reactivity on nucleophilic carbenes. PMID- 23742109 TI - The effects of alpha-pinene versus toluene-derived secondary organic aerosol exposure on the expression of markers associated with vascular disease. AB - To investigate the toxicological effects of biogenic- versus anthropogenic-source secondary organic aerosol (SOA) on the cardiovascular system, the Secondary Particulate Health Effects Research program irradiation chamber was used to expose atherosclerotic apolipoprotein E null (Apo E-/-) mice to SOA from the oxidation of either alpha-pinene or toluene for 7 days. SOA atmospheres were produced to yield 250-300 MUg/m(3) of particulate matter and ratios of 10:1:1 alpha-pinene:nitrogen oxide (NOx):ammonia (NH3); 10:1:1:1 alpha pinene:NOx:NH3:sulfur dioxide (SO2) or 10:1:1 toluene:NOx:NH3; and 10:1:1:1 toluene:NOx:NH3:SO2. Resulting effects on the cardiovascular system were assessed by measurement of vascular lipid peroxidation (thiobarbituric acid reactive substance (TBARS)), as well as quantification of heme-oxygenase (HO)-1, endothelin (ET)-1, and matrix metalloproteinase (MMP)-9 mRNA expression for comparison to previous program exposure results. Consistent with similar previous studies, vascular TBARS were not increased significantly with any acute SOA exposure. However, vascular HO-1, MMP-9, and ET-1 observed in Apo E-/- mice exposed to alpha-pinene + NOx + NH3 + SO2 increased statistically, while alpha pinene + NOx + NH3 exposure to either toluene + NOx + NH3 or toluene +NOx + NH3 + SO2 resulted in a decreased expression of these vascular factors. Such findings suggest that the specific chemistry created by the presence or absence of acidic components may be important in SOA-mediated toxicity in the cardiovascular system and/or progression of cardiovascular disease. PMID- 23742110 TI - Assessments of population exposure to environmental pollutants using air quality measurements during Commonwealth Games-2010. AB - During the "Commonwealth Games" 2010 (CWG-2010) in Delhi, the Indian government has implemented an ambitious project "System of Air quality Forecasting And Research (SAFAR)" for monitoring and forecasting air-quality scenario. Using high precision spatio-temporal measurements of criteria pollutants from the SAFAR network, the number of cases are estimated for total, cardiovascular and respiratory mortalities and hospital admissions. In a thinly populated airport area, the excess number of cases for total mortality show ~10 for PM2.5 and 25 for PM10, whereas, ~110 for PM2.5 and ~300 for PM10 in most populous Delhi University (DU) area. Cardiovascular mortality in airport area show ~5 and <10 for PM2.5 and PM10, respectively, but, in DU area show ~55 for PM2.5 and ~140 for PM10. In DU locality, respiratory mortality shows ~7 and ~20 for PM2.5 and PM10 and, hospital admissions show ~11 and ~30 for PM2.5 and PM10, respectively. In airport area, excess cases of respiratory mortality and hospital admission tends to one for exposure to PM2.5 or PM10 levels indicating effective exposure is the key factor for health hazards. As public health gains, low air pollution levels were observed before the CWG due to effective washout by monsoonal rain and during CWG under policy-induced air quality measures could increase the life expectancy as against to post-CWG period. These results are important for the megacities in developing world as the SAFAR project is internationally recognized by the Global Urban Research Meteorology and Environment of the World Meteorological Organization. PMID- 23742111 TI - Ozone exposure-response model for lung function changes: an alternate variability structure. AB - CONTEXT: A statistical model that accurately predicts human forced expiratory volume in one second (FEV1) response to ozone exposure has been identified and proposed as the foundation for future risk assessments for ambient ozone. We believe that the assumptions about intra-subject variability in the published model can be improved and hypothesize that more realistic assumptions will improve the fit of the model and the accuracy of risk assessments based on the model. OBJECTIVE: Identify alternate assumptions about intra-subject variability and compare goodness-of-fit for models with various variability structures. MATERIALS AND METHODS: Models were fit to an existing data set using a statistical program for fitting nonlinear mixed models. Goodness-of-fit was assessed using Akaike's Information Criteria (AIC) and visual examination of graphical figures showing observed and predicted values. RESULTS: The AIC indicated that a model that assumed intra-subject variability was related to the magnitude of individual response fit the data better than a model that assumes intra-subject variability is constant across individuals and exposures (the original model). This finding was consistent with the variability of observed responses for filtered air exposures and for exposures predicted to be below the threshold for response. CONCLUSION: An ozone exposure-response model that assumes intra-subject variability increases with individual mean FEV1 response appears to fit the data better than one that assumes constant variability. PMID- 23742112 TI - Cytotoxicity evaluation of electronic cigarette vapor extract on cultured mammalian fibroblasts (ClearStream-LIFE): comparison with tobacco cigarette smoke extract. AB - CONTEXT: Electronic cigarettes (ECs) are used as alternatives to smoking; however, data on their cytotoxic potential are scarce. OBJECTIVE: To evaluate the cytotoxic potential of 21 EC liquids compared to the effects of cigarette smoke (CS). METHODS: Cytotoxicity was evaluated according to UNI EN ISO 10993-5 standard. By activating an EC device, 200 mg of liquid was evaporated and was extracted in 20 ml of culture medium. CS extract from one cigarette was also produced. The extracts, undiluted (100%) and in five dilutions (50%, 25%, 12.5%, 6.25% and 3.125%), were applied to cultured murine fibroblasts (3T3), and viability was measured after 24-hour incubation by 3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyltetrazolium bromide assay. Viability of less than 70% was considered cytotoxic. RESULTS: CS extract showed cytotoxic effects at extract concentrations above 12.5% (viability: 89.1 +/- 3.5% at 3.125%, 77.8 +/- 1.8% at 6.25%, 72.8 +/- 9.7% at 12.5%, 5.9 +/- 0.9% at 25%, 9.4 +/- 5.3% at 50% and 5.7 +/- 0.7% at 100% extract concentration). Range of fibroblast viability for EC vapor extracts was 88.5-117.8% at 3.125%, 86.4-115.3% at 6.25%, 85.8-111.7% at 12.5%, 78.1-106.2% at 25%, 79.0-103.7% at 50% and 51.0-102.2% at 100% extract concentration. One vapor extract was cytotoxic at 100% extract concentration only (viability: 51.0 +/- 2.6%). However, even for that liquid, viability was 795% higher relative to CS extract. CONCLUSIONS: This study indicates that EC vapor is significantly less cytotoxic compared tobacco CS. These results should be validated by clinical studies. PMID- 23742114 TI - Moving beyond the therapeutic relationship: a selective review of intimacy in the sexual health encounter in nursing practice. AB - AIMS AND OBJECTIVES: For the purposes of this study, a selective review of the literature was undertaken with the aim of examining nurses' preparedness to engage in intimate interactions within the context of sexual health care. Kirk's (2007) model of interactional intimacy is used as a lens to examine the literature. BACKGROUND: The provision of sexual health care is often a neglected area of nursing care despite being recognised as a component of holistic nursing practice. Despite theoretical discussion about various forms of intimacy and intimate care, there has been little examination of the interface between intimacy and sexual health care that usefully informs practice. DESIGN: Selective review and synthesis of the literature. CONCLUSION: The literature of humanistic interpretations of caring that has dominated nursing discourse over the last half century has limited progress on defining and developing forms of clinical interaction that are suited to promoting nurses engagement in sexual health care. We propose that Kirk's model has useful utility in preparing nurses to engage more readily with sexual health care as a routine component of their practice. RELEVANCE TO CLINICAL PRACTICE: Sexual health adversity can often accompany ill health, and therefore, the provision of appropriate care is required to negate detrimental outcomes and promote positive well-being. Although sexual health care is often not prioritised in practice, nurses are in a prime position to promote sexual health care and well-being. By conducting sexual health assessments and providing sexual health care routinely, the gap that exists between patients' sexual healthcare needs and the lack of sexual health care provided can be minimised. PMID- 23742113 TI - Placental DNA hypomethylation in association with particulate air pollution in early life. AB - BACKGROUND: There is evidence that altered DNA methylation is an important epigenetic mechanism in prenatal programming and that developmental periods are sensitive to environmental stressors. We hypothesized that exposure to fine particles (PM2.5) during pregnancy could influence DNA methylation patterns of the placenta. METHODS: In the ENVIRONAGE birth cohort, levels of 5'-methyl deoxycytidine (5-mdC) and deoxycytidine (dC) were quantified in placental DNA from 240 newborns. Multiple regression models were used to study placental global DNA methylation and in utero exposure to PM2.5 over various time windows during pregnancy. RESULTS: PM2.5 exposure during pregnancy averaged (25th-75th percentile) 17.4 (15.4-19.3) MUg/m3. Placental global DNA methylation was inversely associated with PM2.5 exposures during whole pregnancy and relatively decreased by 2.19% (95% confidence interval [CI]: -3.65, -0.73%, p = 0.004) for each 5 MUg/m3 increase in exposure to PM2.5. In a multi-lag model in which all three trimester exposures were fitted as independent variables in the same regression model, only exposure to PM2.5 during trimester 1 was significantly associated with lower global DNA methylation (-2.13% per 5 MUg/m3 increase, 95% CI: -3.71, -0.54%, p = 0.009). When we analyzed shorter time windows of exposure within trimester 1, we observed a lower placental DNA methylation at birth during all implantation stages but exposure during the implantation range (6-21d) was strongest associated (-1.08% per 5 MUg/m3 increase, 95% CI: -1.80, -0.36%, p = 0.004). CONCLUSIONS: We observed a lower degree of placental global DNA methylation in association with exposure to particulate air pollution in early pregnancy, including the critical stages of implantation. Future studies should elucidate genome-wide and gene-specific methylation patterns in placental tissue that could link particulate exposure during in utero life and early epigenetic modulations. PMID- 23742115 TI - Metabolite analysis of the effects of elevated CO2 and nitrogen fertilization on the association between tall fescue (Schedonorus arundinaceus) and its fungal symbiont Neotyphodium coenophialum. AB - Atmospheric CO2 is expected to increase to between 550 ppm and 1000 ppm in the next century. CO2-induced changes in plant physiology can have ecosystem-wide implications and may alter plant-plant, plant-herbivore and plant-symbiont interactions. We examined the effects of three concentrations of CO2 (390, 800 and 1000 ppm) and two concentrations of nitrogen fertilizer (0.004 g N/week versus 0.2 g N/week) on the physiological response of Neotyphodium fungal endophyte-infected and uninfected tall fescue plants. We used quantitative PCR to estimate the concentration of endophyte under altered CO2 and N conditions. We found that elevated CO2 increased the concentration of water-soluble carbohydrates and decreased the concentration of plant total amino acids in plants. Fungal-derived alkaloids decreased in response to elevated CO2 and increased in response to nitrogen fertilization. Endophyte concentration (expressed as the number of copies of an endophyte-specific gene per total genomic DNA) increased under elevated CO2 and nitrogen fertilization. The correlation between endophyte concentration and alkaloid production observed at ambient conditions was not observed under elevated CO2. These results suggest that nutrient exchange dynamics important for maintaining the symbiotic relationship between fungal endophytes and their grass hosts may be altered by changes in environmental variables such as CO2 and nitrogen fertilization. PMID- 23742117 TI - Growth of all-carbon horizontally aligned single-walled carbon nanotubes nucleated from fullerene-based structures. AB - All-carbon single-walled carbon nanotubes (SWCNTs) were successfully synthesized, nucleated using a fullerene derivative. A systematic investigation into the initial preparation of C60 fullerenes as growth nucleators for the SWCNTs was conducted. Enhancement in the yield of the produced SWCNT has been achieved with exploring different dispersing media for the fullerenes, the period, and environment of the initial thermal treatment of the fullerenes in addition to the use of different fullerene-based structures. The systematic studies significantly advance our understanding of the growth of the all-carbon catalyst-free single walled carbon nanotubes. Field-effect transistors were fabricated using the catalyst-free SWCNT and then electrically characterized, showing current capacity as high as the well-studied catalyst-assisted nanotubes. PMID- 23742118 TI - A novel echocardiographic predictor of atrial fibrillation recurrence: L-wave. AB - Diastolic dysfunction leads to atrial fibrillation (AF) by increasing left atrial pressure and also increases recurrence rate after cardioversion. So, L-wave, which is associated with severe diastolic dysfunction, could predict recurrent AF after cardioversion. The aim of this study was to investigate predictive value of L-wave for AF recurrence at first month after electrical cardioversion. A total of 127 patients with persistent AF were evaluated for this study and finally 73 patients were included according to the study criteria. Echocardiographic examinations were performed for all patients before and at 24th hour after electrical cardioversion. Heart rates and rhythms were followed with electrocardiography monitor and 12-lead ECG at first week and first month. Seventy patients achieved sinus rhythm (SR) after cardioversion and 3 patients who did not go into SR excluded from the study. Patients were divided into 2 groups according to having (group 1) or not having (group 2) L-wave on echocardiography. Twenty-two patients (6 men, 16 women) had L-wave and 48 patients (19 men, 29 women) did not have L-wave. Duration of AF was longer in group 1 as compared to group 2 (P = 0.03). Mean heart rate was lower in group 1 than in group 2 (P < 0.001). Duration of AF and presence of L-wave were significant parameters for AF recurrence in univariate analysis, however, presence of L-wave was the only significant parameter for AF recurrence in multivariate analysis. Ten patients in group 1 (45.5%) and 7 patients (14.6%) in group 2 (P = 0.005) had AF recurrence at the end of first month after cardioversion. L-wave did predict AF recurrence with 59% sensitivity, 77% specificity, 45% positive predictive value, and 85% negative predictive value at 1 month. Echocardiographic L-wave could predict the AF recurrence. PMID- 23742116 TI - Perceived stereotyping and seeking care for chronic vulvar pain. AB - OBJECTIVES: We examined stereotyping of chronic pain sufferers among women aged 18-40 years and determined whether perceived stereotyping affects seeking care for women with chronic vulvar pain. DESIGN: Cross-sectional study using a community-based survey of vulvodynia asking if "Doctors think that people with chronic pain exaggerate their pain," and if "People believe that vulvar pain is used as an excuse to avoid having sex". SETTING AND PARTICIPANTS: Twelve thousand eight hundred thirty-four women aged 18-40 years in metropolitan Minneapolis/St. Paul, Minnesota. OUTCOME MEASURES: Women were considered to have a history of chronic vulvar pain if they reported vulvar burning lasting more than 3 months or vulvar pain on contact. RESULTS: Four thousand nine hundred eighty-seven (38.9%) women reported a chronic pain condition; 1,651 had chronic vulvar pain. Women experiencing chronic pain were more likely than those without to perceive stereotyping from both doctors and others; a dose-response with the number of pain conditions existed. Women with chronic vulvar pain were more likely to believe that people think vulvar pain is an excuse to avoid intercourse. Half of the women with chronic vulvar pain did not seek medical care for it; of these, 40.4% perceived stereotyping from doctors. However, it was women who actually sought care (45.1%) who were more likely to feel stigmatized by doctors (adjusted relative risk = 1.11, 95% confidence interval: 1.01-1.23). CONCLUSIONS: Perceived negative stereotyping among chronic pain sufferers is common, particularly negative perceptions about physicians. In fact, chronic vulvar pain sufferers who felt stigmatized were more likely to have sought care than those who did not feel stigmatized. PMID- 23742119 TI - Clinical dehydration and glomerular filtration rate in acute paediatric gastroenteritis. AB - AIM: To evaluate changes in glomerular filtration rate in acute gastroenteritis. METHODS: The correlation between two clinical diagnostic scales and glomerular filtration rate has been investigated in 113 children with acute gastroenteritis in a paediatric emergency setting. RESULTS: A significant reduction of GFR was found in 10% children less than, and 5% children higher than, 2 years of age with acute gastroenteritis. CONCLUSION: The differences observed as for risk of renal hypoperfusion suggests to consider the age of children as an important determinant to consider the dehydration status in acute gastroenteritis. PMID- 23742120 TI - Characterization of aryloxyalkanoate dioxygenase-12, a nonheme Fe(II)/alpha ketoglutarate-dependent dioxygenase, expressed in transgenic soybean and Pseudomonas fluorescens. AB - Aryloxyalkanoate dioxygenase-12 (AAD-12) was discovered from the soil bacterium Delftia acidovorans MC1 and is a nonheme Fe(II)/alpha-ketoglutarate-dependent dioxygenase, which can impart herbicide tolerance to transgenic plants by catalyzing the degradation of certain phenoxyacetate, pyridyloxyacetate, and aryloxyphenoxypropionate herbicides. (1) The development of commercial herbicide tolerant crops, in particular AAD-12-containing soybean, has prompted the need for large quantities of the enzyme for safety testing. To accomplish this, the enzyme was produced in Pseudomonas fluorescens (Pf) and purified to near homogeneity. A small amount of AAD-12 was partially purified from transgenic soybean and through various analytical, biochemical, and in vitro activity analyses demonstrated to be equivalent to the Pf-generated enzyme. Furthermore, results from in vitro kinetic analyses using a variety of plant endogenous compounds revealed activity with trans-cinnamate and indole-3-acetic acid (IAA). The catalytic efficiencies (kcat/Km) of AAD-12 using trans-cinnamate (51.5 M(-1) s(-1)) and IAA (8.2 M(-1) s(-1)) as substrates were very poor when compared to the efficiencies of plant endogenous enzymes. The results suggest that the presence of AAD-12 in transgenic soybean would not likely have an impact on major plant metabolic pathways. PMID- 23742121 TI - mEH Tyr113His polymorphism and the risk of ovarian cancer development. AB - BACKGROUND: The causes of ovarian cancer are complex and may be influenced by many factors, including polymorphism in the microsomal epoxide hydrolase (mEH) gene. Previous work suggests an association between the Tyr113His mEH polymorphism rs1051740 and susceptibility to ovarian cancer, but the results have been inconsistent. METHODS: PubMed, EMBASE, Google Scholar, and Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association between Tyr113His mEH polymorphism and susceptibility to ovarian cancer. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. RESULTS: Five studies involving 2,566 cases and 2,839 controls were included. Although the polymorphism did not affect ovarian cancer risk in the allelic contrast model (OR = 0.99, 95% CI = 0.83-1.17, P = 0.86), the mutant CC genotype was significantly associated with increased risk in the homozygote comparison (OR = 1.20, 95% CI = 1.01-1.43, P = 0.04) and recessive genetic models (OR = 1.20, 95% CI = 1.01-1.41, P = 0.03). The wild-type TT genotype was not associated with higher or lower ovarian cancer risk in the dominant genetic model (OR = 1.04, 95% CI = 0.83-1.29, P = 0.74). These results were robust to sensitivity analysis. CONCLUSIONS: The CC genotype of Tyr113His mEH may confer increased risk of ovarian cancer. These conclusions should be verified in large and well-designed studies. PMID- 23742122 TI - Transplanting pediatric deceased-donor kidneys into adult recipients: an Iranian experience. AB - OBJECTIVES: This study sought to evaluate graft outcome of kidneys from deceased donor pediatric donors in adult recipients, and compare it with outcomes of kidney transplants from adult donors. MATERIALS AND METHODS: This historical cohort study involved 2 groups. Group 1 included 23 first kidney adult recipients who received their first renal transplant from pediatric deceased-donor donors. Group 2 consisted of 33 first renal transplant adult recipients with kidneys coming from adult deceased donors. The Kaplan-Meier method was used to generate graft survival and patient survival curves. The log-rank test was done to compare differences between survival outcomes. RESULTS: Graft survival rates at 1 and 5 years were 96% and 85% in group 1, and 91% and 85% in group 2. No significant difference existed in graft survival rates between the groups. Patient survival rates at 1 and 5 years in group 1 were 94% and 94% compared with 91% and 91% for group 2. No significant difference existed in graft survival rates between the groups. CONCLUSIONS: This study demonstrates that with our experience, improvement in surgical technique and immunosuppressive therapy, pediatric deceased-donor kidneys may be considered as an alternate option for adult recipients. Renal transplants from pediatric donors into adult recipients is associated with good graft and patient survival outcomes. PMID- 23742123 TI - A new method for the rapid diagnosis of protein N-linked congenital disorders of glycosylation. AB - The Congenital Disorders of Glycosylation (CDG) are a devastating group of genetic disorders that encompass a spectrum of glycosylation defects and are characterized by the underglycosylation of or the presence of abnormal glycans on glycoproteins. The N-linked CDG disorders (Type I and II) are usually diagnosed in chemical pathology laboratories by an abnormal serum transferrin isoelectric focusing (IEF) pattern. Transferrin has been the protein of choice for CDG analysis because it is well characterized, highly abundant, and easily detected in plasma. However, IEF provides limited information on the glycosylation defect and requires a separate and extensive glycan analysis to diagnose CDG Type II. We have therefore developed a simple bead-based immunoaffinity and mass spectrometry based assay to address these issues. Our method uses immuno-purified transferrin and proteolytic digestion followed by a rapid 30 min mass spectral analysis and allows us to identify both micro- and macroheterogeneity of transferrin by sequencing of peptides and glycopeptides. In summary, we have developed a simple, rapid test for N-linked glycosylation disorders that is a significant improvement on existing laboratory tests currently used for investigating defective N-linked glycosylation. PMID- 23742124 TI - Neuregulin1 signaling promotes dendritic spine growth through kalirin. AB - The biological functions of the neuregulin 1 (NRG1) and ERBB4 genes have received much recent attention due to several studies showing associations between these genes and schizophrenia. Moreover, reduced forebrain dendritic spine density is a consistent feature of schizophrenia. It is thus important to understand the mechanisms whereby NRG1 and erbB4 modulate spine morphogenesis. Here, we show that long-term incubation with NRG1 increases both spine size and density in cortical pyramidal neurons. NRG1 also enhances the content of alpha-amino-3 hydroxy-5-methylisoxazole-4-propionate receptors in spines. Knockdown of ERBB4 expression prevented the effects of NRG1 on spine size, but not on spine density. The effects of NRG1 and erbB4 on spines were mediated by the RacGEF kalirin, a well-characterized regulator of dendritic spines. Finally, we show that environmental enrichment, known to promote spine growth, robustly enhances the levels of erbB4 protein in the forebrain. These findings provide a mechanistic link between NRG1 signaling and spine morphogenesis PMID- 23742125 TI - Open-label clinical trial comparing the clinical and economic effectiveness of using a polyurethane film surgical dressing with gauze surgical dressings in the care of post-operative surgical wounds. AB - Surgical site infection (SSI) is a common postoperative complication and can cause avoidable morbidity and excessive costs for the health service. Novel dressings, designed specifically for postoperative wounds, can help to reduce the risk of SSI and other complications such as blistering. This study compared the use of a new polyurethane film surgical dressing (Opsite Post-Op Visible, Smith & Nephew, Hull, UK) with gauze and tape in the management of postoperative wounds. The results show that the polyurethane film dressing results in a significant reduction in SSI (1.4% versus 6.6%, P = 0.006) as well as a reduction in other postoperative wound complications (e.g. blistering and erythema). Economic analysis conducted alongside the study suggests that these improved outcomes can be achieved at a lower treatment cost than gauze and tape dressings. The modest incremental cost of the polyurethane film surgical dressing is easily offset by the reduction in the costs related to treating SSI and other wound complications associated with gauze and tape dressings. PMID- 23742127 TI - Stress response assessment of Lactobacillus sakei strains selected as potential autochthonous starter cultures by flow cytometry and nucleic acid double-staining analyses. AB - AIMS: The aim of this study was to apply the flow cytometry to Lactobacillus sakei strains, selected as potential autochthonous starters, to investigate dynamics and physiological heterogeneity of microbial behaviour under different stress conditions. METHODS AND RESULTS: A simultaneous nucleic acid double staining assay was applied to discriminate cell populations in different physiological states after exposure to heat (50 and 55 degrees C) and acid (pH 2.5 and 3.0) stresses. Alive cells with intact membranes, damaged cells still alive but with injured membranes, so with even a recovery ability, and dead cells with a permanent membrane damage were differentiated with a significant increase in damaged cells after stronger stress treatments. CONCLUSIONS: The existence and characteristics of subpopulations displaying heterogeneity in particular conditions are highly relevant, because specific subpopulations may show improved survival, changes and dynamics under stress conditions. SIGNIFICANCE AND IMPACT OF STUDY: This assay has potential for physiological research on lactic acid bacteria and for application in the food industry. The assessment of intermediate physiological states in Lb. sakei strains with recovery possibility could be an important criterion for application of potential starter cultures. Application of flow cytometry and characterization of sorted subpopulations may contribute to further understanding of diversity and heterogeneity in physiology of bacterial populations. PMID- 23742126 TI - Lipid-based signaling modulates DNA repair response and survival against Klebsiella pneumoniae infection in host cells and in mice. AB - Klebsiella pneumoniae causes serious infections in the urinary tract, respiratory tract, and blood. Lipid rafts, also known as membrane microdomains, have been linked to the pathogenesis of bacterial infection. However, whether lipid rafts affect K. pneumoniae internalization into host cells remains unknown. Here, we show for the first time that K. pneumoniae was internalized into lung cells by activating lipid rafts. Disrupting lipid rafts by methyl-beta-cyclodextrin inhibited pathogen internalization, impairing host defense. A deficient mutant of capsule polysaccharide (CPS) showed a higher internalization rate than a wild type strain, indicating that CPS may inhibit bacterial entry to host cells. Furthermore, lipid rafts may affect the function of extracellular regulated kinase (ERK)-1/2, and knocking down ERK1/2 via short, interfering RNA increased apoptosis in both alveolar macrophages and epithelial cells after infection. To gain insights into bacterial pathogenesis, we evaluated the impact of lipid rafts on DNA integrity, and showed that raft aggregates also affect DNA damage and DNA repair responses (i.e., 8-oxoguanine DNA glycosylase [Ogg1]) through the regulation of reactive oxygen species. Importantly, cells overexpressing Ogg1 demonstrated reduced cytotoxicity during bacterial infection. Taken together, these results suggest that lipid rafts may modulate bacterial internalization, thereby affecting DNA damage and repair, which is critical to host defense against K. pneumoniae. PMID- 23742128 TI - Gold nanorod@chiral mesoporous silica core-shell nanoparticles with unique optical properties. AB - The design and fabrication of chiral nanostructures is a promising approach to realize enantiomeric recognition and separation. In our work, gold nanorod@chiral mesoporous silica core-shell nanoparticles (GNR@CMS NPs) have been successfully synthesized. This novel material exhibits strong and tunable circular dichroism signals in the visible and near-infrared regions due to the optical coupling between the CMS shells and the GNR cores. When chiral cysteine molecules are loaded in the porous shells, the corresponding surface enhanced Raman scattering spectroscopy demonstrates a distinct chiral recognition effect, which can be used to semiquantitatively measure the composition of chiral enantiomers. A detailed sensing mechanism has been disclosed by density functional theory calculations. PMID- 23742129 TI - Computational framework to support integration of biomolecular and clinical data within a translational approach. AB - BACKGROUND: The use of the knowledge produced by sciences to promote human health is the main goal of translational medicine. To make it feasible we need computational methods to handle the large amount of information that arises from bench to bedside and to deal with its heterogeneity. A computational challenge that must be faced is to promote the integration of clinical, socio-demographic and biological data. In this effort, ontologies play an essential role as a powerful artifact for knowledge representation. Chado is a modular ontology oriented database model that gained popularity due to its robustness and flexibility as a generic platform to store biological data; however it lacks supporting representation of clinical and socio-demographic information. RESULTS: We have implemented an extension of Chado - the Clinical Module - to allow the representation of this kind of information. Our approach consists of a framework for data integration through the use of a common reference ontology. The design of this framework has four levels: data level, to store the data; semantic level, to integrate and standardize the data by the use of ontologies; application level, to manage clinical databases, ontologies and data integration process; and web interface level, to allow interaction between the user and the system. The clinical module was built based on the Entity-Attribute-Value (EAV) model. We also proposed a methodology to migrate data from legacy clinical databases to the integrative framework. A Chado instance was initialized using a relational database management system. The Clinical Module was implemented and the framework was loaded using data from a factual clinical research database. Clinical and demographic data as well as biomaterial data were obtained from patients with tumors of head and neck. We implemented the IPTrans tool that is a complete environment for data migration, which comprises: the construction of a model to describe the legacy clinical data, based on an ontology; the Extraction, Transformation and Load (ETL) process to extract the data from the source clinical database and load it in the Clinical Module of Chado; the development of a web tool and a Bridge Layer to adapt the web tool to Chado, as well as other applications. CONCLUSIONS: Open-source computational solutions currently available for translational science does not have a model to represent biomolecular information and also are not integrated with the existing bioinformatics tools. On the other hand, existing genomic data models do not represent clinical patient data. A framework was developed to support translational research by integrating biomolecular information coming from different "omics" technologies with patient's clinical and socio-demographic data. This framework should present some features: flexibility, compression and robustness. The experiments accomplished from a use case demonstrated that the proposed system meets requirements of flexibility and robustness, leading to the desired integration. The Clinical Module can be accessed in http://dcm.ffclrp.usp.br/caib/pg=iptrans. PMID- 23742130 TI - Understanding how and why health is integrated into foreign policy - a case study of health is global, a UK Government Strategy 2008-2013. AB - BACKGROUND: Over the past decade, global health issues have become more prominent in foreign policies at the national level. The process to develop state level global health strategies is arguably a form of global health diplomacy (GHD). Despite an increase in the volume of secondary research and analysis in this area, little primary research, particularly that which draws directly on the perspectives of those involved in these processes, has been conducted. This study seeks to fill this knowledge gap through an empirical case study of Health is Global: A UK Government Strategy 2008-2013. It aims to build understanding about how and why health is integrated into foreign policy and derive lessons of potential relevance to other nations interested in developing whole-of-government global health strategies. METHODS: The major element of the study consisted of an in-depth investigation and analysis of the UK global health strategy. Document analysis and twenty interviews were conducted. Data was organized and described using an adapted version of Walt and Gilson's policy analysis triangle. A general inductive approach was used to identify themes in the data, which were then analysed and interpreted using Fidler's health and foreign policy conceptualizations and Kingdon's multiples streams model of the policymaking process. RESULTS: The primary reason that the UK decided to focus more on global health is self-interest - to protect national and international security and economic interests. Investing in global health was also seen as a way to enhance the UK's international reputation. A focus on global health to primarily benefit other nations and improve global health per se was a prevalent through weaker theme. A well organized, credible policy community played a critical role in the process and a policy entrepreneur with expertise in both international relations and health helped catalyze attention and action on global health when the time was right. Support from the Prime Minister and from the Foreign and Commonwealth Office was essential. The process to arrive at a government-wide strategy was complex and time-consuming, but also broke down silos. Significant negotiation and compromise were required from actors with widely varying perspectives on global health and conflicting priorities. CONCLUSIONS: As primarily an exploratory study, this research sheds significant light on the global health policymaking process at the level of the state. It provides a useful and important starting point for further hypothesis driven empirical research that focuses on the integration of health in foreign policy, how and why this happens and whether or not it makes an impact on improving global health. PMID- 23742131 TI - Microarray analysis of two single-nucleotide polymorphisms of transforming growth factor alpha in patients with nonsyndromic cleft of north china. AB - OBJECTIVE: To investigate the association between the TGFA:c.3851T > C (rs11466285) and TGFA:c.3822G > A (rs3771523) single-nucleotide polymorphisms (SNPs) and nonsyndromic cleft lip and/or cleft palate (CL/P) with microarray in north China. DESIGN AND SETTING: Test association by both case-control and case parent analysis. SUBJECTS AND METHODS: Two SNPs of 150 controls, 166 cases, and 271 of their parents were genotyped using microarray based on the allele-specific primer extension, and chi-square statistics and family-based association test analyses were performed. RESULTS: Both sequencing and microarray analysis produced identical results. We found significant evidence of overtransmission of the C allele of c.3851T > C and the A allele of c.3822G > A in case-parent trios for CL/P but not for cleft palate only (CP). Significant differences for both genotypic and allelic distributions between cases and controls were found at c.3822G > A and c.3851T > C for CL/P but not for CP. The TGFA [C; G] and [T; A] haplotypes showed significant overtransmission. CONCLUSIONS: These results support that two SNPs are associated with nonsyndromic CL/P but not for CP in northern Chinese populations. It was demonstrated that this microarray is suitable to test SNPs associated with nonsyndromic CL/P. PMID- 23742132 TI - In vitro and in vivo evaluation of polymer hydrogels for hemorrhage control. AB - In vitro and in vivo experimentation of various synthetic polymer hydrogels was conducted to establish some of the integral material properties that influence hemostasis. In vitro swelling experiments suggested that positive electrostatic charge was a key determinant of the ability of a polymer hydrogel to absorb physiological fluids, e.g. human plasma and blood. In vitro testing using unadulterated sheep blood suggested positive electrostatic charge and crosslink density were key determinants of the ability of a material to induce or enhance clot formation. Hydrogel formulations composed of higher amounts of positive electrostatic charge and lower crosslink density were able to effectively induce and enhance clot formation in the presence of a coagulation cascade activator. In vivo experimentation confirmed that hydrogels containing higher electrostatic charge and low crosslink density are more effective at fostering the formation of a robust hemostatic plug to control blood loss. PMID- 23742133 TI - Glucose oxidase encapsulated polyvinyl alcohol-silica hybrid films for an electrochemical glucose sensing electrode. AB - An amperometric glucose enzyme electrode was developed by the immobilization of glucose oxidase (GOD) in a composite material based on polyvinyl alcohol (PVA) and partially prehydrolyzed tetraethyl orthosilicate (pphTEOS) on the surface of "in-house" fabricated graphite electrodes. For comparison, silver and gold nanoparticles (Ag/AuNPs) embedded in the PVA-pphTEOS matrix was prepared through a novel method via sol-gel process based on the in situ chemical reduction of Ag or Au ions using PVA as a reducing agent and stabilizer. The successful incorporation of Ag and AuNPs ranging from 5 to 7.5 and 4.5-11 nm, respectively, in the PVA-pphTEOS matrix was confirmed by UV-Vis spectroscopy, TEM, and EDX analysis. The PVA-TEOS matrix was also characterized by FTIR spectroscopy. The analytical performance of the enzyme electrodes were studied in terms of linear ranges, sensitivities, response times, limits of detection, reproducibility and stability. PMID- 23742134 TI - Laser-induced growth of nanocrystals embedded in porous materials. AB - Space localization of the linear and nonlinear optical properties in a transparent medium at the submicron scale is still a challenge to yield the future generation of photonic devices. Laser irradiation techniques have always been thought to structure the matter at the nanometer scale, but combining them with doping methods made it possible to generate local growth of several types of nanocrystals in different kinds of silicate matrices. This paper summarizes the most recent works developed in our group, where the investigated nanoparticles are either made of metal (gold) or chalcogenide semiconductors (CdS, PbS), grown in precursor-impregnated porous xerogels under different laser irradiations. This review is associated to new results on silver nanocrystals in the same kind of matrices. It is shown that, depending on the employed laser, the particles can be formed near the sample surface or deep inside the silica matrix. Photothermal and/or photochemical mechanisms may be invoked to explain the nanoparticle growth, depending on the laser, precursor, and matrix. One striking result is that metal salt reduction, necessary to the production of the corresponding nanoparticles, can efficiently occur due to the thermal wrenching of electrons from the matrix itself or due to multiphoton absorption of the laser light by a reducer additive in femtosecond regime. Very localized semiconductor quantum dots could also be generated using ultrashort pulses, but while PbS nanoparticles grow faster than CdS particles due to one-photon absorption, this better efficiency is counterbalanced by a sensitivity to oxidation. In most cases where the reaction efficiency is high, particles larger than the pores have been obtained, showing that a fast diffusion of the species through the interconnected porosity can modify the matrix itself. Based on our experience in these techniques, we compare several examples of laser-induced nanocrystal growth in porous silica xerogels, which allows extracting the best experimental conditions to obtain an efficient particle production and to avoid stability or oxidation problems. PMID- 23742135 TI - Replication protein A subunit 3 and the iron efficiency response in soybean. AB - In soybean [Glycine max (L.) Merr.], iron deficiency results in interveinal chlorosis and decreased photosynthetic capacity, leading to stunting and yield loss. In this study, gene expression analyses investigated the role of soybean replication protein A (RPA) subunits during iron stress. Nine RPA homologs were significantly differentially expressed in response to iron stress in the near isogenic lines (NILs) Clark (iron efficient) and Isoclark (iron inefficient). RPA homologs exhibited opposing expression patterns in the two NILs, with RPA expression significantly repressed during iron deficiency in Clark but induced in Isoclark. We used virus induced gene silencing (VIGS) to repress GmRPA3 expression in the iron inefficient line Isoclark and mirror expression in Clark. GmRPA3-silenced plants had improved IDC symptoms and chlorophyll content under iron deficient conditions and also displayed stunted growth regardless of iron availability. RNA-Seq comparing gene expression between GmRPA3-silenced and empty vector plants revealed massive transcriptional reprogramming with differential expression of genes associated with defense, immunity, aging, death, protein modification, protein synthesis, photosynthesis and iron uptake and transport genes. Our findings suggest the iron efficient genotype Clark is able to induce energy controlling pathways, possibly regulated by SnRK1/TOR, to promote nutrient recycling and stress responses in iron deficient conditions. PMID- 23742136 TI - Child and family health nurses working with families of preschool-aged children. AB - AIMS AND OBJECTIVES: To examine child and family health nurses' perceptions of and practices related to working with families of preschool-aged children about their child's behaviour. BACKGROUND: Emotional and behavioural problems in young children are of increasing concern. Child and family health nurses are well placed to support parents and provide education about behavioural concerns. DESIGN: A qualitative interpretive study informed by ethnography was used. METHODS: Forty-eight nurses participated in focus groups. Of these nurses, 11 participated in observations of clinical interactions with 23 mothers. Eight managers were interviewed. RESULTS: Three themes and two subthemes emerged from the data: Parents as deficit and nurse as expert; Parents have strengths and nurse as partner; Shaping practice - Time pressures and Wanting respect and to be valued. CONCLUSIONS: Child and family health nurses enjoy working with preschool aged children; however, complex issues and tensions are evident. Nurses need support at all levels within the health service if they are to negotiate an environment of ongoing change and to be enabled to work in partnership with parents and families and thereby promote the emotional and behavioural development of preschool-aged children. RELEVANCE TO CLINICAL PRACTICE: The universal role of child and family health nurses provides unique opportunities to support parents about child behaviour concerns. Without appropriate support, nurses continue to work within an expert model that may alienate parents and families from using this service. PMID- 23742137 TI - The fractionalization of physical activity throughout the week is associated with the cardiometabolic health of children and youth. AB - BACKGROUND: The influence of the fractionalization of moderate- to vigorous- intensity physical activity (MVPA) throughout the week on the health of children is unknown. We compared cardiometabolic risk factors in physically active children who accumulated their weekly MVPA in different patterns. METHODS: We studied 745 participants aged 6-19 years. MVPA was measured using accelerometers over 7 days. Three groups were created: Insufficiently Active, <60 minutes/day of MVPA on average; Infrequently Active, >=60 minutes/day of MVPA on average but exceeding the 60 minute target <5 days; and Frequently Active, >=60 minutes/day MVPA on average and exceeding the 60 minute target >=5 days. Percentile scores for 8 cardiometabolic risk factors were determined. RESULTS: The least favorable cardiometabolic risk factor profile was observed in the Insufficiently Active group. The Frequently Active group had more favorable (5-6 percentile unit difference) diastolic blood pressure, HDL-cholesterol, insulin resistance, and metabolic syndrome scores than the Infrequently Active group, although only the difference for insulin resistance was statistically significant (P < 0.05). These differences remained after controlling for the weekly volume of MVPA. CONCLUSION: The fractionalization of MVPA throughout the week was associated with insulin resistance. PMID- 23742138 TI - Altered hepatic gene expression profiles associated with improved fatty liver, insulin resistance, and intestinal permeability after hydroxypropyl methylcellulose (HPMC) supplementation in diet-induced obese mice. AB - The effect of hydroxypropyl methylcellulose (HPMC) on hepatic gene expression was analyzed by exon microarray and real-time PCR from livers of diet-induced obese (DIO) mice fed a high-fat (HF) diet supplemented with either 6% HPMC or 6% microcrystalline cellulose (MCC). HPMC-fed mice exhibited significantly reduced body weight gain (55% lower compared to MCC), liver weight (13%), plasma LDL cholesterol concentration (45%), and HF diet-increased intestinal permeability (48%). HPMC significantly reduced areas under the curve for 2 h insulin and glucose responses, indicating enhanced insulin sensitivity and glucose metabolism. HPMC up-regulated hepatic genes related to fatty acid oxidation, cholesterol and bile acid synthesis, and cellular activation of glucocorticoid (bile acid recycling) and down-regulated genes related to oxidative stress, triglyceride synthesis, and polyunsaturated fatty acid elongation. In conclusion, HPMC consumption ameliorates the effects of a HF diet on intestinal permeability, insulin resistance, hepatic lipid accumulation, glucocorticoid-related bile acid recycling, oxidative stress, and weight gain in DIO mice. PMID- 23742139 TI - Low-dose combination of alendronate and atorvastatin reduces ligature-induced alveolar bone loss in rats. AB - BACKGROUND AND OBJECTIVE: Atorvastatin (ATV) has bone anabolic properties, and alendronate (ALD) is an important antiresorptive drug. This study aimed to evaluate the effects of the combination of ALD and ATV on ligature-induced alveolar bone loss in rats. MATERIAL AND METHODS: Periodontitis was induced by ligature in 78 Wistar rats. Groups of six rats prophylactically received 0.9% saline (SAL), ALD (0.01 or 0.25 mg/kg subcutaneously) or ATV (0.3 or 27 mg/kg by gavage). Then, groups of six rats received the combination of ALD+ATV (0.25 mg/kg + 27 mg/kg, 0.01 mg/kg + 0.3 mg/kg, 0.25 mg/kg + 0.3 mg/kg or 0.01 mg/kg + 27 mg/kg) prophylactically. An extra group of six rats received therapeutic SAL or a lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) therapeutically. Three extra groups of six rats each received SAL or a lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) prophylactically or therapeutically for histometric and immunohistochemical analyses. The rats were killed on day 11 after ligature placement, and the maxillae were removed and processed for macroscopic, histomorphometric and TRAP immunohistochemical analyses. Gingival samples were collected to evaluate myeloperoxidase (MPO) activity. Blood samples were collected to measure serum bone-specific alkaline phosphatase (BALP) and transaminase levels and for hematological studies. Rats were weighed daily. RESULTS: All combined therapies prevented alveolar bone loss when compared with SAL or low doses of monotherapy (ALD or ATV) (p < 0.05). The lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively), administered either prophylactically (39.0%) or therapeutically (53.5%), prevented alveolar bone loss. Decreases in bone and cementum resorption, in leukocyte infiltration and in immunostaining for TRAP and MPO activity corroborated the morphometric findings. The lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) prevented BALP reduction (p < 0.05) and did not alter the level of serum transaminases. Moreover, the lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) also reduced neutrophilia and lymphomonocytosis and did not cause weight loss when compared with administration of SAL. CONCLUSION: The lower-dose combination of ALD+ATV (0.01 mg/kg + 0.3 mg/kg, respectively) demonstrated a protective effect on alveolar bone loss. PMID- 23742140 TI - Role of fibronectin in normal wound healing. AB - Fibronectin is an adhesive molecule that plays a crucial role in wound healing, particularly in extracellular matrix (ECM) formation and also in reepithelialisation. Fibronectin plays many different roles in the wound healing process because of the presence of specific function domains and binding sites in its structure. Fibronectin interacts with different cell types, cytokines and the ECM. The main role of fibronectin is ECM formation. First, plasma fibronectin forms a provisional fibrin-fibronectin matrix, which will later be replaced by the mature ECM-containing tissue fibronectin. PMID- 23742142 TI - Oil cakes - a by-product of agriculture industry as a fortificant in bakery products. AB - Groundnut cake (GNC) and soybean cake (SBC) by-product of agriculture industry had protein and protein digestibility in the range of 42.7-50.5 and 71.3-76.8%, respectively. Polyphenols present in GNC and SBC were cholorogenic acid, syringic acid and p-coumaric acid. The number of bands separated in soybean meal was greater than the bands observed in GNC flour as seen in SDS-PAGE pattern, respectively. SEM of groundnut flour showed distension of protein bodies due to roasting of the oil cakes. The water absorption of wheat flour GNC blends decreased from 59.2 to 57.3% and increased in wheat flour SBC blends from 59.2 to 68.3% with an increase in oil cake from 0 to 20%. With increase in either GNC or SBC, the biscuits became harder. Addition of glycerol monostearate and sodium stearoyl lactylate in combination with 20% blend of GNC/SBC decreased the breaking strength values and increased the sensory parameters of the biscuits. Nutritionally rich biscuits were thus prepared by incorporating GNC/SBC. PMID- 23742141 TI - Medical comorbidity is associated with persistent index hip pain after total hip arthroplasty. AB - OBJECTIVE: To characterize whether medical comorbidity predicts persistent moderate-severe pain after total hip arthroplasty (THA). METHODS: We analyzed the prospectively collected data from the Mayo Clinic Total Joint Registry for patients who underwent primary or revision THA between 1993 and 2005. Using multivariable-adjusted logistic regression analyses, we examined whether certain medical comorbidities were associated with persistent moderate-severe hip pain 2 or 5 years after primary or revision THA. Odds ratios (ORs), along with 95% confidence intervals (CIs) and P value, are presented. RESULTS: The primary THA cohort consisted of 5,707 THAs and 3,289 THAs at 2 and 5 years, and revision THA, 2,687 and 1,627 THAs, respectively. In multivariable-adjusted logistic regression models, in the primary THA cohort, renal disease was associated with lower odds of moderate-severe hip pain (OR 0.6; 95% CI 0.3, 1.0) at 2 years. None of the comorbidities were significantly associated at 5 years. In the revision THA cohort, heart disease was significantly associated with higher risk (OR 1.7; 95% CI 1.1, 2.6) at 2 years and connective tissue disease with lower risk (OR 0.5; 95% CI 0.3, 0.9) of moderate-severe hip pain at 5-year follow-up. CONCLUSION: This study identified new correlates of moderate-severe hip pain after primary or revision THA, a much-feared outcome of hip arthroplasty. Patients with these comorbidities should be informed regarding the risk of moderate-severe index hip pain, so that they can have a fully informed consent and realistic expectations. PMID- 23742143 TI - Patients' experiences of cold exposure during ambulance care. AB - BACKGROUND: Exposure to cold temperatures is often a neglected problem in prehospital care. Cold exposure increase thermal discomfort and, if untreated causes disturbances of vital body functions until ultimately reaching hypothermia. It may also impair cognitive function, increase pain and contribute to fear and an overall sense of dissatisfaction. The aim of this study was to investigate injured and ill patients' experiences of cold exposure and to identify related factors. METHOD: During January to March 2011, 62 consecutively selected patients were observed when they were cared for by ambulance nursing staff in prehospital care in the north of Sweden. The field study was based on observations, questions about thermal discomfort and temperature measurements (mattress air and patients' finger temperature). Based on the observation protocol the participants were divided into two groups, one group that stated it was cold in the patient compartment in the ambulance and another group that did not. Continuous variables were analyzed with independent sample t-test, paired sample t-test and dichotomous variables with cross tabulation. RESULTS: In the ambulance 85% of the patients had a finger temperature below comfort zone and 44% experienced the ambient temperature in the patient compartment in the ambulance to be cold. There was a significant decrease in finger temperature from the first measurement indoor compared to measurement in the ambulance. The mattress temperature at the ambulance ranged from -22.3 degrees C to 8.4 degrees C. CONCLUSION: Cold exposure in winter time is common in prehospital care. Sick and injured patients immediately react to cold exposure with decreasing finger temperature and experience of discomfort from cold. Keeping the patient in the comfort zone is of great importance. Further studies are needed to increase knowledge which can be a base for implications in prehospital care for patients who probably already suffer for other reasons. PMID- 23742144 TI - A multiparametric clinical and echocardiographic score to risk stratify patients with chronic systolic heart failure: derivation and testing. AB - Although echo Doppler and biomarkers are the most common examinations performed worldwide in heart failure (HF), they are rarely considered in risk scores. In outpatients with chronic HF and left ventricular ejection fraction (LVEF) <=45%, data on clinical status, echo Doppler variables, aminoterminal pro-type B natriuretic peptide (NT-proBNP), estimated glomerular filtration rate (eGFR), and drug therapies were combined to build up a multiparametric score. We randomly selected 250 patients to produce a derivation cohort and 388 patients were used as a testing cohort. Follow-up lasted 29 +/- 23 months. The univariable predictors that entered into the multivariable Cox model were as follows: furosemide daily dose >25 mg, inability to tolerate angiotensin converting enzyme (ACE) inhibitors, inability to tolerate beta-blockers, age >75 years, New York Heart Association (NYHA) >2, eGFR<60 mL/min, NT-proBNP plasma levels above the median, tricuspid plane systolic excursion (TAPSE) <=14 mm, LV end-diastolic volume index (LVEDVi) >96 mL/m(2) , moderate-to-severe mitral regurgitation (MR) and LVEF <30%. The scores of prognostic factors were obtained with the respective odds ratio divided by the lower odd ratio: 4 points for furosemide dose, 3 points for age, NT-proBNP, LVEDVi, TAPSE, 2 points for inability to tolerate beta blockers, inability to tolerate ACE inhibitors, NYHA, eGFR<60 mL/min, moderate-to severe MR, 1 point for LVEF. The multiparametric score predicted all-cause mortality either in the derivation cohort (68.4% sensitivity, 79.5% specificity, area under the curve [AUC] 78.7%) or in the testing cohort (73.7% sensitivity, 71.3% specificity, AUC 77.2%). All-cause mortality significantly increased with increasing score both in the derivation and in the testing cohort (P < 0.0001). In conclusion, this multiparametric score is able to predict mortality in chronic systolic HF. PMID- 23742145 TI - Polyanionic (phosphates, silicates, sulfates) frameworks as electrode materials for rechargeable Li (or Na) batteries. PMID- 23742146 TI - Intraoperative transeophageal echocardiography to diagnose an anomalous circumflex artery. AB - We describe a 43-year-old male presenting for hemiarch replacement and possible aortic valve replacement. Intraoperative transesophageal echocardiography (TEE) demonstrated an atypical coronary vessel, enabling proper diagnosis of an anomalous circumflex artery and appropriate operative planning. PMID- 23742147 TI - Large-scale extraction of accurate drug-disease treatment pairs from biomedical literature for drug repurposing. AB - BACKGROUND: A large-scale, highly accurate, machine-understandable drug-disease treatment relationship knowledge base is important for computational approaches to drug repurposing. The large body of published biomedical research articles and clinical case reports available on MEDLINE is a rich source of FDA-approved drug disease indication as well as drug-repurposing knowledge that is crucial for applying FDA-approved drugs for new diseases. However, much of this information is buried in free text and not captured in any existing databases. The goal of this study is to extract a large number of accurate drug-disease treatment pairs from published literature. RESULTS: In this study, we developed a simple but highly accurate pattern-learning approach to extract treatment-specific drug disease pairs from 20 million biomedical abstracts available on MEDLINE. We extracted a total of 34,305 unique drug-disease treatment pairs, the majority of which are not included in existing structured databases. Our algorithm achieved a precision of 0.904 and a recall of 0.131 in extracting all pairs, and a precision of 0.904 and a recall of 0.842 in extracting frequent pairs. In addition, we have shown that the extracted pairs strongly correlate with both drug target genes and therapeutic classes, therefore may have high potential in drug discovery. CONCLUSIONS: We demonstrated that our simple pattern-learning relationship extraction algorithm is able to accurately extract many drug-disease pairs from the free text of biomedical literature that are not captured in structured databases. The large-scale, accurate, machine-understandable drug-disease treatment knowledge base that is resultant of our study, in combination with pairs from structured databases, will have high potential in computational drug repurposing tasks. PMID- 23742149 TI - Psychometric evaluation of the Generalized Problematic Internet Use Scale 2 in an Italian sample. AB - The 15-item Generalized Problematic Internet Use Scale 2 (GPIUS2) is one of the few theory-driven instruments to measure problematic Internet use (PIU). Since PIU has emerged in several cultural contexts, it seems relevant to evaluate the psychometric properties of the scale across various cultures. The aim of the present study was to test the psychometric properties (i.e., dimensionality, reliability, and validity) of the Italian version of the GPIUS2. The sample consisted of 371 participants (128 males and 243 females), and their age ranged from 14 to 33 years (M=18.07 years, SD=5.58). The GPIUS2 and the Internet Addiction Test (IAT) were administered individually in both high school and college classes. With regard to scale dimensionality, the best-fit measurement model includes four first-order factors: preference for online social interaction, mood regulation, deficient self-regulation, and negative outcomes (Satorra-Bentler scaled chi-square [S-Bchi(2)]/df=2.27; comparative fit index [CFI]=0.94; Tucker-Lewis index [TLI]=0.93; root mean square error of approximation [RMSEA]=0.05). With regard to reliability, internal-consistency Cronbach's alpha ranged from 0.78 to 0.89. Convergent validity is demonstrated with significant correlations between GPIUS2 (total score and all the subscale scores) and IAT score. Results showed that GPIUS2 scores significantly discriminated between high school and undergraduate students. The overall findings of the present study provide evidence that the Italian version of the GPIUS2 appears to be an adequate measure of generalized PIU cognitions, behaviors, and outcomes. Suggestions for further research are provided. PMID- 23742148 TI - Ephrin-B2 reverse signaling increases alpha5beta1 integrin-mediated fibronectin deposition and reduces distal lung compliance. AB - Alveolar growth abnormalities and severe respiratory dysfunction are often fatal. Identifying mechanisms that control epithelial proliferation and enlarged, poorly septated airspaces is essential in developing new therapies for lung disease. The membrane-bound ligand ephrin-B2 is strongly expressed in lung epithelium, and yet in contrast to its known requirement for arteriogenesis, considerably less is known regarding the function of this protein in the epithelium. We hypothesize that the vascular mediator ephrin-B2 governs alveolar growth and mechanics beyond the confines of the endothelium. We used the in vivo manipulation of ephrin-B2 reverse signaling to determine the role of this vascular mediator in the pulmonary epithelium and distal lung mechanics. We determined that the ephrin-B2 gene (EfnB2) is strongly expressed in alveolar Type 2 cells throughout development and into adulthood. The role of ephrin-B2 reverse signaling in the lung was assessed in Efnb2(LacZ/6YFDeltaV) mutants that coexpress the intracellular truncated ephrin-B2-beta-galactosidase fusion and an intracellular point mutant ephrin-B2 protein that is unable to become tyrosine-phosphorylated or to interact with either the SH2 or PDZ domain-containing downstream signaling proteins. In these viable mice, we observed pulmonary hypoplasia and altered pulmonary mechanics, as evidenced by a marked reduction in lung compliance. Associated with the reduction in lung compliance was a significant increase in insoluble fibronectin (FN) basement membrane matrix assembly with FN deposition, and a corresponding increase in the alpha5 integrin receptor required for FN fibrillogenesis. These experiments indicate that ephrin-B2 reverse signaling mediates distal alveolar formation, fibrillogenesis, and pulmonary compliance. PMID- 23742150 TI - What makes people read an online review? The relative effects of posting time and helpfulness on review readership. AB - This study explores the factors that make online customers select which reviews to read among the various ones on the Web. While most of literature on online consumer reviews has conveniently assumed that more helpful reviews would be read by more customers, no empirical study has tested whether the helpfulness assessment actually increases readership. Hence, this study explores various factors affecting consumer review readership and proposes that although helpfulness assessment promotes the readership of a review, the most dominant factor contributing to readership is the time of posting. A review posted late loses a significant chance of being read by consumers even if it is assessed as helpful by other readers. The hypotheses are tested using the data collected from Amazon.com , and the result of the study advises practitioners to display reviews in a manner that lessens the impact of posting time while enhancing the helpfulness voting systems. PMID- 23742151 TI - Using low-loss phase-change materials for mid-infrared antenna resonance tuning. AB - We show tuning of the resonance frequency of aluminum nanoantennas via variation of the refractive index n of a layer of phase-change material. Three configurations have been considered, namely, with the antennas on top of, inside, and below the layer. Phase-change materials offer a huge index change upon the structural transition from the amorphous to the crystalline state, both stable at room temperature. Since the imaginary part of their permittivity is negligibly small in the mid-infrared spectral range, resonance damping is avoided. We present resonance shifting to lower as well as to higher wavenumbers with a maximum shift of 19.3% and a tuning figure of merit, defined as the resonance shift divided by the full-width at half-maximum (FWHM) of the resonance peak, of 1.03. PMID- 23742152 TI - Ultrathin and ultralong single-crystal platinum nanowire assemblies with highly stable electrocatalytic activity. AB - Ultrathin one-dimensional (1D) nanostructures such as nanowires and nanorods have drawn considerable attention due to their promising applications in various fields. Despite the numerous reports on 1D nanostructures of noble metals, one pot solution synthesis of Pt 1D nanostructures still remains a great challenge, probably because of the intrinsic isotropic crystal growth behavior of Pt. Herein, we demonstrate the facile solvothermal synthesis of nanowire assemblies composed of ultrathin (ca. 3 nm) and ultralong (up to 10 MUm) Pt nanowires without involving any template. The oriented attachment mechanism is found to be partially responsible for the formation of such ultrathin Pt nanowires. The amine molecules generated during the reaction might assist the formation of nanowire assemblies. Importantly, the present system can be extended to synthesize Pt based alloy nanowire assemblies such as Pt-Au and Pt-Pd. These Pt nanowires can be easily cast into a free-standing membrane, which exhibits excellent electrocatalytic activity and very high stability for formic acid and methanol oxidation and the oxygen reduction reaction. PMID- 23742153 TI - Solitary myofibroma of the sigmoid colon: case report and review of the literature. AB - A 58-year-old woman presented with a solitary myofibroma that arose in the sigmoid colon. Computed tomography revealed a highly enhanced intramural mass (1.3-cm maximum diameter) in the proximal sigmoid colon. Histologically, the tumor exhibited a biphasic growth pattern, which comprised haphazardly arranged, interwoven fascicles of plump, myoid-appearing spindle cells with elongated nuclei and abundant eosinophilic cytoplasm, and more cellular areas of primitive appearing polygonal cells that were arranged in a hemangiopericytomatous pattern. The tumor cells were positive for smooth muscle actin (SMA), and negative for desmin, h-caldesmon, CD34, cytokeratin, S100 protein, and CD117. The Ki-67 labeling index was not high (up to 7%). Based on these histologic and immunohistochemical features, our patient was diagnosed with a myofibroma of the sigmoid colon. The presence of solitary myofibroma in the intestine of an adult requires attention to avoid misdiagnosis as a more aggressive mesenchymal tumor. VIRTUAL SLIDES: The virtual silde(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2096403796957687. PMID- 23742154 TI - Ambient synthesis of high-quality ruthenium nanowires and the morphology dependent electrocatalytic performance of platinum-decorated ruthenium nanowires and nanoparticles in the methanol oxidation reaction. AB - We report for the first time (a) the synthesis of elemental ruthenium nanowires (Ru NWs), (b) a method for modifying their surfaces with platinum (Pt), and (c) the morphology-dependent methanol oxidation reaction (MOR) performance of high quality Pt-modified Ru NW electrocatalysts. The synthesis of our elemental Ru NWs has been accomplished utilizing a template-based method under ambient conditions. As-prepared Ru NWs are crystalline and elementally pure, maintain electrochemical properties analogous to elemental Ru, and can be generated with average diameters ranging from 44 to 280 nm. We rationally examine the morphology-dependent performance of the Ru NWs by comparison with commercial Ru nanoparticle (NP)/carbon (C) systems after decorating the surfaces of these structures with Pt. We have demonstrated that the deposition of Pt onto the Ru NWs (Pt~Ru NWs) results in a unique hierarchical structure, wherein the deposited Pt exists as discrete clusters on the surface. By contrast, we find that the Pt-decorated commercial Ru NP/C (Pt~Ru NP/C) results in the formation of an alloy-type NP. The Pt~Ru NPs (0.61 A/mg of Pt) possess nearly 2-fold higher Pt mass activity than analogous Pt~Ru NW electrocatalysts (0.36 A/mg of Pt). On the basis of a long term durability test, it is apparent that both catalysts undergo significant declines in performance, potentially resulting from aggregation and ripening in the case of Pt~Ru NP/C and the effects of catalyst poisoning in the Pt~Ru NWs. At the conclusion of the test, both catalysts maintain comparable performance, despite a slightly enhanced performance in Pt~Ru NP/C. In addition, the measured mass-normalized MOR activity of the Pt~Ru NWs (0.36 A/mg of Pt) was significantly enhanced as compared with supported elemental Pt (Pt NP/C, 0.09 A/mg of Pt) and alloy-type PtRu (PtRu NP/C, 0.24 A/mg of Pt) NPs, both serving as commercial standards. PMID- 23742155 TI - Pulmonary coccidioidomycosis after a renal transplant in a nonendemic region. AB - Coccidioidomycosis is a fungal infection caused by the Coccidioides species, endemic to the southwestern United States. In healthy people, manifestations range mainly from asymptomatic to mild influenza-like signs, whereas in immunosuppressed patients (eg, transplant recipients) this infection is often a severe disseminated disease. We report a case of primary pulmonary coccidioidomycosis in a 61-year-old man with a renal transplant 7 months earlier. The patient had nonspecific symptoms of pulmonary infection, including weakness, anorexia, and weight loss. Both spherules and endospores of Coccidioides immitis were seen histologically after a transbronchial biopsy of a cavitary lesion. The patient was treated with amphotericin B. At the time of this writing (8 months), he remains disease free. PMID- 23742157 TI - Dietary supplementation and engaging in physical activity as predictors of coronary artery disease among middle-aged women. AB - AIM AND OBJECTIVES: To explore risk factors for coronary artery disease (CAD) among middle-aged women in Taiwan. BACKGROUND: Coronary artery disease is a leading cause of death among females. Risk factors for CAD vary due to differences in ethnicity, gender and age. However, few studies have documented risk factors among middle-aged women. DESIGN: We employed a cross-sectional, comparative study design. METHODS: Sixty-five middle-aged women who were suspected of having CAD and who received cardiac catheterisation were purposively sampled and divided into a CAD group (with at least one coronary artery with > 50% stenosis) and a control group, according to the results of catheterisation. Individual questionnaires regarding their medical history, blood test results, sociodemographic characteristics, metabolism, biomarkers and lifestyle risk factors were administered and quantified. RESULTS: The mean age of the 65 women (31 CAD and 34 controls) was 56.2 years. Within the CAD group, there was a greater incidence of women with a history of diabetes mellitus (DM), increased fasting blood glucose and increased diastolic blood pressure. Comparatively fewer women within the CAD category used dietary supplements or had a lower level of physical activity. After adjusting for other confounders, it was discovered that women who used dietary supplements (OR = 0.28; p = 0.04) and engaged in physical activities (OR = 0.16; p = 0.02) were less likely to develop CAD. CONCLUSIONS: Use of dietary supplements and engaging in physical activities can significantly predict the incidence of CAD among middle-aged women in Taiwan. RELEVANCE TO CLINICAL PRACTICE: Middle-aged women should be encouraged to take appropriate dietary supplements and engage in physical activity in order to prevent CAD. PMID- 23742156 TI - Delivery of small interfering RNAs in human cervical cancer cells by polyethylenimine-functionalized carbon nanotubes. AB - Carbon nanotubes are capable of penetrating the cell membrane and are widely considered as potential carriers for gene or drug delivery. Because the C-C and C=C bonds in carbon nanotubes are nonpolar, functionalization is required for carbon nanotubes to interact with genes or drugs as well as to improve their biocompatibility. In this study, polyethylenimine (PEI)-functionalized single wall (PEI-NH-SWNTs) and multiwall carbon nanotubes (PEI-NH-MWNTs) were produced by direct amination method. PEI functionalization increased the positive charge on the surface of SWNTs and MWNTs, allowing carbon nanotubes to interact electrostatically with the negatively charged small interfering RNAs (siRNAs) and to serve as nonviral gene delivery reagents. PEI-NH-MWNTs and PEI-NH-SWNTs had a better solubility in water than pristine carbon nanotubes, and further removal of large aggregates by centrifugation produced a stable suspension of reduced particle size and improved homogeneity and dispersity. The amount of grafted PEI estimated by thermogravimetric analysis was 5.08% (w/w) and 5.28% (w/w) for PEI NH-SWNTs and PEI-NH-MWNTs, respectively. For the assessment of cytotoxicity, various concentrations of PEI-NH-SWNTs and PEI-NH-MWNTs were incubated with human cervical cancer cells, HeLa-S3, for 48 h. PEI-NH-SWNTs and PEI-NH-MWNTs induced cell deaths in a dose-dependent manner but were less cytotoxic compared to pure PEI. As determined by electrophoretic mobility shift assay, siRNAs directed against glyceraldehyde-3-phosphate dehydrogenase (siGAPDH) were completely associated with PEI-NH-SWNTs or PEI-NH-MWNTs at a PEI-NH-SWNT/siGAPDH or PEI-NH MWNT/siGAPDH mass ratio of 80:1 or 160:1, respectively. Furthermore, PEI-NH-SWNTs and PEI-NH-MWNTs successfully delivered siGAPDH into HeLa-S3 cells at PEI-NH SWNT/siGAPDH and PEI-NH-MWNT/siGAPDH mass ratios of 1:1 to 20:1, resulting in suppression of the mRNA level of GAPDH to an extent similar to that of DharmaFECT, a common transfection reagent for siRNAs. Our results indicate that the PEI-NH-SWNTs and PEI-NH-MWNTs produced in this study are capable of delivering siRNAs into HeLa-S3 cells to suppress gene expression and may therefore be considered as novel nonviral gene delivery reagents. PMID- 23742159 TI - Clustering cliques for graph-based summarization of the biomedical research literature. AB - BACKGROUND: Graph-based notions are increasingly used in biomedical data mining and knowledge discovery tasks. In this paper, we present a clique-clustering method to automatically summarize graphs of semantic predications produced from PubMed citations (titles and abstracts). RESULTS: SemRep is used to extract semantic predications from the citations returned by a PubMed search. Cliques were identified from frequently occurring predications with highly connected arguments filtered by degree centrality. Themes contained in the summary were identified with a hierarchical clustering algorithm based on common arguments shared among cliques. The validity of the clusters in the summaries produced was compared to the Silhouette-generated baseline for cohesion, separation and overall validity. The theme labels were also compared to a reference standard produced with major MeSH headings. CONCLUSIONS: For 11 topics in the testing data set, the overall validity of clusters from the system summary was 10% better than the baseline (43% versus 33%). While compared to the reference standard from MeSH headings, the results for recall, precision and F-score were 0.64, 0.65, and 0.65 respectively. PMID- 23742160 TI - Are older adults with chronic musculoskeletal pain less active than older adults without pain? A systematic review and meta-analysis. AB - OBJECTIVE: To compare the overall levels of physical activity of older adults with chronic musculoskeletal pain and asymptomatic controls. REVIEW METHODS: A systematic review of the literature was conducted using a Cochrane methodology and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Major electronic databases were searched from inception until December 2012, including the Cochrane Library, CINAHL, EBSCO, EMBASE, Medline, PubMed, PsycINFO, and the international prospective register of systematic reviews. In addition, citation chasing was undertaken, and key authors were contacted. Eligibility criteria were established around participants used and outcome measures focusing on daily physical activity. A meta-analysis was conducted on appropriate studies. RESULTS: Eight studies met the eligibility criteria, four of these reported a statistically lower level of physical activity in the older adult sampl e with chronic pain compared with the asymptomatic group. It was possible to perform a non-heterogeneous meta-analysis on five studies. This established that 1,159 older adults with chronic pain had a significantly lower level of physical activity (-0.20, confidence interval 95% = 0.34 to -0.06, p = 0.004) compared with 576 without chronic pain. CONCLUSION: Older adults with chronic pain appear to be less active than asymptomatic controls. Although this difference was small, it is likely to be clinically meaningful. It is imperative that clinicians encourage older people with chronic pain to remain active as physical activity is a central non-pharmacological strategy in the management of chronic pain and is integral for healthy aging. Future research should prioritize the use of objective measurement of physical activity. PMID- 23742161 TI - Adherence and biofilm formation of Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium abscessus to household plumbing materials. AB - AIMS: Measure adherence and biofilm formation by cells of Mycobacterium avium, Mycobacterium intracellulare and Mycobacterium abscessus on common household plumbing materials namely stainless steel, glass, zinc-galvanized steel, copper and polyvinyl chloride (PVC). METHODS AND RESULTS: Coupons in a CDC biofilm reactor were exposed to cell suspensions containing 10(5) NTM colony forming units (CFU) per ml and adherence measured for 6 h. Biofilm formation (increased numbers of adherent CFU) was measured weekly to 21 days in the absence of substantial numbers of suspended mycobacterial cells. Adherence was rapid and substantial with 2000-15 000 CFU cm(-2) adhering within 1-6 h at room temperature. Biofilm numbers reached as high as 10(7) CFU cm(-2) . Biofilm-grown cells of Myco. avium were more adherent compared with suspension-grown cells. CONCLUSIONS: Mycobacterium avium, Myco. intracellulare and Myco. abscessus readily adhered and formed biofilms on all types of plumbing materials. Factors influencing adherence and biofilm formation were species, plumbing material and prior growth. PMID- 23742162 TI - A systematic review on the critical size defect model. AB - OBJECTIVES: To systematically review the literature data regarding the critical size defect (CSD) in adult rat calvaria and to determine which defect dimensions could be considered as being critical size. MATERIAL AND METHODS: A literature search was conducted at Ovid Medline and Embase up to July 2012. Studies presenting with at least one of the primary outcomes of interest (number of defects with complete closure and the percentage of new bone formation (%NBF) in rat calvaria) were included. Screening, data extraction and quality assessment were conducted independently and in duplicate. RESULTS: From 1461 citations, 257 full-text papers were screened and 61 papers were included in the analysis. Fourteen of 937 evaluated defects presented complete closure. Only 7 and 6 untreated sites in 5.0- and 6.0-mm-diameter defects, respectively, showed complete closure. A great variability among the preclinical models was seen, and the meta-analysis result showed a high heterogeneity regarding the mean %NBF. The mean %NBF according to the defect dimension was as follows: 18.29% and 21.44% for 5.0 mm central single defects at 1 and 3 months, respectively; 17.55%, 20.24% and 22.65% for 5.0 mm bilateral defects; 9.81%, 12.56% and 7.96% for 8.0 mm single defect; 11.18%, 9.48% and 26.24% for 9.0 mm single defects at 1, 2 and 3 months, respectively. CONCLUSION: Calvarial defects with a diameter of 5.0 mm could be considered as a CSD. However, there is a necessity for further standardization of the rat calvaria model to enable more accurate comparison among future studies. PMID- 23742164 TI - Impact of atrioventricular compliance on clinical outcome of patients undergoing successful percutaneous balloon mitral valvuloplasty. AB - OBJECTIVE: We aimed to assess the impact of atrioventricular compliance (Cn) on the clinical outcome, after successful percutaneous balloon mitral valvuloplasty (PBMV). METHODS AND RESULTS: Using Doppler echocardiography Cn was estimated from the equation that has been previously validated. Mitral valve area (MVA), tricuspid annular plane systolic excursion (TAPSE), pulmonary artery pressure (PAP), and degree of tricuspid regurgitation (TR) severity were evaluated before, immediately, and every 6 months with a median duration of 32 months after successful PBMV in 150 consecutive patients. An immediate drop in PAP and significant improvement of right ventricle (RV) function was observed after PBMV. Cn was negatively correlated pre and post-PBMV, with the degree of pulmonary artery systolic pressure (PAPs), TAPSE (P < 0.0001). Patients with Cn <= 3.75 mL/mmHg had higher incidence of adverse outcome (developing atrial fibrillation [AF], worsening RV function, progressive left atrial dilation, and redo intervention). Multivariate regression analysis showed that the Cn was the strongest independent predictor of PAPs and RV function before and after successful PBMV (P < 0.0001). Cn <= 3.75 mL/mmHg was the cutoff value for prediction of clinical events at follow-up. CONCLUSIONS: Atrioventricular compliance was significantly lower in patients with mitral stenosis (MS) with unfavorable outcome after successful PBMV. The RV function and pulmonary hypertension were significantly correlated with the degree of Cn. This suggests a significant role of Cn in patients with MS, providing a good insight for intervention and utilizing Cn as a noninvasive hemodynamic index for risk stratification and proper timing for intervention in patients with MS. PMID- 23742165 TI - Theoretical study on molecules of interstellar interest. I. Radical cation of noncompact polycyclic aromatic hydrocarbons. AB - Polycyclic aromatic hydrocarbons (PAHs), in particular, their radical cation (PAH(+)), have long been postulated to be the important molecular species in connection with the spectroscopic observations in the interstellar medium. Motivated by numerous important observations by stellar as well as laboratory spectroscopists, we undertook detailed quantum mechanical studies of the structure and dynamics of electronically excited PAH(+) in an attempt to establish possible synergism with the recorded data. In this paper, we focus on the quantum chemistry and dynamics of the doublet ground (X) and low-lying excited (A, B, and C) electronic states of the radical cation of tetracene, pentacene, and hexacene molecule. This study is aimed to unravel photostability, spectroscopy, and time-dependent dynamics of their excited electronic states. In order to proceed with the theoretical investigations, we construct suitable multistate and multimode Hamiltonians for these systems with the aid of extensive ab initio calculations of their electronic energy surfaces. The diabatic coupling surfaces are derived from the calculated adiabatic electronic energies. First principles nuclear dynamics calculations are then carried out employing the constructed Hamiltonians and with the aid of time-independent and time-dependent quantum mechanical methods. The theoretical results obtained in this study are found to be in good accord with those recorded in experiments. The lifetime of excited electronic states is estimated from their time-dependent dynamics and compared with the available data. PMID- 23742163 TI - Enhanced electron-transfer reactivity of nonheme manganese(IV)-oxo complexes by binding scandium ions. AB - One and two scandium ions (Sc(3+)) are bound strongly to nonheme manganese(IV) oxo complexes, [(N4Py)Mn(IV)(O)](2+) (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2 pyridyl)methylamine) and [(Bn-TPEN)Mn(IV)(O)](2+) (Bn-TPEN = N-benzyl-N,N',N' tris(2-pyridylmethyl)-1,2-diaminoethane), to form Mn(IV)(O)-(Sc(3+))1 and Mn(IV)(O)-(Sc(3+))2 complexes, respectively. The binding of Sc(3+) ions to the Mn(IV)(O) complexes was examined by spectroscopic methods as well as by DFT calculations. The one-electron reduction potentials of the Mn(IV)(O) complexes were markedly shifted to a positive direction by binding of Sc(3+) ions. Accordingly, rates of the electron transfer reactions of the Mn(IV)(O) complexes were enhanced as much as 10(7)-fold by binding of two Sc(3+) ions. The driving force dependence of electron transfer from various electron donors to the Mn(IV)(O) and Mn(IV)(O)-(Sc(3+))2 complexes was examined and analyzed in light of the Marcus theory of electron transfer to determine the reorganization energies of electron transfer. The smaller reorganization energies and much more positive reduction potentials of the Mn(IV)(O)-(Sc(3+))2 complexes resulted in remarkable enhancement of the electron-transfer reactivity of the Mn(IV)(O) complexes. Such a dramatic enhancement of the electron-transfer reactivity of the Mn(IV)(O) complexes by binding of Sc(3+) ions resulted in the change of mechanism in the sulfoxidation of thioanisoles by Mn(IV)(O) complexes from a direct oxygen atom transfer pathway without metal ion binding to an electron-transfer pathway with binding of Sc(3+) ions. PMID- 23742166 TI - Placing individual molecules in the center of nanoapertures. AB - While nanophotonic devices are unfolding their potential for single-molecule fluorescence studies, metallic quenching and steric hindrance, occurring within these structures, raise the desire for site-specific immobilization of the molecule of interest. Here, we refine the single-molecule cut-and-paste technique by optical superresolution routines to immobilize single fluorescent molecules in the center of nanoapertures. By comparing their fluorescence lifetime and intensity to stochastically immobilized fluorophores, we characterize the electrodynamic environment in these nanoapertures and proof the nanometer precision of our loading method. PMID- 23742167 TI - Thermodynamics of HIV-1 reverse transcriptase in action elucidates the mechanism of action of non-nucleoside inhibitors. AB - HIV-1 reverse transcriptase (RT) is a heterodimeric enzyme that converts the genomic viral RNA into proviral DNA. Despite intensive biochemical and structural studies, direct thermodynamic data regarding RT interactions with its substrates are still lacking. Here we addressed the mechanism of action of RT and of non nucleoside RT inhibitors (NNRTIs) by isothermal titration calorimetry (ITC). Using a new incremental-ITC approach, a step-by-step thermodynamic dissection of the RT polymerization activity showed that most of the driving force for DNA synthesis is provided by initial dNTP binding. Surprisingly, thermodynamic and kinetic data led to a reinterpretation of the mechanism of inhibition of NNRTIs. Binding of NNRTIs to preformed RT/DNA complexes is hindered by a kinetic barrier and NNRTIs mostly interact with free RT. Once formed, RT/NNRTI complexes bind DNA either in a seemingly polymerase-competent orientation or form high-affinity dead end complexes, both RT/NNRTI/DNA complexes being unable to bind the incoming nucleotide substrate. PMID- 23742168 TI - Walking with insects: molecular mechanisms behind parasitic manipulation of host behaviour. AB - Parasitic infections are often followed by changes in host behaviour. Numerous and exquisite examples of such behavioural alterations are known, covering a broad spectrum of parasites and hosts. Most descriptions of such parasite-induced changes in host behaviour are observational reports, while experimentally confirmed examples of parasite genes inducing these changes are limited. In this study, we review changes in invertebrate host behaviour observed upon infection by parasites and discuss such changes in an evolutionary context. We then explore possible mechanisms involved in parasite-induced changes in host behaviour. Genes and pathways known to play a role in invertebrate behaviour are reviewed, and we hypothesize how parasites (may) affect these pathways. This review provides the state of the art in this exciting, interdisciplinary field by exploring possible pathways triggered in hosts, suggesting methodologies to unravel the molecular mechanisms that lead to changes in host behaviour. PMID- 23742169 TI - Kinetics of silica nanoparticles in the human placenta. AB - The potential medical applications of nanoparticles (NPs) warrant their investigation in terms of biodistribution and safety during pregnancy. The transport of silica NPs across the placenta was investigated using two models of maternal-foetal transfer in human placenta, namely, the BeWo b30 choriocarcinoma cell line and the ex vivo perfused human placenta. Nanotoxicity in BeWo cells was examined by the MTT assay which demonstrated decreased cell viability at concentrations >100 ug/mL. In the placental perfusion experiments, antipyrine crossed the placenta rapidly, with a foetal:maternal ratio of 0.97 +/- 0.10 after 2 h. In contrast, the percentage of silica NPs reaching the foetal perfusate after 6 h was limited to 4.2 +/- 4.9% and 4.6 +/- 2.4% for 25 and 50 nm NPs, respectively. The transport of silica NPs across the BeWo cells was also limited, with an apparent permeability of only 1.54 * 10(-6) +/- 1.56 * 10(-6) cm/s. Using confocal microscopy, there was visual confirmation of particle accumulation in both BeWo cells and in perfused placental tissue. Despite the low transfer of silica NPs to the foetal compartment, questions regarding biocompatibility could limit the application of unmodified silica NPs in biomedical imaging or therapy. PMID- 23742170 TI - Programmable nanoengineering templates for fabrication of three-dimensional nanophotonic structures. AB - Porous anodic alumina membranes (AAMs) have attracted great amount of attention due to their potential application as templates for nanoengineering. Template guided fabrication and assembly of nanomaterials based on AAMs are cost-effective and scalable methods to program and engineer the shape and morphology of nanostructures and nanomaterials. In this work, perfectly ordered AAMs with the record large pitch up to 3 MUm have been fabricated by properly controlling the anodization conditions and utilization of nanoimprint technique. Due to the capability of programmable structural design and fabrication, a variety of nanostructures, including nanopillar arrays, nanotower arrays, and nanocone arrays, have been successfully fabricated using nanoengineered AAM templates. Particularly, amorphous Si nanocones have been fabricated as three-dimensional nanophotonic structures with the characterization of their intriguing optical anti-reflection property. These results directly indicate the potential application of the reported approach for photonics and optoelectronics. PMID- 23742171 TI - A corn oil-based diet protects against combined ethanol and iron-induced liver injury in a mouse model of hemochromatosis. AB - BACKGROUND: Combined iron overload and alcohol may promote synergistic chronic liver injury and toxicity. The role of specific dietary fats in influencing the development of co-toxic alcoholic liver disease needs further evaluation and is investigated in this study. METHODS: Wild-type (WT) and the iron-loaded Hfe-null (Hfe(-/-) ) mice were fed chow (CC), a AIN-93G standard control (SC), or a corn oil-modified, AIN-93G-based (CO) diet with or without the addition of 20% ethanol (EtOH) in the drinking water for 8 weeks and assessed for liver injury. RESULTS: WT mice on CC, SC, and CO diets had no liver injury, although mild steatosis developed in the SC and CO groups. The addition of EtOH resulted in mild steatohepatitis in WT mice fed SC but not those on a CO diet. EtOH administration in Hfe(-/-) animals on the CC and SC diets caused marked oxidative stress, inflammatory activity, and subsinusoidal and portal-portal tract linkage fibrosis with significant up-regulation of genes involved in cellular stress signaling and fibrogenic pathways. These effects were abrogated in the CO-fed mice, despite elevated serum EtOH levels and hepatic iron concentrations, reduced hepatic glutathione and mitochondrial superoxide dismutase activities. Feeding with the CO diet led to increased hepatic glutathione peroxidase and catalase activities and attenuated alcohol-induced hepatic steatosis in the Hfe(-/-) animals. Iron and EtOH feeding markedly reduced p-STAT3 and p-AMPK protein levels, but this effect was significantly attenuated when a CO diet was consumed. CONCLUSIONS: A CO-based diet is protective against combined EtOH- and iron-induced liver toxicity, likely via attenuation of hepatic steatosis and oxidative stress and may have a role in the prevention of fibrosis development in chronic liver disease. PMID- 23742172 TI - Isolated hypoplastic circumflex coronary artery: a rare cause of haemorrhagic myocardial infarction in a young athlete. AB - Hypoplastic coronary artery disease is a rare condition that may lead to myocardial infarction and sudden death. Here we describe for the first time an isolated hypoplasia of the left circumflex artery (LCX). An otherwise healthy and athletically active 16-year-old boy was admitted to the intensive care unit (ICU) after out-of-hospital cardiac arrest. He died 12 hours after the initial event. Autopsy revealed an isolated hypoplastic LCX and acute haemorrhagic infarction in the posterolateral myocardium. The existence of isolated hypoplasia of the LCX challenges our understanding of coronary artery development. Virtual slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1558483061962648. PMID- 23742174 TI - The acute, developmental, genetic and inhalation toxicology of 2,3,3,3 tetrafluoropropene (HFO-1234yf). AB - 2,3,3,3-Tetrafluoropropene (HFO-1234yf) is being developed as a refrigerant because it has a very low global warming potential (less than 10), as contrasted to the hydrofluorocarbons, which is intended to replace with values of over 500. Several toxicology studies were conducted to develop a toxicology profile for this material. There was no lethality in mice and rats receiving single 4-hour exposures up to 101,850 or 405,800 ppm, respectively. Additionally, there was no mortality or clinical signs of toxicity when rabbits were exposed to 100,000 ppm for 1 hour. Exposures up to 120,000 ppm did not induce cardiac sensitization to adrenalin in dogs. Rats were exposed to HFO-1234yf at levels of 5000, 20,000 and 50,000 ppm 6 hours/day 5 days/week for 2 weeks and at levels of 5000, 15,000 and 50,000 ppm for 4 weeks and for 90 days. No treatment-related adverse effects were noted in these studies. HFO-1234yf was not genotoxic in a mouse and a rat micronucleus assay, and unscheduled DNA synthesis assay and was not clastogenic in human lymphocytes. HFO-1234yf was mutagenic to Salmonella typhimurium TA 100 and Escherichia coli (WP2 uvrA) at concentrations of 20% and higher in the presence of metabolic activation only. There were no biologically significant effects in a rat developmental toxicity study with exposures up to 50,000 ppm. PMID- 23742173 TI - Relaxin improves multiple markers of wound healing and ameliorates the disturbed healing pattern of genetically diabetic mice. AB - Diabetic mice are characterized by a disrupted expression pattern of VEGF (vascular endothelial growth factor), and impaired vasculogenesis during healing. Experimental evidence suggests that RLX (relaxin) can improve several parameters associated with wound healing. Therefore we investigated the effects of porcine derived RLX in diabetes-related wound-healing defects in genetically diabetic mice. An incisional wound model was produced on the back of female diabetic C57BL/KsJ-m+/+Lept(db) (db+/db+) mice and their normal littermates (db(+/+)m). Animals were treated daily with porcine RLX (25 MUg/mouse per day, subcutaneously) or its vehicle. Mice were killed on 3, 6 and 12 days after skin injury for measurements of VEGF mRNA and protein synthesis, SDF-1alpha (stromal cell-derived factor-1alpha) mRNA and eNOS (endothelial NO synthase) expression. Furthermore, we evaluated wound-breaking strength, histological changes, angiogenesis and vasculogenesis at day 12. Diabetic animals showed a reduced expression of VEGF, eNOS and SDF-1alpha compared with non-diabetic animals. At day 6, RLX administration resulted in an increase in VEGF mRNA expression and protein wound content, in eNOS expression and in SDF-1alpha mRNA. Furthermore, the histological evaluation indicated that RLX improved the impaired wound healing, enhanced the staining of MMP-11 (matrix metalloproteinase-11) and increased wound-breaking strength at day 12 in diabetic mice. Immunohistochemistry showed that RLX in diabetic animals augmented new vessel formation by stimulating both angiogenesis and vasculogenesis. RLX significantly reduced the time to complete skin normalization and this effect was abrogated by a concomitant treatment with antibodies against VEGF and CXCR4 (CXC chemokine receptor 4), the SDF-1alpha receptor. These data strongly suggest that RLX may have a potential application in diabetes-related wound disorders. PMID- 23742175 TI - Effects of work surface height on muscle activity and posture of the upper extremity during simulated pipetting. AB - In order to examine the effects of work surface height (WSH) on muscle activity, posture and discomfort during simulated pipetting, an experimental study was conducted using electromyography, electrogoniometry, video techniques and also qualitative data. The experimental design consisted of one independent variable (WSH with six heights) and 13 dependent variables. The levels of muscle strain and discomfort were significantly lower at the shoulder when the WSHs were low but thumb muscle activities and neck flexion levels were markedly higher at these WSHs compared to higher WSHs. To reduce shoulder strain, without raising thumb and neck strain beyond acceptable limits, the findings suggest that the height of a laboratory workbench should be at the level of the pipette tip when held in a standing position with the hand at elbow height. It was also found that pipetting should not be done in a seated posture. PRACTITIONER SUMMARY: An experimental study was conducted to examine the effects of work surface height on upper extremity muscle activity, posture and discomfort during simulated pipetting. The findings suggest that the laboratory workbench height should be at the pipette tip level when held in a standing position with the hand at elbow height. PMID- 23742176 TI - Evaluation of correlation between aortic elastic parameters and atrial electromechanical abnormalities in hypertensive patients. AB - OBJECTIVES: Arterial hypertension leads to instability and heterogeneity in atrial conduction by these hemodynamic and morphological changes in heart and aorta. These changes can be evaluated by transthoracic echocardiography. The aim of this study was to evaluate the correlation of aortic elastic parameters and atrial electromechanical delay (AEMD) parameters in patients with hypertension. METHODS: Eighty-one hypertensive patients and 55 control subjects were included in the study. All subjects underwent transthoracic echocardiography for detecting aortic elastic parameters and AEMD parameters. RESULTS: There was no difference between HT and control groups regarding age and gender. Aortic strain (8.1 +/- 4.3% vs. 10.3 +/- 5.1%, P = 0.008) and aortic distensibility (0.35 +/- 0.18 cm(2) /dyn vs. 0.45 +/- 0.23 cm(2) /dyn, P = 0.003) were decreased in hypertensive patients than in controls. Intra-left AEMD (25.5 +/- 7.3 vs. 21.8 +/- 9.2 P < 0.009) was significantly higher in hypertensive patients compared to control subjects. No statistically significant difference was found in intra-right AEMD and inter-AEMD between the groups. There was a positive significant moderate correlation between aortic strain and intra-left AEMD (r = 0.501, P < 0.001). CONCLUSIONS: This study demonstrated that intra-left AEMD was increased in hypertensive patients and aortic elastic parameters was correlated with intra left AEMD. These findings may be related to similar structural and functional changes in heart and aorta in hypertension. PMID- 23742178 TI - Photoinduced electron transfer in perylene-TiO2 nanoassemblies. AB - The photosensitization effect of three perylene dye derivatives on titanium dioxide nanoparticles (TiO2 NPs) has been investigated. The dyes used, 1,7 dibromoperylene-3,4,9,10-tetracarboxy dianhydride (1), 1,7-dipyrrolidinylperylene 3,4,9,10-tetracarboxy dianhydride (2) and 1,7-bis(4-tert-butylphenyloxy)perylene 3,4,9,10-tetracarboxy dianhydride (3) have in common bisanhydride groups that convert into TiO2 binding groups upon hydrolysis. The different substituents on the bay position of the dyes enable tuning of their redox properties to yield significantly different driving forces for photoinduced electron transfer (PeT). Recently developed TiO2 NPs having a small average size and a narrow distribution (4 +/- 1 nm) are used in this work to prepare the dye-TiO2 systems under study. Whereas successful sensitization was obtained with 1 and 2 as evidenced by steady state spectral shifts and transient absorption results, no evidence for the attachment of 3 to TiO2 was observed. The comparison of the rates of PeT (kPeT ) for 1- and 2-TiO2 systems studied in this work with those obtained for previously reported analogous systems, having TiO2 NPs covered by a surfactant layer (Hernandez et al. [2012] J. Phys. Chem. B., 117, 4568-4581), indicates that kPeT for the former systems is slower than that for the later. These results are interpreted in terms of the different energy values of the conduction band edge in each system. PMID- 23742179 TI - Lactobacillus brevis G-101 ameliorates colitis in mice by inhibiting NF-kappaB, MAPK and AKT pathways and by polarizing M1 macrophages to M2-like macrophages. AB - AIM: We isolated Lactobacillus brevis G-101 from kimchi lactic acid bacteria (LAB) strains, which induced IL-10 expression in lipopolysaccharide (LPS) stimulated peritoneal macrophages. To evaluate the inflammatory effect of G-101, we examined its inhibitory effect in 2,4,6-trinitrobenzene sulfonic acid (TNBS) induced colitic mice. MATERIALS AND RESULTS: The colitic mice were prepared by intrarectal injection of TNBS. We measured intestinal mucosal cytokines by enzyme linked immunosorbent assay; activation of transcription factors, by immunoblotting; and macrophage polarization markers, by real-time polymerase chain reaction. Of 200 LAB strains tested, Lact. brevis G-101 showed most potent activity for induction of IL-10 expression in LPS-stimulated peritoneal macrophages. However, it significantly inhibited the expression of TNF-alpha, IL 1beta and IL-6 and the phosphorylation of IRAK1 and AKT, and activated NF-kappaB and MAPKs. Treatment with TNBS caused colon shortening; increased myeloperoxidase activity; and increased IL-1beta, IL-6 and TNF-alpha expression in mice. Oral administration of Lact. brevis G-101 significantly inhibited these activities. Lactobacillus brevis G-101 inhibited TNBS-induced IRAK-1 phosphorylation and NF kappaB activation, as well as the expression of COX-2 and iNOS. Lactobacillus brevis G-101 inhibited the expression of M1 macrophage markers, but increased the expression of M2 macrophages in the colons of TNBS-treated mice. CONCLUSIONS: Lactobacillus brevis G-101 may improve colitis by inhibiting the IRAK1/NF-kappaB, MAPK and AKT pathways and by polarizing M1 macrophages to M2-like macrophages. SIGNIFICANCE AND IMPACT OF THE STUDY: These results suggest that IL-10 expression inducing LAB can ameliorate colitis by inhibiting NF-kappaB activation and macrophage polarization. PMID- 23742180 TI - Tissue inhibitor of metalloproteinases-3 moderates the proinflammatory status of macrophages. AB - Tissue inhibitor of metalloproteinases-3 (TIMP-3) has emerged as a key mediator of inflammation. Recently, we reported that the resolution of inflammation is impaired in Timp3(-/-) mice after bleomycin-induced lung injury. Here, we demonstrate that after LPS instillation (another model of acute lung injury), Timp3(-/-) mice demonstrate enhanced and persistent neutrophilia, increased numbers of infiltrated macrophages, and delayed weight gain, compared with wild type (WT) mice. Because macrophages possess broad immune functions and can differentiate into cells that either stimulate inflammation (M1 macrophages) or are immunosuppressive (M2 macrophages), we examined whether TIMP-3 influences macrophage polarization. Comparisons of the global gene expression of unstimulated or LPS-stimulated bone marrow-derived macrophages (BMDMs) from WT and Timp3(-/-) mice revealed that Timp3(-/-) BMDMs exhibited an increased expression of genes associated with proinflammatory (M1) macrophages, including Il6, Il12, Nos2, and Ccl2. Microarray analyses also revealed a baseline difference in gene expression between WT and Timp3(-/-) BMDMs, suggesting altered macrophage differentiation. Furthermore, the treatment of Timp3(-/-) BMDMs with recombinant TIMP-3 rescued this altered gene expression. We also examined macrophage function, and found that Timp3(-/-) M1 cells exhibit significantly more neutrophil chemotactic activity and significantly less soluble Fas ligand induced caspase-3/7 activity, a marker of apoptosis, compared with WT M1 cells. Macrophage differentiation into immunosuppressive M2 cells is mediated by exposure to IL-4/IL-13, and we found that Timp3(-/-) M2 macrophages demonstrated a lower expression of genes associated with an anti-inflammatory phenotype, compared with WT M2 cells. Collectively, these findings indicate that TIMP-3 functions to moderate the differentiation of macrophages into proinflammatory (M1) cells. PMID- 23742177 TI - The primary vascular dysregulation syndrome: implications for eye diseases. AB - Vascular dysregulation refers to the regulation of blood flow that is not adapted to the needs of the respective tissue. We distinguish primary vascular dysregulation (PVD, formerly called vasospastic syndrome) and secondary vascular dysregulation (SVD). Subjects with PVD tend to have cold extremities, low blood pressure, reduced feeling of thirst, altered drug sensitivity, increased pain sensitivity, prolonged sleep onset time, altered gene expression in the lymphocytes, signs of oxidative stress, slightly increased endothelin-1 plasma level, low body mass index and often diffuse and fluctuating visual field defects. Coldness, emotional or mechanical stress and starving can provoke symptoms. Virtually all organs, particularly the eye, can be involved. In subjects with PVD, retinal vessels are stiffer and more irregular, and both neurovascular coupling and autoregulation capacity are reduced while retinal venous pressure is often increased. Subjects with PVD have increased risk for normal-tension glaucoma, optic nerve compartment syndrome, central serous choroidopathy, Susac syndrome, retinal artery and vein occlusions and anterior ischaemic neuropathy without atherosclerosis. Further characteristics are their weaker blood-brain and blood-retinal barriers and the higher prevalence of optic disc haemorrhages and activated astrocytes. Subjects with PVD tend to suffer more often from tinnitus, muscle cramps, migraine with aura and silent myocardial ischaemic and are at greater risk for altitude sickness. While the main cause of vascular dysregulation is vascular endotheliopathy, dysfunction of the autonomic nervous system is also involved. In contrast, SVD occurs in the context of other diseases such as multiple sclerosis, retrobulbar neuritis, rheumatoid arthritis, fibromyalgia and giant cell arteritis. Taking into consideration the high prevalence of PVD in the population and potentially linked pathologies, in the current article, the authors provide recommendations on how to effectively promote the field in order to create innovative diagnostic tools to predict the pathology and develop more efficient treatment approaches tailored to the person. PMID- 23742181 TI - Detection of Escherichia coli, Salmonella species, and Vibrio cholerae in tap water and bottled drinking water in Isfahan, Iran. AB - BACKGROUND: The quality of drinking water has an important role in human infection and disease. This study was aimed at comparing polymerase chain reaction and culture in detecting Escherichia coli, Salmonella species and Vibrio cholera in tape water and bottled drinking water in various seasons in Isfahan province, Iran. METHODS: A total of 448 water samples from tap water and bottled mineral water were taken over 6 months, from July 2010 to December 2010, and after filtration, samples were examined by culture and polymerase chain reaction methods for detection of Escherichia coli, Salmonella species, and Vibrio cholerae. RESULTS: The culture method showed that 34 (7.58%), 4 (0.89%) and 3 (0.66%) of all 448 water samples were positive for Escherichia coli, Salmonella species, and Vibrio cholera, respectively. The uidA gene from Escherichia coli, IpaB gene from Salmonella species, and epsM gene from Vibrio cholera were detected in 38 (26.38%), 5 (3.47%), and 3 (2.08%) of 144 tap-water samples, respectively. Escherichia coli was detected in 8 (2.63%) of 304 samples of bottled drinking water from 5 companies. The water of southern part of Isfahan and company 5 had the highest prevalence of bacteria. The Escherichia coli water contamination was significantly higher (P < 0.05) in the hot seasons (July August) than cold (November-December) seasons and in company 5 than other companies. There were significant differences (P < 0.05) for the prevalence of bacteria between the tap waters of southern part and tap waters of central part of Isfahan. CONCLUSIONS: This study showed that the polymerase chain reaction assays can be an extremely accurate, fast, safe, sensitive and specific approach to monitor drinking water quality from purification facilities and bottled water companies. Also, our study confirmed the presence of Escherichia coli, Salmonella species, and Vibrio cholerae as water-borne pathogens in tap water and bottled drinking water of Isfahan, Iran. The present study showed the important public health problem in Isfahan, Iran. PMID- 23742182 TI - Ontogenetic shifts in male mating preference and morph-specific polyandry in a female colour polymorphic insect. AB - BACKGROUND: Sexual conflict over mating rates may favour the origin and maintenance of phenotypes with contrasting reproductive strategies. The damselfly Ischnura elegans is characterised by a female colour polymorphism that consists of one androchrome and two gynochrome female morphs. Previous studies have shown that the polymorphism is genetic and to a high extent maintained by negative frequency-dependent mating success that varies temporally and spatially. However, the role of learning in male mating preferences has received little attention. We used molecular markers to investigate differences in polyandry between female morphs. In addition, we experimentally investigated innate male mating preferences and experience-dependent shifts in male mating preferences for female morphs. RESULTS: Field and molecular data show that androchrome females were less polyandrous than gynochrome females. Interestingly, we found that naive males showed significantly higher sexual preferences to androchrome than to gynochrome females in experimental trials. In contrast, experienced males showed no preference for androchrome females. CONCLUSIONS: The ontogenetic change in male mate preferences occurs most likely because of learned mate recognition after experience with females, which in this case does not result in a preference for one of the morphs, but rather in the loss of an innate preference for androchrome females. PMID- 23742183 TI - Double-side-coated nanomechanical membrane-type surface stress sensor (MSS) for one-chip-one-channel setup. AB - With their capability for real-time and label-free detection of targets ranging from gases to biological molecules, nanomechanical sensors are expected to contribute to various fields, such as medicine, security, and environmental science. For practical applications, one of the major issues of nanomechanical sensors is the difficulty of coating receptor layers on their surfaces to which target molecules adsorb or react. To have measurable deflection, a single-side coating is commonly applied to cantilever-type geometry, and it requires specific methods or protocols, such as inkjet spotting or gold-thiol chemistry. If we can apply a double-side coating to nanomechanical sensors, it allows almost any kind of coating technique including dip coating methods, making nanomechanical sensors more useful with better user experiences. Here we address the feasibility of the double-side coating on nanomechanical sensors demonstrated by a membrane-type surface stress sensor (MSS) and verify its working principle by both finite element analysis (FEA) and experiments. In addition, simple hand-operated dip coating is demonstrated as a proof of concept, achieving practical receptor layers without any complex instrumentation. Because the double-side coating is compatible with batch protocols such as dip coating, double-side-coated MSS represents a new paradigm of one-chip-one-channel (channels on a chip are all coated with the same receptor layers) shifting from the conventional one-chip multiple-channel (channels on a chip are coated with different receptor layers) paradigm. PMID- 23742184 TI - Pilot study on quality of life and sexual function in men-who-have-sex-with-men treated for prostate cancer. AB - INTRODUCTION: There is limited data on post-treatment quality of life (QoL) for men-who-have-sex-with-men (MSM) with prostate cancer (PCa). QoL in MSM may not be reflected by assessment tools designed for the heterosexual population. AIMS: Our goals were to evaluate post-treatment QoL in PCa patients who are MSM, and to investigate the utility of current QoL assessment tool. METHODS: PCa patients treated with surgery and/or radiation were recruited from the local MSM community. Each participant completed the Expanded Prostate Cancer Index Composite (EPIC) questionnaire, Male Sexual Health Questionnaire (MSHQ), and a questionnaire focused on insertive and receptive roles of anal intercourse. MAIN OUTCOME MEASURES: Response scores were calculated based on questionnaire design and compared by treatment modality. RESULTS: Seven participants treated with surgery (mean age 58) and eight participants treated with radiation (mean age 67) were recruited. No participant in the surgical group received androgen deprivation therapy (ADT) while two in radiation group were treated with ADT. The sample size of this study did not permit formal statistical analysis, although potential differences in Urinary and Bowel Domains from EPIC and Ejaculation Scale from MSHQ were observed. More participants from the radiation group seemed to be able to maintain both insertive and receptive anal intercourse roles after treatment compared to participants who received surgery. CONCLUSIONS: While the two validated assessment tools suggested similar QoL scores including sexual function for both surgical and radiation groups, post-treatment sexual function related to anal intercourse may be better in the radiation group, as compared to the surgical group. Larger studies in PCa patients from MSM community are warranted to verify these data. PMID- 23742185 TI - Large area of walled-off pancreatic necrosis successfully treated by endoscopic necrosectomy using a grasping-type scissors forceps. AB - Endoscopic necrosectomy (EN) for walled-off pancreatic necrosis (WOPN) is less invasive than surgical treatment and has become the first choice for pancreatic abscess. EN is usually carried out with several devices including snares, baskets, and grasping forceps. Occasionally, we have encountered cases in which EN has not been satisfactorily carried out, and there is pressure for further innovation in EN. Here, we describe a case of a large area of WOPN that was successfully treated by EN with endoscopic submucosal dissection and associated techniques, which facilitated removal of necrotic tissues. A 60-year-old man was referred to our hospital for WOPN as a complication of necrotizing pancreatitis. As a result of his complicating conditions including ischemic heart disease, uncontrollable arrhythmia, chronic renal failure, and persistent pleural effusion, he was deemed a poor surgical candidate. Although EN with conventional devices was carried out for five sessions, we could not remove the dense and massive necrotic tissues. At the sixth EN session, the Clutch Cutter device (Fujifilm, Tokyo, Japan) was used to remove the necrotic tissues, without major complications. This is believed to be the first report of EN using the Clutch Cutter for successful treatment of WOPN. PMID- 23742186 TI - A small molecule angiotensin II type 2 receptor (AT2R) antagonist produces analgesia in a rat model of neuropathic pain by inhibition of p38 mitogen activated protein kinase (MAPK) and p44/p42 MAPK activation in the dorsal root ganglia. AB - OBJECTIVE: There is an unmet clinical need for novel analgesics for neuropathic pain. This study was designed to elucidate the mechanism through which EMA300, a small molecule antagonist of the angiotensin II type 2 receptor (AT2R) with >1,000-fold selectivity over the angiotensin II type 1 receptor, produces analgesia in a rodent model of neuropathic pain. DESIGN AND METHODS: Groups of AT2R knockout, hemizygotes, and wild-type mice with a chronic constriction injury (CCI) of the sciatic nerve received single intraperitoneal (i.p.) bolus doses of EMA300 (100 or 300 mg/kg), and analgesic efficacy was assessed. Groups of control, sham-operated, and CCI rats were euthanized and perfusion fixed. Lumbar dorsal root ganglia (DRGs) were removed for investigation of the mechanism through which EMA300 alleviates neuropathic pain. RESULTS: EMA300 analgesia was abolished in AT2R knockout CCI mice with intermediate responses in the hemizygotes, affirming the AT2R as the target mediating EMA300 analgesia. In CCI rats, DRG immunofluorescence (IF) levels for angiotensin II, the main endogenous ligand of the AT2R, were increased ~1.5-2.0-fold (P < 0.05) cf. sham-controls. Mean DRG IF levels for activated p38 (pp38) and activated p44/p42 (pp44/pp42) MAPK were also increased ~1.5-2.0-fold (P < 0.05) cf. sham-controls. At the time of peak EMA300 analgesia in CCI rats, mean DRG levels of pp38 MAPK and pp44/pp42 MAPK (but not angiotensin II) were reduced to match the respective levels in sham controls. CONCLUSION: Augmented angiotensin II/AT2R signaling in the DRGs of CCI rats is attenuated by EMA300 to block p38 MAPK and p44/p42 MAPK activation, a mechanism with clinical validity for alleviating neuropathic pain. PMID- 23742187 TI - Phosphine-catalyzed [4 + 2] annulation of gamma-substituent allenoates: facile access to functionalized spirocyclic skeletons. AB - The first phosphine-catalyzed [4 + 2] annulation of gamma-substituted allenoates with 2-arylidene-1H-indene-1,3(2H)-diones is disclosed. In the reaction, the gamma-substituted allenoate serves as a new type of 1,4-dipolar synthon; this broadens the application of gamma-substituted allenoates. This method also offers a powerful approach to the construction of highly substituted spiro[4.5]dec-6-ene skeletons in excellent yields, and with complete regioselectivity and high diastereoselectivity. PMID- 23742188 TI - Nanomolar E-selectin antagonists with prolonged half-lives by a fragment-based approach. AB - Selectins, a family of C-type lectins, play a key role in inflammatory diseases (e.g., asthma and arthritis). However, the only millimolar affinity of sialyl Lewis(x) (sLe(x)), which is the common tetrasaccharide epitope of all physiological selectin ligands, has been a major obstacle to the development of selectin antagonists for therapeutic applications. In a fragment-based approach guided by NMR, ligands binding to a second site in close proximity to a sLe(x) mimic were identified. A library of antagonists obtained by connecting the sLe(x) mimic to the best second-site ligand via triazole linkers of different lengths was evaluated by surface plasmon resonance. Detailed analysis of the five most promising candidates revealed antagonists with K(D) values ranging from 30 to 89 nM. In contrast to carbohydrate-lectin complexes with typical half-lives (t(1/2)) in the range of one second or even less, these fragment-based selectin antagonists show t1/2 of several minutes. They exhibit a promising starting point for the development of novel anti-inflammatory drugs. PMID- 23742189 TI - An echocardiographic presentation of a massive, reverse flow caused by an electrical failure of the left ventricular assist device. The continuous flow device dysfunction. PMID- 23742190 TI - Conformational transformation in squaric acid induced by near-IR laser light. AB - Two conformers of monomeric squaric acid (3,4-dihydroxy-3-cyclobutene-1,2-dione) were studied using the matrix-isolation method. Both forms of the compound, differing in rotation of one of the OH groups by 180 degrees , were trapped from the gas phase into a low-temperature nitrogen matrix, whereas only the lowest energy conformer was trapped in solid argon and in solid neon. Narrowband near infrared laser light was used to induce transformation of the most stable form of squaric acid (having C2v symmetry) into the higher-energy conformer (Cs symmetry). Effective stabilization of the photogenerated species occurred only for the compound isolated in a nitrogen matrix. Moreover, the stabilization of the higher-energy Cs conformer of squaric acid by the solid nitrogen environment was found to strongly depend on the trapping site in the matrix. The spectroscopic characterization of the higher energy Cs conformer is reported here for the first time. PMID- 23742191 TI - Symbiosis between photoactive nanoparticles and their organic ligands. AB - Photoactive spherical metal and semiconductor nanoparticles (NPs) are smart systems that exhibit unique properties, such as a high surface-to-volume ratio, a broad absorption spectrum and size-dependent properties. They are capped with a considerable number of ligands required to give rise to stable organic and aqueous NP colloidal solutions. In addition, the ligands can also be used to introduce functionality at the NP periphery. In this case, the NP could act as a 3D-scaffold, which would make a high local concentration of a functional moiety at the NP periphery possible, moreover, the photophysical properties of the NP could be tuned. The combined action of the organic capping and the inorganic core can exert an encapsulating effect, i.e. the organic capping could establish specific interactions with nearby molecules and this would enable the molecules to approach or interact with the NP surface. Therefore, the NP core and the ligand can work together providing the overall hybrid system with new properties or capacities. The relevance of the cooperative action between the spherical photoactive core and the capping are shown in this report with several recent examples developed by my research group, some of them in collaboration with other groups. PMID- 23742192 TI - Long-term outcome following ablation of atrial tachycardias occurring after mitral valve replacement in patients with rheumatic heart disease. AB - BACKGROUND: Atrial tachycardia (AT) is a frequent late sequel of surgical valve replacement procedures in patients with rheumatic heart disease (RHD). The aim of this study was to evaluate the acute and long-term outcome of catheter ablation in such patients. METHODS AND RESULTS: A total of 21 consecutive RHD patients with AT after a valve replacement were enrolled in this study. The mean interval between the occurrence of symptomatic AT and the surgical intervention was 38.2 +/- 48.7 months. The initial procedure was performed 8.4 +/- 8.9 months after first onset of AT. During the first procedure, an electroanatomic mapping was completed for 25 ATs, 18 of which were cavotricuspid isthmus-dependent atrial flutter, five that were right atrial free wall AT, and two that were left AT. Acute success was obtained in 95% (20/21) patients. Nine patients with recurrent AT had repeat radiofrequency catheter ablation, and newly developed left AT was identified in five patients after the first right AT ablation. After a mean follow-up of 42.7 +/- 17.3 months, only 33% of the patients remained free of ATs, while 14% and 53% of the patients had AT recurrence and the development of atrial fibrillation (AF), respectively. CONCLUSION: Right but not left macroreentry is the most common AT postmitral valve replacement in patients with RHD. The incidence of AF is very high after AT ablation in such patients during the long term follow-up. PMID- 23742193 TI - Detection of rabbit and hare processed material in compound feeds by TaqMan real time PCR. AB - Food and feed traceability has become a priority for governments due to consumer demand for comprehensive and integrated safety policies. In the present work, a TaqMan real-time PCR assay targeting the mitochondrial 12S rRNA gene was developed for specific detection of rabbit and hare material in animal feeds and pet foods. The technique is based on the use of three species-specific primer/probe detection systems targeting three 12S rRNA gene fragments: one from rabbit species, another one from hare species and a third fragment common to rabbit and hare (62, 102 and 75 bp length, respectively). A nuclear 18S rRNA PCR system, detecting a 77-bp amplicon, was used as positive amplification control. Assay performance and sensitivity were assessed through the analysis of a batch of laboratory-scale feeds treated at 133 degrees C at 3 bar for 20 min to reproduce feed processing conditions dictated by European regulations. Successful detection of highly degraded rabbit and hare material was achieved at the lowest target concentration assayed (0.1%). Furthermore, the method was applied to 96 processed commercial pet food products to determine whether correct labelling had been used at the market level. The reported real-time PCR technique detected the presence of rabbit tissues in 80 of the 96 samples analysed (83.3%), indicating a possible labelling fraud in some pet foods. The real-time PCR method reported may be a useful tool for traceability purposes within the framework of feed control. PMID- 23742194 TI - Prospective evaluation of term neonate brain damage following preceding hypoxic sentinel events using enhanced T2* weighted angiography (eSWAN). AB - PURPOSE: To evaluate the brain damage of term neonates with evidence of a preceding hypoxic sentinel event using eSWAN prospectively. METHODS: The study was approved by the institutional research ethics committee. Among the neonates who were examined during the first 8 days after birth with conventional magnetic resonance imaging (MRI), diffusion-weighted imaging (DWI) and eSWAN, 39 neonates with a preceding acute hypoxic sentinel event were divided into two groups: the hypoxic ischaemic encephalopathy (HIE) group and the high-risk group. Twenty-five neonates were normal control subjects. Conventional MRI, DWI, and T2* and R2* maps from eSWAN were assessed. T2* and R2* values from T2* and R2* maps were calculated in predefined regions in the HIE and high-risk groups and then compared with those in control subjects. RESULTS: The neonates in the HIE and high-risk groups showed a high percentage of cerebral oedema and periventricular white-matter (PWM) lesions. Cerebral oedema and haemorrhagic lesions of PWM were more highly visible on the T2* map compared with conventional MRI: cerebral oedema was illustrated as a high T2* area and haemorrhagic lesions had a significantly lower T2* on the T2* map. Lower R2* values of lentiform nuclei (LN) and a higher T2* and lower R2* of frontal white matter (FWM) were found in neonates in the HIE group relative to those of normal controls. The T2* value of LN in the high-risk group was higher than that of the normal controls. CONCLUSIONS: The T2* map from eSWAN is useful in detecting cerebral oedema and haemorrhagic lesions of PWM in neonates. The measurement of T2* and R2* values is helpful in assessing the LN and FWM damage in neonates following a hypoxic sentinel event. PMID- 23742195 TI - Should activated charcoal be given after tramadol overdose? PMID- 23742196 TI - Glycine restores glutathione and protects against oxidative stress in vascular tissue from sucrose-fed rats. AB - The attenuation of oxidative stress could be an important mechanism whereby the incidence of vascular complications in the MS (metabolic syndrome) may be diminished. The present study was undertaken to investigate the mechanism by which glycine, supplemented to the diet of SF (sucrose-fed) rats, modulates glutathione biosynthesis and protects against oxidative stress and altered endothelium-dependent relaxation in isolated aorta. Glycine reduced O2*- (superoxide anion radical) release in the presence of NADPH, and decreased protein carbonyl and lipid peroxidation. This effect of glycine could be because of the increased amount of glutathione synthetase, which may be responsible for increased glutathione (GSH) content in vascular tissue from SF rats. Moreover, glycine increased the amount of Cu,Zn-SOD (copper/zinc superoxide dismutase) and eNOS (endothelial NO synthase) in aorta from SF animals. Finally, it improved the relaxation response to ACh (acetylcholine) found impaired in aortic rings from SF rats. In the presence of NAC (N-acetylcysteine), a precursor of GSH, an improved ACh-mediated aortic relaxation of aortic rings from SF rats was observed, whereas BSO (buthionine sulfoximine), an inhibitor of glutathione biosynthesis, inhibited the relaxing effect of NAC in aortas from both control and SF rats. This experiment emphasizes the role of GSH in endothelial function in SF rats. The present data suggest that glycine rectifies vascular reactivity by increasing the biosynthesis of glutathione. Glutathione protects vascular tissue against oxidative stress, and enhances the availability of NO, which exerts its relaxing effect, thus contributing to the reduction of high BP (blood pressure) in the SF rats. PMID- 23742197 TI - Evaluation of the use of digital study models in postgraduate orthodontic programs in the United States and Canada. AB - OBJECTIVE: To investigate the extent, experience, and trends associated with digital model use, as well as the advantages of using a particular study model type (digital or plaster) in postgraduate orthodontic programs in the United States and Canada. MATERIALS AND METHODS: An electronic survey consisting of 14 questions was sent to 72 program directors or chairpersons of accredited orthodontic postgraduate programs in the United States and Canada. RESULTS: Fifty one responded for a 71% response rate. Sixty-five percent of the schools use plaster study models compared with 35% that use digital models. The most common advantages of plaster models were a three-dimensional feel and the ability for them to be mounted on an articulator. The most common advantages of digital models were the ease of storage and retrieval, and the residents' exposure to new technology. About one third of the plaster model users reported that they wanted to switch to digital models in the future, with 12% planning to do so within 1 year. CONCLUSIONS: Based on our study, 35% of accredited orthodontic postgraduate programs in the United States and Canada are using digital study models in most cases treated in their programs, and the trend is for increased digital model use in the future. PMID- 23742198 TI - Factors associated with the pressure pain threshold in healthy Chinese men. AB - OBJECTIVE: The goal of present study was to examine the influence of demographic characteristics, lifestyle, and metabolic factors on pressure-induced pain threshold. DESIGN AND SETTING: The study population comprised 2,517 healthy men at second-phase recruitment of a population-based cohort in China. The pressure pain threshold (PPT) at two locations, triceps and inguinal lines, was obtained using a digital pressure algometer. Education and occupation, as well as lifestyle factors, were self-reported in a face-to-face interview. Blood lipid and fasting glucose were measured as a routine healthy check-up program. RESULTS: A lower PPT was found among men with younger age, higher level of education, and non-manual occupation. In addition, men with central obesity and moderate leisure time physical exercise were more sensitive to muscle mechanical stimuli. PPT was significantly correlated with high-density lipoprotein cholesterol (beta for triceps = 0.064, and beta for inguinal lines = 0.052) in a multivariate linear regression model, after controlling for multiple variables. Elevated PPT was also found among subjects with hyperglycemia (both P for triceps and inguinal lines <0.001) and excess drinking (P for triceps = 0.005). CONCLUSIONS: It is important for physicians and researchers to consider these variables when evaluating pain sensitivity in clinic and in research. The underling mechanisms between these factors and pressure pain perception are worthy of further exploration. PMID- 23742199 TI - InSb-added TiO2 nanocomposite films by RF sputtering. AB - This study investigates the preparation of InSb-added TiO2 nanocomposite films by RF sputtering. The optical absorption spectra are obviously shifted to visible and near-infrared regions. High-resolution transmission electron microscopy indicates that sphere-shaped InSb nanocrystals with a size of about 15 nm are dispersed in a matrix. The X-ray diffraction result reveals that the matrix forms a phase mixture of TiO2 and In2O3, which is also produced by decomposing the InSb during postannealing at 723 K. Therefore, the absorption shift is clearly due to quantum size effects of the InSb nanocrystals embedded in the wide-gap oxides TiO2 and In2O3. PMID- 23742200 TI - Preclinical models of multiple myeloma: a critical appraisal. AB - INTRODUCTION: Preclinical models, by definition, are an approximation of reality, and their use in developing anticancer drugs is eagerly explored. Positive clinical correlations have been identified with different test systems, in addition to limitations and a need to improve preclinical model systems. Predicting whether a potential new anticancer agent will have a positive therapeutic index in patients remains a challenge. AREAS COVERED: We here review the fundamental requirements and remarkable progress of preclinical in vitro and in vivo assays used to assess the therapeutic potential of experimental anticancer drugs in multiple myeloma (MM). In MM, the interaction with the bone marrow microenvironment (BMM) plays a crucial role in disease progression, including resistance to antimyeloma agents. In vitro and in vivo approaches are, therefore, discussed with respect to their ability to mimic the important characteristics of MM and its BMM. In general, MM models should parallel the biological, genetic, etiological, immunological and therapeutic properties of the human disease. EXPERT OPINION: All models discussed here have their defined strengths, but also limitations with respect to their predictive features. Understanding the preclinical models in a more profound way should lead to optimized clinical trials, thereby expanding the therapeutic arsenal and improving patient outcome further. PMID- 23742201 TI - Infant feeding in the context of HIV: a qualitative study of health care workers' knowledge of recommended infant feeding options in Papua New Guinea. AB - BACKGROUND: Interventions to prevent mother to child transmission of human immunodeficiency virus (HIV) during childbirth and breastfeeding can reduce HIV infections in infants to less than 5% in low and middle income countries. The World Health Organization (WHO) recommends all mothers, regardless of their HIV status, practice exclusive breastfeeding for the first six months of an infant's life. In line with these recommendations and to protect, promote and support breastfeeding, in 2009 the PNG National Department of Health revised their National HIV infant feeding guidelines, reinforcing the WHO recommendation of exclusive breastfeeding for the first six months followed by the introduction of other food and fluids, while continuing breastfeeding.The overall aim of this paper is to explore health care workers' knowledge regarding infant feeding options in PNG, specifically as they relate to HIV exposed infants. METHODS: As part of a study investigating women's and men's experiences of prevention of mother to child transmission (PMTCT) services in two sites in PNG, 28 key informant interviews were undertaken. This paper addresses one theme that emerged from thematic data analysis: Health care workers' knowledge regarding infant feeding options, specifically how this knowledge reflects the Papua New Guinea National HIV Care and Treatment Guidelines on HIV and infant feeding (2009). RESULTS: Most informants mentioned exclusive breastfeeding, the majority of whom reflected the most up-to-date National Guidelines of exclusive breastfeeding for six months. The importance of breastfeeding continuing beyond this time, along with the introduction of food and fluids was less well understood. The most senior people involved in PMTCT were the informants who most accurately reflected the national guidelines of continuing breastfeeding after six months. CONCLUSION: Providing advice on optimal infant feeding in resource poor settings is problematic, especially in relation to HIV transmission. Findings from our study reflect those found elsewhere in identifying that key health care workers are not aware of up-to-date information relating to infant feeding, especially within the context of HIV. Greater emphasis needs to be placed on ensuring the most recent feeding guidelines are disseminated and implemented in clinical practice in PNG. PMID- 23742202 TI - Shaping parents: impact of contrasting professional counseling on parents' decision making for children with disorders of sex development. AB - INTRODUCTION: The management of disorders or differences of sex development (DSD) remains complex, especially with respect to parents' decision for or against early genitoplasty. Most parents still tend to disfavor postponing surgery until the child is old enough to provide consent. AIM: To identify the determinants of parental decisions for or against early sex assignment surgery in DSD children, and in particular to assess the influence of contrasting behavior of health-care professionals and the information they dispense. METHODS: Preliminary data analysis from a focus group identified two broad approaches to counseling information. Two six-minute counseling videos were produced on this basis: one medicalized, by an endocrinologist, the other demedicalized, by a psychologist. Third-year medical students (N = 89) were randomized to watch either video as prospective parents and report its impact on their decision in a self administered questionnaire. MAIN OUTCOME MEASURES: Statistical analysis of questionnaire responses regarding decisions for or against surgery, including self-assessed impact of potential determinants. RESULTS: Thirty-eight of eighty nine "parents" (43%) chose early surgery for "their" child, including 27/41 "parents" (66%) shown the medicalized video vs. 11/48 (23%) shown the demedicalized video (P < 0.001). Desired aims for "their" child also differed significantly depending on the counseling approach viewed. Yet "parents" perceived their personal attitudes on a four-point Likert scale as the main influence on their decision although their "attitude" was significantly shaped by the video. CONCLUSIONS: Parental decisions concerning early sex assignment surgery for DSD children depend on the health professional counseling received, to a degree of which neither parents nor professionals appear fully aware. In the absence of conclusive data for or against early surgery, there is a danger of medicalized or demedicalized parentalism resulting in irreversible and inadequately grounded decisions, regardless of the consensus statement of 2005 and the subsequent call for multidisciplinary management. PMID- 23742203 TI - Association of the family environment with behavioural and cognitive outcomes in children with chromosome 22q11.2 deletion syndrome. AB - BACKGROUND: Children with 22q11.2 deletion syndrome (22q11DS) are at risk for social-behavioural and neurocognitive sequelae throughout development. The current study examined the impact of family environmental characteristics on social-behavioural and cognitive outcomes in this paediatric population. METHOD: Guardians of children with 22q11DS were recruited through two medical genetics clinics. Consenting guardians were asked to complete several questionnaires regarding their child's social, emotional and behavioural functioning, as well as family social environment and parenting styles. Children with 22q11DS were asked to undergo a cognitive assessment, including IQ and achievement testing, and measures of attention, executive function and memory. RESULTS: Modest associations were found between aspects of the family social environment and parenting styles with social-behavioural and cognitive/academic outcomes. Regression models indicated that physical punishment, socioeconomic status, parental control and family organisation significantly predicted social behavioural and cognitive outcomes in children with 22q11DS. CONCLUSION: Characteristics of the family social environment and parenting approaches appear to be associated with functional outcomes of children with 22q11DS. Understanding the impact of environmental variables on developmental outcomes can be useful in determining more effective targets for intervention. This will be important in order to improve the quality of life of individuals affected by 22q11DS. PMID- 23742204 TI - Self-assembly and hierarchical patterning of aligned organic nanowire arrays by solvent evaporation on substrates with patterned wettability. AB - The controlled growth and alignment of one-dimensional organic nanostructures at well-defined locations considerably hinders the integration of nanostructures for electronic and optoelectronic applications. Here, we demonstrate a simple process to achieve the growth, alignment, and hierarchical patterning of organic nanowires on substrates with controlled patterns of surface wettability. The first-level pattern is confined by the substrate patterns of wettability. Organic nanostructures are preferentially grown on solvent wettable regions. The second level pattern is the patterning of aligned organic nanowires deposited by controlling the shape and movement of the solution contact lines during evaporation on the wettable regions. This process is controlled by the cover-hat controlled method or vertical evaportation method. Therefore, various new patterns of organic nanostructures can be obtained by combing these two levels of patterns. This simple method proves to be a general approach that can be applied to other organic nanostructure systems. Using the as-prepared patterned nanowire arrays, an optoelectronic device (photodetector) is easily fabricated. Hence, the proposed simple, large-scale, low-cost method of preparing patterns of highly ordered organic nanostructures has high potential applications in various electronic and optoelectronic devices. PMID- 23742205 TI - Structural and evolutionary adaptation of rhoptry kinases and pseudokinases, a family of coccidian virulence factors. AB - BACKGROUND: The widespread protozoan parasite Toxoplasma gondii interferes with host cell functions by exporting the contents of a unique apical organelle, the rhoptry. Among the mix of secreted proteins are an expanded, lineage-specific family of protein kinases termed rhoptry kinases (ROPKs), several of which have been shown to be key virulence factors, including the pseudokinase ROP5. The extent and details of the diversification of this protein family are poorly understood. RESULTS: In this study, we comprehensively catalogued the ROPK family in the genomes of Toxoplasma gondii, Neospora caninum and Eimeria tenella, as well as portions of the unfinished genome of Sarcocystis neurona, and classified the identified genes into 42 distinct subfamilies. We systematically compared the rhoptry kinase protein sequences and structures to each other and to the broader superfamily of eukaryotic protein kinases to study the patterns of diversification and neofunctionalization in the ROPK family and its subfamilies. We identified three ROPK sub-clades of particular interest: those bearing a structurally conserved N-terminal extension to the kinase domain (NTE), an E. tenella-specific expansion, and a basal cluster including ROP35 and BPK1 that we term ROPKL. Structural analysis in light of the solved structures ROP2, ROP5, ROP8 and in comparison to typical eukaryotic protein kinases revealed ROPK specific conservation patterns in two key regions of the kinase domain, surrounding a ROPK-conserved insert in the kinase hinge region and a disulfide bridge in the kinase substrate-binding lobe. We also examined conservation patterns specific to the NTE-bearing clade. We discuss the possible functional consequences of each. CONCLUSIONS: Our work sheds light on several important but previously unrecognized features shared among rhoptry kinases, as well as the essential differences between active and degenerate protein kinases. We identify the most distinctive ROPK-specific features conserved across both active kinases and pseudokinases, and discuss these in terms of sequence motifs, evolutionary context, structural impact and potential functional relevance. By characterizing the proteins that enable these parasites to invade the host cell and co-opt its signaling mechanisms, we provide guidance on potential therapeutic targets for the diseases caused by coccidian parasites. PMID- 23742206 TI - A practical method for the synthesis of highly enantioenriched trans-1,2-amino alcohols. AB - A highly enantioselective addition of phenyl carbamate to meso-epoxides has been developed to efficiently generate protected trans-1,2-amino alcohols. This transformation is promoted by an oligomeric (salen)Co-OTf catalyst and has been used to prepare two useful 2-aminocycloalkanol hydrochlorides in enantiopure form on a multigram scale from commercially available starting materials. PMID- 23742207 TI - Disinfection effectiveness of slightly acidic electrolysed water in swine barns. AB - AIMS: To evaluate the disinfection effectiveness of slightly acidic electrolysed water (SAEW, pH 6.25-6.53), a new environmental friendly agent for inactivating micro-organisms adhered to the facility and aerosolized in the air of the swine barns and to explore the application of SAEW in livestock industries. METHODS AND RESULTS: Bacteria and fungi were isolated from the swine house air and treated by SAEW. The SAEW solution was flushed onto surfaces and sprayed within the whole swine barn. SAEW with an available chlorine concentration (ACC) of 300 mg l(-1) can inhibit isolated microbes completely. The usage of SAEW (300 mg l(-1) ) resulted in a significant (P < 0.05) reduction in microbes on the wall, rail and floor after flushing disinfection. Additionally, spraying SAEW at an ACC of 300 mg l(-1) reduced 59% of the airborne organisms in 30 min and kept the population of microbes at a reduced level for at least 8 h. SAEW treatment also reduced pathogens on surfaces (P < 0.03) after spraying disinfection except on the surface of the wall. CONCLUSIONS: SAEW may be a potential alternative disinfectant to reduce infections in swine barns. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this study provide information on the antimicrobial efficiency of SAEW on the airborne bacteria and fungi in swine barns. PMID- 23742208 TI - A randomised controlled trial testing a web-based, computer-tailored self management intervention for people with or at risk for chronic obstructive pulmonary disease: a study protocol. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality. Effective self-management support interventions are needed to improve the health and functional status of people with COPD or at risk for COPD. Computer-tailored technology could be an effective way to provide this support. METHODS/DESIGN: This paper presents the protocol of a randomised controlled trial testing the effectiveness of a web-based, computer-tailored self management intervention to change health behaviours of people with or at risk for COPD. An intervention group will be compared to a usual care control group, in which the intervention group will receive a web-based, computer-tailored self management intervention. Participants will be recruited from an online panel and through general practices. Outcomes will be measured at baseline and at 6 months. The primary outcomes will be smoking behaviour, measuring the 7-day point prevalence abstinence and physical activity, measured in minutes. Secondary outcomes will include dyspnoea score, quality of life, stages of change, intention to change behaviour and alternative smoking behaviour measures, including current smoking behaviour, 24-hour point prevalence abstinence, prolonged abstinence, continued abstinence and number of quit attempts. DISCUSSION: To the best of our knowledge, this will be the first randomised controlled trial to test the effectiveness of a web-based, computer-tailored self management intervention for people with or at risk for COPD. The results will be important to explore the possible benefits of computer-tailored interventions for the self-management of people with or at risk for COPD and potentially other chronic health conditions. DUTCH TRIAL REGISTER: NTR3421. PMID- 23742209 TI - Concurrent cationic vinyl-addition and ring-opening copolymerization using B(C6F5)3 as a catalyst: copolymerization of vinyl ethers and isobutylene oxide via crossover propagation reactions. AB - Alkyl vinyl ethers and isobutylene oxide were concurrently copolymerized through cationic vinyl addition and ring opening using B(C6F5)3 as a catalyst. NMR analyses and acid hydrolysis of the products demonstrated that the copolymerization successfully proceeded through crossover reactions between vinyl and cyclic monomers to yield multiblock-like copolymers. Appropriate catalyst and monomer combinations with suitable reactivities were key for copolymerization. PMID- 23742210 TI - Age- and gender-dependent left ventricular remodeling. AB - BACKGROUND: The effect of age and gender on left ventricular (LV) size, muscle mass, and systolic function as determined by two-dimensional echocardiography has not yet been investigated in a large population. METHODS: Normal transthoracic two-dimensional echocardiography studies of 5307 subjects (47% males) performed between March 1990 and December 2011 were analyzed. LV end-diastolic volume index (LVEDVI), LV muscle mass index (LVMMI), LV ejection fraction (LVEF), and LV fractional shortening (LVFS) were compared in different age groups. RESULTS: LVMMI increased in females from 66.4 +/- 1.3 g/m(2) (7-20 years) to 76.3 +/- 0.9 g/m(2) (60-80 years; P < 0.0001) and in males from 81.9 +/- 1.7 g/m(2) (7-20 years) to 94.6 +/- 1.3 g/m(2) (60-80 years; P < 0.0001). LVEDVI decreased in females from 49.8 +/- 0.9 mL/m(2) (7-20 years) to 42.8 +/- 0.6 mL/m(2) (60-80 years; P < 0.0001) and in males from 56.6 +/- 0.8 mL/m(2) (7-20 years) to 49.0 +/ 0.7 mL/m(2) (60-80 years; P < 0.0001). A significant increase in LVEF was observed with age (P < 0.0001 for both genders), but it was more pronounced in females (62 +/- 0.5% [age 7-20 years] vs. 65 +/- 0.3% [age 60-80 years]) than in males (62 +/- 0.5% [age 7-20 years] vs. 64 +/- 0.3% [age 60-80 years]). Similarly, LVFS increased in females from 37.7 +/- 0.5% (7-20 years) to 42.4 +/- 0.4% (60-80 years; P < 0.001) and in males from 37.3 +/- 0.5% (7-20 years) to 39.4 +/- 0.5% (60-80 years; P < 0.001). CONCLUSIONS: LVEF, LVFS, and LVMMI increase with advancing age, in particular in females. In contrast, LVEDVI decreases with age. These findings indicate that the LV undergoes a lifelong remodeling. PMID- 23742211 TI - Factors affecting the estimated probabilistic acute dietary exposure to captan from apple consumption. AB - The effect of the number of pesticide residue values below the LOQ/LOD of analytical methods, the variability of residues in individual fruits, mass of fruit units and the number of bootstrap iterations was studied on the probabilistically estimated acute exposure of consumers. The 4720 daily apple consumption data and the results of 1239 apple sample analyses for captan residues, performed within the Hungarian monitoring programme between 2005 and 2011, were used in this study as model matrix. Up to about 95th percentile exposure (ug/(kg bw.day)), simply multiplying each residue in composite samples with each consumption value gave similar estimates to those obtained with the complex procedure taking also into account the mass of and residues in individual fruits. However, the exposure above the 95th percentile calculated with the complex procedure gradually increased with increasing percentile level compared to the simple procedure. Including the high number of non-detects reduced the estimated exposure, which was the highest when only the residues measured in treated fruits were taken into account. The number of bootstrap iterations between 100 and 10,000 did not significantly affect the calculated exposure. The 99.99th percentile exposure amounted to 17.9% of the acute reference dose of 300 ug/(kg bw.day) for women of childbearing age. PMID- 23742212 TI - Morphological and structural changes in lung tissue infected by Paracoccidioides brasiliensis: FTIR photoacoustic spectroscopy and histological analysis. AB - This study evaluated physical, chemical and morphological changes in lungs of mice infected with Paracoccidioides brasiliensis. The animals were inoculated with 0.1 mL of fungal suspension of the P. brasiliensis 18 isolate and were euthanized 1, 2, 4 and 8 weeks after inoculation. The upper left lobe of the lung was isolated, fixed and processed for paraffin embedding. The sections were stained with H&E for histopathological study, with Gomori-Grocott to locate and identify the fungus, and with TUNEL immunostaining to detect the occurrence of programmed cell death. The lower and middle right lobes were analyzed by Fourier Transform Infrared Photoacoustic Spectrocopy (FTIR-PAS) to investigate physical and chemical features of the infected lungs. The results showed that lungs infected by P. brasiliensis underwent structural changes that varied according to the time period analyzed, and that changes in the absorption bands of different chemical groups resulted from these morphological changes. The results suggest that the combination of FTIR-PAS spectroscopy with morphological evaluation is an effective procedure for the study of paracoccidioidomycosis, one of the most important systemic mycoses that can damage the lung architecture and consequently impair the respiratory function. PMID- 23742213 TI - Computing loss of efficiency in optimal Bayesian decoders given noisy or incomplete spike trains. AB - We investigate Bayesian methods for optimal decoding of noisy or incompletely observed spike trains. Information about neural identity or temporal resolution may be lost during spike detection and sorting, or spike times measured near the soma may be corrupted with noise due to stochastic membrane channel effects in the axon. We focus on neural encoding models in which the (discrete) neural state evolves according to stimulus-dependent Markovian dynamics. Such models are sufficiently flexible that we may incorporate realistic stimulus encoding and spiking dynamics, but nonetheless permit exact computation via efficient hidden Markov model forward-backward methods. We analyze two types of signal degradation. First, we quantify the information lost due to jitter or downsampling in the spike-times. Second, we quantify the information lost when knowledge of the identities of different spiking neurons is corrupted. In each case the methods introduced here make it possible to quantify the dependence of the information loss on biophysical parameters such as firing rate, spike jitter amplitude, spike observation noise, etc. In particular, decoders that model the probability distribution of spike-neuron assignments significantly outperform decoders that use only the most likely spike assignments, and are ignorant of the posterior spike assignment uncertainty. PMID- 23742214 TI - Identification of left atrial ganglionated plexi by dense epicardial mapping as ablation targets for the treatment of concomitant atrial fibrillation. AB - BACKGROUND: Autonomic ganglionated plexi (GPs) play a significant role in the initiation and maintenance of atrial fibrillation (AF). GPs are key targets for a maze procedure. The purpose of this study was to identify the location of the left atrial GPs based on dense epicardial mapping during a maze procedure in patients with concomitant AF. METHODS: Sixteen patients (age, 68 +/- 10 years; 11 males, 69%) with heart failure and concomitant AF (duration 55 +/- 86 months) underwent intraoperative epicardial electrophysiological mapping and a GP ablation using the maze procedure at our institution. Twenty-four-site, high frequency stimulation (1,000/min; output, 18 V; pulse width, 0.75 ms) was performed by placing tweezers directly onto the potential GP sites on the left atrial epicardium. RESULTS: Active GPs were found in 13 (81%) of the 16 patients, and 12 (92%) of 13 patients had active GPs between the right pulmonary veins (PVs) and the interatrial groove. For those patients with active locations, a 7 day event-loop recording demonstrated that 12 (92%) of 13 patients were maintained in sinus rhythm 3 months after the operation. CONCLUSION: Dense epicardial mapping in the potential GP areas identified active GP locations in a high percentage of patients. GPs between the PVs and interatrial groove have a high potential as ablation targets for treatment of concomitant AF. PMID- 23742216 TI - The unusual DRB1*08:01 haplotype carrying DRB3*02:02 confirmed in a Dutch family. PMID- 23742215 TI - The diagnosis of food allergy: protocol for a systematic review. AB - BACKGROUND: The literature on diagnostic tests for food allergy currently lacks clear consensus regarding the accuracy and safety of different investigative approaches. The European Academy of Allergy and Clinical Immunology is in the process of developing its Guideline for Food Allergy and Anaphylaxis, and this systematic review is one of seven inter-linked evidence syntheses that are being undertaken in order to provide a state-of-the-art synopsis of the current evidence base in relation to epidemiology, prevention, diagnosis and clinical management, and impact on quality of life, which will be used to inform the formulation of clinical recommendations. The aim of this systematic review will be to assess the diagnostic accuracy of tests aimed at supporting the clinical diagnosis of IgE-mediated food allergy. METHODS: The following databases from inception to September 30, 2012 will be searched for studies of diagnostic tests: Cochrane Library (Wiley&Sons); MEDLINE (OVID); Embase (OVID); CINAHL (Ebscohost); ISI Web of Science (Thomson Web of Knowledge); TRIP Database (web http://www.tripdatabase.com); and Clinicaltrials.gov (NIH web). These database searches will be supplemented by contacting an international panel of experts. Studies evaluating APT, SPT, specific-IgE, and component specific-IgE in participants of any age with suspected food allergy will be included. The reference standard will be DBPCFC in at least 50% of the participants. Studies will be quality assessed by using the QUADAS-2 instrument. We will report summary statistics such as sensitivity, specificity, and/or likelihood ratios. We will use the hierarchical summary ROC (HSROC) model to summarize the accuracy of each test and to compare the accuracy of two or more tests. DISCUSSION: Decisions on which tests to use need to be guided by availability of tests, populations being cared for, risks, financial considerations and test properties. This review will examine papers from around the world, covering children and adults with suspected food allergy in varying populations and concentrated on four type of tests: APT, SPT, specific-IgEs, and component specific-IgEs. PMID- 23742218 TI - Surface roughness effects on the frequency tuning performance of a nanoelectromechanical resonator. AB - Electrothermal heating is one of radio frequency tuning method in nanoelectromechanical resonators with magnetomotive transduction. This study confirmed that the surface roughness of the nanoresonator affects the electrothermal tuning performance under moderate conditions at room temperature. The effect of surface roughness on electrothermal tuning is complicated and involves interactions of mechanical and electrical properties. In addition, the electrothermal damping varied depending on the nanoscale molecular solid structure. These factors affect the signal-to-noise ratio, the effective stress of the beam, and the quality Q-factor of the nanoresonator. PMID- 23742217 TI - Toward systematic reviews to understand the determinants of wait time management success to help decision-makers and managers better manage wait times. AB - BACKGROUND: Long waits for core specialized services have consistently been identified as a key barrier to access. Governments and organizations at all levels have responded with strategies for better wait list management. While these initiatives are promising, insufficient attention has been paid to factors influencing the implementation and sustainability of wait time management strategies (WTMS) implemented at the organizational level. METHODS: A systematic review was conducted using the main electronic databases, such as CINAHL, MEDLINE, and Cochrane Database of Systematic Reviews, to identify articles published between 1990 and 2011 on WTMS for scheduled care implemented at the organizational level or higher and on frameworks for analyzing factors influencing their success. Data was extracted on governance, culture, resources, and tools. We organized a workshop with Canadian healthcare policy-makers and managers to compare our initial findings with their experience. RESULTS: Our systematic review included 47 articles: 36 related to implementation and 11 to sustainability. From these, we identified a variety of WTMS initiated at the organizational level or higher, and within these, certain factors that were specific to either implementation or sustainability and others common to both. The main common factors influencing success at the contextual level were stakeholder engagement and strong funding, and at the organizational level, physician involvement, human resources capacity, and information management systems. Specific factors for successful implementation at the contextual level were consultation with front-line actors and common standards and guidelines, and at the organizational level, financial incentives and dedicated staffing. For sustainability, we found no new factors. The workshop participants identified the same major factors as found in the articles and added others, such as information sharing between physicians and managers. CONCLUSIONS: Factors related to implementation were studied more than those related to sustainability. However, this finding was useful in developing a tool to help managers at the local level monitor the implementation of WTMS and highlighted the need for more research on specific factors for sustainability and to assess the unintended consequences of introducing WTMS in healthcare organizations. PMID- 23742219 TI - Undiagnosed mood disorders and sleep disturbances in primary care patients with chronic musculoskeletal pain. AB - OBJECTIVE: The study aims to determine the prevalence of undiagnosed comorbid mood disorders in patients suffering chronic musculoskeletal pain in a primary care setting and to identify sleep disturbances and other associated factors in these patients, and to compare the use of health services by chronic musculoskeletal pain patients with and without comorbid mood disorders. DESIGN: Cross-sectional study. SUBJECTS: A total of 1,006 patients with chronic musculoskeletal pain from a representative sample of primary care centers were evaluated. OUTCOME MEASURES: Pain was measured using a visual analog scale and the Primary Care Evaluation of Mental Disorders questionnaire was used to measure mood disorders. RESULTS: We observed a high prevalence of undiagnosed mood disorders in chronic musculoskeletal pain patients (74.7%, 95% confidence interval [CI] 71.9-77.4%), with greater comorbidity in women (adjusted odds ratio [OR] = 1.91, 95% CI 1.37-2.66%) and widow(er)s (adjusted OR = 1.87, 95% CI 1.19 2.91%). Both sleep disturbances (adjusted OR = 1.60, 95% CI 1.17-2.19%) and pain intensity (adjusted OR = 1.02, 95% CI 1.01-1.02%) displayed a direct relationship with mood disorders. Moreover, we found that chronic musculoskeletal pain patients with comorbid mood disorders availed of health care services more frequently than those without (P < 0.001). CONCLUSIONS: The prevalence of undiagnosed mood disorders in patients with chronic musculoskeletal pain is very high in primary care settings. Our findings suggest that greater attention should be paid to this condition in general practice and that sleep disorders should be evaluated in greater detail to achieve accurate diagnoses and select the most appropriate treatment. PMID- 23742221 TI - Influence of vascular comorbidities and race on erectile dysfunction after prostate cancer radiotherapy. AB - INTRODUCTION: Vascular comorbidities (VC) (hypertension, diabetes, and hyperlipidemia) are known factors related to erectile dysfunction (ED) in men. However, no data are yet available for the effects of VC on ED incidence after prostate cancer radiotherapy (XRT). AIM: To investigate the influence of VC on post-XRT ED incidence and to further characterize ED incidence by racial groups. MAIN OUTCOME MEASURES: ED incidence. METHODS: We reviewed 732 charts of patients (267 Caucasian and 465 African American [AA]) who received prostate XRT (external beam radiotherapy and/or brachytherapy) with or without hormone therapy between 1999 and 2010. The number of pre-XRT VC (0, 1, 2, or 3) was determined by medical history and medication list. ED (defined by use of erectile aids or by documentation of moderate or high sexual dysfunction on patient history) was determined pre-XRT as well as 1, 2, and 4 years post-XRT. RESULTS: ED incidence progressively increased from 22% pre-XRT to 58% 4 years post-XRT (P < 0.01). Additionally, ED incidence significantly increased with number of VC-4-year incidence between patients with 1 vs. 0 (P = 0.02), 2 vs. 0 (P < 0.01), 3 vs. 0 (P < 0.01), 3 vs. 1 (P < 0.01), and 3 vs. 2 (P = 0.04) VC (2 vs. 1 VC was nonsignificant). Compared with the Caucasian patients, ED incidences were slightly higher for the AA group with 0, 1, 2, and 3 comorbidities at 4 years follow-up (but statistically nonsignificant). CONCLUSIONS: The number of VCs have a significant effect on development of post-XRT ED. Pre- and post-XRT ED appear to be independent of race when number of VCs are considered. Our results can be used to guide physicians in counseling patients on the incidence of ED by number of VC and as preliminary data for prospective efforts aimed at reducing post-XRT ED. PMID- 23742222 TI - Aerobic training improved low-grade inflammation in obese women with intellectual disability. AB - BACKGROUND: Obesity is a major health problem in people with intellectual disabilities. It is also widely accepted that low-grade systemic inflammation associated to obesity plays a key role in the pathogenic mechanism of several disorders. Fortunately, physical activity has shown to improve inflammation in people with metabolic syndrome and type 2 diabetes. Accordingly, we assessed the influence of aerobic training on pro-inflammatory cytokines and acute phase proteins in women with Down syndrome. METHODS: To achieve this outcome, 20 premenopausal obese young women with Down syndrome volunteered for this study. Eleven were randomly assigned to the intervention group and performed a 10-week aerobic training programme, three sessions per week, consisting of a warm-up then a 30- to 40-min treadmill exercise at a work intensity of 55-65% of peak heart rate followed by a cooling-down period. The control group included nine age-, sex and body mass index-matched women with Down syndrome. Fat mass percentage and fat distribution were measured. Plasmatic levels of tumour necrosis factor (TNF) alpha, interleukin (IL)-6 and fibrinogen were assessed by commercial enzyme linked immunosorbent assay kits. C-reactive protein (CRP) was assessed by nephelometry. RESULTS: Plasmatic levels of TNF-alpha (11.7 +/- 1.6 vs. 9.2 +/- 1.3 pg/ml; P = 0.022), IL-6 (8.2 +/- 1.1 vs. 6.1 +/- 0.9 pg/ml; P = 0.014) and high sensitive CRP (0.62 +/- 0.11 vs. 0.53 +/- 0.09 mg/dl; P = 0.009) were significantly reduced in the intervention group. Further, significant correlations between plasmatic and anthropometric parameters were found. CONCLUSION: A 10-week training programme reduced pro-inflammatory cytokines and acute phase proteins in obese young women with Down syndrome. Long-term, well conducted studies are still required to determine whether correction of this low grade inflammation improves clinical outcomes of women with trisomy 21. PMID- 23742223 TI - Biotemplated syntheses of macroporous materials for bone tissue engineering scaffolds and experiments in vitro and vivo. AB - The macroporous materials were prepared from the transformation of cuttlebone as biotemplates under hydrothermal reactions and characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetric/differential thermal analyses (TG-DTA), and scanning electron microscopy (SEM). Cell experimental results showed that the prepared materials as bone tissue engineering scaffolds or fillers had fine biocompatibility suitable for adhesion and proliferation of the hMSCs (human marrow mesenchymal stem cells). Histological analyses were carried out by implanting the scaffolds into a rabbit femur, where the bioresorption, degradation, and biological activity of the scaffolds were observed in the animal body. The prepared scaffolds kept the original three-dimensional frameworks with the ordered porous structures, which made for blood circulation, nutrition supply, and the cells implantation. The biotemplated syntheses could provide a new effective approach to prepare the bone tissue engineering scaffold materials. PMID- 23742224 TI - Wing shape allometry and aerodynamics in calopterygid damselflies: a comparative approach. AB - BACKGROUND: Wing size and shape have important aerodynamic implications on flight performance. We explored how wing size was related to wing shape in territorial males of 37 taxa of the damselfly family Calopterygidae. Wing coloration was also included in the analyses because it is sexually and naturally selected and has been shown to be related to wing shape. We studied wing shape using both the non dimensional radius of the second moment of wing area (RSM) and geometric morphometrics. Lower values of the RSM result in less energetically demanding flight and wider ranges of flight speed. We also re-analyzed previously published data on other damselflies and dragonflies. RESULTS: The RSM showed a hump-shaped relationship with wing size. However, after correcting for phylogeny using independent contrast, this pattern changed to a negative linear relationship. The basal genus of the study family, Hetaerina, was mainly driving that change. The obtained patterns were specific for the study family and differed from other damselflies and dragonflies. The relationship between the RSM and wing shape measured by geometric morphometrics was linear, but relatively small changes along the RSM axis can result in large changes in wing shape. Our results also showed that wing coloration may have some effect on RSM. CONCLUSIONS: We found that RSM showed a complex relationship with size in calopterygid damselflies, probably as a result of other selection pressures besides wing size per se. Wing coloration and specific behavior (e.g. courtship) are potential candidates for explaining the complexity. Univariate measures of wing shape such as RSM are more intuitive but lack the high resolution of other multivariate techniques such as geometric morphometrics. We suggest that the relationship between wing shape and size are taxa-specific and differ among closely-related insect groups. PMID- 23742225 TI - Development of a novel phage-mediated immunoassay for the rapid detection of viable Mycobacterium avium subsp. paratuberculosis. AB - AIMS: The objective of this study was to develop a novel screening method for detection of viable Mycobacterium avium subsp. paratuberculosis (Map) in milk and faeces, as a rapid alternative to Map culture. METHODS AND RESULTS: The new method couples Map-specific peptide-mediated magnetic separation technique with an optimized phage amplification assay followed by detection of released progeny phage by ELISA in a competition assay format using polyclonal antibody produced against the D29 mycobacteriophage involved in the phage assay. Sample matrices were found not to interfere with the developed method, and the dynamic range of the assay was 3 * 10(2) -6 * 10(8 ) phage ml(-1) . When low numbers of Map were present (10(2) CFU ml(-1) ), the burst size of a single host Map cell was maximal (10(3) phage per cell) resulting in a highly sensitive screening assay. CONCLUSION: A rapid, sensitive immuno-based screening method suitable for the detection of viable Map in milk and faeces was developed. SIGNIFICANCE AND IMPACT OF THE STUDY: The novel PMS-phage-ELISA permits sensitive, qualitative detection of viable Map in milk or faeces samples within 48 h, representing a substantial decrease in time to detection compared with current culture methods for Map. PMID- 23742226 TI - Toxicological evaluation of Terminalia paniculata bark extract and its protective effect against CCl4-induced liver injury in rodents. AB - BACKGROUND: Based on the reported antioxidant and anti-inflammatory potential of Terminalia paniculata, the bark aqueous extract (TPW) was investigated against liver damage. METHODS: Intrinsic cytotoxicity was tested on normal human liver (Chang) cell lines, followed by acute and sub-chronic toxicity studies in mice. TPW was then evaluated against CCl4-induced liver toxicity in rats. Liver enzymes (AST, ALT, and ALP) and antioxidant markers were assessed. The effect of TPW on isolated hepatic cells, post-CCl4 administration, was assessed by isolated mitochondrial membrane staining. The actions of TPW on apoptotic pathway in CCl4 treated Chang cells were also elucidated. RESULTS: TPW was found to be safe at all doses tested in both in vitro and in vivo toxicity studies. TPW (400 mg/kg, p.o.) significantly (*p <0.05) improved liver enzyme activity as compared to CCl4. Also, it improved antioxidant status (GSH, GST, MDA and total thiol) and preserved hepatic cell architecture. TPW pre-treatment significantly attenuated the levels of phospho-p53, p53, cleaved caspase-3, phospho-Bad, Bad and cleaved PARP in CCl4-treated Chang cells, improving the viability considerably. CONCLUSION: The findings support a protective role for Terminalia paniculata in pathologies involving oxidative stress. PMID- 23742227 TI - Stress cardiomyopathy with an "inverse" takotsubo pattern in a patient with acute aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Subarachnoid hemorrhage (SAH) induced myocardial dysfunction (often labeled neurogenic stunned myocardium) encompasses a spectrum of clinical presentations ranging from an isolated elevation of cardiac enzymes to cardiogenic shock. OBJECTIVE: We describe a case of stress cardiomyopathy in a patient following acute aneurysmal subarachnoid hemorrhage that showed an "inverse" or reverse takotsubo pattern on echocardiography. CASE REPORT: The patient was a 46-year-old female who presented with acute cardiogenic shock following acute subarachnoid hemorrhage necessitating aggressive cardiorespiratory in the ICU. Her admission echo showed a depressed left ventricular ejection fraction of 25%. The basal 2/3 of the left ventricle (LV) was severely hypokinetic and the apical 1/3 of the LV was hypercontractile, i.e. the reverse or inverse takotsubo pattern of regional wall motion abnormality. With ongoing aggressive support her cardiovascular function steadily improved and on day 6 her follow up echo showed LV ejection fraction increased to 60-65% with resolution of the previous regional wall motion abnormality. The patient was discharged to a neuro-rehabilitation facility on day 16. SUMMARY: The "inverse" or "reverse" takotsubo pattern of regional wall motion abnormalities, i.e. with preserved apical LV contractility and hypokinesis of the basal walls of the LV is more common in patients following acute SAH. PMID- 23742228 TI - Nanoemulsion contrast agents with sub-picomolar sensitivity for xenon NMR. AB - A new type of contrast agent for Xe NMR based on surfactant-stabilized perfluorocarbon-in-water nanoemulsions has been produced. The contrast agent uses dissolved hyperpolarized xenon gas as a nonperturbing reporting medium, as xenon freely exchanges between aqueous solution and the perfluorocarbon interior of the droplets, which are spectroscopically distinguishable and allow for chemical exchange saturation transfer (CEST) detection of the agent. Nanoemulsions with droplet diameters between 160 and 310 nm were produced and characterized using hyperpolarized (129)Xe combined with CEST detection. Saturation parameters were varied and data were modeled numerically to determine the xenon exchange dynamics of the system. Nanoemulsion droplets were detected at concentrations as low as 100 fM, corresponding to <1 MUL of perfluorocarbon per liter of solution. The straightforward, inexpensive production of these agents will facilitate future development toward molecular imaging and chemical sensing applications. PMID- 23742230 TI - A possible prebiotic origin on volcanic islands of oligopyrrole-type photopigments and electron transfer cofactors. AB - Tetrapyrroles are essential to basic biochemical processes such as electron transfer and photosynthesis. However, it is not known whether these evolutionary old molecules have a prebiotic origin. We have serendipitously obtained pyrroles, which are the corresponding monomers, in laboratory experiments that simulated the interaction of amino acid-containing seawater with molten lava. The thermal pyrrole formation from amino acids, which so far has only been reported for special cases, can be explained by the observation that the amino acids become metal bonded, for example in (CaCl2)3(Hala)2.6H2O (Hala=DL-alanine), when the seawater evaporates. At a few hundred degrees Celsius, sea salt crusts also release hydrochloric acid (HCl). On primordial volcanic islands, the volatile pyrroles and HCl must have condensed at cooler locations, for example, in rock pools. There, pyrrole oligomerization may have occurred. To study this possibility, we added formaldehyde and nitrite, two species for which plausible prebiotic sources are known, to 2,4-diethylpyrrole and HCl. We found that even at high dilution conjugated (oxidized) oligomers, including octaethylporphyrin and other cyclic and open-chain tetrapyrroles, were formed. All experiments were conducted under rigorously oxygen-free conditions. Our results suggest that primitive versions of present-day biological cofactors such as chlorophylls, bilins, and heme were spontaneously abiotically synthesized on primordial volcanic islands and thus may have been available to the first protocells. PMID- 23742229 TI - Molecular hydrogen: an overview of its neurobiological effects and therapeutic potential for bipolar disorder and schizophrenia. AB - Hydrogen gas is a bioactive molecule that has a diversity of effects, including anti-apoptotic, anti-inflammatory and anti-oxidative properties; these overlap with the process of neuroprogression in major psychiatric disorders. Specifically, both bipolar disorder and schizophrenia are associated with increased oxidative and inflammatory stress. Moreover, lithium which is commonly administered for treating bipolar disorder has effects on oxidative stress and apoptotic pathways, as do valproate and some atypical antipsychotics for treating schizophrenia. Molecular hydrogen has been studied pre-clinically in animal models for the treatment of some medical conditions including hypoxia and neurodegenerative disorders, and there are intriguing clinical findings in neurological disorders including Parkinson's disease. Therefore, it is hypothesized that administration of hydrogen molecule may have potential as a novel therapy for bipolar disorder, schizophrenia, and other concurrent disorders characterized by oxidative, inflammatory and apoptotic dysregulation. PMID- 23742231 TI - Abiotic production of methane in terrestrial planets. AB - On Earth, methane is produced mainly by life, and it has been proposed that, under certain conditions, methane detected in an exoplanetary spectrum may be considered a biosignature. Here, we estimate how much methane may be produced in hydrothermal vent systems by serpentinization, its main geological source, using the kinetic properties of the main reactions involved in methane production by serpentinization. Hydrogen production by serpentinization was calculated as a function of the available FeO in the crust, given the current spreading rates. Carbon dioxide is the limiting reactant for methane formation because it is highly depleted in aqueous form in hydrothermal vent systems. We estimated maximum CH4 surface fluxes of 6.8*10(8) and 1.3*10(9) molecules cm(-2) s(-1) for rocky planets with 1 and 5 M?, respectively. Using a 1-D photochemical model, we simulated atmospheres with volume mixing ratios of 0.03 and 0.1 CO2 to calculate atmospheric methane concentrations for the maximum production of this compound by serpentinization. The resulting abundances were 2.5 and 2.1 ppmv for 1 M? planets and 4.1 and 3.7 ppmv for 5 M? planets. Therefore, low atmospheric concentrations of methane may be produced by serpentinization. For habitable planets around Sun like stars with N2-CO2 atmospheres, methane concentrations larger than 10 ppmv may indicate the presence of life. PMID- 23742232 TI - Synthesis of pyridine-fused perylene imides with an amidine moiety for hydrogen bonding. AB - Pyridine-fused perylene tetracarboxylic acid bisimides (PBIs) were synthesized via Suzuki-Miyaura coupling and acid condensation. The fused PBIs with electron donating substituents exhibited an intramolecular charge transfer interaction. One of the N-alkyl substituents was selectively removed with BBr3 to create an amidine guest binding site. A hydrogen bonding interaction with pentafluorobenzoic acid changed the absorption spectra and enhanced fluorescence. PMID- 23742233 TI - Preclinical investigations towards the first spacer gel application in prostate cancer treatment during particle therapy at HIT. AB - BACKGROUND: The application of spacer gel represents a promising approach to reliably spare the rectal frontal wall during particle therapy (IJROBP 76:1251 1258, 2010). In order to qualify the spacer gel for the clinical use in particle therapy, a variety of measurements were performed in order to ensure the biological compatibility of the gel, its physical stability during and after the irradiation, and a proper definition of the gel in terms of the Hounsfield Unit (HU) values for the treatment planning system. The potential for the use of the spacer gel for particle therapy monitoring with off-line Positron Emission Tomography (PET) was also investigated. RESULTS: The spacer gel implanted to the prostate patient in direct neighbourhood to the clinical target volume does not interfere with the particle therapy treatment planning procedure applied at Heidelberg Ion Beam Therapy Centre (HIT). The performed measurements show that Bragg-peak position of the particles can be properly predicted on the basis of computed tomography imaging with the treatment planning system used at HIT (measured water equivalent path length of 1.011 +/-0.011 (2sigma), measured Hounsfield Unit of 28.9 +/-6.1 (2sigma)). The spacer gel samples remain physically unchanged after irradiation with a dose exceeding the therapeutic dose level. The independently measured Bragg-Peak position does not change within the time interval of 10 weeks. CONCLUSIONS: As a result of the presented experiments, the first clinical application of spacer gel implant during prostate cancer treatment with carbon ions and protons was possible at HIT in 2012. The reported pre-clinical investigations demonstrate that use of spacer gel is safe in particle therapy in presence of therapy target motion and patient positioning induced particle range variations. The spacer gel injected between prostate and rectum enlarge the distance between both organs, which is expected to clinically significantly decrease the undesirable exposure of the most critical organ at risk, i.e. rectal frontal wall. Further research on the composition of spacer gel material might lead to additional clinical benefits by validation of particle therapy of prostate via post-therapeutic PET-imaging or by patient positioning based on the gel as a radio-opaque marker. PMID- 23742234 TI - Versatile electrochemiluminescent biosensor for protein-nucleic acid interaction based on the unique quenching effect of deoxyguanosine-5'-phosphate on electrochemiluminescence of CdTe/ZnS quantum dots. AB - In this paper, the efficient quenching effect of deoxyguanosine-5'-phosphate (dGMP) on anodic electrochemiluminescence (ECL) of the CdTe/ZnS quantum dots (QDs) is reported for the first time. This ECL quenching was found to be specific for free dGMP and not observed for dGMP residues in different DNA structures. The unique dGMP-based QDs ECL quenching was then utilized to develop a versatile biosensing strategy to determine various protein-DNA interactions with the assistance of exonuclease, Exo I, to hydrolyze DNA and liberate dGMP. Taking single-stranded DNA binding protein (SSB) and thrombin as examples, two novel detection modes have been developed based on dGMP-QDs ECL strategy. The first method used hairpin probes and SSB-promoted probe cleavage by Exo I for facile signal-off detection of SSB, with a wide linear range of 1-200 nM and a low detection limit of 0.1 nM. The second method exploited aptamer-thrombin binding to protect probes against Exo I degradation for sensitive signal-on detection of thrombin, giving a linear response over a range of 1-150 nM and a detection limit as low as 0.1 nM. Both methods were homogeneous and label-free without QDs or DNA modification. Therefore, this dGMP-specific QDs ECL quenching presents a promising detection mechanism suitable for probing various protein-nucleic acid interactions. PMID- 23742236 TI - Carry-over of veterinary drugs from medicated to non-medicated feeds in commercial feed manufacturing plants. AB - Different compound feeds have to be manufactured in the same production line. As a consequence, traces of the first produced feed may remain in the production and get mixed with the next feed batches. This "carry-over" is unavoidable, and so non-medicated feed can be contaminated with veterinary drugs like antibiotics added to the previous batch of medicated feed. To monitor the carry-over of antibiotics in the Netherlands, 21 feed mills were visited and 140 samples of flushing feeds were collected and analysed for containing residues of antibiotics. Results show that 87% of all samples contain concentrations of antibiotics in the range of 0.1-154 mg/kg. It is expected that these levels - which are in the same range as previously found for the nowadays banned antimicrobial growth promoters (AMGPs) - have an effect on the occurrence of microbial resistance. Analysis of a second set of samples collected at four different feed mills directly after the production of oxytetracycline-medicated feed demonstrated that the first part of a flushing feed has much higher contamination than the last part of the batch. Furthermore, it was demonstrated that the carry-over percentage shows no correlation with the carry-over determined by one of the standard GMP+ procedures. These observations, unavoidable carry-over, inhomogeneous batches of feed with antibiotics and difficulties to predict the carry-over levels, together with the awareness of the increasing problem of microbial resistance, motivated the NEVEDI, association of Dutch Feed Producers, to announce that they will voluntarily stop the production of medicated feed in 2011. The alternatives for medicated feed are for example water or milk medication or the use of top-dressings at the farm. The consequences and possible new risks of carry-over at the farm are not completely clear yet. PMID- 23742237 TI - The value of the hospital-based nurse practitioner role: development of a team perspective framework. AB - There is a need to understand nurse practitioner (NP) interprofessional practice within hospital teams to inform effective role integration and evolution. To begin this understanding a supplementary analysis of 30 hospital team member focus groups was carried out using constructivist grounded theory methodology. This conceptual rendering of the team members' shared perspective of NP actions provides insight into the meaning and importance of the NP role. Participants emphasized three hospital-based (HB) NP practice foci as the meaning of role value; easing others' workload, holding patient care together and evolving practice. Trust emerged as a pre-requisite condition for HB NP role efficacy. A team member perspective framework of HB NP practice is presented as the first stage in developing a model of HB NP interprofessional practice within hospitals. The framework provides multiple perspectives to the meaning and value of the HB NP role beyond basic role description. The framework may be used by healthcare professionals, operational leaders, academia and HB NPs to enhance role respect and understanding. PMID- 23742235 TI - Hypoxia, such as encountered at high altitude, promotes deep vein thrombosis in mice. PMID- 23742238 TI - iXora: exact haplotype inferencing and trait association. AB - BACKGROUND: We address the task of extracting accurate haplotypes from genotype data of individuals of large F1 populations for mapping studies. While methods for inferring parental haplotype assignments on large F1 populations exist in theory, these approaches do not work in practice at high levels of accuracy. RESULTS: We have designed iXora (Identifying crossovers and recombining alleles), a robust method for extracting reliable haplotypes of a mapping population, as well as parental haplotypes, that runs in linear time. Each allele in the progeny is assigned not just to a parent, but more precisely to a haplotype inherited from the parent. iXora shows an improvement of at least 15% in accuracy over similar systems in literature. Furthermore, iXora provides an easy-to-use, comprehensive environment for association studies and hypothesis checking in populations of related individuals. CONCLUSIONS: iXora provides detailed resolution in parental inheritance, along with the capability of handling very large populations, which allows for accurate haplotype extraction and trait association. iXora is available for non-commercial use from http://researcher.ibm.com/project/3430. PMID- 23742239 TI - Gambling and problem gambling in The Netherlands. AB - AIMS: To provide an overview of gambling in the Netherlands, focusing on historical background, policy, legislation, prevalence of problem gambling, availability of treatment options and research base. METHODS: Literature review. RESULTS: Contradictions between gambling policy and practice have been present in the past 15-20 years, and have led to an increasingly stricter gambling regulation to retain the government policy to restrict gambling within a national monopoly. Conversely, political efforts have been made to legalize internet gambling, but have not yet been approved. Compared to other European countries, slot machine gambling and casino gambling are relatively popular, whereas betting is relatively unpopular. Last-year problem gambling prevalence (South Oaks Gambling Screen score > 5) is estimated at 0.22-0.15% (2005, 2011). Treatment for problem gambling is covered by health insurance under the same conditions as substance dependence, but only a small proportion of Dutch problem gamblers seeks help at addiction treatment centres. CONCLUSIONS: Gambling policy in the Netherlands has become stricter during recent last years in order to maintain the Dutch gambling monopoly. Problem gambling in the Netherlands is relatively stable. Dutch research on problem gambling has a lack of longitudinal studies. Most of the epidemiological gambling studies are reported in non-peer-reviewed research reports, which diminishes control by independent peers on the methodology and interpretation of results. Recent efforts to enhance consistency in research methods between gambling studies over time could enhance knowledge on changes in (problem) gambling in the Netherlands. PMID- 23742241 TI - Synthesis of anatase TiO2 nanosheets with enhanced pseudocapacitive contribution for fast lithium storage. AB - Anatase TiO2 nanosheets (ATNs) are successfully prepared by a biomimetic layer-by layer titania mineralization approach, and the electrochemical performance of the ATNs as negative electrode for lithium-ion batteries is investigated by the galvanostatic chronopotentiometry and cyclic voltammetry. A high initial discharge capacity (311 mA h g(-1)) and initial Coulombic efficiency (81.7%) were obtained for ATNs, and capacities of 252, 202, 186, 158, 136, and 119 mA h g(-1) were obtained at 0.2, 1, 5, 10, 20, and 30 C, respectively. Particularly, the ATNs can still maintains a capacity of 108 mA h g(-1) after 4000 cycles at 30 C (only a capacity loss of 10%), which indicated a superior rate capabilities and cyclability. The CVs analysis revealed that the ANTs have both diffusive lithium storage in the bulk and pseudocapacitive lithium storage at the surface (also called interfacial lithium storage), and the pseudocapacitive lithium storage dominates the total capacity when the scan rates are above 1 mV s(-1). The fast and stable lithium storage of ATNs might be attributed to the high pseudocapacitive lithium storage contribution in the material, and it was suggested the pseudocapacitive lithium storage could occurred at grain-grain interfaces as well as nanosheet surfaces. PMID- 23742240 TI - Insulinotropic actions of the frog skin host-defense peptide alyteserin-2a: a structure-activity study. AB - Alyteserin-2a (ILGKLLSTAAGLLSNL.NH2 ) stimulated the rate of insulin release from BRIN-BD11 clonalbeta cells at a concentration of 30 nm (p < 0.05) with a response of 296 +/- 26% of basal release at 3 MUm (p < 0.001). The insulinotropic actions of analogs containing substitutions by l-lysine, d-lysine, or l-tryptophan at sites that maintain amphipathicity were evaluated. The [G11K], [S7k], [S7k,G11k], and [G11k,N15K] analogs were the most potent stimulating insulin release at 0.01 nm (p < 0.05). The [S7K], [G11K], [S14K], [N15K], [G11k], and [S7K,G11K] analogs were the most effective producing an approximately twofold greater (p < 0.001) release of insulin at 3 MUm compared with alyteserin-2a. The [T8W] and [A9W] analogs were less active than alyteserin-2a. No peptide-stimulated release of lactate dehydrogenase at concentrations up to 3 MUm, indicating that the integrity of the plasma membrane had been preserved. Membrane depolarization and an increase in intracellular Ca(2+) concentration are involved in the mechanism of action of the peptides. Administration of [G11k]alyteserin-2a (75 nmol/kg body weight) to high-fat-fed mice with obesity and insulin resistance significantly (p < 0.01) enhanced insulin release and improved glucose tolerance during the 60-min period following an intraperitoneal glucose load. PMID- 23742242 TI - Mortality of subjects with alcohol-related seizures increased after alcohol cheapening. AB - OBJECTIVE: To investigate whether the reduction of alcohol prices in Finland (March 1, 2004) associated with an increase in mortality of subjects with alcohol related seizures. PATIENTS AND METHODS: All subjects with head trauma in Oulu University Hospital during 1999 (n = 827) were identified and thereafter followed up until death or the end of 2009. We used National Hospital Discharge Register, hospital charts, and death records from Official Cause-of-Death Statistics to identify seizure visits and alcohol-related deaths. Kaplan-Meier survival curves were used to characterize the effect of alcohol price reduction on risk of death. Cox proportional hazards model was used to identify independent predictors of death. RESULTS: Twenty-five subjects had alcohol-related seizures before the alcohol price reduction. Their cumulative mortality rate was significantly higher (P = 0.015) than that of other head trauma subjects during the follow-up and it clearly increased after the price reduction. Age (HR 1.06 per year, 95% CI 1.05 1.07, P < 0.001), moderate-to-severe traumatic brain injury (HR 2.04 95% CI 1.37 3.04, P < 0.001), and alcohol-related seizure (HR 3.02, 95% CI 1.48-6.16, P = 0.002) were independent predictors of death after adjustment for confounding factors. CONCLUSION: We conclude that the political decision to lower alcohol price associated with a significant increase in the mortality rate of subjects with alcohol-related seizures. PMID- 23742243 TI - Prospective comparison of real-time tissue elastography and serum fibrosis markers for the estimation of liver fibrosis in chronic hepatitis C patients. AB - AIM: Real-time tissue elastography (RTE) is a non-invasive method for the measurement of tissue elasticity using ultrasonography. Liver fibrosis (LF) index is a quantitative method for evaluation of liver fibrosis calculated by RTE image features. This study aimed to investigate the significance of LF index for predicting liver fibrosis in chronic hepatitis C patients. METHODS: In this prospective study, 115 patients with chronic hepatitis C who underwent liver biopsy were included, and the diagnostic accuracy of LF index and serum fibrosis markers was evaluated. RESULTS: RTE imaging was successfully performed on all patients. Median LF index in patients with F0-1, F2, F3 and F4 were 2.61, 3.07, 3.54 and 4.25, respectively, demonstrating a stepwise increase with liver fibrosis progression (P < 0.001). LF index (odds ratio [OR] = 5.3, 95% confidence interval [CI] = 2.2-13.0) and platelet count (OR = 0.78, 95% CI = 0.68-0.89) were independently associated with the presence of advanced fibrosis (F3-4). Further, LF index was independently associated with the presence of minimal fibrosis (F0 1) (OR = 0.25, 95% CI = 0.11-0.55). The area under the receiver-operator curve (AUROC) of LF index for predicting advanced fibrosis (0.84) was superior to platelets (0.82), FIB-4 index (0.80) and aspartate aminotransferase/platelet ratio index (APRI) (0.76). AUROC of LF index (0.81) was superior to platelets (0.73), FIB-4 index (0.79) and APRI (0.78) in predicting minimal fibrosis. CONCLUSION: LF index calculated by RTE is useful for predicting liver fibrosis, and diagnostic accuracy of LF index is superior to serum fibrosis markers. PMID- 23742244 TI - Cardiac tamponade with only left heart collapse in a child with severe pulmonary artery hypertension. PMID- 23742245 TI - Expressing one's feelings and listening to others increases emotional intelligence: a pilot study of Asian medical students. AB - BACKGROUND: There has been considerable interest in Emotional Intelligence (EI) in undergraduate medical education, with respect to student selection and admissions, health and well-being and academic performance. EI is a significant component of the physician-patient relationship. The emotional well-being of the physician is, therefore, a significant component in patient care. The aim is to examine the measurement of TEIQue-SF in Asian medical students and to explore how the practice of listening to the feelings of others and expressing one's own feelings influences an individual's EI, set in the context of the emotional well being of a medical practitioner. METHODS: A group of 183 international undergraduate medical students attended a half-day workshop (WS) about mental health and well-being. They completed a self-reported measure of EI on three occasions, pre- and post-workshop, and a 1-year follow-up. RESULT: The reliability of TEIQue-SF was high and the reliabilities of its four factors were acceptable. There were strong correlations between the TEIQue-SF and personality traits. A paired t-test indicated significant positive changes after the WS for all students (n=181, p=.014), male students (n=78, p=.015) and non-Japanese students (n=112, p=.007), but a repeated measures analysis showed that one year post-workshop there were significant positive changes for all students (n=55, p=.034), female students (n=31, p=.007), especially Japanese female students (n=13, p=.023). Moreover, 80% of the students reported that they were more attentive listeners, and 60% agreed that they were more confident in dealing with emotional issues, both within themselves and in others, as a result of the workshop. CONCLUSION: This study found the measurement of TEIQue-SF is appropriate and reliable to use for Asian medical students. The mental health workshop was helpful to develop medical students' EI but showed different results for gender and nationality. The immediate impact on the emotional awareness of individuals was particularly significant for male students and the non-Japanese group. The impact over the long term was notable for the significant increase in EI for females and Japanese. Japanese female students were more conscious about emotionality. Emotion-driven communication exercises might strongly influence the development of students' EI over a year. PMID- 23742247 TI - Identification of thresholds for dichotomizing DNA methylation data. AB - : DNA methylation plays an important role in many biological processes by regulating gene expression. It is commonly accepted that turning on the DNA methylation leads to silencing of the expression of the corresponding genes. While methylation is often described as a binary on-off signal, it is typically measured using beta values derived from either microarray or sequencing technologies, which takes continuous values between 0 and 1. If we would like to interpret methylation in a binary fashion, appropriate thresholds are needed to dichotomize the continuous measurements. In this paper, we use data from The Cancer Genome Atlas project. For a total of 992 samples across five cancer types, both methylation and gene expression data are available. A bivariate extension of the StepMiner algorithm is used to identify thresholds for dichotomizing both methylation and expression data. Hypergeometric test is applied to identify CpG sites whose methylation status is significantly associated to silencing of the expression of their corresponding genes. The test is performed on either all five cancer types together or individual cancer types separately. We notice that the appropriate thresholds vary across different CpG sites. In addition, the negative association between methylation and expression is highly tissue specific. PMID- 23742246 TI - Structural and energetic basis of carbohydrate-aromatic packing interactions in proteins. AB - Carbohydrate-aromatic interactions mediate many biological processes. However, the structure-energy relationships underpinning direct carbohydrate-aromatic packing interactions in aqueous solution have been difficult to assess experimentally and remain elusive. Here, we determine the structures and folding energetics of chemically synthesized glycoproteins to quantify the contributions of the hydrophobic effect and CH-pi interactions to carbohydrate-aromatic packing interactions in proteins. We find that the hydrophobic effect contributes significantly to protein-carbohydrate interactions. Interactions between carbohydrates and aromatic amino acid side chains, however, are supplemented by CH-pi interactions. The strengths of experimentally determined carbohydrate CH-pi interactions do not correlate with the electrostatic properties of the involved aromatic residues, suggesting that the electrostatic component of CH-pi interactions in aqueous solution is small. Thus, tight binding of carbohydrates and aromatic residues is driven by the hydrophobic effect and CH-pi interactions featuring a dominating dispersive component. PMID- 23742248 TI - Biotin-responsive basal ganglia disease should be renamed biotin-thiamine responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases. AB - BACKGROUND: Biotin-responsive basal ganglia disease (BBGD) is an autosomal recessive neurometabolic disorder. It is characterized by sub acute encephalopathy with confusion, seizure, dysarthria and dystonia following a history of febrile illness. If left untreated with biotin, the disease can progress to severe quadriparesis and even death. METHOD: A retrospective chart review of 18 patients with BBGD from two tertiary institutions describing their clinical, magnetic resonance imaging and molecular findings was conducted. RESULT: Eighteen children from 13 families seen over a period of nine years (2003 2012) were included. (Age range: 14month to 23 years, M: F: 1:1). The clinical features included sub acute encephalopathy, ataxia (n= 18), seizures (n= 13) dystonia (n=12) ,dysarthria (n= 9), quadriparesis and hyperreflexia (n=9). Magnetic resonance imaging demonstrated abnormal signal intensity with swelling in the basal ganglia during acute crises (n= 13/13) and atrophy of the basal ganglia and necrosis during follow up (n= 13/13). One-third of the present patients showed the recurrence of acute crises while on biotin therapy alone, but after the addition of thiamine, crises did not recur. All of the patients have a homozygous missense mutation in exon 5 of the SLC19A3 gene. The frequency of acute crises, delay in diagnosis and initiation of treatment significantly influenced the outcome. On follow up, four patients died, two had spastic quadriplegia, six had normal outcome and the rest had speech and motor dysfunctions. CONCLUSION: Clinicians should suspect BBGD in any child presenting with sub acute encephalopathy, abnormal movement and MRI findings as described above. Both biotin and thiamine are essential for disease management. Since biotin alone could not prevent the recurrence of crises in some patients, a more appropriate term to describe the disease would be biotin-thiamine-responsive basal ganglia disease (BTBGD). PMID- 23742249 TI - Synthesis and conformational dynamics of the reported structure of xylopyridine A. AB - Natural products have served as a rich source for the discovery of new nucleic acid targeting molecules for more than half a century. However, our ability to design molecules that bind nucleic acid motifs in a sequence- and/or structure selective manner is still in its infancy. Xylopyridine A, a naturally occurring molecule of unprecedented architecture, has been found to bind DNA by a unique mode of intercalation. Here we show that the structure proposed for xylopyridine A is not consistent with the characterization in the original isolation report and does not bind B-form DNA. Instead, we report that the originally proposed structure for xylopyridine A represents a new class of conformationally dynamic structure-selective quadruplex nucleic acid binder. The unique molecular conformation locks out nonspecific intercalative binding modes and provides a starting point for the design of a new class of structure-specific nucleic acid binder. PMID- 23742250 TI - 2-(2'-Hydroxyphenyl)benzimidazole and 9,10-phenanthroimidazole chelates and borate complexes: solution- and solid-state emitters. AB - The synthesis, structural, and optical properties of a series of luminescent N alkylated 2-(2'-hydroxyphenyl)benzimidazole (HBI) or N-arylated 9,10 phenanthroimidazole (HPI) borate complexes are described. The optical properties of these complexes as well as their corresponding ligands were evaluated in solution and the solid state. Efficient emission in the blue-green region was obtained with quantum yields up to 91% in CH2Cl2 and 27% in the solid state. These emissions originate from excited state intramolecular proton transfer (ESIPT) for the ligands and from a singlet excited state for the borate complexes. PMID- 23742251 TI - Plastic, fantastic! Phenotypic variance in the transcriptional landscape of the grape berry. AB - Evaluation of the common grapevine Vitis vinifera across multiple harvests and field locations provides important insights into crop transcriptional plasticity under diverse agricultural regimes. PMID- 23742252 TI - Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2 isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2 (isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. AB - The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients. PMID- 23742254 TI - American Thyroid Association statement on outpatient thyroidectomy. AB - BACKGROUND: The primary goals of this interdisciplinary consensus statement are to define the eligibility criteria for outpatient thyroidectomy and to explore preoperative, intraoperative, and postoperative factors that should be considered in order to optimize the safe and efficient performance of ambulatory surgery. SUMMARY: A series of criteria was developed that may represent relative contraindications to outpatient thyroidectomy, and these fell into the following broad categories: clinical, social, and procedural issues. Intraoperative factors that bear consideration are enumerated, and include choice of anesthesia, use of nerve monitoring, hemostasis, management of the parathyroid glands, wound closure, and extubation. Importantly, postoperative factors are described at length, including suggested discharge criteria and recognition of complications, especially bleeding, airway distress, and hypocalcemia. CONCLUSIONS: Outpatient thyroidectomy may be undertaken safely in a carefully selected patient population provided that certain precautionary measures are taken to maximize communication and minimize the likelihood of complications. PMID- 23742253 TI - The inter-association task force for preventing sudden death in secondary school athletics programs: best-practices recommendations. PMID- 23742255 TI - Uncertainty of international sensitivity index and international normalized ratio. PMID- 23742256 TI - Mitochondria protection with ginkgolide B-loaded polymeric nanocapsules prevents diethylnitrosamine-induced hepatocarcinoma in rats. AB - AIM: Hepatocellular carcinoma (HCC) has no successful pharmacotherapeutic remedy. The aim of this study was to ascertain whether ginkgolide B (GB)-loaded polymeric nanocapsules can prevent diethylnitrosamine (DEN)-induced HCC in rats. MATERIALS & METHODS: GB was fabricated in two types of nanocapsules of which one was polyethylene glycol coated (N1GB) and the other was uncoated (N2GB). These nanocapsules were orally gavaged during DEN-induced HCC development in rats. RESULTS: Nanocapsulation of GB enabled aqueous suspension and slow time-dependent release of the compound. Anticarcinogenic potential of N2GB was reflected by its ability in the management of DEN-induced reactive oxygen species generation, mitochondrial dysfunction, p53, NF-kappaB, inducible nitric oxide synthase, COX-2 and VEGF expressions, and induction of apoptosis in cancer cells in the rat liver. CONCLUSION: Positive zeta-potential on N2GB surface might have offered higher hepatic accumulation of GB, especially at the electron-dense organelle mitochondria. Mitochondria protection against DEN-induced oxidative damage ensured HCC prevention. PMID- 23742258 TI - Detection of new mutant sites of HIV-1 coreceptor CCR5 among Saudi populations. AB - The genetic association of CCR5 with human immunodeficiency virus-1 (HIV-1) pathogenesis is well known. The HIV-1 entry into target cells is initiated by the binding of the viral envelope glycoproteins (gp120-gp41) with the cell surface receptor (CD4) and the coreceptor (CCR5), followed by fusion of the viral and cell membranes. Genetic variants of the gene-encoding HIV-1 coreceptor are implicated in the susceptibility to HIV-1 infection. The prevalence of these mutations may vary according to population ethnicity. In the current study, characterization and frequency distribution of the HIV-related gene variants in 135 samples of the Saudi populations were conducted. Polymerase chain reaction (PCR) of 276 bp amplicons was used to rapidly detect Delta32 deletion in the initial sample of DNA. The direct sequence of 2 overlapping PCR amplicons flanking 1,059 bp was used to detect single-nucleotide polymorphisms. A single hetrozygous Delta32 deletion allele and 6 single-nucleotide polymorphisms were detected. Only one of the identified haplotypes, Taif-1, which was found in the majority of the tested sample, is identical to CCR5 wild-type alleles. Furthermore, the results of this study raised a concern about the prospective role of the mutations detected among Saudi nationals in the HIV pathogenesis and the clinical use of CCR5 antagonists, which are currently being developed as therapeutics for HIV-1 and inflammatory diseases. PMID- 23742259 TI - Rapid analysis of single droplets of lanthanide-ligand solutions by electrospray ionization mass spectrometry using an induction-based fluidics source. AB - Electrospray ionization mass spectra of lanthanide coordination complexes were measured by launching nanoliter-sized droplets directly into the aperture of an electrospray ionization mass spectrometer. Droplets ranged in size from 102 nL to 17 nL, while metal concentrations were 293 MUM. The sample solution was delivered to a source capillary by a nanoliter dispenser at a rate of 21 nL/s, and droplets were ejected from the capillary by pulsing a potential onto the capillary. The end of the capillary was situated in front of the mass spectrometer and aimed directly at the aperture. The period and power of the electrical pulse was controlled by a digital energy source. The intensity of the extracted ion time profiles from the experiment showed reproducible production of lanthanide nitrato anion complexes (Ce, Tb, and Lu). The integrated ion intensities of the complexes were reproducible, having relative standard deviations on the order 10% for anions, and 10-30% for cations. The integrated ion intensities were proportional to the droplet size, and the response was linear from about 100 to 650 pmol. However, the intercept is not zero, indicating a nonlinear response at lower analyte quantities or droplet sizes. Cation complexes were generated in separate experiments that corresponded to lanthanide nitrate ion pairs coordinated with the separations ligand octyl,phenyl,(N,N-diisobutylcarbamoyl)methylphosphine oxide (CMPO). Experiments showed a preference for formation of CMPO complexes with Ln(3+) having larger ionic radii. The relative standard deviation values of the cation abundance measurements were somewhat higher for the more highly coordinated complexes, which are also less stable. The mass spectral quality was high enough to measure the ratios of the minor isotopic ions to a high degree of accuracy. The approach suggests that the methodology has utility for analysis of solutions where the sample quantity is limited, or where the sampling efficiency of a normal ESI source is limiting on account of hazards derived from the sample solution. PMID- 23742261 TI - Fabrication and evaluation of magnetic/hollow double-shelled imprinted sorbents formed by Pickering emulsion polymerization. AB - Magnetic/hollow double-shelled imprinted polymers (MH-MIPs) were synthesized by Pickering emulsion polymerization. In this method, attapulgite (ATP) particles were used as stabilizers to establish a stable oil-in-water emulsion, and a few hydrophilic Fe3O4 nanoparticles were allowed to be magnetic separation carriers. The imprinting system was fabricated by radical polymerization in the presence of the functional and polymeric monomers in the oil phase. The results of characterization indicated that MH-MIPs exhibited magnetic sensitivity (Ms = 4.76 emu g(-1)), thermal stability (especially below 200 degrees C), and hollow structure and were composed of exterior ATP shells and interior imprinted polymers shells. Then MH-MIPs were evaluated as sorbents for the selective binding of lambda-cyhalothrin as a result of their magnetism, enhanced mechanical strength, hydrophilic surface, and recognition ability. The kinetic properties of MH-MIPs were well described by the pseudo-second-order equation, indicating that the chemical process could be the rate-limiting step in the adsorption process for lambda-cyhalothrin. The equilibrium adsorption capacity of MH-MIPs was 60.06 MUmol g(-1) at 25 degrees C, and the Langmuir isotherm model gave a better fit to the experimental data, indicating the monolayer molecular adsorption for lambda-cyhalothrin. The selective recognition experiments also demonstrated the high affinity and selectivity of MH-MIIPs toward lambda-cyhalothrin over fenvalerate and diethyl phthalate. PMID- 23742260 TI - Novel membrane frizzled-related protein gene mutation as cause of posterior microphthalmia resulting in high hyperopia with macular folds. AB - PURPOSE: We present a genetic and clinical analysis of two sisters, 3 and 4 years of age, with nanophthalmos and macular folds. METHODS: Ophthalmological examination, general paediatric examination and molecular genetic analysis of the MFRP gene were performed in both affected siblings. RESULTS: Clinical analysis showed high hyperopia (+11 D and +12 D), short axial lengths (15 mm) and the presence of macular folds and optic nerve head drusen. Autofluorescence of the retina was generally normal with subtle macular abnormalities. Sequence analysis showed compound heterozygosity for severe MFRP mutations in both sisters: a previously reported p.Asn167fs (c.498dupC) and a novel stop codon mutation p.Gln91X (c.271C>T). CONCLUSION: These are the youngest nanophthalmos patients in the literature identified with severe loss of MFRP function, showing already the known structural abnormalities for this disease. Adult patients affected by homozygous or compound heterozygous MFRP mutations generally show signs of retinal dystrophy, with ERG disturbances and RPE abnormalities on autofluorescence imaging. ERG examination could not be performed in these children, but extensive RPE abnormalities were not seen at this young age. PMID- 23742262 TI - A multicentre survey of hepatitis C awareness in a high-risk population. AB - AIMS: To assess the awareness of hepatitis C virus (HCV) infection status in a high-risk population. METHODS: A targeted population survey of clients of methadone maintenance clinics in metropolitan and rural New South Wales, using an interviewer-administered face-to-face questionnaire. Main outcome measures include awareness of HCV status, time elapsed since last tested and children's HCV status. RESULTS: A total of 329 clients completed the survey, of which 97% perceived to have been tested for HCV in the past. One hundred and seventy (52%) participants considered themselves to be negative for HCV. Of these the median time since last tested was 2 years (2 weeks-25 years). Although 94% of all parents believed that their child's HCV status was negative, only 49% of respondents stated that their children had been tested for HCV. Voluntary testing was offered to all clients and their children with only one accepting. CONCLUSIONS: Awareness of HCV infection status in this high-risk population is suboptimal. This indicates that existing educational strategies are inadequate and that there is a disconnect between their health needs and the medical care they receive. Novel approaches need to be considered to improve the knowledge of HCV transmission and hopefully improve HCV-associated health outcomes in high risk populations. PMID- 23742263 TI - Toll-like receptors 3, 4 and 9 in hepatocellular carcinoma: Relationship with clinicopathological characteristics and prognosis. AB - AIM: Hepatocellular carcinoma (HCC) is in the 10 leading cancer types, being difficult to detect as most of patients who develop this tumor have no symptoms other than those related to their long-standing liver disease. The liver is constantly exposed to bacterial products, viral infection, alcohol or other products, which may be the cause of chronic liver damage, and thus an increasing risk for HCC. Toll-like receptors (TLR) have gained an extraordinary interest in cancer research due to their role in several biological processes such as innate immune responses, the induction of adaptive immune responses, regulation of inflammation, would healing and carcinogenesis. Therefore, the aim of this study was to investigate the expression and clinical relevance of TLR3, 4 and 9 in HCC. METHODS: The expression levels of TLR3, TLR4 and TLR9 were analyzed in tumors from 30 patients with HCC. The analysis was performed by immunohistochemistry. Results were correlated with various clinicopathological findings and with overall survival. RESULTS: TLR3 was significantly high in large tumors (>4 cm in diameter) compared with small tumors (P < 0.05). Our results demonstrated that patients whose tumors showed both TLR4 and TLR9 positive immunostaining had poor prognosis. In addition, TLR9 expression by fibroblast-like cells was significantly associated with a shortened overall survival (P = 0.015). CONCLUSION: The results demonstrated an association between TLR3, TLR4 and TLR9 expression and tumor aggressiveness and poor prognosis in HCC. PMID- 23742265 TI - Investigating the use of patient involvement and patient experience in quality improvement in Norway: rhetoric or reality? AB - BACKGROUND: Patient involvement in health care decision making is part of a wider trend towards a more bottom-up approach to service planning and provision, and patient experience is increasingly conceptualized as a core dimension of health care quality.The aim of this multi-level study is two-fold: 1) to describe and analyze how governmental organizations expect acute hospitals to incorporate patient involvement and patient experiences into their quality improvement (QI) efforts and 2) to analyze how patient involvement and patient experiences are used by hospitals to try to improve the quality of care they provide. METHODS: This multi-level case study combines analysis of national policy documents and regulations at the macro level with semi-structured interviews and non participant observation of key meetings and shadowing of staff at the meso and micro levels in two purposively sampled Norwegian hospitals. Fieldwork at the meso and micro levels was undertaken over a 12-month period (2011-2012). RESULTS: Governmental documents and regulations at the macro level demonstrated wide ranging expectations for the integration of patient involvement and patient experiences in QI work in hospitals. The expectations span from systematic collection of patients' and family members' experiences for the purpose of improving service quality through establishing patient-oriented arenas for ongoing collaboration with staff to the support of individual involvement in decision making. However, the extent of involvement of patients and application of patient experiences in QI work was limited at both hospitals. Even though patient involvement was gaining prominence at the meso level - and to a lesser extent at the micro level - relevant tools for measuring and using patient experiences in QI work were lacking, and available measures of patient experience were not being used meaningfully or systematically. CONCLUSIONS: The relative lack of expertise in Norwegian hospitals of adapting and implementing tools and methods for improving patient involvement and patient experiences at the meso and micro levels mark a need for health care policymakers and hospital leaders to learn from experiences of other industries and countries that have successfully integrated user experiences into QI work. Hospital managers need to design and implement wider strategies to help their staff members recognize and value the contribution that patient involvement and patient experiences can make to the improvement of healthcare quality. PMID- 23742266 TI - Efficient enantioselective synthesis of dihydropyrans using a chiral N,N'-dioxide as organocatalyst. AB - The bifunctional organocatalyst C3 N,N'-dioxide has been successfully applied to the asymmetric cascade Michael/hemiacetalization reaction of alpha-substituted cyano ketones and beta,gamma-unsaturated alpha-ketoesters for the synthesis of multifunctionalized chiral dihydropyrans. The corresponding products were obtained in excellent yields (up to 99%) with high to excellent enantioselectivities (up to 99% ee). PMID- 23742267 TI - Chemical synthesis of 1'-deoxy-1'-fluorosucrose. AB - The first chemical synthesis of 1'-deoxy-1'-fluorosucrose has been accomplished in eight steps from sucrose by an unlikely, but ultimately successful, SN2 displacement reaction. PMID- 23742268 TI - Statistical ensemble analysis for simulating extrinsic noise-driven response in NF-kappaB signaling networks. AB - BACKGROUND: Gene expression profiles and protein dynamics in single cells have a large cell-to-cell variability due to intracellular noise. Intracellular fluctuations originate from two sources: intrinsic noise due to the probabilistic nature of biochemical reactions and extrinsic noise due to randomized interactions of the cell with other cellular systems or its environment. Presently, there is no systematic parameterization and modeling scheme to simulate cellular response at the single cell level in the presence of extrinsic noise. RESULTS: In this paper, we propose a novel statistical ensemble method to simulate the distribution of heterogeneous cellular responses in single cells. We capture the effects of extrinsic noise by randomizing values of the model parameters. In this context, a statistical ensemble is a large number of system replicates, each with randomly sampled model parameters from biologically feasible intervals. We apply this statistical ensemble approach to the well studied NF-kappaB signaling system. We predict several characteristic dynamic features of NF-kappaB response distributions; one of them is the dosage-dependent distribution of the first translocation time of NF-kappaB. CONCLUSION: The distributions of heterogeneous cellular responses that our statistical ensemble formulation generates reveal the effect of different cellular conditions, e.g., effects due to wild type versus mutant cells or between different dosages of external stimulants. Distributions generated in the presence of extrinsic noise yield valuable insight into underlying regulatory mechanisms, which are sometimes otherwise hidden. PMID- 23742269 TI - Reduced brain corticotropin-releasing factor receptor activation is required for adequate maternal care and maternal aggression in lactating rats. AB - The brain corticotropin-releasing factor (CRF) system triggers a variety of neuroendocrine and behavioural responses to stress. Whether maternal behaviour and emotionality in lactation are modulated by CRF has rarely been investigated. In the present study, we measured CRF mRNA expression within the parvocellular part of the paraventricular nucleus in virgin and lactating Wistar rats bred for high (HAB) and low (LAB) anxiety-related behaviour or non-selected for anxiety (NAB). Further, we intracerebroventricularly infused synthetic CRF or the CRF receptor (CRF-R) antagonist D-Phe to manipulate CRF-R1/2 non-specifically in lactating HAB, LAB, and NAB dams, and monitored maternal care, maternal motivation, maternal aggression, and anxiety. The CRF mRNA expression in the parvocellular part of the paraventricular nucleus was higher in HAB vs. LAB rats independent of reproductive status. The lactation-specific decrease of CRF mRNA was confirmed in LAB and NAB dams but was absent in HAB dams. Intracerebroventricular CRF decreased maternal care under basal conditions in the home cage in all breeding lines and reduced attack behaviour in HAB and LAB dams during maternal defence. In contrast, D-Phe rescued maternal care after exposure to maternal defence in the home cage without influencing maternal aggression. Furthermore, D-Phe decreased and CRF tended to increase anxiety in HAB/NAB and LAB dams, respectively, suggesting an anxiogenic effect of CRF in lactating females. In conclusion, low CRF-R activation during lactation is an essential prerequisite for the adequate occurrence of maternal behaviour. PMID- 23742270 TI - Epilepsy surgery in children with drug-resistant epilepsy, a long-term follow-up. AB - OBJECTIVES: In this follow-up study, we wanted to present the long-term outcome (5-21 years) in terms of seizure freedom, seizure reduction, and the cognitive development in the first 47 children who underwent epilepsy surgery at the University Hospital in Lund from 1991 to 2007. MATERIALS AND METHODS: All children who underwent epilepsy surgery in the southern region of Sweden were assessed for cognitive function before surgery and at follow-up. A review of medical documents for demographic data and seizure-related characteristics was made by retrospectively examining the clinical records. RESULTS: Forty-seven children with a median age at surgery of 8 years (range 0.5-18.7 years) were included. Twenty-three children achieved seizure freedom, six demonstrated >75% improvement in seizure frequency, and none of the children experienced an increase in seizure frequency. Twenty-one children required a reoperation to achieve satisfactory seizure outcomes. Cognitive functional level was preserved, and the majority of patients, 34 (76%), followed their expected cognitive trajectory. The patients who became seizure free significantly improved their cognitive processing speed, even after long-term follow-up. CONCLUSIONS: Epilepsy surgery in children offers suitable candidates a good chance of significantly improved outcome and low rates of complications. Several children, however, required a reoperation to achieve satisfactory seizure outcomes. Cognitive level was preserved, and the majority of patients followed their expected cognitive trajectory. Cognitive improvements in processing speed appear to occur in parallel with seizure control and were even more pronounced in subjects with no anti-epilepsy drugs. These improvements persisted even after long-term follow-up. PMID- 23742271 TI - Altered mitral inflow orifice in severe aortic regurgitation: real time three dimensional echocardiographic findings. AB - We present the case of a young man with severe eccentric aortic regurgitation, obstructing mitral inflow and provoking an audible Austin Flint murmur at clinical examination. Two-dimensional color Doppler echocardiography depicts the remarkable mechanical interaction between aortic regurgitant jet and anterior mitral leaflet opening. Three-dimensional transesophageal echocardiography aids in understanding the geometric and hemodynamic consequences of the regurgitant jet and in the genesis of the Austin Flint murmur. This case accentuates the incremental value of three-dimensional echocardiography when evaluating valvular pathology, and offers more insight in the interaction between aortic regurgitant flow and mitral leaflet dynamics. PMID- 23742272 TI - PARP inhibitor with selectivity toward ADP-ribosyltransferase ARTD3/PARP3. AB - Inhibiting ADP-ribosyl transferases with PARP-inhibitors is considered a promising strategy for the treatment of many cancers and ischemia, but most of the cellular targets are poorly characterized. Here, we describe an inhibitor of ADP-ribosyltransferase-3/poly(ADP-ribose) polymerase-3 (ARTD3), a regulator of DNA repair and mitotic progression. In vitro profiling against 12 members of the enzyme family suggests selectivity for ARTD3, and crystal structures illustrate the molecular basis for inhibitor selectivity. The compound is active in cells, where it elicits ARTD3-specific effects at submicromolar concentration. Our results show that by targeting the nicotinamide binding site, selective inhibition can be achieved among the closest relatives of the validated clinical target, ADP-ribosyltransferase-1/poly(ADP-ribose) polymerase-1. PMID- 23742275 TI - Interventional effects of plumbagin on experimental ulcerative colitis in mice. AB - Plumbagin (1) is a naphthoquinone constituent of plants that have been used in traditional systems of medicine since ancient times. In the present study, the role of 1 was examined on the amelioration of ulcerative colitis, an inflammatory bowel disease that is not curable currently. Plumbagin was tested at a dose of 6 10 mg/kg body weight in acute and chronic disease models. Diseased mice receiving 1 at 8-10 mg/kg demonstrated a significant suppression of disease symptoms in both models. However, body weight loss was not restored in either of the models. Levels of proinflammatory cytokines (TNF-alpha, IFN-gamma, and IL-17) were reduced significantly by 1 in mice suffering from chronic disease, while cytokine levels remained unaffected in mice with acute disease. However, the percentage of inflammatory (CD14+/CD16+) monocytes present in peripheral blood was significantly reduced by >3-fold (p < 0.05) in treatment groups relative to controls in the acute model. Histological evaluations exhibited the restoration of goblet cells, crypts, and the submucosa along with a significant reduction in monocyte aggregation in colon sections from mice receiving treatment with 1. Restoration in colon size was also observed in the treatment groups. PMID- 23742274 TI - B cell homeostasis is disturbed by immunosuppressive therapies in patients with ANCA-associated vasculitides. AB - B-lymphocytes play a pivotal role in ANCA-associated vasculitides (AAV). The homeostasis of peripheral human B-lymphocyte subpopulations is tightly regulated, but may be disturbed in autoimmune disease or following immunosuppressive therapies. To elucidate the effect of immunosuppression and the relevance of B lymphocyte disturbances, the B-lymphocyte compartment was analysed in 61 AAV patients. After immunosuppressive treatment a general B-lymphocytopenia developed in AAV patients. Within the B-lymphocyte subpopulations transitional B cells are the first maturation stage found in the peripheral blood. Transitional B lymphocytes were significantly lower in AAV patients after immunosuppressive therapy compared to healthy controls. Furthermore, marginal zone B cells--a B lymphocyte population protecting against encapsulated bacteria--were markedly lowered after immunosuppressive therapy in AAV patients. AAV patients treated with immunosuppressants had lower numbers of naive and memory B-lymphocytes. Numbers of marginal zone B cells, memory B cells and plasmablasts correlated with concentrations of immunoglobulins. We evaluated plasmablasts for a potential correlation with disease activity. Different from what has been reported for e.g. large vessel vasculitis, absolute numbers of plasmablasts were not increased in patients with AAV and showed no correlation to disease activity. As low transitional B cells after treatment with immunosuppressants indicated an impaired early B-lymphocyte development, seven patients treated with the B cell depleting agent rituximab (RTX) because of relapsing disease activity were analysed for their B cell repopulation kinetics. In the majority of these patients repopulation of the peripheral B cell compartment by newly formed transitional B cells after RTX treatment was constricted and delayed. PMID- 23742273 TI - Time-dependent changes in gene expression induced by secreted amyloid precursor protein-alpha in the rat hippocampus. AB - BACKGROUND: Differential processing of the amyloid precursor protein liberates either amyloid-beta, a causative agent of Alzheimer's disease, or secreted amyloid precursor protein-alpha (sAPPalpha), which promotes neuroprotection, neurotrophism, neurogenesis and synaptic plasticity. The underlying molecular mechanisms recruited by sAPPalpha that underpin these considerable cellular effects are not well elucidated. As these effects are enduring, we hypothesised that regulation of gene expression may be of importance and examined temporally specific gene networks and pathways induced by sAPPalpha in rat hippocampal organotypic slice cultures. Slices were exposed to 1 nM sAPPalpha or phosphate buffered saline for 15 min, 2 h or 24 h and sAPPalpha-associated gene expression profiles were produced for each time-point using Affymetrix Rat Gene 1.0 ST arrays (moderated t-test using Limma: p < 0.05, and fold change +/- 1.15). RESULTS: Treatment of organotypic hippocampal slice cultures with 1 nM sAPPalpha induced temporally distinct gene expression profiles, including mRNA and microRNA associated with Alzheimer's disease. Having demonstrated that treatment with human recombinant sAPPalpha was protective against N-methyl d-aspartate-induced toxicity, we next explored the sAPPalpha-induced gene expression profiles. Ingenuity Pathway Analysis predicted that short-term exposure to sAPPalpha elicited a multi-level transcriptional response, including upregulation of immediate early gene transcription factors (AP-1, Egr1), modulation of the chromatin environment, and apparent activation of the constitutive transcription factors CREB and NF-kappaB. Importantly, dynamic regulation of NF-kappaB appears to be integral to the transcriptional response across all time-points. In contrast, medium and long exposure to sAPPalpha resulted in an overall downregulation of gene expression. While these results suggest commonality between sAPPalpha and our previously reported analysis of plasticity-related gene expression, we found little crossover between these datasets. The gene networks formed following medium and long exposure to sAPPalpha were associated with inflammatory response, apoptosis, neurogenesis and cell survival; functions likely to be the basis of the neuroprotective effects of sAPPalpha. CONCLUSIONS: Our results demonstrate that sAPPalpha rapidly and persistently regulates gene expression in rat hippocampus. This regulation is multi-level, temporally specific and is likely to underpin the neuroprotective effects of sAPPalpha. PMID- 23742277 TI - Evaluation of intracavity optogalvanic spectroscopy for radiocarbon measurements. AB - Ever since the first publication of intracavity optogalvanic spectroscopy (ICOGS) in 2008, this novel technique for measuring the (14)C/(12)C ratio in carbon dioxide has rendered considerable attention. As a result, there are currently at least five different research groups pursuing research on ICOGS. With a claimed limit of detection of 10(-15) ((14)C/(12)C), i.e., in the same order as accelerator mass spectroscopy, achieved with a relatively inexpensive and uncomplicated table-top system, ICOGS has major scientific and commercial implications. However, during the past 5 years, no research group has been able to reproduce these results or present additional proof for ICOGS's capability of unambiguous (14)C detection, including the authors of the original publication. Starting in 2010, our group has set up a state-of-the-art ICOGS laboratory and has investigated the basic methodology of ICOGS in general and tried to reproduce the reported experiments in particular. We have not been able to reproduce the reported results concerning the optogalvanic signals dependence on (14)C concentration and wavelength and, ultimately, not seen any evidence of the capability of ICOGS to unambiguously detect (14)C at all. Instead, we have found indications that the reported results can be products of measurement uncertainties and mistakes. Furthermore, our results strongly indicate that the reported limit of detection is likely to be overestimated by at least 2 orders of magnitude, based on the results presented in the original publication. Hence, we conclude that the original reports on ICOGS cannot be confirmed and therefore must be in error. PMID- 23742276 TI - A genome-wide association study to detect genetic variation for postpartum dysgalactia syndrome in five commercial pig breeding lines. AB - Postpartum dysgalactia syndrome (PDS) in sows is an important disease after parturition with a relevant economic impact, affecting the health and welfare of both sows and piglets. The genetic background of this disease has been discussed and its heritability estimated, but further genetic analyses are lacking in detail. The aim of the current study was to detect loci affecting the susceptibility to PDS through a genome-wide association approach. The study was designed as a family-based association study with matched sampling of affected sows and healthy half- or full-sib control sows on six farms. For the study, 597 sows (322 affected vs. 275 healthy control sows) were genotyped on 62 163 single nucleotide polymorphisms (SNPs) using the Illumina PorcineSNP60 BeadChip. After quality control, 585 sows (314 affected vs. 271 healthy control sows) and 49 740 SNPs remained for further analysis. Statistics were performed mainly with the r package genabel and included a principal component analysis. A statistically significant genome-wide associated SNP was identified on porcine chromosome (SSC) 17. Further promising results with moderate significance were detected on SSC 13 and on an unplaced scaffold with an older annotation on SSC 15. The PRICKLE2 and NRP2 genes were identified as candidate genes near associated SNPs. Several quantitative trait loci (QTL) have been previously described in these genomic regions, including QTL for mammary gland condition, as teat number and non functional nipples QTL, as well as QTL for body temperature and gestation length. PMID- 23742278 TI - Approach to diagnosing lower extremity ulcers. AB - Chronic leg ulcers (as differentiated from wound of the foot) are most often due to venous disease, arterial insufficiency (peripheral arterial disease), or a combination of both. Treatment modalities vary depending on the etiology of the ulcer, so it is important to make an appropriate diagnosis of the wound. Like for most medical illnesses, the determination of the etiology of these wounds is based on history, physical examination, and testing. PMID- 23742279 TI - Evidence-based management of common chronic lower extremity ulcers. AB - Chronic lower extremity ulcers are a significant burden on patients and health care systems worldwide. Although relatively common, these wounds can be difficult to treat and present a challenge to physicians. Treatment has often been based on anecdotal accounts; however, there is a growing emphasis on using evidence-based conclusions to guide clinical decisions. In this review article, the standard of care and adjuvant therapies of venous leg ulcers and diabetic foot ulcers are presented from an evidence-based perspective. PMID- 23742280 TI - Dressings for chronic wounds. AB - Covering wounds, acute and chronic, is one of the most fundamental activities of any medical practitioner. Although wound dressings primarily serve to contain the "good" and keep out the "bad," research has characterized more specifically the sophisticated interaction between the human wound bed and its dressing counterpart. Wound dressings for today's chronic wounds come in many flavors, ranging from the classic types of moisture-retentive dressings to silver-coated varieties to biologic dressings serving as skin substitutes. Moisture-retentive dressing types include foams, films, hydrogels, hydrocolloids, and alginates. Appropriate use of these dressings can help to keep the wound bed moist, which allows for epithelial migration, angiogenesis, retention of growth factors, autolytic debridement, and maintenance of electrical gradients. PMID- 23742281 TI - Hyperbaric oxygen for chronic wounds. AB - Hyperbaric oxygen therapy (HBOT), the administration of pressurized 100% oxygen, is used as an adjunct to aid healing in selected chronic wounds. Though the therapy has had a controversial history, research is now elucidating the mechanisms by which HBOT helps to heal wounds. HBOT increases growth factors and local wound signaling, while also promoting a central stem cell release of endothelial progenitor cells from the bone marrow via nitric oxide pathways. The clinical data continue to accumulate in support of HBOT to help hasten wound healing, and reduce the amputation rate in diabetic ulcers. In appropriate patients, HBOT is an effective, noninvasive, adjunct modality that can be used to hasten chronic wound healing. PMID- 23742282 TI - Advanced therapies for chronic wounds: NPWT, engineered skin, growth factors, extracellular matrices. AB - Advanced wound care implies the use of products or procedures that are specialized. Although dermatologists are used to being specialists of the skin, hair, and nails, chronic wound care has evolved such that there are some specific treatment options that are more commonly ordered and performed in wound care clinics. Wound care clinics are staffed by specialists and generalists including dermatologists, but also orthopedic surgeons, vascular surgeons, infectious disease specialists, internists, family practitioners, hyperbaric oxygen-trained physicians from a variety of backgrounds, podiatrists, physician assistants, and nurse practitioners. The care of chronic wounds has almost become its own specialty, with so-called advanced therapies now including the use of growth factors, extracellular matrices, engineered skin, and negative pressure wound therapy. It is critical that the dermatologists understand the treatments such that they can appropriately apply or order them directly, or be involved with the care of their patients receiving these therapies. PMID- 23742283 TI - Atypical ulcers. AB - Atypical ulcers of the skin challenge the dermatologist with respect to recognition, diagnosis, management, and treatment. The entire gamut of pathogenic categories including vascular, inflammatory, neoplastic, genetic, medication related, and infectious processes may give rise to atypical ulcers. By definition, these ulcers are unusual, and accurate diagnosis may ultimately require the clinician to violate the dictum that "common things are common." Atypical ulcers may present with features that the clinician has not previously encountered, or may present with seemingly typical features that actually mislead due to phenotypic mimicry. Because skin ulcers are inherently tissue-destructive, and may reflect an underlying systemic disease process, there is heightened urgency to achieving an accurate diagnosis and initiating appropriate therapy. PMID- 23742284 TI - Updating on understanding and managing chronic wound. AB - The art of healing wounds is quite complex. It requires the patient's local condition in conjunction with their systemic condition to provide the most ideal wound environment. As wound care is expanding with advances in technology, we are facing a variety of different wound care products based on an assortment of bioengineered skin substances, growth factors, oxygen therapies, low frequency ultrasound and even low energy light. While these emerging evidence-based treatments prove to be promising in improving clinical outcomes and quality of life, it challenges providers to provide cost-effective treatment plans. The goal of this paper is to introduce a discussion regarding practical clinical application of various forms of advanced wound technologies in order to optimize the art of wound healing. PMID- 23742285 TI - Omalizumab in chronic urticaria: a retrospective series of 15 cases. AB - Omalizumab is a monoclonal anti-IgE antibody approved for the treatment of severe allergic asthma. There is increasing evidence in the literature of its usefulness in chronic urticaria. Herein, we report a retrospective case series of 15 patients with chronic idiopathic urticaria treated with omalizumab. We reviewed their medical records to assess the improvement achieved after 3 and 6 months of treatment. Complete response was defined as symptom disappearance that could be followed by discontinuation of antihistamines, and partial response as symptom improvement, but with symptom worsening when attempting to discontinue antihistamines. After 3 months of treatment, 12 patients responded, with partial response in 9 and complete response in 3. At 6 months, 8 of 10 patients continuing on omalizumab had a complete response and 2 a partial response. The results of the present retrospective series show the effectiveness of omalizumab in most treated patients, which is consistent with other recently published series and studies. These data support its role in the management of patients with chronic urticaria refractory to conventional treatments. PMID- 23742286 TI - Conservative surgical treatment of a thin acral lentiginous melanoma of the thumb with no recurrences: a case report. AB - Surgical treatment for acral lentiginous melanoma (ALM) is usually radical and severely invalidating, given its distinctly aggressive nature and poor prognosis. We report on a 76-year-old male patient with ALM of the left thumb who refused total amputation that would limit his gripping function. A "surgical degloving" was consequently performed, followed by plastic reconstruction with a radial antebrachial (the so-called Chinese) flap. A year after surgery, the patient was able to perform most finalized thumb movements without difficulty, and no metastases were recorded over a 5-year follow-up. The authors discuss the indications for such a treatment for thinner ALM in relation to the biological behavior of ALM. PMID- 23742287 TI - Thalidomide improves clinical symptoms of primary cutaneous amyloidosis: report of familiar and sporadic cases. AB - Primary cutaneous amyloidosis (PCA), either familial or sporadic, poses a therapeutic challenge. We conducted an open trial using thalidomide to treat three cases of familial and three cases of sporadic PCA, at initial dose of 100 mg/day. Dosage adjustment was made according to improvement of symptoms or patient's own choice. All except one sporadic case experienced moderate to significant relief on the symptoms of itching, over an observational period of 8 weeks by visual analog score (from 8.08 +/- 0.88 to 1.60 +/- 0.68, on average) as well as clinical amelioration of symptoms. Side effects included fatigue, drowsiness, numbness, and facial and leg edema in some of the patients. From the present observation, it seems that thalidomide is a promising drug to treat PCA. PMID- 23742288 TI - The use of green tea extract in cosmetic formulations: not only an antioxidant active ingredient. AB - Green tea (GT) extracts contain polyphenols, known to be effective free radical scavengers, and other ingredients that could also provide benefits to the skin. This is a report on clinical studies using objective, noninvasive methods to evaluate the effects of cosmetic formulations containing GT. Experimental formulations were supplemented or not (vehicle) with 6% Camellia sinensis glycolic leaf extracts (GT). These formulations were applied to the forearm skin of 24 volunteers, and their effects were evaluated before and after 2 hours, 15 and 30 days according to the following parameters: stratum corneum water content, transepidermal water loss, skin viscoelastic-to-elastic ratio (Uv/Ue), and microrelief. The volunteers were instructed not to apply any formulation in an area of the forearm (control area). Experimental formulations (GT) increased skin moisture in the long-term study, indicating that GT has a prolonged moisturizing effect. The Uv/Ue was significantly enhanced after 30 days of topical application of the experimental formulation when compared with vehicle and control. After 15 30 days, skin microrelief was significantly improved due to a reduction in skin roughness. The results suggest that GT-containing cosmetic formulations have pronounced moisturizing effects and improve skin microrelief. PMID- 23742289 TI - proMetalloproteinase-10 is associated with brain damage and clinical outcome in acute ischemic stroke. AB - BACKGROUND: Matrix metalloproteinases (MMPs) mediate tissue injury during stroke but also neurovascular remodeling and we have shown that MMP-10 is involved in atherothrombosis. OBJECTIVE: The purpose of this study was to examine the relationship between proMMP-10 and clinical outcome, assessing inflammatory and proteolytic markers, in patients with acute ischemic stroke. METHODS: We prospectively studied 76 patients with ischemic stroke treated with tPA within the first 3 h from symptom onset, compared with 202 non-tPA-treated ischemic stroke patients and 83 asymptomatic subjects. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). Hemorrhagic transformation (HT) and severe brain edema were diagnosed by cranial CT. Good functional outcome was defined as a modified Rankin scale score <= 2 at 90 days. Serum levels of MMP-9, proMMP-10, TIMP-1, tumor necrosis factor-alpha (TNFalpha), interleukin-6 and cellular fibronectin were measured at admission. The effect of TNFalpha on endothelial proMMP-10 was assessed in vitro. RESULTS: Serum proMMP-10 concentration in ischemic stroke patients, non-treated or treated with t-PA, which was higher than age-matched healthy subjects (P < 0.0001), was independently associated with higher infarct volume, severe brain edema, neurological deterioration and poor functional outcome at 3 months (all P < 0.05), but not with HT. proMMP-10 levels were also independently and positively associated with circulating levels of TNFalpha (P < 0.0001), which induced its endothelial expression in vitro, both mRNA and protein. MMP-9, however, was only associated with HT and severe edema (all P < 0.05). CONCLUSIONS: Increased serum proMMP-10 after acute ischemic stroke, associated with TNFalpha, is a new marker of brain damage and poor outcome. PMID- 23742290 TI - The results of selective use of radioactive iodine on survival and on recurrence in the management of papillary thyroid cancer, based on Memorial Sloan-Kettering Cancer Center risk group stratification. AB - BACKGROUND: The American Thyroid Association guidelines recommend the routine use of radioactive iodine for remnant ablation (RRA) in all T3 or greater primary tumors, and selective use in patients with intrathyroidal disease >1 cm, or evidence of nodal metastases. The guidelines recognize that there is conflicting and inadequate data to make firm recommendations for most patients. The aim of this study was to analyze our institutional experience of the use of RRA in the management of papillary thyroid cancer, with a particular focus on outcomes for those patients selected not to receive RRA. METHODS: We retrospectively reviewed 1129 consecutive patients who underwent total thyroidectomy at the Memorial Sloan Kettering Cancer Center between 1986 and 2005. Of these, 490 were pT1-2 N0, 193 pT1-2 N1, and 444 pT3-4. Details on recurrence and disease-specific survival were recorded by the Kaplan-Meier method and compared using the log-rank test. RESULTS: The five-year disease-specific survival and recurrence-free survival in the pT1/T2 N0, pT1-2 N1, and pT3-4 were 100% and 92%, 100% and 92%, and 98% and 87% respectively. Low-risk patients who were managed without RRA (who tended to have limited primary disease, pT1-2, and low-volume metastatic disease in the neck, pT1-2 N1-fewer than five nodes, all <1 cm greatest dimension) had five-year recurrence-free survival of >97%. In the group with advanced local tumors (pT3 4), those patients who did not receive RRA (who tended to have pT3 N0 disease) had five-year recurrence-free survival of >90%. CONCLUSION: Following appropriate surgical management, the majority of patients with low-risk local disease and even some patients with more advanced-stage (pT3) tumors or regional metastases have low rates of recurrence and high rates of survival when managed without RRA. PMID- 23742292 TI - Effectiveness of the Comalli Stroop Test as a measure of negative response bias. AB - Practice guidelines recommend the use of multiple performance validity tests (PVTs) to detect noncredible performance during neuropsychological evaluations, and PVTs embedded in standard cognitive tests achieve this goal most efficiently. The present study examined the utility of the Comalli version of the Stroop Test as a measure of response bias in a large sample of "real world" noncredible patients (n = 129) as compared with credible neuropsychology clinic patients (n=233). The credible group performed significantly better than the noncredible group on all trials, but particularly on word-reading (Stroop A) and color-naming (Stroop B); cut-scores for Stroop A and Stroop B trials were associated with moderate sensitivity (49-53%) as compared to the low sensitivity found for the color interference trial (29%). Some types of diagnoses (including learning disability, severe traumatic brain injury, psychosis, and depression), very advanced age (?80), and lowered IQ were associated with increased rates of false positive identifications, suggesting the need for some adjustments to cut-offs in these subgroups. Despite some previous reports of an inverted Stroop effect (i.e., color-naming worse than color interference) in noncredible subjects, individual Stroop word reading and color naming trials were much more effective in identifying response bias. PMID- 23742294 TI - Occurrence of Listeria spp. in retail meat and dairy products in the area of Addis Ababa, Ethiopia. AB - BACKGROUND: Listeriosis, a bacterial disease in humans and animals, is mostly caused by ingestion of Listeria monocytogenes via contaminated food and/or water, or by a zoonotic infection. Globally, listeriosis has in general a low incidence but a high case fatality rate. OBJECTIVE: The objective of this study was to investigate the occurrence, antimicrobial profiles, and genetic relatedness of L. monocytogenes from raw meat and dairy products (raw milk, cottage cheese, cream cake), collected from the capital and five neighboring towns in Ethiopia. METHODS: Two hundred forty food samples were purchased from July to December 2006 from food vendors, shops, and supermarkets, using a cross-sectional study design. L. monocytogenes were isolated and subjected to molecular serotyping. The genetic relatedness and antimicrobial susceptibility patterns were investigated using pulsed-field gel electrophoresis (PFGE) and minimum inhibitory concentration determinations. RESULTS: Of 240 food samples tested, 66 (27.5%) were positive for Listeria species. Of 59 viable isolates, 10 (4.1%) were L. monocytogenes. Nine were serotype 4b and one was 2b. Minimum inhibitory concentration determination and PFGE of the 10 L. monocytogenes isolates showed low occurrence of antimicrobial resistance among eight different PFGE types. DISCUSSION AND CONCLUSIONS: The findings in this study correspond to similar research undertaken in Ethiopia by detecting L. monocytogenes with similar prevalence rates. Public education is crucial as regards the nature of this organism and relevant prevention measures. Moreover, further research in clinical samples should be carried out to estimate the prevalence and carrier rate in humans, and future investigations on foodborne outbreaks must include L. monocytogenes. PMID- 23742293 TI - Designing the next generation of medicines for malaria control and eradication. AB - In the fight against malaria new medicines are an essential weapon. For the parts of the world where the current gold standard artemisinin combination therapies are active, significant improvements can still be made: for example combination medicines which allow for single dose regimens, cheaper, safer and more effective medicines, or improved stability under field conditions. For those parts of the world where the existing combinations show less than optimal activity, the priority is to have activity against emerging resistant strains, and other criteria take a secondary role. For new medicines to be optimal in malaria control they must also be able to reduce transmission and prevent relapse of dormant forms: additional constraints on a combination medicine. In the absence of a highly effective vaccine, new medicines are also needed to protect patient populations. In this paper, an outline definition of the ideal and minimally acceptable characteristics of the types of clinical candidate molecule which are needed (target candidate profiles) is suggested. In addition, the optimal and minimally acceptable characteristics of combination medicines are outlined (target product profiles). MMV presents now a suggested framework for combining the new candidates to produce the new medicines. Sustained investment over the next decade in discovery and development of new molecules is essential to enable the long-term delivery of the medicines needed to combat malaria. PMID- 23742295 TI - Presence of Shiga toxin-producing Escherichia coli O-groups in small and very small beef-processing plants and resulting ground beef detected by a multiplex polymerase chain reaction assay. AB - Shiga toxin-producing Escherichia coli (STEC) are associated with foodborne illnesses, including hemolytic uremic syndrome in humans. Cattle and consequently, beef products are considered a major source of STEC. E. coli O157:H7 has been regulated as an adulterant in ground beef since 1996. The United States Department of Agriculture Food Safety and Inspection Service began regulating six additional STEC (O145, O121, O111, O103, O45, and O26) as adulterants in beef trim and raw ground beef in June 2012. Little is known about the presence of STEC in small and very-small beef-processing plants. Therefore, we propose to determine whether small and very-small beef-processing plants are a potential source of non-O157:H7 STEC. Environmental swabs, carcass swabs, hide swabs, and ground beef from eight small and very-small beef-processing plants were obtained from October 2010 to December 2011. A multiplex polymerase chain reaction assay was used to determine the presence of STEC O-groups: O157, O145, O121, O113, O111, O103, O45, and O26 in the samples. Results demonstrated that 56.6% (154/272) of the environmental samples, 35.0% (71/203) of the carcass samples, 85.2% (23/27) of the hide samples, and 17.0% (20/118) of the ground beef samples tested positive for one or more of the serogroups. However, only 7.4% (20/272) of the environmental samples, 4.4% (9/203) of the carcass samples, and 0% (0/118) ground beef samples tested positive for both the serogroup and Shiga toxin genes. Based on this survey, small and very-small beef processors may be a source of non-O157:H7 STEC. The information from this study may be of interest to regulatory officials, researchers, public health personnel, and the beef industry that are interested in the presence of these pathogens in the beef supply. PMID- 23742296 TI - Production and evaluation of chicken egg-yolk-derived antibodies against Campylobacter jejuni colonization-associated proteins. AB - Campylobacter jejuni is one of the most important causes of foodborne gastroenteritis. Chickens are considered a reservoir host of C. jejuni, and epidemiological studies have shown that contaminated chicken meat is a primary source of human infection. The objective of this study was to produce chicken egg yolk-derived antibody (IgY) against the five C. jejuni colonization-associated proteins or CAPs (CadF, FlaA, MOMP, FlpA, and CmeC). Recombinant C. jejuni CAPs were expressed in Escherichia coli and were purified by affinity chromatography. Specific-pathogen-free laying hens were hyperimmunized with each recombinant CAP to induce production of alpha-CAP-specific IgY. Egg yolks were collected from immunized and nonimmunized hens and were lyophilized to obtain egg-yolk powder (EYP) with or without alpha-C. jejuni CAP-specific IgY. IgY was purified from EYP, and the antibody response in serum and egg yolk was tested by indirect enzyme-linked immunosorbent assay. The alpha-C. jejuni CAP-specific IgY levels were significantly (p<0.05) higher in both serum and EYP obtained from immunized hens as compared with the nonimmunized hens. Each alpha-C. jejuni CAP-specific IgY reacted with the C. jejuni cells and recombinant CAPs as detected by immunofluorescence microscopy and Western blot assays, respectively. We also show that alpha-CadF, alpha-MOMP, and alpha-CmeC IgY significantly reduced adherence of C. jejuni to the chicken hepatocellular carcinoma (LMH) cells, suggesting that these alpha-C. jejuni CAP-specific IgY may be useful as a passive immunotherapeutic to reduce C. jejuni colonization in chickens. PMID- 23742297 TI - On assay robustness: the importance of early determination and science-driven decision-making. PMID- 23742298 TI - Regulated bioanalysis in Japan: where do we come from and where are we going? PMID- 23742299 TI - Current status of vitamin D assays: are they reliable and sufficiently informative for clinical studies? PMID- 23742300 TI - Micro-LC-MS/MS: the future of bioanalysis. PMID- 23742301 TI - Establishment of glycomic research center. PMID- 23742302 TI - Interview with Dr Bowsher. PMID- 23742303 TI - Bioanalysis young investigator: award 2013. PMID- 23742304 TI - LC-MS and chemometrics for steroid biomarker profiles in view of the future diagnostics of diseases? PMID- 23742305 TI - Rapid determination of hexapeptides by hydrophilic interaction LC-MS/MS for in vitro skin-penetration studies. AB - BACKGROUND: A sensitive analytical method is needed for assessing penetration of topically applied peptides for in vitro skin-penetration studies. RESULTS: A rapid hydrophilic interaction LC (HILIC)-MS/MS method for analyzing the polar peptides Ac-EEMQRR-amide and H2N-EEMQRR-amide in various skin layers and matrices has been developed and evaluated. The matrices included emulsion, receptor fluids, cotton-tipped applicators, stratum corneum tape strips, epidermis and dermis of the skin. Stable isotopically labeled analogues were used as internal standards to correct for recovery and matrix effects. A HILIC-SPE procedure was optimized to minimize significant ion suppression in the more complex matrices. CONCLUSION: This HILIC-MS/MS method is applicable to the determination of Ac EEMQRR-amide and H2N-EEMQRR-amide in complex skin samples and other matrices generated during in vitro skin-penetration studies. PMID- 23742306 TI - Dual universal peptide approach to bioanalysis of human monoclonal antibody protein drug candidates in animal studies. AB - BACKGROUND: There is a need for general and reliable LC-MS assays capable of supporting the bioanalysis of a variety of human monoclonal antibody-based therapeutic drug candidates in animal PK/TK studies. RESULTS: We present herein improvements in our previously reported universal peptide approach to the bioanalysis of human monoclonal antibody protein drug candidates in animal studies. These improvements include incorporation of a second, light chain-based universal peptide into the assay, thus introducing the concept of a dual universal peptide assay; and incorporation of a universal stable isotope-labeled monoclonal antibody into the assay. CONCLUSION: Improvements reported herein to the universal peptide assay will enable more reliable quantification of human monoclonal antibody protein drug candidates in animal studies. PMID- 23742307 TI - Parallel artificial liquid membrane extraction: micro-scale liquid-liquid-liquid extraction in the 96-well format. AB - BACKGROUND: This paper reports development of a new approach towards analytical liquid-liquid-liquid membrane extraction termed parallel artificial liquid membrane extraction. A donor plate and acceptor plate create a sandwich, in which each sample (human plasma) and acceptor solution is separated by an artificial liquid membrane. Parallel artificial liquid membrane extraction is a modification of hollow-fiber liquid-phase microextraction, where the hollow fibers are replaced by flat membranes in a 96-well plate format. RESULTS: Four basic drugs (pethidine, nortriptyline, methadone and haloperidol) were extracted from human plasma in 30 min, followed by analysis with LC-MS/MS. Extraction recoveries for the model analytes were in the range of 34-74% from human plasma. LOQs were in the range of 0.01-0.35 ng/ml, linearity above 0.9955 for all drugs and with RSD values below 12%. CONCLUSION: Liquid-liquid-liquid membrane extraction was successfully performed in a slightly modified commercially available 96-well plate format. PMID- 23742308 TI - The advantages of microflow LC-MS/MS compared with conventional HPLC-MS/MS for the analysis of methotrexate from human plasma. AB - BACKGROUND: In support of bioanalysis, there has always been a desire to improve detection limits and reduce scale. Microflow LC (MFLC) coupled with MS accomplishes both of these goals. RESULTS: As such, MFLC coupled with an MS system was used to generate bioanalytical validation data that met US FDA criteria. The MFLC-MS/MS data was compared with the same method with the use of conventional HPLC-MS/MS and a more than 14* S/N improvement was found with the MFLC-MS/MS method. Methotrexate was used as a model molecule to demonstrate the validation of the method from human plasma. The MFLC-MS/MS method was demonstrated to be accurate (+/-7%) and precise (12.9% at the LLOQ and a maximum of 11.6% at all other concentrations) across the dynamic range of the assay (1 1000 ng/ml) and compared well with the HPLC-MS/MS method. The MFLC bioanalytical validation was performed at a flow rate of 35 ul/min on a 0.5-mm inner diameter (I.D.) column, whereas, for the same linear velocities on the 2.0-mm I.D. column, the conventional HPLC bioanalytical validation was performed at 700 ul/min. Since the flow rate of the MFLC system is 20-times less than the HPLC system, the consumable solvent and disposal cost to perform the MFLC validation was significantly less. CONCLUSION: MFLC-MS/MS can be used to perform bioanalytical method validations with increased MS signal, reduced source contamination and reduced solvent consumption. PMID- 23742310 TI - A critical review of microextraction by packed sorbent as a sample preparation approach in drug bioanalysis. AB - Sample preparation is widely accepted as the most labor-intensive and error-prone part of the bioanalytical process. The recent advances in this field have been focused on the miniaturization and integration of sample preparation online with analytical instrumentation, in order to reduce laboratory workload and increase analytical performance. From this perspective, microextraction by packed sorbent (MEPS) has emerged in the last few years as a powerful sample preparation approach suitable to be easily automated with liquid and gas chromatographic systems applied in a variety of bioanalytical areas (pharmaceutical, clinical, toxicological, environmental and food research). This paper aims to provide an overview and a critical discussion of recent bioanalytical methods reported in literature based on MEPS, with special emphasis on those developed for the quantification of therapeutic drugs and/or metabolites in biological samples. The advantages and some limitations of MEPS, as well as its comparison with other extraction techniques, are also addressed herein. PMID- 23742309 TI - A simple LC-MS/MS method for determination of kynurenine and tryptophan concentrations in human plasma from HIV-infected patients. AB - BACKGROUND: Indoleamine 2,3-dioxygenase, catalyzing tryptophan (Trp) metabolism through the kynurenine (Kyn) metabolic pathway, plays important roles in immune suppression and the CNS. In this article, we report a simple, rapid and specific LC-MS/MS method for accurate determination of Kyn and Trp concentrations in human plasma from HIV-infected patients. RESULTS: The human plasma sample (100 ul) was mixed with Kyn-d4 and Trp-d5 internal standards and then precipitated with trifluoroacetic acid. The supernatant was directly analyzed by LC-MS/MS. The assay using surrogate matrix calibrators was validated for precision, accuracy, matrix effect, extraction efficiency and stability. Some assay validation issues for endogenous substance bioanalysis using an LC-MS/MS method are discussed. CONCLUSION: A simple, specific and reproducible LC-MS/MS method has been developed and validated for measuring Kyn and Trp in human plasma samples. PMID- 23742311 TI - Noninvasive analysis of volatile biomarkers in human emanations for health and early disease diagnosis. AB - Early disease diagnosis is crucial for human healthcare and successful therapy. Since any changes in homeostatic balance can alter human emanations, the components of breath exhalations and skin emissions may be diagnostic biomarkers for various diseases and metabolic disorders. Since hundreds of endogenous and exogenous volatile organic compounds (VOCs) are released from the human body, analysis of these VOCs may be a noninvasive, painless, and easy diagnostic tool. Sampling and preconcentration by sorbent tubes/traps and solid-phase microextraction, in combination with GC or GC-MS, are usually used to analyze VOCs. In addition, GC-MS-olfactometry is useful for simultaneous analysis of odorants and odor quality. Direct MS techniques are also useful for the online real-time detection of VOCs. This review focuses on recent developments in sampling and analysis of volatile biomarkers in human odors and/or emanations, and discusses future use of VOC analysis. PMID- 23742313 TI - Adult-onset leukoencephalopathy, brain calcifications and cysts: a case report. AB - INTRODUCTION: Leukoencephalopathy, brain calcifications and cysts, known as Labrune syndrome, is a rare syndrome. The etiology is unknown; in some cases it is difficult to differentiate from Coats plus syndrome and diagnosed as cerebroretinal microangiopathy with calcifications and cysts. We present the case of a patient with adult leukoencephalopathy, brain calcifications and cysts and discuss recently described entities in view of the relevant literature. CASE PRESENTATION: A previously healthy 19-year-old Chinese man presented with weakness of his right limbs that rapidly worsened over a short interval. Computed tomography and magnetic resonance imaging showed numerous low-density cysts, calcifications, and abnormal signal change of white matter. A visual field examination showed irregular visual field defects in both eyes. A neuro ophthalmologic examination did not find evidence of Coats retinopathy. A larger excisional biopsy was carried out and a diagnosis of leukoencephalopathy, brain calcifications and cysts was confirmed. CONCLUSIONS: We present an example of adult-onset leukoencephalopathy, brain calcifications and cysts and have expanded the clinical spectrum of features associated with this syndrome. Previous reports have not, to the best of our knowledge, previously reported visual field defects. Based on the latest findings, we believe that leukoencephalopathy, brain calcifications and cysts and Coats plus syndrome are genetically distinct entities. PMID- 23742314 TI - Origins of increased airway smooth muscle mass in asthma. AB - Asthma is characterized by both chronic inflammation and airway remodeling. Remodeling--the structural changes seen in asthmatic airways--is pivotal in the pathogenesis of the disease. Although significant advances have been made recently in understanding the different aspects of airway remodeling, the exact biology governing these changes remains poorly understood. There is broad agreement that, in asthma, increased airway smooth muscle mass, in part due to smooth muscle hyperplasia, is a very significant component of airway remodeling. However, significant debate persists on the origins of these airway smooth muscle cells. In this review article we will explore the natural history of airway remodeling in asthma and we will discuss the possible contribution of progenitors, stem cells and epithelial cells in mesenchymal cell changes, namely airway smooth muscle hyperplasia seen in the asthmatic airways. PMID- 23742316 TI - RHD*weak partial 4.0 is associated with an altered RHCE*ce(48C, 105T, 733G, 744C, 1025T) allele in the Tunisian population. AB - BACKGROUND AND OBJECTIVES: D is the most immunogenic blood group antigen. About 1% of whites carry an altered RHD allele leading to quantitative or qualitative changes in the antigen D expression. T201R and F223V encoded by 602C>G and 667T>G are specific amino acid substitutions of the weak D type 4 cluster of African origin, comprising the alleles RHD*09.01, RHD*09.02, RHD*09.03, RHD*09.04 and RHD*09.05. The purpose of this study was to estimate the presence of these RHD genotypes in the Tunisian population. MATERIALS AND METHODS: Ethylenediaminetetraacetate blood samples from 907 D+ and 93 D- blood donors were tested for markers 602G and 667G by allele-specific primer-polymerase chain reaction (PCR-ASP). Samples with positive reactions were re-evaluated by DNA sequencing for RHD and RHCE exons 1-10 and adjacent intronic sequences. RESULTS: Among 907 D+ samples, 19 individuals were identified to harbour the RHD*weak partial 4.0 allele. RHCE sequencing post-haplotype-specific extraction (HSE) revealed an altered RHCE*ce(48C, 105T, 733G, 744C, 1025T) in those samples. The linkage of the RHCE polymorphisms to one haplotype was proven by DNA sequencing post-HSE. CONCLUSION: The RHD*weak partial 4.0 allele syn. RHD*09.03 was estimated to occur 1 in 47 among D+ Tunisians. There was no evidence for other RHD alleles included in the weak D type 4 cluster. PMID- 23742315 TI - Impaired retinal vasodilator responses in prediabetes and type 2 diabetes. AB - PURPOSE: In diabetes, endothelial dysfunction and subsequent structural damage to blood vessels can lead to heart attacks, retinopathy and strokes. However, it is unclear whether prediabetic subjects exhibit microvascular dysfunction indicating early stages of arteriosclerosis and vascular risk. The purpose of this study was to examine whether retinal reactivity may be impaired early in the hyperglycaemic continuum and may be associated with markers of inflammation. METHODS: Individuals with prediabetes (n = 22), type 2 diabetes (n = 25) and healthy age and body composition matched controls (n = 19) were studied. We used the Dynamic Vessel Analyzer to assess retinal vasoreactivity (percentage change in vessel diameter) during a flickering light stimulation. Fasting highly sensitive c reactive protein (hs-CRP), a marker of inflammation, was measured in blood plasma. RESULTS: Prediabetic and diabetic individuals had attenuated peak vasodilator and relative amplitude changes in retinal vein diameters to the flickering light stimulus compared with healthy controls (peak dilation: prediabetic subjects 3.3 +/- 1.8%, diabetic subjects 3.3 +/- 2.1% and controls 5.6 +/- 2.6%, p = 0.001; relative amplitude: prediabetic subjects 4.3 +/- 2.2%, diabetic subjects 5.0 +/- 2.6% and control subjects 7.2 +/- 3.2%, p = 0.003). Similar findings were observed in retinal arteries. Levels of hs-CRP were not associated with either retinal vessel response parameters. CONCLUSION: Retinal reactivity was impaired in prediabetic and type 2 diabetic individuals in parallel with reduced insulin sensitivity but not associated with levels of hs CRP. Retinal vasoreactivity measurements may be a sensitive tool to assess early vascular risk. PMID- 23742317 TI - Reproducibility and optimization of analysis parameters of tissue Doppler-derived strain and strain rate measurements for very low birth weight infants. AB - AIMS: To assess the effects of region of interest (ROI) size and strain length (SL) on the quality of analysis and to determine the feasibility and reproducibility of tissue Doppler-derived cardiac strain (S) and strain rate (SR) measurements for preterm infants <1500 g birth weight. METHODS AND RESULTS: The beat-to-beat variation (BBV) for different combinations of ROI width (RW), ROI length (RL), and SL was determined from 60 good quality images of left and right free walls and the interventricular septum. We examined the impact of RW, RL, and SL on BBV and estimated inter- and intra-operator variability. BBV was smallest for RW = 2 mm. Raising SL (even at the cost of RL) led to a decrease in BBV. Several combinations provided a low BBV without significant difference. Coefficients of variation for intra- and inter-operator variability ranged from 15.1% to 65.2%. Both were lower for systolic than for diastolic values. CONCLUSION: Tissue Doppler imaging-derived S and SR measurements are feasible in very low birth weight infants. Reproducibility is comparable to older infants for systolic S and SR. For optimal analysis quality, SL and RW should be high while RL should be small (though inside segment size). Best results were obtained with RW = 2 mm, RL = 1 mm, and SL = 6 mm. PMID- 23742318 TI - Backbone-base interactions critical to quantum stabilization of transfer RNA anticodon structure. AB - Transfer RNA (tRNA) anticodons adopt a highly ordered 3'-stack without significant base overlap. Density functional theory at the M06-2X/6-31+G(d,p) level in combination with natural bond orbital analysis was utilized to calculate the intramolecular interactions within the tRNA anticodon that are responsible for stabilizing the stair-stepped conformation. Ten tRNA X-ray crystal structures were obtained from the PDB databank and were trimmed to include only the anticodon bases. Hydrogenic positions were added and optimized for the structures in the stair-stepped conformation. The sugar-phosphate backbone has been retained for these calculations, revealing the role it plays in RNA structural stability. It was found that electrostatic interactions between the sugar-phosphate backbone and the base provide the most stability, rather than the traditionally studied interbase stacking. Base-stacking interactions, though present, were weak and inconsistent. Aqueous solvation was found to have little effect on the intramolecular interactions. PMID- 23742320 TI - Hypoxia and bicarbonate could limit the expression of iron acquisition genes in Strategy I plants by affecting ethylene synthesis and signaling in different ways. AB - In a previous work, it was shown that bicarbonate (one of the most important factors causing Fe chlorosis in Strategy I plants) can limit the expression of several genes involved in Fe acquisition. Hypoxia is considered another important factor causing Fe chlorosis, mainly on calcareous soils. However, to date it is not known whether hypoxia aggravates Fe chlorosis by affecting bicarbonate concentration or by specific negative effects on Fe acquisition. Results found in this work show that hypoxia, generated by eliminating the aeration of the nutrient solution, can limit the expression of several Fe acquisition genes in Fe deficient Arabidopsis, cucumber and pea plants, like the genes for ferric reductases AtFRO2, PsFRO1 and CsFRO1; iron transporters AtIRT1, PsRIT1 and CsIRT1; H(+) -ATPase CsHA1; and transcription factors AtFIT, AtbHLH38, and AtbHLH39. Interestingly, the limitation of the expression of Fe-acquisition genes by hypoxia did not occur in the Arabidopsis ethylene constitutive mutant ctr1, which suggests that the negative effect of hypoxia is related to ethylene, an hormone involved in the upregulation of Fe acquisition genes. As for hypoxia, results obtained by applying bicarbonate to the nutrient solution suggests that ethylene is also involved in its negative effect, since ACC (1-aminocyclopropane 1-carboxylic acid; ethylene precursor) partially reversed the negative effect of bicarbonate on the expression of Fe acquisition genes. Taken together, the results obtained show that hypoxia and bicarbonate could induce Fe chlorosis by limiting the expression of Fe acquisition genes, probably because each factor negatively affects different steps of ethylene synthesis and/or signaling. PMID- 23742319 TI - The additional ACh binding site at the alpha4(+)/alpha4(-) interface of the (alpha4beta2)2alpha4 nicotinic ACh receptor contributes to desensitization. AB - BACKGROUND AND PURPOSE: Nicotinic ACh (alpha4beta2)2alpha4 receptors are highly prone to desensitization by prolonged exposure to low concentrations of agonist. Here, we report on the sensitivity of the three agonist sites of the (alpha4beta2)2alpha4 to desensitization induced by prolonged exposure to ACh. We present electrophysiological data that show that the agonist sites of the (alpha4beta2)2alpha4 receptor have different sensitivity to desensitization and that full receptor occupation decreases sensitivity to desensitization. EXPERIMENTAL APPROACH: Two-electrode voltage-clamp electrophysiology was used to study the desensitization of concatenated (alpha4beta2)2alpha4 receptors expressed heterologously in Xenopus oocytes. Desensitization was assessed by measuring the degree of functional inhibition caused by prolonged exposure to ACh, as measured under equilibrium conditions. We used the single-point mutation alpha4W182A to measure the contribution of individual agonist sites to desensitization. KEY RESULTS: (alpha4beta2)2alpha4 receptors are less sensitive to activation and desensitization by ACh than (alpha4beta2)2beta2 receptors. Incorporation of alpha4W182A into any of the agonist sites of concatenated (alpha4beta2)2alpha4 receptors decreased sensitivity to activation and desensitization but the effects were more pronounced when the mutation was introduced into the alpha4(+)/alpha4(-) interface. CONCLUSIONS AND IMPLICATIONS: The findings suggest that the agonist sites in (alpha4beta2)2alpha4 receptors are not functionally equivalent. The agonist site at the alpha4(+)/alpha4(-) interface defines the sensitivity of (alpha4beta2)2alpha4 receptors to agonist induced activation and desensitization. Functional differences between (alpha4beta2)2alpha4 and (alpha4beta2)2beta2 receptors might shape the physiological and behavioural responses to nicotinic ligands when the receptors are exposed to nicotinic ligands for prolonged periods of times. PMID- 23742321 TI - Inaccuracy in the treatment of multiple-order diffraction by secondary-edge source methods. AB - Existing secondary-edge-source methods based on the Biot-Tolstoy solution for diffraction from an infinite wedge compute multiple-order diffraction by cascading the integration over secondary sources used to determine first-order diffraction from the edge. It is demonstrated here that this approach errs in some important cases because it neglects slope-diffraction contributions. This error is illustrated by considering the case of an infinite slit in a thin, hard screen. Comparisons with measurements for this case and analytical solutions for the case of a circular aperture in a thin, hard screen are used as a basis to gauge the magnitude of the error. PMID- 23742322 TI - Spatial release from masking as a function of the spectral overlap of competing talkers. AB - This study tested the hypothesis that the reduced spatial release from speech-on speech masking typically observed in listeners with sensorineural hearing loss results from increased energetic masking. Target sentences were presented simultaneously with a speech masker, and the spectral overlap between the pair (and hence the energetic masking) was systematically varied. The results are consistent with increased energetic masking in listeners with hearing loss that limits performance when listening in speech mixtures. However, listeners with hearing loss did not exhibit reduced spatial release from masking when stimuli were filtered into narrow bands. PMID- 23742323 TI - An integral equation formulation for the diffraction from convex plates and polyhedra. AB - A formulation of the problem of scattering from obstacles with edges is presented. The formulation is based on decomposing the field into geometrical acoustics, first-order, and multiple-order edge diffraction components. An existing secondary-source model for edge diffraction from finite edges is extended to handle multiple diffraction of all orders. It is shown that the multiple-order diffraction component can be found via the solution to an integral equation formulated on pairs of edge points. This gives what can be called an edge source signal. In a subsequent step, this edge source signal is propagated to yield a multiple-order diffracted field, taking all diffraction orders into account. Numerical experiments demonstrate accurate response for frequencies down to 0 for thin plates and a cube. No problems with irregular frequencies, as happen with the Kirchhoff-Helmholtz integral equation, are observed for this formulation. For the axisymmetric scattering from a circular disc, a highly effective symmetric formulation results, and results agree with reference solutions across the entire frequency range. PMID- 23742324 TI - The wave-field from an array of periodic emitters driven simultaneously by a broadband pulse. AB - The use of phased array methods are commonplace in ultrasonic applications, where controlling the variation of the phase between the narrowband emitters in an array facilitates beam steering and focusing of ultrasonic waves. An approach is presented here whereby emitters of alternating polarity arranged in a one dimensional array are pulsed simultaneously, and have sufficiently wide, controlled bandwidth to emit a two-dimensional wave. This pulsed approach provides a rapid means of simultaneously covering a region of space with a wave front, whereby any wave that scatters or reflects off a body to a detector will have a distinct arrival time and frequency. This is a general wave phenomenon with a potential application in radar, sonar, and ultrasound. The key result is that one can obtain a smooth, continuous wave-front emitted from the array, over a large solid angle, whose frequency varies as a function of angle to the array. Analytic and finite element models created to describe this phenomenon have been validated with experimental results using ultrasonic waves in metal samples. PMID- 23742325 TI - Surface contributions to radiated sound power. AB - This paper presents a method to identify the surface areas of a vibrating structure that contribute to the radiated sound power. The surface contributions of the structure are based on the acoustic radiation modes and are computed for all boundaries of the acoustic domain. The surface contributions are compared to the acoustic intensity, which is a common measure for near-field acoustic energy. Sound intensity usually has positive and negative values that correspond to energy sources and sinks on the surface of the radiating structure. Sound from source and sink areas partially cancel each other and only a fraction of the near field acoustic energy reaches the far-field. In contrast to the sound intensity, the surface contributions are always positive and no cancelation effects exist. The technique presented here provides a method to localize the relevant radiating surface areas on a vibrating structure. To illustrate the method, the radiated sound power from a baffled square plate is presented. PMID- 23742326 TI - Anisotropy of dynamic acoustoelasticity in limestone, influence of conditioning, and comparison with nonlinear resonance spectroscopy. AB - Anisotropy of wave velocity and attenuation induced by a dynamic uniaxial strain is investigated by dynamic acoustoelastic testing in limestone. Nonlinear resonance spectroscopy is performed simultaneously for comparison. A compressional resonance of the sample at 6.8 kHz is excited to produce a dynamic strain with an amplitude varied from 10(-7) to 10(-5). A sequence of ultrasound pulses tracks variations in ultrasonic velocity and attenuation. Variations measured when the ultrasound pulses propagate in the direction of the uniaxial strain are 10 times larger than when the ultrasound propagation occurs perpendicularly. Variations consist of a "fast" variation at 6.8 kHz and an offset. Acoustically induced conditioning is found to reduce wave velocity and enhance attenuation (offset). It also modifies "fast" nonlinear elastodynamics, i.e., wave amplitude dependencies of ultrasonic velocity and attenuation. At the onset of conditioning and beyond, different excitation amplitudes bring the material to non-equilibrium states. After conversion of velocity-strain dynamic relations into elastic modulus-strain dynamic relations and integration with respect to strain, the dynamic stress-strain relation is obtained. Analysis of stress-strain hysteresis shows that hysteretic nonlinear elasticity is not a significant source of the amplitude-dependent dissipation measured by nonlinear resonance spectroscopy. Mechanisms causing conditioning are likely producing amplitude-dependent dissipation as well. PMID- 23742327 TI - A general derivation of the subharmonic threshold for non-linear bubble oscillations. AB - The paper describes an approximate but rather general derivation of the acoustic threshold for a subharmonic component to be possible in the sound scattered by an insonified gas bubble. The general result is illustrated with several specific models for the mechanical behavior of the surface coating of bubbles used as acoustic contrast agents. The approximate results are found to be in satisfactory agreement with fully non-linear numerical results in the literature. The amplitude of the first harmonic is also found by the same method. A fundamental feature identified by the analysis is that the subharmonic threshold can be considerably lowered with respect to that of an uncoated free bubble if the mechanical response of the coating varies rapidly in the neighborhood of certain specific values of the bubble radius, e.g., because of buckling. PMID- 23742328 TI - Bubble cluster dynamics in an acoustic field. AB - A mathematical model describing dynamics of the cluster of gas bubbles in an acoustic field is presented. According to this model a cluster is considered as a large drop with microbubbles inside. The proposed model is used as a basis (1) for an analytical study of small bubble oscillations in mono- and polydisperse clusters and (2) for numerical investigations of nonlinear bubble oscillations and of the diffusion stability of gas bubbles in the cluster. A synchronization of the collapse phases of bubbles with different radii and collapse intensification for bubbles of one size in the presence of bubbles of other size is found. These effects are explained by the interaction between the bubbles of different radii in the cluster. For the cluster with one radius bubbles the numerical values are obtained for the initial gas concentrations in the liquid at which the bubbles tend to one of two equilibrium states because of rectified diffusion. It is found that the cluster with the bubbles of two different radii tends to become a cluster with the bubbles of one radius due to rectified diffusion. PMID- 23742329 TI - Efficacy of spatial averaging of infrasonic pressure in varying wind speeds. AB - Wind noise reduction (WNR) is important in the measurement of infrasound. Spatial averaging theory led to the development of rosette pipe arrays. The efficacy of rosettes decreases with increasing wind speed and only provides a maximum of ~20 dB WNR due to a maximum size limitation. An Optical Fiber Infrasound Sensor (OFIS) reduces wind noise by instantaneously averaging infrasound along the sensor's length. In this study two experiments quantify the WNR achieved by rosettes and OFISs of various sizes and configurations. Specifically, it is shown that the WNR for a circular OFIS 18 m in diameter is the same as a collocated 32 inlet pipe array of the same diameter. However, linear OFISs ranging in length from 30 to 270 m provide a WNR of up to ~30 dB in winds up to 5 m/s. The measured WNR is a logarithmic function of the OFIS length and depends on the orientation of the OFIS with respect to wind direction. OFISs oriented parallel to the wind direction achieve ~4 dB greater WNR than those oriented perpendicular to the wind. Analytical models for the rosette and OFIS are developed that predict the general observed relationships between wind noise reduction, frequency, and wind speed. PMID- 23742330 TI - Time-domain solver in curvilinear coordinates for outdoor sound propagation over complex terrain. AB - The current work aims at developing a linearized Euler equations solver in curvilinear coordinates to account for the effects of topography on sound propagation. In applications for transportation noise, the propagation environment as well as the description of acoustic sources is complex, and time domain methods have proved their capability to deal with both atmospheric and ground effects. First, equations in curvilinear coordinates are examined. Then time-domain boundary conditions initially proposed for a Cartesian coordinate system are implemented in the curvilinear solver. Two test cases dealing with acoustic scattering by an impedance cylinder in a two-dimensional geometry and by an impedance sphere in a three-dimensional geometry are considered to validate the boundary conditions. Accurate solutions are obtained for both rigid and impedance surfaces. Finally, the solver is used to examine a typical outdoor sound propagation problem. It is shown that it is well-suited to study coupled effects of topography, mixed impedance ground and meteorological conditions. PMID- 23742331 TI - The attenuation of sound by turbulence in internal flows. AB - The attenuation of sound waves due to interaction with low Mach number turbulent boundary layers in internal flows (channel or pipe flow) is examined. Dynamic equations for the turbulent Reynolds stress on the sound wave are derived, and the analytical solution to the equation provides a frequency dependent eddy viscosity model. This model is used to predict the attenuation of sound propagating in fully developed turbulent pipe flow. The predictions are shown to compare well with the experimental data. The proposed dynamic equation shows that the turbulence behaves like a viscoelastic fluid in the interaction process, and that the ratio of turbulent relaxation time near the wall and the sound wave period is the parameter that controls the characteristics of the attenuation induced by the turbulent flow. PMID- 23742332 TI - Ray convergence in a flux-like propagation formulation. AB - The energy flux formulation of waveguide propagation is closely related to the incoherent mode sum, and its simplicity has led to development of efficient computational algorithms for reverberation and target echo strength, but it lacks the effects of convergence or modal interference. By starting with the coherent mode sum and rejecting the most rapid interference but retaining beats on a scale of a ray cycle distance it is shown that convergence can be included in a hybrid formulation requiring minimal extra computation. Three solutions are offered by evaluating the modal intensity cross terms using Taylor expansions. In the most efficient approach the double summation of the cross terms is reduced to a single numerical sum by solving the other summation analytically. The other two solutions are a local range average and a local depth average. Favorable comparisons are made between these three solutions and the wave model Orca with, and without, spatial averaging in an upward refracting duct. As a by-product, it is shown that the running range average is very close to the mode solution excluding its fringes, given a relation between averaging window size and effective number of modes which, in turn, is related to the waveguide invariant. PMID- 23742333 TI - Physical and non-physical energy in scattered wave source-receiver interferometry. AB - Source-receiver interferometry allows Green's functions between sources and receivers to be estimated by means of convolution and cross-correlation of other wavefields. Source-receiver interferometry has been observed to work surprisingly well in practical applications when theoretical requirements (e.g., complete enclosing boundaries of other sources and receivers) are contravened: this paper contributes to explain why this may be true. Commonly used inter-receiver interferometry requires wavefields to be generated around specific stationary points in space which are controlled purely by medium heterogeneity and receiver locations. By contrast, application of source-receiver interferometry constructs at least kinematic information about physically scattered waves between a source and a receiver by cross-convolution of scattered waves propagating from and to any points on the boundary. This reduces the ambiguity in interpreting wavefields generated using source-receiver interferometry with only partial boundaries (as is standard in practical applications), as it allows spurious or non-physical energy in the constructed Green's function to be identified and ignored. Further, source-receiver interferometry (which includes a step of inter-receiver interferometry) turns all types of non-physical or spurious energy deriving from inter-receiver interferometry into what appears to be physical energy. This explains in part why source-receiver interferometry may perform relatively well compared to inter-receiver interferometry when constructing scattered wavefields. PMID- 23742334 TI - Near resonance acoustic scattering from organized schools of juvenile Atlantic bluefin tuna (Thunnus thynnus). AB - Schools of Atlantic bluefin tuna (Thunnus thynnus) can exhibit highly organized spatial structure within the school. This structure was quantified for dome shaped schools using both aerial imagery collected from a commercial spotter plane and 400 kHz multibeam echo sounder data collected on a fishing vessel in 2009 in Cape Cod Bay, MA. Observations from one school, containing an estimated 263 fish within an approximately ellipsoidal volume of 1900 m(3), were used to seed an acoustic model that estimated the school target strength at frequencies between 10 and 2000 Hz. The fish's swimbladder resonance was estimated to occur at approximately 50 Hz. The acoustic model examined single and multiple scattering solutions and also a completely incoherent summation of scattering responses from the fish. Three levels of structure within the school were examined, starting with fish locations that were constrained by the school boundaries but placed according to a Poisson process, then incorporating a constraint on the distance to the nearest neighbor, and finally adding a constraint on the bearing to the nearest neighbor. Results suggest that both multiple scattering and spatial organization within the school should be considered when estimating the target strength of schools similar to the ones considered here. PMID- 23742335 TI - Tracking dolphin whistles using an autonomous acoustic recorder array. AB - Dolphins are known to produce nearly omnidirectional whistles that can propagate several kilometers, allowing these sounds to be localized and tracked using acoustic arrays. During the fall of 2007, a km-scale array of four autonomous acoustic recorders was deployed offshore of southern California in a known dolphin habitat at ~800 m depth. Concurrently with the one-month recording, a fixed-point marine mammal visual survey was conducted from a moored research platform in the center of the array, providing daytime species and behavior visual confirmation. The recordings showed three main types of dolphin acoustic activity during distinct times: primarily whistling during daytime, whistling and clicking during early night, and primarily clicking during late night. Tracks from periods of daytime whistling typically were tightly grouped and traveled at a moderate rate. In one example with visual observations, traveling common dolphins (Delphinus sp.) were tracked for about 10 km with an average speed of ~2.5 m s(-1) (9 km h(-1)). Early night recordings had whistle localizations with wider spatial distribution and slower travel speed than daytime recordings, presumably associated with foraging behavior. Localization and tracking of dolphins over long periods has the potential to provide insight into their ecology, behavior, and potential response to stimuli. PMID- 23742336 TI - Assessing the low frequency acoustic characteristics of Macrocystis pyrifera, Egregia menziessi, and Laminaria solidungula. AB - The acoustic properties of kelp forests are not well known, but are of interest for the development of environmental remote sensing applications. This study examined the low-frequency (0.2-4.5 kHz) acoustic properties of three species of kelp (Macrocystis pyrifera, Egregia menziessi, and Laminaria solidungula) using a one-dimensional acoustic resonator. Acoustic observations and measurements of kelp morphology were then used to test the validity of Wood's multi-phase medium model in describing the acoustic behavior of the kelp. For Macrocystis and Egregia, the two species of kelp possessing pneumatocysts, the change in sound speed was highly dependent on the volume of free air contained in the kelp. The volume of air alone, however, was unable to predict the effective sound speed of the multi-phase medium using a simple two-phase (air + water) form of Wood's model. A separate implementation of this model (frond + water) successfully yielded the acoustic compressibility of the frond structure for each species (Macrocystis = 1.39 +/- 0.82 * 10(-8) Pa(-1); Egregia = 2.59 +/- 5.75 * 10(-9) Pa(-1); Laminaria = 8.65 +/- 8.22 * 10(-9) Pa(-1)). This investigation demonstrates that the acoustic characteristics of kelp are species-specific, biomass-dependent, and differ between species with and without pneumatocyst structures. PMID- 23742337 TI - Numerical and analytical calculation of modal excitability for elastic wave generation in lossy waveguides. AB - In the analysis of elastic waveguides, the excitability of a given mode is an important feature defined by the displacement-force ratio. Useful analytical expressions have been provided in the literature for modes with real wavenumbers (propagating modes in lossless waveguides). The central result of this paper consists in deriving a generalized expression for the modal excitability valid for modes with complex wavenumbers (lossy waveguides or non-propagating modes). The analysis starts from a semi-analytical finite element method and avoids solving the left eigenproblem. Analytical expressions of modal excitability are then deduced. It is shown that the fundamental orthogonality property to be used indeed corresponds to a form of Auld's real orthogonality relation, involving both positive- and negative-going modes. Finally, some results obtained from the generalized excitability are compared to the approximate lossless expression. PMID- 23742338 TI - Reference-free damage detection, localization, and quantification in composites. AB - In this study, a reference-free damage characterization technique is developed not only to identify but also to locate and quantify damage in composite structures subject to varying temperature conditions. First, damage is characterized in terms of a damage index (m-value) defined as the ratio of damage size to the wavelength of the A0 mode within the damage. Then, a feasible solution space defining all possible combinations of the damage location and size are estimated without using any prior baseline data obtained from the pristine condition of a structure or different paths. When additional information such as the A0 mode group velocity within the pristine region of the structure becomes available, the estimates for the damage location and size are updated with better accuracy. The uniqueness of this study lies in that damage localization and quantification as well as identification are all performed without comparing current Lamb wave signals with the ones obtained from the pristine condition of the target structure, making the proposed technique more attractive for online monitoring. Numerical and experimental tests are presented to demonstrate the effectiveness of the proposed damage detection technique under varying temperature. PMID- 23742339 TI - Nonlinear acoustic fields in acoustic metamaterial based on a cylindrical pipe with periodically arranged side holes. AB - Nonlinear acoustic fields in transmission-line acoustic metamaterials based on a cylindrical pipe with periodically arranged side holes are studied, in which the dispersions and characteristic parameters of the nonlinear acoustic waves are obtained with the Bloch theory, and meanwhile the distributions of the fundamental wave (FW) and second harmonic wave (SHW) in the metamaterial are simulated. Three characteristic frequency bands are defined according to the relations between the frequencies of the FW, SHW, and the low-frequency forbidden band (LFB) in the metamaterial. Especially, when the FW is in the LFB while the SHW is outside the LFB, the SHW can transmit through the metamaterial although the FW is blocked, which exhibits the possibility to extract the information from the SHW instead of the FW. In addition, experiments are carried out to measure the distributions of the acoustic pressures for the FW and SHW along the metamaterial and the experimental results are in agreement with the theory. PMID- 23742341 TI - Guided wave mode selection for health monitoring of sub-surface hidden defects on fuel weep holes. AB - The in situ health monitoring of defects on the blind side of open holes using ultrasonic plate waves is a challenging problem. Scattering phenomena in this hard-to-inspect region can be used indicate the presence of the defect. This is especially advantageous if these phenomena give rise to the scattering of a wave mode that is unique to the interaction between the incident wave mode and defect. When the defect in question is located within an inaccessible structure, an understanding of how the incident ultrasonic elastic wave field can be scattered from this hidden defect propagates to the accessible surface is important. This paper presents a series of computational investigations to highlight the essential physics that explains the scattering phenomena by a defect located on the blind side of an open hole. The work presented is relevant to the monitoring of defects located in hard-to-inspect regions of future unitized metallic and composite structures. The outcomes advance the knowledge base of inspection of hard-to-access regions with actuators and sensors placed in easily accessible locations. PMID- 23742340 TI - A theoretical investigation of photoacoustic contrast agents. AB - Photoacoustic imaging offers significant potential as a biomedical imaging modality. For some applications, however, there is a need for contrast enhancement. In this paper, a theoretical comparison is presented of the efficacy of three different designs for photoacoustic contrast agents (PACAs), specifically, a droplet of dye, a bubble filled with gas coated by a dye loaded shell, and a droplet of volatile dye. For each case, the governing equations describing the dynamics of a single PACA in a homogenous incompressible fluid are derived. The coupled sets of equations describing the bubble oscillation and resulting radiated pressure, the photo-acoustic energy equation, and the equation of state are then solved numerically. The numerical results predict a stronger radiated acoustic signal for the same optical source energy density in the case of the volatile dye droplet by a factor of up to two orders of magnitude compared with the other two types of agent. PMID- 23742342 TI - Piezoelectric slotted ring transducer. AB - Analytical treatment of a slotted piezoelectric ceramic ring transducer vibrating in flexure is presented. The mode shape of the slotted ring vibration is determined, and parameters of the equivalent electromechanical circuit of the transducer are calculated. Possibilities to optimize the effective electromechanical coupling coefficient of the transducer by combining active and passive materials are considered. Acoustic loading for typical projectors made from slotted rings is estimated. Challenges in implementing the slotted ring transducers in terms of depth limitation and radiated power are discussed. PMID- 23742343 TI - Reproduction of random pressure fields based on planar nearfield acoustic holography. AB - This article discusses an open-loop approach based on planar nearfield acoustic holography (P-NAH) for the reproduction of random pressure fields, mainly intended for the measurement of vibroacoustic properties of plane panels. The main application is the simulation of turbulent boundary layer excitation in a laboratory environment, as an alternative to in-flight or wind tunnel experiments. The problem under study is the synthesis of random pressure distributions on a plane reproduction surface using acoustic monopoles distributed on a plane source surface facing the reproduction surface. The problem of reproducing a pressure distribution on a plane surface is addressed using the theoretical framework of P-NAH, which is extended to random pressure fields with corresponding imposed cross-spectral density functions. Results of numerical simulations are presented for the reproduction of a diffuse acoustic field, and a subsonic and supersonic turbulent boundary layer. The influence on the reproduction accuracy of the respective sizes of the two planes, their separation and the reproduction source separation are studied. The reproduction approach shows to be effective for the reproduction of diffuse acoustic field and turbulent boundary layer, but with different requirements in terms of plane separation and reproduction sources separation. In the specific case of subsonic turbulent boundary layer and associated sub-wavelength correlation scales reproduction, possible improvements of the method are suggested. PMID- 23742344 TI - The effect of bone conduction microphone placement on intensity and spectrum of transmitted speech items. AB - Speech signals can be converted into electrical audio signals using either conventional air conduction (AC) microphone or a contact bone conduction (BC) microphone. The goal of this study was to investigate the effects of the location of a BC microphone on the intensity and frequency spectrum of the recorded speech. Twelve locations, 11 on the talker's head and 1 on the collar bone, were investigated. The speech sounds were three vowels (/u/, /a/, /i/) and two consonants (/m/, /?/). The sounds were produced by 12 talkers. Each sound was recorded simultaneously with two BC microphones and an AC microphone. Analyzed spectral data showed that the BC recordings made at the forehead of the talker were the most similar to the AC recordings, whereas the collar bone recordings were most different. Comparison of the spectral data with speech intelligibility data collected in another study revealed a strong negative relationship between BC speech intelligibility and the degree of deviation of the BC speech spectrum from the AC spectrum. In addition, the head locations that resulted in the highest speech intelligibility were associated with the lowest output signals among all tested locations. Implications of these findings for BC communication are discussed. PMID- 23742345 TI - Effects of mean flow on transmission loss of orthogonally rib-stiffened aeroelastic plates. AB - This paper investigates the sound transmission loss (STL) of aeroelastic plates reinforced by two sets of orthogonal rib-stiffeners in the presence of external mean flow. Built upon the periodicity of the structure, a comprehensive theoretical model is developed by considering the convection effect of mean flow. The rib-stiffeners are modeled by employing the Bernoulli-Euler beam theory and the torsional wave equation. While the solution for the transmission loss of the structure based on plate displacement and acoustic pressures is given in the form of space-harmonic series, the corresponding coefficients are obtained from the solution of a system of linear equations derived from the plate-beam coupling vibration governing equation and Helmholtz equation. The model predictions are validated by comparing with existing theoretical and experimental results in the absence of mean flow. A parametric study is subsequently performed to quantify the effects of mean flow as well as structure geometrical parameters upon the transmission loss. It is demonstrated that the transmission loss of periodically rib-stiffened structure is increased significantly with increasing Mach number of mean flow over a wide frequency range. The STL value for the case of sound wave incident downstream is pronouncedly larger than that associated with sound wave incident upstream. PMID- 23742346 TI - Long-term effects of noise reduction measures on noise annoyance and sleep disturbance: the Norwegian facade insulation study. AB - The Norwegian facade insulation study includes one pre-intervention and two post intervention surveys. The facade-insulating measures reduced indoor noise levels by 7 dB on average. Before the intervention, 43% of the respondents were highly annoyed by noise. Half a year after the intervention, the proportion of respondents who were highly annoyed by road traffic noise had been significantly reduced to 15%. The second post-intervention study (2 yr after the first post intervention study) showed that the proportion of highly annoyed respondents had not changed since the first post-intervention study. The reduction in the respondents' self-reported sleep disturbances (due to traffic noise) also remained relatively stable from the first to the second post-intervention study. In the control group, there were no statistically significant differences in annoyance between the pre-intervention and the two post-intervention studies. Previous studies of traffic changes have reported that people "overreact" to noise changes. This study indicated that when considering a receiver measure, such as facade insulation, the effect of reducing indoor noise levels could be predicted from exposure-response curves based on previous studies. Thus no evidence of an "overreaction" was found. PMID- 23742347 TI - Reverberation-based urban street sound level prediction. AB - Street reverberation can strongly increase sound pressure levels in urban streets. In noise mapping models on the other hand, including a sufficient number of reflections is computationally very costly. A simple regression model is developed in this study, based on typical street width and facade height or facade roughness in old city centers of many European cities. This model is based on measurements with a mobile setup in 99 streets in the city of Ghent, Belgium, representative for common European city morphology. The reflection ratio (RR) is used as a parameter to determine the energy contained in the reverberation part of the sound field. The model has been successfully validated by detailed measurements at different source-receiver distances in an urban street canyon. PMID- 23742348 TI - The role of diffusive architectural surfaces on auditory spatial discrimination in performance venues. AB - In musical or theatrical performance, some venues allow listeners to individually localize and segregate individual performers, while others produce a well blended ensemble sound. The room acoustic conditions that make this possible, and the psycho-acoustic effects at work are not fully understood. This research utilizes auralizations from measured and simulated performance venues to investigate spatial discrimination of multiple acoustic sources in rooms. Signals were generated from measurements taken in a small theater, and listeners in the audience area were asked to distinguish pairs of speech sources on stage with various spatial separations. This experiment was repeated with the proscenium splay walls treated to be flat, diffusive, or absorptive. Similar experiments were conducted in a simulated hall, utilizing 11 early reflections with various characteristics, and measured late reverberation. The experiments reveal that discriminating the lateral arrangement of two sources is possible at narrower separation angles when reflections come from flat or absorptive rather than diffusive surfaces. PMID- 23742349 TI - Converting Sabine absorption coefficients to random incidence absorption coefficients. AB - Absorption coefficients measured by the chamber method are referred to as Sabine absorption coefficients, which sometimes exceed unity due to the finite size of a sample and non-uniform intensity in the reverberation chambers under test. In this study, conversion methods from Sabine absorption coefficients to random incidence absorption coefficients are proposed. The overestimations of the Sabine absorption coefficient are investigated theoretically based on Miki's model for porous absorbers backed by a rigid wall or an air cavity, resulting in conversion factors. Additionally, three optimizations are suggested: An optimization method for the surface impedances for locally reacting absorbers, the flow resistivity for extendedly reacting absorbers, and the flow resistance for fabrics. With four porous type absorbers, the conversion methods are validated. For absorbers backed by a rigid wall, the surface impedance optimization produces the best results, while the flow resistivity optimization also yields reasonable results. The flow resistivity and flow resistance optimization for extendedly reacting absorbers are also found to be successful. However, the theoretical conversion factors based on Miki's model do not guarantee reliable estimations, particularly at frequencies below 250 Hz and beyond 2500 Hz. PMID- 23742350 TI - Combination of acoustical radiosity and the image source method. AB - A combined model for room acoustic predictions is developed, aiming to treat both diffuse and specular reflections in a unified way. Two established methods are incorporated: acoustical radiosity, accounting for the diffuse part, and the image source method, accounting for the specular part. The model is based on conservation of acoustical energy. Losses are taken into account by the energy absorption coefficient, and the diffuse reflections are controlled via the scattering coefficient, which defines the portion of energy that has been diffusely reflected. The way the model is formulated allows for a dynamic control of the image source production, so that no fixed maximum reflection order is required. The model is optimized for energy impulse response predictions in arbitrary polyhedral rooms. The predictions are validated by comparison with published measured data for a real music studio hall. The proposed model turns out to be promising for acoustic predictions providing a high level of detail and accuracy. PMID- 23742351 TI - Investigation on the effect of aperture sizes and receiver positions in coupled rooms. AB - Some recent concert hall designs have incorporated coupled reverberation chambers to the main hall that have stimulated a range of research activities in architectural acoustics. The coupling apertures between two or more coupled volume systems are of central importance for sound propagation and sound energy decays throughout the coupled-volume systems. In addition, positions of sound sources and receivers relative to the aperture also have a profound influence on the sound energy distributions and decays. This work investigates the effect of aperture size on the behavior of coupled-volume systems using both acoustic scale models and diffusion equation models. In these physical and numerical models, the sound source and receiver positions relative to the aperture are also investigated. Through systematic comparisons between results achieved from both physical scale models and numerical models, this work reveals valid ranges and limitations of the diffusion equation model for room-acoustic modeling. PMID- 23742352 TI - Acoustic imaging of a duct spinning mode by the use of an in-duct circular microphone array. AB - An imaging method of acoustic spinning modes propagating within a circular duct simply with surface pressure information is introduced in this paper. The proposed method is developed in a theoretical way and is demonstrated by a numerical simulation case. Nowadays, the measurements within a duct have to be conducted using in-duct microphone array, which is unable to provide information of complete acoustic solutions across the test section. The proposed method can estimate immeasurable information by forming a so-called observer. The fundamental idea behind the testing method was originally developed in control theory for ordinary differential equations. Spinning mode propagation, however, is formulated in partial differential equations. A finite difference technique is used to reduce the associated partial differential equations to a classical form in control. The observer method can thereafter be applied straightforwardly. The algorithm is recursive and, thus, could be operated in real-time. A numerical simulation for a straight circular duct is conducted. The acoustic solutions on the test section can be reconstructed with good agreement to analytical solutions. The results suggest the potential and applications of the proposed method. PMID- 23742353 TI - Spherical array processing for acoustic analysis using room impulse responses and time-domain smoothing. AB - Room impulse responses (RIRs) have been widely used for room acoustics analysis. One of the major objectives in room acoustics analysis is characterizing the directions of arrival (DOA) of the direct sound and early room reflections. In the past, spherical microphone arrays have been used to sample the sound field, taking advantage of their spatial symmetry, and various optimal array processing methods have been suggested for DOA estimation. However, these methods fail when the sound field is composed of highly correlated components, such as room reflections, since the cross-spectrum matrix may be of deficient rank. Recently, a preprocessing method incorporating smoothing of the cross-correlation matrix in the frequency domain has been suggested to overcome the rank deficiency. However, when using low-order spherical arrays, this method also fails due to the need to estimate the DOA of a group of reflections simultaneously. In this paper, an alternative time-domain smoothing approach is suggested. The method utilizes the time behavior of the RIR to separate early reflections, together with representation of the signal in the spherical-harmonics domain, to achieve improved performance over current methods. Simulation and experimental studies illustrate the limitations of the former method and the advantages of the suggested method. PMID- 23742354 TI - Ultrasonic recording system without intrinsic limits. AB - Today state-of-the-art bioacoustic research requires high-sample-rate, multi channel, and often long-term recording systems. Commercial systems are very costly. This paper proposes and demonstrates an ultrasonic recording system design that is arbitrarily scalable. The system is modular and based on retail components and open source software/hardware. Each module has four microphones and modules can be combined to extend the coverage area, obtain higher spatial recording resolution, and/or add recording redundancy. The system is designed to have no inherent scalability limits. The system has been deployed in four different test settings. The first setup tests the system's ability to make medium-term recordings (1 to 2 min) with many microphones. The second setup tests the robustness of the system, being deployed throughout the Danish winter with only minor issues. The third setup integrates the system in a mobile robot as an echolocating guidance system, while the fourth setup demonstrates full-spectrum transducer calibration. In most respects this system's hardware specification surpasses all competitors on the market at a quarter of the price. Tests demonstrate that large deployments are feasible and accurate ultrasonic measurements can be obtained. PMID- 23742355 TI - Use of mode subspace projections for depth discrimination with a horizontal line array: theory and experimental results. AB - A solution to the problem of acoustic source depth discrimination in a downward refracting, shallow-water ocean waveguide is presented for the case of a horizontal line array at endfire. The approach exploits the phenomenon of mode trapping, wherein a shallow acoustic source cannot excite the lowest order waveguide modes due to its evanescent amplitude dependence near the surface. The important implication of this "trapping" behavior is that, given sufficient spatial aperture, it provides a mechanism for differentiating a shallow acoustic noise source from one at depth. The method does not require array cant, or physical vertical aperture of any kind, but instead relies only on the sensitivity of a line array at endfire to differences in horizontal wave number to resolve low and high order mode subspace excitations. The only inputs to the algorithm are an approximate sound speed profile, water depth, and bottom type. The theoretical basis for the test statistic is first reviewed, followed by discussion of key requirements, and illustration of the concept using results from a RAM PE simulation for a downward refracting environment. Finally, the algorithm is experimentally demonstrated using data from a bottom-mounted HLA deployed in the moderately cluttered continental shelf environment of the Florida Straits. PMID- 23742356 TI - Bayesian approach of nearfield acoustic reconstruction with particle filters. AB - This paper demonstrates that inverse source reconstruction can be performed using a methodology of particle filters that relies primarily on the Bayesian approach of parameter estimation. In particular, the proposed approach is applied in the context of nearfield acoustic holography based on the equivalent source method (ESM). A state-space model is formulated in light of the ESM. The parameters to estimate are amplitudes and locations of the equivalent sources. The parameters constitute the state vector which follows a first-order Markov process with the transition matrix being the identity for every frequency-domain data frame. Filtered estimates of the state vector obtained are assigned weights adaptively. The implementation of recursive Bayesian filters involves a sequential Monte Carlo sampling procedure that treats the estimates as point masses with a discrete probability mass function (PMF) which evolves with iteration. The weight update equation governs the evolution of this PMF and depends primarily on the likelihood function and the prior distribution. It is evident from the simulation results that the inclusion of the appropriate prior distribution is crucial in the parameter estimation. PMID- 23742357 TI - An investigation of acoustic beam patterns for the sonar localization problem using a beam based method. AB - Target localization can be accomplished through an ultrasonic sonar system equipped with an emitter and two receivers. Time of flight of the sonar echoes allows the calculation of the distance of the target. The orientation can be estimated from knowledge of the beam pattern of the receivers and the ratio, in the frequency domain, between the emitted and the received signals after compensation for distance effects and air absorption. The localization method is described and, as its performance strongly depends on the beam pattern, the search of the most appropriate sonar receiver in order to ensure the highest accuracy of target orientation estimations is developed in this paper. The structure designs considered are inspired by the ear shapes of some bat species. Parameters like flare rate, truncation angle, and tragus are considered in the design of the receiver structures. Simulations of the localization method allow us to state which combination of those parameters could provide the best real world implementation. Simulation results show the estimates of target orientations are, in the worst case, 2 degrees with SNR = 50 dB using the receiver structure chosen for a potential practical implementation of a sonar system. PMID- 23742358 TI - Passive sonic detection and ranging for locating sound sources. AB - A passive sonic detection and ranging (SODAR) technology is developed to locate sound sources that emit arbitrarily time-dependent signals in a typical environment encountered in practice in real time. This passive SODAR is built on a comprehensive approach including the pre-processing of input data to enhance the signal-to-noise ratio, acoustic modeling of sound radiation from a point source, iterative triangulations, and post-processing of output data to ensure the accuracy in source localization. Moreover, it employs an optimization process to extend the source detection range and improve the source localization accuracy in a highly non-ideal environment that involves a large number of unspecified reflected and diffracted sound waves. This is accomplished through computations based on the source locations predicted by the individual units of four microphones that are not lying on the same plane. Experimental results confirm that passive SODAR works for arbitrarily time-dependent signals that include continuous, transient, impulsive, random, narrow-, and broadband sounds with frequencies above 20 Hz. The minimum number of microphones that are required in passive SODAR is six. These microphones can be mounted anywhere as long as they are not on the same plane and the lines of sight from sound sources remain unblocked. PMID- 23742359 TI - Processing advances for localization of beaked whales using time difference of arrival. AB - This paper is concerned with the localization of clicking Blainville's beaked whales (Mesoplodon densirostris) using an array of widely spaced bottom-mounted hydrophones. A set of signal and data processing advances are presented that together make reliable tracking a possibility. These advances include a species specific detector, elimination of spurious time-difference-of-arrival (TDOA) estimates, improved tracking of TDOA estimates, positive association of TDOA estimates using different hydrophone pairs, and joint localization of multiple whales. A key innovation in three of these advances is the principle of click matching. The methods are demonstrated using real data. PMID- 23742360 TI - A beam based method for target localization: inspiration from bats' directivity and binaural reception for ultrasonic sonar. AB - The process of echolocation is accomplished by bats partly using the beam profiles associated with their ear shapes that allow for discrimination between different echo directions. Indeed, knowledge of the emitted signal characteristic and measurement of the echo travel time from a target make it possible to compensate for attenuation due to distance, and to focus on filtering through the receivers' beam profiles by comparing received echoes to the original signal at all frequencies in the spectrum of interest. From this basis, a beam profile method to localize a target in three-dimensional space for an ultrasonic sensor system equipped with an emitter and two receivers is presented. Simulations were conducted with different noise levels, and only the contribution of the receivers' beam profiles was considered to estimate the orientation of the target with respect to the receivers. The beam pattern of the Phyllostomus discolor's ear was adopted as that of a receiver. Analyses of beam resolution and frequency ranges were conducted to enhance the accuracy of orientation estimates. The choice of appropriate resolution and frequency ranges guarantee that error mean values for most of the orientations are within [0.5 degrees , 1.5 degrees ], even in noisy situations: Signal-to-noise ratio values considered in this work are 35 and 50 dB. PMID- 23742361 TI - Non-intrusive planar velocity-based nearfield acoustic holography in moving fluid medium. AB - Nearfield Acoustic Holography (NAH) is a powerful acoustic imaging method, but its application in aeronautics can be limited by intrusive measurements of acoustic field. In this paper, a moving fluid medium NAH procedure using non intrusive velocity measurements is proposed. This method is based on convective Kirchhoff-Helmholtz integral formula. Convective equations and convective Green's function are used to derive convective real-space propagators including airflow effects. Discrete Fourier transforms of these propagators allow the assessment of acoustic fields from acoustic pressure or normal acoustic velocity measurements. As the aim is to derive an in-flow velocity-based NAH method, this study is especially focused on real convective velocity-to-pressure propagator. In order to validate this procedure, simulations in the case of monopole sources radiating in various uniform subsonic flows have been performed. NAH provides very favorable results when compared to the simulated fields. A comparison of results obtained by the real propagator and those obtained by the wave number-frequency domain one developed by Kwon et al. [J. Acoust. Soc. Am. 128(4), 1823-1832 (2010)] shows the interest of using the real-form in the case of pressure backward propagation from velocity measurements. The efficiency of the developed procedure is confirmed by a wind tunnel campaign with a flush-mounted loudspeaker and non-intrusive Laser Doppler Velocimetry velocity measurements. PMID- 23742362 TI - Generation place of the long- and short-latency components of transient-evoked otoacoustic emissions in a nonlinear cochlear model. AB - Time-domain numerical solutions of a nonlinear active cochlear model forced by click stimuli are analyzed with a time-frequency wavelet technique to identify the components of the otoacoustic response associated with different generation mechanisms/places. Previous experimental studies have shown evidence for the presence of at least two components in the transient otoacoustic response: A long latency response, growing compressively with increasing stimulus level, and a shorter-latency response, characterized by faster growth. The possible mechanisms for the generation of the two components are discussed using the results of the numerical simulations. The model is a one-dimensional (1-D) transmission line model with nonlinear and nonlocal active terms representing the anti-damping action of the "cochlear amplifier." The dependence on the stimulus level of latency and level was measured for the different components of the response. The generation mechanisms/places of the different components were identified by varying the stimulus level and by turning off the cochlear roughness in well defined cochlear regions. The results suggest that reflections from roughness coming from basal regions of the cochlea may give a relevant contribution to the early otoacoustic response, whereas nonlinear mechanisms seem to produce a much smaller additional contribution. PMID- 23742363 TI - Place specificity of monopolar and tripolar stimuli in cochlear implants: the influence of residual masking. AB - This experiment investigated whether place specificity of neural activity evoked by cochlear implant stimulation is improved in tripolar compared to monopolar mode using a forward masking protocol addressing some limitations of previous methods of measurement and analysis. The amount of residual masking (masking remaining at long masker-probe delays) was also measured, and its potential influence on the specificity measures was evaluated. The masker stimulus comprised equally loud interleaved mono- or tripolar stimulation on two electrodes equidistant from a central probe electrode in an apical and basal direction, reducing the influence of off-site listening. The effect of masker probe distance on the threshold shift of the tripolar probe was analyzed to derive a measure of place specificity. On average, tripolar maskers were more place specific than monopolar maskers, although the mean effect was small. There was no significant effect of masker level on specificity or on the differences observed between modes. The mean influence of residual masking on normalized masking functions was similar for the two modes and, therefore, did not influence the comparison of specificity between the modes. However, variability in amount of residual masking was observed between subjects, and therefore should be considered in forward masking studies that compare place specificity across subjects. PMID- 23742364 TI - Compensation for channel interaction in a simultaneous cochlear implant coding strategy. AB - This study evaluated a concept to reduce detrimental effects of spatial channel interaction in case of simultaneous stimulation with cochlear implants. The hypothesis was that effects of simultaneous channel interaction can be compensated by an algorithm such that no difference in hearing performance between simultaneous pulsatile stimulation and a strictly sequential reference strategy can be found. The simultaneous strategies used in this study stimulated two or three electrodes simultaneously in a monopolar configuration and used a specific compensation algorithm to reduce detrimental effects of simultaneous channel interaction. Overall stimulation rate was kept constant throughout conditions. Three of the configurations applied extended pulse phase durations. The German Oldenburg sentence and a German vowel test were used to measure speech recognition in 12 cochlear implant users. The results support the initial hypothesis. No significant differences in performance were found. A small spatial distance between simultaneous electrodes yielded slightly better results than a large distance. Extending the pulse phase durations had no significant effect on hearing performance. However, it significantly reduced stimulation amplitudes. Thus strategies implementing channel interaction compensated simultaneous stimulation with extended pulse phase durations might be a viable option for reducing power consumption and increasing battery life in cochlear implants. PMID- 23742365 TI - A bond graph approach to modeling the anuran vocal production system. AB - Air-driven vocal production systems such as those found in mammals, birds, and anurans (frogs and toads) combine pneumatic and mechanical elements in species specific ways to produce a diversity of communication signals. This study uses bond graphs to model a generalized anuran vocal production system. Bond graphs allow an incremental approach to modeling dynamic physical systems involving different domains. Anurans provide an example of how signal diversity results from variation in the structure and behavior of vocal system elements. This paper first proposes a bond graph model of the integrated anuran vocal system as a framework for future study. It then presents a simulated submodel of the anuran sound source that produces sustained oscillations in vocal fold displacement and air flow through the larynx. The modeling approach illustrated here should prove of general applicability to other biological sound production systems, and will allow researchers to study the biomechanics of vocal production as well as the functional congruence and evolution of groups of traits within integrated vocal systems. PMID- 23742366 TI - Estimating peripheral gain and compression using fixed-duration masking curves. AB - Estimates of human basilar membrane gain and compression obtained using temporal masking curve (TMC) and additivity of forward masking (AFM) methods with long duration maskers or long masker-signal silent intervals may be affected by olivocochlear efferent activation, which reduces basilar membrane gain. The present study introduces a fixed-duration masking curve (FDMC) method, which involves a comparison of off- and on-frequency forward masker levels at threshold as a function of masker and signal duration, with the total masker-signal duration fixed at 25 ms to minimize efferent effects. Gain and compression estimates from the FDMC technique were compared with those from TMC (104-ms maskers) and AFM (10- and 200-ms maskers) methods. Compression estimates over an input-masker range of 40-60 dB sound pressure level were similar for the four methods. Maximum compression occurred at a lower input level for the FDMC compared to the TMC method. Estimates of gain were similar for TMC and FDMC methods. The FDMC method may provide a more reliable estimate of BM gain and compression in the absence of efferent activation and could be a useful method for estimating effects of efferent activity when used with a precursor sound (to trigger efferent activation), presented prior to the combined masker-signal stimulus. PMID- 23742368 TI - Masking functions and fixed-signal functions for low-level 1000-Hz tones. AB - Masking functions and fixed-signal functions were constructed using a narrow range of pedestal intensities for 10-ms, 1000-Hz gated tones. Data from three experiments agreed with previously reported data, clearly demonstrating negative masking and the pedestal effect. The data extend earlier findings by showing (1) the resilience of the pedestal effect when a background noise masker is introduced; (2) a possible indifference of the fixed-signal function to stimulus duration; (3) the ability of a set of psychometric functions to produce both masking and fixed-signal functions; (4) depending on method, the impact of unit choice on the interpretation of both the pedestal effect and negative masking data. Results are discussed in relation to current psychophysical models, and suggest that accounting for the auditory system's sensitivity to differences in low-level sounds remains a challenge. PMID- 23742367 TI - Infants' detection and discrimination of sounds in modulated maskers. AB - Adults and 7-month-old infants were compared in detection and discrimination of sounds in modulated maskers. In two experiments, the level of a target sound was varied to equate listeners' performance in unmodulated noise, and performance was assessed at that level in a noise modulated with the envelope of single-talker speech. While adults' vowel discrimination and tone detection were better in the modulated than in the unmodulated masker, infants' vowel discrimination was poorer in the modulated than in the unmodulated masker. Infants' tone detection was the same in the two maskers. In two additional experiments, each age group was tested at one level with order of testing in modulated and unmodulated maskers counterbalanced across subjects. Both infants and adults discriminated between vowels better in single-talker modulated and sinusoidally amplitude modulated (SAM) maskers than in an unmodulated masker, but infants' modulated unmodulated difference was smaller than than that of adults. Increasing the modulation depth of the SAM masker did not affect the size of infants' modulated unmodulated difference. However, infants' asymptotic performance in a modulated masker limits the extent to which their performance could improve. Infants can make use of information in masker dips, but masker modulation may also interfere with their ability to process the target. PMID- 23742369 TI - Age-related differences in the sequential organization of speech sounds. AB - This study investigated the effects of age on listeners' tendency to group speech tokens into one or two auditory streams. Younger and older adults were presented with sequences of four vowel sounds, which were arranged according to the proximity of first-formant frequencies between adjacent vowels. In Experiment 1, participants were less accurate in identifying the order of the four vowels and more likely to report hearing two streams when the first-formant alternated between low and high frequency and the overall difference between adjacent vowels was large. This effect of first-formant continuity on temporal order judgments and probability of hearing two streams was higher in younger than in older adults. In Experiment 2, participants indicated whether there was rhythm irregularity in an otherwise isochronous sequence of four vowels. Young adults' thresholds were lower when successive first-formants ascended or descended monotonically (condition promoting integration) than when they alternated discontinuously (condition promoting streaming). This effect was not observed in older adults whose thresholds were comparable for both types of vowel sequences. These two experiments provide converging evidence for an age-related deficit in exploiting first-formant information between consecutive vowels, which appear to impede older adults' ability to sequentially group speech sounds over time. PMID- 23742370 TI - Reverberation suppression in cochlear implants using a blind channel-selection strategy. AB - Reverberation severely degrades speech intelligibility for cochlear implant (CI) users. The ideal reverberant mask (IRM), a binary mask for reverberation suppression which is computed using signal-to-reverberant ratio, was found to yield substantial intelligibility gains for CI users even in highly reverberant environments (e.g., T60 = 1.0 s). Motivated by the intelligibility improvements obtained from IRM, a monaural blind channel-selection criterion for reverberation suppression is proposed. The proposed channel-selection strategy is blind, meaning that prior knowledge of neither the room impulse response nor the anechoic signal is required. By the use of a residual signal obtained from linear prediction analysis of the reverberant signal, the residual-to-reverberant ratio (RRR) of individual frequency channels was employed as the channel-selection criterion. In each frame, the channels with RRR less than an adaptive threshold were retained while the rest were zeroed out. Performance of the proposed strategy was evaluated via intelligibility listening tests conducted with CI users in simulated rooms with two reverberation times of 0.6 and 0.8 s. The results indicate significant intelligibility improvements in both reverberant conditions (over 30 and 40 percentage points in T60 = 0.6 and 0.8 s, respectively). The improvement is comparable to that obtained with the IRM strategy. PMID- 23742371 TI - Finite element computation of elliptical vocal tract impedances using the two microphone transfer function method. AB - A two-microphone transfer function (TMTF) method is adapted to a numerical framework to compute the radiation and input impedances of three-dimensional vocal tracts of elliptical cross-section. In its simplest version, the TMTF method only requires measuring the acoustic pressure at two points in an impedance duct and the postprocessing of the corresponding transfer function. However, some considerations are to be taken into account when using the TMTF method in the numerical context, which constitute the main objective of this paper. In particular, the importance of including absorption at the impedance duct walls to avoid lengthy numerical simulations is discussed and analytical complex axial wave numbers for elliptical ducts are derived for this purpose. It is also shown how the direct impedance of plane wave propagation can be computed beyond the TMTF maximum threshold frequency by appropriate location of the virtual microphones. Virtual microphone spacing is also discussed on the basis of the so-called singularity factor. Numerical examples include the computation of the radiation impedance of vowels /a/, /i/, and /u/ and the input impedance of vowel /a/, for simplified vocal tracts of circular and elliptical cross-sections. PMID- 23742372 TI - Development of speech motor control: lip movement variability. AB - This study examined variability of lip movements across repetitions of the same utterance as a function of age in Swedish speakers. The specific purpose was to extend earlier findings by examining variability in both phase and amplitude. Subjects were 50 typically developed native Swedish children and adults (28 females, 22 males, aged 5 to 31 yr). Lip movements were recorded during 15 to 20 repetitions of a short Swedish phrase using three-dimensional articulography. After correction for head movements, the kinematic records were expressed in a maxilla-based coordinate system. Movement onset and offset of the utterance were identified using kinematic landmarks. The Euclidean distance between receivers on the upper and lower lips was calculated and subjected to functional data analysis to assess both phase and amplitude variability. Results show a decrease in both indices as a function of age, with a greater reduction of amplitude variability. There was no difference between males and females for either index. The two indices were moderately correlated with each other, suggesting that they capture different aspects of speech production. Utterance duration also decreased with age, but variability was unrelated to duration. The standard deviation of utterance duration also decreased with age. The present results thus suggest that age related changes in speech motor control continue up until 30 years of age. PMID- 23742373 TI - Explaining coherence in coherence masking protection for adults and children. AB - Coherence masking protection (CMP) is the phenomenon in which a low-frequency target (typically a first formant) is labeled accurately in poorer signal-to noise levels when combined with a high-frequency cosignal, rather than presented alone. An earlier study by the authors revealed greater CMP for children than adults, with more resistance to disruptions in harmonicity across spectral components [Nittrouer and Tarr (2011). Atten. Percept. Psychophys. 73, 2606 2623]. That finding was interpreted as demonstrating that children are obliged to process speech signals as broad spectral patterns, regardless of the harmonic structure of the spectral components. The current study tested three alternative, auditory explanations for the observed coherence of target + cosignal: (1) unique spectral shapes of target + cosignal support labeling, (2) periodicity of target + cosignal promotes coherence, and (3) temporal synchrony across target + cosignal reinforces temporal expectancies. Adults, eight-year-olds, and five-year olds labeled stimuli in five conditions: F1 only and F1 + a constant cosignal (both used previously) were benchmarks for comparing thresholds for F1 + 3 new cosignals. Children again showed greater CMP than adults, but none of the three hypotheses could explain their CMP. It was again concluded that children are obliged to recognize speech signals as broad spectral patterns. PMID- 23742375 TI - Perceptual and production training of intervocalic /d, r, r/ in American English learners of Spanish. AB - This study investigates the effectiveness of three high variability training paradigms in training 42 speakers of American English to correctly perceive and produce Spanish intervocalic /d, r, r/. Since Spanish spirantization and English flapping both affect /d/ intervocalically, the acquisition of the /d/-/r/ contrast proves difficult for English learners of Spanish. The acquisition of the trill /r/ is also problematic because it is a new phoneme for English learners and is articulatorily difficult to produce. Past research reported that high variability perceptual training improves both perception and production [Bradlow et al., J. Acoust. Soc. Am. 101, 2299-2310 (1997); Wang et al., J. Acoust. Soc. Am. 113, 1033-1043 (2003)] and that production training improves both as well [Hirata, Comp. Assisted Lang. Learning 17, 357-376 (2004)]. However, trainees were able to listen to stimuli during production training, making it unclear whether production training alone transfers to perception. This study systematically controls both training modalities so they can be directly compared and introduces a third training methodology that includes both perception and production. All three training paradigms proved effective. While perception and production trainees primarily made gains in perception, combination trainees made gains in production. The effectiveness of each training modality depended on the nature of the contrast being trained and the modality of the test. PMID- 23742374 TI - The developmental trajectory of children's perception and production of English /r/-/l/. AB - The English /l-r/ distinction is difficult to learn for some second language learners as well as for native-speaking children. This study examines the use of the second (F2) and third (F3) formants in the production and perception of /l/ and /r/ sounds in 4-, 4.5-, 5.5-, and 8.5-yr-old English-speaking children. The children were tested with elicitation and repetition tasks as well as word recognition tasks. The results indicate that whereas young children's /l/ and /r/ in both production and perception show fairly high accuracy and were well defined along the primary acoustic parameter that differentiates them, F3 frequency, these children were still developing in regard to the integration of the secondary cue, F2 frequency. The pattern of development is consistent with the distribution of these features in the ambient input relative to the /l/ and /r/ category distinction: F3 is robust and reliable, whereas F2 is less reliable in distinguishing /l/ and /r/. With delayed development of F2, cue weighting of F3 and F2 for the English /l-r/ categorization seems to continue to develop beyond 8 or 9 yr of age. These data are consistent with a rather long trajectory of phonetic development whereby native categories are refined and tuned well into childhood. PMID- 23742376 TI - Cross-language similarities and differences in the uptake of place information. AB - Cross-language differences in the use of coarticulatory cues for the identification of fricatives have been demonstrated in a phoneme detection task: Listeners with perceptually similar fricative pairs in their native phoneme inventories (English, Polish, Spanish) relied more on cues from vowels than listeners with perceptually more distinct fricative contrasts (Dutch and German). The present gating study further investigated these cross-language differences and addressed three questions. (1) Are there cross-language differences in informativeness of parts of the speech signal regarding place of articulation for fricative identification? (2) Are such cross-language differences fricative specific, or do they extend to the perception of place of articulation for plosives? (3) Is such language-specific uptake of information based on cues preceding or following the consonantal constriction? Dutch, Italian, Polish, and Spanish listeners identified fricatives and plosives in gated CV and VC syllables. The results showed cross-language differences in the informativeness of coarticulatory cues for fricative identification: Spanish and Polish listeners extracted place of articulation information from shorter portions of VC syllables. No language-specific differences were found for plosives, suggesting that greater reliance on coarticulatory cues did not generalize to other phoneme types. The language-specific differences for fricatives were based on coarticulatory cues into the consonant. PMID- 23742377 TI - Predicting the effect of hearing loss and audibility on amplified speech reception in a multi-talker listening scenario. AB - Auditive and cognitive influences on speech perception in a complex situation were investigated in listeners with normal hearing (NH) and hearing loss (HL). The speech corpus used was the Nonsense-Syllable Response Measure [NSRM; Woods and Kalluri, (2010). International Hearing Aid Research Conference, pp. 40-41], a 12-talker corpus which combines 154 nonsense syllables with 8 different carrier phrases. Listeners heard NSRM sentences in quiet, background noise, and in background noise plus other "jammer" NSRM sentences. All stimuli were linearly amplified. A "proficiency" value, determined from the results in quiet and the quiet-condition speech intelligibility index (SII), was used with the SII in predicting results in the other conditions. Results for nine of ten NH subjects were well-predicted (within the limits of binomial variability) in the noise condition, as were eight of these subjects in the noise-plus-jammers condition. All 16 HL results were well-predicted in the noise condition, as were 9 of the HL in the noise-plus-jammers condition. Hierarchical regression partialling out the effects of age found proficiency in noise-plus-jammers significantly correlated with results of "trail-making" tests, thought to index processing speed and attention-deployment ability, and proficiency in quiet and noise was found significantly correlated with results from a backward digit-span memory test. PMID- 23742378 TI - The role of first formant information in simulated electro-acoustic hearing. AB - Cochlear implant (CI) recipients with residual hearing show improved performance with the addition of low-frequency acoustic stimulation (electro-acoustic stimulation, EAS). The present study sought to determine whether a synthesized first formant (F1) signal provided benefit to speech recognition in simulated EAS hearing and to compare such benefit with that from other low-frequency signals. A further aim was to determine if F1 amplitude or frequency was more important in determining benefit and if F1 benefit varied with formant bandwidth. In two experiments, sentence recordings from a male speaker were processed via a simulation of a partial insertion CI, and presented to normal hearing listeners in combination with various low-frequency signals, including a tone tracking fundamental frequency (F0), low-pass filtered speech, and signals based on F1 estimation. A simulated EAS benefit was found with F1 signals, and was similar to the benefit from F0 or low-pass filtered speech. The benefit did not differ significantly with the narrowing or widening of the F1 bandwidth. The benefit from low-frequency envelope signals was significantly less than the benefit from any low-frequency signal containing fine frequency information. Results indicate that F1 provides a benefit in simulated EAS hearing but low frequency envelope information is less important than low frequency fine structure in determining such benefit. PMID- 23742379 TI - Synchrony capture filterbank: auditory-inspired signal processing for tracking individual frequency components in speech. AB - A processing scheme for speech signals is proposed that emulates synchrony capture in the auditory nerve. The role of stimulus-locked spike timing is important for representation of stimulus periodicity, low frequency spectrum, and spatial location. In synchrony capture, dominant single frequency components in each frequency region impress their time structures on temporal firing patterns of auditory nerve fibers with nearby characteristic frequencies (CFs). At low frequencies, for voiced sounds, synchrony capture divides the nerve into discrete CF territories associated with individual harmonics. An adaptive, synchrony capture filterbank (SCFB) consisting of a fixed array of traditional, passive linear (gammatone) filters cascaded with a bank of adaptively tunable, bandpass filter triplets is proposed. Differences in triplet output envelopes steer triplet center frequencies via voltage controlled oscillators (VCOs). The SCFB exhibits some cochlea-like responses, such as two-tone suppression and distortion products, and possesses many desirable properties for processing speech, music, and natural sounds. Strong signal components dominate relatively greater numbers of filter channels, thereby yielding robust encodings of relative component intensities. The VCOs precisely lock onto harmonics most important for formant tracking, pitch perception, and sound separation. PMID- 23742380 TI - Auditory perception of note transitions in simulated complex bowing patterns. AB - Recent motion-capture measurements of violin bowing revealed an interesting coordination behavior in fast repetitive bowing patterns involving bow changes and string crossings; bow changes were consistently lagging behind string crossings, and the relative timing appeared to be an integral part of the bow movement patterns. The aim of the current study was to investigate if there might be a perceptual explanation for the observed coordination behavior. For this purpose a virtual violin was used, controlled by simulated bowing gestures. A simplified coordination model is presented, which was implemented to allow real time control of complex bowing patterns. This synthesis approach was employed in a perceptual experiment in which the participants were asked to optimize the sound by adjusting a slider controlling the main coordination parameters. It was found that the resulting coordination patterns were similar to those observed in performance, implying that complex bowing trajectories for an important part emerge from auditory-motor interaction. Further analysis of the responses shed light on temporal and spatial constraints of the simulated gestures associated with the note transitions. The results raise interesting questions with regard to auditory-motor interaction in complex instrumental control gestures. PMID- 23742381 TI - Baird's beaked whale echolocation signals. AB - Echolocation signals from Baird's beaked whales were recorded during visual and acoustic shipboard surveys of cetaceans in the California Current ecosystem and with autonomous, long-term recorders in the Southern California Bight. The preliminary measurement of the visually validated Baird's beaked whale echolocation signals from towed array data were used as a basis for identifying Baird's signals in the autonomous recorder data. Two distinct signal types were found, one being a beaked whale-like frequency modulated (FM) pulse, the other being a dolphin-like broadband click. The median FM inter-pulse interval was 230 ms. Both signal types showed a consistent multi-peak structure in their spectra with peaks at ~9, 16, 25, and 40 kHz. Depending on signal type, as well as recording aspect and distance to the hydrophone, these peaks varied in relative amplitude. The description of Baird's echolocation signals will allow for studies of their distribution and abundance using towed array data without associated visual sightings and from autonomous seafloor hydrophones. PMID- 23742382 TI - Rayleigh wave propagation method for the characterization of a thin layer of biomaterials. AB - An experimental method based on Rayleigh wave propagation was developed for quantifying the frequency-dependent viscoelastic properties of a small volume of expensive biomaterials over a broad frequency range. Synthetic silicone rubber and gelatin materials were fabricated and tested to evaluate the proposed method. Planar harmonic Rayleigh waves at different frequencies, from 80 to 4000 Hz, were launched on the surface of a sample composed of a substrate with known material properties coated with a thin layer of the soft material to be characterized. A transfer function method was used to obtain the complex Rayleigh wavenumber. An inverse wave propagation problem was solved and a complex nonlinear dispersion equation was obtained. The complex shear and elastic moduli of the sample materials were then calculated through the numerical solution of the obtained dispersion equation using the measured wavenumbers. The results were in good agreement with those of a previous independent study. The proposed method was found to be reliable and cost effective for the measurement of viscoelastic properties of a thin layer of expensive biomaterials, such as phonosurgical biomaterials, over a wide frequency range. PMID- 23742437 TI - Improved vocal tract reconstruction and modeling using an image super-resolution technique. AB - Magnetic resonance imaging has been widely used in speech production research. Often only one image stack (sagittal, axial, or coronal) is used for vocal tract modeling. As a result, complementary information from other available stacks is not utilized. To overcome this, a recently developed super-resolution technique was applied to integrate three orthogonal low-resolution stacks into one isotropic volume. The results on vowels show that the super-resolution volume produces better vocal tract visualization than any of the low-resolution stacks. Its derived area functions generally produce formant predictions closer to the ground truth, particularly for those formants sensitive to area perturbations at constrictions. PMID- 23742438 TI - Attenuation as a function of the canal length of custom-molded earplugs: a pilot study. AB - Custom-molded earplugs (CMEPs) whose canal segments extend beyond the second bend of the ear canal can provide excellent attenuation but can sometimes be uncomfortable. Attenuation was measured for CMEPs whose canal segments were shortened in 2-mm increments. The within-subjects design permitted illustration of the form of the function relating attenuation to canal segment length for individuals. Reduction of attenuation due to canal segment shortening was generally more pronounced for frequencies <=1000 Hz. Some regions of the canal segments were more critical than others in maintaining attenuation. The relationship between comfort and canal segment length was not straightforward. PMID- 23742439 TI - Longitudinal trends in speech tempo: the case of Queen Beatrix. AB - Older talkers speak slower than young ones, but speech tempo has increased in the last decades. Have present-day older talkers slowed down with age or have they sped up with their community? This study investigates longitudinal patterns in articulation rate in formal speeches presented annually by Queen Beatrix between her ages 42 and 74. Her tempo decreased first and then increased in the last decade. Within a speech, acceleration and shortening increased longitudinally. These results suggest that this talker's preferred tempo has not decreased but increased longitudinally, presumably in accommodation to an increasing tempo in the Dutch language community. PMID- 23742440 TI - On autocorrelation analysis of jet noise. AB - Meaningful use of the autocorrelation in jet noise analysis is examined. The effect of peak frequency on the autocorrelation function width is removed through a temporal scaling prior to making comparisons between measurements or drawing conclusions about source characteristics. In addition, a Hilbert transform-based autocorrelation envelope helps to define consistent characteristic time scales. Application of these processes to correlation functions based on large and fine scale similarity spectra reveal that the large-scale noise radiation from an F 22A deviates from the similarity spectrum model. PMID- 23742441 TI - Underwater noise from offshore oil production vessels. AB - Underwater acoustic recordings of six Floating Production Storage and Offloading (FPSO) vessels moored off Western Australia are presented. Monopole source spectra were computed for use in environmental impact assessments of underwater noise. Given that operations on the FPSOs varied over the period of recording, and were sometimes unknown, the authors present a statistical approach to noise level estimation. No significant or consistent aspect dependence was found for the six FPSOs. Noise levels did not scale with FPSO size or power. The 5th, 50th (median), and 95th percentile source levels (broadband, 20 to 2500 Hz) were 188, 181, and 173 dB re 1 MUPa @ 1 m, respectively. PMID- 23742442 TI - Identifying a temporal threshold of tolerance for silent gaps after requests. AB - This study addresses whether there is a threshold, some particular length of silent gap between two speakers' turns, at which negative social attributions emerge. The effect of such inter-turn silence was tested by constructing dialogues where responses to requests were identical and affirmative so that study participants' (n = 380) ratings about "willingness" would be colored by lag time, not semantics. 100 ms intervals between 200 and 1200 ms were tested in a between groups design. There was a notable drop-off in ratings at 600 ms and a statistically significant difference in ratings between 700 and 800 ms. PMID- 23742443 TI - Ultrasound assessment of polymer-shelled magnetic microbubbles used as dual contrast agents. AB - This letter describes an ultrasound imaging assessment of novel contrast agents that are detectable by both medical ultrasound and magnetic resonance imaging. Such agents are created by including superparamagnetic particles in polymer shelled microbubbles through two different approaches. The reduced echogenicity and nonlinearity of the microbubbles are observed, depending on the strategy used to include the particles and the resulting density. The best results are obtained using imaging techniques that exploit the third-order nonlinear term, which is especially true when the microbubbles are excited by means of chirp pulses. PMID- 23742444 TI - Sonic crystal acoustic switch device. AB - This study reports a wave-controlled sonic crystal switch device that exhibits a destructive interference-based wave to wave reverse switching effect. By applying control waves, this acoustic device, composed of a two-dimensional square lattice sonic crystal block, reduces acoustic wave transmission from input to output. The finite difference time domain simulation and experimental results confirm the wave-to-wave reverse switching effect at the peak frequencies of the second band. The proposed sonic crystal switch prototype provides a contrast rate of 86% at 11.3 kHz frequency. This wave-to-wave switching effect is useful for controlling wave propagation for smart structure applications. PMID- 23742445 TI - Skewness and shock formation in laboratory-scale supersonic jet data. AB - Spatial properties of noise statistics near unheated, laboratory-scale supersonic jets yield insights into source characteristics and near-field shock formation. Primary findings are (1) waveforms with positive pressure skewness radiate from the source with a directivity upstream of maximum overall level and (2) skewness of the time derivative of the pressure waveforms increases significantly with range, indicating formation of shocks during propagation. These results corroborate findings of a previous study involving full-scale engine data. Further, a comparison of ideally and over-expanded laboratory data show that while derivative skewness maps are similar, waveform skewness maps are substantially different for the two cases. PMID- 23742446 TI - Communication: photoelectron angular distributions of CH(-) reveal a temporary anion state. AB - Photoelectron imaging has broadened the scope of traditional photoelectron spectroscopy by combining a simultaneous photoelectron angular distribution, PAD, measurement with kinetic energy analysis. A fundamental understanding of PADs has been largely limited to simple atomic systems. However, a new model has recently been developed that predicts PADs as a function of electron kinetic energy for a simple linear combination of s and p atomic orbitals. We used CH(-) to test this model by acquiring PADs in a photoelectron imaging spectrometer at wavelengths from 600 to 355 nm. The PADs for electron detachment from the HOMO (1pi) of CH(-) fit model predictions. However, the PADs associated with detachment from the HOMO 1 (3sigma) orbital exhibit anomalous behavior at low electron kinetic energies because of a resonant process that arises from a previously undetected excited state of CH(-). PMID- 23742447 TI - Communication: existence of the doubly excited state that mediates the photoionization of azulene. AB - We use the high-level electronic structure computations based on the equation-of motion coupled-cluster (EOMCC) theory to show that the previously postulated [V. Blanchet et al., J. Chem. Phys. 128, 164318 (2008)] doubly excited state of azulene, located below the ionization threshold and mediating the 1 + 2' multi photon ionization that leads to a Rydberg fingerprint, exists. This supports the crucial role of doubly excited states in the Rydberg fingerprint spectroscopy, while demonstrating the usefulness of EOMCC methods in capturing such states. PMID- 23742448 TI - A combined DFT and restricted open-shell configuration interaction method including spin-orbit coupling: application to transition metal L-edge X-ray absorption spectroscopy. AB - A novel restricted-open-shell configuration interaction with singles (ROCIS) approach for the calculation of transition metal L-edge X-ray absorption spectra is introduced. In this method, one first calculates the ground state and a number of excited states of the non-relativistic Hamiltonian. By construction, the total spin is a good quantum number in each of these states. For a ground state with total spin S excited states with spin S' = S, S - 1, and S + 1 are constructed. Using Wigner-Eckart algebra, all magnetic sublevels with MS = S,..., -S for each multiplet of spin S are obtained. The spin-orbit operator is represented by a mean-field approximation to the full Breit-Pauli spin-orbit operator and is diagonalized over this N-particle basis. This is equivalent to a quasi-degenerate treatment of the spin-orbit interaction to all orders. Importantly, the excitation space spans all of the molecular multiplets that arise from the atomic Russell-Saunders terms. Hence, the method represents a rigorous first-principles approach to the complicated low-symmetry molecular multiplet problem met in L edge X-ray absorption spectroscopy. In order to gain computational efficiency, as well as additional accuracy, the excitation space is restricted to single excitations and the configuration interaction matrix is slightly parameterized in order to account for dynamic correlation effects in an average way. To this end, it is advantageous to employ Kohn-Sham rather than Hartree-Fock orbitals thus defining the density functional theory/ROCIS method. However, the method can also be used in an entirely non-empirical fashion. Only three global empirical parameters are introduced and have been determined here for future application of the method to any system containing any transition metal. The three parameters were carefully calibrated using the L-edge X-ray absorption spectroscopy spectra of a test set of coordination complexes containing first row transition metals. These parameters are universal and transferable. Hence, there are no adjustable parameters that are used to fit experimental X-ray absorption spectra. Thus, the new approach classifies as a predictive first-principles method rather than an analysis tool. A series of calculations on transition metal compounds containing Cu, Ti, Fe, and Ni in various oxidation and spin states is investigated and a detailed comparison to experimental data is reported. In most cases, the approach yields good to excellent agreement with experiment. In addition, the origin of the observed spectral features is discussed in terms of the electronic structure of the investigated compounds. PMID- 23742449 TI - Kinetics of molecular transitions with dynamic disorder in single-molecule pulling experiments. AB - Macromolecular transitions are subject to large fluctuations of rate constant, termed as dynamic disorder. The individual or intrinsic transition rates and activation free energies can be extracted from single-molecule pulling experiments. Here we present a theoretical framework based on a generalized Langevin equation with fractional Gaussian noise and power-law memory kernel to study the kinetics of macromolecular transitions to address the effects of dynamic disorder on barrier-crossing kinetics under external pulling force. By using the Kramers' rate theory, we have calculated the fluctuating rate constant of molecular transition, as well as the experimentally accessible quantities such as the force-dependent mean lifetime, the rupture force distribution, and the speed-dependent mean rupture force. Particular attention is paid to the discrepancies between the kinetics with and without dynamic disorder. We demonstrate that these discrepancies show strong and nontrivial dependence on the external force or the pulling speed, as well as the barrier height of the potential of mean force. Our results suggest that dynamic disorder is an important factor that should be taken into account properly in accurate interpretations of single-molecule pulling experiments. PMID- 23742450 TI - Nonlocal van der Waals functionals: the case of rare-gas dimers and solids. AB - Recently, the nonlocal van der Waals (vdW) density functionals [M. Dion, H. Rydberg, E. Schroder, D. C. Langreth, and B. I. Lundqvist, Phys. Rev. Lett. 92, 246401 (2004)] have attracted considerable attention due to their good performance for systems where weak interactions are important. Since the physics of dispersion is included in these functionals, they are usually more accurate and show less erratic behavior than the semilocal and hybrid methods. In this work, several variants of the vdW functionals have been tested on rare-gas dimers (from He2 to Kr2) and solids (Ne, Ar, and Kr) and their accuracy compared to standard semilocal approximations, supplemented or not by an atom-pairwise dispersion correction [S. Grimme, J. Antony, S. Ehrlich, and H. Krieg, J. Chem. Phys. 132, 154104 (2010)]. An analysis of the results in terms of energy decomposition is also provided. PMID- 23742451 TI - Localized orbitals from basis sets augmented with diffuse functions. AB - Orbital localization of occupied and virtual Hartree-Fock orbitals generated from basis sets augmented with diffuse functions is performed using the Pipek-Mezey, Boys, powers of the second central moment, and powers of the fourth central moment localizations. The locality of the obtained orbital sets are presented in terms of second and fourth moment orbital spreads. The results show that both local occupied and virtual orbitals may be obtained when using powers of the second central moment and powers of the fourth central moment localizations, while the Pipek-Mezey and Boys localizations fail to produce sets of local virtual orbitals. The locality of the fourth central moment virtual orbitals exhibits a locality similar to the locality of a Boys localization for non augmented basis sets. PMID- 23742452 TI - Isolated catalyst sites on amorphous supports: a systematic algorithm for understanding heterogeneities in structure and reactivity. AB - Methods for modeling catalytic sites on amorphous supports lag far behind methods for modeling catalytic sites on metal surfaces, zeolites, and other crystalline materials. One typical strategy for amorphous supports uses cluster models with arbitrarily chosen constraints to model the rigid amorphous support, but these constraints arbitrarily influence catalyst site activity. An alternative strategy is to use no constraints, but this results in catalytic sites with unrealistic flexibility. We present a systematic ab initio method to model isolated active sites on insulating amorphous supports using small cluster models. A sequential quadratic programming framework helps us relate chemical properties, such as the activation energy, to active site structure. The algorithm is first illustrated on an empirical valence bond model energy landscape. We then use the algorithm to model an off-pathway kinetic trap in olefin metathesis by isolated Mo sites on amorphous SiO2. The cluster models were terminated with basis set deficient fluorine atoms to mimic the properties of an extended silica framework. We also discuss limitations of the current algorithm formulation and future directions for improvement. PMID- 23742453 TI - Data driven Langevin modeling of biomolecular dynamics. AB - Based on a given time series, the data-driven Langevin equation proposed by Hegger and Stock [J. Chem. Phys. 130, 034106 (2009)] aims to construct a low dimensional dynamical model of the system. Adopting various simple model problems of biomolecular dynamics, this work presents a systematic study of the theoretical virtues and limitations as well as of the practical applicability and performance of the method. As the method requires only local information, the input data need not to be Boltzmann weighted in order to warrant that the Langevin model yields correct Boltzmann-distributed results. Moreover, a delay embedding of the state vector allows for the treatment of memory effects. The robustness of the modeling with respect to wrongly chosen model parameters or low sampling is discussed, as well as the treatment of inertial effects. Given sufficiently sampled input data, the Langevin modeling is shown to successfully recover the correct statistics (such as the probability distribution) and the dynamics (such as the position autocorrelation function) of all considered problems. PMID- 23742454 TI - SCC-DFTB calculation of the static first hyperpolarizability: from gas phase molecules to functionalized surfaces. AB - The performance of the self-consistent charge density functional tight binding (SCC-DFTB) method for calculating the first hyperpolarizability of pi-conjugated compounds has been assessed with respect to results obtained with high-level ab initio methods and density functional theory (DFT). The SCC-DFTB method performs similarly or better than DFT with the PBE XC functional. Thus, if for small pi conjugated linkers SCC-DFTB can reproduce trends, for longer chains the first hyperpolarizabilities are overestimated. In the case of push-pull thiophenes, the beta values are strongly overestimated, as it is also the case with the B3LYP and PBE XC functionals. On the other hand, the SCC-DFTB method closely reproduces the evolution of beta in p-disubstituted benzenes as a function of the donor and acceptor groups, as estimated at the MP2 level. The reliability of SCC-DFTB to determine the bond length alternation and the dihedral angles between the aromatic rings has also been tackled, demonstrating that both are underestimated. Overall, the SCC-DFTB calculations are of the same quality as those performed with the conventional PBE XC functional on which the method was parameterized but the SCC-DFTB calculations are computationally very little demanding, and it can therefore be adopted for very large systems for screening nonlinear optical materials as well as for assessing structure-property relationships. This is illustrated with an application on the first hyperpolarizability of an indolino oxazolidine molecular switch grafted on a SiO2 surface. This has enabled to pinpoint (i) the effect of the surface on the donor/acceptor character of the linking substituent, (ii) the impact of molecular orientation, (iii) the role of a spacer between the pi-conjugated switch and the surface, (iv) the global effect of the surface on the beta contrast, and also (v) the fact that the molecular switches can maintain this contrast when adsorbed. PMID- 23742455 TI - Statistically testing the validity of analytical and computational approximations to the chemical master equation. AB - The master equation is used extensively to model chemical reaction systems with stochastic dynamics. However, and despite its phenomenological simplicity, it is not in general possible to compute the solution of this equation. Drawing exact samples from the master equation is possible, but can be computationally demanding, especially when estimating high-order statistical summaries or joint probability distributions. As a consequence, one often relies on analytical approximations to the solution of the master equation or on computational techniques that draw approximative samples from this equation. Unfortunately, it is not in general possible to check whether a particular approximation scheme is valid. The main objective of this paper is to develop an effective methodology to address this problem based on statistical hypothesis testing. By drawing a moderate number of samples from the master equation, the proposed techniques use the well-known Kolmogorov-Smirnov statistic to reject the validity of a given approximation method or accept it with a certain level of confidence. Our approach is general enough to deal with any master equation and can be used to test the validity of any analytical approximation method or any approximative sampling technique of interest. A number of examples, based on the Schlogl model of chemistry and the SIR model of epidemiology, clearly illustrate the effectiveness and potential of the proposed statistical framework. PMID- 23742456 TI - Non-covalent interactions and thermochemistry using XDM-corrected hybrid and range-separated hybrid density functionals. AB - The exchange-hole dipole-moment model (XDM) for dispersion is combined with a collection of semilocal, hybrid, and range-separated hybrid functionals. The resulting XDM-corrected functionals are tested against standard benchmarks for non-covalent interactions at and away from equilibrium, conformer ranking in water clusters, thermochemistry, and kinetics. We show that functionals with the correct -1/r tail of the exchange potential yield superior accuracy for weak interactions. Thus, balancing long-range exchange with dispersion interactions in XDM is essential in the correct description of dimers with significant non dispersion contributions to binding. With the exception of the noble gases, the performance of PW86PBE-XDM is improved upon at the semilocal (BLYP), hybrid (B3LYP), and range-separated hybrid (LC-omegaPBE) levels. Based on its excellent performance, we propose LC-omegaPBE-XDM as an accurate functional for hard and soft matter. PMID- 23742457 TI - Nuclear spin-induced Cotton-Mouton effect in molecules. AB - In nuclear magneto-optic spectroscopy, effects of nuclear magnetization are detected in light passing through a sample containing spin-polarized nuclei. An optical analogue of nuclear magnetic resonance (NMR) chemical shift has been predicted and observed in the nuclear spin optical rotation of linearly polarized light propagating parallel to the nuclear magnetization. A recently proposed magneto-optic analogue of the NMR spin-spin coupling, the nuclear spin-induced Cotton-Mouton (NSCM) effect entails an ellipticity induced to linearly polarized light when passing through a medium with the nuclear spins polarized in a direction perpendicular to the light beam. Here we present a first-principles electronic structure formulation of NSCM in terms of response theory as well as ab initio and density-functional theory calculations for small molecules. The roles of basis set (we use completeness-optimized sets), electron correlation, and relativistic effects are discussed. It is found that the explicitly temperature-dependent contribution to NSCM, arising from the partial orientation of the molecules due to the nuclear magnetization, typically dominates the effect. This part of NSCM is proportional to the tensor product of molecular polarizability and the NMR direct dipolar coupling tensor. Hence, NSCM provides a means of investigating the dipolar coupling and, thus, molecular structure in a formally isotropic medium. Overall ellipticities of the order of magnitude of 10( 8)...10(-7) rad/(M cm) are predicted for fully polarized nuclei. These should be detectable with modern instrumentation in the Voigt setup. PMID- 23742458 TI - Accurate complex scaling of three dimensional numerical potentials. AB - The complex scaling method, which consists in continuing spatial coordinates into the complex plane, is a well-established method that allows to compute resonant eigenfunctions of the time-independent Schrodinger operator. Whenever it is desirable to apply the complex scaling to investigate resonances in physical systems defined on numerical discrete grids, the most direct approach relies on the application of a similarity transformation to the original, unscaled Hamiltonian. We show that such an approach can be conveniently implemented in the Daubechies wavelet basis set, featuring a very promising level of generality, high accuracy, and no need for artificial convergence parameters. Complex scaling of three dimensional numerical potentials can be efficiently and accurately performed. By carrying out an illustrative resonant state computation in the case of a one-dimensional model potential, we then show that our wavelet-based approach may disclose new exciting opportunities in the field of computational non-Hermitian quantum mechanics. PMID- 23742459 TI - On the Kohn-Luttinger conundrum. AB - Kohn and Luttinger [Phys. Rev. 118, 41 (1960)] showed that the conventional finite-temperature extension of the second-order many-body perturbation theory had the incorrect zero-temperature limit in metals and, on this basis, argued that the theory was incorrect. We show that this inconsistency arises from the noninclusion of the temperature effect in the energies of the zeroth-order eigenstates of the perturbation theory, which causes not only the Kohn-Luttinger conundrum but also another inconsistency with the zero-temperature many-body perturbation theory, namely, the different rates of divergence of the correlation energy in a homogeneous electron gas (HEG). We propose a renormalized many-body perturbation theory derivable from the finite-temperature extension of the normal ordered second quantization applied to the denominators of the energy expression, which involves the energies of the zeroth-order states, as well as to the numerators. The renormalized theory is shown to have the correct zero-temperature limit and the same rate of divergence in a HEG as the zero-temperature counterpart, and is, therefore, the correct finite-temperature many-body perturbation theory. PMID- 23742460 TI - Large-scale Dirac-Fock-Breit method using density fitting and 2-spinor basis functions. AB - We present an efficient theory and algorithm for computing four-component relativistic Dirac-Fock wave functions using the Coulomb, Gaunt, and full Breit interactions. Our implementation is based on density fitting, and is routinely applicable to systems with 100 atoms and a few heavy elements. The small components are expanded using 2-spinor basis functions. We show that the factorization of 3-index half-transformed integrals before building Coulomb and exchange matrices is essential for efficient evaluation of the Fock matrix. With the Coulomb interaction, the computational cost for evaluating the Fock operator has been found to be only 70-90 times that in the non-relativistic density-fitted Hartree-Fock method. The prefactors have been 170 and 350-450 for the Gaunt and Breit interactions, respectively. The largest molecule to which we have applied the Dirac-Fock-Coulomb method is an Ac(III) motexafin complex (130 atoms, 556 electrons, 1289 basis functions), for which one self-consistent iteration takes around 1100 s using 1024 CPU cores. In addition, we have found that, while the standard fitting basis sets are accurate for Dirac-Fock-Coulomb calculations, their accuracy is very poor for Dirac-Fock-Gaunt and Breit calculations. We report a prototype of accurate fitting basis sets for these cases. PMID- 23742461 TI - Bridging single and multireference coupled cluster theories with universal state selective formalism. AB - The universal state selective (USS) multireference approach is used to construct new energy functionals which offer a possibility of bridging single and multireference coupled cluster theories (SR/MRCC). These functionals, which can be used to develop iterative and non-iterative approaches, utilize a special form of the trial wavefunctions, which assure additive separability (or size consistency) of the USS energies in the non-interacting subsystem limit. When the USS formalism is combined with approximate SRCC theories, the resulting formalism can be viewed as a size-consistent version of the method of moments of coupled cluster equations employing a MRCC trial wavefunction. Special cases of the USS formulations, which utilize single reference state specific CC [V. V. Ivanov, D. I. Lyakh, and L. Adamowicz, Phys. Chem. Chem. Phys. 11, 2355 (2009)] and tailored CC [T. Kinoshita, O. Hino, and R. J. Bartlett, J. Chem. Phys. 123, 074106 (2005)] expansions are also discussed. PMID- 23742462 TI - Using optimally tuned range separated hybrid functionals in ground-state calculations: consequences and caveats. AB - Optimally tuned range separated hybrid functionals are a new class of implicitly defined functionals. Their important new aspect is that the range separation parameter in these functionals is determined individually for each system by iteratively tuning it until a fundamental, non-empirical condition is fulfilled. Such functionals have been demonstrated to be extremely successful in predicting electronic excitations. In this paper, we explore the use of the tuning approach for predicting ground state properties. This sheds light on one of its downsides the violation of size consistency. By analyzing diatomic molecules, we reveal size consistency errors up to several electron volts and find that binding energies cannot be predicted reliably. Further consequences of the consistent ground-state use of the tuning approach are potential energy surfaces that are qualitatively in error and an incorrect prediction of spin states. We discuss these failures, their origins, and possibilities for overcoming them. PMID- 23742463 TI - Eigenvalues of normalized Laplacian matrices of fractal trees and dendrimers: analytical results and applications. AB - The eigenvalues of the normalized Laplacian matrix of a network play an important role in its structural and dynamical aspects associated with the network. In this paper, we study the spectra and their applications of normalized Laplacian matrices of a family of fractal trees and dendrimers modeled by Cayley trees, both of which are built in an iterative way. For the fractal trees, we apply the spectral decimation approach to determine analytically all the eigenvalues and their corresponding multiplicities, with the eigenvalues provided by a recursive relation governing the eigenvalues of networks at two successive generations. For Cayley trees, we show that all their eigenvalues can be obtained by computing the roots of several small-degree polynomials defined recursively. By using the relation between normalized Laplacian spectra and eigentime identity, we derive the explicit solution to the eigentime identity for random walks on the two treelike networks, the leading scalings of which follow quite different behaviors. In addition, we corroborate the obtained eigenvalues and their degeneracies through the link between them and the number of spanning trees. PMID- 23742464 TI - Assessing the two-body diffusion tensor calculated by the bead models. AB - The diffusion tensor of complex macromolecules in Stokes flow is often approximated by the bead models. The bead models are known to reproduce the experimental diffusion coefficients of a single macromolecule, but the accuracy of their calculation of the whole multi-body diffusion tensor, which is important for Brownian dynamics simulations, has not been closely investigated. As a first step, we assess the accuracy of the bead model calculated diffusion tensor of two spheres. Our results show that the bead models produce very accurate diffusion tensors for two spheres where a reasonable number of beads are used and there is no bead overlap. PMID- 23742465 TI - On the subsystem formulation of linear-response time-dependent DFT. AB - A new and thorough derivation of linear-response subsystem time-dependent density functional theory (TD-DFT) is presented and analyzed in detail. Two equivalent derivations are presented and naturally yield self-consistent subsystem TD-DFT equations. One reduces to the subsystem TD-DFT formalism of Neugebauer [J. Chem. Phys. 126, 134116 (2007)]. The other yields Dyson type equations involving three types of subsystem response functions: coupled, uncoupled, and Kohn-Sham. The Dyson type equations for subsystem TD-DFT are derived here for the first time. The response function formalism reveals previously hidden qualities and complications of subsystem TD-DFT compared with the regular TD-DFT of the supersystem. For example, analysis of the pole structure of the subsystem response functions shows that each function contains information about the electronic spectrum of the entire supersystem. In addition, comparison of the subsystem and supersystem response functions shows that, while the correlated response is subsystem additive, the Kohn-Sham response is not. Comparison with the non-subjective partition DFT theory shows that this non-additivity is largely an artifact introduced by the subjective nature of the density partitioning in subsystem DFT. PMID- 23742466 TI - The effect of Thole functions on the simulation of ionic liquids with point induced dipoles at various densities. AB - Point-induced dipoles are used to mimic electronic degrees of freedom in molecular dynamics simulations. Ultrashort distance interactions of these induced dipoles are damped by the so-called Thole functions to avoid the "polarization catastrophe." This study aims at the overall impact of Thole functions on structure as well as single-particle and collective dynamics of the ionic liquid 1-ethyl-3-methylimidazolium trifluoromethylsulfonate and thereby extends common studies of the effect of Thole functions on energy minimized geometries. PMID- 23742467 TI - Measurement of the Soret coefficients for a ternary hydrocarbon mixture in low gravity environment. AB - While the Soret coefficients of binary mixtures have been widely measured in the past, here we report the first measurement of the Soret coefficient of a ternary mixture in a low gravity environment on board the International Space Station. The sample was contained in a 10 mm * 10 mm * 5 mm (w, l, h) cell and was monitored by means of a Mach-Zehnder interferometer at two wavelengths. The analyzed sample was a mixture of tetrahydronaphthalene, isobutylbenzene, and dodecane at the weight fraction of 0.1/0.8/0.1. While the lateral walls of the cell did not possess complete thermal isolation, the separation of the components in the central region of the cavity was comparable to purely diffusive behavior. The same experimental parameters have been monitored in Run7 and Run12 of the Selectable Optical Diagnostics Instrument-Diffusion and Soret Coefficient experiment in order to verify the accuracy of the setup. The similarity of the results demonstrates the repeatability of thermodiffusion experiments in a microgravity environment. There was nearly equal separation of the tetrahydronaphthalene and isobutylbenzene components in opposite directions, while dodecane experienced a weak separation in the same direction as isobutylbenzene. Finally, Fourier image processing and calculations of the transient separation of the components were used to analyze the heat transfer in the system and to measure the Soret coefficients for this ternary mixture. The successful measurements shown in this work can serve as the standard for ground experiments and for numerical modeling of hydrocarbon mixtures. PMID- 23742468 TI - Spatially encoded multiple-quantum excitation. AB - In this work, we present a simple method to spatially encode the transition frequencies of nuclear spin transitions and to read out these frequencies within a single scan. The experiment works by combining pulsed field gradients with an excitation sequence that selectively excites spin transitions within certain sample regions. After the initial excitation, imaging the resulting z magnetization is used to determine the locations where the excitations occurred, from which the corresponding transition frequencies are determined. Simple experimental demonstrations of this technique on one- and two-spin systems are presented. PMID- 23742469 TI - Correlation between a photoelectron and a fragment ion in dissociative ionization of ethanol in intense near-infrared laser fields. AB - The two dissociative ionization channels of ethanol (C2H5OH) induced by an intense near-infrared laser pulse (lambda ~ 783 nm), C2H5OH -> CH2OH(+) + CH3 + e(-) and C2H5OH -> C2H5(+) + OH + e(-), are investigated using photoelectron photoion coincidence method. It is shown that both the electronic ground state and the first electronically excited state of C2H5OH(+) are produced at the moment of photoelectron emission. From the observed correlation between the electronic states of C2H5OH(+) prepared at the moment of photoelectron emission and the kinetic energy release of the fragment ions, it is revealed that C2H5OH(+) prepared in the electronic ground state at the photoelectron emission gains larger internal energy in the end than that prepared in the electronically excited state. The averaged internal energy of C2H5OH(+) just before the dissociation is found to increase when the laser field intensity increases from 9 to 23 TW/cm(2) and when the laser pulse duration increases from 35 to 800 fs. PMID- 23742470 TI - Flowing afterglow measurements of the density dependence of gas-phase ion-ion mutual neutralization reactions. AB - We have studied the dependence of several ion-ion mutual neutralization (MN) reactions on helium density in the range from 1.6 * 10(16) to 1.5 * 10(17) cm(-3) at 300 K, using the Variable Electron and Neutral Density Attachment Mass Spectrometry method. The rate coefficients of the reactions Ar(+) + Br2(-), Ar(+) + SF6(-), and Ar(+) + C7F14(-) were found to be independent of gas density over the range studied, in disagreement with earlier observations that similar MN reactions are strongly enhanced at the same gas densities. The cause of the previous enhancement with density is traced to the use of "orbital-motion-limit" theory to infer ion densities from the currents collected by ion-attracting Langmuir probes in a region where it is not applicable. PMID- 23742471 TI - Theoretical insight into electronic spectra of carbon chain carbenes H2Cn (n = 3 10). AB - Ground-state geometries of carbenes H2Cn (n = 3-10) have been fully optimized with the C2nu-symmetry constraint at the density functional theory and restricted spin coupled-cluster single-double plus perturbative triple excitation levels of theory, respectively. Comparison of structures corresponding to the X(1)A1 and B(1)B1 electronic states has been made by the complete active space self consistent field calculations. Parity alternation effect on various properties of the ground-state geometries has been discovered in the present study, which generally gives illustration for the relative stabilities of the titled carbon chains. Further calculations on their electronic spectra have been carried out by means of the complete active space second-order perturbation theory method along with the cc-pVTZ basis set. It is found that the vertical excitation energies of the dipole-allowed B(1)B1 <- X(1)A1 transition in the gas phase are 2.28, 4.75, 1.69, 3.66, 1.30, 2.94, 1.12, and 2.49 eV, respectively, which agree very well with the available experimental result for H2C3 (2.27 eV). In addition, the vertical excitation energies for both transitions B(1)B1 <- X(1)A1 and A(1)A2 <- X(1)A1 are found to obey a nonlinear DeltaE-n relationship as a function of chain size by performing curves fitting. PMID- 23742472 TI - Obtaining the lattice energy of the anthracene crystal by modern yet affordable first-principles methods. AB - The non-covalent interactions in organic molecules are known to drive their self assembly to form molecular crystals. We compare, in the case of anthracene and against experimental (electronic-only) sublimation energy, how modern quantum chemical methods are able to calculate this cohesive energy taking into account all the interactions between occurring dimers in both first-and second-shells. These include both O(N(6))- and O(N(5))-scaling methods, Local Pair Natural Orbital-parameterized Coupled-Cluster Single and Double, and Spin-Component Scaled-Moller-Plesset perturbation theory at second-order, respectively, as well as the most modern family of conceived density functionals: double-hybrid expressions in several variants (B2-PLYP, mPW2-PLYP, PWPB95) with customized dispersion corrections (-D3 and -NL). All-in-all, it is shown that these methods behave very accurately producing errors in the 1-2 kJ/mol range with respect to the experimental value taken into account the experimental uncertainty. These methods are thus confirmed as excellent tools for studying all kinds of interactions in chemical systems. PMID- 23742473 TI - Pseudo Jahn-Teller coupling in trioxides XO3((0,1,-1)) with 22 and 23 valence electrons. AB - D3h and C2v geometries and energies, vertical excitation energies, as well as minimal energy paths as function of the O(1)(z)-X-O(2) angle alpha were obtained for XO3((0,1,-1)) (X = B, Al, Ga; C, Si, Ge; N, P, As; S, Se) molecules and ions with 22 and 23 valence electrons (VE), using density functional theory (DFT), coupled cluster with single and double substitutions with noniterative triple excitations (CCSD(T)), equation of motion (EOM)-CCSD, time-dependent DFT, and multi-reference configuration interaction methods. It is shown that pseudo Jahn Teller (PJT) coupling increases as the central atom X becomes heavier, due to decreases in excitation energies. As is well known for CO3, the excited (1)E' states of the 22 VE systems SiO3, GeO3; NO3(+), PO3(+), AsO3(+); BO3(-), AlO3(-), GaO3(-) have strong vibronic coupling with the (1)A1' ground state via the e' vibrational modes, leading to a C2v minimum around alpha = 145 degrees . For first and second row X atoms, there is an additional D3h minimum (alpha = 120 degrees ). Interacting excited states have minima around 135 degrees . In the 23 VE systems CO3(-), SiO3(-); NO3, PO3; SO3(+), coupling of the excited (2)E' with the (2)A2' ground state via the e' mode does not generate a C2v state. Minima of interacting excited states are close to 120 degrees . However, due to very strong PJT coupling, a double-well potential is predicted for GeO3(-), AsO3, and SeO3(+), with a saddle point at D3h symmetry. Interaction of the b2 highest occupied molecular orbital with the b2 lowest unoccupied molecular orbital, both oxygen lone pair molecular orbitals, is seen as the reason for the C2v stabilization of 22 VE molecules. PMID- 23742474 TI - Thermalization of rotational states of NO A(2)Sigma+(v = 0) in an atmospheric pressure plasma. AB - Laser induced fluorescence (LIF) measurements of nitric oxide (NO) are performed in an atmospheric pressure microwave plasma jet, operated with a mixture of He and 3% air. The fluorescence signal of NO A(2)Sigma(+)(v = 0) is measured time and fluorescence wavelength resolved. Based on the evolution of the rotational spectrum at different positions in the plasma, we determined the thermalization time of the rotational distribution of NO A after pumping a single transition, at temperatures in the range 300-1500 K. Also, a LIF-RET (rotational energy transfer) model is developed to simulate the RET and to calculate the thermalization time. The RET rate coefficients are calculated using the energy corrected sudden-exponential power scaling law. It was found that it is necessary to take the fine structure of the rotational states into account. At room temperature the results of the measurement and the simulation are consistent, and the thermalization occurs during the laser pulse (11 +/- 1 ns). At elevated temperatures the measurements show a large increase in thermalization time, up to 35 +/- 4 ns at 1474 K. This time is much longer than the laser pulse, and of the order of the NO A lifetime. This means that for spectroscopy measurements of the rotational states of NO A, the RET has to be taken into account to derive gas temperatures from the rotational distribution of NO A. PMID- 23742475 TI - Dynamics of vortex assisted metal condensation in superfluid helium. AB - Laser ablation of copper and silver targets immersed in bulk normal and superfluid (4)He was studied through time-resolved shadowgraph photography. In normal fluid, only a sub-millimeter cavitation bubble is created and immediate formation of metal clusters is observed within a few hundred microseconds. The metal clusters remain spatially tightly focused up to 15 ms, and it is proposed that this observation may find applications in particle image velocimetry. In superfluid helium, the cavitation bubble formation process is distinctly different from the normal fluid. Due to the high thermal conductivity and an apparent lag in the breakdown of superfluidity, about 20% of the laser pulse energy was transferred directly into the liquid and a large gas bubble, up to several millimeters depending on laser pulse energy, is created. The internal temperature of the gas bubble is estimated to exceed 9 K and the following bubble cool down period therefore includes two separate phase transitions: gas-normal liquid and normal liquid-superfluid. The last stage of the cool down process was assigned to the superfluid lambda transition where a sudden formation of large metal clusters is observed. This is attributed to high vorticity created in the volume where the gas bubble previously resided. As shown by theoretical bosonic density functional theory calculations, quantized vortices can trap atoms and dimers efficiently, exhibiting static binding energies up to 22 K. This, combined with hydrodynamic Bernoulli attraction, yields total binding energies as high as 35 K. For larger clusters, the static binding energy increases as a function of the volume occupied in the liquid to minimize the surface tension energy. For heliophobic species an energy barrier develops as a function of the cluster size, whereas heliophilics show barrierless entry into vortices. The present theoretical and experimental observations are used to rationalize the previously reported metal nanowire assembly in both superfluid bulk liquid helium and helium droplets, both of which share the common element of a rapid passage through the lambda point. The origin of vorticity is tentatively assigned to the Zurek-Kibble mechanism. Implications of the large gas bubble formation by laser ablation to previous experiments aimed at implanting atomic and dimeric species in bulk superfluid helium are also discussed, and it is proposed that the developed visualization method should be used as a diagnostic tool in such experiments to avoid measurements in dense gaseous environments. PMID- 23742476 TI - Electron scattering from gas phase cis-diamminedichloroplatinum(II): quantum analysis of resonance dynamics. AB - We present scattering calculations of electron collisions with the platinum containing compound cis-diamminedichloroplatinum (CDDP), commonly known as cisplatin, between 0.5 eV and 6 eV, and the corresponding isolated Pt atom from 0.1 eV to 10 eV. We find evidence of resonances in e(-)-CDDP scattering, using an ab initio description of the target. We computed scattering matrix elements from equations incorporating exchange and polarization effects through the use of the static-exchange plus density functional correlation potential. Additionally, we made use of a purely local adiabatic model potential that allows Siegert eigenstates to be calculated, thereby allowing inspection of the possible resonant scattering wave functions. The total cross section for electron scattering from (5d(10)) (1)S Pt displays a large magnitude, monotonic decay from the initial collision energies, with no apparent resonance scattering features in any scattering symmetry. By contrast, the e(-)-CDDP scattering cross section shows a small feature near 3.8 eV, which results from a narrow, well localized resonance of b2 symmetry. These findings are then related to the possible electron-mediated mechanism of the action of CDDP on DNA replication as suggested by recent experiments. PMID- 23742477 TI - Geometrical effects on energy transfer in disordered open quantum systems. AB - We explore various design principles for efficient excitation energy transport in complex quantum systems. We investigate energy transfer efficiency in randomly disordered geometries consisting of up to 20 chromophores to explore spatial and spectral properties of small natural/artificial Light-Harvesting Complexes (LHC). We find significant statistical correlations among highly efficient random structures with respect to ground state properties, excitonic energy gaps, multichromophoric spatial connectivity, and path strengths. These correlations can even exist beyond the optimal regime of environment-assisted quantum transport. For random configurations embedded in spatial dimensions of 30 A or 50 A, we observe that the transport efficiency saturates to its maximum value if the systems contain around 7 or 14 chromophores, respectively. Remarkably, these optimum values coincide with the number of chlorophylls in the Fenna-Matthews Olson protein complex and LHC II monomers, respectively, suggesting a potential natural optimization with respect to chromophoric density. PMID- 23742478 TI - Growth of polyphenyls via ion-molecule reactions: an experimental and theoretical mechanistic study. AB - The reactivity of biphenylium cations C12H9(+) with benzene C6H6 is investigated in a joint experimental and theoretical approach. Experiments are performed by using a triple quadruple mass spectrometer equipped with an atmospheric pressure chemical ion source to generate C12H9(+) via dissociative ionization of various isomers of the neutral precursor hydroxybiphenyl (C12H10O). C-C coupling reactions leading to hydrocarbon growth are observed. The most abundant ionic products are C18H15(+), C18H13(+), C17H12(+), and C8H7(+). The dependence of product ion yields on the kinetic energy of reagent ions, as well as further experiments performed using partial isotopic labelling of reagents, support the idea that the reaction proceeds via a long lived association product, presumably the covalently bound protonated terphenyl C18H15(+). Its formation is found to be exothermic and barrierless and, therefore, might occur under the low pressure and temperature conditions typical of planetary atmospheres and the interstellar medium. Theoretical calculations have focussed on the channel leading to C8H7(+) plus C10H8, identifying, as the most probable fragments, the phenylethen-1-ylium cation and naphthalene, thus suggesting that the pathway leading to them might be of particular interest for the synthesis of polycyclic aromatic hydrocarbons. Both experiments and theory agree in finding this channel exoergic but hampered by small barriers of 2.7 and 3.7 kcal mol(-1) on the singlet potential energy surface. PMID- 23742479 TI - N2O ionization and dissociation dynamics in intense femtosecond laser radiation, probed by systematic pulse length variation from 7 to 500 fs. AB - We have made a series of measurements, as a function of pulse duration, of ionization and fragmentation of the asymmetric molecule N2O in intense femtosecond laser radiation. The pulse length was varied from 7 fs to 500 fs with intensity ranging from 4 * 10(15) to 2.5 * 10(14) W/cm(2). Time and position sensitive detection allows us to observe all fragments in coincidence. By representing the final dissociation geometry with Dalitz plots, we can identify the underlying breakup dynamics. We observe for the first time that there are two stepwise dissociation pathways for N2O(3+): (1) N2O(3+) -> N(+) + NO(2+) -> N(+) + N(+) + O(+) and (2) N2O(3+) -> N2 (2+) + O(+) -> N(+) + N(+) + O(+) as well as one for N2O(4+) -> N(2+) + NO(2+) -> N(2+) + N(+) + O(+). The N2 (2+) stepwise channel is suppressed for longer pulse length, a phenomenon which we attribute to the influence which the structure of the 3+ potential has on the dissociating wave packet propagation. Finally, by observing the total kinetic energy released for each channel as a function of pulse duration, we show the increasing importance of charge resonance enhanced ionization for channels higher than 3+. PMID- 23742480 TI - Ab initio potential energy surface and predicted rotational spectra for the Ne H2O complex. AB - A new three-dimensional potential energy surface for the Ne-H2O complex was calculated using the coupled-cluster singles and doubles with noniterative inclusion of connected triples [CCSD(T)] with a large basis set supplemented with bond functions. The interaction energies were obtained by the supermolecular approach with the full counterpoise correction for the basis set superposition error. The CCSD(T) potential was found to have a planar T-shaped global minimum, two first-order saddle points, and a second-order saddle point. The global minimum is located at R = 3.23 A, theta = 101.4 degrees , and phi = 0.0 degrees with a well depth of 64.14 cm(-1). The radial discrete variable representation/angular finite basis representation method and the Lanczos algorithm were employed to calculate the rovibrational energy levels for four isotopic species (20)Ne-H2 (16)O, (22)Ne-H2 (16)O, (20)Ne-H2 (17)O, and (20)Ne-H2 (18)O. Rotational spectra within two internal rotor states, namely, the Sigma(000) and Sigma(101) states, were predicted. The average structural parameters of four Ne-H2O isotopomers on the two states were also calculated and analyzed. PMID- 23742481 TI - Excitonic splitting and vibronic coupling in 1,2-diphenoxyethane: conformation specific effects in the weak coupling limit. AB - Vibrationally and rotationally resolved electronic spectra of 1,2-diphenoxyethane (C6H5-O-CH2-CH2-O-C6H5, DPOE) are reported for the isolated molecule under jet cooled conditions. The spectra demonstrate that the two excited surfaces are within a few cm(-1) of one another over significant regions of the torsional potential energy surfaces that modulate the position and orientation of the two aromatic rings with respect to one another. Two-color resonant two-photon ionization (2C-R2PI) and laser-induced fluorescence excitation spectra were recorded in the near-ultraviolet in the region of the close-lying S0-S1 and S0-S2 states (36,400-36,750 cm(-1)). In previous work, double resonance spectroscopy in the ultraviolet and alkyl CH stretch regions of the infrared was used to identify and assign transitions to two conformational isomers differing primarily in the central C-C dihedral angle, a tgt conformation with C2 symmetry and a ttt conformation with C2h symmetry [E. G. Buchanan, E. L. Sibert, and T. S. Zwier, J. Phys. Chem. A 117, 2800 (2013)]. Comparison of 2C-R2PI spectra recorded in the m/z 214 (all (12)C) and m/z 215 (one (13)C) mass channels demonstrate the close proximity of the S1 and S2 excited states for both conformations, with an upper bound of 4 cm(-1) between them. High resolution spectra of the origin band of the tgt conformer reveal it to consist of two transitions at 36,422.91 and 36,423.93 cm(-1), with transition dipole moments perpendicular to one another. These are assigned to the S0-S1 and S0-S2 origin transitions with excited states of A and B symmetry, respectively, and an excitonic splitting of only 1.02 cm(-1). The excited state rotational constants and transition dipole coupling model directions prove that the electronic excitation is delocalized over the two rings. The ttt conformer has only one dipole-allowed electronic transition (Ag >Bu) giving rise to a pure b-type band at 36,508.77 cm(-1). Here, the asymmetry induced by a single (13)C atom in one of the rings is sufficient to localize the electronic excitation in one or the other ring. Dispersed fluorescence (DFL) spectra are used to provide assignments for all vibronic structure in the first 200 cm(-1)of both conformers. In the tgt conformer, both "a" and "b" symmetry fundamentals are observed, consistent with extensive vibronic coupling between the two dipole-allowed, nearly degenerate excited states. In the ttt conformer, the lowest frequency vibronic transition located 46 cm(-1) above the Bu origin is assigned to a bu fundamental (labeled R[overline]) built off the dipole-forbidden Ag state origin. The DFL spectrum of the Ag(R[overline](1)) level contains strong transitions to v(")(R[overline]) = 0, 1, and 2, seemingly at odds with vibronic coupling models. Studies of the DFL spectrum of this band as a function of distance from the nozzle reveal that much of the intensity in v(") = 1 arises from collisions of DPOE while in the excited state Ag(vb' = 1) level with He, producing Bu(R[overline] = 1) levels with large collision cross section. The remaining intensity in the fundamental at large x/D is ascribed to emission from the (13)C isotopomer, for which this emission is dipole-allowed. PMID- 23742482 TI - Spin-orbit quenching of the C+(2P) ion by collisions with para- and ortho-H2. AB - Spin-orbit (de-)excitation of C(+)((2)P) by collisions with H2, a key process for astrochemistry, is investigated. Quantum-mechanical calculations of collisions between C(+) ions and para- and ortho-H2 have been performed in order to determine the cross section for the C(+) (2)P3/2 -> (2)P1/2 fine-structure transition at low and intermediate energies. The calculation are based on new ab initio potential energy surfaces obtained using the multireference configuration interaction method. Corresponding rate coefficients were obtained for temperatures ranging from 5 to 500 K. These rate coefficients are compared to previous estimations, and their impact is assessed through radiative transfer computation. They are found to increase the flux of the (2)P3/2 -> (2)P1/2 line at 158 MUm by up to 30% for typical diffuse interstellar cloud conditions. PMID- 23742483 TI - Suppression and enhancement of coexisting super-fluorescence and multi-wave mixing processes in sodium vapor. AB - Different aspects of the properties of the coexisting super-fluorescence (SFL), multi-wave mixing with the fluorescence signal in the sodium vapor are studied both theoretically and experimentally. First, by scanning the dressed-state, the properties of these coexisting processes, such as the SFL signal modulated by using the dark and bright states, the interplay between dressed-states, are observed for the first time. Then, by scanning the probe field, the interplay between the one-photon and two-photon processes of the coexisting signals is obtained with or without the external dressing fields. Such control on each process in such coexisting system has an important potential application in quantum communication. PMID- 23742484 TI - Electron attachment to CF3 and CF3Br at temperatures up to 890 K: experimental test of the kinetic modeling approach. AB - Thermal rate constants and product branching fractions for electron attachment to CF3Br and the CF3 radical have been measured over the temperature range 300-890 K, the upper limit being restricted by thermal decomposition of CF3Br. Both measurements were made in Flowing Afterglow Langmuir Probe apparatuses; the CF3Br measurement was made using standard techniques, and the CF3 measurement using the Variable Electron and Neutral Density Attachment Mass Spectrometry technique. Attachment to CF3Br proceeds exclusively by the dissociative channel yielding Br( ), with a rate constant increasing from 1.1 * 10(-8) cm(3) s(-1) at 300 K to 5.3 * 10(-8) cm(3) s(-1) at 890 K, somewhat lower than previous data at temperatures up to 777 K. CF3 attachment proceeds through competition between associative attachment yielding CF3 (-) and dissociative attachment yielding F(-). Prior data up to 600 K showed the rate constant monotonically increasing, with the partial rate constant of the dissociative channel following Arrhenius behavior; however, extrapolation of the data using a recently proposed kinetic modeling approach predicted the rate constant to turn over at higher temperatures, despite being only ~5% of the collision rate. The current data agree well with the previous kinetic modeling extrapolation, providing a demonstration of the predictive capabilities of the approach. PMID- 23742485 TI - Matrix isolation ESR spectroscopy and magnetic anisotropy of D3h symmetric septet trinitrenes. AB - The fine-structure (FS) parameters D of a series of D3h symmetric septet trinitrenes were analyzed theoretically using density functional theory (DFT) calculations and compared with the experimental D values derived from ESR spectra. ESR studies show that D3h symmetric septet 1,3,5-trichloro-2,4,6 trinitrenobenzene with D = -0.0957 cm(-1) and E = 0 cm(-1) is the major paramagnetic product of the photolysis of 1,3,5-triazido-2,4,6-trichlorobenzene in solid argon matrices at 15 K. Trinitrenes of this type display in the powder X band ESR spectra intense Z1-transition at very low magnetic fields, the position of which allows one to precisely calculate the parameter D of such molecules. Thus, our revision of the FS parameters of well-known 1,3,5-tricyano-2,4,6 trinitrenobenzene [E. Wasserman, K. Schueller, and W. A. Yager, Chem. Phys. Lett. 2, 259 (1968)] shows that this trinitrene has [line]D[line] = 0.092 cm(-1) and E = 0 cm(-1). DFT calculations reveal that, unlike C2v symmetric septet trinitrenes, D3h symmetric trinitrenes have the same orientations of the spin spin coupling tensor D[^]SS and the spin-orbit coupling tensor D[^]SOC and, as a result, have negative signs for both the DSS and DSOC values. The negative magnetic anisotropy of septet 2,4,6-trinitrenobenzenes is considerably strengthened on introduction of heavy atoms in the molecules, owing to an increase in contributions of various excitation states to the DSOC term. PMID- 23742486 TI - Pure rotational spectroscopy of the H2O-trans-HOCO complex. AB - Pure rotational spectra of the H2O-trans-HOCO complex have been observed by Fourier transform microwave (FTMW) spectroscopy and millimeter-wave FTMW double resonance spectroscopy. The complex was produced in a supersonic jet by discharging a mixture gas of CO and H2O diluted in Ar. The observed rotational lines consist of two groups of transitions with different hyperfine patterns. This is explained by considering the internal rotation of the H2O monomer in the complex. The molecular constants including the fine and hyperfine coupling constants have been determined for the two groups of lines. The hydrogen bond distance between H2O and the trans-HOCO monomer has also been determined with other structural parameters fixed to ab initio values. The hydrogen bond distance, 1.794 A, is much shorter than that of the water dimer, and similar to those of water-acid complexes. The Fermi coupling constant of the proton of HOCO is compared with that of the trans-HOCO monomer, leading to the conclusion that there is an induced effect on the spin density on the proton of HOCO by the complex formation. PMID- 23742487 TI - Dielectric relaxation in weakly ergodic dilute dipole systems. AB - We introduce a method for calculating dipole correlations in systems containing hopping processes exhibiting weak ergodicity breaking. Modeled after the original Kirkwood-Frohlich theory, the new method provides a bridge extending Frohlich's insights from the realm of rigid dipoles into weakly non-ergodic fluctuating virtual dipolar entities. Relevant for the investigation of any system containing transport processes, it provides a testable parameter derived primarily from the static dielectric parameters. Three examples of systems including porous silicon, porous glass, and ferroelectric crystals are brought to demonstrate the model's versatility, including direct confirmation of Frohlich's original idea. PMID- 23742488 TI - Effect of pressure on decoupling of ionic conductivity from structural relaxation in hydrated protic ionic liquid, lidocaine HCl. AB - Broadband dielectric spectroscopy and pressure-temperature-volume methods are employed to investigate the effect of hydrostatic pressure on the conductivity relaxation time (tausigma), both in the supercooled and glassy states of protic ionic liquid lidocaine hydrochloride monohydrate. Due to the decoupling between the ion conductivity and structural dynamics, the characteristic change in behavior of tausigma(T) dependence, i.e., from Vogel-Fulcher-Tammann-like to Arrhenius-like behavior, is observed. This crossover is a manifestation of the liquid-glass transition of lidocaine HCl. The similar pattern of behavior was also found for pressure dependent isothermal measurements. However, in this case the transition from one simple volume activated law to another was noticed. Additionally, by analyzing the changes of conductivity relaxation times during isothermal densification of the sample, it was found that compression enhances the decoupling of electrical conductivity from the structural relaxation. Herein, we propose a new parameter, dlogRtau/dP, to quantify the pressure sensitivity of the decoupling phenomenon. Finally, the temperature and volume dependence of tausigma is discussed in terms of thermodynamic scaling concept. PMID- 23742489 TI - Microscopic structure of water in a water/oil emulsion. AB - We have determined the microscopic structure of water within a water/oil emulsion, by combining neutron diffraction data, exploiting the isotopic H/D substitution, and a fully atomistic Monte Carlo simulation of a portion of a water droplet, containing the water/oil interface. The dependence of the data on the simulation box size and the reliability of the water-water radial distribution functions are discussed. Although water in the emulsion forms shorter and stronger hydrogen bonds compared to pure bulk water, its overall microscopic structure looks more disordered. PMID- 23742490 TI - Polarization effects on the solvation dynamics of coumarin C153 in ionic liquids: components and their cross-correlations. AB - The solvation dynamics of coumarin C153 dissolved in three selected molecular ionic liquids - EMIM(+)BF4(-), EMIM(+)TfO(-), and BMIM(+)BF4(-) - was studied by molecular dynamics simulations including polarization forces. The solvation response function was decomposed with respect to permanent and induced charge distributions, cationic and anionic contributions, and translational and non translational motions. The latter decomposition was accomplished by an appropriate multipole expansion. Furthermore, the difference in solvation energy was resolved radially. The dynamics in the sub-picosecond regime was elucidated as the mutual translational motion of the solute and the cage formed by the first solvation shell. For a qualitative interpretation, solvent molecules can be reduced to "quasi-atomic" ions carrying a net charge at their molecular center of mass. Towards a quantitative description, the dipole moment serves as a measure of charge anisotropy. PMID- 23742491 TI - Association effects in the {methanol + inert solvent} system via Monte Carlo simulations. I. Structure. AB - In this work, the clusters residing in the {methanol + inert solvent} binary system have been characterized using a specific methodology in the framework of Monte Carlo molecular simulations. The cluster classification scheme considered distinguishes into five types: linear chains, cyclic clusters or isolated rings, branched linear chains, branched cyclic clusters, and composite rings. The procedure allows one to compute the next rich structural information: the fraction of molecules in the monomer or associated state, the fraction of each type of aggregate with a given size (and of molecules belonging to them), and the most probable and average cluster size for each type; likewise, the degree of branching in branched linear chains and the size distribution of the inner ring in branched cyclic clusters can be quantified. Specifically, all these properties were obtained for the {Optimized Potential for Liquid Simulation methanol + Lennard-Jones spheres} system at 298.15 K and 1 bar throughout the composition range. The results have provided a complete structural picture of this mixture describing comprehensively the effect of dilution into the hydrogen-bonded network of the pure associated fluid. PMID- 23742492 TI - Association effects in the {methanol + inert solvent} system via Monte Carlo simulations. II. Thermodynamics. AB - Mixtures containing associated substances show a singular thermodynamic behaviour that has attracted to scientific community during the last century. Particularly, binary systems composed of an associating fluid and an inert solvent, where association occurs only between molecules of the same kind, have been extensively studied. A number of theoretical approaches were used in order to gain insights into the effect of the association on the macroscopic behaviour, especially on the second-order thermodynamic derivatives (or response functions). Curiously, to our knowledge, molecular simulations have not been used to that end despite describing the molecules and their interactions in a more complete and realistic way than theoretical models. With this in mind, a simple methodology developed in the framework of Monte Carlo molecular simulation is used in this work to quantify the association contribution to a wide set of thermodynamic properties for the {methanol + Lennard Jones} specific system under room conditions and throughout the composition range. Special attention was paid to the response functions and their respective excess properties, for which a detailed comparison with selected previous works in the field has been established. PMID- 23742493 TI - A systematic development of a polarizable potential of water. AB - Based on extensive studies of existing potentials we propose a new molecular model for water. The new model is rigid and contains three Gaussian charges. Contrary to other models, all charges take part in the polarization of the molecule. They are connected by harmonic springs to their gas-phase positions: the negative charge to a prescribed point on the main axis of the molecule; the positive charges to the hydrogens. The mechanical equilibrium between the electrostatic forces and the spring forces determines the polarization of the molecule which is established by iteration at every timestep. The model gives excellent estimates for ambient liquid properties and reasonably good results from high-pressure solids to gas-phase clusters. We present a detailed description of the development of this model and a large number of calculated properties compared to the estimates of the nonpolarizable TIP4P/2005 [J. L. F. Abascal and C. Vega, J. Chem. Phys. 123, 234505 (2005)], the polarizable GCPM [P. Paricaud, M. Predota, A. A. Chialvo, and P. T. Cummings, J. Chem. Phys. 122, 244511 (2005)], and our earlier BKd3 model [P. T. Kiss and A. Baranyai, J. Chem. Phys. 137, 084506 (2012)]. The best overall performance is shown by the new model. PMID- 23742494 TI - Thermionic current densities from first principles. AB - We present a density functional theory-based method for calculating thermionic emission currents from a cathode into vacuum using a non-equilibrium Green's function approach. It does not require semi-classical approximations or crude simplifications of the electronic structure used in previous methods and thus provides quantitative predictions of thermionic emission for adsorbate-coated surfaces. The obtained results match well with experimental measurements of temperature-dependent current densities. Our approach can thus enable computational design of composite electrode materials. PMID- 23742495 TI - Ab initio and classical molecular dynamics studies of the structural and dynamical behavior of water near a hydrophobic graphene sheet. AB - The behavior of water near a graphene sheet is investigated by means of ab initio and classical molecular dynamics simulations. The wetting of the graphene sheet by ab initio water and the relation of such behavior to the strength of classical dispersion interaction between surface atoms and water are explored. The first principles simulations reveal a layered solvation structure around the graphene sheet with a significant water density in the interfacial region implying no drying or cavitation effect. It is found that the ab initio results of water density at interfaces can be reproduced reasonably well by classical simulations with a tuned dispersion potential between the surface and water molecules. Calculations of vibrational power spectrum from ab initio simulations reveal a shift of the intramolecular stretch modes to higher frequencies for interfacial water molecules when compared with those of the second solvation later or bulk like water due to the presence of free OH modes near the graphene sheet. Also, a weakening of the water-water hydrogen bonds in the vicinity of the graphene surface is found in our ab initio simulations as reflected in the shift of intermolecular vibrational modes to lower frequencies for interfacial water molecules. The first principles calculations also reveal that the residence and orientational dynamics of interfacial water are somewhat slower than those of the second layer or bulk-like molecules. However, the lateral diffusion and hydrogen bond relaxation of interfacial water molecules are found to occur at a somewhat faster rate than that of the bulk-like water molecules. The classical molecular dynamics simulations with tuned Lennard-Jones surface-water interaction are found to produce dynamical results that are qualitatively similar to those of ab initio molecular dynamics simulations. PMID- 23742496 TI - Dynamics of acetone photooxidation on TiO2(110): state-resolved measurements of methyl photoproducts. AB - State-resolved laser techniques were used to study the internal state distributions of gas phase methyl radicals which are produced during the photooxidation of acetone on TiO2(110). This approach was used as a means of understanding the nature of the bimodal kinetic energy distributions for these radicals. Specifically, we investigated the population of the nu2 "umbrella mode" which has been shown to be important in similar photodissociation reactions where methyl radicals are liberated. We observed that for methyl radicals undergoing prompt dissociation (EK = 0.15 eV), the vibrational population in the umbrella mode is quite cold and can be characterized by a Tvib = 151 +/- 15 K. Methyl radicals in this channel were also characterized by a rotational energy distribution of Trot = 325 +/- 25 K which is comparable to the gas phase value obtained by acetone photolysis. State-resolved energy distributions also show that methyl radicals which are vibrationally excited have an overall kinetic energy distribution which is ~35 meV less than those which are in their vibrational ground state. This value is comparable to, but not exactly in agreement with, the known vibrational spacing of the nu2 mode and suggests that vibrationally excited methyl radicals have less energy available for translation. PMID- 23742497 TI - On the thermoelectric transport properties of graphyne by the first-principles method. AB - Graphyne, another two-dimensional carbon allotrope, has received increased attentions in recent years. By using the first-principles density functional calculations combined with the non-equilibrium Green's function formalism, we investigated the electronic, thermal, and thermoelectric transport properties of graphyne systematically and comparatively. It is found that the phonon thermal conductance of graphyne is greatly reduced compared to that of graphene in most temperature regions while larger than that of graphene at low temperatures, which is attributed to the different bond strengths and phonon spectra of graphyne and graphene. Due to the semiconductor property of graphyne, the thermoelectric power (TEP) is found to be one magnitude larger than that of graphene. Besides, distinct peak value regions of TEP in the contour of chemical potential and temperature are displayed for graphyne and graphene. Finally, the thermoelectric figure of merit (ZT) of graphyne is found to be much larger than that of graphene as a result of large TEP and greatly reduced thermal conductance in graphyne, which indicates preferred thermoelectric applications for graphyne. PMID- 23742498 TI - A microscopic picture of surface charge trapping in semiconductor nanocrystals. AB - Several different compositions of semiconductor nanocrystals are subjected to numerous spectroscopic techniques to elucidate the nature of surface trapping in these systems. We find a consistent temperature-dependent relationship between core and surface photoluminescence intensity and marked differences in electron phonon coupling for core and surface states based on ultrafast measurements and Resonance Raman studies, respectively. These results support a minimal model of surface charge trapping applicable to a range of nanocrystal systems involving a single surface state in which the trapped charge polarization leads to strong phonon couplings, with transitions between the surface and band edge excitonic states being governed by semiclassical electron-transfer theory. PMID- 23742499 TI - Absorption induced modulation of magnetism in two-dimensional metal phthalocyanine porous sheets. AB - Metal-phthalocyanine porous sheets have uniformly dispersed metal sites in Pc framework, making absorption happen naturally. Here, we explore the effects of absorption of chlorine atoms on magnetism in transition metal embedded phthalocyanine (poly-TMPc) sheets with TM = Cr, Mn, and Fe. We show that when one Cl is absorbed on the TM, the strong square planar crystal field becomes weak in a square pyramidal configuration and the TM is in the +3 oxidized state, resulting in the magnetic moment of 3, 4, and 5 MUB for Cr, Mn, and Fe, respectively, with weak antiferromagnetic couplings. When another Cl is introduced to the TM on the other side, it extracts one electron from the Pc framework making the substrate p-doped. The magnetic coupling is antiferromagnetic for poly-CrPc-2Cl and the poly-FePc-2Cl, while it becomes ferromagnetic for poly-MnPc-2Cl, suggesting that absorption can effectively modulate the bonding environment and tune the magnetic properties of the systems, and the controlled absorption can be used to tailor materials. PMID- 23742500 TI - Stretching tethered polymer chains: density functional approach. AB - We propose application of density functional theory to calculate the force acting on a selected segment of a tethered polymer chain that leads to stretching the chain. The density functional allows one to determine the effects due to the presence of other chains and solvent molecules. For high and moderate solvent densities the plot of the force versus the distance of the segment from the surface exhibits oscillatory behavior that has not been predicted by other approaches. PMID- 23742501 TI - Effect of compressibility in bubble formation in closed systems. AB - We analyze the stability of small bubbles in a closed system with fixed volume, temperature, and number of molecules. We show that there exists a minimum stable size of a bubble. Thus there exists a range of densities where no stable bubbles are allowed and the system has a homogeneous density which is lower than the coexistence density of the liquid. This becomes possible due to the finite liquid compressibility. Capillary analysis within the developed "modified bubble" model illustrates that the existence of the minimum bubble size is associated to the compressibility and it is not possible when the liquid is strictly incompressible. This finding is expected to have very important implications in cavitation and boiling. PMID- 23742502 TI - On the structure of Si(100) surface: importance of higher order correlations for buckled dimer. AB - We revisit a dangling theoretical question of whether the surface reconstruction of the Si(100) surface would energetically favor the symmetric or buckled dimers on the intrinsic potential energy surfaces at 0 K. This seemingly simple question is still unanswered definitively since all existing density functional based calculations predict the dimers to be buckled, while most wavefunction based correlated treatments prefer the symmetric configurations. Here, we use the doubly hybrid density functional (DHDF) geometry optimizations, in particular, XYGJ-OS, complete active space self-consistent field theory, multi-reference perturbation theory, multi-reference configuration interaction (MRCI), MRCI with the Davidson correction (MRCI + Q), multi-reference average quadratic CC (MRAQCC), and multi-reference average coupled pair functional (MRACPF) methods to address this question. The symmetric dimers are still shown to be lower in energy than the buckled dimers when using the CASPT2 method on the DHDF optimized geometries, consistent with the previous results using B3LYP geometries [Y. Jung, Y. Shao, M. S. Gordon, D. J. Doren, and M. Head-Gordon, J. Chem. Phys. 119, 10917 (2003)]. Interestingly, however, the MRCI + Q, MRAQCC, and MRACPF results (which give a more refined description of electron correlation effects) suggest that the buckled dimer is marginally more stable than its symmetric counterpart. The present study underlines the significance of having an accurate description of the electron-electron correlation as well as proper multi-reference wave functions when exploring the extremely delicate potential energy surfaces of the reconstructed Si(100) surface. PMID- 23742503 TI - The ice-like water monolayer near the wall makes inner water shells diffuse faster inside a charged nanotube. AB - Using molecular dynamics simulations, we have investigated the impact of the ice like water monolayer inside the tube and nearest to the tube wall on the diffusion properties of other inner water shells confined within a charged nanotube. We find that the axial diffusion coefficient of the first water monolayer near the wall monotonously decreases with the charge size on the nanotube, indicating a tighter control of the first monolayer from the larger sized charge. However, for the other water shells, the diffusion coefficients increase when the charge is larger than a critical value qc (~1.0 e). This unexpected phenomenon is attributed to the decreased number of hydrogen bonds between the first monolayer and other inner water shells caused by the very unique hydrogen-bond network patterns in the first ice-like monolayer, which makes it behave like a "hydrophobic water layer." Our findings may have implications for water treatment, non-fouling surfaces, catalysis engine, and biological sensor. PMID- 23742504 TI - Alcohol-induced drying of carbon nanotubes and its implications for alcohol/water separation: a molecular dynamics study. AB - Alcohols are important products in chemical industry, but separating them from their aqueous solutions is very difficult due to the hydrophilic nature of alcohols. Based on molecular dynamics simulations, we observe a striking nanoscale drying phenomenon and suggest an energy-saving and efficient approach toward alcohol/water separation by using single-walled carbon nanotubes (SWNTs). We use various common linear alcohols including C1-C6 1-alcohols and glycerol for demonstration (the phenol is also used as comparison). Our simulations show that when SWNTs are immersed in aqueous alcohols solutions, although the alcohols concentration is low (1 M), all kinds of alcohols can induce dehydration (drying) of nanotubes and accumulate inside wide [(13, 13)] and narrow [(6, 6) or (7, 7)] SWNTs. In particular, most kinds of alcohols inside the narrow SWNTs form nearly uniform 1D molecular wires. Detailed energetic analyses reveal that the preferential adsorption of alcohols over water inside nanotubes is attributed to the stronger dispersion interactions of alcohols with SWNTs than water. Interestingly, we find that for the wide SWNT, the selectivity for 1-alcohols increases with the number of alcohol's carbon atoms (Ncarbon) and exhibits an exponential law with respect to Ncarbon for C1-C5 1-alcohols; for narrow SWNTs, the selectivity for 1-alcohols is very high for methanol, ethanol, and propanol, and reaches a maximum when Ncarbon = 3. The underlying physical mechanisms and the implications of these observations for alcohol/water separation are discussed. Our findings provide the possibility for efficient dehydration of aqueous alcohols (and other hydrophilic organic molecules) by using SWNT bundles/membranes. PMID- 23742505 TI - A comparative DFT study of the mechanical and electronic properties of greigite Fe3S4 and magnetite Fe3O4. AB - Greigite (Fe3S4) and its analogue oxide, magnetite (Fe3O4), are natural minerals with an inverse spinel structure whose atomic-level properties may be difficult to investigate experimentally. Here, [D. Rickard and G. W. Luther, Chem. Rev. 107, 514 (2007)] we have calculated the elastic constants and other macroscopic mechanical properties by applying elastic strains on the unit cells. We also have carried out a systematic study of the electronic properties of Fe3S4 and Fe3O4, where we have used an ab initio method based on spin-polarized density functional theory with the on-site Coulomb repulsion approximation (Ueff is 1.0 and 3.8 eV for Fe3S4 and Fe3O4, respectively). Comparison of the properties of Fe3S4 and Fe3O4 shows that the sulfide is more covalent than the oxide, which explains the low magnetization of saturation of greigite cited in several experimental reports. PMID- 23742506 TI - Nonlocal electron-phonon coupling in organic semiconductor crystals: the role of acoustic lattice vibrations. AB - We discuss, in the context of a tight-binding description, how the electronic and charge-transport properties in single crystals of molecular organic semiconductors are affected by the nonlocal electron-phonon coupling to both acoustic and optical lattice vibrations. While the nonlocal electron-phonon interactions can in general be divided into contributions from symmetric modes and antisymmetric modes, we show that only the antisymmetric coupling mechanism is operational in the case of acoustic vibrations. Interestingly, when the quantum nature of the phonons can be neglected, the effect of electron-phonon interactions with acoustic phonons is found to be equivalent to that of the electron-phonon interactions with optical phonons, in the case where contributions from symmetric and antisymmetric modes are equal. PMID- 23742507 TI - Low temperature phase properties of water confined in mesoporous silica MCM-41: thermodynamic and neutron scattering study. AB - The phase properties of water confined in mesoporous silica MCM-41 were investigated over a temperature range of 100-298 K as a function of pore size by specific heat capacity and inelastic neutron scattering (INS) measurements. The water content of the samples was carefully controlled to ensure the capillary filled state and no overloading of water. The values of heat capacity of the pore water are higher than those of bulk ice and liquid water over the whole temperature range measured. The contribution of water in the inner part of pores (abbreviated as the internal water) was elucidated by using the heat capacity data of monolayer water measured. The entropy of the internal water was then estimated from integration of the heat capacity of the internal water. The entropy values of the internal water increase by confinement in the pores of MCM 41 in both liquid and frozen regions, indicating an increase in the deformation of the structure and/or a change in the dynamics in both regions. The INS spectra show the density of states for the librational motion of water frozen at 50 K, suggesting that the confined water is similar to amorphous ice rather than to crystalline ice. When the sample is warmed to melt, the band edge of the librational motion for water frozen in large pores (diameter of 3.6 nm) shifts to a lower energy side, indicating the weakening of intermolecular hydrogen bonds. For water in small pores (2.1 nm), on the contrary, the librational band shifts slightly to a higher energy side, suggesting the low density liquid to high density liquid transition (L-L transition) at 225-250 K. A plausible mechanism of the L-L transition of water in confinement is proposed in terms of incomplete growth of homogeneous nucleation of ice due to an interfacial free energy effect to inhibit crystallization of water confined in small pores. PMID- 23742508 TI - Restricted primitive model for electrolyte solutions in slit-like pores with grafted chains: microscopic structure, thermodynamics of adsorption, and electric properties from a density functional approach. AB - We apply a density functional theory to describe properties of a restricted primitive model of an ionic fluid in slit-like pores. The pore walls are modified by grafted chains. The chains are built of uncharged or charged segments. We study the influence of modification of the pore walls on the structure, adsorption, ion selectivity, and the electric double layer capacitance of ionic fluid under confinement. The brush built of uncharged segments acts as a collection of obstacles in the walls vicinity. Consequently, separation of charges requires higher voltages, in comparison to the models without brushes. At high grafting densities the formation of crowding-type structure is inhibited. The double layer structure becomes more complex in various aspects, if the brushes are built of charged segments. In particular, the evolution of the brush height with the bulk fluid density and with the charge on the walls depends on the length of the blocks of charged spheres as well as on the distribution of charged species along chains. We also investigated how the dependence of the double layer capacitance on the electrostatic potential (or on the charge on the walls) changes with grafting density, the chain length, distribution of charges along the chain, the bulk fluid density, and, finally, with the pore width. The shape of the electric double layer capacitance vs. voltage changes from a camel like to bell-like shape, if the bulk fluid density changes from low to moderate and high. If the bulk density is appropriately chosen, it is possible to alter the shape of this curve from the double hump to single hump by changing the grafting density. Moreover, in narrow pores one can observe the capacitance curve with even three humps for a certain set of parameters describing brush. This behavior illustrates how strong the influence of brushes on the electric double layer properties can be, particularly for ionic fluids in narrow pores. PMID- 23742509 TI - Magnetoelectric coupling in 4,4'-stilbenedinitrene. AB - We investigated the optical properties of 4,4'-stilbenedinitrene at low temperature and in high magnetic fields and compared the results with complementary first principles calculations. Both physical tuning parameters allow us to manipulate the singlet-triplet equilibrium, and by doing so, control the optical contrast (which is on the order of -2.5 * 10(2) cm(-1) at 555 nm and 35 T). Moreover, analysis of the magneto-optical response using a combined population and Beer's law framework reveals the singlet-triplet spin gap and identifies particular features in the absorption difference spectrum as deriving from singlet or triplet state excitations. These findings deepen our understanding of coupling in open shell molecules and show how chemical structure modification can modulate charge-spin interactions in organic biradicals. PMID- 23742510 TI - An atomistic description of the nematic and smectic phases of 4-n-octyl-4' cyanobiphenyl (8CB). AB - We report the results of atomistic molecular dynamics simulations of 4-n-octyl-4' cyanobiphenyl (8CB) on samples of 750 and 3000 molecules showing the spontaneous formation of the nematic phase and then of smectic layers by gradually cooling down from the isotropic phase. Orientational, positional, and mixed order parameters, layer spacing, translational diffusion tensor components and their temperature dependence are reported. A detailed comparison with available experimental data validates the model and force field employed and clarifies the molecular organization of this important liquid crystal often used as reference smectic material. PMID- 23742511 TI - Dynamics of discrete semiflexible chains under dihedral constraints: analytic results. AB - Here we consider the dynamics of semiflexible polymers subject both to angular and to dihedral constraints. We succeed in obtaining analytically the dynamical matrix of such systems by extending the formalism developed by Dolgushev and Blumen [J. Chem. Phys. 131, 044905 (2009)]. This leads to a set of Langevin equations whose eigenvalues determine many dynamical properties. Exemplarily, we display the mechanical relaxation loss moduli [G"(omega)] as a function of several, distinct sets of microscopic stiffness parameters; it turns out that such differences lead to macroscopically distinct patterns. PMID- 23742512 TI - Dynamics of polymer translocation through a nanopore induced by different sizes of crowding agents. AB - Using both theoretical analysis and Langevin dynamics simulations in two dimensions, we investigate the dynamics of polymer translocation through a nanopore induced by different sizes of the mobile crowding agents, where the crowding agents have equal area fraction phi and their diameters are sigma and sigmab >= sigma at cis and trans sides, respectively. The chain prefers moving to the side with bigger crowding agents as expected, however, we find the size difference between crowding agents plays a complicated role in the probability of polymer translocation from cis to trans side, the translocation time tau and its distribution, and the translocation exponent. In particular, with increasing sigmab, the translocation probability shows a maximum value and tau has a minimum value. These results can be interpreted by the effective driving force, which always increases with increasing phi but has a maximum value with increasing sigmab. PMID- 23742513 TI - Effect of ion pair formation on the structure of polymer micelles with ionic amphiphilic coronae. AB - We report a theoretical study of micelles from diblock copolymers with an insoluble core-forming block and an amphiphilic ionic corona-forming block. We calculate the micelle structural parameters depending on the composition of the coronal block (ratio between the non-polar and ion-containing groups) as well as solvent quality and polarity for the coronal block. We focus on the effect of ion pair formation in a low polar corona medium and predict the existence of novel micelles with ionomer-type coronae. In these micelles most part of counterions is bound with ions in polymer chains. Two consecutive jump-like first-order phase transitions between different-type micelles can take place in the solution upon change of hydrophobic/polyelectrolyte balance within the micelle corona: large micelles with polyelectrolyte collapsed coronae -> large micelles with ionomer type coronae -> small micelles with polyelectrolyte swollen coronae. These transitions are accompanied by non-monotonous change in the micelle aggregation number. New insight into the role of counterions is important for design of stimuli responsive systems. PMID- 23742514 TI - The phase behavior of linear and partially flexible hard-sphere chain fluids and the solubility of hard spheres in hard-sphere chain fluids. AB - The liquid crystal phase behavior of linear and partially flexible hard-sphere chain fluids and the solubility of hard spheres in hard-sphere chain fluids are studied by constant pressure Monte Carlo simulations. An extensive study on the phase behavior of linear fluids with a length of 7, 8, 9, 10, 11, 12, 13, 14, 15, and 20 beads is carried out. The phase behavior of partially flexible fluids with a total length of 8, 10, 14, and 15 beads and with different lengths for the linear part is also determined. A precise description of the reduced pressure and of the packing fraction change at the isotropic-nematic coexistence was achieved by performing long simulation runs. For linear fluids, a maximum in the isotropic to nematic packing fraction change is observed for a chain length of 15 beads. The infinite dilution solubility of hard spheres in linear and partially flexible hard-sphere chain fluids is calculated by the Widom test-particle insertion method. To identify the effect of chain connectivity and molecular anisotropy on free volume, solubility is expressed relative to that of hard spheres in a hard sphere fluid at same packing fraction as relative Henry's law constants. A linear relationship between relative Henry's law constants and packing fraction is observed for all linear fluids. Furthermore, this linearity is independent of liquid crystal ordering and seems to be independent of chain length for linear chains of 10 beads and longer. The same linear relationship was observed for the solubility of hard spheres in nematic forming partially flexible fluids for packing fractions up to a value slightly higher than the nematic packing fraction at the isotropic-nematic coexistence. At higher packing fractions, the small flexibility of these fluids seems to improve solubility in comparison with the linear fluids. PMID- 23742515 TI - Hardening transition in a one-dimensional model for ferrogels. AB - We introduce and investigate a coarse-grained model for quasi one-dimensional ferrogels. In our description the magnetic particles are represented by hard spheres with a magnetic dipole moment in their centers. Harmonic springs connecting these spheres mimic the presence of a cross-linked polymer matrix. A special emphasis is put on the coupling of the dipolar orientations to the elastic deformations of the matrix, where a memory effect of the orientations is included. Although the particles are displaced along one spatial direction only, the system already shows rich behavior: as a function of the magnetic dipole moment, we find a phase transition between "soft-elastic" states with finite interparticle separation and finite compressive elastic modulus on the one hand, and "hardened" states with touching particles and therefore diverging compressive elastic modulus on the other hand. Corresponding phase diagrams are derived neglecting thermal fluctuations of the magnetic particles. In addition, we consider a situation in which a spatially homogeneous magnetization is initially imprinted into the material. Depending on the strength of the magneto-mechanical coupling between the dipole orientations and the elastic deformations, the system then relaxes to a uniaxially ferromagnetic, an antiferromagnetic, or a spiral state of magnetization to minimize its energy. One purpose of our work is to provide a largely analytically solvable approach that can provide a benchmark to test future descriptions of higher complexity. From an applied point of view, our results could be exploited, for example, for the construction of novel damping devices of tunable shock absorbance. PMID- 23742516 TI - Screening properties of Gaussian electrolyte models, with application to dissipative particle dynamics. AB - We investigate the screening properties of Gaussian charge models of electrolyte solutions by analysing the asymptotic behaviour of the pair correlation functions. We use a combination of Monte Carlo simulations with the hyper-netted chain integral equation closure, and the random phase approximation, to establish the conditions under which a screening length is well defined and the extent to which it matches the expected Debye length. For practical applications, for example, in dissipative particle dynamics, we are able to summarise our results in succinct rules-of-thumb which can be used for mesoscale modeling of electrolyte solutions. We thereby establish a solid foundation for future work, such as the systematic incorporation of specific ion effects. PMID- 23742517 TI - A Monte Carlo density functional theory for the competition between inter and intramolecular association in inhomogeneous fluids. AB - A Monte Carlo density functional theory is developed for chain molecules which both intra and intermolecularly associate. The approach can be applied over a range of chain lengths. The theory is validated for the case of an associating 4 mer fluid in a planar hard slit pore. Once validated, the new theory is used to study the effect of chain length and temperature on the competition between intra and intermolecular association near a hard wall. We show that this competition enhances intramolecular association near wall contact and inverts the chain length dependence of the fraction bonded intermolecularly in the inhomogeneous region. PMID- 23742518 TI - Driven translocation of a semi-flexible chain through a nanopore: a Brownian dynamics simulation study in two dimensions. AB - We study translocation dynamics of a semi-flexible polymer chain through a nanoscopic pore in two dimensions using Langevin dynamics simulation in presence of an external bias F inside the pore. For chain length N and stiffness parameter kappab considered in this paper, we observe that the mean first passage time increases as ~lp(aN) , where kappab and lp are the stiffness parameter and persistence length, respectively, and aN is a constant that has a weak N dependence. We monitor the time dependence of the last monomer xN(t) at the cis compartment and calculate the tension propagation time (TP) ttp directly from simulation data for ~ t as alluded in recent nonequlibrium TP theory [T. Sakaue, Phys. Rev. E 76, 021803 (2007)] and its modifications to Brownian dynamics tension propagation theory [T. Ikonen, A. Bhattacharya, T. Ala-Nissila, and W. Sung, Phys. Rev. E 85, 051803 (2012); and J. Chem. Phys. 137, 085101 (2012)] originally developed to study translocation of a fully flexible chain. We also measure ttp from peak position of the waiting time distribution W(s) of the translocation coordinate s (i.e., the monomer inside the pore), and explicitly demonstrate the underlying TP picture along the chain backbone of a translocating chain to be valid for semi-flexible chains as well. From the simulation data, we determine the dependence of ttp on chain persistence length lp and show that the ratio ttp/ is independent of the bias F. PMID- 23742519 TI - Dynamics simulation of the interaction between serine and water. AB - Using the first principles density functional theory (DFT), we simulated the neutron scattering spectra of the hydration dynamics of serine. Experimental data analyses have shown that dissociative H2O molecules were more likely to form hydrogen bonds (H-bonds) with an -OH group in monohydrated serine and easily shift to a -NH3 (+) group at a higher hydration level [P. Zhang, Y. Zhang, S. H. Han, Q. W. Yan, R. C. Ford, and J. C. Li, J. Phys. Chem. A 110, 5000 (2006)]. We set the 1:1 ratio hydrated compounds at the two positions and found that the H2O could be optimized to form H-bonds with -OH and -NH3 (+) separately. When the simulated phonon signals of the -OH...H2O and -NH3(+)...H2O combinations were summed on a 3:1 scale, the calculating spectra were in good agreement with the experimental results, especially for the peak at 423 cm(-1) of the -OH...H2O combination and the peak at 367 cm(-1) of the -NH3(+)...H2O combination, which mutually complemented the real spectrum. We confirm that H2O may break the intermolecular H-bonds of the interlaced binding -OH to form a new structure, and that with the skeleton deformation of serine, H2O forms stronger H-bonds more often with the -NH3 (+) side indicating the flexible dynamic mechanism of the serine hydration process. PMID- 23742520 TI - Instantaneous normal mode analysis of the vibrational relaxation of the amide I mode of alanine dipeptide in water. AB - Nonequilibrium Molecular Dynamics (MD) simulations coupled to instantaneous normal modes (INMs) analysis are used to study the vibrational relaxation of the acetyl and amino-end amide I modes of the alanine dipeptide (AlaD) molecule dissolved in water (D2O). The INMs are assigned in terms of the equilibrium normal modes using the Effective Atomic Min-Cost algorithm as adapted to make use of the outputs of standard MD packages, a method which is well suited for the description of flexible molecules. The relaxation energy curves of both amide I modes show multiexponential decays, in good agreement with the experimental findings. It is found that ~85%-90% of the energy relaxes through intramolecular vibrational redistribution. The main relaxation pathways are also identified. The rate at which energy is transferred into the solvent is similar for the acetyl end and amino-end amide I modes. The conformational changes occurring during relaxation are investigated, showing that the populations of the alpha and beta region conformers are altered by energy transfer in such a way that it takes 15 ps for the equilibrium conformational populations to be recovered after the initial excitation of the AlaD molecule. PMID- 23742521 TI - Helix untwisting and bubble formation in circular DNA. AB - The base pair fluctuations and helix untwisting are examined for a circular molecule. A realistic mesoscopic model including twisting degrees of freedom and bending of the molecular axis is proposed. The computational method, based on path integral techniques, simulates a distribution of topoisomers with various twist numbers and finds the energetically most favorable molecular conformation as a function of temperature. The method can predict helical repeat, openings loci, and bubble sizes for specific sequences in a broad temperature range. Some results are presented for a short DNA circle recently identified in mammalian cells. PMID- 23742525 TI - Invited article: Coherent imaging using seeded free-electron laser pulses with variable polarization: first results and research opportunities. AB - FERMI@Elettra, the first vacuum ultraviolet and soft X-ray free-electron laser (FEL) using by default a "seeded" scheme, became operational in 2011 and has been opened to users since December 2012. The parameters of the seeded FERMI FEL pulses and, in particular, the superior control of emitted radiation in terms of spectral purity and stability meet the stringent requirements for single-shot and resonant coherent diffraction imaging (CDI) experiments. The advantages of the intense seeded FERMI pulses with variable polarization have been demonstrated with the first experiments performed using the multipurpose experimental station operated at the diffraction and projection imaging (DiProI) beamline. The results reported here were obtained with fixed non-periodic targets during the commissioning period in 2012 using 20-32 nm wavelength range. They demonstrate that the performance of the FERMI FEL source and the experimental station meets the requirements of CDI, holography, and resonant magnetic scattering in both multi- and single-shot modes. Moreover, we present the first magnetic scattering experiments employing the fully circularly polarized FERMI pulses. The ongoing developments aim at pushing the lateral resolution by using shorter wavelengths provided by double-stage cascaded FERMI FEL-2 and probing ultrafast dynamic processes using different pump-probe schemes, including jitter-free seed laser pump or FEL-pump/FEL-probe with two color FEL pulses generated by the same electron bunch. PMID- 23742526 TI - Fiber-optic Fourier transform infrared spectroscopy for remote label-free sensing of medical device surface contamination. AB - As a potential major source of biochemical contamination, medical device surfaces are of critical safety concerns in the clinical practice and public health. The development of innovative sensing methods for accurate and real-time detection of medical device surface contamination is essential to protect patients from high risk infection. In this paper, we demonstrate an alternative fiber-optic Fourier Transform Infrared (FTIR) spectroscopy based sensing approach for remote, non contact, and label-free detection of biochemical contaminants in the mid-infrared (mid-IR) region. The sensing probe is designed using mid-IR hollow fibers and FTIR measurements are carried out in reflection mode. Bovine Serum Albumin (BSA) and bacterial endotoxin of different concentrations under thoroughly dry condition are used to evaluate the detection sensitivity. The devised system can identify <=0.0025% (<=4 * 10(11) molecules) BSA and 0.5% (0.5 EU/ml) endotoxin concentration. The developed sensing approach may be applied to detect various pathogens that pose public health threats. PMID- 23742528 TI - Optical design of the short pulse x-ray imaging and microscopy time-angle correlated diffraction beamline at the Advanced Photon Source. AB - The short pulse x-ray imaging and microscopy beamline is one of the two x-ray beamlines that will take full advantage of the short pulse x-ray source in the Advanced Photon Source (APS) upgrade. A horizontally diffracting double crystal monochromator which includes a sagittally focusing second crystal will collect most of the photons generated when the chirped electron beam traverses the undulator. A Kirkpatrick-Baez mirror system after the monochromator will deliver to the sample a beam which has an approximately linear correlation between time and vertical beam angle. The correlation at the sample position has a slope of 0.052 ps/MUrad extending over an angular range of 800 MUrad for a cavity deflection voltage of 2 MV. The expected time resolution of the whole system is 2.6 ps. The total flux expected at the sample position at 10 keV with a 0.9 eV energy resolution is 5.7 * 10(12) photons/s at a spot having horizontal and vertical full width at half maximum of 33 MUm horizontal by 14 MUm vertical. This new beamline will enable novel time-dispersed diffraction experiments on small samples using the full repetition rate of the APS. PMID- 23742527 TI - A seven-crystal Johann-type hard x-ray spectrometer at the Stanford Synchrotron Radiation Lightsource. AB - We present a multicrystal Johann-type hard x-ray spectrometer (~5-18 keV) recently developed, installed, and operated at the Stanford Synchrotron Radiation Lightsource. The instrument is set at the wiggler beamline 6-2 equipped with two liquid nitrogen cooled monochromators--Si(111) and Si(311)--as well as collimating and focusing optics. The spectrometer consists of seven spherically bent crystal analyzers placed on intersecting vertical Rowland circles of 1 m of diameter. The spectrometer is scanned vertically capturing an extended backscattering Bragg angular range (88 degrees -74 degrees ) while maintaining all crystals on the Rowland circle trace. The instrument operates in atmospheric pressure by means of a helium bag and when all the seven crystals are used (100 mm of projected diameter each), has a solid angle of about 0.45% of 4pi sr. The typical resolving power is in the order of E/DeltaE ~ 10,000. The spectrometer's high detection efficiency combined with the beamline 6-2 characteristics permits routine studies of x-ray emission, high energy resolution fluorescence detected x ray absorption and resonant inelastic x-ray scattering of very diluted samples as well as implementation of demanding in situ environments. PMID- 23742529 TI - Improving the accuracy of optical rotation measurement based on optical null methods by curve-fitting. AB - An optical rotation measuring system using optical null methods is set up. The system is based on a step-motor rotating stage structure and a modulated laser, which both are controlled by digital signal processor. By introducing a curve fitting method, the optical rotation angle is obtained from the step difference between the crossed positions in light signal curves with or without sample. The principle of this method is studied, and the system performance is investigated experimentally. We achieved an accuracy of the order of 10(-3) degree in at least +/-45 degrees range, which is an improvement compared with the resolution of 0.01 degrees for step-motor rotation stage. PMID- 23742530 TI - Modified Fabry-Perot interferometer for displacement measurement in ultra large measuring range. AB - Laser interferometers have demonstrated outstanding measuring performances for high precision positioning or dimensional measurements in the precision industry, especially in the length measurement. Due to the non-common-optical-path structure, appreciable measurement errors can be easily induced under ordinary measurement conditions. That will lead to the limitation and inconvenience for in situ industrial applications. To minimize the environmental and mechanical effects, a new interferometric displacement measuring system with the common optical-path structure and the resistance to tilt-angle is proposed. With the integration of optomechatronic modules in the novel interferometric system, the resolution up to picometer order, high precision, and ultra large measuring range have been realized. For the signal stabilization of displacement measurement, an automatic gain control module has been proposed. A self-developed interpolation model has been employed for enhancing the resolution. The novel interferometer can hold the advantage of high resolution and large measuring range simultaneously. By the experimental verifications, it has been proven that the actual resolution of 2.5 nm can be achieved in the measuring range of 500 mm. According to the comparison experiments, the maximal standard deviation of the difference between the self-developed Fabry-Perot interferometer and the reference commercial Michelson interferometer is 0.146 MUm in the traveling range of 500 mm. With the prominent measuring characteristics, this should be the largest dynamic measurement range of a Fabry-Perot interferometer up till now. PMID- 23742531 TI - Absolute photo-destruction and photo-fragmentation cross section measurements using an electrostatic ion beam trap. AB - We describe a technique to measure absolute photo-induced cross sections for cluster anions stored in an electrostatic ion beam trap (EIBT) with a central deflector. The setup allows determination of total photo-destruction cross sections as well as partial cross sections for fragmentation and electron detachment. The unique properties of this special EIBT setup are investigated and illustrated using small Al(n)(-) clusters. PMID- 23742532 TI - A testbed for wide-field, high-resolution, gigapixel-class cameras. AB - The high resolution and wide field of view (FOV) of the AWARE (Advanced Wide FOV Architectures for Image Reconstruction and Exploitation) gigapixel class cameras present new challenges in calibration, mechanical testing, and optical performance evaluation. The AWARE system integrates an array of micro-cameras in a multiscale design to achieve gigapixel sampling at video rates. Alignment and optical testing of the micro-cameras is vital in compositing engines, which require pixel-level accurate mappings over the entire array of cameras. A testbed has been developed to automatically calibrate and measure the optical performance of the entire camera array. This testbed utilizes translation and rotation stages to project a ray into any micro-camera of the AWARE system. A spatial light modulator is projected through a telescope to form an arbitrary object space pattern at infinity. This collimated source is then reflected by an elevation stage mirror for pointing through the aperture of the objective into the micro optics and eventually the detector of the micro-camera. Different targets can be projected with the spatial light modulator for measuring the modulation transfer function (MTF) of the system, fiducials in the overlap regions for registration and compositing, distortion mapping, illumination profiles, thermal stability, and focus calibration. The mathematics of the testbed mechanics are derived for finding the positions of the stages to achieve a particular incident angle into the camera, along with calibration steps for alignment of the camera and testbed coordinate axes. Measurement results for the AWARE-2 gigapixel camera are presented for MTF, focus calibration, illumination profile, fiducial mapping across the micro-camera for registration and distortion correction, thermal stability, and alignment of the camera on the testbed. PMID- 23742533 TI - Capacitive readout and gating of superconducting single photon detectors. AB - We propose and develop a readout scheme for superconducting single-photon detectors based on an integrated circuit, relaxing the need for large bandwidth amplification and resulting in voltage steps proportional to the number of detected photons. We also demonstrate time gating, to filter scattered light in time and reduce dark counts. This could lead to a higher signal-to-noise ratio. The gate pulse is generated on the detection of a photon created by a spontaneous parametric down-conversion source, heralding the presence of a second photon. These two schemes could find applications within advanced multi-array imaging detection systems. PMID- 23742534 TI - Compact integrated X-ray intensity and beam position monitor based on rare gas scintillation. AB - We have created and tested a compact integrated X-ray beam intensity and position monitor using Ar-gas scintillation. The light generated inside the device's cavity is detected by diametrically opposed PIN diodes located above and below the beam. The intensity is derived from the sum of the top and bottom signals, while the beam position is calculated from the difference-over-sum of the two signals. The device was tested at Cornell High Energy Synchrotron Source with both 17 keV and 59 keV x-rays. For intensity monitoring, the Ar-scintillation monitor performance is comparable to standard ion chambers in terms of precision. As an X-ray beam position monitor the new device response is linear with vertical beam position over a 2 mm span with a precision of 2 MUm. PMID- 23742535 TI - Self-standing quasi-mosaic crystals for focusing hard X-rays. AB - A quasi mosaic bent crystal for high-resolution diffraction of X and gamma rays has been realized. A net curvature was imprinted to the crystal thanks to a series of superficial grooves to keep the curvature without external devices. The crystal highlights very high diffraction efficiency due to quasi mosaic curvature. Quasi mosaic crystals of this kind are proposed for the realization of a high-resolution focusing Laue lens for hard X-rays. PMID- 23742536 TI - Compact cryogenically cooled Ti:Sapphire dual multi-kilohertz amplifiers for synchrotron radiation ultra-fast x-ray applications. AB - A titanium-doped sapphire regenerative dual-amplifier array operating at multi kHz repetition rates has been developed for synchrotron radiation ultra-fast x ray applications. The thermal lensing of the crystal in the amplifiers is virtually eliminated by cryogenic cooling of the laser crystal. The output energy of the amplifiers is measured to be greater than 2.6 mJ and the pulse length was compressed to less than 70 fs. The output laser mode is a near perfect Gaussian TEM00 with an M(2) factor of 1.02. The performance of the amplifier system is in excellent agreement with theoretical calculation. PMID- 23742537 TI - DELICIOUS III: a multipurpose double imaging particle coincidence spectrometer for gas phase vacuum ultraviolet photodynamics studies. AB - We present a versatile double imaging particle coincidence spectrometer operating in fully continuous mode, named DELICIOUS III, which combines a velocity map imaging device and a modified Wiley-McLaren time of flight momentum imaging analyzer for photoelectrons and photoions, respectively. The spectrometer is installed in a permanent endstation on the DESIRS vacuum ultraviolet (VUV) beamline at the French National Synchrotron Radiation Facility SOLEIL, and is dedicated to gas phase VUV spectroscopy, photoionization, and molecular dynamics studies. DELICIOUS III is capable of recording mass-selected threshold photoelectron photoion coincidence spectra with a sub-meV resolution, and the addition of a magnifying lens inside the electron drift tube provides a sizeable improvement of the electron threshold/ion mass resolution compromise. In fast electron mode the ultimate kinetic energy resolution has been measured at DeltaE/E = 4%. The ion spectrometer offers a mass resolution--full separation of adjacent masses--of 250 amu for moderate extraction fields and the addition of an electrostatic lens in the second acceleration region allows measuring the full 3D velocity vector for a given mass with an ultimate energy resolution of DeltaE/E = 15%, without sacrificing the mass resolution. Hence, photoelectron images are correlated both to the mass and to the ion kinetic energy and recoil direction, to access the electron spectroscopy of size-selected species, to study the photodissociation processes of state-selected cations in detail, or to measure in certain cases photoelectron angular distributions in the ion recoil frame. The performances of DELICIOUS III are explored through several examples including the photoionization of N2, NO, and CF3. PMID- 23742538 TI - Compact inline optical electron polarimeter. AB - A compact optical electron polarimeter using a helium target is described. It offers a maximum fluorescence detection efficiency of ~20 Hz/nA, which is an order of magnitude higher than that of earlier designs. With an argon target, this device is expected to have a polarimetric figure-of-merit of 270 Hz/nA. By relying on a magnetic field to guide a longitudinally spin-polarized electron beam, the present instrument employs fewer electrodes. It also uses a commercially available integrated photon counting module. These features allow it to occupy a smaller volume and make it easier to operate. PMID- 23742539 TI - Generation of first hard X-ray pulse at Tsinghua Thomson Scattering X-ray Source. AB - Tsinghua Thomson Scattering X-ray Source (TTX) is the first-of-its-kind dedicated hard X-ray source in China based on the Thomson scattering between a terawatt ultrashort laser and relativistic electron beams. In this paper, we report the experimental generation and characterization of the first hard X-ray pulses (51.7 keV) via head-on collision of an 800 nm laser and 46.7 MeV electron beams. The measured yield is 1.0 * 10(6) per pulse with an electron bunch charge of 200 pC and laser pulse energy of 300 mJ. The angular intensity distribution and energy spectra of the X-ray pulse are measured with an electron-multiplying charge coupled device using a CsI scintillator and silicon attenuators. These measurements agree well with theoretical and simulation predictions. An imaging test using the X-ray pulse at the TTX is also presented. PMID- 23742540 TI - Thomson spectrometer-microchannel plate assembly calibration for MeV-range positive and negative ions, and neutral atoms. AB - We report on the absolute calibration of a microchannel plate (MCP) detector, used in conjunction with a Thomson parabola spectrometer. The calibration delivers the relation between a registered count numbers in the CCD camera (on which the MCP phosphor screen is imaged) and the number of ions incident on MCP. The particle response of the MCP is evaluated for positive, negative, and neutral particles at energies below 1 MeV. As the response of MCP depends on the energy and the species of the ions, the calibration is fundamental for the correct interpretation of the experimental results. The calibration method and arrangement exploits the unique emission symmetry of a specific source of fast ions and atoms driven by a high power laser. PMID- 23742541 TI - Development of a fast scintillator based beam phase measurement system for compact superconducting cyclotrons. AB - In an isochronous cyclotron, measurements of central phase of the ion beam with respect to rf and the phase width provide a way to tune the cyclotron for maximum energy gain per turn and efficient extraction. We report here the development of a phase measurement system and the measurements carried out at the Variable Energy Cyclotron Centre's (VECC's) K = 500 superconducting cyclotron. The technique comprises detecting prompt gamma-rays resulting from the interaction of cyclotron ion beam with an aluminium target mounted on a radial probe in coincidence with cyclotron rf. An assembly comprising a fast scintillator and a liquid light-guide inserted inside the cyclotron was used to detect the gamma rays and to transfer the light signal outside the cyclotron where a matching photo-multiplier tube was used for light to electrical signal conversion. The typical beam intensity for this measurement was a few times 10(11) pps. PMID- 23742542 TI - High precision measurements of carbon disulfide negative ion mobility and diffusion. AB - High precision measurements were made of reduced mobility, lateral and longitudinal diffusion of CS2(-) ions in 40 Torr CS2 and a 30-10 Torr CS2-CF4 gas mixture. The reduced mobility was found to be 0.4645 +/- 0.0006 cm(2) atm/s V in CS2 and 0.523 +/- 0.001 cm(2) atm/s V in the CS2-CF4 gas mixture at STP. The lateral diffusion temperatures for these two gases (295 +/- 15 K and 297 +/- 6 K) were found to be in good agreement with room temperature. By contrast longitudinal diffusion temperature was found to be slightly elevated (319 +/- 10 (stat) +/- 8 (sys) K and 310 +/- 20 (stat) +/- 6 (sys) K) though given the errors, room temperature diffusion cannot be ruled out. For lateral diffusion, significant capture distances (0.21 +/- 0.07 mm and 0.15 +/- 0.03 mm) were measured while for longitudinal diffusion the results were not conclusive. PMID- 23742543 TI - Photon-induced positron annihilation lifetime spectroscopy using ultrashort laser Compton-scattered gamma-ray pulses. AB - High-energy ultrashort gamma-ray pulses can be generated via laser Compton scattering with 90 degrees collisions at the UVSOR-II electron storage ring. As an applied study of ultrashort gamma-ray pulses, a new photon-induced positron annihilation lifetime spectroscopy approach has been developed. Ultrashort gamma ray pulses with a maximum energy of 6.6 MeV and pulse width of 2.2 ps created positrons throughout bulk lead via pair production. Annihilation gamma rays were detected by a BaF2 scintillator mounted on a photomultiplier tube. A positron lifetime spectrum was obtained by measuring the time difference between the RF frequency of the electron storage ring and the detection time of the annihilation gamma rays. We calculated the response of the BaF2 scintillator and the time jitter caused by the variation in the total path length of the ultrashort gamma ray pulses, annihilation gamma rays, and scintillation light using a Monte Carlo simulation code. The positron lifetime for bulk lead was successfully measured. PMID- 23742544 TI - Magnetic field calculation for a 10 MeV positron emission tomography cyclotron. AB - The magnetic field calculation and correction for a 10 MeV positron emission tomography cyclotron is presented. 3D TOSCA analysis results are compared with the measured data, and the calculation error is used to calibrate the B-H curve to obtain a very precise finite element method estimator, which is used to predict the correction of the magnet pole for achieving the isochronous field. The isochronous field error is approximated with the effects of a set of standard patches. On the assumption that the effect of each small patch is proportional to its surface, the correction of the magnet pole is found by solving a system of equations using the least square scheme. The magnet shimming is performed and the measured magnetic field is found in good agreement with the prediction, with an error less than 2 G. PMID- 23742545 TI - Development of the gas-puff imaging diagnostic in the TEXTOR tokamak. AB - Gas puff imaging (GPI) [S. J. Zweben, D. P. Stotler et al., Phys. Plasmas 9, 1981 (2002); R. J. Maqueda, G. A. Wurden et al., Rev. Sci. Instrum. 74, 2020 (2003)] is a powerful diagnostic that permits a two-dimensional measurement of turbulence in the edge region of a fusion plasma and is based on the observation of the local emission of a neutral gas, actively puffed into the periphery of the plasma. The developed in-vessel GPI telescope observes the emission from the puffed gas along local (at the puff) magnetic field lines. The GPI telescope is specially designed to operate in severe TEXTOR conditions and can be treated as a prototype for the GPI systems on next generation machines. Also, the gas puff nozzle is designed to have a lower divergence of the gas flow than previous GPI diagnostics. The resulting images show poloidally and radially propagating structures, which are associated with plasma blobs. We demonstrate that the local gas puff does not disturb plasma properties. Our results indicate also that the neutral gas emission intensity is more sensitive to the electron density than the electron temperature. Here, we present implementation details of the GPI system on TEXTOR and discuss some design and diagnostic issues related to the development of GPI systems in general. PMID- 23742546 TI - Data processing and analysis of the imaging Thomson scattering diagnostic system on HT-7 tokamak. AB - A high spatial resolution imaging Thomson scattering diagnostic system was developed in ASIPP (Institute of Plasma Physics, Chinese Academy of Sciences). After about one month trial running on the superconducting HT-7 (Hefei Tokamak-7) tokamak, the system was proved to be capable of measuring plasma electron temperature. The system setup and data calibration are described in this paper and then the instrument function is studied in detail, as well as the measurement capability, an electron temperature of 50 eV to 2 keV and density beyond 1 * 10(19) m(-3). Finally, the data processing method and experimental results are presented. PMID- 23742547 TI - Hard x-ray tomographic studies of the destruction of an energetic electron ring. AB - A tomography system was designed and built at the Large Plasma Device to measure the spatial distribution of hard x-ray (100 KeV-3 MeV) emissivity. The x-rays were generated when a hot electron ring was significantly disrupted by a shear Alfven wave. The plasma is pulsed at 1 Hz (1 shot/s). A lead shielded scintillator detector with an acceptance angle defined by a lead pinhole is mounted on a rotary gimbal and used to detect the x-rays. The system measures one chord per plasma shot using only one detector. A data plane usually consists of several hundred chords. A novel Dot by Dot Reconstruction (DDR) method is introduced to calculate the emissivity profile from the line integrated data. In the experiments, there are often physical obstructions, which make measurements at certain angles impossible. The DDR method works well even in this situation. The method was tested with simulated data, and was found to be more effective than previously published methods for the specific geometry of this experiment. The reconstructed x-ray emissivity from experimental data by this method is shown. PMID- 23742548 TI - Modification of tokamak edge plasma turbulence and transport by biasing and resonant helical magnetic field. AB - In this paper, both Resonant Helical magnetic Field (RHF) and limiter biasing have been applied to the tokamak. We have investigated their effects on the turbulence and transport of the particles at the edge of the plasma. The biased limiter voltage has been fixed at 200 V and RHF has L = 2 and L = 3. Also, the effects of the time order of the application of RHF and biasing to the tokamak have been explored. The experiment has been performed under three conditions. At first, the biasing and RHF were applied at t = 15 ms and at t = 20 ms. In the next step, RHF and biasing were applied at t = 15 ms and t = 20 ms, respectively. Finally, both of them were turned on at t = 15 ms until the end of the shot. For this purpose, the ion saturation current (I(sat)) and the floating potential (V(f)) have been measured by the Langmuir probe at r/a = 0.9. Moreover, the power spectra of I(sat) and floating potential gradient (?V(f)), the coherency, the phase between them, and the particle diffusion coefficient have been calculated. The density fluctuations of the particles have been measured by the Rake probe and they have been analyzed with the Probability Distribution Function (PDF) technique. Also the particle diffusion coefficient has been determined by the Fick's law. The results show that, when RHF and biasing were applied at the same time to the plasma (during flatness region of plasma current), the radial particle density gradient, the radial particle flux, and the particle diffusion coefficient decrease about 50%, 60%, and 55%, respectively, compared to the other conditions. For more precision, the average values of the particle flux and the particle density gradient were calculated in the work. When the time is less than 15 ms, the average values of the particle flux and the particle density gradient are identical under all conditions, but in the other time interval they change. They reduce with the simultaneous application of biasing and RHF. The same results obtain from the histogram of the particle flux and the gradient of the particle density and the particle diffusion coefficient. Consequently, the simultaneous application of biasing and RHF is more effective for the plasma confinement. PMID- 23742549 TI - Two-dimensional-spatial distribution measurement of electron temperature and plasma density in low temperature plasmas. AB - A real-time measurement method for two-dimensional (2D) spatial distribution of the electron temperature and plasma density was developed. The method is based on the floating harmonic method and the real time measurement is achieved with little plasma perturbation. 2D arrays of the sensors on a 300 mm diameter wafer shaped printed circuit board with a high speed multiplexer circuit were used. Experiments were performed in an inductive discharge under various external conditions, such as powers, gas pressures, and different gas mixing ratios. The results are consistent with theoretical prediction. Our method can measure the 2D spatial distribution of plasma parameters on a wafer-level in real-time. This method can be applied to plasma diagnostics to improve the plasma uniformity of plasma reactors for plasma processing. PMID- 23742550 TI - Application of dynamic displacement current for diagnostics of subnanosecond breakdowns in an inhomogeneous electric field. AB - The breakdown of different air gaps at high overvoltages in an inhomogeneous electric field was investigated with a time resolution of up to 100 ps. Dynamic displacement current was used for diagnostics of ionization processes between the ionization wave front and a plane anode. It is demonstrated that during the generation of a supershort avalanche electron beam (SAEB) with amplitudes of ~10 A and more, conductivity in the air gaps at the breakdown stage is ensured by the ionization wave, whose front propagates from the electrode of small curvature radius, and by the dynamic displacement current between the ionization wave front and the plane electrode. The amplitude of the dynamic displacement current measured by a current shunt is 100 times greater than the SAEB. It is shown that with small gaps and with a large cathode diameter, the amplitude of the dynamic displacement current during a subnanosecond rise time of applied pulse voltage can be higher than 4 kA. PMID- 23742551 TI - Scanning ion sensitive probe for plasma profile measurements in the boundary of the Alcator C-Mod tokamak. AB - A new Ion Sensitive Probe head has been created for the outer-midplane scanning probe system on the Alcator C-Mod tokamak. The new probe head contains three elements: an ion sensitive probe to measure ion temperature and plasma potential, a Langmuir probe to measure electron temperature, density, and floating potential, and a second Langmuir probe to measure ion saturation current and the density fluctuations arising from ''blob'' events. The ion sensitive probe current is normalized to this measurement to reduced deleterious effects of the strong fluctuations. Design of the high heat flux probe (>100 MW/m(2)) and initial results are presented. PMID- 23742552 TI - Simultaneous immersion Mirau interferometry. AB - A novel technique for label-free imaging of live biological cells in aqueous medium that is insensitive to ambient vibrations is presented. This technique is a spin-off from previously developed immersion Mirau interferometry. Both approaches utilize a modified Mirau interferometric attachment for a microscope objective that can be used both in air and in immersion mode, when the device is submerged in cell medium and has its internal space filled with liquid. While immersion Mirau interferometry involves first capturing a series of images, the resulting images are potentially distorted by ambient vibrations. Overcoming these serial-acquisition challenges, simultaneous immersion Mirau interferometry incorporates polarizing elements into the optics to allow simultaneous acquisition of two interferograms. The system design and production are described and images produced with the developed techniques are presented. PMID- 23742553 TI - Wide-area scanner for high-speed atomic force microscopy. AB - High-speed atomic force microscopy (HS-AFM) has recently been established. The dynamic processes and structural dynamics of protein molecules in action have been successfully visualized using HS-AFM. However, its maximum scan ranges in the X- and Y-directions have been limited to ~1 MUm and ~4 MUm, respectively, making it infeasible to observe the dynamics of much larger samples, including live cells. Here, we develop a wide-area scanner with a maximum XY scan range of ~46 * 46 MUm(2) by magnifying the displacements of stack piezoelectric actuators using a leverage mechanism. Mechanical vibrations produced by fast displacement of the X-scanner are suppressed by a combination of feed-forward inverse compensation and the use of triangular scan signals with rounded vertices. As a result, the scan speed in the X-direction reaches 6.3 mm/s even for a scan size as large as ~40 MUm. The nonlinearity of the X- and Y-piezoelectric actuators' displacements that arises from their hysteresis is eliminated by polynomial approximation-based open-loop control. The interference between the X- and Y scanners is also eliminated by the same technique. The usefulness of this wide area scanner is demonstrated by video imaging of dynamic processes in live bacterial and eukaryotic cells. PMID- 23742554 TI - Differential interference contrast microscopy using light-emitting diode illumination in conjunction with dual optical traps. AB - Differential interference contrast (DIC) microscopy is a common mode of biological light microscopy used to achieve maximal resolution and contrast with label-free, weakly absorbing specimens such as cells. Maintaining the polarization state of the illuminating light is essential for the technique, and this requirement can conflict with optical trapping. We describe how to optimize DIC imaging using a light-emitting diode illumination source in a microscope while integrating a dual optical trap into the set up. Every time a polarized light beam reflects off or transmits through a dichroic mirror in the beam path, its polarization state will change if it is not polarized exactly parallel (p) or perpendicular (s) to the plane of incidence. We observe wavelength-dependent optical rotation and depolarization effects in our illumination light upon reflection from/transmission through dichroic mirrors in the beam path, resulting in significant degradation of image quality. We describe a method to compensate for these effects by introducing quarter-waveplates and a laser clean-up filter into the imaging pathway. We show that this approach achieves a full recovery of image quality. PMID- 23742555 TI - Theoretical and experimental study on two-stage-imaging microscopy using ellipsometric contrast for real-time visualization of molecularly thin films. AB - A two-stage-imaging ellipsometric-contrast microscope (TIEM) has been developed to measure the distribution of film thickness over a wide area of molecularly thin liquid films with a high lateral resolution, wide field of view, high thickness resolution, and high-speed. Moreover, this ellipsometric microscope enables us to achieve simultaneous measurements with other measurement apparatuses. We present the principle used to parallelize an object image to an imaging sensor and to reduce the incident angle entering the imaging sensor. In addition, we discuss the characteristic shape deformation of the object image due to oblique observation. The performance of the actual setup for TIEM was experimentally studied. A lateral resolution of about 1 MUm was obtained by measuring the modulation transfer function of the TIEM. We also found that the shape deformation approximately agreed with that from theory. Furthermore, for molecularly thin films, we confirmed linearity between the film thickness and the light intensity measured with TIEM, which enables us to quantify the thickness of the films. TIEM can open up a new field of real-time imaging of thin films such as visualization of a liquid lubricant film under shear. PMID- 23742556 TI - High-frequency annular array with coaxial illumination for dual-modality ultrasonic and photoacoustic imaging. AB - This paper presents a combined ultrasound and photoacoustic (PA) imaging (PAI) system used to obtain high-quality, co-registered images of mouse-embryo anatomy and vasculature. High-frequency ultrasound (HFU, >20 MHz) is utilized to obtain high-resolution anatomical images of small animals while PAI provides high contrast images of the vascular network. The imaging system is based on a 40 MHz, 5-element, 6 mm aperture annular-array transducer with a 800 MUm diameter hole through its central element. The transducer was integrated in a cage-plate assembly allowing for a collimated laser beam to pass through the hole so that the optical and acoustic beams were collinear. The assembly was mounted on a two axis, motorized stage to enable the simultaneous acquisition of co-registered HFU and PA volumetric data. Data were collected from all five elements in receive and a synthetic-focusing algorithm was applied in post-processing to beamform the data and increase the spatial resolution and depth-of-field (DOF) of the HFU and PA images. Phantom measurements showed that the system could achieve high resolution images (down to 90 MUm for HFU and 150 MUm for PAI) and a large DOF of >8 mm. Volume renderings of a mouse embryo showed that the scanner allowed for visualizing morphologically precise anatomy of the entire embryo along with corresponding co-registered vasculature. Major head vessels, such as the superior sagittal sinus or rostral vein, were clearly identified as well as limb bud vasculature. PMID- 23742557 TI - Sensorless enhancement of an atomic force microscope micro-cantilever quality factor using piezoelectric shunt control. AB - The image quality and resolution of the Atomic Force Microscope (AFM) operating in tapping mode is dependent on the quality (Q) factor of the sensing micro cantilever. Increasing the cantilever Q factor improves image resolution and reduces the risk of sample and cantilever damage. Active piezoelectric shunt control is introduced in this work as a new technique for modifying the Q factor of a piezoelectric self-actuating AFM micro-cantilever. An active impedance is placed in series with the tip oscillation voltage source to modify the mechanical dynamics of the cantilever. The benefit of using this control technique is that it removes the optical displacement sensor from the Q control feedback loop to reduce measurement noise in the loop and allows for a reduction in instrument size. PMID- 23742558 TI - A platform for retaining native morphology at sub-second time scales in cryogenic transmission electron microscopy. AB - The advantage of cryogenic transmission electron microscopy for morphological analysis of complex fluids is the ability to capture native specimen morphology in solution. This is often limited by available sample preparation devices and procedures, which expose the sample to high shear rates leading to non-native artifacts, are unable to capture evolving samples at a time resolution shorter than a few seconds, and often non-specifically adsorb sample species from suspension resulting in a non-native sample concentration on the grid. In this paper we report the development of a new sample preparation device based on capillary action that overcomes all of these limitations. The use of a removal capillary placed parallel to the grid results in reduced shear and lower absorption of particulate material from the sample. A deposition capillary placed perpendicular to the grid allows for precise and sub-second resolution for time resolved studies. We demonstrate each of the features of this platform using model samples, and where appropriate, compare our results to those prepared using current vitrification platforms. Our results confirm that this new sample vitrification device opens up previously unattainable regimes for sample preparation and imaging and is a powerful new tool for cryogenic transmission electron microscopy. PMID- 23742560 TI - Relaxation calorimeter for hydrogen thermoporometry. AB - A relaxation calorimeter for measuring the heat capacity of hydrogen isotopes in nanoporous solids is described. Apparatus' features include (i) cooling by a pulse tube refrigerator, (ii) a modular design, allowing for rapid reconfiguration and sample turn around, (iii) a thermal stability of ?1 mK, and (iv) a bottom temperature of ~5 K. The calorimeter is tested on effective heat capacity measurements of H2 in Vycor (silica) nanoporous glass, yielding a very detailed pore size distribution analysis with an effectively sub-Angstrom resolution. PMID- 23742559 TI - High frame-rate fluorescence confocal angle-resolved linear dichroism microscopy. AB - Angle-resolved linear dichroism is a recent technique that exploits images recorded using an illumination field whose polarization angle is sequentially rotated during acquisition. It allows to retrieve orientation information of the fluorescent molecules, namely the average orientation angle and the amplitude of the fluctuations around this average. In order to boost up the acquisition speed without sacrificing the axial sectioning, we propose to combine a spinning disk confocal excitation scheme together with an electrooptical polarization switching and a camera acquisition. The polarization distortions induced when passing through the spinning disk system have been quantified and effectively compensated. The signal to noise features of the camera have been analyzed in detail so that the precision of the method can be quantified. The technique has been successfully tested on giant unilamellar vesicles and on living cells labeled with different fluorescent lipid probes, DiIC18 and di-8-ANEPPQ. It was able to acquire precise orientation images at full frame rates in the range of a second, ultimately limited by the fluorophore brightness and the camera sensitivity. PMID- 23742561 TI - Quantum state-resolved gas/surface reaction dynamics probed by reflection absorption infrared spectroscopy. AB - We report the design and characterization of a new molecular-beam/surface-science apparatus for quantum state-resolved studies of gas/surface reaction dynamics combining optical state-specific reactant preparation in a molecular beam by rapid adiabatic passage with detection of surface-bound reaction products by reflection absorption infrared spectroscopy (RAIRS). RAIRS is a non-invasive infrared spectroscopic detection technique that enables online monitoring of the buildup of reaction products on the target surface during reactant deposition by a molecular beam. The product uptake rate obtained by calibrated RAIRS detection yields the coverage dependent state-resolved reaction probability S(theta). Furthermore, the infrared absorption spectra of the adsorbed products obtained by the RAIRS technique provide structural information, which help to identify nascent reaction products, investigate reaction pathways, and determine branching ratios for different pathways of a chemisorption reaction. Measurements of the dissociative chemisorption of methane on Pt(111) with this new apparatus are presented to illustrate the utility of RAIRS detection for highly detailed studies of chemical reactions at the gas/surface interface. PMID- 23742563 TI - Sensitive thermal transitions of nanoscale polymer samples using the bimetallic effect: application to ultra-thin polythiophene. AB - A sensitive nanocalorimetric technology based on microcantilever sensors is presented. The technology, which combines very short response times with very small sample consumption, uses the bimetallic effect to detect thermal transitions. Specifically, abrupt variations in the Young's modulus and the thermal expansion coefficient produced by temperature changes have been employed to detect thermodynamic transitions. The technology has been used to determine the glass transition of poly(3-thiophene methyl acetate), a soluble semiconducting polymer with different nanotechnological applications. The glass transition temperature determined using microcantilevers coated with ultra-thin films of mass = 10(-13) g is 5.2 degrees C higher than that obtained using a conventional differential scanning calorimeter for bulk powder samples of mass = 5 * 10(-3) g. Atomistic molecular dynamics simulations on models that represent the bulk powder and the ultra-thin films have been carried out to provide understanding and rationalization of this feature. Simulations indicate that the film-air interface plays a crucial role in films with very small thickness, affecting both the organization of the molecular chains and the response of the molecules against the temperature. PMID- 23742562 TI - Numerical simulation and experiment on multilayer stagger-split die. AB - A novel ultra-high pressure device, multilayer stagger-split die, has been constructed based on the principle of "dividing dies before cracking." Multilayer stagger-split die includes an encircling ring and multilayer assemblages, and the mating surfaces of the multilayer assemblages are mutually staggered between adjacent layers. In this paper, we investigated the stressing features of this structure through finite element techniques, and the results were compared with those of the belt type die and single split die. The contrast experiments were also carried out to test the bearing pressure performance of multilayer stagger split die. It is concluded that the stress distributions are reasonable and the materials are utilized effectively for multilayer stagger-split die. And experiments indicate that the multilayer stagger-split die can bear the greatest pressure. PMID- 23742564 TI - Development and application of an instrument for spatially resolved Seebeck coefficient measurements. AB - The Seebeck coefficient is a key indicator of the majority carrier type (electrons or holes) in a material. The recent trend toward the development of combinatorial materials research methods has necessitated the development of a new high-throughput approach to measuring the Seebeck coefficient at spatially distinct points across any sample. The overall strategy of the high-throughput experiments is to quickly identify the region of interest on the sample at some expense of accuracy, and then study this region by more conventional techniques. The instrument for spatially resolved Seebeck coefficient measurements reported here relies on establishing a temperature difference across the entire compositionally graded thin-film and consecutive mapping of the resulting voltage as a function of position, which facilitates the temperature-dependent measurements up to 400 degrees C. The results of the designed instrument are verified at ambient temperature to be repeatable over 10 identical samples and accurate to within 10% versus conventional Seebeck coefficient measurements over the -100 to +150 MUV/K range using both n-type and p-type conductive oxides as test cases. The developed instrument was used to determine the sign of electrical carriers of compositionally graded Zn-Co-O and Ni-Co-O libraries prepared by combinatorial sputtering. As a result of this study, both cobalt-based materials were determined to have p-type conduction over a broad single-phase region of chemical compositions and small variation of the Seebeck coefficient over the entire investigated range of compositions and temperature. PMID- 23742565 TI - Rapid thermal conductivity measurements for combinatorial thin films. AB - A simple and inexpensive automated method for determining the thermal conductivity of a combinatorial library of thin films is demonstrated by measuring the thermal conductivity of a sputtered silicon dioxide film of varying thickness deposited on single crystal silicon. Using 3omega measurements, two methods for calculating the substrate thermal conductivity and two methods for determining the film thermal conductivity are demonstrated and compared. The substrate thermal conductivity was found to be 139 +/- 3 W/m.K. Using the measured variation in film thickness, the film thermal conductivity was found to be 1.11 +/- 0.05 W/m.K, in excellent agreement with published values for sputtered SiO2, demonstrating the accuracy of the method. PMID- 23742566 TI - High temperature and pressure electrochemical test station. AB - An electrochemical test station capable of operating at pressures up to 100 bars and temperatures up to 400 degrees C has been established. It enables control of the partial pressures and mass flow of O2, N2, H2, CO2, and H2O in a single or dual environment arrangement, measurements with highly corrosive media, as well as localized sampling of gas evolved at the electrodes for gas analysis. A number of safety and engineering design challenges have been addressed. Furthermore, we present a series of electrochemical cell holders that have been constructed in order to accommodate different types of cells and facilitate different types of electrochemical measurements. Selected examples of materials and electrochemical cells examined in the test station are provided, ranging from the evaluation of the ionic conductivity of liquid electrolytic solutions immobilized in mesoporous ceramic structures, to the electrochemical characterization of high temperature and pressure alkaline electrolysis cells and the use of pseudo-reference electrodes for the separation of each electrode contribution. A future perspective of various electrochemical processes and devices that can be developed with the use of the established test station is provided. PMID- 23742567 TI - Versatile plug flow catalytic cell for in situ transmission/fluorescence x-ray absorption fine structure measurements. AB - A novel flow-through catalytic cell has been developed for in situ x-ray absorption spectroscopy (XAS) experiments on heterogeneous catalysts under working conditions and in the presence of a liquid and a gas phase. The apparatus allows to carry out XAS measurements in both the transmission and fluorescence modes, at moderate temperature (from RT to 50-80 degrees C) and low-medium gas pressure (up to 7-8 bars). The materials employed are compatible with several chemicals such as those involved in the direct synthesis of hydrogen peroxide (O2, H2, H2O2, methanol). The versatile design of the cell allows to fit it to different experimental setups in synchrotron radiation beamlines. It was used successfully for the first time to test nanostructured Pd catalysts during the direct synthesis of hydrogen peroxide (H2O2) in methanol solution from dihydrogen and dioxygen. PMID- 23742568 TI - Dedicated vertical wind tunnel for the study of sedimentation of non-spherical particles. AB - A dedicated 4-m-high vertical wind tunnel has been designed and constructed at the University of Geneva in collaboration with the Groupe de competence en mecanique des fluides et procedes energetiques. With its diverging test section, the tunnel is designed to study the aero-dynamical behavior of non-spherical particles with terminal velocities between 5 and 27 ms(-1). A particle tracking velocimetry (PTV) code is developed to calculate drag coefficient of particles in standard conditions based on the real projected area of the particles. Results of our wind tunnel and PTV code are validated by comparing drag coefficient of smooth spherical particles and cylindrical particles to existing literature. Experiments are repeatable with average relative standard deviation of 1.7%. Our preliminary experiments on the effect of particle to fluid density ratio on drag coefficient of cylindrical particles show that the drag coefficient of freely suspended particles in air is lower than those measured in water or in horizontal wind tunnels. It is found that increasing aspect ratio of cylindrical particles reduces their secondary motions and they tend to be suspended with their maximum area normal to the airflow. The use of the vertical wind tunnel in combination with the PTV code provides a reliable and precise instrument for measuring drag coefficient of freely moving particles of various shapes. Our ultimate goal is the study of sedimentation and aggregation of volcanic particles (density between 500 and 2700 kgm(-3)) but the wind tunnel can be used in a wide range of applications. PMID- 23742569 TI - High-temperature superconducting radiofrequency probe for magnetic resonance imaging applications operated below ambient pressure in a simple liquid-nitrogen cryostat. AB - The present work investigates the joined effects of temperature and static magnetic field on the electrical properties of a 64 MHz planar high-temperature superconducting (HTS) coil, in order to enhance the signal-to-noise ratio (SNR) in nuclear magnetic resonance (NMR) applications with a moderate decrease of the HTS coil temperature (T(HTS)). Temperature control is provided with accuracy better than 0.1 K from 80 to 66 K by regulating the pressure of the liquid nitrogen bath of a dedicated cryostat. The actual temperature of the HTS coil is obtained using a straightforward wireless method that eliminates the risks of coupling electromagnetic interference to the HTS coil and of disturbing the static magnetic field by DC currents near the region of interest. The resonance frequency (f0) and the quality factor (Q) of the HTS coil are measured as a function of temperature in the 0-4.7 T field range with parallel and orthogonal orientations relative to the coil plane. The intrinsic HTS coil sensitivity and the detuning effect are then analyzed from the Q and f0 data. In the presence of the static magnetic field, the initial value of f0 in Earth's field could be entirely recovered by decreasing T(HTS), except for the orthogonal orientation above 1 T. The improvement of Q by lowering T(HTS) was substantial. From 80 to 66 K, Q was multiplied by a factor of 6 at 1.5 T in orthogonal orientation. In parallel orientation, the maximum measured improvement of Q from 80 K to 66 K was a factor of 2. From 80 to 66 K, the improvement of the RF sensitivity relative to the initial value at the Earth's field and ambient pressure was up to 4.4 dB in parallel orientation. It was even more important in orthogonal orientation and continued to increase, up to 8.4 dB, at the maximum explored field of 1.5 T. Assuming that the noise contributions from the RF receiver are negligible, the SNR improvement using enhanced HTS coil cooling in NMR experiments was extracted from Q measurements either with or without the presence of the sample. Notably, the additional cooling in the presence of conductive samples appears more beneficial at higher field strengths and with an orthogonal incidence than with parallel. The temperature range accessible here, involving a relatively straightforward cryogenic design, brings a gain in RF sensitivity that is of great significance to cutting-edge applications with very weakly conducting samples, small biological specimens, or small animals in vivo. This work also demonstrates a better tolerance to thin-film orientation misalignments relative to the magnetic field, and this could eventually play a role in designing effective non-planar HTS coils or coil arrays which include elements of various orientations. Finally, the data provided in this work may help understand some critical aspects in the design of HTS coils for NMR and MRI applications and accounts for the presence of the static magnetic field, particularly regarding the SNR loss due to a decreased quality factor and detuning issues. PMID- 23742570 TI - A digital magnetic resonance imaging spectrometer using digital signal processor and field programmable gate array. AB - A digital spectrometer for low-field magnetic resonance imaging is described. A digital signal processor (DSP) is utilized as the pulse programmer on which a pulse sequence is executed as a subroutine. Field programmable gate array (FPGA) devices that are logically mapped into the external addressing space of the DSP work as auxiliary controllers of gradient control, radio frequency (rf) generation, and rf receiving separately. The pulse programmer triggers an event by setting the 32-bit control register of the corresponding FPGA, and then the FPGA automatically carries out the event function according to preset configurations in cooperation with other devices; accordingly, event control of the spectrometer is flexible and efficient. Digital techniques are in widespread use: gradient control is implemented in real-time by a FPGA; rf source is constructed using direct digital synthesis technique, and rf receiver is constructed using digital quadrature detection technique. Well-designed performance is achieved, including 1 MUs time resolution of the gradient waveform, 1 MUs time resolution of the soft pulse, and 2 MHz signal receiving bandwidth. Both rf synthesis and rf digitalization operate at the same 60 MHz clock, therefore, the frequency range of transmitting and receiving is from DC to ~27 MHz. A majority of pulse sequences have been developed, and the imaging performance of the spectrometer has been validated through a large number of experiments. Furthermore, the spectrometer is also suitable for relaxation measurement in nuclear magnetic resonance field. PMID- 23742571 TI - All solid-state high power microwave source with high repetition frequency. AB - An all solid-state, megawatt-class high power microwave system featuring a silicon carbide (SiC) photoconductive semiconductor switch (PCSS) and a ferrimagnetic-based, coaxial nonlinear transmission line (NLTL) is presented. A 1.62 cm(2), 50 kV 4H-SiC PCSS is hard-switched to produce electrical pulses with 7 ns full width-half max (FWHM) pulse widths at 2 ns risetimes in single shot and burst-mode operation. The PCSS resistance drops to sub-ohm when illuminated with approximately 3 mJ of laser energy at 355 nm (tripled Nd:YAG) in a single pulse. Utilizing a fiber optic based optical delivery system, a laser pulse train of four 7 ns (FWHM) signals was generated at 65 MHz repetition frequency. The resulting electrical pulse train from the PCSS closely follows the optical input and is utilized to feed the NLTL generating microwave pulses with a base microwave-frequency of about 2.1 GHz at 65 MHz pulse repetition frequency (prf). Under typical experimental conditions, the NLTL produces sharpened output risetimes of 120 ps and microwave oscillations at 2-4 GHz that are generated due to damped gyromagnetic precession of the ferrimagnetic material's axially pre biased magnetic moments. The complete system is discussed in detail with its output matched into 50 Omega, and results covering MHz-prf in burst-mode operation as well as frequency agility in single shot operation are discussed. PMID- 23742572 TI - Measurement of ultra-low power oscillators using adaptive drift cancellation with applications to nano-magnetic spin torque oscillators. AB - This work presents a technique for measuring ultra-low power oscillator signals using an adaptive drift cancellation method. We demonstrate this technique through spectrum measurements of a sub-pW nano-magnet spin torque oscillator (STO). We first present a detailed noise analysis of the standard STO characterization apparatus to estimate the background noise level, then compare these results to the noise level of three measurement configurations. The first and second share the standard configuration but use different spectrum analyzers (SA), an older model and a state-of-the-art model, respectively. The third is the technique proposed in this work using the same old SA as for the first. Our results show that the first and second configurations suffer from a large drift that requires ~30 min to stabilize each time the SA changes the frequency band, even though the SA has been powered on for longer than 24 h. The third configuration introduced in this work, however, shows absolutely no drift as the SA changes frequency band, and nearly the same noise performance as with a state of-the-art SA, thus providing a reliable method for measuring very low power signals for a wide variety of applications. PMID- 23742573 TI - Integration of strain feedback and charge drive for high-performance of piezoelectric actuators. AB - This paper introduces a hybrid control method that combines strain feedback control and charge driver. Strain feedback control method has good stability at low frequencies but suffers from limited resolution at high frequencies. The charge driver provides good linearity at high frequencies but exhibits drift at low frequencies. This study combines these two control methods to demonstrate that high stability at low frequencies as well as good linearity and high resolution at high frequencies can be achieved. Theoretical analyses are provided in detail. Experimental results demonstrate the proposed hybrid control method can provide excellent stability, good linearity and high resolution from 0.01 Hz to 50 Hz. PMID- 23742574 TI - A 100 kV, 60 A solid state 4 kHz switching modulator for high power klystron driving. AB - A solid state high power modulator capable of delivering 120 kV and 60 A developed in collaboration with the JEMA Corporation, ESS Bilbao, and the SNS (ORNL) for driving high power klystrons is presented. Pulses with less than 10 MUs risetime and flatness under 0.1% are obtained with programmable frequency pulses between 2 and 50 Hz. Eight solid state switches combined with custom air insulated high voltage transformers working at a switching frequency of 4 kHz produce high quality pulses by phase shifting the transformer drives. Each relative high frequency stage pumps a double stage high voltage Marx generator that supplies the output pulse shape and frequency. This merged topology between a Marx generator and direct modulator takes advantage of the strengths of both approaches. Low energy storage in the output stages assures safe operation in case of a load arc discharge. Real time voltage correction during the pulse is also provided to compensate for the droop inherent with the use of low energy storage in the output stages. Data at full power with a dummy resistive load are presented. PMID- 23742575 TI - Narrow bandpass cryogenic filter for microwave measurements. AB - An ultra-wide stopband hairpin bandpass filter with integrated nonuniform transmission lines was designed and fabricated for highly sensitive measurements at cryogenic temperatures down to millikelvin and a frequency range of 10 Hz-10 GHz. The scattering matrices of the filter were characterized at T = 4.2 K. The filter provides a stopband from 10 Hz to 2.2 GHz and from 2.3 GHz to 10 GHz with more than 50 dB and 40 dB of amplitude suppression, respectively. The center frequency of the passband is f0 = 2.25 GHz with a bandwidth Deltaf = 80 MHz. The maximum insertion loss in the passband is 4 dB. The filter has a 50 Omega input and output impedance, SubMiniature version A connector termination, and significantly reduced form factor. The wide stopband frequency range and narrow passband in conjunction with small dimensions make the filter suitable to use it as a part of a high sensitive readout for superconducting quantum circuits, such as superconducting quantum bits and cryogenic parametric amplifiers. PMID- 23742576 TI - The role of lock-in phase setting in ac susceptibility measurement. AB - Method in which lock-in detectors process signals from standard ac susceptometers, particularly in the detection of higher harmonics, is analyzed in details. The exact formulas have been derived and checked experimentally by measurements on soft ferromagnetic sample, using several available lock-in amplifiers. The reasons why the proper phase adjustment has to be implemented in the protocol of higher harmonics measurements have been elaborated. The procedure of the lock-in phase adjustment is described, enabling separation of Fourier or Taylor components of hysteretic ac susceptibility into real and imaginary sectors. PMID- 23742577 TI - Apparatus for measurement of acoustic wave propagation under uniaxial loading with application to measurement of third-order elastic constants of piezoelectric single crystals. AB - We describe an apparatus for the measurement of acoustic wave propagation under uniaxial loading featuring a special mechanism designed to assure a uniform mechanical load on a cube-shaped sample of piezoelectric material. We demonstrate the utility of the apparatus by determining the effects of stresses on acoustic wave speed, which forms a foundation for the final determination of the third order elastic constants of langasite and langatate single crystals. The transit time method is used to determine changes in acoustic wave velocity as the loading is varied. In order to minimize error and improve the accuracy of the wave speed measurements, the cross correlation method is used to determine the small changes in the time of flight. Typical experimental results are presented and discussed. PMID- 23742578 TI - A steady-state high-temperature method for measuring thermal conductivity of refractory materials. AB - A new methodology and an instrumental setup for the thermal conductivity estimation of isotropic bulk graphite and different carbides at high temperatures are presented. The method proposed in this work is based on the direct measurement of temperature and emissivity on the top surface of a sample disc of known dimensions. Temperatures measured under steady-state thermal equilibrium are then used to estimate the thermal conductivity of the sample by making use of the inverse parameter estimation technique. Thermal conductivity values obtained in this way are then compared to the material data sheets and values found in literature. The reported work has been developed within the Research and Development framework of the SPES (Selective Production of Exotic Species) project at INFN-LNL (Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali di Legnaro). PMID- 23742579 TI - Apparatus for measuring Seebeck coefficient and electrical resistivity of small dimension samples using infrared microscope as temperature sensor. AB - An apparatus for measuring the Seebeck coefficient (alpha) and electrical resistivity (rho) was designed to operate under an infrared microscope. A unique feature of this apparatus is its capability of measuring alpha and rho of small dimension (sub-millimeter) samples without the need for microfabrication. An essential part of this apparatus is a four-probe assembly that has one heated probe, which combines the hot probe technique with the Van der Pauw method for "simultaneous" measurements of the Seebeck coefficient and electrical resistivity. The repeatability of the apparatus was investigated over a temperature range of 40 degrees C-100 degrees C using a nickel plate as a standard reference. The results show that the apparatus has an uncertainty of +/ 4.9% for Seebeck coefficient and +/-5.0% for electrical resistivity. The standard deviation of the apparatus against a nickel reference sample is -2.43 MUVK(-1) ( 12.5%) for the Seebeck coefficient and -0.4 MUOmega cm (-4.6%) for the electrical resistivity, respectively. PMID- 23742580 TI - Dual beam differential photopyroelectric setup for broadband thermal effusivity investigation of glass transitions in polymers. AB - The behaviour of the thermal effusivity squared over the glass transition in polystyrene is measured over a considerable frequency range using a novel dual beam front detection photopyroelectric configuration, which ensures a very effective processing of the obtained signal. This has enabled the detection of the very small changes taking place in such a parameter, despite the non favourable sensitivity conditions due to the large mismatch between the thermal effusivities of the pyroelectric transducer and of the sample. The effect of the thermal contact resistance between the sample and the pyroelectric detector is also considered and discussed. PMID- 23742581 TI - Design and implementation of a novel rotary micropositioning system driven by linear voice coil motor. AB - Limited-angle rotary micropositioning stages are required in precision engineering applications where an ultrahigh-precision rotational motion within a restricted range is needed. This paper presents the design, fabrication, and control of a compliant rotary micropositioning stage dedicated to the said applications. To tackle the challenge of achieving both a large rotational range and a compact size, a new idea of multi-stage compound radial flexure is proposed. A compact rotary stage is devised to deliver an over 10 degrees rotational range while possessing a negligible magnitude of center shift. The stage is driven by a linear voice coil motor and its output motion is measured by laser displacement sensors. Analytical models are derived to facilitate the parametric design, which is validated by conducting finite element analysis. The actuation and sensing issues are addressed to guarantee the stage performance. A prototype is fabricated and a proportional-integral-derivative control is implemented to achieve a precise positioning. Experimental results demonstrate a resolution of 2 MUrad over 10 degrees rotational range as well as a low level of center shift of the rotary micropositioning system. PMID- 23742582 TI - Prototyping a compact system for active vibration isolation using piezoelectric sensors and actuators. AB - Being small in size and weight, piezoelectric transducers hold unique positions in vibration sensing and control. Here, we explore the possibility of building a compact vibration isolation system using piezoelectric sensors and actuators. The mechanical resonances of a piezoelectric actuator around a few kHz are suppressed by an order of magnitude via electrical damping, which improves the high frequency response. Working with a strain gauge located on the piezoelectric actuator, an auxiliary control loop eliminates the drift associated with a large servo gain at dc. Following this approach, we design, optimize, and experimentally verify the loop responses using frequency domain analysis. The vibration isolation between 1 Hz and 200 Hz is achieved and the attenuation peaks at 60 near vibration frequency of 20 Hz. Restrictions and potentials for extending the isolation to lower vibration frequencies are discussed. PMID- 23742583 TI - An automated steady state photocarrier grating experiment. AB - The design of an automated steady state photocarrier grating (SSPG) experiment is presented that matches most of the requirements of an industrial environment. We first briefly recall the bases of the SSPG technique and that the minority carrier diffusion length deduced from this experiment is a key parameter in the fabrication of thin film solar devices. We then underline the main drawbacks of the use of the classical SSPG technique as an industrial and systematic characterization technique mostly that all the adjustments have to be done manually. We show that this issue can be overcome to end with a compact (90 * 60 cm(2)), fast, reliable, and easy-to-use system that could become a routine characterization technique for research laboratories and thin film solar industry. We illustrate the possibilities of this new system by showing some of the results obtained with it on very different thin films. PMID- 23742584 TI - Tracking an imploding cylinder with photonic Doppler velocimetry. AB - Cylindrical implosion offers a path to extreme material states, reaching considerably higher pressures than planar geometry. However, diagnosing compressed material in cylindrical geometry is challenging. Time-resolved velocimetry, a standard technique in planar compression, is difficult to incorporate into cylindrical experiments. This paper describes the use of photonic Doppler velocimetry (PDV) in magnetically driven cylindrical compression experiments at the Sandia Z machine. With this diagnostic, it is possible to track the interior of an imploding cylinder beyond 20 km/s. A "leapfrog" implementation is described to support velocities well above the bandwidth limits of standard PDV measurements. PMID- 23742585 TI - An innovative method for coordinate measuring machine one-dimensional self calibration with simplified experimental process. AB - In this paper, an innovative method for CMM (Coordinate Measuring Machine) self calibration is proposed. In contrast to conventional CMM calibration that relies heavily on a high precision reference standard such as a laser interferometer, the proposed calibration method is based on a low-cost artefact which is fabricated with commercially available precision ball bearings. By optimizing the mathematical model and rearranging the data sampling positions, the experimental process and data analysis can be simplified. In mathematical expression, the samples can be minimized by eliminating the redundant equations among those configured by the experimental data array. The section lengths of the artefact are measured at arranged positions, with which an equation set can be configured to determine the measurement errors at the corresponding positions. With the proposed method, the equation set is short of one equation, which can be supplemented by either measuring the total length of the artefact with a higher precision CMM or calibrating the single point error at the extreme position with a laser interferometer. In this paper, the latter is selected. With spline interpolation, the error compensation curve can be determined. To verify the proposed method, a simple calibration system was set up on a commercial CMM. Experimental results showed that with the error compensation curve uncertainty of the measurement can be reduced to 50%. PMID- 23742586 TI - New developments for the investigation of hard X-rays emitted by peeling adhesive tapes. AB - We realized an advanced apparatus for the investigation of emitted X-rays produced by peeling adhesive tape rolls under vacuum conditions. Two stepper motors can unwind and rewind a tape roll, and an additional roller with an optical encoder provides measurement and control of the tape speed. This way reproducible and consecutive experiments are feasible without having to change the tape or break the vacuum. The dependence of the X-ray emission on tape speed, gas pressure, type of adhesive tape, and detector angle has been investigated. The resulting spectra are continuous and span an X-ray energy range of typically 2-60 keV with high intensity. Furthermore, the new apparatus allows the in situ metalization of adhesive tape rolls by a gold sputter source. A significantly increased X-ray emission was observed for adhesive tapes with a metal coating. Thin metal foils have been placed between the tape and the detector, different K- and L-absorption edges could be measured. A considerable enhancement of the emission was achieved under the influence of the magnetic field of an NdFeB permanent magnet. PMID- 23742587 TI - A system for acoustical and optical analysis of encapsulated microbubbles at ultrahigh hydrostatic pressures. AB - Acoustics are commonly used for borehole (i.e., oil well) imaging applications, under conditions where temperature and pressure reach extremes beyond that of conventional medical ultrasonics. Recently, there has been an interest in the application of encapsulated microbubbles as borehole contrast agents for acoustic assessment of fluid composition and flow. Although such microbubbles are widely studied under physiological conditions for medical imaging applications, to date there is a paucity of information on the behavior of encapsulated gas-filled microbubbles at high pressures. One major limitation is that there is a lack of experimental systems to assess both optical and acoustic data of micrometer-sized particles data at these extremes. In this paper, we present the design and application of a high-pressure cell designed for acoustical and optical studies of microbubbles at hydrostatic pressures up to 27.5 MPa (271 atm). PMID- 23742588 TI - Simulation of a suite of generic long-pulse neutron instruments to optimize the time structure of the European Spallation Source. AB - We here describe the result of simulations of 15 generic neutron instruments for the long-pulsed European Spallation Source. All instruments have been simulated for 20 different settings of the source time structure, corresponding to pulse lengths between 1 ms and 2 ms; and repetition frequencies between 10 Hz and 25 Hz. The relative change in performance with time structure is given for each instrument, and an unweighted average is calculated. The performance of the instrument suite is proportional to (a) the peak flux and (b) the duty cycle to a power of approximately 0.3. This information is an important input to determining the best accelerator parameters. In addition, we find that in our simple guide systems, most neutrons reaching the sample originate from the central 3-5 cm of the moderator. This result can be used as an input in later optimization of the moderator design. We discuss the relevance and validity of defining a single figure-of-merit for a full facility and compare with evaluations of the individual instrument classes. PMID- 23742589 TI - Precision electromagnetic calibration technique for micro-Newton thrust stands. AB - This paper introduces a new direct non-contact electromagnetic calibration technique for high precision measurements of micro-thrust and impulse. A ring shaped electromagnet with an air gap is used in the calibration. The calibration force is produced by the interaction of a uniform magnetic field with a copper wire current in the air gap. This force depends linearly on this current as well as the steady angular displacement of the torsion arm of the thrust stand. The range of calibration force is very large and the calibration force is easy to generate and insensitive to the arm displacement. The calibration uncertainty for a 150-MUN force is 4.17 MUN. The more influential factor on the calibration uncertainty is the magnetization of the electromagnet core due to the copper wire current. In the impulse calibration, the exerted impulse is linearly dependent on the maximal angular displacement of the torsion arm. The uncertainty in the impulse calibration is determined by uncertainties in both the force calibration and the pulse time. PMID- 23742590 TI - The extended wedge method: atomic force microscope friction calibration for improved tolerance to instrument misalignments, tip offset, and blunt probes. AB - One of the major challenges in understanding and controlling friction is the difficulty in bridging the length and time scales of macroscale contacts and those of the single asperity interactions they comprise. While the atomic force microscope (AFM) offers a unique ability to probe tribological surfaces in a wear free single-asperity contact, instrument calibration challenges have limited the usefulness of this technique for quantitative nanotribological studies. A number of lateral force calibration techniques have been proposed and used, but none has gained universal acceptance due to practical considerations, configuration limitations, or sensitivities to unknowable error sources. This paper describes a simple extension of the classic wedge method of AFM lateral force calibration which: (1) allows simultaneous calibration and measurement on any substrate, thus eliminating prior tip damage and confounding effects of instrument setup adjustments; (2) is insensitive to adhesion, PSD cross-talk, transducer/piezo tube axis misalignment, and shear-center offset; (3) is applicable to integrated tips and colloidal probes; and (4) is generally applicable to any reciprocating friction coefficient measurement. The method was applied to AFM measurements of polished carbon (99.999% graphite) and single crystal MoS2 to demonstrate the technique. Carbon and single crystal MoS2 had friction coefficients of MU = 0.20 +/- 0.04 and MU = 0.006 +/- 0.001, respectively, against an integrated Si probe. Against a glass colloidal sphere, MoS2 had a friction coefficient of MU = 0.005 +/- 0.001. Generally, the measurement uncertainties ranged from 10%-20% and were driven by the effect of actual frictional variation on the calibration rather than calibration error itself (i.e., due to misalignment, tip-offset, or probe radius). PMID- 23742591 TI - Characterization system for research on energy storage capacitors. AB - In this work a characterization system for high energy-density capacitors is described and demonstrated. Capacitors are being designed using thin-film technology in an attempt to achieve higher energy-density levels by operating the devices at a high voltage. These devices are fabricated from layers of 100 nm aluminum and a layer of polyvinylidene fluoride-hexafluoropropylene on a polyethylene naphthalate plastic substrate. The devices have been designed to store electrical charge at up to 200 V. Characterizations of these devices focus on the measurement of capacitance vs bias voltage and temperature, equivalent series resistance, and charge/discharge cycles. For the purpose of the characterization of these capacitors, an electronic charge/discharge interface was designed and tested. PMID- 23742592 TI - Time-domain reflectometry of high-voltage nonlinear loads with picosecond resolution. AB - The construction and characterization of a measuring module for high voltage time domain reflectometry with picosecond resolution is presented. The device provides registration of low-distortion reflections from the load at conditions of irregular shape and pronounced instability of an incident probing pulse with amplitude of hundreds of kilovolts and a width/front up to ~2 ns. This is achieved with registration of differential reflecting signals by using two voltage probes, whose original signals are shifted in time and have a calibrated delay. Specially designed voltage dividers based on coaxial coupled lines with equalized dielectric constant of insulation meet the requirements of voltage probes identity. Reflectometry allows one to study dynamic changes of the loads for a specific time range of ~10(-10) s and faster. An example of reflectometry based analysis for variations in breakdown development rate of atmospheric discharge gap supplied with the pulses of ~100-kV amplitude and a front slope of ~4 * 10(14) V/s is presented. PMID- 23742593 TI - A high-impedance attenuator for measurement of high-voltage nanosecond-range pulses. AB - A novel kind of high-impedance cable attenuator for measurement of high-voltage ns-range pulses is investigated in this paper. The input and output ports of the proposed attenuator were both high-impedance ports, and good pulse response characteristics of the proposed attenuator were obtained with pulse response time less than 1 ns. According to the requirement of measurement, two attenuators with lengths at 14 m and 0.7 m were developed with response time of 1 ns and 20 ns, and the attenuation coefficient of 96 and 33.5, respectively. The attenuator with the length of 14 m was used as a secondary-stage attenuator of a capacitive divider to measure the high-voltage pulses at several hundred ns range. The waveform was improved by the proposed attenuator in contrast to the result only measured by the same capacitive divider and a long cable line directly. The 0.7 m attenuator was also used as a secondary-stage attenuator of a standard resistant divider for an accurate measurement of high-voltage pulses at 100 ns range. The proposed cable attenuator can be used to substitute the traditional secondary stage attenuators for the measurement of high-voltage pulses. PMID- 23742594 TI - A nuclear magnetic resonance spectrometer concept for hermetically sealed magic angle spinning investigations on highly toxic, radiotoxic, or air sensitive materials. AB - A concept to integrate a commercial high-resolution, magic angle spinning nuclear magnetic resonance (MAS-NMR) probe capable of very rapid rotation rates (70 kHz) in a hermetically sealed enclosure for the study of highly radiotoxic materials has been developed and successfully demonstrated. The concept centres on a conventional wide bore (89 mm) solid-state NMR magnet operating with industry standard 54 mm diameter probes designed for narrow bore magnets. Rotor insertion and probe tuning take place within a hermetically enclosed glovebox, which extends into the bore of the magnet, in the space between the probe and the magnet shim system. Oxygen-17 MAS-NMR measurements demonstrate the possibility of obtaining high quality spectra from small sample masses (~10 mg) of highly radiotoxic material and the need for high spinning speeds to improve the spectral resolution when working with actinides. The large paramagnetic susceptibility arising from actinide paramagnetism in (Th(1-x)U(x))O2 solid solutions gives rise to extensive spinning sidebands and poor resolution at 15 kHz, which is dramatically improved at 55 kHz. The first (17)O MAS-NMR measurements on NpO(2+x) samples spinning at 55 kHz are also reported. The glovebox approach developed here for radiotoxic materials can be easily adapted to work with other hazardous or even air sensitive materials. PMID- 23742595 TI - Focusing giga-electronvolt heavy ions to micrometers at the Institute of Modern Physics. AB - To study the radiation effect of cosmic heavy ions of low fluxes in electronics and living samples, a focusing heavy ion microbeam facility, for ions with energies of several MeV/u up to 100 MeV/u, was constructed in the Institute of Modern Physics of the Chinese Academy of Sciences. This facility has a vertical design and an experiment platform for both in-vacuum analysis and in-air irradiation. Recently, microbeam of (12)C(6+) with energy of 80.55 MeV/u was successfully achieved at this interdisciplinary microbeam facility with a full beam spot size of 3 MUm * 5 MUm on target in air. Different from ions with energy of several MeV/u, the very high ion energy of hundred MeV/u level induces problems in beam micro-collimation, online beam spot diagnosis, radiation protection, etc. This paper presents the microbeam setup, difficulties in microbeam formation, and the preliminary experiments performed with the facility. PMID- 23742596 TI - Novel high-temperature and pressure-compatible ultrasonic levitator apparatus coupled to Raman and Fourier transform infrared spectrometers. AB - We describe an original apparatus comprising of an acoustic levitator enclosed within a pressure-compatible process chamber. To characterize any chemical and physical modifications of the levitated particle, the chamber is interfaced to complimentary, high-sensitivity Raman (4390-170 cm(-1)), and Fourier transform infrared (FTIR) (10,000-500 cm(-1)) spectroscopic probes. The temperature of the levitated particle can be accurately controlled by heating using a carbon dioxide laser emitting at 10.6 MUm. The advantages of levitating a small particle combined with the two spectroscopic probes, process chamber, and infrared laser heating makes novel experiments possible relevant to the fields of, for example, planetary science, astrobiology, and combustion chemistry. We demonstrate that this apparatus is well suited to study the dehydration of a variety of particles including minerals and biological samples; and offers the possibility of investigating combustion processes involving micrometer-sized particles such as graphite. Furthermore, we show that the FTIR spectrometer enables the study of chemical reactions on the surfaces of porous samples and scientifically and technologically relevant, micrometer-thick levitated sheets. The FTIR spectrometer can also be used to investigate non-resonant and resonant scattering from small, irregularly-shaped particles across the mid-infrared range from 2.5 MUm to 25 MUm, which is relevant to scattering from interplanetary dust and biological, micrometer-sized samples but cannot be accurately modelled using Mie theory. PMID- 23742598 TI - Cryogenic cooling with cryocooler on a rotating system. AB - We developed a system that continuously maintains a cryocooler for long periods on a rotating table. A cryostat that holds the cryocooler is set on the table. A compressor is located on the ground and supplies high-purity (>99.999%) and high pressure (1.7 MPa) helium gas and electricity to the cryocooler. The operation of the cryocooler and other instruments requires the development of interface components between the ground and rotating table. A combination of access holes at the center of the table and two rotary joints allows simultaneous circulation of electricity and helium gas. The developed system provides two innovative functions under the rotating condition, cooling from room temperature and the maintenance of a cold condition for long periods. We have confirmed these abilities as well as temperature stability under a condition of continuous rotation at 20 rpm. The developed system can be applied in various fields, e.g., in tests of Lorentz invariance, searches for axion, radio astronomy, and cosmology, and application of radar systems. In particular, there is a plan to use this system for a radio telescope observing cosmic microwave background radiation. PMID- 23742597 TI - First storage of ion beams in the Double Electrostatic Ion-Ring Experiment: DESIREE. AB - We report on the first storage of ion beams in the Double ElectroStatic Ion Ring ExpEriment, DESIREE, at Stockholm University. We have produced beams of atomic carbon anions and small carbon anion molecules (C(n)(-), n = 1, 2, 3, 4) in a sputter ion source. The ion beams were accelerated to 10 keV kinetic energy and stored in an electrostatic ion storage ring enclosed in a vacuum chamber at 13 K. For 10 keV C2 (-) molecular anions we measure the residual-gas limited beam storage lifetime to be 448 s +/- 18 s with two independent detector systems. Using the measured storage lifetimes we estimate that the residual gas pressure is in the 10(-14) mbar range. When high current ion beams are injected, the number of stored particles does not follow a single exponential decay law as would be expected for stored particles lost solely due to electron detachment in collision with the residual-gas. Instead, we observe a faster initial decay rate, which we ascribe to the effect of the space charge of the ion beam on the storage capacity. PMID- 23742599 TI - Note: Magnetic noise from the inner wall of a magnetically shielded room. AB - We measured the thermal magnetic noise generated by the inner high-permeability wall of a magnetically shielded room. This room houses a magnetoencephalogram (MEG), which contains 102 "small" identical magnetometers. For the measurement, we created two large magnetometers by summing the outputs of 46 magnetometers equally on the helmet's left and right side, to look at the summed noise of the right and left vertical walls. From these summed outputs, we calculated the rms noise amplitude due to all six walls at the MEG location to be ~0.5 f T/?Hz at 100 Hz, only slowly rising with lower frequency. This is well below the system noise of each small MEG magnetometer, hence is negligible for the MEG. PMID- 23742600 TI - Note: Nonlinearity error compensated absolute planar position measurement using a two-dimensional phase-encoded binary grating. AB - This Note presents a new absolute planar position measurement method using a two dimensional phase-encoded binary grating and a sub-division process where nonlinearity error is compensated inherently. Two orthogonally accumulated intensity profiles of the image of the binary grating are analyzed separately to obtain the absolute position values in each axis. The nonlinearity error caused by the non-ideal sinusoidal signals in the intensity profile is compensated by modifying the configuration of the absolute position binary code and shift averaging the intensity profile. Using an experimental setup, we measured a circular trajectory of 100 nm radius, and compared the measurement result with that of a laser interferometer. Applying the proposed compensation method, the nonlinearity error was reduced to less than 15 nm. PMID- 23742601 TI - Note: High-performance HeNe laser feedback interferometer with birefringence feedback cavity scanned by piezoelectric transducer. AB - We demonstrate a high-performance HeNe laser feedback interferometer (HLFI) based on a birefringence feedback cavity scanned by a piezoelectric transducer (PZT). The PZT scanning technique leads to a significant improvement in the HLFI's anti jamming capability. The null drift under general laboratory conditions is approximately +/-32 nm, corresponding to +/-2 pulses. The phase difference between the two measurement signals does not vary when the feedback cavity length changes. This ensures a large measurement range for the HLFI. The HLFI presented here features a large measurement range (>1 m), nanometer-scale resolution (15.82 nm), a compact configuration, and low cost. PMID- 23742602 TI - Note: Single-polarity high-voltage amplifier to drive coarse-approach slip-stick piezoelectric motors. AB - Scanning probe microscopies typically rely on coarse-approach slip-stick piezoelectric motors that work by exciting piezoelectric stacks with sawtooth signals of hundreds of V and some kHz. For this application, we introduce a single-polarity high-voltage amplifier based on discrete MOSFET-technology components with improved output current desirable for low-temperature actuation. The amplifier has an output signal of 600 V, 100 mA output current, noise level below 2 MUV/?Hz, 4 kHz high-voltage bandwidth, 2 V/MUs slew-rate, and rise and fall times of 80 MUs (when loaded with 30 nF). The circuit was successfully applied to drive a home-made scanning tunnelling microscope. PMID- 23742603 TI - Note: Mobile micro-Raman analyzer integrated with a lab-on-a-chip. AB - A mobile micro-Raman microfluidic analyzer was designed and built for label-free, nondestructive, fingerprint detection of samples on microfluidic chip systems. It mainly includes an optical module (including the Raman detection system and the microscopic imaging system), 3-axis stages with step motors and other auxiliary circuits. The setup of the analyzer was designed with fully considering the characters of the microfluidics system. The experimental results prove that this microfluidics analyzer is practical and very convenient to use. This micro-Raman microfluidics analyzer with high performance to cost ratio has wide application potential in lab-on-a-chip fields as a powerful analytical tool. PMID- 23742604 TI - Note: A compact, rigid, and easy-to-build piezo motor: the intact-tube GeckoDrive. AB - We report an extremely simple, rigid, low machine tolerance, yet high performance piezoelectric motor, in which two rings are coaxially glued at the ends of one intact piezotube, respectively, using the proper gluing method. A central shaft is pushed to press against the inner edges of the rings by a spring strip at a proper axial position and in the gap between the shaft and the inner wall of the piezotube. It is compared with other important forms of three-friction driven motors and shows advantageous structure and unexpectedly excellent performance, hence deserving a new name: the GeckoDrive. PMID- 23742605 TI - Note: Operation of gamma-ray microcalorimeters at elevated count rates using filters with constraints. AB - Microcalorimeter sensors operated near 0.1 K can measure the energy of individual x- and gamma-ray photons with significantly more precision than conventional semiconductor technologies. Both microcalorimeter arrays and higher per pixel count rates are desirable to increase the total throughput of spectrometers based on these devices. The millisecond recovery time of gamma-ray microcalorimeters and the resulting pulse pileup are significant obstacles to high per pixel count rates. Here, we demonstrate operation of a microcalorimeter detector at elevated count rates by use of convolution filters designed to be orthogonal to the exponential tail of a preceding pulse. These filters allow operation at 50% higher count rates than conventional filters while largely preserving sensor energy resolution. PMID- 23742606 TI - Note: A simple-structured anode exchangeable X-ray tube. AB - An anode exchangeable X-ray tube of very simple structure was developed. Aluminum, chromium, and copper anode targets were prepared and used to investigate X-ray spectra. X-ray images of a thin wood plate were taken using those targets. The measured energies of the characteristic X-rays of each target agreed well with the presented results. The difference of resolution and brightness of each image was found based on MTF values and intensities. The developed X-ray tube can give high durability, and higher quality X-ray images of an arbitrary object by exchanging anode targets. PMID- 23742607 TI - Note: Thickness determination of freestanding ultra-thin foils using a table top laboratory extreme ultraviolet source. AB - We present a versatile and handy method allowing a thickness determination of freestanding thin plastic foils by its transmission characteristics in the extreme ultraviolet (EUV) spectrum. The method is based on a laser induced plasma source, emitting light in the EUV region, a compact double-mirror EUV monochromator operating at a fixed wavelength of 18.9 nm, and a CCD camera. The measurement delivers transmission values with a standard deviation of DeltaT = 0.005 enabling foils thickness characterization with nm-accuracy at a given foil density and stoichiometric composition. Well characterized freestanding ultra thin foils can be directly implemented in, e.g., high intensity laser matter experiments without further manipulation. PMID- 23742608 TI - Note: Readout of a micromechanical magnetometer for the ITER fusion reactor. AB - We present readout instrumentation for a MEMS magnetometer, placed 30 m away from the MEMS element. This is particularly useful when sensing is performed in high radiation environment, where the semiconductors in the readout cannot survive. High bandwidth transimpedance amplifiers are used to cancel the cable capacitances of several nanofarads. A frequency doubling readout scheme is used for crosstalk elimination. Signal-to-noise ratio in the range of 60 dB was achieved and with sub-percent nonlinearity. The presented instrument is intended for the steady-state magnetic field measurements in the ITER fusion reactor. PMID- 23742609 TI - Note: Neutron shutter for Kolkata superconducting cyclotron. AB - In particle accelerator facilities, experimental areas are isolated from active accelerator area with thick concrete walls. A neutron shutter is used to isolate the experimental areas from the active accelerator area in the beam line. These shutters are provided primarily to reduce the secondary radiations like neutrons in the experimental areas to permissible limit when the primary beam is blocked in the accelerator area. The reduced radiation level in the experimental areas makes the experimental areas accessible. The shutters should allow the primary beam to pass to the experimental caves when they retracted from the beam line. A new neutron shutter has been designed and fabricated. This shutter incorporates compact features with considerable reduction in length, surface area and volume. The attenuation of secondary radiations is evaluated using Monte-Carlo radiation transport code FLUKA. It is found that the features of the shutter are sufficiently good enough to reduce the diffused secondary radiations well within the permissible levels. PMID- 23742610 TI - Note: Simple and compact piezoelectric mirror actuator with 100 kHz bandwidth, using standard components. AB - We propose a mounting scheme to control the displacement of a mirror (or other small object) by a cylindrical piezoelectric actuator, giving uniform response and no phase lag up to high frequencies. This requires a simple ring holder, and unmodified off-the-shelf components. In our implementation, the piezo-mirror assembly has its first mechanical resonance around 120 kHz, close to the resonance for the bare piezo. The idea is to decouple the fundamental elongation mode of the piezo-mirror assembly from the holder by side-clamping the assembly at its zero-displacement plane for this mode. The main drawback is a reduced mirror displacement, by a factor 2 in our case (mirror displacement is ~2.5 MUm). Also, the mirror needs to be light with respect to the piezo: still, we use a standard half-inch mirror. The resulting system is very compact as it fits inside a 1-in. commercial steering mirror post. PMID- 23742611 TI - Note: Thermal analysis of the long line source electron gun. AB - We performed thermal analysis for our previously reported [M. Iqbal, K. Masood, M. Rafiq, M. A. Chaudhry, and F. Aleem, Rev. Sci. Instrum. 74, 4616 (2003)], long linear filament electron gun assembly using ANSYS software. The source was set under a thermal load of 3000 degrees C, to evaluate temperature distribution, thermal strain, and heat flux at various components of the gun. We calculated the maximum heat flux (9.0 W/mm(2)) that produced a thermal strain of 0.05 at the focusing electrodes. However, the minimum value of the heat flux (0.3 W/mm(2)) was at the anode electrodes which correspond to a negligible thermal strain. The gun was validated experimentally showing a uniform cross section of the beam at the molybdenum work plate comparable to the size of the filament. Our experimental and theoretical results are in agreement. The gun had been in continuous operation for several hours at high temperatures without any thermal run-out. PMID- 23742615 TI - Impact of children's influenza-like illnesses on parental quality of life: a qualitative study. AB - AIMS: Influenza and influenza-like illness (ILI) in otherwise healthy children has considerable impact on their parents. This study explored the impact of children's ILI on parental quality of life (QoL). METHODS: We conducted qualitative in-depth interviews with parents of children aged 6 months-3 years with severe ILI. Children from childcare centres in Sydney, Australia were followed through the 2010 influenza season. Questions covered child's symptoms, parents' experiences including medical care visits, impact on the family's daily routine, and emotional, physical and social well-being. Interviews were analysed using a modified grounded theory approach. RESULTS: We conducted 21 interviews with 23 parents. Five main themes emerged: 'sudden changes in daily life', 'emotional impact', 'social isolation and relationship changes', 'importance of family and friend support' and 'interaction with the medical system'. Perceived practical and emotional support from family and/or friends and consultations with the doctor appeared to moderate the impact. CONCLUSIONS: Severe ILI in children has a considerable impact on their parents' QoL, through disruptions of normal life routine, social isolation and stress in coping with the sick child. These impacts should be considered when introducing flexible workplace policies designed to minimise the impact on parental QoL. Prevention strategies such as vaccinating children against influenza may help alleviate this impact at a population level. PMID- 23742617 TI - Vitexin inhibits inflammatory pain in mice by targeting TRPV1, oxidative stress, and cytokines. AB - The flavonoid vitexin (1) is a flavone C-glycoside (apigenin-8-C-beta-D glucopyranoside) present in several medicinal and other plants. Plant extracts containing 1 are reported to possess antinociceptive, anti-inflammatory, and antioxidant activities. However, the only evidence that 1 exhibits antinociceptive activity was demonstrated in the acetic acid-induced writhing model. Therefore, the analgesic effects and mechanisms of 1 were evaluated. In the present investigation, intraperitoneal treatment with 1 dose-dependently inhibited acetic acid-induced writhing. Furthermore, treatment with 1 also inhibited pain-like behavior induced by phenyl-p-benzoquinone, complete Freund's adjuvant (CFA), capsaicin (an agonist of transient receptor potential vanilloid 1, TRPV1), and both phases of the formalin test. It was also observed that inhibition of carrageenan-, capsaicin-, and chronic CFA-induced mechanical and thermal hyperalgesia occurred. Regarding the antinociceptive mechanisms of 1, it prevented the decrease of reduced glutathione levels, ferric-reducing ability potential, and free-radical scavenger ability, inhibited the production of hyperalgesic cytokines such as TNF-alpha, IL-1beta, IL-6, and IL-33, and up regulated the levels of the anti-hyperalgesic cytokine IL-10. These results demonstrate that 1 exhibits an analgesic effect in a variety of inflammatory pain models by targeting TRPV1 and oxidative stress and by modulating cytokine production. PMID- 23742618 TI - Comparative anatomy of the ophthalmic rete and its relationship to ocular blood flow in three species of marine mammal. AB - OBJECTIVE: To examine the blood supply to the eyes of bottlenose dolphin (Tursiops truncatus), spotted seal (Phoca largha), and California sea lion (Zalophus californianus). Emphasis is placed on exploring the anatomic function in the context of aquatic life. PROCEDURE: Methyl methacrylate casts were prepared and studied using a scanning electron microscope. Infrared images of the eye were recorded using a thermocamera. RESULTS: In all three marine species, blood is supplied to the ophthalmic rete. The main source of blood supply to the rete is the basilar rete via the spinal rete in the dolphin and via the ophthalmic artery in the seal and sea lion. The retinal and choroidal arteries are derived from the rete. The dolphin rete showed a very well-developed arterial network occupying most of the orbit. The rete in pinnipeds was less developed with several entwining arteries, unlike that in cetaceans. Thermographic examination revealed that the eye shows a higher degree of thermal emission than adjacent areas of the skin in these 3 species. DISCUSSION: The role of the rete in aquatic mammals appears to conserve ocular temperature so that the appropriate operating temperature for photoreceptors and ocular muscles can be maintained in a cold ambient temperature. Additionally, the rete might have a flow-damping effect by maintaining resistance to blood flow in the orbit. This study highlights the special nature of ocular vascular anatomy and function that enabled the unique adaptation of aquatic mammals to life in aquatic habitats. PMID- 23742620 TI - Annual cost of relapses and relapse-related hospitalizations in adults with schizophrenia: results from a 12-month, double-blind, comparative study of lurasidone vs quetiapine extended-release. AB - PURPOSE: To model the economic impact of annual relapses/relapse-related hospitalizations among adults with schizophrenia treated with lurasidone or quetiapine extended-release (XR). METHODS: A probabilistic model estimating per patient-per-year (PPPY) direct mental healthcare (MH) cost differences due to relapses/relapse-related hospitalizations was developed using relapse and relapse related hospitalization rates from a 12-month, double-blind, parallel-group, global comparison study of lurasidone vs quetiapine XR (all patients previously treated with lurasidone or quetiapine XR for 6 weeks). Analyses were conducted for both all subjects and clinical responders. Direct costs associated with inpatient and outpatient mental healthcare-related services were obtained from a large, prospective, observational study of schizophrenia treatment in usual-care settings for relapsing and non-relapsing patients, including psychiatric hospitalizations, emergency services, medication management, and outpatient individual therapy. Model robustness was tested using univariate and probabilistic sensitivity analyses. RESULTS: Model-estimated PPPY MH cost savings associated with relapse-related hospitalization rates in all subjects were $3276 for lurasidone vs quetiapine XR. Lurasidone resulted in PPPY MH cost savings of $2702 vs quetiapine XR in all subjects, using relapse rates. Sensitivity analyses indicated lurasidone had lower 1-year MH costs than quetiapine XR in 100% and 99.7% of simulations, using relapse-related hospitalization rates and relapse rates, respectively, in all subjects. Similar results were seen in clinical responders. LIMITATIONS: The model represents a simplification of treatment patterns and response to treatment. Cost of treatment with lurasidone and quetiapine XR was not included in the model. Estimates of cost savings are likely conservative, as the model did not assess the impact of long-term cardiometabolic consequences. Indirect costs associated with relapses and non-mental health related costs were also excluded from the model. CONCLUSION: Adults treated for schizophrenia with lurasidone are predicted to have lower 12-month MH costs compared to those treated with quetiapine XR due to fewer relapses and relapse related hospitalizations. PMID- 23742619 TI - Insight into the specific virulence related genes and toxin-antitoxin virulent pathogenicity islands in swine streptococcosis pathogen Streptococcus equi ssp. zooepidemicus strain ATCC35246. AB - BACKGROUND: Streptococcus equi ssp. zooepidemicus (S. zooepidemicus) is an important pathogen causing swine streptococcosis in China. Pathogenicity islands (PAIs) of S. zooepidemicus have been transferred among bacteria through horizontal gene transfer (HGT) and play important roles in the adaptation and increased virulence of S. zooepidemicus. The present study used comparative genomics to examine the different pathogenicities of S. zooepidemicus. RESULTS: Genome of S. zooepidemicus ATCC35246 (Sz35246) comprises 2,167,264-bp of a single circular chromosome, with a GC content of 41.65%. Comparative genome analysis of Sz35246, S. zooepidemicus MGCS10565 (Sz10565), Streptococcus equi. ssp. equi. 4047 (Se4047) and S. zooepidemicus H70 (Sz70) identified 320 Sz35246-specific genes, clustered into three toxin-antitoxin (TA) systems PAIs and one restriction modification system (RM system) PAI. These four acquired PAIs encode proteins that may contribute to the overall pathogenic capacity and fitness of this bacterium to adapt to different hosts. Analysis of the in vivo and in vitro transcriptomes of this bacterium revealed differentially expressed PAI genes and non-PAI genes, suggesting that Sz35246 possess mechanisms for infecting animals and adapting to a wide range of host environments. Analysis of the genome identified potential Sz35246 virulence genes. Genes of the Fim III operon were presumed to be involved in breaking the host-restriction of Sz35246. CONCLUSION: Genome wide comparisons of Sz35246 with three other strains and transcriptome analysis revealed novel genes related to bacterial virulence and breaking the host-restriction. Four specific PAIs, which were judged to have been transferred into Sz35246 genome through HGT, were identified for the first time. Further analysis of the TA and RM systems in the PAIs will improve our understanding of the pathogenicity of this bacterium and could lead to the development of diagnostics and vaccines. PMID- 23742621 TI - Noniatrogenic neonatal gastric perforation: the role of interstitial cells of Cajal. AB - Noniatrogenic neonatal gastric perforation is a rare and life-threatening condition whose etiology is often unclear. Interstitial cells of Cajal act as gastrointestinal pacemaker cells and express the proto-oncogene c-Kit. Six new cases were identified at our institution which presented with no mechanical, pharmacologic, or otherwise medical-related intervention prior to rupture. The number of interstitial cells of Cajal in nonnecrotic muscularis propria from five random high-power fields per specimen was compared using immunohistochemical stains for c-Kit. The authors show that a lack of interstitial cells of Cajal in the stomach musculature may be implicated in the development of noniatrogenic gastric perforation (p = 0.008). Further large-scale studies, including molecular and genetic analysis, may help to better understand this phenomenon. PMID- 23742623 TI - Genome-wide linkage scan in affected sibling pairs identifies novel susceptibility region for venous thromboembolism: Genetics In Familial Thrombosis study. AB - BACKGROUND: Venous thromboembolism (VTE) is a multicausal disorder involving environmental and genetic risk factors. In many thrombophilic families the clustering of thrombotic events cannot be explained by known genetic risk factors, indicating that some remain to be discovered. OBJECTIVES: We aimed to identify novel thrombosis susceptibility alleles in a large panel of small thrombophilic families: the Genetics In Familial Thrombosis (GIFT) study. PATIENTS/METHODS: In the GIFT study, 201 families were recruited consisting of 438 siblings with an objectively confirmed VTE at a young age. Multipoint linkage analysis (402 SSR markers) and fine mapping were performed, followed by genotyping of tagging SNPs in positional candidate genes. RESULTS: Established genetic risk factors such as factor V Leiden, ABO blood group non-O, prothrombin 20210A, fibrinogen gamma 10034T and deficiencies of antithrombin, protein C and protein S were more frequent in GIFT patients than in unselected VTE patients. Linkage supported the presence of novel thrombosis susceptibility loci on 7p21.3 22.2 (LOD score = 3.23) and Xq24-27.3 (LOD score = 1.95). Simulation analysis showed that the chr7 signal was genome-wide statistically significant (P = 0.022). Tagging SNPs (n = 157) in eight positional candidate genes (LOD drop 1.5 regions) were genotyped in GIFT patients and 332 healthy controls. Five chr7 SNPs associated with VTE. SNP THSD7A rs2074597 was responsible for part of the chr7 signal. CONCLUSIONS: The GIFT panel is rich in established genetic risk factors for VTE, but genetic factors remain unidentified in many families. Genome-wide linkage failed to identify the previously established genetic risk factors for VTE, but identified a novel VTE susceptibility locus on chr7. PMID- 23742624 TI - Self-assembly of Janus ellipsoids II: Janus prolate spheroids. AB - In self-assembly, the anisotropy of the building blocks and their formation of complex structures have been the subject of considerable recent research. Extending recent research on Janus particles and completing the study of Janus spheroids, we conduct a systematic investigation on the self-assembly of Janus prolate spheroids based on a primitive model that we proposed. Janus prolate spheroids are particles that have a prolate spheroidal body and two hemi-surfaces along the major axis coded with different chemical properties. Using Monte Carlo simulations, we investigate the effects of the aspect ratio on the self-assembly process. In contrast to the vesicle-like aggregates for Janus oblate spheroids, we obtain various ordered cluster structures for Janus prolate spheroids through self-assembly. With an increasing aspect ratio, we find a transition of cluster morphology, from vesicles to tubular micelles and micelles. In particular, a relatively small change in the aspect ratio leads to a rather significant change in morphology. We apply a cluster analysis to understand the mechanism associated with such a transition. PMID- 23742625 TI - Bleeding risk in patients with esophageal varices undergoing transesophageal echocardiography. AB - BACKGROUND: Bleeding from esophageal varices is a major potential concern during transesophageal echocardiography (TEE) in patients with cirrhosis of the liver. As there are limited data on its risk in these patients, this was retrospectively assessed at our institution. METHODS: The hospital electronic medical record database at our university affiliated teaching hospital was searched for all patients with esophageal varices undergoing TEE from 2000 to 2012 and patient charts were reviewed for procedure-related bleeding complications. RESULTS: Twenty-four patients with esophageal varices were found (18 men, 57 +/- 14 years). Nine patients had grade 2 esophageal varices, 15 patients had grade 1 varices, and 12 patients had portal hypertensive gastropathy. Alcoholic liver disease (9) and hepatitis C (8) were the most common etiologies of the cirrhosis with an average MELD score of 15. The most common indication for TEE was for possible endocarditis (15). Medications potentially increasing bleeding risk included warfarin in 2 and aspirin in 7 patients. Twelve patients were taking beta-blockers for portal hypertension. There were no immediate bleeding complications and none of these patients were readmitted with bleeding. CONCLUSIONS: TEE can be performed without serious bleeding risk in patients with grade 1 or 2 esophageal varices. PMID- 23742622 TI - NAD+ metabolism: a therapeutic target for age-related metabolic disease. AB - Nicotinamide adenine dinucleotide (NAD) is a central metabolic cofactor by virtue of its redox capacity, and as such regulates a wealth of metabolic transformations. However, the identification of the longevity protein silent regulator 2 (Sir2), the founding member of the sirtuin protein family, as being NAD+-dependent reignited interest in this metabolite. The sirtuins (SIRT1-7 in mammals) utilize NAD+ to deacetylate proteins in different subcellular compartments with a variety of functions, but with a strong convergence on optimizing mitochondrial function. Since cellular NAD+ levels are limiting for sirtuin activity, boosting its levels is a powerful means to activate sirtuins as a potential therapy for mitochondrial, often age-related, diseases. Indeed, supplying excess precursors, or blocking its utilization by poly(ADP-ribose) polymerase (PARP) enzymes or CD38/CD157, boosts NAD+ levels, activates sirtuins and promotes healthy aging. Here, we discuss the current state of knowledge of NAD+ metabolism, primarily in relation to sirtuin function. We highlight how NAD+ levels change in diverse physiological conditions, and how this can be employed as a pharmacological strategy. PMID- 23742626 TI - Universal drag tag for direct quantitative analysis of multiple microRNAs. AB - Using microRNA (miRNA) as molecular markers of diseases requires a method for accurate measurement of multiple miRNAs in biological samples. Direct quantitative analysis of multiple miRNAs (DQAMmiR) has been recently developed based on a classical hybridization approach. In DQAMmiR, miRNAs are hybridized with excess fluorescently labeled complementary DNA probes. Capillary electrophoresis (CE) is used to separate the unreacted probes from the hybrids and the hybrids from each other. The challenging separation is achieved by using two types of mobility modifiers. Single-strand DNA binding protein (SSB) is added to the running buffer to bind and shift the single-stranded unreacted probes from the double-stranded hybrids. Different drag tags are built into the probes to introduce significant differential mobility between their respective hybrids. For the method to be practical it requires a universal extendable drag tag. Polymers are a logical choice for making extendable drag tags. Our recent theoretical work suggested that short peptides could provide a sufficient mobility shift to facilitate DQAMmiR. Here, we experimentally confirm this prediction in the analysis of five miRNAs: mir10b, mir21, mir125b, mir145, and mir155. We conjugated four fluorescently labeled DNA molecules with peptides of 5, 10, 15, or 20 neutral amino acids in length; the fifth probe was peptide-free. The peptide tags showed no interference with SSB binding to the probes and facilitated separation of the five hybrids. The mobilities of the five hybrids were used to refine the previously suggested theory. The analysis was performed in both a pure buffer and in cell lysate. Our analysis of the experimental data suggests that using DNA-peptide probes can readily facilitate simultaneous analysis of more than 10 miRNAs. PMID- 23742627 TI - Early changes in gene expression induced by blue light irradiation of A2E-laden retinal pigment epithelial cells. AB - PURPOSE: Accumulation of bisretinoids as lipofuscin in retinal pigment epithelial (RPE) cells is implicated in the pathogenesis of some blinding diseases including age-related macular degeneration (AMD). To identify genes whose expression may change under conditions of bisretinoid accumulation, we investigated the differential gene expression in RPE cells that had accumulated the lipofuscin fluorophore A2E and were exposed to blue light (430 nm). METHODS: A2E-laden RPE cells were exposed to blue light (A2E/430 nm) at various time intervals. Cell death was quantified using Dead Red staining, and RNA levels for the entire genome was determined using DNA microarrays (Affymetrix GeneChip Human Genome 2.0 Plus). Array results for selected genes were confirmed by real-time reverse transcriptase polymerase chain reaction. RESULTS: Principal component analysis revealed that the A2E-laden RPE cells irradiated with blue light were clearly distinguishable from the control samples. We found differential regulation of genes belonging to the following functional groups: transcription factors, stress response, apoptosis and immune response. Among the last mentioned were downregulation of four genes that coded for proteins that have an inhibitory effect on the complement cascade: (complement factor H, complement factor H related 1, complement factor I and vitronectin) and of two belonging to the classical pathway (complement component 1, s subcomponent and complement component 1, r subcomponent). CONCLUSION: This study demonstrates that blue light irradiation of A2E-laden RPE cells can alter the transcription of genes belonging to different functional pathways including stress response, apoptosis and the immune response. We suggest that these molecules may be associated to the pathogenesis of AMD and can potentially serve as future therapeutic targets. PMID- 23742628 TI - Which factors influence psychiatric diagnosing in substance abuse treatment? AB - BACKGROUND: The importance of diagnosing and treating co-occurring psychiatric disorders among substance abusers in treatment has received much attention. The aim of this study was to investigate to which extent co-occurring psychiatric disorders are diagnosed in a clinical population of substance abusers, and which factors (including the use of MINI-Plus) that influence the diagnosing of co occurring psychiatric disorders. METHODS: Patients (N = 275) who received inpatient substance use treatment in five different units in Northern Norway participated in the study. The patients' clinicians gave information on diagnoses given during the stay in the units, and whether a systematic diagnostic tool was used for the diagnosing (MINI-Plus). Predictors of independent co-occurring psychiatric disorders were examined utilizing hierarchical regression analysis. RESULTS: One third of the patients were given an independent psychiatric diagnosis. Less than half of the patients were assessed using a diagnostic tool. The main predictor of diagnosing of independent psychiatric disorders was the use of the diagnostic tool MINI-Plus. Younger patients and patients that used less alcohol, were given independent psychiatric diagnoses more frequently. CONCLUSIONS: The number of co-occurring independent psychiatric diagnoses was lower compared to other studies using standardized diagnostic tools. The low number of patients assessed by such a tool, and the strong relationship between the use of such a tool and the diagnosing of co-occurring psychiatric disorders, suggest that the implementation of standardized diagnostic tools should be addressed in the units. Generally, patients suffering from substance use disorders should be systematically screened for other psychiatric disorders, in order to improve their treatment and health. PMID- 23742629 TI - Home telehealth: facilitators, barriers, and impact of nurse support among high risk dialysis patients. AB - OBJECTIVE: The value of home telehealth self-monitoring with nurse oversight has been demonstrated; however, there is a dearth of objective documentation of patients' experiences with such a model. We used a mixed methods approach to examine the value of home telehealth monitoring with remote care nurse (RCN) support from the perspective of participants in our study. MATERIALS AND METHODS: Thirty-three patients who used remote technology to self-monitor their health at home participated in a semistructured interview. The instrument was designed to help identify facilitators and barriers and to evaluate patient satisfaction with and effectiveness of home telehealth self-monitoring. RESULTS: Overall, patients reported high levels of satisfaction with RCN support as they received efficient feedback, were better able to identify changes in their health status, and experienced enhanced accountability, self-efficacy, and motivation to make health behavior changes. The most frequently cited barriers related to malfunctioning equipment or trouble with Internet connections, forgetfulness, and feeling poorly. CONCLUSIONS: The results suggest that home telehealth self-monitoring with RCN support is effective in empowering patients to take a more active role in their healthcare and indirectly improve quality of life for those living with chronic illness. PMID- 23742630 TI - Bilateral squamous cell carcinoma of the feet associated with human papillomavirus type 16 infection. PMID- 23742631 TI - Car-Parrinello molecular dynamics/molecular mechanics (CPMD/MM) simulation study of coupling and uncoupling mechanisms of Cytochrome P450cam. AB - The relevance of the pathway through which the second proton is delivered to the active site of P450cam and the subsequent coupling/uncoupling reactions has been investigated using Car-Parrinello molecular dynamics/molecular mechanics (CPMD/MM) dynamics simulations. Five models have been prepared, representing delivery pathways in the wild-type enzyme and its mutants in which Thr252 mutated into other residues with different side-chain length and hydrophobicity. In the simulations, coupling reaction is observed in the wild-type enzyme (Model A) and its T252S mutant (Model B), while the uncoupling products are obtained in the other three models (C, D, and E). Different from previous studies, a dynamic process of the last stage of coupling/uncoupling was observed. We found that the peroxide bond cleavage in coupling, the Fe-O bond stretching in uncoupling, proton transfer, and electron delivery take place spontaneously. Moreover, besides the intrinsic chemical differences between the two peroxide oxygen atoms, water molecules in the active site and the proton transfer pathway may play an important role in the determination of coupling/uncoupling. We conclude that by maintaining a specific proton transfer channel, Asp251-Thr252 channel, the wild type enzyme could efficiently deliver the second proton to the ideal position for coupling reaction. PMID- 23742632 TI - Wnt/beta-catenin signaling and adipogenic genes are associated with intramuscular fat content in the longissimus dorsi muscle of Korean cattle. AB - Intramuscular fat (IMF) is an important trait that influences beef quality. In two studies, we examined the possible involvement of the Wnt/beta-catenin signaling pathway in IMF deposition in Korean cattle. In study 1, using a group of bulls and steers, we found that castration, a non-genetic factor, decreased (P < 0.01) the expression of both the WNT10B and CTNNB1 genes, whereas it increased the expression of the Wnt antagonist secreted frizzled-related proteins 4 (SFRP4, P < 0.001) and the adipogenic CCAAT/enhancer binding protein (C/EPB), alpha (CEBPA, P < 0.001) and peroxisome proliferator-activated receptor gamma (PPARG, P < 0.05) genes in longissimus dorsi muscle (LM) tissue. The WNT10B and CTNNB1 mRNA levels showed strong (P < 0.001) negative correlations (r = -0.68 and r = -0.73 respectively) with the IMF content, whereas the SFRP4, CEBPA and PPARG mRNA levels showed strong (P < 0.01) positive correlations (r = 0.70, 0.70 and 0.64 respectively) with the IMF content. Large variation still exists in the IMF content of steers, implying that genetic factors affect IMF deposition. Using a different group of steers, a correlation analysis in study 2 also showed that the expression of the WNT10B and CTNNB1 genes, and SFRP4 and adipogenic genes was negatively and positively associated with the IMF content respectively. Our findings suggest that downregulation of the Wnt/beta-catenin signaling pathway genes, but upregulation of Wnt antagonist SFRP4 and adipogenic gene expression following castration, contributes to increased IMF deposition in the LM. Our results demonstrate that both non-genetic factors (castration) and genetic variation within the steer group affect the gene expression pattern of the Wnt/beta-catenin signaling pathway. PMID- 23742633 TI - Evaluation of the malaria rapid diagnostic test VIKIA malaria Ag Pf/PanTM in endemic and non-endemic settings. AB - BACKGROUND: Malaria rapid diagnostic tests (RDTs) are a useful tool in endemic malaria countries, where light microscopy is not feasible. In non-endemic countries they can be used as complementary tests to provide timely results in case of microscopy inexperience. This study aims to compare the new VIKIA Malaria Ag Pf/PanTM RDT with PCR-corrected microscopy results and the commonly used CareStartTM RDT to diagnose falciparum and non-falciparum malaria in the endemic setting of Bamako, Mali and the non-endemic setting of Lyon, France. METHODS: Blood samples were collected during a 12-months and six-months period in 2011 from patients suspected to have malaria in Lyon and Bamako respectively. The samples were examined by light microscopy, the VIKIA Malaria Ag Pf/PanTM test and in Bamako additionally with the CareStartTM RDT. Discordant results were corrected by real-time PCR. Sensitivity, specificity, positive predictive value and negative predictive value were used to evaluate test performance. RESULTS: Samples of 877 patients from both sites were included. The VIKIA Malaria Ag Pf/PanTM had a sensitivity of 98% and 96% for Plasmodium falciparum in Lyon and Bamako, respectively, performing similar to PCR-corrected microscopy. CONCLUSIONS: The VIKIA Malaria Ag Pf/PanTM performs similar to PCR-corrected microscopy for the detection of P. falciparum, making it a valuable tool in malaria endemic and non-endemic regions. PMID- 23742634 TI - The microvascular response to transdermal iontophoresis of insulin is mediated by nitric oxide. AB - OBJECTIVE: Insulin has direct effects on blood flow in various tissues, most likely due to endothelial NO production. We investigated whether insulin delivered to the skin by iontophoresis increases microvascular perfusion and whether this effect is partly or completely mediated by the release of NO. METHODS: In healthy subjects, regular insulin and monomeric insulin were delivered to the skin by cathodal iontophoresis. The skin was pretreated either with L-NAME or control solution (PBS) using anodal iontophoresis. Microvascular responses were measured using laser Doppler flowmetry. RESULTS: A dose-dependent increase in perfusion was observed during iontophoresis of regular and monomeric insulin. The maximum perfusion was significantly elevated compared with control after PBS (regular insulin 53.6 (12.7-95.6) PU vs. 4.2 (3.4-4.8) PU, p = 0.002; monomeric insulin 32.6 (8.9-92.6) PU vs. 5.9 (3.4-56.0) PU, p = 0.03). The microvascular response to insulin was abolished after L-NAME (regular insulin: 25.6 (11.6-54.4) PU vs. control: 4.7 (2.9-11.5) PU, p = 0.15; monomeric insulin 10.9 (5.4-56.8) PU vs. control: 4.7 (2.9-11.5) PU, p = 0.22). CONCLUSIONS: The main finding is that iontophoresis of insulin induces a dose-dependent vasodilation in the skin, which could be suppressed after pretreatment with a NO synthase inhibitor. This suggests that vasodilation in the skin after iontophoresis of insulin is mediated by the NO pathway. PMID- 23742635 TI - Short communication: The relationship between mitochondrial dysfunction and insulin resistance in HIV-infected children receiving antiretroviral therapy. AB - Mitochondrial abnormalities may lead to metabolic complications in HIV-infected children who have been receiving long-term antiretroviral treatment. We conducted a matched, case-control study comparing 21 HIV-infected children with insulin resistance (cases) to 21 HIV-infected children without insulin resistance (controls) to assess differences in mitochondrial DNA (mtDNA) copies/cell and oxidative phosphorylation NADH dehydrogenase (C1) and cytochrome c oxidase (C4) enzyme activities in peripheral blood mononuclear cells. MtDNA copies/cell tended to be lower in cases, and fasting serum glucose levels were inversely and significantly correlated with C1 enzyme activity, more so in cases. Larger pediatric studies should evaluate mitochondrial etiologies of insulin resistance and determine the role of antiretroviral therapies or HIV infection on mitochondrial dysfunction. PMID- 23742636 TI - Aromatic naphthenic acids in oil sands process-affected water, resolved by GCxGC MS, only weakly induce the gene for vitellogenin production in zebrafish (Danio rerio) larvae. AB - Process waters from oil sands industries (OSPW) have been reported to exhibit estrogenic effects. Although the compounds responsible are unknown, some aromatic naphthenic acids (NA) have been implicated. The present study was designed to investigate whether aromatic NA might cause such effects. Here we demonstrate induction of vitellogenin genes (vtg) in fish, which is a common bioassay used to indicate effects consistent with exposure to exogenous estrogens. Solutions in water of 20-2000 MUg L(-1) of an extract of a total OSPW NA concentrate did not induce expression of vtg in larval zebrafish, consistent with earlier studies which showed that much higher NA concentrations of undiluted OSPW were needed. Although 20-2000 MUg L(-1) of an esterifiable NA subfraction of the OSPW NA concentrate did induce expression, this was of much lower magnitude to that induced by much lower concentrations of 17alpha-ethynyl estradiol, indicating that the effect of the total NAs was only weak. However, given the high NA concentrations and large volumes of OSPW extant in Canada, it is important to ascertain which of these esterifiable NA in the OSPW produce the effect. Up to 1000 MUg L(-1) of an OSPW subfraction containing only alicyclic NA, and considered by most authors to be NA sensu stricto, did not produce induction; but, as predicted, 10-1000 MUg L(-1) of an aromatic NA fraction did. Such effects by the aromatic acids are again consistent with those of only a weak estrogenic substance. These findings may help to focus studies of the most environmentally significant OSPW-related pollutants, if reproduced in a greater range of OSPW. PMID- 23742637 TI - Immunoregulatory properties of clinical grade mesenchymal stromal cells: evidence, uncertainties, and clinical application. AB - Mesenchymal stromal cell (MSC)-based therapy holds great promise for treating immune disorders and for regenerative medicine in agreement with their paracrine trophic and immunosuppressive activities. Various processes have been developed worldwide to produce clinical grade MSCs but, so far, it is not known if one given MSC is more efficient than another. In addition, while their broad activity on innate and adaptative immune cell subsets is now widely admitted, the precise mechanisms supporting their immunoregulatory capacities are still a matter of debate. Finally, quantitative immunological potency assays correlated to clinical efficacy and clinically relevant immunomonitoring approaches for MSC-treated patients are sorely needed. Multiple parameters could influence the immunomodulatory potential of therapeutic MSCs. The most important challenge is now to differentiate, within a high number of poorly comparable and even contradictory pre-clinical studies, the parameters that could have some clinical impact from those that are only due to uncontrolled experimental variability. Importantly, besides MSC-related differences, primarily linked to production processes, several important variables associated with immune assays themselves, including selection of effector immune cells, activation signals, and read-out techniques, should be carefully considered to obtain solid results with potential therapeutic application. In this review, we establish a core of common and reproducible immunological properties of MSCs, shed light on technical issues concerning immunomodulatory potential assessment, and put them into perspective when considering clinical application. PMID- 23742638 TI - Bioprobes based on AIE fluorogens. AB - Fluorescent bioprobes are powerful tools for analytical sensing and optical imaging, which allow direct visualization of biological analytes at the molecular level and offer useful insights into complex biological structures and processes. The sensing and imaging sensitivity of a bioprobe is determined by the brightness and contrast of its fluorescence before and after analyte binding. Emission from a fluorophore is often quenched at high concentration or in aggregate state, which is notoriously known as concentration quenching or aggregation-caused quenching (ACQ). The ACQ effect limits the label-to-analyte ratio and forces researchers to use very dilute solutions of fluorophores. It compels many probes to operate in a fluorescence "turn-off" mode with a narrow scope of practical applications. The unique aggregation-induced emission (AIE) process offers a straightforward solution to the ACQ problem. Typical AIE fluorogens are characterized by their propeller-shaped rotorlike structures, which undergo low frequency torsional motions as isolated molecules and emit very weakly in solutions. Their aggregates show strong fluorescence mainly due to the restriction of their intramolecular rotations in the aggregate state. This fascinating attribute of AIE fluorogens provides a new platform for the development of fluorescence light-up molecules and photostable nanoaggregates for specific analyte detection and imaging. In this Account, we review our recent AIE work to highlight the utility of AIE effect in the development of new fluorescent bioprobes, which allows the use of highly concentrated fluorogens for biosensing and imaging. The simple design and fluorescence turn-on feature of the molecular AIE bioprobes offer direct visualization of specific analytes and biological processes in aqueous media with higher sensitivity and better accuracy than traditional fluorescence turn-off probes. The AIE dot-based bioprobes with different formulations and surface functionalities show advanced features over quantum dots and small molecule dyes, such as large absorptivity, high luminosity, excellent biocompatibility, free of random blinking, and strong photobleaching resistance. These features enable cancer cell detection, long term cell tracing, and tumor imaging in a noninvasive and high contrast manner. Recent research has significantly expanded the scope of biological applications of AIE fluorogens and offers new strategies to fluorescent bioprobe design. We anticipate that future development on AIE bioprobes will combine one- or multiphoton fluorescence with other modalities (e.g., magnetic resonance imaging) or functionalities (e.g. therapy) to fully demonstrate their potential as a new generation of theranostic reagent. In parallel, the advances in molecular biology will provide more specific bioreceptors, which will enable the development of next generation AIE bioprobes with high selectivity and sensitivity for molecular sensing and imaging. PMID- 23742639 TI - Dissecting the pharmacophore of curcumin. Which structural element is critical for which action? AB - The dietary phenolic curcumin (1a) is the archetypal network pharmacological agent, but is characterized by an ill-defined pharmacophore. Nevertheless, structure-activity studies of 1a have mainly focused on a single biological end point and on a single structural element, the aliphatic bis-enoyl moiety. The comparative investigation of more than one end-point of curcumin and the modification of its aromatic region have been largely overlooked. To address these issues, we have investigated the effect of aromatic C-prenylation in the three archetypal structural types of curcuminoids, namely, curcumin itself (1a), its truncated analogue 2a (C5-curcumin), and (as the reduced isoamyl version) the tetrahydro derivative 3a, comparatively evaluating reactivity with thiols and activity in biochemical (inhibition of NF-kappaB, HIV-1-Tat transactivation, Nrf2 activation) and phenotypic (anti-HIV action) assays sensitive, to a various extent, to thia-Michael addition. Prenylation, a validated maneuver for bioactivity modulation in plant phenolics, had no effect on Michael reactivity, but was detrimental for all biological end-points investigated, dissecting thiol trapping from activity, while hydrogenation attenuated, but did not completely abrogate, the activity of 1a. The C5-curcuminoid 2a outperformed the natural product in all end-points investigated and was identified as a novel high-potency anti-HIV lead in a cellular model of HIV infection. Taken together, these observations show that Michael reactivity is a critical element of the curcumin pharmacophore, but also reveal a surprising sensitivity of bioactivity to C prenylation of the vanillyl moiety. PMID- 23742640 TI - Patient and provider perspectives on cellular phone-based technology to improve HIV treatment adherence. AB - Innovative techniques, potentially using technology, to improve adherence to antiretroviral therapy (ART) may help patients with HIV who struggle with self care. This qualitative study compared patient and provider participants' perspectives on ART adherence and text messaging as a tool to promote adherence. Thirteen providers and 14 HIV-infected patients identified four main themes: (1) facilitators, (2) barriers to using text message reminders as a medium for ART medication reminders, (3) framing of text message reminders, and (4) patient responsibility and autonomy in the management of their health and wellness. Ease of use, access, convenience, and confidentiality were cited as benefits of a text message-based adherence intervention; while access, cost, difficulty manipulating cellular phones, lack of knowledge/education, and confidentiality were cited as potential barriers. Providers, but not patients, also identified patient apathy and time burden as potential barriers to a text message-based adherence reminder system. Patients and providers felt that personalization of messages, attention to timing, and confidentiality of messages were key factors for a successful text message-based adherence reminder system. Both providers and patients felt that patient responsibility and autonomy over an individual's own health care is an important issue in adherence to medical care. The majority of patients and providers felt that a text message-based adherence reminder system would be beneficial. While patients and providers had many similar views on factors influencing adherence with ART and the use of text messaging to improve adherence, there were some divergent views between the two groups. PMID- 23742641 TI - A comparison of epidural analgesia provided by bupivacaine alone, bupivacaine + morphine, or bupivacaine + dexmedetomidine for pelvic orthopedic surgery in dogs. AB - OBJECTIVE: To compare the analgesic efficacy of bupivacaine, bupivacaine + morphine, or bupivacaine + dexmedetomidine administered epidurally in dogs undergoing pelvic limb orthopedic surgery. STUDY DESIGN: Prospective, randomized, double blinded clinical trial. ANIMALS: Sixty dogs weighing (mean +/- SD) 35 +/- 15.7 kg, aged 5 +/- 3 years. METHODS: Dogs were assigned to receive a lumbosacral epidural containing bupivacaine (B) 0.5%, 1 mg kg(-1) ; B, bupivacaine 0.5%, 1 mg kg(-1) + morphine 1%, 0.1 mg kg(-1) ; B + M, or bupivacaine 0.5%, 1 mg kg(-1) + dexmedetomidine 0.05%, 4 MUg kg(-1) ; B + D. The anesthetic protocol was standardized. The median expired isoflurane concentration (E'Iso) and requirement for additional induction agent preventing purposeful movement were recorded. Pain was scored using visual analog (VAS) and modified University of Melbourne (UMPS) pain scales. Sedation was assessed using a 0-4 scale. All parameters were recorded preoperatively, and at extubation (t = 0), then at 1, 2, 4, 8, 12, 16, and 20-24 hours. Hydromorphone was administered postoperatively to patients with a VAS >= 35 and/or UMPS >= 9. Time to first voluntary urination and first motor activity were recorded. RESULTS: Postoperatively, B + D had a lower UMPS pain score than B at t = 1 hour (p = 0.013), but not compared to B + M. The B + D group had a shorter time to urination (p = 0.0131) and a longer time for return of motor function (p = 0.0068). There were no other differences between the treatments. CONCLUSION AND CLINICAL RELEVANCE: Epidurally administered B, B + M, or B + D in dogs all provided acceptable analgesia to manage post-operative orthopedic pelvic limb pain. Epidural administration of B + D is an effective alternative to the analgesia provided by B or B + M, but is associated with increased time to return of motor function. The direct neurotoxic effects of epidural dexmedetomidine have not been fully tested. PMID- 23742642 TI - Contribution of condensed tannins and mimosine to the methane mitigation caused by feeding Leucaena leucocephala. AB - Leucaena (Leucaena leucocephala), a leguminous shrub promising to cope with feed scarcity in the tropics, may help in mitigating ruminal methane (CH4) emission in the tropics as well. Two experiments were conducted to evaluate the effect of Leucaena and major secondary compounds of this plant in ruminants. At first, effects of Leucaena tannins and mimosine on ruminal CH4 and nutrient degradability were tested in vitro. Incubations were made with Leucaena without or with polyethylene glycol (PEG) to exclude the tannins effects, as well as with Bermuda grass (Tifton) and lucerne hays, both either untreated or supplemented with mimosine at the same concentration that has been provided by the tested Leucaena (6.52 mg/g DM). Furthermore, in an in vivo experiment a control diet (per kg DM 700 g Tifton hay) and Leucaena diets (per kg DM 350 g Tifton hay and 350 g Leucaena), either with or without 20 g PEG/d per head, were evaluated in six Santa Ines sheep following a double Latin square design. In vitro, Leucaena resulted in the lowest (p < 0.05) gas and CH4 production and the highest (p < 0.05) partitioning factor, a measure for microbial efficiency, whereas the amount of truly degraded organic matter (TDOM) was lowest (p < 0.05) with Tifton among the experimental forage plants. Mimosine addition to lucerne and Tifton as well as PEG addition to Leucaena had no effect on ruminal CH4 and TDOM. In vivo Leucaena, compared to the Tifton diet, enhanced (p < 0.05) intake, faecal nitrogen excretion, body nitrogen retention and the excretion of urinary purine derivatives as an indicator for microbial protein synthesis and availability. This was independent of PEG addition. Leucaena also decreased (p < 0.001) CH4 emission per unit of digested organic matter by 14.1% and 10.8%, without and with PEG, respectively. No significant diet differences were observed in total-tract nutrient digestibility. The study demonstrated efficiency of Leucaena to mitigate in vivo methane emission of sheep, but did not reveal which constituent of Leucaena was primarily responsible for that since no clear efficiency of either tannins or mimosine could be demonstrated. PMID- 23742643 TI - Effects of niacin supplementation and dietary concentrate proportion on body temperature, ruminal pH and milk performance of primiparous dairy cows. AB - The objective of this study was to investigate the effects of niacin and dietary concentrate proportion on body temperature, ruminal pH and milk production of dairy cows. In a 2 * 2 factorial design, 20 primiparous Holstein cows (179 +/- 12 days in milk) were assigned to four dietary treatments aimed to receive either 0 or 24 g niacin and 30% (low) or 60% (high) concentrate with the rest being a partial mixed ration (PMR) composed of 60% corn and 40% grass silage (on dry matter basis). Ambient temperature and relative humidity were determined and combined by the calculation of temperature humidity index. Respiration rates, rectal, skin and subcutaneous temperatures were measured. Milk production and composition were determined. Ruminal pH and temperature were recorded at a frequency of 5 min using wireless devices for continuous intra-ruminal measurement (boluses). pH values were corrected for pH sensor drift. The climatic conditions varied considerably but temporarily indicated mild heat stress. Niacin did not affect skin, rectal and subcutaneous temperatures but tended to increase respiration rates. High concentrate reduced skin temperatures at rump, thigh and neck by 0.1-0.3 degrees C. Due to the technical disturbances, not all bolus data could be subjected to statistical evaluation. However, both niacin and high concentrate influenced mean ruminal pH. High concentrate increased the time spent with a pH below 5.6 and ruminal temperatures (0.2-0.3 degrees C). Niacin and high concentrate enhanced milk, protein and lactose yield but reduced milk fat and protein content. Milk fat yield was slightly reduced by high concentrate but increased due to niacin supplementation. In conclusion, niacin did not affect body temperature but stimulated milk performance. High concentrate partially influenced body temperatures and had beneficial effects on milk production. PMID- 23742644 TI - Influence of partial replacement of soya bean meal by faba beans or peas in heavy pigs diet on meat quality, residual anti-nutritional factors and phytoestrogen content. AB - The study evaluated the partial substitution of soybean meal by faba beans (18%) or peas (20%) as additional protein sources in diets destined for typical Italian heavy pig production. It compared animal performances, meat quality, the presence of residual anti-nutritional factors (ANF) and phytoestrogens in plasma and meat and the possible effects on pig health, by evaluating oxidative, inflammatory and pro-atherogenic markers. The results showed that the productive performances, expressed as body weight and feed conversion ratio, of pigs fed with faba bean and pea diets were similar to those of pigs fed only the soybean meal. Meat quality of pigs fed with the three diets was similar in colour, water-holding capacity, tenderness and chemical composition. Despite the higher levels of phytoestrogen in the plasma of pigs fed only the soybean meal, phytoestrogen concentration in the muscle was equivalent to that of animals fed diets with faba beans, whereas pigs fed a diet with peas showed a lower concentration. Inflammation and pro-atherogenic parameters did not show significant differences among the three diets. Overall, the partial substitution of soybean meal by faba beans appears more interesting than with peas, particularly in relation to the higher amount of polyphenols in the diet and the highest concentration of phytoestrogens found in the plasma and muscle of animals, while the pyrimidine anti-nutritional compounds present in the diet did not appear to accumulate and had no effect on the growth performance of animals. PMID- 23742645 TI - Performance, organ zinc concentration, jejunal brush border membrane enzyme activities and mRNA expression in piglets fed with different levels of dietary zinc. AB - This study aimed at investigating the effect of dietary zinc on performance, jejunal brush border membrane enzyme activities and mRNA levels of enzymes and two zinc transporters in piglets. A total of 126 piglets were weaned at 26 +/-1 days of age and randomly allocated into three groups fed with diets 50, 150 and 2500 mg zinc/kg. Performance was recorded and at weekly intervals, eight piglets per group were killed. The activities of isolated brush border membrane enzymes including lactase, maltase, sucrase, aminopeptidase-N and intestinal alkaline phosphatase (IAP), and the relative transcript abundance of aminopeptidase-N (APN), sucrase-isomaltase (SUC), IAP and the two zinc transporters SLC39A4 (ZIP4) and SLC30A1 (ZnT1) were investigated in the jejunum. Feeding pharmacological zinc levels increased weight gain (p < 0.001) during the first week, but performance was lower (p < 0.05) in the third week. Organ zinc concentrations were increased by high dietary zinc level. The activity of IAP was higher (p < 0.05) with the highest dietary zinc level, no effects were determined for other enzymes. Dietary zinc level had no effect on transcript abundance of digestive enzymes. The mRNA levels decreased (p < 0.001) for ZIP4, and increased for ZnT1 (p < 0.05) with pharmacological zinc levels. In conclusion, pharmacological zinc levels improved performance in the short-term. Intestinal mRNA level of zinc transporters changed with high zinc supply, but this did not prevent zinc accumulation in tissues, suggesting hampered homoeostatic regulation. This might cause impaired performance during longer supply. PMID- 23742646 TI - Critical roles for Akt kinase in controlling HIV envelope-mediated depletion of CD4 T cells. AB - BACKGROUND: The cell surface receptors CD4 and CCR5 bind CCR5-tropic HIV Envelope (Env) glycoprotein during virus attachment. These same receptors have signaling activities related to normal immune cell functions. We also know that Env binds to CCR5 present at high levels on CD4-negative gammadelta T cells where it signals through p38 MAP kinase to activate caspases and Fas-independent cell death. Here, we asked whether Env signaling through cellular receptors is responsible for death among uninfected CD4+/CCR5+ T cells and what are the effects of Env on CD4+/CCR5-negative cells that might impact HIV infection. The outcomes of Env binding are analyzed in terms of signal transduction and the effects on cell activation or cell death pathways. RESULTS: Env binding to CD4 signals through Erk and Akt kinases. Activation of Erk/Akt suppresses p38 due to CCR5 binding, and allows cell survival. When CD4 signaling was blocked by soluble CD4 or protein kinase inhibitors, p38 activation and Fas-independent cell death were increased among uninfected CD4+ CCR5+ T cells. We also noted specific effects of CD4 signaling on CCR5-negative CD4 T cells in tonsil lymphocyte cultures. Exposure to CCR5-tropic HIV Env (BaL strain) increased expression of CXCR5, PD-1, Fas and FasL. Among CD4+/CCR5- T cells expressing high levels of CXCR5 and PD-1, there were substantial amounts of Fas-dependent cell death. Increased CXCR5 and PD-1 expression was blocked by soluble CD4 or specific inhibitors of the Akt kinase, showing a direct relationship between CD4 signaling, T cell activation and Fas-dependent cell death. CONCLUSIONS: Specific inhibition of Akt activation increased Env-dependent cell death of CCR5+ CD4 T cells. The same inhibitor, antibodies blocking the CD4 binding site on gp120, or soluble CD4 also prevented the increase in expression of CXCR5 or PD-1, and reduced the levels of Fas-dependent cell death. The Akt kinase and related signaling events, are key to cell survival that is needed for productive infection, and may be targets for the development of antivirals. Specific inhibitors of Akt would decrease productive infection, by favoring cell death during virus attachment to CD4+ CCR5+ target cells, and reduce immune activation to prevent Fas-dependent death of uninfected CXCR5+ PD-1+ CD4 T cells including T follicular helper cells that share this phenotype. PMID- 23742647 TI - Cytotoxic withanolides from the leaves of Moroccan Withania frutescens. AB - CONTEXT: Withania species are a rich source of interesting phytochemical substances (withanolides) which have shown several biological properties. OBJECTIVE: To investigate the cytotoxic potential of Withania frutescens (L.) Pauquy (Solanaceae) leaf extracts and isolated active compounds against cultured tumor cell lines. MATERIALS AND METHODS: The crude methanol extract of W. frutescens leaves was partitioned with dichloromethane, ethyl acetate and n butanol. MeOH extract and its fractions were tested for their cytotoxic activity against cancer cell lines (HepG2 and HT29) using the MTT [3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyltetrazolium bromide] assay. Bioassay-guided fractionation was performed for the active CH2Cl2 fraction employing column chromatography and preparative high-performance liquid chromatography. Structural elucidation of the isolated active compounds was carried out mainly by 1D and 2D NMR and mass spectrometry. The compounds were then tested for their cytotoxic activity. RESULTS: The CH2Cl2 fraction was the most active against HT29 cell line. The fractionation procedure resulted in the isolation of 4beta,17alpha,27-trihydroxy 1-oxo-22-R-witha-2,5,24-trienolide (1), 5beta,6beta-epoxy-4beta,17alpha,27 trihydroxy-1-oxowitha-2,24-dienolide (2) and 2,3-dihydroxywithaferin A-3beta-O sulfate (3). The latter exhibited the strongest cytotoxic activity against HT29 cancer cell lines (IC50 of 1.78 +/- 0.09 uM) which was comparable to that of 5 fluorouracil (5-FU) used as the positive antimitotic control. DISCUSSION AND CONCLUSION: Compounds 2 and 3 were isolated from W. frutescens for the first time. Data obtained suggest that the sulfated steroidal lactone (3) can be considered as a compound with potential application in the new anticancer drugs development field. PMID- 23742648 TI - Laminin adsorption on nanostructures: switching the molecular orientation by local curvature changes. AB - This work addresses the influence that the nanometric features of biologically relevant surfaces have on the conformation and properties of adsorbed laminin. It was observed that the adsorption kinetics and the nanomorphology of laminin were affected by the change in local curvature of chemically homogeneous nanostructured surfaces. The nanostructured surfaces were prepared by exploiting the self-assembly process of carboxylated polystyrene NPs, with diameters of 45, 109, and 209 nm, onto a polyelectrolyte multilayer formed by alternate deposition of poly(acrylic acid) and poly(allylamine hydrochloride) on gold. The anchored polymeric NPs were finally coated with a homogeneous layer of poly(allylamine hydrochloride), providing three surfaces with different nanometric local curvature. Atomic force microscopy was employed to characterize the relevant morphological parameters of the nanostructured surfaces. Quartz crystal microbalance with dissipation monitoring was employed to determine the adsorbed mass of laminin as well as its adsorption rate as a function of the local surface curvature. A model is proposed to explain the higher and faster laminin adsorption on surfaces with lower local curvature, where a switching of laminin anchoring orientation from a side-on to an end-on geometry can be predicted by a simple curvature-dependent parameter, gamma, connecting the average nanostructure height h and the macromolecule radius of gyration R(g). The results provide a framework to understand the dependence of biomolecule orientation on local nanostructure. PMID- 23742649 TI - Early aggressive macrovascular disease and type 1 diabetes mellitus without chronic complications: a case report. AB - BACKGROUND: Type 1 diabetes (T1DM) is considered to be one of the most significant risk factors for the development of coronary artery disease (CAD). However, the specific risk predictor models for T1DM are subject to many limitations. CASE PRESENTATION: We report the case of a 42-year-old Caucasian woman presenting with T1DM for 26 years. During her chronic hyperglycemic evolution (mean of HbA1c > 3 percentage points above the superior limit) without microvascular complications, this patient presented with early and aggressive coronary artery disease, despite the lack of classical risk factors for CAD CONCLUSIONS: The rapidly progressive macrovascular disease observed in this case demonstrates the different degrees of aggressiveness and unpredictable clinical evolution observed in some cases. It also confirms the need for a multi factorial, early and optimized clinical management regime. PMID- 23742650 TI - Short-term cognitive-behavioral treatment in multicultural primary care of patients with longstanding backache. AB - The efficacy of cognitive-behavioral therapy in multi-cultural primary care patients with longstanding backache is not evaluated. The purpose of this study was to investigate the outcome of a four weekly-treatment given by primary care physicians regarding pain-related worry, depression and severe pain and to determine which social, clinical or gender factors were associated with outcome.The study group consisted of 245 patients in consecutive order from 19 countries, 18 to 45 years, entering rehabilitation program because of longstanding backache. Prevalences of pain-related worry and depression and severe pain was counted and compared before and after. Logistic regression was used to calculate the odds (OR; 95% CI) for persistent pain-related worry and/or persistent depression and severe pain (VAS >= 50). The prevalences of pain related worry and depression were both significantly lower after treatment (pain related worry 83% before vs. 38% after; depression 43% before vs. 31% after). Also the number of patients scoring >= 50 VAS was a little, but significantly, fewer (68% vs. 61%). Use of interpreter doubled the risk of having persistent pain-related worry (OR 2.1; 95% CI 1.1-4.1) but the risk was not significant regarding persistent depression (OR 1.8; 0.6-5.4). The rating of VAS rating >= 50 after treatment was twice as high, OR 2.3 (95% CI 1.1-4.6) in the 38-45 year old age group. To conclude, a focus on pain ideas reduced pain-related worry and depression in these patients with various sociocultural backgrounds and longstanding backache. PMID- 23742652 TI - C-Kit SCF receptor (CD117) expression and KIT gene mutation in conjunctival pigmented lesions. AB - PURPOSE: To investigate the presence of KIT gene mutations and immunoreactivity in 85 conjunctival melanocytic tumours and to clarify the role of KIT as a potential therapeutic target in this group of patients. METHODS: Eighty-five conjunctival pigmented tumours [27 melanomas, 12 primary acquired melanosis (PAMs) and 46 nevi] were immunostained for KIT. Intensity and pattern of expression were evaluated. Molecular analysis to identify KIT mutations was performed in 15 selected cases (tumour-rich areas >50%). KIT immunostaining score and pattern were statistically related to patients' age, sex, diagnostic category, presence of relapse, disease-free survival, presence of metastases, metastasis-free survival, limbal versus nonlimbal tumour location and thickness of melanomas. RESULTS: KIT stains were documented in 48% of melanomas, 50% of PAMs and 24% of nevi. The mean score of KIT staining in the melanomas/PAMs group was significantly different from nevi (p = 0.0076). No statistically significant differences were detected between either c-kit immunostaining score or pattern and each of the other clinico-pathologic parameters considered. No KIT gene mutations were detected in melanomas and nevi. A silent mutation/polymorphism in KIT exon 13 was found in one PAM. CONCLUSIONS: Despite the high level of KIT immunostains in PAMs and melanomas, this parameter seems not to be a good predictor of the presence of molecular mutations. KIT-activating mutations should be considered an uncommon event in this tumour. PMID- 23742651 TI - The sepsis model: an emerging hypothesis for the lethality of inhalation anthrax. AB - Inhalation anthrax is often described as a toxin-mediated disease. However, the toxaemia model does not account for the high mortality of inhalation anthrax relative to other forms of the disease or for the pathology present in inhalation anthrax. Patients with inhalation anthrax consistently show extreme bacteraemia and, in contrast to animals challenged with toxin, signs of sepsis. Rather than toxaemia, we propose that death in inhalation anthrax results from an overwhelming bacteraemia that leads to severe sepsis. According to our model, the central role of anthrax toxin is to permit the vegetative bacteria to escape immune detection. Other forms of B. anthracis infection have lower mortality because their overt symptoms early in the course of disease cause patients to seek medical care at a time when the infection and its sequelae can still be reversed by antibiotics. Thus, the sepsis model explains key features of inhalation anthrax and may offer a more complete understanding of disease pathology for researchers as well as those involved in the care of patients. PMID- 23742653 TI - Characterization of phenol and alkyl phenols in organic matrixes with monoethylene glycol extraction and multidimensional gas chromatography/mass spectrometry. AB - The use of monoethylene glycol as an extraction medium for removing phenol and alkyl phenols in organic matrixes such as hydrocarbons is introduced and combined with a practical analytical multidimensional gas chromatography approach. The analytical approach has been successfully developed for the characterization of phenol, cresols, xylenols, and alkyl phenols like 4-ethylphenol and 2,3,5 trimethylphenol. The technique employs a single-step extraction of the analytes with monoethylene glycol and sonication, followed by multidimensional gas chromatography with mass spectrometry in selected ion monitoring mode for the detection and quantitation. Extraction efficiency of phenol approached 100% while cresols, xylenols, and 4-ethylphenol were 97% or higher and 2,3,5-trimethylphenol was better than 91% under the analytical conditions used. With the technique described, a complete analysis can be conducted in less than 16 min. Reproducibility of area counts at two levels, namely, 5 ppm(w) and 50 ppm(w) over a period of 2 days were found to be less than 4% (n = 20). The analytes of interest was found to be linear over a range from 100 ppb(w) to 250 ppm(w) with correlation coefficient of at least 0.999 and detection limit of 50 ppb(w) . Spike recoveries from 500 ppb(w) to 250 ppm(w) for all analytes range from 96 to 102%. PMID- 23742654 TI - HIV type 1 subtype C remains the predominant subtype in men having sex with men in Senegal. AB - HIV-1 epidemics are expanding among men who have sex with men in low- and middle income countries. To confirm and further explore preliminary data in Senegal, we aimed to determine 3 years after a first study the HIV-1 genetic diversity in three different viral regions. From 109 samples available in 2007, 93 were sequenced in gag, 77 in env, and 60 in pol. Phylogenetic analysis showed that subtype C predominated (38-52%), followed by CRF02_AG (30-40%), subtype B (13 17%), and CRF09_cpx (2.6-5%). Subsubtype A3 and strains tightly linked to CRF43_02G were identified in env and gag, respectively, and 12% of the samples were unique recombinants. Six transmission chains involving two to seven individuals were identified. Some strains carried resistance mutations inside transmission chains. This study confirmed the existence of a dual epidemic in Senegal and emphasized the need to strengthen prevention programs to avoid strains intermixing between low-risk women and high-risk men. PMID- 23742655 TI - Water permeation through a charged channel. AB - Transport properties of water molecules through hydrophobic channels have been explored extensively in recent years; however, our knowledge about the transport properties of hydrophilic channels is still rather poor. Herein, we use molecular dynamics simulations to study the permeation of water molecules through a charged channel. For comparison, we first consider the pristine hydrophobic channel without charge, and we find an analytic expression that can predict the water flow through it. For uniformly charged channels, with the increase of charge density, the water flow decreases, due to the increase of roughness in the free energy profile experienced by a water molecule along the channel; while the ion flow exhibits a maximum, because of the competition between the increasing ion number and ion-channel attraction. Surprisingly, the water occupancy for positive and negative channels varies in the opposite direction, which is strongly related to the excluded volume effect of ions. Additionally, we also discuss the effect of surface charge patterns and channel sizes. These results not only enrich our understanding of the transport properties of hydrophilic channels, but also have deep implications for the design of nanometer water gates. PMID- 23742657 TI - Equine developmental orthopaedic diseases--a genome-wide association study of first phalanx plantar osteochondral fragments in Standardbred trotters. AB - Palmar/plantar osteochondral fragments (POF) in fetlock joints commonly affect and influence the athletic performance of horses. In this study, we used the Equine SNP50 BeadChip(r) to perform a genome-wide association study of metatarsophalangeal POF in 176 Norwegian Standardbred trotter yearlings. Putative quantitative trait loci (QTL) for medial and/or lateral POF, and medial POF only were identified on ECA1, 2, 7, 9 and 31, whereas for lateral POF, only on ECA7, 11, 27 and X. The moderate number of QTL evidences a complex inheritance and suggests various genes controlling POF development in medial and lateral locations. PMID- 23742656 TI - Transcriptional adaptation of pneumococci and human pharyngeal cells in the presence of a virus infection. AB - BACKGROUND: Viral upper respiratory tract infections are associated with increased colonization by Streptococcus pneumoniae but the mechanisms underlying this relationship are unclear. The objective of this study is to describe a comprehensive picture of the cellular interaction between the adhering bacteria and host cells in the presence or absence of a viral co-infection. RESULTS: Gene expression profiles of Detroit-562 pharyngeal cells, which were either mock infected or infected with human respiratory syncytial virus (RSV) or human parainfluenza virus 3 (HPIV3), were analyzed using human microarrays. Transcription response of S. pneumoniae strain TIGR4 (serotype 4) in the presence of either mock- or viral-infected cells was analyzed by pneumococcal microarray. Significantly regulated genes were identified by both significance analysis of microarray (SAM) and a >= 2-fold change ratio cut-off. The adherence of S. pneumoniae to human pharyngeal cells was significantly augmented in the presence of RSV or HPIV3 infection. Global gene expression profiling of the host cells during infection with RSV or HPIV3 revealed increased transcription of carcinoembryonic antigen-related cell adhesion molecules (CEACAM1), CD47, fibronectin, interferon-stimulated genes and many other host cell adhesion molecules. Pneumococci increased transcription of several genes involved in adhesive functions (psaA, pilus islet), choline uptake and incorporation (lic operon), as well as transport and binding. CONCLUSIONS: We have identified a core transcriptome that represents the basic machinery required for adherence of pneumococci to D562 cells infected or not infected with a virus. These bacterial genes and cell adhesion molecules can potentially be used to control pneumococcal adherence occurring secondary to a viral infection. PMID- 23742658 TI - Coronary flow reserve and myocardial performance index in newly diagnosed diabetic patients. AB - BACKGROUND: Patients with diabetes mellitus (DM) are at high risk of left ventricular (LV) dysfunction. A reduction of coronary flow reserve (CFR) has been demonstrated in diabetic patients without coronary artery stenosis. In this study, we investigated the association between LV myocardial diastolic and systolic functions and the CFR in newly diagnosed diabetic patients in the absence of coronary artery disease. METHOD: We studied 88 patients (mean age 49 +/- 10 years) with newly diagnosed DM and 40 healthy control subjects (mean age 50 +/- 9 years). All subjects underwent transthoracic echocardiography. The myocardial performance index (MPI) was determined by using pulsed-wave Doppler. The CFR was calculated as the hyperemic to resting coronary diastolic peak velocities ratio. RESULTS: Patients with diabetes had significantly longer mitral E-wave deceleration time and higher MPI value than control group (P = 0.023 and P < 0.001, respectively). The mean CFR was lower in diabetic patients compared with controls (P = 0.001). The MPI was significantly correlated with CFR (r = -0.371, P < 0.001), LV ejection fraction (r = -0.274, P = 0.018) E/A ratio (r = -0.244, P = 0.024), and glycosylated hemoglobin (HbA1c) (r = 0.476, P < 0.001). Multivariate regression analysis showed that MPI was independently associated with CFR (beta = -0.292, P < 0.0001) and HbA1c level (beta = 0.372, P < 0.0001). CONCLUSIONS: The MPI was independently associated with CFR in newly diagnosed diabetic patients. The decrease in CFR may cause LV systolic and diastolic dysfunction in asymptomatic diabetic patients. PMID- 23742659 TI - The effects of increased dietary protein yogurt snack in the afternoon on appetite control and eating initiation in healthy women. AB - BACKGROUND: A large portion of daily intake comes from snacking. One of the increasingly common, healthier snacks includes Greek-style yogurt, which is typically higher in protein than regular yogurt. This study evaluated whether a 160 kcal higher-protein (HP) Greek-style yogurt snack improves appetite control, satiety, and delays subsequent eating compared to an isocaloric normal protein (NP) regular yogurt in healthy women. This study also identified the factors that predict the onset of eating. FINDINGS: Thirty-two healthy women (age: 27 +/- 2y; BMI: 23.0 +/- 0.4 kg/m2) completed the acute, randomized crossover-design study. On separate days, participants came to our facility to consume a standardized lunch followed by the consumption of the NP (5.0 g protein) or HP (14.0 g protein) yogurt at 3 h post-lunch. Perceived hunger and fullness were assessed throughout the afternoon until dinner was voluntarily requested; ad libitum dinner was then provided. Snacking led to reductions in hunger and increases in fullness. No differences in post-snack perceived hunger or fullness were observed between the NP and HP yogurt snacks. Dinner was voluntarily requested at approximately 2:40 +/- 0:05 h post-snack with no differences between the HP vs. NP yogurts. Ad libitum dinner intake was not different between the snacks (NP: 686 +/- 33 kcal vs. HP: 709 +/- 34 kcal; p = 0.324). In identifying key factors that predict eating initiation, perceived hunger, fullness, and habitual dinner time accounted for 30% of the variability of time to dinner request (r = 0.55; p < 0.001). CONCLUSIONS: The additional 9 g of protein contained in the high protein Greek yogurt was insufficient to elicit protein-related improvements in markers of energy intake regulation. PMID- 23742660 TI - Viral load and humoral immune response in association with disease severity in Puumala hantavirus-infected patients--implications for treatment. AB - Hantaviruses are the causative agents of haemorrhagic fever with renal syndrome (HFRS) in Eurasia and of hantavirus cardiopulmonary syndrome (HCPS) in the Americas. The case fatality rate varies between different hantaviruses and can be up to 40%. At present, there is no specific treatment available. The hantavirus pathogenesis is not well understood, but most likely, both virus-mediated and host-mediated mechanisms are involved. The aim of the present study was to investigate the association among Puumala hantavirus (PUUV) viral RNA load, humoral immune response and disease severity in patients with HFRS. We performed a study of 105 PUUV-infected patients that were followed during the acute phase of disease and for up to 1-3 months later. Fifteen of the 105 patients (14%) were classified as having moderate/severe disease. A low PUUV-specific IgG response (p <0.05) and also a higher white blood cell count (p <0.001) were significantly associated with more severe disease. The PUUV RNA was detected in a majority of patient plasma samples up to 9 days after disease onset; however, PUUV RNA load or longevity of viraemia were not significantly associated with disease severity. We conclude that a low specific IgG response was associated with disease severity in patients with HFRS, whereas PUUV RNA load did not seem to affect the severity of HFRS. Our results raise the possibility of passive immunotherapy as a useful treatment for hantavirus-infected patients. PMID- 23742662 TI - Thermal effects on surface structures and properties of Bacillus anthracis spores on nanometer scales. AB - Bacterial spores, one of the hardiest forms of life known, can survive severe environmental stresses such as high temperature. Using thermal atomic force microscopy (AFM), we show that the surface structures and properties of Bacillus anthracis spores when exposed to elevated temperatures undergo substantial changes on nanometer scales. Thermal-blister-like nanostructures, which grow in size with increasing temperature, are formed on the spore surface when it is heated by a thermal tip. Although thermal damage to the spore surface is persistent upon cooling heat-treated spores to room temperature, thermal effects on surface properties of the spores are complex. The thermally induced nanostructures show a lower surface-tip adhesion and a higher modulus than the surrounding spore surface. The overall trend is for the adhesion to decrease with increasing temperature. However, the adhesion of heat-treated spores may be smaller than, equal to, or larger than that of untreated spores, depending upon the degree of surface damage induced by heat. Although the overall spore dimensions show few changes during and after heat treatment, the size of the spore substructures decreases significantly. In addition, we demonstrate a nanoscratch AFM method for imaging the subsurface structures of spores. PMID- 23742661 TI - Are children and adolescents with psychiatric illness at risk for increased future body weight? A systematic review. AB - The aim of this paper was to review the longitudinal relationship between early onset depression and disruptive behaviour and adult body weight. A systematic review of prospective longitudinal studies was conducted of articles in which (1) initial assessment occurred during childhood or adolescence (<18 y); and (2) the primary outcome reported as body mass index (BMI), overweight (BMI>25-<30 kg/m(2)), obesity (BMI >= 30 kg/m(2)), or depression; and (3) validated assessment measures for assessment of depressive symptoms or disruptive behaviour problems were employed. A total number of 16 articles were identified for review. Obese adolescent females are more likely to develop depressive illness in adulthood than their non-obese peers. Conversely, depressed adolescent females, and possibly males, are more likely to become overweight adults than non depressed adolescents. There are insufficient data addressing future depression risk among overweight, non-obese, adolescents to evaluate the potentially interactive nature of this relationship. Studies to date are consistent in reporting that children with behaviour problems are at increased risk of future overweight, though whether this risk is conferred by conduct symptoms, ADHD symptoms, or both, is less clear. Care providers of children with disruptive behaviour problems and depressed adolescents should monitor weight gain. Among obese adolescent females, mood should be followed. PMID- 23742663 TI - High levels of bisexual behavior and factors associated with bisexual behavior among men having sex with men (MSM) in Nigeria. AB - Nigerian men who have sex with men (MSM) have a high burden of HIV infection and are known to engage in bisexual behavior. This study presents the first data on characteristics and correlates of Nigerian men having sex with men and women (MSMW) in three Nigerian cities. Five hundred and fifty-seven MSM who engaged in anal sex with men completed a behavioral survey; 48.1% of these MSM also engaged in sex with women in the previous 2 months. MSMW displayed high levels of risky sexual behavior with female sex partners; casual (56.0%) and multiple female partners were common (69.0%) and 66.0% had unprotected vaginal sex. As much as 45.1% MSMW had anal sex with female partners of which 74.0% did not use protection in the 2 months prior. In bivariate analyses, bisexual behavior was associated (p<0.05) with being married or living with a women (OR 5.0, 95% CI = 2.6-9.4), less education (OR 2.0, 95% CI = 1.4-3.0), bisexual/straight identity (OR 2.3, 95% CI = 1.6-3.2), being an insertive partner (OR 3.0, 95% CI = 1.9 4.5), being HIV-negative (OR 1.6, 95% CI = 1.1-2.5), living in Lagos (OR 2.3, 95% CI = 1.7-2.2), being Muslim (OR 1.7, 95% CI = 1.1-2.5), and being away from home (OR 1.5, 95% CI = 1.0-2.1). In the multivariate model, being married to or living with a woman (AOR = 5.1; 95% CI = 2.5-10.3), bisexual/straight identity (AOR = 2.2; 95% CIs = 1.5-3.3), being an insertive partner (AOR = 3.0; 95% CI = 1.9 4.9), being away from home (AOR = 1.6; 95% CI = 1.1-2.3) and living in Lagos (AOR = 1.7; 95% CI = 1.0-2.8) remained significant (p< 0.05). High levels of bisexual behavior exist among Nigerian MSM, and these men engage in risky sexual behaviors with both male and female sex partners. While decriminalization of same-sex behavior in Nigeria will promote access to HIV prevention programs, current MSM interventions must incorporate information on safe sex with both male and female sex partners. PMID- 23742664 TI - Dry eye disease in French elderly subjects: the Alienor Study. AB - PURPOSE: To describe dry eye disease in French elderly subjects. METHODS: The Alienor Study is a population-based study on age-related eye disease in 963 residents of Bordeaux (France), aged 73 years or more. Self-reported dry eye disease and use of artificial tears were documented through face-to-face interview. Dry eye symptoms were assessed using the Ocular Surface Disease Index (OSDI) questionnaire and tear film stability by tear break-up time measurements (TBUT). Definite dry eye disease was defined as self-reported dry eye, confirmed by use of artificial tears and/or OSDI greater or equal to 22. RESULTS: Nine hundred and fifteen subjects, with mean age of 80 +/- 4 years, returned the OSDI questionnaire. Of these, 271 (29.6%) subjects reported a dry eye disease and 135 (14.7%) were using artificial tears. An OSDI score > 22 was found in 359 (39.2%) subjects and a TBUT < 5 seconds in 335/746 (44.9%) subjects. Overall, definite dry eye affected 21.9% of subjects and was more frequent in women (27.1%) than in men (13.6%). After multivariate adjustment, dry eye disease was also significantly less frequent in subjects with high educational level (odds ratio (OR) = 0.49, 95% confidence interval (CI): 0.31-0.78 for long secondary school) and more frequent in subjects with ocular hypertension (OR = 1.61, 95% CI: 1.02 2.57) and those using anxiolytics (OR = 1.53, 95% CI: 1.02-2.29). CONCLUSIONS: This large observational study confirmed the high prevalence of dry eye symptoms among elderly subjects and confirmed some of the previously identified risk factors (in particular female gender and use of anxiolytics). PMID- 23742665 TI - Djeen (Database for Joomla!'s Extensible Engine): a research information management system for flexible multi-technology project administration. AB - BACKGROUND: With the advance of post-genomic technologies, the need for tools to manage large scale data in biology becomes more pressing. This involves annotating and storing data securely, as well as granting permissions flexibly with several technologies (all array types, flow cytometry, proteomics) for collaborative work and data sharing. This task is not easily achieved with most systems available today. FINDINGS: We developed Djeen (Database for Joomla!'s Extensible Engine), a new Research Information Management System (RIMS) for collaborative projects. Djeen is a user-friendly application, designed to streamline data storage and annotation collaboratively. Its database model, kept simple, is compliant with most technologies and allows storing and managing of heterogeneous data with the same system. Advanced permissions are managed through different roles. Templates allow Minimum Information (MI) compliance. CONCLUSION: Djeen allows managing project associated with heterogeneous data types while enforcing annotation integrity and minimum information. Projects are managed within a hierarchy and user permissions are finely-grained for each project, user and group.Djeen Component source code (version 1.5.1) and installation documentation are available under CeCILL license from http://sourceforge.net/projects/djeen/files and supplementary material. PMID- 23742667 TI - Fine mapping of the chicken congenital loco locus on chromosome 12. AB - Congenital loco in chicks is characterized by an apparent lack of control of the muscles of the neck. This disorder is inherited as a simple Mendelian recessive disease, caused by an autosomal recessive gene, lo. To date, there are no reports on the localization of this gene. The objective of this study was therefore to identify the genomic region of the lo locus. The experimental congenital loco population used here were selected from a Rhode Island Red (RIR) line and consisted of six generations, resulting in 124 chickens. A total of 113 DNA samples from offspring of four generations (G3, G4, G5, and G6) were used for genotyping. At first, genome-wide linkage mapping was performed using 122 microsatellite markers on 22 autosomal chromosomes, and the lo locus was mapped to chromosome 12. We then performed fine mapping in two steps on chromosome 12. First, the lo locus was mapped to the interval between GGA12_5 and GGA12_11 using 13 new polymorphic markers. In the second step, fine mapping was performed by adding new families and 11 additional new polymorphic markers. Linkage mapping and haplotype information enabled the localization of the lo locus to a 1.1-Mb region between GGA12_28 and GGA12_30. Genetic markers between GGA12_28 and GGA12_30 may be used to remove the carriers of congenital loco through this RIR line. PMID- 23742666 TI - Randomized controlled trial of expressive writing for psychological and physical health: the moderating role of emotional expressivity. AB - The current study assessed main effects and moderators (including emotional expressiveness, emotional processing, and ambivalence over emotional expression) of the effects of expressive writing in a sample of healthy adults. Young adult participants (N=116) were randomly assigned to write for 20 minutes on four occasions about deepest thoughts and feelings regarding their most stressful/traumatic event in the past five years (expressive writing) or about a control topic (control). Dependent variables were indicators of anxiety, depression, and physical symptoms. No significant effects of writing condition were evident on anxiety, depressive symptoms, or physical symptoms. Emotional expressiveness emerged as a significant moderator of anxiety outcomes, however. Within the expressive writing group, participants high in expressiveness evidenced a significant reduction in anxiety at three-month follow-up, and participants low in expressiveness showed a significant increase in anxiety. Expressiveness did not predict change in anxiety in the control group. These findings on anxiety are consistent with the matching hypothesis, which suggests that matching a person's naturally elected coping approach with an assigned intervention is beneficial. These findings also suggest that expressive writing about a stressful event may be contraindicated for individuals who do not typically express emotions. PMID- 23742669 TI - Changes in implicit and explicit self-esteem following cognitive and psychodynamic therapy in social anxiety disorder. AB - The present investigation is the first to analyse changes in implicit and explicit self-esteem following cognitive therapy (CT) and psychodynamic therapy (PDT) in social anxiety disorder (SAD). We assessed a sub-sample of patients with SAD (n=27 per treatment group, n=12 waitlist condition) in the course of a randomized controlled trial prior to and following individual treatment or wait assessment with an Implicit Association Test and the Rosenberg Self-Esteem Scale. Both CT and PDT consisted of 25 sessions. Treatments were effective in enhancing implicit and explicit self-esteem. In CT and PDT, changes in explicit self-esteem were associated with SAD symptom change. No such relationships were found in implicit self-esteem. The results seem to indicate that both CT and PDT are effective in establishing a positive implicit and explicit self-esteem in SAD. The differential relationships of changes in implicit and explicit self-esteem to treatment effects on social phobic symptoms are discussed. PMID- 23742668 TI - Evaluation of electrical nerve stimulation for epidural catheter positioning in the dog. AB - OBJECTIVE: To evaluate the accuracy of epidural catheter placement at different levels of the spinal cord guided solely by electrical nerve stimulation and resultant segmental muscle contraction. STUDY DESIGN: Prospective, experiment. ANIMALS: Six male and two female Beagles, age (1 +/- 0.17 years) and weight (12.9 +/- 1.1 kg). METHODS: Animals were anesthetized with propofol and maintained with isoflurane. An insulated epidural needle was used to reach the lumbosacral epidural space. A Tsui epidural catheter was inserted and connected to a nerve stimulator (1.0 mA, 0.1 ms, 2 Hz) to assess positioning of the tip at specific spinal cord segments. The catheter was advanced to three different levels of the spinal cord: lumbar (L2-L5), thoracic (T5-T10) and cervical (C4-C6). Subcutaneous needles were previously placed at these spinal levels and the catheter was advanced to match the needle location, guided only by corresponding muscle contractions. Catheter position was verified by fluoroscopy. If catheter tip and needle were at the same vertebral body a score of zero was assigned. When catheter tip was cranial or caudal to the needle, positive or negative numbers, respectively, corresponding to the number of vertebrae between them, were assigned. The mean and standard deviation of the number of vertebrae between catheter tip and needle were calculated to assess accuracy. Results are given as mean +/- SD. RESULTS: The catheter position in relation to the needle was within 0.3 +/- 2.0 vertebral bodies. Positive predictive values (PPV) were 57%, 83% and 71% for lumbar, thoracic and cervical regions respectively. Overall PPV was 70%. No significant difference in PPV among regions was found. CONCLUSION AND CLINICAL RELEVANCE: Placement of an epidural catheter at specific spinal levels using electrical nerve stimulation was feasible without radiographic assistance in dogs. Two vertebral bodies difference from the target site may be clinically acceptable when performing segmental epidural regional anesthesia. PMID- 23742670 TI - Molecular characterization of unique intersubtype HIV type 1 A1/C recombinant strain circulating in Pune, India. AB - An increasing number of circulating recombinant forms (CRFs) and unique recombinant forms (URFs) all over the world has necessitated being vigilant about new recombinants. Since the first report of a recombinant virus with an A1/C mosaic in 1998 more and more B/C and A/C recombinant viruses are being reported from India. Here we report the identification and characterization of a unique HIV-1 A1/C recombinant circulating in Western India. Analysis of the full-length genome using RIP, SimPlot, and jpHMM@Gobics has confirmed its mosaic structure with insertion of subtype A1 in the backbone of subtype C at three positions: gag pol (1973+/-15-2617+/-47), pol-vif (4879+/-37-5582+/-32), and gp41 (8437+/-106 8811+/-8); however, RIP and SimPlot showed one more small insertion in integrase (4343-4519). Phylogenetic analysis confirmed that the recombinant virus has an insertion of clade A1 in the backbone of subtype C, which has come from Indian subtype C. PMID- 23742671 TI - Septic shock in older people: a prospective cohort study. AB - BACKGROUND: Septic shock is the first cause of death in Intensive Care Units. Despite experimental data showing increased inflammatory response of aged animals following infection, the current accepted hypothesis claims that aged patients are immunocompromised, when compared to young individuals. RESULTS: Here, we describe a prospective cohort study designed to analyze the immune profile of this population. CONCLUSION: Older people are as immunocompetent as the young individual, regarding the cytokines, chemokines and growth factors response to devastating infection. PMID- 23742672 TI - Nanoscale superstructures assembled by polymerase chain reaction (PCR): programmable construction, structural diversity, and emerging applications. AB - Polymerase chain reaction (PCR) is an essential tool in biotechnology laboratories and is becoming increasingly important in other areas of research. Extensive data obtained over the last 12 years has shown that the combination of PCR with nanoscale dispersions can resolve issues in the preparation DNA-based materials that include both inorganic and organic nanoscale components. Unlike conventional DNA hybridization and antibody-antigen complexes, PCR provides a new, effective assembly platform that both increases the yield of DNA-based nanomaterials and allows researchers to program and control assembly with predesigned parameters including those assisted and automated by computers. As a result, this method allows researchers to optimize to the combinatorial selection of the DNA strands for their nanoparticle conjugates. We have developed a PCR approach for producing various nanoscale assemblies including organic motifs such as small molecules, macromolecules, and inorganic building blocks, such as nanorods (NRs), metal, semiconductor, and magnetic nanoparticles (NPs). We start with a nanoscale primer and then modify that building block using the automated steps of PCR-based assembly including initialization, denaturation, annealing, extension, final elongation, and final hold. The intermediate steps of denaturation, annealing, and extension are cyclic, and we use computer control so that the assembled superstructures reach their predetermined complexity. The structures assembled using a small number of PCR cycles show a lower polydispersity than similar discrete structures obtained by direct hybridization between the nanoscale building blocks. Using different building blocks, we assembled the following structural motifs by PCR: (1) discrete nanostructures (NP dimers, NP multimers including trimers, pyramids, tetramers or hexamers, etc.), (2) branched NP superstructures and heterochains, (3) NP satellite-like superstructures, (4) Y-shaped nanostructures and DNA networks, (5) protein-DNA co assembly structures, and (6) DNA block copolymers including trimers and pentamers. These results affirm that this method can produce a variety of chemical structures and in yields that are tunable. Using PCR-based preparation of DNA-bridged nanostructures, we can program the assembly of the nanoscale blocks through the adjustment of the primer intensity on the assembled units, the number of PCR cycles, or both. The resulting structures are highly complex and diverse and have interesting dynamics and collective properties. Potential applications of these materials include chirooptical materials, probe fabrication, and environmental and biomedical sensors. PMID- 23742674 TI - Visual detection of copper(II) ions based on an anionic polythiophene derivative using click chemistry. AB - We have developed a novel approach for the rapid visual detection of Cu(2+) based on an anionic polythiophene derivative (sodium poly(2-(4-methyl-3 thienyloxy)propanesulfonate, PMTPS) using click chemistry. The method relies on the disassembly of PMTPS aggregates in the presence of cationic surfactant through electrostatic and hydrophobic interactions. In the assay of Cu(2+) detection, a cationic surfactant was formed via a click reaction catalyzed by copper(I), which was derived in situ from copper(II) and promoted the disassembly of PMTPS aggregates leading to the distinct solution color change from purple to yellow. This polymer probe has excellent sensitivity and selectivity for Cu(2+) with a detectable range in the micromolar regime by naked eyes and can be used for monitoring Cu(2+) concentrations below the safety limit in real-world samples. PMID- 23742673 TI - Association between a rare novel TP53 variant (rs78378222) and melanoma, squamous cell carcinoma of head and neck and lung cancer susceptibility in non-Hispanic Whites. AB - Recently, several studies have investigated the association between a newly reported rare functional single nucleotide polymorphism (SNP) in TP53 (rs78378222) and cancer risk, but generated inconsistent findings. The present study further investigated this association with risk of melanoma, squamous cell carcinoma of head and neck (SCCHN) and lung cancer. Using volunteers of non Hispanic Whites recruited for three large case-control studies, we genotyped the TP53 rs78378222 SNP in 1329 patients with melanoma, 1096 with SCCHN, 1013 with lung cancer and 3000 cancer-free controls. Overall, we did not observe any variant homozygotes in this study population, nor significant associations between the TP53 rs78378222AC genotype or C allele and risk for melanoma (P = 0.680 and 0.682 respectively) and lung cancer (P = 0.379 and 0.382 respectively), but a protection against SCCHN (P = 0.008 and 0.008 respectively), compared with the AA genotype or A allele. An additional meta-analysis including 19,423 cancer patients and 54,050 controls did not support such a risk association either. Our studies did not provide statistical evidence of an association between this rare TP53 variant and increased risk of melanoma, nor of lung cancer, but a possible protection against SCCHN. PMID- 23742675 TI - Non-volatile polymer electrolyte based on poly(propylene carbonate), ionic liquid, and lithium perchlorate for electrochromic devices. AB - A series of solvent-free ionic liquid (IL)-based polymer electrolytes composed of amorphous and biodegradable poly(propylene carbonate) (PPC) host, LiClO4, and 1 butyl-3-methylimidazolium tetrafluoroborate (BMIM(+)BF4(-)) were prepared and characterized for the first time. FTIR studies reveal that the interaction between PPC chains and imidazolium cations weakens the complexation between PPC chains and Li(+) ions. Thermal analysis (DSC and TGA) results show that the incorporation of BMIM(+)BF4(-) into PPC/LiClO4 remarkably decreases the glass transition temperature and improves the thermal stability of the electrolytes. AC impedance results show that the ionic conductivities of the electrolytes are significantly increased with the increase of BMIM(+)BF4(-) amount, the ambient ionic conductivity of the electrolyte at a PPC/LiClO4/BMIM(+)BF4(-) weight ratio of 1/0.2/3 is 1.5 mS/cm, and the ionic transport behavior follows the Arrhenius equation. Both PPC/LiClO4/BMIM(+)BF4(-) and PPC/BMIM(+)BF4(-) electrolytes were applied in electrochromic devices with polyaniline as the electrochromic layer. The PPC/LiClO4/BMIM(+)BF4(-)-based device exhibits much better electrochromic performance in terms of optical contrast and switching time due to the presence of much smaller cations. PMID- 23742676 TI - Evaluation of atrial electromechanical delay and diastolic functions in patients with hyperthyroidism. AB - AIM: Hyperthyroidism is a well-known cause of atrial fibrillation (AF) which is associated with increased morbidity and mortality. Atrial electromechanical delay (EMD) is a significant predictor of AF. The aim of this study was to assess the atrial EMD and diastolic functions in subclinical and overt hyperthyroidism by using tissue Doppler imaging (TDI). METHODS AND RESULTS: The study population consisted of 3 groups: group I (30 healthy subjects), group II (38 patients with subclinical hyperthyroidism), and group III (25 patients with overt hyperthyroidism). Atrial electromechanical coupling was measured with TDI. Standard echocardiographic measurements and parameters of diastolic function were obtained by conventional echocardiography and TDI. Intra- and inter-atrial EMD were significantly prolonged in subclinical and overt hyperthyroidism compared with control group (P = 0.03 and P < 0.001 for intra-atrial EMD; P < 0.001 for inter-atrial EMD). In groups II and III, mitral A velocity (P = 0.005 and P = 0.001) and mitral E-wave deceleration time (P < 0.001 and P = 0.02) were significantly increased, and mitral E/A ratio (P = 0.005 and P = 0.001) was significantly decreased compared with the control group. The lateral mitral Em /Am ratio in group II and group III was significantly lower than controls (P = 0.001). Mitral Em /Am ratio (beta = -0.32, P = 0.002) and thyroid stimulating hormone (TSH) level (beta = -0.27, P = 0.009) were negatively and independently correlated with inter-atrial EMD. CONCLUSION: This study showed that intra- and inter-atrial electromechanical intervals were prolonged and diastolic function was impaired in both overt and subclinical hyperthyroidism. TSH level and mitral Em /Am ratio were found as independent predictors of atrial EMD. PMID- 23742678 TI - Simplifying healthful choices: a qualitative study of a physical activity based nutrition label format. AB - BACKGROUND: This study used focus groups to pilot and evaluate a new nutrition label format and refine the label design. Physical activity equivalent labels present calorie information in terms of the amount of physical activity that would be required to expend the calories in a specified food item. METHODS: Three focus groups with a total of twenty participants discussed food choices and nutrition labeling. They provided information on comprehension, usability and acceptability of the label. A systematic coding process was used to apply descriptive codes to the data and to identify emerging themes and attitudes. RESULTS: Participants in all three groups were able to comprehend the label format. Discussion about label format focused on issues including gender of the depicted figure, physical fitness of the figure, preference for walking or running labels, and preference for information in miles or minutes. Feedback from earlier focus groups was used to refine the labels in an iterative process. CONCLUSIONS: In contrast to calorie labels, participants shown physical activity labels asked and answered, "How does this label apply to me?" This shift toward personalized understanding may indicate that physical activity labels offer an advantage over currently available nutrition labels. PMID- 23742679 TI - A comparative study on anticoagulant activities of three Chinese herbal medicines from the genus Panax and anticoagulant activities of ginsenosides Rg1 and Rg2. AB - CONTEXT: Chemical compositions of three herbal plants from the family Araliaceae genus Panax [Panax ginseng C. A. Mey, P. quinquefolius L. and P. notoginseng (Burk.) F. H. Chen] are quite similar; however, their medicinal natures vary greatly. The reason for differences has been explained in traditional Chinese medicine theory and partially verified by modern pharmacological investigations, such as antiplatelet aggregation. Aside from platelet aggregation, a variety of plasma coagulation factors are also involved in blood coagulation. The anticoagulation profiles of three herbs have not been investigated. OBJECTIVE: The current research compared the inhibitory effects of three herbal extracts from Panax spp. and the purified ginsenosides from P. ginseng on blood coagulation. MATERIALS AND METHODS: Human plasma was mixed with the water extracts (0.05 and 0.1 mg/mL) from roots of P. ginseng, P. quinquefolius and P. notoginseng and ginsenosides Rg1 and Rg2 (0.05 and 0.1 mg/mL), the blood clotting time of activated partial thromboplastin, prothrombin and thrombin were measured by a biochemical analyzer. RESULTS: The water extracts (0.05 mg/mL) of P. ginseng, P. quinquefolius and P. notoginseng could significantly extend blood clotting time as compared to the control group. Among three herbal medicines, 0.05 mg/mL of water extract from P. ginseng exhibited the strongest anticoagulation effects, followed by P. notoginseng, while P. quinquefolius presented the weakest effects. Both ginsenosides Rg1 and Rg2 could significantly extend blood clotting time in all three tests; ginsenoside Rg2 exhibited relative stronger anticoagulation effects as compared to ginsenoside Rg1. DISCUSSION AND CONCLUSION: Among three herbs tested, P. ginseng as well as its active component ginsenoside Rg2 shows the strongest anticoagulation activity; current results indicate that P. ginseng and ginsenoside Rg2 have great potential to be an anticoagulation drug. PMID- 23742680 TI - Supercritical carbon dioxide extraction of fucoxanthin from Undaria pinnatifida. AB - Undaria pinnatifida, commonly known as wakame in Japan, is one species of brown seaweeds containing valuable bioactive organic compounds such as fucoxanthin, a carotenoid, which has numerous functional properties. However, most of the seaweeds that do not meet strict quality standards are normally discarded as wastes or returned to the sea, a situation which is becoming an environmental concern. In this research, supercritical carbon dioxide (SCCO2) extraction was investigated for the isolation of fucoxanthin. SCCO2 extraction experiments were carried out at temperature range of 25-60 degrees C and pressure range of 20-40 MPa, at a carbon dioxide flow rate of 1.0-4.0 mL/min. Results showed that fucoxanthin recovery closed to 80% could be obtained at 40 degrees C and 40 MPa in extraction time of 180 min. The recovery increased with decreasing temperature and increasing pressure. Pretreatment with microwave (MW) also enhanced the efficiency of extraction due most likely to disruption of the cell membrane. Application of SCCO2, generally regarded as safe and environmentally benign solvent, for extraction of useful bioactive compounds from unwanted or substandard seaweeds look promising in the near future. The extracts obtained using the method can be utilized as food and pharmaceutical additive, and can be used in the development of new health supplements. PMID- 23742681 TI - Preventive cancer screening practices in HIV-positive patients. AB - As patients with HIV age, they are at risk of developing non-AIDS defining malignancies. We performed a questionnaire study to evaluate colorectal and breast cancer screening among HIV-positive and HIV-negative patients seeking care from either an integrated (HIV/primary care), nonintegrated (specialized HIV), or general internal medicine clinic between August 2010 and July 2011. We performed a logistic regression to determine the odds of cancer screening. A total of 813 surveys were collected, and 762 were included in the analysis. As much as 401 were from HIV-positive patients. Patients with HIV were less likely to be current with their colorectal cancer screening (CRCS) (54.4% versus 65.0%, p=0.009); mammography rates were 24.3% versus 62.3% if done during the past year (p<0.001), and 42.0% versus 86.7% if done during the past 5 years (p<0.001). In adjusted models, the odds of colorectal cancer screening in HIV-positive patients compared to negative controls was not statistically significant (OR 0.8; 95% CI 0.5-1.3); however, HIV-positive women remained significantly less likely to be current with breast cancer screening (BCS) whether their mammogram was completed within 1 year (OR 0.1, 95% CI 0.1-0.2) or within 5 years (OR 0.1, 95% CI 0.0-0.2). Integrated care was not associated with improved screening; however, having frequent visits to a primary care physician (PCP) increased the likelihood of getting screened. BCS was lower in HIV-positive compared to HIV-negative women. Frequent visits to a PCPs improved cancer screening. PMID- 23742682 TI - The fighting hypothesis in combat: how well does the fighting hypothesis explain human left-handed minorities? AB - The strong population bias in hand preference in favor of right-handedness seems to be a typical human trait. An elegant evolutionary hypothesis explaining this trait is the so-called fighting hypothesis that postulates that left-handedness is under frequency-dependent selection. The fighting hypothesis assumes that left handers, being in the minority because of health issues, are still maintained in the population since they would have a greater chance of winning in fights than right-handers due to a surprise effect. This review critically evaluates the assumptions and evidence for this hypothesis and concludes that some evidence, although consistent with the fighting hypothesis, does not directly support it and may also be interpreted differently. Other supportive data are ambiguous or open for both statistical and theoretical criticism. We conclude that, presently, evidence for the fighting hypothesis is not particularly strong, but that there is little evidence to reject it either. The hypothesis thus remains an intuitively plausible explanation for the persistent left-hand preference in the population. We suggest alternative explanations and several ways forward for obtaining more crucial data for testing this frequently cited hypothesis. PMID- 23742683 TI - The fighting hypothesis as an evolutionary explanation for the handedness polymorphism in humans: where are we? AB - The ubiquitous and persistent handedness polymorphism in humans requires an evolutionary explanation. It has been suggested that left-handers have a frequency-dependent advantage during a fight, such that this advantage decreases when their frequency increases. Many independent studies are providing data from interactive sports (a specific class of fights), and are very supportive of the fighting hypothesis. The only intercultural study on traditional societies is also consistent with the fighting hypothesis, although it has not yet been replicated. The frequencies of left-handers in the few remaining violent societies are likely to be rapidly decreasing, due to Western colonization (long range weapons, religion, and money market) dramatically affecting the frequency dependent selection associated with handedness. Clearly, more data are urgently needed outside the Western influence. PMID- 23742684 TI - Biased semantics for right and left in 50 Indo-European and non-Indo-European languages. AB - The negative bias accompanying the terms left and left-handers has long interested researchers. This paper examines a large number of languages of Indo European and non-Indo-European origin for such biasing. One surprising outcome is that, within the Indo-European language family, the terms for right and left do not go back to one set of antonyms but have their etymological roots in a number of different core semantic concepts. As in the non-Indo-European languages, right is almost always thought of positively, whereas left is negatively connotated. This is interpreted as the outcome of a universal human evaluation process, partly based on the principle of embodiment. The terms for right never have, in any of the examined languages, a negative bias; the words for left, usually never positively biased, were turned into euphemisms in three language groups (Scandinavian, Greek, and Avestan). On one interpretation, this seems to be an act of historical political correctness, corroborating the negative attitude cultures have for left-handers, very likely an outcome of discrimination of minorities. PMID- 23742685 TI - Introduction to the evolution of human handedness. PMID- 23742686 TI - Multiple locations of advance care planning documentation in an electronic health record: are they easy to find? AB - BACKGROUND: The ambulatory care setting is a new frontier for advance care planning (ACP). While electronic health records (EHR) have been expected to make ACP documentation more retrievable, the literature is silent on the locations of ACP documentation in EHRs and how readily they can be found. OBJECTIVE: The study's objective is to identify the locations of ACP documentation in EpicCare EHR and to determine which patient and primary care provider (PCP) characteristics are associated with having a scanned ACP document. A scanned document (SD) is the only documentation containing signatures (unsigned documents are not legally valid). DESIGN: The study design is a retrospective review of EpicCare EHR records. The search of terms included advance directives, living will, Physician Orders for Life-Sustaining Treatments (POLST), power of attorney, and do-not-resuscitate. SETTING/SUBJECTS: Subjects were patients in a multispecialty practice in California age 65 or older who had at least one ACP documentation in the EHR. MEASUREMENTS: Measurements were types and locations of documentation, and characteristics of patients and physicians. RESULTS: About 50.9% of patients age 65 or older had at least one ACP documentation in the EHR (n=60,105). About 33.5% of patients with ACP documentation (n=30,566) had an SD. Patients' age, gender, race, illnesses, and when their physician started at the medical group were statistically significantly associated with the probability of having a scanned ACP document. CONCLUSIONS: Only 33.5% of patients with ACP documentation somewhere in the EHR had an SD. Standardizing the location of these documents should become a priority to improve care. Actions are needed to eliminate disparities. PMID- 23742687 TI - Increased adsorption of sulfamethoxazole on suspended carbon nanotubes by dissolved humic acid. AB - Although dissolved organic matter (DOM) could effectively disperse carbon nanotubes (CNTs), sorption characteristics of DOM-suspended CNTs are unclear. In this study, we evaluated the relative contribution to the overall sorption from dissolved humic acid (DHA) coating (decreased sorption) and CNT dispersion (increased sorption). We observed that the sorption coefficients of sulfamethoxazole (SMX) on DHA-suspended CNTs were up to 2 orders of magnitude higher than that on aggregated CNTs. Although the mass percent of suspended CNTs were low (generally less than 1%), their contributions to SMX adsorption were up to 20%. Because DHA and SMX did not interact with each other due to their negative charges, the suspended CNTs may not be completely coated by DHA and they had considerable hydrophobic surface exposed. Importantly, this study provided the first evidence in aqueous phase of the significantly increased surface area of DHA-suspended CNTs relative to the aggregated ones based on (1)H NMR relaxometry measurements. This study emphasizes that in comparison to aggregated CNTs, the suspended ones have amply exposed surface area and thus have greater environmental impacts, such as enhancing the mobility, transport, and possibly exposure of organic contaminants. PMID- 23742688 TI - Six-month ischemic mice show sensorimotor and cognitive deficits associated with brain atrophy and axonal disorganization. AB - AIMS: To identify long-term sensorimotor and cognitive deficits and to evaluate structural alterations in brain ischemic mice. METHODS: C57Bl/6J male mice were subjected to 30 min transient middle cerebral artery occlusion (tMCAo) or sham surgery. Sensorimotor deficits, exploratory behavior, and cognitive functions were evaluated up to 6 months. Cortical and subcortical damage were analyzed by MRI multiparameter analysis and histopathology. RESULTS: tMCAo mice showed significant sensorimotor deficits in the rotarod, negative geotaxis, neuroscore, and beam walk tests. They also showed impairment in exploratory behavior in the open field test and in spatial learning in the Morris water maze. T2-weighted MRI revealed a volume reduction in injured brain areas at 12 and 24 weeks postinjury. Brain atrophy was shown by MRI and conventional postmortem analysis. Diffusion tensor imaging on the external capsule showed increased values of axial and radial diffusivity. Fiber tracking revealed a reduction in the number and length of ipsilateral fibers. CONCLUSIONS: tMCAo in mice induces sensorimotor and cognitive impairments detectable at least up to 6 months postinjury, associated with brain atrophy, and axonal and myelin damage of the external capsule. These behavioral tests and anatomical investigations may represent important tools in translational studies in cerebral ischemia. PMID- 23742689 TI - Repeatability and precision of a weighted centroid method for estimating dynamic in vivo tibiofemoral surface interactions in sheep. AB - Persistent changes in joint biomechanics resulting from knee injury are thought to contribute to progressive cartilage damage and post-traumatic osteoarthritis (PTOA). The identification and quantification of in vivo tibiofemoral surface interactions are critical to understanding them, particularly abnormal interactions that are damaging to articular cartilage and other structures of the knee. In this study, we describe an approach for understanding such potential interactions by using a weighted centroid derived from in vivo stifle kinematics in sheep. Collectively, repeatability and sensitivity analyses indicate that the magnitude of the changes in tibiofemoral centroid location resulting from combined ligament transection is greater than the repeatability and precision of the current weighted centroid approach, making this method useful for describing the changes in dynamic surface interactions that may be relevant in the pathogenesis of PTOA in this stifle injury model. PMID- 23742690 TI - Physical properties of single-wall carbon nanotubes in cell culture and their dispersal due to alveolar epithelial cell response. AB - Concern over the influence of carbon nanotubes (CNTs) on human health has arisen due to advances; however, little is known about the potential toxicity of CNTs. In this study, impurity-free single-wall carbon nanotubes (SWCNTs), with different physical properties in cell culture medium, were prepared by a novel dispersion procedure. SWCNTs with small bundles (short linear shape) and SWCNTs with large bundles (long linear shape) did not cause a significant inhibition of cell proliferation, induction of apoptosis or arrest of cell cycle progression in A549 alveolar epithelial cells. Expression of many genes involved in the inflammatory response, apoptosis, response to oxidative stress and degradation of the extracellular matrix were not markedly upregulated or downregulated. However, SWCNTs with relatively large bundles significantly increased the level of intracellular reactive oxygen species (ROS) in a dose-dependent manner, and the levels of these ROS were higher than those of SWCNTs with relatively small bundles or commercial SWCNTs with residual metals. Transmission electron microscopy (TEM) revealed that impurity-free SWCNTs were observed in the cytoplasm and vacuoles of cells after 24 h. These results suggested that the physical properties, especially the size and length of the bundles of the SWCNTs dispersed in cell culture medium, contributed to a change in intracellular ROS generation, even for the same bulk SWCNTs. Additionally, the residual metals associated with the manufacturing of SWCNTs may not be a definitive parameter for intracellular ROS generation in A549 cells. PMID- 23742691 TI - Use of expressed sequence tags as an alternative approach for the identification of Taenia solium metacestode excretion/secretion proteins. AB - BACKGROUND: Taenia solium taeniasis/cysticercosis is a zoonotic helminth infection mainly found in rural regions of Africa, Asia and Latin America. In endemic areas, diagnosis of cysticercosis largely depends on serology, but these methods have their drawbacks and require improvement. This implies better knowledge of the proteins secreted and excreted by the parasite. In a previous study, we used a custom protein database containing protein sequences from related helminths to identify T. solium metacestode excretion/secretion proteins. An alternative or complementary approach would be to use expressed sequence tags combined with BLAST and protein mapping to supercontigs of Echinococcus granulosus, a closely related cestode. In this study, we evaluate this approach and compare the results to those obtained in the previous study. FINDINGS: We report 297 proteins organized in 106 protein groups based on homology. Additional classification was done using Gene Ontology information on biological process and molecular function. Of the 106 protein groups, 58 groups were newly identified, while 48 groups confirmed previous findings. Blast2GO analysis revealed that the majority of the proteins were involved in catalytic activities and binding. CONCLUSIONS: In this study, we used translated expressed sequence tags combined with BLAST and mapping strategies to both confirm and complement previous research. Our findings are comparable to recent studies on other helminth genera like Echinococcus, Schistosoma and Clonorchis, indicating similarities between helminth excretion/secretion proteomes. PMID- 23742692 TI - Bioinspired multiple-interaction model revealed in adsorption of low-density lipoprotein to surface containing saccharide and alkanesulfonate. AB - A new "multiple-interaction model" for low-density lipoprotein (LDL) adsorption to a specific surface containing saccharide and alkanesulfonate ligands is proposed. The model suggests that there are interactions of the saccharide component beyond electrostatic interactions of the alkanesulfonate component that both influence the LDL adsorption process. This concept of multiple interactions between saccharide and LDL was inspired by the similarity in structures of LDL receptors (LDLR), heparin, and heparans used in LDL-apheresis. The model was confirmed by SPR analysis by the adsorption maxima on SAM surfaces with different compositions of saccharide and alkanesulfonate and additionally by CD detection of the conformation of LDL when in contact with saccharide. PMID- 23742693 TI - Folk beliefs and fracking. PMID- 23742694 TI - Evaluation of sedation for standing clinical procedures in horses using detomidine combined with buprenorphine. AB - OBJECTIVES: To examine the effect of including buprenorphine with detomidine for sedation of horses undergoing clinical procedures. STUDY DESIGN: Partially blinded, randomised, prospective clinical field trial. ANIMALS: Eighty four client-owned horses scheduled for minor surgery or diagnostic investigation under standing sedation. METHODS: The effects of buprenorphine (5 MUg kg(-1) ) (Group B, n = 46) or placebo (5% glucose solution) (Group C, n = 38) in combination with detomidine (10 MUg kg(-1) ) were compared in standing horses undergoing minor clinical procedures. The primary outcome measure was successful completion of the procedure. The degree of sedation and ataxia were scored using simple descriptive scales. Heart and respiratory rates were recorded at 15-30 minute intervals. Parametric data from each group were compared using anova or t-test and non parametric data using the Mann-Whitney U test. RESULTS: The procedure was carried out successfully in 91% of Group B and 63% of Group C (p < 0.01). Repeat dosing was required in 24% of Group B and 32% of Group C (p < 0.05). Sedation was more profound and lasted longer (60 versus 45 minutes) in Group B (p < 0.01). Ataxia occurred after detomidine, increased after buprenorphine but not glucose administration, was more profound in group B and lasted longer (60 versus 30 minutes) p < 0.001). Heart and respiratory rates remained within normal limits in both groups and there were no serious adverse events. CONCLUSIONS AND CLINICAL RELEVANCE: Buprenorphine 5 and 10 MUg kg(-1) enhanced the sedation produced by detomidine 10 and 20 MUg kg(-1) with minor side effects similar to other alpha2 agonist/opioid combinations. Detomidine-buprenorphine sedation is suitable for standing procedures in horses. PMID- 23742695 TI - Differential expression of mitogen activating protein kinases in periodontitis. AB - AIM: Following toll-like receptor (TLR) engagement, lipopolysaccharide (LPS) can stimulate the expression of pro-inflammatory cytokines thus activating the innate immune response. The production of inflammatory cytokines results, in part, from the activation of kinase-induced signalling cascades and transcriptional factors. Of the four distinct classes of mitogen-activated protein kinases (MAPK) described in mammals, p38, c-Jun N-terminal activated kinases (JNK1-3) and extracellular activated kinases (ERK1,2) are the best studied. Previous data have established that p38 MAPK signalling is required for inflammation and bone loss in periodontal disease pre-clinical animal models. MATERIALS & METHODS: In this study, we obtained healthy and diseased periodontal tissues along with clinical parameters and microbiological parameters. Excised fixed tissues were immunostained with total and phospho-specific antibodies against p38, JNK and ERK kinases. RESULTS: Intensity scoring from immunostained tissues was correlated with clinical periodontal parameters. Rank correlations with clinical indices were statistically significantly positive (p-value < 0.05) for total p38 (correlations ranging 0.49-0.68), phospho-p38 (range 0.44-0.56), and total ERK (range 0.52-0.59) levels, and correlations with JNK levels also supported association (range 0.42-0.59). Phospho-JNK and phospho-ERK showed no significant positive correlation with clinical parameters of disease. CONCLUSION: These data strongly implicate p38 MAPK as a major MAPK involved in human periodontal inflammation and severity. PMID- 23742696 TI - Crematoenones - a novel substance class exhibited by ants functions as appeasement signal. AB - BACKGROUND: Parasitic, commensalistic, and mutualistic guests in social insect colonies often circumvent their hosts' nestmate recognition system to be accepted. These tolerance strategies include chemical mimicry and chemical insignificance. While tolerance strategies have been studied intensively in social parasites, little is known about these mechanisms in non-parasitic interactions.Here, we describe a strategy used in a parabiotic association, i.e. two mutualistic ant species that regularly share a common nest although they have overlapping food niches. One of them, Crematogaster modiglianii, produces an array of cuticular compounds which represent a substance class undescribed in nature so far. They occur in high abundances, which suggests an important function in the ant's association with its partner Camponotus rufifemur. RESULTS: We elucidated the structure of one of the main compounds from cuticular extracts using gas chromatography, mass spectrometry, chemical derivatizations and nuclear magnetic resonance spectroscopy (NMR). The compound consists of two fused six membered rings with two alkyl groups, one of which carries a keto functionality. To our knowledge, this is the first report on the identification of this substance class in nature. We suggest naming the compound crematoenone.In behavioural assays, crematoenones reduced interspecific aggression. Camponotus showed less aggression to allospecific cuticular hydrocarbons when combined with crematoenones. Thus, they function as appeasement substances. However, although the crematoenone composition was highly colony-specific, interspecific recognition was mediated by cuticular hydrocarbons, and not by crematoenones. CONCLUSIONS: Crematenones enable Crematogaster to evade Camponotus aggression, and thus reduce potential costs from competition with Camponotus. Hence, they seem to be a key factor in the parabiosis, and help Crematogaster to gain a net benefit from the association and thus maintain a mutualistic association over evolutionary time.To our knowledge, putative appeasement substances have been reported only once so far, and never between non-parasitic species. Since most organisms associated with social insects need to overcome their nestmate recognition system, we hypothesize that appeasement substances might play an important role in the evolution and maintenance of other mutualistic associations as well, by allowing organisms to reduce costs from antagonistic behaviour of other species. PMID- 23742697 TI - Crosstalk between hydrogen sulfide and nitric oxide in endothelial cells. AB - Hydrogen sulfide (H2 S) and nitric oxide (NO) are major gasotransmitters produced in endothelial cells (ECs), contributing to the regulation of vascular contractility and structural integrity. Their interaction at different levels would have a profound impact on angiogenesis. Here, we showed that H2 S and NO stimulated the formation of new microvessels. Incubation of human umbilical vein endothelial cells (HUVECs-926) with NaHS (a H2 S donor) stimulated the phosphorylation of endothelial NO synthase (eNOS) and enhanced NO production. H2 S had little effect on eNOS protein expression in ECs. L-cysteine, a precursor of H2 S, stimulated NO production whereas blockage of the activity of H2 S generating enzyme, cystathionine gamma-lyase (CSE), inhibited this action. CSE knockdown inhibited, but CSE overexpression increased, NO production as well as EC proliferation. LY294002 (Akt/PI3-K inhibitor) or SB203580 (p38 MAPK inhibitor) abolished the effects of H2 S on eNOS phosphorylation, NO production, cell proliferation and tube formation. Blockade of NO production by eNOS-specific siRNA or nitro-L-arginine methyl ester (L-NAME) reversed, but eNOS overexpression potentiated, the proliferative effect of H2 S on ECs. Our results suggest that H2 S stimulates the phosphorylation of eNOS through a p38 MAPK and Akt-dependent pathway, thus increasing NO production in ECs and vascular tissues and contributing to H2 S-induced angiogenesis. PMID- 23742698 TI - Substrate water exchange for the oxygen evolving complex in PSII in the S1, S2, and S3 states. AB - Detailed mechanisms for substrate water exchange in the oxygen evolving complex in photosystem II have been determined with DFT methods for large models. Existing interpretations of the experimental water exchange results have been quite different. By many groups, these results have been the main argument against the water oxidation mechanism suggested by DFT, in which the oxygen molecule is formed between a bridging oxo and an oxyl radical ligand in the center of the OEC. That mechanism is otherwise in line with most experiments. The problem has been that the mechanism requires a rather fast exchange of a bridging oxo ligand, which is not a common finding for smaller Mn-containing model systems. However, other groups have actually favored a substrate derived oxo ligand partly based on the same experiments. In the present study, three S-states have been studied, and the rates have been well reproduced by the calculations. The surprising experimental finding that water exchange in S1 is slower than the one in S2 is reproduced and explained. The key to this rate difference is the ease by which one of the manganese centers (Mn3) is reduced. This reduction has to occur to release the substrate water from Mn3. The similar rate of the slow exchange in S2 and S3 has been rationalized on the basis of earlier experiments combined with the present calculations. The results strongly support the previous DFT-suggested water oxidation mechanism. PMID- 23742700 TI - Morphology study of peroxide-induced dynamically vulcanized polypropylene/ethylene-propylene-diene monomer/zinc dimethacrylate blends during tensile deformation. AB - Polypropylene (PP)/ethylene-propylene-diene monomer (EPDM)/zinc dimethacrylate (ZDMA) blend (EPDM/PP ratio of 30/70) with remarkable extensibility was successfully prepared via peroxide dynamic vulcanization. The uniaxial tensile properties, crystallization behavior, structure, and morphology during stretching were investigated. The tensile process study showed that the PP/EPDM/ZDMA blend exhibited the rubbery-like behavior with an elongation beyond 600%. The ZDMA graft-product domain increased the compatibility and interfacial adhesion between rubber and PP phases, while it reduced the crystallinity of the PP phase. On the basis of TEM and SEM analyses, we found that the cross-linked rubber particles could be elongated and oriented along the tensile direction, whereas the ZDMA graft-product domain "encapsulated" rubber phase together, acting as a "bridge" between elongated rubber phases and the PP phase during uniaxial stretching. The stress could be effectively transferred from the PP phase to the numerous elongated rubber phases due to the excellent compatibility and interfacial adhesion between rubber and PP phases, resulting in the rubbery-like behavior. PMID- 23742699 TI - Lung clearance index as an outcome measure for clinical trials in young children with cystic fibrosis. A pilot study using inhaled hypertonic saline. AB - RATIONALE: Lung clearance index (LCI), measured by multiple breath washout (MBW), is a noninvasive measure of ventilation inhomogeneity that holds promise as an objective physiologic endpoint for clinical trials in infants and preschool children with cystic fibrosis (CF). OBJECTIVES: To study the feasibility of using LCI to assess treatment effect outcomes in CF trials of infants and preschoolers. METHODS: The Infant Study of Inhaled Saline trial was a multicenter, randomized, controlled trial of hypertonic (7%) versus isotonic (0.9%) saline inhaled twice daily for 48 weeks in children with CF under 6 years of age. LCI measurements were performed in a single-center pilot substudy at baseline and 48 weeks using a respiratory mass spectrometer and sulfur hexafluoride as the tracer gas. LCI measurements were standardized using published normative data (zLCI) to account for height-related changes in LCI during early childhood. A generalized estimating equation model with an interaction between treatment group and test occasion was used to estimate a treatment effect. MEASUREMENTS AND MAIN RESULTS: A total of 27 participants were randomized; 25 participants, aged (median [range]) 2.6 (0.34-4.95) years, had acceptable baseline and follow-up LCI measures. On average, LCI decreased in the hypertonic saline group (n = 12) by 1.19 z-scores units (95% confidence interval [CI] = -2.46 to 0.06), and remained stable in the isotonic saline group (n = 13) at 0.81 (95% CI = -0.40 to 2.02). A significant treatment effect was observed for zLCI (2.01; 95% CI = 0.26 to 3.76; P = 0.025). CONCLUSIONS: MBW testing is feasible in an interventional study in infants and preschool children with CF. These pilot findings support the development of MBW and LCI as an objective outcome measure in interventional trials in young children with CF, and provide estimates for sample size calculations for future studies. PMID- 23742701 TI - Antioxidant activity of different parts of Tetrataenium lasiopetalum. AB - CONTEXT: In Iranian traditional medicine, different species of the genus Tetrataenium are used as antiseptic, spice and food additives. OBJECTIVE: The present study examined the possible antioxidant effects of hydro-alcoholic extracts of different parts of Tetrataenium lasiopetalum (Boiss.) Manden (Apiaceae). MATERIALS AND METHODS: Laminas, stems, petioles, fruits, peduncles and flowers of T. lasiopetalum were collected, dried and then extracted by ethanol and water (70:30). Antioxidant activities of extracts were examined by employing different in vitro assays, i.e., 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, metal chelating, reducing power activities and hemoglobin induced linoleic acid system. Also, total phenolic and flavonoid contents of the extracts were evaluated. RESULTS: Hydro-alcoholic extract of T. lasiopetalum flower showed the highest activity in scavenging of DPPH (IC50 = 170 +/- 7 MUg/mL). In metal chelating assay, lamina extract possesses a better iron ion chelating activity than other extracts (230 +/- 10 MUg/mL). Lamina hydro alcoholic extract demonstrated better activity in reducing the power and hemoglobin-induced linoleic acid system than other parts of T. lasiopetalum. DISCUSSION AND CONCLUSION: These results showed the antioxidant activity of different parts of T. lasiopetalum based on its usage in traditional medicine. PMID- 23742702 TI - Amla (Emblica officinalis Gaertn.) extract inhibits lipopolysaccharide-induced procoagulant and pro-inflammatory factors in cultured vascular endothelial cells. AB - Amla (Emblica officinalis Gaertn.) has been used for many centuries in traditional Indian Ayurvedic formulations for the prevention and treatment of many inflammatory diseases. The present study evaluated the anti-inflammatory and anticoagulant properties of amla fruit extract. The amla fruit extract potentially and significantly reduced lipopolysaccharide (LPS)-induced tissue factor expression and von Willebrand factor release in human umbilical vein endothelial cells (HUVEC) in vitro at clinically relevant concentrations (1-100 MUg/ml). In a leucocyte adhesion model of inflammation, it also significantly decreased LPS-induced adhesion of human monocytic cells (THP-1) to the HUVEC, as well as reduced the expression of endothelial-leucocyte adhesion molecule-1 (E selectin) in the target cells. In addition, the in vivo anti-inflammatory effects were evaluated in a LPS-induced endotoxaemia rat model. Oral administration of the amla fruit extract (50 mg/kg body weight) significantly decreased the concentrations of pro-inflammatory cytokines, TNF-alpha and IL-6 in serum. These results suggest that amla fruit extract may be an effective anticoagulant and anti-inflammatory agent. PMID- 23742703 TI - Nondenaturing size-exclusion chromatography-mass spectrometry to measure stress induced aggregation in a complex mixture of monoclonal antibodies. AB - During therapeutic candidate selection, diverse panels of monoclonal antibodies (mAbs) are routinely subjected to various stress conditions, and assayed for biophysical and biochemical stability. A novel high throughput method has been developed to differentiate candidate molecules in a mixture based on their propensity for forming aggregates when subjected to agitation (vortexing) stress. Protein monomers are separated from soluble and insoluble aggregates using size exclusion chromatography, under nondenaturing conditions, and the individual components in the mixture are identified by mass spectrometry and quantitated relative to an unstressed control. An internal standard was added to the mixture after stress, and used to correct for differences in ionization between samples. Treatment of the samples with the enzyme IdeS (FabRICATOR) significantly reduces sample complexity, and allows for a large number of candidate molecules to be assessed in a single analysis. Simple and robust, the method is well suited for measuring relative aggregation propensity (RAP) in conjunction with molecule selection and coformulation development. PMID- 23742704 TI - Associations between serum hepcidin, ferritin and Hb concentrations and type 2 diabetes risks in a Han Chinese population. AB - Systemic Fe overload can contribute to abnormal glucose metabolism and the onset of type 2 diabetes (T2D). Although hepcidin is the master regulator of systemic Fe homeostasis, few studies have systematically evaluated the associations of serum hepcidin concentrations with Fe metabolism parameters and risks for the development of T2D. In this regard, whether hepcidin concentrations are associated with T2D remains controversial. We measured serum hepcidin and ferritin concentrations in a case-control study of 1259 Han Chinese participants to evaluate the possible associations of serum hepcidin concentrations with Fe metabolism parameters and risks of T2D. Individuals with diabetes (n 555) and control participants (n 704) were recruited and serum hepcidin and ferritin concentrations were quantified. Additionally, selected biochemical and anthropometric variables were determined. A logistic regression analysis was performed to evaluate the association of serum hepcidin and ferritin concentrations with T2D. A linear regression analysis was used to test for associations between serum hepcidin and ferritin concentrations and a number of clinical, demographic and diabetes-associated variables. We found that serum hepcidin concentrations correlated with Hb and serum ferritin concentrations. No differences in hepcidin concentrations were found between the group with diabetes and the control group. Hepcidin concentrations were not significantly correlated with T2D risk factors. We also found that serum ferritin concentrations were elevated in individuals with diabetes and were positively correlated with both Hb concentrations and T2D risk factors. The present findings suggest that serum ferritin concentrations correlate with T2D risk factors, while serum hepcidin concentrations are positively associated with Hb and serum ferritin concentrations, but do not correlate with T2D. PMID- 23742705 TI - Early detection of memory impairment in people over 65 years old consulting at Health Examination Centers for the French health insurance: the EVATEM protocol. AB - BACKGROUND: Only half of those living with Alzheimer's disease in France are currently diagnosed, and only one patient in three is supported during the early stages of dementia. This study aims to evaluate three cognitive tests for their predictive ability to diagnose mild cognitive impairments and Alzheimer's disease and related disorders. For people aged 65 years or over, presenting with a memory complaint, these tests can be performed easily during a preventative consultation. METHOD/DESIGN: The EVATEM (evaluation des troubles de l'equilibre et de la memoire (evaluation of balance and memory problems)) cohort study was designed to prospectively assess the predictive value of tests for the diagnosis of mild cognitive impairments and Alzheimer's disease in elderly subjects aged 65 years or over. Subjects were recruited from three health examination centers that are part of the French health insurance system. If a memory complaint was identified (using a dedicated questionnaire), the five-word test, the cognitive disorders examination test and the verbal fluency test were administered during a preventative consultation. A memory consultation was performed at a University Hospital to diagnosis any potential cognitive disorder and a one-year follow-up consultation was also scheduled. We recorded 2041 cases of memory complaint at our Health Examination Centers. Cognitive tests were refused by 33.6% of people who had a memory complaint. The number of subjects sent to a University Hospital memory consultation was 832 and 74.5% of them completed this consultation. The study population therefore includes 620 subjects. DISCUSSION: Tests for the early diagnosis of a mild cognitive impairment or Alzheimer's disease and related disorders should be used in centers dedicated to disease prevention. These should guide subjects with memory impairment to full memory consultations at hospitals and improve the access to early medical and behavioral support. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01316562. PMID- 23742706 TI - Longitudinal change in energy expenditure and effects on energy requirements of the elderly. AB - BACKGROUND: Very little is known about the longitudinal changes in energy requirements in late life. The purposes of this study were to: (1) determine the energy requirements in late life and how they changed during a 7 year time-span, (2) determine whether changes in fat free mass (FFM) were related to changes in resting metabolic rate (RMR), and (3) determine the accuracy of predicted total energy expenditure (TEE) to measured TEE. METHODS: TEE was assessed via doubly labeled water (DLW) technique in older adults in both 1999 (n = 302; age: 74 +/- 2.9 yrs) and again in 2006 (n = 87 age: 82 +/- 3.1 yrs). RMR was measured with indirect calorimetry, and body composition was assessed with dual-energy x-ray absorptiometry. RESULTS: The energy requirements in the 9th decade of life were 2208 +/- 376 kcal/d for men and 1814 +/- 337 kcal/d for women. This was a significant decrease from the energy requirements in the 8th decade of life in men (2482 +/- 476 kcal/d vs. 2208 +/- 376 kcal/d) but not in women (1892 +/- 271 kcal/d vs. 1814 +/- 337 kcal/d). In addition to TEE, RMR, and activity EE (AEE) also decreased in men, but not women, while FFM decreased in both men and women. The changes in FFM were correlated with changes in RMR for men (r = 0.49, p < 0.05) but not for women (r = -0.08, ns). Measured TEE was similar to Dietary Reference Intake (DRI) predicted TEE for men (2208 +/- 56 vs. 2305 +/- 35 kcal/d) and women (1814 +/- 42 vs. 1781 +/- 20 kcal/d). However, measured TEE was different than the World Health Organization (WHO) predicted TEE in men (2208 +/- 56 vs. 2915 +/- 31 kcal/d (p < 0.05)) and women (1814 +/- 42 vs. 2315 +/- 21 kcal/d (p < 0.05)). CONCLUSIONS: TEE, RMR and AEE decreased in men, but not women, from the 8th to 9th decade of life. The DRI equation to predict TEE was comparable to measured TEE, while the WHO equation over-predicted TEE in our elderly population. PMID- 23742708 TI - Uranium(VI) interactions with mackinawite in the presence and absence of bicarbonate and oxygen. AB - Mackinawite, Fe(II)S, samples loaded with uranium (10(-5), 10(-4), and 10(-3) mol U/g FeS) at pH 5, 7, and 9, were characterized using X-ray absorption spectroscopy and X-ray diffraction to determine the effects of pH, bicarbonate, and oxidation on uptake. Under anoxic conditions, a 5 g/L suspension of mackinawite lowered 5 * 10(-5) M uranium(VI) to below 30 ppb (1.26 * 10(-7) M) U. Between 82 and 88% of the uranium removed from solution by mackinawite was U(IV) and was nearly completely reduced to U(IV) when 0.012 M bicarbonate was added. Near-neighbor coordination consisting of uranium-oxygen and uranium-uranium distances indicates the formation of uraninite in the presence and absence of bicarbonate, suggesting reductive precipitation as the dominant removal mechanism. Following equilibration in air, mackinawite was oxidized to mainly goethite and sulfur and about 76% of U(IV) was reoxidized to U(VI) with coordination of uranium to axial and equatorial oxygen, similar to uranyl. Additionally, uranium-iron distances, typical of coprecipitation of uranium with iron oxides, and uranium-sulfur distances indicating bidentate coordination of U(VI) to sulfate were evident. The affinity of mackinawite and its oxidation products for U(VI) provides impetus for further study of mackinawite as a potential reactive medium for remediation of uranium-contaminated water. PMID- 23742707 TI - PI3K, ERK, p38 MAPK and integrins regulate CCR3-mediated secretion of mouse and human eosinophil-associated RNases. AB - BACKGROUND: Eosinophils have the capacity to secrete varied cytotoxic proteins. Among the proteins are the eosinophil-associated RNases (EARs): the human eosinophil-derived neurotoxin and eosinophilic cationic protein, and their murine ortholog EARs, which have been shown to be involved in host defense, tissue remodeling, and immunity regulation. However, the signal transduction that regulates EARs secretion in response to physiological stimuli, such as chemokines, has been little studied in human and scarcely in mouse eosinophils, the foremost animal model for eosinophil-associated human diseases. OBJECTIVE: In this study, we aimed to understand the signal transduction involved in the secretion of enzymatically active EARs following chemokine stimulation. METHODS: Fresh mouse and human eosinophils were stimulated with CCL11 and CCL24, and the secretion of enzymatically active EARs was detected using an RNase activity assay. The involvement of signaling factors or integrins was probed using specific inhibitors and blocking antibodies. Adhesion was evaluated by microscopy. RESULTS: We found that secretion of mouse EARs in response to CCL11 and CCL24 was Galphai -dependent. Both mouse and human eosinophils required the activation of PI3K, ERK, and p38 MAPK. In addition, the adhesion molecules beta1 and beta2 integrins were found to be crucial for EAR secretion, and we suggest a mechanism in which spreading is obligatory for EAR secretion. CONCLUSIONS: Collectively, these data suggest a common CCR3-mediated signaling pathway that leads to EAR secretion in both mouse and human eosinophils. These findings are applicable for eosinophil-mediated host defense and eosinophil-associated diseases. PMID- 23742709 TI - Leishmaniasis sand fly vector density reduction is less marked in destitute housing after insecticide thermal fogging. AB - BACKGROUND: Insecticide thermal fogging (ITF) is a tool to control vector borne diseases. Insecticide application success for vector control has been associated with housing materials and architecture. Vector abundance is correlated with weather changes. Nevertheless, housing quality and weather impacts on vector abundance have been unaccounted for in most New World insecticide control trials for leishmaniasis vectors. METHODS: We conducted a 15 month insecticide control trial that included two deltamethrin [6 mg a.i.m-2] based ITF interventions in 12 of 24 monitored houses at Trinidad de Las Minas, a hyperendemic cutaneous leishmaniasis transmission village in western Panama. During the study we followed sand fly (SF) abundance, keeping track of rainfall and quantified housing quality using an index based on architecture and construction materials. RESULTS: We found a 50 to 80% reduction in SF density in the fogged houses when compared with control houses, while controlling for seasonal changes in SF abundance associated with rainfall. We found heterogeneities in the reductions, as abundance changed according to SF species: Lutzomyia gomezi, Lu. panamensis, Lu. dysponeta and Lu. triramula reduced in density between 40% and 90% after ITF. In contrast, Lu. trapidoi density increased 5% after ITF. Differences in the impact of ITF were associated with housing quality, the most destitute houses, i.e., those with features that ease insect entrance, had a disproportionally larger SF abundance, in some cases with increased domiciliary SF density following the ITF. CONCLUSION: Our results suggest the potential of insecticide application to control SF density and leishmaniasis transmission could depend on housing quality beyond insecticide efficiency. PMID- 23742710 TI - Effect of simulated gastric and intestinal digestion on temporal stability and immunoreactivity of peanut, almond, and pine nut protein allergens. AB - Current models of digestibility utilize pepsin stability to assess the safety of allergenic versus nonallergenic food proteins. Dietary protein digestion in vivo, however, requires acid denaturation and protease cleavage by pepsin, trypsin, and/or chymotrypsin. The ability of this approach to identify food protein stability in the mammalian gut may be limited. We determined the temporal stability and immunoreactivity of almond, pine nut, and peanut allergenic proteins under simulated physiologic gastric and intestinal digestive conditions in vitro. Gel electrophoresis and immunoblot analyses were used to determine protein stability and immunoreactivity, respectively. Peanut, almond, and pine nut proteins were pepsin- and pancreatin-stable and immunoreactive for up to 1 h after initiation of digestion. Moreover, successive acid denaturation and pepsin and pancreatin cleavage were necessary to hydrolyze these allergenic proteins and reduce their IgG- and IgE-binding capacity, which suggests that digestibility models must be improved for more accurate safety assessment of food allergens. PMID- 23742711 TI - Use of emergency contraception among women aged 15-44: United States, 2006-2010. AB - Emergency contraception can be used by women after sexual intercourse in an effort to prevent an unintended pregnancy. Roughly one-half of all pregnancies in the United States are unintended (1,2). The FDA first approved emergency contraceptive pills in 1998, but there is evidence of limited use of hormonal contraceptives for emergency contraception since the 1960s (3,4). Now, there are at least four brands of emergency contraceptive pills; most are available over the counter for women aged 17 and over (5). Although insertion of a copper intrauterine device can be used for emergency contraception (1,4), this report focuses only on emergency contraceptive pills. This report describes trends and variation in the use of emergency contraception and reasons for use among sexually experienced women aged 15-44 using the 2006-2010 National Survey of Family Growth. PMID- 23742712 TI - Population-level administration of AlcoholEdu for college: an ARIMA time-series analysis. AB - Autoregressive integrated moving averages (ARIMA) is a powerful analytic tool for conducting interrupted time-series analysis, yet it is rarely used in studies of public health campaigns or programs. This study demonstrated the use of ARIMA to assess AlcoholEdu for College, an online alcohol education course for first-year students, and other health and safety programs introduced at a moderate-size public university in the South. From 1992 to 2009, the university administered annual Core Alcohol and Drug Surveys to samples of undergraduates (Ns = 498 to 1032). AlcoholEdu and other health and safety programs that began during the study period were assessed through a series of quasi-experimental ARIMA analyses. Implementation of AlcoholEdu in 2004 was significantly associated with substantial decreases in alcohol consumption and alcohol- or drug-related negative consequences. These improvements were sustained over time as succeeding first-year classes took the course. Previous studies have shown that AlcoholEdu has an initial positive effect on students' alcohol use and associated negative consequences. This investigation suggests that these positive changes may be sustainable over time through yearly implementation of the course with first-year students. ARIMA time-series analysis holds great promise for investigating the effect of program and policy interventions to address alcohol- and drug-related problems on campus. PMID- 23742713 TI - Characterization of a population of neural progenitor cells in the infant hippocampus. AB - AIMS: Abnormalities of the hippocampus are associated with a range of diseases in children, including epilepsy and sudden death. A population of rod cells in part of the hippocampus, the polymorphic layer of the dentate gyrus, has long been recognized in infants. Previous work suggested that these cells were microglia and that their presence was associated with chronic illness and sudden infant death syndrome. Prompted by the observations that a sensitive immunohistochemical marker of microglia used in diagnostic practice does not typically stain these cells and that the hippocampus is a site of postnatal neurogenesis, we hypothesized that this transient population of cells were not microglia but neural progenitors. METHODS: Using archived post mortem tissue, we applied a broad panel of antibodies to establish the immunophenotype of these cells in 40 infants dying suddenly of causes that were either explained or remained unexplained, following post mortem investigation. RESULTS: The rod cells were consistently negative for the microglial markers CD45, CD68 and HLA-DR. The cells were positive, in varying proportions, for the neural progenitor marker, doublecortin, the neural stem cell marker, nestin and the neural marker, TUJ1. CONCLUSIONS: These data support our hypothesis that the rod cells of the polymorphic layer of the dentate gyrus in the infant hippocampus are not microglia but a population of neural progenitors. These findings advance our understanding of postnatal neurogenesis in the human hippocampus in health and disease and are of diagnostic importance, allowing reactive microglia to be distinguished from the normal population of neural progenitors. PMID- 23742714 TI - Dephosphorylation of D-peptide derivatives to form biofunctional, supramolecular nanofibers/hydrogels and their potential applications for intracellular imaging and intratumoral chemotherapy. AB - D-Peptides, as the enantiomers of the naturally occurring L-peptides, usually resist endogenous proteases and are presumably insensitive to most enzymes. But, it is unclear whether or how a phosphatase catalyzes the dephosphorylation from D peptides. In this work, we examine the formation of the nanofibers of D-peptides via enzymatic dephosphorylation. By comparing the enzymatic hydrogelation of L peptide and D-peptide based hydrogelators, we find that the chirality of the precursors of the hydrogelators affects little on the enzymatic hydrogelation resulted from the removal of the phosphate group from a tyrosine phosphate residue. The attachment of a therapeutic agent (e.g., taxol) or a fluorophore (e.g., 4-nitro-2,1,3-benzoxadiazole) to the D-peptide based hydrogelators affords a new type of biostable or biocompatible hydrogelators, which may find applications in intratumoral chemotherapy or intracellular imaging, respectively. This work, as the first comprehensive and systematic study of the unexpected enzymatic dephosphorylation of D-peptides, illustrates a useful approach to generate supramolecular hydrogels that have both biostability and other desired functions. PMID- 23742715 TI - Will reducing sugar-sweetened beverage consumption reduce obesity? Evidence supporting conjecture is strong, but evidence when testing effect is weak. AB - We provide arguments to the debate question and update a previous meta-analysis with recently published studies on effects of sugar-sweetened beverages (SSBs) on body weight/composition indices (BWIs). We abstracted data from randomized controlled trials examining effects of consumption of SSBs on BWIs. Six new studies met these criteria: (i) human trials, (ii) >= 3 weeks duration, (iii) random assignment to conditions differing only in consumption of SSBs and (iv) including a BWI outcome. Updated meta-analysis of a total of seven studies that added SSBs to persons' diets showed dose-dependent increases in weight. Updated meta-analysis of eight studies attempting to reduce SSB consumption showed an equivocal effect on BWIs in all randomized subjects. When limited to subjects overweight at baseline, meta-analysis showed a significant effect of roughly 0.25 standard deviations (more weight loss/less weight gain) relative to controls. Evidence to date is equivocal in showing that decreasing SSB consumption will reduce the prevalence of obesity. Although new evidence suggests that an effect may yet be demonstrable in some populations, the integrated effect size estimate remains very small and of equivocal statistical significance. Problems in this research area and suggestions for future research are highlighted. PMID- 23742716 TI - Work readiness of graduate nurses and the impact on job satisfaction, work engagement and intention to remain. AB - BACKGROUND AND AIM: Graduate work readiness is a relatively new construct that can predict graduate potential. Its impact on graduate work outcomes however, is unknown. The current study aimed to explore the relationships between work readiness and a number of work outcomes (job satisfaction, work engagement, and intention to remain). DESIGN AND PARTICIPANTS: A survey design was used. A sample of 96 graduate nurses from two regional hospitals in Victoria, Australia participated in this study. METHOD: Data were collected using quantitative surveys RESULTS: Three of the four work readiness dimensions (organisational acumen, clinical competence and social intelligence) were found to predict job satisfaction and work engagement. Moreover, both job satisfaction and work engagement were found to mediate the relationship between organisational acumen and intention to remain. The findings indicate that dimensions of work readiness uniquely predict work outcomes. CONCLUSION: Findings support prior research, which suggests that graduate work readiness is a multidimensional construct comprising skills and attributes beyond discipline-specific competence. PMID- 23742718 TI - Health inequality and governance in Scotland since 2007. PMID- 23742717 TI - Evolution of a reassortant North American gull influenza virus lineage: drift, shift and stability. AB - BACKGROUND: The role of gulls in the ecology of avian influenza (AI) is different than that of waterfowl. Different constellations of subtypes circulate within the two groups of birds and AI viruses isolated from North American gulls frequently possess reassortant genomes with genetic elements from both North America and Eurasian lineages. A 2008 isolate from a Newfoundland Great Black-backed Gull contained a mix of North American waterfowl, North American gull and Eurasian lineage genes. METHODS: We isolated, sequenced and phylogenetically compared avian influenza viruses from 2009 Canadian wild birds. RESULTS: We analyzed six 2009 virus isolates from Canada and found the same phylogenetic lineage had persisted over a larger geographic area, with an expanded host range that included dabbling and diving ducks as well as gulls. All of the 2009 virus isolates contained an internal protein coding set of genes of the same Eurasian lineage genes except PB1 that was from a North American lineage, and these genes continued to evolve by genetic drift. We show evidence that the 2008 Great Black backed Gull virus was derived from this lineage with a reassortment of a North American PA gene into the more stable core set of internal protein coding genes that has circulated in avian populations for at least 2 years. From this core, the surface glycoprotein genes have switched several times creating H13N6, H13N2, and H16N3 subtypes. These gene segments were from North American lineages except for the H16 and N3 vRNAs. CONCLUSIONS: This process appears similar to genetic shifts seen with swine influenza where a stable "triple reassortant internal gene" core has circulated in swine populations with genetic shifts occurring with hemaggluttinin and neuraminidase proteins getting periodically switched. Thus gulls may serve as genetic mixing vessels for different lineages of avian influenza, similar to the role of swine with regards to human influenza. These findings illustrate the need for continued surveillance in gull and waterfowl populations, both on the Pacific and especially Atlantic coasts of North America, to document virus intercontinental movement and the role of gull species in the evolution and epidemiology of AI. PMID- 23742719 TI - Health inequality and governance in Scotland since 2007. PMID- 23742720 TI - Health inequality and governance in Scotland since 2007. PMID- 23742721 TI - Health inequality and governance in Scotland since 2007. PMID- 23742722 TI - Different emergence phenology of European grapevine moth (Lobesia botrana, Lepidoptera: Tortricidae) on six varieties of grapes. AB - The phenology of insect emergence affects reproductive success and is especially critical in short-lived species. An increasing number of studies have documented the effects of thermal and other climatic variations and of unpredictable habitats on the timing of adult insect emergence within and between populations and years. Numerous interacting factors may affect the phenology of adult emergence. Host-plant quality and availability is a key factor that has been largely neglected in studies of the phenology of phytophagous insects. The purpose of this study was to determine the effect of host plant characteristics on the rate of larval growth and the pattern of emergence in a wild population of Lobesia botrana (European grapevine moth), a significant pest in European vineyards. The phenology of emergence differed significantly among the six tested varieties of grapes. The percentage of bunches harboring pupae was similar among the different grape varieties, and the total number of pupae collected was similar to the number of emerging adults per bunch. Among the six varieties of grapes, 0-25 pupae were produced on each bunch. Each of the grape varieties had a single wave of emergence, in which males emerged before females, but their emergence phenology differed significantly in Chardonnay, Chasselas, and Pinot grapes. Both genders had extended durations of emergence in Merlot grapes. Together, the present results show that the characteristics of the grape host plant affect the emergence phenology of L. botrana. PMID- 23742724 TI - Glycoform remodeling generates a synthetic T cell phenotype. AB - The glycan of specific proteins can dictate the response of cells to stimuli, and thus their phenotype. We describe a chemical strategy to modify the cellular glycoform of T cells, which resulted in a modified cellular response. Our data indicate that chemical modification of the phosphatase CD45 is responsible for the observed differences in response to receptor cross-linking. By increasing the content of galactose epitopes in the glycocalyx of a lymphoma cell line, we were able to increase the response of the cell to lectin stimulation through the glycoprotein receptor, CD45. The method described here exploits metabolic labeling of a cell to reprogram the cellular response to external stimuli though changes in the number of lectin binding sites on the cell surface. PMID- 23742723 TI - In situ spectroscopic quantification of protein-ice interactions. AB - FTIR and confocal Raman microspectroscopy were used to measure interactions between albumin and ice in situ during quasi-equilibrium freezing in dimethyl sulfoxide (DMSO) solutions. At temperatures of -4 and -6 degrees C, albumin was found to be preferentially excluded from the ice phase during near-equilibrium freezing. This behavior reversed at lower temperatures. Instead, DMSO was preferentially excluded from the ice phase, resulting in an albumin concentration in the freeze-concentrated liquid phase that was lower than predicted. It is hypothesized that this was caused by the albumin in the freeze-concentrated liquid getting adsorbed onto the ice surface or becoming entrapped in the ice phase. It was observed that, under certain freezing protocols, as much as 20% of the albumin in solutions with starting concentrations of 32-53 mg/mL may be adsorbed onto the ice interface or entrapped in the ice phase. PMID- 23742725 TI - Molecular weight of barley beta-glucan influences energy expenditure, gastric emptying and glycaemic response in human subjects. AB - Barley beta-glucan (BG) has been shown to reduce glycaemic response (GR) in some studies. It is hypothesised that this reduction may be a function of its physical properties that delay gastric emptying (GE). The effect of these changes in GR and GE on diet-induced thermogenesis (DIT) is not known. The aim of the present study was to assess the effect of BG of different molecular weights and purities on GR, GE and DIT in healthy subjects. This was a randomised, single-blind, repeated-measures design where fifteen healthy subjects were tested on three occasions following an overnight fast. Following the baseline measurements, the volunteers were fed a soup containing high-molecular-weight BG (HBG), a soup containing low-molecular-weight BG (LBG) or a control soup with no BG (CHO). Following the consumption of the breakfast, GR was measured using finger-prick blood samples, GE was determined using the 13C-octanoic acid breath test and DIT was measured using indirect calorimetry. There was a difference in GR AUC between the soups after 60 min but not after 120 min. The CHO and LBG meals had a greater GR than the HBG meal. There were differences in all GE time points, with the HBG meal having the slowest GE time. There was a correlation between the GR and the initial GE times. There were differences in total DIT between the three test meals with the HBG meal having the lowest DIT. The present study indicates that HBG has the ability to delay GE due to increased viscosity, resulting in a decreased GR and DIT. PMID- 23742726 TI - Development of water-in-oil microemulsions with the potential of prolonged release for oral delivery of L-glutathione. AB - Oral delivery of L-L-glutathione is quite a challenge due to the enzymatic and physical barriers in the gastrointestinal tract (GIT). Colloidal delivery systems such as microemulsions (ME) can be valuable for oral delivery of L-glutathione, because they may protect L-glutathione from enzymatic degradation and enhance its permeability across the intestinal epithelium. The aim of this study was to identify ME systems capable of accommodating maximum amounts of L-glutathione in internal aqueous phase intended for oral delivery. Pseudoternary phase diagrams for the systems based on a single or a blend of two oily components, one or two nonionic surfactants and an aqueous phase loaded with L-glutathione were constructed, identified and characterized in terms of morphological, rheological and in vitro release studies. Among the tested formulations, the coarse emulsions resulted in the highest release rate, while the ME and liquid crystal systems provided sustained release of L-glutathione in vitro. There was a linear relationship between the cumulative amount of L-glutathione released from the ME and the liquid crystals, and the square root of time indicting a diffusion controlled process. The release of L-glutathione from the ME and the liquid crystal was related to the concentration of L-glutathione remaining in the formulations. In conclusion, two novel delivery colloidal systems of L glutathione loaded water-in-oil ME and liquid crystal systems were developed and characterized. In addition, a simple isocratic HPLC analytic method was developed and validated, and was used for the qualitative and quantitative analysis of L glutathione released from the selected formulations. PMID- 23742727 TI - Investigation of different emulsion systems for dermal delivery of nicotinamide. AB - Nicotinamide (NA) has been shown to have beneficial effects on several skin diseases such as tumor, acne vulgaris, photodamage, cellulite and atopic dermatitis. The purpose of this study was to develop a multiple emulsion and a microemulsion formulation as delivery systems for NA. A two-step process was used to prepare the W/O/W multiple emulsion. Optimum microemulsion formulation was selected by using construction of pseudo-ternary phase diagram. The physicochemical properties such as droplet size and viscosity measurements, stability studies were also evaluated. Ex-vivo permeation studies were performed with Franz-type diffusion cells and the samples were analysed by high performance liquid chromatography (HPLC). The permeation data showed that there was no significant difference between multiple emulsion and microemulsion (p > 0.05). Transepidermal water loss (TEWL) was also measured. As a result of TEWL studies, a slight increase of TEWL values was observed for microemulsion formulation on rat skin when compared with multiple emulsion and commercial formulation. The results suggested that microemulsion and multiple emulsion formulations could be new and alternative dosage forms for topical application of NA. PMID- 23742728 TI - Evaluating the cognitive effects of donepezil 23 mg/d in moderate and severe Alzheimer's disease: analysis of effects of baseline features on treatment response. AB - BACKGROUND: Treatment of Alzheimer's disease with acetylcholinesterase inhibitors can result in symptomatic benefits, but patients often show variable responses. The objective of this post hoc analysis was to investigate relationships between easily identifiable baseline characteristics/demographics and cognitive response in patients treated with either donepezil 23 mg/d or 10 mg/d and to identify factors potentially influencing response. METHODS: A post hoc analysis was conducted using data from a large, 24-week, randomized, double-blind, international study enrolling patients with moderate to severe Alzheimer's disease (baseline Mini-Mental State Examination [MMSE], 0-20) (NCT 00478205). Cognitive changes in subgroups of patients based on selected baseline and demographic characteristics were compared using the least squares mean changes in Severe Impairment Battery scores at Week 24. Univariate and multivariate analyses were also performed. RESULTS: Donepezil 23 mg/d provided statistically significant incremental cognitive benefits over donepezil 10 mg/d irrespective of baseline functional severity, measured by scores on the Alzheimer's Disease Cooperative Study-Activities of Daily Living-severe version (P < 0.05). When patients were categorized by baseline cognitive severity (MMSE score), significant benefits of donepezil 23 mg/d over 10 mg/d were seen in both subgroups when based on MMSE scores of 0-9 versus 10-20 (P < 0.02 and P < 0.01, respectively), and in the more severe subgroup when based on MMSE scores of 0-16 versus 17-20 (P < 0.0001 and P > 0.05). Statistically significant incremental cognitive benefits of donepezil 23 mg/d over 10 mg/d were also observed regardless of age, gender, weight, or prestudy donepezil 10 mg/d treatment duration (P < 0.05). In the multivariate analysis, the only significant interaction was between treatment and baseline MMSE score. CONCLUSIONS: The cognitive benefits of donepezil 23 mg/d over 10 mg/d were achieved regardless of the patient's age, gender, weight, duration of prior donepezil 10 mg/d, and functional severity. The influence of baseline cognitive severity on response seemed to be dependent on the level of impairment, with cognitive benefits of donepezil 23 mg/d over 10 mg/d most apparent in those patients at a more advanced stage of disease. These data may be useful in helping practicing physicians make informed decisions for their patients with advanced Alzheimer's disease. PMID- 23742729 TI - Role of CXCL13 in cigarette smoke-induced lymphoid follicle formation and chronic obstructive pulmonary disease. AB - RATIONALE: The B cell-attracting chemokine CXCL13 is an important mediator in the formation of tertiary lymphoid organs (TLOs). Increased numbers of ectopic lymphoid follicles have been observed in lungs of patients with severe chronic obstructive pulmonary disease (COPD). However, the role of these TLOs in the pathogenesis of COPD remains unknown. OBJECTIVES: By neutralizing CXCL13 in a mouse model of chronic cigarette smoke (CS) exposure, we aimed at interrogating the link between lymphoid follicles and development of pulmonary inflammation, emphysema, and airway wall remodeling. METHODS: We first quantified and localized CXCL13 in lungs of air- or CS-exposed mice and in lungs of never smokers, smokers without airflow obstruction, and patients with COPD by reverse transcriptase polymerase chain reaction, ELISA, and immunohistochemistry. Next, CXCL13 signaling was blocked by prophylactic or therapeutic administration of anti CXCL13 antibodies in mice exposed to air or CS for 24 weeks, and several hallmarks of COPD were evaluated. MEASUREMENTS AND MAIN RESULTS: Both mRNA and protein levels of CXCL13 were increased in lungs of CS-exposed mice and patients with COPD. Importantly, expression of CXCL13 was observed within B-cell areas of lymphoid follicles. Prophylactic and therapeutic administration of anti-CXCL13 antibodies completely prevented the CS-induced formation of pulmonary lymphoid follicles in mice. Interestingly, absence of TLOs attenuated destruction of alveolar walls and inflammation in bronchoalveolar lavage but did not affect airway wall remodeling. CONCLUSIONS: CXCL13 is produced within lymphoid follicles of patients with COPD and is crucial for the formation of TLOs. Neutralization of CXCL13 partially protects mice against CS-induced inflammation in bronchoalveolar lavage and alveolar wall destruction. PMID- 23742730 TI - The enhanced total body wrap--the new frontier in dressing care for burns. AB - The management of extensive burns with their associated high fluid exudate following burn excision and skin grafting has always posed a challenge in burn wound care. The ideal dressing should protect the wound from physical damage and micro-organisms; be comfortable and durable; allow high humidity at the wound; and be able to allow maximal activity for wound healing without retarding or inhibiting any stage of the process. The dressing technique described in this paper fulfils all the criteria above and at the same time provides an efficient channel to effectively clear the excessive exudate produced while keeping the wounds moist. Advantages conferred include accurate charting of wound exudate; reduced frequency of dressing changes; lower infection rates through prevention of strike-through; and securing and improving the viability of skin grafts. An enhancement to a technique previously described by us through the use of long thin strips of VAC sponges to transmit negative pressure, the enhanced Total Body Wrap aims to provide ideal conditions to promote healing in burns. Using negative pressure wound therapy (NPWT), this technique is simple and straightforward enough to be applied in majority of tertiary centres around the world. PMID- 23742731 TI - Determination of hydraulic conductivity from grain-size distribution for different depositional environments. AB - Over 400 unlithified sediment samples were collected from four different depositional environments in global locations and the grain-size distribution, porosity, and hydraulic conductivity were measured using standard methods. The measured hydraulic conductivity values were then compared to values calculated using 20 different empirical equations (e.g., Hazen, Carman-Kozeny) commonly used to estimate hydraulic conductivity from grain-size distribution. It was found that most of the hydraulic conductivity values estimated from the empirical equations correlated very poorly to the measured hydraulic conductivity values with errors ranging to over 500%. To improve the empirical estimation methodology, the samples were grouped by depositional environment and subdivided into subgroups based on lithology and mud percentage. The empirical methods were then analyzed to assess which methods best estimated the measured values. Modifications of the empirical equations, including changes to special coefficients and addition of offsets, were made to produce modified equations that considerably improve the hydraulic conductivity estimates from grain size data for beach, dune, offshore marine, and river sediments. Estimated hydraulic conductivity errors were reduced to 6 to 7.1 m/day for the beach subgroups, 3.4 to 7.1 m/day for dune subgroups, and 2.2 to 11 m/day for offshore sediments subgroups. Improvements were made for river environments, but still produced high errors between 13 and 23 m/day. PMID- 23742732 TI - A systematic review and meta-analysis of the use of oral zinc in the treatment of hepatic encephalopathy. AB - BACKGROUND AND AIM: Because low serum zinc levels precipitate hepatic encephalopathy, zinc supplementation is considered a potential therapeutic option. The aim of this study was to assess the effects of oral zinc supplementation in the treatment of hepatic encephalopathy. METHODS: For this systematic review and meta-analysis, data sources included electronic databases (CENTRAL, MEDLINE, EMBASE) and manual searching. Randomized clinical trials of adult patients diagnosed with liver cirrhosis and hepatic encephalopathy were included. The types of interventions considered were any oral zinc supplementation versus no intervention, placebo, or other interventions for the management of hepatic encephalopathy. The data were analyzed by calculating the RR for each trial and expressing the uncertainty as 95% CI. Continuous data were analyzed by calculating the standard mean differences (SMD) between groups within each trial and their 95% CI. Statistical heterogeneity was defined as a P-value > 0.10 (chi2) or I2 > 25%. RESULTS: Four trials with a total of 233 patients were included. Oral zinc supplementation was associated with a significant improvement in performance on the number connection test (SMD -0.62; 95% CI -1.12 to -0.11) reported in three trials (n = 189), but not with encephalopathy recurrence reduction (RR 0.64; 95% CI 0.26 to 1.59) reported in two trials (n = 169). Other clinically significant outcomes (mortality, liver related morbidity, quality of life) were not reported. CONCLUSION: Oral zinc supplementation improved performance on the number connection test, but no evidence about other clinical or biochemical outcomes was available. PMID- 23742733 TI - Molecular tectonics: control of the dimensionality in tetramercaptothiacalixarenes based coordination networks. AB - Combinations of tetramercaptotetrathiacalix[4]arene pyridyl-appended positional isomers with HgCl2 lead to the formation of neutral coordination networks with their dimensionality imposed by the position of the N atom on the pyridyl group. PMID- 23742735 TI - Fentanyl for the relief of refractory breathlessness: a systematic review. AB - CONTEXT: Fentanyl is a potent opioid that has been proven to provide effective treatment for breakthrough cancer pain. Although opioids are the only drug group with evidence for the symptomatic treatment of breathlessness, evidence about the efficacy of fentanyl for the relief of breathlessness is unknown. OBJECTIVES: We performed a systematic review to evaluate the current evidence for the use of fentanyl for the relief of breathlessness. METHODS: The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses recommendation for systematic reviews. Four databases (MEDLINE, EMBASE, Cochrane Library, International Pharmaceutical Abstracts) were screened using "fentanyl" and "dyspnoea" (and synonyms) as search terms. Hand search and contact with relevant authors completed the search. RESULTS: A total of 622 references were retrieved, 13 of which met the inclusion criteria for this review. Two randomized controlled trials (RCTs) evaluated fentanyl for breathlessness, but one only included two patients. The other studies were before-after (n = 2) and case studies (n = 9). All studies reported successful relief of breathlessness after fentanyl application, but the only (pilot-) RCT failed to demonstrate a statistically significant difference compared with placebo. The nature and incidence of adverse events were comparable with other opioids, and no respiratory depression was observed. CONCLUSION: Descriptive studies yielded promising results for the use of fentanyl for the relief of breathlessness; however, efficacy trials are lacking. Fully powered RCTs are warranted to determine the efficacy of fentanyl for breathlessness relief, but these require pilot studies to evaluate effective size, study procedures, and outcome measures. PMID- 23742734 TI - Impact of advance directives and a health care proxy on doctors' decisions: a randomized trial. AB - CONTEXT: Advance directives or proxy designations are widely recommended, but how they affect doctors' decision making is not well known. OBJECTIVES: The aim of this study was to quantify the influence of advance directives and proxy opinions on doctors' decisions. METHODS: We mailed to all the generalists and internists in French-speaking Switzerland (N = 1962) three vignettes describing difficult decisions involving incapacitated patients. In each case, the advance directive requested that further care be withheld. One vignette tested the impact of a written advance directive vs. a proxy. Another compared the impact of a handwritten directive vs. a formalized document. The third vignette compared the impact of a family member vs. a doctor as a proxy. Each vignette was prepared in three or four versions, including a control version in which no directive or proxy was present. Vignettes were randomly allocated to respondents. We used logistic regression to predict the decision to forgo a medical intervention. RESULTS: Compared with the control condition, the odds of forgoing a medical intervention were increased by the written advance directive (odds ratio [OR] 7.3; P < 0.001), the proxy (OR 7.9; P < 0.001), and the combination of the two (OR 35.7; P < 0.001). The handwritten directive had the same impact (OR 13.3) as the formalized directive (OR 13.8). The effect of proxy opinion was slightly stronger when provided by a doctor (OR 11.3) rather than by family (OR 7.8). CONCLUSION: Advance directives and proxy opinions are equally effective in influencing doctors' decisions, but having both has the strongest effect. The format of the advance directive and the identity of the proxy have little influence on decisions. PMID- 23742736 TI - Palliative sedation versus euthanasia: an ethical assessment. AB - The aim of this article was to review the ethical debate concerning palliative sedation. Although recent guidelines articulate the differences between palliative sedation and euthanasia, the ethical controversies remain. The dominant view is that euthanasia and palliative sedation are morally distinct practices. However, ambiguous moral experiences and considerable practice variation call this view into question. When heterogeneous sedative practices are all labeled as palliative sedation, there is the risk that palliative sedation is expanded to include practices that are actually intended to bring about the patients' death. This troublesome expansion is fostered by an expansive use of the concept of intention such that this decisive ethical concept is no longer restricted to signify the aim in guiding the action. In this article, it is argued that intention should be used in a restricted way. The significance of intention is related to other ethical parameters to demarcate the practice of palliative sedation: terminality, refractory symptoms, proportionality, and separation from other end-of-life decisions. These additional parameters, although not without ethical and practical problems, together formulate a framework to ethically distinguish a more narrowly defined practice of palliative sedation from practices that are tantamount to euthanasia. Finally, the article raises the question as to what impact palliative sedation might have on the practice of palliative care itself. The increasing interest in palliative sedation may reemphasize characteristics of health care that initially encouraged the emergence of palliative care in the first place: the focus on therapy rather than care, the physical dimension rather than the whole person, the individual rather than the community, and the primacy of intervention rather than receptiveness and presence. PMID- 23742737 TI - A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. AB - CONTEXT: Neuropathic pain caused by chemotherapy limits dosing and duration of potentially life-saving anti-cancer treatment and impairs quality of life. Chemotherapeutic neuropathy responds poorly to conventional treatments, and there is an urgent medical need for new treatments. Recent preclinical studies demonstrate that cannabinoid agonists suppress established chemotherapy-evoked neuropathy. OBJECTIVES: This was a pilot trial to begin to investigate a currently available cannabinoid agent, nabiximols (oral mucosal spray containing cannabinoids), in the treatment of chemotherapy-induced neuropathic pain. METHODS: A randomized, placebo-controlled crossover pilot study was done in 16 patients with established chemotherapy-induced neuropathic pain. A 0-10 point numeric rating scale for pain intensity (NRS-PI) was used as the primary outcome measure. RESULTS: When examining the whole group, there was no statistically significant difference between the treatment and the placebo groups on the NRS PI. A responder analysis demonstrated that there were five participants who reported a two-point or greater reduction in pain that trended toward statistical significance and the number needed to treat was five. CONCLUSION: Chemotherapy induced neuropathic pain is particularly resistant to currently available treatments. This pilot trial found a number needed to treat of five and an average decrease of 2.6 on an 11-point NRS-PI in five "responders" (as compared with a decrease of 0.6 with placebo) and supports that it is worthwhile to study nabiximols in a full randomized, placebo-controlled trial of chemotherapy-induced neuropathic pain. PMID- 23742738 TI - Epidural abscess overlooked in a patient receiving chronic opioid therapy. PMID- 23742739 TI - Beyond intuition: patient fever symptom experience. AB - CONTEXT: Fever is an important sign of inflammation recognized by health care practitioners and family caregivers. However, few empirical data obtained directly from patients exist to support many of the long-standing assumptions about the symptoms of fever. Many of the literature-cited symptoms, including chills, diaphoresis, and malaise, have limited scientific bases, yet they often represent a major justification for antipyretic administration. OBJECTIVES: To describe the patient experience of fever symptoms for the preliminary development of a fever assessment questionnaire. METHODS: Qualitative interviews were conducted with 28 inpatients, the majority (86%) with cancer diagnoses, who had a recorded temperature of >=38 degrees C within approximately 12 hours before the interview. A semi-structured interview guide was used to elicit patient fever experiences. Thematic analyses were conducted by three independent research team members, and the data were verified through two rounds of consensus building. RESULTS: Eleven themes emerged. The participants reported experiences of feeling cold, weakness, warmth, sweating, nonspecific bodily sensations, gastrointestinal symptoms, headaches, emotional changes, achiness, respiratory symptoms, and vivid dreams/hallucinations. CONCLUSION: Our data not only confirm long-standing symptoms of fever but also suggest new symptoms and a level of variability and complexity not captured by the existing fever literature. Greater knowledge of patients' fever experiences will guide more accurate assessment of symptoms associated with fever and the impact of antipyretic treatments on patient symptoms in this common condition. Results from this study are contributing to the content validity of a future instrument that will evaluate patient outcomes related to fever interventions. PMID- 23742740 TI - Living with the dying: an early AIDS experience. AB - The HIV/AIDS epidemic in boys and men with hemophilia began in the early 1980s with the puzzling occurrence of systemic illness and fatal opportunistic infections in patients who had received plasma-derived clotting factor concentrates. This brief narrative describes one physician's experience in caring for patients with hemophilia and HIV infection early in the epidemic. PMID- 23742741 TI - Distinct functions for RIP140 in development, inflammation, and metabolism. AB - Nuclear receptors (NRs) regulate tissue development and function by controlling transcription from distinct sets of genes in response to fluctuating levels of hormones or cues that modulate receptor activity. Such target gene activation or repression depends on the recruitment of coactivators or corepressors that lead to chromatin remodelling in the vicinity of target genes. Similarly to receptors, coactivators and corepressors often serve pleiotropic functions, and Nrip1 (RIP140) is no exception, playing roles in animal development and physiology. At first sight, however, RIP140 is unusual in its ability to function either as a coactivator or as a corepressor, and also serve a cytoplasmic role. The functions of RIP140 in different tissues will be summarised together with its potential contribution to disease. PMID- 23742742 TI - Trends in intake of energy and macronutrients in children and adolescents from 1999-2000 through 2009-2010. AB - Between 1999-2000 and 2009-2010, the prevalence of obesity increased among boys, but not among girls. There was no change however, in the prevalence of obesity between 2007-2008 and 2009-2010 for either boys or girls (1). It is unclear if the changes in the prevalence of obesity were associated with corresponding changes in energy and macronutrient intakes in children and adolescents during this time frame. An earlier publication reported trends in energy and macronutrient intake in adults between 1999 and 2008 (2). The objective of this report is to present trends in energy and macronutrient intakes among U.S. children and adolescents aged 2-19 years between 1999 and 2010. These results are presented by sex, age group, and race and ethnicity. PMID- 23742744 TI - Muscarinic acetylcholine receptors in the mouse esophagus: focus on intraganglionic laminar endings (IGLEs). AB - BACKGROUND: IGLEs represent the only low-threshold vagal mechanosensory terminals in the tunica muscularis of the esophagus. Previously, close relationships of vesicular glutamate transporter 2 (VGLUT2) immunopositive IGLEs and cholinergic varicosities suggestive for direct contacts were described in almost all mouse esophageal myenteric ganglia. Possible cholinergic influence on IGLEs requires specific acetylcholine receptors. In particular, the occurrence and location of neuronal muscarinic acetylcholine receptors (mAChR) in the esophagus were not yet characterized. METHODS: This study aimed at specifying relationships of VGLUT2 immunopositive IGLEs and vesicular acetylcholine transporter (VAChT) immunopositive varicosities using pre-embedding electron microscopy and the location of mAChR1-3 (M1-3) within esophagus and nodose ganglia using multilabel immunofluorescence and retrograde tracing. KEY RESULTS: Electron microscopy confirmed synaptic contacts between cholinergic varicosities and IGLEs. M1- and M2-immunoreactivities (-iry; -iries) were colocalized with VGLUT2-iry in subpopulations of IGLEs. Retrograde Fast Blue tracing from the esophagus showed nodose ganglion neurons colocalizing tracer and M2-iry. M1-3-iries were detected in about 80% of myenteric ganglia and in about 67% of myenteric neurons. M1- and M2-iry were present in many fibers and varicosities within myenteric ganglia. Presynaptic M2-iry was detected in all, presynaptic M3-iry in one-fifth of motor endplates of striated esophageal muscles. M1-iry could not be detected in motor endplates of the esophagus, but in sternomastoid muscle. CONCLUSIONS & INFERENCES: Acetylcholine probably released from varicosities of both extrinsic and intrinsic origin may influence a subpopulation of esophageal IGLEs via M2 and M1-receptors. PMID- 23742743 TI - Relative stability of different DNA guanine quadruplex stem topologies derived using large-scale quantum-chemical computations. AB - We provide theoretical predictions of the intrinsic stability of different arrangements of guanine quadruplex (G-DNA) stems. Most computational studies of nucleic acids have applied Molecular Mechanics (MM) approaches using simple pairwise-additive force fields. The principle limitation of such calculations is the highly approximate nature of the force fields. In this study, we for the first time apply accurate QM computations (DFT-D3 with large atomic orbital basis sets) to essentially complete DNA building blocks, seven different folds of the cation-stabilized two-quartet G-DNA stem, each having more than 250 atoms. The solvent effects are approximated by COSMO continuum solvent. We reveal sizable differences between MM and QM descriptions of relative energies of different G DNA stems, which apparently reflect approximations of the DNA force field. Using the QM energy data, we propose correction to earlier free energy estimates of relative stabilities of different parallel, hybrid, and antiparallel G-stem folds based on classical simulations. The new energy ranking visibly improves the agreement between theory and experiment. We predict the 5'-anti-anti-3' GpG dinucleotide step to be the most stable one, closely followed by the 5'-syn-anti 3' step. The results are in good agreement with known experimental structures of 2-, 3-, and 4-quartet G-DNA stems. Besides providing specific results for G-DNA, our study highlights basic limitations of force field modeling of nucleic acids. Although QM computations have their own limitations, mainly the lack of conformational sampling and the approximate description of the solvent, they can substantially improve the quality of calculations currently relying exclusively on force fields. PMID- 23742745 TI - Proline modulates the effect of bisphosphonate on calcium levels and adenosine triphosphate production in cell lines derived from bovine Echinococcus granulosus protoscoleces. AB - Bisphosphonates have been proposed as pharmacological agents against parasite and cancer cell growth. The effect of these compounds on helminthic cell viability and acellular compartment morphology, however, has not yet been studied. The effects of different types of bisphosphonates, namely etidronate (EHDP), pamidronate (APD), alendronate (ABP), ibandronate (IB) and olpadronate (OPD), and their interaction with amiloride, 1,25-dihydroxycholecalciferol (D3) and proline were evaluated on a cell line derived from bovine Echinococcus granulousus protoscoleces (EGPE) that forms cystic colonies in agarose. The EGPE cell line allowed testing the effect of bisphosphonates alone and in association with other compounds that could modulate calcium apposition/deposition, and were useful in measuring the impact of these compounds on cell growth, cystic colony formation and calcium storage. Decreased cell growth and cystic colony formation were found with EHDP, IB and OPD, and increased calcium storage with EHDP only. Calcium storage in EGPE cells appeared to be sensitive to the effect of amiloride, D3 and proline. Proline decreased calcium storage and increased colony formation. Changes in calcium storage may be associated with degenerative changes of the cysts, as shown in the in vitro colony model and linked to an adenosine triphosphate (ATP) decrease. In conclusion, bisphosphonates could be suitable tempering drugs to treat cestode infections. PMID- 23742746 TI - Quantitation of gamma-hydroxybutyric acid in dried blood spots: feasibility assessment for newborn screening of succinic semialdehyde dehydrogenase (SSADH) deficiency. AB - OBJECTIVE: SSADH deficiency, the most prevalent autosomal recessive disorder of GABA degradation, is characterized by elevated gamma-hydroxybutyric acid (GHB). Neurological outcomes may be improved with early intervention and anticipatory guidance. Morbidity has been compounded by complications, e.g. hypotonia, in undiagnosed infants with otherwise routine childhood illnesses. We report pilot methodology on the feasibility of newborn screening for SSADH deficiency. METHOD: Dried blood spot (DBS) cards from patients affected with SSADH deficiency were compared with 2831 archival DBS cards for gamma-hydroxybutyric acid content. Following extraction with methanol, GHB in DBS was separated and analyzed using ultra high-performance liquid chromatography tandem mass spectrometry. RESULTS: Methodology was validated to meet satisfactory accuracy and reproducibility criteria, including intra-day and inter-day validation. Archival refrigerated dried blood spot samples of babies, infants and children (N = 2831) were screened for GHB, yielding a mean +/- S.D. of 8 +/- 5 nM (99.9%-tile 63 nM) (Min 0.0 Max 78 nM). The measured mean and median concentrations in blood spots derived from seven SSADH deficient patients were 1182 nM and 699 nM respectively (Min 124, Max 4851 nM). CONCLUSIONS: GHB concentration in all 2831 dried blood spot cards was well below the lowest concentration of affected children. These data provide proof-of-principle for screening methodology to detect SSADH deficiency with applicability to newborn screening and earlier diagnosis. PMID- 23742747 TI - A glimpse into past, present, and future DNA sequencing. AB - Current advances in DNA sequencing technologies are dropping down sequencing cost while increasing throughput at a pace never shown before. Past-decade great milestones, as the establishment of a reference human genome (amongst others) and large-scale human genetic variation study in the 1000 Genome project are, in conjunction with the use of these techniques, triggering advances in many areas of basic and applied science. These tools, stored in and combined with the vast amount of information present in biological online databases are, with the use of automated interpretation and analysis tools, allowing the fulfillment of increasingly ambitious studies in many areas and also are democratizing the access to information, interpretation and technologies, being the first opportunity for researchers to assess the influence of genetics in complex events as multifactorial diseases, evolutionary studies, metagenomics, transcriptomics, etc. In this review, we present the current state of the art of these technologies, focusing on second generation sequencing, from sample and library preparation to sequencing chemistries and bioinformatic software available for final data analysis and visualisation, with its possible applications. We also make an overview of first and third generation, due to its historical importance and for being the upcoming future tools for genetic analysis, respectively. PMID- 23742748 TI - Direct targeting of proteins to lipid droplets demonstrated by time-lapse live cell imaging. AB - A protein that specifically targets lipid droplets (LDs) was created by connecting two domains of nonstructural protein 4B containing amphipathic helices from hepatitis C virus. We demonstrated its direct targeting and accumulation to the LD surface by time-lapse live cell imaging, comparable to those observed with adipose differentiation-related protein. PMID- 23742750 TI - Intermolecular/interionic vibrations of 1-methyl-3-n-octylimidazolium tetrafluoroborate ionic liquid and benzene mixtures. AB - Intermolecular/interionic vibrational spectra of mixtures composed of 1-methyl-3 n-octylimidazolium tetrafluoroborate ionic liquid and benzene at mole fractions of 0 (i.e., neat ionic liquid), 0.2, 0.4, 0.6, 0.8, and 1.0 (i.e., neat benzene) have been investigated using femtosecond Raman-induced Kerr effect spectroscopy. The line shape of the low-frequency Kerr spectra obtained from Fourier transform analyses of the Kerr transients is strongly dependent on the composition of the mixture. By comparing the experimental spectra to calculated spectra based on experimental spectra of the neat liquids, it is evident that the spectrum is not achieved by simply combining those of the neat liquids and taking the mole fraction into consideration. Close examination of the spectral comparison results in a microscopic picture involving specific stacking of imidazolium and benzene rings that is not sufficiently stable to affect the ring librations. The quantum chemistry calculation results also support this proposal. No clear correlation between the first moment of the spectrum and the bulk parameter (i.e., the square root of the surface tension divided by the liquid density), which occurs for neat liquids, is evident. PMID- 23742749 TI - Analysis of the use of codon pairs in the HE gene of the ISA virus shows a correlation between bias in HPR codon-pair use and mortality rates caused by the virus. AB - BACKGROUND: Segment 6 of the ISA virus codes for hemoagglutinin-esterase (HE). This segment is highly variable, with more than 26 variants identified. The major variation is observed in what is called the high polymorphism region (HPR). The role of the different HPR zones in the viral cycle or evolution remains unknown. However viruses that present the HPR0 are avirulent, while viruses with important deletions in this region have been responsible for outbreaks with high mortality rates. In this work, using bioinformatic tools, we examined the influence of different HPRs on the adaptation of HE genes to the host translational machinery and the relationship to observed virulence. METHODS: Translational efficiency of HE genes and their HPR were estimated analyzing codon-pair bias (CPB), adaptation to host codon use (codon adaptation index-CAI) and the adaptation to available tRNAs (tAI). These values were correlated with reported mortality for the respective ISA virus and the DeltaG of RNA folding. tRNA abundance was inferred from tRNA gene numbers identified in the Salmo salar genome using tRNAScan-SE. Statistical correlation between data was performed using a non-parametric test. RESULTS: We found that HPR0 contains zones with codon pairs of low frequency and low availability of tRNA with respect to salmon codon-pair usage, suggesting that HPR modifies HE translational efficiency. Although calculating tAI was impossible because one third of tRNAs (~60.000) were tRNA-ala, translational efficiency measured by CPB shows that as HPR size increases, the CPB value of the HE gene decreases (P = 2x10-7, rho = -0.675, n = 63) and that these values correlate positively with the mortality rates caused by the virus (rho = 0.829, P = 2x10-7, n = 11). The mortality associated with different virus isolates or their corresponding HPR sizes were not related with the DeltaG of HPR RNA folding, suggesting that the secondary structure of HPR RNA does not modify virulence. CONCLUSIONS: Our results suggest that HPR size affects the efficiency of gene translation, which modulates the virulence of the virus by a mechanism similar to that observed in production of live attenuated vaccines through deoptimization of codon-pair usage. PMID- 23742751 TI - Nutritional impacts of a fruit and vegetable subsidy programme for disadvantaged Australian Aboriginal children. AB - Healthy food subsidy programmes have not been widely implemented in high-income countries apart from the USA and the UK. There is, however, interest being expressed in the potential of healthy food subsidies to complement nutrition promotion initiatives and reduce the social disparities in healthy eating. Herein, we describe the impact of a fruit and vegetable (F&V) subsidy programme on the nutritional status of a cohort of disadvantaged Aboriginal children living in rural Australia. A before-and-after study was used to assess the nutritional impact in 174 children whose families received weekly boxes of subsidised F&V organised through three Aboriginal medical services. The nutritional impact was assessed by comparing 24 h dietary recalls and plasma carotenoid and vitamin C levels at baseline and after 12 months. A general linear model was used to assess the changes in biomarker levels and dietary intake, controlled for age, sex, community and baseline levels. Baseline assessment in 149 children showed low F&V consumption. Significant increases (P< 0.05) in beta-cryptoxanthin (28.9 nmol/l, 18%), vitamin C (10.1 MUmol/l, 21%) and lutein-zeaxanthin (39.3 nmol/l, 11%) levels were observed at the 12-month follow-up in 115 children, although the self reported F&V intake was unchanged. The improvements in the levels of biomarkers of F&V intake demonstrated in the present study are consistent with increased F&V intake. Such dietary improvements, if sustained, could reduce non-communicable disease rates. A controlled study of healthy food subsidies, together with an economic analysis, would facilitate a thorough assessment of the costs and benefits of subsidising healthy foods for disadvantaged Aboriginal Australians. PMID- 23742752 TI - A robust, sensitive assay for genomic uracil determination by LC/MS/MS reveals lower levels than previously reported. AB - Considerable progress has been made in understanding the origins of genomic uracil and its role in genome stability and host defense; however, the main question concerning the basal level of uracil in DNA remains disputed. Results from assays designed to quantify genomic uracil vary by almost three orders of magnitude. To address the issues leading to this inconsistency, we explored possible shortcomings with existing methods and developed a sensitive LC/MS/MS based method for the absolute quantification of genomic 2'-deoxyuridine (dUrd). To this end, DNA was enzymatically hydrolyzed to 2'-deoxyribonucleosides and dUrd was purified in a preparative HPLC step and analyzed by LC/MS/MS. The standard curve was linear over four orders of magnitude with a quantification limit of 5 fmol dUrd. Control samples demonstrated high inter-experimental accuracy (94.3%) and precision (CV 9.7%). An alternative method that employed UNG2 to excise uracil from DNA for LC/MS/MS analysis gave similar results, but the intra-assay variability was significantly greater. We quantified genomic dUrd in Ung(+/+) and Ung(-/-) mouse embryonic fibroblasts and human lymphoblastoid cell lines carrying UNG mutations. DNA-dUrd is 5-fold higher in Ung(-/-) than in Ung(+/+) fibroblasts and 11-fold higher in UNG2 dysfunctional than in UNG2 functional lymphoblastoid cells. We report approximately 400-600 dUrd per human or murine genome in repair proficient cells, which is lower than results using other methods and suggests that genomic uracil levels may have previously been overestimated. PMID- 23742753 TI - A risk score for identifying methicillin-resistant Staphylococcus aureus in patients presenting to the hospital with pneumonia. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) represents an important pathogen in healthcare-associated pneumonia (HCAP). The concept of HCAP, though, may not perform well as a screening test for MRSA and can lead to overuse of antibiotics. We developed a risk score to identify patients presenting to the hospital with pneumonia unlikely to have MRSA. METHODS: We identified patients admitted with pneumonia (Apr 2005-Mar 2009) at 62 hospitals in the US. We only included patients with lab evidence of bacterial infection (e.g., positive respiratory secretions, blood, or pleural cultures or urinary antigen testing). We determined variables independently associated with the presence of MRSA based on logistic regression (two-thirds of cohort) and developed a risk prediction model based on these factors. We validated the model in the remaining population. RESULTS: The cohort included 5975 patients and MRSA was identified in 14%. The final risk score consisted of eight variables and a potential total score of 10. Points were assigned as follows: two for recent hospitalization or ICU admission; one each for age < 30 or > 79 years, prior IV antibiotic exposure, dementia, cerebrovascular disease, female with diabetes, or recent exposure to a nursing home/long term acute care facility/skilled nursing facility. This study shows how the prevalence of MRSA rose with increasing score after stratifying the scores into Low (0 to 1 points), Medium (2 to 5 points) and High (6 or more points) risk. When the score was 0 or 1, the prevalence of MRSA was < 10% while the prevalence of MRSA climbed to > 30% when the score was 6 or greater. CONCLUSIONS: MRSA represents a cause of pneumonia presenting to the hospital. This simple risk score identifies patients at low risk for MRSA and in whom anti MRSA therapy might be withheld. PMID- 23742754 TI - Patient experiences with involuntary out-of-network charges. AB - BACKGROUND: Approximately 40 percent of individuals using out-of-network physicians experience involuntary out-of-network care, leading to unexpected and sometimes burdensome financial charges. Despite its prevalence, research on patient experiences with involuntary out-of-network care is limited. Greater understanding of patient experiences may inform policy solutions to address this issue. OBJECTIVE: To characterize the experiences of patients who encountered involuntary out-of-network physician charges. METHODS: Qualitative study using 26 in-depth telephone interviews with a semi-structured interview guide. Participants were a purposeful sample of privately insured adults from across the United States who experienced involuntary out-of-network care. They were diverse with regard to income level, education, and health status. Recurrent themes were generated using the constant comparison method of data analysis by a multidisciplinary team. RESULTS: Four themes characterize the perspective of individuals who experienced involuntary out-of-network physician charges: (1) responsibilities and mechanisms for determining network participation are not transparent; (2) physician procedures for billing and disclosure of physician out of-network status are inconsistent; (3) serious illness requiring emergency care or hospitalization precludes ability to choose a physician or confirm network participation; and (4) resources for mediation of involuntary charges once they occur are not available. CONCLUSIONS: Our data reveal that patient education may not be sufficient to reduce the prevalence and financial burden of involuntary out-of-network care. Participants described experiencing involuntary out-of network health care charges due to system-level failures. As policy makers seek solutions, our findings suggest several potential areas of further consideration such as standardization of processes to disclose that a physician is out-of network, holding patients harmless not only for out-of-network emergency room care but also for non-elective hospitalization, and designation of a mediator for involuntary charges. PMID- 23742755 TI - Equity in the distribution of CT and MRI in China: a panel analysis. AB - INTRODUCTION: China is facing a daunting challenge to health equity in the context of rapid economic development. This study adds to the literature by examining equity in the distribution of high-technology medical equipment, such as CT and MRI, in China. METHODS: A panel analysis was conducted with information about four study sites in 2006 and 2009. The four provincial-level study sites included Shanghai, Zhejiang, Shaanxi, and Hunan, representing different geographical, economic, and medical technology levels in China. A random sample of 71 hospitals was selected from the four sites. Data were collected through questionnaire surveys. Equity status was assessed in terms of CT and MRI numbers, characteristics of machine, and financing sources. The assessment was conducted at multiple levels, including international, provincial, city, and hospital level. In addition to comparison among the study sites, the sample was compared with OECD countries in CT and MRI distributions. RESULTS: China had lower numbers of CTs and MRIs per million population in 2009 than most of the selected OECD countries while the increases in its CT and MRI numbers from 2006 to 2009 were higher than most of the OECD countries. The equity status of CT distribution remained at low inequality level in both 2006 and 2009 while the equity status of MRI distribution improved from high inequality in 2006 to moderate inequality in 2009. Despite the equity improvement, the distributions of CTs and MRIs were significantly positively correlated with economic development level across all cities in the four study sites in either 2006 or 2009. Our analysis also revealed that Shanghai, the study site with the highest level of economic development, had more advanced CT and MRI machine, more imported CTs and MRIs, and higher government subsidies on these two types of equipment. CONCLUSIONS: The number of CTs and MRIs increased considerably in China from 2006 to 2009. The equity status of CTs was better than that of MRIs although the equity status in MRI distribution got improved from 2006 to 2009. Still considerable inequality exists in terms of characteristics and financing of CTs and MRIs. PMID- 23742756 TI - Death in the United States, 2011. AB - In 2011, the age-adjusted death rate for the United States was 740.6 per 100,000 population (1). This rate represents a 0.9% drop from the rate in 2010 (747.0), and is a record low. The highest mortality was observed for the non-Hispanic black population (903.9), followed by the non-Hispanic white population (753.9). Death rates for all race groups of the U.S. population generally have been decreasing since 1935 (2), and the rates for the Hispanic population have been declining since the late 1990s (3). Data for 2011 maintain that trend. The figures presented in this report are based on preliminary mortality data for 2011 and final data for 2000-2010. PMID- 23742757 TI - Characterization of human FCRLA isoforms. AB - FCRLA is an ER-resident B-cell specific protein. The exact function of this protein remains unclear although human FCRLA has been recently shown to interact with IgM, IgG and IgA. The retention of FCRLA in ER is mediated by the N-terminal domain. The major human FCRLA isoform is encoded by five exons, of which one encodes a short signal peptide (SSP) and the others code four protein domains. Here we show that human tissues also produce transcripts which contain an additional exon and encode proteins with signal peptide that is six residues longer (LSP). Transfection experiments demonstrated that the extension of the signal peptide had no visible effect on the topology and molecular mass of the processed four-domain FCRLA isoform. However, the length of the signal peptide was found to affect processing of two-domain FCRLA isoforms composed of the third and fourth domains (FCRLAd2). The signal peptide was not cleaved in the SSP FCRLAd2 and this isoform was found to accumulate in the ER. In contrast, the LSP containing FCRLAd2 isoform was processed, O-glycosylated and secreted. The secreted FCRLAd2 isoform did not interact with IgG- or IgM-immunosorbents. PMID- 23742758 TI - Combined Cathepsin S and hs-CRP predicting inflammation of abdominal aortic aneurysm. AB - OBJECTIVES: Cathepsin S (Cat S) protein expression is increased in human abdominal aortic aneurysm (AAA) lesions and Cat S has been suggested a direct role by promoting inflammatory response partly in experimental AAA. The purpose of this study is to observe the expression of serum Cat S and hs-CRP and its clinical significance in AAA patients. DESIGN AND METHODS: We collected serum samples from 31 AAA patients and 32 controls. Cat S and hs-CRP levels were measured by a sandwich-type enzyme-linked immunosorbent assay (ELISA) and an enhanced immunoturbidimetric assay respectively. The maximum diameter of the AAA was identified by ultrasonography. RESULTS: The patients with AAA had higher serum Cat S and hs-CRP levels than the controls (p<0.05). Furthermore, human serum Cat S levels were strongly correlated with hs-CRP by the nonparametric Spearman correlation tests (B=0.849, p<0.05). Based on Pearson's correlation test, human serum Cat S and hs-CRP levels were positively correlated with AAA diameter size (p<0.05). Cat S was correlated independently with the hs-CRP in all subjects (p<0.01). After adjustment for the maximum diameter of the abdominal aorta-associated variables, Cat S combined hs-CRP (R(2)=0.801) is better than Cat S (R(2)=0.740) in predicting the maximum diameter of AAA lesions. CONCLUSION: Combined serum Cat S and hs-CRP levels are better in predicting the inflammatory activity of AAA lesions in the clinical setting. PMID- 23742759 TI - Associations between genetic polymorphisms of paraoxonase genes and coronary artery disease in a Taiwanese population. AB - OBJECTIVE: We evaluated the relationship between polymorphisms of the paraoxonase (PON) gene and the risk of coronary artery disease (CAD) in Taiwanese patients. METHODS: Our sample set included 369 volunteers, classified into two groups: 162 healthy volunteers and 207 CAD patients aged 60.0 +/- 9.7 and 64.3 +/- 12.3 years, respectively. Polymorphisms of the PON1 and PON2 genes were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR RFLP) techniques. RESULTS: The results indicate that for the PON1 gene, the homozygous genotype RR was found significantly more often among the CAD group compared with the healthy group (OR=1.965, 95% CI=1.223-3.159, p=0.005). Furthermore, for the PON2 gene, the homozygous genotype CC was found significantly more often among the CAD group compared with the control group (OR=2.525, 95% CI=1.103-5.780, p=0.026). CONCLUSIONS: Individuals homozygous for the R allele of the PON1 gene and the C allele of the PON2 gene are more likely to have an increased risk of CAD. PMID- 23742760 TI - Prion formation correlates with activation of translation-regulating protein 4E BP and neuronal transcription factor Elk1. AB - Cellular mechanisms play a role in conversion of the normal prion protein PrP(C) to the disease-associated protein PrP(Sc). The cells provide not only PrP(C), but also still largely undefined factors required for efficient prion replication. Previously, we have observed that interference with ERK and p38-JNK MAP kinase pathways has opposing effects on the formation of prions indicating that the process is regulated by a balance in intracellualar signaling pathways. In order to obtain a "flow-chart" of such pathways, we here studied the activation of MEK/ERK and mTORC1 downstream targets in relation to PrP(Sc) accumulation in GT1 1 cells infected with the RML or 22L prion strains. We show that inhibition of mTORC1 with rapamycin causes a reduction of PrP(Sc) accumulation at similar low levels as seen when the interaction between the translation initiation factors eIF4E and eIF4G downstream mTORC1 is inhibited using 4EGI-1. No effect is seen following the inhibition of molecules (S6K1 and Mnk1) that links MEK/ERK signaling to mTORC1-mediated control of translation. Instead, stimulation (high [KCl] or [serum]) or inhibition (MEK-inhibitor) of prion formation is associated with increased or decreased phosphorylation of the neuronal transcription factor Elk1, respectively. This study shows that prion formation can be modulated by translational initiating factors, and suggests that MEK/ERK signaling plays a role in the conversion of PrP(C) to PrP(Sc) via an Elk1-mediated transcriptional control. Altogether, our studies indicate that prion protein conversion is under the control of intracellular signals, which hypothetically, under certain conditions may elicit irreversible responses leading to progressive neurodegenerative diseases. PMID- 23742761 TI - Defective synaptic transmission and structure in the dentate gyrus and selective fear memory impairment in the Rsk2 mutant mouse model of Coffin-Lowry syndrome. AB - The Coffin-Lowry syndrome (CLS) is a syndromic form of intellectual disability caused by loss-of-function of the RSK2 serine/threonine kinase encoded by the rsk2 gene. Rsk2 knockout mice, a murine model of CLS, exhibit spatial learning and memory impairments, yet the underlying neural mechanisms are unknown. In the current study, we examined the performance of Rsk2 knockout mice in cued, trace and contextual fear memory paradigms and identified selective deficits in the consolidation and reconsolidation of hippocampal-dependent fear memories as task difficulty and hippocampal demand increase. Electrophysiological, biochemical and electron microscopy analyses were carried out in the dentate gyrus of the hippocampus to explore potential alterations in neuronal functions and structure. In vivo and in vitro electrophysiology revealed impaired synaptic transmission, decreased network excitability and reduced AMPA and NMDA conductance in Rsk2 knockout mice. In the absence of RSK2, standard measures of short-term and long term potentiation (LTP) were normal, however LTP-induced CREB phosphorylation and expression of the transcription factors EGR1/ZIF268 were reduced and that of the scaffolding protein SHANK3 was blocked, indicating impaired activity-dependent gene regulation. At the structural level, the density of perforated and non perforated synapses and of multiple spine boutons was not altered, however, a clear enlargement of spine neck width and post-synaptic densities indicates altered synapse ultrastructure. These findings show that RSK2 loss-of-function is associated in the dentate gyrus with multi-level alterations that encompass modifications of glutamate receptor channel properties, synaptic transmission, plasticity-associated gene expression and spine morphology, providing novel insights into the mechanisms contributing to cognitive impairments in CLS. PMID- 23742762 TI - Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age. AB - Mutations in the DYNC1H1 gene encoding for dynein heavy chain cause two closely related human motor neuropathies, dominant spinal muscular atrophy with lower extremity predominance (SMA-LED) and axonal Charcot-Marie-Tooth (CMT) disease, and lead to sensory neuropathy and striatal atrophy in mutant mice. Dynein is the molecular motor carrying mitochondria retrogradely on microtubules, yet the consequences of dynein mutations on mitochondrial physiology have not been explored. Here, we show that mouse fibroblasts bearing heterozygous or homozygous point mutation in Dync1h1, similar to human mutations, show profoundly abnormal mitochondrial morphology associated with the loss of mitofusin 1. Furthermore, heterozygous Dync1h1 mutant mice display progressive mitochondrial dysfunction in muscle and mitochondria progressively increase in size and invade sarcomeres. As a likely consequence of systemic mitochondrial dysfunction, Dync1h1 mutant mice develop hyperinsulinemia and hyperglycemia and progress to glucose intolerance with age. Similar defects in mitochondrial morphology and mitofusin levels are observed in fibroblasts from patients with SMA-LED. Last, we show that Dync1h1 mutant fibroblasts show impaired perinuclear clustering of mitochondria in response to mitochondrial uncoupling. Our results show that dynein function is required for the maintenance of mitochondrial morphology and function with aging and suggest that mitochondrial dysfunction contributes to dynein-dependent neurological diseases, such as SMA-LED. PMID- 23742763 TI - An ASK1-p38 signalling pathway mediates hydrogen peroxide-induced toxicity in NG108-15 neuronal cells. AB - Reactive oxygen species (ROS) are believed to be involved in many forms of neurodegeneration, including ischaemic infarct damage and Alzheimer's disease. Despite the known involvement of p38 and JNK MAP kinases in mediating apoptosis and cell death in a variety of cell types, the details of the signalling pathways activated in neuronal cells by ROS are poorly characterised. Recently TAK1 (MAP3K7), a kinase upstream of JNK and p38, has attracted attention as a possible mediator of ischaemic cell death. This study tested the hypothesis that hydrogen peroxide (H2O2), which produces ROS, induces apoptosis in the NG108-15 neuronal cell line via activation of either TAK1 or the related kinase ASK1 (MAP3K5). H2O2 caused a concentration-dependent reduction in cell viability associated with caspase 3 activation. Loss of cell viability was inhibited by a selective caspase 3 inhibitor, and by the p38 inhibitor SB203580, but was not affected by the JNK inhibitor SP600125. The selective TAK1 inhibitor 5Z-7-oxozeaenol (5Z-7) exacerbated the loss of cell viability, whereas the ASK1 inhibitor NQDI-1 completely prevented caspase activation and cell death. These results show that pharmacological inhibition of ASK1 is neuroprotective, implicating an ASK1-p38 signalling pathway in ROS-induced apoptosis in neurones. The results also imply that the role of TAK1 may be neuroprotective rather than pro-degenerative. PMID- 23742764 TI - In vivo efficacy of PF1022A and nicotinic acetylcholine receptor agonists alone and in combination against Nippostrongylus brasiliensis. AB - The cyclooctadepsipeptide PF1022A and the aminophenylamidines amidantel, deacylated amidantel (dAMD) and tribendimidine were tested as examples for drug classes potentially interesting for development as anthelmintics against human helminthiases. These compounds and levamisole were tested alone and in combination to determine their efficacy against the rat hookworm Nippostrongylus brasiliensis. After three oral treatments, intestinal worms were counted. Drug effects on parasite morphology were studied using scanning electron microscopy (SEM). Plasma pharmacokinetics were determined for tribendimidine and dAMD. All drugs reduced worm burden in a dose-dependent manner, however amidantel was significantly less active than the other aminophenylamidines. Combinations of tribendimidine and dAMD with levamisole or PF1022A at suboptimal doses revealed additive effects. While PF1022A caused virtually no changes in morphology, levamisole, dAMD and tribendimidine caused severe contraction, particularly in the hind body region. Worms exposed to combinations of PF1022A and aminophenylamidines were indistinguishable from worms exposed only to aminophenylamidines. After oral treatment with tribendimidine, only the active metabolite dAMD was detectable in plasma and concentrations were not significantly different for oral treatment with dAMD. The results support further evaluation of cyclooctadepsipeptides alone and in combination with cholinergic drugs to improve efficacy. Combining these with registered drugs may help to prevent development of resistance. PMID- 23742766 TI - National guidelines for donation after cardiac death in China. PMID- 23742765 TI - Sequencing viral genomes from a single isolated plaque. AB - BACKGROUND: Whole genome sequencing of viruses and bacteriophages is often hindered because of the need for large quantities of genomic material. A method is described that combines single plaque sequencing with an optimization of Sequence Independent Single Primer Amplification (SISPA). This method can be used for de novo whole genome next-generation sequencing of any cultivable virus without the need for large-scale production of viral stocks or viral purification using centrifugal techniques. METHODS: A single viral plaque of a variant of the 2009 pandemic H1N1 human Influenza A virus was isolated and amplified using the optimized SISPA protocol. The sensitivity of the SISPA protocol presented here was tested with bacteriophage F_HA0480sp/Pa1651 DNA. The amplified products were sequenced with 454 and Illumina HiSeq platforms. Mapping and de novo assemblies were performed to analyze the quality of data produced from this optimized method. RESULTS: Analysis of the sequence data demonstrated that from a single viral plaque of Influenza A, a mapping assembly with 3590-fold average coverage representing 100% of the genome could be produced. The de novo assembled data produced contigs with 30-fold average sequence coverage, representing 96.5% of the genome. Using only 10 pg of starting DNA from bacteriophage F_HA0480sp/Pa1651 in the SISPA protocol resulted in sequencing data that gave a mapping assembly with 3488-fold average sequence coverage, representing 99.9% of the reference and a de novo assembly with 45-fold average sequence coverage, representing 98.1% of the genome. CONCLUSIONS: The optimized SISPA protocol presented here produces amplified product that when sequenced will give high quality data that can be used for de novo assembly. The protocol requires only a single viral plaque or as little as 10 pg of DNA template, which will facilitate rapid identification of viruses during an outbreak and viruses that are difficult to propagate. PMID- 23742767 TI - Pancreatic duct disruption and nonoperative management: the SEALANTS approach. PMID- 23742768 TI - Comprehensive application of modern technologies in precise liver resection. AB - BACKGROUND: Liver surgery has gone through the phases of wedge liver resection, regular resection of hepatic lobes, irregular and local resection, extracorporeal hepatectomy, hemi-extracorporeal hepatectomy and Da Vinci surgical system assisted hepatectomy. Taking advantage of modern technologies, liver surgery is stepping into an age of precise liver resection. This review aimed to analyze the comprehensive application of modern technologies in precise liver resection. DATA SOURCE: PubMed search was carried out for English-language articles relevant to precise liver resection, liver anatomy, hepatic blood inflow blockage, parenchyma transection, and down-staging treatment. RESULTS: The 3D image system can imitate the liver operation procedures, conduct risk assessment, help to identify the operation feasibility and confirm the operation scheme. In addition, some techniques including puncture and injection of methylene blue into the target Glisson sheath help to precisely determine the resection. Alternative methods such as Pringle maneuver are helpful for hepatic blood inflow blockage in precise liver resection. Moreover, the use of exquisite equipment for liver parenchyma transection, such as cavitron ultrasonic surgical aspirator, ultrasonic scalpel, Ligasure and Tissue Link is also helpful to reduce hemorrhage in liver resection, or even operate exsanguinous liver resection without blocking hepatic blood flow. Furthermore, various down-staging therapies including transcatheter arterial chemoembolization and radio-frequency ablation were appropriate for unresectable cancer, which reverse the advanced tumor back to early phase by local or systemic treatment so that hepatectomy or liver transplantation is possible. CONCLUSIONS: Modern technologies mentioned in this paper are the key tool for achieving precise liver resection and can effectively lead to maximum preservation of anatomical structural integrity and functions of the remnant liver. In addition, large randomized trials are needed to evaluate the usefulness of these technologies in patients with hepatocellular carcinoma who have undergone precise liver resection. PMID- 23742769 TI - Perioperative antiviral therapy for chronic hepatitis B-related hepatocellular carcinoma. AB - BACKGROUND: After effective treatment with antiviral agent, patients with low serum hepatitis B virus (HBV) DNA level had a low incidence of hepatocellular carcinoma (HCC). HBV reactivation after HCC surgery is associated with HCC recurrence. To date, there are no universal guidelines for the perioperative antiviral treatment of patients with chronic hepatitis B, let alone antiviral therapy in patients with HBV-related HCC. The present analysis is trying to develop a perioperative anti-HBV treatment protocol. DATA SOURCES: A literature search of PubMed was performed, the key words were "perioperative" "antiviral therapy", "hepatocellular carcinoma" and "chronic hepatitis B". All of the information was collected. RESULTS: Relevant documents showed that reactivation of HBV replication played a direct role in the late recurrence of HCC after surgical resection. The well control of viral load before and after operation significantly increased tumor-free survival. Many drugs are used in antiviral therapy including interferon alpha and nucleoside analogues. Foscarnet, two-agent or even multiagent of nucleoside analogues is necessary for perioperative antiviral treatment of patients with chronic hepatitis B related HCC. CONCLUSIONS: HBV reactivation after HCC surgery induces hepatitis flare and hepatocarcinogenesis, thus lifelong and vigorous control of HBV is very important in patients with chronic hepatitis B and HBV-related HCC. A uniform guideline is necessary to rapidly reduce HBV DNA to a lower level in perioperation. PMID- 23742770 TI - Survival outcomes of right-lobe living donor liver transplantation for patients with high Model for End-stage Liver Disease scores. AB - BACKGROUND: Controversy exists over whether living donor liver transplantation (LDLT) should be offered to patients with high Model for End-stage Liver Disease (MELD) scores. This study tried to determine whether a high MELD score would result in inferior outcomes of right-lobe LDLT. METHODS: Among 411 consecutive patients who received right-lobe LDLT at our center, 143 were included in this study. The patients were divided into two groups according to their MELD scores: a high-score group (MELD score >=25; n=75) and a low-score group (MELD score <25; n=68). Their demographic data and perioperative conditions were compared. Univariable and multivariable analyses were performed to identify risk factors affecting patient survival. RESULTS: In the high-score group, more patients required preoperative intensive care unit admission (49.3% vs 2.9%; P<0.001), mechanical ventilation (21.3% vs 0%; P<0.001), or hemodialysis (13.3% vs 0%; P=0.005); the waiting time before LDLT was shorter (4 vs 66 days; P<0.001); more blood was transfused during operation (7 vs 2 units; P<0.001); patients stayed longer in the intensive care unit (6 vs 3 days; P<0.001) and hospital (21 vs 15 days; P=0.015) after transplantation; more patients developed early postoperative complications (69.3% vs 50.0%; P=0.018); and values of postoperative peak blood parameters were higher. However, the two groups had comparable hospital mortality. Graft survival and patient overall survival at one year (94.7% vs 95.6%; 95.9% vs 96.9%), three years (91.9% vs 92.6%; 93.2% vs 95.3%), and five years (90.2% vs 90.2%; 93.2% vs 95.3%) were also similar between the groups. CONCLUSIONS: Although the high-score group had significantly more early postoperative complications, the two groups had comparable hospital mortality and similar satisfactory rates of graft survival and patient overall survival. Therefore, a high MELD score should not be a contraindication to right-lobe LDLT if donor risk and recipient benefit are taken into full account. PMID- 23742771 TI - Surgical treatment of hepatocellular carcinoma with inferior vena cava tumor thrombus: a new classification for surgical guidance. AB - BACKGROUND: Hepatic resection is the main treatment modality for hepatic tumors. Advances in diagnostic technique, preoperative preparation, surgical technique, and postoperative management increased the success rate. The present study aimed to evaluate hepatectomy and resection of inferior vena cava tumor thrombus (IVCTT) in patients with hepatocellular carcinoma, and the relationship between IVCTT classification and selection of surgical technique. METHODS: We retrospectively reviewed 13 patients with hepatocellular carcinoma who had undergone hepatectomy with IVCTT resection between May 1997 and August 2009. Age, gender, diagnosis, findings of physical examination, results of preoperative laboratory investigations, radiological examination, criteria for resection, postoperative pathological results, incisions, operative technique, intraoperative transfusion, drains, and intraoperative and postoperative complications were evaluated for all patients. RESULTS: Type I IVCTT (10 patients) was posterior to the liver and below the diaphragm; type II IVCTT (2 patients) was above the diaphragm but still outside the atrium; and type III IVCTT (1 patient) was above the diaphragm and in the right atrium. Type I was treated by radical hepatectomy and removal of IVCTT with total hepatic vascular exclusion. Type II was treated by radical hepatectomy and removal of IVCTT by incision of the diaphragm. Type III was treated by hepatectomy and resection of the thrombus from the right atrium under cardiopulmonary bypass. There were no surgical complications and one patient has been survived for 4 years with cancer free status. The median survival time was 18.2 months, and the 1- and 2-year survival rates were 53.8% and 15.4%, respectively. CONCLUSION: Surgical treatment is safe and feasible for treatment of IVCTT in patients with hepatocellular carcinoma, and surgical resectability can be judged according to the classification of tumor thrombus. PMID- 23742772 TI - Liver resection versus radiofrequency ablation in the treatment of cirrhotic patients with hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma is the most common type of primary liver tumor and its incidence is increasing worldwide. The study aimed to compare patients subjected to liver resection or radiofrequency ablation. METHODS: One hundred and forty cirrhotic patients in stage A or B of Child-Pugh with single nodular or multinodular hepatocellular carcinoma were included in this retrospective study. Among them, 87 underwent surgical resection, and 53 underwent percutaneous radiofrequency ablation. Patient characteristics, survival, and recurrence-free survival were analyzed. RESULTS: Recurrence-free survival was longer in the resection group in comparison to the radiofrequency group with a median recurrence-free time of 36 versus 26 months, respectively (P=0.01, HR=1.52, 95% CI: 1.05-2.25). In the resection group, median survival was 46 months, with the 1-, 3- and 5-year survival rates of 89.7%, 72.4% and 40.2%. In the radiofrequency group, median survival was 32 months, with the 1-, 3- and 5 year survival rates of 83.0%, 43.4% and 22.6% (P<0.01). CONCLUSIONS: Surgical resection improves the overall survival and recurrence-free survival in comparison with radiofrequency ablation. New evidences are needed to define the real role of the percutaneous technique as an alternative to surgery. PMID- 23742773 TI - Staged management of Budd-Chiari syndrome caused by co-obstruction of the inferior vena cava and main hepatic veins. AB - BACKGROUND: Collateralized intra- and extra-hepatic routes in patients with Budd Chiari syndrome (BCS) were important. This study aimed to investigate the feasibility and clinical outcomes of the staged management of BCS based on the degree of compensation provided by intra- or extra-hepatic collateral circulations. METHODS: A total of 103 adult patients with BCS caused by co obstruction of the inferior vena cava (IVC) and main hepatic veins (MHVs) between March 2001 and October 2009 were enrolled in this study. Based on the pathological classification and degree of hemodynamic compensation by collateral circulations, treatment priority for IVC hypertension was determined in the first stage treatment. Patients were deemed eligible for second-stage treatment when the first-stage treatment failed to relieve. RESULTS: Imaging results revealed that most patients had collateral circulations to different extents. Based on the degree of compensation provided by these collateral circulations, 74 patients underwent single-stage treatment for IVC hypertension, i.e., radiologic intervention (RI) for 61 patients and surgical procedures (SPs) for 13. One patient was treated for portal hypertension. Twenty-nine patients underwent second-stage treatment (25 underwent RI and SP, and 4 only SP). The general morbidity and mortality after all procedures were 8.3% and 1.5%, respectively. After a median follow-up of 35 months, 4 patients underwent second-stage treatment and 7 underwent recanalization of the IVC/MHVs. Two patients died of hepatocellular carcinoma and 1 died of graft obstruction. CONCLUSION: Staged management produces excellent outcomes for patients with BCS caused by co obstruction of the IVC and MHVs. PMID- 23742774 TI - Notch1 and Notch4 are markers for poor prognosis of hepatocellular carcinoma. AB - BACKGROUND: Notch signaling is critical to physiologic angiogenesis and has been implicated in tumor angiogenesis and metastasis. Notch signaling was reported to exert either oncogenic or tumor-suppressive function in hepatocellular carcinoma (HCC) tumorigenesis. However, the prognostic significance of Notch receptors in HCC remains uncertain. In this study, we investigated the roles of Notch receptors in the prognosis of HCC. METHODS: We investigated the expressions of Notch receptors in tumor tissue microarrays of 288 patients with primary HCC who had undergone curative resection using immunohistochemistry. Additionally, prognostic factors of HCC were examined by univariate and multivariate analyses. The median follow-up period was 97.1 months. Tumor recurrence was detected in 189 patients (65.6%), and 99 (34.4%) died of HCC. RESULTS: Cytoplasmic expression of Notch1, cytoplasmic expression of Notch3, coexistent nuclear expression of Notch3, and cytoplasmic Notch4 overexpression were observed in 145 (50.3%), 60 (20.8%), 17 (5.9%), and 172 (59.7%) of the 288 HCCs, respectively. Multivariate analyses revealed that Notch1 expression (P=0.029), Edmondson grade III (P=0.038), and higher BCLC stage (P<0.001) were independent predictors of shorter disease-free survival. Cytoplasmic Notch3 expression tended to be an independent predictor of shorter disease-free survival (P=0.055). Notch1 expression (P=0.039), Notch4 overexpression (P=0.012), and higher BCLC stage (P<0.001) were independent predictors of shorter disease-specific survival. On univariate analysis, Notch1 expression tended to show an unfavorable influence on disease specific survival (P=0.063) and Notch4 overexpression did not show an unfavorable influence on disease-specific survival (P=0.103). CONCLUSIONS: Notch1 expression might be an independent predictor of both shorter disease-free survival and shorter disease-specific survival in HCC patients after curative resection. Notch4 overexpression might be an independent predictor of shorter disease specific survival. Notch1 could be used as an immunohistochemical biomarker to detect patients with a high-risk of recurrence. Notch1 and Notch4 could be used as immunohistochemical biomarkers to detect patients with a shorter disease specific survival. PMID- 23742776 TI - Propofol inhibits the adhesion of hepatocellular carcinoma cells by upregulating microRNA-199a and downregulating MMP-9 expression. AB - BACKGROUND: Propofol is one of the extensively and commonly used intravenous anesthetics and has the ability to influence the proliferation, motility, and invasiveness of many cancer cells. In this study, the effects of propofol on hepatocellular carcinoma cells invasion ability were examined. METHODS: We assessed the invasion ability of HepG2 cells in vitro by determining enzyme activity and protein expression of MMP-9 using gelatin zymography assay and Western blot. The real-time PCR was used to evaluate the effect of propofol on microRNA-199a (miR-199a) expression, and miR-199a-2 precursor to evaluate whether over-expression of miR-199a can affect MMP-9 expression. Finally, the effect of miR-199a on propofol-induced anti-tumor activity using anti-miR-199a was assessed. RESULTS: Propofol significantly elevated the expression of miR-199a and inhibited the invasiveness of HepG2 cells. Propofol also efficiently decreased enzyme activity and protein expression of MMP-9. Moreover, the over-expression of miR-199a decreased MMP-9 protein level. Interestingly, the neutralization of miR 199a by anti-miR-199a antibody reversed the effect of propofol on alleviation of tumor invasiveness and inhibition of MMP-9 activity in HepG2 cells. CONCLUSION: Propofol decreases hepatocellular carcinoma cell invasiveness, which is partly due to the down-regulation of MMP-9 expression by miR-199a. PMID- 23742775 TI - Desensitization of G-protein-coupled receptors induces vascular hypocontractility in response to norepinephrine in the mesenteric arteries of cirrhotic patients and rats. AB - BACKGROUND: The increased beta-arrestin-2 and its combination with G-protein coupled receptors (GPCRs) lead to GPCRs desensitization. The latter may be responsible for decreased contractile reactivity in the mesenteric arteries of cirrhotic patients and rats. The present study is to investigate the machinery changes of alpha-adrenergic receptors and G proteins and their roles in the contractility of mesenteric arteries of cirrhotic patients and animal models. METHODS: Patients with cirrhosis due to hepatitis B and cirrhotic rats induced by CCl4 were studied. Mesenteric artery contractility in response to norepinephrine was determined by a vessel perfusion system. The contractile effect of G protein coupled receptor kinase-2 (GRK-2) inhibitor on the mesenteric artery was evaluated. The protein expression of the alpha1 adrenergic receptor, G proteins, beta-arrestin-2, GRK-2 as well as the activity of Rho associated coiled-coil forming protein kinase-1 (ROCK-1) were measured by Western blot. In addition, the interaction of alpha1 adrenergic receptor with beta-arrestin-2 was assessed by co immunoprecipitation. RESULTS: The portal vein pressure of cirrhotic patients and rats was significantly higher than that of controls. The dose-response curve to norepinephrine in mesenteric arteriole was shifted to the right, and EC50 was significantly increased in cirrhotic patients and rats. There were no significant differences in the expressions of the alpha1 adrenergic receptor and G proteins in the cirrhotic group compared with the controls. However, the protein expressions of GRK-2 and beta-arrestin-2 were significantly elevated in cirrhotic patients and rats compared with those of the controls. The interaction of the alpha1 adrenergic receptor and beta-arrestin-2 was significantly aggravated. This interaction was significantly reversed by GRK-2 inhibitor. Both the protein expression and activity of ROCK-1 were significantly decreased in the mesenteric artery in patients with cirrhosis compared with those of the controls, and this phenomenon was not shown in the cirrhotic rats. Norepinephrine significantly increased the activity of ROCK-1 in normal rats but not in cirrhotic ones. Norepinephrine significantly increased ROCK-1 activity in cirrhotic rats when GRK 2 inhibitor was used. CONCLUSIONS: beta-arrestin-2 expression and its interaction with GPCRs are significantly upregulated in the mesenteric arteries in patients and rats with cirrhosis. These upregulations result in GPCR desensitization, G protein dysfunction and ROCK inhibition. These may explain the decreased contractility of the mesenteric artery in response to vasoconstrictors. PMID- 23742777 TI - Double-blind randomized sham controlled trial of intraperitoneal bupivacaine during emergency laparoscopic cholecystectomy. AB - BACKGROUND: Intraperitoneal local anesthesia (IPLA) during elective laparoscopic cholecystectomy (el-LC) decreases post-operative pain. None of the studies have explored the efficacy of IPLA at emergency laparoscopic cholecystectomy (em-LC). A longer operative duration, the greater frequency of washing, and the inflammation associated with cholecystitis or pancreatitis are a few reasons why it cannot be assumed that a benefit in pain scores will be seen in em-LC with IPLA. This study was undertaken to assess the efficacy of IPLA in patients undergoing em-LC. METHODS: Double-blind randomized sham controlled trial was conducted of 41 consecutive subjects undergoing em-LC. IPLA was delivered by a combination of injection to the diaphragmatic and topical wash over the liver and gallbladder with bupivacaine or saline. The primary outcome was visual analogue scale pain scores until discharge. Secondary outcomes included pain scores in theatre recovery and analgesic consumption. RESULTS: One patient had a procedure converted to open and was excluded. There was no significant difference in pain scores in the ward or theatre recovery. Analgesic use, respiratory rate, oxygen saturation, duration to ambulation, eating, satisfaction scores, and time to discharge were comparable between the two groups. CONCLUSIONS: IPLA during em-LC does not influence postoperative pain. Other modalities of analgesia should be explored for decreasing the interval between diagnosis of acute admission and em LC. PMID- 23742778 TI - Clinical features and outcomes of patients with severe acute pancreatitis complicated with gangrenous cholecystitis. AB - BACKGROUND: The effects of gangrenous cholecystitis (GC) and consequent surgical interventions on the clinical outcomes and prognosis of patients with severe acute pancreatitis are not clear. The present study was to characterize the clinical outcomes of patients with severe acute pancreatitis complicated with GC. METHODS: We retrospectively analyzed 253 consecutive patients hospitalized for acute pancreatitis in intensive care unit. Among them, 68 were diagnosed as having severe acute pancreatitis; 10 out of the 68 patients had GC. We compared these 10 patients with GC and 58 patients without GC. The indices analyzed included sepsis/septic shock, pancreatic encephalopathy, acute respiratory distress syndrome, acute renal failure, multiple organ dysfunction syndrome, and death. RESULTS: Specific CT images of GC in patients with severe acute pancreatitis included enlarged and high-tensioned gallbladder, wall thickening, lumenal emphysema, discontinuous and/or irregular enhancement of mucosa, and pericholecystic effusion. The rates of severe sepsis/septic shock (70.0% vs 24.1%, P<0.01), pancreatic encephalopathy (50.0% vs 17.2%, P<0.05), acute respiratory distress syndrome (90.0% vs 41.4%, P<0.01), multiple organ dysfunction syndrome (70.0% vs 24.1%, P<0.01), acute renal failure (40.0% vs 27.6%, P<0.05), and death (40.0% vs 13.8%, P<0.05) were significantly higher in patients with GC than in those without GC. CONCLUSION: CT scans can help to identify early GC in patients with severe acute pancreatitis; early diagnosis and intervention for patients with GC can reduce morbidity and mortality. PMID- 23742779 TI - Risk factors for the occurrence of insulinoma: a case-control study. AB - BACKGROUND: The etiology of insulinoma is poorly understood. Few studies investigated the possible roles of environmental factors and lifestyle in the pathogenesis of insulinoma. The aim of this study is to identify risk factors associated with occurrence of insulinoma in the Chinese population. METHODS: This study consisted of 196 patients with insulinoma and 233 controls. Demographic information of the patients and controls and risk factors of the disease were analyzed. Univariate and unconditional multivariable logistic regression analyses were made to estimate odds ratios (ORs) and possible risk factors. RESULTS: Approximately 68.88% (135/196) of the patients were from rural areas in contrast to 10.30% (24/233) of the controls (P<0.0001). This difference was confirmed by the multivariate analysis (OR=4.950; 95% CI: 2.928-8.370). Family history of pancreatic endocrine tumor (OR=16.754; 95% CI: 2.125-132.057) and other cancers (OR=2.360; 95% CI: 1.052-5.291) was also related to a high-risk population of insulinoma. CONCLUSION: Rural residents or people who have a family history of pancreatic endocrine tumor and other cancers are a high-risk population of insulinoma. PMID- 23742780 TI - Inferior vena cava obstruction and collateral circulation as unusual manifestations of hepatobiliary cystadenocarcinoma. AB - BACKGROUND: Hepatobiliary cystadenocarcinoma represents a rare epithelial malignant tumor derived from the intrahepatic bile duct. METHODS: A 71-year-old woman, who had undergone laparoscopic drainage of a cystic lesion of the right hepatic lobe, was misdiagnosed as having hepatic echinococcal disease, and received intracystic infusion of 95% ethanol four years ago. She was admitted to our hospital for further treatment. RESULTS: Physical examination revealed dilated superficial veins across the right abdominal wall. After mapping the direction of blood flow in these vessels, we assumed that this was a sign of inferior vena cava obstruction. Abdominal ultrasound, computed tomography, magnetic resonance imaging combined with magnetic resonance angiography showed a large cystic mass in the right upper quadrant and epigastrium, displacing the adjacent structures, adherent to the inferior vena cava, which was not patent, resulting in dilation of superficial epigastric veins. The patient underwent an exploratory laparotomy. Total excision of the huge mass measuring 16X15 cm was possible under selective vascular exclusion of the liver. Removal of the tumor resulted in immediate restoration of flow in the inferior vena cava. On the basis of the pathology and findings of immunohistochemical analysis, a hepatobiliary cystadenocarcinoma was diagnosed. CONCLUSIONS: In the present case, hepatobiliary cystadenocarcinoma was accompanied by dilated superficial venous collaterals due to inferior vena cava obstruction. Selective vascular exclusion of the liver allowed a safe oncological resection of the tumor. PMID- 23742781 TI - Pancreatic Castleman disease treated with laparoscopic distal pancreatectomy. AB - BACKGROUND: Castleman disease is an uncommon lymphoproliferative disorder most frequently occurring in the mediastinum. Abdominal forms are less frequent, with pancreatic localization of the disease in particular being extremely rare. Only seventeen cases have been described in the world literature. METHOD: This report describes an interesting and unusual case of pancreatic Castleman disease treated with laparoscopic resection. RESULTS: A 48-year-old woman presented with epigastric pain. CT scan showed a well-encapsulated mass on the ventral border of the pancreas. Endosonography with fine needle aspiration biopsy was performed. Biopsy showed lymphoid elements and structures of a normal lymph node. The patient was treated with laparoscopic distal pancreatectomy. The pancreas was transected with a Ligasure device and the pancreatic stump was secured with a manual suture. One year after surgery the patient was complaint-free and showed no signs of recurrence of the disease. CONCLUSIONS: Laparoscopic distal pancreatectomy is a feasible and safe method for the treatment of lesions in the body and tail of the pancreas. Transection of the pancreas with a Ligasure device offers the advantages of low bleeding and low risk of pancreatic fistula. PMID- 23742782 TI - A meta-analytic review on treatment dropout in child and adolescent outpatient mental health care. AB - A large proportion (28% up to 75%) of the treatments in youth mental health care results in premature termination (dropout). It is important to gain knowledge of the determinants of dropout because it can have very severe consequences. The aim of our meta-analytic review was to provide an overview of findings from empirical studies on this subject. We structured the often contradicting results from two perspectives. First, we compared studies with efficacy and effectiveness designs. Second, we compared studies which used a dropout definition based on the opinion of therapists, with those that took the number of predetermined completed sessions as a criterion. Third, we studied three groups of predictors, i.e., pre treatment child variables, pre-treatment family or parent variables, and treatment and therapist variables or treatment participation barriers. The meta analytic review showed that dropout percentages were strongly influenced by study design: Percentages were lower in efficacy than in effectiveness studies. Within effectiveness studies, the dropout percentages were lower when the therapist's opinion was used rather than when the number of sessions was used as a criterion. In efficacy studies on the contrary, the dropout percentages were similar for studies using the first or the second criterion. With respect to dropout predictors, results were less clear. Some of the dropout predictors were influenced by study design or dropout definition, but for most predictors this influence could not be analyzed because they were not studied in all groups of studies or because the effect sizes were small or non-significant. Treatment and therapist variables or experienced treatment participation barriers were overall stronger dropout predictors than the pre-treatment child variables and pre treatment family or parent variables, although some strong predictive pre treatment variables emerged as well. PMID- 23742783 TI - [Seizure outcomes of cerebral hemispherectomy in adults: A systematic review and individual patient data meta-analysis]. AB - OBJECTIVE: The objective of our study was to determine the seizure control rate of cerebral hemispherectomies in adult patients with drug-resistant epilepsy. MATERIALS AND METHODS: A systematic review and individual patient data meta analysis was carried out. Seven international databases and scientific meeting proceedings were reviewed. Individual patient data were analysed to establish potential factors associated with postoperative seizure control. RESULTS: Eight articles that satisfied the pre-established selection criteria were identified. After a median follow-up of 70 months (interquartile range, 29-175.5), 79.4% of patients remained seizure-free. There were no statistically significant differences in age at onset of epilepsy, duration of epilepsy, age at surgery, time of follow-up, gender, surgical-laterality, aetiology and ictal EEG abnormalities between seizure-free patients and those with recurrences. CONCLUSIONS: Cerebral hemispherectomy has a high seizure control rate in adult patients with drug-resistant epilepsy. None of the variables analysed in the present study were associated with surgical success. PMID- 23742784 TI - Coronary artery ectasia and inflammatory cytokines: link with a predominant Th-2 immune response? AB - OBJECTIVE: The role of inflammation in coronary artery ectasia (CAE) remains controversial. We evaluated the hypothesis that CAE might be associated with a specific pattern of T helper (Th) lymphocyte activation by measuring the Th-1 cytokine, interleukin-2 (IL-2) and the Th-2 cytokines, interleukin-4 (IL-4) and interleukin-6 (IL-6) in patients with CAE, obstructive coronary artery disease (CAD) and controls. METHODS: Serum levels of IL-2, IL-4 and IL-6 were measured in 74 patients undergoing an elective cardiac catheterization due to angina pectoris and positive or equivocal non-invasive screening for cardiac ischaemia: 34 had CAE and non-obstructive CAD (Group A), 22 had obstructive CAD (Group B) and 18 had normal coronaries (Group C). RESULTS: Group A had significantly higher IL-4 than Group B and Group C (p<0.001 and p=0.006, respectively). In contrast, Group A had markedly lower IL-2 than Group B and Group C (p<0.001 for both comparisons). Group C had higher IL-4 and lower IL-2 than Group B (p<0.001 for both comparisons). Interleukin-6 was significantly higher in Groups A and B compared to Group C (p<0.001 for both comparisons), whilst it was comparable between Group A and Group B. Multivariate logistic regression analysis showed that higher levels of IL-4 and lower levels of IL-2 were the strongest independent predictors associated with CAE (OR: 3.846, CI: 1.677-8.822, p=0.001 and OR: 0.567, CI: 0.387-0.831, p=0.004, respectively). CONCLUSIONS: Our data demonstrates that Th-2 immune response, exhibited through increased IL-4 and low IL-2, constitutes a fundamental feature of CAE. PMID- 23742785 TI - The disulfide bond between cysteine 10 and cysteine 34 is required for CCL18 activity. AB - Asthma is a Th2-mediated disease that involves Th2 cell and eosinophil migration into the bronchial mucosa which is dependent upon the expression of a specific set of chemokines within the lung. Among them, CCL18 seems to play a key role because of its preferential expression in the lung, and its up-regulation by Th2 cytokines. Here, we show that the optimal naive T cell and basophil chemotaxis, and basophil histamine release induced by rhCCL18 occurred at a 100 time lower concentration with CHO-derived rhCCL18 than with E. coli-derived rhCCL18. FT-ICR mass spectrometry of the intact chemokines showed that the rhCCL18 produced by CHO cells contained the 2 disulfide bonds Cys10-Cys34 and Cys11-Cys50, in clear contrast to the rhCCL18 derived from E. coli where the Cys10-Cys34 bond was absent. We found that reduction of the Cys10-Cys34 of the CHO-derived rhCCL18 resulted in a shift of its activity, reaching the same level as the E. coli derived rhCCL18. These results demonstrate that the Cys10-Cys34 disulfide bond is involved in the function of CCL18. PMID- 23742786 TI - The associations between diurnal cortisol patterns, self-perceived social support, and sleep behavior in Chinese breast cancer patients. AB - OBJECTIVE: This study examined the relationships between diurnal cortisol patterns and sleep behavior, social support, psychological factors, and perceived health status in breast cancer patients. METHODS: One hundred and eighty-one breast cancer patients completed a self-report questionnaire that combined the Hospital Anxiety and Depression Scale, the Yale Social Support Scale, and self perceived measures of physical health, stress, sleep quality, total sleep hours, and time of awakening. Salivary cortisol was collected upon waking, at 1200h, 1700h, and 2100h on two consecutive days. Multiple regression analysis was performed on the diurnal cortisol slope that was derived from slope analysis of the log-transformed cortisol data. RESULTS: Controlling for the initial cortisol level, a flatter diurnal cortisol slope was significantly associated with a later time of awakening, higher negative social support, poorer perceived health, poorer sleep quality, and shorter total sleep hours. Anxiety and depression were not significantly correlated with the slope. CONCLUSIONS: The results indicate a subtle dysregulation in hypothalamic-pituitary-adrenal axis functioning in patients with highly negative social support, poor perceived health, poor sleep quality, a later time of awakening, and insufficient sleep hours. PMID- 23742787 TI - Mortality from Alzheimer's disease in the United States: data for 2000 and 2010. AB - In 2010, Alzheimer's disease was the underlying cause for a total of 83,494 deaths and was classified as a contributing cause for an additional 26,488 deaths (1). Mortality from Alzheimer's disease has steadily increased during the last 30 years. Alzheimer's disease is the sixth leading cause of death in the United States and the fifth leading cause for people aged 65 years and over (1). An estimated 5.4 million persons in the United States have Alzheimer's disease (2). The cost of health care for people with Alzheimer's disease and other dementia was estimated to be 200 billion dollars in 2012, including 140 billion dollars in costs to Medicare and Medicaid and is expected to reach 1.1 trillion dollars in 2050 (2). Alzheimer's disease mortality varies by age, sex, race, Hispanic origin, and geographic area. This report presents mortality data on Alzheimer's disease based on data from the National Vital Statistics System from 2000 through 2010, the most recent year for which detailed data are available. PMID- 23742788 TI - Challenges in managing a mother with a dual diagnosis of peripartum cardiomyopathy and paranoid schizophrenia - a case report. AB - INTRODUCTION: Psychotic illness has a low incidence in the puerperal period. Peripartum cardiomyopathy as a complication of pregnancy is also rare. CLINICAL CASE: We report a case where the above two conditions occurred simultaneously in a patient and posed significant difficulties in the clinical management. She was diagnosed as having paranoid schizophrenia and peripartum cardiomyopathy. Many of the antipsychotics were contraindicated, and electroconvulsive therapy could not be administered due to the added risks involved with regard to anesthesia. She was therefore managed with clonazepam and olanzapine. DISCUSSION: This case highlights the challenges in a patient with a psychiatric illness presenting with comorbid physical illness. PMID- 23742789 TI - Prenotification had no additional effect on the response rate and survey quality: a randomized trial. AB - OBJECTIVES: To determine the effect of prenotification package on survey quality, including response rates, response time, percentage of nonresponse items, and cost. STUDY DESIGN AND SETTING: Participants were randomized into two groups. In the first round mailing, participants in prenotification group received a prenotification package, whereas direct questionnaire mailing group participants received a questionnaire with prepaid return envelope only. In the second round mailing, both groups received the questionnaires. The trial was integrated into a study among 35-65-year-old female nurses in Hong Kong. RESULTS: A total of 367 nurses were included in the trial. A total of 362 mails were successfully delivered. The initial response rate in the first round mailing were 8.79% and 8.89% for prenotification and direct questionnaire mailing groups, respectively. After the second round mailing, the final response rate in prenotification and direct questionnaire mailing groups were 17.58% and 17.22%, respectively; no significant difference was found between the groups. There were no differences with respect to percentage of nonresponse items or response time, but the cost of prenotification group was HK$ 15.11 per response higher than direct mailing group. CONCLUSION: Prenotification had no additional effect on the response rate and other survey quality compared with direct questionnaire mailing in a Hong Kong population. PMID- 23742790 TI - Nerve growth factor enhances cough via a central mechanism of action. AB - The mechanisms involved in enhanced cough induced by central and inhaled NGF in guinea pigs were investigated. Cough and airway function were assessed by plethysmography following inhaled or intracerebroventricular (i.c.v.) NGF treatment. Expression of TrkA and/or TRPV1 was determined in bronchi and/or brainstem by real-time PCR and immunoblotting. I.c.v. and inhaled NGF enhanced citric acid induced-cough and airway obstruction. Pretreatment (i.c.v.) with antagonists of TrkA (K252a) or TRPV1 (IRTX) significantly reduced both the NGF (i.c.v.) enhanced cough and airway obstruction whereas the NK1 antagonist (FK888) inhibited only cough. The H1 antagonist (cetirizine) did not affect either. Inhaled NGF increased phosphorylation of TrkA receptors in the bronchi but not the brainstem at 0.5h post-treatment. TrkA mRNA was elevated at 0.5h in the bronchi and at 24h in the brainstem while TRPV1 mRNA was elevated from 0.5h to 24h in brainstem and at 24h in the bronchi. Pretreatment (i.c.v.) with IRTX, but not K252a, significantly inhibited the inhaled NGF-enhanced cough. Central NGF administration enhances cough and airway obstruction by mechanisms dependent on central activation of TrkA, TRPV1 and NK1 receptors while inhaled NGF enhances cough via a mechanism dependent on central TRPV1 and not TrkA receptors. These data show that NGF, in addition to its effects on the airways, has an important central mechanism of action in the enhancement of cough. Therefore, therapeutic strategies targeting NGF signaling in both the airways and CNS may be more effective in the management of cough. PMID- 23742791 TI - [Ultrasound-assisted approach to blocking the intercostal nerves in the mid axillary line for non-reconstructive breast and axilla surgery]. AB - INTRODUCTION: Several nerve blocks have recently been used for pain treatment in breast surgery. The main objective of our study was to determine the efficacy and safety of ultrasound-assisted blocking of the anterior and lateral cutaneous branches of the intercostal nerves in the mid-axillary line for non reconstructive breast and axilla surgery. MATERIAL AND METHODS: A prospective observational study was conducted on 30 patients scheduled for non-reconstructive breast and axilla surgery. An intercostal branches block was performed in the mid axillary line with 0,5% levobupivacaine (3ml in each intercostal space). Clinical efficacy was assessed by standard intraoperative hemodynamic response to surgical stimulus and the need for opioids, and in the postoperative period, by assessing pain intensity as a verbal numerical scale and the need for rescue treatment. We also evaluated the quality of sleep the first night after surgery, any adverse events that occurred, and the satisfaction of patients and surgeons with the anesthetic technique. RESULTS: The intercostal branches block in the mid-axillary line was effective in most cases, with only 2 patients requiring intraoperative opioids, and in one case analgesic rescue was necessary in the postoperative period. The duration of postoperative analgesia was 19+/-4h. There were no notable adverse events or complications. The satisfaction with the chosen technique was assessed as "very good" in all patients, and by 97% of the surgeons. CONCLUSIONS: Intercostal branches block in the mid-axillary line provides adequate intraoperative and postoperative analgesia for non reconstructive breast and axilla surgery. It is a simple, reproducible technique in most patients of this study, with an easy to understand ultrasound anatomy, in which adequate analgesia could be provided through a single puncture, and may be an alternative to neuroaxial blocks. PMID- 23742792 TI - A role for suggestion in differences in brain responses after placebo conditioning in high and low hypnotizable subjects. PMID- 23742793 TI - Examining the evidence about psychological treatments for chronic pain: time for a paradigm shift? PMID- 23742794 TI - Microstructural brain reorganization in chronic gastrointestinal disorders. PMID- 23742796 TI - Cut points for mild, moderate, and severe pain on the VAS for children and adolescents: what can be learned from 10 million ANOVAs? AB - Cut points that classify pain intensity into mild, moderate, and severe levels are widely used in pain research and clinical practice. At present, there are no agreed-upon cut points for the visual analog scale (VAS) in pediatric samples. We applied a method based on Serlin and colleagues' procedure (Serlin RC, Mendoza TR, Nakamura Y, Edwards KR, Cleeland CS. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. PAIN((r)) 1995;61:277-84) that was previously only used for the 0 to 10 numerical rating scale to empirically establish optimal cut points (OCs) for the VAS and used bootstrapping to estimate the variability of these thresholds. We analyzed data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) study and defined OCs both for parental ratings of their children's pain and adolescents' self-ratings of pain intensity. Data from 2276 children (3 to 10 years; 54% female) and 2982 adolescents (11 to 17 years; 61% female) were analyzed. OCs were determined in a by-millimeter analysis that tested all possible 4851 OC combinations, and a truncated analysis were OCs were spaced 5 mm apart, resulting in 171 OC combinations. The OC method identified 2 different OCs for parental ratings and self-report, both in the by-millimeter and truncated analyses. When we estimated the variability of the by-millimeter analysis, we found that the specific OCs were only found in 11% of the samples. The truncated analysis revealed, however, that cut points of 35:60 are identified as optimal in both samples and are a viable alternative to separate cut points. We found a set of cut points that can be used both parental ratings of their children's pain and self-reports for adolescents. Adopting these cut points greatly enhances the comparability of trials. We call for more systematic assessment of diagnostic procedures in pain research. PMID- 23742795 TI - Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. AB - Quantitative sensory testing (QST) is a psychophysical method used to quantify somatosensory function in response to controlled stimuli in healthy subjects and patients. Although QST shares similarities with the quantitative assessment of hearing or vision, which is extensively used in clinical practice and research, it has not gained a large acceptance among clinicians for many reasons, and in significant part because of the lack of information about standards for performing QST, its potential utility, and interpretation of results. A consensus meeting was convened by the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG) to formulate recommendations for conducting QST in clinical practice and research. Research studies have confirmed the utility of QST for the assessment and monitoring of somatosensory deficits, particularly in diabetic and small fiber neuropathies; the assessment of evoked pains (mechanical and thermal allodynia or hyperalgesia); and the diagnosis of sensory neuropathies. Promising applications include the assessment of evoked pains in large-scale clinical trials and the study of conditioned pain modulation. In clinical practice, we recommend the use QST for screening for small and large fiber neuropathies; monitoring of somatosensory deficits; and monitoring of evoked pains, allodynia, and hyperalgesia. QST is not recommended as a stand-alone test for the diagnosis of neuropathic pain. For the conduct of QST in healthy subjects and in patients, we recommend use of predefined standardized stimuli and instructions, validated algorithms of testing, and reference values corrected for anatomical site, age, and gender. Interpretation of results should always take into account the clinical context, and patients with language and cognitive difficulties, anxiety, or litigation should not be considered eligible for QST. When appropriate standards, as discussed here, are applied, QST can provide important and unique information about the functional status of somatosensory system, which would be complementary to already existing clinical methods. PMID- 23742797 TI - Nuclear maturation and embryo development of porcine oocytes vitrified by cryotop: effect of different stages of in vitro maturation. AB - The present study was designed to evaluate the viability, meiotic competence and subsequent development of porcine oocytes vitrified using the cryotop method at different stages of in vitro maturation (IVM). Cumulus-oocyte complexes (COCs) were cultured in IVM medium supplemented with 1mM dibutyryl cAMP (dbcAMP) for 22 h and then for an additional 22 h without dbcAMP in the medium. Germinal vesicle (GV), germinal vesicle breakdown (GVBD), metaphase I (MI), anaphase I/telophase I (AI/TI) and metaphase II (MII) were found to occur predominantly at 0-22, 26, 32, 38 and 44 h of IVM, respectively. Oocytes were exposed to cryoprotectant (CPA) or vitrified after different durations of IVM (0, 22, 26, 32, 38 and 44 h). After CPA exposure and vitrification, surviving oocytes that were treated before completion of the 44 h maturation period were placed back into IVM medium for the remaining maturation period, and matured oocytes were incubated for 2h. CPA treatment did not affect the viability of oocytes matured for 26, 32, 38 or 44 h, but significantly decreased survival rate of oocytes matured for 0 or 22 h. CPA treatment had no effect on the ability of surviving oocytes to develop to the MII stage regardless of the stage during IVM; however, blastocyst formation following PA was severely lower (P<0.05) than that in the control. At 2h post-warming, the survival rates of oocytes vitrified at 26, 32, 38 and 44 h of IVM were similar but were higher (P<0.05) than those of oocytes vitrified at 0 or 22 h of IVM. The MII rates of surviving oocytes vitrified at 0 and 38 h of IVM did not differ from the control and were higher (P<0.05) than those of oocytes vitrified at 22, 26 or 32 h of IVM. After parthenogenetic activation (PA), both cleavage and blastocyst rates of vitrified oocytes matured for 22, 26, 32, 38 and 44 h did not differ, but all were lower (P<0.05) than those matured 0 h. In conclusion, our data indicate that survival, nuclear maturation and subsequent development of porcine oocytes may be affected by their stage of maturation at the time of vitrification; a higher percentage of blastocyst formation can be obtained from GV oocytes vitrified before the onset of maturation. PMID- 23742798 TI - Involvement of transmitters in the anxiolytic action of urocortin 3 in mice. AB - Urocortin 3 (Ucn 3) was tested for anxiolytic action in mice an elevated plus maze. For detection of the possible involvement of neurotransmitters, the mice were pretreated with receptor blockers: haloperidol, phenoxybenzamine, propranolol, atropine, methysergide, bicuculline or naloxone. The peptide was administered into the lateral brain ventricle; the receptor blockers were applied intra- peritoneally. Ucn 3 alone elicited dose-dependent bell-shaped anxiolytic action. The most effective dose was 0.5 MUg. In the combined testing a 0.5 MUg dose was used. Haloperidol, propranolol, atropine, methysergide, and naloxone, blocked the Ucn 3-induced anxiolytic action, while phenoxybenzamine and bicuculline were ineffective. The results suggest that dopaminergic, beta adrenergic, cholinergic, serotonergic and opiate transmissions are involved in the anxiolytic action of Ucn 3. PMID- 23742799 TI - Acute food deprivation reverses morphine-induced locomotion deficits in M5 muscarinic receptor knockout mice. AB - Lesions of the pedunculopontine tegmental nucleus (PPT), one of two sources of cholinergic input to the ventral tegmental area (VTA), block conditioned place preference (CPP) for morphine in drug-naive rats. M5 muscarinic cholinergic receptors, expressed by midbrain dopamine neurons, are critical for the ability of morphine to increase nucleus accumbens dopamine levels and locomotion, and for morphine CPP. This suggests that M5-mediated PPT cholinergic inputs to VTA dopamine neurons critically contribute to morphine-induced dopamine activation, reward and locomotion. In the current study we tested whether food deprivation, which reduces PPT contribution to morphine CPP in rats, could also reduce M5 contributions to morphine-induced locomotion in mice. Acute 18-h food deprivation reversed the phenotypic differences usually seen between non-deprived wild-type and M5 knockout mice. That is, food deprivation increased morphine-induced locomotion in M5 knockout mice but reduced morphine-induced locomotion in wild type mice. Food deprivation increased saline-induced locomotion equally in wild type and M5 knockout mice. Based on these findings, we suggest that food deprivation reduces the contribution of M5-mediated PPT cholinergic inputs to the VTA in morphine-induced locomotion and increases the contribution of a PPT independent pathway. The contributions of cholinergic, dopaminergic and GABAergic neurons to the effects of acute food deprivation are discussed. PMID- 23742800 TI - The effects of high- and low-risk environments on cognitive function in rats following 2-vessel occlusion of the carotid arteries: a behavioral study. AB - In a prospective study of environmental factors affecting cognitive recovery from stroke, adult male rats were reared for 3 months in a high-risk (relatively isolated, low activity, high-fat diet, high-stress) or low-risk (social, healthy diet, low-stress, physically active) environment. They then received cognitive testing to assess various aspects of learning and memory before undergoing 2 vessel occlusion (2VO) of the carotid arteries, or sham surgery. Rats were returned to their respective environments post-operatively. Relative to pre operative levels, 2VO rats exhibited significant cognitive losses that were consistently greater in the high-risk group than its low-risk counterpart. As well, the high-risk 2VO group was impaired, relative to the low-risk 2VO group on tests of new learning introduced post-operatively. At 3-month follow-up testing, rats that had undergone 2VO surgery exhibited further decline on some tests but recovery on others, with recovery generally slower in the high-risk 2VO group. The high-risk environment also affected rats' pre-operative cognitive performance and, to a lesser extent, their performance following sham surgery. Overall, the study shows that rats experiencing cerebral ischemia are more likely to experience severe cognitive deficits if exposed to a high-risk environment and recover more slowly than ischemic rats in a more favorable environment. The results underscore the importance of lifestyle factors with respect to the impact of stroke on cognition and in assessing prospects for recovery of function. PMID- 23742801 TI - Emotions and voluntary action: what link in children with autism? AB - This research focuses on the impact of emotions--defined as "motivational states" -on the organization of goal directed locomotion in children with autism. Walking toward a goal involves both cognitive processes responsible for movement planning and automatic processes linked to movement programming. To these processes, motivation leading to achieving the goal is added. For some authors, a deficit of planning and/or programming processes is highlighted in autism. Others stand for some impairment of the emotional system. The aim of this research is to link these two viewpoints and to determine if, in children with autism, the organization of locomotion is affected by a positive/aversive emotion conferred to an object to fetch. Twenty-nine children participated in the study (11 children with autism--mean age 122 months; 9 mental age-matched controls--mean age 36 months; and 9 chronological age-matched controls--mean age 122 months). They were instructed to go and get a positive or aversive emotional valence object located straight ahead, at 30 degrees to the right or straight ahead then moved at mid-distance to the right. Gait analysis was performed using the Vicon system. The main results suggest that a positive emotional context promotes the cognitive processes involved in movement planning while an aversive emotional context blocks it or disturbs it in children with autism. No emotions effect is observed on movement programming. It is suggested that emotions triggered off and modulated movement planning and that the deficit observed was related to a developmental impairment rather than to a developmental delay. PMID- 23742802 TI - Bacteremia due to Achromobacter xylosoxidans in neonates: clinical features and outcome. AB - OBJECTIVE: We report an outbreak of Achromobacter xylosoxidans at a neonatal intensive care unit. We aimed to present clinical, laboratory and treatment data of the patients. MATERIALS AND METHODS: All consecutive episodes of bacteremia due to A. xylosoxidans at our neonatal intensive care unit, beginning with the index case detected at November 2009 until cessation of the outbreak in April 2010, were evaluated retrospectively. RESULTS: Thirty-four episodes of bacteremia occurred in 22 neonates during a 6-month period. Among the affected, 90% were preterm newborns with gestational age of 32 weeks or less and 60% had birth weight of 1000g or less. Endotracheal intubation, intravenous catheter use, total parenteral nutrition and prolonged antibiotic therapy were the predisposing conditions. Presenting features were abdominal distention, thrombocytopenia and neutropenia. The mortality rate was 13.6% and the majority of isolates were susceptible to piperacillin-tazobactam, carbapenems and trimethoprim sulfametoxazole, and resistant to gentamycin. More than half were breakthrough infections. Despite intensive efforts to control the outbreak by standard methods of hand hygiene, patient screening and isolation, containment could be achieved only after the neonatal intensive care unit was relocated. The investigation was not able to single out the source of the outbreak. CONCLUSION: A. xylosoxidans has the potential to cause serious infections in premature babies. More studies are needed to determine the importance of different sources of infection in hospital units. PMID- 23742803 TI - Contribution of different mechanisms to the resistance to fluoroquinolones in clinical isolates of Salmonella enterica. AB - OBJECTIVES: To study the potential factors include gene mutation, efflux pump and alteration of permeability associated with quinolone-resistance of Salmonella enterica strains isolated from patients with acute gastroenteritis and to evaluate the degree of synergistic activity of efflux pump inhibitors when combined with ciprofloxacin against resistant isolates. METHODS: Antimicrobial resistance patterns of fifty-eight Salmonella isolates were tested. Five isolates were selected to study the mechanism of resistance associated with quinolone group, including mutation in topoisomerase-encoding gene, altered cell permeability, and expression of an active efflux system. In addition, the combination between antibiotics and efflux pump inhibitors to overcome the microbial resistance was evaluated. RESULTS: Five Salmonella isolates totally resistant to all quinolones were studied. All isolates showed alterations in outer membrane proteins including disappearance of some or all of these proteins (Omp-A, Omp-C, Omp-D and Omp-F). Minimum inhibitory concentration values of ciprofloxacin were determined in the presence/absence of the efflux pump inhibitors: carbonyl cyanide m-chlorophenylhydrazone, norepinephrin and trimethoprim. Minimum inhibitory concentration values for two of the isolates were 2-4 fold lower with the addition of efflux pump inhibitors. All five Salmonella isolates were amplified for gyrA and parC genes and only two isolates were sequenced. S. Enteritidis 22 had double mutations at codon 83 and 87 in addition to three mutations at parC at codons 67, 76 and 80 whereas S. Typhimurium 57 had three mutations at codons 83, 87 and 119, but no mutations at parC. CONCLUSIONS: Efflux pump inhibitors may inhibit the major AcrAB-TolC in Salmonella efflux systems which are the major efflux pumps responsible for multidrug resistance in Gram-negative clinical isolates. PMID- 23742804 TI - Psychopathology and psychosocial adjustment in patients with HIV-associated lipodystrophy. AB - OBJECTIVE: To study whether patients with HIV-1 associated lipodystrophy (LD) on highly active antiretroviral treatment (HAART) have more psychopathology and worse psychosocial adjustment than a similar group without this syndrome. METHODS: In a cross-sectional, observational study we compared 47 HIV-1 infected patients with LD (LD group) with 39 HIV-1 infected patients without LD (non-LD group). All participants were on HAART. The Beck Depression Inventory (BDI), the State and Trait Anxiety Inventory (STAI) and the Goldberg Health Questionnaire (GHQ-60) were administered. Levels of familial, work and social adjustment and adjustment to stressful events were evaluated in a semi-structured interview. Clinical information was extracted from the clinical records. RESULTS: In the univariate analysis patients with LD showed higher state anxiety scores (p=0.009) and worse work adjustment (p=0.019) than those without LD. A total of 45.3% of LD patients scored above the cut-off point on the trait anxiety scale, and over 33.3% scored above the cut-off point on the BDI, GHQ and state anxiety scales. However, in multivariate analyses LD was not independently associated with psychopathology or with worse adjustment in the studied areas. CONCLUSIONS: The finding that LD was not a predictor of greater psychopathology or worse psychosocial adjustment in HIV-1 infected patients, despite the high scores found, suggests that factors not taken into account in this study, such as LD severity and self-perception should have been included in the analysis. Further studies including a greater number of variables and a larger sample size will advance our understanding of this complex condition. PMID- 23742805 TI - The insufficiency of left anterior oblique and the usefulness of right anterior oblique projection for correct localization of a computed tomography-verified right ventricular lead into the midseptum. AB - BACKGROUND: The aim of the study was to verify the correct anchoring location for the tip of the right ventricular lead using cardiac computed tomography and to assess the best fluoroscopic and ECG criteria associated with the correct location of the electrode into the midseptum. METHODS AND RESULTS: Patients indicated to pacemaker implantation were prospectively enrolled. The right ventricular lead was implanted into the midseptum according to standard criteria in left anterior oblique 40 view. The cardiac shadow on the right anterior oblique 30 was divided into 4 quadrants perpendicular to the lateral cardiac silhouette and the position of the lead tip was analyzed. The exact position of the lead tip was assessed using computed tomography. Of 51 patients, the right ventricular lead was anchored midseptum in 21 (41.2%; MS group). In 30 patients (58.8%; non-MS group), the lead was anchored in the adjacent anterior wall. The angle between the lead and horizontal axis on the left anterior oblique was similar in both groups. The non-MS group was associated with shorter distances between the tip and the cardiac contours in the right anterior oblique 30 (96.7% of leads in the non-MS group were in the outer quadrant versus 9.6% in the MS group; P<0.001). The presence of the lead in the middle or inferior quadrants was independently associated with correct midseptum placement with positive predictive value of 94.7%. CONCLUSIONS: Despite the optimal shape of the left anterior oblique, substantial numbers of leads were not anchored in the midseptum. Knowing the right anterior oblique 30 lead position can ensure proper midseptal placement. PMID- 23742806 TI - Prevalence of insomnia and associated factors in a community sample of elderly individuals in South Korea. AB - BACKGROUND: Insomnia is a common psychiatric complaint among elderly individuals. This study investigates the prevalence and sociodemographic correlates of insomnia by considering a community sample of elderly individuals in South Korea. METHODS: A face-to-face household survey was conducted in five regions of South Korea from June 2008 to August 2008. Among a total of 3,074 individuals aged 65 years and over, 2,002 participants were interviewed. The presence of insomnia was defined as having at least one of four sleep complaints that included difficulty in initiating sleep (DIS), difficulty in maintaining sleep (DMS), early morning awakening (EMA), and non-restorative sleep (NRS) more than three times per week in the last month. The Restless Legs Syndrome (RLS) Questionnaire, a short form of the Geriatric Depression scale (GDS), and a medical review of systems were implemented. RESULTS: Insomnia was found in 29.2% of the participants. DIS, DMS, EMA, and NRS accounted for 19.4%, 21.7%, 19.6%, and 8.0% of the participants respectively. Insomnia accompanied by daytime consequences accounted for 17.1% of the participants. The participants who were females, had no education, lived alone, showed symptoms of RLS or depression, and had a lifetime history of physical illness were significantly more likely to report insomnia. The prevalence of DIS, DMS, EMA, or insomnia increased slightly with age, whereas that of NRS decreased slightly. The lifetime history of head trauma, hyperlipidemia, heart disease, anemia, or depression was significantly related to insomnia. CONCLUSION: Sleep problems are common among elderly individuals and are closely related to their lifetime history of physical illness. PMID- 23742807 TI - Synthesis of a 2(1H)-pyridone library via rhodium-catalyzed formation of isomunchones. AB - Through the use of the dipolar cycloaddition of isomunchones with olefins the 2(1H)-pyridone ring system has been synthesized. (1) The use of different cyclization partners followed by diversification of the initial scaffold has provided libraries of 4-hydroxy-2(1H)-pyridones. There are no examples of this ring system in either PubChem or the MLSMR. PMID- 23742808 TI - Two fully automated web-based interventions for risky alcohol use: randomized controlled trial. AB - BACKGROUND: Excessive alcohol use is a widespread problem in many countries, especially among young people. To reach more people engaging in high-risk drinking behaviors, a number of online programs have been developed in recent years. Change Your Drinking is a German, diary-based, fully automated alcohol intervention. In 2010, a revised version of the program was developed. It is more strongly oriented to concepts of relapse prevention than the previous version, includes more feedback, and offers more possibilities to interact with the program. Moreover, the program duration was extended from 10 to 14 days. OBJECTIVE: This paper examines whether the revised version of Change Your Drinking is more effective in reducing alcohol consumption than the original version. METHODS: The effectiveness of both program versions was compared in a Web-based, open, randomized controlled trial with follow-up surveys 6 weeks and 3 months after registration. Participants were recruited online and were randomly assigned to either the original or the revised version of Change Your Drinking. The following self-assessed outcomes were used: alcohol use days, alcohol intake in grams, the occurrence of binge drinking and risky drinking (all referring to the past 7 days prior to each survey), and the number of alcohol-related problems. RESULTS: A total of 595 participants were included in the trial. Follow up rates were 58.0% after 6 weeks and 49.6% after 3 months. No significant group differences were found in any of the outcomes. However, the revised version was used by more participants (80.7%) than the original version (55.7%). A significant time effect was detected in all outcomes (alcohol use days: P=.002; alcohol intake in grams: P<.001; binge drinking: P<.001; alcohol-related problems: P=.004; risky drinking: P<.001). CONCLUSIONS: The duration and complexity of the program played a minor role in reducing alcohol consumption. However, differences in program usage between the versions suggest the revised version was more attractive to participants. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 31586428; http://www.controlled-trials.com/ISRCTN31586428/ (Archived by WebCite at http://www.webcitation.org/6BFxApCUT). PMID- 23742810 TI - UV-induced Nucleotide Excision Repair (NER) and Photoreactivation Repair (PER) in two trout fish cell lines used in ecotoxicological assessment studies. AB - A better knowledge of DNA repair capacities in permanent fish cell lines would contribute to establish their interest in genotoxicity testing for environmental risk assessment studies including the effects of an increase in solar UV radiations on aquatic organisms. NER (Nucleotide Excision Repair) and PER (Photoreactivation Repair) are the two repair pathways of choice for UV-induced photo-lesions. In the present paper, these repair processes were characterized in the two rainbow trout cell lines, RTGill-W1 and RTL-W1 (liver), by means of a T4 modified comet assay which allowed to follow the cyclobutane pyrimidine dimers repair kinetics specifically. Both repair processes have been found in the cell lines, PER repairing much faster UV lesions than NER, and NER being slightly more efficient in the gill cell line than in the liver one. PMID- 23742809 TI - Hck contributes to bone homeostasis by controlling the recruitment of osteoclast precursors. AB - In osteoclasts, Src controls podosome organization and bone degradation, which leads to an osteopetrotic phenotype in src(-/-) mice. Since this phenotype was even more severe in src(-/-)hck(-/-) mice, we examined the individual contribution of Hck in bone homeostasis. Compared to wt mice, hck(-/-) mice exhibited an osteopetrotic phenotype characterized by an increased density of trabecular bone and decreased bone degradation, although osteoclastogenesis was not impaired. Podosome organization and matrix degradation were found to be defective in hck(-/-) osteoclast precursors (preosteoclast) but were normal in mature hck(-/-) osteoclasts, probably through compensation by Src, which was specifically overexpressed in mature osteoclasts. As a consequence of podosome defects, the 3-dimensional migration of hck(-/-) preosteoclasts was strongly affected in vitro. In vivo, this translated by altered bone homing of preosteoclasts in hck(-/-) mice: in metatarsals of 1-wk-old mice, when bone formation strongly depends on the recruitment of these cells, reduced numbers of osteoclasts and abnormal developing trabecular bone were observed. This phenotype was still detectable in adults. In summmary, Hck is one of the very few effectors of preosteoclast recruitment described to date and thereby plays a critical role in bone remodeling. PMID- 23742811 TI - [Links between obesity and diabetes mellitus]. PMID- 23742812 TI - Electrical nerve stimulation and the relief of chronic pain through regulation of the accumulation of synaptic Arc protein. AB - Electrical nerve stimulation (ENS) is used in clinical settings for the treatment of chronic pain, but the mechanism underlying its effects remains unknown. ENS has been found to mimic neural activity, inducing the accumulation of Arc in synapses. Activity-dependent synaptic accumulation of Arc protein has been shown to reduce synaptic strength by promoting endocytosis of the AMPA receptors in the synaptic membrane. These receptors play a decisive role in central sensitization, which is one of the main mechanisms underlying chronic pain. It is here hypothesized that ENS induces Arc expression in synapses, where Arc promotes endocytosis of membrane AMPARs that are up-regulated during chronic pain. High frequency and high intensity are characteristics of ENS, which may be effective in the treatment of chronic pain. Stimulation-site of ENS may also influence the outcome of ENS. PMID- 23742813 TI - Cognitive control of response inhibition and switching: hemispheric lateralization and hand preference. AB - Changing environmental constraints often make already prepared responses unnecessary or inappropriate. Under such circumstances, cognitive control enables to suppress the response or switch to alternative behavior. Here, we examine the neural dynamics of both functions in left- and right-handers who performed two variants of a paradigm that required either inhibition of the response or switching the response between hands. The EEG coherence data showed strengthening of interregional coupling in the alpha band (8-12 Hz) following the target cues with an essential contribution of fronto-medial circuitry and a specific involvement of parietal areas in response switching. Brain-behavioral correlations revealed the functional significance of left-sided regions for successful response inhibition and switching, underlining the significant role of the left hemisphere for the organization of goal-directed activities. This lateralization pattern was observed for both left- and right-handers and suggests dominance of higher-order aspects of action planning in the left hemisphere. PMID- 23742814 TI - The pilot study of dual-energy CT gemstone spectral imaging on the image quality of hand tendons. AB - PURPOSE: The aim of this study was to evaluate the image quality of hand tendons using dual-energy computed tomographic gemstone spectral imaging (DECT GSI) compared with conventional CT images. MATERIALS AND METHODS: Forty patients scanned with GSI mode on DECT were enrolled. The 65-keV optimal contrast-to-noise ratio for viewing hand tendons was selected. The image quality of monochromatic GSI images (65 keV) and conventional CT images was compared with two different methods including a subjective method and an objective method by two radiologists, respectively. RESULTS: In the subjective method, the image quality in GSI images was superior to conventional CT images (P<.05). And in the objective method, the beam-hardening artifacts in the phalanges of finger space were reduced markedly, with hand tendons displaying more clearly in GSI images (P<.05). There was no significant difference between the two radiologists in both methods, with good correlation (kappa=0.75, kappa=0.85). CONCLUSION: DECT GSI with the optimal 65-keV monochromatic images could reduce the artifacts and increase image quality significantly in hand tendons imaging. It might be very useful in detecting tendon diseases in routine work. PMID- 23742815 TI - A rare cause of hydronephrosis: entrapment effect of giant iliac artery aneurysm. PMID- 23742816 TI - Neutrophils LL-37 migrate to the nucleus during overwhelming infection. AB - LL-37 is the only cathelicidin produced by human cells. It is secreted by a variety of cell types, including monocyte/macrophages, neutrophils, mast cells, keratinocytes and epithelial cells, acting on the extracellular milieu by directly killing bacteria or boosting innate immunity. Here, we show that LL-37 translocates to the nucleus following overwhelming infection, putting in evidence that its role may be even broader, with new potential important implications to cell biology. Future studies are necessary to address if LL-37 is able to induce or affect transcription, since it can lead to a novel cell signaling pathway that probably will contribute to the understanding of complex diseases. PMID- 23742817 TI - Molecular characterization and comparison of four Anisakis allergens between Anisakis simplex sensu stricto and Anisakis pegreffii from Japan. AB - It remains unclear whether allergens are the same among the sibling species of Anisakis simplex sensu lato. This study was carried out to compare the amino acid sequences of three major (Ani s 1, 2 and 12) and one minor (Ani s 9) Anisakis allergens between A. simplex s.s. and Anisakis pegreffii. We found 2 (out of 163), 1 (out of 869), and 29 (out of 266) amino acid variable sites for Ani s 1, 2, and 12, respectively. However, as both intra- and inter-species variations were present at the same amino acid positions, no amino acid variations clearly distinguished the two sibling species. IgE-binding epitopes (Ani s 1) and a binding motif of human leukocyte antigen (Ani s 2 and 9) demonstrated by previous studies were conserved. The similarities of the amino acid sequences of the allergens indicate possible similar allergy-associated health risks in humans infected with or accidentally ingesting either Anisakis species. PMID- 23742818 TI - Speech outcomes of early palatal repair with or without intravelar veloplasty in children with complete unilateral cleft lip and palate. AB - We compared the early speech outcomes of 40 consecutive children with complete unilateral cleft lip and palate (UCLP) who had been treated according to different 2-stage protocols: the Malek protocol (soft palate closure without intravelar veloplasty at 3 months; lip and hard palate repair at 6 months) (n=20), and the Talmant protocol (cheilorhinoplasty and soft palate repair with intravelar veloplasty at 6 months; hard palate closure at 18 months) (n=20). We compared the speech assessments obtained at a mean (SD) age of 3.3 (0.35) years after treatment by the same surgeon. The main outcome measures evaluated were acquisition and intelligibility of speech, velopharyngeal insufficiency, and incidence of complications. A delay in speech articulation of one year or more was seen more often in patients treated by the Malek protocol (11/20) than in those treated according to the Talmant protocol (3/20, p=0.019). Good intelligibility was noted in 15/20 in the Talmant group compared with 6/20 in the Malek group (p=0.010). Assessment with an aerophonoscope showed that nasal air emission was most pronounced in patients in the Malek group (p=0.007). Velopharyngeal insufficiency was present in 11/20 in the Malek group, and in 3/20 in the Talmant group (p=0.019). No patients in the Talmant group had an oronasal fistula (p<0.001). All other outcomes were similar. Despite later closure of the soft and hard palate, early speech outcomes were better in the Talmant group because intravelar veloplasty was successful and there were no fistulas after closure of the hard palate in 2 layers. PMID- 23742819 TI - Use of baculovirus expression system for generation of virus-like particles: successes and challenges. AB - The baculovirus expression system (BES) has been one of the versatile platforms for the production of recombinant proteins requiring multiple post-translational modifications, such as folding, oligomerization, phosphorylation, glycosylation, acylation, disulfide bond formation and proteolytic cleavage. Advances in recombinant DNA technology have facilitated application of the BES, and made it possible to express multiple proteins simultaneously in a single infection and to produce multimeric proteins sharing functional similarity with their natural analogs. Therefore, the BES has been used for the production of recombinant proteins and the construction of virus-like particles (VLPs), as well as for the development of subunit vaccines, including VLP-based vaccines. The VLP, which consists of one or more structural proteins but no viral genome, resembles the authentic virion but cannot replicate in cells. The high-quality recombinant protein expression and post-translational modifications obtained with the BES, along with its capacity to produce multiple proteins, imply that it is ideally suited to VLP production. In this article, we critically review the pros and cons of using the BES as a platform to produce both enveloped and non-enveloped VLPs. PMID- 23742820 TI - Trends in inpatient hospital deaths: National Hospital Discharge Survey, 2000 2010. AB - In 2000, there were 2.4 million deaths in the United States, and in 2010 there were 2.5 million (1,2). In both years, about one-third of these deaths occurred in short-stay, general hospitals (3), despite research that found that most Americans prefer to die in their own homes (4-6). This report presents National Hospital Discharge Survey (NHDS) data from 2000 through 2010 on patients who died during hospitalization. PMID- 23742821 TI - Potential of magnetic resonance for imaging the fetal heart. AB - Significant congenital heart disease (sCHD) affects 3.6 per 1000 births, and is often associated with extracardiac and chromosomal anomalies. Although early mortality has been substantially reduced and the rate of long-term survival has improved, sCHD is, after preterm birth, the second most frequent cause of neonatal infant death. The prenatal detection of cardiac and vascular abnormalities enables optimal parental counselling and perinatal management. Echocardiography (ECG) is the first-line examination and gold standard by which cardiac malformations are defined. However, adequate examination by an experienced healthcare provider with modern technical imaging equipment is required. In addition, maternal factors and the gestational age may lower the image quality. Fetal magnetic resonance imaging (MRI) has been implemented over the last several years and is already used in the clinical routine as a second line approach to assess fetal abnormalities. MRI of the fetal heart is still not routinely performed. Nevertheless, fetal cardiac MRI has the potential to complement ultrasound in detecting cardiovascular malformations and extracardiac lesions. The present work reviews the potential of MRI to delineate the anatomy and pathologies of the fetal heart. This work also deals with the limitations and continuing developments designed to overcome the current problems in cardiac imaging, including fast fetal heart rates, the lack of ECG-gating, and the presence of fetal movements. PMID- 23742822 TI - Bacteria of the genus Dyella can chronically colonise the airways of patients with cystic fibrosis and elicit a pronounced antibody response. AB - A patient with cystic fibrosis became chronically colonised with an unusual non fermenting Gram-negative rod that could be cultured on Burkholderia cepacia selective agar. Phenotypic characterisation by VITEK-2 suggested identification as Elizabethkingia meningoseptica, however 16S rRNA gene sequencing revealed it belonged to a putative novel species of genus Dyella. Thirty months after the initial detection, the patient produced a high level of precipitating antibodies against the bacterium. PMID- 23742823 TI - Speech and orofacial apraxias in Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) affects not only memory but also other cognitive functions, such as orientation, language, praxis, attention, visual perception, or executive function. Most studies on oral communication in AD focus on aphasia; however, speech and orofacial apraxias are also present in these patients. The aim of this study was to investigate the presence of speech and orofacial apraxias in patients with AD with the hypothesis that apraxia severity is strongly correlated with disease severity. METHODS: Ninety participants in different stages of AD (mild, moderate, and severe) underwent the following assessments: Clinical Dementia Rating, Mini-Mental State Examination, Lawton Instrumental Activities of Daily Living, a specific speech and orofacial praxis assessment, and the oral agility subtest of the Boston diagnostic aphasia examination. RESULTS: The mean age was 80.2 +/- 7.2 years and 73% were women. Patients with AD had significantly lower scores than normal controls for speech praxis (mean difference=-2.9, 95% confidence interval (CI)=-3.3 to -2.4) and orofacial praxis (mean difference=-4.9, 95% CI=-5.4 to -4.3). Dementia severity was significantly associated with orofacial apraxia severity (moderate AD: beta = 19.63, p= 0.011; and severe AD: beta =-51.68, p < 0.001) and speech apraxia severity (moderate AD: beta = 7.07, p = 0.001; and severe AD: beta =8.16, p < 0.001). CONCLUSION: Speech and orofacial apraxias were evident in patients with AD and became more pronounced with disease progression. PMID- 23742825 TI - Low ATP level is sufficient to maintain the uncommitted state of multipotent mesenchymal stem cells. AB - BACKGROUND: Multipotent mesenchymal stromal cells (MMSCs) are minimally differentiated precursors with great potential to transdifferentiate. These cells are quite resistant to oxygen limitation, suggesting that a hypoxic milieu can be physiological for MMSCs. METHODS: Human MMSCs isolated from adipose tissue were grown at various oxygen concentrations. Alteration in cell immunophenotype was determined by flow cytometry after staining with specific antibodies. Concentrations of glucose and lactate were determined using the Biocon colorimetric test. Cellular respiration was assessed using oxygen electrode. The modes of cell death were analyzed by flow cytometry after staining with Annexin V and propidium iodide. RESULTS: We found that permanent oxygen deprivation attenuated cellular ATP levels in these cells, diminishing mitochondrial ATP production but stimulating glycolytic ATP production. At the same time, permanent hypoxia did not affect MMSCs' viability, stimulated their proliferation and reduced their capacity to differentiate. Further, permanent hypoxia decreased spontaneous cell death by MMSCs. CONCLUSIONS: Under hypoxic conditions glycolysis provides sufficient energy to maintain MMSCs in an uncommitted state. GENERAL SIGNIFICANCE: These findings are of interest not only for scientific reasons, but also in practical terms. Oxygen concentration makes an essential contribution to MMSC physiology and should be taken into account in the setting of protocols for cellular therapy. PMID- 23742824 TI - Kinetics of extracellular ATP in mastoparan 7-activated human erythrocytes. AB - BACKGROUND: The peptide mastoparan 7 (MST7) stimulated ATP release in human erythrocytes. We explored intra- and extracellular processes governing the time dependent accumulation of extracellular ATP (i.e., ATPe kinetics). METHODS: Human erythrocytes were treated with MST7 in the presence or absence of two blockers of pannexin 1. ATPe concentration was monitored by luciferin-luciferase based real time luminometry. RESULTS: Exposure of human erythrocytes to MST7 led to an acute increase in [ATPe], followed by a slower increase phase. ATPe kinetics reflected a strong activation of ATP efflux and a low rate of ATPe hydrolysis by ectoATPase activity. Enhancement of [ATPe] by MST7 required adhesion of erythrocytes to poly D-lysin-coated coverslips, and correlated with a 31% increase of cAMP and 10% cell swelling. However, when MST7 was dissolved in a hyperosmotic medium to block cell swelling, ATPe accumulation was inhibited by 49%. Erythrocytes pre-exposure to 10MUM of either carbenoxolone or probenecid, two blockers of pannexin 1, exhibited a partial reduction of ATP efflux. Erythrocytes from pannexin 1 knockout mice exhibited similar ATPe kinetics as those of wild type mice erythrocytes exposed to pannexin 1 blockers. CONCLUSIONS: MST7 induced release of ATP required either cell adhesion or strong activation of cAMP synthesis. Part of this release required cell swelling. Kinetic analysis and a data driven model suggested that ATP efflux is mediated by two ATP conduits displaying different kinetics, with one conduit being fully blocked by pannexin 1 blockers. GENERAL SIGNIFICANCE: Kinetic analysis of extracellular ATP accumulation from human erythrocytes and potential effects on microcirculation. PMID- 23742826 TI - Extracellular ATP regulates FoxO family of transcription factors and cell cycle progression through PI3K/Akt in MCF-7 cells. AB - BACKGROUND: Forkhead Box-O (FoxO) transcription factors regulate the expression of many genes involved in suppression. Released nucleotides can regulate intracellular signaling pathways through membrane-bound purinergic receptors, to promote or prevent malignant cell transformation. We studied the role of extracellular ATP in the modulation of Forkhead Box O (FoxO) transcription factors and of cell cycle progression in MCF-7 breast cancer cells. METHODS: Western blot analysis, cell transfections with siRNA against Akt, immunocytochemistry, subcellular fractionation studies and flow cytometry analysis were performed. RESULTS: ATP induced the phosphorylation of FoxO1/3a at threonine 24/32, whereas reduced the expression of FoxO1. In addition, ATP increased the expression of the cyclins D1 and D3 and down-regulated the cell cycle inhibitory proteins p21Cip1 and p27Kip1. The use of the phosphatidylinositol 3 kinase (PI3K) inhibitor, Ly294002, and/or of siRNA to reduce the expression of the serine/threonine kinase Akt showed that these effects are mediated by the PI3K/Akt signaling pathway. ATP induced the translocation of FoxO3a from the nucleus to the cytoplasm. Also, ATP increased the number of cells in the S phase of cell cycle; this effect was reverted by the use of Ly294002 and the proteasome inhibitor bortezomib. CONCLUSION: Extracellular ATP induces the inactivation of FoxO transcription factors and cell cycle progression through the PI3K/Akt pathway in MCF-7 cells. GENERAL SIGNIFICANCE: These findings provide new molecular basis for further understanding the mechanisms involved in ATP signal transduction in breast cancer cells, and should be considered for the development of effective breast cancer therapeutic strategies. PMID- 23742827 TI - Clinical phenotype of bipolar disorder with comorbid binge eating disorder. AB - BACKGROUND: To explore the relationship between binge eating disorder (BED) and obesity in patients with bipolar disorder (BP). METHODS: 717 patients participating in the Mayo Clinic Bipolar Biobank completed structured diagnostic interviews and questionnaires for demographic and illness-related variables. They also had weight and height measured to determine body mass index (BMI). The effects of BED and obesity (BMI>=30 kg/m(2)), as well as their interaction, were assessed on one measure of general medical burden and six proxies of psychiatric illness burden. RESULTS: 9.5% of patients received a clinical diagnosis of BED and 42.8% were obese. BED was associated with a significantly elevated BMI. Both BED and obesity were associated with greater psychiatric and general illness burden, but illness burden profiles differed. After controlling for obesity, BED was associated with suicidality, psychosis, mood instability, anxiety disorder comorbidity, and substance abuse comorbidity. After controlling for BED status, obesity was associated with greater general medical comorbidity, but lower substance abuse comorbidity. There were no significant interaction effects between obesity and BED, or BMI and BED, on any illness burden outcome. LIMITATIONS: There may have been insufficient power to detect interactions between BED and obesity. CONCLUSIONS: Among patients with BP, BED and obesity are highly prevalent and correlated, but associated with different profiles of enhanced illness burden. As the association of BED with greater psychiatric illness burden remained significant even after accounting for the effect of obesity, BP with BED may represent a clinically important sub-phenotype. PMID- 23742828 TI - Predictors of alcohol-related problems among depressed and non-depressed women. AB - BACKGROUND: Depression and alcohol-related problems are often comorbid in women, but not all depressed women have comorbid alcohol-related problems. The current study investigated intrapersonal (drinking expectancies), interpersonal (interpersonal pressure to drink), and familial (mother's and father's drinking history) predictors of alcohol-related problems among women with and without a major depressive episode in the past year. METHOD: Participants were 853 women ages 21-90 from a U.S. national probability sample. Depression diagnosis was determined via interviewer administration of the Diagnostic Interview Schedule (DIS) depression module. Participants completed self-report measures of alcohol related problems and intrapersonal, interpersonal, and familial predictors of drinking. RESULTS: Regression analyses indicated that an episode of depression in the past year, more positive drinking expectancies, greater interpersonal pressure to drink, and higher levels of maternal (but not paternal) drinking predicted alcohol-related problems; moreover, the relationships between alcohol related problems and maternal drinking, paternal drinking, and interpersonal pressure to drink were significantly stronger among women with an episode of major depression in the past year than among women without an episode. LIMITATIONS: Study data was cross-sectional and obtained through self-report, thus limiting causal explanations of results. CONCLUSIONS: Findings suggest that depression may enhance the impact of interpersonal and familial risk factors on women's alcohol misuse. Implications of findings for transdiagnostic models of psychopathology and for prevention and treatment of alcohol-related problems in women presenting with depressive symptoms are discussed. PMID- 23742829 TI - Do urban environments increase the risk of anxiety, depression and psychosis? An epidemiological study. AB - BACKGROUND: The present study aimed to investigate whether there is an association between type of living environment (urban versus rural) and anxiety, depression and psychosis in the Scottish population. METHODS: Data were obtained from the Scottish Neighbourhood Statistics database on Scottish Index of Multiple Deprivation and urban-rural classifications for 6505 data zones across Scotland. Multiple regression was used to test the association between prescriptions for psychotropic medication for anxiety, depression and psychosis, and type of living environment according to urban-rural classification, controlling for a range of socio-economic factors. RESULTS: Urban-rural classification significantly predicted poorer mental health both before (beta=-.29) and after (beta=-.20) controlling for a large number of socio-economic variables, with more urban areas having higher rates of prescription for psychotropic medication for anxiety, depression and psychosis. LIMITATIONS: The current study focussed on macro-level variables and did not include individual level data. As such, the study did not include data on individual diagnoses, but instead used drug prescriptions for anxiety, depression and psychosis as a proxy for level of affective disorders within data zones. CONCLUSION: More urban living environments in Scotland are associated with higher rates of prescription for psychotropic medication for anxiety, depression and psychosis. PMID- 23742830 TI - The significance of serum urokinase plasminogen activation receptor (suPAR) in the diagnosis and follow-up of febrile neutropenic patients with hematologic malignancies. AB - OBJECTIVES: The purpose of this study was to investigate serum levels of serum urokinase plasminogen activation receptor (suPAR) during the first week of febrile neutropenia and to demonstrate the significance of this biomarker in the diagnosis and follow-up of febrile neutropenic patients with hematologic malignancies. METHODS: The study was performed between January 2011 and January 2012 at Karadeniz Technical University, Turkey. For neutropenic patients with hematologic malignancies, the day before the onset of fever and the first day of the febrile neutropenia attack were taken as days 0 and 1, respectively. Blood samples were obtained from patients with hematologic malignancies on days 0, 1, 3, 5, and 7. Sixty-eight healthy volunteers were enrolled as the control group. suPAR levels were determined using an ELISA kit following the manufacturer's protocols. Twenty-six male and 14 female patients with hematologic malignancies, the majority with acute/myeloid/lymphocytic leukemia, aged 19-78 years (mean 46.8 years), were included. Fifty febrile neutropenic attacks were investigated in these patients. RESULTS: The mean serum levels of the controls and suPAR 0 were 3.9 +/- 1.5 ng/ml and 5.8 +/- 2.7 ng/ml, respectively. Serum levels of suPAR rose earlier than levels of C-reactive protein and procalcitonin. Serum suPAR levels increased in patients with hematologic malignancies and were found to represent an important serum biomarker for the early prediction of neutropenic fever. A decrease in serum suPAR levels was found to be correlated with treatment response due to antibiotics in this patient group. There were significant differences in suPAR 1 levels between patients with documented infection and those with fever of unknown origin in favor of the former. When the suPAR 1 results were analyzed using the receiver operating characteristics (ROC) curve method, the optimum diagnostic cut-off point was 5.87 ng/ml, the area underneath the ROC curve (AUC) was 0.81 (95% confidence interval 0.68-0.91), sensitivity was 100%, specificity was 69%, negative predictive value (NPV) was 100%, and positive predictive value (PPV) was 70%. CONCLUSIONS: We conclude that suPAR is an important biomarker that can predict infections in the early stage of febrile neutropenia with high sensitivity and NPV for patients with hematologic malignancies. It is also advantageous since it shows the response to treatment with antibiotherapy in the early stage. PMID- 23742831 TI - Evaluation of the in vitro activity of fosfomycin tromethamine against Gram negative bacterial strains recovered from community- and hospital-acquired urinary tract infections in Turkey. AB - OBJECTIVES: The aim of this study was to evaluate the in vitro activities of antimicrobial agents including fosfomycin tromethamine against Gram-negative isolates recovered from urine samples. METHODS: A total of 2334 strains (1562 Escherichia coli, 509 Klebsiella spp, 85 Proteus spp, 75 Pseudomonas spp, 45 Enterobacter spp, 37 Acinetobacter baumannii, 8 Citrobacter spp, 7 Morganella morganii, and 6 Serratia spp) were identified by VITEK 2 during the study period, November 2008 to June 2012. Antimicrobial susceptibilities of the strains were also evaluated using the Kirby-Bauer disk diffusion method, in accordance with the Clinical and Laboratory Standards Institute guidelines. RESULTS: Overall, 2160 (92.5%) of the isolates tested were susceptible to fosfomycin tromethamine. Higher resistance rates were observed among inpatients compared to outpatients. Resistance rates by strain were: 2.0% for E. coli, 4.4% for Enterobacter spp, 6.9% for Klebsiella spp, 9.4% for Proteus spp, 48.6% for A. baumannii, 56.0% for Pseudomonas spp, and 100% for Morganella morganii. All Serratia spp and Citrobacter spp strains were susceptible. Extended-spectrum beta-lactamase (ESBL) producing isolates displayed higher fosfomycin resistance rates than negative strains (19.2% vs. 2.9%). The highest in vitro activity was detected for amikacin, piperacillin-tazobactam, and imipenem for all strains including ESBL producers. CONCLUSIONS: Regardless of ESBL production, the excellent activity of fosfomycin against E. coli, Enterobacter spp, Serratia spp, and Citrobacter spp, indicates that the drug is a valuable therapeutic option for urinary tract infections, even those with co-trimoxazole- and ciprofloxacin-resistant isolates, but not in ESBL-producing Klebsiella spp, Pseudomonas spp, A. baumannii, and Proteus spp. Further studies should be carried out to determine the in vivo drug activity among Enterobacteriaceae other than E. coli. PMID- 23742832 TI - Recurrence after liver transplantation for hepatocellular carcinoma according to up-to-seven criteria. AB - BACKGROUND/AIMS: The Up7 criteria for HCC have recently emerged to identify potential candidates for OLT. The aim of this study was to assess the validity of the Up7 criteria according to the pathological analysis of the explanted livers. METHODOLOGY: For recurrence risk calculation 669 HCC transplanted patients were classified according to both the pathological Milan and Up7 criteria. In order to identify potential predictors of recurrence, selected biological tumor markers and morphological features were then tested by Cox regression. RESULTS: The 5 year HCC recurrence rate for the Milan out/Up7 in subgroup (n=87), was significantly higher than patients meeting Milan criteria (n=299), 15.8% vs. 9.4% (p=0.0290). For patients within the Up7 criteria (n=383), only pre-OLT AFP level >1000ng/mL and microvascular invasion were significant predictors for recurrence, and for those beyond the Up7 criteria (n=286), pre-OLT AFP level >1000ng/mL, poor differentiation grade and microvascular invasion remained significant. CONCLUSIONS: Compared to the current Milan staging system, HCC patients within the pathological Up7 criteria were associated with a higher, but acceptable risk of recurrence after OLT, and along with tumor burden, other parameters can potentially be used for further refinement of HCC staging, such as AFP levels and microvascular invasion. PMID- 23742833 TI - Identification and characterisation of the putative phage-related endolysins through full genome sequence analysis in Acinetobacter baumannii ATCC 17978. AB - Acinetobacter baumannii has recently emerged as a major cause of healthcare associated infections owing to an increase in its antimicrobial resistance to virtually all available drugs. The ability of endolysins (lysozymes) to digest cell walls when applied exogenously to bacterial cells has enabled their use as novel antibacterials. In order to utilise endolysins as a therapeutic alternative to antibiotics, we surveyed the genome sequence of A. baumannii ATCC 17978 and successfully identified two phage-related endolysin genes, A1S_1600 and A1S_2016 (termed lysAB3 and lysAB4, respectively). Following cloning and expression/purification, various antibacterial activities of these two phage related endolysins were determined in vitro. Zymographic assays showed that only purified LysAB3 could lyse the peptidoglycan of the A. baumannii cell wall. When applied exogenously, both LysAB3 and LysAB4 were active against most Acinetobacter spp. tested but had virtually no activity against other non Acinetobacter spp. Scanning electron microscopy revealed that exposure to 100MUg/mL LysAB3 and LysAB4 for up to 60min caused a remarkable modification of the cell shape of A. baumannii. These results indicate that the genes encoding phage-related endolysins can be readily isolated from the bacterial genome and have potential for the development of novel antimicrobial agents. PMID- 23742834 TI - Effects of preoperative iron deficiency on transfusion requirements in liver transplantation recipients: a prospective observational study. AB - The aims of this study were to determine the frequency of preoperative iron deficiency in adult living donor liver transplantation patients and to investigate its relationship with the need for intraoperative transfusion. Between September 1, 2011, and June 1, 2012, 103 patients scheduled for liver transplantation were included in this prospective study. Patients were divided into 2 groups according to baseline iron status: an iron-deficient group and a non deficient (normal iron profile) group. Iron deficiency was assessed on the basis of several parameters, including transferrin saturation, levels of ferritin, soluble transferrin receptor, C-reactive protein, and peripheral blood smear. Preoperative iron deficiency was diagnosed in 62 patients. Preoperative iron deficiency was associated with low preoperative hemoglobin levels (P = .01) and a high rate of intraoperative transfusion (P < .0001). Preoperative iron deficiency is prognostic factor for predicting intraoperative transfusion requirements. These findings have important implications for transfusion practices for liver transplant recipients. PMID- 23742835 TI - Lipoxin A4 attenuates acute rejection via shifting TH1/TH2 cytokine balance in rat liver transplantation. AB - AIMS: To study the role of lipoxin A4 (LXA4) in rat liver transplant rejection. METHODS: An acute rejection model of liver transplantation was established in inbred rats DA to LEW that were randomly divided into a control group and a LXA4 group. Liver morphologic changes were examined using hematoxylin/eosin staining. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were quantified to measure liver injury. Intragraft mRNA and protein expressions of interferon (IFN)-gamma interleukin and (IL)-10 were detected by real-time polymerase chain reaction and Western blots, respectively. The serum levels of IFN-gamma and IL-10 were assayed by enzyme-linked immunosorbent assay. RESULTS: LXA4 treatment improved hepatic tissue injury as indicated by morphologic analysis. Serum ALT and AST levels were significantly decreased at day 7 post transplantation (P < .05). Concurrently, expression of IFN-gamma was downregulated (P < .05) and secretion of IL-10 was enhanced (P < .05). CONCLUSIONS: LXA4 attenuated acute rejection with a parallel shift from Th1 to Th2 responses in rat liver transplantation. PMID- 23742836 TI - A novel experience in living donor renal transplantation: voluntary exchange kidney transplantation. AB - Organ supply is an important problem worldwide with an ever-increasing number of patients on the waiting lists. Various strategies are implemented in the centers to increase the number of transplantations. Paired kidney exchange or nondirected organ donation to an exchange list is being performed for a while. However, the number of renal transplantations has failed to achieve the targeted levels. The present study aimed to provide information regarding 1-year outcomes of voluntary exchange kidney transplantation, which is performed in our center, and to raise awareness about the method. Compatible donor-recipient pairs and ABO-mismatched donor-recipient pairs were invited to participate in the model of voluntary exchange kidney transplantation. Of 42 donor-recipient pairs fulfilling the criteria, 22 (52.4%) accepted to participate in the model. In 4 of these 22 donor recipient pairs, patients received a kidney transplant from their own donor due to the lack of another suitable donor on the waiting list. Thus, the remaining 18 donor-recipient pairs were included in the model of voluntary exchange kidney transplantation. Sixteen two-way, 1 three-way, and 1 four-way exchange kidney transplantations were performed. Thus, this provided 21 more patients an opportunity to have a renal transplant. Accordingly, the number of living donor transplantations performed in our center increased by 6.1% using this method. We anticipate that the number of patients on the waiting lists for transplantation would be decreased by the widespread use of voluntary exchange kidney transplantation. PMID- 23742837 TI - What should we expect from psychotherapy? AB - In addressing the very general question of what we should expect from psychotherapy, this article begins by discussing what constitutes relevant evidence on which to base the efficacy and effectiveness of psychotherapy. In this context, an important distinction is made between empirically supported treatments and evidence-based practice. Although there is evidence that psychotherapy does indeed work, there are also findings that there are times when our patients are harmed by our interventions. It is noted that the therapeutic alliance plays an extremely important role in the change process, and that ruptures in the alliance can contribute to our therapeutic failures. In pointing to directions for the future, modifications of how we investigate the outcome of treatment, as well as how to close the gap between research and practice, are offered. PMID- 23742838 TI - Cluap1 localizes preferentially to the base and tip of cilia and is required for ciliogenesis in the mouse embryo. AB - Qilin is one of several genes in zebrafish whose mutation results in cystic kidney. We have now studied the role of its mouse ortholog, Cluap1, in embryonic development by generating Cluap1 knockout (Cluap1-/-) mice. Cluap1-/- embryos died mid-gestation manifesting impairment of ciliogenesis in various regions including the node and neural tube. The basal body was found to be properly docked to the apical membrane of cells in the mutant, but the axoneme failed to grow. Cluap1 is a ciliary protein and is preferentially localized at the base and tip of cilia. Hedgehog signaling, as revealed with a Pacthed1-lacZ reporter gene, was lost in Cluap1-/- embryos at embryonic day (E) 8.5 but was ectopically expanded at E9.0. The Cluap1 knockout embryos also failed to manifest left-right asymmetric expression of Nodal in the lateral plate, most likely as a result of the loss of Hedgehog signaling in node crown cells that in turn leads to pronounced down-regulation of Gdf1 expression in these cells. Crown cell-specific restoration of Cluap1 expression rescued Gdf1 expression in crown cells and left sided Nodal expression in the lateral plate of mutant embryos. Our results suggest that Cluap1 contributes to ciliogenesis by regulating the intraflagellar transport (IFT) cycle at the base and tip of the cilium. PMID- 23742839 TI - In-situ integrity control of frozen-hydrated, vitreous lamellas prepared by the cryo-focused ion beam-scanning electron microscope. AB - Recently a number of new approaches have been presented with the intention to produce electron beam transparent cryo-sections (lamellas in FIB-SEM terminology) from hydrated vitreously frozen cryo samples with a Focused Ion Beam (FIB) system, suitable for cryo-Transmission Electron Microscopy (cryo-TEM). As the workflow is still challenging and time consuming, it is important to be able to determine the integrity and suitability (cells vs. no cells; vitreous vs. crystalline) of the lamellas. Here we present an in situ method that tests both conditions by using the cryo-Scanning Electron Microscope (cryo-SEM) in transmission mode (TSEM; Transmission Scanning Electron Microscope) once the FIB made lamella is ready. Cryo-TSEM imaging of unstained cells yields strong contrast, enabling direct imaging of material present in the lamellas. In addition, orientation contrast is shown to be suitable for distinguishing crystalline lamellas from vitreous lamellas. Tilting the stage a few degrees results in changes of contrast between ice grains as a function of the tilt angle, whereas the contrast of areas with vitreous ice remains unchanged as a function of the tilt angle. This orientation contrast has subsequently been validated by cryo-Electron BackScattered Diffraction (EBSD) in transmission mode. Integration of the presented method is discussed and the role it can play in future developments for a new and innovative all-in-one cryo-FIB-SEM life sciences instrument. PMID- 23742840 TI - In situ electron microscopy studies of calcium carbonate precipitation from aqueous solution with and without organic additives. AB - For the understanding of mineral formation processes from solution it is important to obtain a deeper insight into the dynamics of crystal growth. In this study we applied for this purpose a novel atmospheric scanning electron microscope that allows the investigation of CaCO3 particle formation in solution under atmospheric conditions with a resolution of approximately 10nm. Furthermore it permits the in situ observation of the dynamics of crystal evolution. With this tool the precipitation of CaCO3 was studied in the absence and presence of additives, namely poly(acrylic acid) and poly(styrene sulfonate-co-maleic acid) which are known to influence the crystal growth rate and morphology. We determined particle growth rates and investigated the formation and dissolution dynamics of an observed transient phase, believed to be amorphous calcium carbonate. This technique also enabled us to study the depletion zones, areas of lower intensity due to reduced ion concentrations. Ion flux rates were obtained from the depletion zone width, which amounted to several MUm assuming the formation and dissolution dynamics of amorphous calcium carbonate being the rate determining process. This assumption was confirmed since the obtained fluxes were found to be in good agreement with fluxes derived from the experimentally observed crystal growth rates. PMID- 23742841 TI - On the nature of sonority in spoken word production: evidence from neuropsychology. AB - The concept of sonority - that speech sounds can be placed along a universal sonority scale that affects syllable structure - has proved valuable in accounting for a wide spectrum of linguistic phenomena and psycholinguistic findings. Yet, despite the success of this concept in specifying principles governing sound structure, several questions remain about sonority. One issue that needs clarification concerns its locus in the processes involved in spoken language production, and specifically whether sonority affects the computation of abstract word form representations (phonology), the encoding of context-specific features (phonetics), or both of these processes. This issue was examined in the present study investigating two brain-damaged individuals with impairment arising primarily from deficits affecting phonological and phonetic processes, respectively. Clear effects of sonority on production accuracy were observed in both individuals testing word onsets and codas in word production. These findings indicate that the underlying principles governing sound structure that are captured by the notion of sonority play a role at both phonological and phonetic levels of processing. Furthermore, aspects of the errors recorded from our participants revealed features of syllabic structure proposed under current phonological theories (e.g., articulatory phonology). PMID- 23742842 TI - Splicing and beyond: the many faces of the Prp19 complex. AB - The conserved Prp19 complex (Prp19C) - also known as NineTeen Complex (NTC) - functions in several processes of paramount importance for cellular homeostasis. NTC/Prp19C was discovered as a complex that functions in splicing and more specifically during the catalytic activation of the spliceosome. More recent work revealed that NTC/Prp19C plays a role in transcription elongation in Saccharomyces cerevisiae and in genome maintenance in higher eukaryotes. In addition, mouse PRP19 might ubiquity late proteins targeted for degradation and guide them to the proteasome. Furthermore, NTC/Prp19C has been implicated in lipid droplet biogenesis. In the future, the molecular function of NTC/Prp19C in all of these processes needs to be refined or elucidated. Most of NTC/Prp19C's functions have been shown in only one or few organisms. However, since this complex is highly conserved it is likely that it has the same functions across all species. Moreover, one NTC/Prp19C or different subcomplexes could function in the above-mentioned processes. Intriguingly, NTC/Prp19C might link these different processes to ensure an optimal coordination of cellular processes. Thus, many important questions about the functions of this interesting complex remain to be investigated. In this review we discuss the different functions of NTC/Prp19C focusing on the novel and emerging ones as well as open questions. PMID- 23742843 TI - The role of ubiquitin modification in the regulation of p53. AB - The p53 tumor suppressor protein is involved in regulating a wide variety of stress responses, from senescence and apoptosis to more recently discovered roles in allowing adaptation to metabolic and oxidative stress. After 34years of research, significant progress has been made in unraveling the complexity of the p53 network, and it is clear that the regulation of p53 protein stability is critical in the control of p53 activity. This article focuses on our current understanding of how the level and activity of p53 is controlled by this seemingly simple mechanism. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf. PMID- 23742844 TI - No untoward effects of smoking cues in anti-smoking public service announcements. AB - BACKGROUND: Anti-smoking public service announcements (PSAs) often include smoking-related cues; however, visual drug cues can trigger acute cravings that may impede cognitive processing of the anti-smoking message. This experiment evaluated effects of smoking cues in PSAs on smoking urges, immediate smoking behavior, and persuasion measures in daily smokers. METHODS: Three-hundred and eighteen non-treatment seeking smokers completed a single laboratory session during which they viewed sets of PSAs differentiated by presence of smoking cues (central to the PSA's argument, peripheral, or no cues) and argument strength (high versus low). After viewing the PSAs, participants completed self-report measures of smoking urges, attitudes toward quitting, self-efficacy, and intentions to quit smoking. Smoking behavior was recorded during a 1-h ad libitum smoking period immediately following PSA viewing and assessment. RESULTS: There was a significant positive effect of argument strength on attitudes toward quitting smoking (p=0.012). There were no main effects of smoking cues or smoking cue by argument strength interactions on any of the outcome measures. CONCLUSIONS: Visual smoking cues in PSAs do not increase urges to smoke, nor is there evidence that the inclusion of such cues impedes the recall or persuasive effects of anti-smoking arguments. PMID- 23742845 TI - Atrial septal aneurysms in childhood: prevalence, classification, and concurrent abnormalities. AB - OBJECTIVES: This study sought to investigate the prevalence of atrial septal aneurysms in the paediatric population and to define coexisting abnormalities and their incidence. BACKGROUND: Few papers refer to the prevalence of atrial septal aneurysms in childhood. METHODS: We enrolled a total of 4522 children aged more than 12 months who underwent a transthoracic echocardiography. Atrial septal aneurysm was defined as a protrusion of the interatrial septum or part of it >15 mm beyond the plane of the atrial septum or phasic excursion of the interatrial septum during the cardiorespiratory cycle of at least 15 mm in total amplitude and a diameter of the base of the aneurysm of at least 15 mm. RESULTS: Atrial septal aneurysms were found in 47 children (1.04%). They involved almost the entire septum in 14 patients (28.89%) and were limited to the fossa ovalis in 33 (71.11%). An atrial septal aneurysm was an isolated structural defect in 17 (35.56%). In 30 (64.44%) patients, it was associated with interatrial shunting - atrial septal defect and patent foramen ovale. At the echo follow-up after a year, no changes were recorded. CONCLUSIONS: Prevalence of atrial septal aneurysms is almost 1%. The most common abnormalities associated are interatrial shunts, that is, a patent foramen ovale and an atrial septal defect. From a medical point of view, it is suggested that no action is to be taken during childhood, as a child with an atrial septal aneurysm is not at increased risk compared with a child without one. Follow-up is scheduled on an individual basis. PMID- 23742846 TI - Upregulation of voltage-gated Ca2+ channels in mouse astrocytes infected with Theiler's murine encephalomyelitis virus (TMEV). AB - Theiler's murine encephalomyelitis virus (TMEV) induces demyelination in susceptible strains of mice through a CD4(+) Th1 T cell-mediated immunopathological process. TMEV infection produces a syndrome in mice that resembles multiple sclerosis. In this work, we focused on the increased expression of the genes encoding voltage-gated Ca(2+) channel subunits in SJL/J mouse astrocytes infected in culture with a BeAn strain of TMEV. Affymetrix DNA murine genome U74v2 DNA microarray hybridized with cRNA from mock- and TMEV infected astrocytes revealed the upregulation of four sequences encoding Ca(2+) binding and Ca(2+) channel subunit proteins. The DNA hybridization results were further validated using conventional RT-PCR and quantitative RT-PCR, demonstrating the increased expression of mRNA encoding channel subunit proteins. Western blotting also showed the increased synthesis of L- and N-type channel subunit specific proteins after infection. The reduced expression and the functional upregulation of functional voltage-gated Ca(2+) channels in mock- and TMEV-infected cells, respectively, was demonstrated using voltage clamp experiments. TMEV infection in mouse astrocytes induced a Ca(2+) current with a density proportional to the amount of viral particles used for infection. The use of Ca(2+) channel blockers, nimodipine and omega-conotoxin-GVIA, showed that both functional L- and N-type Ca(2+) channels were upregulated in infected astrocytes. The upregulation of Ca(2+) channels in astrocytes after TMEV infection provides insight into the molecular processes and potential role of astrocyte Ca(2+) dysregulation in the pathophysiology of encephalomyelitis and is important for the development of novel therapeutic strategies leading to prevention of neurodegeneration. PMID- 23742847 TI - Influence of perinatal trans fat on behavioral responses and brain oxidative status of adolescent rats acutely exposed to stress. AB - Because consumption of processed foods has increased in the last decades and so far its potential influence on emotionality and susceptibility to stress is unknown, we studied the influence of different fatty acids (FA) on behavioral and biochemical parameters after acute restrain stress (AS) exposure. Two sequential generations of female rats were supplemented with soybean oil (control group; C SO), fish oil (FO) and hydrogenated vegetable fat (HVF) from pregnancy and during lactation. At 41days of age, half the animals of each supplemented group were exposed to AS and observed in open field and elevated plus maze task, followed by euthanasia for biochemical assessments. The HVF-supplemented group showed higher anxiety-like symptoms per se, while the C-SO and FO groups did not show these behaviors. Among groups exposed to AS, HVF showed locomotor restlessness in the open field, while both C-SO and HVF groups showed anxiety-like symptoms in the elevated plus maze, but this was not observed in the FO group. Biochemical evaluations showed higher lipoperoxidation levels and lower cell viability in cortex in the HVF group. In addition, HVF-treated rats showed reduced catalase activity in striatum and hippocampus, as well as increased generation of reactive species in striatum, while FO was associated with increased cell viability in the hippocampus. Among groups exposed to AS, HVF increased reactive species generation in the brain, decreased cell viability in the cortex and striatum, and decreased catalase activity in the striatum and hippocampus. Taken together, our findings show that the type of FA provided during development and growth over two generations is able to modify the brain oxidative status, which was particularly adversely affected by trans fat. In addition, the harmful influence of chronic consumption of trans fats as observed in this study can enhance emotionality and anxiety parameters resulting from stressful situations of everyday life, which can trigger more severe neuropsychiatric conditions. PMID- 23742848 TI - Strategies used by adults to reduce their prescription drug costs. AB - In 2011, Americans spent $45 billion out-of-pocket on retail prescription drugs (1). Some adults reduce prescription drug costs by skipping doses and delaying filling prescriptions (2). Some cost-reduction strategies used by adults have been associated with negative health outcomes. For example, adults who do not take prescription medication as prescribed have been shown to have poorer health status and increased emergency room use, hospitalizations, and cardiovascular events (3,4). This report analyzes different strategies used by U.S. adults to reduce their prescription drug costs, by age, health insurance status, and poverty status, using data from the 2011 National Health Interview Survey (NHIS). PMID- 23742849 TI - Microbial profile of diabetic foot infections in Trinidad and Tobago. AB - AIMS: To examine the microbiologic profile of diabetic foot infections in order to guide empiric antibiotic choices. METHODS: All patients with moderate-severe diabetic foot infections at a tertiary care facility were identified from July 2011 to June 2012. Culture samples were routinely collected before empiric antibiotics were commenced. Retrospective chart review was performed to extract the following data: demographics, clinical details, empiric antibiotic choice and microbiologic data. Descriptive analyses were performed using SPSS 12.0. RESULTS: There were 139 patients at a mean age of 56.9 +/- 12.4 years. Mixed poly microbial infections were present in 56.8% of cases. Of 221 organisms isolated, 64.7% were gram-negative aerobes, 32.1% were gram-positive aerobes and 3.2% were obligate anaerobes. Multidrug resistant organisms were encountered in 25.9% of cases and included ESBL producers (11.3%), MRSA (4.5%) and VRE (1.4%). Both ciprofloxacin and ceftazidime had good overall anti-microbial activity against gram-negative (68% and 62%, respectively) and gram-positive pathogens (69% and 48%, respectively). Obligate anaerobes were uncommonly isolated due to institutional constraints. CONCLUSION: In this environment, both ciprofloxacin and ceftazidime provide good broad-spectrum anti-microbial activity against the commonly isolated pathogens. Either agent can be used as single agent empiric therapy in patients with moderate/severe diabetic infections in our setting. Although institutional limitations precluded isolation of anaerobes in most cases, there is sufficient evidence for anti-anaerobic agents to be recommended as a part of empiric therapy. PMID- 23742851 TI - Showcasing geographies of health: an introduction to selected research from the 14th International Medical Geography Symposium, Durham, UK, July 2011. PMID- 23742850 TI - Benefits and relationship of steps walked per day to cardiometabolic risk factor in Brazilian middle-aged men. AB - OBJECTIVES: We evaluated the benefits and relationship of the number of steps per day to the cardiometabolic risk factors: adiposity indicators; insulin resistance; and metabolic syndrome (MetS) in apparently healthy Brazilian middle aged men. DESIGN: Cross-sectional. METHODS: Apparently healthy men (age: 50 +/- 5 years; n=299) were studied. The number of steps per day was measured by pedometer. The adiposity indicators (waist circumference, total body fat, android and gynoid body fat), serum insulin, glucose and triglycerides, triglycerides/high-density lipoprotein cholesterol (HDL-c) ratio, homeostasis model assessment of insulin resistance (HOMA-IR) and MetS were assessed. Subjects were placed in groups to reflect different levels of steps per day (average of 7 consecutive days): Group 1<10,000 and Group 2 >= 10,000. Relationships among variables were measured by multiple linear regressions and the Spearman correlation coefficient as appropriate (p<0.05). RESULTS: The cardiometabolic risk factors were lower (p<0.05) in Group 2 than in Group 1. The number of steps per day was a negative predictive factor for total body fat, android and gynoid body fat and HOMA-IR independent of age, working position, android fat, overweight/obesity prevalence, and triglycerides/HDL-c ratio. Moreover, there was a negative correlation between the number of steps and total body fat, android and gynoid body fat, HOMA-IR and MetS. CONCLUSIONS: Brazilian middle-aged men performing more than 10,000 steps per day have better cardiometabolic conditions than those walking fewer than 10,000 steps. The number of steps per day is inversely related to the indicators of total and regional adiposity, insulin resistance and MetS. PMID- 23742852 TI - Reduction of leaf area and symptom severity as proxies of disease-induced plant mortality: the example of the Cauliflower mosaic virus infecting two Brassicaceae hosts. AB - Disease induced effects on host survival are important to understand the evolution of parasitic virulence and host resistance/tolerance. Unfortunately, experiments evaluating such effects are in most cases logistically demanding justifying the measurement of survival proxies. For plant hosts commonly used proxies are leaf area and the nature and severity of visual qualitative disease symptoms. In this study we tested whether these traits are indeed correlated to the host mortality rate induced by viral infection. We infected Brassica rapa and Arabidopsis thaliana plants with different natural isolates of Cauliflower mosaic virus (CaMV) and estimated over time the development of symptoms and the relative reduction of leaf area compared to healthy plants and followed plant mortality. We observed that the mortality of infected plants was correlated with the relative reduction of leaf area of both B. rapa and A. thaliana. Measures of mortality were also correlated with the severity of visual qualitative symptoms but the magnitude of the correlations and the time frame at which they were significant depended on the host plant: stronger and earlier correlations were observed on A. thaliana. PMID- 23742853 TI - Rabbit and human hepatitis E virus strains belong to a single serotype. AB - Hepatitis E virus (HEV) is a zoonotic pathogen and all four established genotypes of HEV belong to a single serotype. The recently identified rabbit HEV is antigenically and genetically related to human HEV. It is unclear whether rabbit HEV belongs to the same serotype as human HEV. The purpose of this study was to determine the serotypic relationship between rabbit and human HEVs. HEV ORF2 recombinant capsid protein p166 (amino acids 452-617) of four known HEV genotypes and rabbit HEV were used to induce immune serum, which were evaluated for their ability to neutralize human HEV genotype 1, 4, and rabbit HEV strains by an in vitro PCR-based HEV neutralization assay. Immune sera of five kinds of p166 proteins were all found to neutralize or cross-neutralize the three different HEV strains, suggesting a common neutralization epitope(s) existing between human and rabbit HEV. Rabbit models of a second-passage rabbit HEV strain, JS204-2, and a genotype 4 human HEV strain, NJ703, were established as evidenced by fecal virus shedding, viremia and anti-HEV IgG seroconversion. Six rabbits, recovered from JS204 infection, were challenged with NJ703, and another six recovered from NJ703 infection were challenged with JS204-2. After challenge, viremia was not detected, shorter fecal virus shedding durations and obvious early stage declines in anti-HEV IgG values were observed. The results from this study indicate that rabbit HEV belongs to the same serotype as human HEV. PMID- 23742854 TI - Image-guided percutaneous gastrostomy using modified large balloon as access target. AB - BACKGROUND/AIMS: To develop a novel percutaneous radiologic gastrostomy using a large-bore, rupture-free, balloon (RFB) catheter in patients with a swallowing disturbance due to a neurological disorder. METHODOLOGY: Consecutive patients underwent percutaneous gastrostomy placement using a balloon catheter with a 5.0 cm 5.0-cm, large-bore, rupture-free balloon on the tip between August 2010 and December 2011. The large balloon in the stomach was percutaneously punctured by the needle, the guide wire was inserted through the abdominal wall, and the push type gastrostomy tube was finally inserted over the guide wire via the oral cavity. Technical success and complications were evaluated. RESULTS: Fifteen patients (10 men, 5 women; age range, 47-82 years; mean age, 71.7 years) who had cerebral infarction (n=8), intracerebral hemorrhage (n=4), and subarachnoid hemorrhage (n=3) underwent percutaneous radiologic gastrostomy. The procedures were technically successful in all patients. The mean procedure time was 34+- 9 (SD) min (range, 20-47 min). The average follow-up was 158 days (range, 14 - 655 days). No major complications related to the procedure were encountered. CONCLUSION: Image-guided gastrostomy using a large-bore RFB catheter is an effective method of gastric feeding in patients with swallowing disturbance due to a neurological disorder. PMID- 23742855 TI - Serotonergic genes and suicide: a systematic review. AB - Suicide is one of the leading causes of death in the world. Its aetiology is complex and diverse, however, epidemiological studies show that suicidal behavior is partly heritable. Neurobiological evidence implicates serotonergic dysfunction in suicidality, stimulating genetic research to focus on genes related to the serotonergic system. In this paper, we review evidence from studies examining the association between various serotonergic genes (Tryptophan Hydroxylase genes: TPH1; TPH2, Serotonin Transporter gene: 5-HTTLPR in SLC6A4, Serotonin Receptor genes: HTR1A, HTR2A, HTR1B, HTR2C and Monoamine Oxidase A gene: MAOA) and suicidal behavior. The data show associations between variation on the TPH1 gene and 5-HTTLPR gene and violent suicidal behavior in Caucasian populations, with the least inconsistencies. Results are mixed for the TPH2 gene and serotonin receptor genes, but for some genes, studies that include haplotypic analyses or that examine a larger coding region of the genes tend to provide more reliable results. Findings on endophenotypes of suicidality, such as aggression and impulsivity traits, show positive associations for the TPH1, HTR2A, and MAOA genes, but need further replication, since negative associations are also occasionally reported. Since genes can only partially explain suicidal risk, several studies during the past decade have tried to incorporate environmental factors in the susceptibility model. Studies to date show that variation on the 5 HTTLPR, MAOA and HTR2A gene can interact with stressful life events to increase risk for suicidal behavior. Limitations of case-control studies are discussed and future considerations are put forward with regard to endophenotypic measurements and gene-environment interactions. PMID- 23742856 TI - 3, 4-seco-labdane diterpenoids from the leaves of Callicarpa nudiflora and their inhibitory effects on nitric oxide production. AB - As a part of our ongoing search for bioactive compounds from the leaves of Callicarpa nudiflora that inhibit nitric oxide (NO) production, the 90% EtOH fraction eluted by macroporous resin adsorption was found to show significant inhibitory activity against the production of NO in RAW 264.7 stimulated by lipopolysaccharide (LPS). Bioactivity-guided isolation of the fraction yielded three new bioactive diterpenoids, named ent-3, 4-seco-14-carbonyl-15, 16-epoxy 4(18), 8(17), 13(14)-labdatrien-3-oic acid (1), syn-3, 4-seco-12R-hydroxy-15, 16 epoxy-4(18), 8(17), 13(16), 14(15)-labdatetraen-3-oic acid (2) and syn-3, 4-seco 12S-hydroxy-15, 16-epoxy-4(18), 8(17), 13(16), 14(15)-labdatetraen-3-oic acid (3). Their structures and configurations were elucidated by comprehensive spectroscopic analysis. All the three compounds exhibited potent inhibitory activity on NO production in LPS-activated RAW 264.7 macrophage cells. PMID- 23742857 TI - Effects of rhinacanthin-C on function and expression of drug efflux transporters in Caco-2 cells. AB - Rhinacanthin-C is a bioactive naphthoquinone ester found in Rhinacanthus nasutus Kurz (Acanthaceae). This compound has potential therapeutic value as an anticancer and antiviral agent. The purposes of this study were to determine the effects of this compound on the function and the expression of P-glycoprotein (P gp) and multidrug resistance-associated protein 2 (MRP2), using the in vitro model of Caco-2 cells. The activities of P-gp and MRP2 were determined by following the intracellular accumulation of calcein and 5(6)-carboxy-2',7' dichlorofluorescein in the uptake assays with fluorescence spectroscopy. The expression of P-gp after prolonged exposure was evaluated by flow cytometry with the use of a fluorescein isothiocyanate-conjugated anti-human P-gp antibody. Our results showed that the inhibitory effect of rhinacanthin-C was more potent toward P-gp than MRP2, and was reversible. Short-term exposure of Caco-2 cells with rhinacanthin-C (100 MUM) resulted in increase in P-gp expression without any significant change in its function. Extended exposure of Caco-2 cells to the naphthoquinone at the highest non-cytotoxic concentration (0.625 MUM) for 7 days had no effect on the expression and the function of P-gp. These findings suggested that rhinacanthin-C might raise the problem of herb-drug interaction when co-administered with other P-gp substrates. PMID- 23742858 TI - The H+/K+-ATPase inhibitory activities of Trametenolic acid B from Trametes lactinea (Berk.) Pat, and its effects on gastric cancer cells. AB - Trametenolic acid B (TAB), the bioactive component in the Trametes lactinea (Berk.) Pat, was reported to possess cytotoxic activities and thrombin inhibiting effects. This study was performed to investigate the effects of TAB on H(+)/K(+) ATPase and gastric cancer. The H(+)/K(+)-ATPase inhibitory activity was determined by gastric parietal cells. Compared to the normal control group, TAB (10, 20, 40 and 80 MUg/mL) inhibited the H(+)/K(+)-ATPase activity by 15.97, 16.96, 24.86 and 16.25%, respectively. In the study, 36 Kunming mice were randomly divided into six groups: control, model, TAB-L (TAB, 5 mg/kg/day, i.g.), TAB-M (TAB, 20 mg/kg/day, i.g.), TAB-H (TAB, 40 mg/kg/day, i.g.) and omeprazole (OL, 10 mg/kg/day, i.g.). All mice except the control group were administrated with anhydrous alcohol (5.0 mL/kg, i.g.) for induced gastric-ulcer 1h after the 5th day. At the same time, the control mice were given the same volume of physiological saline. After 4h, TAB was evaluated for H(+)/K(+)-ATPase inhibitory activities of ulcerative gaster, gastric ulcer index and ulcer inhibition. In vitro, the anti-proliferation effect of TAB to gastric cancer cell (HGC-27) in acid environment was detected by MTT, and the apoptosis morphological changes were also observed by Hoechst 33258 dye assay. The results indicated that TAB inhibited moderately H(+)/K(+)-ATPase activity in vitro. Compared to the model group, TAB showed anti-ulcer effects in gastric tissue with the dosages of 20 and 5 mg/kg in vivo. Apart from that, TAB could selectively inhibit gastric cancer cell viability and reduce cell apoptosis against HGC-27 cells at low doses in acid environment. PMID- 23742859 TI - Solajiangxins A-C, three new cytotoxic sesquiterpenoids from Solanum lyratum. AB - One new eudesmane-type (1, named solajiangxin A) and two new eudesmane-related sesquiterpenoids (2-3, named solajiangxins B-C) were isolated from the whole plant of Solanum lyratum. Their structures were elucidated on the basis of integrated spectroscopic techniques. In vitro, three new sesquiterpenoids were found to show significant cytotoxicities against three human cancer lines (P-388, HONE-1 and HT-29), and gave ED50 values in the range of 1.9-3.7 MUg/ml. PMID- 23742860 TI - Closing the osteoporosis treatment gap. PMID- 23742861 TI - Propofol infusion syndrome: a lethal condition in critically injured patients eliminated by a simple screening protocol. AB - Propofol infusion syndrome (PIS) is defined by arrhythmia, rhabdomyolysis, lactic acidosis, and unrecognized leads to death. We sought to determine the incidence of PIS in trauma patients and evaluate the efficacy of a prospective screening protocol in this patient population. MATERIALS AND METHODS: In Phase I of the before-and-after study (1st January, 2005-31st December, 2005), trauma patients who received propofol were evaluated. Records were reviewed for demographics, injury severity, propofol time, dose, and rates, laboratory values, and adverse events. Patients were identified with PIS based on two of the following criteria: (1) cardiac arrhythmia/collapse, (2) metabolic acidosis, (3) rhabdomyolysis, and (4) acute kidney injury. Phase II (1st January, 2006-31st December, 2011) consisted of a prospective screening protocol (elevated lactate or creatine phosphokinase (CPK)) to identify patients at risk for PIS. RESULTS: 207 patients were identified in Phase I. 6 (2.9%) developed PIS with a 50% mortality. No differences were seen in age, gender, or mechanism. PIS patients were more injured (median ISS 44 vs 26, p=0.04; median head AIS 5 vs 4, p=0.003) and received more propofol (median 50,350 vs 9770 mg, p=0.001) with longer infusion times (413 vs 65 h, p=0.001). Sodium, creatinine, and CPK levels were higher in those that developed PIS (160 vs 145 mmol/L, p=0.001; 4.3 vs 1.1mg/dL, p=0.005; 59,871 vs 520 U/L; p=0.002). Pre-screening PIS incidence was 2.9% (6/207), but after screening (January 2006) the incidence dropped to 0.19% (2/1038, p<0.001). CONCLUSIONS: PIS is a morbid and lethal entity associated with sedation of critically injured patients. A simple screening procedure utilizing serum CPK (<5000 U/L) can essentially eliminate the development of PIS. PMID- 23742862 TI - Pulchellamin G, an amino acid-sesquiterpene lactone, from Saussurea pulchella suppresses lipopolysaccharide-induced inflammatory responses via heme oxygenase-1 expression in murine peritoneal macrophages. AB - Saussurea pulchella (Asteraceae) is widely distributed in Korea and has been used in Korean folk medicine for the treatment of inflammation, hypertension, hepatitis, and arthritis. Pulchellamin G is an amino acid-sesquiterpene lactone conjugate isolated from S. pulchella. In the present study, we focused on the anti-inflammatory effect of pulchellamin G, which acts by inducing the expression of heme oxygenase (HO)-1. HO-1 plays important roles in cytoprotection since it has antioxidant, anti-inflammatory, antiproliferative, and antiapoptotic properties. Pulchellamin G inhibited the mRNA and protein expression of inducible nitric oxide synthase (iNOS), iNOS-derived nitric oxide (NO), and cyclooxygenase (COX)-2 and COX-derived prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-stimulated murine peritoneal macrophages. The compound also reduced tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) production and suppressed the phosphorylation and degradation of IkappaB-alpha and nuclear translocation of p65 in murine peritoneal macrophages in response to LPS stimulus. The inhibitory effects of pulchellamin G on nuclear factor kappa B (NF kappaB) translocation was impaired by co-treatment of the cells with HO activity inhibitor tin protoporphyrin (SnPP). By using SnPP, we verified that the inhibitory effects of pulchellamin G on the pro-inflammatory mediators NO, PGE2, TNF-alpha, and IL-1beta are associated with induction of HO-1 expression. Our data suggest that pulchellamin G might have potent therapeutic effects and it should be considered in the development of treatments for various inflammatory diseases. PMID- 23742863 TI - Inflammation and peripheral 5-HT7 receptors: the role of 5-HT7 receptors in carrageenan induced inflammation in rats. AB - The aim of this study was: (1) to investigate possible role for 5-HT7 receptors in carrageenan induced inflammatory paw oedema in rats; (2) to determine the presence of 5-HT7 receptors in rat paw tissue; (3) to observe the effects of 5 HT7 receptor agonist and antagonist administration on inflammation; and (4) to determine a unique mechanism for inflammatory processes via 5-HT7 receptors. Effects of 5-HT7 receptor agonist, antagonist and indomethacin were investigated in carrageenan induced paw oedema in rats. Blood and tissue samples were collected and evaluated biochemically for serum cytokine levels, tissue oxidant antioxidant balance and histopathologically for inflammatory cell accumulation. We performed Real Time PCR analyses for tissue 5-HT7 receptor and COX mRNA expressions. The 5-HT7 receptor agonist AS-19 exerted significant anti inflammatory effect both alone and in combination with indomethacin. Antagonist, SB269970, did not affect inflammation alone but decreased the effects of agonist when co-administered. 5-HT7 mRNA levels were higher in the carrageenan group than healthy control. Carrageenan+indometacin group decreased the mRNA expression of 5 HT7 when compared to carrageenan group. While agonist administration decreased 5 HT7 mRNA expression when compared to carrageenan group. Agonist decreased paw COX expression. Agonist also decreased serum cytokine levels and tissue oxidative stress. In conclusion, this study demonstrated for the first time that 5-HT7 receptors are expressed in rat paw tissue and that this expression responds to inflammatory stimuli. The 5-HT7 receptor may be a promising new therapeutic target for prevention of inflammation and inflammatory disorders and may also provide a new glimpse into inflammation pathophysiology. PMID- 23742864 TI - Some properties of horn equation model of ultrasonic system vibration and of transfer matrix and equivalent circuit methods of its solution. AB - Traditional technique of horn equation solved by transfer matrices as a model of vibration of ultrasonic systems consisting of sectional transducer, horn and load is discussed. Expression of vibration modes as a ratio of solutions of two Schrodinger equations gives better insight to the structure of a transfer matrix and properties of amplitudes of displacement and strain, and enables more systematic search for analytic solutions. Incorrectness of impedance matrix method and of equivalent circuit method on one hand and correctness and advantages of transfer matrix method in avoiding numerical artifacts and revealing the real features of the model on the other hand are demonstrated on examples. Discontinuous dependence of the nth resonant value on parameters of ultrasonic system, recently described in Sturm-Liouville theory, and consequently, a jump from half-wave to full-wave mode, is observed in a transducer model. PMID- 23742865 TI - Association between antidepressant side effects and functional impairment in patients with major depressive disorders. AB - Patients with depression may not well be aware of antidepressant adverse events (AEs); however, no studies have assessed how these AEs affect their daily function. Therefore, to evaluate the relationship between the quality of AEs and functional impairment, we studied 482 outpatients with depressive disorders who were not receiving any antidepressant treatment prior to the baseline visit and started it thereafter in usual clinical settings. The Quick Inventory for Depressive Symptomatology Self-Report Japanese version and antidepressant AEs for subjective assessment (antiAS) were performed at baseline and 10 days after antidepressant initiation (i.e. second visit). Functional impairment was evaluated with the Sheehan Disability Scale (SDS) on the second visit. As a result, the SDS was positively associated with the number of AEs (beta=0.089, p=0.022) in multiple linear regression analysis (adjusted R(2)=0.357, p<0.001). Subjects who experienced vertigo, nausea and insomnia had significantly more functional impairment than those who did not. Additionally, the number of severe AEs (beta=0.151, p<0.001) was associated with a higher SDS score, and those AEs with a negative causal attribution to antidepressants in the antiAS significantly affected the SDS (beta=0.105, p=0.008). AEs of antidepressants should be carefully monitored since they could negatively affect their daily function. PMID- 23742866 TI - Molecular characterization and expression analysis of TLR 7 and TLR 8 homologs in large yellow croaker (Pseudosciaena crocea). AB - The two toll-like receptor (TLR) genes, LycTLR7 and LycTLR8, were cloned from large yellow croaker (Pseudosciaena crocea), an economically important marine fish in China. The full-length cDNAs of LycTLR7 and LycTLR8 are 3544 and 3593 bp, with an open reading frame (ORF) of 3165 and 3093 bp, encoding 1053 and 1030 amino acids, respectively. The TLR family motifs, such as leucine rich repeat (LRR) and Toll/interleukin (IL)-1 receptor (TIR) domain, are conserved in the LycTLR7 and LycTLR8, with 17 and 14 LRRs, and with a TIR domain, respectively. It is also noted that an LRR N-terminal domain (LRR-NT, residues 24-60) is present in the LycTLR7 but not in the LycTLR8. Both LycTLR7 and LycTLR8 contain a conserved extracellular CxRCxxxxxPCxxC motif, which was found in TLR7/TLR8 of other species and required for stimulus-induced signal transduction. Homology comparison shows that LycTLR7 has 79%, 71.9%, 65.9% and 65.8% identity to fugu, rainbow trout, carp and catfish TLR7, while LycTLR8 has 67.1%, 60.7%, 60.6%, 52.4%, and 51.5% identity to fugu TLR8, rainbow trout TLR8a1, rainbow trout TLR8a2, catfish TLR8-2, and catfish TLR8-1, respectively. Subcellular localization analysis revealed that both LycTLR7 and LycTLR8 are located in the endoplasmic reticulum of epithelioma papulosum cyprini (EPC) cells, which is similar to TLR7/TLR8 in mammals. The two TLRs were constitutively expressed in all tissues tested, especially in immune-related tissues such as spleen, head kidney and gills. An increased expression of LycTLR7 and LycTLR8 was observed in head kidney and spleen of large yellow croakers stimulated by poly (I:C), a viral mimic. In head kidney, their mRNA expression was up-regulated more than 10 times compared to the controls at 12 h after poly (I:C) stimulation. These results suggested that LycTLR7 and LycTLR8 may play a role in the defense against viral infection like their mammalian homologs. PMID- 23742867 TI - Identification and expression analysis on bactericidal permeability-increasing protein (BPI)/lipopolysaccharide-binding protein (LBP) of ark shell, Scapharca broughtonii. AB - Bactericidal permeability-increasing protein (BPI) and lipopolysaccharide-binding protein (LBP) are the numbers of the lipid transfer protein/lipopolysaccharide binding protein family and play crucial roles in the innate immune response to Gram-negative bacteria. A novel Sb-BPI/LBP1 from ark shell Scapharca broughtonii was isolated by expressed sequence tag (EST) and RACE techniques. The Sb-BPI/LBP1 cDNA encoded a polypeptide of 484 amino acids with a putative signal peptide of 21 amino acid residues and a mature protein of 463 amino acids. The deduced amino acid sequence of Sb-BPI/LBP1 contained an N-terminal BPI/LBP/CETP domain BPI1 with three functional regions that display LPS-binding activity, and a C-terminal BPI/LBP/CETP domain BPI2. In structure and sequence, Sb-BPI/LBP1 showed highly similar to those of the BPI/LBPs from invertebrate and non-mammalian vertebrate, the LBPs and BPIs from mammal. By quantitative real-time RT-PCR, Sb-BPI/LBP1 transcripts could be detected in all normal tested tissues, including hepatopancreas, adductor muscle, mantle margin, heart, gonad, gill and hemocytes, and was universally up-regulatable at 24 h post LPS challenge. The mRNA expression of Sb-BPI/LBP1 in hemocytes was the most sensitive to LPS challenge, significantly up-regulated at 12 h post LPS challenge and peaked at 24 h (16.76 fold, P < 0.05). These results suggested that Sb-BPI/LBP1 was a constitutive and inducible acute-phase protein contributing to the host immune defense against Gram-negative bacterial infection in ark shell S. broughtonii. PMID- 23742868 TI - Expression profiles of toll-like receptors in channel catfish (Ictalurus punctatus) after infection with Ichthyophthirius multifiliis. AB - Toll-like receptors (TLRs) play a crucial role in the innate immune system, but to date the roles of fish TLRs in response to parasitic infection are still poorly understood. In the present study, we used channel catfish (Ictalurus punctatus) and the ciliate parasite Ichthyophthirius multifiliis as a model to investigate whether and which fish TLRs play important roles in the immune response against parasitic pathogens by detecting the expression profiles of a complete set of TLRs in catfish at different time points after infection with I. multifiliis. The expression profiles of TLR1 and TLR2 were similar, and both were significantly up-regulated in the skin and head kidney at most time points after infection. Furthermore, the expression of TLR2 was also up-regulated in the gill and spleen. TLR9 was induced in the skin and gill, whereas TLR21 was induced in the head kidney and spleen after infection. For TLR19, significant up-regulation was observed in the skin and gill, but significant down-regulation was detected in the head kidney and spleen. In contrast to TLR19, TLR25 was significantly up regulated in the head kidney and spleen at some time points. No significant changes were observed for the rest of the TLRs at most time points. The results indicated that some TLRs may play essential roles in catfish defense against I. multifiliis infection. PMID- 23742869 TI - Effects of dietary isoleucine on the immune response, antioxidant status and gene expression in the head kidney of juvenile Jian carp (Cyprinus carpio var. Jian). AB - This study was conducted to evaluate the effects of dietary isoleucine (Ile) on the immune response, antioxidant status and gene expression in the head kidney of juvenile Jian carp (Cyprinus carpio var. Jian). Six semi-purified isonitrogenous diets (4.2, 7.0, 9.5, 11.9, 13.9 and 16.9 g Ile kg(-1) diet) were fed to Jian carp (6.9 +/- 0.03 g) for 60 days. The results showed that Ile supplementation improved the head kidney index, red and white blood cell counts, anti-hydroxyl radical capacity and the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase (P < 0.05), and decreased the malondialdehyde, protein carbonyl and glutathione contents in the head kidney (P < 0.05). After a 60 day feeding trial, an Aeromonas hydrophila challenge study was conducted for 17 days. Differences in survival rate, leucocyte phagocytic activity, serum lysozyme activity, acid phosphatase activity, haemagglutination titre, complement components 3 and 4, immunoglobulin M level and A. hydrophila agglutination antibody titre followed the same trend as that of the head kidney index (P < 0.05). Furthermore, real time polymerase chain reaction revealed that relative mRNA expression of transforming growth factor beta2 and target of rapamycin (TOR) in the head kidney significantly increased with increasing Ile levels (P < 0.05). Conversely, the relative mRNA expression of tumour necrosis factor alpha, interleukin 10 and eIF4E-binding protein (4E-BP) in the head kidney showed a downward trend (P < 0.05). Collectively, this study indicates that dietary Ile improves the fish immune response, regulates the antioxidant status and cytokine, TOR and 4E-BP gene expression in the head kidney. PMID- 23742870 TI - Toward genome-wide identification of Bateson-Dobzhansky-Muller incompatibilities in yeast: a simulation study. AB - The Bateson-Dobzhansky-Muller (BDM) model of reproductive isolation by genetic incompatibility is a widely accepted model of speciation. Because of the exceptionally rich biological information about the budding yeast Saccharomyces cerevisiae, the identification of BDM incompatibilities in yeast would greatly deepen our understanding of the molecular genetic basis of reproductive isolation and speciation. However, despite repeated efforts, BDM incompatibilities between nuclear genes have never been identified between S. cerevisiae and its sister species S. paradoxus. Such negative results have led to the belief that simple nuclear BDM incompatibilities do not exist between the two yeast species. Here, we explore an alternative explanation that such incompatibilities exist but were undetectable due to limited statistical power. We discover that previously employed statistical methods were not ideal and that a redesigned method improves the statistical power. We determine, under various sample sizes, the probabilities of identifying BDM incompatibilities that cause F1 spore inviability with incomplete penetrance, and confirm that the previously used samples were too small to detect such incompatibilities. Our findings call for an expanded experimental search for yeast BDM incompatibilities, which has become possible with the decreasing cost of genome sequencing. The improved methodology developed here is, in principle, applicable to other organisms and can help detect epistasis in general. PMID- 23742871 TI - Adapting to an initial self-regulatory task cancels the ego depletion effect. AB - The resource-based model of self-regulation provides a pessimistic view of self regulation that people are destined to lose their self-control after having engaged in any act of self-regulation because these acts deplete the limited resource that people need for successful self-regulation. The cognitive control theory, however, offers an alternative explanation and suggests that the depletion effect reflects switch costs between different cognitive control processes recruited to deal with demanding tasks. This account implies that the depletion effect will not occur once people have had the opportunity to adapt to the self-regulatory task initially engaged in. Consistent with this idea, the present study showed that engaging in a demanding task led to performance deficits on a subsequent self-regulatory task (i.e. the depletion effect) only when the initial demanding task was relatively short but not when it was long enough for participants to adapt. Our results were unrelated to self-efficacy, mood, and motivation. PMID- 23742872 TI - Decreased cognitive function in extended family members from the single late onset-Alzheimer's-disease pedigree. AB - A family history of dementia is associated with an increased risk of developing Alzheimer's disease (AD) late in life (LOAD). This study marked the first attempt to assess the familial contribution to differences in cognitive performance in a large family-based group in the Chinese community. We enrolled 168 participants without dementia from a single pedigree with 9 probable AD patients diagnosed after age 65. These participants were evaluated with a comprehensive neuropsychological battery, the Chinese version of the Mini Mental State Examination, and the Alzheimer Disease Assessment Scale-Cognitive Subscale. Analyses found that extended family members of the LOAD pedigree showed similar performance on measures of global cognitive function and semantic memory compared to controls, but lower scores on episodic memory, attention, and executive function measures. These results indicate that the genetic influences on certain sub-cognitive domains are more detectable despite normal global cognitive function, and that family members with the LOAD pedigree are at risk for developing LOAD by virtue of their family history with an additive risk due to increased age. The findings in this study support the importance of documenting if there is a positive family history of AD in clinical evaluations. PMID- 23742873 TI - Fibromyalgia syndrome--novel therapeutic targets. AB - Fibromyalgia is a syndrome characterized by the presence of chronic widespread pain, representing sensitization of the central nervous system. The pthophysiology of fibromyalgia is a complex and remains in evolution, encompassing diverse issues such as disturbed patterns of sleep, alter processing and decreased conditioned pain modulation at the spinal level, as well as increased connectivity between various pain - processing areas of the brain. This evolution is continuously uncovering potential novel therapeutic targets. Treatment of fibromyalgia is a multi - faceted endeavor, inevitably combining pharmacological as well as non - pharmacological approaches. 2delta ligands and selective nor-epinephrine - serotonin reuptake inhibitors are the current mainstays of pharmacological treatment. Novel re-uptake inhibitors targeting both nor -epinephrine and dopamine are potential additions to this armamentarium as are substance P antagonists, Opiod antagonism is another intriguing possibility. Canabinoid agonists hold promise in the treatment of fibromyalgia although current evidence is incomplete. Sodium Oxybate is a unique sleep - promoting medication while drugs those promot arousals such as modafilnil are also under investigation. In the current review, current and emerging therapeutic options for the syndrome of fibromyalgia are covered. PMID- 23742874 TI - Trends in allergic conditions among children: United States, 1997-2011. AB - Allergic conditions are among the most common medical conditions affecting children in the United States (1-5). An allergic condition is a hypersensitivity disorder in which the immune system reacts to substances in the environment that are normally considered harmless (6,7). Food or digestive allergies, skin allergies (such as eczema), and respiratory allergies (such as hay fever) are the most common allergies among children. Allergies can affect a child's physical and emotional health and can interfere with daily activities, such as sleep, play, and attending school (8,9). A severe allergic reaction with rapid onset, anaphylaxis, can be life threatening. Foods represent the most common cause of anaphylaxis among children and adolescents (10,11). Early detection and appropriate interventions can help to decrease the negative impact of allergies on quality of life (6). This report presents recent trends in the prevalence of allergies and differences by selected sociodemographic characteristics for children under age 18 years. PMID- 23742875 TI - Right care, every time -- reliability in the ED. PMID- 23742876 TI - Tumour angiogenesis: an elusive target in castration-resistant prostate cancer. PMID- 23742877 TI - Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. AB - BACKGROUND: Docetaxel plus prednisone is standard first-line chemotherapy for men with metastatic castrate-resistant prostate cancer. Aflibercept is a recombinant human fusion protein that binds A and B isoforms of VEGF and placental growth factor, thereby inhibiting angiogenesis. We assessed whether the addition of aflibercept to docetaxel and prednisone would improve overall survival in men with metastatic castrate-resistant prostate cancer compared with the addition of placebo to docetaxel and prednisone. METHODS: VENICE was a phase 3, multicentre, randomised double-blind placebo-controlled parallel group study done in 31 countries (187 sites). Men with metastatic castrate-resistant prostate cancer, adequate organ function, and no prior chemotherapy were treated with docetaxel (75 mg/m(2) intravenously every 3 weeks) and oral prednisone (5 mg twice daily) and randomly allocated (1:1) to receive aflibercept (6 mg/kg) or placebo, intravenously, every 3 weeks. Treatment allocation was done centrally via an interactive voice response system, using a computer-generated sequence with a permuted-block size of four and stratified according Eastern Co-operative Group performance status (0-1 vs 2). Patients, investigators, and other individuals responsible for study conduct and data analysis were masked to treatment assignment. Aflibercept or placebo vials were supplied in identical boxes. The primary endpoint was overall survival using intention-to-treat analysis. This is the primary analysis of the completed trial. The study is registered with ClinicalTrials.gov, number NCT00519285 FINDINGS: Between Aug 17, 2007, and Feb 11, 2010, 1224 men were randomly allocated to treatment: 612 to each group. At final analysis, median follow-up was 35 months (IQR 29-41) and 873 men had died. Median overall survival was 22.1 months (95.6% CI 20.3-24.1) in the aflibercept group and 21.2 months (19.6-23.8) in the placebo group (stratified hazard ratio 0.94, 95.6% CI 0.82-1.08; p=0.38). We recorded a higher incidence of grade 3-4 gastrointestinal disorders (182 [30%] vs 48 [8.0%]), haemorrhagic events (32 [5.2%] vs ten [1.7%]), hypertension (81 [13%] vs 20 [3.3%]), fatigue (97 [16%] vs 46 [7.7%]), infections (123 [20%] vs 60 [10%]) and treatment-related fatal adverse events (21 [3.4%] vs nine [1.5%]) in the aflibercept group than in the placebo group. INTERPRETATION: Aflibercept in combination with docetaxel and prednisone given as first-line chemotherapy for men with metastatic castrate resistant prostate cancer resulted in no improvement in overall survival and added toxicity compared with placebo. Docetaxel plus prednisone remains the standard treatment for such men who need first-line chemotherapy. FUNDING: Sanofi and Regeneron Pharmaceuticals Inc. PMID- 23742878 TI - Drug delivery systems based on nucleic acid nanostructures. AB - The field of DNA nanotechnology has progressed rapidly in recent years and hence a large variety of 1D-, 2D- and 3D DNA nanostructures with various sizes, geometries and shapes is readily accessible. DNA-based nanoobjects are fabricated by straight forward design and self-assembly processes allowing the exact positioning of functional moieties and the integration of other materials. At the same time some of these nanosystems are characterized by a low toxicity profile. As a consequence, the use of these architectures in a biomedical context has been explored. In this review the progress and possibilities of pristine nucleic acid nanostructures and DNA hybrid materials for drug delivery will be discussed. For the latter class of structures, a distinction is made between carriers with an inorganic core composed of gold or silica and amphiphilic DNA block copolymers that exhibit a soft hydrophobic interior. PMID- 23742879 TI - Self-reinforced endocytoses of smart polypeptide nanogels for "on-demand" drug delivery. AB - The pH and reduction dual-responsive polypeptide nanogels with self-reinforced endocytoses were prepared through ring-opening polymerization of l-glutamate N carboxyanhydrides, deprotection of benzyl group and subsequent quaternization reaction between gamma-2-chloroethyl-l-glutamate unit in polypeptide block and 2,2'-dithiobis(N,N-dimethylethylamine). The nanogels were revealed to exhibit smart pH and reduction dual-responsiveness, and excellent biocompatibilities, which expressed great potential as antitumor drug nanocarriers. Doxorubicin (DOX) as a model antitumor drug was loaded into nanogels through dispersion. DOX-loaded nanogels displayed a stable core-cross-linked structure under normal physiological condition (pH7.4), while rapidly releasing the payloads in the mimicking endosomal (pH5.3), tumor tissular (pH6.8) or intracellular reductive microenvironments (10.0mM glutathione). Confocal fluorescence microscopy demonstrated that DOX-loaded nanogels could deliver DOX into HepG2 cells (a human hepatoma cell line) more efficiently than the parent DOX-loaded micelle and free DOX. The enhanced cellular internalizations of DOX-loaded nanogels were more significant under tumor tissular acidic condition (pH6.8) ascribed to the quaternary ammonium groups in the cores. In addition, DOX-loaded nanogels exhibited improved in vitro and in vivo antitumor activities, and in vivo securities compared with DOX-loaded micelle and free DOX. These excellent features of the smart nanogels with quaternary ammonium groups were endowed with a bright prospect for intracellular targeting antitumor drug delivery. PMID- 23742880 TI - Cationic polypeptide micelle-based antigen delivery system: a simple and robust adjuvant to improve vaccine efficacy. AB - Modern subunit vaccines with purified or recombinant antigens are important alternatives to the traditional vaccines. However, there remains a big challenge to elicit potent antibody production and CD8 T cell response. Nanoparticle-based antigen delivery systems have emerged as an innovative strategy to improve the efficacy of subunit vaccines. The present study reported self-assembled cationic micelles based on poly(ethylene glycol)-b-poly(L-lysine)-b-poly(L-leucine) (PEG PLL-PLLeu) hybrid polypeptides as a simple and potent vaccine delivery system. The results showed that the PEG-PLL-PLLeu micelles spontaneously encapsulated OVA antigens with great loading capacity (LC=55%) and stability. More importantly, the polypeptide micelle formulations robustly enhanced vaccine-induced antibody production by 70-90 fold, which could be due to their capability of inducing dendritic cell maturation, enhancing antigen uptake and presentation, as well as promoting germinal center formation. Furthermore, the polypeptide micelles could simultaneously encapsulate OVA and polyriboinosinic: polyribocytidylic acid (PIC), a TLR3 agonist, to synergistically augment tumor specific cytotoxic-T lymphocyte (CTL) response. Hence, the polypeptide micelle-based antigen delivery system could be a robust adjuvant to enhance vaccine-induced immune responses. PMID- 23742881 TI - Hypoxia as a target for tissue specific gene therapy. AB - Hypoxia is a hallmark of various ischemic diseases such as ischemic heart disease, ischemic limb, ischemic stroke, and solid tumors. Gene therapies for these diseases have been developed with various therapeutic genes including growth factors, anti-apoptotic genes, and toxins. However, non-specific expression of these therapeutic genes may induce dangerous side effects in the normal tissues. To avoid the side effects, gene expression should be tightly regulated in an oxygen concentration dependent manner. The hypoxia inducible promoters and enhancers have been evaluated as a transcriptional regulation tool for hypoxia inducible gene therapy. The hypoxia inducible UTRs were also used in gene therapy for spinal cord injury as a translational regulation strategy. In addition to transcriptional and translational regulations, post-translational regulation strategies have been developed using the HIF-1alpha ODD domain. Hypoxia inducible transcriptional, translational, and post-translational regulations are useful for tissue specific gene therapy of ischemic diseases. In this review, hypoxia inducible gene expression systems are discussed and their applications are introduced. PMID- 23742882 TI - Droplet-born air blowing: novel dissolving microneedle fabrication. AB - The microneedle-mediated drug delivery system has been developed to provide painless self-administration of drugs in a patient-friendly manner. Current dissolving microneedle fabrication methods, however, require harsh conditions for biological drugs and also have problems standardizing the drug dose. Here, we suggested the droplet-born air blowing (DAB) method, which provides gentle (4-25 degrees C) and fast (<=10min) microneedle fabrication conditions without drug loss. The amount of drug in the microneedle can be controlled by the pressure and time of droplet dispenser and the air blowing shapes this droplet to the microneedle, providing a force sufficient to penetrate skin. Also, the introduction of a base structure of two layered DAB-microneedle could provide complete drug delivery without wasting of drug. The DAB-based insulin loaded microneedle shows similar bioavailability (96.6+/-2.4%) and down regulation of glucose level compared with subcutaneous injection. We anticipate that DAB described herein will be suitable to design dissolving microneedles for use in biological drug delivery to patients. PMID- 23742885 TI - Into the deep: a phylogenetic approach to the bivalve subclass Protobranchia. AB - A molecular phylogeny of Protobranchia, the subclass of bivalve mollusks sister to the remaining Bivalvia, has long proven elusive, because many constituent lineages are deep-sea endemics, which creates methodological challenges for collecting and preserving genetic material. We obtained 74 representatives of all 12 extant protobranch families and investigated the internal phylogeny of this group using sequence data from five molecular loci (16S rRNA, 18S rRNA, 28S rRNA, cytochrome c oxidase subunit I, and histone H3). Model-based and dynamic homology parsimony approaches to phylogenetic reconstruction unanimously supported four major clades of Protobranchia, irrespective of treatment of hypervariable regions in the nuclear ribosomal genes 18S rRNA and 28S rRNA. These four clades correspond to the superfamilies Nuculoidea (excluding Sareptidae), Nuculanoidea (including Sareptidae), Solemyoidea, and Manzanelloidea. Salient aspects of the phylogeny include (1) support for the placement of the family Sareptidae with Nuculanoidea; (2) the non-monophyly of the order Solemyida (Solemyidae+Nucinellidae); (3) and the non-monophyly of most nuculoid and nuculanoid genera and families. In light of this first family-level phylogeny of Protobranchia, we present a revised classification of the group. Estimation of divergence times in concert with analyses of diversification rates demonstrate the signature of the end-Permian mass extinction in the phylogeny of extant protobranchs. PMID- 23742884 TI - Guidelines for the diagnosis and treatment of idiopathic pulmonary fibrosis. Sociedad Espanola de Neumologia y Cirugia Toracica (SEPAR) Research Group on Diffuse Pulmonary Diseases. AB - Idiopathic pulmonary fibrosis is defined as a chronic fibrosing interstitial pneumonia limited to the lung, of unknown cause, with poor prognosis and few treatment options. In recent years there has been an increase in their prevalence, probably due to the optimization of diagnostic methods and increased life expectancy. The ATS/ERS Consensus (2000) established the diagnostic criteria and recommendations for the assessment of the disease course and treatment. Later studies have helped to redefine diagnostic criteria and treatment options. In 2011, an international consensus was published, establishing diagnostic criteria and new treatment strategies. These guidelines have been updated with the newest aspects of diagnosis and treatment of idiopathic pulmonary fibrosis. A level of evidence has been identified for the most relevant questions, particularly with regard to treatment options. PMID- 23742886 TI - Phylogenetic relationships within the lizard clade Xantusiidae: using trees and divergence times to address evolutionary questions at multiple levels. AB - Xantusiidae (night lizards) is a clade of small-bodied, cryptic lizards endemic to the New World. The clade is characterized by several features that would benefit from interpretation in a phylogenetic context, including: (1) monophyletic status of extant taxa Cricosaura, Lepidophyma, and Xantusia; (2) a species endemic to Cuba (Cricosaura typica) of disputed age; (3) origins of the parthenogenetic species of Lepidophyma; (4) pronounced micro-habitat differences accompanied by distinct morphologies in both Xantusia and Lepidophyma; and (5) placement of Xantusia riversiana, the only vertebrate species endemic to the California Channel Islands, which is highly divergent from its mainland relatives. This study incorporates extensive new character data from multiple gene regions to investigate the phylogeny of Xantusiidae using the most comprehensive taxonomic sampling available to date. Parsimony and partitioned Bayesian analyses of more than 7 kb of mitochondrial and nuclear sequence data from 11 loci all confirm that Xantusiidae is monophyletic, and comprises three well-supported clades: Cricosaura, Xantusia, and Lepidophyma. The Cuban endemic Cricosaura typica is well supported as the sister to all other xantusiids. Estimates of divergence time indicate that Cricosaura diverged from the (Lepidophyma+Xantusia) clade ~ 81 million years ago (Ma), a time frame consistent with the separation of the Antilles from North America. Our results also confirm and extend an earlier study suggesting that parthenogenesis has arisen at least twice within Lepidophyma without hybridization, that rock-crevice ecomorphs evolved numerous times (>9) within Xantusia and Lepidophyma, and that the large bodied Channel Island endemic X. riversiana is a distinct, early lineage that may form the sister group to the small-bodied congeners of the mainland. PMID- 23742883 TI - Understanding the correlation between in vitro and in vivo immunotoxicity tests for nanomedicines. AB - Preclinical characterization of novel nanotechnology-based formulations is often challenged by physicochemical characteristics, sterility/sterilization issues, safety and efficacy. Such challenges are not unique to nanomedicine, as they are common in the development of small and macromolecular drugs. However, due to the lack of a general consensus on critical characterization parameters, a shortage of harmonized protocols to support testing, and the vast variety of engineered nanomaterials, the translation of nanomedicines into clinic is particularly complex. Understanding the immune compatibility of nanoformulations has been identified as one of the important factors in (pre)clinical development and requires reliable in vitro and in vivo immunotoxicity tests. The generally low sensitivity of standard in vivo toxicity tests to immunotoxicities, inter-species variability in the structure and function of the immune system, high costs and relatively low throughput of in vivo tests, and ethical concerns about animal use underscore the need for trustworthy in vitro assays. Here, we consider the correlation (or lack thereof) between in vitro and in vivo immunotoxicity tests as a mean to identify useful in vitro assays. We review literature examples and case studies from the experience of the NCI Nanotechnology Characterization Lab, and highlight assays where predictability has been demonstrated for a variety of nanomaterials and assays with high potential for predictability in vivo. PMID- 23742887 TI - Genetic diversity of the golden potato cyst nematode Globodera rostochiensis and determination of the origin of populations in Quebec, Canada. AB - The golden cyst nematode (Globodera rostochiensis), native to South America, has been introduced in many parts of the world, including Europe and North America. Recently, it was found for the first time in the province of Quebec, Canada in the locality of St. Amable near Montreal. To date, very few studies have examined the population genetics of this pest. Consequently, there is a lack of knowledge about the genetic structure and evolution of this nematode. In this study, twelve new microsatellite markers were developed in order to explore these questions. These markers were used to genotype fifteen populations originating from different regions of the world, including five from Canada. Within populations, the highest genetic diversity was consistently observed in the populations from Bolivia, the postulated region of origin of the golden nematode, and the lowest in populations from British Columbia (Canada) and New York (USA). The two Quebec populations were very similar to each other and to the population found in Newfoundland, but surprisingly, they were significantly different from three other North American populations including those from New York and British Columbia. Based on our results, we conclude that the golden cyst nematode has been introduced in North America at least twice from distinct regions of the world. PMID- 23742888 TI - Mechanistic insight into sonochemical biodiesel synthesis using heterogeneous base catalyst. AB - The beneficial effect of ultrasound on transesterification reaction is well known. Heterogeneous (or solid) catalysts for biodiesel synthesis have merit that they do not contaminate the byproduct of glycerol. In this paper, we have attempted to identify the mechanistic features of ultrasound-enhanced biodiesel synthesis with the base-catalyst of CaO. A statistical design of experiments (Box Behnken) was used to identify the influence of temperature, alcohol to oil molar ratio and catalyst loading on transesterification yield. The optimum values of these parameters for the highest yield were identified through Response Surface Method (with a quadratic model) and ANOVA. These values are: temperature=62 degrees C, molar ratio=10:1 and catalyst loading=6 wt.%. The activation energy was determined as 82.3 kJ/mol, which is higher than that for homogeneous catalyzed system (for both acidic and basic catalyst). The experimental results have been analyzed vis-a-vis simulations of cavitation bubble dynamics. Due to 3 phase heterogeneity of the system, the yield was dominated by intrinsic kinetics, and the optimum temperature for the highest yield was close to boiling point of methanol. At this temperature, the influence of cavitation bubbles (in terms of both sonochemical and sonophysical effect) is negligible, and ultrasonic micro streaming provided necessary convection in the system. The influence of all parameters on the reaction system was found to be strongly inter-dependent. PMID- 23742889 TI - The complete mitochondrial genome of Sasakia funebris (Leech) (Lepidoptera: Nymphalidae) and comparison with other Apaturinae insects. AB - Sasakia funebris, a member of the lepidopteran family, Nymphalidae (superfamily Papilionoidea) is a rare species and is found only in some areas of South China. In this study, the 15,233 bp long complete mitochondrial genome of S. funebris was determined, and harbors the gene arrangement identical to all other sequenced lepidopteran insects. The nucleotide composition of the genome is highly A+T biased, accounting for 81.2%. All protein-coding genes (PCGs) start with typical ATN codons, except for COI which begins with the CGA codon. All tRNAs have a typical clover-leaf secondary structure, except for tRNASer(AGN), the dihydrouridine (DHU) arm of which forms a simple loop. The S. funebris A+T-rich region of 370 bp contains several features common to the Lepidoptera insects, including the motif ATAGA followed by a 19 bp poly-T stretch, and two tandem repeats consisting of 18 bp repeat units and 14 bp repeat units. The phylogenetic analyses of Apaturinae based on mitogenome sequences showed: (S. funebris+Sasakia charonda)+(Apatura metis+Apatura ilia). This result is consistent with the morphological classification. PMID- 23742890 TI - A truncated Danio rerio PKZ isoform functionally interacts with eIF2alpha and inhibits protein synthesis. AB - A protein kinase containing Z-DNA binding domains (PKZ), which resembles protein kinase R (PKR) in domain organization, was recently discovered to be a member of the eIF2alpha kinase family in fish. PKR has roles in antiviral immunity through inhibiting protein synthesis and activating NF-kappaB; therefore, it is thought that PKZ may have a similar role in fish antiviral immunity. In the present study, the roles of two Danio rerio PKZ isoforms (DrPKZ-A and DrPKZ-B) in eIF2alpha phosphorylation and protein synthesis regulation were explored. DrPKZ-A and DrPKZ-B possess N-terminal Z-DNA binding domains and a conserved eIF2alpha kinase domain; however, they have domains of differing lengths inserted between kinase subdomains IV and V. DrPKZ-A has an insert domain of 73 amino acids (aa), whereas DrPKZ-B has an insert sequence of only 10 aa, suggesting that DrPKZ-B could be a dysfunctional isoform or could interact with different substrates. Our results show that both DrPKZ-A and DrPKZ-B functionally interact with eIF2alpha and inhibit protein synthesis, although DrPKZ-B possesses attenuated kinase activity. Our results also show that deletion of the insert in either isoform results in the complete abrogation of kinase activity, suggesting that the insert is critical for PKZ kinase activity. Kinase activity appears to be independent of insert length but may depend on the presence of specific amino acids within the insert domain. Furthermore, the effects of the N-terminal regulatory domain on kinase activity were analyzed. Deletion of the N-terminus results in reduced kinase activity of these isoforms relative to the wild-type forms, indicating that the isolated kinase domain is sufficient for eIF2alpha phosphorylation and that DrPKZ-A and DrPKZ-B may be regulated in a similar manner. Overall, our results show that DrPKZ-B is a functional kinase in zebrafish and contribute to our understanding of the function of PKZ in fish. PMID- 23742891 TI - Binding sites and mechanisms of cadmium to the dried sewage sludge biomass. AB - The Cd biosorption on the dried sewage sludge biomass were experimentally evaluated and mathematically modeled at different pH values. The potentiometric titration of the biomass was well fitted by the four-site model, which consists of three-negative and one-positive sites. The main functional groups were identified through the FTIR study. The pH edge study showed that both the carboxyl and phosphonate groups played an important role in the binding of Cd. From the dynamic biosorption experiments, the H(+)/Cd(2+) exchange ratios at pH 4, 5 and 6 were estimated; thereby the binding mechanisms were established to be complexation with carboxyl and phosphonate groups. Finally, biosorption model was developed based upon the binding mechanism, which was successfully applied for predicting the isotherms and pH edges. Using the developed model equation, the contribution of each functional group on Cd binding could be predicted and visualized. PMID- 23742892 TI - Sorption behavior of 17 phthalic acid esters on three soils: effects of pH and dissolved organic matter, sorption coefficient measurement and QSPR study. AB - This work studies the sorption behaviors of phthalic acid esters (PAEs) on three soils by batch equilibration experiments and quantitative structure property relationship (QSPR) methodology. Firstly, the effects of soil type, dissolved organic matter and pH on the sorption of four PAEs (DMP, DEP, DAP, DBP) are investigated. The results indicate that the soil organic carbon content has a crucial influence on sorption progress. In addition, a negative correlation between pH values and the sorption capacities was found for these four PAEs. However, the effect of DOM on PAEs sorption may be more complicated. The sorption of four PAEs was promoted by low concentrations of DOM, while, in the case of high concentrations, the influence of DOM on the sorption was complicated. Then the organic carbon content normalized sorption coefficient (logKoc) values of 17 PAEs on three soils were measured, and the mean values ranged from 1.50 to 7.57. The logKoc values showed good correlation with the corresponding logKow values. Finally, two QSPR models were developed with 13 theoretical parameters to get reliable logKoc predictions. The leave-one-out cross validation (CV-LOO) indicated that the internal predictive power of the two models was satisfactory. PMID- 23742893 TI - Changes in Lumbriculus variegatus metabolites under hypoxic exposure to benzo(a)pyrene, chlorpyrifos and pentachlorophenol: consequences on biotransformation. AB - The regulation of endogenous metabolites is still not fully understood in aquatic invertebrates exposed concurrently to toxicants and hypoxia. Despite the prevalence of hypoxia in the aquatic environment, toxicity estimations seldom account for multiple stressors thereby differing from natural conditions. In this study, we examined the influence of hypoxia (<30% O2) on contaminant uptake and the composition of intracellular metabolites in Lumbriculus variegatus exposed to benzo(a)pyrene (B(a)P, 3MUgL(-1)), chlorpyrifos (CPF, 100MUgL(-1)) or pentachlorophenol (PCP, 100MUgL(-1)). Tissue extracts of worms were analyzed for 123 metabolites by gas chromatography-mass spectrometry and metabolite levels were then related to treatments and exposure time. Hypoxia markedly increased the accumulation of B(a)P and CPF, which underlines the significance of oxygen in chemical uptake. The oxygen effect on PCP uptake was less pronounced. Succinate and glycerol-3-phosphate increased significantly (p<0.0001) following hypoxic treatment, whereas sugars, cysteine, and cholesterol were effectively repressed. The buildup of succinate coupled with the corresponding decline in intracellular 2-oxo- and 2-hydroxy glutaric acid is indicative of an active hypoxia inducible factor mechanism. Glutamate, and TCA cycle intermediates (fumarate, and malate) were disturbed and evident in their marked suppression in worms exposed concurrently to hypoxia and PCP. Clearly, hypoxia was the dominant stressor for individuals exposed to B(a)P or CPF, but to a lesser extent upon PCP treatment. And since oxygen deprivation promotes the accumulation of different toxicants, there may be consequences on species composition of metabolites in natural conditions. PMID- 23742894 TI - Reply to Comment by Sierra Rayne on "QSPR modeling of bioconcentration factor of nonionic compounds using Gaussian processes and theoretical descriptors derived from electrostatic potentials on molecular surface [Chemosphere 83 (2011) 1045 1052]". PMID- 23742895 TI - ALS/FTLD-linked TDP-43 regulates neurite morphology and cell survival in differentiated neurons. AB - Tar-DNA binding protein of 43kDa (TDP-43) has been characterized as a major component of protein aggregates in brains with neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). However, physiological roles of TDP-43 and early cellular pathogenic effects caused by disease associated mutations in differentiated neurons are still largely unknown. Here, we investigated the physiological roles of TDP-43 and the effects of missense mutations associated with diseases in differentiated cortical neurons. The reduction of TDP-43 by siRNA increased abnormal neurites and decreased cell viability. ALS/FTLD-associated missense mutant proteins (A315T, Q331K, and M337V) were partially mislocalized to the cytosol and neurites when compared to wild-type and showed abnormal neurites similar to those observed in cases of loss of TDP-43. Interestingly, cytosolic expression of wild-type TDP-43 with mutated nuclear localization signals also induced abnormal neurtie morphology and reduction of cell viability. However, there was no significant difference in the effects of cytosolic expression in neuronal morphology and cell toxicity between wild-type and missense mutant proteins. Thus, our results suggest that mislocalization of missense mutant TDP-43 may contribute to loss of TDP-43 function and affect neuronal morphology, probably via dominant negative action before severe neurodegeneration in differentiated cortical neurons. PMID- 23742898 TI - Characterization of dual-phase steel microstructure by combined submicrometer EBSD and EPMA carbon measurements. AB - Electron backscatter diffraction (EBSD) and electron probe microanalysis (EPMA) measurements are combined to characterize an industrial produced dual-phase steel containing some bainite fraction. High-resolution carbon mappings acquired on a field emission electron microprobe are utilized to validate and improve the identification of the constituents (ferrite, martensite, and bainite) performed by EBSD using the image quality and kernel average misorientation. The combination eliminates the ambiguity between the identification of bainite and transformation-induced dislocation zones, encountered if only the kernel average misorientation is considered. The detection of carbon in high misorientation regions confirms the presence of bainite. These results are corroborated by secondary electron images after nital etching. Limitations of this combined method due to differences between the spatial resolution of EBSD and EPMA are assessed. Moreover, a quantification procedure adapted to carbon analysis is presented and used to measure the carbon concentration in martensite and bainite on a submicrometer scale. From measurements on reference materials, this method gives an accuracy of 0.02 wt% C and a precision better than 0.05 wt% C despite unavoidable effects of hydrocarbon contamination. PMID- 23742896 TI - Cardiomyocyte FGF signaling is required for Cx43 phosphorylation and cardiac gap junction maintenance. AB - Cardiac remodeling resulting from impairment of myocardial integrity leads to heart failure, through still incompletely understood mechanisms. The fibroblast growth factor (FGF) system has been implicated in tissue maintenance, but its role in the adult heart is not well defined. We hypothesized that the FGF system plays a role in the maintenance of cardiac homeostasis, and the impairment of cardiomyocyte FGF signaling leads to pathological cardiac remodeling. We showed that FGF signaling is required for connexin 43 (Cx43) localization at cell-cell contacts in isolated cardiomyocytes and COS7 cells. Lack of FGF signaling led to decreased Cx43 phosphorylation at serines 325/328/330 (S325/328/330), sites known to be important for assembly of gap junctions. Cx43 instability induced by FGF inhibition was restored by the Cx43 S325/328/330 phospho-mimetic mutant, suggesting FGF-dependent phosphorylation of these sites. Consistent with these in vitro findings, cardiomyocyte-specific inhibition of FGF signaling in adult mice demonstrated mislocalization of Cx43 at intercalated discs, whereas localization of N-cadherin and desmoplakin was not affected. This led to premature death resulting from impaired cardiac remodeling. We conclude that cardiomyocyte FGF signaling is essential for cardiomyocyte homeostasis through phosphorylation of Cx43 at S325/328/330 residues which are important for the maintenance of gap junction. PMID- 23742897 TI - Designing the WHO Safe Childbirth Checklist program to improve quality of care at childbirth. AB - BACKGROUND: Poor-quality care during institutional births in low- and middle income countries is a major contributing factor to preventable maternal and newborn harm, but progress has been slow in identifying effective methods to address these deficiencies at scale. Based on the success of checklist programs in other disciplines, WHO led the design and field testing of the WHO Safe Childbirth Checklist-a 29-item tool that targets the major causes of maternal and newborn mortality globally. METHODS: The development process consisted of comprehensive evidence and guideline review, in-person consultation with content experts and other key stakeholders, iterative refinement through ongoing discussions with a wide collaborator network, and field evaluation for usability in 9 countries, primarily in Africa and Asia. Pilot testing in South India demonstrated major improvement in health workers' delivery of essential safety practices after introduction of the program. RESULTS: WHO has launched a global effort to support further evaluation of the program in a range of contexts, and a randomized trial is underway in North India to measure the effectiveness of the program in reducing severe maternal, fetal, and newborn harm. CONCLUSION: A novel checklist program has been developed to support health workers in low-resource settings to prevent avoidable childbirth-related deaths. PMID- 23742899 TI - Subsequent Epstein-Barr virus-associated gastric carcinoma shortly after chemotherapy for colonic cancer. PMID- 23742900 TI - Taiwan faces challenges on the emerging avian influenza A (H7N9) virus in China. PMID- 23742901 TI - Distribution of airborne microbes and antibiotic susceptibility pattern of bacteria during Gwalior trade fair, Central India. AB - BACKGROUND/PURPOSE: Research into the distribution of bioaerosols during events associated with huge groups of people is lacking, especially in developing countries. The purpose of this study was to understand the distribution pattern of bioaerosols during an annual trade fair in the historical city of Gwalior, central India, a very important historical fair that was started by the King of Gwalior Maharaja Madho Rao in 1905. METHODS: Air samples were collected from six different sites at the fair ground and three different sites in a residential area before/during/after the fair using an impactor sampler on microbial content test agar and rose bengal agar for total bacteria and fungi, respectively. The representative strains of bacteria and fungi were further identified and selected bacterial strains were subjected to antibiotic susceptibility testing according to US Clinical and Laboratory Standards Institute (CLSI) guidelines. RESULTS: The bacterial bioaerosol count [colony-forming units (CFU)/m(3)] at fair sites was found to be 9.0 * 10(3), 4.0 * 10(4), and 1.0 * 10(4) before the start of the fair, during the fair, and after the fair, respectively. The fungal bioaerosol count at fair sites was 2.6 * 10(3) CFU/m(3), 6.3 * 10(3) CFU/m(3), and 1.7 * 10(3) CFU/m(3) before the fair, during the fair, and after the fair, respectively. Bacterial/fungal bioaerosols during-fair were increased significantly from the bacterial/fungal bioaerosols of the before-fair period (p < 0.05); they were also significantly higher than the bacterial/fungal bioaerosols at non-fair sites during the event (p < 0.0001). The proportion of antibiotic-resistant bacteria over the fair ground was significantly increased during-fair and was still higher in the after-fair period. Methicillin-resistant staphylococci (MRS) were also reported at the fair ground. CONCLUSION: The study indicates significantly higher bacterial and fungal bioaerosols during the fair event. Therefore, further research is needed to explore the health aspects and guidelines to control microbial load during such types of events. PMID- 23742902 TI - Is avian influenza A (H7N9) virus staggering its way to humans? AB - BACKGROUND/PURPOSE: Human infections by a new avian influenza A (H7N9) virus have been reported. As of April 23, 2013, there were 108 confirmed cases including 22 deaths in China. METHODS: Influenza protein sequences were downloaded from the Influenza Virus Resource and GISAID EpiFlu databases. Pairwise nucleotide identities were computed for assessing the evolutionary distance of H7N9 to other known avian and human viruses, and multiple sequence alignments with their position-specific entropy values were used in discussing how mutations on species associated signature positions were introduced in the new H7N9 which may steer its way to human infection. RESULTS: This report analyzed the genomic characteristics of this new H7N9 virus. Nucleotide sequence analysis clearly reveals its origin from avian viruses. In this article, we particularly focus on its internal genes that are found to derive from H9N2-another subtype of avian influenza A virus which has been circulating in birds for years. Amino acid sequences at species-specific genomic positions were examined. Although the new virus contains mostly avian-like residues at these signature positions, it does contain several human-like signatures. For instance, at the position 627 of PB2, the new virus has human-characteristic K instead of avian-characteristic E; in addition, PB2-627K, PA-100A, PA-356R, and PA-409N are also human-like signatures in the new H7N9 virus. CONCLUSION: The new H7N9 is an avian influenza A virus; however, it does harbor several human virus-like signatures, which raises great concern that it may have a higher probability to cross species barriers and infect humans. PMID- 23742903 TI - Oral trail making task as a discriminative tool for different levels of cognitive impairment and normal aging. AB - The Trail Making Test (TMT) is a useful measure of executive dysfunction in elderly subjects. This study aims to investigate the discriminative validity of the oral version of the TMT (OTMT), which can be administered to subjects with visual or motor disabilities, in elderly patients with Mild Cognitive Impairment (MCI; n = 30), Alzheimer's disease (AD; n = 30), and healthy controls (HCs; n = 25). The WAIS-R Digit Span Backwards Subscale, written form of the Trail Making Task, the Clock Drawing Test, the AD Assessment Scale-Cognitive Subscale, and the OTMT were also administered to all participants in order to examine the concurrent validity of the OTMT. The OTMT part B discriminated between patients with MCI, AD, and HC correctly. The OTMT completion time was not correlated with age, but was negatively correlated with education. In conclusion, the OTMT (mostly part B) is a valid and practical measurement tool for different levels of cognitive impairment, especially for patients with visual or motor disabilities for whom the classical written form is not feasible. PMID- 23742904 TI - Pediatric endonasal endoscopic dacryocystorhinostomy. AB - OBJECTIVE: Nasolacrimal duct obstruction is a relatively common problem among children. Although spontaneous resolution is possible and various conservative treatment options are available, dacryocystorhinostomy is recommended for persistent epiphora. The aim of this study was to report our experience of performing 83 procedures of pediatric endoscopic dacryocystorhinostomy. METHODS: This retrospective study included 71 children who underwent endonasal endoscopic dacryocystorhinostomy between 2000 and 2011. Thirteen of these children had bilateral procedures. The diagnosis of nasolacrimal duct obstruction was based on the presence of eye discharge, the patient's history obtained from his or her parents and the results of testing the patency of the nasolacrimal canal by irrigating the lacrimal sac. The procedure was considered to be successful if the patient's eye discharge was completely resolved and the dacryocystorhinostomy ostium was patent at end of the postoperative first year. RESULTS: Eighty-three dacrycystorhinostomy procedures were performed in 71 children. There were 35 (49.3%) male and 36 (50.7%) female patients. The age of the patients ranged between 11 months and 14 years, with a mean of 8.9 years. The mean follow-up period was 27.1 months (range of 14-84 months). The overall success rate for primary endoscopic dacryocystorhinostomy was 92.7%. No major complications were encountered in any of the surgical procedures. CONCLUSION: Pediatric endonasal endoscopic dacryocystorhinostomy is a safe and effective procedure to correct nasolacrimal system obstruction in cases that are unresponsive to conservative treatments. It has a high success rate and a low incidence of complications. PMID- 23742906 TI - Modelling of crowded polymers elucidate effects of double-strand breaks in topological domains of bacterial chromosomes. AB - Using numerical simulations of pairs of long polymeric chains confined in microscopic cylinders, we investigate consequences of double-strand DNA breaks occurring in independent topological domains, such as these constituting bacterial chromosomes. Our simulations show a transition between segregated and mixed state upon linearization of one of the modelled topological domains. Our results explain how chromosomal organization into topological domains can fulfil two opposite conditions: (i) effectively repulse various loops from each other thus promoting chromosome separation and (ii) permit local DNA intermingling when one or more loops are broken and need to be repaired in a process that requires homology search between broken ends and their homologous sequences in closely positioned sister chromatid. PMID- 23742907 TI - MCPath: Monte Carlo path generation approach to predict likely allosteric pathways and functional residues. AB - Allosteric mechanism of proteins is essential in biomolecular signaling. An important aspect underlying this mechanism is the communication pathways connecting functional residues. Here, a Monte Carlo (MC) path generation approach is proposed and implemented to define likely allosteric pathways through generating an ensemble of maximum probability paths. The protein structure is considered as a network of amino acid residues, and inter-residue interactions are described by an atomistic potential function. PDZ domain structures are presented as case studies. The analysis for bovine rhodopsin and three myosin structures are also provided as supplementary case studies. The suggested pathways and the residues constituting the pathways are maximally probable and mostly agree with the previous studies. Overall, it is demonstrated that the communication pathways could be multiple and intrinsically disposed, and the MC path generation approach provides an effective tool for the prediction of key residues that mediate the allosteric communication in an ensemble of pathways and functionally plausible residues. The MCPath server is available at http://safir.prc.boun.edu.tr/clbet_server. PMID- 23742908 TI - SPEDRE: a web server for estimating rate parameters for cell signaling dynamics in data-rich environments. AB - Cell signaling pathways and metabolic networks are often modeled using ordinary differential equations (ODEs) to represent the production/consumption of molecular species over time. Regardless whether a model is built de novo or adapted from previous models, there is a need to estimate kinetic rate constants based on time-series experimental measurements of molecular abundance. For data rich cases such as proteomic measurements of all species, spline-based parameter estimation algorithms have been developed to avoid solving all the ODEs explicitly. We report the development of a web server for a spline-based method. Systematic Parameter Estimation for Data-Rich Environments (SPEDRE) estimates reaction rates for biochemical networks. As input, it takes the connectivity of the network and the concentrations of the molecular species at discrete time points. SPEDRE is intended for large sparse networks, such as signaling cascades with many proteins but few reactions per protein. If data are available for all species in the network, it provides global coverage of the parameter space, at low resolution and with approximate accuracy. The output is an optimized value for each reaction rate parameter, accompanied by a range and bin plot. SPEDRE uses tools from COPASI for pre-processing and post-processing. SPEDRE is a free service at http://LTKLab.org/SPEDRE. PMID- 23742909 TI - Consumption of added sugars among U.S. adults, 2005-2010. AB - Increased consumption of added sugars, which are sweeteners added to processed and prepared foods, has been linked to a decrease in intake of essential micronutrients (1,2) and an increase in body weight (3). The Dietary Guidelines for Americans, 2010 recommends limiting total intake of discretionary calories, including both added sugars and solid fats, to 5%-15% per day (4). Recent analyses indicate that children and adolescents obtain approximately 16% of their total caloric intake from added sugars (5). This data brief presents results for consumption of added sugars among U.S. adults for 2005-2010. Results are presented by sex, age, race and ethnicity, income, type of food consumed (food or beverage), and location of consumption. PMID- 23742910 TI - [EVOLVE: between disappointment and optimism]. PMID- 23742911 TI - Is fatigue in primary biliary cirrhosis cured by transplantation? PMID- 23742912 TI - Similar evolution of hepatitis B virus quasispecies in patients with incomplete adefovir response receiving tenofovir/emtricitabine combination or tenofovir monotherapy. AB - BACKGROUND & AIMS: Adefovir (ADV) resistance mutations induce low-level cross resistance to tenofovir in vitro. Our aim was to compare viral kinetics, nucleos(t)ide analog resistance mutations, and quasispecies (QS) evolution during therapy with tenofovir disoproxil fumarate (TDF) or emtricitabine + TDF (FTC/TDF) in selected patients with incomplete ADV responses. METHODS: Patients with chronic hepatitis B and incomplete response to ADV were randomized in a double blind trial of TDF vs. FTC/TDF. Extensive analysis of QS evolution was performed in 17 patients through 48 weeks of treatment. RESULTS: At week 24, 48% of patients (9/17) achieved HBV DNA undetectability (<69 IU/ml) with no difference between treatment groups. ADV and/or LAM resistance mutations were detected in all 17 patients at baseline and in 5/6 analyzable patients at week 48. A total of 1224 reverse transcriptase clones were analyzed. Clonal analysis revealed no significant difference at baseline in QS complexity or diversity between treatment groups. There was a trend in both treatment groups for an increase in QS complexity at week 12, followed by a decrease in complexity and diversity by week 48. Analysis of individual patients showed no consistent selection/accumulation of specific viral resistance patterns during treatment, but at week 48, mutations at rtA181 persisted in 4 patients. CONCLUSIONS: TDF or FTC/TDF demonstrated strong viral suppression in patients with an incomplete response to ADV and no significant selective pressure on pre-existing ADV or LAM resistant strains. TDF monotherapy and FTC/TDF combination therapy had a comparable impact on QS evolution. PMID- 23742913 TI - Defective thymopoiesis and poor peripheral homeostatic replenishment of T-helper cells cause T-cell lymphopenia in cirrhosis. AB - BACKGROUND & AIMS: Depletion of circulating CD4(+) T-helper (Th) lymphocytes, especially naive Th cells, is common in cirrhosis. Little is known about the pathogenetic mechanisms involved in Th-cell depletion in cirrhosis. We investigated the mechanisms involved in circulating Th-cell lymphopenia in cirrhosis. METHODS: Circulating naive and memory Th cells were analyzed by flow cytometry in 60 patients with cirrhosis and 40 sex- and age-matched healthy controls. Thymopoiesis, apoptosis, cell activation, and proliferation were assessed through CD31, annexin-V, HLA-DR and Ki-67 expression, respectively. Lipopolysaccharide (LPS)-binding protein (LBP) and spleen size were measured as indicators of bacterial translocation and splenic pooling, respectively. RESULTS: Compared to controls, patients showed reduced numbers of Th cells involving a greater depletion of the naive than memory Th-cell compartment (2.7- vs. 1.5 fold, respectively). Recent thymic emigrants were diminished (p < 0.01), and each patient had a lower number of CD31(+) naive Th cells than the matched-control. Spontaneous and induced apoptosis (Annexin-V(+)) of Th cells was increased in patients. Activated (HLA-DR(+)) and proliferating (Ki-67(+)) memory Th cells were increased in patients (p < 0.01), and they directly correlated with plasma LBP (p < 0.05) and negatively with naive Th cells (p < 0.01), respectively. Naive Th cells were inversely correlated (p < 0.01) with their frequencies of apoptosis and of activated memory Th cells, LBP, and spleen size. On multivariate analysis, defective thymic generation of naive Th cells, increased memory Th-cell activation, and splenomegaly were independently associated with Th-cell depletion. CONCLUSIONS: Th-cell immunodeficiency in cirrhosis is explained by a universal defect in thymopoiesis exacerbated by splenic pooling and activation driven cell-death induced by bacterial translocation. PMID- 23742914 TI - Anti-platelet therapy in the prevention of hepatitis B virus-associated hepatocellular carcinoma. AB - Previous studies in mouse models of self-limited viral hepatitis showed that platelets contribute to acute liver damage by promoting the intrahepatic accumulation of virus-specific CD8 T cells and, secondarily, virus-non-specific inflammatory cells. Built on these observations, a recent preclinical study took advantage of a previously established hepatitis B virus (HBV) transgenic mouse model of immune-mediated chronic hepatitis that progresses to hepatocellular carcinoma (HCC), to demonstrate that clinically achievable doses of the anti platelet drugs aspirin and clopidogrel - administered continuously after the onset of liver disease - can prevent hepatocarcinogenesis and greatly improve overall survival. These outcomes were preceded by and associated with reduced hepatic accumulation of virus-specific CD8 T cells and virus-non-specific inflammatory cells, reduced hepatocellular injury and hepatocellular proliferation, and reduced severity of liver fibrosis. The observation that anti platelet therapy inhibits HCC development identifies platelets as key players in the pathogenesis of HBV-associated liver cancer and supports the notion that a sustained immune-mediated necroinflammatory liver disease is sufficient to trigger HCC. The results abovementioned and their clinical implications are discussed in this report. PMID- 23742915 TI - Muscle fatigue and metabolic responses following three different antagonist pre load resistance exercises. AB - PURPOSE: Preload of antagonist muscles can be achieved by reciprocal actions (RAs) or by opposing muscle actions. However, evidence concerning neuromuscular and fatigue responses are scarce. OBJECTIVE: To compare the effects of different knee flexor (KF) preload methods on knee extension (KE) vastus medialis muscle fatigue, based on EMG-spectral index (FI), load range (LR), total work (TW), blood lactate (LAC) and biceps femoris co-activation (BFc) during resistance exercise. METHODS: Twenty-four healthy men (23.5+/-3.6yrs) performed three antagonist pre-load isokinetic exercises (4 sets, 10 repetitions, 60 degrees s( 1), 1min rest between sets): RA (KF contraction immediately followed by KE); Superset (SS; one KF set immediately followed by one KE set); Multiple Set (MS; four KF sets followed by four KE sets). RESULTS: Total work was significantly greater in RA. There was no significant decrease in LR between sets in RA. The BFc did not differ between protocols (p=0.063). However, RA presented greater biceps femoriscoactivation. The FI was greater during SS compared to RA and MS (p<0.05). The SS had greater LAC when compared to MS and RA (p=0.005 and p=0.007, respectively). CONCLUSION: It is suggested that the RA protocol is more neuromuscular and metabolic efficient during the performance of knee extension resistance exercise. PMID- 23742916 TI - Identification of contraction onset during explosive contractions. Response to Thompson et al. "Consistency of rapid muscle force characteristics: influence of muscle contraction onset detection methodology" [J Electromyogr Kinesiol 2012;22(6):893-900]. PMID- 23742918 TI - The role of eEF2 pathway in learning and synaptic plasticity. AB - One of the hallmarks of learning processes in any species studied so far is that they require intact protein synthesis machinery in order to consolidate memories. Interestingly, synaptic plasticity and consolidation processes share similar molecular mechanisms. In recent years, different laboratories have been studying regulation of translation machinery as a molecular entity underlying the consolidation process. Protein synthesis consists of three phases: initiation, elongation, and termination. The initiation step is considered the rate limiting step of protein synthesis. However, there is growing evidence that critical regulation of protein synthesis occurs at the elongation phase as well. Here, we focus on the eukaryotic elongation factor 2 (eEF2) pathway as a major regulator of protein synthesis, synaptic plasticity and memory consolidation. PMID- 23742919 TI - Hippocampal activation during the recall of remote spatial memories in radial maze tasks. AB - Temporally graded retrograde amnesia is observed in human patients with medial temporal lobe lesions as well as in animal models of medial temporal lobe lesions. A time-limited role for these structures in memory recall has also been suggested by the observation that the rodent hippocampus and entorhinal cortex are activated during the retrieval of recent but not of remote memories. One notable exception is the recall of remote memories for platform locations in the water maze, which requires an intact hippocampus and results in hippocampal activation irrespective of the age of the memory. These findings raise the question whether the hippocampus is always involved in the recall of spatial memories or, alternatively, whether it might be required for procedural computations in the water maze task, such as for calculating a path to a hidden platform. We performed spatial memory testing in radial maze tasks to distinguish between these possibilities. Radial maze tasks require a choice between spatial locations on a center platform and thus have a lesser requirement for navigation than the water maze. However, we used a behavioral design in the radial maze that retained other aspects of the standard water maze task, such as the use of multiple start locations and retention testing in a single trial. Using the immediate early gene c-fos as a marker for neuronal activation, we found that all hippocampal subregions were more activated during the recall of remote compared to recent spatial memories. In areas CA3 and CA1, activation during remote memory testing was higher than in rats that were merely reexposed to the testing environment after the same time interval. Conversely, Fos levels in the dentate gyrus were increased after retention testing to the extent that was also observed in the corresponding exposure control group. This pattern of hippocampal activation was also obtained in a second version of the task that only used a single start arm instead of multiple start arms. The CA3 and CA1 activation during remote memory recall is consistent with the interpretation that an older memory might require increased pattern completion and/or relearning after longer time intervals. Irrespective of whether the hippocampus is required for remote memory recall, the hippocampus might engage in computations that either support recall of remote memories or that update remote memories. PMID- 23742917 TI - Role of nucleus accumbens dopamine receptor subtypes in the learning and expression of alcohol-seeking behavior. AB - These studies examined the roles of dopamine D1- and D2-like receptors within the nucleus accumbens (Acb) in the acquisition and expression of ethanol-induced (2g/kg) conditioned place preference (CPP) in adult male DBA/2J mice. Bilateral intra-Acb infusions of the D1-like dopamine receptor antagonist SCH23390 (0.05, 0.5MUg/side) or the D2-like dopamine receptor antagonist raclopride (0.5 5.0MUg/side) were administered 30min before each ethanol conditioning trial (acquisition studies) or before preference tests (expression studies). CPP was conditioned to tactile cues using an unbiased apparatus and procedure. Intra-Acb infusion of SCH23390 prevented CPP acquisition, whereas intra-Acb infusion of raclopride did not. Intra-Acb infusion of both antagonists, however, dose dependently reduced ethanol-stimulated locomotor activity during conditioning. In contrast, intra-Acb antagonist infusion had no effect on ethanol CPP expression, suggesting that dopamine's role in the Acb is limited to neurobiological processes engaged during the learning of the relationship between contextual cues and ethanol reward. Control experiments showed that intra-Acb injection of SCH23390 alone produced no place conditioning and did not interfere with the acquisition of conditioned place aversion induced by lithium chloride, suggesting that the antagonist's effect on ethanol CPP was not due to a more general detrimental effect on associative learning. Overall, these data suggest that D1 like (but not D2-like) dopamine Acb receptors play an important role in the learning of context-ethanol associations, either by modulating the magnitude of ethanol reward or the rate of learning about ethanol reward. PMID- 23742921 TI - [Impact of the national rare disease plan on the management of anorectal malformations]. PMID- 23742920 TI - [Neonatal parechovirus infection, fever, irritability and myositis]. AB - Human parechovirus (HPeV) is associated with central nervous system infection and sepsis-like illness in newborn infants. The most frequent signs are fever, seizures, irritability, rash, and encephalitis. We report 4 cases of full-term infants with HPeV infection. They were admitted from home to the pediatric emergency unit of our hospital in October 2012. The median age at onset of symptoms was 15 days. They all developed sepsis-like illness with predominantly gastrointestinal disease and irritability. Two patients developed respiratory problems and 2 a skin rash (concerning only the extremities for one). Two patients required hospitalization in an intensive care unit. There was normal or mild inflammatory syndrome, normal white blood cell or mild leukopenia, hepatitis. We describe for the first time elevation of muscular enzymes in 3 of these patients. The diagnosis of HPeV infection was made by positive HPeV real time PCR in cerebrospinal fluid (including the patient without pleocytosis) and/or blood. HPeV may cause severe disease in the neonatal period and patients presenting with such signs should be evaluated for HPeV. It also should be considered in sudden infant death syndrome. PMID- 23742922 TI - Adsorption kinetics of DPPG liposome layers: a quantitative analysis of surface roughness. AB - Roughness of a positively charged poly(allylamine hydrochloride) (PAH) polyelectrolyte surface was shown to strongly influence the adsorption of 1.2 dipalmitoyl-sn-3-glycero-[phosphorrac-(1-glycerol)] (DPPG) liposomes on it. The adsorption kinetic curves of DPPG liposomes onto a low-roughness PAH layer reveal an adsorbed amount of 5 mg/m2, pointing to liposome rupture, whereas a high roughness surface leads to adsorbed amounts of 51 mg/m2, signifying adsorption of intact liposomes. The adsorption kinetic parameters calculated from adsorption kinetic curves allow us to conclude that the adsorption process is due to electrostatic interactions and also depends on processes such as diffusion and reorganization of lipids on the surface. Analysis of the roughness kinetics enabled us to calculate a growth exponent of 0.19 +/- 0.07 and a roughness exponent of around 0.84, revealing that DPPG liposomes adsorbed onto rough surfaces follow the Villain self-affine model. By relating self-affine surfaces with hydrophobicity, the liposome integrity was explained by the reduction in the number of water molecules on the PAH surface, contributing to counterion anchorage near PAH ionic groups, reducing the liposome/PAH layer electrostatic forces and, consequently, avoiding liposome rupture. PMID- 23742923 TI - Novel approaches for studying amyloidogenic peptides/proteins. AB - A growing number of important human diseases are associated with the aggregation and deposition of incorrectly folded proteins in the form of highly structured amyloid fibrils. The aggregation process involves the formation of intermediate oligomeric assemblies with toxic properties. There are many commonalities among the different amyloid diseases, that is, similarities in structural features of amyloid fibrils or determinants of oligomer toxicity. Thus, a better knowledge of the general mechanisms of protein aggregation, the characterization of the aggregate's toxicity, and the identification of compounds interfering with these processes, may help for developing therapeutic strategies for different diseases. A variety of analytical methods are currently applied for these purposes. Here we focus on new applications of consolidated technologies which allow one to obtain informative data in a rapid and convenient manner. In particular, we discuss new applications of Surface Plasmon Resonance to study fibril elongation and to specifically recognize oligomers, as well as to screen for ligands of aggregated species and inhibitors of oligomer formation. We also review new advances in the use of wild-type or transgenic Caenorhabditis elegans as suitable in vivo models for the rapid and relatively inexpensive analysis of oligomer toxicity and for testing putative antagonists against this toxicity. PMID- 23742924 TI - Prevention and endothelial therapy of coronary artery disease. AB - Functional integrity of endothelial cells is an indicator and a prerequisite for vascular health and counteracts the development of atherosclerosis. This concept of 'endothelial therapy' was developed in the late 1990s as an approach to preserve or restore endothelial cell health given that 'the knowledge of the mechanisms involved in 'endothelial dysfunction' allows us to interfere specifically with pathogenic pathways at very early time points and to slow down the progression of disease'. In the present review, the principles underlying endothelial cell health will be discussed as well as the role of endothelial therapy as a preventive measure to reduce the prevalence of coronary artery disease or to delay disease progression in patients with chronic coronary artery disease. This article also highlights the importance of active participation, the need to reduce the number of future patients in view of the rising prevalence of childhood obesity, and the potential of endothelial therapy to improve survival, reduce disability and health costs, and to improve overall quality of life in patients at risk for or already diagnosed with coronary artery disease. The preventive and therapeutic approaches and considerations described herein can be applied by physicians, patients, parents, educators, health agencies, and political decision makers to help reducing the global cardiovascular disease burden in the decades to come. PMID- 23742925 TI - Pulmonary therapeutics: rethinking the regimens and re-imagining the targets. PMID- 23742926 TI - Microparticles are novel effectors of immunity. AB - Microparticles represent an intercellular communication and delivery mechanism for the efficient and effective transfer of biological information. These cargo vectors contain packages of material selectively assimilated from their parental cell, which includes bioactive lipids, integrins, cytokines, enzymes, mRNA and micro-RNA that can reprogramme recipient cells. Elevated levels of circulating microparticles are associated with a number of cardiovascular and inflammatory pathologies making them useful biomarkers for disease activity. Yet their full contribution to disease pathogenesis and its timely resolution remains to be elucidated. An emerging notion is that microparticles originating from different cell types or because of differential stimuli can exert deleterious or protective immunomodulatory actions. Herein, we discuss the bioactions of various microparticle components including genetic material, proteins and lipids and how they influence cellular behavior and ultimately host immunity. PMID- 23742927 TI - The adequacy of myocardial revascularization in patients with multivessel coronary artery disease. AB - In patients with multi-vessel coronary artery disease (MVCAD) myocardial revascularization may be accomplished either on all diseased lesions--complete myocardial revascularization--or on selectively targeted coronary segments by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Complete revascularization has a potential long-term prognostic benefit, but is more complex and may increase in-hospital events when compared with incomplete revascularization. No conclusive agreement has been yet reached on the "optimal" extent of revascularization, and guidelines have only recently mentioned the adequacy of revascularization in the decision whether to submit a patient to CABG or PCI. In the absence of any trial specifically designed to assess the relative benefit of either strategy, the present review explores current concepts about the completeness of revascularization, the growing evidence on the relevance of lesion and myocardial functional evaluation, and analyzes currently available data in relation to different clinical settings, including acute coronary syndromes, diabetes, chronic kidney disease and impaired left ventricular function. Considerations on the adequacy of revascularization should guide the choice among PCI and CABG in patients with MVCAD during the decision-making process, taking into account the clinical presentation, the extent and relevance of ischemia and the presence of other comorbidities. PMID- 23742929 TI - Fish oil administration in older adults with cardiovascular disease or cardiovascular risk factors: is there potential for adverse events? A systematic review of the literature. PMID- 23742930 TI - Preliminary study of serum tenascin-C levels as a diagnostic or prognostic biomarker of type B acute aortic dissection. PMID- 23742928 TI - Defining cardiac adaptations and safety of endurance training in patients with m.3243A>G-related mitochondrial disease. AB - BACKGROUND: Cardiac hypertrophic remodelling and systolic dysfunction are common in patients with mitochondrial disease and independent predictors of morbidity and early mortality. Endurance exercise training improves symptoms and skeletal muscle function, yet cardiac adaptations are unknown. METHODS AND RESULTS: Before and after 16-weeks of training, exercise capacity, cardiac magnetic resonance imaging and phosphorus-31 spectroscopy, disease burden, fatigue, quality of life, heart rate variability (HRV) and blood pressure variability (BPV) were assessed in 10 adult patients with m.3243A>G-related mitochondrial disease, and compared to age- and gender-matched sedentary control subjects. At baseline, patients had increased left ventricular mass index (LVMI, p<0.05) and LV mass to end-diastolic volume ratio, and decreased longitudinal shortening and myocardial phosphocreatine/adenosine triphosphate ratio (all p<0.01). Peak arterial-venous oxygen difference (p<0.05), oxygen uptake (VO2) and power were decreased in patients (both p<0.01) with no significant difference in cardiac power output. All patients remained stable and completed >=80% sessions. With training, there were similar proportional increases in peak VO2, anaerobic threshold and work capacity in patients and controls. LVMI increased in both groups (p<0.01), with no significant effect on myocardial function or bioenergetics. Pre- and post exercise training, HRV and BPV demonstrated increased low frequency and decreased high frequency components in patients compared to controls (all p<0.05). CONCLUSION: Patients with mitochondrial disease and controls achieved similar proportional benefits of exercise training, without evidence of disease progression, or deleterious effects on cardiac function. Reduced exercise capacity is largely mediated through skeletal muscle dysfunction at baseline and sympathetic over-activation may be important in pathogenesis. PMID- 23742931 TI - Exclusive prenatal exposure to a 16 PAH mixture does not impact anxiety-related behaviours and regional brain metabolism in adult male rats: a role for the period of exposure in the modulation of PAH neurotoxicity. AB - Polycyclic aromatic hydrocarbons (PAHs) are persistent organic pollutants originating from incomplete combustion processes. Humans are mainly exposed through contaminated food ingestion. PAHs are neurotoxic compounds both for human and rodents, and may be found in placenta, umbilical cord blood and breast milk, suggesting that early exposure may impact developing central nervous system. In a previous study we showed that PAH exposure during both gestation and lactation periods in rats increased anxiety-related behaviours and decreased cerebral metabolism in several key structures linked to the limbic system on male pups at the adult stage. The aim of the present study was to assess the effects of an exclusive gestational PAH exposure on the same aspects of brain functionality. Female rats were exposed through diet to a 16 PAH mixture at doses of 2 MUg/kg/day or 200 MUg/kg/day during gestation. Late neurotoxic effects were evaluated by carrying out behavioural and cognitive tests and histochemical analyses using cytochrome oxidase activity as a cerebral metabolism marker in different brain areas. The results of this study revealed that behaviour and cerebral metabolism on prenatally PAH exposed adult rats was not significantly affected by the exposure to these pollutants. Finally this work highlights that the exposure period to pollutants such as PAHs at very early stages of development play a key role on the neurological impairment induced. PMID- 23742932 TI - Detection of scale-freeness in brain connectivity by functional MRI: signal processing aspects and implementation of an open hardware co-processor. AB - An outstanding issue in graph-theoretical studies of brain functional connectivity is the lack of formal criteria for choosing parcellation granularity and correlation threshold. Here, we propose detectability of scale-freeness as a benchmark to evaluate time-series extraction settings. Scale-freeness, i.e., power-law distribution of node connections, is a fundamental topological property that is highly conserved across biological networks, and as such needs to be manifest within plausible reconstructions of brain connectivity. We demonstrate that scale-free network topology only emerges when adequately fine cortical parcellations are adopted alongside an appropriate correlation threshold, and provide the full design of the first open-source hardware platform to accelerate the calculation of large linear regression arrays. PMID- 23742933 TI - The beginning of the Upper Paleolithic in the Iranian Zagros. A taphonomic approach and techno-economic comparison of Early Baradostian assemblages from Warwasi and Yafteh (Iran). AB - Southwest Asia is a key region in current debates surrounding the appearance of the first cultures attributed to anatomically modern humans, particularly the Aurignacian and preceding cultural units of the Iranian Zagros, Levant, and the Balkans (Baradostian, Ahmarien, Kozarnikien, etc.). The Zagros mountain range encompasses an immense territory that remains understudied with regard to the Upper Paleolithic as well as the first bladelet industries traditionally presumed to be the work of anatomically modern humans. Concerning the emergence of the Aurignacian, the sites of Warwasi rockshelter and Yafteh cave in the central Zagros are considered to show evidence of in situ evolution of the Upper Paleolithic from the local Mousterian. This hypothesis is tested by way of a taphonomic, techno-typological and economic approach applied to the Upper Paleolithic levels of Warwasi (spits LL-AA) and Yafteh (the series from the lower part of the sequence). A comparison of the techno-economic features of both assemblages demonstrates a conceptual bond with contemporaneous techno-complexes from Levant and Europe (Ahmarian, Protoaurignacian, etc.). The techno-typological Middle Paleolithic character of the Warwasi lithic assemblage permits a discussion of a possible in situ dependence/continuum from the Mousterian or perhaps particular activities linked to the type of the occupation of the site. However, bladelet technology cannot be considered as rooted in the Zagros Mousterian. Consequently the origin of the Aurignacian sensu stricto has to be reconsidered. PMID- 23742934 TI - MicroRNA-7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells. AB - Our study demonstrated the functions of microRNA-7 (miR-7) in cervical cancer. The overexpression of miR-7 in the cervical cancer cell lines HeLa and C-33A suppressed cell viability and promoted cell apoptosis, whereas the inhibition of miR-7 had opposite effects. Furthermore, an oncogene, X-linked inhibitor of apoptosis protein (XIAP), was identified as a new target of miR-7, and the ectopic expression of XIAP rescued the effects induced by miR-7 in HeLa and C-33A cells. These results indicate that miR-7 targeted and downregulated the oncogene XIAP to regulate the effect of miR-7 on apoptosis and malignant behaviors of HeLa and C-33A cells. PMID- 23742935 TI - Functional evaluation of Asp76, 84, 102 and 150 in human arsenic(III) methyltransferase (hAS3MT) interacting with S-adenosylmethionine. AB - We prepared eight mutants (D76P, D76N, D84P, D84N, D102P, D102N, D150P and D150N) to investigate the functions of residues Asp76, 84, 102 and 150 in human arsenic(III) methyltransferase (hAS3MT) interacting with the S-adenosylmethionine (SAM)-binding. The affinity of all the mutants for SAM were weakened. All the mutants except for D150N completely lost their methylation activities. Residues Asp76, 84, 102 and 150 greatly influenced hAS3MT catalytic activity via affecting SAM-binding or methyl transfer. Asp76 and 84 were located in the SAM-binding pocket, and Asp102 significantly affected SAM-binding via forming hydrogen bonds with SAM. PMID- 23742936 TI - Effect of phenol-induced changes in lipid composition on conformation of OmpF like porin of Yersinia pseudotuberculosis. AB - The present work aimed to compare the effects of different lysophosphatidylethanolamine (LPE) content in lipids derived from Yersinia pseudotuberculosis cells exposed and not exposed to phenol on the conformation of OmpF-like porin of these bacteria. Differential scanning calorimetry and intrinsic protein fluorescence showed that the 2.5-fold increase of LPE content and the corresponding increase in the phase transition temperature of bacterial lipids were accompanied by enhanced protein thermostability. Integral conformational rearrangement of protein was supported by drastic changes in the microenvironment of the tryptophan residues, likely resulting in a convergence of monomers in trimeric porin and exposure of outer tryptophan residues to the water environment. These conformational changes may impede the porin channel permeability under stress conditions in bacteria. PMID- 23742937 TI - Recognition of intermolecular G-quadruplexes by full length nucleophosmin. Effect of a leukaemia-associated mutation. AB - Nucleophosmin (NPM) is a nucleolar protein involved in ribosome biogenesis. NPM1 gene is frequently mutated in acute myeloid leukaemia (AML), correlating with aberrant cytoplasmic localization of the protein. NPM attachment to the nucleolus in physiological conditions probably depends on binding to nucleic acids, and this recognition could be altered in AML. NPM associates to guanine-rich DNA sequences, able to fold as "G-quadruplexes". We have analyzed the interaction of pentameric, full length NPM with G-rich oligonucleotides, finding that the protein binds preferentially high-order G-quadruplexes. AML-associated mutation significantly hampers DNA binding, pointing to a possible mechanism contributing to pathological mislocalization of NPM. PMID- 23742938 TI - Alopecia areata: a possible extraintestinal manifestation of Crohn's disease. PMID- 23742939 TI - Plasma vitamin D and biomarkers of cardiometabolic disease risk in adult Canadians, 2007-2009. AB - INTRODUCTION: Vitamin D may modulate cardiometabolic disease risk, although the relationship has not been investigated in the general Canadian population. Understanding this relationship may inform public health strategies to curb the incidence of cardiometabolic disease in Canada and elsewhere. The objectives of this study were to examine the association between vitamin D and traditional and novel biomarkers of cardiometabolic disease and to describe the extent of the month-to-month fluctuations of vitamin D in the Canadian population. METHODS: We examined the association between plasma 25-hydroxyvitamin D and a range of cardiometabolic risk biomarkers in participants (n = 1,928; age range, 16-79 years) from the Canadian Health Measures Survey. We conducted linear regressions analyses (adjusted for sex, waist circumference, physical activity, hormone use, and season) to assess the relationship between 25-hydroxyvitamin D and biomarkers of dysglycemia, dyslipidemia, and inflammation in the study population. We repeated analyses stratified by sex, and we evaluated monthly fluctuations in 25 hydroxyvitamin D in men and women. RESULTS: We observed wide month-to-month variations in 25-hydroxyvitamin D; fluctuations were more pronounced in men. Plasma 25-hydroxyvitamin D was inversely associated with insulin, insulin resistance, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and the ratio of total to high-density lipoprotein cholesterol but not with fasting glucose, apolipoprotein A1, apolipoprotein B, C-reactive protein, fibrinogen, or homocysteine. This pattern varied between men and women. CONCLUSION: Vitamin D may modulate various metabolic processes and may influence cardiometabolic disease risk in Canadians. These findings may have public health implications when recommending vitamin D for the prevention of cardiometabolic disease and related conditions. PMID- 23742940 TI - A church-based diet and physical activity intervention for rural, lower Mississippi Delta African American adults: Delta Body and Soul effectiveness study, 2010-2011. AB - INTRODUCTION: Obesity, diabetes, and hypertension have reached epidemic levels in the largely rural Lower Mississippi Delta (LMD) region. We assessed the effectiveness of a 6-month, church-based diet and physical activity intervention, conducted during 2010 through 2011, for improving diet quality (measured by the Healthy Eating Index-2005) and increasing physical activity of African American adults in the LMD region. METHODS: We used a quasi-experimental design in which 8 self-selected eligible churches were assigned to intervention or control. Assessments included dietary, physical activity, anthropometric, and clinical measures. Statistical tests for group comparisons included chi(2), Fisher's exact, and McNemar's tests for categorical variables, and mixed-model regression analysis for continuous variables and modeling intervention effects. RESULTS: Retention rates were 85% (176 of 208) for control and 84% (163 of 195) for intervention churches. Diet quality components, including total fruit, total vegetables, and total quality improved significantly in both control (mean [standard deviation], 0.3 [1.8], 0.2 [1.1], and 3.4 [9.6], respectively) and intervention (0.6 [1.7], 0.3 [1.2], and 3.2 [9.7], respectively) groups, while significant increases in aerobic (22%) and strength/flexibility (24%) physical activity indicators were apparent in the intervention group only. Regression analysis indicated that intervention participation level and vehicle ownership were significant positive predictors of change for several diet quality components. CONCLUSION: This church-based diet and physical activity intervention may be effective in improving diet quality and increasing physical activity of LMD African American adults. Components key to the success of such programs are participant engagement in educational sessions and vehicle access. PMID- 23742941 TI - Using geographic information systems to compare municipal, county, and commercial parks data. AB - INTRODUCTION: Parks are an integral part of a favorable built environment, and several studies have found a positive association between a favorable built environment and physical activity. Parks data are available to researchers from various sources; however, the accuracy of data sources in representing parks is unknown. This study compared secondary parks data obtained from a commercial vendor with data from municipal/county government records, all of which were verified by using Internet searches, telephone inquiries, or on-the-ground audits. METHODS: We studied large metropolitan areas in 3 states: North Carolina (1,837 sq mi), Maryland (1,351 sq mi), and New York (260 sq mi). We collected information on park land area (shapefiles) from municipal/county governments from 2009 through 2012 and from a commercial source in 2010. RESULTS: Commercial parks data did not include 31.1% (119/383, 20.3 sq mi) of North Carolina, 42.9% (187/436, 21.8 sq mi) of Maryland, and 71.7% (640/892, 13.5 sq mi) of New York parks that we found and verified from municipal/county sources. Municipal/county data did not include 15.7% (60/383, 9.9 sq mi) of North Carolina parks, 27.5% (120/436, 74.6) of Maryland parks, and 9.0% (80/892, 6.3 sq mi) of New York parks that we found and verified from commercial sources. CONCLUSION: In this study, the combination of commercial and municipal/county data sources that were verified provided the most complete and accurate shapefile. The quality of secondary sources of parks data should be checked prior to use and, if needed, methods incorporated to improve the capture of parks. PMID- 23742942 TI - No financial disincentive for choosing more healthful entrees on children's menus in full-service restaurants. AB - Children are eating restaurant foods more than ever before, and price is among the top considerations for food choices. We categorized and enumerated entrees on children's menus from 75 full-service restaurant chains to compare prices of more healthful and less healthful entrees to test the assumption that more healthful food is more expensive. The mean (standard deviation) price of more healthful entrees ($5.38 [$2.01]) was not significantly different from the price of less healthful entrees ($5.27 [$2.04]). In contrast to research demonstrating that more healthful foods tend to be more expensive in grocery stores, more healthful entrees on children's menus in restaurants were not more expensive than less healthful entrees. PMID- 23742944 TI - Screening for feeding disorders. Creating critical values using the behavioural pediatrics feeding assessment scale. AB - The aim of the current study was to discriminate between clinical and non clinical samples on the Behavioural Pediatrics Feeding Assessment Scale (BPFAS). The objective was to present a cut-off value, that was derived statistically, which could be used to screen for feeding disorders. A sample of five hundred and seventy-three families with a target child ranging in age from 20 to 85 months took part in the current study. Sixty-four children had a known diagnosis of a feeding disorder and were embedded into a typically developing sample of families that had not sought professional intervention. All families completed the BPFAS in order to provide a known database to measure discriminative statistics. The Receiver Operating Characteristic (ROC) analysis indicated that the cut off value for the BPFAS was a Child Frequency score of 61 and a Child Problem score of six. This offered an 87% accuracy rate at these values. The current study offered definitive evidence that the BPFAS was accurate (both sensitive and specific) to determine differences between clinical and non-clinical samples in the United Kingdom. It is therefore advocated that BPFAS should be adopted in future studies exploring the impact of feeding disorders and problems in both clinical and research settings. PMID- 23742943 TI - Relation of subclinical coronary artery atherosclerosis to cerebral white matter disease in healthy subjects from families with early-onset coronary artery disease. AB - White matter disease (WMD) of the brain is associated with incident stroke. Similarly, subclinical calcified coronary artery plaque has been associated with incident coronary artery disease (CAD) events. Although atherogenesis in both vascular beds may share some common mechanisms, the extent to which subclinical CAD is associated with WMD across age ranges in subjects with a family history of early-onset CAD remains unknown. We screened 405 apparently healthy participants in the Genetic Study of Atherosclerotic Risk for CAD risk factors and for the presence of noncalcified and calcified coronary plaque using dual-source multidetector cardiac computed tomographic angiography. The presence and volumes of WMD were assessed by 3-Tesla brain magnetic resonance imaging. Participants were 60% women, 36% African-American, mean age 51.6 +/- 10.6 years. The overall prevalence of coronary plaque was 43.0%. Subjects with coronary plaque had significantly greater WMD volumes (median 1,222 mm3, interquartile range 448 to 3,871) compared with those without coronary plaque (median 551 mm3, interquartile range 105 to 1,523, p <0.001). In multivariate regression analysis, adjusting for age, gender, race, traditional risk factors, total brain volume, and intrafamilial correlations, the presence of coronary plaque was independently associated with WMD volume (p = 0.05). This study shows a significant association between WMD and noncalcified and calcified coronary plaque in healthy subjects, independent of age and risk factors. In conclusion, these findings support the premise of possible shared causal pathways in 2 vascular beds in families at increased risk for early-onset vascular disease. PMID- 23742945 TI - The relationship of acute myocardial infarction with or without ST-segment elevation and viscosity. AB - We compared hemorheological parameters in 42 male patients with acute myocardial infarction (AMI), with (n = 22) or without (n = 20) ST-segment elevation and in 20 controls. Plasma and blood viscosity (cP), plasma protein (g/dL) and fibrinogen (mg/dL) concentrations, red (10(6)/uL) and white (10(3)/uL) blood cell counts, hemoglobin concentration (g/dL), and hematocrit (%) were compared. Plasma viscosity was significantly higher in patients with AMI with (P = .012) and without (P = .046) ST-segment elevation than in controls. Patients with AMI with and without ST-segment elevation had significantly lower albumin (P = .002 and P = .009) and globulin (P = .001 and P = .007) concentrations, red blood cell counts (P = .0001 and P = .004), and hematocrit (P = .014 and P = .040) and significantly higher fibrinogen concentrations (P = .0001 and P = .001) than controls. These findings suggest that AMI in males is associated with increased plasma viscosity and fibrinogen concentrations and with decreased albumin and globulin concentrations, erythrocyte count, and hematocrit, regardless of ST segment elevation. PMID- 23742946 TI - Specificity of quantitative latex agglutination assay for D-dimer in exclusion of pulmonary embolism in the emergency department. AB - We assessed the prevalence of elevated quantitative latex agglutination assay for D-dimer in patients in the emergency department in whom pulmonary embolism (PE) was excluded. D-dimer was normal (<230 ng/mL) in 435 (83%) of the 522 patients. D dimer was normal in 88% of the patients with musculoskeletal or related chest pain, 74% with pleurisy or pleuritic chest pain, and 85% with upper respiratory tract infection. D-dimer was 230 to 500 ng/mL in 65 (75%) of the 87 in whom D dimer was elevated. Clinical probability was low in 31 (48%) of the 65 patients with D-dimer levels of 230 to 500 ng/mL. D-dimer was 230 to 500 ng/mL and clinical probability was low in 31 (36%) of the 87 patients who had computed tomographic (CT) angiograms because of elevated D-dimer. Negative likelihood ratio for PE is sufficiently low that PE can be excluded with reasonable certainty in such patients. Tailoring cutoff value to 500 ng/mL in patients with low clinical probability would have reduced CT angiograms by 36%. PMID- 23742947 TI - Impact of anticoagulation on coronary flow in patients with non-ST elevation acute coronary syndrome. AB - The effect of anticoagulation by heparin on patients with non-ST elevation acute coronary syndrome (NSTE-ACS), receiving early dual antiplatelet therapy, has not been fully evaluated. We classified 355 patients with NSTE-ACS according to the adequacy of anticoagulation (percentage of low activated partial thromboplastin time [APTT] level). The 6-hour APTT level was optimal in only 23.1% of the patients treated with unfractionated heparin. The rate of poor preprocedural coronary blood flow (thrombolysis in myocardial infarction grade <3, 39.1%, 30.5%, 30.3%, and 33.9% in the 100% low-, 99%~50% low-, 49%~1% low-, and 0% low APTT group, respectively, P = .632) and bleeding events did not differ between the groups. Instead, in multivariate analysis, the diagnosis of myocardial infarction was the only independent predictor of poor coronary flow. For bleeding events, the usage of glycoprotein IIb/IIIa inhibitor appeared to be a sole risk factor. In conclusion, inadequate preprocedural anticoagulation was not associated with adverse outcomes in patients with NSTE-ACS treated with dual antiplatelet agents. PMID- 23742948 TI - Predictors of anticoagulant treatment in patients with nonvalvular atrial fibrillation: results from atrial fibrillation in Turkey: epidemiologic registry. AB - The aim of the study was to assess the factors associated with the anticoagulation treatment in patients with atrial fibrillation (AF). A total of 2242 consecutive patients who had been admitted with AF on their electrocardiogram were included in the study. After excluding valvular AF, 1745 patients with nonvalvular AF were analyzed. Mean CHA2DS2-VASc score [cardiac failure, hypertension, age >= 75 (doubled), diabetes, stroke (doubled), vascular disease, age 65 -74 and sex category (female)], frequency of persistent/permanent AF, hypertension, diabetes mellitus (DM), stroke history, body mass index, and left atrial diameter were significantly higher in patients receiving anticoagulant therapy. Stroke history, persistent/permanent AF, hypertension, DM, age, heart failure, and left atrial diameter were independent predictors of warfarin prescription. Labile international normalized ratio was the only independent negative predictor of effective treatment with warfarin. In this study, we demonstrated that stroke history, persistent/permanent AF, hypertension, DM, and left atrial diameter were positive predictors, whereas advanced age and heart failure were negative predictors of oral anticoagulant use in patients with nonvalvular AF. PMID- 23742949 TI - Network properties derived from deep sequencing of human B-cell receptor repertoires delineate B-cell populations. AB - The adaptive immune response selectively expands B- and T-cell clones following antigen recognition by B- and T-cell receptors (BCR and TCR), respectively. Next generation sequencing is a powerful tool for dissecting the BCR and TCR populations at high resolution, but robust computational analyses are required to interpret such sequencing. Here, we develop a novel computational approach for BCR repertoire analysis using established next-generation sequencing methods coupled with network construction and population analysis. BCR sequences organize into networks based on sequence diversity, with differences in network connectivity clearly distinguishing between diverse repertoires of healthy individuals and clonally expanded repertoires from individuals with chronic lymphocytic leukemia (CLL) and other clonal blood disorders. Network population measures defined by the Gini Index and cluster sizes quantify the BCR clonality status and are robust to sampling and sequencing depths. BCR network analysis therefore allows the direct and quantifiable comparison of BCR repertoires between samples and intra-individual population changes between temporal or spatially separated samples and over the course of therapy. PMID- 23742950 TI - Cyclooxygenase and cytokine regulation in lung fibroblasts activated with viral versus bacterial pathogen associated molecular patterns. AB - Cyclooxygenase (COX) is required for prostanoid (e.g. prostaglandin PGE2) production. Constitutive COX-1 and inducible COX-2 are implicated in lung diseases, such as idiopathic pulmonary fibrosis (IPF). Using lung fibroblasts from humans and wild type, COX-1(-/-) and COX-2(-/-) mice, we investigated how COX activity modulates cell growth and inflammatory responses induced by activators of Toll-like receptors (TLRs) 1-8. In mouse tissue, PGE2 release from fresh lung was COX-1 driven, in lung in culture (24h) COX-1 and COX-2 driven, and from proliferating lung fibroblasts exclusively COX-2 driven. COX-2 limited proliferation in lung fibroblasts and both isoforms limited KC release induced by a range of TLR agonists. Less effect of COX was seen on TLR-induced IP-10 release. In human lung fibroblasts inhibition of COX with diclofenac was associated with increased release of IL-8 and IP-10. Our results may have implications for the treatment of IPF. PMID- 23742951 TI - Eicosanoid biosynthesis during mucociliary and mucous metaplastic differentiation of bronchial epithelial cells. AB - The purpose of this study was to examine the profile of eicosanoids secreted by human bronchial epithelial cells (HBEC) during their in vitro differentiation toward mucociliary or mucous metaplastic phenotype. Eicosanoids were measured in supernatants by mass spectrometry, and corresponding gene expression by real-time PCR. Primary HBEC produced mainly prostaglandins (PGE2, PGD2) and epoxides (e.g. 14,15-EET), but during further mucociliary differentiation we observed a gradual increase in secretion of lipoxygenase derived HETEs. Treatment with IL-13 and IL 4 induced mucous metaplasia and resulted in downregulation of PG pathway, and potent induction of 15-lipoxygenase (marked release of 15-HETE). The deficiency in PG production sustained during long term culture of mucous metaplastic epithelia. In conclusions, Th2-type cytokines induce changes in eicosanoid metabolism of airway epithelial cells, resulting in an immense induction of 15 lipoxygenase pathway, and inhibition of PG pathways. Deficient production of immunomodulatory PGs may promote chronic inflammation and airway remodeling. PMID- 23742952 TI - Dark ambient degradation of Bisphenol A and Acid Orange 8 as organic pollutants by perovskite SrFeO3-delta metal oxide. AB - Current advanced oxidation processes (AOPs) are chemically and energetically intensive processes, which are undesirable for cost-effective and large-scale system water treatment and wastewater recycling. This study explored the Strontium Ferrite (SFO) metal oxide on the degradation of highly concentrated organic pollutants under dark ambient condition without any external stimulants. The SFO particles with single perovskite structure were successfully synthesized with a combined high temperature and high-energy ball milling process. An endocrine disruptor, Bisphenol A (BPA) and an azo dye, Acid Orange 8 (AO8) were used as probe organic pollutants. BPA was completely degraded with 83% of mineralization in 24 h while rapid decoloration of AO8 was achieved in 60 min and complete breakdown into primary intermediates and aliphatic acids occurred in 24 h under the treatment of dispersed SFO metal oxide in water. Such efficient degradation could be attributed to the enhanced adsorption of these anionic pollutants on positively charged ball-milled SFO metal oxide surface, resulted in higher degradation activity. Preliminary degradation mechanisms of BPA and AO8 under the action of SFO metal oxide were proposed. These results showed that the SFO metal oxide could be an efficient alternative material as novel advanced oxidation technology for low cost water treatment. PMID- 23742953 TI - Preparation and characterization of a novel nano-absorbent based on multi cyanoguanidine modified magnetic chitosan and its highly effective recovery for Hg(II) in aqueous phase. AB - A new kind of nano-absorbent with the entirely novel structure, nano-absorbent of multi-cyanogunidine modified magnetic chitosan (CG-MCS nano-absorbent), has been firstly synthesized by using the functionalized chitosan and cross-linking agent with cyanoguanidine group simultaneously. The resulting nano-absorbent was characterized by means of the Fourier transform infrared spectra (FT-IR), transmission electron microscope (TEM), X-ray diffraction (XRD), elemental analysis and vibrating sample magnetometer (VSM). The resulting nano-absorbent basen on multi-cyanoguanidine modified magnetic chitosan has been demonstrated holding highly effective recovery for mercury ions, in other words, it showed both the extraordinary adsorption capacity for Hg(II) at high initial concentration and the strong removal ability for it at low concentration, the maximum adsorption capacity was up to 285 mg g(-1) and the removal percentage could reach 96% at low concentration. Meanwhile, the resulting CG-MCS nano absorbent also showed a high selectivity adsorption for Hg(II) among coexisting heavy metals and the good regeneration performance. PMID- 23742954 TI - Decomposition of dimethylamine gas with dielectric barrier discharge. AB - The decomposition of dimethylamine (DMA) with gas under high flow rate was investigated with dielectric barrier discharge (DBD) technology. Different parameters including removal efficiency, energy yield, carbon balance and CO2 selectivity, secondary products, as well as pathways and mechanisms of DMA degradation were studied. The experimental results showed that removal efficiency of DMA depended on applied voltage and gas flow rate, but had no obvious correlation with initial concentration. Excellent energy performance was obtained using present DBD technology for DMA abatement. When experiment conditions were controlled at: gas flow rate of 14.9 m(3)/h, initial concentration of 2104 mg/m(3), applied voltage of 4.8 kV, removal efficiency of DMA and energy yield can reach 85.2% and 953.9 g/kWh, respectively. However, carbon balance (around 40%) was not ideal due to shorter residence time (about 0.1s), implying that some additional conditions should be considered to improve the total oxidation of DMA. Moreover, secondary products in outlet gas stream were detected via gas chromatogram-mass spectrum and the amounts of NO3(-) and NO2(-) were analyzed by ion chromatogram. The obtained data demonstrated that NOx might be suppressed due to reductive NH radical form DMA dissociation. The likely reaction pathways and mechanisms for the removal of DMA were suggested based on products analysis. Experimental results demonstrated the application potential of DBD as a clean technology for organic nitrogen-containing gas elimination from gas streams. PMID- 23742955 TI - Different nanostructured In2O3 for photocatalytic decomposition of perfluorooctanoic acid (PFOA). AB - Perfluorooctanoic acid (PFOA), an emerging persistent organic pollutant, recently receives worldwide concerns including methods for its efficient decomposition. Three kinds of nanostructured In2O3 materials including porous microspheres, nanocubes and nanoplates were obtained by dehydration of the corresponding In(OH)3 nanostructures at 500 degrees C for 2 h. The In(OH)3 nanostructures with different morphologies were solvothermally synthesized by using different mixed solvents. As-obtained In2O3 nanomaterials showed great photocatalytic activity for PFOA decomposing. The decomposition rates of PFOA by different In2O3 materials, i.e. porous microspheres, nanoplates and nanocubes were 74.7, 41.9 and 17.3 times as fast as that by P25 TiO2, respectively. The In2O3 porous microspheres showed the highest activity, by which the half-life of PFOA was shortened to 5.3 min. The roles of surface oxygen vacancies on the adsorption and photocatalytic decomposition of PFOA were discussed, and it was found that In2O3 materials with higher oxygen vacancy defects show better activity. PMID- 23742956 TI - Use of scanning electron microscopy to monitor nanofibre/cell interaction in digestive epithelial cells. AB - We provide data obtained by scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) on the interaction of ingested tungsten nanofibers with epithelial cells of the digestive tubes of a test organism Porcellio scaber. Conventional toxicity endpoints including feeding behaviour, weight loss and mortality were also measured in each investigated animal. No toxicity was detected in any of exposed animals after 14 days of feeding on tungsten nanofiber dosed food, but when nanofibers enter the digestive system they can react with epithelial cells of the digestive tubes, becoming physically inserted into the cells. In this way, nanofibers can injure the epithelial cells of digestive gland tubes when they are ingested with food. Our SEM data suggest that peristaltic forces may have an important role, not predicted by in vitro experiments, in the interactions of nanomaterials with digestive intestinal cells. PMID- 23742957 TI - Predictors and persistence of new-onset clinical remission in rheumatoid arthritis patients. AB - OBJECTIVE: To determine the prevalence and persistence of new-onset clinical remission in rheumatoid arthritis (RA) patients. METHODS: The Consortium of Rheumatology Researchers of North America (CORRONA) cohort was used to examine the prevalence of remission and associated comorbidities and RA therapies according to the 2011 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) remission criteria. Factors influencing the likelihood of remaining in remission were identified by logistic regression with generalized estimating equations. Analysis of variance and Tukey's test were used to determine differences in disability according to whether RA patients had been in remission or only low disease activity (LDA). RESULTS: A total of 2105 individuals met ACR/EULAR remission criteria at the most recent visit within CORRONA, yielding an 8% point prevalence of remission. Patients with certain comorbidities (e.g., heart failure) were significantly less likely to achieve or remain in remission compared to those without these conditions (p < 0.001 for each). Among prednisone users, the prevalence of remission was 1-6% (depending on dose) higher compared to those not on prednisone (10%). More than 50% of patients who had consistently been in remission for >=1 year were able to remain in remission over the next year. Patients consistently in remission had less disability than patients who achieved LDA or who fluctuated between remission and LDA. CONCLUSION: Patients consistently in remission for at least 1 year had a high likelihood to remain in remission. These individuals might be considered the most likely candidates for de-escalation or withdrawal of RA treatments. PMID- 23742958 TI - Evidence-based recommendations for the practical management of Familial Mediterranean Fever. AB - AIM: Familial Mediterranean Fever (FMF) is the most common recurrent autoinflammatory fever syndrome. Still, many issues-e.g.: colchicine dosage adjustment, maximum dosage of colchicine in children and adults, definition of colchicine resistance, alternative treatment solutions in colchicine-resistant patients, and genetic screening for asymptomatic siblings-have not yet been standardized. The current paper aims at summarizing consensus recommendations to approach these issues. METHODS: A literature review concerning these practical management questions was performed through PubMed. On the basis of this analysis, expert recommendations were developed during a consensus meeting of caregivers from France and Israel. RESULTS: A patient experiencing more than four FMF attacks a year needs colchicine dose adjustment. In case of persistent attacks (>=6 per year) in patients with maximum doses of colchicine (2 mg in children; 3 mg in adults), alternative treatment to colchicine with IL1 inhibitors should be considered. Routine genetic testing for MEFV mutations in asymptomatic siblings of an index case is not recommended. CONCLUSION: This is a first attempt to resolve practical questions in the daily management of FMF patients. PMID- 23742959 TI - Swallowing-sparing intensity-modulated radiotherapy for head and neck cancer patients: treatment planning optimization and clinical introduction. AB - PURPOSE: To report on the potential benefits of swallowing-sparing intensity modulated radiation therapy (SW-IMRT) in the first 100 SW-IMRT treated patients, as well as on the factors that influence the potential benefit of SW-IMRT relative to standard parotid sparing (ST)-IMRT. MATERIAL AND METHODS: One hundred consecutive head and neck cancer patients, scheduled for primary radiotherapy, were included in this prospective cohort study. For each patient, ST-IMRT and SW IMRT treatment plans were created. All patients were eventually treated with SW IMRT. Objectives for SW-IMRT were identical to those with ST-IMRT, with additional objectives to spare the swallowing organs at risk (SWOARs). After 20 patients, interim results were evaluated by a multidisciplinary committee. RESULTS: The mean gain of SW-IMRT relative to ST-IMRT in the first 20 patients was less than expected based on our previous planning comparative study. A critical review of all plans revealed that the results with SW-IMRT could be improved by: (1) gaining experience and attempting to reduce SWOAR dose as much as possible; (2) accepting a moderate shift of dose to unspecified tissues; (3) maximizing SWOAR sparing while keeping PTV coverage exactly according to protocol. In the additional 80 patients, the mean dose to the various SWOARs was further reduced significantly compared to ST-IMRT. Dose reductions with SW-IMRT were largest for patients who received neck irradiation, had a tumour located in the larynx, oropharynx, nasopharynx or oral cavity, and had <75% overlap between SWOARs and PTVs. The mean absolute reduction in predicted physician-rated RTOG grade 2-4 swallowing dysfunction for patients numbered 21-100 was 6.1%, ranging from 0.0% to 17.2%. CONCLUSIONS: The benefit of SW-IMRT depends significantly on neck radiotherapy, tumour site and the amount of overlap between SWOARs and PTVs. Optimal clinical introduction requires a detailed evaluation and comparison between the standard (ST-IMRT) and new technique (SW-IMRT) in order to fully exploit the potential benefits. PMID- 23742960 TI - Population-based outcomes of boost versus salvage radiosurgery for brain metastases after whole brain radiotherapy. AB - PURPOSE: We conducted a retrospective population-based study to examine the survival outcomes in patients with brain metastases treated with salvage stereotactic radiosurgery (SRS), compared to boost SRS, after previous whole brain radiotherapy (WBRT). METHODS AND MATERIALS: From January 2000 to June 2011, 191 patients treated with WBRT and SRS for brain metastases in British Columbia were studied. Patients were divided into a boost cohort and a salvage cohort. The criteria used to determine eligibility for SRS were: 1-3 metastases, <=4cm size, Karnofsky performance status >= 70, and control of extracranial disease. RESULTS: Diagnosis by primary site was 84 lung, 47 breast, 15 melanoma, 12 renal, 9 colorectal, and 24 other. There were 113 patients (59%) in the boost cohort and 78 patients (41%) in the salvage cohort. The median overall survival from WBRT for the whole population was 17.7months: 12.1 months for the boost cohort and 22.7 months for the salvage cohort. There was no difference in median survival after SRS for the boost and salvage cohorts (11.2 vs. 11.2 months, p=0.78). CONCLUSIONS: In selected patients with brain metastases treated with WBRT, survival following salvage SRS is as good as survival after WBRT + boost SRS. PMID- 23742961 TI - Breast-conserving therapy with partial or whole breast irradiation: ten-year results of the Budapest randomized trial. AB - BACKGROUND AND PURPOSE: To report the long-term results of a single-institution randomized study comparing the results of breast-conserving treatment with partial breast irradiation (PBI) or conventional whole breast irradiation (WBI). PATIENTS AND METHODS: Between 1998 and 2004, 258 selected women with pT1 pN0-1mi M0, grade 1-2, non-lobular breast cancer without the presence of extensive intraductal component and resected with negative margins were randomized after BCS to receive 50 Gy WBI (n=130) or PBI (n=128). The latter consisted of either 7 * 5.2 Gy high-dose-rate (HDR) multi-catheter brachytherapy (BT; n=88) or 50 Gy electron beam (EB) irradiation (n=40). Primary endpoint was local recurrence (LR) as a first event. Secondary endpoints were overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and cosmetic results. RESULTS: After a median follow up of 10.2 years, the ten-year actuarial rate of LR was 5.9% and 5.1% in PBI and WBI arms, respectively (p=0.77). There was no significant difference in the ten-year probability of OS (80% vs 82%), CSS (94% vs 92%), and DFS (85% vs 84%), either. The rate of excellent-good cosmetic result was 81% in the PBI, and 63% in the control group (p<0.01). CONCLUSIONS: Partial breast irradiation delivered by interstitial HDR BT or EB for a selected group of early stage breast cancer patients produces similar ten-year results to those achieved with conventional WBI. Significantly better cosmetic outcome can be achieved with HDR BT implants compared with the outcome after WBI. PMID- 23742962 TI - Re-irradiation and hyperthermia after surgery for recurrent breast cancer. AB - PURPOSE: Evaluation of efficacy and side effects of combined re-irradiation and hyperthermia electively or for subclinical disease in the management of locoregional recurrent breast cancer. METHODS AND MATERIALS: Records of 198 patients with recurrent breast cancer treated with re-irradiation and hyperthermia from 1993 to 2010 were reviewed. Prior treatments included surgery (100%), radiotherapy (100%), chemotherapy (42%), and hormonal therapy (57%). Ninety-one patients were treated for microscopic residual disease following resection or systemic therapy and 107 patients were treated electively for areas at high risk for local recurrences. All patients were re-irradiated to 28-36Gy (median 32) and treated with 3-8 hyperthermia treatments (mean 4.36). Forty percent of the patients received concurrent hormonal therapy. Patient and tumor characteristics predictive for actuarial local control (LC) and toxicity were studied in univariate and multivariate analysis. RESULTS: The median follow-up was 42months. Three and 5year LC-rates were 83% and 78%. Mean of T90 (tenth percentile of temperature distribution), maximum and average temperatures were 39.8 degrees C, 43.6 degrees C, and 41.2 degrees C, respectively. Mean of the cumulative equivalent minutes (CEM43) at T90 was 4.58min. Number of previous chemotherapy and surgical procedures were most predictive for LC. Cumulative incidence of grade 3 and 4 late toxicity at 5years was 11.9%. The number of thermometry sensors and depth of treatment volume were associated with acute hyperthermia toxicity. CONCLUSIONS: The combination of re-irradiation and hyperthermia results in a high LC-rate with acceptable toxicity. PMID- 23742963 TI - Radiation-induced myosin IIA expression stimulates collagen type I matrix reorganization. AB - BACKGROUND AND PURPOSE: Extracellular matrix (ECM) reorganization critically contributes to breast cancer (BC) progression and radiotherapy response. We investigated the molecular background and functional consequences of collagen type I (col-I) reorganization by irradiated breast cancer cells (BCC). MATERIALS AND METHODS: Radiation-induced (RI) col-I reorganization was evaluated for MCF 7/6, MCF-7/AZ, T47D and SK-BR-3 BCC. Phase-contrast microscopy and a stressed matrix contraction assay were used for visualization and quantification of col-I reorganization. Cell-matrix interactions were assessed by the inhibition of beta1 integrin (neutralizing antibody 'P5D2') or focal adhesion kinase (FAK; GSK22560098 small molecule kinase inhibitor). The role of the actomyosin cytoskeleton was explored by western blotting analysis of myosin II expression and activity; and by gene silencing of myosin IIA and pharmacological inhibition of the actomyosin system (blebbistatin, cytochalasin D). BCC death was evaluated by propidium iodide staining. RESULTS: We observed a radiation dose-dependent increase of col-I reorganization by BCC. beta1 Integrin/FAK-mediated cell-matrix interactions are essential for RI col-I reorganization. Irradiated BCC are characterized by increased myosin IIA expression and myosin IIA-dependent col-I reorganization. Moreover, RI col-I reorganization by BCC is associated with decreased BCC death, as suggested by pharmacological targeting of the beta1 integrin/FAK/myosin IIA pathway. CONCLUSIONS: Our data indicate the role of myosin IIA in col-I reorganization by irradiated BCC and reciprocal BCC death. PMID- 23742964 TI - Body mass index is inversely associated with mortality in patients with peripheral vascular disease. AB - BACKGROUND: Current guidelines contain no advice on how to manage obesity and underweight in patients with peripheral vascular disease (PVD). OBJECTIVES: The aim of this study was to assess the association of underweight, overweight and obesity with mortality in patients with PVD. PATIENTS AND METHODS: We recruited 1472 patients with a broad range of presentations of PVD. Underweight, overweight and obesity were defined by body mass index (BMI) and associated with mortality using Kaplan Meier and Cox proportional hazard analyses. RESULTS: Survival at 3 years was 37.5, 78.1, 86.8 and 87.0% for patients that were underweight, normal weight, overweight and obese at recruitment, respectively, p<0.001. Patients that were underweight had approximately twice the risk of dying (RR 2.15, 95% CI 1.31 3.55, p=0.003), while patients that were overweight (RR 0.67, 95% CI 0.49-0.91, p=0.011) or obese (RR 0.59, 95% CI 0.41-0.85, p=0.005) had approximately half the risk of dying, after adjustment for other risk factors and using normal weight subjects as the reference group. 823 patients had waist circumference measured at recruitment. Patients with waist circumference in the top quartile had half the risk of dying (RR 0.50, 95% CI 0.26-0.98, p=0.045). In 267 patients we assessed the relationship between BMI and abdominal fat volumes using computed tomography. BMI was highly correlated with both intra-abdominal and subcutaneous fat volumes. CONCLUSIONS: Obesity whether assessed by BMI or central fat deposition is associated with reduced risk of dying in patients with established PVD. Underweight is highly predictive of early mortality in patients with PVD. PMID- 23742966 TI - Exploring network theory for mass drug administration. AB - Network theory is a well-established discipline that uses mathematical graphs to describe biological, physical, and social systems. The topologies across empirical networks display strikingly similar organizational properties. In particular, the characteristics of these networks allow computational analysis to contribute data unattainable from examining individual components in isolation. However, the interdisciplinary and quantitative nature of network analysis has yet to be exploited by public health initiatives to distribute preventive chemotherapies. One notable application is the 2012 World Health Organization (WHO) Roadmap for Neglected Tropical Diseases (NTDs) where there is a need to upscale distribution capacity and to target systematic noncompliers. An understanding of local networks for analysing the distributional properties of community-directed treatment may facilitate sustainable expansion of mass drug administration (MDA) programs. PMID- 23742967 TI - Pathogenesis of malaria-associated acute respiratory distress syndrome. AB - Malaria-associated acute respiratory distress syndrome (MA-ARDS) is an increasingly reported, often lethal, and incompletely understood complication of malaria. We discuss and compare the pathogenesis of MA-ARDS in patients and in different murine models, including recent models without cerebral involvement, and summarize the roles of different leukocyte subclasses, adhesion molecules, cytokines, and chemokines. In patients as well as in mice, severe edema and impaired gas exchange are associated with abundant inflammatory infiltrates consisting of mainly mononuclear cells and parasite sequestration, and the pathogenesis appears different from cerebral malaria (CM). Experimental anti inflammatory interventions are successful in mice and remain to be validated in patients. PMID- 23742968 TI - Frequency tuning of individual auditory receptors in female mosquitoes (Diptera, Culicidae). AB - The acoustic sensory organs in mosquitoes (Johnston organs) have been thoroughly studied; yet, to date, no data are available on the individual tuning properties of the numerous receptors that convert sound-induced vibrations into electrical signals. All previous measurements of frequency tuning in mosquitoes have been based on the acoustically evoked field potentials recorded from the entire Johnston organ. Here, we present evidence that individual receptors have various frequency tunings and that differently tuned receptors are unequally represented within the Johnston organ. We devised a positive feedback stimulation paradigm as a new and effective approach to test individual receptor properties. Alongside the glass microelectrode technique, the positive feedback stimulation paradigm has allowed us to obtain data on receptor tuning in females from three mosquito species: Anopheles messeae, Aedes excrucians and Culex pipiens pipiens. The existence of individually tuned auditory receptors implies that frequency analysis in mosquitoes may be possible. PMID- 23742969 TI - Effect of lead trajectory on the response of essential head tremor to deep brain stimulation. AB - BACKGROUND: Essential tremor (ET) is one of the most common movement disorders. Normally ET affects the distal upper extremities, but it can also be accompanied by midline symptoms. Ventralis intermedius (VIM) thalamic deep brain stimulation (DBS) has been shown to be effective in reducing hand tremor, but its effects on head tremor have been inconsistent. METHODS: Twenty-nine DBS patients with a diagnosis of ET met inclusion criteria. All implantations targeted VIM. The factors examined included age, gender, disease duration, presence or absence of head tremor, handedness, and the Fahn-Tolosa-Marin rating scale (TRS). This analysis specifically focused on TRS head tremor sub-scores at baseline, 6 months and 12 months post-DBS. Additionally, DBS lead entry angles were examined. RESULTS: Twenty-three ET patients underwent unilateral DBS and six underwent staged bilateral DBS. At both 6 and 12 months following DBS, stimulation resulted in diminished head tremor (ON vs OFF; p < 0.0001). The most important predictor of head tremor suppression was the entry angle of the DBS lead in the sagittal projection relative to the AC-PC axial plane (AC-PC angle). Head tremor reduction was greater among more vertical AC-PC angles. CONCLUSION: A more vertical AC-PC angle of the DBS lead trajectory was associated with improved head tremor suppression. Further studies will be necessary to confirm this potentially important finding. PMID- 23742971 TI - For the special IJP issue "poorly soluble drugs". PMID- 23742970 TI - Moving from physician-centered care towards patient-centered care for Parkinson's disease patients. AB - Today's society is changing rapidly and individuals increasingly favor an active role in designing their own lives. Contemporary patients are no exception, but the present health care system-which is organized primarily from the provider's perspective-is not yet prepared for this development. Here, we argue that an alternative way to organize health care, namely more from the patient's perspective, may help to contain costs, while improving the quality, safety and access to care. This involves a redefinition of the patient-doctor relationship, such that patients are no longer regarded as passive objects, but rather as active subjects who work as partners with health care professionals to optimize health ('participatory medicine'). The opportunities that come with such a collaborative and patient-centered care model are reviewed within the context of patients with Parkinson's disease. We also discuss societal and Parkinson specific barriers that could impede implementation of this alternative care model to the management of Parkinson's disease and other chronic conditions. PMID- 23742972 TI - Synthesis, in vitro and in vivo evaluation of new norcantharidin-conjugated hydroxypropyltrimethyl ammonium chloride chitosan derivatives as polymer therapeutics. AB - New norcantharidin-conjugated hydroxypropyltrimethyl ammonium chloride chitosan derivatives (NCTD-HACCs) were synthesized and characterized by (1)H NMR, Fourier transform infrared spectroscopy (FT-IR), and wide-angle X-ray diffraction (WAXD). Two NCTD-HACCs with different degrees of substitution (DS) (12.2% and 24.8%) were obtained, which had good water solubility. NCTD was released from the NCTD-HACCs via hydrolysis, faster in pH 5.0 than pH 7.4 and presenting one biphasic drug release pattern with rapid release at the initial stage and slow release later. Fluorescence microscope and flow cytometry analysis demonstrated that the NCTD HACC was endocytosized into MGC80-3 cells and the uptaken amount increased as incubation time. Compared with free NCTD, the NCTD-HACCs showed lower in vitro anti-tumor activity against human gastric cancer MGC80-3 cells, but higher in vivo tumor growth inhibition in S180 tumor-bearing mice. The in vivo near infrared (NIR) fluorescence real-time imaging result showed the fluorescence intensity in tumor was much higher than that in heart, liver, spleen and lung (except kidney) after i.v. injection of the FITC-labeled NCTD-HACC2, indicating specific accumulation of the NCTD-HACC in tumor. PMID- 23742973 TI - Enhancement of water solubility of indomethacin by complexation with protein hydrolysate. AB - Complex formation between indomethacin (Indo) and casein hydrolysate was developed as a novel technique for enhancing the water solubility of Indo. The complex (Indo-Pep) was prepared by mixing an ethanol solution of Indo and an aqueous solution of peptide mixture, followed by lyophilization. The water solubility of Indo-Pep under weakly acidic and neutral conditions is much higher than that of Indo alone. The water solubility of Indo increased with increasing quantity of peptide. Characterization of Indo-Pep using scanning electron microscopy, differential scanning calorimetry, and X-ray diffraction showed that Indo was incorporated in Indo-Pep in an amorphous state. The fluorescence quenching of Indo-Pep also suggested complexation between Indo and the peptides. An aqueous solution of Indo-Pep was fractioned by centrifugation followed by filtration using membrane filters and ultrafilters. Analysis of the fractions by dynamic light scattering and ultraviolet-visible spectroscopy showed that Indo Pep consisted of small particles and was not a hydrocolloidal material. PMID- 23742974 TI - Effects of pharmaceutical excipients on membrane permeability in rat small intestine. AB - Pharmaceutical excipients should not disturb the effects of drug therapy. In recent years, however, it has been reported that excipients induce some changes to the tight junction (TJ) and P-glycoprotein (P-gp), which can affect drug disposition. In this study, we examined the effects of 20 common pharmaceutical excipients from different classes on mucosal membrane and the differences of such effects among regions of the small intestine. We used the in vitro sac method in rat jejunum and ileum to study the effects of excipients on the membrane permeation of 5(6)-carboxyfluorescein (5-CF). 5-CF was used as a model of water soluble compounds. In some dosage conditions of methyl-beta-cyclodextrin, the membrane permeability of 5-CF was significantly increased in the jejunum, but such change was not observed in the ileum. Similarly, in the cases of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and croscarmellose sodium, the membrane permeability of 5-CF was significantly increased in the jejunum, but no change was observed in the ileum. On the other hand, in both the jejunum and the ileum, the membrane permeation of 5-CF was decreased with 0.02% (w/v) hydroxypropyl cellulose, but significantly increased with it at 0.20% (w/v). It was shown that excipients affected the membrane permeability of water soluble compounds via the paracellular route, and these effects on absorption differed among regions of the small intestine. Moreover, in the case of 20 excipients, not only an increase in membrane permeability but also a decrease was observed. Therefore, it was suggested that a more effective formulation could be designed by changing the combination of excipients. PMID- 23742975 TI - Roll compaction of mannitol: compactability study of crystalline and spray-dried grades. AB - Purpose of this project was to investigate the roll compaction behavior of various mannitol grades. Therefore, five spray-dried grades as well as unprocessed beta-d-mannitol were roll compacted with different compaction forces. The resulting granules were characterized with regard to their particle size distribution, flow properties, and BET surface area and compressed to tablets. Granules of unprocessed mannitol, even when applying high compaction forces during dry granulation, were characterized by a high amount of fines (about 21%), a small surface area (0.83 m(2)/g), and solely fair flowability (ffc=7.2). Tablets revealed either high friability or insufficient disintegration behavior. However, the use of spray-dried mannitol led to better results. Granules showed improved flow properties and a reduced amount of fines. Robust tablets with low friability were produced. Within the various spray-dried grades huge differences concerning the compactability were observed. Large BET surface areas of the granules resulted in advanced tensile strengths of the tablets, but acceptable disintegration behavior was maintained. These findings are relevant for the development of mannitol based drug formulations, in particular (oro)dispersible tablets containing a low dose or poor flowing active pharmaceutical ingredient, where direct compression is inappropriate and a granulation process prior to tableting is mandatory. PMID- 23742976 TI - The interaction between human breast cancer resistance protein (BCRP) and five bisbenzylisoquinoline alkaloids. AB - BCRP is one of the key factors to drug absorption, distribution and elimination. Bisbenzylisoquinoline alkaloids are a large family of natural phytochemicals with great potential for clinical use. In this study, the interaction between BCRP and five bisbenzylisoquinoline alkaloids (neferine, isoliensinine, liensinine, dauricine and tetrandrine) were evaluated using LLC-PK1/BCRP cell model. The intracellular accumulation and bi-directional transport studies were conducted, and then molecular docking analysis was carried out employing a homology model of BCRP. Our study revealed that the permeability of these five alkaloids was not high, the Papp values were all less than 6.5 * 10(-6)cm/s. Liensinine and dauricine were substrates of BCRP: at lower concentration (10 MUM), the net efflux ratios were 2.87 and 1.64 respectively. And their cellular accumulation was lower in LLC-PK1/BCRP cells than in LLC-PK1 cells. On the other hand, tetrandrine, isoliensinine and neferine were not substrates of BCRP. On the basis of docking studies, a direct hydrogen bond was formed between liensinine and arginine 482 which is a hot spot of BCRP for substrate specificity; and dauricine had hydrophobic interaction with BCRP. In conclusion, our study indicated that BCRP could mediate the excretion of liensinine and dauricine, thus influence their pharmacological activity and disposition. PMID- 23742977 TI - Determination of haloperidol in biological samples using molecular imprinted polymer nanoparticles followed by HPLC-DAD detection. AB - In this study an extraction procedure using molecular imprinted polymer nanoparticles for the determination of haloperidol in biological samples is proposed. The haloperidol imprinted polymer nanoparticles were synthesized successfully by precipitation polymerization in a flask containing haloperidol as a template, ethyleneglycoldimethacrylate as a crosslinking agent, methacrylic acid as a functional monomer, and 2,2'-azobisisobutyronitrile as an initiator. The leached and unleached polymer nanoparticles have been characterized by infrared spectroscopy and scanning electron microscopy. The effect of different variables such as the pH of solution, uptake and elution time, type, and the least amount of eluent for elution of haloperidol from polymer was evaluated. Extraction efficiencies more than 97% were obtained by elution of the polymer with 1.5 mL of methanol-acetic acid-trifluoroacetic acid 79.9:20:0.1. Under optimal conditions maximum adsorption capacity was obtained 153.84 mg g(-1). The detection limit of the proposed procedure was between 0.2 and 0.35 MUg L(-1). Finally this method was applied to the determination of haloperidol in plasma and urine samples and satisfactory results were achieved (RSD<6.9%). PMID- 23742978 TI - Continuous PTH modulates alkaline phosphatase activity in human PDL cells via protein kinase C dependent pathways in vitro. AB - Periodontal ligament (PDL) cells, a major component of the tooth supporting apparatus, share osteoblastic characteristics including their responsiveness to parathyroid hormone (PTH). Clinical studies have already pointed to the benefit of PTH in supporting regenerative processes in the craniofacial region. However, those reports did not analyze which cells mediated the PTH effect on the alveolar bone. The aim of the present study has been to further elucidate the mechanism of action of continuous PTH application on human PDL-cells mimicking a local bolus application and to analyze its intracellular signalling pathways to widen the theoretical basis for future development of reliable local PTH delivery protocols. Analyses of PDL of extracted human teeth as well as cultured human PDL cells demonstrated strong expression of PTH-receptor-1 by immune fluorescencecytochemistry/histochemistry. To examine the effect of short time continuous PTH treatment on PDL-cell osteogenic differentiation, PDL-cells were stimulated for 48h. Analyses for mRNA and protein expression of the early osteogenic marker alkaline-phosphatase revealed an enhanced expression. Pathways analyses mediating the PTH effect resulted in a similar effect when PDL-cells were stimulated with either the signal specific fragments lacking the PKA activating domain PTH(3-34), PTH(7-34), second-messenger-analogues PKC (PMA) or inhibitors for PKA (H8). Inhibition of the PKC-dependent pathway by stimulation with PTH(1-31), PKA second-messenger-analogue (forskolin) or PKA-inhibitor (RO-32 0432) abolished the PTH effect These data indicate abundant expression of PTH1R within the PDL and a stimulatory effect of short time continuous PTH on PDL cell differentiation towards an osteogenic phenotype and suggested local PTH application protocols as a possible treatment option in periodontal therapy. PMID- 23742979 TI - Scanning electron microscopic evidence for physical segmental boundaries in the anterior presomitic mesoderm. AB - The metameric pattern of the axial skeleton is established during embryogenesis by somite formation from the unsegmented paraxial mesoderm (presomitic mesoderm). Here, we have investigated the morphology of the anterior presomitic mesoderm of chick embryos using scanning electron microscopy. We found periodically arranged transverse clefts in the anterior region of the presomitic mesoderm. These gaps can be regarded as physical boundaries between prospective somites in the determined zone of the presomitic mesoderm. This study provides additional evidence suggesting that prospective somite boundaries are not only marked by defined zones of gene expression, but are also accompanied by changes in cellular morphology that give rise to identifiable morphological segments. PMID- 23742980 TI - Heterotopic and orthotopic autologous chondrocyte implantation using a minipig chondral defect model. AB - Implantation of non-articular (heterotopic) chondrocyte-based implants might be an alternative approach to articular cartilage repair. This strategy could be helpful in cases in which there are no or too few articular chondrocytes available. Therefore, this study was undertaken to compare joint cartilage defect healing in the minipig model after implantation of heterotopic auricular and orthotopic articular chondrocytes. Poly-glycolic acid (PGA) associated three dimensional (3D) constructs were prepared culturing autologous minipig-derived articular and auricular chondrocytes for 7 days in a dynamic culture system. Chondrocyte PGA constructs were implanted into 8mm diameter and ~1.1mm deep chondral defects within the medial and lateral condyles of the minipig knee joints. Empty defects served as controls for assessment of the intrinsic healing response. Defect healing was monitored 6 months post implantation using a macroscopic and microscopic score system and biomechanical analysis. Neo cartilage formation could be observed in the PGA constructs seeded with articular and auricular chondrocytes in vivo. The defect healing did not significantly differ at the macroscopic and histological level in response to implantation of either autologous articular or auricular chondrocytes seeded constructs compared with the empty defects. Although the differences were not significant, the auricular chondrocytes-based implants led to a slightly inferior repair quality at the macroscopic level, but a histologically superior healing response when compared with the empty defect group. However, biomechanical analysis revealed a higher stiffness in repair tissues produced by auricular chondrocyte implantation compared with the other groups. Deduced from these results, articular chondrocytes represent the preferable cell source for implantation. PMID- 23742981 TI - Development of the oxytalan fiber system in the periodontal space of rat incisors. AB - The present study clarifies developmental organization of the oxytalan fiber system in the periodontal space of both the enamel (labial) and cementum (lingual) sides of rat incisors. The number of oxytalan fibers per unit area (MUm(2)) was counted in rat incisors at stages of embryonic day 20 (E20) to postnatal day 35 (P35). Oxytalan fibers in the periodontal space of the enamel side were apt to decrease in number during the postnatal period, whereas their number remained almost unchanged on the cementum side during the developmental period. When the incisor emerged through the gum at P11, thinner oxytalan fibers distributed in the apical growing periodontium of the cementum side seemed to be fused with one another to become thicker fibers as has been reported for rat molars (Inoue et al., 2012). Thus, the oxytalan fiber system in the periodontal space represented significant differences in its distributional density between the enamel and cementum sides after E23. At the stage of P35, oxytalan fibers presented significantly denser distribution in all territories of the periodontal ligament of the cementum side versus the enamel side. The present findings claim that the oxytalan fiber system might bind the tooth to the periodontal ligament and provide equilibrium of vascular system and control of blood flow in the periodontal ligament of the cementum side, while it might exclusively regulate the high level of physiologically adapted vasculature in the periodontal space of the enamel side. PMID- 23742982 TI - iAnn: an event sharing platform for the life sciences. AB - SUMMARY: We present iAnn, an open source community-driven platform for dissemination of life science events, such as courses, conferences and workshops. iAnn allows automatic visualisation and integration of customised event reports. A central repository lies at the core of the platform: curators add submitted events, and these are subsequently accessed via web services. Thus, once an iAnn widget is incorporated into a website, it permanently shows timely relevant information as if it were native to the remote site. At the same time, announcements submitted to the repository are automatically disseminated to all portals that query the system. To facilitate the visualization of announcements, iAnn provides powerful filtering options and views, integrated in Google Maps and Google Calendar. All iAnn widgets are freely available. AVAILABILITY: http://iann.pro/iannviewer CONTACT: manuel.corpas@tgac.ac.uk. PMID- 23742983 TI - REDItools: high-throughput RNA editing detection made easy. AB - SUMMARY: The reliable detection of RNA editing sites from massive sequencing data remains challenging and, although several methodologies have been proposed, no computational tools have been released to date. Here, we introduce REDItools a suite of python scripts to perform high-throughput investigation of RNA editing using next-generation sequencing data. AVAILABILITY AND IMPLEMENTATION: REDItools are in python programming language and freely available at http://code.google.com/p/reditools/. CONTACT: ernesto.picardi@uniba.it or graziano.pesole@uniba.it SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23742984 TI - Selection of human tissue-specific elementary flux modes using gene expression data. AB - MOTIVATION: The analysis of high-throughput molecular data in the context of metabolic pathways is essential to uncover their underlying functional structure. Among different metabolic pathway concepts in systems biology, elementary flux modes (EFMs) hold a predominant place, as they naturally capture the complexity and plasticity of cellular metabolism and go beyond predefined metabolic maps. However, their use to interpret high-throughput data has been limited so far, mainly because their computation in genome-scale metabolic networks has been unfeasible. To face this issue, different optimization-based techniques have been recently introduced and their application to human metabolism is promising. RESULTS: In this article, we exploit and generalize the K-shortest EFM algorithm to determine a subset of EFMs in a human genome-scale metabolic network. This subset of EFMs involves a wide number of reported human metabolic pathways, as well as potential novel routes, and constitutes a valuable database where high throughput data can be mapped and contextualized from a metabolic perspective. To illustrate this, we took expression data of 10 healthy human tissues from a previous study and predicted their characteristic EFMs based on enrichment analysis. We used a multivariate hypergeometric test and showed that it leads to more biologically meaningful results than standard hypergeometric. Finally, a biological discussion on the characteristic EFMs obtained in liver is conducted, finding a high level of agreement when compared with the literature. PMID- 23742985 TI - Automated design of paralogue ratio test assays for the accurate and rapid typing of copy number variation. AB - MOTIVATION: Genomic copy number variation (CNV) can influence susceptibility to common diseases. High-throughput measurement of gene copy number on large numbers of samples is a challenging, yet critical, stage in confirming observations from sequencing or array Comparative Genome Hybridization (CGH). The paralogue ratio test (PRT) is a simple, cost-effective method of accurately determining copy number by quantifying the amplification ratio between a target and reference amplicon. PRT has been successfully applied to several studies analyzing common CNV. However, its use has not been widespread because of difficulties in assay design. RESULTS: We present PRTPrimer (www.prtprimer.org) software for automated PRT assay design. In addition to stand-alone software, the web site includes a database of pre-designed assays for the human genome at an average spacing of 6 kb and a web interface for custom assay design. Other reference genomes can also be analyzed through local installation of the software. The usefulness of PRTPrimer was tested within known CNV, and showed reproducible quantification. This software and database provide assays that can rapidly genotype CNV, cost effectively, on a large number of samples and will enable the widespread adoption of PRT. AVAILABILITY: PRTPrimer is available in two forms: a Perl script (version 5.14 and higher) that can be run from the command line on Linux systems and as a service on the PRTPrimer web site (www.prtprimer.org). PMID- 23742986 TI - Zyxin regulates cell migration and differentiation in EMT during chicken AV valve morphogenesis. AB - During heart valve development, epithelial-mesenchymal transformation (EMT) is a key process for valve formation. EMT leads to the generation of mesenchymal cells that will eventually become the interstitial cells (fibroblasts) of the mature valve. During EMT, cell architecture and motility change markedly; significant changes are also observed in various signaling pathways. Here we systematically examined the expression, localization, and function of zyxin, a focal adhesion protein, in EMT during atrioventricular (AV) valve morphogenesis. Expression and localization studies showed that zyxin was expressed in the AV canal region during crucial stages of valve development. An in vitro 3D collagen gel culture system was used to determine zyxin function either after siRNA gene knockdown or after overexpression. Our studies revealed that zyxin overexpression inhibited endocardial cell migration and cell differentiation and also led to a decrease in the number of migrating mesenchymal cells. Moreover, correlative cytoskeletal changes were apparent in response to both overexpression and knockdown treatments. Thus, zyxin appears to play a role as a regulator of cell migration and differentiation during EMT in chicken AV valve formation. PMID- 23742988 TI - Age-related CXC chemokine receptor-4-deficiency impairs osteogenic differentiation potency of mouse bone marrow mesenchymal stromal stem cells. AB - Cysteine (C)-X-C chemokine receptor-4 (CXCR4) is the primary transmembrane receptor for stromal cell-derived factor-1 (SDF-1). We previously reported in mouse or human bone marrow-derived mesenchymal stromal stem cells (BMSCs) that deleting or antagonizing CXCR4 inhibits bone morphogenetic protein-2 (BMP2) induced osteogenic differentiation. The goal of this study was to determine whether CXCR4-deficiency in BMSCs is an age-related effect in association with impaired osteogenic differentiation potency of aged BMSCs. Using BMSCs derived from C57BL/6J wild type mice at ages ranging from 3 to 23 months old, we detected decreased CXCR4 mRNA and protein expression as well as SDF-1 secretion with advancing aging. Moreover, CXCR4-deficient BMSCs from elderly vs. young mice exhibited impaired osteogenic differentiation in response to BMP2 stimulation or when cultured in dexamethasone (Dex)-containing osteogenic medium, evidenced by decreased alkaline phosphatase activity, osteocalcin synthesis, and calcium deposition (markers for immature and mature osteoblasts). Mechanistically, impaired BMP2- or Dex-osteoinduction in BMSCs of elderly mice was mediated by inhibited phosphorylation of intracellular R-Smads and Erk1/2 or Erk1/2 and p38 proteins, and decreased Runx2 and Osx expression (osteogenesis "master" regulators) were also detected. Furthermore, adenovirus-mediated repair of CXCR4 expression in BMSCs of elderly mice restored their osteogenic differentiation potentials to both BMP2 treatment and osteogenic medium. Collectively, our results demonstrate for the first time that CXCR4 expression in mouse BMSCs declines with aging, and this CXCR4-deficiency impairs osteogenic differentiation potency of aged BMSCs. These findings provide novel insights into mechanisms underlying age-related changes in BMSC-osteogenesis, and will potentiate CXCR4 as a therapeutic target to improve BMSC-based bone repair and regeneration in broad orthopedic situations. PMID- 23742989 TI - Mechanism of the dehydrogenase reaction of DmpFG and analysis of inter-subunit channeling efficiency and thermodynamic parameters in the overall reaction. AB - The bifunctional, microbial enzyme DmpFG is comprised of two subunits: the aldolase, DmpG, and the dehydrogenase, DmpF. DmpFG is of interest due to its ability to channel substrates between the two spatially distinct active sites. While the aldolase is well studied, significantly less is known about the dehydrogenase. Steady-state kinetic measurements of the reverse reaction of DmpF confirmed that the dehydrogenase uses a ping-pong mechanism, with substrate inhibition by acetyl CoA indicating that NAD(+)/NADH and CoA/acetyl CoA bind to the same site in DmpF. The Km of DmpF for exogenous acetaldehyde as a substrate was 23.7 mM, demonstrating the necessity for the channel to deliver acetaldehyde directly from the aldolase to the dehydrogenase active site. A channeling assay on the bifunctional enzyme gave an efficiency of 93% indicating that less than 10% of the toxic acetaldehyde leaks out of the channel into the bulk media, prior to reaching the dehydrogenase active site. The thermodynamic activation parameters of the reactions catalyzed by the aldolase, the dehydrogenase and the DmpFG complex were determined. The Gibb's free energy of activation for the dehydrogenase reaction was lower than that obtained for the full DmpFG reaction, in agreement with the high kcat obtained for the dehydrogenase reaction in isolation. Furthermore, although both the DmpF and DmpG reactions occur with small, favorable entropies of activation, the full DmpFG reaction occurs with a negative entropy of activation. This supports the concept of allosteric structural communication between the two enzymes to coordinate their activities. PMID- 23742987 TI - Clinical and economic evaluation of laparoscopic surgery compared with medical management for gastro-oesophageal reflux disease: 5-year follow-up of multicentre randomised trial (the REFLUX trial). AB - BACKGROUND: Despite promising evidence that laparoscopic fundoplication provides better short-term relief of gastro-oesophageal reflux disease (GORD) than continued medical management, uncertainty remains about whether benefits are sustained and outweigh risks. OBJECTIVE: To evaluate the long-term clinical effectiveness, cost-effectiveness and safety of laparoscopic surgery among people with GORD requiring long-term medication and suitable for both surgical and medical management. DESIGN: Five-year follow-up of a randomised trial (with parallel non-randomised preference groups) comparing a laparoscopic surgery-based policy with a continued medical management policy. Cost-effectiveness was assessed alongside the trial using a NHS perspective for costs and expressing health outcomes in terms of quality-adjusted life-years (QALYs). SETTING: Follow up was by annual postal questionnaire and selective hospital case notes review; initial recruitment in 21 UK hospitals. PARTICIPANTS: Questionnaire responders among the 810 original participants. At entry, all had documented evidence of GORD and symptoms for > 12 months. Questionnaire response rates (years 1-5) were from 89.5% to 68.9%. INTERVENTIONS: Three hundred and fifty-seven participants were recruited to the randomised comparison (178 randomised to surgical management and 179 randomised to continued medical management) and 453 to the preference groups (261 surgical management and 192 medical management). The surgeon chose the type of fundoplication. MAIN OUTCOME MEASURES: Primary: disease specific outcome measure (the REFLUX questionnaire); secondary: Short Form questionnaire-36 items (SF-36), European Quality of Life-5 Dimensions (EQ-5D), NHS resource use, reflux medication, complications. RESULTS: The randomised groups were well balanced. By 5 years, 63% in the randomised surgical group and 13% in the randomised medical management group had received a total or partial wrap fundoplication (85% and 3% in the preference groups), with few perioperative complications and no associated deaths. At 1 year (and 5 years) after surgery, 36% (41%) in the randomised surgical group - 15% (26%) of those who had surgery - were taking proton pump inhibitor medication compared with 87% (82%) in the randomised medical group. At each year, differences in the REFLUX score significantly favoured the randomised surgical group (a third of a SD; p< 0.01 at 5 years). SF-36 and EQ-5D scores also favoured surgery, but differences attenuated over time and were generally not statistically significant at 5 years. The worse the symptoms at trial entry, the larger the benefit observed after surgery. Those randomised to medical management who subsequently had surgery had low baseline scores that markedly improved after surgery. Following fundoplication, 3% had surgical treatment for a complication and 4% had subsequent reflux-related operations - most often revision of the wrap. Dysphagia, flatulence and inability to vomit were similar in the two randomised groups. The economic analysis indicated that surgery was the more cost-effective option for this patient group. The incremental cost-effectiveness ratio for surgery in the base case was L7028 per additional QALY; these findings were robust to changes in approaches and assumptions. The probability of surgery being cost-effective at a threshold of L20,000 per additional QALY was > 0.80 for all analyses. CONCLUSIONS: After 5 years, laparoscopic fundoplication continues to provide better relief of GORD symptoms with associated improved health-related quality of life. Complications of surgery were uncommon. Despite being initially more costly, a surgical policy is highly likely to be cost-effective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15517081. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 22. See the HTA programme website for further project information. PMID- 23742990 TI - Discrimination of cultivated silk and wild silk by conventional instrumental analyses. AB - In Japan, recent trends have seen wild silk preferred over cultivated silk because of its texture. Some cases of fraud have occurred where cultivated silk garments are sold as wild silk. Samples from these cases, morphological observation using light microscope and polarized microscope have been conducted in forensic science laboratories. Sometimes scanning electron microscopy was also carried out. However, the morphology of silk shows quite wide variation, which makes it difficult to discriminate wild and cultivated silks by this method. In this report, silk discrimination was investigated using conventional instrumental analyses commonly available in forensic laboratories, such as Fourier-transfer infrared spectrometry (FT-IR), pyrolysis-gas chromatography/mass spectrometry (pyr-GC/MS) and differential thermal analysis (DTA). By FT-IR, cultivated and wild silk gave similar infrared spectra, but wild silk had a characteristic peak at 965 cm(-1) from the deformation vibration of the carbon-carbon double bond of the indole ring. Comparison of the pyrograms of cultivated and wild silk showed that wild silk had large indole and skatole peaks that cultivated silk did not, and these peaks might arise from tryptophan. The results of thermogravimetry/DTA showed that the endothermic peak was about 40 degrees C higher for wild silk than for cultivated silk. Using a combination of these results, cultivated and wild silk could be discriminated by common forensic instrumental techniques. PMID- 23742991 TI - An electrochemiluminescence assay for analysis of rabies virus glycoprotein content in rabies vaccines. AB - Vaccine potency testing is necessary to evaluate the immunogenicity of inactivated rabies virus (RABV) vaccine preparations before human or veterinary application. Currently, the NIH test is recommended by the WHO expert committee to evaluate RABV vaccine potency. However, numerous disadvantages are inherent concerning cost, number of animals and biosafety requirements. As such, several in vitro methods have been proposed for the evaluation of vaccines based on RABV glycoprotein (G) quality and quantity, which is expected to correlate with vaccine potency. In this study an antigen-capture electrochemiluminescent (ECL) assay was developed utilizing anti-RABV G monoclonal antibodies (MAb) to quantify RABV G. One MAb 2-21-14 was specific for a conformational epitope so that only immunogenic, natively folded G was captured in the assay. MAb 2-21-14 or a second MAb (62-80-6) that binds a linear epitope was used for detection of RABV G. Vaccine efficacy was also assessed in vivo using pre-exposure vaccination of mice. Purified native RABV G induced a RABV neutralizing antibody (rVNA) response with a geometric mean titer of 4.2IU/ml and protected 100% of immunized mice against RABV challenge, while an experimental vaccine with a lower quality and quantity of G induced a rVNA titer<0.05IU/ml and protected <50% of immunized mice. These preliminary results support the hypothesis that in vivo immunogenicity may be predicted from the in vitro measurement of RABV G using an ECL assay. Based upon these results, the ECL assay may have utility in replacement of the NIH test. PMID- 23742992 TI - The case for Zostavax vaccination in systemic lupus erythematosus. PMID- 23742993 TI - A recombinant measles vaccine expressing chikungunya virus-like particles is strongly immunogenic and protects mice from lethal challenge with chikungunya virus. AB - Chikungunya virus (CHIKV), a mosquito-transmitted alphavirus, recently reemerged in the Indian Ocean, India and Southeast Asia, causing millions of cases of severe polyarthralgia. No specific treatment to prevent disease or vaccine to limit epidemics is currently available. Here we describe a recombinant live attenuated measles vaccine (MV) expressing CHIKV virus-like particles comprising capsid and envelope structural proteins from the recent CHIKV strain La Reunion. Immunization of mice susceptible to measles virus induced high titers of CHIKV antibodies that neutralized several primary isolates. Specific cellular immune responses were also elicited. A single immunization with this vaccine candidate protected all mice from a lethal CHIKV challenge, and passive transfer of immune sera conferred protection to naive mice. Measles vaccine is one of the safest and most effective human vaccines. A recombinant MV-CHIKV virus could make a safe and effective vaccine against chikungunya that deserves to be further tested in human trials. PMID- 23742994 TI - Development of a simple, rapid, sensitive, high-throughput luciferase reporter based microneutralization test for measurement of virus neutralizing antibodies following Respiratory Syncytial Virus vaccination and infection. AB - We have established a new reporter gene-based RSV neutralization test using Renilla luciferase. The RSV-Luciferase Neutralization Test (RSV-Luc-NeuT) is a simple, rapid, high throughput, and less labor intensive functional serological assay than the traditional RSV-PRNT, capable of measuring a broad range of anti RSV neutralizing antibodies targeting both RSV-F and RSV-G proteins. Specificity and sensitivity of the RSV-Luc-NeuT are comparable to the RSV-PRNT. Panels of pre vaccination and post-vaccination animal sera, monoclonal antibodies and animal polyclonal anti-RSV sera confirmed assay specificity. A panel of 60 human sera demonstrated high assay sensitivity for measurement of RSV neutralizing antibodies that strongly correlated with the RSV-PRNT titers (R(2)=0.864). Neutralization in the presence of guinea pig complement (GPC) increased PRNT titers more than the RSV-Luc-NeuT neutralizing antibody titers for these human sera. This newly developed simple, high throughput, RSV-Luc-NeuT could be easily automated and applied in measurement of RSV neutralization titers in large vaccine trials. PMID- 23742995 TI - A novel method for evaluating natural and vaccine induced serological responses to Bordetella pertussis antigens. AB - We studied the time course of serum IgG antibodies against 3 different pertussis vaccine antigens: PT (pertussis toxin), FHA (filamentous hemagglutinin), Prn (pertactin) in sera from individuals vaccinated with four different pertussis vaccines at 4 years of age: (N=44, 44, 23 and 23, respectively,) and compared the responses to/after natural infection with Bordetella pertussis (N=44, age 1-8 years). These longitudinal data were analyzed with a novel method, using a mathematical model to describe the observed responses, and their variation among subjects. This allowed us to estimate biologically meaningful characteristics of the serum antibody response, like peak level and decay rate, and to compare these among natural infections and vaccine responses. Compared to natural infection, responses to PT after vaccination with the tested vaccines are smaller in magnitude and tend to decay slightly faster. When present in vaccines, FHA and Prn tend to produce high peak levels, higher than those in naturally infected patients, but these decay faster. As expected, the Dutch whole cell vaccine produced lower antibody responses than the acellular vaccines. This model allows a better comparison of the kinetics of vaccine induced antibody responses and after natural infection over a long follow up period. PMID- 23742996 TI - Characterization of chemically defined poly-N-isopropylacrylamide based copolymeric adjuvants. AB - PNiPAAm is a thermo-responsive polymer with an adjuvant activity. To identify the minimal chemical structure present within PNiPAAm responsible for its adjuvant property, three different constituent polymers with specific functional groups were synthesized through free radical reaction and tested their adjuvant potential along with PNiPAAm. Among them, polymer with isopropyl attached to an amide showed maximal adjuvant activity in rodents followed by polymer with amide or ketone functional groups. However, secondary amine containing polymer did not show any adjuvant activity. In addition, to improve the adjuvant properties of PNiPAAm, we incorporated an affinity ligand, boronate. At first, we synthesized and characterized the dual responsive copolymers PNiPAAm-co-VPBA and PNiPAAm-co VPBA-co-DMAEMA. Biocompatibility of these copolymers was confirmed both in vitro and in vivo. Mice injected with these copolymers mixed with collagen (CII) developed significant levels of anti-CII antibodies comprising of all the major IgG subclasses and an increased T cell activation. At the injection site, massive infiltration of immune cells was observed. However, only PNiPAAm-co-VPBA-co DMAEMA-CII induced arthritis in mice after injection of 0.5M fructose confirming the importance of effective release of CII from the polymer for its adjuvant activity. Thus, a fine balance of hydrophobicity and hydrophilicity promotes adjuvant properties and continuous release of antigen, in this case CII, from polymer is essential for its adjuvant activity. PMID- 23742997 TI - Immunogenicity and protective efficacy of cold-adapted X-31 live attenuated pre pandemic H5N1 influenza vaccines. AB - Despite global efforts to control influenza viruses, they have taken a heavy toll on human public health worldwide. Among particular threats is highly pathogenic avian H5N1 influenza virus (HPAI) due to not only its high mortality in humans but also possible human-to-human transmission either through reassortment with other human influenza viruses such as 2009 pandemic H1N1 influenza virus, or by genetic mutations. With the aim of developing effective vaccines against the H5N1 viruses, we generated two live attenuated H5N1 vaccine candidates against A/Indonesia/05/2005 (clade 2.1) and A/chicken/Korea/ES/2003 (clade 2.5) strains, in the genetic background of the cold-adapted donor strain of X-31. In mice, a single dose of immunization with each of the two vaccines was highly immunogenic inducing high titers of serum viral-neutralizing and hemagglutinin-inhibiting antibodies against the homologous H5N1 strain. Furthermore, significant levels of cross-clade antibody responses were induced by the vaccines, suggesting a broad spectrum cross-reactivity against the heterologous H5N1 strains. The immunizations provided solid protections against heterologous lethal challenges with H5N2 virus, significantly reducing the morbidity and challenge virus replications in the respiratory tracts. The robustness of the antibody responses against both the homologous and heterologous strains, together with efficient protection against the lethal H5N2 challenge, strongly support the protection against wild type H5N1 infections. These results could serve as an experimental basis for the development of safe and effective H5N1 pre-pandemic vaccines while further addressing the biosecurity concerns associated with H5N1 HPAI. PMID- 23742998 TI - Oligomannose-coated liposome-entrapped dense granule protein 7 induces protective immune response to Neospora caninum in cattle. AB - Neospora caninum is an intracellular protozoan parasite that causes abortion in cows. Vaccination is an important strategy for control of neosporosis, and a safe and effective vaccine suitable for cattle is required. Dense granule protein 7 of N. caninum (NcGRA7) is a secretory protein with high antigenicity in hosts. We demonstrated previously that NcGRA7 entrapped in liposomes coated with mannotriose (M3-NcGRA7) could induce a parasite-specific T-helper type 1 immune response and produce humoral antibodies that resulted in increased offspring survival and decreased infection in the brains of mice dams. In the present study, the efficacy of M3-NcGRA7 as a vaccine candidate against N. caninum has been evaluated in cattle (n=12). Cattle were immunized with M3-NcGRA7 containing 50 MUg (n=4) or 200 MUg NcGRA7 (n=4) subcutaneously twice with a 4-week interval and all cattle including the non-immunized controls (n=4) were inoculated with 10(7) tachyzoites of Nc-1 strain 27 days after the second immunization and euthanized at 85-87 days post infection (dpi). In immunized cattle, NcGRA7 specific antibody production and IFN-gamma production in PBMC was induced before challenge. At 3 dpi, body temperature and concentration of serum IFN-gamma tended to be higher in control cattle than in the immunized cattle. Furthermore, the parasite load in the brain significantly decreased in cattle immunized with 50 MUg M3-NcGRA7 compared with controls. These results suggest that M3-NcGRA7 can induce protective immune responses to N. caninum tachyzoites in cattle, which could lead to practical application of safe and effective subunit vaccines. PMID- 23742999 TI - The C-terminal flanking peptide of progastrin induces gastric cell apoptosis and stimulates colonic cell division in vivo. AB - Progastrin (PG) is processed into a number of smaller peptides including amidated gastrin (Gamide), non-amidated glycine-extended gastrin (Ggly) and the C-terminal flanking peptide (CTFP). Several groups have reported that PG, Gamide and Ggly are biologically active in vitro and in vivo, and are involved in the development of gastrointestinal cancers. CTFP is bioactive in vitro but little is known of its effects in vivo. This study investigated the bioactivity of CTFP in vivo in normal tissues using gastrin deficient (GASKO) mice and in two mouse models of cancer (SCID mice bearing xenograft tumors expressing normal or knocked-down levels of gastrin and a mouse model of hepatic metastasis). As with Ggly, CTFP treatment stimulated colonic proliferation in GASKO mice compared to control. CTFP also significantly increased apoptosis in the gastric mucosa of male GASKO mice. CTFP did not appear to effect xenograft growth or the incidence of liver metastases. This is the first demonstration that CTFP has specific biological activity in vivo in the colon and stomach. PMID- 23743000 TI - [Management of arterial hypertension in adults: 2013 guidelines of the French Society of Arterial Hypertension]. AB - To improve the management of hypertension in the French population, the French Society of Hypertension has decided to update the national guidelines with the following characteristics: usefulness for practice, synthetic form, good readability, comprehensive writing for non-doctors, emphasizing the role of patient education in the management of hypertension, wide dissemination to health professionals and the population of hypertensive subjects, impact assessment among health professionals and the public health goals. These guidelines include the following 15 recommendations, divided in three chapters, according to the timing of the medical management. BEFORE STARTING TREATMENT: 1. Confirm the diagnosis, with blood pressure measurements outside the doctor's office. 2. Implement lifestyle measures. 3. Conduct an initial assessment. 4. Arrange a dedicated information and hypertension announcement consultation. INITIAL TREATMENT PLAN (FIRST 6 MONTHS): 5. MAIN OBJECTIVE: control of blood pressure in the first 6 months (SBP: 130-139 and DBP<90 mmHg). 6. Favour the five classes of antihypertensive agents that have demonstrated prevention of cardiovascular complications in hypertensive patients. 7. Individualized choice of the first antihypertensive treatment, taking into account persistence. 8. Promote the use of (fixed) combination therapy in case of failure of monotherapy. 9. Monitor safety. LONG-TERM CARE PLAN: 10. Uncontrolled hypertension at 6 months despite appropriate triple-drug treatment should require specialist's opinion after assessment of compliance and confirmation of ambulatory hypertension. 11. In case of controlled hypertension, visits every 3 to 6 months. 12. Track poor adherence to antihypertensive therapy. 13. Promote and teach how to practice home blood pressure measurement. 14. After 80 years, change goal BP (SBP<150 mmHg) without exceeding three antihypertensive drugs. 15. After cardiovascular complication, treatment adjustment with maintenance of same blood pressure goal. We hope that a vast dissemination of these simple guidelines will help to improve hypertension control in the French population from 50 to 70 %, an objective expected to be achieved in 2015 in France. PMID- 23743001 TI - Stimulus size for perimetry in patients with glaucoma. PMID- 23743002 TI - National trends in pelvic inflammatory disease among adolescents in the emergency department. AB - PURPOSE: In 2002, the Centers for Disease Control and Prevention (CDC) broadened the pelvic inflammatory disease (PID) diagnostic criteria to increase detection and prevent serious sequelae of untreated PID. The impact of this change on PID detection is unknown. Our objectives were to estimate trends in PID diagnosis among adolescent emergency department (ED) patients before and after the revised CDC definition and to identify factors associated with PID diagnoses. METHODS: We performed a retrospective repeated cross-sectional study using the National Hospital Ambulatory Medical Care Survey from 2000 to 2009 of ED visits by 14- to 21-year-old females. We calculated national estimates of PID rates and performed multivariable logistic regression analyses and tests of trends. RESULTS: During 2000-2009, of the 77 million female adolescent ED visits, there were an estimated 704,882 (95% confidence interval [CI], 571,807-837,957) cases of PID. After the revised criteria, PID diagnosis declined from 5.4 cases per 1,000 United States adolescent females to 3.9 cases per 1,000 (p = .03). In a multivariable model, age >=17 years (odds ratio, 2.14; 95% CI, 1.25-3.64) and black race (odds ratio, 2.04; 95% CI, 1.36-3.07) were associated with PID diagnosis. CONCLUSIONS: Despite broadened CDC diagnostic criteria, PID diagnoses did not increase over time. This raises concern about awareness and incorporation of the new guidelines into clinical practice. PMID- 23743004 TI - Human resource inequalities at the base of India's public health care system. AB - This paper examines the extent of inequalities in human resource provision at India's Heath Sub-Centres (HSC)--first level of service provision in the public health system. 'Within state' inequality explained about 71% and 'between state' inequality explained the remaining 29% of the overall inter-HSC inequality. The Northern states had a lower health worker share relative to the extent of their HSC provision. Contextual factors that contributed to 'between' and 'within' district inequalities were the percentages of villages connected with all-weather roads and having primary schools. Analysis demonstrates a policy and programming need to address 'within State' inequalities as a priority. PMID- 23743003 TI - Receipt of sexual health information from parents, teachers, and healthcare providers by sexually experienced U.S. adolescents. AB - OBJECTIVE: To describe the extent to which sexually experienced adolescents in the United States receive sexual health information (SHI) from multiple of three sources: parents, teachers, and healthcare providers. DESIGN: Descriptive analysis. SETTING: 2006-2010 National Survey of Family Growth. PARTICIPANTS: Heterosexually experienced, unmarried/non-cohabiting females (n = 875) and males (n = 1,026) ages 15-19 years. MAIN OUTCOME MEASURES: Self-reported receipt of birth control, sexually transmitted infection/human immunodeficiency virus (STI/HIV), and condom information from parents, teachers, and healthcare providers. RESULTS: Parent and teacher SHI sources were reported by 55% and 43% of sexually experienced female and male adolescents, respectively, for birth control information; and by 59% and 66%, respectively, for STI/HIV information. For sexually experienced adolescents reporting both parent and teacher sources, about one-third also reported healthcare provider as a source of birth control information, and one-quarter of females and one-third of males reported a healthcare provider as a source of STI/HIV information, respectively. For sexually experienced adolescents reporting no SHI from either parent or teacher sources, only one in ten reported healthcare providers as a source of birth control information, with a similar proportion reporting healthcare providers as a source of STI/HIV information. SHI receipt was found to vary by gender with more females than males reporting birth control information receipt from parents and teachers, and about one in six males reporting no birth control or condom information receipt from either source. CONCLUSIONS: Study findings highlight gaps in sexual health information receipt from parents, teachers, and healthcare providers among sexually experienced adolescents, as well as gender differences across information sources. PMID- 23743005 TI - Changes in smoking, sports participation and overweight: does neighborhood prevalence matter? AB - We investigated whether the prevalence of health-related behaviors and overweight in neighborhoods is associated with changes in smoking, sports participation and overweight over 13 years of follow-up in Dutch adults residing in 86 neighborhoods of Eindhoven in 1991. We showed that living in neighborhoods with a high prevalence of non-smoking, no sports participation and overweight increased the odds of quitting smoking, quitting sports and becoming overweight. After adjustments for age, gender, education and neighborhood deprivation this association remained significant for becoming overweight. Neighborhood prevalence of health-related behaviors and overweight appears to be a currently neglected but relevant determinant of changes in health-related behaviors. PMID- 23743006 TI - Amino acid residues in the N-terminal region of the BinB subunit of Lysinibacillus sphaericus binary toxin play a critical role during receptor binding and membrane insertion. AB - The binary toxin produced by Lysinibacillus sphaericus is composed of BinA and BinB subunits that work together in governing toxicity against mosquito larvae. BinA is proposed to be important for toxicity, whereas BinB has been shown to act as a specific receptor-binding component. The precise function of both subunits, however, is not well established. Here, we investigated the function of the N terminal region of BinB subunit initially by introducing triple alanine substitutions at positions 35PEI37 and 41FYN43. Both block mutations abolished the larvicidal activity. Single point mutations (P35A, E36A, I37A, F41A, Y42A, N43A) were generated in order to identify amino acids that are critical for the toxin activity. Mosquito-larvicidal activity was significantly reduced in P35A, E36A, F41A and Y42A mutants. However, these mutants retained ability to form in vitro interaction with the BinA counterpart. Immunohistochemistry analysis revealed that P35A, F41A and N43A bind to the larval midgut membrane at comparable levels to that of the wild type BinB. In contrast, greatly reduced binding activity was observed in the Y42A, suggesting an important role of this residue in receptor binding. Alanine substitution at P35 resulted in a marked decrease in membrane penetration, indicating its functional importance for the membrane insertion. These results suggest the important roles of the N-terminal region of BinB in both the receptor recognition and the membrane interaction. PMID- 23743007 TI - Simultaneous extraction of metabolome and lipidome with methyl tert-butyl ether from a single small tissue sample for ultra-high performance liquid chromatography/mass spectrometry. AB - A common challenge for scientists working with animal tissue or human biopsy samples is the limitation of material and consequently, the difficulty to perform comprehensive metabolic profiling within one experiment. Here, we present a novel approach to simultaneously perform targeted and non-targeted metabolomics as well as lipidomics from one small piece of liver or muscle tissue by ultra-high performance liquid chromatography/mass spectrometry (UHPLC/MS) following a methyl tert-butyl ether (MTBE)-based extraction. Equal relative amounts of the resulting polar and non-polar fractions were pooled, evaporated and reconstituted in the appropriate solvent for UHPLC/MS analysis. This mix was comparable or superior in yield and reproducibility to a standard 80% methanol extraction for the profiling of polar and lipophilic metabolites (free carnitine, acylcarnitines and FFA). The mix was also suitable for non-targeted metabolomics, an easy measure to increase the metabolite coverage by 30% relative to using the polar fraction alone. Lipidomics was performed from an aliquot of the non-polar fraction. This novel strategy could successfully be applied to one mouse soleus muscle with a dry weight of merely 2.5 mg. By enabling a simultaneous profiling of lipids and metabolites with mixed polarity while saving material for molecular, biochemical or histological analyses, our approach may open up new perspectives toward a comprehensive investigation of small, valuable tissue samples. PMID- 23743008 TI - Tunable secondary dimension selectivity in comprehensive two-dimensional gas chromatography. AB - In this paper two tunable two-dimensional gas chromatography setups are compared and described in which the secondary dimension consists of two different capillary columns coupled in series. In the first setup the selectivity of the second dimension can be tuned by adjusting the effective column length of the first secondary dimension column, simply by sliding it stepwise back or forward through the GC*GC modulator. In the second setup, in which the first secondary dimension column is installed in a separate GC-oven (oven-2), the overall selectivity of the second dimension can be tuned by adjusting the oven-2 temperature offset with respect to the main oven. The contribution of the first secondary dimension column to the overall secondary dimension separation can be decreased by applying a higher temperature offset. A real-life sample, the headspace of a coffee powder, was used to demonstrate the added value of tunable GC*GC by solving coelutions of some specific aroma compounds. Besides optimizing the overall GC*GC separation, by altering the second dimension column selectivity, these set-ups also offer enhanced possibilities for qualitative analysis. By stepwise altering the selectivity of the second dimension, classes of compounds showing similar retention behavior could be discriminated. PMID- 23743009 TI - Factors affecting the current status of transfusion medicine education in South Africa. AB - Education in transfusion medicine, aimed at clinical transfusion practice, is limited in most South African pre- and postgraduate medical training programs. A number of local and global factors impact on the need for and provision of transfusion medicine education programs in South Africa, which are discussed in this paper. A perspective is provided on the effects of issues such as global versus local training need, blood safety, appropriate use of blood in resource restrained environments, the presence or absence of national blood policies, standardization of training, medical migration and workforce diversity. Harnessing support for the development of training programs for medical doctors and new opportunities for developing a career in transfusion medicine are discussed. Commentary is also provided on online learning, social networking and integration of modern paradigms of learning, such as screencasting and online learning, into teaching programs. This article should provide anyone in medical education or program development, in particular in the field of transfusion medicine, with an indication of the factors that should be considered when embarking on such an endeavor. PMID- 23743010 TI - N-acylhomoserine lactone-degrading bacteria isolated from hatchery bivalve larval cultures. AB - Quorum sensing (QS) systems, which depend on N-acylhomoserine lactone (AHL) signal molecules, mediate the production of virulence factors in many pathogenic microorganisms. One hundred and forty-six bacterial strains, isolated from a bivalve hatchery, were screened for their capacity to degrade five synthetic AHLs [N-butyryl-DL-homoserine lactone (C4-HSL), N-hexanoyl-DL-homoserine lactone (C6 HSL), N-octanoyl-DL-homoserine lactone (C8-HSL), N-decanoyl-DL-homoserine lactone (C10-HSL) and N-dodecanoyl-DL-homoserine lactone (C12-HSL)] using well diffusion agar-plate assays with three biosensors, Chromobacterium violaceum CV026, C. violaceum VIR07 and Agrobacterium tumefaciens NTL4 (pZLR4). The results of these assays led to our choosing four strains (PP2-67, PP2-459, PP2-644 and PP2-663) that were able to degrade all five synthetic AHLs, thus showing a wide spectrum of quorum quenching (QQ) activity. We subsequently confirmed and measured the QQ activity of the four strains by high-performance liquid chromatography plus mass spectrometry analysis (HPLC-MS). One of the strains which showed the highest AHL degrading activity, PP2-459, identified as being a member of the genus Thalassomonas was chosen for further study. Finally, using thin-layer chromatography (TLC), we went on to confirm this strain's capacity to degrade the AHLs produced by other non-pathogenic and pathogenic bacteria not taxonomically related. PMID- 23743011 TI - A review of the neurological and neurosurgical implications of Down syndrome in children. AB - Down syndrome is the most commonly encountered chromosomal translation and has been associated with significant congenital abnormalities in various organ systems. Along with classic facial findings, it may involve the gastroenterologic, cardiac, ophthalmologic, endocrine, immunologic, orthopedic, or neurologic systems. With respect to the neurological system, a higher incidence of moyamoya, seizure disorders, strokes, and spinal ligamentous laxity has been described in these children. We have summarized the current available literature with respect to children who have Down syndrome and the varying neurological pathologic entities associated to help health care providers better understand these patients. PMID- 23743012 TI - Advice for families traveling to developing countries with young children. AB - Young children are most likely to travel to developing countries with their parents to visit relatives. Preparation for such travel must include careful counseling and optimal use of preventive vaccines and chemoprophylaxis. For infants and very young children, data defining safety and efficacy of these agents are often limited. However, accumulated experience suggests that young travelers may be managed similarly to older children and adults. PMID- 23743013 TI - Spermatogenesis recovery in protein-restricted rats subjected to a normal protein diet after weaning. AB - This study investigated the pre- and postnatal effects of protein restriction (8% vs 20% crude protein) on different parameters of spermatogenesis in adult rat offspring. Body and testis weights as well as the seminiferous tubular diameter were reduced in those animals that received the protein-restricted diet after weaning, although these parameters recovered when a 20% protein diet was offered subsequently. The numbers of spermatogonia, spermatocytes, spermatids and Leydig cells were reduced in undernourished animals, whilst the Sertoli cell number did not change. Prenatal programming effect was observed only in the spermatogonial or proliferative phase of spermatogenesis. However, the intake of the normal protein diet after weaning brought many of the testicular parameters evaluated back to normal in 70-day-old rats. A significant reduction of the meiotic index, Sertoli cell supporting capacity and spermatogenic efficiency was observed in animals subjected to protein undernutrition throughout their lives. The data presented show that protein restriction impairs the normal development of the testis in different ways, depending on the period during which the restriction was imposed, and the negative effects on spermatogenesis are more severe when undernutrition occurs from conception to adulthood; however, the return to a normal protein diet after weaning recovers the spermatogenic process. PMID- 23743014 TI - Cytogenetic analysis in 16-year follow-up study of a mother and fetus exposed in a radiation accident in Xinzhou, China. AB - In November 1992, a radiation accident occurred in Xinzhou, due to the collection by a farmer of an unused (60)Co source; 37 individuals were exposed to ionizing radiation. Three individuals died and the farmer's 19-weeks-pregnant wife suffered acute radiation symptoms. Conventional chromosome analysis, cytokinesis block micronuclei (CBMN) assay and fluorescence in situ hybridization (FISH) painting with three pairs of whole chromosome probes were used to analyze chromosomal aberrations for the pregnant female and her baby during the 16 years following the accident. The yields of dicentrics and rings (dic+r) continually declined between 41 days and 16 years after the accident. The frequency of binucleated MN also decreased over time for both mother and daughter. Sixteen years after exposure, the yields of dic+r and binucleated MN decreased to normal levels, but the reciprocal translocation frequencies remained elevated, for both mother and daughter. FISH results showed a decreasing yield of translocations with time. Based on the changes in maternal translocation frequency, the daughter's dose at the time of exposure was estimated as 1.82 (1.35-2.54)Gy. This was consistent with the clinical manifestations of severe mental retardation and low IQ score. FISH-based translocation analysis can be used for follow-up studies on accidental exposure and, after correction, for retrospective dose estimation for individuals prenatally exposed to radiation. PMID- 23743015 TI - Circulating bacterial-derived DNA fragments as a marker of systemic inflammation in peritoneal dialysis. AB - BACKGROUND: Endotoxemia is common in peritoneal dialysis (PD) patients, and circulating lipopolysaccharide (LPS) level is related to the degree of systemic inflammation and atherosclerosis. We hypothesize that circulating bacterial DNA, another microbial component, correlates with the degree of systemic inflammation and predicts the survival of new PD patients. METHODS: We measured the plasma bacterial DNA level in the archive blood samples of 300 consecutive new PD patients. The result was compared with serum C-reactive protein (CRP) level, patient survival and peritonitis-free survival. RESULTS: The average age was 57.8 +/- 12.1 years, average plasma bacterial DNA level 34.3 +/- 1.3 cycles and average follow-up 37.9 +/- 22.2 months. The plasma bacterial DNA level correlated with serum CRP (r = 0.565, P < 0.001) and LPS levels (r = 0.224, P = 0.029). At 36 months, the patient survival were 77.5, 78.3, 74.6 and 65.2% for plasma bacterial DNA level quartiles I, II, III and IV, respectively (log-rank test, P = 0.034). By multivariate analysis with the Cox proportional hazard model to adjust for confounders, the plasma bacterial DNA level had no independent effect. Similarly, peritonitis-free survival were 60.6, 59.8, 60.3 and 50.4% for plasma bacterial DNA level quartiles I, II, III and IV, respectively, at 36 months (P = 0.020), and the difference was not significant after adjusting for confounding factors. CONCLUSION: We found that the plasma bacterial DNA level correlated with the degree of systemic inflammatory state in PD patients. Although plasma bacterial DNA level seems to predict patient survival and peritonitis-free survival, the association disappears after adjusting for confounding factors. Further prospective studies are needed to delineate the role of plasma bacterial DNA as a prognostic marker of renal failure patients. PMID- 23743016 TI - Renal transplantation normalizes baroreflex sensitivity through improvement in central arterial stiffness. AB - BACKGROUND: In end-stage renal disease (ESRD) patients, the most common cause of mortality and morbidity are cardiovascular events. This could be attributed to the impaired baroreflex function observed in this group of patients. The effect of renal transplantation (RT) on the baroreflex sensitivity (BRS) in ESRD patients has been inadequately addressed. Therefore, we investigated baroreflex function and its relation to arterial stiffness indices and cardiovascular variability parameters (heart rate and blood pressure variability--HRV and BPV) in ESRD patients before and after transplantation to decipher the underlying mechanism of attenuated BRS in ESRD patients. METHODS: We studied 23 ESRD patients (mean age; 36 years) prospectively before and at 3 and 6 months after RT. Baroreflex function was determined by spontaneous method (sequence and spectral indices). Short-term HRV and BPV were assessed using power spectrum analysis of RR intervals and systolic blood pressure by frequency domain analysis. Arterial stiffness indices were assessed by carotid-femoral pulse-wave velocity (PWV), augmentation index (AI) and central pulse pressure using Sphygmocor Vx device (AtCor Medical, Australia). RESULTS: RT was associated with the normalization of BRS by 6 months. Arterial stiffness indices, such as AI and central pulse pressure, showed a significant reduction as early as 3 months after RT. PWV and frequency domain measures of HRV after RT did not show statistically significant changes except the LF/HF ratio which had a significant increase at 6 months when compared with baseline. Systolic BPV total power showed a significant reduction by 3 months after RT. CONCLUSIONS: Our data suggest that RT normalizes BRS in ESRD patients by 6 months which follows the improvement in the AI and central pulse pressure. PMID- 23743017 TI - Altering plasma sodium concentration rapidly changes blood pressure during haemodialysis. AB - BACKGROUND: Plasma sodium is increased following each meal containing salt. There is an increasing interest in the effects of plasma sodium concentration, and it has been suggested that it may have direct effects on blood pressure (BP) and possibly influences endothelial function. Experimental increases of plasma sodium concentration rapidly raise BP even when extracellular volume falls. METHODS: Ten patients with end-stage renal failure established on haemodialysis were studied during the first 2 h of dialysis without fluid removal during this period. They were randomized to receive haemodialysis with (i) dialysate sodium concentration prescribed to 135 mmol/L and (ii) 145 mmol/L in random order in a prospective, single-blinded crossover study. BP measurements and blood samples were taken every 30 min. RESULTS: Pre-dialysis sitting BP was 137/76 +/- 7/3 mmHg. Lower dialysate sodium concentration (135 mmol/L) reduced plasma sodium concentration [139.49 +/- 0.67 to 135.94 +/- 0.52 mmol/L (P < 0.001)], whereas plasma sodium concentration was not altered by higher dialysate sodium (145 mmol/L) (140.17 +/- 0.66 mmol/L at baseline to 140.72 +/- 0.43 mmol/L at 120 min). Systolic BP was lower with dialysate sodium concentration 135 mmol/L [area under the curve (AUC) 15823.50 +/- 777.15 (mmHg)min] compared with 145 mmol/L [AUC 17018.20 +/- 1102.17 (mmHg)min], mean difference 1194.70 +/- 488.41 (mmHg)min, P < 0.05. There was a significant positive relationship between change in plasma sodium concentration and change in systolic BP. This direct relationship suggests that a fall of 1 mmol/L in plasma sodium concentration would be associated with a 1.7 mmHg reduction in systolic BP (P < 0.05). CONCLUSIONS: The potential mechanism for the increase in BP seen with salt intake may be through small but significant changes in plasma sodium concentration. PMID- 23743018 TI - Serum creatinine level, a surrogate of muscle mass, predicts mortality in peritoneal dialysis patients. AB - BACKGROUND: In hemodialysis patients, higher serum creatinine (Cr) concentration represents larger muscle mass and predicts greater survival. However, this association remains uncertain in peritoneal dialysis (PD) patients. METHODS: In a cohort of 10 896 PD patients enrolled from 1 July 2001 to 30 June 2006, the association of baseline serum Cr level and change during the first 3 months after enrollment with all-cause mortality was examined. RESULTS: The cohort mean +/- SD age was 55 +/- 15 years old and included 52% women, 24% African-Americans and 48% diabetics. Compared with patients with serum Cr levels of 8.0-9.9 mg/dL, patients with serum Cr levels of <4.0 mg/dL and 4.0-5.9 mg/dL had higher risks of death {HR 1.36 [95% confidence interval (95% CI) 1.19-1.55] and 1.19 (1.08-1.31), respectively} whereas patients with serum Cr levels of 10.0-11.9 mg/dL, 12.0-13.9 mg/dL and >=14.0 mg/dL had lower risks of death (HR 0.88 [95% CI 0.79-0.97], 0.71 [0.62-0.81] and 0.64 [0.55-0.75], respectively) in the fully adjusted model. Decrease in serum Cr level over 1.0 mg/dL during the 3 months predicted an increased risk of death additionally. The serum Cr-mortality association was robust in patients with PD treatment duration of >=12 months, but was not observed in those with PD duration of <3 months. CONCLUSIONS: Muscle mass reflected in serum Cr level may be associated with survival even in PD patients. However, the serum Cr-mortality association is attenuated in the early period of PD treatment, suggesting competing effect of muscle mass versus residual renal function on mortality. PMID- 23743020 TI - The biological consequence of obesity on the kidney. AB - Obesity is a worldwide epidemic that is associated with several health issues, including kidney diseases. A specific kidney disease, referred to as obesity related glomerulopathy, has been described in earlier publications. Obesity can affect the prognosis of other types of kidney diseases. Body-weight reduction with caloric restriction is an essential therapy, although strictly controlling food intake coupled with an appropriate evaluation is challenging. Low birthweight can be an important factor for obesity and results in kidney dysfunction. In this review, we analyse the consequences of obesity on kidney prognosis and potential strategies for combating obesity-associated kidney injury. PMID- 23743019 TI - Association of segmental wall motion abnormalities occurring during hemodialysis with post-dialysis fatigue. AB - BACKGROUND: Post-dialysis fatigue (PDF) is a common, debilitating symptom that remains poorly understood. Cardiac wall motion abnormalities (WMAs) may worsen during dialysis, but it is unknown whether WMA are associated with PDF. METHODS: Forty patients were recruited from University of California San Francisco affiliated dialysis units between January 2010 and February 2011. Participants underwent echocardiograms before and during the last hour of 79 dialysis sessions. Myocardial segments were graded 1-4 by a blinded reviewer, with four representing the worst WMA, and the segmental scores were summed for each echocardiogram. Patients completed questionnaires about their symptoms. Severe PDF (defined as lasting >2 h after dialysis) was analysed using a generalized linear model with candidate predictors including anemia, intradialytic hemodynamics and cardiac function. RESULTS: Forty-four percent of patients with worsened WMA (n=9) had severe PDF, compared with 13% of patients with improved or unchanged WMA (P = 0.04). A one-point increase in the WMA score during dialysis was associated with a 10% higher RR of severe PDF [RR: 1.1, 95% CI (1.1, 1.2), P < 0.001]. After multivariable adjustment, every point increase in the WMA score was associated with a 2-fold higher risk of severe PDF [RR: 1.9, 95% CI (1.4, 2.6), P < 0.001]. History of depression was associated with severe PDF after adjustment for demographics and comorbidities [RR: 3.4, 95% CI (1.3, 9), P = 0.01], but anemia, hemodynamics and other parameters of cardiac function were not. CONCLUSIONS: Although cross-sectional, these results suggest that some patients may experience severe PDF as a symptom of cardiac ischemia occurring during dialysis. PMID- 23743021 TI - T-type Ca2+ channels regulate the exit of cardiac myocytes from the cell cycle after birth. AB - T-type Ca(2+) channels (TTCCs) are expressed in the fetal heart and then disappear from ventricular myocytes after birth. The hypothesis examined in this study was the alpha1G TTCCs' influence in myocyte maturation and their rapid withdrawal from the cell cycle after birth. METHODS: Cardiac myocytes were isolated from neonatal and adult wild type (WT), alpha1G-/- and alpha1G over expressing (alpha1GDT) mice. Bromodeoxyuridine (BrdU) uptake, myocyte nucleation, cell cycle analysis, and T-type Ca(2+) currents were measured. RESULTS: All myocytes were mono-nucleated at birth and 35% of WT myocytes expressed functional TTCCs. Very few neonatal myocytes had functional TTCCs in alpha1G-/- hearts. By the end of the first week after birth no WT or alpha1G-/- had functional TTCCs. During the first week after birth about 25% of WT myocytes were BrdU+ and became bi-nucleated. Significantly fewer alpha1G-/- myocytes became bi-nucleated and fewer of these myocytes were BrdU+. Neonatal alpha1G-/- myocytes were also smaller than WT. Adult WT and alpha1G-/- hearts were similar in size, but alpha1G /- myocytes were smaller and a greater % were mono-nucleated. alpha1G over expressing hearts were smaller than WT but their myocytes were larger. CONCLUSIONS: The studies performed show that loss of functional TTCCs is associated with bi-nucleation and myocyte withdrawal from the cell cycle. Loss of alpha1G TTCCs slowed the transition from mono- to bi-nucleation and resulted in an adult heart with a greater number of small cardiac myocytes. These results suggest that TTCCs are involved in the regulation of myocyte size and the exit of myocytes from the cell cycle during the first week after birth. PMID- 23743022 TI - Genetic and environmental contributions to long-term sick leave and disability pension: a population-based study of young adult Norwegian twins. AB - Although exclusion from the workforce due to long-term sick leave (LTSL) and disability pension (DP) is a major problem in many Western countries, the etiology of LTSL and DP is not well understood. These phenomena have a strong association as most patients receiving DP have first been on LTSL. However, only a few of those on LTSL end up with DP. The present study aimed to investigate the common and specific genetic and environmental risk factors for LTSL and DP. The present study utilizes a population-based sample of 7,710 young adult twins from the Norwegian Institute of Public Health Twin Panel, which has been linked to the Historical-Event Database (FD-Trygd; 1998-2008). Univariate and bivariate twin models were fitted to determine to what degree genetic and environmental factors contribute to variation in LTSL and DP. The estimated heritabilities of LTSL and DP were 0.49 and 0.66, respectively. There was no evidence for shared environmental or sex-specific factors. The phenotypic-, genetic-, and non familial environmental correlations between the variables were 0.86, 0.82, and 0.94, respectively. Our results indicate that familial transmission of LTSL and DP is due to genetic and not environmental factors. The risk factors contributing to LTSL and DP were mainly shared, suggesting that what increases risk for LTSL also increases risk for DP. However, a non-negligible part of the genetic variance was not shared between the variables, which may contribute to explaining why some progress from LTSL to DP, whereas others return to work. PMID- 23743023 TI - A report on the high prevalence of Anaplasma sp. in buffaloes from two provinces in Pakistan. AB - The present study was designed to use a PCR-RFLP protocol for the molecular detection of Anaplasma sp. and to compare its prevalence in blood samples from buffaloes (Bubalus bubalis) from 2 provinces of Pakistan and to determine the risk factors associated with the spread of Anaplasma infection. A total of 281 blood samples were collected from adults and calves of buffaloes from 4 sampling sites in Southern Punjab (Bahawalnagar, Burewala, Layyah, and Multan districts) and 2 in Khyber Pukhtoon Khwa (Peshawer and Kohat districts) from randomly selected herds. Data on the characteristics of the animals (gender, age, tick presence or absence, prior treatment for Anaplasma infection) and the herd (location, size, dogs associated with the herds, tick burden of dogs associated with the herds) were collected through questionnaires. One hundred and sixteen blood samples (41% of total) produced the 577-base pairs DNA fragment specific for the 16S rRNA gene of Anaplasma sp. by PCR amplification. Twenty of the 116 Anaplasma sp.-positive PCR products were confirmed to be Anaplasma marginale upon restriction with BssNa1, specific to cut A. marginale sequences. ANOVA results revealed a highly significant association between sampling sites and prevalence of Anaplasma sp. (P<0.001) indicating that Anaplasma sp. prevalence was variable among all 6 sampling sites. Risk factor analysis indicated that the association of dogs with the herd was the only significant (P=0.029) risk factor associated with the spread of Anaplasma sp. in buffaloes while sex, age, presence of ticks on animals or herd size showed no association with Anaplasma infection. PMID- 23743025 TI - Selecting the best set of gas chromatography-derived fatty acids to discriminate between two finishing diets using linear discriminant analysis. AB - Linear discriminant analysis (LDA) was investigated as a method for identifying the type of finishing diet fed to bulls (n=169) based on gas chromatography fatty acid (FA) analysis. The bulls were fed ad libitum a high concentrate diet comprised of a cereal-soybean meal based concentrate plus straw offered separately (HC) or a total mixed ration made of cereal, soybean meal, maize silage and straw (TMR). Eleven variables (10 FA and one FA ratio) were selected as statistically significant predictors out of 41 variables tested. The Mahalanobis squared distance between the HC and TMR groups was 3.386 and F-test of the distance was highly significant (P>0.001). In cross-validated classification matrices, 18 cases were misclassified in the HC group and 16 cases were misclassified in the TMR group. As a result, 79.9% of original grouped cases were classified correctly. We concluded that it was possible to classify beef samples according to their finishing diets using LDA. PMID- 23743024 TI - UBE3B and ZRANB1 polymorphisms and transcript abundance are associated with water holding capacity of porcine M. longissimus dorsi. AB - The degradation of myofibrillar proteins during meat maturation affects the water holding capacity (WHC) of meat. Our study sought to identify polymorphisms in UBE3B and ZRANB1, genes encoding proteins involved in ubiquitination, and to evaluate the relationship between genotype, transcript abundance, and WHC of pork. A single SNP of ZRANB1, c.552A>G (p.Ile153Val), and two silent SNPs of UBE3B, c.1921A>T and c.4292C>T, were associated with muscle pH, conductivity, meat colour, or drip loss in German Landrace (GL, n=266) and Pietrain*(Large White*German Landrace) (PiF1, n=316). Further, carriers of the minor alleles at the SNPs tended to have increased transcript abundance. Consistent with the protein degradation promoting and inhibiting effects of UBE3B and ZRANB1, respectively, and the expected impact on WHC, their expressions were positively and negatively associated with WHC. The results implicate that the SNPs in both genes are in linkage with a causal site that affects transcript abundance and WHC. PMID- 23743026 TI - Thiol oxidation and protein cross-link formation during chill storage of pork patties added essential oil of oregano, rosemary, or garlic. AB - The effect of two levels (0.05% and 0.4%) of essential oil of rosemary, oregano, or garlic on protein oxidation in pork patties was studied during storage under modified atmosphere (MAP: 70% O2: 20% CO2: 10% N2) or under aerobic conditions (AE) at 4 degrees C. The oxidative stability of the meat proteins was evaluated as loss of thiols for up to 9 days of storage, and as formation of myosin cross links analyzed by SDS-PAGE after 12 days of storage. Protein thiols were lost during storage to yield myosin disulfide cross-links. Essential oils of rosemary and oregano were found to retard the loss of thiols otherwise resulting in myosin cross-links. Garlic essential oil, on the contrary, was found to promote protein oxidation, as seen by an extreme loss in thiol groups, and elevated myosin cross link formation compared to control. PMID- 23743027 TI - Efficacy of knife disinfection techniques in meat processing. AB - EU Regulation 853/2004 requires that knives used in meat processing be disinfected by submerging them in hot water (+82 degrees C). Alternative procedures are permitted if the efficacy is proved to be equivalent. In the present study, various time-temperature combinations together with pure water, water with lactic acid (2 %), and the use of ultrasound with and without lactic acid (2%) were investigated. Steel plates were covered with fat and protein and then inoculated with a standardized bacterial contamination assembled according to the composition of bacterial contamination found in a previous field trial conducted with regard to the slaughter of pigs. Several combinations with diverse temperatures and time intervals were tested until no microbial load was detectable by using a wet-dry-swab technique that had previously been tested to ensure maximum bacterial recovery. The following were effective in bringing the tested bacterial flora below the detection limit: * 70 degrees C water bath for 10 s * 60 degrees C water bath + ultrasound for 5 s * 40 degrees C water bath + lactic acid (2%) for 10 s * 40 degrees C water bath + ultrasound + lactic acid (2%) for 5 s In particular, the use of lactic acid permitted a relevant reduction of the temperature, while providing effective sterilization. The use of such non hazardous food-safe additives is particularly suitable for successful disinfection at lower temperatures. PMID- 23743028 TI - Combined antimicrobial effect of oregano essential oil and caprylic acid in minced beef. AB - Oregano essential oil (OEO) and caprylic acid (CA) are highly aromatic natural antimicrobials with limited individual application in food. We proved their combined additive effect when used in meat. Application of 0.5% CA and 0.2% OEO (v/w) with 0.1% of citric acid in vacuum packed minced beef inoculated with Listeria monocytogenes at a concentration of 5 log cells/g reduced counts of lactic acid bacteria by 1.5 log CFU/g and counts of psychrotrophic bacteria and L. monocytogenes by more than 2.5 log CFU/g at the end of storage at 3 degrees C for 10 days. In sensory evaluation the samples with OEO showed during the whole experiment statistically better scores than control, whereas the samples treated with CA showed worse colour attributes. PMID- 23743029 TI - Relationship between the solubility, dosage and antioxidant capacity of carnosic acid in raw and cooked ground buffalo meat patties and chicken patties. AB - Antioxidant capacity of oil soluble and water dispersible carnosic acid (CA) extracted from dried rosemary leaves using HPLC was evaluated at two different dosages (22.5 ppm vs 130 ppm) in raw and cooked ground buffalo meat patties and chicken patties. Irrespective of total phenolic content, CA extracts reduced (p<0.05) the thiobarbituric acid reactive substances (TBARS) by 39%-47% and 37% 40% in cooked buffalo meat and chicken patties at lower dosage (22.5 ppm) relative to control samples. However, at higher dosage (130 ppm) the TBARS values were reduced (p<0.05) by 86%-96% and 78%-87% in cooked buffalo meat and chicken patties compared to controls. The CA extracts were also effective in inhibiting (p<0.05) peroxide value and free fatty acids in cooked buffalo meat and chicken patties. The CA extracts when used at higher dosage, were also effective in stabilizing raw buffalo meat color. PMID- 23743030 TI - Animal welfare versus food quality: factors influencing organic consumers' preferences for alternatives to piglet castration without anaesthesia. AB - Surgical piglet castration without pain relief has been banned in organic farming in the EU since the beginning of 2012. Alternative methods therefore need to be implemented that improve animal welfare and solve the underlying problem of boar taint. This paper explores German organic consumers' preferences for piglet castration without pain relief and three alternative methods. In an innovative approach using a multi-criteria decision making procedure, qualitative data from focus group discussions were compared with quantitative results from Vickrey auctions. Overall, participants preferred all alternatives to castration without pain relief. Different aspects influenced willingness-to-pay for the methods. Animal welfare was important for the evaluation of castration without pain relief and castration with anaesthesia. Food safety played a major role for willingness to-pay for immunocastration, while taste and, to some extent, animal welfare were dominant factors for fattening of boars. These differences should be considered when communicating the alternatives. PMID- 23743031 TI - Use of dietary supplementation with beta-guanidinopropionic acid to alter the muscle phosphagen system, postmortem metabolism, and pork quality. AB - Rate and extent of postmortem metabolism control pork quality development. Our objective was to evaluate the role of the phosphagen system (phosphocreatine, PCr; and creatine, Cr) on metabolism and pork quality. Muscle PCr and Cr were manipulated by feeding pigs the creatine analogue, beta-guanidinopropionic acid (beta-GPA). In experiment 1, pigs received standard (control) diet or beta-GPA supplemented (2%) diet (1 wk or 2 wk). Supplementation with beta-GPA (2 wk) decreased total Cr (PCr+Cr; P=0.02) and improved pork color (decreased reflectance, P=0.003); however, beta-GPA supplementation reduced growth performance (P=0.007). To separate effects of phosphagen system and growth, a second experiment was conducted with control, pair-fed, and 2 wk beta-GPA (1%) supplementation; pigs were also offered a control or beta-GPA supplemented flavored beverage. Neither treatment influenced pork quality. Immediately postmortem, ATP/ADP was higher in control compared to pair-fed (P<0.05); subsequently, ATP/ADP was similar among all groups. Loss of the phosphagen system may lead to adaptive changes that promote conservation of cellular ATP. PMID- 23743032 TI - Technological and safety properties of lactic acid bacteria isolated from Spanish dry-cured sausages. AB - Technological and safety-related properties were analyzed in lactic acid bacteria isolated from Spanish dry-cured sausages in order to select them as starter cultures. In relation to technological properties, all the strains showed significative nitrate reductase activity; Lactobacillus plantarum, Lactobacillus paracasei and 52% of the Enterococcus faecium strains showed lipolytic activity and only Lactobacillus sakei strains (43%) were able to form biofilms. Related to safety aspects, E. faecium strains were the most resistant to antibiotics, whereas, L. sakei strains were the most sensitive. In relation to virulence factors, in the E. faecium strains analyzed, only the presence of efaA gene was detected. The analysis of biogenic amine production showed that most E. faecium strains and L. sakei Al-142 produced tyramine. In conclusion, L. paracasei Al-128 and L. sakei Al-143 strains possess the best properties to be selected as adequate and safe meat starter cultures. PMID- 23743033 TI - Proteolytic pattern of myofibrillar protein and meat tenderness as affected by breed and aging time. AB - The effects of breed and aging time (1, 7, 14, 21 days) were evaluated on meat tenderness and on proteolysis in 24 young bulls from Romagnola*Podolian crossbreed, Podolian and Friesian breed. Shear force decreased with aging in all breeds and showed the highest values at 1 and 7 days in Podolian meat. Myofibrillar fragmentation index significantly increased in Podolian meat throughout aging whereas in Friesian and in Crossbreed meat it increased only in the first week. Proteolysis was investigated by SDS-PAGE and 2-dimensional electrophoresis showing a different quantity and expression profile of myofibrillar proteins among breeds. In all breeds a decrease of troponin-T and an increase of troponin-T derived polypeptides during aging were observed. The highest decrease of troponin-T together with the presence of fragments of MHC in Podolian meat during aging was an outcome of a more extensive proteolysis in this breed. Data suggest that tenderness and proteolytic changes during aging are related to animal's breed. PMID- 23743034 TI - Effects of grape seed extract on the oxidative and microbial stability of restructured mutton slices. AB - The antioxidant and antimicrobial efficacy of grape seed extract (GSE) was studied in restructured mutton slices (RMS) under aerobic and vacuum packaging conditions during refrigerated storage. The RMS treated with grape seed extract (GSE) had significantly (P<0.05) lower thiobarbituric acid reactive substance (TBARS) values and free fatty acids (FFA) % compared to control (C) and butylated hydroxy anisole (BHA) treated RMS during storage at 4+/-1 degrees C. Addition of GSE significantly (P<0.05) reduced the total psychrophilic and coliform counts in RMS during refrigerated storage. The GSE treated mutton slices recorded significantly (P<0.05) superior scores of color, flavor, juiciness and overall palatability than C and BHA treated RMS. The TBARS values, FFA % and microbial counts increased significantly (P<0.05) during storage. It can be concluded that GSE has excellent antioxidant and antimicrobial properties compared to control and BHA treated RMS during refrigerated storage under aerobic and vacuum conditions. PMID- 23743035 TI - One new dicoumarol-based fluorescent compound: synthesis, crystal structure and metal ions recognition. AB - A new dicoumarol-based compound (C6H4)[CH2NHCO(C9O2H4)N(C2H5)2]21 was synthesized and characterized by IR, UV spectroscopy and single-crystal X-ray diffraction analysis. The structure of 1 exhibits a transoid formation with the two coumarin containing arms sited on the two sides of the center benzene ring. In the crystal packing the molecule further interact with each other and form a three dimensional framework through pi-pi stacking interactions and multiform hydrogen bonds. The compound 1 shows the main emission peak at 540 nm corresponding to the green hue in the solid state. The fluorescence recognition behaviors for various metal ions were investigated and 1 exhibits a highly fluorescence-quenching selectivity for Fe(III) ion in the mixed CH3CN-H2O solvent. PMID- 23743036 TI - A new look into conformational, vibrational and electronic structure analysis of 3,4-dimethoxybenzonitrile. AB - The FTIR and FT-Raman spectra of 3,4-dimethoxybenzonitrile (34DMBN) have been analysed. Quantum chemical studies were performed with B3LYP method using 6 311++G(d,p), 6-31G(d,p) and cc-pVTZ basis sets. The electron donating effect of OCH3 and electron withdrawing effect of -C=N groups on the ring parameters were thoroughly analysed. The structural parameters, energies, thermodynamic properties, vibrational frequencies and the NBO charges of 34DMBN were determined. The (1)H and (13)C chemical shifts with respect to TMS were investigated and also calculated theoretically using the gauge independent atomic orbital method and compared with the experimental data. The delocalisation energy of different types of bonding interactions was investigated. PMID- 23743037 TI - A new selective fluorescent sensor for Fe3+ based on a pyrazoline derivative. AB - A new pyrazoline derivative was designed and synthesized. The structure of the pyrazoline was confirmed by single crystal X-ray diffraction and its photophysical properties were studied by absorption and fluorescence spectra. This compound can be used to determine Fe(3+) ion with high selectivity among a series of cations in tetrahydrofuran and even in aqueous tetrahydrofuran. This sensor forms a 1:1 complex with Fe(3+) and displays fluorescent quenching. PMID- 23743038 TI - On the spectroscopic analyses of thioindigo dye. AB - A combined experimental and theoretical study on molecular structure and vibrational frequencies of thioindigo was reported. The FT-IR spectrum of thioindigo is recorded in the solid phase. The equilibrium geometries, harmonic vibrational frequencies, thermo-chemical parameters, total dipole moment and HOMO LUMO energies are calculated by density functional theory DFT/B3LYP utilizing 6 311G(d,p) basis set. Results showed that cis-isomer is highly recommended to be a promising structure for many applications in optoelectronic devices due to its high calculated dipole moment value (3.44 Debye) which indicates its high reactivity to interact with the surrounding molecules as compared to the trans isomer which has no dipole moment. Both isomers have a similar HOMO-LUMO energy gap, of 3.02 eV (cis-isomer) and 2.78 eV (trans-isomer). PMID- 23743039 TI - Vibrational spectra of bis(maltolato)zinc(II), an interesting insulin mimetic agent. AB - The FTIR and FT-Raman spectra of the zinc(II) complex of 3-hydroxy-2-methyl-4 pyrone (maltol), bis(maltolato)zinc(II), were recorded and briefly discussed by comparison with the spectra of uncoordinated maltol and with some related maltolato complexes. PMID- 23743040 TI - Luminescent one-dimensional nanostructures of perylene bisimides. AB - Perylene bisimides form a unique class of organic semiconductors, in this investigation two symmetrical perylene bisimides caped with 1-butyl (B-PTCDI) and 4,4-diethoxybutyl (DB-PTCDI) have been synthesized and characterized. The compounds self-assembled as a network of nanobelts and nanorods in the solution based self-assembly process. Morphologies of these self-assembled structures were characterized by optical, fluorescence, scanning and transmission electronic microscopic techniques. One-dimensional self-assemblies of B-PTCDI and DB-PTCDI molecules are due to the strong pi-pi stacking ability of perylene core and assistance given by the side chains and solvent. Observed molecular self-assembly and electronic properties of the molecules. The observed self-assembly was supported by molecular modeling studies using density functional theory. PMID- 23743041 TI - Synthesis, spectral characterization and biological activity of metal(II) complexes with 4-aminoantipyrine derivatives. AB - Novel metal(II) complexes derived from furfurylidene-4-aminoantipyrine and 2 aminobenzothiazole were synthesized and characterized by spectroscopic (IR, (1)H NMR, UV-Vis., ESR and DART-MS) and other analytical methods. IR spectral studies indicate the binding sites of the ligand with the metal ion. Molar conductance data and magnetic susceptibility measurements provide evidence for monomeric and neutral nature of the complexes. The X band ESR spectrum of the Cu(II) complex at 300 and 77K was recorded. The electrochemical behaviour of the complexes in MeCN at 298 K was studied. Thermal studies of the ligand and its complexes show the presence of coordinated water in the complexes. The grain size of the complex was calculated by Scherrer formula using powder XRD. The surface morphology of the complexes was studied using SEM. The in vitro biological screening of the ligand and its complexes were tested against bacterial species S. aureus, E. coli, K. pneumoniae, P. vulgaris and P. aeruginosa and fungal species A. niger, R. stolonifer, A. flavus, R. bataicola and C. albicans. The DNA binding and cleavage activity of the ligand and its complexes were studied. Super oxide dismutase (SOD) activities of the ligand and its complexes have also been measured. PMID- 23743042 TI - Synthesis, spectroscopic studies, molecular modeling and antimicrobial activity of binuclear Co(II) and Cu(II) complexes of 4,6-diacetylresorcinol. AB - Reactions of 4,6-diacetylresorcinol with different cobalt(II) and copper(II) salts viz., OAc(-), Cl(-), NO3(-) and SO4(2-), yielded a new series of binuclear metal complexes. Reactions of the ligand with these metal ions in the presence of a secondary ligand (L') [O,O-donor; acetylacetone, N,O-donor; 8-hydroxyquinoline or N,N-donor; 1,10-phenanthroline and N,N,N',N'-tetramethylethylenediamine] in 1:2:2 (L:M:L') molar ratio yielded mixed-ligand complexes with different molar ratios. The metal complexes were characterized by elemental and thermal analyses, IR, electronic, ESR and mass spectra as well as conductivity and magnetic susceptibility measurements. The analytical and spectroscopic data suggested that the H2L ligand behaves as a neutral, monobasic or dibasic tetradentate ligand, depending on the type of the anion and secondary ligand used, through the two phenolic and two carbonyl groups. Electronic spectra, magnetic and conductivity measurements showed that all complexes are octahedral with non-electrolytic nature. The profile of ESR spectra of copper(II) complexes suggested the octahedral geometry and the spin Hamiltonian parameters of the complexes were calculated and discussed. Molecular orbital calculations were performed for metal complexes using Hyperchem 7.52 program on the bases of PM3 level and the results correlated with the experimental data. The free ligand and some of its metal complexes showed antimicrobial activity towards some of Gram-positive and Gram negative bacteria, yeast (Candida albicans) and fungus (Aspergillus fumigatus). PMID- 23743043 TI - Decentralisation of multidrug-resistant-tuberculosis care and management. PMID- 23743044 TI - Universal access to care for multidrug-resistant tuberculosis: an analysis of surveillance data. AB - BACKGROUND: The prospects for global tuberculosis control in the near future will be determined by the effectiveness of the response of countries to their burden of multidrug-resistant (MDR; resistance to, at least, isoniazid and rifampicin) tuberculosis. During the 2009 World Health Assembly, countries committed to achieve universal access to MDR-tuberculosis care by 2015. We assessed the progress towards the 2015 targets achieved by countries accounting for 90% of the estimated MDR-tuberculosis cases in the world in 2011. METHODS: We analysed data reported to WHO by 30 countries expected to have more than 1000 MDR-tuberculosis cases among notified patients with pulmonary tuberculosis in 2011. FINDINGS: In the 30 countries, 18% of the estimated MDR-tuberculosis cases were enrolled on treatment in 2011. Belarus, Brazil, Kazakhstan, Peru, South Africa, and Ukraine each detected and enrolled on treatment more than 50% of their estimated cases of MDR-tuberculosis. In Ethiopia, India, Indonesia, the Philippines, and Russia, enrolments increased steadily between 2009 and 2011 with a mean yearly change greater than 50%: however, in these countries enrolment in 2011 was low, ranging from 4% to 43% of the estimated cases. In the remaining countries (Afghanistan, Angola, Azerbaijan, Bangladesh, China, Democratic Republic of the Congo, Kenya, Kyrgyzstan, Moldova, Mozambique, Burma, Nepal, Nigeria, North Korea, Pakistan, South Korea, Thailand, Uzbekistan, and Vietnam) progress in detection and enrolment was slower. In 23 countries, a median of 53% (IQR 41-71) patients with MDR-tuberculosis successfully completed their treatment after starting it in 2008 09. INTERPRETATION: Six countries (Belarus, Brazil, Kazakhstan, Peru, South Africa, and Ukraine) can achieve universal access to MDR-tuberculosis care by 2015 should they sustain their current pace of progress. In other countries a radical scale-up will be needed for them to have an effect on their MDR tuberculosis burden. Unless barriers to diagnosis and successful treatment are urgently overcome, and new technologies in diagnostics and treatment effectively implemented, the global targets for 2015 are unlikely be achieved. FUNDING: WHO. PMID- 23743045 TI - In situ investigations of Fe3+ induced complexation of adsorbed Mefp-1 protein film on iron substrate. AB - A range of in situ analytical techniques and theoretical calculations were applied to gain insights into the formation and properties of the Mefp-1 film on iron substrate, as well as the protein complexation with Fe(3+) ions. Adsorption kinetics of Mefp-1 and the complexation were investigated using QCM-D. The results suggest an initially fast adsorption, with the molecules oriented preferentially parallel to the surface, followed by a structural change within the film leading to molecules extending toward solution. Exposure to a diluted FeCl3 solution results in enhanced complexation within the adsorbed protein film, leading to water removal and film compaction. In situ Peak Force Tapping AFM was employed for determining morphology and nano-mechanical properties of the surface layer. The results, in agreement with the QCM-D observations, demonstrate that addition of Fe(3+) induces a transition from an extended and soft protein layer to a denser and stiffer one. Further, in situ ATR-FTIR and Confocal Raman Micro spectroscopy (CRM) techniques were utilized to monitor compositional/structural changes in the surface layer due to addition of Fe(3+) ions. The spectroscopic analyses assisted by DFT calculations provide evidence for formation of tri Fe(3+)/catechol complexes in the surface film, which is enhanced by Fe(3+) addition. PMID- 23743046 TI - Optically transparent electrorheological fluid with urea-modified silica nanoparticles and its haptic display application. AB - A transparent electrorheological (ER) fluid was fabricated by dispersing urea modified silica nanoparticles in a mixture of halocarbon oil and silicone oil, whose refractive index could be tuned to be the same as that of the dispersed particles. The ER fluid showed considerable enhancement in shear stress and shear viscosity, as determined by a rotational rheometer, as well as improved dielectric spectra measured using a LCR meter. Morphological and thermal characterization by scanning electron microscopy and thermal gravimetric analysis confirmed the modification by urea. The potential applications of the transparent ER fluid as haptic displays were also investigated. PMID- 23743047 TI - Adhesion work and wettability of polytetrafluorethylene and poly(methyl methacrylate) by aqueous solutions of cetyltrimethylammonium bromide and Triton X 100 mixture with ethanol. AB - The contact angle measurements of the aqueous solutions of p-(1,1,3,3 tetramethylbutyl)phenoxypoly(ethylene glycol) (TX-100) and cetyltrimethylammonium bromide (CTAB) mixture with ethanol on polytetrafluoroethylene (PTFE) and poly (methyl methacrylate) (PMMA) were carried out in the range of the total concentration of TX-100 and CTAB mixture from 1*10(-6) to 1*10(-3) M and in the whole range of ethanol concentration. In the surfactant mixture, the mole fraction of TX-100 was equal to 0.2; 0.4; 0.6 and 0.8, respectively. From the obtained results, the critical surface tension of PTFE and PMMA wetting and the adhesion work of the solutions to the polymer surface were established. The PMMA surface tension was calculated from the Neumann's equation. It appeared that for the ethanol concentration higher than that corresponding to the association of its molecules, the surface tension of PMMA calculated from the Neumann's equation is close to the critical surface tension of PMMA wetting. It also appeared that it is possible to predict the work of adhesion of the studied solutions to the PMMA surface by using the PMMA surface tension data determined on the basis of the van Oss et al. approach to the interfacial tension and those from the Neumann's equation. PMID- 23743048 TI - ZnO nanoparticle interactions with phospholipid monolayers. AB - Aqueous ZnO nanoparticle dispersions interaction with a dioleoyl phosphatidylcholine (DOPC) monolayer is reported in this paper. ZnO-DOPC interactions were investigated using rapid cyclic voltammetry (RCV) by focusing on the effect of the interactions on the characteristics of the capacitance current peaks representing two potential induced phase transitions. Results showed: - (1) The order of interaction of common commercially sourced nanoparticles with DOPC coated Hg electrodes was NanoTek>NanoShield>metals basis. This extent of interaction was inversely related to the ZnO particle size where the metals basis nanoparticles were strongly aggregated. The contribution of the non-ionic dispersant added by manufacturer to the NanoTek and NanoShield interaction was uncertain. (2) Freshly prepared aqueous Nanosun ZnO nanoparticle (~25 nm) dispersions interacted with and penetrated DOPC coated Hg electrodes. Aggregation of the nanoparticles, coating of the ZnO with phosphate and coating of the ZnO with fulvic acid minimised ZnO-DOPC interaction. (3) In-house synthesised ZnO nanoparticles of lower primary particle size (~6 nm) than Nanosun ZnO nanoparticles interacted strongly with DOPC coated Hg electrodes with no evidence of penetration of the nanoparticle in the DOPC monolayer. Even after considerable aggregation of the particle to between 1 and 10 MUm, a strong interaction of the in-house synthesised ZnO with DOPC was observed. PMID- 23743049 TI - Silica supported copper and cerium oxide catalysts for ethyl acetate oxidation. AB - The formation of active sites in the silica supported copper and cerium oxide bi component catalysts for total oxidation of ethyl acetate was studied by Nitrogen physisorption, XRD, XPS, UV-Vis, Raman, FTIR of adsorbed CO spectroscopies and TPR. It was found that the interaction between the copper oxide nanoparticles and the supported on the silica ceria ones is realized with the formation of interface layer of penetrated into ceria lattice copper ions in different oxidative state. This type of interaction improves the dispersion of copper oxide particles and provides higher accessibility of the reactants to the copper active sites even at low copper amount. PMID- 23743050 TI - Detecting ICRS grade 1 cartilage lesions in anterior cruciate ligament injury using T1rho and T2 mapping. AB - OBJECTIVE: The purpose of this study was to clarify the detectability of the International Cartilage Repair Society (ICRS) grade 1 cartilage lesions in anterior cruciate ligament (ACL)-injured knees using T1rho and T2 mapping. MATERIALS AND METHODS: We performed preoperative T1rho and T2 mapping and 3D gradient-echo with water-selective excitation (WATS) sequences on 37 subjects with ACL injuries. We determined the detectability on 3D WATS based on arthroscopic findings. The T1rho and T2 values (ms) were measured in the regions of interest that were placed on the weight-bearing cartilage of the femoral condyle. The receiver operating characteristic (ROC) curve based on these values was constructed using the arthroscopic findings as a reference standard. The evaluation of cartilage was carried out only in the weight-bearing cartilage. The cut-off values for determining the presence of a cartilage injury were determined using each ROC curve, and the detectability was calculated for the T1rho and T2 mapping. RESULTS: The cut-off values for the T1rho and T2 were 41.6 and 41.2, respectively. The sensitivity and specificity of T1rho were 91.2% and 89.5%, respectively, while those of T2 were 76.5% and 81.6%, respectively. For the 3D WATS images, the same values were 58.8% and 78.9%, respectively. CONCLUSIONS: Our study demonstrated that the T1rho and T2 values were significantly higher for ICRS grade 1 cartilage lesions than for normal cartilage and that the two mappings were able to non-invasively detect ICRS grade 1 cartilage lesions in the ACL-injured knee with a higher detectability than were 3D WATS images. PMID- 23743051 TI - Intramammary metastases: comparison of mammographic and ultrasound features. AB - PURPOSE: To describe the mammographical and ultrasound features of IM, and to compare radiological patterns of IM arising from different malignancies. MATERIALS AND METHODS: A retrospective search in the statistical database of our institution from January 2000 to December 2009 revealed 51 cases of intramammary metastases from solid malignancies. Additionally, a retrospective search in the Pubmed database was performed. Publications in the time interval from 1980 to 2010 were considered. After thorough analysis, 119 articles with 229 patients were involved in the study. Therefore, together with our cases our analysis comprises 280 patients. Mammographic and ultrasound findings of different IM were analyzed. RESULTS: The detected metastases showed two main radiological patterns: intramammary masses (81.5%) and architectural distortion (18.5%). Carcinomas of the stomach caused more frequently an architectural distortion, whereas other malignancies tended to present as intramammary masses. The size of the masses ranged from 2 to 104 mm. The largest lesions occurred in rhabdomyosarcoma, followed by hepatocellular carcinoma and squamous cell carcinomas of the head and neck region. The smallest lesions arose from malignancies of the thyroid gland carcinoma. Most IM showed circumscribed margins, while breast lesions in rhabdomyosarcoma were rather microlobulated. On ultrasound, IM from lung cancer were usually inhomogenously hypoechoic with circumscribed margins and showed posterior shadowing in almost 50% of the cases. Breast metastases from ovarian carcinoma had typically microlobulated margins and posterior enhancement. CONCLUSION: IM can present with a broad spectrum of radiological features. Their imaging findings vary depending on the primary tumor. PMID- 23743053 TI - Clinical utility and limitations of tumor-feeder detection software for liver cancer embolization. AB - PURPOSE: To evaluate the clinical utility and limitations of a computer software program for detecting tumor feeders of hepatocellular carcinoma (HCC) during transarterial chemoembolization (TACE). MATERIALS AND METHODS: Forty-six patients with 59 HCC nodules underwent nonselective digital subtraction angiography (DSA) and C-arm computed tomography (CT) in the same hepatic artery. C-arm CT data sets were analyzed using the software to identify potential tumor feeders during each TACE session. For DSA analysis, 3 radiologists were independently assigned to identify tumor feeders using the DSA images in a separate session. The sensitivity of the 2 techniques in detecting tumor feeders was compared, with TACE findings as the reference standard. Factors affecting the failure of the software to detect tumor feeders were assessed by univariate and multivariate analyses. RESULTS: We detected 65 tumor feeders supplying 59 HCC nodules during TACE sessions. The sensitivity of the software to detect tumor feeders was significantly higher than that of the manual assessment using DSA (87.7% vs. 71.8%, P<0.001). Multivariate analysis showed that a tumor feeder diameter of <1.0mm (hazard ratio [HR], 56.3; P=0.003) and lipiodol accumulation adjacent to the tumor (HR, 11.4; P=0.044) were the significant predictors for failure to detect tumor feeders. CONCLUSION: The software analysis was superior to manual assessment with DSA in detecting tumor feeders during TACE for HCC. However, the capability of the software to detect tumor feeders was limited by vessel caliber and by prior lipiodol accumulation to the tumor. PMID- 23743052 TI - Breast MRI of pure ductal carcinoma in situ: sensitivity of diagnosis and influence of lesion characteristics. AB - OBJECTIVES: The purpose of the study was to evaluate the sensitivity of breast MRI in the detection of pure DCIS and to analyze the influence of lesion type and nuclear grade. METHODS: 58 consecutive patients with pathologically proven pure DCIS and preoperatively performed breast MRI were retrospectively reviewed and analyzed. Sensitivities in the detection of DCIS were calculated for MRI and mammography (Mx). Influence of MRI lesion type and nuclear grading on DCIS diagnosis was evaluated. RESULTS: MRI detected pure DCIS with a sensitivity of 79.3%. The sensitivity of Mx was lower (69%), but the difference was not statistically significant (p=0.345). 46.2% of the DCIS presented as enhancing mass and 53.8% as non-mass-like enhancement (NMLE). None of the masses but 21.4% (n=6) of the NMLE were underestimated as probably benign (BI-RADS 3). MRI measured lesion sizes showed a moderate correlation (r=0.74) with histopathologically measured lesion sizes. MRI detection rate of DCIS decreased significantly (p=0.0458) with increasing nuclear grade. Calculated sensitivities were 100% for low-grade DCIS, 84.6% for intermediate-grade DCIS, and 66.7% for high-grade DCIS. CONCLUSIONS: In this study MRI could detect pure DCIS more sensitively than Mx. Despite of missing statistically significance preoperative MRI seems to be helpful in patients with DCIS who are eligible for breast conservation. This applies in particular to patients with non-high-grade DCIS because those were significantly more often positive on MRI and significantly more often negative on Mx. Misinterpretation occurs especially in cases of NMLE and high-grade DCIS and therefore a correlation with Mx is also recommended. PMID- 23743054 TI - Clinical utility of ultra high pitch dual source thoracic CT imaging of acute pulmonary embolism in the emergency department: are we one step closer towards a non-gated triple rule out? AB - OBJECTIVES/PURPOSE: Aim of this study was to retrospectively compare the image quality and the radiation dose of an ultra high pitch CT scan for the evaluation of pulmonary embolism and visualization of cardiac structures in comparison to our institution's standard pulmonary embolism protocol. METHOD AND MATERIALS: The study cohort consisted of 115 consecutive patients, 57 underwent CT pulmonary angiography on a dual source 128 slice scanner (Siemens Somatom Definition FLASH) via an ultra high pitch mode (Pitch 2.8) while 58 were scanned on a dual source 64 slice scanner (Siemens Somatom Definition Dual Source) with standard pitch (Pitch 0.9). Qualitative image assessment was determined by two blinded radiologists with 3 and 15 years' experience in chest and cardiac CT. Quantitative image assessment was determined by the signal to noise ratio (SNR) and contrast to noise ratio (CNR). Effective radiation dose was calculated via the product of the dose length product. RESULTS: For the ultra high pitch protocol, 14% (8/57) were positive for pulmonary embolus compared to 13.7% (8/58) for the standard pitch group. 98.2% of the ultra high pitch scans were diagnostic for pulmonary embolus vs. 94.8% of the standard protocol. Visualization of cardiac structures was significantly improved with the ultra high pitch protocol (p<0.0001). Significantly more lung parenchymal motion was observed on the standard protocol (p<0.0001). The mean pulmonary vessel attenuation, SNR, and CNR were not significantly different. The mean effective dose was lower for the ultra high pitch studies (4.09mSv+/-0.78 vs. 7.72mSv+/-2.60, p<0.0001). CONCLUSION: Ultra high pitch CT imaging for pulmonary embolus is a technique which has potential to assess motion free evaluation of most cardiac structures and proximal coronary arteries at lower radiation doses. PMID- 23743055 TI - Lingering fat signals with CHESS in simultaneous imaging of both hands can be improved with rice pads in both 1.5T and 3.0T. AB - OBJECTIVES: To investigate whether rice pads can eliminate lingering fat signals of the complex surface shape of both hands that occur with chemical shift selective (CHESS) at 1.5T and 3.0T. MATERIALS AND METHODS: T1-weighted images were obtained with CHESS using 1.5T and 3.0T systems. The same imaging parameters were used with and without rice pads on the coronal plane of both hands in 10 healthy volunteers. The fat-suppression effects were classified into four categories and scored for images, and visual evaluations were performed by one radiologist and one radiologic technologist. RESULTS: At 1.5T, the mean evaluation score was 1.55 for images obtained without rice pads and 3.50 for images obtained with rice pads. At 3.0T, the mean evaluation score was 1.10 for images obtained without rice pads and 3.20 for images obtained with rice pads. With both systems, images obtained with the rice pads showed significantly better fat suppression effects than images obtained without rice pads (P<0.0001, P<0.0001). CONCLUSIONS: It was confirmed that lingering fat signals are eliminated and good fat-suppressed images are obtained with the use of rice pads at 1.5T and 3.0T. Rice pads are therefore useful with at 1.5T and 3.0T, which are currently becoming more widely used. PMID- 23743056 TI - 3-T direct MR arthrography of the wrist: value of finger trap distraction to assess intrinsic ligament and triangular fibrocartilage complex tears. AB - PURPOSE: To determine the value of applying finger trap distraction during direct MR arthrography of the wrist to assess intrinsic ligament and triangular fibrocartilage complex (TFCC) tears. MATERIALS AND METHODS: Twenty consecutive patients were prospectively investigated by three-compartment wrist MR arthrography. Imaging was performed with 3-T scanners using a three-dimensional isotropic (0.4 mm) T1-weighted gradient-recalled echo sequence, with and without finger trap distraction (4 kg). In a blind and independent fashion, two musculoskeletal radiologists measured the width of the scapholunate (SL), lunotriquetral (LT) and ulna-TFC (UTFC) joint spaces. They evaluated the amount of contrast medium within these spaces using a four-point scale, and assessed SL, LT and TFCC tears, as well as the disruption of Gilula's carpal arcs. RESULTS: With finger trap distraction, both readers found a significant increase in width of the SL space (mean Delta = +0.1mm, p <= 0.040), and noticed more contrast medium therein (p <= 0.035). In contrast, the differences in width of the LT (mean Delta = +0.1 mm, p >= 0.057) and UTFC (mean Delta = 0mm, p >= 0.728) spaces, as well as the amount of contrast material within these spaces were not statistically significant (p = 0.607 and >= 0.157, respectively). Both readers detected more SL (Delta = +1, p = 0.157) and LT (Delta = +2, p = 0.223) tears, although statistical significance was not reached, and Gilula's carpal arcs were more frequently disrupted during finger trap distraction (Delta = +5, p = 0.025). CONCLUSION: The application of finger trap distraction during direct wrist MR arthrography may enhance both detection and characterisation of SL and LT ligament tears by widening the SL space and increasing the amount of contrast within the SL and LT joint spaces. PMID- 23743058 TI - Isolation, identification and molecular docking studies of a new isolated compound, from Onopordon acanthium: a novel angiotensin converting enzyme (ACE) inhibitor. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Onopordon acanthium (also known as Scotch thistle) is a medicinal plant of the Asteraceae family that is widely distributed in Europe and Asia. This plant has been long used in traditional medicine as a hypotensive, cardiotonic and diuretic agent. AIM OF THE STUDY: The present study is designed to isolate an active compound with ACE inhibition activity from O. acanthium, measure antioxidant activity, predict domain specificity and pharmacokinetic properties of the isolated compound. MATERIALS AND METHODS: Methanolic extract of O. acanthium seeds, has been subjected to a repeated column chromatography to give a pure compound with Angiotensin Converting Enzyme (ACE) inhibition activity. The ACE inhibition activity was determined using hippuryl-L histidyl-L-leucine (HHL) as substrate in an in vitro ACE assay. Structure of the pure compound, isolated from O. acanthium has been established by spectroscopic methods, including Infrared (IR), Nuclear Magnetic Resonance (NMR) and Mass spectrum analysis. In addition, antioxidant activity of the new isolated compound, was measured using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and compared with those of BHT and Trolox as positive controls. Enzyme type inhibition and ACE-C or N domain specificity of the new compound was further evaluated through molecular modeling and docking studies. RESULTS: Structure of the pure compound, isolated from O. acanthium (83+/-1% ACE inhibition activity at concentration of 330 MUg/ml), has been established. The isolated compound possessed acceptable antioxidant activity (IC50 value of 2.6+/ 0.04 MUg/ml) in comparison with BHT (IC50 value of 10.3+/-0.15 MUg/ml) and Trolox (IC50 value of 3.2+/-0.06 MUg/ml). Molecular docking predicted competitive type enzyme inhibition and approximately similar affinity of the isolated compound for ACE-C and N domains. CONCLUSION: The results derived from computational and in vitro experiments, confirm the potential of the isolated compound, from O. acanthium as a new antihypertensive compound and give additional scientific support to an anecdotal use of O. acanthium in traditional medicine to treat cardiovascular disease such as hypertension. PMID- 23743059 TI - Effect of vitrification of mouse oocyte on the behavior of adult offspring. AB - OBJECTIVE: To evaluate the effect of vitrification of mouse oocytes on the behavior of adult offspring. STUDY DESIGN: Oocytes from mice were vitrified, warmed and inseminated, and two-cell embryos were transferred to foster mothers. The behavioral characterization of the offspring was detected by the Morris water maze test, forced swimming test, and elevated plus maze test, and compared to that of offspring from fresh oocytes. RESULTS: Offspring produced by vitrified oocytes showed normal motor function. In the Morris water maze test of spatial learning there was a slightly decreased time spent in the quadrant containing the platform relative to mice from fresh oocytes, but the difference did not reach statistical significance. In addition, offspring from vitrified oocytes did not exhibit alterations in emotional behavior. CONCLUSION: No alterations were found in the behavioral characterization of adult offspring from vitrified oocytes compared with those from fresh oocytes. PMID- 23743057 TI - Topical anti-inflammatory and analgesic activities of standardized pomegranate rind extract in comparison with its marker compound ellagic acid in vivo. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Chinese traditional medicine, the peels of Punica granatum L. have been used to treat traumatic hemorrhage, burn, and ulcers. AIMS OF THE STUDY: This study aimed to assess the topical anti inflammatory and analgesic activities of a standardized pomegranate rind extract (SPRE) of which ellagic acid (EA) was the major antioxidant constituent and the marker compound. MATERIAL AND METHODS: The topical anti-inflammatory effects of SPRE were evaluated against acute models (croton oil-induced mouse ear edema and carrageenan-induced rat paw edema) and chronic model (complete Freund's adjuvant (CFA)-induced polyarthritis). The topical analgesic activities of SPRE were investigated in the rat punctuate mechanical hyperalgesia test and in the mouse formalin test. All studies of SPRE were carried out in parallel with its marker compound EA. RESULTS: SPRE (5%, 2.5%, and 1%, w/w) and the equivalent EA (0.65%, 0.325%, and 0.13%, w/w) dose-dependently reduced the croton oil-induced mouse ear edema with a maximal inhibition of 86.30% and 80.82%, respectively. SPRE dose dependently attenuated the inflammatory responses in the carrageenan-induced rat paw edema and in the CFA-induced polyarthritis but the equivalent EA were effective only at the doses of 0.65% and 0.325%. Both SPRE (5%) and EA (0.65%) showed significant topical analgesic activities in the rat punctuate mechanical hyperalgesia test and in the mouse formalin test. CONCLUSIONS: SPRE was more active as an anti-inflammatory agent than EA. The anti-inflammatory and analgesic effects of SPRE were achieved through inhibiting the leukocyte infiltration and modulating the pro-inflammatory cytokines IL-beta and TNF-alpha. These results clearly demonstrated that SPRE is a promising phytomedicine that could find use in the treatment of inflammatory diseases. PMID- 23743060 TI - Fate of the remaining neo-aortic root after autograft valve replacement with a stented prosthesis for the failing ross procedure. AB - BACKGROUND: Aortic root replacement (ARR) is advocated for irreparable autograft failure after the Ross procedure to avoid late aneurysm formation. However, redo ARR is complex and associated with bleeding and coronary injury risks. We examine results of autograft valve replacement (AuVR) with stented prostheses (SP) without ARR with special focus on the fate of the remaining root and need for reintervention. METHODS: Between 1994 and 2011, 50 of 510 Ross patients underwent AuVR with SP. Serial postoperative echocardiograms (n = 342) were analyzed and regression models adjusted for repeated measures were used to model longitudinal change of the remaining root and ascending aorta dimensions after AuVR. RESULTS: Fifty patients, median age 21 years (range 11 to 50 years) underwent AuVR with SP: mechanical (n = 38) or tissue (n = 12). Thirty patients (60%) had concomitant procedures; most commonly mitral valve surgery (n = 20) or conduit change (n = 12). There were no operative deaths and 10-year survival was 95%. Freedom from prosthesis, root, and all-cause reoperations was 97%, 98%, and 90% at 10 years, respectively. Serial echocardiography data showed that there was little but, nevertheless, progressive increase of the remaining root (EST: +0.0190 [0.0041] cm/year, p < 0.001) and ascending aorta diameters (EST: +0.0191 [0.0037] cm/year, p < 0.001). While there was small steady non-statistically significant increase in mean prosthesis gradient (estimate [EST]: +0.16 [0.09] mm Hg/year, p = 0.08); ejection fraction remained stable with time (EST: -0.12 [0.14] %/year, p = 0.41). CONCLUSIONS: Our results indicate that AuVR with SP without ARR for failing autografts is justified as it is associated with low mortality and reoperation risk. Preemptive complex ARR should be reserved for those with significant root dilatation at time of AuVR. Although root reinterventions are rare, patients should be followed for progressive root dilatation. Faster growth is seen in those who fail with regurgitation and dilated annulus. PMID- 23743061 TI - Off-pump and on-pump coronary revascularization in patients with low ejection fraction: a report from the society of thoracic surgeons national database. AB - BACKGROUND: The purpose of this study was to evaluate outcomes of patients with low ejection fraction who underwent surgical coronary revascularization with or without cardiopulmonary bypass (CPB). METHODS: The Society of Thoracic Surgeons National Database was queried from January 1, 2008, to June 30, 2011 for patients with an ejection fraction of less than 0.30 who underwent primary, nonemergent coronary artery bypass (CAB) grafting. The entire cohort of 25,667 patients was divided into those who underwent revascularization with (ONCAB, n = 20,509) and without (OPCAB, n = 5,158) CPB. OPCAB patients who were converted to CPB intraoperatively were counted as intended OPCAB and were included in the OPCAB group. Propensity scores were estimated using 32 covariates, and multivariate logistic regression was used to compare risk-adjusted outcomes between groups. RESULTS: Patients undergoing planned OPCAB were older, more frequently female, and had a lower body mass index than those who underwent ONCAB. The OPCAB cohort also had higher rates of prior stroke, peripheral vascular disease, and chronic lung disease. The predicted mortality risk was 2.3% for the OPCAB cohort vs 2.1% for the ONCAB group (p < 0.0001). Of the 5,158 patients who underwent OPCAB, unplanned conversion to CPB occurred in 270 (5.2%). OPCAB was associated with significantly lower adjusted risk of death (odds ratio [OR], 0.82), stroke (OR, 0.67), major adverse cardiac events (OR, 0.75), and prolonged intubation (OR, 0.78). Postoperative transfusion rates were significantly lower in the OPCAB group (44.8% vs 51.6%, p < 0.001). There were no adverse outcomes that occurred more commonly in OPCAB patients. The advantage associated with OPCAB was found in the entire Society of Thoracic Surgeons National Database and among high-volume and low-volume OPCAB centers. CONCLUSIONS: In The Society of Thoracic Surgeons National Database, OPCAB is associated with significantly reduced adjusted risk of early morbidity and mortality for patients having coronary bypass grafting with an ejection fraction of less than 0.30. PMID- 23743062 TI - Strategies for tricuspid re-repair in Ebstein malformation using the cone technique. AB - BACKGROUND: Successful tricuspid repair for Ebstein malformation (EM) is challenging. Cone repair has recently emerged as the most anatomic repair technique. There are no data on tricuspid re-repair in EM. We reviewed our experience with tricuspid valve (TV) re-repair using a cone technique. METHODS: Between June 2007 and October 2012, 134 patients underwent cone repair. Prior TV repair was performed in 20 patients (10 female, 50%). Median age was 15 years (range, 4 to 68 years). Four patients (20%) had prior bidirectional cavopulmonary anastomosis (BDCPA). Preoperative heart failure was present in 8 patients (40%). Recurrent tricuspid regurgitation (TR) was due to incomplete leaflet coaptation with tethered anterior leaflet in all patients; and 10 patients (50%) had diminutive septal leaflet. Prior repair techniques consisted of annuloplasty maneuvers in all patients with no or incomplete surgical delamination in all patients. RESULTS: The TV re-repair using cone technique was possible in all patients. Plication of atrialized right ventricle was done in 6 patients (30%). Modifications included annuloplasty band in 16 patients (80%) and TV leaflet augmentation in 8 (40%). The BDCPA was performed in 3 patients (15%) and modified Cox-maze procedure was done in 10 (50%). There were no mortalities or reoperations. Mean follow-up was 7.7 +/- 10.7 months; during follow-up, 18 patients had no or mild TR and 2 had moderate TR. CONCLUSIONS: TV re-repair in EM using the cone technique is feasible, particularly when there has been no surgical leaflet delamination at initial operation. Leaflet augmentation facilitates and annuloplasty band stabilizes a competent TV re-repair. Longer follow-up is required to assess durability. PMID- 23743063 TI - Anatomic repair for corrected transposition with left ventricular outflow tract obstruction. AB - BACKGROUND: We investigated the long-term outcomes of anatomic repair for congenitally corrected transposition of great arteries (ccTGA) and its variant associated with left ventricular outflow tract obstruction (LVOTO) and ventricular septal defect (VSD). METHODS: From 1987 to 2011, 47 patients (27 with pulmonary atresia and 20 with pulmonary stenosis) with ccTGA and its variant associated with LVOTO and VSD underwent anatomic repair. The mean operative age was 5.5 +/- 3.7 years old (range, 1.6 to 21.3). The preoperative right ventricular end-diastolic volume was 133% +/- 31% (81 to 222) of their normal size. The atrial switch procedure was Mustard in 31 patients and Senning in 16, with the latter used in all from 2002. RESULTS: The mean follow-up period was 11.6 +/- 7.3 years (maximum, 22.7). The VSD was concomitantly enlarged in 4 patients and Damus-Kaye-Stansel (DKS) anastomosis was added in 9 patients with pulmonary stenosis and restrictive VSD. The overall survival rate at 20 years was 70.2% and no mortality has been observed in 21 consecutive patients since 1997. No patient required reoperation for the postoperative systemic ventricular outflow tract obstruction. A surgical heart block developed in 1 patient (2.1%) who underwent concomitant VSD enlargement. None of the patients developed a moderate or greater aortic or neo-aortic regurgitation. CONCLUSIONS: Recent outcomes after anatomic repair for congenitally corrected transposition of great arteries associated with LVOTO and VSD were excellent. For patients with pulmonary stenosis and restrictive VSD, additional DKS anastomosis seems to be an effective approach to avoid postoperative systemic ventricular outflow tract obstruction and surgical heart block. PMID- 23743064 TI - The society of thoracic surgeons esophageal cancer guideline series. PMID- 23743065 TI - Platelet-activating factor receptor knockout mice are protected from MPTP-induced dopaminergic degeneration. AB - Platelet-activating factor (PAF), a potent mediator of inflammatory and immune responses, plays various roles in neuronal functions. However, little is known about the role of PAF/platelet-activating factor receptor (PAF-R) in Parkinson's disease. Treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) resulted in significant increases in PAF species in the striatum of wild-type mice. These increases paralleled PAF-R gene expression in wild-type mice. Although nuclear factor kappa B (NF-kappaB) DNA-binding activity was increased significantly in MPTP-treated wild-type mice, this increase was not significant in PAF-R antagonist ginkgolide B (GB)-treated mice or PAF-R knockout (PAF-R(-/-)) mice. Pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor, significantly ameliorated the dopaminergic deficits induced by MPTP in wild-type mice. MPTP treatment significantly increased oxidative damage, the immunoreactivity of ionized calcium binding adaptor molecule 1 (Iba-1)-positive microglial cells, and microglial differentiation of the M1 type in the striatum of wild-type mice. Consistently, PDTC significantly attenuated MPTP-induced behavioral impairments in wild-type mice. However, dopaminergic deficits, oxidative damage, reactive microglial cells, and behavioral impairments induced by MPTP were not significantly observed in GB-treated mice or PAF-R(-/-) mice. PDTC did not significantly alter the attenuations evident in MPTP-treated PAF-R(-/-) mice, indicating that NF-kappaB is a critical target for neurotoxic modulation of PAF R. We propose for the first time that PAF/PAF-R can mediate dopaminergic degeneration via an NF-kappaB-dependent signaling process. PMID- 23743066 TI - Improving development of cloned goat embryos by supplementing alpha-lipoic acid to oocyte in vitro maturation medium. AB - alpha-Lipoic acid (LA) is a powerful antioxidant for clinical therapy of some metabolic diseases, but there are few reports about the effect of LA on animal occyte in vitro maturation (IVM). The objective of this study is to investigate the effect of supplementing LA to IVM medium on subsequently developmental competence of goat cloning embryos after somatic cell nucleus transfer (SCNT). Twenty-five micromolars LA significantly increased 12% oocyte maturation rate from control 57.8% to treated group 69.8% (P < 0.05). The reconstructed rate of cloning embryos in LA supplement group (67.3%) was significantly higher than control (56.5%, P < 0.05). Although the SCNT embryo cleavage rates did not have significant difference between the two groups (42.0% vs. 47.9%, P > 0.05), LA supplement group had significantly higher blastocyst formation rate and hatched rate than control (24.0% vs. 18.4% and 37.0% vs. 30.9%, respectively, P < 0.05). In addition, supplementing LA significantly reduced the cellular apoptosis rate of nucleus transfer blastocysts by inhibiting the expression of apoptotic activators, such as Bax, Bad, Caspase-3, and CytC genes and promoting cumulus oocyte complexes to synthesize glutathione (GSH) and express antioxidant enzymes such as GPX4 and SOD genes. In conclusion, supplement of LA to oocyte IVM medium could improve the maturation rate and antioxidant ability of oocytes and increase the developmental competence of oocytes after SCNT. PMID- 23743067 TI - Characterization of the ovarian cycle in the two-toed sloths (Choloepus didactylus): an innovative, reliable, and noninvasive method using fecal hormone analyses. AB - Little is known about reproductive physiology in the two-toed sloth (Choloepus didactylus). Therefore, the aim of this study was to obtain detailed information about the ovarian cycle. Measurements of reliable gonadal steroids in the feces of this species were undertaken. For this purpose, fecal samples were collected one to three times per week from nonpregnant captive females (n = 2) over a 16 month period. Before assay analysis, the fecal samples were extracted with methanol. Radioimmunoassays and enzyme immunoassays for fecal progesterone, estradiol-17beta, pregnanediol-glucuronide (PdG), and estrone sulfate were tested for their ability to detect the ovarian activity. Using the lowest and highest progesterone values, the ovarian cycle length was comparatively analyzed. The ovarian cycle (n = 26) averaged between 31.4 +/- 9.1 days (lowest progesterone) and 32.5 +/- 7.5 days (highest progesterone) throughout the whole year. The length of the follicular phase, as indicated by low progesterone levels, was 18.1 +/- 4.4 days (range 12-25 days), and the length of the luteal phase, as characterized by elevated progesterone levels, was 13.2 +/- 1.8 days (range 11-16 days). In contrast, estradiol-17beta and estrone sulfate were not suitable to detect the cycle due to irregular collection intervals. Fecal progesterone and PdG, as well as estradiol-17beta and estrone sulfate, significantly correlated (r = 0.621, P < 0.01 and r = 0.606, P < 0.01). PdG concentrations (dilution factor (DF) 1:40) were considerably higher than progesterone concentrations (DF 1:10), PdG amounted in the range of 1326.7 +/- 320.2 ng/g wet feces (animal S1) and 1373.8 +/- 468.3 ng/g wet feces (animal S2) compared with progesterone concentrations in the range of 98.0 +/- 17.0 ng/g (S1) and 105.9 +/- 30.0 ng/g (S2). The estrone sulfate levels (DF 1:2) were similar to estradiol-17beta (DF 1:22). The mean fecal estradiol-17beta concentrations were 6.7 +/- 0.9 ng/g for animal S1 and 7.5 +/- 1.6 ng/g for animal S2. In conclusion, the ovarian activity of the two-toed sloth was studied using the noninvasive method by means of the fecal steroid monitoring. Progesterone was the most reliable fecal steroid hormone to determine the duration of the ovarian cycle independent of the weekly defecation rate. The course of progesterone concentrations resulted in a cycle length of 4-5 weeks length in the two-toed sloth. Thus, the reproductive activity of the two-toed sloth does not show any seasonality like the three-toed sloth. PMID- 23743069 TI - Echocardiographic assessment of mitral regurgitation: general considerations. AB - Echocardiography is undoubtedly one of the main tools used in assessment of mitral regurgitation (MR) because it allows characterization of valvular morphology, assessment of the severity of the regurgitation, and its secondary effects. In this article we present an overview of the echocardiographic assessment of MR. PMID- 23743070 TI - How to grade mitral regurgitation: an integrative approach. AB - Evaluation of mitral regurgitation (MR) severity remains complex and challenging. An integrative approach to grading MR is recommended. The use of multiple Doppler methods should be used to help discriminate between grades of severity. Importantly, MR severity should always be considered in the context of clinical data. The emerging inclusion of 3-dimensional echocardiography may provide complementary data for MR quantification and better anatomic and pathophysiological detail of the mitral valve. This article summarizes recommendations for MR assessment and highlights the importance of an integrated approach, using anatomic information as well as qualitative and quantitative Doppler measures. PMID- 23743071 TI - Echocardiographic assessment of mitral stenosis: echocardiographic features of rheumatic mitral stenosis. AB - Echocardiography (echo) is the primary imaging modality for rheumatic mitral stenosis. Portable echo devices are a useful tool for early identification and treatment of rheumatic heart disease, and prevention of chronic sequelae. The salient echo data are mitral valvular morphology, valve area, transmitral gradient, pulmonary hypertension, and concomitant valvular disease. Apart from its diagnostic role, echo aids assessment of patient candidacy for percutaneous balloon valvuloplasty versus surgery. Baseline echocardiographic features are strong independent predictors of procedural success and long-term outcome. Evolving technology such as 3-dimensional echo has the potential to improve the understanding and management of this globally relevant disease. PMID- 23743072 TI - Calcific mitral stenosis. AB - The mitral valve annulus is a complex structure that is an integral part of the mitral valve apparatus. The annulus plays an active role in mitral valve leaflet coaptation and in left atrial and ventricular function. The annulus is susceptible to disease processes that are distinct from those that affect the mitral valve leaflets. Advanced annular calcification may extend onto the mitral valve leaflets, thereby causing increased diastolic gradients across the mitral valve. This review highlights risk factors for mitral annular calcification, features of calcific mitral stenosis, differentiation from rheumatic mitral valve disease, and the echocardiographic approach to this disorder. PMID- 23743068 TI - Anatomy of the mitral valve apparatus: role of 2D and 3D echocardiography. AB - The mitral valve apparatus is a complex 3-dimensional (3D) functional unit that is critical to unidirectional heart pump function. This review details the normal anatomy, histology, and function of the main mitral valve apparatus components: mitral annulus, mitral valve leaflets, chordae tendineae, and papillary muscles. Two-dimensional and 3D echocardiography is ideally suited to examine the mitral valve apparatus and has provided important insights into the mechanism of mitral valve disease. An overview of standardized echocardiography image acquisition and interpretation is provided. Understanding normal mitral valve apparatus function is essential to comprehend alterations in mitral valve disease and the rationale for repair strategies. PMID- 23743073 TI - The role of 3-dimensional echocardiography in the diagnosis and management of mitral valve disease: myxomatous valve disease. AB - Myxomatous mitral valve (MV) disease is a spectrum that ranges from fibroelastic deficiency to Barlow's disease. Diagnosis has been greatly aided by the use of 3 dimensional echocardiography, which improves not only the accuracy of lesion localization but also the quantification of the associated mitral regurgitation. These improvements in turn have altered MV surgical repair techniques and percutaneous interventions. PMID- 23743074 TI - The role of echocardiography in the management of patients with myxomatous disease. AB - Degenerative mitral regurgitation (MR), the leading cause of organic MR in western countries, is primarily characterized by mitral valve prolapse but encompasses a wide spectrum of anatomic lesions from fibroelastic deficiency (localized prolapse segment often associated with ruptured chordae) to diffuse myxomatous degeneration (Barlow's disease, diffuse excessive tissue with multiple valvular segments involved). Echocardiography is the method of choice to evaluate patients with degenerative MR and plays a crucial role in clinical management. It allows accurate assessment of MR severity, left ventricular and atrial consequences, etiology, mechanisms and anatomic lesions and consequently defines the probability of mitral valve repair. PMID- 23743075 TI - Ischemic (functional) mitral regurgitation. AB - Mitral regurgitation (MR) is a frequent complication of myocardial infarction and coronary artery disease that is associated with adverse prognosis. The main mechanism of ischemic MR relates to distortion of the spatial relationships between the mitral valve and papillary muscles secondary to ventricular remodeling. The evidence that treatment of ischemic MR improves long-term survival still remains unclear, and further studies are needed to determine whether correcting ischemic MR will improve survival and/or symptoms. PMID- 23743076 TI - The role of echocardiography during mitral valve percutaneous interventions. AB - Transesophageal echocardiography is routinely used to guide percutaneous interventions involving the mitral valve. Mitral balloon valvuloplasty for rheumatic mitral valve stenosis (MS) was the first percutaneous intervention to gain wide acceptance. New techniques have been developed to treat degenerative and functional mitral regurgitation (MR) as well as paravalvular mitral leak (PVML). This review describes the use of echocardiography for transcatheter treatment of MS, MR, and PVML. PMID- 23743077 TI - 3-dimensional echocardiography and its role in preoperative mitral valve evaluation. AB - Echocardiography plays a key role in the preoperative evaluation of mitral valve disease. 3-dimensional echocardiography is a relatively new development that is being used more and more frequently in the evaluation of these patients. This article reviews the available literature comparing the use of this new technology to classic techniques in the assessment of mitral valve pathology. The authors also review some of the novel insights learned from 3-dimensional echocardiography and how they may be used in surgical decision making and planning. PMID- 23743078 TI - Mitral prosthetic valve assessment by echocardiographic guidelines. AB - Compared with a native valve, the prosthetic valve is inherently obstructive, and the type and size of prosthesis determines what is considered normal function. The assessment of mitral prosthetic valve function requires an integrative process using 2-dimensional, 3-dimensional, and Doppler echocardiographic modalities, in addition to transesophageal and transthoracic echocardiography. The echocardiographic interpretation of function depends on knowing the exact type, size, and even the date of implantation. This review discusses the echocardiographic assessment of prosthetic mitral valve function based on current American and European guidelines. PMID- 23743079 TI - Stress echocardiography and mitral valvular heart disease. AB - The European Society of Cardiology's updated guidelines emphasize the usefulness of exercise stress echocardiography in patients with valvular heart disease. Exercise-induced changes in valve hemodynamics should be assessed in patients with mitral valve disease. In asymptomatic patients with moderate or severe mitral regurgitation without left ventricular dysfunction/dilatation, exercise stress echocardiography may identify a subset of patients with reduced cardiac event-free survival who are at a higher risk of developing symptoms. In patients with mitral stenosis who are asymptomatic, the development of symptoms during exercise is strongly related to the kinetics of the changes in the systolic pulmonary arterial pressure. PMID- 23743080 TI - Echocardiography in mitral valve disease. Preface. PMID- 23743081 TI - Counterpoise between the microbiome, host immune activation and pathology. AB - The role of the mammalian intestinal microbiota in health and disease of the host has long been recognized and extensively studied. Largely, these studies have focused on the bacterial component of the microbiota. However, recent technological advances have shed new light on the microbiome at distinct anatomical locations and uncovered the role of additional microbial symbionts, including the virome and endogenous retroelements. Together, they have revealed interactions more intricate than previously recognized. Here, we review recent advances in our knowledge of this collective microbiome and the interactions with the immune system of their host. PMID- 23743082 TI - Gene regulatory networks in the genomics era. PMID- 23743083 TI - MRI lesions: a surrogate for relapses in multiple sclerosis? PMID- 23743084 TI - MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials. AB - BACKGROUND: A meta-analysis of randomised trials in relapsing-remitting multiple sclerosis published in 2009 showed a quantitative relation between the treatment effects detected on MRI lesions and clinical relapses. We aimed to validate that relation using data from a large and independent set of clinical trials in multiple sclerosis. METHODS: We searched Medline for clinical trials that assessed disease-modifying drugs for relapsing-remitting multiple sclerosis published from Sept 1, 2008, to Oct 31, 2012. We extracted data for the treatment effects on MRI lesions and on relapses from each trial, and the correlation of log transformed relative measures of these treatment effects was assessed with a weighted linear regression analysis. The R(2) value was estimated to quantify the strength of the correlation, and we used an interaction test to test for a difference in slope from the previously estimated equation. We also ran several sensitivity analyses. FINDINGS: We identified 31 eligible trials, which provided data for 18 901 patients with relapsing-remitting multiple sclerosis. The regression equation derived using data from these studies showed a relation between the concurrent treatment effects on MRI lesions and relapses (slope=0.52; R(2)=0.71), much the same as was previously estimated (pinteraction=0.45). Analysis of trials that tested the same drugs in phase 2 and phase 3 studies showed that the effects on MRI lesions over short follow-up periods (6-9 months) can also predict the effects on relapses over longer follow-up periods (12-24 months), with reported effects on relapses that were within the 95% prediction intervals in eight of nine trials. INTERPRETATION: Our findings indicate that the effect of a treatment on relapses can be accurately predicted by the effect of that therapy on MRI lesions, implying that the use of MRI markers as primary endpoints in future clinical trials of treatments for multiple sclerosis can be considered, in specific situations, such as in trials testing generics or biosimilars of drugs with a well known mechanism of action or in paediatric trials testing drugs already approved for adults. FUNDING: None. PMID- 23743085 TI - Temporal sparse free-form deformations. AB - FFD represent a widely used model for the non-rigid registration of medical images. The balance between robustness to noise and accuracy in modelling localised motion is typically controlled by the control point grid spacing and the amount of regularisation. More recently, TFFD have been proposed which extend the FFD approach in order to recover smooth motion from temporal image sequences. In this paper, we revisit the classic FFD approach and propose a sparse representation using the principles of compressed sensing. The sparse representation can model both global and local motion accurately and robustly. We view the registration as a deformation reconstruction problem. The deformation is reconstructed from a pair of images (or image sequences) with a sparsity constraint applied to the parametric space. Specifically, we introduce sparsity into the deformation via L1 regularisation, and apply a bending energy regularisation between neighbouring control points within each level to encourage a grouped sparse solution. We further extend the sparsity constraint to the temporal domain and propose a TSFFD which can capture fine local details such as motion discontinuities in both space and time without sacrificing robustness. We demonstrate the capabilities of the proposed framework to accurately estimate deformations in dynamic 2D and 3D image sequences. Compared to the classic FFD and TFFD approach, a significant increase in registration accuracy can be observed in natural images as well as in cardiac images. PMID- 23743086 TI - Ambulatory thyroidectomy: recommendations from the Association Francophone de Chirurgie Endocrinienne (AFCE). Investigating current practices. AB - BACKGROUND: Cervical hematoma with airway compromise is a severe complication that may be rapidly lethal or result in irreversible cerebral anoxia if the hematoma is not urgently decompressed. It is therefore indispensable to know the essential relevant elements as well as predictive criteria for this complication before envisioning ambulatory thyroidectomy. METHODS: The Association francophone de chirurgie endocrinienne (AFCE) sought to answer several questions raised by the proposal of ambulatory thyroidectomy and to propose recommendations based on a review of the literature, an inquiry sent out to members of the AFCE, and an in depth research of the medicolegal risks involved, based essentially on jurisprudence. The details scrutinized included preoperative selection criteria, the characteristics of the operation and the basic elements of postoperative surveillance. CONCLUSIONS: The standard today is at least an overnight hospital stay. In fact, hospital stay can be less than 24h because the risk of cervical compressive hematoma is very unusual beyond this interval. Ambulatory (outpatient) thyroidectomy (0 nights) is possible under certain conditions for highly selected patients according to criteria described in the literature that also define relative contra-indications. In case of life-threatening or functional complications, the surgeon stands first in the line of responsibility. The surgeon must therefore ensure that the patient and family were fully informed of the contra-indications, the normal course of postoperative events, of pertinent elements of postoperative surveillance and of the conditions under which the patient can be safely discharged. The surgeon must also realize that this type of management is time-consuming. PMID- 23743087 TI - Improving antimicrobial stewardship: AmWeb, a tool for helping microbiologists in England to 'Start Smart' when advising on antibiotic treatment. AB - As part of an antimicrobial stewardship programme, healthcare organizations should have local antibiotic treatment guidelines in place that take account of local antibiotic resistance patterns. The current issue of JAC reports the development of an interactive web tool, called AmWeb, for the local surveillance of resistance by hospital laboratories in England. The application of AmWeb should help to both optimize the management of patients with infection and contribute to efforts to prolong the active life of antibiotics currently available for use. PMID- 23743088 TI - Long-term survival in patients included in a randomized controlled trial of TREAT, a decision support system for antibiotic treatment. AB - OBJECTIVES: TREAT is a computerized decision support system for antibiotic treatment. In a randomized controlled trial it improved significantly the percentage of appropriate empirical antibiotic treatment and shortened hospital stay, while the usage of broad-spectrum antibiotics was reduced. The trial was not powered to show significance for the difference in 1 month mortality rate. In the present analysis we looked at 6 month survival in one of the hospitals (Beilinson Hospital) that participated in the trial. METHODS: We plotted the Kaplan-Meier survival function for all patients [intention to treat (ITT)] and for patients treated according to the TREAT advice [per protocol (PP)]. The analysis was repeated for patients with clinically or bacteriologically documented bacterial infections. RESULTS: At Beilinson Hospital 1683 patients were included in the study, 860 in the intervention arm and 823 in the control arm. In the ITT analysis 180 day survival in control patients was 71% versus 74% in the intervention patients (P = 0.2). In the PP analysis the survival percentages were 71% and 77%, respectively (P = 0.04). In patients with bacterial infections, in the ITT analysis 180 day survival in the control group was 68% versus 71% in the intervention patients (P = 0.1). In the PP analysis the survival percentages were 68% versus 74% (P = 0.04). CONCLUSIONS: The present data support an effect of the TREAT decision support system on 6 month survival, mainly because of its benefit in patients with documented bacterial infections. PMID- 23743089 TI - Emtricitabine compared with lamivudine may preserve future therapeutic options in HIV-1-infected children. PMID- 23743090 TI - An optoelectronic based approach for handwriting capture. AB - Clinical practice for the evaluation of motor and cognitive capabilities often relies upon writing and drawing tests. A non-invasive method to capture handwriting and analyze data is therefore needed. In this work a method to capture motion of a pen through a mo-cap optoelectronic system was developed, which could solve the limits of systems based on graphic tablets. Four IR passive markers were placed on a pen cap. Once a pen was equipped with the cap, track of tip was computed through a numeric algorithm using the 3D coordinates of markers provided by the optoelectronic system. Some tests were performed to estimate the error in track reconstruction and to compare the new protocol with previous reconstruction methods. The results showed a higher accuracy of the new method. The new protocol also overcomes the problems related to pen grasping and marker covering that affected other methods described in the literature and permits the evaluation of writing and drawing kinematics as well as postural behaviour related to them. PMID- 23743092 TI - Effect of CNC-milling on the marginal and internal fit of dental ceramics: a pilot study. AB - OBJECTIVES: Machined restorations have been investigated for their preciseness before, while detailed information on the milling-step itself are lacking. Therefore, the aim of this laboratory study was to quantify the effect of a novel milling-procedure on the marginal and internal fit of ceramic restorations. METHODS: An acrylic model of a lower left first molar was prepared to receive a ceramic partial crown and was duplicated by one step dual viscosity impressions. Gypsum casts were formed and laser-scanned to realize virtual datasets, before restorations were designed, exported (PRE) and machined from lithium disilicate blanks. Crowns were digitized by a structure-light-scanner to obtain post-milling data (POST). PRE and POST were virtually superimposed on the reference tooth and subjected to computer-aided-inspection. Visual fit-discrepancies were displayed with colors, while root mean square deviations (RMSD) and degrees of similarity (DS) were computed and analysed by t-tests for paired samples (n=5, alpha=0.05). RESULTS: The milling procedure resulted in a small increase of the marginal and internal fit discrepancies (RMSD mean: 3MUm and 6MUm, respectively). RMSD differences were not statistically significant (p=0.495 and p=0.160 for marginal and internal fit, respectively). These results were supported by the DS data. SIGNIFICANCE: The products of digital dental workflows are prone to imprecisions. However, the present findings suggest that differences between computer-aided designed and actually milled restorations are small, especially when compared to typical fit discrepancies observed clinically. Imprecisions introduced by digital design or production processes are small. PMID- 23743093 TI - Gerbera micropropagation. AB - Gerbera jamesonii (gerbera) is an important cut-flower in the global floricultural industry. Micropropagation is the main system used to clonally propagate gerbera in vitro resulting in the production of millions of plantlets each year. Numerous types of explants and protocols for micropropagation have been established and used for gerbera. Shoot tips are the commonly used explant while adventitious shoot induction from the capitulum is also a popular method. Most papers in the literature have focused on testing the influence of different types and combinations of plant growth regulators with the aim of improving the regeneration and multiplication stage of one or few cultivars. Genotype is one of the most influential factors on the response of gerbera in vitro. Despite this, no successful universal protocol has yet been developed for multiple cultivars, limiting the usefulness of current protocols for commercial biotechnology labs. Slow-growing endogenous bacteria are one of the most important problems in gerbera micropropagation but require more studies on control and prevention. Individual shoots are normally easy to root, usually in excess of 90% of plantlets, but the acclimatization stage requires improvements and new technologies to increase the survival of plants. Epigenetic variations in micropropagated gerbera are frequently observed only with high concentrations of cytokinins in the culture medium but somaclonal variation is rare. PMID- 23743095 TI - The economics of tobacco use in Jordan. AB - INTRODUCTION: We conducted an independent survey of tobacco use in Jordan following the methods and template of the Global Adult Tobacco Survey. Using data collected on cigarette use and cigarette prices, we estimated the price elasticity of cigarette demand in Jordan. METHODS: We used a 2-part model of cigarette demand. In the first part, we estimate the impact of prices on the decision to smoke while controlling for individual demographic and environmental characteristics. Conditional on smoking, we then estimate the effect of price on the number of cigarettes smoked. RESULTS: The total price elasticity of cigarette demand in Jordan was estimated to be -0.6. Smoking among women was found to be relatively unresponsive to price (elasticity of -0.01), whereas smoking among men was much more responsive to price (elasticity of -0.81). CONCLUSIONS: The price elasticity estimates suggest that significant increases in tobacco taxes are likely to be effective in reducing smoking in Jordan, particularly smoking among men. PMID- 23743096 TI - The influence of prices on youth tobacco use in India. AB - INTRODUCTION: The tobacco epidemic has been rapidly spreading in many of the poorer nations of the world, including India. Although studies assessing the impact of prices on youth smoking in countries such as the United States are abundant, comparable research on Indian youth has been largely unavailable due to lack of data at the national level. This study aims to bridge this disparity in tobacco research. METHODS: We used data from the Global Youth Tobacco Survey, a national survey among 73,356 youth of age 13-15 years in India, to estimate the price elasticity of tobacco use among Indian youth for three tobacco products: cigarettes, bidi, and gutka. RESULTS: Higher prices can be an effective deterrent to youth tobacco use, irrespective of the form of tobacco. Among the products considered, bidis have the highest price elasticity of participation (-2.70), followed by gutka (0.58) and cigarettes (-0.40). In gender-specific analyses, girls have significantly higher participation price elasticities than boys. CONCLUSION: The results of this study indicate that fiscal measures to increase the price of tobacco products would be effective in curbing the tobacco epidemic in India. PMID- 23743094 TI - Prenatal substance exposure: neurobiologic organization at 1 month. AB - OBJECTIVE: To examine the autonomic nervous system and neurobehavioral response to a sustained visual attention challenge in 1-month-old infants with prenatal substance exposure. STUDY DESIGN: We measured heart rate, respiratory sinus arrhythmia, and neurobehavior during sustained visual orientation tasks included in the Neonatal Intensive Care Unit Network Neurobehavioral Scale in 1129 1-month old infants with prenatal substance exposure. Four groups were compared: infants with prenatal cocaine and opiate exposure, infants with cocaine exposure, infants with opiate exposure, and infants with exposure to other substances (ie, alcohol, marijuana, and tobacco). RESULTS: The infants with prenatal exposure to both cocaine and opiates had the highest heart rates and lowest levels of respiratory sinus arrhythmia during a sustained visual attention challenge compared with the other 3 groups. Infants with prenatal cocaine and opiate exposure had poorer quality of movement and more hypertonicity during the Neonatal Intensive Care Unit Network Neurobehavioral Scale examination. They also had more nonoptimal reflexes and stress/abstinence signs compared with infants with prenatal exposure to cocaine only and those with prenatal exposure to alcohol, tobacco, and marijuana. CONCLUSION: Problems with arousal regulation were identified in infants with prenatal substance exposure. Autonomic dysregulation has been implicated as a mechanism by which these difficulties occur. Our results suggest that infants with prenatal exposure to both cocaine and opiates have the greatest autonomic response to the challenge of a sustained visual attention task, possibly putting these infants at risk for problems associated with physiologic and behavioral regulation, a necessary prerequisite for early learning. PMID- 23743097 TI - Management of thyroid follicular proliferation: an ultrasound-based malignancy score to opt for surgical or conservative treatment. AB - This study was conducted to evaluate whether ultrasound characteristics of thyroid nodules with a known cytologic diagnosis of "follicular pattern" (indicative of follicular hyperplasia, follicular adenoma or follicular carcinoma) can be used to define a nodule malignancy score to limit surgery to selected, higher-risk cases. In pre-operative ultrasound results of patients diagnosed with a "follicular pattern" on cytology who subsequently underwent surgery, each nodule feature was given a score from 0 (most likely benign) to 2 (most likely malignant), resulting in a total score ranging from 0 to 11. The total nodule score (total malignancy score) was then compared with the definitive histologic diagnosis. According to our results, surgery is advisable in patients with score >=4 (79% of carcinomas), ultrasound follow-up seems to be appropriate for patients with a score of 3 (21% of carcinomas) and no action is recommended for patients with score <3 (only benign nodules). PMID- 23743098 TI - Arthroscopic ultrasound technique for simultaneous quantitative assessment of articular cartilage and subchondral bone: an in vitro and in vivo feasibility study. AB - Traditional arthroscopic examination is subjective and poorly reproducible. Recently, we introduced an arthroscopic ultrasound method for quantitative diagnostics of cartilage lesions. Here we describe our investigation of the feasibility of ultrasound arthroscopy for simultaneous measurements of articular cartilage and subchondral bone. Human osteochondral samples (n = 13) were imaged using a clinical 9-MHz ultrasound system. Ultrasound reflection coefficients (R, IRC), the ultrasound roughness index (URI) and the apparent integrated backscattering coefficient (AIB) were determined for both tissues. Mechanical testing, histologic analyses and micro-scale computed tomography imaging were the reference methods. Ultrasound arthroscopies were conducted on two patients. The ultrasound reflection coefficient correlated with the Mankin score and Young's modulus of cartilage (|r| > 0.56, p < 0.05). Ultrasound parameters (R, IRC, AIB) for subchondral bone correlated with the bone surface/volume ratio (|r| > 0.70, p < 0.05) and trabecular thickness (|r| > 0.59, p < 0.05). Furthermore, R and subchondral bone mineral density were significantly correlated (|r| > 0.65, p < 0.05). Arthroscopic ultrasound examination provided diagnostically valuable information on cartilage and subchondral bone in vivo. PMID- 23743099 TI - Creating brain lesions with low-intensity focused ultrasound with microbubbles: a rat study at half a megahertz. AB - Low-intensity focused ultrasound was applied with microbubbles (Definity, Lantheus Medical Imaging, North Billerica, MA, USA; 0.02 mL/kg) to produce brain lesions in 50 rats at 558 kHz. Burst sonications (burst length: 10 ms; pulse repetition frequency: 1 Hz; total exposure: 5 min; acoustic power: 0.47-1.3 W) generated ischemic or hemorrhagic lesions at the focal volume revealed by both magnetic resonance imaging and histology. Shorter burst time (2 ms) or shorter sonication time (1 min) reduced the probability of lesion production. Longer pulses (200 ms, 500 ms and continuous wave) caused significant near-field damage. Using microbubbles with focused ultrasound significantly reduced acoustic power levels and, therefore, avoided skull heating issues and potentially can extend the treatable volume of transcranial focused ultrasound to brain tissues close to the skull. PMID- 23743100 TI - Abdominal aortic aneurysm imaging with 3-D ultrasound: 3-D-based maximum diameter measurement and volume quantification. AB - The clinical reliability of 3-D ultrasound imaging (3-DUS) in quantification of abdominal aortic aneurysm (AAA) was evaluated. B-mode and 3-DUS images of AAAs were acquired for 42 patients. AAAs were segmented. A 3-D-based maximum diameter (Max3-D) and partial volume (Vol30) were defined and quantified. Comparisons between 2-D (Max2-D) and 3-D diameters and between orthogonal acquisitions were performed. Intra- and inter-observer reproducibility was evaluated. Intra- and inter-observer coefficients of repeatability (CRs) were less than 5.18 mm for Max3-D. Intra-observer and inter-observer CRs were respectively less than 6.16 and 8.71 mL for Vol30. The mean of normalized errors of Vol30 was around 7%. Correlation between Max2-D and Max3-D was 0.988 (p < 0.0001). Max3-D and Vol30 were not influenced by a probe rotation of 90 degrees . Use of 3-DUS to quantify AAA is a new approach in clinical practice. The present study proposed and evaluated dedicated parameters. Their reproducibility makes the technique clinically reliable. PMID- 23743101 TI - Design and evaluation of a wearable self-applied therapeutic ultrasound device for chronic myofascial pain. AB - Ultrasound therapy for pain and healing is a versatile treatment modality for musculoskeletal conditions that is used daily in rehabilitation clinics around the world. Our group designed and constructed a wearable, battery-operated, low intensity therapeutic ultrasound (LITUS) device that patients could self-apply and operate during daily activity for up to 6 h. Thirty patients with chronic trapezius myofascial pain evaluated the LITUS system in a double-blind, placebo controlled, 10-d study under institutional review board approval. While continuing their prescribed medication regimen, patients with the active device reported on average 1.94* reduction in pain and 1.58* improvement in health relative to placebo devices after 1 h of treatment. Both of these results were statistically significant (p < 0.05) for the first 2 d of the study. Male patients reported the majority of benefit, and there is a sex-treatment confound in the sample. The study indicates that wearable, long-duration LITUS technology improves mobile access to drug-free pain relief. PMID- 23743102 TI - Three-dimensional HDlive rendering images of the fetal heart. AB - Our objective is to describe our experience with reconstruction of normal fetal cardiac structures and congenital heart anomalies using the 3-D HDlive rendering mode with spatiotemporal image correlation (STIC). Four normal fetuses and three fetuses with congenital heart anomalies (Ebstein's anomaly, hypoplastic left heart syndrome and tetralogy of Fallot) at 25-35 wk of gestation were studied using the 3-D HDlive rendering mode with STIC. In normal fetuses, the natural appearance of the dynamic motion of the foramen ovale flap and both atrioventricular valves was clearly visualized in real time in the four-chamber view. Moreover, new, realistic sensations of each leaflet of atrioventricular valves and semilunar valves of the pulmonary artery were obtained in the en face view of both atrioventricular valves and great vessels. In the case of Ebstein's anomaly, the procedure rendered the natural and anatomically realistic appearance of significantly low attachment of the tricuspid valve and atrialized portion of the right ventricle. In hypoplastic left heart syndrome, thickened tricuspid and dysplastic pulmonary valves were clearly revealed. In tetralogy of Fallot, an overriding aorta and ventricular septal defect were realistically depicted. The 3 D HDlive rendering mode with STIC provides entirely new visual experiences for obstetricians and pediatric cardiologists owing to the anatomically realistic depiction of normal and abnormal fetal cardiac structures of the beating heart. PMID- 23743103 TI - Comparative study of standing wave reduction methods using random modulation for transcranial ultrasonication. AB - Various transcranial sonotherapeutic technologies have risks related to standing waves in the skull. In this study, we present a comparative study on standing waves using four different activation methods: sinusoidal (SIN), frequency modulation by noise (FMN), periodic selection of random frequency (PSRF), and random switching of both inverse carriers (RSBIC). The standing wave was produced and monitored by the schlieren method using a flat plane and a human skull. The minimum ratio RSW, which is defined by the ratio of the mean of the difference between local maximal value and local minimal value of amplitude to the average value of the amplitude, was 36% for SIN, 24% for FMN, 13% for PSRF, and 4%for RSBIC for the flat reflective plate, and it was 25% for SIN, 11% for FMN, 13% for PSRF, and 5% for RSBIC for the inner surface of the human skull. This study is expected to have a role in the development of safer therapeutic equipment. PMID- 23743104 TI - Left ventricular longitudinal strain and strain rate measured by 2-D speckle tracking echocardiography in neonates during whole-body hypothermia. AB - The purpose of the study was to assess changes in cardiac performance in newborn infants with hypoxic-ischemic encephalopathy during therapeutic hypothermia and rewarming with two-dimensional speckle tracking echocardiography. For eight asphyxiated neonates (median birth weight (range): 3038 (2725-3253) g; umbilical artery pH: 6.9 (6.8-7.18) undergoing whole-body hypothermia (33-34 degrees C), left ventricular longitudinal strain and strain rate, as well as heart rate, cardiac output and left ventricular fractional shortening, were determined at four points in time: the start (T1) and end of hypothermia (T2), immediately after rewarming (T3) and the age of 5 to 7 d (T4). Mean (standard deviation) heart rate increased from 93 (12) beats/min at T1 to 133 (12) beats/min at T4 (p < 0.001). Cardiac output was low during hypothermia (T1: 207 [43] mL/kg/min, T2: 240 [70] mL/kg/min) and increased significantly (p < 0.001) afterward (T3: 329 [70] mL/kg/min, T4: 388 [78] mL/kg/min). Left ventricular fractional shortening remained unchanged. Left ventricular global longitudinal peak systolic strain did not differ significantly between hypothermia and rewarming, whereas the systolic strain rate increased from -1.1 (0.3) s(-1) at T1 to -1.8 (0.26) s(-1) at T4 (p = 0.001). Hypothermia affects peak systolic strain rate, heart rate and cardiac output, with complete recovery after rewarming, whereas peak systolic strain and fractional shortening remain stable. PMID- 23743105 TI - Second harmonic and subharmonic for non-linear wideband contrast imaging using a capacitive micromachined ultrasonic transducer array. AB - When insonified with suitable ultrasound excitation, contrast microbubbles generate various non-linear scattered components, such as the second harmonic (2H) and the subharmonic (SH). In this study, we exploit the wide frequency bandwidth of capacitive micromachined ultrasonic transducers (CMUTs) to enhance the response from ultrasound contrast agents by selective imaging of both the 2H and SH components simultaneously. To this end, contrast images using the pulse inversion method were recorded with a 64-element CMUT linear array connected to an open scanner. In comparison to imaging at 2H alone, the wideband imaging including both the 2H and SH contributions provided up to 130% and 180% increases in the signal-to-noise and contrast-to-tissue ratios, respectively. The wide frequency band of CMUTs offers new opportunities for improved ultrasound contrast agent imaging. PMID- 23743106 TI - Liver stiffness measurements by means of supersonic shear imaging in patients without known liver pathology. AB - We used supersonic shear imaging to determine the liver stiffness (LS) values of 82 patients without known liver pathology and studied the factors that influence these measurements. Five LS measurements were made in each subject, and the median value, expressed in kilopascals, was calculated. Reliable LS measurements were obtained in 84.5% of patients. Higher body mass index and older age were associated with failure to obtain reliable measurements. The mean value of LS measurements determined by SSI in our cohort of patients without known liver pathology was 6 +/- 1.4 kPa. The mean LS measurements determined by SSI for men were significantly higher than those for women; body mass index did not significantly influence SSI measurements. Thus, 6 kPa is the mean SSI value in patients without known liver pathology, with higher values being obtained in men. PMID- 23743107 TI - tRNA binding, positioning, and modification by the pseudouridine synthase Pus10. AB - Pus10 is the most recently identified pseudouridine synthase found in archaea and higher eukaryotes. It modifies uridine 55 in the TPsiC arm of tRNAs. Here, we report the first quantitative biochemical analysis of tRNA binding and pseudouridine formation by Pyrococcus furiosus Pus10. The affinity of Pus10 for both substrate and product tRNA is high (Kd of 30nM), and product formation occurs with a Km of 400nM and a kcat of 0.9s(-1). Site-directed mutagenesis was used to demonstrate that the thumb loop in the catalytic domain is important for efficient catalysis; we propose that the thumb loop positions the tRNA within the active site. Furthermore, a new catalytic arginine residue was identified (arginine 208), which is likely responsible for triggering flipping of the target uridine into the active site of Pus10. Lastly, our data support the proposal that the THUMP-containing domain, found in the N-terminus of Pus10, contributes to binding of tRNA. Together, our findings are consistent with the hypothesis that tRNA binding by Pus10 occurs through an induced-fit mechanism, which is a prerequisite for efficient pseudouridine formation. PMID- 23743108 TI - Colonoscopy results are not enhanced by use of magnet endoguide in specialist practice. AB - INTRODUCTION: It is discussed whether the use of a magnetic positioning device (OLYMPUS; UPD (unit of magnetic positioning device)) enhances the success of the colonoscopic procedure. Concern for patient compliance and endoscopic efficiency has been voiced in connection with the implementation of colon cancer screening. UPD has been proposed as a tool for optimization of results and reduction of patient discomfort. In this study, we aimed to qualify the debate by examining the success rate and patient discomfort in an unselected colonoscopy population referred to specialist clinics with experienced investigators. Furthermore, the study assessed the effect of using a UPD. MATERIAL AND METHODS: A total of 1,068 consecutive patients referred for colonoscopy were enrolled and randomised for investigation with or without use of UPD. The evaluation endpoints were: success rate (coecum visualised, ileal intubation was carried out at the investigator's discretion), duration of procedure, and patient discomfort indicated by the patient as a visual analogue scale score. RESULTS: No significant differences between the two investigational procedures were demonstrated in relation to the chosen endpoints. CONCLUSION: UPD is convenient to have, but not a necessity for colonoscopy. FUNDING: The study was supported by the Danish Association of Medical Specialists. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency, journal no. 2009-41-3716, the National Ethics Committee, journal no.: H-1-2009-80, and registered with ClinicalTrials.gov., protocol no: NCT01055782. PMID- 23743109 TI - Treatment goals for ambulatory blood pressure and plasma lipids after stroke are often not reached. AB - INTRODUCTION: In Danish health care, secondary prevention after stroke is currently handled mainly by general practitioners using office blood pressure (OBP) assessment of hypertension. The aim of this study was to compare the OBP approach to 24-hour assessment by ambulatory blood pressure (ABP) monitoring. Furthermore, we aimed to record the degree of adherence to recommended therapy goals for blood pressure and plasma lipids. MATERIAL AND METHODS: In a prospective observational study, 45 stroke patients aged 25-64 years who were participating in specialized intensive outpatient rehabilitation were monitored by OBP and ABP on average 1.3 (0.14-4.3) years post stroke. Furthermore, data on additional risk factors and medication for secondary prevention were collected. RESULTS: OBP and daytime ABP exceeded the therapy goal of 130/80 mmHg in 71% and 44% of the patients, respectively. ABP exceeded the night-time therapy goal of 115/65 in 57% of cases. Normal dipping at night was found in only 41% (systolic) and 32% (diastolic) of the patients. Considering both day- and night-time blood pressure, antihypertensive medication was absent or inadequate in 60%. Low density lipid (LDL) levels exceeded the recommended limit of 2.5 mmol/l in 49%. CONCLUSION: For blood pressure (BP) and cholesterol, secondary prevention is far from ideal in post-stroke patients. Compared with OBP, ABP demands more resources, but in turn yields more reliable results and also provides important information about diurnal BP variation. ABP monitoring at least once after stroke should therefore be implemented routinely. FUNDING: Aase og Einar Danielsens Fond. TRIAL REGISTRATION: not relevant. PMID- 23743110 TI - Nitrous oxide provides safe and effective analgesia for minor paediatric procedures--a systematic review. AB - INTRODUCTION: Pain and distress during minor hospital-related procedures is a familiar problem in many children. Inadequate relief of children's procedural pain and distress not only affects the experience of the children and their parents, but also adversely impacts procedural success. We aimed to review the safety and efficacy of nitrous oxide during brief, but painful paediatric procedures and to compare nitrous oxide with some of the commonly used pharmacological and non-pharmacological treatments for relieving anxiety and mild to moderate pain in Denmark. METHOD: We searched MEDLINE (PubMed) and the Cochrane Database of Systematic Reviews with the MeSH term nitrous oxide combined with midazolam, surgical procedures minor, analgesia or conscious sedation. The references in the articles acquired that were not found in the MEDLINE search were further investigated. Only articles written in English and published after 1980 were included to ensure optimal data collection. RESULTS: Nitrous oxide is an effective sedative/analgesic for mildly to moderately painful paediatric procedures. Furthermore, it is safely administrated, particularly for short procedures (< 15 min.). Serious and potentially serious adverse events are rare and occur in less than 0.5% of cases, while minor events typically occur amongst 4-8% of patients. CONCLUSION: Nitrous oxide is a safe and effective method to achieve analgesia and sedation during minor, but painful procedures. It can be safely administered by a dedicated staff member. This helpful method is still underused in Denmark, and we believe that it could be an alternative or the first choice of treatment in emergency and paediatric departments. PMID- 23743111 TI - The content of macronutrients in milk from mothers of very preterm infants is highly variable. AB - INTRODUCTION: The objective of this study was to determine the content of macronutrients in human milk (HM) from mothers who gave birth very prematurely, and to investigate possible associations between macronutrients and certain maternal and infant characteristics. MATERIAL AND METHODS: Mothers of very preterm infants with a gestational age (GA) below 32 weeks expressed milk for analysis two weeks after birth, every second week until discharge, at term, at two, and at four months of corrected age. The milk was analyzed using mid infrared transmission spectroscopy. RESULTS: A total of 214 mothers delivered 736 HM samples for analysis. Two weeks after birth, protein content varied from 1.06 to 2.96 with a mean of 1.76 g/100 ml HM, and the mean protein content decreased significantly until eight weeks after birth (p < 0.04). Previous breastfeeding experience was associated with a lower protein content (p = 0.04) two weeks after birth. HM from mothers of extremely preterm infants (GA < 28 weeks) had a higher fat and energy content two weeks after birth than infants with a GA of 28-32 weeks (p = 0.001). CONCLUSION: Protein content in human milk varies considerably between mothers, and decreases within weeks after very preterm birth. Previous breastfeeding experience and low GA were associated with a lower protein and a higher fat and energy content in HM, respectively. Inter-individual differences in human milk content possibly influences nutrition and this raises the question of the need for an individualized approach when fortifying human milk for preterm infants. FUNDING: This study was funded by the Clinical Institute at the University of Southern Denmark and The Dagmar Marshall Foundation. TRIAL REGISTRATION: Approved by the Danish National Committee on Biomedical Research Ethics (J.no. VF20030208). PMID- 23743112 TI - Pseudomonas aeruginosa in patients without cystic fibrosis is strongly associated with chronic obstructive lung disease. AB - INTRODUCTION: The objective of this study was to investigate the occurrence and consequences of Pseudomonas aeruginosa infection in a group of non-cystic fibrosis (CF) patients with regard to clinical presentation, treatment and change in lung function. MATERIAL AND METHODS: This was a three-year retrospective study of 113 patients with P. aeruginosa-positive airway samples achieved from the Department of Clinical Microbiology, Aarhus University Hospital, Denmark. Medical records were reviewed in order to register patient demographics, symptoms, co morbidity, pulmonary function tests (PFT), treatment, X-ray/computed tomography findings and mortality. Finally, deterioration of lung function was evaluated by comparing the first and last available PFT in the period of observation. RESULTS: Most patients had several co-morbidities and only seven patients had none. 62% had a diagnosis of chronic obstructive pulmonary disease (COPD). We found a significant decrease in lung function within the observation period among patients with P. aeruginosa-infection as evidenced by all measured PFT-parameters except the forced expiratory volume in the first second/forced vital capacity ratio. A total of 27 patients (24%) died within the observation period. CONCLUSION: P. aeruginosa is an opportunistic bacterium infecting primarily patients with severe lung disease. Our data show a significant reduction in lung function among P. aeruginosa-positive non-CF patients over a three-year period of time. The reduction, however, is not different than otherwise reported in COPD patients in general leading to no conclusion as to whether this pathogen is a marker of disease progression or the cause for progression itself. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23743113 TI - T1a glottic cancers may be removed by "cold steel" excision biopsies. AB - INTRODUCTION: Phonosurgical excision biopsies are gradually replacing traditional punch biopsies during direct lar-yngoscopy. As excision aims at removing all pathologic tissue, some malignant lesions may be completely removed. We present our experience with phonosurgical excision biopsies of T1a glottic cancers without primary radiotherapy. MATERIAL AND METHODS: From 2001 till 2010, 24 patients with T1a glottic squamous cell carcinoma did not receive primary radiotherapy as tumours could not be observed at the post-operative control or because of concurrent malignancy or the presence of other co-morbidity. All lesions were excised by instrumental ("cold steel") phonosurgery in which only the epithelial layer above the vocal ligament was removed (type 1 cordectomy). All patients were closely followed by an ear-nose-throat (ENT) surgeon in collaboration with a radiation oncologist. RESULTS: Relapse was observed in nine of the 24 patients (37.5 %), all within 12 months. The per-operative evaluation of resectability and the results of margin biopsies were insufficient for prediction of recurrence risk. Neither tumour size, primary or secondary excision nor differentiation of the carcinoma influenced the relapse rate. CONCLUSION: T1a glottic cancers may be removed by "cold steel" phonosurgical excision biopsies, but this is inferior to treatment with radiotherapy or laser-assisted phonosurgery. As more than half of the patients did not need radiotherapy, phonosurgery may be considered as sole treatment in selected cases, provided close follow-up with videostroboscopy for the first year after surgery is performed. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23743114 TI - Small-bore chest tubes seem to perform better than larger tubes in treatment of spontaneous pneumothorax. AB - INTRODUCTION: The aim of this study was to compare the efficacy and complications of surgical (large-bore) chest tube drainage with smaller and less invasive chest tubes in the treatment of non-traumatic pneumothorax (PT). MATERIAL AND METHODS: This was a retrospective study of 104 cases (94 patients) of non-traumatic PT treated with chest tubes - either by pulmonary physicians (daytime and weekdays) using small-bore chest tubes, or by orthopaedic surgeons (remaining time slots) using large-bore chest tubes. RESULTS: A total of 62 had primary spontaneous PT, 30 had secondary spontaneous PT and 12 had iatrogenic PT. A total of 62 patients were treated with large-bore (20-28 Fr) chest tubes placed with traditional thoracotomy, 42 patients were treated by a pulmonary physician, and in 30 of these cases a True-Close thoracic vent (11-13 Fr) was inserted. Patients treated with surgical chest tubes were comparable with patients treated with smaller chest tubes in terms of demographic data and type and size of PT. Compared with patients treated with smaller chest tubes, patients with surgical large-bore tubes had more complications (27.4% versus 9.5%; p = 0.026), a lower success rate (56.5% versus 85.7%; p = 0.002), and longer duration of chest tube (8.3 versus 4.9 days; p = 0.001) and of hospitalisation (11.8 versus 6.9 days; p = 0.004). CONCLUSION: We found small chest tubes to be superior to large-bore chest tubes with regard to short-term outcomes in the treatment of non-traumatic PT. FUNDING: not relevant. TRIAL REGISTRATION: The project was approved by the Danish Data Protection Agency, file no. 2012-41-0554. PMID- 23743115 TI - Acceptable short-term outcome of laparoscopic subtotal colectomy for inflammatory bowel disease. AB - INTRODUCTION: Laparoscopic colectomy for both benign and malignant disease, including inflammatory bowel disease (IBD), has recently been shown to have many advantages compared with open surgery. This study aimed to compare the effect of laparoscopic versus open subtotal colectomy (STC) for IBD on overall morbidity. MATERIAL AND METHODS: A total of 99 patients undergoing STC for IBD at our institution from 2007 through 2011 were identified. Patients undergoing open STC were compared with patients undergoing laparoscopic STC. Outcomes included 30-day morbidity, conversion to laparotomy, intraoperative blood loss, operative time, admission time, late onset complications and 30-day mortality. Results are presented as median values. RESULTS: A total of 57 patients underwent open STC (Group 1) and 42 patients laparoscopic STC (Group 2). Group 1 comprised 26 males and 31 females, with a median age of 35 years and a body mass index (BMI) of 23.2 kg/m2. Group 2 comprised 18 males and 24 females, with a median age of 34 years and a BMI of 23.5 kg/m2. Group 2 had less morbidity (42.9% versus 75.4%, p < 0.002), reduced blood loss (100 ml versus 200 ml, p < 0.001), longer operative time (193.5 min. versus 128 min., p < 0.001), shorter length of hospital stay (six days versus 16 days, p < 0.001) than Group 1. One patient died (Group 1). There was no difference in late onset complications and no conversions to laparotomy in the laparoscopic group. CONCLUSION: Laparoscopic STC has a longer operative time, but improves short-term outcomes compared with open surgery. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 23743116 TI - Biologic therapy in inflammatory bowel disease. AB - In luminal Crohn's disease with moderate to severe inflammatory activity, infliximab and adalimumab can be used in the case of treatment failure with conventional therapies, such as systemic steroids and immunosuppressive therapy or if this treatment is not tolerated. Further treatment strategy depends on the primary response to induction therapy. Effect of maintenance therapy should be evaluated clinically and paraclinically at least every 26-52 weeks, and maybe supplemented by endoscopy or MRI scan. Decision of treatment discontinuation is based on disease manifestation, treatment response and paraclinical parameters. In fistulising Crohn's disease, treatment with infliximab or adalimumab can be initiated in simple fistula with rectal inflammation or complex fistula when the initial treatment has insufficient effect. Further treatment strategy depends on the primary response to induction therapy. Maintenance therapy is often necessary in complex fistulas. Treatment efficacy and possible discontinuation of treatment is evaluated at least every 26-52 weeks - if possibly with diagnostic imaging. In acute severe ulcerative colitis, treatment with infliximab can be used in patients with partial response after 3-5 days of treatment with a high-dose systemic steroid and when surgical treatment is not preferred or required. Further treatment strategy depends on the response to the first drug administration and colectomy should always be considered as an option. Effect of subsequent initiated maintenance therapy should be evaluated at least every 26-52 weeks on the basis of symptoms, clinical markers, paraclinical parameters and possibly by endoscopy. In chronic active ulcerative colitis, infliximab and adalimumab can be used in the case of treatment with immunosuppressive therapy fails and if surgery is not preferred. Further treatment strategy depends on the response to induction therapy. Treatment efficacy is assessed by symptoms, clinical markers, paraclinical parameters and possibly by endoscopy. Effect of maintenance therapy should be evaluated at least every 26-52 weeks. During treatment with biologic drugs focus should be on possible complications, such as infections, infusion or injection reactions and dermatological side effects. An overview of levels of evidence and recommendations is presented. PMID- 23743117 TI - Complement activation in diseases presenting with thrombotic microangiopathy. AB - The complement system contains a great deal of biological "energy". This is demonstrated by the atypical hemolytic uremic syndrome (aHUS), which is a thrombotic microangiopathy (TMA) characterized by endothelial and blood cell damage and thrombotic vascular occlusions. Kidneys and often also other organs (brain, lungs and gastrointestinal tract) are affected. A principal pathophysiological feature in aHUS is a complement attack against endothelial cells and blood cells. This leads to platelet activation and aggregation, hemolysis, prothrombotic and inflammatory changes. The attacks can be triggered by infections, pregnancy, drugs or trauma. Complement-mediated aHUS is distinct from bacterial shiga-toxin (produced e.g. by E. coli O:157 or O:104 serotypes) induced "typical" HUS, thrombotic thrombocytopenic purpura (TTP) associated with ADAMTS13 (an adamalysin enzyme) dysfunction and from a recently described disease related to mutations in intracellular diacylglycerol kinase epsilon (DGKE). Mutations in proteins that regulate complement (factor H, factor I, MCP/CD46, thrombomodulin) or promote (C3, factor B) amplification of its alternative pathway or anti-factor H antibodies predispose to aHUS. The fundamental defect in aHUS is an excessive complement attack against cellular surfaces. This can be due to 1) an inability to regulate complement on self cell surfaces, 2) hyperactive C3 convertases or 3) complement activation and coagulation promoting changes on cell surfaces. The most common genetic cause is in factor H, where aHUS mutations disrupt its ability to recognize protective polyanions on surfaces where C3b has become attached. Most TMAs are thus characterized by misdirected complement activation affecting endothelial cell and platelet integrity. PMID- 23743118 TI - Is plasma homocysteine related to severity and outcome of atherothrombotic stroke? Comment on: acute phase homocysteine related to severity and outcome of atherothrombotic stroke. PMID- 23743119 TI - Comparison of anticancer activity between lactoferrin nanoliposome and lactoferrin in Caco-2 cells in vitro. AB - The anticancer activities of Lactoferrin (Lf) and Lf nanoliposomes in Caco-2 cells were observed in this study, and mitochondrial function (MTT assay), count kit-8(CCK-8), detection of intracellular reactive oxygen species (ROS) and apoptosis induction (AO/EB staining) assays were used to evaluate the anticancer activity. MTT results demonstrated that Lf nanoliposomes and Lf reduced the mitochondrial activity of cells in a manner of dose and time effect, and the viabilities of Caco-2 cell were significantly decreased in vitro following exposure to Lf nanoliposomes at the concentrations of 5 and 10 mg/mL. LDH leakage and ROS significantly increased in cells exposed to Lf nanoliposomes (>=5 mg/mL), while Lf induced ROS only at higher doses (10mg/mL). CCK-8 evaluation of cell proliferation and AO/EB double staining supported the anti-proliferative effects of Lf liposomes. Our findings demonstrated that the presence of Lf nanoliposome is more significant than Lf in inhibiting human tumor cells proliferation. Therefore, it can be concluded that Lf nanoliposomes are a potential therapeutic modality in the management of tumors. PMID- 23743120 TI - Effects of Korean red ginseng extract on acute renal failure induced by gentamicin and pharmacokinetic changes by metformin in rats. AB - AIM OF THE STUDY: Korean red ginseng is one of the best selling dietary supplements and its individual constituents enhance renal function. Acute renal failure (ARF) is a predisposing complication of diabetes mellitus as a result of combination drug therapy. The combination of antibiotic-antidiabetic drugs can entail toxicities and drug interactions because of the antibiotic resistance in patients with severe bacterial infection. Currently, gentamicin-metformin combination therapy is commonly prescribed for treating bacterial infections and diabetes, even though both drugs are mainly excreted via the kidney. Thus, this study was designed to investigate whether a Korean red ginseng extract (KRG) prevents renal impairment and pharmacokinetic changes by metformin in rats with renal failure induced by gentamicin. MATERIALS AND METHODS: The in vivo pharmacokinetics and in vitro hepatic/intestinal metabolism of metformin were assessed using control (CON), control with Korean red ginseng extract (KRG-CON), acute renal failure induced by gentamicin (ARF), and ARF with Korean red ginseng (KRG-ARF) rats. RESULTS AND CONCLUSIONS: Pharmacokinetic changes of metformin did not occur in KRG-ARF rats because KRG reduce the renal accumulation of gentamicin compared to ARF rats. Thus, KRG seemed to prevent acute renal failure induced by gentamicin treatment. PMID- 23743121 TI - Extensive right ventricular hemangioma. PMID- 23743122 TI - President's page: Honoring those who have served with high quality cardiovascular care. PMID- 23743123 TI - Antiphospholipid syndrome and recurrent thrombotic valve disease. PMID- 23743124 TI - Protein labeling with fluorogenic probes for no-wash live-cell imaging of proteins. AB - Protein labeling by using a protein tag and its specific fluorescent probe is increasingly becoming a useful technique for the real-time imaging of proteins in living cells. Recently, fluorogenic probes for protein labeling were developed. When using these probes, a washing step is not required for the removal of free probes from the cells, thus, allowing rapid detection of proteins in living cells with high signal-to-noise ratio. Various chemical principles have been applied in the designing of probes to include a turn-on fluorescence switch that is activated by the protein labeling reaction. In this review, we describe about the design strategy of the probes and the advances in fluorogenic protein labeling systems. PMID- 23743126 TI - Insights into chronic gamma-herpesvirus infections. PMID- 23743125 TI - Modulation of SAP dependent T:B cell interactions as a strategy to improve vaccination. AB - Generating long-term humoral immunity is a crucial component of successful vaccines and requires interactions between T cells and B cells in germinal centers (GC). In GCs, a specialized subset of CD4+ helper T cells, called T follicular helper cells (Tfh), provide help to B cells; this help directs the magnitude and quality of the antibody response. Tfh cell help influences B cell survival, proliferation, somatic hypermutation, class switch recombination, and differentiation. Sustained contact between Tfh cells and B cells is necessary for the provision of help to B cells. SAP (Signaling lymphocytic activation molecule (SLAM)-associated protein, encoded by Sh2d1a) regulates the duration of T:B cell interactions and is required for long-term humoral immunity in animal models and in humans. SAP binds to SLAM family receptors and mediates signaling that affects cell adhesion, cytokine secretion, and TCR signaling strength. Therefore, the modulation of SAP and SLAM family receptor expression represents a major axis by which the quality and duration of an antibody response is controlled after vaccination. PMID- 23743128 TI - CUDA accelerated method for motion correction in MR PROPELLER imaging. AB - In PROPELLER, raw data are collected in N strips, each locating at the center of k-space and consisting of Mx sampling points in frequency encoding direction and L lines in phase encoding direction. Phase correction, rotation correction, and translation correction are used to remove artifacts caused by physiological motion and physical movement, but their time complexities reach O(Mx*Mx*L*N), O(N*RA*Mx*L*(Mx*L+RN*RN)), and O(N*(RN*RN+Mx*L)) where RN*RN is the coordinate space each strip gridded onto and RA denotes the rotation range. A CUDA accelerated method is proposed in this paper to improve their performances. Although our method is implemented on a general PC with Geforce 8800GT and Intel Core(TM)2 E6550 2.33GHz, it can directly run on more modern GPUs and achieve a greater speedup ratio without being changed. Experiments demonstrate that (1) our CUDA accelerated phase correction achieves exactly the same result with the non accelerated implementation, (2) the results of our CUDA accelerated rotation correction and translation correction have only slight differences with those of their non-accelerated implementation, (3) images reconstructed from the motion correction results of CUDA accelerated methods proposed in this paper satisfy the clinical requirements, and (4) the speed up ratio is close to 6.5. PMID- 23743127 TI - gamma-Herpesvirus-encoded miRNAs and their roles in viral biology and pathogenesis. AB - To date, more than 200 viral miRNAs have been identified mostly from herpesviruses and this rapidly evolving field has recently been summarized in a number of excellent reviews (see [1,2]). Unique to gamma-herpesviruses, like Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus, is their ability to cause cancer. Here, we discuss gamma-herpesvirus-encoded miRNAs and focus on recent findings which support the hypothesis that viral miRNAs directly contribute to pathogenesis and tumorigenesis. The observations that KSHV mimics a human tumorigenic miRNA (hsa-miR-155), which is induced in EBV-infected cells and required for the survival of EBV-immortalized cells, lead to a number of studies demonstrating that perturbing this pathway induces B cell proliferation in vivo and immortalization of human B cells in vitro. Secondly, the application of state of the art ribonomics methods to globally identify viral miRNA targets in virus infected tumor cells provides a rich resource to the KSHV and EBV fields and largely expanded our understanding on how viral miRNAs contribute to viral biology. PMID- 23743129 TI - Acellular vascular grafts generated from collagen and elastin analogs. AB - Tissue-engineered vascular grafts require long fabrication times, in part due to the requirement of cells from a variety of cell sources to produce a robust, load bearing extracellular matrix. Herein, we propose a design strategy for the fabrication of tubular conduits comprising collagen fiber networks and elastin like protein polymers to mimic native tissue structure and function. Dense fibrillar collagen networks exhibited an ultimate tensile strength (UTS) of 0.71+/-0.06 MPa, strain to failure of 37.1+/-2.2% and Young's modulus of 2.09+/ 0.42 MPa, comparing favorably to a UTS and a Young's modulus for native blood vessels of 1.4-11.1 MPa and 1.5+/-0.3 MPa, respectively. Resilience, a measure of recovered energy during unloading of matrices, demonstrated that 58.9+/-4.4% of the energy was recovered during loading-unloading cycles. Rapid fabrication of multilayer tubular conduits with maintenance of native collagen ultrastructure was achieved with internal diameters ranging between 1 and 4mm. Compliance and burst pressures exceeded 2.7+/-0.3%/100 mmHg and 830+/-131 mmHg, respectively, with a significant reduction in observed platelet adherence as compared to expanded polytetrafluoroethylene (ePTFE; 6.8+/-0.05*10(5) vs. 62+/-0.05*10(5) platelets mm(-2), p<0.01). Using a rat aortic interposition model, early in vivo responses were evaluated at 2 weeks via Doppler ultrasound and CT angiography with immunohistochemistry confirming a limited early inflammatory response (n=8). Engineered collagen-elastin composites represent a promising strategy for fabricating synthetic tissues with defined extracellular matrix content, composition and architecture. PMID- 23743130 TI - Cell interactions between human progenitor-derived endothelial cells and human mesenchymal stem cells in a three-dimensional macroporous polysaccharide-based scaffold promote osteogenesis. AB - Several studies have reported the benefits of mesenchymal stem cells (MSCs) for bone tissue engineering. However, vascularization remains one of the main obstacles that must be overcome to reconstruct large bone defects. In vitro prevascularization of the three-dimensional (3-D) constructs using co-cultures of human progenitor-derived endothelial cells (PDECs) with human bone marrow mesenchymal stem cells (HBMSCs) appeared as a potential strategy. However, the crosstalk between the two lineages has been studied in two-dimensional (2-D), but remains unknown in 3-D. The aim of this study is to investigate the cell interactions between PDECs and HBMSCs in a porous matrix composed of polysaccharides. This biodegradable scaffold promotes cell interactions by inducing multicellular aggregates composed of HBMSCs surrounded by PDECs. Cell aggregation contributes to the formation of junctional proteins composed of Connexin43 (Cx43) and VE-cadherin, and an activation of osteoblastic differentiation of HBMSCs stimulated by the presence of PDECs. Inhibition of Cx43 by mimetic peptide 43GAP27 induced a decrease in mRNA levels of Cx43 and all the bone-specific markers. Finally, subcutaneous implantations for 3 and 8 weeks in NOG mice revealed an increase in osteoid formation with the tissue-engineered constructs seeded with HBMSCs/PDECs compared with those loaded with HBMSCs alone. Taking together, these results demonstrate that this 3-D microenvironment favored cell communication, osteogenesis and bone formation. PMID- 23743131 TI - New insights into the pathogenesis of bladder exstrophy-epispadias complex. AB - Bladder exstrophy-epispadias complex (BEEC) is a complex and debilitating congenital disease. Familial and twin studies suggest a possible genetic component in BEEC pathogenesis. Bladder mesenchyme (detrusor) development requires induction by a signal from bladder urothelium, and we and others have shown the Shh-Gli-Bmp4 signalling pathway is likely to be involved. P63 is a master regulator in epithelial stratification and is expressed in urothelium. We have shown that p63 knock-out mice undergo excessive urothelial apoptosis. Failure of mesenchymal induction by epithelium leads to BEEC. We further demonstrated that insertion/deletion (in/del) polymorphisms (1 base pair (bp) ins and 4 bp ins., and 12 bp del) in the DeltaNP63 promoter reduce transcriptional efficiency, and are associated with a statistically significant increase in the risk of BEEC in humans. Furthermore, a Genome-Wide Expression Profiling (GWEP) study suggests possible involvement of PERP in human BEEC. Intriguingly, PERP is a direct target of p63 during development, and is also involved in epithelial stratification. PERP co-localizes with desmosome, and both PERP and desmosome are essential for maintaining tissue integrity by cellular adhesion and epithelial stratification. A recent study showed that PERP and desmosome expression levels are abnormal in human BEEC patients. This review describes the role of the P63 > PERP > desmosome pathway in the development of human bladder during embryogenesis. We hypothesize that disruption of this pathway may increase the risk of BEEC. PMID- 23743132 TI - Do not forget to include testicular torsion in differential diagnosis of lower acute abdominal pain in young males. AB - BACKGROUND: Management and outcomes of pediatric patients with testicular torsion initially presenting as acute abdominal pain were evaluated. PATIENTS AND METHODS: The case records of 84 children operated on for testicular torsion from January 1999 through May 2012 were retrospectively reviewed. Of the total number of operated patients, 9 presented with abdominal pain but without initial scrotal pain, and only they were included in the study. The diagnosis of testicular torsion was made clinically and confirmed by Doppler ultrasound and scrotal exploration. RESULTS: The most common presenting symptoms were abdominal pain and vomiting. The patient's scrotum and testicles were not examined during the first evaluation in 6 cases, while in 3 cases the testicles were examined during the first physical examination. At surgery, 4 testes were salvaged, while 5 have been lost because of testicular necrosis. The mean duration of symptoms was 4 h in the group of salvaged testes and 39 h in the orchidectomy group. There were no major complications. CONCLUSION: Testicular torsion should always be included in differential diagnosis when evaluating lower abdominal pain in young males. The external genital organs should be examined in every child or adolescent with acute abdominal pain. PMID- 23743133 TI - Toxicological effects induced by the nanomaterials fullerene and nanosilver in the polychaeta Laeonereis acuta (Nereididae) and in the bacteria communities living at their surface. AB - Fullerene (nC60) and nanosilver (nAg) are nanomaterials with bactericide properties. The increments in their use raise questions about their potential environmental impacts, including estuarine ones. The polychaete Laeonereis acuta (Nereididae) secretes mucus that is colonized by bacteria communities. We analyzed the antioxidant and oxidative damage responses of anterior, middle and posterior region of L. acuta and bacteria communities after nC60 or nAg exposure during 24 h. Molecular analysis showed a prevalence of Vibrio genera in the communities. Bacteria biomass was lowered in worms exposed to 1.0 mg/L of nAg. nC60 reduced total antioxidant capacity of bacteria from worms exposed to 0.1 mg/L. Worms anterior region presented lower antioxidant capacity after exposure to 1.0 mg nC60/L, and the same was observed in the posterior region of worms exposed to 1.0 mg nAg/L. Lipid peroxidation was reduced in the anterior region of worms exposed to nC60 and the opposite was observed in the posterior region. PMID- 23743134 TI - Can protective factors moderate the detrimental effects of child maltreatment on personality functioning? AB - OBJECTIVE: The aim of this study was to examine whether, and if so, to what extent, education and coping strategies may reduce the detrimental effects of childhood maltreatment on personality functioning. METHODS: We assessed dimensional trait-scores of all 10 DSM-IV personality disorders (PDs), childhood maltreatment, education and three coping styles in 511 subjects of the general population of Zurich, Switzerland, using data from the ZInEP Epidemiology Survey. RESULTS: Childhood maltreatment was associated with all 10 PDs. Low education was related to antisocial, borderline and histrionic PD. Low emotion-focused coping was associated with paranoid, schizoid, borderline, avoidant, and obsessive compulsive PD. Low problem-focused coping was related to schizoid PD and high problem-focused coping to histrionic PD. High dysfunctional coping was significantly related to all 10 PD dimensions. Obsessive-compulsive trait scores were significantly lower in maltreated subjects with high emotion-focused coping. Antisocial, borderline and narcissistic trait scores were significantly higher in maltreated subjects with high dysfunctional coping. CONCLUSION: Education and adaptive coping may have a protective effect on PD symptomatology. Promotion of adaptive coping and suppression of dysfunctional coping may additionally reduce PD symptoms specifically in maltreated subjects. Those findings have important clinical implications. Longitudinal research is needed to address questions of causality and to evaluate potential effects of treatment and intervention. PMID- 23743135 TI - Reduced but broader prefrontal activity in patients with schizophrenia during n back working memory tasks: a multi-channel near-infrared spectroscopy study. AB - BACKGROUND: Caudal regions of the prefrontal cortex, including the dorsolateral (DLPFC) and ventrolateral (VLPFC) prefrontal cortex, are involved in essential cognitive functions such as working memory. In contrast, more rostral regions, such as the frontopolar cortex (FpC), have integrative functions among cognitive functions and thereby contribute crucially to real-world social activity. Previous functional magnetic resonance imaging studies have shown patients with schizophrenia had different DLPFC activity pattern in response to cognitive load changes compared to healthy controls; however, the spatial relationship between the caudal and rostral prefrontal activation has not been evaluated under less constrained conditions. METHOD: Twenty-six patients with schizophrenia and 26 age , sex-, and premorbid-intelligence-matched healthy controls participated in this study. Hemodynamic changes during n-back working memory tasks with different cognitive loads were measured using multi-channel near-infrared spectroscopy (NIRS). RESULTS: Healthy controls showed significant task-related activity in the bilateral VLPFC and significant task-related decreased activity in the DLPFC, with greater signal changes when the task required more cognitive load. In contrast, patients with schizophrenia showed activation in the more rostral regions, including bilateral DLPFC and FpC. Neither decreased activity nor greater activation in proportion to elevated cognitive load occurred. CONCLUSIONS: This multi-channel NIRS study demonstrated that activation intensity did not increase in patients with schizophrenia associated with cognitive load changes, suggesting hypo-frontality as cognitive impairment in schizophrenia. On the other hand, patients had broader prefrontal activity in areas such as the bilateral DLPFC and FpC regions, thus suggesting a hyper-frontality compensatory response. PMID- 23743136 TI - Reply to Silvia Selinski, Daniel Ovsiannikov, Jan G. Hengstler and Klaus Golka's Letter to the editor re: Caroline E. Weibull, Sandra Eloranta, Daniel Altman, Anna L.V. Johansson, Mats Lambe. Childbearing and the risk of bladder cancer: a nationwide population-based cohort study. Eur Urol 2013;63:733-8. PMID- 23743137 TI - Modeling costs for prostate surgery: are we close to reality? PMID- 23743139 TI - Gender and ethnic differences in the prevalence of type 2 diabetes among Asian subgroups in California. AB - AIMS: To investigate gender and ethnic type 2 diabetes (DM) prevalences among California Asian subgroups versus other ethnic groups and if risk factors explain these differences. METHODS: We identified the prevalence of DM and associated risk factors, stratified by gender, among Chinese, Filipino, South Asian, Japanese, Korean, Vietnamese, Mexican, Other Hispanic, African-American, Caucasian, and Native American adults in a large survey conducted in 2009 (n=46,091, projected n=26.6 million). RESULTS: The highest age-adjusted DM prevalence was seen in Native Americans (32.4%), Filipinos (15.8%), and Japanese (11.8%) among men and in Native Americans (16.0%) and African-Americans (13.3%) among women. Caucasian and Mexican men had higher DM prevalences than women. Age and risk factor-adjusted logistic regression showed DM more likely (relative to Caucasians) among women in Koreans (OR=4.6, p<0.01), Native Americans (OR=3.0, p<0.01), and Other Hispanics (OR 2.9, p<0.01) and among men in Filipinos (OR=7.0, p<0.01), South Asians (OR=4.7, p<0.01), and Native Americans (OR=4.7, p<0.01). No specific risk factors accounted for the gender differences. CONCLUSIONS: Ethnic and gender differences in DM prevalence persist, even after adjusting for lifestyle and other risk factors; prevalence is high among certain Asian American subgroups. Different diabetes prevention approaches may be needed across ethnic/gender groups. PMID- 23743140 TI - A rare case of cardiac hemangioma causing ventricular fibrillation. PMID- 23743141 TI - Pulmonary vein ablation in a patient with a massive left atrial paraganglioma. PMID- 23743142 TI - Evolution of pathogen virulence under selective predation: a construction method to find eco-evolutionary cycles. AB - We investigate eco-evolutionary cycles in the joint dynamics of pathogen virulence and predator population density when hosts carrying virulent infections are exposed to increased risk of predation. We introduce a new technique to find trade-off functions under which the model exhibits limit cycles; this technique provides a constructive proof that the system is able to generate limit cycles, and can be applied to other eco-evolutionary models as well. We also study a concrete example to confirm that eco-evolutionary cycles occur in a significant part of the parameter space and to briefly explore other evolutionary outcomes in the same model. PMID- 23743143 TI - Analysis of HRCT-derived xylem network reveals reverse flow in some vessels. AB - Long distance water and nutrient transport in plants is dependent on the proper functioning of xylem networks, a series of interconnected pipe-like cells that are vulnerable to hydraulic dysfunction as a result of drought-induced embolism and/or xylem-dwelling pathogens. Here, flow in xylem vessels was modeled to determine the role of vessel connectivity by using three dimensional xylem networks derived from High Resolution Computed Tomography (HRCT) images of grapevine (Vitis vinifera cv. 'Chardonnay') stems. Flow in 4-27% of the vessel segments (i.e. any section of vessel elements between connection points associated with intervessel pits) was found to be oriented in the direction opposite to the bulk flow under normal transpiration conditions. In order for the flow in a segment to be in the reverse direction, specific requirements were determined for the location of connections, distribution of vessel endings, diameters of the connected vessels, and the conductivity of the connections. Increasing connectivity and decreasing vessel length yielded increasing numbers of reverse flow segments until a maximum value was reached, after which more interconnected networks and smaller average vessel lengths yielded a decrease in the number of reverse flow segments. Xylem vessel relays also encouraged the formation of reverse flow segments. Based on the calculated flow rates in the xylem network, the downward spread of Xylella fastidiosa bacteria in grape stems was modeled, and reverse flow was shown to be an additional mechanism for the movement of bacteria to the trunk of grapevine. PMID- 23743145 TI - Bacteria diversity and arsenic mobilization in rock biofilm from an ancient gold and arsenic mine. AB - In this paper we characterize the biofilm community from an ancient Zloty Stok gold and arsenic mine. Bacterial diversity was examined using a culture independent technique based on 16S rRNA gene amplification, cloning and sequencing. We show that unexpectedly the microbial diversity of this community was extremely high (more than 190 OTUs detected), with the most numerous members from Rhizobiales (alpha-Proteobacteria). Although the level of rock biofilm diversity was similar to the microbial mat community we have previously characterized in the same adit, its taxonomic composition was completely different. Detailed analysis of functional arrA and aioA genes, chemical properties of siderophores found in pore water as well as the biofilm chemical composition suggest that the biofilm community contributes to arsenic pollution of surrounding water in a biogeochemical cycle similar to the one observed in bacterial mats. To interpret our results concerning the biological arsenic cycle, we applied the theory of ecological pyramids of Charles Elton. PMID- 23743146 TI - Impact of selected wastewater constituents on the removal of sulfonamide antibiotics via ultrafiltration and micellar enhanced ultrafiltration. AB - To better understand the environmental mobility of sulfonamide antibiotics and develop improved processes for their removal during wastewater treatment, stirred cell ultrafiltration (UF) experiments were conducted using both synthetic and real wastewater effluent. The interactions between selected sulfonamides (sulfaguanidine, sulfathiazole and sulfamerazine), solids and dissolved organic matter were systematically explored. The further impact of micellar enhanced ultrafiltration (MEUF), a process in which surfactants are added at micellar concentrations to enhance removal of various trace contaminants from aqueous streams, was then explored by using a cationic surfactant, cetyltrimethylammonium bromide (CTAB). Ultrafiltration of sulfonamides in the absence of other materials generally removed only 15-20% of the antibiotics. The presence of micellar solutions of CTAB generally improved removal of sulfonamides over UF alone, with rejections ranging from 20 to 74%. Environmental solids (sediment) further increased retention of sulfonamides using both UF and MEUF, but the presence of DOM did not influence rejection. Similar trends were observed on UF and MEUF of real effluent samples that had been spiked with the sulfonamides, confirming the environmental relevance of the observed interactions between sulfonamides, surfactant, and wastewater constituents. The results demonstrate that MEUF processes can be designed for the selective removal of such trace contaminants as sulfonamide antibiotics. PMID- 23743147 TI - Tributyltin induces oxidative damage, inflammation and apoptosis via disturbance in blood-brain barrier and metal homeostasis in cerebral cortex of rat brain: an in vivo and in vitro study. AB - Tributyltin (TBT), a member of the organotin family, is primarily used for its biocidal activity. Persistent environmental levels of TBT pose threat to the ecosystem. Since neurotoxic influence of TBT remains elusive, we therefore, studied its effect on cerebral cortex of male Wistar rats. A single oral dose of Tributyltin-Chloride (TBTC) (10, 20, 30mg/kg) was administered and the animals were sacrificed on day 3 and day 7. Blood-brain barrier permeability remained disrupted significantly till day 7 with all the doses of TBTC. Pro-oxidant metal levels (Fe, Cu) were increased with a concomitant decrease in Zn. ROS generation was substantially raised resulting in oxidative damage (increased protein carbonylation and lipid peroxidation) with marked decline in tissue antioxidant status (GSH/GSSG levels). Protein expression studies indicated astrocyte activation, upregulation of inflammatory molecules (IL-6, Cox-2 and NF-kappaB) and simultaneous elevation in the apoptotic index (Bax/Bcl2). Neurodegeneration was evident by reduced neurofilament expression and increased calpain cleaved Tau levels. The in-vitro study demonstrated involvement of calcium and signaling molecules (p38), with downstream activation of caspase-3 and -8, and apoptotic cell death was evident by nuclear fragmentation, DNA laddering and Annexin V binding experiments. Ca(2+) inhibitors (BAPTA-AM, EGTA, and RR) and free radical scavengers (NAC and biliprotein [C-PC]) increased cell viability (MTT assay), signifying specific roles of Ca(2+) and ROS. Significance of p38 signaling was evaluated on pro-apoptotic proteins by using SB203580, a selective p38 inhibitor. Our data collectively illustrates that TBTC can disrupt BBB, induce oxidative stress, cause cell death and initiate neurodegeneration in rat brain. PMID- 23743148 TI - Induction of autophagy by TOCP in differentiated human neuroblastoma cells lead to degradation of cytoskeletal components and inhibition of neurite outgrowth. AB - Tri-ortho-cresyl phosphate (TOCP), an organophosphorus ester, can cause neurotoxicity such as organophosphorus ester-induced delayed neuropathy (OPIDN) in humans and sensitive animals. Moreover, it also affects the development of central nervous system and differentiation of neuronal cells. In this study, retinoic acid-induced differentiated human neuroblastoma SH-SY5Y cells are utilized to investigate the effects of TOCP on neurite outgrowth and the underlying mechanisms. We found that low concentrations of TOCP induced autophagy and inhibited neurite outgrowth in a dose-dependent manner with no effect on cell viability. The protein levels of high molecular weight neurofilament (NF-H), low molecular weight neurofilament (NF-L) and beta-tubulin also decreased. Pretreatment cells with 3-methyladenine (3-MA), an autophagy inhibitor, not only inhibited the TOCP-induced autophagy, but also reversed the inhibition of neurite outgrowth and the degradation of NF-H, NF-L, and beta-tubulin by TOCP. Taken together, these results indicated that TOCP treatment induced autophagy in differentiated SH-SY5Y cells, which lead to degradation of cytoskeletal components and inhibition of neurite outgrowth. PMID- 23743150 TI - An immunoaffinity purification method for the proteomic analysis of ubiquitinated protein complexes. AB - Protein ubiquitination plays an important role in the regulation of many cellular processes, including protein degradation, cell cycle regulation, apoptosis, and DNA repair. To study the ubiquitin proteome we have established an immunoaffinity purification method for the proteomic analysis of endogenously ubiquitinated protein complexes. A strong, specific enrichment of ubiquitinated factors was achieved using the FK2 antibody bound to protein G-beaded agarose, which recognizes monoubiquitinated and polyubiquitinated conjugates. Mass spectrometric analysis of two FK2 immunoprecipitations (IPs) resulted in the identification of 296 FK2-specific proteins in both experiments. The isolation of ubiquitinated and ubiquitination-related proteins was confirmed by pathway analyses (using Ingenuity Pathway Analysis and Gene Ontology-annotation enrichment). Additionally, comparing the proteins that specifically came down in the FK2 IP with databases of ubiquitinated proteins showed that a high percentage of proteins in our enriched fraction was indeed ubiquitinated. Finally, assessment of protein-protein interactions revealed that significantly more FK2-specific proteins were residing in protein complexes than in random protein sets. This method, which is capable of isolating both endogenously ubiquitinated proteins and their interacting proteins, can be widely used for unraveling ubiquitin mediated protein regulation in various cell systems and tissues when comparing different cellular states. PMID- 23743149 TI - Characterization of methylene diphenyl diisocyanate-haptenated human serum albumin and hemoglobin. AB - Protein haptenation by polyurethane industrial intermediate 4,4'-methylene diphenyl diisocyanate (MDI) is thought to be an important step in the development of diisocyanate (dNCO)-specific allergic sensitization; however, MDI-haptenated albumins used to screen specific antibody are often poorly characterized. Recently, the need to develop standardized immunoassays using a consistent, well characterized dNCO-haptenated protein to screen for the presence of MDI-specific IgE and IgG from workers' sera has been emphasized and recognized. This has been challenging to achieve due to the bivalent electrophilic nature of dNCOs, leading to the capability to produce multiple cross-linked protein species and polymeric additions to proteins. In the current study, MDI was reacted with human serum albumin (HSA) and hemoglobin (Hb) at molar ratios ranging from 1:1 to 40:1 MDI/protein. Adducts were characterized by (i) loss of available 2,4,6 trinitrobenzene sulfonic acid (TNBS) binding to primary amines, (ii) electrophoretic migration in polyacrylamide gels, (iii) quantification of methylene diphenyl diamine following acid hydrolysis, and (iv) immunoassay. Concentration-dependent changes in all of the above noted parameters were observed, demonstrating increases in both number and complexity of conjugates formed with increasing MDI concentrations. In conclusion, a series of bioanalytical assays should be performed to standardize MDI-antigen preparations across lots and laboratories for measurement of specific antibody in exposed workers that in total indicate degree of intra- and intermolecular cross-linking, number of dNCOs bound, number of different specific binding sites on the protein, and degree of immunoreactivity. PMID- 23743151 TI - Determination of accurate protein monoisotopic mass with the most abundant mass measurable using high-resolution mass spectrometry. AB - While recent developments in mass spectrometry enable direct evaluation of monoisotopic masses (M(mi)) of smaller compounds, protein M(mi) is mostly determined based on its relationship to average mass (Mav). Here, we propose an alternative approach to determining protein M(mi) based on its correlation with the most abundant mass (M(ma)) measurable using high-resolution mass spectrometry. To test this supposition, we first empirically calculated M(mi) and M(ma) of 6158 Escherichia coli proteins, which helped serendipitously uncover a linear correlation between these two protein masses. With the relationship characterized, liquid chromatography-mass spectrometry was employed to measure M(ma) of protein samples in its ion cluster with the highest signal in the mass spectrum. Generally, our method produces a short series of likely M(mi) in 1-Da steps, and the probability of each likely M(mi) is assigned statistically. It is remarkable that the mass error of this M(mi) is as miniscule as a few parts per million, indicating that our method is capable of determining protein M(mi) with high accuracy. Benefitting from the outstanding performance of modern mass spectrometry, our approach is a significant improvement over others and should be of great utility in the rapid assessment of protein primary structures. PMID- 23743152 TI - Hoechst likes to play hide and seek...use it with caution! AB - We describe an unexpected feature of the dye Hoechst 33342 that may lead to misinterpretation of fluorescence assay results. When dissolved in aqueous solvent, Hoechst 33342 massively adsorbs on the polytetrafluoroethylene (PTFE) coated stirrer and on the quartz cuvette. The interaction between the dye and the PTFE is stronger than that between the dye and the quartz. We show that Hoechst 33342 adsorption on quartz is due to its amphiphilic properties, as it depends on the buffer ionic strength and on pH. We suggest a procedure to detect and remove any residual Hoechst 33342. PMID- 23743153 TI - Pain resulting from arteriovenous fistulae: prevalence and impact. AB - INTRODUCTION: The burden of pain from cannulation of arteriovenous fistulae (AVF) and the impact it has on quality of life is poorly described in the literature. METHODOLOGY: A pain score questionnaire was employed for all patients in the West of Scotland dialyzing via AVF (n = 461). Pain was assessed using visual analogue score (VAS) and McGill pain score. Patients with severe pain (VAS > 5) were compared to those with minimal pain. RESULTS: The questionnaire as completed by 97.5% of the patients. Median VAS on cannulation was 3 (IQR 0.5 - 4.5). Of those who had completed the questionnaire, 24.4% had severe pain on cannulation and 3.2% experienced severe chronic pain. 53 patients (11.3%) cut a dialysis session short due to pain. Of the patients with severe chronic pain, 46.7% had a physical complication affecting their AVF (e.g., venous stenosis, pseudoaneurysm). Following treatment of the problem, pain improved in 71.4% and resolved completely in 14.3%. Brachiobasilic AVF was associated with a higher incidence of severe pain than either brachiocephalic or radiocephalic AVF (50%, 23.3% and 24.4% respectively; p = 0.03). There was a trend towards more severe pain with rope-ladder cannulation (27.7%) compared to button-hole cannulation (18.2%); however, this difference did not reach statistical significance (p = 0.09). CONCLUSIONS: Pain from AVF is poorly recognized and an under-reported problem. While severe pain resulting in the avoidance of dialysis is rare, it can lead to significant difficulties and ultimate abandonment of AVF. Pain is often suggestive of an underlying anatomical problem. PMID- 23743154 TI - Oxidative stress and other risk factors for white matter lesions in chronic hemodialysis patients. AB - BACKGROUND: Chronic kidney disease (CKD) is a risk factor for cardiovascular disease and promotes oxidative tress (OS), which has been implicated in the pathogenesis of white matter lesions (WML), a form of small-vessel cerebrovascular disease. The relationship between OS and WML in chronic hemodialysis (HD) patients has not yet been studied. METHODS: We studied 67 chronic HD patients, aged 40 - 65 years (average 54 years) without known cerebrovascular disease. All patients underwent brain magnetic resonance imaging and subcortical and periventricular WML were evaluated using semiquantitative measures. Patients were classified into two groups depending on the presence or absence of WML (Fazekas classification), and the WML were scored. Carotid ultrasonography was also performed to evaluate the presence of carotid artery plaques and/or stenosis. Markers of protein and lipid oxidation (protein carbonyl and oxLDL antibodies), the glutathione system, enzymatic antioxidants (superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase) and total antioxidant capacity (ORAC) were measured. OS markers were compared to those of a group of 36 healthy subjects. RESULTS: WML were present in 54% of the total population. Patients who had WML were older and had lower predialysis diastolic blood pressure than patients without WML. Other potential cardiovascular risk factors for WML, including obesity, hyperlipidemia, diabetes mellitus, presence of carotid artery plaques or stenosis, and duration and adequacy of HD were not related to the presence of WML. Compared to controls, HD patients had increased OS and decreased antioxidant capacity. However, OS did not differ between patients with WML and those without, and we found no association between OS markers and mean WML scores. After adjusting for several factors, only age and low predialysis diastolic blood pressure independently predicted an increased risk of WML. CONCLUSIONS: Our results confirm that chronic HD patients have increased OS, but this is not related to the presence or severity of WML. PMID- 23743155 TI - New protocol for alphaAstree electronic tongue enabling full performance qualification according to ICH Q2. AB - Performance qualification (PQ) of taste sensing systems is mandatory for their use in pharmaceutical industry. According to ICH Q2 (R1) and a recent adaptation for taste sensing systems, non-specificity, log-linear relationships between the concentration of analytes and the sensor signal as well as a repeatability with relative standard deviation (RSD) values <4% were defined as basic requirements to pass a PQ. In the present work, the alphaAstree taste sensing system led to a successful PQ procedure by the use of recent sensor batches for pharmaceutical applications (sensor set #2) and a modified measurement protocol. Log-linear relationships between concentration and responses of each sensor were investigated for different bitter tasting active pharmaceutical ingredients (APIs). Using the new protocol, RSD values <2.1% were obtained in the repeatability study. Applying the visual evaluation approach, detection and quantitation limit could be determined for caffeine citrate with every sensor (LOD 0.05-0.5 mM, LOQ: 0.1-0.5 mM). In addition, the sensor set marketed for food applications (sensor set #5) was proven to show beneficial effects regarding the log-linear relationship between the concentration of quinine hydrochloride and the sensor signal. By the use of our proposed protocol, it is possible to implement the alphaAstree taste sensing system as a tool to assure quality control in the pharmaceutical industry. PMID- 23743156 TI - Clinical and skeletal muscle biopsy characteristics of 25 patients with floppy infant syndrome. AB - AIMS: Floppy infant syndrome (FIS) comprises of a group of disorders with a common symptom of generalized hypotonia at birth or in early life, which causes diagnostic challenge. In the current work, we aimed to describe the clinical and histopathological characteristics of FIS to help improve the diagnosis of this condition. METHODS: We collected information on the clinical characteristics, laboratory data, electrophysiological test results and detailed skeletal muscle biopsy histopathological features of 25 infants with FIS. We then discussed the final diagnoses and analyzed the neuromuscular features. RESULTS: Among the 25 infants with FIS, there were 7 cases of spinal muscular atrophy (SMA), 4 cases of congenital muscular dystrophy (CMD) (3 cases of merosin-deficient CMD and 1 case of Ullrich CMD), 8 cases of congenital myopathy (2 cases of central core disease, 1 case each of nemaline myopathy and centronuclear myopathy, and 4 cases of congenital fiber-type disproportion), and 6 cases of metabolic myopathy (3 cases of lipid storage myopathy, 2 cases of Pompe's disease, and 1 case of Leigh's syndrome). The histopathological characteristics of muscle biopsy were found to be distinct for these subgroups. CONCLUSIONS: FIS is caused by a variety of neuromuscular disorders that have common clinical manifestations, including SMA, CMD, congenital myopathies and metabolic myopathies. Skeletal muscle biopsy is an essential tool for the definite and differential diagnoses of FIS, especially of neuromuscular origin. PMID- 23743157 TI - Enlargement of the Nissl substance as a manifestation of early damage to spinal cord motoneurons in amyotrophic lateral sclerosis. AB - AIMS: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motoneurons. Recent studies indicate that in ALS, degeneration of motoneuron body is late in comparison to degeneration of axons. The morphological consequence of the axonal damage is chromatolysis. Therefore, loss of tigroid in motoneurons as a morphological manifestation of chromatolysis should be a prominent feature seen in an early stage of the disease. To verify that assumption we examined morphologically spinal cord motoneurons in patients with sporadic ALS. MATERIAL AND METHODS: In anterior horn motoneurons of 33 patients tigroid were assessed at light microscopy and morphometrically analyzed. Material was divided into an "acute" ALS group with a duration of the disease of up to 1 year, and a "chronic" ALS group with a clinical course lasting for 4 - 9 years. RESULTS: In the "acute" ALS group, loss of motoneurons was slight, and only a part of them showed central chromatolysis. Instead of chromatolysis the enlargement of the tigroid was found. This phenomenon was observed only in "acute" ALS and confirmed by morphometric analysis. CONCLUSIONS: In ALS, enlargement of the tigroid seems to be an early morphological feature - occuring earlier than central chromatolysis. Its presence may be connected with endoplasmic reticulum stress, disturbed axonal transport or functional compensation of the neuronal deficit. PMID- 23743158 TI - Secondary gliosarcoma with massive invasion of meninges, skull base, and soft tissue, and systemic metastasis. PMID- 23743159 TI - Enhancing the treatment of metabolic syndrome with integrative medicine. PMID- 23743160 TI - Introduction of two novel devices for investigating the influence of non mechanical components such as therapeutic qi in acupuncture. AB - OBJECTIVE: Acupuncture is a complex intervention consisting of specific and non specific components. Acupuncture studies more frequently focus on collecting data from the patients' perspective and response, but the acupuncturist's role remains relatively unclear. In order to investigate potential non-mechanical active factors originating from the acupuncturist and transmitted to the patient during treatment, two novel devices for basic research in acupuncture were designed. The Acuplicator allows the researcher to insert needles without touching the needles themselves, while the Veliusator locks the needle in its place so that no mechanical movement can be transferred. METHODS: The Acuplicator was used to insert needles at Neiguan (PC6) on the right forearm of 23 volunteers. The insertion depth was measured using a depth gauge. The transfer of mechanical movements from the handle to the tip was detected with a precision length gauge with a motoric-tactile sensor. RESULTS: The mean insertion depth was (12.3 +/- 1.5) mm (range 9.5 to 15.0 mm). Even with intense manipulation of the needle handle, no movements within +/- 1 MUm could be detected at the tip when the needle was locked. CONCLUSION: With these two devices it will be possible to investigate the influence of non-mechanical components such as therapeutic qi in acupuncture. PMID- 23743161 TI - Effects of Chinese herbal medicine Yiqi Huaju Qingli Formula in metabolic syndrome patients with microalbuminuria: a randomized placebo-controlled trial. AB - BACKGROUND: Microalbuminuria (MAU) is a key component of metabolic syndrome (MetS) and is an early sign of diabetic nephropathy as well. Although routine Western medicine treatments are given to MetS patients to control high blood pressure, hyperglycemia and dyslipidemia, some patients still experience progressive renal lesions and it is necessary to modify and improve the treatment strategy for MetS patients. OBJECTIVE: To investigate the efficacy of Yiqi Huaju Qingli Herb Formula, a compound traditional Chinese herbal medicine, in MetS patients with MAU when it is combined with routine Western medicine treatment. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: Sixty patients with MetS were randomized into the Chinese herbal formula group (CHF, Yiqi Huaju Qingli formula treatment in combination with Western medicine) and control group (placebo in combination with Western medicine). All treatments were administered for 12 weeks. MAIN OUTCOME MEASURES: Urinary microalbumin (MA), urinary albumin-to creatinine ratio (UACR), 24-hour total urine protein (24-hTP), body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (2-hPPG), glycosylated hemoglobin (HbA1c), homeostasis model assessment for insulin resistance (HOMA-IR), blood lipid profile and blood pressure were observed. RESULTS: Compared with the control group, CHF treatment significantly decreased BMI (P<0.05), WC (P<0.01) and WHR (P<0.01). Both groups had significant decreases in FPG, 2-hPPG, HbA1c, HOMA-IR, MA, and UACR, with CHF treatment showing better effects on these parameters compared with the control treatment (P<0.05). Both treatments significantly reduced the levels of total cholesterol, low-density lipoprotein cholesterol and triacylglycerol (TAG), and a greater reduction in TAG was observed with CHF treatment (P<0.05). The level of high-density lipoprotein cholesterol did not change in the control group after treatment (P>0.05), whereas it significantly increased with CHF treatment (P<0.01). Compared with before the treatment, significant decreases in systolic blood pressure, diastolic blood pressure and mean arterial blood pressure were observed in both groups (P<0.01). However, there was no significant difference between the two groups (P>0.05). CONCLUSION: Combined treatment of Yiqi Huaju Qingli Formula and Western medicine significantly alleviated MAU, which may correlate with the improvement of insulin sensitivity and glucose and lipid metabolism. TRIAL REGISTRATION IDENTIFIER: This trial was registered in the Chinese Clinical Trial Registry with the identifier ChiCTR-TRC-11001633. PMID- 23743162 TI - Effects of Chinese herbal medicine Yiqi Huaju Formula on hypertensive patients with metabolic syndrome: a randomized, placebo-controlled trial. AB - BACKGROUND: Patients with hypertension coupled with metabolic syndrome (MetS) are among the high risk population in cardiovascular and cerebrovascular diseases. To reduce the prevalence of cardiovascular and cerebrovascular diseases, it is essential to appropriately control blood pressure together with other cardiovascular risk factors. OBJECTIVE: The current study was designed to investigate the therapeutic effects on blood pressure, blood pressure variability and other cardiovascular risk factors by giving Yiqi Huaju Formula, a compound traditional Chinese herbal medicine, in addition to routine treatment to hypertensive patients coupled with MetS. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A total of 43 patients with hypertension coupled with MetS were recruited into this study. The enrolled patients were randomly divided into the Chinese herbal formula group (anti-hypertensive drugs plus Yiqi Huaju Formula, CHF) and the control group (anti-hypertensive drugs plus placebo). The CHF group enrolled 22 patients while the control group received 21 cases. Treatments were given for 12 weeks in both groups. MAIN OUTCOME MEASURES: Parameters examined include 24-hour ambulatory blood pressure monitoring, body mass index, waist circumference, waist-to-hip ratio, homeostatic model assessment for insulin resistance (HOMA-IR), fasting glycosylated hemoglobin (HbA1c), fasting plasma glucose, 2-hour postprandial plasma glucose (PPG), fasting plasma insulin, serum lipid, etc. RESULTS: Compared with the control group, the CHF group had significant improvement (P<0.01) in anthropometric parameters, FPG, HOMA-IR, blood pressure amplitude, blood pressure variability and blood pressure load. CONCLUSION: This study showed that integrated traditional Chinese and Western medicine treatment can achieve better results in controlling blood pressure as well as other cardiovascular risk factors. The mechanism of controlling of blood pressure may be associated with the improvement of insulin sensitivity due to the Yiqi Huaju intervention. TRIAL REGISTRATION IDENTIFIER: ChiCTR-TRC-11001633. PMID- 23743164 TI - Effects of electroacupuncture at Zusanli (ST36) on inflammatory cytokines in a rat model of smoke-induced chronic obstructive pulmonary disease. AB - OBJECTIVE: Improvement in lung function was reported after acupuncture treatment of chronic obstructive pulmonary disease (COPD), but little is known about the underlying mechanisms. Because an immune response imbalance could be seen in COPD, we hypothesize that electroacupuncture (EA) may play a role in regulating inflammatory cytokines and contribute to lung protection in a rat model of smoke induced COPD. METHODS: A COPD model using male Sprague-Dawley rats exposed to cigarette smoke was established. The rats were randomly divided into four groups (control, sham, COPD, and COPD plus EA), and COPD model was evaluated by measuring pulmonary pathological changes and lung function. EA was applied to the acupuncture point Zusanli (ST36) for 30 min/d for 14 d in sham and COPD rats. Bronchoalveolar lavage fluid (BALF) was used to measure levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and malonaldehyde (MDA). RESULTS: Compared with the control rats, COPD rats had significant changes in lung resistance (RL) and lung compliance (CL) (both P<0.01), bronchi and bronchiole airway obstruction (P<0.01), and levels of MDA, TNF-alpha, and IL 1beta (P<0.01). There were no significant differences between the control and the sham groups. Compared with the COPD rats, the COPD plus EA rats had decreased RL and increased CL (both P<0.05), and reduced bronchi and bronchiole airway obstruction (P<0.05, P<0.01, respectively), while levels of TNF-alpha, IL-1beta, and MDA in BALF were lowered (P<0.05 and P<0.01, respectively). However, TNF alpha and IL-1beta levels of the EA group rats remained higher than those of the control group (P<0.05). CONCLUSION: EA at ST36 can reduce lung injury in a COPD rat model, and beneficial effects may be related to down-regulation of inflammatory cytokines. The anti-inflammatory and antioxidant effects may prolong the clinical benefit of EA. PMID- 23743163 TI - Constituents of the anti-asthma herbal formula ASHMI(TM) synergistically inhibit IL-4 and IL-5 secretion by murine Th2 memory cells, and eotaxin by human lung fibroblasts in vitro. AB - OBJECTIVE: Anti-asthma herbal medicine intervention (ASHMI(TM)), a combination of three traditional Chinese medicinal herbs developed in our laboratory, has demonstrated efficacy in both mouse models of allergic asthma, and a double-blind placebo-controlled clinical trial in patients with asthma. This study was designed to determine if the anti-inflammatory effects of individual herbal constituents of ASHMI(TM) exhibited synergy. METHODS: Effects of ASHMI and its components aqueous extracts of Lingzhi (Ganoderma lucidum), Kushen (Sophora flavescens) and Gancao (Glycyrrhiza uralensis), on Th2 cytokine secretion by murine memory Th2 cells (D10.G4.1) and eotaxin-1 secretion by human lung fibroblast (HLF-1) cells were determined by measuring levels in culture supernatants by enzyme-linked immunosorbent assay. Potential synergistic effects were determined by computing interaction indices from concentration-effect curve parameters. RESULTS: Individual Lingzhi, Kushen and Gancao extracts and ASHMI (the combination of individual extracts) inhibited production of interleukin (IL) 4 and IL-5 by murine memory Th2 cells and eotaxin-1 production by HLF-1 cells. The mean 25%-inhibitory-concentration (IC25) values (mg/mL) for ASHMI, Lingzhi, Kushen and Gancao for IL-4 production were 30.9, 79.4, 123, and 64.6, respectively; for IL-5 production were 30.2, 263, 123.2 and 100, respectively; for eotaxin-1 were 13.2, 16.2, 30.2, and 25.1, respectively. The IC50 values (mg/mL) for ASHMI, Lingzhi, Kushen and Gancao for IL-4 production were 158.5, 239.9, 446.7, and 281.8, respectively; for eotaxin-1 were 38.1, 33.1, 100, and 158.5, respectively. The interaction indices of ASHMI constituents at IC25 were 0.35 for IL-4, 0.21 for IL-5 and 0.59 for eotaxin-1. The interaction indices at IC50 values were 0.50 for IL-4 and 0.62 for eotaxin-1 inhibition. Inhibition of IL-5 did not reach IC50 values. All interaction indices were below 1 which indicated synergy. CONCLUSION: By comparing the interaction index values, we find that constituents in ASHMI(TM) synergistically inhibited eotaxin-1 production as well as Th2 cytokine production. PMID- 23743165 TI - The beginning of acupuncture in Washington, D.C. and Maryland: an interview with Dr. Yeh-chong Chan. Interview by Fan Arthur Yin and Fan Ziyi. PMID- 23743167 TI - 4-hydroxybenzyl alcohol: a novel inhibitor of tumor angiogenesis and growth. AB - AIMS: The herbal compound 4-hydroxybenzyl alcohol (HBA) is a pleiotropic agent, which has been shown to effectively inhibit the development of new blood vessels by targeting multiple mechanisms of the angiogenic process. Because angiogenesis is a major prerequisite for tumor growth, the aim of this study was to analyze for the first time, whether HBA may be used for anti-cancer therapy. MAIN METHODS: CT26.WT colon carcinoma cells were exposed to different HBA doses to study their viability, migration, invasiveness and protein expression compared to vehicle-treated controls. Moreover, CT26.WT cell spheroids were transplanted into the dorsal skinfold chamber of HBA-treated and vehicle-treated BALB/c mice for the analysis of tumor vascularization and growth by means of repetitive intravital fluorescence microscopy, histology and immunohistochemistry. KEY FINDINGS: As shown by water-soluble tetrazolium (WST)-1 and lactate dehydrogenase (LDH) assays, HBA treatment dose-dependently reduced the viability and integrity of the tumor cells. Moreover, phalloidin staining of HBA-treated cells revealed a disorganized cytoskeleton, which was associated with a decreased cellular migratory and invasive activity. In addition, the cells presented with a significantly increased expression of the apoptosis marker cleaved caspase-3 and a decreased expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-9 when compared to controls. Finally, HBA treatment inhibited the vascularization and growth of newly developing CT26.WT tumors in the mouse dorsal skinfold chamber model without affecting the normal behavior of the animals. SIGNIFICANCE: These novel findings indicate that HBA represents a promising candidate for the establishment of anti-angiogenic treatment strategies in cancer therapy. PMID- 23743166 TI - Postnatal age governs the extent of differentiation of hippocampal CA1 and CA3 subfield neural stem/progenitor cells into neurons and oligodendrocytes. AB - While neural stem/progenitor cells (NSCs) in the dentate gyrus of the hippocampus have been extensively characterized, the behavior of NSCs in the CA1 and CA3 subfields of the hippocampus is mostly unclear. Therefore, we compared the in vitro behavior of NSCs expanded from the micro-dissected CA1 and CA3 subfields of postnatal day (PND) 4 and 12 Fischer 344 rats. A small fraction (~1%) of dissociated cells from CA1 and CA3 subfields of both PND 4 and 12 hippocampi formed neurospheres in the presence of EGF and FGF-2. A vast majority of neurosphere cells expressed NSC markers such as nestin, Sox-2 and Musashi-1. Differentiation assays revealed the ability of these NSCs to give rise to neurons, astrocytes, and oligodendrocytes. Interestingly, the overall neuronal differentiation of NSCs from both subfields decreased with age (23-28% at PND4 to 5-10% at PND12) but the extent of oligodendrocyte differentiation from NSCs increased with age (24-32% at PND 4 to 45-55% at PND 12). Differentiation of NSCs into astrocytes was however unchanged (40-48%). Furthermore, NSCs from both subfields gave rise to GABA-ergic neurons including subclasses expressing markers such as calbindin, calretinin, neuropeptide Y and parvalbumin. However, the fraction of neurons that expressed GABA decreased between PND4 (59-67%) and PND 12 (25-38%). Additional analyses revealed the presence of proliferating NSC-like cells (i.e. cells expressing Ki-67 and Sox-2) in different strata of hippocampal CA1 and CA3 subfields of both PND4 and PND 12 animals. Thus, multipotent NSCs persist in both CA1 and CA3 subfields of the hippocampus in the postnatal period. Such NSCs also retain their ability to give rise to both GABA-ergic and non-GABA ergic neurons. However, their overall neurogenic potential declines considerably in the early postnatal period. PMID- 23743168 TI - The effect of polaprezinc on gastric mucosal protection in rats with ethanol induced gastric mucosal damage: comparison study with rebamipide. AB - AIMS: Polaprezinc (PZ), which consists of l-carnosine and zinc, is widely used to treat gastric ulcers. We compared the effects of PZ with those of rebamipide (RM) on the expression of inflammatory cytokines, antioxidants, growth factors, and heat shock proteins (HSP) in a rat model. MAIN METHODS: Seventy Sprague-Dawley rats were randomly assigned to test groups according to the dose of PZ at 5, 10, or 30 mg/kg or RM at 10, 30, or 100 mg/kg. Next, we obtained ulcer indices from rats with ethanol-induced gastric mucosal damage. Western blot analysis was used to evaluate the expression of various target proteins. KEY FINDINGS: Pathological ulcer indices in the PZ and RM groups were significantly lower than those in the control group. The levels of inflammatory cytokines (interleukin 1beta [IL 1beta], IL-6, IL-8, and tumor necrosis factor alpha) decreased, whereas the levels of platelet-derived growth factor-B, vascular endothelial growth factor, and nerve growth factor significantly increased after PZ administration. Furthermore, the expression of antioxidants (superoxide dismutase 1 [SOD-1], SOD 2, heme oxygenase-1, glutathione S-transferase, peroxidredoxin-1, and peroxidredoxin-5) was significantly higher in the PZ group, and the levels of HSP 90, 70, 60, 47, 27, and 10 significantly increased with an increase in PZ dose. SIGNIFICANCE: In a rat model of ethanol-induced gastric mucosal damage, PZ administration ameliorated ethanol-induced mucosal injury and showed protective effects on the mucosa by reducing the levels of inflammatory cytokines and increasing the expression of antioxidant enzymes and growth factors. Furthermore, PZ showed cytoprotective effects by increasing the HSP levels. PMID- 23743169 TI - Inhibition of metastatic potential of B16-F10 melanoma cell line in vivo and in vitro by biflorin. AB - AIM: The aim of this study was to determine the antimetastatic potential of biflorin using in vivo and in vitro approaches. MAIN METHODS: Biflorin was isolated from Capraria biflora collected in Fortaleza, Ceara, Brazil. Adhesion, migration and invasion assays were performed to avail of the antimetastatic potential of this quinone. Experimental metastasis was performed to avail of the antimetastatic potential of bilflorin using in vivo assay. KEY FINDINGS: Treatment with biflorin (25 and 50mg/kg/day) was shown to be effective in reducing B16-F10 melanoma metastasis in C57BL/6 mice. The administration of biflorin at 25mg/kg/day intraperitoneally inhibited the formation of metastases by about 57% compared to untreated control animals. When the animals were treated with 50mg/kg/day intraperitoneally, there was a 71% decrease in the number of lung metastases. Morphological assays showed the presence of hemosiderin and erythrocytes in the lung parenchyma, indicating the occurrence of hemorrhage, probably a side effect of biflorin. Biflorin at non-toxic concentrations (0.5, 1.0 and 1.5g/mL) was tested directly on B16-F10 cells in vitro, and it inhibited cell adhesion to type I collagen and cell motility using the wound-healing assay. SIGNIFICANCE: These data suggest that biflorin has a promising antimetastatic potential, as shown by its anti-adhesion, anti-migration and anti-invasion properties against a metastatic melanoma cell line. However, further studies are essential to elucidate its mechanism of action. PMID- 23743170 TI - Physical activity and cardiometabolic risk in male children and adolescents: the Balcarce study. AB - AIMS: This study aims to evaluate the relationship between the amount of physical activity and different traditional and novel cardiometabolic risk factors, as well as atheroprotective agents, in male children and adolescents. MAIN METHODS: Cross-sectional study. A total of 337 male children and adolescents aged 7-14 years old from the rural city of Balcarce, Buenos Aires, Argentina were studied. KEY FINDINGS: The main finding of the present study was that, in male children and adolescents, physical activity was inversely associated with lipoprotein associated phospholipase A2 (Lp-PLA2) activity (r=-0.39, p<0.001) and with cholesteryl ester transfer protein activity (r=-0.23, p<0.05) apart from other proatherogenic agents after adjusting for age and BMI. Strikingly, among the parameters evaluated, overweight, hyperglycemia and Lp-PLA2 activity resulted to be independently related to physical activity as shown by stepwise regression analysis. SIGNIFICANCE: The strong negative association between exercise and Lp PLA2 activity and the fact that the latter resulted to be the unique continuous variable that persisted associated with physical activity would add an additional benefit of exercise in early prevention of vascular inflammation and atherogenesis. PMID- 23743171 TI - Amelioration of cognitive, motor and endogenous defense functions with silymarin, piracetam and protocatechuic acid in the cerebral global ischemic rat model. AB - AIMS: The neuroprotective activities of silymarin, piracetam and protocatechuic acid ethyl ester (PCA) on cerebral global ischemic/reperfusion were evaluated in a rat model. MAIN METHODS: A midline ventral incision was made in the throat region. The right and left common carotid arteries were located and a bilateral common carotid artery occlusion (BCCAO) was performed for 30min using atraumatic clamps followed by a 24h period of reperfusion. Neurological/behavioral functions (cognitive and motor), endogenous defense systems (lipid peroxidation, glutathione, catalase, and superoxide dismutase), reduced water content and infarct size and histopathological alterations were then studied. KEY FINDINGS: Silymarin and PCA treatments significantly improved cognitive, motor and endogenous defense functions, histopathological alterations, and, reduced both water content and infarct size compared to the vehicle-treated ischemic control group. Piracetam treatment improved neurological and histopathological alterations, reduced water content and infarct size, but failed to restore/prevent the impaired endogenous defense functions significantly. SIGNIFICANCE: Silymarin showed better neuroprotection than piracetam and PCA in experimentally induced global ischemic/reperfusion and was able to facilitate mnemonic performance. PMID- 23743172 TI - The effect of minocycline on seizures induced by amygdala kindling in rats. AB - PURPOSE: Minocycline is known as a chemical with neuroprotective, anti inflammatory, and antimicrobial properties. In this study, the effects of minocycline on seizures induced by amygdala kindling in rats were studied. METHODS: Kindled Wistar rats were injected intraperitoneally with saline and, on the following day, with minocycline (50, 25, and 12.5mg/kg for the three groups (1-3), respectively). The animals in groups 1-3 had similar protocols. Groups 4 and 5 were given for the rotarod test and received 25 or 50mg/kg minocycline, respectively, without any kindling stimulation. The animals in groups 6 and 7 (seven each) received 25mg/kg minocycline or saline, respectively. All the injections were carried out 1h before kindling stimulation. Seizure parameters, including after discharge duration (ADD), stage 4 latency (S4L), stage 5 duration (S5D), and seizure duration (SD), were recorded and compared with those of the saline groups. RESULTS: Minocycline (50mg/kg) significantly reduced ADD, 1/S4L, S5D, and SD (P<0.001, P<0.05, P<0.001, and P<0.001, respectively) in group 1. While the administration of 25mg/kg of minocycline decreased the ADD and S5D (P<0.05), in group 2. The injection of 12.5mg/kg resulted in decreased S5D (P<0.001) in group 3. The daily injection of minocycline (25mg/kg) significantly decreased ADD, S5D, and SD (P<0.001) in group 6. CONCLUSION: The obtained results revealed that minocycline has anticonvulsant effect on seizures induced by amygdala kindling. Thus, it may be useful for epilepsy treatment. PMID- 23743173 TI - Lateral tongue biting versus biting at the tip of the tongue in differentiating between epileptic seizures and syncope. PMID- 23743174 TI - Comparison of polycarbonate and cellulose acetate membrane filters for isolation of Campylobacter concisus from stool samples. AB - One thousand seven hundred ninety-one diarrheic stool samples were cultivated for Campylobacter spp. We found a high prevalence of Campylobacter concisus with use of a polycarbonate filter (n = 114) compared to a cellulose acetate filter (n = 79) (P < .0001). The polycarbonate filter is superior to the commonly used cellulose acetate filter for detection of C. concisus. PMID- 23743175 TI - Near point-of-care administration by the attending physician of the rapid influenza antigen detection immunochromatography test and the fully automated respiratory virus nucleic acid test: contribution to patient management. AB - Rapid influenza antigen detection tests (RIADTs) using immunochromatography are the most readily available tools for the diagnosis and management of influenza. This study was designed to assess whether near point-of-care administration by primary care physicians of the RIADT and a fully automated respiratory virus nucleic acid test (Verigene Respiratory Virus Plus(r); RV+) would contribute to improved patient management. When viral culture and RT-PCR/bi-directional sequencing were used as the gold standard, sensitivities and specificities for RIADT and RV+ were 58.3% and 90.9%, and 97.2% and 100%, respectively. Within 12 hours from onset of fever, sensitivities were 44.4% and 94.4%, respectively, for RIADT and RV+. In clinical situations where a higher-sensitivity test is needed, such as during pre-admission evaluations, for testing of hospital employees during the prodromal phase of infection, during the therapeutic decision-making process, and during outbreaks, we suggest that patients testing negative by the RIADT can be reassessed with the RV+ test to achieve maximal diagnostic accuracy. PMID- 23743176 TI - A freak of nature. PMID- 23743177 TI - Bone conduction: an explanation for this phenomenon comprising complex mechanisms. AB - Bone conduction hearing inevitably involves vibration of the basilar membrane in response to a pressure gradient on either side of the membrane. The propagated wave that symbolizes this vibration of the basilar membrane can be triggered intentionally, when a bone vibrator is placed on the mastoid bone, or inadvertently when testing hearing of one ear by air conduction while disregarding transmission of the sound to the other side. When hearing is tested with a bone vibrator, the pathways leading to the basilar membrane can be divided into two main categories. The first type of pathway short-circuits the middle ear and comprises three distinct mechanisms: cochlear fluid inertia, compression of the cochlear walls, and pressure changes exerted via cerebrospinal fluid. In the second type of pathway, the stimulus reaches the basilar membrane via the middle ear, either directly or via the outer ear. Although it is difficult to precisely determine the contribution of each of these pathways to the basilar membrane, bone conduction remains the clinically most reliable way of directly testing cochlear function. PMID- 23743178 TI - What is low threshold methadone maintenance treatment? AB - BACKGROUND: Low threshold methadone maintenance (MMT) was developed for clients who do not have abstinence as a treatment goal. We explored how MMT programs in Canada defined low threshold and the challenges they faced. METHODS: Using semi structured interviews, we collected data from clients (n=46), nurses/counsellors (n=15) and physicians (n=9) at three low threshold MMT programs. All participants were asked to define low threshold MMT and describe how it was implemented in practice. Interviews were taped, transcribed, verified and analysed using an iterative thematic coding technique. RESULTS: Low threshold MMT was defined by an explicit rejection of abstinence from opiates and other drugs as an over-arching treatment goal. In the absence of guidelines defining a set of practices as low threshold, programs implemented practices they believed would reduce barriers to admission and help retention. There was not always agreement between professional groups or across the programs regarding these practices. For physicians, there was a tension between accepting poly-drug use during treatment as a means to improve retention, with an obligation to do more good than harm for their patients. Missed prescribing appointments generated few to severe consequences and revealed differential focus on reducing barriers versus encouraging client 'ownership' of treatment. Differences of opinion regarding appropriate urine drug testing practices revealed power dynamics between medical and non-medical staff. CONCLUSION: Our findings show that there are potentially more ways to reduce barriers to MMT than those presented in the current literature. Our findings are important given the growing number of people with opiate dependence across the world and calls to increase access to MMT. To fully develop the low threshold model, it will be important to evaluate what policies and practices can achieve the goals of reducing barriers to admission and improving retention in treatment. PMID- 23743179 TI - Gunshot injuries in Benghazi-Libya in 2011: the Libyan conflict and beyond. AB - BACKGROUND: Since independence, Libya has never experienced personal ownership of arms. That changed during the Libyan conflict where weapons became widespread in the society. As a result gunshot injuries became a concern for surgeons at our principal surgical hospital (Al-Jalaa). This study aims at analyzing the gunshot injuries that took place during 2011 and highlighting the peculiarities in the Libyan scenario. METHODS: Patient records were obtained and gunshot injuries were analyzed for various parameters. Statistical analyses were made taking into consideration situations faced by neighbouring countries. RESULTS: In 2011, 1761 patients were admitted with over 95% being male and over 97% were Libyan. The average age of a GSI patient was 28.32 +/- 10.01 years. Patients aged 18-35 formed over 70% of the cases with half of all cases being treated by the orthopedics department. Sixty-eight percent of cases were injured in the extremities followed by chest (12.5%) and abdomen injuries (7.8%). The mortality rate for GSI's was found to be 5.6% overall with young age, site of injury (i.e. chest and head) and cause of injury (i.e. war or civilian fighting) being important risk factors. CONCLUSIONS: Taking into consideration the difficult operating conditions and limited resources, surgeons at our hospital were able to maintain a low mortality rate. Disarmament needs to begin as soon as possible because these injuries will continue to occur so long firearms are available in society. PMID- 23743180 TI - WITHDRAWN: MUA with steroid injection vs. arthroscopic capsular release for adhesive capsulitis: A prospective randomised study. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23743181 TI - Agreement among dentists' restorative treatment planning thresholds for primary occlusal caries, primary proximal caries, and existing restorations: findings from The National Dental Practice-Based Research Network. AB - OBJECTIVES: The aim of this study was to quantify the agreement among individual National Dental Practice-Based Research Network dentists' self-reported treatment decisions for primary occlusal caries, primary proximal caries, and existing restorations. METHODS: Five hypothetical clinical scenarios were presented: primary occlusal caries; primary proximal caries; and whether three existing restorations should be repaired or replaced. We quantified the probability that dentists who recommended later restorative intervention for primary caries were the same ones who recommended that existing restorations be repaired instead of replaced. RESULTS: Dentists who recommended later restorative treatment of primary occlusal caries and proximal caries at a more-advanced stage were significantly more likely to recommend repair instead of replacement. Agreement among dentists on a threshold stage for the treatment of primary caries ranged from 40 to 68%, while that for repair or replacement of existing restorations was 36 to 43%. CONCLUSIONS: Dentists who recommended repair rather than replacement of existing restorations were significantly more likely to recommend later treatment of primary caries. Conversely, dentists who recommended treatment of primary caries at an earlier stage were significantly more likely to recommend replacement of the entire restoration. Between-dentist agreement for primary caries treatment was better than between-dentist agreement for repair or replacement of existing restorations. CLINICAL IMPLICATIONS: These findings suggest consistency in how individual dentists approach the treatment of primary caries and existing restorations. However, substantial variation was found between dentists in their treatment decisions about the same teeth. PMID- 23743182 TI - Proteomics screen to reveal molecular changes mediated by C722G missense mutation in CHRM2 gene. AB - Previously, we reported a missense mutation (C722G) in the M2-muscarinic acetylcholine receptor (CHRM2) gene associated with familial dilated cardiomyopathy. However, the exact molecular mechanisms by the related protein changes of CHRM2-C722G mutation induced are still unclear. CHRM2 and CHRM2-C722G lentiviral vector was infected to CHO cells. Proteomic analysis by label-free shotgun strategy and the STRING 9.0 software were performed. A total of 102 proteins with at least 2-fold change in the CHRM2-C722G group were identified, 42 proteins were up-regulated, whereas 57 were down-regulated. These altered proteins belong to three broad functional categories: (i) metabolic (e.g. Cytosolic acyl coenzyme A thioester hydrolase, Malate dehydrogenase); (ii) cytoskeletal (e.g. Actin-related protein, Myosin light polypeptide 6 and Alpha actinin-1) and (iii) stress response (e.g. heat shock protein 70, Ras-related protein Rab-10). Interestingly, the marked differences in the expression of selected eight proteins (change >4.0-fold), were connected with many proteins related to apoptosis and immune/inflammatory response such as: FOS, BAX, MYC, TP53 and IL6. This novel study demonstrated for the first time a full-scale screening of the proteomics research by CHRM2-C722G mutation and profiled 102 changed proteins, of which, eight might be critical in cardiac dysfunction for future mapping. SIGNIFICANCE: It was a full-scale screening of the proteomics research by CHRM2-C722G mutation. These proteins might serve as valuable biomarkers that could predict the presence of a precursor field. These proteins might serve to further explore the pathophysiological mechanisms in familial DCM patients with C176W mutation. PMID- 23743183 TI - Neural systems underlying the influence of sound shape properties of the lexicon on spoken word production: do fMRI findings predict effects of lesions in aphasia? AB - Previous behavioral work has shown that the phonetic realization of words in spoken word production is influenced by sound shape properties of the lexicon. A recent fMRI study (Peramunage, Blumstein, Myers, Goldrick, & Baese-Berk, 2011) showed that this influence of lexical structure on phonetic implementation recruited a network of areas that included the supramarginal gyrus (SMG) extending into the posterior superior temporal gyrus (pSTG) and the inferior frontal gyrus (IFG). The current study examined whether lesions in these areas result in a concomitant functional deficit. Ten individuals with aphasia and 8 normal controls read words aloud in which half had a voiced stop consonant minimal pair (e.g. tame; dame), and the other half did not (e.g. tooth; (*)dooth). Voice onset time (VOT) analysis of the initial voiceless stop consonant revealed that aphasic participants with lesions including the IFG and/or the SMG behaved as did normals, showing VOT lengthening effects for minimal pair words compared to non-minimal pair words. The failure to show a functional deficit in the production of VOT as a function of the lexical properties of a word with damage in the IFG or SMG suggests that fMRI findings do not always predict effects of lesions on behavioral deficits in aphasia. Nonetheless, the pattern of production errors made by the aphasic participants did reflect properties of the lexicon, supporting the view that the SMG and IFG are part of a lexical network involved in spoken word production. PMID- 23743184 TI - Primary complement C5 deficiencies - molecular characterization and clinical review of two families. AB - Inherited deficiency states of the terminal complement component C5 are rare and often associated with increased risk of recurrent Neisseria infections. More than 50 cases with primary C5 deficiency have been reported. In spite of this, the molecular basis has only been documented in a few cases. In the present study we investigated two unrelated Caucasian probands with C5 deficiency originating from Norway and Denmark, respectively, and found three previously undescribed mutations. With these data, thirteen mutations associated with C5 deficiency have been described. By genetic screening of the family of the Norwegian patient, previously diagnosed as homozygous C5 deficient and suffering four Neisseria infections, an additional case of C5 deficiency was discovered, who had experienced one episode of Neisseria infections. Detailed review of the clinical history of the patients and their healthy relatives did not reveal any differences between C5 deficient and sufficient individuals with regard to clinical presentation, apart from the susceptibility to Neisseria infections. Of note, one of the patients described here, and several C5 deficient patients from the literature had Neisseria meningitidis serotype B infections, which is not covered by the current vaccines. These data support the clinical guidelines for patients treated with C5 inhibitors, who are functional C5 deficient by the treatment. PMID- 23743185 TI - Triglyceride-coated nanoparticles: skin toxicity and effect of UV/IR irradiation on them. AB - Triglyceride (TG) is an important compound on the skin, produced by sebaceous glands, and may change cytotoxicity of different nanoparticles. To date, there is no report about toxicity of nanoparticles coated with TG. On the other hand, the use of ultraviolet (UV) and infrared (IR) with nanoparticles changes nanoparticle cytotoxicity. The combination of nanoparticles with UV or IR is applicable, because it may be used for treatment or detection of local cancers, surface microbial infections and other skin diseases. In this study, different nanoparticles including titanium dioxide, zinc oxide, magnesium oxide, silver, gold, and TG-coated form of these nanoparticles, were added to suspensions of Balb/c skin cells, and then incubated for 24h at 37 degrees C. Additionally, TG coated nanoparticles were treated with UV and IR irradiation for 1h. Different methods were applied for evaluation of cytotoxicity, including 5-diphenyl tetrazolium bromide assay, lactate dehydrogenase (LDH) assay, cell metabolic assay, ATP assay, and reactive oxygen species (ROS) generation assay. This research showed that TG-coated nanoparticles had less LDH release and ROS generation with higher cell viability, cell metabolic activity, and ATP level, compared with pristine nanoparticles. In contrast, the combination of UV and IR with TG-coated nanoparticles led to higher LDH release and ROS generation with less cell viability, cell metabolic activity, and ATP level, in comparison with pristine nanoparticles. Overall, pristine metal nanoparticles without irradiation had higher cytotoxicity than metal oxide nanoparticles. PMID- 23743186 TI - Role of glycogen synthase kinase 3beta in protective effect of propofol against hepatic ischemia-reperfusion injury. AB - BACKGROUND: It was previously reported that propofol, an intravenously administered hypnotic and anesthetic agent, protects organs from ischemia reperfusion (I/R) injury. However, the underlying mechanisms are largely unknown. Glycogen synthase kinase 3beta (GSK-3beta) is known to play an important role in the oxidative stress-induced apoptosis. In this study, we investigated the role of GSK-3beta and mitochondrial permeability transition pore (MPTP) in the protective effects of propofol against hepatic I/R injury. MATERIALS AND METHODS: The left and median hepatic artery and the portal vein branches were blocked by no-damage artery clips to create the model of partial ischemia (70%), and liver lobes were subjected to warm ischemia for 30, 60, 90 min, respectively. Reperfusion of 120 min was then initiated by the removal of clamp. The MPTP opening was assessed by measuring mitochondrial large amplitude swelling and mitochondrial membrane potential. RESULTS: Pretreatment with propofol in conditions of hepatic I/R inhibits the apoptosis of hepatocytes as evidenced by decreased terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. Importantly, propofol suppressed the mitochondrial GSK-3beta by promoting or preserving its phosphorylation at Ser9, thus restraining the opening of MPTP and preventing the mitochondrial swell and mitochondrial membrane potential collapse. CONCLUSIONS: Propofol protects liver from I/R injury by sustaining the mitochondrial function, which is possibly involved with the modulation of MPTP and GSK-3beta. PMID- 23743189 TI - TRAF2 regulates the cytoplasmic/nuclear distribution of TRAF4 and its biological function in breast cancer cells. AB - Although numerous studies have shown that tumor necrosis factor receptor associated factor 4 (TRAF4) plays an important role in the carcinogenesis of many tumor types, its exact molecular mechanism remains elusive. In this study, we examined the regulation function of TRAF2 to the cytoplasmic/nuclear distribution of TRAF4 in the breast cancer cell line. Using cell immunofluorescent staining, we found that TRAF2 and TRAF4 were co-localized to the cytoplasm in MCF-7 cells. Co-immunoprecipitation showed that TRAF2 could interact with TRAF4 in MCF-10A, MCF-7 and MDA-MB-231 cell lines. Western blotting showed TRAF2 depletion by targeted siRNA in MDA-MB-231 cells led to reduced TRAF4 expression in the cytoplasm and augmented TRAF4 expression in the nucleus. Cytoplasmic expression of TRAF4 was augmented and nuclear expression was reduced when MCF-7 cells were transfected with hTRAF2pLPCX-HA-Flag/P874. MCF-7 cells expressing hTRAF2pLPCX-HA Flag/P874 had enhanced cell proliferation rates. The nuclear expression of NF kappaB significantly increased after TNF-alpha treatment. When hTRAF2pLPCX-HA Flag/P874 and the siRNA-TRAF4 plasmid were cotransfected, the nuclear expression of NF-kappaB was significantly reduced compared with cells transfected with hTRAF2pLPCX-HA-Flag/P874 only. In conclusion, TRAF2 appears to interact with TRAF4 and affect the localization of TRAF4 in breast cancer cell lines. The overexpression of TRAF2 augmented the cytoplasmic expression of TRAF4 which promoted cell proliferation and inhibited cell apoptosis by activating NF-kappaB nuclear transcription. TRAF4 may play an important role in the activation of NF kappaB via TRAF2. PMID- 23743190 TI - Compound A, a dissociated glucocorticoid receptor modulator, reduces dengue virus induced cytokine secretion and dengue virus production. AB - Dengue Virus (DENV) infection is an important mosquito-borne viral disease and its clinical symptoms range from a predominantly febrile disease, dengue fever (DF), to dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Increased levels of cytokines - the so-called 'cytokine storm', contribute to the pathogenesis of DHF/DSS. In this study, we compared the expression of cytokine genes between mock-infected and DENV-infected HepG2 cells using a real-time PCR array and revealed several up-regulated chemokines and cytokines, including CXCL10 and TNF-alpha. Compound A (CpdA), a plant-derived phenyl aziridine precursor containing anti-inflammatory action and acting as a dissociated nonsteroidal glucocorticoid receptor modulator, was selected as a candidate agent to modulate secretion of DENV-induced cytokines. CpdA is not a glucocorticoid but has an anti-inflammatory effect with no metabolic side effects as steroidal ligands. CpdA significantly reduced DENV-induced CXCL10 and TNF-alpha secretion and decreased leukocyte migration indicating for the first time the therapeutic potential of CpdA in decreasing massive immune activation during DENV infection. PMID- 23743191 TI - Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice. AB - Our aims were to evaluate the involvement of heparin-binding EGF-like growth factor (HB-EGF) in liver fibrogenesis of humans and mice and to elucidate the effect of HB-EGF deficiency on cholestatic liver fibrosis using conditional HB EGF knockout (KO) mice. We first demonstrated that gene expression of HB-EGF had a positive significant correlation with that of collagen in human fibrotic livers, and was increased in bile duct ligation (BDL)-induced fibrotic livers in mouse. We then generated conditional HB-EGF knockout (KO) mice using the interferon inducible Mx-1 promoter driven Cre recombinase transgene and wild type (WT) and KO mice were subjected to BDL. After BDL, KO mice exhibited enhanced liver fibrosis with increased expression of collagen, compared with WT mice. Finally, we used mouse hepatic stellate cells (HSCs) to examine the role of HB EGF in the activation of these cells and showed that HB-EGF antagonized TGF-beta induced gene expression of collagen in mouse primary HSCs. Interestingly, HB-EGF did not prevent the TGF-beta-induced nuclear accumulation of Smad3, but did lead to stabilization of the Smad transcriptional co-repressor TG-interacting factor. In conclusion, our data suggest a possible protective role of HB-EGF in cholestatic liver fibrosis. PMID- 23743192 TI - Orally active hypoglycemic protein from Costus igneus N. E. Br.: an in vitro and in vivo study. AB - Plants have been used for the treatment of diabetes since time immemorial. In the present study, insulin-like protein (ILP) is purified from Costus igneus belonging to family Costaceae from Western ghats of India. The ILP showed cross reactivity with murine anti-insulin antibodies hence was purified by affinity chromatography using anti-insulin antibodies. The characterization of ILP showed that it is structurally different from insulin but functionally similar. The ILP showed a hypoglycemic activity in an in vitro assay with insulin responsive cell line RIN 5f. Interestingly ILP showed significant decrease in blood glucose level when administered orally in oral glucose tolerance test. This was compared to insulin a positive control given intraperitoneally in streptozotocine induced diabetic mice. There was no toxic effect seen on animals after administrating the ILP. Therefore we conclude that the ILP purified in the present study from C. igneus is a novel protein having hypoglycemic activity. PMID- 23743194 TI - Synergistic induction of cancer cell death and reduction of clonogenic resistance by cisplatin and FK228. AB - Human urinary bladder cancer is the fifth most common cancer in the United States, and the long-term disease-free survival in patients is still suboptimal with current chemotherapeutic regimens. Development of effective chemotherapeutic regimens is crucial to decrease the morbidity and mortality of this cancer. The goal of this study was to investigate the effectiveness of FK228 in increasing cisplatin's ability to induce bladder cancer cell death and reduce drug resistance. Our study revealed that FK228 combined with cisplatin synergistically induced cell death and reduced clonogenic survival of human urinary bladder cancer cells. The Erk-Nox pathway played an important role in mediating signals highly increased by this combined treatment to induce significantly-elevated levels of reactive oxygen species, leading to substantially-induced caspase activation and synergistically-increased death in cancer cells. Cisplatin was able to enhance the ability of FK228 to significantly reduce glutathione, indicating a novel activity of combined FK228 and cisplatin in reducing drug resistance. The ability of combined FK228 and cisplatin to synergistically induce cell death and reduce clonogenic survival was also applicable to colon cancer cells. Hence, combined use of FK228 with cisplatin should be considered in development of therapeutic strategies to control urinary bladder cancer and other cancer development and recurrence. PMID- 23743193 TI - Suppressed circulating bicyclo-PGE2 levels and leukocyte COX-2 transcripts in children co-infected with P. falciparum malaria and HIV-1 or bacteremia. AB - In holoendemic Plasmodium falciparum transmission regions, malarial anemia is a leading cause of childhood morbidity and mortality. Identifying biomarkers of malaria disease severity is important for identifying at-risk groups and for improved understanding of the molecular pathways that influence clinical outcomes. We have previously shown that decreased cyclooxygenase (COX)-2-derived prostaglandin E2 (PGE2) levels are associated with enhanced clinical severity in cerebral malaria, malarial anemia, and malaria during pregnancy. Since children with malaria often have increased incidence of additional infections, such as bacteremia and HIV-1, we extend our previous findings by investigating COX-2 and PGE2 in children with falciparum malaria and co-infection with either bacteremia or HIV-1. Plasma bicyclo-PGE2/creatinine levels and peripheral blood COX-2 transcripts were significantly reduced in co-infected children relative to those with malaria mono-infection. Furthermore, suppression of circulating bicyclo-PGE2 was significantly associated with reduced hemoglobin levels in both mono- and co infected children with malaria, suggesting that bicyclo-PGE2 may represent both a marker and mediator of malaria pathogenesis. PMID- 23743195 TI - Role of the Rap2/TNIK kinase pathway in regulation of LRP6 stability for Wnt signaling. AB - The Wnt/beta-catenin signaling pathway plays critical roles in early embryonic development, stem cell biology and human diseases including cancers. Although Rap2, a member of Ras GTPase family, is essential for the Wnt/beta-catenin pathway during the body axis specification in Xenopus embryo, the mechanism underlying its regulation of Wnt signaling remains poorly understood. Here, we show that Rap2 is implicated in control of the stability of Wnt receptor, low density lipoprotein receptor-related protein 6 (LRP6). Knockdown of Rap2 resulted in the proteasome and/or lysosome-dependent degradation of LRP6 both in the presence and absence of Wnt ligand stimulation. In line with this, constitutively active LRP6 lacking its extracellular domain, which is constitutively phosphorylated and resides in intracellular vesicles, was also degraded in the Rap2-silenced cells. In addition, Rap2 and LRP6 associated physically with each other. Furthermore, we found that TRAF2/Nck-interacting kinase (TNIK), a member of the Ste20 protein family, acts as a downstream effector of Rap2 in control of LRP6 stabilization. Consistently, TNIK could rescue the inhibitory effects of Rap2 depletion on Wnt-dependent gene transcription, reporter activation and neural crest induction. Taken together, these results suggest that Rap2 acts via TNIK to regulate the stability of LRP6 receptor for Wnt/beta-catenin signaling. PMID- 23743196 TI - Alkylglycerol monooxygenase as a potential modulator for PAF synthesis in macrophages. AB - Alkylglycerol monooxygenase (AGMO, glyceryl ether monooxygenase) is an enzyme known to catalyze the cleavage of the O-alkyl bond of glyceryl ether lipids. Identification of the gene encoding AGMO was reported recently, however, the involvement of AGMO in modulating cellular lipids has not been reported until now. In this report, we investigate a possible role for AGMO in macrophage platelet-activating factor (PAF) production. AGMO mRNA expression levels decreased with lipopolysaccharide (LPS) treatments in mouse peritoneal macrophages and RAW264.7 cells. Tetrahydrobiopterin-dependent conversion of lyso PAF to glycerophosphocholine in the microsomal fraction was also reduced in LPS treated RAW264.7 cells. In the LPS-treated cells, both lyso-PAF and PAF levels increased. Moreover, exogenously expressed AGMO caused a reduction in cellular lyso-PAF and PAF levels in HEK293 cells. Collectively, our results suggest a possible mechanism for AGMO in modulating macrophage PAF production by regulating cellular lyso-PAF levels. PMID- 23743197 TI - Large noncoding RNA HOTAIR enhances aggressive biological behavior and is associated with short disease-free survival in human non-small cell lung cancer. AB - HOTAIR is one of long non-coding RNAs and its expression correlates with the prognosis and metastasis in various cancers. We showed that HOTAIR expression has an important role in the development of non-small cell lung cancer (NSCLC). In this study, we examined the expression of HOTAIR in 77 NSCLCs, their corresponding normal lung tissues and 6 brain metastases by quantitative real time RT-PCR. High expression of HOTAIR (tumor/normal ratio ?2) was detected in 17 patients (22.1%) and was frequently found in patients with advanced stage, lymph node metastasis or lymph-vascular invasion and short disease free interval. Furthermore, brain metastases show significantly higher HOTAIR expression compared to primary cancer tissues. HOTAIR-expressing A549 cells showed induced cell migration and anchorage-independent cell growth in vitro. These results indicate the expression of HOTAIR enhanced the aggressive behavior of NSCLC cells. PMID- 23743198 TI - Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis. AB - Pancreatic cancer accounts for more than 250,000 deaths worldwide each year. Recent studies have shown that belinostat, a novel pan histone deacetylases inhibitor (HDACi) induces apoptosis and growth inhibition in pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In the current study, we found that AMP-activated protein kinase (AMPK) activation was required for belinostat-induced apoptosis and anti-proliferation in PANC-1 pancreatic cancer cells. A significant AMPK activation was induced by belinostat in PANC-1 cells. Inhibition of AMPK by RNAi knockdown or dominant negative (DN) mutation significantly inhibited belinostat-induced apoptosis in PANC-1 cells. Reversely, AMPK activator AICAR and A-769662 exerted strong cytotoxicity in PANC 1 cells. Belinostat promoted reactive oxygen species (ROS) production in PANC-1 cells, increased ROS induced transforming growth factor-beta-activating kinase 1 (TAK1)/AMPK association to activate AMPK. Meanwhile, anti-oxidants N-Acetyl Cysteine (NAC) and MnTBAP as well as TAK1 shRNA knockdown suppressed belinostat induced AMPK activation and PANC-1 cell apoptosis. In conclusion, we propose that belinostat-induced apoptosis and growth inhibition require the activation of ROS TAK1-AMPK signaling axis in cultured pancreatic cancer cells. PMID- 23743199 TI - NGF induces adult stem Leydig cells to proliferate and differentiate during Leydig cell regeneration. AB - Nerve growth factor (NGF) has been reported to be involved in male reproductive physiology. However, few reports have described the activity of NGF during Leydig cell development. The objective of the present study was to examine the role of NGF during stem-Leydig-cell (SLC) regeneration. We investigated the effects of NGF on Leydig-cell (LC) regeneration by measuring mRNA levels in the adult rat testis after ethane dimethanesulfonate (EDS) treatment. Furthermore, we used the established organ culture model of rat seminiferous tubules to examine the regulation of NGF during SLC proliferation and differentiation using EdU staining, real-time PCR and western blotting. Progenitor Leydig cells (PLCs) and immature Leydig cells (ILCs) were also used to investigate the effects of NGF on LCs at different developmental stages. NGF mRNA levels changed significantly during Leydig-cell regeneration in vivo. In vitro, NGF significantly promoted the proliferation of stem Leydig cells and also induced steroidogenic enzyme gene expression and 3beta-HSD protein expression. The data from PLCs and ILCs showed that NGF could increase Cyclin D1 and Hsd 17b3 mRNA levels in PLCs and Cyclin D1 mRNA levels in ILCs. These results indicate that NGF may play an important role during LC regeneration by regulating the proliferation and differentiation of LCs at different developmental stages, from SLCs to PLCs and from PLCs to ILCs. The discovery of this effect of NGF on Leydig cells will provide useful information for developing new potential therapies for PADAM (Partial Androgen Deficiency in the Aging Male). PMID- 23743200 TI - DJ-1 cooperates with PYCR1 in cell protection against oxidative stress. AB - DJ-1, a product of the DJ-1/PARK7 gene, has been suggested to play various functions involved in transcriptional regulation, protease activity, anti oxidative stress activity, and regulation of mitochondrial complex I. Such a variety of functions of DJ-1 are supposed to be realized through interactions with different partner proteins. Among the candidates for DJ-1-partner proteins detected in TOF-MAS analyses of the cellular proteins co-immunoprecipitated with DJ-1, we focused here pyrroline-5-carboxylate reductase 1, PYCR1, a final key enzyme for proline biosynthesis. DJ-1 directly bound to PYCR1 in vivo and in vitro. DJ-1 and PYCR1 colocalized in mitochondria, and both were suggested to be involved in regulation of mitochondrial membrane potential, but differently. DJ-1 enhanced the enzymatic activity of PYCR1 in vitro. The cells knocked down for DJ 1 and PYCR1 showed lower viability under oxidative stress conditions. No additive nor synergistic results were obtained for the cells that had been knocked down for both DJ-1 and PYCR1, suggesting that DJ-1 and PYCR1 are on the same pathway of anti-oxidative stress protection of the cells. PMID- 23743201 TI - Deletion of the calmodulin-binding domain of Grb7 impairs cell attachment to the extracellular matrix and migration. AB - The adaptor Grb7 is a calmodulin (CaM)-binding protein that participates in signaling pathways involved in cell migration, proliferation and the control of angiogenesis, and plays a significant role in tumor growth, its metastatic spread and tumor-associated neo-vasculature formation. In this report we show that deletion of the CaM-binding site of Grb7, located in the proximal region of its pleckstrin homology (PH) domain, impairs cell migration, cell attachment to the extracellular matrix, and the reorganization of the actin cytoskeleton occurring during this process. Moreover, we show that the cell-permeable CaM antagonists N (6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and N-(4-aminobutyl)-5 chloro-2-naphthalenesulfonamide (W-13) both retard the migration of cells expressing wild type Grb7, but not the migration of cells expressing the mutant protein lacking the CaM-binding site (Grb7Delta), underscoring the proactive role of CaM binding to Grb7 during this process. PMID- 23743202 TI - Cloning and functional characterization of the Lymantria dispar initiator caspase dronc. AB - Ld652Y cells from the gypsy moth, Lymantria dispar, are extremely sensitive to various apoptotic stimuli, whereas BM-N cells from the silkworm, Bombyx mori, are relatively resistant to apoptotic stimuli. We previously cloned and characterized a B. mori homologue (bm-dronc) of Drosophila melanogaster dronc. In the present study, we cloned and characterized an L. dispar homologue of dronc (ld-dronc) comparatively with Bm-Dronc. The open reading frame of ld-dronc consisted of 1329bp that was predicted to encode a 443 amino-acid polypeptide with a molecular mass of 50,706Da and 54-57% amino acid sequence identity with Dronc homologues from other lepidopteran insects identified to date. Ld-Dronc had a long prodomain, large p20 domain, and small p10 domain, and a catalytic site composed of (308)QTCRG(312), which was distinct from the sites QACRG in Bm-Dronc and QMCRG in Dronc homologues of several other lepidopteran insects. Transiently expressed Ld-Dronc underwent proteolytic processing in the lepidopteran cell lines L. dispar Ld652Y, Spodoptera frugiperda Sf9, and B. mori BM-N, and dipteran D. melanogaster S2, but only triggered apoptosis in the lepidopteran cell lines. Endogenous Ld-Dronc underwent processing in Ld652Y cells upon infection with vAcDeltap35, but not in mock-infected Ld652Y cells, supporting the involvement of Ld-Dronc in apoptosis induction. In vAcDeltap35-infected apoptotic cells, Ld Dronc underwent proteolytic processing more rapidly and extensively than Bm Dronc. Similar results were obtained for Ld-Dronc and Bm-Dronc expressed transiently in S2, Ld652Y, Sf9, and BM-N cells. Taken together, these findings suggest that the intrinsic properties of Dronc proteinsare responsible, at least in part, for the differing sensitivity of Ld652Y and BM-N to apoptosis induction upon NPV infection. PMID- 23743203 TI - Evidence for a negative feedback control mediated by the 3' untranslated region assuring the low expression level of the RNA binding protein TcRBP19 in T. cruzi epimastigotes. AB - Because of their relevant role in the post-transcriptional regulation of the expression of a multitude of genes, RNA-binding proteins (RBPs) need to be accurately regulated in response to environmental signals in terms of quantity, functionality and localization. Transcriptional, post-transcriptional and post translational steps have all been involved in this tight control. We have previously identified a Trypanosoma cruzi RBP, named TcRBP19, which can barely be detected at the replicative intracellular amastigote stage of the mammalian host. Even though protein coding genes are typically transcribed constitutively in trypanosomes, TcRBP19 protein is undetectable at the epimastigote stage. Here, we show that this protein expression pattern follows the steady-state of its mRNA. Using a T. cruzi reporter gene approach, we could establish a role for the 3' UTR of the tcrbp19 mRNA in transcript down-regulation at the epimastigote stage. In addition, the binding of the TcRBP19 protein to its encoding mRNA was revealed by in vitro pull down followed by qRT-PCR and confirmed by CLIP assays. Furthermore, we found that forced over-expression of TcRBP19 in T. cruzi epimastigotes decreased the stability of the endogenous tcrbp19 mRNA. These results support a negative feedback control of TcRBP19 to help maintain its very low concentration of TcRBP19 in the epimastigote stage. To our knowledge, this is the first RBP reported in trypanosomatids capable of negatively regulating its own mRNA. The mechanism revealed here adds to our limited but growing number of examples of negative mRNA autoregulation in the control of gene expression. PMID- 23743204 TI - Overexpression of dnIKK in mesenchymal stem cells leads to increased migration and decreased invasion upon TNFalpha stimulation. AB - IkappaB kinase 2 (IKK-2) mediates tumor necrosis-factor alpha (TNFalpha) induced invasion of human mesenchymal stem cell (hMSC) to sites of tissue injury. Suppressing IKK-2 activity leads to reduced expression of proteolytic enzymes and impaired invasive capacity. In order to further reveal mechanisms of hMSC recruitment, we here aimed to analyse the impact of IKK-2 on two-dimensional migration upon TNFalpha stimulation in contrast to three-dimensional invasion. An immortalized hMSC line (SCP-1) was transduced with a dominant-negative mutant of IkappaB kinase 2 (SCP-1 dnIKK). Migration was assessed using a linear-gradient chemotaxis chambers by time-lapse analysis. Invasive capacity through human extracellular matrix was analysed using transwell invasion assays. RT-PCR confirmed increased IKK-2 expression levels in SCP-1 dnIKK cells, while TNFalpha receptor I and II expression was not altered. Invasion upon TNFalpha stimulation was significantly reduced by 78% in SCP-1 dnIKK. In contrast, migration was significantly increased, represented by a 60% elevated forward migration index and a 2.1-fold higher mean dislocation of the center of mass towards TNFalpha. In conclusion, our data confirms the impact of IKK-2 in TNFalpha dependent hMSC recruitment. Interestingly, reducing IKK-2 function increases two-dimensional migration towards TNFalpha, while invasive capacity is impaired. These findings contribute to a deeper understanding of MSC's biological properties orchestrating the complex processes of stem cell recruitment and homing. PMID- 23743205 TI - The H19 induction triggers trophoblast lineage commitment in mouse ES cells. AB - Trophoblast lineage differentiation is properly regulated to support embryogenesis. Besides normal developmental process, during germ cell tumor formation or development of other reproductive system diseases, unregulated trophoblast differentiation is also observed and affects the pathogenesis of the diseases. During normal embryogenesis, cell fate of late-stage blastcyst is regulated by a reciprocal repression of the key transcriptional factors; Oct3/4 dominancy inhibits Cdx2 expression in inner cell mass (ICM) and leads them to epiblast/primitive ectoderm but Cdx2 dominancy in trophectoderm (TE) leads them to trophoblast lineage. In contrast during early blastcyst stage, the Cdx2 expression is restricted in TE and not present in ICM, although Oct3/4 signaling does not inhibit the Cdx2 expression in ICM, implying that some factors could be inactivated leading to the suppressed Cdx2 expression in ICM of early blastcyst. ES cells (ESCs), which are derived from ICM, could be a unique model to study trophoblast differentiation in an ectopic context. We previously showed that poly(ADP-ribose) polymerase-1 (Parp-1) deficient ESCs highly expressed non-coding RNA H19 and could differentiate into trophoblast lineage. The expression of H19 is known to start at pre-blastcyst stage during mouse development, and the gene shows high expression only in trophoectoderm (TE) at blastcyst stage. However, its role in trophoblast differentiation has not been clarified yet. Thus, we hypothesized that the H19 activation may act as a trigger for induction of trophoblast differentiation cascade in mouse ESCs. To investigate this issue, we asked whether a forced H19 expression drives ESCs into trophoblast lineage or not. We demonstrated that the H19 induction leads to trophoblast lineage commitment through induction of the Cdx2 expression. We also showed that the expression of Cdx2 is induced in ESCs by forced H19 expression even under a high level of Oct3/4, which could act as a suppressor for Cdx2 expression. It is thus suggested that the H19 induction promotes trophoblast lineage commitment against the repression pressure by Oct3/4 in differentiating ESCs. Taken together, this study suggests that the H19 expression is able to function as a cascade activator of trophoblast lineage commitment possibly by overriding the Oct3/4 action in ESCs. PMID- 23743206 TI - Inference on periodicity of circadian time series. AB - Estimation of the period length of time-course data from cyclical biological processes, such as those driven by the circadian pacemaker, is crucial for inferring the properties of the biological clock found in many living organisms. We propose a methodology for period estimation based on spectrum resampling (SR) techniques. Simulation studies show that SR is superior and more robust to non sinusoidal and noisy cycles than a currently used routine based on Fourier approximations. In addition, a simple fit to the oscillations using linear least squares is available, together with a non-parametric test for detecting changes in period length which allows for period estimates with different variances, as frequently encountered in practice. The proposed methods are motivated by and applied to various data examples from chronobiology. PMID- 23743207 TI - Optimal control of insects through sterile insect release and habitat modification. AB - This paper develops an optimal control framework for an ordinary differential equation model to investigate the introduction of sterile mosquitoes to reduce the incidence of mosquito-borne diseases. Existence of a solution given an optimal strategy and the optimal control is determined in association with the negative effects of the disease on the population while minimizing the cost due to this control mechanism. Numerical simulations have shown the importance of effects of the bounds on the release of sterile mosquitoes and the bounds on the likelihood of egg maturation. The optimal strategy is to maximize the use of habitat modification or insecticide. A combination of techniques leads to a more rapid elimination of the wild mosquito population. PMID- 23743208 TI - Is it too early to include peritrabecular clefting as a diagnostic criterion in fibrous dysplasia? PMID- 23743209 TI - The effect of nitrous oxide inhalation on the hypotensive response to propofol: a randomized controlled trial. AB - OBJECTIVE: Decrease in arterial blood pressure is a prominent adverse reaction during propofol (Disoprivan; AstraZeneca K.K., Osaka, Japan) sedation. The purpose of this prospective randomized study was to explore the effects of nitrous oxide (N2O) on the hypotensive response during propofol sedation. STUDY DESIGN: Twenty-six healthy volunteers received intravenous sedation with propofol alone (group P, n=13) or a combined technique using 20% N2O and propofol (group N+P, n=13). Propofol was administered by a target-controlled infusion system to attain and maintain a plasma propofol concentration of 1.5MUg/mL. Hemodynamic and autonomic parameters were measured. RESULTS: Mean arterial pressure decreased in both groups, the hypotensive response in group N+P being significantly smaller than in group P. Reduction in the low-frequency power of systolic blood pressure variability, indicative of sympathetic nervous activity, was also smaller in group N+P than in group P. CONCLUSIONS: Addition of N2O to propofol sedation can attenuate the hypotensive effect of propofol. PMID- 23743210 TI - On the impartiality of early British clinical trials. AB - Did the impartiality of clinical trials play any role in their acceptance as regulatory standards for the safety and efficacy of drugs? According to the standard account of early British trials in the 1930s and 1940s, their impartiality was just rhetorical: the public demanded fair tests and statistical devices such as randomization created an appearance of neutrality. In fact, the design of the experiment was difficult to understand and the British authorities took advantage of it to promote their own particular interests. I claim that this account is based on a poorly defined concept of experimental fairness (derived from T. Porter's ideas). I present an alternative approach in which a test would be impartial if it incorporates warrants of non-manipulability. With this concept, I reconstruct the history of British trials showing that they were indeed fair and this fairness played a role in their acceptance as regulatory yardsticks. PMID- 23743211 TI - Management of hydrocephalus secondary to pineal region tumors. AB - BACKGROUND: Hydrocephalus is often secondary to pineal region tumors. Hydrocephalus can lead to high intracranial pressure, which in turn results in disturbance of consciousness, cerebral hernia, and even death. Hydrocephalus management is important in the treatment of pineal region tumors. It is still controversial regarding to when and how to treat hydrocephalus secondary to pineal region tumors. The objective of this study is to investigate the management of hydrocephalus secondary to pineal region tumors. METHODS: We retrospectively analyzed records for 51 patients admitted to the department of Neurosurgery, Jinling Hospital from April 1997 to September 2010 with hydrocephalus secondary to pineal region tumors treated through occipital transtentorial approach. RESULTS: Preoperative ventricular drainage was performed on one patient, and ventriculoperitoneal shunts were performed on two patients. Intraoperative ventriculocisternal shunts were performed on 35 patients (the remission rate was 88.6%), no treatments on 15 patients (the remission rate was 46.7%), and ventricular drainages on three patients. VP shunts were performed on 12 patients with no remission after the operation. CONCLUSION: Pineal region tumors resection usually should be performed before shunting, unless there is an acute obstructive hydrocephalus. The posterior third ventricle should be opened after tumor resection. Intraoperative third ventriculostomy and ventriculocisternal shunt are reliable ways to manage hydrocephalus secondary to pineal region tumors. PMID- 23743212 TI - Calculating alcohol risk in a visualization tool for promoting healthy behavior. AB - OBJECTIVE: To investigate effective methods for communicating the personalized risks of alcohol consumption, particularly to young people. METHODS: An interactive computerized blood alcohol content calculator was implemented in Flash based on literature findings for effectively communicating risk. Young people were consulted on attitudes to the animation features and visualization techniques used to display personalized risk based on disclosed alcohol consumption. RESULTS: Preliminary findings reveal the calculator is relatively enjoyable to use for its genre. However, the primary aims of the visualization tool to effectively communicate personalized risk were undermined for some users by technical language. Transparency of risk calculations might further enhance the tool for others. Worryingly, user feedback revealed a tension between accurate presentation of risk and its consequent lack of sensationalism in terms of personal risk to the individual. CONCLUSION: Initial findings suggest the tool may provide a relatively engaging vehicle for exploring the link between action choices and risk outcomes. Suggestions for enhancing risk communication include using intelligent techniques for selecting data presentation formats and for demonstrating the effects of sustained risky behavior. PRACTICE IMPLICATIONS: Effective communication of risk contributes only partially to effecting behavior change; the role of the tool in influencing contributing attitudinal factors is also discussed. PMID- 23743214 TI - Patient behavior and the benefits of artificial intelligence: the perils of "dangerous" literacy and illusory patient empowerment. AB - OBJECTIVE: Artificial intelligence can provide important support of patient health. However, limits to realized benefits can arise as patients assume an active role in their health decisions. METHODS: Distinguishing the concepts of health literacy and patient empowerment, we analyze conditions that bias patient use of the Internet and limit access to and impact of artificial intelligence. RESULTS: Improving health literacy in the face of the Internet requires significant guidance. Patients must be directed toward the appropriate tools and also provided with key background knowledge enabling them to use the tools and capitalize on the artificial intelligence technology. CONCLUSION: Benefits of tools employing artificial intelligence to promote health cannot be realized without recognizing and addressing the patients' desires, expectations, and limitations that impact their Internet behavior. In order to benefit from artificial intelligence, patients need a substantial level of background knowledge and skill in information use-i.e., health literacy. PRACTICE IMPLICATIONS: It is critical that health professionals respond to patient search for information on the Internet, first by guiding their search to relevant, authoritative, and responsive sources, and second by educating patients about how to interpret the information they are likely to encounter. PMID- 23743213 TI - The role of goal management for successful adaptation to arthritis. AB - OBJECTIVE: Persons with polyarthritis often experience difficulties in attaining personal goals due to disease symptoms such as pain, fatigue and reduced mobility. This study examines the relationship of goal management strategies - goal maintenance, goal adjustment, goal disengagement, goal reengagement - with indicators of adaptation to polyarthritis, namely, depression, anxiety, purpose in life, positive affect, participation, and work participation. METHODS: 305 patients diagnosed with polyarthritis participated in a questionnaire study (62% female, 29% employed, mean age: 62 years). Hierarchical multiple-regression analyses were conducted to examine the relative importance of the goal management strategies for adaptation. Self-efficacy in relation to goal management was also studied. RESULTS: For all adaptation indicators, the goal management strategies added substantial explained variance to the models (R(2): .07-.27). Goal maintenance and goal adjustment were significant predictors of adaptation to polyarthritis. Self-efficacy partly mediated the influence of goal management strategies. CONCLUSION: Goal management strategies were found to be important predictors of successful adaptation to polyarthritis. Overall, adjusting goals to personal ability and circumstances and striving for goals proved to be the most beneficial strategies. PRACTICE IMPLICATIONS: Designing interventions that focus on the effective management of goals may help people to adapt to polyarthritis. PMID- 23743215 TI - Patient safety was 'not just another bandwagon'. PMID- 23743216 TI - Two recombinant alpha-like scorpion toxins from Mesobuthus eupeus with differential affinity toward insect and mammalian Na(+) channels. AB - alpha-Scorpion toxins are modulators of voltage-gated Na(+) channels (Navs), which bind to the receptor site 3 to inhibit the fast inactivation of the channels. MeuNaTxalpha-12 and MeuNaTxalpha-13 are two new alpha-scorpion toxin like peptides identified by cDNA cloning from the scorpion Mesobuthus eupeus with unknown functions. Here, we report their recombinant production, oxidative refolding, structural and functional features. By in vitro renaturation from bacterial inclusion bodies and further purification through reverse phase high performance liquid chromatography, we obtained high purity recombinant products with a native-like conformation identified by circular dichroism analysis. Two electrode voltage clamp recordings on five cloned mammalian Nav subtypes (rNav1.1, rNav1.2, rNav1.4, rNav1.5, and mNav1.6) and the insect counterpart DmNav1, all expressed in Xenopus laevis oocytes, showed that these two peptides inhibited rapid inactivation of the sensitive Na(+) channels with significant preference for DmNav1. The half maximal effective concentrations (EC50) of MeuNaTxalpha-12 and MeuNaTxalpha-13 for this channel are 19.95 +/- 2.99 nM and 65.50 +/- 7.28 nM, respectively, showing 45 and 38 folds higher affinities than for rNav1.1, the most sensitive mammalian channel among the five isoforms. Our functional data confirms that these two peptides belong to the alpha-like scorpion toxin group. A combined analysis of the site 3 sequences and the pharmacological data illuminates the importance of the loop LD4:S5-S6 of the channel in interacting with the toxins whereas affinity variations between MeuNaTxalpha-12 and MeuNaTxalpha-13 highlight a key functional role of a cationic side chain at position 28 of MeuNaTxalpha-12. Successful expression together with structural and functional characterization of these two new alpha-like scorpion toxins lays basis for further studies of their structure-function relationship. PMID- 23743217 TI - The impact of calcineurin inhibitors on graft survival. AB - The discovery of the first calcineurin inhibitor (CNI), cyclosporine, represents a watershed event in the history of immunosuppression, as it was the first drug shown to reversibly inhibit T-lymphocyte function, therefore allowing for one of the major breakthroughs in modern medicine, that of organ transplantation. Calcineurin inhibitors remain the most effective and widely used immunosuppressive agents in organ transplantation today. The 2010 OPTN/SRTR Annual Report showed that 96% of renal transplant recipients were on CNI at the time of discharge from hospital. The prolonged use of CNI, however, may result in renal toxicity, renal dysfunction and eventual renal failure in both recipients of renal and other solid organ transplants, as well as in patients treated with these agents for autoimmune diseases. This brief review, while acknowledging that CNI toxicity does indeed exist, will focus on the successful use of CNI in renal transplant recipients, highlighting recent observations that provide alternative explanations for some of the adverse outcomes that have been attributed to CNI nephrotoxicity in the past. PMID- 23743218 TI - A treatment option for nontraumatic adult-type dural arteriovenous fistulas: transarterial venous coil embolization. AB - OBJECTIVE: Transvenous coil embolization of the affected venous outlet is the most effective treatment method for the management of nontraumatic adult dural arteriovenous fistulas (DAVFs). However, such an approach is not always feasible. We discuss nontraumatic adult DAVFs that were treated with transarterial coil embolization of the proximal venous outlet at our facility, as well as cases previously reported in the literature. METHODS: This study included 8 patients who had undergone transarterial coil embolization of the proximal venous outlet for the treatment of nontraumatic adult DAVFs (4 cases in our series and 4 cases in the literature). All clinical, angiographic, and procedural data were retrospectively collected from medical charts or the literature and recorded on standardized forms by a physician. The DAVFs were classified according to the venous drainage pattern. RESULTS: In all 8 patients, occlusion of the proximal venous site of the fistula was possible by using coils through the arterial feeders; this resulted in complete recovery in all patients. The access route for 7 of the 8 cases was the middle meningeal artery, and in 1 case was the meningohypophyseal artery. In all 8 patients the access artery was relatively smooth, with distal enlargement in the fistula region. CONCLUSIONS: If a distally enlarged feeding artery is observed among the multiple feeding arteries, it suggests the existence of a large fistula and may serve as an access route for transarterial venous coil embolization. This procedure may offer a more effective and safer treatment than other endovascular approaches. PMID- 23743219 TI - Effect of scalp blocks with levobupivacaine on recovery profiles after craniotomy for aneurysm clipping: a randomized, double-blind, and controlled study. AB - OBJECTIVE: This study was conducted to evaluate the effect of scalp blocks using levobupivacaine on recovery profiles including postoperative pain, patient controlled analgesia (PCA) consumption, postoperative nausea and vomiting (PONV), and other adverse events in patients undergoing frontoparietal craniotomy for aneurysm clipping. METHODS: Fifty-two patients scheduled for elective frontoparietal craniotomy for unruptured aneurysm clipping were enrolled. After surgery, scalp blocks were performed using normal saline (group C, n = 26) or 0.75% levobupivacaine (group L, n = 26). Postoperative pain scores and PCA consumption were recorded for 72 hours after recovery of consciousness. The time from patient recovery to the first use of PCA drug and rescue analgesics, the requirement for vasoactive agents, and adverse effects related to PCA and local anesthetics also were recorded. RESULTS: Postoperative pain scores and PCA consumption in group L were lower than in group C (P < .05). The time intervals from patient recovery to the first use of PCA drug (P < .001) and rescue analgesics (P = .038) was longer in group L than in group C. Additionally, less antihypertensive agent was required (P = .017), and PONV occurred less frequently (P = .039) in group L than in group C. CONCLUSIONS: Scalp blocks with 0.75% levobupivacaine improved recovery profiles in that it effectively lowered postoperative pain and PCA consumption without severe adverse events and also reduced the requirement for a postoperative antihypertensive agent and the incidence of PONV in patients who underwent frontoparietal craniotomy for aneurysm clipping. PMID- 23743220 TI - [Hypotony maculopathy]. PMID- 23743221 TI - Mechanosensitive regulation of cortactin by p47phox: a new paradigm in cytoskeletal remodeling. PMID- 23743222 TI - Cezanne paints inflammation by regulating ubiquitination. PMID- 23743223 TI - Nuclear receptors and microRNA-144 coordinately regulate cholesterol efflux. PMID- 23743225 TI - The regional myocardial flow-function relationship: a framework for an understanding of acute ischemia, hibernation, stunning and coronary microembolization. 1980. PMID- 23743224 TI - Build a braveheart: the missing linc (RNA). PMID- 23743226 TI - Brian Kobilka: chipping away at the beta2-adrenergic receptor. Interview by Ruth Williams. PMID- 23743229 TI - Lineage of bone marrow-derived cells in atherosclerosis. AB - Atherosclerosis is a chronic inflammatory disease driven by lipids and other atherogenic factors. It is characterized by a dynamic and complex pathological process of bone marrow-derived cells playing divergent roles. Recent studies have begun unraveling the contribution of growing varieties of subsets of immune cells and other bone marrow-derived cells to atherogenesis. For example, bone marrow derived vascular progenitor cells have been shown to play an important role in the pathogenesis of atherosclerosis. This review provides an overview of the current understanding of contributions of bone marrow-derived cells to atherosclerosis. Particular focus is placed on myeloid cells and vascular progenitor cells. We also summarize the uncertainty surrounding cellular lineage identity and functions. Expansion of our understanding of pathological roles of various subsets of bone marrow-derived cells in atherosclerosis may lead to identification of novel cellular and molecular targets for development of therapeutic strategies. PMID- 23743227 TI - Overview of high throughput sequencing technologies to elucidate molecular pathways in cardiovascular diseases. AB - High throughput sequencing technologies have become essential in studies on genomics, epigenomics, and transcriptomics. Although sequencing information has traditionally been elucidated using a low throughput technique called Sanger sequencing, high throughput sequencing technologies are capable of sequencing multiple DNA molecules in parallel, enabling hundreds of millions of DNA molecules to be sequenced at a time. This advantage allows high throughput sequencing to be used to create large data sets, generating more comprehensive insights into the cellular genomic and transcriptomic signatures of various diseases and developmental stages. Within high throughput sequencing technologies, whole exome sequencing can be used to identify novel variants and other mutations that may underlie many genetic cardiac disorders, whereas RNA sequencing can be used to analyze how the transcriptome changes. Chromatin immunoprecipitation sequencing and methylation sequencing can be used to identify epigenetic changes, whereas ribosome sequencing can be used to determine which mRNA transcripts are actively being translated. In this review, we will outline the differences in various sequencing modalities and examine the main sequencing platforms on the market in terms of their relative read depths, speeds, and costs. Finally, we will discuss the development of future sequencing platforms and how these new technologies may improve on current sequencing platforms. Ultimately, these sequencing technologies will be instrumental in further delineating how the cardiovascular system develops and how perturbations in DNA and RNA can lead to cardiovascular disease. PMID- 23743230 TI - Circulation research thematic synopsis: cardiac arrhythmias. PMID- 23743228 TI - Monocyte and macrophage heterogeneity in the heart. AB - Monocytes and macrophages are innate immune cells that reside and accumulate in the healthy and injured heart. The cells and their subsets pursue distinct functions in steady-state and disease, and their tenure may range between hours and months. Some subsets are highly inflammatory, whereas others support tissue repair. This review discusses current concepts of lineage relationships and crosstalk of systems, highlights open questions, and describes tools for studying monocyte and macrophage subsets in the murine and human heart. PMID- 23743231 TI - Whole exome sequencing reveals minimal differences between cell line and whole blood derived DNA. AB - Two common sources of DNA for whole exome sequencing (WES) are whole blood (WB) and immortalized lymphoblastoid cell line (LCL). However, it is possible that LCLs have a substantially higher rate of mutation than WB, causing concern for their use in sequencing studies. We compared results from paired WB and LCL DNA samples for 16 subjects, using LCLs of low passage number (<5). Using a standard analysis pipeline we detected a large number of discordant genotype calls (approximately 50 per subject) that we segregated into categories of "confidence" based on read-level quality metrics. From these categories and validation by Sanger sequencing, we estimate that the vast majority of the candidate differences were false positives and that our categories were effective in predicting valid sequence differences, including LCLs with putative mosaicism for the non-reference allele (3-4 per exome). These results validate the use of DNA from LCLs of low passage number for exome sequencing. PMID- 23743232 TI - The effects of exposure to violence and victimization across life domains on adolescent substance use. AB - This study uses longitudinal data from the Project on Human Development in Chicago Neighborhoods (PHDCN) to examine the effects of exposure to school violence, community violence, child abuse, and parental intimate partner violence (IPV) on youths' subsequent alcohol and marijuana use. We also examine the cumulative effects of being exposed to violence across these domains. Longitudinal data were obtained from 1,655 adolescents and their primary caregivers participating in the PHDCN. The effects of adolescents' exposure to various forms of violence across different life domains were examined relative to adolescents' frequency of alcohol and marijuana use three years later. Multivariate statistical models were employed to control for a range of child, parent, and family risk factors. Exposure to violence in a one-year period increased the frequency of substance use three years later, though the specific relationships between victimization and use varied for alcohol and marijuana use. Community violence and child abuse, but not school violence or exposure to IPV, were predictive of future marijuana use. None of the independent measures of exposure to violence significantly predicted future alcohol use. Finally, the accumulation of exposure to violence across life domains was detrimental to both future alcohol and marijuana use. The findings support prior research indicating that exposure to multiple forms of violence, across multiple domains of life, negatively impacts adolescent outcomes, including substance use. The findings also suggest that the context in which exposure to violence occurs should be considered in future research, since the more domains in which youth are exposed to violence, the fewer "safe havens" they have available. Finally, a better understanding of the types of violence youth encounter and the contexts in which these experiences occur can help inform intervention efforts aimed at reducing victimization and its negative consequences. PMID- 23743233 TI - Anti-tumor selectivity of a novel tubulin and HSP90 dual-targeting inhibitor in non-small cell lung cancer models. AB - Dose-limiting toxicity is a main road blocker for successful cancer chemotherapy. By phenotype screening, a novel chemical agent 2-(2-Chlorophenylimino)-5-(4 dimethylamino-benzylidene) thiazolidin-4-one (CDBT) was found to strongly inhibit the proliferation of non-small cell lung cancer (NSCLC) cells H460 and H322 while displaying no obvious toxicity to normal fast-dividing fibroblast cells NHFB and WI-38 at a concentration 100-fold higher than its EC50 to NSCLC cells. CDBT targets microtubule and heat shock protein 90 (HSP90) simultaneously with moderate affinities compared to microtubule targeting Colchicine and HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygaldanamcyin (17-DMAG). CDBT blocks microtubule formation, decreases cancer-essential proteins CRAF-1, ERBB2 and phosphorylated AKT, and causes G2/M arrest and apoptosis. The moderate inhibitory effects of CDBT on targets require a higher cellular concentration of targets, a situation only exist in cancer cells. This accounts for its good cancer selectivity. Furthermore, CDBT effectively inhibits tumor growth by 62.4% relative to the vehicle control after i.p. administration at 30 mg/kg for 11 days while showing no toxicity to normal tissues in NSCLC H460 xenograft mouse model. PMID- 23743234 TI - Reply to Letter: "To live and let die"--the search for the best way to identify at-risk patients? PMID- 23743235 TI - Carbon dioxide management after cardiac arrest: quite a complex issue. PMID- 23743236 TI - Intravenous valproate in twelve patients with post-anoxic status epilepticus. PMID- 23743237 TI - Prophylactic lidocaine for post resuscitation care of patients with out-of hospital ventricular fibrillation cardiac arrest. AB - BACKGROUND: Antiarrhythmic drugs like lidocaine are usually given to promote return of spontaneous circulation (ROSC) during ongoing out-of-hospital cardiac arrest (OHCA) from ventricular fibrillation/tachycardia (VF/VT). Whether administering such drugs prophylactically for post-resuscitation care after ROSC prevents re-arrest and improves outcome is unstudied. METHODS: We evaluated a cohort of 1721 patients with witnessed VF/VT OHCA who did (1296) or did not receive prophylactic lidocaine (425) at first ROSC. Study endpoints included re arrest, hospital admission and survival. RESULTS: Prophylacic lidocaine recipients and non-recipients were comparable, except for shorter time to first ROSC and higher systolic blood pressure at ROSC in those receiving lidocaine. After initial ROSC, arrest from VF/VT recurred in 16.7% and from non-shockable arrhythmias in 3.2% of prophylactic lidocaine recipients, 93.5% of whom were admitted to hospital and 62.4% discharged alive, as compared with 37.4%, 7.8%, 84.9% and 44.5%, of corresponding non-recipients (all p<0.0001). Adjusted for pertinent covariates, prophylactic lidocaine was independently associated with reduced odds of re-arrest from VF/VT, odds ratio, (95% confidence interval) 0.34 (0.26-0.44) and from nonshockable arrhythmias (0.47 (0.29-0.78)); a higher hospital admission rate (1.88, (1.28-2.76)) and improved survival to discharge (1.49 (1.15-1.95)). However in a propensity score-matched sensitivity analysis, lidocaine's only beneficial association with outcome was in a lower incidence of recurrent VF/VT arrest. CONCLUSIONS: Administration of prophylactic lidocaine upon ROSC after OHCA was consistently associated with less recurrent VF/VT arrest, and therapeutic equipoise for other measures. The prospect of a promising association between lidocaine prophylaxis and outcome, without evidence of harm, warrants further investigation. PMID- 23743238 TI - Arterial carbon dioxide tension and outcome in patients admitted to the intensive care unit after cardiac arrest (reply). PMID- 23743239 TI - Structural modelling studies and immunoprophylactic potential of Brugia malayi DEAD Box RNA helicase. AB - DEAD Box RNA helicases are essential enzymes that are involved in RNA metabolic processes such as transcription, pre-mRNA splicing, translation initiation and RNA decay. We have previously over-expressed and biochemically characterized an immunodominant cDNA clone encoding DEAD box RNA helicase (BmL3-Helicase) isolated by immunoscreening of the larval stage cDNA library of Brugia malayi. In the current study, the 3D structure was determined and the immunoprophylactic efficacy of BmL3-Helicase was investigated by immunizing Mastomys coucha with the recombinant protein and subsequently challenging with B. malayi infective larvae. The immunization had an adverse outcome on the establishment of challenged larvae resulting in a 67.4% reduction in adult parasite recovery, a 86.7% decrease in the microfilarial density and profound sterility of the recovered female worms. The immune response thus generated was investigated by measuring the levels of specific antibodies including IgG subclasses, reactive oxygen species and cytokines. PMID- 23743240 TI - Molecular cloning and characterization of NcROP2Fam-1, a member of the ROP2 family of rhoptry proteins in Neospora caninum that is targeted by antibodies neutralizing host cell invasion in vitro. AB - Recent publications demonstrated that a fragment of a Neospora caninum ROP2 family member antigen represents a promising vaccine candidate. We here report on the cloning of the cDNA encoding this protein, N. caninum ROP2 family member 1 (NcROP2Fam-1), its molecular characterization and localization. The protein possesses the hallmarks of ROP2 family members and is apparently devoid of catalytic activity. NcROP2Fam-1 is synthesized as a pre-pro-protein that is matured to 2 proteins of 49 and 55 kDa that localize to rhoptry bulbs. Upon invasion the protein is associated with the nascent parasitophorous vacuole membrane (PVM), evacuoles surrounding the host cell nucleus and, in some instances, the surface of intracellular parasites. Staining was also observed within the cyst wall of 'cysts' produced in vitro. Interestingly, NcROP2Fam-1 was also detected on the surface of extracellular parasites entering the host cells and antibodies directed against NcROP2Fam-1-specific peptides partially neutralized invasion in vitro. We conclude that, in spite of the general belief that ROP2 family proteins are intracellular antigens, NcROP2Fam-1 can also be considered as an extracellular antigen, a property that should be taken into account in further experiments employing ROP2 family proteins as vaccines. PMID- 23743241 TI - Seroprevalence and GIS-supported risk factor analysis of Fasciola hepatica infections in dairy herds in Germany. AB - A total of 20 749 bulk tank milk (BTM) samples was collected in November 2008 from all over Germany, corresponding to 20.9% of all German dairy herds. The BTM samples were analysed for antibodies against Fasciola hepatica using the excretory-secretory (ES) ELISA. A geospatial map was drawn to show herd prevalences per postal code area. Various spatial risk factors were tested for potential statistical associations with the ELISA results in logistic regression supported by a geographical information system (GIS). The mean seroprevalence was 23.6% and prevalences in different German federal states varied between 2.6% and 38.4%. GIS analysis revealed statistically significant positive associations between the proportion of grassed area and water bodies per postal code area and positive BTM ELISA results. This can be explained by the biology of the intermediate host, the amphibious snail Galba (Lymnea) truncatula and the pasture borne nature of fasciolosis. The full logistic regression model had a Pseudo-R 2 of 22%, while the final model obtained by controlled stepwise model building revealed a Pseudo-R 2 of 14%, indicating that additional, unrecorded factors and random effects contributed substantially to the occurrence of positive ELISA results. Considering the high seroprevalences in some areas and the economic impact of fasciolosis, farmers and veterinarians should be strongly advised to implement effective liver fluke control programmes. PMID- 23743242 TI - Measurement of tamsulosin in human serum by liquid chromatography-tandem mass spectrometry. AB - A simple, sensitive and robust method to extract tamsulosin from human serum, and quantify by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated and is applicable as a measure of compliance in clinical research. Tamsulosin was extracted from human serum (100MUL) via liquid-liquid extraction with methyl tert-butyl ether (2mL) following dilution with 0.1M ammonium hydroxide (100MUL), achieving 99.9% analyte recovery. Internal standard, d9-finasteride, was synthesised in-house. Analyte and internal standard were separated on an Ascentis((r)) Express C18 (100mm*3mm, 2.7MUm) column using a gradient elution with mobile phases methanol and 2mM aqueous ammonium acetate (5:95, v/v). Total run-time was 6min. Tamsulosin was quantified using a triple quadrupole mass spectrometer operated in multi-reaction-monitoring (MRM) mode using positive electrospray ionisation. Mass transitions monitored for quantitation were: tamsulosin m/z 409->228 and d9-finasteride m/z 382->318, with the structural formulae of ions confirmed by Fourier transform ion cyclotron resonance mass spectrometry (within 10ppm). The limit of quantitation was 0.2ng/mL, and the method was validated in the linear range 0.2-50ng/mL with acceptable inter- and intra-assay precision and accuracy and stability suitable for routine laboratory practice. The method was successfully applied to samples taken from research volunteers in a clinical study of benign prostatic hyperplasia. PMID- 23743243 TI - Primary central nervous system lymphoma with lymphomatosis cerebri in an immunocompetent child: MRI and 18F-FDG PET-CT findings. AB - Primary central nervous system lymphoma (PCNSL) is extremely rare in immunocompetent children. We present the magnetic resonance imaging (MRI) and (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography-computed tomography (PET-CT) findings of such a case in a 14-year old immunocompetent boy. In this patient, PCNSL was associated with lymphomatosis cerebri. Familiarity with the findings of this rare condition will improve the diagnostic confidence of the nuclear radiologist and avoid misdiagnosis. PMID- 23743244 TI - All together for the nuclear medicine. PMID- 23743245 TI - Early initiation of new oral anticoagulants in acute stroke and TIA patients with nonvalvular atrial fibrillation. AB - BACKGROUND AND PURPOSE: The aim of this study was to investigate whether early initiation of new oral anticoagulants (NOAC) for acute stroke or transient ischemic attack (TIA) patients with nonvalvular atrial fibrillation (NVAF) are safe. METHODS: Between March 2011 and September 2012, stroke or TIA patients with NVAF who started NOAC within 2 weeks were enrolled retrospectively. Symptomatic intracerebral hemorrhage (ICH), hemorrhagic transformation (HT) on T2*-weighted MRI, recurrence of stroke or TIA, systemic embolism and any bleeding complications after initiation of NOAC were evaluated. RESULTS: 41 patients (25 males; mean age 76.2 years) started NOAC; of which, 39 (95%) patients had stroke, and 2 (5%) had TIA. The median (interquartile range) interval from onset to treatment with NOAC was 2 (1-6) days. Symptomatic ICH was not observed. HT on initial T2* and new HT on follow-up T2* were 5 (12%) and 11 (31%), but it was asymptomatic. Of 5 patients who had HT on the initial T2*, enlargement of hemorrhage on follow-up T2* (hemorrhagic infarction (HI) Type 1->HI Type 2) was observed in 1 patient, but it was asymptomatic. None of the patients had recurrent stroke or TIA, systemic embolism, and any bleeding complications. CONCLUSIONS: The NOAC may be safe in acute stroke or TIA patients with NVAF. A large, prospective study is needed to confirm this. PMID- 23743246 TI - Familial adult-onset Alexander disease with a novel mutation (D78N) in the glial fibrillary acidic protein gene with unusual bilateral basal ganglia involvement. AB - In this report, we describe the case of a new Japanese family (32 to 64 years old; 2 females and 1 male) affected by adult-onset Alexander disease. Clinically, one member (age at onset, 56 years old) developed cerebellar ataxia, another (age at onset, 55 years old) showed cerebellar ataxia and pseudobulbar signs, and one member (32 years old) was asymptomatic. Marked atrophy of the medulla oblongata and spinal cord was detected in the two symptomatic patients by magnetic resonance imaging (MRI). However, in the asymptomatic patient, cervicomedullary atrophy was mild. Hyperintensity signals in the medulla oblongata were detected in the two symptomatic patients, but not in the asymptomatic patient. In addition, there are symmetrical hyperintensity signals in the posterior part of the globus pallidus on T2-weighted images in the two symptomatic patients, which are rarely observed in adult-onset Alexander disease. Molecular genetic analysis revealed a novel missense mutation (p. D78N) in the glial fibrillary acidic protein (GFAP) gene in this family. The typical atrophy of the medulla oblongata and upper cervical cord detected by MRI is the diagnostic feature of adult-onset Alexander disease. Genetic analysis of the GFAP gene is recommended for all patients with late-onset progressive ataxia and suspected of having adult-onset Alexander disease on the basis of MRI findings. Additionally, these characteristic MRI patterns might even lead to the identification of asymptomatic cases, as in one of our cases. PMID- 23743247 TI - Neuromodulatory control of sleep in Drosophila melanogaster: integration of competing and complementary behaviors. AB - The transition between wake and sleep states is characterized by rapid and generalized changes in both sensory and motor processing. Sleep is antagonistic to the expression of important behaviors, like feeding, reproduction and learning whose relative importance to an individual will depend on its circumstances at that moment. An understanding of how the decision to sleep is affected by these other drives and how this process is coordinated across the entire brain remains elusive. Neuromodulation is an important regulatory feature of many behavioral circuits and the reconfiguring of these circuits by modulators can have both long term and short-term consequences. Drosophila melanogaster has become an important model system for understanding the molecular and genetic bases of behaviors and in recent years neuromodulatory systems have been shown to play a major role in regulation of sleep and other behaviors in this organism. The fly, with its increasingly well-defined behavioral circuitry and powerful genetic tools, is a system poised to provide new insight into the complex issue of how neuromodulation can coordinate situation-specific behavioral needs with the brain's arousal state. PMID- 23743248 TI - Notch activation promotes endothelial survival through a PI3K-Slug axis. AB - RATIONALE: Loss of endothelial viability correlates with initiation and progress of vascular pathology. However, much remains to be learned about pathways required to maintain the balance between cell viability and apoptosis. Notch activation can enhance or inhibit apoptosis but its role in maintaining the endothelium needs further delineation. OBJECTIVE: This study aims to identify the mechanisms by which Notch activation regulates endothelial viability. METHODS AND RESULTS: Endothelial cells transduced with active Notch were treated with lipopolysaccharide (LPS) or homocysteine to induce endothelial apoptosis. Notch protected against LPS-induced cell death but exacerbated homocysteine-induced apoptosis. Inhibition of PI3K revealed that ligand-induced activation of endogenous Notch initiates parallel death and survival pathways and exhibits a differential effect on endothelial survival depending on the apoptotic stimulus. PI3K activity regulated the expression of Slug, which was required for survival in Notch-activated endothelial cells. Homocysteine, but not LPS, blocked both PI3K activity and Slug expression in Notch-activated cells, leading to increased endothelial apoptosis. CONCLUSIONS: Notch signaling leads to activation of parallel survival and apoptotic pathways in endothelial cells. The interaction of Notch with other signaling pathways plays an important contextual role in regulating endothelial viability. PMID- 23743249 TI - Computational study on thrombus formation regulated by platelet glycoprotein and blood flow shear. AB - Thrombogenesis results from the interaction between glycoprotein receptors and their ligands, although a thrombus is affected by multiple factors such as blood flow, platelet interactions, and changes in ligand characteristics. In this study, we propose a platelet adhesion and aggregation model, focusing on the interaction between the glycoprotein receptor and its ligand. First, we conducted thrombogenesis simulations to compare physiological and pathological conditions. The results suggested that simulations of thrombogenesis differed in distribution, volume, and stability of the thrombus based on disorders of platelet adhesion, aggregation, and the activation. For example, distribution and volume were affected by the activation of GPIIb/IIIa with a GPIb/IX/V deficiency. The thrombus was also unstable, but formed from the upstream side of the injured site, with a GPIIb/IIIa deficiency. Second, we investigated thrombogenesis enhanced by the shear-induced platelet aggregation (SIPA) mechanism. The results demonstrated that the degree of SIPA decreased gradually with thrombus growth in a straight vessel. This result suggests that SIPA is a key hemostasis mechanism in an injured healthy arteriole, although it can lead to the formation of an occlusive thrombus in stenosed vessels. PMID- 23743250 TI - Occurrence of halogenated contaminants in inland and coastal fish from Ghana: levels, dietary exposure assessment and human health implications. AB - Fish consumption is known to have several health benefits for humans. However, the accumulation of toxic contaminants, such as PCBs, PBDEs and HBCDs in fish could pose health hazards. These contaminants were measured in tilapia fish species collected from Ghana. Mean levels were PCBs (62 ng/g lw), PBDEs (7.3 ng/g lw) and HBCDs (1.2 ng/g lw) and the predominance of CB-153, CB-138, CB-180, BDE 47 and alpha-HBCD is in concordance with scientific literature. The congener profiles of PBDEs and PCBs in the fish suggest that sources of Penta- and Deca BDE technical mixtures as well as technical PCB mixture (Clophen A60) exist in Ghana, while textile operations and associated release of untreated wastewater are likely to be significant sources of HBCDs. Comparison of the results with some reported studies showed moderate contamination in Ghana although Ghana is a developing country in Africa. Concentrations of PCBs measured in all the specimens in this study were below the food safety guidelines issued by the Food and Drug Administration, USA and the European Commission. The calculated hazard index levels of the target contaminants were below the threshold value of one, indicating that the levels of the target contaminants do not seem to constitute a health risk via fish consumption, with regard to PCBs, PBDEs and HBCDs, based on the limited number of samples that was accounted for in this study. However, due to the continuous discharge of untreated effluents, follow up studies are warranted as the consumption of fish is the primary route of human exposure to PCBs. This maiden report on the status of PBDEs and HBCDs in fish from Ghana will contribute to the knowledge about environmental contamination by POPs in a less industrialized region of the world so far sparsely covered in the literature. PMID- 23743251 TI - Seasonal variation of phytoplankton nutrient limitation in Lake Taihu, China: a monthly study from year 2011 to 2012. AB - Lake Taihu is the third largest freshwater lake in China with severe eutrophication issues. However, it remains ambiguous how its phytoplankton growth is limited by various nutrients in different seasons. A series of bottle enrichment assays in Meiliang Bay was thus performed once a month from July, 2011 to June, 2012 in the present study. The initial chlorophyll a concentration and phytoplankton cell density ranged from 4.70 to 34.6 MUg/l and from 1.25*10(6) to 6.72*10(8) cells/l with three peaks in July, November, and March. Although Cyanophyta was dominant (30.9-99.2 percent) in most cases, other phyla like Chlorophyta, Bacillariophyta, and Cryptophyta could account for as much as 69.1 percent of total phytoplankton in cold seasons. The microcystin-LR content in the particulate phase followed a similar seasonal pattern as Cyanophyta. It further went up exponentially with the proportion of cyanobacteria in phytoplankton suggesting more toxigenic species and (or) upregulated microcystin synthesis when the contribution of Cyanophyta was enhanced. On the other hand, the dissolved concentrations of various nitrogen and phosphorus species reached their maxima in late spring and autumn, respectively. According to its growth response to nutrient addition, phytoplankton in Meiliang Bay was restricted by nitrogen in August, October, and November. No nutrient limitation occurred in July, September, and April, whereas phosphorus deficiency prevailed in the other months. Overall, nutrient limitation in Lake Taihu and possibly other aquatic ecosystems worldwide may be more dynamic than what we thought before, which should be considered to eliminate eutrophication. PMID- 23743253 TI - Attention allocation patterns in naturalistic driving. AB - The key to safe driving is the adequate distribution of the driver's attention to the forward area and to other non-forward focal points. However, thus far, current methods are not able to well quantify the entire process of a driver's attention allocation. Therefore, this study proposed a novel concept of renewal cycles for representing and analyzing driver attention allocation. Using the 100 car naturalistic glance data, this study found that 90.74% of drivers' attention allocations were 2-glance renewal cycles. The findings suggest that the sample drivers usually separated their lapses of attention from the forward direction into several sequences by directing their vision back to the forward direction after each visual shift away from it. In addition, although a markedly smaller number of cycles were more than 3-glances (2.09% renewal cycles), drivers were certainly less aware of the frontal area and at a higher risk of having an accident during such cycles. This finding might have striking implications for accident prevention. This area of study deserves further attention. Among the generated renewal cycles, lots of them repeated frequently, especially cycles related to invehicle distractions. To analyze the different characteristics among various attributes, distribution of the common renewal cycles under different conditions was examined. As expected, drivers displayed different renewal cycles under various road conditions and with various driver intentions. Although these sample drivers were not representative, the preliminary research results were promising and fruitful for potential applications, particularly educating novice drivers. PMID- 23743252 TI - Debiasing overoptimistic beliefs about braking capacity. AB - We investigated, using questionnaires, different strategies for removing drivers' overoptimism (Svenson et al., 2012a) about how fast their speed could be decreased when they were speeding compared with braking at the speed limit speed. Three different learning groups and a control group made collision speed judgments. The first learning group had the distance a car travels during a driver's reaction time for each problem. The second group had this information and also feedback after each judgment (correct speed). The third group judged collision speed but also braking distance and received correct facts after each problem. The control group had no information at all about reaction time and the distance traveled during that time. The results suggested the following rank order from poor to improved performance: control, group 1, group 3 and group 2 indicating that information about distance driven during a driver's reaction time improved collision speed judgments and that adding stopping distance information did not add to this improvement. PMID- 23743254 TI - Polymer-hybridized liposomes of poly(amino acid) derivatives as transepidermal carriers. AB - This work describes the use of a novel transepidermal drug carrier system composed of phospholipids and amphiphilc poly(amino acid)s. We polymerized poly(asparagine) grafted with octadecylamine (PAsn-g-C18), poly(aspartic acid) grafted with octadecylamine (PAsp-g-C18), and poly(aspartic acid) grafted with phytosphingosine (PAsp-g-PHS). We then prepared polymer hybridized liposomes (PHL) anchored with alkyl grafted poly(amino acid)s and encapsulated hydrolyzed ginseng saponins (HGS). We confirmed that the liposomes and PHL reduce the cytotoxicity of HGS, which was not observed with polymeric nano-carriers. A quantitative analysis of the amount of penetrated HGS using the Franz cell method revealed that skin permeation of the lipophilic drugs loaded in liposomes was enhanced by the incorporation of amphiphilic poly(amino acid)s. Fluorescence microscopy observations also demonstrated excellent skin permeation performance of PHL anchored with PAsp-g-PHS. PHL showed better structural stability than liposomes in an O/W emulsion. PHL considerably improved the chemical stability of HGS compared to the liposomes. It is thought that the skin permeability of encapsulated bioactive molecules could be affected by the vesicle structure, membrane fluidity, and the type of anchored polymer. PMID- 23743255 TI - Flurbiprofen PLGA-PEG nanospheres: role of hydroxy-beta-cyclodextrin on ex vivo human skin permeation and in vivo topical anti-inflammatory efficacy. AB - In this study, flurbiprofen (FB) loaded poly(d,l-lactide-co-glycolide) (PLGA) and PLGA with poly(ethylene glycol) (PLGA-PEG) nanospheres (NSs) with and without hydroxypropyl-beta-cyclodextrin (HPbetaCD) were developed as skin controlled delivery systems. X-ray diffraction was used to determine the physical state of the entrapped drug. Results showed that the drug in PLGA NSs was present in the form of a molecular dispersion (dissolved state) in the polymers, whereas in PLGA PEG NSs, the drug was present in both molecular dispersion and crystalline forms. Furthermore, HPbetaCD provided solubilization of the free FB present on the surface of the PLGA-PEG NSs and a complete amorphosization of the drug was obtained. Optical analyses using TurbiscanLab((r)) demonstrated that HPbetaCD provided an efficient steric stability of the NSs, preventing particle aggregation. The ex vivo permeation profiles of the NSs and conventional FB solution were evaluated using human skin. Results demonstrated that only PLGA-PEG NSs showed slight permeation improvement. However, after 24h, the FB retained in the skin was about 9-fold higher with NSs compared with the control solution, attributed to the reservoir effect of NSs acting as a depot, sustaining the drug and limiting its systemic absorption. In vivo performance of NSs was evaluated by assessing anti-inflammatory efficacy in TPA-induced mouse ear edema. Topically applied NSs significantly decreased in vivo inflammation compared to the control solution and the anti-inflammatory efficacy of HPbetaCD NSs was stronger than NSs without HPbetaCD. In vivo skin irritation evaluated by the in vivo Draize test showed no irritation of the formulations tested. PMID- 23743256 TI - Integration of pain score and morphine consumption in analgesic clinical studies. AB - In pain clinical trials, the rescue analgesic medication such as patient controlled analgesia morphine is often made available for patients for breakthrough pain. The patient-controlled analgesia morphine usage decreases the study agent's effect on pain relative to placebo and introduces greater variability in attainment of pain scores. For assessment of analgesic efficacy, the isolated statistical analysis of pain score or morphine consumption as a surrogate marker for pain not only loses statistical efficiency but also may incur increased false-positive findings because of multiple testing. The aim of this article is to review the research to date for choices of statistical tests for pain or morphine consumption outcome, with a focus on systematically evaluating a means for collective analgesic assessment of pain and morphine consumption using an integrated outcome. A case example is illustrated for data visualization, statistical comparison, and effect size estimation using the new endpoint. Some implications for clinical practice and further research are discussed. PERSPECTIVE: This article provides statistical evidence to conclude that an integrated outcome of pain score and morphine consumption provides an efficient means for integrated analgesic assessment. PMID- 23743258 TI - Effort-reward imbalance at work and pre-clinical biological indices of ill health: the case for salivary immunoglobulin A. AB - Physiological indices of stress and ill-health (cortisol and salivary immunoglobulin A) were assessed to determine if they were predicted by Siegrist's effort-reward imbalance model (ERI) with an aim of identifying employees at risk of illness. Male Australian dairy farmers (N=66) completed the Perceived Stress Scale, Work related Questions II & III, Eysenck Personality Questionnaire Revised -Short and demographic questions and provided morning saliva samples (at awakening and 30 min post awakening) on a working day, which were subsequently analysed for cortisol and salivary immunoglobulin A (sIgA) concentration levels. A high percentage (45.5%) of the sample reported an imbalance between efforts and rewards in the workplace that may place them 'at risk' for ill-health. After controlling for disposition, sIgA scores were more successfully predicted by the ERI than the cortisol assessments. Although both efforts and rewards were significantly associated with sIgA, efforts were most strongly associated. The dispositional trait overcommitment, did not moderate the experience of stress on the physiologic indices. The current investigation supports the continued use of sIgA in studies that use biomarkers to assess occupational stress. ERI ratio scores >1 aligned with previous findings that suggest elevated risk of illness for these employees. PMID- 23743257 TI - Functional connectivity of the default mode network and its association with pain networks in irritable bowel patients assessed via lidocaine treatment. AB - The default mode network (DMN), a group of brain regions implicated in passive thought processes, has been proposed as a potentially informative neural marker to aid in novel treatment development. However, the DMN's internal connectivity and its temporal relationship (ie, functional network connectivity) with pain related neural networks in chronic pain conditions is poorly understood, as is the DMN's sensitivity to analgesic effects. The current study assessed how DMN functional connectivity and its temporal association with 3 pain-related networks changed after rectal lidocaine treatment in irritable bowel syndrome patients. Eleven females with irritable bowel syndrome underwent a rectal balloon distension paradigm during functional magnetic resonance imaging in 2 conditions: natural history (ie, baseline) and lidocaine. Results showed increased DMN connectivity with pain-related regions during natural history and increased within-network connectivity of DMN structures under lidocaine. Further, there was a significantly greater lag time between 2 of the pain networks, those involved in cognitive and in affective pain processes, comparing lidocaine to natural history. These findings suggest that 1) DMN plasticity is sensitive to analgesic effects, and 2) reduced pain ratings via analgesia reflect DMN connectivity more similar to pain-free individuals. Findings show potential implications of this network as an approach for understanding clinical pain management techniques. PERSPECTIVE: This study shows that lidocaine, a peripheral analgesic, significantly altered DMN connectivity and affected its relationship with pain related networks. These findings suggest that the DMN, which is hypothesized to represent non-goal-oriented activity, is sensitive to analgesic effects and could be useful to understand pain treatment mechanisms. PMID- 23743259 TI - Artificial light at night alters delayed-type hypersensitivity reaction in response to acute stress in Siberian hamsters. AB - Several physiological and behavioral processes rely on precisely timed light information derived from the natural solar cycle. Using this information, traits have adapted to allow individuals within specific niches to optimize survival and reproduction, but urbanization by humans has significantly altered natural habitats. Nighttime light exposure alters immune function in several species, which could lead to decreased fitness or survival, particularly in the face of an environmental challenge. We exposed male Siberian hamsters (Phodopus sungorus) to five lux of light at night for four weeks, and then administered six hours of acute restraint stress. Delayed-type hypersensitivity (DTH) response was assessed immediately following stress. Acute restraint increased the DTH reaction in dark nights, but exposure to nighttime light prevented this response. Exposure to light at night prolonged the DTH response in non-stressed control hamsters. These results suggest that light pollution may significantly alter physiological responses in Siberian hamsters, particularly in response to a salient environmental challenge such as stress. PMID- 23743260 TI - Cortisol and induced cognitive fatigue: effects on memory activation in healthy males. AB - We investigated the relationship between individual differences in acute fatigue and endogenous cortisol changes elicited by the sustained performance of cognitively demanding tasks (fatigue condition). Healthy males provided salivary cortisol measurements and subjective fatigue ratings, and were scanned (functional magnetic resonance imaging) during memory encoding and recognition tasks in fatigue and control conditions. A group of 15 'responders' showed significantly higher cortisol levels in the fatigue condition than 12 'non responders'. Responders showed higher subjective fatigue and reduced encoding and recognition activation than non-responders in the fatigue condition. An interaction in activation changes in the right hippocampus during encoding reflected decreased activation in responders, but somewhat increased activation in non-responders in the fatigue compared to control condition. Moreover, decreased hippocampal activation in responders was associated with increased subjective fatigue. Findings are consistent with a central role for the hippocampus in differences between responders and non-responders and also implicate the right hippocampus in individual differences in induced cognitive fatigue effects. PMID- 23743261 TI - Thalamocortical relationships and network synchronization in a new genetic model "in mirror" for absence epilepsy. AB - Electroencephalographic generalized spike and wave discharges (SWD), the hallmark of human absence seizures, are generated in thalamocortical networks. However, the potential alterations in these networks in terms of the efficacy of the reciprocal synaptic activities between the cortex and the thalamus are not known in this pathology. Here, the efficacy of these reciprocal connections is assessed in vitro in thalamocortical slices obtained from BS/Orl mice, which is a new genetic model of absence epilepsy. These mice show spontaneous SWD, and their features can be compared to that of BR/Orl mice, which are free of SWD. In addition, since gap junctions may modulate the efficacy of these connections, their implications in pharmacologically-induced epileptiform discharges were studied in the same slices. The thalamus and neocortex were independently stimulated and the electrically-evoked responses in both structures were recorded from the same slice. The synaptic efficacy of thalamocortical and corticothalamic connections were assessed by measuring the dynamic range of synaptic field potential changes in response to increasing stimulation strengths. The connection efficacy was weaker in epileptic mice however, this decrease in efficacy was more pronounced in thalamocortical afferents, thus introducing an imbalance in the reciprocal connections between the cortex and thalamus. However, short-term facilitation of the thalamocortical responses were increased in epileptic mice compared to non-epileptic animals. These features may favor occurrence of rhythmical activities in thalamocortical networks. In addition, carbenoxolone (a gap junction blocker) decreased the cumulative duration of 4-aminopyridine induced ictal-like activities, with a slower time course in epileptic mice. However, the 4-aminopyridine-induced GABA-dependent negative potentials, which appeared to trigger the ictal-like activities, remained. Our results show that the balance of the reciprocal connections between the thalamus and cortex is altered in favor of the corticothalamic connections in epileptic mice, and suggest that gap junctions mediate a stronger cortical synchronization in this strain. PMID- 23743262 TI - Inhaled nitric oxide improves short term memory and reduces the inflammatory reaction in a mouse model of mild traumatic brain injury. AB - Although the mechanisms underlying mild traumatic brain injury (mTBI) are becoming well understood, treatment options are still limited. In the present study, mTBI was induced by a weight drop model to produce a closed head injury to mice and the effect of inhaled nitric oxide (INO) was evaluated by a short term memory task (object recognition task) and immunohistochemical staining of glial fibrillary acidic protein (GFAP) and CD45 for the detection of reactive astrocytes and microglia. Results showed that mTBI model did not produce brain edema, skull fracture or sensorimotor coordination dysfunctions. Mice did however exhibit a significant deficit in short term memory (STM) and strong inflammatory reaction in the ipsilateral cortex and hippocampus compared to sham-injured controls 24h after mTBI. Additional groups of untreated mice tested 3 and 7 days later, demonstrated that recognition memory had recovered to normal levels by Day 3. Mice treated with 10ppm INO for 4 or 8h, beginning immediately after TBI demonstrated significantly improved STM at 24h when compared with room air controls (p<0.05). Whereas mice treated with 10ppm INO for 24h showed no improvement in STM. Mice treated with INO 10ppm for 8h exhibited significantly reduced microglia and astrocyte activation compared with room air controls. These data demonstrate that mTBI produces a disruption of STM which is evident 24h after injury and persists for 2-3 days. Treatment with low concentration or short durations of INO prevents this memory loss and also attenuates the inflammatory response. These findings may have relevance for the treatment of patients diagnosed with concussion. PMID- 23743263 TI - Data-driven honeybee antennal lobe model suggests how stimulus-onset asynchrony can aid odour segregation. AB - Insects have a remarkable ability to identify and track odour sources in multi odour backgrounds. Recent behavioural experiments show that this ability relies on detecting millisecond stimulus asynchronies between odourants that originate from different sources. Honeybees, Apis mellifera, are able to distinguish mixtures where both odourants arrive at the same time (synchronous mixtures) from those where odourant onsets are staggered (asynchronous mixtures) down to an onset delay of only 6ms. In this paper we explore this surprising ability in a model of the insects' primary olfactory brain area, the antennal lobe. We hypothesize that a winner-take-all inhibitory network of local neurons in the antennal lobe has a symmetry-breaking effect, such that the response pattern in projection neurons to an asynchronous mixture is different from the response pattern to the corresponding synchronous mixture for an extended period of time beyond the initial odourant onset where the two mixture conditions actually differ. The prolonged difference between response patterns to synchronous and asynchronous mixtures could facilitate odoursegregation in downstream circuits of the olfactory pathway. We present a detailed data-driven model of the bee antennal lobe that reproduces a large data set of experimentally observed physiological odour responses, successfully implements the hypothesised symmetry breaking mechanism and so demonstrates that this mechanism is consistent with our current knowledge of the olfactory circuits in the bee brain. This article is part of a Special Issue entitled Neural Coding 2012. PMID- 23743264 TI - Downstaging to liver resection by radioembolization: a difficult to reach strategy? PMID- 23743265 TI - Discarded leukoreduction filters: a new source of stem cells for research, cell engineering and therapy? AB - New adult stem cell sources, devoid of the technical/ethical/economical barriers of those presently available, would favor the ongoing development of in vitro cell engineering and transplantation. Hematopoietic transplantation opened the way to and remains the most successful cell transplantation procedure. CD34+ cells that include hematopoietic stem cells (HSCs) and hematopoietic progenitors (HPs) are presently harvested from bone marrow (BM), cord blood or peripheral blood (after being mobilized from BM). The panel of potential donors, the quantities of collected cells and some other technical/medical problems still represent limiting factors to their transplantation in some patients. Steady state peripheral blood (SSPB) contains very low frequencies of CD34+ cells. They are trapped in leukoreduction filters (LRFs), which are discarded after the preparation of therapeutic red blood cell concentrates from individual blood donations. We recently developed a procedure allowing the easy and rapid elution of CD34+ cells from LRFs and we showed that they are functionally similar to those harvested from other sources. After providing an overview of the sources, interests and limitations of therapeutic HSCs presently available, we will provide arguments based on our and others' results suggesting that SSPB could become an attractive source of HSCs for hematopoietic transplantation and of other cell types for various research/development procedures. PMID- 23743266 TI - Porous carbon material containing CaO for acidic gas capture: preparation and properties. AB - A one-step process for the preparation of CaO-containing porous carbons is described. Mixtures of poly(ethylene terephthalate) with natural limestone were pyrolyzed and thus hybrid sorbents could be easily obtained. The polymeric material and the mineral served as a carbon precursor and CaO delivering agent, respectively. We discuss effects of the preparation conditions and the relative amounts of the raw materials used for the preparations on the porosity of the hybrid products. The micropore areas and volumes of the obtained products tended to decrease with increasing CaO contents. Increase in the preparation temperature entailed a decrease in the micropore volume, whereas the mesopore volume increased. The pore creation mechanism is proposed on the basis of thermogravimetric and temperature-programmed desorption measurements. The prepared CaO-containing porous carbons efficiently captured SO2 and CO2 from air. Washing out of CaO from the hybrid materials was confirmed as a suitable method to obtain highly porous carbon materials. PMID- 23743267 TI - Isolation and structural characterization of a (Kdo-isosteric) D-glycero-alpha-D talo-oct-2-ulopyranosidonic acid (Ko) interlinking lipid A and core oligosaccharide in the lipopolysaccharide of Acinetobacter calcoaceticus NCTC 10305. AB - In Acinetobacter calcoaceticus NCTC 10305 and A. haemolyticus NCTC 10305 lipopolysaccharide (LPS) a Kdo (3-deoxy-D-manno-oct-2-ulosonic acid)-related octulosonic acid (Ko) interlinks the lipid A with the core-oligosaccharide. This Ko replaces the first Kdo (Kdo(I)) attached to the lipid A backbone in the LPS. The only structural difference between Kdo and Ko is the 3-hydroxylation. After the discovery of the final step in Ko-biosynthesis it is now generally accepted that Ko is structurally related to Kdo, although a final proof so far is lacking. In the present paper we describe the stereochemical determination of the natural Ko isolated from the LPS of A. calcoaceticus NCTC 10305 by chemical, mass spectrometry (MS), and (1)H and (13)C NMR spectroscopy. Our results show that in A. calcoaceticusd-glycero-alpha-D-talo-oct-2-ulopyranosonic acid (DgalphaDt-Kop) represents the Kdo-related sugar interlinking the core-oligosaccharide and the lipid A backbone. PMID- 23743268 TI - Drivers of estuarine benthic species distribution patterns following a restoration of a seagrass bed: a functional trait analyses. AB - We integrate information on functional diversity (FD) patterns from estuarine intertidal benthic communities from different habitats and along a temporal disturbance gradient, to understand the drivers of species coexistence patterns. Species and traits' biomass levels seemed to be first determined by habitat filtering, selecting those traits better adapted to the biologically challenging estuarine environment. Within that subset of traits and within each habitat, biotic interactions were probably high, as evidenced by high alpha-diversity and community weighted mean differences. The former patterns hold for the disturbance/recovery scenario considered. However, as the estuary recovered, biomass became more distributed among different trait categories, consistent with increases in FD when the seagrass started to increase. Policy towards the restoration of seagrass bed and other biogenic structures, and improving the connectivity within adjacent systems were confirmed and suggested, as this would imply higher FD and potentially higher resilience to disturbance within the estuarine intertidal system. PMID- 23743269 TI - Effects of an oil spill on benthic community production and respiration on subtropical intertidal sandflats. AB - This study determined effects of an oil spill on subtropical benthic community production and respiration by monitoring CO2 fluxes in benthic chambers on intertidal sandflats during emersion before and after an accidental spill. The oil spill decreased sediment chlorophyll a concentrations, altered benthic macrofaunal community, and affected ecological functioning by suppressing or even stopping microalgal production, increasing bacterial respiration, and causing a shift from an autotrophic system to a heterotrophic system. Effects of the oil spill on the macrofauna were more severe than on benthic microalgae, and affected sedentary infauna more than motile epifauna. Despite the oil spill's impact on the benthic community and carbon metabolism, the affected area appeared to return to normal in about 23 days. Our results suggest that the prompt response of benthic metabolism to exposure to petroleum hydrocarbons can serve as a useful indicator of the impact of an oil spill. PMID- 23743270 TI - Distribution of the genus Alexandrium (Halim) and paralytic shellfish toxins along the coastline of New South Wales, Australia. AB - Blooms of Alexandrium species, in particular the species Alexandrium catenella, accounted for more than 50% of algal related, shellfish aquaculture harvest zone closures in New South Wales (NSW) Australia since 2005. While there are indications that species of Alexandrium are more abundant than they were formerly, there is little data available on the spatial and temporal distribution and abundance of the genus in NSW. A six and a half year dataset comprising a total of 8649 fortnightly samples from 31 estuaries spread over 2000 km of NSW coastline was analysed. The greatest abundances of Alexandrium spp. were observed during the austral Spring and Summer, in estuaries in the mid and southern latitudes of the state. In identifying these high risk zones, we propose variables such as season, temperature, rainfall and estuarine flushing to be targeted in intensive site specific studies, to support the development of predictive tools for resource managers. PMID- 23743271 TI - Polybrominated diphenyl ethers do not affect metamorphosis but alter the proteome of the invasive slipper limpet Crepidula onyx. AB - Man-made polybrominated diphenyl ethers (PBDEs) used as flame retardants in various consumer products may be harmful to marine organisms. Larvae of some marine invertebrates, especially invasive species, can develop resistance to PBDEs through altered protein expression patterns or proteome plasticity. This is the first report of a proteomics approach to study BDE-47 induced molecular changes in the invasive limpet Crepidula onyx. Larvae of C. onyx were cultured for 5 days (hatching to metamorphosis) in the presence of BDE-47 (1 MUg L(-1)). Using a 2-DE proteomics approach with triple quadrupole and high-resolution TOF MS, we showed that BDE-47 altered the proteome structure but not the growth or metamorphosis of C. onyx larvae. We found eight significant differentially expressed proteins in response to BDE-47, deemed the protein expression signature, consisting of cytoskeletal, stress tolerance, metabolism and energy production related proteins. Our data suggest C. onyx larvae have adequate proteome plasticity to tolerate BDE-47 toxicity. PMID- 23743272 TI - Fine scale distribution constrains cadmium accumulation rates in two geographical groups of Franciscana dolphin from Argentina. AB - Franciscana dolphin is an endemic cetacean in the southwestern Atlantic Ocean and is classified as Vulnerable A3d by the International Union for Conservation of Nature. Cadmium accumulation was assessed in two geographic groups from Argentina; one inhabits the La Plata River estuary, a high anthropogenic impacted environment, and the other is distributed in marine coastal, with negligible pollution. Despite the environment, marine dolphins showed an increase of renal Cd concentrations since trophic independence; while in estuarine dolphins was from 6 years. This is associated with dietary Argentine anchovy which was absent in the diet of estuarine dolphins, being a trophic vector of cadmium in shelf waters of Argentina. Cluster analysis also showed high levels of cd in association with the presence of anchovy in the stomach. The difference in the fine scale distribution of species influences dietary exposure to Cd and, along with other data, indicates two stocks in Argentina. PMID- 23743274 TI - Testosterone, cortisol and anxiety in elite field hockey players. AB - The aim of the present study was to assess the change in the levels of testosterone and cortisol after victory and defeat in male field hockey players during an important tournament. In the beginning of the game series, the players were ranked very closely to achieve (for the first time) the championship rising to The Honor Division-A, the highest status national category. The first game resulted in a 7-4 victory, the second game resulted in a 6-1 victory, and the third game resulted in a 1-2 defeat. As expected, there were changes in testosterone levels after the competition, dropping in the game which ended in defeat, and rising slightly in the two games which ended in victory; there were also changes in cortisol levels, rising in the game which ended in defeat, and showing no variations in the games which ended in victory; correlational analyses congruently showed that defeat led to rises in cortisol whereas victory led to rises in testosterone; anticipatory somatic anxiety was related to cortisol levels prior to games, and physical exertion during competition was related to the change in testosterone levels (suggesting an inhibitory effect) but not to the change in cortisol levels. Hence, this pattern of hormonal responses to a real-life dominance challenge complied with Mazur's (1985) [16] biosocial model of status and dominance motivation, by showing that testosterone and cortisol are linked to victory and defeat in a theoretically predictable fashion. PMID- 23743273 TI - Maternal high-fat diet programs rat offspring hypertension and activates the adipose renin-angiotensin system. AB - OBJECTIVE: A maternal high-fat diet creates an increased risk of offspring obesity and systemic hypertension. Although the renal renin-angiotensin system (RAS) is known to regulate blood pressure, it is now recognized that the RAS is also activated in adipose tissue during obesity. We hypothesized that programmed offspring hypertension is associated with the activation of the adipose tissue RAS in the offspring of obese rat dams. STUDY DESIGN: At 3 weeks of age, female rats were weaned to a high-fat diet (60% k/cal; n = 6) or control diet (10% k/cal; n = 6). At 11 weeks of age, these rats were mated and continued on their respective diets during pregnancy. After birth, at 1 day of age, subcutaneous adipose tissue was collected; litter size was standardized, and pups were cross fostered to either control or high-fat diet dams, which created 4 study groups. At 21 days of age, offspring were weaned to control or high-fat diet. At 6 months of age, body fat and blood pressure were measured. Thereafter, subcutaneous and retroperitoneal adipose tissue was harvested from male offspring. Protein expression of adipose tissue RAS components were determined by Western blotting. RESULTS: The maternal high-fat diet induced early and persistent alterations in offspring adipose RAS components. These changes were dependent on the period of exposure to the maternal high-fat diet, were adipose tissue specific (subcutaneous and retroperitoneal), and were exacerbated by a postnatal high-fat diet. Maternal high-fat diet increased adiposity and blood pressure in offspring, regardless of the period of exposure. CONCLUSION: These findings suggest that programmed adiposity and the activation of the adipose tissue RAS are associated with hypertension in offspring of obese dams. PMID- 23743275 TI - Human behavior in different TDRAs. AB - Operative temperature is a synthesis index for radiant temperature and air temperature. The objective of this paper was to investigate human behavior in the environment that the temperature difference between radiant and air temperature (TDRA) was 0, 5, 8 and 10 degrees C. The four types of TDRA were controlled in two operative temperatures, 28 and 32 degrees C. The skin temperatures, thermal sensation vote (TSV) and thermal comfort vote (TCV) were recorded. The results showed that when TDRA was 0-5 degrees C, the mean skin temperature (MST) had no change, and the local skin temperature (LST) had little change except for face and upper arm. However, when TDRA was above 5 degrees C, the MST and LST decreased with the increment of TDRA. During the whole course that TDRA increased from 0 to 10 degrees C, the thermal sensation changed from warm to cool. So in high radiant temperature, human body could keep normal skin temperature and thermal comfort by decreasing air temperature. The conclusions were significant for the physiological behavior of human. PMID- 23743276 TI - Left renal vein division during open surgery of abdominal aortic disease: a propensity score-matched case-control study. AB - OBJECTIVE: To investigate the impact of left renal vein division (LRVD) on the postoperative renal function of abdominal aortic aneurysm (AAA) or aortic occlusive disease (AOD). METHODS: Between January 2000 and January 2012, 238 patients, including 179 AAAs and 59 AODs underwent open surgery in our institution (patients who required suprarenal aortic clamping were excluded). 49 patients (38 AAAs, 11 AODs) required LRVD during the operation. Patients in the LRVD and non-LRVD groups were matched using propensity score method in a 1:2 ratio. Pre- and postoperative renal function, major complications, in-hospital mortality and long-term renal function were compared. Late survival rate was estimated using the Kaplan-Meier method. RESULTS: Overall, the LRVD group had a significantly higher male/female ratio (39/10 vs.122/67, p = .045), higher ruptured AAA ratio (36.7% vs. 20.1%, p = .014), higher American Society of Anesthesiologists (ASA) classification 3 (53.1% vs. 30.2%, p = .003), higher co morbidities of coronary artery disease (51.0% vs. 33.3%, p = .022), higher preoperative shock (22.4% vs. 8.5%, p = .006) and longer operative time (164.2 +/ 43 vs. 150.1 +/- 41 min, p = .035). With propensity score matching (PSM), 48 patients in the LRVD group and 96 in the non-LRVD group were enrolled in this study. The baseline characteristics were well balanced in the groups (p < .05) after PSM. There were no statistically significant differences in preoperative glomerular filtration rate (GFR, expressed as mL/min/1.73 m(2)) (62.0 +/- 13.1 vs. 62.9 +/- 12.9, p = .695), and postoperative GFR on day 1 (60.3 +/- 13.7 vs. 61.3 +/- 13.1, p = .671), day 3 (54.6 +/- 16.8 vs. 58.8 +/- 14.3, p = .120), day 7 (62.1 +/- 16.8 vs. 63.7 +/- 13.4 p = .537) and in the long term (>12 months) (62.4 +/- 14.0 vs. 64.7 +/- 11.8 p = .302). There were no statistically significant differences in in-hospital mortality (6.3% vs. 9.2%, p = .522) and late survival rate estimated by the Kaplan-Meier method (p = .96). CONCLUSION: LRVD may be a safe maneuver during abdominal aortic surgery as it did not increase the risks of early or late mortality and morbidity. PMID- 23743277 TI - Potent MCH-1 receptor antagonists from cis-1,4-diaminocyclohexane-derived indane analogs. AB - Benzimidazole and indane are the two key fragments in our potent and selective MCH-1 receptor (MCHR1) antagonists. To identify novel linkers connecting the two fragments, we investigated diamino-cycloalkane-derived analogs and discovered highly potent antagonists with cis-1,4-diaminocyclohexane as a unique spacer in this chemical class. Structural overlay suggested that cis-1-substituted-4 aminocyclohexane functions as a bioisostere of 4-substituted-piperidine and that the active conformation adopts a U-shaped orientation. PMID- 23743278 TI - Design, synthesis and evaluation of inhibitor of apoptosis protein (IAP) antagonists that are highly selective for the BIR2 domain of XIAP. AB - We recently reported the systematic ligand-based rational design and synthesis of monovalent Smac mimetics that bind preferentially to the BIR2 domain of the anti apoptotic protein XIAP. Expanded structure-activity relationship (SAR) studies around these peptidomimetics led to compounds with significantly improved selectivity (>60-fold) for the BIR2 domain versus the BIR3 domain of XIAP. The potent and highly selective IAP antagonist 8q (ML183) sensitized TRAIL-resistant prostate cancer cells to apoptotic cell death, highlighting the merit of this probe compound as a valuable tool to investigate the biology of XIAP. PMID- 23743279 TI - Synthesis of oligonucleotides with glucosamine at the 3'-position and evaluation of their biological activity. AB - Short interfering RNA (siRNA) has been proven to be an utilizable tool for post transcriptional gene silencing research. In this study, we designed and synthesized two glucosamine analogues and tried to modify the siRNA using these two glucosamine analogues at the 3'-overhang region of siRNAs to improve the nuclease resistance and to overcome some other weak points. The siRNAs modified with glucosamine analogues had almost no effect of the thermal stability and showed strong resistance to nuclease degradation. Some of them kept the same gene silencing activity level as unmodified siRNA. PMID- 23743280 TI - Construction and functionalization of pyranone ring fused with pyran moiety: design and synthesis of novel pyrano[4,3-b]pyran-5(4H)-ones as potential inhibitors of sirtuins. AB - Novel pyrano[4,3-b]pyran-5(4H)-one based small molecules were designed as potential inhibitors of sirtuins (i.e., yeast sir2, a homolog of human SIRT1). Elegant synthesis of these compounds was performed via a multi-step sequence consisting of MCR, Sandmeyer type iodination, Sonogashira type coupling followed by iodocyclization and then Pd-mediated various C-C bond forming reactions. The overall strategy involved the construction of a pyran ring followed by the fused pyranone moiety and subsequent functionalization at C-8 position of the resultant core pyrano[4,3-b]pyran-5(4H)-one framework. The crystal structure analysis of a representative iodolactonized product (6d) is presented. Some of the synthesized compounds showed promising inhibitory activities when tested against yeast sir2 in vitro. The compound 6g showed dose dependent inhibition (IC50=78.05MUM) of yeast sir2 and good interactions with this protein in silico. PMID- 23743281 TI - Synthesis and in vitro evaluation of [18F]BMS-754807: a potential PET ligand for IGF-1R. AB - Radiosynthesis and in vitro evaluation of [(18)F](S)-1-(4-((5-cyclopropyl-1H pyrazol-3-yl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)-N-(6-fluoropyridin-3-yl)-2 methylpyrrolidine-2-carboxamide ([(18)F]BMS-754807 or [(18)F]1) a specific IGF-1R inhibitor was performed. [(18)F]1 demonstrated specific binding in vitro to human cancer tissues. Synthesis of reference standard 1 and corresponding bromo derivative (1a), the precursor for radiolabeling were achieved from 2,4 dichloropyrrolo[2,1-f][1,2,4]triazine (4) in three steps with 50% overall yield. The radioproduct was obtained in 8% yield by reacting 1a with [(18)F]TBAF in DMSO at 170 degrees C at high radiochemical purity and specific activity (1-2Ci/MUmol, N=10). The proof of concept of IGF-IR imaging with [(18)F]1 was demonstrated by in vitro autoradiography studies using pathologically identified surgically removed grade IV glioblastoma, breast cancer and pancreatic tumor tissues. These studies indicate that [(18)F]1 can be a potential PET tracer for monitoring IGF 1R. PMID- 23743282 TI - Inhibitory constituents of the heartwood of Dalbergia odorifera on nitric oxide production in RAW 264.7 macrophages. AB - Two new isoflavanones (1 and 13), along with 25 known compounds (2-12, 14-27), were isolated from the EtOAc-soluble fraction of the heartwood of Dalbergia odorifera by following their potential to inhibit the LPS-induced nitric oxide production in RAW 264.7 cells. The structures of the isolated compounds were established by spectroscopic data such as (1)D, (2)D NMR and MS spectrometry. Among the isolated compounds, (2S)-pinocembrin (26), showed the most potent inhibitory effect with IC50 value of 18.1MUM. PMID- 23743283 TI - PEG conjugates of potent alpha4 integrin inhibitors, maintaining sustained levels and bioactivity in vivo, following subcutaneous administration. AB - Mitsunobu reactions were employed to link t-butyl esters of alpha4 integrin inhibitors at each of the termini of a three-arm, 40 kDa, branched PEG. Cleavage of the t-butyl esters using HCO2H provided easily isolated PEG derivatives, which are potent alpha4 integrin inhibitors, and which achieve sustained levels and bioactivity in vivo, following subcutaneous administration to rats. PMID- 23743284 TI - Synthesis and biological evaluation of pyrrolidine derivatives as novel and potent sodium channel blockers for the treatment of ischemic stroke. AB - A novel series of pyrrolidine derivatives as Na(+) channel blockers was synthesized and evaluated for their inhibitory effects on neuronal Na(+) channels. Structure-activity relationship (SAR) studies of a pyrrolidine analogue 2 led to the discovery of 5e as a potent Na(+) channel blocker with a low inhibitory action against human ether-a-go-go-related gene (hERG) channels. Compound 5e showed remarkably neuroprotective activity in a rat transient middle cerebral artery occlusion (MCAO) model, suggesting that 5e would act as a neuroprotectant for ischemic stroke. PMID- 23743285 TI - De novo design of novel DNA-gyrase inhibitors based on 2D molecular fingerprints. AB - As increasing drug-resistance poses an emerging threat to public health, the development of novel antibacterial agents is critical. We developed a workflow consisting of various methods for de novo design. In the workflow, 2D-QSAR model based on molecular fingerprints was constructed to extract the bioactive molecular fingerprints from a data set of DNA-gyrase inhibitors with new structure and mechanism. These fingerprints were converted into molecular fragments which were recombined to generate compound library. The new compound library was virtually screened by LigandFit and Gold docking, and the results were further investigated by pharmacophore validation and binding mode analysis. The workflow successfully achieved a potential DNA-gyrase inhibitor. It could be applied to design more novel potential DNA-gyrase inhibitors and provide theoretical basis for further optimization of the hit compounds. PMID- 23743286 TI - De novo tyrosinase inhibitor: 4-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)benzene 1,3-diol (MHY1556). AB - In this study, we have synthesized and studied de novo tyrosinase inhibitor, MHY1556, which showed significantly better efficacy than other pre-existing tyrosinase inhibitors in vitro experiments. The IC50 value of MHY1556 was 0.50MUM which was significantly lower than that of kojic acid (IC50=53.95MUM), which is a well-known tyrosinase inhibitor and was used as a positive control in this study. We predicted the tertiary structure of tyrosinase, simulated the docking with compound MHY1556 and confirmed that the compound strongly interacts with mushroom tyrosinase residues. Substitutions with a hydroxy group at both R1 and R3 of the phenyl ring indicated that these groups play a major role in the high binding affinity to tyrosinase, especially through the hydrogen bonding interaction of the hydroxyl group at R1 with GLY281. In addition, MHY1556 showed concentration dependent inhibitory effects in melanin content assay where B16F10 melanoma cells were treated with alpha-melanocyte stimulating hormone (alpha-MSH), and also there is no significant cytotoxicity of this compound in cell viability assay conducted in B16F10 melanoma cells. The tyrosinase activity assay results with MHY1556 also support its potent inhibitory effects. Therefore, our data strongly suggest MHY1556 suppresses the melanogenesis via a tyrosinase inhibitory effect. PMID- 23743287 TI - 2-Aminothiazole based P2Y(1) antagonists as novel antiplatelet agents. AB - ADP receptors, P2Y1 and P2Y12 have been recognized as potential targets for antithrombotic drugs. A series of P2Y1 antagonists that contain 2-aminothiazoles as urea surrogates were discovered. Extensive SAR of the thiazole ring is described. The most potent compound 7j showed good P2Y1 binding (Ki=12nM), moderate antagonism of platelet aggregation (PA IC50=5.2MUM) and acceptable PK in rats. PMID- 23743288 TI - Recent progress and future options in the development of GLP-1 receptor agonists for the treatment of diabesity. AB - The dramatic rise of the twin epidemics, type 2 diabetes and obesity is associated with increased mortality and morbidity worldwide. Based on this global development there is clinical need for anti-diabetic therapies with accompanied weight reduction. From the approved therapies, the injectable glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the only class of agents which are associated with a modest weight reduction. Physiological effects of the gastro intestinal hormone GLP-1 are improvement of glycemic control as well as a reduction in appetite and food intake. Different approaches are currently under clinical evaluation to optimize the therapeutic potential of GLP-1 RAs directed to once-weekly up to once-monthly administration. The next generation of peptidic co-agonists comprises the activity of GLP-1 plus additional gastro-intestinal hormones with the potential for increased therapeutic benefits compared to GLP-1 RAs. PMID- 23743289 TI - A rapid alternative to X-ray crystallography for chiral determination: case studies of vibrational circular dichroism (VCD) to advance drug discovery projects. AB - The absolute stereochemistry of chiral drugs is usually established via X-ray crystallography. However, vibrational circular dichroism (VCD) spectroscopy coupled with quantum mechanics simulations offers a rapid alternative to crystallography and is readily applied to both crystalline and non-crystalline samples. VCD is an effective complement to X-ray analysis of drug candidates, and it can be used as a high-throughput means of assessing absolute stereochemistry at all phases of the discovery process (hundreds of assignments per year). The practical implementation (or fee-for-service outsourcing) of VCD and selected case studies are illustrated with an emphasis on providing utility and impact to pharmaceutical discovery programs. PMID- 23743290 TI - Hydrogen: a promising novel treatment for hepatic encephalopathy? PMID- 23743292 TI - Reprint of: revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease-resemblance to the effect of amphetamine drugs of abuse. AB - Parkinson disease (PD) is a chronic and progressive neurological disease associated with a loss of dopaminergic neurons. In most cases the disease is sporadic but genetically inherited cases also exist. One of the major pathological features of PD is the presence of aggregates that localize in neuronal cytoplasm as Lewy bodies, mainly composed of alpha-synuclein (alpha-syn) and ubiquitin. The selective degeneration of dopaminergic neurons suggests that dopamine itself may contribute to the neurodegenerative process in PD. Furthermore, mitochondrial dysfunction and oxidative stress constitute key pathogenic events of this disorder. Thus, in this review we give an actual perspective to classical pathways involving these two mechanisms of neurodegeneration, including the role of dopamine in sporadic and familial PD, as well as in the case of abuse of amphetamine-type drugs. Mutations in genes related to familial PD causing autosomal dominant or recessive forms may also have crucial effects on mitochondrial morphology, function, and oxidative stress. Environmental factors, such as MPTP and rotenone, have been reported to induce selective degeneration of the nigrostriatal pathways leading to alpha-syn positive inclusions, possibly by inhibiting mitochondrial complex I of the respiratory chain and subsequently increasing oxidative stress. Recently, increased risk for PD was found in amphetamine users. Amphetamine drugs have effects similar to those of other environmental factors for PD, because long-term exposure to these drugs leads to dopamine depletion. Moreover, amphetamine neurotoxicity involves alpha-syn aggregation, mitochondrial dysfunction, and oxidative stress. Therefore, dopamine and related oxidative stress, as well as mitochondrial dysfunction, seem to be common links between PD and amphetamine neurotoxicity. PMID- 23743294 TI - Incidence trends and long-term survival analysis of sinonasal rhabdomyosarcoma. AB - PURPOSE: Sinonasal rhabdomyosarcoma (SNRMS) is a rare malignancy which often presents with nasal obstruction, rhinorrhea and epistaxis. It is the most common sarcoma in children. In this study, we analyze the incidence and long-term survival for SNRMS using a national population-based database. METHODS: The United States National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry was utilized to calculate incidence and survival trends for SNRMS between 1973 and 2009. In addition, data were grouped by age, gender, race, and histopathological subtype. RESULTS: A total of 181 cases of SNRMS were analyzed for incidence trends, showing a 1.23:1 female to male ratio. While the overall incidence of SNRMS increased by 1.02% annually over the last 20years, this pattern was not equal amongst gender and racial groups. The incidence in males has increased, while in females incidence has decreased. An increase in incidence was noted in white and "others," but decreased in blacks. Using a total of 314 cases for survival analysis, we found that the rate in the white population has been consistently highest with a 5-year survival of 49.45%, 10- and 20-year survival of 48.81%. Survival rates in cases of embryonal SNRMS were also consistently higher than in cases of alveolar SNRMS. CONCLUSION: Overall incidence of SNRMS is increasing. Histologic subtype and race are important considerations in the long-term prognosis of SNRMS. Future studies will further elucidate gender and race related trends. PMID- 23743293 TI - A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification. AB - Besides helping to maintain a reducing intracellular environment, the thioredoxin (Trx) system impacts bioenergetics and drug metabolism. We show that hepatocyte specific disruption of Txnrd1, encoding Trx reductase-1 (TrxR1), causes a metabolic switch in which lipogenic genes are repressed and periportal hepatocytes become engorged with glycogen. These livers also overexpress machinery for biosynthesis of glutathione and conversion of glycogen into UDP glucuronate; they stockpile glutathione-S-transferases and UDP-glucuronyl transferases; and they overexpress xenobiotic exporters. This realigned metabolic profile suggested that the mutant hepatocytes might be preconditioned to more effectively detoxify certain xenobiotic challenges. Hepatocytes convert the pro toxin acetaminophen (APAP, paracetamol) into cytotoxic N-acetyl-p-benzoquinone imine (NAPQI). APAP defenses include glucuronidation of APAP or glutathionylation of NAPQI, allowing removal by xenobiotic exporters. We found that NAPQI directly inactivates TrxR1, yet Txnrd1-null livers were resistant to APAP-induced hepatotoxicity. Txnrd1-null livers did not have more effective gene expression responses to APAP challenge; however, their constitutive metabolic state supported more robust GSH biosynthesis, glutathionylation, and glucuronidation systems. Following APAP challenge, this effectively sustained the GSH system and attenuated damage. PMID- 23743295 TI - Evaluation of protection conferred by a Salmonella Typhimurium inactivated vaccine in Salmonella-infected finishing pig farms. AB - The efficacy of an inactivated S. Typhimurium vaccine administered to pigs at the beginning of the fattening period was evaluated in four clinical trials (trials A, B, C and D). Faecal shedding and the systemic antibody response during fattening, as well as, the cecal contents and mesenteric lymph nodes collected after slaughtering were used to assess the outcome. Salmonella shedders prevalence in the control groups was six times higher than in the treated groups in trials A and D, both herds infected by S. Typhimurium. The risk of positive pens was also four or five times higher for the pens housing control pigs in trials A and C. Lower prevalence of Salmonella was observed in the slaughter samples from the vaccinated pigs in trial D and in the cecal content samples in trial A, when just the S. Typhimurium results were compared. The results suggest the effective homologous protection of the vaccinated pigs; however, the high humoral response elicited in the vaccinated pigs complicates their use in farms under serological surveillance programmes. PMID- 23743291 TI - The effects of dietary restriction on oxidative stress in rodents. AB - Oxidative stress is observed during aging and in numerous age-related diseases. Dietary restriction (DR) is a regimen that protects against disease and extends life span in multiple species. However, it is unknown how DR mediates its protective effects. One prominent and consistent effect of DR in a number of systems is the ability to reduce oxidative stress and damage. The purpose of this review is to comprehensively examine the hypothesis that dietary restriction reduces oxidative stress in rodents by decreasing reactive oxygen species (ROS) production and increasing antioxidant enzyme activity, leading to an overall reduction of oxidative damage to macromolecules. The literature reveals that the effects of DR on oxidative stress are complex and likely influenced by a variety of factors, including sex, species, tissue examined, types of ROS and antioxidant enzymes examined, and duration of DR. Here we present a comprehensive review of the existing literature on the effect of DR on mitochondrial ROS generation, antioxidant enzymes, and oxidative damage. In a majority of studies, dietary restriction had little effect on mitochondrial ROS production or antioxidant activity. On the other hand, DR decreased oxidative damage in the majority of cases. Although the effects of DR on endogenous antioxidants are mixed, we find that glutathione levels are the most likely antioxidant to be increased by dietary restriction, which supports the emerging redox-stress hypothesis of aging. PMID- 23743296 TI - Motorcyclists violating hook-turn area at intersections in Taiwan: an observational study. AB - Research has suggested that the most typical and catastrophic automobile motorcycle crash takes place when an automobile manoeuvres into the path of an oncoming motorcycle at intersection, which involves a motorist infringing upon the motorcycle's right of way (ROW). In Taiwan, motorcycles, on the other hand, are the one that has been observed to violate the ROW of approaching automobiles at intersections. Such a ROW-violation by left-turn motorcyclists in front of approaching traffic is a safety problem in terms of its frequency and accident consequence. Using high-definition video cameras to capture motorcycles' behaviours, the present study empirically analyses the determinants of motorcyclists violating the hook-turn area (HTA) that has been implemented in Taiwan to deter motorcyclists from violating the ROW of approaching vehicles. Mixed (random parameters) logit models are found to be superior in fitting the data to traditional binary logit models. Main findings include that there was an increased likelihood of HTA-violation at T/Y intersections, in rural areas, during non rush hours, when the riders were females, younger, when riders were travelling on mopeds or heavier motorcycles, when traffic volume was less, and when riders were with half-style helmets. Implications of the research findings, the concluding remarks, and recommendations for future research are finally provided. PMID- 23743297 TI - Cyclist activity and injury risk analysis at signalized intersections: a Bayesian modelling approach. AB - This study proposes a two-equation Bayesian modelling approach to simultaneously study cyclist injury occurrence and bicycle activity at signalized intersections as joint outcomes. This approach deals with the potential presence of endogeneity and unobserved heterogeneities and is used to identify factors associated with both cyclist injuries and volumes. Its application to identify high-risk corridors is also illustrated. Montreal, Quebec, Canada is the application environment, using an extensive inventory of a large sample of signalized intersections containing disaggregate motor-vehicle traffic volumes and bicycle flows, geometric design, traffic control and built environment characteristics in the vicinity of the intersections. Cyclist injury data for the period of 2003 2008 is used in this study. Also, manual bicycle counts were standardized using temporal and weather adjustment factors to obtain average annual daily volumes. Results confirm and quantify the effects of both bicycle and motor-vehicle flows on cyclist injury occurrence. Accordingly, more cyclists at an intersection translate into more cyclist injuries but lower injury rates due to the non-linear association between bicycle volume and injury occurrence. Furthermore, the results emphasize the importance of turning motor-vehicle movements. The presence of bus stops and total crosswalk length increase cyclist injury occurrence whereas the presence of a raised median has the opposite effect. Bicycle activity through intersections was found to increase as employment, number of metro stations, land use mix, area of commercial land use type, length of bicycle facilities and the presence of schools within 50-800 m of the intersection increase. Intersections with three approaches are expected to have fewer cyclists than those with four. Using Bayesian analysis, expected injury frequency and injury rates were estimated for each intersection and used to rank corridors. Corridors with high bicycle volumes, located mainly in the central neighbourhoods of Montreal, have lower risk of injury. These results may reflect the "safety in numbers" hypothesis or cyclist preference towards safer intersections and corridors. Despite these corridors having a lower individual risk, they are nevertheless associated with a greater number of injuries. PMID- 23743298 TI - Risk factors associated with traffic violations and accident severity in China. AB - With the recent economic boom in China, vehicle volume and the number of traffic accident fatalities have become the highest in the world. Meanwhile, traffic accidents have become the leading cause of death in China. Systematically analyzing road safety data from different perspectives and applying empirical methods/implementing proper measures to reduce the fatality rate will be an urgent and challenging task for China in the coming years. In this study, we analyze the traffic accident data for the period 2006-2010 in Guangdong Province, China. These data, extracted from the Traffic Management Sector-Specific Incident Case Data Report, are the only officially available and reliable source of traffic accident data (with a sample size>7000 per year). In particular, we focus on two outcome measures: traffic violations and accident severity. Human, vehicle, road and environmental risk factors are considered. First, the results establish the role of traffic violations as one of the major risks threatening road safety. An immediate implication is: if the traffic violation rate could be reduced or controlled successfully, then the rate of serious injuries and fatalities would be reduced accordingly. Second, specific risk factors associated with traffic violations and accident severity are determined. Accordingly, to reduce traffic accident incidence and fatality rates, measures such as traffic regulations and legislation-targeting different vehicle types/driver groups with respect to the various human, vehicle and environment risk factors-are needed. Such measures could include road safety programs for targeted driver groups, focused enforcement of traffic regulations and road/transport facility improvements. Data analysis results arising from this study will shed lights on the development of similar (adjusted) measures to reduce traffic violations and/or accident fatalities and injuries, and to promote road safety in other regions. PMID- 23743300 TI - Immunomodulation with donor regulatory T cells armed with Fas-ligand alleviates graft-versus-host disease. AB - Infusion of large numbers of donor regulatory T cells (Tregs) is an effective approach to suppress graft-versus-host disease (GvHD). We have reported previously that enhancing the killing activity of CD25(+) Tregs by decoration with short-lived Fas-ligand (FasL) protein (killer Tregs) is effective in abrogation of autoimmunity. In this study, we assessed the therapeutic efficacy of killer Tregs in murine models of lethal GvHD. In a model in which disease associated mortality was not prevented by infusion of naive donor Tregs (3 days after transplant) at an effector:suppressor ratio of 10:1, killer Tregs rescued 70% of the mice and improved the clinical and histologic scores. We found that both effector lymphocytes and therapeutic Tregs migrate to and proliferate in the mesenteric lymph nodes of irradiated recipients; however, only killer Tregs increased fractional apoptosis of effector lymphocytes. Although the lymphoid organs were primarily reconstituted from the bone marrow with little contribution of the infused effector and suppressor subsets, immunomodulation with FasL caused a durable rise in fractions of CD4(+)FoxP3(+) Tregs. Our findings demonstrate that a short-lived apoptotic protein increases the suppressive activity of Tregs and ameliorates GvHD severity. PMID- 23743299 TI - KIT GNNK splice variants: expression in systemic mastocytosis and influence on the activating potential of the D816V mutation in mast cells. AB - Stem cell factor-dependent KIT activation is an essential process for mast cell homeostasis. The two major splice variants of KIT differ by the presence or absence of four amino acids (GNNK) at the juxta-membrane region of the extracellular domain. We hypothesized that the expression pattern of these variants differs in systemic mastocytosis and that transcripts containing the KIT D816V mutation segregate preferentially to one GNNK variant. A quantitative real time PCR assay to assess GNNK(-) and GNNK(+) transcripts from bone marrow mononuclear cells was developed. The GNNK(-)/GNNK(+) copy number ratio showed a trend toward a positive correlation with the percentage of neoplastic mast cell involvement, and KIT D816V containing transcripts displayed a significantly elevated GNNK(-)/GNNK(+) copy number ratio. Relative expression of only the GNNK( ) variant correlated with increasing percentage of neoplastic mast cell involvement. A mast cell transfection system revealed that the GNNK(-) isoform of wild type KIT was associated with increased granule formation, histamine content, and growth. When accompanying the KIT D816V mutation, the GNNK(-) isoform enhanced cytokine-free metabolism and moderately reduced sensitivity to the tyrosine kinase inhibitor, PKC412. These data suggest that neoplastic mast cells favor a GNNK(-) variant predominance, which in turn enhances the activating potential of the KIT D816V mutation and thus could influence therapeutic sensitivity in systemic mastocytosis. PMID- 23743301 TI - Tributyltin-induced endoplasmic reticulum stress and its Ca(2+)-mediated mechanism. AB - Organotin compounds, especially tributyltin chloride (TBT), have been widely used in antifouling paints for marine vessels, but exhibit various toxicities in mammals. The endoplasmic reticulum (ER) is a multifunctional organelle that controls post-translational modification and intracellular Ca(2+) signaling. When the capacity of the quality control system of ER is exceeded under stress including ER Ca(2+) homeostasis disruption, ER functions are impaired and unfolded proteins are accumulated in ER lumen, which is called ER stress. Here, we examined whether TBT causes ER stress in human neuroblastoma SH-SY5Y cells. We found that 700nM TBT induced ER stress markers such as CHOP, GRP78, spliced XBP1 mRNA and phosphorylated eIF2alpha. TBT also decreased the cell viability both concentration- and time-dependently. Dibutyltin and monobutyltin did not induce ER stress markers. We hypothesized that TBT induces ER stress via Ca(2+) depletion, and to test this idea, we examined the effect of TBT on intracellular Ca(2+) concentration using fura-2 AM, a Ca(2+) fluorescent probe. TBT increased intracellular Ca(2+) concentration in a TBT-concentration-dependent manner, and Ca(2+) increase in 700nM TBT was mainly blocked by 50MUM dantrolene, a ryanodine receptor antagonist (about 70% inhibition). Dantrolene also partially but significantly inhibited TBT-induced GRP78 expression and cell death. These results suggest that TBT increases intracellular Ca(2+) concentration by releasing Ca(2+) from ER, thereby causing ER stress. PMID- 23743302 TI - Proteomic analysis of rat cerebral cortex following subchronic acrolein toxicity. AB - Acrolein, a member of reactive alpha,beta-unsaturated aldehydes, is a major environmental pollutant. Acrolein is also produced endogenously as a toxic by product of lipid peroxidation. Because of high reactivity, acrolein may mediate oxidative damages to cells and tissues. It has been shown to be involved in a wide variety of pathological states including pulmonary, atherosclerosis and neurodegenerative diseases. In this study we employed proteomics approach to investigate the effects of subchronic oral exposures to 3mg/kg of acrolein on protein expression profile in the brain of rats. Moreover effects of acrolein on malondialdehyde (MDA) levels and reduced glutathione (GSH) content were investigated. Our results revealed that treatment with acrolein changed levels of several proteins in diverse physiological process including energy metabolism, cell communication and transport, response to stimulus and metabolic process. Interestingly, several differentially over-expressed proteins, including beta synuclein, enolase and calcineurin, are known to be associated with human neurodegenerative diseases. Changes in the levels of some proteins were confirmed by Western blot. Moreover, acrolein increases the level of MDA, as a lipid peroxidation biomarker and decreased GSH concentrations, as a non-enzyme antioxidant in the brain of acrolein treated rats. These findings suggested that acrolein induces the oxidative stress and lipid peroxidation in the brain, and so that may contribute to the pathophysiology of neurological disorders. PMID- 23743304 TI - High-dose fluoroquinolones in short-course regimens for treatment of MDR-TB: the way forward? PMID- 23743305 TI - A breath of hot air? PMID- 23743303 TI - Apigenin suppresses migration and invasion of transformed cells through down regulation of C-X-C chemokine receptor 4 expression. AB - Environmental exposure to arsenic is known to cause various cancers. There are some potential relationships between cell malignant transformation and C-X-C chemokine receptor type 4 (CXCR4) expressions. Metastasis, one of the major characteristics of malignantly transformed cells, contributes to the high mortality of cells. CXCR4 and its natural chemokine ligand C-X-C motif ligand 12 (CXCL12) play a critical role in metastasis. Therefore, identification of nutritional factors which are able to inhibit CXCR4 is important for protection from environmental arsenic-induced carcinogenesis and for abolishing metastasis of malignantly transformed cells. The present study demonstrates that apigenin (4',5,7-trihydroxyflavone), a natural dietary flavonoid, suppressed CXCR4 expression in arsenic-transformed Beas-2B cells (B-AsT) and several other types of transformed/cancer cells in a dose- and time-dependent manner. Neither proteasome nor lysosome inhibitor had any effect in reducing the apigenin-induced down-regulation of CXCR4, indicating that apigenin-induced down-regulation of CXCR4 is not due to proteolytic degradation. The down-regulation of CXCR4 is mainly due to the inhibition of nuclear factor kappaB (NF-kappaB) transcriptional activity. Apigenin also abolished migration and invasion of transformed cells induced by CXCL12. In a xenograft mouse model, apigenin down-regulated CXCR4 expression and suppressed tumor growth. Taken together, our results show that apigenin is a novel inhibitor of CXCR4 expression. This dietary flavonoid has the potential to suppress migration and invasion of transformed cells and prevent environmental arsenic-induced carcinogenesis. PMID- 23743306 TI - Screening for active tuberculosis: methodological challenges in implementation and evaluation. AB - As active screening strategies for tuberculosis (TB) continue to rise globally, it has become increasingly important to consider the methodological challenges in designing and implementing these strategies. The key challenges associated with TB screening can be summarized in terms of four continua or spectra, namely those of 1) TB disease and diagnostic yield, 2) TB risk and resource availability, 3) TB screening strategies, and 4) outcomes and impact measurements of screening programs. In this review, we provide a discussion of these challenges to help guide development of TB screening strategies that will be effective in a given epidemiological setting. PMID- 23743308 TI - Association between Mycobacterium tuberculosis lineage and time to sputum culture conversion. AB - SETTING: Mycobacterium tuberculosis comprises four principal genetic lineages: one evolutionarily ancestral (Indo-Oceanic) and three modern. Whether response to tuberculosis (TB) treatment differs among the lineages is unknown. OBJECTIVE: To examine the association between M. tuberculosis lineage and time to sputum culture conversion in response to standard first-line drug therapy. DESIGN: We conducted an exploratory retrospective cohort analysis of time to sputum culture conversion among pulmonary tuberculosis (PTB) cases reported in the United States from 2004 to 2007. RESULTS: The analysis included 13,170 PTB cases with no documented resistance to first-line drugs who received a standard four-drug treatment regimen. Among cases with baseline positive sputum smear results, relative to cases with Euro-American lineage, cases with Indo-Oceanic lineage had higher adjusted hazards of sputum culture conversion (aHR 1.32, 95%CI 1.20-1.45), whereas cases with East-African-Indian or East-Asian lineage did not differ (aHR 1.05, 95%CI 0.88-1.25 and aHR 0.99, 95%CI 0.91-1.07, respectively). Among cases with baseline negative sputum smear results, time to sputum culture conversion did not differ by lineage. CONCLUSION: Although these results are exploratory, they suggest that the eradication of viable bacteria may occur sooner among cases with Indo-Oceanic lineage than among those with one of the three modern lineages. Prospective studies of time to sputum culture conversion by lineage are required. PMID- 23743307 TI - Data needs for evidence-based decisions: a tuberculosis modeler's 'wish list'. AB - Infectious disease models are important tools for understanding epidemiology and supporting policy decisions for disease control. In the case of tuberculosis (TB), such models have informed our understanding and control strategies for over 40 years, but the primary assumptions of these models--and their most urgent data needs--remain obscure to many TB researchers and control officers. The structure and parameter values of TB models are informed by observational studies and experiments, but the evidence base in support of these models remains incomplete. Speaking from the perspective of infectious disease modelers addressing the broader TB research and control communities, we describe the basic structure common to most TB models and present a 'wish list' that would improve the evidence foundation upon which these models are built. As a comprehensive TB research agenda is formulated, we argue that the data needs of infectious disease models--our primary long-term decision-making tools--should figure prominently. PMID- 23743309 TI - Sublineages of lineage 4 (Euro-American) Mycobacterium tuberculosis differ in genotypic clustering. AB - SETTING: Mycobacterium tuberculosis is classified into six phylogenetic lineages, each of which can be divided into sublineages. Sublineages of the same lineage have phenotypic differences, including their capacity to cause disease (pathogenicity). OBJECTIVE: 1) To test the hypothesis that different sublineages of lineage 4, which causes most of the tuberculosis (TB) in the United States, have varying ability to cause secondary cases as determined by genotypic clustering, a proxy for pathogenicity; and 2) to determine if spoligotype and mycobacterial interspersed repetitive units (MIRU) typing could infer sublineage. DESIGN: We included TB cases caused by lineage 4 strains from our community-based study in San Francisco. Sublineage was determined by regions of difference. Genotypic clustering was determined by insertion sequence 6110 and polymorphic guanine-cytosine-rich sequence. Associations between sublineages and patient characteristics were evaluated with adjusted and unadjusted analyses. RESULTS: The most frequent sublineage was H37Rv-like. In the adjusted analysis, sublineage 183 was associated with clustering and homelessness. We found that strains from different sublineages had convergent spoligotype and MIRU types. CONCLUSIONS: Sublineage 183 is associated with genotypic clustering, evidence of its being more able to cause secondary cases than the other lineage 4 sublineages. This finding suggests that bacterial factors contribute to the pathogenesis of TB. Spoligotype and MIRU type cannot be used to infer sublineage. PMID- 23743310 TI - Changes in QuantiFERON(r)-TB Gold In-Tube results during treatment for tuberculous infection. AB - SETTING: Randomised trial comparing 9 months of isoniazid with 4 months of rifampicin for the treatment of high-risk tuberculin skin test positive subjects in Rio de Janeiro, Brazil. OBJECTIVES: To compare QuantiFERON(r)-TB Gold In-Tube (QFT-GIT) responses before and 1, 4 and 9 months after starting treatment for latent tuberculous infection (LTBI) according to adherence to one of the two regimens. DESIGN: Participants in the trial were invited to undergo serial QFT GIT. Within-subject differences at different time points were analysed as quantitative responses and categorised as positive or negative using different cut-off points. RESULTS: Of 215 participants, 118 completed treatment, of whom 58 underwent all three tests; and 97 did not complete treatment, of whom 10 underwent all tests. After 1 month of treatment, there was no significant difference in QFT-GIT response between the groups. After 4 and 9 months, reversions were more frequent in non-adherent subjects. Marked within-subject fluctuations were observed. No cut-off point could be established at which QFT GIT responses were consistently positive or associated with adherence or type of treatment. CONCLUSION: Frequent within-subject variability in QFT-GIT responses, not associated with LTBI treatment, makes it difficult for clinicians to interpret QFT-GIT conversions and reversions. PMID- 23743311 TI - Elevated IP-10 and IL-6 from bronchoalveolar lavage cells are biomarkers of non cavitary tuberculosis. AB - BACKGROUND: Active TB disease can destroy lung parenchyma leading to cavities. Immune responses that predispose or protect individuals from lung damage during TB are poorly defined. OBJECTIVE: To sample lung immune cells and assay bronchoalveolar lavage (BAL) cell cytokine production. DESIGN: Enrolled subjects (n = 73) had bilateral infiltrates and underwent BAL. RESULTS: All had sputum culture demonstrating Mycobacterium tuberculosis and 22/73 (30%) had cavities on their chest radiograph. Those with cavities at presentation had a higher percentage of polymorphonuclear neutrophils (PMN) in BAL as well as lower inducible protein (IP) 10 (P < 0.01) and interleukin (IL) 6 (P = 0.013) in BAL cell supernatants compared to those without cavities. There was no correlation between cavities and other BAL or serum cytokines. IP-10 was negatively associated with BAL PMN. IP-10 and IL-6 expression above median reduces the odds of cavities by 79% and 78% in logistic regression models. IP-10 and IL-6 clustered with interferon-gamma and tumour necrosis factor-alpha in a principal component analysis, while IL-4 clustered with PMN. CONCLUSION: Increasing IP-10 and IL-6 production by BAL cells is associated with non-cavitary TB in patients who present with radiographically advanced TB. IP-10 and IL-6 may reflect an effective T-helper 1 immune control pathway for TB, attenuating tuberculous lung destruction. PMID- 23743312 TI - Increased risk of pulmonary tuberculosis in patients with previous non tuberculous mycobacterial disease. AB - OBJECTIVE: To investigate whether or not there is an increased risk of pulmonary tuberculosis (PTB) after non-tuberculous mycobacterial (NTM) disease. DESIGN: A retrospective cohort study of 212 NTM patients and 4240 control cases. RESULTS: Patients with previous NTM disease had a significantly higher incidence of PTB than controls (incidence rate ratio [IRR] 14.74, 95%CI 8.71-24.94, P < 0.0001). Cox's proportional hazards analysis yielded an adjusted hazards ratio (aHR) of 10.15 (95%CI 5.67-18.17, P < 0.05) for NTM-associated PTB. The majority of the PTB cases (17/23, 73.9%) were diagnosed within 6 months after the diagnosis of NTM disease. Older age (>=65 years, aHR 4.45, 95%CI 1.94-10.22, P < 0.05), male sex (aHR 1.75, 95%CI 1.01-3.13, P < 0.05), human immunodeficiency virus (HIV) infection (aHR 12.49, 95%CI 3.20-48.79, P < 0.05) and chronic obstructive pulmonary disease (aHR 4.46, 95%CI 2.19-9.10, P < 0.05) were independent risk factors for developing PTB after NTM disease. The cumulative incidence of PTB in patients with previous NTM disease was significantly higher than in controls (P < 0.0001, Kaplan-Meier analysis). However, there was no significant difference in the survival rates in the two cohorts. CONCLUSION: Increased PTB prevalence after NTM disease was demonstrated. HIV infection was the greatest independent risk factor for subsequent development of PTB. PMID- 23743313 TI - Hepatotoxicity due to first-line anti-tuberculosis drugs: a five-year experience in a Taiwan medical centre. AB - BACKGROUND: Hepatotoxicity with first-line drugs, a major complication of anti tuberculosis treatment, has not been studied by time-dependent analysis. DESIGN: Adult patients diagnosed with pulmonary tuberculosis (PTB) from 2005 to 2009 were reviewed retrospectively. Hepatotoxicity during anti-tuberculosis treatment was defined by symptomatic elevation of liver transaminases >=3 times the upper limit of normal, or >=5 times if asymptomatic. Risk factors for hepatotoxicity were investigated using time-dependent Cox regression analysis. RESULTS: Of 926 patients identified and followed for 4122.9 person-months (pm), 111 (12.0%) developed hepatotoxicity after a median 38.0 days from start of treatment. Around 3.5% had severe hepatotoxicity. The most common symptoms were general malaise and poor appetite. The incidence rate of hepatotoxicity was 0.59, 0.69 and 3.71/100 pm for isoniazid, rifampicin (RMP) and pyrazinamide (PZA), respectively. Old age, female sex, autoimmune disease, human immunodeficiency virus infection, more days with PZA in the last 8-14 days, and fewer days with RMP in the last 15-21 days before hepatotoxicity were independent risk factors for hepatotoxicity during treatment. CONCLUSION: A significant number of adult patients on first-line treatment experience hepatotoxicity. PZA is the most common causative drug. For high-risk patients, careful adjustment of the anti-tuberculosis regimen and regular monitoring of liver transaminases are necessary. PMID- 23743314 TI - Assessment of health-related quality of life in patients with pulmonary tuberculosis under programme conditions. AB - SETTING: Newly diagnosed pulmonary tuberculosis (PTB) patients starting treatment under the Revised National Tuberculosis Control Programme (RNTCP) in a North Indian city. OBJECTIVE: To quantify impairment in health-related quality of life (HRQoL) of PTB patients at the time of diagnosis and during treatment, and to assess the utility of these assessments as a measure of outcome under programme conditions. DESIGN: HRQoL was assessed using the Hindi version of the 26-item World Health Organization Quality of Life (WHOQOL-BREF) scale at the start and end of the intensive phase and at completion of treatment. Four domain scores physical, psychological, social relationships and environment-were calculated and compared between groups, based on different patient and disease characteristics. Psychometric evaluation was conducted by assessing acceptability, validity and responsiveness of the questionnaire. RESULTS: A total of 2654 HRQoL assessments were performed among 1034 patients. Domain scores were generally better among men, urban residents, younger patients, patients with higher socio-economic status and those with less severe disease. The WHOQOL-BREF demonstrated good psychometric properties, and domain scores improved with treatment. Residual HRQoL impairment was noted in some patients even at treatment completion. CONCLUSION: HRQoL is impaired in patients with PTB, and improves rapidly and significantly with programme-based treatment. HRQoL assessment can be used as an adjunct outcome measure for patients treated by the RNTCP. PMID- 23743315 TI - Social, economic, and psychological impacts of MDR-TB treatment in Tijuana, Mexico: a patient's perspective. AB - SETTING: The State of Baja California, Mexico, had the highest prevalence of multidrug-resistant tuberculosis (MDR-TB) in Mexico in 2009. OBJECTIVE: To understand the socio-economic burden of MDR-TB disease and its treatment on patients in Tijuana and Mexicali, Mexico. DESIGN: From July to November 2009, qualitative interviews were conducted with 12 patients enrolled in a US-Mexico binational MDR-TB treatment program, Puentes de Esperanza (Bridges of Hope), which was designed to support MDR-TB patients. In-depth interviews were coded to identify major themes in patient experiences of MDR-TB diagnosis and care. RESULTS: While some patients were able to maintain their pre-MDR-TB lives to a limited extent, most patients reported losing their sense of identity due to their inability to work, social isolation, and stigmatization from family and friends. The majority of participants expressed appreciation for Puentes' role in 'saving their lives'. CONCLUSION: Being diagnosed with MDR-TB and undergoing treatment imposes significant psychological, social and economic stress on patients. Strong social support elements within Puentes helped alleviate these burdens. Improvements to the program might include peer-support groups for patients undergoing treatment and transitioning back into the community after treatment. PMID- 23743316 TI - Overall and cause-specific mortality among patients with tuberculosis and multidrug-resistant tuberculosis. AB - OBJECTIVE: To assess overall and cause-specific mortality among patients with tuberculosis (TB) and multidrug-resistant tuberculosis (MDR-TB) in Estonia. DESIGN: A total of 2449 patients diagnosed with active respiratory TB from 1 January 2002 to 31 December 2009 were followed up retrospectively until 31 December 2011. To estimate the risk of death, standardised mortality ratios (SMR) and mortality rate ratios (RR) were calculated. RESULTS: The SMR for all-cause mortality among those diagnosed with TB was 5.30 (95%CI 4.85-5.75) in males and 10.00 (95%CI 8.25-11.74) in females. The relative risk of death from TB was higher among MDR-TB patients (adjusted RR in males 2.98, 95%CI 2.00-4.44, and in females 3.26, 95%CI 1.42-7.50) than among non-MDR-TB patients. Among the cohort of successfully treated patients, the SMR for all-cause mortality was 3.46 (95%CI 3.08-3.84) in males and 6.24 (95%CI 4.86-7.88) in females. Lower education level and foreign ethnicity contributed to the higher risk of mortality. Previous history of successfully treated MDR-TB did not increase the risk of death compared to successfully treated non-MDR-TB. CONCLUSIONS: Mortality among successfully treated TB and MDR-TB patients remained higher than among the general population. It was influenced by foreign ethnicity and lower education but, importantly, not by previous history of MDR-TB. PMID- 23743317 TI - Increased exhaled breath temperature in subjects with uncontrolled asthma. AB - BACKGROUND: Increased vascularity of the airway mucosa in asthma potentially increases heat loss in the airways. OBJECTIVE: To determine if the inflamed airways of subjects with uncontrolled asthma show increased exhaled breath temperature (EBT). PATIENTS AND METHODS: In 100 patients with persistent asthma and 50 healthy volunteers, we measured lung function by post-bronchodilator forced spirometry, the asthma control test (ACT) and EBT. RESULTS: Patients with asthma, of whom 49 (49%) were female, with a mean (+/- standard error of the mean) age of 44 (+/-17) years and a predicted forced expiratory volume in one second of 71% (+/-16), had a significantly increased EBT, particularly those with uncontrolled asthma (n = 50, ACT <= 19, EBT 34.9 +/- 0.8 degrees C), compared to patients with controlled asthma (n = 50, ACT >= 20, EBT 33.7 +/- 0.8 degrees C) and healthy volunteers (n = 50, EBT 33.2 +/- 0.2 degrees C, P < 0.001). CONCLUSION: We observed a higher temperature on exhaled breath in subjects with uncontrolled asthma than in subjects with controlled asthma and healthy controls. The increase in exhaled breath temperature may be a proxy for a raised airway inflammatory state in asthma patients. PMID- 23743318 TI - Early incidence of occupational asthma is not accelerated by atopy in the bakery/pastry and hairdressing sectors. AB - SETTING: Occupational asthma (OA) is most likely to develop in the very early years of exposure. OBJECTIVE: To describe the early incidence of OA among bakers/pastry-makers (BP) and hairdressers and to explore the role of atopy. DESIGN: Following a retrospective follow-up design, subjects were invited to undergo telephone interviews. Those who declared work-related respiratory or rhinitis symptoms and a sample group of others were offered a medical visit for OA investigations. Data from interviews and from medical visits were used to estimate the incidence of OA according to increasing durations of exposure. RESULTS: A total of 866 subjects were interviewed (mean age 25.3 years, 43.8% females), of whom 282 underwent a medical visit. Total estimated incidence rates of 'confirmed or probable' OA during the first 12 years of exposure were high in BP (2.63 per 100 person-years [py]) and in hairdressers (0.58/100 py), particularly in the first 4 years. Atopy is a strong risk factor for incidence among BP but, irrespective of the occupational sector, it does not influence the timing of OA symptoms. CONCLUSION: OA symptoms occur soon after the start of exposure. Our results suggest that atopy does not precipitate the occurrence of symptoms in two different allergen exposure settings. PMID- 23743319 TI - Prevalence of asthma and respiratory symptoms in children in a low socio-economic status area of Nigeria. AB - SETTING: Warri and environs in the Niger Delta, in the Southern region of Nigeria. OBJECTIVE: To investigate the burden of respiratory illness in children in the Niger Delta. DESIGN: A cross-sectional survey of 1397 schoolchildren aged 7-14 years in areas of low socio-economic status (SES), using written questionnaires in English based on the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, with explanation of symptoms. RESULTS: The prevalence of doctor-diagnosed asthma was 0.9% (95%CI 0.4-1.3), and wheeze in the last 12 months was 5.4% (95%CI 4.3-6.6). The prevalence of other respiratory symptoms was high, in particular night cough 23.3% (95%CI 21.1-25.5), rhinitis 19.2% (95%CI 17.1-21.3) and phlegm production 16.6% (95%CI 14.7-18.6). Risk of wheeze in the younger age groups was twice (OR 2.09, 95%CI 1.29-3.39) that of older ages after controlling for sex and geographical area. Risk of asthma in urban children was reduced (OR 0.15, 95%CI 0.05-0.50) compared to rural children after controlling for age and sex. Urban children also had a lower risk of rhinitis, exercise limitations and absenteeism due to respiratory illness than rural children. CONCLUSION: The prevalence of symptoms of allergic disease was lower than in the African centres in the ISAAC surveys conducted in urban centres. Doctor-diagnosed asthma is likely to be a poor indicator of asthma in low SES areas of developing countries due to health care access issues. PMID- 23743320 TI - Primary pulmonary botryomycosis: a bacterial lung infection mimicking lung cancer. AB - Primary pulmonary botryomycosis, or bacterial pseudomycosis, is an unusual bacterial infection characterised by the formation of eosinophilic granules that resemble those of Actinomyces species infection. The diagnosis of botryomycosis is based on culture of the granules revealing gram-positive cocci or gram negative bacilli. The bacterial pathogen most frequently found is Staphylococcus aureus. The pathobiology remains unknown. Pulmonary botryomycosis can resemble actinomycosis, tuberculosis or invasive carcinoma. Definitive treatment requires a combination of both surgical debridement and long-term antimicrobial therapy. We present a case of primary pulmonary botryomycosis in an immunocompetent patient. PMID- 23743321 TI - [Green urine due to propofol]. PMID- 23743322 TI - [Atrial fibrillation in clinical practice: more answers are required]. PMID- 23743323 TI - Health information exchange system usage patterns in three communities: practice sites, users, patients, and data. AB - OBJECTIVES: Public and private organizations are implementing systems for query based health information exchange (HIE), the electronic aggregation of patient data from multiple institutions. However, existing studies of query-based HIE system usage have addressed a limited number of settings. Our goal was to quantify the breadth and depth of usage of a query-based HIE system implemented across multiple communities with diverse care settings and patient populations. METHODS: We performed a cross-sectional study in three communities in New York State using system access log files from January 2009 to May 2011 to measure usage patterns of a query-based HIE web portal system with respect to practice sites, users, patients, and data. RESULTS: System access occurred from 60% (n=200) of practice sites registered to use the system in Community A, 59% (n=156) in Community B, and 82% (n=28) in Community C. In Communities A and B, users were primarily non-clinical staff in outpatient settings, while in Community C inpatient physicians were the main users. Across communities, proportions of patients whose data were accessed varied with 5% (n=11,263) in Community A, 60% (n=212,586) in Community B, and 1% (n=1107) in Community C. In Community B, users updated patient consent through the HIE portal, whereas in the other communities, users updated patient consent through a separate system. Across communities, users most frequently accessed only patient summary data displayed by default followed by detailed laboratory and radiology data. CONCLUSIONS: This study is among the first to illustrate large-scale usage of a query-based HIE system implemented across multiple communities. Patient summary data displayed by default may be an important feature of query-based HIE systems. User role, practice site type, and patient consent workflow may affect patterns of query-based HIE web portal system usage in the communities studied and elsewhere. PMID- 23743324 TI - Translating genome wide association study results to associations among common diseases: in silico study with an electronic medical record. AB - OBJECTIVE: To develop a map of disease associations exclusively using two publicly available genetic sources: the catalog of single nucleotide polymorphisms (SNPs) from the HapMap, and the catalog of Genome Wide Association Studies (GWAS) from the NHGRI, and to evaluate it with a large, long-standing electronic medical record (EMR). METHODS: A computational model, In Silico Bayesian Integration of GWAS (IsBIG), was developed to learn associations among diseases using a Bayesian network (BN) framework, using only genetic data. The IsBIG model (I-Model) was re-trained using data from our EMR (M-Model). Separately, another clinical model (C-Model) was learned from this training dataset. The I-Model was compared with both the M-Model and the C-Model for power to discriminate a disease given other diseases using a test dataset from our EMR. Area under receiver operator characteristics curve was used as a performance measure. Direct associations between diseases in the I-Model were also searched in the PubMed database and in classes of the Human Disease Network (HDN). RESULTS: On the basis of genetic information alone, the I-Model linked a third of diseases from our EMR. When compared to the M-Model, the I-Model predicted diseases given other diseases with 94% specificity, 33% sensitivity, and 80% positive predictive value. The I-Model contained 117 direct associations between diseases. Of those associations, 20 (17%) were absent from the searches of the PubMed database; one of these was present in the C-Model. Of the direct associations in the I-Model, 7 (35%) were absent from disease classes of HDN. CONCLUSION: Using only publicly available genetic sources we have mapped associations in GWAS to a human disease map using an in silico approach. Furthermore, we have validated this disease map using phenotypic data from our EMR. Models predicting disease associations on the basis of known genetic associations alone are specific but not sensitive. Genetic data, as it currently exists, can only explain a fraction of the risk of a disease. Our approach makes a quantitative statement about disease variation that can be explained in an EMR on the basis of genetic associations described in the GWAS. PMID- 23743325 TI - Tumor growth suppression by gadolinium-neutron capture therapy using gadolinium entrapped liposome as gadolinium delivery agent. AB - Neutron capture therapy (NCT) is a promising non-invasive cancer therapy approach and some recent NCT research has focused on using compounds containing gadolinium as an alternative to currently used boron-10 considering several advantages that gadolinium offers compared to those of boron. In this study, we evaluated gadolinium-entrapped liposome compound as neutron capture therapy agent by in vivo experiment on colon-26 tumor-bearing mice. Gadolinium compound were injected intravenously via tail vein and allowed to accumulate into tumor site. Tumor samples were taken for quantitative analysis by ICP-MS at 2, 12, and 24 h after gadolinium compound injection. Highest gadolinium concentration was observed at about 2 h after gadolinium compound injection with an average of 40.3 MUg/g of wet tumor tissue. We performed neutron irradiation at JRR-4 reactor facility of Japan Atomic Energy Research Institute in Tokaimura with average neutron fluence of 2*1012 n/cm2. The experimental results showed that the tumor growth suppression of gadolinium-injected irradiated group was revealed until about four times higher compared to the control group, and no significant weight loss were observed after treatment suggesting low systemic toxicity of this compound. The gadolinium-entrapped liposome will become one of the candidates for Gd delivery system on NCT. PMID- 23743326 TI - Electrochemical affinity biosensors for detection of mycotoxins: A review. AB - This review discusses the current state of electrochemical biosensors in the determination of mycotoxins in foods. Mycotoxins are highly toxic secondary metabolites produced by molds. The acute toxicity of these results in serious human and animal health problems, although it has been only since early 1960s when the first studied aflatoxins were found to be carcinogenic. Mycotoxins affect a broad range of agricultural products, most important cereals and cereal based foods. A majority of countries, mentioning especially the European Union, have established preventive programs to control contamination and strict laws of the permitted levels in foods. Official methods of analysis of mycotoxins normally requires sophisticated instrumentation, e.g. liquid chromatography with fluorescence or mass detectors, combined with extraction procedures for sample preparation. For about sixteen years, the use of simpler and faster analytical procedures based on affinity biosensors has emerged in scientific literature as a very promising alternative, particularly electrochemical (i.e., amperometric, impedance, potentiometric or conductimetric) affinity biosensors due to their simplicity and sensitivity. Typically, electrochemical biosensors for mycotoxins use specific antibodies or aptamers as affinity ligands, although recombinant antibodies, artificial receptors and molecular imprinted polymers show potential utility. This article deals with recent advances in electrochemical affinity biosensors for mycotoxins and covers complete literature from the first reports about sixteen years ago. PMID- 23743327 TI - Capability of parasulfonato calix[6]arene, as an anion dopant, and organic solvents in enhancing the sensitivity and loading of glucose oxidase (GOx) on polypyrrole film in a biosensor: a comparative study. AB - In this study, the effects of two solvents (acetonitrile and water) and an anion dopant (para sulfonato calix[6]arene ((C[6]S)(-6))), on the manufacturing and properties of a polypyrrole (Ppy)-based, glucose oxidase amperometric biosensor were studied. Pyrrole was polymerized using galvanostatic mode in two different solvents, and the effect of (C[6]S)(-6) was studied in aqueous solution. The morphology of the obtained polypyrrole films was studied by scanning electron microscopy (SEM). Glucose oxidase (GOx) was adsorbed on the Ppy films via cross linking method. Then the amperometric responses of the Pt/Ppy/GOx electrodes were measured using the amperometric method at the potential of 0.7 V in steps of adding a glucose solution to a potassium phosphate buffer. We found that acetonitrile and (C[6]S)(-6) increase the sensitivity of the enzyme electrode up to 79.30 uA M(-1)cm(-2) in comparison with 31.60 MUA M(-1)cm(-2) for the electrode synthesized in calixarene free aqueous solvent. Also (C[6]S)(-6) has the main role in preventing leaching the enzyme from the electrode. This fact increases loading of the enzyme and stability of the biosensor. So that the steady state current density of the aforementioned electrode increases linearly with increasing glucose concentration up to 190 mM. Whereas the linearity was observed up to 61 mM and 80 mM for the electrodes made using calixarene free acetonitrile and aqueous solutions, respectively. PMID- 23743328 TI - Label-free and reagentless electrochemical detection of microRNAs using a conducting polymer nanostructured by carbon nanotubes: application to prostate cancer biomarker miR-141. AB - In this paper, a label-free and reagentless microRNA sensor based on an interpenetrated network of carbon nanotubes and electroactive polymer is described. The nanostructured polymer film presents very well-defined electroactivity in neutral aqueous medium in the cathodic potential domain from the quinone group embedded in the polymer backbone. Addition of microRNA miR-141 target (prostate cancer biomarker) gives a "signal-on" response, i.e. a current increase due to enhancement of the polymer electroactivity. On the contrary, non complementary miRNAs such as miR-103 and miR-29b-1 do not lead to any significant current change. A very low detection limit of ca. 8 fM is achieved with this sensor. PMID- 23743329 TI - Sensitive detection of methylated DNA using the short linear quencher-fluorophore probe and two-stage isothermal amplification assay. AB - DNA methylation is an important epigenetic modification of genomes and is associated with various human diseases. Here, we develop a sensitive approach for DNA methylation assay using the short linear quencher-fluorophore DNA probe (QF probe) and two-stage isothermal amplification. With bisulfite treatment, the methylated DNA target is able to hybridize with the template to initiate the strand displacement amplification (SDA), generating abundant triggers which can further hybridize with the QF probes to form the DNA duplexes. The subsequent recognition of DNA duplexes and the cleavage of QF probes by the nicking enzyme can initiate the nicking enzyme signal amplification (NESA), inducing a significant fluorescence enhancement. While in the absence of methylated DNA, neither SDA nor NESA reaction can be initiated and no fluorescence enhancement is observed. This method exhibits high sensitivity with a detection limit of 0.78 pM, and can distinguish as low as 0.1% methylation level from the mixture of methylated and unmethylated DNA. Notably, the introduction of SDA into NESA can improve the detection sensitivity by up to 2 orders of magnitude as compared with the NESA assay, and it can even discriminate single-base mismatched methylated DNA. PMID- 23743330 TI - Lycium barbarum polysaccharides reduce intestinal ischemia/reperfusion injuries in rats. AB - Inflammation and oxidative stress exert important roles in intestinal ischemia reperfusion injury (IRI). Lycium barbarum polysaccharides (LBPs) have shown effective antioxidative and immunomodulatory functions in different models. The purpose of the present study was to assess the effects and potential mechanisms of LBPs in intestinal IRI. Several free radical-generating and lipid peroxidation models were used to assess the antioxidant activities of LBPs in vitro. A common IRI model was used to induce intestinal injury by clamping and unclamping the superior mesenteric artery in rats. Changes in the malondialdehyde (MDA), tumor necrosis factor (TNF)-alpha, activated nuclear factor (NF)-kappaB, intracellular adhesion molecule (ICAM)-1, E-selectin, and related antioxidant enzyme levels, polymorphonuclear neutrophil (PMN) accumulation, intestinal permeability, and intestinal histology were examined. We found that LBPs exhibited marked inhibitory action against free radicals and lipid peroxidation in vitro. LBPs increased the levels of antioxidant enzymes and reduced intestinal oxidative injury in animal models of intestinal IRI. In addition, LBPs inhibited PMN accumulation and ICAM-1 expression and ameliorated changes in the TNF-alpha level, NF-kappaB activation, intestinal permeability, and histology. Our results indicate that LBPs treatment may protect against IRI-induced intestinal damage, possibly by inhibiting IRI-induced oxidative stress and inflammation. PMID- 23743331 TI - The long-term effects of prenatal nicotine exposure on response inhibition: an fMRI study of young adults. AB - The long-term effects of prenatal nicotine exposure on response inhibition were investigated in young adults using functional magnetic resonance imaging (fMRI). Participants were members of the Ottawa Prenatal Prospective Study, a longitudinal study that collected a unique body of information on participants from infancy to young adulthood, which allowed for the measurement of an unprecedented number of potentially confounding drug exposure variables including: prenatal marijuana and alcohol exposure and current marijuana, nicotine and alcohol use. Twelve young adults with prenatal nicotine exposure and 13 non-exposed controls performed a Go/No-Go task while fMRI blood oxygen level dependent responses were examined. Despite similar task performance, participants prenatally exposed to nicotine demonstrated significantly greater activity in several regions of the brain that typically subserve response inhibition including the inferior frontal gyrus, the inferior parietal lobe, the thalamus and the basal ganglia. In addition, prenatally exposed participants showed greater activity in relatively large posterior regions of the cerebellum. These results suggest that prenatal nicotine exposure leads to altered neural functioning during response inhibition that continues into adulthood. This alteration is compensated for by recruitment of greater neural resources within regions of the brain that subserve response inhibition and the recruitment of additional brain regions to successfully perform the task. Response inhibition is an important executive functioning skill and impairments can impede functioning in much of everyday life. Thus, awareness of the continued long-term neural physiological effects of prenatal nicotine exposure is critical. PMID- 23743332 TI - Charcot-Marie-Tooth disease: frequency of genetic subtypes in a German neuromuscular center population. AB - Charcot-Marie-Tooth (CMT) neuropathies belong to the most common neurogenetic disorders. To date, mutations in more than 40 genes are known to be able to cause CMT. This genetic heterogeneity is a challenge for genetic diagnostics. Data on frequencies of mutations in CMT genes from large patient cohorts are needed to develop strategies for efficient genetic testing. In this study we have analysed patient histories, electrophysiological and genetic testing data in our cohort of 776 patients. In electrophysiologically demyelinating CMT, PMP22 duplication was the most common genetic cause, followed by mutations in GJB1 and MPZ. In axonal CMT, GJB1 was the most commonly affected gene, followed by MFN2 and MPZ. In CMT1, the clearance rate was 66%, in CMT2 it was 35%. Overall, the genetic clearance rate in our patient cohort was 58%. We found a higher rate of genetic diagnosis in patients seen in our neuromuscular center compared to out-of-clinic patients whose DNA was tested in our laboratory. This study provides further data on frequencies of CMT genes and subtypes and points to the importance of a thorough clinical and electrophysiological work-up for the direction of genetic testing. PMID- 23743333 TI - Steroids in Duchenne dystrophy. PMID- 23743334 TI - HCN4 dynamically marks the first heart field and conduction system precursors. AB - RATIONALE: To date, there has been no specific marker of the first heart field to facilitate understanding of contributions of the first heart field to cardiac lineages. Cardiac arrhythmia is a leading cause of death, often resulting from abnormalities in the cardiac conduction system (CCS). Understanding origins and identifying markers of CCS lineages are essential steps toward modeling diseases of the CCS and for development of biological pacemakers. OBJECTIVE: To investigate HCN4 as a marker for the first heart field and for precursors of distinct components of the CCS, and to gain insight into contributions of first and second heart lineages to the CCS. METHODS AND RESULTS: HCN4CreERT2, -nuclear LacZ, and -H2BGFP mouse lines were generated. HCN4 expression was examined by means of immunostaining with HCN4 antibody and reporter gene expression. Lineage studies were performed using HCN4CreERT2, Isl1Cre, Nkx2.5Cre, and Tbx18Cre, coupled to coimmunostaining with CCS markers. Results demonstrated that, at cardiac crescent stages, HCN4 marks the first heart field, with HCN4CreERT2 allowing assessment of cell fates adopted by first heart field myocytes. Throughout embryonic development, HCN4 expression marked distinct CCS precursors at distinct stages, marking the entire CCS by late fetal stages. We also noted expression of HCN4 in distinct subsets of endothelium at specific developmental stages. CONCLUSIONS: This study provides insight into contributions of first and second heart lineages to the CCS and highlights the potential use of HCN4 in conjunction with other markers for optimization of protocols for generation and isolation of specific conduction system precursors. PMID- 23743335 TI - Circulating p53-responsive microRNAs are predictive indicators of heart failure after acute myocardial infarction. AB - RATIONALE: Despite a recent decline of in-hospital mortality attributable to acute myocardial infarction (AMI), the incidence of ischemic heart failure (HF) in post-AMI patients is increasing. Although various microRNAs have been proposed as diagnostic indicators for AMI, no microRNAs have been established as predictors of ischemic HF that develops after AMI. OBJECTIVE: We attempted to identify circulating microRNAs that can serve as reliable predictors of ischemic HF in post-AMI patients. METHODS AND RESULTS: Using sera collected a median of 18 days after AMI onset, we screened microRNAs in 21 patients who experienced development of HF within 1 year after AMI and in 65 matched controls without subsequent cardiovascular events after discharge. Among the 377 examined microRNAs, the serum level of only miR-192 was significantly upregulated in AMI patients with development of ischemic HF. Because miR-192 is reported to be p53 responsive, the serum levels of 2 other p53-responsive microRNAs, miR-194 and miR 34a, also were investigated. Interestingly, both microRNAs were coordinately increased with miR-192, particularly in exosomes, suggesting that these microRNAs function as circulating regulators of HF development via the p53 pathway. Furthermore, miR-194 and miR-34a expression levels were significantly correlated with left ventricular end-diastolic dimension 1 year after AMI. CONCLUSIONS: In the sera of post-AMI patients who experienced development of de-novo HF within 1 year of AMI onset, the levels of 3 p53-responsive microRNAs had been elevated by the early convalescent stage of AMI. Further investigations are warranted to confirm the usefulness of these circulating microRNAs for predicting the risk of development of ischemic HF after AMI. PMID- 23743336 TI - Clust&See: a Cytoscape plugin for the identification, visualization and manipulation of network clusters. AB - BACKGROUND AND SCOPE: Large networks, such as protein interaction networks, are extremely difficult to analyze as a whole. We developed Clust&See, a Cytoscape plugin dedicated to the identification, visualization and analysis of clusters extracted from such networks. IMPLEMENTATION AND PERFORMANCE: Clust&See provides the ability to apply three different, recently developed graph clustering algorithms to networks and to visualize: (i) the obtained partition as a quotient graph in which nodes correspond to clusters and (ii) the obtained clusters as their corresponding subnetworks. Importantly, tools for investigating the relationships between clusters and vertices as well as their organization within the whole graph are supplied. PMID- 23743337 TI - The regulatory network that controls the differentiation of T lymphocytes. AB - There is a vast amount of molecular information regarding the differentiation of T lymphocytes, in particular regarding in vitro experimental treatments that modify their differentiation process. This publicly available information was used to infer the regulatory network that controls the differentiation of T lymphocytes into CD4(+) and CD8(+) cells. Hereby we present a network that consists of 50 nodes and 97 regulatory interactions, representing the main signaling circuits established among molecules and molecular complexes regulating the differentiation of T cells. The network was converted into a continuous dynamical system in the form of a set of coupled ordinary differential equations, and its dynamical behavior was studied. With the aid of numerical methods, nine fixed point attractors were found for the dynamical system. These attractors correspond to the activation patterns observed experimentally for the following cell types: CD4(-)CD8(-), CD4(+)CD8(+), CD4(+) naive, Th1, Th2, Th17, Treg, CD8(+) naive, and CTL. Furthermore, the model is able to describe the differentiation process from the precursor CD4(-)CD8(-) to any of the effector types due to a specific series of extracellular signals. PMID- 23743338 TI - Affinity analysis of differentially expressed genes in hepatocytes expressing HCV core genotype 1b or 3a. AB - Chronic hepatitis C patients display many genotype-specific clinical features of HCV infection. The core proteins encoded by different genotypes dysregulate numerous sets of distinct host genes. In this study we tested the hypothesis that HCV core proteins 1b and 3a would actually act on a limited number of independent cellular players, as well as on several functionally linked gene products. Structural and functional tests identified a core set of host genes dysregulated by HCV core genotypes 1b and 3a. The core proteins of HCV genotypes 1b and 3a target specifically limited sets of functionally related gene products, which may be responsible for the variations in the clinical spectra associated with HCV infection. PMID- 23743339 TI - Non-linear molecular pattern classification using molecular beacons with multiple targets. AB - In vitro pattern classification has been highlighted as an important future application of DNA computing. Previous work has demonstrated the feasibility of linear classifiers using DNA-based molecular computing. However, complex tasks require non-linear classification capability. Here we design a molecular beacon that can interact with multiple targets and experimentally shows that its fluorescent signals form a complex radial-basis function, enabling it to be used as a building block for non-linear molecular classification in vitro. The proposed method was successfully applied to solving artificial and real-world classification problems: XOR and microRNA expression patterns. PMID- 23743340 TI - Pupillary response predicts multiple object tracking load, error rate, and conscientiousness, but not inattentional blindness. AB - Research on inattentional blindness (IB) has uncovered few individual difference measures that predict failures to detect an unexpected event. Notably, no clear relationship exists between primary task performance and IB. This is perplexing as better task performance is typically associated with increased effort and should result in fewer spare resources to process the unexpected event. We utilized a psychophysiological measure of effort (pupillary response) to explore whether differences in effort devoted to the primary task (multiple object tracking) are related to IB. Pupillary response was sensitive to tracking load and differences in primary task error rates. Furthermore, pupillary response was a better predictor of conscientiousness than primary task errors; errors were uncorrelated with conscientiousness. Despite being sensitive to task load, individual differences in performance and conscientiousness, pupillary response did not distinguish between those who noticed the unexpected event and those who did not. Results provide converging evidence that effort and primary task engagement may be unrelated to IB. PMID- 23743341 TI - Emergence of the go/no-go Simon effect by means of practice and mixing paradigms. AB - In two experiments, we tested whether the emergence of the go/no-go Simon effect could be determined by the strengthening of one specific S-R link in location relevant trials performed right before (practice paradigm) or simultaneously (mixing paradigm) with the location-irrelevant (Simon) trials. Results showed a clear carry-over effect of the association between stimulus position and spatial response from the first task to the second one (Experiment 1) and when the two tasks were performed simultaneously (Experiment 2), even if participants were required to respond with the same key to only half of the stimuli (go/no-go tasks). We found that associative learning between the stimulus and response positions occurring during the go/no-go compatibility task, that is when location was relevant, influenced the way the go/no-go location-irrelevant task (Simon task) was performed. Our findings suggest that the STM links formed during a go/no-go spatial compatibility task are strong enough to influence the go/no-go Simon task. PMID- 23743342 TI - The aesthetic aha: on the pleasure of having insights into Gestalt. AB - Are challenging stimuli appreciated due to perceptual insights during elaboration? Drawing on the literature regarding aesthetic appreciation, several approaches can be identified. For instance, fluency of processing as well as perceptual challenge are supposed to increase appreciation: One group (Reber, Schwarz, & Winkielman, 2004) claims that fluency of processing increases appreciation. Others link aesthetics to engagement: Creation and manipulation of sense itself should be rewarding (Ramachandran & Hirstein, 1999). We experimentally tested the influence of insights during elaboration on liking. Pairs of stimuli - hardly detectable two-tone images including a face (Mooney face) and meaningless stimuli matched for complexity - were presented repeatedly. Having an insight as well as the intensity of the insight predicted subsequent gains in liking. This paper qualifies the role of insight (-aha!) on aesthetic appreciation through the effects of elaboration and problem-solving on understanding the processing of modern art. PMID- 23743343 TI - Conflict adjustment devoid of perceptual selection. AB - Task performance suffers when an aspect of a stimulus is associated with an incorrect response, thereby evoking cognitive conflict. Such impairment is reduced after recent or frequent conflict occurrence, suggesting attentional adjustment. We examined adjustment to conflict evoked by a temporarily irrelevant S-R rule when participants frequently switched between two semantic classification tasks by manipulating the proportion of conflict trials in one of them. Controlling stimulus-specific presentation frequencies, we found reduced conflict effects under conditions of a higher proportion of conflict trials in the task to which the manipulation was applied, whereas there was no such effect in the other task. Additional analyses demonstrated task-specificity regarding trial-to-trial conflict adjustment. Because conflict was evoked in the absence of perceptually distinct target and distractor stimulus features, these adjustment effects cannot be attributed to perceptual selection. PMID- 23743344 TI - Early perceptual interactions shape the time course of cueing. AB - Performance in spatial cueing tasks is characterized by a rapid attentional enhancement with increasing cue-target SOA. We recently found that this enhancement function also applies when the cue and the target are presented invariably at a single central location, suggesting a universal cueing time course [Wilschut et al., 2011, PLoS ONE, 6, e27661]. However, using a very similar cueing task, Nieuwenstein et al. [2009, JoV, 9, 1-14] have found a rather different pattern, namely a U-shaped deficit in performance after a cue-like stimulus. The present study varied the properties of the cue and the target in order to investigate the mechanisms underlying the different time functions. In four experiments, cueing was found to either improve or decrease performance with increasing SOA, depending on the type of target that was used. In addition, the level of performance at the shortest cue-target intervals (33-83ms) was dependent on the relative strength of the cue and the target, akin to what has been found in visual masking studies. The results suggest that cueing shapes performance via two mechanisms, one sensory-related and one attention-related, the combination of which results in either U-shaped or monotonic patterns. PMID- 23743345 TI - Evaluation of a novel real-time RT-PCR using TOCE technology compared with culture and Seeplex RV15 for simultaneous detection of respiratory viruses. AB - BACKGROUND: Various kinds of commercial molecular systems have been developed for fast and more accurate detection of respiratory viruses. AnyplexTM II RV16 [RV16] was designed for simultaneous detection of 16 respiratory viruses using multiplex PCR coupled with TOCETM technology. OBJECTIVES: To compare the performance of RV16 with those of culture and Seeplex((r)) RV15 ACE [RV15] by determining their sensitivity and specificity. STUDY DESIGN: Seven hundred and thirty respiratory samples were tested by modified shell vial culture method, RV16, and RV15. For molecular tests, automated nucleic acid extraction and liquid handling system using MICROLAB Nimbus IVD (Hamilton, USA) was adopted to maximize the workflow and accuracy. Performance of each assay was determined against a composite reference standard. RESULTS: Two hundred and one samples (28%) out of 730 samples were positive by culture, while additional 281 (39%) were positive by RV16 or RV15. Sensitivities of RV16, RV15, and culture for virus tested were as follows: 100/93/63% for influenza A, 90/80/69% for influenza B, 98/94/63% for RSV, 98/52/23% for adenovirus, and 100/75/46% for PIV. For viruses not covered by culture, sensitivities of RV16 and RV15 were as follows: 99/81% for rhinovirus, 92/100% for coronavirus OC43, 100/56% for coronavirus 229E/NL63, 92/88% for metapneumovirus, 100/62% for bocavirus, and 91/91% for enterovirus. Overall, the specificities of culture, RV16, and RV15 (Seegene) were 100/99.9/99.9%. CONCLUSIONS: RV16 assay was superior to culture method and RV15 and will be a promising tool for patient management and public health epidemiology. PMID- 23743346 TI - Hepatitis E virus infections in HIV-infected patients in Ghana and Cameroon. AB - BACKGROUND: Chronic hepatitis E virus (HEV) infections have recently been described in HIV-infected patients. Only few data are available for sub-Saharan Africa, where HIV and HEV are highly co-endemic, and where liver pathology is common in HIV-infected individuals. OBJECTIVES: To assess the prevalence of HEV viremia, anti-HEV antibodies, and serum aminotransferase levels in HIV patients in Ghana and Cameroon. STUDY DESIGN: We retrospectively surveyed a cross-section of patients who were enrolled in cohort studies in Ghana (West Africa), and Cameroon (Central Africa). Plasma samples from 1029 HIV patients from Ghana and 515 patients from Cameroon including 214 children were analyzed for HEV-RNA by two reverse transcription PCR methods. In a subset of 791 patients, anti-HEV IgG and IgM antibodies were analyzed. RESULTS: No HEV-RNA was detected in any of the plasma samples of 1544 patients. HEV seroprevalence was high in adult HIV patients from Ghana (45.3%, n=402) and Cameroon (14.2%, n=289), but low in pediatric HIV patients from Cameroon (2.0%, n=100). Elevations of alanine aminotransferase and aspartate aminotransferase levels were common in adult patients from Ghana (20.8% and 25.4%) and Cameroon (38.9% and 69.8%). The prevalence of hepatitis B virus surface antigen was 11.8% and of hepatitis C virus antibodies 2.5% in our adult Cameroonian study population. CONCLUSIONS: Acute or chronic HEV infections did not play a role in liver pathology in two HIV cohorts in Ghana and Cameroon. A better understanding of the epidemiology and genotype-specific characteristics of HEV infections in HIV patients in sub Saharan Africa is needed. PMID- 23743347 TI - Lordosis facilitation by leptin in ovariectomized, estrogen-primed rats requires simultaneous or sequential activation of several protein kinase pathways. AB - The present study tested the hypothesis that the Janus kinase 2, Src tyrosine kinases, and mitogen-activated protein kinase interact to regulate lordosis behavior induced by leptin in ovariectomized, estrogen-primed rats. The role of protein kinase A and protein kinase C in lordosis facilitation by leptin was also assessed. In experiment 1, the intracerebroventricular administration of leptin to ovariectomized, estradiol-primed rats significantly stimulated lordosis behavior at 1, 2 and 4 h post-injection tests. In experiment 2, the Janus kinase 2 inhibitor AG490, the Src tyrosine kinase inhibitor PP2 and the mitogen activated protein kinase inhibitor PD98059 were administered into the right lateral ventricle before leptin. The lordosis quotient and the lordosis score induced by leptin were significantly decreased by each of these kinase inhibitors. In experiment 3, we examined the effects of RpcAMPS and bisindolylmaleimide, protein kinase A and protein kinase C inhibitors on the lordosis elicited by leptin administration. Lordosis behavior induced by leptin was significantly decreased by both the protein kinase A and protein kinase C inhibitors at 1 h post-leptin injection. The results confirm that multiple intracellular pathways participate in the expression of lordosis behavior in estrogen-primed rats elicited by leptin. PMID- 23743348 TI - Fatty acid transport proteins chronically relocate to the transverse-tubules in muscle from obese Zucker rats but are resistant to further insulin-induced translocation. AB - OBJECTIVES: Recently, we have demonstrated that FA transport proteins are located within the t-tubule fraction of rodent muscle, and that insulin stimulation causes their translocation to this membrane fraction. Chronic relocation of the FA transport protein FAT/CD36 to the sarcolemma is observed in obese rodents and humans, and correlates with intramuscular lipid accumulation and insulin resistance. It is not known whether in an obese, insulin resistant state FA transporters also chronically relocate to the t-tubules. Furthermore, it is not known whether the insulin-stimulated translocation of the various FA transport proteins to the t-tubules is impaired in insulin resistance. METHODS: Sarcolemmal and t-tubule membrane fractions were isolated via differential centrifugation from muscles of lean and obese female Zucker rats during basal or insulin stimulated conditions. FA transport proteins were measured via western blot on both membrane fractions. RESULTS: Our results demonstrate that in muscle from insulin resistant Zucker rats, FAT/CD36, FABPpm and FATP1 are all increased on the t-tubules in the basal state (+72%, +120%, and +69%, respectively), potentially contributing to the accumulation of intramuscular lipids. Insulin failed to increase the content of the FA transport proteins on either the t tubule or sarcolemma above the elevated basal levels, analogous to the well characterized impairment of insulin-stimulated GLUT4 translocation to both membrane domains in obesity. CONCLUSION: FA transport proteins chronically relocate to the t-tubule domain in insulin resistant muscle, potentially contributing to lipid accumulation. Further translocation of the FA transport proteins to this domain during insulin stimulation, however, is impaired. PMID- 23743349 TI - Regional distribution and metabolic effect of PCSK9 insLEU and R46L gene mutations and apoE genotype. AB - BACKGROUND: Natural loss-of-function mutations in the proprotein convertase subtilisin/kexin type-9 gene (PCSK9) are associated with lower cholesterol and cardiovascular risk. Because a founder effect exists in French Canadians for many lipid-related genes, we sought to investigate PCSK9 mutations and associated variables in this population. We also investigated the combined effect of PCSK9 mutations and the apolipoprotein E (apoE) polymorphism on metabolic variables. METHODS: Gene sequencing and screening was carried out in 1745 healthy individuals ages 9, 13, and 16 years from a provincially representative population sample. In parallel, we measured related metabolic markers and used appropriate statistical methods. RESULTS: We report herein that the carrier rates of the R46L single-nucleotide polymorphism were higher in the French Canadian population (4.8%) than previously seen in Caucasian individuals (2.4%). This is second to the most common variant, insertion of leucine, at a carrier rate of 24%, making it the most common PCSK9 loss-of-function mutation in French Canadian individuals. In R46L carriers, the contribution of the apoE genotype better explains the cholesterol phenotype than the R46L mutation alone. Patients, with both the R46L and apoE3/E2 genotype also showed a tendency toward insulin resistance as indicated by a 2-fold increase in insulin, homeostasis model assessment of insulin resistance, and leptin concentrations, compared with those without apoE3/E2. CONCLUSIONS: R46L and insertion of leucine mutations were more frequent in French Canadian individuals and showed a specific geographic distribution. This might represent a gene selection to overcome clustering genes harbouring familial hypercholesterolemia and might suggest a founder effect. Subjects with the apoE3/E2 genotype and R46L have increased plasma insulin, homeostasis model assessment of insulin resistance, and leptin, an intriguing finding that warrants further investigation. PMID- 23743350 TI - When does intimate partner violence continue after separation? AB - Over their lifetime, approximately 10% of all women become victims of postseparation stalking or assault. We use a nationally representative survey of separated Swedish women to examine whether men who strive to control their partners during their relationships are more likely to stalk or assault their ex partners after separation. The empirical analysis shows that basic measures of control behaviors explain 18% of the variance in stalking victimization and 8% of the assault victimization. Moreover, the predictive values of our measures of control by far surpass those of other common risk markers included in the analysis. PMID- 23743351 TI - The effects of receiving a rape disclosure: college friends' stories. AB - Research suggests that college women are at greater risk for rape and sexual assault than women in the general population or in a comparable age group. College women, away from home and family, may turn to friends for support. Friends may experience emotional reactions that affect their own functioning and may not feel they have anywhere to turn. In this study, we interviewed male and female college students who had received a rape disclosure from a friend. Their unique stories provide insight into the secondary effects of rape disclosure on friends. Implications of these findings for college campuses are discussed. PMID- 23743352 TI - The influence of plaintiff gender on the judicial decision to grant civil restraining orders: a replication and analysis. AB - Our knowledge of the role of plaintiff gender in shaping the judicial decision to issue restraining orders rests upon only two studies. Both conclude that judges discriminate against male victims. Each is constrained by small male sample size, few control variables, and limited statistical analysis. We replicate one of these studies. In the issuance of temporary orders we find a gender difference, though with a greatly reduced effect size compared to the earlier study. Legally relevant gender differences may explain this disparity. Plaintiff gender had no effect on the judicial decision to set hearing dates or to issue a permanent order. PMID- 23743353 TI - The extended subtemporal transtentorial approach: the impact of trochlear nerve dissection and tentorial incision. AB - The subtemporal transtentorial approach provides excellent exposure of the incisural space. Incision of the tentorium improves access to the interpeduncular cistern, basilar artery, and rostral ventral pons. Description of the starting and termination points of the tentorial incision has varied greatly. We assessed the impact on surgical exposure of freeing the trochlear nerve (TN) from its dural canal (DC) in addition to dividing and retracting the tentorium. A subtemporal approach was performed on 10 hemispheres of cadaveric specimens. Following exposure of the middle tentorial incisura, the TN is dissected from its DC over a few millimeters. Two retraction sutures are placed along the tentorial edge, posterior to the TN entrance in its DC. The tentorial incision is started between the sutures. Dissection of TN from its DC continues for a short distance. The tentorial incision is extended straight up towards the superior petrosal sinus. Dissection of the TN DC continues anteriorly, up to its entry into the cavernous sinus. The tentorial incision can then be extended, just over the entrance to Meckel's cave, and the flap reflected far anterolateraly. Using this technique, the exposure of the interpeduncular cistern and its content increased by a mean of 8.2 mm (standard deviation [SD] 3.9 mm) in the anteroposterior axis and by 5.5mm (SD 1.9 mm) in the rostrocaudal axis. Tentorial incision following dissection of the TN from its DC optimizes reflection of the tentorium flap anterolateraly, maximizes the exposure, and improves lighting and visibility as well as maneuverability within the interpeduncular and rostral pre-pontine cisterns. PMID- 23743356 TI - [Design and validation of the scales for the assessment of the psychological impact of past life events: the role of ruminative thought and personal growth]. AB - INTRODUCTION: Older people's emotional distress is often related to rumination processes focused on past vital events occurred during their lives. The specific coping strategies displayed to face those events may contribute to explain older adults' current well-being: they can perceive that they have obtained personal growth after those events and/or they can show a tendency to have intrusive thoughts about those events. This paper describes the development and analysis of the psychometric properties of the Scales for the Assessment of the Psychological Impact of Past Life Events (SAPIPLE): the past life events-occurrence scale (LE O), ruminative thought scale (LE-R) and personal growth scale (LE-PG). MATERIAL AND METHODS: Participants were 393 community dwelling elderly (mean age=71.5 years old; SD=6.9). In addition to the SAPIPLE scales, depressive symptomatology, anxiety, psychological well-being, life satisfaction, physical function and vitality have been assessed. RESULTS: The inter-rater agreement's analysis suggests the presence of two factors in the LE-O: positive and negative vital events. Confirmatory Factor Analysis (CFA) supported this two-dimensional structure for both the LE-R and the LE-PG. Good internal consistency indexes have been obtained for each scale and subscale, as well as good criterion and concurrent validity indexes. CONCLUSIONS: Both ruminative thoughts about past life events and personal growth following those events are related to older adults' current well-being. The SAPIPLE presents good psychometric properties that justify its use for elderly people. PMID- 23743354 TI - Emmprin and KSHV: new partners in viral cancer pathogenesis. AB - Emmprin (CD147; basigin) is a multifunctional glycoprotein expressed at higher levels by cancer cells and stromal cells in the tumor microenvironment. Through direct effects within tumor cells and promotion of tumor-stroma interactions, emmprin participates in induction of tumor cell invasiveness, angiogenesis, metastasis and chemoresistance. Although its contribution to cancer progression has been widely studied, the role of emmprin in viral oncogenesis still remains largely unclear, and only a small body of available literature implicates emmprin associated mechanisms in viral pathogenesis and tumorigenesis. We summarize these data in this review, focusing on the role of emmprin in pathogenesis associated with the Kaposi sarcoma-associated herpesvirus (KSHV), a common etiology for cancers arising in the setting of immune suppression. We also discuss future directions for mechanistic studies exploring roles for emmprin in viral cancer pathogenesis. PMID- 23743357 TI - [Mechanical restraints in the elderly: technical proposals and recommendations for use in the social environment]. AB - There is some confusion in the national gerontological literature in the use of terms that refer to mechanical restraints. There is a lack of dialogue as regards ethical conflicts that suggest their use, as well as a significant generalization of the claims against, and the absence of positive references despite its high prevalence as shown by some authors. This paper presents some technical proposals on the definition, the use of terms, and the use of mechanical restraints in the social environment, such as putting the ethical dialogue to arguments based on the prevalence, define them in terms of their intent, agree on a classification of the different restraint methods, identify the types and levels of risk, and intervene specifically in accordance with these proposals. Finally, recommendations are added with regards to risks, the decision process, prescription and the withdrawal process. PMID- 23743358 TI - [Profile of the elderly institutionalised in private residences in the Abadengo area in Salamanca]. PMID- 23743355 TI - Tight junction proteins: from barrier to tumorigenesis. AB - The tight junction is a multi-protein complex and is the apical most junctional complex in certain epithelial and endothelial cells. A great deal of attention has been devoted to the understanding of these proteins in contributing to the barrier function - that is, regulating the paracellular flux or permeability between adjacent cells. However, tight junction proteins are now recognized as having functions beyond the barrier. The focus of this review is to discuss the barrier function of the tight junction and to summarize the literature with a focus on the role of tight junction proteins in proliferation, transformation, and metastasis. PMID- 23743359 TI - Structural elucidation of a novel water-soluble fructan isolated from Wedelia prostrata. AB - A new heteropolysaccharide, WPP60A, with a molecular weight of 2.4 kDa, was isolated from Wedelia prostrata by hot water extraction, and purified by DEAE Sepharose fast flow and Sephacryl S-200 high-resolution chromatography. Compositional analysis, and methylation analysis, combined with (1)H, (13)C NMR spectroscopy including 2D NMR (COSY, TOCSY, HMQC, NOESY, and HMBC) experiments demonstrated that WPP60A was composed of primarily fructose and low glucose. Results indicated that this new heteropolysaccharide consists of a repeating unit with the following structure: [Formula: see text]. PMID- 23743360 TI - Modifications in the nitric acid oxidation of D-mannose: X-ray crystal structure of N,N'-dimethyl D-mannaramide. AB - Nitric acid oxidation of D-mannose was carried out under an oxygen atmosphere using a computer controlled reactor. The process represents a catalytic oxidation of D-mannose with oxygen as the terminal oxidant. The crude oxidation product was esterified with methanolic HCl and the esterified product directly converted to crystalline N,N'-dimethyl-D-mannaramide with methylamine. Treatment of the diamide in aqueous sodium hydroxide gave solid disodium D-mannarate. The X-ray crystal structure of N,N'-dimethyl-D-mannaramide was determined as a model for the repeating D-mannaramide units of stereoregular poly(alkylene-D-mannaramides). Disodium D-mannarate was prepared as a precursor of esterified D-mannaric acid for use as a reactive diacid monomer to prepare poly-D-mannaramides. PMID- 23743361 TI - Role of the 4,6-O-acetal in the regio- and stereoselective conversion of 2,3-di-O sulfonyl-beta-D-galactopyranosides to D-idopyranosides. AB - The recently reported conversion of 2,3-di-O-sulfonyl-D-galactopyranosides to D idopyranosides has provided an efficient route to obtaining orthogonally protected idopyranoside building blocks with a beta-1,2-cis glycosidic linkage. In an effort to expand the scope of this process and better understand the regio- and stereoselectivity observed in the key di-inversion step of the method, a small library of 4,6-O-acetal protected galactopyranosides has been synthesized and used as substrates in the process, together with a number of substrates that lack the acetal functionality. The results suggest that although the substituent at the acetal center does not contribute to the observed selectivity of the process, the acetal group is indeed required for efficient conversion by reducing the conformational flexibility of the substrate, resulting in enhanced reaction rates at both the O-transsulfonylation and epoxide ring-opening steps. PMID- 23743362 TI - Re: Avoiding never events: improving nasogastric intubation practice and standards. A reply. PMID- 23743363 TI - A radiologist's guide to small bowel and multivisceral transplantation. AB - This review will describe the indications for the various small bowel containing transplants. The importance of early referral will be highlighted. Radiologists play a central role in assessing these complex patients prior to transplantation. Furthermore, in the postoperative period, radiologists play an important part in diagnosing and treating complications. PMID- 23743364 TI - Testosterone implants modify the steroid hormone balance and the gonadal physiology of gilthead seabream (Sparus aurata L.) males. AB - Androgens can induce complete spermatogenesis in immature or prepubertal teleost fish; however, many aspects of the role of androgens in adult teleost spermatogenesis remain elusive. We used the in situ forming microparticle (ISM) system containing 1mg of testosterone (T)/kg body weight (T-ISM) in a homogenous population of gilthead seabream at testicular involution stage to study in vivo the effects of T on the sex steroid hormone balance and on the physiology of the gilthead seabream gonad. The levels of T, 11-ketotestosterone (11KT) and 17beta estradiol (E2) in plasma, gonad and liver were determined in T-ISM implanted specimens after 7, 14, 21 and 28 days. The effect of T-ISM was evaluated on (i) de novo synthesis and metabolism of T in the gonad and liver by measuring the gene expression levels of the main steroidogenic proteins involved, (ii) the progress of spermatogenesis, (iii) the presence of different leukocyte cell types in the gonad, and (iv) the mRNA expression of some genes involved in the leukocyte migratory influx into the gonad and of some immune-relevant molecules. T-ISM implants promote an increase of T up to supra-physiological levels which induce a depletion of E2 levels and maintain the 11KT levels at physiological concentrations. The gene expression profile of some steroidogenic enzymes in gonad and liver ruled out the transformation of T into estrogenic compounds following T-ISM implantation. Moreover, androgens may also be involved in the leukocyte migratory influx, which occurred even when cytokine, chemokine and cell adhesion molecule gene expressions were down-regulated. Moreover, T-ISM implants block germ cell proliferation, although increased dmrt1 gene expression may prevent the complete depletion of germ cells in the gonad. Furthermore, T down regulated the expression of several tlr genes, which may result in the inhibition of the immune response in the gonad through the impaired ability to recognize and respond to pathogens. PMID- 23743365 TI - Extraperitoneal closure of persistent gastrocutaneous fistula in children. AB - BACKGROUND AND OBJECTIVES: Gastrostomy feeding in children is well established for nutritional support. Gastrostomy tubes may be permanent or temporary. After removal, spontaneous closure may occur, but persistence of the tract requires surgical repair. Laparotomy with gastric repair and fascial closure is the standard technique for treatment of a persistent gastrocutaneous fistula. We describe a technique of extraperitoneal excision of the fistulous tract and our results using this method. METHODS: We reviewed 21 cases of extraperitoneal gastrocutaneous fistula closure in which a Foley catheter traction technique was used and were performed over the last 8 y. The technique involves insertion of a small Foley catheter with traction applied to the fistulous tract and core excision with electrocautery. Closure of the tract without fascial separation was accomplished and early feedings were allowed. RESULTS: Ten males and 11 females underwent closure with this technique. The duration of the gastrostomy ranged from 1 y to 6 y, with a mean of 3.3 y. The time from removal to surgical repair was 3 wk to 1 y, with a mean of 4.3 mo; 15 had gastrostomy alone, and 6 had gastrostomy in combination with Nissen fundoplication. Open gastrostomy had been done in 10 patients and laparoscopic gastrostomy in 11 patients. Half of the patients had an ambulatory procedure. One patient developed a superficial wound infection, and there was 1 recurrence requiring intraperitoneal closure. CONCLUSION: Extraperitoneal closure for gastrocutaneous fistula is safe and effective. The technique allows for rapid resumption of feeds and a shortened length of stay. Minimal morbidity occurs with this technique, and it is well tolerated in the pediatric population. PMID- 23743366 TI - Single-port laparoscopic right hemicolectomy: intermediate results. AB - BACKGROUND: Single-port laparoscopic colectomy was first described in 2008 as a new technique for colorectal surgery. No available reports have stated the intermediate- or long-term outcome. We report our intermediate results for the first 20 single-port laparoscopic right hemicolectomies performed by a single laparoscopically trained surgeon at our institution. DESIGN: Between February 2009 and September 2010, 20 consecutive patients with an indication for right hemicolectomy who were candidates for laparoscopic surgery underwent a single port laparoscopic approach. The only exclusion was a previous midline laparotomy. The patients were followed for outcomes after a median of 27 months (range: 15 to 35). RESULTS: The mean age was 65 years (range: 59 to 88). The mean body mass index was 28 (range: 20 to 35). Seventy five percent of patients had significant comorbidities, with an American Society of Anesthesiologists class of III or IV. The median estimated blood loss was 25 mL (range: 25 to 250). The mean number of lymph nodes was 13 (range: 0 to 29). There was one conversion to hand-assisted laparoscopic colectomy and one to open colectomy secondary to bleeding. The mean hospital stay was 5 days (range: 3 to 7). Thirty-day postoperative complications included 1 wound infection, 1 patient with alcohol withdrawal, and 1 incidence of colitis caused by Clostridium difficile infection. At a median follow-up of 27 months, there were no local recurrences or distant metastases. One death occurred at 17 months from myocardial infarction. Two patients developed incisional hernias, with one requiring a laparoscopic hernia repair. One patient required a completion proctocolectomy for a pathological diagnosis of hyperplastic polyposis syndrome. CONCLUSIONS: Single-port laparoscopic right hemicolectomy has been safely performed in patients who are candidates for conventional laparoscopic hemicolectomy. This small series indicates that intermediate-term results are similar to conventional laparoscopic surgery in efficacy, safety, and oncological outcomes. Larger datasets are necessary to determine cost-effectiveness, differences in postoperative outcomes, and patient satisfaction. PMID- 23743367 TI - Vacation appendicitis. AB - OBJECTIVE: When someone plans a vacation, one of the last things taken into consideration is the possibility of contracting an illness while away. Unfortunately, if people develop abdominal pain while planning for a vacation, they usually proceed with the vacation and do not consider getting medical attention for their pain. The purpose of this study was to examine the effect of being on vacation and its association with ruptured appendicitis. METHODS: From January 1, 2007 to December 31, 2008, the incidence of ruptured appendicitis cases at Florida Hospital-Celebration Health, located 5 miles from Walt Disney World, was compared with that of Florida Hospital-Orlando, approximately 30 miles away from Walt Disney World. We evaluated whether patients "on vacation" versus residents of Orlando have an increased incidence of ruptured appendicitis. RESULTS: Of patients treated for presumed appendicitis, 60.59% at Florida Hospital-Celebration Health had ruptured appendicitis during this time versus 20.42% at Florida Hospital-Orlando. Of those 266 patients seen at Florida Hospital-Celebration Health, 155 were on vacation versus only 21 at Florida Hospital-Orlando. CONCLUSION: Although there is not a direct cause and effect, it is clear that there is a higher incidence of ruptured appendicitis in patients on vacation versus in the regular community in the Orlando, Florida area. PMID- 23743368 TI - Meta-analysis of laparoscopic versus open repair of perforated peptic ulcer. AB - BACKGROUND AND OBJECTIVES: Laparoscopic treatment of perforated peptic ulcer (PPU) has been introduced as an alternative procedure to open surgery. It has been postulated that the minimally invasive approach involves less operative stress and results in decreased morbidity and mortality. METHODS: We conducted a meta-analysis of randomized trials to test this hypothesis. Medline, EMBASE, and the Cochrane Central Register of Randomized Trials databases were searched, with no date or language restrictions. RESULTS: Our literature search identified 4 randomized trials, with a cumulative number of 289 patients, that compared the laparoscopic approach with open sutured repair of perforated ulcer. Analysis of outcomes did not favor either approach in terms of morbidity, mortality, and reoperation rate, although odds ratios seemed to consistently support the laparoscopic approach. Results did not determine the comparative efficiency and safety of laparoscopic or open approach for PPU. CONCLUSION: In view of an increased interest in the laparoscopic approach, further randomized trials are considered essential to determine the relative effectiveness of laparoscopic and open repair of PPU. PMID- 23743369 TI - Open versus laparoscopic hiatal hernia repair. AB - BACKGROUND: The literature reports the efficacy of the laparoscopic approach to paraesophageal hiatal hernia repair. However, its adoption as the preferred surgical approach and the risks associated with paraesophageal hiatal hernia repair have not been reviewed in a large database. METHOD: The Nationwide Inpatient Sample dataset was queried from 1998 to 2005 for patients who underwent repair of a complicated (the entire stomach moves into the chest cavity) versus uncomplicated (only the upper part of the stomach protrudes into the chest) paraesophageal hiatal hernia via the laparoscopic, open abdominal, or open thoracic approach. A multivariate analysis was performed controlling for demographics and comorbidities while looking for independent risk factors for mortality. RESULTS: In total, 23,514 patients met the inclusion criteria. By surgical approach, 55% of patients underwent open abdominal, 35% laparoscopic, and 10% open thoracic repairs. Length of stay was significantly reduced for all patients after laparoscopic repair (P < .001). Age >=60 years and nonwhite ethnicity were associated with significantly higher odds of death. Laparoscopic repair and obesity were associated with lower odds of death in the uncomplicated group. CONCLUSION: Laparoscopic repair of paraesophageal hiatal hernia is associated with a lower mortality in the uncomplicated group. However, older age and Hispanic ethnicity increased the odds of death. PMID- 23743370 TI - Costs and clinical outcomes of conventional single port and micro-laparoscopic cholecystectomy. AB - BACKGROUND AND OBJECTIVE: This study compares hospital costs and clinical outcomes for conventional laparoscopic, single-port, and mini-laparoscopic cholecystectomy from US hospitals. METHODS: Eligible patients were aged >=18 years and undergoing laparoscopic cholecystectomy with records in the Premier Hospital Database from 2009 through the second quarter of 2010. Patients were categorized into 3 groups-conventional laparoscopic, single port, or mini laparoscopic-based on the International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes and hospital charge descriptions for surgical tools used. A procedure was considered mini laparoscopic if no single-port surgery products were identified in the charge master descriptions and the patient record showed that at least 1 product measuring 5 mm was used, not more than 1 product measuring <5 mm was used, and the measurements of the other products identified equaled >5 mm. Summary statistics were generated for all 3 groups. Multivariable analyses were performed on hospital costs and clinical outcomes. Models were adjusted for demographics, patient severity, comorbid conditions, and hospital characteristics. RESULTS: In the outpatient setting, for single-port surgery, hospital costs were approximately $834 more than those for mini-laparoscopic surgery and $964 more than those for conventional laparoscopic surgery (P < .0001). Adverse events were significantly higher (P < .0001) for single-port surgery compared with mini laparoscopic surgery (95% confidence interval for odds ratio, 1.38-2.68) and single-port surgery versus conventional surgery (95% confidence interval for odds ratio, 1.37-2.35). Mini-laparoscopic surgery hospital costs were significantly (P < .0001) lower than the costs for conventional surgery by $211, and there were no significant differences in adverse events. CONCLUSIONS: These findings should inform practice patterns, treatment guidelines, and payor policy in managing cholecystectomy patients. PMID- 23743371 TI - Complications of liver resection: laparoscopic versus open procedures. AB - BACKGROUND AND OBJECTIVE: Minimally invasive surgery for liver resection remains controversial. This study was designed to compare open versus laparoscopic surgical approaches to liver resection. METHODS: We performed a single-center retrospective chart review. RESULTS: We compared 45 laparoscopic liver resections with 17 open cases having equivalent resections based on anatomy and diagnosis. The overall complication rate was 25.8%. More open resection patients had complications (52.9% vs 15.5%, P < .008). The conversion rate was 11.1%. The mean blood loss was 667.1 +/- 1450 mL in open cases versus 47.8 +/- 89 mL in laparoscopic cases (P < .0001). Measures of intravenous narcotic use, intensive care unit length of stay, and hospital length of stay all favored the laparoscopic group. Patients were more likely to have complications or morbidity in the open resection group than in the laparoscopic group for both the anterolateral (P < .085) and posterosuperior (P < .002) resection subgroups. CONCLUSION: In this series comparing laparoscopic and open liver resections, there were fewer complications, more rapid recovery, and lower morbidity in the laparoscopic group, even for those resections involving the posterosuperior segments of the liver. PMID- 23743372 TI - Robotic liver resection: initial experience with three-arm robotic and single port robotic technique. AB - BACKGROUND AND OBJECTIVE: Robotic-assisted surgery offers a solution to fundamental limitations of conventional laparoscopic surgery, and its use is gaining wide popularity. However, the application of this technology has yet to be established in hepatic surgery. METHODS: A retrospective analysis of our prospectively collected liver surgery database was performed. Over a 6-month period, all consecutive patients who underwent robotic-assisted hepatic resection for a liver neoplasm were included. Demographics, operative time, and morbidity encountered were evaluated. RESULTS: A total of 7 robotic-assisted liver resections were performed, including 2 robotic-assisted single-port access liver resections with the da Vinci-Si Surgical System (Intuitive Surgical Sunnyvalle, Calif.) USA. The mean age was 44.6 years (range, 21-68 years); there were 5 male and 2 female patients. The mean operative time (+/- SD) was 61.4 +/- 26.7 minutes; the mean operative console time (+/- SD) was 38.2 +/- 23 minutes. No conversions were required. The mean blood loss was 100.7 mL (range, 10-200 mL). The mean hospital stay (+/- SD) was 2 +/- 0.4 days. No postoperative morbidity related to the procedure or death was encountered. CONCLUSION: Our initial experience with robotic liver resection confirms that this technique is both feasible and safe. Robotic-assisted technology appears to improve the precision and ergonomics of single-access surgery while preserving the known benefits of laparoscopic surgery, including cosmesis, minimal morbidity, and faster recovery. PMID- 23743373 TI - Sleeve gastrectomy as a stand-alone bariatric operation for severe, morbid, and super obesity. AB - BACKGROUND: The laparoscopic sleeve gastrectomy (LSG) is emerging as an effective bariatric operation and is especially attractive in high-risk populations. In this study we examine the efficacy of LSG as a stand-alone operation in the veteran population. METHODS: This is a retrospective review of consecutive patients who underwent LSG as a stand-alone procedure at the Palo Alto Veterans Affairs medical center with a minimum 12-month follow-up. RESULTS: Of 205 patients undergoing bariatric surgery, 71 patients had a sleeve gastrectomy, 40 of whom had the operation performed at least 12 months previously. Thirty-six (90%) were available for 1-year follow-up, with a mean follow-up duration of 22 months (range: 12-42), a mean body mass index of 48.3 kg/m(2), and an 83% male population. Mean percent excess weight loss was 61% at an average of 22 months, with no significant difference between severely obese, morbidly obese, and super obese cohorts. Diabetes remission was seen in 56% of patients, hypertension remission in 51.6%, and obstructive sleep apnea remission in 46.4%, and gastroesophageal reflux disease improved or did not change in 83%. Medication use significantly decreased after surgery. CONCLUSION: LSG is safe and effective as a stand-alone bariatric operation in the high-risk veteran population. It is effective in severely obese, morbidly obese, and super obese patients. LSG induces remission or improvement in comorbidities of nearly all patients, translating to a decrease in medication use. PMID- 23743374 TI - Pancreaticojejunostomy sleeve reconstruction after pancreaticoduodenectomy in laparoscopic and open surgery. AB - INTRODUCTION: Laparoscopic procedures for pancreatic surgery have been significantly improved recently; however, only a limited number of successful laparoscopic or laparoscopy-assisted pancreaticoduodenectomy (PD) have been reported. The limitations could be attributed to the complexity of the reconstruction procedures under laparoscopic observation and the high incidence of complications. Postoperative pancreatic fistula (POPF) has been regarded traditionally as the most frequent major complication and is a potentially serious and life-threatening event. It remains the single most important cause of morbidity after PD and contributes significantly to prolonged mortality. Several modified methods of pancreas anastomosis were introduced to prevent POPF. However, few methods with a satisfactory leakage rate have yet to be seen. Collating principle of theoretical mechanics, we introduce a new method of reconstruction by performing an asymmetric sleeving-joint pancreaticojejunostomy (SJPJ). The aim of this study is to summarize the results of a new technique that is designed to decrease the POPF. METHODS: From January 2004 to December 2010, SJPJ was performed on 86 patients undergoing PD by 1 surgeon: a laparoscopic reconstruction was completed in 9 cases, a hand-assisted laparoscopic reconstruction in 2 cases, and an open SJPJ reconstruction in 75 cases. DISCUSSION: We used SJPJ, an asymmetric pancreaticojejunostomy (PJ). The time of operation ranged from 300 minutes to 640 minutes. Postoperatively there were no major morbidities and no deaths. Although POPF was observed in the laparoscopic SJPJ group with pancreatic adenocarcinoma, 3 patients developed POPF in the open SJPJ group with ampullary adenocarcinoma (n=1) and pancreatic adenocarcinoma (n=2). The POPF rate was 9.30% in the open SJPJ group and 9.10% in the laparoscopic SJPJ group. The SJPJ procedure facilitates PJ, both laparoscopically and in open surgery. It is safe, effective, and feasible in experience hands. PMID- 23743375 TI - Laparoscopic inguinal exploration and mesh placement for chronic pelvic pain. AB - BACKGROUND AND OBJECTIVE: Chronic pelvic pain affects 15% of women. Our objective was to evaluate empiric laparoscopic inguinal exploration and mesh placement in this population. METHODS: Retrospective cohort with follow-up questionnaire of women with lateralizing chronic pelvic pain (right or left), ipsilateral inguinal tenderness on pelvic examination, no clinical hernia on abdominal examination, and ipsilateral empiric laparoscopic inguinal exploration with mesh placement (2003-2009). Primary outcome was pain level at the last postoperative visit. Secondary outcomes were pain level and SF-36 scores from the follow-up questionnaire. RESULTS: Forty-eight cases met the study criteria. Surgery was done empirically for all patients, with only 7 patients (15%) found to have an ipsilateral patent processus vaginalis (shallow peritoneal dimple or a deeper defect (occult hernia)). Of 43 cases informative for the primary outcome, there was pain improvement in 15 patients (35%); pain improvement then return of the pain in 18 patients (42%); and pain unchanged in 9 patients (21%) and worse in 1 patient (2%). Improvement in pain was associated with a positive Carnett's test in the ipsilateral abdominal lower quadrant (P = .024). Thirteen patients returned the questionnaire (27%), and the pain was now described as improved in 9 patients (69%), unchanged in 4 patients (31%), and worse in none. Three SF-36 subscales showed improvement (physical functioning, social functioning, and pain). CONCLUSION: In select women with chronic pelvic pain, empiric laparoscopic inguinal exploration and mesh placement results in moderate improvement in outcome. A positive Carnett's test in the ipsilateral abdominal lower quadrant is a predictor of better outcome. PMID- 23743376 TI - Laparoscopic appendectomy in women without identifiable pathology undergoing laparoscopy for chronic pelvic pain. AB - OBJECTIVES: To assess the effectiveness of appendectomy in women undergoing laparoscopy for chronic pelvic pain without identifiable pathology. METHODS: This retrospective cohort study included women aged 15 to 50 years who underwent laparoscopic surgery for chronic pelvic pain without identifiable pathology. The cohort was divided into 2 groups: women who underwent appendectomy and women who had not undergone appendectomy at laparoscopic surgery. Postoperative pain was assessed at 6-week follow-up and by subsequent mailed questionnaire. RESULTS: Women who underwent appendectomy (n = 19) were significantly more likely to report improvement in pain at 6-week follow-up than women who did not undergo appendectomy (n = 76) (93% vs 16%; P < .001). Thirty-six patients (38%) responded to the questionnaire at a median of 4.2 years after surgery, when the median change (improvement) in reported pain was greater in the appendectomy group than in the nonappendectomy group. CONCLUSION: Appendectomy is effective therapy for patients with chronic pelvic pain of unknown etiology who are undergoing laparoscopy. PMID- 23743377 TI - A pilot feasibility multicenter study of patients after excision of endometriosis. AB - OBJECTIVE: To serve as a pilot feasibility study for a randomized study of excision versus ablation in the treatment of endometriosis by (1) estimating the magnitude of change in symptoms after excision only at multiple referral centers and (2) determining the proportion of women willing to participate in a randomized trial. METHODS: We performed a multicenter prospective study of women undergoing excision for endometriosis (Canadian Task Force class II-3) at Duke University Center for Endometriosis Research & Treatment (currently the Saint Louis University Center for Endometriosis), Center for Endometriosis Care, Northshore University Health System, Memorial University (Canada), and Florida Hospital. The study comprised 100 female patients, aged 18 to 55 years, with endometriosis-suspected pelvic pain. The intervention was laparoscopic excision only of the abnormal peritoneum suspicious for endometriosis. The main outcome measures were quality of life, pelvic pain, dysmenorrhea, dyspareunia, and bowel and bladder symptoms. RESULTS: The mean follow-up period was 8.5 months. Excision of endometriosis showed a significant reduction in all pain scores except bowel symptoms, as well as significant improvement in quality of life. Of the patients, 84% were willing to participate in a randomized study. CONCLUSIONS: Quality of life is a needed primary outcome for any randomized study comparing excision versus ablation. A multicenter comparative trial is feasible, although quality assurance would have to be addressed. Patients were willing to be randomized even at surgical referral centers. PMID- 23743378 TI - Robotic-assisted hysterectomy for the management of severe endometriosis: a retrospective review of short-term surgical outcomes. AB - OBJECTIVES: The primary objective was to examine the safety and feasibility of robotic-assisted laparoscopy in a cohort of women treated surgically for stage III and IV endometriosis. The secondary objective was to explore whether the stage of endometriosis affected surgical outcome. METHODS: In this cohort study, 43 women with severe endometriosis were treated with robot-assisted laparoscopic hysterectomy with unilateral or bilateral salpingooophorectomy for stage III (n = 19) or stage IV (n = 24) disease. RESULTS: Histopathologic evaluation confirmed endometriosis in all patients, and fibroids were also shown in 12 patients. The median actual operative time was 145 min (range, 67-325 min), and the median blood loss was 100 mL (range, 20 - 400 mL). All but one of the procedures were completed successfully robotically. The length of hospital stay was 1 d for 95% of patients (41 of 43), and 2 patients had prolonged stays of 4 d and 5 d, respectively. One patient was readmitted for a vaginal cuff abscess; this represented the only complication identified in this series. CONCLUSIONS: Robot assisted laparoscopic surgery appears to be a reasonably safe and feasible method for the definitive surgical management of women with severe endometriosis. PMID- 23743379 TI - Perioperative outcomes of robotic versus laparoscopic hysterectomy for benign disease. AB - BACKGROUND AND OBJECTIVES: We compared the perioperative outcomes of hysterectomy performed by robotic (RH) versus laparoscopic (LH) routes for benign indications using the Dindo-Clavien scale for classification of the surgical complications. METHODS: Retrospective chart review of all patients who underwent robotic (n=288) and laparoscopic (n=257) hysterectomies by minimally invasive surgeons at the University of Michigan from March 2001 until June 2010. RESULTS: Age, body mass index, operative time, and estimated blood loss were not statistically different between groups. The RH subgroup had a larger uterine weight (LH 186.4+/-130.6 g vs RH 234.9+/-193.9 g, P=.001), higher prevalence of severe adhesions (13.2% vs 23.3%, respectively, P=.003), and stage III-IV endometriosis (4.7% vs 15.3%, respectively, P<.05). There were no differences in the rates of Dindo-Clavien grade I, grade II, and grade III surgical complications between the RH and LH groups (9.7%, 13.2%, and 3.1%, respectively, in the RH group vs 6.2%, 9.3%, and 5.8%, respectively, in the LH group, P>.05). However, the rates of urinary tract infection were higher in the RH group (LH 2.7% vs RH 6.9%, P=.02), whereas the conversion to laparotomy rate was higher in the LH group (LH 6.2% vs RH 1.7%, P=.007). CONCLUSIONS: Perioperative outcomes for laparoscopic and robotic hysterectomy for benign indications appear to be equivalent. PMID- 23743380 TI - Postoperative patient satisfaction after laparoscopic supracervical hysterectomy. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate postoperative patient satisfaction in women after laparoscopic supracervical hysterectomy (LASH). METHODS: A retrospective study by a mailed questionnaire among 2334 women who underwent hysterectomy via LASH at the MIC-Klinik, Berlin, between 1998 and 2004 was conducted. Indications for LASH were uterus myomatosus, adenomyosis uteri, disorders of bleeding, and genital descensus. The LASH operation technique was standardized and remained consistent throughout the observation period. Pearson's test for metric variables, Spearman's rank correlation test for ordinal data, Mann-Whitney U test, and Kruskal-Wallis test were used. RESULTS: Of the 2334 questionnaires mailed, 1553 were returned and 1431 (61.3%) of those could be analyzed. Almost 94% (93.9%) of the women were highly satisfied with the outcome, 5.6% reported medium satisfaction, and 0.5% were not satisfied. There was no significant difference in patient satisfaction with regard to the different indication for LASH. CONCLUSION: This study demonstrates high postoperative patient satisfaction after LASH. The rate of highly satisfied women might be increased by carefully choosing the right indications for LASH and improving operation techniques. This is important for widening acceptance of this innovative new operation standard. PMID- 23743381 TI - Total microlaparoscopic radical hysterectomy in early cervical cancer. AB - BACKGROUND AND OBJECTIVE: In less than 2 decades, laparoscopy has contributed to modification in the management of early cervical cancer patients, and all comparisons between open and laparoscopic-based radical operations showed an identical oncological outcome. The aim of this study is to describe surgical instrumentations and technique to perform total microlaparoscopy radical hysterectomy in early cervical cancer patients and report our preliminary results in terms of operative time and perioperative outcomes. METHODS: Between January 1, 2012, and March 25, 2012, 4 consecutive early cervical cancer patients were enrolled in this study. RESULTS: We performed 3 type B2 and 1 type C1-B2 total microlaparoscopy radical hysterectomy, and in all cases concomitant bilateral salpingo-oophorectomy and pelvic lymphadenectomy were carried out. Median operative time was 165 minutes (range: 155 to 215) (mean: 186), and median estimated blood loss was 30 mL (range: 20 to 50). Median number of pelvic lymph nodes removed was 12 (range: 11 to 15). All procedures were completed without 5 mm port insertion and without conversion. No intraoperative or early postoperative complications were reported. CONCLUSIONS: This report suggests a role of microlaparoscopy in the surgical management of early cervical cancer with adequate oncological results, superimposable operative time, and perioperative outcomes with respect to standard laparoscopy. PMID- 23743382 TI - Comparison of robotic, laparoscopic, and abdominal myomectomy in a community hospital. AB - BACKGROUND AND OBJECTIVES: To evaluate the operative outcomes between robotic, laparoscopic, and abdominal myomectomies performed by a private gynecologic oncology practice in a suburban community hospital. METHODS: The medical records of 322 consecutive robotic, laparoscopic, and abdominal myomectomies performed from January 2007 through December 2009 were reviewed. The outcomes were collected from a retrospective review of patient medical records. RESULTS: Records for 14/322 (4.3%) patients were incomplete. Complete data were available for 308 patients, including 169 (54.9%) abdominal, 73 (23.7%) laparoscopic, and 66 (21.4%) robotic-assisted laparoscopic myomectomies. Patients were similar in age, body mass index, parity, and previous abdominopelvic surgery. Median operative time for robotic surgery (140 min) was significantly longer (P<.005) compared to laparoscopic (70 min) and abdominal (72 min) myomectomies. Robotic and laparoscopic myomectomies had significantly less estimated blood loss and hospital stay compared to abdominal myomectomies. There was no significant difference in complications or in the median size of the largest myoma removed between the different modalities. However, the median aggregate weight of myomas removed abdominally (200g; range, 1.4 to 2682) was significantly larger than that seen laparoscopically (115g; range, 1 to 602) and robotically (129g; range 9.4 to 935). Postoperative transfusion was significantly less frequent in robotic myomectomies compared to laparoscopic and abdominal myomectomies. CONCLUSION: While robotic-assisted laparoscopic myomectomies had longer operative times, laparoscopic and robotic assisted laparoscopic myomectomies demonstrated shorter hospital stays, less blood loss, and fewer transfusions than abdominal myomectomies. Robotic myomectomy offers a minimally invasive alternative for management of symptomatic myoma in a community hospital setting. PMID- 23743383 TI - Laparoscopic ureteroneocystostomy for ureteral injuries after hysterectomy. AB - OBJECTIVES: To examine the feasibility of early laparoscopic ureteroneocystostomy for ureteral obstruction due to hysterectomy injury. METHODS: We retrospectively reviewed a 10-y experience from 2 institutions in patients who underwent early (<30 d) or late (>30 d) laparoscopic ureteroneocystostomy for ureteral injury after hysterectomy. Evaluation of the surgery included the cause of the stricture and intraoperative and postoperative outcomes. RESULTS: A total of 9 patients with distal ureteral injury after hysterectomy were identified. All injuries were identified and treated as early as 21 d after hysterectomy. Seven of 9 patients underwent open hysterectomy, and the remaining patients had vaginal and laparoscopic radical hysterectomy. All ureteroneocystostomy cases were managed laparoscopically without conversion to open surgery and without any intraoperative complications. The Lich-Gregoir reimplantation technique was applied in all patients, and 2 patients required a psoas hitch. The mean operative time was 206.6 min (range, 120-280 min), the mean estimated blood loss was 122.2 cc (range, 25-350 cc), and the mean admission time was 3.3 d (range, 1 7 d). Cystography showed no urine leak when the ureteral stent was removed at 4 to 6 wk after the procedure. Ureteroneocystostomy patency was followed up with cystography at 6 mo and at least 10 y after ureteroneocystostomy. CONCLUSION: Early laparoscopic ureteral reimplantation may offer an alternative surgical approach to open surgery for the management of distal ureteral injuries, with favorable cosmetic results and recovery time from ureteral obstruction due to hysterectomy injury. PMID- 23743384 TI - Laparoscopic surgery for kidney orthotopic transplant in the pig model. AB - BACKGROUND AND OBJECTIVES: Laparoscopic surgery has rapidly expanded in surgical practice with well-accepted benefits of minimal incision, less analgesia, better cosmetics, and quick recovery. The surgical technique for kidney transplantation has remained unchanged since the first successful kidney transplant in the 1950s. Over the past decade, there were only a few case reports of kidney transplantation by laparoscopic or robotic surgery. Therefore, the aim of this study is to develop a laparoscopic technique for kidney transplantation at the region of the native kidney. METHODS: After initial development of the laparoscopic technique for kidney transplant in cadaveric pigs, 5 live pigs (Sus scrofa, weighing 45-50 kg) underwent laparoscopic kidney transplant under general anesthesia. First, laparoscopic donor nephrectomy was performed, and then the kidney was perfused and preserved with cold Ross solution. The orthotopic auto transplant was subsequently performed using the laparoscopic technique. The blood flow of the kidney graft was assessed using Doppler ultrasonography, and urine output was monitored. RESULTS: The laparoscopic kidney transplant was successful in 4 live pigs. Immediate urine output was observed in 3 pigs. The blood flow in the kidney was adequate, as determined using Doppler ultrasonography. CONCLUSION: It has been shown that laparoscopic kidney orthotopic transplant is feasible and safe in the pig model. Immediate kidney graft function can be achieved. A further study will be considered to identify the potential surgical morbidity and mortality after recovery in a pig model before translating the technique to clinical human kidney transplantation. PMID- 23743385 TI - Laparoscopic excision of splenic artery aneurysm. AB - INTRODUCTION: Splenic artery aneurysm is more frequently diagnosed today with the advancement and liberal use of imaging modalities. A symptomatic aneurysm, an aneurysm of any diameter in a pregnant woman or a woman of childbearing age, and an aneurysm >2 cm are all strong indications for surgery because of a significantly increased risk for splenic artery rupture. CASE DESCRIPTION: A 35 year-old, morbidly obese, African American woman presented with constant left flank pain for 4 weeks. Angiography confirmed a 2.5-cm splenic artery aneurysm near the splenic hilum. Because angioembolization was unlikely to succeed because of extensive collaterals and the aneurysm's proximity to the splenic hilum, laparoscopic excision of the aneurysm with splenectomy was performed. DISCUSSION: We report the successful laparoscopic surgical treatment of a 2.5-cm splenic artery aneurysm. Any splenic artery aneurysm with a significantly increased risk of rupture requires a prompt intervention. Although percutaneous embolization of the splenic artery is the most frequently applied therapy today, surgical repair is preferred for all symptomatic aneurysms because of the greater likelihood of success. PMID- 23743386 TI - Transvaginal liver surgery using a tethered magnet and a laparoscopic rein. AB - INTRODUCTION: A novel technique was used to remove a large liver cyst via culdolaparoscopy. CASE DESCRIPTION: We used laparoscopic instruments, a gastroscope, a laparoscopic rein, and magnets. The magnets consist of an external magnet and a specially modified tethered neodymium internal magnet, safe for use in transvaginal endoscopic surgery. DISCUSSION: These technologies offer some advantages when they are used together: magnets and the rein to aid in exposure, traction-retraction, and triangulation. Previous reports have been published on the removal of benign liver lesions transvaginally, but none to date has involved the use of magnets. This article reports on the role of magnets and reins in an incision reduction approach to the removal of a liver cyst. PMID- 23743387 TI - Gallstone-related abdominal abscess 8 years after laparoscopic cholecystectomy. AB - BACKGROUND: A common intraoperative complication during laparoscopic cholecystectomy is gallbladder perforation with spillage of gallstones. The undesirable consequence of spilled gallstones is the formation of abscesses months or years after an operation. CASE DESCRIPTION: Our clinical report describes an intraabdominal abscess formation in an 82-year-old man that developed 8 years after a laparoscopic cholecystectomy. A computed tomography scan of the abdomen showed an elongated fluid collection in the right abdominal compartment musculature at the level of the internal oblique muscle. Abdominal ultrasonography confirmed a large fluid collection, with 2 echogenic masses in the dependent portion. Incision and drainage of the abscess were performed, and 2 gallstones were found. CONCLUSION: Any unusual collection of fluid in the perihepatic space and abdominal wall in the area of the surgical incision in a patient with a remote history of cholecystectomy should be evaluated for abscess related to retained gallstone. Early abscess formation is usually diagnosed and treated by the surgeon. However, the late manifestation might be a clinical problem seen in the primary care physician's office. Therefore, the primary care physician should incorporate diagnosis of gallstone related abscess in patients with abdominal abscess formation of unknown etiology. PMID- 23743388 TI - Laparoscopic completion cholecystectomy and common bile duct exploration for retained gallbladder after single-incision cholecystectomy. AB - BACKGROUND: Recent enthusiasm in the surgical community for less invasive surgical approaches has resulted in widespread application of single-incision techniques. This has been most commonly applied in laparoscopic cholecystectomy in general surgery. Cosmesis appears to be improved, but other advantages remain to be seen. Feasibility has been demonstrated, but there is little description in the current literature regarding complications. PATIENT AND METHODS: We report the case of a patient who previously underwent single-incision laparoscopic cholecystectomy for symptomatic gallstone disease. After a brief symptom-free interval, she developed acute pancreatitis. At evaluation, imaging results of ultrasonography and magnetic resonance cholangiopancreatography demonstrated a retained gallbladder with cholelithiasis. The patient was subsequently referred to our hospital, where she underwent further evaluation and surgical intervention. RESULTS: Our patient underwent 4-port laparoscopic remnant cholecystectomy with transcystic common bile duct exploration. Operative exploration demonstrated a large remnant gallbladder and a partially obstructed cystic duct with many stones. Transcystic exploration with balloon extraction resulted in duct clearance. The procedure took 75 minutes, with minimal blood loss. The patient's postoperative course was uneventful. Final pathology results demonstrated a remnant gallbladder with cholelithiasis and cholecystitis. CONCLUSION: This report is the first in the literature to describe successful laparoscopic remnant cholecystectomy and transcystic common bile duct exploration after previous single-port cholecystectomy. Although inadvertent partial cholecystectomy is not unique to this technique, single-port laparoscopic procedures may result in different and significant complications. PMID- 23743389 TI - Catastrophic bleeding from a marginal ulcer after gastric bypass. AB - Marginal ulceration at the gastrojejunal anastomosis is a common complication following Roux-Y gastric bypass (RYGB). Hemodynamically significant hemorrhagic marginal ulcers are usually treated either endoscopically or surgically. We describe a unique case of life-threatening hemorrhagic marginal ulcer eroding into the main splenic artery. This condition was initially managed with angiographic embolization, followed by surgical intervention. PMID- 23743390 TI - Endoclip closure of a large colonic perforation following colonoscopic leiomyoma excision. AB - BACKGROUND AND OBJECTIVE: Endoscopic removal of large colonic submucosal lesions can lead to a higher risk of perforation. Although not as common following diagnostic and therapeutic colonoscopy, it does occur more often following therapeutic colonoscopy. We present a case of a large submucosal mass excised endoscopically, resulting in a large perforation that was closed using endoclips. While endoclips are typically used for smaller perforations, we have found that they can be used safely on a larger defect. METHODS: A 68-y-old woman presented with a 2.9-cm benign submucosal mass found in the hepatic flexure. It was removed via endoscopic polypectomy, leaving a perforation of 3cm x 3cm. The perforation was closed with endoscopic clips. RESULTS: Histology of the specimen showed clear margins. At 4-wk follow-up, the patient had no complications. A colonoscopy at 6 mo follow-up showed only a scar at the procedure site with no complaints. CONCLUSIONS: Large iatrogenic colonic perforations can be managed successfully using endoclips, particularly in a prepped colon. PMID- 23743391 TI - Robotic repair of uterine dehiscence. AB - BACKGROUND AND OBJECTIVES: During the past few decades, there has been a significant increase in the number of cesarean deliveries, and thus an increase in the number of complications. A common complication of multiple cesarean deliveries is symptomatic uterine scar dehiscence, for which there are no treatment guidelines available. We report a case of uterine scar dehiscence-the repair of it by robotic surgery-and review the literature on this defect. CASE: The patient was a 39-year-old woman, gravida 4 para 2022, complaining of persistent vaginal spotting for the prior 5 months with a history of a cesarean delivery 3 months before the onset of the symptoms. DISCUSSION: We report a case of a successful robotic repair of a symptomatic cesarean scar defect. CONCLUSION: We propose further studies that include more patients so this technique may become the standard for cesarean scar defect. PMID- 23743392 TI - Laparoscopic removal of abdominal cerclage at 19 weeks' gestation. AB - We discuss laparoscopic removal of an abdominal cerclage in a 39-year-old woman, gravida 4, para 0, abortus 3, who presented at 19 weeks' gestation with ruptured membranes. This patient had a failed previous vaginal cerclage. An abdominal cerclage was performed at the time of abdominal myomectomy. A subsequent pregnancy was diagnosed, with ruptured membranes at 19 weeks' gestation, and the patient opted for pregnancy termination. After laparoscopic removal of the cerclage, cervical laminaria were placed, and the patient underwent an uncomplicated dilation and curettage procedure the following day. PMID- 23743393 TI - Single-incision laparoscopic adnexectomy in an obese patient with previous laparotomies. AB - INTRODUCTION: No case of single-incision laparoscopic surgery in obese patients who had previously undergone multiple midline vertical laparotomies has been described in the literature to date. Hence we report the first case of single port laparoscopic salpingo-oophorectomy in an obese patient who was affected by a left adnexal mass and who had previously undergone 3 midline vertical laparotomies. CASE DESCRIPTION: A postmenopausal 57-year-old woman with a body mass index of 31.2 kg/m(2) and a history of 3 midline vertical cesarean deliveries and a right salpingooophorectomy was diagnosed with a left adnexal mass and underwent a single-incision laparoscopic salpingo-oophorectomy. DISCUSSION: The patient was treated successfully. The operative blood loss was minimal. The postoperative hospital stay lasted 18 hours, and postoperative pain was short-lasting. No early or long-term postoperative complications were registered. On histopathologic examination, a diagnosis of ovarian serous cystadenoma was made. Even though this unique case is the first to be reported in the literature, its encouraging results suggest the use of this new surgical technique in similar clinical situations to verify whether the feasibility and safety reported in this article are confirmed. PMID- 23743394 TI - Small bowel injury during laparoendoscopic single-site surgery for simple nephrectomy. AB - BACKGROUND AND OBJECTIVES: A 71-year-old man underwent a right simple nephrectomy via the laparoendoscopic single-site surgery (LESS) approach for intractable right flank pain and gross hematuria. A postoperative diagnosis of duodenal injury was suspected by physical findings and confirmed by computed tomography imaging. METHODS: Emergency exploratory laparotomy revealed a <5-mm full thickness perforation of the duodenum and an accompanying 1-cm seromuscular injury. RESULTS: The subsequent postoperative course was unremarkable except for a right intraabdominal seroma that resolved without intervention. CONCLUSION: LESS nephrectomy is an effective surgical approach, but more data are needed regarding its surgical outcomes and complications. This case shows that the LESS approach is not without the risk of life-threatening complications, and it must be performed by experienced surgeons in select patients who are notably interested in improved cosmesis, after an informed consent that includes the potential for complications. PMID- 23743395 TI - Contrasting effects of fatigue on multifinger coordination in young and older adults. AB - We investigated the effects of fatigue produced by timed maximal voluntary contraction (MVC) of the index finger of the right hand on performance in MVC and accurate cyclic force production tasks in right-handed young (Young group) and strength-matched elderly (Elderly group) participants. We hypothesized that, before fatigue, the Elderly group would show weaker force-stabilizing synergies and smaller adaptive changes in the synergy index during fatigue. Synergies were defined as covaried adjustments of neural commands to fingers (finger modes) across trials that stabilize total force. Fatigue caused a significant reduction in the MVC, which was larger in the Young group compared with the Elderly group for both fatigued finger (index finger) and four fingers (index, middle, ring, and little fingers pressing together). Indexes of finger enslaving (lack of individuation) increased with fatigue in both groups. The index of force stabilizing synergies was similar for the two groups before fatigue, while its increase with fatigue was significantly larger in the Elderly group compared with the Young group. We infer that changes in the indexes of finger interaction (enslaving) and coordination (synergy) with age seem to be correlated with changes in muscle strength. This correlation may be causally related to the progressive death of neurons at different levels of the neuromotor hierarchy. The surprisingly large changes in the synergy index with fatigue in older adults suggest that, by itself, aging does not necessarily lead to impairment in synergic control. Strength training may be a method to avoid age-related decrement in finger interaction and coordination. PMID- 23743396 TI - Diastolic chamber properties of the left ventricle assessed by global fitting of pressure-volume data: improving the gold standard of diastolic function. AB - In cardiovascular research, relaxation and stiffness are calculated from pressure volume (PV) curves by separately fitting the data during the isovolumic and end diastolic phases (end-diastolic PV relationship), respectively. This method is limited because it assumes uncoupled active and passive properties during these phases, it penalizes statistical power, and it cannot account for elastic restoring forces. We aimed to improve this analysis by implementing a method based on global optimization of all PV diastolic data. In 1,000 Monte Carlo experiments, the optimization algorithm recovered entered parameters of diastolic properties below and above the equilibrium volume (intraclass correlation coefficients = 0.99). Inotropic modulation experiments in 26 pigs modified passive pressure generated by restoring forces due to changes in the operative and/or equilibrium volumes. Volume overload and coronary microembolization caused incomplete relaxation at end diastole (active pressure > 0.5 mmHg), rendering the end-diastolic PV relationship method ill-posed. In 28 patients undergoing PV cardiac catheterization, the new algorithm reduced the confidence intervals of stiffness parameters by one-fifth. The Jacobian matrix allowed visualizing the contribution of each property to instantaneous diastolic pressure on a per patient basis. The algorithm allowed estimating stiffness from single-beat PV data (derivative of left ventricular pressure with respect to volume at end diastolic volume intraclass correlation coefficient = 0.65, error = 0.07 +/- 0.24 mmHg/ml). Thus, in clinical and preclinical research, global optimization algorithms provide the most complete, accurate, and reproducible assessment of global left ventricular diastolic chamber properties from PV data. Using global optimization, we were able to fully uncouple relaxation and passive PV curves for the first time in the intact heart. PMID- 23743397 TI - Short-term acetaminophen consumption enhances the exercise-induced increase in Achilles peritendinous IL-6 in humans. AB - Through an unknown mechanism, the cyclooxygenase inhibitor and antipyretic acetaminophen (APAP) alters tendon mechanical properties in humans when consumed during exercise. Interleukin-6 (IL-6) is produced by tendon during exercise and is a potent stimulator of collagen synthesis. In nontendon tissue, IL-6 is upregulated in the presence of cyclooxygenase inhibitors and may contribute to alterations in extracellular matrix turnover, possibly due to inhibition of prostaglandin E2 (PGE2). We evaluated the effects of APAP on IL-6 and PGE2 in human Achilles peritendinous tissue after 1 h of treadmill exercise. Subjects were randomly assigned to a placebo (n = 8, 26 +/- 1 yr) or APAP (n = 8, 25 +/- 1 yr) group. Each subject completed a nonexercise and exercise experiment consisting of 6 h of microdialysis. Drug (APAP, 1,000 mg) or placebo was administered in a double-blind manner during both experiments. PGE2 and IL-6 were determined via enzyme immunoassay and APAP via high-performance liquid chromatography. In subjects given APAP, peritendinous APAP levels increased to 4.08 +/- 0.65 MUg/ml (P < 0.05). PGE2 did not increase with exercise in either group (P > 0.05), nor was PGE2 significantly reduced in the APAP group. IL-6 levels increased with exercise in both groups (P < 0.05), but this increase was greater in the APAP group (P < 0.05). Our findings suggest that APAP enhances tendon IL-6 production after exercise. Peak levels of APAP obtained in the peritendinous space were twofold lower than values reported in plasma or skeletal muscle. These findings provide insight into the effects of APAP on tendon and provide novel information on the kinetics of APAP in tendon tissue after oral APAP consumption. PMID- 23743398 TI - Does hypercapnia-induced impairment of cerebral autoregulation affect neurovascular coupling? A functional TCD study. AB - Neurovascular coupling (NVC) and dynamic cerebral autoregulation (dCA) are both impaired in the acute phase of ischemic stroke, but their reciprocal interactions are difficult to predict. To clarify these aspects, the present study explored NVC in a healthy volunteer population during a surrogate state of impaired dCA induced by hypercapnia. This study aimed to test whether hypercapnia leads to a depression of NVC through an impairment of dCA. Continuous recordings of middle cerebral arteries cerebral blood flow velocity (CBFv), blood pressure (BP), heart rate, and end-tidal CO2 were performed in 19 right-handed subjects (aged >45 yr) before, during, and after 60 s of a passive paradigm during normocapnia and hypercapnia. The CBFv response was broken down into subcomponents describing the relative contributions of BP (VBP), critical closing pressure (VCrCP), and resistance area product (VRAP). VRAP reflects myogenic activity in response to BP changes, whereas VCrCP is more indicative of metabolic control. The results revealed that hypercapnia significantly affected NVC, with significant reductions in the relative contribution of VCrCP to the paradigm-induced increase in CBFv. The present study suggests that hypercapnia impairs both dCA and NVC, probably acting through an impairment of the metabolic component of CBF control. PMID- 23743399 TI - Registration-based assessment of regional lung function via volumetric CT images of normal subjects vs. severe asthmatics. AB - The purpose of this work was to explore the use of image registration-derived variables associated with computed tomographic (CT) imaging of the lung acquired at multiple volumes. As an evaluation of the utility of such an imaging approach, we explored two groups at the extremes of population ranging from normal subjects to severe asthmatics. A mass-preserving image registration technique was employed to match CT images at total lung capacity (TLC) and functional residual capacity (FRC) for assessment of regional air volume change and lung deformation between the two states. Fourteen normal subjects and thirty severe asthmatics were analyzed via image registration-derived metrics together with their pulmonary function test (PFT) and CT-based air-trapping. Relative to the normal group, the severely asthmatic group demonstrated reduced air volume change (consistent with air trapping) and more isotropic deformation in the basal lung regions while demonstrating increased air volume change associated with increased anisotropic deformation in the apical lung regions. These differences were found despite the fact that both PFT-derived TLC and FRC in the two groups were nearly 100% of predicted values. Data suggest that reduced basal-lung air volume change in severe asthmatics was compensated by increased apical-lung air volume change and that relative increase in apical-lung air volume change in severe asthmatics was accompanied by enhanced anisotropic deformation. These data suggest that CT-based deformation, assessed via inspiration vs. expiration scans, provides a tool for distinguishing differences in lung mechanics when applied to the extreme ends of a population range. PMID- 23743400 TI - Ankle morphology amplifies calcaneus movement relative to triceps surae muscle shortening. AB - The present study investigated the mechanical role of the dorsoventral curvature of the Achilles tendon in the conversion of the shortening of the plantarflexor muscles into ankle joint rotation. Dynamic, sagittal-plane magnetic resonance spin-tagged images of the ankle joint were acquired in six healthy subjects during both passive and active plantarflexion movements driven by a magnetic resonance compatible servomotor-controlled foot-pedal device. Several points on these images were tracked to determine the 1) path and deformation of the Achilles tendon, 2) ankle's center of rotation, and 3) tendon moment arms. The degree of mechanical amplification of joint movement was calculated as the ratio of the displacements of the calcaneus and myotendinous junction. In plantarflexion, significant deflection of the Achilles tendon was evident in both the passive (165.7 +/- 7.4 degrees ; 180 degrees representing a straight tendon) and active trials (166.9 +/- 8.8 degrees ). This bend in the dorsoventral direction acts to move the Achilles tendon closer to the ankle's center of rotation, resulting in an ~5% reduction of moment arm length. Over the entire range of movement, the overall displacement of the calcaneus exceeded the displacement of the myotendinous junction by ~37%, with the mechanical gains being smaller in dorsi- and larger in plantarflexed joint positions. This is the first study to assess noninvasively and in vivo using MRI the curvature of the Achilles tendon during both passive and active plantarflexion movements. The dorsoventral tendon curvature amplifies the shortening of the plantarflexor muscles, resulting in a greater displacement of the tendon's insertion into the calcaneus compared with its origin. PMID- 23743401 TI - To beet or not to beet? PMID- 23743402 TI - Shunt volume dynamics in stroke patients with patent foramen ovale. AB - A variation in right atrial and pulmonary arterial pressure might result in a shunt dynamic across a patent foramen ovale (PFO). In the present study we tested if peak exercise facilitates a restoration of right to left shunt (RLS) in stroke patients who demonstrated a functional PFO closure (no evidence of RLS across an initially demonstrated PFO). In stroke patients with PFO demonstrating a functional closure, the RLS was reassessed on peak exercise using contrast enhanced transcranial Doppler sonography. The exercise procedure consisted of a cardiopulmonary exercise test with supplementary stress echocardiography for assessment of pulmonary circulation. Four stroke patients with initially PFO curtain pattern and a subsequent functional PFO closure (no evidence for RLS) underwent the procedure. In all four patients a RLS could be resurrected during peak physical exercise after a Valsalva strain. While in two patients peak exercise led to an RLS in a countable range of microembolic signals, in two patients a curtain pattern was obtained. One patient showed evidence for reoccurrence of RLS on peak exercise without a Valsalva strain. The patients with curtain pattern had a better peak exercise performance. Although the systolic pulmonary arterial pressure increased during exercise in all patients, there was no direct correlation with the detected RLS. After a functional PFO closure peak exercise combined with a Valsalva strain facilitates the reoccurrence of RLS in stroke patients. PMID- 23743403 TI - Removal of sedimentation decreases relative deposition of coarse particles in the lung periphery. AB - Lung deposition of >0.5-MUm particles is strongly influenced by gravitational sedimentation, with deposition being reduced in microgravity (MUG) compared with normal gravity (1G). Gravity not only affects total deposition, but may also alter regional deposition. Using gamma scintigraphy, we measured the distribution of regional deposition and retention of radiolabeled particles ((99m)Tc-labeled sulfur colloid, 5-MUm diameter) in five healthy volunteers. Particles were inhaled in a controlled fashion (0.5 l/s, 15 breaths/min) during multiple periods of MUG aboard the National Aeronautics and Space Administration Microgravity Research Aircraft and in 1G. In both cases, deposition scans were obtained immediately postinhalation and at 1 h 30 min, 4 h, and 22 h postinhalation. Regional deposition was characterized by the central-to-peripheral ratio and by the skew of the distribution of deposited particles on scans acquired directly postinhalation. Relative distribution of deposition between the airways and the alveolar region was derived from data acquired at the various time points. Compared with inhalation in 1G, subjects show an increase in central-to peripheral ratio (P = 0.043), skew (P = 0.043), and tracheobronchial deposition (P < 0.001) when particles were inhaled in MUG. The absence of gravity caused fewer particles to deposit in the lung periphery than in the central region where deposition occurred mainly in the airways in MUG. Furthermore, the increased skew observed in MUG likely illustrates the presence of localized areas of deposition, i.e., "hot spots", resulting from inertial impaction. In conclusion, gravity has a significant effect on deposition patterns of coarse particles, with most of deposition occurring in the alveolar region in 1G but in the large airways in MUG. PMID- 23743404 TI - Oral sapropterin acutely augments reflex vasodilation in aged human skin through nitric oxide-dependent mechanisms. AB - Functional constitutive nitric oxide synthase (NOS) and its cofactor tetrahydrobiopterin (BH4) are required for full reflex cutaneous vasodilation and are attenuated in primary aging. Acute, locally administered BH4 increases reflex vasodilation through NO-dependent mechanisms in aged skin. We hypothesized that oral sapropterin (Kuvan, shelf-stable pharmaceutical formulation of BH4) would augment reflex vasodilation in aged human skin during hyperthermia. Nine healthy human subjects (76 +/- 1 yr) ingested sapropterin (10 mg/kg) or placebo in a randomized double-blind crossover design. Venous blood samples were collected prior to, and 3 h following, ingestion of sapropterin for measurement of plasma BH4. Three intradermal microdialysis fibers were placed in the forearm skin for local delivery of 1) lactated Ringer's solution, 2) 10 mM BH4, and 3) 20 mM N(G) nitro-l-arginine methyl ester (l-NAME) to inhibit NOS. Red cell flux was measured at each site by laser-Doppler flowmetry (LDF) as reflex vasodilation was induced using a water-perfused suit. At 1 degrees C rise in oral temperature, mean body temperature was clamped and 20 mM l-NAME was perfused at each site. Cutaneous vascular conductance was calculated (CVC = LDF/MAP) and expressed as a percentage of maximum (%CVCmax 28 mM sodium nitroprusside and local heat 43 degrees C). Plasma concentrations of BH4 were significantly elevated 3 h after ingestion of sapropterin (0 h: 19.1 +/- 2 pmol/ml vs. 3 h: 43.8 +/- 3 pmol/ml; P < 0.001). Sapropterin increased NO-dependent vasodilation at control site (placebo: 14 +/- 1 %CVCmax vs. sapropterin: 25 +/- 4 %CVCmax; P = 0.004). Local BH4 administration increased NO-dependent vasodilation compared with control in placebo trials only (control: 14 +/- 1 %CVCmax vs. BH4-treated: 24 +/- 3 %CVCmax; P = 0.02). These data suggest oral sapropterin increases bioavailable BH4 in aged skin microvasculature sufficiently to increase NO synthesis through NOS and that sapropterin may be a viable intervention to increase skin blood flow during hyperthermia in healthy aged humans. PMID- 23743405 TI - A novel method to produce solid lipid nanoparticles using n-butanol as an additional co-surfactant according to the o/w microemulsion quenching technique. AB - Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) are novel medicinal carriers for controlled drug release and drug targeting in different roots of administration such as parenteral, oral, ophthalmic and topical. These carriers have some benefits such as increased drug stability, high drug payload, the incorporation of lipophilic and hydrophilic drugs, and no biotoxicity. Therefore, due to the cost-efficient, proportionally increasable, and reproducible preparation of SLN/NLC and the avoidance of organic solvents used, the warm microemulsion quenching method was selected from among several preparation methods for development in this research. To prepare the warm O/W microemulsion, lipids (distearin, stearic acid, beeswax, triolein alone or in combination with others) were melted at a temperature of 65 degrees C. After that, different ratios of Tween60 (10-22.5%) and glyceryl monostearate (surfactant and co-surfactant) and water were added, and the combination was stirred. Then, 1-butanol (co-surfactant) was added dropwise until a clear microemulsion was formed and titration continued to achieve cloudiness (to obtain the microemulsion zone). The warm o/w microemulsions were added dropwise into 4 degrees C water (1:5 volume ratio) while being stirred at 400 or 600 rpm. Lipid nanosuspensions were created upon the addition of the warm o/w microemulsion to the cold water. The SLN were obtained over a range of concentrations of co surfactants and lipids and observed for microemulsion stability (clearness). For selected preparations, characterization involved also determination of mean particle size, polydispersity and shape. According to the aim of this study, the optimum formulations requiring the minimum amounts of 1-butanol (1.2%) and lower temperatures for creation were selected. Mono-disperse lipid nanoparticles were prepared in the size range 77 +/- 1 nm to 124 +/- 21 nm according to a laser diffraction particle size analyzer and transmission electron microscopy. This method for preparing lipid nanoparticles by warm o/w microemulsion quenching was found to be more cost efficient and proportionally increasable in comparison with other preparation methods such as high pressure homogenization. These lipid nanoparticles, due to the combination of hard lipids with soft and/or liquid lipids, become good candidates for a wide range of medicaments as carriers for pharmaceutical and medicinal purposes. PMID- 23743407 TI - Social media likes and dislikes. PMID- 23743406 TI - Entrapment neuropathies and polyneuropathies in joint hypermobility syndrome/Ehlers-Danlos syndrome. AB - OBJECTIVE: This study aims to investigate the involvement of the peripheral nervous system in Ehlers-Danlos syndromes/hypermobility type patients with particular attention to entrapment syndromes. METHODS: We consecutively enrolled Ehlers-Danlos syndromes/hypermobility type patients. Patients underwent clinical, neurophysiological and ultrasound evaluations. Dynamic ultrasound evaluation was also performed in healthy subjects as control group. RESULTS: Fifteen Ehlers Danlos syndromes/hypermobility type patients and fifteen healthy subjects were enrolled. Most of patients presented tingling, numbness, cramps in their hands or feet. Clinical evaluation was normal in all patients. One patient was affected with carpal tunnel syndrome and one with ulnar nerve entrapment at elbow. One patient had an increased and hypoechoic ulnar nerve at elbow at ultrasound evaluation. Dynamic ultrasound evaluation of ulnar nerve at elbow showed, in patients, twelve subluxations and three luxations. In the control group dynamic evaluation showed one case of ulnar nerve luxation. CONCLUSION: Statistical analysis showed a significant difference in the occurrence of ulnar nerve subluxation and luxation between patients and control subjects. SIGNIFICANCE: The study shows an inconsistency between symptoms and neurophysiological and ultrasound evidences of focal or diffuse nerve involvement. The high prevalence of ulnar nerve subluxation/luxation at elbow in Ehlers-Danlos syndromes/hypermobility type patients could be explained by the presence of Osborne ligament laxity. PMID- 23743408 TI - Animal curiosity. PMID- 23743409 TI - Ciliary secretion: switching the cellular antenna to 'transmit'. AB - Cilia are microtubule/membrane-based protrusions that mediate cell motility or transduce sensory information. New work in Chlamydomonas demonstrates that cilia can also act as secretory organelles by budding enzyme-containing vesicles from the flagellar membrane for post-mitotic hatching of daughters from the mother cell wall. PMID- 23743410 TI - Coral reefs: building a better crystal ball. AB - Reef corals are ancient taxa, yet they are highly sensitive to environmental change. Recent research indicates that unless global CO2 emissions are dramatically reduced, we are just decades away from the collapse of coral reef ecosystems. PMID- 23743411 TI - Genetics: swinging ciliates' seven sexes. AB - Ciliates are well known for their unusual tricks of nuclear remodeling. A roulette-like method for mating type choice in Tetrahymena adds an interesting new twist to their repertoire. PMID- 23743412 TI - Object recognition: visual crowding from a distance. AB - Immediately before a large eye movement, a target object is crowded by clutter near the target's future location. This new finding, from a recent study, shows that the brain's remapping for the anticipated eye movement unavoidably combines features from the target's current and future retinal locations into one perceptual object. PMID- 23743413 TI - Plant cytoskeleton: DELLA connects gibberellins to microtubules. AB - A new study reveals that DELLA proteins directly interact with the prefoldin complex, thus regulating tubulin subunit availability in a gibberellin-dependent manner. This finding provides a mechanistic link between the growth-promoting plant hormone gibberellin and cortical microtubule organization. PMID- 23743414 TI - Neuropeptide signaling: from the gut. AB - In the defecation motor program of Caenorhabditis elegans, a pacemaker rhythm generated by the intestine leads to the activation of motor neurons controlling enteric muscle contraction. A new study demonstrates that this signal is conveyed by a neuropeptide that is released from intestinal cells and acutely depolarizes the motorneurons, acting much like a classical neurotransmitter. PMID- 23743415 TI - Visual perception: one world from two eyes. AB - Binocular vision requires us to match up the different views of the world seen by each eye. Computational models of primary visual cortex describe how the brain begins this process. Recurrent connections help suppress the response to false matches. PMID- 23743416 TI - Social evolution: reciprocity there is. AB - The theory of cooperation predicts that altruism can be established by reciprocity, yet empirical evidence from nature is contentious. Increasingly though, experimental results from social vertebrates challenge the nearly exclusive explanatory power of relatedness for the evolution of cooperation. PMID- 23743417 TI - Learning without training. AB - Achieving high-level skills is generally considered to require intense training, which is thought to optimally engage neuronal plasticity mechanisms. Recent work, however, suggests that intensive training may not be necessary for skill learning. Skills can be effectively acquired by a complementary approach in which the learning occurs in response to mere exposure to repetitive sensory stimulation. Such training-independent sensory learning induces lasting changes in perception and goal-directed behaviour in humans, without any explicit task training. We suggest that the effectiveness of this form of learning in different sensory domains stems from the fact that the stimulation protocols used are optimized to alter synaptic transmission and efficacy. While this approach directly links behavioural research in humans with studies on cellular plasticity, other approaches show that learning can occur even in the absence of an actual stimulus. These include learning through imagery or feedback-induced cortical activation, resulting in learning without task training. All these approaches challenge our understanding of the mechanisms that mediate learning. Apparently, humans can learn under conditions thought to be impossible a few years ago. Although the underlying mechanisms are far from being understood, training-independent sensory learning opens novel possibilities for applications aimed at augmenting human cognition. PMID- 23743418 TI - How does physician BMI impact patient trust and perceived stigma? AB - OBJECTIVE: The objective is to evaluate whether physician body mass index (BMI) impacts their patients' trust or perceptions of weight-related stigma. METHODS: We used a national cross-sectional survey of 600 non-pregnant overweight and obese patients conducted between April 5 and April 13, 2012. The outcome variables were patient trust (overall and by type of advice) and patient perceptions of weight-related stigma. The independent variable of interest was primary care physician (PCP) BMI. We conducted multivariate regression analyses to determine whether trust or perceived stigma differed by physician BMI, adjusting for covariates. RESULTS: Patients reported high levels of trust in their PCPs, regardless of the PCPs body weight (normal BMI=8.6; overweight=8.3; obese=8.2; where 10 is the highest). Trust in diet advice was significantly higher among patients seeing overweight PCPs as compared to normal BMI PCPs (87% vs. 77%, p=0.04). Reports of feeling judged by their PCP were significantly higher among patients seeing obese PCPs (32%; 95% confidence interval (CI): 23 41) as compared to patients seeing normal BMI PCPs (14%; 95% CI: 7-20). CONCLUSION: Overweight and obese patients generally trust their PCP, but they more strongly trust diet advice from overweight PCPs as compared to normal BMI PCPs. PMID- 23743419 TI - Evaluation of the efficacy of selamectin spot-on in cats infested with Aelurostrongylus abstrusus (Strongylida, Filariodidae) in a Central Italy cat shelter. AB - In recent years Aelurostrongylus abstrusus has often been reported in Italy. This lungworm is very common in cat colonies due to its route of transmission. Deciding a therapeutic approach can be difficult in such colonies, because there is no certainty whether oral medicines administered with food, or with what dose, will be taken. In this field study, stool samples were taken from 42 cats and analysed for A. abstrusus L1 larvae with Baermann technique. Ten cats testing positive were treated with a spot-on formulation of selamectin 45 mg. Clinical examinations and laboratory tests, repeated four times in two months, demonstrated the success of the treatment in 9 of the 10 cats. Improvements in respiratory signs and general clinical condition were reported after treatment. PMID- 23743420 TI - The diagnosis of fasciolosis in feces of sheep by means of a PCR and its application in the detection of anthelmintic resistance in sheep flocks naturally infected. AB - The aim of this study was to develop a PCR for the diagnosis of Fasciola hepatica infection in feces of sheep based on the ribosomal internal transcribed spacer. Detection of infection was possible from the second week post-infection in experimentally infected sheep by amplification of a 292bp fragment. This PCR was employed for the detection of anthelmintic resistance (AR) in naturally infected sheep flocks, and results were compared with techniques such as the fecal egg count reduction test (FECRT) and the copro-antigen reduction test (CRT). The FECRT was carried out in two flocks, Santillan de la Vega (SV) and Corullon (CR), with sheep treated with albendazole (ABZ), clorsulon (CL), or triclabendazole (TCBZ). Feces were collected from individuals on days 0, 7, 15, and 30 post treatment (pt). The FECRT showed adult F. hepatica to be resistant to ABZ and CL in both flocks. All parasite stages in the SV flock were susceptible to TCBZ, while in the CR flock, adult flukes showed resistance and immature forms were susceptible to the treatment. To compare FECRT and the PCR results, we calculated the percent of positive sheep on day 1 pt. In both flocks, the percent positive sheep was consistently higher by PCR than by sedimentation, confirming that the PCR is a more sensitive method of diagnosing infection and therefore to detect the resistance in infected animals. The CRT was carried out in the SV flock using a sandwich ELISA kit. The percent of sheep found positive by PCR was higher than with ELISA. Comparison of FECRT, CRT, and PCR for the detection of AR showed PCR to be the most sensitive. PMID- 23743421 TI - Methanogenic activities of sulfide and nitric oxide amended mesophilic, methanogenic culture: role of nitrososufides complex. AB - Sulfide (S(2-)) and nitric oxide (NO) can be formed in anaerobic digester if nitrate and sulfate were presented in the influent streams. This study noted by 4,5-diaminofluorescein diacetate (DAF-2DA) staining and confocal laser scanning microscopy (CLSM) the presence of nitrososulfides (SNO) complex in the S(2-)+NO amended methanogenic sludge. Kinetic analysis suggested two-step kinetics involving chemical equilibrium between S(2-), NO and SNO as step 1 and the slow conversion from SNO to N2O as step 2. The SNO complex was claimed to have higher inhibition effect than S(2-) or NO alone on the methangenic activities. Comments were made on the role of SNO complex for the interactions between sulfur, nitrogen and carbon metabolisms in anaerobic digestion. PMID- 23743422 TI - Bioconversion of glycerol to 1,3-propanediol: a mathematical model-based nutrient feeding approach for high production using Clostridium diolis. AB - 1,3-Propanediol (1,3-PD) is a bifunctional organic compound of particular importance in the polymer industry for the synthesis of polyesters, polyethers and polyurethanes. Its biotechnological production from glycerol features inherent problems of nutrient limitation and inhibition(s) by substrate and product. In the present study 1,3-PD batch mathematical model developed using average batch kinetics data and independently obtained inhibition data was used to identify fresh nutrient feeding strategies (off-line on the computer) for enhanced production of 1,3-PD. Experimental implementation of one such model based fed-batch cultivation strategy involving pseudo-steady state of substrate featured a 1,3-PD concentration of 63.5 g/L with a 1,3-PD productivity of 1.35 g/L/h which were significantly higher than batch fermentation results. This demonstrated the potential application of developed model for the design of suitable nutrient feeding strategies for high production of 1,3-PD. The methodology can also be easily adopted for other cultivations. PMID- 23743423 TI - Mechanical biological treatment of organic fraction of MSW affected dissolved organic matter evolution in simulated landfill. AB - The aim of this paper was to study the evolution of DOM during 1 year of observation in simulated landfill, of aerobically treated vs. untreated organic fraction of MSW. Results obtained indicated that aerobic treatment of organic fraction of MSW permitted getting good biological stability so that, successive incubation under anaerobic condition in landfill allowed biological process to continue getting a strong reduction of soluble organic matter (DOM) that showed, also, an aromatic character. Incubation of untreated waste gave similar trend, but in this case DOM decreasing was only apparent as inhibition of biological process in landfill did not allow replacing degraded/leached DOM with new material coming from hydrolysis of fresh OM. PMID- 23743424 TI - Structure and adsorption properties of sewage sludge-derived carbon with removal of inorganic impurities and high porosity. AB - Purified sludge carbon (PSC) with removal of inorganic 'impurities' (Si, Al, etc.) is prepared from sewage sludge. Morphological structure, textural properties, surface elements and functional groups of sludge carbon (SC) and PSC are compared. SBET and pore volume of PSC are about three times higher than those of SC. PSC with large fluffy cavities remains some memory of SC parent structure. Removed fractions can be considered as a natural template for producing a hierarchical porous structure in PSC. Abundant oxygen-containing groups including hydroxyl and epoxide are generated in PSC, which are favorable for organic contaminant removal from wastewater. Diffraction peaks at 2theta = 45 degrees , bending modes of Si-O-Si and Na1s peaks (1070.5 eV) jointly confirm that only a trace of adsorbed impurities (Na2O.(SiO2)x (x >= 1)) is retained on PSC surface. PSC is superior to SC and comparable to commercial activated carbon for rhodamine B and phenol adsorption capacity. PMID- 23743425 TI - Sulfite-formaldehyde pretreatment on rice straw for the improvement of enzymatic saccharification. AB - Rice straw is one of the most abundant agricultural residues in China. It is considered as a promising raw material for bioethanol production. In this work, rice straw was pretreated by sodium sulfite-formaldehyde (SF) for improving enzymatic saccharification. The SF pretreatment, using proven technology and industrialized equipment, showed efficient delignification selectivity and high carbohydrates retention in pretreated solid. The highest sugar yields of 79.0%, 88.8% and 71.1% for total sugar, glucan and xylan, respectively were obtained at an enzyme loading of 40 FPU/g-substrate after the raw material pretreated with 12% sodium sulfite at 160 degrees C. About 75% of lignin was dissolved in pretreatment spent liquor and 78% of silica was retained in the residue of enzymatic hydrolysis. The results proved sulfite-formaldehyde as a promising pretreatment for the production of bioethanol as well as potential high value added by-products of silica nanoparticles and lignosulfonate. PMID- 23743426 TI - Pseudomonas putida KT2442 as a platform for the biosynthesis of polyhydroxyalkanoates with adjustable monomer contents and compositions. AB - The beta-oxidation weakened Pseudomonas putida were established as a platform for the production of polyhydroxyalkanoates (PHA) with adjustable monomer compositions and micro-structures. When mutant P. putida KTOYO6DeltaC (phaPCJA.c) was cultivated on mixtures of sodium butyrate and sodium hexanoate (C4:C6), random copolymers of P(3HB-co-3HHx) consisting of 3-hydroxybutyrate (3HB), 3 hydroxyhexanoate (3HHx), were accumulated with 3HHx content ranged from 19 mol% to 75 mol%. While recombinant P. putida KTQQ20 grown on mixtures of sodium hexanoate and decanoic acid (C6:C10), produced random copolymers of P(3HHx-co 3HD) consisting of 3-hydroxyhexanoate (3HHx) and 3-hydroxydecanoate (3HD), the monomer fraction of 3HHx ranged from 16 mol% to 63 mol%. The comonomer compositions were easily regulated by varying the fatty acid concentrations. P. putida KTQQ20 produced a novel diblock copolymer P3HHx-b-P(3HD-co-3HDD) consisting of 49 mol% P3HHx and 51 mol% P(3HD-co-3HDD) [35.25 mol% 3HDD (3 hydroxydodecanoate)], which was characterized by (13)C NMR, HMBC NMR, DSC, GPC and universal testing machine. PMID- 23743427 TI - Butyrate as preferred substrate for polyhydroxybutyrate production. AB - In this study, the suitability of butyrate as substrate for polyhydroxyalkanoate (PHA) production by microbial enrichment cultures was assessed. Two sequencing batch reactors were operated under feast-famine conditions: one fed with butyrate, and another with mixed acetate and butyrate. The obtained results were compared to previous results with acetate as sole substrate. In all three reactors Plasticicumulans acidivorans dominated the enrichment culture. The carbon uptake rate and PHA yield were significantly higher on butyrate than on acetate, resulting in a higher PHA production rate. When both substrates were available the bacteria strongly preferred the uptake of butyrate. Only after butyrate depletion acetate was taken up at a high rate. The molar substrate uptake rate remained the same, suggesting that substrate uptake is the rate limiting step. The results show that for optimized waste-based PHA production the pre-fermentation process should be directed towards butyrate production. PMID- 23743428 TI - Enhancement effect of silver nanoparticles on fermentative biohydrogen production using mixed bacteria. AB - Silver nanoparticles were added into anaerobic batch reactors to enhance acidogenesis and fermentative hydrogen production simultaneously. The effects of silver nanoparticles concentration (0-200 nmol L(-1)) and inorganic nitrogen concentration (0-4.125 g L(-1)) on cell growth and hydrogen production were investigated using glucose-fed mixed bacteria dominated by Clostridium butyricum. The tests with silver nanoparticles exhibited much higher H2 yields than the blank, and the maximum hydrogen yield (2.48 mol/mol glucose) was obtained at the silver concentration of 20 nmol L(-1). Presence of silver nanoparticles reduced the yield of ethanol, but increased the yield of acetic acid. The high silver nanoparticles had higher cell biomass production rate. Further study using the alkaline pretreated culture as inoculum was carried out to verify the positive effect of silver nanoparticles on H2 production. Results demonstrated that silver nanoparticles could not only increase the hydrogen yield, but reduce the lag phase for hydrogen production simultaneously. PMID- 23743429 TI - Enhanced phytotransformation of Navy Blue RX dye by Petunia grandiflora Juss. with augmentation of rhizospheric Bacillus pumilus strain PgJ and subsequent toxicity analysis. AB - This study reveals the beneficial synergistic phytoremediation potential of Petunia grandiflora Juss. with its rhizospheric bacterial isolate Bacillus pumilus strain PgJ to decolorize reactive Navy Blue RX (NBRX) dye by their active enzymatic machinery. In vitro cultures of P. grandiflora and B. pumilus gave 80.01% and 76.80% while their consortium decolorized NBRX up to 96.86% within 36 h. Significant induction in the enzyme activities of lignin peroxidase (207%), tyrosinase (133%), laccase (161%), riboflavin reductase (78%) were seen in the roots of tissue cultured plants while enzymes tyrosinase (660%), laccase (689%), riboflavin reductase (528%) were induced significantly in the B. pumilus cells. Metabolites of treated NBRX were analyzed using UV-vis spectroscopy, gas chromatography and biotransformation was visualized using high performance thin layer chromatography profile. Metabolites of the dye exhibited reduced phytotoxicity Sorghum vulgare and Phaeseolus mungo and significant reduction in cytogenotoxicity on Allium cepa roots when compared to NBRX. PMID- 23743430 TI - Fatty acid shifts and metabolic activity changes of Schizochytrium sp. S31 cultured on glycerol. AB - DHA production by Schizochytrium sp. S31 was studied in batch cultures on glycerol with stepwise dissolved oxygen strategy. Three growth stages were identified as cell growth, lipid accumulation and lipid turnover. It was revealed that fatty acid (FA) shifts during the three growth stages involved the activity changes of glycerol kinase (GK), FAD(+)-dependent glycerol-3-phosphate dehydrogenase (FAD(+)-G-3-PDH), malic enzyme (ME), ATP citrate lyase (ACL) and NAD(+)-dependent isocitrate dehydrogenase (NAD(+)-ICDH). Glycerol dissimilation in Schizochytrium sp. S31 was suggested via a phosphorylation by GK and a following oxidation by FAD(+)-G-3-PDH. Lipid accumulation of this strain was a growth-associated process, but the assimilable nitrogen depletion enhanced the accumulation of lipids. The exhaustion of glycerol induced the lipid turnover stage, where the short chain fatty acids were preferentially degraded and converted into lipid-free biomass (Xf) which was correlated to the increase of DHA content in biomass. PMID- 23743431 TI - Aerobic SMBR/reverse osmosis system enhanced by Fenton oxidation for advanced treatment of old municipal landfill leachate. AB - A novel combined process of Fenton oxidation, submerged membrane bioreactor (SMBR) and reverse osmosis (RO) was applied as an appropriate option for old municipal landfill leachate treatment. Fenton process was designed to intensively solve the problem of non-biodegradable organic pollutant removal and low biodegradability of leachate, although the removal of ammonia-nitrogen was similar to 10%. After SMBR treatment, it not only presented a higher removal efficiency of organics, but also exhibited high ammonia-nitrogen removal of 80% on average. The variation of extracellular polymeric substance (EPS) content, zeta potential, and particle size of flocs after Fenton effluent continually fed in SMBR was found to be benefit for alleviating membrane fouling. Finally, three kinds of RO membranes (RE, CPA, and BW) were applied to treat SMBR effluents and successfully met wastewater re-utilization requirement. Compared with simple RO process, the troublesome membrane fouling can be effectively reduced in the combined process. PMID- 23743432 TI - Microbial monitoring by molecular tools of an upflow anaerobic filter treating abattoir wastewaters. AB - The performance of anaerobic digestion of abattoir wastewaters (AW) in an upflow anaerobic filter (UAF) was investigated under mesophilic (37 degrees C) and thermophilic (55 degrees C) conditions. The effects of increasing temperature on the performance of the UAF and on the dynamics of the microbial community of the anaerobic sludge were studied. The results showed that chemical oxygen demand (COD) removal efficiency of 90% was achieved for organic loading rates (OLRs) up to 4.5g CODL(-1)d(-1) in mesophilic conditions, while in thermophilic conditions, the highest OLRs of 9 g CODL(-1)d(-1) led to the efficiency of 72%. The use of molecular and microbiological methods to recover microbial populations involved in this process showed that fermentative bacteria were the prominent members of the sludge microbial community. Three novel strains were identified as Macellibacteroides fermentans, Desulfotomaculum peckii and Defluviitalea saccharophila. PMID- 23743433 TI - Patient-reported outcome measures (PROMs) in paediatric ophthalmology: a systematic review. AB - AIM: To identify patient-reported outcome measures (PROMs) specifically developed and used to assess the impact of ophthalmic disorders in children and to systematically assess their quality as a basis for recommendations about their use in clinical and research settings. METHODS: A systematic review of the literature was performed in MEDLINE, EMBASE, PsychINFO, CINAHL and AMED, supplemented by a grey literature search. Papers reporting development and validation of questionnaire instruments for assessing patient-reported outcomes of an ophthalmic disorder in patients aged 2-18 years were included. Quality was assessed by examining the purpose and psychometric properties of the instruments. Strengths and limitations were summarised with recommendations regarding use. RESULTS: Search identified 17 instruments. Of these, 11 were condition-specific and six were intended for a broader population of children and young people with visual impairment regardless of the ophthalmic condition. Three were developed for use in a specific trial and two are still in development. CONCLUSIONS: Paediatric ophthalmology PROM development and application is a developing field and new instruments are needed. There is scope for improvement in this area through (a) clarity of definitions of the underlying constructs intended to be measured at the onset of development of new instruments, (b) application of child centred approaches and (c) adherence to extant guidance and best practice in questionnaire instrument development. PMID- 23743434 TI - Sarcoidosis of the lacrimal sac--an unusual case. PMID- 23743435 TI - Valuing the benefits of genetic testing for retinitis pigmentosa: a pilot application of the contingent valuation method. AB - BACKGROUND: Technological advances present an opportunity for more people with, or at risk of, developing retinitis pigmentosa (RP) to be offered genetic testing. Valuation of these tests using current evaluative frameworks is problematic since benefits may be derived from diagnostic information rather than improvements in health. This pilot study aimed to explore if contingent valuation method (CVM) can be used to value the benefits of genetic testing for RP. METHODS: CVM was used to elicit willingness-to-pay (WTP) values for (1) genetic counselling and (2) genetic counselling with genetic testing. Telephone and face to-face interviews with a purposive sample of individuals with (n=25), and without (n=27), prior experience of RP were used to explore the feasibility and validity of CVM in this context. RESULTS: Faced with a hypothetical scenario, the majority of participants stated that they would seek genetic counselling and testing in the context of RP. Between participant groups, respondents offered similar justifications for stated WTP values. Overall stated WTP was higher for genetic counselling plus testing (median=L524.00) compared with counselling alone (median=L224.50). Between-group differences in stated WTP were statistically significant; participants with prior knowledge of the condition were willing to pay more for genetic ophthalmology services. CONCLUSIONS: Participants were able to attach a monetary value to the perceived potential benefit that genetic testing offered regardless of prior experience of the condition. This exploratory work represents an important step towards evaluating these services using formal cost-benefit analysis. PMID- 23743436 TI - Optical coherence tomography of the suprachoroid after CyPass Micro-Stent implantation for the treatment of open-angle glaucoma. AB - BACKGROUND/AIMS: To evaluate the supraciliary space (SCS) with anterior segment optical coherence tomography (OCT) imaging after CyPass Micro-Stent implantation. METHODS: The SCS was imaged with OCT after microstent implantation at 1, 6 months, and 1 year. Images were graded on a scale of 0-4 for morphological features indicative of fluid presence within, or drainage through, the SCS. RESULTS: 35 patients underwent ab-interno microstent implantation. Mean age was 68.6+/-10.2 years. Baseline mean intraocular pressure (IOP) was 21.9+/-6.1 mm Hg on average of 3.0 topical medications. At 1 month, the fluid space grade was >=1 for 96% (24/25) of patients for tenting, 79% (15/19) for fluid posterior to the microstent, and 89% (8/9) for fluid surrounding the microstent. The mean (composite) score for all features was 2.5+/-0.99. The majority of patients maintained aqueous fluid through 12 months. CONCLUSIONS: OCT imaging provides adequate visualisation of the angle, the SCS and aqueous fluid drainage after implantation of a suprachoroidal microstent into the SCS. PMID- 23743437 TI - Bimatoprost 0.03% preservative-free ophthalmic solution versus bimatoprost 0.03% ophthalmic solution (Lumigan) for glaucoma or ocular hypertension: a 12-week, randomised, double-masked trial. AB - BACKGROUND/AIM: To evaluate efficacy and safety of bimatoprost 0.03% preservative free (PF) ophthalmic solution versus bimatoprost 0.03% (Lumigan) ophthalmic solution for glaucoma or ocular hypertension. METHODS: In this double-masked, parallel-group study, patients were randomised to bimatoprost PF or bimatoprost for 12 weeks. The primary analysis for non-inferiority was change from baseline in worse eye intraocular pressure (IOP) in the per-protocol population at week 12. For equivalence, it was average eye IOP in the intent-to-treat population at each time point at weeks 2, 6 and 12. RESULTS: 597 patients were randomised (bimatoprost PF, n=302 and bimatoprost, n=295). The 95% CI upper limit for worse eye IOP change from baseline was <1.5 mm Hg at each week 12 time point, meeting prespecified non-inferiority criteria. The 95% CI upper limit for the treatment difference for average IOP was 0.69 mm Hg and the lower limit was -0.50 mm Hg at all follow-up time points (hours 0, 2 and 8 at weeks 2, 6 and 12), meeting equivalence criteria. Both treatments showed decreases in mean average eye IOP at all follow-up time points (p<0.001), were safe and well tolerated. CONCLUSIONS: Bimatoprost PF is non-inferior and equivalent to bimatoprost in its ability to reduce IOP-lowering with a safety profile similar to bimatoprost. PMID- 23743438 TI - Topical cyclosporine in the treatment of allergic conjunctivitis: a meta analysis. AB - PURPOSE: To assess the efficacy and safety of topical cyclosporine versus placebo in the treatment of allergic conjunctivitis. DESIGN: Systematic review and meta analysis. PARTICIPANTS: Seven qualified studies incorporating 306 eyes of 153 patients were analyzed. METHODS: Searches of randomized controlled trials were conducted in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. MAIN OUTCOME MEASURES: We assessed the methodologic quality of individual included trials and performed meta-analyses using the random effects model if P<0.1 in the test for heterogeneity, or otherwise used the fixed effects model. We assessed scores of composite signs and symptoms, reduction in steroid eye drop use in steroid-dependent patients, and safety outcomes (i.e., stinging or burning sensation). RESULTS: At 2 weeks of follow-up or longer, evidence suggests a statistically significant improvement in the composite signs (standardized mean difference [SMD], -1.21; 95% confidence interval [CI], -1.80 to -0.62; I(2) = 71%) and symptoms (SMD, -0.84; 95% CI, 1.51 to -0.16; I(2) = 80%) after topical cyclosporine treatment for allergic conjunctivitis regardless of the dosage of treatment. There was a significant reduction (mean difference, -61.16; 95% CI, -101.61 to -20.72; I(2) = 58%) in the use of steroid eye drops in patients with steroid-dependent allergic conjunctivitis. Stinging or burning sensation (odds ratio, 2.56; 95% CI, 0.19 35.06; I(2) = 73%) was common in both the cyclosporine and placebo groups. CONCLUSIONS: This systematic review and meta-analysis suggests topical cyclosporine could be an effective and safe treatment method for allergic conjunctivitis. Further randomized controlled trials with larger sample sizes and standardized outcome measurements, follow-up periods, and cyclosporine concentrations are warranted to determine the short- and long-term efficacy and safety and the minimal effective dosage of topical cyclosporine for allergic conjunctivitis. PMID- 23743439 TI - Aqueous flare and choroidal thickness in patients with chronic hepatitis C virus infection: a pilot study. AB - PURPOSE: To investigate the status of the blood-aqueous barrier and to evaluate the subfoveal choroidal thickness (SCT) in patients with asymptomatic untreated chronic hepatitis C virus (HCV) infection without any anterior or posterior ocular involvement and to search for possible correlations. DESIGN: Observational case-control study. PARTICIPANTS AND CONTROLS: A total of 80 eyes of 20 HCV positive patients (male-to-female ratio, 12:8; mean age, 46.9+/-7.23 years) and 20 healthy controls (male-to-female ratio, 10:10; mean age, 48.2+/-8.71 years) were examined. METHODS: Participants underwent a complete ophthalmologic examination. Aqueous flare was quantified objectively by using the noninvasive laser flare cell meter FC-500 (Kowa Company Ltd, Tokyo, Japan), whereas SCT was evaluated by using enhanced depth imaging optical coherence tomography (Spectralis OCT; Heidelberg Engineering GmbH, Heidelberg, Germany). A Wilcoxon rank-sum test was performed to compare ocular findings between HCV patients and controls, and correlations were assessed by using the Spearman rank test. MAIN OUTCOME MEASURES: Retinal and choroidal thickness and anterior chamber inflammation of HCV patients and healthy controls. RESULTS: Patients with HCV showed significantly higher aqueous flare values (8.37+/-2.25 photon counts/ms vs. 4.56+/-1.45 photon counts/ms; P<0.0001) and a significantly increased SCT (362.7+/-46.5 MUm vs. 320.25+/-32.82 MUm; P<0.0001) than healthy controls. Moreover, subjects with liver fibrosis had higher flare values than those with no significant hepatic fibrosis (9.62+/-1.99 photon counts/ms vs. 6.97+/-2.19 photon counts/ms; P = 0.0003) and thicker choroids (379.15+/-44.75 MUm vs. 346.3+/-43.27 MUm; P = 0.024). Statistical analysis revealed that there was a positive correlation between aqueous flare values and SCT in HCV patients (r = 0.69; P<0.0001) and between flare and the degree of liver fibrosis (r = 0.67; P = 0.0001). CONCLUSIONS: This study showed that impairment of the blood-aqueous barrier and thickened choroids are features of asymptomatic HCV patients, and that choroidal thickness increases as the degree of subclinical inflammation of the anterior chamber increases. Patients with significant liver fibrosis have the highest flare values and the thickest choroids. PMID- 23743440 TI - Synthesis and bioactive evaluation of novel hybrids of metronidazole and berberine as new type of antimicrobial agents and their transportation behavior by human serum albumin. AB - A series of novel hybrids of metronidazole and berberine as new type of antimicrobial agents were synthesized and characterized by (1)H NMR, (13)C NMR, IR, MS and HRMS spectra. Bioactive assay manifested that most of the prepared compounds exhibited effective antibacterial and antifungal activities and some showed comparable or superior potency against Methicillin-resistant Staphylococcus aureus to reference drugs Norfloxacin, Chloromycin and Berberine. The transportation behavior of human serum albumin (HSA) to the highly active compound 5g was evaluated and revealed that the association of imidazole derivative 5g with HSA was spontaneous and the electrostatic interactions played important roles in the transportation of HSA to 5g. The calculated parameters indicated that compound 5g could be effectively stored and carried by HSA. PMID- 23743441 TI - C3'-endo-puckered pyrrolidine containing PNA has favorable geometry for RNA binding: novel ethano locked PNA (ethano-PNA). AB - A novel peptide nucleic acid (PNA) analogue is designed with a constraint in the aminoethyl segment of the aegPNA backbone so that the dihedral angle beta is restricted within 60-80 degrees , compatible to form PNA:RNA duplexes. The designed monomer is further functionalized with positively charged amino /guanidino-groups. The appropriately protected monomers were synthesized and incorporated into aegPNA oligomers at predetermined positions and their binding abilities with cDNA and RNA were investigated. A single incorporation of the modified PNA monomer into a 12-mer PNA sequence resulted in stronger binding with complementary RNA over cDNA. No significant changes in the CD signatures of the derived duplexes of modified PNA with complementary RNA were observed. PMID- 23743442 TI - Inhibition of hepatitis B virus replication in cultured cells and in vivo using 2'-O-guanidinopropyl modified siRNAs. AB - Silencing hepatitis B virus (HBV) gene expression with exogenous activators of the RNA interference (RNAi) pathway has shown promise as a new mode of treating infection with the virus. However, optimizing efficacy, specificity, pharmacokinetics and stability of RNAi activators remains a priority before clinical application of this promising therapeutic approach is realised. Chemical modification of synthetic short interfering RNAs (siRNAs) provides the means to address these goals. This study aimed to assess the benefits of incorporating nucleotides with 2'-O-guanidinopropyl (GP) modifications into siRNAs that target HBV. Single GP residues were incorporated at nucleotide positions from 2 to 21 of the antisense strand of a previously characterised effective antiHBV siRNA. When tested in cultured cells, siRNAs with GP moieties at selected positions improved silencing efficacy. Stability of chemically modified siRNAs in 80% serum was moderately improved and better silencing effects were observed without evidence for toxicity or induction of an interferon response. Moreover, partially complementary target sequences were less susceptible to silencing by siRNAs with GP residues located in the seed region. Hydrodynamic co-injection of siRNAs with a replication-competent HBV plasmid resulted in highly effective knock down of markers of viral replication in mice. Evidence for improved efficacy, reduced off target effects and good silencing in vivo indicate that GP-modifications of siRNAs may be used to enhance their therapeutic utility. PMID- 23743443 TI - Synthesis and anti-HCMV activity of 1-[omega-(phenoxy)alkyl]uracil derivatives and analogues thereof. AB - HCMV infection represents a life-threatening condition for immunocompromised patients and newborn infants and novel anti-HCMV agents are clearly needed. In this regard, a series of 1-[omega-(phenoxy)alkyl]uracil derivatives were synthesized and examined for antiviral properties. Compounds 17, 20, 24 and 28 were found to exhibit highly specific and promising inhibitory activity against HCMV replication in HEL cell cultures with EC50 values within 5.5-12MUM range. Further studies should be undertaken to elucidate the mechanism of action of these compounds and the structure-activity relationship for the linker region. PMID- 23743444 TI - Sequence variation and differential splicing of the midgut cadherin gene in Trichoplusia ni. AB - The insect midgut cadherin serves as an important receptor for the Cry toxins from Bacillus thuringiensis (Bt). Variation of the cadherin in insect populations provides a genetic potential for development of cadherin-based Bt resistance in insect populations. Sequence analysis of the cadherin from the cabbage looper, Trichoplusia ni, together with cadherins from 18 other lepidopterans showed a similar phylogenetic relationship of the cadherins to the phylogeny of Lepidoptera. The midgut cadherin in three laboratory populations of T. ni exhibited high variability, although the resistance to Bt toxin Cry1Ac in the T. ni strain is not genetically associated with cadherin gene mutations. A total of 142 single nucleotide polymorphisms (SNPs) were identified in the cadherin cDNAs from the T. ni strains, including 20 missense mutations. In addition, insertion and deletion polymorphisms (indels) were also identified in the cadherin alleles in T. ni. More interestingly, the results from this study reveal that differential splicing of mRNA also occurs in the cadherin gene expression. Therefore, variation of the midgut cadherin in insects may not only be caused by cadherin gene mutations, but could also result from alternative splicing of its mRNA regulated by factors acting in trans. Analysis of cadherin gene alleles in F2, F3 and F4 progenies from the cross between the Cry1Ac resistant and the susceptible strain after consecutive selections with Cry1Ac for three generations showed that selection with Cry1Ac did not result in an increase of frequencies of the cadherin alleles originated from the resistant strain. PMID- 23743445 TI - Direct writing on graphene 'paper' by manipulating electrons as 'invisible ink'. AB - The combination of self-assembly (bottom up) and nano-imprint lithography (top down) is an efficient and effective way to record information at the nanoscale by writing. The use of an electron beam for writing is quite a promising strategy; however, the 'paper' on which to save the information is not yet fully realized. Herein, graphene was selected as the thinnest paper for recording information at the nanoscale. In a transmission electron microscope, in situ high precision writing and drawing were achieved on graphene nanosheets by manipulating electrons with a 1 nm probe (probe current ~2 * 10(-9) A m(-2)) in scanning transmission electron microscopy (STEM) mode. Under electron probe irradiation, the carbon atom tends to displace within a crystalline specimen, and dangling bonds are formed from the original sp(2) bonding after local carbon atoms have been kicked off. The absorbed random foreign amorphous carbon assembles along the line of the scanning direction induced by secondary electrons and is immobilized near the edge. With the ultralow secondary electron yield of the graphene, additional foreign atoms determining the accuracy of the pattern have been greatly reduced near the targeting region. Therefore, the electron probe in STEM mode serves as invisible ink for nanoscale writing and drawing. These results not only shed new light on the application of graphene by the interaction of different forms of carbon, but also illuminate the interaction of different carbon forms through electron beams. PMID- 23743446 TI - Reply. Letter to the editor. Hillemanns Peter, Hepp Hermann, Letter to the Editor: K. Gemzell-Danielsson et al. Emergency contraception - mechanisms of action. PMID- 23743447 TI - What's new for ESC Congress 2013? (Amsterdam 30th August-4th September 2013). PMID- 23743448 TI - CCRK depletion inhibits glioblastoma cell proliferation in a cilium-dependent manner. AB - Loss of primary cilia is frequently observed in tumour cells, including glioblastoma cells, and proposed to benefit tumour growth, but a causal link has not been established. Here, we show that CCRK (cell cycle-related kinase) and its substrate ICK (intestinal cell kinase) inhibit ciliogenesis. Depletion of CCRK leads to accumulation of ICK at ciliary tips, altered ciliary transport and inhibition of cell cycle re-entry in NIH3T3 fibroblasts. In glioblastoma cells with deregulated high levels of CCRK, its depletion restores cilia through ICK and an ICK-related kinase MAK, thereby inhibiting glioblastoma cell proliferation. These results indicate that inhibition of ciliogenesis might be a mechanism used by cancer cells to provide a growth advantage. PMID- 23743450 TI - Oral contraceptive pills as primary prevention for ovarian cancer: a systematic review and meta-analysis. AB - OBJECTIVE: To estimate the overall reduction in ovarian cancer risk associated with the use of oral contraceptive pills (OCPs) and whether reduction in risk is affected by specifics of OCP use, such as formulation or duration of use. DATA SOURCES: We searched PubMed, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published from January 1990 to June 2012, with primary analysis of studies published since January 2000. METHODS OF STUDY SELECTION: We reviewed 6,476 citations. We included English-language controlled studies with human participants reporting a quantitative association between exposure to OCPs (in which the explicit or implicit indication for OCP use was prevention of pregnancy or ovarian cancer) compared with no use of OCPs. Two investigators independently reviewed the title and abstract and full-text of articles for inclusion or exclusion decision; discordant decisions were resolved by team review and consensus. TABULATION, INTEGRATION, AND RESULTS: Fifty-five studies met inclusion criteria. A random-effects meta-analysis of 24 case-control and cohort studies showed significant reduction in ovarian cancer incidence in ever-users compared with never-users (odds ratio 0.73, 95% confidence interval 0.66-0.81). There was a significant duration-response relationship, with reduction in incidence of more than 50% among women using OCPs for 10 or more years. The lifetime reduction in ovarian cancer attributable to the use of OCPs is approximately 0.54% for a number-needed-to-treat of approximately 185 for a use period of 5 years. CONCLUSION: Significant duration-dependent reductions in ovarian cancer incidence in the general population are associated with OCP use. PMID- 23743452 TI - Clinical validation of risk stratification criteria for peripartum hemorrhage. AB - OBJECTIVES: To determine whether the California Maternal Quality Care Collaborative risk groups predicted the risk of peripartum hemorrhage and to determine which women should have peripartum pretransfusion testing performed. METHODS: Over a 1-year period, 10,134 women who delivered at a single hospital were included in this retrospective cohort study. The majority of the California Maternal Quality Care Collaborative risk factors were assessed retrospectively. Each mother was assigned to one of the three peripartum hemorrhage risk groups according to the guidelines. The individual peripartum hemorrhage risk factors and the three risk groups correlated with the occurrence of a significant peripartum hemorrhage (a hemorrhage requiring transfusion of 1 unit or more of red blood cells). Other risk factors for peripartum hemorrhage were assessed and a modified high-risk category was created. RESULTS: The incidence of a significant peripartum hemorrhage within each group was as follows: low (0.8%); medium (2.0%); and high (7.3%). High included an increase that was statistically significant (P<.001). All of the assessed California Maternal Quality Care Collaborative risk criteria were significantly associated with an increased peripartum hemorrhage rate (P<=.02) except macrosomnia and morbid obesity. Other risk factors not included in the California Maternal Quality Care Collaborative criteria (preterm delivery, uterine rupture, hypertension, previous cesarean delivery, and a model of accreta or percreta) also correlated with peripartum hemorrhage. This modified risk group included 85% of those women with significant hemorrhage; however, 45% of women were included and only 2.6% of this modified group hemorrhaged. CONCLUSION: The California Maternal Quality Care Collaborative risk stratification showed an increasing risk for transfusion as the risk grade increased. Women in the California Maternal Quality Care Collaborative high-risk group (or as determined by their providers) should have pretransfusion testing performed. LEVEL OF EVIDENCE: II. PMID- 23743449 TI - Approaches and tools for modeling signaling pathways and calcium dynamics in neurons. AB - Signaling pathways are cascades of intracellular biochemical reactions that are activated by transmembrane receptors, and ultimately lead to transcription in the nucleus. In neurons, both calcium permeable synaptic and ionic channels as well as G protein coupled receptors initiate activation of signaling pathway molecules that interact with electrical activity at multiple spatial and time scales. At small temporal and spatial scales, calcium modifies the properties of ionic channels, whereas at larger temporal and spatial scales, various kinases and phosphatases modify the properties of ionic channels, producing phenomena such as synaptic plasticity and homeostatic plasticity. The elongated structure of neuronal dendrites and the organization of multi-protein complexes by anchoring proteins imply that the spatial dimension must be explicit. Therefore, modeling signaling pathways in neurons utilizes algorithms for both diffusion and reactions. The small size of spines coupled with small concentrations of some molecules implies that some reactions occur stochastically. The need for stochastic simulation of many reaction and diffusion events coupled with the multiple temporal and spatial scales makes modeling of signaling pathways a difficult problem. Several different software programs have achieved different aspects of these capabilities. This review explains some of the mathematical formulas used for modeling reactions and diffusion. In addition, it briefly presents the simulators used for modeling reaction-diffusion systems in neurons, together with scientific problems addressed. PMID- 23743454 TI - Primary cesarean delivery in the United States. AB - OBJECTIVES: To characterize the indications for primary cesarean delivery in a large national cohort and to identify opportunities to lower the U.S. primary cesarean delivery rate. METHODS: A retrospective cohort study of the 38,484 primary cesarean deliveries among the 228,562 deliveries at sites participating in the Consortium on Safe Labor from 2002 to 2008. RESULTS: The primary cesarean delivery rate was 30.8% for primiparous women and 11.5% for multiparous women. The most common indications for primary cesarean delivery were failure to progress (35.4%), nonreassuring fetal heart rate tracing (27.3%), and fetal malpresentation (18.5%), although frequencies for each indication varied by parity. Among women with failure to progress, 42.6% of primiparous women and 33.5% of multiparous women never progressed beyond 5 cm of dilation before delivery. Among women who reached the second stage of labor, 17.3% underwent cesarean delivery for arrest of descent before 2 hours and only 1.1% were given a trial of operative vaginal delivery. Of all primary cesarean deliveries, 45.6% were performed on primiparous women at term with a singleton fetus in cephalic presentation. CONCLUSION: Using 6 cm as the cut-off for active labor, allowing adequate time for the second stage of labor, and encouraging operative vaginal delivery, when appropriate, may be important strategies to reduce the primary cesarean delivery rate. These actions may be particularly important in the primiparous woman at term with a singleton fetus in cephalic presentation. LEVEL OF EVIDENCE: III. PMID- 23743456 TI - Authentic compassion. PMID- 23743455 TI - Short interpregnancy intervals in the United States. AB - OBJECTIVE: To investigate the prevalence and correlates of short interpregnancy intervals in the United States. METHODS: We analyzed pregnancy data from a nationally representative sample of 12,279 women from the 2006-2010 National Survey of Family Growth. We limited our sample to second and higher-order births within 5 years of the interview. Interpregnancy intervals were calculated as the interval between the delivery date of the preceding live birth and the conception date of the index pregnancy, with short interpregnancy intervals defined as intervals less than 18 months. We used simple and multivariate logistic regression analyses to examine associations between short interpregnancy intervals and maternal demographic and childbearing characteristics, including pregnancy intention. RESULTS: Among the 2,253 pregnancies in our sample, one third (35%) were conceived within 18 months of a previous birth. After adjusting for sociodemographic and childbearing characteristics, women were significantly more likely to have a short interpregnancy interval if they were aged 15-19 years or married at the time of conception of the index pregnancy, initiated childbearing after age 30 years, or reported the pregnancy as unintended. Short interpregnancy intervals were more likely to be intended among more advantaged women (married, non-Hispanic white, college-educated, or non-Medicaid delivery). We estimate that preventing unintended pregnancies would reduce the proportion of short interpregnancy intervals from 35% to 23%. CONCLUSION: Providing counseling about the potential negative consequences of short interpregnancy intervals and improving women's contraceptive use to reduce rates of unintended pregnancy likely would reduce the proportion of short interpregnancy interval pregnancies in the United States. LEVEL OF EVIDENCE: II. PMID- 23743453 TI - Maternal 25-hydroxyvitamin d and preterm birth in twin gestations. AB - OBJECTIVE: To assess whether there was an independent association between maternal 25-hydroxyvitamin D concentrations at 24-28 weeks of gestation and preterm birth in a multicenter U.S. cohort of twin pregnancies. METHODS: Serum samples from women who participated in a clinical trial of 17 alpha hydroxyprogesterone caproate for the prevention of preterm birth in twin gestations (2004-2006) were assayed for 25-hydroxyvitamin D concentrations using liquid chromatography tandem mass spectrometry (n=211). Gestational age was determined early in pregnancy using a rigorous algorithm. Preterm birth was defined as delivery of the first twin or death of either twin at less than 35 weeks of gestation. RESULTS: The mean serum 25-hydroxyvitamin D concentration was 82.7 nmol/L (standard deviation 31.5); 40.3% of women had concentrations less than 75 nmol/L. Preterm birth at less than 35 weeks of gestation occurred in 49.4% of women with 25-hydroxyvitamin D concentrations less than 75 nmol/L compared with 26.2% among those with concentrations of 75 nmol/L or more (P<.001). After adjustment for maternal race and ethnicity, study site, parity, prepregnancy body mass index, season, marital status, education, gestational age at blood sampling, smoking status, and 17 alpha-hydroxyprogesterone caproate treatment, maternal 25-hydroxyvitamin D concentration of 75 nmol/L or more was associated with a 60% reduction in the odds of preterm birth compared with concentrations less than 75 nmol/L (adjusted odds ratio [OR] 0.4, 95% confidence interval [CI] 0.2-0.8). A similar protective association was observed when studying preterm birth at less than 32 weeks of gestation (OR 0.2, 95% CI 0.1 0.6) and after confounder adjustment. CONCLUSIONS: Late second-trimester maternal 25-hydroxyvitamin D concentrations less than 75 nmol/L are associated with an increase in the risk of preterm birth in this cohort of twin pregnancies. LEVEL OF EVIDENCE: II. PMID- 23743457 TI - Maternal obesity, mode of delivery, and neonatal outcome. AB - OBJECTIVE: To evaluate whether adverse neonatal outcome, defined as birth injuries or severe illnesses in the newborn, was associated with maternal body mass index (BMI) in singleton pregnancies overall and depending on mode of delivery. METHODS: This was a cohort study including 1,024,471 women. Data were collected from the Swedish Medical Birth Registry. Women were categorized into six classes of BMI. Obese women were compared with normal weight women regarding adverse neonatal outcome after suitable adjustments. Four modes of delivery were evaluated: vaginal delivery; instrumental vaginal delivery; elective cesarean delivery; and emergency cesarean delivery. RESULTS: Compared with neonates born to women of normal weight, neonates born to women with BMIs of 40 or more (morbidly obese) were at increased risk of birth injury to the peripheral nervous system (odds ratio [OR] 3.80, 95% confidence interval [CI] 2.83-5.12; 0.2% compared with 0.6%), birth injury to the skeleton (OR 2.59, 95% CI 2.10-3.21; 0.5% compared with 1.1%), respiratory distress syndrome (OR 2.08, 95% CI 1.88 2.30; 2.9 compared with 5.8%), bacterial sepsis (OR 2.90, 95% CI 2.43-3.46; 0.6% compared with 1.7%), convulsions (OR 3.43, 95% CI 2.63-4.47; 0.2% compared with 0.8%), and hypoglycemia (OR 3.48, 95% CI 3.20-3.78; 2.4% compared with 7.9%). For morbidly obese women, elective cesarean delivery and vaginal delivery were associated with twice the increased risk of adverse neonatal outcomes when compared with women of normal weight. CONCLUSION: Neonates born to morbidly obese women are at markedly increased risk of adverse neonatal outcome regardless of mode of delivery. Obstetricians should not disregard the neonatal problems associated with elective cesarean delivery for morbidly obese women. LEVEL OF EVIDENCE: II. PMID- 23743458 TI - Teaching surgical skills using video internet communication in a resource-limited setting. AB - OBJECTIVE: To study the feasibility and acceptability of using video Internet communication to teach and evaluate surgical skills in a low-resource setting. METHODS: This case-controlled study used video Internet communication for surgical skills teaching and evaluation. We randomized intern physicians rotating in the Obstetrics and Gynecology Department at Mulago Hospital at Makerere University in Kampala, Uganda, to the control arm (usual practice) or intervention arm (three video teaching sessions with University of California, San Francisco faculty). We made preintervention and postintervention videos of all interns tying knots using a small video camera and uploaded the files to a file hosting service that offers cloud storage. A blinded faculty member graded all of the videos. Both groups completed a survey at the end of the study. RESULTS: We randomized 18 interns with complete data for eight in the intervention group and seven in the control group. We found score improvement of 50% or more in six of eight (75%) interns in the intervention group compared with one of seven (14%) in the control group (P=.04). Scores declined in five of the seven (71%) controls but in none in the intervention group. Both intervention and control groups used attendings, colleagues, and the Internet as sources for learning about knot-tying. The control group was less likely to practice knot tying than the intervention group. The trainees and the instructors felt this method of training was enjoyable and helpful. CONCLUSION: Remote teaching in low resource settings, where faculty time is limited and access to visiting faculty is sporadic, is feasible, effective, and well-accepted by both learner and teacher. LEVEL OF EVIDENCE: II. PMID- 23743459 TI - Hormonal therapy for women with stage IA endometrial cancer of all grades. AB - OBJECTIVE: To estimate the oncologic and pregnancy outcomes after oral progestin treatment of women of reproductive age with stage IA endometrial adenocarcinoma with stage IA, grade 1 differentiation with superficial myometrial invasion or stage IA, grade 2-3 differentiation with or without superficial myometrial invasion. METHODS: Medical records of 48 women (age 40 years or younger) with endometrioid adenocarcinoma of the uterus who met inclusion criteria and were treated conservatively with oral progestin were reviewed. Follow-up was performed primarily with imaging techniques followed by endometrial biopsy when indicated. RESULTS: The median age was 30 years (range, 23-40 years). Fourteen patients (29.2%) received daily oral megestrol acetate (median dose 160 mg per day, range 40-240 mg per day) and 34 (70.8%) received daily oral medroxyprogesterone acetate (median dose 500 mg per day, range 80-1,000 mg per day). Complete responses were observed for 37 patients (77.1%) after the median treatment duration of 10 months (range 3-20 months). Complete response rates were 76.5%, 73.9%, and 87.5% for patients with stage IA, grade 2-3 without myometrial invasion (n=17), for patients with stage IA, grade 1 with superficial myometrial invasion (n=23), and for patients with stage IA, grade 2-3 with superficial myometrial invasion (n=8), respectively (P=.731). Recurrence rates for 37 patients who achieved complete response after a median follow-up time of 48 months (range 7-136 months) were 23.1%, 47.1%, and 71.4%, respectively (P=.104). None experienced disease progression or died of the disease. Nine patients gave birth to 10 healthy newborns. CONCLUSION: Progestin treatment appears to be reasonably effective for patients with stage IA, grade 2-3 differentiation without myometrial invasion and patients with stage IA grade 1 differentiation with superficial myometrial invasion. LEVEL OF EVIDENCE: III. PMID- 23743460 TI - Transcending politics to promote women's health. PMID- 23743461 TI - Relationship of the length of the first stage of labor to the length of the second stage. AB - OBJECTIVE: To evaluate the relationship between the lengths of the first and second stages of labor. METHODS: In this observational study of women delivering at our hospital, the onset of the first stage of labor was defined as admission at 3-cm to 4-cm dilatation in the presence of uterine contractions with or without rupture of membranes. This study was limited to nulliparous women with a singleton, cephalic live birth at 37 0/7 weeks of gestation or more. Women presenting with more advanced cervical dilatation (greater than 4 cm), prior cesarean delivery, diabetes, hypertension, and placental accidents were excluded. Each woman was analyzed based on her specific lengths of first and second stages of labor, that is, paired observations for each woman. RESULTS: Between January 1, 2001, and June 30, 2012, a total of 172,522 women were delivered and 12,523 (7.3%) met the inclusion criteria. The 95 percentile was 15.6 and 2.9 hours for the first and second stages, respectively. Women with first stages greater than the 95 percentile had a 16.3% rate of a second-stage length greater than the 95 percentile compared with 4.5% (P<.001) in women with first stages less than the 95 percentile. This relationship persisted when analyzed for variables influencing labor to include neonate birth weight, epidural analgesia, or maternal size. CONCLUSION: Overall, the length of the second stage significantly increased concomitantly with increasing length of the first stage (P<.001). LEVEL OF EVIDENCE: II. PMID- 23743462 TI - Effect of rotation on perineal lacerations in forceps-assisted vaginal deliveries. AB - OBJECTIVE: To determine the difference in the rates of severe perineal lacerations between forceps-assisted vaginal deliveries in the occiput-posterior position compared with forceps-assisted vaginal deliveries in which the fetal head was rotated to occiput-anterior before delivery. METHODS: We studied a retrospective cohort of 148 women who had a forceps-assisted vaginal delivery from 2008 to 2011 at the University of Pittsburgh. Mild perineal lacerations were defined as first or second degree, and severe lacerations were defined as third or fourth degree. chi and t tests were used for bivariate and logistic regression was used for multivariable analyses. P<.05 was considered statistically significant. RESULTS: Of 148 forceps-assisted deliveries, 81 delivered occiput anterior after either manual or forceps rotation, 10 delivered in the occiput posterior or occiput-transverse position after an unsuccessful rotation, and 57 delivered occiput-posterior without attempted rotation. No significant differences were found among demographic, obstetric, and neonatal characteristics of the groups. Overall, 86 (67.7%) women had mild lacerations and 41 (32.3%) had severe lacerations. A significantly greater rate of severe perineal lacerations was found in the occiput-posterior nonrotated compared with the rotated group (43.4% compared with 24.3%; P=.02). In multivariable analyses, adjusted for age, race, insurance, body mass index, gestational age, parity, episiotomy, and birth weight, forceps-assisted vaginal delivery in the occiput-posterior position without rotation remained significantly more likely to be associated with severe lacerations (odds ratio 3.67, 95% confidence interval 1.42-9.47). CONCLUSION: Forceps-assisted vaginal delivery after rotation of an occiput-posterior position to an occiput-anterior position is associated with less severe maternal perineal trauma than forceps-assisted delivery in the occiput-posterior position. LEVEL OF EVIDENCE: II. PMID- 23743463 TI - What is new in obstetric anal sphincter injuries?: Best articles from the past year. AB - This month, we focus on current research in obstetric anal sphincter injuries. Dr. Fischer discusses four recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 23743464 TI - Treatment of severe insulin resistance in pregnancy with 500 units per milliliter of concentrated insulin. AB - OBJECTIVE: To evaluate glycemic control and pregnancy outcomes among pregnant women with severe insulin resistance treated with 500 units/mL concentrated insulin. METHODS: Retrospective analysis of gravid women with severe insulin resistance (need for greater than 100 units of insulin per injection or greater than 200 units/d) treated with either 500 units/mL concentrated insulin or conventional insulin therapy. We performed a two-part analysis: 1) between gravid women treated with and without 500 units/mL concentrated insulin; and 2) among gravid women treated with 500 units/mL concentrated insulin, comparing glycemic control before and after its initiation. RESULTS: Seventy-three pregnant women with severe insulin resistance were treated with 500 units/mL concentrated insulin and 78 with conventional insulin regimens. Patients treated with 500 units/mL concentrated insulin were older and more likely to have type 2 diabetes mellitus. Average body mass index was comparable between both groups (38.6 compared with 40.4, P=.11) as were obstetric and perinatal outcomes and glycemic control during the last week of gestation. Within the 500 units/mL concentrated insulin cohort, after initiation of this medication, fasting and postprandial blood glucose concentrations improved. However, the rates of blood glucose values less than 60 mg/dL and less than 50 mg/dL were higher in the 500 units/mL concentrated insulin group after initiation than before, 4.8% compared with 2.0% (P<.01) and 2.0% compared with 0.7% (P<.01), respectively. CONCLUSION: The use of 500 units/mL concentrated insulin in severely obese insulin-resistant pregnant women confers similar glycemic control compared with traditional insulin regimens but may increase the risk of hypoglycemia. LEVEL OF EVIDENCE: II. PMID- 23743465 TI - Cost analysis of maternal disease associated with suboptimal breastfeeding. AB - OBJECTIVE: To estimate the U.S. maternal health burden from current breastfeeding rates both in terms of premature death as well as economic costs. METHODS: Using literature on associations between lactation and maternal health, we modeled the health outcomes and costs expected for a U.S. cohort of 15-year-old females followed to age 70 years. In 2002, this cohort included 1.88 million individuals. Using Monte Carlo simulations, we compared the outcomes expected if 90% of mothers were able to breastfeed for at least 1 year after each birth with outcomes under the current 1-year breastfeeding rate of 23%. We modeled cases of breast cancer, premenopausal ovarian cancer, hypertension, type 2 diabetes mellitus, and myocardial infarction considering direct costs, indirect costs, and cost of premature death (before age 70 years) expressed in 2011 dollars. RESULTS: If observed associations between breastfeeding duration and maternal health are causal, we estimate that current breastfeeding rates result in 4,981 excess cases of breast cancer, 53,847 cases of hypertension, and 13,946 cases of myocardial infarction compared with a cohort of 1.88 million U.S. women who optimally breastfed. Using a 3% discount rate, suboptimal breastfeeding incurs a total of $17.4 billion in cost to society resulting from premature death (95% confidence interval [CI] $4.38-24.68 billion), $733.7 million in direct costs (95% CI $612.9 859.7 million), and $126.1 million indirect morbidity costs (95% CI $99.00-153.22 million). We found a nonsignificant difference in number of deaths before age 70 years under current breastfeeding rates (4,396 additional premature deaths, 95% CI -810-7,918). CONCLUSIONS: Suboptimal breastfeeding may increase U.S. maternal morbidity and health care costs. Thus, investigating whether the observed associations between suboptimal breastfeeding and adverse maternal health outcomes are causal should be a research priority. PMID- 23743466 TI - Alcohol use disorders and hospital-acquired infections in women undergoing cesarean delivery. AB - OBJECTIVE: To determine the risk of hospital-acquired infection in women with alcohol use disorders undergoing cesarean delivery. METHODS: Using the Nationwide Inpatient Sample, we conducted a retrospective cohort study of women undergoing cesarean delivery from 2002 to 2010. Women with a diagnosis of alcohol use disorder were compared with women without alcohol use disorders. Hospital acquired infections include surgical site infection, endometritis, urinary tract infection, sepsis, and pneumonia. RESULTS: A total of 12,081 women with alcohol use disorders were identified and matched with 11,960 women without alcohol use disorders. Women with alcohol use disorders were more likely to have development of urinary tract infection and sepsis. By multivariable analyses, women with alcohol use disorders had higher odds of hospital-acquired infections (odds ratio 2.2, 95% confidence interval [CI] 1.9-2.7; P=2*10; 397 among those with alcohol use disorders and 179 among those without alcohol use disorders; number needed to harm 55). Length of stay was longer in women with alcohol use disorders, but this was unexplained by hospital-acquired infection (3.3 days; 95% CI 3.2-3.3 compared with 3.1 days; 95% CI 3.0-3.1; P=4*10). CONCLUSION: Women with alcohol use disorders undergoing cesarean delivery have increased risk of hospital-acquired infections. Interventions aimed at decreasing alcohol use disorders during pregnancy may reduce maternal and fetal complications. LEVEL OF EVIDENCE: II. PMID- 23743467 TI - Perioperative oxygen supplementation and surgical site infection after cesarean delivery: a randomized trial. AB - OBJECTIVE: To evaluate whether supplemental perioperative oxygen decreases surgical site wound infections or endometritis. STUDY DESIGN: This was a prospective, randomized trial. Patients who were to undergo cesarean delivery were recruited and randomly allocated to either 30% or 80% oxygen during the cesarean delivery and for 1 hour after surgery. The obstetricians and patients were blinded to the concentration of oxygen used. Patients were evaluated for wound infection or endometritis during their hospital stay and by 6 weeks postpartum. The primary end point was a composite of either surgical site infection or endometritis. RESULTS: Eight hundred thirty-one patients were recruited. Of these, 415 participants received 30% oxygen perioperatively and 416 received 80% oxygen. The groups were well matched for age, race, parity, diabetes, number of previous cesarean deliveries, and scheduled compared with unscheduled cesarean deliveries. An intention-to-treat analysis was used. There was no difference in the primary composite outcome (8.2% in women who received 30% oxygen compared with 8.2% in women who received 80% oxygen, P=.89), no difference in surgical site infection in the two groups (5.5% compared with 5.8%, P=.98), and no significant difference in endometritis in the two groups (2.7% compared with 2.4%, P=.66), respectively. CONCLUSION: Women who received 80% supplemental oxygen perioperatively did not have a lower rate of a surgical site infection or endometritis as compared with women who received 30% supplemental oxygen concentration. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clincaltrials.gov, NCT00876005. LEVEL OF EVIDENCE: I. PMID- 23743468 TI - Cerebral palsy and perinatal infection in children born at term. AB - OBJECTIVE: To investigate the link between infection-related risk factors for cerebral palsy subtypes in children born at term. METHODS: A case-control study was performed in a population-based series of children with cerebral palsy born at term (n=309) matched with a control group (n=618). The cases were divided into cerebral palsy subtypes: spastic hemiplegia, spastic diplegia, spastic tetraplegia, and dyskinetic cerebral palsy. All forms of spastic cerebral palsy were also analyzed together. All records were examined for maternal and neonatal signs of infection. Univariate and adjusted analyses were performed. RESULTS: Infection-related risk factors were shown to be independent risk factors for spastic cerebral palsy in the adjusted analyses. This was especially pronounced in the subgroup with spastic hemiplegia in which bacterial growth in urine during pregnancy (n=11 [7.5%], odds ratio [OR] 4.7, 95% confidence interval [CI] 1.5 15.2), any infectious disease during pregnancy (n=57 [39.0%], OR 2.9, 95% CI 1.7 4.8), severe infection during pregnancy (n=12 [8.2%], OR 15.4, 95% CI 3.0-78.1), antibiotic therapy once during pregnancy (n=33 [22.6%], OR 6.3, 95% CI 3.0-15.2) as well as several times during pregnancy (n=9 [6.2%], OR 15.6, 95% CI 1.8-134.2) constituted strong independent risk factors. However, only neonatal infection (n=11 [9.1%], OR 14.7, 95% CI 1.7-126.5) was independently significantly associated with an increased risk of spastic diplegia and tetraplegia. CONCLUSIONS: Infection-related factors are strong independent risk factors for the subgroup with spastic hemiplegia in children with cerebral palsy born at term. The finding is less pronounced in the subgroups with spastic diplegia or tetraplegia. LEVEL OF EVIDENCE: II. PMID- 23743469 TI - Every woman, every time. PMID- 23743470 TI - Short-acting sulfonamides near term and neonatal jaundice. AB - OBJECTIVE: To investigate the association between maternal use of sulfamethizole near term and the risk of neonatal jaundice. METHODS: We conducted a nationwide population-based retrospective cohort study using Danish registers. All Danish women giving birth between 1995 and 2007 were included from the Danish Fertility Database. Women redeeming a prescription for sulfamethizole up to 4 weeks before giving birth were identified from the National Prescription Register. The primary outcome was the number of neonates diagnosed with jaundice between birth and age 28 days identified in the National Hospital Register. Risk of neonatal jaundice was calculated as odds ratios (ORs) with linear logistic regression with and without adjustment for confounders. RESULTS: We identified 841,900 births. Of 1,823 (0.2%) neonates exposed to sulfamethizole up to 4 weeks before birth, 197 (10.8%) developed neonatal jaundice. The OR of developing neonatal jaundice after exposure to sulfamethizole was 2.35 (95% confidence interval [CI] 2.02-2.72). Adjustment for maternal age, education, household income, parity, and period of conception left OR unchanged at 2.29 (95% CI 1.97-2.67). After further adjustment for gestational age, the risk associated with sulfamethizole was rendered insignificant (OR 1.03, 95% CI 0.86-1.22). Narrowing exposure time to the last week before birth did not change the estimates. Broken into gestational age groups, the rate of neonates with jaundice after exposure was similar to the rate of unexposed neonates with jaundice. CONCLUSIONS: We found no association between redeeming a prescription of sulfamethizole near term and increased risk of neonatal jaundice. We showed that the presumed association is the result of preterm birth, which can be caused by maternal urinary tract infection. LEVEL OF EVIDENCE: II. PMID- 23743471 TI - Buccal misoprostol compared with synthetic osmotic cervical dilator before surgical abortion: a randomized controlled trial. AB - OBJECTIVE: To compare the efficacy and acceptability of buccal misoprostol or a synthetic osmotic cervical dilator for cervical preparation before same-day late first-trimester and early second-trimester surgical abortion. METHODS: In this randomized, double-blind trial, we compared 400 micrograms of buccal misoprostol with one synthetic osmotic cervical dilator administered 3-4 hours before surgical abortion among women at 12-15 weeks of gestation. The primary outcome was mean cervical circumferential dilation at the time of surgery. Randomization was stratified by parity and sample size calculated to detect a 3-French difference between groups with 90% power with a two-sided alpha of .05. Secondary outcomes included ease of further mechanical dilation, procedure time, complications, ripening and procedural pain, and participants' satisfaction. RESULTS: One hundred twenty-five women were randomized with a mean gestational age of 13 3/7 weeks. Treatment with the synthetic osmotic dilator and buccal misoprostol resulted in similar preoperative dilation (mean French 33.9 compared with 32.1, P=.065). Procedure time, procedural pain, number of complications, and participants' satisfaction and preferences did not differ between treatment groups. Misoprostol participants experienced more pain during ripening (P=.008). All but six participants, three in each arm, required mechanical dilation at the time of the procedure. This manual dilation was subjectively easier in participants who received the synthetic osmotic cervical dilator (P=.015). All participants were able to have their procedure in 1 day without further cervical preparation. CONCLUSION: Either buccal misoprostol or a synthetic osmotic cervical dilator provides adequate dilation for same-day late first-trimester and early second-trimester abortion. Despite more pain with misoprostol, patient satisfaction with misoprostol and the synthetic dilator is similar. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, NCT00835731. LEVEL OF EVIDENCE: I. PMID- 23743472 TI - Postoperative gum chewing after gynecologic laparoscopic surgery: a randomized controlled trial. AB - OBJECTIVE: To investigate the effect of postoperative gum chewing on bowel motility after laparoscopic gynecologic surgery. METHODS: In this randomized controlled trial, patients were allocated to either postoperative gum chewing every 2 hours for 15 minutes or standard postoperative care without gum chewing. The study's primary end points were time to first regular bowel sounds and time to first passage of flatus after surgery. Secondary end points were time of operation to first defecation, patient satisfaction concerning postoperative gum chewing, potential side effects of postoperative gum chewing, and potential effect of gum chewing on postoperative pain therapy. RESULTS: One hundred seventy nine patients were included in this trial. We found a significantly shorter interval between surgery and passage of first flatus in the intervention group compared with the control group (median 6.2 hours compared with 8.1 hours; P=.002) and a significantly higher rate of regular bowel sounds 3 hours (76% compared with 47%; P<.001) and 5 hours (91% compared with 78%; P=.01) after surgery. Fewer opioid analgetics were administered to patients allocated to the intervention group (P=.02). There was no significant difference in time to first defecation between groups (median 26.3 hours compared with 29.0 hours, P=.165). Gum chewing was well tolerated and well accepted by patients, and no intervention related side effects were observed. CONCLUSION: Gum chewing seems to have beneficial effects on bowel motility when used as an adjunct treatment in postoperative care after minimally invasive surgery. Gum chewing should be recommended to patients after gynecologic laparoscopic surgery. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, NCT 01549353. LEVEL OF EVIDENCE: I. PMID- 23743474 TI - Rapid identification of dairy mesophilic and thermophilic sporeforming bacteria using DNA high resolution melt analysis of variable 16S rDNA regions. AB - Due to their ubiquity in the environment and ability to survive heating processes, sporeforming bacteria are commonly found in foods. This can lead to product spoilage if spores are present in sufficient numbers and where storage conditions favour spore germination and growth. A rapid method to identify the major aerobic sporeforming groups in dairy products, including Bacillus licheniformis group, Bacillus subtilis group, Bacillus pumilus group, Bacillus megaterium, Bacillus cereus group, Geobacillus species and Anoxybacillus flavithermus was devised. This method involves real-time PCR and high resolution melt analysis (HRMA) of V3 (~70 bp) and V6 (~100 bp) variable regions in the 16S rDNA. Comparisons of HRMA curves from 194 isolates of the above listed sporeforming bacteria obtained from dairy products which were identified using partial 16S rDNA sequencing, allowed the establishment of criteria for differentiating them from each other and several non-sporeforming bacteria found in samples. A blinded validation trial on 28 bacterial isolates demonstrated complete accuracy in unambiguous identification of the 7 different aerobic sporeformers. The reliability of HRMA method was also verified using boiled extractions of crude DNA, thereby shortening the time needed for identification. The HRMA method described in this study provides a new and rapid approach to identify the dominant mesophilic and thermophilic aerobic sporeforming bacteria found in a wide variety of dairy products. PMID- 23743476 TI - Inflammation: IL-1alpha comes to the fore. PMID- 23743475 TI - 25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end. AB - Chronic hepatitis caused by infection with hepatitis C virus C (HCV) (therefore known as chronic hepatitis C (CHC)) is a leading cause of liver disease worldwide. For the past 25 years, recombinant interferon-alpha (IFNalpha) has been the main component of treatments for HCV infection. Treatment efficacy has shown a stepwise improvement following the pegylation of IFNalpha and its use in combination with other antiviral drugs. However, viral escape mechanisms, refractory IFNalpha signalling in the liver and substantial drug toxicity still limit the efficacy of this treatment. A new generation of HCV-specific antiviral drugs will probably improve response rates and might replace IFNs in CHC treatment in the next few years. This Timeline article summarizes the history of CHC treatment using recombinant IFNalpha with an emphasis on the mechanisms of action and the causes of non-response. PMID- 23743477 TI - Mucosal immunology: ILCs broker peace deals in the gut. PMID- 23743478 TI - Tumour immunology: cracking the combination. PMID- 23743479 TI - [Glucocorticoid-induced adverse events in patients with giant cell arteritis or polymyalgia rheumatica]. AB - Giant cell arteritis and polymyalgia rheumatica are common reasons for prescribing long-term glucocorticoid therapy. Glucocorticoids efficacy in these patients is rapid and undeniable, but it is often overshadowed by adverse events, appearing more or less early during treatment course. These adverse events are usually minor but some of them may be life threatening. Because of the absence of randomized, controlled trials comparing glucocorticoids to placebo in this indication and in this aged population, it is difficult to precise the role of corticosteroids in the occurrence of some complications that can also be precipitated by the disease itself (e.g., vascular complications) or related to aging. In this context, analysis of the crude morbidity and mortality can help in anticipating the potential problems that these patients will encounter. In addition, the long duration of glucocorticoid exposure should prompt physicians to be particularly vigilant regarding some adverse events that are minimally symptomatic on the short term but have a major long-term impact. PMID- 23743480 TI - [The myeloproliferative neoplasms-related glomerulopathy]. AB - PURPOSE: Myeloproliferative neoplasms (MPN) are hematological disorders characterized by clonal expansion of one or more medullary lines. Renal complications are rare, chiefly as acute renal failure. Glomerular involvement is exceptional METHODS: We report on a retrospective multicenter case series of eight patients who presented with a glomerulopathy (GP) associated with MPN RESULTS: All GP were revealed by a major proteinuria frequently associated with nephrotic syndrome and oedema. Histology was mainly characterized by lesions of focal segmental glomerulosclerosis associated with increased mesangial cellularity. The pathophysiology is still unclear but platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta), which play a central role in the MPN may be involved. A majority of patients developed chronic renal failure despite of a therapy intended to block the renin-angiotensin system CONCLUSION: Monitoring of proteinuria during the follow-up of MPN would allow earlier diagnosis of renal involvement. Further studies on a larger scale are needed to specify the pathophysiological mechanisms involved and the management of these complications. PMID- 23743481 TI - Synthesis of porous Fe3O4 hollow microspheres/graphene oxide composite for Cr(vi) removal. AB - A composite of porous Fe3O4 hollow microspheres/graphene oxide (Fe3O4/GO) has been fabricated through a facile self-assembly approach. Driven by the mutual electrostatic interactions, the amine-functionalized Fe3O4 microspheres prepared by a hydrothermal method and then modified by 3-aminopropyltrimethoxysilane were decorated with negatively-charged GO sheets. The Fe3O4 microspheres were hollow with porous surfaces and the surfaces were successfully modified with the amine, which was confirmed by Fourier transform infrared spectroscopy. The specific saturation magnetization of Fe3O4/GO was 37.8 emu g(-1). The sorption performance of Fe3O4/GO for Cr(vi) was evaluated. The maximum sorption capacity for Cr(vi) on Fe3O4/GO was 32.33 mg g(-1), which was much higher than that of Fe3O4 microspheres. The GO sheets could not only prevent agglomeration of the Fe3O4 microspheres and enable a good dispersion of these oxide microspheres, but also substantially enhance the specific surface area of the composite. The Fe3O4/GO composite may be a promising sorption material for the separation and preconcentration of heavy metal ions from aqueous solutions in environmental pollution cleanup. PMID- 23743483 TI - A new versatile underground gamma-ray spectrometry system. AB - The newest development in IRMM's underground analytical facility is a large lead shield lined with copper that is versatile and can host several detectors of different types. The characteristics and the background performance of the shield are described for four different detector configurations involving HPGe-detectors and NaI-detectors. The shield has been designed to swap detectors, while still maintaining a low background. This enables testing of detectors for other experiments and optimisation of detection limits for specific radionuclides in different projects. PMID- 23743482 TI - A randomized controlled trial of soap opera videos streamed to smartphones to reduce risk of sexually transmitted human immunodeficiency virus (HIV) in young urban African American women. AB - BACKGROUND: Love, Sex, and Choices (LSC) is a soap opera video series created to reduce HIV sex risk in women. METHODS: LSC was compared to text messages in a randomized trial in 238 high-risk mostly Black young urban women. 117 received 12 weekly LSC videos, 121 received 12-weekly HIV prevention messages on smartphones. Changes in unprotected sex with high risk partners were compared by mixed models. RESULTS: Unprotected sex with high risk men significantly declined over 6 months post-intervention for both arms, from 21-22 acts to 5-6 (p < 0.001). This reduction was 18 % greater in the video over the text arm, though this difference was not statistically significant. However, the LSC was highly popular and viewers wanted the series to continue. CONCLUSION: This is the first study to report streaming soap opera video episodes to reduce HIV risk on smartphones. LSC holds promise as an Internet intervention that could be scaled-up and combined with HIV testing. PMID- 23743484 TI - Highly ordered cubic mesoporous electrospun SiO2 nanofibers. AB - Cubic (Im3[combining macron]m) mesoporous silica nanofibers were successfully prepared using a new F127-PVA-SiO2 tri-constituent assembly approach by the electrospinning technique. PVA was used to protect the F127 directed cubic micelles which usually deform during electrospinning. The preformed Au NPs can be loaded inside the mesopores of the nanofibers. PMID- 23743485 TI - Novel ZnO nanorod films by chemical solution deposition for planar device applications. AB - Smooth and continuous ZnO films consisting of densely packed ZnO nanorods (NRs), which can be used for electronic device fabrication, were synthesized using a hydro-thermo-chemical solution deposition method. Such devices would have the novelty of high performance, benefiting from the inherited unique properties of the nanomaterials, and can be fabricated on these smooth films using a conventional, low cost planar process. Photoluminescence measurements showed that the NR films have much stronger shallow donor to valence band emissions than those from discrete ZnO NRs, and hence have the potential for the development of ZnO light emission diodes and lasers, etc. The NR films have been used to fabricate large area surface acoustic wave devices by conventional photolithography. These demonstrated two well-defined resonant peaks and their potential for large area device applications. The chemical solution deposition method is simple, reproducible, scalable and economic. These NR films are suitable for large scale production on cost-effective substrates and are promising for various fields such as sensing systems, renewable energy and optoelectronic applications. PMID- 23743486 TI - Acute decompensated heart failure: update on new and emerging evidence and directions for future research. AB - Acute decompensated heart failure (ADHF) is a complex clinical event associated with excess morbidity and mortality. Managing ADHF patients is challenging because of the lack of effective treatments that both reduce symptoms and improve clinical outcomes. Existing guideline recommendations are largely based on expert opinion, but several recently published trials have yielded important data to inform both current clinical practice and future research directions. New insight has been gained regarding volume management, including dosing strategies for intravenous loop diuretics and the role of ultrafiltration in patients with heart failure and renal dysfunction. Although the largest ADHF trial to date (ASCEND HF, using nesiritide) was neutral, promising results with other investigational agents have been reported. If these findings are confirmed in phase III trials, novel compounds, such as relaxin, omecamtiv mecarbil, and ularitide, among others, may become therapeutic options. Translation of research findings into quality clinical care can not be overemphasized. Although many gaps in knowledge exist, ongoing studies will address issues around delivery of evidence-based care to achieve the goal of improving the health status and clinical outcomes of patients with ADHF. PMID- 23743487 TI - Clinical course of patients with hyponatremia and decompensated systolic heart failure and the effect of vasopressin receptor antagonism with tolvaptan. AB - BACKGROUND: Patients with decompensated heart failure, volume overload, and hyponatremia are challenging to manage. Relatively little has been documented regarding the clinical course of these patients during standard in-hospital management or with vasopressin antagonism. METHODS AND RESULTS: The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan database was examined to assess the short-term clinical course of patients hospitalized with heart failure and hyponatremia and the effect of tolvaptan on outcomes. In the placebo group, patients with hyponatremia (serum Na(+) <135mEq/L; n = 232), compared with those with normonatremia at baseline (n = 1785), had less relief of dyspnea despite receiving higher doses of diuretics (59.2% vs 69.2% improved; P < .01) and worse long-term outcomes. In the hyponatremia subgroup from the entire trial cohort (n = 475), tolvaptan was associated with greater likelihood of normalization of serum sodium than placebo (58% vs 20% and 64% vs 29% for day 1 and discharge, respectively; P < .001 for both comparisons), greater weight reduction at day 1 and discharge (0.7 kg and 0.8 kg differences, respectively; P < .001 and P = .008), and greater relief of dyspnea (P = .03). Among all hyponatremic patients, there was no effect of tolvaptan on long-term outcomes compared with placebo. In patients with pronounced hyponatremia (<130 mEq/L; n = 92), tolvaptan was associated with reduced cardiovascular morbidity and mortality after discharge (P = .04). CONCLUSIONS: In patients with decompensated heart failure and hyponatremia, standard therapy is associated with less weight loss and dyspnea relief, and unfavorable longer-term outcomes compared to those with normonatremia. Tolvaptan is associated with more favorable in-hospital effects and, possibly, long-term outcomes in patients with severe hyponatremia. PMID- 23743488 TI - Hyponatremia in heart failure: time for a trial. PMID- 23743489 TI - Clinical effectiveness of anticoagulation therapy among older patients with heart failure and without atrial fibrillation: findings from the ADHERE registry linked to Medicare claims. AB - BACKGROUND: Patients with heart failure are at higher risk for thromboembolic events, even in the absence of atrial fibrillation, but the effect of anticoagulation therapy on outcomes is uncertain. METHODS AND RESULTS: With data from a clinical registry linked to Medicare claims, we estimated the adjusted associations between anticoagulation and 1-year outcomes with the use of inverse probability of treatment weighting. Eligible patients had an ejection fraction <=35%, had no concurrent atrial fibrillation, were alive at discharge, and had not received anticoagulation therapy before admission. Of 13,217 patients in 276 hospitals, 1,140 (8.6%) received anticoagulation therapy at discharge. Unadjusted rates of thromboembolic events and major adverse cardiovascular events did not differ by receipt of anticoagulation therapy. Patients discharged on anticoagulation therapy had lower unadjusted rates of all-cause mortality (27.2% vs 32.3%; P < .001) and readmission for heart failure (29.4% vs 35.4%; P < .001) and higher rates of bleeding events (5.2% vs 2.8%; P < .001). After adjustment for probability of treatment and discharge medications, there were no differences in all-cause mortality (hazard ratio 0.92; 95% confidence interval 0.80-1.06) or readmission for heart failure (0.91, 0.81-1.02), but patients receiving anticoagulation therapy were at higher risk for bleeding events (2.09, 1.47 2.97). CONCLUSIONS: Anticoagulation therapy at discharge is infrequent among older patients with heart failure and without atrial fibrillation. There were no statistically significant propensity-weighted associations between anticoagulation therapy and 1-year outcomes, except for a higher risk of bleeding. PMID- 23743490 TI - Clinical predictors and hemodynamic consequences of elevated peripheral chemosensitivity in optimally treated men with chronic systolic heart failure. AB - AIMS: Augmented peripheral chemoreflex response is an important mechanism in the pathophysiology of chronic heart failure (CHF). This study characterizes prevalence and clinical predictors of this phenomenon in optimally managed male CHF patients, and seeks to describe the hemodynamic consequences of chemoreceptor hypersensitivity. METHODS AND RESULTS: Thirty-four optimally managed CHF patients and 16 control subjects were prospectively studied. Hypoxic ventilatory response (HVR)-a measure of peripheral chemosensitivity-was calculated with the use of short nitrogen gas administrations. Systolic blood pressure (SBP) and heart rate (HR) following transient hypoxic challenges were recorded with a Nexfin monitor. Hemodynamic responses to hypoxia were expressed by the linear slopes between oxygen saturation (%) and SBP (mm Hg) or HR (beats/min). Elevated HVR was present in 15 (44%) of the CHF patients. Patients with elevated HVR exhibited higher levels of N-terminal pro-B-type natriuretic peptide, lower left ventricular ejection fraction, and higher prevalence of atrial fibrillation. CHF patients with elevated HVR had significantly greater SBP and HR responses to hypoxia than CHF patients with normal HVR. CONCLUSIONS: Despite comprehensive pharmacotherapy, elevated HVR is prevalent in CHF patients, related to severity of the disease and associated with augmented hemodynamic responses to hypoxia. CHF patients with elevated HVR may be prone to unfavorable hemodynamic changes. PMID- 23743492 TI - Endothelial dysfunction is a marker of systemic response to the cardiac resynchronization therapy in heart failure. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) induces a significant improvement in patients with heart failure (HF), who are often characterized by the presence of endothelial dysfunction (ED) with impaired flow-mediated vasodilation (FMD). We aimed to study the ED in patients with HF candidates to CRT with defibrillator (CRT-D). METHODS AND RESULTS: We studied 57 consecutive patients affected by HF and undergoing CRT-D. At the baseline we recorded a high prevalence of ED (64.9%) with impaired FMD (4.1 +/- 3.8%). After 12 months of CRT, we reported a marked increase of the mean FMD (8.8 +/- 4.8% vs 4.1 +/- 3.8%; P < .05) along with significant improvement of left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), New York Heart Association (NYHA) functional class, and 6-minute walk test (6MWT); 42 patients (73.7%) were classified as responders according to standard criteria. FMD was related to LVEF (r = 0.169; P < .05), LVESV (r = -0.169; P < .05), NYHA functional class (r = 0.27; P < .051), and 6MWT (r = 0.360; P < .01). CONCLUSIONS: ED is not an independent predictor of CRT response, but it is able to intercept the systemic effects of CRT and is an affordable marker of response to CRT, especially in patients unable to perform the 6MWT. PMID- 23743491 TI - Chemoreflexes, sympathetic excitation, and heart failure-challenges and opportunities. PMID- 23743493 TI - Incidence of appropriate shock in implantable cardioverter-defibrillator patients with improved ejection fraction. AB - BACKGROUND: Heart failure with recovered ejection fraction (EF) is a recently described clinical entity. There is insufficient information on the management of implantable-cardioverter defibrillator (ICD) patients with improved EF at generator replacement. METHODS AND RESULTS: We examined the incidence of appropriate shocks in 91 consecutive patients with ICDs for primary prevention of sudden death who underwent generator replacement. Improved EF was defined as both EF >35% at generator replacement and increase in EF by >=10% since original implantation. Patients were 70 +/- 11 years old, and 76% had ischemic cardiomyopathy. At generator replacement, 25 patients (27%) had improved EF (0.49 +/- 0.08 vs 0.31 +/- 0.07 at baseline; P < .0001). Over 6.2 +/- 2.2 years of follow-up after original implantation, 9 patients (36%) with improved EF versus 19 (29%) with unchanged EF had appropriate ICD shocks (P = .51). Incidence of appropriate ICD shocks was similar between the two groups before (P = .90) and after (P = .97) generator replacement. Of the 9 improved EF patients with appropriate shock, 4 had shocks before generator replacement, 2 had shocks before and after generator replacement, and 3 patients, who never had shocks before, had their first shock after generator replacement. CONCLUSIONS: Some ICD patients whose EF improves to >35% at generator replacement remain at risk for appropriate ICD shocks. PMID- 23743495 TI - The relationship between oxidative stress and nonalcoholic fatty liver disease: Its effects on the development of nonalcoholic steatohepatitis. AB - Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the most common underlying causes of chronic liver injury. They are associated with a wide spectrum of hepatic disorders including basic steatosis, steatohepatitis, and cirrhosis. The molecular and cellular mechanisms underlying hepatic injury in NAFLD and NASH are still unknown. This review describes the roles of oxidative stress and inflammatory responses in the pathogenesis of NAFLD and its progression to NASH. PMID- 23743494 TI - Sleep-disordered breathing in heart failure: identifying and treating an important but often unrecognized comorbidity in heart failure patients. AB - Sleep-disordered breathing (SDB) is the most common comorbidity in patients with heart failure (HF) and has a significant impact on quality of life, morbidity, and mortality. A number of therapeutic options have become available in recent years that can improve quality of life and potentially the outcomes of HF patients with SDB. Unfortunately, SDB is not part of the routine evaluation and management of HF, so it remains untreated in most HF patients. Although recognition of the role of SDB in HF is increasing, clinical guidelines for the management of SDB in HF patients continue to be absent. This article provides an overview of SDB in HF and proposes a clinical care pathway to help clinicians to better recognize and treat SDB in their HF patients. PMID- 23743497 TI - Antimuscarinics for the treatment of neurogenic detrusor overactivity. PMID- 23743496 TI - Functional proteomics, human genetics and cancer biology of GIPC family members. AB - GIPC1, GIPC2 and GIPC3 consist of GIPC homology 1 (GH1) domain, PDZ domain and GH2 domain. The regions around the GH1 and GH2 domains of GIPC1 are involved in dimerization and interaction with myosin VI (MYO6), respectively. The PDZ domain of GIPC1 is involved in interactions with transmembrane proteins [IGF1R, NTRK1, ADRB1, DRD2, TGFbetaR3 (transforming growth factorbeta receptor type III), SDC4, SEMA4C, LRP1, NRP1, GLUT1, integrin alpha5 and VANGL2], cytosolic signaling regulators (APPL1 and RGS19) and viral proteins (HBc and HPV-18 E6). GIPC1 is an adaptor protein with dimerizing ability that loads PDZ ligands as cargoes for MYO6-dependent endosomal trafficking. GIPC1 is required for cell-surface expression of IGF1R and TGFbetaR3. GIPC1 is also required for integrin recycling during cell migration, angiogenesis and cytokinesis. On early endosomes, GIPC1 assembles receptor tyrosine kinases (RTKs) and APPL1 for activation of PI3K-AKT signaling, and G protein-coupled receptors (GPCRs) and RGS19 for attenuation of inhibitory Galpha signaling. GIPC1 upregulation in breast, ovarian and pancreatic cancers promotes tumor proliferation and invasion, whereas GIPC1 downregulation in cervical cancer with human papillomavirus type 18 infection leads to resistance to cytostatic transforming growth factorbeta signaling. GIPC2 is downregulated in acute lymphocytic leukemia owing to epigenetic silencing, while Gipc2 is upregulated in estrogen-induced mammary tumors. Somatic mutations of GIPC2 occur in malignant melanoma, and colorectal and ovarian cancers. Germ-line mutations of the GIPC3 or MYO6 gene cause nonsyndromic hearing loss. As GIPC proteins are involved in trafficking, signaling and recycling of RTKs, GPCRs, integrins and other transmembrane proteins, dysregulation of GIPCs results in human pathologies, such as cancer and hereditary deafness. PMID- 23743498 TI - Neurogenic detrusor overactivity in adults: a review on efficacy, tolerability and safety of oral antimuscarinics. AB - OBJECTIVES: This review analyzed efficacy, tolerability and safety of oral antimuscarinic (AM) drugs in adults suffering from neurogenic detrusor overactivity (NDO). METHODS: A comprehensive search of major literature bases was conducted to identify all references. RESULTS: Thirty studies, thereof 16 randomized controlled trials (RCT), enrolling 1479 patients were identified and included in the review. Results were grouped in dose-finding, placebo- and active controlled, flexible dose and combined high-dose AM drugs, and various studies. Key urodynamic outcome parameters, such as maximum detrusor pressure and maximum cystometric bladder capacity, demonstrated the efficacy of AM in NDO, following 2 3 weeks of treatment. Contrary to idiopathic detrusor overactivity (IDO), no placebo effects manifested. Other important parameters, such as impact on the upper urinary tract function and morphology, issues of continence, post-void residual urine, catheterisation, urinary tract infections and quality of life, were investigated to a limited extent only. Incidence rates of adverse events were comparable for NDO and IDO. Most of the studies, especially RCT, were undertaken with oxybutynin immediate release (IR), trospium chloride IR, propiverine IR and propiverine extended release. In NDO, these drugs are best investigated. CONCLUSIONS: AM drugs are effective in NDO, they normalize the intravesical pressure and increase cystometric bladder capacity. However, other important parameters are not adequately investigated so far and should be recognized in future studies. PMID- 23743499 TI - A prospective evaluation of hemodynamic management in acute spinal cord injury patients. AB - STUDY DESIGN: Prospective observational study of acute spinal cord-injured (SCI) patients. OBJECTIVES: To determine how effectively mean arterial blood pressure (MAP) and spinal cord perfusion pressure (SCPP) are maintained at target levels in acute SCI patients. SETTING: Single-institution study at a Canadian level-one trauma center. METHODS: Twenty-one individuals with cervical or thoracic SCI were enrolled within 48 h of injury. A lumbar intrathecal drain was inserted for monitoring intrathecal cerebrospinal fluid pressure (ITP). The MAP was monitored concurrently with ITP, and the SCPP was calculated. Data was recorded hourly from the time of first assessment until at least the end of the 5th day post injury. RESULTS: All subjects had at least one recorded episode with a MAP below 80 mm Hg, and 81% had at least one episode with a MAP below 70 mm Hg. On average, subjects with cervical injuries had 18.4% of their pressure recordings below 80 mm Hg. Subjects with thoracic cord injuries had on average 35.9% of their MAP recordings <80 mm Hg. CONCLUSION: It is common practice to establish MAP targets for optimizing cord perfusion in acute SCI. This study suggests that even in an acute SCI referral center, when prospectively scrutinized, the actual MAP may frequently fall below the intended targets. Such results raise awareness of the vigilance that must be kept in the hemodynamic management of these patients, and the potential discrepancy between routinely setting target MAP according to 'practice guidelines' and actually achieving them. PMID- 23743500 TI - Creating guidelines and treating patients when there are no trials or systematic reviews. PMID- 23743501 TI - Why don't patients get out of bed postoperatively? PMID- 23743502 TI - When comparing apples and oranges is all bananas! PMID- 23743504 TI - Effectiveness of tobacco use cessation interventions delivered by pharmacy personnel: a systematic review. AB - BACKGROUND: Tobacco use remains the leading cause of preventable morbidity and mortality. Implementation of tobacco use cessation interventions however requires strategies that reach large proportions of the population. Pharmacy personnel are therefore a potential human resource for delivering tobacco use cessation interventions. OBJECTIVE: This review aimed to identify, describe and synthesis currently available evidence on the effectiveness of tobacco use cessation interventions delivered by pharmacy personnel. METHODS: The following electronic databases were searched for studies published until May 2012: MEDLINE, EMBASE, PSYCINFO, Cochrane Library, Web of Knowledge and the Current Controlled Trials Register. This review considered controlled clinical trials and randomized controlled trials, which were comparing any pharmacy personnel delivered tobacco use cessation intervention to no treatment, usual care or other active treatments. The outcomes of interest were: abstinence (e.g., point prevalence; continuous abstinence) and relapse (e.g., time to relapse) as measured by the respective studies. The results were not pooled due to high levels of clinical heterogeneity. RESULTS: Ten eligible studies with a total of 20,133 participants were identified. Results suggest pharmacy personnel delivered non-pharmacological interventions offering behavioral counseling or support for tobacco use cessation could be beneficial, particularly from 6 months follow-up onwards. Combining these non-pharmacological with pharmacological interventions could also be beneficial. The results for the effectiveness of nicotine replacement therapy (NRT) were mixed with some findings suggesting intervention benefits, and others suggesting no clear benefit. CONCLUSIONS: Pharmacy personnel-delivered non pharmacological tobacco use cessation interventions offering behavioral counseling or support, and those combining these non-pharmacological interventions with NRT/pharmacological approaches, are potentially effective. No clear benefit has been demonstrated on pharmacy personnel-delivered NRT interventions. However, these findings are based on a very limited number of studies and hence more evidence is needed before more robust conclusions can be made. PMID- 23743503 TI - Glutathione and thioredoxin type 1 cooperatively denitrosate HepG2 cells-derived cytosolic S-nitrosoproteins. AB - In this study, we present experimental evidence that glutathione acts in concert with human thioredoxin type 1 in the denitrosation of cytosolic S-nitrosoproteins (PSNOs) from HepG2 cells. PMID- 23743506 TI - Characterization of low power research reactor neutrons for the validation of k(0)-INAA standardization based on k(0)-IAEA software. AB - Channel Bsite2 of Ghana research reactor-1 has been characterized for k0-INAA application. Cadmium ratio and bare multi-monitor were used to determine flux parameters using 0.1%Au-Al, Fe, and Zr wire as flux monitors. The parameters determined were 18.36+/-1.91, 0.0479+/-0.012, 5.12*10(11)+/-0.42*10(11) ncm(-2)s( 1), 2.74*10(10)+/-0.14*10(10) ncm(-2)s(-1), 7.73*10(10)+/-0.16*10(10) ncm(-2)s( 1) and 16.75+/-1.58, -0.034+/-0.0028, 4.28*10(11)+/-1.71*10(11) ncm(-2)s(-1), 2.55*10(10)+/-0.15*10(10) ncm(-2)s(-1) respectively for thermal-to-epithermal flux ratio, alpha, thermal neutron, epithermal neutron and fast neutron flux using cadmium ratio and multi-monitor method accordingly. The k0-INAA performance assessment based on z-score distributions showed most results within |z|<2. PMID- 23743505 TI - Determination of oxycodone, noroxycodone and oxymorphone by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry in human matrices: in vivo and in vitro applications. AB - The opioid analgesic oxycodone is widely abused and increasingly associated with overdose deaths. A sensitive analytical method was developed for oxycodone and its metabolites, noroxycodone and oxymorphone, in human plasma, urine (+/ enzymatic hydrolysis at 50 degrees C for 16 h) and liver microsomes (HLMs). Liquid-liquid extraction was followed by high-performance liquid chromatography electrospray ionization-tandem mass spectrometry. The calibration range was 0.2 250 ng/mL for plasma and HLM and 10-5000 ng/mL for urine. Intra- and interrun accuracies were within 13.3% of target; precisions were within 12.8% for all matrices. Recoveries from plasma were: oxycodone, 75.6%; noroxycodone, 37.4% and oxymorphone, 18.2%. Analytes exhibited room temperature stability in plasma and urine up to 24 h, and freeze-thaw stability in plasma up to three cycles. In 24-h hydrolyzed urine from subjects administered intranasal oxycodone (30 mg/70 kg, n = 5), mean concentrations (ng/mL) and % daily doses excreted were: oxycodone, 1150, 6.53%; noroxycodone, 1330, 7.81% and oxymorphone, 3000, 17.1%. Oxycodone incubated with HLM produced more noroxycodone than oxymorphone. With a panel of recombinant human cytochrome P450s (CYPs), CYP2C18 and CYP3A4 produced the most noroxycodone, whereas CYP2D6 produced the most oxymorphone. These results demonstrate a new method suitable for both in vivo and in vitro metabolism and pharmacokinetic studies of oxycodone. PMID- 23743507 TI - Cigarettes, culture, and Korean American emerging adults: an exploratory qualitative study. AB - Korean American emerging adults (KAEA) constitute an understudied, at-risk group for smoking and related health consequences. The cultural meanings of smoking and cessation among KAEA were explored. Sixty-seven KAEA participated in 10 focus groups. Themes from the sessions were identified and domain analysis was conducted. Regarding reasons for smoking, we identified (a) association between the culture of origin and gender identification, (b) access/availability of cigarettes in homes/community, and (c) competing social environments where KAEA adjust their health behaviors. Regarding contexts for cessation, we identified (a) a sense of invincibility/denial, (b) lack of role models or pressure to quit, and (c) lack of significant life events. Using cessation aids represented lacking personal discipline/willpower. The results show that smoking among KAEA is highly contextualized in the culture of origin, despite U.S. tobacco control policies. Implications for culturally sensitive prevention/cessation programs for KAEA include modifying culturally based norms and social spaces regarding cigarettes and cessation. PMID- 23743508 TI - The relationship between safety culture and patient outcomes: results from pilot meta-analyses. AB - Patient safety continues to be a serious health concern in acute-care hospitals. Safety culture has been a frequent target for patient safety improvement over the past decade, based on recommendations from the Institute of Medicine and its use in industry. However, the relationship between safety culture and patient safety in acute-care hospitals has yet to be systematically examined. Thus, a meta analysis was devised to examine the relationship between patient safety outcomes and safety culture in that setting. Due to the limited empirical research reports available, five small pilot meta-analyses were conducted, examining the relationship between safety culture and each of the following: pressure ulcers, falls, medication errors, nurse-sensitive outcomes, and post-operative outcomes. No significant relationships of any size were identified. An assessment of the relevant literature is presented, offering potential explanations for this surprising finding and an agenda for future research. PMID- 23743509 TI - Assessment of fatty degeneration of the gluteal muscles in patients with THA using MRI: reliability and accuracy of the Goutallier and quartile classification systems. AB - The purpose of this study was to quantify the performance of the Goutallier classification for assessing fatty degeneration of the gluteus muscles from magnetic resonance (MR) images and to compare its performance to a newly proposed system. Eighty-four hips with clinical signs of gluteal insufficiency and 50 hips from asymptomatic controls were analyzed using a standard classification system (Goutallier) and a new scoring system (Quartile). Interobserver reliability and intraobserver repeatability were determined, and accuracy was assessed by comparing readers' scores with quantitative estimates of the proportion of intramuscular fat based on MR signal intensities (gold standard). The existing Goutallier classification system and the new Quartile system performed equally well in assessing fatty degeneration of the gluteus muscles, both showing excellent levels of interrater and intrarater agreement. While the Goutallier classification system has the advantage of being widely known, the benefit of the Quartile system is that it is based on more clearly defined grades of fatty degeneration. PMID- 23743510 TI - Revision knee arthroplasty for bone loss: choosing the right degree of constraint. AB - Revision total knee arthroplasty (TKA) in the setting of bone deficiency requires varied levels of constraint to restore knee stability. However, the outcomes between different levels remain controversial. Clinical outcomes for 183 AORI Type I knees, 168 Type II knees and 124 Type III knees utilizing posterior stabilized (PS), unlinked constrained (UC) or hinged prostheses were evaluated with standardized clinical assessment tools and radiographic results over an average of 7.4 years. PS yielded superior knee scores in AORI Type I patients (P<0.05), UC in Type II and III aseptic patients (P<0.05), and a hinge was preferred in septic Type II or III knees (P<0.05). Revision TKA conducted with increased constraint appears effective in the setting of increased bone deficiency. PMID- 23743511 TI - Investigating dominant processes in ZVI permeable reactive barriers using reactive transport modeling. AB - The reactive and hydraulic efficacy of zero valent iron permeable reactive barriers (ZVI PRBs) is strongly affected by geochemical composition of the groundwater treated. An enhanced version of the geochemical simulation code MIN3P was applied to simulate dominating processes in chlorinated hydrocarbons (CHCs) treating ZVI PRBs including geochemical dependency of ZVI reactivity, gas phase formation and a basic formulation of degassing. Results of target oriented column experiments with distinct chemical conditions (carbonate, calcium, sulfate, CHCs) were simulated to parameterize the model. The simulations demonstrate the initial enhancement of anaerobic iron corrosion due to carbonate and long term inhibition by precipitates (chukanovite, siderite, iron sulfide). Calcium was shown to enhance long term corrosion due to competition for carbonate between siderite, chukanovite, and aragonite, with less inhibition of iron corrosion by the needle like aragonite crystals. Application of the parameterized model to a field site (Bernau, Germany) demonstrated that temporarily enhanced groundwater carbonate concentrations caused an increase in gas phase formation due to the acceleration of anaerobic iron corrosion. PMID- 23743512 TI - Tick bites and red meat allergy. AB - PURPOSE OF REVIEW: A novel form of anaphylaxis has been described that is due to IgE antibody (Ab) directed against a mammalian oligosaccharide epitope, galactose alpha-1,3-galactose (alpha-gal). Ongoing work regarding the cause and distribution of this IgE response is reviewed. RECENT FINDINGS: Our recent work has identified a novel IgE Ab response that has been associated with two distinct forms of anaphylaxis: immediate-onset anaphylaxis during first exposure to intravenous cetuximab and delayed-onset anaphylaxis 3-6 h after ingestion of mammalian food products (e.g. beef and pork). Further studies strongly suggested that tick bites were a cause, if not the only significant cause, of IgE Ab responses to alpha-gal in the United States and internationally. SUMMARY: Large numbers of patients with IgE Ab to alpha-gal continue to be identified in the USA and globally. Clinicians should be aware of this IgE response as the reactions often appear to be idiopathic because of the significant delay between eating mammalian meat and the appearance of symptoms. PMID- 23743513 TI - Angioedema induced by angiotensin-converting enzyme inhibitors. AB - PURPOSE OF REVIEW: Since angiotensin-converting enzyme inhibitors (ACEIs) were first introduced in the 1980s for treatment of hypertension and congestive heart failure, there has been progressive increase in use due to these and other new indications. This fact has led to a parallel increase in adverse effects induced by ACEIs, mainly angioedema, with different degrees of severity. RECENT FINDINGS: Different studies indicate that ACEI-induced angioedema is associated with high levels of bradykinin of different origin and this preferentially occurs in females and in African-American populations. The diagnosis of ACEI-induced angioedema can be difficult, due to its variable latency period from the initiation of treatment. Differential diagnosis of other causes of angioedema must be considered. The management of ACEI-induced angioedema involves the withdrawal of the causative drug and the treatment of the reaction with different drugs depending on its severity. Some studies have shown that angiotensin II receptor blockers (ARBs) may be an alternative, although some patients (<10%) with ACEI-associated angioedema also develop angioedema episodes after ARB intake. Therefore, ARBs may be reserved for patients with high therapeutic need for angiotensin inhibition. SUMMARY: The present review will focus on current and relevant aspects of ACEI-induced angioedema. The pathological mechanism, epidemiology and risk factors, differential diagnosis, patient management and treatment will be discussed. PMID- 23743514 TI - An update on self-injectable epinephrine. AB - PURPOSE OF REVIEW: Epinephrine is an important life-saving treatment in patients with anaphylaxis. However, despite the guidelines recommending the use of epinephrine in the management of all patients with anaphylaxis, many patients are either not prescribed epinephrine auto-injectors (EAIs) or remain hesitant to use them. RECENT FINDINGS: In this review, we examine our current knowledge base regarding EAIs, including issues related to dosing, medication availability and new modes of administration. Our findings suggest that all patients at risk for anaphylaxis should always carry two epinephrine doses. Once an EAI is prescribed, the patient should receive appropriate education on when and how to use it and it should be administered without delay. Current EAI devices have been redesigned to address limitations and decrease unintentional injury. SUMMARY: Epinephrine remains the cornerstone of anaphylaxis treatment and EAIs are critical because of their ability to rapidly deliver this potentially life-saving medication outside of a medical setting. Continued efforts are needed to establish evidence-based parameters for delivery of this medication and to optimize education of healthcare providers and patients on the use of EAIs. PMID- 23743515 TI - Nonimmediate hypersensitivity reactions to iodinated contrast media. AB - PURPOSE OF REVIEW: To provide a detailed analysis of the latest findings on the mechanisms underlying the nonimmediate reactions to iodinated contrast media and comment on the recent advances in diagnosis, focusing on the roles of the skin test, drug provocation test (DPT), and lymphocyte transformation test (LTT). RECENT FINDINGS: Several studies have reported new findings supporting an important role for T-lymphocytes in the nonimmediate reactions to iodinated contrast media. The LTT has been used as an in-vitro tool for diagnosis, but with variable results. However, the inclusion of autologous monocyte-derived dendritic cells as professional antigen-presenting cells has improved the sensitivity of this test. Regarding in-vivo diagnosis, although skin testing has been routine, it has now been shown that its sensitivity and negative predictive value are low. Recent studies have demonstrated that the DPT is a well tolerated and useful procedure that is necessary to confirm the diagnosis of nonimmediate hypersensitivity reactions to iodinated contrast media. SUMMARY: Nonimmediate reactions to contrast media are usually T-cell mediated. Diagnosis is based on skin testing, although its sensitivity and negative predictive value are not optimal. Consequently, drug provocation testing is often needed to confirm the diagnosis and also to seek alternative contrast media that can be tolerated. PMID- 23743516 TI - Characteristics and rates of mental health problems among Indian and White adolescents in two English cities. AB - BACKGROUND: Sampling techniques for national surveys have constrained the statistical power in estimating prevalence rates of child mental health problems in minority ethnic groups. AIMS: To establish the prevalence rates of mental health problems in ethnic Indian adolescents in England and compare these with matched White adolescents living in the same areas. METHOD: A cross-sectional survey with oversampling of Indian adolescents aged 13-15 years of age. RESULTS: The sample size was 2900 (71% response rate) with 1087 (37%) Indian and 414 (14%) White adolescents. Ethnically Indian adolescents had lower rates of all types of mental health problems (5% v. 13% and 21% v. 30% for abnormal Strengths and Difficulties Questionnaire and Short Mood and Feelings Questionnaire scores, respectively) and substance misuse (18% v. 57%, 5% v.15% and 6% v. 9% for regular alcohol, smoking and drug use, respectively), with the exception of eating disorders, compared with their White counterparts. The odds of an abnormal score on the mental health questionnaires were worse for White compared with Indian children irrespective of sociodemographic variables. CONCLUSIONS: Factors relating to how Indian adolescents are parented or their social support networks may be influencing their mental health and may warrant further investigation. PMID- 23743517 TI - Childhood maltreatment and methylation of the glucocorticoid receptor gene NR3C1 in bipolar disorder. AB - BACKGROUND: Early-life adversities represent risk factors for the development of bipolar affective disorder and are associated with higher severity of the disorder. This may be the consequence of a sustained alteration of the hypothalamic-pituitary-adrenal (HPA) axis resulting from epigenetic modifications of the gene coding for the glucocorticoid receptor (NR3C1). AIMS: To investigate whether severity of childhood maltreatment is associated with increased methylation of the exon 1F NR3C1 promoter in bipolar disorder. METHOD: A sample of people with bipolar disorder (n = 99) were assessed for childhood traumatic experiences. The percentage of NR3C1 methylation was measured for each participant. RESULTS: The higher the number of trauma events, the higher was the percentage of NR3C1 methylation (beta = 0.52, 95% CI 0.46-0.59, P<<0.0001). The severity of each type of maltreatment (sexual, physical and emotional) was also associated with NR3C1 methylation status. CONCLUSIONS: Early-life adversities have a sustained effect on the HPA axis through epigenetic processes and this effect may be measured in peripheral blood. This enduring biological impact of early trauma may alter the development of the brain and lead to adult psychopathological disorder. PMID- 23743518 TI - Methodological quality of a systematic review on physical therapy for temporomandibular disorders: influence of hand search and quality scales--reply to a letter to the author. PMID- 23743519 TI - Number of accessory or nutrient canals in the human mandible. AB - OBJECTIVES: The aim of the study was to assess the presence, location and the number of accessory or nutrient canals in the body of the mandible by means of cone beam CT images, obtained with the Planmeca ProMax(r) 3D Max device. MATERIAL AND METHODS: Seventy-four cone beam images of the mandible from adult patients (37 males and 37 females) who were imaged for dental implantology planning or third molar extraction were used to assess the number and location of accessory or nutrient canals. All images were taken with the same machine (Planmeca(r) ProMax 3D Max) at 200-, 400- or 600-MUm resolution. Distinction was made between canals entering or exiting the mandible superior or inferior of the inferior alveolar canal and between similar canals superior or inferior of the genial tubercula. RESULTS: The number of accessory canals varied between nil to 11. No statistical significant difference between males and females was found with regard to the number or location of accessory canals in the mandible. Only 5.4% of patients had no accessory canals. One to five accessory canals were found in 71.6%, and 23% of patients had more than five accessory canals. The majority (81%) of patients had between two and six accessory canals. CONCLUSION: It seems that subjects showing no accessory canals whatsoever should be considered exceptional as more subjects with than without accessory canals in the body of the mandible were found. CLINICAL RELEVANCE: These results are clinically relevant for mandibular surgery and mandibular local anaesthesia. PMID- 23743520 TI - A green and facile route for constructing flower-shaped TiO2 nanocrystals assembled on graphene oxide sheets for enhanced photocatalytic activity. AB - We have demonstrated an environmentally friendly in situ assembly method for the preparation of novel three-dimensional TiO2/graphene oxide (TiO2/GO) nanostructures with favorable flower-shaped architectures. Very little information on such a morphology of TiO2/GO nanostructures is available in the literature. The as-synthesized sample was characterized by x-ray diffraction, scanning electron microscopy, transmission electron microscopy, N2 adsorption desorption measurements and Raman spectroscopy. Also the TiO2/GO composites exhibited enhanced photocatalytic properties. PMID- 23743521 TI - Decreased respiratory rate variability during mechanical ventilation is associated with increased mortality. AB - OBJECTIVE: Patients on ventilatory support often experience significant changes in respiratory rate. Our aim was to determine the possible association between respiratory rate variability (RRV) and outcomes in these patients. DESIGN: A longitudinal, prospective, observational study of patients mechanically ventilated for at least 12 h performed in a medical-surgical intensive care unit. Patients were enrolled within 24 h of the initiation of ventilatory support. We measured airway signals continuously for the duration of ventilatory support and calculated expiratory flow frequency spectra at 2.5-min intervals. We assessed RRV using the amplitude ratio of the flow spectrum's first harmonic to the zero frequency component. Measures of the amplitude ratio were averaged over the total monitored time. Patients with time-averaged amplitude ratios <40 % were classified as high RRV and those >=40 % as low RRV. All-cause mortality rates were assessed at 28 and 180 days from enrollment with a Cox proportional hazards model adjusted for disease acuity by the simplified acute physiology score II. RESULTS: We enrolled 178 patients, of whom 47 had high RRV and 131 low RRV. Both groups had similar disease acuity upon enrollment. The 28- and 180-day mortality rates were greater for low RRV patients with hazard ratios of 4.81 (95 % CI 1.85 12.65, p = 0.001) and 2.26 (95 % CI 1.21-4.20, p = 0.01), respectively. Independent predictors of 28-day mortality were low RRV, i.v. vasopressin, and SAPS II. CONCLUSIONS: Decreased RRV during ventilatory support is associated with increased mortality. The mechanisms responsible for this finding remain to be determined. PMID- 23743522 TI - Quality of reporting of randomized controlled trials published in Intensive Care Medicine from 2001 to 2010. AB - PURPOSE: To evaluate the methodological quality of randomized controlled trials (RCTs) published in Intensive Care Medicine from 2001 to 2010, and to compare it with a previous review of RCTs published from 1975 to 2000. METHODS: We assessed the quality of reporting of randomization, blinding and participant flow, both individually and combined within the Jadad scale, and compared them with findings from our previous review. For RCTs published from 2001 to 2010, we also evaluated the frequency of distorted finding presentation (spin) and inflated predicted treatment effect (delta inflation). RESULTS: In the 221 RCTs from 2001 to 2010, the sample size was significantly larger than in the older series, and there was a higher proportion of studies with negative findings. Reporting of the rationale for sample size estimation and allocation concealment increased significantly, but reporting of other important individual methodological components did not change substantially compared with the previous period and remained low. Among RCTs from 2001 to 2010, a spin strategy was used in 69 of 111 RCTs with statistically negative results, while delta inflation was present in 7 of 11 RCTs evaluating survival as a primary outcome. Papers with higher Jadad scores were cited more often than the others. CONCLUSIONS: Quality of reporting of RCTs published in Intensive Care Medicine has only partly improved over time, and spin and delta bias are of frequent occurrence. There is a need for stronger adherence to CONSORT recommendations, with special emphasis on accurate description of randomization and blindness, and correct reporting of statistically non significant results. PMID- 23743523 TI - Diagnostic ability of retinal nerve fiber layer maps to detect localized retinal nerve fiber layer defects. AB - PURPOSE: To evaluate and compare the diagnostic ability of spectral domain optical coherence tomography (SD-OCT) for detecting localized retinal nerve fiber layer (RNFL) defects in topographic RNFL maps and circumpapillary RNFL (cpRNFL) thickness measurements. METHODS: Sixty-four eyes with localized RNFL defects in red-free RNFL photographs and 72 healthy eyes were included. All participants were imaged with SD-OCT. The area and angular width of the localized RNFL defects were measured with ImageJ software on RNFL thickness map, significance map (yellow pixels, <5% level), and red-free RNFL photographs. The sensitivity, specificity, and area under the receiver operating characteristic curves (AUCs) were calculated for cpRNFL thickness, macular inner retina thickness, and RNFL maps (thickness, significance) according to the quantitative measurements and a <5% level of classification to distinguish eyes with localized RNFL defects from healthy eyes. RESULTS: RNFL thickness map (sensitivity 96.9-98.4%, specificity 86.1-98.6%, and AUCs 0.915-0.992) and significance map (sensitivity 96.9-98.4%, specificity 88.9-95.8%, and AUCs 0.937-0.983) showed superior performance in detecting localized RNFL defects compared with other parameters (P-value 0.001 0.024) except for 36 sector cpRNFL thickness (sensitivity 92.2%, specificity 87.5%, and AUCs 0.898; P-value 0.080-0.545). The sensitivity for detecting RNFL defects was related to the angular width, area, and depth of the RNFL defects in the cpRNFL (4 sector, 12 sector) and macular inner retinal measurements. RNFL thickness and significance maps showed a constant sensitivity regardless of variations in angular width, area, and depth of the RNFL defects. CONCLUSION: RNFL thickness and significance maps could be used to distinguish eyes with localized RNFL defects from healthy eyes more effectively than cpRNFL thickness and macular inner retina thickness measurements. PMID- 23743524 TI - Does the timing of treatment affect the ocular phenotype in patients with Mucopolysaccharidosis I homozygous for the L490P mutation? PMID- 23743525 TI - Association study of genetic variants on chromosome 7q31 with susceptibility to normal tension glaucoma in a Japanese population. AB - The caveolin 1 to caveolin 2 (CAV1-CAV2) gene region on chromosome 7q31 has been reported to be associated with susceptibility to primary open angle glaucoma (POAG) and normal tension glaucoma (NTG) in previous studies. We investigated whether genetic variants in the CAV1-CAV2 region are associated with NTG in Japanese patients. Two hundred and ninety-two Japanese patients with NTG and 352 Japanese healthy controls were recruited. We genotyped three single-nucleotide polymorphisms; that is, rs1052990, rs4236601, and rs7795356, in the CAV1-CAV2 gene region and assessed the allelic diversity among cases and controls. The frequency of the minor allele (G) of rs1052990 was significantly decreased in NTG cases compared with controls (P=0.014, OR=0.71), whereas NTG or POAG cases had a significantly higher frequency of the allele than controls in previous studies. Conversely, rs7795356 did not show any significant association with NTG cases, and rs4236601 was monomorphic in the Japanese study population. Our findings did not correspond with previous positive results, suggesting that CAV1-CAV2 variants studied in the present study are not important risk factors for NTG susceptibility in all populations. Further studies are needed to elucidate the possible contribution of the CAV1-CAV2 region to the development of glaucoma. PMID- 23743526 TI - Sequential selective same-day suture removal in the management of post keratoplasty astigmatism. AB - AIMS: In a previous study, we proposed that corneal topography performed 30-40 min after the initial suture removal can identify the next set of sutures requiring removal, for the treatment of post-keratoplasty astigmatism. The aim of this study was to evaluate the effect of removing subsequent sets of sutures at the same sitting. METHODS: 10/0 nylon interrupted sutures were placed, to secure the graft-host junction, at the time of keratoplasty. Topography was performed using Pentacam (Oculus) before suture removal. The sutures to be removed in the steep semi-meridians were identified and removed at the slit-lamp biomicroscope. Topography was repeated 30-40 min post suture removal, the new steep semi meridians determined, and the next set of sutures to be removed were identified and removed accordingly. Topography was repeated 4-6 weeks later and the magnitude of topographic astigmatism was recorded. A paired-samples t-test was used to evaluate the impact of selective suture removal on reducing the magnitude of topographic and refractive astigmatism. RESULTS: Twenty eyes of 20 patients underwent sequential selective same-day suture removal (SSSS) after corneal transplantation. This study showed that the topographic astigmatism decreased by about 46.7% (3.68 D) and the refractive astigmatism decreased by about 37.7% (2.61 D) following SSSS. Vector calculations also show a significant reduction of both topographic and refractive astigmatism (P<0.001). CONCLUSION: SSSS may help patients to achieve satisfactory vision more quickly and reduce the number of follow-up visits required post keratoplasty. PMID- 23743527 TI - Relevance of TSH-receptor antibody levels in predicting disease course in Graves' orbitopathy: comparison of the third-generation TBII assay and Mc4-TSI bioassay. AB - AIMS: To investigate if TSH-receptor antibody (TRAb) levels measured in early Graves' orbitopathy (GO) stages are predictive of clinical disease course beyond 1 year after initial GO diagnosis and to compare performance of two newly developed TRAb assays (third-generation thyrotropin-binding inhibitor immunoglobulin (TBII) assay vs Mc4-thyroid-stimulating immunoglobulin (TSI) bioassay) in predicting disease course. METHODS: Newly diagnosed, untreated GO patients whose duration of ocular symptoms was less than 6 months were included. One year after initial diagnosis, all patients were classified as presenting either a mild (Group 1) or severe course (Group 2) according to their clinical manifestations. The measurements of two TRAb assays at initial GO diagnosis were used for analysis. RESULTS: Data from 112 patients were available for analysis. Seventy-three patients (65.2%) were designated as Group 1, and 39 patients (34.8%) as Group 2. Patients with higher initial TRAb levels demonstrated a higher risk of severe disease course upon multiple regression analysis (P<0.01). The cutoff values for the prediction of severe course of the third-generation TBII and Mc4-TSI assays were 10.67 IU/l and 555.10%, respectively, with assay specificities of 84.9 and 89.0%. The TBII assay predictive power (area under the curve (AUC)=0.817; 95% confidence interval (CI) =0.732-0.902) was equivalent to the TSI bioassay (AUC=0.868, 95% CI=0.803-0.934) (P=0.203). CONCLUSIONS: The predictive power of the third-generation TBII assay and Mc4-TSI bioassay are similarly strong. Measurement of TRAb using either third-generation TBII or Mc4 TSI in early GO periods would provide important prognostic information on future GO course. PMID- 23743528 TI - Post-brachytherapy tumor endoresection for treatment of toxic maculopathy in choroidal melanoma. AB - PURPOSE: Toxic tumor syndrome may occur when the irradiated choroidal melanoma releases cytokines, by exudation from irradiated ischemic tissue. We report our experience and outcomes in a series of post-brachytherapy tumor endoresection to mediate radiation complications. METHODS: Patients who underwent endoresection of a choroidal melanoma treated with iodine-125 plaque brachytherapy were evaluated. Baseline patient and tumor parameters were tabulated. RESULTS: Five patients underwent post-brachytherapy tumor endoresection with intraocular gas or silicone oil tamponade. Three of the five patients underwent concomitant phacoemulsification with intraocular lens placement. Initial tumor height ranged from 2.03-8.91 mm (mean 5.81 mm). Time between brachytherapy and endoresection ranged from 13-62 months (mean 26.8 months), and total follow-up time from brachytherapy ranged from 2.5-9.75 years (mean 5.2 years). Vision post brachytherapy and pre-endoresection ranged from 20/30 to 20/400. Final visual acuity ranged from 20/70 to no light perception. One patient developed neovascular glaucoma. Radiation maculopathy increased in all patients. One patient developed metastasis at last follow-up. No patient developed exudative retinal detachment, none had local treatment failure, and none required enucleation. CONCLUSION: Although tumor endoresection post-brachytherapy is a technically feasible procedure, all patients in our series experienced progressive radiation maculopathy with gradual visual decline. PMID- 23743529 TI - What makes a good operation great? Factors determining patient satisfaction with local anaesthesia in cataract surgery. PMID- 23743530 TI - 23- vs 20-gauge pars plana vitrectomy in combination with bimanual microincisional cataract surgery (b-MICS) for the treatment of macular hole and cataract as a one-step procedure. AB - BACKGROUND/AIMS: 23-gauge pars plana vitrectomy (ppv) is a new method for vitreo retinal surgery. It may reduce operation time, the risk of complications, and patient discomfort, especially in combination with simultaneous bimanual microincisional cataract surgery (b-MICS). METHODS: Seventy-five consecutive patients who underwent combined cataract surgery and ppv at our center between 1 January 2008 and 31 December 2010 were included. The first 36 patients were treated with 20-gauge ppv, the following 39 patients with 23-gauge ppv. Study end points 8 weeks after surgery were duration of the procedure, improvement of visual acuity, and occurrence of complications. RESULTS: Duration of surgery was reduced in 23- vs 20-gauge ppv (54.0 +/- 11.6 vs 61.0 +/- 19.0 min, P=0.08). Visual acuity improved significantly in both the groups (20-gauge: logMAR 0.750 +/- 0.304 before and 0.369 +/- 0.273 after surgery; 23-gauge: logMAR 0.663 +/- 0.340 before and 0.339 +/- 0.273 after surgery). There were no appreciable group differences in baseline or post-treatment visual acuity. CONCLUSIONS: 23-gauge ppv in combination with b-MICS is a suitable, safe, and effective method for the treatment of combined cataract and vitreo-retinal diseases. The procedure is somewhat shorter and patient discomfort during and after surgery is improved. In terms of efficacy and safety, 23-gauge ppv is equivalent with conventional 20 gauge ppv. PMID- 23743531 TI - Partial posterior hyaloidectomy for macular disorders. AB - PURPOSE: To evaluate the effect of partial posterior hyaloidectomy (PPH) in preventing iatrogenic retinal breaks related to the induction of a posterior vitreous detachment (IPVD). METHODS: Fifty-nine patients who necessitated IPVD for an epiretinal membrane or macular hole were included in this prospective, interventional case series. Extensive removal of vitreous gel, close to the retina, was conducted before IPVD under 23 G (gauge)-vitrectomy system. The PPH involved the limited extent of IPVD and limited removal of the outermost vitreous cortex to an area slightly beyond the margin of the temporal major vascular arcade. The incidence of retinal breaks related to the surgery was compared with 57 eyes that had undergone conventional 23-G total vitrectomy accompanied by extensive IPVD using chi(2)-test. RESULTS: Patients were followed-up for a mean of 14.3 months (6-30 months) after the surgery. The incidence of peripheral retinal breaks after the PPH was 3.4% (2/59 eyes), which was significantly lower than that in the eyes that underwent conventional 23 G vitrectomy (15.8%, 9/57 eyes, P=0.023) for the same disorders that required an IPVD. No patient complained of postoperative floaters, postoperatively. CONCLUSIONS: PPH would be an efficient procedure to prevent iatrogenic peripheral retinal breaks related to an IPVD. PMID- 23743532 TI - Two-year results of intravitreal ranibizumab for polypoidal choroidal vasculopathy with recurrent or residual exudation. AB - AIM: To clarify the 2-year efficacy of ranibizumab for patients with polypoidal choroidal vasculopathy (PCV) with recurrent or residual exudation from branching vascular networks after previous photodynamic therapy (PDT). METHODS: We retrospectively reviewed 26 eyes of 26 Japanese patients (22 men, 4 women) in this pilot study. All eyes had PCV with complete regression of polypoidal lesions resulting from PDT detected by indocyanine green angiography (ICGA), but recurrent or residual leakage from branching vascular networks on fluorescein angiography and evidence of persistent fluid on optical coherence tomography (OCT). Three consecutive intravitreal injections of ranibizumab (0.5 mg/0.05 ml) were administered to all eyes. RESULTS: The mean logarithm of the minimum angle of resolution best-corrected visual acuity (BCVA) improved significantly from 0.55 at baseline to 0.35 at 12 months (P<0.0001) and 0.43 at 24 months (P=0.0012). The mean increases in the BCVA 12 and 24 months after baseline were 1.95 and 1.23 lines, respectively. The mean central retinal thickness significantly decreased from 295 MUm at baseline to 189 MUm at 12 months (P<0.0038) and 163 MUm at 24 months (P<0.001). The mean numbers of intravitreal ranibizumab (IVR) injections at months 12 and 24, including the initial treatments, were 5.8 and 8.8, respectively. Five (19.2%) eyes had recurrent polypoidal lesions on ICGA at a mean of 15.7 months after baseline. At month 24, OCT showed no exudation in 17 (65.4%) of the 26 eyes. No adverse events developed. CONCLUSIONS: IVR injections maintained or improved the VA and retinal thickness at 24 months in eyes with PCV with recurrent or residual exudation from branching vascular networks after previous PDT. PMID- 23743533 TI - Changes in choroidal thickness, axial length, and ocular perfusion pressure accompanying successful glaucoma filtration surgery. AB - PURPOSE: To investigate the changes in choroidal thickness (CT), axial length (AL), and ocular perfusion pressure (OPP) accompanying intraocular pressure (IOP) reduction after trabeculectomy. methods: Thirty-nine eyes of 39 patients with primary open-angle glaucoma uncontrolled by medical therapy were included in this prospective and interventional study. All patients underwent a fornix-based trabeculectomy. The CT was measured by enhanced depth imaging-optical coherence tomography. IOP, AL, and systolic/diastolic blood pressure were also measured, and OPP was calculated. All measurements were performed at baseline and 1 month after surgery. RESULTS: The mean IOP was 25.0 +/- 5.8 mm Hg at baseline and 11.7 +/- 2.6 mm Hg after trabeculectomy (P<0.001), and the mean subfoveal CT was 295 +/- 84 mm Hg at baseline and 331 +/- 82 mm Hg after trabeculectomy (P<0.001). The mean AL was 23.64 +/- 0.98 mm at baseline and 23.54 +/- 0.96 mm after trabeculectomy (P<0.001), whereas the mean OPP was 38.8 +/- 6.2 mm Hg preoperatively, and 51.1 +/- 7.3 mm Hg postoperatively (P<0.001). The change in CT negatively correlated with the change in IOP (r=-0.785, P<0.001) and AL (r= 0.693, P<0.001), whereas it positively correlated with the change in OPP (r=0.418, P=0.008). CONCLUSION: These results suggest that the large IOP decrease following trabeculectomy causes choroidal thickening. In addition, CT changes are associated with IOP and AL reduction as well as OPP increase. PMID- 23743534 TI - Kyrieleis plaques in herpes zoster virus-associated acute retinal necrosis: a case report. PMID- 23743535 TI - Is it necessary to use three mandatory loading doses when commencing therapy for neovascular age-related macular degeneration using bevacizumab? (BeMOc Trial). AB - PURPOSE: To determine whether a Pro Re Nata (PRN) regimen with three initial mandatory loading doses results in better functional and anatomical outcome compared with a PRN regimen without initial loading when using intravitreal bevacizumab in patients with minimal classic or occult choroidal neovascularisation secondary to age-related macular degeneration. METHODS: Patients were randomised (1 : 1) to Loading (LD group) or No Loading (NLD group) and treated with open label intravitreal bevacizumab. In the LD group, patients received two mandatory doses after the baseline dose before entering the PRN phase and in the NLD group, patients did not receive mandatory doses after the baseline dose. Six-weekly evaluations were performed up to week 54 and retreatment was done based on OCT criteria. Visual stability and reduction in central retinal thickness were compared between groups. RESULTS: 49 patients were in the NLD group and 50 patients were in the LD group. At the 12-month end point, 84% of the patients in the LD group achieved visual stability (<15 letter loss) compared with 67% of the patients in the NLD group (P<0.05). The mean reduction in central macular thickness was 105.35 MUm in the LD group and 81.45 MUm in the NLD group (P>0.05). There was no significant difference in scores of VFQ-25 questionnaire testing between the two groups and no serious ocular or systemic side effects were observed. CONCLUSION: The results supported our hypothesis that a loading dose leads to slightly better visual stability in terms of proportions of patients experiencing moderate visual loss, but did not support the hypothesised difference in anatomical outcome. PMID- 23743536 TI - Prehospital paediatric emergencies treated by an Australian helicopter emergency medical service. AB - OBJECTIVES: The aim of this study was to describe the mechanism and severity of injuries in the paediatric population treated by an Australian helicopter emergency medical service and to examine the frequency and nature of interventions performed. This information is important for planning education and continuing professional development in prehospital medicine. METHODS: The study is a retrospective cohort analysis of 349 patients under the age of 16 treated by CareFlight in Sydney, Australia, between April 2007 and April 2012. Data collected included age, type of incident, medication and fluid administered, procedures performed, receiving hospital, 24 h and 30-day mortality and injuries sustained. RESULTS: Falls (33%), motor vehicle incidents (30%), sport injury (14%) and immersion injury (12%) were the most common mechanisms. A total of 27 children died within 30 days; nontrauma cases were proportionally overrepresented in the deaths. With respect to tasking, 59% cases involved a severely or significantly injured child. Among the children, 97% with a traumatic mechanism were transferred directly to a paediatric trauma centre.In addition, 81% of children had at least one intervention by the helicopter emergency medical services team at the incident scene, most commonly intravenous cannulation (61%), crystalloid bolus (29%), intubation (21%) and intravenous analgesia administration (15%). CONCLUSION: Paediatric prehospital patients can be of high dependency, requiring urgent critical care procedures. Training in prehospital medicine should include paediatrics. It is essential that practitioners maintain skills in venous access, airway management and provision of adequate analgesia in children. PMID- 23743538 TI - Primary non-Hodgkin lymphoma in the pterygopalatine fossa. A peculiar diagnosis with a minimally invasive endoscopic approach. PMID- 23743537 TI - Interactions between Arabidopsis acyl-CoA-binding proteins and their protein partners. AB - Protein-protein interactions are at the core of cellular interactomics and are essential for various biological functions. Since proteins commonly function as macromolecular complexes, it is important to identify their interacting partners to better understand their function and the significance in these interactions. The acyl-CoA-binding proteins (ACBPs) of eukaryotes show conservation in the presence of a lipid-binding acyl-CoA-binding domain. In Arabidopsis thaliana, four of six members from the AtACBP family possess ankyrin repeats (AtACBP1 and AtACBP2) or kelch motifs (AtACBP4 and AtACBP5), which can potentially mediate protein-protein interactions. Through yeast two-hybrid screens, a dozen putative protein partners interacting with AtACBPs have been isolated from an Arabidopsis cDNA library. Investigations in the past decade on the interaction between AtACBPs and their protein partners have revealed novel roles for AtACBPs, including functions in mediating oxidative stress responses, heavy metal tolerance and oxygen sensing. Recent progress and current questions on AtACBPs and their interactors are discussed in this review. PMID- 23743539 TI - Upregulation of innate immune responses in a T cell/histiocyte-rich large B cell lymphoma patient with significant autoimmune disorders mimicking systemic lupus erythematosus. PMID- 23743540 TI - Acute kidney injury after cardiac surgery according to Risk/Injury/Failure/Loss/End-stage, Acute Kidney Injury Network, and Kidney Disease: Improving Global Outcomes classifications. AB - PURPOSE: The epidemiology of acute kidney injury (AKI) after cardiac surgery depends on the definition used. Our aims were to evaluate the Risk/Injury/Failure/Loss/End-stage (RIFLE) criteria, the AKI Network (AKIN) classification, and the Kidney Disease: Improving Global Outcomes (KDIGO) classification for AKI post-cardiac surgery and to compare the outcome of patients on renal replacement therapy (RRT) with historical data. METHODS: Retrospective analysis of 1881 adults who had cardiac surgery between May 2006 and April 2008 and determination of the maximum AKI stage according to the AKIN, RIFLE, and KDIGO classifications. RESULTS: The incidence of AKI using the AKIN and RIFLE criteria was 25.9% and 24.9%, respectively, but individual patients were classified differently. The area under the receiver operating characteristic curve for hospital mortality was significantly higher using the AKIN compared with the RIFLE criteria (0.86 vs 0.78, P = .0009). Incidence and outcome of AKI according to the AKIN and KDIGO classification were identical. The percentage of patients who received RRT was 6.2% compared with 2.7% in 1989 to 1990. The associated hospital mortality fell from 82.9% in 1989 to 1990 to 15.6% in 2006 to 2008. CONCLUSIONS: The AKIN classification correlated better with mortality than did the RIFLE criteria. Mortality of patients needing RRT after cardiac surgery has improved significantly during the last 20 years. PMID- 23743541 TI - Pneumococcal bacterial load colonization as a marker of mixed infection in children with alveolar community-acquired pneumonia and respiratory syncytial virus or rhinovirus infection. AB - BACKGROUND: The main aim of this study was to evaluate whether nasopharyngeal Streptococcus pneumoniae colonization in children with alveolar community acquired pneumonia (CAP) and respiratory syncytial virus (RSV) or rhinovirus (RV) infection indicates a mixed lung infection. METHODS: The nasopharyngeal secretions of 530 children with radiographically confirmed CAP were tested using the Luminex x TAG respiratory virus panel fast assay. Real-time polymerase chain reaction for the autolysin-A (LytA) and wzg (cpsA) genes of S. pneumoniae was performed on the RSV- and RV-positive samples. RESULTS: Sixty-five of the 126 RSV positive children (51.6%) were colonized with S. pneumoniae. Mean bacterial load was significantly higher in the patients with alveolar involvement (4.54+/-1.47 log10 DNA copies/mL vs. 3.75+/-1.62 log10 DNA copies/mL; P=0.04). Serotypes 5 and 19A were almost exclusively identified in the children with RSV and alveolar CAP, although the difference was statistically significant only for serotype 19A (P=0.03). Eighty-three of the 134 RV-positive children (61.9%) were colonized with S. pneumoniae and again mean bacterial load was significantly higher in the patients with alveolar involvement (4.21+/-1.37 log10 DNA copies/mL vs. 3.41+/ 1.47 log10 DNA copies/mL; P=0.03). Serotypes 1, 5 and 19A were more frequently identified in the children with RV and alveolar CAP, although the difference was statistically significant only for serotype 5 (P=0.04). CONCLUSIONS: In children with alveolar CAP and RSV or RV infection, the determination of nasopharyngeal pneumococcal bacterial load and identification of the serotypes can contribute to the diagnosis of mixed lung infection. PMID- 23743542 TI - Stevens-Johnson syndrome and HIV in children in Swaziland. AB - BACKGROUND: Stevens-Johnson syndrome (SJS) can be a severe and life-threatening reaction with many potential causes, including multiple medications used in HIV care and treatment. Specific risk factors, especially in children, are not currently well-understood. METHODS: We describe a series of cases of SJS that occurred from 2006 to 2010 in an HIV-focused clinic in Mbabane, Swaziland. The electronic medical and pharmacy records of all pediatric patients <20 years old were reviewed to identify cases of SJS. Patient demographic, immunosuppression and outcome data were also collected. RESULTS: A total of 19 cases of SJS were documented. Eighty-four percent of cases were attributed to nevirapine (NVP) exposure whereas the remaining cases were caused by cotrimoxazole (11%) and efavirenz (5%). Median symptom onset was 22 days after initiation of the offending medication (interquartile range = 14-25 days). At time of SJS, 84% had advanced or severe immunosuppression. Forty-two percent of patients required hospitalization, and no SJS-associated deaths were known to occur. Use of efavirenz was attempted in 8 NVP-associated cases after SJS resolution and was successful in all except 1. CONCLUSIONS: SJS occurrence was rare in this population, with the majority of cases being associated with NVP. All occurred within 32 days of medication initiation, providing a target window for intensified monitoring and anticipatory guidance. SJS can occur in children at any age, with any level of immunosuppression, and can occur during the lead-in dosing period of NVP. PMID- 23743543 TI - A pediatric case of New Delhi metallo-beta-lactamase-1-producing Enterobacteriaceae in the United States. AB - We report the second pediatric case of New Delhi metallo-beta-lactamase-1 producing Enterobacteriaceae in the United States. Laboratory methods included various phenotypic antimicrobial susceptibility testing assays, as well as polymerase chain reaction assays for carbapenemase-encoding genes. Laboratory challenges and the limited number of effective antimicrobial agents and the lack of pediatric-specific safety and efficacy data for these drugs are discussed. PMID- 23743544 TI - A neonatal case of Japanese spotted fever. AB - We herein present the case of a 28-day-old female with Japanese spotted fever, who is the youngest reported patient so far. Tick-borne diseases, including Japanese spotted fever, should be included in the differential diagnosis of eruptive fever even in neonates because a treatment delay can lead to a fatal outcome. PMID- 23743545 TI - Clinical manifestations of Campylobacter concisus infection in children. AB - BACKGROUND: There is only sparse information about the clinical impact of Campylobacter concisus infections in children. METHODS: A study was performed during a 2-year period to determine the clinical manifestations in C. concisus positive children with gastroenteritis. A case patient was defined as a child or teenager (<18 years) with a C. concisus-positive stool sample during the study period. Clinical data were obtained with use of a questionnaire study supplemented with the patients' medical records. The clinical manifestations in these patients were compared with those of patients with Campylobacter jejuni/coli infection. RESULTS: Two thousand three hundred seventy-two diarrheic stool samples from 1867 children were cultured for pathogenic enteric bacteria during the study period, and 85 and 109 children with C. concisus and C. jejuni/coli, respectively, were identified. Comparison of the acute clinical manifestations in 44 C. concisus patients with those in 64 C. jejuni/coli patients showed a significantly lower prevalence of fever, chills and blood in stools in the former. However, half of C. concisus patients compared with one fourth of C. jejuni/coli patients had prolonged diarrhea for more than 2 weeks and two-thirds of all children with C. concisus reported loose stools after 6 month follow-up. CONCLUSIONS: C. concisus infection in children seems to have a milder course of acute gastroenteritis compared with C. jejuni/coli infection but is associated with more prolonged diarrhea. Children with C. concisus have the same degree of late gastrointestinal complaints as children diagnosed with C. jejuni/coli infection. PMID- 23743546 TI - Using major ions and delta15N-NO3(-) to identify nitrate sources and fate in an alluvial aquifer of the Baiyangdian lake watershed, North China Plain. AB - In semi-arid regions, most human activities occur in alluvial fan areas; however, NO3(-) pollution has greatly threatened the shallow groundwater quality. In this paper, delta(15)N-NO3(-) and multi-tracers were used to identify the origin and fate of NO3(-) in groundwater of the Baiyangdian lake watershed, North China Plain. The investigation was conducted in two typical regions: one is the agricultural area located in the upstream of the watershed and another is the region influenced by urban wastewater in the downstream of the watershed. Results indicate that the high NO3(-) concentrations of the upstream shallow groundwater were sourced from fertilizer and manure or sewage leakage, whilst the mixture and denitrification caused the decrease in the NO3(-) concentration along the flow path of the groundwater. In the downstream, industrial and domestic effluent has a great impact on groundwater quality. The contaminated rivers contributed from 45% to 76% of the total recharge to the groundwater within a distance of 40 m from the river. The mixture fraction of the wastewater declined with the increasing distance away from the river. However, groundwater with NO3(-) concentrations larger than 20 mg l(-1) was only distributed in areas near to the polluted river or the sewage irrigation area. It is revealed that the frontier and depression regions of an alluvial fan in a lake watershed with abundant organics, silt and clay sediments have suitable conditions for denitrification in the downstream. PMID- 23743547 TI - Current status of General Pathology training in Spain. AB - BACKGROUND AND OBJECTIVES: One of the core subjects in university training of the physicians has been General Pathology. Responsibility for this has historically fallen on Internal Medicine specialists. However, we are unaware if this situation is currently maintained. METHODS: A questionnaire was sent to the coordinators of the subject of the 39 Spanish medical schools to know, among other things, the current denomination of the subjects (traditionally known as "General Pathology"), number of credits, teaching activities included in the subject and number and specialty of the professors responsible for it. Some data from the medical schools that did not respond were obtained from their web pages. RESULTS: A total of 28 of the 39 (72%) medical schools existing in Spain answered the survey. The current denomination of the subject "General Pathology" varied greatly. The mean number of credits (one credit=20-25 h) was 11.2 (range 3 to 29). In 22 of 34 schools (65%), the subject was taught in the third year of the studies, but in 21% of the schools, it was partially and in 15% of the schools, totally, taught in the second year. More than half of the professors (54%) who taught the subject were Internal Medicine specialists, although this responsibility was shared with other specialists in a large proportion. CONCLUSIONS: Teaching of General Pathology shows a marked heterogeneity that does not seem to be due to teaching or pedagogic criteria among the different schools of Spain. These facts may be due to less presence in the university setting of Internal Medicine compared to other specialties. PMID- 23743549 TI - Photochemistry of Arabidopsis phototropin 1 LOV1: transient tetramerization. AB - The photochemical reaction of the LOV1 (light-oxygen-voltage 1) domain of phototropin 1 from Arabidopsis thaliana was investigated by the time-resolved transient grating method. As with other LOV domains, an absorption spectral change associated with an adduct formation between its chromophore (flavin mononucleotide) and a cysteine residue was observed with a time constant of 1.1 MUs. After this reaction, a significant diffusion coefficient (D) change (D of the reactant = 8.2 * 10(-11) m(2) s(-1), and D of the photoproduct = 6.4 * 10( 11) m(2) s(-1)) was observed with a time constant of 14 ms at a protein concentration of 270 MUM. From the D value of the ground state and the peak position in size exclusion chromatography, we have confirmed that the phot1LOV1 domain exists as a dimer in the dark. The D-value and the concentration dependence of the rate indicated that the phot1LOV1 domain associates to form a tetramer (dimerization of the dimer) upon photoexcitation. We also found that the chromophore is released from the binding pocket of the LOV domain when it absorbs two photons within a pulse duration, which occurs in addition to the normal photocycle reaction. On the basis of these results, we discuss the molecular mechanism of the light dependent role of the phot1LOV1 domain. PMID- 23743550 TI - Single-nucleotide polymorphism array genotyping is equivalent to metaphase cytogenetics for diagnosis of Turner syndrome. AB - PURPOSE: Turner syndrome is a developmental disorder caused by partial or complete monosomy for the X chromosome in 1 in 2,500 females. We hypothesized that single-nucleotide polymorphism (SNP) array genotyping could provide superior resolution in comparison to metaphase karyotype analysis to facilitate genotype phenotype correlations. METHODS: We genotyped 187 Turner syndrome patients with 733,000 SNP marker arrays. All cases met diagnostic criteria for Turner syndrome based on karyotypes (60%) or characteristic physical features. The SNP array results confirmed the diagnosis of Turner syndrome in 100% of cases. RESULTS: We identified a single X chromosome (45,X) in 113 cases. In 58 additional cases (31%), other mosaic cell lines were present, including isochromosomes (16%), rings (5%), and Xp deletions (8%). The remaining cases were mosaic for monosomy X and normal male or female cell lines. Array-based models of X chromosome structure were compatible with karyotypes in 104 of 116 comparable cases (90%). We found that the SNP array data did not detect X-autosome translocations (three cases) but did identify two derivative Y chromosomes and 13 large copy-number variants that were not detected by karyotyping. CONCLUSION: Our study is the first systematic comparison between the two methods and supports the utility of SNP array genotyping to address clinical and research questions in Turner syndrome. PMID- 23743553 TI - A modified mesoporous silica optical nanosensor for selective monitoring of multiple analytes in water. AB - A new modified mesoporous silica nanosensor was synthesized by the co condensation method. Under basic conditions, the obtained mesoporous silica nanosensor responds selectively to Fe(2+) (pH = 8) and Cu(2+) (pH = 12) with a distinguishable colour change perceivable by the naked eye and a detection limit of approximately 50 ppb. PMID- 23743552 TI - Parents' interest in whole-genome sequencing of newborns. AB - PURPOSE: The aim of this study was to assess parents' interest in whole-genome sequencing for newborns. METHODS: We conducted a survey of a nationally representative sample of 1,539 parents about their interest in whole-genome sequencing of newborns. Participants were randomly presented with one of two scenarios that differed in the venue of testing: one offered whole-genome sequencing through a state newborn screening program, whereas the other offered whole-genome sequencing in a pediatrician's office. RESULTS: Overall interest in having future newborns undergo whole-genome sequencing was generally high among parents. If whole-genome sequencing were offered through a state's newborn screening program, 74% of parents were either definitely or somewhat interested in utilizing this technology. If offered in a pediatrician's office, 70% of parents were either definitely or somewhat interested. Parents in both groups most frequently identified test accuracy and the ability to prevent a child from developing a disease as "very important" in making a decision to have a newborn's whole genome sequenced. CONCLUSION: These data may help health departments and children's health-care providers anticipate parents' level of interest in genomic screening for newborns. As whole-genome sequencing is integrated into clinical and public health services, these findings may inform the development of educational strategies and outreach messages for parents. PMID- 23743554 TI - Consciousness and responsiveness: lessons from anaesthesia and the vegetative state. AB - PURPOSE OF REVIEW: The aim of this article is to review recent behavioural and neuroimaging studies in anaesthesia and the vegetative state. RECENT FINDINGS: These studies highlight possible dissociations between consciousness and responsiveness in both these states. SUMMARY: We discuss future avenues of research in the field, in order to improve the detection of awareness during anaesthesia and the vegetative state using neuroimaging and neurophysiologic techniques. PMID- 23743555 TI - Anesthesia for transcatheter aortic valve implantation: an update. AB - PURPOSE OF REVIEW: To summarize and highlight recent advances in the periprocedural management of patients undergoing transcatheter aortic valve implantation (TAVI). RECENT FINDINGS: TAVI has become the new standard of care in inoperable patients with severe aortic valve stenosis and has emerged as an alternative to surgical aortic valve replacement in patients with high operative risk. Although TAVI is mainly performed via the transfemoral route, other access options are available including the transapical approach. Although TAVI has become a routine procedure, it is still associated with potentially life threatening complications. TAVI should ideally be performed in a dedicated hybrid room by a multidisciplinary team involving cardiac anesthesiologists. Owing to a lack of validated risk scores, indication and treatment allocation still have to rely on clinical judgment. Owing to the severity of the underlying disease and the complexity of the procedure, TAVI patients require extensive monitoring and installation. The avoidance of prolonged hypotension is the most important goal to prevent hemodynamic deterioration. Transfemoral TAVI procedures can be performed under conscious sedation. Transesophageal echocardiography is an important tool for procedural guidance and the instantaneous detection of complications. SUMMARY: Anesthesiologists involved in TAVI must have detailed knowledge of valvular heart disease, hemodynamics, echocardiography, the procedure, and associated complications. PMID- 23743556 TI - Pros and cons of etomidate--more discussion than evidence? AB - PURPOSE OF REVIEW: To evaluate the most recent publications in the long-lived debate over the use of etomidate in critically ill septic and trauma patients. RECENT FINDINGS: Virtually without controversy is the hemodynamic stability after its use for induction of anesthesia on the one hand, and its negative effect on steroid synthesis on the other. The rating of the relative importance of both phenomena for the outcome of patients is however a highly controversial issue. We will discuss the most recent publications for two patient groups: trauma and critically ill septic patients. New meta-analyses and smaller studies have been published and might help us to weigh pros and cons in our patients. Sufficiently powered randomized controlled trials remain absent. The question whether supplemented corticosteroids after etomidate improve outcome is answered negatively by two recent studies. SUMMARY: A single dose of etomidate supplies good intubation conditions with hemodynamic stability, but increases the risk for adrenal insufficiency. The relative importance of these characteristics for the patients' outcome remains controversial, as there is a lack of direct evidence. According to the principle 'nihil nocere', reasoning argues against its use, especially in septic patients or in those at major risk to develop septic complications (e.g. trauma patients). PMID- 23743551 TI - The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future. AB - The Electronic Medical Records and Genomics Network is a National Human Genome Research Institute-funded consortium engaged in the development of methods and best practices for using the electronic medical record as a tool for genomic research. Now in its sixth year and second funding cycle, and comprising nine research groups and a coordinating center, the network has played a major role in validating the concept that clinical data derived from electronic medical records can be used successfully for genomic research. Current work is advancing knowledge in multiple disciplines at the intersection of genomics and health-care informatics, particularly for electronic phenotyping, genome-wide association studies, genomic medicine implementation, and the ethical and regulatory issues associated with genomics research and returning results to study participants. Here, we describe the evolution, accomplishments, opportunities, and challenges of the network from its inception as a five-group consortium focused on genotype phenotype associations for genomic discovery to its current form as a nine-group consortium pivoting toward the implementation of genomic medicine. PMID- 23743557 TI - Perioperative glycemic control: what is worth the effort? AB - PURPOSE OF REVIEW: Diabetes mellitus and its related comorbidities present a growing challenge in perioperative medicine. And also largely independent from a history of diabetes, dysregulations of glucose homeostasis occur as part of the body's stress response. Dysregulations of glucose homeostasis, acute or chronic, are closely correlated with impaired prognosis in perioperative medicine. Treatment strategies remain somewhat controversial, as both the affliction and its correction have a blind side. RECENT FINDINGS: Anesthesia requires vigilant attention to diabetes-related comorbidities such as neuropathy, angiopathy, cardiopathy and immune dysfunction. Dysregulations of glycemia of any kind, in other words, hypoglycemia and hyperglycemia and fluctuations of blood glucose, should be avoided. Target glycemia remains a matter of discussion: moderate, achievable glycemic target below 180 or 150 mg/dl appears to be reasonable. Modern technical developments like continuous glucose measurement devices and computer-assisted control algorithms are under development, and will hopefully facilitate perioperative glycemic control in the future. SUMMARY: Literature clearly shows that leaving glycemic control out of focus is dangerous for the patient; efforts to control glycemia to a moderate target improve the patient's outcome. PMID- 23743558 TI - Cough sound analysis can rapidly diagnose childhood pneumonia. AB - Pneumonia annually kills over 1,800,000 children throughout the world. The vast majority of these deaths occur in resource poor regions such as the sub-Saharan Africa and remote Asia. Prompt diagnosis and proper treatment are essential to prevent these unnecessary deaths. The reliable diagnosis of childhood pneumonia in remote regions is fraught with difficulties arising from the lack of field deployable imaging and laboratory facilities as well as the scarcity of trained community healthcare workers. In this paper, we present a pioneering class of technology addressing both of these problems. Our approach is centred on the automated analysis of cough and respiratory sounds, collected via microphones that do not require physical contact with subjects. Cough is a cardinal symptom of pneumonia but the current clinical routines used in remote settings do not make use of coughs beyond noting its existence as a screening-in criterion. We hypothesized that cough carries vital information to diagnose pneumonia, and developed mathematical features and a pattern classifier system suited for the task. We collected cough sounds from 91 patients suspected of acute respiratory illness such as pneumonia, bronchiolitis and asthma. Non-contact microphones kept by the patient's bedside were used for data acquisition. We extracted features such as non-Gaussianity and Mel Cepstra from cough sounds and used them to train a Logistic Regression classifier. We used the clinical diagnosis provided by the paediatric respiratory clinician as the gold standard to train and validate our classifier. The methods proposed in this paper could separate pneumonia from other diseases at a sensitivity and specificity of 94 and 75% respectively, based on parameters extracted from cough sounds alone. The inclusion of other simple measurements such as the presence of fever further increased the performance. These results show that cough sounds indeed carry critical information on the lower respiratory tract, and can be used to diagnose pneumonia. The performance of our method is far superior to those of existing WHO clinical algorithms for resource-poor regions. To the best of our knowledge, this is the first attempt in the world to diagnose pneumonia in humans using cough sound analysis. Our method has the potential to revolutionize the management of childhood pneumonia in remote regions of the world. PMID- 23743559 TI - Therapy of chronic hepatitis C with PEG-IFN alpha-2b plus ribavirin in patients with genotype 2 or 3: 16 versus 24 weeks, clinical outcome and direct cost analyses. AB - INTRODUCTION: Short antiviral therapy has been proposed for patients with chronic hepatitis C, easy genotypes, low fibrosis score, low viral load at baseline, and rapid virological response (RVR). However, this approach is not completely accepted. OBJECTIVES: The aims of this study were (a) to evaluate the sustained virological response (SVR) in noncirrhotic patients with genotype 2 or 3, achieving an RVR, randomized to receive pegylated-interferon (IFN) alpha-2b plus ribavirin for either 16 or 24 weeks and (b) to carry out direct cost analysis comparing patients treated for 16 versus 24 weeks. RESULTS: Of the 142 initially evaluated patients, 130 were enrolled according to the selection criteria, but independent of the viral load. According to the intention-to-treat analysis, SVR was achieved in 104 patients (80%). Logistic regression analysis showed that RVR (P<0.001) and genotype 2 (P<0.03) were the most important factors independently associated with SVR. Among patients with RVR, SVR was comparable between patients treated for 16 weeks and those treated for 24 weeks (86.2 vs. 89.7%, P=NS). The mean direct costs were ?4003.7 for patients treated for 16 weeks and ?5676.7 for those treated for 24 weeks, with a 30% difference between the two arms. CONCLUSION: In patients achieving an RVR, a 16-week treatment with pegylated interferon plus ribavirin was comparable to a 24-week treatment. Short treatment in patients with RVR allows us to save 30% of the direct costs, independent of the viral load at baseline. PMID- 23743560 TI - Determination of hepatitis C virus genotypes circulating in different districts of Punjab (Pakistan). AB - INTRODUCTION: Hepatitis C virus (HCV) is a principal cause of severe liver diseases worldwide and a possible source of significant morbidity and fatality in the long term. Information on the genotype is more significant because it has prognostic value in the response to antiviral therapy. OBJECTIVES: This study aimed to determine the frequency of various HCV genotypes circulating in the different districts of Punjab and to show the pattern distribution of HCV genotypes in different age groups and sexes. MATERIALS AND METHODS: A total of 542 HCV-positive patients were selected from various districts of the province and were subjected to an HCV genotype-specific assay. Among 542 positive patients, 300 (55.35%) were men and 242 (44.65%) were women. There were 245 (45.20%), 61 (11.25%), 56 (10.33%), 56 (10.33%), 53 (9.77%), 27 (5%), 20 (3.69%), 16 (3%), and eight (1.47%) HCV-positive patients from Lahore, Sargodha, Multan, Toba Tek Singh, Faisalabad, Rawalpindi, Mandi Bahauddin Gujranwala, and Sahiwal districts, respectively. RESULTS: Of a total of 542 serum samples analyzed, 476 (88%) were successfully genotyped whereas 66 (12%) samples were undetermined genotypes. Among the typable genotypes, 1a was found in 37 (7%), 1b in 18 (3%), 3a in 386 (71%), and genotype 3b in five (1%) patients. Thirty patients (6%) were identified to be infected with mixed HCV genotypes. Genotypes 3a (P=0.0001), 1a (P=0.001), and untypable genotypes (P=0.03) were circulating significantly in all the studied districts. All the genotypes were distributed evenly in male and female patients. The most affected age range of patients was 21-40 years as compared with teenage and older age groups. CONCLUSION: The study found a significantly high prevalence of HCV among the patients of Punjab. In addition, genotype 1a was found to be a significantly and rapidly increasing genotype in the study area. It appears that HCV-3a (the most prevalent genotype) may be replaced by genotype 1a. If this occurs, it will make the present scenario more complex in terms of response to therapy and economic burden on the health sector of Pakistan. HCV infection is more common in the age group of 21-40 years. All the genotypes were distributed at the same frequency in men and women. PMID- 23743561 TI - Men with celiac disease are shorter than their peers in the general population. AB - OBJECTIVE: Late diagnosis of celiac disease (CD) is increasingly common, the implications of which are largely unknown. Although short stature is a common sign of childhood CD, the data on the height of adult CD patients is conflicting. This study investigates the final height of men and women diagnosed with CD in adulthood and attempts to identify influencing factors. PATIENTS AND METHODS: We performed a cross-sectional study of 585 adults at the Celiac Disease Center at Columbia University, comparing their height with the control population (NHANES). Patients were included if they were older than 18 years of age at diagnosis and if baseline height and weight were available. In addition, we examined for differences in demographic and physical features, mode of presentation, and concomitant illnesses in shorter versus taller celiac patients. RESULTS: Men (n=162) with CD diagnosed in adulthood were shorter than men in the general population (CD: 169.3 +/- 10.5 vs. 177.3 +/- 7.0 cm, P<0.01) whereas women (n=423) were not (CD: 166.3 +/- 9.4 vs. 163.2 +/- 6.7 cm). There were no statistically significant differences in age at diagnosis, BMI, concomitant autoimmune illnesses (hypothyroidism, type I diabetes, dermatitis herpetiformis), or mode of presentation in shorter versus taller CD patients of either sex. Hemoglobin was associated with short stature in CD men (short: 13.9 g/dl, tall: 14.6 g/dl; P=0.01), but not women (short: 12.9 g/dl, tall: 13.0 g/dl, P=0.41). CONCLUSION: Short stature is a well described phenomenon in pediatric CD with the potential for 'catch-up growth' on a gluten-free diet. However, among adults with CD who had attained final height before diagnosis, we found that men, not women, are shorter relative to the general population. PMID- 23743562 TI - MAX mutations status in Swedish patients with pheochromocytoma and paraganglioma tumours. AB - Pheochromocytoma (PCC) and Paraganglioma are rare tumours originating from neuroendocrine cells. Up to 60% of cases have either germline or somatic mutation in one of eleven described susceptibility loci, SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127 and MYC associated factor-X (MAX). Recently, germline mutations in MAX were found to confer susceptibility to PCC and paraganglioma (PGL). A subsequent multicentre study found about 1% of PCCs and PGLs to have germline or somatic mutations in MAX. However, there has been no study investigating the frequency of MAX mutations in a Scandinavian cohort. We analysed tumour specimens from 63 patients with PCC and PGL treated at Uppsala University hospital, Sweden, for re-sequencing of MAX using automated Sanger sequencing. Our results show that 0% (0/63) of tumours had mutations in MAX. Allele frequencies of known single nucleotide polymorphisms rs4902359, rs45440292, rs1957948 and rs1957949 corresponded to those available in the Single Nucleotide Polymorphism Database. We conclude that MAX mutations remain unusual events and targeted genetic screening should be considered after more common genetic events have been excluded. PMID- 23743563 TI - The prevalence of small intestinal polyps in patients with familial adenomatous polyposis: a prospective capsule endoscopy study. AB - Familial adenomatous polyposis (FAP) is a genetic disorder in which multiple colorectal polyps and cancers develop. However, the prevalence of small intestinal tumors in patients with FAP remains unclear. We elucidated the prevalence of polyps in the small intestine and duodenum using capsule endoscopy (CE). Patients with FAP receiving a periodic screening colonoscopy at Kyoundo Hospital were encouraged to participate in the study. All study participants underwent esophagogastroduodenoscopy (EGD) within 2 weeks before CE. Outcome measurements were the prevalence of duodenal polyps (DP) and small intestinal polyp (SIP), detectability of the ampulla of Vater, and concordance of the duodenal findings between CE and EGD. Twenty-three patients (mean age, 47 years; 15 males) were enrolled in the study. CE showed DPs in 11 patients (52%) and SIPs in nine patients (43 %). The mean numbers of DPs and SIPs was 11.5 +/- 6.2 and 11.9 +/- 10.9, respectively. SIPs were more often detected in patients with DPs versus those without (62 vs. 13%, P = 0.07). The ampulla of Vater was observed by CE in four patients (21%). EGD showed DPs in 13 patients (62%). EGD missed DPs in two of 11 patients with DPs detected by CE. EGD found DPs in four of 10 patients without DPs using CE. The kappa index was 0.422. Patients with FAP have a high prevalence of polyps in the small intestine. Although the clinical significance of small intestinal polyps remains unclear, patients with FAP seem to be good candidates for CE. PMID- 23743564 TI - A human rights approach to human trafficking for organ removal. AB - Human trafficking for organ removal (HTOR) should not be reduced to a problem of supply and demand of organs for transplantation, a problem of organized crime and criminal justice, or a problem of voiceless, abandoned victims. Rather, HTOR is at once an egregious human rights abuse and a form of human trafficking. As such, it demands a human-rights based approach in analysis and response to this problem, placing the victim at the center of initiatives to combat this phenomenon. Such an approach requires us to consider how various measures impact or disregard victims/potential victims of HTOR and gives us tools to better advocate their interests, rights and freedoms. PMID- 23743565 TI - Facile preparation of transparent and conductive polymer films based on silver nanowire/polycarbonate nanocomposites. AB - Silver nanowires (AgNW) synthesized by a solvothermal method were incorporated into a polycarbonate matrix by a solution mixing procedure. Films with a thickness around 18 MUm were obtained, showing a good distribution of the wires within the polymer matrix. The thermal stability of the polymer matrix increased significantly, with the main decomposition peak shifting up to 74 degrees C for an AgNW loading of 4.35 wt%. The percolation threshold was obtained at very low AgNW content (0.04 wt%), and the composite electrical conductivity at the maximum loading (4.35 wt%) was 41.3 Omega cm. Excellent transparency was obtained at the percolation threshold, with negligible reduction in the transmittance of the polymer matrix (from 88.2 to 87.6% at 0.04 wt% loading of AgNW). In addition, the polymer matrix protected the silver nanowires from oxidation, as demonstrated by the XPS analysis. PMID- 23743566 TI - Antibiotic treatment decreases microbial burden associated with pseudomyxoma peritonei and affects beta-catenin distribution. AB - PURPOSE: Pseudomyxoma peritonei is an understudied cancer in which an appendiceal neoplasm invades the peritoneum and forms tumor foci on abdominal organs. Previous studies have shown that bacteria reside within pseudomyxoma peritonei tumors and mucin. Thus, we sought to analyze the effect of antibiotics on bacterial density and beta-catenin expression within pseudomyxoma peritonei samples. EXPERIMENTAL DESIGN: The study included 48 patients: 19 with disseminated peritoneal adenomucinosis (DPAM) and 29 with peritoneal mucinous carcinomatosis (PMCA). Fourteen patients were given antibiotics (30 mg lansoprazole, 1 g amoxicillin, and 500 mg clarithromycin) twice a day for 14 days. One week after completion of therapy, surgery was conducted and specimens were harvested for pathology, bacterial culture, ISH, and immunohistochemistry. RESULTS: ISH showed the presence of bacteria in 83% of the patient samples, with a higher Helicobacter pylori density observed in PMCA versus DPAM. PMCA patients treated with antibiotics had a significantly lower bacterial density and decreased beta-catenin levels in the cytoplasm, the cell nuclei, and mucin associated cells. Although not significant, similar trends were observed in DPAM patients. Cell membrane beta-catenin was significantly increased in both DPAM and PMCA patients receiving antibiotics. CONCLUSIONS: Bacteria play an important role in pseudomyxoma peritonei. Antibiotic treatment improved the histopathology of tissue, particularly in PMCA patients. In PMCA, antibiotics decreased bacterial density and were associated with a significant beta-catenin decrease in the cytoplasm, cell nuclei, and mucin along with a small membrane increase. These results suggest that antibiotics offer potential protection against cell detachment, cellular invasion, and metastasis. PMID- 23743567 TI - IL-10 promotes tumor aggressiveness via upregulation of CIP2A transcription in lung adenocarcinoma. AB - PURPOSE: Interleukin-10 (IL-10) determines virus persistent infection and promotes viral-associated tumor progression via tumor immune escape. However, the role of IL-10 in tumor progression and prognosis in lung adenocarcinoma remains controversial. EXPERIMENTAL DESIGN: To investigate how IL-10 is regulated by HPV E6, IL-10 promoter was constructed to understand which transcriptional factor could be responsible for its transcription. To verify which molecule could be responsible for IL-10-mediated soft agar growth and invasion capability, PCR array and mechanistic strategies were conducted. IL-10 and CIP2A mRNA levels in lung tumors from patients with lung cancer were determined by real-time reverse transcription PCR. The prognostic value of both molecules on survival was estimated by Cox regression model. RESULTS: Mechanistic studies showed that IL-10 protein and mRNA expression was decreased in E6 knockdown TL1 cells and increased in E6- overexpressing TL4 cells. In addition, IL-10 transcription was predominantly regulated by E6-mediated phosphorylation of cAMP response element binding protein (CREB) and C/enhancer-binding protein beta (C/EBPbeta) via phosphoinositide 3-kinase (PI3K) signaling pathway. IL-10-mediated tumor aggressiveness in vitro and in vivo occurs through increased CIP2A expression via PI3K signaling pathway. Among patients, IL-10 mRNA expression in lung tumors was positively correlated with CIP2A mRNA expression. Cox-regression analysis showed that IL-10 and CIP2A mRNA levels may independently predict survival in patients with lung adenocarcinoma, especially in patients with E6-positive tumors. CONCLUSION: IL-10 production from lung tumors and immune cells promotes lung adenocarcinoma aggressiveness and patients with poor survival. We thus suggest that PI3K inhibitor combined with chemotherapy may potentially enhance tumor regression and improve patients' outcome and life quality. PMID- 23743568 TI - Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. AB - PURPOSE: Immune-related response criteria (irRC) was developed to adequately assess tumor response to immunotherapy. The irRC are based on bidimensional measurements, as opposed to unidimensional measurements defined by Response Evaluation Criteria in Solid Tumors, which has been widely used in solid tumors. We aimed to compare response assessment by bidimensional versus unidimensional irRC in patients with advanced melanoma treated with ipilimumab. EXPERIMENTAL DESIGN: Fifty-seven patients with advanced melanoma treated with ipilimumab in a phase II, expanded access trial were studied. Bidimensional tumor measurement records prospectively conducted during the trial were reviewed to generate a second set of measurements using unidimensional, longest diameter measurements. The percent changes of measurements at follow-up, best overall response, and time to-progression (TTP) were compared between bidimensional and unidimensional irRC. Interobserver variability for bidimensional and unidimensional measurements was assessed in 25 randomly selected patients. RESULTS: The percent changes at follow up scans were highly concordant between the 2 criteria (Spearman r: 0.953-0.965, first to fourth follow-up). The best immune-related response was highly concordant between the 2 criteria (kappaw = 0.881). TTP was similar between the bidimensional and unidimensional assessments (progression-free at 6 months: 70% vs. 81%, respectively). The unidimensional measurements were more reproducible than bidimensional measurements, with the 95% limits of agreement of (-16.1%, 5.8%) versus (-31.3%, 19.7%), respectively. CONCLUSION: irRC using the unidimensional measurements provided highly concordant response assessment compared with the bidimensional irRC, with less measurement variability. The use of unidimensional irRC is proposed to assess response to immunotherapy in solid tumors, given its simplicity, higher reproducibility, and high concordance with the bidimensional irRC. PMID- 23743569 TI - Phase II study of everolimus in patients with metastatic colorectal adenocarcinoma previously treated with bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens. AB - PURPOSE: Dysregulation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is seen in 40% to 60% of patients with colorectal cancer. Everolimus, an oral inhibitor of mTOR, showed efficacy in patients with metastatic colorectal cancers in phase I studies. EXPERIMENTAL DESIGN: In sequential phase II studies assessing two dosing schedules, patients with metastatic colorectal cancers refractory to bevacizumab-, fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens received everolimus 70 mg/wk (n = 99) or 10 mg/d (n = 100). Primary endpoints were disease control rate (DCR) and objective response rate; secondary endpoints included progression-free survival (PFS), overall survival (OS), and duration of response or stable disease (SD). Tumor tissue was collected from all patients for predefined exploratory biomarker analyses. RESULTS: Seventy-one patients were included in the per-protocol set for each cohort. DCRs of 31.0% and 32.4% (all SD) were seen in the weekly and daily schedules, respectively. Median duration of SD was 3.9 months in each cohort. Median PFS and OS were 1.8 and 4.9 months and 1.8 and 5.9 months, respectively, for the weekly and daily schedules. Among patients receiving daily everolimus, those with a KRAS mutation experienced significantly shorter median OS (P = 0.008) and lower DCR (P = 0.035) compared with those with wild-type KRAS in exploratory biomarker analyses. CONCLUSIONS: Everolimus 70 mg/wk or 10 mg/d was well tolerated but did not confer meaningful efficacy in heavily pretreated patients with metastatic colorectal cancers. Future studies may consider evaluating everolimus in combination with other agents or in patients with dysregulation of the PI3K/Akt/mTOR pathway. PMID- 23743571 TI - Metastability of anatase: size dependent and irreversible anatase-rutile phase transition in atomic-level precise titania. AB - Since crystal phase dominantly affects the properties of nanocrystals, phase control is important for the applications. To demonstrate the size dependence in anatase-rutile phase transition of titania, we used quantum-size titania prepared from the restricted number of titanium ions within dendrimer templates for size precision purposes and optical wave guide spectroscopy for the detection. Contrary to some theoretical calculations, the observed irreversibility in the transition indicates the metastablity of anatase; thermodynamics cannot explain the formation of metastable states. Therefore, we take into account the kinetic control polymerization of TiO6 octahedral units to explain how the crystal phase of the crystal-nucleus-size titania is dependent on which coordination sites, cis or trans-, react in the TiO6 octahedra, suggesting possibilities for the synthetic phase control of nanocrystals. In short, the dendrimer templates give access to crystal nucleation chemistry. The paper will also contribute to the creation of artificial metastable nanostructures with atomic-level precision. PMID- 23743570 TI - Ketogenic diets enhance oxidative stress and radio-chemo-therapy responses in lung cancer xenografts. AB - PURPOSE: Ketogenic diets are high in fat and low in carbohydrates as well as protein which forces cells to rely on lipid oxidation and mitochondrial respiration rather than glycolysis for energy metabolism. Cancer cells (relative to normal cells) are believed to exist in a state of chronic oxidative stress mediated by mitochondrial metabolism. The current study tests the hypothesis that ketogenic diets enhance radio-chemo-therapy responses in lung cancer xenografts by enhancing oxidative stress. EXPERIMENTAL DESIGN: Mice bearing NCI-H292 and A549 lung cancer xenografts were fed a ketogenic diet (KetoCal 4:1 fats: proteins+carbohydrates) and treated with either conventionally fractionated (1.8 2 Gy) or hypofractionated (6 Gy) radiation as well as conventionally fractionated radiation combined with carboplatin. Mice weights and tumor size were monitored. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modified proteins as a marker of oxidative stress as well as proliferating cell nuclear antigen (PCNA) and gammaH2AX as indices of proliferation and DNA damage, respectively. RESULTS: The ketogenic diets combined with radiation resulted in slower tumor growth in both NCI-H292 and A549 xenografts (P < 0.05), relative to radiation alone. The ketogenic diet also slowed tumor growth when combined with carboplatin and radiation, relative to control. Tumors from animals fed a ketogenic diet in combination with radiation showed increases in oxidative damage mediated by lipid peroxidation as determined by 4HNE-modified proteins as well as decreased proliferation as assessed by decreased immunoreactive PCNA. CONCLUSIONS: These results show that a ketogenic diet enhances radio-chemo therapy responses in lung cancer xenografts by a mechanism that may involve increased oxidative stress. PMID- 23743572 TI - Inhibition of the PI3K/Akt pathway increases the chemosensitivity of gastric cancer to vincristine. AB - The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway plays a crucial role in tumorigenesis and tumor progression by promoting cell proliferation and inhibiting apoptosis, a process closely associated with multidrug resistance (MDR) of tumors. LY294002 is a commonly used pharmacological inhibitor that acts at the ATP-binding site of the PI3K enzyme, selectively inhibiting the PI3K/Akt pathway. In the present study, we evaluated the effect of LY294002 on the chemosensitivity of gastric cancer cells to vincristine (VCR) in vitro and in vivo and investigated the possible underlying cellular mechanisms. The effect of LY294002 on cell viability, apoptosis induction and inhibition of tumor growth was analyzed using MTT and TUNEL assay in in vitro and in vivo models of gastric cancer. Intracellular accumulation of VCR was determined by high performance liquid chromatography. The activity of the PI3K/Akt pathway was evaluated by western blot analysis. Furthermore, reverse transcription PCR and immunohistochemistry were performed to determine the mRNA and protein expression levels of MDR1/ P-glycoprotein (P-gp) and apoptosis-related factors. We found that gastric cancer cells treated with LY294002 showed a significant inhibition of PI3K/Akt activity. The PI3K inhibitor LY294002 combined with VCR worked synergistically to promote growth inhibition, induce apoptosis and increase the intracellular drug accumulation in gastric cancer cell lines. Similarly, LY294002 could cooperate with VCR to reduce tumor growth in a gastric cancer model in vivo. Finally, LY294002 was able to decrease the expression of MDR1/P-gp, Bcl-2 and XIAP, and upregulate expression of Bax and caspase-3, thereby enhancing chemosensitivity to VCR by inhibiting a drug pump and inducing apoptosis. These results suggested that the PI3K/Akt inhibitor LY294002 can enhance chemosensitivity of human gastric cancer to VCR. This preclinical evaluation of a rational combination of LY294002 and VCR may provide a new strategy to resolve the MDR of gastric cancer. PMID- 23743573 TI - System dynamics model for hospital waste characterization and generation in developing countries. AB - Waste management policy makers always face the problem of how to predict the future amount and composition of medical solid waste, which, in turn, helps to determine the most appropriate treatment, recycling and disposal strategy. An accurate prediction can assist in both the planning and design of medical solid waste management systems. Insufficient budget and unavailable management capacity are the main reasons for the scarcity of medical solid waste quantities and components historical records, which are so important in long-term system planning and short-term expansion programs. This article presents a new technique, using System Dynamics modeling, to predict generated medical solid waste in a developing urban area, based on a set of limited samples from Jenin District hospitals, Palestine. The findings of the model present the trend of medical solid waste generation together with its different components and indicate that a new forecasting approach may cover a variety of possible causative models and track inevitable uncertainties when traditional statistical least-squared regression methods are unable to handle such issues. PMID- 23743574 TI - Developing evidence-based physical therapy clinical practice guidelines. AB - PURPOSE: Recommended strategies for developing evidence-based clinical practice guidelines (CPGs) are provided. KEY POINTS: The intent is that future CPGs developed with the support of the Section on Pediatrics of the American Physical Therapy Association would consistently follow similar developmental processes to yield consistent quality and presentation. Steps in the process of developing CPGs are outlined and resources are provided to assist CPG developers in carrying out their task. These recommended processes may also be useful to CPG developers representing organizations with similar structures, objectives, and resources. PMID- 23743575 TI - The effectiveness of fish oil supplementation in asthmatic rats is limited by an inefficient action on ASM function. AB - Episodes of acute exacerbation are the major clinical feature of asthma and therefore represent an important focus for developing novel therapies for this disease. There are many reports that the n-3 fatty acids found in fish oil exert anti-inflammatory effects, but there are few studies of the action of fish oil on airway smooth muscle (ASM) function. In the present investigation, we evaluated the effect of fish oil supplementation on smooth muscle force of contraction in ovalbumin-induced asthmatic Wistar rats, and its consequences on static lung compliance, mucus production, leukocyte chemotaxis and production of proinflammatory cytokines. Fish oil supplementation suppressed the infiltration of inflammatory cells into the lung in asthmatic animals (2.04 +/- 0.19 * 10(6) cells vs. 3.33 +/- 0.43 * 10(6) cells in the control asthmatic group; P < 0.05). Static lung compliance increased with fish oil supplementation in asthmatic rats (0.640 +/- 0.053 mL/cm H2O vs. 0.399 +/- 0.043 mL/cm H2O; P < 0.05). However, fish oil did not prevent asthma-associated lung eosinophilia and did not affect the concentrations of tumor necrosis factor-alpha and interleukin-1beta in lung tissue or the proportion of the airways obliterated with mucus. Fish oil had no effect on the force of contraction in asthmatic rats in response to acetylcholine (3.026 +/- 0.274 mN vs. 2.813 +/- 0.364 mN in the control asthmatic group). In conclusion, although fish oil exerts some benefits in this model of asthma, its effectiveness appears to be limited by an inefficient action on airway smooth muscle function. PMID- 23743576 TI - Targeted training of the decision rule benefits rule-guided behavior in Parkinson's disease. AB - The impact of Parkinson's disease (PD) on rule-guided behavior has received considerable attention in cognitive neuroscience. The majority of research has used PD as a model of dysfunction in frontostriatal networks, but very few attempts have been made to investigate the possibility of adapting common experimental techniques in an effort to identify the conditions that are most likely to facilitate successful performance. The present study investigated a targeted training paradigm designed to facilitate rule learning and application using rule-based categorization as a model task. Participants received targeted training in which there was no selective-attention demand (i.e., stimuli varied along a single, relevant dimension) or nontargeted training in which there was selective-attention demand (i.e., stimuli varied along a relevant dimension as well as an irrelevant dimension). Following training, all participants were tested on a rule-based task with selective-attention demand. During the test phase, PD patients who received targeted training performed similarly to control participants and outperformed patients who did not receive targeted training. As a preliminary test of the generalizability of the benefit of targeted training, a subset of the PD patients were tested on the Wisconsin card sorting task (WCST). PD patients who received targeted training outperformed PD patients who did not receive targeted training on several WCST performance measures. These data further characterize the contribution of frontostriatal circuitry to rule-guided behavior. Importantly, these data also suggest that PD patient impairment, on selective-attention-demanding tasks of rule-guided behavior, is not inevitable and highlight the potential benefit of targeted training. PMID- 23743578 TI - Why psychogeriatrics starts right after adolescence. PMID- 23743577 TI - Viewpoint: mismatch between the European and American guidelines on oral antiplatelet P2Y12 inhibitors after acute coronary syndromes. AB - Recent European Society of Cardiology (ESC) Guidelines declare superiority of prasugrel and ticagrelor over clopidogrel in non-ST segment elevation myocardial infarction (NSTEMI) and STEMI patients with acute coronary syndromes (ACS). The recommendations for NSTEMI and especially STEMI are based on a subgroup analyses yielded from a single trial with either prasugrel (TRITON), or ticagrelor (PLATO). In contrast, the United States (US) Guidelines present a more balanced, conservative, and evidence-based outlook suggesting no proven extra benefit of one P2Y12 antagonist over the other(s). It was the purpose of this study to scrutinise the evidence leading to the current ESC ACS Guidelines on oral antiplatelet agents and compare them with US recommendations. Matching the evidence from TRITON and PLATO primary publications with the data reported in the Food and Drug Administration (FDA) official reviews in light of their impact on current regional ACS Guidelines on antiplatelet P2Y12 inhibitors. The available body of evidence on the efficacy and safety of the new oral P2Y12 inhibitors challenge the ESC Guidelines, and supports the US recommendations. Some of the pivotal data with regard to the newer P2Y12 inhibitors (prasugrel and ticagrelor) on event definition, adjudication, questionable efficacy, and serious safety concerns were ignored by the European Task Force Members, while the other "beneficial" findings were exaggerated to a disproportional extent. We conclude that current ESC Guidelines, with regard to their recommendation of superiority of prasugrel or ticagrelor over clopidogrel, in contrast to the US, are overoptimistic, and not evidence based. Low clinical utilisation of prasugrel and especially ticagrelor worldwide in general, and Europe in particular suggests mismatch of prescription habits with issued ESC recommendations. PMID- 23743579 TI - Occurrence, profiling and prioritization of halogenated disinfection by-products in drinking water of China. AB - The occurrence of 28 disinfection by-products (DBPs), which were divided into 5 groups, in 70 drinking water treatment plants in 31 cities across China was investigated, and the toxic potency of each DBP group was calculated using mammalian cell toxicity data from previous studies for profiling. Of the 28 DBPs, 21 were detected with an average frequency of detection of 50%. Trihalomethanes (THM4) and haloacetic acids (HAAs) were the most predominant species, whose median concentration levels were at 10.53 and 10.95 MUg L(-1), respectively. Two of four iodinated trihalomethanes (I-THMs) were detected, and the concentration of the I-THMs ranged from under the detection limit to 5.58 MUg L(-1). The total concentration of haloacetonitriles (HANs) in different water samples ranged from under the limit of detection to 39.20 MUg L(-1), with a median concentration of 1.11 MUg L(-1). Two of four halonitromethanes (HNMs) were detected, and the maximum concentrations of chloronitromethane (CNM) and trichloronitromethane (TCNM) were 0.96 and 0.28 MUg L(-1), respectively. HANs were found to be the most potent DBP group in terms of cytotoxicity, and HANs and HAAs had the same level of genotoxic potency. These results indicate that although at a low concentration level, the toxic potency of the unregulated HANs in drinking water may not be neglected. PMID- 23743580 TI - Patellar denervation with electrocautery in total knee arthroplasty without patellar resurfacing: a meta-analysis. AB - PURPOSE: The impact of patellar denervation with electrocautery in total knee arthroplasty (TKA) on post-operative outcomes has been under debate. This study aims to conduct a meta-analysis and systematic review to compare the benefits and risks of circumpatellar electrocautery with those of non-electrocautery in primary TKAs. METHODS: Comparative and randomized clinical studies were identified by conducting an electronic search of articles dated up to September 2012 in PubMed, EMBASE, Scopus, and the Cochrane databases. Six studies that focus on a total of 849 knees were analysed. A random-effects model was conducted using the inverse-variance method for continuous variables and the Mantel Haenszel method for dichotomous variables. RESULTS: There was no significant difference in the incidence of anterior knee pain between the electrocautery and non-electrocautery groups. In term of patellar score and Knee Society Score, circumpatellar electrocautery improved clinical outcomes compared with non electrocautery in TKAs. The statistical differences were in favour of the electrocautery group but have minimal clinical significance. In addition, the overall complications indicate no statistical significance between the two groups. CONCLUSIONS: This study shows no strong evidence either for or against electrocautery compared with non-electrocautery in TKAs. LEVEL OF EVIDENCE: Therapeutic study (systematic review and meta-analysis), Level III. PMID- 23743581 TI - Association between varus alignment and post-traumatic osteoarthritis after anterior cruciate ligament injury. AB - PURPOSE: To investigate the association between varus alignment and post traumatic osteoarthritis (OA) after an anterior cruciate ligament (ACL) injury. METHODS: One hundred subjects with an acute complete ACL tear were followed for 15 years. Anterior-posterior radiographs of the tibiofemoral joint were obtained with a knee flexion of 20 degrees , and the patellofemoral joint was examined with skyline view at 50 degrees knee flexion. Joint space narrowing and osteophytes were graded in the tibiofemoral and patellofemoral joints in the injured (ACL) and uninjured knee according to the radiographic atlas of the Osteoarthritis Research Society International. The alignment of the uninjured, contralateral knee was measured at follow-up, using full-limb radiographs of leg with the knee in full extension. Alignment was expressed as the hip-knee-ankle (HKA) angle. Alignment was defined as valgus (HKA <=178 degrees ), neutral (179 degrees -181 degrees ) or varus (>=182 degrees ). RESULTS: Data from 68 subjects were included in the analysis. Varus alignment of the uninjured knee at follow-up appeared to be associated with OA of the injured knee 15 years after an ACL injury (odds ratio (95% confidence interval) 3.9 (1.0-15.8, p = 0.052)). CONCLUSIONS: Varus alignment of the uninjured knee at follow-up may be associated with OA of the injured knee 15 years after an ACL injury. LEVEL OF EVIDENCE: II. PMID- 23743582 TI - A comparison of glypican-3 with alpha-fetoprotein as a serum marker for hepatocellular carcinoma: a meta-analysis. AB - BACKGROUNDS: Glypican-3(GPC3) has been reported as one of the most promising serum markers for hepatocellular carcinoma (HCC), while several studies have conflicting results for the diagnostic accuracy between GPC3 and alpha fetoprotein (AFP). METHODS: Studies that explored the diagnostic value of GPC3 and AFP in HCC were searched in MEDLINE, EMBASE, PUBMED, the Cochrane Library and Chinese biomedical literature database (CBM). Sensitivity, specificity and other measures about the accuracy of serum GPC3 and AFP in the diagnosis of HCC were pooled using random effects models. Summary receiver operating characteristic curve (sROC) analysis was used to summarize the overall test performance. RESULTS: Ten studies were included in our meta-analysis. The pooled sensitivity for AFP and GPC3 is 51.9% (95% confidence interval (CI) 0.47-0.56) and 59.2% (95% CI 0.55-0.63), respectively, while the pooled specificity for AFP and GPC3 is 94% (95% CI 92.1-95.6%) and 84.8% (95% CI 82-87.3%), respectively. The pooled diagnostic odds ratio (DOR) for AFP and GPC3 were 23.4 (95% CI 10.3-53.2) and 17.99 (95% CI 5.4-60.4), respectively. Area under sROC for both AFP and GPC3 is 0.81 (95% CI 0.77-0.84). CONCLUSIONS: GPC3 is comparable to AFP as a serum marker for the diagnosis of HCC, combination of AFP and GPC3 can elevate the sensitivity of diagnosis. PMID- 23743589 TI - The ideal crystalloid - what is 'balanced'? AB - PURPOSE OF REVIEW: This review explores the contemporary definition of the term 'balanced crystalloid' and outlines optimal design features and their underlying rationale. RECENT FINDINGS: Crystalloid interstitial expansion is unavoidable, but also occurs with colloids when there is endothelial glycocalyx dysfunction. Reduced chloride exposure may lessen kidney dysfunction and injury with a possible mortality benefit. Exact balance from an acid-base perspective is achieved with a crystalloid strong ion difference of 24 mEq/l. This can be done simply by replacing 24 mEq/l of chloride in 0.9% sodium chloride with bicarbonate or organic anion bicarbonate substitutes. Potassium, calcium and magnesium additives are probably unnecessary. Large volumes of mildly hypotonic crystalloids such as lactated Ringer's solution reduce extracellular tonicity in volunteers and increase intracranial pressure in nonbrain-injured experimental animals. A total cation concentration of 154 mmol/l with accompanying anions provides isotonicity. Of the commercial crystalloids, Ringer's acetate solution is close to balanced from both acid-base and tonicity perspectives, and there is little current evidence of acetate toxicity in the context of volume loading, in contrast to renal replacement. SUMMARY: The case for balanced crystalloids is growing but unproven. A large randomized controlled trial of balanced crystalloids versus 0.9% sodium chloride is the next step. PMID- 23743590 TI - Reappraising Starling: the physiology of the microcirculation. AB - PURPOSE OF REVIEW: Vascular permeability is traditionally explained by Starling's principle, describing two opposing forces across the endothelial cell line to maintain compartments in balance. Several contradictions to this principle have recently questioned its validity. RECENT FINDINGS: Hydraulic conductivity is kept low by a properly working endothelial surface layer, created by binding and intercalating plasma constituents with the structural elements of an endothelial glycocalyx. Limiting fluid filtration is not closely related to the interstitial protein concentration. Rather, the oncotic pressure difference pertinent to fluid homeostasis is built up between the intravascular space and a small protein-free zone beneath the protein-loaded endothelial glycocalyx. This crucial structure, and therefore the resistance of the barrier against outflow of large molecules, is endangered by ischaemia, inflammation and intravascular hypervolaemia. An intact endothelial surface layer retains iso-oncotic preparations of large molecules infused to compensate for acute bleeding. Crystalloids cannot be held back sufficiently, even if preload is warranted. SUMMARY: Starling's principle requires an adaptation to recognize that there is no inward-directed oncotic pressure gradient across the whole anatomical vessel wall. The carrier of vascular barrier competence is the intact endothelial surface layer which might be protected by avoiding intravascular hypervolaemia and limiting inflammation. PMID- 23743591 TI - Hydroxyethyl starch for resuscitation. AB - PURPOSE OF REVIEW: Resuscitation with hydroxyethyl starch (HES) is controversial. In this review, we will present the current evidence for the use of HES solutions including data from recent high-quality randomized clinical trials. RECENT FINDINGS: Meta-analyses of HES vs. control fluids show clear signals of harm including adverse effects on kidney and haemostatic function, and trends towards increased mortality. These results are mainly based on recent large randomized clinical trials comparing tetrastarch (HES 130/0.4 and HES 130/0.42) vs. crystalloid in patients in the ICU. Trials in trauma and surgical patients cannot adequately assess safety issues and do not show clear benefit with the use of HES. There is currently no firm evidence that tetrastarch has better safety profile than the former HES solutions. SUMMARY: There is no evidence for an overall beneficial effect of HES in any subgroup of critically ill patients, but there are clear signs of harm. As safer alternatives exist, we recommend that HES is no longer used in critically ill patients. PMID- 23743592 TI - Influences of surface capping with electrostatically self-assembled PEI on the photoresponse of a TiO2 thin film. AB - The photoresponse of a TiO2 thin film was significantly improved due to the decrease in the Schottky barrier height between Au and TiO2 via the formation of interface dipoles, which was caused by electrostatically self-assembled PEI on the surface of the TiO2 film. PMID- 23743593 TI - Adipocyte differentiation is affected by media height above the cell layer. AB - BACKGROUND: 3T3-L1 cells have been widely used as a model for adipogenesis. However, despite its popularity, differentiation of this cell line has been reported to be inconsistent with low efficiency. OBJECTIVE: To investigate the effect of media height during adipocyte differentiation on lipid accumulation and adipokine secretion in mature adipocytes. METHODS: Three cell lines (3T3-L1, OP9 and ChubS7) were used to test the influence of media volume on adipogenesis. Total lipid content and lipid droplet size and number were quantified. Adipocyte related gene expressions were quantified during the course of differentiation. Secretion of leptin and adiponectin from mature adipocytes were measured using enzyme-linked immunosorbent assays. The influence of oxygen partial pressure on adipogenesis was investigated using three oxygen percentages: 5, 21 and 30%. Insulin sensitivity was measured by insulin inhibition of isoproterenol-induced lipolysis and phosphorylation of insulin receptor substrate-1. RESULTS: A lower media height during adipogenesis increased total lipid accumulation, NEFA release and leptin and adiponectin secretion in mature adipocytes. Insulin sensitivity was not affected by media height during differentiation. CONCLUSION: Media height during adipogenesis was inversely correlated with lipid content in mature adipocytes. To achieve a high lipid content and greater adipokine secretion, it is best to use a low media volume during differentiation. PMID- 23743594 TI - Effects of calcium and copper exposure on lipogenic metabolism, metal element compositions and histology in Synechogobius hasta. AB - The present study was conducted to evaluate the effects of calcium (Ca) and copper (Cu) exposure on growth performance, metal element composition, enzymatic activities and histology in Synechogobius hasta and tested the hypothesis that Ca could protect against Cu-induced toxicity in the fish species. Three hundred sixty S. hasta (initial mean weight 22.6 +/- 0.2 g, mean +/- SEM) were stocked in 18 circular fiberglass tanks (water volume: 300 l), 9 of which were pre-exposed to Ca at a rate of 600 mg Ca/l for 10 days and then exposed to concentrations of 0, 77 and 154 MUg Cu/l for 30 days. Another 9 tanks were cultured in natural seawater (no extra Ca addition) for 10 days and then exposed to concentrations of 0, 77 and 154 MUg Cu/l for 30 days. Both Ca exposure and then waterborne Cu exposure influenced the accumulation of metal elements (Cu, iron, zinc and manganese) in several tissues (muscle, intestine, gill, liver and spleen), changed hepatic lipogenic metabolism and induced histological alterations in liver, gill and spleen. In general, Ca exposure seemed to mitigate the severity of Cu-induced mortality and histopathological injuries, indicating that Ca exposure had the capacity to decrease Cu toxicity in S. hasta. To our knowledge, it is the first study involved in the effects of Ca and Cu exposure on hepatic lipogenic metabolism and metal element compositions in a wide range of tissues and organs in fish, which provides new insight into the protective effect of Ca on toxic metal elements in fish. PMID- 23743595 TI - Intrinsic loss due to unstable modes in graphene. AB - The mechanism of dissipation operative at the nanoscale remains poorly understood for most cases. In this work, using molecular dynamics simulations, we show that the unstable out-of-plane mode leads to the absorption of energy from the in plane motion in graphene. The in-plane vibration modulates the potential energy profile for the out-of-plane modes. For the fundamental out-of-plane mode in the loading direction, the minimum of the potential energy shifts because of in-plane compressive strain. The structure takes a finite amount of time to relax to the new potential energy configuration. A hysteresis in the out-of-plane dynamics is observed when the time period of in-plane excitation becomes comparable to the time required for this relaxation. Increasing the stiffness of the out-of-plane modes by giving an initial tensile strain leads to a considerable decrease in dissipation rate. PMID- 23743596 TI - Systemic treatment after whole-brain radiotherapy may improve survival in RPA class II/III breast cancer patients with brain metastasis. AB - Whole brain radiotherapy (WBRT) is the most widely used treatment for brain metastasis (BM), especially for patients with multiple intracranial lesions. The purpose of this study was to examine the efficacy of systemic treatments following WBRT in breast cancer patients with BM who had different clinical characteristics, based on the classification of the Radiation Therapy Oncology Group recursive partitioning analysis (RPA) and the breast cancer-specific Graded Prognostic Assessment (Breast-GPA). One hundred and one breast cancer patients with BM treated between 2006 and 2010 were analyzed. The median interval between breast cancer diagnosis and identification of BM in the triple-negative patients was shorter than in the luminal A subtype (26 vs. 36 months, respectively; P = 0.021). Univariate analysis indicated that age at BM diagnosis, Karnofsky performance status/recursive partitioning analysis (KPS/RPA) classes, number of BMs, primary tumor control, extracranial metastases and systemic treatment following WBRT were significant prognostic factors for overall survival (OS) (P < 0.05). Multivariate analysis revealed that KPS/RPA classes and systemic treatments following WBRT remained the significant prognostic factors for OS. For RPA class I, the median survival with and without systemic treatments following WBRT was 25 and 22 months, respectively (P = 0.819), while for RPA class II/III systemic treatments significantly improved OS from 7 and 2 months to 11 and 5 months, respectively (P < 0.05). Our results suggested that triple-negative patients had a shorter interval between initial diagnosis and the development of BM than luminal A patients. Systemic treatments following WBRT improved the survival of RPA class II/III patients. PMID- 23743597 TI - Pyrosequencing analysis of oral microbiota in children with severe early childhood dental caries. AB - Severe early childhood caries are a prevalent public health problem among preschool children throughout the world. However, little is known about the microbiota found in association with severe early childhood caries. Our study aimed to explore the bacterial microbiota of dental plaques to study the etiology of severe early childhood caries through pyrosequencing analysis based on 16S rRNA gene V1-V3 hypervariable regions. Forty participants were enrolled in the study, and we obtained twenty samples of supragingival plaque from caries-free subjects and twenty samples from subjects with severe early childhood caries. A total of 175,918 reads met the quality control standards, and the bacteria found belonged to fourteen phyla and sixty-three genera. Our results show the overall structure and microbial composition of oral bacterial communities, and they suggest that these bacteria may present a core microbiome in the dental plaque microbiota. Three genera, Streptococcus, Granulicatella, and Actinomyces, were increased significantly in children with severe dental cavities. These data may facilitate improvements in the prevention and treatment of severe early childhood caries. PMID- 23743598 TI - Diversity of gene cassette promoter variants of class 1 integrons in uropathogenic Escherichia coli. AB - Class 1 integrons play important roles in the emergence and horizontal transfer of antibiotic resistance genes among bacteria. The gene cassette promoter variants Pc or Pc-P2 of class 1 integrons not only drive the transcription of downstream gene cassettes, they also correlate with the excision and integration efficiency of the capture exogenous gene cassettes. In this study, the diversity of Pc or Pc-P2 variants of class 1 integrons and their association with antibiotic resistance phenotypes were analyzed in 132 uropathogenic Escherichia coli strains. Class 1 integrons were detected in 95 (72 %) strains. Sixteen different gene cassettes, 11 different gene cassette arrays and six different Pc or Pc-P2 variants were detected. The most prevalent gene cassettes were those that conferred resistance to trimethoprim, aminoglycosides, and chloramphenicol. The most prevalent promoter was PcH1, a relatively weak promoter. Certain gene cassette arrays or gene cassettes were mainly associated with the same Pc or Pc P2 in different strains. Strains harboring class 1 integrons with relatively strong promoters had higher resistance rates to, or higher MIC(50) for, amikacin, chloramphenicol and tobramycin than those with relatively weak promoters. To the best of our knowledge, this is the first report of the diversity of class 1 integron Pc or Pc-P2 variants in uropathogenic E. coli strains. PMID- 23743599 TI - Adenosine monophosphate affects competence development and plasmid DNA transformation in Escherichia coli. AB - Artificial plasmid DNA transformation of Escherichia coli induced by calcium chloride is a routine technique in molecular biology and genetic engineering processes, but its mechanism has remained elusive. Because adenosine monophosphate (AMP) has been found to regulate natural transformation in Haemophilus influenza, we aimed to investigate the effects of AMP and its derivatives on E. coli transformation by treating competence with different concentrations of them. Analysis of the transformation efficiencies revealed that AMP inhibited the artificial plasmid DNA transformation of E. coli in a concentration- and time-dependent manner. Furthermore, we found that AMP had no effect on the expression of the transformed gene but that the intracellular AMP level of the competent cells rose after a 6 h treatment. These results suggested that the intracellular AMP level had an important role in E. coli transformation. And these have useful implications for the further investigation of the mechanism of E. coli transformation. PMID- 23743600 TI - Identification of household bacterial community and analysis of species shared with human microbiome. AB - Microbial populations in indoor environments, where we live and eat, are important for public health. Various bacterial species reside in the kitchen, and refrigerators, the major means of food storage within kitchens, can be a direct source of food borne illness. Therefore, the monitoring of microbiota in the refrigerator is important for food safety. We investigated and compared bacterial communities that reside in the vegetable compartment of the refrigerator and on the seat of the toilet, which is recognized as highly colonized by microorganisms, in ten houses using high-throughput sequencing. Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes were predominant in refrigerator and toilet samples. However, Proteobacteria was more abundant in the refrigerator, and Firmicutes was more abundant in the toilet. These household bacterial communities were compared with those of human skin and gut to identify potential sources of household bacteria. Bacterial communities from refrigerators and toilets shared more species in common with human skin than gut. Opportunistic pathogens, including Propionibacterium acnes, Bacteroides vulgatus, and Staphylococcus epidermidis, were identified as species shared with human skin and gut microbiota. This approach can provide a general background of the household microbiota and a potential method of source-tracking for public health purposes. PMID- 23743601 TI - Screening of Actinobacillus pleuropneumoniae LuxS inhibitors. AB - LuxS, a conserved bacterial enzyme involved in the activated methyl cycle, catalyzes S-ribosylhomocysteine (SRH) into homocysteine and AI-2 (the inter species quorum-sensing signal molecule). This enzyme has been reported to be essential for the survival of Actinobacillus pleuropneumoniae in its natural host. Therefore, it is a potential drug target against A. pleuropneumoniae, an important swine respiratory pathogen causing great economic losses in the pig industry worldwide. In this study, the enzymatic activity determination method was established using the recombinant LuxS of A. pleuropneumoniae. Thirty-five compounds similar to the shape of SRH were screened from the Specs compound library by the software vROCS and were evaluated for LuxS inhibition. Three compounds could inhibit LuxS activity. Two of them were confirmed to be competitive inhibitors and the third one was uncompetitive. All the three compounds displayed inhibitory effects on the growth of A. pleuropneumoniae and two other important swine pathogens, Haemophilis parasuis and Streptococcus suis, with MIC50 values ranging from 11 to 51 MUg/ml. No significant cytotoxic effect of the compounds was detected on porcine PK-15 cells at the concentration which showed inhibitory effect on bacterial growth. These results suggest that LuxS is an ideal target to develop antimicrobials for porcine bacterial pathogens. The three LuxS inhibitors identified in this study can be used as lead compounds for drug design. PMID- 23743602 TI - Functional analysis of the EspR binding sites upstream of espR in Mycobacterium tuberculosis. AB - The ESX-1 secretion system exports substrate proteins into host cells and is crucial for the pathogenesis of Mycobacterium tuberculosis. EspR is one of the characterized transcriptional regulators that modulates the ESX-1 system by binding the conserved EspR binding sites in the promoter of espA, the encoding gene of EspA, which is also a substrate protein of the ESX-1 system and is required for the ESX-1 activity. EspR is autoregulatory and conserved EspR binding sites are present upstream of espR. In this study, we showed that these EspR sites had varying affinities for EspR, with site B being the strongest one. Point mutations of the DNA sequence at site B abolished binding of EspR to oligonucleotides containing site B alone or with other sites, further suggesting that site B is a major binding site for EspR. Complementation studies showed that constructs containing espR, and the upstream intergenic region fully restored espR expression in a DeltaespR mutant strain. Although recombinant strains with mutations at more than one EspR site showed minimal differences in espR expression, reduced expression of other EspR target genes was observed, suggesting that slight changes in EspR levels can have downstream regulatory effects. These findings contribute to our understanding of the regulation of the ESX-1 system. PMID- 23743603 TI - Givenness, complexity, and the Danish dative alternation. AB - In this study, we investigated the interaction between givenness and complexity on the choice of syntactic structure, via two experiments using speeded acceptability judgments. Experiment 1 showed that for the Danish dative alternation, given-new orders are only easier to process for double-object or NP constructions, whereas PP constructions are unaffected. This replicates previous findings for the English dative alternation. Experiment 2 revealed that when a long NP precedes a short NP-a suboptimal complexity relation-the effect of givenness is neutralized, whereas givenness remains influential when the complexity relation between the NPs in the sentence is optimal. This is consistent with the view that in online parsing, the actual syntactic structure building process is primary, whereas any higher-order computations such as discourse linking are secondary. The relative complexity of the NPs in the double object construction directly affects the structure-building process, whereas the decoding of the discourse structure is a later and less crucial phenomenon, resulting in neutralization of the givenness effect in cases in which the complexity relation is suboptimal. PMID- 23743604 TI - A community's response to suicide through public art: stakeholder perspectives from the Finding the Light Within project. AB - Suicide is a preventable public health problem and a leading cause of death in the United States. Despite recognized need for community-based strategies for suicide prevention, most suicide prevention programs focus on individual-level change. This article presents seven first person accounts of Finding the Light Within, a community mobilization initiative to reduce the stigma associated with suicide through public arts participation that took place in Philadelphia, Pennsylvania from 2011 through 2012. The stigma associated with suicide is a major challenge to suicide prevention, erecting social barriers to effective prevention and treatment and enhancing risk factors for people struggling with suicidal ideation and recovery after losing a loved one to suicide. This project engaged a large and diverse audience and built a new community around suicide prevention through participatory public art, including community design and production of a large public mural about suicide, storytelling and art workshops, and a storytelling website. We present this project as a model for how arts participation can address suicide on multiple fronts-from raising awareness and reducing stigma, to promoting community recovery, to providing healing for people and communities in need. PMID- 23743605 TI - Expression of REG III and prognosis in head and neck cancer. AB - Identification of a reliable biomarker for predicting prognosis in head and neck cancers is highly desirable and has long been sought. There have been several reports that members of the regenerating gene (REG) family are highly expressed in chronic inflammation and in tumors of the digestive organs. In addition, it has been described in several reports that REG expression is associated with the progression of digestive cancers. In the present study, we evaluated the effect of REG expression on the prognosis of hypopharyngeal cancer. We investigated 37 cases with hypopharyngeal squamous cell carcinoma, determined REG mRNA expression, which is easily detected in formalin-fixed paraffin-embedded tissues using the real-time reverse transcriptase-polymerase chain reaction method, and evaluated the survival rate using the Kaplan-Meier method. According to these results, REG III mRNA expression was significantly associated with prolonged survival. Therefore, we constructed hypopharyngeal cancer cell lines transfected with REG III and assessed the cell proliferation and chemosensitivity and/or radiosensitivity in vitro. Cells transfected with REG III exhibited significantly lower cell proliferation and higher chemosensitivity and/or radiosensitivity compared with the control cells. These data suggest that REG III may be a reliable biomarker of prognosis in hypopharyngeal cancer. This is the first report concerning the association of REG III expression and the prognosis of head and neck squamous cell carcinoma including hypopharyngeal cancer. PMID- 23743606 TI - Aortic valve replacement in an elderly patient with factor XI deficiency. AB - Factor XI (FXI) deficiency is rare and associated with bleeding after surgical procedures. We report a case of an 80-year-old woman with severe aortic valve stenosis. FXI deficiency was diagnosed due to prolonged activated partial thromboplastin time. Aortic valve replacement was performed using a porcine bioprosthetic valve. Intra-operation bleeding was controlled by the transfusion of a fresh frozen plasma. The postoperative course was uneventful. PMID- 23743607 TI - Oxygen doped SiC nanocrystals: first principles study of the optical properties. AB - We have studied a typical spherical SiC nanocrystal with a diameter of 1.2 nm (Si43C44H76) using linear combination of atomic orbitals in combination with pesudopotential density functional calculation. The role of fluorine and oxygen impurities was investigated on the electronic and optical properties of the Si43C44H76 nanocrystal. Total energy calculations show that the fluorine doped Si43C44H76 nanocrystals are unstable. Oxygen doped Si43C44H76 have different binding energies in various substitutional and interstitial defects. The maximum binding energy of the oxygen at carbon substitutional defect is about -0.5 eV and at interstitial defect is -0.18 eV. The HOMO-LUMO gap of the pure Si43C44H76 is about 6.71 eV and after doping with oxygen changes on the order of 0.1 eV. Our studies show that the refractive index of the doped Si43C44H76 nanocrystal significantly dispersed in comparison with pure SiC nanocrystal especially at the range of 6 to 8 eV. PMID- 23743608 TI - Summer talks in Santiago III--the Politzer Conference. PMID- 23743609 TI - Air quality and climate--synergies and trade-offs. AB - Air quality and climate are often treated as separate science and policy areas. Air quality encompasses the here-and-now of pollutant emissions, atmospheric transformations and their direct effect on human and ecosystem health. Climate change deals with the drivers leading to a warmer world and the consequences of that. These two science and policy issues are inexorably linked via common pollutants, such as ozone (methane) and black carbon. This short review looks at the new scientific evidence around so-called "short-lived climate forcers" and the growing realisation that a way to meet short-term climate change targets may be through the control of "air quality" pollutants. None of the options discussed here can replace reduction of long-lived greenhouse gases, such as CO2, which is required for any long-term climate change mitigation strategy. An overview is given of the underlying science, remaining uncertainties, and some of the synergies and trade-offs for addressing air quality and climate in the science and policy context. PMID- 23743610 TI - A biomimetic mercury(II)-gated single nanochannel. AB - A simple biomimetic mercury(II)-gated single nanochannel has been developed by incorporating a mercury(II) responsive single stranded DNA (ssDNA) with thymine thymine (T-T) bases into a single polymetic nanochannel. PMID- 23743611 TI - Linking obesity to colorectal cancer: recent insights into plausible biological mechanisms. AB - PURPOSE OF REVIEW: This review will examine the recent scientific literature on the mechanisms that are thought to link obesity to colorectal cancer (CRC) risk. RECENT FINDINGS: Obesity has emerged as a leading environmental risk factor for the development of CRC. However, the mechanisms underlying this relationship have not yet been fully elucidated. Recent literature has focused on inflammatory processes, adipokines, and estrogen. Obesity-enhanced inflammation is largely orchestrated by increases in adipose tissue macrophages leading to the secretion of inflammatory cytokines including tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and interleukin-6, all of which are linked to CRC. Adiponectin is decreased with obesity and has been reported to be negatively associated with CRC, whereas leptin, which is increased, is positively associated with the disease. Estrogen has been shown to influence CRC, although its role remains controversial; some studies have implicated estrogen as being protective, whereas others have suggested it to be a risk factor. We highlight the most important recent advances that have been made on the aforementioned mechanisms that are thought to link obesity to CRC. SUMMARY: A better understanding of the mechanisms linking obesity to CRC risk is necessary for the design of effective treatment approaches in future clinical trials. PMID- 23743613 TI - Control of density and LSPR of Au nanoparticles on graphene. AB - In this study, we introduce the tunable density and localized surface plasmon resonance (LSPR) of plasmonic gold (Au) nanoparticles which were formed on monolayer graphene at room temperature, based on the difference of the reduction potential between graphene and the Au(3+) precursor. The size of the Au nanoparticles was ~40 nm, which is very desirable to provide an optical enhancement effect by LSPR in the full visible range. It is demonstrated that the density of the Au nanoparticles was modulated by the surface energy of the graphene on the substrate as well as the concentration of the Au(3+) precursor. Furthermore, the cycle number of the reduction process strongly affected the distribution of the nanoparticle size and their optical properties. The LSPR of the plasmonic Au nanoparticles was red-shifted from 560 to 620 nm and its full width at half maximum broadened as the Au(3+) precursor concentration was increased and the cyclic reduction process progressed. Based on the optical enhancement of the plasmonic Au nanoparticles and the extraordinary physical characteristics of graphene, the Au/graphene assembly may offer a promising optoelectronic platform for next-generation flexible optical electronics or biosensors. PMID- 23743612 TI - Changes in frailty-related characteristics of the hip fracture population and their implications for healthcare services: evidence from Quebec, Canada. AB - SUMMARY: This study provides evidence that a number of frailty-related characteristics (older age, de novo admission to long-term care (LTC), comorbidities [Charlson Index, osteoporosis, osteoporosis risk factors, sarcopenia risk factors, and dementia]) have increased in the hip fracture population from 2001-2008. This will have significant impact on community resources, as the number of people discharged to the community is also increasing. INTRODUCTION: The aim of this study is to estimate secular changes in the prevalence of selected frailty-related characteristics among the hip fracture population in the Canadian province of Quebec (2001-2008) and the potential impact of these changes on healthcare services. METHODS: The Quebec hospitalization database was used to identify nontraumatic hip fractures for the purposes of calculating age- and sex-specific rates. Also estimated were time trends for selected frailty-related characteristics and discharge destinations. RESULTS: A significant decline in fracture rates was evident for all age groups except for those <65; sex differences were also observed. Almost all frailty related characteristics increased over time, ranging from 2 to 14 % per year, which translates to an estimated increase from 16 to 112 %, over the study period. For those whose prior living arrangement was LTC, rates of hip fractures declined significantly (women OR = 0.93, 0.91-0.95; men OR = 0.97, 0.94-0.99). In hospital mortality and discharge to inpatient rehabilitation decreased, while discharges back to community and to LTC increased. CONCLUSIONS: Although hip fracture rates decreased for older hip fracture patients, the absolute number and prevalence of specific frailty-related characteristics increased. Policy makers should review care models to ensure that adequate resources are provided to the community to offset the expected increase in demand arising from ongoing changes in patients' characteristics. PMID- 23743614 TI - Larval development of the feline lungworm Aelurostrongylus abstrusus in Helix aspersa. AB - The cat lungworm Aelurostrongylus abstrusus affects the domestic cat and other felids all over the world. Feline aelurostrongylosis is of importance in clinical feline medicine and is gaining more and more attention for the present expansion in the geographical range of A. abstrusus. Global warming and changes in phenology of snail intermediate hosts have been incriminated in this spreading. Helix aspersa, a potential vector of A. abstrusus, is endemic in most regions of the world, where it has become recently a pest outside its native Mediterranean range. The present work evaluated key features of larval development of A. abstrusus in H. aspersa at two different temperature conditions. The results showed that A. abstrusus may reach the infective stage in muscular foot and viscera of H. aspersa and that environmental temperatures may influence the biological cycle of the cat lungworm. In particular, the higher the average temperature, the higher the rate of larval development, i.e., about 50% of larvae of A. abstrusus reached the infective stage between temperatures of 18.8-29.5 degrees C, while only 17.8% of larvae completed their development at temperatures of 6.7-22 degrees C. Biological and epidemiological implications are discussed. PMID- 23743615 TI - Differences between ACC/AHA and ESC Guidelines on antiplatelet therapy in patients with acute coronary syndromes. PMID- 23743617 TI - Diagnostic aids for detection of oral precancerous conditions. AB - Oral cancer has a tendency to be detected at late stage which is detrimental to the patients because of its high mortality and morbidity rates. Early detection of oral cancer is therefore important to reduce the burden of this devastating disease. In this review article, the most common oral precancerous lesions are discussed and the importance of early diagnosis is emphasized. In addition, the most common non-invasive oral cancer devices that can aid the general practitioners in early diagnosis are also discussed. PMID- 23743616 TI - Periodontopathogen profile of healthy and oral lichen planus patients with gingivitis or periodontitis. AB - Oral lichen planus (OLP) is a chronic inflammatory disease that is frequently detected in oral tissues. The aim of our study was to identify the prevalence of the detection of periodontopathogenic microorganisms (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia and Treponema denticola in OLP patients and to compare with this prevalence of periodontopathogenic microorganisms in healthy non-OLP patients. Our study included 27 (18 chronic periodontitis (OLPP) and 9 gingivitis (OLPG)) patients diagnosed with OLP along with 26 (13 chronic periodontitis (HP) and 13 gingivitis (HG)) healthy non-OLP patients. The multiplex polymerase chain reaction (PCR) with subsequent reverse hybridization method (micro-IDent) was used for identifying periodontopathogenic microorganisms present in subgingival plaque samples. The percentages of detection for A. actinomycetemcomitans, P. gingivalis, P. intermedia, T. forsythia and T. denticola in subgingival plaque samples taken from OLP patients (OLPG and OLPP) were 18.5%, 85.1%, 81.4%, 88.8% and 74%, respectively. Meanwhile, in the non-OLP patients (HG and HP), these values were 7.6%, 50%, 46.1%, 73% and 57.7%, respectively. Thus, comparing the non-OLP groups with the OLP groups, the periodontopathogens' percentages of detection in the OLP groups were higher than those in the non-OLP groups. According to our study results, OLP patients have higher levels of infection with A. actinomycetemcomitans, P. gingivalis, P. intermedia, T. forsythia and T. denticola than non-OLP patients. We argue that the high percentages in patients with OLP may help identify the importance of periodontopathogenic microorganisms in the progress of periodontal diseases of OLP. PMID- 23743618 TI - Effects of 45S5 bioglass on surface properties of dental enamel subjected to 35% hydrogen peroxide. AB - Tooth bleaching agents may weaken the tooth structure. Therefore, it is important to minimize any risks of tooth hard tissue damage caused by bleaching agents. The aim of this study was to evaluate the effects of applying 45S5 bioglass (BG) before, after, and during 35% hydrogen peroxide (HP) bleaching on whitening efficacy, physicochemical properties and microstructures of bovine enamel. Seventy-two bovine enamel blocks were prepared and randomly divided into six groups: distilled deionized water (DDW), BG, HP, BG before HP, BG after HP and BG during HP. Colorimetric and microhardness tests were performed before and after the treatment procedure. Representative specimens from each group were selected for morphology investigation after the final tests. A significant color change was observed in group HP, BG before HP, BG after HP and BG during HP. The microhardness loss was in the following order: group HP>BG before HP, BG after HP>BG during HP>DDW, BG. The most obvious morphological alteration of was observed on enamel surfaces in group HP, and a slight morphological alteration was also detected in group BG before HP and BG after HP. Our findings suggest that the combination use of BG and HP could not impede the tooth whitening efficacy. Using BG during HP brought better protective effect than pre/post bleaching use of BG, as it could more effectively reduce the mineral loss as well as retain the surface integrity of enamel. BG may serve as a promising biomimetic adjunct for bleaching therapy to prevent/restore the enamel damage induced by bleaching agents. PMID- 23743619 TI - A novel role of three dimensional graphene foam to prevent heater failure during boiling. AB - We report a novel boiling heat transfer (NBHT) in reduced graphene oxide (RGO) suspended in water (RGO colloid) near critical heat flux (CHF), which is traditionally the dangerous limitation of nucleate boiling heat transfer because of heater failure. When the heat flux reaches the maximum value (CHF) in RGO colloid pool boiling, the wall temperature increases gradually and slowly with an almost constant heat flux, contrary to the rapid wall temperature increase found during water pool boiling. The gained time by NBHT would provide the safer margin of the heat transfer and the amazing impact on the thermal system as the first report of graphene application. In addition, the CHF and boiling heat transfer performance also increase. This novel boiling phenomenon can effectively prevent heater failure because of the role played by the self-assembled three-dimensional foam-like graphene network (SFG). PMID- 23743620 TI - Intracellular ion channel CLIC1: involvement in microglia-mediated beta-amyloid peptide(1-42) neurotoxicity. AB - Microglia can exacerbate central nervous system disorders, including stroke and chronic progressive neurodegenerative diseases such as Alzheimer disease. Mounting evidence points to ion channels expressed by microglia as contributing to these neuropathologies. The Chloride Intracellular Channel (CLIC) family represents a class of chloride intracellular channel proteins, most of which are localized to intracellular membranes. CLICs are unusual in that they possess both soluble and integral membrane forms. Amyloid beta-peptide (Abeta) accumulation in plaques is a hallmark of familial Alzheimer disease. The truncated Abeta25-35 species was shown previously to increase the expression of CLIC1 chloride conductance in cortical microglia and to provoke microglial neurotoxicity. However, the highly pathogenic and fibrillogenic full-length Abeta1-42 species was not examined, nor was the potential role of CLIC1 in mediating microglial activation and neurotoxicity by other stimuli (e.g. ligands for the Toll-like receptors). In the present study, we utilized a two chamber TranswellTM cell culture system to allow separate treatment of microglia and neurons while examining the effect of pharmacological blockade of CLIC1 in protecting cortical neurons from toxicity caused by Abeta1-42- and lipopolysaccaride-stimulated microglia. Presentation of Abeta1-42 to the upper, microglia-containing chamber resulted in a progressive loss of neurons over 3 days. Neuronal cell injury was prevented by the CLIC1 ion channel blockers IAA-94 [(R(+)-[(6,7-dichloro-2 cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5yl)-oxy] acetic acid)] and niflumic acid (2-{[3-(trifluoromethyl)phenyl]amino}nicotinic acid) when presented to the upper chamber only. Incubation of microglia with lipopolysaccharide plus interferon-gamma led to neuronal cell injury which, however, was insensitive to inhibition by the CLIC1 channel blockers, suggesting a degree of selectivity in agents leading to CLIC1 activation. PMID- 23743621 TI - Modulation of paraoxonase 2 (PON2) in mouse brain by the polyphenol quercetin: a mechanism of neuroprotection? AB - Quercetin is a common flavonoid polyphenol which has been shown to exert neuroprotective actions in vitro and in vivo. Though quercetin has antioxidant properties, it has been suggested that neuroprotection may be ascribed to its ability of inducing the cell's own defense mechanisms. The present study investigated whether quercetin could increase the levels of paraoxonase 2 (PON2), a mitochondrial enzyme expressed in brain cells, which has been shown to have potent antioxidant properties. PON2 protein, mRNA, and lactonase activity were highest in mouse striatal astrocytes. Quercetin increased PON2 levels, possibly by activating the JNK/AP-1 pathway. The increased PON2 levels induced by quercetin resulted in decreased oxidative stress and ensuing toxicity induced by two oxidants. The neuroprotective effect of quercetin was significantly diminished in cells from PON2 knockout mice. These findings suggest that induction of PON2 by quercetin represents an important mechanism by which this polyphenol may exert its neuroprotective action. PMID- 23743622 TI - Overlooked Alzheimer's smoking gun? AB - Overview of Szutowicz et al. (Neurochem Res 38(8):1523-1542, 2013), is focusing on specific features of acetyl-CoA metabolism in the cholinergic compartment of the brain. Authors are suggesting that deficit of that metabolite can act as a trigger for several cholinergic encephalopathies, with special emphasis on Alzheimer disease (AD). Central role of acetyl-CoA and its metabolic paths in neurodegeneration are charted starting from its synthesis in mitochondria, followed by utilization in energy metabolism, as well as transport into cytoplasm and participation in the synthesis and turnover of neurotransmitter acetylcholine to emergence of diseased states. Various putative pathogenic signals are evaluated that might be responsible for acetyl-CoA deficit ending up in development of neurodegeneration, unraveling exceptional susceptibility of cholinergic system. They are discussed in context of other existing alternative hypotheses on AD etiology. Overview is thoroughly documented (178 references) and is supported by results accomplished by extensive research in Prof. Szutowicz's laboratory (approximately 25 original papers). PMID- 23743623 TI - Glycation of glutamate cysteine ligase by 2-deoxy-d-ribose and its potential impact on chemoresistance in glioblastoma. AB - The antioxidant glutathione (GSH) plays a critical role in maintaining intracellular redox homeostasis but in tumors the GSH biosynthetic pathway is often dysregulated, contributing to tumor resistance to radiation and chemotherapy. Glutamate-cysteine ligase (GCL) catalyzes the first and rate limiting reaction in GSH synthesis, and enzyme function is controlled by GSH feedback inhibition or by transcriptional upregulation of the catalytic (GCLC) and modifier (GCLM) subunits. However, it has recently been reported that the activity of GCLC and the formation of GCL can be modified by reactive aldehyde products derived from lipid peroxidation. Due to the susceptibility of GCLC to posttranslational modifications by reactive aldehydes, we examined the potential for 2-deoxy-D-ribose (2dDR) to glycate GCLC and regulate enzyme activity and GCL formation. 2dDR was found to directly modify both GCLC and GCLM in vitro, resulting in a significant inhibition of GCLC and GCL enzyme activity without altering substrate affinity or feedback inhibition. 2dDR-mediated glycation also inhibited GCL subunit heterodimerization and formation of the GCL holoenzyme complex while not causing dissociation of pre-formed holoenzyme. This PTM could be of particular importance in glioblastoma (GBM) where intratumoral necrosis provides an abundance of thymidine, which can be metabolized by thymidine phosphorylase (TP) to form 2dDR. TP is expressed at high levels in human GBM tumors and shRNA knockdown of TP in U87 GBM cells results in a significant increase in cellular GCL enzymatic activity. PMID- 23743625 TI - Improving patient adherence in schizophrenia and schizophrenia-related disorders. PMID- 23743624 TI - Do impaired memory, cognitive dysfunction and distress play a role in methotrexate-related neutropenia in rheumatoid arthritis patients? A comparative study. AB - We evaluated the roles of sociocultural status, distress and cognitive functions in rheumatoid arthritis (RA) patients who developed methotrexate (MTX)-related neutropenia. The data of 37 RA patients with MTX-related neutropenia who were being followed up at 3 centers were evaluated. The control group included 74 RA patients. The clinical features, biochemical tests and treatment modalities of the patients were obtained from hospital files. The mini-mental state examination (MMSE) test and the Hospital Anxiety and Depression Scale (HADS) were administered for all RA patients with neutropenia as well as the control group. The frequencies of male patients, illiterate patients, patients living alone, patients with serious visual impairment, those with low income, and patients with high creatinine were significantly higher among RA patients with MTX-related neutropenia than in controls (p values <0.05). The RA patients with MTX-related neutropenia had significantly lower MMSE scores, and significantly higher HADS-A and HADS-D scores than controls (p values <0.05). In addition, the proportion of patients with probable dementia was significantly higher in RA patients with MTX related neutropenia than in controls (p < 0.001). Twenty-six of the 37 patients (70.3 %) developed neutropenia with daily dosing. Patients who used MTX daily were more likely to be living alone than those using weekly dosing (p = 0.011). Multivariate analysis showed that having probable dementia on the MMSE test (OR 52.6), low income level (OR 56.8) and age (OR 1.12) were independent risk factors for the development of MTX-related neutropenia. The presence of probable dementia on MMSE, low socioeconomical status and older age are associated with serious toxicity in RA patients using MTX. Measures should be taken to prevent wrong MTX dosing by the patients. Compliance and patient education is of major importance, in particular, in the patients presented in this study. PMID- 23743626 TI - Age similarities in recognizing threat from faces and diagnostic cues. AB - BACKGROUND: Previous research indicates that younger adults (YA) can identify men's tendency to be aggressive based merely on their neutral expression faces. We compared older adults (OA) and YA accuracy and investigated contributing facial cues. METHOD: In Study 1, YA and OA rated the aggressiveness of young men depicted in facial photographs in a control, distraction, or accuracy motivation condition. In Study 2, YA and OA rated how angry, attractive, masculine, and babyfaced the men looked in addition to rating their aggressiveness. These measures plus measured facial width-to-height ratio (FWHR) were used to examine cues to aggressiveness. RESULTS: Accuracy coefficients, calculated by correlating rated aggressiveness with the men's previously measured actual aggressiveness, were significant and equal for OA and YA. Accuracy was not moderated by distraction or accuracy motivation, suggesting automatic processing. A greater FWHR, lower attractiveness, and higher masculinity independently influenced rated aggressiveness by both age groups and also were valid cues to actual aggressiveness. DISCUSSION: Despite previous evidence for positivity biases in OA, they can be just as accurate as YA when it comes to discerning actual differences in the aggressiveness of young men. PMID- 23743627 TI - CXC chemokine ligand 16, inversely correlated with CD99 expression in Hodgkin Reed-Sternberg cells, is widely expressed in diverse types of lymphomas. AB - The present study examined a correlation between CXC chemokine ligand 16 (CXCL16) and cell differentiation antigen 99 (CD99) expression and investigated the role of CXCL16 in human lymphoma cell lines and clinical samples. Cytokine antibody arrays were used to measure the differentially expressed cytokines in tumor tissues. The expression of CXCL16 and CD99 was analyzed by quantitative PCR (qPCR) and western blotting, while the pathways involved were assessed by western blotting and enzyme-linked immunosorbent assay (ELISA). The expression of CXCL16 was investigated in 9 lymphoma cell lines (L428, RPMI-8226, KM3, Jurkat, OCI-Ly1, OCI-Ly8, OCI-Ly10, Karpass299 and Raji) as well as in clinical lymphoma samples using qPCR, western blotting and immunochemistry. Soluble CXCL16 (sCXCL16) levels were measured by ELISA and proliferation was analyzed by CCK-8 proliferation assays. CXCL16 was one of the upregulated chemokines when lymphoma cells where transferred from in vitro to in vivo conditions. The increased expression and secretion of CXCL16 paralleled with a decrease of mCD99L2 and was accompanied by NF-kappaB pathway activation and vice versa. CXCL16 was expressed in all 9 lymphoma cell lines with the highest levels in the Hodgkin lymphoma (HL) cell line L428, the plasma cell-derived cell lines RPMI-8226 and KM3 and the T leukemia-derived cell line Jurkat. Higher levels of sCXCL16 were secreted by L428 cells, the diffuse large B-cell lymphoma (DLBCL)-derived cell lines (OCI-Ly1, OCI Ly8 and OCI-Ly10) and Jurkat cells. CXCL16 was widely expressed in clinical samples of lymphoma patients with higher levels in HL compared to non-Hodgkin lymphoma. Human recombinant CXCL16 had no significant effect on L428 cell proliferation, but was able to stimulate CD4+ T lymphocytes to proliferate. CXCL16, inversely correlated with CD99 expression in Hodgkin Reed-Sternberg (H/RS) cells, is widely expressed in diverse types of lymphomas. PMID- 23743628 TI - Mortality increase in late-middle and early-old age: heterogeneity in death processes as a new explanation. AB - Deviations from the Gompertz law of exponential mortality increases in late middle and early-old age are commonly neglected in overall mortality analyses. In this study, we examined mortality increase patterns between ages 40 and 85 in 16 low-mortality countries and demonstrated sex differences in these patterns, which also changed across period and cohort. These results suggest that the interaction between aging and death is more complicated than what is usually assumed from the Gompertz law and also challenge existing biodemographic hypotheses about the origin and mechanisms of sex differences in mortality. We propose a two-mortality model that explains these patterns as the change in the composition of intrinsic and extrinsic death rates with age. We show that the age pattern of overall mortality and the population heterogeneity therein are possibly generated by multiple dynamics specified by a two-mortality model instead of a uniform process throughout most adult ages. PMID- 23743631 TI - Antimicrobial dyes and mechanosensitive channels. AB - The search for new and effective antimicrobial agents has never been as important; however, since the discovery of antibiotics, exploring the antimicrobial activity of dyes has been forgotten. Antimicrobial dyes are an untapped resource and have the ability to potentially combat the spread of drug resistant bacteria either alone or as antimicrobial adjuvants. The mechanosensitive ion channel of large conductance (MscL) is highly conserved and ubiquitous in bacterial species. There is evidence to suggest that at least one triphenylmethane dye acts through the highly conserved MscL channel and combining the two approaches of exploring the mechanism of action of other triphenylmethane dyes or antimicrobial dyes in general and the novel MscL target provides a new opportunity for further exploration. PMID- 23743632 TI - Bacterial community composition of anthropogenic biochar and Amazonian anthrosols assessed by 16S rRNA gene 454 pyrosequencing. AB - Biochar (BC) is a common minor constituent of soils and is usually derived from the burning of wood materials. In the case of Amazonian dark earth (ADE) soils, the increased amount of this material is believed to be due to anthropogenic action by ancient indigenous populations. In this study, we use 16S rRNA gene pyrosequencing to assess the bacterial diversity observed in the BC found in ADEs as well as in the dark earth itself and the adjacent Acrisol. Samples were taken from two sites, one cultivated with manioc and one with secondary forest cover. Analyses revealed that the community structure found in each sample had unique features. At a coarse phylogenetic resolution, the most abundant phyla in all sequence libraries were Actinobacteria, Acidobacteria, Verrucomicrobia and Proteobacteria that were present in similar relative abundance across all samples. However, the class composition varied between them highlighting the difference between the Acrisol and the remaining samples. This result was also corroborated by the comparison of the OTU composition (at 97 % identity). Also, soil coverage has shown an effect over the community structure observed in all samples. This pattern was found to be significant through unweighted UniFrac as well as P tests. These results indicate that, although the ADEs are found in patches within the Acrisols, the contrasting characteristics found between them led to the development of significantly different communities. PMID- 23743634 TI - Isolation of Thermovenabulum gondwanense from a French hot spring and emended description of the species. AB - An anaerobic thermophilic bacterium designated CA9F1 was isolated from a thermal spring in France. Strain CA9F1 was observed to grow at temperatures between 55 and 70 degrees C (optimum 65 degrees C) and at pH between 6.8 and 9.5 (optimum pH 7.4). Strain CA9F1 does not require salt for growth (0-10 g l(-1) NaCl), with an optimum at 1 g l(-1). The DNA G+C content was determined to be 38.5 mol% (Tm). The major cellular fatty acids identified were C15:0, C16:0, C17:0 iso. Based on phenotypic, chemotaxonomic and genotypic properties, strain CA9F1 was identified as Thermovenabulum gondwanense and this species was studied in more detail. Strain CA9F1 is a Gram-positive bacterium which forms a complex and regular multilayered cell wall structure, here characterised as being due to the presence of an S-layer. The network covers the entire cell surface and forms a hexagonal structure resembling that observed for Deinococcus radiodurans. The main protein component of the S-layer possesses domains comparable to that of the S-layer protein of Halothermothrix orenii. The characteristics of the strain were compared to that of T. gondwanese R270(T) isolated from microbial mats thriving in the thermal waters of a Great Artesian Basin bore runoff channel at 66 degrees C, in Australia. Significant differences were observed between CA9F1 and the type strain. One of the major physiological differences is the inability of CA9F1 to reduce Fe(III). An emended description of T. gondwanense is given. PMID- 23743635 TI - Modelling of impaired cerebral blood flow due to gaseous emboli. AB - Bubbles introduced to the arterial circulation during invasive medical procedures can have devastating consequences for brain function but their effects are currently difficult to quantify. Here we present a Monte Carlo simulation investigating the impact of gas bubbles on cerebral blood flow. For the first time, this model includes realistic adhesion forces, bubble deformation, fluid dynamical considerations, and bubble dissolution. This allows investigation of the effects of buoyancy, solubility, and blood pressure on embolus clearance. Our results illustrate that blockages depend on several factors, including the number and size distribution of incident emboli, dissolution time and blood pressure. We found it essential to model the deformation of bubbles to avoid overestimation of arterial obstruction. Incorporation of buoyancy effects within our model slightly reduced the overall level of obstruction but did not decrease embolus clearance times. We found that higher blood pressures generate lower levels of obstruction and improve embolus clearance. Finally, we demonstrate the effects of gas solubility and discuss potential clinical applications of the model. PMID- 23743636 TI - Subretinal drusenoid deposits with increased autofluorescence in eyes with reticular pseudodrusen. AB - PURPOSE: To characterize a variant type of drusenoid deposit with different imaging features in comparison to reticular pseudodrusen. METHODS: Retrospective observational consecutive case series. Eyes showing atypical drusenoid lesions were sorted out from 257 eyes of 133 patients previously diagnosed as reticular pseudodrusen. Eyes were evaluated using color fundus photography, confocal scanning laser ophthalmoscopy, and spectral domain optical coherence tomography. RESULTS: A variant type of drusenoid deposits showing different imaging features from reticular pseudodrusen was found in 17 eyes of 12 patients (6.6%). The mean age of patients was 62.7 +/- 11.6 years, and all patients were women. These deposits were observed as yellowish white, round to oval lesions on color photographs, located under the sensory retina and above the retinal pigment epithelium on spectral domain optical coherence tomography similar to reticular pseudodrusen. However, they were present in a smaller number as discrete lesions and showed increased autofluorescence. None of them were accompanied by late age related macular degeneration. CONCLUSION: Subretinal drusenoid deposits are not homogeneous and can be classified into two types according to the fundus autofluorescence. Multimodal imaging tests are needed for the differential diagnosis of subretinal drusenoid deposits. PMID- 23743637 TI - Correspondence. PMID- 23743638 TI - Photoreceptor change and visual outcome after idiopathic epiretinal membrane removal with or without additional internal limiting membrane peeling. AB - PURPOSE: To compare the postoperative photoreceptor status and visual outcome after epiretinal membrane removal with or without additional internal limiting membrane (ILM) peeling. METHODS: Medical records of 40 eyes from 37 patients undergoing epiretinal membrane removal with residual ILM peeling (additional ILM peeling group) and 69 eyes from 65 patients undergoing epiretinal membrane removal without additional ILM peeling (no additional peeling group) were reviewed. The length of defects in cone outer segment tips, inner segment/outer segment junction, and external limiting membrane line were measured using spectral domain optical coherence tomography images of the fovea before and at 1, 3, 6, and 12 months after the surgery. RESULTS: Cone outer segment tips and inner segment/outer segment junction line defects were most severe at postoperative 1 month and gradually restored at 12 months postoperatively. The cone outer segment tips line defect in the additional ILM peeling group was significantly greater than that in the no additional peeling group at postoperative 1 month (P = 0.006), and best-corrected visual acuity was significantly worse in the former group at the same month (P = 0.001). There was no significant difference in the defect size and best-corrected visual acuity at subsequent visits and recurrence rates between the two groups. CONCLUSION: Patients who received epiretinal membrane surgery without additional ILM peeling showed better visual and anatomical outcome than those with additional ILM peeling at postoperative 1 month. However, surgical outcomes were comparable between the two groups, thereafter. In terms of visual outcome and photoreceptor integrity, additional ILM peeling may not be an essential procedure. PMID- 23743639 TI - Reply: To PMID 22366905. PMID- 23743640 TI - Diagnostic and therapeutic challenges. PMID- 23743641 TI - Quantification of retinal pigment epithelium tear area in age-related macular degeneration. AB - PURPOSE: To compare different quantification tools based on confocal scanning laser ophthalmoscopy for assessment of retinal pigment epithelium (RPE) tear area size. METHODS: Confocal scanning laser ophthalmoscopy fundus autofluorescence (FAF) and near-infrared reflectance (IR) images were retrospectively evaluated in 23 patients with RPE tear after intravitreal injection for pigment epithelium detachment due to exudative age-related macular degeneration at baseline and additionally in 11 patients after 5.1 +/- 1.8 months of follow-up. Retinal pigment epithelium tear area was measured by three independent readers using three methods: manually on confocal scanning laser ophthalmoscopy FAF images, manually on confocal scanning laser ophthalmoscopy IR images, and using an FAF based semiautomated software. RESULTS: Confidence intervals were 0.08 and 0.12 for FAF, 0.11 and 0.09 for FAF-based semiautomated software, and 0.25 and 0.27 for IR for intraobserver (Reader 1) and interobserver agreements (Readers 1 and 2), respectively. The average values of the square errors of the quantification methods were 0.040 +/- 0.033 mm (FAF), 0.035 +/- 0.060 mm (software), and 0.187 +/- 0.219 mm (IR). Mean area of RPE tears at baseline given as the average measurement of all 3 readers using FAF-based semiautomated software was 5.77 +/- 4.62 mm (range, 0.13-14.74 mm). Follow-up measurements of unilobular RPE tears (8 patients) showed no change in lesion area size (0.14 +/- 0.33 mm); in contrast, multilobular RPE tears (3 patients) showed a progression in lesion area size of 1.80 +/- 0.74 mm. CONCLUSION: Manual FAF-based and semiautomated FAF-based quantifications of RPE tear area are accurate and reproducible and superior to manual IR-based measurement. Retinal pigment epithelium tear area quantification is clinically relevant regarding further intravitreal treatment, particularly in multilobular RPE tears. PMID- 23743642 TI - To the editor. PMID- 23743644 TI - The interplay between the gut microbiota and the immune system in the mechanism of type 1 diabetes. AB - PURPOSE OF REVIEW: Discuss recent data linking the intestinal microbiome with mechanisms of inflammation and islet destruction. RECENT FINDINGS: Type 1 diabetes (T1D) is a proinflammatory disease that results in the loss of insulin producing beta cells. How T1D is triggered is unclear; however, both genetic and environmental factors were implicated in disease mechanisms. Emerging evidence supports the notion that there is a complex interaction between the intestinal microbiome and the immune system and this cross-talk is involved in maintaining normal immune homeostasis in the gut and periphery. Under some circumstances the gut microbiota could lead to pathogenic immune responses resulting in inflammation in the intestine as well as other organs. Indeed, recent data from genetically susceptible individuals suggested that alterations in gut bacterial communities may be involved in the mechanism of islet destruction. Studies performed in animal models of T1D indicated that manipulating the gut microbiome can protect from islet destruction via mechanisms that may involve down regulating both the adaptive and innate immune systems. SUMMARY: Further work is required to identify specific bacterial communities and mechanisms involved in triggering T1D. A better knowledge of the role of the gut microbiome in islet destruction could lead to new clinical interventions to restore healthy homeostasis and prevent disease development. PMID- 23743643 TI - Non-AIDS-defining cancers among HIV-infected patients. AB - In the highly active antiretroviral therapy (HAART) era, the incidence of non AIDS-defining cancers (NADC) has increased and contributes to a growing proportion of mortality in the aging HIV-infected population. The underlying pathogenic mechanisms of increased cancer risk are incompletely understood. Potential contributors include oncogenic effects of the HIV virus, immunosuppression, chronic inflammation and immune activation, exposure to HAART, higher rates of oncogenic viral coinfections and traditional cancer risk factors. HIV-infected patients often present with NADC at younger ages with more aggressive or advanced stage disease. However, when standard cancer therapy is given, treatment outcomes appear similar to the non-HIV population. These facts highlight the importance of clinicians' maintaining a high index of suspicion, performing age-appropriate screening, and optimizing cancer therapy. Development of novel strategies for screening, prevention, and treatment of NADC will be required to reverse these epidemiologic trends and improve the survival of HIV infected patients. PMID- 23743645 TI - Persistent C-peptide: what does it mean? AB - PURPOSE OF REVIEW: The assumption that patients with an extended duration of type 1 diabetes mellitus (T1D) do not retain residual functional beta cells and endogenous insulin production has recently been challenged. The purpose to this review is to highlight some of the key emerging evidence supporting residual insulin and C-peptide secretion in long-standing T1D. RECENT FINDINGS: Recent investigations conducted in a group of type 1 diabetics of long-term duration, characterized clinically and histologically, provided solid evidence to suggest that pancreatic beta cells are still present even after 50 years in a majority of these individuals. These residual beta cells can secrete insulin in a physiologically regulated manner. Several published reports showed promising effects of glucagon-like peptide 1 (GLP-1) agonists on the glycemic control and residual C-peptide production in long-term T1D, although prospective studies are needed to rule out the potential long-term adverse effects of these drugs. SUMMARY: C-peptide is no longer considered an irrelevant by-product of insulin biosynthesis. In-depth basic and translational investigations aimed at understanding the molecular immunology and the pathophysiology are needed to elucidate the mechanisms underlying the residual insulin and C-peptide production in long-term T1D. This may shed light on to the regenerative capacity of beta cells, the genetic susceptibility of the mechanisms of resistance to beta-cell destruction, and possibly identifying new therapeutic strategies for T1D. Studies evaluating the long-term effects of insulin secretogogue agents along with immune intervention hold promise for their use in future clinical trials for long-term T1D. PMID- 23743646 TI - The case for virus-induced type 1 diabetes. AB - PURPOSE OF REVIEW: Type 1 diabetes (T1D) results from the immune-mediated destruction of pancreatic insulin-producing cells because of the interaction among genetic susceptibility, the immune system and environmental factor(s). A possible role of viral infections in T1D pathogenesis has been hypothesized for some time; however, only in the most recent years, studies performed at the molecular and cellular level are starting to shed light on this issue. RECENT FINDINGS: Studies in animal models and in man have shown that viruses can indeed infect pancreatic beta-cells, inducing islet inflammation and functional damage. In addition, recent in-situ investigations performed on pancreatic tissue samples have provided evidence that in addition to adaptive immune response, innate immunity is involved in T1D pathogenesis and the whole pancreas (not only its endocrine portion) is infiltrated by immune-mediated phenomena. SUMMARY: The established role of inflammation in the insulitic process and the increasing evidence in support of the contribution of viral infections to a proinflammatory islet scenario are strongly suggestive that viruses may indeed contribute to beta cell damage and dysfunction, thus setting the stage for the design of antiviral strategies (e.g. vaccines and antiviral drugs) aimed at protecting the beta cells. PMID- 23743647 TI - A mutation-independent therapeutic strategy for dominant dystrophic epidermolysis bullosa. PMID- 23743648 TI - Heterozygous mutations in AAGAB cause type 1 punctate palmoplantar keratoderma with evidence for increased growth factor signaling. PMID- 23743649 TI - Lack of a specific humoral autoreactivity in sera from patients with early erythema exsudativum multiforme majus. PMID- 23743651 TI - Passive breakups of isolated drops and one-dimensional assemblies of drops in microfluidic geometries: experiments and models. AB - Using two different geometries, rectangular obstacles and asymmetric loops, we investigate the breakup dynamics of deformable objects, such as drops and bubbles, confined in microfluidic devices. We thoroughly study two distinct flow configurations that depend on whether object-to-object hydrodynamic interactions are allowed. When such interactions are introduced, we find that the volumes of the daughter objects created after breakup solely depend on the geometrical features of the devices and are not affected by the hydrodynamic and physicochemical variables; these results are in sharp contrast with those obtained for non-interacting objects. For both configurations, we provide simple phenomenological models that capture well the experimental findings and predict the evolution of the volumes of the daughter objects with the controlling dimensionless quantities that are identified. We introduce a mean-field approximation, which permits accounting for the interactions between objects during breakup and we discuss its conditions of validity. PMID- 23743650 TI - The effects of anandamide signaling enhanced by the FAAH inhibitor URB597 on coping styles in rats. AB - RATIONALE: Coping styles are fundamental characteristics of behavior that affect susceptibility to, and resilience during, mental and physical illness. Shifts from passive to active coping are considered therapeutic goals in many stress related disorders, but the neural control of coping is poorly understood. Based on earlier findings, we hypothesized that coping styles are influenced by endocannabinoids. OBJECTIVES: Here, we tested whether FAAH inhibition by URB597 affects behaviors aimed at controlling a critical situation and the degree to which environmental stimuli influence behavior i.e., we studied the impact of URB597 on the two main attributes of coping styles. METHODS: Rats were tested in the tail-pinch test of coping and in the elevated plus-maze test that was performed under highly divergent conditions. RESULTS: Under the effects of URB597, rats focused their behavior more on the discomfort-inducing clamp in the tail-pinch test, i.e., they coped with the challenge more actively. In the elevated plus-maze, URB597-treated rats demonstrated an autonomous behavioral control by reducing both "wariness" induced by aversive conditions and "carelessness" resulting from favorable conditions. CONCLUSIONS: URB597 treatment induced behavioral changes indicated a shift towards active coping with challenges. This behavioral change appears compatible with the previously suggested role of endocannabinoids in emotional homeostasis. Albeit further studies are required to characterize the role of endocannabinoids in coping, these findings suggest that the enhancement of endocannabinoid signaling may become a therapeutic option in emotional disorders characterized by passive coping (e.g., anxiety and depression) and in physical diseases where active coping is therapeutically desirable. PMID- 23743652 TI - Reliability of the nanopheres-DNA immunization technology to produce polyclonal antibodies directed against human neogenic proteins. AB - The molecular domestication of several DNA transposons that occurred during the evolution of the mammalian lineage, has led to the emergence of at least 43 genes, known as neogenes. To date, the limited availability of efficient commercial antibodies directed against most of their protein isoforms hampers investigation of their expression in vitro and in situ. Since immunization protocols using peptides or recombinant proteins have revealed that it is difficult to recover antibodies, we planned to produce antisera in mice using a new technique of nanopheres/DNA immunization, the ICANtibodiesTM technology. Here, we investigate the possibilities of obtaining polyclonal antibodies for 24 proteins or protein domains using this immunization strategy. We successfully obtained 13 antisera that were able to detect neogenic proteins by Western blotting and ELISA in protein extracts of transiently-transfected cells and various cancer cell lines, plus another two that only detected the in ELISA and in in situ hybridizations. The features required for the production of these antibodies are analyzed and discussed, and examples are given of the advantages they offer for the study of neogenic proteins. PMID- 23743654 TI - Overexpression of the glutamine synthetase gene modulates oxidative stress response in rice after exposure to cadmium stress. AB - KEY MESSAGE: Overexpression of OsGS gene modulates oxidative stress response in rice after exposure to cadmium stress. Our results describe the features of transformants with enhanced tolerance to Cd and abiotic stresses. Glutamine synthetase (GS) (EC 6.3.1.2) is an enzyme that plays an essential role in the metabolism of nitrogen by catalyzing the condensation of glutamate and ammonia to form glutamine. Exposure of plants to cadmium (Cd) has been reported to decrease GS activity in maize, pea, bean, and rice. To better understand the function of the GS gene under Cd stress in rice, we constructed a recombinant pART vector carrying the GS gene under the control of the CaMV 35S promoter and OCS terminator and transformed using Agrobacterium tumefaciens. We then investigated GS overexpressing rice lines at the physiological and molecular levels under Cd toxicity and abiotic stress conditions. We observed a decrease in GS enzyme activity and mRNA expression among transgenic and wild-type plants subjected to Cd stress. The decrease, however, was significantly lower in the wild type than in the transgenic plants. This was further validated by the high GS mRNA expression and enzyme activity in most of the transgenic lines. Moreover, after 10 days of exposure to Cd stress, increase in the glutamine reductase activity and low or no malondialdehyde contents were observed. These results showed that overexpression of the GS gene in rice modulated the expression of enzymes responsible for membrane peroxidation that may result in plant death. PMID- 23743656 TI - Prediction of shrinkage of individual parameters using the bayesian information matrix in non-linear mixed effect models with evaluation in pharmacokinetics. AB - PURPOSE: When information is sparse, individual parameters derived from a non linear mixed effects model analysis can shrink to the mean. The objective of this work was to predict individual parameter shrinkage from the Bayesian information matrix (M BF ). We 1) Propose and evaluate an approximation of M BF by First Order linearization (FO), 2) Explore by simulations the relationship between shrinkage and precision of estimates and 3) Evaluate prediction of shrinkage and individual parameter precision. METHODS: We approximated M BF using FO. From the shrinkage formula in linear mixed effects models, we derived the predicted shrinkage from M BF . Shrinkage values were generated for parameters of two pharmacokinetic models by varying the structure and the magnitude of the random effect and residual error models as well as the design. We then evaluated the approximation of M BF FO and compared it to Monte-Carlo (MC) simulations. We finally compared expected and observed shrinkage as well as the predicted and estimated Standard Errors (SE) of individual parameters. RESULTS: M BF FO was similar to M BF MC. Predicted and observed shrinkages were close . Predicted and estimated SE were similar. CONCLUSIONS: M BF FO enables prediction of shrinkage and SE of individual parameters. It can be used for design optimization. PMID- 23743655 TI - Transcriptome analysis of cytoplasmic male sterility and restoration in CMS-D8 cotton. AB - KEY MESSAGE: A global view of differential expression of genes in CMS-D8 of cotton was presented in this study which will facilitate the understanding of cytoplasmic male sterility in cotton. Cytoplasmic male sterility (CMS) is a maternally inherited trait in higher plants which is incapable of producing functional pollen. However, the male fertility can be restored by one or more nuclear-encoded restorer genes. A genome-wide transcriptome analysis of CMS and restoration in cotton is currently lacking. In this study, Affymetrix GeneChips(c) Cotton Genome Array containing 24,132 transcripts was used to compare differentially expressed (DE) genes of flower buds at the meiosis stage between CMS and its restorer cotton plants conditioned by the D8 cytoplasm. A total of 458 (1.9 %) of DE genes including 127 up-regulated and 331 down regulated ones were identified in the CMS-D8 line. Quantitative RT-PCR was used to validate 10 DE genes selected from seven functional categories. The most frequent DE gene group was found to encode putative proteins involved in cell wall expansion, such as pectinesterase, pectate lyase, pectin methylesterase, glyoxal oxidase, polygalacturonase, indole-3-acetic acid-amino synthetase, and xyloglucan endo-transglycosylase. Genes in cytoskeleton category including actin, which plays a key role in cell wall expansion, cell elongation and cell division, were also highly differentially expressed between the fertile and CMS plants. This work represents the first study in utilizing microarray to identify CMS related genes by comparing overall DE genes between fertile and CMS plants in cotton. The results provide evidence that many CMS-associated genes are mainly involved in cell wall expansion. Further analysis will be required to elucidate the molecular mechanisms of male sterility which will facilitate the development of new hybrid cultivars in cotton. PMID- 23743657 TI - The shape/morphology balance: a study of stealth liposomes via fractal analysis and drug encapsulation. AB - PURPOSE: Fractal analysis was used as a tool in order to study the morphological characteristics of PEGylated liposomes. We report on the morphological characteristics of stealth liposomes composed of DPPC and DPPE-PEG 3000 in two dispersion media using fractal analysis. METHODS: Light scattering techniques were used in order to elucidate the size, the morphology and the surface charge of PEGylated liposomes as a function of PEGylated lipid concentration and temperature. Fluorescence spectroscopy studies revealed a microenvironment of low polarity inside the liposomal membranes. RESULTS: All formulations were found to retain their physicochemical characteristics for at least 3 weeks. The hydrodynamic radii (Rh) of stealth liposomes were stable in the process of heating up to 50 degrees C; while the fractal dimension values (df) which correspond to their morphology, have been changed during heating. Hence, these results are a first indication of the presence of a heterogeneous microdomain structure of the stealth liposomal system. The amphiphilic drug indomethacin (IND) was successfully encapsulated within the liposomes and led to an increased size of stealth liposomes, while the morphology of liposomal vectors changed significantly at the highest molar ratio of PEGylated lipid. CONCLUSIONS: We can state that this approach can promote a new analytical concept based on the morphological characteristics and quantify the shape of drug carriers complementary to that of the conventional analytical techniques. PMID- 23743658 TI - How many Orai's does it take to make a CRAC channel? AB - CRAC (Calcium Release-Activated Calcium) channels represent the primary pathway for so-called "store-operated calcium entry" - the cellular entry of calcium induced by depletion of intracellular calcium stores. These channels play a key role in diverse cellular activities, most noticeably in the differentiation and activation of Tcells, and in the response of mast cells to inflammatory signals. CRAC channels are formed by members of the recently discovered Orai protein family, with previous studies indicating that the functional channel is formed by a tetramer of Orai subunits. However, a recent report has shown that crystals obtained from the purified Drosophila Orai protein display a hexameric channel structure. Here, by comparing the biophysical properties of concatenated hexameric and tetrameric human Orai1 channels expressed in HEK293 cells, we show that the tetrameric channel displays the highly calcium-selective conductance properties consistent with endogenous CRAC channels, whilst the hexameric construct forms an essentially non-selective cation channel. PMID- 23743659 TI - Response to letter to the editor by Dr. Yiu Ming Wong: pain induced by rheumatoid arthritis and acupoint skin resistance. PMID- 23743660 TI - Discussing sexual concerns with chronic low back pain patients: barriers and patients' expectations. AB - This study aims to explore patient's concerns when discussing sexual problems caused by chronic low back pain with their healthcare provider. It also aims to identify factors influencing and limiting such communication. A cross-sectional analysis of 100 consenting chronic low back pain sexually active patients was carried out. Patients answered questions on their disease characteristics and sex life. They also mentioned prohibitions of discussing sex with their healthcare provider and their expectations of such discussion. Factors influencing patient's experiences were analyzed. Median of chronic low back pain duration was 36 (24 72) months and back pain intensity using visual analogical scale (0-100 mm) was 50 +/- 10.7 mm. Eighty-one percent of our patients complained of sexual problems, 66 % have never discussed the subject with their healthcare provider. Barriers which prevent discussion on sex include the taboo character of the topic, inappropriateness of visit conditions, and patient disinterest in sex. Ninety three percent of patients expressed the need of sexual problems' management in chronic low back pain consulting. Seventy-four percent expected information and advice from their healthcare provider about recommended intercourse positions so as to avoid pain. Thirty-three percent of patients wanted their partner to be involved in the discussion and 81 % preferred talking with a healthcare provider of the same gender. Ability to communicate on the topic was associated with the decrease of patient sexual satisfaction and limited by patient illiteracy. Our study evidences that sex discussion between patient and healthcare provider is restricted by several barriers and that patients expect more involvement from their healthcare provider on the subject. Illiteracy and level of sexual satisfaction seem to be the strongest factors influencing this communication. PMID- 23743661 TI - Fibromyalgia comorbidity in a community sample of adults with migraine. PMID- 23743663 TI - Spin state modulation of iron spin crossover complexes via hydrogen-bonding self assembly. AB - Iron complexes derived from 6-diaminotriazyl-2,2'-bipyridines display spin crossover behaviour, and hydrogen bonding-controlled self-assembly with a suitable barbiturate partner can modulate the crossover from mixed low and high spin to high spin. This system is the first to use solution-phase self-assembly of complementary hydrogen-bonding organic species to modulate spin state. PMID- 23743662 TI - Baicalein reduces lipopolysaccharide-induced inflammation via suppressing JAK/STATs activation and ROS production. AB - OBJECTIVE: To investigate the precise molecular mechanisms by which baicalein exerts beneficial biochemical activities in RAW264.7 macrophages treated with LPS. MATERIALS AND METHODS: RAW264.7 cells were cultured in the absence or presence of baicalein together with or without LPS. iNOS and COX-2 expression were measured by western blot and RT-PCR analyses. TNF-alpha, IL-1beta, and IL-6 were determined by using double-antibody sandwich ELISA. Phosphorylations of JAK1 and JAK2, and of STAT1 and STAT3 were detected by western blotting. Nuclear translocation of STAT1 and STAT3 was visualized by confocal microscopy. ROS production was detected by ROS assay. RESULTS: Baicalein significantly reduced the phosphorylation of STAT1 and STAT3 and the phosphorylation of JAK1 and JAK2, but without affecting MAPKs phosphorylation in LPS-stimulated RAW264.7 cells. Baicalein suppressed the nuclear translocation of STAT1 and STAT3 and inhibited production of iNOS upon LPS-stimulation, resulting in the inhibition of releases of NO and pro-inflammatory cytokines such as IL-1beta, IL-6, and TNF-alpha, in a dose-dependent manner. In addition, we found that baicalein reduced the LPS induced accumulation of ROS, confirming that baicalein serves as an antioxidant. CONCLUSIONS: Our results suggested that suppressing JAK/STATs activation and interfering with ROS production might contribute to the anti-inflammatory action of baicalein in macrophages. PMID- 23743664 TI - Using UV-absorbance of intrinsic dithiothreitol (DTT) during RP-HPLC as a measure of experimental redox potential in vitro. AB - Many in-vitro experiments performed to study the response of thiol-containing proteins to changes in environmental redox potentials use dithiothreitol (DTT) to maintain a preset redox environment throughout the experiments. However, the gradual oxidation of DTT during the course of the experiments, and the interaction between DTT and other components in the system, can significantly alter the initial redox potential and complicate data interpretation. Having an internal reporter of the actual redox potential of the assayed sample facilitates direct correlation of biochemical findings with experimental redox status. Reversed-phase high-performance liquid chromatography (RP-HPLC) is a widely used, well-established tool for analysis and purification of biomolecules, including proteins and peptides. Here, we describe a simple, robust, and quantitative RP HPLC method we developed and tested for determination of the experimental redox potential of an in-vitro sample at the time of the experiment. It exploits the specific UV-absorbance of the oxidized intrinsic DTT in the samples and retains the high resolving power and high sensitivity of RP-HPLC with UV detection. PMID- 23743665 TI - Letter to the editor regarding "Trapping cells on a stretchable microwell array for single-cell analysis". PMID- 23743666 TI - The relationship between maternal serum iron and zinc levels and their nutritional intakes in early pregnancy with gestational diabetes. AB - The aim of this study was to investigate the association between maternal iron/zinc serum levels and their nutritional intake in early pregnancy with gestational diabetes. The maternal serum zinc/iron levels were measured in 1,033 healthy singleton pregnant women aged 20-35 between 14 and 20 weeks of gestation, within two groups: namely, normal and gestational diabetes, and participants were followed up to 24-28 weeks of gestation. Food frequency questionnaire was used to assess nutritional intakes of iron/zinc. The main outcome was gestational diabetes screened with the 50-g glucose challenge test and diagnosed with oral glucose tolerance test at 24-28 weeks of gestation. Gestational diabetes occurred in 72 (6.96 %) of 1,033 women in study. There was a statistical relationship between early pregnancy maternal serum iron and gestational diabetes, mean (SD), 143.8 (48.7) vs. 112.5 (83.5) MUg/dl, P value of <0.0001. There was no statistical significant difference in zinc levels and iron/zinc nutritional intake between groups. The results remained unchanged after using regression model for adjustment of potential risk factors with an adjusted OR of 1.006 (95 % CI 1.002 to 1.009; P = 0.001) for early pregnancy maternal serum iron to cause gestational diabetes. The receiver-operator characteristic curve identified that a maternal serum iron above 100 MUg/dl in early pregnancy is the optimum cutoff value for predicting gestational diabetes, which showed a sensitivity and specificity of 80.6 and 50.7 %, respectively. In conclusion, high maternal serum iron in early pregnancy could increase the risk of gestational diabetes. Also, it could be used as a sensitive and specific predictor for gestational diabetes. PMID- 23743667 TI - Ciliated micropillars for the microfluidic-based isolation of nanoscale lipid vesicles. AB - We fabricated a microfluidic device consisting of ciliated micropillars, forming a porous silicon nanowire-on-micropillar structure. We demonstrated that the prototype device can preferentially trap exosome-like lipid vesicles, while simultaneously filtering out proteins and cell debris. Trapped lipid vesicles can be recovered intact by dissolving the porous nanowires in PBS buffer. PMID- 23743668 TI - Genetic polymorphisms in ABCB1 influence the pharmacodynamics of tacrolimus. AB - INTRODUCTION: Tacrolimus has a large interindividual pharmacokinetic variability, and quantification of its effect is difficult. It is a substrate of ABCB1, an efflux pump expressed more on CD8 T cells than on CD4 T cells. The ABCB1 3435C>T single-nucleotide polymorphism (SNP) has been associated with interindividual differences in ABCB1 activity and may influence drug efficacy. Here the influence of this SNP on the biological effect of tacrolimus was studied. METHODS: Rhodamine (Rh123) efflux was used to study ABCB1 activity, with or without the addition of the ABCB1 inhibitor verapamil. Intracellular interleukin (IL) 2 production in T cells was used to measure the pharmacodynamic effect of tacrolimus after phorbol-12-myristate-13-acetate/ionomycin stimulation of whole blood. In addition, the ABCB1 genotype of 36 tacrolimus-treated renal transplant patients was related to ABCB1 activity and tacrolimus efficacy. RESULTS: The mean Rh123 efflux was higher in CD8 T cells compared with CD4 T cells: 40% versus 19% of cells, respectively (P < 0.001). Verapamil almost completely blocked Rh123 efflux (to 1.8% of CD4 T cells and 0.5% of CD8 T cells), whereas tacrolimus did not change Rh123 efflux. Tacrolimus 10 ng/mL reduced the production of IL-2 in CD4 and CD8 T cells by 28.9% and 45.4% (P < 0.05). Tacrolimus-mediated inhibition of IL-2 was enhanced by verapamil (P < 0.05). This effect on tacrolimus pharmacodynamics was associated with ABCB1 3435C>T SNP in renal transplant patients: verapamil reduced the percentage of IL-2-producing CD4 and CD8 T cells by 14% and 22% in patients with the CC genotype (P < 0.05) but not in patients with the TT genotype. Moreover, the ratio of tacrolimus C0 over the percent of IL 2-producing CD8 T cells in CC genotype patients was significantly higher compared with TT genotype patients (P < 0.05), showing a smaller pharmacodynamic effect in CC genotype patients. CONCLUSION: The ABCB1 3435C>T SNP influences ABCB1 activity of T cells and the pharmacodynamic effect of tacrolimus in kidney transplant patients. PMID- 23743669 TI - The arrival of JAK inhibitors: advancing the treatment of immune and hematologic disorders. AB - Altered production of cytokines can result in pathologies ranging from autoimmune diseases to malignancies. The Janus kinase family is a small group of receptor associated signaling molecules that is essential to the signal cascade originating from type I and type II cytokine receptors. Inhibition of tyrosine kinase enzymatic activity using small molecules has recently become a powerful tool for treatment of several malignancies. Twenty years after the discovery of these enzymes, two inhibitors for this class of kinases have been approved for clinical use and others are currently in the final stage of development. Here we review the principles of cytokines signaling, summarize our current knowledge of the approved inhibitors, and briefly introduce some of the inhibitors that are currently under development. PMID- 23743671 TI - Magnesium for newborns with hypoxic-ischemic encephalopathy: a systematic review and meta-analysis. AB - OBJECTIVE: Magnesium may have a role in neuroprotection in neonatal hypoxic ischemic encephalopathy (HIE). The objective of this study was to systematically review the efficacy and safety of postnatal magnesium therapy in newborns with HIE. STUDY DESIGN: MEDLINE, EMBASE, CINAHL and CCRCT were searched for studies of magnesium for HIE. Randomized controlled trials that compared magnesium to control in newborns with HIE were selected. The primary outcome was a composite outcome of death or moderate-to-severe neurodevelopmental disability at 18 months. When appropriate, meta-analyses were conducted using random effects model and risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. RESULT: Five studies with sufficient quality were included. There was no difference in the primary outcome between the magnesium and the control groups (RR 0.81, 95% CI 0.36 to 1.84). There was significant reduction in the unfavorable short-term composite outcome (RR 0.48, 95% CI 0.30 to 0.77) but no difference in mortality (RR 1.39, 95% CI 0.85 to 2.27), seizures (RR 0.84, 95% CI 0.59 to 1.19) or hypotension (RR 1.28, 95% CI 0.69 to 2.38) between the magnesium and the control groups. CONCLUSION: The improvement in short-term outcomes without significant increase in side effects indicate the need for further trials to determine if there are long-term benefits of magnesium and to confirm its safety. Mortality was statistically insignificant between the magnesium and the control groups. However, the trend toward increase in mortality in the magnesium group is a major clinical concern and should be monitored closely in future trials. PMID- 23743672 TI - Effect of position of infant during phototherapy in management of hyperbilirubinemia in late preterm and term neonates: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of supine position when compared with periodic change of position during phototherapy in late preterm and term neonates (35 to 42 weeks) with hyperbilirubinemia on the duration of phototherapy. STUDY DESIGN: We randomly allocated enrolled neonates with hyperbilirubinemia to either no change in position (supine group (SG); n=54) or two-hourly change of position from supine to prone and vice versa (turning group (TG); n=46). All the infants received single surface phototherapy by two dedicated compact fluorescent light units. Total serum bilirubin (TSB) was measured at the start of phototherapy and then every 12 +/- 2 h until the end of phototherapy. Phototherapy was stopped when two values were below the cut-off for age and gestational age as per the American Academy of Pediatrics Subcommittee on Hyperbilirubinemia guidelines nomogram for the management of hyperbilirubinemia in infants >35 weeks of gestation. The primary outcome was duration of phototherapy and secondary outcome was rate of fall of bilirubin within the first 24 +/- 2 h after the initiation of phototherapy. RESULT: Baseline characteristics including birth weight (g, 2752 +/ 478 vs 2748 +/- 416 P=0.96), gestation (week, 37.1 +/- 1.2 vs 37.4 +/- 1.3, P=0.26) were similar in the two groups. There was no difference in the duration of phototherapy between the SG (mean +/- s.d., hour, 25.5 +/- 8) and TG (mean +/- s.d., hour, 24.8 +/- 5), mean difference (95% confidence interval), hour, 0.7 ( 2.03, 3.44, P=0.6). Rate of fall of bilirubin was also similar in both supine and turning groups with mean difference of -0.020 (95% confidence interval: -0.061, 0.021, P=0.34). CONCLUSION: Nursing babies in supine position when compared with periodic position change during phototherapy does not decrease the duration of phototherapy. PMID- 23743670 TI - Peptide-mediated targeting of cytokines to tumor vasculature: the NGR-hTNF example. AB - A growing body of evidence suggests that the efficacy of cytokines in cancer therapy can be increased by targeting strategies based on conjugation with ligands that recognize receptors expressed by tumor cells or elements of the tumor microenvironment, including the tumor vasculature. The targeting approach is generally conceived to permit administration of low, yet pharmacologically active, doses of drugs, thereby avoiding toxic reactions. However, it is becoming clear that, in the case of cytokines, this strategy has another inherent advantage, i.e. the possibility of administering extremely low doses that do not activate systemic counter-regulatory mechanisms, which may limit their potential therapeutic effects. This review is focused on the use of tumor vasculature homing peptides as vehicles for targeted delivery of cytokines to tumor blood vessel. In particular, we provide an overview of peptide-cytokine conjugates made with peptides containing the NGR, RGD, isoDGR or RGR sequences and describe, in more details, the biological and pharmacological properties of NGR-hTNF, a peptide-tumor necrosis factor-alpha conjugate that is currently being tested in phase II and III clinical studies. The results of preclinical and clinical studies performed with these products suggest that peptide-mediated vascular targeting is indeed a viable strategy for delivering bioactive amounts of cytokines to tumor endothelial cells without causing the activation of counter regulatory mechanisms and toxic reactions. PMID- 23743673 TI - Determining electrical properties based on B(1) fields measured in an MR scanner using a multi-channel transmit/receive coil: a general approach. AB - Electrical properties tomography (EPT) is a recently developed noninvasive technology to image the electrical conductivity and permittivity of biological tissues at Larmor frequency in magnetic resonance scanners. The absolute phase of the complex radio-frequency magnetic field (B1) is necessary for electrical property calculation. However, due to the lack of practical methods to directly measure the absolute B1 phases, current EPT techniques have been achieved with B1 phase estimation based on certain assumptions on object anatomy, coil structure and/or electromagnetic wave behavior associated with the main magnetic field, limiting EPT from a larger variety of applications. In this study, using a multi channel transmit/receive coil, the framework of a new general approach for EPT has been introduced, which is independent on the assumptions utilized in previous studies. Using a human head model with realistic geometry, a series of computer simulations at 7 T were conducted to evaluate the proposed method under different noise levels. Results showed that the proposed method can be used to reconstruct the conductivity and permittivity images with noticeable accuracy and stability. The feasibility of this approach was further evaluated in a phantom experiment at 7 T. PMID- 23743676 TI - Otostegia persica extraction on healing process of burn wounds. AB - PURPOSE: To investigate if the methanolic extract of the Otostegia persica can accelerating healing process of burn wound because of its anti-inflammatory and antioxidant effects. METHODS: Forty eight male Wistar rats were randomized into three study groups of 16 rats each. Burn wounds were created on dorsal part of shaved rats using a metal rod. In group I the burn wound was left without any treatment. Group was treated with topical silver sulfadiazine pomade. In group III, ointment containing the OP extract was administered. Skin biopsies were harvested from burn area on the 3rd, 5th, 14th and 21st days after burn and examined histologically. RESULTS: Re-epithelialization in the control group and in group II was lower than in group III. Re-epithelialization in groups II and III was significantly different from that in the control group. On the 5th day of the experiment, we assessed lower inflammation in the burn area compared to control group. This means that the inflammation was suppressed by methanolic extract of OP. From day 5 to 14; the fibroblast proliferation peaked and was associated with increased collagen accumulation. It was obvious that angiogenesis improved more in the groups II and III, which facilitated re-epithelialisation. CONCLUSION: Methanolic extract of Otostegia persica exhibited significant healing activity when topically applied on rats. OP is an effective treatment for saving the burn site. PMID- 23743674 TI - Epigenetics: the fine-tuner in inflammatory bowel disease? AB - PURPOSE OF REVIEW: Epigenetic studies are transforming our understanding of a variety of complex pathological conditions including cancer, autoimmune, and inflammatory diseases. A selection of the major recent advances in this area will be reviewed, focusing on the important emerging themes that are relevant to these diseases including inflammatory bowel disease (IBD). RECENT FINDINGS: The main current themes that will be addressed on the role of epigenetics in disease pathogenesis include current understanding of the nature and function of histone modifications and DNA methylation; the connection between epigenetics and metabolic pathways; new studies on the mechanism of heritability of epigenetic changes; the role of stochastic noise and the expanding research on chromatin readers and their potential as selective therapeutic targets. The recent contribution of epigenetic modifications in defining the molecular basis of IBD and how such changes may act as fine-tuners of gene expression in these intestinal disorders are also discussed. SUMMARY: Published evidence over the last 12-18 months indicates that targeting epigenetic factors can be efficacious in cancer and inflammatory disease. All the indications are that future research will continue to reveal new epigenetic targets and mechanisms that will advance the prospects for selective epigenetic therapy for IBD and other complex diseases. PMID- 23743675 TI - A meta-analysis of two genome-wide association studies to identify novel loci for maximum number of alcoholic drinks. AB - Maximum number of alcoholic drinks consumed in a 24-h period (maxdrinks) is a heritable (>50 %) trait and is strongly correlated with vulnerability to excessive alcohol consumption and subsequent alcohol dependence (AD). Several genome-wide association studies (GWAS) have studied alcohol dependence, but few have concentrated on excessive alcohol consumption. We performed two GWAS using maxdrinks as an excessive alcohol consumption phenotype: one in 118 extended families (N = 2,322) selected from the Collaborative Study on the Genetics of Alcoholism (COGA), and the other in a case-control sample (N = 2,593) derived from the Study of Addiction: Genes and Environment (SAGE). The strongest association in the COGA families was detected with rs9523562 (p = 2.1 * 10(-6)) located in an intergenic region on chromosome 13q31.1; the strongest association in the SAGE dataset was with rs67666182 (p = 7.1 * 10(-7)), located in an intergenic region on chromosome 8. We also performed a meta-analysis with these two GWAS and demonstrated evidence of association in both datasets for the LMO1 (p = 7.2 * 10(-7)) and PLCL1 genes (p = 4.1 * 10(-6)) with maxdrinks. A variant in AUTS2 and variants in INADL, C15orf32 and HIP1 that were associated with measures of alcohol consumption in a meta-analysis of GWAS studies and a GWAS of alcohol consumption factor score also showed nominal association in the current meta-analysis. The present study has identified several loci that warrant further examination in independent samples. Among the top SNPs in each of the dataset (p <= 10(-4)) far more showed the same direction of effect in the other dataset than would be expected by chance (p = 2 * 10(-3), 3 * 10(-6)), suggesting that there are true signals among these top SNPs, even though no SNP reached genome-wide levels of significance. PMID- 23743678 TI - Pneumoperitoneum induces morphological alterations in the rat testicle. AB - PURPOSE: To investigate the seminiferous tubule histological morphology after an 8 mmHg pneumoperitoneum in the rat model. METHODS: Fourteen rats were divided into two groups: a Sham group submitted to anesthesia and a pneumoperitoneum (Pp) group submitted to abdominal insufflation at 8 mmHg during three hours, followed by desuflation. All rats were killed after six weeks, testicles were collected and evaluated for the tubule diameter, germinative epithelium height and Johnsen's score. Means were compared by using the Student's-t-test. RESULTS: The seminiferous tubule diameter was diminished by 11.3% in the group submitted to pneumoperitoneum (p<0.05). No significant difference was found among the groups when analyzing the epithelium height and Johnsen's score. CONCLUSION: In the rat model, the seminiferous tubules present structural alterations when subjected to pneumoperitoneum of 8 mmHg during three hours. PMID- 23743677 TI - Experimental ovarian transplantation on stomach for bone repair in ovariohysterectomized rabbits. AB - PURPOSE: To evaluate the bone repair process in ovariohysterectomized rabbit submitted to an ovarian transplant to stomach that may supplying some quantity of estrogen occurs to improve bone healing. METHODS: In 20 female rabbits three holes of 1, 2 and 3mm diameter in tibial shaft were made and after that all animals received OHE through a ventral incision and they were randomly divided into two groups of ten rabbits each. In group one, animals received one of their self-ovaries that transplanted on serosal layer of stomach and group two did not receive treatment. Animals were kept during bone healing for a period of 45 days and radiological, biochemical, biomechanical and histopathological evaluation. RESULTS: The tibial defects in group one healed completely after 45 days and had more callous than second group. There is significant difference between two groups after operation in 21, 28 and 35 days about estrogen, progesterone and phosphatase Alkaline. The maximum forces in group one, were significantly higher than that for the group two. CONCLUSION: Ovarian transplantation prevents the effects of ovariohysterectomized on bone healing of rabbit tibia, suggesting that unilateral transplanted ovaries can substitute for the action of ovaries on the skeleton in ovariohysterectomized animals. PMID- 23743679 TI - Decompressive fasciotomy in testicular torsion of the spermatic cord in rats. AB - PURPOSE: To evaluate the effect of decompression fasciotomy on testes undergoing torsion of the spermatic cord. METHODS: Spermatic cord torsion was induced in 40 Wistar testes for six and 12 hours. At the time of distortion, decompression fasciotomy was performed on half of the animals. After 42 days, the testicles were examined both macroscopically and microscopically. A non-parametric Mann- Whitney U- test was used for statistical analysis. The results were considered significant at p<=0.05. RESULTS: Testicular weight; volume and degree of histological alterations were evaluated. When the groups without and with fasciotomy were compared, a 12-hour torsion subgroup in the fasciotomy group was noted to present larger volume, heavier weight and superior histological classification when compared with the 12-hour subgroup in the without fasciotomy group. No differences between the two groups after six hours of torsion were found. No significant changes were noticed in the contralateral testis. CONCLUSIONS: Testicular fasciotomy (decompression) benefited the macroscopic and histological aspects of the testicles undergoing cord torsion for a 12-hour period. These results demonstrate the role played by compartment syndrome in the pathophysiology of spermatic cord torsion and the need for decompression. PMID- 23743680 TI - Effect of andiroba oil on periodontitis in Wistar rats. AB - PURPOSE: To evaluate the effects of andiroba oil on the periodontitis in rats. METHODS: The periodontitis was induced by the placement of cotton ligatures around the cervix of the second upper molars on fifteen rats, and waiting fifty days. The animals were randomly distributed into three groups: saline group, andiroba oil group and meloxican group, differentiated by substance used in the treatment of periodontitis. The groups received the respective substance by gavage for seven days, after the periodontitis induced. It was analyzed the score of inflammatory cells and the measurement from the cemento-enamel junction to the bone crest. RESULTS: The andiroba oil group (p=0.008) and meloxican group (p=0.0347) show a less score of inflammatory cells than saline group, however there weren't difference between them (p=0.2754). Regarding the analysis of measurement from the cemento-enamel junction to the bone crest, there was no difference between groups studied (p=0.3451). CONCLUSION: Andiroba oil decreased the quantity of inflammatory cells, however, it didn't have an effect on the measurement of alveolar bone loss, like the treatment with Meloxican(r). PMID- 23743681 TI - Effects of bioflavonoid ternatin on liver regeneration and oxidative stress in rats. AB - PURPOSE: To evaluate the effect of bioflavonoid ternatin (TRT) on rat liver regeneration and oxidative stress after 70% partial hepatectomy (PH). METHODS: Thirty six young male Wistar rats were randomly assigned to two groups of 18 animals each - control (G1) and experimental (G2) - and were submitted to PH under inhalatory diethylether anesthesia. G1 rats received daily intraperitoneal (ip) injections of saline (NaCl 0.9% solution) 0.1 mL/kg for 14 days; G2 animals received daily ip injections of TRT 0.1% 1.0mg/kg for 14 days. At 36h (T1), 168h (T2) and 336h (T3) post-PH timepoints, a subgroup of six rats in each group was chosen in a randomized way to complementary hepatectomy (CH) and blood samples haversting. Collected material was saved for laboratory analysis (total bilirubin (TB), D-Glucose, glutathione (GSH) and thiobarbituric acid reactive substances (TBARS) and assessment of liver regeneration. RESULTS: TRT induced a significant decrease in liver and plasma GSH concentrations; liver regeneration process was not affected. TRT promoted a significant decrease in blood glucose levels 168h after partial hepatectomy compared with controls. TB levels remained unchanged. CONCLUSION: Intraperitoneal bioflavonoid ternatin injection in partially hepatectomized rats induces a decrease in oxidative stress and a significant hypoglycemic state, but does not promote any change in the evolution of liver regeneration. PMID- 23743682 TI - Ischemic pre and postconditioning in skeletal muscle injury produced by ischemia and reperfusion in rats. AB - PURPOSE: To investigate the protective effects of ischemic pre and postconditioning, as well as the association of both methods, in skeletal muscle injury produced by ischemia and reperfusion in rats. METHODS: An experimental study was designed using 40 Wistar rats divided in four groups (n=10): Control - rats submitted to ischemia for 240 minutes (min) and reperfusion for 60 min; Ischemic preconditioning (Pre) - animals submitted to three cycles of clamping and releasing the aorta for five min before being submitted to the ischemia/reperfusion procedure; Ischemic postconditioning (Post) - rats submitted to three cycles of clamping and releasing the aorta for one min after the 240 minute ischemic phase; Ischemic pre and postconditioning (Pre-post) - animals submitted to the same procedures of Pre and Post groups. Skeletal muscle injury was evaluated by measuring serum levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatine phosphokinase (CPK); and muscular levels of malondialdehyde (MDA) and glycogen. RESULTS: AST levels were significantly higher in Pre and Pre-post groups (P<.01). There were no differences in LDH and CPK levels. Muscular MDA levels were similar. Glycogen levels were significantly higher in Pre and Pre-post groups (P<.01). CONCLUSIONS: Both preconditioning and its association with postconditioning had a protective effect by avoiding glycogen depletion in skeletal muscle in rats submitted to ischemia and reperfusion. Association of pre and postconditioning did not show advantage compared to preconditioning alone. Postconditioning alone did not show protective effect. PMID- 23743683 TI - Correlation between bursting pressure and breaking strength in colonic anastomosis. AB - PURPOSE: To investigate the correlation between bursting pressure and breaking strength on the 7th postoperative day following left colonic anastomosis in rats. METHODS: Seventy rats were randomly divided into seven groups of ten animals each. All of the animals underwent segmental resection of the left colon and end to-end anastomosis. The animals in groups I to VI underwent surgical laparoscopies with pneumoperitoneums using carbon dioxide or helium at pressures of 5, 12 or 20 mmHg. In Group VII, open laparotomy was performed. The animals were reoperated on postoperative day 7 to measure the bursting pressure and the breaking strength of the anastomosis. RESULTS: The anastomosis bursting pressure in 70 animals was 193.10+/-55.56 mmHg. There was no significant difference between the groups (p=0.786). The breaking strength of the anastomosis was 0.26+/ 0.12 N. There was no significant difference between the groups (p=0.356). Pearson's correlation test showed a low correlation (r=0.231) lacking statistical significance (p=0.054). CONCLUSION: There was no correlation between the bursting pressure and breaking strength of left colonic anastomoses in rats on the 7th postoperative day. PMID- 23743684 TI - Late administration of a specific COX-2 inhibitor does not treat and/or prevent progression of gastric tumors in rats submitted to duodenogastric reflux procedure. AB - PURPOSE: To assess whether late introduction of a specific COX-2 inhibitor (Meloxicam) can treat and/or prevent the progression of tumors in the stomach of rats submitted to duodenogastric reflux. METHODS: Seventy five male Wistar rats, weighing 150 grams, were submitted to the induction of duodenogastric reflux through the pylorus. At 36 weeks of follow-up were established three experimental groups: DGR36 sacrificed immediately, DGR54 and DGR54MLX both sacrificed at 54th week of follow-up . The animals of the latter group were fed with a rat chow premixed with Meloxicam (2.0 mg/ kg feed; 0.3 mg / kg bw / day) and the other two with standard rat chow. The lesions found in the pyloric mucosa and gastrojejunal anastomosis were analyzed macroscopically and histologically. For statistical analysis was adjusted a generalized linear model assuming a binomial distribution with LOGIT link function. RESULTS: No significant differences were found when comparing the incidences of benign tumor lesions (Adenomatous Hyperplasia), p=0.4915, or malignant (Mucinous Adenocarcinoma), p=0.2731, among groups. CONCLUSION: Late introduction of specific COX-2 inhibitor (Meloxicam) did not treat and was not able to prevent the progression of tumoral lesions induced by duodenogastric reflux in the rat stomachs. PMID- 23743685 TI - Surgical risk tests related to cardiopulmonary postoperative complications: comparison between upper abdominal and thoracic surgery. AB - PURPOSE: To investigate if tests used in the preoperative period of upper abdominal or thoracic surgeries are able to differentiate the patients that presented cardiopulmonary postoperative complications. METHODS: Seventy eight patients, 30 submitted to upper abdominal surgery and 48 to thoracic surgery were evaluated. Spirometry, respirometry, manovacuometry, six-minute walk test and stair-climbing test were performed. Complications from immediate postoperative to discharge from hospital were registered. RESULTS: The postoperative complications rate was 17% in upper abdominal surgery and 10% in thoracic surgery. In the univariate regression, the only variable that kept the correlation with postoperative complications in the upper abdominal surgery was maximal expiratory pressure. In thoracic surgery, the maximal voluntary ventilation, six-minute walk test and time in stair-climbing test presented correlation with postoperative complications. After multiple regression only stair-climbing test continued as an important risk predictor in thoracic surgery. CONCLUSION: The respiratory pressure could differentiate patients with complications in upper abdominal surgery, whereas in thoracic surgery, only spirometric values and exercise tests could differentiate them. PMID- 23743686 TI - Surgical research in the north and northeast of Brazil. AB - PURPOSE: To evaluate the scientific production from the surgical areas from the State University of Para (UEPA), Federal Universities of Para (UFPA) and of Paraiba (UFPB), Brazil. METHODS: The scientific productions of professors in the last five years were classified according to the Qualis system of CAPES-Medicine III (http://qualis.capes.gov.br/webqualis/publico/pesquisaPublicaClassificacao.seam?c nversationPropagation=begin) and it was computed the number of guidance of students scientific projects. RESULTS: Seventy-four professors were included, 31 with Master and 43 with PhD degrees. UFPA presented more publications (49% out of the total), which 32% of them in Journals B1 or higher. Otorhinolaryngology presented the greatest number of publications (29% out of the total); however, 98% of them in B3 or lower. Gastroenterological Surgery, which is responsible for 23% out of the total, had 57% of its publications in B1 or higher. The most frequent type of guidance was the one about scientific work of completion of undergraduate course (63%). Gynecology and Obstetrics presented the greatest number of student's guidance (35% out of the total) and Gastroenterological Surgery the largest number of Master's degree and PhD degree supervisions. CONCLUSIONS: The specialties Gynecology and Obstetrics and Gastroenterological Surgery from the State University of Para (UEPA), Federal Universities of Para (UFPA) and of Paraiba (UFPB) presented the greatest number of professors with academic degrees. Gastroenterological Surgery presented the largest scientific productions at higher strata of WebQualis CAPES classification and also the largest number of Master and PhD directed. PMID- 23743687 TI - Magnetic resonance imaging for the clinical management of rectal cancer patients: recommendations from the 2012 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. AB - OBJECTIVES: To develop guidelines describing a standardised approach regarding the acquisition, interpretation and reporting of magnetic resonance imaging (MRI) for clinical staging and restaging of rectal cancer. METHODS: A consensus meeting of 14 abdominal imaging experts from the European Society of Gastrointestinal and Abdominal Radiology (ESGAR) was conducted following the RAND-UCLA Appropriateness Method. Two independent (non-voting) chairs facilitated the meeting. Two hundred and thirty-six items were scored by participants for appropriateness and classified subsequently as appropriate or inappropriate (defined by >= 80 % consensus) or uncertain (defined by < 80 % consensus). Items not reaching 80 % consensus were noted. RESULTS: Consensus was reached for 88 % of items: recommendations regarding hardware, patient preparation, imaging sequences, angulation, criteria for MRI assessment and MRI reporting were constructed from these. CONCLUSIONS: These expert consensus recommendations can be used as clinical guidelines for primary staging and restaging of rectal cancer using MRI. KEY POINTS: * These guidelines recommend standardised imaging for staging and restaging of rectal cancer. * The guidelines were constructed through consensus amongst 14 abdominal imaging experts. * Consensus was reached by in 88 % of 236 items discussed. PMID- 23743689 TI - Should Midazolam Drug-Drug Interactions be of Concern to Palliative Care Physicians? PMID- 23743688 TI - Obesity as a risk factor for poor neurocognitive outcomes in older adults with heart failure. AB - Heart failure (HF) has reached epidemic proportions and is a significant contributor to poor outcomes. HF is an established risk factor for Alzheimer's disease, vascular dementia, and abnormalities on neuroimaging. Moreover, up to 80% of HF patients also exhibit milder impairments on cognitive tests assessing attention, executive function, memory, and language. The mechanisms of cognitive impairment in HF are not entirely clear and involve a combination of physiological processes that negatively impact the brain. Cerebral hypoperfusion and common comorbid conditions in HF are among the most commonly proposed contributors to poor neurocognitive outcomes in this population. Obesity is another likely risk factor for adverse brain changes and cognitive impairment in HF, as it is a known contributor to neurocognitive outcomes in healthy and patient samples. This paper reviews the literature on HF and cognitive function and introduces obesity as a significant risk factor for poor neurocognitive outcomes in this population. PMID- 23743690 TI - Author's Reply to Kotlinska-Lemieszek: "Should Midazolam Drug-Drug Interactions Be of Concern to Palliative Care Physicians?". PMID- 23743691 TI - Stevens-Johnson syndrome/toxic epidermal necrolysis: are drug dictionaries correctly informing physicians regarding the risk? AB - BACKGROUND: Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are severe drug reactions associated with high mortality and multiple incapacitating sequelae. In the past 20 years, two large multinational case control studies, published in 1995 and 2008, had identified different degrees of drug association with SJS/TEN: 'strongly associated', 'associated', 'suspected' and 'not suspected' medications. OBJECTIVE: The aim of this study was to check the adequacy of mention of risk of SJS/TEN in the drug dictionaries most widely used by physicians in five European countries. STUDY DESIGN: In each country one expert investigator looked at the most widely used drug dictionary (2009 edition) for mentions of risk of SJS/TEN. This was done for a predefined list of medications with a different degree of risk. The presence and clarity or absence of warning was compared with available evidence provided by published results from case-control studies. SETTING: The five countries participating in the RegiSCAR group: Austria, France, Germany, The Netherlands and the UK. RESULTS: A total of 3,268 drug descriptions of medications for systemic use were analysed, including all brands of 14 'strongly associated' drugs, 5 'associated' drugs and 12 widely used drugs with no established association. Discrepancies were found by country, and between descriptions for different brands of the same generic. Among 522 descriptions of 14 'strongly associated' drugs, only 5 did not mention the risk. For the 1,013 descriptions of 'associated' drugs, 3 % did not mention the risk. One-third of 'not suspected' drugs contained a specific or less specific warning (e.g. bullous cutaneous eruption). Warnings for 'strongly associated' medications were often as imprecise as those for 'not suspected' drugs. CONCLUSION: Information on the risk of SJS/TEN in drug dictionaries needs improvement to enhance the quality of advice given by general physicians and to raise the understanding of risk by patients. PMID- 23743692 TI - Causality of Drugs Involved in Acute Liver Failure Leading to Transplantation: Results from the Study of Acute Liver Transplant (SALT). AB - BACKGROUND: Several methods have been proposed to assess causality in drug induced liver injury but none have been tested in the specific context of acute liver failure leading to transplantation (ALFT). OBJECTIVE: We took advantage of the Study of Acute Liver Transplant (SALT), a European case-population study of ALFT, to test different causality scales. METHODS: Causality was assessed by experts in SALT, a 7-country case-population study from 2005 to 2007 of adult otherwise unexplained ALFT, for all drugs found within 30 days prior to the date of initial symptoms of liver disease (index date), using information content, causality scales, and data circuit determined from a pilot study, Salome. RESULTS: The consensus points from Salome were to provide full data on drugs including international non-proprietary name (INN) and doses except for non steroidal anti-inflammatory drugs (NSAIDs) and to use the World Health Organization (WHO) causality scale. In SALT, among the 9,479 identified patients, 600 (6.3%) were cases of ALFT, of which 187 had been exposed to drugs within 30 days, without overdose. In 130 (69.5%) of these the causality score was possible, probable, or highly probable. CONCLUSION: In ALFT cases, once other clinical causes have been excluded and drug exposure established within 30 days, the main discriminant characteristic for causality will be previous knowledge of possible hepatotoxicity. PMID- 23743694 TI - Risk factors for adverse symptoms during dipeptidyl peptidase-IV inhibitor therapy: a questionnaire-based study carried out by the Japan Pharmaceutical Association Drug Event Monitoring project in Kumamoto Prefecture. AB - BACKGROUND: Meta-analyses of randomized clinical trials have reported that dipeptidyl peptidase IV (DPP-4) inhibitors are well tolerated and that the incidence of hypoglycemia with the use of DPP-4 inhibitors is similar to that observed with placebos. However, in general, provider-oriented methods using medical record reviews offer lower rates of non-serious, symptomatic adverse drug reactions (ADRs) than patient-oriented methods. Moreover, severe hypoglycemia occurred in three clinical trials using sitagliptin, but in two of these trials this phenomenon has been previously described only in the drug application data in the US. OBJECTIVE: The aim of this study was to assess the profile of patient reported symptomatic ADRs under DPP-4 inhibitor therapy and to detect risk factors for hypoglycemic and non-hypoglycemic adverse symptoms in daily clinical practice. METHODS: We analyzed a subpopulation of participants in the Drug Event Monitoring (DEM) project of the Japan Pharmaceutical Association. An anonymous survey was conducted in February 2012 to assess the self-perception of adverse symptoms during a median 28 (4-88) days after the last prescription of DPP-4 inhibitors by means of interviews of pharmacists using structured questionnaires. RESULTS: A total of 864 males and 686 females were included. The prescribed DPP-4 inhibitors included sitagliptin (75.4 %), alogliptin (15.5 %), vildagliptin (8.8 %) and linagliptin (0.3 %). Mild hypoglycemic symptoms were reported by 34 individuals (2.2 %) receiving monotherapy of sitagliptin (10/402) or alogliptin (3/65), or combination therapy of sitagliptin (15/767) or alogliptin (6/176) with other hypoglycemic agents. In the multiple regression model, hypoglycemic symptoms were found to be significantly associated with liver disease, female sex and alcohol consumption more than three times per week. Non-hypoglycemic symptoms were reported by 57 individuals (3.7 %), the most common symptoms of which were gastrointestinal symptoms (2.1 %). Combination therapy was only found to be associated with nonhypoglycemic symptoms. CONCLUSIONS: The present study suggested that hypoglycemic symptoms under therapy with sitagliptin or alogliptin may be associated with liver disease, female sex and alcohol consumption, all of which are potentially capable of leading to poor gluconeogenesis because they decrease the counter-regulatory hormonal responses to hypoglycemia. PMID- 23743696 TI - [Public health and National Health Service]. PMID- 23743697 TI - [Systematic review of the literature regarding the risk of mortality, cancer and cardiovascular diseases in professional drivers]. AB - BACKGROUND: Possible ill- health effects of exposures incurred by professional drivers have been reported by several studies with more or less statistically significant results, and continue to be debated in the medical literature. The aim of the present study was to review the existing literature regarding the association between working as a professional driver, mortality, cancer and cardio-vascular diseases. METHODS: The authors considered studies published until May 2012. The literature review was conducted by searching PubMed and EMBASE and using the following research entries: "professional drivers", "mortality", "cancer", "cardiovascular diseases", "health risks", "air-pollution" and "urban air". RESULTS: Of 1,497 studies reviewed, 25 were included in the final analysis. Nine studies were found assessing mortality. Of these, one study indicated that professional drivers had a significantly increased risk for all- cause mortality compared to the general population (Standardised Mortality Ratio, SMR=1.15); five studies indicated a significantly higher risk of lung cancer mortality (SMR ranged 1.16 and 2.12). Seven studies evaluating cardio-vascular diseases focused on myocardial infarction. These reported a higher risk in professional drivers with respect to controls, with crude Odds Ratios (OR) between 1.66 and 3.3, Relative Risks (RR) ranging from 1.19 to 1.6. In five of the above studies, potential confounders were considered. Five of 11 studies reported a statistically significant increased risk of lung cancer in professional drivers with respect to the general population or to other workers, with ORs included between 1.21 and 1.85, and RRs between 1.2 and 1.4. CONCLUSIONS: The reviewed studies had many limitations, such as poor exposure assessment and lack of information on relevant confounders. In addition, heterogeneity in the studies led to problems in summarizing the results. Despite this, study findings suggest the existence of an association between this professional activity and risk for lung cancer and cardiovascular diseases. PMID- 23743695 TI - Is maternal use of medicines during pregnancy associated with deciduous molar hypomineralisation in the offspring? A prospective, population-based study. AB - BACKGROUND: The effects of maternal use of medicines during pregnancy on tooth development has scarcely been studied; only negative effects of tetracycline on tooth germs are known (irreversible tooth discoloration and enamel hypoplasia). OBJECTIVE: The aim of this study was to investigate whether antibacterials and anti-allergic and anti-asthma medicines, being the most frequently used medicines during pregnancy, are associated with deciduous molar hypomineralisation (DMH) and, if so, which specific medicines. MATERIALS AND METHODS: To clarify this possible association, the participants of the Generation R Study, a population based prospective cohort study from fetal life until young adulthood, were studied. Data on medicine use during pregnancy were retrieved from pharmacies. Clinical photographs of the second primary molars, which were scored for DMH, were taken with an intra-oral camera in 6,690 children (mean age 6.2 years, standard deviation [SD] +/- 0.53; 49.9 % girls). RESULTS: During pregnancy, 20.3 % of the mothers used antibacterials, 12.3 % anti-asthma medicines and 5.4 % anti allergic medicines. The prevalence of DMH was 9.0 % in the study group. There was no association between the use of anti-asthma medicines, anti-allergic medicines (odds ratio [OR]: 0.97 [95 % CI 0.61-1.54]; OR: 1.04 [0.54-2.03]) or antibacterials (OR: 0.73 [0.49-1.09]) during pregnancy and DMH (all p-values >0.05). The study had sufficient power (80 %) to detect significant associations. CONCLUSION: Maternal use of antibacterials, anti-allergic medicines or anti asthma medicines during pregnancy is not associated with the development of DMH in the offspring. PMID- 23743698 TI - [Global Health: teaching approaches in Italian and foreign University Faculties of Medicine]. AB - Global Health is an academic subject which focuses on the importance of social, economic, political, demographic and environmental determinants on health. This narrative review examines undergraduate and postgraduate teaching approaches to Global Health in the main Faculties of Medicine in Europe, America and Asia. Differences were found in contents, methods and general approaches to teaching medical students about Global Health in the faculties examined. PMID- 23743699 TI - Condom perception and prevention of HIV/AIDS infection in Cameroon: appraisal of knowledge, attitudes and practices among level one students of the University of Dschang. AB - BACKGROUND: With the decreasing HIV epidemiology in Cameroon (5.5% in 2004 to 4.3% in 2011), HIV/AIDS remains a major public health concern, affecting mostly the sexually active population, among which the young University students represent an important target. Since sexual intercourses represent about 90% of HIV transmission, understanding the sexual behaviors of youth could relevantly optimize the design of HIV prevention strategies, through updated and adapted communication strategies for healthy sexual behavioral changes. METHODOLOGY: A qualitative, descriptive and cross-sectional study was conducted in November 2010, among 518 newly registered students in the various faculties of the University of Dschang, Cameroon. In order to evaluate Knowledge, Attitudes and Practices (KAP) toward HIV/AIDS prevention among the study participants, a structured questionnaire was administered to each participant, on the basic knowledge about HIV/AIDS and condoms. Data analysis was performed using Epi Info version 3.5.0 software. RESULTS: The mean age of participants was 20 years, with a slight female predominance (52%). 98.6% of students voted familiar with the theme "condom", with 88.9% giving a satisfactory definition. However, 41.1% do not know the appropriate transmission route of HIV, while 5.4% do not master the correct use of condom; with up to 75.7% being aware of the female condom existence. Although 97.8% of students consider the proper use of condoms as an effective HIV preventive tool, up to 34.5% of them fail to use condoms during sexual intercourses and 69% were not in favor of the use of female condom, mainly due to a decreasing sexual pleasure. CONCLUSION: Despite the existing sensitization campaigns, the perception of condoms is still very poor among young Cameroonian academics; with the non-systematic use of condoms being the major setback. The lack of familiarity to female condom, both among female and male, would also be a contributing drawback. These major sexual behavioral risk factors to HIV infection appear as key points to address during the campaigns to ensure owning of healthy sexual habits, a leading component to reduce HIV incidence among young Cameroonian/Africans. PMID- 23743700 TI - [What criteria are used by home care nurses to decide about frequency of home visits in the follow-up of patients with heart failure?]. AB - BACKGROUND: Factors that directly or indirectly influence nurses' decisions regarding aspects of in-hospital care are well-known. On the other hand, little is known about which elements/criteria are used by home-care nurses to make decisions about the frequency of follow-up visits. OBJECTIVES: The objective of this study was to identify the criteria used for defining the frequency of follow up visits in patients with heart failure. METHODS: Different study methods were used. A cross-sectional questionnaire study was performed to identify what specific aspects are considered for deciding to provide homecare to patients with heart failure. Three focus groups were then held with homecare nurses with experience with heart failure patients, to discuss and reach a consensus regarding the criteria for frequency of follow-up visits. RESULTS: The criteria that guide decision-making about the frequency of follow-up home visits are: a) clinical condition of the patient, b) presence of a caregiver, c) compliance/adherence to drug therapy, d) characteristics of the patient, e) workload, f) professional experience of the healthcare operator, f) assessment by the patient's general practitioner. CONCLUSIONS: The study identified which factors influence home-care nurses' decision-making in defining the frequency of follow-up for patients with heart failure. The decision-making process is based on the evaluation of multiple factors and also considers the organizational context in which home-care nurses work and their workload. Accurate criteria need to be defined. PMID- 23743701 TI - Creosote released from railway-ties recycled and the sanitary risks. AB - Through the history of railways, wooden crossties impregnated with potentially hazardous creosote tar, have been used for years. There are six major classes of compounds in the creosote: aromatic hydrocarbons; tar acids/phenolics; tar bases/nitrogen-containing heterocycles; aromatic amines; sulfur-containing heterocycles; and oxygen-containing heterocycles. The creosote molecules applied in railway crossties can be released in the environment and they can bioaccumulate in animals and vegetables. Some constituents (benzo(a)pyrene and phenolics like benzene) are considered as being carcinogenic which renders the entire complex of creosote to be classified as potentially carcinogenic. After several decades of use the railway-ties are been recycled for varies uses like fences, stakes for agriculture and fruit production or bank protection. In this paper are examined some environmental and sanitary risks from wood impregnated with creosote reported in the literature. PMID- 23743702 TI - [Asbestos and harmful health effects: from denial theories to epidemiological evidence]. AB - The recent episode involving Eternit, a factory in Casale Monferrato (Turin, Italy), culminated in February 2012 with a guilty verdict for the owners of the factory. The indiscriminate use of asbestos, however, continues worldwide, despite evidence of increased risk for conditions such as asbestosis and malignant pleural mesothelioma. In this study we investigate the relationship between epidemiological evidence and denial theories, over the decades and until the present time. Many countries in the world still promote the use of asbestos, with a view to profit and globalization but at the expense of public health. PMID- 23743703 TI - [The transition from paediatric to adult care: a new paradigm]. AB - In healthcare, the child-adult transition is the point of intersection between two health care systems organized in a network (pediatric and adult care), each with its own specificities and dysfunctions. Information, education and empowerment of young adults are crucial in preparing them for the transition to adult care while centrality of the patient, patient preferences, sharing with patients and their families, and multi-disciplinary approach, are the key words of the transition process. Barriers to overcome include the reluctance of patients and their families to separate from the pediatric care system, the tendency of pediatric healthcare workers not to favour the emancipation process and the inability of healthcare workers providing adult care to perceive the sense of insecurity and dependence experienced by young adults. PMID- 23743704 TI - [Public health accessible to all: use of smartphones in the context of healthcare in Italy]. AB - Recent statistics suggest that Italy is the first country in Europe for number of smartphone owners and it is foreseeable that these technological tools will play a key role in health care. In order to examine the main Italian applications for smartphones dealing with disease prevention, health education and health promotion, an extensive research was performed through the main search engines and the results were analyzed critically in order to select the best experiences available. The main applications developed covered the following macro-areas: lifestyles (nutrition, diet and physical activity), self-diagnosis and self treatment, management of infectious and chronic degenerative diseases. PMID- 23743705 TI - [Immunotherapeutic approach for the prevention and treatment of chronic diseases]. AB - Alzheimer disease, diabetes and cardiovascular diseases are among the leading causes of morbidity and mortality worldwide. Different immunotherapeutic approaches for prevention and treatment of these diseases are currently object of several researches. In this paper, recent trials describing active and passive immunotherapy for the management of these pathologies are discussed. The recent immunotherapeutic and preventive approaches for the treatment of Alzheimer's disease are based on the use of beta-amyloid peptides and to tau-based immunization strategies but new possibility are explored. Immunotherapeutic vaccine against angiotensin II showed promising results for the management of hypertension. Heath shock proteins and beta2-glycoprotein I have been tested to reduce atherosclerosis. Insulin agonists were used for preventing type 1 diabetes in mouse; IL-1beta was effective in experimental type 2 diabetes. Research in the field of immunological approach to treatment and prevention of chronic diseases is promising even if the present results have been obtained mainly in animal models. PMID- 23743706 TI - Advancing the pharmacy practice research agenda: views and experiences of pharmacists in Qatar. AB - BACKGROUND: There is little emphasis on pharmacy practice research in Qatar, with a lack of relevant education and training and a notable lack of exposure to processes of research. OBJECTIVE: To describe views and attitudes of pharmacists in Qatar to pharmacy practice research prior to and following a 2 day introductory research workshop. METHOD: All pharmacists (n = 350) were invited to express interest in attending. All participants were required to complete a questionnaire covering views and attitudes relating to research. Workshop sessions were on: research questions; critically appraising literature; developing research methods; collecting and analysing data; and disseminating findings. Participants completed a post-course evaluation questionnaire. RESULTS: Of the ninety expressing interest, 47 were selected and participated in the first training day, with 40 of these also attending the second day. Participants expressed positive views and attitudes towards research. Most (46/47) strongly agreed/agreed that it was their professional duty to be involved; all strongly agreed/agreed with importance of an evidence base to support practice; but there were issues around time, support and training. The research workshops were positively evaluated by participants. CONCLUSION: Findings indicate pharmacists' willingness to participate in research training in Qatar. However, there is a need to ensure that views and attitudes translate into research participation thus enhancing the evidence base. PMID- 23743707 TI - Characterization of long-term memory, resistance to extinction, and influence of temperament during two instrumental tasks in horses. AB - The present study investigated the influence of temperament on long-term recall and extinction of 2 instrumental tasks in 26 horses. In the first task (backward task), horses learned to walk backward, using commands given by an experimenter, in order to obtain a food reward. In the second task (active avoidance task), horses had to cross an obstacle after a bell rang in order to avoid emission of an air puff. Twenty-two months after acquisition, horses exhibited perfect recall performance in both tasks. Accordingly, no influence of temperament on recall performance could be observed for either task. In contrast, in the absence of positive or negative outcomes, the horses' ability to extinguish their response to either task was highly variable. Resistance to extinction was related to some indicators of temperament: The most fearful horses tended to be the most resistant to extinction in the backward task, while the least sensitive horses tended to be the most resistant to extinction in the active avoidance task. These findings reveal extensive long-term memory abilities in horses and suggest an influence of temperament on learning processes other than acquisition. PMID- 23743708 TI - DING proteins: numerous functions, elusive genes, a potential for health. AB - DING proteins, named after their conserved N-terminus, form an overlooked protein family whose members were generally discovered through serendipity. It is characterized by an unusually high sequence conservation, even between distantly related species, and by an outstanding diversity of activities and ligands. They all share a demonstrated capacity to bind phosphate with high affinity or at least a predicted phosphate-binding site. However, DING protein genes are conspicuously absent from databases. The many novel family members identified in recent years have confirmed that DING proteins are ubiquitous not only in animals and plants but probably also in prokaryotes. At the functional level, there is increasing evidence that they participate in many health-related processes such as cancers as well as bacterial (Pseudomonas) and viral (HIV) infections, by mechanisms that are now beginning to be understood. They thus represent potent targets for the development of novel therapeutic approaches, especially against HIV. The few genomic sequences that are now available are starting to give some clues on why DING protein genes and mRNAs are well conserved and difficult to clone. This could open a new era of research, of both fundamental and applied importance. PMID- 23743709 TI - A novel microfluidic co-culture system for investigation of bacterial cancer targeting. AB - Although bacterial cancer targeting in animal models has been previously demonstrated and suggested as a possible therapeutic tool, a thorough understanding of the mechanisms responsible for cancer specificity would be required prior to clinical applications. To visualize bacterial preference for cancer cells over normal cells and to elucidate the cancer-targeting mechanism, a simple microfluidic platform has been developed for in vitro studies. This platform allows simultaneous cultures of multiple cell types in independent culture environments in isolated chambers, and creates a stable chemical gradient across a collagen-filled passage between each of these cell culture chambers and the central channel. The established chemical gradient induces chemotactic preferential migration of bacteria toward a particular cell type for quantitative analysis. As a demonstration, we tested differential bacterial behavior on a two chamber device where we quantified bacterial preference based on the difference in fluorescence intensities of green fluorescence protein (GFP)-expressing bacteria at two exits of the collagen-filled passages. Analysis of the chemotactic behavior of Salmonella typhimurium toward normal versus cancer hepatocytes using the developed platform revealed an apparent preference for cancer hepatocytes. We also demonstrate that alpha-fetoprotein (AFP) is one of the key chemo-attractants for S. typhimurium in targeting liver cancer. PMID- 23743711 TI - Attenuating effect of gossypol on tumor growth in systemic malignancies. PMID- 23743710 TI - Phosphatidylethanolamine from phosphatidylserine decarboxylase2 is essential for autophagy under cadmium stress in Saccharomyces cerevisiae. AB - Cadmium (Cd) is a potent toxic element used in several industries and in the process contaminates air, soil, and water. Exposure of Saccharomyces cerevisiae to Cd increases the major phospholipids, and profound increase was observed in phosphatidylethanolamine (PE). In yeast, there are four different pathways contributing to the biosynthesis of PE, and contribution to PE pool through phosphatidylserine decarboxylase2 (psd2) is not significant in normal conditions. Upon Cd exposure, psd2Delta strain showed a significant decrease in major phospholipids including PE. When exposed to Cd, wild-type (WT) cells depicted an increase in ER stress and autophagy, whereas in psd2, ER stress was noted but autophagy process was impaired. The supplementation of ethanolamine did not overcome the Cd stress and also the autophagy process, whereas overexpression of PSD2 in psd2Delta increased the cellular tolerance, PE levels, and the autophagy process against Cd stress. From our studies, we can suggest that PSD2 of S. cerevisiae has an important role in PE synthesis and in autophagy process under Cd stress. PMID- 23743712 TI - Disruption of fumarylacetoacetate hydrolase causes spontaneous cell death under short-day conditions in Arabidopsis. AB - Fumarylacetoacetate hydrolase (FAH) hydrolyzes fumarylacetoacetate to fumarate and acetoacetate, the final step in the tyrosine (Tyr) degradation pathway that is essential to animals. Deficiency of FAH in animals results in an inborn lethal disorder. However, the role for the Tyr degradation pathway in plants remains to be elucidated. In this study, we isolated an Arabidopsis (Arabidopsis thaliana) short-day sensitive cell death1 (sscd1) mutant that displays a spontaneous cell death phenotype under short-day conditions. The SSCD1 gene was cloned via a map based cloning approach and found to encode an Arabidopsis putative FAH. The spontaneous cell death phenotype of the sscd1 mutant was completely eliminated by further knockout of the gene encoding the putative homogentisate dioxygenase, which catalyzes homogentisate into maleylacetoacetate (the antepenultimate step) in the Tyr degradation pathway. Furthermore, treatment of Arabidopsis wild-type seedlings with succinylacetone, an abnormal metabolite caused by loss of FAH in the Tyr degradation pathway, mimicked the sscd1 cell death phenotype. These results demonstrate that disruption of FAH leads to cell death in Arabidopsis and suggest that the Tyr degradation pathway is essential for plant survival under short-day conditions. PMID- 23743714 TI - Perceiving object dangerousness: an escape from pain? AB - A variety of studies showed that participants are facilitated when responding to graspable objects, while it has not been fully investigated what happens during interactions with graspable objects that are potentially dangerous. The present study focuses on the mechanisms underlying the processing of dangerous objects. In two experiments, we adopted a paradigm that has never been employed in this context, a bisection task. The line was flanked by objects belonging to different categories. We explored the sensitivity to the distinction between neutral and dangerous objects, by measuring whether the performance was biased toward a specific object category. In Experiment 1 both teenagers and adults bisected lines flanked by dangerous and neutral graspable objects, and they misperceived the line midpoint toward the neutral graspable object or, stated differently, on the opposite side of the dangerous graspable object. In Experiment 2 adults bisected lines flanked by dangerous and neutral objects matched on graspability (both graspable and ungraspable, Experiment 2a), or by graspable and ungraspable objects matched on dangerousness (both neutral and dangerous, Experiment 2b). Results confirmed the finding of Experiment 1, but also indicated that participants misperceived the line midpoint toward the ungraspable object when it was presented, being it dangerous or not. This evidence demonstrated sensitivity to object dangerousness maintained across lifespan. The emergence of aversive affordances evoked by dangerous graspable objects strenghtens the importance to consider graspability in the investigation of dangerous objects. Possible neural mechanisms involved in the processing of dangerous graspable objects are discussed. PMID- 23743713 TI - Transcriptomic and metabolic changes associated with photorespiratory ammonium accumulation in the model legume Lotus japonicus. AB - The transcriptomic and metabolic consequences of the lack of plastidic glutamine (Gln) synthetase in the model legume Lotus japonicus were investigated. Wild-type and mutant plants lacking the plastidic isoform of Gln synthetase were grown in conditions that suppress photorespiration and then transferred for different lengths of time to photorespiratory conditions. Transcript and metabolite levels were determined at the different time points considered. Under photorespiratory active conditions, the mutant accumulated high levels of ammonium, followed by its subsequent decline. A coordinate repression of the photorespiratory genes was observed in the mutant background. This was part of a greater modulation of the transcriptome, especially in the mutant, that was paralleled by changes in the levels of several key metabolites. The data obtained for the mutant represent the first direct experimental evidence for a coordinate regulation of photorespiratory genes over time. Metabolomic analysis demonstrated that mutant plants under active photorespiratory conditions accumulated high levels of several amino acids and organic acids, including intermediates of the Krebs cycle. An increase in Gln levels was also detected in the mutant, which was paralleled by an increase in cytosolic Gln synthetase1 gene transcription and enzyme activity levels. The global panoramic of the transcripts and metabolites that changed in L. japonicus plants during the transfer from photorespiration suppressed to photorespiration-active conditions highlighted the link between photorespiration and several other cellular processes, including central carbon metabolism, amino acid metabolism, and secondary metabolism. PMID- 23743715 TI - Action strategies used by children to avoid two vertical obstacles in non confined space. AB - Information used to determine the action strategies necessary to successfully pass through apertures is based on the dimensions of the individual and the mover's action capabilities (Warren in J Exp Psychol 10:683-703, 1984; Warren and Whang in J Exp Psychol 13:371-383, 1987). Previous research has demonstrated that when children must pass through small spaces, they will produce a shoulder rotation at apertures 1.6 times their shoulder width and smaller (i.e., critical point) and their avoidance strategies are based more on dynamic than geometric measures (Snapp-Childs and Bingham in Exp Brain Res 198:527-533, 2009; Wilmut and Barnett in Exp Brain Res 210:185-194, 2011). The question remains as to whether similar strategies exist when children are given a choice in their obstacle avoidance strategy. The current study aimed to determine the action strategies employed by children when confronted with a non-confined obstacle avoidance task. Specifically, the study intended to identify the aperture width that elicited a change in action (e.g., a shoulder rotation or a change in travel path). Children (N = 12, mean age = 7.1 years, +/-0.2) were instructed to walk along a 10-m path toward a visible goal located at the end of the pathway and avoid colliding with the two vertical obstacles placed halfway (5 m) down the path on either side of the midline. The space between the obstacles ranged between 0.6 and 1.8 times the participant's shoulder width (presented in increments of 0.2). Results revealed that when the aperture was too small for straight passage, children choose to circumvent the obstacles rather than rotate their shoulders the majority of the time. However, unlike young and older adults (Hackney and Cinelli in Gait Posture 37:93-97, 2013a, Exp Brain Res 225:419-429, 2013b), this strategy was not used consistently. Instead, changes in travel path were highly variable both across participants and within trials. This variability suggests that a true critical point cannot be established for children in this non-confined task. Variable actions at the time of crossing were significantly correlated with the medial lateral center of mass variability during the approach to the obstacles. These results further support the idea that children's actions may be more affected by dynamic factors than geometric measures. PMID- 23743716 TI - Imagining others' handedness: visual and motor processes in the attribution of the dominant hand to an imagined agent. AB - In a previous study, we found that when required to imagine another person performing an action, participants reported a higher correspondence between their own dominant hand and the hand used by the imagined person when the agent was visualized from the back compared to when the agent was visualized from the front. This suggests a greater involvement of motor representations in the back view perspective, possibly indicating a greater proneness to put oneself in the agent's shoes in such a condition. In order to assess whether bringing to the foreground the right or left hand of an imagined agent can foster the activation of the corresponding motor representations, we required 384 participants to imagine a person-as seen from the right or left side-performing a single manual action and to indicate the hand used by the imagined person during movement execution. The proportion of right- versus left-handed reported actions was higher in the right-view condition than in the left-view condition, suggesting that a lateral vantage point may activate the corresponding hand motor representations, which is in line with previous research indicating a link between the hemispheric specialization of one's own body and the visual representation of others' bodies. Moreover, in agreement with research on hand laterality judgments, the effect of vantage point was stronger for left-handers (who reported a higher proportion of right- than left-handed actions in the right view condition and a slightly higher proportion of left- than right-handed actions in the left-view condition) than for right-handers (who reported a higher proportion of right- than left-handed actions in both view conditions), indicating that during the mental simulation of others' actions, right-handers rely on sensorimotor processes more than left-handers, while left-handers rely on visual processes more than right-handers. PMID- 23743717 TI - The interactive effects of physical fitness and acute aerobic exercise on electrophysiological coherence and cognitive performance in adolescents. AB - The current study examined the effects of physical fitness and aerobic exercise on cognitive functioning and coherence of the electroencephalogram in 30 adolescents between the ages of 13 and 14 years. Participants were first classified as fit or unfit and then performed a modified Eriksen flanker task after a bout of acute exercise and after a period of relaxation. Analysis of behavioural differences between the fit and unfit groups revealed an interaction between fitness levels and acute physical exercise. Specifically, fit participants had significantly faster reaction times in the exercise condition in comparison with the rest condition; unfit, but not fit, participants had higher error rates for NoGo relative to Go trials in the rest condition. Furthermore, unfit participants had higher levels of lower alpha, upper alpha, and beta coherence in the resting condition for NoGo trials, possibly indicating a greater allocation of cognitive resources to the task demands. The higher levels of alpha coherence are of particular interest in light of its reported role in inhibition and effortful attention. The results suggest that physical fitness and acute exercise may enhance cognition by increasing the efficacy of the attentional system. PMID- 23743718 TI - Dosimetric comparison between intra-cavitary breast brachytherapy techniques for accelerated partial breast irradiation and a novel stereotactic radiotherapy device for breast cancer: GammaPodTM. AB - The GammaPodTM device, manufactured by Xcision Medical Systems, is a novel stereotactic breast irradiation device. It consists of a hemispherical source carrier containing 36 Cobalt-60 sources, a tungsten collimator with two built-in collimation sizes, a dynamically controlled patient support table and a breast immobilization cup also functioning as the stereotactic frame for the patient. The dosimetric output of the GammaPodTM was modelled using a Monte Carlo based treatment planning system. For the comparison, three-dimensional (3D) models of commonly used intra-cavitary breast brachytherapy techniques utilizing single lumen and multi-lumen balloon as well as peripheral catheter multi-lumen implant devices were created and corresponding 3D dose calculations were performed using the American Association of Physicists in Medicine Task Group-43 formalism. Dose distributions for clinically relevant target volumes were optimized using dosimetric goals set forth in the National Surgical Adjuvant Breast and Bowel Project Protocol B-39. For clinical scenarios assuming similar target sizes and proximity to critical organs, dose coverage, dose fall-off profiles beyond the target and skin doses at given distances beyond the target were calculated for GammaPodTM and compared with the doses achievable by the brachytherapy techniques. The dosimetric goals within the protocol guidelines were fulfilled for all target sizes and irradiation techniques. For central targets, at small distances from the target edge (up to approximately 1 cm) the brachytherapy techniques generally have a steeper dose fall-off gradient compared to GammaPodTM and at longer distances (more than about 1 cm) the relation is generally observed to be opposite. For targets close to the skin, the relative skin doses were considerably lower for GammaPodTM than for any of the brachytherapy techniques. In conclusion, GammaPodTM allows adequate and more uniform dose coverage to centrally and peripherally located targets with an acceptable dose fall-off and lower relative skin dose than the brachytherapy techniques considered in this study. PMID- 23743719 TI - Cobalt porphyrins as homogeneous catalysts for water oxidation. AB - Three water-soluble cobalt porphyrins have been investigated as water oxidation catalysts via photo-initiation using Ru(II)(bpy)3(2+)/Na2S2O8. The pH dependence of the turnover frequency revealed maximum activity at pH 11. Based on the second order dependence on catalyst concentration for the rate of water oxidation, we suggest a bimolecular radical coupling process as the rate determining step. PMID- 23743720 TI - Thirty years of HIV: what have we learned? PMID- 23743721 TI - The changing epidemiology of HIV in 2013. AB - PURPOSE OF REVIEW: We sought to review the recent epidemiology of HIV-1 and to identify emerging challenges in HIV surveillance and epidemic control. RECENT FINDINGS: There is increasing evidence that HIV epidemics are in decline among general populations worldwide. Critical exceptions to these trends are HIV epidemics among key populations globally; the HIV epidemics in Eastern Europe and Central Asia in injecting drug using populations; the continued high burden epidemics of sexually transmitted HIV among young women and girls in southern sub Saharan Africa, and young men who have sex in men (MSM) in the America, Asia, and Africa. In the new era of ART access, prevalence measures over time are less reliable and new approaches to the measurement of incident infection will be critical to assess trends. The implementation of expanded options for HIV prevention, reducing vertical transmission, and treatment as prevention, will shift focus from individuals to population-level impact. Strong surveillance and information systems will be necessary to meet these expanded surveillance needs. SUMMARY: The epidemiology of HIV infection is changing, dynamic, complex, and progress in epidemic control remains markedly uneven. Without addressing the components of global HIV, in which disease rates continue to expand, current efforts are unlikely to succeed. PMID- 23743723 TI - Immune response to HIV. AB - PURPOSE OF REVIEW: Major advances have been made in the delineation of HIV specific immune response and in the mechanisms of virus escape. The kinetics of the immunological and virological events occurring during primary HIV infection indicate that the establishment of the latent HIV reservoir, the major obstacle to HIV eradication likely occurs during the very early stages of primary infection, that is, the 'eclipse phase', prior to the development of the HIV specific immune response which has limited efficacy in the control of the early events of infection. Therefore, the window of opportunity to develop effective interventions either to clear HIV during primary infection or to prevent rebound of HIV in patients successfully treated who stop antiretroviral therapy is very narrow. RECENT FINDINGS: Genetic factors most strongly associated with nonprogressive infection are human leukocyte antigen (HLA) class I alleles and particularly HLA-B5701. CD4 and CD8 T-cell responses with polyfunctional profile are associated with nonprogressive infection. Broader neutralizing antibodies are detected 3-4 years after infection, generated only in 20% of individuals but show no efficacy in the control of HIV replication. SUMMARY: In the present review, we shall discuss the different components of the HIV-specific immune response elicited by the infection, the kinetics of these responses during primary infection and the changes following transition to the chronic phase of infection, and the functional profile of 'effective' versus 'noneffective' HIV-specific immune responses. PMID- 23743724 TI - Current world literature. Animal models. Thirty years of HIV and AIDS. PMID- 23743722 TI - Progress in HIV-1 vaccine development. AB - PURPOSE OF REVIEW: In this review, examples of recent progress in HIV-1 vaccine research are discussed. RECENT FINDINGS: New insights from the immune correlates analyses of the RV144 efficacy trial have accelerated vaccine development with leads to follow in nonhuman primate studies and improved vaccine designs. Several new vaccine vector approaches offer promise in the exquisite control of acute infection and in improving the breadth of T-cell responses. New targets of broadly neutralizing antibodies (BnAbs) have been elucidated, and improved understanding of how the human host controls BnAb development have emerged from BnAb knock-in mice and from analyses of BnAb maturation and virus evolution in individuals followed from the time of HIV-1 transmission to BnAb induction. SUMMARY: Based on these observations, it is clear that the development of a successful HIV-1 vaccine will require new vaccine approaches and iterative testing of immunogens in well designed animal and human trials. PMID- 23743726 TI - Mental health disorders and solid-organ transplant recipients. AB - Depression affects up to 60% of solid-organ recipients and is independently associated with both mortality (hazard ratio for death of ~2) and de novo malignancy after transplantation, although the mechanism is not clear. Both pretransplantation psychosis and depression occurring more than 2 years after transplantation are associated with increased noncompliance and graft loss. It remains to be shown that effective treatment of depression is associated with improved outcomes and quality of life. Immunosuppressive drugs (especially corticosteroids and calcineurin inhibitors) and physiologic challenges can precipitate deterioration in mental health. All potential transplant candidates should be assessed for mental health problems and preexisting medical conditions that can mimic mental health problems, such as uremic, hepatic, or hypoxic encephalopathy, should be identified and treated appropriately. Expert mental health review of those with identified risk factors (such as previous suicide attempts, history of mental illness or noncompliance with medications) is advisable early in the transplant assessment process to mitigate risk and support the patient. Patients with mental health disorders, when adequately controlled and socially supported, have outcomes similar to the general transplant population. Therefore, exclusion from transplantation based on the diagnosis alone is neither ethically nor medically justified. However, it is ethically and clinically justifiable to deny access to transplantation to those who, despite full support, would have a quality of life that is unacceptable to the candidate or are likely to be noncompliant with treatment or follow-up, which would lead to graft loss. PMID- 23743727 TI - LVAD implant as a bridge to heart transplantation is associated with allosensitization as measured by single antigen bead assay. AB - BACKGROUND: Left ventricular assist devices (LVAD) as a bridge (BTT) to heart transplantation (HTX) may be limited by the formation of anti-human leukocyte antigen antibodies. Whether sensitization occurs with continuous axial flow LVAD implant as assessed by single antigen bead (SAB) assay is unknown. METHODS: Cytotoxic panel-reactive antibody (PRA) and SAB assays were analyzed in HTX recipients undergoing LVAD implant as a BTT. Sensitization was defined as peak anti-human leukocyte antigen antibody values of more than 2000 mean fluorescence intensity because these values have been found to correlate with flow cytometric crossmatch results. RESULTS: LVADs were implanted as BTT in 30 patients. There were 7% (2 of 30) of patients before LVAD implant and no patients after LVAD implant with PRA more than 10%. However, 20% (6 of 30) of patients before LVAD and 53% (16 of 30) after LVAD were sensitized as measured by SAB (P=0.024). At HTX, 47% (14 of 30) of patients remained sensitized. A positive virtual crossmatch was observed in 28% (4 of 14) of the sensitized patients at HTX. There was no difference between the sensitized and nonsensitized groups (P>0.4 for all) in usage of blood products (6411 vs. 6339 units) and time to HTX (28,663 vs. 25,748 days), and 1 year after HTX, there were no differences in rejection (total rejection score 0.30 vs. 0.37) and survival (93% vs. 88%). CONCLUSION: Allosensitization after LVAD is common despite cytotoxic PRA being negative. One year after HTX, this sensitization does not translate into increased acute cellular or antibody-mediated rejection or reduced survival. PMID- 23743728 TI - The national program for deceased organ donation in China. AB - China has developed a new national program for deceased-organ donation to address the need for organ transplantation in the country. The program adheres to the World Health Organization (WHO) guiding principles, is compliant with the Declaration of Istanbul, and respects the cultural and social values of the Chinese people. The experience of pilot trials conducted between 2010 and 2012 was evaluated to generate a comprehensive design of a national program of organ donation and transplantation for implementation throughout China. The legal framework for this program was established from a series of legislative steps since 2007. Accountable national committees have been established to oversee activities of organ donation and transplantation across the nation. The Ministry of Health (MOH) has accredited 164 organ transplant hospitals in China, each of which has an organ procurement organization (OPO) to conduct organ donation and organ recovery. National protocols for deceased-organ donation in China include category I (organ donation after brain death), category II (organ donation after circulatory death), and category III (organ donation after brain death followed by circulatory death). The China Organ Transplant Response System (COTRS) has been developed to allocate organs equitably and transparently. Scientific registries have been established to evaluate the performance of transplant centers and OPOs. China is in the process of implementing a new national program for deceased-organ donation. The program includes a unique approach of organ donation, China category III, which will be promulgated throughout China and is intended to gain widespread acceptance of Chinese society. PMID- 23743729 TI - A welcomed new national policy in China. PMID- 23743730 TI - Production of biomass and filamentous hemagglutinin by Bordetella bronchiseptica. AB - The mammalian pathogen Bordetella bronchiseptica was grown under controlled batch conditions with glutamate as the primary carbon and nitrogen source. First, a Box Behnken statistical design quantified the effect of Mg, sulfate, and nicotinate on the antigen filamentous hemagglutinin (FHA) formation. Using lactic acid as a secondary carbon source for pH control, Mg, and SO4 each negatively affected antigen expression, while nicotinate positively affected antigen expression. Sulfate had a stronger negative effect than Mg with 10 mM eliminating FHA altogether; the highest FHA expression (about 1,000 ng/mL) occurred when either Mg concentration or SO4 concentration, but not both, was about 0.1 mM. Using two Mg and SO4 compositions modeled to yield the greatest antigen expression, three other organic acids were compared as the secondary carbon source: acetate, citrate, and succinate. Mixtures of acetate and glutamate resulted in the greatest organic acid consumption, OD, and FHA concentration (about 1,500 ng/mL), although significant acetate accumulated during these batch processes. The mechanism leading to elevated FHA expression when acetate is the secondary carbon source is unknown, particularly since these cultures were most prone to phase shift to Bvg(-) cultures. PMID- 23743731 TI - Biosynthesis and safety evaluation of ZnO nanoparticles. AB - The secrets gleaned from nature have led to the development of biomimetic approaches for the growth of advanced nanomaterials. Biological methods for nanoparticle synthesis using microorganisms, enzymes, and plants or plant extracts have been suggested as possible ecofriendly alternatives to chemical and physical methods. Here, we report extracellular mycosynthesis of ZnO-NPs by Alternaria alternata (Fr.) Keissl (1912). On treating zinc sulfate solution with fungal culture filtrate, rapid reduction of ZnSO4 was observed leading to the formation of highly stable ZnO-NPs in the solution and up-to-date literature survey showed this was the first report of biosynthesis of ZnO-NPs using this fungus. The particles thereby obtained were characterized by different analytical techniques. EDX-spectrum revealed the presence of zinc and oxygen in the nanoparticles. FTIR spectroscopy confirmed the presence of a protein shell outside the nanoparticles which in turn also support their stabilization. DLS and TEM analysis of the ZnO-NPs indicated that they ranged in size from 45 to 150 nm with average size of 75 +/- 5 nm. But potential negative impacts of nanomaterials are sometimes overlooked during the discovery phase of research. Therefore, in the present study, bio-safety of mycosynthesized ZnO-NPs were evaluated by using cytotoxicity and genotoxicity assays in human lymphocyte cells, in vitro. Cytotoxicity studied as function of membrane integrity and mitochondrial dehydrogenase activity revealed significant (P < 0.05) toxicity at treatment concentration of 500 MUg/ml and above. Additionally, DNA damaging potential was also studied using comet assay. The results revealed significant genotoxicity at the highest concentration (1,000 MUg/ml). PMID- 23743732 TI - A simple and rapid one-time method to evaluate the non-acidic gas content from bioprocesses. AB - This paper presents a rapid less than 2 min and low-cost method involving the use of alkali solution to capture the acidic gasses from a biogas, thereby providing an estimate of the percentage of non-acidic gasses. Such a method was mentioned in the literature but never fully described or optimized. After sampling an aliquot of gas from bioprocess, gas was injected in a sealed flask with a 3 M NaOH solution, and after equilibrium was obtained, the non-acidic gas volume was measured. The method was first calibrated with certified gasses with an accuracy observed between 98 and 105%. Regarding the validation step, certified standard gas mixtures and nine biogas-laboratory batch reactors were used, the overall accuracy reported was 103 + 3%. This rapid and low-cost method may either be used in laboratory conditions as a quick and low cost alternative to standard analysis equipment or in addition as a routine field control method used on full-scale plants. PMID- 23743733 TI - Exploring metal effects and synergistic interactions of ferric stimulation on azo dye decolorization by new indigenous Acinetobacter guillouiae Ax-9 and Rahnella aquatilis DX2b. AB - The first-attempt study deciphered metal-interacting effects on dye-decolorizing capabilities of indigenous bioelectricity-generating strains, Acinetobacter guillouiae Ax-9 and Rahnella aquatilis DX2b. Most of the metallic ions were inhibitory to color removal capabilities of these strains. However, with supplementation of 5 mM ferric chloride, specific decolorization rate (SDR) of Ax 9 increased by 55.48% compared to Fe(3+)-free conditions. In contrast, SDR of DX2b decreased 75.35% due to the inhibition of ferric chloride. On the other hand, ferric citrate could stimulate SDR of DX2b for 21.5% at same dosage. Enzymatic assay indicated that Fe reductase activity was consistent with synergistic effects of ferric chloride on Ax-9, and ferric citrate on DX2b. Protein analysis via SDS-PAGE and identification of Tandem MS/MS afterwards showed that outer membrane protein (Omp) primarily deals with decolorization as a channeling regulation. Moreover, molecular modeling and bioinformatics data also provided detailed evidences to confirm the biological significance of Omp. PMID- 23743734 TI - Prostate biopsy: results and advantages of the transperineal approach--twenty year experience of a single center. AB - PURPOSE: Detection rate for prostate cancer (PCa) and complications following transperineal prostate biopsy (TPBx) were reported. METHODS: From January 1991 to December 2012, 4,000 men underwent TPBx; from 1991 to 2001, the patients underwent biopsy for suspicious DRE or PSA values >4 ng/mL; moreover, from 2002, the indications were abnormal DRE, PSA >10 ng/mL, PSA values between 4.1 and 10, 2.6 and 4 and <2.5 ng/mL with F/T PSA <25, <20 <15 %, respectively. In case of initial biopsy, the number of needles cores increased from 6 (1991-1996) to 12 (1997-2012) and 18 cores (2002-2012); in case of repeat biopsy, since 2005 a saturation biopsy (SPBx) with >24 cores was performed. RESULTS: Overall, PCa, normal parenchyma, HGPIN and ASAP were found in 1,379 (34.5 %), 2,400 (60 %), 175 (4.4 %) and 46 (1.1 %) patients, respectively; in case of initial TPBx, the scheme at 18 showed a greater PCa detection in comparison with scheme at 6-12 cores (p < 0.05). In case of repeat biopsy, a higher detection of microfocus of cancer was found performing a SPBx; moreover, 15 % of cancers were localized in the anterior zone. Incidence of hemospermia and urinary retention were correlated with the number of needle cores resulting equal to 30.4 versus 11.1 % in case of SPBx (p < 0.05); moreover, none developed sepsis. CONCLUSIONS: Transperineal prostate biopsy (TPBx) resets the risk of sepsis; moreover, in case of repeat SPBx, the transperineal approach detects a high number of significant PCa localized in the anterior zone (15 % of the cases). PMID- 23743735 TI - Time to say good bye to shockwave lithotripsy? PMID- 23743736 TI - Bilateral urinary calculi with discordant stone composition. AB - OBJECTIVES: To describe a cohort of bilateral stone formers with significantly different compositions between renal units. METHODS: Patients treated for bilateral nephrolithiasis over a 4-year period (2007-2010) were identified. Stones were categorized by dominant (>=50%) mineralogical component. Patients with significant compositional differences between renal units (discordant stone formers) were compared to patients with a similar stone type in each kidney. RESULTS: Fifteen of the 59 bilateral stone formers (25.4%) were discordant stone formers with significant differences in stone composition between renal units. Forty-four of the 59 patients (74.6%) had the same stone composition on each side. Thirty percent of discordant stones had calcium phosphate as the dominant stone component. Discordant stone formers were younger, had better renal function, and tended to have a larger stone burden (p < 0.05). CONCLUSIONS: A significant minority of bilateral stone formers form a different type of stone in each kidney. Local or micro-environmental etiologies may explain this phenomenon and may also account for failure of preventive therapy in some patients. PMID- 23743737 TI - New developments in the second-line treatment of metastatic colorectal cancer: potential place in therapy. AB - In this review article we discuss the evolution of second-line treatment options for patients with metastatic colorectal cancer (mCRC). The benefits of second line chemotherapy have been established for some time, but in the last decade a number of trials have evaluated combinations of irinotecan- and oxaliplatin-based chemotherapy with molecular-targeted agents; e.g., vascular endothelial growth factor (VEGF)-targeting agents (bevacizumab, aflibercept), epidermal growth factor receptor antibodies (cetuximab, panitumumab), and tyrosine kinase inhibitors (vatalanib). Recent developments include the availability of the new VEGF-targeted agent aflibercept and the new concept of continuing bevacizumab after failure of first-line bevacizumab, which is likely to become a new treatment option in the second-line setting. Choosing the most appropriate second line treatment regimen for mCRC patients remains a complex issue. All of the currently available molecular-targeted agents seem to be active even after patients have received a bevacizumab-based first-line regimen. Overall, the selection of second-line treatment for mCRC depends on several variables and should be determined taking into account the patient's performance and disease status. PMID- 23743738 TI - Ready for 80 more years. PMID- 23743739 TI - Sleep home monitoring: a technical option! PMID- 23743740 TI - Endoscopic surgery to treat inverted papilloma: which are the limits? PMID- 23743741 TI - Hearing aid fitting at SUS (Brazilian Public Health Care System) compared with a compact fitting model. AB - In the present days it is critical to identify the factors that contribute to the quality of the audiologic care provided. The hearing aid fitting model proposed by the Brazilian Unified Health System (SUS) implies multidisciplinary care. This leads to some relevant and current questions. OBJECTIVE: To evaluate and compare the results of the hearing aid fitting model proposed by the SUS with a more compact and streamlined care. METHOD: We conducted a prospective longitudinal study with 174 participants randomly assigned to two groups: SUS Group and Streamline Group. For both groups we assessed key areas related to hearing aid fitting through the International Outcome Inventory for Hearing Aids (IOI-HA) questionnaire, in addition to evaluating the results of Speech Recognition Index (SRI) 3 and 9 months after fitting. RESULTS: Both groups had the same improvement related to the speech recognition after nine months of AASI use, and the IOI-HA didn't show any statically significant difference on three and nine months. CONCLUSION: The two strategies of care did not differ, from the clinical point of view, as regards the hearing aid fitting results obtained upon the evaluation of patients in the short and medium term, thus changes in the current model of care should be considered. PMID- 23743742 TI - Analysis of the Agger nasi cell and frontal sinus ostium sizes using computed tomography of the paranasal sinuses. AB - The Agger nasi cell (ANC) and the frontal sinus ostium (FO) are important structures that can influence the anatomy and physiology of the frontal recess. The aim of this study was to evaluate the presence and size of ANC and the FO and correlate them according to gender, race and among themselves. METHOD: A prospective study with 40 patients who underwent CT of the paranasal sinuses with sagittal reconstruction. MEASUREMENTS: ANC (APAN) anteroposterior diameter, ANC (CCAN) craniocaudal diameter, ANC (LLAN) side-to-side diameter, anteroposterior diameter of the FO (APFO) and side-to-side diameter of the FO (LLFO). RESULTS: Twenty-two patients were male and 18 females, mean age 33.7 years. Most patients were white (45%), followed by browns (32.5%), blacks (20%) and asians (2.5%). The ANC was present in 98.7% of patients. There was statistical difference for APAN on females and LLAN on females and on the total sample. There were no differences for all measurements regarding gender, as well as the race. ANC and FO measurements showed positive correlation, but poor or very poor. CONCLUSION: The prevalence of ANC in our sample was high and did not show a statistically significant difference for most measurements. The correlation between measurements of ANC and the FO was poor or very poor. PMID- 23743743 TI - Is there any effect of coenzyme Q10 on prevention of myringosclerosis? Experimental study with rats. AB - Recent studies have shown that the formation of myringosclerosis could be reduced by the application of antioxidant enzymes and elements. OBJECTIVE: The aim of this study was to investigate the effectiveness of coenzyme Q10 on the prevention of experimentally induced myringosclerosis. METHOD: Forty-eight healthy female wistar albino rats were bilaterally myringotomized and divided into four groups randomly. Group A received no treatment, group B was administered oral coenzyme Q10. Group C was treated with topical saline solution, group D received topically coenzyme Q10. On the 15th day of treatment, tympanic membranes were examined by otomicroscopy. Myringosclerotic lesions were documented semiquantitatively by using 4-point scale. After harvesting tympanic membranes were evaluated histopathologically. RESULTS: In group D (topical coenzyme Q10), we observed otitis within the first four days of the study and this group was excluded from the study. Regarding otomicroscopic examinations, there were no significant differences among groups in myringosclerosis formation (p = 0.241). When group A (non treatment) compared to groups B and C regarding histopathologic examination, the results demonstrated statistical significant differences (p = 0.004; p < 0.001), respectively. There was no statisticaly significant difference between groups B and C (p = 0.160). CONCLUSION: Oral administration of coenzyme Q10 did not reduce myringosclerosis formation in myringotomized rats. PMID- 23743745 TI - Long-term outcomes of endoscopic sinus surgery for chronic rhinosinusitis with and without nasal polyps. AB - Chronic rhinosinusitis (CRS) significantly affects patient quality of life. Medical and surgical treatments aim to clinically manage the condition. OBJECTIVE: To assess the long-term quality of life and clinical management of CRS in patients submitted to endoscopic sinus surgery. METHOD: This prospective cross sectional cohort study enrolled 38 patients and looked into the follow-up data of subjects diagnosed with CRS before surgery, three months after surgery, and at least two years after surgery. The Sinonasal Outcome Test 22 (SNOT-22) was used to assess response to treatment and long-term clinical management of the disease. RESULTS: Significant improvements in the SNOT-22 scores were seen between the preoperative (61.3) and postoperative assessments with three (16.9) and 24 (32.3) months. No statistically significant differences were seen when patients with polyps were compared to polyp-free subjects. Few patients were controlled in both groups, and 7.89% of the subjects had revision surgery during the study. CONCLUSION: Endoscopic sinus surgery significantly improved the quality of life of patients with chronic rhinosinusitis. Clinical control of the condition was acceptable, with few patients requiring re-operation within two years of the first surgery. PMID- 23743744 TI - Digisonic SP(r) Binaural cochlear implant: the coronal tunneled approach. AB - Cochlear implants represent a significant breakthrough in the treatment of hearing loss. Evidence indicates bilateral hearing brings significant benefits to patients, particularly when binaural hearing is offered. OBJECTIVE: To describe the first case of implantation of a Digisonic SP(r) Binaural Neurelec device in Brazil (the third implant placed in the Americas, after Mexico and Colombia) and the chosen surgical approach. METHOD: Description of a surgical approach. RESULTS: The procedure was successfully completed. DISCUSSION: The squelch effect, binaural summation, location of the sound source, and the shadow effect of the head are listed among the reasons to explain the superiority of binaural rehabilitation. Cost of treatment must be considered in the development of public health policies. CONCLUSION: The cost of cochlear implants has been one of the main impediments to bilateral rehabilitation. The Digisonic SP(r) Binaural Neurelec device addresses this issue and exposes patients to less risk through a minimally invasive implantation procedure. PMID- 23743746 TI - Profile of otorhinolaryngology emergency unit care in a high complexity public hospital. AB - Urgent and emergency care are common happenings in ENT practice and most carry low morbidity and mortality. There are but few studies that address the epidemiology of these situations. OBJECTIVE: To evaluate the epidemiological characteristics of care in the emergency department of otorhinolaryngology at a high complexity hospital. METHOD: Epidemiological, cross-sectional study, retrospective with data collection carried out from medical records from the emergency department of otorhinolaryngology of a high complexity hospital in Sao Paulo, for a period of 12 months. DATA COLLECTED: age, gender, clinical diagnosis and management. The cases were divided by subspecialty: otology, rhinology, pharyngolaryngeal-stomatology and head and neck surgery. We evaluated the level of urgency/emergency, etiology and monthly distribution of visits. RESULTS: 17,503 medical records were obtained; 1,863 were excluded. Of the 15,640 cases included, the average age was 36.3 years. 9,818 (62.77%) corresponded to cases considered as emergency/urgency. Among the urgency/emergency cases, 6,422 (65.41%) were diagnosed in the ear and among the 10 most prevalent diagnostics, 7 were in the subspecialty of otology. CONCLUSION: Among the patients seen in the emergency department of otolaryngology evaluated in this study, 62.77% corresponded to cases of urgency/emergency, predominantly in the otology subspecialty. PMID- 23743747 TI - Temporal resolution: assessment procedures and parameters for school-aged children. AB - Temporal resolution enables the identification of fine differences in speech segmental aspects. Random Gap Detection Test (RGDT) and Gaps-In-Noise Test (GIN) evaluate such skills, by using different acoustic parameters. OBJECTIVE: To compare the performance of normal school aged children without learning disabilities and/or hearing complaints in the GIN and RGDT, and analyze potential performance differences in these two procedures. METHOD: Cross sectional contemporary cohort study. 28 children, aged 8-10 years were evaluated. After peripheral audiological evaluation, RGDT and GIN were performed. RESULTS: There were no statistical differences in performance between gender and age on the RGDT and GIN tests, between the right and left ears on the GIN test, and between frequencies on the RGDT test. The mean detection threshold gap for RGDT was 9.25 +/- 3.67 ms, and for GIN was 4.32 +/- 0.61 ms (right ear) and 4.43 +/- 0.79 ms (left ear). The results of the GIN Test were statistically lower than those from the RGDT (p < 0.001). CONCLUSION: Both tests indicated normal temporal resolution for all 28 children. GIN test presents advantages regarding the ease of application, task variable, stimuli and presentations form. However, the RGDT has advantages concerning the time required for administration and scoring. PMID- 23743748 TI - Audiometric evaluation after stapedotomy with Fisch titanium prosthesis. AB - Otosclerosis causes the fixation of the stapes and conductive hearing loss, usually corrected with the use of hearing aids or through stapedotomy and the replacement of the involved stapes with a prosthesis. Titanium has been the most recently used material of choice in stapedotomy prostheses. Only two prostheses are commercially available in Brazil. There are no reports in the literature on the Fisch-type Storz titanium stapes piston prosthesis. OBJECTIVE: This retrospective study aims to look into the auditory outcomes of patients submitted to stapedotomy and titanium stapes piston prosthesis implantation. METHOD: The criteria described by the American Academy of Otolaryngology were used to compare pre and postoperative air-bone gaps seen in audiometry tests. RESULTS: The mean low-frequency postoperative air-bone gap was 12.9 dB; the mean high-frequency air bone gap was 5.2 dB (mean 9.1 dB); median gap was 8.8 dB, with a minimum of 1.3 dB and a maximum of 21.6 dB; standard deviation was 5.7 dB, and p < 0.001. Twenty five (75.8%) patients had air-bone gaps of 10 dB and under; 32 (96.9%) patients had gaps of 20 dB and under; and all patients had gaps of 30 dB and under. CONCLUSION: The Fisch-type titanium stapes piston prosthesis presented outcomes consistent with the literature and can be used safely in stapedotomy procedures. PMID- 23743749 TI - The influence of speech stimuli contrast in cortical auditory evoked potentials. AB - Studies about cortical auditory evoked potentials using the speech stimuli in normal hearing individuals are important for understanding how the complexity of the stimulus influences the characteristics of the cortical potential generated. OBJECTIVE: To characterize the cortical auditory evoked potential and the P3 auditory cognitive potential with the vocalic and consonantal contrast stimuli in normally hearing individuals. METHOD: 31 individuals with no risk for hearing, neurologic and language alterations, in the age range between 7 and 30 years, participated in this study. The cortical auditory evoked potentials and the P3 auditory cognitive one were recorded in the Fz and Cz active channels using consonantal (/ba/-/da/) and vocalic (/i/-/a/) speech contrasts. DESIGN: A crosssectional prospective cohort study. RESULTS: We found a statistically significant difference between the speech contrast used and the latencies of the N2 (p = 0.00) and P3 (p = 0.00) components, as well as between the active channel considered (Fz/Cz) and the P3 latency and amplitude values. These correlations did not occur for the exogenous components N1 and P2. CONCLUSION: The speech stimulus contrast, vocalic or consonantal, must be taken into account in the analysis of the cortical auditory evoked potential, N2 component, and auditory cognitive P3 potential. PMID- 23743750 TI - The effects of hyperbaric oxygen therapy upon ototoxic injuries produced by amikacin in guinea pigs. AB - Hyperbaric oxygen therapy (HBOT) has enhanced the prevention and treatment of auditory ailments such as ototoxicity. OBJECTIVE: To study the effects of HBOT upon ototoxic injuries produced by amikacin. METHOD: This experimental study included 12 albino guinea pigs, whose auditory function was assessed through distortion product otoacoustic emissions (DPOAEs) and brainstem auditory evoked potentials (BAEPs) before and after the administration of amikacin (600 mg/kg/day) and HBOT sessions (2 ATA, 60 minutes). Morphological features were analyzed through scanning electron microscopy. Subjects were divided into four groups, as follows: group 1 - saline solution + HBOT; group 2 - amikacin for 8 days; group 3 - amikacin + seven days of rest; and group 4 - amikacin + HBOT. RESULTS: Group 1 subjects had preserved function and morphology throughout the experiment; Group 2 subjects had statistically significant levels of hair cell injury and functional impairment; Subjects on groups 3 and 4 had statistically significant functional and morphological impairment after the administration of amikacin, which were still present after the proposed procedures had been carried out. CONCLUSION: Hyperbaric oxygen therapy did not change the cochlear hair cell morphology or the electro-physiological thresholds of the guinea pigs given amikacin. PMID- 23743751 TI - Fiberoptic endoscopy evaluation of swallowing in patients with amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a progressive degenerative motor neuron disease that adversely affects the muscles responsible for swallowing. OBJECTIVE: To assess the oral preparatory, oral transit and pharyngeal phases of swallowing in ALS patients through endoscopic evaluation. METHOD: This cross-sectional historical cohort study included ALS patients submitted to endoscopic examination. Eleven patients (six males and five females; mean age of 61.7 years) were enrolled in the study from january to december of 2011. RESULTS: All patients had alterations in phases of the swallowing process, but only 72.7% complained of dysphagia. The oral preparatory phase was altered in 63.6% of the subjects; the oral transit and pharyngeal phases were altered in all studied individuals, regardless of food consistency. Laryngeal penetration or tracheal aspiration were seen in 90.9% of the patients during the pharyngeal phase while they were swallowing fluids. CONCLUSION: Even in the absence of complaints, dysphagia is a frequent comorbidity in ALS patients. The oral transit and pharyngeal phases were the most frequently affected. Laryngeal penetration or tracheal aspiration occurred more frequently during the pharyngeal phase while patients were swallowing fluids. PMID- 23743752 TI - Correlation of three variables describing nasal patency (HD, MCA, NOSE score) in healthy subjects. AB - Rhinoresistometry and acoustic rhinometry are two established apparative methods to objectify the respiratory function of the nose. Both methods use different variables to describe nasal patency: "hydraulic diameter", HD, in rhinoresistometry, and "minimal cross-sectional area", MCA1 (nasal isthmus) and MCA2 (head of the inferior turbinate and cavernous body of the nasal septum), in acoustic rhinometry. OBJECTIVE: This study analyzes the mutual correlation of HD and MCA as a pilot study in patients without nasal pathologies. Additionally, we investigated if these objective variables correlate with the NOSE score, a validated tool to measure subjective perception of nasal patency. METHOD: Planned data collection in a collective of 24 healthy subjects without nasal pathologies. RESULTS: Statistically significant, weak to moderate correlations were found between HD and MCA2 before decongestion. A moderate correlation was found between both HD and MCA2 and the NOSE score on the narrower side. CONCLUSION: In the assessment of nasal patency, it seems advisable to determine HD, MCA1 and MCA2, but also a subjective variable such as the NOSE score, which all seem to be not fully redundant variables. In further studies, the correlation of the variables should be assessed in patients with nasal pathologies. PMID- 23743753 TI - Amplification by bone conduction in congenital malformations: patient benefits and satisfaction. AB - Hearing loss is one of the most common clinical findings in subjects with malformations of the ear. Treatment consists of surgery and/or adapt a hearing aid amplification by bone (HA VO). Early intervention is critical to auditory stimulation and development of speech and language. OBJECTIVE: To characterize the audiological profile of subjects with congenital malformation of the external ear and/or middle and evaluate the benefit and satisfaction of using HA VO. METHOD: A descriptive study, subjects with bilateral congenital malformations of the external ear and/or middle, conductive or mixed hearing loss, moderate or severe and HA VO users. Evaluation of the benefit test using sentence recognition in noise and measures of functional gain and satisfaction assessment questionnaire using international IQ - HA. RESULTS: 13 subjects were evaluated, 61% were male and 80% with moderate conductive hearing loss or severe. There was better performance in the evaluation proposal, provided with HA when compared to the condition without HA. CONCLUSION: HA VO showed advantages for the population studied and should be considered as an option for intervention. Satisfaction was confirmed by elevated scores obtained in IQ - HA. PMID- 23743754 TI - Vestibular rehabilitation with virtual reality in Meniere's disease. AB - Virtual reality technology can provide a wide range of sensory stimuli to generate conflicts of varying degrees of complexity in a safe environment. OBJECTIVE: To verify the effect of a virtual realitybased balance rehabilitation program for patients with Meniere's disease. METHOD: This observational clinical study included 44 patients aged between 18 and 60 years diagnosed with Meniere's disease submitted to a controlled randomized therapeutic intervention. The case and control groups took betahistine and followed a diet. Case group subjects underwent 12 rehabilitation sessions with virtual reality stimuli in a Balance Rehabilitation Unit (BRU TM). Patients were assessed based on DHI scores, the dizziness visual analogue scale, and underwent posturography with virtual reality before and after the intervention. RESULTS: After the intervention, the case group showed significantly lower scores in DHI (p < 0,001) and in the dizziness visual analog scale (p = 0.012), and had significantly greater limit of stability areas (p = 0.016) than controls. CONCLUSION: Virtual reality-based balance rehabilitation effectively improved dizziness, quality of life, and limit of stability of patients with Meniere's disease. PMID- 23743755 TI - Human papillomavirus types in cases of squamous cell carcinoma of head and neck in Colombia. AB - Estimating the type-specific prevalence of human papillomavirus (HPV) in head and neck cancer (HNSCC) is helpful in predicting the impact of HPV immunization. OBJECTIVE: To estimate the overall prevalence, and gender and age-specific prevalence of HPV in HNSCC. METHOD: This cross sectional retrospective study was carried out in four pathology laboratories of Medellin, Colombia. HPV testing was performed by GP5+/6+ PCR-based RLB and HPV 16 and 18 type-specific PCR. RESULTS: 175 primary HNSCC cases consecutively diagnosed between 1999 and 2008 with confirmed diagnosis and amplifiable DNA were included. Overall HPV prevalence was 18.9%. HPV was found in 23.9%, 17.5% and 13.3% of the oral cavity, larynx and oropharynx cases respectively. Among HPV positive cases, 82% were HPV 16 and 18% were HPV 18. No other HPV genotypes were identified. Most patients were males. Male patients were younger that their female counterparts, particularly in oral cavity cancer cases. CONCLUSION: HPV 16 and 18 genotypes were found in nearly 20% of HNSCC cases in Colombian patients. The impact of HPV vaccination for the prevention of HNSCC in this population deserves further evaluation. PMID- 23743756 TI - Measures of quality of life in children with cochlear implant: systematic review. AB - The use of cochlear implant (CI) in children enables the development of listening and communication skills, allowing the child's progress in school and to be able to obtain, maintain and carry out an occupation. However, the progress after the CI has different results in some children, because many children are able to interact and participate in society, while others develop limited ability to communicate verbally. The need for a better understanding of CI outcomes, besides hearing and language benefits, has spurred the inclusion of quality of life measurements (QOL) to assess the impact of this technology. OBJECTIVE: Identify the key aspects of quality of life assessed in children with cochlear implant. METHOD: Through a systematic literature review, we considered publications from the period of 2000 to 2011. CONCLUSION: We concluded that QOL measurements in children include several concepts and methodologies. When referring to children using CI, results showed the challenges in broadly conceptualizing which quality of life domains are important to the child and how these areas can evolve during development, considering the wide variety of instruments and aspects evaluated. PMID- 23743757 TI - Brazilian Academy of Rhinology position paper on topical intranasal therapy. AB - This documents aims at educating those who treat sinonasal diseases - both general practitioners and specialists - about topical nasal treatments. By means of scientific evidence reviews, the Brazilian Academy of Rhinology provides its practical and updated guidelines on the most utilized topical nasal medication, except for the drugs that have topical antibiotics in their formulas. PMID- 23743758 TI - Fifteen years of hoarseness--case report of a rare laryngeal schwannoma. PMID- 23743759 TI - A pedunculated lymphangiomatous polyp of the palatine tonsil: a case report. PMID- 23743760 TI - Schwannoma of the nasal septum: evaluation of unilateral nasal mass. PMID- 23743761 TI - Sialadenoma papilliferum of the tongue mimicking a malignant tumor. PMID- 23743762 TI - Estradiol inhibits osteoblast apoptosis via promotion of autophagy through the ER ERK-mTOR pathway. AB - Estradiol could protect osteoblast against apoptosis, and apoptosis and autophagy were extensively and intimately connected. The aim of the present study was to test the hypothesis that autophagy was present in osteoblasts under serum deprivation and estrogen protected against osteoblast apoptosis via promotion of autophagy. MC3T3-E1 osteoblastic cells were cultured in a serum-free and phenol red-free minimal essential medium (alpha-MEM). Ultrastructural analysis, lysosomal activity assessment and monodansycadaverine (MDC) staining were employed to determine the presence of autophagy, and real time PCR was used to evaluate the expression of autophagic markers. Meanwhile, the osteoblasts were transferred in a serum-free and phenol red-free alpha-MEM containing either vehicle or estradiol. Apoptosis and autophagy was assessed by using the techniques of real-time PCR, Western blot, immunofluorescence assay, and flow cytometry. The possible pathway through which estrogen promoted autophagy in the serum-deprived osteoblasts was also investigated. Real-time PCR demonstrated the expression of LC3, beclin1 and ULK1 genes in osteoblasts under serum deprivation, and immunofluorescence assay verified high expression of proteins of these three autophagic bio-markers. Lysosomes and autolysosomes accumulated in the cytoplasm of osteoblasts were also detected under transmission electron microscopy, MDC staining and lysosomal activity assessment. Meanwhile, estradiol significantly decreased the expression of proteins of the bio-markers of apoptosis, and at the same time increased the expression of proteins of the bio-markers of autophagy in the serum-deprived osteoblasts. Furthermore, the estradiol-promoted autophagy in serum-deprived osteoblasts could be blocked by estrogen receptor (ER) antagonist (ICI 182780), and estradiol failed to rescue the cells pretreated with an inhibitor of vacuolar ATPase (bafilomycin A) from apoptosis. Serum deprivation resulted in apoptosis through activation of Caspase-3 and induced autophagy through inhibition of phospho-mammalian target of rapamycin (p-mTOR). Both 3 methyladenine (3MA) and U0126 led to increase of apoptosis in osteoblasts with serum deprivation. Estradiol failed to over-ride the inhibitory effect of 3MA on phosphorylation of AKT but directly led to dephosphorylation of mTOR and upregulation of LC3 protein expression. However, the estradiol-enhanced LC3 protein expression was significantly suppressed by U0126 through inhibition of phosphorylation of extracellular signal-regulated kinase (ERK). Estradiol rescued osteoblast apoptosis via promotion of autophagy through the ER-ERK-mTOR pathway. PMID- 23743763 TI - Familial acromegaly due to aryl hydrocarbon receptor-interacting protein (AIP) gene mutation in a Turkish cohort. AB - Aryl hydrocarbon receptor-interacting protein (AIP) is associated with 15-20% of familial isolated pituitary adenomas and 50-80% of cases with AIP mutation exhibit a somatotropinoma. Herein we report clinical characteristics of a large family where AIP R304X variants have been identified. AIP mutation analysis was performed on a large (n = 52) Turkish family across six generations. Sella MRIs of 30 family members were obtained. Basal pituitary hormone levels were evaluated in 13 family members harboring an AIP mutation. Thirteen of 52 family members (25%) were found to have a heterozygous nonsense germline R304X mutation in the AIP gene. Seven of the 13 mutation carriers (53.8%) had current or previous history of pituitary adenoma. Of these 7 mutation carriers, all but one had somatotropinoma/somatolactotropinoma (85.7% of the pituitary adenomas). Of the 6 acromegaly patients with AIP mutation (F/M: 3/3) the mean age at diagnosis of acromegaly was 32 +/- 10.3 years while the mean age of symptom onset was 24.8 +/- 9.9 years. Three of the six (50%) acromegaly cases with AIP mutation within the family presented with a macroadenoma and none presented with gigantism. Biochemical disease control was achieved in 66.6% (4/6) of the mutation carriers with acromegaly after a mean follow-up period of 18.6 +/- 17.6 years. Common phenotypic characteristics of familial pituitary adenoma or somatotropinoma due to AIP mutation vary between families or even between individuals within a family. PMID- 23743764 TI - Protein O glycosylation regulates activation of hepatic stellate cells. AB - It was reported that O glycosylation is associated with hepatic stellate cell activation and regulates collagen expression. In this study, we aimed to investigate the effect of O glycosylation on the activation of human hepatic stellate cells. We found that the inhibitor of O glycosylation, benzyl-alpha GalNAc (2 and 4 mM), could significantly inhibit cells proliferation in a dose dependent manner. Moreover, benzyl-alpha-GalNAc decreased the expressions of alpha-smooth muscle actin, collagen I, and collagen III. The results indicate that O glycosylation is involved in the activation of hepatic stellate cells. PMID- 23743765 TI - Idiopathic late-onset cerebellar ataxia with cerebellar atrophy in a patient diagnosed with Chiari I malformation: a case report. PMID- 23743766 TI - The importance of neurophysiological assessment in posterior reversible encephalopathy syndrome: a case report of an eclamptic woman. PMID- 23743768 TI - Using microRNA as an alternative treatment for hyperlipidemia and cardiovascular disease: cardio-miRs in the pipeline. AB - It is now appreciated that over 90% of the human genome is comprised of noncoding RNAs that have the ability to affect other components of the genome and regulate gene expression. This has galvanized the development of RNA-based therapeutics for a myriad of diseases, including cancer, inflammatory conditions, and cardiovascular disease. Several classes of RNA therapeutics are currently under clinical development, including antisense oligonucleotides, small interfering RNA, and microRNA mimetics and inhibitors. The field of antisense technology saw a huge leap forward with the recent Food and Drug Administration approval of the first antisense therapy, directed against apolipoprotein B, for the treatment of familial hypercholesterolemia. In addition, recent progress in the development of approaches to inhibit microRNAs has helped to illuminate their roles in repressing gene networks and also revealed their potential as therapeutic targets. In this review, these exciting opportunities in the field of drug discovery, with a focus on emerging therapeutics in the field of cardiovascular disease, are summarized. PMID- 23743770 TI - Integrating biological vasculature into a multi-organ-chip microsystem. AB - A chip-based system mimicking the transport function of the human cardiovascular system has been established at minute but standardized microsystem scale. A peristaltic on-chip micropump generates pulsatile shear stress in a widely adjustable physiological range within a microchannel circuit entirely covered on all fluid contact surfaces with human dermal microvascular endothelial cells. This microvascular transport system can be reproducibly established within four days, independently of the individual endothelial cell donor background. It interconnects two standard tissue culture compartments, each of 5 mm diameter, through microfluidic channels of 500 MUm width. Further vessel branching and vessel diameter reduction down to a microvessel scale of approximately 40 MUm width was realised by a two-photon laser ablation technique applied to inserts, designed for the convenient establishment of individual organ equivalents in the tissue culture compartments at a later time. The chip layout ensures physiological fluid-to-tissue ratios. Moreover, an in-depth microscopic analysis revealed the fine-tuned adjustment of endothelial cell behaviour to local shear stresses along the microvasculature of the system. Time-lapse and 3D imaging two photon microscopy were used to visualise details of spatiotemporal adherence of the endothelial cells to the channel system and to each other. The first indicative long-term experiments revealed stable performance over two and four weeks. The potential application of this system for the future establishment of human-on-a-chip systems and basic human endothelial cell research is discussed. PMID- 23743769 TI - Cabergoline use and risk of fibrosis and insufficiency of cardiac valves. Meta analysis of observational studies. AB - BACKGROUND: Therapy with ergot-derivative dopamine agonists (ergot-DAs) is suspected to cause or promote the development of insufficiency and regurgitation in previously normal cardiac valves. Thus, we conducted a systematic review and meta-analysis of the literature to determine whether administration of cabergoline, i.e., an ergot-DA used to treat Parkinson's disease (PD) or hyperprolactinemia, is associated with an increased risk of valve regurgitation compared with pharmacological regimens not comprising ergot-DAs or with no therapy. METHODS: Observational studies were selected from the Pubmed and Embase databases. Studies had to have assessed the prevalence, odds, or risk of cardiac valve regurgitation in patients who underwent chronic treatment with cabergoline for PD or hyperprolactinemia compared with patients with the same diseases whose therapy did not include cabergoline or another ergot-DA. Separate meta-analyses were performed for PD and hyperprolactinemia patients. RESULTS: On the basis of five studies, 634 PD patients were taking cabergoline, while 9,120 PD patients were treated with dopa/dopamine decarboxylase inhibitor, alone or associated with a non-ergot DA. Valvular regurgitation of any degree - at one cardiac valve or more - was more frequent in PD patients who were taking cabergoline compared to those treated with a non-ergot DA agent or not treated with any dopamine agonist [adjusted (inverse variance: iv) odds ratio: 7.25 95 % CI: 3.71-14.18; p < 0.0001]. On the other hand, pooled data from seven studies showed that patients with hyperprolactinemia who were taking cabergoline (n = 444) exhibited significantly higher odds of mild- to-moderate tricuspid regurgitation compared to untreated controls (n = 954) [adjusted (iv) odds ratio: 1.92 95 % CI:1.34 2.73; p = 0.0003]. No significant differences in mitral or aortic valve regurgitation were detected between hyperprolactinemic patients taking cabergoline and controls. CONCLUSION: In PD patients, the risk of valvular regurgitation of any grade involving one or more cardiac valves was proven to be strongly associated with cabergoline treatment. Furthermore, based on our results, hyperprolactinemic patients taking cabergoline have an increased risk of mild-to-moderate tricuspid valve regurgitation. PMID- 23743771 TI - SparCLeS: dynamic l1 sparse classifiers with level sets for robust beard/moustache detection and segmentation. AB - Robust facial hair detection and segmentation is a highly valued soft biometric attribute for carrying out forensic facial analysis. In this paper, we propose a novel and fully automatic system, called SparCLeS, for beard/moustache detection and segmentation in challenging facial images. SparCLeS uses the multiscale self quotient (MSQ) algorithm to preprocess facial images and deal with illumination variation. Histogram of oriented gradients (HOG) features are extracted from the preprocessed images and a dynamic sparse classifier is built using these features to classify a facial region as either containing skin or facial hair. A level set based approach, which makes use of the advantages of both global and local information, is then used to segment the regions of a face containing facial hair. Experimental results demonstrate the effectiveness of our proposed system in detecting and segmenting facial hair regions in images drawn from three databases, i.e., the NIST Multiple Biometric Grand Challenge (MBGC) still face database, the NIST Color Facial Recognition Technology FERET database, and the Labeled Faces in the Wild (LFW) database. PMID- 23743767 TI - Why targeting HDL should work as a therapeutic tool, but has not. AB - Atherosclerosis is one of the most common causes of death and disability in the United States today despite the availability of statins, which reduce hyperlipidemia, a risk factor that predisposes individuals to this disease. Epidemiology of human populations has overwhelmingly demonstrated an inverse correlation between the concentration of plasma high-density lipoprotein (HDL) cholesterol (HDL-C) and the likelihood of developing cardiovascular disease (CVD). Decades of observations and mechanistic studies suggest that one protective function of HDL is its central role in reverse cholesterol transport. In this pathway, the ATP-binding cassette transporter A1 releases intracellular cholesterol, which is packaged with apolipoprotein A-I (apoA-I) into nascent HDL particles and released from the plasma membrane. Further lipidation and maturation of HDL occur in plasma with the eventual uptake by the liver where cholesterol is removed. It is generally accepted that CVD risk can be reduced if plasma HDL-C levels are elevated. Several different pharmacological approaches have been tried; the most popular approach targets the movement of cholesteryl ester from HDL to triglyceride-rich particles by cholesteryl ester transfer protein. Inhibition of cholesteryl ester transfer protein increases plasma HDL-C concentration; however, beneficial effects have yet to be demonstrated, likely the result of off-target effects. These revelations have led to a reevaluation of how elevating HDL concentration could decrease risk. A recent, landmark study showed that the inherent cholesterol efflux capacity of an individual's plasma was a better predictor of CVD status than overall HDL-C concentration. Even more provocative are recent studies showing that apoA-I, the principle protein component of HDL modulates cellular inflammation and oxidation. The following will review all these potential routes explaining how HDL apoA-I can reduce the risk of CVD. PMID- 23743772 TI - Cross-domain object recognition via input-output kernel analysis. AB - It is of great importance to investigate the domain adaptation problem of image object recognition, because now image data is available from a variety of source domains. To understand the changes in data distributions across domains, we study both the input and output kernel spaces for cross-domain learning situations, where most labeled training images are from a source domain and testing images are from a different target domain. To address the feature distribution change issue in the reproducing kernel Hilbert space induced by vector-valued functions, we propose a domain adaptive input-output kernel learning (DA-IOKL) algorithm, which simultaneously learns both the input and output kernels with a discriminative vector-valued decision function by reducing the data mismatch and minimizing the structural error. We also extend the proposed method to the cases of having multiple source domains. We examine two cross-domain object recognition benchmark data sets, and the proposed method consistently outperforms the state of-the-art domain adaptation and multiple kernel learning methods. PMID- 23743773 TI - Regularized feature reconstruction for spatio-temporal saliency detection. AB - Multimedia applications such as image or video retrieval, copy detection, and so forth can benefit from saliency detection, which is essentially a method to identify areas in images and videos that capture the attention of the human visual system. In this paper, we propose a new spatio-temporal saliency detection framework on the basis of regularized feature reconstruction. Specifically, for video saliency detection, both the temporal and spatial saliency detection are considered. For temporal saliency, we model the movement of the target patch as a reconstruction process using the patches in neighboring frames. A Laplacian smoothing term is introduced to model the coherent motion trajectories. With psychological findings that abrupt stimulus could cause a rapid and involuntary deployment of attention, our temporal model combines the reconstruction error, regularizer, and local trajectory contrast to measure the temporal saliency. For spatial saliency, a similar sparse reconstruction process is adopted to capture the regions with high center-surround contrast. Finally, the temporal saliency and spatial saliency are combined together to favor salient regions with high confidence for video saliency detection. We also apply the spatial saliency part of the spatio-temporal model to image saliency detection. Experimental results on a human fixation video dataset and an image saliency detection dataset show that our method achieves the best performance over several state-of-the-art approaches. PMID- 23743774 TI - Gaussian blurring-invariant comparison of signals and images. AB - We present a Riemannian framework for analyzing signals and images in a manner that is invariant to their level of blurriness, under Gaussian blurring. Using a well known relation between Gaussian blurring and the heat equation, we establish an action of the blurring group on image space and define an orthogonal section of this action to represent and compare images at the same blur level. This comparison is based on geodesic distances on the section manifold which, in turn, are computed using a path-straightening algorithm. The actual implementations use coefficients of images under a truncated orthonormal basis and the blurring action corresponds to exponential decays of these coefficients. We demonstrate this framework using a number of experimental results, involving 1D signals and 2D images. As a specific application, we study the effect of blurring on the recognition performance when 2D facial images are used for recognizing people. PMID- 23743775 TI - Fast SIFT design for real-time visual feature extraction. AB - Visual feature extraction with scale invariant feature transform (SIFT) is widely used for object recognition. However, its real-time implementation suffers from long latency, heavy computation, and high memory storage because of its frame level computation with iterated Gaussian blur operations. Thus, this paper proposes a layer parallel SIFT (LPSIFT) with integral image, and its parallel hardware design with an on-the-fly feature extraction flow for real-time application needs. Compared with the original SIFT algorithm, the proposed approach reduces the computational amount by 90% and memory usage by 95%. The final implementation uses 580-K gate count with 90-nm CMOS technology, and offers 6000 feature points/frame for VGA images at 30 frames/s and ~ 2000 feature points/frame for 1920 * 1080 images at 30 frames/s at the clock rate of 100 MHz. PMID- 23743776 TI - Corner detection and classification using anisotropic directional derivative representations. AB - This paper proposes a corner detector and classifier using anisotropic directional derivative (ANDD) representations. The ANDD representation at a pixel is a function of the oriented angle and characterizes the local directional grayscale variation around the pixel. The proposed corner detector fuses the ideas of the contour- and intensity-based detection. It consists of three cascaded blocks. First, the edge map of an image is obtained by the Canny detector and from which contours are extracted and patched. Next, the ANDD representation at each pixel on contours is calculated and normalized by its maximal magnitude. The area surrounded by the normalized ANDD representation forms a new corner measure. Finally, the nonmaximum suppression and thresholding are operated on each contour to find corners in terms of the corner measure. Moreover, a corner classifier based on the peak number of the ANDD representation is given. Experiments are made to evaluate the proposed detector and classifier. The proposed detector is competitive with the two recent state-of-the-art corner detectors, the He & Yung detector and CPDA detector, in detection capability and attains higher repeatability under affine transforms. The proposed classifier can discriminate effectively simple corners, Y-type corners, and higher order corners. PMID- 23743777 TI - Classification of time series of multispectral images with limited training data. AB - Image classification usually requires the availability of reliable reference data collected for the considered image to train supervised classifiers. Unfortunately when time series of images are considered, this is seldom possible because of the costs associated with reference data collection. In most of the applications it is realistic to have reference data available for one or few images of a time series acquired on the area of interest. In this paper, we present a novel system for automatically classifying image time series that takes advantage of image(s) with an associated reference information (i.e., the source domain) to classify image(s) for which reference information is not available (i.e., the target domain). The proposed system exploits the already available knowledge on the source domain and, when possible, integrates it with a minimum amount of new labeled data for the target domain. In addition, it is able to handle possible significant differences between statistical distributions of the source and target domains. Here, the method is presented in the context of classification of remote sensing image time series, where ground reference data collection is a highly critical and demanding task. Experimental results show the effectiveness of the proposed technique. The method can work on multimodal (e.g., multispectral) images. PMID- 23743778 TI - Association between spironolactone added to beta-blockers and ACE inhibition and survival in heart failure patients with reduced ejection fraction: a propensity score-matched cohort study. AB - PURPOSE: Heart failure (CHF) guidelines recommend mineralocorticoid receptor antagonists for all symptomatic patients treated with a combination of ACE inhibitors/angiotensin receptor blockers (ARBs) and beta-blockers. As opposed to both eplerenone trials, patients in RALES (spironolactone) received almost no beta-blockers. Since pharmacological properties differ between eplerenone and spironolactone, the prognostic benefit of spironolactone added to this baseline combination therapy needs clarification. METHODS: We included 4,832 CHF patients with chronic systolic dysfunction from the Norwegian Heart Failure Registry and the heart failure outpatients' clinic of the University of Heidelberg. Propensity scores for spironolactone receipt were calculated for each patient and used for matching to patients without spironolactone. RESULTS: During a total follow-up of 17,869 patient-years, 881 patients (27.0 %) died in the non-spironolactone group and 445 (28.4 %) in the spironolactone group. Spironolactone was not associated with improved survival, neither in the complete sample (HR 0.82; 95 % CI 0.64 1.07; HR 1.03; 95 % CI 0.88-1.20; multivariate and propensity score adjusted respectively), nor in the propensity-matched cohort (HR 0.98; 95 % CI 0.82-1.18). CONCLUSION: In CHF outpatients we were unable to observe an association between the use of spironolactone and improved survival when administered in addition to a combination of ACE/ARB and beta-blockers. PMID- 23743779 TI - Survey of users of TOPS, an internet-based system to prevent healthy subjects from over-volunteering for clinical trials. AB - OBJECTIVE: To analyse users' experience of TOPS, an internet-based system that helps UK clinical research units to prevent healthy volunteers from participating in more than one non-therapeutic trial simultaneously, or starting a second trial too soon after the first. METHODS: We sent to all units that currently use TOPS an anonymous questionnaire comprising 18 questions about the effectiveness and ease of use of the system. RESULTS: Of 35 units that currently use TOPS, 31 (85.7 %) returned questionnaires. Most users find TOPS easy to use, had increased their detection rate of over-volunteering, and had rejected subjects as a result of using TOPS. A GP reply alone is not enough to prevent over-volunteering. Ethics committees, the MHRA and sponsors know about TOPS and support its use. CONCLUSIONS: The results confirm that TOPS does prevent healthy subjects from over-volunteering. Consequently, the Health Research Authority has agreed to take over the management of TOPS. Ethics committee approval of a phase 1 trial and MHRA accreditation of the unit will henceforth be conditional on consistent and proper use of TOPS. That should enhance its effectiveness and improve the safety of volunteers in non-therapeutic trials in the UK. PMID- 23743780 TI - Compliance with quality prescribing indicators in terms of their relationship to financial incentives. AB - OBJECTIVE: To develop quality prescribing indicators for general practitioners (GPs) who are non-monitored and not included in pay-for-performance programs, and to determine compliance with incentivized and non-incentivized indicators. STUDY DESIGN: Descriptive cross sectional study. SETTING: Aljarafe Primary Health Care Area (Andalusian Public Health Care Service, Spain), a rural and suburban area with a population of 323,857 inhabitants. Health assistance in this area is provided by 176 GPs in 37 health centers. Prescribing indicators were developed by a multidisciplinary group using a qualitative technique based on consensus. The members of the consensus group searched for updated recommendations focused on clinical evidence. Prescribing data were obtained from the computerised pharmacy records of reimbursed drugs and clinical data from the electronic clinical databases and hospital admission records. RESULTS: Fourteen indicators based on the selection of drugs of different therapeutic groups or linked to patient's clinical information were designed. The compliance with indicators based on the selection of drugs linked to financial incentives was higher than that of indicators not linked to financial incentives. The compliance with indicators based on clinical information varied widely. Inappropriate prescribing ranged from 7 %, in the use of long-acting beta-agonists in asthma, to 86 % in the use of drugs for the prevention of osteoporotic fractures in young women. CONCLUSIONS: This study shows better compliance by GPs with indirect and incentivized quality prescribing indicators, included in pay-for-performance programs, compared with not-incentivized indicators based on the relative use of drugs and on the appropriateness prescribing. PMID- 23743781 TI - Meta-analyses of dose-exposure relationships for gabapentin following oral administration of gabapentin and gabapentin enacarbil. AB - BACKGROUND: Gabapentin exposure following administration of certain doses of gabapentin or its pro-drug gabapentin enacarbil has been previously reported in the literature, with variable results. METHODS: Meta-analyses of dose-exposure relationships were conducted to maximise precision and minimise bias. Study-level mean data for gabapentin systemic exposure, in terms of bioavailable dose and steady-state average plasma concentration, were modelled as a function of daily dose. Several linear and non-linear candidate models were tested. RESULTS: An Emax model best described the dose-exposure relationships for gabapentin. The ED50 was 3,080 mg/day for bioavailable dose or 3,370 mg/day for steady-state concentration; and the maximum exposure was 2,340 mg/day or 16.9 mg/L. For gabapentin enacarbil, a power model was most suitable, with a power of 0.925 for bioavailable dose or 0.844 for steady-state concentration. All parameters were estimated with < 20 % standard error. Simulations confirmed that these models accurately reflected the distribution of the respective data, and bootstrapping showed high precision for the estimated dose-exposure curves. CONCLUSION: The meta-analyses addressed issues associated with between-study variability; and confirmed the highly non-linear nature of dose-exposure relationships for gabapentin and the essentially linear relationships for gabapentin enacarbil. The resulting models could be used to simulate exposure at any clinically relevant dose and bridge therapeutic dose range between the two drugs. PMID- 23743782 TI - Association between neurotensin receptor 1 gene polymorphisms and alcohol dependence in a male Han Chinese population. AB - Neurotensin (NT) is a 13-amino acid multifunctional neuropeptide. Previous studies have demonstrated the roles of NT and its high-affinity receptor 1 (NTR1) in genetically mediated differential sensitivities to alcohol. However, no studies have investigated the association between NTR1 gene single-nucleotide polymorphisms (SNPs) and alcohol dependence (AD). We therefore examined this link. We genotyped three SNPs (rs6090453C/G, rs6011914C/G, and rs2427422A/G) of NTR1 gene in 127 AD patients and 131 healthy controls drawn from Han Chinese males. Allele and genotype frequencies were compared, and linkage disequilibrium and haplotype analysis were performed. For rs6011914C/G, the frequencies of GG genotypes in AD patients showed an increased trend compared with controls (p = 0.057), and the ratio of GG/(CG + CC) for dominant model in AD patients was significantly higher (p = 0.024). For rs2427422A/G, both the frequencies of G alleles and GG genotypes and the ratio of GG/(AG + AA) for dominant model in AD patients were significantly higher compared with controls (p = 0.003, 0.006, 0.002, respectively). There was no significant difference in the frequencies of alleles, genotypes, and dominant or recessive model for rs6090453C/G (all p > 0.05). There were three pairs of SNP linkage disequilibriums, and the haplotype frequencies differed significantly between patients and controls for the CCA (p = 0.005, less frequent in the patients) and CCG (p = 0.002, more frequent in the patients) haplotypes. The current study supported an association between NTR1 gene variants and AD in the Han Chinese population. PMID- 23743783 TI - Mitchell's osteotomy for hallux valgus: comment on Kalender AM, et al. Mitchell's osteotomy with mini-plate and screw fixation for hallux valgus. PMID- 23743784 TI - Response. PMID- 23743785 TI - Comment on "postoperative second metatarsal fractures associated with suture button implant in hallux valgus surgery". PMID- 23743786 TI - Response. PMID- 23743789 TI - Safety of antiretroviral drugs in pregnancy and breastfeeding for mother and child. AB - PURPOSE OF REVIEW: The introduction of combination ART to prevent mother-to-child transmission (MTCT) has substantially decreased MTCT rates. However, there are concerns regarding safety of ART exposure for the mother, pregnancy outcome and infant. Changing MTCT prevention guidelines, with expanded eligibility, have led to a rapid increase of ART-treated women and exposed infants in high prevalence regions. RECENT FINDINGS: Recent studies confirm that ART in HIV-infected mothers decreases disease progression and mortality, also after delivery. However extended duration of ART, especially HAART, during pregnancy has also been associated with premature delivery, small-for-gestational age (SGA) infants and pregnancy complications including hypertension. In the uninfected infant, ART exposure was associated with levels of hematologic and immunological markers, which, in high microbial regions, may be clinically relevant, especially in combination with premature birth and SGA. Altered mitochondrial functioning is reported in ART-exposed children although clinical implications remain difficult to discern. SUMMARY: The benefit of ART in the prevention of MTCT is beyond doubt, but there are reports on adverse effects on pregnancy outcome and infant currently also from high prevalence regions. Further research regarding safety is urgently required, as the number of pregnant women on ART and exposed uninfected infants is rapidly increasing. PMID- 23743788 TI - What is needed to eliminate new pediatric HIV infections: the contribution of model-based analyses. AB - PURPOSE OF REVIEW: Computer simulation models can identify key clinical, operational, and economic interventions that will be needed to achieve the elimination of new pediatric HIV infections. In this review, we summarize recent findings from model-based analyses of strategies for prevention of mother-to child HIV transmission (MTCT). RECENT FINDINGS: In order to achieve elimination of MTCT (eMTCT), model-based studies suggest that scale-up of services will be needed in several domains: uptake of services and retention in care (the PMTCT 'cascade'), interventions to prevent HIV infections in women and reduce unintended pregnancies (the 'four-pronged approach'), efforts to support medication adherence through long periods of pregnancy and breastfeeding, and strategies to make breastfeeding safer and/or shorter. Models also project the economic resources that will be needed to achieve these goals in the most efficient ways to allocate limited resources for eMTCT. Results suggest that currently recommended PMTCT regimens (WHO Option A, Option B, and Option B+) will be cost-effective in most settings. SUMMARY: Model-based results can guide future implementation science, by highlighting areas in which additional data are needed to make informed decisions and by outlining critical interventions that will be necessary in order to eliminate new pediatric HIV infections. PMID- 23743790 TI - The role of family planning in elimination of new pediatric HIV infection. AB - PURPOSE OF REVIEW: We reviewed recent literature on the role of family planning in eliminating new pediatric HIV infections. RECENT FINDINGS: Global commitments to eliminate new pediatric HIV infections recognize that preventing unintended pregnancies among women with HIV is essential to achieving this goal. However, substantial shortcomings exist in translating this policy support into widespread practice. Programs to prevent mother-to-child transmission of HIV continue to be implemented and evaluated as a narrow set of interventions that typically begins in antenatal care, after a woman is already pregnant. In addition, data suggest that women living with HIV experience high rates of unmet need for family planning and unintended pregnancies. Evidence is growing that integrating family planning and HIV services is an effective strategy for increasing access to contraception among women with HIV who do not wish to become pregnant. A number of health system obstacles must be resolved to achieve effective, sustained delivery of integrated services at scale. SUMMARY: Prevention of unintended pregnancies among women with HIV must be elevated as a programmatic priority. By strengthening family planning programs for all women, and better integrating family planning and HIV services, progress toward ending new pediatric HIV infections will be accelerated. PMID- 23743792 TI - Role of intensive training in the growth and maturation of artistic gymnasts. AB - Short stature and later maturation of youth artistic gymnasts are often attributed to the effects of intensive training from a young age. Given limitations of available data, inadequate specification of training, failure to consider other factors affecting growth and maturation, and failure to address epidemiological criteria for causality, it has not been possible thus far to establish cause-effect relationships between training and the growth and maturation of young artistic gymnasts. In response to this ongoing debate, the Scientific Commission of the International Gymnastics Federation (FIG) convened a committee to review the current literature and address four questions: (1) Is there a negative effect of training on attained adult stature? (2) Is there a negative effect of training on growth of body segments? (3) Does training attenuate pubertal growth and maturation, specifically, the rate of growth and/or the timing and tempo of maturation? (4) Does training negatively influence the endocrine system, specifically hormones related to growth and pubertal maturation? The basic information for the review was derived from the active involvement of committee members in research on normal variation and clinical aspects of growth and maturation, and on the growth and maturation of artistic gymnasts and other youth athletes. The committee was thus thoroughly familiar with the literature on growth and maturation in general and of gymnasts and young athletes. Relevant data were more available for females than males. Youth who persisted in the sport were a highly select sample, who tended to be shorter for chronological age but who had appropriate weight-for-height. Data for secondary sex characteristics, skeletal age and age at peak height velocity indicated later maturation, but the maturity status of gymnasts overlapped the normal range of variability observed in the general population. Gymnasts as a group demonstrated a pattern of growth and maturation similar to that observed among short-, normal , late-maturing individuals who were not athletes. Evidence for endocrine changes in gymnasts was inadequate for inferences relative to potential training effects. Allowing for noted limitations, the following conclusions were deemed acceptable: (1) Adult height or near adult height of female and male artistic gymnasts is not compromised by intensive gymnastics training. (2) Gymnastics training does not appear to attenuate growth of upper (sitting height) or lower (legs) body segment lengths. (3) Gymnastics training does not appear to attenuate pubertal growth and maturation, neither rate of growth nor the timing and tempo of the growth spurt. (4) Available data are inadequate to address the issue of intensive gymnastics training and alterations within the endocrine system. PMID- 23743794 TI - Influence of maternal and child lifestyle-related characteristics on the socioeconomic inequality in overweight and obesity among 5-year-old children; the "Be Active, Eat Right" Study. AB - It is unclear whether the socioeconomic inequality in prevalence of overweight and obesity is already present among very young children. This study investigates the association between overweight and socioeconomic status (SES, with maternal educational level as an indicator of SES) among 5-year-old children. This cross sectional study uses baseline data from 5-year-olds of Dutch ethnicity (n = 5,582) and their mothers collected for the "Be active, eat right" study. Compared to children of mothers with the highest educational level, for children of mothers with the lowest educational level the odds ratio (adjusted for demographic characteristics) for having overweight was 2.10 (95% confidence interval: 1.57-2.82), and for having obesity was 4.18 (95% confidence interval: 2.32-7.55). Addition of maternal and child lifestyle-related characteristics decreased the odds ratios for overweight and obesity by 26.4% and 42.1%, respectively. The results show that an inverse SES-overweight/obesity association is already present at elementary school entry, and that watching TV by mother and child, the child consuming breakfast and, especially maternal weight status, are contributing factors in this association. These results should be taken into account when developing policies to reduce inequalities in (childhood) health. PMID- 23743793 TI - Water immersion recovery for athletes: effect on exercise performance and practical recommendations. AB - Water immersion is increasingly being used by elite athletes seeking to minimize fatigue and accelerate post-exercise recovery. Accelerated short-term (hours to days) recovery may improve competition performance, allow greater training loads or enhance the effect of a given training load. However, the optimal water immersion protocols to assist short-term recovery of performance still remain unclear. This article will review the water immersion recovery protocols investigated in the literature, their effects on performance recovery, briefly outline the potential mechanisms involved and provide practical recommendations for their use by athletes. For the purposes of this review, water immersion has been divided into four techniques according to water temperature: cold water immersion (CWI; <=20 degrees C), hot water immersion (HWI; >=36 degrees C), contrast water therapy (CWT; alternating CWI and HWI) and thermoneutral water immersion (TWI; >20 to <36 degrees C). Numerous articles have reported that CWI can enhance recovery of performance in a variety of sports, with immersion in 10 15 degrees C water for 5-15 min duration appearing to be most effective at accelerating performance recovery. However, the optimal CWI duration may depend on the water temperature, and the time between CWI and the subsequent exercise bout appears to influence the effect on performance. The few studies examining the effect of post-exercise HWI on subsequent performance have reported conflicting findings; therefore the effect of HWI on performance recovery is unclear. CWT is most likely to enhance performance recovery when equal time is spent in hot and cold water, individual immersion durations are short (~1 min) and the total immersion duration is up to approximately 15 min. A dose-response relationship between CWT duration and recovery of exercise performance is unlikely to exist. Some articles that have reported CWT to not enhance performance recovery have had methodological issues, such as failing to detect a decrease in performance in control trials, not performing full-body immersion, or using hot showers instead of pools. TWI has been investigated as both a control to determine the effect of water temperature on performance recovery, and as an intervention itself. However, due to conflicting findings it is uncertain whether TWI improves recovery of subsequent exercise performance. Both CWI and CWT appear likely to assist recovery of exercise performance more than HWI and TWI; however, it is unclear which technique is most effective. While the literature on the use of water immersion for recovery of exercise performance is increasing, further research is required to obtain a more complete understanding of the effects on performance. PMID- 23743791 TI - Novel directions in HIV-1 vaccines revealed from clinical trials. AB - PURPOSE OF REVIEW: Considerable HIV-1 vaccine development efforts have been deployed over the past decade. Put into perspective, the results from efficacy trials and the identification of correlates of risk have opened large and unforeseen avenues for vaccine development. RECENT FINDINGS: The Thai efficacy trial, RV144, provided the first evidence that HIV-1 vaccine protection against HIV-1 acquisition could be achieved. The correlate of risk analysis showed that IgG antibodies against the gp120 V2 loop inversely correlated with a decreased risk of infection, whereas Env-specific IgA directly correlated with risk. Further clinical trials will focus on testing new envelope subunit proteins formulated with adjuvants capable of inducing higher and more durable functional antibody responses (both binding and broadly neutralizing antibodies). Moreover, vector-based vaccine regimens that can induce cell-mediated immune responses in addition to humoral responses remain a priority. SUMMARY: Future efficacy trials will focus on prevention of HIV-1 transmission in heterosexual population in Africa and MSM in Asia. The recent successes leading to novel directions in HIV-1 vaccine development are a result of collaboration and commitment among vaccine manufacturers, funders, scientists and civil society stakeholders. Sustained and broad collaborative efforts are required to advance new vaccine strategies for higher levels of efficacy. PMID- 23743795 TI - The soundscape quality in some urban parks in Milan, Italy. AB - Urban parks play an important role in preserving and promoting the health of citizens who are often exposed to noise pollution and the stress of daily life. The present study describes the main results obtained from a survey performed in five urban parks in Milan. Measurements of the acoustic environment were carried out in 29 sites together with interviews with 231 users on certain aspects of the parks not limited to merely sound. Acoustic data show that the surveyed parks mostly do not comply with the noise limit issued by the Italian legislation on protected areas. The unweighted 1/3-octave spectrum centre of gravity G and LA50 perform satisfactorily in discriminating among the acoustic environments. Such clear distinction was not observed in the subjective ratings on the perceived quality of the soundscape, likely due to the influence by non-acoustic factors that act as mediators in the assessment. This hypothesis is supported by the collected data on the perceived quality of quietness, which was rated worse than that of the soundscape. Comparing acoustic data with ratings, the perceived quality of the total environment was found to be less dependent on LAeq than soundscape and quietness. PMID- 23743796 TI - Intimate partner violence among adolescents in Cape Town, South Africa. AB - This study aimed to describe potentially preventable factors in intimate partner violence (IPV) perpetration and victimization among South African 8th grade students. Data were collected during a pilot evaluation of a classroom 8th grade curriculum on gender-based violence prevention in nine public schools in Cape Town through self-completed interviews with 549 8th grade students, 238 boys and 311 girls. Structural equation models (SEM) predicting IPV were constructed with variables a priori hypothesized to be associated. The majority of students (78.5 %) had had a partner in the past 3 months, and they reported high rates of IPV during that period (e.g., over 10 % of boys reported forcing a partner to have sex, and 39 % of girls reported physical IPV victimization). A trimmed version of the hypothesized SEM (CFI = .966; RMSEA = .051) indicated that disagreement with the ideology of male superiority and violence predicted lower risk of IPV (p < .001), whereas the frequency of using negative conflict resolution styles (e.g., walking off angrily, sending angry text messages, or refusing to talk to them) predicted high IPV risk (p < .001) and mediated the impact of heavy alcohol drinking on IPV (Sobel test, z = 3.16; p < .001). The model fit both girls and boys, but heavy drinking influenced negative styles of resolving conflict more strongly among girls than boys. Findings suggest that interventions to reduce IPV among South African adolescents should challenge attitudes supportive of male superiority and violence; encourage use of positive conflict resolution styles; and discourage heavy alcohol use among both boys and girls. PMID- 23743797 TI - The breeding season duration hypothesis: acute handling stress and total plasma concentrations of corticosterone and androgens in male and female striped plateau lizards (Sceloporus virgatus). AB - Acute glucocorticoid elevations can be adaptations to short-term stressors. The breeding season hypothesis predicts reduced glucocorticoid responsiveness to acute stressors in populations or species with short breeding seasons. The striped plateau lizard (Sceloporus virgatus) has a short breeding season in Arizona. We measured plasma corticosterone and total androgen levels (dihydrotestosterone and testosterone) following one of the four stress-handling treatments (0, 10, 60, or 180 min). In both sexes, longer handling stress yielded higher corticosterone; females had higher corticosterone than males at all time points. Androgens did not vary with handling duration, in either sex. Combining treatments, plasma androgens correlated positively with corticosterone (CORT) in females but not in males; plasma CORT and body mass residuals were negatively correlated in both sexes, suggesting lizards in poor body condition and/or not investing heavily in reproduction (follicle mass) have higher acute corticosterone. Total plasma androgens and body mass residuals were positively associated in males, but showed no association in females. The maximal CORT elevation after handling stress in this single-clutching species was of comparable magnitude to responses in related multi-clutching lizard species with longer breeding seasons. Using data from studies of multiple populations of three Sceloporus species, we found no relationship between the relative magnitude of the CORT increase and either latitude or elevation, two variables in the literature correlated with duration of the breeding season, and only weak relationships with geographic elevation and actual (not relative) stress-elevated CORT values in this multi-population comparison. PMID- 23743799 TI - Digestive strategies and food choice in mantled howler monkeys Alouatta palliata mexicana: bases of their dietary flexibility. AB - Mantled howler monkeys (Alouatta palliata) occupy a wide variety of tropical habitats and are the most folivorous of New World primates. However, their diet may include fruits, buds, petioles, and flowers, as well as leaves, suggesting they must cope with variations in the nutrient composition of their food. We studied the physiological basis of the dietary flexibility of these monkeys by comparing food choice, digestive performance and patterns of digesta flow in six adults, fed diets of either leaves or a mixture of fruit and leaves. Although monkeys ate similar amounts of the two diets, they ingested more digestible protein when offered the leaf diet, on which they lost body mass, but they ingested much more soluble sugars when offered fruit and leaves on which they gained mass. Digestibilities of dry matter, fat, energy and fibre did not differ between diets, but those of crude protein, soluble sugars and minerals were higher on the fruit-leaf diet. Mean retention times in the gut of solute (Co EDTA) and particulate markers (Cr-mordanted cell walls) did not differ between diets, but on both diets the monkeys retained the particulate marker (mean retention time ca 55 h) for longer than they did the solute marker (MRT ca 50 h). A lack of selective retention of solutes and small particles in the gastro intestinal tract of howler monkeys probably restricts them to mixed diets but their digestive strategy is sufficiently flexible to allow them to feed on a diet of leaves when fruit is unavailable. PMID- 23743798 TI - Liver glucose-6-phosphatase proteins in suckling and weaned grey seal pups: structural similarities to other mammals and relationship to nutrition, insulin signalling and metabolite levels. AB - Phocid seals have been proposed as models for diabetes because they exhibit limited insulin response to glucose, high blood glucose and increasing insulin resistance when fasting. Liver glucose-6-phosphatase (G6Pase) catalyses the final step in glucose production and is central to glucose regulation in other animals. G6Pase comprises a translocase (SLC37A4) and a catalytic subunit (G6PC). G6PC and SLC37A4 expression and activity are normally regulated by nutritional state and glucostatic hormones, particularly insulin, and are elevated in diabetes. We tested the hypotheses that (1) grey seal G6PC and SLC37A4 cDNA and predicted protein sequences differ from other species' at functional sites, (2) relative G6Pase protein abundances are lower during feeding than fasting and (3) relative G6Pase protein abundances are related to insulin, insulin receptor phosphorylation and key metabolite levels. We show that G6PC and partial SLC37A4 cDNA sequences encode proteins sharing 82-95 % identity with other mammals. Seal G6PC contained no differences in sites responsible for activity, stability or subcellular location. Several substitutions in seal SLC37A4 were predicted to be tolerated with low probability, which could affect glucose production. Suckling pups had higher relative abundance of both subunits than healthy, postweaned fasting pups. Furthermore, relative G6PC abundance was negatively related to glucose levels. These findings contrast markedly with the response of relative hepatic G6Pase abundance to feeding, fasting, insulin, insulin sensitivity and key metabolites in other animals, and highlight the need to understand the regulation of enzymes involved in glucose control in phocids if these animals are to be informative models of diabetes. PMID- 23743800 TI - EMPHYSEMA QUANTIFICATION IN A MULTI-SCANNER HRCT COHORT USING LOCAL INTENSITY DISTRIBUTIONS. AB - This article investigates the suitability of local intensity distributions to analyze six emphysema classes in 342 CT scans obtained from 16 sites hosting scanners by 3 vendors and a total of 9 specific models in subjects with Chronic Obstructive Pulmonary Disease (COPD). We propose using kernel density estimation to deal with the inherent sparsity of local intensity histograms obtained from scarcely populated regions of interest. We validate our approach by leave-one subject-out classification experiments and full-lung analyses. We compare our results with recently published LBP texture-based methodology. We demonstrate the efficacy of using intensity information alone in multi-scanner cohorts, which is a simpler, more intuitive approach. PMID- 23743801 TI - Production of H2 at fast rates using a nickel electrocatalyst in water acetonitrile solutions. AB - We report a synthetic nickel complex containing proton relays, [Ni(P(Ph)2N(C6H4OH)2)2](BF4)2 (P(Ph)2N(C6H4OH)2 = 1,5-bis(p-hydroxyphenyl)-3,7 diphenyl-1,5-diaza-3,7-diphosphacyclo-octane), that catalyzes the production of H2 in aqueous acetonitrile with turnover frequencies of 750-170,000 s(-1) at experimentally determined overpotentials of 310-470 mV. PMID- 23743802 TI - A survey of MRI-based medical image analysis for brain tumor studies. AB - MRI-based medical image analysis for brain tumor studies is gaining attention in recent times due to an increased need for efficient and objective evaluation of large amounts of data. While the pioneering approaches applying automated methods for the analysis of brain tumor images date back almost two decades, the current methods are becoming more mature and coming closer to routine clinical application. This review aims to provide a comprehensive overview by giving a brief introduction to brain tumors and imaging of brain tumors first. Then, we review the state of the art in segmentation, registration and modeling related to tumor-bearing brain images with a focus on gliomas. The objective in the segmentation is outlining the tumor including its sub-compartments and surrounding tissues, while the main challenge in registration and modeling is the handling of morphological changes caused by the tumor. The qualities of different approaches are discussed with a focus on methods that can be applied on standard clinical imaging protocols. Finally, a critical assessment of the current state is performed and future developments and trends are addressed, giving special attention to recent developments in radiological tumor assessment guidelines. PMID- 23743803 TI - Procalcitonin and the inflammatory response to salt in essential hypertension: a randomized cross-over clinical trial. AB - OBJECTIVES: Inflammation is considered as a major effector of arterial damage brought about by salt excess in animal models. In a randomized, single masked, cross-over study in 32 uncomplicated essential hypertensive patients, we assessed the effect of a short-term low-salt diet on biomarkers of innate immunity [procalcitonin (PCT), interleukin-6, C-reactive protein, and tumor necrosis factor-alpha (TNF-alpha)], adiponectin (ADPN, an anti-inflammatory cytokine), and leptin. METHODS: Patients were randomized to either a 10-20 mmol sodium diet and sodium tablets (180 mEq/day) to achieve a 200 mmol intake per day or the same diet and identical placebo tablets, each for 2 weeks. At the end of each of these periods, all patients underwent a 24-h urine collection, a fasting blood sampling, and a 24 h ambulatory blood pressure monitoring. RESULTS: In parallel with expected increase in plasma renin activity and aldosterone (P<0.001), both PCT (+33%) and TNF-alpha (9%) rose at low salt intake (P<=0.007) while ADPN underwent an opposite change (- 17%, P<0.001). In a linear regression analysis for repeated measurements, PCT was significantly and inversely related to urinary salt (weighted r=-0.27, P=0.03). Changes in inflammation biomarkers did not differ in salt-sensitive (n=7) and salt-resistant (n=25) patients. CONCLUSION: In essential hypertensive patients, a very low salt diet generates a pro inflammatory phenotype characterized by an increase in PCT and TNF-alpha and an opposite effect on an anti-inflammatory cytokine like ADPN. PMID- 23743804 TI - Simplified therapeutic intervention to control hypertension and hypercholesterolemia: a cluster randomized controlled trial (STITCH2). AB - BACKGROUND: Notwithstanding improving rates of hypertension control in North America, management of patients with both hypertension and dyslipidemia remains problematic. Based on evidence of improved control utilizing a simplified algorithm for management of hypertension (STITCH), we questioned whether a simplified comprehensive treatment algorithm featuring initial use of single-pill combinations (SPCs) would improve management of participants with both hypertension and dyslipidemia. METHOD: We randomized 35 primary care practices in Ontario to either Guidelines-care (following current Canadian guidelines) or STITCH2-care (following a treatment algorithm featuring SPCs). Practices each enrolled up to 50 participants with at least one risk factor above target at entry based on Canadian guidelines for BP and LDL-cholesterol control. The primary endpoint was achieving targets for both hypertension and dyslipidemia control after 6 months, assessed at the practice level. RESULTS: The primary endpoint was achieved in 31.3% of participants in STITCH2-care practices, compared with 28.1% in Guidelines-care practices, yielding a difference of 3.2% (P = 0.63). Notably, STITCH2-care practices had a significantly greater reduction in SBP while LDL-cholesterol reduction was only marginally greater in STITCH2 practices. CONCLUSION: The STITCH2 algorithm resulted in significantly greater use of any SPC compared with Guidelines-care and greater use of the SPC of calcium channel blocker/statin. Unwillingness of the prescribing physician to advance treatment beyond a monotherapy threshold was found to be an important determinant for failing to achieve blood pressure control. In contrast, the more important determinant for failing to achieve LDL control appeared to be the unwillingness of the prescribing physician to initiate therapy with a statin. PMID- 23743805 TI - Early vascular ageing in translation: from laboratory investigations to clinical applications in cardiovascular prevention. AB - The ageing of the vascular tree is a fundamental reflection of biological ageing in general and a determinant of organ function. In the arterial wall this is characterized by a reduction in the elastin content, as well as by an increased content of collagen and its cross-linkages, leading to increased arterial stiffness and elevated central as well as brachial blood pressure, accompanied by increased SBP variability. In recent years a better understanding of these processes have led to the proposal of a condition named early vascular ageing (EVA) in patients with increased arterial stiffness for their age and sex. This is a condition that could increase cardiovascular risk and is associated with various degrees of cognitive dysfunction, as well as other features of biological ageing. This brief review aims to give an update on EVA and how the concept can be used in clinical practice. PMID- 23743806 TI - Eligibility for percutaneous renal denervation: the importance of a systematic screening. AB - OBJECTIVE: Percutaneous renal denervation (pRDN) is a new and promising therapy for resistant hypertension. Among patients suspected of having resistant hypertension, the actual presence of this condition needs to be well established; pseudoresistant hypertension and significant white-coat effect (WCE) should be excluded. This analysis presents the results of a standardized screening programme for patients referred for pRDN. METHODS: All patients referred to our centre for pRDN underwent a standardized stepwise screening and were subsequently discussed in a multidisciplinary team. The screening included a 24-h ambulatory blood pressure measurement (ABPM), collection of plasma, urine and saliva, and finally imaging of the renal arteries. RESULTS: From August 2010 till October 2012, 181 patients were referred for pRDN. Mean blood pressure (BP) was 182/100 mmHg, and median use was three antihypertensives. Ultimately, 121 patients (67%) were excluded from pRDN. Main reasons for exclusion were BP-related. Twenty-three patients (19%) had an office SBP less than 160 mmHg and 26 patients (22%) showed a WCE. Fourteen patients (12%) had a so far undetected underlying cause of hypertension, the majority being primary aldosteronism (n = 11). Nine patients had an ineligible renal anatomy. CONCLUSION: A high percentage of patients were excluded from treatment with pRDN due to secondary causes of hypertension, WCE or a BP below the currently advised thresholds. Treatment of these excluded patients would lead to inappropriate use of pRDN, leading most likely to little benefit for the patients and a burden to healthcare. Therefore, it is recommended to use a standardized screening before treatment with pRDN. PMID- 23743807 TI - Urinary renin and angiotensinogen in type 2 diabetes: added value beyond urinary albumin? AB - OBJECTIVE: Urinary levels of renin-angiotensin-aldosterone system (RAAS) components may reflect renal RAAS activity and/or the renal efficacy of RAAS inhibition. Our aim was to determine whether urinary angiotensinogen and renin are circulating RAAS-independent markers during RAAS blockade. METHODS: Urinary and plasma levels of angiotensinogen, renin, and albumin were measured in 22 patients with type 2 diabetes, hypertension, and albuminuria, during 2-month treatment periods with placebo, aliskiren, irbesartan, or their combination in random order in a crossover study. RESULTS: Aliskiren and irbesartan both increased plasma renin 3-4-fold, and above 10-fold when combined. Irbesartan decreased plasma angiotensinogen by approximately 25%, and no changes in plasma angiotensinogen were observed during the combination. Urine contained aliskiren at micromolar levels, blocking urinary renin by above 90%. Both blockers reduced urinary angiotensinogen, significant for irbesartan only. Combination blockade reduced urinary angiotensinogen even further. Reductions in urinary angiotensinogen paralleled albuminuria changes, and the urine/plasma concentration ratio of angiotensinogen was identical to that of albumin under all conditions. In contrast, urinary renin did not follow albumin, and remained unaltered after all treatments. Yet, the urine/plasma concentration ratio of renin was more than 100-fold higher than that of angiotensinogen and albumin, and approximately 4-fold reduced by single RAAS blockade, and more than 10-fold by dual RAAS blockade. CONCLUSIONS: Aliskiren filters into urine and influences urinary renin measurements. The urine/plasma renin ratio, but not urinary renin alone, may reflect the renal efficacy of RAAS blockade. Urinary angiotensinogen is a marker of filtration barrier damage rather than intrarenal RAAS activity. PMID- 23743808 TI - Persistent organic pollutants and abnormal geometry of the left ventricle in the elderly. AB - BACKGROUND: Established risk factors for left ventricular hypertrophy (LVH) are hypertension, diabetes, and obesity. However, as these risk factors explain only part of the variation in left ventricular mass, we investigated whether persistent organic pollutants (POPs) might also play a role in LVH, because exposure to polychlorinated biphenyl 126 induced cardiac growth in rats. METHODS: In the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), left ventricular mass index (LVMI), relative wall thickness (RWT), and geometric groups of LVH, were determined by echocardiography and 21 POPs were measured by high-resolution chromatography coupled to high-resolution mass spectrometry (HRGC/HRMS) in 1016 individuals aged 70 years. All individuals with a history of myocardial infarction were excluded from analysis (n = 72). RESULTS: Several of the POPs were related to abnormal left ventricular geometry before adjustment for established risk factors, but lost in significance following adjustment. However, the pesticide hexachlorobenzene (HCB) levels were significantly related to RWT, and concentric left ventricular remodeling, also following adjustment for sex, blood pressure, antihypertensive treatment, diabetes, and BMI (P <0.0001). CONCLUSION: In this cross-sectional study, circulating levels of HCB were related to increased wall thickness of the left ventricle and concentric left ventricular remodeling, independently of LVH risk factors, suggesting a role of this environmental contaminant in abnormal growth of the left ventricle. PMID- 23743809 TI - Increased pulse pressure linked to dementia: further results from the Hypertension in the Very Elderly Trial - HYVET. AB - OBJECTIVES: High blood pressure (BP) has been associated with increased risk of dementia. Concerns have been raised about lowering BP too far in the very elderly and thereby increasing risk. There is some evidence to suggest a potential 'J' shaped relationship between DBP and risk of cognitive impairment. This was investigated using data from the HYpertension in the Very Elderly Trial (HYVET). METHODS: HYVET was a double-blind, placebo-controlled trial of antihypertensives in patients aged at least 80 years with an untreated SBP of 160-199 mmHg. Active medication was indapamide sustained release 1.5 mg+/- perindopril 2-4 mg to reach goal pressure of less than 150/80 mmHg. Incident dementia was a secondary endpoint and was not significantly different between the two treatment groups. The relationship between pressure and incident dementia was assessed using Cox proportional hazards regression with BP entered as either a discrete (quartile analysis) or continuous predictor variable. Achieved BP was calculated as the mean of all pressures from the 9 month visit onwards. RESULTS: During a mean follow-up of 2.2 years 263 incident cases of dementia were diagnosed. After adjustment for various covariates, baseline DBP was inversely related to incident dementia (P=0.0064). Achieved DBP did not predict later dementia in the placebo group (P=0.43), but showed a U-shaped relationship in the active treatment group (P=0.0195). The relationship between incident dementia and DBP did however not differ significantly between the placebo and active treatment groups (P=0.38). SBP was not associated with incident dementia, at baseline (P=0.62) or during follow-up (placebo group P=0.13, active group P=0.36). Wider achieved pulse pressure (PP) was associated with increased risk of dementia in both treatment groups (placebo P=0.032, active P=0.0046). The same tendency was observed for baseline PP (P=0.095). CONCLUSION: Wider PP may possibly indicate an increased risk for dementia. Active treatment may act to change the shape of the relationship between DBP and dementia. Future studies need to focus on exploring the ideal goal pressure for this age group. PMID- 23743810 TI - Is blood pressure load associated, independently of blood pressure level, with target organ damage? AB - OBJECTIVE: Blood pressure (BP) load, defined as the percentage of abnormally elevated BP readings, is usually provided on the report of ambulatory BP monitoring. However, the usefulness of BP load is still uncertain. In the present study, we examined whether BP load would be associated, independently of BP level, with target organ damage. METHODS: We recruited 869 individuals (430 men, mean age 51 years) who were referred for 24-h ambulatory BP monitoring and were off antihypertensive medication for at least 2 weeks. BP load was defined as the percentage of daytime and nighttime SBP/DBP readings at least 135/85 and at least 120/70 mmHg, respectively. Brachial-ankle pulse wave velocity (baPWV) and carotid femoral pulse wave velocity (cfPWV), left ventricular mass index (LVMI) and urinary albumin-to-creatinine ratio (ACR) were determined as measures of target organ damage. RESULTS: SBP and DBP load had a skewed distribution (P<0.001). In multivariate-adjusted categorical analyses, baPWV (13.8, 14.6 and 15.6 m/s), cfPWV (7.4, 7.7 and 8.4 m/s), LVMI (90.1, 94.8 and 100.7 g/m) and ACR (0.47, 0.58 and 0.77 mg/mmol) all increased from tertiles 1-3 of SBP load (P<0.001). However, these differences became nonsignificant (P >= 0.16) after additionally adjusted for 24-h SBP level. In a continuous analysis in individuals with a BP load greater than zero (n=838), adding the logarithmically transformed SBP load did not improve the fit of models relating measures of target organ damage to SBP level (P >= 0.14), except for cfPWV (P=0.01) that was however negatively associated with BP load. Analyses on DBP load produced similar results. CONCLUSION: BP load was associated with target organ damage, but not independently of BP level. PMID- 23743811 TI - Chronic resveratrol consumption improves brachial flow-mediated dilatation in healthy obese adults. AB - BACKGROUND: We have previously demonstrated acute dose-dependent increases of flow-mediated dilatation (FMD) in the brachial artery after resveratrol consumption in mildly hypertensive, overweight/obese adults. Resveratrol supplementation has also been shown to increase cerebral blood flow acutely, without affecting cognition. OBJECTIVES: To evaluate the effects of chronic resveratrol supplementation on both FMD and cognitive performance. METHOD: Twenty eight obese but otherwise healthy adults (BMI: 33.3 +/- 0.6 kg/m) were randomized to take a single 75 mg capsule of trans-resveratrol (Resvida) or placebo daily for 6 weeks each in a double-blind crossover supplementation trial. Blood pressure, arterial compliance, FMD, and performance on the Stroop Color-Word Test were assessed at the end of each 6-week intervention period while fasted and at least 18 h after taking the last daily capsule. An additional capsule of the same supplement was then taken. FMD assessment was repeated 1 h later. RESULTS: Chronic resveratrol supplementation for 6 weeks was well tolerated and resulted in a 23% increase in FMD compared with placebo (P=0.021, paired t-test). The extent of increase correlated negatively with baseline FMD (r=-0.47, P=0.01). A single dose of resveratrol (75 mg) following chronic resveratrol supplementation resulted in a 35% greater acute FMD response than the equivalent placebo supplementation. These FMD improvements remained significant after adjusting for baseline FMD. Blood pressure, arterial compliance, and all components of the Stroop Color-Word Test were unaffected by chronic resveratrol supplementation. CONCLUSION: Daily resveratrol consumption was well tolerated and has the potential to maintain healthy circulatory function in obese adults. PMID- 23743812 TI - Liver-cell patterning lab chip: mimicking the morphology of liver lobule tissue. AB - A lobule-mimetic cell-patterning technique for on-chip reconstruction of centimetre-scale liver tissue of heterogeneous hepatic and endothelial cells via an enhanced field-induced dielectrophoresis (DEP) trap is demonstrated and reported. By mimicking the basic morphology of liver tissue, the classic hepatic lobule, the lobule-mimetic-stellate-electrodes array was designed for cell patterning. Through DEP manipulation, well-defined and enhanced spatial electric field gradients were created for in-parallel manipulation of massive individual cells. With this liver-cell patterning labchip design, the original randomly distributed hepatic and endothelial cells inside the microfluidic chamber can be manipulated separately and aligned into the desired pattern that mimicks the morphology of liver lobule tissue. Experimental results showed that both hepatic and endothelial cells were orderly guided, snared, and aligned along the field induced orientation to form the lobule-mimetic pattern. About 95% cell viability of hepatic and endothelial cells was also observed after cell-patterning demonstration via a fluorescent assay technique. The liver function of CYP450-1A1 enzyme activity showed an 80% enhancement for our engineered liver tissue (HepG2+HUVECs) compared to the non-patterned pure HepG2 for two-day culturing. PMID- 23743813 TI - [Nutrition and renal insufficiency]. AB - Renal failure patients in the intensive care unit comprise a heterogeneous group of subjects with widely differing metabolic patterns and nutritional requirements. This group includes patients with acute kidney injury (AKI), acute on-chronic renal failure, chronic kidney disease, and those on regular hemodialysis therapy. Renal failure is associated with a broad spectrum of specific metabolic alterations. In addition to these alterations and the often underrated impact of renal replacement therapy, the metabolism is also affected by the underlying disease process as well as associated organ failures and complications, especially infections. Nutritional support for renal failure is not fundamentally different from other disease processes, but in designing a nutrition regimen the variations in metabolism and nutrient requirements should be considered. Nutritional needs can differ widely between patients but also in the same patient during the course of disease. Thus, patients with renal failure require an individualized approach to nutritional support. Moreover, because of the altered metabolism of many nutrients and the intolerance of fluids and electrolytes, close monitoring of the nutritional therapy is mandatory in patients with renal failure. PMID- 23743814 TI - Spectrophotometric analysis in umbilical cords of infants with meconium aspiration syndrome. AB - We compared spectrophotometric analysis of the umbilical cords of infants with meconium aspiration syndrome (MAS) or with meconium-stained amniotic fluid (MSAF) and healthy infants. In a prospective study, 15 infants with MAS and 37 infants with MSAF were enrolled. Twenty healthy infants formed a control group. The absorption peak of umbilical cords with meconium was significantly higher in the infants with MAS or MSAF than in controls. Spectrophotometric analysis of the umbilical cords with meconium may be useful to identify developed neonates with MAS or MSAF. PMID- 23743815 TI - Is universal antifungal prophylaxis mandatory in lung transplant patients? AB - PURPOSE OF REVIEW: Lung transplantation remains the main therapy for patients with end-stage lung disease, yet survival remains limited by infection and chronic rejection. Invasive fungal infection, especially invasive aspergillosis, continues to cause a high rate of mortality after lung transplantation, and there is evidence that fungal colonization in itself may have a negative impact as well. This article reviews clinical trials in primary antifungal prophylaxis to determine whether antifungal prophylaxis after lung transplantation is indicated. RECENT FINDINGS: A variety of antifungal regimens have been tested after lung transplantation including itraconazole or voriconazole monotherapy, inhaled amphotericin B products, and combination therapy. Studies using a historical cohort that has not received antifungal prophylaxis show a decrease in the incidence of invasive fungal disease and/or invasive aspergillosis with antifungal prophylaxis, with relatively few safety concerns. Both systemic azoles and inhaled amphotericin B products appear to provide benefit. SUMMARY: Despite multiple reports of antifungal prophylaxis efficacy, a randomized, controlled, multicenter trial has yet to be performed. The optimal agent or agents for prophylaxis and length of therapy posttransplantation remain unknown. However, sufficient evidence exists for the utility of some type of antifungal prophylaxis posttransplantation for the majority of lung transplant recipients. PMID- 23743816 TI - The role of the surface environment in healthcare-associated infections. AB - PURPOSE OF REVIEW: This article reviews the evidence demonstrating the importance of contamination of hospital surfaces in the transmission of healthcare associated pathogens and interventions scientifically demonstrated to reduce the levels of microbial contamination and decrease healthcare-associated infections. RECENT FINDINGS: The contaminated surface environment in hospitals plays an important role in the transmission of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), Clostridium difficile, Acinetobacter spp., and norovirus. Improved surface cleaning and disinfection can reduce transmission of these pathogens. 'No-touch' methods of room disinfection (i.e., devices which produce ultraviolet light or hydrogen peroxide) and 'self disinfecting' surfaces (e.g., copper) also show promise to decrease contamination and reduce healthcare-associated infections. SUMMARY: Hospital surfaces are frequently contaminated with important healthcare-associated pathogens. Contact with the contaminated environment by healthcare personnel is equally as likely as direct contact with a patient to lead to contamination of the healthcare provider's hands or gloves that may result in patient-to-patient transmission of nosocomial pathogens. Admission to a room previously occupied by a patient with MRSA, VRE, Acinetobacter, or C. difficile increases the risk for the subsequent patient admitted to the room to acquire the pathogen. Improved cleaning and disinfection of room surfaces decreases the risk of healthcare-associated infections. PMID- 23743817 TI - Acute effects of light emitting diodes therapy (LEDT) in muscle function during isometric exercise in patients with chronic obstructive pulmonary disease: preliminary results of a randomized controlled trial. AB - Patients with chronic obstructive pulmonary disease (COPD) are susceptible to early muscle fatigue. Light-emitting diodes therapy (LEDT) has been used to minimize muscle fatigue in athletes and healthy subjects. The aim of this study is to investigate the acute effects of LEDT on muscle fatigue and perception of effort in patients with COPD during isometric endurance test of the quadriceps femoris (QF). Ten patients (VEF1 50 +/- 13% of predicted) underwent a single LEDT and sham application, 48 h apart, in a randomized crossover design. The LEDT and sham were applied in three localized areas of the QF (rectus femoris, vastus lateralis, and vastus medialis). Before and after exposure to LEDT and sham, the patients performed an isometric endurance test (60 % of the maximum voluntary isometric contraction), until the limit of tolerance concomitant to surface electromyography recording (median frequency as mean outcome). The slope obtained from linear regression analysis of the median frequency (MF) over endurance time was also used as an endurance index. Endurance time increased significantly after exposure to LEDT (from 26 +/- 2 to 53 +/- 5 s) as compared to sham (from 23 +/- 3 to 30 +/- 4 s) (F = 64, P = 0.0001). A greater decline in MF was observed during isometric endurance test after sham, compared to LEDT (F = 14.6, P = 0.004). The slope of the MF over time was lower post-LEDT compared to post-sham (-0.7 +/- 0.3 vs. -1.5 +/- 0.8; P = 0.004). The dyspnea score corrected for endurance time was lower post-LEDT (P = 0.008) but similar for fatigue both post-LEDT and post-sham. A single application of LEDT minimizes muscle fatigue and increases isometric endurance time. PMID- 23743818 TI - Successful everolimus therapy for SEGA in pediatric patients with tuberous sclerosis complex. AB - PURPOSE: Tuberous sclerosis complex (TSC) is associated with hamartomatous growths including subependymal giant cell astrocytomas (SEGAs). Although, SEGAs are slow-growing glioneuronal tumors, they represent a significant cause of morbidity and mortality due to the risk of sudden death from acute hydrocephalus. Neurosurgical resection has been the mainstay of therapy, since radiotherapy and chemotherapy were proved inefficient in those tumors. Recent studies support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis and suggest it might represent a disease-modifying treatment for other aspects of tuberous sclerosis. METHODS: We describe the clinical and radiological progression of three pediatric patients with definitive diagnosis of TSC and SEGA, which have been treated with everolimus. RESULTS: Up to 34 % sustained SEGA decrease was observed in the three cases. All three patients have experienced seizure control and two of them have showed cognitive and behavioral improvement. Everolimus has been well tolerated by all. No severe adverse events have been observed to date. CONCLUSION: Everolimus offers significant promise in treating SEGAs. Studies are required to explore optimal therapy duration and management upon discontinuing therapy. PMID- 23743819 TI - The assessment of relationship between the skull base development and the severity of frontal plagiocephaly after bilateral fronto-orbital advancement in the early life. AB - PURPOSE: The deformation of the skull base in patients with unilateral frontal plagiocephaly (UFP) is well known, but the mechanism is not still clear. We analyzed the skull base in the patients with UFP who underwent fronto-orbital advancement (FOA) in the early life during the last decade. METHODS: We assessed the treatment results and outcome of FOA performed in six patients, four girls and two boys younger than 2 years, in the last decade. Also, the basal cranium's angles were measured by 3D reconstruction images on computed tomography (CT) scan. RESULTS: The mean patients' age at FOAs was 11 months. Two cases were classified as grade 2A, two cases as grade 2B, and two cases as grade 3 (the classification of Di Rocco and Velardi). The ethmoidal axis was deviated a mean of 8.2 degrees to the affected side. The mean angle between the petrosal pyramids and the midline (anterior-petrosal-sagittal angle, APSA) was 75.3 degrees on the affected side and 66.2 degrees on the normal side. The mean difference of APSA was 9.2 degrees . On the follow-up CT images 5 years after surgery, the deviations of the ethmoidal axis clearly decreased, 5.7 degrees , but the differences of APSA did not change, 8.8 degrees . CONCLUSIONS: The midline distortion of anterior skull base should be considered to be spontaneously corrected during the follow-up periods in patients with all types of UFP who underwent FOA, unlike posterior skull base in the patients with grades 2B and 3 classification. PMID- 23743820 TI - Rapamycin has a beneficial effect on controlling epilepsy in children with tuberous sclerosis complex: results of 7 children from a cohort of 86. AB - PURPOSE: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the formation of hamartomas in various organ systems. We would like share our experience from 86 patients and the results of rapamycin treatment in seven children with TSC. METHODS: Eighty-six children with TSC were enrolled into this retrospective study. The clinical features of seven children treated with oral rapamycin were presented in detail. RESULTS: The most common complaint of administration was convulsion in 77 children (89.5%). Hypopigmented skin lesions, adenoma sebaceum, resistant epilepsy, intracardiac mass, renal angiomyolipomas, and West syndrome were detected (n = 83, 96.5%; n = 47, 54.7%; n = 36, 41.9%; n = 27, 31.4%; n = 18, 20.9%; and n = 13, 15.1%, respectively). Subependymal nodules were the most frequent finding in cranial imaging followed by cortical tubers and subependymal giant cell astrocytomas (n = 75, 87.2%; n = 71, 82.6%; and n = 8, 9.3%, respectively). Of the seven patients treated with rapamycin, the lesions of six children with facial adenoma sebaceum showed regression in various degrees. The frequency of convulsions decreased in five patients with resistant epilepsy within the first 6 months of the treatment, and complete control of convulsion for all patients was achieved in the second 6 months. CONCLUSION: This is the first study that showed that rapamycin is an effective agent for controlling epilepsy without any significant side effect in children with TSC. Rapamycin seems to be effective after 6 months of therapy, and we recommend tapering the dosage after successful management of epilepsy. PMID- 23743821 TI - Duplicated filum terminale in the absence of split cord malformation: a potential cause of failed detethering procedures. AB - INTRODUCTION: A duplicated filum terminale appears to be a rare finding in the absence of a split cord malformation. Herein, we discuss this finding and its potential dysembryology. CASE REPORTS: We report two cases of duplicated filum terminale without split cord malformation. The first case presented as an incidental finding with thickened filum terminale. At time of surgery, a thickened filum was resected and a smaller size filum was transected and both were confirmed with pathologic examination. The second case presented with a lumbar skin hemangioma. Screening MRI showed a duplicated filum terminale with fat signal in both structures. Pathology also confirmed the diagnosis of two fila terminalia. CONCLUSIONS: The neurosurgeon should consider the possibility of two fila terminalia during operation to transect a single filum for tethered spinal cord. PMID- 23743822 TI - Preparation of novel poly(hydroxyethyl methacrylate-co-glycidyl methacrylate) grafted core-shell magnetic chitosan microspheres and immobilization of lactase. AB - Poly(hydroxyethyl methacrylate-co-glycidyl methacrylate)-grafted magnetic chitosan microspheres (HG-MCM) were prepared using reversed-phase suspension polymerization method. The HG-MCM presented a core-shell structure and regular spherical shape with poly(hydroxyethyl methacrylate-co-glycidyl methacrylate) grafted onto the chitosan layer coating the Fe3O4 cores. The average diameter of the magnetic microspheres was 10.67 MUm, within a narrow size distribution of 6.6 17.4 MUm. The saturation magnetization and retentivity of the magnetic microspheres were 7.0033 emu/g and 0.6273 emu/g, respectively. The application of HG-MCM in immobilization of lactase showed that the immobilized enzyme presented higher storage, pH and thermal stability compared to the free enzyme. This indicates that HG-MCM have potential applications in bio-macromolecule immobilization. PMID- 23743823 TI - Autophagy in prostate cancer and androgen suppression therapy. AB - The role of autophagy is known to be highly complex and context-dependent, leading to both cancer suppression and progression in several tumors including melanoma, breast and prostate cancer. In the present review, recent advances in an understanding of the involvement of autophagy in prostate cancer treatment are described. The regulatory effects of androgens on prostate cancer cell autophagy are particularly discussed in order to highlight the effects of autophagy modulation during androgen deprivation. A critical evaluation of the studies examined in the present review suggests the attractive possibility of autophagy inhibition combined with hormonal therapy as a promising approach for prostate cancer treatment. PMID- 23743824 TI - Eviprostat activates cAMP signaling pathway and suppresses bladder smooth muscle cell proliferation. AB - Eviprostat is a popular phytotherapeutic agent for the treatment of lower urinary tract symptoms (LUTS). At present, the signaling mechanisms underlying its therapeutic effects are still poorly understood. Given that cAMP has been reported to suppress cell hyperplasia and hypertrophy in various pathological situations, we asked whether the effect of Eviprostat could be ascribed to the activation of the cAMP signaling pathway. In the study, exposure of cAMP response element (CRE)-secreted alkaline phosphatase (SEAP) (CRE-SEAP)-reporter cells to Eviprostat elevated SEAP secretion, which was associated with an increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) and cAMP-response element-binding protein (CREB), as well as enhanced expression of CRE-regulated protein connexin43, indicating an activation of the cAMP signaling pathway. Consistent with these observations, Eviprostat-induced expression of Cx43 was abolished in the presence of adenylyl cyclase inhibitor SQ22536 or PKA inhibitor H89, whereas it was mimicked by adenylyl cyclase activator, forskolin. Further analysis demonstrated that Eviprostat significantly potentiated the effect of phosphodiesterase 3 (PDE3) inhibitor, but not that of PDE4 inhibitor, on CRE activation. Moreover, Eviprostat suppressed PDGF-induced activation of ERK and Akt and inhibited cell proliferation and hillock formation in both mesangial cells and bladder smooth muscle cells. Collectively, activation of the cAMP signaling pathway could be an important mechanism by which Eviprostat exerts its therapeutic effects for LUTS. PMID- 23743825 TI - Candidate biomarkers for genetic and clinicopathological diagnosis of endometrial cancer. AB - The recent increase in the frequency of endometrial cancer has emphasized the need for accurate diagnosis and improved treatment. The current diagnosis is still based on conventional pathological indicators, such as clinical stage, tumor differentiation, invasion depth and vascular invasion. However, the genetic mechanisms underlying endometrial cancer have gradually been determined, due to developments in molecular biology, leading to the possibility of new methods of diagnosis and treatment planning. New candidate biomarkers for endometrial cancer include those for molecular epigenetic mutations, such as microRNAs. These biomarkers may permit earlier detection of endometrial cancer and prediction of outcomes and are likely to contribute to future personalized therapy for endometrial cancer. PMID- 23743826 TI - Combining hexanoic acid plant priming with Bacillus thuringiensis insecticidal activity against Colorado potato beetle. AB - Interaction between insect herbivores and host plants can be modulated by endogenous and exogenous compounds present in the source of food and might be successfully exploited in Colorado potato beetle (CPB) pest management. Feeding tests with CPB larvae reared on three solanaceous plants (potato, eggplant and tomato) resulted in variable larval growth rates and differential susceptibility to Bacillus thuringiensis Cry3Aa toxin as a function of the host plant. An inverse correlation with toxicity was observed in Cry3Aa proteolytic patterns generated by CPB midgut brush-border membrane vesicles (BBMV) from Solanaceae-fed larvae, being the toxin most extensively proteolyzed on potato, followed by eggplant and tomato. We found that CPB cysteine proteases intestains may interact with Cry3Aa toxin and, in CPB BBMV from larvae fed all three Solanaceae, the toxin was able to compete for the hydrolysis of a papain substrate. In response to treatment with the JA-dependent plant inducer Hexanoic acid (Hx), we showed that eggplant reduced OPDA basal levels and both, potato and eggplant induced JA Ile. CPB larvae feeding on Hx-induced plants exhibited enhanced Cry3Aa toxicity, which correlated with altered papain activity. Results indicated host-mediated effects on B. thuringiensis efficacy against CPB that can be enhanced in combination with Hx plant induction. PMID- 23743827 TI - A Hamiltonian replica exchange molecular dynamics (MD) method for the study of folding, based on the analysis of the stabilization determinants of proteins. AB - Herein, we present a novel Hamiltonian replica exchange protocol for classical molecular dynamics simulations of protein folding/unfolding. The scheme starts from the analysis of the energy-networks responsible for the stabilization of the folded conformation, by means of the energy-decomposition approach. In this framework, the compact energetic map of the native state is generated by a preliminary short molecular dynamics (MD) simulation of the protein in explicit solvent. This map is simplified by means of an eigenvalue decomposition. The highest components of the eigenvector associated with the lowest eigenvalue indicate which sites, named "hot spots", are likely to be responsible for the stability and correct folding of the protein. In the Hamiltonian replica exchange protocol, we use modified force-field parameters to treat the interparticle non bonded potentials of the hot spots within the protein and between protein and solvent atoms, leaving unperturbed those relative to all other residues, as well as solvent-solvent interactions. We show that it is possible to reversibly simulate the folding/unfolding behavior of two test proteins, namely Villin HeadPiece HP35 (35 residues) and Protein A (62 residues), using a limited number of replicas. We next discuss possible implications for the study of folding mechanisms via all atom simulations. PMID- 23743828 TI - Serum metallothioneins in childhood tumours-a potential prognostic marker. AB - Metallothioneins (MT) are low molecular weight, cysteine-rich proteins maintaining metal ions homeostasis. They play a role in carcinogenesis and may also cause chemoresistance. The aim of the study was to explore the importance of MT serum levels in children suffering from malignant tumours. This prospective study involves examination of 865 samples from 172 patients with malignant tumours treated from 2008 to 2011 at University Hospital Motol. MT serum levels were determined using differential pulse voltammetry-Brdicka reaction. Mean MT level was 2.7 +/- 0.5 MUM. There was no statistically significant difference between MT levels in different tumours. We also did not find any correlation between MT levels and response to therapy or clinical stages. However, we found a positive correlation between MT levels and age (p = 0.009) and a negative correlation with absolute lymphocyte number (p = 0.001). The fact that patients who had early disease recurrence had lower MT levels during the treatment (complete remission 2.67 vs. recurring 2.34, p = 0.001) seems to be important for clinical practice. Accordingly we believe that there is benefit in further studies of serum MT levels in tumours. PMID- 23743829 TI - Effect of GABA, a bacterial metabolite, on Pseudomonas fluorescens surface properties and cytotoxicity. AB - Different bacterial species and, particularly Pseudomonas fluorescens, can produce gamma-aminobutyric acid (GABA) and express GABA-binding proteins. In this study, we investigated the effect of GABA on the virulence and biofilm formation activity of different strains of P. fluorescens. Exposure of a psychotropic strain of P. fluorescens (MF37) to GABA (10-5 M) increased its necrotic-like activity on eukaryotic (glial) cells, but reduced its apoptotic effect. Conversely, muscimol and bicuculline, the selective agonist and antagonist of eukaryote GABAA receptors, respectively, were ineffective. P. fluorescens MF37 did not produce biosurfactants, and its caseinase, esterase, amylase, hemolytic activity or pyoverdine productions were unchanged. In contrast, the effect of GABA was associated to rearrangements of the lipopolysaccharide (LPS) structure, particularly in the lipid A region. The surface hydrophobicity of MF37 was marginally modified, and GABA reduced its biofilm formation activity on PVC, but not on glass, although the initial adhesion was increased. Five other P. fluorescens strains were studied, and only one, MFP05, a strain isolated from human skin, showed structural differences of biofilm maturation after exposure to GABA. These results reveal that GABA can regulate the LPS structure and cytotoxicity of P. fluorescens, but that this property is specific to some strains. PMID- 23743830 TI - Enhancement of immune activation activities of Spirulina maxima grown in deep-sea water. AB - In this study, the immuno-modulatory and anticancer activities of marine algae, Spirulina maxima grown in deep-sea water (DSW), were investigated. It was found that the extract of S. maxima, cultured in DSW, effectively suppressed the expression of Bcl2 in A549 cells as well as inhibiting various human cancer cells with concentration dependency, which possibly implies that the extracts may play more important roles in controlling cancer cell growth. The secretion of cytokines IL-6 and TNF-alpha from human B cells was also greatly increased, compared to those of the extract grown in conventional sea-water. The growth of Human Natural Killer (NK) cells in the presence of the extracts from DSW was significantly higher (12.2 * 104 viable cells/mL) when compared to the control (1.1 * 104 viable cells/mL). Based on HPLC analysis, the increase in the biological activities of the extracts from DSW was caused by considerably high amounts of beta-carotene and ascorbic acid because the DSW contained high concentrations and good ratios of several key minerals for biosynthesizing beta carotene and ascorbic acid, as well as maintaining high cell growth. PMID- 23743831 TI - A multidimensional measure of sexual orientation, use of psychoactive substances, and depression: results of a national survey on sexual behavior in france. AB - Using data from a large national representative survey on sexual behavior in France (Contexte de la Sexualite en France), this study analyzed the relationship between a multidimensional measure of sexual orientation and psychoactive substance use and depression. The survey was conducted in 2006 by telephone with a random sample of the continental French speaking population between the ages of 18 and 69 years. The sample used for this analysis consisted of the 4,400 men and 5,472 women who were sexually active. A sexual orientation measure was constructed by combining information on three dimensions of sexual orientation: attraction, sexual behavior, and self-definition. Five mutually exclusive groups were defined for men and women: those with only heterosexual behavior were divided in two groups whether or not they declared any same-sex attraction; those with any same-sex partners were divided into three categories derived from their self-definition (heterosexual, bisexual or homosexual). The consumption of alcohol and cannabis, which was higher in the non-exclusively heterosexual groups, was more closely associated with homosexual self-identification for women than for men. Self-defined bisexuals (both male and female) followed by gay men and lesbians had the highest risk of chronic or recent depression. Self-defined heterosexuals who had same-sex partners or attraction had levels of risk between exclusive heterosexuals and self-identified homosexuals and bisexuals. The use of a multidimensional measure of sexual orientation demonstrated variation in substance use and mental health between non-heterosexual subgroups defined in terms of behavior, attraction, and identity. PMID- 23743832 TI - Scientific Department of Psychiatric Nursing and Mental Health of ABEn. PMID- 23743833 TI - [Conditions and motivations for the work of nurses and physicians in high complexity emergency services]. AB - This study aimed to evaluate the motivations and conditions offered to the work of nurses and doctors in three high complexity emergency services of the city of Recife, Pernambuco. It is a descriptive transversal type study. It was interviewed 42 nurses and 84 doctors, of a total population of 97 nurses and 469 doctors. It was used a questionnaire prepared for this survey and the Scale of Values Related to Work. On the motivation assessment it was found that Professional Realization was the major motivational factor, and Prestige the less important factor. PMID- 23743834 TI - [The nursing process in the opinion of the nursing staff of a teaching hospital]. AB - The aim of this study was to describe the nursing professionals' opinion on the nursing process, in order to base the actions of the implementation of the process in our institution. This is a qualitative study, carried out during an action research with the nursing staff of a pediatric teaching hospital. The nursing process is designed as a tool to organize care and prescribe nursing care. Work routines show the technical activities. Expectations with the implementation of nursing process involve improving the quality of care. The study reinforces the importance of including members of the nursing staff in the implementation stage of the nursing process and shows the challenge of facing the tecnicists routines. PMID- 23743835 TI - [Comfort and communication measures in nursing caring actions for critically ill patients]. AB - Descriptive, quantitative study carried out at a University Hospital in Curitiba PR, Brazil. The objective was to analyze the caring actions performed at a semi intensive care unit, from the perspective of the caring humanization, and also to evaluate the presence of comfort and communication measures in performing these actions. The data collection occurred under a systematic non-participant observation. The caring actions were grouped, according to its frequency, and presented in graphs. The comfort measures were present at 45% of the caring actions performed, and communication establishment was present at 40% of these actions. Even today, the comfort and communication measures, as reflected in the process of caring humanization, remain as an ideal speech. However, they are too far from reality of the health care system's users and workers. PMID- 23743836 TI - [Subset of ICNP(r) diagnostic concepts for patients with chronic kidney disease]. AB - This is a descriptive study, which aimed to propose a subset of nursing diagnoses for chronic renal failure patients in stage five of the disease, developing them according to the guidelines of the ICNP(r) and arranging them according to the concepts of Wanda de Aguiar Horta's Theory of Basic Human Needs; and validate the subset of nursing diagnoses proposed, subjecting them to experts for judging its relevance to chronic renal failure patients in stage five of the disease. It was drawn up, in total, a subset of 77 nursing diagnoses, among which 70 (90%) had a Concordance Index >= 0.80 among judges, being validated. The subset of nursing diagnoses resulting from the study is quite comprehensive, and one believe in its potential to subsidize a more comprehensive nursing care to the chronic renal patient. PMID- 23743837 TI - [Nursing diagnoses related to breastfeeding in a rooming-in unit]. AB - The study aimed to identify, in a Rooming-in unit, diagnoses related to the phenomenon of breastfeeding according to the NANDA-I Taxonomy II. It was conducted a descriptive exploratory study involving 83 mothers and their babies in the period of February to April 2011. Data were collected by means of an instrument based on the Theory of Basic Human Needs and, after statistical analysis, presented in tables. The results showed that the most frequent nursing diagnosis was Effective breastfeeding, identified in 65 (78.3%) cases. It is estimated that the nursing diagnoses related to breastfeeding can contribute to nursing care so that it can be more targeted, in order to promote a more qualified, effective and human care. PMID- 23743838 TI - [Nursing consultation for patient with HIV: perspectives and challenges from nurses' view]. AB - The study aims to examine how the nursing consultation is developed by the nurses workimg in in Outpatient Specialized Services on HIV / AIDS in the city of Fortaleza-CE. This is an exploratory and descriptive study with a qualitative approach that used content analysis as a technique for data analysis. To perform the nursing consultation, listening was reported by nurses as the main mechanism that enables the construction of empathy and trust relationship with the patient, allowing them to express their doubts, fears and anxieties. It also enables the spread of information and guidance about the pathology, as well as the convening of the subject for an active participation in the care process, trying to make them aware about the importance of the adherence to drug treatment. Nursing consultation configure itself as an educational moment, opportune for knowledge exchange and bonding. PMID- 23743839 TI - [Vulnerabilities present in the path experienced by patients with HIV / AIDS in treatment failure]. AB - A major breakthrough in AIDS treatment occurred with the advent of antiretroviral therapy. However, several vulnerabilities may be present in the path experienced by patients during treatment. This study aimed to analyze the vulnerabilities of patients with HIV / AIDS in treatment failure. It is a qualitative study, involving seven users with AIDS considered in treatment failure in an Outpatient Service Unit on HIV / AIDS, in Fortaleza-CE. To interpret the data, it was used the technique of content analysis. In the speeches, it was realized that the deponents faced conflicts in the family and, difficult relationships with people and stigma at work. It was observed that patients had experienced various situations that made them more susceptible to HIV infection and illness. PMID- 23743840 TI - [Inclusion of persons with disabilities in a Reference Center for STD / AIDS of a town in Bahia, Brazil]. AB - This qualitative study sought to ascertain the opinion of health professionals about the inclusion of people with disabilities in the activities of reception, prevention and treatment in a Reference Center for STD/AIDS. The data were submitted to Bardin's content analysis technique. The analysis showed that professionals conduct their service in the sense of inclusion, seeking ways of communication to reach these people as the use of LIBRAS, matching the physical structure, equality of attendance and understanding of the vulnerabilities of this population. Despite the great importance of strategies adopted in facilitating a friendly service to people with disabilities, those strategies leave mostly from isolated and individually activities. It is needed an effective link among the service managers and political actors in the construction and adaptation of materials, programs and public policies to achieve equitable and inclusion of this population. PMID- 23743841 TI - [Perceptions of people with diabetes about the disease: nursing contributions]. AB - This study aimed to identify the perceptions of patients concerning diabetes. This is a descriptive exploratory study with a qualitative approach, which was conducted with 32 subjects, in a hospital in the city of Belem-PA, Brazil. The thematic content analysis was used, from which four categories emerged: Diabetes control: nursing in the self-monitoring of blood glucose; The diabetic individual and nursing: an interaction with self-care; Nursing consultations provided to diabetic individuals: an intervention in the health-disease continuum; Diabetes and its complications: fear of loosing functioning. It was observed that patients start self-care driven by the fear of losing their health, that is, fear forces the patient to practice self-care. Nurses are directly linked to diabetes control as they start providing care and guidance for patients who self-monitor their disease. PMID- 23743843 TI - [Family dynamics in the caring context of adults on the fourth age]. AB - This study aimed to determine the pattern of family functioning on everyday care relationships of adults in the fourth age. This is a study of diagnostic evaluative nature of adults with 80 or more years old who depend on care, and of their relatives as caregivers. The participants were selected among the registered patients of a Family Health Unit in a district in the suburbs of Belem PA, Brazil. They were evaluated according to the dynamics of their family, and quality of life related health lifestyle. Most of the elderly rated their families with good functionality. However, data on the elderly and caregivers' quality of life and caregivers' life style only reached the median level, showing some difficulty in the family functioning system. It was concluded that the multiple results obtained through the assessments indicate some practical implications of care to the family unity and confirm the need for multidimensional assessment about the family intervention. PMID- 23743842 TI - [Gestational diabetes from the perspective of hospitalized pregnant women]. AB - This phenomenological qualitative study aimed to understand the meaning of the experiences lived by women with gestational diabetes mellitus. The sample consisted of 12 patients hospitalized at a maternity hospital in the city of Fortaleza, state of Ceara, Brazil, which expressed their feelings and perceptions through open interviews and drawings. The empirical material was fully transcribed and then organized and analyzed by the phenomenological method. The results revealed two themes: (1) Living experiences that bring happiness and well being, and (2) Living experiences that cause suffering. This phenomenological study showed the experience of women with gestational diabetes mellitus, thus enabling to plan and to implement intervention programs based on a participatory model of health in order to prioritize the subjective aspects involved in high risk pregnancy. PMID- 23743844 TI - [Prevalence of falls in older adults enrolled in a Health Center of Belo Horizonte-MG]. AB - Fall is used as an indicator of quality in healthcare institutions specialized in elderly care and is also considered an important indicator of quality of life of seniors in all environments. This is a cross-sectional study with a convenience sample of 108 elderlies enrolled at a Health Center, in Belo Horizonte, Minas Gerais, in order to determine the occurrence of falls in elderly people and also look for its association with some variables. Data were collected from clinical records and interviews during home healthcare visits using a structured and specific instrument. It was found that 64 (59.3%) of the elderly patients have already suffered falls, and a significant statistical relationship (p=0.01) between the elderly cognitive ability and the occurrence of the falls. It is recommended that nursing care focuses in the early identification of the elderlies that are more likely to suffer falls, especially those who, in addition to the risk of falling are at increased risk of suffering serious injury originated from the falls. PMID- 23743845 TI - [Different configurations of violence in pedagogical relationships between teachers and students of higher education]. AB - The aim of this study was to investigate the different settings of violence in pedagogical relations between teachers and students in a higher education from the theory of violence symbolic power. Twelve interviews were conducted with students from six courses of graduation from a higher educational institution; it was used the content analysis to interpret the data. It was found that violence is configured from the most subtle to the most noticeable way and that, although violence was present in the pedagogical processes of the context studied, this was not fully realized, probably because of the reproduction of the symbolic order, socially constructed and internalized by teachers and students. It is considered that the teaching practice needs to be improved in order to make the classroom democratic spaces and to make the students share responsibility for the pursuit of knowledge. We conclude that violence in relationships pedagogical produces certain effects, changes and consequences both, immediate and delayed, which can be minimized. PMID- 23743846 TI - [Theses and dissertations of nurses about education in nursing and health: a bibliometric study]. AB - The study aimed to describe the panorama of Education in Nursing and Health from abstracts of theses and dissertations published by nurses in Brazil between the years 2001 to 2009. This is a bibliometric, descriptive and quantitative study. Data were collected in the "Catalogue of Theses and Dissertations" from CEPEn/ABEn. After reading the abstracts and systematization of the material, analysis was performed using descriptive statistics. It was reviewed 4.101 studies, 523 of them on the theme of education. From these, 67% were dissertations and 33% of them were theses, predominantly produced in the southeast of Brazil. One conclude that the representation of the theme in the national context is significant and contributes to the advancement of knowledge in the field of Nursing, even though there are regional differences in the production process of this area of knowledge. PMID- 23743847 TI - [Nurses' practices in the nursing and health care management: integrative review]. AB - This study aimed to highlight and analyze the nurses' practices in care management described in the scientific production in Brazil and internationally, through an integrative review. It was examined articles published between 2005 and 2010, in the LILACS, SciELO, BDENF and CINAHL databases, with the descriptors Management and Administration, in conjunction with Care and Nursing, and the terms Nursing Management and Nursing Care, totaling 27 publications. The management of care performed by nurses is directly related to the search for quality care and better working conditions through actions such as: care realization, human and material resources management, leadership, assistance planning, nursing team training, care coordination and evaluation of nursing actions. PMID- 23743848 TI - [Impact of childhood cancer for family caregivers: integrative review]. AB - This is an integrative review that aimed to identify the repercussions of childhood cancer for the family caregiver. The research was done in the databases LILACS, PubMed, SciELO, Adolec and Cochrane, searching articles in English, Portuguese and Spanish; published between 2005 and 2010; using the descriptors: caregivers, children, cancer and nursing. Eighteen articles was found. Through the analysis four themes were identified: feelings experienced by family caregivers; physical repercussions and psychological distress of family caregivers; financial impact of childhood cancer in the caregiver's life, and need for social support to family caregivers. It was concluded that the damage to the caregiver's life can weaken the relationship between child/caregiver, determining the need of effective performance of the health team to offer support, guidance and monitoring. PMID- 23743849 TI - [Public health policies facing the epidemic of AIDS and the assistance for people with the disease]. AB - The study aimed to identify the major public policy on HIV/AIDS in Brazilian society, since 1980; and to reflect on their impact on the assistance for people living with HIV/AIDS. DESCRIPTORS: public health policies, Acquired Immunodeficiency Syndrome and integral health care, we obtained a sample of 23 articles in Medline and Lilacs data bases. After analysis, there were two moments: first, the emergence of public policies in response to the AIDS epidemic, and second, to improve care for people living with HIV/AIDS. Despite the significant advances achieved in terms of public health policies in Brazil, there is a complex way in the pursuit of quality of care for people with HIV/AIDS. PMID- 23743850 TI - [Interconnection between the history of Brazilian nursing education and the ecosystem thoughts]. AB - This paper aimed to recover, through a theoretical-reflexive, a brief history of graduate nursing in Brazil, and its relationship with ecosystem thoughts. In the discussion one tried to reflect on the history of Brazilian nursing perspective grounded in the Thought Ecosystem. The reflection allowed to cover the meant that the higher education systemic element provides with the space in which it operates and how it processes its construction and modifications through the principles of ecosystem integration, cooperation, interrelation, interdependence and influence among both. PMID- 23743851 TI - [Pedagogical strategies for developing ethical and political competence in nursing education]. AB - This study presents a theoretical reflection that aims at identifying teaching strategies for the development of ethical-political dimension of professional competence from the perspective of critical reflection. Professional competence has two dimensions - technical and political, mediated by ethics. Critical reflection renew search ways of thinking and doing in health, with the ultimate goal of intervention in social reality, to improve the living conditions and health of communities. Highlights some educational tools such as portfolio, the field journal and written narratives, which allow producing a clear and objective account of the experience and assigning meaning and significance of what was accomplished. Based on a critical reflection, such instruments helped develop ethical-political dimension of professional competence. PMID- 23743852 TI - [Ethical considerations about research with women in situations of violence]. AB - This essay aims at reflecting on the ethical and methodological principles involved in research with women in situation of violence. The text raises the discussion of the application of the principles of beneficence and non maleficence during researches involving this issue, pointing to recommendations towards privacy, autonomy and immediate contributions for volunteers. Then, taking as theoretical reference the principles of justice and equity, the authors propose a debate on methodological aspects involved in protection of respondents, with a view at improving the quality of the data obtained and possible social contributions. PMID- 23743853 TI - Successful treatment of central nervous system PTLD with rituximab and cranial radiotherapy. AB - BACKGROUND: Primary central nervous system (PCNS) post-transplant lymphoproliferative disorder (PTLD) is a rare complication of solid organ transplantation and is typically an Epstein-Barr virus (EBV)-induced B-cell CD20+ lymphoma. The modalities of treatment include reduction in immunosuppression, cranial radiotherapy (CRT), intravenous and intrathecal rituximab when CD20 is expressed on B-lymphocytes and PTLD cells, and chemotherapy. CASE DIAGNOSIS/TREATMENT: We report the successful treatment of EBV-driven PCNS PTLD by reduction in immunosuppression (RI), CRT, and intravenous rituximab. Our patient was an 11-year-old boy with a living-related renal transplant for end stage renal failure (ESRF) secondary to posterior urethral valves (PUV) and bilateral renal dysplasia (BRD) and on triple immunosuppression with prednisolone, tacrolimus, and azathioprine who had a rising EBV load, which was managed with reduction in tacrolimus dose, withdrawal of azathioprine, and introduction of mycophenolate mofetil (MMF). CONCLUSIONS: The patient presented 7 years post-transplant with a seizure and abnormal neurology secondary to polymorphous hyperplastic lesions in the brain, which responded to rituximab and CRT. PMID- 23743854 TI - An unusual cause of severe rickets. PMID- 23743855 TI - Does self-management counseling in patients with heart failure improve quality of life? Findings from the Heart Failure Adherence and Retention Trial (HART). AB - PURPOSE: Heart failure (HF) is associated with poor health-related quality of life (HRQOL). The purpose of our study is to determine the effect of a self management intervention on HRQOL domains across time, overall, and in prespecified demographic, clinical, and psychosocial subgroups of HF patients. METHODS: HART was a single-center, multi-hospital randomized trial. Patients (n = 902) were randomized either to a self-management intervention with provision of HF educational information or an enhanced education control group which received the same HF educational materials. HRQOL was measured by the Quality of Life Index, Cardiac Version, modified, and the Medical Outcomes Study 36-item Short Form Health Survey physical functioning scale. Analyses included descriptive statistics and mixed-effects regression models. RESULTS: In general, overall, study participants' HRQOL improved over time. However, no significant differences in HRQOL domain were detected between treatment groups at baseline or across time (p > 0.05). Subgroup analyses demonstrated no differences by treatment arm for change in HRQOL from baseline to 3 years later. CONCLUSIONS: We conclude that in our cohort of patients, the self-management intervention had no benefit over enhanced education in improving domains of HRQOL and HRQOL for specified HF subgroups. PMID- 23743856 TI - Psychometric analysis of the Swedish translation of the WHO well-being index. AB - PURPOSE: The purpose of this study is to validate the Swedish translation of the WHO (Ten) and WHO (Five) Well-Being Questionnaires among three samples of Swedes. METHODS: Baseline data collected in 2008 from the Health Assets Project are the data source consisting of three cohorts of Swedes aged 19-64 years: (1) a randomized general population cohort (n = 4,027); (2) employees sick-listed reported by the employer (n = 3,310); and (3) self-certified sick-listed individuals (n = 498). The psychometric properties of the scales are assessed using factor analysis, Cronbach's alpha, and examination of the relationship between scale scores and participants' self-reported adverse health conditions. RESULTS: Factor analysis revealed a unidimensional factor structure for both scales, and Cronbach's alphas are very good to excellent. The scales correlate in the expected direction with almost all of the adverse health conditions considered. CONCLUSIONS: The Swedish translation of the WHO (Ten) and WHO (Five) Well-Being Questionnaires is psychometrically sound, but the first item of both scales has weaker psychometric qualities in comparison with other scale items. PMID- 23743858 TI - A multiparameter flow cytometry immunophenotypic algorithm for the identification of newly diagnosed symptomatic myeloma with an MGUS-like signature and long-term disease control. AB - Achieving complete remission (CR) in multiple myeloma (MM) translates into extended survival, but two subgroups of patients fall outside this paradigm: cases with unsustained CR, and patients that do not achieve CR but return into a monoclonal gammopathy of undetermined significance (MGUS)-like status with long term survival. Here, we describe a novel automated flow cytometric classification focused on the analysis of the plasma-cell compartment to identify among newly diagnosed symptomatic MM patients (N=698) cases with a baseline MGUS-like profile, by comparing them to MGUS (N=497) patients and validating the classification model in 114 smoldering MM patients. Overall, 59 symptomatic MM patients (8%) showed an MGUS-like profile. Despite achieving similar CR rates after high-dose therapy/autologous stem cell transplantation vs other MM patients, MGUS-like cases had unprecedented longer time-to-progression (TTP) and overall survival (OS; ~60% at 10 years; P<0.001). Importantly, MGUS-like MM patients failing to achieve CR showed similar TTP (P=0.81) and OS (P=0.24) vs cases attaining CR. This automated classification also identified MGUS patients with shorter TTP (P=0.001, hazard ratio: 5.53) and ultra-high-risk smoldering MM (median TTP, 15 months). In summary, we have developed a biomarker that identifies a subset of symptomatic MM patients with an occult MGUS-like signature and an excellent outcome, independently of the depth of response. PMID- 23743857 TI - Depression and painful conditions: patterns of association with health status and health utility ratings in the general population. AB - PURPOSE: Preference-weighted HRQoL (utility) ratings are increasingly used to guide clinical and resource allocation decisions, but their performance has not always been adequately explored. We sought to examine patterns of health utility ratings in community populations with depressive disorders and painful conditions. METHODS: We used two Canadian cross-sectional health surveys that obtained Comprehensive Health Status Measurement System/Health Utilities Index Mark 3 (HUI3) ratings and identified people with painful conditions and major depression. We estimated the frequency of item endorsements and mean utility ratings in these groups. RESULTS: Interesting differences between health state ratings and diagnostic categories were noted. For example, 71% of those professionally diagnosed with migraine reported that they usually have "no pain." Despite this, utility ratings were lower in those respondents with depressive episodes and in those with painful conditions. Greater than additive reductions in HUI3 scores were noted in most instances where both depressive disorders and painful conditions were present. CONCLUSIONS: Health utility ratings confirm the clinical impression that painful conditions and depressive disorders magnify each other's impact. Despite weak alignment between the health state definitions incorporated into utility ratings and the diagnostic concepts examined, the HUI3 appeared to capture HRQoL decrements and negative synergies associated with the co-occurrence of depressive episodes and painful conditions. PMID- 23743859 TI - Two-dimensional array Debye ring diffraction protein recognition sensing. AB - We attach 2-D colloidal arrays onto the surface of hydrogels containing biotin. The hydrogel volume shrinks with increasing concentrations of avidin due to the formation of avidin-biotin crosslinks. This causes the Debye diffraction ring diameter to increase, and the 2-D diffraction wavelength to blue-shift. PMID- 23743860 TI - Sodium reduction in populations: insights from the Institute of Medicine committee. PMID- 23743861 TI - Treatment of femoroacetabular impingement: a systematic review. AB - The purpose of this review is to determine if there is a difference in outcomes after: (1) nonsurgical vs surgical treatment of FAI; (2a) surgical dislocation with greater trochanteric osteotomy, (2b) anterior mini-open, (2c) arthroscopic plus mini-open, and (2d) arthroscopic surgery for FAI; (3) difference in complication and re-operation rates; and (4a) labral refixation and (4b) labral debridement for labral injuries. A systematic review of multiple databases was performed after PROSPERO registration and using PRISMA guidelines. Level I-IV evidence clinical studies with minimum 2-year follow-up were included. Data were compared using 2-sample and 2-proportion Z-test calculators. Study methodological quality was analyzed using Modified Coleman Methodology Score (MCMS). Recommendations were made using SORT (Strength Of Recommendation Taxonomy). Twenty-nine studies were included (2369 subjects; 2507 hips). MCMS was poor. Mean subject age was 34.4+/-8.4 years and mean follow-up was 3.1+/-0.9 years. Statistically significant differences were observed following both nonsurgical and surgical treatment, with greater (P < 0.05) improvements following surgery (SORT B), without consistent significant differences observed between different surgical techniques (SORT C). There was a greater (P < 0.05) reoperation and complication rate following surgical dislocation vs mini-open and arthroscopic techniques (SORT A). Clinical outcomes were significantly better (P < 0.05) following labral refixation vs debridement (SORT B). Outcomes of operative treatment of femoroacetabular impingement are significantly better than nonsurgical management. Surgical treatment significantly improves outcomes, with no consistent significant differences exhibited between open and arthroscopic techniques. Open surgical dislocation has significantly greater reoperation and complication rates vs mini-open and arthroscopic techniques. Outcomes of labral refixation are significantly better than debridement in patients with labral injuries. PMID- 23743862 TI - Magnetic resonance imaging and tracking of stem cells. AB - To date, several stem cell labeling protocols have been developed, contributing to a fast growing and promising field of stem cell imaging by MRI (magnetic resonance imaging). Most of these methods utilize iron oxide nanoparticles (MION, SPIO, USPIO, VSIOP) for cell labeling, which provide negative (dark) signal effects on T2-weighted MR images. The following protocol describes stem cell labeling techniques with commercially available gadolinium chelates, which provide positive contrast on T1-weighted MR images, which can be advantageous for specific applications. PMID- 23743867 TI - Death related to Ibuprofen, valdecoxib, and medical errors: case report and medicolegal issues. PMID- 23743868 TI - Weight loss by commercial drivers to reduce the risk of obstructive sleep apnea. PMID- 23743869 TI - Does health risk reduction technology really work? PMID- 23743872 TI - Assessment of ocular hemodynamics after laser in situ keratomileusis using color Doppler imaging. AB - To investigate ocular blood flow changes in healthy myopic patients following laser in situ keratomileusis (LASIK) using color Doppler imaging. Sixteen eyes of 16 myopic patients were studied. LASIK was performed and intraocular pressure was raised to levels >=65 mmHg. Color Doppler images were obtained to study the ophthalmic and central retinal arteries preoperatively and postoperatively at 1 day, 1 week, and 1 month. There was no significant correlation between patient age and preoperative ocular blood flow parameters. A significant positive correlation between the degree of myopia and the peak systolic volume of the ophthalmic artery (r = 0.6, P = 0.01) was found. A highly significant decrease in the peak systolic volume and end-diastolic volume with an increase in the resistive index of both arteries (P < 0.005) was seen at 1 day and 1 week postoperatively. There was no significant difference between the preoperative and postoperative data 1 month after the procedure. The findings of this study show temporary alterations in ocular blood flow parameters after LASIK. LASIK is an increasingly common lifestyle procedure and further studies on larger groups are still recommended. PMID- 23743873 TI - Influence of real-world environments on the motion of catalytic bubble-propelled micromotors. AB - Self-propelled autonomous micromachines have recently been tasked to carry out various roles in real environments. In this study, we expose the microjets to various types of water that are present in the real world, examples include tap water, rain water, lake water and sea water, and we sought to investigate their behaviors under real world conditions. We observed that the viability and mobility of the catalytic bubble jet engines are strongly influenced by the type of environmental water sample. Amongst the four water samples tested, the seawater sample exhibits the strongest influence, completely disabling any motions arising from the microjets. The motion of the microjets is also reduced in tap water, which contains large quantities of inorganic ions that have been purposely introduced into tap water via processing in water treatment plants. Lake water and rain water samples exhibited the least influence on the microjet's motion. All of the four water samples were also characterized by determining their ion compositions and conductivities, and we will show that there is a distinct correlation between the reduced mobility of the microjets with the ion content of the water found in real environments. PMID- 23743874 TI - Association of IL-1 receptor antagonist gene VNTR polymorphism with ischemic stroke in the Chinese Uyghur population. PMID- 23743875 TI - Population genetic study of Fagopyrum tataricum from Western Himalaya using ISSR markers. AB - Inter-simple sequence repeat (ISSR) markers were used to analyze genetic diversity and relatedness of 15 germplasms of Fagopyrum tataricum. Samples representing 75 individuals were collected from a range of altitudes in the Western Himalaya. The 13 ISSR primers revealed 98.1% polymorphism among populations, whereas average polymorphism was extremely low (2.18%) within populations. The coefficient of population differentiation was 0.9750, with limited gene flow (N m) of 0.0128. The average PIC value of the ISSR markers was high (0.812), with a marker ratio of 0.65 and marker index of 6.66. The genetic diversity of F. tataricum significantly correlated with altitude and gene diversity, Shannon's index, and the percentage of polymorphic bands. The genetic diversity among populations showed broad genetic base and provided a developmental strategy for crop improvement. PMID- 23743876 TI - Application of sub-regional analysis to bone mineral density of the lower limb from whole body DXA scans. AB - Bone mineral density at spine and hip is widely used to diagnose osteoporosis. Certain conditions cause changes in bone density at other sites, particularly in the lower limb, with fractures occurring in non-classical locations. Bone density changes at these sites would be of interest for diagnosis and treatment. We describe an application, based on an existing software option for Hologic scanners, which allows reproducible measurement of bone density at six lower limb sites (upper femur, mid-femur, lower femur; upper leg, mid-leg, lower leg). In 30 unselected subjects, referred for bone density, precision (CV%) measured on 2 occasions, separated by repositioning, ranged from 1.7% (mid-femur) to 4.5% at the lowest leg site. Intra-operator precision, measured by three operators on ten subjects on three occasions, was between 1.0% and 2.9%, whilst inter-operator precision was between 1.0% and 3.6%, according to region. These values compare well with those at the spine and upper femur, and in the literature. There was no evidence that this operator agreement improved between occasions 1 and 3. This technique promises to be useful for assessing bone changes at vulnerable sites in the lower limb, in diverse pathological states and in assessing response to treatment. PMID- 23743877 TI - Multicenter study evaluating the clinical performance of the OSNA assay for the molecular detection of lymph node metastases in gastric cancer patients. AB - BACKGROUND: The accurate diagnosis of lymph node (LN) metastasis is important for making treatment decisions for gastric cancer patients. This multicenter study evaluated the clinical performance of the one-step nucleic acid amplification (OSNA) assay (Sysmex Corp.), an automated system that detects cytokeratin 19 (CK19) mRNA, in detecting LN metastases in gastric cancer patients. METHODS: LNs retrieved from patients who had undergone gastric cancer surgery at one of the four Japanese hospitals involved in this study were divided into blocks at 2-mm intervals. Alternate blocks were examined with the OSNA assay and the remaining blocks were assessed histologically. RESULTS: A total of 394 LNs from 61 patients were examined. The concordance rate between the OSNA assay and the histological examination was 0.942 (95 % CI, 0.914-0.963). Sensitivity and specificity of the OSNA assay compared to the histological examination were 0.833 (95 % CI, 0.707 0.921) and 0.959 (95 % CI, 0.932-0.977), respectively. Discordant results were observed in 23 LNs (5.8 %), and these were mainly the result of tissue allocation bias and/or low CK19 protein expression. CONCLUSION: The OSNA assay can detect lymph node metastases in gastric cancer patients as accurately as the histological examination of blocks sectioned at 2-mm intervals. The OSNA assay is a useful tool for the intraoperative diagnosis of LN metastasis in gastric cancer patients. PMID- 23743878 TI - Laparoscopic wedge resection of the stomach for gastrointestinal stromal tumor (GIST): non-touch lesion lifting method. AB - BACKGROUND: Laparoscopic surgery for GIST carries a risk of intraoperative tumor dissemination. To avoid tumor dissemination, we have utilized a "non-touch" method for surgical resection of GIST since 2000. METHODS: Forty-two patients with gastric GIST were treated at our institution between 2000 and 2012. Laparoscopic wedge resection of the stomach was used as the standard procedure for tumors that were 2-5 cm in size. Tumors larger than 5 cm were treated with open surgery. Our non-touch procedure included a lesion-lifting method using traction sutures at the normal stomach wall around the tumor. Intraoperative gastroscopy was utilized to confirm the location of the tumor with laparoscopy. After lifting of the tumor, tumors with a clear operative margin were resected using a linear stapler. Tumors located at the posterior wall of the stomach or located near the esophagogastric junction were resected using traction sutures. RESULTS: Median operative time was 140 min and median blood loss was 0 ml. Postoperative course was uneventful excepting one patient who experienced postoperative bleeding. The median postoperative stay was 7 days. One patient developed liver metastasis after surgery. None of the patients had local recurrence or peritoneal recurrence case. CONCLUSION: This non-touch lesion lifting method was useful for the surgical management of gastric GIST. PMID- 23743879 TI - Efficacy of a multicomponent support programme for the caregivers of disabled persons: a randomised controlled study. AB - AIM: The goal of the present work was to measure the efficacy of a multicomponent programme designed to provide tailored support for the caregivers of disabled persons. SUBJECTS: A total of 135 caregivers-care receiver dyads were randomly divided into an intervention group (n = 66) and a control group (n = 69). One third of the care receivers were demented, and two-thirds had other diseases. SETTING: Health centres (publicly funded primary health care systems) in 8 rural and urban communities in southeast Finland. INTERVENTION: The multicomponent support programme for the caregivers consisted of a 2-week rehabilitation period. The control group received standard care. OUTCOME MEASUREMENTS: Continuation of the caregiver and care receiver relationship, care receiver mortality at the 2 year follow-up as well as the health-related quality of life (15D scale) and Zung's depression scale of the caregiver at the 1-year follow-up were evaluated. RESULTS: At the 2-year follow-up, the caregiver-care receiver relationship was terminated for any reason in 11 cases (17%) in the intervention group, and in 25 cases (36%) in the control group. After adjusting, the primary outcome (i.e., termination of care giving for any reason) indicated statistical significance (p = 0.04) with a hazard rate of 1.83 (95% confidence interval 1.03-3.29). With a similar adjustment, the difference in mortality and placement to institutional care between the two groups demonstrated a trend towards statistical significance. The caregivers' health, as related to quality of life and depressive symptoms, remained unchanged in both groups at the 1-year follow-up. CONCLUSION: These results indicate that a tailored support programme for caregivers may help the caregiver to continue the caregiver-care receiver relationship and delay institutionalization. PMID- 23743880 TI - Quality of life in an ageing society : a comparative analysis of age cohorts in Turkey. AB - The aim of this study is to bring into focus the living conditions of the older adults in Turkey by using quality of life (QoL) criteria through which to highlight dimensions relating to their QoL status in comparison to other age cohorts. Are there specific QoL issues among older adults that would indicate that they display systematic differences in comparison to other age cohorts in Turkey? To what extent are there gender differences among older adults in QoL status? Data from the EQLS conducted in 2007 provided the information for understanding the self-reported conditions of older adults. Analysis shows that, for historical and contemporary reasons, older adults in Turkey form a disadvantaged cohort compared to other groups. The level of deprivation among a large segment of older adults is noteworthy in terms of income, health, material living conditions and social relations. Moreover, current social policies are blind to the low level of welfare, cultural capital, and connectedness of older women, resulting in unacceptable levels of alienation, unhappiness, and marginal status. PMID- 23743881 TI - The prevalence of falls in adults aged 40 years or older in an urban, German population. Results from a telephone survey. AB - BACKGROUND: Single or frequent falls lead to increased morbidity due to fall related injury, fear of falling, impairments in quality of life and loss of independence. To assess the impact of falls, prevalence data are essential. METHODS: In 2006, a telephone survey was performed in a random sample of 1270 inhabitants of the city of Herne, Germany, aged 40 years or older. Participants were asked about falls during the previous 4 weeks and 6 and 12 months, respectively. A fall was defined as an unexpected event in which the individual comes to rest on the ground, floor or a lower level. Participants were also asked about pain and whether or not a medical diagnosis of osteoporosis had ever been made. Standardized prevalences and odds ratios (OR) with 95 % confidence interval are reported. RESULTS: In total, 862 (67.9 %) adults participated. Participants were significantly older than non-participants and more often female than male. Prevalences standardized for the population of Herne for at least one fall within the previous 4 weeks or 12 months or two or more falls within 12 months, respectively, were 3.1 %, 12.1 %, and 4.5 %. Women were more often affected than men. A total of 2.3 % participants reported both at least one fall and a medical diagnosis of osteoporosis. The prevalence of falls increased with increasing age and was also related to musculoskeletal pain. CONCLUSIONS: Our estimates indicate that single and multiple falls affect a substantial proportion of adults in the urban population. Risk groups such as older adults and females with osteoporosis might represent a target group when considering measures for fall prevention. PMID- 23743882 TI - [Gender aspects in cardiovascular diseases]. AB - Cardiovascular diseases are the main cause of death in women and men worldwide, and, especially as far as coronary heart disorders are concerned, this is true of an increasing number of older and elderly persons. For decades, Gender Medicine research has shown gender differences in cardiology to the detriment of women, for example it takes longer for them to receive and they are less likely to have access to high-tech medicine, such as the ICU, heart catheters, bypass surgery, and they have a poorer outcome. Meanwhile, numerous scientific studies and awareness campaigns have been conducted. However, the more recent publications still show the same trends, albeit at a decreasing rate. Thanks to the emphasis placed on prevention and, thus, also the attention called to the leading heart risk factors such as smoking, high blood pressure, blood lipids, diabetes mellitus and overweight, namely for women and men, heart death is no longer exclusively male. In order to promote equal opportunity, Gender Medicine must be further implemented in medical training and post-graduate training, and-above all the scientific findings concerning Gender Medicine must be incorporated into the guidelines of our professional societies. PMID- 23743884 TI - [Caricatures of aging in German newspapers and magazine cartoons. Historical comparison between the 1960s and the present]. AB - BACKGROUND: The focus of this study was the collective images of aging that were unconsciously used despite rationally led social discourse on aging. Hypothesized was that despite changes in aging over the last 50 years these images went unaltered and thereby negative stereotypes of previous generations were maintained. In an effort to verify this hypothesis images of aging in cartoons were empirically examined, a first in the field of German language. METHODS: Using a social scientific operationalization of age stereotypes and culturally historical topoi as a basis, a content analysis was conducted on 2,546 cartoons (with 8,882 characters) from the years 1960-1964 and 2007. RESULTS: In general both young and old age are equally encoded with negative connotations by deficient characteristics and acknowledged stereotypes partially significantly more often in the cartoons from 2007 than from 1960-1964. CONCLUSIONS: The last 50 years have seen no substantial changes in the images of aging as depicted by magazine and newspaper cartoons. Humor requires more frequent analysis as it often unconsciously reveals socially unacceptable images of aging, even those embedded in science. PMID- 23743883 TI - [Serum hepcidin levels in geriatric patients with iron deficiency anemia or anemia of chronic diseases]. AB - BACKGROUND: Iron deficiency anemia (IDA) and anemia of chronic diseases (ACD) are common in the geriatric population. However, differentiation between IDA and ACD is still problematic. Hepcidin is a key regulator of iron homeostasis: downregulation in the presence of iron deficiency allows enteral iron resorption, while upregulation in case of chronic inflammation blocks it. We aimed at studying whether serum hepcidin levels might serve as diagnostic parameter to differentiate between IDA and ACD among elderly. PATIENTS AND METHODS: A total of 37 patients (age 69-97 years) were divided into 4 groups: group I (IDA), group II (ACD), group III (controls), and group IV (IDA/ACD). Serum hepcidin levels were analyzed using a commercially available ELISA kit (DRG Instruments, Marburg, Germany). Differences in hepcidin levels were tested with nonparametric methods. RESULTS: We could show a strong positive correlation between serum hepcidin and ferritin (Spearman rho 0.747) and a statistic significant difference of hepcidin levels among all groups (p = 0.034). Hepcidin levels between ACD and controls differed significantly (p = 0.003). CONCLUSION: Despite the small number of patients included in this study, which reduces the strength of the study's evidence, results conform with the current literature: it can be assumed that hepcidin will be used as a diagnostic parameter to differentiate between IDA and ACD in the future. However, more studies with larger patient groups are urgently needed to answer this question. PMID- 23743885 TI - [World War II and current care provision: impact of war-related trauma on present professional care situations]. AB - BACKGROUND: This study represents the first empirical research into the impact of war-related trauma on present professional care situations in Germany. METHODS: A total of 105 professional caregivers from North Rhine-Westphalia were questioned in a standardized form about the impact of war-related trauma on the daily work. RESULTS: Of the professional caregivers questioned 82%reported that they were already caring for a person suffering from post-war trauma and 77% stated that war-related trauma had an impact on the daily work. Altogether 63% reported that war-related trauma is highly significant for the daily work. The professional caregivers reported that there was often a lack of knowledge and awareness of the topic among colleagues. CONCLUSIONS: The study showed that there is a need for increasing awareness and providing further staff education and training regarding the treatment of people suffering from (war-related) trauma in order to ensure adequate care for those concerned. PMID- 23743886 TI - [Nutrition in old age]. PMID- 23743887 TI - Self-assembly of a 1D hydrogen-bonded polymer from a hexamethyltetraaza macrocyclic nickel(II) complex and isophthalic acid. AB - The compound [Ni(L)(isoph)2][Ni(L)].8H2O (1; L = C-meso-5,5,7,12,12,14-hexamethyl 1,4,8,11-tetraazacyclotetradecane; H2-isoph = isophthalic acid) has been synthesized and structurally characterized. Complex 1 exhibits a geometrically symmetric core with a {4/6} coordination number set. The coordination environment around the Ni(1) ion is a distorted octahedron, while the geometry around the four-coordinate Ni(2) is depicted as square planar in 1D hydrogen-bonded infinite chain. The compound crystallizes in the triclinic system P-1 with a = 8.602(2), b = 10.684(7), c = 16.550(3) A, a = 91.04(4), b = 94.09(2), g = 111.09(4) degrees , V = 1413.9(10) A3, Z = 1. The cyclic voltammogram of 1 undergoes one-electron wave corresponding to NiII/NiI process. The electronic spectra, electrochemical and TGA behavior of the complex are significantly affected by the nature of the hexamethyltetraaza macrocycle and the axial isoph2- ligand. PMID- 23743888 TI - Biomedical importance of indoles. AB - The indole nucleus is an important element of many natural and synthetic molecules with significant biological activity. This review covers some of the relevant and recent achievements in the biological, chemical and pharmacological activity of important indole derivatives in the areas of drug discovery and analysis. PMID- 23743890 TI - The Brazilian Centre for Evidence-based Healthcare: an Affiliate Centre of the Joanna Briggs Institute. PMID- 23743889 TI - HIV and thyroid dysfunction. AB - Human Immunodeficiency virus (HIV) infection and Acquired Immunodeficiency Syndrome (AIDS) are associated with dysfunction of many endocrine organs and their axis. HIV infectivity leads to altered metabolism, poor oral intake and increased prevalence of weight loss and wasting which may have a role in thyroid dysfunction. Overt thyroid dysfunction occurs at similar rates as the general population while subclinical disease such as nonthyroidal illness (sick euthyroid syndrome), subclinical hypothyroidism and isolated low T4 levels are more frequent. Moreover, HAART therapy can complicate thyroid function further through drug interactions and the immune reconstitution inflammatory syndrome (IRIS). In this review we report the common thyroid dysfunctions associated with HIV before and after HAART therapy. We discuss presentation, diagnostic work up, treatment and follow up in each condition. PMID- 23743891 TI - [Prenatal care from puerperal women's point of view: from medicalization to the fragmentation of care]. AB - This qualitative and exploratory-descriptive study aimed to reveal the perceptions of puerperal women about prenatal service care. The data collected through semi-structured interviews were submitted to thematic analysis and consisted of the opinions of eight puerperal women. The access, booking of consultations and provision of priority services in case of complications were highlighted as qualifiers of the prenatal care. The study revealed limitations concerning the comprehensive care, humanization, sheltering, bond absence, indiscriminate use of technologies and unnecessary interventions, which can produce or enhance vulnerabilities. The results indicate the necessity of refocusing attention to the prenatal period and birth, under the longitudinality of care aspect, both in public and private services; pact of actions between the related sectors to promote women's health is necessary to support the formulation of more equitable and positive public policies for comprehensive care perspective. PMID- 23743892 TI - [The promotion of women's autonomy during family health nursing consultations]. AB - We adopted a qualitative approach combined with the methodological framework of Paulo Freire, consisting of thematic investigation, coding and decoding, and critical unveiling, to understand whether nursing consultation promotes women's autonomy in a health center. Six Culture Circles that were each two hours long were conducted, with an average of nine participants each, between May and July 2011. The investigation revealed eight topics of importance, although two were particularly important: the need for dialogue on domestic violence and the relationship between nurses and participants during consultations. The results indicate that consultations may present a space for women to take actions that they may otherwise be fearful to take. Our results highlight the need for multidisciplinary training of nurses with regard to strategies for promotion and intensification of their practices in the Unified Health System. PMID- 23743893 TI - [Women's strategies for coping with urinary incontinence]. AB - This article is part of a more comprehensive qualitative study which used grounded theory and symbolic interactionism as theoretical and methodological frameworks, resulting in the theoretical model entitled, Between suffering and hope: rehabilitation of urinary incontinence as an intervenient component. In order to communicate all the knowledge produced, part of this model is presented, and it refers to the process of coping with urinary incontinence by women without perspectives of access to surgical treatment after failure of conservative procedures. When interrelating the components (categories and subcategories) of these women's experience in order to compare and analyze them to understand their interaction, moral and psychosocial vulnerability were noticed within the experience of the group, which makes them susceptible to health risks and to compromise of their quality of life, observed in the movement of the group's experience. Research is needed to further understand experiences in which there are barriers to surgical treatment due to physicians' disbelief in its effectiveness. PMID- 23743894 TI - [The evaluative limits and possibilities in the family health strategy for gender based violence]. AB - The study aimed to understand the evaluative limits and possibilities of the Family Health Strategy (FHS) in acknowledging and confronting the health needs of women experiencing gender-based violence. This was a case study with a qualitative approach, conducted in a Basic Health Unit that operated under the FHS in Sao Paulo (SP). Data were collected through interviews with health professionals of the multidisciplinary teams, and women users of the service who experienced gender-based violence. The results were analyzed according to the analytical categories: gender, gender-based violence and health needs. Medicalization was seen as the most significant limitation of professional practice. Moreover, there were opportunities related to the bond afforded by the logic of attention brought by the FHS. Such possibilities, however, were still curtailed by the limitations of the biomedical model and the absence of specific technologies to deal with violence. PMID- 23743895 TI - [Adaptation of the O'Leary-Sant and the PUF for the diagnosis of interstitial cystitis for the Brazilian culture]. AB - The aim of this study was to translate and adapt the instruments known as The O'Leary-Sant and PUF to the Brazilian culture used in the diagnosis of interstitial cystitis. We followed the methodological steps recommended by the international literature for cultural adaptation. The steps of translation, synthesis of translations and back translation were performed satisfactorily and evaluation the versions of the synthesis by the panel of experts has resulted in some changes, ensuring the equivalence between the original and translated versions. The PUF was pretested among 40 subjects and The O'Leary-Sant in a sample of 50 individuals due to the need for adjustments due to the low education population. The translation and adaptation process was successful and the instruments, after some modifications, proved easy to understand and complete quickly. However, this is a study prior to the validation process and will be promoting the use of the instrument in new research to assess its measurement properties. PMID- 23743896 TI - [Possibilities for addressing child abuse in systematized nursing consultations]. AB - Child abuse has been increasing, and addressing this phenomenon is within the responsibilities of health services. The International Classification of Nursing Practice in Public Health (Classificacao Internacional das Praticas de Enfermagem em Saude Coletiva - CIPESC(r)) is a tool that systematizes care and identifies child abuse during nursing consultations. The present study aimed to identify the limitations and potential of CIPESC(r) in nursing consultations with children that were victims of domestic violence. The present qualitative descriptive case study examined 15 web-based reports on violence completed by primary care nurses from the Curitiba City Council (Secretaria Municipal de Curitiba) in the state of Parana. Although CIPESC(r) has shown potential, the diagnoses and interventions presented in the classifications were not fully utilized by the respondents. The reports showed worrisome limits regarding the recognition of needs and vulnerabilities involving the phenomenon of violence. In conclusion, it is necessary to contribute to the nomenclature the attributes concerning freedom and autonomy, which are essential for addressing violence, in addition to methods for evidence-based interventions. PMID- 23743897 TI - [Risk factors and cardiovascular events in adult Latin American immigrants in the Macarena District, Seville, Spain: a pilot study]. AB - In order to estimate the prevalence of self-reported risk factors and cardiovascular events in an adult immigrant Latin American population of District 2 (Macarena) in Seville, we conducted a pilot study using cross-sectional descriptive research. We used an anonymous questionnaire with self-reported risk factors and cardiovascular events. 34 people participated (18% of the sample); mean age: 31.8 years, mean residence: 6.5 years, women: 52.9%. Prevalence of risk factors: diabetes 8.8%, high cholesterol 14.7% and high blood pressure 23.5%. Prevalence of coronary events was 8.8%; angina pectoris, myocardial infarction and stroke, 2.9% each. The conclusion is that self-reported prevalence of cardiovascular events was higher than in the literature, this issue deserving the attention of health agencies. This knowledge should be considered by nurses to develop culturally appropriate care plans of the context of immigrants. PMID- 23743898 TI - [Assessment of nursing workload in three groups of patients in a Spanish ICU using the Nursing Activities Score Scale]. AB - The purpose of this study was to assess the nursing workload at admission to and discharge from intensive care of three groups of patients (i.e., acute coronary syndrome, acute respiratory failure, and sepsis). A prospective, descriptive study was performed over a 27-month period and included 563 patients. The workload was assessed using the Nursing Activities Score scale. Significant differences in the workload were determined on the days of admission and discharge: the workload was higher in both cases for patients with acute respiratory failure and sepsis compared with patients diagnosed with acute coronary syndrome. This difference was maintained over the first seven days of their hospital stay. From day 8 on, the difference disappeared, and a workload balance was achieved in the three groups. Good staffing requires adequate tools for measuring care needs and understanding the workload required in the groups of patients who are most frequently admitted to intensive care. PMID- 23743899 TI - [Critical thinking skills in the nursing diagnosis process]. AB - The aim of this study was to identify the critical thinking skills utilized in the nursing diagnosis process. This was an exploratory descriptive study conducted with seven nursing students on the application of a clinical case to identify critical thinking skills, as well as their justifications in the nursing diagnosis process. Content analysis was performed to evaluate descriptive data. Six participants reported that analysis, scientific and technical knowledge and logical reasoning skills are important in identifying priority nursing diagnoses; clinical experience was cited by five participants, knowledge about the patient and application of standards were mentioned by three participants; Furthermore, discernment and contextual perspective were skills noted by two participants. Based on these results, the use of critical thinking skills related to the steps of the nursing diagnosis process was observed. Therefore, that the application of this process may constitute a strategy that enables the development of critical thinking skills. PMID- 23743900 TI - [Quality of life in patients with diabetes mellitus before and after their participation in an educational program]. AB - This quasi-experimental study aimed to evaluate the health-related quality of life in individuals with diabetes mellitus before and after their participation in a five-month educational program in a primary care service in Brazil in 2008. The sample consisted of 51 individuals, 56.9% female and 43.1% male, who had a mean age of 57.65 +/- 11.44 years. Data were collected using the Portuguese version of the SF-36 questionnaire. The instrument had adequate reliability estimates for the study sample. Cronbach's alpha for the two components of the instrument, physical and mental, were 0.83 and 0.89, respectively. The findings suggested improvements in all the domain components; however, only the general health domain, before (63.96 +/- 19.03) and after (70.59 +/- 17.82) the educational program, presented statistically significant mean differences, t(50) = 2.16, p<0.05. Participation in the educational program also contributed to improvements in the perceptions of the individuals regarding their general health status. PMID- 23743901 TI - [Quality of life in hematologic oncology patients undergoing chemotherapy]. AB - This descriptive and cross-sectional study aimed to examine the socio demographic/clinical aspects of health-related quality of life (HRQoL) and assess the HRQoL of onco- hematological patients undergoing chemotherapy. The data collection instrument was a socio-demographic/clinical questionnaire, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC) QLQ-C-30. The sample consisted of 32 patients, eight of whom (25%) were diagnosed with Hodgkin's lymphoma; nine (28.12%), with non Hodgkin's lymphoma; and 15 (46.87%), with leukemia. The data were analyzed using SPSS software. For the functional scales of the QLQ-C-30 (physical, cognitive, emotional, social and role performance), the mean scores ranged from 54.81 to 41.18, demonstrating an unsatisfactory level of functioning. In the symptom scales, there was a predominance of fatigue (64.57), insomnia (56.90) and loss of appetite (50.71). These symptoms interfered with the patients' physical functioning, demonstrating that the emotional and cognitive side effects of the treatment negatively influenced the HRQoL of the patients. PMID- 23743902 TI - [Experiencing acute stroke: the meaning of the illness for hospitalized patients]. AB - The aim was to understand the meaning of the experience of the acute stroke patient. This was a qualitative study, based on the conceptual theory of symbolic interaction. It was conducted in a unit specialized in the treatment of stroke at a tertiary hospital in Fortaleza-CE and the ethical aspects were respected. The study included ten patients and data were collected through open interviews. The data were organized and analyzed according to enunciation techniques. The meaning of the illness experience was constructed based on the perception of the feelings that arose during the hospitalization and was characterized by fear of death and the sequelae of the disease; sorrow for the distance from home; relief, when a patient perceived an improved clinical course; and a desire to change one's lifestyle. The experience of illness due to stroke is complex, as meanings are elaborated from the feelings, actions and behaviors of the subjects. PMID- 23743903 TI - [Nurses of adult intensive care unit: evaluation about direct and indirect blood pressure measurement]. AB - This is a descriptive and cross-sectional study with the aim to evaluate and self evaluate the knowledge of nurses from adult Intensive Care Units about direct and indirect blood pressure measurement. Fifty-four nurses from three Intensive Care Units were approached. They answered a self-administered questionnaire with 65 questions (40 related to blood pressure). Nurses had insufficient performance on the test that assessed knowledge (average score 4.6). Half of the sample felt dissatisfied with their knowledge about blood pressure. After answering the questionnaire the subjects self-rated their knowledge as regular (48.2%), bad (27.8%) and poor (9.3%) indicating they are aware of the importance for the subject to practice. The results show the need of urgent implementation of continuing education for this sample, since they are professionals who work directly with a priority vital sign on care to critical patients. PMID- 23743904 TI - [Perception of cancer causes and risk, family history and preventive behaviors of users in oncogenetic counseling]. AB - The aims of the present study were to describe cancer causes and risk perception, and to associate behaviors adopted for the prevention of tumors and cancer family history in individuals with suspect of hereditary cancer syndromes. A convenience sample of 51 individuals was selected from an oncogenetic counseling outpatient clinic in a university hospital in the countryside of the state of Sao Paulo. An instrument adapted to Brazilian culture was used. The respondents considered their own risk as being the same as the population's risk, and family history was not statistically associated with the performing of preventive exams. These findings highlight the need for intervention by health professionals, especially nurses, who may conduct health education activities for this population, which is an essential component of nursing care in oncogenetics. PMID- 23743905 TI - [Nursing diagnoses and interventions for patients with congestive heart failure using the ICNP (r)]. AB - The aim of this descriptive exploratory study was to construct nursing diagnosis and intervention statements for patients with Congestive Heart Failure. To accomplish this aim, 53 terms were identified in the focus axis of the International Classification for Nursing Practice (ICNP(r)), which guided the construction of these statements using the guidelines of the International Council of Nurses and ISO 18. 104. A total of 92 nursing diagnosis statements were constructed, which resulted in 66 statements after standardization. The standardized statements were separated according to the following pathophysiological models: 13 related to tachycardia, 20 related to dyspnea, 19 related to edema, and 14 related to congestion. A total of 234 interventions were constructed for these statements using the terms from the 7-Axis Model of the ICNP(r), the literature in the area and the clinical experience of the authors. The nursing diagnosis and intervention statements designed are expected to facilitate the evaluation of CHF patients and assist in the construction of a terminological subset for the ICNP(r). PMID- 23743906 TI - [Morbidity and quality of life of elderly individuals with diabetes mellitus living in urban and rural areas]. AB - This study aimed to describe the socio-demographic variables and to compare the morbidities and the quality of life (QoL) of elderly individuals with diabetes mellitus (DM) residing in urban and rural areas. The sample consisted of 271 elderly individuals from urban areas and 104 from rural areas with self-reported DM. A descriptive analysis was used, and in the location comparison, an age adjustment was employed through linear and logistic multiple regression models (p<0.05). The elderly individuals from the rural area were younger, more educated, earned a higher income and were more often married in relation to the urban residents. Furthermore, the rural residents presented a higher QoL score in the physical and social relationships domains and in the autonomy, past, present and future activities, and intimacy facets compared to the urban residents. The elderly individuals residing in the urban area displayed a larger number of verified comorbidities. The elderly DM patients residing in the rural area generally presented better health conditions than those who lived in the urban area. PMID- 23743907 TI - [Prevalence and factors associated with the rates of depression among elderly residents in rural areas]. AB - This study aimed to determine the prevalence of elderly patients with an indication of depression by sex and age group and to identify the factors associated with the indication of depression. Analytical, observational and cross studies were conducted with 850 elderly residents in the rural areas of the municipality of Minas Gerais. For data analysis, we applied the prevalence formula and logistic regression model (p<0.05). The project was approved by the Ethics in Research Human of the Triangulo Mineiro Federal University (Protocol No. 1477). The prevalence of the indicators of depression accounted for 22%, with a greater occurrence among females and individuals aged 60?70 years. In females, a higher number of comorbidities and higher functional disability with respect to performing the activities of daily living remained associated with the indication of depression. These results reinforce the need to implement actions to promote health and disease prevention, focusing on depression. PMID- 23743908 TI - [Elderly women: revealing their experiences and care needs]. AB - This qualitative study used a social phenomenology approach to elucidate the experiences, care needs and expectations of the elderly women. Nine elderly women were interviewed between February and May 2011 using a semi-structured questionnaire. The elderly women referred to their physical, mental, and social limitations. They valued the preservation of their autonomy in daily activities and in self-care and considered their families to be a fundamental support. They had expectations of remaining healthy, pursuing leisure activities, and having improved access to healthcare information and treatment. The absence of prospects at this stage of life was related to the loss of significant people and the loss of health. The results of this study reveal important aspects of the experiences of elderly women and encourage further research and improvement in teaching, clinical practice and management policies in relation to the needs of these women. PMID- 23743909 TI - [Assessment of self-care competence of elderly people with diabetes]. AB - This descriptive, cross-sectional and correlational study aimed to assess the self-care competencies of senior citizens with diabetes using the Scale to Identify Diabetes Mellitus Patients' Competence for Self-Care and personal factors associated with it. The study population consisted of seniors registered in primary healthcare units in Fortaleza, CE, Brazil. Only 6% of the patients were considered to have diabetes self-care competence. Low educational level and decreased visual acuity were identified as factors that influenced these low scores. The results, which showed that a small number of seniors were considered competent to practice self-care, indicated the importance of developing health promotion activities targeted to this population, assessing skills and encouraging self-care practices to facilitate the planning of health interventions. PMID- 23743910 TI - [Identification of users using cluster analysis according to degree of satisfaction with geriatric care services]. AB - The aim of this study was to identify groups of users according to their degree of satisfaction with geriatric care services and determine the primary factors associated with satisfaction. This was a cross-sectional study of 181 people enrolled in 36 modules pertaining to the State Workers Social Security Institute (ISSSTE) in Mexico. Degree of satisfaction was measured according to the following three areas: general characteristics of services offered, friendliness of staff and infrastructure. A cluster analysis was performed to identify groups of users according to their level of satisfaction, and an ordinal logistic regression model was used to determine the associated factors. Fifty-three percent were satisfied with the services, 34.3% were fairly satisfied and 12.7% were dissatisfied. The main characteristics associated with a greater degree of satisfaction were being female, older and the head of household. The health system must address this growing population and ensure the development of quality care to meet their needs. PMID- 23743911 TI - [An approach to touching while providing high-quality affective health care to hospitalized elderly patients]. AB - The aim of the present study was to verify the important factors of tacesics that should be observed while touching the elderly. This qualitative and exploratory field of study was developed using 117 undergraduate students and healthcare professionals who participated in a training course regarding nonverbal communication in gerontology. The results revealed that the majority of the participants were able to identify at least one care factor that must be respected when touching the elderly. The discourses allowed for the construction of nine categories indicating the conditions that are necessary for high-quality affective care provided within the tacesics context; these conditions included the authorization for the touch to occur, location of the touch, intensity of the touch, condition of the elderly person, intentionality and type of touch, duration of the touch, gender and age of the person who touches and of the person being touched, frequency of the touch, and characteristics of the hands that touch. Touch is part of the quotidian practice of healthcare professionals and expresses their dedication and its related emotions, thereby revealing the quality of the care that is provided. PMID- 23743912 TI - [The religiosity in the process of living getting old]. AB - This study aimed to identify how religious and spiritual practices are experienced at different ages during the aging process. The study was cross sectional and observational and conducted in the city of Chapeco, SC, from July 2008 to January 2009. The sample included 2,160 individuals with 720 individuals interviewed in each age group. The analysis was univariate and obtained the absolute and relative frequency of each variable. The final data obtained were statistically analyzed with SPSS 13.0 software. It was observed that 77.6% of the respondents were Catholic and that the older individuals were more religious. A total of 50.6% of the respondents prayed once a day, 38.3% of them to offer thanks and 30.4% in the supine position. We conclude that religiosity is a valuable resource in coping with the crises of everyday life and positively affects physical and mental health, particularly in the elderly. PMID- 23743913 TI - [Delay in seeking initial care for tuberculosis diagnosis]. AB - Descriptive study, which aimed to analyze the time between the perception of TB symptoms onset and the first search for health services, according to TB patient characteristics in Sao Jose do Rio Preto - SP. 97 TB patients in treatment were interviewed with a structured instrument. The delay was identified by the median time between the perception of TB symptom's onset and the patients demand for care (> 15 days). To identify the variables related to delay the prevalence ratio were calculated. There was a delay seeking care among: male patients, aged 18 to 29 and 50 to 59 years, lower education and higher family income, pulmonary cases without HIV co-infection, presenting milder symptoms, users of alcoholic beverages and tobacco, those who did not perform preventive health control, and who sought health services closer to home. The recognition of users' profiles in the search for care is paramount for defining strategies that favor the use of services in a timely manner. PMID- 23743914 TI - [Nursing diagnoses for clients hospitalized in an infectious disease clinic]. AB - The aim of this exploratory descriptive study was to create nursing diagnosis statements for hospitalized clients based on the Database of Special Nursing Language Terms of the Infectious Diseases Clinic of a teaching hospital and on the ICNP(r). Further, we aimed to validate the diagnosis statements with the participation of clinical nurses and nursing teachers who worked at the clinic. Eighty-eight nursing diagnosis statements were constructed. However, only those that achieved a correlation index (CI) >= 0.80, as determined by the experts participating in the study, were validated, resulting in seventy diagnosis statements. The study results showed that the aims were achieved, and the statements will facilitate communication processes among nursing professionals. Furthermore, they will ensure that care is guided by methodological principles, thus providing client care with greater resolvability power. PMID- 23743915 TI - [Pain management in patients with AIDS: analysis of the management structure of a reference hospital]. AB - The objective of this study was to analyze the structure for the management of pain in patients with AIDS in a reference hospital in Fortaleza, Brazil. This is a descriptive study with a qualitative approach, developed in 2010. Twenty interviews were performed with health care professionals (physicians and nurses), and analyzed according to the methodology of content analysis. Data were organized into categories: favorable and unfavorable structural conditions. A prevalence of unfavorable conditions was found in the discourse of the interviewees, such as an emphasis on pharmacologic treatment, absence of specific care strategies for pain, lack of experienced professionals in handling pain, and a high demand and failure in the referral and counter-referral system. It is suggested that a new management care model be instituted for patients with AIDS, emphasizing an interdisciplinary approach to pain, training of health care professionals and improvement of chart records for use in evaluating pain relief methods and more effective treatments. PMID- 23743916 TI - [Legislative knowledge and preparation of health personnel for the care process of death]. AB - The aims of this study were to ascertain the perception that health professionals (doctors, nurses and nursing assistants) have about their preparation for the care of terminally ill patients and to determine their knowledge about palliative care legislation. This cross sectional study was performed at a hospital in Granada (Spain); we administered an ad hoc questionnaire. The results indicated that although most of the staff had worked with terminally ill patients, only half believed that they have been trained to care for them. A significant proportion stated that they did not know about the current palliative care legislation. Most professionals would question the withdrawal of therapies for the maintenance of life; most of them are also unaware of the mechanism for reporting on the completion of a Living Will, as well as a Plan for Palliative Care in Andalusia (Spain). PMID- 23743917 TI - Evaluation of oxidative stress parameters and metabolic activities of nurses working day and night shifts. AB - The aim of this study was to evaluate the oxidative stress and metabolic activities of nurses working day and night shifts. Intensive care unit (ICU) (n=70) and ordinary service (OS) nurses (n=70) were enrolled in the study. Just before and the end of the shifts, blood samples were obtained to measure the participants' oxidative stress parameters. Metabolic activities were analyzed using the SenseWear Armband. Oxidative stress parameters were increased at the end of the shifts for all OS and ICU nurses compared to the beginning of the shifts. Compared to the OS nurses, the ICU nurses' TAS, TOS, and OSI levels were not significantly different at the end of the day and night shifts. The metabolic activities of the OS and ICU nurses were found to be similar. As a result, the OS and ICU nurses' oxidative stress parameters and metabolic activities were not different, and all of the nurses experienced similar effects from both the day and night shifts. PMID- 23743918 TI - [The approach to breastfeeding in the first years of elementary school]. AB - To review the curricula and content of 1st- through 5th-year elementary school science textbooks with respect to the presence or absence of terms related to breastfeeding, we conducted a descriptive study analyzing the curricula and 16 textbooks of 25 public schools in 03 municipalities of Sao Paulo between September 2010 and February 2011. In particular, we defined essential concepts to teach and explain breastfeeding to children. We found that no block themed curriculum explicitly addressed the theme of breastfeeding. Nine of the sixteen predefined concepts were present in eight of the sixteen textbooks adopted. From the analysis, we identified a new category: Support and help the family. Three textbooks used illustrations associated with artificial feeding. In the program and textbooks, there are several opportunities to introduce this topic. We advise integrating this content into all science textbooks in the early years of elementary school. PMID- 23743919 TI - [Project evidencia [evidence]: research and education about accessing scientific databases in Azores]. AB - Project Evidencia [Evidence] intends to promote the use of scientific databases among nurses. This study aims to design educational interventions that facilitate nurses' access to these databases, to determine nurses' habits regarding the use of scientific databases, and to determine the impact that educational interventions on scientific databases have on Azorean nurses who volunteered for this project. An intervention project was conducted, and a quantitative descriptive survey was designed to evaluate the impact two and five months after the educational intervention. This impact was investigated considering certain aspects, namely, the nurses' knowledge, habits and reasons for using scientific databases. A total of 192 nurses participated in this study, and the primary results indicate that the educational intervention had a positive impact based not only on the increased frequency of using platforms or databases of scientific information (DSIs) s but also on the competence and self-awareness regarding its use and consideration of the reasons for accessing this information. PMID- 23743920 TI - [Cytotoxicity of PVC tubes sterilized in ethylene oxide after gamma radiation exposure]. AB - Do materials sterilized using gamma rays become toxic when re-sterilized in ethylene oxide? This question guided the objective of this study, which was to investigate the potential cytotoxic effect of PVC sterilized by gamma radiation and re-sterilized with EO by the agar diffusion method in cell cultures. Nine PVC tubes were subjected to gamma radiation sterilization and were re-sterilized in EO. The tubes were divided into a total of 81 units of analysis that were tested so as to represent the internal and external surfaces and mass of each tube. It was concluded that the PVC materials sterilized in gamma radiation and re sterilized in EO are not cytotoxic. PMID- 23743921 TI - [Transpersonal caring in nursing: an analysis grounded in a conceptual model]. AB - This theoretical study aimed to analyze the attributes, antecedents, and consequences of the transpersonal caring concept through using the Concepts Analysis Model. For this purpose, books published based on Jean Watson's theory in Portuguese and English from 1979 to 2012 were listed. Fulfilled inclusion criteria, only six literary works remained. The time of care and intention to be in relationship were the most cited antecedents. The most present attributes were intersubjectivity and relationships among those ones involved in the process. With regard to consequences, the most present element was the fact that the transpersonal caring provides restoration/reconstitution (healing). The study allowed noting tiny changes in the concept definition over the years and publications of theory. Thus, analyzing the attributes, antecedents, and consequences of concept provided its better understanding and comprehension of its importance in the Human Caring Theory proposed by American theorist. PMID- 23743922 TI - Moral distress: challenges for an autonomous nursing professional practice. AB - Constantly experiencing limiting situations that hinder a professional practice coherent with its principles - of autonomy and advocacy of users' interests -, and often conditioned to experience moral distress, the nursing profession plays a prominent role in the current health model because it has the characteristic of managing the care rendered to users in a perspective of social inclusion, both in the basic health network and in hospitals. Aiming at carrying out a reflection on the nursing practice and the difficulties present in its work routine, and considering its characteristics as a profession, this article sought to make a reflection between the practice of nursing and the numerous moral challenges imposed by the routine, resulting, in many cases, in a value crisis that can reverberate directly on the quality of the service rendered, and in abandonment of the ideals of advocacy for users. PMID- 23743923 TI - Unearthing the root of amino acid similarity. AB - Similarities and differences between amino acids define the rates at which they substitute for one another within protein sequences and the patterns by which these sequences form protein structures. However, there exist many ways to measure similarity, whether one considers the molecular attributes of individual amino acids, the roles that they play within proteins, or some nuanced contribution of each. One popular approach to representing these relationships is to divide the 20 amino acids of the standard genetic code into groups, thereby forming a simplified amino acid alphabet. Here, we develop a method to compare or combine different simplified alphabets, and apply it to 34 simplified alphabets from the scientific literature. We use this method to show that while different suggestions vary and agree in non-intuitive ways, they combine to reveal a consensus view of amino acid similarity that is clearly rooted in physico chemistry. PMID- 23743925 TI - [Precurarization with a non-depolarizing muscle relaxant]. PMID- 23743926 TI - N-site de-methylation in pyrimidine bases as studied by low energy electrons and ab initio calculations. AB - Electron transfer and dissociative electron attachment to 3-methyluracil (3meU) and 1-methylthymine (1meT) yielding anion formation have been investigated in atom-molecule collision and electron attachment experiments, respectively. The former has been studied in the collision energy range 14-100 eV whereas the latter in the 0-15 eV incident electron energy range. In the present studies, emphasis is given to the reaction channel resulting in the loss of the methyl group from the N-sites with the extra charge located on the pyrimidine ring. This particular reaction channel has neither been approached in the context of dissociative electron attachment nor in atom-molecule collisions yet. Quantum chemical calculations have been performed in order to provide some insight into the dissociation mechanism involved along the N-CH3 bond reaction coordinate. The calculations provide support to the threshold value derived from the electron transfer measurements, allowing for a better understanding of the role of the potassium cation as a stabilising agent in the collision complex. The present comparative study gives insight into the dynamics of the decaying transient anion and more precisely into the competition between dissociation and auto-detachment. PMID- 23743927 TI - Succinate dehydrogenase deficiency is associated with decreased 5 hydroxymethylcytosine production in gastrointestinal stromal tumors: implications for mechanisms of tumorigenesis. AB - Gastrointestinal stromal tumors (GISTs) usually harbor activating mutations in KIT or PDGFRA, which promote tumorigenesis through activation of growth factor receptor signaling pathways. Around 15% of GISTs in adults and >90% in children lack such mutations ('wild-type' GISTs). Most gastric wild-type GISTs show loss of function of the Krebs cycle enzyme complex succinate dehydrogenase (SDH). However, the mechanism by which SDH deficiency drives tumorigenesis is unclear. Loss of SDH leads to succinate accumulation, which is thought to inhibit alpha ketoglutarate-dependent dioxygenase enzymes, such as the TET family of DNA hydroxylases. TET proteins catalyze the conversion of 5-methylcytosine to 5 hydroxymethylcytosine (5-hmC), which is required for subsequent DNA demethylation. Thus, TET-mediated 5-hmC production alters global DNA methylation patterns and may thereby influence gene expression. We investigated 5-hmC levels in a cohort of genotyped GISTs to determine whether loss of SDH was associated with inhibition of TET activity. 5-hmC levels were examined via immunohistochemistry in a cohort of 30 genotyped GISTs, including 10 SDH deficient tumors (5 SDHA mutant; 1 SDHB mutant; 1 SDHC mutant; 3 unknown), 14 tumors with KIT mutations (10 in exon 11; 3 in exon 9; 1 in exon 17), and 6 tumors with PDGFRA mutations (all in exon 18). Staining for 5-hmC was negative in 9 of 10 (90%) SDH-deficient GISTs, 3 of 14 (21%) KIT-mutant GISTs, and 1 of 6 (17%) PDGFRA-mutant GISTs. The other SDH-deficient GIST showed weak staining for 5-hmC. Thus, 5-hmC was absent in nearly all SDH-deficient GISTs. These findings suggest that SDH deficiency may promote tumorigenesis through accumulation of succinate and inhibition of dioxygenase enzymes. Inhibition of TET activity may, in turn, alter global DNA methylation and gene expression in SDH-deficient tumors. PMID- 23743928 TI - Testing for ALK rearrangement in lung adenocarcinoma: a multicenter comparison of immunohistochemistry and fluorescent in situ hybridization. AB - Rearrangements of anaplastic lymphoma kinase (ALK) gene in non-small cell lung cancer (NSCLC) define a molecular subgroup of tumors characterized clinically by sensitivity to ALK tyrosine kinase inhibitors such as crizotinib. Although ALK rearrangements may be detected by reverse transcriptase-PCR, immunohistochemistry or fluorescence in situ hybridization (FISH), the optimal clinical strategy for identifying ALK rearrangements in clinical samples remains to be determined. We evaluated immunohistochemistry using three different antibodies (ALK1, 5A4 and D5F3 clones) to detect ALK rearrangements and compared those with FISH. We report the frequency and clinicopathologic features of lung cancers harboring ALK translocations in 594 resected NSCLCs (470 adenocarcinomas; 83 squamous carcinomas, 26 large cell carcinomas and 15 other histological subtypes) using a tissue microarray approach. We identified an ALK gene rearrangement in 7/594 cases (1%) by FISH and all anti-ALK antibodies correctly identified the seven ALK positive cases (100% sensitivity), although the intensity of staining was weak in some cases. These data indicate that the use of antibodies with high sensitivity and avidity to ALK may provide an effective pre-screening technique to complement the more expensive and labor-intensive approach of ALK FISH testing. PMID- 23743929 TI - Analysis of copy number changes on chromosome 16q in male breast cancer by multiplex ligation-dependent probe amplification. AB - Gene copy number changes have an important role in carcinogenesis and could serve as potential biomarkers for prognosis and targets for therapy. Copy number changes mapping to chromosome 16 have been reported to be the most frequent alteration observed in female breast cancer and a loss on 16q has been shown to be associated with low grade and better prognosis. In the present study, we aimed to characterize copy number changes on 16q in a group of 135 male breast cancers using a novel multiplex ligation-dependent probe amplification kit. One hundred and twelve out of 135 (83%) male breast cancer showed copy number changes of at least one gene on chromosome 16, with frequent loss of 16q (71/135; 53%), either partial (66/135; 49%) or whole arm loss (5/135; 4%). Losses on 16q were thereby less often seen in male breast cancer than previously described in female breast cancer. Loss on 16q was significantly correlated with favorable clinicopathological features such as negative lymph node status, small tumor size, and low grade. Copy number gain of almost all genes on the short arm was also significantly correlated with lymph node negative status. A combination of 16q loss and 16p gain correlated even stronger with negative lymph node status (n=112; P=0.012), which was also underlined by unsupervised clustering. In conclusion, copy number loss on 16q is less frequent in male breast cancer than in female breast cancer, providing further evidence that male breast cancer and female breast cancer are genetically different. Gain on 16p and loss of 16q identify a group of male breast cancer with low propensity to develop lymph node metastases. PMID- 23743924 TI - Evolution of the genetic code by incorporation of amino acids that improved or changed protein function. AB - Fifty years have passed since the genetic code was deciphered, but how the genetic code came into being has not been satisfactorily addressed. It is now widely accepted that the earliest genetic code did not encode all 20 amino acids found in the universal genetic code as some amino acids have complex biosynthetic pathways and likely were not available from the environment. Therefore, the genetic code evolved as pathways for synthesis of new amino acids became available. One hypothesis proposes that early in the evolution of the genetic code four amino acids-valine, alanine, aspartic acid, and glycine-were coded by GNC codons (N = any base) with the remaining codons being nonsense codons. The other sixteen amino acids were subsequently added to the genetic code by changing nonsense codons into sense codons for these amino acids. Improvement in protein function is presumed to be the driving force behind the evolution of the code, but how improved function was achieved by adding amino acids has not been examined. Based on an analysis of amino acid function in proteins, an evolutionary mechanism for expansion of the genetic code is described in which individual coded amino acids were replaced by new amino acids that used nonsense codons differing by one base change from the sense codons previously used. The improved or altered protein function afforded by the changes in amino acid function provided the selective advantage underlying the expansion of the genetic code. Analysis of amino acid properties and functions explains why amino acids are found in their respective positions in the genetic code. PMID- 23743930 TI - Next-generation biobanking of metastases to enable multidimensional molecular profiling in personalized medicine. AB - Great advances in analytical technology coupled with accelerated new drug development and growing understanding of biological challenges, such as tumor heterogeneity, have required a change in the focus for biobanking. Most current banks contain samples of primary tumors, but linking molecular signatures to therapeutic questions requires serial biopsies in the setting of metastatic disease, next-generation of biobanking. Furthermore, an integration of multidimensional analysis of various molecular components, that is, RNA, DNA, methylome, microRNAome and post-translational modifications of the proteome, is necessary for a comprehensive view of a tumor's biology. While data using such biopsies are now regularly presented, the preanalytical variables in tissue procurement and processing in multicenter studies are seldom detailed and therefore are difficult to duplicate or standardize across sites and across studies. In the context of a biopsy-driven clinical trial, we generated a detailed protocol that includes morphological evaluation and isolation of high quality nucleic acids from small needle core biopsies obtained from liver metastases. The protocol supports stable shipping of samples to a central laboratory, where biopsies are subsequently embedded in support media. Designated pathologists must evaluate all biopsies for tumor content and macrodissection can be performed if necessary to meet our criteria of >60% neoplastic cells and <20% necrosis for genomic isolation. We validated our protocol in 40 patients who participated in a biopsy-driven study of therapeutic resistance in metastatic colorectal cancer. To ensure that our protocol was compatible with multiplex discovery platforms and that no component of the processing interfered with downstream enzymatic reactions, we performed array comparative genomic hybridization, methylation profiling, microRNA profiling, splicing variant analysis and gene expression profiling using genomic material isolated from liver biopsy cores. Our standard operating procedures for next-generation biobanking can be applied widely in multiple settings, including multicentered and international biopsy-driven trials. PMID- 23743931 TI - Integration of KRAS testing in the diagnosis of pancreatic cystic lesions: a clinical experience of 618 pancreatic cysts. AB - With improvements in abdominal imaging, detection of incidental pancreatic cysts are becoming increasingly common. Analysis of pancreatic cyst fluid from fine needle aspiration is particularly important in identifying intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), which have significant implications in clinical intervention and follow-up. Previous controlled studies have shown that KRAS mutations in cyst fluid are highly specific for mucinous differentiation in pancreatic cysts; however, this has not been examined in the clinical setting. Over a 6-year study period, 618 pancreatic cyst fluids obtained by fine-needle aspiration at the time of endoscopic ultrasound were tested for KRAS mutations as part of routine evaluation for a cystic neoplasm. Of the 618 specimens, 603 (98%) from 546 patients were satisfactory for molecular analysis. Patients ranged in age from 17 to 90 years (mean, 63.9 years) and were predominantly female (68%). Pancreatic cysts were relatively evenly distributed throughout the pancreas and ranged in size from 0.6 to 11.0 cm (mean, 2.3 cm). Mutations in KRAS were detected in 232 of 603 (38%) aspirates. Although sufficient for molecular analysis, 320 of 603 (53%) specimens were either less than optimal (38%) or unsatisfactory (15%) for cytopathologic diagnosis. Surgical follow-up information was available for 142 (26%) patients and consisted of 53 KRAS-mutated and 89 KRAS-wild-type cysts. Overall, KRAS mutations had a specificity of 100%, but a sensitivity of 54% for mucinous differentiation. When stratified by cyst type, KRAS had a sensitivity of 67% and 14% for IPMNs and MCNs, respectively. In summary, KRAS mutations were highly specific for mucinous differentiation, but were inadequate in identifying MCNs. Future molecular studies and the combination of other fluid markers are required to improve the detection and classification of pancreatic mucinous neoplasms by endoscopic ultrasound fine-needle aspiration. PMID- 23743932 TI - Chromogenic in situ hybridization is a reliable assay for detection of ALK rearrangements in adenocarcinomas of the lung. AB - Reliable detection of anaplastic lymphoma kinase (ALK) rearrangements is a prerequisite for personalized treatment of lung cancer patients, as ALK rearrangements represent a predictive biomarker for the therapy with specific tyrosine kinase inhibitors. Currently, fluorescent in situ hybridization (FISH) is considered to be the standard method for assessing formalin-fixed and paraffin embedded tissue for ALK inversions and translocations. However, FISH requires a specialized equipment, the signals fade rapidly and it is difficult to detect overall morphology and tumor heterogeneity. Chromogenic in situ hybridization (CISH) has been successfully introduced as an alternative test for the detection of several genetic aberrations. This study validates a newly developed ALK CISH assay by comparing FISH and CISH signal patterns in lung cancer samples with and without ALK rearrangements. One hundred adenocarcinomas of the lung were included in this study, among them 17 with known ALK rearrangement. FISH and CISH were carried out and evaluated according to the manufacturers' recommendations. For both assays, tumors were considered positive if >=15% of tumor cells showed either isolated 3' signals or break-apart patterns or a combination of both. A subset of tumors was exemplarily examined by using a novel EML4 (echinoderm microtubule-associated protein-like 4) CISH probe. Red, green and fusion CISH signals were clearcut and different signal patterns were easily recognized. The percentage of aberrant tumor cells was statistically highly correlated (P<0.001) between FISH and CISH. On the basis of 86 samples that were evaluable by ALK CISH, we found a 100% sensitivity and 100% specificity of this assay. Furthermore, EML4 rearrangements could be recognized by CISH. CISH is a highly reliable, sensitive and specific method for the detection of ALK gene rearrangements in pulmonary adenocarcinomas. Our results suggest that CISH might serve as a suitable alternative to FISH, which is the current gold standard. PMID- 23743933 TI - Comparison of Oncotype DX and Mammostrat risk estimations and correlations with histologic tumor features in low-grade, estrogen receptor-positive invasive breast carcinomas. AB - Several molecular tests have been developed to estimate risk of distant recurrence and help clinical decision-making regarding adjuvant chemotherapy in patients with early stage breast carcinoma. Both Oncotype DX, a 21-gene expression profile, and Mammostrat, an immunohistochemistry-based assay, are validated to stratify patients into groups with low, intermediate and high risk of distant recurrence. However, they have not been compared head-to-head and little data are available regarding their correlation with clinicopathologic tumor features. In this study, we compared the clinicopathologic tumor features with risk estimations by Oncotype DX and Mammostrat in 106 low-grade estrogen receptor (ER)-positive breast carcinomas. Double immunohistochemical stain for pancytokeratin and Ki-67 was performed to assess cell proliferation in cancer vs stromal/inflammatory cells. Tumors showing intermediate/high risk by Oncotype DX, but not by Mammostrat, showed increased stromal cellularity, presence of inflammatory cells and increased proliferation in stromal/inflammatory cells. Discrepant cases showing intermediate/high risk by Oncotype DX but low risk by Mammostrat were associated with increased stromal cellularity, presence of inflammatory cells and increased proliferation in stromal/inflammatory cells, compared with concordant cases showing low risk by both assays. Our results suggest that low-grade ER-positive breast carcinomas with increased stromal/inflammatory cell proliferation may show an apparent increased risk of distant recurrence as assessed by Oncotype DX, which uses RNA extracted from a mixture of tumor and stromal/inflammatory cells in the assay. Mammostrat, which examines cancer cells only, may provide a better estimation of likely tumor behavior in a subgroup of low-grade breast carcinomas. PMID- 23743934 TI - ZEB1 overexpression associated with E-cadherin and microRNA-200 downregulation is characteristic of undifferentiated endometrial carcinoma. AB - Undifferentiated endometrial carcinomas are very aggressive high-grade endometrial carcinomas that are frequently under-recognized. This study aimed to analyze the molecular alterations underlying the development of these endometrial carcinomas, focusing on those related to dedifferentiation. We assessed a series of 120 tumors: 57 grade 1 and 2 endometrioid endometrial carcinomas, 15 grade 3 endometrioid endometrial carcinomas, 27 endometrial serous carcinomas, and 21 undifferentiated endometrial carcinomas. We found a high frequency of DNA mismatch repair deficiency (38%) and moderate rate of p53 overexpression (~33%) in undifferentiated carcinomas. In contrast to the characteristic endometrioid phenotype, there was a dramatic downregulation of E-cadherin expression in the undifferentiated subtype. Quantitative methylation studies dismissed CDH1 promoter hypermethylation as the mechanism responsible for this change in gene expression, while immunohistochemistry revealed that the E-cadherin repressor ZEB1 was frequently overexpressed (62%) in undifferentiated endometrial carcinomas. This finding was accompanied by a sharp downregulation in the expression of the miR-200 family of microRNAs, well-known targets of ZEB1. Furthermore, there was enhanced expression of epithelial-to-mesenchymal transition markers in undifferentiated endometrial carcinomas, such as N cadherin, cytoplasmic p120, and osteonectin. In addition, HMGA2, a regulator of epithelial-to-mesenchymal transition that is expressed in aggressive endometrial tumors, such as endometrial serous carcinomas and carcinosarcomas, was expressed in >20% of undifferentiated carcinomas. These results suggest that ZEB1 overexpression, associated with E-cadherin and miR-200s downregulation, and the expression of mesenchymal markers might enhance the metastatic potential of undifferentiated endometrial carcinomas, leading to a poor prognosis. In addition, our observations suggest that the immnohistochemical analysis of E cadherin and ZEB1 can aid in the differential diagnosis of the more agressive undifferentiated endometrial carcinomas from grade 3 endometrioid carcinomas. PMID- 23743935 TI - Adjunctive use of medical modeling for head and neck reconstruction. AB - PURPOSE OF REVIEW: To review the developing role of three-dimensional medical modeling in head and neck reconstruction surgery. RECENT FINDINGS: Various methods for three-dimensional modeling have been described with excellent accuracy and reproducibility by most reports. Model use has been applied to several otolaryngologic disease processes including maxillomandibular and orbital reconstruction, craniofacial and orthognathic surgery, and even trauma cases. These prototypes have been shown to aid in diagnostics and surgical preplanning including prefabricating hardware, as well as improving patient and physician education and decreasing operating times. SUMMARY: Although the surgeon should be aware of the possibility of imprecision, three-dimensional modeling has been shown to be accurate and affordable. The added expense may even be regained by the resulting decrease in OR time and the need for secondary procedures. Patients should be selected carefully and the decision to use three-dimensional modeling needs to balance the complexity of the case with timing and feasibility of model production. Recent innovations in rapid prototyping, including improved model biocompatibility and patient-specific tissue engineering, may improve patient outcomes and expand model applications in the future. PMID- 23743936 TI - Updates in forehead flap reconstruction of facial defects. AB - PURPOSE OF REVIEW: The versatile and reliable paramedian forehead flap is the workhorse interpolated flap for nasal reconstruction and its use has been expanded to reconstruct other areas of the face. The goal of this article is to review the recent research describing the modern concepts and techniques in forehead flap reconstruction of facial defects. RECENT FINDINGS: A variety of forehead flap concepts, techniques, and applications have been described in the recent literature in both nasal and facial reconstruction. Recent concepts include the phenomenon of vascular delay as well as more detailed study of the perfusion of the forehead flap at its various stages. Novel techniques include various approaches in staged reconstruction, adoption of the forehead flap for reconstruction of internal lining defects, and flap thinning. SUMMARY: Although basic principles of the forehead flap have remained unchanged over the years, specific techniques and applications continue to be refined. The forehead flap continues to be a mainstay in the armamentarium of facial plastic and reconstructive surgeons. PMID- 23743937 TI - Assessing clinical skills: not just for interns anymore. PMID- 23743938 TI - Intern evaluation strategies in family medicine residency education: what is-and is not-being done. AB - BACKGROUND AND OBJECTIVES: Family medicine interns often have deficiencies that are not initially appreciated. By recognizing those growth opportunities early, programs may be able to better meet their interns' training needs. This study provides a needs assessment to ascertain what evaluation tools are being utilized by residency programs to assess their incoming interns. METHODS: A questionnaire was sent to all US family medicine residency program coordinators (439 programs) via Survey Monkey(c) inquiring about whether intern evaluation is performed and, if so, what strategies are used. A mixed mode methodology was used: mailing with incentive, email prompts, and telephone calls. RESULTS: Of 439 programs, 220 (50%) responded to the survey. Most respondents (145, 66%) think intern evaluation is needed. However, only 79 (36%) programs are actually doing intern evaluations-only 14 (6.4%) extensively. Most programs are performing simulations (81, 45%) and assessing knowledge/comfort levels (79, 36%); less than one third are considering personality/learning styles, and almost no programs are evaluating skills such as typing (three, 1.4%) and math (one, 0.5%). Many programs use evaluations to guide future planning, help with early identification of challenging learners, and to match training to the residents' needs. Several programs expressed concern about how they would use the information once obtained. CONCLUSIONS: The majority of respondents agreed that a baseline intern evaluation is useful; few are actually doing it. This area is not well-described in the literature; residency programs could benefit from information sharing. The next step is to encourage interest in and implementation of such strategies. PMID- 23743939 TI - Family medicine residency program director expectations of procedural skills of medical school graduates. AB - BACKGROUND AND OBJECTIVES: Mismatch between program directors' expectations of medical school graduates and the experience of students in medical school has important implications for patient safety and medical education. We sought to define family medicine residency program directors' expectations of medical school graduates to independently perform various procedural skills and medical school graduates' self-reported competence to perform those skills at residency outset. METHODS: In July of 2011, a paper-based survey was distributed nationwide by mail to 441 family medicine residency program directors and 3,287 medical school graduates enrolled as postgraduate year 1 (PGY-1) residents in family medicine residency programs. Program director expectation of independent performance and recent medical school graduate self-reported ability to independently perform each of 40 procedures was assessed. RESULTS: Surveys were completed and returned from 186 program directors (response rate 42%) and 681 medical school graduates (response rate 21%). At least 66% of program directors expected interns to enter residency able to independently perform 15 of 40 procedures. More than 80% of new interns reported they were able to independently perform five of the 15 procedures expected by program directors. CONCLUSIONS: Incongruity exists between program director expectations and intern self-reported ability to perform common procedures. Both patient safety and medical education may be jeopardized by a mismatch of expectation and experience. Assessment of medical students prior to medical school graduation or at the start of residency training may help detect procedural skill gaps and protect patient safety. PMID- 23743940 TI - Assessing culturally competent diabetes care with unannounced standardized patients. AB - BACKGROUND AND OBJECTIVES: More effective diabetes care is desperately needed, especially for ethnic minority populations. Provider cultural competence promises to be an important means for reducing disparities in outcomes for patients with diabetes. The objectives of this study were to understand the role of cultural competence in the diabetes office visit. METHODS: Unannounced standardized patients (SPs) were sent to the offices of 29 family and internal medicine residents and practicing physicians. The SPs portrayed a Mexican American woman newly diagnosed with type 2 diabetes. Using a checklist developed with the input of experts in Hispanic/Latino health care and cultural competence, the SPs evaluated physicians' cultural competence, diabetes care, and general communications skills. RESULTS: The average total SP Checklist score was 70.7 11.0%, with a range of 43.9% to 90.2%. Physicians scored highly on items that measured general communication skills (95.9%) but were less likely to ask about social history (ie, family and community support issues, 51.9% and 48.1%, respectively). Sixty-seven percent of physicians ordered a hemoglobin A1c, 44% referred to ophthalmology, and 15% performed a monofilament exam. Physicians' inquiry into SPs explanatory model of disease (ie, asking about the SPs' views regarding their disease and its treatment) correlated with the performance of several diabetes treatment-related behaviors, Spearman's rho=.466. CONCLUSIONS: The findings provide support for a relationship between inquiry into patients' explanatory models of disease and effective diabetes care. Social history and explanatory model elicitation skills are vital parts of cultural competence training programs and potentially valuable tools for mitigating health disparities. PMID- 23743941 TI - Integrating improvement learning into a family medicine residency curriculum. AB - BACKGROUND AND OBJECTIVES: Knowledge of improvement practices is a critical skill for family medicine residents who will lead patient-centered medical homes. The Accreditation Council for Graduate Medical Education includes systems-based practice and improvement knowledge as a core competency for residency education. The objective of this report is to describe the 6-year implementation and development of our practice-based improvement curriculum in a family medicine residency. METHODS: In 2006, Oregon Health and Science University Family Medicine Residency implemented an improvement curriculum that focused on clinic-based improvement and involved longitudinal didactics. Over the course of 6 years, the curriculum has been refined to include longitudinal instruction of improvement principles according to the levels of training and clinic-based didactics and experientials that are team oriented. Residents complete ambulatory improvement projects over the cycle of 12 months and present outcomes each year. Residents evaluated their knowledge, experience, confidence, and satisfaction at the end of the academic year. RESULTS: Ninety percent of residents designed and lead improvement projects upon graduation from residency in 2011. Resident confidence to make a change in local health care settings at the end of the curriculum was high and improved from 2009/2010 to 2010/2011. Upon graduation from the program, 100% of residents reported competence or proficiency in their ability to apply knowledge to an improvement project and present results. CONCLUSIONS: We describe a longitudinal, practical, developmental, and clinically based experiential improvement curriculum that has been successfully integrated into a family medicine residency program. PMID- 23743942 TI - Clinical utility of a brief screen for health literacy and numeracy among adults with diabetes mellitus. AB - BACKGROUND AND OBJECTIVES: Our objectives were to (1) compare Newest Vital Sign (NVS) scores and administration characteristics with the short (S) version of the Test of Functional Health Literacy in Adults (S-TOFHLA) and Spoken Knowledge in Low-Literacy Diabetes (SKILLD) tool and (2) gather information from research assistants (RAs) regarding their perceptions of patient understanding of NVS items. METHODS: Adults, age ? 18 years, with diabetes mellitus visiting a primary care clinic were recruited to participate. An RA orally administered a sociodemographic questionnaire. Patients completed, in random order, the NVS, S TOFHLA, and SKILLD. Completion time for each tool was electronically recorded, while patients assessed tool difficulty using a 5-point Likert-type scale. RAs' comments regarding patients' understanding of individual NVS items were tallied. RESULTS: A total of 226 patients (mean age=53.8 years, 31% male, 45.1% African American, 28.8% high school graduate) participated. African Americans were significantly less likely to score ?4 on the NVS (adjusted OR=0.23, 95% CI=0.13, 0.42) as compared to Caucasians. NVS scores were highly correlated with S-TOFHLA scores, rho=0.62, and moderately correlated with SKILLD scores, rho=0.39. NVS scores were inversely correlated with completion time, rho=-0.25 and difficulty rating, rho=-0.37. CONCLUSIONS: Related to the care of patients with diabetes, the most important feature of the NVS is that it can quickly provide a clinician with valuable insight regarding their patients' ability to complete a practical skill (ie, interpreting a food label) needed to achieve tight blood glucose control. PMID- 23743943 TI - Behavioral health assessments and interventions of residents and psychology trainees during dual interviewing: a descriptive study. AB - BACKGROUND AND OBJECTIVES: Family medicine residents increasingly work collaboratively with psychology trainees. One type of collaborative experience involves dual interviewing of clinic patients. The goal of this observational study was to provide an initial description of what occurs during dual interviews as it relates to behavioral health assessments and interventions. METHODS: Psychology trainees provided detailed descriptions of 550 collaborative patient encounters involving 348 patients from the Wayne State University/Crittenton Family Medicine Residency clinic. Psychology trainees coded the frequency of behavioral health assessments and interventions by the resident, psychology trainee, or both. RESULTS: Eighty percent of the encounters contained a behavioral health assessment, and 29% contained a behavioral health intervention. Most of these clinical activities were collaboratively done. Interestingly, residents and psychology trainees tended to provide different behavioral health interventions. Moreover, residents provided different behavioral health interventions in repeat dual interviews (n=202) as opposed to first-time visits (n=348), while psychology trainees did not. CONCLUSIONS: Little is known about the process of dual interviewing, and this study is an important first step in describing how residents and psychology trainees actually interact during these encounters. More research is needed about the impact of dual interviewing on residents' behavior. PMID- 23743944 TI - Reliability in patient-centered observations of family physicians. AB - BACKGROUND AND OBJECTIVES: Patient-centered communication is an important component of primary care and related to improved patient health outcomes and satisfaction. The Patient-Centered Observation Form (PCOF) was developed as an educational assessment tool to improve resident physician-patient communication. However, reliability of the tool has not been tested. METHODS: Residents and patients were observed in routine medical encounters in a Midwestern family medicine residency center as part of a prospective, quasi-experimental study. Four independent observers (two faculty clinicians and two social scientists) used the PCOF to rate videorecorded patient encounters in the areas of establishing rapport, maintaining relationships, agenda setting, efficiency, information gathering, assessing patient perspectives, effective and open use of the electronic medical record (EMR), sharing information, discussion of behavior changes, co-creating a plan, and shared decision making. RESULTS: A total of 13 physician-patient encounters were observed. Mean overall reliability for the PCOF was 0.67 using four raters, 0.45 for clinicians only, and 0.62 for social scientists. Adequate reliability (>0.7) was found for behavior change discussion (0.89) in clinician ratings but not with social scientists (0.62). Social scientists had adequate reliability in assessing patients' perspectives on health (0.86) and shared decision making (0.78), but these were not considered reliable among clinicians (0.46 and 0.00, respectively). CONCLUSIONS: Reliability of the PCOF for assessing patient-centered competence is dependent on the content of communication being scored and the training history of the evaluator. These results challenge researchers and physicians to develop more reliable scoring instructions and tools for assessing patient-centered competence. PMID- 23743945 TI - My advising session. PMID- 23743946 TI - Too much too late: primary care frustrations. PMID- 23743947 TI - Rites of passage. PMID- 23743948 TI - My favorite teacher. PMID- 23743949 TI - Advocacy and self-reliance. PMID- 23743950 TI - Unique association of Waldenstrom macroglobulinemia with optic neuritis and monoclonal T cell expansion. AB - Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma characterized by production of the immunoglobulin M (IgM) monoclonal protein. Commonly involved sites are the bone marrow, lymph nodes, and spleen. Lymphoplasmacytic infiltration of the central nervous system (CNS), in contrast, is referred to as Bing-Neel syndrome, and is an extremely rare phenomenon. Here, we present a unique case of Waldenstrom macroglobulinemia with optic neuritis accompanied by monoclonal expansion of T cells, which recovered after administration of CNS targeting chemotherapy. Although the underlying causal relationships in this case remain obscure, aberrantly expanded T cells may have contributed to the development of optic neuritis, and we should be reminded that some types of cranial neuropathy in Waldenstrom macroglobulinemia may be reversible. PMID- 23743951 TI - Re: Acute myeloid leukemia associated with FGFR1 abnormalities. PMID- 23743952 TI - Molecularly stabilised ultrasmall gold nanoparticles: synthesis, characterization and bioactivity. AB - Gold nanoparticles (AuNPs) are widely used as contrast agents in electron microscopy as well as for diagnostic tests. Due to their unique optical and electrical properties and their small size, there is also a growing field of potential applications in medical fields of imaging and therapy, for example as drug carriers or as active compounds in thermotherapy. Besides their intrinsic optical properties, facile surface decoration with (bio)functional ligands renders AuNPs ideally suited for many industrial and medical applications. However, novel AuNPs may have toxicological profiles differing from bulk and therefore a thorough analysis of the quantitative structure-activity relationship (QSAR) is required. Several mechanisms are proposed that cause adverse effects of nanoparticles in biological systems. Catalytic generation of reactive species due to the large and chemically active surface area of nanomaterials is well established. Because nanoparticles approach the size of biological molecules and subcellular structures, they may overcome natural barriers by active or passive uptake. Ultrasmall AuNPs with sizes of 2 nm or less may even behave as molecular ligands. These types of potential interactions would imply a size and ligand dependent behaviour of any nanomaterial towards biological systems. Thus, to fully understand their QSAR, AuNPs bioactivity should be analysed in biological systems of increasing complexity ranging from cell culture to whole animal studies. PMID- 23743954 TI - Metabolic engineering of Escherichia coli for enhanced biosynthesis of poly(3 hydroxybutyrate) based on proteome analysis. AB - We have previously analyzed the proteome of recombinant Escherichia coli producing poly(3-hydroxybutyrate) [P(3HB)] and revealed that the expression level of several enzymes in central metabolism are proportional to the amount of P(3HB) accumulated in the cells. Based on these results, the amplification effects of triosephosphate isomerase (TpiA) and fructose-bisphosphate aldolase (FbaA) on P(3HB) synthesis were examined in recombinant E. coli W3110, XL1-Blue, and W lacI mutant strains using glucose, sucrose and xylose as carbon sources. Amplification of TpiA and FbaA significantly increased the P(3HB) contents and concentrations in the three E. coli strains. TpiA amplification in E. coli XL1-Blue lacI increased P(3HB) from 0.4 to 1.6 to g/l from glucose. Thus amplification of glycolytic pathway enzymes is a good strategy for efficient production of P(3HB) by allowing increased glycolytic pathway flux to make more acetyl-CoA available for P(3HB) biosynthesis. PMID- 23743955 TI - Expression of exoinulinase genes in Saccharomyces cerevisiae to improve ethanol production from inulin sources. AB - To improve inulin utilization and ethanol fermentation, exoinulinase genes from the yeast Kluyveromyces marxianus and the recently identified yeast, Candida kutaonensis, were expressed in Saccharomyces cerevisiae. S. cerevisiae harboring the exoinulinase gene from C. kutaonensis gave higher ethanol yield and productivity from both inulin (0.38 vs. 0.34 g/g and 1.35 vs. 1.22 g l(-1) h(-1)) and Jerusalem artichoke tuber flour (0.47 vs. 0.46 g/g and 1.62 vs. 1.54 g l(-1) h(-1)) compared with the strain expressing the exoinulinase gene from K. marxianus. Thus, the exoinulinase gene from C. kutaonensis is advantageous for engineering S. cerevisiae to improve ethanol fermentation from inulin sources. PMID- 23743956 TI - Construction, characterization and application of molecular tools for metabolic engineering of Synechocystis sp. AB - An integrative gene expression system has been constructed for the directional assembly of biological components in Synechocystis PCC6803. We have characterized 11 promoter parts with various expression efficiencies for genetic engineering of Synechocystis for the production of fatty alcohols. This was achieved by integrating several genetic modifications including the expression of multiple copies of fatty acyl-CoA reductase (FAR) under the control of strong promoters, disruption of the competing pathways for poly-beta-hydroxybutyrate and glycogen synthesis, and for peptide truncation of the FAR. In shake-flask cultures, the production of fatty alcohols was significantly improved with a yield of 761 +/- 216 MUg/g cell dry weight in Synechocystis, which is the highest reported to date. PMID- 23743957 TI - Towards the development of systems for high-yield production of microbial lipases. AB - Microbial lipases are a versatile and attractive class of biocatalysts for a wide variety of applications. Lipases can be produced by bacteria, yeasts or filamentous fungi. Nevertheless, they are often not optimal for direct use in industrial conditions due to low yields, low specific activities and a limited spectrum of activities. Improvements in the productivity of lipases have been made by genetic manipulation of the cell factory production hosts and by optimizing production media and conditions. Advances in protein engineering technology, ranging from directed evolution to rational design, have also been able to tailor lipases to particular applications. This review describes various approaches used to improve lipase production and applications. PMID- 23743958 TI - Virtual and concrete manipulatives: a comparison of approaches for solving mathematics problems for students with autism spectrum disorder. AB - Students with autism spectrum disorder (ASD) are included in general education classes and expected to participate in general education content, such as mathematics. Yet, little research explores academically-based mathematics instruction for this population. This single subject alternating treatment design study explored the effectiveness of concrete (physical objects that can be manipulated) and virtual (3-D objects from the Internet that can be manipulated) manipulatives to teach single- and double-digit subtraction skills. Participants in this study included three elementary-aged students (ages ranging from 6 to 10) diagnosed with ASD. Students were selected from a clinic-based setting, where all participants received medically necessary intensive services provided via one-to one, trained therapists. Both forms of manipulatives successfully assisted students in accurately and independently solving subtraction problem. However, all three students demonstrated greater accuracy and faster independence with the virtual manipulatives as compared to the concrete manipulatives. Beyond correctly solving the subtraction problems, students were also able to generalize their learning of subtraction through concrete and virtual manipulatives to more real world applications. PMID- 23743959 TI - Primary lymph node gastrinoma: a rare cause of abdominal pain in childhood. AB - Gastrinoma is a hormone-secreting tumor associated with the Zollinger-Ellison syndrome. It is quite rare among children. The discovery of gastrinomas in unusual locations such as lymph nodes, bones, ovaries, and the liver poses a diagnostic dilemma as to whether the tumor is primary or metastatic. Here, we present a case of a primary gastrinoma within a lymph node. PMID- 23743960 TI - Efficacy and safety of micafungin for febrile neutropenia in pediatric patients with hematological malignancies: a multicenter prospective study. AB - BACKGROUND: Invasive fungal infections are a major cause of infectious mortality in neutropenic patients receiving chemotherapy or hematopoietic stem cell transplantation. However, little is known about the efficacy and safety of micafungin (MCFG), an echinocandin antifungal agent, in pediatric patients with febrile neutropenia (FN). PROCEDURE: This study was conducted as a prospective multicenter trial to evaluate the efficacy and safety of MCFG for FN in pediatric patients with hematological diseases. Efficacy was assessed based on the response to the 5 composite endpoints established by Walsh and colleagues in addition to body temperature and C-reactive protein values. RESULTS: Thirty episodes of FN were enrolled in the study. The median dose and duration of MCFG treatment were 3.0 mg/kg/d and 13.5 days, respectively. Using the criteria of Walsh and colleagues, MCFG was effective in 56.7% of the patients. No breakthrough invasive fungal infection occurred during MCFG treatment. Body temperatures on the last day of neutropenia during administration of MCFG and on the last day of MCFG therapy and C-reactive protein values after administration of MCFG were significantly lower than on the day MCFG therapy was started. Adverse effects in the form of mild liver dysfunction were seen in only 2 patients. CONCLUSIONS: MCFG is a very effective and safe antifungal drug for FN in children. Physicians should administer MCFG early in febrile episode in patients in whom first-line antibiotics are not effective in treating FN. PMID- 23743961 TI - Ferrous sulfate (Fe2+) had a faster effect than did ferric polymaltose (Fe3+) on increased oxidant status in children with iron-deficiency anemia. AB - OBJECTIVE: The purpose of this study was to compare the total oxidant and antioxidant effect of different oral iron preparations in children with iron deficiency anemia (IDA). METHODS: A total of 65 children with IDA were randomized to receive 5 mg Fe/kg/d iron (II) sulfate (Fe(2+) group, n=33) or iron (III) hydroxide polymaltose complex (Fe(3+) group, n=32); healthy controls (n=28) were also included in the study. Serum total thiol (-SH), total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), and hematological profile were evaluated at the baseline and on day 8 and day 30 of the therapy. RESULTS: Serum TOS and OSI levels were significantly higher and total -SH and total antioxidant capacity levels were significantly lower in the study groups at the beginning of therapy than in the controls (P>0.001). In multivariate analysis, after controlling for multiple confounding factors, on days 8 and 30, serum TOS and OSI levels were not different in the Fe(3+) group, whereas they were significantly reduced in the Fe(2+) group (P<=0.033). CONCLUSIONS: Serum total oxidant status was significantly increased in children with IDA, and Fe(2+) was highly effective in correcting elevated oxidative status. PMID- 23743962 TI - COMPUTATIONAL VASCULAR MORPHOMETRY FOR THE ASSESSMENT OF PULMONARY VASCULAR DISEASE BASED ON SCALE-SPACE PARTICLES. AB - We present a fully automatic computational vascular morphometry (CVM) approach for the clinical assessment of pulmonary vascular disease (PVD). The approach is based on the automatic extraction of the lung intraparenchymal vasculature using scale-space particles. Based on the detected features, we developed a set of image-based biomarkers for the assessment of the disease using the vessel radii estimation provided by the particle's scale. The biomarkers are based on the interrelation between vessel cross-section area and blood volume. We validate our vascular extraction method using simulated data with different complexity and we present results in 2,500 CT scans with different degrees of chronic obstructive pulmonary disease (COPD) severity. Results indicate that our CVM pipeline may track vascular remodeling present in COPD and it can be used in further clinical studies to assess the involvement of PVD in patient populations. PMID- 23743963 TI - [Traffic-related occupational injuries]. PMID- 23743964 TI - [Archivos 2011: regularity as a value (and antidote against crisis)]. PMID- 23743965 TI - [Archivos Evidencia, in the mood for evidence based occupational health practice]. PMID- 23743966 TI - [Opinion of undergraduate health sciences students towards ethical issues related to HIV-positive persons in schools, workplaces and health centers]. AB - OBJECTIVE: To describe the opinion of undergraduate health sciences students in the Basque Country universities (UPV/EHU) regarding ethical issues related to HIV positive persons in schools, workplaces and health centers. METHODS: Our population consisted of medical, nursing and dental undergraduate students attending UPV/EHU. An opinion survey was conducted among students attending lectures, on a randomly selected date in 2002-2003. The questionnaire included several items on ethical conflicts related to HIV-positive persons in different settings. Item responses consisted of a Likert-type scale with five possible levels of agreement (from "strongly disagree" to "strongly agree"), as well as the option "I do not want to answer/I have no opinion about this". RESULTS: 529 completed questionnaires were collected. 69% of respondents reported total disagreement with refusing to admit HIV+ students to primary schools, and 77% with dismissal of HIV+ workers. Approximately 90% of respondents felt managers should be aware of the HIV+ status of their employees. 78% of the students did not report disagreement with having HIV+ schoolmates in classrooms. Respondents generally disagreed with employment limitations for HIV+ health care workers, 60% strongly disagreed with health workers refusing to treat HIV+ persons, 69% considered that HIV testing should be compulsory for health workers, and 55% that health workers should know their patients' HIV status. CONCLUSIONS: In general terms, our students are against social and employment limitations targeting HIV+ persons, but favor disclosure of HIV status in schools and health centres. PMID- 23743967 TI - [Functional dysphonia and benign vocal cord lesions in professional voice users]. AB - OBJECTIVE: The aim of this study was to examine the frequency of benign vocal cord lesions (VC-BL) among patients diagnosed with functional dysphonia and to explore their associations with job performance as professional voice users (PVUs). METHODS: A case series of 132 patients diagnosed with functional dysphonia. Direct videolaryngoscopy was performed to objectively document the presence of VC-BL. Information on occupation, sociodemographic variables and non occupational risk factors was collected.We performed a descriptive analysis of the series, and stratified results by occupational exposure variables (PVU and Non-PVU) and sex.We explored bivariate associations between the presence of VC-BL and the other variables. RESULTS: Patients were mainly women (58.3%), with a mean age and standard deviation of 48 +/-13 years; 40% were PVUs. Forty-seven percent of all patients had evidence of VC-BL. The most prevalent lesions were polyps and/or nodules (29%). PVUs with functional dysphonia showed a higher prevalence of VC-BL (57%) than Non-PVUs (40%). PVUs showed an increased risk of VC-BL (crude prevalence odds ratio [cPOR]=1.48; 95CI%=0.74-2.98), mainly with polyps/nodules (cPOR=1.77; 95%CI=0.82-3.78) and chronic laryngitis (cPOR=2.31; 95%CI=0.37 14.32). Smoking was significantly associated with an increased risk of polyps and/or nodules in the entire patient population (cPOR=2.95; 95%CI=1.33-6.53). CONCLUSIONS: Performing a job as PVU was associated with an increased risk of VC BL, mainly polyps/nodules and chronic laryngitis. Occupational health services should always evaluate this risk when the voice is a primary working tool, in order to implement early preventive measures. PMID- 23743969 TI - The effects of caffeinated "energy shots" on time trial performance. AB - An emerging trend in sports nutrition is the consumption of energy drinks and "energy shots". Energy shots may prove to be a viable pre-competition supplement for runners. Six male runners (mean +/- SD age and VO2max: 22.5 +/- 1.8 years and 69.1 +/- 5.7 mL.kg-1.min-1) completed three trials [placebo (PLA; 0 mg caffeine), Guayaki Yerba Mate Organic Energy ShotTM (YM; 140 mg caffeine), or Red Bull Energy ShotTM (RB; 80 mg caffeine)]. Treatments were ingested following a randomized, placebo-controlled crossover design. Participants ran a five kilometer time trial on a treadmill. No differences (p > 0.05) in performance were detected with RB (17.55 +/- 1.01 min) or YM ingestion (17.86 +/- 1.59 min) compared to placebo (17.44 +/- 1.25 min). Overall, energy shot ingestion did not improve time-trial running performance in trained runners. PMID- 23743968 TI - Does excess weight interfere with bone mass accumulation during adolescence? AB - Obesity and osteoporosis are important global health problems characterized by increasing prevalence with high impact on morbidity and mortality. The objective of this review was to determine whether excess weight during adolescence interferes with bone mass accumulation. If bone mineral gain can be optimized during puberty, adults are less likely to suffer from the devastating complications of osteoporosis. The increased fracture risk in obese children has also been attributed to a lower bone mass for weight compared to non-obese children. Thus, adiposity present in this age group may not result in the protection of bone mass, in contrast to what has been observed in adults. However, studies involving adolescents have reported both protective and detrimental effects of obesity on bone. The results and mechanisms of these interactions are controversial and have not been fully elucidated, a fact highlighting the extreme relevance of this topic and the need to monitor intervening and interactive variables. PMID- 23743970 TI - Caffeine-containing medicines increase the risk of hemorrhagic stroke. AB - BACKGROUND AND PURPOSE: Research on the relationship between caffeine-containing medicines (CCMs) and the risk of hemorrhagic stroke (HS) is sparse. The aim of this study is to evaluate the association between CCMs and the risk of HS. METHODS: We performed a multicenter case-control study in South Korea, from 2002 to 2004. A total of 940 patients with nontraumatic acute HS, aged 30 to 84 years without a history of stroke, 940 community, and 940 hospital controls, age and sex matched to each case, were included. We obtained information on all medications taken in the 14 days before the date (index date) and time of stroke onset (zero-time) for case subjects or matched zero-time for control subjects. Exposure to CCMs was defined by use on the index date before zero-time or during the preceding 3 days. The adjusted odds ratios and their 95% confidence intervals (CIs) were estimated by conditional logistic regression. RESULTS: The adjusted odds ratio for the association between the use of CCM and risk for HS was 2.23 (95% CI, 1.41-3.69) for all HS, 2.24 (95% CI, 1.08-4.66) for subarachnoid hemorrhage, and 2.49 (95% CI, 1.29-4.80) for intracerebral hemorrhage. Stratified by daily coffee intake, adjusted odds ratio of CCMs for HS was 2.95 (95% CI, 1.45 5.98) for those who did not drink coffee on a daily basis. CONCLUSIONS: These results suggest that use of CCMs is associated with increased risk of HS, both subarachnoid hemorrhage and intracerebral hemorrhage. PMID- 23743971 TI - Life's Simple 7 and risk of incident stroke: the reasons for geographic and racial differences in stroke study. AB - BACKGROUND AND PURPOSE: The American Heart Association developed Life's Simple 7 (LS7) as a metric defining cardiovascular health. We investigated the association between LS7 and incident stroke in black and white Americans. METHODS: The Reasons for Geographic And Racial Differences in Stroke (REGARDS) is a national population-based cohort of 30 239 blacks and whites, aged >=45 years, sampled from the US population from 2003 to 2007. Data were collected by telephone, self administered questionnaires, and an in-home examination. Incident strokes were identified through biannual participant contact followed by adjudication of medical records. Levels of the LS7 components (blood pressure, cholesterol, glucose, body mass index, smoking, physical activity, and diet) were each coded as poor (0 point), intermediate (1 point), or ideal (2 points) health. An overall LS7 score was categorized as inadequate (0-4), average (5-9), or optimum (10-14) cardiovascular health. RESULTS: Among 22 914 subjects with LS7 data and no previous cardiovascular disease, there were 432 incident strokes over 4.9 years of follow-up. After adjusting for demographics, socioeconomic status, and region of residence, each better health category of the LS7 score was associated with a 25% lower risk of stroke (hazard ratios, 0.75; 95% confidence interval, 0.63 0.90). The association was similar for blacks and whites (interaction P value=0.55). A 1-point higher LS7 score was associated with an 8% lower risk of stroke (hazard ratios, 0.92; 95% confidence interval, 0.88-0.95). CONCLUSIONS: In both blacks and whites, better cardiovascular health, on the basis of the LS7 score, is associated with lower risk of stroke, and a small difference in scores was an important stroke determinant. PMID- 23743972 TI - Ultra-sensitive molecular MRI of vascular cell adhesion molecule-1 reveals a dynamic inflammatory penumbra after strokes. AB - BACKGROUND AND PURPOSE: Our aim was to assess the spatiotemporal evolution of the cerebrovascular inflammation occurring after ischemic and hemorrhagic strokes using a recently developed, fast, and ultra-sensitive molecular MRI method. METHODS: We first assessed longitudinally the cerebrovascular inflammation triggered by collagenase-induced hemorrhage and by permanent/transient middle cerebral artery occlusion in mice, using MRI after injection of microparticles of iron oxide targeted to vascular cell adhesion molecule-1 (MPIOs-alphaVCAM-1). Thereafter, we used this method to study the anti-inflammatory effects of celecoxib, atorvastatin, and dipyridamole after stroke. RESULTS: Using multiparametric MRI, we demonstrated that the level and the kinetics of cerebrovascular VCAM-1 expression depend on several parameters, including stroke pathogenesis, the natural history of the disease, and the administration of inflammation-modulating drugs. Interestingly, in transient middle cerebral artery occlusion and intracranial hemorrhage models, VCAM-1 expression was maximal at 24 hours and almost returned to baseline 5 days after stroke onset. In contrast, after permanent middle cerebral artery occlusion, VCAM-1 overexpression was sustained between 24 hours and 5 days, and was particularly significant in the peri-infarct areas. Our results suggest that these perilesional areas expressing VCAM-1 constitute an inflammatory penumbra that is recruited by the ischemic core during the subacute phase. Using MPIOs-alphaVCAM-1-enhanced imaging, we also provided evidence that celecoxib and atorvastatin (but not dipyridamole) alleviate VCAM-1 overexpression after stroke and prevent formation of the inflammatory penumbra. CONCLUSIONS: MPIOs-alphaVCAM-1-enhanced imaging seems to be promising in the detection of individuals presenting with severe cerebrovascular responses after stroke, which could therefore benefit from anti inflammatory treatments. PMID- 23743973 TI - Displacement of sensory maps and disorganization of motor cortex after targeted stroke in mice. AB - BACKGROUND AND PURPOSE: Recovery from stroke is hypothesized to involve the reorganization of surviving cortical areas. To study the functional organization of sensorimotor cortex at multiple time points before and after stroke, we performed longitudinal light-based motor mapping of transgenic mice expressing light-sensitive channelrhodopsin-2 in layer 5 cortical neurons. METHODS: Pulses of light stimulation were targeted to an array of cortical points, whereas evoked forelimb motor activity was recorded using noninvasive motion sensors. Intrinsic optical signal imaging produced maps of the forelimb somatosensory cortex. The resulting motor and sensory maps were repeatedly generated for weeks before and after small (0.2 mm3) photothrombotic infarcts were targeted to forelimb motor or sensory cortex. RESULTS: Infarcts targeted to forelimb sensory or motor areas caused decreased motor output in the infarct area and spatial displacement of sensory and motor maps. Strokes in sensory cortex caused the sensory map to move into motor cortex, which adopted a more diffuse structure. Stroke in motor cortex caused a compensatory increase in peri-infarct motor output, but did not affect the position or excitability of sensory maps. CONCLUSIONS: After stroke in motor cortex, decreased motor output from the infarcted area was offset by peri-infarct excitability. Sensory stroke caused a new sensory map to form in motor cortex, which maintained its center position, despite becoming more diffuse. These data suggest that surviving regions of cortex are able to assume functions from stroke damaged areas, although this may come at the cost of alterations in map structure. PMID- 23743974 TI - Modulating the motor system by action observation after stroke. AB - BACKGROUND AND PURPOSE: Much recent interest surrounds the use of action observation, which is observing another individual performing a motor task, in stroke rehabilitation, to promote motor recovery by engaging similar brain regions to action execution. This may be especially useful in individuals with limited mobility. Here, we assess how cortical motor activity during action observation is affected by stroke and by stroke-related motor deficits. METHODS: We used functional MRI to compare brain activity during right and left hand action observation in right-handed nondisabled participants and participants who were right-handed before left hemisphere stroke. All participants performed the same actions after their functional MRI. RESULTS: Nondisabled participants show greater bilateral cortical motor activity when observing actions made using the left hand, whereas participants with stroke show greater ipsilesional cortical motor activity when observing actions made using the right (paretic) hand (P<0.05; corrected). For both groups, action processing is modulated by motor capability: cortical motor activity is greater when observing the hand with lower motor scores (P<0.05; corrected). Furthermore, for stroke, the extent of ipsilesional activity correlates with lesion volume (P=0.049), in a pattern that suggests adaptive plasticity. CONCLUSIONS: We found that action observation activates specific motor plans in damaged motor circuits after stroke, and this activity is related to motor capability to perform the same actions. Cortical motor activity during action observation may be relevant to motor learning, and to motor relearning in stroke rehabilitation. PMID- 23743975 TI - Lipoprotein receptor-related protein-6 protects the brain from ischemic injury. AB - BACKGROUND AND PURPOSE: Loss-of-function mutations of the lipoprotein receptor related protein-6 (LRP6), a coreceptor in the Wingless-related integration site beta-catenin prosurvival pathway, have been implicated in myocardial ischemia and neurodegeneration. However, it remains to be established whether LRP6 is also involved in ischemic brain injury. We used LRP6+/- mice to examine the role of this receptor in the mechanisms of focal cerebral ischemia. METHODS: Focal cerebral ischemia was induced by transient occlusion of the middle cerebral artery. Motor deficits and infarct volume were assessed 3 days later. Glycogen synthase-kinase-3beta (GSK-3beta) phosphorylation was examined by Western blotting with phosphospecific antibodies, and the mitochondrial membrane potential changes induced by Ca2+ were also assessed. RESULTS: LRP6+/- mice have larger stroke and more severe motor deficits, effects that were independent of intraischemic cerebral blood flow, vascular factors, or cytosolic beta-catenin levels. Rather, LRP6 haploinsufficiency increased the activating phosphorylation and decreased the inhibitory phosphorylation of GSK-3beta, a kinase involved in proinflammatory signaling and mitochondrial dysfunction. Accordingly, postischemic inflammatory gene expression was enhanced in LRP6+/- mice. Furthermore, the association of mitochondria with activated GSK-3beta was increased in LRP6+/- mice, resulting in a reduction in the Ca2+ handling ability of mitochondria. The mitochondrial dysfunction was reversed by pharmacological inhibition of GSK-3beta. CONCLUSIONS: LRP6 activates an endogenous neuroprotective pathway that acts independently of beta-catenin by controlling GSK-3beta activity and preventing its deleterious mitochondrial and proinflammatory effects. The findings raise the possibility that emerging treatment strategies for diseases attributable to LRP6 loss-of-function mutations could also lead to new therapeutic avenues for ischemic stroke. PMID- 23743976 TI - Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation. AB - BACKGROUND AND PURPOSE: Intracranial hemorrhage rates are higher in Asians than non-Asians, especially in patients receiving warfarin. This randomized evaluation of long-term anticoagulation therapy subgroup analysis assessed dabigatran etexilate (DE) and warfarin effects on stroke and bleeding rates in patients from Asian and non-Asian countries. METHODS: There were 2782 patients (15%) from 10 Asian countries and 15 331 patients from 34 non-Asian countries. A Cox regression model, with terms for treatment, region, and their interaction was used. RESULTS: Rates of stroke or systemic embolism in Asians were 3.06% per year on warfarin, 2.50% per year on DE 110 mg BID (DE 110), and 1.39% per year on DE 150 mg BID (DE 150); in non-Asians, the rates were 1.48%, 1.37%, and 1.06% per year with no significant treatment-by-region interactions. Hemorrhagic stroke on warfarin occurred more often in Asians than non-Asians (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.3-4.7; P=0.007), with significant reductions for DE compared with warfarin in both Asian (DE 110 versus warfarin HR, 0.15; 95% CI, 0.03-0.66 and DE 150 versus warfarin HR, 0.22; 95% CI, 0.06-0.77) and non-Asian (DE 110 versus warfarin HR, 0.37; 95% CI, 0.19-0.72 and DE 150 versus warfarin HR, 0.28; 95% CI, 0.13-0.58) patients. Major bleeding rates in Asians were significantly lower on DE (both doses) than warfarin (warfarin 3.82% per year, DE 110 2.22% per year, and DE 150 2.17% per year). CONCLUSIONS: Hemorrhagic stroke rates were higher on warfarin in Asians versus non-Asians, despite similar blood pressure, younger age, and lower international normalized ratio values. Hemorrhagic strokes were significantly reduced by DE in both Asians and non Asians. DE benefits were consistent across Asian and non-Asian subgroups. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600. PMID- 23743977 TI - Effects of microvascular permeability changes on contrast-enhanced T1 and pharmacokinetic MR imagings after ischemia. AB - BACKGROUND AND PURPOSE: Brain enhancement on contrast-enhanced T1-weighted imaging (CET1-WI) after ischemic stroke is generally accepted as an indicator of the blood-brain barrier disruption. However, this phenomenon usually starts to become visible at the subacute phase. The purpose of this study was to evaluate the time-course profiles of K(trans), cerebral blood volume (vp), and CET1-WI with early detection of blood-brain barrier changes on K(trans) maps and their role for prediction of subsequent hemorrhagic transformation in acute middle cerebral arterial infarct. METHODS: Twenty-six patients with acute middle cerebral arterial stroke and early spontaneous reperfusion, whose MR images were obtained at predetermined stroke stages, were included. T2*-based MR perfusion weighted images were acquired using the first-pass pharmacokinetic model to derive K(trans) and vp. Parenchymal enhancement observed on maps of K(trans), vp, and CET1-WI at each stage was compared. Association among these measurements and hemorrhagic transformation was analyzed. RESULTS: K(trans) map showed significantly higher parenchymal enhancement in ischemic parenchyma as compared with that of vp map and CET1-WI at early stroke stages (P<0.05). The increased K(trans) at acute stage was not associated with parenchymal enhancement in CET1 WI at the same stage. Parenchymal enhancement in CET1-WI started to occur at the late subacute stage and tended to be luxury reperfusion-dependent. Patients with hemorrhagic transformation showed higher mean K(trans) values as compared with patients without hemorrhagic transformation (P=0.02). CONCLUSIONS: Postischemic brain enhancement on routine CET1-WI seems to be closely related to the luxury reperfusion at the late subacute stage and is not dependent on microvascular permeability changes at the acute stage. PMID- 23743978 TI - Spatiotemporal uptake characteristics of [18]F-2-fluoro-2-deoxy-D-glucose in a rat middle cerebral artery occlusion model. AB - BACKGROUND AND PURPOSE: Alterations of cerebral glucose metabolism are well anticipated during cerebral ischemia. However, detailed spatiotemporal characteristics of disturbed cerebral glucose metabolism during acute ischemia remain largely elusive. This study aims to delineate spatiotemporal distributions of [18]F-2-fluoro-2-deoxy-D-glucose (FDG) uptake using positron emission tomography imaging, particularly at the peri-ischemic zone, and its correlation with tissue outcome. METHODS: The intraluminal suture middle cerebral artery occlusion model was used to induce focal cerebral ischemia in rats (n=48). All animals underwent sequential MRI and FDG positron emission tomography imaging at different times (30-150 minutes) after middle cerebral artery occlusion. MR and positron emission tomography images were coregistered. FDG uptake in the peri ischemic zone was assessed in relation to middle cerebral artery occlusion duration, cerebral blood flow, apparent diffusion coefficient, and 24-hour T2 lesions. RESULTS: Elevated FDG uptake was consistently observed at the peri ischemic zone surrounding the presumed ischemic core with low FDG uptake. Both the spatial volume and the uptake level of the hyper-uptake region were inversely correlated with the duration of middle cerebral artery occlusion. The hyper uptake regions exhibited a mild reduction of cerebral blood flow (28.2+/-3.2%) and apparent diffusion coefficient (9.1+/-1.4%) when compared with that in the contralateral hemisphere. Colocalization analysis revealed that, with reperfusion, an average of 12.1+/-1.7% of the hyper-uptake volume was recruited into final infarction. CONCLUSIONS: Elevated FDG uptake at the peri-ischemic zone is consistently observed during acute cerebral ischemia. The region with elevated FDG uptake likely reflects viable tissues that can be salvaged with reperfusion. Therefore, acute FDG positron emission tomography imaging might hold promise in the management of patients with acute stroke. PMID- 23743979 TI - Size ratio can highly predict rupture risk in intracranial small (<5 mm) aneurysms. AB - BACKGROUND AND PURPOSE: Management strategies for unruptured intracranial aneurysms (UIAs) are controversial. This study aimed to identify surrogate parameters that highly predict the rupture risk of small (<5 mm) UIAs. METHODS: Radiological data were collected from 854 patients with aneurysmal subarachnoid hemorrhages who were enrolled in the Sapporo SAH Study. They had a total of 854 ruptured intracranial aneurysms and 180 UIAs. The size, aneurysm-to-vessel size ratio, and distribution were precisely compared between ruptured intracranial aneurysms and UIAs. RESULTS: For all aneurysms, the size was significantly larger in ruptured intracranial aneurysms (7.0+/-1.3 mm) than in the UIAs (3.7+/-1.2 mm; P<0.001). Size ratio was also significantly higher in ruptured intracranial aneurysms (4.3+/-1.9) than in the UIAs (2.2+/-1.6; P<0.001). Multivariate logistic analysis showed that size and size ratio were correlated with aneurysm rupture. However, in small aneurysms, multivariate logistic regression revealed that only size ratio was associated with ruptured aneurysms (P=0.008; odds ratio, 9.1). There were no significant differences in size or aneurysm location. A receiver operating characteristic analysis was performed for size ratio in small aneurysms, and the threshold separating ruptured and unruptured groups was 3.12 and the area under the curve was 0.801. CONCLUSIONS: This study revealed that the size ratio, and not the absolute size, may highly predict the risk of rupture in small UIAs. Size ratio measurements are very simple and provide useful information for determining treatment and follow-up strategies for patients with small UIAs. PMID- 23743980 TI - Pretreatment weight status and weight loss among head and neck cancer patients receiving definitive concurrent chemoradiation therapy: implications for nutrition integrated treatment pathways. AB - PURPOSE: The purpose was to examine the effect of pretreatment weight status on loco-regional progression for patients with squamous cell carcinoma of the head and neck (SCCHN) after receiving definitive concurrent chemoradiation therapy (CCRT). METHODS: In an expanded cohort of 140 patients, we retrospectively reviewed weight status and loco-regional progression of SCCHN patients treated with CCRT between 2004 and 2010. RESULTS: Pretreatment ideal body weight percentage (IBW%) was statistically significantly different for patients with disease progression than for those without progression (p = 0.02) but was not an independent predictor of progression. Median pretreatment IBW% was 118 (72-193) for the progression-free group and was 101.5 (73-163) for the group with progression. Both groups suffered clinically severe weight loss of approximately 9 % from baseline to end treatment. CONCLUSIONS: Pretreatment weight status, a very crude indicator of nutrition status, may have prognostic value in patients with SCCHN undergoing definitive CCRT. Inadequate nutritional status in these patients has been associated with poor clinical outcomes and decreased quality of life. Based on this report and others, the best next steps include routine validated malnutrition screening and the testing of evidence-based nutrition care protocols with the goals of minimizing weight loss and improvement of quality of life. PMID- 23743982 TI - [Update]. PMID- 23743983 TI - [Skin as manifestation organ for inflammatory rheumatic diseases]. PMID- 23743981 TI - Current status of bone graft options for anterior interbody fusion of the cervical and lumbar spine. AB - Anterior cervical discectomy and fusion (ACDF) and anterior lumbar interbody fusion (ALIF) are common surgical procedures for degenerative disc disease of the cervical and lumbar spine. Over the years, many bone graft options have been developed and investigated aimed at complimenting or substituting autograft bone, the traditional fusion substrate. Here, we summarise the historical context, biological basis and current best evidence for these bone graft options in ACDF and ALIF. PMID- 23743984 TI - [Paradoxical skin reactions under therapy with TNF-alpha antagonists]. AB - Tumor necrosis factor alpha (TNF alpha) antagonists are an effective and established therapy option for chronic inflammatory diseases in rheumatology, gastroenterology and dermatology. However, some undesired but rare side effects of TNF alpha antagonists, so-called paradoxical skin reactions, have been observed. These are mostly in the form of psoriasiform skin alterations, including pustular variants, eczema, vasculitis and other rare skin diseases. This article provides an overview of the different variants of paradoxical skin reactions due to TNF alpha inhibitors and gives practical advice on the therapeutic consequences. PMID- 23743985 TI - [Cutaneous lupus erythematosus and skin manifestations in systemic lupus erythematosus]. AB - Skin manifestations are frequently observed in lupus erythematosus (LE) and are manifold. Nonspecific and specific symptoms can be differentiated with the latter belonging to the dermatologically well-characterized clinical entities of acute cutaneous, subacute cutaneous, chronic cutaneous as well as intermittent cutaneous LE. These forms are differentially related to systemic LE. Patient history and clinical examinations, laboratory and immunoserological findings as well as organ imaging results determine the time point as well as the intensity of therapy. Apart from cessation of smoking and alcohol consumption as well as stringent UV protection, topical therapy with corticosteroids or calcineurin inhibitors may suffice with limited forms of the disease. In many cases, however, systemic treatment with antimalarial drugs as a basic treatment is mandatory. Several immunosuppressive agents can alternatively be used in conjunction with systemic corticosteroids. Early and effective therapy is important to prevent irreversible scarring of the skin and to avoid internal organ damage. PMID- 23743986 TI - [Skin manifestations of different forms of vasculitis]. AB - The skin not only represents the organ which often reveals the first signs of systemic vasculitis, but also the organ which is most frequently involved in vasculitis. These diseases encompass systemic vasculitides and those which appear to involve the skin only. Among those vasculitides restricted to the skin, some are yet typically associated with other systemic diseases, such as nodular vasculitis, which often occurs during infections by M. tuberculosis, or erythema elevatum diutinum in patients with gammopathy. The type and localization of skin lesions give valuable indications as to the type of vasculitis. Subcutaneous nodules which ulcerate and are surrounded by livedo racemosa are suggestive of polyarteritis nodosa, a palpable purpura with predilection for the lower legs is almost pathognomonic for immune complex vasculitis (e.g. IgA vasculitis or cutaneous leukocytoclastic vasculitis), hemorrhagic papules and necrotic plaques which occur in acral areas after cooling indicate cryoglobulinemic vasculitis, hemorrhagic papules and macules which develop in patients who start to feel worse and develop fever should arouse suspicion of septic vasulitis, while the simultaneous presence of ulcerating nodules and hemorrhagic papules without predilection for the lower legs will suggest ANCA-associated vasculitis. The different morphology of the cutaneous signs of the various vasculitides depends to a large extent on the size of the vessels primarily involved. In this review the cutaneous signs of vasculitides will be presented with reference to the revised nomenclature of the Chapel Hill Consensus Conference from 2012. PMID- 23743987 TI - [ANCA-associated vasculitis]. AB - Granulomatosis with polyangiitis, microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis belong to the anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitides (AAV). They share the feature of vasculitic manifestations in small to medium-size vessel beds which can occur in nearly any organ system. The treatment of AAV is dependent on stage and activity and is carried out on the basis of randomized controlled trials with an initial remission induction regimen followed by maintenance treatment. Apart from glucocorticoids, conventional immunosuppressants are the basis of treatment whereby biologics, such as rituximab have emerged as new treatment options. PMID- 23743988 TI - [Announcements]. PMID- 23743989 TI - [Announcements of the DRL]. PMID- 23743990 TI - Lupus anticoagulant, warfarin, and alternative laboratory monitoring of anticoagulation. PMID- 23743991 TI - The current role of percutaneous chemolysis in the management of urolithiasis: review and results. AB - The treatment of urolithiasis has changed dramatically over the past several decades. Novel technologies have led to new management protocols. Percutaneous chemolysis as a primary or adjuvant treatment for urinary tract stones has widely been neglected. We present our own experience with it and discuss it in the light of an extensive literature review. From a MEDLINE search on percutaneous chemolysis we evaluated the most important studies, a total of 58 articles, 43 case series and 15 review articles. In our unit between 2001 and 2011, 29 patients (mean age 62 years) with infectious staghorn calculi were treated with adjuvant percutaneous chemolysis post-percutaneous nephrolithotripsy. There were 17 women, with 10 complete and 14 partial staghorn stones (mean size 32 mm). Patients were generally deemed at high risk to undergo another procedure in the future. Suby G solution was used following an established protocol. Sixteen patients (55.1 %) were stone free after chemolysis, eight stones showed partial dissolution, half of them with so-called "insignificant" residual fragments <4 mm. Patients with residual stones underwent SWL. Mean follow-up was 5.25 years (1 11). One stone-free patient (6 %) and three of eight patients (37.5 %) with residual fragments post local chemolysis, developed new stones during follow-up. The often neglected percutaneous chemolysis represents a significant and effective. PMID- 23743992 TI - [From historical all-rounder to modern specialists: surgical further education in Germany from 1994 to 2012]. PMID- 23743993 TI - [Regional treatment of malignant pleural mesothelioma: results from the tumor centre Regensburg]. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) is an aggressive, malignant tumor of the pleural surface and is strongly associated with asbestos exposure. Incidence of MPM will reach its peak over the coming years. Most patients present with advanced tumor stages and therefore surgical options are limited. PATIENTS AND METHODS: Retrospective analysis of all patients with MPM reported to the tumor centre Regensburg between January 1998 and August 2011. RESULTS: A total of 118 patients (85 % male) with cytologically or histologically confirmed MPM were reported. The mean age at diagnosis was 67 years (range 45-84 years) and 65 % of patients had a history of asbestos exposure. The incidence of MPM at the tumor centre Regensburg was 0.8/100,000 inhabitants with obvious regional differences depending on asbestos exposure. Staging was completed in 81 patients (67 %): stage I 9 %, stage II 22 %, stage III 23 % and stage IV 46 %. Of the patients 87 (74 %) underwent at least one surgical procedure: diagnostic thoracoscopy with biopsy (n = 37, 43 %), debulking surgery or talcum pleurodesis (n = 33, 38 %) and potentially curative resection (n = 17, 19 %). After a mean follow-up of 20 months the overall median survival was 14 months (1 year survival rate 62 %, 3 year survival rate 15 %). Patients had a significantly better median survival of 18 months after curative resection. CONCLUSIONS: The distribution of MPM varies according to regional and industrial asbestos exposure. Screening and diagnostics should concentrate on locations with higher incidence of MPM to facilitate surgical therapy in a multimodal treatment regime. PMID- 23743994 TI - [Liver transplantation as effective treatment for non-resectable liver metastases of neuroendocrine tumors]. PMID- 23743996 TI - Photothermal ablation cancer therapy using homogeneous CsxWO3 nanorods with broad near-infra-red absorption. AB - Recently, photothermal ablation therapy (PTA) employing near-infrared radiation (NIR) has been extensively investigated as an emerging modality for cancer management. However, the clinical translation of this promising approach is limited by the lack of PTA agents with broad NIR absorption, low cost and high photothermal conversion efficiency. Herein, we have developed PEGylated homogeneous CsxWO3 nanorods (a mean size ~69.3 nm * 12.8 nm) with broad photo absorption (780-2500 nm) as a novel NIR absorbent for PTA treatment of human cancer. The prepared CsxWO3 nanocrystals displayed strong near-infrared optical absorption with a high molar extinction coefficient (e.g. 4.8 * 10(10) M(-1) cm( 1) at 980 nm), thus generated significant amounts of heat upon excitation with near-infrared light. The PTA study in two human carcinoma cell lines (i.e. A549 lung cancer cells and HeLa ovarian cancer cells) demonstrated that CsxWO3 nanorods can efficiently cause cell death via hyperthermia induced lysosome destruction, cytoskeleton protein degradation, DNA damage and thereafter cellular necrosis or apoptosis. Our study also confirmed the migration of healthy cells migrated from unirradiated areas to dead cell cycle, which is essential for tissue reconstruction and wound healing after photodestruction of tumor tissue. The prompted results reported in the current study imply the promising potential of CsxWO3 nanorods for application in PTA cancer therapy. PMID- 23743995 TI - Collagen VI regulates satellite cell self-renewal and muscle regeneration. AB - Adult muscle stem cells, or satellite cells have essential roles in homeostasis and regeneration of skeletal muscles. Satellite cells are located within a niche that includes myofibers and extracellular matrix. The function of specific extracellular matrix molecules in regulating SCs is poorly understood. Here, we show that the extracellular matrix protein collagen VI is a key component of the satellite cell niche. Lack of collagen VI in Col6a1(-/-) mice causes impaired muscle regeneration and reduced satellite cell self-renewal capability after injury. Collagen VI null muscles display significant decrease of stiffness, which is able to compromise the in vitro and in vivo activity of wild-type satellite cells. When collagen VI is reinstated in vivo by grafting wild-type fibroblasts, the biomechanical properties of Col6a1(-/-) muscles are ameliorated and satellite cell defects rescued. Our findings establish a critical role for an extracellular matrix molecule in satellite cell self-renewal and open new venues for therapies of collagen VI-related muscle diseases. PMID- 23743997 TI - Hollow three-dimensional endothelialized microvessel networks based on femtosecond laser ablation. AB - In this study, a novel method for the fabrication of hollow three-dimensional (3D) poly(lactic-co-glycolic acid) (PLGA) microvessel scaffolds is proposed. In this novel fabrication method, a salt ingot, which was used as a temporary frame to define the shape of the desired scaffold, was fabricated by extrusion molding. The salt ingot was immersed in a PLGA solution and the PGLA enveloped the ingot entirely. The femtosecond laser ablation technique was used for ablating the desired pattern on the PLGA layer and then the salt ingot was completely dissolved in distilled deionized water. A hollow 3D PLGA scaffold was obtained using this process on which bovine endothelial cells (BECs) were then cultured. Scanning electron microscopy (SEM) and fluorescent images of the cell seeding demonstrate that the BECs adhered and grew well on both the side-wall of the branches and the surroundings of each branch. PMID- 23743998 TI - Nuclear spin-spin coupling anisotropy in the van der Waals-bonded 129Xe dimer. AB - The spin-spin coupling constant, J, in the van der Waals-bonded (129)Xe-(129)Xe dimer cannot be determined experimentally because of the magnetic equivalence of the two nuclei. In contrast, the anisotropy of the coupling tensor, DeltaJ, can be obtained from the so called effective dipole-dipole coupling determined in a solid state inclusion compound whose cages accommodate two xenon atoms. For the determination of the experimental DeltaJ((129)Xe, (129)Xe) we exploited the data reported earlier in this journal. [D. H. Brouwer et al., Phys. Chem. Chem. Phys., 2007, 9, 1093.] The experimental value and the value obtained from relativistic first-principles computation are in perfect agreement. To the best of our knowledge this is the first investigation of spin-spin coupling anisotropy in a van der Waals-bonded system. PMID- 23743999 TI - Sodium thiosulfate: mythical treatment for a mysterious disease? PMID- 23744000 TI - Five policies to promote palliative care for patients with ESRD. AB - Patients with ESRD experience complex and costly care that does not always meet their needs. Palliative care, which focuses on improving quality of life and relieving suffering for patients with serious illnesses, could address a large unmet need among patients with ESRD. Strengthening palliative care is a top policy priority for health reform efforts based on strong evidence that palliative care improves value. This commentary outlines palliative care policies for patients with ESRD and is directed at policymakers, dialysis providers, nephrology professional societies, accreditation organizations, and funding agencies who play a key role in the delivery and determination of quality of ESRD care. Herein we suggest policies to promote palliative care for patients with ESRD by addressing key barriers, including the lack of access to palliative care, lack of capacity to deliver palliative care, and a limited evidence base. We also provide examples of how these policies could be implemented within the existing ESRD care infrastructure. PMID- 23744001 TI - Fostering innovation, advancing patient safety: the kidney health initiative. AB - To respond to the serious and underrecognized epidemic of kidney disease in the United States, the US Food and Drug Administration and the American Society of Nephrology have founded the Kidney Health Initiative-a public-private partnership designed to create a collaborative environment in which the US Food and Drug Administration and the greater kidney community can interact to optimize the evaluation of drugs, devices, biologics, and food products. The Kidney Health Initiative will bring together all the necessary stakeholders, including patients, regulators, industry, health care providers, academics, and other governmental agencies, to improve patient safety and foster innovation. This initiative is intended to enable the kidney community as a whole to provide the right drug, device, or biologic for administration to the right patient at the right time by fostering partnerships that will facilitate development and delivery of those products and addressing challenges that currently impede these goals. PMID- 23744002 TI - Mediterranean diet, kidney function, and mortality in men with CKD. AB - BACKGROUND AND OBJECTIVES: Adherence to a Mediterranean diet may link to a better preserved kidney function in the community as well as a favorable cardiometabolic profile and reduced mortality risk in individuals with manifest CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Dietary habits were determined by 7-day dietary records in a population-based cohort of 1110 Swedish men (age 70 years) from 1991 to 1995, 506 of whom were considered to have CKD because of a GFR<60 ml/min per 1.73 m(2). A Mediterranean Diet Score was calculated, and participants were categorized as having low, medium, or high adherence. Adequate dietary reporters were identified with Goldberg cutoffs (n=597). Deaths were registered during a median follow-up of 9.9 years. RESULTS: Compared with low adherents, medium and high adherents were 23% and 42% less likely to have CKD, respectively (adjusted odds ratio [95% confidence interval]=0.77 [0.57 to 1.05] and 0.58 [0.38 to 0.87], respectively, P for trend=0.04). Among those individuals with CKD, phosphate intake and net endogenous acid production were progressively lower across increasing adherence groups. No differences were observed regarding other cardiometabolic risk factors across adherence groups. As many as 168 (33%) CKD individuals died during follow-up. Compared with low adherents, proportional hazards regression associated medium and high adherents to a 25% and 23% lower mortality risk, respectively (adjusted hazard ratio [95% confidence interval]=0.75 [0.52 to 1.06] and 0.77 [0.44 to 1.36], respectively, P for trend=0.10). Sensitivity analyses showed significant and stronger associations when only adequate dietary reporters were considered. CONCLUSIONS: Adherence to a Mediterranean dietary pattern is associated with lower likelihood of CKD in elderly men. A greater adherence to this diet independently predicted survival in those patients with manifest CKD. Clinical trials are warranted to test the hypothesis that following such a diet could improve outcomes (independent of other healthy lifestyles) in CKD patients. PMID- 23744003 TI - World incidence of AKI: a meta-analysis. AB - BACKGROUND AND OBJECTIVES: The burden of AKI around the globe has not been systematically examined. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A systematic review (2004-2012) of large cohort studies was conducted to estimate the world incidence of AKI and its stages of severity and associated mortality, and to describe geographic variations according to countries, regions, and their economies. AKI definitions were reclassified according to the Kidney Disease Improving Global Outcomes (KDIGO) staging system. Random-effects model meta analyses and meta-regressions were used to generate summary estimates and explore sources of heterogeneity. RESULTS: There were 312 studies identified (n=49,147,878) , primarily in hospital settings. Most studies originated from North America, Northern Europe, and Eastern Asia, from high-income countries, and from nations that spent >=5% of the gross domestic product on total health expenditure. Among the 154 studies (n=3,585,911) that adopted a KDIGO-equivalent AKI definition, the pooled incidence rates of AKI were 21.6% in adults (95% confidence interval [95% CI], 19.3 to 24.1) and 33.7% in children (95% CI, 26.9 to 41.3). The pooled AKI-associated mortality rates were 23.9% in adults (95% CI, 22.1 to 25.7) and 13.8% in children (95% CI, 8.8 to 21.0). The AKI-associated mortality rate declined over time, and was inversely related to income of countries and percentage of gross domestic product spent on total health expenditure. CONCLUSIONS: Using the KDIGO definition, 1 in 5 adults and 1 in 3 children worldwide experience AKI during a hospital episode of care. This analysis provides a platform to raise awareness of AKI with the public, government officials, and health care professionals. PMID- 23744004 TI - Re-envisioning Fistula First in a patient-centered culture. AB - The main options for vascular access in hemodialysis patients are arteriovenous fistulas (AVFs), arteriovenous grafts, and tunneled cuffed central venous catheters. AVFs have the lowest complication rate and require the fewest interventions and lowest cost to maintain. There has been a dramatic national increase in prevalent AVFs among patients with ESRD in the United States driven, in part, by the Fistula First Breakthrough Initiative. The Fistula First Breakthrough Initiative has engaged stakeholders in the dialysis community to disseminate best practices and quality improvement activities to increase AVF prevalence in suitable candidates. In the pursuit of maximizing AVF placement and prevalence, less emphasis has been placed on the individual patient context. An AVF may not be the best access choice in a subset of patients, particularly those with poor long-term prognoses or comorbid chronic diseases with a short life expectancy, those patients more likely to die than to have their CKD progress to ESRD requiring dialysis, and those with vascular anatomy not amenable to successful AVF placement. Placement of an AVF in these patients subjects them to uncomfortable and likely unnecessary and/or unsuccessful surgeries at an expense, while doing little to improve their clinical outcome or their individual experience of care. AVF prevalence as a pay-for-performance measure without the appropriate case-mix adjustment may penalize providers for accepting higher-risk patients. Although a functioning AVF that provides reliable hemodialysis remains the gold standard for vascular access for most patients, it may not be the most suitable option for every patient. PMID- 23744005 TI - Association of plasma des-acyl ghrelin levels with CKD. AB - BACKGROUND AND OBJECTIVES: There are no effective therapies for malnutrition in CKD/ESRD patients. This study hypothesized that ghrelin, an endogenous orexigenic hormone, would correlate with renal function and might suggest therapeutic interventions for CKD/ESRD malnutrition. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fifty-one CKD and 15 hemodialysis patients were enrolled. Acyl ghrelin (AG) and des-acyl ghrelin (DG) were determined using separate two-site specific assays. Leptin, insulin, growth hormone, insulin-link growth factor-1, C reactive protein, TNF-alpha, and IL-6 were also measured. RESULTS: Univariate correlation analyses showed that CKD stage was highly, positively correlated with the levels of preprandial and postprandial DG and positively correlated with TNF alpha, IL-6, leptin, and age. Multivariate partial-correlation analyses showed that CKD was independently associated with the proportion of preprandial and postprandial DG, whereas TNF-alpha, IL-6, leptin, insulin, and age were not independently associated with either. Geometric mean (GM) preprandial and postprandial AG were comparable between CKD stages <=2 and >2, whereas GM preprandial DG and postprandial DG were 1.95-fold and 2.17-fold greater, respectively, for CKD stage >2 versus stage <=2. DG was the dominant form of ghrelin preprandially and postprandially for both CKD stages <=2 and >2. Dialysis had no effect on AG, but reduced DG by 73% to levels even lower (GM 48.7 pg/ml) than those seen postprandially in CKD stage <=2 patients (GM 77.0 pg/ml). CONCLUSIONS: This study shows a strong and independent correlation of DG with CKD stage. Postprandial suppression of ghrelin is impaired with reduced renal function. Hemodialysis selectively removes DG but not AG. PMID- 23744007 TI - The nutrition researcher cohort: toward a new generation of nutrition research and health optimization. PMID- 23744006 TI - Association of nocturnal hypoxemia with progression of CKD. AB - BACKGROUND AND OBJECTIVES: Nocturnal hypoxemia is highly prevalent among patients with CKD. Nocturnal hypoxemia contributes to systemic inflammation, oxidative stress, endothelial cell dysfunction, and activation of the renin-angiotensin system, which are common pathologic mechanisms of CKD progression. This study investigated whether nocturnal hypoxemia is independently associated with CKD progression. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This two-center retrospective cohort study included 161 patients with stages 3-4 CKD enrolled from January of 2009 to July of 2011 with a body mass index less than 25.0 kg/m(2). The 4% oxygen desaturation index, the number of events per hour in which oxygen saturation decreases by >4% during sleep, was measured, and the declining rate of the estimated GFR was followed over 1 year. The severity of nocturnal hypoxemia was categorized as none (oxygen desaturation index<5.0), mild (5.0<=oxygen desaturation index<15.0), or moderate to severe (15.0<=oxygen desaturation index). RESULTS: The mean estimated GFR of the total cohort at baseline was 31 ml/min per 1.73 m(2). Eighty patients (49.7%) were diagnosed with nocturnal hypoxemia; 64 patients were diagnosed with mild nocturnal hypoxemia, and 16 patients were diagnosed with moderate-to-severe nocturnal hypoxemia. The estimated GFR declined three- to fourfold faster in patients with moderate-to severe nocturnal hypoxemia than patients with no or mild nocturnal hypoxemia (the mean values [95% confidence intervals] were -2.14 [-1.06 to -3.21], -3.02 [-1.31 to -4.74], and -8.59 [-2.00 to -15.2] ml/min per 1.73 m(2) per year in the no, mild, and moderate-to-severe nocturnal hypoxemia groups, respectively; P=0.003). Nocturnal hypoxemia remained a significant predictor of decline in estimated GFR after adjustment for various baseline clinical factors. CONCLUSIONS: In nonobese patients with CKD, nocturnal hypoxemia is an independent risk factor of a rapid decline in kidney function. PMID- 23744008 TI - Influence of genotype on the modulation of gene and protein expression by n-3 LC PUFA in rats. AB - It is becoming increasingly apparent that responsiveness to dietary fat composition is heterogeneous and dependent on the genetic make-up of the individual. The aim of this study was to evidence a genotype-related differential effect of n-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFA) on the modulation of hepatic genes involved in cholesterol metabolism. Fourteen spontaneously hypertensive (SH) rats, which present a naturally occurring variation in the gene encoding for sterol responsive element binding protein 1 (SREBP-1), contributing to their inherited variation in lipid metabolism, and 14 Wistar-Kyoto (WK) rats were fed a control diet or an n-3 LC-PUFA enriched diet for 90 days. Plasma lipid profile, total lipid fatty acid composition in plasma and liver, and the expression of SREBP-1 and 2, 3-hydroxy-3-methyl-glutaryl-CoA reductase, low-density lipoprotein receptor, and acyl-CoA:cholesterol acyltransferase 2 encoding genes and proteins were determined. The positive effect of the enriched diet on the serum lipid profile, particularly on total cholesterol and triglyceride level, was clearly evidenced in both WK and SH rats, but n-3 LC-PUFA acted through a different modulation of gene and protein expression that appeared related to the genetic background. Our study evidences a different transcriptional effect of specific nutrients related to genetic variants. PMID- 23744010 TI - [DSM-5 and ICD-10: what comes to us?]. PMID- 23744009 TI - Synchronization of delayed coupled neurons in presence of inhomogeneity. AB - In principle, two directly coupled limit cycle oscillators can overcome mismatch in intrinsic rates and match their frequencies, but zero phase lag synchronization is just achievable in the limit of zero mismatch, i.e., with identical oscillators. Delay in communication, on the other hand, can exert phase shift in the activity of the coupled oscillators. In this study, we address the question of how phase locked, and in particular zero phase lag synchronization, can be achieved for a heterogeneous system of two delayed coupled neurons. We have analytically studied the possibility of inphase synchronization and near inphase synchronization when the neurons are not identical or the connections are not exactly symmetric. We have shown that while any single source of inhomogeneity can violate isochronous synchrony, multiple sources of inhomogeneity can compensate for each other and maintain synchrony. Numeric studies on biologically plausible models also support the analytic results. PMID- 23744011 TI - [The TK-project quality monitoring in outpatient psychotherapy from the perspective of the evaluation team - a plea for more psychotherapy research in Germany]. AB - This commentary discusses the view of the evaluation team on the first study in Germany to evaluate a new quality assurance and feedback tool with regard to its practical feasibility in routine care. The representative of the sample is issued and design topics which made it necessary to control for differences of approved ses-sions between control and intervention groups are explained. Key findings of the study are the high patient satisfaction in the feedback condition, the acceptance of feedback as well as the use of the feedback system by therapists. It is argued, that an extension of psychotherapy research into routine practice is necessary to hold the high standard of the German service system and that the establishment of an ongoing progress monitoring in real world psychotherapy would have several benefits for patients, therapists and researchers. PMID- 23744012 TI - [Conflict coping strategies in patients with somatoform disorders]. AB - 245 patients presenting with allergic complaints were interviewed with SCID for the diagnosis of a somatoform disorder and filled in the "ques-tionnaire of conflict coping strategies (FKBS)" 55 patients with insect allergy and 100 depressed patients served as controls. Only depressed patients diverged from the FKBS reference scores, particularly with respect to "turning against self". PMID- 23744013 TI - [Standards in prevention research?]. PMID- 23744014 TI - [Psychosomatic aspects of organ transplantation]. PMID- 23744015 TI - [Releases from the German College of Psychosomatic Medicine]. PMID- 23744016 TI - [Indoor radon. A neglected carcinogen at work]. PMID- 23744017 TI - [2012, MEDLINE's year. Before and after for Archivos]. PMID- 23744018 TI - [Adverse effects of seasonal flu vaccine and new influenza A (H1N1) vaccine in health care workers]. AB - OBJECTIVES: To assess and compare adverse effects of Seasonal Influenza Vaccine (SIV) and new Influenza A(H1N1) Vaccine (AIV) in health care workers. METHODS: Multicenter cross-sectional study in health care workers from acute care hospitals, primary health care centers, social centers, mental health centers and a geriatric hospital participating in the 2009 vaccination campaign. Self administered questionnaires were sent to all workers vaccinated with SIV and/or AIV. RESULTS: 527 valid questionnaires were collected out of 1123 sent to SIV vaccinated workers (46.9%), and 241 out of 461 sent to AIV vaccinated workers (52.%%). Participant workers include 527 vaccinated only with SIV, 117 first vaccinated with SIV and later with AIV (SIV+AIV), and 125 vaccinated only with AIV. Overall, 18.4% (95%CI 15.1-21.7) of workers vaccinated only with SIV reported adverse effects, as compared to 45.3% (95I 36.3-54.3) reporting adverse effects to AIV in the SIV+AIV group and 46.4% (95%CI 37.7-55.1) of workers vaccinated only with AIV. In all participants the most common adverseeffect was a local reaction. Women wre more reactive to both SIV and AIV than men. In all age groups SIV vaccination alone caused fewer reactions that either AIV only or the combination of SIV+AIV, with the exception of workers below 29 years of age. CONCLUSIONS: AIV was associated with more reactions than SIV, with no differences observed in relation to administration sequence. There were differences by sex and age, but reactions always occurred more commonly with AIV. PMID- 23744019 TI - [Tasks, roles and expectations of safety practitioners at free-standing occupational health and safety services in Spain]. AB - OBJECTIVES: To describe the professional activities commonly performed by occupational health and safety professionals and their level of satisfaction. METHODS: We conducted a survey in a sample of 236 health and safety practitioners employed in free-standing occupational health services located in the Balearic Islands, Andalusia and Madrid between November 2009 and May 2010. The survey instrument was based on the questionnaire proposed by the International Social Security Association and the European Network of Safety & Health Practitioner Organisations (ISSA-ENSHPO). FINDINGS: The tasks most frequently performed by health and safety professionals in our sample (described as being performed at least monthly by 80% or more of respondents) are risk assessment, proposing preventive measures, providing information and training. Certain tasks, such as establishing staff selection criteria or performing cost-benefit analyses, are generally considered (by more than 50% of respondents) to be outside the scope of work for health and safety practitioners. Respondents would like to devote more time to their tasks, especially those related to their own continuing education and communication within the company. CONCLUSIONS: Health and safety professionals in our sample mostly perform tasks related to technical assessments of the workplace, worker training and information dissemination. There is a desire for greater involvement in professional knowledge management and human relations in the company. PMID- 23744020 TI - [Termination without cause of a worker with bipolar disorder]. AB - We describe the case of a worker with bipolar disorder who was terminated for incompetence, following a determination of being unfit for duty based on a periodic medical examination. The judge reversed the dismissal on the basis of failing to comply with the provisions of Article 52 a) of the Spanish Workers' Law. Social and labor integration of people with bipolar disorder presents challenges due both to the clinical characteristics of the disease and its chronic course, and the limitations associated with continued treatment. These situations can benefit from an evaluation of fitness for duty by an occupational physician and the implementation of preventive measures by the company, as it is necessary to exhaust all options before considering an extreme decision such as work unfitness and subsequent termination. The initial objective should be the social and labor integration of the affected worker, while minimizing risk to self and others. PMID- 23744021 TI - Intra-articular nodular fasciitis of the knee in a 4-year-old girl: a case report and review of the literature. AB - Nodular fasciitis is a benign, proliferative lesion of myofibroblasts developed from the fascia. It arises commonly in the upper extremities of adults and in the head and neck region of infants and children. Involvement of the knee is exceedingly rare. We report a case of a 4-year-old girl with a knee mass, causing limitation of knee flexion and pain. Arthroscopic examination was performed followed by arthrotomy and tumor excision. Pathologic findings revealed clusters of spindle cells with arrangement of storiform pattern in a loosely textured mucoid matrix. To the best of our knowledge, this is the youngest patient associated with articular nodular fasciitis in the knee joint. PMID- 23744022 TI - The examination and management of nerve injury in supracondylar fractures of the humerus. PMID- 23744023 TI - Response to letter to the editor from Dr. Safer et al. regarding the article "age related changes in body composition in a sample of Czech women aged 18-89 years: a cross-sectional study," published in European Journal of Nutrition. PMID- 23744024 TI - Comment to "age-related changes in body composition in a sample of Czech women aged 18-89 years: a cross-sectional study". PMID- 23744026 TI - Ventilator-associated pneumonia caused by OXA-48-producing Escherichia coli complicated by ciprofloxacin-associated rhabdomyolysis. AB - We report the emergence of OXA-48 carbapenemase-producing Escherichia coli in Austria causing ventilator-associated pneumonia in a traveler returning from Egypt. Depending on resistance testing, quinolones may remain a therapeutic option for infections caused by these multiple resistant pathogens, as this class of drugs has a favorable safety and tolerability profile when compared to the alternatives. In this patient, however, the clinical course was dramatically complicated by the development of ciprofloxacin-associated rhabdomyolysis. PMID- 23744025 TI - Antioxidant nutrients and age-related cognitive decline: a systematic review of population-based cohort studies. AB - PURPOSE: To further inform the debate on the possible cognitive benefits of antioxidant nutrients in the elderly, we systematically reviewed available prospective studies while paying a special attention to their methodological quality. METHODS: This is a systematic review of studies involving major antioxidant nutrients and change in cognitive performance. Abstracts were independently reviewed; studies were selected based on prespecified criteria. Methodological quality of primary studies was assessed using a methodological checklist for cohort studies. Findings were presented using a narrative synthesis and tabulation of results. RESULTS: Eight-hundred and fifty potentially eligible studies were identified; 10 met the inclusion criteria and were retained for data extraction and appraisal. The main supportive evidence came from two studies, both judged to be of high quality: The first observed an accelerated decline in global cognition, attention, and psychomotor speed over 9 years, concomitant to a decrease in plasma selenium levels over the same period; the second study reported a slower rate of global cognitive decline over 3 years in persons in the highest quartile of intake of vitamins C, E, and carotenes. All associations persisted after adjustment for confounding factors. Evidence in favor of beneficial associations of higher dietary intake of vitamin E and flavonoids, as well as higher serum beta carotene levels, came from further studies of only adequate quality. CONCLUSIONS: There is a possibility for protective effects of antioxidant nutrients against decline in cognition in older people although the supportive evidence is still limited in number. This association deserves further examination in additional quality investigations. PMID- 23744027 TI - Bandgap engineering and shape control of colloidal Cd(x)Zn(1-x)O nanocrystals. AB - Bandgap engineering and shape control are important and advantageous for potential applications involving colloidal ZnO nanocrystals. Here we demonstrate the syntheses of high quality alloyed Cd(x)Zn(1-x)O nanocrystals with well defined shapes, from faceted particles to tetrapods and ultrathin nanowires. By comparing the optical bandgaps of the pure ZnO, Cd(x)Zn(1-x)O and Mg(x)Zn(1-x)O nanocrystals with various dimensions, we conclude that bandgap engineering of colloidal ZnO nanocrystals via cadmium alloying effectively narrows the bandgaps. Our study may shed light on the design and syntheses of colloidal alloyed oxide nanocrystals with controlled band structures and shapes. PMID- 23744029 TI - Limited generalisability of UPLIFT findings to clinical practice. AB - BACKGROUND: The findings of the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) study may be poorly generalisable to tiotropium use in clinical practice. METHODS: An audit of 226 patients admitted to Wellington Hospital with a chronic obstructive pulmonary disease exacerbation determined the proportion of patients prescribed tiotropium on discharge that would have been ineligible for inclusion in the UPLIFT study. RESULTS: Among 100 patients prescribed tiotropium, 38/100; 38% (95% CI 28.5% to 48.3%) would have been ineligible for UPLIFT at the time of the hospital discharge due to recent cardiovascular comorbidity or moderate to severe renal impairment. CONCLUSIONS: The UPLIFT findings have limited generalisability to over a third of patients prescribed tiotropium following a hospital admission with a chronic obstructive pulmonary disease exacerbation in New Zealand. PMID- 23744028 TI - The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin dependent and ghrelin-independent mechanisms. AB - The G protein-coupled receptor 83 (Gpr83) is widely expressed in brain regions regulating energy metabolism. Here we report that hypothalamic expression of Gpr83 is regulated in response to nutrient availability and is decreased in obese mice compared with lean mice. In the arcuate nucleus, Gpr83 colocalizes with the ghrelin receptor (Ghsr1a) and the agouti-related protein. In vitro analyses show heterodimerization of Gpr83 with Ghsr1a diminishes activation of Ghsr1a by acyl ghrelin. The orexigenic and adipogenic effect of ghrelin is accordingly potentiated in Gpr83-deficient mice. Interestingly, Gpr83 knock-out mice have normal body weight and glucose tolerance when fed a regular chow diet, but are protected from obesity and glucose intolerance when challenged with a high-fat diet, despite hyperphagia and increased hypothalamic expression of agouti-related protein, Npy, Hcrt and Ghsr1a. Together, our data suggest that Gpr83 modulates ghrelin action but also indicate that Gpr83 regulates systemic metabolism through other ghrelin-independent pathways. PMID- 23744030 TI - Soft stethoscope for detecting asthma wheeze in young children. AB - Asthma is a chronic disease that is commonly suffered by children. Asthmatic children have a lower quality of life than other children. Physicians and pediatricians recommend that parents record the frequency of attacks and their symptoms to help manage their children's asthma. However, the lack of a convenient device for monitoring the asthmatic condition leads to the difficulties in managing it, especially when it is suffered by young children. This work develops a wheeze detection system for use at home. A small and soft stethoscope was used to collect the respiratory sound. The wheeze detection algorithm was the Adaptive Respiratory Spectrum Correlation Coefficient (RSACC) algorithm, which has the advantages of high sensitivity/specificity and a low computational requirement. Fifty-nine sound files from eight young children (one to seven years old) were collected in the emergency room and analyzed. The results revealed that the system provided 88% sensitivity and 94% specificity in wheeze detection. In conclusion, this small soft stethoscope can be easily used on young children. A noisy environment does not affect the effectiveness of the system in detecting wheeze. Hence, the system can be used at home by parents who wish to evaluate and manage the asthmatic condition of their children. PMID- 23744031 TI - [Primary antiphospholipid syndrome: newly developed leg ulcer and history of stroke]. AB - Antiphospholipid syndrome features not only deep vessel thrombosis but also may have cutaneous manifestations such as Raynaud phenomenon, acral necrosis, livedo reticularis, subcutaneous nodules, and leg ulcers. A 72-year-old man presented with a rapidly progressing leg ulcer. He was already on anticoagulation with warfarin due to atrial fibrillation and disclosed a history of stroke with temporary paresis of the left leg. Histopathology of a biopsy of the edge of the ulcer revealed occlusive arteriosclerosis of medium-sized arteries. Serology showed autoantibodies against cardiolipin, beta2- glycoprotein I, and phosphatidylserine which led to the diagnosis of antiphospholipid syndrome. Therapy with low molecular weight heparin, dexamethasone, and azathioprine in combination with stage-adjusted wound care led to complete healing of the ulcer within 5 months. PMID- 23744032 TI - [MYC amplification distinguishes between atypical vascular lesion and radiation induced angiosarcoma of the breast]. PMID- 23744033 TI - Cloning, molecular characterization and expression of a DNA-ligase from a new bacteriophage: Phax1. AB - DNA ligases join 3' hydroxyl and 5' phosphate ends in double stranded DNA and are necessary for maintaining the integrity of genome. The gene encoding a new Escherichia phage (Phax1) DNA ligase was cloned and sequenced. The gene contains an open reading frame with 1,428 base pairs, encoding 475 amino acid residues. Alignment of the entire amino acid sequence showed that Phax1 DNA ligase has a high degree of sequence homology with ligases from Escherichia (vB_EcoM_CBA120), Salmonella (PhiSH19 and SFP10), Shigella (phiSboM-AG3), and Deftia (phiW-14) phages. The Phax1 DNA ligase gene was expressed under the control of the T7lac promoter on the pET-16b (+) in Escherichia coli Rossetta gami. The enzyme was then homogeneously purified by a metal affinity column. Enzymatic activity of the recombinant DNA ligase was assayed by an in-house PCR-based method. PMID- 23744034 TI - Identification of a potential fungal species by 18S rDNA for ligninases production. AB - Fungal species for ligninases production was investigated by 18S ribosomal DNA sequence analysis. Two primer sets were chosen to amplify a major part of the 18S rDNA, which resulted in intense PCR product of approximately 550-820 bp in size per sample. The results suggest that the 18S rDNA-based approach is a useful tool for identification of unknown potential fungal species for ligninases production. The isolated fungal species produces mainly manganese peroxidase (MnP). The enzyme oxidized a variety of the usual MnP substrates, including lignin related polyphenols. Time course studies showed that maximum production of ligninolytic enzymes MnP (64 IU L-1), lignin peroxidase (26.35 IU L-1), and laccase (5.44 IU L 1), respectively, were achieved after 10 days of cultivation under optimum conditions. Furthermore, the biological decolorization of Remazol Brilliant Blue R dye following 10 days of cultivation was 94 %. NCBI BLAST was used to search for closest matched sequences in the GenBank database and based on sequence homology the first BLAST hit was Dothioraceae sp. LM572 with accession number EF060858.1. PMID- 23744036 TI - Mutations and the age pattern of death. PMID- 23744035 TI - The use of fusion mass screws in revision spinal deformity surgery. AB - STUDY DESIGN: To report the use of a posterior based 'fusion mass screw' (FMS) as a primary or salvage fixation point in a revision spinal deformity following a previous posterior spinal fusion (PSF). Our experience of this technique in a case report and the clinical and radiological results are reported. OBJECTIVES: To describe the technique and uses of the FMS as a primary/salvage fixation point in osteotomies in previously arthrodesed spinal deformity surgery. Obtaining fixation points to correct and stabilize a spinal deformity with coronal and sagittal imbalance in a previously arthrodesed spine during revision surgery can be challenging. Several alternate pedicle fixation techniques and laminar screw techniques have been described in the literature. However, there is no description of these techniques in the presence of a spinal fusion with distorted anatomy. A pedicle screw placed coronally across a thick posterior fusion mass can provide an alternate method of fixation in these cases with complex anatomy. METHODS: Two cases of complex spinal deformity and corrective spinal osteotomies using fusion mass screws (FMSs) placed coronally across the posterior fusion mass are described. The first case is an 8-year-old patient with Marfan's syndrome who developed a crank shaft phenomenon and severe thoracolumbar kyphoscoliosis following a previous PSF. The second case is a 53-year-old patient with coronal imbalance following PSF as a child using Harrington instrumentation who developed distal degeneration with stenosis in her remaining mobile segments. Both patients underwent vertebral column resection and osteotomy closure plus stabilisation using FMS. The clinical and radiological results and technique for insertion of the FMS are described. CONCLUSION: In this report, we present a novel method of using posterior FMSs to achieve fixation and correction in cases of revision deformity surgery with difficult anatomy. While we feel pedicle screws are the gold standard in deformity correction, knowledge of alternatives such as the FMS can allow surgeons to achieve stable constructs when faced with challenging situations. PMID- 23744037 TI - An MLL-dependent network sustains hematopoiesis. AB - The histone methyltransferase Mixed Lineage Leukemia (MLL) is essential to maintain hematopoietic stem cells and is a leukemia protooncogene. Although clustered homeobox genes are well-characterized targets of MLL and MLL fusion oncoproteins, the range of Mll-regulated genes in normal hematopoietic cells remains unknown. Here, we identify and characterize part of the Mll-dependent transcriptional network in hematopoietic stem cells with an integrated approach by using conditional loss-of-function models, genomewide expression analyses, chromatin immunoprecipitation, and functional rescue assays. The Mll-dependent transcriptional network extends well beyond the previously appreciated Hox targets, is comprised of many characterized regulators of self-renewal, and contains target genes that are both dependent and independent of the MLL cofactor, Menin. Interestingly, PR-domain containing 16 emerged as a target gene that is uniquely effective at partially rescuing Mll-deficient hematopoietic stem and progenitor cells. This work highlights the tissue-specific nature of regulatory networks under the control of MLL/Trithorax family members and provides insight into the distinctions between the participation of MLL in normal hematopoiesis and in leukemia. PMID- 23744038 TI - Evolutionarily conserved Wolbachia-encoded factors control pattern of stem-cell niche tropism in Drosophila ovaries and favor infection. AB - Wolbachia are intracellular bacteria that infect invertebrates at pandemic levels, including insect vectors of devastating infectious diseases. Although Wolbachia are providing novel strategies for the control of several human pathogens, the processes underlying Wolbachia's successful propagation within and across species remain elusive. Wolbachia are mainly vertically transmitted; however, there is also evidence of extensive horizontal transmission. Here, we provide several lines of evidence supporting Wolbachia's targeting of ovarian stem cell niches--referred to as "niche tropism"--as a previously overlooked strategy for Wolbachia thriving in nature. Niche tropism is pervasive in Wolbachia infecting the Drosophila genus, and different patterns of niche tropism are evolutionarily conserved. Phylogenetic analysis, confirmed by hybrid introgression and transinfection experiments, demonstrates that bacterial factors are the major determinants of differential patterns of niche tropism. Furthermore, bacterial load is increased in germ-line cells passing through infected niches, supporting previous suggestions of a contribution of Wolbachia from stem-cell niches toward vertical transmission. These results support the role of stem-cell niches as a key component for the spreading of Wolbachia in the Drosophila genus and provide mechanistic insights into this unique tissue tropism. PMID- 23744039 TI - Reduction potentials of heterometallic manganese-oxido cubane complexes modulated by redox-inactive metals. AB - Understanding the effect of redox-inactive metals on the properties of biological and heterogeneous water oxidation catalysts is important both fundamentally and for improvement of future catalyst designs. In this work, heterometallic manganese-oxido cubane clusters [MMn3O4] (M = Sr(2+), Zn(2+), Sc(3+), Y(3+)) structurally relevant to the oxygen-evolving complex (OEC) of photosystem II were prepared and characterized. The reduction potentials of these clusters and other related mixed metal manganese-tetraoxido complexes are correlated with the Lewis acidity of the apical redox-inactive metal in a manner similar to a related series of heterometallic manganese-dioxido clusters. The redox potentials of the [SrMn3O4] and [CaMn3O4] clusters are close, which is consistent with the observation that the OEC is functional only with one of these two metals. Considering our previous studies of [MMn3O2] moieties, the present results with more structurally accurate models of the OEC ([MMn3O4]) suggest a general relationship between the reduction potentials of heterometallic oxido clusters and the Lewis acidities of incorporated cations that applies to diverse structural motifs. These findings support proposals that one function of calcium in the OEC is to modulate the reduction potential of the cluster to allow electron transfer. PMID- 23744040 TI - Target inference from collections of genomic intervals. AB - Finding regions of the genome that are significantly recurrent in noisy data are a common but difficult problem in present day computational biology. Cores of recurrent events (CORE) is a computational approach to solving this problem that is based on a formalized notion by which "core" intervals explain the observed data, where the number of cores is the "depth" of the explanation. Given that formalization, we implement CORE as a combinatorial optimization procedure with depth chosen from considerations of statistical significance. An important feature of CORE is its ability to explain data with cores of widely varying lengths. We examine the performance of this system with synthetic data, and then provide two demonstrations of its utility with actual data. Applying CORE to a collection of DNA copy number profiles from single cells of a given tumor, we determine tumor population phylogeny and find the features that separate subpopulations. Applying CORE to comparative genomic hybridization data from a large set of tumor samples, we define regions of recurrent copy number aberration in breast cancer. PMID- 23744041 TI - Stable carbon isotopes and human evolution. PMID- 23744042 TI - Transport properties of binuclear metal complexes of the VIII group using a simplified NEGF-DFT approach. AB - We report on a theoretical study of the electronic transport properties of binuclear complexes of metals of the VIII group bridged by pyrazine. Metal porphyrazine units have been combined in order to investigate symmetric and non symmetric species with particular focus on their current rectification properties. Transmission functions and I-V characteristics of the various species have been computed using a Non-Equilibrium Green Function with a simplified treatment of the molecule-lead interaction. The results obtained show an overall moderate asymmetry in the current along the molecules, which is of the donor sigma-acceptor type and follow the trend of the ionization potential of the metals in the binuclear system. The bias-dependent rectification ratio, which is significant in a limited voltage window, can be explained in terms of the alignment of the occupied orbitals of the metallic fragments that contribute to the HOMO and HOMO - 1 of the supermolecule. The possible improvement of the rectification performance of such a class of molecules has also been investigated exploiting suitable substitution by electron-withdrawing groups. PMID- 23744043 TI - Efficacy of screening in preventing cervical cancer among older women. AB - BACKGROUND: Although the effectiveness of cervical cancer screening has been firmly established in reproductive-age women, its usefulness in older women is unclear. We sought to evaluate the efficacy of cervical cancer screening in older women. METHODS: We conducted a case-control study within two integrated health care systems in the northwestern United States. Cases (n = 69) were women aged 55 79 years who were diagnosed with invasive cervical cancer during 1980-1999. Controls (n = 208) were women with an intact uterus and no diagnosis of cervical cancer, but otherwise similar to cases in terms of age and length of enrollment in the health plan. We reviewed medical records to ascertain screening history during the 7 years prior to reference date. RESULTS: Compared to cases, controls were more likely to have received a Pap test. After adjustment for age and current smoking status, screening prior to an estimated 1-year duration of the occult invasive phase of cervical cancer was associated with a substantial reduction in risk [odds ratio (OR) 0.23; 95% CI 0.11-0.44]. Similar results were obtained using different estimates of the duration of the occult invasive phase. Analysis of the relative incidence of invasive cervical cancer in relation to the time following a negative screening test suggested a large reduction during the first year (OR 0.09; 95% CI 0.03-0.24). The incidence remained low for several years thereafter, returning to the incidence among unscreened women after 5-7 years. CONCLUSIONS: Cervical cancer screening by means of cytology is highly efficacious in older women. Our findings also suggest that five-yearly screening is approximately as efficacious as more frequent screening. PMID- 23744044 TI - Obesity in relation to lung cancer incidence in African American women. AB - PURPOSE: Although a number of studies have found an inverse association between body mass index (BMI) and risk of lung cancer, there is little information on this relation in African Americans, who experience a higher incidence of lung cancer. METHODS: We assessed the relation of BMI to incidence of lung cancer in the Black Women's Health Study, an ongoing prospective follow-up of 59,000 women in the USA. Cox proportional hazard models were used to estimate hazard ratios for various levels of BMI relative to BMI 18.5-24.9 kg/m2 ("normal weight") with adjustment for age, education, pack-years of smoking, and other covariates. Two other anthropometric measures, waist circumference (WC) and waist/hip ratio (WHR), were also assessed. A total of 323 primary lung cancer cases were identified from 1995 to 2011. RESULTS: The hazard ratio (HR) for BMI >= 30 relative to BMI 18.5-24.9 was 0.69 (95% CI 0.51-0.92). As expected, cigarette smoking was strongly associated with increased risk of lung cancer. In analyses stratified by smoking status, the HR for BMI >= 30 relative to BMI 18.5-24.9 was 0.62 (0.38-1.00) among current smokers, 0.90 (0.56-1.42) among former smokers, and 0.83 (0.41-1.70) among never smokers (p for interaction = 0.28). Control for pack-years of smoking or age started smoking had little effect on the hazard ratios. WC and WHR were not materially associated with lung cancer risk. CONCLUSION: Our results indicate that high BMI is associated with a lower risk of lung cancer in African American women, particularly among current smokers. PMID- 23744046 TI - Current world literature. Refractive surgery, corneal and external disorders. PMID- 23744045 TI - Cognitive-behavioral therapy for insomnia and sleep hygiene in fibromyalgia: a randomized controlled trial. AB - Sleep disturbances play an important role in the exacerbation of pain and other troubling symptoms reported by patients with fibromyalgia (FM). The objective of this trial was to analyze the efficacy of a cognitive-behavioral therapy for insomnia (CBT-I) versus a sleep hygiene (SH) education program at improving sleep and other clinical manifestations in FM. Sixty-four FM women with insomnia were randomly assigned to the CBT-I or the SH groups, and 59 completed the treatments (30 in the CBT-I group and 29 in the SH group). Participants completed several self-report questionnaires at pre-, post-treatment and follow-ups. The CBT-I group reported significant improvements at post-treatment in several sleep variables, fatigue, daily functioning, pain catastrophizing, anxiety and depression. The SH group only improved significantly in subjective sleep quality. Patients in the CBT-I group showed significantly greater changes than those in the SH group in most outcome measures. The findings underscore the usefulness of CBT-I in the multidisciplinary management of FM. PMID- 23744048 TI - Trends in underweight and overweight/obesity prevalence in Chinese youth, 2004 2009. AB - BACKGROUND: There is a paucity of recent data on Chinese childhood overweight and underweight prevalence especially since 2004. PURPOSE: The purpose of this study was to examine trends in underweight and overweight/obesity ("overweight" hereafter) prevalence and energy balance-related behaviors of Chinese youth from 2004 to 2009. METHODS: Data from the China Health and Nutrition Survey, 2004-2009 (N = 4,061 students aged 6-18 years), were analyzed. Trained health workers took anthropometric measures at the participant's house or at a local clinic following a reference protocol recommended by the World Health Organization. The international age- and sex-specific body mass index reference standard proposed by the International Obesity Task Force was used to define underweight and overweight children in this study. RESULTS: Among 6- to 11-year-old boys, underweight prevalence increased from 14.5% (2004) to 20.1% (2009, p = 0.068). Among 12- to 18-year-old boys, however, overweight prevalence increased from 7.5 to 12.6% (p = 0.034). From 2004 to 2009, after-school sedentary behavior increased from 2.3 to 3.4 h/day for 6- to 11-year-olds (p < 0.001) and from 2.2 to 3.1 h/day for 12- to 18-year-olds (p < 0.01). Meanwhile, the total energy intake decreased 7% for 6- to 11-year-olds (p < 0.05) and 10% for 12- to 18-year olds (p < 0.01). CONCLUSIONS: Both underweight and overweight Chinese students are increasing, with underweight increases more pronounced in 6- to 11-year-olds and overweight increases more pronounced in 12- to 18-year-olds. Nationwide efficacious interventions are needed that improve the diet, decrease sedentary behavior, and encourage a healthy and realistic body image in Chinese youth. PMID- 23744049 TI - Pesticides in urban streams and prespawn mortality of Pacific coho salmon. AB - The listing of several runs of Pacific salmon as threatened or endangered and associated federal, state, and local efforts to restore/enhance salmon habitat in the Pacific Northwest make it imperative that the factors associated with these population declines are understood. Prespawn mortality (PSM) has been documented in coho salmon (Oncorhynchus kisutch) within urban streams in western Washington since the late 1990s and is characterized by a suite of neurological and respiratory symptoms with mortality occurring shortly thereafter. Mortality rates in returning adults have ranged between 17 and 100%. The cause of PSM is not known, but the presence of pesticide residues within urban streams led to a hypothesis that PSM in coho salmon and pesticides in urban streams were linked. We exposed pairs of "green" (unripe) prespawn male and female coho salmon to a pesticide mixture ("cocktail") reported in urban streams in western Washington State, USA. Longevity, ripening in female salmon, and brain acetylcholinesterase were not significantly affected by continuous exposure to the maximum reported concentrations of the pesticides. Fertilization, hatching success, and growth of fry were also not affected when green adults were exposed to these concentrations for 96 h. The absence of effects suggests it is unlikely that pesticides within stormwater are singularly responsible for PSM in coho salmon or that they impair the reproductive capability of exposed adults. PMID- 23744050 TI - Use of Lithobates catesbeianus tadpoles in a multiple biomarker approach for the assessment of water quality of the Reconquista River (Argentina). AB - The water quality of the Reconquista River (Argentina) water was monitored between 2009 and 2010 by means of a multiparametric approach. This periurban river is affected by agricultural, urban, and industrial discharges. Water samples were collected at a dam located in the headwaters and at 18 km downstream (M). Physicochemical profile and two water-quality indices (WQIs) were determined. Laboratory bioassays were performed by exposing Lithobates catesbeianus tadpoles to environmental samples for 96 h and determining the following parameters: (1) brain: acetylcholinesterase (AChE) activity; (2) gill: catalase and glutathione-S-transferase (GST) activities and glutathione (GSH) content; (3) liver: CAT and GST activities, superoxide dismutase, lipid peroxidation, and GSH content; (4) condition factor and hepatosomatic index; and (5) genotoxicity [micronucleus (MN) test in erythrocytes]. Physicochemical profile and WQIs corresponded with extensive pollution in M. Important temporal and spatial variability in biomarkers of tadpoles exposed to samples was found. Multivariate analyses showed that AChE in brain, MN frequency, liver and gill GST activities, and GSH content were key biomarkers. PMID- 23744051 TI - Urinary concentrations of parabens in Chinese young adults: implications for human exposure. AB - Parabens are widely used as preservatives in foods, cosmetics, and pharmaceuticals. However, recent studies have indicated that high and systemic exposure to parabens can be harmful to human health. Although a few studies have reported urinary paraben levels in western countries, studies on paraben exposure in the Chinese population are limited. China is currently a major producer of parabens in the world. In this study, 109 urine samples collected from Chinese young adults (approximately 20 years old) were analyzed for five parabens (methyl , ethyl-, propyl-, butyl-, and benzyl-parabens) by high-performance liquid chromatography-tandem mass spectrometry. Methyl-, propyl-, and ethyl-parabens were the three major paraben analogues found in all (100%) samples. The concentration of the sum of the five parabens ranged from 0.82 to 728 ng/mL with a geometric mean value of 17.4 ng/mL. Urinary concentration of parabens was 2 fold greater in females than in males. Based on the measured urinary concentrations, daily intake of parabens by the Chinese young adults was estimated and compared with those reported for United States adults. The estimated daily intakes (EDIurine) of parabens were 18.4 and 40.8 MUg/kg bw/day for Chinese males and females, respectively, values that were lower than those reported for United States adults (74.7 MUg/kg bw/day). Based on the reported concentrations of parabens in foods from China and the United States, the contribution of dietary intake to EDIurine was estimated to be 5.5, 2.6, and 0.42% for Chinese males, Chinese females, and United States adults, respectively, which indicates the significance of nondietary sources of parabens to human exposures. PMID- 23744052 TI - AUTOMATIC AIRWAY ANALYSIS FOR GENOME-WIDE ASSOCIATION STUDIES IN COPD. AB - We present an image pipeline for airway phenotype extraction suitable for large scale genetic and epidemiological studies including genome-wide association studies (GWAS) in Chronic Obstructive Pulmonary Disease (COPD). We use scale space particles to densely sample intraparenchymal airway locations in a large cohort of high-resolution CT scans. The particle methodology is based on a constrained energy minimization problem that results in a set of candidate airway points situated in both physical space and scale. Those points are further clustered using connected components filtering to increase their specificity. Finally, we use the particle locations to perform airway wall detection using an edge detector based on the zero-crossing of the second order derivative. Given the airway wall locations, we compute three phenotypes for airway disease: wall thickening (Pi10,WA%) and luminal remodeling (P%). We validate the airway extraction technique and present results in 2,500 scans for the association of the extracted phenotypes with clinical outcomes that will be deployed as part of the COPDGene study GWAS analysis. PMID- 23744053 TI - Currencies of mutualisms: sources of alkaloid genes in vertically transmitted epichloae. AB - The epichloae (Epichloe and Neotyphodium species), a monophyletic group of fungi in the family Clavicipitaceae, are systemic symbionts of cool-season grasses (Poaceae subfamily Pooideae). Most epichloae are vertically transmitted in seeds (endophytes), and most produce alkaloids that attack nervous systems of potential herbivores. These protective metabolites include ergot alkaloids and indole diterpenes (tremorgens), which are active in vertebrate systems, and lolines and peramine, which are more specific against invertebrates. Several Epichloe species have been described which are sexual and capable of horizontal transmission, and most are vertically transmissible also. Asexual epichloae are mainly or exclusively vertically transmitted, and many are interspecific hybrids with genomic contributions from two or three ancestral Epichloe species. Here we employ genome-scale analyses to investigate the origins of biosynthesis gene clusters for ergot alkaloids (EAS), indole-diterpenes (IDT), and lolines (LOL) in 12 hybrid species. In each hybrid, the alkaloid-gene and housekeeping-gene relationships were congruent. Interestingly, hybrids frequently had alkaloid clusters that were rare in their sexual ancestors. Also, in those hybrids that had multiple EAS, IDT or LOL clusters, one cluster lacked some genes, usually for late pathway steps. Possible implications of these findings for the alkaloid profiles and endophyte ecology are discussed. PMID- 23744054 TI - Limited stability of microcystins in oligopeptide compositions of Microcystis aeruginosa (Cyanobacteria): implications in the definition of chemotypes. AB - The occurrence of diverse oligopeptides in cyanobacteria, including the cyanotoxins microcystins, has been recently used to classify individual clones into sub-specific oligopeptide chemotypes, whose composition and dynamics modulate microcystin concentrations in cyanobacterial blooms. Cyanobacterial chemotyping allows the study of the ecology of chemotypical subpopulations, which have been shown to possess dissimilar ecological traits. However, the stability of chemotypes under changing abiotic conditions is usually assumed and has not been assessed in detail. We monitored oligopeptide patterns of three strains of Microcystis aeruginosa under different nutrient and light conditions. MALDI-TOF MS revealed alterations in the microcystins signatures under N and P poor conditions and high light intensities (150 and 400 MUmol photons m-2s-1). Variations in the general oligopeptide composition were caused by a gradual disappearance of microcystins with low relative intensity signals from the fingerprint. The extent of such variations seems to be closely related to physiological stress caused by treatments. Under identical clonal compositions, alterations in the oligopeptide fingerprint may be misinterpreted as apparent shifts in chemotype succession. We discuss the nature of such variations, as well as the consequent implications in the use of cyanobacterial chemotyping in studies at the subpopulation level and propose new guidance for the definition of chemotypes as a consistent subpopulation marker. PMID- 23744055 TI - Reduction of streptolysin O (SLO) pore-forming activity enhances inflammasome activation. AB - Pore-forming toxins are utilized by bacterial and mammalian cells to exert pathogenic effects and induce cell lysis. In addition to rapid plasma membrane repair, macrophages respond to pore-forming toxins through activation of the NLRP3 inflammasome, leading to IL-1beta secretion and pyroptosis. The structural determinants of pore-forming toxins required for NLRP3 activation remain unknown. Here, we demonstrate using streptolysin O (SLO) that pore-formation controls IL 1beta secretion and direct toxicity. An SLO mutant incapable of pore-formation did not promote direct killing, pyroptosis or IL-1beta production. This indicated that pore formation is necessary for inflammasome activation. However, a partially active mutant (SLO N402C) that was less toxic to macrophages than wild type SLO, even at concentrations that directly lysed an equivalent number of red blood cells, enhanced IL-1beta production but did not alter pyroptosis. This suggests that direct lysis may attenuate immune responses by preventing macrophages from successfully repairing their plasma membrane and elaborating more robust cytokine production. We suggest that mutagenesis of pore-forming toxins represents a strategy to enhance adjuvant activity. PMID- 23744056 TI - Impact of Hey2 and COUP-TFII on genes involved in arteriovenous differentiation in primary human arterial and venous endothelial cells. AB - Arteries and veins show marked differences in their anatomy, physiology and genetic expression pattern. In this study, we analyzed impact of overexpression or downregulation of arterial marker gene Hey2 and venous marker gene COUP-TFII in human venous and arterial endothelial cells on genes involved in arteriovenous differentiation. Lentiviral overexpression of venous marker gene COUP-TFII in arterial endothelial cells led to downregulation of NICD4, arterial marker gene Hey2 and EphrinB2. Downregulation of Hey2 could be mediated by direct binding of COUP-TFII to Hey2 promoter as shown by ChIP, EMSA and promoter analysis. Downregulation of Hey2 by shRNA causes downregulation of EphrinB2 expression. Overexpression of arterial marker Hey2 in venous endothelial cells did not change expression pattern of COUP-TFII. Downregulation of venous marker gene COUP-TFII in venous endothelial cells resulted in upregulation of VEGF-A, Dll4 and EphrinB2 expression. Our data support an important role of Hey2 and COUP-TFII in arteriovenous differentiation of human endothelial cells. PMID- 23744057 TI - Endoplasmic reticulum stress contributes to heart protection induced by cyclophilin D inhibition. AB - Preventing cyclophilin D (cypD) translocation to the inner mitochondrial membrane can limit lethal reperfusion injury through the inhibition of the opening of the mitochondrial permeability transition pore. Inhibition or loss of function of cypD may also result into an endoplasmic reticulum (ER) stress that has been shown to alter cell survival. We therefore questioned whether ER stress might play a role in the protection induced by CypD deficiency or inhibition. CypD-KO and NIM811 (a CypD inhibitor)-treated mice were subjected to a prolonged ischemia reperfusion (I/R). Area at risk and infarct size was measured using blue dye and triphenyltetrazolium chloride staining. ER stress markers were measured in the hearts during the reperfusion phase. As expected, cypD-KO mice exhibited a decreased infarct size when compared to wild-type mice (8 +/- 1 vs. 20 +/- 4% of left ventricular weight; p < 0.01). CypD-deficient mice displayed an increased expression of ER stress proteins such as eukaryotic initiation factor 2alpha (eIF2alpha) or glucose regulated protein 78 (Grp78 or Bip). The ER stress inhibitor TUDCA prevented the infarct size reduction afforded by the loss of cypD function (mean infarct size averaged 21 +/- 4% of LV weight, p < 0.01 vs. cypD KO). Similar results were obtained when NIM811, an analog of cyclosporine A, was used to pharmacologically (instead of genetically) inhibit cypD function. This study suggests that the ER stress induced by the inhibition of cypD function plays a key role in protecting the heart against lethal ischemia-reperfusion injury. PMID- 23744058 TI - SIRT1 mediates the protective function of Nkx2.5 during stress in cardiomyocytes. AB - Nkx2.5 plays protective roles in cardiac homeostasis and survival in the postnatal hearts. However, the underlying molecular mechanisms that mediate the protective functions of Nkx2.5 remain unknown. Here, we showed that Nkx2.5 was downregulated in response to various stresses and was required for protection against the stress-induced apoptosis of cardiomyocytes. SIRT1, a member of the sirtuin family of proteins, was found to be a direct transcriptional target of Nkx2.5 and was required for the Nkx2.5-mediated protection of cardiomyocytes from doxorubicin (DOX)-induced apoptosis. Moreover, using chromatin immunoprecipitation assays, we found that Nkx2.5 was able to bind to the SIRT1 promoter and that this binding was significantly decreased in DOX-treated mouse hearts. Furthermore, the cardiac-specific overexpression of SIRT1 decreased the DOX-induced apoptosis of cardiomyocytes in SIRT1 transgenic mouse hearts compared with the hearts of their wild-type littermates. These findings demonstrate that SIRT1 acts as a direct transcriptional target of Nkx2.5 that maintains cardiomyocyte homeostasis and survival. PMID- 23744059 TI - Controlling the assembly of graphene oxide by an electrolyte-assisted approach. AB - In this work, we studied the effects of salts on the self-assembly of two dimensional graphene oxide (GO) driven by the dissolution of a sub-microliter droplet. Two kinds of structures were obtained. One was a GO snowball with small salt crystals inserted between sheets, which formed with a low initial concentration of insoluble salt in the GO dispersion. The other was a hybrid nanostructure containing NaCl or KCl crystals on a GO snowball, which formed with a high initial salt concentration in the suspension. In addition, we report the novel nanodent-decorated GO snowballs formed by templating the spontaneously formed microdroplets through ouzo effects. Such highly crumpled snowball structures may find applications in super-capacitors or catalyst supports. PMID- 23744060 TI - Survival in systemic sclerosis with pulmonary arterial hypertension has not improved in the modern era. AB - BACKGROUND: The impact of modern therapy on survival in pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc) is not clear. We sought to determine associations among commonly used clinical and hemodynamic variables, treatment, and long-term survival in PAH associated with SSc compared with PAH defined as idiopathic, familial, or associated with anorexigens. METHODS: The observation period (1996-2010) included the option for epoprostenol and the availability of oral agents in 2002 (modern era of endothelin antagonists and phosphodiesterase-5 inhibitors). Primary outcome was all-cause mortality. RESULTS: Eighty-three patients had SSc (mean age, 59 years), and 120 had PAH (mean age, 51 years) (P < .0001, > 80% were functional class III or IV in both groups). Compared with PAH, SSc had a lower mean pulmonary artery pressure (48 mm Hg vs 58 mm Hg, P < .0001) and pulmonary vascular resistance (10 resistance units vs 15 resistance units, P < .0001), and a higher cardiac index (2.3 L/min/m2 vs 1.8 L/min/m2, P < .0001). PAH was more often treated with prostacyclin (71% vs 44%, P < .0001), but there were no differences in the use of monotherapy or combination oral therapy. SSc had a twofold-higher mortality over the 14 years. The 5-year survival in the modern era for PAH was 87%, compared with 51% for SSc (P < .001). CONCLUSIONS: Despite an improvement in clinical status, unlike in PAH, mortality in SSc has not improved since the introduction of epoprostenol. PMID- 23744061 TI - Adolescents' experiences of receiving and living with sequential cochlear implants: an interpretative phenomenological analysis. AB - There is currently a unique opportunity to examine the experiences of young people who receive a second sequential cochlear implant (SCI), after only having had 1 cochlear implant (CI) for most of their lives. Eleven young people who had opted to receive an SCI were interviewed. Interpretative phenomenological analysis resulted in the identification of 6 master themes. Most participants enjoyed improved confidence and social well-being following their SCI and felt that 2 CIs were superior to 1. The majority identified themselves as hearing and deaf, but not culturally Deaf, as they strived to live in the hearing world. However, this was not without challenges and many young people experienced feelings of difference in the hearing world. These findings have clinical implications in terms of the role of clinical psychologists and other mental health professionals in CI clinics and in providing information to families making decisions about CIs. These findings add to the emergent deaf identity development literature in young people with CIs. PMID- 23744062 TI - A scanning transmon qubit for strong coupling circuit quantum electrodynamics. AB - Like a quantum computer designed for a particular class of problems, a quantum simulator enables quantitative modelling of quantum systems that is computationally intractable with a classical computer. Superconducting circuits have recently been investigated as an alternative system in which microwave photons confined to a lattice of coupled resonators act as the particles under study, with qubits coupled to the resonators producing effective photon-photon interactions. Such a system promises insight into the non-equilibrium physics of interacting bosons, but new tools are needed to understand this complex behaviour. Here we demonstrate the operation of a scanning transmon qubit and propose its use as a local probe of photon number within a superconducting resonator lattice. We map the coupling strength of the qubit to a resonator on a separate chip and show that the system reaches the strong coupling regime over a wide scanning area. PMID- 23744063 TI - Comparison between consecutive and intermittent steroid pulse therapy combined with tonsillectomy for clinical remission of IgA nephropathy. AB - BACKGROUND: In recent years, tonsillectomy and steroid pulse (TSP) therapy have been widely performed in Japan. However, there is no consensus about the treatment protocol and indication. METHODS: In this retrospective analysis, we compared patients who received tonsillectomy plus intermittent steroid pulse (SP) therapy three times in 6 months (ISP group, n = 44) with patients who received tonsillectomy plus 3 weeks of consecutive SP therapy (CSP group, n = 46) within 1 year after renal biopsy. These two different protocols were performed at two different institutions. We analyzed the clinical and histological background and clinical remission (CR), defined as disappearance of urine abnormalities at 18 months after starting treatment. RESULTS: Before treatment, there was no significant difference in the clinical findings except for sex between the two groups. In ISP group and CSP group, mean estimated glomerular filtration rate was 82.1 +/- 20.9 and 85.9 +/- 19.1 ml/min/1.73 m(2), median proteinuria was 0.55 and 0.56 g/day, and median urinary red blood cells were 20 (10-20) and 20 (6-30)/high power filed. The histological (H) grade was lower in the CSP than the ISP group (p = 0.022). The remission rate of proteinuria, hematuria, and rate of CR by the Kaplan-Meier method and logrank test were significantly higher in the CSP group than in the ISP group (CSP vs. ISP group; proteinuria: 97.8 vs. 77.3 %, p < 0.001, hematuria: 97.8 vs. 75.0 %, p = 0.005, CR: 95.6 vs. 63.6 %, p < 0.001). In the Cox proportional hazard model (forced entry), SP protocol and proteinuria before treatment were significantly associated with CR [SP protocol: hazard ratio (HR) 2.50, 95 % confidence interval (CI) 1.46-4.30, p = 0.001, proteinuria: HR 0.81, 95 % CI 0.68-0.96, p = 0.013)]. However H-grade was associated with remission of proteinuria (H-grade: hazard ratio (HR) 0.56, 95 % confidence interval (CI) 0.37-0.85, p = 0.006), and this result meant histological bias affected the remission of proteinuria. CONCLUSIONS: The difference of the protocol of TSP therapy may have some effect on the CR of IgAN, though the histological bias was observed in this study. The appropriate protocol and indication of TSP therapy must be analyzed and determined in the randomized controlled trial. PMID- 23744064 TI - Lipid, detergent, and Coomassie Blue G-250 affect the migration of small membrane proteins in blue native gels: mitochondrial carriers migrate as monomers not dimers. AB - Blue native gel electrophoresis is a popular method for the determination of the oligomeric state of membrane proteins. Studies using this technique have reported that mitochondrial carriers are dimeric (composed of two ~32-kDa monomers) and, in some cases, can form physiologically relevant associations with other proteins. Here, we have scrutinized the behavior of the yeast mitochondrial ADP/ATP carrier AAC3 in blue native gels. We find that the apparent mass of AAC3 varies in a detergent- and lipid-dependent manner (from ~60 to ~130 kDa) that is not related to changes in the oligomeric state of the protein, but reflects differences in the associated detergent-lipid micelle and Coomassie Blue G-250 used in this technique. Higher oligomeric state species are only observed under less favorable solubilization conditions, consistent with aggregation of the protein. Calibration with an artificial covalent AAC3 dimer indicates that the mass observed for solubilized AAC3 and other mitochondrial carriers corresponds to a monomer. Size exclusion chromatography of purified AAC3 in dodecyl maltoside under blue native gel-like conditions shows that the mass of the monomer is ~120 kDa, but appears smaller on gels (~60 kDa) due to the unusually high amount of bound negatively charged dye, which increases the electrophoretic mobility of the protein-detergent-dye micelle complex. Our results show that bound lipid, detergent, and Coomassie stain alter the behavior of mitochondrial carriers on gels, which is likely to be true for other small membrane proteins where the associated lipid-detergent micelle is large when compared with the mass of the protein. PMID- 23744066 TI - Identification of serpin determinants of specificity and selectivity for furin inhibition through studies of alpha1PDX (alpha1-protease inhibitor Portland) serpin B8 and furin active-site loop chimeras. AB - alpha1-Protease inhibitor Portland (alpha1PDX) is an engineered serpin family inhibitor of the proprotein convertase (PC), furin, that exhibits high specificity but limited selectivity for inhibiting furin over other PC family proteases. Here, we characterize serpin B8, a natural inhibitor of furin, together with alpha1PDX-serpin B8 and furin-PC chimeras to identify determinants of serpin specificity and selectivity for furin inhibition. Replacing reactive center loop (RCL) sequences of alpha1PDX with those of serpin B8 demonstrated that both the P4-P1 RXXR recognition sequence as well as the P1'-P5' sequence are critical determinants of serpin specificity for furin. Alignments of PC catalytic domains revealed four variable active-site loops whose role in furin reactivity with serpin B8 was tested by engineering furin-PC loop chimeras. The furin(298 300) loop but not the other loops differentially affected furin reactivity with serpin B8 and alpha1PDX in a manner that depended on the serpin RCL-primed sequence. Modeling of the serpin B8-furin Michaelis complex identified serpin exosites in strand 3C close to the 298-300 loop whose substitution in alpha1PDX differentially affected furin reactivity depending on the furin loop and serpin RCL-primed sequences. These studies demonstrate that RCL-primed residues, strand 3C exosites, and the furin(298-300) loop are critical determinants of serpin reactivity with furin, which may be exploited in the design of specific and selective alpha1PDX inhibitors of PCs. PMID- 23744065 TI - Enhanced fasting glucose turnover in mice with disrupted action of TUG protein in skeletal muscle. AB - Insulin stimulates glucose uptake in 3T3-L1 adipocytes in part by causing endoproteolytic cleavage of TUG (tether containing a ubiquitin regulatory X (UBX) domain for glucose transporter 4 (GLUT4)). Cleavage liberates intracellularly sequestered GLUT4 glucose transporters for translocation to the cell surface. To test the role of this regulation in muscle, we used mice with muscle-specific transgenic expression of a truncated TUG fragment, UBX-Cter. This fragment causes GLUT4 translocation in unstimulated 3T3-L1 adipocytes. We predicted that transgenic mice would have GLUT4 translocation in muscle during fasting. UBX-Cter expression caused depletion of PIST (PDZ domain protein interacting specifically with TC10), which transmits an insulin signal to TUG. Whereas insulin stimulated TUG proteolysis in control muscles, proteolysis was constitutive in transgenic muscles. Fasting transgenic mice had decreased plasma glucose and insulin concentrations compared with controls. Whole-body glucose turnover was increased during fasting but not during hyperinsulinemic clamp studies. In muscles with the greatest UBX-Cter expression, 2-deoxyglucose uptake during fasting was similar to that in control muscles during hyperinsulinemic clamp studies. Fasting transgenic mice had increased muscle glycogen, and GLUT4 targeting to T-tubule fractions was increased 5.7-fold. Whole-body oxygen consumption (VO2), carbon dioxide production (VCO2), and energy expenditure were increased by 12-13%. After 3 weeks on a high fat diet, the decreased fasting plasma glucose in transgenic mice compared with controls was more marked, and increased glucose turnover was not observed; the transgenic mice continued to have an increased metabolic rate. We conclude that insulin stimulates TUG proteolysis to translocate GLUT4 in muscle, that this pathway impacts systemic glucose homeostasis and energy metabolism, and that the effects of activating this pathway are maintained during high fat diet induced insulin resistance in mice. PMID- 23744067 TI - c-Cbl, a ubiquitin E3 ligase that targets active beta-catenin: a novel layer of Wnt signaling regulation. AB - Regulation of transcriptionally active nuclear beta-catenin during the Wnt-on phase is crucial to ensure controlled induction of Wnt target genes. Several ubiquitin E3 ligases are known to regulate cytosolic beta-catenin during the Wnt off phase, but little is known about the fate of active nuclear beta-catenin in the Wnt-on phase. We now describe ubiquitination of active beta-catenin in the Wnt-on phase by a RING finger ubiquitin E3 ligase, Casitas B-lineage lymphoma (c Cbl) in endothelial cells. c-Cbl binds preferentially to nuclearly active beta catenin in the Wnt-on phase via the armadillo repeat region. Wild-type c-Cbl suppresses and E3 ligase-deficient c-Cbl-70Z increases Wnt signaling. Wnt induces nuclear translocation of c-Cbl where it ubiquitinates nuclear beta-catenin. Deletion of the c-Cbl UBA domain abrogates its dimerization, binding to beta catenin, Wnt-induced c-Cbl nuclear translocation, and ubiquitination of nuclear beta-catenin. c-Cbl activity inhibits pro-angiogenic Wnt targets IL-8 and VEGF levels and angiogenesis in a beta-catenin-dependent manner. This study defines for the first time c-Cbl as a ubiquitin E3 ligase that targets nuclearly active beta-catenin in the Wnt-on phase and uncovers a novel layer of regulation of Wnt signaling. PMID- 23744068 TI - Differential contribution of insulin and amino acids to the mTORC1-autophagy pathway in the liver and muscle. AB - Autophagy is a highly inducible intracellular degradation process. It is generally induced by nutrient starvation and suppressed by food intake. Mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1) is considered to be the major regulator of autophagy, but the precise mechanism of in vivo regulation remains to be fully characterized. Here, we examined the autophagy-suppressive effect of glucose, insulin, and amino acids in the liver and muscle in mice starved for 1 day. Refeeding after starvation with a standard mouse chow rapidly suppressed autophagy in both tissues, and this suppression was inhibited by rapamycin administration almost completely in the liver and partially in muscle, confirming that mTORC1 is indeed a crucial regulator in vivo. As glucose administration showed no major suppressive effect on autophagy, we examined the role of insulin and amino acids using hyperinsulinemic-euglycemic clamp and intravenous amino acid infusion techniques. Insulin administration showed a clear effect on the mTORC1-autophagy pathway in muscle, but had only a very weak effect in the liver. By contrast, amino acids were able to regulate the mTORC1-autophagy pathway in the liver, but less effectively in muscle. These results suggest that autophagy is differentially regulated by insulin and amino acids in a tissue dependent manner. PMID- 23744069 TI - Altered cortical GABAA receptor composition, physiology, and endocytosis in a mouse model of a human genetic absence epilepsy syndrome. AB - Patients with generalized epilepsy exhibit cerebral cortical disinhibition. Likewise, mutations in the inhibitory ligand-gated ion channels, GABAA receptors (GABAARs), cause generalized epilepsy syndromes in humans. Recently, we demonstrated that heterozygous knock-out (Hetalpha1KO) of the human epilepsy gene, the GABAAR alpha1 subunit, produced absence epilepsy in mice. Here, we determined the effects of Hetalpha1KO on the expression and physiology of GABAARs in the mouse cortex. We found that Hetalpha1KO caused modest reductions in the total and surface expression of the beta2 subunit but did not alter beta1 or beta3 subunit expression, results consistent with a small reduction of GABAARs. Cortices partially compensated for Hetalpha1KO by increasing the fraction of residual alpha1 subunit on the cell surface and by increasing total and surface expression of alpha3, but not alpha2, subunits. Co-immunoprecipitation experiments revealed that Hetalpha1KO increased the fraction of alpha1 subunits, and decreased the fraction of alpha3 subunits, that associated in hybrid alpha1alpha3betagamma receptors. Patch clamp electrophysiology studies showed that Hetalpha1KO layer VI cortical neurons exhibited reduced inhibitory postsynaptic current peak amplitudes, prolonged current rise and decay times, and altered responses to benzodiazepine agonists. Finally, application of inhibitors of dynamin-mediated endocytosis revealed that Hetalpha1KO reduced base-line GABAAR endocytosis, an effect that probably contributes to the observed changes in GABAAR expression. These findings demonstrate that Hetalpha1KO exerts two principle disinhibitory effects on cortical GABAAR-mediated inhibitory neurotransmission: 1) a modest reduction of GABAAR number and 2) a partial compensation with GABAAR isoforms that possess physiological properties different from those of the otherwise predominant alpha1betagamma GABAARs. PMID- 23744070 TI - A mixed mirror-image DNA/RNA aptamer inhibits glucagon and acutely improves glucose tolerance in models of type 1 and type 2 diabetes. AB - Excessive secretion of glucagon, a functional insulin antagonist, significantly contributes to hyperglycemia in type 1 and type 2 diabetes. Accordingly, immunoneutralization of glucagon or genetic deletion of the glucagon receptor improved glucose homeostasis in animal models of diabetes. Despite this strong evidence, agents that selectively interfere with endogenous glucagon have not been implemented in clinical practice yet. We report the discovery of mirror image DNA-aptamers (Spiegelmer(r)) that bind and inhibit glucagon. The affinity of the best binding DNA oligonucleotide was remarkably increased (>25-fold) by the introduction of oxygen atoms at selected 2'-positions through deoxyribo- to ribonucleotide exchanges resulting in a mixed DNA/RNA-Spiegelmer (NOX-G15) that binds glucagon with a Kd of 3 nm. NOX-G15 shows no cross-reactivity with related peptides such as glucagon-like peptide-1, glucagon-like peptide-2, gastric inhibitory peptide, and prepro-vasoactive intestinal peptide. In vitro, NOX-G15 inhibits glucagon-stimulated cAMP production in CHO cells overexpressing the human glucagon receptor with an IC50 of 3.4 nm. A single injection of NOX-G15 ameliorated glucose excursions in intraperitoneal glucose tolerance tests in mice with streptozotocin-induced (type 1) diabetes and in a non-genetic mouse model of type 2 diabetes. In conclusion, the data suggest NOX-G15 as a therapeutic candidate with the potential to acutely attenuate hyperglycemia in type 1 and type 2 diabetes. PMID- 23744071 TI - alpha-Synuclein oligomers impair neuronal microtubule-kinesin interplay. AB - Early alpha-synuclein (alpha-Syn)-induced alterations are neurite pathologies resulting in Lewy neurites. alpha-Syn oligomers are a toxic species in synucleinopathies and are suspected to cause neuritic pathology. To investigate how alpha-Syn oligomers may be linked to aberrant neurite pathology, we modeled different stages of alpha-Syn aggregation in vitro and investigated the interplay of alpha-Syn aggregates with proteins involved in axonal transport. The interaction of wild type alpha-Syn (WTS) and alpha-Syn variants (E57K, A30P, and aSyn(30-110)) with kinesin, tubulin, and the microtubule (MT)-associated proteins, MAP2 and Tau, is stronger for multimers than for monomers. WTS seeds but not alpha-Syn oligomers significantly and dose-dependently reduced Tau promoted MT assembly in vitro. In contrast, MT gliding velocity across kinesin coated surfaces was significantly decreased in the presence of alpha-Syn oligomers but not WTS seeds or fibrils (aSyn(30-110) multimers). In a human dopaminergic neuronal cell line, mild overexpression of the oligomerizing E57K alpha-Syn variant significantly impaired neurite network morphology without causing profound cell death. In accordance with these findings, MT stability, neuritic kinesin, and neuritic kinesin-dependent cargoes were significantly reduced by the presence of alpha-Syn oligomers. In summary, different alpha-Syn species act divergently on the axonal transport machinery. These findings provide new insights into alpha-Syn oligomer-driven neuritic pathology as one of the earliest events in synucleinopathies. PMID- 23744072 TI - Carbamazepine as a novel small molecule corrector of trafficking-impaired ATP sensitive potassium channels identified in congenital hyperinsulinism. AB - ATP-sensitive potassium (KATP) channels consisting of sulfonylurea receptor 1 (SUR1) and the potassium channel Kir6.2 play a key role in insulin secretion by coupling metabolic signals to beta-cell membrane potential. Mutations in SUR1 and Kir6.2 that impair channel trafficking to the cell surface lead to loss of channel function and congenital hyperinsulinism. We report that carbamazepine, an anticonvulsant, corrects the trafficking defects of mutant KATP channels previously identified in congenital hyperinsulinism. Strikingly, of the 19 SUR1 mutations examined, only those located in the first transmembrane domain of SUR1 responded to the drug. We show that unlike that reported for several other protein misfolding diseases, carbamazepine did not correct KATP channel trafficking defects by activating autophagy; rather, it directly improved the biogenesis efficiency of mutant channels along the secretory pathway. In addition to its effect on channel trafficking, carbamazepine also inhibited KATP channel activity. Upon subsequent removal of carbamazepine, however, the function of rescued channels was recovered. Importantly, combination of the KATP channel opener diazoxide and carbamazepine led to enhanced mutant channel function without carbamazepine washout. The corrector effect of carbamazepine on mutant KATP channels was also demonstrated in rat and human beta-cells with an accompanying increase in channel activity. Our findings identify carbamazepine as a novel small molecule corrector that may be used to restore KATP channel expression and function in a subset of congenital hyperinsulinism patients. PMID- 23744073 TI - Castration induces Parkinson disease pathologies in young male mice via inducible nitric-oxide synthase. AB - Although Parkinson disease (PD) is a progressive neurodegenerative disorder, available animal models do not exhibit irreversible neurodegeneration, and this is a major obstacle in finding out an effective drug against this disease. Here we delineate a new irreversible model to study PD pathogenesis. The model is based on simple castration of young male mice. Levels of inducible nitric-oxide synthase (iNOS), glial markers (glial fibrillary acidic protein and CD11b), and alpha-synuclein were higher in nigra of castrated male mice than normal male mice. On the other hand, after castration, the level of glial-derived neurotrophic factor (GDNF) markedly decreased in the nigra of male mice. Accordingly, castration also induced the loss of tyrosine hydroxylase-positive neurons in the nigra and decrease in tyrosine hydroxylase-positive fibers and neurotransmitters in the striatum. Reversal of nigrostriatal pathologies in castrated male mice by subcutaneous implantation of 5alpha-dihydrotestosterone pellets validates an important role of male sex hormone in castration-induced nigrostriatal pathology. Interestingly, castration was unable to cause glial activation, decrease nigral GDNF, augment the death of nigral dopaminergic neurons, induce the loss of striatal fibers, and impair neurotransmitters in iNOS(-/-) male mice. Furthermore, we demonstrate that iNOS-derived NO is responsible for decreased expression of GDNF in activated astrocytes. Together, our results suggest that castration induces nigrostriatal pathologies via iNOS mediated decrease in GDNF. These results are important because castrated young male mice may be used as a simple, toxin-free, and nontransgenic animal model to study PD-related nigrostriatal pathologies, paving the way for easy drug screening against PD. PMID- 23744074 TI - Precisely ordered phosphorylation reactions in the p38 mitogen-activated protein (MAP) kinase cascade. AB - The MAP kinase cascades, composed of a MAP3K, a MAP2K, and a MAPK, control switch responses to extracellular stimuli and stress in eukaryotes. The most important feature of these modules is thought to be the two double phosphorylation reactions catalyzed by MAP3Ks and MAP2Ks. We addressed whether the reactions are sequential or random in the p38 MAP kinase module. Mass spectrometry was used to track the phosphorylation of the MAP2K MEK6 by two MAP3Ks, TAO2 and ASK1, and the subsequent phosphorylation of p38alpha by MEK6/S*T* (where S (Ser) and T (Thr) are the two phosphorylation sites and * denotes phosphorylation). Both double phosphorylation reactions are precisely ordered. MEK6 is phosphorylated first on Thr-211 and then on Ser-207 by both MAP3Ks. This is the first demonstration of a precise reaction order for a MAP2K. p38alpha is phosphorylated first on Tyr-182 and then on Thr-180, the same reaction order observed previously in ERK2. Thus, intermediates were MEK6/ST* and p38alpha/TY*. Similarly, the phosphorylation of the p38alpha transcription factor substrate ATF2 occurs in a precise sequence. Progress curves for the appearance of intermediates were fit to kinetic models. The models confirmed the reaction order, revealed processivity in the phosphorylation of MEK6 by ASK1, and suggested that the order of phosphorylation is dictated by both binding and catalysis rates. PMID- 23744075 TI - Pancreatic acinar cell nuclear factor kappaB activation because of bile acid exposure is dependent on calcineurin. AB - Biliary pancreatitis is the most common etiology of acute pancreatitis, accounting for 30-60% of cases. A dominant theory for the development of biliary pancreatitis is the reflux of bile into the pancreatic duct and subsequent exposure to pancreatic acinar cells. Bile acids are known to induce aberrant Ca(2+) signals in acinar cells as well as nuclear translocation of NF-kappaB. In this study, we examined the role of the downstream Ca(2+) target calcineurin on NF-kappaB translocation. Freshly isolated mouse acinar cells were infected for 24 h with an adenovirus expressing an NF-kappaB luciferase reporter. The bile acid taurolithocholic acid-3-sulfate caused NF-kappaB activation at concentrations (500 MUm) that were associated with cell injury. We show that the NF-kappaB inhibitor Bay 11-7082 (1 MUm) blocked translocation and injury. Pretreatment with the Ca(2+) chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, the calcineurin inhibitors FK506 and cyclosporine A, or use of acinar cells from calcineurin Abeta-deficient mice each led to reduced NF-kappaB activation with taurolithocholic acid-3-sulfate. Importantly, these manipulations did not affect LPS-induced NF-kappaB activation. A critical upstream regulator of NF-kappaB activation is protein kinase C, which translocates to the membranes of various organelles in the active state. We demonstrate that pharmacologic and genetic inhibition of calcineurin blocks translocation of the PKC-delta isoform. In summary, bile-induced NF-kappaB activation and acinar cell injury are mediated by calcineurin, and a mechanism for this important early inflammatory response appears to be upstream at the level of PKC translocation. PMID- 23744076 TI - Cyclin-dependent kinase 9 links RNA polymerase II transcription to processing of ribosomal RNA. AB - Ribosome biogenesis is a process required for cellular growth and proliferation. Processing of ribosomal RNA (rRNA) is highly sensitive to flavopiridol, a specific inhibitor of cyclin-dependent kinase 9 (Cdk9). Cdk9 has been characterized as the catalytic subunit of the positive transcription elongation factor b (P-TEFb) of RNA polymerase II (RNAPII). Here we studied the connection between RNAPII transcription and rRNA processing. We show that inhibition of RNAPII activity by alpha-amanitin specifically blocks processing of rRNA. The block is characterized by accumulation of 3' extended unprocessed 47 S rRNAs and the entire inhibition of other 47 S rRNA-specific processing steps. The transcription rate of rRNA is moderately reduced after inhibition of Cdk9, suggesting that defective 3' processing of rRNA negatively feeds back on RNAPI transcription. Knockdown of Cdk9 caused a strong reduction of the levels of RNAPII-transcribed U8 small nucleolar RNA, which is essential for 3' rRNA processing in mammalian cells. Our data demonstrate a pivotal role of Cdk9 activity for coupling of RNAPII transcription with small nucleolar RNA production and rRNA processing. PMID- 23744077 TI - Anti-HIV host factor SAMHD1 regulates viral sensitivity to nucleoside reverse transcriptase inhibitors via modulation of cellular deoxyribonucleoside triphosphate (dNTP) levels. AB - Newly identified anti-HIV host factor, SAMHD1, restricts replication of lentiviruses such as HIV-1, HIV-2, and simian immunodeficiency virus in macrophages by enzymatically hydrolyzing and depleting cellular dNTPs, which are the substrates of viral DNA polymerases. HIV-2 and some simian immunodeficiency viruses express viral protein X (VPX), which counteracts SAMHD1 and elevates cellular dNTPs, enhancing viral replication in macrophages. Because nucleoside reverse transcriptase inhibitors (NRTIs), the most commonly used anti-HIV drugs, compete against cellular dNTPs for incorporation into proviral DNA, we tested whether SAMHD1 directly affects the efficacy of NRTIs in inhibiting HIV-1. We found that reduction of SAMHD1 levels with the use of virus-like particles expressing Vpx- and SAMHD1-specific shRNA subsequently elevates cellular dNTPs and significantly decreases HIV-1 sensitivity to various NRTIs in macrophages. However, virus-like particles +Vpx treatment of activated CD4(+) T cells only minimally reduced NRTI efficacy. Furthermore, with the use of HPLC, we could not detect SAMHD1-mediated hydrolysis of NRTI-triphosphates, verifying that the reduced sensitivity of HIV-1 to NRTIs upon SAMHD1 degradation is most likely caused by the elevation in cellular dNTPs. PMID- 23744078 TI - Kdm4b histone demethylase is a DNA damage response protein and confers a survival advantage following gamma-irradiation. AB - DNA damage evokes a complex and highly coordinated DNA damage response (DDR) that is integral to the suppression of genomic instability. Double-strand breaks (DSBs) are considered the most deleterious form damage. Evidence suggests that trimethylation of histone H3 lysine 9 (H3K9me3) presents a barrier to DSB repair. Also, global levels of histone methylation are clinically predictive for several tumor types. Therefore, demethylation of H3K9 may be an important step in the repair of DSBs. The KDM4 subfamily of demethylases removes H3K9 tri- and dimethylation and contributes to the regulation of cellular differentiation and proliferation; mutation or aberrant expression of KDM4 proteins has been identified in several human tumors. We hypothesize that members of the KDM4 subfamily may be components of the DDR. We found that Kdm4b-enhanced GFP (EGFP) and KDM4D-EGFP were recruited rapidly to DNA damage induced by laser micro irradiation. Focusing on the clinically relevant Kdm4b, we found that recruitment was dependent on poly(ADP-ribose) polymerase 1 activity as well as Kdm4b demethylase activity. The Kdm4 proteins did not measurably accumulate at gamma irradiation-induced gammaH2AX foci. Nevertheless, increased levels of Kdm4b were associated with decreased numbers of gammaH2AX foci 6 h after irradiation as well as increased cell survival. Finally, we found that levels of H3K9me2 and H3K9me3 were decreased at early time points after 2 gray of gamma-irradiation. Taken together, these data demonstrate that Kdm4b is a DDR protein and that overexpression of Kdm4b may contribute to the failure of anti-cancer therapy that relies on the induction of DNA damage. PMID- 23744079 TI - tBid undergoes multiple conformational changes at the membrane required for Bax activation. AB - Bid is a Bcl-2 family protein that promotes apoptosis by activating Bax and eliciting mitochondrial outer membrane permeabilization (MOMP). Full-length Bid is cleaved in response to apoptotic stimuli into two fragments, p7 and tBid (p15), that are held together by strong hydrophobic interactions until the complex binds to membranes. The detailed mechanism(s) of fragment separation including tBid binding to membranes and release of the p7 fragment to the cytoplasm remain unclear. Using liposomes or isolated mitochondria with fluorescently labeled proteins at physiological concentrations as in vitro models, we report that the two components of the complex quickly separate upon interaction with a membrane. Once tBid binds to the membrane, it undergoes slow structural rearrangements that result in an equilibrium between two major tBid conformations on the membrane. The conformational change of tBid is a prerequisite for interaction with Bax and is, therefore, a novel step that can be modulated to promote or inhibit MOMP. Using automated high-throughput image analysis in cells, we show that down-regulation of Mtch2 causes a significant delay between tBid and Bax relocalization in cells. We propose that by promoting insertion of tBid via a conformational change at the mitochondrial outer membrane, Mtch2 accelerates tBid-mediated Bax activation and MOMP. Thus the interaction of Mtch2 and tBid is a potential target for therapeutic control of Bid initiated cell death. PMID- 23744082 TI - Time-resolved photoelectron spectroscopy of adenine and adenosine in aqueous solution. AB - Time-resolved photoelectron spectroscopy is applied to study the excited state dynamics of the DNA base adenine and its ribonucleoside adenosine in aqueous solution for pump and probe photon energies in the range between 4.66 eV and 5.21 eV. We follow the evolution of the prepared excited state on the potential energy surface and retrieve lifetimes of the S1 state under different excitation conditions. PMID- 23744081 TI - Chitotriosidase is a biomarker for the resistance to World Trade Center lung injury in New York City firefighters. AB - PURPOSE: World Trade Center (WTC) exposure caused airflow obstruction years after exposure. Chitinases and IgE are innate and humoral mediators of obstructive airway disease. We investigated if serum expression of chitinases and IgE early after WTC exposure predicts subsequent obstruction. METHODS: With a nested case control design, 251 FDNY personnel had chitotriosidase, YKL-40 and IgE measured in serum drawn within months of 9/11/2001. The main outcome was subsequent Forced Expiratory Volume after 1 second/Forced Vital Capacity (FEV1/FVC) less than the lower limit of normal (LLN). Cases (N = 125) had abnormal FEV1/FVC whereas controls had normal FEV1/FVC (N = 126). In a secondary analysis, resistant cases (N = 66) had FEV1 (>=107%) one standard deviation above the mean. Logistic regression adjusted for age, BMI, exposure intensity and post-exposure FEV1/FVC modeled the association between early biomarkers and later lung function. RESULTS: Cases and Controls initially lost lung function. Controls recovered to pre-9/11 FEV1 and FVC while cases continue to decline. Cases expressed lower serum chitotriosidase and higher IgE levels. Increase in IgE increased the odds of airflow obstruction and decreased the odds of above average FEV1. Alternately, increasing chitotriosidase decreased the odds of abnormal FEV1/FVC and increased the odds of FEV1 >= 107%. Serum YKL-40 was not associated with FEV1/FVC or FEV1 in this cohort. CONCLUSIONS: Increased serum chitotriosidase reduces the odds of developing obstruction after WTC-particulate matter exposure and is associated with recovery of lung function. Alternately, elevated IgE is a risk factor for airflow obstruction and progressive lung function decline. PMID- 23744083 TI - Femoral shortening in the congenital dislocation of the knee joint: results of mid-term follow-up. AB - Femoral shortening has an advantage of gaining reduction in severe grades of congenital dislocation of the knee joint without release or lengthening of the quadriceps tendon, thereby reducing the incidence of extensor lag. We report our mid-term functional results in six patients (10 knees) with grade III congenital dislocation of the knee joint who were treated with femoral shortening. At an average follow-up of 4.1 years, the mean active range of motion was -0.5 to 107 degrees and none of the patients had extensor lag. The results in arthrogryposis multiplex congenita were noteworthy for the absence of extensor weakness, postoperative deformity, or recurrence. PMID- 23744080 TI - Receptor-type protein-tyrosine phosphatase zeta is a functional receptor for interleukin-34. AB - Interleukin-34 (IL-34) is highly expressed in brain. IL-34 signaling via its cognate receptor, colony-stimulating factor-1 receptor (CSF-1R), is required for the development of microglia. However, the differential expression of IL-34 and the CSF-1R in brain suggests that IL-34 may signal via an alternate receptor. By IL-34 affinity chromatography of solubilized mouse brain membrane followed by mass spectrometric analysis, we identified receptor-type protein-tyrosine phosphatase zeta (PTP-zeta), a cell surface chondroitin sulfate (CS) proteoglycan, as a novel IL-34 receptor. PTP-zeta is primarily expressed on neural progenitors and glial cells and is highly expressed in human glioblastomas. IL-34 selectively bound PTP-zeta in CSF-1R-deficient U251 human glioblastoma cell lysates and inhibited the proliferation, clonogenicity, and motility of U251 cells in a PTP-zeta-dependent manner. These effects were correlated with an increase in tyrosine phosphorylation of the previously identified PTP-zeta downstream effectors focal adhesion kinase and paxillin. IL 34 binding to U251 cells was abrogated by chondroitinase ABC treatment, and CS competed with IL-34 for binding to the extracellular domain of PTP-zeta and to the cells, indicating a dependence of binding on PTP-zeta CS moieties. This study identifies an alternate receptor for IL-34 that may mediate its action on novel cellular targets. PMID- 23744084 TI - [Dermatomyositis with tonsillar carcinoma. Rare presentation as paraneoplastic syndrome]. AB - BACKGROUND: Malignant tumors occur in up to 15 % of patients with paraneoplastic syndromes. The temporal association between malignancy and paraneoplasia is variable. Dermatomyositis belongs to the facultative cutaneous paraneoplasia. CASE REPORT: A patient presented with a cervical swelling and preexisting dermatomyositis. Staging revealed a tonsillar carcinoma with cervical, mediastinal and bone metastasis, and meningeal carcinomatosis. Systemic intrathecal chemotherapy was initiated. CONCLUSION: Dermatomyositis has only been described four times worldwide as a paraneoplastic disease with tonsillar carcinoma. Upon occurrence of a paraneoplastic syndrome, an intensive search for tumours is required at regular intervals until the primary tumor is diagnosed. PMID- 23744085 TI - [User benefit of modern hearing aids. A comparative study]. AB - BACKGROUND: In the face of the rapid development of hearing aid system technology it is helpful to regularly study the user benefit of the current generation. TEST PERSONS AND METHODS: To contribute to the question on how the user benefit of current hearing aids compares with the benefit of the previous generation of hearing aids, a multicentre study was carried out in cooperation with 79 hearing aid acoustics companies in Germany. The user benefit of modern hearing aids in everyday life was assessed by asking end users to participate in a survey by completing a questionnaire. The questionnaire consisted of 20 items, 10 of which were taken from validated international inventories (SSQ: Speech, Spatial and Qualities of Hearing scale, IOI-HA: International Outcome Inventory for Hearing Aids) and the other 10 were formulated particularly for this purpose. RESULTS: A total of 664 usable questionnaires were returned whereby 421 responders were first time users and 243 responders were previous hearing aid users. The results of the present study showed that modern hearing aid system technology provides significant extra benefits at the 5 % level relative to the previous generation of hearing aids for all variables tested in this study. CONCLUSIONS: Even though the amount of gain in terms of user benefit may be overestimated due to well known placebo effects, an obvious net effect was evident. Correlations between the level of hearing aid benefit and possible influencing factors, such as age, gender, subjects own hearing aid, duration of use or hearing loss, could not be identified. PMID- 23744086 TI - [Oropharynx reconstruction. Use of free and pedicled flaps]. AB - Oropharyngeal cancer surgery often does not allow primary wound closure; furthermore, surgery of tumors in the base of the tongue, the soft palate and the lateral pharyngeal wall often lead to swallowing disorders and nasal twang which severely impair quality of life. Secondary scarring may also result in fixation of the tongue or stenosis of the pharynx. Therefor reconstructive techniques with free or pedicled flaps are essential to reduce functional impairment. In addition, after trauma or due to malformations, reconstructive surgery using flap techniques is sometimes indicated. PMID- 23744088 TI - [Utricular function. Correlation of three investigations carried out in routine practice]. AB - BACKGROUND: For vestibular disorders competence in otorhinolaryngology (ENT) is required to diagnose disorders in the complete vestibular system. It seems difficult, however, to evaluate otolithic functions although the influence and importance regarding vestibular dysfunction could be relevant. Currently it is possible to unilaterally diagnose different functions of the saccule by recording cervically registered vestibular evoked myogenic potentials (c-VEMP). Partial functions of the utricle can be checked through the so-called turn-over manoeuvre during thermal examination, a gravitation-dependant caloric examination. Ocular recorded VEMPs and registration of the subjective visual vertical (SVV) are further tools for the discrimination of utricular function. This paper evaluates whether the results using these diagnostic tools are in agreement for distinct ENT-relevant vestibular disorders. PATIENTS AND METHODS: In this study 100 unselected patients attending the vestibular outpatient department of the tinnitus clinic Dr. Hesse in Bad Arolsen and who were suffering from various forms of dizziness were consecutively and prospectively examined. In addition to standard diagnostic examinations (i.e. caloric testing, rotary chair, optocinetics and posturography) the turnover manoeuvre during caloric testing, o VEMP recording and registration of the SVV were also performed. RESULTS: For 62 % of the patients all 3 methods that measure partial functions of the utricle concurred. For an additional 6 % the results of the turnover manoeuvre and o-VEMP matched. The most conformity, with respect to sufficient utricular function was found for patients with non-vestibular dizziness, psychogenic vertigo and for the majority of patients with Meniere's disease. CONCLUSIONS: In the context of specific vestibular examinations it is possible to test utricular function through o-VEMO recordings and the turnover manoeuvre during caloric (cold) testing which allow clear conclusions especially with sufficient (positive) function. With 68% conformity between o-VEMP and the turnover manoeuvre it is obvious that both tests give strong indications for possible utricular dysfunction but do not give complete proof alone. The SVV is easy to register but is discriminating for utricular function only in cases of acute disorders. PMID- 23744087 TI - [Otitis media with effusion : frequency, diagnosis, and therapy in early childhood]. AB - BACKGROUND: Otitis media with effusion (OME) as the most common cause of hearing loss in childhood plays an important role in the follow-up after failed newborn hearing screening (NHS). The introduction of the NHS allows OME to be diagnosed and treated in the first months of life. MATERIAL AND METHODS: In 715 children referred to the Department of Phoniatrics and Pedaudiology of the Ear, Nose, Throat University Hospital of Magdeburg during the period 2006-2010, the prevalence and therapy process of OME during follow-up could be determined. RESULTS: OME was diagnosed in 16 % of the patients. Spontaneous resolution was observed in 37 % of the cases, while 46 % of the children were treated surgically. A substantially increased risk for persistent OME was observed in children with craniofacial dysmorphia or cleft palate. CONCLUSION: Using NHS, OME can be diagnosed and treated early, thus, preventing potential problems in the linguistic, social and intellectual development of children. PMID- 23744089 TI - [Perceptual and automatic voice and speech analysis of chronic laryngitis and T1 vocal cord cancer]. AB - BACKGROUND: Patients with chronic laryngitis and T1 vocal cord cancer were compared using perceptual and text-based objective voice and speech analyses in order to determine which group is more affected in its ability to communicate and whether a distinction between the two pathologies is possible. PATIENTS AND METHODS: In all, 13 patients with histologically proven chronic laryngitis and 13 patients with T1 vocal cord cancer were compared perceptually by five speech therapists on the basis of seven criteria and objectively by a speech recognition system and prosodic analysis. RESULTS: Both, the data of the five speech therapists and the results of the automatic analysis revealed no significant differences between the two patient groups. CONCLUSION: A distinction between chronic laryngitis and T1 vocal cord carcinoma by mere voice and speech analysis is not possible, because the patient groups do not show significant differences in their voice quality. PMID- 23744090 TI - Visual impairment, uncorrected refractive error, and objectively measured balance in the United States. AB - IMPORTANCE: Further research is crucial to better understand the reason for falls in individuals with visual impairment (VI) and to develop appropriate fall prevention strategies. OBJECTIVE: To compare balance measures in individuals with normal vision, VI, and uncorrected refractive error (URE). DESIGN AND SETTING: Cross-sectional study based on a national survey sample. PARTICIPANTS: A total of 4590 adults, 40 years or older, participating in the 2001 through 2004 National Health and Nutrition Examination Survey. MAIN OUTCOME MEASURES: Participants completed tests of standing balance with eyes open or eyes closed on a firm or compliant (foam) surface. Eyes-closed testing on a foam surface primarily assessed vestibular balance by minimizing visual and proprioceptive inputs. The main outcome measure was time to balance failure on firm and foam surface testing. Participants also self-reported difficulty with falling during the last year. RESULTS: Failure during eyes-open balance testing conditions or eyes-closed balance testing on a firm surface was not more common among participants with VI associated or URE-associated vision loss (P > .22). In eyes-closed foam surface balance testing, multivariable models demonstrated higher rates of balance loss with VI-associated vision loss (P = .02) and with URE-associated vision loss (P = .04) (hazard ratio, 1.7 per logarithm of the minimum angle of resolution [logMAR] unit change [10 lines] for both). Self-reported falling difficulty was associated with worse VI (odds ratio, 3.7 per logMAR unit change; P = .03) but not with worse URE (odds ratio, 3.4 per logMAR unit change; P = .14). CONCLUSIONS AND RELEVANCE: The vestibular contribution to balance (measured with eyes closed on a foam surface) was worse for individuals with VI or URE. Reduced visual inputs may weaken the vestibulo-ocular reflex, an important system that maintains the effectiveness of vestibular balance. Alternately, common degenerative pathways or lower physical activity levels may affect balance, particularly among those with VI. PMID- 23744092 TI - Chronic infections of the spine. AB - Chronic infections following posterior fusion are relatively uncommon. They develop in a previous asymptomatic patient at a distant time from the surgery. Chronic infections arise from direct inoculation or hematogenous seeding. To eradicate a chronic infection, the pathogens, biofilm, non-viable tissues, adherence on surfaces, and instrumentation must be removed. The appropriate antibiotherapy is used in a short (4 weeks) or long protocol (9 weeks). Some patients may need repeated surgeries (leaving the instrumentation in situ) to avoid progressive deformity or symptomatic pseudoarthrosis in cases of implant removal. PMID- 23744091 TI - Engineered antibody Fc variant with selectively enhanced FcgammaRIIb binding over both FcgammaRIIa(R131) and FcgammaRIIa(H131). AB - Engaging inhibitory FcgammaRIIb by Fc region has been recently reported to be an attractive approach for improving the efficacy of antibody therapeutics. However, the previously reported S267E/L328F variant with enhanced binding affinity to FcgammaRIIb, also enhances binding affinity to FcgammaRIIa(R131) allotype to a similar degree because FcgammaRIIb and FcgammaRIIa(R131) are structurally similar. In this study, we applied comprehensive mutagenesis and structure-guided design based on the crystal structure of the Fc/FcgammaRIIb complex to identify a novel Fc variant with selectively enhanced FcgammaRIIb binding over both FcgammaRIIa(R131) and FcgammaRIIa(H131). This novel variant has more than 200 fold stronger binding affinity to FcgammaRIIb than wild-type IgG1, while binding affinity to FcgammaRIIa(R131) and FcgammaRIIa(H131) is comparable with or lower than wild-type IgG1. This selectivity was achieved by conformational change of the C(H)2 domain by mutating Pro to Asp at position 238. Fc variant with increased binding to both FcgammaRIIb and FcgammaRIIa induced platelet aggregation and activation in an immune complex form in vitro while our novel variant did not. When applied to agonistic anti-CD137 IgG1 antibody, our variant greatly enhanced the agonistic activity. Thus, the selective enhancement of FcgammaRIIb binding achieved by our Fc variant provides a novel tool for improving the efficacy of antibody therapeutics. PMID- 23744093 TI - Knee pain after anterior cruciate ligament reconstruction: evaluation of a rehabilitation protocol. AB - INTRODUCTION: Anterior knee pain (AKP) is a rare and difficult complication following anterior cruciate ligament (ACL) reconstruction. This disabling pain is persistent with conventional rehabilitation protocols. The aim of this work is to validate a new rehabilitation protocol that may improve the patients and allow return to daily activities including sports. MATERIALS AND METHODS: Forty-three patients identified with functional AKP after ACL reconstruction was enrolled in the rehabilitation protocol between 2009 and 2011. The series included twenty-six patients with hamstring grafting and seventeen patients with patellar tendon transplant. This study compares the functional outcomes and pain scores before and after the isokinetic protocol until the last follow-up at an average of 25.7 months after surgery. The evaluation was performed according to the International Knee Documentation Committee (IKDC) and included a pain assessment using the visual analog scale. Statistical analysis used Student's t-test for unpaired data and the Pearson correlation test for the variables. The IKDC scores were compared by the Wilcoxon test. RESULTS: Functional outcomes and pain are significantly improved (p<0.0001). The average IKDC score improved with 28 points and the pain improved with 3.2 points on the visual analog scale (VAS). The results are correlated with the follow-up time (p=0.008) but not correlated with the delay between the surgery and the beginning of the isokinetic protocol. DISCUSSION: Isokinetic rehabilitation provides a significant improvement in the knee function as measured by the IKDC score and by the VAS, regardless of the painful period preceding the program. The function improvement continues after the end of the protocol, but the pain may not completely disappear. The isokinetic rehabilitation program may resume functional AKP related to muscular deficit and may be used as the starter of other physical therapy protocols. LEVEL OF EVIDENCE: IV. PMID- 23744094 TI - Urothelial cell intracytoplasmic inclusions after treatment of promyelocytic leukemia with arsenic trioxide. AB - Intramitochondrial inclusions containing arsenite that occur within urothelial cells have been previously described in mice exposed to high concentrations of arsenic but not in rats. In epidemiology studies, similar urothelial cell inclusions have also been observed in the urine of humans exposed to high concentrations of arsenic in the drinking water; however, these inclusions were mistakenly identified as micronuclei. To further examine the urothelial cell inclusions that occur in inorganic arsenic-exposed humans, we evaluated two patients with a history of acute promyelocytic leukemia treated for disease relapse with a combination of all-trans retinoic acid and arsenic trioxide. Posttreatment examination of the patients' urine cytology specimens by light and electron microscopy demonstrated cytoplasmic inclusions in exfoliated superficial urothelial cells similar to those seen in mice. The inclusions were present in decreasing quantities at 3 and 7 months after completion of treatment. No comparable inclusions were detected in exfoliated urothelial cells in urine from six individuals not treated with arsenic trioxide. Based on the results of the examination by light and electron microscopy, we have determined that urothelial cell inclusions in the urine of humans previously identified as micronuclei are instead intracytoplasmic inclusions similar to those found in arsenic-treated mice. PMID- 23744096 TI - Building a strong healthcare infrastructure for adolescents. PMID- 23744095 TI - Impact of pregnancy on the pharmacokinetics of dibenzo[def,p]chrysene in mice. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants generated during combustion. Dibenzo[def,p]chrysene (DBC) is a high molecular weight PAH classified as a 2B carcinogen by the International Agency for Research on Cancer. DBC crosses the placenta in exposed mice, causing carcinogenicity in offspring. We present pharmacokinetic data of DBC in pregnant and nonpregnant mice. Pregnant (gestational day 17) and nonpregnant female B6129SF1/J mice were exposed to 15mg/kg DBC by oral gavage. Subgroups of mice were sacrificed up to 48h postdosing, and blood, excreta, and tissues were analyzed for DBC and its major diol and tetrol metabolites. Elevated maximum concentrations and areas under the curve of DBC and its metabolites were observed in blood and tissues of pregnant animals compared with naive mice. Using a physiologically based pharmacokinetic (PBPK) model, we found observed differences in pharmacokinetics could not be attributed solely to changes in tissue volumes and blood flows that occur during pregnancy. Measurement of enzyme activity in naive and pregnant mice by activity-based protein profiling indicated a 2- to 10-fold reduction in activities of many of the enzymes relevant to PAH metabolism. Incorporating this reduction into the PBPK model improved model predictions. Concentrations of DBC in fetuses were one to two orders of magnitude below maternal blood concentrations, whereas metabolite concentrations closely resembled those observed in maternal blood. PMID- 23744097 TI - Cutaneous manifestations of primary immunodeficiency. AB - PURPOSE OF REVIEW: To show that skin symptoms help in the recognition of primary immunodeficiencies (PIDs). To analyze whether recent molecular data help in understanding genotype/phenotype relations. RECENT FINDINGS: Erythroderma in Omenn syndrome may be caused by either mutations in genes associated with severe combined immunodeficiency (SCID) in which the generation of some T cells is possible, which results in potentially autoreactive lymphoid clones, or by selective proliferation of revertant CD8 T cells in the skin due to clonal expansion in response to infections or autoantigens.The newborn eczematous eruption, which occurs mainly in the signal-transducer-and-activator-of transcription-3 (STAT3) variant, helps to differentiate STAT3 from Dedicator of Cytokinesis 8-related Hyper-IgE-syndrome (HIES).Impaired T helper 17 cell (TH17) immunity [HIES and defects of autoimmune regulator element (AIRE), STAT-1, and interleukin17 receptor(IL17(R))] may give rise to localized chronic mucocutaneous candidiasis, whereas a defective innate immune system predisposes to systemic candidiasis [congenital neutropenia, neutrophil dysfunction, and caspase recruitment domain 9 (CARD9) deficiency].Noninfectious granulomas may be the presenting symptom in innate immunity defects [such as chronic granulomatous disease (CGD) or in predominantly humoral immunodeficiencies such as common variable immunodeficiency], as well as ataxia teleangiectasia or rare recombination-activating gene-deficient cases. SUMMARY: The skin is important in the diagnosis of PIDs. In particular eczematous lesions, erythroderma, noninfectious granuloma, and microbial manifestations may help to direct further diagnostic laboratory analysis. PMID- 23744098 TI - Addressing social determinants of health in the adolescent medical home. AB - PURPOSE OF REVIEW: To provide a framework for addressing the social determinants of health (SDH) in the adolescent medical home. RECENT FINDINGS: There has been recent recognition worldwide that SDH affect health throughout the life-course. Adolescents are a vulnerable population, with health behaviors, access, and outcomes shaped by social and environmental contexts. Medical homes have aimed to reduce the health inequities by facilitating connections with community resources. Interventions have been described in the literature for triaging social needs, connecting patients to resources, and utilizing multidisciplinary team members. SUMMARY: SDH should be incorporated into the routine adolescent healthcare. Screening tools and referral programs should be developed and evaluated in the adolescent population. Programs utilizing multidisciplinary team members would be effective in reaching adolescents and facilitating connections to resources. PMID- 23744099 TI - Temperature variations at nano-scale level in phase transformed nanocrystalline NiTi shape memory alloys adjacent to graphene layers. AB - The detection and control of the temperature variation at the nano-scale level of thermo-mechanical materials during a compression process have been challenging issues. In this paper, an empirical method is proposed to predict the temperature at the nano-scale level during the solid-state phase transition phenomenon in NiTi shape memory alloys. Isothermal data was used as a reference to determine the temperature change at different loading rates. The temperature of the phase transformed zone underneath the tip increased by ~3 to 40 degrees C as the loading rate increased. The temperature approached a constant with further increase in indentation depth. A few layers of graphene were used to enhance the cooling process at different loading rates. Due to the presence of graphene layers the temperature beneath the tip decreased by a further ~3 to 10 degrees C depending on the loading rate. Compared with highly polished NiTi, deeper indentation depths were also observed during the solid-state phase transition, especially at the rate dependent zones. Larger superelastic deformations confirmed that the latent heat transfer through the deposited graphene layers allowed a larger phase transition volume and, therefore, more stress relaxation and penetration depth. PMID- 23744100 TI - N-terminal pro-brain natriuretic peptide (NT proBNP) as a predictive indicator of initial intravenous immunoglobulin treatment failure in children with Kawasaki disease: a retrospective study. AB - Intravenous immunoglobulin (IVIG) administered in the acute stage of Kawasaki disease (KD) is the standard therapy. Few reports describe nonresponders to initial treatment with IVIG in KD, which remains the most consistent risk factor for coronary artery lesions (CALs). This study aimed to investigate whether the serum level of N-terminal pro-brain natriuretic peptide (NT-proBNP) can be a predictive indicator for identifying patients with KD at higher risk of IVIG treatment failure. In this study, 135 patients with a diagnosis of KD admitted for IVIG treatment were retrospectively enrolled for analysis. Of these 135 patients, 22 were nonresponders who received additional rescue therapy because they had an elevated body temperature 36 h after completion of initial IVIG treatment. The NT-proBNP concentration was significantly higher in the nonresponder group (2,465.36 +/- 3,293.24 pg/mL) than in the responder group (942.38 +/- 1,293.48 pg/mL) (p < 0.05). The optimal sensitivity and specificity cutoff point for predicted nonresponders was 1,093.00 pg/mL or higher. The sensitivity and specificity for prediction of IVIG response were respectively 70.0 and 76.5 %. The findings show that NT-proBNP is a helpful marker in determining patients at risk for not responding to initial IVIG treatment. The authors suggest that patients with an NT-proBNP level of 1,093.00 pg/dL or higher are likely to fail initial IVIG and may require further rescue therapy. PMID- 23744101 TI - ICD implantation without intraoperative testing does not increase the rate of system modifications and does not impair defibrillation efficacy tested in follow up. AB - AIM: The need for implantable cardioverter-defibrillator (ICD) defibrillation testing (DT) and subsequent intraoperative system modifications is discussed controversially. The study's goal was to prove that consequent abdication of intraoperative DT does not impair defibrillation efficacy and does not increase the rate of postoperative system revisions. METHODS: In a prospective single center observational study, 609 out of 648 consecutive patients underwent transvenous ICD implantation (left-sided, active can, dual coil lead, and biphasic shock waveform) waiving intraoperative DT. Defibrillation efficacy was validated prior to hospital discharge (PHD) by applying two 10 J safety margin (SM) shocks. RESULTS: Following "schockless" implantation 580 out of 609 patients (95.2 %) met a 10 J SM with default programming. Shock path reversal provided 10 J SM in 13 out of 29 cases with initially failed DT. In four patients (0.7 %) maximum energy shocks were ineffective. There was no morbidity or mortality related to DT. The total rate of surgical ICD revisions was 1.8 %. CONCLUSION: Routine ICD implantation without intraoperative DT does not lead to an increased rate of postoperative system modifications and does not decrease defibrillation efficacy as tested PHD. PMID- 23744102 TI - The CCM3-GCKIII partnership. AB - Specific mutations in the CCM3 gene predispose to the development of cerebral cavernous malformations, a special type of vascular lesions. This calls for an elucidation of the precise nature of the CCM3 protein and a deep understanding of its molecular regulation. In this review, we outline our current knowledge of the different CCM3 protein complexes. We focus on the GCKIII family of kinases as partners of CCM3 and discuss the functional consequences of this partnership, putting forward a putative model for the activation of these kinases. PMID- 23744103 TI - Brillouin cavity optomechanics with microfluidic devices. AB - Cavity optomechanics allows the parametric coupling of phonon- and photon-modes in microresonators and is presently investigated in a broad variety of solid state systems. Optomechanics with superfluids has been proposed as a path towards ultra-low optical- and mechanical-dissipation. However, there have been no optomechanics experiments reported with non-solid phases of matter. Direct liquid immersion of optomechanics experiments is challenging, as the acoustic energy simply leaks out to the higher-impedance liquid surrounding the device. Here we confine liquids within hollow resonators to circumvent this issue and to enable optical excitation of mechanical whispering-gallery modes at frequencies ranging from 2 to 11,000 MHz. Our device enables optomechanical investigation with liquids, while light is conventionally coupled from the outer dry side of the capillary, and liquids are provided by means of a standard microfluidic inlet. PMID- 23744104 TI - Influence of naturally occurring simian foamy viruses (SFVs) on SIV disease progression in the rhesus macaque (Macaca mulatta) model. AB - We have investigated the influence of naturally occurring simian foamy viruses (SFVs) on simian immunodeficiency virus (SIV) infection and disease in Indian rhesus macaques. Animals were divided into two groups based upon presence or absence of SFV; in each group, eight monkeys were injected with SIV(mac239) virus obtained from a molecular clone and four were injected with medium. Blood was collected every two weeks for evaluation of SIV infection based upon T cell subsets, plasma viral load, development and persistence of virus-specific antibodies, and clinical changes by physical examination and hematology. Comparative analysis of SFV+/SIV+ and SFV-/SIV+ monkey groups indicated statistically significant differences in the plasma viral load between 6-28 weeks, particularly after reaching plateau at 20-28 weeks, in the CD4+ and CD8+ T cell numbers over the entire study period (2-43 weeks), and in the survival rates evaluated at 49 weeks. There was an increase in the plasma viral load, a decreasing trend in the CD4+ T cells, and a greater number of animal deaths in the SFV+/SIV+ group. The results, although based upon a small number of animals, indicated that pre-existing SFV infection can influence SIV infection and disease outcome in the rhesus macaque model. The study highlights consideration of the SFV status in evaluating results from SIV pathogenesis and vaccine challenge studies in monkeys and indicates the potential use of the SFV/SIV monkey model to study the dynamics of SFV and HIV-1 dual infections, recently reported in humans. PMID- 23744105 TI - Percutaneous calcaneoplasty in displaced intraarticular calcaneal fractures. AB - The ideal treatment for displaced intraarticular calcaneal fractures is still under debate. Open reduction and internal fixation is the most popular surgical procedure; however, wound complications, hardware failure and infection remain a major concern. The aim of this study was to evaluate the results of a new minimally-invasive surgical procedure: closed reduction technique combined with balloon-assisted fracture augmentation with cement or calcium phosphate (minimally-invasive percutaneous calcaneoplasty). We retrospectively reviewed 11 patients that sustained Sander's type II and III calcaneal fractures treated in our institution from January 2008 to June 2010. The same approach and technique was utilized in all cases. Conventional X-rays and CT scan have been performed pre- and post-operatively. The average follow-up was 24 months. The American Orthopaedic Foot and Ankle Society ankle/hindfoot score has been utilized for clinical evaluation and Bohler's angle to assess bone reduction. All cases obtained bony union in 2/3 months, with average Bohler's angle of 22.97 degrees (from 14.21 degrees to 32.83 degrees ). No skin complications or adverse reactions were observed, with only one patient complaining of residual pain in the hindfoot. Minimally-invasive percutaneous calcaneoplasty can represent an alternative to open reduction internal fixation in the treatment of calcaneal fractures, allowing stable reduction without plating, early function recovery and short hospital stay. PMID- 23744107 TI - Behavioral health services influence medical treatment utilization among primary care patients with comorbid substance use and depression. AB - Although research has shown benefits of integrating psychological care in primary care settings, it is unclear how this form of treatment impacts individuals with comorbid substance use and depression. The findings are also mixed concerning how frequently this comorbid population seeks primary care services. This study examined the associations between substance use, depression, and medical treatment utilization among 224 primary care patients. The aim of the investigation was twofold. First, to determine if depression increases medical treatment utilization among patients with substance use disorders; second, to evaluate if behavioral health treatment reduces medical service utilization. A moderated mediation model with bootstrapping analyses revealed that depression strengthened the relationship between substance use and primary care treatment utilization (both medical and behavioral health). The model also indicated that behavioral health services were associated with fewer primary care visits for individuals with comorbid substance use and depression. Clinical and social implications are discussed. PMID- 23744106 TI - Epidemiology and long-term clinical and biologic risk factors for pneumonia in community-dwelling older Americans: analysis of three cohorts. AB - BACKGROUND: Preventing pneumonia requires better understanding of incidence, mortality, and long-term clinical and biologic risk factors, particularly in younger individuals. METHODS: This was a cohort study in three population-based cohorts of community-dwelling individuals. A derivation cohort (n = 16,260) was used to determine incidence and survival and develop a risk prediction model. The prediction model was validated in two cohorts (n = 8,495). The primary outcome was 10-year risk of pneumonia hospitalization. RESULTS: The crude and age adjusted incidences of pneumonia were 6.71 and 9.43 cases/1,000 person-years (10 year risk was 6.15%). The 30-day and 1-year mortality were 16.5% and 31.5%. Although age was the most important risk factor (range of crude incidence rates, 1.69-39.13 cases/1,000 person-years for each 5-year increment from 45-85 years), 38% of pneumonia cases occurred in adults < 65 years of age. The 30-day and 1 year mortality were 12.5% and 25.7% in those < 65 years of age. Although most comorbidities were associated with higher risk of pneumonia, reduced lung function was the most important risk factor (relative risk = 6.61 for severe reduction based on FEV1 by spirometry). A clinical risk prediction model based on age, smoking, and lung function predicted 10-year risk (area under curve [AUC] = 0.77 and Hosmer-Lemeshow [HL] C statistic = 0.12). Model discrimination and calibration were similar in the internal validation cohort (AUC = 0.77; HL C statistic, 0.65) but lower in the external validation cohort (AUC = 0.62; HL C statistic, 0.45). The model also calibrated well in blacks and younger adults. C reactive protein and IL-6 were associated with higher pneumonia risk but did not improve model performance. CONCLUSIONS: Pneumonia hospitalization is common and associated with high mortality, even in younger healthy adults. Long-term risk of pneumonia can be predicted in community-dwelling adults with a simple clinical risk prediction model. PMID- 23744110 TI - Atomic-level 2-dimensional chemical mapping and imaging of individual dopants in a phosphor crystal. AB - The ability to visualize and identify individual dopants, as well as measure their local physical and chemical environments in a bulk, provides deep insight for designing new functional materials and predicting their properties. However, a full understanding of dopants inside a solid has been limited by currently available characterization techniques. We demonstrate the first atomic-level 2 dimensional elemental maps of Pr dopants using the electron energy-loss spectroscopy (EELS) technique and we image Al dopants located in a lattice. Based on spectroscopic and imaging evidence we provide plausible local defect configurations of implanted Pr(+) and Al(+) ions within SrTiO3 single crystals. Our results demonstrate the detection of single Pr atoms and the formation of Al rich nanoscale clusters ranging from 1 to 3 nm in size randomly distributed in the implanted lattice. These results provide insight into the mechanism of red light emission in doped SrTiO3. PMID- 23744108 TI - Regulation of gap junctions in melanoma and their impact on Melan-A/MART-1 specific CD8+ T lymphocyte emergence. AB - Gap junctions (GJs) enable intercellular communication between adjacent cells through channels of connexins. Using a three-dimensional construct, we previously showed that endothelial and tumor cells formed GJs, allowing melanoma-specific T lymphocytes to recognize and kill melanoma-derived endothelial cells. We demonstrate here on histological sections of melanoma biopsies that GJ formation occurs in vivo between tumor and endothelial cells and between T lymphocytes and target cells. We also show an in vitro increase of GJ formation in melanoma and endothelial cells following dacarbazin and interferon gamma (IFN-gamma) treatment or hypoxic stress induction. Our data indicate that although connexin 43 (Cx43), the main GJ protein of the immune system, was localized at the immunological synapse between T lymphocyte and autologous melanoma cells, its over-expression or inhibition of GJs does not interfere with cytotoxic T lymphocyte (CTL) clone lytic function. In contrast, we showed that inhibition of GJs by oleamide during stimulation of resting PBMCs with Melan-A natural and analog peptides resulted in a decrease in antigen (Ag) specific CD8(+) T lymphocyte induction. These Ag specific CD8(+) cells displayed paradoxically stronger reactivity as revealed by CD107a degranulation and IFN-gamma secretion. These findings indicate that Cx43 does not affect lytic function of differentiated CTL, but reveal a major role for GJs in the regulation of antigen CD8(+)-naive T lymphocyte activation. KEY MESSAGE: GJ formation occurs in vivo between T lymphocytes and tumor cells Cx43 localized at the immunological synapse between T and autologous melanoma cells Inhibition of GJs resulted in a decrease in Ag-specific CD8(+) T lymphocyte induction A role for GJs in the regulation of antigen CD8(+)-naive T lymphocyte activation. PMID- 23744109 TI - Aicardi-Goutieres syndrome: clues from the RNase H2 knock-out mouse. AB - Ribonuclease H2 (RNase H2) belongs to the family of RNase H enzymes, which process RNA/DNA hybrids. Apart from cleaving the RNA moiety of a plain RNA/DNA hybrid, RNase H2 participates in the removal of single ribonucleotides embedded in a DNA duplex. Mutations in RNase H2 lead to the chronic inflammatory disorder Aicardi-Goutieres syndrome (AGS), which has significant phenotypic overlaps with the autoimmune disease systemic lupus erythematosus. RNase H2 knock-out mice are embryonic lethal. Mouse embryos lacking RNase H2 accumulate DNA damage and exhibit a p53-mediated growth arrest commencing at gastrulation. On a molecular level, the knock-out mice reveal that RNase H2 represents an essential DNA repair enzyme, whose main cellular function is the removal of accidentally misincorporated ribonucleotides from genomic DNA. Ribonucleotides strongly accumulate within the genomic DNA of RNase H2-deficient cells, in turn resulting in a massive build-up of DNA damage in these cells. The DNA lesions that arise from misincorporated ribonucleotides constitute the by far most frequent type of naturally occurring DNA damage. AGS-causing mutations have also been found in the genes of the 3'-exonuclease TREX1, the dNTP triphosphatase SAMHD1, as well as the RNA-editing enzyme ADAR1, defining defects in nucleic acid metabolism pathways as a common hallmark of AGS pathology. However, recent evidence gathered from RNase H2 knock-out mice might provide additional insight into the molecular mechanisms underlying AGS development and a potential role of DNA damage as a trigger of autoimmunity is discussed. PMID- 23744113 TI - Effect of blanching temperature and dipping time on drying time of broccoli. AB - Drying characteristics of broccoli was experimentally studied in cabinet-type convective dryer. Experiments were conducted using constant air velocity of 2 m/s and air temperature of 60 . Drying rate increased with increasing blanching temperature and thus reduced the drying time. The experimental drying data were used to fit twelve drying models and drying rate constants and coefficients of the models were determined by non-linear regression analysis. Estimations by the Midilli et al. model were in good agreement with the experimental data obtained. Fick's second law was used to calculate the effective moisture diffusivity, which varied from 1.987 to 3.577 * 10(-8) m(2)/s for the given blanching temperature range. The rehydration ratio was observed to increase with increasing blanching temperature. PMID- 23744114 TI - Influence of some packaging materials and of natural tocopherols on the sensory properties of breakfast cereals. AB - The combined effect of natural antioxidants and packaging materials on the quality decay of breakfast cereals during storage was evaluated. Corn flakes were produced on industrial scale, using different packages and adding natural tocopherols to the ingredients, and stored for 1 year. The samples were then submitted to sensory analysis and HS-solid phase microextraction/gas chromatography/mass spectrometry (SPME/GC/MS) analysis. The packaging had a significant influence on the sensory profile of the aged product: metallized polypropylene gave the highest levels of oxidation compounds and sensory defects. The sensory profile was improved using polypropylene and especially high-density polyethylene. Natural tocopherols reduced the sensory decay of the flakes and the oxidative evolution of the volatile profile. They gave the most remarkable improvement in polypropylene (either metallized or not) packs. Polypropylene showed a barrier effect on the scalping of volatiles outside of the pack. This led to higher levels of oxidation volatiles and faster rates of the further oxidative processes involving the volatiles. PMID- 23744115 TI - Kinetics of color development of melanoidins formed from fructose/amino acid model systems. AB - The formation of soluble melanoidins from a single combination of sugar (fructose) and amino acid model systems were evaluated kinetically. The selected amino acids, commonly found in apple juice and highly reactive in the Maillard reaction, were asparagine, aspartic acid, and glutamic acid. The effect of these reagents and the treatment at different temperatures (50 , 85 , and 100 ) during 96 h on the color intensity of the melanoidin formed was measured by absorbance at different wavelengths (280, 325, 405, and 420 nm). The absorbance of the melanoidin formed from all model systems was located on the wavelength of 405 nm, that is, the area of the visible spectrum close to the UV region. The color of the melanoidins was directly measured using the CIELAB color space system. A first-order kinetic model was applied to the evolution of the DeltaE * (color difference) and L * (lightness) of the color. The fructose/aspartic acid model system values of a * (redness) and b * (yellowness) were found in the brown-red zone. Therefore, the color development of the melanoidins was influenced by the type of amino acid and temperature. Especially, it is thought that the a * and b * values can be used to explain the differences among the amino acids in the color development of melanoidins. PMID- 23744116 TI - Ohmic pre-drying of tomato paste. AB - In this study, the effects of ohmic pre-drying technique on moisture ratio, drying rate, drying time, specific energy consumption, drying efficiency, and effective moisture diffusivity of tomato paste were investigated. Pre-drying experiments were carried out in an ohmic laboratory dryer at voltage gradient levels of 6, 8, 10, 12, 14, and 16 V/cm and oven at 105 and 1.0 m/s air velocity (control sample). Pre-drying was accomplished till the moisture content of the tomato paste reduced from initial moisture content of 90% (w.b.) to a safer level of 70% (w.b.). The ohmic pre-drying reduced the drying time of tomato paste by 80 97%, compared with the hot air drying. Pre-drying took place mainly in warming up, constant rate, and falling rate periods. Six available moisture-ratio models were fitted to the pre-drying data. The results showed that the Midilli et al. model is the most appropriate model for pre-drying behavior of tomato paste. The effective moisture diffusivity varied from 5.39 * 10(-8) to 3.91 * 10(-7)m(2)/s with an activation energy of 2.082 (V/g.cm). Both specific energy consumption and drying efficiency were considerably enhanced by increasing voltage gradient. It was found that the specific energy consumption and drying efficiency varied from 3.72 to 2.29 MJ/kg water and 67.8 to 83.8%, respectively. PMID- 23744117 TI - Relationship of dough thermomechanical properties with oil uptake, cooking and textural properties of instant fried noodles. AB - Instant noodles were prepared from fifteen diverse wheat cultivars varying widely in their flour quality and dough rheology. Dough thermomechanical parameters obtained by Mixolab and flour analytical properties were correlated with the quality of instant noodles including oil uptake, cooking quality and textural attributes. The Mixolab parameters dough development time and dough stability showed significant positive correlation with cooking time, cooked weight, overall acceptability, hardness, springiness, cohesiveness and chewiness of noodles, while negatively correlated with oil uptake and cooking loss, therefore, exhibiting a marked positive effect on quality of instant noodles. Lower protein breakdown represented by C2 torque was also positively related with overall acceptability, hardness, springiness, cohesiveness and chewiness of noodles. Stickiness/adhesiveness of noodles was revealed to be mainly conferred by falling number values (R (2 )= 0.671) and damaged starch (R (2 )= 0.523) content of wheat flour samples. Flour samples with lesser values of protein content, sodium dodecyl sulphate sedimentation volume, thermal stability of proteins, dough stability and dough development time were found to be linked with poor noodle quality. Medium strong flours performed better in noodle making, while weaker flours demonstrated poor noodle quality. Dough rheology of good noodle making flours was characterized with higher dough development time, dough stability, C2, C3, C4 as well as C5 values. Noodles with higher overall acceptability showed a more continuous and uniform protein starch matrix in comparison to the poor counterparts. PMID- 23744118 TI - Sensory characteristics and volatile composition of a cereal beverage fermented with Bifidobacterium breve NCIMB 702257. AB - Most of the commercialized lactic acid fermented products are dairy-based. Hence, the development of non-dairy fermented products with probiotic properties draws significant attention within the functional foods industry. The microorganisms used in such products have complex enzyme systems through which they generate diverse metabolites (volatile and non-volatile) that provide significant flavour attributes of importance for fermented foods. The correlation of the volatile flavour compounds of a malt beverage fermented with a Bifidobacterium breve strain with its unique sensory characteristics was performed. The volatile composition analysis exposed the presence of 12 components. Eight of these flavour volatiles were produced through the metabolic activity of the bifidobacteria strain. Notably acetic acid, of reported sour flavour characteristics, exhibited the greatest intensity. Four components of considerable organoleptic characteristics were identified as Maillard-derived products, namely maltol, pyranone, 2 (5H)-furanmethanol and 3-furanmethanol. The sensory evaluation exhibited that the fermented cereal beverage had a sour flavour with mild sweet and malty notes. These results indicate that the volatile compounds identified can be appointed as significant flavour markers of the novel fermented cereal beverage. PMID- 23744119 TI - Use of spent osmotic solutions for the production of fructooligosaccharides by Aspergillus oryzae N74. AB - In the food industry, osmotic dehydration can be an important stage to obtain partially dry foodstuffs. However, the remaining spent osmotic solution at the end of the process could become a waste with an important environmental impact due to the large amount of organic compounds that it might contain. Since one of the most important osmotic agents used in osmotic dehydration is sucrose, this spent osmotic solution could be used to be biotransformed to produce fructooligosaccharides by a fructosyltransferase. This study evaluated the production of fructooligosaccharides using the fructosyltransferase produced by Aspergillus oryzae N74, and the spent osmotic solution that resulted in the osmotic dehydration of Andes berry (Rubus glaucus) and tamarillo (Cyphomandra betacea). Assays were conducted at small and bioreactor scales, using spent osmotic solution with or without re-concentration. At small scale no significant difference (p > 0.05) was observed in the fructooligosaccharides production yield, ranging from 31.18% to 34.98% for spent osmotic solution from tamarillo osmotic dehydration, and from 33.16% to 37.52% for spent osmotic solution from Andes berry osmotic dehydration, using either the SOS with or without re concentration. At bioreactor scale the highest fructooligosaccharides yield of 58.51 +/- 1.73% was obtained with spent osmotic solution that resulted from tamarillo osmotic dehydration. With the spent osmotic solution from Andes berry osmotic dehydration the yield was 49.17 +/- 2.82%. These results showed the feasibility of producing fructooligosaccharides from spent osmotic solution that is considered a waste in food industry. PMID- 23744120 TI - Determination of the moisture sorption behavior of osmotically dehydrated mackerel fillets by means of binary and ternary solutions. AB - In this study, the moisture sorption isotherm of osmotically dehydrated mackerel fillets (Scomber japonicus) was experimentally determined. The fillets were osmotically dehydrated with solutions of salt (NaCl) (120 and 180 g per liter of solution) or in combination with sugar (350 to 700 g per liter of solution). The sorption isotherms were determined using the static gravimetric methodology with six salts for the water activity range of 0.33-0.98 at 5 degrees C and 25 degrees C. All the sorption curves were found to be type III. Temperature and the final tissue salt content had significant (p < 0.05) effects on the sorption isotherms. A regression program was used to fit the Halsey, Oswin and Smith moisture sorption isotherm models. Oswin equation gave the best fit for the whole range of water activity and temperatures. The Smith equation only presented valuable results for the mackerel fillets samples with the higher salt content. PMID- 23744121 TI - Use of whole grain and refined flour from tannin and non-tannin sorghum (Sorghum bicolor (L.) Moench) varieties in frybread. AB - Frybreads were prepared using wheat flour and wheat-sorghum composite flours (refined and whole grain; white, tannin-free and red, tannin-containing) at 0, 25, 50, and 75% sorghum flour. Hardness, volume, specific volume, color, and oil uptake were determined. Frybreads made with refined white, tannin-free sorghum were also evaluated in a sensory panel. Substitution of sorghum flour for wheat flour reduced the volume and increased the darkness of the fried dough pieces compared with wheat flour controls. Oil absorption was unaffected when using white, tannin-free sorghum. When using red, tannin-containing sorghum, oil absorption increased for refined flour and decreased for whole grain flour, suggesting that a component only present in the whole grain tannin-containing Sorghum--perhaps tannins themselves--may decrease oil uptake. Panelists rated frybreads containing up to 50% white, tannin-free sorghum flour as not significantly different from control frybreads made with refined wheat flour. PMID- 23744122 TI - Effects of nitric oxide treatment on the cell wall softening related enzymes and several hormones of papaya fruit during storage. AB - Papaya fruits (Carica papaya L. cv 'Sui you 2') harvested with < 5% yellow surface at the blossom end were fumigated with 60 microL/L of nitric oxide for 3 h and then stored at 20 degrees C with 85% relative humility for 20 days. The effects of nitric oxide treatment on ethylene production rate, the activities of cell wall softening related enzymes including polygalacturonase, pectin methyl esterase, pectate lyase and cellulase and the levels of hormones including indole acetic acid, abscisic acid, gibberellin and zeatin riboside were examined. The results showed that papaya fruits treated with nitric oxide had a significantly lower rate of ethylene production and a lesser loss of firmness during storage. A decrease in polygalacturonase, pectin methyl esterase, pectate lyase and cellulase activities was observed in nitric oxide treated fruit. In addition, the contents of indole acetic acid, abscisic acid and zeatin riboside were reduced in nitric oxide treated fruit, but no significant reduction in the level of gibberellin was found. These results indicate that nitric oxide treatment can effectively delay the softening and ripening of papaya fruit, likely via the regulation of cell wall softening related enzymes and certain hormones. PMID- 23744125 TI - Scimitar sign. PMID- 23744123 TI - Whole-body cryostimulation as an effective method of reducing low-grade inflammation in obese men. AB - This study was aimed to evaluate anti-inflammatory effect of the whole body cryostimulation in obese men. Fourteen subjects (BMI >30 kg m(-2)), divided into two subgroups according to cardiorespiratory fitness: higher (HCF) or lower (LCF), have been exposed to 10 sessions in a cryogenic chamber (-110 degrees C). Blood samples were collected before, 30 min and 24 h after the first, fifth and last cryostimulation. Coldness exposures affected blood cytokine profile; however, the response depended on subjects' fitness capacity. Concentrations of pro-inflammatory cytokines in the LCF decreased by 19, 6.8, and 7.4 % in IL-6, resistin, and visfatin, respectively. TNFalpha in the LCF dropped 4.3-fold compared to baseline, while in the HCF, changes were smaller, yet significant. Anti-inflammatory cytokine IL-10 increased in both groups. No changes in adiponectin and leptin were observed in either group. Obtained results suggest that whole body cryostimulation can be a supplementary method for obese in reducing systemic inflammation. PMID- 23744124 TI - Vitreoretinal presentation of secondary large B-cell lymphoma in patients with systemic lymphoma. AB - IMPORTANCE: Intraocular lymphomas represent a diverse group of hematologic malignant neoplasms involving different tissues within the eye. Predominant involvement of the retina and vitreous without uveal infiltration in systemic lymphoma, mimicking a primary vitreoretinal lymphoma, is extremely rare. Our study emphasizes the importance of systemic evaluation in addition to central nervous system evaluation in all patients with newly diagnosed vitreoretinal lymphoma. OBJECTIVE: To determine the incidence of secondary intraocular lymphoma presenting as vitreoretinal infiltrates without central nervous system involvement, mimicking primary vitreoretinal lymphoma in patients with systemic lymphoma. DESIGN Retrospective review of all vitreous aspiration biopsy samples acquired because malignant neoplasm was suspected clinically that were obtained at our institution from January 1, 2000, through December 31, 2010. Review included patient clinical history, radiographic study findings, cytologic and/or histologic preparations, immunophenotypic study findings, treatment, and outcomes. SETTING Mayo Clinic pathology database. PARTICIPANTS: Fifty-five patients with vitreous specimens available for review. EXPOSURES: Vitreous aspiration biopsy. MAIN OUTCOME AND MEASURE: Confirmation of the diagnosis of diffuse large B-cell lymphoma (DLBCL). RESULTS: Of the 55 patients with vitreous specimens available for review, 3 (5%) had a DLBCL infiltration in the vitreous without any central nervous system involvement as a manifestation of systemic lymphoma. All 3 patients were men, aged 54, 66, and 73 years, and had blurred vision and floaters for several weeks before undergoing diagnostic vitrectomy. Ophthalmic examinations revealed clumps of vitreous cells but no choroidal involvement. One patient had no history of lymphoma; the diagnosis of vitreoretinal lymphoma was followed by DLBCL after a lymph node biopsy. The other 2 patients had low-grade B-cell lymphoma and chronic lymphocytic leukemia for 29 and 7 months before large-cell transformation in the eye. Patients were treated with systemic chemotherapy plus intraocular injections of rituximab or methotrexate sodium. CONCLUSIONS AND RELEVANCE: Vitreoretinal symptoms of DLBCL in patients with systemic lymphoma may be more frequent than previously thought (5% in our study). Not all lymphomas with vitreoretinal involvement represent primary intraocular lymphomas; thorough ophthalmologic evaluation in patients with visual symptoms and complete staging in patients with documented ocular lymphoma are of utmost importance. PMID- 23744126 TI - Coronary and cardiac computed tomography in the emergency room: current status and future directions. AB - In the United States, chest pain is the second leading reason for patients to present to an emergency department (ED). Previously, those patients suspected to have acute coronary syndrome were monitored for 24 hours to determine the presence of serum biomarkers consistent with myocardial injury. However, more recently, imaging has been used to more efficiently triage these individuals and even discharge them directly from the ED. There are multiple cardiac imaging modalities; however, cardiac computed tomography now plays a significant role in the evaluation of patients with suspected acute coronary syndrome who present to the ED. In this review, we discuss the available state-of-the-art techniques for evaluating this cohort of patients, including clinical evaluation, serum biomarkers, and imaging options. Further, we analyze in detail evidence for the use of coronary computed tomography angiography to determine whether these patients can safely be discharged from the ED. Finally, we review some of the related future techniques that may become part of the accepted clinical management of these patients in the future. PMID- 23744128 TI - The amount of dysfunctional but viable myocardium predicts long-term survival in patients with ischemic cardiomyopathy and left ventricular dysfunction. AB - To evaluate the prognostic significance of combined myocardial perfusion SPECT and [18F]FDG PET viability scanning for the prediction of survival in patients with ischemic cardiomyopathy (iCMP) and left ventricular dysfunction. 244 patients (64.0 +/- 10.6 years, 86 % men) with iCMP and LVEF <= 45 % underwent SPECT/PET. Percent scar tissue and SPECT/PET-mismatch (%-mismatch) were calculated and correlated with event-free survival according to the type of therapy (medical therapy with/out revascularization) provided after imaging. Death from any cause was defined as the primary endpoint. Early revascularization (ER) was performed in 113/244 (46 %) patients within 32 +/- 52 days (26 bypass surgeries and 87 percutaneous coronary interventions). 65 patients died during follow-up for a median of 33 months. Kaplan-Meier analysis showed that those patients with >= 5 % mismatch not undergoing ER had significantly higher mortality than did the group with similar mismatch who did receive ER. Cox analysis identified both SPECT/PET-mismatch and the interaction of SPECT/PET mismatch with ER as independent predictors for death due to all causes. A threshold of >= 5 % SPECT/PET-mismatch predicted best which patients with iCMP and LV dysfunction would benefit from ER in terms of long-term survival. PMID- 23744129 TI - Factors associated with abnormal T-wave axis and increased QRS-T angle in type 2 diabetes. AB - Frontal plane T-wave axis and QRS-T angle are novel electrocardiographic ventricular repolarization parameters that have been scarcely evaluated in type 2 diabetes. The aim was to investigate the factors associated with these parameters of abnormal ventricular repolarization in a cross-sectional analysis of 594 patients with type 2 diabetes. Clinical, laboratory, 2D-echocardiographic, ambulatory blood pressure (BP) monitoring, aortic pulse wave velocity (PWV) and carotid ultrasonographic data were obtained. Digital 12-lead ECG was recorded, and frontal plane T-wave axis and QRS-T angle were automatically measured. T-wave axis was considered abnormal if >75 degrees or <15 degrees and QRS-T angle if >=73 degrees in men and >=67 degrees in woman. Associations were assessed by bivariate tests and multivariate logistic regressions. One hundred and four (20.9 %) patients had abnormal T-wave axis, and 84 (14 %) had increased QRS-T angle. Patients with abnormal ventricular repolarization were older and had greater prevalence of micro- and macrovascular diabetic complications than patients with normal repolarization. They had higher office and ambulatory BPs, greater prevalence of the non-dipping pattern, and greater left ventricular mass, aortic PWV and carotid intima-media thickness. On multivariate analysis, abnormal ventricular repolarization parameters were independently associated with left ventricular hypertrophy, non-dipping pattern, higher ambulatory systolic BPs, glycated hemoglobin and common carotid intima-media thickness, and with the presence of coronary artery disease. In conclusion, abnormal frontal plane T-wave axis and QRS-T angle are independently associated with several markers of pre clinical atherosclerotic disease; whether these associations represent additional cardiovascular risk in type 2 diabetes shall be confirmed in prospective studies. PMID- 23744127 TI - Imaging of early modification in cardiomyopathy: the doxorubicin-induced model. AB - Doxorubicin chemotherapy is effective and widely used to treat acute lymphoblastic leukemia. However, its effectiveness is hampered by a wide spectrum of dose-dependent cardiotoxicity including both morphological and functional changes, affecting primarily the myocardium. Non-invasive imaging techniques are used for the diagnosis and monitoring of these cardiotoxic effects. The purpose of this review is to summarize and compare the most common imaging techniques used in early detection and therapeutic monitoring of doxorubicin-induced cardiotoxicity and the suggested mechanisms of such side effects. Imaging techniques using echocardiography including conventional 2D and 3D echocardiography along with MRI sequences including Tagging, Cine, and quantitative MRI in detecting early myocardial damage are also reviewed. As there is a multitude of reported indices and imaging methods to assess particular functional alterations, we limit this review to the most relevant techniques based on their clinical application and their potential to early detection of doxorubicin-induced cardiotoxic effects. PMID- 23744130 TI - The shape of Au8: gold leaf or gold nugget? AB - The size at which nonplanar isomers of neutral, pristine gold nanoclusters become energetically favored over planar ones is still debated amongst theoreticians and experimentalists. Spectroscopy confirms planarity is preferred at sizes up to Au7, however, starting with Au8, the uncertainty remains for larger nanoclusters. Au8 computational studies have had different outcomes: the planar D4h "cloverleaf" isomer competes with the nonplanar Td, C2v and D2d "nugget" isomers for greatest energetic stability. We here examine the 2D vs. 3D preference in Au8 by presenting our own B2PLYP, MP2 and CCSD(T) calculations on these isomers: these methods afford a better treatment of long-range correlation, which is at the root of gold's characteristic aurophilicity. We then use findings from these high-accuracy computations to evaluate two less expensive DFT approaches, applicable to much larger nanoclusters: alongside the standard functional PBE, we consider M06-L (highly parametrized to incorporate long-range dispersive interactions). We find that increasing basis set size within the B2PLYP framework has a greater destabilizing effect on the nuggets than it has on the Au8 cloverleaf. Our CCSD(T) and B2PLYP predictions, replicated by DFT-PBE, all identify the cloverleaf as the most stable isomer; MP2 and DFT-M06-L show overestimation of aurophilicity, and favor, respectively, the nonplanar D2d and Td nuggets in its stead. We conclude that PBE, which more closely reproduces CCSD(T) findings, may be a better candidate density functional for the simulation of gold nanoclusters in this context. PMID- 23744131 TI - Evaluation of the total oxidant and antioxidant status of the plasma of dogs anaesthetised with isoflurane. PMID- 23744132 TI - TEMPORAL REGISTRATION OF PARTIAL DATA USING PARTICLE FILTERING. AB - We propose a particle filtering framework for rigid registration of a model image to a time-series of partially observed images. The method incorporates a model based segmentation technique in order to track the pose dynamics of an underlying observed object with time. An applicable algorithm is derived by employing the proposed framework for registration of a 3D model of an anatomical structure, which was segmented from preoperative images, to consecutive axial 2D slices of a magnetic resonance imaging (MRI) scan, which are acquired intraoperatively over time. The process is fast and robust with respect to image noise and clutter, variations of illumination, and different imaging modalities. PMID- 23744133 TI - Sticker shock. AB - A recent plea by oncologists condemning inflated prices for some cancer drugs has ignited a debate on this topic between clinicians and pharmaceutical companies and highlights the need for a broader assessment of drug valuation. PMID- 23744134 TI - Charged by GSK investment, battery of electroceuticals advance. PMID- 23744135 TI - 'Basket studies' will hold intricate data for cancer drug approvals. PMID- 23744136 TI - Heavy drugs draw heavy interest from pharma backers. PMID- 23744137 TI - Straight talk with... Tom Inglesby. Interview by Kevin Jiang. AB - When letters containing anthrax spores were mailed to several US senators and media offices in September 2001, just one week after the 9/11 attacks, bioterrorism catapulted to the national stage. Political leaders and public health officials, desperate for guidance on this once-theoretical scenario, turned to experts including Tom Inglesby, then deputy director of the Johns Hopkins Center for Civilian Biodefense Strategies, a bioterrorism research and analysis think tank in Baltimore. In the years that followed, Inglesby and his colleagues ran exercises to simulate bioterror incidents, established a peer reviewed journal on biodefense and advised government agencies on how to reduce the public health impact of biological threats.Today, he continues his work with the think tank, which moved to the University of Pittsburgh Medical Center (UPMC) in 2003 (although it stayed headquartered in Baltimore) and which was recently renamed the UPMC Center for Health Security. As director and chief executive officer for the past four years, Inglesby has expanded the center's focus toward preventing public health crises arising from infectious diseases, pandemics and major natural disasters, in addition to biological, chemical and nuclear accidents or threats. Inglesby spoke with Kevin Jiang about how responses to bioterrorism, pandemics and natural disasters aren't all that different. PMID- 23744139 TI - An updated Declaration of Helsinki will provide more protection. AB - Almost 50 years ago, the World Medical Association adopted the Declaration of Helsinki as an ethical guide for research involving human subjects. There are now proposed revisions under consideration that will provide additional protection for study participants as well as increased clarity regarding the responsibilities of those conducting the research. Making these changes is important in a complex environment where what is ethical is not always self evident. PMID- 23744141 TI - Nitric oxide quenches the fire in heart mitochondria. PMID- 23744142 TI - TGF-beta and osteoarthritis--the good and the bad. PMID- 23744143 TI - It takes nerves to recover from chemotherapy. PMID- 23744145 TI - Mast cells fuel the fire of malaria immunopathology. PMID- 23744144 TI - How the antiviral immune response boosts liver fat. PMID- 23744146 TI - Glucagon's yin and yang effects on hepatic glucose production. PMID- 23744147 TI - Tracking tumor resistance using 'liquid biopsies'. PMID- 23744148 TI - Treating the brain deep down: Brain surgery for anorexia nervosa? AB - Using brain surgery, specific areas in the brain can be stimulated with electrical impulses to reversibly change their activity and alleviate symptoms related to mental illnesses. This so-called deep brain stimulation and other methodological advances that even more selectively activate specific groups of neurons can give us clues as to what neural circuitry is involved in a particular mental disorder and whether therapeutic activation of these brain areas and neurons may be effective. In "Bedside to Bench", Eric Nestler discusses two trials of individuals with anorexia nervosa in which deep brain stimulation of different brain areas resulted in improvement of behavioral domains associated with the syndrome. The results and potential of this technique in animals and humans may bring us closer to understanding the neurobiology of anorexia nervosa, which still remains a mystery and poses a challenge for treatment. In "Bench to Bedside", Jennifer Warner-Schmidt peruses recent findings that uncover the functional connectivity of brain regions involved in depression and how activation of cortical regions can result in antidepressant effects that can compensate for the malfunction of other brain circuits that results in depression. PMID- 23744149 TI - Treating the brain deep down: Short-circuiting depression. PMID- 23744159 TI - Application of spectrometric analysis to the identification of pollution sources causing cultural heritage damage. AB - Black crusts are recognized to have been, up to now, one of the major deterioration forms affecting the built heritage in urban areas. Their formation is demonstrated to occur mainly on carbonate building materials, whose interaction with an SO2-loaded atmosphere leads to the transformation of calcium carbonate (calcite) into calcium sulfate dihydrate (gypsum) which, together with embedded carbonaceous particles, consequently forms the black crusts on the stone surface. An analytical study was carried out on black crust samples collected from limestone monumental buildings and churches belonging to the European built Heritage, i.e., the Corner Palace in Venice (Italy), the Cathedral of St. Rombouts in Mechelen (Belgium), and the Church of St. Eustache in Paris (France). For a complete characterization of the black crusts, an approach integrating different and complementary techniques was used, including laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), Fourier transform infrared spectroscopy, optical and scanning electron microscopy. In particular, the application of LA-ICP-MS permitted to obtain a complete geochemical characterization in terms of trace elements of the black crusts from the inner parts to the external layers contributing to the identification of the major combustion sources responsible for the deterioration over time of the monuments under study. In addition, the obtained results revealed a relation between the height of sampling and the concentration of heavy metals and proved that the crust composition can be a marker to evaluate the variation of the fuels used over time. PMID- 23744158 TI - Progress toward treatments for synaptic defects in autism. AB - Autism spectrum disorder (ASD) encompasses a range of disorders that are characterized by social and communication deficits and repetitive behaviors. For the majority of affected individuals, the cause of ASD remains unknown, but in at least 20% of the cases, a genetic cause can be identified. There is currently no cure for ASD; however, results from mouse models indicate that some forms of the disorder could be alleviated even at the adult stage. Genes involved in ASD seem to converge on common pathways altering synaptic homeostasis. We propose, given the clinical heterogeneity of ASD, that specific 'synaptic clinical trials' should be designed and launched with the aim of establishing whether phenotype 'reversals' could also occur in humans. PMID- 23744160 TI - Effects of copper sulfate on growth and physiological responses of Limoniastrum monopetalum. AB - A glasshouse study of the coastal shrub Limoniastrum monopetalum was carried out to evaluate its tolerance and capacity to accumulate copper. We investigate the effects of Cu from 0 to 60 mmol l(-1) on the growth, photosynthetic apparatus, and nutrient uptake of L. monopetalum, by measuring gas exchange, chlorophyll fluorescence parameters, photosynthetic pigments, and total copper, nitrogen, phosphorus, sulfur, calcium, and magnesium content in the plant tissues. Although L. monopetalum did not survive at 60 mmol l(-1) Cu, the species demonstrated a high tolerance to Cu-induced stress, since all plants survived external Cu concentrations of up to 35 mmol l(-1) and displayed similar growth in the Cu enriched medium as in the control treatment of up to the external level of 15 mmol Cu l(-1) (1,000 mg Cu l(-1)). The reduced growth registered in plants exposed to 35 mmol Cu l(-1) can be attributed to reduced photosynthetic carbon assimilation associated with the adverse effect of the metal on the photochemical apparatus and a reduction in the absorption of essential nutrients. Copper tolerance was associated with the capacity of the plant to accumulate the metal in its roots and effectively prevent its translocation to photosynthetic tissues. L. monopetalum has the characteristics of a Cu-excluder plant and could be used in the revegetation of Cu-contaminated soils. PMID- 23744161 TI - Microbial degradation characteristics and kinetics of novel pyrimidynyloxybenzoic herbicide ZJ0273 by a newly isolated Bacillus sp. CY. AB - ZJ0273 (propyl 4-(2-(4,6-demethoxy pyrimidin-2-yloxy)benzylamino)benzoate) is a novel herbicide developed in China for oilseed crop. Sixteen bacteria capable of utilizing ZJ0273 as the sole carbon source were isolated from soils. One of the isolates was designated as Bacillus sp. CY based on its physiological and biochemical characteristics and phylogenetic analysis of 16S rDNA sequences. The present study aimed to investigate the ZJ0273 degradation characteristics and kinetics by Bacillus sp. CY which has the ability to utilize ZJ0273 as the sole source of carbon and energy under aerobic conditions. The optimum biodegradation temperature, pH, and ZJ0273 initial concentration were 20-40 degrees C, 5.0-9.0, and 50-400 mg/l, respectively. Strain CY degraded 65 % of ZJ0273 (initial concentration of 50 mg/l) during 30 days of incubation in basal mineral medium at pH 8.0 and 35 degrees C. DT50 (half-life value), k (degradation rate constant of ZJ0273), and R (2) are 19.20 days, 0.0361 day(-1), and 0.9464, respectively. PMID- 23744162 TI - Growth dynamics of Chinese wingnut (Pterocarya stenoptera) seedlings and its effects on soil chemical properties under simulated water change in the Three Gorges Reservoir Region of Yangtze River. AB - Pterocarya stenoptera is a native deciduous tree species and a candidate for reforestation in the riparian zones of the Three Gorges Reservoir Region of Yangtze River in China. Water treatments of continuous flooding (CF) and periodic flooding-drought (PF) were applied to examine the growth dynamics of 4-month-old P. stenoptera seedlings and its effects on soil chemical properties. Results showed that P. stenoptera seedlings in both CF and PF significantly decreased leaf biomass accumulation and the height and diameter growth as compared to that in control (CK; treatment with well-watered, well-drained soil), respectively. There was no significant difference in stem biomass among the three groups, but root biomass in PF showed severe reduction compared to that in both CK and CF. Total biomass in PF was significantly decreased compared to that in CK, but comparable to that in CF. Furthermore, no significant difference was found between CF and CK in total biomass. Water treatments in the unplanted soil pots significantly influenced soil pH, soil organic matter (OM), total nitrogen (TN), and alkali hydrolysable nitrogen (AN) contents, in contrast to no significant effects in total phosphorus (TP), total potassium (TK), available phosphorus (AP), and available potassium (AK) contents. In P. stenoptera soils, there were significant effects by water treatment, time, and treatment * time in the eight tested soil chemical properties, except treatment in TK and time effect in OM content. Compared to unplanted soils, the growth of P. stenoptera seedlings significantly increased soil pH value and OM, TN, TP, and TK contents, while decreasing AN, AP, and AK contents in CK group, augmented the mean value of each of the tested soil chemical properties with an exception of AK content in CF group, and increased soil pH value and TN, AN, TP, and AP contents with no significant differences in OM, TK, and AK contents in PF group. Given the fact that TN and TP contents significantly increased in P. stenoptera soils as compared to those in unplanted soils, growth of P. stenoptera seedlings should be a successful candidate for restoration within the highly dynamic hydrologic zone of the riparian zones of the Three Gorges Reservoir Region. PMID- 23744163 TI - Evaluation of COPD progression based on spirometry and exercise capacity. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is characterized by an airflow limitation that is usually progressive. The progression of COPD expressed as the rate of an annual decline in FEV 1 is very heterogeneous. Exercise capacity in COPD patients is often diminished and becomes worsened over the time. The purpose of the study was to examine how the change in FEV 1 and exercise capacity would deteriorate over long-term observation. MATERIAL AND METHODS: A total of 22 men with COPD were examined. At the beginning the average age was 59 +/- 8.1 years and the mean post-bronchodilator FEV 1 was 52 +/- 14.9% predicted. Pulmonary function testing was performed at entry and then each year for 10 years, and exercise testing on a cycle ergometer was performed at entry and after 10 years. RESULTS: FEV 1 and maximum oxygen uptake (VO2max), maximum mechanical work (W max ), maximum minute ventilation (V Emax ) and maximum tidal volume (V Tmax ) declined significantly over the observation time. The mean annual decline in FEV 1 was 42 +/- 37 mL, and the mean decline for VO 2max was 30 +/- 15 mL/min/yr and 0.44 +/- 0.25 mL/min/kg/yr. Regression analysis revealed that the changes in FEV 1 do not predict changes in VO2max. We observed a correlation between the annual change in V Emax and annual change in VO2max (r = 0.51 p < 0.05). The baseline FEV 1 (expressed as a percentage of predicted and in absolute values) is the predictor of FEV 1 annual decline (r = 0.74 and 0.82; p < 0.05). CONCLUSIONS: We observed over time deterioration in exercise capacity in COPD patients which is independent of decline in airflow limitation. The long term follow-up of exercise capacity is important in monitoring of COPD patients in addition to pulmonary function. PMID- 23744164 TI - The presence of HER2 exon 20 insertion in patients with central nervous system metastases from non-small lung cancer--a potential application in classification for therapy. AB - INTRODUCTION: HER2 (ErbB2/neu) is a member of the ErbB family of four structurally related receptors of tyrosine kinase activity. Overexpression of ErbB-1 (EGFR) and HER2 is found in many human cancers, but the presence of these genes mutations determines the effectiveness of EGFR and HER2 tyrosine kinase inhibitors in the therapy of non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: To search for insertions of the HER2 gene in exon 20 in 150 brain metastases of non-small cell lung cancer patients, we used a PCR technique based on analysis of amplified DNA fragment lengths. We also compared the HER2 mutational status with clinicopathologic features and the presence of EGFR and BRAF mutations. RESULTS: HER2 mutation was present in one male, non-smoking patient with low differentiated adenocarcinoma (0.67% of all patients and 1.5% of patients with adenocarcinoma). The mutations of EGFR and BRAF genes were not found in HER2-mutated patient. CONCLUSIONS: The literature data suggests that patients with HER2 mutations may be sensitive to tyrosine kinase inhibitors of both EGFR and HER2 receptors (e.g. afatinib). Therefore, the identification of new driver mutations in NSCLC can improve the quality of patient care by enabling the use of correct molecularly targeted therapies. PMID- 23744165 TI - Identification and analysis of mutations in the katG gene in multidrug-resistant Mycobacterium tuberculosis clinical isolates. AB - INTRODUCTION: A major role in the development of resistance of Mycobacterium tuberculosis to isoniazid (INH) is attributed to mutations in the katG gene coding for the catalase/peroxidase, an enzyme required for obtaining a pharmacologically active form of the drug. Analysis of mutations in the katG gene in M. tuberculosis strains may contribute to the development of reliable and rapid tests for detection of INH resistance. The aim of the study was to identify and characterize mutations in the katG gene in multidrug-resistant M. tuberculosis clinical isolates. MATERIAL AND METHODS: The study included 46 strains of M. tuberculosis, recovered from MDR-TB patients in Poland in 2004. Mutations in the katG gene were detected by comparing DNA sequences with the corresponding sequence of a wild-type reference laboratory strain (M. tuberculosis H37Rv). The obtained results were interpreted in the context of MIC values of INH and catalase activity of the strains tested. RESULTS: A total of 43 (93%) strains contained mutations in the katG gene. The most frequently observed were mutations at codon 315, found in 34 (74%) strains. Mutations at other codons were rare: 4 strains contained mutations at codon 463, 2 at codon 131 and another 2 at codon 234. Mutations at codons 68, 91, 101, 126, 128 and 194 were found in single strains only. Two strains, for which no mutations at codon 315 of the katG gene were identified, had a unique translation termination mutation, which would invariably result in polypeptide truncation leading to the generation of dysfunctional catalase polypeptides. Both these strains presented the highest MIC values for INH (80 and 100 MUg/mL) and showed a complete loss of catalase activity. For the remaining 41 strains with katG mutations, the MICs of INH were within the range 0.2-10 MUg/mL. Thirty-six (88%) of those strains retained their catalase activity. CONCLUSIONS: Mutations at codon 315 within the katG gene, depending on their type might be useful for the prediction of INH resistance. Whereas the missense mutations do not affect the catalase activity or the level of INH resistance, the nonsense mutations result in high-level resistance to INH and a total loss of catalase activity. PMID- 23744166 TI - Association of genetic dependences between lung cancer and chronic obstructive pulmonary disease. AB - INTRODUCTION: Recent studies have shown an increased risk of lung cancer in patients with bronchial obstructive changes, including patients with COPD. It seems that there are common factors of pathogenesis of both diseases associated with oxidative stress. In the present paper the genes linked to the repair of oxidative damage of DNA, associated with cancer, of iron metabolism and coding proteolytic enzymes were assessed. MATERIAL AND METHODS: The study was conducted in two groups of patients: 53 patients with non-small cell lung cancer and chronic obstructive pulmonary disease, and 54 patients only with chronic obstructive pulmonary disease. The polymorphisms of the single nucleotide were determined in the case of the majority of genes using the PCR-RFLP method. The statistical analysis of quantitative variables was executed using the Mann Withney U-test and the test of medians; the analysis of genetic variables was executed using the chi2 test. RESULTS: Regarding the polymorphisms of genes involved in iron metabolism, statistically significant differences between the two groups have been demonstrated only in the case of haptoglobin gene HP1/2. A higher incidence of form 1/1 was found in patients with COPD and a higher incidence of form 1/2 in patients with lung cancer and COPD. Analysis of gene polymorphisms of proteolytic enzymes and inhibitors of the enzyme gene showed statistically significant differences between the two groups only for the MMP3 gene 6A/5A. In the case of the MMP12 gene polymorphism (A-82G) a tendency toward differences in the occurrence of specific alleles was identified. CONCLUSIONS: These results indicate that patients with coincidence of COPD and lung cancer have disorders of the genes involved in iron metabolism, and they have different genetic polymorphisms of proteolytic enzymes comparing to COPD patients. PMID- 23744167 TI - Incidence of alpha-1 antitrypsin Z and S alleles in patients with granulomatosis with polyangiitis--pilot study. AB - INTRODUCTION: Inherited alpha-1 antitrypsin (AAT) deficiency is one of the three most common genetic disorders in Caucasians. It considerably increases the risk of progressive obstructive lung diseases, mostly chronic obstructive pulmonary disease. It has also been suggested that AAT deficiency might be instrumental vasculitis associated with the anti-neutrophil cytoplasm antibodies (cANCA) and subsequent lung tissue injury. MATERIAL AND METHODS: We present the results from a pilot study involving 51 patients with granulomatosis with polyangiitis, formerly known as Wegener's granulomatosis (GPA), 43 of whom were cANCA positive. The control group consisted of 658 individuals. AAT blood concentration assessment by nephelometry, phenotyping by isoelectrofocusing and real-time PCR genotyping were performed. RESULTS: Deficiency alleles PI*Z and PI*S were detected in 3 (5.88%) and in 2 patients (3.92%) with GPA, respectively. All of them were cANCA positive. In the controls, PI*Z was observed in 2.8% while PI*S in 1.5% of cases. Accordingly, the increased incidence of main deficiency alleles was demonstrated in GPA, and particularly in cANCA+GPA patients, when compared to the controls. The estimated frequency for PI*Z in GPA, cANCA+GPA patients and controls was, respectively, 29.4/1000, 34.9/1000 and 13.7/1000, whereas for PI*S it was 19.2/1000, 23.2/10,00 and 7.6/1000. However, the observed differences did not reach statistical significance due to the considerable size disproportion between groups. CONSCLUSIONS: We believe that our preliminary data confirm the clinical importance of AAT deficiency in GPA patients and the need to screen for AAT deficiency alleles. The study is on-going. PMID- 23744168 TI - [Guidelines of Polish Respiratory Society concerning diagnosis, treatment and prevention of tuberculosis in adults and in child]. PMID- 23744169 TI - [Non-invasive ventilation in treatment of adults with chronic respiratory failure]. AB - Non-invasive mechanical ventilation (NIV) is a modern method of chronic respiratory failure (CRF) treatment. With the development of medicine and society known as "western", the number of elderly people, in whom there is overlapping of chronic diseases such as COPD, is growing. In adult population NIV is used in the treatment of neuromuscular diseases such as amyotrophic lateral sclerosis (ALS) or spinal muscular atrophy. The other main indications include restrictive diseases such as kyphoscoliosis, pulmonary diseases with COPD which is the primary indication, and various forms of central apnea syndrome with epidemiologically essential role of obesity hypoventilation syndrome (OHS). In each of those indications, and in different patients, the mode and ventilation intensity may significantly differ. The aim of this review is to disseminate knowledge on the potential role of NIV in adults with CRF. This paper attempts to analyze the available knowledge concerning NIV in adults with CRF. Special attention is paid to the potential pathomechanisms which should become the subject of future research. PMID- 23744170 TI - Pulmonary hypertension in chronic obstructive pulmonary disease. AB - Pulmonary hypertension (PH) is a common complication of advanced chronic obstructive pulmonary disease (COPD) and is defined by a mean pulmonary artery pressure (PAP) >= 25 mm Hg at rest in the supine position. Owing to its frequency, COPD is a common cause of PH; in fact, it is the second most frequent cause of PH, just after left heart diseases. PH is due to the elevation of pulmonary vascular resistance, which is caused by functional and morphological factors, chronic alveolar hypoxia being the most important. In COPD PH is generally mild to moderate, PAP usually ranging between 25 and 35 mm Hg in a stable state of the disease. A small proportion of COPD patients may present a severe or "disproportionate" PH with a resting PAP > 35-40 mm Hg. The prognosis is particularly poor in these patients. In COPD PH worsens during exercise, sleep and severe exacerbations of the disease, and these acute increases in afterload may favour the development of right heart failure. The diagnosis of PH relies on Doppler echocardiography, and right heart catheterization is needed in a minority of patients. Treatment of PH in COPD relies on long-term oxygen therapy (>= 16h/day) which generally stabilizes or at least attenuates the progression of PH. Vasodilator drugs, which are commonly used in idiopathic pulmonary arterial hypertension, have rarely been used in COPD, and we lack studies in this field. Patients with severe PH should be referred to a specialist PH centre where the possibility of inclusion in a controlled clinical trial should be considered. PMID- 23744171 TI - Severe Legionella pneumophila pneumonia and non-invasive ventilation: presentation of two cases and brief review of the literature. AB - Legionella pneumophila is an agent also well known to be frequently responsible for severe community acquired pneumonia. Recent studies regarding severe community-acquired pneumonia have shown that Legionella pneumophila is the second most common cause of admission to ICU, not far behind pneumococcal pneumonia. The mortality of severe Legionella pneumonia is high (30%). We report two cases of severe respiratory failure due to Legionella pneumophila type 1 treated with non invasive ventilation in the Respiratory Intermediate Care Unit of a Department of Respiratory Medicine with good outcomes. Severe community-acquired pneumonia is the most common cause of ARDS, and it is the primary reason for Intensive Care Unit admission with invasive mechanical ventilation. Delay in ICU admission is probably associated with a poorer outcome. The use of non-invasive ventilation in severe community acquired pneumonia is controversial. However, after recent pandemics, the number of studies reporting good rates of success for NIV has increased. Both our patients were managed in a respiratory intermediate care unit, avoiding invasive ventilation and invasive monitoring, which lowered costs yet was equally effective in providing a good outcome when compared to intubation in the Intensive Care Unit. PMID- 23744172 TI - [Diffuse alveolar hemorrhage as the only manifestation of antiphospholipid syndrome]. AB - The antiphospholipid syndrome is characterized by the presence of antiphospholipid antibodies and the association of protean clinical manifestations as a result of both venous and arterial thrombosis. While pulmonary embolism (secondary to deep vein thrombosis) is common and well-known disturbance in antiphospholipid syndrome, recently there are growing number of case reports describing nonthrombotic lung pathologies in APS. We present here a young male with antiphospholipid syndrome, whose the only manifestation was diffuse alveolar hemorrhage. PMID- 23744175 TI - Suggestions for the role of video laryngoscopy as a new paradigm in airway management. PMID- 23744173 TI - Incidence and risk factors of Legionella pneumophila pneumonia during anti-tumor necrosis factor therapy: a prospective French study. AB - OBJECTIVE: Our objective was to describe the incidence and risk factors of legionellosis associated with tumor necrosis factor (TNF)-alpha antagonist use. METHODS: From February 1, 2004, to January 31, 2007, we prospectively collected all cases of legionellosis among French patients receiving TNF-alpha antagonists in the Research Axed on Tolerance of Biotherapies (RATIO) national registry. We conducted an incidence study with the French population as a reference and a case control analysis with four control subjects receiving TNF-alpha antagonists per case of legionellosis. RESULTS: Twenty-seven cases of legionellosis were reported. The overall annual incidence rate of legionellosis for patients receiving TNF-alpha antagonists, adjusted for age and sex, was 46.7 (95% CI, 0.0 125.7) per 100,000 patient-years. The overall standardized incidence ratio (SIR) was 13.1 (95% CI, 9.0-19.1; P < .0001) and was higher for patients receiving infliximab (SIR, 15.3 [95% CI, 8.5-27.6; P < .0001]) or adalimumab (SIR, 37.7 [95% CI, 21.9-64.9; P < .0001]) than etanercept (SIR, 3.0 [95% CI, 1.00-9.2; P = .06]). In the case-control analysis, exposure to adalimumab (OR, 8.7 [95% CI, 2.1 35.1]) or infliximab (OR, 9.2 [95% CI, 1.9-45.4]) vs etanercept was an independent risk factor for legionellosis. CONCLUSIONS: The incidence rate of legionellosis for patients receiving TNF-alpha antagonists is high, and the risk is higher for patients receiving anti-TNF-alpha monoclonal antibodies than soluble TNF-receptor therapy. In case of pneumonia occurring during TNF-alpha antagonist therapy, specific urine antigen detection should be performed and antibiotic therapy should cover legionellosis. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00224562; URL: www.clinicaltrials.gov. PMID- 23744174 TI - Explaining variations in breast cancer screening across European countries. AB - OBJECTIVE: In this study I aim to explore the statistical causes of country differences in mammography screening among women aged 50-69 years in 13 European countries. I focus on the relative importance of individual (e.g. age, education, etc.) and institutional (e.g. public screening programmes) factors in explaining these differences. DATA AND METHODS: I use individual level data from the first three waves (2004-2006-2009) of the SHARE as well as regional and country level data on institutional factors. The analytical approach is based on multilevel statistical models, which allow me to analyse the contribution of individual and institutional factors in explaining the variation in breast cancer screening across European countries. RESULTS: I find that the standard deviation in screening rates across countries increases slightly from 19.5 to 20.8 per cent after controlling for individual factors. Observed individual factors such as age, education, health status, etc., do not significantly contribute to the explanation of cross-country differences. In contrast, after controlling for observed institutional factors such as the availability of an organised screening programme, the standard deviation drops from 20.86 to 12.92 per cent. These factors can statistically explain about 40 per cent of the between-country differences in screening rates. Moreover, I found that these institutional factors seem to prevent a woman from considering a mammogram "not necessary". CONCLUSION: This analysis provides important insights about patient's attitudes and understanding of benefits of breast cancer prevention and highlights the importance of the availability of an organised screening programme for screening differences across European countries. PMID- 23744177 TI - [Sports injuries]. PMID- 23744178 TI - [Arthrodesis versus total joint replacement of the ankle]. AB - In general, for the treatment of end-stage osteoarthritis of the ankle joint arthrodesis is considered to be the gold standard based on its versatility and eligibility for numerous indications. Nowadays, total ankle arthroplasty represents a viable alternative to ankle arthrodesis taking into account distinct premises as both procedures provide a calculable reduction of the preoperative pain level and a comparable functional gain. Furthermore, current 10-year survival rates of total ankle replacement are reported to range between 76 % and 89 %. Revision rates of up to 10 % for both techniques have been reported with manifest differences within the respective spectrum of complications. Due to the fact that more than two thirds of patients suffer from post-traumatic osteoarthritis with a relatively low average of age concomitant malalignment, soft tissue damage or instability may frequently occur. A restoration of anatomic axes and an adequate centering of the talus under the tibia appear to be crucial for the outcome as well as an adequate soft tissue balancing, in particular in total ankle replacement. Thus, the selection of the correct indication and the right choice of treatment on the basis of complete preoperative diagnostics considering necessary additive surgical measures are of paramount importance for the final outcome. PMID- 23744179 TI - Endoscopic laryngeal patterns in vagus nerve stimulation therapy for drug resistant epilepsy. AB - In 30% of patients with epilepsy seizure control cannot be achieved with medications. When medical therapy is not effective, and epilepsy surgery cannot be performed, vagus nerve stimulator (VNS) implantation is a therapeutic option. Laryngeal patterns in vagus nerve stimulation have not been extensively studied yet. The objective was to evaluate laryngeal patterns in a cohort of patients affected by drug-resistant epilepsy after implantation and activation of a vagus nerve stimulation therapy device. 14 consecutive patients underwent a systematic otolaryngologic examination between 6 months and 5 years after implantation and activation of a vagus nerve stimulation therapy device. All patients underwent fiberoptic endoscopic evaluation, which was recorded on a portable device allowing a convenient slow-motion analysis of laryngeal patterns. All recordings were blindly evaluated by two of the authors. We observed three different laryngeal patterns. Four patients showed left vocal cord palsy at the baseline and during vagus nerve stimulation; seven showed left vocal cord palsy at the baseline and left vocal cord adduction during vagus nerve stimulation; and three patients showed a symmetric pattern at the baseline and constant left vocal cord adduction during vagus nerve stimulation. These laryngeal findings are here described for the first time in the literature and can be only partially explained by existing knowledge of laryngeal muscles and vagus nerve physiology. This might represent a new starting point for studies concerning laryngeal physiology and phonation, while the vagus nerve stimulation therapy could act as a new and ethical experimental model for human laryngeal physiology. PMID- 23744180 TI - Detection of Helicobacter pylori in oropharyngeal lymphatic tissue with real-time PCR and assessment of its carcinogenic potential. AB - Helicobacter pylori (HP) is considered a major gastric pathogen with oncogenic potential. The aim of this study was to determine whether HP is present in oropharyngeal lymphoid tissue and whether oropharyngeal HP strains carry virulence factor genes known to be involved in gastric carcinogenesis. The study included 104 subjects (41 patients with tonsillar carcinoma, 38 with chronic tonsillitis and 25 with obstructive sleep apnoea syndrome--OSAS). Detection of specific serum anti-HP antibodies was performed with an ELISA. The presence of HP in tissue was determined by culture and real-time PCR. Detection of virulence factors genes was also performed. Specific antibodies were found in 78.05% of tumour cases, 34.21% of chronic tonsillitis cases, and 72.0% of OSAS cases. The presence of HP in the tissue was detected in 73.91% of tonsillar tumours, 70.0% of tonsillitis cases, and 69.23% of OSAS specimens. The results of the virulence factor gene analysis showed the majority of the s1b (52.4%) and m2 (59.5%) alleles of vacA gene and limited abundance of cagA gene (12.5%). Results confirm that HP may colonise oropharyngeal lymphoid tissue. Oropharyngeal HP colonisation was frequently found in the oropharyngeal cancer group and in patients with benign oropharyngeal diseases. A virulence factor gene analysis showed differences from the predominant strains most commonly found in the stomach. The strains obtained from the oropharynx differed primarily by the lower abundance of the cagA gene and carried the less virulent vacA gene allele combination. PMID- 23744181 TI - Operative findings of conductive hearing loss with intact tympanic membrane and normal temporal bone computed tomography. AB - Despite recent technological advances in diagnostic methods including imaging technology, it is often difficult to establish a preoperative diagnosis of conductive hearing loss (CHL) in patients with an intact tympanic membrane (TM). Especially, in patients with a normal temporal bone computed tomography (TBCT), preoperative diagnosis is more difficult. We investigated middle ear disorders encountered in patients with CHL involving an intact TM and normal TBCT. We also analyzed the surgical results with special reference to the pathology. We reviewed the medical records of 365 patients with intact TM, who underwent exploratory tympanotomy for CHL. Fifty nine patients (67 ears, eight bilateral surgeries) had a normal preoperative TBCT findings reported by neuro radiologists. Demographic data, otologic history, TM findings, preoperative imaging findings, intraoperative findings, and pre- and postoperative audiologic data were obtained and analyzed. Exploration was performed most frequently in the second and fifth decades. The most common postoperative diagnosis was stapedial fixation with non-progressive hearing loss. The most commonly performed hearing restoring procedure was stapedotomy with piston wire prosthesis insertion. Various types of hearing-restoring procedures during exploration resulted in effective hearing improvement, especially with better outcome in the ossicular chain fixation group. In patients with CHL who have intact TM and normal TBCT, we should consider an exploratory tympanotomy for exact diagnosis and hearing improvement. Information of the common operative findings from this study may help in preoperative counseling. PMID- 23744182 TI - Imaging features of pancreatic tumors in children: 13-year experience at a pediatric tertiary hospital. AB - BACKGROUND: Pancreatic tumors are rare in children, resulting in limited information regarding their frequency and imaging appearances. OBJECTIVE: To review all pancreatic tumors seen in children over a decade at a large tertiary pediatric institution and to describe multimodality imaging findings. MATERIALS AND METHODS: We conducted a retrospective review of imaging studies performed in children with pancreatic tumors between January 2000 and December 2012, analyzing imaging features on available US, CT and MR examinations. We reviewed patient charts for clinical features, management and final diagnosis. RESULTS: We included 23 children in this study. Of these, 12 had solid and papillary epithelial neoplasms (SPEN), 3 had neuroendocrine tumors, 3 had lymphoma, and 1 each had hemangioendothelioma, benign congenital cysts with adipose tissue, dendritic cell sarcoma, metastatic rhabdomyosarcoma, and lipoma. All children with SPEN were teenage girls. SPEN showed characteristic imaging features including well-defined margins with surrounding capsule, solid-cystic components and hemorrhage. CONCLUSION: Pancreatic tumors are uncommon in children. SPEN is the most common tumor and is seen predominantly in teenage girls and shows characteristic imaging features. PMID- 23744183 TI - Bilateral effect of unilateral bevacizumab injection in retinopathy of prematurity. PMID- 23744184 TI - Medical genetics and genetic counseling in Chile. AB - In the South American Republic of Chile genetic counseling is not currently recognized as an independent clinical discipline, and in general is provided by physicians with training in clinical genetics. At present only one genetic counselor and 28 clinical geneticists practice in this country of over 16 million inhabitants. Pediatric dysmorphology constitutes the primary area of practice in clinical genetics. Although the country has a universal health care system and an adequate level of health care, genetic conditions are not considered a health care priority and there is a lack of clinical and laboratory resources designated for clinical genetics services. Multiple educational, cultural and financial barriers exist to the growth and development of genetic counseling services in Chile. However, during the last 10 years increased awareness of the importance of identifying individuals at risk for inherited cancer syndromes led to growing interest in the practice of cancer genetics. PMID- 23744185 TI - Mg composition dependent band offsets of Zn(1-x)Mg(x)O/ZnO heterojunctions. AB - The valence band offsets (DeltaEV) of Zn(1-x)Mg(x)O/ZnO heterojunctions grown by plasma-assisted molecular beam epitaxy were measured by photoelectron spectroscopy. From the directly obtained DeltaEV values, the related conduction band offsets (DeltaEC) were deduced. All the Zn(1-x)Mg(x)O/ZnO heterojunctions exhibit a type-I band alignment with the DeltaEC/DeltaEV estimated to be 1.5, 1.8, 2.0 for x = 0.10, 0.15 and 0.20, respectively. The band offsets of Zn(1 x)Mg(x)O/ZnO heterojunctions depend on Mg composition. The accurate determination of energy band alignment of Zn(1-x)Mg(x)O/ZnO is helpful for designing ZnO based optoelectronic devices. PMID- 23744187 TI - Paediatric dentistry: a BDJ themed issue. PMID- 23744186 TI - Genotoxicity of hydroquinone in A549 cells. AB - Hydroquinone (HQ) is found in natural and anthropogenic sources including food, cosmetics, cigarette smoke, and industrial products. In addition to ingestion and dermal absorption, human exposure to HQ may also occur by inhaling cigarette smoke or polluted air. The adverse effects of HQ on respiratory systems have been studied, but genotoxicity HQ on human lung cells is unclear. The aim of this study was to investigate the cytotoxicity and genotoxicity of HQ in human lung alveolar epithelial cells (A549). We found that HQ induced a dose response in cell growth inhibition and DNA damage which was associated with an increase in oxidative stress. Cytotoxicity results demonstrated that HQ was most toxic after 24 h (LC50 = 33 MUM) and less toxic after 1 h exposure (LC50 = 59 MUM). Genotoxicity of HQ was measured using the Comet assay, H2AX phosphorylation, and chromosome aberration formation. Results from the comet assay revealed that DNA damage was highest during the earlier hours of exposure (1 and 6 h) and thereafter was reduced. A similar pattern was observed for H2AX phosphorylation suggesting that damage DNA may be repaired in later exposure hours. An increase in chromosomal aberration corresponded with maximal DNA damage which further confirmed the genotoxic effects of HQ. To investigate whether oxidative stress was involved in the cytotoxic and genotoxic effects of HQ, cellular glutathione and 8-Oxo-deoguanisone (8-Oxo-dG) formation were measured. A decrease in the reduced glutathione (GSH) and an increase oxidized glutathione (GSSG) was observed during the early hours of exposure which corresponded with elevated 8 Oxo-dG adducts. Together these results demonstrate that HQ exerts its cytotoxic and genotoxic effects in A549 lung cells, probably through DNA damage via oxidative stress. PMID- 23744188 TI - Perplexing ipsilateral involvement. PMID- 23744189 TI - Aggressive flossing. PMID- 23744190 TI - Quality of evidence. PMID- 23744192 TI - Slightly rose-tinted. PMID- 23744193 TI - Severe bilateral click. PMID- 23744194 TI - Leadership roles. PMID- 23744195 TI - Argument by anecdote. PMID- 23744196 TI - Overwhelming generosity. PMID- 23744207 TI - Improving oral healthcare for children--a great opportunity. AB - Changes in commissioning and contracting of NHS dental services will impact on oral healthcare delivery, providing new challenges and opportunities for children's oral healthcare. Now is the time to assess clinical networks and specialised services to understand how the oral healthcare needs of all children can be met appropriately and effectively so that when change comes it can be embraced for the better. PMID- 23744208 TI - Caries detection and diagnosis, sealants and management of the possibly carious fissure. AB - The diagnosis and management of 'stained' or possibly carious pits and fissures is a difficult clinical problem. Historically, clinicians have restoratively intervened at an early stage because of concern that caries will progress unless completely removed and a restoration placed. However, this approach is destructive of tooth tissue and in the longer term may compromise the tooth as it enters the restoration re-restoration cycle. This paper aims to update the reader on developments in sealant technology and the use of sealants in caries prevention and management with an emphasis on the options available to manage the questionable fissure. PMID- 23744209 TI - Modern approaches to caries management of the primary dentition. AB - When prevention of dental caries fails, and a child is exposed to the risk of pain and infection, the disease must be managed to reduce this risk. There is growing evidence supporting more 'biological' and fewer 'surgical' approaches to managing dental caries in primary teeth. These biological methods include partial and stepwise caries removal procedures, as well as techniques where no caries is removed. An overview of clinical trials comparing these biological methods to complete caries removal shows that they perform as well as traditional methods and have the advantage of reducing the incidence of iatrogenic pulpal exposures. The Hall Technique is one biological approach to managing caries in primary molars which involves sealing caries beneath preformed metal (stainless steel) crowns. The crown is cemented over the tooth without caries removal, tooth preparation or use of local anaesthesia. The clinical steps for the Hall Technique are straightforward but, as with all dental care provision, appropriate treatment planning for the procedure requires skill. The Hall Technique offers another method of managing early to moderately advanced, active carious lesions in primary molars, with good evidence of effectiveness and acceptability. This evidence aligns with the positive findings of other studies on biological strategies for managing caries in primary teeth. PMID- 23744214 TI - Summary of: Influence of dental care on children's oral health and wellbeing. AB - BACKGROUND: Dental problems in early childhood can have a very significant effect not only on the oral health of young children but on their quality of life and that of their families. Added to this are the long term risks they carry into the permanent dentition. AIM: To review current literature on the management of early childhood caries and its influence on wider oral and general health. RESULTS: Recent studies suggest that the risks for dental caries, periodontal disease, malocclusion and other general health problems including overweight and obesity may be increased in children who have had early childhood caries. Traditional restoration of damaged primary teeth has been shown to have only moderate outcomes depending on the techniques and materials used and the ability of children to cooperate because of age or other factors. CONCLUSIONS: More recent interesting approaches that seal enamel caries, only partially remove carious dentine or attempt to entirely seal carious dentine lesions merit not only discussion but also longer term investigation. With increasing demands on health funding, dentistry must look at how the most appropriate care can be provided to allow children to reach adulthood with healthy permanent dentitions - something that less than half the population currently achieve. PMID- 23744215 TI - Summary of: A study of factors that influence the number of visits following traumatic dental injuries. AB - OBJECTIVE: To investigate in children the factors that influence the number of visits per tooth following traumatic dental injuries (TDI) to the permanent dentition. METHOD: A retrospective convenient sample of 100 children who had been treated for TDI at Leeds Dental Institute was identified. A multilevel negative binomial regression model was developed to identify factors influencing the number of visits per tooth. Data including age, gender, postcode, number of visits, treatment provided, number of teeth injured, type of periodontal and hard tissue diagnoses, healing modality, root maturity, pulp and tooth survival, and any history of previous or subsequent trauma to same tooth were analysed using SPSS 18.0 and MLWIN. RESULTS: 186 teeth were affected by trauma in 100 patients. Median total number of visits per tooth was six visits with a range of 1-22 visits. The factors that were found to influence number of visits included: distance travelled, hard tissue diagnosis, periodontal injury diagnosis and pulp survival (P < 0.05). A mile increase in distance travelled from home to clinic led to a 1.2% reduction in the number of visits per month (-0.012; SE 0.005), a diagnosis of a severe hard tissue injury was associated with 44% increase (0.362; SE 0.105) compared to no hard tissue injury, a diagnosis of a complicated periodontal injury compared to no periodontal injury was associated with a 30% increase (0.260; SE 0.124), a diagnosis of a uncomplicated periodontal injury compared to no periodontal injury was associated with a 31% increase (0.271; SE 0.124) and a diagnosis and treatment for a non-vital tooth in comparison to a vital tooth led to a 26% increase (0.230; SE 0.080) in the number of visits. There was a significant variation in the number of treatment visits at patient level (0.260; SE 0.048). CONCLUSION Complicated hard tissue injuries, complicated and uncomplicated periodontal injuries, diagnosis and treatment for pulp necrosis and the distance between clinic and patient's home all significantly influenced the number of visits needed to treat TDI. PMID- 23744216 TI - Evaluation of a pilot peer observation of teaching scheme for chair-side tutors at Glasgow University Dental School. AB - AIM: To introduce and examine a pilot peer observation of teaching (POT) scheme within the Department of Paediatric Dentistry at Glasgow Dental School and its associated outreach centres. METHODS: All tutors teaching paediatric dentistry were invited to be involved in evaluation of the POT scheme. Participants were randomly paired with a peer, who then observed their teaching and provided constructive feedback. For those consenting to be involved in the evaluation of the scheme, semi-structured, one-to-one interviews were carried out by the principal investigator. RESULTS: POT was found by all participants to be a beneficial process, reassuring those of their teaching styles and giving them ideas to adapt their teaching. CONCLUSION: POT is an effective method for engaging chair-side tutors in the reflection and development of their teaching practice via observations and scholarly discussion. PMID- 23744217 TI - Involving children in research, audit and service evaluation. PMID- 23744218 TI - Achieving good oral health in children: the importance of a current, relevant and unbiased evidence base in paediatric dentistry. AB - The Cochrane Collaboration was founded in 1993 as an international, non-profit and independent organisation dedicated to making up-to-date, accurate and reliable information about healthcare readily available. This paper discusses how the Cochrane Oral Health Group reviews have contributed to the oral health evidence base used in the development of many international and U.K. dental guidance documents, particularly in the field of paediatric dentistry. PMID- 23744219 TI - Fluoride balance in infants and young children in the U.K. and its clinical relevance for the dental team. AB - This paper provides an overview of the main sources of fluoride (F) in children and discusses the importance of assessing F exposure at an individual and community level. It describes some of the methods used to assess F exposure by estimating F intake and excretion, together with the development and use of biomarkers for F and their importance. The paper focuses on what recent F research has shown in terms of significant sources of dietary F intake in U.K. infants and young children and the proportion of F intake that derives from F ingestion of toothpaste. This information is considered in the context of clinical dental practice and the implications of this research for oral health discussed. PMID- 23744240 TI - Influence of dental care on children's oral health and wellbeing. AB - BACKGROUND: Dental problems in early childhood can have a very significant effect not only on the oral health of young children but on their quality of life and that of their families. Added to this are the long term risks they carry into the permanent dentition. AIM: To review current literature on the management of early childhood caries and its influence on wider oral and general health. RESULTS: Recent studies suggest that the risks for dental caries, periodontal disease, malocclusion and other general health problems including overweight and obesity may be increased in children who have had early childhood caries. Traditional restoration of damaged primary teeth has been shown to have only moderate outcomes depending on the techniques and materials used and the ability of children to cooperate because of age or other factors. CONCLUSIONS: More recent interesting approaches that seal enamel caries, only partially remove carious dentine or attempt to entirely seal carious dentine lesions merit not only discussion but also longer term investigation. With increasing demands on health funding, dentistry must look at how the most appropriate care can be provided to allow children to reach adulthood with healthy permanent dentitions - something that less than half the population currently achieve. PMID- 23744241 TI - A study of factors that influence the number of visits following traumatic dental injuries. AB - OBJECTIVE: To investigate in children the factors that influence the number of visits per tooth following traumatic dental injuries (TDI) to the permanent dentition. METHOD: A retrospective convenient sample of 100 children who had been treated for TDI at Leeds Dental Institute was identified. A multilevel negative binomial regression model was developed to identify factors influencing the number of visits per tooth. Data including age, gender, postcode, number of visits, treatment provided, number of teeth injured, type of periodontal and hard tissue diagnoses, healing modality, root maturity, pulp and tooth survival, and any history of previous or subsequent trauma to same tooth were analysed using SPSS 18.0 and MLWIN. RESULTS: 186 teeth were affected by trauma in 100 patients. Median total number of visits per tooth was six visits with a range of 1-22 visits. The factors that were found to influence number of visits included: distance travelled, hard tissue diagnosis, periodontal injury diagnosis and pulp survival (P < 0.05). A mile increase in distance travelled from home to clinic led to a 1.2% reduction in the number of visits per month (-0.012; SE 0.005), a diagnosis of a severe hard tissue injury was associated with 44% increase (0.362; SE 0.105) compared to no hard tissue injury, a diagnosis of a complicated periodontal injury compared to no periodontal injury was associated with a 30% increase (0.260; SE 0.124), a diagnosis of a uncomplicated periodontal injury compared to no periodontal injury was associated with a 31% increase (0.271; SE 0.124) and a diagnosis and treatment for a non-vital tooth in comparison to a vital tooth led to a 26% increase (0.230; SE 0.080) in the number of visits. There was a significant variation in the number of treatment visits at patient level (0.260; SE 0.048). CONCLUSION: Complicated hard tissue injuries, complicated and uncomplicated periodontal injuries, diagnosis and treatment for pulp necrosis and the distance between clinic and patient's home all significantly influenced the number of visits needed to treat TDI. PMID- 23744242 TI - Mitral valve repair for Staphylococcus lugdunensis infective endocarditis: report of a case. AB - A 55-year-old male with an intermittent high-grade fever was diagnosed with infective endocarditis. He was indicated for surgery because periodic echocardiography revealed worsening mitral regurgitation and growing vegetation despite medication. An aneurysm of the P2 portion and all vegetations were removed via quadrangular resection of the P2 leaflet, and then the defect was repaired. An intraoperative assessment identified Staphylococcus lugdunensis as the causative bacterium. After postoperative antibiotic therapy for 5 weeks, the patient was discharged without either mitral regurgitation or signs of infection. Infective endocarditis caused by aggressive and destructive S. lugdunensis should be promptly and accurately treated via a surgical approach that prevents progressive tissue destruction and simplifies the surgical procedure for repair, rather than replacement. PMID- 23744243 TI - The interplay between carbon nanomaterials and amyloid fibrils in bio nanotechnology. AB - Recent advances in bio-nanotechnology have not only rapidly broadened the applications and scope of hybrid nanomaterials in biological fields, but also greatly enriched the examples of ordered materials based on supramolecular self assembly. Among eminent examples of functional nanostructured materials of undisputed impact in nanotechnology and biological environments, carbon nanomaterials (such as fullerenes, carbon nanotubes and graphene) and amyloid fibrils have attracted great attention because of their unique architectures and exceptional physical properties. Nonetheless, combination of these two classes of nanomaterials into functional hybrids is far from trivial. For example, the presence of carbon nanomaterials can offer either an inhibitory effect or promotion of amyloid fibrillation, depending on the structural architectures of carbon nanomaterials and the starting amyloid proteins/peptides considered. To date, numerous studies have been devoted to evaluating both the biological toxicity of carbon nanomaterials and their use in developing therapies for amyloidosis. At the same time, hybridization of these two classes of nanomaterials offers new possibilities for combining some of their desirable properties into nanocomposites of possible use in electronics, actuators, sensing, biomedicine and structural materials. This review describes recent developments in the hybridization of carbon nanomaterials and amyloid fibrils and discusses the current state of the art on the application of carbon nanomaterial amyloid fibril hybrids in bio-nanotechnology. PMID- 23744244 TI - [Hand-foot syndrome with tyrosine kinase inhibitor therapy: treatment recommendations]. AB - A significant component of advanced renal cell carcinoma therapy is treatment with tyrosine kinase inhibitors. Hand-foot syndrome is a frequent adverse reaction and the quality of life of patients can be considerably affected depending on the severity. Effective treatment options are, therefore, essential and standardization of treatment recommendations is desirable. In this article practical and standardized recommendations for the treatment of outpatients with hand-foot syndrome are introduced and several strategies for prophylaxis and therapy are discussed. PMID- 23744245 TI - [Cognitive decline in Alzheimer's disease. A follow three or more years of a sample of patients]. AB - INTRODUCTION: The rates of cognitive decline in patients with Alzheimer's disease show variations due to various factors. AIM. To determine the influence of age, education, gender, activities of daily living (ADL) and acetylcholinesterase inhibitors (IAChE) and memantine in the rhythm and rate of cognitive decline. PATIENTS AND METHODS: Retrospective study of a sample of 383 patients with Alzheimer's disease, with neuropsychological assessments over three years. Cognitive measure was used as the Cambridge Cognitive Examination (CAMCOG). Patients were grouped according to their rate of annual decline (RAD) and performed a bivariate and multivariate regression analysis using as dependent variable the difference in scores on the CAMCOG (baseline-final). RESULTS: The younger age (beta = -0.23; p < 0.001), more educated (beta = 0.26; p < 0.001) and the greater deterioration of ADL (beta = 0.24; p < 0.001) were associated with a greater decline in all patients. The drugs had a beneficial effect (beta = -0.18; p = 0.011) in the group with lower and slower decline (RAD < 5%). CONCLUSIONS: The lower age, higher education and the deterioration of ADL are associated with a greater cognitive decline. The IAChE and memantine had a beneficial effect, slowing the decline in the group of patients with lower RAD. PMID- 23744246 TI - [Home-based rehabilitation in the functional recovery of patients with cerebrovascular disease]. AB - INTRODUCTION: The study of the effectiveness of rehabilitation treatment applied to patients with sequelae following a cerebrovascular disease (CVD) plays a decisive role nowadays in planning their management in public healthcare and to improve existing guidelines regarding assessment and treatment. AIM: To describe the characteristics presented by patients who have suffered a CVD and were treated in mobile rehabilitation-physiotherapy units (MRPU) and how such treatment affects their functional recovery. PATIENTS AND METHODS: Descriptive, prospective study conducted on 124 patients referred to the MRPUs in the province of Almeria between 2008 and 2011. The variables analysed (both pre- and post treatment) included personal history and characteristics, Barthel index, Modified Ashworth Spasticity Scale, pain (shoulder) and the Canadian Neurological Scale. RESULTS: The final sample consisted of 106 participants (mean age: 73.72 years). The disabling process was ischaemic in 77.4% and hypertension was the most prevalent risk factor (81%). The mean initial Barthel index was 31.04 and the mean final index was 57.62 (t = -11.75; p < 0.001). The Canadian Neurological Scale showed a favourable progression in the level of consciousness, orientation and language (p < 0.001). Altogether 56.2% of the patients were discharged as a result of the improvement of their condition, and did not require any further outpatient rehabilitation. CONCLUSIONS: The results obtained reflect an important functional improvement in patients treated in the MRPUs. Home-based rehabilitation is considered a necessary tool for persons with greater clinical vulnerability and no access to outpatient care, which provides them with the benefits of effective treatment. PMID- 23744247 TI - [Mental illness, personality traits and quality of life in epilepsy: control study of patients with juvenile myoclonic epilepsy and other epilepsies]. AB - INTRODUCTION: The association of epilepsy with mental illness is described for years. Current is trying to relate certain epilepsies, such as juvenile myoclonic epilepsy (JME) with certain personality traits marked by emotional instability. SUBJECTS AND METHODS: We study a group of patients with JME and his mental state, with emphasis on the personality traits, presence of clinical anxiety or depression and quality of life, with other epilepsy patients versus a control group. RESULTS: Patients with epilepsy have more marked personality traits and symptoms of anxiety and depression, making a more negative assessment of their quality of life than the control group. Patients with others epilepsy have a higher other personality disorder and a poorer perception of their quality of life than patients with JME. CONCLUSIONS: Differences are obtained among patients with epilepsy and control groups in all the variables analyzed (personality, anxiety, depression and quality of life). JME patients have better scores on personality and quality of life than those in the other group of epilepsies. PMID- 23744248 TI - [MCT8-specific thyroid hormone cell transporter deficiency: a case report and review of the literature]. AB - INTRODUCTION: MCT8 is a specific transporter for the T4 and T3 thyroid hormones that allows their entry in the brain and other organs. Mutations in MCT8 (Allan Herndon-Dudley syndrome) lead to a severe form of X-linked psychomotor retardation, which is characterised by elevated plasma T3 and low T4. AIM: We describe the first case diagnosed in Spain with this syndrome and review the published literature about this topic. We both review the various clinical presentations, genetic advances, differential diagnosis and therapeutic perspectives of this syndrome and propose a diagnostic algorithm for it. CASE REPORT: A 5 year-old boy, with a clinical picture compatible with Pelizaeus Merzbacher disease. PLP1 gene sequencing showed no abnormalities. All the genetic and metabolic studies conducted were normal. Finally, a complete study of thyroid profile revealed abnormalities that were consistent with MCT8 transporter deficiency. The sequencing of the SLC16A2 gene (MCT8) showed a mutation in exon 3 and the study made at a cellular level, has confirmed that this mutation changes the properties of the protein. CONCLUSIONS: In the last five years, there have been many publications about this syndrome, with the identification of more than 50 families worldwide. It is important to both know and suspect this syndrome, because the diagnosis is easy, cheap and accessible (thyroid profile) and, although it has no specific treatment, early diagnosis prevents unnecessary testing and allows to offer genetic counseling to the families affected by it. PMID- 23744249 TI - [Brainstem auditory evoked potentials and somatosensory evoked potentials in Chiari malformation]. AB - INTRODUCTION: Chiari malformations (CM) include a series of congenital anomalies involving the descent of the cerebellar tonsils below the foramen magnum, which may be associated with compression in the brainstem, upper spinal cord, and cranial nerves, consequently altering the responses of brainstem auditory evoked potentials (BAEP) and somatosensory evoked potentials (SSEP). However, only a small number of authors have described the indications of these tests in CM, and study groups to date have been small and heterogeneous. AIM: To review the results of BAEPs and SSEPs in published studies of patients with Chiari type 1 malformation (CM-1) or Chiari type 2 malformation (CM-2) as well as the indications of both tests in the diagnosis, treatment, and monitoring of both diseases, especially CM-1. DEVELOPMENT: We present a review article analyzing data from all published studies in Medline starting in 1966, located through PubMed, using combinations of the following keywords: 'Chiari malformation', 'Arnold-Chiari malformation', 'Chiari type 1 malformation', 'Arnold-Chiari type 1 malformation', 'evoked potentials', 'brainstem auditory evoked potentials' and 'somatosensory evoked potentials' as well as records of patients with CM-1 from the neurosurgery and neurophysiology departments at the Hospital Universitari Vall d'Hebron. CONCLUSIONS: Common findings of SSEP are a reduction in cortical amplitude from the posterior tibial nerve, a reduction or absence of cervical median nerve potential, and an increased N13-N20 interval. In BAEP, the most frequent findings are an increased I-V interval and a peripheral or cochlear auditory disturbance. PMID- 23744251 TI - [Adhesive arachnoiditis and dorsal syringomyelia secondary to subarachnoid haemorrhage]. PMID- 23744252 TI - Application of a quantitative 1H-NMR method for the determination of amygdalin in Persicae semen, Armeniacae semen, and Mume fructus. AB - A quantitative (1)H-NMR method (qHNMR) was used to measure the amygdalin content of Persicae semen, Armeniacae semen, and Mume fructus, in each of which amygdalin constitutes a major component. The purity of amygdalin was calculated from the ratio of the intensity of the amygdalin H-2 signal at delta 6.50 ppm in pyridine d 5 to that of the hexamethyldisilane (HMD) signal at 0 ppm. The HMD concentration was corrected by the International System of Units (SI) traceability with certified reference material (CRM)-grade bisphenol A. qHNMR revealed the amygdalin contents to be 2.72 and 3.13% in 2 lots of Persicae semen, 3.62 and 5.19% in 2 lots of Armeniacae semen, and 0.23% in Mume fructus. Thus, we demonstrated the utility of this method for the quantitative analysis of crude drugs. PMID- 23744254 TI - Neovascular glaucoma treatment with extraction of anterior chamber fibrovascular tissue. AB - The use of antibody to vascular endothelial growth factor to treat neovascular glaucoma yields good anatomic results in most cases. However, this type of glaucoma can cause angle closure with decompensation of intraocular pressure secondary to fibrovascular tissue contraction in the anterior chamber. Our surgical technique treats the cause by removing the anterior chamber fibrous complex after administration of antibody to vascular endothelial growth factor, thus restoring the chamber angle. PMID- 23744253 TI - Involvement of NF kappa B in potentiated effect of Mn-containing dithiocarbamates on MPP(+) induced cell death. AB - Humans are exposed to various chemical mixtures daily. The toxic response to a mixture of chemicals could be potentiated or suppressed. This study demonstrates that non-toxic doses of pesticides can induce cellular changes that increase cell sensitivity to other toxins or stress. Pesticide exposure is an environmental risk factor for Parkinson's disease. Manganese (Mn) is essential but high dose exposure may results in neurological dysfunction. Mn-containing dithiocarbamates, maneb (MB) and mancozeb (MZ), are primarily used as pesticides. Studies have shown that MB can augment dopaminergic damage triggered by sub-toxic doses of Parkinsonian mimetic MPTP. However, the mechanism underlying this effect is not clear. Activation of nuclear factor kappa B (NF-kappaB) has been implicated in MPTP toxicity. Mn stimulates the activation of NF-kappaB and subsequently induces neuronal injury via an NF-kappaB dependent mechanism. We speculate that MB and MZ enhance MPTP active metabolite (methyl-4-phenylpyridine ion, MPP(+)) toxicity by activating NF-kappaB. The activation of NF-kappaB was observed using Western blot analysis and NF-kappaB response element driven Luciferase reporter assay. Western blot data demonstrated the nuclear translocation of NF-kappaB p65 and the degradation of IkBalpha after MB and MZ 4-h treatments. Results of NF-kappaB response element luciferase reporter assay confirmed that MB and MZ activated NF kappaB. The NF-kappaB inhibitor (SN50) was also shown to alleviate cytotoxicity induced by co-treatment of MB or MZ and MPP(+). This study demonstrates that activation of NF-kappaB is responsible for the potentiated toxic effect of MB and MZ on MPP(+) induced cytotoxicity. PMID- 23744256 TI - Abstract art by shape classification. AB - This paper shows that classifying shapes is a tool useful in nonphotorealistic rendering (NPR) from photographs. Our classifier inputs regions from an image segmentation hierarchy and outputs the "best" fitting simple shape such as a circle, square, or triangle. Other approaches to NPR have recognized the benefits of segmentation, but none have classified the shape of segments. By doing so, we can create artwork of a more abstract nature, emulating the style of modern artists such as Matisse and other artists who favored shape simplification in their artwork. The classifier chooses the shape that "best" represents the region. Since the classifier is trained by a user, the "best shape" has a subjective quality that can over-ride measurements such as minimum error and more importantly captures user preferences. Once trained, the system is fully automatic, although simple user interaction is also possible to allow for differences in individual tastes. A gallery of results shows how this classifier contributes to NPR from images by producing abstract artwork. PMID- 23744257 TI - Advanced interactive preintegrated volume rendering with a power series. AB - Preintegrated volume rendering produces high-quality renderings without increased sampling rates. However, a look-up table of a conventional preintegrated volume rendering requires a dimensionality of two, which disturbs interactive renderings when the transfer function is changed. Furthermore, as the resolution of the volume data set increases, the memory space required is impractical or inefficient, especially on GPUs. In the past, several approximation methods have been proposed to reduce the complexity of both the time and memory requirement, but most of them do not correctly present thin opaque structures within slabs and ignore the self-attenuation. We propose an advanced interactive preintegrated volume rendering algorithm that achieves not only high-quality renderings comparable to the conventional ones, but also $(O(n))$ time and memory space requirements even with the self-attenuation within the slabs applied. The algorithm proposed in this paper decomposes the exponential term of the ray integration equation into a power series of a finite order in the form of a linear combination to build a one-dimensional look-up table. Moreover, the proposed algorithm effectively applies the self-attenuation that is caused by fully opaque isosurfaces, by introducing an opaque prediction table. Experimental results demonstrate that the proposed algorithm offers renderings visibly identical to existing preintegrated volume renderings without degrading rendering speed. PMID- 23744255 TI - Effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline on the protective action of various antiepileptic drugs in the maximal electroshock-induced seizure model: a type II isobolographic analysis. AB - The aim of this study was to characterize the interaction between 1-methyl 1,2,3,4-tetrahydroisoquinoline (1-MeTHIQ-an endogenous parkinsonism-preventing substance) and various antiepileptic drugs [AEDs: clonazepam (CZP), ethosuximide (ETS), gabapentin (GBP), levetiracetam (LEV), tiagabine (TGB) and vigabatrin (VGB)] in the mouse maximal electroshock (MES)-induced seizure model. Results indicate that 1-MeTHIQ in combination with CZP (at the fixed ratios of 50:1 and 25:1), ETS (1:10) and GBP (1:1, 1:2, 1:5 and 1:10) exerted supra-additive (synergistic) interactions in the mouse MES model. In contrast, 1-MeTHIQ in combination with CZP (200:1 and 100:1), ETS (1:1, 1:2 and 1:5), LEV and VGB (1:1, 1:2, 1:5 and 1:10), and TGB (200:1, 100:1, 50:1 and 25:1) produced additive interaction in the mouse MES model. Total brain AED concentrations were unaffected by 1-MeTHIQ, and inversely, CZP, ETS and GBP had no impact on total brain concentrations of 1-MeTHIQ, indicating pharmacodynamic nature of synergistic interactions between 1-MeTHIQ and the tested AEDs in the mouse MES model. In conclusion, the supra-additive interactions of 1-MeTHIQ with CZP (at the fixed ratios of 50:1 and 25:1), ETS (1:10) and GBP (1:1, 1:2, 1:5 and 1:10) in the mouse MES model appear to be particularly favorable combinations from a clinical viewpoint. The additive combinations of 1-MeTHIQ with CZP (100:1, 50:1), ETS (1:1, 1:2 and 1:5), LEV and VGB (1:1, 1:2, 1:5, and 1:10), and TGB (200:1, 100:1, 50:1 and 25:1) seem to be neutral and worthy of consideration in further clinical practice. PMID- 23744258 TI - A local model of light interaction with transparent crystalline media. AB - The paper is devoted to the derivation of a bidirectional distribution function for crystals, which specifies all outgoing rays for a ray coming to the boundary of two transparent crystalline media with different optical properties, i.e., a particular mineral, directions of optical axes if they exist, and other features. A local model of interaction based on the notion of polarized light ray is introduced, which is specified by a geometric ray, its polarization state, light intensity, and so on. The computational algorithm that is suggested allows computing the directions and other properties of all (up to four) outgoing rays. In this paper, isotropic, uniaxial, and biaxial crystals are processed in a similar manner. The correctness of the model is validated by comparison of photos of real uniaxial crystals with corresponding computed images. The case of biaxial crystals is validated by testing the effect of conical refraction. Specifications of a series of tests devoted to rendering of optically different objects is presented also. PMID- 23744259 TI - Changing perspective in stereoscopic images. AB - Traditional image editing techniques cannot be directly used to edit stereoscopic ("3D") media, as extra constraints are needed to ensure consistent changes are made to both left and right images. Here, we consider manipulating perspective in stereoscopic pairs. A straightforward approach based on depth recovery is unsatisfactory: Instead, we use feature correspondences between stereoscopic image pairs. Given a new, user-specified perspective, we determine correspondence constraints under this perspective and optimize a 2D warp for each image that preserves straight lines and guarantees proper stereopsis relative to the new camera. Experiments verify that our method generates new stereoscopic views that correspond well to expected projections, for a wide range of specified perspective. Various advanced camera effects, such as dolly zoom and wide angle effects, can also be readily generated for stereoscopic image pairs using our method. PMID- 23744260 TI - Choking loops on surfaces. AB - We present a method for computing "choking" loops--a set of surface loops that describe the narrowing of the volumes inside/outside of the surface and extend the notion of surface homology and homotopy loops. The intuition behind their definition is that a choking loop represents the region where an offset of the original surface would get pinched. Our generalized loops naturally include the usual 2g handles/tunnels computed based on the topology of the genus-g surface, but also include loops that identify chokepoints or bottlenecks, i.e., boundaries of small membranes separating the inside or outside volume of the surface into disconnected regions. Our definition is based on persistent homology theory, which gives a measure to topological structures, thus providing resilience to noise and a well-defined way to determine topological feature size. More precisely, the persistence computed here is based on the lower star filtration of the interior or exterior 3D domain with the distance field to the surface being the associated 3D Morse function. PMID- 23744261 TI - Memory-efficient single-pass GPU rendering of multifragment effects. AB - Rendering multifragment effects using graphics processing units (GPUs) is attractive for high speed. However, the efficiency is seriously compromised, because ordering fragments on GPUs is not easy and the GPU's memory may not be large enough to store the whole scene geometry. Hitherto, existing methods have been unsuitable for large models or have required many passes for data transmission from CPU to GPU, resulting in a bottleneck for speedup. This paper presents a stream method for accurate rendering of multifragment effects. It decomposes the model into parts and manages these in an efficient manner, guaranteeing that the parts can easily be ordered with respect to any viewpoint, and that each part can be rendered correctly on the GPU. Thus, we can transmit the model data part by part, and once a part has been loaded onto the GPU, we immediately render it and composite its result with the results of the processed parts. In this way, we need only a single pass for data access with a very low bounded memory requirement. Moreover, we treat parts in packs for further acceleration. Results show that our method is much faster than existing methods and can easily handle large models of any size. PMID- 23744262 TI - Real-time volume rendering in dynamic lighting environments using precomputed photon mapping. AB - We present a framework for precomputed volume radiance transfer that achieves real-time rendering of global illumination effects for volume data sets such as multiple scattering, volumetric shadows, and so on. Our approach incorporates the volumetric photon mapping method into the classical precomputed radiance transfer pipeline. We contribute several techniques for light approximation, radiance transfer precomputation, and real-time radiance estimation, which are essential to make the approach practical and to achieve high frame rates. For light approximation, we propose a new discrete spherical function that has better performance for construction and evaluation when compared with existing rotational invariant spherical functions such as spherical harmonics and spherical radial basis functions. In addition, we present a fast splatting-based radiance transfer precomputation method and an early evaluation technique for real-time radiance estimation in the clustered principal component analysis space. Our techniques are validated through comprehensive evaluations and rendering tests. We also apply our rendering approach to volume visualization. PMID- 23744263 TI - Representing flow patterns by using streamlines with glyphs. AB - Most professional wind visualizations show wind speed and direction using a glyph called a wind barb in a grid pattern. Research into flow visualization has suggested that streamlines better represent flow patterns but these methods lack a key property-unlike the wind barb, they do not accurately convey the wind speed. With the goal of improving the perception of wind patterns, and at least equaling the quantitative quality of wind barbs, we designed two variations on the wind barb and designed a new quantitative glyph. All of our new designs space glyph elements along equally spaced streamlines. To evaluate these designs, we used a North American mesoscale forecast model. We tested the ability of subjects to determine direction and speed using two different densities each of three new designs as well as the classic wind barb. A second experiment evaluated how effectively each of the designs represented wind patterns. The results showed that the new design is superior to the classic, but they also showed that the classic barb can be redesigned and substantially improved. We suggest that flow patterns with integrated glyphs may have widespread application in flow visualization. PMID- 23744264 TI - Similarity measures for enhancing interactive streamline seeding. AB - Streamline seeding rakes are widely used in vector field visualization. We present new approaches for calculating similarity between integral curves (streamlines and pathlines). While others have used similarity distance measures, the computational expense involved with existing techniques is relatively high due to the vast number of euclidean distance tests, restricting interactivity and their use for streamline seeding rakes. We introduce the novel idea of computing streamline signatures based on a set of curve-based attributes. A signature produces a compact representation for describing a streamline. Similarity comparisons are performed by using a popular statistical measure on the derived signatures. We demonstrate that this novel scheme, including a hierarchical variant, produces good clustering results and is computed over two orders of magnitude faster than previous methods. Similarity-based clustering enables filtering of the streamlines to provide a nonuniform seeding distribution along the seeding object. We show that this method preserves the overall flow behavior while using only a small subset of the original streamline set. We apply focus + context rendering using the clusters which allows for faster and easier analysis in cases of high visual complexity and occlusion. The method provides a high level of interactivity and allows the user to easily fine tune the clustering results at runtime while avoiding any time-consuming recomputation. Our method maintains interactive rates even when hundreds of streamlines are used. PMID- 23744265 TI - Spatially and temporally optimized video stabilization. AB - Properly handling parallax is important for video stabilization. Existing methods that achieve the aim require either 3D reconstruction or long feature trajectories to enforce the subspace or epipolar geometry constraints. In this paper, we present a robust and efficient technique that works on general videos. It achieves high-quality camera motion on videos where 3D reconstruction is difficult or long feature trajectories are not available. We represent each trajectory as a Bezier curve and maintain the spatial relations between trajectories by preserving the original offsets of neighboring curves. Our technique formulates stabilization as a spatial-temporal optimization problem that finds smooth feature trajectories and avoids visual distortion. The Bezier representation enables strong smoothness of each feature trajectory and reduces the number of variables in the optimization problem. We also stabilize videos in a streaming fashion to achieve scalability. The experiments show that our technique achieves high-quality camera motion on a variety of challenging videos that are difficult for existing methods. PMID- 23744266 TI - Stack zooming for multifocus interaction in skewed-aspect visual spaces. AB - Many 2D visual spaces have a virtually one-dimensional nature with very high aspect ratio between the dimensions: examples include time-series data, multimedia data such as sound or video, text documents, and bipartite graphs. Common among these is that the space can become very large, e.g., temperature measurements could span a long time period, surveillance video could cover entire days or weeks, and documents can have thousands of pages. Many analysis tasks for such spaces require several foci while retaining context and distance awareness. In this extended version of our IEEE PacificVis 2010 paper, we introduce a method for supporting this kind of multifocus interaction that we call stack zooming. The approach is based on building hierarchies of 1D strips stacked on top of each other, where each subsequent stack represents a higher zoom level, and sibling strips represent branches in the exploration. Correlation graphics show the relation between stacks and strips of different levels, providing context and distance awareness for the foci. The zoom hierarchies can also be used as graphical histories and for communicating insights to stakeholders and can be further extended with annotation and integrated statistics. PMID- 23744267 TI - StereoPasting: interactive composition in stereoscopic images. AB - We propose "StereoPasting," an efficient method for depth-consistent stereoscopic composition, in which a source 2D image is interactively blended into a target stereoscopic image. As we paint "disparity" on a 2D image, the disparity map of the selected region is gradually produced by edge-aware diffusion, and then blended with that of the target stereoscopic image. By considering constraints of the expected disparities and perspective scaling, the 2D object is warped to generate an image pair, which is then blended into the target image pair to get the composition result. The warping is formulated as an energy minimization, which could be solved in real time. We also present an interactive composition system, in which users can edit the disparity maps of 2D images by strokes, while viewing the composition results instantly. Experiments show that our method is intuitive and efficient for interactive stereoscopic composition. A lot of applications demonstrate the versatility of our method. PMID- 23744268 TI - The Helmholtz-Hodge decomposition--a survey. AB - The Helmholtz-Hodge Decomposition (HHD) describes the decomposition of a flow field into its divergence-free and curl-free components. Many researchers in various communities like weather modeling, oceanology, geophysics, and computer graphics are interested in understanding the properties of flow representing physical phenomena such as incompressibility and vorticity. The HHD has proven to be an important tool in the analysis of fluids, making it one of the fundamental theorems in fluid dynamics. The recent advances in the area of flow analysis have led to the application of the HHD in a number of research communities such as flow visualization, topological analysis, imaging, and robotics. However, because the initial body of work, primarily in the physics communities, research on the topic has become fragmented with different communities working largely in isolation often repeating and sometimes contradicting each others results. Additionally, different nomenclature has evolved which further obscures the fundamental connections between fields making the transfer of knowledge difficult. This survey attempts to address these problems by collecting a comprehensive list of relevant references and examining them using a common terminology. A particular focus is the discussion of boundary conditions when computing the HHD. The goal is to promote further research in the field by creating a common repository of techniques to compute the HHD as well as a large collection of example applications in a broad range of areas. PMID- 23744269 TI - Trajectory optimization for full-body movements with complex contacts. AB - This paper presents the first method for full-body trajectory optimization of physics-based human motion that does not rely on motion capture, specified key poses, or periodic motion. Optimization is performed using a small set of simple goals, for example, one hand should be on the ground, or the center-of-mass should be above a particular height. These objectives are applied to short spacetime windows which can be composed to express goals over an entire animation. Specific contact locations needed to achieve objectives are not required by our method. We show that the method can synthesize many different kinds of movement, including walking, hand walking, breakdancing, flips, and crawling. Most of these movements have never been previously synthesized by physics-based methods. PMID- 23744270 TI - View management of projected labels on nonplanar and textured surfaces. AB - This paper presents a new label layout technique for projection-based augmented reality (AR) that determines the placement of each label directly projected onto an associated physical object with a surface that is normally inappropriate for projection (i.e., nonplanar and textured). Central to our technique is a new legibility estimation method that evaluates how easily people can read projected characters from arbitrary viewpoints. The estimation method relies on the results of a psychophysical study that we conducted to investigate the legibility of projected characters on various types of surfaces that deform their shapes, decrease their contrasts, or cast shadows on them. Our technique computes a label layout by minimizing the energy function using a genetic algorithm (GA). The terms in the function quantitatively evaluate different aspects of the layout quality. Conventional label layout solvers evaluate anchor regions and leader lines. In addition to these evaluations, we design our energy function to deal with the following unique factors, which are inherent in projection-based AR applications: the estimated legibility value and the disconnection of the projected leader line. The results of our subjective experiment showed that the proposed technique could significantly improve the projected label layout. PMID- 23744271 TI - Evaluating the interfacial reaction kinetics of the bipolar membrane interface in the bipolar membrane fuel cell. AB - A reaction kinetic model of the bipolar membrane interface in the bipolar membrane fuel cell (BPMFC) was proposed based on the p-n junction theory and chemical reaction kinetics. It verified the self-humidification feasibility of the BPMFC successfully. PMID- 23744272 TI - Timing of mTOR activation affects tuberous sclerosis complex neuropathology in mouse models. AB - Tuberous sclerosis complex (TSC) is a dominantly inherited disease with high penetrance and morbidity, and is caused by mutations in either of two genes, TSC1 or TSC2. Most affected individuals display severe neurological manifestations - such as intractable epilepsy, mental retardation and autism - that are intimately associated with peculiar CNS lesions known as cortical tubers (CTs). The existence of a significant genotype-phenotype correlation in individuals bearing mutations in either TSC1 or TSC2 is highly controversial. Similar to observations in humans, mouse modeling has suggested that a more severe phenotype is associated with mutation in Tsc2 rather than in Tsc1. However, in these mutant mice, deletion of either gene was achieved in differentiated astrocytes. Here, we report that loss of Tsc1 expression in undifferentiated radial glia cells (RGCs) early during development yields the same phenotype detected upon deletion of Tsc2 in the same cells. Indeed, the same aberrations in cortical cytoarchitecture, hippocampal disturbances and spontaneous epilepsy that have been detected in RGC targeted Tsc2 mutants were observed in RGC-targeted Tsc1 mutant mice. Remarkably, thorough characterization of RGC-targeted Tsc1 mutants also highlighted subventricular zone (SVZ) disturbances as well as STAT3-dependent and independent developmental-stage-specific defects in the differentiation potential of ex-vivo-derived embryonic and postnatal neural stem cells (NSCs). As such, deletion of either Tsc1 or Tsc2 induces mostly overlapping phenotypic neuropathological features when performed early during neurogenesis, thus suggesting that the timing of mTOR activation is a key event in proper neural development. PMID- 23744273 TI - Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality. AB - Neural crest cells (NCCs) participate in the remodeling of the cardiac outflow tract and pharyngeal arch arteries during cardiovascular development. Integrin linked kinase (ILK) is a serine/threonine kinase and a major regulator of integrin signaling. It links integrins to the actin cytoskeleton and recruits other adaptor molecules into a large complex to regulate actin dynamics and integrin function. Using the Cre-lox system, we deleted Ilk from NCCs of mice to investigate its role in NCC morphogenesis. The resulting mutants developed a severe aneurysmal arterial trunk that resulted in embryonic lethality during late gestation. Ilk mutants showed normal cardiac NCC migration but reduced differentiation into smooth muscle within the aortic arch arteries and the outflow tract. Within the conotruncal cushions, Ilk-deficient NCCs exhibited disorganization of F-actin stress fibers and a significantly rounder morphology, with shorter cellular projections. Additionally, absence of ILK resulted in reduced in vivo phosphorylation of Smad3 in NCCs, which correlated with reduced alphaSMA levels. Our findings resemble those seen in Pinch1 and beta1 integrin conditional mutant mice, and therefore support that, in neural crest-derived cells, ILK and Pinch1 act as cytoplasmic effectors of beta1 integrin in a pathway that protects against aneurysms. In addition, our conditional Ilk mutant mice might prove useful as a model to study aortic aneurysms caused by reduced Smad3 signaling, as occurs in the newly described aneurysms-osteoarthritis syndrome, for example. PMID- 23744274 TI - Premature aging in telomerase-deficient zebrafish. AB - The study of telomere biology is crucial to the understanding of aging and cancer. In the pursuit of greater knowledge in the field of human telomere biology, the mouse has been used extensively as a model. However, there are fundamental differences between mouse and human cells. Therefore, additional models are required. In light of this, we have characterized telomerase-deficient zebrafish (Danio rerio) as the second vertebrate model for human telomerase driven diseases. We found that telomerase-deficient zebrafish show p53-dependent premature aging and reduced lifespan in the first generation, as occurs in humans but not in mice, probably reflecting the similar telomere length in fish and humans. Among these aging symptoms, spinal curvature, liver and retina degeneration, and infertility were the most remarkable. Although the second generation embryos died in early developmental stages, restoration of telomerase activity rescued telomere length and survival, indicating that telomerase dosage is crucial. Importantly, this model also reproduces the disease anticipation observed in humans with dyskeratosis congenita (DC). Thus, telomerase haploinsufficiency leads to anticipation phenomenon in longevity, which is related to telomere shortening and, specifically, with the proportion of short telomeres. Furthermore, p53 was induced by telomere attrition, leading to growth arrest and apoptosis. Importantly, genetic inhibition of p53 rescued the adverse effects of telomere loss, indicating that the molecular mechanisms induced by telomere shortening are conserved from fish to mammals. The partial rescue of telomere length and longevity by restoration of telomerase activity, together with the feasibility of the zebrafish for high-throughput chemical screening, both point to the usefulness of this model for the discovery of new drugs able to reactivate telomerase in individuals with DC. PMID- 23744276 TI - Prognostic significance of the extent of lymph node involvement in stage II-N1 non-small cell lung cancer. AB - BACKGROUND: The non-small cell lung cancer (NSCLC) staging system (published in 2009 in the seventh edition of the cancer staging manuals of the Union for International Cancer Control and American Joint Commission on Cancer) did not include any changes to current N descriptors for NSCLC. However, the prognostic significance of the extent of lymph node (LN) involvement (including the LN zones involved [hilar/interlobar or peripheral], cancer-involved LN ratios [LNRs], and the number of involved LNs) remains unknown. The aim of this report is to evaluate the extent of LN involvement and other prognostic factors in predicting outcome after definitive surgery among Chinese patients with stage II-N1 NSCLC. METHODS: We retrospectively reviewed the clinicopathologic characteristics of 206 patients with stage II (T1a-T2bN1M0) NSCLC who had undergone complete surgical resection at Shanghai Chest Hospital from June 1999 to June 2009. Overall survival (OS) and disease-free survival (DFS) were compared using Kaplan-Meier statistical analysis. Stratified and Cox regression analyses were used to evaluate the relationship between the LN involvement and survival. RESULTS: Peripheral zone LN involvement, cancer-involved LNR, smaller tumor size, and squamous cell carcinoma were shown to be statistically significant indicators of higher OS and DFS by univariate analyses. Visceral pleural involvement was also shown to share a statistically significant relationship with DFS by univariate analyses. Multivariate analyses showed that tumor size and zone of LN involvement were significant predictors of OS. CONCLUSIONS: Zone of N1 LN, LN ratios, and tumor size were found to provide independent prognostic information in patients with stage II NSCLC. This information may be used to stratify patients into groups by risk for recurrence. PMID- 23744275 TI - The responses of Vitreoscilla hemoglobin-expressing hybrid aspen (Populus tremula * tremuloides) exposed to 24-h herbivory: expression of hemoglobin and stress related genes in exposed and nonorthostichous leaves. AB - The responses of transcriptome and phenolic compounds were determined with Populus tremula L. * Populus tremuloides Michx. expressing the hemoglobin (Hb) of Vitreoscilla (VHb) and non-transformant (wt) line. After 24-h exposure of leaves to Conistra vaccinii L., the transcript levels of endogenous non-symbiotic class 1 Hb (PttHb1) and truncated Hb (PttTrHb) genes were modestly reduced and increased, respectively, in both wt and VHb-expressing line. Besides the herbivory exposed leaves showing the most significant transcriptome changes, alterations were also detected in the transcriptome of nonorthostichous leaves positioned directly above the exposed leaves. Both wt and VHb-expressing line displayed similar herbivory-induced effects on gene expression, although the extent of responses was more pronounced in the wt than in the VHb-expressing line. The contents of phenolic compounds were not altered due to herbivory and they were alike in the wt and VHb-expressing line. In addition, we determined the relative growth rates (RGRs) of Orthosia gothica L., Ectropis crepuscularia Denis & Schiff. and Orgyia antiqua L. larvae, and found no variation in the RGRs between the lines. Thus, VHb-expressing P. tremula * tremuloides lines showed to be comparable with wt in regards to the food quality of leaves. PMID- 23744277 TI - Genital findings in boys suspected for sexual abuse. AB - Injuries in the genital region of boys are mostly caused by accidents. In this study, three cases of child abuse and one case suspicious for child abuse but explainable by a congenital undiscovered malformation are presented. Injuries or findings in the genital region are especially suspicious for child abuse, including sexual abuse. Because of the possible misinterpretation and the consequences of a false confirmation of a child abuse, an interdisciplinary cooperation between pediatrics, forensic experts, and pediatric urologist should be carried out in doubtful cases. PMID- 23744278 TI - Recognising the benefits and harms of breast cancer screening: an opportunity to target improvement. PMID- 23744279 TI - Mortality benefits and overdiagnosis estimates for women attending breast screening. PMID- 23744280 TI - Breast cancer screening: time to target women at risk. PMID- 23744282 TI - Breast screening remains a controversial issue. PMID- 23744283 TI - The Marmot report: accepting the poisoned chalice. PMID- 23744284 TI - Gender preference for the endoscopist among Hispanics: the results of a prospective study. AB - We aim to assess the gender preferences for endoscopists among Hispanics and factors influencing such preferences. Cross-sectional study in prospectively enrolled Hispanic patients using a pre-endoscopy questionnaire regarding their gender preferences for the endoscopist and the reasons for such preferences. Multivariate logistic regression model was used for the statistical analysis. We enrolled total 200 Hispanic patients (100 males, 100 females) in our study. Their mean age was 51 +/- 14 years. 30 % of Hispanics expressed a gender preference for the endoscopist. Gender preference was more common among Hispanic women than men (38 % vs. 22 %, p = 0.014). Gender preference for primary care provider was independently associated with the gender preference for the endoscopist (odds ratio 66, 95 % CI 25-182, p < 0.0001). We found significant number of Hispanic patients with gender preference for the endoscopist (female more than male). The odds of such preferences were strongly associated with the gender preference for the primary care physician. PMID- 23744285 TI - Comparative analysis on determinants of self-rated health among non-Hispanic White, Hispanic, and Asian American older adults. AB - The purpose of the study is (1) to compare the effects of factors on self-rated health (SRH) among older non-Hispanic Whites (NHW), Hispanic, and Asian Californians and (2) to provide estimated influence size of each factor on SRH. This study analyzed secondary data drawn from the 2005 California Health Interview Survey. Binary logit regressions were used to analyze data with the Jackknife replication sampling weights. Significant differences were found in SRH among the three groups. Hispanics and Asians reported poorer health than NHW. Socioeconomic status, acculturation, and health access significantly accounted for an association between ethnicity and SRH. However, the magnitudes of their effects on SRH varied across the groups and by the factors examined. This study discusses and concludes with some recommendations on the opportunities presented by the Affordable Care Act and Healthy People 2020. PMID- 23744281 TI - The benefits and harms of breast cancer screening: an independent review. PMID- 23744286 TI - Engineering redox cofactor utilization for detoxification of glycolaldehyde, a key inhibitor of bioethanol production, in yeast Saccharomyces cerevisiae. AB - Hot-compressed water treatment of lignocellulose liberates numerous inhibitors that prevent ethanol fermentation of yeast Saccharomyces cerevisiae. Glycolaldehyde is one of the strongest fermentation inhibitors and we developed a tolerant strain by overexpressing ADH1 encoding an NADH-dependent reductase; however, its recovery was partial. In this study, to overcome this technical barrier, redox cofactor preference of glycolaldehyde detoxification was investigated. Glycolaldehyde-reducing activity of the ADH1-overexpressing strain was NADH-dependent but not NADPH-dependent. Moreover, genes encoding components of the pentose phosphate pathway, which generates intracellular NADPH, was upregulated in response to high concentrations of glycolaldehyde. Mutants defective in pentose phosphate pathways were sensitive to glycolaldehyde. Genome wide survey identified GRE2 encoding a NADPH-dependent reductase as the gene that confers tolerance to glycolaldehyde. Overexpression of GRE2 in addition to ADH1 further improved the tolerance to glycolaldehyde. NADPH-dependent glycolaldehyde conversion to ethylene glycol and NADP+ content of the strain overexpressing both ADH1 and GRE2 were increased at 5 mM glycolaldehyde. Expression of GRE2 was increased in response to glycolaldehyde. Carbon metabolism of the strain was rerouted from glycerol to ethanol. Thus, it was concluded that the overexpression of GRE2 together with ADH1 restores glycolaldehyde tolerance by augmenting the NADPH-dependent reduction pathway in addition to NADH-dependent reduction pathway. The redox cofactor control for detoxification of glycolaldehyde proposed in this study could influence strategies for improving the tolerance of other fermentation inhibitors. PMID- 23744287 TI - Antifungal activity of the lipopeptides produced by Bacillus amyloliquefaciens anti-CA against Candida albicans isolated from clinic. AB - The bacterium Bacillus amyloliquefaciens anti-CA isolated from mangrove system was found to be able to actively kill Candida albicans isolated from clinic. The bacterial strain anti-CA could produce high level of bioactive substance, amylase and protease in the cheap medium containing 2.0 % soybean meal, 2.0 % wheat flour, pH 6.5 within 26 h. After purification, the main bioactive substance was confirmed to be a cyclic lipopeptide containing a heptapeptide, L-Asp->L-Leu->L Leu->L-Val->L-Val->L-Glu->L-Leu and a 3-OH fatty acid (15 carbons). In addition to C. albicans, the purified lipopeptide can also kill many yeast strains including Metschnikowia bicuspidata, Candida tropicalis, Yarrowia lipolytica and Saccharomyces cerevisiae. After treated by the purified lipopeptide, both the whole cells and protoplasts of C. albicans were destroyed. PMID- 23744288 TI - Force dependency of biochemical reactions measured by single-molecule force-clamp spectroscopy. AB - Here we describe a protocol for using force-clamp spectroscopy to precisely quantify the effect of force on biochemical reactions. A calibrated force is used to control the exposure of reactive sites in a single polyprotein substrate composed of repeated domains. The use of polyproteins allows the identification of successful single-molecule recordings from unambiguous mechanical unfolding fingerprints. Biochemical reactions are then measured directly by detecting the length changes of the substrate held at a constant force. We present the layout of a force-clamp spectrometer along with protocols to design and conduct experiments. These experiments measure reaction kinetics as a function of applied force. We show sample data of the force dependency of two different reactions, protein unfolding and disulfide reduction. These data, which can be acquired in just a few days, reveal mechanistic details of the reactions that currently cannot be resolved by any other technique. PMID- 23744290 TI - Sub-millisecond ligand probing of cell receptors with multiple solution exchange. AB - The accurate knowledge of receptor kinetics is crucial to our understanding of cell signal transduction in general and neural function in particular. The classical technique of probing membrane receptors on a millisecond scale involves placing a recording micropipette with a membrane patch in front of a double barrel (theta-glass) application pipette mounted on a piezo actuator. Driven by electric pulses, the actuator can rapidly shift the theta-glass pipette tip, thus exposing the target receptors to alternating ligand solutions. However, membrane patches survive for only a few minutes, thus normally restricting such experiments to a single-application protocol. In order to overcome this deficiency, we have introduced pressurized supply microcircuits in the theta glass channels, thus enabling repeated replacement of application solutions within 10-15 s. This protocol, which has been validated in our recent studies and takes 20-60 min to implement, allows the characterization of ligand-receptor interactions with high sensitivity, thereby also enabling a powerful paired sample statistical design. PMID- 23744289 TI - Small-molecule ligand docking into comparative models with Rosetta. AB - Structure-based drug design is frequently used to accelerate the development of small-molecule therapeutics. Although substantial progress has been made in X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, the availability of high-resolution structures is limited owing to the frequent inability to crystallize or obtain sufficient NMR restraints for large or flexible proteins. Computational methods can be used to both predict unknown protein structures and model ligand interactions when experimental data are unavailable. This paper describes a comprehensive and detailed protocol using the Rosetta modeling suite to dock small-molecule ligands into comparative models. In the protocol presented here, we review the comparative modeling process, including sequence alignment, threading and loop building. Next, we cover docking a small-molecule ligand into the protein comparative model. In addition, we discuss criteria that can improve ligand docking into comparative models. Finally, and importantly, we present a strategy for assessing model quality. The entire protocol is presented on a single example selected solely for didactic purposes. The results are therefore not representative and do not replace benchmarks published elsewhere. We also provide an additional tutorial so that the user can gain hands-on experience in using Rosetta. The protocol should take 5-7 h, with additional time allocated for computer generation of models. PMID- 23744291 TI - Risk factors associated with recurrent homelessness after a first homeless episode. AB - Alcohol and drug use are commonly associated with the experience of homelessness. In order to better understand this, we explored the prevalence of drug and alcohol use as it related to successful re-housing within a sample of first-time single homeless adults at municipal shelters. From within this sample, we compared the features of recurrent homelessness with those of chronic homelessness and of being stably housed. We interviewed 344 subjects upon shelter entry and followed each one every six months for 18 months using standardized social and mental health measures. We analyzed baseline assessments relative to housing experiences during follow-up using Chi square and multinomial logistic regression. Eighty-one percent (N = 278) obtained housing over 18 months, of which 23.7 % (N = 66) experienced homelessness again. Recurrent homelessness was more common among those with a high school education and if initially re-housed with family. Bivariate analysis resulted in the observation of the highest rate of alcohol and other drug use among this recurrent group and multinomial logistic regression supported this only with the coupling of arrest history and diagnosed antisocial personality disorder. With relatively high rates of recurrent homelessness, there were differences between subjects who experienced recurrent homelessness compared to those who were stably housed and with chronic homelessness. That alcohol and other substance use disorders were associated with recurrent homelessness only if they were linked to other risk factors highlights the complexity of causes for homelessness and a resultant need to organize them into constellations of causal risk factors. Consistent with this, there should be initiatives that span bureaucratic boundaries so as to flexibly meet multiple complex service needs, thus improving outcomes concerning episodes of recurrent homelessness. PMID- 23744293 TI - Age-related macular degeneration, anti-VEGF therapy, and ophthalmic imaging: is there a best practice? PMID- 23744292 TI - A pilot test of a peer navigator intervention for improving the health of individuals with serious mental illness. AB - Individuals with serious mental illness (SMI) are at considerably higher risk for morbidity and mortality than those in the general population. The current pilot trial is a preliminary examination of a peer health navigation intervention for improving health and healthcare utilization called the Bridge. Twenty-four individuals with SMI were randomly assigned to either peer navigation or treatment as usual (TAU). Navigators encouraged development of self-management of healthcare through a series of psychoeducation and behavioral strategies. Outcomes included a range of health consequences, as well as health utilization indices. After 6 months, compared to the TAU group, participants receiving the intervention experienced fewer pain and health symptoms. Participants changed their orientation about seeking care to a primary care provider (44.4 % vs. 83.3 %, chi(2) = 3.50, p < .05) rather than the emergency room (55.6 % vs. 0 %, chi(2) = 8.75, p < .01). Therefore, the Bridge intervention demonstrated considerable promise through positively impacting health and healthcare utilization. PMID- 23744295 TI - Mouse granzyme A induces a novel death with writhing morphology that is mechanistically distinct from granzyme B-induced apoptosis. AB - Human and mouse granzyme (Gzm)B both induce target cell apoptosis in concert with pore-forming perforin (Pfp); however the mechanisms by which other Gzms induce non-apoptotic death remain controversial and poorly characterised. We used timelapse microscopy to document, quantitatively and in real time, the death of target cells exposed to primary natural killer (NK) cells from mice deficient in key Gzms. We found that in the vast majority of cases, NK cells from wild-type mice induced classic apoptosis. However, NK cells from syngeneic Gzm B-deficient mice induced a novel form of cell death characterised by slower kinetics and a pronounced, writhing, 'worm-like' morphology. Dying cells initially contracted but did not undergo membrane blebbing, and annexin-V staining was delayed until the onset of secondary necrosis. As it is different from any cell death process previously reported, we tentatively termed this cell death 'athetosis'. Two independent lines of evidence showed this alternate form of death was due to Gzm A: first, cell death was revealed in the absence of Gzm B, but was completely lost when the NK cells were deficient in both Gzm A and B; second, the athetotic morphology was precisely reproduced when recombinant mouse Gzm A was delivered by an otherwise innocuous dose of recombinant Pfp. Gzm A-mediated athetosis did not require caspase activation, early mitochondrial disruption or generation of reactive oxygen species, but did require an intact actin cytoskeleton and was abolished by latrunculin B and mycalolide B. This work defines an authentic role for mouse Gzm A in granule-induced cell death by cytotoxic lymphocytes. PMID- 23744294 TI - Contribution of humoral immune responses to the antitumor effects mediated by anthracyclines. AB - Immunogenic cell death induced by cytotoxic compounds contributes to the success of selected chemotherapies by eliciting a protective anticancer immune response, which is mediated by CD4(+) and CD8(+) T cells producing interferon-gamma. In many instances, cancer progression is associated with high titers of tumor specific antibodies, which become detectable in the serum, but whose functional relevance is elusive. Here, we explored the role of humoral immune responses in the anticancer efficacy of anthracyclines. Chemotherapy reduced the number of tumor-infiltrating B cells, and failed to promote humoral responses against immunodominant tumor antigens. Although anthracycline-based anticancer chemotherapies failed in T cell-deficient mice, they successfully reduced the growth of cancers developing in mice lacking B lymphocytes (due to the injection of a B-cell-depleting anti-CD20 antibody), immunoglobulins (Igs) or Ig receptors (Fc receptor) due to genetic manipulations. These results suggest that the humoral arm of antitumor immunity is dispensable for the immune-dependent therapeutic effect of anthracyclines against mouse sarcoma. In addition, we show here that the titers of IgA and IgG antibodies directed against an autoantigen appearing at the cell surface of tumor cells post chemotherapy (calreticulin, CRT) did not significantly increase in patients treated with anthracyclines, and that anti-CRT antibodies had no prognostic or predictive significance. Collectively, our data indicate that humoral anticancer immune responses differ from cellular responses in, thus far, that they do not contribute to the success of anthracycline-mediated anticancer therapies in human breast cancers and mouse sarcomas. PMID- 23744297 TI - Conjugated polymer nanoparticles: preparation, properties, functionalization and biological applications. AB - In the past few years, conjugated polymer nanoparticles (CPNs) have been successfully prepared and applied in the biological field because of their unique opto-electronic properties. The rapid development of CPNs is mainly attributed to their simple synthesis procedures and easy separation steps. The advantages of CPNs include high brightness, excellent photostability, low cytotoxicity, high quantum yield and versatile surface modification. The functionalization of CPNs with specific recognition elements imparts them good ability for targeted recognition and imaging in vitro and in vivo. CPNs can be applied to deliver drug and gene, and simultaneously to real-time monitor the release process due to their self-luminous characteristics. Moreover, CPNs can sensitize oxygen molecules to generate reactive oxygen species (ROS) which can kill adjacent bacteria and tumor cells. In this tutorial review, we provide a recent development of the preparation methods, properties, and functionalization strategies of CPNs, especially discussing their biological applications in targeted imaging, drug/gene delivery and biomedicine. The challenges and outlooks in this field will also be discussed. PMID- 23744296 TI - Obatoclax (GX15-070) triggers necroptosis by promoting the assembly of the necrosome on autophagosomal membranes. AB - Obatoclax (GX15-070), a small-molecule inhibitor of antiapoptotic Bcl-2 proteins, has been reported to trigger cell death via autophagy. However, the underlying molecular mechanisms have remained elusive. Here, we identify GX15-070-stimulated assembly of the necrosome on autophagosomal membranes as a key event that connects GX15-070-stimulated autophagy to necroptosis. GX15-070 predominately induces a non-apoptotic form of cell death in rhabdomyosarcoma cells, as evident by lack of typical apoptotic features such as DNA fragmentation or caspase activation and by insensitivity to the broad-range caspase inhibitor zVAD.fmk. Instead, GX15-070 triggers massive accumulation of autophagosomes, which are required for GX15-070-induced cell death, as blockade of autophagosome formation by silencing of Atg5 or Atg7 abolishes GX15-070-mediated cell death. Co immunoprecipitation studies reveal that GX15-070 stimulates the interaction of Atg5, a constituent of autophagosomal membranes, with components of the necrosome such as FADD, RIP1 and RIP3. This GX15-070-induced assembly of the necrosome on autophagosomes occurs in a Atg5-dependent manner, as knockdown of Atg5 abrogates formation of this complex. RIP1 is necessary for GX15-070-induced cell death, as both genetic and pharmacological inhibition of RIP1 by shRNA-mediated knockdown or by the RIP1 inhibitor necrostatin-1 blocks GX15-070-induced cell death. Similarly, RIP3 knockdown rescues GX15-070-mediated cell death and suppression of clonogenic survival. Interestingly, RIP1 or RIP3 silencing has no effect on GX15 070-stimulated autophagosome formation, underlining that RIP1 and RIP3 mediate cell death downstream of autophagy induction. Of note, GX15-070 significantly suppresses tumor growth in a RIP1-dependent manner in the chorioallantoic membrane model in vivo. In conclusion, GX15-070 triggers necroptosis by promoting the assembly of the necrosome on autophagosomes. These findings provide novel insights into the molecular mechanisms of GX15-070-induced non-apoptotic cell death. PMID- 23744298 TI - In children with premature adrenarche, bone age advancement by 2 or more years is common and generally benign. AB - BACKGROUND: Premature adrenarche (PA) is often associated with bone age (BA) advanced by >=2 years, which increases the concern for underlying pathology, but the frequency and clinical significance of this is unknown. Our objective was to identify the proportion of PA patients with very advanced BA and normal BA and compare the clinical characteristics of the two groups. METHODS: Charts of 427 patients aged 5-9 years, referred for early puberty over a 2-year period, were reviewed for clinical diagnosis, growth, parental heights, hormone levels and BA. We divided the PA patients into three separate groups based on degree of BA advancement. Predicted adult heights (PAH) were calculated and compared to mid parental target height (TH). RESULTS: Of 427 patients, 266 (62%) had PA (82% female). Of the 121 with BA, 30.6% had very advanced BA (>=2 years) and this group was taller (Ht SD+1.72 vs. +0.72, p<0.00001) and had higher BMI (SD+1.70 vs. +0.99, p<0.001) than patients with BA advanced by <1 year, but hormone levels were quite similar. Mean PAH was slightly less than TH for patients with very advanced BA, but there were no girls with PAH <60 inches 152.4 cm or boys with PAH <65 inches 165.1 cm in height. CONCLUSIONS: Very advanced BA is common in PA, and patients were significantly taller and more overweight than their peers. The impact of advanced BA on PAH appears to be minor. We question the need for ordering a BA in patients with PA, and suggest that extensive testing is unnecessary simply because of advanced BA. PMID- 23744299 TI - Morbidity characteristics of patients with congenital insensitivity to pain with anhidrosis (CIPA). AB - BACKGROUND: Congenital insensitivity to pain with anhidrosis (CIPA) is a congenital autonomic sensory neuropathy. In southern Israel, there are many patients with this disease. We here tried to characterize the different infections acquired by children with CIPA. METHODS: We collected all the available data about CIPA patients in southern Israel in the year 1991-2005, including the lesion types, area in the body where the infection occurs, and the treatment given. RESULTS: The current study included 30 children with CIPA, out of 44 known CIPA patients in southern Israel (68.2%). A total of 382 different episodes of infections, fever, orthopedic lesions, and jaw and mouth lesions led our patients to our outpatient clinic or resulted in hospitalization. CONCLUSION: We found that children with CIPA mainly have infections of the skin and skeleton, and that the most frequent pathogen is Staphylococcus aureus. We also found that a fair amount of these pathogens are resistant to conventional treatment regimens. PMID- 23744300 TI - Inferring latent gene regulatory network kinetics. AB - Regulatory networks consist of genes encoding transcription factors (TFs) and the genes they activate or repress. Various types of systems of ordinary differential equations (ODE) have been proposed to model these networks, ranging from linear to Michaelis-Menten approaches. In practice, a serious drawback to estimate these models is that the TFs are generally unobserved. The reason is the actual lack of high-throughput techniques to measure abundance of proteins in the cell. The challenge is to infer their activity profile together with the kinetic parameters of the ODE using level expression measurements of the genes they regulate. In this work we propose general statistical framework to infer the kinetic parameters of regulatory networks with one or more TFs using time course gene expression data. Our approach is also able to predict the activity levels of the TF. We use a penalized likelihood approach where the ODE is used as a penalty. The main advantage is that the solution of the ODE is not required explicitly as it is common in most proposed methods. This makes our approach computationally efficient and suitable for large systems with many components. We use the proposed method to study a SOS repair system in Escherichia coli. The reconstructed TF exhibits a similar behavior to experimentally measured profiles and the genetic expression data are fitted properly. PMID- 23744301 TI - Solution phase van der Waals epitaxy of ZnO wire arrays. AB - As an incommensurate epitaxy, van der Waals epitaxy allows defect-free crystals to grow on substrates even with a large lattice mismatch. Furthermore, van der Waals epitaxy is proposed as a universal platform where heteroepitaxy can be achieved irrespective of the nature of the overlayer material and the method of crystallization. Here we demonstrate van der Waals epitaxy in solution phase synthesis for seedless and catalyst-free growth of ZnO wire arrays on phlogopite mica at low temperature. A unique incommensurate interface is observed even with the incomplete initial wetting of ZnO onto the substrate. Interestingly, the imperfect contacting layer does not affect the crystalline and optical properties of other parts of the wires. In addition, we present patterned growth of a well ordered array with hexagonal facets and in-plane alignment. We expect our seedless and catalyst-free solution phase van der Waals epitaxy synthesis to be widely applicable in other materials and structures. PMID- 23744302 TI - News from epidemiological studies on Alzheimer's and Parkinson's disease: a personal perspective. PMID- 23744303 TI - The clinical and anatomical heterogeneity of environmental dependency phenomena. AB - Following damage to the frontal lobes, the observation of patients presenting with environmental dependency syndrome (EDS), particularly with its two main components--grasping and imitation behavior, provides a unique opportunity to gain new insights into the neural bases of human autonomy and free-will. In the present study, thirty-nine patients with frontal lobe dysfunction [21 with progressive supranuclear palsy (PSP), and 18 with the behavioral variant of frontotemporal dementia, (bvFTD)] were tested for environmental dependency phenomena and underwent neuropsychological evaluation and T1-weighted 3D brain MRI. We correlated scores obtained by assessing grasping, imitation and utilization behaviors with both neuropsychological executive test performance and grey matter density on MRI using Voxel-Based Morphometry (VBM). This study confirms the high frequency of two environmental dependency phenomena- grasping and imitation- in patients with frontal lobe syndrome (34/39 patients) and the rarity of utilization behavior (2/39). The grasping score was significantly and positively correlated with those obtained in all executive tests except the Stroop test, while the imitation score was not. In the VBM study, while the grasping score was correlated with grey matter density in the right superior frontal gyrus and both inferior temporal gyri, the imitation score was correlated with changes in the right insula, left medial frontal gyrus and left precuneus. Environmental dependency is associated with the dysfunction of a frontoparietal network. Within this large network, grasping and imitation behaviors can be dissociated from both neuropsychological and anatomical standpoints, underlining the clinical and anatomical heterogeneity of environmental dependency phenomena. PMID- 23744304 TI - Dual modality intravascular imaging of unstable, symptomatic but "hemodynamically insignificant" carotid stenosis. PMID- 23744305 TI - Cesare Vigna (1819-1892). PMID- 23744306 TI - The use of intermediate endpoints in the design of type 1 diabetes prevention trials. AB - AIMS/HYPOTHESIS: This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials. METHODS: Relatives of individuals diagnosed with type 1 diabetes were enrolled on the TrialNet Natural History Study and screened for diabetes related autoantibodies. Those with two or more such autoantibodies were analysed with respect to increased HbA1c, decreased C-peptide following an OGTT, or abnormal OGTT values as intermediate markers of disease progression. RESULTS: Over 2 years, a 10% increase in HbA1c, and a 20% or 30% decrease in C-peptide from baseline, or progression to abnormal OGTT, occurred with a frequency between 20% and 41%. The 3- to 5-year risk of type 1 diabetes following each intermediate endpoint was high, namely 47% to 84%. The lower the incidence of the endpoint being reached, the higher the risk of diabetes. A diabetes prevention trial using these intermediate endpoints would require a 30% to 50% smaller sample size than one using type 1 diabetes as the endpoint. CONCLUSIONS/INTERPRETATION: The use of an intermediate endpoint in diabetes prevention is based on the generally held view of disease progression from initial occurrence of autoantibodies through successive immunological and metabolic changes to manifest type 1 diabetes. Thus, these markers are suitable for randomised phase 2 trials, which can more rapidly screen promising new therapies, allowing them to be subsequently confirmed in definitive phase 3 trials. PMID- 23744307 TI - Whole-genome sequence analysis of a Korean G11P[25] rotavirus strain identifies several porcine-human reassortant events. AB - A rare rotavirus, RVA/Human-wt/KOR/CAU12-2/2012/G11P[25], was isolated from a 16 year-old female with fever and diarrhea during the 2012 rotavirus surveillance in South Korea using a cell culture system, and its full genome sequence was determined and analyzed. Strain CAU12-2 exhibited a G11-P[25]-I12-R1-C1-M1-A1-N1 T1-E1-H1 genotype constellation. Phylogenetic analysis of this strain revealed that it is a human-porcine reassortant of two distant relatives of the G11 strains circulating in the world. The VP7 and VP4 genes are most closely related to those of human G11P[25] viruses (Dhaka6, KTM368, and N-38 strains) identified in South Asia, whereas the VP1 gene originated from a porcine G11P[7] virus (YM strain) that was identified in South America. The VP6 gene was found to belong to the new genotype I12. This study indicates that the G11-P[25]-I12 genotype was introduced into the South Korean population by interspecies transmissions of human and animal rotaviruses, followed by multiple reassortment events. PMID- 23744308 TI - Wild-type rabies virus phosphoprotein is associated with viral sensitivity to type I interferon treatment. AB - Rabies virus (RABV) is a single-stranded, negative-sense RNA virus that causes a fatal neurological disease in humans and animals. Our previous studies have shown that lab-adapted, but not wild-type (wt), RABV enhances innate immune responses including type I interferon (IFN) and chemokines. To determine if treatment with type I IFN can inhibit RABV infection, mouse neuroblastoma and baby hamster kidney cells were treated with IFN-alpha before being infected with lab-adapted or wt RABV. It was found that lab-adapted, but not the wt, RABV was able to replicate in IFN-alpha-pretreated cells. To determine the genes in wt RABV that confer sensitivity to IFN-alpha treatment, the P and the glycoprotein (G) genes from the wt RABV were used to replace the respective genes in the lab-adapted RABV. The results revealed that it is the P, not the G, gene that is associated with IFN sensitivity. Further studies have identified the regions containing the self-association domain (residues 59-139) and the C-terminal (residue 175-297) region on the P that might be associated with IFN sensitivity. The expression of ISGs, such as ISG15, ISG56, PKR, OAS-1G, was also investigated and found to be greatly increased in wt, but not in lab-adapted RABV-infected cells. It is possible that the P protein from the lab-adapted RABV can interfere with the downstream events in the interferon-signaling cascade. PMID- 23744309 TI - [Mutation analysis of FLG gene in 10 Chinese families with ichthyosis vulgaris]. AB - OBJECTIVE: To detect FLG gene mutations in 10 families affected with ichthyosis vulgaris and to explore mutational hot spot of the FLG gene in Chinese Han population. METHODS: PCR and direct sequencing were carried out to identify potential mutations of the FLG gene in above families. One hundred healthy individuals were analyzed as normal controls. RESULTS: Three mutations (3321delA, 5757delCCAG and S2706X) were identified in 7 families. A homozygous mutation 3321delA was also detected in two unrelated patients. No mutations were found in the remaining three families. Neither of the null mutations (5757delCCAG and S2706X) was found in the 100 controls. However, for 3321delA, a heterozygous mutation was also found in two of the controls. CONCLUSION: Three FLG mutations have been identified in the selected families with ichthyosis vulgaris, and the 3321delA mutation was most prevalent (46.9%). Mutations 5757delCCAG and S2706X were first found in patients with ichthyosis vulgaris. Other candidate genes may underlie the disease in those without a FLG mutation. PMID- 23744310 TI - [Clinical and genetic study of Wilson's disease in affected twins and siblings]. AB - OBJECTIVE: To study the clinical and genetic characteristics of twins and siblings affected with Wilson's disease (WD). METHODS: Clinical data and blood samples were collected from the subjects after informed consent was obtained. Genomic DNA was extracted and potential mutations in the exons in ATP7B gene were detected with PCR-DNA sequencing. Short tandem repeat (STR) genotyping was performed to determine the zygosity of the twins. RESULTS: The 5 pairs of twins have all met the diagnostic criteria for WD. STR genotyping has confirmed that 4 pairs were monozygotic twins. 3 pairs of twins had an onset with liver symptoms, the other 2 had an onset with brain symptoms. ATP7B gene mutations were detected in 4 pairs of twins, which have all located in exons 8 and 13. A heterozygous p.R778W mutation in exon 8 and homozygous p.P992L mutation in exon 13 were detected in all patients from one family, whose parents have carried a heterozygous p.R778W mutation and p.P992L heterozygous mutation, respectively, which suggested loss of heterozygosity (LOH). In one family, no mutation was detected in all exons of the ATP7B gene in the patients and their parents. For a triplet, one female was with definite WD and brain symptoms at the onset, one male had subclinical type with WD, whilst another female was completely normal. The triplets and their mother have all carried a p.P992L heterozygous mutation . CONCLUSION: Above results have confirmed an important role for genetic factors in the pathogenesis of WD. In addition to point mutations, LOH is also involved in the pathogenesis for WD. PMID- 23744311 TI - [Mutation analysis of CRYBB1 gene and prenatal diagnosis for a Chinese kindred featuring autosomal dominant congenital nuclear cataract]. AB - OBJECTIVE: To perform mutation screening and prenatal diagnosis for a five generation Chinese pedigree with autosomal dominant congenital nuclear cataract from Henan province by DNA sequencing. METHODS: Blood samples were taken from the family members. Four candidate genes (CRYBA1/A3, CRYBB1, CRYBB2 and CRYGD) were screened for mutations using direct sequencing. Prenatal genetic diagnosis was provided for a fetus at early gestation through chorionic villus sampling. RESULTS: A missense mutation, c.387C to A, was detected in exon 4 of the CRYBB1 gene in all of the patients. The mutation has resulted in a p.S129R transversion. The same mutation was not found in the fetus of the proband, who was confirmed to be healthy by one-year follow-up. CONCLUSION: A missense mutation p.S129R of the CRYBB1 gene probably underlies the autosomal dominant congenital nuclear cataract in this pedigree. Detection of the mutation also facilitated prenatal genetic testing for the family. PMID- 23744312 TI - [Identification of a novel c.822 G>T mutation of EDA gene in a Chinese family with X-linked hypohidrotic ectodermal dysplasia]. AB - OBJECTIVE: To identify potential mutation of ectodysplasin A (EDA) gene in a Chinese family affected with X-linked hypohidrotic ectodermal dysplasia. METHODS: Blood samples were collected from the affected male proband, his family members and 103 unrelated individuals. Following extraction of genomic DNA, coding sequence of the EDA gene was amplified with PCR, and DNA sequencing was performed to detect potential mutation. RESULTS: A novel missense mutation, c.822G>T (p.W274C), was identified in exon 7 of the EDA gene in the proband, whilst his mother was found to be a heterozygous carrier. The same mutation was also found in 5 other family members including one affected male and four females, but was absent in unaffected males and 103 unrelated individuals. CONCLUSION: A c.822G>T mutation in exon 7 of the EDA gene probably underlies the disease in this Chinese family. PMID- 23744313 TI - [Analysis of EDA gene mutation for a family affected with X-linked hypohidrotic ectodermal dysplasia]. AB - OBJECTIVE: To detect potential mutations of EDA gene for a Chinese family affected with X-linked hypohidrotic ectodermal dysplasia (XLHED). METHODS: Genomic DNA was extracted from peripheral blood of the proband, his relatives and 50 non-related healthy controls. Exonic sequences of the EDA gene were subjected to polymerase chain reaction amplification and direct sequencing. RESULTS: A c.467G> A mutation (R156H) was detected in exon 3 of the EDA gene in the proband, his mother, 2 uncles, and 1 aunt. The same mutation was not detected in the 50 non-related healthy controls. CONCLUSION: A c.467G>A mutation of the EDA gene probably underlies the disease in the family. PMID- 23744314 TI - [Practicality of rapid prenatal screening for Down syndrome with PCR-short tandem repeat method]. AB - OBJECTIVE: To assess the practicality of rapid prenatal screening for Down syndrome (DS) by polymerase chain reaction-short tandem repeat (PCR-STR) method, and to determine the genotypes of 7 STR loci in ethnic Chinese Han from Weifang region. METHODS: Seven STR markers (D21S11, D21S1411, D21S1412, D21S1413, D21S1414, D21S1432 and D21S2039) from chromosome 21q22.1-22.2 region were selected. Amniotic samples from 978 high-risk pregnancies and peripheral blood samples from 82 patients suspected with DS were tested with PCR-STR. And the results were verified with G-banding analysis. RESULTS: (1) All of the 1060 samples were successfully tested by PCR-STR. For normal individuals, the patterns obtained by PCR-STR were two bands with 1:1 area ratio or a single band. For DS cases, by contrast, the patterns revealed either three bands with area ratio of 1:1:1 for two STR loci, or three bands with area ratio of 1:1:1 for one STR loci and two bands with 2:1 or 1:2 area ratio for two STR loci. Based on analysis of the 7 STR markers, 14 amniotic fluid samples and 26 peripheral blood samples were regarded as DS positive. (2) For the 978 amniotic fluid samples, cytogenetic analysis was successful in 961 (98.3%), among which 44 had an abnormal karyotype. These included 14 trisomy 21 (12 standard type, 1 mosaicism and 1 translocation). 17 cases which failed amniocytic culture were normal upon fetal blood karyotyping. (3) Cytogenetic analysis was successful in all of the 82 peripheral blood samples, and has identified 30 (36.6%) abnormal karyotypes, among which 26 were trisomy 21 (including 4 with translocation form). (4) For DS positive cases, STR 1-4 showed three bands with area ratio of 1:1:1, or there were 2-4 loci with two bands with an area ratio of 2:1 or 1:2. All of the DS cases detected by PCR STR were confirmed by karyotyping. (5) All of the 7 selected loci were informative, with their degrees of heterozygosity ranging between 0.624 and 0.812. D21S2039 and D21S1412 had the highest heterozygosities (> 0.80), D21S1411 and D21S1432 had the lowest (< 0.70). D21S11 and D21S2039 showed the highest rate (>= 40%) of three bands with area ratio 1:1:1. However, D21S1411, D21S1432 and D21S1413 markers had the highest rate of homozygosity (>= 30%). CONCLUSION: PCR STR assay may provide an effective alternative for rapid prenatal DS screening. The 7 selected STR markers are highly informative. The result has featured good accuracy and reliability. PMID- 23744315 TI - [A preliminary study on the application of array comparative genomic hybridization for preimplantaion genetic diagnosis]. AB - OBJECTIVE: To assess the value of array comparative genomic hybridization (array CGH) technique for preimplantation genetic diagnosis (PGD). METHODS: Array CGH was performed on three types of cells, which included 3-5 cells isolated from B2/C38/A1 embryonic stem cell lines, single cells isolated from two discarded normal fertilized embryos, and 10 blastocysts biopsied from 5 couples undergoing PGD for chromosomal translocations. For the 10 blastocysts, 8 were abnormal embryos, 1 appeared to be normal but showed arrested development, and 1 embryo was without any fluorescence signals. 24sure V3 or 24sure+ array chips were applied for CGH analysis. The results were analyzed with a BlueFuse Multi software. RESULTS: (1) The results of cells from B2/C3/A1 embryo stem cells by array CGH were consistent with karyotyping analysis. (2) For the 6 single cell samples from two discarded embryos, 2 blastomeres from one embryo were diagnosed as with aneuploidy and a normal karyotype, respectively. Two out of 4 blastomeres biopsied from another embryo were normal, whilst the remaining two were diagnosed with aneuploidies of -22 and +13. Repeated detection with 24sure+ array was consistent with the 24sure V3 result. (3) Ten cell masses from 10 embryos in PGD cycles were successfully analyzed with array CGH, among which four were confirmed with fluorescence in situ hybridization (FISH) on day 3. In two of them, array CGH confirmed FISH diagnosis. For the remaining two, additional aneuploidies for chromosomes not tested by FISH were discovered by array CGH. Another embryo diagnosed as no signal by FISH was found to have trisomy 13 by array CGH. The remaining 5 embryos also showed discordant results by FISH and array CGH. One embryo from a Robertsonian translocation carrier was found to have monosomy 13 by FISH but trisomy 14 and additional aneuploidies by both 24sure V3 and 24sure+ chips. One embryo with many fragments and arrested development by D5 showed discordant results by FISH and array CGH. However, the FISH and array CGH results for other two embryos from this reciprocal translocation carrier were consistent. Three embryos with inconsistent results by FISH and array CGH had a chromosomal translocation involving q11 region. CONCLUSION: Array CGH is useful for PGD applications for its capability to detect structural chromosomal abnormalities through screening of aneuploidies. However, the 24sure V3 array may not suit detection of translocations with breakpoints close to the q11 region of chromosomes. PMID- 23744316 TI - [Application of array-CGH and MLPA for detection of 4 cryptic unbalanced translocations]. AB - OBJECTIVE: To use array comparative genomic hybridization (array-CGH) and multiplex ligation-dependent probe amplification (MLPA) to detect unbalanced rearrangements in 4 cases suspected to have chromosome disease but were undetected with conventional karyotype analysis, and to assess the applicability of array-CGH and MLPA for detection of unbalanced translocation. METHODS: Genomic DNA was extracted with standard procedures. All cases were analyzed by array-CGH and subtelomeric MLPA. RESULTS: All of the cases were identified to have unbalanced translocations by array-CGH analysis, among which 3 were consistent with subtelomeric MLPA analysis. For the remaining one, its chromosomal abnormality was not detected by MLPA as the imbalance has occurred outside of target regions. CONCLUSION: Both array-CGH and MLPA techniques can complement conventional karyotyping for detecting unbalanced translocations. The combination features both high resolution and efficiency for clinical use. PMID- 23744317 TI - [Expression of FOS protein in glioma and its effect on the growth of human glioma cells]. AB - OBJECTIVE: To study the expression of FOS protein in human glioma tissues and its effect on tumor growth. METHODS: FOS protein expression in glioma tissues was determined with immunohistochemical (IHC) staining. Subsequently, 3-(4,5) dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide (MTT) assay, flow cytometry, transwell invasion and Western blotting were used to assay U87 and U251 cells with reduced FOS expression. RESULTS: The expression of FOS in glioma was increased and strongly correlated with its pathological grade. Abrogating expression of FOS has suppressed proliferation and invasion, and delayed cell cycle at G1 phrase for both U87 and U251 cells. CONCLUSION: The expression of FOS protein in human glioma was strong. FOS protein probably plays a critical role in the progression of gliomas. PMID- 23744318 TI - [Expression of WNK4 gene regulated by aldosterone]. AB - OBJECTIVE: To study the expression and mechanism of WNK4 gene regulated by aldosterone. METHODS: Wistar rats were treated with aldosterone and potassium water. Serum aldosterone and ion as well as urine ion were measured. The expression of WNK4 gene in kidney tissues was detected by real-time PCR. Kidney derived HEK293 cells were cultured, transfected with pGL3-WNK4, and then stimulated by aldosterone. After 24 h of transfection, luciferase activities of the plasmid were detected. RESULTS: Compared with those of the controls, serum aldosterone and urine K(+) of experimental rats were significantly elevated, whilst urine Na(+) was significantly decreased. And urine Cl(-) was significantly increased only in the group of high K(+). Serum K(+), Na(+) and Cl(-) showed no significant difference. Expression of WNK4 gene in kidney tissues was significantly decreased. The luciferase activity of pGL3-WNK4-484 plasmid has decreased after stimulated with aldosterone, while the activity of pGL3-WNK4-275 showed no change. CONCLUSION: Aldosterone can down-regulate the expression of WNK4 through binding with regulatory element in the upstream of the gene. PMID- 23744319 TI - [Detection of pathogenic mutations in Marfan syndrome by targeted next-generation semiconductor sequencing]. AB - OBJECTIVE: To detect pathogenic mutations in Marfan syndrome (MFS) using an Ion Torrent Personal Genome Machine (PGM) and to validate the result of targeted next generation semiconductor sequencing for the diagnosis of genetic disorders. METHODS: Peripheral blood samples were collected from three MFS patients and a normal control with informed consent. Genomic DNA was isolated by standard method and then subjected to targeted sequencing using an Ion Ampliseq(TM) Inherited Disease Panel. Three multiplex PCR reactions were carried out to amplify the coding exons of 328 genes including FBN1, TGFBR1 and TGFBR2. DNA fragments from different samples were ligated with barcoded sequencing adaptors. Template preparation and emulsion PCR, and Ion Sphere Particles enrichment were carried out using an Ion One Touch system. The ion sphere particles were sequenced on a 318 chip using the PGM platform. Data from the PGM runs were processed using an Ion Torrent Suite 3.2 software to generate sequence reads. After sequence alignment and extraction of SNPs and indels, all the variants were filtered against dbSNP137. DNA sequences were visualized with an Integrated Genomics Viewer. The most likely disease-causing variants were analyzed by Sanger sequencing. RESULTS: The PGM sequencing has yielded an output of 855.80 Mb, with a > 100 * median sequencing depth and a coverage of > 98% for the targeted regions in all the four samples. After data analysis and database filtering, one known missense mutation (p.E1811K) and two novel premature termination mutations (p.E2264X and p.L871FfsX23) in the FBN1 gene were identified in the three MFS patients. All mutations were verified by conventional Sanger sequencing. CONCLUSION: Pathogenic FBN1 mutations have been identified in all patients with MFS, indicating that the targeted next-generation sequencing on the PGM sequencers can be applied for accurate and high-throughput testing of genetic disorders. PMID- 23744320 TI - [Analysis of gene mutation in a family featuring autosomal dominant May-Hegglin anomaly]. AB - OBJECTIVE: To analyze clinical features and mutation in MYH9 gene for a family featuring autosomal dominant May-Hegglin anomaly. METHODS: Clinical and pathological features of all family members were analyzed. Blood samples were collected from the proband and other family members, and genomic DNA was extracted. Potential mutations of MYH9 gene exons 10, 25, 26, 30, 38 and 40 were screened with PCR and direct sequencing. After a mutation was identified in the proband, other affected members as well as healthy members from this family were analyzed with a pair of primers to amplify the mutant site. The PCR products were digested with Taq I enzyme and analyzed with agarose gel electrophoresis. RESULTS: All affected members had bleeding tendency and typical features including giant platelets, thrombocytopenia and characteristic Dohle body-like leukocyte inclusions. A heterozygous missense mutation c.5521G>A (p.Glu1841Lys) in exon 38 of the MYH9 gene was identified in all affected members from this family. CONCLUSION: The variant, c.5521G>A (p.Glu1841Lys) of MYH9, has co segregated with the phenotype in the family. The mutant site is a hot spot in Chinese population. PMID- 23744321 TI - [A rare p phenotype caused by a 26-bp deletion in alpha 1,4-galactosyltransferase gene]. AB - OBJECTIVE: To delineate serological features and genetic basis for a rare p phenotype of P1Pk blood group system found in a Chinese individual. METHODS: Serological assaying was carried out for a proband with unexpected antibody found in his serum using specific antibodies and panel cells. Coding regions and flanking introns of alpha 1,4-galactosyltransferase gene (A4GALT) associated with the p phenotype were screened with polymerase chain reaction and DNA sequencing. RESULTS: A rare p phenotype of the P1Pk blood group system has been identified with red blood cells from the proband, whose serum contained anti-Tja antibody which can agglutinate and hemolyze with other common red blood cells. Other members of the proband's family were all normal with P1 or P2 phenotype. DNA sequencing has identified in the proband a homozygous 26 bp deletion at position 972 to 997 of the A4GALT gene. The deletion has caused a shift of the reading frame, resulting in a variant polypeptide chain with additional 83 amino acid residues compared with the wild-type protein. Other family members were either heterozygous for above deletion or non-deleted. CONCLUSION: A 26 bp deletion at position 972 to 997 of the A4GALT gene has been identified in a Chinese individual with p phenotype. PMID- 23744322 TI - [Identification of a novel mutation of factor XII gene in a family with coagulation FXII deficiency]. AB - OBJECTIVE: To analyze genetic mutation and molecular pathogenesis in a family affected with inherited coagulation factor XII(FXII) deficiency. METHODS: Activated partial thromboplastin time (APTT), FXII procoagulant activity (FXII:C), FXII antigen (FXII:Ag) and other coagulants were measured. For affected members of the family, exons 1-14 and flanking intronic regions of the FXII gene were amplified with polymerase chain reaction (PCR) and sequenced thereafter. Expression plasmids containing mutant FXII cDNA was constructed and transfected into COS7 cells transiently. Expressions of FXII:Ag and FXII:C were analyzed. RESULTS: The proband has manifested a prolonged APTT of 108.1 s (reference range: 27.0-41.0 s). Her husband has a normal APTT. Other members of the family had slightly increased APTT. The FXII:C and FXII:Ag of the proband have both dropped to about 0.01 (reference range: 0.72-1.13). The FXII:C levels of her husband, son, daughter and grandchild were 0.57, 0.24, 0.14, 0.16, respectively. And the FXII:Ag levels in her husband, son, daughter and grandchild were 0.55, 0.27, 0.15, 0.21, respectively. The proband and her daughter have both carried a heterozygous deletional mutation 6800-6808delAGCTGGGAG (6800-6808del9bp) in exon 9. For the promoter region of the FXII gene, the genotypes of the proband, her son, daughter and grandchild was TT, whilst that of her husband was CT. Expression study has shown that, whilst the mutant FXII protein has accumulated in the cells similar to wild-type protein, its secretion has reduced approximately by half. CONCLUSION: A novel deletional mutation 6800-6808del9bp has been identified in the FXII gene. Although mutant FXII protein can still accumulate in cells, its secretion has become insufficient. The 6800-6808del9bp mutation and 46T/T have both contributed to the pathogenesis of FXII deficiency in the family, but may have not been the sole cause. PMID- 23744323 TI - [A de novo mutation of P gene causes oculocutaneous albinism type 2 with prenatal diagnosis]. AB - OBJECTIVE: To determine the genotype of a family affected with oculocutaneous albinism (OCA) and to provide genetic counseling and prenatal diagnosis. METHODS: To determine the genotypes and mutational sites through PCR and sequencing for all exons and exon-intron junctions of 4 OCA genes in the proband and the P gene of her parents. Prenatal genotyping of the fetus was carried out using amniocentesis sample. RESULTS: The patient was diagnosed with OCA2 based on a genotype of c.1327G>A/c.2360C>T. Her father was heterozygous for c.2360C> T, whilst her mother has none of the two mutations. c.1327G>A is therefore a maternal de novo mutation. Neither of the mutations was found in the fetus. CONCLUSION: A maternally inherited de novo mutation c.1327G>A has been identified in the patient. In order to detect de novo mutations, full sequence analysis is necessary. PMID- 23744324 TI - [A novel mutation of cartilage oligomeric matrix protein gene underlies multiple epiphyseal dysplasia]. AB - OBJECTIVE: To perform mutation analysis for a female with multiple epiphyseal dysplasia (MED) and provide pre-symptomatic and prenatal diagnosis. METHODS: Mutation screening of cartilage oligomeric matrix protein (COMP) gene was carried out through targeted next-generation DNA sequencing and Sanger sequencing. RESULTS: A novel c.956 A>T resulting in substitution of Aspartic acid 319 for Valine (p.Asp319Val) has been identified in exon 9 of the COMP gene in the patient. As predicted by a SIFT software, above mutation can cause damage to the structure of COMP protein. CONCLUSION: A novel c.956 A>T substitution mutation has been identified in a patient featuring MED. PMID- 23744325 TI - [Molecular basis and clinical blood transfusion for cases with ABO typing discrepancy]. AB - OBJECTIVE: To investigate the molecular genetic basis of samples with ABO typing discrepancy and provide the guidline for identification and clinical transfusion for these samples. METHODS: Six cases with similar serological characteristics were collected. Serological method, PCR-SSP and direct sequencing of ABO gene were used to explore the underlying mechanism. Condition of clinical transfusion of patients was also reviewed. RESULTS: Three conditions were related with the ABO blood type discrepancy, which included weaken antigen (2 cases), weakened antibody (3 cases) and ABO subtype (1 case). The satisfactory effect of transfusion was achieved in all patients with the principle of the same blood type or the compatible crossmatch. CONCLUSION: Heterogeneity has existed with the ABO group. Indivianals with same reaction pattern may result in different mechanisms. PMID- 23744326 TI - [Analysis of null alleles for 17 Y chromosome-short tandem repeat loci in infertile males]. AB - OBJECTIVE: To investigate the characteristics of null allele for 17 Y-chromosomal short tandem repeats (Y-STR) loci in a group of infertile males. METHODS: Two hundred thirty six infertile males featuring non-obstructive azoospermia and severe oligozoospermia were analyzed with an AmpFISTR ((R)) Yfiler (TM) kit. Deletions of azoospermia factor (AZF) fragments were confirmed with Y chromosome sequence-tagged sites (STSs) analysis using modified multiplex PCR. RESULTS: The overall prevalence of AZF microdeletions was 16.95% (40/236). In the non obstructive azoospermia group, 13 cases had AZFc deletion, 6 cases had AZFb+c deletion, 2 cases had AZFa deletion, 1 case had AZFb deletion. In the severe oligozoospermia group, 17 cases had AZFc deletion and 1 had AZFb deletion. No AZFa+b+c deletion was detected. Forty cases showed null alleles by scanning of the 17 STR loci. Deletions of DYS438, DYS439, DYS437, DYS389I and DYS389II were found in the 2 cases with AZFa deletion. In patients with AZFb deletion, DYS392 and DYS385a/b were found deleted. Deletions of DYS448 were detected in all of the 30 cases with AZFc deletion. Deletions of DYS392, DYS385a/b, and DYS448 were found in 6 cases with AZFb+c deletion. CONCLUSION: Deletions of the Y chromosome AZF regions are associated with azoospermia and severe oligozoospermia. Null allele due to complete absence of AZFa, AZFb and AZFc regions may lead to misinterpretation in the sexual assault cases. Revealing the locus heterogeneity in male infertility population can enrich the Y-STR database and facilitate interpretation STR data in forensic DNA testing. PMID- 23744327 TI - [Association of P53 gene polymorphisms with susceptibility to endometriosis]. AB - OBJECTIVE: To assess the association of a single nucleotide polymorphism(SNP) in tumor suppressor gene P53 with the risk of endometriosis (EM) in Han Chinese women. METHODS: For 460 EM patients, 113 patients with endometrial carcinoma and 530 matched unrelated controls, a rs1042522(C/G) SNP of the P53 gene was genotyped by polymerase chain reaction-single strand polymorphism (PCR-SSP) and DNA sequencing. RESULTS: A significant difference has been detected in the distribution of rs1042522 alleles and genotypes between the EM patients and controls (P< 0.01). Allele G has increased the risk of EM by 1.209 times, while allele C has reduced this risk by 0.837 times. Compared with GG genotype, GC and CC genotypes have both increased the risk for EM (OR=2.073, 95%CI: 1.521-2.820, and OR=1.930, 95%CI: 1.363-2.733, respectively). Significant differences were also detected in the distribution of rs1042522 alleles and genotypes between endometrial carcinoma patients and controls (P< 0.01). Allele G has increased the risk to endometrial carcinoma by 1.311 times, while allele C has reduced this risk by 0.757 times. Compared with GG genotypes, individuals with GC and CC genotypes are more likely to be affected with endometrial carcinoma (OR=2.778, 95%CI: 1.585-4.870, and OR=2.864, 95%CI: 1.557-5.263, respectively). CONCLUSION: Our study has suggested a significant association between the rs1042522(G/C) polymorphism and susceptibility to EM in Han Chinese women. The mechanism of EM is similar to carcinoma from genetics point of view. PMID- 23744328 TI - [Association between CACNB2 gene polymorphisms and essential hypertension]. AB - OBJECTIVE: To assess the association between single nucleotide polymorphisms (SNPs) of calcium channel beta 2 subunit (CACNB2) gene and essential hypertension (EH) in ethnic Han Chinese in Wenzhou area, and to study the influence of rs7069292 alleles on gene expression with luciferase reporter technique. METHODS: Sixty hundred and thirty seven Han Chinese with EH and 600 normal controls were enrolled. Genotypes of 6 SNP within CACNB2 gene including rs2228645, rs2357928, rs7069292, rs7099380, rs10764319 and rs11014166 were determined with matrix assisted laser desorption ionization/time of flight mass spectrometer (MALDI-TOF MS). A luciferase reporter gene plasmid containing the fragment flanking rs7069292 (-2831 bp to -2460 bp) in the 5' regulatory region of CACNB2 was constructed. RESULTS: Compared with the control, CT and TT genotypes for the rs7069292 locus were significantly more common in EH group (5.20% vs. 2.17%, 2.59% vs. 1.08%, P< 0.05). CC genotype was not found. Promoter activity for allele C of the rs7069292 locus was significantly increased compared with allele T (P< 0.05). No significant difference was detected for other 5 SNPs in terms of genotypes and allele frequency. CONCLUSION: The rs7069292 CT polymorphism of the CACNB2 gene is associated with EH in ethnic Han Chinese from Wenzhou area. A T>C mutation may affect the expression of CACNB2. PMID- 23744329 TI - [Association of MK2 and ZFP36 gene polymorphisms with high density lipoprotein cholesterol in Uygur population from Hetian area of Xinjiang]. AB - OBJECTIVE: To assess the association of genetic polymorphisms of mitogen activated protein kinase activated protein kinase 2 gene (MK2) and zinc finger protein 36 gene (ZFP36) with high density lipoprotein cholesterol (HDL-C) in Xinjiang Urgur population. METHODS: Nine hundred thirty Uygur individuals were randomly recruited from Hetian area. Single nucleotide polymorphisms (SNP) in MK2 gene (rs44890 and rs45514798) and ZFP36 gene (rs251864 and rs3746083) were determined with Taqman-PCR. All subjects were investigated with questionnaire, physical examination and measurement of lipid levels and plasma tumor necrosis factor-alpha. RESULTS: (1)In Uygur men younger than 50 years old, SNP rs45514798 was associated with HDL-C [dominant model P=0.054, OR(95%CI)0.261(0.082-0.833) after age, smoking, drinking, abdominal circumference, waist/hip ratio and body mass index and tumor necrosis factor were controlled]. (2) For males younger than 50 years old, the concentration of total cholesterol, HDL-C, low density lipoprotein cholesterol were different in dominant model of rs45514798(P< 0.05). Female: total cholesterol, low density lipoprotein cholesterol were different in dominant model of rs45514798(P< 0.05). (3) The distribution of genotype of ZFP36 gene did not differ significantly between the low HDL-C groups and the control group. CONCLUSION: MK2 gene rs45514798 polymorphisms may be associated with HDL-C in Uygur men younger than 50 years old from Hetian area of Xinjiang. ZFP36 gene is not associated with HDL-C in Uygur people from Xinjiang. PMID- 23744330 TI - [Association study of MC1R gene polymorphisms with freckles in Chinese Han population from Chengdu]. AB - OBJECTIVE: To assess the association between single nucleotide polymorphisms (SNPs) of melanocortin-1 receptor gene (MC1R) and freckles in Chinese Han population from Chengdu. METHODS: Twenty randomly selected samples were used to select SNPs of the MC1R gene through DNA sequencing. Pyrosequencing in combination with DNA pooling technique was used to assess allelic frequencies of the selected SNPs in 111 individuals with freckles and 124 normal controls. Representative SNPs were selected based on their functional implications and minimum allele frequency (MAF> 0.05). Genotype of the SNPs were determined with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or pyrosequencing. RESULTS: Based on results of DNA sequencing and pyrosequencing, 4 SNPs (rs2228479, rs885479, rs33932559 and rs2228478) were selected to determine the genotype for each sample. Comparison of genotypic and allelic frequencies of the 4 SNPs with chi (2) test has found no significant difference between the two groups (P> 0.05). For rs33932559, the frequencies of T allele were respectively 90.09% and 91.94% for individuals with freckles and normal controls. For rs2228479 and rs2228478, the frequencies of G and A allele were both about 77%. For rs885479, the frequency of T allele was about 60%. None of the above 3 SNPs showed a significant difference between the two groups in terms of allelic or genotypic frequencies. CONCLUSION: No association between the selected SNPs of MC1R gene has been found with development of freckles for the selected Chinese Han population from Chengdu. PMID- 23744331 TI - [Variation of sperm DNA fragmentation index in male partners from infertile couples]. AB - OBJECTIVE: To investigate variation of sperm DNA fragmentation index (DFI) in male partners of infertile couples. METHODS: A total of 539 males between April 2009 and April 2012 were analyzed. At least one repeated routine semen analysis and sperm DNA fragmentation test were performed for each sample by sperm chromatin dispersion (SCD) analysis following World Health Organization guidelines. Coefficient of variation (CV) for DFI was calculated. RESULTS: Respectively, 1, 2, 3 and 4 repeated SCD analyses were carried out on 473, 59, 6 and 1 semen samples. The median interval between the first and repeated SCD measurements was 3.0 (1.0-11.0) months. For the first tested samples, the between sample coefficient of variation (CVB) for DFI was 71.2%. A significant difference has been found between DFI of the first measurement and DFI of repeated measurement in 0.5 to 3 months, 3 to 12 months and 12 to 34 months (P< 0.01). Compared with the first test, 26.3% of males were on both sides of the cut-off point of 18%. The median within-subject coefficient of variation (CVw) for DFI of 539 men was 26.0% (12.6%-42.8%). And the median CVw DFI was significantly lower compared with CVw of sperm count, concentration, progressive motility and normal morphology (P< 0.01). Significant correlations were found between the CVw DFI and sperm count, concentration and interval among the samples (P< 0.05). CONCLUSION: DFI of male partners for infertile couples is a parameter with substantial variation, repeated SCD measurements are therefore recommended. PMID- 23744332 TI - [Prevalence of chromosome 9 abnormalities among pediatric specimens]. AB - OBJECTIVE: To perform cytogenetic analysis for children, especially newborns suspected for chromosome abnormalities. METHODS: Peripheral blood or born marrow specimens were respectively cultured in proper media. Karyograms were analyzed following G-banding. RESULTS: Of 154 blood specimens, numerical chromosomal abnormalities were identified in 20 patients, which included 19 with trisomy 21. Structural aberrations were identified in 13 patients, among which chromosome 9 aberrations were seen in 6 cases. These included 3 inversions, 1 deletion, 1 insertion and 1 duplication. All aberrations were located in pericentromere region of chromosome 9 with clinical manifestations including congenital heart disease, peculiar facial appearance, paralysis, dysplasia and/or movement disorder. Chromosome polymorphisms were found in 20 patients, most of which had absence of satellites or variation of heterochromatin on chromosome 9. Of 10 bone marrow specimens from children suspected for acute leukemia, chromosome abnormalities were identified in 5 patients. CONCLUSION: Cytogenetic analysis is useful for children featuring multiple congenital abnormalities. Chromosome 9 abnormalities and their clinical relevance should attract more attention. PMID- 23744333 TI - [Polymorphisms of (CAG)n and(GGN)n repeats of androgen receptor gene among ethnic Hui and Han Chinese from Ningxia]. AB - OBJECTIVE: To compare the distribution of (CAG)n and (GGN)n repeats polymorphisms of androgen receptor (AR) gene between Hui and Han ethnic Chinese from Ningxia. METHODS: Genotypes of above repeats were determined with DNA sequencing method. RESULTS: The distribution of (GGN)n repeats was significantly different between the two ethnic groups (P< 0.01), though no such difference was detected with (CAG)n repeats (P> 0.05). Particularly, Han Chinese women carrying 23 GGN repeats were significantly fewer (48.4%) than Hui women (64.7%, P=0.01). CONCLUSION: The distribution of GGN repeat is significantly differently among Hui and Han Chinese ethnics from Ningxia. PMID- 23744334 TI - [A pedigree with systemic lupus erythematosus and ankylosing spondylitis]. PMID- 23744335 TI - [Familial nonmedullary thyroid cancinoma in two pedigrees with nine cases]. PMID- 23744336 TI - [A pedigree with blepharophimosis-ptosis-epicanthus inversus syndrome]. PMID- 23744337 TI - [A pedigree with big Y chromosome and congenital ectrodactyly]. PMID- 23744338 TI - Chrysin promotes osteogenic differentiation via ERK/MAPK activation. AB - The effect of the anti-inflammatory flavonoid chrysin on osteogenesis was determined in preosteoblast MC3T3-E1 cells. Results demonstrated that chrysin could induce osteogenic differentiation in the absence of other osteogenic agents. Chrysin treatment promoted the expression of transcription factors (Runx2 and Osx) and bone formation marker genes (Col1A1, OCN, and OPN) as well as enhanced the formation of mineralized nodules. During osteogenic differentiation, chrysin preferentially activated ERK1/2, but not JNK nor the p38 MAPKs. Further experiments with inhibitors revealed the co-treatment of U0126, PD98059, or ICI182780 (a general ER antagonist) with chrysin effectively abrogated the chrysin-induced osteogenesis and ERK1/2 activation. Thus, the effect of chrysin on osteogenesis is ERK1/2-dependent and involves ER. Therefore, chrysin has the significant potential to enhance osteogenesis for osteoporosis prevention and treatment. PMID- 23744339 TI - Angiotensin IV upregulates the activity of protein phosphatase 1alpha in Neura-2A cells. AB - The peptide angiotensin IV (Ang IV) is a derivative of angiotensin II. While insulin regulated amino peptidase (IRAP) has been proposed as a potential receptor for Ang IV, the signalling pathways of Ang IV through IRAP remain elusive. We applied high-resolution mass spectrometry to perform a systemic quantitative phosphoproteome of Neura-2A (N2A) cells treated with and without Ang IV using sta ble-isotope labeling by amino acids in cell culture (SILAC), and identified a reduction in the phosphorylation of a major Ser/Thr protein phosphorylase 1 (PP1) upon Ang IV treatment. In addition, spinophilin (spn), a PP1 regulatory protein that plays important functions in the neural system, was expressed at higher levels. Immunoblotting revealed decreased phosphorylation of p70S6 kinase (p70(S6K)) and the major cell cycle modulator retinoblastoma protein (pRB). These changes are consistent with an observed decrease in cell proliferation. Taken together, our study suggests that Ang IV functions via regulating the activity of PP1. PMID- 23744341 TI - Ultrafast, accurate, and robust localization of anisotropic dipoles. AB - The resolution of single molecule localization imaging techniques largely depends on the precision of localization algorithms. However, the commonly used Gaussian function is not appropriate for anisotropic dipoles because it is not the true point spread function. We derived the theoretical point spread function of tilted dipoles with restricted mobility and developed an algorithm based on an artificial neural network for estimating the localization, orientation and mobility of individual dipoles. Compared with fitting-based methods, our algorithm demonstrated ultrafast speed and higher accuracy, reduced sensitivity to defocusing, strong robustness and adaptability, making it an optimal choice for both two-dimensional and three-dimensional super-resolution imaging analysis. PMID- 23744340 TI - UV-B-induced photomorphogenesis in Arabidopsis. AB - Ultraviolet-B (UV-B) is a relatively minor component of sunlight, but can induce stress-related physiological processes or UV-B-specific photomorphogenic responses in plants. In the last decade, significant progress has been made in understanding the UV-B photomorphogenic pathway, including identification of the key components in the pathway, molecular characterization of UV-B photoreceptor and perception mechanism, and elucidation of the signal transduction mechanisms from the photoactivated UV-B receptor to downstream gene expression. This review summarizes the key players identified to date in the UV-B photomorphogenic pathway and their roles in mediating UV-B signal transduction. PMID- 23744342 TI - The increment in standardized uptake value determined using dual-phase 18F-FDG PET is a promising prognostic factor in non-small-cell lung cancer. AB - PURPOSE: We aimed to determine whether the increment in the maximal standardized uptake value (SUVmax) of the primary lung tumour between the initial and delayed imaging by dual-phase (18)F-FDG PET has prognostic value in patients with non small-cell lung cancer (NSCLC). METHODS: We reviewed the records of patients with NSCLC who underwent pretreatment dual-phase (18)F-FDG PET/CT scans acquired at 1 h and 2 h after injection. The SUVmax increment (SUVinc) of the primary lung tumour was the 2-h SUVmax minus the 1-h SUVmax. Univariate and multivariate analyses were used to assess the prognostic significance of SUVinc, retention index, whole-body total metabolic tumour volume, whole-body total lesion glycolysis (TLGwb), 1-h SUVmax, 2-h SUVmax, gender, age, performance status, histological subtype, T stage, N stage and clinical stage. RESULTS: The records of 187 consecutive patients were reviewed. The median follow-up time was 3.9 years. The estimated median progression-free survival (PFS) and overall survival (OS) were 1.3 years and 4.4 years, respectively. An SUVinc cut-off value of >1 had the best discriminative yield for PFS. The 3-year PFS and OS were 61.6 % and 87.8 % in patients with SUVinc <= 1 versus 21.1 % and 46.2 % in patients with SUVinc >1 (all P < 0.01). Using the forward stepwise multivariate Cox proportional hazards model, SUVinc, TLGwb, and clinical stage were significant factors for PFS (all P < 0.01). A subgroup analysis of 117 patients treated with surgery showed that SUVinc (P = 0.02) and clinical stage (P < 0.01) were significant prognostic factors for PFS. Furthermore, in stage I patients treated with surgery alone, SUVinc was the only significant prognostic factor (HR 28.07; 95 % CI 2.42 - 326.41). CONCLUSION: SUVinc determined from dual-phase (18)F-FDG PET is a promising prognostic factor for NSCLC. It adds to the value of dual phase (18)F-FDG PET. PMID- 23744344 TI - Tumor-suppressive effects of miR-29c on gliomas. AB - Although miR-29c has been shown to be expressed less in various kinds of solid cancers, its expression pattern and tumor-suppressive effects in gliomas remain largely unknown. In this study, we detected miR-29c in 10 nontumoral brain tissues and 60 gliomas of various grades and found that its labeling indexes were significantly lower in gliomas (53.7% for the nontumoral brain tissues, and 18.9, 5.5, and 1.8% for the WHO grade I-II, grade III, and grade IV glioma groups, respectively). We then overexpressed miR-29c in the SNB19 glioblastoma cell line and found that it markedly downregulated the expression level of CDK6, and accordingly increased the percentage of the tumor cells in the G1 phase from 44.5 to 69.1% and decreased the colony formation efficiency from 81.1 to 51.5%. miR 29c overexpression also increased the percentage of apoptotic cells from 27.2 to 54.8%, and led to a more than 50% decrease in the migratory and invasive abilities of the tumor cells. Our study shows that miR-29c can effectively block the proliferation of glioblastoma cells by inducing G1 arrest, promote their apoptosis, and inhibit their migration and invasion. At least some of its tumor suppressive effects are mediated by specifically downregulating the expression of CDK6. Therefore, miR-29c can be used as a tumor suppressor in the gene therapy of malignant gliomas. PMID- 23744345 TI - Repulsive guidance molecule a regulates hippocampal mossy fiber branching in vitro. AB - Repulsive guidance molecule a (RGMa), which binds to its receptor neogenin, has been well determined as a repulsive axon guidance molecule. However, whether RGMa affects the growth of hippocampal mossy fibers, the axons of dentate granule cells, has been unknown. In the present study, we found that the primary neurons in the hippocampus express both RGMa and neogenin in the postnatal rats. To examine the role of RGMa in the mossy fiber growth, the morphology of granule cells was clearly visualized by transfecting membrane-targeted green fluorescent protein using a single-cell electroporation method in cultured hippocampal slices. In the slice cultures, we found that intrinsic RGMa is required to inhibit excess branching of the hippocampal mossy fibers. Furthermore, hyperexcitability-induced aberrant branching of the mossy fibers in the cultured slices was blocked by applying the recombinant RGMa protein. Therefore, this study suggests that RGMa regulates the proper axonal branching of hippocampal mossy fibers. PMID- 23744346 TI - Apolipoprotein E-dependent differences in innate immune responses of maturing human neuroepithelial progenitor cells exposed to HIV-1. AB - HIV enters the brain early during infection and induces a chronic inflammatory state that can result in neurological abnormalities in a subset of infected individuals. To investigate the effects of HIV exposure on neurogenesis and neuronal survival in the brain, we have used a model system consisting of human neuroepithelial progenitor (NEP) cells that undergo directed differentiation into astrocytes and neurons in vitro. Changes in gene expression in NEP cultures as a result of HIV exposure were investigated using gene expression microarrays with the Illumina HT-12 V4_0_R1 platform array. Through this approach, we identified a group of genes specifically upregulated by exposure to virus that are strongly related to interferon induced responses and antigen presentation. When the data were stratified by their apolipoprotein genotype, this innate immune response was more robust in the apolipoprotein E3/E3 genotype cultures than in the apolipoprotein E3/E4 counterparts. Biological processes as defined by the gene ontology (GO) program were also differently affected upon virus exposure in cultures of the two genotypes, particularly those related to antigen presentation and the actions of interferons. Differences occurred in both in numbers of genes affected and their significance in the GO processes in which they participate, with apoE3/E3 > apoE3/E4. These data suggest that maturing NEP cultures recognize HIV and respond to it by mounting an innate immune response with a vigor that is influenced by the apolipoprotein E genotype of the cells. PMID- 23744348 TI - Mass media interventions for smoking cessation in adults. AB - BACKGROUND: Mass media tobacco control campaigns can reach large numbers of people. Much of the literature is focused on the effects of tobacco control advertising on young people, but there are also a number of evaluations of campaigns targeting adult smokers, which show mixed results. Campaigns may be local, regional or national, and may be combined with other components of a comprehensive tobacco control policy. OBJECTIVES: To assess the effectiveness of mass media interventions in reducing smoking among adults. SEARCH METHODS: The Cochrane Tobacco Addiction Group search strategy was combined with additional searches for any studies that referred to tobacco/smoking cessation, mass media and adults. We also searched the Cochrane Register of Controlled Trials (CENTRAL) and a number of electronic databases. The last search was carried out in February 2013. SELECTION CRITERIA: Controlled trials allocating communities, regions or states to intervention or control conditions; interrupted time series. Adults, 25 years or older, who regularly smoke cigarettes. Studies which cover all adults as defined in studies were included. Mass media are defined here as channels of communication such as television, radio, newspapers, billboards, posters, leaflets or booklets intended to reach large numbers of people, and which are not dependent on person-to-person contact. The purpose of the mass media campaign must be primarily to encourage smokers to quit. They could be carried out alone or in conjunction with tobacco control programmes. The primary outcome was change in smoking behaviour. This could be reported as changes in prevalence, changes in cigarette consumption, quit rates, odds of being a smoker. DATA COLLECTION AND ANALYSIS: Two authors independently assessed all studies for inclusion criteria and for study quality. One author (MB) extracted data, and a second author (LS) checked them.Results were not pooled due to heterogeneity of the included studies and are presented narratively and in table form. MAIN RESULTS: Eleven campaigns met the inclusion criteria for this review. Studies differed in design, settings, duration, content and intensity of intervention, length of follow-up, methods of evaluation and also in definitions and measures of smoking behaviour used. Among nine campaigns reporting smoking prevalence, significant decreases were observed in the California and Massachusetts statewide tobacco control campaigns compared with the rest of the USA. Some positive effects on prevalence in the whole population or in the subgroups were observed in three of the remaining seven studies. Three large-scale campaigns of the seven presenting results for tobacco consumption found statistically significant decreases. Among the seven studies presenting abstinence or quit rates, four showed some positive effect, although in one of them the effect was measured for quitting and cutting down combined. Among the three that did not show significant decreases, one demonstrated a significant intervention effect on smokers and ex-smokers combined. AUTHORS' CONCLUSIONS: There is evidence that comprehensive tobacco control programmes which include mass media campaigns can be effective in changing smoking behaviour in adults, but the evidence comes from a heterogeneous group of studies of variable methodological quality. One state-wide tobacco control programme (Massachusetts) showed positive results up to eight years after the campaign. Another (California) showed positive results during the period of adequate funding and implementation and in final evaluation since the beginning of the programme. Six of nine studies carried out in communities or regions showed some positive effects on smoking behaviour and at least one significant change in smoking prevalence (Sydney). The intensity and duration of mass media campaigns may influence effectiveness, but length of follow-up and concurrent secular trends and events can make this difficult to quantify. No consistent relationship was observed between campaign effectiveness and age, education, ethnicity or gender. PMID- 23744347 TI - Opioid antagonists for smoking cessation. AB - BACKGROUND: The reinforcing properties of nicotine may be mediated through release of various neurotransmitters both centrally and systemically. People who smoke report positive effects such as pleasure, arousal, and relaxation as well as relief of negative affect, tension, and anxiety. Opioid (narcotic) antagonists are of particular interest to investigators as potential agents to attenuate the rewarding effects of cigarette smoking. OBJECTIVES: To evaluate the efficacy of opioid antagonists in promoting long-term smoking cessation. The drugs include naloxone and the longer-acting opioid antagonist naltrexone. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialised Register for trials of naloxone, naltrexone and other opioid antagonists and conducted an additional search of MEDLINE using 'Narcotic antagonists' and smoking terms in April 2013. We also contacted investigators, when possible, for information on unpublished studies. SELECTION CRITERIA: We considered randomised controlled trials comparing opioid antagonists to placebo or an alternative therapeutic control for smoking cessation. We included in the meta-analysis only those trials which reported data on abstinence for a minimum of six months. We also reviewed, for descriptive purposes, results from short-term laboratory-based studies of opioid antagonists designed to evaluate psycho-biological mediating variables associated with nicotine dependence. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the study population, the nature of the drug therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months follow-up in patients smoking at baseline. Abstinence at end of treatment was a secondary outcome. We extracted cotinine- or carbon monoxide-verified abstinence where available. Where appropriate, we performed meta-analysis, pooling risk ratios using a Mantel Haenszel fixed-effect model. MAIN RESULTS: Eight trials of naltrexone met inclusion criteria for meta-analysis of long-term cessation. One trial used a factorial design so five trials compared naltrexone versus placebo and four trials compared naltrexone plus nicotine replacement therapy (NRT) versus placebo plus NRT. Results from 250 participants in one long-term trial remain unpublished. No significant difference was detected between naltrexone and placebo (risk ratio (RR) 1.00; 95% confidence interval (CI) 0.66 to 1.51, 445 participants), or between naltrexone and placebo as an adjunct to NRT (RR 0.95; 95% CI 0.70 to 1.30, 768 participants). The estimate was similar when all eight trials were pooled (RR 0.97; 95% CI 0.76 to 1.24, 1213 participants). In a secondary analysis of abstinence at end of treatment, there was also no evidence of any early treatment effect, (RR 1.03; 95% CI 0.88 to 1.22, 1213 participants). No trials of naloxone or buprenorphine reported abstinence outcomes. AUTHORS' CONCLUSIONS: Based on data from eight trials and over 1200 individuals, there was no evidence of an effect of naltrexone alone or as an adjunct to NRT on long-term smoking abstinence, with a point estimate strongly suggesting no effect and confidence intervals that make a clinically important effect of treatment unlikely. Although further trials might narrow the confidence intervals they are unlikely to be a good use of resources. PMID- 23744349 TI - Interventions for the restorative care of amelogenesis imperfecta in children and adolescents. AB - BACKGROUND: Amelogenesis imperfecta (AI) is a tooth development disorder in which the teeth are covered with thin, abnormally formed enamel. This enamel is easily fractured and damaged, which affects the appearance of the teeth, especially if left untreated. Negative psychological outcomes, due to compromised appearance and function, in patients with AI, have been found to compromise a person's attractiveness and reduce social interaction. The treatment used depends on the severity of the problem. OBJECTIVES: To compare the success rates of different restorative materials and techniques used for the restoration of anterior and posterior teeth with AI in terms of patient satisfaction (aesthetics and sensitivity) and function. SEARCH METHODS: We searched the Cochrane Oral Health Group's Trials Register (to 18 April 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 3), MEDLINE via OVID (1946 to 18 April 2013), EMBASE via OVID (1980 to 18 April 2013), CINAHL via EBSCO (1980 to 18 April 2013), Abstracts of the Conference Proceedings of the International Association for Dental Research (2001 to 18 April 2013) and reference lists of relevant articles. There were no restrictions on language or date of publication in the electronic searches. SELECTION CRITERIA: Randomised controlled trials where children and adolescents with AI who required restoration of teeth were allocated to different restoration techniques would have been selected. Outcomes which would have been evaluated were patient satisfaction, aesthetics, masticatory function and longevity of restorations. DATA COLLECTION AND ANALYSIS: Two review authors would have extracted data and assessed the risk of bias in included studies independently. Disagreement between the two authors would have been resolved by consulting a third review author. First authors were contacted for additional information and unpublished data. MAIN RESULTS: No studies met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: We found no randomised controlled trials of restorative treatments for children and adolescents with AI, and therefore there is no evidence as to which is the best restoration. Well defined randomised controlled trials which recruit children and adolescents and focus on the type and severity of the disorder should be undertaken to determine the best intervention for restoring teeth affected by AI. PMID- 23744350 TI - Consequences of the combined loss of BOK and BAK or BOK and BAX. AB - The multi-BCL-2 homology domain pro-apoptotic BCL-2 family members BAK and BAX have critical roles in apoptosis. They are essential for mitochondrial outer membrane permeabilization, leading to the release of apoptogenic factors such as cytochrome-c, which promote activation of the caspase cascade and cellular demolition. The BOK protein has extensive amino-acid sequence similarity to BAK and BAX and is expressed in diverse cell types, particularly those of the female reproductive tissues. The BOK-deficient mice have no readily discernible abnormalities, and its function therefore remains unresolved. We hypothesized that BOK may exert functions that overlap with those of BAK and/or BAX and examined this by generating Bok(-/-)Bak(-/-) and Bok(-/-)Bax(-/-) mice. Combined loss of BOK and BAK did not elicit any noticeable defects, although it remains possible that BOK and BAK have critical roles in developmental cell death that overlap with those of BAX. In most tissues examined, loss of BOK did not exacerbate the abnormalities caused by loss of BAX, such as defects in spermatogenesis or the increase in neuronal populations in the brain and retina. Notably, however, old Bok(-/-)Bax(-/-) females had abnormally increased numbers of oocytes from different stages of development, indicating that BOK may have a pro-apoptotic function overlapping with that of BAX in age-related follicular atresia. PMID- 23744351 TI - Protogenin prevents premature apoptosis of rostral cephalic neural crest cells by activating the alpha5beta1-integrin. AB - The bones and connective tissues of the murine jaws and skull are partly derived from cephalic neural crest cells (CNCCs). Here, we report that mice deficient of protogenin (Prtg) protein, an immunoglobulin domain-containing receptor expressed in the developing nervous system, have impairments of the palatine and skull. Data from lineage tracing experiments, expression patterns of neural crest cell (NCC) marker genes and detection of apoptotic cells indicate that the malformation of bones in Prtg-deficient mice is due to increased apoptosis of rostral CNCCs (R-CNCCs). Using a yeast two-hybrid screening, we found that Prtg interacts with Radil, a protein previously shown to affect the migration and survival of NCCs in zebrafish with unknown mechanism. Overexpression of Prtg induces translocation of Radil from cytoplasm to cell membrane in cultured AD293 cells. In addition, overexpression of Prtg and Radil activates alpha5beta1 integrins to high-affinity conformational forms, which is further enhanced by the addition of Prtg ligand ERdj3 into cultured cells. Blockage of Radil by RNA interference abolishes the effect of ERdj3 and Prtg on the alpha5beta1-integrin, suggesting that Radil acts downstream of Prtg. Prtg-deficient R-CNCCs display fewer activated alpha5beta1-integrins in embryos, and these cells show reduced migratory ability in in vitro transwell assay. These results suggest that the inside-out activation of the alpha5beta1-integrin mediated by ERdj3/Prtg/Radil signaling is crucial for proper functions of R-CNCCs, and the deficiency of this pathway causes premature apoptosis of a subset of R-CNCCs and malformation of craniofacial structures. PMID- 23744352 TI - Potassium channel activation inhibits proliferation of breast cancer cells by activating a senescence program. AB - Traditionally the hERG1 potassium channel has been known to have a fundamental role in membrane excitability of several mammalian cells including cardiac myocytes. hERG1 has recently been found to be expressed in non-excitable cancer cells of different histogenesis, but the role of this channel in cancer biology is unknown. Results form recent studies on the effect hERG1 inhibition in some breast cancer cells are controversial as it can lead to apoptosis or protect against cell death. Nevertheless, these data suggest that the hERG1 channel could have an important role in cancer biology. Here we report the effects of hyperstimulation of hERG1 channel in human mammary gland adenocarcinoma-derived cells. Application of the hERG1 activator, the diphenylurea derivative NS1643, inhibits cell proliferation irreversibly. This event is accompanied by a preferential arrest of the cell cycle in G0/G1 phase without the occurrence of apoptotic events. Consequently, cells responded to NS1643 by developing a senescence-like phenotype associated with increased protein levels of the tumor suppressors p21 and p16(INK4a) and by a positive beta-galactosidase assay. These data suggest that prolonged stimulation of the hERG1 potassium channel may activate a senescence program and offers a compelling opportunity to develop a potential antiproliferative cancer therapy. PMID- 23744353 TI - A novel Osmium-based compound targets the mitochondria and triggers ROS-dependent apoptosis in colon carcinoma. AB - Engagement of the mitochondrial-death amplification pathway is an essential component in chemotherapeutic execution of cancer cells. Therefore, identification of mitochondria-targeting agents has become an attractive avenue for novel drug discovery. Here, we report the anticancer activity of a novel Osmium-based organometallic compound (hereafter named Os) on different colorectal carcinoma cell lines. HCT116 cell line was highly sensitive to Os and displayed characteristic features of autophagy and apoptosis; however, inhibition of autophagy did not rescue cell death unlike the pan-caspase inhibitor z-VAD-fmk. Furthermore, Os significantly altered mitochondrial morphology, disrupted electron transport flux, decreased mitochondrial transmembrane potential and ATP levels, and triggered a significant increase in reactive oxygen species (ROS) production. Interestingly, the sensitivity of cell lines to Os was linked to its ability to induce mitochondrial ROS production (HCT116 and RKO) as HT29 and SW620 cell lines that failed to show an increase in ROS were resistant to the death inducing activity of Os. Finally, intra-peritoneal injections of Os significantly inhibited tumor formation in a murine model of HCT116 carcinogenesis, and pretreatment with Os significantly enhanced tumor cell sensitivity to cisplatin and doxorubicin. These data highlight the mitochondria-targeting activity of this novel compound with potent anticancer effect in vitro and in vivo, which could have potential implications for strategic therapeutic drug design. PMID- 23744354 TI - B4GALT family mediates the multidrug resistance of human leukemia cells by regulating the hedgehog pathway and the expression of p-glycoprotein and multidrug resistance-associated protein 1. AB - beta-1, 4-Galactosyltransferase gene (B4GALT) family consists of seven members, which encode corresponding enzymes known as type II membrane-bound glycoproteins. These enzymes catalyze the biosynthesis of different glycoconjugates and saccharide structures, and have been recognized to be involved in various diseases. In this study, we sought to determine the expressional profiles of B4GALT family in four pairs of parental and chemoresistant human leukemia cell lines and in bone marrow mononuclear cells (BMMC) of leukemia patients with multidrug resistance (MDR). The results revealed that B4GALT1 and B4GALT5 were highly expressed in four MDR cells and patients, altered levels of B4GALT1 and B4GALT5 were responsible for changed drug-resistant phenotype of HL60 and HL60/adriamycin-resistant cells. Further data showed that manipulation of these two gene expression led to increased or decreased activity of hedgehog (Hh) signaling and proportionally mutative expression of p-glycoprotein (P-gp) and MDR associated protein 1 (MRP1) that are both known to be related to MDR. Thus, we propose that B4GALT1 and B4GALT5, two members of B4GALT gene family, are involved in the development of MDR of human leukemia cells, probably by regulating the activity of Hh signaling and the expression of P-gp and MRP1. PMID- 23744355 TI - Cotargeting histone deacetylases and oncogenic BRAF synergistically kills human melanoma cells by necrosis independently of RIPK1 and RIPK3. AB - Past studies have shown that histone deacetylase (HDAC) and mutant BRAF (v-Raf murine sarcoma viral oncogene homolog B1) inhibitors synergistically kill melanoma cells with activating mutations in BRAF. However, the mechanism(s) involved remains less understood. Here, we report that combinations of HDAC and BRAF inhibitors kill BRAF(V600E) melanoma cells by induction of necrosis. Cotreatment with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) or panobinostat (LBH589) and the BRAF inhibitor PLX4720 activated the caspase cascade, but caspases appeared dispensable for killing, in that inhibition of caspases did not invariably block induction of cell death. The majority of dying cells acquired propidium iodide positivity instantly when they became positive for Annexin V, suggesting induction of necrosis. This was supported by caspase independent release of high-mobility group protein B1, and further consolidated by rupture of the plasma membrane and loss of nuclear and cytoplasmic contents, as manifested by transmission electron microscopic analysis. Of note, neither the necrosis inhibitor necrostatin-1 nor the small interference RNA (siRNA) knockdown of receptor-interacting protein kinase 3 (RIPK3) inhibited cell death, suggesting that RIPK1 and RIPK3 do not contribute to induction of necrosis by combinations of HDAC and BRAF inhibitors in BRAF(V600E) melanoma cells. Significantly, SAHA and the clinically available BRAF inhibitor vemurafenib cooperatively inhibited BRAF(V600E) melanoma xenograft growth in a mouse model even when caspase-3 was inhibited. Taken together, these results indicate that cotreatment with HDAC and BRAF inhibitors can bypass canonical cell death pathways to kill melanoma cells, which may be of therapeutic advantage in the treatment of melanoma. PMID- 23744356 TI - PARG dysfunction enhances DNA double strand break formation in S-phase after alkylation DNA damage and augments different cell death pathways. AB - Poly(ADP-ribose) glycohydrolase (PARG) is the primary enzyme responsible for the degradation of poly(ADP-ribose). PARG dysfunction sensitizes cells to alkylating agents and induces cell death; however, the details of this effect have not been fully elucidated. Here, we investigated the mechanism by which PARG deficiency leads to cell death in different cell types using methylmethanesulfonate (MMS), an alkylating agent, and Parg(-/-) mouse ES cells and human cancer cell lines. Parg(-/-) mouse ES cells showed increased levels of gamma-H2AX, a marker of DNA double strand breaks (DSBs), accumulation of poly(ADP-ribose), p53 network activation, and S-phase arrest. Early apoptosis was enhanced in Parg(-/-) mouse ES cells. Parg(-/-) ES cells predominantly underwent caspase-dependent apoptosis. PARG was then knocked down in a p53-defective cell line, MIAPaCa2 cells, a human pancreatic cancer cell line. MIAPaCa2 cells were sensitized to MMS by PARG knockdown. Enhanced necrotic cell death was induced in MIAPaCa2 cells after augmenting gamma-H2AX levels and S-phase arrest. Taken together, these data suggest that DSB repair defect causing S-phase arrest, but p53 status was not important for sensitization to alkylation DNA damage by PARG dysfunction, whereas the cell death pathway is dependent on the cell type. This study demonstrates that functional inhibition of PARG may be useful for sensitizing at least particular cancer cells to alkylating agents. PMID- 23744357 TI - Wentilactone B induces G2/M phase arrest and apoptosis via the Ras/Raf/MAPK signaling pathway in human hepatoma SMMC-7721 cells. AB - Hepatocellular carcinoma (HCC) is generally acknowledged as the most common primary malignant tumor, and it is known to be resistant to conventional chemotherapy. Wentilactone B (WB), a tetranorditerpenoid derivative extracted from the marine algae-derived endophytic fungus Aspergillus wentii EN-48, has been shown to trigger apoptosis and inhibit metastasis in HCC cell lines. However, the mechanisms of its antitumor activity remain to be elucidated. We report here that WB could significantly induce cell cycle arrest at G2 phase and mitochondrial-related apoptosis, accompanying the accumulation of reactive oxygen species (ROS). Additionally, treatment with WB induced phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), but not p38 MAP kinase. Among the pathway inhibitors examined, only SP600125 (JNK inhibitor) markedly reversedWB-induced apoptosis, and only U0126 (ERK inhibitor) significantly blocked WB-triggered G2 phase arrest. We also found that WB treatment increased both Ras and Raf activation, and transfection of cells with dominant-negative Ras (RasN17) abolishedWB-induced apoptosis and G2 phase arrest in SMMC-7721 cells. Furthermore, the results of inverse docking (INVDOCK) analysis suggested that WB could bind to Ras-GTP, and the direct binding affinity was also confirmed by surface plasmon resonance (SPR). Finally, in vivo, WB suppressed tumor growth in mouse xenograft models. Taken together, these results indicate that WB induced G2/M phase arrest and apoptosis in human hepatoma SMMC 7721 cells via the Ras/Raf/ERK and Ras/Raf/JNK signaling pathways, and this agent may be a potentially useful compound for developing anticancer agents for HCC. PMID- 23744358 TI - Organopalladium compound 7b targets mitochondrial thiols and induces caspase dependent apoptosis in human myeloid leukemia cells. AB - The advances in the treatment of chronic myeloid leukemia (CML) during the last years were also accompanied by the development of evading strategies by tumor cells, resulting in chemotherapy resistance in some patients. Patented organopalladium compounds derived from the reaction of N,N-dimethyl-1 phenethylamine (dmpa) with [1,2-ethanebis(diphenylphosphine)] (dppe) exhibited a potent antitumor activity in vivo and in vitro in melanoma cells. We showed here that the cyclopalladated derivative [Pd2(R(+))C(2), N-dmpa)2(MU-dppe)Cl2], named compound 7b, was highly effective to promote cell death in the K562 human leukemia cells and its mechanisms of action were investigated. It was shown that compound 7b was able to promote exclusively apoptotic cell death in K562 cells associated to cytochrome c release and caspase 3 activation. This cytotoxic effect was not observed in normal peripheral mononuclear blood cells. The compound 7b-induced intrinsic apoptotic pathway was triggered by the protein thiol oxidation that resulted in the dissipation of the mitochondrial transmembrane potential. The preventive effect of the dithiothreitol on the compound 7b-induced cell death and all downstream events associated to apoptosis confirmed that death signal was elicited by the thiol oxidation. These findings contribute to the elucidation of the palladacycle 7b-induced cell death mechanism and present this compound as a promising drug in the CML antitumor chemotherapy. PMID- 23744359 TI - miR-129 promotes apoptosis and enhances chemosensitivity to 5-fluorouracil in colorectal cancer. AB - Resistance to fluoropyrimidine-based chemotherapy is the major reason for the failure of advanced colorectal cancer (CRC) treatment. The lack of ability of tumor cells to undergo apoptosis after genotoxic stress is the key contributor to this intrinsic mechanism. Mounting evidence has demonstrated that non-coding microRNAs (miRNAs) are crucial regulators of gene expression, in particular, under acute genotoxic stress. However, there is still limited knowledge about the role of miRNAs in apoptosis. In this study, we discovered a novel mechanism mediated by microRNA-129 (miR-129) to trigger apoptosis by suppressing a key anti apoptotic protein, B-cell lymphoma 2 (BCL2). Ectopic expression of miR-129 promoted apoptosis, inhibited cell proliferation and caused cell-cycle arrest in CRC cells. The intrinsic apoptotic pathway triggered by miR-129 was activated by cleavage of caspase-9 and caspase-3. The expression of miR-129 was significantly downregulated in CRC tissue specimens compared with the paired normal control samples. More importantly, we demonstrated that miR-129 enhanced the cytotoxic effect of 5-fluorouracil both in vitro and in vivo. These results suggest that miR-129 has a unique potential as a tumor suppressor and a novel candidate for developing miR-129-based therapeutic strategies in CRC. PMID- 23744360 TI - Redox cycling of endogenous copper by thymoquinone leads to ROS-mediated DNA breakage and consequent cell death: putative anticancer mechanism of antioxidants. AB - Plant-derived dietary antioxidants have attracted considerable interest in recent past for their chemopreventive and cancer therapeutic abilities in animal models. Thymoquinone (TQ) is the major bioactive constituent of volatile oil of Nigella sativa and has been shown to exert various pharmacological properties, such as anti-inflammatory, cardiovascular, analgesic, anti-neoplastic, anticancer and chemopreventive. Although several mechanisms have been suggested for the chemopreventive and anticancer activity of TQ, a clear mechanism of action of TQ has not been elucidated. TQ is a known antioxidant at lower concentrations and most of the studies elucidating the mechanism have centered on the antioxidant property. However, recent publications have shown that TQ may act as a prooxidant at higher concentrations. It is well known that plant-derived antioxidants can switch to prooxidants even at low concentrations in the presence of transition metal ions such as copper. It is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies. Copper is an important metal ion present in the chromatin and is closely associated with DNA bases, particularly guanine. Using human peripheral lymphocytes and comet assay, we first show that TQ is able to cause oxidative cellular DNA breakage. Such a DNA breakage can be inhibited by copper-chelating agents, neocuproine and bathocuproine, and scavengers of reactive oxygen species. Further, it is seen that TQ targets cellular copper in prostate cancer cell lines leading to a prooxidant cell death. We believe that such a prooxidant cytotoxic mechanism better explains the anticancer activity of plant-derived antioxidants. PMID- 23744361 TI - Cell cycle-arrested tumor cells exhibit increased sensitivity towards TRAIL induced apoptosis. AB - Resting tumor cells represent a huge challenge during anticancer therapy due to their increased treatment resistance. TNF-related apoptosis-inducing ligand (TRAIL) is a putative future anticancer drug, currently in phases I and II clinical studies. We recently showed that TRAIL is able to target leukemia stem cell surrogates. Here, we tested the ability of TRAIL to target cell cycle arrested tumor cells. Cell cycle arrest was induced in tumor cell lines and xenografted tumor cells in G0, G1 or G2 using cytotoxic drugs, phase-specific inhibitors or RNA interference against cyclinB and E. Biochemical or molecular arrest at any point of the cell cycle increased TRAIL-induced apoptosis. Accordingly, when cell cycle arrest was disabled by addition of caffeine, the antitumor activity of TRAIL was reduced. Most important for clinical translation, tumor cells from three children with B precursor or T cell acute lymphoblastic leukemia showed increased TRAIL-induced apoptosis upon knockdown of either cyclinB or cyclinE, arresting the cell cycle in G2 or G1, respectively. Taken together and in contrast to most conventional cytotoxic drugs, TRAIL exerts enhanced antitumor activity against cell cycle-arrested tumor cells. Therefore, TRAIL might represent an interesting drug to treat static-tumor disease, for example, during minimal residual disease. PMID- 23744362 TI - Hyperosmotic stress induces cell cycle arrest in retinal pigmented epithelial cells. AB - Osmotic changes occur in many tissues and profoundly influence cell function. Herein, we investigated the effect of hyperosmotic stress on retinal pigmented epithelial (RPE) cells using a microarray approach. Upon 4-h exposure to 100 mM NaCl or 200 mM sucrose, 79 genes were downregulated and 72 upregulated. Three gene ontology categories were significantly modulated: cell proliferation, transcription from RNA polymerase II promoter and response to abiotic stimulus. Fluorescent-activated cell sorting analysis further demonstrated that owing to hyperosmotic stimulation for 24 h, cell count and cell proliferation, as well as the percentage of cells in G0/G1 and S phases were significantly decreased, whereas the percentage of cells in G2/M phases increased, and apoptosis and necrosis remained unaffected. Accordingly, hyperosmotic conditions induced a decrease of cyclin B1 and D1 expression, and an activation of the p38 mitogen activated protein kinase. In conclusion, our results demonstrate that hypertonic conditions profoundly affect RPE cell gene transcription regulating cell proliferation by downregulation cyclin D1 and cyclin B1 protein expression. PMID- 23744363 TI - Characterization and Streptococcus mutans adhesion on air polishing dentin. AB - Air polishing is known as an effective and time saving tooth cleaning method. However, this method increased surface roughness and bacterial adhesion on dentin surface. The aim of this study was to characterize and examine Streptococcus mutans adhesion on dentin surface after air polishing as compared to the conventional method. The dentin blocks (4 * 4 * 1 mm) were polished by a rubber cup with polishing material (Polishing) and air-polished by 25 MUm glycine (G25), 65 MUm glycine (G65), and 65 MUm sodium bicarbonate (NHC65) microparticles. Surface roughness (Ra) was measured by a laser electron microscope. The amount of adhered S. mutans was quantified using a resazurin reduction assay (alamarBlue((r))). The Ra of G25 and G65 was significantly (p < 0.01) smaller than that of NHC65 and greater than that of Polishing. However, there was no significant difference in S. mutans adhesion among Polishing, G25, and G65, while NHC65 showed significantly (p < 0.01) higher S. mutans adhesion. Within the limitations of this in vitro study, air polishing using glycine microparticles conditioned S. mutans adhesion on dentin surface in a similar fashion than the conventional method, and less than air polishing using sodium bicarbonate microparticles. PMID- 23744364 TI - ?Glycopyrronium for COPD. AB - ?Glycopyrronium powder for inhalation (Seebri Breezhaler-Novartis) is a long acting muscarinic receptor antagonist (LAMA), licensed as a maintenance bronchodilator treatment to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD).1 This is the third long-acting agent that has recently been licensed in the UK for use in people with COPD (see ?Indacaterol for COPD2 and ?Aclidinium for COPD?3). The company's promotional material claims that 'Seebri is a once daily LAMA which supports cost effective prescribing at all stages of COPD'.4 In this article we review the evidence for glycopyrronium and assess its place in the management of COPD. PMID- 23744366 TI - The Foot-Reading Cult of Japan. AB - Ho-no-Hana-Sanpogyo was a Japanese new religious movement referred to as the "foot-reading cult" in the media. Its founder, Fukunaga Hogen, claimed to have divine authority and the ability to diagnose physical illness by studying the soles of an individual's feet. The purpose of this paper is to provide an overview of the history of Ho-no-Hana-Sanpogyo and Fukunaga's practice of foot reading. PMID- 23744365 TI - Abnormal expression of Toll-like receptor 4 is associated with susceptibility to ethanol-induced gastric mucosal injury in mice. AB - BACKGROUND AND AIMS: Toll-like receptor 4 (TLR4) contributes to ethanol-induced gastric mucosal injury. This study aimed to determine its precise role in this pathogenic state and the related signaling pathway. METHODS: Ethanol-induced gastric mucosal injury models were generated in TLR4(-/-) mice (C3H/HeJ: point mutation; C57BL/10ScNJ: gene deletion), their respective TLR4(+/+) wild-type counterparts, and heterozygous TLR4(+/-) mice. Lipopolysaccharide (LPS) or pyrrolidine dithiocarbamate (PDTC) was injected intraperitoneally 1 h or 30 min before ethanol administration. At 1 h post-ethanol treatment, gastric or serum specimens were evaluated. RESULTS: Ethanol intra-gastric administration induced significant gastric mucosal injury in all mice, but the damaged area was larger in TLR4(-/-) mice. LPS preconditioning and up-regulated TLR4 expression led to significantly larger areas of gastric mucosal damage. Upon ethanol administration, TLR4(+/+), and not TLR4(-/-), mice showed significant increases in TLR4, myeloid differentiation factor 88 (MyD88), cytoplasmic high mobility group box 1 (HMGB1), and nuclear factor-kappa B p65 (NF-kappaB p65). PDTC pretreatment significantly attenuated the ethanol-induced gastric mucosal damaged areas, inhibited nuclear NF-kappaB p65 expression, and suppressed HMGB1 translocation out of the nucleus. In addition, PDTC pretreatment reduced ethanol stimulated expression of the inflammatory modulators, interleukin-1beta (IL 1beta) and tumor necrosis factor-alpha (TNF-alpha), in serum. CONCLUSIONS: Both deficient and excessive expression of TLR4 promotes ethanol-induced gastric mucosal injury. The underlying mechanism involves the MyD88/NF-kappaB signaling pathway and the HMGB1, TLR4 activator ligand. The increased expression of HMGB1 may lead to increased secretion and binding to TLR4, further stimulating the TLR4/MyD88/NF-kappaB signaling pathway and aggravating the ethanol-induced gastric mucosal injury. PMID- 23744367 TI - Crystal structure and thermal properties of a square-planar Ni(II) complex of cyanide and a tricyclic bis-amidine ligand formed in situ under solvothermal conditions. AB - The reaction of N(1),N(1')-(ethane-1,2-diyl)bis(propane-1,3-diamine) (bapen), K2[Ni(CN)4].H2O and dimethylformamide in the presence of Gd(NO3)3.6H2O under solvothermal conditions yielded yellow crystals of dicyanido(2,3,4,6,7,9,10,11 octahydropyrimido[2',1':3,4]pyrazino[1,2-a]pyrimidine)nickel(II) hemihydrate, [Ni(CN)2(C10H16N4)].0.5H2O, (I), the crystal structure of which is composed of [Ni(CN)2(pdpm)] molecules (pdpm is 2,3,4,6,7,9,10,11 octahydropyrimido[2',1':3,4]pyrazino[1,2-a]pyrimidine) on general positions linked by O-H...N hydrogen bonds to water molecules located on twofold axes. This structural unit is further linked by nonclassical C-H...N interactions to form a warped two-dimensional net perpendicular to the unit-cell b axis. The nets are stacked, with C-H...O contacts joining successive units. The Ni(II) cation is coordinated with square-planar geometry by a chelating pdpm ligand and two cyanide ligands in mutually cis positions. Complex (I) is stable up to 360 K, at which point dehydration takes place; the ligands start to decompose at 558 K. PMID- 23744368 TI - An approach to creating novel anions: silylated triel compounds with -CH2- and -O linkers, [InCl2{O(HO)Si(t-Bu)2}]2 and Li[B(CH2SiMe3)4]. AB - Bis[MU-di-tert-butyl(hydroxy)silanolato]bis[chloridoindium(III)], [In2(C8H19O2Si)2Cl4], (I), is a centrosymmetric two-centre indium complex featuring a system of three annulated four-membered rings; the structure is the first example of an In2O2 ring which is annulated with two Si-O units to form a ring system composed of three rings. The coordination environment of the In centres is a distorted trigonal bipyramid. The crystal packing of (I) is characterized by chains of molecules connected by O-H...Cl hydrogen bonds. The crystal of (I) was a nonmerohedral twin. There is no known example of an In2O2 ring in which the In atoms carry any two halogen ligands. The structure of tetrakis(tetrahydrofuran)lithium tetrakis[(trimethylsilyl)methyl]borate, [Li(C4H8O)4](C16H44BSi4), (II), is composed of discrete cations and anions. The coordination geometries of the Li and B centres is tetrahedral. The cations and anions lie in planes parallel to the ab plane. There are no short contacts between the cations and anions. Compound (II) is the first example of a B centre bonded to four -CH2Si units. PMID- 23744369 TI - catena-Poly[[(tetrahydrofuran-kappaO)potassium]-MU-(eta5:eta5)-2,3,4,5 tetramethyl-1-n-pentylcyclopentadienyl]. AB - The title compound, [K(C14H23)(C4H8O)]n, comprises zigzag chains of alternating bridging 2,3,4,5-tetramethyl-1-n-pentylcyclopentadienyl ligands and potassium ions, with an ancillary tetrahydrofuran ligand in the coordination environment of potassium. The coordination polymer strands so formed extend by 21 screw symmetry in the b-axis direction. The chemically modified cyclopentadienyl ligand, with a tethered n-pentyl group, was synthesized from 2,3,4,5-tetramethylcyclopent-2 enone by a Grignard reaction. PMID- 23744370 TI - Poly[[tetrachlorido{MU4-tetrakis[(pyridin-4-yl)oxymethyl]methane kappa4N:N':N'':N'''}dizinc(II)] dimethylformamide tetrasolvate]. AB - A novel metal-organic framework, {[Zn2Cl4(C25H24N4O4)].4C3H7NO}n, has been synthesized solvothermally by assembling the semi-rigid tetrahedral ligand tetrakis[(pyridin-4-yl)oxymethyl]methane (tpom) and zinc nitrate in dimethylformamide (DMF). The crystal structure is noncentrosymmetric (P42(1)c). Each Zn(II) cation has a tetrahedral coordination environment (C2 symmetry), which is formed by two chloride ligands and two pyridine N atoms from two tpom ligands. The tetrahedral tetradentate tpom linker has a quaternary C atom located on the crystallographic -4 axis. This linker utilizes all the peripheral pyridine N atoms to connect four Zn(II) cations, thereby forming a wave-like two dimensional sheet along the c axis. The two-dimensional layer can be topologically simplified as a typical uninodal 4-connected sql/Shubnikov net, which is represented by the Schlafli symbol {4(4),6(2)}. Adjacent layers are further packed into a three-dimensional structure by C-H...Cl hydrogen bonds. PMID- 23744371 TI - A novel hexairon cluster with one disulfide and two Ph2PCS(3-) ligands. AB - The title compound, hexadecacarbonylbis{MU3 [(diphenylphosphanyl)methanediidyl]sulfanido}-MU4-disulfido(2-)-hexairon(4 Fe Fe), [Fe6(C13H10PS)2(S2)(CO)16], contains two inversion-related [Fe3(Ph2PCS)(CO)8] subclusters linked by an equatorial disulfide bond [S-S = 2.1490 (9) A]. Each Ph2PCS(3-) ligand is coordinated to a triiron core in a MU3 kappaP:kappa(2)C:kappa(2)S fashion. PMID- 23744372 TI - Chlorido(dimethyl 2,2'-bipyridine-4,4'-dicarboxylate-kappa2N,N')(eta5 pentamethylcyclopentadienyl)rhodium(III) chloride 1-hydroxypyrrolidine-2,5-dione disolvate. AB - The title complex, [Rh(C10H15)Cl(C14H12N2O4)]Cl.2C4H5NO3, has been synthesized by a substitution reaction of the precursor [bis(2,5-dioxopyrrolidin-1-yl) 2,2' bipyridine-4,4'-dicarboxylate]chlorido(pentamethylcyclopentadienyl)rhodium(III) chloride with NaOCH3. The Rh(III) cation is located in an RhC5N2Cl eight coordinated environment. In the crystal, 1-hydroxypyrrolidine-2,5-dione (NHS) solvent molecules form strong hydrogen bonds with the Cl(-) counter-anions in the lattice and weak hydrogen bonds with the pentamethylcyclopentadienyl (Cp*) ligands. Hydrogen bonding between the Cp* ligands, the NHS solvent molecules and the Cl(-) counter-anions form links in a V-shaped chain of Rh(III) complex cations along the c axis. Weak hydrogen bonds between the dimethyl 2,2' bipyridine-4,4'-dicarboxylate ligands and the Cl(-) counter-anions connect the components into a supramolecular three-dimensional network. The synthetic route to the dimethyl 2,2'-bipyridine-4,4'-dicarboxylate-containing rhodium complex from the [bis(2,5-dioxopyrrolidin-1-yl) 2,2'-bipyridine-4,4' dicarboxylate]rhodium(III) precursor may be applied to link Rh catalysts to the surface of electrodes. PMID- 23744373 TI - Two polyoxometallate-based supramolecular compounds influenced by the ratio between the polyoxometallate anion and organic cation. AB - Two polyoxometallate-based compounds, tris[1,1'-(butane-1,4-diyl)bis(1H-imidazol 3-ium)] bis[tetracosa-MU2-oxido-dodecaoxido-MU12-phosphato-dodecamolybdenum(VI)], (C10H16N4)3[PMo12O40]2, (I), and 1,1'-(butane-1,4-diyl)bis(1H-imidazol-3-ium) 1 [4-(1H-imidazol-1-yl)butyl]-1H-imidazol-3-ium tetracosa-MU2-oxido-dodecaoxido MU12-phosphato-dodecamolybdenum(VI) dihydrate, (C10H16N4)(C10H15N4)[PMo12O40].2H2O, (II), were synthesized by hydrothermal techniques at different pH values. The stoichiometric ratio between the polyoxometallate (POM) anions and organic cations is 2:3 in (I), with one of the cations lying on an inversion centre. The doubly protonated 1,1'-(butane-1,4 diyl)diimidazole (BIM) cations are linked to the [PMo12O40](3-) anions by hydrogen bonds to form a three-dimensional supramolecular network. The stoichiometric ratio of POM anions and organic cations is 1:2 in (II), and the anion is located about a centre of inversion. The partly protonated BIM cations and solvent water molecules form hydrogen bonds with the [PMo12O40](3-) anions, yielding a two-dimensional supramolecular layer. The different lattice architectures of (I) and (II) may be governed by the ratio between the POM anions and organic cations, which, in turn, is determined by the pH value. PMID- 23744374 TI - catena-Poly[[[2-(2-chlorophenoxy)-N'-(2-oxidobenzylidene-kappaO)acetohydrazidato kappa2N',O]copper(II)]-MU-morpholine-kappa2N:O]. AB - In the title compound, {[Cu(C15H11ClN2O3)(C4H9NO)]n, the Cu(II) cation has square pyramidal geometry. The morpholine ligand serves as a bridge to link two symmetry related metal atoms, resulting in an infinite chain structure along the a axis. Adjacent chains are extended into a two-dimensional layered structure via hydrogen bonds formed between morpholine and amide N atoms [N-H...N = 2.971 (3) A]. PMID- 23744375 TI - Magnetic investigations of a two-dimensional coordination polymer with a three dimensional supramolecular framework: poly[[bis[MU2-1,4-bis(1,2,4-triazol-1 yl)butane]bis(thiocyanato-kappaN)cobalt(II)] dihydrate]. AB - In the title mixed-ligand metal-organic polymeric complex, {[Co(NCS)2(C8H12N6)2].2H2O}n, the asymmetric unit contains a divalent Co(II) cation, which sits on an inversion centre, two halves of two crystallographically distinct and centrosymmetric 1,4-bis(1,2,4-triazol-1-yl)butane (BTB) ligands, one N-bound thiocyanate ligand and one solvent water molecule. The Co(II) atom possesses a distorted {CoN6} octahedral geometry, with the equatorial positions taken up by triazole N atoms from four different BTB ligands. The axial positions are filled by thiocyanate N atoms. In the crystal, each Co(II) atom is linked covalently to four others through the distal donors of the tethering BTB ligands, forming a neutral (4,4)-topology two-dimensional rhomboid grid layer motif, which is coincident with the (121) crystal planes. Magnetic investigations show that weak antiferromagnetic coupling exists between Co(II) atoms in the complex. PMID- 23744376 TI - The coordination chemistry of two symmetric double-armed oxadiazole-bridged organic ligands with copper salts. AB - Two new symmetric double-armed oxadiazole-bridged ligands, 4-methyl-{5-[5-methyl 2-(pyridin-3-ylcarbonyloxy)phenyl]-1,3,4-oxadiazol-2-yl}phenyl pyridine-3 carboxylate (L1) and 4-methyl-{5-[5-methyl-2-(pyridin-4-ylcarbonyloxy)phenyl] 1,3,4-oxadiazol-2-yl}phenyl pyridine-4-carboxylate (L2), were prepared by the reaction of 2,5-bis(2-hydroxy-5-methylphenyl)-1,3,4-oxadiazole with nicotinoyl chloride and isonicotinoyl chloride, respectively. Ligand L1 can be used as an organic clip to bind Cu(II) cations and generate a molecular complex, bis(4 methyl-{5-[5-methyl-2-(pyridin-3-ylcarbonyloxy)phenyl]-1,3,4-oxadiazol-2 yl}phenyl pyridine-3-carboxylate)bis(perchlorato)copper(II), [Cu(ClO4)2(C28H20N4O5)2], (I). In compound (I), the Cu(II) cation is located on an inversion centre and is hexacoordinated in a distorted octahedral geometry, with the pyridine N atoms of two L1 ligands in the equatorial positions and two weakly coordinating perchlorate counter-ions in the axial positions. The two arms of the L1 ligands bend inward and converge at the Cu(II) coordination point to give rise to a spirometallocycle. Ligand L2 binds Cu(I) cations to generate a supramolecule, diacetonitriledi-MU3-iodido-di-MU2-iodido-bis(4-methyl-{5-[5 methyl-2-(pyridin-4-ylcarbonyloxy)phenyl]-1,3,4-oxadiazol-2-yl}phenyl pyridine-4 carboxylate)tetracopper(I), [Cu4I4(CH3CN)2(C28H20N4O5)2], (II). The asymmetric unit of (II) indicates that it contains two Cu(I) atoms, one L2 ligand, one acetonitrile ligand and two iodide ligands. Both of the Cu(I) atoms are four coordinated in an approximately tetrahedral environment. The molecule is centrosymmetric and the four I atoms and four Cu(I) atoms form a rope-ladder-type [Cu4I4] unit. Discrete units are linked into one-dimensional chains through pi-pi interactions. PMID- 23744377 TI - Chlorido[N,N'-dibenzyl-N''-(trichloroacetyl)phosphoramidato-kappa2O,O'](1,10 phenanthroline-kappa2N,N')copper(II). AB - In the title complex, [Cu(C16H16Cl3N3O2P)Cl(C12H8N2)], the Cu(II) cation presents a square-pyramidal environment, where the CuO2N2 base is formed by two O atoms from carbonyl and phosphoryl groups, and by two N atoms from a 1,10 phenanthroline molecule. A coordinated Cl atom occupies the apex. N-H...Cl hydrogen bonds link the molecules into one-dimensional chains. The trichloromethyl group is rotationally disordered over two positions, with occupancies of 0.747 (7) and 0.253 (7). PMID- 23744378 TI - A novel two-dimensional CuSCN network templated by 2,2'-dimethyl-1,1'-(butane-1,4 diyl)bis(1H-imidazol-3-ium) cations. AB - The cation-templated self-assembly of 1,4-bis(2-methyl-1H-imidazol-1-yl)butane (bmimb) with CuSCN gives rise to a novel two-dimensional network, namely catena poly[2,2'-dimethyl-1,1'-(butane-1,4-diyl)bis(1H-imidazol-3-ium) [tetra-MU2 thiocyanato-kappa(4)S:S;kappa(4)S:N-dicopper(I)]], {(C12H20N4)[Cu2(NCS)4]}n. The Cu(I) cation is four-coordinated by one N and three S atoms, giving a tetrahedral geometry. One of the two crystallographically independent SCN(-) anions acts as a MU2-S:S bridge, binding a pair of Cu(I) cations into a centrosymmetric [Cu2(NCS)2] subunit, which is further extended into a two-dimensional 4(4)-sql net by another kind of SCN(-) anion with an end-to-end MU2-S:N coordination mode. Interestingly, each H2bmimb dication, lying on an inversion centre, threads through one of the windows of the two-dimensional 4(4)-sql net, giving a pseudorotaxane-like structure. The two-dimensional 4(4)-sql networks are packed into the resultant three-dimensional supramolecular framework through bmimb-SCN N H...N hydrogen bonds. PMID- 23744379 TI - Di-MU2-chlorido-dichloridobis(dimethylformamide)tetrakis[MU3-1-(2-oxidobenzoyl)-2 (2-oxo-2-phenylethanethioyl)hydrazine-1,2-diido]octacopper(II) dimethylformamide disolvate. AB - The title compound, [Cu8(C15H10N3O3S)4Cl4(C3H7NO)2].2C3H7NO, consisting of eight Cu(II) cations, four trianionic 1-(2-oxidobenzoyl)-2-(2-oxo-2 phenylethanethioyl)hydrazine-1,2-diide ligands, four chloride ligands and two coordinated and two solvent dimethylformamide molecules, crystallizes with the octanuclear molecule located on an inversion centre. The two halves of the molecule are connected by two bridging Cl atoms. This is the first example of an octanuclear complex based on a thiosemicarbazone-derived ligand. PMID- 23744380 TI - Reversible high-temperature phase transition of a manganese(II) formate framework with imidazolium cations. AB - A new metal-formate framework, poly[1H-imidazol-3-ium [tri-MU2-formato manganese(II)]], {(C3H5N2)[Mn(HCOO)3]}n, was synthesized and its structural phase transition was studied by thermal analysis and variable-temperature X-ray diffraction analysis. The transition temperature is around 435 K. The high temperature phase is tetragonal and the low-temperature phase is monoclinic, with a beta angle close to 90 degrees . The relationship of the unit cells between the two phases can be described as: a(HT) = 0.5a(LT) + 0.5b(LT); b(HT) = -0.5a(LT) + 0.5b(LT); c(HT) = 0.5c(LT). In the high-temperature phase, both the framework and the guest 1H-imidazol-3-ium (HIm) cations are disordered; the HIm cations are located about 2mm sites and were modelled as fourfold disordered. The Mn and a formate C atom are located on fourfold rotary inversion axes, while another formate C atom is on a mirror plane. The low-temperature structure is ordered and consists of two crystallographically independent HIm cations and two crystallographically independent Mn(2+) ions. The phase transition is attributable to the order-disorder transition of the HIm cations. PMID- 23744381 TI - A novel two-dimensional coordination polymer: poly[diaquatetra-MU2-chlorido-[MU2 2,2'-(piperazine-1,4-diium-1,4-diyl)diacetate]dicadmium(II)]. AB - In the crystal structure of the title two-dimensional metal-organic polymeric complex, [Cd2Cl4(C8H14N2O4)(H2O)2]n, the asymmetric unit contains a crystallographically independent Cd(II) cation, two chloride ligands, an aqua ligand and half a 2,2'-(piperazine-1,4-diium-1,4-diyl)diacetate (H2PDA) ligand, the piperazine ring centroid of which is located on a crystallographic inversion centre. Each Cd(II) centre is six-coordinated in an octahedral environment by an O atom from an H2PDA ligand and an O atom from an aqua ligand in a trans disposition, and by four chloride ligands arranged in the plane perpendicular to the O-Cd-O axis. The complex forms a two-dimensional layer polymer containing [CdCl2]n chains, which are interconnected into an extensive three-dimensional hydrogen-bonded network by C-H...O, C-H...Cl and O-H...O hydrogen bonds. PMID- 23744382 TI - Bromidobis[2-(pyridin-2-yl)methanol-kappa(2)N,O]copper(II) bromide monohydrate. AB - The title compound, [CuBr(C6H7NO)2]Br.H2O, is an ionic mononuclear complex in which the [CuBr(C6H7NO)2](+) cation possesses distorted square-pyramidal geometry. The Cu(II) centre is coordinated by two neutral 2-(pyridin-2 yl)methanol (2-pyMeOH) ligands and a terminal bromide ligand. The 2-pyMeOH ligands are coordinated in a bidentate chelating manner through the pyridine N and hydroxy O atoms, forming a five-membered chelate ring with the Cu(II) centre. The planes of the pyridine rings are twisted by 58.71 (14) degrees with respect to each other. The charge is balanced by a noncoordinating bromide anion which, together with a solvent water molecule, links the components through hydrogen bonds into infinite chains propagating along the a axis. The mononuclear cations appear to associate in pairs through weak interactions between the metal atom of one cation and the halogen atom of an adjacent cation. PMID- 23744383 TI - Bromine-bromine interactions in the packing of cis,trans,cis-1,2,3,4 tetrakis(bromomethyl)cyclobutane. AB - The title compound, C8H12Br4, displays crystallographic inversion symmetry, so that the cyclobutane ring is exactly planar. The ring C-C bond with eclipsed substituents is lengthened somewhat to 1.572 (5) A. The packing can be described in terms of three Br...Br contacts; two of these combine to form layers of molecules parallel to the ac plane, while the third crosslinks the layers in the third dimension. A simple topological descriptor for systems involving Br...Br contacts is proposed. PMID- 23744384 TI - An orthorhombic polymorph of a cyclization product of perindopril. AB - Low-temperature X-ray diffraction experiments were employed to investigate the crystal structures of an orthorhombic polymorph of the intramolecular cyclization product of perindopril, a popular angiotensive-converting enzyme (ACE) inhibitor, namely ethyl (2S)-2-[(3S,5aS,9aS,10aS)-3-methyl-1,4-dioxo-5a,6,7,8,9,9a,10,10a octahydro-3H-pyrazino[1,2-a]indol-2-yl]pentanoate, C19H30N2O4, (Io), and its tetragonal equivalent, (It), which was previously reported at ambient temperature [Bojarska et al. (2013). J. Chil. Chem. Soc. 58, 1415-1417]. Polymorph (Io) crystallizes in the orthorhombic space group P2(1)2(1)2(1) with two molecules in the asymmetric unit, while tetragonal form (It) crystallizes in the space group P4(1)2(1)2 with one molecule in the asymmetric unit. The geometric parameters of (Io) are very similar to those of (It). The six-membered rings in both polymorphs adopt a slightly deformed chair conformation and the piperazinedione rings are in a boat conformation. However, the proline rings adopt an envelope conformation in (Io), while in (It) the ring exists in a slightly deformed half-chair conformation. The most significant difference between the two structures is the orientation of the ethyl pentanoate chain. Molecules associate in pairs in a head to-tail manner forming infinite columns. In (Io), molecules are related by a twofold screw axis forming identical columns, while in (It), molecules in successive neighbouring columns are related by alternating twofold screw axes and fourfold screw axes. In both cases, the crystal packing is stabilized by weak intermolecular C-H...O interactions only. PMID- 23744385 TI - Synthesis and photophysical properties of 2,5,8,11-tetrakis(5-hexylthiophen-2 yl)tetrathieno[2,3-a:3',2'-c:2'',3''-f:3''',2'''-h]naphthalene. AB - The title compound, C58H64S8, has been prepared by Pd-catalysed direct C-H arylation of tetrathienonaphthalene (TTN) with 5-hexyl-2-iodothiophene and recrystallized by slow evaporation from dichloromethane. The crystal structure shows a completely planar geometry of the TTN core, crystallizing in the monoclinic space group P2(1)/c. The structure consists of slipped pi-stacks and the interfacial distance between the mean planes of the TTN cores is 3.456 (5) A, which is slightly larger than that of the comparable derivative of tetrathienoanthracene (TTA) with 2-hexylthiophene groups. The packing in the two structures is greatly influenced by both the aromatic core of the structure and the alkyl side chains. PMID- 23744386 TI - A comparison of 3,4,6a,7,10,10a-hexahydro-7,10-epoxypyrimido[2,1-a]isoindol-6(2H) one and 2-(2-aminoethyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H) dione: structural and reactivity differences of two homologous tricyclic imides. AB - The crystal structures of 3,4,6a,7,10,10a-hexahydro-7,10-epoxypyrimido[2,1 a]isoindol-6(2H)-one, C11H12N2O2, and 2-(2-aminoethyl)-3a,4,7,7a-tetrahydro-1H 4,7-epoxyisoindole-1,3(2H)-dione, C10H12N2O3, two tricyclic imides, show one and two molecules in the asymmetric unit, respectively. Intermolecular hydrogen bonding interactions are observed in both compounds. PMID- 23744387 TI - N-H...O and N-H...N interactions in three pyran derivatives. AB - The three pyran structures 6-methylamino-5-nitro-2,4-diphenyl-4H-pyran-3 carbonitrile, C19H15N3O3, (I), 4-(3-fluorophenyl)-6-methylamino-5-nitro-2-phenyl 4H-pyran-3-carbonitrile, C19H14FN3O3, (II), and 4-(4-chlorophenyl)-6-methylamino 5-nitro-2-phenyl-4H-pyran-3-carbonitrile, C19H14ClN3O3, (III), differ in the nature of the aryl group at the 4-position. The heterocyclic ring in all three structures adopts a flattened boat conformation. The dihedral angle between the pseudo-axial phenyl substituent and the flat part of the pyran ring is 89.97 (1) degrees in (I), 80.11 (1) degrees in (II) and 87.77 (1) degrees in (III). In all three crystal structures, a strong intramolecular N-H...O hydrogen bond links the flat conjugated H-N-C=C-N-O fragment into a six-membered ring. In (II), molecules are linked into dimeric aggregates by N-H... O(nitro) hydrogen bonds, generating an R2(2)(12) graph-set motif. In (III), intermolecular N-H...N and C H...N hydrogen bonds link the molecules into a linear chain pattern generating C(8) and C(9) graph-set motifs, respectively. PMID- 23744388 TI - (2S,3S)-2,6-dimethylheptane-1,3-diol, the oxygenated side chain of 22(S) hydroxycholestrol, and its synthetic precursor (R)-4-benzyl-3-[(2R,3S)-3-hydroxy 2,6-dimethylheptanoyl]-1,3-oxazolidin-2-one. AB - (2S,3S)-2,6-dimethylheptane-1,3-diol, C9H20O2, (I), was synthesized from the ketone (R)-4-benzyl-3-[(2R,3S)-3-hydroxy-2,6-dimethylheptanoyl]-1,3-oxazolidin-2 one, C19H27NO4, (II), containing C atoms of known chirality. In both structures, strong hydrogen bonds between the hydroxy groups form tape motifs. The contribution from weaker C-H...O hydrogen bonds is much more evident in the structure of (II), which furthermore contains an example of a direct short Osp(3)...Csp(2) contact that represents a usually unrecognized type of intermolecular interaction. PMID- 23744389 TI - meso-Tetrakis[4-(heptyloxy)phenyl]porphyrin. AB - The core of the novel title centrosymmetric porphyrin derivative, C72H86N4O4, with long flexible hexyloxy substituents, is almost planar, which is anticipated to facilitate pi-electron delocalization and lead to a significant deviation between the planes of the benzene rings and the molecular plane. The two N-bound H atoms on the pyrrole rings are disordered and the occupancy factors refined to a ratio of 0.28 (2):0.72 (2). PMID- 23744390 TI - Alkyl levulinates as 'green chemistry' precursors: butane-1,4-diyl bis(4 oxopentanoate) and hexane-1,6-diyl bis(4-oxopentanoate). AB - Levulinic acid derivatives are potential 'green chemistry' renewably sourced molecules with utility in industrial coatings applications. Suitable single crystals of the centrosymmetric title compounds, C14H22O6 and C16H26O6, respectively, were obtained with difficulty. The data for the latter hexane-1,6 diyl compound were extracted from the major fragment of a three-component twinned crystal. Both compounds crystallize in similar-sized unit cells with identical symmetry, utilizing the same weak nonconventional attractive C-H...O(ketone) hydrogen bonds via C(4) and C(5) motifs, which expand to R(2)(2)(30) ring and C(2)(2)(14) chain motifs. Their different packing orientations in similar-sized unit cells suggest that crystal growth involving packing mixes could lead to intergrowths or twins. PMID- 23744391 TI - Three salts from the reactions of cysteamine and cystamine with L-(+)-tartaric acid. AB - Reaction between cysteamine (systematic name: 2-aminoethanethiol, C2H7NS) and L (+)-tartaric acid [systematic name: (2R,3R)-2,3-dihydroxybutanedioic acid, C4H6O6] results in a mixture of cysteamine tartrate(1-) monohydrate, C2H8NS(+).C4H5O6(-).H2O, (I), and cystamine bis[tartrate(1-)] dihydrate, C4H14N2S2(2+).2C4H5O6(-).2H2O, (III). Cystamine [systematic name: 2,2' dithiobis(ethylamine), C4H12N2S2], reacts with L-(+)-tartaric acid to produce a mixture of cystamine tartrate(2-), C4H14N2S2(2+).C4H4O6(2-), (II), and (III). In each crystal structure, the anions are linked by O-H...O hydrogen bonds that run parallel to the a axis. In addition, hydrogen bonding involving protonated amino groups in all three salts, and water molecules in (I) and (III), leads to extensive three-dimensional hydrogen-bonding networks. All three salts crystallize in the orthorhombic space group P2(1)2(1)2(1). PMID- 23744392 TI - Supramolecular study, Hirshfeld analysis and theoretical study of 6 methoxyquinoline N-oxide dihydrate. AB - In the crystal structure of 6-methoxyquinoline N-oxide dihydrate, C10H9NO2.2H2O, (I), the presence of two-dimensional water networks is analysed. The water molecules form unusual water channels, as well as two intersecting mutually perpendicular columns. In one of these channels, the O atom of the N-oxide group acts as a bridge between the water molecules. The other channel is formed exclusively by water molecules. Confirmation of the molecular packing was performed through the analysis of Hirshfeld surfaces, and (I) is compared with other similar isoquinoline systems. Calculations of bond lengths and angles by the Hartree-Fock method or by density functional theory B3LYP, both with 6 311++G(d,p) basis sets, are reported, together with the results of additional IR, UV-Vis and theoretical studies. PMID- 23744393 TI - (E)-2-(1,3-benzothiazol-2-yl)-3-(4-fluorophenyl)acrylonitrile: a chain of pi stacked hydrogen-bonded rings. AB - The title compound, C16H9FN2S, crystallizes as a nonmerohedral twin with twin rotation about the reciprocal-lattice vector [101]*. The molecules are nearly planar and the dihedral angle between the planes of the two aryl rings is only 4.4 (2) degrees . The molecules are linked by pairs of C-H...N hydrogen bonds to form cyclic centrosymmetric R2(2)(18) dimers, which are linked into chains by an aromatic pi-pi stacking interaction. Comparisons are made with some related 3 aryl-2-thienylacrylonitriles. PMID- 23744394 TI - Alogliptin and its benzoate salt. AB - The crystal structure of the free base of the antidiabetic drug alogliptin [systematic name: 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4 tetrahydropyrimidin-1-yl}methyl)benzonitrile], C18H21N5O2, displays a two dimensional N-H...O hydrogen-bonded network. It contains two independent molecules, which have the same conformation but differ in their hydrogen-bond connectivity. In the crystal structure of the benzoate salt (systematic name: (3R)-1-{3-[(2-cyanophenyl)methyl]-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin 4-yl}piperidin-3-aminium benzoate), C18H22N5O2(+).C7H5O2(-), the NH3(+) group of the cation is engaged in three intermolecular N-H...O hydrogen bonds to yield a hydrogen-bonded layer structure. The benzoate salt and the free base differ fundamentally in the conformations of their alogliptin moieties. PMID- 23744395 TI - Translationally related nearly identical molecules: 4-methoxyphenyl 4-O-[6-O acetyl-2-azido-3-O-benzyl-2-deoxy-4-O-(fluoren-9-ylmethoxycarbonyl)-alpha-D glucopyranosyl]-2-O-benzoyl-3-O-benzyl-6-O-chloroacetyl-beta-D-glucopyranoside. AB - The title compound, C59H56ClN3O16, is an important dissacharide precursor to novel therapeutics for the treatment of Alzheimer's disease. It crystallizes with two independent enantiomerically identical molecules in almost exactly the same orientation in the cell, being one half cell-edge apart. Apart from the conformation of a single benzyl group, the molecules are superimposable. They are bound efficiently using complementary C-H...O(carbonyl) hydrogen bonds, principally along the 'duplicating' axis. The absolute configurations were determined. PMID- 23744396 TI - Characterization of supramolecular gels. AB - Supramolecular gels are a fascinating class of soft materials. Their gelators can self-assemble into nano- or micro-scale superstructures, such as fibers, ribbons, sheets and spheres in an appropriate solvent, thereby resulting in the formation of 3D networks. The dynamic and reversible nature of the non-covalent interactions that contribute to the formation of these network structures together gives these supramolecular gels the inherent ability to respond to external stimuli. However, the dynamic nature of supramolecular gels, which endows them with unique properties, makes their characterization diversified at the same time. Therefore, we present here a review summarizing various methods for characterizing supramolecular gels, including nuclear magnetic resonance spectroscopy, computational techniques, X-ray techniques, microscopy techniques, dynamic light scattering, thermal analysis, and rheology. Based on the gelation mechanisms and influencing factors of supramolecular gels, suitable and sufficient characterization methods should be carefully employed to make full use of their respective advantages to better investigate these materials. PMID- 23744397 TI - Non-biological selectivity in amino acids polymerization on TiO2 nanoparticles. AB - For the first, time a strong selectivity is evidenced in inorganic peptide synthesis. When an equimolar mixture of Ala and Arg monomers is added to the synthesis medium of TiO2 nanoparticles from Ti(IV) isopropoxide in benzyl alcohol, the Ala-Arg dipeptide is observed by 13C NMR in the resulting solid, at the exclusion of other dipeptides or higher peptides. PMID- 23744398 TI - Mechanism of the cardiovascular responses caused by L-proline microinjected into the supraoptic nucleus of the hypothalamus in unanesthetized rats. AB - In the present study, we report on the cardiovascular effects caused by the microinjection of L-proline (L-Pro) into the supraoptic nucleus (SON) in unanesthetized rats: the possible involvement of ionotropic glutamate receptors in the SON, as well as the peripheral mechanisms involved in the mediation of its cardiovascular effects. We compared the L-Pro effects with those caused by the injection of L-glutamate (L-Glu) into the SON. Microinjection of increasing doses of L-Pro into the SON caused dose-related cardiovascular responses in unanesthetized rats that were similar to those observed after the injection of L Glu. Pretreatment of the SON with either a selective non-NMDA (NBQX) or a selective NMDA (LY235959) glutamate receptor antagonist blocked the cardiovascular response to L-Pro. The dose-effect curve for the pretreatment with increasing doses of LY235959 was shifted to the left in relation to the curve for NBQX, showing that LY235959 is more potent than NBQX in inhibiting the cardiovascular response to L-Pro. On the other hand, the cardiovascular response to L-Glu was only significantly reduced by pretreatment with NBQX (2 nmol/100 nL), but not affected by LY235959 (2 nmol/100 nL). The pressor response to L-Pro was not affected by intravenous pretreatment with the ganglion blocker pentolinium, but it was blocked by intravenous pretreatment with the V1 vasopressin receptor antagonist dTyr(CH2)5(Me)AVP. In conclusion, these results suggest that L-Pro has a selective receptor that is sensitive to ionotropic glutamate receptor antagonists. Its activation in the SON results in vasopressin release into the systemic circulation, causing pressor and bradycardiac responses. PMID- 23744399 TI - Taurine prevented cell cycle arrest and restored neurotrophic gene expression in arsenite-treated SH-SY5Y cells. AB - The study investigated the effect of taurine on cell viability and neurotrophic gene expression in arsenite-treated human neuroblastoma SH-SY5Y cells. Arsenite induced intracellular reactive oxygen species (ROS) and interrupted cell cycle in SH-SY5Y cells. In addition, arsenite reduced mitochondria membrane potential (MMP) and decreased neurotrophic gene expressions such as n-myc downstream regulated gene 4 (NDRG-4), brain-derived neurotrophic factor (BDNF) and sirtuin-1 (SIRT-1) in SH-SY5Y cells. In parallel, taurine prevented cell cycle, restored MMP and reduced the intracellular ROS level, and taurine recovered NDRG-4, BDNF and SIRT-1 gene expressions in arsenite-treated SH-SY5Y cells while taurine alone has no effect on these parameters. PMID- 23744400 TI - A new method to synthesize creatine derivatives. AB - Creatine is an amino acid that has a pivotal role in energy metabolism of cells. Creatine acts as an "ATP shuttle", carrying ATP to the sites where it is utilized, through its reversible phosphorylation by creatine kinase. Moreover, the creatine-phosphocreatine system delays ATP depletion during anoxia or ischemia, thus exerting a neuroprotective role during those pathological conditions. Thus, its administration has been advocated as a treatment or prevention of several conditions involving the central nervous system. However, creatine crosses poorly the blood-brain barrier and the cell plasma membrane, thus its administration has but a limited effect. The use of more lipophilic creatine derivatives has thus been suggested. However, such a synthesis is complicated by the intrinsic characteristics of the creatine molecule that hardly reacts with other molecules and easily cyclizes to creatinine. We obtained amide derivatives from creatine starting from a new protected creatine molecule synthesized by us, the so-called (Boc)2-creatine. We used a temporary protection only on the creatine guanidine group while allowing a good reactivity on the carboxylic group. This temporary protection ensured efficient creatine dissolution in organic solvents and offered simultaneous protection of creatine toward intramolecular cyclization to creatinine. In this manner, it was possible to selectively conjugate molecules on the carboxylic group. The creatine guanidine group was easily released from the protection at the end of the reaction, thus obtaining the desired creatine derivative. PMID- 23744401 TI - Peptides for immunological purposes: design, strategies and applications. AB - The development of new vaccines remains an attractive goal for disease prevention and therapy, in combination or alternative to drug-based treatment. In parallel, a growing awareness of the importance of early diagnosis in successful disease management is driving the demand for new reliable diagnostic tools. As a consequence, over the last decades an impressive amount of work has been directed toward the search for new solutions to address vaccine design and biomarker discovery. In this context, peptides have generated considerable interest thanks to their general accessibility and ease of manipulation. The aim of this review is to provide the reader a general picture of the traditional peptide-based strategies adopted in immunology and to report on recent advances made in this field, highlighting advantages and limitations of classic versus innovative approaches. Case studies are described to provide illustrative examples, and cross references to more topic-focused and exhaustive reviews are proposed throughout the text. PMID- 23744402 TI - L-arginine induces protein aggregation and transformation of supramolecular structures of the aggregates. AB - Protein misfolding, self-assembly, and aggregation are an essential problem in cell biology, biotechnology, and biomedicine. The protein aggregates are very different morphologically varying from soluble amorphous aggregates to highly ordered amyloid-like fibrils. The objective of this study was to elucidate the role of the amino acid L-arginine (Arg), a widely used suppressor of protein aggregation, in the regulation of transformations of soluble aggregation-prone proteins into supramolecular structures of higher order. However, a striking potential of Arg to govern the initial events in the process of protein aggregation has been revealed under environment conditions where the protein aggregation in its absence was not observed. Using dynamic light scattering we have demonstrated that Arg (10-100 mM) dramatically accelerated the dithiothreitol-induced aggregation of acidic model proteins. The inhibitory effect on the protein aggregation was revealed at higher concentrations of Arg. Using atomic force microscopy it was shown that aggregation of alpha-lactalbumin from bovine milk induced upon addition of Arg reached a state of formation of supramolecular structures of non-fibrillar species profoundly differing from those of the individual protein in type, size, and shape. The interaction of another positively charged amino acid L-lysine with alpha-lactalbumin also resulted in profound acceleration of the aggregation process and transformation of supramolecular structures of the aggregates. PMID- 23744403 TI - High-sensitivity C-reactive protein is a predictive factor of adiposity in children: results of the identification and prevention of dietary- and lifestyle induced health effects in children and infants (IDEFICS) study. AB - BACKGROUND: Whereas cross-sectional studies have shown that obesity is associated with increased C-reactive protein (CRP) levels in children, little is known about the impact of low-grade inflammation on body mass changes during growth. METHODS AND RESULTS: We assessed cross-sectionally and longitudinally the association of high-sensitivity (hs)-CRP levels with overweight/obesity and related cardiometabolic risk factors in the Identification and prevention of Dietary- and lifestyle-induced health Effects in Children and InfantS (IDEFICS) cohort. 16 224 children from 8 European countries (2 to 9 years) were recruited during the baseline survey (T0). After the exclusion of 7187 children because of missing hs CRP measurements and 2421 because of drug use during the previous week, the analysis was performed on 6616 children (Boys=3347; Girls=3269; age=6.3 +/- 1.7 years). Of them, 4110 were reexamined 2 years later (T1). Anthropometric variables, blood pressure, hs-CRP, blood lipids, glucose and insulin were measured. The population at T0 was divided into 3 categories, according to the baseline hs-CRP levels. Higher hs-CRP levels were associated with significantly higher prevalence of overweight/obesity, body mass index (BMI) z-score and central adiposity indices (P values all <0.0001), and with higher blood pressure and lower HDL-cholesterol levels. Over the 2-year follow-up, higher baseline hs CRP levels were associated with a significant increase in BMI z-score (P<0.001) and significantly higher risk of incident overweight/obesity. CONCLUSIONS: Higher hs-CRP levels are associated to higher body mass and overweight/obesity risk in a large population of European children. Children with higher baseline levels of hs CRP had a greater increase in BMI z-score and central adiposity over time and were at higher risk of developing overweight/obesity during growth. PMID- 23744404 TI - Lack of reduction of left ventricular mass in treated hypertension: the strong heart study. AB - BACKGROUND: Hypertensive left ventricular mass (LVM) is expected to decrease during antihypertensive therapy, based on results of clinical trials. METHODS AND RESULTS: We assessed 4-year change of echocardiographic LVM in 851 hypertensive free-living participants of the Strong Heart Study (57% women, 81% treated). Variations of 5% or more of the initial systolic blood pressure (SBP) and LVM were categorized for analysis. At baseline, 23% of men and 36% of women exhibited LV hypertrophy (LVH, P<0.0001). At the follow-up, 3% of men and 10% of women had regression of LVH (P<0.0001 between genders); 14% of men and 15% of women, free of baseline LVH, developed LVH. There was an increase in LVM over time, more in men than in women (P<0.001). Participants whose LVM did not decrease had similar baseline SBP and diastolic BP, but higher body mass index (BMI), waist/hip ratio, heart rate (all P<0.008), and urinary albumin/creatinine excretion (P<0.001) than those whose LVM decreased. After adjusting for field center, initial LVM index, target BP, and kinship degree, lack of decrease in LVM was predicted by higher baseline BMI and urinary albumin/creatinine excretion, independently of classes of antihypertensive medications, and significant effects of older age, male gender, and percentage increase in BP over time. Similar findings were obtained in the subpopulation (n=526) with normal BP at follow-up. CONCLUSIONS: In a free living population, higher BMI is associated with less reduction of hypertensive LVH; lack of reduction of LVM is independent of BP control and of types of antihypertensive treatment, but is associated with renal damage. PMID- 23744405 TI - Porphothionolactones: synthesis, structure, physical, and chemical properties of a chemodosimeter for hypochlorite. AB - The conversion of the lactone functionality of porpholactones, porphyrin analogs in which a porphyrin beta,beta'-double bond was replaced by a lactone moiety, to a thionolactone functionality using Lawesson's reagent is described. The resulting novel thionolactones were spectroscopically characterized and their electronic structure defined using experimental (UV-vis, fluorescence, cyclic voltammetry) and theoretical methods (molecular modelling at the B3LYP/6-31G(d) level). The structures of two benchmark thionolactones were determined by single crystal X-ray diffractometry. The idealized planarity of the chromophores rationalize the bathochromically shifted optical spectra of the thionolactones when compared to the lactones on electronic grounds. The thionolactone moiety can be used as a synthetic handle in the preparation of oxazolochlorins using RANEY(r) nickel-induced hydrodesulfurization reactions. Importantly, the meso pentafluorophenyl-based porphothionolactone fluoresces by at least a factor of 60 less compared to the corresponding lactone. The hypochlorite-selective conversion of the thionolactone to the lactone is the basis for the use of this thionolactone as a switch-on chemodosimeter for hypochlorite, a widely used disinfectant and molecule of biological significance in some inflammatory processes. PMID- 23744406 TI - Presence of brown adipocytes in retroperitoneal fat from patients with benign adrenal tumors: relationship with outdoor temperature. AB - CONTEXT: Brown adipose tissue (BAT) is a metabolically highly active organ with increased thermogenic activity in rodents exposed to cold temperature. Recently its presence in the cervical adipose tissue of human adults and its association with a favorable metabolic phenotype have been reported. OBJECTIVE: The objective of the study was to determine the prevalence of retroperitoneal BAT in human adults. DESIGN: This was an observational cohort study. SETTING: The study was conducted at a tertiary referral hospital. PATIENTS: Fifty-seven patients who underwent surgery for benign adrenal tumors were included in this study. MAIN OUTCOME MEASURES: Prevalence of retroperitoneal BAT adjacent to the removed adrenal tumor as determined by uncoupling protein 1 (UCP1) protein and mRNA expression was measured. RESULTS: Using protein and mRNA expression analysis, we detected UCP1 protein in 26 of 57 patients (45.6%) as well as high mRNA expression of genes characteristic for brown adipocytes, independent of the adrenal tumor type. The presence of brown adipocytes within the retroperitoneal fat was associated with a significantly lower outdoor temperature during the month prior to surgery. Importantly, UCP1 expression on both mRNA and protein level was inversely correlated to outdoor temperature, whereas body mass index, sex, age, and diabetes status were not. CONCLUSIONS: These findings suggest that human retroperitoneal adipose tissue can acquire a BAT phenotype, thereby adapting to environmental challenges. These adaptive processes might provide a valuable therapeutic target in the treatment of obesity and insulin resistance. PMID- 23744407 TI - Decreased concentrations of the lipoprotein lipase inhibitor angiopoietin-like protein 4 and increased serum triacylglycerol are associated with increased neonatal fat mass in pregnant women with gestational diabetes mellitus. AB - CONTEXT: Angiopoietin-like protein 4 (ANGPTL4) is an extracellular inhibitor of lipoprotein lipase (LPL) activity. No studies have been done in pregnancy in which hypertriglyceridemia and tissue-specific changes in LPL activity are present. OBJECTIVE: The objective of the study was to determine the relationship between neonatal fat mass (FM) and concentrations of ANGPTL4 and triacylglycerols (TAG) in maternal and cord serum of pregnant women with gestational diabetes mellitus (GDM) compared with controls. DESIGN: Maternal blood samples (control, n = 90, and GDM, n= 80) and umbilical cord blood were drawn before and after vaginal delivery, respectively. Control and GDM subjects were grouped separately into 3 subgroups, according to neonatal FM: 0-25th percentiles, 25th-75th percentiles, and 75th-100th percentiles. OUTCOME MEASURES: Glucose, insulin, TAG, nonesterified fatty acids (NEFAs), and ANGPTL4 were determined in maternal and neonatal serum. RESULTS: Age and pregestational body mass index did not differ between GDM and control women in any subgroups. Maternal serum of GDM pregnant women who delivered the newborn with the highest FM showed the highest concentrations of TAG and NEFAs and lowest concentration of ANGPTL4, despite glucose and insulin concentrations being independent of changes in neonatal FM. However, cord serum of neonates of GDM patients with the highest FM showed higher concentrations of insulin and lower concentrations of TAG than those with lower neonatal FM but no significant differences in NEFAs or ANGPTL4 concentrations. CONCLUSIONS: In well-controlled GDM pregnancies, decreased maternal ANGPTL4 concentrations and a gradient of TAG toward the fetus are related with higher neonatal FM. However, in GDM fetuses with the highest FM, the potential effect of ANGPTL4 inhibiting adipose tissue LPL activity could be overcome by their hyperinsulinemia. PMID- 23744409 TI - Thyroid diseases and adverse pregnancy outcomes in a contemporary US cohort. AB - CONTEXT: Thyroid diseases are inconsistently reported to increase risk for pregnancy complications. OBJECTIVE: The objective of this study was to study pregnancy complications associated with common and uncommon thyroid diseases. DESIGN, SETTING, AND PARTICIPANTS: We analyzed singleton pregnancies (N = 223 512) from a retrospective US cohort, the Consortium on Safe Labor (2002-2008). Thyroid diseases and outcomes were derived from electronic medical records. Multivariable logistic regression with generalized estimating equations estimated adjusted odds ratios (ORs) with 99% confidence intervals (99% CI). MAIN OUTCOME MEASURES: Hypertensive diseases, diabetes, preterm birth, cesarean sections, inductions, and intensive care unit (ICU) admissions were analyzed. RESULTS: Primary hypothyroidism was associated with increased odds of preeclampsia (OR = 1.47, 99% CI = 1.20-1.81), superimposed preeclampsia (OR = 2.25, 99% CI = 1.53 3.29), gestational diabetes (OR = 1.57, 99% CI = 1.33-1.86), preterm birth (OR = 1.34, 99% CI = 1.17-1.53), induction (OR = 1.15, 99% CI = 1.04-1.28), cesarean section (prelabor, OR = 1.31, 99% CI = 1.11-1.54; after spontaneous labor OR = 1.38, 99% CI = 1.14-1.66), and ICU admission (OR = 2.08, 99% CI = 1.04-4.15). Iatrogenic hypothyroidism was associated with increased odds of placental abruption (OR = 2.89, 99% CI = 1.14-7.36), breech presentation (OR = 2.09, 99% CI = 1.07-4.07), and cesarean section after spontaneous labor (OR = 2.05, 99% CI = 1.01-4.16). Hyperthyroidism was associated with increased odds of preeclampsia (OR = 1.78, 99% CI = 1.08-2.94), superimposed preeclampsia (OR = 3.64, 99% CI = 1.82-7.29), preterm birth (OR = 1.81, 99% CI = 1.32-2.49), induction (OR = 1.40, 99% CI = 1.06-1.86), and ICU admission (OR = 3.70, 99% CI = 1.16-11.80). CONCLUSIONS: Thyroid diseases were associated with obstetrical, labor, and delivery complications. Although we lacked information on treatment during pregnancy, these nationwide data suggest either that there is a need for better thyroid disease management during pregnancy or that there may be an intrinsic aspect of thyroid disease that causes poor pregnancy outcomes. PMID- 23744410 TI - A novel liver function evaluation system using radiopharmacokinetic modeling of technetium-99m-DTPA-galactosyl human serum albumin. AB - BACKGROUND: A new kinetic model of technetium-99m-labeled diethylenetriaminepentaacetic acid-galactosyl human serum albumin (Tc-GSA) was developed to show the speed of asialoglycoprotein receptor-mediated endocytosis. MATERIALS AND METHODS: Ten healthy volunteers and 17 patients with liver cirrhosis were intravenously injected with 185 MBq of Tc-GSA, and dynamic planar images were acquired. The absolute amounts of Tc-GSA in the liver and extrahepatic blood were estimated from the time-activity curves for the liver, heart, and lungs. A two-compartment model was represented with two parameters as variables to estimate the uptake index (UI) of Tc-GSA transport through the hepatic cell membrane from the total plasma at any given time. RESULTS: The dynamic curve of Tc-GSA uptake by the liver was generated. Analysis of individuals with normal livers and patients with liver cirrhosis showed statistically significant differences in their UI. The UI for normal livers was high and that for cirrhotic livers was low. Linear regression correlation of UI with albumin, prealbumin, and prothrombin time was 0.841, 0.746, and -0.723, respectively. CONCLUSION: UI reflects the cellular transport of asialoglycoproteins as ascertained by the two-compartment model on the basis of GSA dynamic images. It is useful for measuring liver function. PMID- 23744408 TI - Multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma: an update. AB - CONTEXT: Over the last decade, our knowledge of the multiple endocrine neoplasia (MEN) type 2 syndromes MEN2A and MEN2B and familial medullary thyroid carcinoma (FMTC) has expanded greatly. In this manuscript, we summarize how recent discoveries have enhanced our understanding of the molecular basis of these diseases and led to improvements in the diagnosis and management of affected patients. EVIDENCE ACQUISITION: We reviewed the English literature through PubMed from 2000 to the present, using the search terms medullary thyroid carcinoma, multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma, RET proto-oncogene, and calcitonin. EVIDENCE SYNTHESIS: Over 70 RET mutations are known to cause MEN2A, MEN2B, or FMTC, and recent findings from studies of large kindreds with these syndromes have clouded the relationship between genotype and phenotype, primarily because of the varied clinical presentation of different families with the same RET mutation. This clinical variability has also confounded decisions about the timing of prophylactic thyroidectomy for MTC, the dominant endocrinopathy associated with these syndromes. A distinct advance has been the demonstration through phase II and phase III clinical trials that molecular targeted therapeutics are effective in the treatment of patients with locally advanced or metastatic MTC. CONCLUSIONS: The effective management of patients with MEN2A, MEN2A, and FMTC depends on an understanding of the variable behavior of disease expression in patients with a specific RET mutation. Information gained from molecular testing, biochemical analysis, and clinical evaluation is important in providing effective management of patients with either early or advanced-stage MTC. PMID- 23744411 TI - Dr. Gert Schulze, M.D. (1941-2013). In memoriam. PMID- 23744412 TI - Vitamin D and the central nervous system. AB - Vitamin D is formed in human epithelial cells via photochemical synthesis and is also acquired from dietary sources. The so-called classical effect of this vitamin involves the regulation of calcium homeostasis and bone metabolism. Apart from this, non-classical effects of vitamin D have recently gained renewed attention. One important yet little known of the numerous functions of vitamin D is the regulation of nervous system development and function. The neuroprotective effect of vitamin D is associated with its influence on neurotrophin production and release, neuromediator synthesis, intracellular calcium homeostasis, and prevention of oxidative damage to nervous tissue. Clinical studies suggest that vitamin D deficiency may lead to an increased risk of disease of the central nervous system (CNS), particularly schizophrenia and multiple sclerosis. Adequate intake of vitamin D during pregnancy and the neonatal period seems to be crucial in terms of prevention of these diseases. PMID- 23744413 TI - Fever development in neuroleptic malignant syndrome during treatment with olanzapine and clozapine. AB - Neuroleptic malignant syndrome (NMS) is the most dangerous life-threatening complication of antipsychotic medication. It's development is connected with the blockade of dopaminergic transmission (D2 receptors) in the nigrostriatal system of the brain. Fever is one of the main symptoms of this syndrome and it's elevation is due to the activation of the immune system. Numerous studies report that treatment with clozapine (doses 37.5-600 mg) or olanzapine (doses 10-25 mg) or the use of these drugs in polytherapy cause pyrexia between 37.8-40.6 degrees C. Additionally, levels of proinflammatory interleukins such as IL-6, IL-1,TNF alpha were increased. The aim of this article is to describe how olanzapine and clozapine influence fever development in NMS, in relation to the dose of the drug taken by schizophrenic patients including changes in immunological system. PMID- 23744414 TI - Oxidative stress, polyunsaturated fatty acids-derived oxidation products and bisretinoids as potential inducers of CNS diseases: focus on age-related macular degeneration. AB - Many pathologies of the central nervous system (CNS) originate from excess of reactive free radicals, notably reactive oxygen species (ROS), and oxidative stress. A phenomenon which usually runs in parallel with oxidative stress is unsaturated lipid peroxidation, which, via a chain reaction, contributes to the progression of disbalanced redox homeostasis. Among long-chain (LC) polyunsaturated fatty acids (PUFAs) abundantly occurring in the CNS, docosahexaenoic acid (DHA), a member of omega-3 LC-PUFAs, deserves special attention, as it is avidly retained and uniquely concentrated in the nervous system, particularly in retinal photoreceptors and synaptic membranes; owing to the presence of the six double bonds between carbon atoms in its polyene chain (C=C), DHA is exquisitely sensitive to oxidative damage. In addition to oxidative stress and LC-PUFAs peroxidation, other stress-related mechanisms may also contribute to the development of various CNS malfunctions, and a good example of such mechanisms is the process of lipofuscin formation occurring particularly in the retina, an integral part of the CNS. The retinal lipofuscin is formed and accumulated by the retinal pigment epithelial (RPE) cells as a consequence of both visual process taking place in photoreceptor-RPE functional complex and metabolic insufficiency of RPE lysosomal compartment. Among various retinal lipofuscin constituents, bisretinoids, originating from all-trans retinal substrate--a photometabolite of visual pigment cofactor 11-cis-retinal (responsible for photon capturing), are endowed with cytotoxic and complement activating potential which increases upon illumination and oxidation. This survey deals with oxidative stress, PUFAs (especially DHA) peroxidation products of carboxyalkylpyrrole type and bisretinoids as potential inducers of the CNS pathology. A focus is put on vision-threatening disease, i.e., age-related macular degeneration (AMD), as an example of the CNS disorder whose pathogenesis has strong background in both oxidative stress and lipid peroxidation products. PMID- 23744415 TI - Mydriasis model in rats as a simple system to evaluate alpha2-adrenergic activity of the imidazol(in)e compounds. AB - Imidazol(in)e compounds show the diversity of pharmacological effects including mydriasis, hypotension, sedation, bradycardia and hypothermia. At first it was postulated that these effects are mediated via alpha2-adrenoceptors exclusively. Clonidine is well known as a model agent to produce pupillary dilation in rats. However, it became obvious later that clonidine-like imidazol(in)e adrenoceptor agonists which produced mydriasis in rats, exhibit also a high affinity for imidazoline I1-receptors. That short report attempts to review the present status of studies to confirm that the mydriasis model in rats can be a selective system to evaluate the alpha2-adrenergic activity of potential pharmacologically active compounds of imidazol(in)e structure. PMID- 23744416 TI - Biochemical and pharmacological characterization of isatin and its derivatives: from structure to activity. AB - Isatin, 1H-indole-2,3-dione, is a heterocyclic compound of significant importance in medicinal chemistry. It is a synthetically versatile molecule, a precursor for a large number of pharmacologically active compounds. Isatin and its derivatives have aroused great attention in recent years due to their wide variety of biological activities, relevant to application as insecticides and fungicides and in a broad range of drug therapies, including anticancer drugs, antibiotics and antidepressants. The purpose of this review is to provide an overview of the pharmacological activities of isatin and its synthetic and natural derivatives. Molecular modifications to tailor the properties of isatin and its derivatives are also discussed. PMID- 23744417 TI - Attenuation of stress-induced behavioral deficits by lithium administration via serotonin metabolism. AB - BACKGROUND: Although the mood stabilizing role of lithium is well established and the cognitive effects of lithium are also best demonstrated, but its primary effect on neurochemical profile and behaviors under stress remain ambiguous. Earlier studies have suggested that a single exposure to 2 h immobilization stress alters memory in various memory tasks, decreases exploratory activity in open field test and increases serotonin metabolism. This study is designed to investigate the stress relieving effect of lithium in rats. METHODS: Rats were orally administered with lithium carbonate (1 mg/kg/ml) while controls received an equal volume of water for 21 days. After 21 days, each group of rats was sub divided into stressed and unstressed groups. Animals of stressed group received immobilization stress for 2 h and 24 h following stress behavioral analysis was performed, after which animals were decapitated and their brain samples were collected for neurochemical estimation by HPLC-EC. RESULTS: Results of the present study show that 2 h immobilization stress decreases locomotor activity while impairs memory performance. Prior administration of lithium attenuates memory impairment and locomotion suppressant effects of stress by reversing the stress induced brain serotonin metabolism in lithium treated rats. CONCLUSION: Thus, the results of this study suggest that lithium may recover behavioral and neurochemical impairments induced by stress. PMID- 23744418 TI - sigma Receptor antagonist attenuation of methamphetamine-induced neurotoxicity is correlated to body temperature modulation. AB - BACKGROUND: Methamphetamine (METH) causes hyperthermia and dopaminergic neurotoxicity in the rodent striatum. METH interacts with sigma receptors and sigma receptor antagonists normally mitigate METH-induced hyperthermia and dopaminergic neurotoxicity. The present study was undertaken because in two experiments, pretreatment with sigma receptor antagonists failed to attenuate METH-induced hyperthermia in mice. This allowed us to determine whether the ability of sigma receptor antagonists (AZ66 and AC927) to mitigate METH-induced neurotoxicity depends upon their ability to modulate METH-induced hyperthermia. METHODS: Mice were treated using a repeated dosing paradigm and body temperatures recorded. Striatal dopamine was measured one week post-treatment. RESULTS: The data indicate that the ability of sigma receptor antagonists to attenuate METH induced dopaminergic neurotoxicity is linked to their ability to block METH induced hyperthermia. CONCLUSION: The ability of sigma receptor antagonists to mitigate METH-induced hyperthermia may contribute to its neuroprotective actions. PMID- 23744419 TI - Nisoxetine blocks sodium currents and elicits spinal anesthesia in rats. AB - BACKGROUND: Although nisoxetine has been shown to elicit infiltrative cutaneous local anesthesia, the inhibition of voltage-gated Na(+) channels by nisoxetine has not been reported. The aim of this study was to evaluate the effect of nisoxetine on Na(+) currents and its efficacy on spinal anesthesia. METHODS: In in vitro studies, the voltage-clamp method was employed to examine whether nisoxetine blocked Na(+) currents in mouse neuroblastoma N2A cells. RESULTS: Mepivacaine showed concentration- and state-dependent effect on tonic blockade of voltage-gated Na(+) currents (IC50 of 3.7 and 74.2 MUM at holding potentials of 70 and -100 mV, respectively). Nisoxetine was more potent (IC50 of 1.6 and 28.6 MUM at holding potentials of -70 and -100 mV, respectively). In in vivo studies, after rats were intrathecally injected with nisoxetine and mepivacaine, the dose response curves were constructed. Nisoxetine acted like local anesthetic mepivacaine and induced spinal anesthesia with a more sensory-selective action (p < 0.05) over motor blockade in a dose-related fashion. Intrathecal 5% dextrose (vehicle) produced no spinal anesthesia. On the 50% effective dose (ED50) basis, nisoxetine elicited more potent spinal anesthesia than did mepivacaine (p < 0.05). CONCLUSIONS: Our results showed that nisoxetine displayed a more potent and prolonged spinal anesthesia with a more sensory/nociceptive-selective action over motor blockade, compared with mepivacaine. The local anesthetic effect of nisoxetine could be probably due to the suppression of Na(+) currents. PMID- 23744420 TI - Antinociceptive synergy between diclofenac and morphine after local injection into the inflamed site. AB - BACKGROUND: Combinations of non-steroidal anti-inflammatory drugs with opioids are frequently used to reduce opioid doses required in the clinical management of acute pain. The present study was designed to evaluate the possible antinociceptive interaction between morphine and diclofenac at peripheral level in male rats. METHODS: Drugs were chosen based on their efficacy in the treatment of this kind of pain and as representative drugs of their respective analgesic groups. For the formalin test, 50 MU of 1% formalin solution was injected subcutaneously into the right hind paw. The interaction between morphine and diclofenac was evaluated by using isobolographic analysis and interaction index. Drug interaction was examined by administering fixed-ratio combinations of morphine-diclofenac (1 : 1 and 3 : 1) of their respective ED30 fractions. RESULTS: Diclofenac and morphine reduced flinching behavior in a dose-dependent manner during phase 2 but not phase 1 of the formalin test. Isobolographic analysis showed a synergistic interaction for the combination of morphine and diclofenac after local peripheral administration. CONCLUSIONS: Data suggest that the combination of morphine with diclofenac at the site of injury is synergistic and could be useful in the treatment of wounds, bruises, rheumatisms and other painful peripheral conditions associated with an inflammatory process. PMID- 23744421 TI - Changes in the Egr1 and Arc expression in brain structures of pentylenetetrazole kindled rats. AB - BACKGROUND: Epileptogenesis is regarded as a complicated and relatively poorly understood phenomenon. Some of immediate early genes (IEGs) as egr1 (zif268) or arc (arg3.1) are believed to play an important role in the process of epileptogenesis. However, how these genes are engaged in epilepsy is not fully elucidated. METHODS: In this study, we sought to explore how the spread of epileptiform activity (pentylenetetrazole (PTZ)-induced kindling) in the brain activates egr1, the early growth response gene, a member of the immediate early gene (IEG) family, and arc (activity-regulated cytoskeleton-associated protein) expression. We also wanted to map the specific brain regions that undergo kindling-related neuroplastic changes in rats. RESULTS: When compared to animals that had been administered only a single PTZ injection (35 mg/kg), the animals at stage 5 of kindling had significantly higher Egr1 and Arc expression in the CA1 region of the hippocampus and the dentate gyrus. Increased expression of Egr1 was also observed in the CA3 region of the hippocampus, and Arc expression was also significantly higher in the entorhinal and the piriform cortices. The fastest and most potent increase in Egr1 expression during PTZ-induced kindling was found in the piriform and entorhinal cortices. The pattern of Arc expression was different than that of Egr1. The most prominent increase in Arc expression during kindling was present in the entorhinal cortex, the dentate gyrus, and the basolateral nucleus of the amygdala. CONCLUSION: Our results demonstrate that the IEGs, egr1 and arc, may significantly contribute to synaptic reorganization induced by the kindling of seizures. PMID- 23744422 TI - Effect of acute and chronic tianeptine on the action of classical antiepileptics in the mouse maximal electroshock model. AB - BACKGROUND: The aim of the study was to analyze the influence of acute and chronic treatment with tianeptine, an antidepressant selectively accelerating presynaptic serotonin reuptake, on the protective activity of classical antiepileptic drugs in the maximal electroshock test in mice. METHODS: Electroconvulsions were produced by means of an alternating current (50 Hz, 25 mA, 0.2 s) delivered via ear-clip electrodes. Motor impairment and long-term memory deficits in animals were quantified in the chimney test and in the passive avoidance task, respectively. Brain concentrations of antiepileptic drugs were measured by fluorescence polarization immunoassay. RESULTS: Acute and chronic treatment with tianeptine (25-50 mg/kg) did not affect the electroconvulsive threshold. Furthermore, tianeptine applied in both acute and chronic protocols enhanced the anticonvulsant action of valproate and carbamazepine, but not that of phenytoin. Neither acute nor chronic tianeptine changed the brain concentrations of valproate, carbamazepine or phenytoin. On the other hand, both single and chronic administration of tianeptine diminished the brain concentration of phenobarbital. In spite of this pharmacokinetic interaction, the antidepressant enhanced the antielectroshock action of phenobarbital. In terms of adverse effects, acute/chronic tianeptine (50 mg/kg) and its combinations with classic antiepileptic drugs did not impair motor performance or long-term memory in mice. CONCLUSION: The obtained results justify the conclusion that tianeptine may be beneficial in the treatment of depressive disorders in the course of epilepsy. PMID- 23744423 TI - Effects of N-(morpholinomethyl)-p-isopropoxyphenylsuccinimide on the protective action of different classical antiepileptic drugs against maximal electroshock induced tonic seizures in mice. AB - BACKGROUND: The aim of this study was to determine the effects of N (morpholinomethyl)-p-isopropoxy-phenylsuccinimide (MMIPPS) on the protective action of four classical antiepileptic drugs (AEDs: carbamazepine [CBZ], phenobarbital [PB], phenytoin [PHT] and valproate [VPA]) against maximal electroshock (MES)-induced seizures in mice. METHODS: Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Total brain concentrations of AEDs were measured to determine the characteristics of interaction between MMIPPS and classical AEDs in the mouse MES model. RESULTS: MMIPPS administered intraperitoneally (ip) at 100 mg/kg significantly elevated the threshold for electroconvulsions in mice (p < 0.01). MMIPPS at doses of 25 and 50 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, MMIPPS (50 mg/kg) significantly enhanced the anticonvulsant activity of PB and VPA (p < 0.05), but not that of CBZ or PHT, in the MES test in mice. Pharmacokinetic studies revealed that MMIPPS (50 mg/kg) did not alter total brain concentrations of PB, but significantly elevated total brain concentrations of VPA in mice (p < 0.05). CONCLUSIONS: The enhanced anticonvulsant action of PB by MMIPPS in the mouse MES model and lack of any pharmacokinetic interaction between drugs make the combination of MMIPPS with PB of pivotal importance for further experimental and clinical studies. Pharmacokinetic increase in total brain VPA concentration seems to be responsible for the enhanced anticonvulsant action of VPA by MMIPPS in the mouse MES model. The combinations of MMIPPS with CBZ and PHT are neutral from a preclinical viewpoint. PMID- 23744424 TI - Single centre 20 year survey of antiepileptic drug-induced hypersensitivity reactions. AB - BACKGROUND: Epilepsy is a chronic neurological disease which affects about 1% of the human population. There are 50 million patients in the world suffering from this disease and 2 million new cases per year are observed. The necessary treatment with antiepileptic drugs (AEDs) increases the risk of adverse reactions. In case of 15% of people receiving AEDs, cutaneous reactions, like maculopapular or erythematous pruritic rash, may appear within four weeks of initiating therapy with AEDs. METHODS: This study involved 300 epileptic patients in the period between September 1989 and September 2009. A cutaneous adverse reaction was defined as a diffuse rash, which had no other obvious reason than a drug effect, and resulted in contacting a physician. RESULTS: Among 300 epileptic patients of Neurological Practice in Kielce (132 males and 168 females), a skin reaction to at least one AED was found in 30 patients. As much as 95% of the reactions occurred during therapies with carbamazepine, phenytoin, lamotrigine or oxcarbazepine. One of the patients developed Stevens-Johnson syndrome. CONCLUSION: Some hypersensitivity problems of epileptic patients were obviously related to antiepileptic treatment. Among AEDs, gabapentin, topiramate, levetiracetam, vigabatrin, and phenobarbital were not associated with skin lesions, although the number of patients in the case of the latter was small. PMID- 23744425 TI - Effects of sesquiterpene, flavonoid and coumarin types of compounds from Artemisia annua L. on production of mediators of angiogenesis. AB - BACKGROUND: In addition to recognized antimalarial effects, Artemisia annua L. (Qinghao) possesses anticancer properties. The underlying mechanisms of this activity are unknown. The aim of our experiments was to investigate the effects of distinct types of compounds isolated from A. annua on the immune-activated production of major mediators of angiogenesis playing a crucial role in growth of tumors and formation of metastasis. METHODS: Included in the study were the sesquiterpene lactones artemisinin and its biogenetic precursors arteannuin B and artemisinic acid. The semi-synthetic analogue dihydroartemisinin was used for comparative purposes. The flavonoids were represented by casticin and chrysosplenol D, the coumarin type of compounds by 4-methylesculetin. Their effects on the lipopolysaccharide (LPS)-induced in vitro production of nitric oxide (NO) were analyzed in rat peritoneal cells using Griess reagent. The LPS activated production of prostaglandin E2 (PGE2) and cytokines (VEGF, IL-1beta, IL 6 and TNF-alpha) was determined in both rat peritoneal cells and human peripheral blood mononuclear cells using ELISA. RESULTS: All sesquiterpenes (artemisinin, dihydroartemisinin, artemisinic acid, arteannuin B) significantly reduced production of PGE2. Arteannuin B also inhibited production of NO and secretion of cytokines. All NO, PGE2 and cytokines were suppressed by flavonoids casticin and chrysosplenol D. The coumarin derivative, 4-methylesculetin, was ineffective to change the production of any of these factors. CONCLUSIONS: The inhibition of immune mediators of angiogenesis by sesquiterpene lactones and flavonoids may be one of the mechanisms of anticancer activity of Artemisia annua L. PMID- 23744426 TI - Changes in antioxidant capacity of blood due to mutual action of electromagnetic field (1800 MHz) and opioid drug (tramadol) in animal model of persistent inflammatory state. AB - BACKGROUND: The biological effects and health implications of electromagnetic field (EMF) associated with cellular mobile telephones and related wireless systems and devices have become a focus of international scientific interest and world-wide public concern. It has also been proved that EMF influences the production of reactive oxygen species (ROS) in different tissues. METHODS: Experiments were performed in healthy rats and in rats with persistent inflammatory state induced by Complete Freund's Adjuvant (CFA) injection, which was given 24 h before EMF exposure and drug application. Rats were injected with CFA or the same volume of paraffin oil into the plantar surface of the left hind paw. Animals were exposed to the far-field range of an antenna at 1800 MHz with the additional modulation which was identical to that generated by mobile phone GSM 1800. Rats were given 15 min exposure, or were sham-exposed with no voltage applied to the field generator in control groups. Immediately before EMF exposure, rats were injected intraperitoneally with tramadol in the 20 mg/kg dose or vehicle in the 1 ml/kg volume. RESULTS: Our study revealed that single EMF exposure in 1800 MHz frequency significantly reduced antioxidant capacity both in healthy animals and those with paw inflammation. A certain synergic mode of action between applied electromagnetic fields and administered tramadol in rats treated with CFA was observed. CONCLUSIONS: The aim of the study was to examine the possible, parallel/combined effects of electromagnetic radiation, artificially induced inflammation and a centrally-acting synthetic opioid analgesic drug, tramadol, (used in the treatment of severe pain) on the antioxidant capacity of blood of rats. The antioxidant capacity of blood of healthy rats was higher than that of rats which received only tramadol and were exposed to electromagnetic fields. PMID- 23744427 TI - Lymphocyte-suppressing, endothelial-protective and systemic anti-inflammatory effects of metformin in fenofibrate-treated patients with impaired glucose tolerance. AB - BACKGROUND: No previous clinical study has been designed to assess the additive effect of metformin and a fibrate on lymphocyte secretory function. The aim of our study was to investigate whether metformin produces any effect on lymphocyte cytokine release in fibrate-treated patients with early glucose metabolism abnormalities. METHODS: The study included 80 patients with isolated impaired glucose tolerance and normal plasma lipids who complied with lifestyle modifications and received chronic fenofibrate treatment. These subjects were randomly assigned to 90 days' treatment with either high-dose metformin (3 g daily in three divided doses) or placebo. Plasma lipids, glucose homeostasis markers, plasma C-reactive protein and intercellular adhesion molecule-1 levels, as well as lymphocyte release of proinflammatory cytokines were determined before randomization and at the end of the treatment. RESULTS: Beyond improving glucose homeostasis, metformin reduced plasma C-reactive protein levels and lymphocyte release of tumor necrosis factor-alpha and interferon-gamma, as well as tended to reduce interleukin-2 release and plasma intercellular adhesion molecule-1. CONCLUSIONS: Our study shows that metformin potentiates lymphocyte-suppressing, endothelial-protective and systemic anti-inflammatory effects of fenofibrate, and suggests that patients with impaired glucose tolerance may benefit the most from the combined treatment with a fibrate and high-dose metformin. PMID- 23744428 TI - Anisomycin suppresses Jurkat T cell growth by the cell cycle-regulating proteins. AB - BACKGROUND: Recent studies have shown that anisomycin significantly inhibits mammalian cell proliferation, but its mechanism remains unclear. In this study, Jurkat T cells were used to first explore a relationship between effect of anisomycin on them and alteration of cell cycle-regulating proteins. METHODS: Cell colony formation, CCK-8 assay, flow cytometry, RT-PCR and western blot were employed to evaluate correlation of ten cell cycle-regulating proteins with suppression of the cell proliferation and arrest of the cell cycle by anisomycin. RESULTS: Our data showed that anisomycin inhibited the colony-formation and proliferation of Jurkat T cells in a dose-dependent manner, and arrested the cells into S and G2/M phases with the production of sub-diploid cells. The levels of P21, P-P27 and P53/P-P53 reached their peaks 4 h after anisomycin treatment, presenting a positive correlation with anisomycin concentration, and P16, P-P21, P27, P57, P73/P-P73 and P-Rb changed little with the prolonged exposure time or increased concentrations of anisomycin. But the level of Rb protein was increased at 24 h after the treatment of anisomycin. The expression of an inverted CCAAT box binding protein (ICBP90) in Jurkat T cells came to decrease 12 h after the treatment of anisomycin, presenting a negative correlation with anisomycin concentration. Subsequently, the expression of P-CDK2 was also decreased at 24 h, presenting an obviously negative correlation, whereas P-CDK1 showed no differences among the differently treated Jurkat T cells. Furthermore, the level of P21 and P53 mRNA was increased with the enhanced concentrations of anisomycin. CONCLUSION: The results indicate that anisomycin may activate the P53/P21/P27 signaling to decrease the expression of ICBP90, inhibit expression of P-CDK2 to block the cells into S and G2/M phases, and finally result in proliferation inhibition of Jurkat T cells. PMID- 23744429 TI - In vivo effect of oracin on doxorubicin reduction, biodistribution and efficacy in Ehrlich tumor bearing mice. AB - BACKGROUND: The limitation of carbonyl reduction represents one possible way to increase the effectiveness of anthracycline doxorubicin (DOX) in cancer cells and decrease its toxicity in normal cells. In vitro, isoquinoline derivative oracin (ORC) inhibited DOX reduction and increased the antiproliferative effect of DOX in MCF-7 breast cancer cells. Moreover, ORC significantly decreases DOX toxicity in non-cancerous MCF-10A breast cells and in hepatocytes. The present study was designed to test in mice the in vivo effect of ORC on plasma and tissue concentrations of DOX and its main metabolite DOXOL. The effect of ORC on DOX efficacy in mice bearing solid Ehrlich tumors (EST) was also studied. METHODS: DOX and DOX + ORC combinations were iv administered to healthy mice. Blood samples, livers and hearts were collected during the following 48 h. DOX and DOXOL concentrations were assayed using HPLC. The mice with inoculated EST cells were treated repeatedly iv with DOX and DOX + ORC combinations, and the growth of tumors was monitored. RESULTS: ORC in combination with DOX significantly decreased DOXOL plasma concentrations during four hours after administration, but this significantly affected neither DOX plasma concentrations nor DOX or DOXOL concentrations in the liver and heart at any of intervals tested. In EST bearing mice, ORC did not significantly affect DOX efficacy on tumor growth. However, EST was shown to be an improper model for the testing of ORC efficacy in vivo, as ORC did not inhibit DOXOL formation in EST. CONCLUSIONS: In vivo, ORC was able to retard DOXOL formation but was not able to improve DOX efficacy in EST-bearing mice. PMID- 23744430 TI - Synergistic anti-cancer activity of the combination of dihydroartemisinin and doxorubicin in breast cancer cells. AB - BACKGROUND: Dihydroartemisinin (DHA) exhibits potent anti-malarial and anti cancer activities. This study aimed to investigate the anti-proliferative effects of a combination of DHA and doxorubicin (DOX) on human breast cancer cells. METHODS: MTT assay and the combination index (CI) were used to show the anti proliferative effects and calculate the synergism potential, respectively. Flow cytometry assay was used to detect apoptosis and the intracellular accumulation of DOX. JC-1 staining was used to determine the mitochondrial membrane potential. Western blot analysis was used to detect the protein expression of some apoptosis related molecules. RESULTS: Asynergistic anti-proliferative effect was found, and the enhanced anti-cancer activity was observed to be accompanied by the prompt onset of apoptosis in MCF-7 cells. The combinative treatment remarkably decreased the mitochondrial membrane potential and activated caspase cascades more than the mono-treatment. Pretreatment with DHA also did not influence the accumulation of DOX in MCF-7 cells. CONCLUSION: This study presented a new opportunity to enhance the effectiveness of future treatment regimens of breast cancer using DOX. PMID- 23744431 TI - In vivo and ex vivo responses of CLL cells to purine analogs combined with alkylating agent. AB - BACKGROUND: The heterogeneity of chronic lymphocytic leukemia (CLL) is thought to be due to differences in the expression of factors that regulate apoptosis and cell cycle, giving rise to diverse apoptotic disturbances and tumor properties. Therefore, the primary goal in CLL treatment is to overcome resistance to apoptosis and efficiently trigger this process in leukemic cells. METHODS: Mononuclear cells were obtained from the blood of CLL patients by Histopaque-1077 sedimentation. CLL cell samples from the blood of drug treated patients, (cladribine or fludarabine with cyclophosphamide; CC or FC), as well as the cell samples of untreated patients exposed to the used drug combinations (CM, FM) or mafosfamide alone for 48 h were fractionated into nuclear and cytoplasmic fractions or were lysed. DNA fragmentation was evaluated by agarose electrophoresis and also cytometrically as sub-G1 population. The expression of apoptosis related proteins and H1.2 histone translocation were evaluated in lysates and nuclear and cytoplasmic fractions, respectively with appropriate antibodies. RESULTS: Cladribine (C) and fludarabine (F) combined with cyclophosphamide/mafosfamide in vivo, as well as ex vivo trigger apoptosis in CLL cells. These drug combinations (CC; FC/CM; FM) induce leukemic cell apoptosis confirmed by DNA fragmentation, sub-G1 cell number, down-regulation of anti apoptotic proteins (Mcl-1, Bcl-2), and H1.2 histone translocation in comparison with appropriate control cells, however, to a different degree. CONCLUSIONS: The kinetics and rate of drug-induced apoptosis in leukemic cells under ex vivo experiments differ between patients, mirroring the differences noticed during in vivo treatment. Individual model cell samples indicate comparable susceptibility to the used drug combinations under in vivo and ex vivo conditions. PMID- 23744432 TI - Effects of vitamin D3 derivative--calcitriol on pharmacological reactivity of aortic rings in a rodent PCOS model. AB - BACKGROUND: The aim of this study was to examine the effects of the hyperandrogenic state in dihydrotestosterone (DHT)-induced polycystic ovary syndrome (PCOS), the vascular responses to different vasoactive agents, and the modulatory role of vitamin D3. METHODS: APCOS model was induced by DHT application in 20 female Wistar rats. Ten of the DHT treated rats simultaneously received calcitriol treatment. After 10 weeks, myographs were used to test the reactivity of isolated thoracic aortic rings to norepinephrine and acetylcholine. Thereafter, the vascular rings were incubated with the NO-synthase blocker (nitro L-arginine methyl ester) or the cyclooxygenase inhibitor (indomethacin) for 20 min, and the effects of norepinephrine and acetylcholine were re-evaluated. RESULTS: Norepinephrine-induced vasoconstriction was enhanced after DHT treatment, but this effect was attenuated by calcitriol administration. Vasorelaxation of DHT-treated thoracic aortic rings was impaired, but this could be partly reversed by calcitriol application. Impaired NO-dependent vasorelaxation in DHT-treated animals was mostly reversed by concomitant calcitriol administration, but this effect was diminished by prostanoid-dependent vasoconstriction. CONCLUSIONS: These studies show that the enhanced sensitivity to vasoconstrictors and impaired NO-dependent vasorelaxation in hyperandrogenic PCOS rats could be partially reversed by calcitriol treatment. PMID- 23744433 TI - Effects of single and repeated in vitro exposure of three forms of parabens, methyl-, butyl- and propylparabens on the proliferation and estradiol secretion in MCF-7 and MCF-10A cells. AB - BACKGROUND: Here, we analyzed the dose- (0.2, 2, 20, 200 nM or 2 MUM) and time- (48, 96, 144 and 196 h) dependent activity of a single or repeated exposure of methyl-, butyl- and propylparaben on the proliferation of MCF-7 human breast cancer cells and MCF-10A human breast epithelial cells. Additionally, the effect on estradiol secretion, gene and protein expression of aromatase (CYP19A1) was investigated. METHODS: Cell proliferation was determined by AlamarBlue assay, and estradiol secretion by ELISA kits. Gene and protein expression of CYP19A1 was measurement using real time PCR and western blot, respectively. RESULTS: Stimulatory effect of a single exposure of all doses of tested parabens and time dependent effect of repeated exposure to methylparaben, propylparaben and butylparaben, the same as that of 17beta-estradiol, on proliferation of MCF-7 cells was observed. Only at low doses methyl- and butylparabens increased MCF-10A cells proliferation after single exposure, but no effect of repeated exposure was noted. Exposure at low doses of all of the parabens significantly increased 17beta-estradiol (E2) secretion in MCF-7 cells but had the opposite effect on MCF 10A cells. It was correlated with gene and protein expression of CYP19A1 in MCF-7 and MCF-10 cells. CONCLUSIONS: In summary, present study indicates a different mechanism of proliferative action of parabens in investigated cell lines. In MCF 7 breast cancer cell line it is probably due to stimulatory action on estradiol secretion and aromatase activity. In MCF-10A by an unknown mechanism, independent on stimulatory action on estradiol section, which requires further investigation. PMID- 23744434 TI - Luminal melatonin stimulates pancreatic enzyme secretion via activation of serotonin-dependent nerves. AB - BACKGROUND: Serotonin (5-HT) is released from enterochromaffin cells in the gastrointestinal tract. 5-HT, via the activation of 5-HT2 and 5-HT3 receptors on vagal fibers, mediates pancreatic secretion through the mechanism independent from cholecystokinin. Melatonin (5-HT derivative) or L-tryptophan (melatonin or 5 HT precursor) given systemically or intraduodenally to the rats stimulate amylase secretion, but the mechanism is not clear. The aim of this study was to investigate the involvement of 5-HT in the pancreatostimulatory effect of melatonin or L-tryptophan, administered intraduodenally. METHODS: Wistar rats were surgically equipped with silicone catheters; inserted into pancreato-biliary duct and into the duodenum. Melatonin, L-tryptophan or 5-HT were given to the rats as a bolus. Combination of 5-HT2 or 5-HT3 receptor antagonists: ketanserin (100 MUg/kg) and MDL72222 (250 MUg/kg) was given intraperitoneally to the animals, 15 min. prior to the administration of the examined substances. The role of the vagal nerve, sensory fibers and CCK in the control of pancreatic exocrine function were determined. Blood samples were taken for the determination of 5-HT. RESULTS: Melatonin, 5-HT or L-tryptophan increased pancreatic amylase secretion. The stimulatory effect of the above substances was decreased by pretreatment of the rats with ketanserin and MDL72222. Bilateral vagotomy completely abolished the increase of amylase output caused by 5-HT, while capsaicin deactivation of sensory nerves or blockade of CCK1 receptor only partially reversed the stimulatory effect of 5-HT on the pancreas. Intraduodenal L-tryptophan, but not melatonin, increased plasma 5-HT concentrations in a dose- and time-dependent manner. CONCLUSION: Stimulation of pancreatic exocrine function caused by intraluminal administration of melatonin, or L-tryptophan is modified, at least in part, by serotoninergic mechanisms and vagal nerves. PMID- 23744435 TI - Benzylpenicillin inhibits the renal excretion of acyclovir by OAT1 and OAT3. AB - BACKGROUND: Acyclovir is acyclic guanosine derivative. Benzylpenicillin (PCG) is a beta-lactam antibiotic. The purpose of this study was to investigate the pharmacokinetic drug-drug interaction (DDI) between PCG and acyclovir. METHOD: When acyclovir and PCG were co-administered, plasma concentration of acyclovir, urinary excretion of acyclovir in vivo, uptake of acyclovir in kidney slices and uptake of acyclovir in human (h) OAT1/hOAT3- HEK293 cells were determined to examine the effect of PCG on urinary excretion of acyclovir. RESULTS: The plasma concentration of acyclovir was increased markedly and accumulative renal excretion and renal clearance of acyclovir were decreased significantly after intravenous administration of acyclovir in combination with PCG. PCG could decrease the uptake of acyclovir in kidney slices and in hOAT1-/hOAT3-human embryonic kidney (HEK293) cells. CONCLUSIONS: It indicates that acyclovir is a substrate for OAT1 and OAT3. PCG inhibits the renal excretion of acyclovir by inhibiting renal transporters OAT1 and OAT3 in vivo and in vitro. These results suggest important information for DDI between PCG and acyclovir in kidney. PMID- 23744436 TI - Orexins/hypocretins stimulate accumulation of inositol phosphate in primary cultures of rat cortical neurons. AB - BACKGROUND: Orexins A and B (also named hypocretins 1 and 2) are hypothalamic peptides with pleiotropic activity. They signal through two G protein-coupled receptors: OX1R and OX2R. We have previously demonstrated that both types of orexin receptors are expressed in cultured rat cortical neurons, and stimulation of the predominant OX2R inhibits cyclic AMP synthesis. In the present work, we examined effects of orexins on inositol phosphate (IP) accumulation in rat cortical neurons. METHODS: Experiments were performed on primary neuronal cell cultures prepared from Wistar rat embryos on day 17 of gestation. Following 1 h incubation with orexins, IP levels were measured using the ELISA IP-One assay kit. RESULTS: Orexins A and B increased, in a concentration-dependent manner, IP accumulation in primary neuronal cell cultures from rat cerebral cortex. Both peptides acted with a similar potency. The calculated EC50 values were 6.0 nM and 10.4 nM for orexin A and orexin B, respectively. CONCLUSION: The results indicate that in cultured rat cortical neurons orexin receptors are also coupled to inositol phosphates signaling pathway. PMID- 23744437 TI - How to combine non-compartmental analysis with the population pharmacokinetics? A study of tobacco smoke's influence on the bioavailability of racemic citalopram in rats. AB - BACKGROUND: Citalopram (CIT) is an antidepressant drug from the group of selective serotonin reuptake inhibitors in which it is the most potent selective inhibitor of serotonin uptake currently available. Patients treated with CIT are often heavy cigarette smokers. Individual pharmacokinetic parameters cannot be directly estimated if full pharmacokinetic profiles are not available for each subject. Sparse sampling is common to experiments using small animals, such as the case that our study is concerned with. METHODS: The aim of the study was to demonstrate how the two (non-compartmental analysis (NCA) and nonlinear mixed effect (NLME)) approaches, used simultaneously, can help overcome specific limitations of these separate methods whilst at the same time preserve their respective benefits. RESULTS: Despite the ultra-sparse design, the NLME approach enabled us to develop a pharmacostatistic model with the required covariate- exposition to the tobacco smoke. CONCLUSIONS: A tobacco smoke slows down the absorption of the CIT and at the same time makes it more effective. The consistency of results obtained both with NCA and NLME decreased the risk of model misspecification and increased confidence in the final conclusions. Combining NLME with NCA may therefore be recommended for investigating pharmacokinetic properties of the drug in the sparse designs. PMID- 23744438 TI - Down-regulation of thymic stromal lymphopoietin by curcumin. AB - BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a cytokine implicated in the pathogenesis of allergic diseases such as asthma, atopic dermatitis and allergic rhinitis. Curcumin has various effects such as antidepressant, antioxidant, antihyperglycemic, antitumor and anti-inflammatory. However, the effect of curcumin on the production of TSLP has not been clarified. Thus, we investigated how curcumin inhibits the expression and production of TSLP in the human mast cell line, HMC-1 cells. METHODS: We used enzyme-linked immunosorbent assay, reverse transcription-polymerase chain reaction, luciferase assay, and caspase-1 assay to investigate the effects of curcumin. RESULTS: The results show that curcumin inhibited the production and mRNA expression of TSLP in HMC-1 cells: the maximal inhibition rate of TSLP production by curcumin (50 MUM) was 59.16 +/- 4.20%. In addition, curcumin suppressed the nuclear factor-kappaB luciferase activity induced by phorbol myristate acetate plus A23187. In the activated HMC-1 cells, caspase-1 activity was increased, whereas caspase-1 activity was decreased by pretreatment with curcumin. CONCLUSION: These results suggest that curcumin can be used to treat inflammatory and atopic diseases through the suppression of TSLP. PMID- 23744439 TI - Accuracy of MDCT in the preoperative definition of Peritoneal Cancer Index (PCI) in patients with advanced ovarian cancer who underwent peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC). AB - PURPOSE: To evaluate the accuracy of MDCT in the preoperative definition of Peritoneal Cancer Index (PCI) in patients with advanced ovarian cancer who underwent a peritonectomy and hyperthermic intraperitoneal chemotherapy (HIPEC) after neoadjuvant chemotherapy to obtain a pre-surgery prognostic evaluation and a prediction of optimal cytoreduction surgery. MATERIALS AND METHODS: Pre-HIPEC CT examinations of 43 patients with advanced ovarian cancer after neoadjuvant chemotherapy were analyzed by two radiologists. The PCI was scored according to the Sugarbaker classification, based on lesion size and distribution. The results were compared with macroscopic and histologic data after peritonectomy and HIPEC. To evaluate the accuracy of MDCT to detect and localize peritoneal carcinomatosis, both patient-level and regional-level analyses were conducted. A correlation between PCI CT and histologic values for each patient was searched according to the PCI grading. RESULTS: Considering the patient-level analysis, CT shows a sensitivity, specificity, PPV, NPV, and an accuracy in detecting the peritoneal carcinomatosis of 100 %, 40 %, 93 % 100 %, and 93 %, respectively. Considering the regional level analysis, a sensitivity, specificity, PPV, NPV, and diagnostic accuracy of 72 %, 80 %, 66 %, 84 %, and 77 %, respectively were obtained for the correlation between CT and histology. CONCLUSION: Our results encourage the use of MDCT as the only technique sufficient to select patients with peritoneal carcinomatosis for cytoreductive surgery and HIPEC on the condition that a CT examination will be performed using a dedicated protocol optimized to detect minimal peritoneal disease and CT images will be analyzed by an experienced reader. PMID- 23744440 TI - Hepatic pseudolymphoma: imaging-pathologic correlation with special reference to hemodynamic analysis. AB - OBJECTIVES: To clarify radiological findings and hemodynamic characteristics of hepatic pseudolymphoma, as compared with the histopathological findings. METHODS: Radiological findings of ten histopathologically confirmed hepatic pseudolymphomas in seven patients were examined using US, CT, and MRI. Six patients also underwent angiography-assisted CT, including CT during arterial portography (CTAP) and CT during hepatic arteriography (CTHA) to analyze hemodynamics. RESULTS: The nodules were depicted as hypoechoic on US, hypodense on precontrast CT, hypointense on T1-weighted images, and hyperintense on T2 weighted images. On contrast-enhanced CT/MRI, they showed various degrees of enhancement, and sometimes, perinodular enhancement was observed at the arterial dominant and/or equilibrium phase. On CTAP, the nodules showed portal perfusion defects, including some in the perinodular liver parenchyma. On CTHA, irregular bordered enhancement was observed in perinodular liver parenchyma on early phase, and continued until delayed phase. Some nodules had preserved intra-tumoral portal tracts. Histopathologically, the nodules consisted of marked lymphoid cells. In perinodular liver parenchyma, stenosis or disappearance of portal venules, caused by lymphoid cell infiltration in the portal tracts, was observed. CONCLUSIONS: Hepatic pseudolymphoma showed some characteristic radiological findings including hemodynamics on CT, MRI, and angiography-assisted CT. These findings are useful in the differentiation from hepatocellular carcinoma and other tumors. PMID- 23744441 TI - A two-stage epidemiologic study on prevalence of eating disorders in female university students in Wuhan, China. AB - BACKGROUND: The community prevalence of eating disorders among Chinese young women may now be similar to their western counterparts. AIM: To investigate the prevalence of eating disorders (ED) in female university students in Wuhan, China, using a two-stage design. METHOD: In stage one, 99.1% (N = 8,444) of eligible students (N = 8,521) completed the eating disorder inventory-1 (EDI-1) and a survey of relevant anthropomorphic data. A total of 421 women scored above the cut-off for EDE-1, as defined by a set of criteria similar to those of Keski Rahkonen (Int J Eat Disord 39:754-762, 2006). 257 (61%) of these case-positive women and a random sample of case-negative women (312 out of 8,023, 4%) whose scores did not exceed the defined cut-off were interviewed using the eating disorder examination (EDE) and the structured clinical interview for DSM-IV axis I disorders (SCID-I). RESULTS: On interview with the SCID-I, 79 women were diagnosed with an ED. Among them, 10 had anorexia nervosa (AN), 21 bulimia nervosa (BN), and 48 binge eating disorder (BED) The results showed a prevalence rate of 1.05% (95% CI = 0.02-2.08) for AN, 2.98% (95% CI = 1.21-4.74) for BN, and 3.53% (95% CI = 1.75-5.30) for BED. CONCLUSION: The prevalence of ED among female university students in China is now similar to that of their western counterparts, and BED is the most common ED followed by BN and AN similarly. PMID- 23744442 TI - Psychotic experiences and social functioning: a longitudinal study. AB - PURPOSE: Both adolescent psychotic experiences and poor social functioning precede psychotic disorder; however, whether poor social functioning is also a risk factor for rather than a consequence of adolescent psychotic experiences is not clear. We investigate this question as well as whether deterioration in social functioning confers the strongest risk of psychotic experiences and whether theory of mind ability mediates any association, in a large community sample. METHODS: Measures of social functioning (peer problems and prosocial behaviour) at ages 7 and 11 and theory of mind ability and psychotic experiences at age 12 were collected in a large community sample (n = 3,592). The association between social functioning and psychotic experiences was examined using logistic regression models at each age and any additional impact of deterioration in social functioning between ages 7 and 11. The potential role of theory of mind as a mediator was also investigated. RESULTS: Peer problems at both ages were independently associated with psychotic experiences at age 12 (7 years OR 1.11 95 % CI 1.03, 1.20), (11 years OR 1.13 95 % CI 1.05, 1.22). Theory of mind ability did not mediate this association. The association was not restricted to those with deteriorating social functioning (interaction term; p = 0.49). CONCLUSIONS: Poor childhood social functioning precedes adolescent psychotic experiences. There was no evidence that those with deteriorating social functioning were at greatest risk. PMID- 23744443 TI - The risk of adolescent suicide across patterns of drug use: a nationally representative study of high school students in the United States from 1999 to 2009. AB - OBJECTIVE: Substance use is associated with suicidal ideation, planning and attempts among adolescents, but it is unclear how this association varies across different types and number of substances. This study examined the association between patterns of substance use and suicidality among a nationally representative sample of high school students in the United States during the last decade. METHOD: Data from the 2001 to 2009 Youth Risk Behavior Survey including 73,183 high school students were analyzed. Logistic regression analyses examined the association between lifetime use of ten common substances of abuse (alcohol, cocaine, ecstasy, hallucinogens, heroin, inhalants, marijuana, methamphetamines, steroids, and tobacco) and four measures of suicidality over the last year (suicidal ideation, suicide plan, suicide attempt, and severe suicide attempt requiring medical attention), controlling for potential confounders (socio-demographic variables, interpersonal violence, sexual intercourse, and symptoms of depression and eating disorder). RESULTS: Among the ten substances, univariate analysis demonstrates that adolescents reporting a history of heroin use have the strongest association with suicidal ideation, suicide plan, suicide attempts and severe suicide attempts in the last year (odds ratio = 5.0, 5.9, 12.0, and 23.6 compared to non-users), followed by users of methamphetamines (OR = 4.3-13.1) and steroids (OR = 3.7-11.8). Cocaine, ecstasy, hallucinogens and inhalants had a moderate association with suicidality (OR = 3.1 10.8). Users of marijuana, alcohol and tobacco also had an increased odds ratio of suicidality (OR = 1.9-5.2). The association between each of ten substances and the four measures of suicidality remained significant with multivariate analysis controlling for multiple confounders (p < 0.05), except for the association between alcohol use and severe suicide attempts. The seven illicit substances had a stronger association with severe suicide attempts as compared to all other confounding risk factors except depression. The number of substances used had a graded relationship to suicidality. CONCLUSIONS: Substance abuse is a strong risk factor for suicidal thoughts and behaviors among American high school students, with the strength of this relationship dramatically increasing with particular illicit drugs and a higher number of substances. The findings reinforce the importance of routine screening for substance abuse in the assessment of adolescent suicide risk. PMID- 23744444 TI - Parental socio-economic position during childhood as a determinant of self-harm in adolescence. AB - PURPOSE: Socio-economic position (SEP) during childhood and parental social mobility have been associated with subsequent health outcomes in adolescence and adulthood. This study investigates whether parental SEP during childhood is associated with subsequent self-harm in adolescence. METHODS: This study uses data from a prospective birth-cohort study (the Avon Longitudinal Study of Parents and Children) which followed 14,610 births in 1991-1992 to age 16-18 years (n = 4,810). The association of parental SEP recorded pre-birth and throughout childhood with self-harm was investigated using logistic regression models, with analyses conducted separately for those reporting self-harm (a) with and (b) without suicidal intent. The impact of missing data was investigated using multiple imputation methods. RESULTS: Lower parental SEP was associated with increased risk of offspring self-harm with suicidal intent, with less consistent associations evident for self-harm without suicidal intent. Associations were somewhat stronger in relation to measures of SEP in later childhood. Depressive symptoms appeared to partially mediate the associations. Adolescents of parents reporting consistently low income levels during childhood were approximately 1.5 times more likely to engage in SH than those never to report low income. CONCLUSIONS: Lower SEP during childhood is associated with the subsequent risk of self-harm with suicidal intent in adolescence. This association is stronger in those experiencing consistently lower SEP. PMID- 23744446 TI - Automatic segmentation of brain MR images using an adaptive balloon snake model with fuzzy classification. AB - Skull-stripping in magnetic resonance (MR) images is one of the most important preprocessing steps in medical image analysis. We propose a hybrid skull stripping algorithm based on an adaptive balloon snake (ABS) model. The proposed framework consists of two phases: first, the fuzzy possibilistic c-means (FPCM) is used for pixel clustering, which provides a labeled image associated with a clean and clear brain boundary. At the second stage, a contour is initialized outside the brain surface based on the FPCM result and evolves under the guidance of an adaptive balloon snake model. The model is designed to drive the contour in the inward normal direction to capture the brain boundary. The entire volume is segmented from the center slice toward both ends slice by slice. Our ABS algorithm was applied to numerous brain MR image data sets and compared with several state-of-the-art methods. Four similarity metrics were used to evaluate the performance of the proposed technique. Experimental results indicated that our method produced accurate segmentation results with higher conformity scores. The effectiveness of the ABS algorithm makes it a promising and potential tool in a wide variety of skull-stripping applications and studies. PMID- 23744445 TI - Active inference, sensory attenuation and illusions. AB - Active inference provides a simple and neurobiologically plausible account of how action and perception are coupled in producing (Bayes) optimal behaviour. This can be seen most easily as minimising prediction error: we can either change our predictions to explain sensory input through perception. Alternatively, we can actively change sensory input to fulfil our predictions. In active inference, this action is mediated by classical reflex arcs that minimise proprioceptive prediction error created by descending proprioceptive predictions. However, this creates a conflict between action and perception; in that, self-generated movements require predictions to override the sensory evidence that one is not actually moving. However, ignoring sensory evidence means that externally generated sensations will not be perceived. Conversely, attending to (proprioceptive and somatosensory) sensations enables the detection of externally generated events but precludes generation of actions. This conflict can be resolved by attenuating the precision of sensory evidence during movement or, equivalently, attending away from the consequences of self-made acts. We propose that this Bayes optimal withdrawal of precise sensory evidence during movement is the cause of psychophysical sensory attenuation. Furthermore, it explains the force-matching illusion and reproduces empirical results almost exactly. Finally, if attenuation is removed, the force-matching illusion disappears and false (delusional) inferences about agency emerge. This is important, given the negative correlation between sensory attenuation and delusional beliefs in normal subjects--and the reduction in the magnitude of the illusion in schizophrenia. Active inference therefore links the neuromodulatory optimisation of precision to sensory attenuation and illusory phenomena during the attribution of agency in normal subjects. It also provides a functional account of deficits in syndromes characterised by false inference and impaired movement--like schizophrenia and Parkinsonism--syndromes that implicate abnormal modulatory neurotransmission. PMID- 23744447 TI - Contribution of N-methyl-DL-aspartic acid (NMDA)-sensitive neurons to generating oscillatory potentials in Royal College of Surgeons rats. AB - PURPOSE: We investigated how the N-methyl-DL-aspartic acid (NMDA) receptor contributes to generating oscillatory potentials (OPs) of the electroretinogram (ERG) in the Royal College of Surgeons (RCS) rat. METHODS: Scotopic ERGs were recorded from dystrophic and wild-type congenic (WT) RCS rats (n = 20 of each) at 25, 30, 35, and 40 days of age. The stimulus intensity was increased from -2.82 to 0.71 log cd-s/m(2) to obtain intensity-response function. NMDA was injected into the vitreous cavity of the right eyes. The left eyes were injected with saline as controls. The P3 obtained by a-wave fitting was digitally subtracted from the scotopic ERG to isolate the P2. For the OPs, the P2 was digitally filtered between 65 and 500 Hz. The amplitudes of OP1, OP2, OP3, and OP4 were then measured and summed and designated as SigmaOPs. The implicit times of OP1, OP2, and OP3 were also measured. The frequency spectra of the OPs were analyzed using fast Fourier transform (FFT). RESULTS: The maximum ERG a- and b-waves as well as SigmaOPs amplitudes reduced with age in dystrophic rats. Compared with intravitreal saline injection, administration of NMDA decreased SigmaOPs amplitudes from 30 days of age in dystrophic rats, while it did not attenuate SigmaOPs amplitudes in WT rats. The implicit times of the OPs of the maximum ERG were prolonged by NMDA injections in WT and dystrophic rats. NMDA/saline ratios of SigmaOPs amplitudes area under the FFT curves were significantly lower in dystrophic rats from 30 days of age than that in WT rats. CONCLUSION: In the early stage of photoreceptor degeneration, intravitreal NMDA injection attenuated OPs amplitudes in dystrophic rats. This indicates that NMDA receptors play a significant role in generating OPs amplitudes with advancing photoreceptor degeneration. PMID- 23744449 TI - Iron therapy for improving psychomotor development and cognitive function in children under the age of three with iron deficiency anaemia. AB - BACKGROUND: Iron deficiency and iron deficiency anaemia (IDA) are common in young children. It has been suggested that the lack of iron may have deleterious effects on children's psychomotor development and cognitive function. To evaluate the benefits of iron therapy on psychomotor development and cognitive function in children with IDA, a Cochrane review was carried out in 2001. This is an update of that review. OBJECTIVES: To determine the effects of iron therapy on psychomotor development and cognitive function in iron deficient anaemic children less than three years of age. SEARCH METHODS: We searched the following databases in April 2013: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, LILACS, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (ICTRP). We also searched the reference lists of review articles and reports, and ran citation searches in the Science Citation Index for relevant studies identified by the primary search. We also contacted key authors. SELECTION CRITERIA: Studies were included if children less than three years of age with evidence of IDA were randomly allocated to iron or iron plus vitamin C versus a placebo or vitamin C alone, and assessment of developmental status or cognitive function was carried out using standardised tests by observers blind to treatment allocation. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts retrieved from the searches and assessed full-text copies of all potentially relevant studies against the inclusion criteria. The same review authors independently extracted data and assessed the risk of bias of the eligible studies. Data were analysed separately depending on whether assessments were performed within one month of beginning iron therapy or after one month. MAIN RESULTS: We identified one eligible study in the update search that had not been included in the original review. In total, we included eight trials.Six trials, including 225 children with IDA, examined the effects of iron therapy on measures of psychomotor development and cognitive function within 30 days of commencement of therapy. We could pool data from five trials. The pooled difference in pre- to post-treatment change in Bayley Scale Psychomotor Development Index (PDI) between iron and placebo groups was -1.25 (95% confidence interval (CI) -4.56 to 2.06, P value = 0.65; I(2) = 33% for heterogeneity, random effects meta-analysis; low quality evidence) and in Bayley Scale Mental Development Index (MDI) was 1.04 (95% CI -1.30 to 3.39, P value = 0.79; I(2) = 31% for heterogeneity, random-effects meta-analysis; low quality evidence).Two studies, including 160 randomised children with IDA, examined the effects of iron therapy on measures of psychomotor development and cognitive function more than 30 days after commencement of therapy. One of the studies reported the mean number of skills gained after two months of iron therapy using the Denver Developmental Screening Test. The intervention group gained 0.8 (95% CI -0.18 to 1.78, P value = 0.11, moderate quality of evidence) more skills on average than the control group. The other study reported that the difference in pre- to post treatment change in Bayley Scale PDI between iron-treated and placebo groups after four months was 18.40 (95% CI 10.16 to 26.64, P value < 0.0001; moderate quality evidence) and in Bayley Scale MDI was 18.80 (95% CI 10.17 to 27.43, P value < 0.0001; moderate quality evidence). AUTHORS' CONCLUSIONS: There is no convincing evidence that iron treatment of young children with IDA has an effect on psychomotor development or cognitive function within 30 days after commencement of therapy. The effect of longer-term treatment remains unclear. There is an urgent need for further large randomised controlled trials with long term follow-up. PMID- 23744448 TI - Delayed luminance and chromatic contrast sensitivity in infants with spontaneously regressed retinopathy of prematurity. AB - BACKGROUND: The current study assessed whether contrast sensitivity is affected in preterm infants with a history of spontaneously regressed retinopathy of prematurity (ROP, Stages 1-3). Specifically, we employed luminance (light/dark) and chromatic (red/green) stimuli, which are mediated by the magnocellular (M) and parvocellular (P) subcortical pathways, respectively. METHODS: Contrast sensitivity (CS) was measured using forced-choice preferential looking testing in 21 infants with a history of ROP and 41 control preterm infants who were born prematurely but did not develop ROP, tested between 8 and 47 weeks (2-11 months) postterm age. Infants were presented with chromatic and luminance drifting sinusoidal gratings, which appeared randomly on the left or right side of the monitor in each trial. The contrast of the stimuli varied across trials and was defined in terms of root mean squared cone contrast for long- and medium wavelength cones. RESULTS: Between 8 and 25 weeks postterm, ROP infants had significantly worse CS, and there was a trend for greater impairment for luminance than chromatic CS. This delay was not seen at older ages between 26 and 47 weeks postterm. CONCLUSIONS: These findings are consistent with the concept that early maturation of the M pathway is vulnerable to biological insult, as in the case of ROP, to a greater extent than in the P pathway. PMID- 23744450 TI - Ready-to-use therapeutic food for home-based treatment of severe acute malnutrition in children from six months to five years of age. AB - BACKGROUND: Malnourished children have a higher risk of death and illness. Treating severe acute malnourished children in hospitals is not always desirable or practical in rural settings, and home treatment may be better. Home treatment can be food prepared by the carer, such as flour porridge, or commercially manufactured food such as ready-to-use therapeutic food (RUTF). RUTF is made according to a standard, energy-rich composition defined by the World Health Organization (WHO). The benefits of RUTF include a low moisture content, long shelf life without needing refrigeration and that it requires no preparation. OBJECTIVES: To assess the effects of home-based RUTF on recovery, relapse and mortality in children with severe acute malnutrition. SEARCH METHODS: We searched the following electronic databases up to April 2013: Cochrane Central Register of Clinical Trials (CENTRAL), MEDLINE, MEDLINE In-process, EMBASE, CINAHL, Science Citation Index, African Index Medicus, LILACS, ZETOC and three trials registers. We also contacted researchers and clinicians in the field and handsearched bibliographies of included studies and relevant reviews. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials where children between six months and five years of age with severe acute malnutrition were treated at home with RUTF compared to a standard diet, or different regimens and formulations of RUTFs compared to each other. We assessed recovery, relapse and mortality as primary outcomes, and anthropometrical changes, time to recovery and adverse outcomes as secondary outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial eligibility using prespecified criteria, and three review authors independently extracted data and assessed trial risk of bias. MAIN RESULTS: We included four trials (three having a high risk of bias), all conducted in Malawi with the same contact author. One small trial included children infected with human immunodeficiency virus (HIV). We found the risk of bias to be high for the three quasi-randomised trials while the fourth trial had a low to moderate risk of bias. Because of the sparse data for HIV, we reported below the main results for all children together. RUTF meeting total daily requirements versus standard dietWhen comparing RUTF with standard diet (flour porridge), we found three quasi-randomised cluster trials (n = 599). RUTF may improve recovery slightly (risk ratio (RR) 1.32; 95% confidence interval (CI) 1.16 to 1.50; low quality evidence), but we do not know whether RUTF improves relapse, mortality or weight gain (very low quality evidence). RUTF supplement versus RUTF meeting total daily requirementsWhen comparing RUTF supplement with RUTF that meets total daily nutritional requirements, we found two quasi randomised cluster trials (n = 210). For recovery, relapse, mortality and weight gain the quality of evidence was very low; therefore, the effects of RUTF are unknown. RUTF containing less milk powder versus standard RUTFWhen comparing a cheaper RUTF containing less milk powder (10%) versus standard RUTF (25% milk powder), we found one trial that randomised 1874 children. For recovery, there was probably little or no difference between the groups (RR 0.97; 95% CI 0.93 to 1.01; moderate quality evidence). RUTF containing less milk powder may lead to slightly more children relapsing (RR 1.33; 95% CI 1.03 to 1.72; low quality evidence) and to less weight gain (mean difference (MD) -0.5 g/kg/day; 95% CI 0.75 to -0.25; low-quality evidence) than standard RUTF. We do not know whether the cheaper RUTF improved mortality (very low quality evidence). AUTHORS' CONCLUSIONS: Given the limited evidence base currently available, it is not possible to reach definitive conclusions regarding differences in clinical outcomes in children with severe acute malnutrition who were given home-based ready-to-use therapeutic food (RUTF) compared to the standard diet, or who were treated with RUTF in different daily amounts or formulations. For this reason, either RUTF or flour porridge can be used to treat children at home depending on availability, affordability and practicality. Well-designed, adequately powered pragmatic randomised controlled trials of HIV-uninfected and HIV-infected children with severe acute malnutrition are needed. PMID- 23744451 TI - Suggested excisional margins for cutaneous malignant lesions based on Mohs micrographic surgery. AB - IMPORTANCE: Surgical excision of skin cancer is a common treatment, yet the proper surgical margin remains unclear. This study reviews data on lesions and their margins as defined by Mohs micrographic surgery. OBJECTIVE: To review margins as defined by Mohs micrographic surgery. DESIGN: Retrospective review of data from patients with skin cancer. SETTING: Academic medical center. PARTICIPANTS: All patients with nonmelanoma skin cancer. MAIN OUTCOME AND MEASURE: Size and final defect size were compared to calculate the margins needed. All lesions were categorized based on histologic characteristics. RESULTS: A total of 495 lesions were reviewed. All tumors and defects had precise measurements. The mean margins for low-risk basal cell carcinomas, high-risk basal cell carcinomas, low-risk squamous cell carcinomas, and high-risk squamous cell carcinomas were 2.4 mm, 3.7 mm, 2.6 mm, and 5.3 mm, respectively. Statistical differences in surgical margins were found between all low- and high risk cancer types. Established high-risk zones (H-zone) for basal cell carcinoma and squamous cell carcinoma were not associated with larger margins. Margins required to excise completely 95% of all the low-risk basal cell carcinomas, high risk basal cell carcinomas, low-risk squamous cell carcinomas, and high-risk squamous cell carcinomas, were 4.75 mm, 8 mm, 5 mm, and 13.25 mm, respectively. CONCLUSIONS AND RELEVANCE: Differences are noted between low- and high-risk cutaneous lesions. When primary excision instead of Mohs micrographic surgery is the only option, the aforementioned margins may be considered guidelines. The relevance of this study is to guide future management and margins for primary excision. LEVEL OF EVIDENCE: 3. PMID- 23744452 TI - A longitudinal study of somatic complaints in urban adolescents: the role of internalizing psychopathology and somatic anxiety. AB - Despite the frequent association between anxiety and somatization, the role of somatic anxiety--a tendency to experience somatic sensations, when anxious--in relationship to persistent somatic complaints has not been addressed previously. This study assessed the predictive role of internalizing psychopathology (anxiety, posttraumatic stress, depression) and somatic anxiety for somatic complaints over a 1-year period in a community sample of urban youth. The Social and Health Assessment, a self-report survey, was administered to 2,524 (mean age = 12.8, 54 % female) American urban adolescents in two consecutive years. There was significant continuity of somatic complaints over 1 year. Girls reported higher levels of somatic complaints and somatic anxiety than boys. All types of internalizing psychopathology significantly predicted somatic complaints over time. Somatic anxiety was associated with somatic complaints over and above the role of internalizing symptoms. Internalizing psychopathology and somatic anxiety should both be considered in the assessment and treatment of youth with persistent somatic complaints. PMID- 23744453 TI - Social exclusion: the interplay of group goals and individual characteristics. AB - Past research has shown that adolescents justify social exclusion based on concerns for group functioning, and yet, to date, no study has evaluated whether group functioning justifications shift or remain stable across different exclusion contexts. In this study, we systematically manipulated exclusion context (i.e., competitive or noncompetitive soccer groups) and individual characteristics of the target of exclusion to test the nature of the interaction between these factors during exclusion judgments. Adolescents' (N = 201; 61% Female) exclusion judgments differed across contexts only when an individual's ability was under consideration. Intergroup (i.e., gender, nationality) and interpersonal (i.e., aggression, shyness) characteristics overwhelmed contextual considerations. Results indicate the complexity of factors weighed by adolescents when making exclusion judgments, and suggest the need for extension of the present findings to understand more fully the interaction between the context of exclusion and individual characteristics in exclusion judgments. PMID- 23744454 TI - Off-therapy durability of response to entecavir therapy in hepatitis B e antigen negative chronic hepatitis B patients. AB - The optimal duration of nucelos(t)ide analog (Nuc) treatment in hepatitis B e antigen (HBeAg)-negative patients with chronic hepatitis B virus (HBV) infection is unknown. The Asian Pacific Association for the Study of the Liver (APASL) guidelines recommend that treatment can be discontinued if undetectable HBV-DNA has been documented on three occasions >= 6 months apart. This study aimed to test this stopping rule in HBeAg-negative chronic hepatitis B (CHB) patients treated with entecavir (ETV). Ninety-five patients (39 cirrhosis) were treated with ETV for a median of 721 (395-1,762) days before stopping therapy and were then monitored with serum HBV DNA and alanine aminotransferase (ALT) at least every 3 months. Within 1 year after stopping ETV therapy, "clinical relapse" (an episode of ALT elevation >2 * upper limit of normal plus HBV-DNA >2,000 IU/mL) occurred in 43 (45.3%) of the 95 patients. Of the 39 cirrhosis patients, 17 (43.6%) relapsed and one (2.6%) developed decompensation. The median duration until relapse was 230 days (74.4% >6 months). Logistic regression analysis showed that baseline HBV-DNA <= 2 * 10(5) IU/mL was the only significant independent factor for sustained response. The 1-year relapse rate was 29% in patients with a baseline HBV DNA <= 2 * 10(5) IU/mL versus 53% in those with HBV DNA >2 * 10(5) IU/mL (P = 0.027). For the latter, consolidation therapy >64 weeks reduced the relapse rate to 33.3% in patients without cirrhosis. CONCLUSION: With an overall 1-year relapse rate of 45% and 29% in those with a baseline serum HBV DNA <= 2 * 10(5) IU/mL, the APASL stopping rule for HBeAg-negative CHB patients with proper off-therapy monitoring is adequate even in patients with cirrhosis. Consolidation therapy >64 weeks seems more appropriate for those with higher baseline HBV DNA. PMID- 23744455 TI - More to rasburicase than uric Acid. PMID- 23744456 TI - Unusual parotid gland lesions: a pictorial review. AB - This is a pictorial essay of unusual parotid gland lesions that may be encountered in routine clinical practice. PMID- 23744457 TI - Preliminary assessment of balance with the Berg Balance Scale in adults who have a leg amputation and dwell in the community: Rasch rating scale analysis. AB - BACKGROUND: Self-report measures of balance and multidimensional mobility assessments are common for people with a leg amputation, yet clinical assessment of balance ability remains less explored. The Berg Balance Scale (BBS), typically used for other populations with impaired balance, has been used for young people with a high level of functioning after traumatic amputation but rarely for older people after vascular amputation. OBJECTIVE: The study objective was to examine the psychometric properties of the BBS with Rasch rating scale analysis to determine the validity and utility of the BBS in assessing balance ability in adults who have a leg amputation and dwell in the community. DESIGN: Rating scale analysis was applied to BBS scores obtained from a single assessment. METHODS: Adult volunteers (men and women) who had a leg amputation (any level and etiology) and dwelled in the community were recruited from a hospital-based community support group and a prosthetic clinic. Rating scale analysis of the BBS was used to assess unidimensionality, internal validity, goodness of fit, structural integrity, and person and item analyses. RESULTS: The study participants were 40 people (26 men and 14 women; 57.8 [SD=9.7] years old) with leg amputations (24 transtibial, 13 transfemoral, and 3 bilateral) of mixed etiology (32 vascular and 8 nonvascular). The psychometric properties of the BBS confirmed that it measures the unidimensional construct of balance ability with adequate validity and with goodness of fit and structural integrity that meet the acceptability criteria. Person measures revealed that some participants scored near the top of the BBS, suggesting a ceiling effect; item measures revealed that participants with leg amputations had the most difficulty performing the following tasks: standing with 1 leg in front, turning 360 degrees, and placing alternate foot on a stool. LIMITATIONS: Limitations included a convenience sample and a lack of rater reliability testing. CONCLUSIONS: The BBS cohered with the unidimensional construct of balance ability and had strong internal validity for use in a variety of people with leg amputations. PMID- 23744458 TI - Survey of the reporting characteristics of systematic reviews in rehabilitation. AB - BACKGROUND: Systematic reviews (SRs) have become increasingly important for informing clinical practice; however, little is known about the reporting characteristics and the quality of the SRs relevant to the practice of rehabilitation health professionals. OBJECTIVE: The purpose of this study was to examine the reporting quality of a representative sample of published SRs on rehabilitation, focusing on the descriptive, reporting, and bias-related characteristics. METHODS: A cross-sectional study was conducted by searching MEDLINE for aggregative and configurative SRs indexed in 2011 that focused on rehabilitation as restorative of functional limitations. Two reviewers independently screened and selected the SRs and extracted data using a 38-item data collection form derived from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The data were analyzed descriptively. RESULTS: Eighty-eight SRs published in 59 journals were sampled. The median compliance with the PRISMA items was 17 (63%) out of 27 items (interquartile ratio=13-22 [48%-82%]). Two thirds of the SRs (n=66) focused on interventions for which efficacy is best addressed through a randomized controlled trial (RCT) design, and almost all of these SRs included RCTs (63/66 [95%]). More than two thirds of the SRs assessed the quality of primary studies (74/88 [84%]). Twenty eight reviews (28/88 [32%]) meta-analyzed the results for at least one outcome. One half of the SRs reported positive statistically significant findings (46%), whereas a detrimental result was present only in one review. CONCLUSIONS: This sample of SRs in the rehabilitation field showed heterogeneous characteristics and a moderate quality of reporting. Poor control of potential source of bias might be improved if more widely agreed-upon evidence-based reporting guidelines will be actively endorsed and adhered to by authors and journals. PMID- 23744459 TI - Autism spectrum disorders are associated with fetal growth extremely below or above average for gestational age. PMID- 23744461 TI - From the editor. PMID- 23744460 TI - Effects of CXCR4 gene silencing by lentivirus shRNA on proliferation of the EC9706 human esophageal carcinoma cell line. AB - CXCL12/CXCR4 has been studied as an important biomarker for many human malignancies, but studies are limited for esophageal squamous cell carcinoma (ESCC). In this study, an effective RNAi sequence targeting the CXCR4 gene was selected, a lentiviral shRNA vector was constructed to specifically silence CXCR4 expression in the EC9706 ESCC cell line, and the effects of CXCR4 silencing on cell growth in vitro and tumour growth in nude mice were then evaluated. The expression of CXCR4 in EC9706 was significantly downregulated after transfection with a lentiviral shRNA vector. The expression of the apoptosis-related gene Bcl 2 was decreased. In addition, after CXCR4 inhibition, cell growth was considerably inhibited, increased apoptosis in the EC9706 cells was found, the G0/G1 percentage was significantly increased, and the number of cells in S phase was reduced. Moreover, tumour growth in nude mice was inhibited. In conclusion, the downregulation of CXCR4 expression by transfection with a lentiviral shRNA vector in ESCC cells could inhibit tumour proliferation. Our data may provide an avenue for finding new ESCC treatments. PMID- 23744462 TI - We have enough guidance and information to shape the future of our nation's health care. PMID- 23744463 TI - Into the next ERA: an interview with Susan Lacey, PhD, RN, FAAN, and Karen Cox, PhD, RN, FAAN. Interview by Kathleen D. Sanford. PMID- 23744464 TI - Practice-academia collaboration in nursing: contexts and future directions. AB - At a time of profound challenges in health care delivery and professional education characterized by imperatives to improve quality, responsiveness to client needs and efficient use of existing resources, the relationship between nursing education and service is in deep need of reinforcement and rethinking. Important directions for the future include attending to the complementary roles of academia and service in ensuring patient- and family-centered care, building reciprocity in the relationship between clinical agencies and universities, clarifying the intersecting roles of clinical agencies in the generation of various types of research and scholarship, engaging nurses and trainees at all roles within the profession in local- and higher-level health policy, and reinventing joint roles between service and academia. PMID- 23744465 TI - Building a culture of innovation by maximizing the role of the RN. AB - By the year 2020, as hospitals morph into entirely different kinds of service providers, nurses too will look altogether different. Those with the capacity to embrace disruptive innovation, along with all the unknowns that accompany it, will be successful at guiding their organizations into the future. Nurse executives must act now to build nursing cultures capable of massive and transformational change--change that will alter the way patient care is perceived, delivered, and evaluated. One hospital system is using a Think Tank approach to pilot demonstration projects that aim to maximize the role of the registered nurse and redefine expectations around patient care delivery. Early work indicates that new thinking combined with "permission to fail" from nursing leadership is essential to success. Lean Six Sigma principles and creativity tools from inside and outside of health care are being adopted with promising results. Exemplars show that by creating a sense of urgency around a big opportunity, this health care system is developing change initiatives that are literally transforming culture. PMID- 23744466 TI - Engaging patients and families in system-level improvement: a safety imperative. AB - Health care organizations have focused considerable effort and resources on improving patient safety and health care quality. Yet, despite these efforts, patients continue to experience harm events within our institutions. Family engagement is a powerful and often untapped resource to improve the quality and safety of organizations. While the value patients and families bring as partners in improving the safety and quality of health care is implicitly recognized, the adoption of structures to actively involve health care consumers has been slow, particularly in organizational or overall system work. Patients and families can stimulate and drive improved health care services through their involvement at the clinical/point of care, policy/design, and governance levels of the organization. For successful implementation, organization leaders must establish family engagement as a system-level priority. Roles to support the development of a family engagement program, methods to evaluate the level of family engagement, and strategies to enhance and sustain family engagement are described. Although there is limited evidence-based knowledge related to the best practices for family engagement, opportunities exist to drive the family engagement agenda at a regional and national level through participation in networks such as the Centers for Medicare & Medicaid Services Partnership for Patients campaign Hospital Engagement Networks. PMID- 23744467 TI - The Affordable Care Act, science, and childhood adversity: a call for pediatric nurses and physicians to lead. AB - The Patient Protection and Affordable Care Act aims to increase access to many who were previously uninsured, to increase the quality of health care, and to decrease costs. Accountable Care Organizations are a manifestation of these new health care reforms. A proactive approach focused on primary prevention to address modifiable determinants of health holds the promise of a healthier population while being cost-effective. Exposure to toxic stress in childhood places many children on a trajectory for poor immediate and long-term health outcomes. A lifecourse approach to disease prevention offers opportunities at every age and stage to build resilience, which buffers and protects children from the effects of adversity and toxic stress. The American Academy of Pediatrics, recognizing that many adult diseases are rooted in experiences in early childhood, has proposed an ecobiodevelopmental framework that expands the role of pediatricians and embraces a preventive lifecourse approach to health and well being. Exposure to adversity and toxic stress in childhood is a serious public health problem. A new kind of leadership is required to address these issues. Pediatric nurses and physicians are trusted healers and in a position to seek solutions skillfully and intentionally. PMID- 23744468 TI - Implementing an organization-wide quality improvement initiative: insights from project leads, managers, and frontline nurses. AB - With the movement to advance quality care and improve health care outcomes, organizations have increasingly implemented quality improvement (QI) initiatives to meet these requirements. Key to implementation success is the multilevel involvement of frontline clinicians and leadership. To explore the perceptions and experiences of frontline nurses, project leads, and managers associated with an organization-wide initiative aimed at engaging nurses in quality improvement work. To address the aims of this study, a qualitative research approach was used. Two focus groups were conducted with a total of 13 nurse participants, and individual interviews were done with 10 managers and 6 project leads. Emergent themes from the interview data included the following: improving care in a networked approach; driving QI and having a sense of pride; and overcoming challenges. Specifically, our findings elucidate the value of communities of practice and ongoing mentorship for nurses as key strategies to acquire and apply QI knowledge to a QI project on their respective units. Key challenges emerged including workload and time constraints, as well as resistance to change from staff. Our study findings suggest that leaders need to provide learning opportunities and protected time for frontline nurses to participate in QI projects. PMID- 23744469 TI - Linking evidence-based nursing practice and patient-centered care through patient preferences. AB - Calls for both patient-centered care and evidence-based practice (EBP) have increased dramatically over the last decade despite a tension between the two. Patient preferences, one of the cornerstones of EBP, can provide the link between the two. Although current research supports the added value of patient preferences in care, there is currently a "gap" between EBP and patient-centered care, with the two often viewed as opposing ideas. The purpose of this article is to provide an overview of patient preferences, summarize research on patient preferences, and discuss implications for nursing and nursing administration. Efforts to incorporate patient preferences into nursing care must be multifaceted, targeting multiple levels from individual nurses to organizations and systems. Four critical elements have been identified for integrating patient preferences into EBP: (1) health care redesign, (2) decision support, (3) empowered organizational culture, and (4) informed and empowered nurses. PMID- 23744470 TI - Achieving patient and family engagement through the implementation and evolution of advisory councils across a large health care system. AB - Over the past decade, hospitals and health care systems have responded to the call for increased patient engagement and person-centered care. Organizations across the country have developed models and tools to assist in the effort toward patient and family engagement in health care delivery. In addition, current literature and trends suggest that patient satisfaction and quality outcomes are improved when patients and families become partners in their own health care and the delivery of that care. However, to formalize a patient-centric structure and process across a large health care system that is aimed at patient and family engagement can be a daunting activity. Utilizing well-established tools, Catholic Health Initiatives was successful in implementing the structures to deploy the ideas of patients and families in multiple facilities and care settings across 19 states. Nursing leaderships, in partnership with patients and their families within this health care delivery system, were the key contributors to the implementation of formalized patient and family advisory councils in hospitals across the enterprise. PMID- 23744471 TI - Building blocks for successful patient and family advisory boards: collaboration, communication, and commitment. AB - The mission of our hospital states: "Patients and their families are treated with compassion in a family-centered care environment that recognizes their physical, emotional, financial, and spiritual needs." Family-centered care is an approach to health care that shapes policies, programs, facility design, and day-to-day interactions among patients and their families, physicians, nurses, and other health care professionals. Health care professionals across all disciplines and in all care environments have the opportunity to advance the practice of patient- and family-centered care. They do so by welcoming patients and their families as partners in care-acknowledging patient and family expertise and strengths, encouraging their input, and acknowledging the value of their observations and perceptions. There is a growing recognition of the importance of patient and family care experiences as a key part of quality care. Through this partnership, patients and their families are viewed as valuable sources of information that can impact the quality of the care they receive. Their perspective on the care they receive can be used to shape effective solutions and target practice improvements in the care delivery experience. As an organization, we have been focused on implementing patient- and family-centered care for many years. We are unique in that we have parents of patients on the hospital staff and regularly seek their input, along with that of our Family Advisory Boards (English and Spanish speaking) and Teen Advisory Board. You have to ask yourself the question, "Are you ready to incorporate patient- and family-centered care into your practice?" PMID- 23744472 TI - Patients of the future: a survey of school nurse competencies with implications for nurse executives in the acute care settings. AB - School nursing in the United States has been in existence for many decades but has become increasingly more complex, as student health needs have escalated and the role itself has expanded in scope of practice. Given the changes in health care delivery mandated by the Patient Safety and Affordable Care Reform Act, and the increasing complexity of school nursing practice, it is important to determine whether nurses who enter this area of practice are educationally prepared to do so. The objective of this study was to determine the perceptions of currently practicing school nurses regarding their baccalaureate nursing education and whether they felt adequately prepared to effectively practice as a school nurse. The survey The Perceptions of School Nurses' Educational Preparation: Survey of Washington State School Nurses was sent to school nurses in Washington State. This was a descriptive, quantitative online survey that asked school nurses to assess their initial nursing education and whether their baccalaureate preparation adequately prepared them for this specialty role. There are a total of 17 school nurse standards, and 8 of the standards (47%) were identified as minimally achieved upon graduation. In addition, school nurses self assessed gaps in their ongoing continuing educational needs, such as needing additional education regarding special education laws (81%), 504 accommodations (90.5%), diabetic care (76%), and delegation skills (68.6%). The findings from this study have illustrated the need for additional didactic and clinical practicum components that could be incorporated into baccalaureate nursing programs to better prepare graduates for school nursing practice in Washington State. Participants were able to identify areas in need of further education within their baccalaureate program, and also during their orientation to the role and responsibilities of a school nurse. Nurse executives must be able to use this knowledge to support staff nurses with an understanding of school nurses' increasing responsibilities to improve both inpatient care and outpatient support. PMID- 23744473 TI - The TIGER continues to ROAR: launching the virtual learning environment! PMID- 23744474 TI - Advancing diversity leadership in health care. PMID- 23744475 TI - Evidence-driven nurse remediation: competency validation. PMID- 23744476 TI - Roles of NIA/NR/NOA1-dependent nitric oxide production and HY1 expression in the modulation of Arabidopsis salt tolerance. AB - Despite substantial evidence on the separate roles of Arabidopsis nitric oxide associated 1 (NOA1)-associated nitric oxide (NO) production and haem oxygenase 1 (HY1) expression in salt tolerance, their integrative signalling pathway remains largely unknown. To fill this knowledge gap, the interaction network among nitrate reductase (NIA/NR)- and NOA1-dependent NO production and HY1 expression was studied at the genetic and molecular levels. Upon salinity stress, the majority of NO production was attributed to NIA/NR/NOA1. Further evidence confirmed that HY1 mutant hy1-100, nia1/2/noa1, and nia1/2/noa1/hy1-100 mutants exhibited progressive salt hypersensitivity, all of which were significantly rescued by three NO-releasing compounds. The salinity-tolerant phenotype and the stronger NO production in gain-of-function mutant of HY1 were also blocked by the NO synthetic inhibitor and scavenger. Although NO- or HY1-deficient mutants showed a compensatory mode of upregulation of HY1 or slightly increased NO production, respectively, during 2 d of salt treatment, downregulation of ZAT10/12-mediated antioxidant gene expression (cAPX1/2 and FSD1) was observed after 7 d of treatment. The hypersensitive phenotypes and stress-related genes expression profiles were differentially rescued or blocked by the application of NO- (in particular) or carbon monoxide (CO)-releasing compounds, showing a synergistic mode. Similar reciprocal responses were observed in the nia1/2/noa1/hy1-100 quadruple mutant, with the NO-releasing compounds exhibit the maximal rescuing responses. Overall, the findings present the combination of compensatory and synergistic modes, linking NIA/NR/NOA1-dependent NO production and HY1 expression in the modulation of plant salt tolerance. PMID- 23744477 TI - Ficolin-2 and ficolin-3 in women with malignant and benign ovarian tumours. AB - Ficolins are serum pattern recognition molecules. They have opsonic properties and are able to activate complement via the lectin pathway. This paper reports investigations concerning ficolin-2 and ficolin-3 in ovarian cancer (OC). Their serum levels, single nucleotide polymorphisms of the corresponding FCN2 and FCN3 genes and specific mRNA expression in ovarian sections were investigated in 128 patients suffering from primary OC and 197 controls operated on for reasons other than malignancies. The latter consisted of two reference groups: those with benign tumours (n = 123) and those with normal ovaries (NO) (n = 74). Serum ficolin-2 and ficolin-3 concentrations were higher among patients with malignant disease when compared with either of the reference groups. A significant correlation between ficolin-2 and ficolin-3 concentrations was found, while no correlations with CA125 antigen or CRP were observed. No differences in the frequency of single nucleotide polymorphisms at sites -64, -4 (promoter), +6359, or +6424 (exon 8) (FCN2 gene) nor in the frame-shift mutation 1637delC (FCN3 gene) were found between investigated groups. In contrast to serum concentrations, the expression of FCN2 gene (reported for the first time in ovarian sections) was significantly lower in women with OC in comparison with patients with NO but not with benign ovarian tumours. In case of FCN3 gene, its expression levels in OC group inversely correlated with serum ficolin-3 and were lower in comparison with controls. PMID- 23744478 TI - Pelvis width associated with bone mass distribution at the proximal femur in children 10-11 years old. AB - Differences in skeletal geometry may generate different patterns of mechanical loading to bone. Impact and muscle loading during physical activity have been shown to influence skeletal geometry. The purpose of this study was to compare geometric measures of the pelvis and proximal femur (PF) of young children and to analyze the contribution and potential interaction of these geometric measures with physical activity on PF bone mass distribution. Participants were 149 girls and 145 boys, aged 10-11 years. Total body and left hip DXA scans were used to derive pelvic and PF geometric measures and PF bone mineral density (BMD) at the femoral neck (FN), trochanter (TR), and intertrochanter (IT). These subregions were used to represent bone mass distribution via three BMD ratios: FN:PF, TR:PF, and IT:PF. Physical activity was objectively measured using accelerometry, and maturity was estimated as the years of distance from peak height velocity. When compared to boys, girls had a wider pelvic diameter and greater interacetabular distances (p < 0.001), lower BMD at FN, TR, and IT (p < 0.05), and higher TR:PF (p < 0.001). After controlling for maturity, body height, and lean body mass, the interacetabular distance in girls explained 21.1 % (beta = 0.713, p < 0.001) in TR:PF and 2.9 % (beta = -0.179, p = 0.031) in the IT:PF. Neck-shaft angle explained 5.6 % (beta = -0.265, p = 0.001) of the IT:PF and 3.1 % (beta = 0.194, p = 0.018) of the FN:PF. In boys, FN axis length explained 2.9 % (beta = 0.195, p = 0.040) of TR:PF. There was no main effect of physical activity or interaction effect with pelvic geometry in explaining BMD differences among the subregions of the PF. Even before sexual dimorphism, girls have a wider pelvis than boys, which accounted for proportionally greater BMD of the TR than other subregions of the PF. PMID- 23744480 TI - Challenges and advances in the field of self-assembled membranes. AB - Self-assembled membranes are of vital importance in biological systems e.g. cellular and organelle membranes, however, more focus is being put on synthetic self-assembled membranes not only as an alternative for lipid membranes but also as an alternative for lithographic methods. More investigations move towards self assembly processes because of the low-cost preparations, structural self regulation and the ease of creating composite materials and tunable properties. The fabrication of new smart membrane materials via self-assembly is of interest for delivery vessels, size selective separation and purification, controlled release materials, sensors and catalysts, scaffolds for tissue engineering, low dielectric constant materials for microelectronic devices, antireflective coatings and proton exchange membranes for polymer electrolyte membrane fuel cells. Polymers and nanoparticles offer the most straightforward approaches to create membrane structures. However, alternative approaches using small molecules or composite materials offer novel ultra-thin membranes or multi-functional membranes, respectively. Especially, the composite material membranes are regarded as highly promising since they offer the possibility to combine properties of different systems. The advantages of polymers which provide elastic and flexible yet stable matrices can be combined with nanoparticles being either inorganic, organic or even protein-based which offers pore-size control, catalytic activity or permeation regulation. It is therefore believed that at the interface of different disciplines with each offering different materials or approaches, the most novel and interesting membrane structures are going to be produced. The combinations and approaches presented in this review offer non conventional self-assembled membrane materials which exhibit a high potential to advance membrane science and find more practical applications. PMID- 23744479 TI - To grab the stroma by the horns: from biology to cancer therapy with mesenchymal stem cells. AB - Mesenchymal stem or stromal cells (MSCs) are precursor cells that play important roles in tumorigenesis. MSCs are recruited to tumors from local and distant sources to form part of the tumor microenvironment. MSCs influence tumor progression by interacting with cancer cells, endothelial cells, immune cells, and cancer stem cells, in a context-dependent network. This review aims to synthesize this emerging yet controversial field to identify key questions regarding the mechanisms of MSC mobilization and survival in blood; homing to tumors, metastases, and premetastatic sites; spatiotemporal organization and differentiation; and interaction with immune cells and cancer stem cells. Understanding the fundamental biology underlying mesenchymal stem cell and tumor interactions has the potential to inform our knowledge of cancer initiation and progression as well as lead to novel therapeutics for cancer. Furthermore, knowledge of endogenous mechanisms can be used to "program" exogenous MSCs for targeted chemotherapeutic delivery to tumors and metastases. Emerging studies will provide crucial insight into the mechanisms of tumor interactions with the whole organism including MSCs. PMID- 23744482 TI - Identification of ABC transporter genes in gonad tissue of two Mediterranean sea urchin species: black, Arbacia lixula L., and rocky, Paracentrotus lividus L. AB - Multixenobiotic resistance (MXR) represents an important cellular detoxification mechanism in aquatic organisms as it provides them robustness toward natural and man-made contaminants. Several ABC transporters have major roles in the MXR phenotype - P-gp/ABCB1, MRP1-3/ABCC1-3 and BCRP/ABCG2. In this study, we identified the presence of ABC transporters involved in the MXR mechanism of Arbacia lixula and Paracentrotus lividus. AlABCB1/P-gp, AlABCC3/MRP3, AlABCC9/SUR like and AlABCG-like transcripts were identified in A. lixula; and PlABCC1/P-gp, PlABCC3/MRP3, PlABCC5/MRP5, and PlABCC9/SUR-like transcripts in P. lividus. For each of the new partial sequences, we performed detailed phylogenetic and identity analysis as a first step toward full characterization and understanding of the ecotoxicological role of these ABC transporters. PMID- 23744481 TI - Altered spinal microRNA-146a and the microRNA-183 cluster contribute to osteoarthritic pain in knee joints. AB - The objective of this study was to examine whether altered expression of microRNAs in central nervous system components is pathologically linked to chronic knee joint pain in osteoarthritis. A surgical animal model for knee joint OA was generated by medial meniscus transection in rats followed by behavioral pain tests. Relationships between pathological changes in knee joint and development of chronic joint pain were examined by histology and imaging analyses. Alterations in microRNAs associated with OA-evoked pain sensation were determined in bilateral lumbar dorsal root ganglia (DRG) and the spinal dorsal horn by microRNA array followed by individual microRNA analyses. Gain- and loss of-function studies of selected microRNAs (miR-146a and miR-183 cluster) were conducted to identify target pain mediators regulated by these selective microRNAs in glial cells. The ipsilateral hind leg displayed significantly increased hyperalgesia after 4 weeks of surgery, and sensitivity was sustained for the remainder of the 8-week experimental period (F = 341, p < 0.001). The development of OA-induced chronic pain was correlated with pathological changes in the knee joints as assessed by histological and imaging analyses. MicroRNA analyses showed that miR-146a and the miR-183 cluster were markedly reduced in the sensory neurons in DRG (L4/L5) and spinal cord from animals experiencing knee joint OA pain. The downregulation of miR-146a and/or the miR-183 cluster in the central compartments (DRG and spinal cord) are closely associated with the upregulation of inflammatory pain mediators. The corroboration between decreases in these signature microRNAs and their specific target pain mediators were further confirmed by gain- and loss-of-function analyses in glia, the major cellular component of the central nervous system (CNS). MicroRNA therapy using miR-146a and the miR-183 cluster could be powerful therapeutic intervention for OA in alleviating joint pain and concomitantly regenerating peripheral knee joint cartilage. PMID- 23744483 TI - Parental exposure to methyl methane sulfonate of three-spined stickleback: contribution of DNA damage in male and female germ cells to further development impairment in progeny. AB - Data regarding the link between DNA integrity of germ cells and the quality of progeny in fish exposed to genotoxicant are scarce although such information is of value to understand genotoxic effects of contaminants in aquatic fauna. This work aimed at studying the consequences of a parental exposure during the breeding season on offspring quality in three-spined stickleback. After in vivo exposure of adult fish to methyl methane sulfonate, a model alkylating compound, a clear increase in DNA damage was observed in erythrocytes of both genders, here used as a biomarker of exposure. MMS exposure significantly affected sperm DNA integrity but neither female fecundity nor fertilization success. In order to understand the contribution of each sex to potential deleterious effects in progeny due to parental exposure, mating of males and females exposed or not to MMS, was carried out. Exposure of both males and females or of males alone led to a significant increase in both mortality during embryo-larval stages and abnormality rate at hatching that appeared to be sensitive stages. Thus, in accordance with recent studies carried out in other freshwater fish species, such development defects in progeny were clearly driven by male genome, known to be devoid of DNA repair capacity in spermatozoa. The next step will be to investigate the link between DNA damage in stickleback sperm and reproductive impairment in natural populations exposed to complex mixture of genotoxicants. PMID- 23744484 TI - Crystal structure analysis of L-fuculose-1-phosphate aldolase from Thermus thermophilus HB8 and its catalytic action: as explained through in silico. AB - Fuculose phosphate aldolase catalyzes the reversible cleavage of fuculose-1 phosphate to dihydroxyacetone phosphate and L-lactaldehyde. A tetramer by nature, this enzyme from Thermus thermophilus HB8 represents the group of Class II aldolases. The structure was solved in two different space groups using the crystals obtained from slow evaporation vapour-diffusion and microbatch techniques. The detailed crystallization description has been reported previously. In this study, the structural features of fuculose phosphate aldolase from T. thermophilus have been explored extensively through sequence and structure comparisons with fuculose phosphate aldolases of different species. Finally, an in silico analysis using induced fit docking was attempted to deduce the binding mode of fuculose phosphate aldolase with its natural substrate fuculose-1-phosphate along with a substrate analog dihydroxyacetone phosphate and phosphoglycolohydroxymate--a potential aldolase inhibitor. The results show the mechanism of action may be similar to that of Escherichia coli fuculose aldolase. PMID- 23744486 TI - Analysis of expression of membrane-bound tumor markers in ductal carcinoma in situ of the breast: paving the way for molecular imaging. AB - PURPOSE: Achieving radicality during breast conserving surgery for pure ductal carcinoma in situ (DCIS) of the breast and invasive cancer surrounded by DCIS is challenging. Molecular imaging holds promise here, when applied as a tool for image-guided surgery of DCIS. METHODS: Tissue microarrays containing 24 pure DCIS and 63 DCIS with adjacent invasive breast cancer cases were stained by immunohistochemistry for a panel of membrane-bound targets. RESULTS: GLUT1 expression was present in 60.9%, IGF1-R in 55.2% HER2 in 28.7%, MET in 18.4%, EGFR in 16.1%, CD44v6 in 69%, carbonic anhydrase XII (CAXII) in 24.1% and Mammaglobin in 14.9% of DCIS cases. No expression differences between pure DCIS and DCIS with adjacent cancer were observed. Further, HER2 and EGFR expression were correlated with high grade DCIS (p=0.001) and CAXII with low grade DCIS (p=0.027). A putative panel containing HER2, EGFR, GLUT1 and IGF1-R had a detection rate of 90.2% for DCIS and 78.3% for adjacent breast cancer. CONCLUSIONS: We found that membrane-bound targets are more frequently expressed in DCIS than in invasive breast cancer, but that single membrane proteins are too infrequently expressed to serve as single imaging targets for the detection of DCIS. However, a panel of markers consisting of IGF1-R, CD44v6, GLUT1, EGFR, and HER2 was found to be positive in 96.3% of DICS based on marker expression in the adjacent invasive breast cancer as described earlier. This implies that detection of DCIS based on marker expression in the adjacent invasive breast cancer during breast conserving surgery should be possible with a panel of molecular imaging tracers targeting CD44v6, GLUT1, HER2, IGF1-R, and EGFR. PMID- 23744487 TI - The effect of reactive oxygen species on the myogenic tone of rat ophthalmic arteries with and without endothelium. AB - BACKGROUND: Reactive oxygen species (ROS) play an important role in the pathogenesis of various ocular diseases. ROS can induce vasodilation or vasoconstriction depending on the species, the tested vessel bed, and the condition of the vessel. This study investigates the effect of different dosages of ROS on the tone of rat ophthalmic arteries. METHODS: Freshly dissected rat ophthalmic arteries were pressurized in a perfusion setup in steps of 10 mmHg to 180 mmHg in three consecutive cycles. The first cycle was run under mostly physiological conditions, the second cycle was run after ROS treatment, and the third cycle as passive dilation after all Ca(2+) was removed from the solution. ROS-induced dilation or constriction was calculated in relation to the passive dilation. All experiments were performed with or without endothelium. RESULTS: For vessels with endothelium, dilation in control experiments was 20.0 +/- 0.1%; after 5 s of ROS dilation was 74.4 +/- 0.6%, and after 20 s 87.4 +/- 0.3%. ANOVA revealed significant differences between these groups (P = 0.048). For vessels without endothelium, a slight dilation was seen in control experiments (14.5 +/- 0.4%), which was also present after 5 s of ROS treatment (15.4 +/- 0.4%). Treatment with ROS for 20 s led to a constriction of the vessel preparations ( 16.6 +/- 0.5%; P = 0.831). CONCLUSIONS: ROS led to a vasodilation in vessels with endothelium that was not seen in vessels without endothelium. Endothelial function seems to determine the effect of ROS on the vessel tone in isolated rat ophthalmic arteries. PMID- 23744488 TI - Anti-allergic effect of Pleuran (beta-glucan from Pleurotus ostreatus) in children with recurrent respiratory tract infections. AB - Recurrent respiratory tract infections (RRTIs) present a very important problem in paediatric praxis. As true immunodeficiencies are rare, one of the most important factors assumed to contribute to increased respiratory morbidity is atopy. Several preparations of natural origin have been used for the prevention of RRTIs, and some of the most effective immunomodulators are biologically active polysaccharides - e.g. beta-glucans. In our randomised, double-blind, placebo controlled study, we investigated the prevalence of atopy in a group of children with RRTIs and the potential anti-allergic effect of pleuran (beta-glucan isolated from Pleurotus ostreatus) on basic laboratory markers of allergic inflammation. We confirmed that atopy may be an important factor contributing to the increased respiratory morbidity in children with RRTIs. The active treatment with pleuran resulted in a significant reduction of peripheral blood eosinophilia and stabilised the levels of total IgE in serum. This was more evident in atopic subjects. Pleuran showed a potential anti-allergic effect. This previously non described effect could expand the application of this natural immunomodulator also as a complementary adjuvant therapy in allergic patients. PMID- 23744489 TI - Dual-energy subtraction radiography improves laryngeal delineation in patients with moderate to severe cervical spondylosis. AB - PURPOSE: To investigate the feasibility of dual-energy subtraction (DES) in patients with moderate-severe cervical spondylosis for improving delineation of the larynx on flat panel detector (FPD) radiography. MATERIALS AND METHODS: For 118 patients, we graded conventional/DES anterior-posterior views for delineation of the vocal cords, subglottis, and pyriform sinus using a 5-point scale and lateral views from conventional laryngeal FPD radiography to determine cervical spondylosis severity on a scale from 0 (none) to 3 (severe). We compared the delineation of each anatomical structure in both groups of grades 0-1 and grades 2-3 of spondylosis severity between conventional and DES methods and the improved delineation rate for each anatomical structure by DES compared to the conventional method between both groups. RESULTS: With DES, the delineation of each anatomical structure was significantly better than with conventional radiography for both groups (P < 0.0001). The improved delineation rate of the vocal cord and subglottis using DES was significantly higher in grades 2-3 than in grades 0-1 (P < 0.05), although there was no significant difference in the delineation rate of the pyriform sinus between the groups (P = 0.847). CONCLUSION: DES provides better delineation of the laryngeal anatomy than conventional FPD radiography predominantly in patients with moderate-severe cervical spondylosis. PMID- 23744490 TI - MEKing it easier to prevent GVHD. PMID- 23744491 TI - Extracellular microRNAs turn on NK cells via TLR1. PMID- 23744492 TI - Congenital dyserythropoietic anemias: III's a charm. PMID- 23744493 TI - Development of Hodgkin lymphoma in homozygotic triplets with constitutional deletion in MKL1. PMID- 23744494 TI - Novel childhood ALL susceptibility locus BMI1-PIP4K2A is specifically associated with the hyperdiploid subtype. PMID- 23744495 TI - Gender influences the birth order effect in HLA-identical stem cell transplantation. PMID- 23744496 TI - Blood pressure variability and the risk of all-cause mortality, incident myocardial infarction, and incident stroke in the cardiovascular health study. AB - BACKGROUND: Recent reports have linked variability in visit-to-visit systolic blood pressure (SBP) to risk of mortality and stroke, independent of the effect of mean SBP level. This study aimed to evaluate whether variability in SBP is associated with all-cause mortality, incident myocardial infarction (MI), and incident stroke, independent of mean SBP or trends in SBP levels over time. METHODS: The Cardiovascular Health Study is a longitudinal cohort study of vascular risk factors and disease in the elderly. Participants who attended their first 5 annual clinic visits and experienced no event before the 5th visit were eligible (n = 3,852). Primary analyses were restricted to participants not using antihypertensive medications throughout the first 5 clinic visits (n = 1,642). Intraindividual SBP variables were defined using each participant's 5-visit blood pressure measures. Cox proportional hazards models estimated adjusted hazard ratios (HRs) per SD increase in intraindividual SBP variability, adjusted for intraindividual SBP mean and change over time. RESULTS: Over a mean follow-up of 9.9 years, there were 844 deaths, 203 MIs, and 195 strokes. Intraindividual SBP variability was significantly associated with increased risk of mortality (HR = 1.13; 95% confidence interval (CI) = 1.05-1.21) and of incident MI (HR = 1.20; 95%CI = 1.06-1.36), independent of the effect from adjustment factors. Intraindividual SBP variability was not associated with risk of stroke (HR = 1.03; 95% CI = 0.89-1.21). CONCLUSIONS: Long-term visit-to-visit SBP variability was independently associated with a higher risk of subsequent mortality and MI but not stroke. More research is needed to determine the relationship of BP variability with cardiovascular risk and the clinical implications. PMID- 23744497 TI - Association of pathogen burden and hypertension: the Persian Gulf Healthy Heart Study. AB - BACKGROUND: Chronic infection with cytomegalovirus (CMV), Chlamydia pneumoniae, herpes simplex virus 1 (HSV-1), and Helicobacter pylori may contribute to essential hypertension. However, the evidence now available does not clarify whether the aggregate number of pathogens (pathogen burden) may be associated with hypertension. METHODS: Sera from 1,754 men and women aged >=25 years were analyzed for immunoglobulin G antibodies to C. pneumoniae, HSV-1, H. pylori, and CMV using enzyme-linked immunosorbent assay. The aggregate number of seropositives to the studied viral and bacterial agents was defined as pathogen burden. Hypertension was defined according to World Health Organization criteria. RESULTS: A total of 459 (26.3%) of the subjects had hypertension. In the hypertensive group, 4.2% had 0 or 1 pathogens present, 20.6% had 2, 43.2% had 3, and 32.1% had 4; in the normotensive group, 7.9% had 0 or 1, 28.4% had 2, 42.7% had 3, and 21.0% had 4. Of the 4 studied pathogens, H. pylori seropositivity showed a significant independent association with hypertension (odds ratio (OR) =1.37; 95% confidence interval (CI) =1.05-1.79; P = 0.02). In multiple logistic regression analyses, the pathogen burden did not show a significant independent association with hypertension. Coinfection with H. pylori and C. pneumoniae was significantly associated with hypertension compared with double seronegativity after adjustment for age, sex, chronic low-grade inflammation, and cardiovascular risk factors (OR = 1.68; 95% CI = 1.14-2.47; P = 0.008]. CONCLUSIONS: The pathogen burden was not associated with hypertension. However, coinfection with C. pneumoniae and H. pylori showed a significant association with essential hypertension, independent of cardiovascular risk factors and chronic low-grade inflammation. PMID- 23744499 TI - After implementation of a new 'track and trigger' model, nursing staff showed improved self-assessed knowledge and confidence in detection and management of deteriorating patients. PMID- 23744498 TI - SDF-1 fused to a fractalkine stalk and a GPI anchor enables functional neovascularization. AB - The facilitated recruitment of vascular progenitor cells (VPCs) to ischemic areas might be a therapeutic target for neovascularization and repair. However, efficient and directed attraction of VPCs remains a major challenge in clinical application. To enhance VPC homing, we developed a fusion protein (S1FG), based on the biology of stroma-derived factor-1/CXCL12 and the mucin backbone taken from fractalkine/CXCL12. A GPI-anchor was included to link the fusion-protein to the cell surface. HUVECs transfected with S1FG were capable of increasing firm adhesion of CXCR4+-mononuclear cells (THP-1) under shear stress conditions in vitro. In an in vivo rabbit model of chronic hind limb ischemia, local S1FG application enhanced the recruitment of adoptively transferred embryonic EPCs (eEPCs) to the ischemic muscles 2.5-fold. S1FG combined with eEPC(low) (2 * 10(6)) yielded similar capillary growth as eEPC(high) (5 * 10(6)) alone. Compared to controls, collateral formation was increased in the S1FG eEPC(low) group, but not the eEPC(high) group without S1FG, whereas perfusion was found enhanced in both groups. In addition, S1FG also increased collateral formation and flow when combined with AMD3100 treatment, to increase circulating levels of endogenous VPC. These data demonstrate that the fusion protein S1FG is capable of enhancing the recruitment of exogenously applied or endogenously mobilized progenitor cells to sites of injury. Recombinant versions of S1FG applied via catheters in combination with progenitor cell mobilization may be useful in the treatment of chronic ischemic syndromes requiring improved perfusion. PMID- 23744500 TI - No need for broad-spectrum empirical antibiotic coverage after surgical drainage of orthopaedic implant infections. AB - PURPOSE: Empirical broad-spectrum antibiotic treatment for orthopaedic implant infections after surgical lavage is common practice while awaiting microbiological results, but lacks evidence. METHODS: This was a single-centre cohort study from 1996 to 2010 with a follow-up of two years. RESULTS: We retrieved 342 implant infections and followed them up for a median of 3.5 years (61 recurred, 18%). Infected implants were arthroplasties (n = 186), different plates, nails or other osteosyntheses. The main pathogens were S. aureus (163, 49 methicillin-resistant) and coagulase-negative staphylococci (60, 45 methicillin resistant). Median duration of empirical antibiotic coverage after surgical drainage was three days before switching to targeted therapy. Vancomycin was the most frequent initial empirical agent (147), followed by intravenous co-amoxiclav (44). Most empirical antibiotic regimens (269, 79%) proved sensitive to the causative pathogen, but were too broad in 111 episodes (32%). Cephalosporins and penicillins were used only in 44 and ten cases, respectively, although they would have covered 59% of causative pathogens identified later. Multivariate Cox regression analysis showed that neither susceptible antibiotic coverage (compared to non-susceptible; hazard ratio 0.7, 95% confidence interval 0.4-1.2) nor broad spectrum use (hazard ratio 1.1, 0.8-1.5) changed remission rates. CONCLUSIONS: Provided that surgical drainage is performed, broad-spectrum antibiotic coverage does not enhance remission of orthopaedic implant infections during the first three days. If empirical agents are prescribed from the first day of infection, narrow-spectrum penicillins or cephalosporins can be considered to avoid unnecessary broad-spectrum antibiotic use. PMID- 23744501 TI - Comment on Wang et al.: Single-stage posterior instrumentation and anterior debridement for active tuberculosis of the thoracic and lumbar spine with kyphotic deformity. PMID- 23744502 TI - Long-term survival of the uncemented Balgrist total hip replacement cup. AB - PURPOSE: The purpose of this study was to evaluate the long-term clinical and radiographic outcomes of the Balgrist total hip replacement cup. METHODS: We report the results of a retrospective review of 195 total hip prostheses with Balgrist cup implanted in 178 patients. There were 59 men and 119 women with a mean age at surgery of 52.3 years (range, 19-72). Cox regression was used to determine the influence of independent variables on the survivorship of the prosthesis. RESULTS: There were 117 (66 %) of 178 patients, and 131 (67 %) of 195 hips available for assessment at a mean follow-up of 17.4 years. A total of 21 patients (22 hips) were lost from follow-up (12 %). A total of 25 patients (27 hips) required some type of re-operation during the follow-up period. Eight of 27 re-operations (30 %) were directly caused by the Balgrist cup failure due to fatigue fracture of the metallic shell (n = 5; 19 %), polyethylene wear (n = 2; 7 %) and aseptic loosening (n = 1; 4 %). The mean polyethylene wear rate was 0.068 mm/year (range, 0.008-0.230; SD = 0.043). The risk of re-operation for any reason was decreased with dysplastic hip as a primary diagnosis (hazard ratio; HR = 0.250; 95 % CI 0.086-0.725) and with greater age at the time of surgery (HR = 0.923; 95 % CI 0.880-0.969). The 19-year survivorship with re-operation for any reason was 75.6 % (95 % CI 67.0-84.2). The 19-year survivorship with re-operation for the Balgrist cup failure was 90.5 % (95 % CI 83.4-97.6). CONCLUSIONS: The Balgrist cup continues to provide excellent clinical and radiological outcomes. This is associated at least in part with a low polyethylene wear rate. The main reason for the Balgrist cup failure is fatigue fracture of the metallic shell. PMID- 23744503 TI - Reply to comment on Wang et al.: Single-stage posterior instrumentation and anterior debridement for active tuberculosis of the thoracic and lumbar spine with kyphotic deformity. PMID- 23744505 TI - Dr. Google: what about the human papillomavirus vaccine? AB - OBJECTIVES: To assess and analyze the information and recommendations provided by Google Web SearchTM (Google) in relation to web searches on the HPV vaccine, indications for females and males and possible adverse effects. RESULTS: In the comprehensive analysis of results, 72.2% of websites offer information favorable to HPV vaccination, with varying degrees of content detail, vs. 27.8% with highly dissuasive content in relation to HPV vaccination. The most frequent type of site is the blog or forum. The information found is frequently incomplete, poorly structured, and often lacking in updates, bibliography and adequate citations, as well as sound credibility criteria (scientific association accreditation and/or trust mark system). MATERIALS AND METHODS: Descriptive cross-sectional study of the results of 14 web searches. Comprehensive analysis of results based on general recommendation given (favorable/dissuasive), as well as compliance with pre-established criteria, namely design, content and credibility. Sub-analysis of results according to site category: general information, blog / forum and press. CONCLUSIONS: Google, as a tool which users employ to locate medical information and advice, is not specialized in providing information that is necessarily rigorous or valid from a scientific perspective. Search results and ranking based on Google's generalized algorithms can lead users to poorly grounded opinions and statements, which may impact HPV vaccination perception and subsequent decision making. PMID- 23744504 TI - The rise (and fall?) of parental vaccine hesitancy. AB - Parental vaccine hesitancy is a growing problem affecting the health of children and the larger population. This article describes the evolution of the vaccine hesitancy movement and the individual, vaccine-specific and societal factors contributing to this phenomenon. In addition, potential strategies to mitigate the rising tide of parent vaccine reluctance and refusal are discussed. PMID- 23744506 TI - Long-term persistence of immunity after vaccination of pre-adolescents with low doses of a recombinant hepatitis B vaccine. AB - BACKGROUND AND AIMS: Recent studies have shown no detectable antibodies and no response to a challenge dose of vaccine 10-20 y after receiving low doses (2.5-5 ug) of recombinant hepatitis B vaccine during first months of life. Little information is available on long-term persistence of immunity after vaccinating pre-adolescents with low doses of hepatitis B vaccine. RESULTS: The results of 560 subjects were included in this analysis. All subjects had a seroprotective antibody titer (>=10 IU/L) one month post-primary vaccination; 5, 10 and 15 y post-vaccination 95%, 95% and 87% had detectable antibodies, and 82%, 86%, and 68% had a seroprotective antibody titer; GMTs were 73 IU/L, 89 IU/L, and 28 IU/L, respectively. More than 99.4% of subjects had an anamnestic response to a challenge dose of vaccine given 5, 10, or 15 y post-vaccination. Five and ten years post-booster dose 97% and 95% of subjects still have a seroprotective anti HBs titer with GMTs 16-18-fold higher when compared with those observed 5-10 y post-primary vaccination. MATERIALS AND METHODS: This randomized trial was initiated in 1996 with the main objective to assess the persistence of antibodies and immune memory 5, 10 and 15 y after vaccinating 8-10 y-old children with three doses of Recombivax 2.5 ug, as well as the short and long-term effect of a booster dose given at different intervals. CONCLUSIONS: Virtually all children vaccinated at the age of 8-10 y with low doses of hepatitis B vaccine still have an excellent immune memory up to age of 25 y. The results of this study do not support the use of booster doses. PMID- 23744507 TI - Does a monovalent inactivated human rotavirus vaccine induce heterotypic immunity? Evidence from animal studies. AB - There is substantial evidence for broad cross-reactive immunity and heterotypic protection among human rotavirus strains in children with natural infection or with monovalent Rotarix vaccination. In this commentary, we addressed this same topic by testing sera of guinea pigs and gnotobiotic piglets that were intramuscularly immunized with an inactivated human rotavirus vaccine and also demonstrated a broad cross-protective immunity among human rotavirus strains. Our findings from a single human strain in animal studies bode well for a low cost and efficacious inactivated vaccine to protect children against rotavirus disease throughout the world. PMID- 23744508 TI - Progress on the research and development of inactivated EV71 whole-virus vaccines. AB - The prevalence of diseases caused by EV71 infection has become a serious public health problem in the Western Pacific region. Due to a lack of effective treatment options, controlling EV71 epidemics has mainly focused on the research and development (R&D) of EV71 vaccines. Thus far, five organizations have completed pre-clinical studies focused on the development of inactivated EV71 whole-virus vaccines, including vaccine strain screening, process optimization, safety and immunogenicity evaluation, and are in different stages of clinical trials. Among these organizations, three companies in Mainland China [Beijing Vigoo Biological Co., Ltd. (Vigoo), Sinovac Biotech Ltd. (Sinovac) and Institute of Medical Biology, Chinese Academy of Medical Science (CAMS)] have recently completed Phase III trials for the vaccines they developed. In addition, the other two vaccines, developed by National Health Research Institutes (NHRI) of Taiwan and Inviragen Pte., Ltd (Inviragen), of Singapore, have also completed Phase I clinical trials. Published clinical trial results indicate that the inactivated EV71 vaccines have good safety and immunogenicity in the target population (infants) and confer a relatively high rate of protection against EV71 infection-related diseases. The results of clinical trials suggest a promising future for the clinical use of EV71 vaccines. Here, we review and highlight the recent progress on the R&D of inactivated EV71 whole-virus vaccines. PMID- 23744510 TI - Powerful inhibition of experimental human pancreatic cancers by receptor targeted cytotoxic LH-RH analog AEZS-108. AB - Pancreatic carcinoma is one of the cancers with the worse prognosis, thus any therapeutic improvement is imperative. Cytotoxic LH-RH analog, AN-152 (proprietary designation, AEZS-108), consisting of doxorubicin (DOX) conjugated to D-Lys6LH-RH, is now in clinical trials for targeted therapy of several sex hormone-dependent tumors that express LH-RH receptors. We investigated LH-RH receptors in human pancreatic carcinoma and the effects of AN-152 (AEZS-108) on experimental pancreatic cancers. We determined LH-RH receptor presence in human pancreatic cancer samples by immunohistochemistry and, in three human pancreatic cancer lines (SW-1990, Panc-1 and CFPAC-1), by binding assays and Western blotting. The effects of the cytotoxic LH-RH analog were investigated on growth of these same cancer lines xenografted into nude mice. We also analyzed differences between the antitumor effects of the cytotoxic analog and its cytotoxic radical alone, doxorubicin (DOX), on the expression of cancer-related genes by PCR arrays. LH-RH receptors were expressed in two randomly selected surgically removed human pancreatic cancer samples and in all three cancer lines. Cytotoxic LH-RH analogs powerfully inhibited growth of all three tumor lines in nude mice; AN-152 was significantly stronger than DOX on Panc-1 and CFPAC-1 cancers. PCR array showed that cytotoxic LH-RH analog AN-152 affected the expression of genes associated with cellular migration, invasion, metastasis and angiogenesis more favorably than DOX, however the changes in gene expression varied considerably among the three cancer lines. Cytotoxic LH-RH analog, AEZS 108, may be a useful agent for the treatment of LH-RH receptor positive advanced pancreatic carcinoma. PMID- 23744509 TI - Concomitant administration of hepatitis A vaccine with measles/mumps/rubella/varicella and pneumococcal vaccines in healthy 12- to 23 month-old children. AB - This open-label, multicenter, randomized, comparative study evaluated immunogenicity, safety and tolerability of concomitant (Group 1; n=330) vs. non concomitant (Group 2; n=323) VAQTATM (25U/0.5 mL) (hepatitis A vaccine; HAV) with ProQuadTM (measles/mumps/rubella/varicella; MMRV) and PrevnarTM (7-valent pneumococcal; PCV-7) in healthy, 12-23 mo old children. Group 1 received HAV/MMRV/PCV-7 concomitantly on Day 1 and second doses of HAV/MMRV at Week 24. Group 2 received MMRV/PCV-7 on Day 1, HAV at Weeks 6 and 30 and MMRV at Week 34. Hepatitis A seropositivity rate (SPR: >=10 mIU/mL; 4 weeks postdose 2), varicella zoster-virus (VZV) SPR (>=5 gpELISA units/mL) and geometric mean titers (GMT) to S. pneumoniae were examined. Injection-site and systemic adverse experiences (AEs) and daily temperatures were collected. Hepatitis A SPR were 100% for Group 1 and 99.4% for Group 2 after two HAV doses; risk difference=0.7 (95%CI: 1.4,3.8, non-inferior) regardless of initial serostatus. VZV SPR was 93.3% for Group 1 and 98.3% for Group 2; risk difference=-5.1 (95%CI: -9.3, -1.4; non inferior). S. pneumoniae GMT fold-difference (7 serotypes) ranged from 0.9 to 1.1; non-inferior. No statistically significant differences in the incidence of individual AEs were seen when HAV was administered concomitantly vs. non concomitantly. Three (all Group 2 post-administration of MMRV/PCV-7) of 11 serious AEs were considered possibly vaccine-related: dehydration and gastroenteritis (same subject) on Day 52; febrile seizure on Day 9. No deaths were reported. Antibody responses to each vaccine given concomitantly were non inferior to HAV given non-concomitantly with MMRV and PCV-7. Administration of HAV with PCV-7 and MMRV had an acceptable safety profile in 12- to 23-mo-old children. PMID- 23744511 TI - Building reactive copper centers in human carbonic anhydrase II. AB - Reengineering metalloproteins to generate new biologically relevant metal centers is an effective a way to test our understanding of the structural and mechanistic features that steer chemical transformations in biological systems. Here, we report thermodynamic data characterizing the formation of two type-2 copper sites in carbonic anhydrase and experimental evidence showing one of these new, copper centers has characteristics similar to a variety of well-characterized copper centers in synthetic models and enzymatic systems. Human carbonic anhydrase II is known to bind two Cu(2+) ions; these binding events were explored using modern isothermal titration calorimetry techniques that have become a proven method to accurately measure metal-binding thermodynamic parameters. The two Cu(2+)-binding events have different affinities (K a approximately 5 * 10(12) and 1 * 10(10)), and both are enthalpically driven processes. Reconstituting these Cu(2+) sites under a range of conditions has allowed us to assign the Cu(2+)-binding event to the three-histidine, native, metal-binding site. Our initial efforts to characterize these Cu(2+) sites have yielded data that show distinctive (and noncoupled) EPR signals associated with each copper-binding site and that this reconstituted enzyme can activate hydrogen peroxide to catalyze the oxidation of 2-aminophenol. PMID- 23744512 TI - In vivo evidence for a prodrug activation mechanism during colibactin maturation. AB - Releasing the cytopath: We have identified an N-myristoyl-D-asparagine (1) as the free N-terminal prodrug scaffold in cytopathogenic Escherichia coli strains expressing the colibactin gene cluster. Colibactin is released in vivo upon cleavage of precolibactin. We provide for the first time in vivo evidence of the prodrug-like release mechanism of colibactin. PMID- 23744514 TI - Cbl-family proteins as regulators of cytoskeleton-dependent phenomena. AB - Although the role of Cbl-family proteins as key cellular regulators has been established, phenomena regulated in a Cbl-dependent fashion are multiple and the mechanisms mediating the effects of Cbl proteins are diverse. This finding makes it important to consider different phenomena affected by functions of Cbl proteins individually. Among effects of Cbl on various biological functions there are many cases of regulation of cellular phenomena related to cytoskeletal rearrangements, such as cell adhesion, motility and invasion. Some of these regulatory functions are mediated by adaptor-type interactions of Cbl, especially by Cbl-dependent modulation of phosphatidyl-inositol-3' kinase (PI3K), while others are caused by Cbl-dependent ubiquitylation of various cytoskeletal and regulatory proteins, identified and unidentified. The role of Cbl in regulation of cytoskeleton-dependent cellular functions is discussed in this review. PMID- 23744513 TI - Does hormone replacement normalize bone geometry in adolescents with anorexia nervosa? AB - Young women with anorexia nervosa (AN) have reduced secretion of dehydroepiandrosterone (DHEA) and estrogen contributing to skeletal deficits. In this randomized, placebo-controlled trial, we investigated the effects of oral DHEA + combined oral contraceptive (COC) versus placebo on changes in bone geometry in young women with AN. Eighty women with AN, aged 13 to 27 years, received a random, double-blinded assignment to micronized DHEA (50 mg/day) + COC (20 ug ethinyl estradiol/0.1 mg levonorgestrel) or placebo for 18 months. Measurements of areal bone mineral density (aBMD) at the total hip were obtained by dual-energy X-ray absorptiometry at 0, 6, 12, and 18 months. We used the Hip Structural Analysis (HSA) program to determine BMD, cross-sectional area (CSA), and section modulus at the femoral neck and shaft. Each measurement was expressed as a percentage of the age-, height-, and lean mass-specific mean from an independent sample of healthy adolescent females. Over the 18 months, DHEA + COC led to stabilization in femoral shaft BMD (0.0 +/- 0.5% of normal mean for age, height, and lean mass/year) compared with decreases in the placebo group (-1.1 +/ 0.5% per year, p = 0.03). Similarly, CSA, section modulus, and cortical thickness improved with treatment. In young women with AN, adrenal and gonadal hormone replacement improved bone health and increased cross-sectional geometry. Our results indicate that this combination treatment has a beneficial impact on surrogate measures of bone strength, and not only bone density, in young women with AN. PMID- 23744515 TI - Second-trimester prenasal and prefrontal skin thickening - association with MECP2 triplication syndrome. AB - MECP2 triplication syndrome is a rare and usually lethal genetic disorder characterized by progressive neurologic and cognitive regression. None of the four reported cases describe prenatal sonographic features of affected offspring. We report a second-trimester fetus with marked prefrontal and prenasal skin thickening, retrognathia, and later, third-trimester mild cerebral ventriculomegaly. Amniocyte karyotype was normal male, but newborn whole-genome oligonucleotide microarray showed duplication and triplication of chromosome Xq28 containing the MECP2 gene. Comparative genomic hybridization may be diagnostic in fetuses with prefrontal and prenasal skin thickening, additional sonographic findings, and normal karyotype. PMID- 23744516 TI - Nutritional screening for improving professional practice for patient outcomes in hospital and primary care settings. AB - BACKGROUND: Given the prevalence of under-nutrition and reports of inadequate nutritional management of patients in hospitals and the community, nutritional screening may play a role in reducing the risks of malnutrition. Screening programmes can invoke costs to health systems and patients. It is therefore important to assess the effectiveness of nutritional screening programmes. OBJECTIVES: To examine the effectiveness of nutritional screening in improving quality of care (professional practice) and patient outcomes compared with usual care. SEARCH METHODS: We searched the following databases: CENTRAL (The Cochrane Library), MEDLINE, EMBASE and CINAHL up to June 2012 to find relevant studies. SELECTION CRITERIA: Randomised controlled studies, controlled clinical trials, controlled before-after studies and interrupted time series studies assessing the effectiveness of nutritional screening were eligible for inclusion in the review. We considered process outcomes (for example patient identification, referral to dietitian) and patient outcomes (for example mortality, change in body mass index (BMI)). Participants were adult patients aged 16 years or over. We included studies conducted in different settings, including hospitals, out-patient clinics, primary care or long term care settings. DATA COLLECTION AND ANALYSIS: We independently assessed the risk of bias and extracted data from the included studies. Meta-analysis was considered but was not conducted due to the discrepancies between the studies. The studies were heterogeneous in their design, setting, intervention and outcomes. We analysed the data using a narrative synthesis approach. MAIN RESULTS: After conducting initial searches and screening the titles and abstracts of the identified literature, 77 full text papers were retrieved and read. Ultimately three studies were included. Two controlled before-after studies were conducted in hospital settings (one in the UK and one in the Netherlands) and one cluster randomised controlled trial was conducted in a primary care setting (in the USA).The study conducted in primary care reported that physicians were receptive to the screening intervention, but the intervention did not result in any improvements in the malnutrition detection rate or nutritional intervention rate. The two studies conducted in hospitals had important methodological limitations. One study reported that as a result of the intervention, the recording of patients' weight increased in the intervention wards. No significant changes were observed in the referral rates to dietitians or care at meal time. The third study reported weight gains and a reduction in hospital acquired infection rate in the intervention hospital. They found no significant differences in length of stay, pressure sores, malnutrition and treatment costs per patient between the two hospitals. AUTHORS' CONCLUSIONS: Current evidence is insufficient to support the effectiveness of nutritional screening, although equally there is no evidence of no effect. Therefore, more high quality studies should be conducted to assess the effectiveness of nutritional screening in different settings. PMID- 23744517 TI - Inverse odds ratio-weighted estimation for causal mediation analysis. AB - An important scientific goal of studies in the health and social sciences is increasingly to determine to what extent the total effect of a point exposure is mediated by an intermediate variable on the causal pathway between the exposure and the outcome. A causal framework has recently been proposed for mediation analysis, which gives rise to new definitions, formal identification results and novel estimators of direct and indirect effects. In the present paper, the author describes a new inverse odds ratio-weighted approach to estimate so-called natural direct and indirect effects. The approach, which uses as a weight the inverse of an estimate of the odds ratio function relating the exposure and the mediator, is universal in that it can be used to decompose total effects in a number of regression models commonly used in practice. Specifically, the approach may be used for effect decomposition in generalized linear models with a nonlinear link function, and in a number of other commonly used models such as the Cox proportional hazards regression for a survival outcome. The approach is simple and can be implemented in standard software provided a weight can be specified for each observation. An additional advantage of the method is that it easily incorporates multiple mediators of a categorical, discrete or continuous nature. PMID- 23744518 TI - Effects of oxygen vacancy on the electronic structure and multiferroics in sol gel derived Pb(0.8)Co(0.2)TiO3 thin films. AB - The single phase Pb(0.8)Co(0.2)TiO3 thin films were synthesized on a Pt/Ti/SiO2/Si substrate by the sol-gel route. The present films exhibited homogeneous microstructure with low porosity. O 1s X-ray photoelectron spectroscopy (XPS) was used to detect the amount of oxygen vacancies. The ferroelectric measurements showed that the ferroelectricity deteriorates with the increase in the number of oxygen vacancies. X-ray absorption spectroscopy (XAS) and XPS were used to study the electronic structure. The results indicated that the decreased ferroelectricity might be ascribed to the weakened hybridization between O 2p and Pb 6s and Ti 3d orbitals. The ferromagnetic behaviors were also observed in the thin films and saturated magnetization raised monotonously with the oxygen vacancy rising due to the enhanced F-center exchange interaction. Magnetoelectric coupling of the films weakened with oxygen vacancy increase. PMID- 23744519 TI - Fluoroquinolones for treating tuberculosis (presumed drug-sensitive). AB - BACKGROUND: Currently the World Health Organization only recommend fluoroquinolones for people with presumed drug-sensitive tuberculosis (TB) who cannot take standard first-line drugs. However, use of fluoroquinolones could shorten the length of treatment and improve other outcomes in these people. This review summarises the effects of fluoroquinolones in first-line regimens in people with presumed drug-sensitive TB. OBJECTIVES: To assess fluoroquinolones as substitute or additional components in antituberculous drug regimens for drug sensitive TB. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; CENTRAL (The Cochrane Library 2013, Issue 1); MEDLINE; EMBASE; LILACS; Science Citation Index; Databases of Russian Publications; and metaRegister of Controlled Trials up to 6 March 2013. SELECTION CRITERIA: Randomized controlled trials (RCTs) of antituberculous regimens based on rifampicin and pyrazinamide and containing fluoroquinolones in people with presumed drug-sensitive pulmonary TB. DATA COLLECTION AND ANALYSIS: Two authors independently applied inclusion criteria, assessed the risk of bias in the trials, and extracted data. We used the risk ratio (RR) for dichotomous data and the fixed-effect model when it was appropriate to combine data and no heterogeneity was present. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We identified five RCTs (1330 participants) that met the inclusion criteria. None of the included trials examined regimens of less than six months duration. Fluoroquinolones added to standard regimensA single trial (174 participants) added levofloxacin to the standard first-line regimen. Relapse and treatment failure were not reported. For death, sputum conversion, and adverse events we are uncertain if there is an effect (one trial, 174 participants, very low quality evidence for all three outcomes). Fluoroquinolones substituted for ethambutol in standard regimens Three trials (723 participants) substituted ethambutol with moxifloxacin, gatifloxacin, and ofloxacin into the standard first-line regimen. For relapse, we are uncertain if there is an effect (one trial, 170 participants, very low quality evidence). No trials reported on treatment failure. For death, sputum culture conversion at eight weeks, or serious adverse events we do not know if there was an effect (three trials, 723 participants, very low quality evidence for all three outcomes). Fluoroquinolones substituted for isoniazid in standard regimens A single trial (433 participants) substituted moxifloxacin for isoniazid. Treatment failure and relapse were not reported. For death, sputum culture conversion, or serious adverse events the substitution may have little or no difference (one trial, 433 participants, low quality evidence for all three outcomes). Fluoroquinolines in four month regimensSix trials are currently in progress testing shorter regimens with fluoroquinolones. AUTHORS' CONCLUSIONS: Ofloxacin, levofloxacin, moxifloxacin, and gatifloxacin have been tested in RCTs of standard first-line regimens based on rifampicin and pyrazinamide for treating drug-sensitive TB. There is insufficient evidence to be clear whether addition or substitution of fluoroquinolones for ethambutol or isoniazid in the first-line regimen reduces death or relapse, or increases culture conversion at eight weeks. Much larger trials with fluoroquinolones in short course regimens of four months are currently in progress. PMID- 23744520 TI - Hepatitis C virus-related heat-insoluble cryoglobulinemia and thrombotic microangiopathy. AB - Heat-insoluble cryoglobulinemia is rare, and its pathogenesis and comorbidities remain poorly understood. Here, the authors report a case of hepatitis C virus (HCV)-related heat-insoluble cryoglobulinemia associated with thrombotic microangiopathy and cryoglobulin-occlusive membranoproliferative glomerulonephritis. The patient, a 57-year-old woman, presented with acute kidney injury, thrombocytopenia, anemia with schistocytes, high levels of serum HCV RNA of HCV genotype 2a, rheumatoid factor positivity and high levels of serum immunoglobulin (Ig) M and Igkappa. The patient's serum was positive for cryoglobulin at 4 degrees C, and the precipitate required heating to 47 degrees C for dissolution. Cryoglobulin immunofixation was positive for monoclonal IgM and Igkappa and polyclonal IgG. However, immunofixation of the cryoglobulin supernatant was negative. Histological examination of renal biopsy revealed a membranoproliferative type I glomerulonephritis. The patient was treated with plasmapheresis, corticosteroids and antiviral therapy of peginterferon plus ribavirin, but symptoms only partially resolved. PMID- 23744522 TI - Clear cell tumor of the lung: a retrospective analysis. AB - BACKGROUND: There have been no clinical reports on clear cell tumor of the lung (CCTL) based on large studies or epidemiological surveys in the literature. The purpose of this study was to provide a retrospective analysis of CCTL patients in China by reviewing the clinical data of reported CCTL cases. METHODS: The China academic journals full-text database search engines were used to collect the related cases from January 1979 to June 2011. The analysis was performed on patients' age, gender, symptom, nodular number, tumor size, lesion localization, chest radiograph or chest computed tomography. RESULTS: Thirty-nine cases of CCTL were reported in China. The ratio of male:female was 1.29:1. The average age at diagnosis was 43 +/- 17 years. Most of them were accidentally discovered on routine chest roentgenogram or computed tomography. The ratio of asymptomatic:symptomatic was 2.25:1 (27:12). Cough, fever, sputum, dyspnea and chest pain occurred frequently in symptomatic patients. Solitary pulmonary nodule on chest radiography was found in 38 patients, and no specific lobar distribution had been noted. The average tumor size was 3.6 +/- 2.4 cm in diameter. All patients were diagnosed after thoracotomy, and the postoperative courses were all uneventful. CONCLUSIONS: CCTL is a rare benign tumor with special features of clinical characteristics, radiology and pathology. The diagnosis is based on distinct pathological characteristics. Earlier operation with long-term follow-up is recommended. PMID- 23744523 TI - Sperm storage and sperm competition across ovarian cycles in the dragon lizard, Ctenophorus fordi. AB - Female sperm storage can influence male reproductive success and may favour males that produce sperm that remain viable across several ovarian cycles. Here we show that sperm are viable in the female reproductive tract across ovarian cycles in the mallee dragon, Ctenophorus fordi. Based on experimental mating trials, we show that stored sperm were generally less likely to fertilize eggs than recently inseminated sperm. The fertilization success of stored sperm increased with male body size relative to rivals. This may be due to differences in ejaculate volume or sperm number transferred by males of different sizes. However, there was no evidence that copulation time, which is correlated with ejaculate volume, contributed to fertilization success. We suggest that sperm storage across ovarian cycles may be common in small, multi-clutched lizards and that its impact on selection on male phenotypes could contribute to the evolution of lizard mating systems. PMID- 23744524 TI - How pharmaceutical industry employees manage competing commitments in the face of public criticism. AB - The pharmaceutical industry has been criticised for pervasive misconduct. These concerns have generally resulted in increasing regulation. While such regulation is no doubt necessary, it tends to assume that everyone working for pharmaceutical companies is equally motivated by commerce, without much understanding of the specific views and experiences of those who work in different parts of the industry. In order to gain a more nuanced picture of the work that goes on in the "medical affairs" departments of pharmaceutical companies, we conducted 15 semi-structured interviews with professionals working in medical departments of companies in Sydney, Australia. We show that this group of pharmaceutical professionals are committed to their responsibilities both to patients, research participants, and the public and to their companies. Despite the discrepancies between these commitments, our participants did not express much cognitive dissonance, and this appeared to stem from their use of two dialectically related strategies, one of which embraces commerce and the other of which resists the commercial imperative. We interpret these findings through the lens of institutional theory and consider their implications for pharmaceutical ethics and governance. PMID- 23744525 TI - It is not your fault: suggestions for building ethical capacity in individuals through structural reform to health care organisations : comment on "moral distress in uninsured health care" by Anita Nivens and Janet Buelow. PMID- 23744526 TI - Mammalian SOD2 is exclusively located in mitochondria and not present in peroxisomes. AB - Superoxide dismutases (SODs) are metalloenzymes that belong to the essential antioxidant enzyme systems of virtually all oxygen-respiring organisms. SODs catalyze the dismutation of highly reactive superoxide radicals into hydrogen peroxide and molecular oxygen. For the subcellular localization of the manganese superoxide dismutase (SOD2) in eukaryotic cells, a dual mitochondrial localization and peroxisomal localization were proposed in the literature. However, our own observation from immunofluorescence preparations of human and mouse tissues suggested that SOD2 serves as an excellent marker protein for mitochondria but never co-localized with peroxisomes. To clarify whether our observations were correct, we have carefully reinvestigated the subcellular localization of SOD2 using sensitive double-immunofluorescence methods on frozen and paraffin sections as well as in cell culture preparations. In addition, ultrastructural analyses were performed with post-embedding immunoelectron microscopy on LR White sections as well as labeling of ultrathin cryosections with various immunogold techniques. In all morphological experiments, the SOD2 localization was compared to one of the catalase, a typical marker protein for peroxisomes, solely localized in these organelles. Moreover, biochemical subcellular fractions of mouse liver was used to isolate enriched organelles and highly purified peroxisomal fractions for Western blot analyses of the exact subcellular distributions of SOD2 and catalase. All results with the various methodologies, tissues, and cell types used revealed that catalase and SOD2 were always confined to distinct and separate subcellular compartments. SOD2 was unequivocally in mitochondria, but never present in peroxisomes. Furthermore, our results are supported by accumulating database information on organelle proteomes that also indicate that SOD2 is a pure mitochondrial protein. PMID- 23744527 TI - From lamins to lamina: a structural perspective. AB - Lamin proteins are the major constituents of the nuclear lamina, a proteinaceous network that lines the inner nuclear membrane. Primarily, the nuclear lamina provides structural support for the nucleus and the nuclear envelope; however, lamins and their associated proteins are also involved in most of the nuclear processes, including DNA replication and repair, regulation of gene expression, and signaling. Mutations in human lamin A and associated proteins were found to cause a large number of diseases, termed 'laminopathies.' These diseases include muscular dystrophies, lipodystrophies, neuropathies, and premature aging syndromes. Despite the growing number of studies on lamins and their associated proteins, the molecular organization of lamins in health and disease is still elusive. Likewise, there is no comprehensive view how mutations in lamins result in a plethora of diseases, selectively affecting different tissues. Here, we discuss some of the structural aspects of lamins and the nuclear lamina organization, in light of recent results. PMID- 23744528 TI - In focus in Prague: intermediate filaments. PMID- 23744529 TI - Serum hepatitis B surface antigen kinetics in severe reactivation of hepatitis B e antigen negative chronic hepatitis B patients receiving nucleoside/nucleotide analogues. AB - BACKGROUND: Kinetics of serum hepatitis B surface antigen (HBsAg) level in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients presented with severe reactivation and received oral antiviral therapy is unknown. We aimed to investigate the kinetics of HBsAg level among these patients. METHODS: HBeAg negative patients on antiviral therapy with follow-up for 2 years were studied. Those presented with severe reactivation (alanine aminotransferase [ALT] >=5 times of normal) were compared to those with mild hepatitis. Serum HBsAg level was measured by Elecsys HBsAg II Quant assay (Roche) at baseline and 6-monthly. RESULTS: A total of 192 (74 severe reactivation) patients were studied. Eighty one (42%), 74 (39%) and 37 (19%) patients were on lamivudine, entecavir and telbivudine, respectively. Forty-four (23%) patients had early HBsAg decline, that is, >=0.5 log10 reduction, at month 6. Patients with severe reactivation had higher serum baseline ALT (1,415 +/-897 versus 73 +/-39 IU/l), HBV DNA (6.4 +/ 1.6 versus 5.2 +/-1.2 log10 IU/ml) and HBsAg (3.3 +/-1.0 versus 2.9 +/-0.6 log10 IU/ml), as well as an earlier HBsAg decline (50% versus 6%; all P<0.001) than those without. The HBsAg change of patients with severe reactivation was higher at months 0-6 (-0.58 +/--1.26 versus -0.01 +/--0.26 log10 IU/ml; P<0.001) but then became comparable from months 6-24 (-0.19 +/--0.60 versus -0.13 +/--0.19 log10 IU/ml; P=0.85), compared to those presented with mild hepatitis. CONCLUSIONS: Patients who presented with severe reactivation of HBeAg-negative hepatitis were more likely to develop early HBsAg decline during antiviral therapy. It may indicate a transient strong immune clearance with rapid initial reduction in serum HBsAg, which cannot be sustained due to a faster clearance of serum HBsAg. PMID- 23744530 TI - Fascia iliaca compartment block: its efficacy in pain control for patients with proximal femoral fracture. AB - BACKGROUND: Proximal femoral fractures are common in elderly patients. Recently, use of regional blockade has gained popularity as a means of relieving pain among this patient population. Among the procedures, fascia iliaca compartment block (FICB) is believed to be advantageous because of its safety and efficacy. METHODS: In this study fifty-six consecutive patients who sustained a proximal femoral fracture were assigned to two groups. For 31 patients in group 1, FICB was used to control pre and postoperative pain. FICB was performed by an orthopaedic resident on arrival of the patient at the hospital and in the immediate postoperative period. Systemic administration of non-steroidal anti inflammatory drugs (NSAIDs) alone was adopted for pain control for 25 patients in group 2. The severity of pain was assessed by use of a visual analog scale (VAS). RESULTS: Neither blockade-associated complications nor analgesic failure were encountered among patients who underwent FICB (group 1). In this group of patients, the mean preoperative VAS scores before FICB and at 10 min and 12 h after the blockade were 91, 31, and 36 respectively, indicating significant pain reduction. The corresponding values for group 2 patients were 92, 92, and 81. In addition, postoperative pain was also successfully managed by FICB with mean VAS scores at immediate, 6-h and 12-h time points of 15, 22, and 31 respectively, whereas the corresponding values for the group 2 patients were 62, 49, and 59. Consequently, significant differences in VAS scores were demonstrated between the groups in both the pre and postoperative periods. CONCLUSION: FICB is clinically safe and efficient, providing consistent analgesic effects irrespective of the performing doctor's experience of elderly patients with proximal femoral fracture. PMID- 23744531 TI - Bromocriptine modulates the expression of PTHrP receptor, Indian hedgehog, and Runx2 proteins in the growth plate of lactating rats. AB - In lactating rats, the endochondral bone growth is markedly enhanced, leading to the lengthening of long bone. This lactation-induced bone elongation could be abolished by a dopaminergic D2 receptor agonist bromocriptine, but how bromocriptine altered the expression of major chondroregulatory proteins in the growth plate cartilage was elusive. Here, we performed a quantitative immunohistochemical analysis to determine the expression of various peptides and transcription factors known to control the growth plate chondrocyte proliferation and differentiation [i.e., parathyroid hormone-related protein (PTHrP), PTHrP receptor, Indian hedgehog (Ihh), and runt-related transcription factor 2 (Runx2)], in bromocriptine-treated lactating rats. The results showed that bromocriptine markedly increased Ihh expression in hypertrophic chondrocytes during early and mid-lactation, while the expression of PTHrP receptor, but not its ligand PTHrP, was upregulated in the proliferative and hypertrophic zones during mid and late lactation. In contrast, the expression of Runx2, an important transcription factor for chondrocyte differentiation, was suppressed in the hypertrophic chondrocytes of bromocriptine-treated rats. In conclusion, bromocriptine increased Ihh and PTHrP receptor expressions and decreased Runx2 expression, which might, in turn, enhance chondrocyte proliferation and delay chondrocyte hypertrophy, thereby slowing down endochondral bone growth. This finding could explain how bromocriptine compromised the lactation-induced bone elongation. PMID- 23744532 TI - Expression of miR-126 suppresses migration and invasion of colon cancer cells by targeting CXCR4. AB - A previous study demonstrated that miR-126 expression was significantly downregulated in highly metastatic colon cancer cells. This study was to investigate the biological function of miR-126 and its regulation of target genes in colon cancer cells. Quantitative PCR was used to detect miR-126 expression in colon cancer SW480 and SW620 cells. MTT assay was to measure the changed cell viability after miR-126 mimics transfection. Wound healing and Transwell migration and invasion assays measured capacity of tumor cell migration and invasion of SW480 and SW620 cells after miR-126 transfection. Luciferase reporter assay and Western blot were used to assess both transcriptional and expression levels of one of the miR-126 target genes (i.e., CXCR4). Levels of miR-126 expression were lower in colon cancer SW480 and SW620 cells than in the adjacent normal epithelial tissues (P < 0.05). Transfection of miR-126 mimics significantly reduced colon cancer cell viability compared to NC cells (P < 0.05). The wound healing and Transwell migration and invasion assays showed that miR-126 mimics inhibited SW480 and SW620 cell migration and invasion capacity. Bioinformatics predicted that CXCR4 is one of the miR-126 target genes. Indeed, luciferase reporter assay and Western blot confirmed that CXCR4 is a miR-126 target gene. Expression of miR-126 inhibited colon cancer cell viability and reduced tumor cell migration and invasion capacity by its negative regulation of CXCR4 expression. PMID- 23744533 TI - Mechanism of mitotic arrest induced by dolastatin 15 involves loss of tension across kinetochore pairs. AB - Dolastatin 15 (DL15) is a potent, tubulin-targeted, vinca-site binding, anticancer agent that induces mitotic arrest and inhibit cell proliferation in a variety of cell types. Several analogs of DL15, including LU 103793 and tasidotin, have been progressed to clinical trials for different types of cancer. DL15 has been known to interfere with cellular microtubules and purified tubulin in vitro. However, the molecular mechanism with which the peptide arrests cells in mitosis is poorly understood. This study reports a possible antimitotic mechanism of action of DL15. DL15 inhibited HeLa cell proliferation in a concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 2.8 +/- 0.3 nM, induced mitotic arrest, disrupted cellular microtubules near its IC50 for cell proliferation, and inhibited the re-polymerization of cellular microtubules. By staining the centrosomes of DL15-treated cells with anti-gamma tubulin antibodies, the study found a significant reduction in interpolar distances in mitotic HeLa cells, indicating a disruption in the normal assembly dynamics of the microtubules. The study further found that DL15 induced a loss of tension across the kinetochore pairs as indicated by a reduction in interkinetochore distance. In response to this loss of tension, the tension sensing checkpoint protein BuBR1 accumulated at the kinetochores, promoting mitotic arrest. In vitro, DL15 promoted formation of curved and fragmented polymers of microtubule proteins and inhibited tubulin decay in a manner similar to vinca-site binding agents such as phomopsin A. Together, the data indicate that the mitotic arrest induced by DL15 involves a loss of tension across the kinetochore pairs due to disruption of normal assembly dynamics of microtubules. PMID- 23744534 TI - Emodin can induce K562 cells to erythroid differentiation and improve the expression of globin genes. AB - In China, the traditional Chinese medicine "YiSui ShenXu Granule" has been used for treating beta-thalassemia over 20 years and known to be effective in clinic. Several purified components from "YiSui ShenXu Granule" are tested in K562 cells to reveal its effect on globin expression and erythroid differentiation, and one of the purified components, emodin, was demonstrated to increase the expression of alpha-, epsilon-, gamma-globin, CD235a, and CD71 in K562 cells. Moreover, the increase of their expression is emodin concentration-dependent. The mRNA and microRNA (miRNA) expression profiles are further analyzed and 417 mRNAs and 35 miRNAs with differential expression between untreated and emodin-treated K562 cells were identified. Among them, two mRNAs that encode known positive regulators of erythropoiesis, ALAS2, and c-KIT respectively, increased during emodin-induced K562 erythroid differentiation, meanwhile, two negative regulators, miR-221 and miR-222, decreased during this process. These results indicate that emodin can improve the expression of globin genes in K562 cells and also induce K562 cells to erythroid differentiation possibly through up regulating ALAS2 and c-KIT and down-regulating miR-221 and miR-222. PMID- 23744535 TI - 'Bad apples': time to redefine as a type of systems problem? PMID- 23744536 TI - Reduction of unnecessary use of indwelling urinary catheters. AB - BACKGROUND: The most effective way to reduce catheter-associated urinary tract infections (CA-UTIs) is to avoid unnecessary urinary catheterisation and to minimise the duration of catheterisation. AIM: To implement and assess the effect of an intervention to reduce the duration of urinary tract catheterisation. METHODS: This quality improvement project was set up as a before-after comparison consisting of a 2-month pre-intervention period, a period in which the intervention was implemented and a 2-month post-intervention period. The intervention included educational sessions to increase physicians' awareness and the daily reassessment of catheter use. The primary endpoint was the duration of catheterisation. Secondary endpoints were the catheter utilisation ratio, the length of hospital stay, the number of hospital-acquired symptomatic CA-UTIs and the number of appropriate indications for catheterisation. RESULTS: During the total study period, 149 patients (18.3%) were catheterised at some time during their hospital stay. There was a statistically significant decrease in the duration of catheterisation (median 7 vs 5 days; p<0.01), length of hospital stay (median 13 vs 9 days; p<0.01), and number of hospital-acquired CA-UTIs (4 vs 0, p=0.04) in the pre-intervention versus post-intervention period. CONCLUSIONS: An intervention to raise more awareness of the risks of inappropriate catheterisation can reduce the duration of catheterisation along with the length of hospital stay and the number of hospital-acquired symptomatic CA- UTIs, even in a short period of time. PMID- 23744537 TI - Huddling for high reliability and situation awareness. AB - BACKGROUND: Studies show that implementing huddles in healthcare can improve a variety of outcomes. Yet little is known about the mechanisms through which huddles exert their effects. To help remedy this gap, our study objectives were to explore hospital administrator and frontline staff perspectives on the benefits and challenges of implementing a tiered huddle system; and propose a model based on our findings depicting the mediating pathways through which implementing a huddle system may reduce patient harm. METHODS: Using qualitative methods, we conducted semi-structured interviews and focus groups to obtain a deeper understanding of the huddle system and its outcomes as implemented in an academic tertiary care children's hospital with 539 inpatient beds. We recruited healthcare providers representing all levels using a snowball sampling technique (10 interviews), and emails, flyers, and paper invitations (six focus groups). We transcribed recordings and analysed the data using established techniques. RESULTS: Five themes emerged and provided the foundational constructs of our model. Specifically we propose that huddle implementation leads to improved efficiencies and quality of information sharing, increased levels of accountability, empowerment, and sense of community, which together create a culture of collaboration and collegiality that increases the staff's quality of collective awareness and enhanced capacity for eliminating patient harm. CONCLUSIONS: While each construct in the proposed model is itself a beneficial outcome of implementing huddles, conceptualising the pathways by which they may work allows us to design ways to evaluate other huddle implementation efforts designed to help reduce failures and eliminate patient harm. PMID- 23744538 TI - Liver iron modulates hepcidin expression during chronically elevated erythropoiesis in mice. AB - The liver-derived peptide hepcidin controls the balance between iron demand and iron supply. By inhibiting the iron export activity of ferroportin, hepcidin modulates iron absorption and delivery from the body's stores. The regulation of hepcidin, however, is not completely understood and includes a variety of different signals. We studied iron metabolism and hepcidin expression in mice constitutively overexpressing erythropoietin (Epo) (Tg6 mice), which leads to excessive erythropoiesis. We observed a very strong down-regulation of hepcidin in Tg6 mice that was accompanied by a strong increase in duodenal expression of ferroportin and divalent metal tranporter-1, as well as enhanced duodenal iron absorption. Despite these compensatory mechanisms, Tg6 mice displayed marked circulating iron deficiency and low levels of iron in liver, spleen, and muscle. To elucidate the primary signal affecting hepcidin expression during chronically elevated erythropoiesis, we increased iron availability by either providing iron (thus further increasing the hematocrit) or reducing erythropoiesis-dependent iron consumption by means of splenectomy. Both treatments increased liver iron and up-regulated hepcidin expression and the BMP6/SMAD pathway despite continuously high plasma Epo levels and sustained erythropoiesis. This suggests that hepcidin expression is not controlled by erythropoietic signals directly in this setting. Rather, these results indicate that iron consumption for erythropoiesis modulates liver iron content, and ultimately BMP6 and hepcidin. Analysis of the BMP6/SMAD pathway targets showed that inhibitor of DNA binding 1 (ID1) and SMAD7, but not transmembrane serine protease 6 (TMPRSS6), were up regulated by increased iron availability and thus may be involved in setting the upper limit of hepcidin. CONCLUSION: We provide evidence that under conditions of excessive and effective erythropoiesis, liver iron regulates hepcidin expression through the BMP6/SMAD pathway. PMID- 23744539 TI - Chinese herbal medicines for hypertriglyceridaemia. AB - BACKGROUND: Hypertriglyceridaemia is associated with many diseases including atherosclerosis, diabetes, hypertension and chylomicronaemia. Chinese herbal medicines have been used for a long time as lipid-lowering agents. OBJECTIVES: To assess the effects and safety of Chinese herbal medicines for hypertriglyceridaemia. SEARCH METHODS: We searched a number of databases including The Cochrane Library, MEDLINE, EMBASE and several Chinese databases (all until May 2012). SELECTION CRITERIA: Randomised controlled trials in participants with hypertriglyceridaemia comparing Chinese herbal medicines with placebo, no treatment, and pharmacological or non-pharmacological interventions. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the risk of bias. Any disagreement was resolved by discussion and a decision was achieved based on consensus. We assessed trials for risk of bias against key criteria: random sequence generation, allocation concealment, blinding of participants, incomplete outcome data, selective outcome reporting and other sources of bias. MAIN RESULTS: We included three randomised trials with 170 participants. Ninety participants were randomised to the Chinese herbal medicines groups and 80 to the comparator groups with numbers ranging from 50 to 60 participants per trial. The duration of treatment varied from four to six weeks. All the included trials were conducted in China and published in Chinese. Overall, the risk of bias of included trials was unclear. There were no outcome data in any of the trials on death from any cause, cardiovascular or cerebrovascular events, health-related quality of life, or costs.Three different herbal medicines, including Zhusuan Huoxue decoction, Huoxue Huayu Tongluo decoction, and Chushi Huayu decoction were evaluated. All three trials investigating Chinese herbal medicines treatment alone (two studies) or in combination with gemfibrozil (one study) reported results on serum triglyceride (TG) in favour of the herbal treatment. We did not perform a meta-analysis due to significant clinical heterogeneity between the studies.No relevant differences in adverse effects occurred and no serious adverse events were noted. AUTHORS' CONCLUSIONS: The present systematic review suggests that Chinese herbal medicines may have positive effects on hypertriglyceridaemia. The trials did not report serious adverse effects following Chinese herbal medicines treatment. However, based on an unclear risk of bias in included studies and lack of patient important long-term outcomes, no definite conclusion could be reached. PMID- 23744540 TI - Optimization of the design of extremely thin absorber solar cells based on electrodeposited ZnO nanowires. AB - The properties of the components of ZnO/CdSe/CuSCN extremely thin absorber (ETA) solar cells based on electrodeposited ZnO nanowires (NWs) were investigated. The goal was to study the influence of their morphology on the characteristics of the solar cells. To increase the energy conversion efficiency of the solar cell, it was generally proposed to increase the roughness factor of the ZnO NW arrays (i.e. to increase the NW length) with the purpose of decreasing the absorber thickness, improving the light scattering, and consequently the light absorption in the ZnO/CdSe NW arrays. However, this strategy increased the recombination centers, which affected the efficiency of the solar cell. We developed another strategy that acts on the optical configuration of the solar cells by increasing the diameter of the ZnO NW (from 100 to 330 nm) while maintaining a low roughness factor. We observed that the scattering of the ZnO NW arrays occurred over a large wavelength range and extended closer to the CdSe absorber bandgap, and this led to an enhancement in the effective absorption of the ZnO/CdSe NW arrays and an increase in the solar cell characteristics. We found that the thicknesses of CuSCN above the ZnO/CdSe NW tips and the CdSe coating layer were optimized at 1.5 MUm and 30 nm, respectively. Optimized ZnO/CdSe/CuSCN solar cells exhibiting 3.2% solar energy conversion efficiency were obtained by using 230 nm diameter ZnO NWs. PMID- 23744541 TI - A new estimation with minimum trace of asymptotic covariance matrix for incomplete longitudinal data with a surrogate process. AB - Missing data is a very common problem in medical and social studies, especially when data are collected longitudinally. It is a challenging problem to utilize observed data effectively. Many papers on missing data problems can be found in statistical literature. It is well known that the inverse weighted estimation is neither efficient nor robust. On the other hand, the doubly robust (DR) method can improve the efficiency and robustness. As is known, the DR estimation requires a missing data model (i.e., a model for the probability that data are observed) and a working regression model (i.e., a model for the outcome variable given covariates and surrogate variables). Because the DR estimating function has mean zero for any parameters in the working regression model when the missing data model is correctly specified, in this paper, we derive a formula for the estimator of the parameters of the working regression model that yields the optimally efficient estimator of the marginal mean model (the parameters of interest) when the missing data model is correctly specified. Furthermore, the proposed method also inherits the DR property. Simulation studies demonstrate the greater efficiency of the proposed method compared with the standard DR method. A longitudinal dementia data set is used for illustration. PMID- 23744542 TI - Regulation of E2F1 by the von Hippel-Lindau tumour suppressor protein predicts survival in renal cell cancer patients. AB - Biallelic mutations of the von Hippel-Lindau (VHL) gene are the most common cause of sporadic and inherited renal cell carcinoma (RCC). Loss of VHL has been reported to affect cell proliferation by deregulating cell cycle-associated proteins. We report that the VHL gene product (pVHL) inhibits E2F1 expression at both mRNA and protein level in zebrafish and human RCC cells, while loss of VHL increases E2F1 expression in patient kidney tumour tissue and RCC cells, resulting in a delay of cell cycle progression. RCCs from von Hippel-Lindau patients with known germline VHL mutations express significantly more E2F1 compared to sporadic RCCs with either clear-cell (cc) or non-cc histology. Analysis of 138 primary RCCs reveals that E2F1 expression is significantly higher in tumours with a diameter <=7 cm and with a favourable American Joint Committee on Cancer (AJCC) stage. The expression of E2F1 in RCC significantly correlates with p27 expression, suggesting that increased expression of E2F1 in RCC induces tumour cell senescence via p27. Cox regression analysis shows significant prediction of E2F1 expression for disease-free survival and overall survival, implying that E2F1 expression in kidney tumour is a novel prognostic factor for patients with RCC. PMID- 23744550 TI - Alpha-synuclein gene duplication: marked intrafamilial variability in two novel pedigrees. AB - BACKGROUND: Multiplications of the SNCA gene that encodes alpha-synuclein are a rare cause of autosomal dominant Parkinson's disease (PD). METHODS: Here, we describe 2 novel families in which there is autosomal dominant PD associated with SNCA duplication, and we compare the clinical features of all known patients carrying 3 or 4 SNCA copies. RESULTS: Affected members in family A presented with early onset PD that was variably associated with nonmotor features, such as dysautonomia, cognitive deficits, and psychiatric disturbances. In family B, the clinical presentation ranged from early onset PD-dementia with psychiatric disturbances to late onset PD with mild cognitive impairment. CONCLUSIONS: The presence of 4 SNCA copies is associated with a rich phenotype, characterized by earlier onset of motor and nonmotor features compared with patients who bear 3 SNCA copies. The clinical spectrum associated with SNCA duplications is wide, even within a single family, suggesting a role for as yet unidentified genetic or environmental modifiers. PMID- 23744551 TI - Contrast-enhanced ultrasound of liver lesions related to arterial thrombosis in adult liver transplantation. AB - PURPOSE: To describe the contrast-enhanced ultrasound (CEUS) features of liver and biliary lesions related to hepatic artery thrombosis in adult patients with orthotopic liver transplantation. METHODS: Gray-scale ultrasound (US), Doppler US, and CEUS using a hexafluoride-based US contrast media were performed on a series of eight patients with liver transplantation and hepatic artery thrombosis. RESULTS: Six of the cases presented infarctions, seen as parenchymal geographic areas of lack of enhancement. Biliary necrosis, seen as nonenhancing periportal cuff, was seen in one case. Infected biloma, seen as a nonenhancing hilar collection, was present in two cases. Infarction and biloma coexisted in one patient. Two abscesses were seen as a late complication in one case. One of them was seen as a typical necrotic abscess with a central nonenhancing area and peripheral rim enhancement higher than the surrounding liver. The other one was seen as a partially liquefied abscess. CONCLUSION: CEUS was useful to diagnose lesions related to hepatic artery thrombosis in liver transplantation. It enabled distinguishing between them and to define their size and extension better than conventional gray-scale US. PMID- 23744552 TI - Anticonvulsants for preventing seizures in patients with chronic subdural haematoma. AB - BACKGROUND: Anticonvulsant therapy is sometimes used prophylactically in patients with chronic subdural haematoma, although the benefit is unclear. OBJECTIVES: To assess the effects of prophylactic anticonvulsants in patients with chronic subdural haematoma, in both the pre- and post-operative periods. SEARCH METHODS: We searched the Cochrane Injuries Group's Specialised Register, CENTRAL (The Cochrane Library), MEDLINE (OvidSP), EMBASE (OvidSP), PubMed, LILACS, and the databases clinicaltrials.gov, the WHO International Clinical Trials Registry Platform, and Current Controlled Trials. The search was through 27th March 2013. SELECTION CRITERIA: Randomised controlled trials comparing any anticonvulsant versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: Three authors screened the search results to identify relevant studies. No studies met the inclusion criteria for the review. MAIN RESULTS: No randomised controlled trials were identified. AUTHORS' CONCLUSIONS: No formal recommendations can be made about the use of prophylactic anticonvulsants in patients with chronic subdural haematoma based on the literature currently available. There are no randomised controlled trials on this topic, and non-controlled studies have conflicting results. There is an urgent need for well-designed randomised controlled trials. PMID- 23744553 TI - Oxidative DNA damage in Barrett mucosa: correlation with telomeric dysfunction and p53 mutation. AB - BACKGROUND: Barrett esophagus develops in a scenario of chronic inflammation, linked to free radical formation and oxidative DNA damage. Eight hydroxydeoxyguanosine, the main oxidative DNA adduct, is partially repaired by a glycosylase (OGG1) whose polymorphism is associated to a reduced repair capacity. Telomeres are particularly prone to oxidative damage, which leads to shortening and cell senescence, while elongation, by telomerase activity, is linked to cell immortalization and cancer. Limited data are available on this point with respect to Barrett esophagus. This study aimed to evaluate the link among 8 hydroxydeoxyguanosine, OGG1 polymorphism, telomerase activity, telomere length, and p53 mutation in Barrett progression. METHODS: Forty consecutive patients with short- and long-segment Barrett esophagus and 20 controls with gastroesophageal reflux disease without Barrett esophagus were recruited. Analysis of biopsy samples was undertaken to study 8-hydroxydeoxyguanosine levels, OGG1 polymorphism, telomerase activity, and telomere length. Serum samples were obtained for p53 mutation. RESULTS: Controls had significantly lower levels of 8 hydroxydeoxyguanosine and telomerase activity, with normal telomere length and no p53 mutation. In short-segment Barrett esophagus, 8-hydroxydeoxyguanosine levels were higher and telomeres underwent significant shortening, with stimulation of telomerase activity but no p53 mutations. In long-segment Barrett esophagus, 8 hydroxydeoxyguanosine reached maximal levels, with telomere elongation, and 42 % of the patients showed p53 mutation. CONCLUSIONS: In Barrett patients, with disease progression, oxidative DNA damage accumulates, causing telomere instability, telomerase activation, and, in a late phase, mutations in the p53 gene, thus abrogating its activity as the checkpoint of proliferation and apoptosis, and facilitating progression to cancer. PMID- 23744554 TI - Aspirin in the secondary prevention of unprovoked thromboembolism: the WARFASA and ASPIRE studies. PMID- 23744555 TI - Effects of growth hormone (GH) transgene and nutrition on growth and bone development in common carp. AB - Limited information is available on effects of growth hormone transgene and nutrition on growth and development of aquatic animals. Here, we present a study to test these effects with growth-enhanced transgenic common carp under two nutritional conditions or feeding rations (i.e., 5% and 10% of fish body weight per day). Compared with the nontransgenic fish, the growth rates of the transgenic fish increased significantly in both feeding rations. The shape of the pharyngeal bone was similar among treatments, but the transgenic fish had relatively smaller and lighter pharyngeal bone compared with the nontransgenic fish. Calcium content of the pharyngeal bone of the transgenic fish was significantly lower than that of the nontransgenic fish. Feeding ration also affected growth rate but less of an effect on bone development. By manipulating intrinsic growth and controlling for both environment (e.g., feeding ration) and genetic background or genotype (e.g., transgenic or not), this study provides empirical evidence that the genotype has a stronger effect than the environment on pharyngeal bone development. The pharyngeal bone strength could be reduced by decreased calcium content and calcification in the transgenic carp. PMID- 23744556 TI - Assessing physiological tipping point of sea urchin larvae exposed to a broad range of pH. AB - Our ability to project the impact of global change on marine ecosystem is limited by our poor understanding on how to predict species sensitivity. For example, the impact of ocean acidification is highly species-specific, even in closely related taxa. The aim of this study was to test the hypothesis that the tolerance range of a given species to decreased pH corresponds to their natural range of exposure. Larvae of the green sea urchin Strongylocentrotus droebachiensis were cultured from fertilization to metamorphic competence (29 days) under a wide range of pH (from pHT = 8.0/pCO2 ~ 480 MUatm to pHT = 6.5/pCO2 ~ 20 000 MUatm) covering present (from pHT 8.7 to 7.6), projected near-future variability (from pHT 8.3 to 7.2) and beyond. Decreasing pH impacted all tested parameters (mortality, symmetry, growth, morphometry and respiration). Development of normal, although showing morphological plasticity, swimming larvae was possible as low as pHT >= 7.0. Within that range, decreasing pH increased mortality and asymmetry and decreased body length (BL) growth rate. Larvae raised at lowered pH and with similar BL had shorter arms and a wider body. Relative to a given BL, respiration rates and stomach volume both increased with decreasing pH suggesting changes in energy budget. At the lowest pHs (pHT <= 6.5), all the tested parameters were strongly negatively affected and no larva survived past 13 days post fertilization. In conclusion, sea urchin larvae appeared to be highly plastic when exposed to decreased pH until a physiological tipping point at pHT = 7.0. However, this plasticity was associated with direct (increased mortality) and indirect (decreased growth) consequences for fitness. PMID- 23744557 TI - Interaction of CCN1 with alphavbeta3 integrin induces P-glycoprotein and confers vinblastine resistance in renal cell carcinoma cells. AB - Renal cell carcinoma (RCC) ranks among the most chemoresistant tumors, and P glycoprotein (P-gp) predominates multidrug resistance mechanisms by reducing the accumulation of intracellular chemotherapy drugs such as vinblastine (VBL), which is considered the most effective chemotherapeutic agent for this neoplasia. Unfortunately, the mechanism by which the expression of P-gp is regulated and the ways to inhibit the function of P-gp are poorly understood. Our study was carried out to determine the possible role of CCN1 in P-pg-mediated drug resistance on the basis of the validated function of CCN1, an extracellular matrix protein, in promoting chemoresistance. As expected, CCN1 was overexpressed in VBL-resistant cell lines (ACHN/VBL, A498/VBL, Caki-1/VBL, and Caki-2/VBL) as measured by enzyme linked immunosorbent assay. We then transfected non-VBL-resistant cell lines with Ad-CCN1 and observed that the IC50 of VBL increased by about 3-5 times. Furthermore, both CCN1 antibody neutralization and alphavbeta3 integrin antibody blockade decreased the IC50 of VBL, which showed that CCN1 and alphavbeta3 are associated with resistance to VBL in RCC. Simultaneously, the enhanced expression of CCN1 triggered the intracellular PI3K/Akt pathway by binding alphavbeta3 integrin, as shown by western blot. P-gp expression was augmented in response to activation of the PI3K/Akt pathway, which could be modified by PI3K inhibitor LY294002 or multidrug resistance siRNA transfection. Therefore, targeted restraint of CCN1 or alphavbeta3 integrin in combination with the administration of VBL may be beneficial in the treatment of primary and metastatic RCC. PMID- 23744558 TI - Inhibition of angiogenesis: a novel antitumor mechanism of the herbal compound arctigenin. AB - Arctigenin, a functional ingredient of several traditional Chinese herbs, has been reported to have potential antitumor activity. However, its mechanisms of action are still not well elucidated. Because the establishment and metastatic spread of tumors is crucially dependent on angiogenesis, here we investigated whether arctigenin inhibits tumor growth by disturbing blood vessel formation. For this purpose, human dermal microvascular endothelial cells were exposed to different arctigenin doses to study their viability, proliferation, protein expression, migration, and tube formation compared with vehicle-treated controls. In addition, arctigenin action on vascular sprouting was analyzed in an aortic ring assay. Furthermore, we studied direct arctigenin effects on CT26.WT colon carcinoma cells. Spheroids of these tumor cells were transplanted into the dorsal skinfold chamber of arctigenin-treated and vehicle-treated BALB/c mice for the in vivo analysis of tumor vascularization and growth by intravital fluorescence microscopy, histology, and immunohistochemistry. We found that noncytotoxic doses of arctigenin dose dependently reduced the proliferation of human dermal microvascular endothelial cells without affecting their migratory and tube forming capacity. Arctigenin treatment also resulted in a decreased cellular expression of phosphorylated serine/threonine protein kinase AKT, vascular endothelial growth factor receptor 2, and proliferating cell nuclear antigen and inhibited vascular sprouting from aortic rings. In addition, proliferation, but not secretion of vascular endothelial growth factor, was decreased in arctigenin treated tumor cells. Finally, arctigenin suppressed the vascularization and growth of engrafting CT26.WT tumors in the dorsal skinfold chamber model. Taken together, these results show for the first time an antiangiogenic action of arctigenin, which may contribute considerably toward its antitumor activity. PMID- 23744559 TI - Reduced Toll-like receptor 3 expression in chronic hepatitis B patients and its restoration by interferon therapy. AB - BACKGROUND: Toll-like receptor (TLR)3 gene variants may correlate with clinical significance of chronic viral infections including HBV. We aimed to investigate the expression of TLR3 in peripheral blood mononuclear cells (PBMCs) and liver cells of chronic hepatitis B (CHB) patients and its response to pegylated interferon or nucleoside analogue therapy. METHODS: We consecutively enrolled 127 CHB patients and 64 hepatitis B surface antigen-negative, anti-HCV-negative healthy individuals as controls. We compared the TLR3 expressions on fresh PBMCs and liver cells from patients and controls, before and during pegylated interferon or nucleoside analogue therapy. RESULTS: Compared to controls, patients had a lower TLR3 mean fluorescence intensity (MFI) on PBMCs (mean +/- sd 14.61 +/- 13.49 versus 9.70 +/- 4.61; P < 0.001), independent of age, gender and alanine aminotransferase (ALT; -13.466, 95% CI -17.202, -9.730; P < 0.001). Patients had limited TLR3 stains on Kupffer cells, whereas controls had diffuse stains on Kupffer and hepatocytes. Hepatic TLR3 messenger RNA was lower in patients than controls (0.47 +/- 0.30 versus 1-fold). Using pretreatment TLR3 MFI as a referent, among 5 of 12 pegylated-interferon-treated patients with sustained virological response (SVR), TLR3 MFI was restored to a mean of 1.5- to 1.7-folds immediately after treatment. Among seven non-responders or relapsers, TLR3 MFI reduced to a mean of 0.5- to 0.7-fold. Among 10 entecavir-treated patients with on-treatment virological response, TLR3 MFI gradually was restored to a mean of 1.2-folds during 48-week therapy. CONCLUSIONS: CHB patients have reduced TLR3 expression on PBMCs, independent of age, gender and ALT, and on liver cells. Patients with pegylated-interferon-induced SVR have a more significant restoration of TLR3 expression than those under entecavir. PMID- 23744560 TI - Hormone replacement therapy for women with type 1 diabetes mellitus. AB - BACKGROUND: There is conflicting information about the impact of the menopause on glycaemic control amongst women with type 1 diabetes. Some menopausal women with type 1 diabetes are treated with hormone replacement therapy (HRT) but the effects of this treatment have, to date, not been established. OBJECTIVES: To assess the effects of HRT for women with type 1 diabetes mellitus. SEARCH METHODS: We searched The Cochrane Library, MEDLINE, EMBASE, CINAHL and PsycINFO from their inception to June 2012. The last search was run for all databases on 18 June 2012. SELECTION CRITERIA: We selected randomised controlled trials or controlled clinical trials that involved peri- or postmenopausal women with type 1 diabetes undergoing HRT as an intervention. DATA COLLECTION AND ANALYSIS: Two researchers independently applied the inclusion criteria to the identified studies and assessed risk of bias. Disagreements were resolved by discussion or by intervention by a third party. Descriptive analysis was conducted for the review. MAIN RESULTS: Ninety-two publications were screened. No studies met the inclusion criteria exclusively but one study that included both type 1 and type 2 diabetes participants was considered. This randomised clinical trial (RCT) compared HRT (N = 27) with placebo (N = 29) over 12 months. The outcome measures were cardiovascular risk factors, including lipid profile, glycaemic control, blood pressure and body weight. No significant differences between placebo and HTR were detected. Patient-important outcomes like all-cause mortality, cardiovascular disease, diabetic complications or health-related quality of life were not investigated. AUTHORS' CONCLUSIONS: There is a lack of evidence around the use of HRT in women with type 1 diabetes. The one study that has been undertaken in this area is underpowered. More RCTs are required in the area to examine the impact of HRT on glycaemic control and cardiovascular outcomes. PMID- 23744561 TI - Immunomodulators and immunosuppressants for multiple sclerosis: a network meta analysis. AB - BACKGROUND: Different therapeutic strategies are available for treatment of multiple sclerosis (MS) including immunosuppressants, immunomodulators, and monoclonal antibodies. Their relative effectiveness in the prevention of relapse or disability progression is unclear due to the limited number of direct comparison trials. A summary of the results, including both direct and indirect comparisons of treatment effects, may help to clarify the above uncertainty. OBJECTIVES: To estimate the relative efficacy and acceptability of interferon beta-1b (IFNbeta-1b) (Betaseron), interferon beta-1a (IFNbeta-1a) (Rebif and Avonex), glatiramer acetate, natalizumab, mitoxantrone, methotrexate, cyclophosphamide, azathioprine, intravenous immunoglobulins, and long-term corticosteroids versus placebo or another active agent in participants with MS and to provide a ranking of the treatments according to their effectiveness and risk-benefit balance. SEARCH METHODS: We searched the Cochrane Database of Systematic Reviews, the Cochrane MS Group Trials Register, and the Food and Drug Administration (FDA) reports. The most recent search was run in February 2012. SELECTION CRITERIA: Randomized controlled trials (RCTs) that studied one of the 11 treatments for use in adults with MS and that reported our pre-specified efficacy outcomes were considered for inclusion. DATA COLLECTION AND ANALYSIS: Identifying search results and data extraction were performed independently by two authors. Data synthesis was performed by pairwise meta-analysis and network meta-analysis that was performed within a Bayesian framework. The body of evidence for outcomes within the pairwise meta-analysis was assessed according to GRADE, as very low, low, moderate, or high quality. MAIN RESULTS: Forty-four trials were included in this review, in which 17,401 participants had been randomised. Twenty-three trials included relapsing-remitting MS (RRMS) (9096 participants, 52%), 18 trials included progressive MS (7726, 44%), and three trials included both RRMS and progressive MS (579, 3%). The majority of the included trials were short-term studies, with the median duration being 24 months. The results originated mostly from 33 trials on IFNbeta, glatiramer acetate, and natalizumab that overall contributed outcome data for 9881 participants (66%).From the pairwise meta-analysis, there was high quality evidence that natalizumab and IFNbeta-1a (Rebif) were effective against recurrence of relapses in RRMS during the first 24 months of treatment compared to placebo (odds ratio (OR) 0.32, 95% confidence interval (CI) 0.24 to 0.43; OR 0.45, 95% CI 0.28 to 0.71, respectively); they were more effective than IFNbeta 1a (Avonex) (OR 0.28, 95% CI 0.22 to 0.36; OR 0.19, 95% CI 0.06 to 0.60, respectively). IFNbeta-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having clinical relapses compared to placebo (OR 0.55, 95% CI 0.31 to 0.99; OR 0.15, 95% CI 0.04 to 0.54, respectively) but the quality of evidence for these treatments was graded as moderate. From the network meta-analysis, the most effective drug appeared to be natalizumab (median OR versus placebo 0.29, 95% credible intervals (CrI) 0.17 to 0.51), followed by IFNbeta-1a (Rebif) (median OR versus placebo 0.44, 95% CrI 0.24 to 0.70), mitoxantrone (median OR versus placebo 0.43, 95% CrI 0.20 to 0.87), glatiramer acetate (median OR versus placebo 0.48, 95% CrI 0.38 to 0.75), IFNbeta-1b (Betaseron) (median OR versus placebo 0.48, 95% CrI 0.29 to 0.78). However, our confidence was moderate for direct comparison of mitoxantrone and IFNB-1b vs placebo and very low for direct comparison of glatiramer vs placebo. The relapse outcome for RRMS at three years' follow-up was not reported by any of the included trials.Disability progression was based on surrogate markers in the majority of included studies and was unavailable for RRMS beyond two to three years. The pairwise meta-analysis suggested, with moderate quality evidence, that natalizumab and IFNbeta-1a (Rebif) probably decreased the odds of the participants with RRMS having disability progression at two years' follow-up, with an absolute reduction of 14% and 10%, respectively, compared to placebo. Natalizumab and IFNbeta-1b (Betaseron) were significantly more effective (OR 0.62, 95% CI 0.49 to 0.78; OR 0.35, 95% CI 0.17 to 0.70, respectively) than IFNbeta-1a (Avonex) in reducing the number of the participants with RRMS who had progression at two years' follow-up, and confidence in this result was graded as moderate. From the network meta-analyses, mitoxantrone appeared to be the most effective agent in decreasing the odds of the participants with RRMS having progression at two years' follow-up, but our confidence was very low for direct comparison of mitoxantrone vs placebo. Both pairwise and network meta-analysis revealed that none of the individual agents included in this review were effective in preventing disability progression over two or three years in patients with progressive MS.There was not a dose-effect relationship for any of the included treatments with the exception of mitoxantrone. AUTHORS' CONCLUSIONS: Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNbeta-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNbeta-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNbeta-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNbeta-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNbeta-1a (Rebif) or between azathioprine and IFNbeta-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory. PMID- 23744562 TI - Isoflavones for hypercholesterolaemia in adults. AB - BACKGROUND: Hypercholesterolaemia is a significant risk factor for cardiovascular diseases. Isoflavones may be effective in improving hypercholesterolaemia. OBJECTIVES: To assess the effects of isoflavones for hypercholesterolaemia. SEARCH METHODS: We searched the following databases: The Cochrane Library (Issue 9, 2012), MEDLINE, EMBASE, Chinese BioMedical Database and China National Knowledge Infrastructure (all to September 2012). SELECTION CRITERIA: We considered randomized controlled clinical trials in hypercholesterolaemic participants comparing isoflavones versus placebo, or soy isolated protein added with isoflavones versus soy isolated protein alone. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted relevant population and intervention characteristics. We resolved any disagreements through discussion, or if required by a third party. We assessed the risk of bias of trials against key criteria: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias. MAIN RESULTS: We included five randomized trials (208 participants, 104 in the intervention group and 104 in the control group). Interventions ranged from three to six months. Four trials reported results in non-Asian populations published in English. One trial reported results in Chinese people published in Chinese. Overall, the risk of bias of included trials was high or unclear. There were no outcome data on death from any cause, morbidity, complications, health-related quality of life and costs. Two trials reported adverse effects, including gastrointestinal discomfort (bloating and constipation) and an increased number of hot flushes. None of the trials found serious adverse events. There was a slight significant effect on triglycerides in favour of isoflavones when compared with placebo (mean difference (MD) -0.46 mmol/L (95% confidence interval (CI) -0.84 to -0.09; P = 0.02; 52 participants; 2 trials). No statistically significant effects on total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol were shown in favour of isoflavones. AUTHORS' CONCLUSIONS: We found no evidence for effects of isoflavones on patient-important outcomes or lowering of cholesterol levels in people with hypercholesterolaemia. Our findings have to be interpreted with caution due to high or unclear risk of bias in several risk of bias domains, and low number of participants in trials. PMID- 23744563 TI - Selenium supplementation for Hashimoto's thyroiditis. AB - BACKGROUND: Hashimoto's thyroiditis is a common auto-immune disorder. The most common presenting symptoms may include anxiety, negative mood, depression, dry skin, cold intolerance, puffy eyes, muscle cramps and fatigue, deep voice, constipation, slow thinking and poor memory. Clinical manifestations of the disease are defined primarily by low levels of thyroid hormones; therefore it is treated by hormone replacement therapy, which usually consists of levothyroxine (LT4). Selenium might reduce antibody levels and result in a decreased dosage of LT4 and may provide other beneficial effects (e.g. on mood and health-related quality of life). OBJECTIVES: To assess the effects of selenium supplementation on Hashimoto's thyroiditis. SEARCH METHODS: We searched the following databases up to 2 October 2012: CENTRAL in The Cochrane Library (2012, Issue 10), MEDLINE, EMBASE, and Web of Science; we also screened reference lists of included studies and searched several online trial registries for ongoing trials (5 November 2012). SELECTION CRITERIA: Randomised controlled clinical trials that assessed the effects of selenium supplementation for adults diagnosed with Hashimoto's thyroiditis. DATA COLLECTION AND ANALYSIS: Study selection, data extraction, assessment of risk of bias, and analyses were carried out by two independent review authors. We assessed the quality of the evidence of included studies using GRADE. We were unable to conduct a meta-analysis because clinical heterogeneity between interventions that were investigated is substantial. MAIN RESULTS: Four studies at unclear to high risk of bias comprising 463 participants were included. The mean study duration was 7.5 months (range 3 to 18 months). One of our primary outcomes-'change from baseline in health related quality of life'-and two of our secondary outcomes-'change from baseline in LT4 replacement dosage at end of the study' and 'economic costs'-were not assessed in any of the studies. One study at high risk of bias showed statistically significant improvement in subjective well-being with sodium selenite 200 MUg plus titrated LT4 compared with placebo plus titrated LT4 (relative risk (RR) 4.67, 95% confidence interval (CI) 1.61 to 13.50; P = 0.004; 36 participants; number needed to treat (NNT) = 2 (95% CI 2 to 3)).Selenomethionine 200 MUg reduced the serum levels of anti thyroid peroxidase antibodies compared with placebo in two studies (mean difference (MD) -917 U/mL, 95% CI -1056 to -778; P < 0.001; 85 participants) and (MD -345 IU/mL, 95% CI -359 to -331; P < 0.001; 169 participants). Pooling of the studies was not feasible due to marked clinical heterogeneity (I(2) = 99%). In a further comparison within the first study where selenomethionine was combined with LT4 the reduction in TPO antibodies was even more noticeable (MD -1508 U/mL, 95% CI -1671 to -1345; P < 0.001; 86 participants). In a third study, where LT4 was added to both intervention arms, a reduction in serum levels of anti-thyroid peroxidase antibodies favoured the selenomethionine arm as well (MD -235 IU/mL, 95% CI -374 to -95; P = 0.001; 88 participants). Although the changes from baseline were statistically significant in these three studies, their clinical relevance is unclear. Serum antibodies were not statistically significantly affected in the study comparing sodium selenite 200 MUg plus titrated LT4 with placebo plus titrated LT4 (MD -25, 95% CI -181 to 131; P = 0.75; 36 participants).Adverse events were reported in two studies (1 of 85 and 1 of 88 participants, respectively). Selenium supplementation did not appear to have a statistically significant impact on the incidence of adverse events (RR 2.93, 95% CI 0.12 to 70.00; and RR 2.63, 95% CI 0.11 to 62.95). AUTHORS' CONCLUSIONS: Results of these four studies show that evidence to support or refute the efficacy of selenium supplementation in people with Hashimoto's thyroiditis is incomplete. The current level of evidence for the efficacy of selenium supplementation in the management of people with Hashimoto's thyroiditis is based on four randomised controlled trials assessed at unclear to high risk of bias; this does not at present allow confident decision making about the use of selenium supplementation for Hashimoto's thyroiditis. This review highlights the need for randomised placebo-controlled trials to evaluate the effects of selenium in people with Hashimoto's thyroiditis and can ultimately provide reliable evidence to help inform clinical decision making. PMID- 23744564 TI - In Brief: Chromothripsis and cancer. AB - Chromothripsis is a one-step catastrophic event which plays an important role during cancer development. During chromothripsis, tens to hundreds of genomic rearrangements can occur within localized regions of the genome, and lead to the simultaneous creation of multiple cancer-driving aberrations. Given that chromothripsis has a cancer-wide incidence of 2-3%, its recent discovery has significant implications for our understanding of tumour biology and evolution. PMID- 23744565 TI - Homeostatic generation of reactive oxygen species protects the zebrafish liver from steatosis. AB - Nonalcoholic fatty liver disease is the most common liver disease in both adults and children. The earliest stage of this disease is hepatic steatosis, in which triglycerides are deposited as cytoplasmic lipid droplets in hepatocytes. Through a forward genetic approach in zebrafish, we found that guanosine monophosphate (GMP) synthetase mutant larvae develop hepatic steatosis. We further demonstrate that activity of the small GTPase Rac1 and Rac1-mediated production of reactive oxygen species (ROS) are down-regulated in GMP synthetase mutant larvae. Inhibition of Rac1 activity or ROS production in wild-type larvae by small molecule inhibitors was sufficient to induce hepatic steatosis. More conclusively, treating larvae with hydrogen peroxide, a diffusible ROS that has been implicated as a signaling molecule, alleviated hepatic steatosis in both GMP synthetase mutant and Rac1 inhibitor-treated larvae, indicating that homeostatic production of ROS is required to prevent hepatic steatosis. We further found that ROS positively regulate the expression of the triglyceride hydrolase gene, which is responsible for the mobilization of stored triglycerides in hepatocytes. Consistently, inhibition of triglyceride hydrolase activity in wild-type larvae by a small molecule inhibitor was sufficient to induce hepatic steatosis. CONCLUSION: De novo GMP synthesis influences the activation of the small GTPase Rac1, which controls hepatic lipid dynamics through ROS-mediated regulation of triglyceride hydrolase expression in hepatocytes. PMID- 23744567 TI - Honor killing attitudes amongst adolescents in Amman, Jordan. AB - The present study examines attitudes towards honor crimes amongst a sample of 856 ninth grade students (mean age = 14.6, SD = 0.56) from 14 schools in Amman, Jordan. Descriptive findings suggest that about 40% of boys and 20% of girls believe that killing a daughter, sister, or wife who has dishonored the family can be justified. A number of theoretically meaningful predictors were examined: Findings suggest that attitudes in support of honor killings are more likely amongst adolescents who have collectivist and patriarchal world views, believe in the importance of female chastity amongst adolescents, and morally neutralize aggressive behavior in general. Findings for parental harsh discipline are mixed: While the father's harsh discipline is predictive of honor killing attitudes, the mother's behavior is not. Furthermore, support for honor killing is stronger amongst male adolescents and adolescents for low education backgrounds. After controlling for other factors religion and the intensity of religious beliefs are not associated with support for honor killings. Models were tested separately for male and female respondents and suggested no systematic differences in predictors. Limitations and implications are discussed. PMID- 23744568 TI - Lack of polysomnographic Non-REM sleep changes in early Parkinson's disease. AB - BACKGROUND: Polysomnography (PSG) data are rare in patients who have early stage idiopathic Parkinson's disease (IPD). METHODS: Thirty-three patients who had IPD with a disease duration <= 3 years and 37 age-matched controls were recruited. PSG analysis was performed on current medication. RESULTS: Patients with IPD had a reduced mean percentage of muscle atonia during rapid eye movement (REM) sleep (80% vs 93%; P < 0.05). Total sleep time, sleep efficiency, indices/hour of arousals, awakenings, apnea/hypopnea, and periodic leg movements were similar in both groups. Age, but not dopaminergic medication, had a negative impact on sleep architecture in patients with IPD. There was no correlation between sleep efficiency assessed by PSG and sleep quality assessed by questionnaire. CONCLUSIONS: The results confirmed a reduction in muscle atonia during REM sleep as a characteristic finding in early IPD. However, there were no further disease inherent or medication-induced changes in sleep architecture. Although sleep disturbances are considered to be an integral part of IPD, PSG cannot yet identify them objectively at an early stage. PMID- 23744569 TI - MR compatible positioning device for guiding a focused ultrasound system for the treatment of brain deseases. AB - BACKGROUND: A prototype magnetic resonance imaging (MRI)-compatible positioning device that navigates a high intensity focused ultrasound (HIFU) transducer is presented. The positioning device has three user-controlled degrees of freedom that allow access to brain targets using a lateral coupling approach. The positioning device can be used for the treatment of brain cancer (thermal mode ultrasound) or ischemic stroke (mechanical mode ultrasound). MATERIALS AND METHODS: The positioning device incorporates only MRI compatible materials such as piezoelectric motors, ABS plastic, brass screws, and brass rack and pinion. RESULT: The robot has the ability to accurately move the transducer thus creating overlapping lesions in rabbit brain in vivo. The registration and repeatability of the system was evaluated using tissues in vitro and gel phantom and was also tested in vivo in the brain of a rabbit. CONCLUSION: A simple, cost effective, portable positioning device has been developed which can be used in virtually any clinical MRI scanner since it can be placed on the table of the MRI scanner. This system can be used to treat in the future patients with brain cancer and ischemic stroke. PMID- 23744570 TI - Leishmaniasis: clinical syndromes and treatment. AB - Leishmaniasis is a global term for cutaneous and visceral anthroponotic and zoonotic diseases caused by the vector-borne parasites of the genus Leishmania. These diseases afflict at least 2 million people each year with more than 350 million at risk in 98 countries worldwide. These are diseases mostly of the impoverished making prevention, diagnosis and treatment difficult. Therapy of leishmaniasis ranges from local treatment of cutaneous lesions to systemic, often toxic, therapy for disseminated cutaneous, mucocutaneous and deadly visceral disease. This review is a summary of the clinical syndromes caused by Leishmania and treatment regimens currently used for various forms of leishmaniasis. PMID- 23744571 TI - Safety of intravenous thrombolysis for ischemic stroke in patients treated with warfarin. AB - OBJECTIVE: Controversy surrounds the safety of intravenous (IV) tissue plasminogen activator (tPA) in ischemic stroke patients treated with warfarin. The European tPA license precludes its use in anticoagulated patients altogether. American guidelines accept IV tPA use with an international normalized ratio (INR) <= 1.7. The influence of warfarin on symptomatic intracerebral hemorrhage (SICH), arterial recanalization, and long-term functional outcome in stroke thrombolysis remains unclear. METHODS: We analyzed data from 45,074 patients treated with IV tPA enrolled in the Safe Implementation of Thrombolysis in Stroke (SITS) International Stroke Thrombolysis Register. A total of 768 patients had baseline warfarin treatment with INR <= 1.7. Outcome measures were SICH, arterial recanalization, mortality, and functional independence at 3 months. RESULTS: Patients on warfarin with INR <= 1.7 were older, had more comorbidities, and had more severe strokes compared to patients without warfarin. There were no significant differences between patients with and without warfarin in SICH rates (adjusted odds ratio [aOR] = 1.23, 95% confidence interval [CI] = 0.72-2.11 per SITS-MOST; aOR = 1.26, 95% CI = 0.82-1.70 per European Cooperative Acute Stroke Study II) after adjustment for age, stroke severity, and comorbidities. Neither did warfarin independently influence mortality (aOR = 1.05, 95% CI = 0.83-1.35) or functional independence at 3 months (aOR = 1.01, 95% CI = 0.81-1.24). Arterial recanalization by computed tomography/magnetic resonance angiography trended higher in warfarin patients (62% [37 of 59] vs 55% [776/1,475], p = 0.066). Recanalization approximated by disappearance at 22 to 36 hours of a baseline hyperdense middle cerebral artery sign was increased (63% [124 of 196] vs 55% [3,901 of 7,099], p = 0.022). INTERPRETATION: Warfarin treatment with INR <= 1.7 did not increase the risk for SICH or death, and had no impact on long-term functional outcome in patients treated with IV tPA for acute ischemic stroke. PMID- 23744572 TI - HIV-1 drug resistance in treatment-naive chronically infected patients in Jamaica. AB - BACKGROUND: HIV-1 drug resistance in treatment-naive patients has a significant impact on the individual patient as well as implications for the wider population. These effects are amplified in the context of resource-limited settings, which are rapidly expanding access to antiretroviral therapy. METHODS: This cross-sectional survey at a single treatment site in Kingston, Jamaica was designed to identify the prevalence of HIV-1 drug-resistant mutations in chronically infected, treatment-naive patients. Mutations were identified using the Stanford HIV database algorithm and the World Health Organization (WHO) HIV Drug Resistance (HIVDR) surveillance mutations. RESULTS: The inclusion of 103 cases in the study resulted in 79 (76.6%) amplifiable samples. Genotype analysis revealed that 12.6% (95% CI 5.3, 19.9) were identified as having clinically significant mutations, while 10.1% (95% CI 3.5, 16.7) had WHO HIVDR surveillance mutations. CONCLUSIONS: According to the WHO standard, this study population has a moderate level of HIVDR in treatment-naive patients and strongly implies the need to introduce HIVDR surveillance in Jamaica. PMID- 23744573 TI - The impacts of climate change and human activities on biogeochemical cycles on the Qinghai-Tibetan Plateau. AB - With a pace of about twice the observed rate of global warming, the temperature on the Qinghai-Tibetan Plateau (Earth's 'third pole') has increased by 0.2 degrees C per decade over the past 50 years, which results in significant permafrost thawing and glacier retreat. Our review suggested that warming enhanced net primary production and soil respiration, decreased methane (CH(4)) emissions from wetlands and increased CH(4) consumption of meadows, but might increase CH(4) emissions from lakes. Warming-induced permafrost thawing and glaciers melting would also result in substantial emission of old carbon dioxide (CO(2)) and CH(4). Nitrous oxide (N(2)O) emission was not stimulated by warming itself, but might be slightly enhanced by wetting. However, there are many uncertainties in such biogeochemical cycles under climate change. Human activities (e.g. grazing, land cover changes) further modified the biogeochemical cycles and amplified such uncertainties on the plateau. If the projected warming and wetting continues, the future biogeochemical cycles will be more complicated. So facing research in this field is an ongoing challenge of integrating field observations with process-based ecosystem models to predict the impacts of future climate change and human activities at various temporal and spatial scales. To reduce the uncertainties and to improve the precision of the predictions of the impacts of climate change and human activities on biogeochemical cycles, efforts should focus on conducting more field observation studies, integrating data within improved models, and developing new knowledge about coupling among carbon, nitrogen, and phosphorus biogeochemical cycles as well as about the role of microbes in these cycles. PMID- 23744574 TI - Analysis of video-polysomnographic sleep findings in dementia with Lewy bodies. AB - Knowledge of sleep architecture and disorders of nocturnal sleep in dementia with Lewy bodies (DLB) is limited by a lack of systematic video-polysomnographic (video-PSG) investigations. We describe video-PSG findings in 29 consecutive subjects diagnosed with DLB. All the patients underwent a clinical interview and overnight video-PSG monitoring. Twenty-nine nondemented patients with Parkinson's disease (PD) matched for age and sex with the DLB cases were selected for comparison. The DLB subjects showed less 1NREM sleep (P = .000) and more 2NREM sleep (P = .000) than the PD subjects. Sleep apnea (30.7% vs. 34.8%) and periodic limb movements (60.9% versus 50.0%) were frequent in both groups. Disruptive motor behavioral manifestations were more frequent in subjects with DLB (69.6% vs. 26.9%, P = .008) and consisted of not only REM sleep behavior disorder (RBD) but also confusional events (30.3% vs. 3.8%, P = .020) and arousal-related episodes mimicking RBD. Subjects with DLB in whom a sleep disturbance had been the presenting symptom performed better than those with other onset symptoms on both the Mini-Mental State Examination (22.2 +/- 4.1 vs. 18.1 +/- 4.6, P = .019) and the Frontal Assessment Battery (15.8 vs. 10.3, P = .010). Polysomnographic findings in DLB show a complex mix of overlapping sleep alterations: impaired sleep structure, sleep comorbidities, and various motor-behavioral events (not restricted to RBD). Clinicians should be aware of the possibility of misleading symptoms and of the risk of overlooking sleep comorbidities, and consider performing polysomnographic sleep investigations in selected cases. We found evidence that a sleep disturbance as the presenting symptom might indicate a different phenotype of the disease, characterized by milder cognitive impairment. PMID- 23744575 TI - Perspectives on a pharmacokinetics legend: C versus T (contributions over time). PMID- 23744576 TI - Multicenter Evaluation of Rectal cancer ReImaging pOst Neoadjuvant (MERRION) Therapy. AB - OBJECTIVE: The aim of this study was to evaluate the utility of reimaging rectal cancer post-CRT (chemoradiotherapy) with magnetic resonance (MR) imaging of the pelvis for local staging and computed tomography of thorax, abdomen, and pelvis (CT TAP) to identify distant metastases. BACKGROUND: The success of neoadjuvant CRT for locally advanced rectal cancer has changed an already complex management algorithm. There is no consensus whether patients should be restaged before surgery. METHODS: Data from 5 institutions with prospectively maintained databases including patients who received neoadjuvant CRT for locally advanced rectal cancer were acquired. Only patients who had been staged pre- and post-CRT with MR imaging and CT TAP were included. MR findings were correlated with histopathological stage using weighted kappa (kappa) statistics to test agreement, where a kappa value of less than 0.5 was deemed unacceptable. RESULTS: A total of 285 patients fulfilled the criteria for the study; 84% had American Joint Committee for Cancer stage 3 disease pre-CRT, and the remainder had stage 2 disease. Fourteen patients did not proceed to surgery post-CRT-2 were observed as "complete responders," and the remainder either had unresectable disease or were unfit for surgery. MR imaging could not predict T stage (kappa = 0.212) or nodal involvement (kappa = 0.336). Most pertinently, MR imaging was unable to detect a complete pathological response (kappa = 0.021), nor could it discriminate T4 disease (kappa = 0.445). CT TAP restaging altered management in 6.7% of patients, who had metastatic disease. CONCLUSIONS: MR reimaging using standard protocols is of limited value in determining surgical approaches; a better modality of local restaging is required. PMID- 23744577 TI - Impact of rapid point-of-care screening tests for the identification of chronic hepatitis C infection. PMID- 23744579 TI - Evaluation of an experimental Ti-Co alloy for dental restorations. AB - Precision and surface quality of pure titanium (Ti) castings for dental and biomedical uses are limited because of the high melting temperature and the violent reactivity of Ti with mold materials during casting procedures. This feasibility study evaluates an experimental low-melting Ti-Co alloy in term of its microstructure and physical and mechanical properties. Tensile samples of Ti 12 wt % Co alloy were cast under a protective argon atmosphere. The melting range of the cast samplers was determined. Cast samples were annealed at 1010 degrees C for various time intervals in order to homogenize microstructures. Microstructures were examined by optical and scanning electron microscopy. Tensile strength and microhardness tests were performed and correlated with microstructures resulting from annealing processes. Ti2Co intermetallic compound coexisted with Ti-Co solid solution in all samples. The melting range of the alloy was 1062-1088 degrees C, which is 568 degrees C lower than that of Ti. The thickness of the surface oxide scale on cast samples was dramatically reduced to 1-3 MUm because of the low-melting nature of the alloy. Solution treatment at 1010 degrees C for 100 h yields the highest tensile strength. Ultimate tensile strength is measured from 852 to 1240 MPa which is stronger than currently used dental alloys. Microhardness values were ranged from 341 to 488 KHN and elongation was from 1.2 to 1.8%. Both microhardness and percentage elongation are similar to those of dental Co-Cr alloys. One hundred hours of annealing dissolved dendritic boundaries and transformed the alloy to a more microductitle matrix, however, the intermetallic compound of Ti2Co remained. PMID- 23744580 TI - Study of rat hypothalamic proteome by HPLC/ESI ion trap and HPLC/ESI-Q-TOF MS. AB - The proteomic profile of hypothalamus, a key organ of CNS, is explored here by employing two widely used MS techniques, i.e. HPLC/ESI-ion trap and HPLC/ESI quadrupole-TOF MS. Strong cation exchange is used for the fractionation of peptides and protein search engine MASCOT is employed for data query. One hundred and thirty six proteins with 10 973 peptides were identified by HPLC/ESI-ion trap MS, while 140 proteins with 32 183 peptides were characterized by HPLC/ESI quadrupole-TOF MS. Among the total 198 proteins identified in both experiments, 78 proteins were common in both sets of conditions. The rest of the 120 proteins were identified distinctly in both MS strategies, i.e. 58 unique proteins were found using the quadrupole-TOF while 62 were found with the HPLC/ESI-ion trap. Moreover, these proteins were classified into groups based on their functions performed in the body. Results presented here identified some important signal and cellular defense proteins inevitable for survival in stressed conditions. Additionally, it is also shown that any single MS strategy is not reliable for good results due to loss of data depending on sensitivity of the instrument used. PMID- 23744578 TI - Effectiveness and cost-effectiveness of home palliative care services for adults with advanced illness and their caregivers. AB - BACKGROUND: Extensive evidence shows that well over 50% of people prefer to be cared for and to die at home provided circumstances allow choice. Despite best efforts and policies, one-third or less of all deaths take place at home in many countries of the world. OBJECTIVES: 1. To quantify the effect of home palliative care services for adult patients with advanced illness and their family caregivers on patients' odds of dying at home; 2. to examine the clinical effectiveness of home palliative care services on other outcomes for patients and their caregivers such as symptom control, quality of life, caregiver distress and satisfaction with care; 3. to compare the resource use and costs associated with these services; 4. to critically appraise and summarise the current evidence on cost-effectiveness. SEARCH METHODS: We searched 12 electronic databases up to November 2012. We checked the reference lists of all included studies, 49 relevant systematic reviews, four key textbooks and recent conference abstracts. We contacted 17 experts and researchers for unpublished data. SELECTION CRITERIA: We included randomised controlled trials (RCTs), controlled clinical trials (CCTs), controlled before and after studies (CBAs) and interrupted time series (ITSs) evaluating the impact of home palliative care services on outcomes for adults with advanced illness or their family caregivers, or both. DATA COLLECTION AND ANALYSIS: One review author assessed the identified titles and abstracts. Two independent reviewers performed assessment of all potentially relevant studies, data extraction and assessment of methodological quality. We carried out meta analysis where appropriate and calculated numbers needed to treat to benefit (NNTBs) for the primary outcome (death at home). MAIN RESULTS: We identified 23 studies (16 RCTs, 6 of high quality), including 37,561 participants and 4042 family caregivers, largely with advanced cancer but also congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), HIV/AIDS and multiple sclerosis (MS), among other conditions. Meta-analysis showed increased odds of dying at home (odds ratio (OR) 2.21, 95% CI 1.31 to 3.71; Z = 2.98, P value = 0.003; Chi(2) = 20.57, degrees of freedom (df) = 6, P value = 0.002; I(2) = 71%; NNTB 5, 95% CI 3 to 14 (seven trials with 1222 participants, three of high quality)). In addition, narrative synthesis showed evidence of small but statistically significant beneficial effects of home palliative care services compared to usual care on reducing symptom burden for patients (three trials, two of high quality, and one CBA with 2107 participants) and of no effect on caregiver grief (three RCTs, two of high quality, and one CBA with 2113 caregivers). Evidence on cost-effectiveness (six studies) is inconclusive. AUTHORS' CONCLUSIONS: The results provide clear and reliable evidence that home palliative care increases the chance of dying at home and reduces symptom burden in particular for patients with cancer, without impacting on caregiver grief. This justifies providing home palliative care for patients who wish to die at home. More work is needed to study cost-effectiveness especially for people with non-malignant conditions, assessing place of death and appropriate outcomes that are sensitive to change and valid in these populations, and to compare different models of home palliative care, in powered studies. PMID- 23744581 TI - Flow-injection chemiluminescence determination of gentamicin: optimization by central composite design. AB - A simple and sensitive flow-injection chemiluminescence (CL) method has been developed for the determination of gentamicin sulfate. The method is based on the inhibitory effect of gentamicin on the CL emission accompanying oxidation of luminol by H2 O2 in an alkaline medium in the presence of Cu(II) as a catalyst. Inhibition was caused by the formation of a strong complex between analyte and the catalyst. Experimental variables, including the concentrations of luminol (umol/L), H2 O2 (mol/L), Cu(II) (mol/L) and NaOH (mol/L), were optimized using a central composite design. Under optimum conditions, the plot of CL intensity versus gentamicin concentration was found to have two linear ranges. One range was at low concentrations from 1.0 to 10.0 mg/L and the other was from 10.0 to 30.0 mg/L. Precision was calculated by analyzing samples containing 5.0 mg/L gentamicin (n = 11) and the relative standard deviation (RSD) was 1.7%. Also, a high injection throughput of 120 samples/h was achieved. This method was successfully applied to the determination of gentamicin sulfate in pharmaceutical formulations and water samples. PMID- 23744582 TI - Ribosomal and hematopoietic defects in induced pluripotent stem cells derived from Diamond Blackfan anemia patients. AB - Diamond Blackfan anemia (DBA) is a congenital disorder with erythroid (Ery) hypoplasia and tissue morphogenic abnormalities. Most DBA cases are caused by heterozygous null mutations in genes encoding ribosomal proteins. Understanding how haploinsufficiency of these ubiquitous proteins causes DBA is hampered by limited availability of tissues from affected patients. We generated induced pluripotent stem cells (iPSCs) from fibroblasts of DBA patients carrying mutations in RPS19 and RPL5. Compared with controls, DBA fibroblasts formed iPSCs inefficiently, although we obtained 1 stable clone from each fibroblast line. RPS19-mutated iPSCs exhibited defects in 40S (small) ribosomal subunit assembly and production of 18S ribosomal RNA (rRNA). Upon induced differentiation, the mutant clone exhibited globally impaired hematopoiesis, with the Ery lineage affected most profoundly. RPL5-mutated iPSCs exhibited defective 60S (large) ribosomal subunit assembly, accumulation of 12S pre-rRNA, and impaired erythropoiesis. In both mutant iPSC lines, genetic correction of ribosomal protein deficiency via complementary DNA transfer into the "safe harbor" AAVS1 locus alleviated abnormalities in ribosome biogenesis and hematopoiesis. Our studies show that pathological features of DBA are recapitulated by iPSCs, provide a renewable source of cells to model various tissue defects, and demonstrate proof of principle for genetic correction strategies in patient stem cells. PMID- 23744583 TI - Long-term decline in intelligence among adult survivors of childhood acute lymphoblastic leukemia treated with cranial radiation. AB - Survivors of childhood acute lymphoblastic leukemia (ALL) treated with cranial radiation therapy (CRT) are at risk for cognitive impairment, although whether impairment progresses with age into adulthood is unknown. We report change in intelligence for 102 adult survivors of childhood ALL (age range, 26.6-54.7 years) during a median interval of 28.5 years. Survivors demonstrated lower Performance intelligence (mean, 95.3; standard deviation, 16.5; P = .005) but not Verbal IQ (mean, 97.4; standard deviation, 15.44; P = .09) at initial testing. Verbal intelligence declined an average of 10.3 points (P < .0001) during the follow-up interval with no decline in Performance intelligence. Decline was associated with current attention problems (P = .002) but not gender, CRT dose, age at CRT exposure, or years between testing. Results suggest long-term survivors of childhood ALL treated with CRT are at risk for progressive decline in verbal intellect, which may be driven by attention deficits. This trial was registered at clinicaltrials.gov as no. NCT00760656. PMID- 23744584 TI - Prolylcarboxypeptidase promotes angiogenesis and vascular repair. AB - Prolylcarboxypeptidase (PRCP) is associated with leanness, hypertension, and thrombosis. PRCP-depleted mice have injured vessels with reduced Kruppel-like factor (KLF)2, KLF4, endothelial nitric oxide synthase (eNOS), and thrombomodulin. Does PRCP influence vessel growth, angiogenesis, and injury repair? PRCP depletion reduced endothelial cell growth, whereas transfection of hPRCP cDNA enhanced cell proliferation. Transfection of hPRCP cDNA, or an active site mutant (hPRCPmut) rescued reduced cell growth after PRCP siRNA knockdown. PRCP-depleted cells migrated less on scratch assay and murine PRCP(gt/gt) aortic segments had reduced sprouting. Matrigel plugs in PRCP(gt/gt) mice had reduced hemoglobin content and angiogenic capillaries by platelet endothelial cell adhesion molecule (PECAM) and NG2 immunohistochemistry. Skin wounds on PRCP(gt/gt) mice had delayed closure and reepithelialization with reduced PECAM staining, but increased macrophage infiltration. After limb ischemia, PRCP(gt/gt) mice also had reduced reperfusion of the femoral artery and angiogenesis. On femoral artery wire injury, PRCP(gt/gt) mice had increased neointimal formation, CD45 staining, and Ki-67 expression. Alternatively, combined PRCP(gt/gt) and MRP 14(-/-) mice were protected from wire injury with less neointimal thickening, leukocyte infiltration, and cellular proliferation. PRCP regulates cell growth, angiogenesis, and the response to vascular injury. Combined with its known roles in blood pressure and thrombosis control, PRCP is positioned as a key regulator of vascular homeostasis. PMID- 23744586 TI - Excuses, excuses: a meta-analytic review of how mitigating information can change aggression and an exploration of moderating variables. AB - Research in the aggression domain has been mixed regarding the effectiveness of using mitigating information (e.g., excuses, apologies) to reduce aggressive behavior after a provocation. Aggression theory (e.g., general aggression model) posits that mitigating information may cues re-appraisal processes to potentially change aggressive behavior. If re-appraisal processes are engaged, aggressive behavior is likely to decrease. Currently, no published study has synthesized the literature to test such theoretical claims. The current study used meta-analysis to test this effect and examine the influence of several possible moderators. Results showed a significant negative effect size, suggesting that mitigating information does indeed reduce aggressive behavior after a provocation. However, these results were qualified by several significant moderators. Results showed that mitigating information reduces aggression when (a) the information did not come from an apology, (b) the non-apologetic mitigating information was high quality, and c) the provocation was mild (vs. strong). Theoretical extensions are discussed. PMID- 23744585 TI - CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia. AB - The association between cytomegalovirus (CMV) reactivation and relapse was evaluated in a large cohort of patients with acute myeloid leukemia (AML) (n = 761), acute lymphoblastic leukemia (ALL) (n = 322), chronic myeloid leukemia (CML) (n = 646), lymphoma (n = 254), and myelodysplastic syndrome (MDS) (n = 371) who underwent allogeneic hematopoietic cell transplantation (HCT) between 1995 and 2005. In multivariable models, CMV pp65 antigenemia was associated with a decreased risk of relapse by day 100 among patients with AML (hazard ratio [HR] = 0.56; 95% confidence interval [CI], 0.3-0.9) but not in patients with ALL, lymphoma, CML, or MDS. The effect appeared to be independent of CMV viral load, acute graft-versus-host disease, or ganciclovir-associated neutropenia. At 1 year after HCT, early CMV reactivation was associated with reduced risk of relapse in all patients, but this did not reach significance for any disease subgroup. Furthermore, CMV reactivation was associated with increased nonrelapse mortality (HR = 1.31; 95% CI, 1.1-1.6) and no difference in overall mortality (HR = 1.05; 95% CI, 0.9-1.3). This report demonstrates a modest reduction in early relapse risk after HCT associated with CMV reactivation in a large cohort of patients without a benefit in overall survival. PMID- 23744587 TI - Predicting species-specific responses of fungi to climatic variation using historical records. AB - Although striking changes have been documented in plant and animal phenology over the past century, less is known about how the fungal kingdom's phenology has been changing. A few recent studies have documented changes in fungal fruiting in Europe in the last few decades, but the geographic and taxonomic extent of these changes, the mechanisms behind these changes, and their relationships to climate are not well understood. Here, we analyzed herbarium data of 274 species of fungi from Michigan to test the hypotheses that fruiting times of fungi depend on annual climate and that responses depend on taxonomic and functional groups. We show that the fungal community overall fruits later in warmer and drier years, which has led to a shift toward later fruiting dates for autumn-fruiting species, consistent with existing evidence. However, we also show that these effects are highly variable among species and are partly explained by basic life-history characteristics. Resulting differences in climate sensitivities are expected to affect community structure as climate changes. This study provides a unique picture of the climate dependence of fungal phenology in North America and an approach for quantifying how individual species and broader fungal communities will respond to ongoing climate change. PMID- 23744588 TI - Synthesis, HPLC enantioresolution, and X-ray analysis of a new series of C5 methyl pyridazines as N-formyl peptide receptor (FPR) agonists. AB - The synthesis of three racemates and the corresponding non-chiral analogues of a C5-methyl pyridazine series is described here, as well as the isolation of pure enantiomers and their absolute configuration assignment. In order to obtain optically active compounds, direct chromatographic methods of separation by HPLC UV were investigated using four chiral stationary phases (CSPs: Lux Amylose-2, Lux Cellulose-1, Lux Cellulose-2 and Lux Cellulose-3). The best resolution was achieved using amylose tris(5-chloro-2-methylphenylcarbamate) (Lux Amylose-2), and single enantiomers were isolated on a semipreparative scale with high enantiomeric excess, suitable for biological assays. The absolute configuration of optically active compounds was unequivocally established by X-ray crystallographic analysis and comparative chiral HPLC-UV profile. All compounds of the series were tested for formyl peptide receptor (FPR) agonist activity, and four were found to be active, with EC50 values in the micromolar range. PMID- 23744589 TI - Confounding underlies the apparent month of birth effect in multiple sclerosis. AB - OBJECTIVE: Several groups have reported apparent association between month of birth and multiple sclerosis. We sought to test the extent to which such studies might be confounded by extraneous variables such as year and place of birth. METHODS: Using national birth statistics from 2 continents, we assessed the evidence for seasonal variations in birth rate and tested the extent to which these are subject to regional and temporal variation. We then established the age and regional origin distribution for a typical multiple sclerosis case collection and determined the false-positive rate expected when comparing such a collection with birth rates estimated by averaging population-specific national statistics. RESULTS: We confirm that seasonality in birth rate is ubiquitous and subject to highly significant regional and temporal variations. In the context of this variation we show that birth rates observed in typical case collections are highly likely to deviate significantly from those obtained by the simple unweighted averaging of national statistics. The significant correlations between birth rates and both place (latitude) and time (year of birth) that characterize the general population indicate that the apparent seasonal patterns for month of birth suggested to be specific for multiple sclerosis (increased in the spring and reduced in the winter) are expected by chance alone. INTERPRETATION: In the absence of adequate control for confounding factors, such as year and place of birth, our analyses indicate that the previous claims for association of multiple sclerosis with month of birth are probably false positives. PMID- 23744590 TI - Autosomal dominant osteopetrosis revisited: lessons from recent studies. AB - Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schonberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis. PMID- 23744591 TI - Parathyroidectomy eliminates arrhythmic risk in primary hyperparathyroidism, as evaluated by exercise test. AB - OBJECTIVE: To investigate whether parathyroidectomy (PTx) reverses risk factors for arrhythmias related to the QT dynamic changes evaluated during bicycle ergometry exercise test (ET). METHODS: Twenty-four postmenopausal women with primary hyperparathyroidism (PHPT) (mean age 60.08.4 years) and 30 sex- and age matched controls underwent ET, echocardiography, and biochemical evaluation. The following stages were considered during ET: rest, peak exercise, and recovery. The patients were randomized to two groups: 12 underwent PTx (group A) and 12 were followed-up conservatively (group B). After 6 months, the patients were studied again. RESULTS: Groups A and B showed no differences in mean baseline biochemical values, echocardiographic parameters, and QTC interval. PHPT patients showed an increased occurrence of ventricular premature beats (VPBS) during ET compared with controls (37.0 vs 6.6%, P=0.03). Serum calcium level was a predictor of VPBS (P=0.05). Mean value of QTC was in the normal range at baseline (Group A: 401+/-16.9; group B: 402.25+/-13.5 ms) but significantly lower than controls (417.8+/-25.1 ms, P<0.01). A negative correlation was found between QTc and calcium values (P=0.03). Physiological reduction of QTc interval from rest to peak exercise was not observed in PHPT patients before surgery. After PTx, group A had a significant reduction in VPBs compared with baseline (at baseline, 5 of 12 vs none of 12 patients after PTx, P=0.03) and a restored normal QT adaptation during ET. Group B showed no significant changes after a 6-month period. CONCLUSIONS: PTx reduces the occurrence of VPBs and restored the QTc adaptation during ET. PMID- 23744592 TI - Comparative proteomics analysis reveals roles for FADD in the regulation of energy metabolism and proteolysis pathway in mouse embryonic fibroblast. AB - Fas-associated death domain-containing protein (FADD) is a classical apoptotic pathway adaptor. Further studies revealed that it also plays essential roles in nonapoptotic processes, which is assumed to be regulated by its phosphorylation. However, the exact mechanisms are still poorly understood. To study the nonapoptotic effects of FADD, a comprehensive strategy of proteomics identification combined with bioinformatic analysis was undertaken to identify proteins differentially expressed in three cell lines containing FADD and its mutant, FADD-A and FADD-D. The cell lines were thought to bear wild-type FADD, unphosphorylated FADD mimic and constitutive phosphorylated FADD mimic, respectively. A total of 47 proteins were identified to be significantly changed due to FADD phosphorylation. Network analysis using MetaCoreTM identified a number of changed proteins that were involved in cellular metabolic process, including lipid metabolism, fatty acid metabolism, glycolysis, and oxidative phosphorylation. The finding that FADD-D cell line showed an increase in fatty acid oxidation argues that it could contribute to the leaner phenotype of FADD-D mice as reported previously. In addition, six proteins related to the ubiquitin proteasome pathway were also specifically overexpressed in FADD-D cell line. Finally, the c-Myc gene represents a convergent hub lying at the center of dysregulated pathways, and was upregulated in FADD-D cells. Taken together, these studies allowed us to conclude that impaired mitochondrial function and proteolysis might play pivotal roles in the dysfunction associated with FADD phosphorylation-induced disorders. PMID- 23744594 TI - Utility of gastric-retained alginate gels to modulate pharmacokinetic profiles in rats. AB - A gastric-retentive formulation amenable to dosing in rodents has the potential to enable sustained release in a preclinical setting. This may be useful to provide systemic exposure over a longer duration or to increase duration of exposure for compounds with targets localized in the gastrointestinal tract. Previous work has shown that a mixture of 1% sodium alginate and 0.625% karaya gum in the presence of a calcium chelator can form gels in situ that are gastric retained in rats. The aim of this work was to define the physicochemical boundaries of compounds within this technology and their relation to in vivo release using a series of model compounds with high permeability but varying solubility. In vitro data demonstrated a good correlation between solubility and initial release rates from the gels. In vivo studies were conducted in Sprague Dawley rats to compare the exposure profile of compounds dosed in gel relative to a standard formulation. In vivo data were consistent with trends from the in vitro studies. These data suggest that, in conjunction with an understanding of compound solubility, sodium alginate/karaya gum gels may be a useful tool to modulate exposure profiles in rodent models in a preclinical setting. PMID- 23744595 TI - Synchronous fluorescence determination of ferulic acid with Ce(IV) and sodium tripolyphosphate. AB - In this study, a synchronous fluorescence detection method for ferulic acid (FA) is proposed based on a redox reaction between FA and Ce(IV) sulfate in dilute sulfuric acid medium at room temperature. It was found that FA could reduce Ce(IV) to Ce(III) in acidic medium, and sodium tripolyphosphate could further enhance the intrinsic fluorescence of the Ce(III) produced. The enhanced extent of synchronous fluorescence intensity was in proportion to the concentration of FA over the range 3.0 * 10(-8) to 1.0 * 10(-5) mol/L. The corresponding limit of determination (S/N = 3) was 1.3 * 10(-8) mol/L. The proposed method was applied to the determination of sodium ferulate for injection sample with satisfactory results. PMID- 23744596 TI - Surgery versus thrombolysis for initial management of acute limb ischaemia. AB - BACKGROUND: Peripheral arterial thrombolysis is technique used in the management of peripheral arterial ischaemia. Much is known about the indications, risks and benefits of thrombolysis. However, it is not known whether thrombolysis works better than surgery in the initial treatment of acute limb ischaemia. OBJECTIVES: To determine the preferred initial treatment, surgery or thrombolysis, for acute limb ischaemia. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched March 2013) and CENTRAL (2013, Issue 2). SELECTION CRITERIA: All randomised studies comparing thrombolysis and surgery for the initial treatment of acute limb ischaemia. DATA COLLECTION AND ANALYSIS: Each author independently assessed trial quality and extracted data. Agreement was reached by consensus. MAIN RESULTS: Five trials with a total of 1283 participants were included. There was no significant difference in limb salvage or death at 30 days, six months or one year between initial surgery and initial thrombolysis. However, stroke was significantly more frequent at 30 days in thrombolysis participants (1.3%) compared to surgery participants (0%) (Odds ratio (OR) 6.41; 95% confidence interval (CI) 1.57 to 26.22). Major haemorrhage was more likely at 30 days in thrombolysis participants (8.8%) compared to surgery participants (3.3%) (OR 2.80; 95% CI 1.70 to 4.60); and distal embolization was more likely at 30 days in thrombolysis participants (12.4%) compared to surgery participants (0%) (OR 8.35; 95% CI 4.47 to 15.58).Participants treated by initial thrombolysis underwent a less severe degree of intervention (OR 5.37; 95% CI 3.99 to 7.22) and displayed equivalent overall survival compared to initial surgery (OR 0.87; 95% CI 0.61 to 1.25). AUTHORS' CONCLUSIONS: Universal initial treatment with either surgery or thrombolysis cannot be advocated on the available evidence. There is no overall difference in limb salvage or death at one year between initial surgery and initial thrombolysis. Thrombolysis may be associated with a higher risk of ongoing limb ischaemia and haemorrhagic complications including stroke. The higher risk of complications must be balanced against risks of surgery in each person. PMID- 23744597 TI - Ginkgo biloba for intermittent claudication. AB - BACKGROUND: People with intermittent claudication (IC) suffer from pain in the muscles of the leg occurring during exercise which is relieved by a short period of rest. Symptomatic relief can be achieved by (supervised) exercise therapy and pharmacological treatments. Ginkgo biloba is a vasoactive agent and is used to treat IC. OBJECTIVES: To assess the effect of Ginkgo biloba on walking distance in people with intermittent claudication. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (March 2013) and CENTRAL (2013, Issue 2). SELECTION CRITERIA: Randomised controlled trials of Ginkgo biloba extract, irrespective of dosage, versus placebo in people with IC. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for selection, assessed study quality and extracted data. We extracted number of patients, mean walking distances or times and standard deviations. To standardise walking distance or time, caloric expenditures were used to express the difference between the different treadmill protocols, which were calculated from the speed and incline of the treadmill. MAIN RESULTS: Fourteen trials with a total of 739 participants were included. Eleven trials involving 477 participants compared Ginkgo biloba with placebo and assessed the absolute claudication distance (ACD). Following treatment with Ginkgo biloba at the end of the study the ACD increased with an overall effect size of 3.57 kilocalories (confidence interval (CI) -0.10 to 7.23, P = 0.06), compared with placebo. This translates to an increase of just 64.5 ( CI -1.8 to 130.7) metres on a flat treadmill with an average speed of 3.2 km/h. Publication bias leading to missing data or "negative" trials is likely to have inflated the effect size. AUTHORS' CONCLUSIONS: Overall, there is no evidence that Ginkgo biloba has a clinically significant benefit for patients with peripheral arterial disease. PMID- 23744598 TI - Mechanical properties of methacrylate-based model dentin adhesives: effect of loading rate and moisture exposure. AB - The aim of this study is to investigate the mechanical behavior of model methacrylate-based dentin adhesives under conditions that simulate the wet oral environment. A series of monotonic and creep experiments were performed on rectangular beam samples of dentin adhesive in three-point bending configuration under different moisture conditions. The monotonic test results show a significant effect of loading rate on the failure strength and the linear limit (yield point) of the stress-strain response. In addition, these tests show that the failure strength is low, and the failure occurs at a smaller deformation when the test is performed under continuously changing moisture conditions. The creep test results show that under constant moisture conditions, the model dentin adhesives can have a viscoelastic response under certain low loading levels. However, when the moisture conditions vary under the same low loading levels, the dentin adhesives have an anomalous creep response accompanied by large secondary creep and high strain accumulation. PMID- 23744600 TI - American Psychiatric Association explains DSM-5. PMID- 23744599 TI - Recent findings on the mechanisms involved in tenofovir resistance. AB - Since its approval for clinical use in 2001, tenofovir (TFV) has become one of the most frequently prescribed nucleotide analogues used in combination with other antiretroviral agents against HIV-1 infection. Although reverse transcriptase inhibitors (RTIs) including TFV have been shown to be highly potent with reasonable safety profiles in the clinic, drug resistance hinders the effectiveness of current therapies and even causes treatment failure. Therefore, understanding the resistance mechanisms of RT and exploring the potential antiviral synergy between the different RTIs in combination therapies against the resistance mechanisms would greatly improve the long-term efficacy of existing and future regimens. We have studied the pyrophosphorolytic removal of TFV, a major resistance mechanism that RT utilizes, from two different viral sequences and observed interesting outcomes associated with the sequence context. Furthermore, addition of efavirenz, a non-nucleoside RTI, inhibits this removal process confirming the synergistic antiviral effects. This article highlights our recently published work on the viral sequence context contributing to the study of anti-HIV drug resistance in conjunction with the benefits of combining various RTIs that may have been neglected previously. PMID- 23744601 TI - Asymmetric sensory ganglionopathy: a case series. AB - INTRODUCTION: Sensory ganglionopathies are uncommon but potentially very disabling. They have heterogeneous etiologies including autoimmune, paraneoplastic, toxic, and inflammatory although many remain idiopathic despite intensive investigation. Asymmetric sensory loss is relatively common at the onset, but with time, symptoms usually spread to involve all limbs symmetrically. METHODS: We report 6 patients with a persistent strikingly asymmetrical sensory ganglionopathy with acute or subacute onset and slow progression. RESULTS: Peripheral nerve biopsies in 5 patients showed axonal loss without significant inflammation; a dorsal root ganglion biopsy in 1 patient showed neuronal loss and inflammatory infiltrate. Four patients received immunomodulatory treatment, but overall the response to treatment was poor. CONCLUSIONS: Asymmetrical sensory ganglionopathies may have an inflammatory basis. Immunomodulatory therapy may be considered early in the disease course, although in this series there was a limited response to treatment. PMID- 23744602 TI - Enantiomerically pure bithiophene diphosphine oxides as catalysts for direct double aldol reactions. AB - The direct aldol reaction between aryl methyl ketones with aromatic aldehydes in the presence of tetrachlorosilane and a catalytic amount of a chiral bithiophene diphosphine oxide was studied; the product of double aldol addition was isolated as diacetate in good diastereoselectivity (up to 95:5) and enantioselectivities up to 91%. The reaction with heteroaromatic aldehydes was also investigated leading to the corresponding 1,3 diols, in some cases with excellent stereoselectivities. PMID- 23744603 TI - Regional decline in growth rates of massive Porites corals in Southeast Asia. AB - This study reports the first well-replicated analysis of continuous coral growth records from warmer water reefs (mean annual sea surface temperatures (SST) >28.5 degrees C) around the Thai-Malay Peninsula in Southeast Asia. Based on analyses of 70 colonies sampled from 15 reefs within six locations, region-wide declines in coral calcification rate (ca. 18.6%), linear extension rate (ca. 15.4%) and skeletal bulk density (ca. 3.9%) were observed over a 31-year period from 1980 to 2010. Decreases in calcification and linear extension rates were observed at five of the six locations and ranged from ca. 17.2-21.6% and ca. 11.4-19.6%, respectively, whereas decline in skeletal bulk density was a consequence of significant reductions at only two locations (ca. 6.9% and 10.7%). A significant link between region-wide growth rates and average annual SST was found, and Porites spp. demonstrated a high thermal threshold of ca. 29.4 degrees C before calcification rates declined. Responses at individual locations within the region were more variable with links between SST and calcification rates being significant at only four locations. Rates of sea temperature warming at locations in the Andaman Sea (Indian Ocean) (ca. 1.3 degrees C per decade) were almost twice those in the South China Sea (Pacific Ocean) (ca. 0.7 degrees C per decade), but this was not reflected in the magnitude of calcification declines at corresponding locations. Considering that massive Porites spp. are major reef builders around Southeast Asia, this region-wide growth decline is a cause for concern for future reef accretion rates and resilience. However, this study suggests that the future rates and patterns of change within the region are unlikely to be uniform or dependent solely on the rates of change in the thermal environment. PMID- 23744604 TI - Proteomic characterization of Pseudomonas aeruginosa PAO1 inner membrane. AB - Pseudomonas aeruginosa is a Gram-negative bacterium that can inhabit a wide variety of environments and infect different hosts. Human infections by this microbe are nowadays perceived as a major health problem due notably to its multiresistance. The present data set provides the first description of P. aeruginosa inner membrane proteome. To achieve this, we combined efficient separation of membranes from PAO1 reference strain using discontinuous sucrose gradient centrifugation and MS-based proteomic analysis. A core list of 991 nonredundant proteins was established and analyzed in terms of trans-membrane domains, signal peptide, and lipobox sequence prediction. Furthermore, functional insights into membrane-spanning and membrane-associated protein complexes have been explored. All mass spectrometry data have been deposited in the ProteomeXchange with identifier PXD000107. PMID- 23744606 TI - The effect of ethylene oxide sterilization on the surface chemistry and in vitro cytotoxicity of several kinds of chitosan. AB - The surfaces of three chitosan samples, differing only in their degrees of deacetylation and of carboxyethyl chitosan were chemically characterized by X-ray photoelectron spectroscopy, time-of-flight secondary ion mass spectroscopy, X-ray diffraction, and Fourier transform infrared, both before and after sterilization with ethylene oxide. Unexpected elemental ratios suggest that surface chemical modification occurred during the processing of the original chitin, with further surface modification on subsequent sterilization, despite previous reports to the contrary. Cell viability was evaluated by direct contact methyl thiazole tetrazolium and lactate dehydrogenase assays between the chitosan particles and A549 human epithelial cells, which demonstrated that the modifications incurred on sterilization are reflected in biocompatibility changes. All the samples were found to be biocompatible and nontoxic before sterilization and remained so subsequently. (c) 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013. PMID- 23744605 TI - Investigation of Rett syndrome using pluripotent stem cells. AB - Rett syndrome (RTT) is one of most prevalent female neurodevelopmental disorders. De novo mutations in X-linked MECP2 are mostly responsible for RTT. Since the identification of MeCP2 as the underlying cause of RTT, murine models have contributed to understanding the pathophysiology of RTT and function of MeCP2. Reprogramming is a procedure to produce induced pluripotent stem cells (iPSCs) by overexpression of four transcription factors. iPSCs obtain similar features as embryonic stem cells and are capable of self-renewing and differentiating into cells of all three layers. iPSCs have been utilized in modeling human diseases in vitro. Neurons differentiated from RTT-iPSCs showed the recapitulation of RTT phenotypes. Despite the early success, genetic and epigenetic instability upon reprogramming and ensuing maintenance of iPSCs raise concerns in using RTT-iPSCs as an accurate in vitro model. Here, we update the current iPSC-based RTT modeling, and its concerns and challenges. PMID- 23744607 TI - A closed-loop anesthetic delivery system for real-time control of burst suppression. AB - OBJECTIVE: There is growing interest in using closed-loop anesthetic delivery (CLAD) systems to automate control of brain states (sedation, unconsciousness and antinociception) in patients receiving anesthesia care. The accuracy and reliability of these systems can be improved by using as control signals electroencephalogram (EEG) markers for which the neurophysiological links to the anesthetic-induced brain states are well established. Burst suppression, in which bursts of electrical activity alternate with periods of quiescence or suppression, is a well-known, readily discernible EEG marker of profound brain inactivation and unconsciousness. This pattern is commonly maintained when anesthetics are administered to produce a medically-induced coma for cerebral protection in patients suffering from brain injuries or to arrest brain activity in patients having uncontrollable seizures. Although the coma may be required for several hours or days, drug infusion rates are managed inefficiently by manual adjustment. Our objective is to design a CLAD system for burst suppression control to automate management of medically-induced coma. APPROACH: We establish a CLAD system to control burst suppression consisting of: a two-dimensional linear system model relating the anesthetic brain level to the EEG dynamics; a new control signal, the burst suppression probability (BSP) defining the instantaneous probability of suppression; the BSP filter, a state-space algorithm to estimate the BSP from EEG recordings; a proportional-integral controller; and a system identification procedure to estimate the model and controller parameters. MAIN RESULTS: We demonstrate reliable performance of our system in simulation studies of burst suppression control using both propofol and etomidate in rodent experiments based on Vijn and Sneyd, and in human experiments based on the Schnider pharmacokinetic model for propofol. Using propofol, we further demonstrate that our control system reliably tracks changing target levels of burst suppression in simulated human subjects across different epidemiological profiles. SIGNIFICANCE: Our results give new insights into CLAD system design and suggest a control-theory framework to automate second-to-second control of burst suppression for management of medically-induced coma. PMID- 23744608 TI - A prediction model for monitoring ribbed roller compacted ribbons. AB - The application of near infrared (NIR) spectroscopy for real-time monitoring of the critical quality attributes of ribbed roller compacted ribbons was studied. Three NIR probes (QR 200, QR 400, and QR 600) of lens diameters, 200, 400, and 600 MUm, respectively were used at various fixed distances from the ribbon surface to determine the calibration model with optimum predictive ability for monitoring the roller compaction process. The ribbon attributes studied were micronized chlorpheniramine maleate concentration, roll force, roll speed, ribbon density, and tensile strength. The custom-made belt conveying system was used to simulate the ribbon manufacturing process for NIR spectra capture. Simulation results obtained were then compared with the experimental results. The outcome of this study indicated that QR 400 was the best NIR probe for modeling, followed by QR 200 and QR 600. Of the five spectra measuring distance settings (d = 0.3, 0.6, 0.9, 1.2, and 1.5 mm), there was good correlation between simulation and experimental findings indicating that the calibration models for bigger probe sizes were better if the measuring distance was smaller. PMID- 23744609 TI - Implementation of maternal blood cell-free DNA testing in early screening for aneuploidies. AB - OBJECTIVE: To explore the feasibility of routine maternal blood cell-free (cf) DNA testing in screening for trisomies 21, 18 and 13 at 10 weeks' gestation. METHOD: In this prospective study, women attending The Fetal Medicine Centre in London, UK, between October 2012 and April 2013, with singleton pregnancy and live fetus with CRL 32-45 mm, were screened for trisomies 21, 18 and 13 by cfDNA testing at 10 weeks and the combined test at 12 weeks. RESULTS: cfDNA testing was performed in 1005 singleton pregnancies with a median maternal age of 37 (range, 20-49) years. Risks for trisomies were provided for 957 (95.2%) cases and in 98.0% these were available within 14 days from sampling. In 48 (4.8%) cases no result was provided due to problems with delivery to the laboratory, low fetal fraction or assay failure. Repeat sampling was performed in 40 cases and a result obtained in 27 (67.5%) of these. In 11 cases the risk score for trisomy 21 and in five cases that for trisomy 18 was > 99%, in one the risk for trisomy 13 was 34% and in 968 the risk for each of the three trisomies was < 0.01%. The suspected trisomies were confirmed by karyotyping after chorionic villus sampling (CVS), except in one case of trisomy 18 in which the karyotype was normal. On the basis of the maternal age distribution of the study population, the expected and observed numbers for each of the three trisomies were similar. Both cfDNA and combined testing detected all trisomies, but the estimated false-positive rates (FPR) were 0.1% and 3.4%, respectively. CONCLUSION: Routine screening for trisomies 21, 18 and 13 by cfDNA testing at 10 weeks is feasible and has a lower FPR than does combined testing, but abnormal results require confirmation by CVS. PMID- 23744610 TI - Protein kinase A-dependent pSer(675) -beta-catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis. AB - Genetically determined loss of fibrocystin function causes congenital hepatic fibrosis (CHF), Caroli disease (CD), and autosomal recessive polycystic kidney disease (ARPKD). Cystic dysplasia of the intrahepatic bile ducts and progressive portal fibrosis characterize liver pathology in CHF/CD. At a cellular level, several functional morphological and signaling changes have been reported including increased levels of 3'-5'-cyclic adenosine monophosphate (cAMP). In this study we addressed the relationships between increased cAMP and beta catenin. In cholangiocytes isolated and cultured from Pkhd1(del4/del4) mice, stimulation of cAMP/PKA signaling (forskolin 10 MUM) stimulated Ser(675) phosphorylation of beta-catenin, its nuclear localization, and its transcriptional activity (western blot and TOP flash assay, respectively) along with a down-regulation of E-cadherin expression (immunocytochemistry and western blot); these changes were inhibited by the PKA blocker, PKI (1 MUM). The Rho GTPase, Rac-1, was also significantly activated by cAMP in Pkhd1(del4/del4) cholangiocytes. Rac-1 inhibition blocked cAMP-dependent nuclear translocation and transcriptional activity of pSer(675) -beta-catenin. Cell migration (Boyden chambers) was significantly higher in cholangiocytes obtained from Pkhd1(del4/del4) and was inhibited by: (1) PKI, (2) silencing beta-catenin (siRNA), and (3) the Rac-1 inhibitor NSC 23766. CONCLUSION: These data show that in fibrocystin-defective cholangiocytes, cAMP/PKA signaling stimulates pSer(675) phosphorylation of beta-catenin and Rac-1 activity. In the presence of activated Rac-1, pSer(675) -beta-catenin is translocated to the nucleus, becomes transcriptionally active, and is responsible for increased motility of Pkhd1(del4/del4) cholangiocytes. beta-Catenin-dependent changes in cell motility may be central to the pathogenesis of the disease and represent a potential therapeutic target. PMID- 23744611 TI - Selective serotonin reuptake inhibitors for premenstrual syndrome. AB - BACKGROUND: Premenstrual syndrome (PMS) is a common cause of physical, psychological and social problems in women of reproductive age. The key characteristic of PMS is the timing of symptoms, which occur only during the two weeks leading up to menstruation (the luteal phase of the menstrual cycle). Selective serotonin reuptake inhibitors (SSRIs) are increasingly used as first line therapy for PMS. SSRIs can be taken either in the luteal phase or else continuously (every day). SSRIs are generally considered to be effective for reducing premenstrual symptoms but they can cause adverse effects. OBJECTIVES: The objective of this review was to evaluate the effectiveness and safety of SSRIs for treating premenstrual syndrome. SEARCH METHODS: Electronic searches for relevant randomised controlled trials (RCTs) were undertaken in the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, PsycINFO, and CINAHL (February 2013). Where insufficient data were presented in a report, attempts were made to contact the original authors for further details. SELECTION CRITERIA: Studies were considered in which women with a prospective diagnosis of PMS, PMDD or late luteal phase dysphoric disorder (LPDD) were randomised to receive SSRIs or placebo for the treatment of premenstrual syndrome. DATA COLLECTION AND ANALYSIS: Two review authors independently selected the studies, assessed eligible studies for risk of bias, and extracted data on premenstrual symptoms and adverse effects. Studies were pooled using random effects models. Standardised mean differences (SMDs) with 95% confidence intervals (CIs) were calculated for premenstrual symptom scores, using separate analyses for different types of continuous data (that is end scores and change scores). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for dichotomous outcomes. Analyses were stratified by type of drug administration (luteal or continuous) and by drug dose (low, medium, or high). We calculated the number of women who would need to be taking a moderate dose of SSRI in order to cause one additional adverse event (number needed to harm: NNH). The overall quality of the evidence for the main findings was assessed using the GRADE working group methods. MAIN RESULTS: Thirty-one RCTs were included in the review. They compared fluoxetine, paroxetine, sertraline, escitalopram and citalopram versus placebo. SSRIs reduced overall self-rated symptoms significantly more effectively than placebo. The effect size was moderate when studies reporting end scores were pooled (for moderate dose SSRIs: SMD -0.65, 95% CI -0.46 to -0.84, nine studies, 1276 women; moderate heterogeneity (I(2) = 58%), low quality evidence). The effect size was small when studies reporting change scores were pooled (for moderate dose SSRIs: SMD -0.36, 95% CI -0.20 to -0.51, four studies, 657 women; low heterogeneity (I(2)=29%), moderate quality evidence).SSRIs were effective for symptom relief whether taken only in the luteal phase or continuously, with no clear evidence of a difference in effectiveness between these modes of administration. However, few studies directly compared luteal and continuous regimens and more evidence is needed on this question.Withdrawals due to adverse effects were significantly more likely to occur in the SSRI group (moderate dose: OR 2.55, 95% CI 1.84 to 3.53, 15 studies, 2447 women; no heterogeneity (I(2) = 0%), moderate quality evidence). The most common side effects associated with a moderate dose of SSRIs were nausea (NNH = 7), asthenia or decreased energy (NNH = 9), somnolence (NNH = 13), fatigue (NNH = 14), decreased libido (NNH = 14) and sweating (NNH = 14). In secondary analyses, SSRIs were effective for treating specific types of symptoms (that is psychological, physical and functional symptoms, and irritability). Adverse effects were dose related.The overall quality of the evidence was low to moderate, the main weakness in the included studies being poor reporting of methods. Heterogeneity was low or absent for most outcomes, though (as noted above) there was moderate heterogeneity for one of the primary analyses. AUTHORS' CONCLUSIONS: SSRIs are effective in reducing the symptoms of PMS, whether taken in the luteal phase only or continuously. Adverse effects are relatively frequent, the most common being nausea and asthenia. Adverse effects are dose-dependent. PMID- 23744612 TI - Postcolonoscopy colorectal cancers are preventable: a population-based study. AB - OBJECTIVE: The quality of colonoscopy is key for ensuring protection against colorectal cancer (CRC). We therefore aimed to elucidate the aetiology of postcolonoscopy CRCs (PCCRCs), and especially to identify preventable factors. METHODS: We conducted a population-based study of all patients diagnosed with CRC in South-Limburg from 2001 to 2010 using colonoscopy and histopathology records and data from the Netherlands Cancer Registry. PCCRCs were defined as cancers diagnosed within 5 years after an index colonoscopy. According to location, CRCs were categorised into proximal or distal from the splenic flexure and, according to macroscopic aspect, into flat or protruded. Aetiological factors for PCCRCs were subdivided into procedure-related (missed lesions, inadequate examination/surveillance, incomplete resection) and biology-related (new cancers). RESULTS: We included a total of 5107 patients with CRC, of whom 147 (2.9% of all patients, mean age 72.8 years, 55.1% men) had PCCRCs diagnosed on average 26 months after an index colonoscopy. Logistic regression analysis, adjusted for age and gender, showed that PCCRCs were significantly more often proximally located (OR 3.92, 95% CI 2.71 to 5.69), smaller in size (OR 0.78, 95% CI 0.70 to 0.87) and more often flat (OR 1.70, 95% CI 1.18 to 2.43) than prevalent CRCs. Of the PCCRCs, 57.8% were attributed to missed lesions, 19.8% to inadequate examination/surveillance and 8.8% to incomplete resection, while 13.6% were newly developed cancers. CONCLUSIONS: In our experience, 86.4% of all PCCRCs could be explained by procedural factors, especially missed lesions. Quality improvements in performance of colonoscopy, with special attention to the detection and resection of proximally located flat precursors, have the potential to prevent PCCRCs. PMID- 23744613 TI - Mortality and causes of death in Crohn's disease: results from 20 years of follow up in the IBSEN study. AB - OBJECTIVE: Population-based studies have shown a slightly decreased life expectancy in patients with Crohn's disease (CD). The primary aim of the present study was to evaluate mortality and causes of death 20 years after the diagnosis in a well defined population-based cohort of CD patients in Norway. DESIGN: The Inflammatory Bowel South-Eastern Norway study has prospectively followed all patients diagnosed with CD in the period between 1 January 1990 and 31 December 1993 in four geographically well-defined areas. All patients (n=237) were age and sex matched with 25 persons from the same county selected at random from the general population. Data on death and causes of deaths were collected from the Norwegian Causes of Death Register. All causes and cause-specific mortality (gastrointestinal cancer, cancer and heart disease) were modelled with Cox regression model stratified by matched sets. Results are expressed as HRs with 95% CIs. RESULTS: There was no significant difference between CD patients and controls in overall mortality (HR=1.35, 95% CI 0.94 to 1.94, p=0.10). Furthermore, there were no marked differences in deaths from gastrointestinal cancer, other cancers or cardiovascular diseases in the CD group compared with the controls. In the CD group, 13.9% had died compared with 12.7% in the control group (p=0.578). CONCLUSIONS: In our population-based inception cohort followed for 20 years, there was no increased mortality or more deaths from cancer compared with the general population. PMID- 23744614 TI - The role of endocannabinoids in pregnancy. AB - Endocannabinoids are a family of lipid signalling molecules. As with prostaglandins (PGs), endocannabinoids are derived from polyunsaturated fatty acids and affect cell function via receptor-mediated mechanisms. They also bind to PG receptors, although at a lower affinity. The endocannabinoid network is regulated in pregnancy from embryo development to labour onset. Even small changes in endocannabinoid exposure can retard embryo development and affect implantation success. There is now compelling evidence that aberrant expression of factors involved in the endocannabinoid pathway in the placenta and circulating lymphocytes results in spontaneous miscarriage and poor pregnancy outcomes. It is likely that competition between endocannabinoids, PGs and other similar lipids ultimately determines how phospholipid/fatty acid substrates are metabolised and, thus, the balance between the uterotonic and tocolytic activities. We, therefore, hypothesise that endocannabinoid profiles may be used as a biomarker to predict and/or identify spontaneous labour onset. PMID- 23744615 TI - Heat stress effects on the cumulus cells surrounding the bovine oocyte during maturation: altered matrix metallopeptidase 9 and progesterone production. AB - When the effects of heat stress are detrimental during maturation, cumulus cells are intimately associated with the oocyte. To determine the extent to which heat stress affects these cells, in this study, transcriptome profiles of the cumulus that surrounded control and heat-stressed oocytes (41 degrees C during the first 12 h only and then shifted back to 38.5 degrees C) during in vitro maturation (IVM) were compared using Affymetrix bovine microarrays. The comparison of cumulus-derived profiles revealed a number of transcripts whose levels were increased (n=11) or decreased (n=13) >= twofold after heat stress exposure (P<0.01), sufficient to reduce the development of blastocysts by 46.4%. In a separate study, quantitative PCR (qPCR) was used to confirm heat-induced differences in the relative abundances of the transcripts of five different genes (caveolin 1, matrix metallopeptidase 9, FSH receptor, Indian hedgehog homolog, and inducible nitric oxide synthase). Heat stress exposure resulted in >1.7-fold decrease in the protein levels of latent matrix metallopeptidase 9 (proMMP9). Heat-induced reductions in transcript levels were noted at 6 h IVM with reductions in proMMP9 protein levels at 18 h IVM (P=0.0002). Independent of temperature, proMMP9 levels at 24 h IVM were positively correlated with the development rate of blastocysts (R2=0.36; P=0.002). The production of progesterone increased during maturation; heat-induced increases were evident by 12 h IVM (P=0.002). Both MMP9 and progesterone are associated with the developmental competence of the oocyte; thus, it seems plausible for some of the negative consequences of heat stress on the cumulus-oocyte complex to be mediated through heat-induced perturbations occurring in the surrounding cumulus. PMID- 23744616 TI - Application of a novel cell-permeable peptide-driven protein delivery in mouse blastocysts. AB - Cell-permeable peptides (CPPs) mediate the delivery of macromolecules into cells. However, whether CPPs are usable in mammalian oocytes and embryos for the modulation of protein expression has not been widely investigated. We have previously designed a novel 12-mer CPP from the conserved region of the human papillomavirus L1 capsid protein. In this study, we tested whether this peptide, LDP12, effectively delivers a protein cargo to mouse oocytes and preimplantation embryos. We prepared a LDP12-EGFP fusion protein having LDP12 as an N-terminal tag. This fusion protein readily enters HeLa cells, a cervical cancer cell line. The entry of LDP12-EGFP was partially blocked by amiloride, while cytochalasin D or methyl-beta-cyclodextrin slightly increased the uptake. LDP12-EGFP shows efficient transduction in mouse blastocysts, but not in oocytes, two-cell-stage, or morula-stage-preimplantation embryos. LDP12-mediated delivery of EGFP-LC3, a widely used marker of autophagic activation, is successful in HeLa cells and mouse blastocysts, as it enters cells and exhibits a signature punctate pattern. The lipidation of EGFP-LC3 also normally occurs after transduction, suggesting that the transduced protein retains the functional characteristics. Collectively, we show that LDP12-driven protein delivery is a fast and convenient method applicable to mouse blastocysts and reproductive cancer cells. PMID- 23744617 TI - Late-phase inflammatory response as a feature of in-stent restenosis after drug eluting stent implantation. AB - OBJECTIVES: The aim of this study was to compare pathological features among in stent restenosis lesions after drug-eluting stent (DES) placement, those after bare metal stent (BMS) placement, and de-novo atherosclerotic lesions. BACKGROUND: Restenosis after stenting is an over-reaction of the wound-healing response after vascular injury, which is characterized by a sequence of inflammation, granulation, extracellular matrix remodeling, and smooth muscle cell proliferation and migration. Recent advances in DES technology could considerably succeed in inhibiting this sequence of events. Thus, we hypothesized that the mechanism of in-stent restenosis after DES stenting might be different from that after BMS stenting as well as atherosclerosis. METHODS: Tissues obtained by directional atherectomy (DES: seven specimens, BMS: 17 specimens, and de-novo: 15 specimens) were immunostained for T lymphocytes (CD45), macrophages (CD68), smooth muscle cells (alpha-smooth muscle actin), endothelial cells (von Willebrand factor), and activated platelets (P-selectin). RESULTS: The accumulation of T lymphocytes tended to increase and that of macrophages increased significantly in the DES lesions compared with BMS lesions. No significant differences were observed for the other parameters evaluated. CONCLUSION: Pathological features of restenotic tissues after DES implantation showed a stronger inflammatory response compared with those after BMS implantation. Thus, the mechanism of restenosis after DES implantation may be different from that observed after BMS implantation. PMID- 23744618 TI - Typical angina without significant coronary stenosis: comparison of clinical profile, circadian presentation, and long-term follow-up between patients with and patients without vasospastic angina. AB - OBJECTIVES: The spectrum of patients with 'angina and normal coronary arteries' ranges from severe vasospasm to atypical chest pain. Among those with typical angina, however, little is known about similarities in the clinical profile and circadian presentation between typical nonvasospastic angina and normal coronary arteries (tANCA) and vasospastic angina (VA). MATERIALS AND METHODS: Clinical, ECG, and angiographic features as well as the circadian characteristics of angina were compared between 384 tANCA and 273 VA patients. Follow-up events were also analyzed. RESULTS: tANCA patients had greater female predominance (61 vs. 18%), higher incidence of dyspnea to moderate exertion (49 vs. 12%), lower incidence of tobacco smoking (25 vs. 67%), but a similar low rate of diabetes (8.9 vs. 4.4%). In both groups, however, dyspnea and smoking were associated with female and male sex, respectively. tANCA patients showed lower but non-negligible frequency of early morning (25 vs. 67%) and evening angina (37 vs. 54%), similar rate of nocturnal angina (47 vs. 50%), and higher rate of emotional angina (49 vs. 31%). Moreover, a high proportion of patients gained pain relief with nitroglycerin (97% in VA, 246/253, and 76% in tANCA, 231/306). At 140 months, frequent angina (>10 episodes/year) was rare (VA: 7.1% vs. tANCA: 6.3%) as was the rate of cardiac death/myocardial infarction (7.3 vs. 6.0%, P=0.524). CONCLUSION: Despite differences in the clinical profile between VA and tANCA patients, there is notable sharing of circadian presentation of rest angina, response to nitroglycerin, and long-term presence and frequency of angina that suggests more similarities in underlying mechanisms than heretofore suspected. PMID- 23744619 TI - A core cross-linked polymeric micellar platium(IV) prodrug with enhanced anticancer efficiency. AB - A core cross-linked polymeric micellar cisplatin(IV) conjugate prodrug is prepared by attaching the cisplatin(IV) to mPEG-b-PLL biodegradable copolymers to form micellar nanoparticles that can disintegrate to release the active anticancer agent cisplatin(II) in a mild reducing environment. Moreover, in vitro studies show that this cisplatin(IV) conjugate prodrug displays enhanced cytotoxicity against HepG2 cancer cells compared with cisplatin(II). Further studies demonstrate that the high cellular uptake and platinum-DNA adduct of this cisplatin(IV) conjugate prodrug can induce more cancer-cell apoptosis than cisplatin(II), which is responsible for its enhanced anticancer activity. PMID- 23744620 TI - Large-scale graphene micropattern nano-biohybrids: high-performance transducers for FET-type flexible fluidic HIV immunoassays. AB - Large-scale FET-type graphene micropattern (GM) nano-biohybrid-based immunosensor (GMNS) is fabricated in a controlled fashion to detect human immunodeficiency virus 2 antibody. Flexible GMNS shows a highly sensitive response and excellent mechanical bendability. The flexible GMNS in fluidic systems also has a stable response. This is the first experimental demonstration of a large-scale flexible fluidic FET-type immunoassay based on GM nano-biohybrids. PMID- 23744621 TI - Stachydrine ameliorates high-glucose induced endothelial cell senescence and SIRT1 downregulation. AB - Hyperglycaemia, a characteristic feature of diabetes mellitus, induces endothelial dysfunction and vascular complications by accelerating endothelial cell (EC) senescence and limiting the proliferative potential of these cells. Here we aimed to investigate the effect of stachydrine, a proline betaine present in considerable quantities in juices from fruits of the Citrus genus, on EC under high-glucose stimulation, and its underlying mechanism. The senescence model of EC was set up by treating cells with high-glucose (30 mM) for different times. Dose-dependent (0.001-1 mM) evaluation of cell viability revealed that stachydrine does not affect cell proliferation with a similar trend up to 72 h. Noticeable, stachydrine (0.1 mM) significantly attenuated the high-glucose induced EC growth arrest and senescence. Indeed, co-treatment with high-glucose and stachydrine for 48 h kept the percentage of EC in the G0 /G1 cell cycle phase near to control values and significantly reduced cell senescence. Western blot analysis and confocal-laser scanning microscopy revealed that stachydrine also blocked the high-glucose induced upregulation of p16(INK4A) and downregulation of SIRT1 expression and enzyme activity. Taken together, results here presented are the first evidence that stachydrine, a naturally occurring compound abundant in citrus fruit juices, inhibits the deleterious effect of high-glucose on EC and acts through the modulation of SIRT1 pathway. These results may open new prospective in the identification of stachydrine as an important component of healthier eating patterns in prevention of cardiovascular diseases. PMID- 23744622 TI - Wear of novel ceramic-on-ceramic bearings under adverse and clinically relevant hip simulator conditions. AB - Further development of ceramic materials for total hip replacement aim to increase fracture toughness and further reduce the incidence of bearing fracture. Edge loading due to translational mal positioning (microseparation) has replicated stripe wear, wear rates, and bimodal wear debris observed on retrievals. This method has replicated the fracture of early zirconia ceramic-on ceramic bearings. This has shown the necessity of introducing microseparation conditions to the gait cycle when assessing the tribological performance of new hip replacement bearings. Two novel ceramic matrix composite materials, zirconia toughened alumina (ZTA) and alumina-toughened zirconia (ATZ), were developed by Mathys Orthopadie GmbH. In this study, ATZ-on-ATZ and ZTA-on-ZTA bearing combinations were tested and compared with alumina-on-alumina (Al2O3-on-Al2O3) bearings under adverse microseparation and edge loading conditions using the Leeds II physiological anatomical hip joint simulator. The wear rate (+/-95% confidence limit) of ZTA-on-ZTA was 0.14 +/- 0.10 mm(3)/million cycles and that of ATZ-on-ATZ was 0.06 +/- 0.004 mm(3)/million cycles compared with a wear rate of 0.74 +/- 1.73 mm(3)/million cycles for Al2O3-on-Al2O3 bearings. Stripe wear was evident on all bearing combinations; however, the stripe formed on the ATZ and ZTA femoral heads was thinner and shallower that that formed on the Al2O3 heads. Posttest phase composition measurements for both ATZ and ZTA materials showed no significant change in the monoclinic zirconia content. ATZ-on-ATZ and ZTA-on-ZTA showed superior wear resistance properties when compared with Al2O3-on Al2O3 under adverse edge loading conditions. PMID- 23744623 TI - Changes in the timing of hay cutting in Germany do not keep pace with climate warming. AB - A unique long-term phenological data set of over 110 000 records of 1st cutting dates for haymaking across Germany, spanning the years 1951-2011 was examined. In addition, we analyzed a long-term data set in the beginning of flowering of meadow foxtail (Alopecurus pratensis) covering the last 20 years. We tested whether hay-cutting dates (based on a human decision when to cut) showed trends, temperature relationships and spatial distribution similar to the development of this grassland species, and if these trends could be related to climate change. The timing of 1st hay cut was strongly influenced (P < 0.001) by altitude, latitude and longitude, revealing in particular an east-west gradient. Over the past 60 years, there have been changes in the timing of hay cutting, with the majority of German federal states having significant (P < 0.05) advances of approximately 1 day per decade. Overall, the response to mean March-May temperature was highly significant (-2.87 days degrees C(-1); P < 0.001). However, in the last 20 years, no federal state experienced a significant advance and two were even significantly delayed. The temperature response in this post 1991 period became less or non-significant for most of the federal states. We suggest that differences in agricultural land use and unequal uptakes of Agri Environment Schemes (AES, which encourage later cutting) were likely to be responsible for the regional differences, while the general increase in AES appears to have confounded the overall trend in hay cutting in the last 20 years. Trends over time and responses to temperature were small relative to those associated with the phenology of meadow foxtail. The advance in phenology of this species is greater than the advance in hay cutting, implying that hay cutting may not be keeping pace with a changing climate, which may have a positive effect on grassland ecology. PMID- 23744624 TI - The utility of multichannel local field potentials for brain-machine interfaces. AB - OBJECTIVE: Local field potentials (LFPs) that carry information about the subject's motor intention have the potential to serve as a complement or alternative to spike signals for brain-machine interfaces (BMIs). The goal of this study is to assess the utility of LFPs for BMIs by characterizing the largely unknown information coding properties of multichannel LFPs. APPROACH: Two monkeys were implanted, each with a 16-channel electrode array, in the parietal reach region where both LFPs and spikes are known to encode the subject's intended reach target. We examined how multichannel LFPs recorded during a reach task jointly carry reach target information, and compared the LFP performance to simultaneously recorded multichannel spikes. MAIN RESULTS: LFPs yielded a higher number of channels that were informative about reach targets than spikes. Single channel LFPs provided more accurate target information than single channel spikes. However, LFPs showed significantly larger signal and noise correlations across channels than spikes. Reach target decoders performed worse when using multichannel LFPs than multichannel spikes. The underperformance of multichannel LFPs was mostly due to their larger noise correlation because noise de-correlated multichannel LFPs produced a decoding accuracy comparable to multichannel spikes. Despite the high noise correlation, decoders using LFPs in addition to spikes outperformed decoders using only spikes. SIGNIFICANCE: These results demonstrate that multichannel LFPs could effectively complement spikes for BMI applications by yielding more informative channels. The utility of multichannel LFPs may be further augmented if their high noise correlation can be taken into account by decoders. PMID- 23744625 TI - Regular treatment with formoterol and inhaled steroids for chronic asthma: serious adverse events. AB - BACKGROUND: Epidemiological evidence has suggested a link between beta2-agonists and increases in asthma mortality. Much debate has surrounded possible causal links for this association and whether regular (daily) long-acting beta2-agonists are safe when used alone or in conjunction with inhaled corticosteroids. This is an updated Cochrane Review. OBJECTIVES: To assess the risk of fatal and non-fatal serious adverse events in people with chronic asthma given regular formoterol with inhaled corticosteroids versus the same dose of inhaled corticosteroids alone. SEARCH METHODS: Trials were identified using the Cochrane Airways Group Specialised Register of trials. Web sites of clinical trial registers were checked for unpublished trial data; Food and Drug Administration (FDA) submissions in relation to formoterol were also checked. The date of the most recent search was August 2012. SELECTION CRITERIA: Controlled clinical trials with a parallel design were included if they randomly allocated people of any age and severity of asthma to treatment with regular formoterol and inhaled corticosteroids for at least 12 weeks. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. Unpublished data on mortality and serious adverse events were obtained from the sponsors. We assessed the quality of evidence using GRADE recommendations. MAIN RESULTS: Following the 2012 update, we have included 20 studies on 10,578 adults and adolescents and seven studies on 2788 children and adolescents. We found data on all-cause fatal and non-fatal serious adverse events for all studies, and we judged the overall risk of bias to be low.Six deaths occurred in participants taking regular formoterol with inhaled corticosteroids, and one in a participant administered regular inhaled corticosteroids alone. The difference was not statistically significant (Peto odds ratio (OR) 3.56, 95% confidence interval (CI) 0.79 to 16.03, low-quality evidence). All deaths were reported in adults, and one was believed to be asthma-related.Non-fatal serious adverse events of any cause were very similar for each treatment in adults (Peto OR 0.98, 95% CI 0.76 to 1.27, moderate-quality evidence), and weak evidence suggested an increase in events in children on regular formoterol (Peto OR 1.62, 95% CI 0.80 to 3.28, moderate-quality evidence).In contrast with all-cause serious adverse events, the addition of new trial data means that asthma-related serious adverse events associated with formoterol are now significantly fewer in adults taking regular formoterol with inhaled corticosteroids (Peto OR 0.49, 95% CI 0.28 to 0.88, moderate-quality evidence). Although a greater number of asthma-related events were reported in children receiving regular formoterol, this finding was not statistically significant (Peto OR 1.49, 95% CI 0.48 to 4.61, low-quality evidence). AUTHORS' CONCLUSIONS: From the evidence in this review, it is not possible to reassure people with asthma that regular use of inhaled corticosteroids with formoterol carries no risk of increasing mortality in comparison with use of inhaled corticosteroids alone. On the other hand, we have found no conclusive evidence of serious harm, and only one asthma-related death was registered during more than 4200 patient-years of observation with formoterol.In adults, no significant difference in all-cause non-fatal serious adverse events was noted with regular formoterol with inhaled corticosteroids, but a significant reduction in asthma-related serious adverse events was observed in comparison with inhaled corticosteroids alone.In children the number of events was too small, and consequently the results too imprecise, to allow determination of whether the increased risk of all-cause non-fatal serious adverse events found in a previous meta-analysis on regular formoterol alone is abolished by the additional use of inhaled corticosteroids.We await the results of large ongoing surveillance studies mandated by the Food and Drug Administration (FDA) for more information. Clinical decisions and information provided to patients regarding regular use of formoterol have to take into account the balance between known symptomatic benefits of formoterol and the degree of uncertainty associated with its potential harmful effects. PMID- 23744626 TI - First-trimester contingent screening for trisomy 21 by biomarkers and maternal blood cell-free DNA testing. AB - OBJECTIVE: To define risk cut-offs with corresponding detection rates (DR) and false-positive rates (FPR) in screening for trisomy 21 using maternal age and combinations of first-trimester biomarkers in order to determine which women should undergo contingent maternal blood cell-free (cf) DNA testing. METHODS: From singleton pregnancies undergoing screening for aneuploidies at three UK hospitals between March 2006 and May 2012, we analyzed prospectively collected data on the following biomarkers: fetal nuchal translucency thickness (NT) and ductus venosus pulsatility index for veins (DV-PIV) at 11 + 0 to 13 + 6 weeks' gestation and serum free beta-human chorionic gonadotropin (beta-hCG), pregnancy associated plasma protein-A (PAPP-A), placental growth factor (PlGF) and alpha fetoprotein (AFP) at 8 + 0 to 13 + 6 weeks. Estimates of risk cut-offs, DRs and FPRs were derived for combinations of biomarkers and these were used to define the best strategy for contingent cfDNA testing. RESULTS: In contingent screening, detection of 98% of fetuses with trisomy 21 at an overall invasive testing rate < 0.5% can be potentially achieved by offering cfDNA testing to about 36%, 21% and 11% of cases identified by first-line screening using the combined test alone, using the combined test with the addition of serum PlGF and AFP and using the combined test with the addition of PlGF, AFP and DV-PIV, respectively. CONCLUSIONS: Effective first-trimester screening for trisomy 21, with DR of 98% and invasive testing rate < 0.5%, can be potentially achieved by contingent screening incorporating biomarkers and cfDNA testing. PMID- 23744627 TI - Sleep-wake abnormalities in patients with cirrhosis. AB - A considerable proportion of patients with cirrhosis exhibit insomnia, delayed sleep habits, and excessive daytime sleepiness. These have been variously attributed to hepatic encephalopathy and impaired hepatic melatonin metabolism, but the understanding of their pathophysiology remains limited and their treatment problematic. Sleep is regulated by the interaction of a homeostatic and a circadian process. The homeostatic process determines sleep propensity in relation to sleep-wake history, thus the need to sleep increases with the duration of the waking period. The circadian process, which is marked by the 24 hour rhythm of the hormone melatonin, is responsible for the alternation of high/low sleep propensity in relation to dark/light cues. Circadian sleep regulation has been studied in some depth in patients with cirrhosis, who show delays in the 24-hour melatonin rhythm, most likely in relation to reduced sensitivity to light cues. However, while melatonin abnormalities are associated with delayed sleep habits, they do not seem to offer a comprehensive explanation to the insomnia exhibited by these patients. Fewer data are available on homeostatic sleep control: it has been recently hypothesized that patients with cirrhosis and hepatic encephalopathy might be unable, due to excessive daytime sleepiness, to accumulate the need/ability to produce restorative sleep. This review will describe in some detail the features of sleep-wake disturbances in patients with cirrhosis, their mutual relationships, and those, if any, with hepatic failure/hepatic encephalopathy. A separate section will cover the available information on their pathophysiology. Finally, etiological treatment will be briefly discussed. PMID- 23744628 TI - Chinese translation and validation of the questionnaire on the process of recovery in schizophrenia and other psychotic disorders. AB - Individuals recovering from schizophrenia and other psychotic disorders who have residual symptoms can achieve relatively normal work and social functioning in the community. This research aimed to test the psychometric properties of a Chinese version of the 22-item Questionnaire about the Process of Recovery. The translated Chinese QPR had satisfactory semantic equivalence with the original scale and high Cronbach alpha coefficients and test-retest stability at a 2-week interval. When tested in 300 outpatients with psychosis, the Chinese version was found to consist of three factors (Self-Empowerment, Rebuilding Life, and Effective Interpersonal Relationships) with satisfactory correlations with patients' quality of life, self-efficacy, and functioning. The Chinese version appears reliable and valid as a measure of psychotic patients' perceived levels of recovery. PMID- 23744629 TI - Mechanistic dichotomy in the asymmetric allylation of aldehydes with allyltrichlorosilanes catalyzed by chiral pyridine N-oxides. AB - Detailed kinetic and computational investigation of the enantio- and diastereoselective allylation of aldehydes 1 with allyltrichlorosilanes 5, employing the pyridine N-oxides METHOX (9) and QUINOX (10) as chiral organocatalysts, indicate that the reaction can proceed through a dissociative (cationic) or associative (neutral) mechanism: METHOX apparently favors a pentacoordinate cationic transition state, while the less sterically demanding QUINOX is likely to operate via a hexacoordinate neutral complex. In both pathways, only one molecule of the catalyst is involved in the rate- and selectivity-determining step, which is supported by both experimental and computational data. PMID- 23744630 TI - Imaging UVC-induced DNA damage response in models of minimal cancer. AB - We have previously demonstrated that the ultraviolet (UV) light is effective against a variety of cancer cells in vivo as well as in vitro. In the present report, we imaged the DNA damage repair response of minimal cancer after UVC irradiation. DNA-damage repair response to UV irradiation was imaged on tumors growing in 3D culture and in superficial tumors grown in vivo. UV-induced DNA damage repair was imaged with GFP fused to the DNA damage response (DDR)-related chromatin-binding protein 53BP1 in MiaPaCa-2 human pancreatic cancer cells. Three dimensional Gelfoam(r) histocultures and confocal imaging enabled 53BP1-GFP nuclear foci to be observed within 1 h after UVC irradiation, indicating the onset of DNA damage repair response. A clonogenic assay showed that UVC inhibited MiaPaCa-2 cell proliferation in a dose-dependent manner, while UVA and UVB showed little effect on cell proliferation. Induction of UV-induced 53BP1-GFP focus formation was limited up to a depth of 40 um in 3D-culture of MiaPaCa-2 cells. The MiaPaCa-2 cells irradiated by UVC light in a skin-flap mouse model had a significant decrease of tumor growth compared to untreated controls. Our results also demonstrate that 53BP1-GFP is an imageable marker of UV-induced DNA damage repair response of minimal cancer and that UVC is a useful tool for the treatment of residual cancer since UVC can kill superficial cancer cells without damage to deep tissue. PMID- 23744631 TI - The International Study on Career Choice in Psychiatry: A preliminary report. PMID- 23744632 TI - WPA educational activities. PMID- 23744633 TI - WPA scientific meetings. PMID- 23744634 TI - WPA contribution to the development of the chapter on mental disorders of the ICD 11: An update. PMID- 23744635 TI - Laser fabrication of porous silicon-based platforms for cell culturing. AB - In this study, we explore the selective culturing of human mesenchymal stem cells (hMSCs) on Si-based diffractive platforms. We demonstrate a single-step and flexible method for producing platforms on nanostructured porous silicon (nanoPS) based on the use of single pulses of an excimer laser to expose phase masks. The resulting patterns are typically 1D patterns formed by fringes or 2D patterns formed by circles. They are formed by alternate regions of almost unmodified nanoPS and regions where the nanoPS surface has melted and transformed into Si nanoparticles. The patterns are produced in relatively large areas (a few square millimeters) and can have a wide range of periodicities and aspect ratios. Direct binding, that is, with no previous functionalization of the pattern, alignment, and active polarization of hMSCs are explored. The results show the preferential direct binding of the hMSCs along the transformed regions whenever their width compares with the dimensions of the cells and they escape from patterns for smaller widths suggesting that the selectivity can be tailored through the pattern period. (c) 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013. PMID- 23744637 TI - Global patterns of nitrogen limitation: confronting two global biogeochemical models with observations. AB - Projections of future changes in land carbon (C) storage using biogeochemical models depend on accurately modeling the interactions between the C and nitrogen (N) cycles. Here, we present a framework for analyzing N limitation in global biogeochemical models to explore how C-N interactions of current models compare to field observations, identify the processes causing model divergence, and identify future observation and experiment needs. We used a set of N fertilization simulations from two global biogeochemical models (CLM-CN and O-CN) that use different approaches to modeling C-N interactions. On the global scale, net primary productivity (NPP) in the CLM-CN model was substantially more responsive to N fertilization than in the O-CN model. The most striking difference between the two models occurred for humid tropical forests, where the CLM-CN simulated a 62% increase in NPP at high N addition levels (30 g N m(-2) yr(-1)), while the O-CN predicted a 2% decrease in NPP due to N fertilization increasing plant respiration more than photosynthesis. Across 35 temperate and boreal forest sites with field N-fertilization experiments, we show that the CLM CN simulated a 46% increase in aboveground NPP in response to N, which exceeded the observed increase of 25%. In contrast, the O-CN only simulated a 6% increase in aboveground NPP at the N-fertilization sites. Despite the small response of NPP to N fertilization, the O-CN model accurately simulated ecosystem retention of N and the fate of added N to vegetation when compared to empirical (15) N tracer application studies. In contrast, the CLM-CN predicted lower total ecosystem N retention and partitioned more losses to volatilization than estimated from observed N budgets of small catchments. These results point to the need for model improvements in both models in order to enhance the accuracy with which global C-N cycle feedbacks are simulated. PMID- 23744636 TI - Performance of chronic kidney disease epidemiology collaboration creatinine cystatin C equation for estimating kidney function in cirrhosis. AB - Conventional creatinine-based glomerular filtration rate (GFR) equations are insufficiently accurate for estimating GFR in cirrhosis. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) recently proposed an equation to estimate GFR in subjects without cirrhosis using both serum creatinine and cystatin C levels. Performance of the new CKD-EPI creatinine-cystatin C equation (2012) was superior to previous creatinine- or cystatin C-based GFR equations. To evaluate the performance of the CKD-EPI creatinine-cystatin C equation in subjects with cirrhosis, we compared it to GFR measured by nonradiolabeled iothalamate plasma clearance (mGFR) in 72 subjects with cirrhosis. We compared the "bias," "precision," and "accuracy" of the new CKD-EPI creatinine-cystatin C equation to that of 24-hour urinary creatinine clearance (CrCl), Cockcroft-Gault (CG), and previously reported creatinine- and/or cystatin C-based GFR-estimating equations. Accuracy of CKD-EPI creatinine-cystatin C equation as quantified by root mean squared error of difference scores (differences between mGFR and estimated GFR [eGFR] or between mGFR and CrCl, or between mGFR and CG equation for each subject) (RMSE = 23.56) was significantly better than that of CrCl (37.69, P = 0.001), CG (RMSE = 36.12, P = 0.002), and GFR-estimating equations based on cystatin C only. Its accuracy as quantified by percentage of eGFRs that differed by greater than 30% with respect to mGFR was significantly better compared to CrCl (P = 0.024), CG (P = 0.0001), 4-variable MDRD (P = 0.027), and CKD-EPI creatinine 2009 (P = 0.012) equations. However, for 23.61% of the subjects, GFR estimated by CKD-EPI creatinine-cystatin C equation differed from the mGFR by more than 30%. CONCLUSION: The diagnostic performance of CKD-EPI creatinine-cystatin C equation (2012) in patients with cirrhosis was superior to conventional equations in clinical practice for estimating GFR. However, its diagnostic performance was substantially worse than reported in subjects without cirrhosis. PMID- 23744638 TI - Epigenetic modifications during sex change repress gonadotropin stimulation of cyp19a1a in a teleost ricefield eel (Monopterus albus). AB - In vertebrates, cytochrome P450 aromatase, encoded by cyp19a1, converts androgens to estrogens and plays important roles in gonadal differentiation and development. The present study examines whether epigenetic mechanisms are involved in cyp19a1a expression and subsequent gonadal development in the hermaphroditic ricefield eel. The expression of the ricefield eel cyp19a1a was stimulated by gonadotropin via the cAMP pathway in the ovary but not the ovotestis or testis. The CpG within the cAMP response element (CRE) of the cyp19a1a promoter was hypermethylated in the ovotestis and testis compared with the ovary. The methylation levels of CpG sites around CRE in the distal region (region II) and around steroidogenic factor 1/adrenal 4 binding protein sites and TATA box in the proximal region (region I) were inversely correlated with cyp19a1a expression during the natural sex change from female to male. In vitro DNA methylation decreased the basal and forskolin-induced activities of cyp19a1a promoter. Chromatin immunoprecipitation assays indicated that histone 3 (Lys9) in both regions I and II of the cyp19a1a promoter were deacetylated and trimethylated in the testis, and in contrast to the ovary, phosphorylated CRE binding protein failed to bind to these regions. Lastly, the DNA methylation inhibitor 5-aza-2'-deoxycytidine reversed the natural sex change of ricefield eels. These results suggested that epigenetic mechanisms involving DNA methylation and histone deacetylation and methylation may abrogate the stimulation of cyp19a1a by gonadotropins in a male-specific fashion. This may be a mechanism widely used to drive natural sex change in teleosts as well as gonadal differentiation in other vertebrates. PMID- 23744640 TI - The two kisspeptin neuronal populations are differentially organized and activated by estradiol in mice. AB - In rodents, kisspeptin-expressing neurons are localized in 2 hypothalamic brain nuclei (anteroventral periventricular nucleus/periventricular nucleus continuum [AVPv/PeN] and arcuate nucleus [ARC]) and modulated by sex steroids. By using wild-type (WT) and aromatase knockout (ArKO) mice (which cannot convert testosterone into estradiol) and immunohistochemistry, we observed that WT females showed a continuous increase in kisspeptin peptide expression in the ARC across postnatal ages (postnatal day 5 [P5] to P25), whereas WT males did not show any expression before P25. Kisspeptin peptide expression was also present in ArKO females but did not increase over this early postnatal period, suggesting that kisspeptin peptide expression in the ARC is organized by estradiol-dependent and -independent mechanisms. We also compared kisspeptin peptide expression between groups of adult male and female mice that were left gonadally intact or gonadectomized and treated or not with estradiol (E(2)) or DHT. In the ARC, kisspeptin peptide expression decreased after gonadectomy but was completely rescued by either E(2) or DHT treatment in each sex/genotype. However, kisspeptin peptide expression was lower in ArKO compared with WT subjects. In the AVPv/PeN, ArKO females showed a male-typical kisspeptin peptide expression, and adult E(2) treatment partially restored kisspeptin peptide expression. Finally, we showed that, after E2 treatment of WT and ArKO mice between either P5 and P15 or P15 and P25, AVPv/PeN kisspeptin peptide expression could be still masculinized at P5, but was feminized from P15 onward. In conclusion, the 2 kisspeptin neuronal populations (AVPv/PeN vs ARC) seem to be differentially organized and activated by E(2). PMID- 23744639 TI - Kisspeptin activation of TRPC4 channels in female GnRH neurons requires PIP2 depletion and cSrc kinase activation. AB - Kisspeptin signaling via its Galphaq-coupled receptor GPR54 plays a crucial role in modulating GnRH neuronal excitability, which controls pituitary gonadotropins secretion and ultimately reproduction. Kisspeptin potently depolarizes GnRH neurons primarily through the activation of canonical transient receptor potential (TRPC) channels, but the intracellular signaling cascade has not been elucidated. Presently, we have established that kisspeptin activation of TRPC channels requires multiple membrane and intracellular signaling molecules. First, phosphatidylinositol-4,5-bisphosphate (PIP(2)) hydrolysis by phospholipase Cbeta is required because whole-cell dialysis of Dioctanoylglycerol-PIP(2) (DiC8 PIP(2)) inhibited the kisspeptin activation of TRPC channels, and the phosphatidylinositol 4-kinase inhibitor wortmannin, which attenuates PIP(2) synthesis, prolonged TRPC channel activation. Using single cell RT-PCR, we identified that the mRNA for the PIP(2)-interacting TRPC channel subunit, TRPC4alpha, is expressed in GnRH neurons. Depletion of intracellular Ca(2+) stores by thapsigargin and inositol 1,4,5-trisphosphate had no effect, indicating that the TRPC channels are not store-operated. Neither removing extracellular Ca(2+) nor buffering intracellular Ca(2+) with EGTA or BAPTA had any effect on the kisspeptin activation of the TRPC channels. However, the Ca(2+) channel blocker Ni(2+) inhibited the kisspeptin-induced inward current. Moreover, inhibition of protein kinase C by bisindolylmaleimide-I or calphostin C had no effect, but activation of protein kinase C by phorbol 12,13-dibutyrate occluded the kisspeptin-activated current. Finally, inhibition of the cytoplasmic tyrosine kinase cSrc by genistein or the pyrazolo-pyrimidine PP2 blocked the activation of TRPC channels by kisspeptin. Therefore, TRPC channels in GnRH neurons are receptor-operated, and kisspeptin activates TRPC channels through PIP(2) depletion and cSrc tyrosine kinase activation, which is a novel signaling pathway for peptidergic excitation of GnRH neurons. PMID- 23744641 TI - Neurokinin B activates arcuate kisspeptin neurons through multiple tachykinin receptors in the male mouse. AB - Kisspeptin neurons located in the arcuate nucleus (ARN) coexpress dynorphin and neurokinin B (NKB) and may interact to influence gonadotropin secretion. Using a kisspeptin-green fluorescent protein mouse model, the present study examined whether the neuropeptides kisspeptin, dynorphin, and NKB modulate the electrical activity of ARN kisspeptin neurons in the adult male mouse. Cell-attached recordings showed that kisspeptin itself had no effect on kisspeptin neuron firing. Dynorphin and the kappa-opioid receptor agonist U50-488 evoked a potent suppression of all ARN kisspeptin neuron firing that was blocked completely by the kappa-opioid receptor antagonist nor-Binaltorphimine. Both NKB and Senktide, a neurokinin 3 receptor agonist, exerted a potent stimulatory action on ~95% of ARN kisspeptin neurons. Although the selective neurokinin 3 receptor antagonists SB222200 and SR142801 blocked the effects of Senktide on kisspeptin neurons, they surprisingly had no effect on NKB activation of firing. Studies with selective neurokinin 1 receptor (SDZ-NKT343) and neurokinin 2 receptor (GR94800) antagonists revealed that the activation of kisspeptin neurons by NKB was only blocked completely by a cocktail of antagonists against all 3 tachykinin receptors. Whole-cell recordings revealed that individual kisspeptin neurons were activated directly by all 3 tachykinins substance, P, neurokinin A, and NKB. These experiments show that dynorphin and NKB have opposing actions on the electrical activity of kisspeptin neurons supporting the existence of an interconnected network of kisspeptin neurons in the ARN. However, the effects of NKB result from an unexpected activation of multiple tachykinin receptors. PMID- 23744643 TI - Inhibition of geranylgeranyltransferase attenuates neutrophil accumulation and tissue injury in severe acute pancreatitis. AB - Leukocyte infiltration and acinar cell necrosis are hallmarks of severe AP, but the signaling pathways regulating inflammation and organ injury in the pancreas remain elusive. In the present study, we investigated the role of geranylgeranyltransferase in AP. Male C57BL/6 mice were treated with a geranylgeranyltransferase inhibitor GGTI-2133 (20 mg/kg) prior to induction of pancreatitis by infusion of taurocholate into the pancreatic duct. Pretreatment with GGTI-2133 reduced plasma amylase levels, pancreatic neutrophil recruitment, hemorrhage, and edema formation in taurocholate-evoked pancreatitis. Moreover, administration of GGTI-2133 decreased the taurocholate-induced increase of MPO activity in the pancreas and lung. Treatment with GGTI-2133 markedly reduced levels of CXCL2 in the pancreas and IL-6 in the plasma in response to taurocholate challenge. Notably, geranylgeranyltransferase inhibition abolished neutrophil expression of Mac-1 in mice with pancreatitis. Finally, inhibition of geranylgeranyltransferase had no direct effect on secretagogue-induced activation of trypsinogen in pancreatic acinar cells in vitro. A significant role of geranylgeranyltransferase was confirmed in an alternate model of AP induced by L arginine challenge. Our findings show that geranylgeranyltransferase regulates neutrophil accumulation and tissue damage via expression of Mac-1 on neutrophils and CXCL2 formation in AP. Thus, these results reveal new signaling mechanisms in pancreatitis and indicate that targeting geranylgeranyltransferase might be an effective way to ameliorate severe AP. PMID- 23744642 TI - Regulation of arcuate neurons coexpressing kisspeptin, neurokinin B, and dynorphin by modulators of neurokinin 3 and kappa-opioid receptors in adult male mice. AB - Pulsatile GnRH release is essential to fertility and is modulated by gonadal steroids, most likely via steroid-sensitive afferents. Arcuate neurons coexpressing kisspeptin, neurokinin B (NKB), and dynorphin (KNDy neurons) are steroid-sensitive and have been postulated to both generate GnRH pulses and mediate steroid feedback on pulse frequency. KNDy neurons are proposed to interact with one another via NKB and dynorphin to activate and inhibit the KNDy network, respectively, and thus alter kisspeptin output to GnRH neurons. To test the roles of NKB and dynorphin on KNDy neurons and the steroid sensitivity of these actions, targeted extracellular recordings were made of Tac2(NKB)-GFP identified neurons from castrate and intact male mice. Single-cell PCR confirmed most of these cells had a KNDy phenotype. The neurokinin 3 receptor (NK3R) agonist senktide increased action potential firing activity of KNDy neurons. Dynorphin reduced spontaneous KNDy neuron activity, but antagonism of kappa opioid receptors (KOR) failed to induce firing activity in quiescent KNDy neurons. Senktide-induced activation was greater in KNDy neurons from castrate mice, whereas dynorphin-induced suppression was greater in KNDy neurons from intact mice. Interactions of dynorphin with senktide-induced activity were more complex; dynorphin treatment after senktide had no consistent inhibitory effect, whereas pretreatment with dynorphin decreased senktide-induced activity only in KNDy neurons from intact but not castrate mice. These data suggest dynorphin mediated inhibition of senktide-induced activity requires gonadal steroid feedback. Together, these observations support the hypotheses that activation of NK3R and KOR, respectively, excites and inhibits KNDy neurons and that gonadal steroids modulate these effects. PMID- 23744644 TI - Retinoic acid, acting as a highly specific IgA isotype switch factor, cooperates with TGF-beta1 to enhance the overall IgA response. AB - The present study demonstrates that RA has activity of an IgA switch factor and is more specific than TGF-beta1. RA independently caused only IgA switching, whereas TGF-beta1 caused IgA and IgG2b switching. We found that RA increased IgA production and that this was a result of its ability to increase the frequency of IgA-secreting B cell clones. Increased IgA production was accompanied by an increase of GLTalpha. RA activity was abrogated by an antagonist of the RAR. Additionally, RA affected intestinal IgA production in mice. Surprisingly, RA, in combination with TGF-beta1, notably enhanced not only IgA production and GLTalpha expression but also CCR9 and alpha4beta7 expression on B cells. These results suggest that RA selectively induces IgA isotype switching through RAR and that RA and TGF-beta have important effects on the overall gut IgA antibody response. PMID- 23744645 TI - RIG-I activation inhibits HIV replication in macrophages. AB - The RIG-I signaling pathway is critical in the activation of the type I IFN dependent antiviral innate-immune response. We thus examined whether RIG-I activation can inhibit HIV replication in macrophages. We showed that the stimulation of monocyte-derived macrophages with 5'ppp-dsRNA, a synthetic ligand for RIG-I, induced the expression of RIG-I, IFN-alpha/beta, and several IRFs, key regulators of the IFN signaling pathway. In addition, RIG-I activation induced the expression of multiple intracellular HIV-restriction factors, including ISGs, several members of the APOBEC3 family, tetherin and CC chemokines, the ligands for HIV entry coreceptor (CCR5). The inductions of these factors were associated with the inhibition of HIV replication in macrophages stimulated by 5'ppp-dsRNA. These observations highlight the importance of RIG-I signaling in macrophage innate immunity against HIV, which can be beneficial for the treatment of HIV disease, where intracellular immune defense is compromised by the virus. PMID- 23744646 TI - MGL signaling augments TLR2-mediated responses for enhanced IL-10 and TNF-alpha secretion. AB - DCs orchestrate immune responses to infectious pathogens and disturbances in tissue integrity. Equipped with C-type lectins, DCs can respond to environmental changes in glycosylation. Many C-type lectins are capable of modulating TLR activation, thereby facilitating tailor-made immune reactions. Here, we investigated the signaling properties of the C-type lectin MGL and show that MGL engagement by agonistic antibodies or carbohydrate ligands couples to TLR signal transduction for increased IL-10 and TNF-alpha secretion by human monocyte derived DCs. MGL triggering especially synergized with TLR2-induced pathways, leading to elevated IL-10 mRNA levels and enhanced TNF-alpha mRNA stability. In addition, MGL signaling promoted phosphorylation of the MAPK ERK and the transcription factor CREB. Whereas specific inhibitors of p90RSK blocked the MGL induced cytokine secretion, AP-1 was not involved. Strikingly, NF-kappaB was only crucial for the IL-10 response and dispensable for TNF-alpha production. Together, our results demonstrate that MGL activation of the ERK-p90RSK-CREB axis converges with TLR2-induced pathways, thereby fine-tuning the DC maturation phenotype. PMID- 23744649 TI - Statistics notes: missing outcomes in randomised trials. PMID- 23744648 TI - The secretome signature of colon cancer cell lines. AB - The definition of the secretome signature of a cancer cell line can be considered a potential tool to investigate tumor aggressiveness and a preclinical exploratory study required to optimize the search of cancer biomarkers. Dealing with a cell-specific secretome limits the contamination by the major components of the human serum and reduces the range of dynamic concentrations among the secreted proteins, thus favouring under-represented tissue-specific species. The aim of the present study is to characterize the secretome of two human colon carcinoma cell lines, CaCo-2 and HCT-GEO, in order to evaluate differences and similarities of two colorectal cancer model systems. In this study, we identified more than 170 protein species, 64 more expressed in the secretome of CaCo-2 cells and 54 more expressed in the secretome of HCT-GEO cells; 58 proteins were shared by the two systems. Among them, more than 50% were deemed to be secretory according to their Gene Ontology annotation and/or to their SignalP or SecretomeP scores. Such a characterization allowed corroborating the potential of a cell culture-based model in order to describe the cell-specific invasive properties and to provide a list of putative cancer biomarkers. PMID- 23744647 TI - B7-1/B7-2 blockade overrides the activation of protective CD8 T cells stimulated in the absence of Foxp3+ regulatory T cells. AB - Although T cell activation has been classically described to require distinct, positive stimulation signals that include B7-1 (CD80) and B7-2 (CD86) costimulation, overriding suppression signals that avert immune-mediated host injury are equally important. How these opposing stimulation and suppression signals work together remains incompletely defined. Our recent studies demonstrate that CD8 Teff activation in response to cognate peptide stimulation is actively suppressed by the Foxp3(+) subset of CD4 cells, called Tregs. Here, we show that the elimination of Treg suppression does not bypass the requirement for positive B7-1/B7-2 costimulation. The expansion, IFN-gamma cytokine production, cytolytic, and protective features of antigen-specific CD8 T cells stimulated with purified cognate peptide in Treg-ablated mice were each neutralized effectively by CTLA-4-Ig that blocks B7-1/B7-2. In turn, given the efficiency whereby CTLA-4-Ig overrides the effects of Treg ablation, the role of Foxp3(+) cell-intrinsic CTLA-4 in mitigating CD8 Teff activation was also investigated. With the use of mixed chimera mice that contain CTLA-4-deficient Tregs exclusively after the ablation of WT Foxp3(+) cells, a critical role for Treg CTLA-4 in suppressing the expansion, cytokine production, cytotoxicity, and protective features of peptide-stimulated CD8 T cells is revealed. Thus, the activation of protective CD8 T cells requires positive B7-1/B7-2 costimulation even when suppression by Tregs and in particular, Treg-intrinsic CTLA-4 is circumvented. PMID- 23744650 TI - Report highlights potential benefits of mobile communication devices for health. PMID- 23744651 TI - Doctors must lead efforts to reduce waste and variation in practice. PMID- 23744652 TI - Institute of Medicine outlines research plan on US gun violence. PMID- 23744653 TI - Report on chemical exposure is criticised for panicking pregnant women. PMID- 23744654 TI - Linear free-energy correlations for the vinylheptafulvene ring closure: a probe for Hammett sigma values. AB - Linear free-energy relationships, like Hammett correlations, are fundamental in physical organic chemistry for the elucidation of reaction mechanisms. In this work, we show that Hammett correlations exist for the ring closure of six different model systems of vinylheptafulvenes (VHFs) to their corresponding dihydroazulenes (DHAs). These first-order reactions were easily followed by UV/Vis absorption spectroscopy on account of the significantly different absorption characteristics between VHFs and DHAs. Opposing effects displayed by substituent groups at two different positions are conveniently accounted for by simply subtracting the two Hammett sigma values of each group. The linear correlations readily allow us to obtain unknown and approximate Hammett sigma values for previously uninvestigated substituents. We also show that they can provide alternative values to the standard ones. We present values for a variety of substituent groups ranging from alkynes, sulfones, sulfoxides, and different heteroaromatics. The electronic effects exerted by substituent groups on VHFs are also reflected in their absorption maxima. Thus, we have established an empirical relationship between the absorption maximum of the VHF and the Hammett sigma values of its substituents. This fine-tuning of electronic properties is particularly important for the ongoing efforts of using the DHA/VHF molecular switch in molecular electronics devices. PMID- 23744655 TI - A modified generalized series approach: application to sparsely sampled FMRI. AB - In functional MRI, it is often desirable to reduce the readout duration to make the acquired data less prone to T2* susceptibility artifacts. In addition, a shorter readout length allows for a shorter minimum TE, which is important for optimizing SNR. This can be achieved by undersampling the k-space. However, the conventional Fourier transform-based reconstruction method suffers from under sampling artifacts such as high-frequency ringing and loss of resolution. To address this problem, we revisit the constrained-model approach using the generalized-series (GS) which has been proposed to address the undersampling problem for dynamic MRI. We propose a modification to the conventional use of the model in order to reflect small hemodynamic signal changes typical in fMRI. Specifically, while realizing that having high model order is necessary to capture missing information, we found that it is not necessary to span all frequencies of GS basis functions uniformly. Instead, having k -space and GS "sampling" trajectories covering low-frequencies uniformly while spanning high frequencies sparsely, was observed to be an efficient strategy. The ability of the method over the conventional GS approach in improving resolution of functional images and activation maps while reducing undersampling ringing is demonstrated by simulations and experiments at 3T. Reduction in the readout time allowed an increase of statistical signal power as compared to the fully sampled acquisition. Unlike compressed sensing approaches, the proposed method is linear and hence has lower computational complexity. The method could prove useful for other imaging modalities where the signal change is smaller than the baseline component. PMID- 23744656 TI - A flexible base electrode array for intraspinal microstimulation. AB - In this paper, we report the development of a flexible base array of penetrating electrodes which can be used to interface with the spinal cord. A customizable and feasible fabrication protocol is described. The flexible base arrays were fabricated and implanted into surrogate cords which were elongated by 12%. The resulting strains were optically measured across the cord and compared to those associated with two types of electrodes arrays (one without a base and one with a rigid base connecting the electrodes). The deformation behavior of cords implanted with the flexible base arrays resembled the behavior of cords implanted with individual microwires that were not connected through a base. The results of the strain test were used to validate a 2-D finite element model. The validated model was used to assess the stresses induced by the electrodes of the three types of arrays on the cord, and to examine how various design parameters (thickness, base modulus, etc.,) impact the mechanical behavior of the electrode array. Rigid base arrays induced higher stresses on the cord than the flexible base arrays which in turn imposed higher stresses than the individual microwire implants. The developed flexible base array showed improvement over the rigid base array; however, its stiffness needs to be further reduced to emulate the mechanical behavior of individual microwire arrays without a base. PMID- 23744657 TI - High-resolution cardiovascular MRI by integrating parallel imaging with low-rank and sparse modeling. AB - Magnetic resonance imaging (MRI) has long been recognized as a powerful tool for cardiovascular imaging because of its unique potential to measure blood flow, cardiac wall motion, and tissue properties jointly. However, many clinical applications of cardiac MRI have been limited by low imaging speed. In this paper, we present a novel method to accelerate cardiovascular MRI through the integration of parallel imaging, low-rank modeling, and sparse modeling. This method consists of a novel image model and specialized data acquisition. Of particular novelty is the proposed low-rank model component, which is specially adapted to the particular low-rank structure of cardiovascular signals. Simulations and in vivo experiments were performed to evaluate the method, as well as an analysis of the low-rank structure of a numerical cardiovascular phantom. Cardiac imaging experiments were carried out on both human and rat subjects without the use of ECG or respiratory gating and without breath holds. The proposed method reconstructed 2-D human cardiac images up to 22 fps and 1.0 mm * 1.0 mm spatial resolution and 3-D rat cardiac images at 67 fps and 0.65 mm * 0.65 mm * 0.31 mm spatial resolution. These capabilities will enhance the practical utility of cardiovascular MRI. PMID- 23744658 TI - Automatic delineation of the myocardial wall from CT images via shape segmentation and variational region growing. AB - Prognosis and diagnosis of cardiac diseases frequently require quantitative evaluation of the ventricle volume, mass, and ejection fraction. The delineation of the myocardial wall is involved in all of these evaluations, which is a challenging task due to large variations in myocardial shapes and image quality. In this paper, we present an automatic method for extracting the myocardial wall of the left and right ventricles from cardiac CT images. In the method, the left and right ventricles are located sequentially, in which each ventricle is detected by first identifying the endocardium and then segmenting the epicardium. To this end, the endocardium is localized by utilizing its geometric features obtained on-line from a CT image. After that, a variational region-growing model is employed to extract the epicardium of the ventricles. In particular, the location of the endocardium of the left ventricle is determined via using an active contour model on the blood-pool surface. To localize the right ventricle, the active contour model is applied on a heart surface extracted based on the left ventricle segmentation result. The robustness and accuracy of the proposed approach is demonstrated by experimental results from 33 human and 12 pig CT images. PMID- 23744659 TI - Robust pulse rate from chrominance-based rPPG. AB - Remote photoplethysmography (rPPG) enables contactless monitoring of the blood volume pulse using a regular camera. Recent research focused on improved motion robustness, but the proposed blind source separation techniques (BSS) in RGB color space show limited success. We present an analysis of the motion problem, from which far superior chrominance-based methods emerge. For a population of 117 stationary subjects, we show our methods to perform in 92% good agreement ( +/ 1.96sigma) with contact PPG, with RMSE and standard deviation both a factor of 2 better than BSS-based methods. In a fitness setting using a simple spectral peak detector, the obtained pulse-rate for modest motion (bike) improves from 79% to 98% correct, and for vigorous motion (stepping) from less than 11% to more than 48% correct. We expect the greatly improved robustness to considerably widen the application scope of the technology. PMID- 23744660 TI - Computer-aided diagnosis in phase contrast imaging X-ray computed tomography for quantitative characterization of ex vivo human patellar cartilage. AB - Visualization of ex vivo human patellar cartilage matrix through the phase contrast imaging X-ray computed tomography (PCI-CT) has been previously demonstrated. Such studies revealed osteoarthritis-induced changes to chondrocyte organization in the radial zone. This study investigates the application of texture analysis to characterizing such chondrocyte patterns in the presence and absence of osteoarthritic damage. Texture features derived from Minkowski functionals (MF) and gray-level co-occurrence matrices (GLCM) were extracted from 842 regions of interest (ROI) annotated on PCI-CT images of ex vivo human patellar cartilage specimens. These texture features were subsequently used in a machine learning task with support vector regression to classify ROIs as healthy or osteoarthritic; classification performance was evaluated using the area under the receiver operating characteristic curve (AUC). The best classification performance was observed with the MF features perimeter (AUC: 0.94 +/-0.08 ) and "Euler characteristic" (AUC: 0.94 +/-0.07 ), and GLCM-derived feature "Correlation" (AUC: 0.93 +/-0.07). These results suggest that such texture features can provide a detailed characterization of the chondrocyte organization in the cartilage matrix, enabling classification of cartilage as healthy or osteoarthritic with high accuracy. PMID- 23744661 TI - Unobtrusive, continuous, in-home gait measurement using the Microsoft Kinect. AB - A system for capturing habitual, in-home gait measurements using an environmentally mounted depth camera, the Microsoft Kinect, is presented. Previous work evaluating the use of the Kinect sensor for in-home gait measurement in a lab setting has shown the potential of this approach. In this paper, a single Kinect sensor and computer were deployed in the apartments of older adults in an independent living facility for the purpose of continuous, in home gait measurement. In addition, a monthly fall risk assessment protocol was conducted for each resident by a clinician, which included traditional tools such as the timed up a go and habitual gait speed tests. A probabilistic methodology for generating automated gait estimates over time for the residents of the apartments from the Kinect data is described, along with results from the apartments as compared to two of the traditionally measured fall risk assessment tools. Potential applications and future work are discussed. PMID- 23744662 TI - Characterization and modeling of muscle sympathetic nerve spiking. AB - Muscle sympathetic nerve activity is a primary source of cardiovascular control in humans. Traditional analyses smooth away the fine temporal structure of the sympathetic recordings, limiting our understanding of sympathetic activation mechanisms. We use multifiber spike trains extracted from standard microneurography voltage trace to characterize the sympathetic spiking at rest and during sympathoexcitation. Our analysis corroborates known features of sympathetic activity, such as bursting behavior, cardiac rhythmicity, and long conduction delays. It also elucidates new features such as large heartbeat-to heartbeat variability of firing rates and precise pattern of spiking within cardiac cycles. We find that at low firing rates, spikes occur uniformly throughout the cardiac cycle, but at higher rates, they tend to cluster in bursts around a particular latency. This latency shortens and the clusters tighten as the firing rates grow. Sympathoexcitation increases firing rates and shifts the burst latency later. Negative rate/latency correlation and the sympathoexcitatory shift suggest that spike production of the individual fibers contributes significantly to the control of the sympathetic bursts strength. Access to fine scale temporal information, more physiologically accurate description of nerve activity, and new hypotheses about the nervous outflow control establishes sympathetic spiking as a valuable tool for the cardiovascular research. PMID- 23744663 TI - Estimating conditional probabilities for the detection of unfavorable copy number alterations in a targeted therapy. AB - Emerging targeted therapies have shown benefits such as less toxicity and higher effectiveness in specific types of cancer treatment; however, the accessibility of these advantages may rely on correct identification of suitable patients, which remains highly immature. We assume that copy number profiles, being accessible genomic data via microarray techniques, can provide useful information regarding drug response and shed light on personalized therapy. Based on the mechanism of action (MOA) of trastuzumab in the HER2 signaling pathway, a Bayesian network model in which copy number alterations (CNAs) serve as latent parents modifying signal transduction is applied. Two model parameters M-score and R -value which stand for the qualitative and quantitative effects of CNAs on drug effectiveness and are functions of conditional probabilities (CPs), are defined. An expectation-maximization (EM) algorithm is developed for estimating CPs, M-scores, and R-values from continuous measures, such as microarray data. We show through simulations that the EM algorithm can outperform classical threshold based methods in the estimation of CPs and thereby provide improved performance for the detection of unfavorable CNAs. Several candidates of unfavorable CNAs to the trastuzumab therapy in breast cancer are provided in a real data example. PMID- 23744664 TI - Coordinator Traffic Diffusion for Data-Intensive Zigbee Transmission in Real-time Electrocardiography Monitoring. AB - Zigbee is expected to have an explosive growth in wireless medical monitoring systems because it possesses the advantages of low cost, safe power strength, and easy deployment. However, limited work focuses on solving the bottleneck issue at the Zigbee coordinator in a data-intensive system to guarantee transmission reliability of life-critical data. This paper proposes coordinator traffic diffusion (CTD) method to redirect excessive traffic from coordinator to the sink in electrocardiography (ECG) medical application. CTD router, which implements CTD design, automatically redirects ECG data traffic to the sink node without involving the coordinator, and thus reliable real-time ECG monitoring service can be delivered precisely. CTD design is tested in both TI CC2530 Zigbee platform and NS2 simulation. Experimental result demonstrates that a CTD design can assist routers in successfully delivering real-time ECG data samples reliably with the best transmission rate, 24 kb/s. This performance cannot be achieved by the original Zigbee design. PMID- 23744666 TI - Type testing of a head band dosemeter for measuring eye lens dose in terms of H(P)(3). AB - A new head band dosemeter, for the measurement of eye lens dose in terms of Hp(3), has been type tested by Public Health England's Centre for Radiation, Environmental and Chemical Hazards [formerly part of the UK Health Protection Agency (HPA)]. The type tests were based on the International Standard ISO 12794, drawing also upon earlier work at HPA. The results show that, unlike many existing dosemeters, the new head band dosemeter correctly measures Hp(3) for beta radiations as well as photons. PMID- 23744667 TI - Effect of hydroxyapatite spheres, whiskers, and nanoparticles on mechanical properties of a model BisGMA/TEGDMA composite initially and after storage. AB - This study investigated the effect of shape, size, and surface modification of hydroxyapatite (HAP) fillers on the degree of conversion (DC) and mechanical properties of a model BisGMA/TEGDMA composite initially and after 4 weeks of storage. Ten percent of conventional glass fillers were replaced by HAP spheres (Sph), silicon-doped spheres (SphSi), whiskers (Wh), silicon-doped whiskers (WhSi), and nanosized HAP particles (Nano). Spheres were specifically structured agglomerates consisting of a central void and radially orientated primary particles, whereas whiskers were compact monocrystals. DC, Vickers hardness (HV), flexural strength (Fs), flexural modulus (Ef), compressive strength (Cs), and compressive modulus (Ec) were tested. There were no significant differences in the DC between all tested groups. HV decreased by 5.4-17% with the addition of HAP, while Fs increased by 13.9-29% except in Nano group (decrease by 13%). After storage, Sph and SphSi groups showed similar HV, Ef, Cs and Ec and higher Fs than the control. The fracture mode of HAP spheres was through the central void whereas whiskers showed longitudinal delamination, transverse, and mixed fractures. HAP spheres with or without silicon- doping have a potential to be part of the filler content of dental composites. PMID- 23744668 TI - Proportional hazards modeling of saccadic response times during reading. AB - In this article we use proportional hazards models to examine how low-level processes affect the probability of making a saccade over time, through the period of fixation, during reading. We apply the Cox proportional hazards model to investigate how launch distance (relative to word beginning), fixation location (relative to word center), and word frequency affect the hazard of a saccadic response. This model requires that covariates have a constant impact on the hazard over time, the assumption of proportional hazards. We show that this assumption is not supported. The impact of the covariates changes with the time passed since fixation onset. To account for the non-proportional hazards we fit step functions of time, resulting in a model with time-varying effects on the hazard. We evaluate the ability to predict the timing of saccades on held-out fixation data. The model with time-varying effects performs better in predicting the timing of saccades for fixations as short as 100 ms and as long as 500 ms, when compared both to a baseline model without covariates and a model which assumes constant covariate effects. This result suggests that the time-varying effects model better recovers the time course of low-level processes that influence the decision to move the eyes. PMID- 23744669 TI - X-ray CT metal artifact reduction using wavelet domain L0 sparse regularization. AB - X-ray computed tomography (CT) imaging of patients with metallic implants usually suffers from streaking metal artifacts. In this paper, we propose a new projection completion metal artifact reduction (MAR) algorithm by formulating the completion of missing projections as a regularized inverse problem in the wavelet domain. The Douglas-Rachford splitting (DRS) algorithm was used to iteratively solve the problem. Two types of prior information were exploited in the algorithm: 1) the sparsity of the wavelet coefficients of CT sinograms in a dictionary of translation-invariant wavelets and 2) the detail wavelet coefficients of a prior sinogram obtained from the forward projection of a segmented CT image. A pseudo- L0 synthesis prior was utilized to exploit and promote the sparsity of wavelet coefficients. The proposed L0-DRS MAR algorithm was compared with standard linear interpolation and the normalized metal artifact reduction (NMAR) approach proposed by Meyer using both simulated and clinical studies including hip prostheses, dental fillings, spine fixation and electroencephalogram electrodes in brain imaging. The qualitative and quantitative evaluations showed that our algorithm substantially suppresses streaking artifacts and can outperform both linear interpolation and NMAR algorithms. PMID- 23744670 TI - Automated abdominal multi-organ segmentation with subject-specific atlas generation. AB - A robust automated segmentation of abdominal organs can be crucial for computer aided diagnosis and laparoscopic surgery assistance. Many existing methods are specialized to the segmentation of individual organs and struggle to deal with the variability of the shape and position of abdominal organs. We present a general, fully-automated method for multi-organ segmentation of abdominal computed tomography (CT) scans. The method is based on a hierarchical atlas registration and weighting scheme that generates target specific priors from an atlas database by combining aspects from multi-atlas registration and patch-based segmentation, two widely used methods in brain segmentation. The final segmentation is obtained by applying an automatically learned intensity model in a graph-cuts optimization step, incorporating high-level spatial knowledge. The proposed approach allows to deal with high inter-subject variation while being flexible enough to be applied to different organs. We have evaluated the segmentation on a database of 150 manually segmented CT images. The achieved results compare well to state-of-the-art methods, that are usually tailored to more specific questions, with Dice overlap values of 94%, 93%, 70%, and 92% for liver, kidneys, pancreas, and spleen, respectively. PMID- 23744671 TI - Analytic model of energy-absorption response functions in compound X-ray detector materials. AB - The absorbed energy distribution (AED) in X-ray imaging detectors is an important factor that affects both energy resolution and image quality through the Swank factor and detective quantum efficiency. In the diagnostic energy range (20-140 keV), escape of characteristic photons following photoelectric absorption and Compton scatter photons are primary sources of absorbed-energy dispersion in X ray detectors. In this paper, we describe the development of an analytic model of the AED in compound X-ray detector materials, based on the cascaded-systems approach, that includes the effects of escape and reabsorption of characteristic and Compton-scatter photons. We derive analytic expressions for both semi infinite slab and pixel geometries and validate our approach by Monte Carlo simulations. The analytic model provides the energy-dependent X-ray response function of arbitrary compound materials without time-consuming Monte Carlo simulations. We believe this model will be useful for correcting spectral distortion artifacts commonly observed in photon-counting applications and optimal design and development of novel X-ray detectors. PMID- 23744672 TI - Evaluation of imaging systems using the posterior variance of emission counts. AB - We investigate an approach to evaluation of emission-tomography (ET) imaging systems used for region-of-interest (ROI) estimation tasks. In the evaluation we employ the concept of "emission counts" (EC), which are the number of events per voxel emitted during a scan. We use the reduction in posterior variance of ROI EC, compared to the prior ROI EC variance, as the metric of primary interest, which we call the "posterior variance reduction index" (PVRI). Systems that achieve a higher PVRI are considered superior to systems with lower PVRI. The approach is independent of the reconstruction method and is applicable to all photon-limited data types including list-mode data. We analyzed this approach using a model of 2-D tomography, and compared our results to the classical theory of tomographic sampling. We found that performance evaluations using the PVRI index were consistent with the classical theory. System evaluation based on EC posterior variance is an intuitively appealing and physically meaningful method that is useful for evaluation of system performance in ROI quantitation tasks. PMID- 23744673 TI - Simultaneous truth and performance level estimation through fusion of probabilistic segmentations. AB - Recent research has demonstrated that improved image segmentation can be achieved by multiple template fusion utilizing both label and intensity information. However, intensity weighted fusion approaches use local intensity similarity as a surrogate measure of local template quality for predicting target segmentation and do not seek to characterize template performance. This limits both the usefulness and accuracy of these techniques. Our work here was motivated by the observation that the local intensity similarity is a poor surrogate measure for direct comparison of the template image with the true image target segmentation. Although the true image target segmentation is not available, a high quality estimate can be inferred, and this in turn allows a principled estimate to be made of the local quality of each template at contributing to the target segmentation. We developed a fusion algorithm that uses probabilistic segmentations of the target image to simultaneously infer a reference standard segmentation of the target image and the local quality of each probabilistic segmentation. The concept of comparing templates to a hidden reference standard segmentation enables accurate assessments of the contribution of each template to inferring the target image segmentation to be made, and in practice leads to excellent target image segmentation. We have used the new algorithm for the multiple-template-based segmentation and parcellation of magnetic resonance images of the brain. Intensity and label map images of each one of the aligned templates are used to train a local Gaussian mixture model based classifier. Then, each classifier is used to compute the probabilistic segmentations of the target image. Finally, the generated probabilistic segmentations are fused together using the new fusion algorithm to obtain the segmentation of the target image. We evaluated our method in comparison to other state-of-the-art segmentation methods. We demonstrated that our new fusion algorithm has higher segmentation performance than these methods. PMID- 23744674 TI - Data-driven MRSI spectral localization via low-rank component analysis. AB - Magnetic resonance spectroscopic imaging (MRSI) is a powerful tool capable of providing spatially localized maps of metabolite concentrations. Its utility, however, is often depreciated by spectral leakage artifacts resulting from low spatial resolution measurements through an effort to reduce acquisition times. Though model-based techniques can help circumvent these drawbacks, they require strong prior knowledge, and can introduce additional artifacts when the underlying models are inaccurate. We introduce a novel scheme in which a generative model is estimated from the raw MRSI data via a regularized variational framework that minimizes the model approximation error within a measurement-prescribed subspace. As additional a priori information, our approach relies only upon a measured field inhomogeneity map at high spatial resolution. We demonstrate the feasibility of our approach on both synthetic and experimental data. PMID- 23744675 TI - Antidepressant use during early pregnancy and the risk of congenital anomalies. AB - STUDY OBJECTIVE: To estimate and compare the prevalence of congenital anomalies among the offspring of women exposed and not exposed to antidepressants during early pregnancy. DESIGN: Matched cohort study. DATA SOURCE: United Kingdom's General Practice Research Database. SUBJECTS: Women exposed to tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressants during the first trimester of pregnancy (3276 women) and a sample of women matched in a 2:1 ratio who had no exposure to any antidepressant during the first trimester of pregnancy (6617 women). MEASUREMENTS AND MAIN RESULTS: The prevalence of any congenital anomaly was 31.0 (95% confidence interval [CI] 27.0-35.5) per 1000 pregnancies among women not exposed to antidepressants and 27.2 (95% CI 22.1-33.4) per 1000 pregnancies among women exposed to antidepressants. The relative risk of having a child with an anomaly in mothers who were exposed to tricyclics and SSRIs during the first trimester compared with mothers not exposed to these drugs was 0.9 (95% CI 0.7-1.1). The relative risks for any anomaly among women exposed to antidepressants were 0.9 (95% CI 0.6-1.2) for tricylics and 0.9 (95% CI 0.7-1.2) for SSRIs. We found no statistically significant, stable increases in the risk of specific anomaly subtypes among women exposed to these antidepressants; however, the number of exposed cases was small. CONCLUSION: Exposure to tricyclics and SSRIs during the first trimester of pregnancy was not associated with a statistically significant increased risk of congenital anomalies in the offspring of mothers exposed to these drugs. PMID- 23744676 TI - Dissipation of soil fumigants from soil following repeated applications. AB - BACKGROUND: The dissipation of pesticides in soil and the occurrence of accelerated degradation following repeated applications are well-known phenomena with many pesticides, but much less so with soil fumigants. The fate of various soil fumigants was studied in different agricultural soils following repeated applications of chloropicrin. RESULTS: Fumigant dissipation reflected by Sigmaconcentration * time (SigmaC * T) and half-life values varied widely among the tested soils. Methyl iodide (MI) had the slowest dissipation rate compared with other fumigants in all tested soils. Elimination of biotic agents by soil sterilization prior to MI application did not affect MI concentration in Oxnard soil. Clay content and fumigant dose (SigmaC * T values) of chloropicrin, 1,3 dichloropropene and MI were significantly correlated. No significant correlations were found between soil properties and SigmaC * T values following metam sodium and methyl bromide (MBr) application. CONCLUSION: The fate of the tested soil fumigants is highly dependent on and specific to the fumigant, previous fumigant application and soil type. This study suggests that biotic factors are more essential in the dissipation of metam sodium and MBr than abiotic factors. By contrast, MI dissipation from the tested soils is affected more by abiotic factors than by biotic activities. PMID- 23744677 TI - Bandlimited reconstruction of multidimensional images from irregular samples. AB - We examine different sampling lattices and their respective bandlimited spaces for reconstruction of irregularly sampled multidimensional images. Considering an irregularly sampled dataset, we demonstrate that the non-tensor-product bandlimited approximations corresponding to the body-centered cubic and face centered cubic lattices provide a more accurate reconstruction than the tensor product bandlimited approximation associated with the commonly-used Cartesian lattice. Our practical algorithm uses multidimensional sinc functions that are tailored to these lattices and a regularization scheme that provides a variational framework for efficient implementation. Using a number of synthetic and real data sets we record improvements in the accuracy of reconstruction in a practical setting. PMID- 23744678 TI - Incorporating anatomical side information into PET reconstruction using nonlocal regularization. AB - With the introduction of combined positron emission tomography (PET)/computed tomography (CT) or PET/magnetic resonance imaging (MRI) scanners, there is an increasing emphasis on reconstructing PET images with the aid of the anatomical side information obtained from X-ray CT or MRI scanners. In this paper, we propose a new approach to incorporating prior anatomical information into PET reconstruction using the nonlocal regularization method. The nonlocal regularizer developed for this application is designed to selectively consider the anatomical information only when it is reliable. As our proposed nonlocal regularization method does not directly use anatomical edges or boundaries which are often used in conventional methods, it is not only free from additional processes to extract anatomical boundaries or segmented regions, but also more robust to the signal mismatch problem that is caused by the indirect relationship between the PET image and the anatomical image. We perform simulations with digital phantoms. According to our experimental results, compared to the conventional method based on the traditional local regularization method, our nonlocal regularization method performs well even with the imperfect prior anatomical information or in the presence of signal mismatch between the PET image and the anatomical image. PMID- 23744679 TI - DCT/DST-based transform coding for intra prediction in image/video coding. AB - In this paper, we present a DCT/DST based transform scheme that applies either the conventional DCT or type-7 DST for all the video-coding intra-prediction modes: vertical, horizontal, and oblique. Our approach is applicable to any block based intra prediction scheme in a codec that employs transforms along the horizontal and vertical direction separably. Previously, Han, Saxena, and Rose showed that for the intra-predicted residuals of horizontal and vertical modes, the DST is the optimal transform with performance close to the KLT. Here, we prove that this is indeed the case for the other oblique modes. The optimal choice of using DCT or DST is based on intra-prediction modes and requires no additional signaling information or rate-distortion search. The DCT/DST scheme presented in this paper was adopted in the HEVC standardization in March 2011. Further simplifications, especially to reduce implementation complexity, which remove the mode-dependency between DCT and DST, and simply always use DST for the 4 * 4 intra luma blocks, were adopted in the HEVC standard in July 2012. Simulation results conducted for the DCT/DST algorithm are shown in the reference software for the ongoing HEVC standardization. Our results show that the DCT/DST scheme provides significant BD-rate improvement over the conventional DCT based scheme for intra prediction in video sequences. PMID- 23744680 TI - Regional bit allocation and rate distortion optimization for multiview depth video coding with view synthesis distortion model. AB - In this paper, we propose a view synthesis distortion model (VSDM) that establishes the relationship between depth distortion and view synthesis distortion for the regions with different characteristics: color texture area corresponding depth (CTAD) region and color smooth area corresponding depth (CSAD), respectively. With this VSDM, we propose regional bit allocation (RBA) and rate distortion optimization (RDO) algorithms for multiview depth video coding (MDVC) by allocating more bits on CTAD for rendering quality and fewer bits on CSAD for compression efficiency. Experimental results show that the proposed VSDM based RBA and RDO can improve the coding efficiency significantly for the test sequences. In addition, for the proposed overall MDVC algorithm that integrates VSDM based RBA and RDO, it achieves 9.99% and 14.51% bit rate reduction on average for the high and low bit rate, respectively. It can improve virtual view image quality 0.22 and 0.24 dB on average at the high and low bit rate, respectively, when compared with the original joint multiview video coding model. The RD performance comparisons using five different metrics also validate the effectiveness of the proposed overall algorithm. In addition, the proposed algorithms can be applied to both INTRA and INTER frames. PMID- 23744681 TI - A no-reference perceptual based contrast enhancement metric for ocean scenes in fog. AB - In this paper, we develop a perceptually based contrast enhancement metric as a means to solve the problem of autonomously enhancing images degraded by fog that are perceptually pleasing to humans. A learning based approach is considered to develop the contrast enhancement using human observations and low-level contrast enhancement metrics based on the human vision system. In addition, we provide new low-level metrics based on the physics of the scene to improve the performance of existing contrast enhancement metrics. This paper shows that a contrast enhancement metric can be designed to mimic human preference. PMID- 23744682 TI - Optimizing apparent display resolution enhancement for arbitrary videos. AB - Display resolution is frequently exceeded by available image resolution. Recently, apparent display resolution enhancement (ADRE) techniques show how characteristics of the human visual system can be exploited to provide super resolution on high refresh rate displays. In this paper, we address the problem of generalizing the ADRE technique to conventional videos of arbitrary content. We propose an optimization-based approach to continuously translate the video frames in such a way that the added motion enables apparent resolution enhancement for the salient image region. The optimization considers the optimal velocity, smoothness, and similarity to compute an appropriate trajectory. In addition, we provide an intuitive user interface that allows to guide the algorithm interactively and preserves important compositions within the video. We present a user study evaluating apparent rendering quality and show versatility of our method on a variety of general test scenes. PMID- 23744683 TI - Salient region detection improved by principle component analysis and boundary information. AB - Salient region detection is useful for several image-processing applications, such as adaptive compression, object recognition, image retrieval, filter design, and image retargeting. A novel method to determine the salient regions of images is proposed in this paper. The L0 smoothing filter and principle component analysis (PCA) play important roles in our framework. The L0 filter is extremely helpful in characterizing fundamental image constituents, i.e., salient edges, and can simultaneously diminish insignificant details, thus producing more accurate boundary information for background merging and boundary scoring. PCA can reduce computational complexity as well as attenuate noise and translation errors. A local-global contrast is then used to calculate the distinction. Finally, image segmentation is used to achieve full-resolution saliency maps. The proposed method is compared with other state-of-the-art saliency detection methods and shown to yield higher precision-recall rates and F-measures. PMID- 23744684 TI - Compressive blind image deconvolution. AB - We propose a novel blind image deconvolution (BID) regularization framework for compressive sensing (CS) based imaging systems capturing blurred images. The proposed framework relies on a constrained optimization technique, which is solved by a sequence of unconstrained sub-problems, and allows the incorporation of existing CS reconstruction algorithms in compressive BID problems. As an example, a non-convex lp quasi-norm with is employed as a regularization term for the image, while a simultaneous auto-regressive regularization term is selected for the blur. Nevertheless, the proposed approach is very general and it can be easily adapted to other state-of-the-art BID schemes that utilize different, application specific, image/blur regularization terms. Experimental results, obtained with simulations using blurred synthetic images and real passive millimeter-wave images, show the feasibility of the proposed method and its advantages over existing approaches. PMID- 23744685 TI - Retina verification system based on biometric graph matching. AB - This paper presents an automatic retina verification framework based on the biometric graph matching (BGM) algorithm. The retinal vasculature is extracted using a family of matched filters in the frequency domain and morphological operators. Then, retinal templates are defined as formal spatial graphs derived from the retinal vasculature. The BGM algorithm, a noisy graph matching algorithm, robust to translation, non-linear distortion, and small rotations, is used to compare retinal templates. The BGM algorithm uses graph topology to define three distance measures between a pair of graphs, two of which are new. A support vector machine (SVM) classifier is used to distinguish between genuine and imposter comparisons. Using single as well as multiple graph measures, the classifier achieves complete separation on a training set of images from the VARIA database (60% of the data), equaling the state-of-the-art for retina verification. Because the available data set is small, kernel density estimation (KDE) of the genuine and imposter score distributions of the training set are used to measure performance of the BGM algorithm. In the one dimensional case, the KDE model is validated with the testing set. A 0 EER on testing shows that the KDE model is a good fit for the empirical distribution. For the multiple graph measures, a novel combination of the SVM boundary and the KDE model is used to obtain a fair comparison with the KDE model for the single measure. A clear benefit in using multiple graph measures over a single measure to distinguish genuine and imposter comparisons is demonstrated by a drop in theoretical error of between 60% and more than two orders of magnitude. PMID- 23744686 TI - Changes of pituitary gland volume in Kennedy disease. AB - BACKGROUND AND PURPOSE: Kennedy disease is a rare X-linked neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the androgen receptor gene. Apart from neurologic signs, this mutation can cause a partial androgen insensitivity syndrome with typical alterations of gonadotropic hormones produced by the pituitary gland. The aim of the present study was therefore to evaluate the impact of Kennedy disease on pituitary gland volume under the hypothesis that endocrinologic changes caused by partial androgen insensitivity may lead to morphologic changes (ie, hypertrophy) of the pituitary gland. MATERIALS AND METHODS: Pituitary gland volume was measured in sagittal sections of 3D T1-weighted 3T-MR imaging data of 8 patients with genetically proven Kennedy disease and compared with 16 healthy age-matched control subjects by use of Multitracer by a blinded, experienced radiologist. The results were analyzed by a univariant ANOVA with total brain volume as a covariant. Furthermore, correlation and linear regression analyses were performed for pituitary volume, patient age, disease duration, and CAG repeat expansion length. Intraobserver reliability was evaluated by means of the Pearson correlation coefficient. RESULTS: Pituitary volume was significantly larger in patients with Kennedy disease (636 [+/-90] mm(3)) than in healthy control subjects (534 [+/-91] mm(3)) (P = .041). There was no significant difference in total brain volume (P = .379). Control subjects showed a significant decrease in volume with age (r = -0.712, P = .002), whereas there was a trend to increasing gland volume in patients with Kennedy disease (r = 0.443, P = .272). Gland volume correlated with CAG repeat expansion length in patients (r = 0.630, P = .047). The correlation coefficient for intraobserver reliability was 0.94 (P < .001). CONCLUSIONS: Patients with Kennedy disease showed a significantly higher pituitary volume that correlated with the CAG repeat expansion length. This could reflect hypertrophy as the result of elevated gonadotropic hormone secretion caused by the androgen receptor mutation with partial androgen insensitivity. PMID- 23744687 TI - Regional analysis of the magnetization transfer ratio of the brain in mild Alzheimer disease and amnestic mild cognitive impairment. AB - BACKGROUND AND PURPOSE: Manually drawn VOI-based analysis shows a decrease in magnetization transfer ratio in the hippocampus of patients with Alzheimer disease. We investigated with whole-brain voxelwise analysis the regional changes of the magnetization transfer ratio in patients with mild Alzheimer disease and patients with amnestic mild cognitive impairment. MATERIALS AND METHODS: Twenty patients with mild Alzheimer disease, 27 patients with amnestic mild cognitive impairment, and 30 healthy elderly control subjects were examined with high resolution T1WI and 3-mm-thick magnetization transfer images. Whole-brain voxelwise analysis of magnetization transfer ratio maps was performed by use of Statistical Parametric Mapping 8 software and was supplemented by the analysis of the magnetization transfer ratio in FreeSurfer parcellation-derived VOIs. RESULTS: Voxelwise analysis showed 2 clusters of significantly decreased magnetization transfer ratio in the left hippocampus and amygdala and in the left posterior mesial temporal cortex (fusiform gyrus) of patients with Alzheimer disease as compared with control subjects but no difference between patients with amnestic mild cognitive impairment and either patients with Alzheimer disease or control subjects. VOI analysis showed that the magnetization transfer ratio in the hippocampus and amygdala was significantly lower (bilaterally) in patients with Alzheimer disease when compared with control subjects (ANOVA with Bonferroni correction, at P < .05). Mean magnetization transfer ratio values in the hippocampus and amygdala in patients with amnestic mild cognitive impairment were between those of healthy control subjects and those of patients with mild Alzheimer disease. Support vector machine-based classification demonstrated improved classification performance after inclusion of magnetization transfer ratio-related features, especially between patients with Alzheimer disease versus healthy subjects. CONCLUSIONS: Bilateral but asymmetric decrease of magnetization transfer ratio reflecting microstructural changes of the residual GM is present not only in the hippocampus but also in the amygdala in patients with mild Alzheimer disease. PMID- 23744688 TI - Analysis of morphologic and hemodynamic parameters for unruptured posterior communicating artery aneurysms with oculomotor nerve palsy. AB - BACKGROUND AND PURPOSE: Posterior communicating artery aneurysms with oculomotor nerve palsy may imply sudden enlargement of the aneurysm sac and have a high risk of rupture. Our aim was to identify the morphologic and hemodynamic parameters in this special period of aneurysm progression and to assess related rupture risk indices. MATERIALS AND METHODS: We analyzed the morphologic and hemodynamic parameters of 9 unruptured posterior communicating artery aneurysms with oculomotor nerve palsy and 9 ruptured ones. The morphologic parameters were measured and calculated from patient-specific 3D rotational angiographic images, and pulsatile computational fluid dynamic simulation was then performed for hemodynamic parameters. RESULTS: There was no significant statistical difference between the 2 groups in size, aspect ratio, size ratio, aneurysm angle, or vessel angle; analysis only demonstrated a significantly lower wall shear stress of the aneurysm wall in the symptomatic unruptured group in hemodynamics (P = .024), whereas there were no differences in wall shear stress of the parent artery, low wall shear stress area, and oscillatory shear index. CONCLUSIONS: From morphologic and hemodynamic perspectives, we demonstrated that posterior communicating artery aneurysms with oculomotor nerve palsy had characteristics similar to those of ruptured ones, except for lower wall shear stress on the aneurysm wall, which might indicate an important role in aneurysm rupture. PMID- 23744689 TI - Patterns of brain structural changes in first-contact, antipsychotic drug-naive patients with schizophrenia. AB - BACKGROUND AND PURPOSE: Previous studies have suggested that structural changes do occur in the brain of patients with schizophrenia compared with healthy control participants. However, findings from such studies are inconclusive, probably because of the different methodologic approaches, the clinical heterogeneity of patient samples, and also the fact that patients enrolled were treated with antipsychotic drugs. The aim of this study was to investigate brain GM volumes and intrinsic structural WM changes in first-contact, antipsychotic drug-naive patients with schizophrenia. MATERIALS AND METHODS: A total of 43 first-contact, drug-naive, patients with schizophrenia and 17 age-matched control participants were studied. All participants underwent T1-weighted MR imaging and DTI scans. Voxel-based morphometry and tract-based spatial statistics were used to compare GM volumes and WM DTI metrics between groups. MR imaging measures were correlated with the duration of the untreated psychosis and the clinical positive and negative symptoms. RESULTS: Compared with control participants, patients with schizophrenia showed smaller volumes of the temporal, parietal, and occipital GM, and a pattern of decreased mean diffusivity and increased fractional anisotropy in the brain stem and cerebellum bilaterally, interhemispheric and cortico cortical connections bilaterally, and right anterior and posterior limb of the internal capsule. In patients, decreased mean diffusivity and increased fractional anisotropy in several brain regions were related to a longer duration of the untreated psychosis and the severity of positive symptoms. CONCLUSIONS: First-contact, drug-naive, patients with schizophrenia present with volumetric and DTI changes, which correlated with their clinical features. This study increases our knowledge on the neural networks involved in the pathophysiologic mechanisms of schizophrenia. PMID- 23744690 TI - Improved T2* imaging without increase in scan time: SWI processing of 2D gradient echo. AB - BACKGROUND AND PURPOSE: 2D gradient-echo imaging is sensitive to T2* lesions (hemorrhages, mineralization, and vascular lesions), and susceptibility-weighted imaging is even more sensitive, but at the cost of additional scan time (SWI: 5 10 minutes; 2D gradient-echo: 2 minutes). The long acquisition time of SWI may pose challenges in motion-prone patients. We hypothesized that 2D SWI/phase unwrapped images processed from 2D gradient-echo imaging could improve T2* lesion detection. MATERIALS AND METHODS: 2D gradient-echo brain images of 50 consecutive pediatric patients (mean age, 8 years) acquired at 3T were retrospectively processed to generate 2D SWI/phase unwrapped images. The 2D gradient-echo and 2D SWI/phase unwrapped images were compared for various imaging parameters and were scored in a blinded fashion. RESULTS: Of 50 patients, 2D gradient-echo imaging detected T2* lesions in 29 patients and had normal findings in 21 patients. 2D SWI was more sensitive than standard 2D gradient-echo imaging in detecting T2* lesions (P < .0001). 2D SWI/phase unwrapped imaging also improved delineation of normal venous structures and nonpathologic calcifications and helped distinguish calcifications from hemorrhage. A few pitfalls of 2D SWI/phase unwrapped imaging were noted, including worsened motion and dental artifacts and challenges in detecting T2* lesions adjacent to calvaria or robust deoxygenated veins. CONCLUSIONS: 2D SWI and associated phase unwrapped images processed from standard 2D gradient-echo images were more sensitive in detecting T2* lesions and delineating normal venous structures and nonpathologic mineralization, and they also helped distinguish calcification at no additional scan time. SWI processing of 2D gradient-echo images may be a useful adjunct in cases in which longer scan times of 3D SWI are difficult to implement. PMID- 23744691 TI - Does stent-assisted coiling still have a place in the management of intracranial aneurysms? PMID- 23744692 TI - Automated quantitation of the posterior scleral flattening and optic nerve protrusion by MRI in idiopathic intracranial hypertension. AB - BACKGROUND AND PURPOSE: Subjective determination of the posterior sclera flattening and optic nerve protrusion in MRI is challenging because of the 3D nature of the globe morphology. This study aims to develop and compare quantitative measures of globe flattening and optic nerve protrusion with subjective rating, and assess relationships with papilledema grade and intraocular and CSF pressures. MATERIALS AND METHODS: Data of 34 globes from 7 overweight female patients with idiopathic intracranial hypertension and 6 age- and weight-matched healthy female control subjects were assessed, as well as a subcohort of 4 of the patients with idiopathic intracranial hypertension who underwent follow-up MR imaging 2 weeks after lumbar puncture and initiation of treatment with acetazolamide. MR imaging examination included a 3D CISS sequence on 1.5T and 3T scanners with 0.6-mm isotropic resolution. Subjective ratings of globe flattening were obtained by experienced and inexperienced readers. Quantitative measures of globe flattening, nerve protrusion, and maximal deformation were derived by use of a 2D map of the distances from the globe center to the posterior wall. RESULTS: Contingency coefficients for globe flattening agreements with subjective rating by the experienced and inexperienced readers were 0.72 and 0.56, respectively. Mean values of the 3 deformation measures were significantly poorer in the idiopathic intracranial hypertension group, with nerve protrusion demonstrating the strongest difference (P = .0002). Nerve protrusion was most strongly associated with papilledema grade with a contingency coefficient of 0.74 (P = .01), whereas globe flattening was negatively correlated with intraocular pressure (R = -0.75, P < .0001). Maximal deformation was negatively associated with CSF opening pressure (R = -0.86, P = .0001). After treatment, only the changes in nerve protrusion and maximal deformation were significant. CONCLUSIONS: Automated measures of globe deformation improve reliability over subjective rating. Of the 2 globe deformation measures, nerve protrusion had the strongest predictive value for papilledema grade and had the highest sensitivity for assessment of treatment efficacy in idiopathic intracranial hypertension. PMID- 23744693 TI - Potential for the use of the Solitaire stent for recanalization of middle cerebral artery occlusion without a susceptibility vessel sign. AB - BACKGROUND AND PURPOSE: Absence of the MCA susceptibility vessel sign (negative MCA susceptibility vessel sign) on gradient recalled-echo MR imaging in acute stroke is commonly associated with in situ stenosis and thrombotic occlusion. We evaluated the effectiveness and safety of the Solitaire stent as the first-line device for the recanalization of MCA occlusion with a negative MCA susceptibility vessel sign. MATERIALS AND METHODS: Thirty-eight consecutive patients presenting with acute ischemic stroke due to MCA occlusion were treated by using the Solitaire AB stent alone or combined with thrombolytic drugs. Among these patients, 11 (7 men and 4 women; median age, 70 years; range, 49-89 years) who underwent multimodal stroke MR imaging before the endovascular procedure and had no MCA susceptibility vessel sign on the initial gradient recalled-echo MR imaging were included in this study. The primary end point was the recanalization of the occluded artery evaluated by the arterial occlusive lesion score. Clinical outcome was assessed at discharge and 90 days, as was the degree of residual MCA stenosis or reocclusion. RESULTS: Successful recanalization (arterial occlusive lesion score >= II) without balloon angioplasty was obtained in 9 patients (81.8%). Six patients (54.5%) had an mRS score of <=2 at 90 days. After a median of 147 days, no patient showed reocclusion on follow-up imaging. There were no symptomatic intracerebral hemorrhages. CONCLUSIONS: The Solitaire stent is a feasible tool as the first-line device for multimodal endovascular recanalization therapy in acute ischemic stroke with a negative MCA susceptibility vessel sign. It has a good rate of successful and complete recanalization and is a fast yet safe procedure. PMID- 23744694 TI - Comparison of multiecho postprocessing schemes for SWI with use of linear and nonlinear mask functions. AB - BACKGROUND AND PURPOSE: SWI is an MR technique conventionally implemented with single-echo gradient-echo data. The purpose of this study was to compare single echo SWI processing and 2 multiecho SWI processing schemes: postaverage, where an SWI image is created for each echo and then averaged to create a single volume; and frequency-based, where a SWI image is generated from an average frequency image. Linear and nonlinear mask functions were investigated for all 3 processing schemes. MATERIALS AND METHODS: Comprehensive optimizations were performed. Single and multigradient-echo data were acquired at 3T in 10 volunteers. Contrast to-noise ratio was measured in various structures. Visibilities of the same structures were ranked in different SWI images by trained raters. RESULTS: When image evaluation was based on measurements of contrast-to-noise ratio, the nonlinear mask and frequency-based scheme were superior. However, when image evaluation was based on ranks of qualitative visibility, the linear mask and postaverage scheme were superior. Although the nonlinear mask and frequency-based scheme allow increased contrast of paramagnetic perturbers such as the globus pallidus, periventricular veins, red nucleus, and subthalamic nucleus, they do not necessarily increase the information content of the image; rather, they result in a harsh contrast that is visually unpleasing to radiologists and wherein more subtle structure is relatively less apparent. CONCLUSIONS: Linearly masked postaverage SWI is the recommended implementation of multiecho SWI for radiologic use; however, nonlinearly masked frequency-based SWI may have use in computer-based segmentation or registration. PMID- 23744695 TI - Are routine intensive care admissions needed after endovascular treatment of unruptured aneurysms? AB - SUMMARY: Routine intensive care unit monitoring is common after elective embolization of unruptured intracranial aneurysms. In this series of 200 consecutive endovascular procedures for unruptured intracranial aneurysms, 65% of patients were triaged to routine (non-intensive care unit) floor care based on intraoperative findings, aneurysm morphology, and absence of major co morbidities. Only 1 patient (0.5%) required subsequent transfer to the intensive care unit for management of a perioperative complication. The authors conclude that patients without major co-morbidities, intraoperative complications, or complex aneurysm morphology can be safely observed in a regular ward rather than being admitted to the intensive care unit. PMID- 23744696 TI - Mechanical thrombectomy after IMS III, synthesis, and MR-RESCUE. PMID- 23744697 TI - Evaluation of Parkinson disease and Alzheimer disease with the use of neuromelanin MR imaging and (123)I-metaiodobenzylguanidine scintigraphy. AB - BACKGROUND AND PURPOSE: Progressive changes in the substantia nigra pars compacta and locus ceruleus of patients with Parkinson disease and Alzheimer disease visualized by neuromelanin MRI and cardiac postganglionic sympathetic nerve function on (123)I-metaiodobenzylguanidine scintigraphy have not been fully evaluated. We compared the diagnostic value of these modalities among patients with early Parkinson disease, late Parkinson disease, and Alzheimer disease. MATERIALS AND METHODS: We compared contrast ratios of signal intensity in medial and lateral regions of the substantia nigra pars compacta and locus ceruleus with those of the tegmentum of the midbrain and the pons, respectively, by use of neuromelanin MRI in patients with early Parkinson disease (n = 13), late Parkinson disease (n = 31), Alzheimer disease (n = 6), and age-matched healthy control subjects (n = 20). We calculated heart-to-mediastinum ratios on (123)I metaiodobenzylguanidine scintigrams after setting regions of interest on the left cardiac ventricle and upper mediastinum. RESULTS: The signal intensity of the lateral substantia nigra pars compacta on neuromelanin MRI was significantly reduced in early and late Parkinson disease, and that of the medial substantia nigra pars compacta was gradually and stage-dependently reduced in Parkinson disease. The signal intensity of the locus ceruleus was obviously reduced in late Parkinson disease. Signal reduction was not significant in the substantia nigra pars compacta and locus ceruleus of patients with Alzheimer disease. The heart-to mediastinum ratio on (123)I-metaiodobenzylguanidine scintigrams was stage dependently reduced in Parkinson disease and normal in Alzheimer disease. The signal intensity ratios in substantia nigra pars compacta and locus ceruleus on neuromelanin MRI positively correlated with the heart-to-mediastinum ratio on (123)I-metaiodobenzylguanidine scintigrams. CONCLUSIONS: Both neuromelanin MRI and (123)I-metaiodobenzylguanidine scintigraphy can help to evaluate disease progression in Parkinson disease and are useful for differentiating Parkinson disease from Alzheimer disease. PMID- 23744698 TI - Forecasting range expansion into ecological traps: climate-mediated shifts in sea turtle nesting beaches and human development. AB - Some species are adapting to changing environments by expanding their geographic ranges. Understanding whether range shifts will be accompanied by increased exposure to other threats is crucial to predicting when and where new populations could successfully establish. If species overlap to a greater extent with human development under climate change, this could form ecological traps which are attractive to dispersing individuals, but the use of which substantially reduces fitness. Until recently, the core nesting range for the Critically Endangered Kemp's ridley sea turtle (Lepidochelys kempii) was ca. 1000 km of sparsely populated coastline in Tamaulipas, Mexico. Over the past twenty-five years, this species has expanded its range into populated areas of coastal Florida (>1500 km outside the historical range), where nesting now occurs annually. Suitable Kemp's ridley nesting habitat has persisted for at least 140 000 years in the western Gulf of Mexico, and climate change models predict further nesting range expansion into the eastern Gulf of Mexico and northern Atlantic Ocean. Range expansion is 6 12% more likely to occur along uninhabited stretches of coastline than are current nesting beaches, suggesting that novel nesting areas will not be associated with high levels of anthropogenic disturbance. Although the high breeding-site fidelity of some migratory species could limit adaptation to climate change, rapid population recovery following effective conservation measures may enhance opportunities for range expansion. Anticipating the interactive effects of past or contemporary conservation measures, climate change, and future human activities will help focus long-term conservation strategies. PMID- 23744699 TI - Stability radius as a method for comparing the dynamics of neuromechanical systems. AB - Robust motor behaviors emerge from neuromechanical interactions that are nonlinear, have delays, and contain redundant neural and biomechanical components. For example, in standing balance a subject's muscle activity (neural control) decreases as stance width (biomechanics) increases when responding to a lateral perturbation, yet the center-of-mass motion (behavior) is nearly identical regardless of stance width. We present stability radius, a technique from robust control theory, to overcome the limitations of classical stability analysis tools, such as gain margin, which are insufficient for predicting how concurrent changes in both biomechanics (plant) and neural control (controller) affect system behavior. We first present the theory and then an application to a neuromechanical model of frontal-plane standing balance with delayed feedback. We show that stability radius can quantify differences in the sensitivity of system behavior to parameter changes, and predict that narrowing stance width increases system robustness. We further demonstrate that selecting combinations of stance width (biomechanics) and feedback gains (neural control) that have the same stability radius produce similar center-of-mass behavior in simulation. Therefore, stability radius may provide a useful tool for understanding neuromechanical interactions in movement and could aid in the design of devices and therapies for improving motor function. PMID- 23744700 TI - Towards a new modality-independent interface for a robotic wheelchair. AB - This work presents the development of a robotic wheelchair that can be commanded by users in a supervised way or by a fully automatic unsupervised navigation system. It provides flexibility to choose different modalities to command the wheelchair, in addition to be suitable for people with different levels of disabilities. Users can command the wheelchair based on their eye blinks, eye movements, head movements, by sip-and-puff and through brain signals. The wheelchair can also operate like an auto-guided vehicle, following metallic tapes, or in an autonomous way. The system is provided with an easy to use and flexible graphical user interface onboard a personal digital assistant, which is used to allow users to choose commands to be sent to the robotic wheelchair. Several experiments were carried out with people with disabilities, and the results validate the developed system as an assistive tool for people with distinct levels of disability. PMID- 23744701 TI - Evaluation of reach and grasp robot-assisted therapy suggests similar functional recovery patterns on proximal and distal arm segments in sub-acute hemiplegia. AB - This paper provides some additional evidence in support of the hypothesis that robot therapies are clinically beneficial in neurorehabilitation. Although only four subjects were included in the study, the design of the intervention and the measures were done so as to minimize bias. The results are presented as single case studies, and can only be interpreted as such due to the study size. The intensity of intervention was 16 h and the therapy philosophy (based on Carr and Shepherd) was that coordinated movements are preferable to joint based therapies, and that coordinating distal movements (in this case grasps) helps not only to recover function in these areas, but has greater value since the results are immediately transferable to daily skills such as reach and grasp movements. PMID- 23744702 TI - Adaptive SSVEP-based BCI system with frequency and pulse duty-cycle stimuli tuning design. AB - This study aims to design a steady state visual evoked potentials (SSVEP) based brain-computer interface (BCI) system with only three electrodes. It is known that low frequency flickering induces more intensive SSVEP, but might cause users feel uncomfortable and easily tired. Therefore, this paper proposes a novel middle/high frequency flickering stimulus. However, users show different SSVEP responses when gazing at the same stimuli. It is improper to design fixed frequency flickering stimuli for all users. This study firstly proposes a strategy to adjust the stimuli frequency for each user that could cause better SSVEP. Moreover, to further enhance the SSVEP, this study incorporates flickering duty-cycle for stimuli design, which has been discussed less for SSVEP-based BCI systems. The proposed system consists of two modes, flicker frequency/duty-cycle selection mode and application mode. The flicker frequency/duty-cycle selection mode obtains two best frequencies between 24 and 36 Hz with their related optimal duty-cycle. Then the system goes into the application mode to control the devices. A new fact that has been found is that the optimal flicker frequency and duty-cycle do not vary with time. It means once the optical flicker frequency and duty-cycle is determined the first time, flicker frequency/duty-cycle selection mode does not need to operate the next time. Furthermore, the phase coding technology is used to extend the one command/one frequency to multi command/one frequency. Experimental results show the proposed system has good performance with average accuracy 95% and average command transfer interval 4.4925 s per command. PMID- 23744703 TI - Andrographolide suppresses high glucose-induced fibronectin expression in mesangial cells via inhibiting the AP-1 pathway. AB - Mesangial cells (MCs) proliferation and accumulation of glomerular matrix proteins such as fibronectin (FN) are the early features of diabetic nephropathy, with MCs known to upregulate matrix protein synthesis in response to high glucose. Recently, it has been found that andrographolide has renoprotective effects on diabetic nephropathy. However, the molecular mechanism underlying these effects remains unclear. Cell viability and proliferation was evaluated by MTT. FN expression was examined by immunofluorescence and immunoblotting. Activator protein-1 (AP-1) activation was assessed by immunoblotting, luciferase reporter and electrophoretic mobility shift assays. Andrographolide significantly decreased high glucose-induced cell proliferation and FN expression in MCs. Exposure of MCs to high glucose markedly stimulated the expression of phosphorylated c-jun, whereas the stimulation was inhibited by andrographolide. Plasmid pAP-1-Luc luciferase reporter assay showed that andrographolide blocked high glucose-induced AP-1 transcriptional activity. EMSA assay demonstrated that increased AP-1 binding to an AP-1 binding site at -1,029 in the FN gene promoter upon high glucose stimulation, and the binding were disrupted by andrographolide treatment. These data indicate that andrographolide suppresses high glucose induced FN expression by inhibiting AP-1-mediated pathway. PMID- 23744704 TI - Changes in oral health-related quality of life reports in children during orthodontic treatment and the possible role of self-esteem: a follow-up study. AB - OBJECTIVES: As a continuation of a baseline study on oral health-related quality of life (OHRQoL) and the role of self-esteem (SE), the aim of this research is to investigate the changes in OHRQoL reports in children during orthodontic treatment and the influence of SE. SUBJECTS AND METHODS: This longitudinal study comprised 109 children (50 boys and 59 girls) aged 11-16 years, all receiving orthodontic treatment. Questionnaires were administered at baseline and at follow up (1 year after start of orthodontic treatment). OHRQoL was assessed by the child perception questionnaire (CPQ). The Dutch adaptation of the Harter's Self Perception Profile for Adolescents was used to assess SE and the Index of Orthodontic Treatment Need defined the need for treatment. The questionnaires also included questions related to motivation for treatment. Spearman correlations, Wilcoxon signed rank tests and Mann-Whitney U-tests were performed. RESULTS: A significant increase in total CPQ score was found during orthodontic treatment. This increase was also significant for the subdomains functional limitations, oral symptoms, and social well-being, whereas for the subdomain emotional well-being a non-significant decrease in CPQ score was found. Children with high SE at baseline showed significantly lower variability in OHRQoL measures at follow-up. CONCLUSIONS: OHRQoL deteriorates in children during orthodontic treatment. There is evidence that SE can be a protective factor in OHRQoL during orthodontic treatment. PMID- 23744705 TI - Well-dispersed Pt cubes on porous Cu foam: high-performance catalysts for the electrochemical oxidation of glucose in neutral media. AB - The investigation of highly efficient catalysts for the electrochemical oxidation of glucose is the most critical challenge to commercialize nonenzymatic glucose sensors, which display a few attractive superiorities including the sufficient stability of their properties and the desired reproducibility of results over enzyme electrodes. Herein we propose a new and very promising catalyst: Pt cubes well-dispersed on the porous Cu foam, for the the electrochemical oxidation reaction of glucose in neutral media. The catalyst is fabricated in situ on a homemade screen-printed carbon electrode (SPCE) substrate through initially synthesizing the three-dimensional (3D) porous Cu foam using a hydrogen evolution assisted electrodeposition strategy, followed by electrochemically reducing the platinic precursor simply and conveniently. Field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) proofs demonstrate that Pt cubes, with an average size (the distance of opposite faces) of 185.1 nm, highly dispersed on the macro/nanopore integrated Cu foam support can be reproducibly obtained. The results of electrochemical tests indicate that the cubic Pt-based catalyst exhibits significant enhancement on the catalytic activity towards the electrooxidation of glucose in the presence of chloride ions, providing a specific activity 6.7 times and a mass activity 5.3 times those of commercial Pt/C catalysts at -0.4 V (vs. Ag/AgCl). In addition, the proposed catalyst shows excellent stability of performance, with only a 2.8% loss of electrocatalytic activity after 100 repetitive measurements. PMID- 23744707 TI - The structure of FemX(Wv) in complex with a peptidyl-RNA conjugate: mechanism of aminoacyl transfer from Ala-tRNA(Ala) to peptidoglycan precursors. PMID- 23744706 TI - An intact connexin43 is required to enhance signaling and gene expression in osteoblast-like cells. AB - The cytoplasmic C-terminus of connexin43 (Cx43) interacts with numerous signaling complexes. We hypothesize that signal complex docking to the Cx43 C-terminus (CT) is required to propagate the molecules being shared by gap junctions. We have previously shown that Cx43 impacts the responsiveness of osteoblasts to FGF2 in a PKCdelta- and ERK-dependent manner, converging on Runx2 activity. Here, we mapped the interaction domain of Cx43 and PKCdelta to amino acids 243-302 of the Cx43 CT by GST pulldown assay. Using Runx2-responsive luciferase reporter assays, a Cx43 deletion construct (Cx43 S244Stop), which lacks the C-terminus (amino acids 244 382), failed to support the Cx43-dependent potentiation of transcription following FGF2 treatment in MC3T3 osteoblast-like cells. Similarly, overexpression of Cx43 S244Stop could not mimic the ability of the full length Cx43 to stimulate expression of osteoblast genes. In contrast to full length Cx43, overexpression of just the Cx43 CT (amino acids 236-382) inhibited both transcription from a Runx2 reporter and signaling via PKCdelta and ERK. Inhibition of signaling by the CT did not occur in HeLa cells, which lack endogenous Cx43. In summary, the data support a model in which an intact Cx43 is required for both signal propagation/permeability (i.e., channel function) and local recruitment of signaling complexes to the CT (i.e., docking function) in order to mediate its cellular effects. Further, while the CT alone has channel independent activity, it is opposing to the effect of overexpression of the full length Cx43 channel in this cell context. PMID- 23744708 TI - Predicting drug-induced QT prolongation and torsades de pointes: a review of preclinical endpoint measures. AB - Compound-induced prolongation of the cardiac QT interval is a major concern in drug development and this unit discusses approaches that can predict QT effects prior to undertaking clinical trials. The majority of compounds that prolong the QT interval block the cardiac rapid delayed rectifier potassium current, IKr (hERG). Described in this overview are different ways to measure hERG, from recent advances in automated electrophysiology to the quantification of channel protein trafficking and binding. The contribution of other cardiac ion channels to hERG data interpretation is also discussed. In addition, endpoint measures of the integrated activity of cardiac ion channels at the single-cell, tissue, and whole-animal level, including for example the well-established action potential to the more recent beat-to-beat variability, transmural dispersion of repolarization, and field potential duration, are described in the context of their ability to predict QT prolongation and torsadogenicity in humans. PMID- 23744709 TI - An overview of QT interval assessment in safety pharmacology. AB - Medicinal products that prolong cardiac repolarization, as assessed in terms of prolongation of the QT interval of the electrocardiogram, may trigger torsade de pointe, a potentially fatal arrhythmia. The lethality of this risk necessitates a detailed preclinical evaluation before initiating clinical trials. The strategy for assessing the potential of new chemical entities to cause QT interval prolongation involves two complementary approaches. An in vivo test provides information on the potential of the agent to prolong the QT interval under near physiological conditions. The results are mostly descriptive, providing little insight into the mechanisms of action. In vitro experiments provide more mechanistic data, although the test procedure is far removed from the clinical situation. While both approaches have reasonable predictive value, the results may depend largely on the experimental conditions employed. Discussed in this unit are experimental issues that should be considered when testing agents for their potential to cause arrhythmias, as well as general strategies for understanding the problems associated with this cardiovascular risk. PMID- 23744711 TI - Primary human non-small cell lung and pancreatic tumorgraft models--utility and applications in drug discovery and tumor biology. AB - The number of therapeutic options for lung and pancreatic cancer is increasing because of the identification of new druggable molecular targets and development of new drug combinations. Reproducible, biologically relevant in vivo pre clinical models are critical for this effort. The generation of patient-derived tumor xenografts has proven useful for integrating drug screening with biomarker discovery, discovering fundamental information in tumor biology, prioritizing drugs for clinical investigation, and personalizing treatments for these tumors. The protocol described in this unit details how to establish a direct in vivo subcutaneous primary tumorgraft and maintenance passages. The predictive value of a tumorgraft platform to guide personalized medicine is illustrated with the case of a patient with refractory advanced non-small cell lung cancer (NSCLC). The outcome of a patient for whom their own pancreatic tumorgraft revealed a remarkable sensitivity to mitomycin C based on a PALB2 mutation is also detailed. PMID- 23744710 TI - Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy. AB - The identification of small subpopulations of cancer stem cells (CSCs) from blood mononuclear cells in human acute myeloid leukemia (AML) in 1997 was a landmark observation that recognized the potential role of CSCs in tumor aggressiveness. Two critical properties contribute to the functional role of CSCs in the establishment and recurrence of cancerous tumors: their capacity for self-renewal and their potential to differentiate into unlimited heterogeneous populations of cancer cells. These findings suggest that CSCs may represent novel therapeutic targets for the treatment and/or prevention of tumor progression, since they appear to be involved in cell migration, invasion, metastasis, and treatment resistance-all of which lead to poor clinical outcomes. The identification of CSC specific markers, the isolation and characterization of CSCs from malignant tissues, and targeting strategies for the destruction of CSCs provide a novel opportunity for cancer research. This overview describes the potential implications of several common CSC markers in the identification of CSC subpopulations that are restricted to common malignant diseases, e.g., leukemia, and breast, prostate, pancreatic, and lung cancers. The role of microRNAs (miRNAs) in the regulation of CSC function is also discussed, as are several methods commonly used in CSC research. The potential role of the antidiabetic drug metformin- which has been shown to have effects on CSCs, and is known to function as an antitumor agent-is discussed as an example of this new class of chemotherapeutics. PMID- 23744712 TI - Models of depression: unpredictable chronic mild stress in mice. AB - Major depression is a complex psychiatric disorder characterized by affective, cognitive, and physiological impairments that lead to maladaptive behavior. The high lifetime prevalence of this disabling condition, coupled with limitations in existing medications, make necessary the development of improved therapeutics. This requires animal models that allow investigation of key biological correlates of the disorder. Described in this unit is the unpredictable chronic mild stress mouse model that is used to screen for antidepressant drug candidates. Originally designed for rats, this model has been adapted for mice to capitalize on the advantages of this species as an experimental model, including inter-strain variability, which permits an exploration of the contribution of genetic background, the ability to create transgenic animals, and lower cost. Thus, by combining genetic features and socio-environmental chronic stressful events, the unpredictable, chronic mild stress model in mice can be used to study the etiological and developmental components of major depression, and to identify novel treatments for this condition. PMID- 23744713 TI - Suppression of Botrytis cinerea on necrotic grapevine tissues by early-season applications of natural products and biological control agents. AB - BACKGROUND: Necrotic tissues within grape (Vitis vinifera) bunches represent an important source of Botrytis cinerea inoculum for Botrytis bunch rot (BBR) at harvest in vineyards. This research quantified the incidence of B. cinerea on necrotic floral and fruit tissues and the efficacy of biologically based treatments for suppression of B. cinerea secondary inoculum within developing bunches. RESULTS: At veraison (2009 and 2010), samples of aborted flowers, aborted fruits and calyptras were collected, and the incidence and sporulation of B. cinerea were determined. Aborted fruits presented significantly higher incidence in untreated samples. Early-season applications of Candida sake plus Fungicover(r), Fungicover alone or Ulocladium oudemansii significantly reduced B. cinerea incidence on aborted flowers and calyptras by 46-85%. Chitosan treatment significantly reduced B. cinerea incidence on calyptras. None of the treatments reduced B. cinerea incidence on aborted fruits. Treatments significantly reduced sporulation severity by 48% or more. CONCLUSIONS: Treatments were effective at reducing B. cinerea secondary inoculum on necrotic tissues, in spite of the variable control on aborted fruits. This is the first report to quantify B. cinerea on several tissues of bunch trash and to describe the effective suppression of saprophytic B. cinerea inoculum by biologically based treatments. PMID- 23744714 TI - Error analysis of idealized nanopore sequencing. AB - This numerical study provides an error analysis of an idealized nanopore sequencing method in which ionic current measurements are used to sequence intact single-stranded DNA in the pore, while an enzyme controls DNA motion. Examples of systematic channel errors when more than one nucleotide affects the current amplitude are detailed, which if present will persist regardless of coverage. Absent such errors, random errors associated with tracking through homopolymer regions are shown to necessitate reading known sequences (Escherichia coli K-12) at least 140 times to achieve 99.99% accuracy (Q40). By exploiting the ability to reread each strand at each pore in an array, arbitrary positioning on an error rate versus throughput tradeoff curve is possible if systematic errors are absent, with throughput governed by the number of pores in the array and the enzyme turnover rate. PMID- 23744716 TI - 'Healthy' individuals' perceptions of type 1 and type 2 diabetes cause and management: a 'think-aloud', mixed-methods study using video-based vignettes. AB - This study investigated 'healthy' participants' perceptions of types 1 and 2 diabetes using mixed methods. A total of 38 participants were asked about their perceptions of both types of diabetes using video-based vignettes of four cases. Participants answered standardised questionnaires while thinking aloud and could expand during semi-structured interview sections. Four themes were identified: knowledge of diabetes, power to influence diabetes, limitations of responsibility or blame for diabetes and feelings about individuals with diabetes. Perceived controllability of causes and perceptions of illness management informs understanding of stigma and risk and emphasises the importance of comparing perceptions of both types of diabetes. PMID- 23744717 TI - The influence of personality on reported pain and self-efficacy for pain management in older cancer patients. AB - This study examines the relationship of personality traits and affect on cancer related pain in 150 older adults receiving outpatient treatment at a comprehensive cancer center. Regression analyses revealed extraversion as a significant predictor of current pain, with openness to experience as a significant indicator of average pain. Similarly, positive affect and negative affect were significant predictors of self-efficacy for pain management. Moderation models showed that conscientiousness and extraversion were significant moderators in the relationship between self-efficacy for pain management and worst pain. These findings suggest that different personality types may influence perceptions of pain severity. PMID- 23744715 TI - Topographical control of ocular cell types for tissue engineering. AB - Visual impairment affects over 285 million people worldwide and has a major impact on an individual's quality of life. Tissue engineering has the potential to increase the quality of life for many of these patients by preventing vision loss or restoring vision using cell-based therapies. However, these strategies will require an understanding of the microenvironmental factors that influence cell behavior. The eye is a well-organized organ whose structural complexity is essential for proper function. Interactions between ocular cells and their highly ordered extracellular matrix are necessary for maintaining key tissue properties including corneal transparency and retinal lamination. Therefore, it is not surprising that culturing these cells in vitro on traditional flat substrates result in irregular morphology. Instead, topographically patterned biomaterials better mimic native extracellular matrix and have been shown to elicit in vivo like morphology and gene expression which is essential for tissue engineering. Herein we review multiple methods for producing well-controlled topography and discuss optimal biomaterial scaffold design for cells of the cornea, retina, and lens. PMID- 23744718 TI - Is cunnilingus-assisted orgasm a male sperm-retention strategy? AB - We secured data from 243 men in committed, sexual, heterosexual relationships to test the sperm retention hypothesis of oral sex. We predicted that, among men who perform cunnilingus on their partner, those at greater risk of sperm competition are more likely to perform cunnilingus until their partner achieves orgasm (Prediction 1), and that, among men who ejaculate during penile-vaginal intercourse and whose partner experiences a cunnilingus-assisted orgasm, ejaculation will occur during the brief period in which female orgasm might function to retain sperm (Prediction 2). The results support Prediction 1 but not Prediction 2. We discuss limitations of the current research and discuss how these results may be more consistent with alternative hypotheses regarding female orgasm and oral sex. PMID- 23744720 TI - Induction of hepatocyte-like cells from mouse embryonic stem cells by lentivirus mediated constitutive expression of Foxa2/Hnf4a. AB - Hepatocytes can be generated from embryonic stem cells (ESCs) using inducers such as chemical compounds and cytokines, but issues related to low differentiation efficiencies remain to be resolved. Recent work has shown that overexpression of lineage-specific transcription factors can directly cause cells phenotypic changes, including differentiation, trans-differentiation, and de differentiation. We hypothesized that lentivirus-mediated constitutive expression of forkhead box A2 (Foxa2) and hepatocyte nuclear factor 4 alpha (Hnf4a) could promote inducing mouse ESCs to hepatocyte-likes cells. First, ESC lines that stably expressed Foxa2, Hnf4a, or Foxa2/Hnf4a were constructed via lentiviral expression vectors. Second, observations of cell morphology changes were made during the cell culture process, followed by experiments examining teratoma formation. Then, the effects of constitutive expression of Foxa2 and Hnf4a on hepatic differentiation and maturation were determined by measuring the marker gene expression levels of Albumin, alpha-fetoprotein, Cytokeratin18, and alpha1 antitrypsin. The results indicate that constitutive expression of Foxa2 and Hnf4a does not affect ESCs culture, teratoma formation, or the expression levels of the specific hepatocyte genes under autonomous differentiation. However, with some assistance from inducing factors, Foxa2 significantly increased the hepatic differentiation of ESCs, whereas the expression of Hnf4a alone or Foxa2/Hnf4a could not. Differentiated CCE-Foxa2 cells were more superior in expressing several liver-specific markers and protein, storing glycogen than differentiated CCE cells. Therefore, our method employing the transduction of Foxa2 would be a valuable tool for the efficient generation of functional hepatocytes derived from ESCs. PMID- 23744721 TI - Comparable graft and patient survival in lean and obese liver transplant recipients. AB - Obesity is among the great health problems facing Americans today. More than 32% of the US population is considered obese on the basis of a body mass index (BMI) exceeding 30 kg/m(2) . Obesity increases the risk for numerous perioperative complications, but how obesity affects the outcome of liver transplantation remains unclear. We compared graft/patient survival after orthotopic liver transplantation performed at the Cleveland Clinic between April 2005 and June 2011 in 2 groups: obese patients with a BMI >= 38 kg/m(2) and lean patients with a BMI between 20 and 26 kg/m(2) . We included 47 obese patients and 183 lean patients, whose demographics and baseline characteristics were well balanced after weighting with the inverse propensity score. After we controlled for observed confounding, no significant differences were observed in graft/patient survival between obese and lean patients (P = 0.30). The estimated hazard ratio for obese patients to experience graft failure or death was 1.19 [95% confidence interval (CI) = 0.85-1.67]. There were 134 patients who had follow-up for more than 3 years, and they included 27 obese patients and 107 lean patients. Within this subset, the odds of having metabolic syndrome were significantly greater for obese patients (46%) versus lean patients (21%; odds ratio = 4.76, 99.5% CI = 1.66-13.7, P < 0.001). However, no significant association between obesity and any other long-term adverse outcomes was found. In conclusion, this study shows that transplant outcomes were comparable for lean and obese recipients. We thus recommend that even morbid obesity per se should not exclude patients from consideration for transplantation. PMID- 23744722 TI - Stepwise coordination of Pt(II)-180 degrees and Pd(II)-90 degrees metal fragments to the purine nucleobase 9-methylhypoxanthine affords a closed octadecanuclear Pt6Pd12 cluster. AB - Crossing the line: A pH-induced "crossover" in 3D shapes of supramolecular constructs derived from trans(NH3)2Pt(II), [Pd(II)(en)], and the purine model nucleobase 9-methylhypoxanthine (see figure) is reported in which [Pd(en)(H2O)](2+) and [Pd(en)(OH)](+) are the decisive players (en = ethylenediamine). PMID- 23744723 TI - Vascular pattern in monochorionic placentas with spontaneous TAPS and TTTS with residual anastomoses after laser: a case-control study. AB - OBJECTIVE: This study aimed to compare the angio-architecture of monochorionic placentas of spontaneous twin anaemia-polycythemia sequence (TAPS) with placenta of twin-to-twin transfusion syndrome (TTTS) with residual anastomoses after laser coagulation and placentas of uncomplicated monochorionic twin pregnancies. METHODS: This case-control study compares the angio-architecture of monochorionic placentas of spontaneous TAPS (n = 12) with that of monochorionic placentas of TTTS treated by laser coagulation with residual anastomoses (TTTS + RA; n = 20) and placentas of monochorionic pregnancies without complications (n = 24), matched for gestational age. Placental sharing and angio-architecture were assessed by injection of colored dye. RESULTS: The median diameter of the arterio venous (AV) anastomoses in TAPS placentas was 2.26, 0.215 with TTTS + RA and 4.17 mm in normal monochorionic pregnancies (p < .03). The mean diameter of the arterio-arterial (AA) anastomoses in monochorionic placentas with spontaneous TAPS was 0.2 mm versus 0.15 mm in TTTS + RA and 2.0 mm in normal pregnancies, respectively (p < 0.03, p < 0.007). The number of AA anastomoses was lower with TAPS (0.3 versus 0.50 and 1, respectively, p < 0.015, p < 0.0001). Besides, unequal sharing was more frequent in TAPS as compared with monochorionic normal pregnancies (75% versus 29%, p = 0.03). CONCLUSION: Age matched placentas of spontaneous TAPS are characterized by very small AV anastomoses and very few AA anastomoses of smaller diameter than placentas of monochorionic twins with TTTS or without obvious complications. PMID- 23744724 TI - Quality of carrots as affected by pre- and postharvest factors and processing. AB - The aim of this review is to provide an update on factors contributing to quality of carrots, with special focus on the role of pre- and postharvest factors and processing. The genetic factor shows the highest impact on quality variables in carrots, causing a 7-11-fold difference between varieties in content of terpenes, beta-carotene, magnesium, iron and phenolics as well as a 1-4-fold difference in falcarindiol, bitter taste and sweet taste. Climate-related factors may cause a difference of up to 20-fold for terpenes, 82% for total sugars and 30-40% for beta-carotene, sweet taste and bitter taste. Organic farming in comparison with conventional farming has shown 70% higher levels for magnesium and 10% for iron. Low nitrogen fertilisation level may cause up to 100% increase in terpene content, minor increase in dry matter (+4 to +6%) and magnesium (+8%) and reduction in beta-carotene content (-8 to -11%). Retail storage at room temperature causes the highest reduction in beta-carotene (-70%) and ascorbic acid (-70%). Heat processing by boiling reduces shear force (-300 to -1000%) and crispiness (-67%) as well as content of phenolics (-150%), terpenes (-85%) and total carotenes (-20%) and increases the risk of furan accumulation. Sensory and chemical quality parameters of carrots are determined mainly by genetic and climate-related factors and to a minor extent by cultivation method. Retail temperature and storage atmosphere as well as heating procedure in processing have the highest impact in quality reduction. PMID- 23744725 TI - Cytotoxicity of adhesive systems of different hydrophilicities on cultured odontoblast-like cells. AB - This study evaluated the cytotoxicity of experimental adhesive systems (EASs) on odontoblast-like cells. Paper discs (n = 132) were impregnated with 10 uL of each EAS-R1, R2, R3, R4, and R5 (in an ascending order of hydrophilicity), followed by photoactivation. R1 and R2 are nonsolvated hydrophobic blends, R3 represents a simplified etch-and-rinse adhesive system, and R4 and R5 represent simplified self-etch adhesive systems. Discs were immersed in Dulbecco's modified Eagle's medium for 24 h to obtain eluates applied on MDPC-23 cell cultures. No material was applied on discs used as control (R0). Cell viability [3-(4,5-dimethythiazol 2-yl)-2,5-diphenyl tetrazolium bromide assay], total protein (TP) production, alkaline phosphatase (ALP) activity, type of cell death, and degree of monomer conversion Fourier transform infrared (%DC-FTIR) were evaluated. Data were analyzed by Kruskal-Wallis and Mann-Whitney tests (alpha = 0.05). Considering R0 (control) as having 100% of cell viability, R1, R2, R3, R4, and R5 reduced the metabolic activity of cells by 36.4, 3.1, 0.2, 21.5, and 65.7%, respectively, but only R1 and R5 differed from R0. Comparing with R0, lower TP production was observed for R1, R4, and R5, while ALP activity decreased for R1 and R5. Necrotic cell death was predominant for all EASs, but only R1, R4, and R5 differed from R0. Only R5 presented a different apoptotic cell death ratio from R0. R1 presented the lowest %DC (ca. 37%), whereas R4 and R5 presented the highest (ca. 56%). In conclusion, R2 and R3 were not toxic to the MDPC-23 cells, suggesting that the degree of hydrophilicity or %DC of the EASs alone were not responsible for their cytopathic effects. PMID- 23744726 TI - Variation in inflammatory markers and glycemic parameters after 12 months of exenatide plus metformin treatment compared with metformin alone: a randomized placebo-controlled trial. AB - STUDY OBJECTIVE: To evaluate the effects of exenatide on some inflammatory markers and to quantify the effect of exenatide on beta-cell function. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Seven hospitals in Italy. PATIENTS: A total of 174 white treatment-naive adults with type 2 diabetes and a glycated hemoglobin (HbA(1c)) level higher than 7.5%. INTERVENTION: After an open-label run-in period of 8 +/- 2 months with metformin, patients were randomized to take exenatide (5 MUg twice/day for the first 4 weeks, 10 MUg twice/day thereafter) or a placebo volume equivalent for 12 months. MEASUREMENTS AND MAIN RESULTS: Body mass index, HbA(1c), fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index, homeostasis model assessment beta-cell function index (HOMA-beta), fasting plasma proinsulin (FPPr), proinsulin-to-fasting plasma insulin ratio (Pr:FPI ratio), C-peptide, glucagon, vaspin, chemerin, and resistin were evaluated at baseline, at randomization, and at 3, 6, 9, and 12 months. Patients also underwent a combined euglycemic, hyperinsulinemic, and hyperglycemic clamp with subsequent arginine stimulation to assess insulin sensitivity and insulin secretion. HbA(1c) was significantly improved with exenatide plus metformin compared with placebo plus metformin. Exenatide plus metformin was also significantly more effective than placebo plus metformin in increasing HOMA-beta C-peptide, and all measures of beta-cell function after the euglycemic hyperinsulinemic and hyperglycemic clamp. We observed that exenatide plus metformin also reduced resistin compared with placebo plus metformin. No variations in vaspin and chemerin were noted in group-to-group comparisons. We observed a significant correlation between M value increase, an index of insulin sensitivity, and a decrease in inflammatory parameters in the exenatide plus metformin group. CONCLUSIONS: The combination of exenatide plus metformin was more effective than metformin alone in improving glycemic control, beta-cell function, and inflammatory parameters. PMID- 23744727 TI - Nanosolvation-induced stabilization of a protonated peptide dimer isolated in the gas phase. PMID- 23744728 TI - Immunocytochemical demonstration of feline infectious peritonitis virus within cerebrospinal fluid macrophages. AB - A 4-month-old female entire domestic shorthair cat presented with an acute onset of blindness, tetraparesis and subsequent generalised seizure activity. Haematology and serum biochemistry demonstrated a moderate, poorly regenerative anaemia, hypoalbuminaemia and hyperglobulinaemia with a low albumin:globulin ratio. Serology for feline coronavirus antibody was positive with an elevated alpha-1 acid glycoprotein. Analysis of cisternal cerebrospinal fluid (CSF) demonstrated markedly elevated protein and a mixed, predominately neutrophilic pleocytosis. Immunocytochemistry for feline coronavirus was performed on the CSF, with positive staining observed inside macrophages. The cat was subsequently euthanased, and both histopathology and immunohistochemistry were consistent with a diagnosis of feline infectious peritonitis. This is the first reported use of immunocytochemistry for detection of feline coronavirus within CSF macrophages. If this test proves highly specific, as for identification of feline coronavirus within tissue or effusion macrophages, it would be strongly supportive of an ante mortem diagnosis of feline infectious peritonitis in cats with central nervous system involvement without the need for biopsy. PMID- 23744729 TI - Vasoactive intestinal peptide attenuates liver ischemia/reperfusion injury in mice via the cyclic adenosine monophosphate-protein kinase a pathway. AB - Hepatic ischemia/reperfusion injury (IRI), an exogenous, antigen-independent, local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The nervous system maintains extensive crosstalk with the immune system through neuropeptide and peptide hormone networks. This study examined the function and therapeutic potential of the vasoactive intestinal peptide (VIP) neuropeptide in a murine model of liver warm ischemia (90 minutes) followed by reperfusion. Liver ischemia/reperfusion (IR) triggered an induction of gene expression of intrinsic VIP; this peaked at 24 hours of reperfusion and coincided with a hepatic self healing phase. Treatment with the VIP neuropeptide protected livers from IRI; this was evidenced by diminished serum alanine aminotransferase levels and well preserved tissue architecture and was associated with elevated intracellular cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling. The hepatocellular protection rendered by VIP was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and increased hepatic interleukin-10 (IL-10) expression. Strikingly, PKA inhibition restored liver damage in otherwise IR-resistant VIP treated mice. In vitro, VIP not only diminished macrophage tumor necrosis factor alpha/IL-6/IL-12 expression in a PKA-dependent manner but also prevented necrosis/apoptosis in primary mouse hepatocyte cultures. In conclusion, our findings document the importance of VIP neuropeptide-mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Because the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to managing liver IRI in transplant patients. PMID- 23744730 TI - Breakpoint regions of ETO gene involved in (8; 21) leukemic translocations are enriched in acetylated histone H3. AB - One of the most frequent chromosomal translocation found in patients with acute myeloid leukemia (AML) is the t(8;21). This translocation involves the RUNX1 and ETO genes. The breakpoints regions for t(8;21) are located at intron 5 and intron 1 of the RUNX1 and ETO gene respectively. To date, no homologous sequences have been found in these regions to explain their recombination. The breakpoint regions of RUNX1 gene are characterized by the presence of DNasaI hypersensitive sites and topoisomerase II cleavage sites, but no information exists about complementary regions of ETO gene. Here, we report analysis of chromatin structure of ETO breakpoint regions. Chromatin immunoprecipitation (ChIP) were performed with antibodies specific to acetylated histone H3, H4, and total histone H1. Nucleosomal distribution at the ETO locus was evaluated by determining total levels of histone H3. Our data show that in myeloid cells, the breakpoint regions at the ETO gene are enriched in hyperacetylated histone H3 compared to a control region of similar size where no translocations have been described. Moreover, acetylated H4 associates with both the whole ETO breakpoint regions as well as the control intron. Interestingly, we observed no H1 association either at the breakpoint regions or the control region of the ETO gene. Our data indicate that a common chromatin structure enriched in acetylated histones is present in breakpoint regions involved in formation of (8;21) leukemic translocation. PMID- 23744731 TI - Effects of whole-body exposure to 915 MHz RFID on secretory functions of the thyroid system in rats. AB - As a part of an investigation on the potential risks of radiofrequency identification (RFID) on human health, we studied whether exposure to 915 MHz RFID in rats significantly affected the secretory function of the thyroid system. A reverberation chamber was used as a whole-body exposure system. Male Sprague Dawley rats were exposed for 8 h per day, 5 days per week, for a duration of 2, 4, 8, or 16 weeks. The estimated whole-body average specific absorption rate (SAR) varied from 3.2 to 4.6 W/kg depending on the age/mass of the animals for the field of the 915 MHz RFID reader. Plasma levels of triiodothyronine (T3), thyroxine (T4), and thyroid-stimulating hormone (TSH) were evaluated via enzyme linked immunosorbent assay. Morphological changes in the thyroid gland were then analyzed. No changes in T3, T4, or TSH were observed over time between the sham- and RFID-exposed groups. We suggest that subchronic exposure to 915 MHz RFID at a SAR of 4 W/kg does not cause significant effects on thyroid secretory function. PMID- 23744732 TI - Effects of climatic control on tomato yield and nutritional quality in Mediterranean screenhouse. AB - BACKGROUND: The quality of vegetables for fresh consumption is a complex issue. In this study the yield and quality of cherry tomato fruits were assessed under different environmental control conditions, namely in a screenhouse (S), in a screenhouse equipped with a fogging system (SF) and in a screenhouse with complements such as plastic sheeting to maintain the microclimate created by the fogging system (SFS), as well as under open field (OF) cultivation. Levels of vitamin C, carotenoids (lycopene, beta-carotene and lutein), phenolic compounds (flavonoids and phenolic acids), sugars (fructose, glucose and sucrose), organic acids (citric acid and malic acid) and flavour indices were measured. The aim of the study was to determine how different environmental control technologies could influence production and quality traits in tomato cherry fruits cultivated in a Mediterranean area. RESULTS: The results showed that the fogging system treatment's decline in maximum vapour pressure deficit (by 0.7 kPa compared with OF cultivation), increase in mean fruit weight (by about 4 g per fruit) and low radiation and temperature values may exert a positive effect on lycopene accumulation. CONCLUSION: For the production and nutritional parameters measured, it is postulated that the fogging system treatment offers a better balance between production and nutritional quality. This treatment proved to be best in terms of productivity, vitamin C and lycopene contents and antioxidant capacity. PMID- 23744734 TI - Dynamics of a nanometer-sized uranyl cluster in solution. AB - A class of uranyl peroxide clusters was discovered before as nanometer-sized ions that form spontaneously in aqueous solutions. The uranyl(VI) cluster investigated here is approximately 2 nm in diameter, contains 24 uranyl moieties, and 12 pyrophosphate units. NMR spectroscopy shows that the ion has two distinct forms that interconvert in milliseconds to seconds depending on the temperature and the size of the counterions. P blue, O red, U yellow. PMID- 23744733 TI - Synthetic, spectroscopic, and DFT studies of iron complexes with iminobenzo(semi)quinone ligands: implications for o-aminophenol dioxygenases. AB - The oxidative C-C bond cleavage of o-aminophenols by nonheme Fe dioxygenases is a critical step in both human metabolism (the kynurenine pathway) and the microbial degradation of nitroaromatic pollutants. The catalytic cycle of o-aminophenol dioxygenases (APDOs) has been proposed to involve formation of an Fe(II)/O2/iminobenzosemiquinone complex, although the presence of a substrate radical has been called into question by studies of related ring-cleaving dioxygenases. Recently, we reported the first synthesis of an iron(II) complex coordinated to an iminobenzosemiquinone (ISQ) ligand, namely, [Fe((Ph2)Tp)((tBu)ISQ)] (2a; where (Ph2)Tp=hydrotris(3,5-diphenylpyrazol-1 yl)borate and (tBu)ISQ is the radical anion derived from 2-amino-4,6-di-tert butylphenol). In the current manuscript, density functional theory (DFT) calculations and a wide variety of spectroscopic methods (electronic absorption, Mossbauer, magnetic circular dichroism, and resonance Raman) were employed to obtain detailed electronic-structure descriptions of 2a and its one-electron oxidized derivative [3a](+). In addition, we describe the synthesis and characterization of a parallel series of complexes featuring the neutral supporting ligand tris(4,5-diphenyl-1-methylimidazol-2-yl)phosphine ((Ph2)TIP). The isomer shifts of about 0.97 mm s(-1) obtained through Mossbauer experiments confirm that 2a (and its (Ph2)TIP-based analogue [2b](+)) contain Fe(II) centers, and the presence of an ISQ radical was verified by analysis of the absorption spectra in light of time-dependent DFT calculations. The collective spectroscopic data indicate that one-electron oxidation of the Fe(II)-ISQ complexes yields complexes ([3a](+) and [3b](2+)) with electronic configurations between the Fe(III)-ISQ and Fe(II)-IBQ limits (IBQ=iminobenzoquinone), highlighting the ability of o-amidophenolates to access multiple oxidation states. The implications of these results for the mechanism of APDOs and other ring-cleaving dioxygenases are discussed. PMID- 23744735 TI - Polyaniline as a material for hydrogen storage applications. AB - The main challenge of commercialization of the hydrogen economy is the lack of convenient and safe hydrogen storage materials, which can adsorb and release a significant amount of hydrogen at ambient conditions. Finding and designing suitable cost-effective materials are vital requirements to overcome the drawbacks of investigated materials. Because of its outstanding electronic, thermal, and chemical properties, the electrically conducting polyaniline (PANI) has a high potential in hydrogen storage applications. In this review, the progress in the use of different structures of conducting PANI, its nanocomposites as well as activated porous materials based on PANI as hydrogen storage materials is presented and discussed. The effect of the unique electronic properties based on the pi-electron system in the backbone of these materials in view of the hydrogen uptake and the relevant mechanisms are highlighted. PMID- 23744736 TI - Coaxial electrospinning of P(LLA-CL)/heparin biodegradable polymer nanofibers: potential vascular graft for substitution of femoral artery. AB - Electrospinning is one of the most simple and effective methods to prepare polymer fibers with the diameters ranging from nanometer to several micrometers. Poly(L-lactide)-co-poly (E-caprolactone) (P(LLA-CL)) fibers and P(LLA-CL)/heparin coaxial composite fibers herein were successfully prepared by single electrospinning and coaxial electrospinning, respectively. The prepared endothelialized P(LLA-CL) and P(LLA-CL)/heparin vascular grafts were used in the Beagle dogs experiment to evaluate the feasibility of thus made different scaffolds for substitution of dog femoral artery in early period, medium term, and long term, meanwhile the pure P(LLA-CL) vascular graft was used as the control group during all the experiments. The animal model was established by using the graft materials to anastomose both femoral arteries of dogs. The vascular grafts patency rates (i.e., the unobstructed capacity of blood vessel) were detected by color Doppler flow imaging technology and digital subtraction angiography. To observe the histological morphology at different periods, the vascular grafts were removed after 7, 14, and 30 days, and the corresponding histological changes were evaluated by hematoxylin and eosin staining. The experimental results show that in the early period, the patency rates of pure P(LLA-CL) graft, endothelial P(LLA-CL) graft, and P(LLA-CL)/heparin graft were 75%, 75%, and 100%, respectively; in the medium term, the patency rates of pure P(LLA-CL) graft and endothelial P(LLA-CL) graft were 25%, whereas that of P(LLA CL)/heparin graft was 50%; the patency rates of pure P(LLA-CL) graft and endothelial P(LLA-CL) graft were down to 0%, whereas the patency rate of P(LLA CL)/heparin graft was 25% in the long term. This preliminary study has demonstrated that P(LLA-CL)/heparin coaxial composite fiber maybe a reliable artificial graft for the replacement of femoral artery. (c) 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013. PMID- 23744737 TI - Heparan sulfate on intestinal epithelial cells plays a critical role in intestinal crypt homeostasis via Wnt/beta-catenin signaling. AB - Heparan sulfate (HS), a constituent of HS proteoglycans (HSPGs), is a linear polysaccharide present on the cell surface. HSPGs modulate functions of several growth factors and signaling molecules. We examined whether small intestinal epithelial HS plays some roles in crypt homeostasis using intestinal epithelium cell (IEC)-specific HS-deficient C57Bl/6 mice. Survival rate after total body irradiation was significantly reduced in HS-deficient mice due to profound intestinal injury. HS-deficient IECs exhibited Wnt/beta-catenin pathway disruption, decreased levels of beta-catenin nuclear localization, and reduced expression of Wnt target genes, including Lgr5 during crypt regeneration. Moreover, epithelial HS increased Wnt binding affinity of IECs, promoted phosphorylation of Wnt coreceptor LRP6, and enhanced Wnt/beta-catenin signaling following ex vivo stimulation with Wnt3a, whereas activation of canonical Wnt signaling following direct inhibition of glycogen synthase kinase-3beta by lithium chloride was similar between HS-deficient and wild-type mice. Thus HS influences the binding affinity of IECs to Wnt, thereby promoting activation of canonical Wnt signaling and facilitating regeneration of small intestinal crypts after epithelial injury. PMID- 23744738 TI - Mammalian colonocytes possess a carrier-mediated mechanism for uptake of vitamin B3 (niacin): studies utilizing human and mouse colonic preparations. AB - Niacin (vitamin B3; nicotinic acid) plays an important role in maintaining redox state of cells and is obtained from endogenous and exogenous sources. The latter source has generally been assumed to be the dietary niacin, but another exogenous source that has been ignored is the niacin that is produced by the normal microflora of the large intestine. For this source of niacin to be bioavailable, it needs to be absorbed, but little is known about the ability of the large intestine to absorb niacin and the mechanism involved. Here we addressed these issues using the nontransformed human colonic epithelial NCM460 cells, native human colonic apical membrane vesicles (AMV) isolated from organ donors, and mouse colonic loops in vivo as models. Uptake of 3H-nicotinic acid by NCM460 cells was: 1) acidic pH (but not Na+) dependent; 2) saturable (apparent Km = 2.5 +/- 0.8 MUM); 3) inhibited by unlabeled nicotinic acid, nicotinamide, and probenecid; 4) neither affected by other bacterially produced monocarboxylates, monocarboxylate transport inhibitor, or by substrates of the human organic anion transporter-10; 5) affected by modulators of the intracellular protein tyrosine kinase- and Ca2+-calmodulin-regulatory pathways; and 6) adaptively regulated by extracellular nicotinate level. Uptake of nicotinic acid by human colonic AMV in vitro and by mouse colonic loops in vivo was also carrier mediated. These findings report, for the first time, that mammalian colonocytes possess a high affinity carrier-mediated mechanism for nicotinate uptake and show that the process is affected by intracellular and extracellular factors. PMID- 23744741 TI - Enzymatic activity preservation and protection through entrapment within degradable hydrogels. AB - This work aims to develop a repeatable enzyme entrapment method that preserves activity within an amicable environment while resisting activity reduction in the presence of environmental challenges. Advances in such methods have wide potential use in biosensor applications. In this work beta-galactosidase (lactase) enzyme was entrapped within hydrogel matrices of acrylamide (ACR) crosslinked with N,N'-methylenebisacrylamide (BIS, non-degradable) or poly(ethylene glycol) diacrylate (PEGDA, degradable) to create "biogels." Diffusivity studies of control, enzyme free, hydrogel constructs showed near Fickian swelling behavior in PBS regardless of crosslinker type or density. As expected, the swelling rate, Ks , decreased when increasing the crosslink density from 78.6 to 14.7 min-1 over a range of 1-20 mol% PEGDA indicating that diffusivity into the matrix is dependent on crosslink density. Fabricated biogels were evaluated for maintained enzyme activity in the 7 and 8 pH range. PEGDA crosslinked gels consistently showed improved enzymatic activity retention as compared to BIS crosslinked gels. As PEGDA crosslink density increased from 5 to 10 mol%, enzymatic activity retention post-initial entrapment increased. Higher PEGDA crosslink densities between 15% and 40% decreased enzymatic activity due to assumed steric hindrance of the entrapped enzyme and also decreased substrate and product diffusion. Increased enzymatic stability was observed in 40 mol% PEGDA crosslinked gels. The biogels were pH challenged to 8.0 and stability, measured as retention of activity, was observed to be 91%. Free, non-entrapped, solution based enzyme conversion only retained 23% activity under the same pH challenge conditions. No significant loss of active enzyme was determined to elute out of the biogels during storage in PBS or during biogel wash and recycling. This entrapment method illustrates the potential to sterically hinder and diffusively impede enzymes from performing their function. Degradation of the network crosslinks can then potentially enable the reactivation of the enzyme at a site and time dictated by the user. PMID- 23744739 TI - Regulated traffic of anion transporters in mammalian Brunner's glands: a role for water and fluid transport. AB - The Brunner's glands of the proximal duodenum exert barrier functions through secretion of glycoproteins and antimicrobial peptides. However, ion transporter localization, function, and regulation in the glands are less clear. Mapping the subcellular distribution of transporters is an important step toward elucidating trafficking mechanisms of fluid transport in the gland. The present study examined 1) changes in the distribution of intestinal anion transporters and the aquaporin 5 (AQP5) water channel in rat Brunner's glands following second messenger activation and 2) anion transporter distribution in Brunner's glands from healthy and disease-affected human tissues. Cystic fibrosis transmembrane conductance regulator (CFTR), AQP5, sodium-potassium-coupled chloride cotransporter 1 (NKCC1), sodium-bicarbonate cotransporter (NBCe1), and the proton pump vacuolar ATPase (V-ATPase) were localized to distinct membrane domains and in endosomes at steady state. Carbachol and cAMP redistributed CFTR to the apical membrane. cAMP-dependent recruitment of CFTR to the apical membrane was accompanied by recruitment of AQP5 that was reversed by a PKA inhibitor. cAMP also induced apical trafficking of V-ATPase and redistribution of NKCC1 and NBCe1 to the basolateral membranes. The steady-state distribution of AQP5, CFTR, NBCe1, NKCC1, and V-ATPase in human Brunner's glands from healthy controls, cystic fibrosis, and celiac disease resembled that of rat; however, the distribution profiles were markedly attenuated in the disease-affected duodenum. These data support functional transport of chloride, bicarbonate, water, and protons by second messenger-regulated traffic in mammalian Brunner's glands under physiological and pathophysiological conditions. PMID- 23744740 TI - CTRP3 attenuates diet-induced hepatic steatosis by regulating triglyceride metabolism. AB - CTRP3 is a secreted plasma protein of the C1q family that helps regulate hepatic gluconeogenesis and is downregulated in a diet-induced obese state. However, the role of CTRP3 in regulating lipid metabolism has not been established. Here, we used a transgenic mouse model to address the potential function of CTRP3 in ameliorating high-fat diet-induced metabolic stress. Both transgenic and wild type mice fed a high-fat diet showed similar body weight gain, food intake, and energy expenditure. Despite similar adiposity to wild-type mice upon diet-induced obesity (DIO), CTRP3 transgenic mice were strikingly resistant to the development of hepatic steatosis, had reduced serum TNF-alpha levels, and demonstrated a modest improvement in systemic insulin sensitivity. Additionally, reduced hepatic triglyceride levels were due to decreased expression of enzymes (GPAT, AGPAT, and DGAT) involved in triglyceride synthesis. Importantly, short-term daily administration of recombinant CTRP3 to DIO mice for 5 days was sufficient to improve the fatty liver phenotype, evident as reduced hepatic triglyceride content and expression of triglyceride synthesis genes. Consistent with a direct effect on liver cells, recombinant CTRP3 treatment reduced fatty acid synthesis and neutral lipid accumulation in cultured rat H4IIE hepatocytes. Together, these results establish a novel role for CTRP3 hormone in regulating hepatic lipid metabolism and highlight its protective function and therapeutic potential in attenuating hepatic steatosis. PMID- 23744742 TI - Engineering of a hybrid biotransformation system for cytochrome P450sca-2 in Escherichia coli. AB - P450sca-2 is an industrially important enzyme that stereoselectively converts mevastatin into pravastatin. However, little information or engineering efforts have been reported for this enzyme or its redox partner. In this study, we successfully reconstituted the P450sca-2 activity in Escherichia coli by co expression with putidaredoxin reductase (Pdr) and putidaredoxin (Pdx) from the Pseudomonas putida cytochrome P450cam system. With an HPLC-based screening assay, random mutagenesis was applied to yield a mutant (R8-5C) with a pravastatin yield of the whole-cell biotransformation 4.1-fold that of the wild type. P450sca-2 wild-type and R8-5C were characterized in terms of mevastatin binding and hydroxylation, electron transfer, and circular dichroism spectroscopy. R8-5C showed an active P450 expression level that was 3.8-fold that of the wild type, with relatively smaller changes in the apparent k(cat)/K(M) with respect to the substrate mevastatin (1.3-fold) or Pdx (1.5-fold) compared with the wild type. Thus, the increase in the pravastatin yield of the whole-cell biotransformation primarily came from the improved active P450 expression, which has resulted largely from better heme incorporation, although none of the six mutations of R8 5C are located near the heme active site. These results will facilitate further engineering of this P450sca-2 system and provide useful clues for improving other hybrid P450 systems. PMID- 23744743 TI - Anticoagulation control with daily low-dose vitamin k to reduce clinically adverse outcomes and international normalized ratio variability: a systematic review and meta-analysis. AB - STUDY OBJECTIVES: Difficulties managing warfarin therapy have led to speculation that daily supplementation with a low dose of vitamin K might improve anticoagulation control and clinical outcomes. Thus we sought to review the available medical literature systematically examining the effectiveness of low dose vitamin K supplementation for the reduction of clinically relevant adverse events due to vitamin K antagonist (VKA) use and for stabilization of the international normalized ratio (INR). DESIGN: We searched the Medline and Embase databases, the Cochrane Library, International Pharmaceutical Abstracts, and the U.S. National Institutes of Health clinical trials registry for randomized controlled trials of vitamin K supplementation versus placebo in patients receiving a VKA. We evaluated the outcomes of hemorrhage, thromboembolic events, and percentage of time in therapeutic range (TTR) of INRs by using the Grading of Recommendations Assessment, Development and Evaluation system for rating quality of evidence in the abstracted studies. SETTING: All randomized controlled trials studies published between 1970 and August 2012 which fitted our search strategy. PATIENTS: Patients over the age of 18 years on VKA therapy. RESULTS: Of the 624 studies we identified and screened, three studies (626 patients) were included in the meta-analysis. Most of the patients had a satisfactory TTR at baseline. We found low-quality evidence--downgraded for imprecision and risk of bias (i.e., limitation in study design and/or execution)--of no effect of vitamin K use (100 to 200 MUg) on hemorrhagic events (relative risk [RR] 3.2, 95% confidence interval [CI] 0.2-64.2) and thromboembolic events (RR 2.2, 95% CI 0.1-47.5) and a significant but clinically unimportant effect on TTR with an absolute increase of 3.5% (95% CI 1.1-6.0). CONCLUSION: This meta-analysis, despite the few studies and overall low quality, suggests no beneficial role of low-dose (100 to 200 MUg) vitamin K supplementation on the reduction of clinically relevant adverse events in patients taking VKAs, despite a small improvement of the TTR. Data were insufficient, however, from patients with unstable INRs. PMID- 23744744 TI - Shedding light on organocatalysis-light-assisted asymmetric ion-pair catalysis for the enantioselective hydrogenation of pyrylium ions. AB - A new light-driven asymmetric ion-pair catalysis procedure for the metal-free enantioselective hydrogenation of in situ generated pyrylium ions from readily available chalcones was developed (see scheme). The photo-assisted Bronsted acid catalyzed procedure has broad scope and allows, for the first time, access to valuable 4H-chromenes in good yields and with excellent enantioselectivities. PMID- 23744745 TI - pH-Switchable macroscopic assembly through host-guest inclusion. AB - A novel pH-switchable macroscopic assembly is reported using alginate-based hydrogels functionalized with host (alpha-cyclodextrin, alphaCD) and guest (diethylenetriamine, DETA) moieties. Since the interaction of alphaCD and DETA is pH sensitive, the host hydrogel and guest hydrogel could adhere together when the pH is 11.5 and separate when the pH is 7.0. Furthermore, this pH-controlled adhesion and dissociation shows a good reversibility. The host and guest polymers have good biocompatibility; therefore, this pH-sensitive macroscopic assembly shows great potential in biotechnological and biomedical applications. PMID- 23744746 TI - Ultrathin PtPdTe nanowires as superior catalysts for methanol electrooxidation. AB - Ultrathin and ultralong: Highly uniform, ultrathin (diameter 5-7 nm), and ultralong (aspect ratio >10(4)) PtPdTe nanowires (NWs) were synthesized by using a facile method employing Te NWs as both sacrificial templates and reducing agents. Fine-tuning of the molar ratios of Pt and Pd precursors afforded PtPdTe NWs with different compositions and enhanced electroactivity in the methanol oxidation reaction in comparison with a commercial Pt/C catalyst. PMID- 23744747 TI - New nutritional composition data on selected traditional foods consumed in Black Sea Area countries. AB - BACKGROUND: Traditional foods are an important part of the culture, history, identity and heritage of a region or country and are key elements in dietary patterns. In most countries there is limited information on the nutritional composition of such foods and therefore there is a need to investigate, register and promote traditional foods. One of the aims within the 'Sustainable exploitation of bioactive components from the Black Sea Area traditional foods' (BaSeFood) project is to generate for the first time new data on the nutritional composition of traditional foods from six Black Sea Area countries to promote their sustainable development and exploitation. RESULTS: Thirty-three traditional foods were analysed in an accredited laboratory to determine their nutritional composition, and the data were fully documented. The nutrient content varied widely because of the nature and variety of the analysed foods. The energy content ranged between 4 kcal per 100 g for kvass southern and 900 kcal per 100 g for mustard oil, with the exception of the analysed teas, which did not contribute to energy intake. CONCLUSION: The use of a common methodology for the study of traditional foods will enable countries to further investigate these foods. Moreover, a new nutritional knowledge base of traditional foods from Black Sea Area countries will contribute to promote local biodiversity and sustainable diets by maintaining healthy dietary patterns within local cultures. PMID- 23744748 TI - Surgical site infections in liver transplant recipients in the model for end stage liver disease era: an analysis of the epidemiology, risk factors, and outcomes. AB - In recipients of liver transplantation (LT), surgical site infection (SSIs) are among the most common types of infection occurring in the first 60 days after LT. In 2007, the Model for End-Stage Liver Disease (MELD) scoring system was adopted as the basis for prioritizing organ allocation. Patients with higher MELD scores are at higher risk for developing SSIs as well as other health care-associated infections. However, there have been no studies comparing the incidence of SSIs in the pre-MELD era with the incidence in the period since its adoption. Therefore, the objectives of this study were to evaluate the incidence, etiology, epidemiology, and outcomes of post-LT SSIs in those 2 periods and to identify risk factors for SSIs. We evaluated all patients who underwent LT over a 10-year period (2002-2011). SSI cases were identified through active surveillance. The primary outcome measure was an SSI during the first 60 days after LT. Risk factors were analyzed via logistic regression, and 60-day survival rates were evaluated via Cox regression. We evaluated 543 patients who underwent LT 597 times. The SSI rates in the 2002-2006 and 2007-2011 periods were 30% and 24%, respectively (P = 0.21). We identified the following risk factors for SSIs: retransplantation, the transfusion of more than 2 U of blood during LT, dialysis, cold ischemia for >400 minutes, and a cytomegalovirus infection. The overall 60 day survival rate was 79%. Risk factors for 60-day mortality were retransplantation, dialysis, and a longer surgical time. The use of the MELD score modified the incidence and epidemiology of SSIs only during the first year after its adoption. Risks for SSIs were related more to intraoperative conditions and intercurrences after LT than to a patient's status before LT. PMID- 23744749 TI - The clinical efficacy and safety of sodium glucose cotransporter-2 inhibitors in adults with type 2 diabetes mellitus. AB - The use of currently available antihyperglycemic agents can be limited by contraindications; cost; renal and hepatic dosage adjustments; dosing schedules; and adverse effects such as gastrointestinal upset, weight gain, and hypoglycemia. These limitations have led the pharmaceutical industry to identify and pursue alternative therapies. Sodium glucose cotransporter-2 (SGLT-2) inhibitors belong to a new class of diabetes drugs and have a novel mechanism of action. These agents are unique in that they increase glucose excretion, independent of insulin secretion, by inhibiting the renal reabsorption of glucose, inducing glycosuria. To summarize the current evidence for SGLT-2 inhibitor therapy, we reviewed abstracts and published data from human trials evaluating the efficacy and safety of dapagliflozin, canagliflozin, and empagliflozin through February 2013. Data from these trials suggest that SGLT-2 inhibitors are able to lower hemoglobin A1c and fasting blood glucose when used as either monotherapy or combination therapy. Cardiometabolic benefits included a reduction in systolic blood pressure, reduction in triglycerides, and weight loss of up to 3 kg. Common and serious adverse effects including infections, cancer, and pollakiuria were identified and reviewed. Although these agents have generally demonstrated efficacy, the adverse effects associated with dapagliflozin have caused a delay in its regulatory approval. Continued research in this area will determine the risk:benefit ratio of SGLT-2 inhibitor therapy. PMID- 23744750 TI - Extracellular enzymatic activities and physiological profiles of yeasts colonizing fruit trees. AB - Yeasts form a significant and diverse part of the phyllosphere microbiota. Some yeasts that inhabit plants have been found to exhibit extracellular enzymatic activities. The aim of the present study was to investigate the ability of yeasts isolated from leaves, fruits, and blossoms of fruit trees cultivated in Southwest Slovakia to produce extracellular enzymes, and to discover whether the yeasts originating from these plant organs differ from each other in their physiological properties. In total, 92 strains belonging to 29 different species were tested for: extracellular protease, beta-glucosidase, lipase, and polygalacturonase activities; fermentation abilities; the assimilation of xylose, saccharose and alcohols (methanol, ethanol, glycerol); and for growth in a medium with 33% glucose. The black yeast Aureobasidium pullulans showed the largest spectrum of activities of all the species tested. Almost 70% of the strains tested demonstrated some enzymatic activity, and more than 90% utilized one of the carbon compounds tested. Intraspecies variations were found for the species of the genera Cryptococcus and Pseudozyma. Interspecies differences of strains exhibiting some enzymatic activities and utilizing alcohols were also noted. The largest proportion of the yeasts exhibited beta-glucosidase activity and assimilated alcohols independently of their origin. The highest number of strains positive for all activities tested was found among the yeasts associated with leaves. Yeasts isolated from blossoms assimilated saccharose and D-xylose the most frequently of all the yeasts tested. The majority of the fruit-inhabiting yeasts grew in the medium with higher osmotic pressure. PMID- 23744751 TI - Nanoparticles under the light: click functionalization by photochemical thiol-yne reaction, towards double click functionalization. AB - A light click away: The first application of the thiol-yne reaction to nanoparticle functionalization is described (see figure). This metal-free click chemistry approach is compatible with the addition of various molecules at the surface and can be combined with CuAAC methodology to perform chemoselective double functionalization. PMID- 23744752 TI - Dorsal and ventral stimuli in sandwich-like microenvironments. Effect on cell differentiation. AB - While most of the in vivo extracellular matrices are 3D, most of the in vitro cultures are 2D--where only ventral adhesion is permitted--thus modifying cell behavior as a way to self-adaptation to this unnatural environment. We hypothesize that the excitation of dorsal receptors in cells already attached on a 2D surface (sandwich culture) could cover the gap between 2D and 3D cell material interactions and result in a more physiological cell behavior. In this study we investigate the role of dorsal stimulation on myoblast differentiation within different poly(L-lactic acid) (PLLA) sandwich-like microenvironments, including plain material and aligned fibers. Enhanced cell differentiation levels were found for cells cultured with dorsal fibronectin-coated films. Seeking to understand the underlying mechanisms, experiments were carried out with (i) different types of dorsal stimuli (FN, albumin, FN after blocking the RGD integrin-binding site and activating dorsal cell integrin receptors), (ii) in the presence of an inhibitor of cell contractility, and (iii) increasing the frequency of culture medium changes to assess the effect of paracrine factors. Furthermore, FAK and integrin expressions, determined by Western blotting, revealed differences between cell sandwiches and 2D controls. Results show a stimuli-dependent response to dorsal excitation, proving that integrin outside-in signaling is involved in the enhanced cell differentiation. Due to their easiness and versatility, these sandwich-like systems are excellent candidates to get deeper insights into the study of 3D cell behavior and to direct cell fate within multilayer constructs. PMID- 23744753 TI - A novel melt stable and high tensile strength biopolymer (polyhydroxyalkanoates) from Bacillus megaterium (MTCC10086) and its characterization. AB - In the present investigation, we have defined a novel biopolymer from Bacillus megaterium strain with novel melt stability, high tensile strength, and elongation to break properties higher to polypropylene and similar to polyethylene the polymers available commercially. The polymer was characterized with FTIR and XRD. The percent crystalinity was found to 44.09% with tensile strength 42 (Mpa) and elongation to break (%) 142 higher than polypropylene. The polymeric properties were confirmed by differential scanning calorimeter and universal testing. PMID- 23744754 TI - Ultraviolet index and racial differences in prostate cancer incidence and mortality. AB - BACKGROUND: Studies suggest that low levels of vitamin D may be associated with prostate cancer, and darker skin reduces the body's ability to generate vitamin D from sunshine. The impact of sunshine on racial disparities in prostate cancer incidence and mortality is unknown. METHODS: Using the Surveillance, Epidemiology, and End Results program database, the authors calculated age adjusted prostate cancer incidence rates among black and white men aged >= 45 years by race and county between 2000 and 2009 (N = 906,381 men). Similarly, county-level prostate cancer mortality rates were calculated from the National Vital Statistics System (N = 288,874). These data were linked with the average monthly solar ultraviolet (UV) radiation index by county and data regarding health, wellness, and demographics. Multivariable regression analysis was used to assess whether increases in the UV index (in deciles) moderated the association between black race and the incidence and mortality of prostate cancer. RESULTS: Compared with counties in the lowest UV index decile, prostate cancer incidence rates for white and black men were lower in counties with a higher UV index (all Ps <= 0.051). Incidence rates were higher for black men versus white men, but the difference by race was less for counties in the fourth to fifth UV index deciles versus those in the first decile (Ps <= 0.02). Mortality rates also were found to decrease with increasing UV index for white men (Ps <= 0.003), but increase for black men, and an unexplained increase in racial differences in mortality rates was observed with an increasing UV index. CONCLUSIONS: Racial disparities in the incidence of prostate cancer were larger in some areas with less sunshine. Additional research should confirm the findings of the current study and assess whether optimizing vitamin D levels among black men can reduce disparities. PMID- 23744755 TI - Stable single-photon emission by quantum dot/polymer hybrid particles. AB - Colloidal quantum dots are well-established probes for quantum optical experiments. However, they possess a limited stability toward their environment. Herein, the generation of hybrid particles composed of a high optical quality quantum dot centered in a polymer particle by means of a miniemulsion polymerization procedure is reported. This embedding strongly enhances emission intensity and photochemical stability of these single-photon emitters. At the same time, their colloidal mobile nature is not compromised. PMID- 23744756 TI - Quantitation of cholesterol and phospholipid sorption on silicone hydrogel contact lenses. AB - The introduction of silicone hydrogel (SiHy) contact lenses to the consumer marketplace necessitates study of the susceptibility of these lenses to spontaneous deposition by hydrophobic lipid components of ocular tears. The use of radioisotopes to measure lipid sorption on SiHy contact lenses gives precise and accurate results but requires institutional infrastructure and compels efficient lipid removal from the lens. This study compares three methods of quantitating phospholipid and cholesterol sorption on SiHy lenses using radiolabeled cholesterol and phosphatidylcholine that were sorbed on lenses from an artificial tear fluid. A triple extraction technique using n-propanol gives the most reliable results. Comparison of sorption on SiHy lenses shows that balafilcon A and senofilcon A lenses sorb similar amounts, while lotrafilcon B lenses sorb comparatively less. PMID- 23744757 TI - Photoactivatable chemokines--controlling protein activity by light. PMID- 23744758 TI - Metabolic costs of amino acid and protein production in Escherichia coli. AB - Escherichia coli is the most popular microorganism for the production of recombinant proteins and is gaining increasing importance for the production of low-molecular weight compounds such as amino acids. The metabolic cost associated with the production of amino acids and (recombinant) proteins from glucose, glycerol and acetate was determined using three different computational techniques to identify those amino acids that put the highest burden on the biosynthetic machinery of E. coli. Comparing the costs of individual amino acids, we find that methionine is the most expensive amino acid in terms of consumed mol of ATP per molecule produced, while leucine is the most expensive amino acid when taking into account the cellular abundances of amino acids. Moreover, we show that the biosynthesis of a large number of amino acids from glucose and particularly from glycerol provides a surplus of energy, which can be used to balance the high energetic cost of amino acid polymerization. PMID- 23744759 TI - Single-dose and multiple-dose pharmacokinetics and dose proportionality of intravenous and intramuscular HPbetaCD-diclofenac (Dyloject) compared with other diclofenac formulations. AB - STUDY OBJECTIVE: To evaluate single- and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-beta-cyclodextrin (HPbetaCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration. DESIGN: Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study. SETTING: Clinical research center. SUBJECTS: Healthy adult volunteers. INTERVENTION: Study 1: Subjects received HPbetaCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPbetaCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48 hour washout period between treatment periods. MEASUREMENTS AND MAIN RESULTS: Study 1: IV HPbetaCD-diclofenac had a higher peak plasma concentration (Cmax ) and earlier time to reach maximum plasma concentration (Tmax ), but equivalent plasma exposure (area under the curve from time zero to t [AUC0-t ]) to IV Voltarol. The geometric mean ratio of HPbetaCD-diclofenac (IV) to Voltarol (IV) for AUC0-t was 106.27%. The geometric mean ratio of HPbetaCD-diclofenac (IM) to Voltarol (IM) for AUC0-t was 110.91%. The geometric mean ratio of HPbetaCD diclofenac (IV) to HPbetaCD-diclofenac (IM) for AUC0-t was 101.25%. The geometric mean ratio of HPbetaCD-diclofenac (IM) to Voltarol (IV) for AUC0-t was 104.96%. Study 2: Cmax for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPbetaCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ng.hour/ml) and 37.5 mg (1843 ng.hour/ml) IV HPbetaCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ng.hour/ml). CONCLUSIONS: Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPbetaCD-diclofenac compared with Voltarol and after IM administration of HPbetaCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPbetaCD-diclofenac was equivalent to IV administration of HPbetaCD-diclofenac and IV administration of Voltarol. Study 2: HPbetaCD diclofenac showed dose proportionality after single- and multiple-dose administration and no accumulation of HPbetaCD-diclofenac. HPbetaCD-diclofenac was safe and well tolerated following IV and IM administration. PMID- 23744761 TI - Solvatochromic pyrene analogues of Prodan exhibiting extremely high fluorescence quantum yields in apolar and polar solvents. AB - True colors: Novel pyrene analogues of Prodan exhibit outstanding photophysical properties with remarkably high fluorescence quantum yield (QY) in solvents ranging from apolar hexane to polar methanol (see figure). This is accompanied by strong solvatochromism and large Stokes shifts. These properties have not been previously achieved in enormous solvatochromic dyes, but are quite useful for emitting materials and imaging tools. PMID- 23744760 TI - Soluble human epidermal growth factor receptor 2 (HER2) levels in patients with HER2-positive breast cancer receiving chemotherapy with or without trastuzumab: results from North Central Cancer Treatment Group adjuvant trial N9831. AB - BACKGROUND: Increased soluble human epidermal growth factor receptor 2 (sHER2) is an indicator of a poor prognosis in HER2-positive metastatic breast cancer. In this study, the authors evaluated levels of sHER2 during treatment and at the time of disease recurrence in the adjuvant North Central Cancer Treatment Group N9831 clinical trial. METHODS: The objectives were to describe sHER2 levels during treatment and at the time of recurrence in patients who were randomized to treatment arms A (standard chemotherapy), B (standard chemotherapy with sequential trastuzumab), and C (standard chemotherapy with concurrent trastuzumab). Baseline samples were available from 2318 patients, serial samples were available from 105 patients, and recurrence samples were available from 124 patients. The cutoff sHER2 value for the assay was 15 ng/mL. Statistical methods included repeated measures linear models, Wilcoxon rank-sum tests, and Cox regression models. RESULTS: There were differences between groups in terms of age, menopausal status, and hormone receptor status. Within treatment arms A, B, and C, patients who had baseline sHER2 levels >=15 ng/mL had worse disease-free survival than patients who had baseline sHER2 levels <15 ng/mL (arm A: hazard ratio, 1.81; P = .0014; arm B: hazard ratio, 2.08; P = .0015; arm C: hazard ratio, 1.96; P = .01). Among the 124 patients who experienced disease recurrence, sHER2 levels increased from baseline to the time of recurrence in arms A and B but remained unchanged in arm C. Patients who had recurrence sHER2 levels >=15 ng/mL had a shorter survival after recurrence with a 3-year overall survival rate of 51% compared with 77% for those who had recurrence sHER2 levels <15 ng/mL (hazard ratio, 2.36; 95% confidence interval, 1.19-4.70; P = .01). CONCLUSIONS: In patients with early stage, HER2-positive breast cancer, a high baseline sHER2 level was identified as a prognostic marker associated with shorter disease-free survival, and a high sHER2 level at recurrence was predictive of shorter survival. PMID- 23744762 TI - Loss of histone deacetylases 1 and 2 in hepatocytes impairs murine liver regeneration through Ki67 depletion. AB - Histone deacetylases 1 and 2 (HDAC1 and HDAC2) are ubiquitously expressed in tissues, including the liver, and play critical roles in numerous physiopathological processes. Little is known regarding the role of HDAC1 and HDAC2 in liver regeneration. In this study we generated mice in which Hdac1, Hdac2 or both genes were selectively knocked out in hepatocytes to investigate the role of these genes in liver regeneration following hepatic injury induced by partial hepatectomy or carbon tetrachloride administration. The loss of HDAC1 and/or HDAC2 (HDAC1/2) protein resulted in impaired liver regeneration. HDAC1/2 inactivation did not decrease hepatocytic 5-bromo-2-deoxyuridine uptake or the expression of proliferating cell nuclear antigen, cyclins, or cyclin-dependent kinases. However, the levels of Ki67, a mitotic marker that is expressed from the mid-G1 phase to the end of mitosis and is closely involved in the regulation of mitotic progression, were greatly decreased, and abnormal mitosis lacking Ki67 expression was frequently observed in HDAC1/2-deficient livers. The down regulation of either HDAC1/2 or Ki67 in the mouse liver cancer cell line Hepa1-6 resulted in similar mitotic defects. Finally, both HDAC1 and HDAC2 proteins were associated with the Ki67 gene mediated by CCAAT/enhancer-binding protein beta. CONCLUSION: Both HDAC1 and HDAC2 play crucial roles in the regulation of liver regeneration. The loss of HDAC1/2 inhibits Ki67 expression and results in defective hepatocyte mitosis and impaired liver regeneration. PMID- 23744763 TI - The changing roles of steroid nuclear receptors with prostate cancer progression. AB - Estrogens were once used for the treatment of prostate cancer (PC). They may still be used in various parts of the world to that effect. Recent developments in the understanding of a role for estrogen receptor beta (ERbeta) in the development and progression of this disease resurrect the discussion on the intertwined roles of ERbeta and the androgen receptor (AR) in promoting PC. A new article by Zellweger et al. in Endocrine-Related Cancer investigates the expression and assesses the activity of ERalpha and ERbeta as well as the AR, in addition to a phosphorylated form of AR in hormone-naive and castration-resistant PC. PMID- 23744764 TI - Transrepression of the estrogen receptor promoter by calcitriol in human breast cancer cells via two negative vitamin D response elements. AB - Calcitriol (1,25-dihydroxyvitamin D3), the hormonally active metabolite of vitamin D, exerts its anti-proliferative activity in breast cancer (BCa) cells by multiple mechanisms including the downregulation of the expression of estrogen receptor alpha (ER). We analyzed an ~3.5 kb ER promoter sequence and demonstrated the presence of two potential negative vitamin D response elements (nVDREs), a newly identified putative nVDRE upstream at -2488 to -2473 bp (distal nVDRE) and a previously published sequence (proximal nVDRE) at -94 to -70 bp proximal to the P1 start site. Transactivation analysis using ER promoter deletion constructs and heterologous promoter-reporter constructs revealed that both nVDREs functioned to mediate calcitriol transrepression. In the electrophoretic mobility shift assay, the vitamin D receptor (VDR) showed strong binding to both nVDREs in the presence of calcitriol, and the chromatin immunoprecipitation assay demonstrated the recruitment of the VDR to the distal nVDRE site. Mutations in the 5' hexameric DNA sequence of the distal nVDRE resulted in the loss of calcitriol-mediated transrepression and the inhibition of protein-DNA complex formation, demonstrating the importance of these nucleotides in VDR DNA binding and transrepression. A putative nuclear factor-Y (NFY) binding site, identified within the distal nVDRE, led to the findings that NFY bound to the distal nVDRE site interfered with the binding of the VDR at the site and reduced calcitriol mediated transrepression. In conclusion, the ER promoter region contains two negative VDREs that act in concert to bind to the VDR and both nVDREs are required for the maximal inhibition of ER expression by calcitriol. The suppression of ER expression and estrogen-mediated signaling by calcitriol in BCa cells suggests that vitamin D may be useful in the treatment of ER+ BCa. PMID- 23744765 TI - Thyroid cancer and co-occurring RET mutations in Hirschsprung disease. AB - The objective of this study was to assess the occurrence of thyroid cancer and co occurring RET mutations in a population-based cohort of adult Hirschsprung disease (HD) patients. All 156 patients operated for HD in a tertiary center during 1950-1986 were followed for thyroid malignancies up to 2010 through the nationwide Finnish Cancer Registry. Ninety-one individuals participated in clinical and genetic screening, which included serum calcitonin and thyroid ultrasound (US) with cytology. Exons 10, 11, 13, and 16 were sequenced in all, and all exons of RET in 43 of the subjects, including those with thyroid cancer, RET mutations, suspicious clinical findings, and familial or long-segment disease. Through the cancer registry, two cases (aged 35 and 37 years) of medullary thyroid cancer (MTC) were observed; the incidence for MTC was 340-fold (95% CI 52-1600) compared with average population. These individuals had C611R and C620R mutations in exon 10. One papillary thyroid cancer without RET mutations was detected by clinical screening. Four subjects (aged 31-50 years) with co-occurring RET mutations in exons 10 (C609R; n=1) and 13 (Y791F, n=3) had sporadic short-segment HD with normal thyroid US and serum calcitonin. Three novel mutations and five single-nucleotide polymorphisms were found outside exons 10 and 13 without associated signs of thyroid cancer. MTC-associated RET mutations were restricted to exons 10 and 13 affecting ~5% of unselected adults with HD. Clinical thyroid assessment did not improve accuracy of genetic screening, which should not be limited to patients with familial or long-segment disease. PMID- 23744766 TI - Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy. AB - Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine men undergoing ADT for prostate cancer and ten healthy men with normal testosterone levels underwent 12 weeks of endurance training. Primary endpoints were insulin sensitivity (euglycemic-hyperinsulinemic clamps with concomitant glucose-tracer infusion) and body composition (dual-energy X-ray absorptiometry and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (P<0.0001). The patients and controls demonstrated an increase in peripheral tissue insulin sensitivity of 14 and 11% respectively (P<0.05), with no effect on hepatic insulin sensitivity (P=0.32). Muscle protein content of GLUT4 (SLC2A4) and total AKT (AKT1) was also increased in response to the training (P<0.05 and P<0.01 respectively). Body weight (P<0.0001) and whole-body fat mass (FM) (P<0.01) were reduced, while lean body mass (P=0.99) was unchanged. Additionally, reductions were observed in abdominal (P<0.01), subcutaneous (P<0.05), and visceral (P<0.01) FM amounts. The concentrations of plasma markers of systemic inflammation were unchanged in response to the training. No group * time interactions were observed, except for thigh intermuscular adipose tissue (IMAT) (P=0.01), reflecting a significant reduction in the amount of IMAT in the controls (P<0.05) not observed in the patients (P=0.64). In response to endurance training, ADT-treated prostate cancer patients exhibited improved insulin sensitivity and body composition to a similar degree as eugonadal men. PMID- 23744767 TI - Poor uptake of hepatitis B vaccine in India has several causes, study finds. PMID- 23744768 TI - National data on women's health mask inequalities, conference hears. PMID- 23744769 TI - Emphasise benefits of reconfiguration to support change, says report. PMID- 23744770 TI - Sequester to force $1.5 bn cut in NIH budget. PMID- 23744771 TI - MPs reject plan to spend L1.2 bn of NHS surplus on social care to ease pressure on emergency departments. PMID- 23744772 TI - Proposal for GPs to take back some out of hours care sparks debate. PMID- 23744773 TI - Failure to test for HIV in rural Ethiopia: knowledge and belief correlates and implications for universal test and treat strategies. AB - Goals of universal "test and treat" will never be fully realized if testing acceptance remains low, including rural areas, where HIV is increasingly recognized. We surveyed 250 randomly selected households from a rural Ethiopian town (Arba Minch) and surrounding villages about HIV testing experience, knowledge, and attitudes. Of the 558 adults, 45% were never HIV tested. Those never tested for HIV were more likely to be (P < .05) >=45 years, rural villagers, and unaware of the benefits of antiretroviral therapy treatment and that persons with HIV can appear healthy; they were more likely to believe HIV infected persons would be stigmatized and unsupported by their communities. Of those never tested, 70% were interested in HIV testing if offered. Despite recommendations that all persons be HIV tested, almost half of the adult residents in this rural community were never tested. Programs to increase HIV testing must include measures to address stigma/discrimination and knowledge deficits including benefits of early diagnosis and treatment. PMID- 23744774 TI - A pharmacy-only refill program at a large HIV clinic in Uganda: experience and satisfaction of patients. AB - BACKGROUND: The purpose of this study was to assess patients' experience and satisfaction with pharmacy-only refill program (PRP) and to compare those who were removed from the PRP with those still in the program. METHODS: A sample of 446 patients was selected from 1503 patients on antiretroviral therapy that had been enrolled in the PRP for at least 24 months. The study used interviewer administered questionnaires to assess patients' experience and satisfaction with PRP. RESULTS: Of the 446 patients, 133 (29.8%) were removed from the PRP. By multivariate analysis, it was found that wanting to see a clinician before their scheduled clinic visit, Christian religion, and not understanding why they were enrolled in PRP were associated with having been removed from the PRP. Patients felt that the greatest benefit from the program was the time that they saved to do other activities. Patients preferred to collect their medication every 3 months instead of every month. CONCLUSION: All patients interviewed scored the program high, and all recommended that the PRP should continue. Stable patients prefer to see clinicians less frequently and visit clinic less often. PMID- 23744775 TI - The Potentials of Fas Receptors and Ligands in Monitoring HIV-1 Disease in Children in Yaounde, Cameroon. AB - OBJECTIVE: Difficulties in systematically monitoring HIV viral load in resource limited settings prompt the search for alternate approaches. The authors aimed at assessing the correlation between the plasma levels of soluble forms of Fas receptors (Fas) and Fas ligands (FasL) with standard indicators of HIV disease progression in children. METHODS: Twenty-two HIV-1-positive children were enrolled in Yaounde. CD4 counts, CD4% counts, plasma levels of Fas, FasL, and HIV 1 RNA levels were assayed. RESULTS: The correlation coefficients (P values) between FasL levels and each of HIV-1 viral load, CD4 counts, and CD4% were, respectively, .56 (.01), -.29 (.18), and .30 (.18). On the other hand, the respective correlation coefficients (P values) with Fas levels were .12 (.60), .30 (.18), and -.29 (.19). CONCLUSION: The significant correlation between levels of HIV-1 viral load and FasL suggests that the latter needs to be further studied as a potential biomarker to monitor HIV-1 disease progression in children in resource-limited setting. PMID- 23744776 TI - Space partitioning without territoriality in gannets. AB - Colonial breeding is widespread among animals. Some, such as eusocial insects, may use agonistic behavior to partition available foraging habitat into mutually exclusive territories; others, such as breeding seabirds, do not. We found that northern gannets, satellite-tracked from 12 neighboring colonies, nonetheless forage in largely mutually exclusive areas and that these colony-specific home ranges are determined by density-dependent competition. This segregation may be enhanced by individual-level public information transfer, leading to cultural evolution and divergence among colonies. PMID- 23744777 TI - Structure of the repulsive guidance molecule (RGM)-neogenin signaling hub. AB - Repulsive guidance molecule family members (RGMs) control fundamental and diverse cellular processes, including motility and adhesion, immune cell regulation, and systemic iron metabolism. However, it is not known how RGMs initiate signaling through their common cell-surface receptor, neogenin (NEO1). Here, we present crystal structures of the NEO1 RGM-binding region and its complex with human RGMB (also called dragon). The RGMB structure reveals a previously unknown protein fold and a functionally important autocatalytic cleavage mechanism and provides a framework to explain numerous disease-linked mutations in RGMs. In the complex, two RGMB ectodomains conformationally stabilize the juxtamembrane regions of two NEO1 receptors in a pH-dependent manner. We demonstrate that all RGM-NEO1 complexes share this architecture, which therefore represents the core of multiple signaling pathways. PMID- 23744778 TI - Interactions of multisensory components perceptually rescue tungara frog mating signals. AB - Sexual signals are often complex and perceived by multiple senses. How animals integrate signal components across sensory modalities can influence signal evolution. Here we show that two relatively unattractive signals that are perceived acoustically and visually can be combined in a pattern to form a signal that is attractive to female tungara frogs. Such unanticipated perceptual effects suggest that the evolution of complex signals can occur by alteration of the relationships among already-existing traits. PMID- 23744779 TI - Varied response of western Pacific hydrology to climate forcings over the last glacial period. AB - Atmospheric deep convection in the west Pacific plays a key role in the global heat and moisture budgets, yet its response to orbital and abrupt climate change events is poorly resolved. Here, we present four absolutely dated, overlapping stalagmite oxygen isotopic records from northern Borneo that span most of the last glacial cycle. The records suggest that northern Borneo's hydroclimate shifted in phase with precessional forcing but was only weakly affected by glacial-interglacial changes in global climate boundary conditions. Regional convection likely decreased during Heinrich events, but other Northern Hemisphere abrupt climate change events are notably absent. The new records suggest that the deep tropical Pacific hydroclimate variability may have played an important role in shaping the global response to the largest abrupt climate change events. PMID- 23744780 TI - Nanoscale atoms in solid-state chemistry. AB - We describe a solid-state material formed from binary assembly of atomically precise molecular clusters. [Co6Se8(PEt3)6][C60]2 and [Cr6Te8(PEt3)6][C60]2 assembled into a superatomic relative of the cadmium iodide (CdI2) structure type. These solid-state materials showed activated electronic transport with activation energies of 100 to 150 millielectron volts. The more reducing cluster Ni9Te6(PEt3)8 transferred more charge to the fullerene and formed a rock-salt related structure. In this material, the constituent clusters are able to interact electronically to produce a magnetically ordered phase at low temperature, akin to atoms in a solid-state compound. PMID- 23744782 TI - Timing of the hepatic arterial phase at Gd-EOB-DTPA-enhanced hepatic dynamic MRI: comparison of the test-injection and the fixed-time delay method. AB - PURPOSE: To compare the fixed-time- and the test-injection method with respect to the image quality of hypervascular hepatocellular carcinoma (HCC) and the adequacy of timing of the hepatic arterial phase (HAP) in Gd-EOB-DTPA (EOB) enhanced MRI. MATERIALS AND METHODS: We studied 63 patients with computed tomography (CT) -proven hypervascular HCC: 30 (group 1) were scanned HAP using the fixed-time delay method (protocol 1); in the other 33 (group 2), we applied the test-injection method (protocol 2). We compared the protocols with respect with tumor-to-liver contrast (TLC), contrast-to-noise-ratio (CNR), and relative enhancement of the liver and tumor (REL , RET ) during HAP. Two radiologists compared the adequacy of HAP, image contrast, image noise, and overall image quality. RESULTS: Under protocol 2, TLC, CNR, and REL and RET of hypervascular HCC were significantly higher (P < 0.01). The proportion of optimal HAP was significantly higher for protocol 2 than protocol 1 (P < 0.01). The visual score of the image contrast and the overall image quality were significantly higher in group 2 than group 1 (P = 0.02 and P = 0.01, respectively). CONCLUSION: At EOB enhanced hepatic dynamic MRI, the test-injection method yielded better image quality of hypervascular HCC and improved adequacy of timing of HAP. PMID- 23744781 TI - A secreted PTEN phosphatase that enters cells to alter signaling and survival. AB - Phosphatase and tensin homolog on chromosome ten (PTEN) is a tumor suppressor and an antagonist of the phosphoinositide-3 kinase (PI3K) pathway. We identified a 576-amino acid translational variant of PTEN, termed PTEN-Long, that arises from an alternative translation start site 519 base pairs upstream of the ATG initiation sequence, adding 173 N-terminal amino acids to the normal PTEN open reading frame. PTEN-Long is a membrane-permeable lipid phosphatase that is secreted from cells and can enter other cells. As an exogenous agent, PTEN-Long antagonized PI3K signaling and induced tumor cell death in vitro and in vivo. By providing a means to restore a functional tumor-suppressor protein to tumor cells, PTEN-Long may have therapeutic uses. PMID- 23744783 TI - Bioactive plasma electrolytic oxidation coatings--the role of the composition, microstructure, and electrochemical stability. AB - A Plasma electrolytic oxidation (PEO) process was used to produce bioactive coatings on Ti. PEO coatings with Ca/P atomic ratio of 1.7 and 4.0 were fabricated and characterized with respect to their morphology, composition, and microstructure. AC and DC electrochemical tests were used to evaluate the effect of (i) organic additives (amino acids, proteins, vitamins, and antibiotics) in alpha-minimum essential medium (alpha-MEM) on electrochemical stability of noncoated and PEO-coated Ti and (ii) coating composition, microstructure, and corrosion behavior on the cell response in alpha-MEM. PEO-coated Ti showed higher corrosion resistance than the noncoated Ti in MEM with and without organic additives by an order of magnitude. The corrosion resistance in alpha-MEM decreased with time for nonmodified Ti and increased for PEO-coated Ti; the latter was because of the adsorption of the proteins in the coating pores which increased the diffusion resistance. The presence of Ca and P in titanium oxide coating at the Ca/P ratio exceeding that of any stoichiometric Ca-P-O and Ca-P-O H compounds facilitates faster osteoblast cell adhesion. PMID- 23744784 TI - Protecting-group-free total synthesis of (-)-rhazinilam and (-)-rhazinicine using a gold-catalyzed cascade cyclization. PMID- 23744785 TI - Ascorbic acid synthesis and metabolism in maize are subject to complex and genotype-dependent feedback regulation during endosperm development. AB - L-ascorbic acid (vitamin C) is an antioxidant and electron donor whose metabolism in plants is under strict feedback control. The factors that influence L-ascorbic acid accumulation in staple crops are only partially understood. One way to gain insight into the regulation of L-ascorbic acid metabolism is to investigate the endogenous pathways in various genetic backgrounds and characterize their interactions with transgenes encoding relevant enzymes. In an initial step, we investigated the developmental profile of L-ascorbic acid accumulation in the endosperm of three diverse maize genotypes and a transgenic line expressing rice dehydroascorbate reductase, which enhances L-ascorbic acid recycling. We determined the transcript levels of all the key genes in the L-ascorbic acid metabolic pathways as well as the specific levels of ascorbic acid and dehydroascorbate. L-ascorbic acid levels were high 20 days after pollination and declined thereafter. We found significant genotype-dependent variations in the transcript levels of some genes, with particular complexity in the ascorbic acid recycling pathway. Our data will help to elucidate the complex mechanisms underlying the regulation of L-ascorbic acid metabolism in plants, particularly the impact of genetic background on the strict regulation of ascorbic acid metabolism in endosperm cells. PMID- 23744786 TI - The Omaha System: a systematic review of the recent literature. AB - BACKGROUND: The Omaha System (OS) is one of the oldest of the American Nurses Association recognized standardized terminologies describing and measuring the impact of healthcare services. This systematic review presents the state of science on the use of the OS in practice, research, and education. AIMS: (1) To identify, describe and evaluate the publications on the OS between 2004 and 2011, (2) to identify major trends in the use of the OS in research, practice, and education, and (3) to suggest areas for future research. METHODS: Systematic search in the largest online healthcare databases (PUBMED, CINAHL, Scopus, PsycINFO, Ovid) from 2004 to 2011. Methodological quality of the reviewed research studies was evaluated. RESULTS: 56 publications on the OS were identified and analyzed. The methodological quality of the reviewed research studies was relatively high. Over time, publications' focus shifted from describing clients' problems toward outcomes research. There was an increasing application of advanced statistical methods and a significant portion of authors focused on classification and interoperability research. There was an increasing body of international literature on the OS. Little research focused on the theoretical aspects of the OS, the effective use of the OS in education, or cultural adaptations of the OS outside the USA. CONCLUSIONS: The OS has a high potential to provide meaningful and high quality information about complex healthcare services. Further research on the OS should focus on its applicability in healthcare education, theoretical underpinnings and international validity. Researchers analyzing the OS data should address how they attempted to mitigate the effects of missing data in analyzing their results and clearly present the limitations of their studies. PMID- 23744787 TI - The use of open source electronic health records within the federal safety net. AB - OBJECTIVE: To conduct a federally funded study that examines the acquisition, implementation and operation of open source electronic health records (EHR) within safety net medical settings, such as federally qualified health centers (FQHC). METHODS AND MATERIALS: The study was conducted by the National Opinion Research Center (NORC) at the University of Chicago from April to September 2010. The NORC team undertook a comprehensive environmental scan, including a literature review, a dozen key informant interviews using a semistructured protocol, and a series of site visits to West Virginia, California and Arizona FQHC that were currently using an open source EHR. RESULTS: Five of the six sites that were chosen as part of the study found a number of advantages in the use of their open source EHR system, such as utilizing a large community of users and developers to modify their EHR to fit the needs of their provider and patient communities, and lower acquisition and implementation costs as compared to a commercial system. DISCUSSION: Despite these advantages, many of the informants and site visit participants felt that widespread dissemination and use of open source was restrained due to a negative connotation regarding this type of software. In addition, a number of participants stated that there is a necessary level of technical acumen needed within the FQHC to make an open source EHR effective. CONCLUSIONS: An open source EHR provides advantages for FQHC that have limited resources to acquire and implement an EHR, but additional study is needed to evaluate its overall effectiveness. PMID- 23744788 TI - Influenza surveillance using electronic health records in the American Indian and Alaska Native population. AB - OBJECTIVE: Increasing use of electronic health records (EHRs) provides new opportunities for public health surveillance. During the 2009 influenza A (H1N1) virus pandemic, we developed a new EHR-based influenza-like illness (ILI) surveillance system designed to be resource sparing, rapidly scalable, and flexible. 4 weeks after the first pandemic case, ILI data from Indian Health Service (IHS) facilities were being analyzed. MATERIALS AND METHODS: The system defines ILI as a patient visit containing either an influenza-specific International Classification of Disease, V.9 (ICD-9) code or one or more of 24 ILI-related ICD-9 codes plus a documented temperature >=100 degrees F. EHR-based data are uploaded nightly. To validate results, ILI visits identified by the new system were compared to ILI visits found by medical record review, and the new system's results were compared with those of the traditional US ILI Surveillance Network. RESULTS: The system monitored ILI activity at an average of 60% of the 269 IHS electronic health databases. EHR-based surveillance detected ILI visits with a sensitivity of 96.4% and a specificity of 97.8% based on chart review (N=2375) of visits at two facilities in September 2009. At the peak of the pandemic (week 41, October 17, 2009), the median time from an ILI visit to data transmission was 6 days, with a mode of 1 day. DISCUSSION: EHR-based ILI surveillance was accurate, timely, occurred at the majority of IHS facilities nationwide, and provided useful information for decision makers. EHRs thus offer the opportunity to transform public health surveillance. PMID- 23744789 TI - Quantitative characterization of mesenchymal stem cell adhesion to the articular cartilage surface. AB - There has been great interest in use of mesenchymal stem cell (MSC)-based therapies for cartilage repair. Most recently, treatments involving intra articular injection of MSCs have shown great promise for cartilage repair and arthritis therapy, which rely on MSC adhesion to cartilage. While there is some information on chondrocyte adhesion to cartilage, there is relatively little known about the kinetics and strength of MSC adhesion to cartilage. The goals of this study were as follows: (1) to quantify the kinetics and strength of adhesion of marrow-derived MSCs to articular cartilage using standard laboratory hardware; (2) to compare this adhesion behavior to that of articular chondrocytes; and (3) to assess the effect of serial monolayer culture on MSC adhesion. First through fourth passage MSCs and primary articular chondrocytes were allowed to adhere to the articular surface of cartilage disks for up to 30 h and the number of adhered cells was recorded to quantify adhesion kinetics. After 30 h, adherent cells were subjected to centrifugal shear to determine adhesion strength, quantified as the shear necessary to detach half the adhered cells (sigma50 ). The number of adhered MSCs and adhesion strength increased with passage number and MSCs adhered more strongly than did primary articular chondrocytes. As such, the kinetics and strength of MSC adhesion to cartilage is not dramatically lower than that for articular chondrocytes. This protocol for assessing cell adhesion to cartilage is simple to implement and may represent an important screening tool for assessing the efficacy of cell-based therapies for cartilage repair. PMID- 23744790 TI - Bright mono-aqua europium complexes based on triazacyclononane that bind anions reversibly and permeate cells efficiently. AB - A series of five europium(III) complexes has been prepared from heptadentate N5O2 ligands that possess a brightness of more than 10 mM(-1) cm(-1) in water, following excitation over the range lambda=330-355 nm. Binding of several oxy anions has been assessed by emission spectral titrimetric analysis, with the binding of simple carboxylates, lactate and citrate involving a common ligation mode following displacement of the coordinated water. Selectivity for bicarbonate allows the rapid determination of this anion in human serum, with K(d)=37 mM (295 K). The complexes are internalised quickly into mammalian cells and exhibit a mitochondrial localisation at early time points, migrating after a few hours to reveal a predominant lysosomal distribution. Herein, we report the synthesis and complexation behaviour of strongly emissive europium (III) complexes that bind oxy-anions in aqueous media with an affinity and selectivity profile that is distinctively different from previously studied systems. PMID- 23744791 TI - Cancer research in the United States: dying by a thousand paper cuts. PMID- 23744792 TI - Clinicians' attitudes regarding withdrawal of left ventricular assist devices in patients approaching the end of life. AB - AIMS: Left ventricular assist devices (LVADs) are implanted to support the circulation of patients with advanced heart failure. Patients approaching death, or their surrogates, may request withdrawal of LVAD support. We sought to study the attitudes and practices of heart failure clinicians regarding withdrawal of LVAD support in patients approaching death. METHODS AND RESULTS: Using internet based and secure methods, we surveyed members of the European Society of Cardiology-Heart Failure Association (ESC-HFA), the International Society for Heart and Lung Transplantation (ISHLT), and the Heart Failure Society of America (HFSA) to assess their attitudes and practices regarding LVAD withdrawal for patients approaching death. The results indicated that clinicians have varied attitudes and practices regarding withdrawing LVAD support in these patients. Furthermore, ESC-HFA clinicians (primarily European) and ISHLT and HFSA clinicians (primarily North American) differed in their attitudes and practices regarding withdrawal of LVAD support, particularly its ethical and legal permissibility. For example, more European clinicians than North American clinicians regarded withdrawing LVAD support as a form of euthanasia. CONCLUSION: Opinions and level of comfort with LVAD withdrawal vary among clinicians. Clinicians should be aware of suggested approaches or guidelines for managing requests for withdrawal of LVAD therapy. PMID- 23744793 TI - Emerging quantitative magnetic resonance imaging biomarkers of hepatic steatosis. PMID- 23744794 TI - Association between statin adherence and cholesterol level reduction from baseline in a veteran population. AB - STUDY OBJECTIVE: To investigate the association between statin adherence and changes in lipid panel outcomes from baseline in a veteran population. DESIGN: Retrospective cohort study using multiple linear regression models. SETTING: Veterans Affairs health care system within the Veterans Integrated Service Network 22, a network of Veterans Affairs facilities in the southwest region of the United States that includes Los Angeles, San Diego, Loma Linda, and Long Beach, California, and Las Vegas, Nevada, with an enrollment of approximately 1.4 million veterans. PATIENTS: A total of 5365 patients who were new statin users between December 1, 2006, and November 30, 2007; 2674 patients were in the adherent group and 2691 were in the nonadherent group. MEASUREMENTS AND MAIN RESULTS: Adherence was determined by the medication possession ratio. Patients were categorized as adherent if the medication possession ratio at follow-up was 0.80 or more. Adherent patients exhibited significant differences in baseline demographic and clinical characteristics than nonadherent patients in our study sample. Baseline laboratory values for adherent patients were significantly lower for low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), non-high-density lipoprotein cholesterol (non-HDL), and total cholesterol levels. The primary outcome was change in LDL level from baseline at 12 months. Secondary outcomes were changes in non-HDL and total cholesterol levels from baseline at 12 months. Independent variables controlled for in the multiple linear regression included age, sex, body mass index, race-ethnicity, baseline lipid panel (LDL, HDL, total cholesterol, and triglycerides), statin copayment status, income quintile (according to ZIP code median household income), baseline medication count, statin prescribed, and comorbidities. Multiple linear regression revealed that adherent patients demonstrated significantly greater reductions in LDL of 20.98 mg/dl versus nonadherent patients (p<0.0001). Adherent patients similarly demonstrated larger reductions of 24.31 mg/dl in non-HDL and 24.06 mg/dl in total cholesterol versus nonadherent patients (p<0.0001 for both comparisons). CONCLUSION: Patients adherent to statin therapy had significant associations with clinically relevant reductions in LDL, non-HDL, and total cholesterol from baseline at 12 months compared with nonadherent patients when controlling for potential confounders. Adherence to statin therapy may have important consequences in decreasing clinical outcomes such as myocardial infarctions, strokes, and mortality due to large reductions in lipid panel outcomes from baseline at 12 months. PMID- 23744795 TI - Effect of amitriptyline in treatment interstitial cystitis or bladder pain syndrome according to two criteria: does ESSIC criteria change the response rate? AB - AIMS: The European Society for the Study of Interstitial Cystitis (ESSIC) recommended that interstitial cystitis (IC) should be replaced by bladder pain syndrome (BPS), which focused more attention on the painful or discomfort feeling related to bladder and weakened the importance of cystoscopy in diagnosis process. Our study aimed to explore whether this alteration changed the treatment outcomes of amitriptyline and whether cystoscopy was meaningful for the treatment of this disease. METHODS: We conducted a retrospective study including 25 IC patients fulfilled the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) criteria and 42 BPS patients diagnosed according to ESSIC criteria. All the patients received amitriptyline with a self-uptitration protocol. We compared the response rates of two groups by a patient reported global response assessment after 3 months and reclassified all the 67 patients according to ESSIC criteria, the response rates of different BPS types were also assessed. RESULTS: There was no significant difference of response rate between IC patients (12/25, 48%) and BPS patients (19/42, 45.2%) according to different criteria (P = 0.337). The response rate of BPS type 1 (13/30, 43.3%) was similar to that of type 2 or 3 (18/37, 48.6%) (P = 0.664). CONCLUSIONS: ESSIC criteria did not decrease the response rate of amitriptyline treatment for BPS patients compared to IC patients with complaint of bladder pain or discomfort. Cystoscopy showed no predictive effect for the treatment outcome of amitriptyline. PMID- 23744796 TI - Direct comparison of intra-articular versus intravenous delayed gadolinium enhanced MRI of hip joint cartilage. AB - PURPOSE: To investigate the potential of delayed gadolinium-enhanced magnetic resonance imaging in cartilage (dGEMRIC) after intra-articular (ia) contrast agent administration at 3 Tesla (T), a paired study comparing intravenous (iv) dGEMRIC (standard) with ia-dGEMRIC was performed. MATERIALS AND METHODS: Thirty five symptomatic patients with suspected cartilage damage underwent ia- and iv dGEMRIC. MRI was performed with a 3T system wherein the interval between both measurements was 2 weeks. For iv-dGEMRIC, FDA approved Gd-DOTA(-) was injected intravenously 45 min before the MRI scan. For ia-dGEMRIC, 10-20 mL of a 2 mM solution of Gd- DOTA(-) was injected under fluoroscopic guidance 30 min before the MRI scan. RESULTS: Both ia- and iv-dGEMRIC demonstrated the typical T1Gd pattern in hip joint cartilage with increasing values toward the superior regions in acetabular cartilage reflecting the higher glycosaminoglycan (GAG) content in the main weight-bearing area. Correlation analysis revealed a moderate correlation between both techniques (r = 0.439, P-value < 0.001), whereas the T1Gd values for iv-dGEMRIC were significantly higher than those for ia-dGEMRIC. This corresponds with the Bland-Altman plot analysis, which revealed a systemic bias (higher T1Gd values after iv gadolinium application) of ~70 ms. CONCLUSION: Ia-dGEMRIC was able to reveal the characteristic T1Gd pattern in hip joint cartilage confirming the sensitivity of ia-dGEMRIC for GAG. In addition, there was a significant correlation between iv-dGEMRIC and ia-dGEMRIC. However, the T1Gd values after ia contrast media application were significantly lower than those after iv application that has to be considered for future studies. PMID- 23744797 TI - Quantitative characterization of porous commercial and experimental bone graft substitutes with microcomputed tomography. AB - A large number of resorbable bone graft substitutes are being marketed as porous, but the total porosity being referred does not take into account many of the biologically important physical aspects of porosity. Therefore, to allow the direct comparison of different commercial products, there is a need to adopt guidelines for a standardized characterization. The aim of the study was to assess a microcomputed tomography-based method for the characterization of porous biomaterials to allow head-to-head comparison of these materials. The study included two commercial biomaterials (Actifuse((r)) and ChronOs((r))) and three experimental biomaterials (sintered bioactive glass microspheres, porous alginate (Alg), and porous Alg/hydroxyapatite composite). In addition to porosity and pore size distributions, the interconnectivity of the pores was assessed by an iterative blocking of interconnections. The biomaterials were characterized in their original morphologies (granules or cones). Differences between the materials were demonstrated. Actifuse((r)) had the broadest distributions of pores and interconnections. ChronOs((r)) had a substantial fraction of closed pores (10%). Other materials had closed porosity below 1%. Due to the thinner walls of the lattice, the Alg-based materials had high total porosity (>80%). Discrepancies were found between the porosity values reported by the manufacturers and the values obtained in this study. The proposed method is plausible for the systematic characterization of porous biomaterials. PMID- 23744798 TI - Baseline dependency of nicotine's sensory gating actions: similarities and differences in low, medium and high P50 suppressors. AB - Reduced suppression of the P50 auditory event-related potential in schizophrenia patients relative to normal controls is indicative of a sensory gating deficit and is one of the most robust findings reported for functional brain abnormalities in this disorder. However, there is considerable gating variability in patients and controls and there is little understanding as to how inter individual differences moderate gating responses to drugs and nicotinic agonists in particular, which have shown potential to reverse gating deficits. In this study the effects of acutely administered nicotine (gum, 6 mg) on sensory gating in a paired (S1-S2) auditory stimulus paradigm were investigated in 57 healthy, non-smoking volunteers stratified as low (n = 19), medium (n = 19) and high (n = 19) P50 suppressors on the basis of three separate baseline derived gating indices, P50 ratios, P50 difference scores, and gating difference waveforms. Relative to placebo, nicotine consistently improved gating in low suppressors as stratified with all three gating indices, exerted no effects in medium suppressors and reduced gating in high suppressors. Analysis of individual stimulus (S2, S2) amplitudes showed distinctly different mechanisms of action underlying nicotine effects in individuals with low and high baseline suppression. The results parallel similar findings of baseline-dependency in the gating effects of several antipsychotic drugs in healthy volunteers and support the use of group segmentation as a translational model in novel cognitive drug development for schizophrenia. PMID- 23744799 TI - Nitrogen-rich porous adsorbents for CO2 capture and storage. AB - The construction of physical or chemical adsorbents for CO2 capture and sequestration (CCS) is a vital technology in the interim period on the way towards a sustainable low-carbon future. The search for efficient materials to satisfy the increasing demand for CCS has become extremely important. Porous materials, including porous silica, porous carbons, and newly developed metal organic frameworks and porous organic polymers, possessing regular and well defined porous geometry and having a high surface area and pore volume, have been widely studied for separations on laboratory scale. On account of the dipole quadrupole interactions between the polarizable CO2 molecule and the accessible nitrogen site, the investigations have indicated that the incorporation of accessible nitrogen-donor groups into the pore walls of porous materials can improve the affinity to CO2 and increase the CO2 uptake capacity and selectivity. The CO2 -adsorption process based on solid nitrogen-rich porous adsorbents does generally not require heating of a large amount of water (60-70 wt%) for regeneration, while such a heating approach cannot be avoided in the regeneration of amine-based solution absorption processes. Thus, nitrogen-rich porous adsorbents show good regeneration properties without sacrificing high separation efficiency. As such, nitrogen-rich porous materials as highly promising CO2 adsorbents have been broadly fabricated and intensively investigated. This Focus Review highlights recent significant advances in nitrogen-rich porous materials for CCS. PMID- 23744800 TI - Ocular paradoxical movement and severity of Parkinson's disease. PMID- 23744801 TI - Mixed genotype hepatitis C infections and implications for treatment. PMID- 23744802 TI - A molecular toolkit for the functionalization of titanium-based biomaterials that selectively control integrin-mediated cell adhesion. AB - We present a click chemistry-based molecular toolkit for the biofunctionalization of materials to selectively control integrin-mediated cell adhesion. To this end, alpha5beta1-selective RGD peptidomimetics were covalently immobilized on Ti-based materials, and the capacity to promote the selective binding of alpha5beta1 was evaluated using a solid-phase integrin binding assay. This functionalization strategy yielded surfaces with a nine-fold increased affinity for alpha5beta1, in comparison to control samples, and total selectivity against the binding of the closely related integrin alphavbeta3. Moreover, our methodology allowed the screening of several phosphonic acid containing anchoring units to find the best spacer-anchor moiety required for establishing an efficient binding to titanium and to promote selective integrin binding. The integrin subtype specificity of these biofunctionalized surfaces was further examined in vitro by inducing selective adhesion of genetically modified fibroblasts, which express exclusively the alpha5beta1 integrin. The versatility of our molecular toolkit was proven by shifting the cellular specificity of the materials from alpha5beta1- to alphavbeta3-expressing fibroblasts by using an alphavbeta3-selective peptidomimetic as coating molecule. The results shown here represent the first functionalization of Ti-based materials with alpha5beta1- or alphavbeta3 selective peptidomimetics that allow an unprecedented control to discriminate between alpha5beta1- and alphavbeta3-mediated adhesions. The role of these two integrins in different biological events is still a matter of debate and is frequently discussed in literature. Thus, such bioactive titanium surfaces will be of great relevance for the study of integrin-mediated cell adhesion and the development of new biomaterials targeting specific cell types. PMID- 23744803 TI - Graphene oxide nanoribbons from the oxidative opening of carbon nanotubes retain electrochemically active metallic impurities. PMID- 23744804 TI - Characterization of pea (Pisum sativum) seed protein fractions. AB - BACKGROUND: Legume seed proteins have to be chemically characterized in order to properly link their nutritional effects with their chemical structure. RESULTS: Vicilin and albumin fractions devoid of cross-contamination, as assessed by mass peptide fingerprinting analysis, were obtained from defatted pea (Pisum sativum cv. Bilbo) meal. The extracted protein fractions contained 56.7-67.7 g non-starch polysaccharides kg-1. The vicilin fraction was higher than legumins in arginine, isoleucine, leucine, phenylalanine and lysine. The most abundant amino acids in the albumin fraction were aspartic acid, glutamic acid, lysine and arginine, and the amounts of methionine were more than double than those in legumins and vicilins. The pea albumin fraction showed a clear enrichment of protease inhibitory activity when compared with the seed meal. In vitro digestibility values for pea proteins were 0.63 +/- 0.04, 0.88 +/- 0.04 and 0.41 +/- 0.23 for legumins, vicilins and albumins respectively. CONCLUSION: Vicilin and albumin fractions devoid of cross-contamination with other proteins were obtained from pea seed meal. The vicilin fraction also contained low amounts of soluble non starch polysaccharides and was enriched in isoleucine, leucine, phenylalanine and lysine. In vitro digestibility values for pea proteins were similar or even numerically higher than those for control proteins. PMID- 23744805 TI - The economic impact of H1N1 on Mexico's tourist and pork sectors. AB - By examining tourist arrivals and pork output and trade statistics, this analysis estimates the economic impact to the Mexican tourism and pork sectors because of the H1N1 influenza pandemic. It also assesses the role of the international response in the context of this economic impact. For tourism, losing almost a million overseas visitors translated into losses of around $US2.8bn, which extended over a five-month period, mostly because of the slow return of European travellers. For the pork industry, temporal decreases in output were observed in most of the country and related to H1N1 incidence (p = 0.048, r = 0.37). By the end of 2009, Mexico had a pork trade deficit of $US27m. The losses derived from this pandemic were clearly influenced by the risk perception created in tourist supplying and pork trade partners. Results suggest that the wider economic implications of health-related emergencies can be significant and need to be considered in preparedness planning. For instance, more effective surveillance and data gathering would enable policy to target emergency funding to the sectors and regions hardest hit. These results also stress the importance of being familiar with trade networks so as to be able to anticipate the international response and respond accordingly. PMID- 23744806 TI - Lymph node management in patients with paratesticular rhabdomyosarcoma: a population-based analysis. AB - BACKGROUND: Paratesticular rhabdomyosarcoma (PTRMS) is the most common primary solid tumor arising from the mesenchymal tissue of the testis. Traditionally, retroperitoneal lymph node dissection is not recommended for children aged <10 years because of the morbidity of the procedure and low risk of retroperitoneal lymph node involvement. In the current study, the authors analyzed the patient and tumor characteristics of PTRMS as well as survival outcomes associated with lymph node dissection status. METHODS: A total of 255 cases of PTRMS were identified from the patient data reported by the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute from 1973 through 2009. RESULTS: Among 173 patients aged >= 10 years, lymph node dissection was found to improve the 5-year overall survival (OS) rate from 64% to 86% (P < 0.01). Conversely, patients aged <10 years fared extremely well regardless of lymph node dissection status; the 5-year OS rate was 100% and 97%, respectively, for patients who did versus those who did not undergo lymph node dissection (P = .37). The yield of positive lymph nodes was approximately >= 20% when < 11 lymph nodes were removed. The incidence of lymph node involvement was also higher in older patients compared with younger patients (40% vs 8%). Radiotherapy improved the OS rate in patients with lymph node involvement (5-year OS rate: 90% with vs 36% without radiation; P < .0001). CONCLUSIONS: Lymph node dissection is recommended in patients aged >=10 years. Radiotherapy is beneficial in patients with lymph node-positive disease. PMID- 23744807 TI - Molecular evolution and expression of archosaurian beta-keratins: diversification and expansion of archosaurian beta-keratins and the origin of feather beta keratins. AB - The archosauria consist of two living groups, crocodilians, and birds. Here we compare the structure, expression, and phylogeny of the beta (beta)-keratins in two crocodilian genomes and two avian genomes to gain a better understanding of the evolutionary origin of the feather beta-keratins. Unlike squamates such as the green anole with 40 beta-keratins in its genome, the chicken and zebra finch genomes have over 100 beta-keratin genes in their genomes, while the American alligator has 20 beta-keratin genes, and the saltwater crocodile has 21 beta keratin genes. The crocodilian beta-keratins are similar to those of birds and these structural proteins have a central filament domain and N- and C-termini, which contribute to the matrix material between the twisted beta-sheets, which form the 2-3 nm filament. Overall the expression of alligator beta-keratin genes in the integument increases during development. Phylogenetic analysis demonstrates that a crocodilian beta-keratin clade forms a monophyletic group with the avian scale and feather beta-keratins, suggesting that avian scale and feather beta-keratins along with a subset of crocodilian beta-keratins evolved from a common ancestral gene/s. Overall, our analyses support the view that the epidermal appendages of basal archosaurs used a diverse array of beta-keratins, which evolved into crocodilian and avian specific clades. In birds, the scale and feather subfamilies appear to have evolved independently in the avian lineage from a subset of archosaurian claw beta-keratins. The expansion of the avian specific feather beta-keratin genes accompanied the diversification of birds and the evolution of feathers. PMID- 23744809 TI - Spelling errors in text copying by children with dyslexia and ADHD symptoms. AB - Spelling errors are usually studied in dictations, but teachers report that children with school difficulties often make spelling mistakes when they copy a text too. The present study examines the performance on a text copying task and a text dictation task of two groups of children known for their difficulties in spelling, that is, 22 with symptoms of ADHD and 13 with dyslexia, comparing them with matched controls to see whether children with spelling difficulties make more copying task errors than do controls, whether they make fewer mistakes when copying than when writing under dictation, and whether the pattern of errors remains the same or differs in copy and dictation tasks. Our results show that although children with spelling difficulties made fewer errors in the copying task than under dictation, they still made phonological errors and mistakes relating to accents and duplicates. The pattern of errors differed slightly between the children with dyslexia and those with ADHD, presumably as a consequence of their different underlying weaknesses-related mainly to phonology and orthographic representation in the case of dyslexia and to attentional control in the case of ADHD. PMID- 23744808 TI - Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice. AB - Acetaminophen (APAP) overdose is a major cause of hepatotoxicity and acute liver failure in the U.S., but the pathophysiology is incompletely understood. Despite evidence for apoptotic signaling, hepatic cell death after APAP is generally considered necrotic in mice and in humans. Recent findings suggest that the receptor interacting protein kinase 3 (RIP3) acts as a switch from apoptosis to necrosis (programmed necrosis). Thus, the aim of the current investigation was to determine if RIP3 is involved in APAP-induced liver cell death. APAP (200-300 mg/kg) caused glutathione depletion and protein adduct formation, oxidant stress, mitochondrial release of apoptosis inducing factor, and nuclear DNA fragmentation resulting in centrilobular necrosis in C57Bl/6J mice. Inhibiting RIP3 protein induction with antisense morpholinos in wild-type animals or using RIP3-deficient mice had no effect on protein adduct formation but attenuated all other parameters, including necrotic cell death, at 6 hours after APAP. In addition, cultured hepatocytes from RIP3-deficient mice showed reduced injury compared to wild-type cells after 24 hours. Interestingly, APAP-induced mitochondrial translocation of dynamin-related protein 1 (Drp1), the initiator of mitochondrial fission, was inhibited by reduced RIP3 protein expression and the Drp1 inhibitor MDIVI reduced APAP-induced cell death at 24 hours. All of these protective effects were lost after 24 hours in vivo or 48 hours in vitro. CONCLUSION: RIP3 is an early mediator of APAP hepatotoxicity, involving modulation of mitochondrial dysfunction and oxidant stress. Controlling RIP3 expression could be a promising new approach to reduce APAP-induced liver injury, but requires complementary strategies to control mitochondrial dysfunction for long-term protection. PMID- 23744810 TI - Tenofovir-emtricitabine therapy for the prevention of hepatitis B recurrence in four patients after liver transplantation. AB - In patients infected with chronic hepatitis B virus (HBV) that goes untreated, therapeutic options are limited once the disease decompensates, and orthotopic liver transplantation is often the only treatment available to save the patient's life. After liver transplantation, combined therapy with hepatitis B immune globulin (HBIG) and a nucleos(t)ide analog is the standard of practice for the prevention of HBV recurrence. Historically, nucleos(t)ide analogs such as lamivudine and adefovir have been used with low-dose HBIG for the prevention of HBV recurrence after liver transplantation. However, these analogs are ineffective when used alone due the emergence of resistance mutations. Newer nucleos(t)ide analogs such as tenofovir disoproxil fumarate have demonstrated higher resistance thresholds and effective viral suppression when paired with low dose HBIG. In this case series, we evaluated the safety and efficacy of switching four patients from low-dose HBIG plus nucleos(t)ide analog therapy for the prevention of HBV recurrence to a combination tenofovir-emtricitabine regimen. At the end of follow-up, all patients remained hepatitis B surface antigen negative and had HBV DNA levels of less than 10 IU/ml. Additionally, no tenofovir associated nephrotoxicity was observed among the four patients. Tenofovir emtricitabine monotherapy in lieu of HBIG plus nucleos(t)ide analog therapy demonstrated prevention of HBV recurrence without tenofovir-associated nephrotoxicity after 9 months of follow-up in all four patients and up to 15 months in one patient. PMID- 23744811 TI - Probing the dimerization interface of Leishmania infantum trypanothione reductase with site-directed mutagenesis and short peptides. AB - Binding at the interface: We tested the inhibitory activity of a set of peptide sequences derived from an alpha-helix of the dimeric trypanothione reductase from Leishmania infantum. Replacement of a glutamic acid residue with a lysine promoted monomer dissociation and enzyme inhibition. PMID- 23744812 TI - Degenerate two-photon absorption and effective optical-power-limiting properties of multipolar chromophores derived from 2,3,8-trisubstituted indenoquinoxaline. AB - Two analogous multipolar chromophores (1 and 2) that contained 2,3,8 trisubstituted indenoquinoxaline moieties have been synthesized and characterized for their two-photon absorption properties, both in the femtosecond and nanosecond time regimes. We demonstrated that their multi-branched framework structures, which incorporated appropriately functionalized indenoquinoxaline units, afforded large molecular nonlinear absorptivities within the studied spectroscopic range. Effective optical-power-limiting and stabilization behaviors in the nanosecond regime of dye molecule (2) were also investigated and the results indicated that such a structural motif could be a useful approach to the molecular design of highly active two-photon systems for quick-response and related broadband optical-suppressing applications, in particular for confronting laser pulses of a long duration. PMID- 23744813 TI - Bioactive-rich extracts of persimmon, but not nettle, Sideritis, dill or kale, increase eNOS activation and NO bioavailability and decrease endothelin-1 secretion by human vascular endothelial cells. AB - BACKGROUND: There is increasing evidence that consumption of plant bioactives such as polyphenols and glucosinolates reduces cardiovascular disease risk and improves endothelial function. In the Black Sea area, a number of plants are consumed alone and as ingredients in traditional foods, and dill, nettle, kale, Sideritis and persimmon were identified as bioactive-rich traditional food plants. The present study investigated the effects of plant extracts on cellular markers of endothelial function (eNOS activation and expression and ET-1 secretion). RESULTS: Treatment of human umbilical vein endothelial cells with persimmon extract significantly increased Akt and eNOS phosphorylation and nitric oxide metabolites and significantly decreased secretion of ET-1 to the media after 24 h compared with a vehicle control (all P < 0.01). None of the other plant extracts significantly altered any markers of endothelial function. CONCLUSION: These findings suggest that persimmon fruit contains bioactives that can improve endothelial function via activation of eNOS and reduction in ET-1 secretion, but that dill, kale, Sideritis and nettle do not. PMID- 23744814 TI - Prevalence and nature of adverse medical device events in hospitalized children. AB - Our objective was to describe the prevalence and nature of adverse medical device events (AMDEs) in tertiary care children's hospitals. In our retrospective cohort study of patients at 44 children's hospitals in the Pediatric Health Information System (PHIS), we included all inpatient stays with an AMDE-related diagnosis from January 1, 2004 to December 31, 2011. We identified AMDEs by diagnoses that specified a device in their definition. We included events present on admission as well as those complicating hospital stays. We described the characteristics of these admissions and patients, and stratified analysis by device category and presence of a complex chronic condition. Of 4,115,755 admissions in the PHIS database during the study period, 136,465 (3.3%) had at least 1 AMDE. Vascular access and nervous system devices together represented 44.4% of pediatric AMDE admissions. The majority (75.5%) of AMDE admissions were of children with complex chronic conditions. The most common age group was patients aged 2 years or less at the time of their first AMDE-related admission. AMDEs occur commonly in a population cared for in tertiary children's hospitals. Research to more specifically delineate AMDEs and their predictors are next steps to understand and improve device safety in children. PMID- 23744815 TI - Hepatocellular carcinoma complicating recurrent hepatitis C after liver transplantation. PMID- 23744816 TI - Assessment of warfarin dosing requirements after bariatric surgery in patients requiring long-term warfarin therapy. AB - STUDY OBJECTIVE: To quantify the change in weekly warfarin dose after bariatric surgery in patients requiring long-term warfarin therapy. DESIGN: Retrospective matched-cohort study. SETTING: Anticoagulation management service in an integrated health care delivery system. PATIENTS: Patients receiving long-term warfarin anticoagulation who underwent bariatric surgery between January 1, 1996, and December 31, 2010 (27 patients), were matched by date of surgery (+/- 2 years), age (+/- 5 years), and target international normalized ratio (INR) range to patients receiving long-term anticoagulation therapy who underwent other abdominal surgical procedures: cholecystectomy or endoscopic retrograde cholangiopancreatography (59 patients [control group]). MEASUREMENT AND MAIN RESULTS: The main end point was change in postoperative warfarin dose from baseline (preoperative dose), measured at weekly postoperative intervals from weeks 1 to 8 and again at months 3 and 6. After surgery, patients in the bariatric surgery group had statistically significant decreases in weekly warfarin doses compared with preoperative dose at all postoperative time points (week 1 dose vs preoperative dose, p<0.01; doses at all other time points vs preoperative dose, p<0.001), except at 6 months (p>0.05). No statistically significant decreases in warfarin dose were detected at any postoperative time points in the control group. Twenty patients (74.1%) in the bariatric surgery group experienced a 20% or more decrease in weekly warfarin dose compared with 19 patients (32.2%) in the control group (p=0.004). No significant differences in warfarin-related adverse events were noted between groups. CONCLUSION: Weekly warfarin doses decreased in the immediate postoperative period in anticoagulated patients after bariatric surgery but returned to their preoperative doses after approximately 6 months. A similar pattern was not observed in patients in the control group who underwent other types of abdominal surgery. Compared with preoperative anticoagulation control, this resulted in reduced anticoagulation control despite close INR monitoring. If a causal relationship between bariatric surgery and warfarin sensitivity is established in future research, developing and validating a postbariatric surgery warfarin-dosing algorithm would be valuable. PMID- 23744817 TI - Multi-phosphorylation of the intrinsically disordered unique domain of c-Src studied by in-cell and real-time NMR spectroscopy. AB - Intrinsically disordered regions (IDRs) are preferred sites for post translational modifications essential for regulating protein function. The enhanced local mobility of IDRs facilitates their observation by NMR spectroscopy in vivo. Phosphorylation events can occur at multiple sites and respond dynamically to changes in kinase-phosphatase networks. Here we used real-time NMR spectroscopy to study the effect of kinases and phosphatases present in Xenopus oocytes and egg extracts on the phosphorylation state of the "unique domain" of c Src. We followed the phosphorylation of S17 in oocytes, and of S17, S69, and S75 in egg extracts by NMR spectroscopy, MS, and western blotting. Addition of specific kinase inhibitors showed that S75 and S69 are phosphorylated by CDKs (cyclin-dependent kinases) differently from Cdk1. Moreover, although PKA (cAMP dependent protein kinase) can phosphorylate S17 in vitro, this was not the major S17 kinase in egg extracts. Changes in PKA activity affected the phosphorylation levels of CDK-dependent sites, thus suggesting indirect effects of kinase phosphatase networks. This study provides a proof-of-concept of the use of real time in vivo NMR spectroscopy to characterize kinase/phosphatase effects on intrinsically disordered regulatory domains. PMID- 23744818 TI - Patients' inability to perform a preoperative cardiopulmonary exercise test or demonstrate an anaerobic threshold is associated with inferior outcomes after major colorectal surgery. AB - BACKGROUND: Surgical patients with poor functional capacity, determined by oxygen consumption at anaerobic threshold (AT) during cardiopulmonary exercise testing (CPET), experience longer hospital stays and worse short- and medium-term survival. However, previous studies excluded patients who were unable to perform a CPET or who failed to demonstrate an AT. We hypothesized that such patients are at risk of inferior outcomes after elective surgery. METHODS: All patients undergoing major colorectal surgery attempted CPET to assist in the planning of care. Patients were stratified by their test results into Fit (AT >= 11.0 ml O2 kg(-1) min(-1)), Unfit (AT < 11.0 ml O2 kg(-1) min(-1)), or Unable to CPET groups (failed to pedal or demonstrate an AT). For each group, we determined hospital stay and mortality. RESULTS: Between March 2009 and April 2010, 269 consecutive patients were screened, and proceeded to bowel resection. Median hospital stay was 8 days (IQR 5.1-13.4) and there were 44 deaths (16%) at 2 yr; 26 (9.7%) patients were categorized as Unable to CPET, 69 (25.7%) Unfit and 174 (64.7%) Fit. There were statistically significant differences between the three groups in hospital stay [median (IQR) 14.0 (10.5-23.8) vs 9.9 (5.5-15) vs 7.1 (4.9-10.8) days, P < 0.01] and mortality at 2 yr [11/26 (42%) vs 14/69 (20%) vs 19/174 (11%), respectively (P < 0.01)] although the differences between Unable and Unfit were not statistically different. CONCLUSIONS: Patients' inability to perform CPET is associated with inferior outcomes after major colorectal surgery. Future studies evaluating CPET in risk assessment for major surgery should report outcomes for this subgroup. PMID- 23744819 TI - Effect of ketamine as an adjunct to intravenous patient-controlled analgesia, in patients at high risk of postoperative nausea and vomiting undergoing lumbar spinal surgery. AB - BACKGROUND: We evaluated the effect of ketamine as an adjunct to a fentanyl-based i.v. patient-controlled analgesia (IV-PCA) on postoperative nausea and vomiting (PONV) in patients at high risk of PONV undergoing lumbar spinal surgery. METHODS: Fifty non-smoking female patients were evenly randomized to either the control or ketamine group. According to randomization, patients received either ketamine 0.3 mg kg(-1) i.v. or normal saline after anaesthetic induction with fentanyl-based IV-PCA either with or without ketamine mixture (3 mg kg(-1) in 180 ml). The incidence and severity of PONV, volume of IV-PCA consumed, and pain intensity were assessed in the postanaesthesia care unit, and at postoperative 6, 12, 24, 36, and 48 h. RESULTS: The overall incidence of PONV during the first 48 h after surgery was similar between the two groups (68 vs 56%, ketamine and control group, P=0.382). The total dose of fentanyl used during the first 48 h after operation was lower in the ketamine group than in the control group [mean (SD), 773 (202) MUg vs 957 (308) MUg, P=0.035]. The intensity of nausea (11-point verbal numerical rating scale) was higher in the ketamine group during the first 6 h after operation [median (interquartile range), 6 (3-7) vs 2 (1.5-3.5), P=0.039], postoperative 12-24 h [5 (4-7) vs 2 (1-3), P=0.014], and postoperative 36-48 h [5 (4-7) vs 2 (1-3), P=0.036]. Pain intensities were similar between the groups. CONCLUSIONS: Ketamine did not reduce the incidence of PONV and exerted a negative influence on the severity of nausea. It was, however, able to reduce postoperative fentanyl consumption in patients at high-risk of PONV. PMID- 23744820 TI - A clinician's guide to systematic reviews. AB - The purpose of this article is to discuss systematic reviews, how they are performed, and their associated strengths and limitations. A systematic review is an assessment of evidence involving exact methods to systematically identify, select, and critically evaluate all available literature on a particular topic. Unlike most narrative reviews, systematic reviews have defined methods established a priori for searching, evaluating, extracting, synthesizing, and reporting available evidence. Key characteristics differentiating systematic reviews from most narrative reviews include: clearly stated objectives, pre defined inclusion/exclusion criteria, an explicit reproducible methodology, systematic exhaustive searches to identify all sources of evidence, an assessment of the validity for each included study, and a systematic presentation of the study characteristics/results. Though there are significant advantages to systematic reviews, there are also clear limitations such as: the quality of included evidence; heterogeneity and homogeneity of included studies; and publication bias. Even with these limitations, systematic reviews are beneficial to front line clinicians when the quantity of evidence is so substantial that reviewing and synthesizing it is not feasible, available evidence is conflicting, or when the robustness of available evidence is unknown. PMID- 23744821 TI - Improved hydrogen-storage thermodynamics and kinetics for an RbF-doped Mg(NH2)2-2 LiH system. AB - The introduction of RbF into the Mg(NH2)2-2 LiH system significantly decreased its (de-)hydrogenation temperatures and enhanced its hydrogen-storage kinetics. The Mg(NH2)2-2 LiH-0.08 RbF composite exhibits the optimal hydrogen-storage properties as it could reversibly store approximately 4.76 wt % hydrogen through a two-stage reaction with the onset temperatures of 80 degrees C for dehydrogenation and 55 degrees C for hydrogenation. At 130 degrees C, approximately 70 % of hydrogen was rapidly released from the 0.08 RbF-doped sample within 180 min, and the fully dehydrogenated sample could absorb approximately 4.8 wt % of hydrogen at 120 degrees C. Structural analyses revealed that RbF reacted readily with LiH to convert to RbH and LiF owing to the favorable thermodynamics during ball-milling. The newly generated RbH participated in the following dehydrogenation reaction, consequently resulting in a decrease in the reaction enthalpy change and activation energy. PMID- 23744822 TI - Effect of thermostable alpha-amylase injection on mechanical and physiochemical properties for saccharification of extruded corn starch. AB - BACKGROUND: In industry, a jet cooker is used to gelatinize starch by mixing the starch slurry with steam under pressure at 100-175 degrees C. A higher degree of starch hydrolysis in an extruder is possible with glucoamylase. Unfortunately, it is difficult to carry out liquefaction and saccharification in parallel, because the temperature of gelatinization will be too high and will inactivate glucoamylase. Since the temperature for liquefaction and saccharification is different, it is hard to change the temperature from high (required for liquefaction) to low (required for saccharification). The industrial gelatinization process is usually carried out with 30-35% (w/w) dry solids starch slurry. Conventional jet cookers cannot be used any more at high substrate concentrations owing to higher viscosity. In this study, therefore, corn starch was extruded at different melt temperatures to overcome these limitations and to produce the highest enzyme-accessible starch extrudates. RESULTS: Significant effects on physical properties (water solubility index, water absorption index and color) and chemical properties (reducing sugar and % increase in reducing sugar after saccharification) were achieved by addition of thermostable alpha amylase at melt temperatures of 115 and 135 degrees C. However, there was no significant effect on % increase in reducing sugar of extruded corn starch at 95 degrees C. CONCLUSION: The results show the great potential of extrusion with thermostable alpha-amylase injection at 115 and 135 degrees C as an effective pretreatment for breaking down starch granules, because of the significant increase (P < 0.05) in % reducing sugar and enzyme-accessible extrudates for saccharification yield. PMID- 23744823 TI - Cocoa and human health. PMID- 23744824 TI - Glutamic acid-rich proteins in cassava (Manihot esculenta Crantz) storage roots. PMID- 23744828 TI - HIF-1alpha is upregulated in human mesenchymal stem cells. AB - Human mesenchymal stem cells (hMSCs) are multipotent cells that have aroused great expectations in regenerative medicine. They are assumed to originate from hypoxic stem cell niches, especially in the bone marrow. This suggests that O2 is of importance in their regulation. In order to characterize regulation of the oxygen sensing pathway in these cells, we studied hMSCs isolated from three origins, adult and pediatric bone marrow and umbilical cord blood (UCB). Surprisingly, pediatric bone marrow and UCB MSCs showed normoxic stabilization of hypoxia-inducible factor-1alpha (HIF-1alpha) that is normally degraded completely by HIF prolyl 4-hydroxylases in the presence of oxygen. This was due to a high expression level of HIF-1alpha mRNA rather than inappropriate post-translational degradation of HIF-1alpha protein. HIF-1alpha mRNA was also induced in normoxic adult bone marrow MSCs, but 40% less than in the pediatric cells, and this was apparently not enough to stabilize the protein. The high normoxic HIF expression in all the hMSCs studied was accompanied by increased expression of a large number of glycolytic HIF target genes and increased glycolysis. Osteogenic differentiation of bone marrow-derived hMSCs reduced HIF-1alpha mRNA and protein expression and the expression of glycolytic mRNAs, resulting in decreased glycolysis and induction of oxidative metabolism. Induced mitochondrial biogenesis, changes in mitochondrial morphology and size indicative of increased oxidative phosphorylation, and induction of extracellular matrix synthesis were observed following osteogenic differentiation. Altogether, these data suggest that HIF-1alpha is a general regulator controlling the metabolic fate and multipotency of the hMSCs. PMID- 23744829 TI - A single PLP-dependent enzyme PctV catalyzes the transformation of 3 dehydroshikimate into 3-aminobenzoate in the biosynthesis of pactamycin. AB - Natural amino donation: A PLP-dependent aminotransferase PctV, encoded in the pactamycin biosynthetic gene cluster, was found to catalyze the formation of 3 aminobenzoate from 3-dehydroshikimate with L-glutamate as the amino donor. The PctV reaction comprises a transamination and two dehydration reactions. This is the first report of a simple 3-ABA synthase in nature. PMID- 23744830 TI - Development of acneiform rash does not predict response to lapatinib treatment in patients with breast cancer. AB - STUDY OBJECTIVE: To determine if development of acneiform rash is a predictor of objective response rate with lapatinib. DESIGN: Subanalysis of data from a prospective, phase II study. SETTING: Academic breast care clinic. PATIENTS: Forty-nine treatment-naive patients with human epidermal growth factor receptor-2 (HER2)-positive locally advanced breast cancer, who were treated with neoadjuvant lapatinib monotherapy for 6 weeks; 47 patients were included in the final analysis. MEASUREMENTS AND MAIN RESULTS: Of the 49 patients enrolled, 33 (67%) developed a rash of any type, and 26 (55%) had acneiform rash. Of the 26 evaluable patients with acneiform rash (55%), 19 (73%) responded to lapatinib and 7 (27%) did not. Of the 21 evaluable patients without acneiform rash, 11 (67%) responded to treatment and 7 (33%) did not. Thus, no association was found between the occurrence of acneiform rash and response to lapatinib monotherapy. CONCLUSION: This study does not support the development of the acneiform rash as a predictor of clinical efficacy of lapatinib in the treatment of breast cancer. PMID- 23744831 TI - New electron-donor/acceptor-substituted tetraphenylethylenes: aggregation-induced emission with tunable emission color and optical-waveguide behavior. AB - Herein, we report the synthesis of new tetraphenylethylene derivatives 1-5 that feature electron-donating (methoxy) and -accepting (dicyanomethane) groups as AIE active molecules with tunable emission colors. The crystal structures of compounds 3 and 4 are described and the intermolecular interactions within their crystals agree with the observation that they exhibit strong solid-state emission. Compounds 1-4 exhibit typical AIE behavior and their emission maxima are red-shifted in the order: 1<2<3<4. Such red-shifts are ascribed to the fact that intramolecular interactions between the electron donor and the electron acceptor become stronger with increasing number of methoxy groups. The solid state emission colors of compounds 1-4 are successfully tuned from yellow-green to red. Compound 5 shows AIE behavior, but its emission is only slightly enhanced after aggregation and its solid shows a low quantum yield. Furthermore, microplates of compound 3 exhibit 2D optical-waveguide behavior. PMID- 23744833 TI - Correlation of pharmacokinetic/pharmacodynamic-derived predictions of antibiotic efficacy with clinical outcomes in severely ill patients with Pseudomonas aeruginosa pneumonia. AB - STUDY OBJECTIVE: To use pharmacokinetic/pharmacodynamic (PK/PD) modeling to correlate predicted antibiotic efficacy with actual clinical outcomes in patients with serious infections. DESIGN: Retrospective cohort analysis. SETTING: University medical center. PATIENTS: A total of 182 adult intensive care patients with Pseudomonas aeruginosa pneumonia during a 5-year period from 2000 to 2004. MEASUREMENTS AND MAIN RESULTS: The primary study end point was correlation of predicted antibiotic efficacy as determined by PK/PD modeling with actual clinical outcomes in individual patients. PK/PD analyses were conducted by determination of PD indexes using calculated patient-specific PK parameters and known pathogen minimum inhibitory concentrations, and by determination of predicted PD target attainment by using Monte Carlo simulation. Patients achieving PD targets were predicted to have clinically responded to therapy; patients not achieving PD targets were predicted to have failed therapy. A total of 128 patients (70%) apparently achieved desired PD targets; however, PK/PD modeling correctly predicted actual clinical outcome in only 47% of patients (86 of 182) with sensitivity of 49% and specificity of 43%. Percentages of patients apparently achieving PD targets were similar among those experiencing clinical response or clinical failure (67% vs 74%, respectively; p=0.344). Predicted achievement of PD targets was significantly associated only with reduction in intensive care unit and hospital lengths of stay. Achievement of PD targets was not significantly associated with clinical response by univariate or multivariate analysis, but factors related to severity of illness were significantly associated with clinical response. CONCLUSION: PK/PD modeling did not accurately predict clinical or microbiologic success in patients with P. aeruginosa pneumonia. This study highlights the difficulties in applying PK/PD modeling at the level of the individual patient due to extreme PK variability and issues such as severity of illness. Antibiotic dosing based on sound PK/PD principles is strongly advocated, but additional studies are needed to confirm the role of PK/PD modeling in optimizing outcomes of patients with serious bacterial infections. PMID- 23744832 TI - Parallel RNA interference screens identify EGFR activation as an escape mechanism in FGFR3-mutant cancer. AB - Activation of fibroblast growth factor receptors (FGFR) is a common oncogenic event. Little is known about the determinants of sensitivity to FGFR inhibition and how these may vary between different oncogenic FGFRs. Using parallel RNA interference (RNAi) genetic screens, we show that the EGF receptor (EGFR) limits sensitivity to FGFR inhibition in FGFR3-mutant and -translocated cell lines, but not in other FGFR-driven cell lines. We also identify two distinct mechanisms through which EGFR limits sensitivity. In partially FGFR3-dependent lines, inhibition of FGFR3 results in transient downregulation of mitogen-activated protein kinase signaling that is rescued by rapid upregulation of EGFR signaling. In cell lines that are intrinsically resistant to FGFR inhibition, EGFR dominates signaling via repression of FGFR3, with EGFR inhibition rescued by delayed upregulation of FGFR3 expression. Importantly, combinations of FGFR and EGFR inhibitors overcome these resistance mechanisms in vitro and in vivo. Our results illustrate the power of parallel RNAi screens in identifying common resistance mechanisms to targeted therapies. SIGNIFICANCE: Our data identify a novel therapeutic approach to the treatment of FGFR3-mutant cancer, emphasizing the potential of combination approaches targeting both FGFR3 and EGFR. Our data extend the role of EGFR in mediating resistance to inhibitors targeting a mutant oncogene, showing that EGFR signaling can repress mutant FGFR3 to induce intrinsic resistance to FGFR targeting. PMID- 23744834 TI - Methane adsorption on aggregates of fullerenes: site-selective storage capacities and adsorption energies. AB - Methane adsorption on positively charged aggregates of C60 is investigated by both mass spectrometry and computer simulations. Calculated adsorption energies of 118-281 meV are in the optimal range for high-density storage of natural gas. Groove sites, dimple sites, and the first complete adsorption shells are identified experimentally and confirmed by molecular dynamics simulations, using a newly developed force field for methane-methane and fullerene-methane interaction. The effects of corrugation and curvature are discussed and compared with data for adsorption on graphite, graphene, and carbon nanotubes. PMID- 23744835 TI - Effects of topical copper tripeptide complex on wound healing in an irradiated rat model. AB - OBJECTIVES: To evaluate clinical and immunohistopathological effects of topical glycyl-histidyl-lysine-copper (GHK-Cu) on in vivo irradiated rat wounds. DESIGN: Animal model. SETTING: Academic institution. SUBJECTS AND METHODS: After dorsal irradiation and a 28-day recovery period, 2 * 8 cm cranially based dorsal flaps were created in Sprague-Dawley rats. Twice daily GHK-Cu gel (test) or aquaphilic ointment (control) was applied for 10 days. Animals were euthanized, digital images of flaps were taken, and harvested tissues were immunohistochemically stained for a vascular endothelium marker, caveolin-1, and vascular endothelial growth factor (VEGF). Digital image analysis was used for outcome measures. Unpaired t-tests were used for statistical analyses; significance of P < .01 accounted for multiple comparisons. RESULTS: By digital analysis of clinical images, 13 test and 10 control animals showed mean ischemic areas of 5.0 cm(2) (SD = 0.9) for tests and 3.8 cm(2) (SD = 1.1; P = .011) for controls. Whole slide digitized images allowed quantification of caveolin-1-stained blood vessels and VEGF expression in fibroblasts at the interface of healing flaps. Caveolin-1 analyses showed a mean of 209.0 vessels (SD = 111.1) and a mean vessel luminal area of 525.7 um(2) (SD = 191.0) in tests and 207.4 vessels (SD = 109.4; P = .973) and 422.8 um(2) (SD = 109.7; P = .118) in controls. VEGF quantified as the percentage of pixels exceeding a colorimetric threshold, with higher fractions of positive pixels indicating more intense staining, showed a mean intensity score of 0.34 (SD = 0.19) in tests and 0.54 (SD = 0.41; P = .169) in controls. CONCLUSIONS: Irradiated dorsal rat flaps treated with topical GHK-Cu gel demonstrated no difference in flap ischemia, blood vessel number or area, or VEGF expression compared to controls. PMID- 23744836 TI - A new supporting material for fascia grafting during myringoplasty: polyglycolic acid sheets. AB - We used polyglycolic acid (PGA) sheets, a reinforcing material, as supporting devices for securing the fascia instead of fibrin glue or Gelfoam in patients with tympanic membrane (TM) perforations. PGA sheets were placed lateral to the fascia graft attached using the underlay grafting technique in 6 patients. In each case, the PGA sheet had been macerated and had merged into the fascia within 1 week of the procedure. At 2 to 3 postoperative weeks, parts of the sheet had become dehydrated and detached from the fascia, revealing a new epithelialized TM underneath. Eventually, the sheet had disappeared, and complete epithelialization had been achieved at 4 to 5 postoperative weeks, resulting in the successful closure of the perforation. The repair of TM remained stable throughout the follow-up period of at least 6 months in all patients. These results suggest that PGA sheets have the potential to secure fascia grafts and to guide the epithelialization of new tissue. PMID- 23744837 TI - Progesterone receptor signaling in the microenvironment of endometrial cancer influences its response to hormonal therapy. AB - Progesterone, an agonist for the progesterone receptor (PR), can be an efficacious and well-tolerated treatment in endometrial cancer. The clinical use of progesterone is limited because of the lack of biomarkers that predict hormone sensitivity. Despite its efficacy in cancer therapy, mechanisms and site of action for progesterone remain unknown. Using an in vivo endometrial cancer mouse model driven by clinically relevant genetic changes but dichotomous responses to hormonal therapy, we show that signaling through stromal PR is necessary and sufficient for progesterone antitumor effects. Endometrial cancers resulting from epithelial loss of PTEN (PTENKO) were hormone sensitive and had abundant expression of stromal PR. Stromal deletion of PR as a single genetic change in these tumors induced progesterone resistance indicating that paracrine signaling through the stroma is essential for the progesterone therapeutic effects. A hormone-refractory endometrial tumor with low levels of stromal PR developed when activation of KRAS was coupled with PTEN-loss (PTENKO/Kras). The innate progesterone resistance in PTENKO/Kras tumors stemmed from methylation of PR in the tumor microenvironment. Add-back of stromal PR expressed from a constitutively active promoter sensitized these tumors to progesterone therapy. Results show that signaling through stromal PR is sufficient for inducing hormone responsiveness. Our findings suggest that epigenetic derepression of stromal PR could be a potential therapeutic target for sensitizing hormone-refractory endometrial tumors to progesterone therapy. On the basis of these results, stromal expression of PR may emerge as a reliable biomarker in predicting response to hormonal therapy. PMID- 23744838 TI - Beneficial effect of sesame oil on heavy metal toxicity. AB - Heavy metals become toxic when they are not metabolized by the body and accumulate in the soft tissue. Chelation therapy is mainly for the management of heavy metal-induced toxicity; however, it usually causes adverse effects or completely blocks the vital function of the particular metal chelated. Much attention has been paid to the development of chelating agents from natural sources to counteract lead- and iron-induced hepatic and renal damage. Sesame oil (a natural edible oil) and sesamol (an active antioxidant) are potently beneficial for treating lead- and iron-induced hepatic and renal toxicity and have no adverse effects. Sesame oil and sesamol significantly inhibit iron induced lipid peroxidation by inhibiting the xanthine oxidase, nitric oxide, superoxide anion, and hydroxyl radical generation. In addition, sesame oil is a potent inhibitor of proinflammatory mediators, and it attenuates lead-induced hepatic damage by inhibiting nitric oxide, tumor necrosis factor-alpha, and interleukin-1beta levels. Because metal chelating therapy is associated with adverse effects, treating heavy metal toxicity in addition with sesame oil and sesamol may be better alternatives. This review deals with the possible use and beneficial effects of sesame oil and sesamol during heavy metal toxicity treatment. PMID- 23744839 TI - Risk factors for the development of catheter-related bloodstream infections in patients receiving home parenteral nutrition. AB - BACKGROUND: Risk factors for development of catheter-related bloodstream infections (CRBSI) were studied in 125 adults and 18 children who received home parenteral nutrition (HPN). METHODS: Medical records from a national home care pharmacy were reviewed for all patients that had HPN infused at least twice weekly for a minimum of two years from January 1, 2006-December 31, 2011. Infection and risk factor data were collected during this time period on all patients although those patients who received HPN for a longer period had data collected since initiation of HPN. RESULTS: In adults, 331 central venous catheters (CVCs) were placed. Total catheter years were 1157. Median CVC dwell time was 730 days. In children, there were 53 CVCs placed. Total catheter years were 113.1. Median CVC dwell time was 515 days. There were 147 CRBSIs (0.13/catheter year;0.35/1000 catheter days). In children there were 33 CRBSIs (0.29/catheter year;0.80/1000 days; P < .001 versus adults). In adults, univariate analysis showed use of subcutaneous infusion ports instead of tunneled catheters (P = .001), multiple lumen catheters (P = .001), increased frequency of lipid emulsion infusion (P = .001), obtaining blood from the CVC (P < 0.001), and infusion of non-PN medications via the CVC (P < .001) were significant risk factors for CRBSI. Increased PN frequency was associated with increased risk of CRBSI (P = .001) in children, but not in adults. Catheter disinfection with povidone-iodine was more effective than isopropyl alcohol alone. There were insufficient patients to evaluate chlorhexidine-containing regimens. CONCLUSION: Numerous risk factors for CRBSI were identified for which simple and current countermeasures already exist. PMID- 23744840 TI - Detection of delirium in palliative care unit patients: a prospective descriptive study of the Delirium Observation Screening Scale administered by bedside nurses. AB - BACKGROUND: The Delirium Observation Screening Scale (DOS) is designed to detect delirium by nurses' observations and has shown good psychometric properties. Its use in palliative care unit patients has not been studied. AIM: To determine diagnostic and concurrent validity, internal consistency, and user-friendliness of the Delirium Observation Screening Scale administered by bedside nurses in palliative care unit patients. DESIGN: In this descriptive study, psychometric properties of the Delirium Observation Screening Scale were tested by comparing the performance on the Delirium Observation Screening Scale (bedside nurses) to the algorithm of the Confusion Assessment Method and the Delirium Index (DI) (researchers). Paired observations were collected on three time points. Afterward, the user-friendliness of the Delirium Observation Screening Scale was determined by bedside nurses using a questionnaire. SETTING/PARTICIPANTS: In total, 48 patients were recruited from one palliative care unit (PCU) of a university hospital. Of the 14 eligible bedside nurses of the palliative care unit, 10 participated in the study. RESULTS: Delirium was present in 22.9% of patients. Diagnostic validity of the Delirium Observation Screening Scale was very good (area under the curve = 0.933), with 81.8% sensitivity, 96.1% specificity, 69.2% positive, and 98% negative predictive value. Concurrent validity of the Delirium Observation Screening Scale with the Delirium Index was moderate (rSpearman = 0.53, p = 0.001). The Cronbach's alpha for all Delirium Observation Screening Scale shift scores was 0.772. Generally, bedside nurses experienced the Delirium Observation Screening Scale as user-friendly. However, most Delirium Observation Screening Scale items (n = 11/13 items) need verbally active patients to perform the observations correctly. CONCLUSION: The Delirium Observation Screening Scale can be used for delirium screening in verbally active palliative care unit patients. The scale was rated as easy to use and relevant. Further validation studies in this population are required. PMID- 23744841 TI - Family members' perceptions of inpatient palliative care consult services: a qualitative study. AB - BACKGROUND: Family members are commonly involved in end-of-life decision making and typically involved in inpatient palliative care consultations. Although much research has documented patient outcomes following inpatient palliative care consultation, little is known about family member perceptions of the consultation. AIM: The purpose of this study was to determine how inpatient palliative care consultations impacted family members' understanding of the patient's condition, knowledge of available care options, and decision-making ability. DESIGN: An exploratory, qualitative study was conducted employing individual interviews among family members of seriously ill patients, recruited purposively. Interviews were conducted in person, at the hospital, or via telephone, using a semistructured protocol. SETTING/PARTICIPANTS: Family members of seriously ill patients were recruited from a nonprofit, community hospital. RESULTS: Interviews were conducted among 23 family members. Four themes were identified and included: perceived qualities of the inpatient palliative care consultation, family readiness, impact on decision-making process, and focus on comfort and quality of life. While most comments reflected positive aspects of the inpatient palliative care consult, such as improved pain control and communication, and increased access to medical professionals and time to discuss patient conditions, some themes reflected a lack of adequate preparation for the inpatient palliative care consultation and readiness for discussing prognosis. CONCLUSION: Family members report discussion with the inpatient palliative care team results in improved communication and knowledge, which contributes to decision-making ability. However, palliative care consultation may be improved by developing stronger protocols for introducing palliative care and by including the attending physician in the process to preclude conflicting, inconsistent information and recommendations. PMID- 23744842 TI - A rare complication of coronary angiography: 'iodide mumps'. PMID- 23744843 TI - Analyses of RANK and RANKL in the post-GWAS context: functional evidence of vitamin D stimulation through a RANKL distal region. AB - Over the past decade, many genome-wide association studies (GWAs) and meta analyses have identified genes and regions involved in osteoporotic phenotypes. Nevertheless, the large majority of these results were not tested at any functional level. GWA-associated single-nucleotide polymorphisms (SNPs) near candidate genes such as RANK and RANKL suggest that these SNPs and/or other variants nearby may be involved in bone phenotype determination. This study focuses on SNPs along these two genes, which encode proteins with a well established role in the bone remodeling equilibrium. Thirty-three SNPs, chosen for their location in evolutionary conserved regions or replicated from previous studies, were genotyped in the BARCOS cohort of 1061 postmenopausal women and tested for association with osteoporotic phenotypes. SNP rs9594738, which lies 184 kb upstream of the RANKL gene, was the only SNP found to be associated with a bone phenotype (dominant model: beta coefficient = -0.034, p = 1.5 * 10(-4) , for lumbar spine bone mineral density). Functional experiments exploring a distal region (DR) of 831 bp that harbors this SNP in a centered position (nt 470) demonstrated its capacity to inhibit the RANKL promoter in reporter gene assays. Remarkably, this DR inhibition was significantly reduced in the presence of vitamin D. In conclusion, the GWA-associated SNP rs9594738 lies in a region involved in transcription regulation through which vitamin D could be regulating RANKL expression and bone mineral density. PMID- 23744844 TI - Author's response to: Disparity of neural and behavioral handedness in evaluating candidates for POCD. PMID- 23744845 TI - Disparity of neural and behavioral handedness in evaluating candidates for POCD. PMID- 23744846 TI - The effect of retrograde autologous priming on intraoperative blood product transfusion in coronary artery bypass grafting. AB - INTRODUCTION: Retrograde autologous priming (RAP) of the cardiopulmonary bypass (CPB) circuit could reduce the degree of haemodilution associated with priming with acellular solutions. However, there is no strong evidence to prove that the practice of RAP reduced intraoperative packed red cell (PRC) or blood product transfusion. OBJECTIVE: To evaluate the effect of RAP on intraoperative PRC usage in coronary artery bypass grafting (CABG). METHODS: This study is a prospective, observational study on patients who underwent first-time, isolated CABG using CPB between April 2012 and July 2012. Two groups of patients were identified: 1. Non RAP group (n=128) and 2. RAP group (n=73). The primary outcome for the study was the amount of PRC and blood product usage between the induction of anaesthesia and the cessation of CPB. RESULTS: Use of PRC and blood products in the operating room was comparable in both groups. Univariate logistic regression showed that RAP was not an independent predictor of PRC or blood product transfusion (p=0.43). Multivariate logistic regression showed that CPB time, preoperative haemoglobin (Hb) levels and creatinine clearance were independent predictors of blood product transfusion. CONCLUSION: Practising RAP with mean volumes of 300 ml does not necessarily reduce PRC and other blood product transfusion requirements during CABG. In our practice, RAP was performed, aiming at displacing CPB circuit prime volume with which the perfusionist felt comfortable and dictated by haemodynamic parameters prior to commencing CPB. We presume this is the case in many units around the world. This practice, in our opinion, is not enough to achieve the benefits of RAP, if any, in the form of a reduction of packed red cell transfusion requirements. The true advantages of RAP in cardiac surgery need to be studied in a prospective, randomized, controlled trial. PMID- 23744847 TI - Effect of the colloids gelatin and HES 130/0.4 on blood coagulation in cardiac surgery patients: a randomized controlled trial. AB - OBJECTIVE: The choice of the prime solution for cardiopulmonary bypass can play an important role in limiting the effect on blood coagulation, but it is still unclear what the effect of colloids on blood coagulation is. The aim of this study was to investigate the effect of synthetic colloids on blood loss and blood coagulation in patients after on-pump coronary artery bypass graft (CABG) procedures. METHODS: Sixty elective, on-pump CABG patients were randomly assigned to receive the prime solutions lactated Ringer's solution combined with hydroxyethyl starch 130/0.4 (HES, 6% Volulyte, Fresenius Kabi Nederland BV, Zeist, the Netherlands) (HES group) or gelatin (Gelofusin((r)), B Braun Melsung AG, Melsungen, Germany) (Gelo group). Blood loss was assessed using post operative chest tube output; secondary endpoints were number of blood component transfusions, routine coagulation test values and rotation thromboelastometry values (Rotem((r)) delta, Pentapharm GmbH, Munich, Germany). RESULTS: Total post operative chest tube output was 500 +/- 420 ml in the HES group versus 465 +/- 390 ml in the Gelo group (p = 0.48). No significant differences were observed in any of the routine coagulation tests values, thromboelastometry parameters or number of blood component transfusions between the groups. CONCLUSIONS: In this randomized, controlled trial of adults after on-pump CABG procedures, there was no significant difference in blood loss or blood coagulation between the HES group and the Gelo group. PMID- 23744848 TI - Transition from ECMO to left ventricular support via trans-septal cannula using a single CentriMag device. AB - A 67-year-old male presented in cardiogenic shock and multi-system organ failure requiring emergent venous-arterial extracorporeal membrane oxygenation (ECMO). He was deemed ineligible for heart transplantation and a left ventricular assist device (LVAD) was thought to be high risk due to persistent right heart failure. To determine if he could tolerate left ventricular support alone, a trans-septal cannula was placed via the left femoral vein. Transition from veno-arterial ECMO to isolated left-sided support allowed for risk assessment for LVAD implantation and extubation, providing the patient an opportunity to participate in further clinical decision making. PMID- 23744849 TI - Lone atrial fibrillation as a positive predictor of left atrial volume reduction following ablation of atrial fibrillation. AB - AIMS: We investigated predictors of left atrial volume reduction (LAVR) in patients with atrial fibrillation (AF) undergoing AF ablation. METHODS AND RESULTS: Sixty patients with AF underwent pulmonary vein isolation (PVI) using a pulmonary vein ablation catheter (PVAC). All patients underwent cardiac imaging by computed tomography or magnetic resonance imaging to determine LAV 1 day before and 140 +/- 9.5 days after PVI. Clinical follow-up and 72 h electrocardiogram Holter monitoring were performed 1, 3, and 6 months after ablation, and every 6 months thereafter. Significant LAVR (n = 60, 89.3 +/- 3.9 vs. 79.5 +/- 3.6 mL, P < 0.0001) was shown for the study group as a whole, caused particularly by the subgroup of patients with ablation success (n = 45, 85.2 +/- 4.6 vs. 72.5 +/- 3.7 mL, P < 0.0001). In addition, significant LAVR was shown for patients with lone AF (n = 25, 88.8 +/- 6.8 vs. 72.7 +/- 5.3 mL, P < 0.0001), but not for patients with AF and concomitant arterial hypertension (n = 32, 89 +/- 4.8 vs. 86.7 +/- 5 mL, P = 0.3), coronary artery disease (n = 12, 91.6 +/- 7.8 vs. 89.1 +/- 7.8 mL, P = 0.26), or left ventricular hypertrophy (n = 10, 86.3 +/- 5.5 vs. 83.1 +/- 5.3 mL, P = 0.27). Multivariate analysis revealed absence of arterial hypertension, lone AF, ablation success, and initial LA enlargement as independent predictors for significant LAVR following ablation (each P < 0.05). CONCLUSION: Based on the subgroup of patients with lone AF, PVI leads to a significant LAVR 4 months after the procedure, especially in patients with clinical success in terms of AF freedom. Comorbidities such as arterial hypertension may prevent this reverse atrial remodelling, despite AF freedom. Clinical implications need to be further elucidated. PMID- 23744850 TI - Imaging before cryoablation of atrial fibrillation: is phrenic nerve palsy predictable? AB - AIMS: Multidetector computerized tomography (MDCT) with improved temporal and spatial resolution is one of the most commonly used non-invasive tests for evaluation of pulmonary veins (PVs) and adjacent structures before cryoablation of atrial fibrillation (AF). Identification of spatial neighbouring of phrenic nerves is important to decrease likelihood of phrenic nerve palsy (PNP). The purpose of our study is to clarify the course of right phrenic nerve, its relations to PVs using 64-slice MDCT, and effect on occurrence of PNP. METHODS AND RESULTS: A total of 162 patients underwent MDCT with 3D reconstruction of left atrium prior to cryoablation for AF. The location of the right pericardiophrenic artery (RPA) was identified on axial images and artery distance to the right upper PV (RUPV) ostium was measured in 3D image. Right pericardiophrenic artery was detectable in 145 of 162 (89.5%) patients (52.4% male, age 54.5 +/- 10.1 years, and 80.7% paroxysmal AF). Acute procedural success rate was 96.2%. Mean procedural and fluoroscopy times were 74.4 +/- 6.2 and 15.7 +/- 4.3 min. Transient right PNP was developed in four (2.75%) patients. RUPV ostium to RPA distance was lower in patients with PNP (P = 0.033). In multivariate regression analysis, only RUPV ostium to RPA distance (odds ratio: 2.95; 95% confidence interval: 1.76-4.66, P = 0.001) was the independent predictor of PNP occurrence during cryoablation. CONCLUSION: Our results revealed that pre-ablation cardiac imaging with 64-slice MDCT adequately detected RPA bordering the phrenic nerve, which was an important determinant of PNP development during cryoballoon-based AF ablation. PMID- 23744851 TI - Thyroid neurofibroma in a female patient with neurofibromatosis type I: report of a case. AB - Neurofibromas are benign tumours arising from the Schwann cells of peripheral nerves. They usually occur on the limbs and rarely present at other sites such as the thyroid gland. Lesions associated with the thyroid are usually benign but should be closely followed up. When the presence of a plexiform neurofibroma in the thyroid gland is confirmed by radiological investigations, total thyroidectomy is the treatment of choice because of the substantial risk of malignant transformation. This case report details a rare case of thyroid plexiform neurofibroma in a young female patient with known Von Recklinghausen disease. PMID- 23744852 TI - Absolute constipation caused by sigmoid volvulus in a young man. AB - We describe a challenging case of sigmoid volvulus where a previously unrecognised anatomical condition, rather than the patient's age, was the main predisposing factor. A man in his thirties presented to the emergency department with a 3-day history of constipation and acute abdominal pain. Initial assessment and studies were inconclusive, but a CT scan revealed torsion of the large bowelSigmoid volvulus is a frequent cause of bowel obstruction that can be missed if appropriate imaging is not available. Clinical presentation and blood analysis can be similar to the findings in acute abdomen caused by other more common causes. PMID- 23744853 TI - Late Streptococcus bovis infection of total knee replacement complicated by infective endocarditis and associated with colonic ulcers. AB - Streptococcus bovis is rare cause of late infections after total knee replacement (TKR). This report presents a case of confirmed late septic arthritis following TKR caused by S bovis that was further complicated with infective endocarditis resulting in aortic valve insufficiency in an immunecompetent patient. As an association between S bovis and gastrointestinal malignancies is suggested, a workup for such malignancies was performed that revealed non-malignant ulcers in patient's ascending colon. The patient is currently recovering from his aortic valve replacement surgery and is scheduled to have annual colonoscopies. His knee joint has improved; however, he developed constant pain because of underlying chronic infection in the affected joint and has difficulties mobilising. Therefore, a revision TKR is considered but postponed until he fully recovers from his heart valve surgery. PMID- 23744854 TI - Cardiopulmonary complications in a patient with bezoar. AB - We report a case of a 17-year-old institutionalised male with a medical history of fragile X syndrome, bilateral congenital glaucoma, cataracts and pica disorder. He was transferred to our paediatric intensive care unit owing to respiratory failure and hypotension. On transoesophageal echocardiogram, he presented left atrium compression. A CT of the thorax and mediastinum revealed an unknown heterogeneous material in the lumen of the stomach and oesophagus, with a lung parenchyma suggestive of alveolar foreign material. Endoscopic evaluation showed diaper fragments inside the oesophagus and stomach. Fragmentation and suction of diaper material was made. Medical treatment was performed with inotropic support, conventional mechanical ventilation and antibiotics. PMID- 23744855 TI - A case series of patients on chemotherapy with dyspnoea and pulmonary infiltrates. AB - Clinicians often assume that patients who develop pulmonary symptoms and radiographic infiltrates while receiving cytotoxic chemotherapy have opportunistic pulmonary infection or chemotherapy-related interstitial lung disease. We describe two cases of rare complications of commonly used chemotherapeutic agents (gemcitabine-induced eosinophilic pneumonia and rituximab induced hypersensitivity pneumonitis) that vindicate this assumption but a third case of scleroderma-associated interstitial lung disease that became clinically manifest in a patient who was receiving chemotherapy. The latter case highlights the need for vigilance for other causes of interstitial lung disease in patients receiving chemotherapy. PMID- 23744856 TI - High-grade GI lymphoma presenting with diarrhoea. AB - A 63-year-old male carpenter presented with diarrhoea after returning from a holiday in Egypt with no other abdominal features. Physical examination showed generalised lymphadenopathy and splenomegaly. Blood tests including inflammatory markers were within normal limits. Microbiological stool sample analysis was unremarkable. Endoscopies of the large bowel showed patchy inflammation from the rectum to the hepatic flexure with multiple tiny polyps. Histology revealed a lymphocytic infiltrate suggestive of multiple lymphomatous polyposis. Some time later, he presented with small bowel obstruction requiring emergency laparotomy and ileostomy. After recovery from surgery he started definite treatment with chemotherapy resulting in complete remission. PMID- 23744857 TI - Management of a simple renal cyst in a complex patient. AB - Renal cysts are generally classified as simple or complex and are further characterised under the Bosniak classification system. Most simple cysts are benign, asymptomatic and discovered incidentally. However, over time, these simple cysts can enlarge, become symptomatic and develop complications, requiring intervention. We present a case of a 70-year-old man with multiple comorbidities who presented with left lower quadrant abdominal pain and haematuria. An abdominal CT scan revealed a large, 26 cm exophytic cyst with high attenuation areas, septations and haemorrhage. Given the patient's tenuous condition and poor functional status, an interventional radiology-guided renal cyst aspiration was performed, resulting in successful reduction of size and symptom resolution. A follow-up ultrasound at 6 months showed no evidence of recurrence. Primary care providers should be aware of the prevalence of renal cysts and their complications, especially haemorrhage, particularly in high risk and elderly patients on anticoagulation or antiplatelet therapy. PMID- 23744858 TI - Unilateral movement disorder as a presenting sign of paediatric post-varicella angiopathy. AB - Diagnosing ischaemic stroke in children is often difficult. Post-varicella angiopathy (PVA) is a well-recognised and frequent cause of childhood ischaemic stroke, particularly affecting the basal ganglia. When a previously healthy child presents with unilateral abnormal involuntary movements, cerebral infarction should be included in the differential diagnosis and PVA should be considered, even when there is no recent history of rash and cerebrospinal fluid is normal. Medical history and intracranial vascular imaging are important for early diagnosis and treatment. PMID- 23744859 TI - Bleomycin-induced flagellate hyperpigmentation. AB - Bleomycin is a chemotherapeutic agent used in the treatment of different tumours. It has several side effects, including flagellate hyperpigmentation, which is a unique and a well-documented side effect of bleomycin therapy. We report a case of a 23-year-old woman with a personal history of ovarian dysgerminoma, who developed flagellate hyperpigmentation on trunk after bleomycin therapy. PMID- 23744861 TI - Lou Gehrig, Angelina Jolie, and cancer genetics. PMID- 23744860 TI - Fatal re-expansion pulmonary edema in a young adult following tube thoracostomy for spontaneous pneumothorax. AB - Re-expansion pulmonary edema (RPE) is a rare but potentially fatal complication that can occur following rapid lung expansion while managing patients with pleural effusion or pneumothorax. In this case, fatal outcome occurred due to RPE in a previously healthy young adult male patient subsequent to tube thoracostomy for spontaneous pneumothorax. While managing patients with pneumothorax or large pleural effusions, precautions should be taken to avoid rapid re-expansion of the previously collapsed lung in order to reduce the probability of development of this complication. PMID- 23744862 TI - Cancer health disparities and the cost of cancer care: payment model issues. PMID- 23744863 TI - Treatment of early-stage esophageal adenocarcinoma. AB - Although T2,N0,M0 esophageal adenocarcinoma is grouped with other locoregional disease by NCCN, no consensus exists about how it should be treated. One of the inherent complexities of treating T2,N0,M0 esophageal adenocarcinoma is the inaccuracy of the clinical staging. In addition, conflicting evidence exists about whether neoadjuvant therapy adds any benefit to esophagectomy. A 52-year old patient recently seen at the Robert H. Lurie Comprehensive Cancer Center illustrates the complexity of these issues. PMID- 23744864 TI - Non-small cell lung cancer, version 2.2013. AB - These NCCN Guidelines Insights focus on the diagnostic evaluation of suspected lung cancer. This topic was the subject of a major update in the 2013 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer. The NCCN Guidelines Insights focus on the major updates in the NCCN Guidelines and discuss the new updates in greater detail. PMID- 23744865 TI - Rationing cancer care: a survey among the members of the german society of hematology and oncology. AB - Rising costs of cancer care and the growing burden of cancer in a world of finite resources seem to make rationing in oncology inevitable. Information is currently lacking about oncologists' strategies in responding to resource constraints and the prevalence of withholding costly treatments. An online survey was offered via e-mail to physician members of the German Society of Hematology and Oncology. Those actively practicing were asked to complete an online questionnaire asking how limited resources were currently affecting their clinical practice. Two thirds of 345 participating oncologists reported withholding costly treatments in at least some instances. Regarding their rationale, 70% stated that evidence for costly intervention was not convincing enough, and 59% said that they rationed approved treatments because of an unfavorable cost/benefit calculation. Only 29% reported being explicit about their rationing decision if the patient did not know or inquire about the respective intervention. Withholding expensive procedures from individual patients was widespread among the respondents. Oncologists withheld treatments not only if they perceived the scientific evidence to be questionable but also if they perceived reimbursement prospects or the cost/benefit ratio to be unfavorable, a behavior that could be called rationing. Currently this mostly refers to costly procedures with limited additional benefits. Although this result may be interpreted as indicating that oncologists assume responsibility for spending the resources in a justified way, more transparency and an open discussion on cost-effectiveness and the just allocation of costly treatments is needed. PMID- 23744866 TI - The phosphoinositide-3-kinase-Akt-mTOR pathway as a therapeutic target in breast cancer. AB - The phosphoinositide-3-kinase (PI3-kinase)-Akt-mTOR pathway is a central signal transduction pathway that regulates many critical aspects of normal and cancer physiology, including cell proliferation, apoptosis, cell morphology and migration, protein synthesis, and integration of metabolism. In breast cancer, somatic mutations that activate the pathway occur in more than 50% of tumors, underscoring the potentially broad impact of targeting the pathway for therapy. A vast body of preclinical data demonstrates the efficacy of pathway inhibition on tumor growth, and evidence also shows that activation of the pathway occurs in models of acquired resistance to hormonal therapy. This preclinical work led to the investigation of allosteric mTOR inhibitors, everolimus and temsirolimus, in metastatic hormone receptor-positive breast cancer. The recent BOLERO-2 trial comparing everolimus plus exemestane versus placebo plus exemestane in women with resistance to nonsteroidal aromatase inhibitors demonstrated a 6-month improvement in progression-free survival and led to FDA approval of everolimus for this indication in the United States. This landmark trial is the first demonstration of significant clinical benefit using drugs targeting this pathway in breast cancer. Many questions remain about the role of everolimus and other pathway-targeting drugs in clinical development in breast cancer treatment. This article reviews the role of the PI3-kinase-Akt-mTOR pathway in breast cancer biology and the clinical trial evidence available to date. PMID- 23744868 TI - Bone cancer. AB - Primary bone cancers are extremely rare neoplasms, accounting for fewer than 0.2% of all cancers. The evaluation and treatment of patients with bone cancers requires a multidisciplinary team of physicians, including musculoskeletal, medical, and radiation oncologists, and surgeons and radiologists with demonstrated expertise in the management of these tumors. Long-term surveillance and follow-up are necessary for the management of treatment late effects related to surgery, radiation therapy, and chemotherapy. These guidelines discuss the management of chordoma, giant cell tumor of the bone, and osteosarcoma. PMID- 23744867 TI - Controversies in the evaluation and management of atypical melanocytic proliferations in children, adolescents, and young adults. AB - The rising incidence of melanoma in children has brought increased attention to the clinical and pathologic diagnosis of pigmented lesions in the pediatric age group. Although melanoma in infancy and early childhood is often associated with large congenital nevi, in older children and teenagers it is most often sporadic, occurring in patients with a low skin phototype and substantial sun exposure. The rarity of this potentially fatal disorder demands astute clinical attention and a high index of suspicion for atypical lesions in pediatric patients. The challenges include the difficult decision of whether to biopsy and an often equivocal pathologic diagnosis. These diagnostically challenging and equivocal lesions lead to a degree of uncertainty regarding additional workup, prognosis, potential therapy, and follow-up plans. Consultation with a specialty dermatopathologist can be very helpful, and advanced molecular diagnostic techniques may be used in selected circumstances. Although still controversial, good evidence exists to justify a role for sentinel lymph node biopsy. Patients with atypical melanocytic proliferations have a high rate of positive sentinel lymph nodes; however, their outcomes are clearly better than in similarly staged adults with conventional melanoma. With the multiple variables involved and the relative lack of prospectively derived evidence, clinical decision-making is challenging and patients and families may experience considerable stress. This article provides data and weighs the pros and cons of a rationale for decision making in pediatric and young adult patients with diagnostically challenging melanocytic lesions. PMID- 23744869 TI - Diagnosis and treatment of chordoma. AB - Chordoma is a primary bone cancer arising on the midline from the skull base to the sacrum. Diagnosis is often delayed because of insidious onset and nonspecific symptoms. Chordomas appear histologically low-grade but are highly invasive and often recur locally. Management centers primarily on radical en bloc surgical resection when possible. Radiation therapy using protons and/or photons is often necessary because complete resection is seldom possible due to critical location and invasion of the cancer cells into surrounding structures. No approved medical therapy exists. The high rate of recurrence is reflected by a median survival of 6 to 7 years. This article reviews the clinical management of chordoma and discusses ongoing research in the field. PMID- 23744870 TI - More than the sum of its parts: how multidisciplinary cancer care can benefit patients, providers, and health systems. PMID- 23744874 TI - General cognitive ability and the psychological refractory period: individual differences in the mind's bottleneck. AB - Identifying the precise locus of general cognitive ability (g) in the flow of information between perception and action is an important goal of differential psychology. To localize the negative correlation between g and reaction time to a specific processing stage, we administered a speeded number-comparison task to two groups differing in average g. The participants had to respond to two stimuli in each trial, which produced the well-known slowing of the second reaction time known as the psychological refractory period. The difference in the second reaction time favoring the high-g group doubled as the stimulus onsets became very close together. This finding affirms that the faster reaction times of higher-g individuals reflect an advantage exclusively in the serial bottleneck of central processing and not in the parallel peripheral stages. PMID- 23744875 TI - Predictive and reactive mechanisms in smile reciprocity. AB - During face-to-face interactions, people reciprocate their conversation partners' genuine and polite smiles with matching smiles. In the research reported here, we demonstrated that predictive mechanisms play a role in this behavior. In natural interactions (Study 1), participants anticipated a substantial proportion of genuine smiles but almost no polite ones. We propose that reinforcement-learning mechanisms underpin this social prediction and that smile-reciprocity differences arise because genuine smiles are more rewarding than polite smiles. In Study 2, we tested this idea using a learning task in which correct responses were rewarded with genuine or polite smiles. We measured participants' smile reactions with electromyography (EMG). As in natural interactions, people mimicked polite smiles reactively, after seeing them appear. Interestingly, the EMG data showed predictive responding to genuine smiles only. These results demonstrate that anticipating social rewards drives predictive social responding and therefore represent a significant advance in understanding the mechanisms that underpin the neural control of real-world social behavior. PMID- 23744876 TI - Different patterns, but equivalent predictors, of growth in reading in consistent and inconsistent orthographies. AB - All alphabetic orthographies use letters in printed words to represent the phonemes in spoken words, but they differ in the consistency of the relationship between letters and phonemes. English appears to be the least consistent alphabetic orthography phonologically, and, consequently, children learn to read more slowly in English than in languages with more consistent orthographies. In this article, we report the first longitudinal evidence that the growth of reading skills is slower and follows a different trajectory in English than in two much more consistent orthographies (Spanish and Czech). Nevertheless, phoneme awareness, letter-sound knowledge, and rapid automatized naming measured at the onset of literacy instruction did not differ in importance as predictors of variations in reading development among the three languages. These findings suggest that although children may learn to read more rapidly in more consistent than in less consistent orthographies, there may nevertheless be universal cognitive prerequisites for learning to read in all alphabetic orthographies. PMID- 23744878 TI - Riluzole: validation of stability-indicating HPLC, D1 and DD1 spectrophotometric assays. AB - A stability-indicating reversed-phase high-performance liquid chromatographic assay procedure has been developed and validated for riluzole in the presence of alkaline and oxidative degradation products. The liquid chromatographic separation was achieved and compared isocratically on C18 Zorbax ODS and Poroshell 120 EC-C18 columns by using a mobile phase containing methanol-water, pH = 3.10 (70:30, v/v), at a flow rate of 1 mL/min and ultraviolet detection at 264 nm. The method was linear over the concentration ranges of 20-200 ug/mL (r = 0.9997) and 10-200 ug/mL (r = 0.9995). The limit of detection and quantitation for the two columns were 2 and 6 ug/mL and 1 and 3 ug/mL, respectively. Moreover, spectrophotometric methods were applied for the determination of riluzole in the presence of its oxidative degradation products by using first derivative spectrophotometry at 252.5 and 275.0 nm. The method was linear over the concentration range of 1-20 ug/mL (r = 0.9995 and 0.9996) at the studied wavelengths, with limits of detection and quantitation of 0.1 and 0.3 ug/mL. In addition, the first derivative ratio spectrophotometry (DD1) method was applied for the determination of riluzole in the presence of its alkaline degradation product at 252.0, 278.5 and 306.3 nm by using 100 ug/mL of alkaline degraded riluzole as a divisor; riluzole was additionally determined in the presence of its hydrogen peroxide oxidative degradation products at 252.5, 275.0 and 305.0 nm by using 200 ug/mL of oxidative degraded riluzole as a divisor. The DD1 method was linear over the concentration range of 1-20 ug/mL (r = 0.9996, 0.9995 and 0.9996 for the alkaline degradation product at the three studied wavelengths, respectively; and r = 0.9995, 0.9996 and 0.9995 for the oxidative degradation product at the three studied wavelengths, respectively), with limits of detection and quantitation of 0.1 and 0.3 ug/mL for both alkaline and oxidative degradation products. The two studied chromatographic and spectrophotometric methods were comparable and display the required accuracy, selectivity, sensitivity and precision to assay riluzole in bulk and pharmaceutical dosage forms. Degradation products resulting from the stress studies did not interfere with the detection of riluzole, which indicates that these are stability-indicating assays. PMID- 23744877 TI - Benign breast disease, mammographic breast density, and the risk of breast cancer. AB - BACKGROUND: Benign breast disease and high breast density are prevalent, strong risk factors for breast cancer. Women with both risk factors may be at very high risk. METHODS: We included 42818 women participating in the Breast Cancer Surveillance Consortium who had no prior diagnosis of breast cancer and had undergone at least one benign breast biopsy and mammogram; 1359 women developed incident breast cancer in 6.1 years of follow-up (78.1% invasive, 21.9% ductal carcinoma in situ). We calculated hazard ratios (HRs) using Cox regression analysis. The referent group was women with nonproliferative changes and average density. All P values are two-sided. RESULTS: Benign breast disease and breast density were independently associated with breast cancer. The combination of atypical hyperplasia and very high density was uncommon (0.6% of biopsies) but was associated with the highest risk for breast cancer (HR = 5.34; 95% confidence interval [CI] = 3.52 to 8.09, P < .001). Proliferative disease without atypia (25.6% of biopsies) was associated with elevated risk that varied little across levels of density: average (HR = 1.37; 95% CI = 1.11 to 1.69, P = .003), high (HR = 2.02; 95% CI = 1.68 to 2.44, P < .001), or very high (HR = 2.05; 95% CI = 1.54 to 2.72, P < .001). Low breast density (4.5% of biopsies) was associated with low risk (HRs <1) for all benign pathology diagnoses. CONCLUSIONS: Women with high breast density and proliferative benign breast disease are at very high risk for future breast cancer. Women with low breast density are at low risk, regardless of their benign pathologic diagnosis. PMID- 23744879 TI - Rapid quantification of tobramycin and vancomycin by UPLC-TQD and application to osteomyelitis patient samples. AB - Tobramycin and vancomycin are the most commonly used antibiotics for the treatment of osteomyelitis. A sensitive and rapid method was developed for the analysis of tobramycin and vancomycin in human drainage tissue fluid. The procedure involved a simple liquid-liquid extraction of tobramycin, vancomycin and atenolol (internal standard) and separation by ultra-high performance liquid chromatography on an Acquity UPLC BEH C18 column (2.1 * 100 mm, 1.7 um) with a mobile phase consisting of 0.1% (v/v) formic acid water solution and 0.1% (v/v) formic acid acetonitrile solution at a flow rate of 0.3 mL/min. Detection was performed by positive ion electrospray ionization in multiple reaction monitoring mode (m/z 468 -> 163 transitions for tobramycin; m/z 725 -> 144 for vancomycin; m/z 267 -> 74 for the internal standard). The retention times of tobramycin, vancomycin, and the internal standard were 0.68, 3.62 and 3.03 min, respectively. The total analysis time was less than 10 min. Excellent linear relationships (correlation coefficient > 0.99) were demonstrated between the area under the peak ratios of tobramycin and vancomycin to the internal standard in the drainage tissue fluid, and the concentration ranges were 1.25-100.00 mg/L and 0.50-150.00 mg/L for tobramycin and vancomycin, respectively. The intra-day and inter-day accuracy and precision (coefficient of variation) acceptance criteria for each quality control was <= 7.8% and the mean accuracy values were < 5.0% for tobramycin and < 4.0% for vancomycin. All experiments suggested the high throughput potential of the proposed method. The method was successfully applied to investigate local delivery of tobramycin and vancomycin in four calcaneal osteomyelitis patients who had accepted drug-loaded artificial bone implantation. PMID- 23744880 TI - Determination of phthalates in Jordanian bottled water using GC-MS and HPLC-UV: environmental study. AB - A simple, accurate and reliable method was presented and validated for the simultaneous monitoring of six phthalates at trace level concentrations in seven different brands of commercial bottled mineral water from Jordan. Liquid-liquid extraction with a mixture of methylene chloride-petroleum ether (20:80, v/v) was used for isolation and enrichment of the phthalates and sample cleanup. This was followed by gas chromatography-mass spectrometry (GC-MS) for identification and high-performance liquid chromatography (HPLC) with ultraviolet detection for quantification. The linear range of the GC-MS calibration curve was 0.3-1.2 ug/L with a mean correlation coefficient (R(2)) of 0.9920 +/- 0.0063, the detection limit was < 0.1 ug/L and the percentage recovery was >90%. For HPLC, the linear range was 0.5-10 mg/L with R(2) = 0.9985 +/- 0.0012 and an average detection limit of 0.20 +/- 0.15 ug/L. The results indicated that the Jordanian bottled water was contaminated with dibutyl-, di-2-ethylhexyl- and di-n-octyl-phthalate, with total phthalate concentrations between 8.1 and 19.8 ug/L. Increasing the storage temperature of the bottled water increased the content of leached phthalates in the water (total concentration of 23-29.2 ug/L). PMID- 23744881 TI - Enhanced trimethylation of histone h3 mediates impaired expression of hepatic glucose 6-phosphatase expression in offspring from rat dams exposed to hypoxia during pregnancy. AB - Given that hepatic glucose 6-phosphatase (G6Pase, involved in gluconeogenesis) has been demonstrated to be altered long term in animal models of intrauterine growth restriction (IUGR), we hypothesized that hypoxia in utero may regulate G6Pase expression via epigenetic mechanisms. To address this further, a rat model of maternal hypoxia leading to IUGR and impaired liver growth was utilized. In the 12-month-old male offspring of pregnant rat dams exposed to 11.5% atmospheric oxygen from gestational day (gd) 15 to gd 21, nonfasting glucose was lower in association with decreased hepatic G6Pase messenger RNA and protein levels. This was concomitant with enhanced methylation of histone H3 [K9] surrounding the promoter of G6Pase. Moreover, when McA-RH7777 hepatoma cells were exposed to various concentrations of oxygen for 48 hours, we observed an oxygen-dependent decrease in G6Pase expression associated with enhanced histone H3 [K9] methylation. Collectively, these results indicate that hypoxia directly and indirectly impairs G6Pase expression through enhanced methylation of histone H3 [K9]. PMID- 23744882 TI - High-risk human papillomavirus DNA test: could it be useful in low-grade cervical lesion triage? Five-year follow-up. AB - We conducted a retrospective, observational study in order to evaluate the role of high-risk human papillomavirus (hrHPV)-DNA test in patients with first diagnosis of low-grade squamous intraepithelial lesions (L-SILs).Patients were divided into group A, annual Papanicolaou test and hrHPV-DNA tests (167 patients) and group B, immediate colposcopy, followed by annual papanicolaou test and hrHPV DNA tests (164 patients). We assessed sensitivity, specificity, negative predictive value (NPV), positive predictive value, positive-negative likelihood ratio of hrHPV-DNA test, and 5-year relative risk of cervical intraepithelial neoplasia grade 2 in hrHPV-DNA+. Colposcopy is still considered the best choice for women with L-SIL and hrHPV-DNA+ test. High sensitivity and NPV of hrHPV-DNA test permit to use it in the follow-up of L-SIL with a HPV-negative status, without necessity of referring to colposcopy. PMID- 23744883 TI - Increased levels of cell-free human placental lactogen mRNA at 28-32 gestational weeks in plasma of pregnant women with placenta previa and invasive placenta. AB - We compared the levels of cell-free human placental lactogen (hPL) messenger RNA (mRNA) in maternal plasma at 28 to 32 weeks of gestation between women with diagnosis of placenta previa or invasive placenta and women with an uneventful pregnancy. Sensitivity and specificity of hPL mRNA for the prediction of invasive placenta were further explored. Plasma hPL mRNA were quantified by real-time reverse-transcriptase polymerase chain reaction in women with placenta previa (n = 13), invasive placenta (n = 5), and normal pregnancies (n = 92). Median (range) hPL mRNA was significantly higher in women with placenta previa, 782 (10-2301) copies/mL of plasma, and in those with invasive placenta, 615 (522-2102) copies/mL of plasma, when compared to normal pregnancies, 90 (4-4407) copies/mL of plasma, P < .01 and P < .05, respectively. We found a sensitivity of 100% and a specificity of 61.5% for the prediction of invasive placenta among women with placenta previa. In conclusion, expression of hPL mRNA is increased in plasma of women with placenta previa and invasive placenta at 28 to 32 weeks of gestation. PMID- 23744884 TI - Effects of nanoparticle zinc oxide on emotional behavior and trace elements homeostasis in rat brain. AB - Over recent years, nanotoxicology and the potential effects on human body have grown in significance, the potential influences of nanosized materials on the central nervous system have received more attention. The aim of this study was to determine whether zinc oxide (ZnO) nanoparticles (NPs) exposure cause alterations in emotional behavior and trace elements homeostasis in rat brain. Rats were treated by intraperitoneal injection of ZnO NPs (20-30 nm) at a dose of 25 mg/kg body weight. Sub -: acute ZnO NPs treatment induced no significant increase in the zinc content in the homogenate brain. Statistically significant decreases in iron and calcium concentrations were found in rat brain tissue compared to control. However, sodium and potassium contents remained unchanged. Also, there were no significant changes in the body weight and the coefficient of brain. In the present study, the anxiety-related behavior was evaluated using the plus-maze test. ZnO NPs treatment modulates slightly the exploratory behaviors of rats. However, no significant differences were observed in the anxious index between ZnO NP-treated rats and the control group (p > 0.05). Interestingly, our results demonstrated minimal effects of ZnO NPs on emotional behavior of animals, but there was a possible alteration in trace elements homeostasis in rat brain. PMID- 23744885 TI - Temporal trends in fracture rates and postdischarge outcomes among hemodialysis patients. AB - Patients with ESRD have a substantially increased risk of bone fractures, but the burden of fractures has not been sufficiently characterized in this population. Here, we analyzed fracture rates and postdischarge outcomes using Medicare data from hemodialysis patients in the United States between 2000 and 2009. We assessed adjusted quarterly fracture rates (inpatient and outpatient) and consequences of postfracture hospitalization for seven categories of fracture location. Pelvis/hip, vertebral, and lower leg fractures were the most prevalent fracture types. Pelvis/hip fractures declined slightly from 29.6 to 20.6 per 1000 patient-years between early 2000 and late 2009, but the incidence rates for all other fracture types remained relatively constant. Median lengths of stay for the primary fracture hospitalization ranged from 5 days (interquartile range [IQR], 3 9 days) for forearm/wrist fractures to 8 days (IQR, 5-12 days) for femur fractures. The proportion of patients discharged from the primary hospitalization to a skilled-nursing facility ranged from 28% (ribs/sternum) to 47% (pelvis/hip). A negative binomial regression model suggested that patients had an adjusted mean of 3.8-5.2 additional hospitalizations during the year after discharge from the index hospitalization, varying by fracture type, comprising a mean of 33-52 inpatient days. Case-mix-adjusted mortality rates after discharge ranged from 0.43 to 0.91 per patient-year and were highest for vertebral, pelvis/hip, and femur fractures. In conclusion, fractures in the dialysis population are common and are associated with a substantially increased risk for death and hospitalization. PMID- 23744886 TI - AqF026 is a pharmacologic agonist of the water channel aquaporin-1. AB - Aquaporin-1 (AQP1) facilitates the osmotic transport of water across the capillary endothelium, among other cell types, and thereby has a substantial role in ultrafiltration during peritoneal dialysis. At present, pharmacologic agents that enhance AQP1-mediated water transport, which would be expected to increase the efficiency of peritoneal dialysis, are not available. Here, we describe AqF026, an aquaporin agonist that is a chemical derivative of the arylsulfonamide compound furosemide. In the Xenopus laevis oocyte system, extracellular AqF026 potentiated the channel activity of human AQP1 by >20% but had no effect on channel activity of AQP4. We found that the intracellular binding site for AQP1 involves loop D, a region associated with channel gating. In a mouse model of peritoneal dialysis, AqF026 enhanced the osmotic transport of water across the peritoneal membrane but did not affect the osmotic gradient, the transport of small solutes, or the localization and expression of AQP1 on the plasma membrane. Furthermore, AqF026 did not potentiate water transport in Aqp1-null mice, suggesting that indirect mechanisms involving other channels or transporters were unlikely. Last, in a mouse gastric antrum preparation, AqF026 did not affect the Na-K-Cl cotransporter NKCC1. In summary, AqF026 directly and specifically potentiates AQP1-mediated water transport, suggesting that it deserves additional investigation for applications such as peritoneal dialysis or clinical situations associated with defective water handling. PMID- 23744889 TI - ASN presidential address 2012: Time to cure kidney disease. PMID- 23744888 TI - Adult renal mesenchymal stem cell-like cells contribute to juxtaglomerular cell recruitment. AB - The renin-angiotensin-aldosterone system (RAAS) regulates BP and salt-volume homeostasis. Juxtaglomerular (JG) cells synthesize and release renin, which is the first and rate-limiting step in the RAAS. Intense pathologic stresses cause a dramatic increase in the number of renin-producing cells in the kidney, termed JG cell recruitment, but how this occurs is not fully understood. Here, we isolated renal CD44(+) mesenchymal stem cell (MSC)-like cells and found that they differentiated into JG-like renin-expressing cells both in vitro and in vivo. Sodium depletion and captopril led to activation and differentiation of these cells into renin-expressing cells in the adult kidney. In summary, CD44(+) MSC like cells exist in the adult kidney and can differentiate into JG-like renin producing cells under conditions that promote JG cell recruitment. PMID- 23744887 TI - Ouabain protects against Shiga toxin-triggered apoptosis by reversing the imbalance between Bax and Bcl-xL. AB - Hemolytic uremic syndrome, a life-threatening disease often accompanied by acute renal failure, usually occurs after gastrointestinal infection with Shiga toxin 2 (Stx2)-producing Escherichia coli. Stx2 binds to the glycosphingolipid globotriaosylceramide receptor, expressed by renal epithelial cells, and triggers apoptosis by activating the apoptotic factor Bax. Signaling via the ouabain/Na,K ATPase/IP3R/NF-kappaB pathway increases expression of Bcl-xL, an inhibitor of Bax, suggesting that ouabain might protect renal cells from Stx2-triggered apoptosis. Here, exposing rat proximal tubular cells to Stx2 in vitro resulted in massive apoptosis, upregulation of the apoptotic factor Bax, increased cleaved caspase-3, and downregulation of the survival factor Bcl-xL; co-incubation with ouabain prevented all of these effects. Ouabain activated the NF-kappaB antiapoptotic subunit p65, and the inhibition of p65 DNA binding abolished the antiapoptotic effect of ouabain in Stx2-exposed tubular cells. Furthermore, in vivo, administration of ouabain reversed the imbalance between Bax and Bcl-xL in Stx2-treated mice. Taken together, these results suggest that ouabain can protect the kidney from the apoptotic effects of Stx2. PMID- 23744891 TI - An early prediction of delirium in the acute phase after stroke. AB - BACKGROUND: We developed and validated a risk score to predict delirium after stroke which was derived from our prospective cohort study where several risk factors were identified. METHODS: Using the beta coefficients from the logistic regression model, we allocated a score to values of the risk factors. In the first model, stroke severity, stroke subtype, infection, stroke localisation, pre existent cognitive decline and age were included. The second model included age, stroke severity, stroke subtype and infection. A third model only included age and stroke severity. The risk score was validated in an independent dataset. RESULTS: The area under the curve (AUC) of the first model was 0.85 (sensitivity 86%, specificity 74%). In the second model, the AUC was 0.84 (sensitivity 80%, specificity 75%). The third model had an AUC of 0.80 (sensitivity 79%, specificity 73%). In the validation set, model 1 had an AUC of 0.83 (sensitivity 78%, specificity 77%). The second had an AUC of 0.83 (sensitivity 76%, specificity 81%). The third model gave an AUC of 0.82 (sensitivity of 73%, specificity 75%). We conclude that model 2 is easy to use in clinical practice and slightly better than model 3 and, therefore, was used to create risk tables to use as a tool in clinical practice. CONCLUSIONS: A model including age, stroke severity, stroke subtype and infection can be used to identify patients who have a high risk to develop delirium in the early phase of stroke. PMID- 23744890 TI - Novel SOD1 mutation discovered in atypical ALS by whole exome sequencing. PMID- 23744892 TI - Characterising aggressive multiple sclerosis. AB - OBJECTIVE: To explore the occurrence and characteristics of aggressive multiple sclerosis (AMS) in adult-onset multiple sclerosis (MS) patients. METHODS: Prospectively collected data (1980-2009) from British Columbia, Canada, were retrospectively analysed. AMS was defined in three different ways (AMS1, 2 and 3): 'AMS1'--confirmed Expanded Disability Status Scale (EDSS) >= 6 within 5 years of MS onset; 'AMS2'--confirmed EDSS >= 6 by age 40; and 'AMS3'--secondary progressive MS within 3 years of a relapsing-onset course. Three respective 'non aggressive' MS comparison cohorts were selected. Patients' characteristics were compared between aggressive and non-aggressive cohorts using multivariable logistic regression, with findings expressed as adjusted OR (AOR) and 95% CI. RESULTS: Application of the three definitions to the source population of 5891 patients resulted in 235/4285 (5.5%) patients fulfilling criteria for AMS1 (59.6% were female; 74.5% had relapsing-onset MS), 388/2762 (14.0%) for AMS2 (65.2% were female; 92.8% had relapsing-onset MS) and 195/4918 (4.0%) patients for AMS3 (61.0% were female). Compared to the respective control cohorts, those with AMS were more likely to be male (AOR=1.5, 95% CI 1.1 to 2.0 (AMS1); 1.6, 95% CI 1.3 to 2.1 (AMS2); 1.8, 95% CI 1.3 to 2.4 (AMS3)), older at MS symptom onset (AOR=1.1; 95% CI 1.1 to 1.1 (AMS1 and AMS3)) and have primary progressive MS (AOR=2.3, 95% CI 1.6 to 3.3 (AMS1); 2.7, 95% CI 1.7 to 4.4 (AMS2)). CONCLUSIONS: AMS was identified in 4-14% of patients, depending on the definition used. Although there was a relative preponderance of men and primary progressive MS presenting with AMS, the majority of patients were still women and those with relapsing-onset MS. PMID- 23744893 TI - PAK1 regulates breast cancer cell invasion through secretion of matrix metalloproteinases in response to prolactin and three-dimensional collagen IV. AB - p21-Activated serine-threonine kinase (PAK1) is implicated in breast cancer. We have shown previously that PAK1 is tyrosyl phosphorylated by prolactin (PRL) activated Janus tyrosine kinase (JAK2). Although a role for both PRL and PAK1 in breast cancer is widely acknowledged, the mechanism remains poorly understood. In the present study, PRL-activated PAK1 stimulates the invasion of TMX2-28 human breast cancer cells through Matrigel. Three-dimensional (3D) collagen IV stimulates the secretion of the matrix proteases, metalloproteinase (MMP)-1 and 3 that is further enhanced by the PRL-dependent tyrosyl phosphorylation of PAK1. 3D collagen IV also stimulates the expression and secretion of MMP-2, but in contrast to MMP-1 and -3, PRL/PAK1 signaling down-regulates MMP-2 expression and secretion. In contrast, MMP-9 expression and secretion are stimulated by 3D collagen I, not collagen IV, and are not affected by PRL but are down-regulated by PAK1. MMP-1 and -3 are required and MMP-2 contributes to PRL-dependent invasion. ERK1/2 signaling appears to be required for the enhanced expression and secretion of MMP-1 and -3 and enhanced PRL-dependent invasion. p38 MAPK and c-Jun N-terminal kinase 1/2 pathways participate in production of MMP-1 and -3 as well as in PRL/PAK1-dependent cell invasion. Together, these data illustrate the complex interaction between the substratum and PRL/PAK1 signaling in human breast cancer cells and suggest a pivotal role for PRL-dependent PAK1 tyrosyl phosphorylation in MMP secretion. PMID- 23744895 TI - How does vitrification affect oocyte viability in oocyte donation cycles? A prospective study to compare outcomes achieved with fresh versus vitrified sibling oocytes. AB - STUDY QUESTION: How does vitrification affect oocyte viability? SUMMARY ANSWER: Vitrification does not affect oocyte viability in oocyte donation cycles. WHAT IS KNOWN ALREADY: Oocyte vitrification is performed routinely and successfully in IVF and oocyte donation programs. STUDY DESIGN, SIZE, DURATION: This is a prospective study performed between June 2009 and February 2012 to compare ongoing pregnancy rates and other indices of viability between fresh and vitrified oocytes. A total of 99 donations with more than 16 oocytes (MII) in which oocytes were allocated both to a synchronous recipient (fresh oocytes) and to an asynchronous recipient (vitrified oocytes) were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: The participants were consenting couples (donors and recipients) from the oocyte donation program. On the day of retrieval, the oocytes allocated to the synchronous recipient were inseminated and those allocated for banking were denuded of cumulus and vitrified. Vitrified oocytes were microinjected with spermatozoa 2 h after warming. Embryo transfer was performed on Day 2 of development in both groups, and the remaining embryos were cryopreserved on Day 3. Clinical pregnancy was defined by a positive fetal heartbeat at 6 weeks. MAIN RESULTS AND ROLE OF CHANCE: A total of 989 oocytes were warmed and 85.6% survived. No significant differences were observed between fresh and vitrified oocytes: fertilization rate (80.7 versus 78.2%), ongoing embryo rate (71.0 versus 68.2%) or good-quality embryo rate (54.1 versus 49.8%). The mean number of embryos transferred was similar in both groups (1.82 +/- 0.44 versus 1.90 +/- 0.34). The implantation rate (33.3 versus 34.0%) and the multiple pregnancy rate (27.7 versus 20.8) were also similar between both groups (P > 0.05). The live birth rate per cycle was 38.4% in the recipients of fresh oocytes and 43.4% in the recipients of vitrified oocytes (P > 0.05). Eighty five frozen embryo transfers were also evaluated. Comparing embryos from fresh and vitrified oocytes there were no significant differences in the embryo survival rate (70.1 versus 65.8%), clinical pregnancy rate (40.8 versus 33.3%) or implantation rate (21.8 versus 26.8%). LIMITATIONS, REASONS FOR CAUTION: The oocytes were donated by healthy, young women (<=35 years) and these results cannot be extrapolated to other populations. WIDER IMPLICATIONS OF THE FINDINGS: Outcomes obtained with vitrified oocytes are as good as with fresh oocytes and the use of vitrification can be extended to new applications, e.g. accumulation of oocytes from successive stimulations for preimplantation genetic diagnosis, for patients at risk of ovarian hyperstimulation syndrome or in patients needing to preserve their fertility. STUDY FUNDING/COMPETING INTEREST(S): This work was done under the auspices of the Catedra d'Investigacio en Obstetricia i Ginecologia of the Universitat Autonoma de Barcelona. PMID- 23744894 TI - Minireview: Dopaminergic regulation of insulin secretion from the pancreatic islet. AB - Exogenous dopamine inhibits insulin secretion from pancreatic beta-cells, but the lack of dopaminergic neurons in pancreatic islets has led to controversy regarding the importance of this effect. Recent data, however, suggest a plausible physiologic role for dopamine in the regulation of insulin secretion. We review the literature underlying our current understanding of dopaminergic signaling that can down-regulate glucose-stimulated insulin secretion from pancreatic islets. In this negative feedback loop, dopamine is synthesized in the beta-cells from circulating L-dopa, serves as an autocrine signal that is cosecreted with insulin, and causes a tonic inhibition on glucose-stimulated insulin secretion. On the whole animal scale, L-dopa is produced by cells in the gastrointestinal tract, and its concentration in the blood plasma increases following a mixed meal. By reviewing the outcome of certain types of bariatric surgery that result in rapid amelioration of glucose tolerance, we hypothesize that dopamine serves as an "antiincretin" signal that counterbalances the stimulatory effect of glucagon-like peptide 1. PMID- 23744896 TI - Four different strategies for repair of aortic coarctation accompanied by cardiac lesions. AB - OBJECTIVES: Coarctation accompanied by cardiac lesions is a complex clinical situation due to the presence of two different pathologies that necessitate surgical treatment. An individual strategy, according to the severity of the disease, is important to reduce perioperative mortality and morbidity. METHODS: We report here on 25 patients with coarctation accompanied by cardiac lesions who were treated by various surgical approaches. Coarctation and associated disease were treated in 14 patients in a single stage by an ascending-to-descending bypass (n = 11) or by a hybrid procedure (n = 3). The remaining 11 patients underwent a two-stage operation for their treatment. Six of these 11 patients who had coronary artery disease or signs of congestive heart failure were first operated for their cardiac disease, whereas in the remaining five patients, who did not have any congestive signs, coarctation repair was performed first. RESULTS: All the patients were male, between the ages of 20 and 24 years, except for one 45-year-old woman. The mean cross-clamp times, cardiopulmonary bypass times and operation times were 52 +/- 14.5, 102.3 +/- 28.5 and 174 +/- 24.8 min in the extra-anatomical bypass group; 29.8 +/- 11.7, 55.5 +/- 17.6 and 116 +/- 22 min in the two-stage groups and 49 +/- 19.8, 63 +/- 18.7 and 159 +/- 21.3 min in the hybrid patients, respectively. One patient who underwent extra-anatomical bypass died on the 14th postoperative day. There were no events during the follow up period for the other patients. Also, there were no gradients between the extremities and no graft-related complications. CONCLUSIONS: As a consequence of the progress in the development of endovascular techniques, hybrid treatment is becoming a more popular option for the treatment of coarctation accompanied by cardiac diseases. Two-stage procedures and extra-anatomical bypass might be alternative techniques if endovascular procedures are contraindicated or failing. PMID- 23744901 TI - Synthetic biology: biology by design. PMID- 23744902 TI - Phage insertion in mlrA and variations in rpoS limit curli expression and biofilm formation in Escherichia coli serotype O157: H7. AB - Biofilm formation in Escherichia coli is a tightly controlled process requiring the expression of adhesive curli fibres and certain polysaccharides such as cellulose. The transcriptional regulator CsgD is central to biofilm formation, controlling the expression of the curli structural and export proteins and the diguanylate cyclase adrA, which indirectly activates cellulose production. CsgD itself is highly regulated by two sigma factors (RpoS and RpoD), multiple DNA binding proteins, small regulatory RNAs and several GGDEF/EAL proteins acting through c-di-GMP. One such transcription factor MlrA binds the csgD promoter to enhance the RpoS-dependent transcription of csgD. Bacteriophage, often carrying the stx1 gene, utilize an insertion site in the proximal mlrA coding region of E. coli serotype O157 : H7 strains, and the loss of mlrA function would be expected to be the major factor contributing to poor curli and biofilm expression in that serotype. Using a bank of 55 strains of serotype O157 : H7, we investigated the consequences of bacteriophage insertion. Although curli/biofilm expression was restored in many of the prophage-bearing strains by a wild-type copy of mlrA on a multi-copy plasmid, more than half of the strains showed only partial or no complementation. Moreover, the two strains carrying an intact mlrA were found to be deficient in biofilm formation. However, RpoS mutations that attenuated or inactivated RpoS-dependent functions such as biofilm formation were found in >70 % of the strains, including the two strains with an intact mlrA. We conclude that bacteriophage interruption of mlrA and RpoS mutations provide major obstacles limiting curli expression and biofilm formation in most serotype O157 : H7 strains. PMID- 23744904 TI - Dissecting the role of G-protein signalling in primary metabolism in the wheat pathogen Stagonospora nodorum. AB - Mutants of the wheat pathogenic fungus Stagonospora nodorum lacking G-protein subunits display a variety of phenotypes including melanization defects, primary metabolic changes and a decreased ability to sporulate. To better understand the causes of these phenotypes, Stagonospora nodorum strains lacking a Galpha, Gbeta or Ggamma subunit were compared to a wild-type strain using metabolomics. Agar plate growth at 22 degrees C revealed a number of fundamental metabolic changes and highlighted the influential role of these proteins in glucose utilization. A further characterization of the mutants was undertaken during prolonged storage at 4 degrees C, conditions known to induce sporulation in these sporulation deficient signalling mutants. The abundance of several compounds positively correlated with the onset of sporulation including the dissacharide trehalose, the tryptophan degradation product tryptamine and the secondary metabolite alternariol; metabolites all previously associated with sporulation. Several other compounds decreased or were absent during sporulation. The levels of one such compound (Unknown_35.27_2194_319) decreased from being one of the more abundant compounds to absence during pycnidial maturation. This study has shed light on the role of G-protein subunits in primary metabolism during vegetative growth and exploited the cold-induced sporulation phenomenon in these mutants to identify some key metabolic changes that occur during asexual reproduction. PMID- 23744903 TI - The type 1 pili regulator gene fimX and pathogenicity island PAI-X as molecular markers of uropathogenic Escherichia coli. AB - Uropathogenic Escherichia coli (UPEC) fall within a larger group of isolates producing extraintestinal disease. UPEC express type 1 pili as a critical virulence determinant mediating adherence to and invasion into urinary tract tissues. Type 1 pili expression is under regulation by a family of site-specific recombinases, including FimX, which is encoded from a genomic island called PAI-X for pathogenicity island of FimX. Using a new multiplex PCR, fimX and the additional PAI-X genes were found to be highly associated with UPEC (144/173 = 83.2 %), and more prevalent in UPEC of lower urinary tract origin (105/120 = 87.5 %) than upper urinary tract origin (39/53 = 74 %; P<0.05) or commensal isolates (28/78 = 36 %; P<=0.0001). The Fim-like recombinase gene fimX is the only family member that has a significant association with UPEC compared to commensal isolates. Our results indicate PAI-X genes, including the type 1 pili regulator gene fimX, are highly prevalent among UPEC isolates and have a strong positive correlation with genomic virulence factors, suggesting a potential role for PAI-X in the extraintestinal pathogenic E. coli lifestyle. PMID- 23744905 TI - Genomic and proteomic characterization of Gordonia sp. NB4-1Y in relation to 6 : 2 fluorotelomer sulfonate biodegradation. AB - Gordonia sp. strain NB4-1Y was isolated from vermicompost using bis-(3 pentafluorophenylpropyl)-sulfide as the sole added sulfur source and was found to have a broad capacity for metabolizing organosulfur compounds. NB4-1Y is closely related to G. desulfuricans and was found to metabolize 6 : 2 fluorotelomer sulfonate (6 : 2 FTS) to 5 : 3 fluorotelomer acid (5 : 3 acid) via 6 : 2 fluorotelomer acid (6 : 2 FTCA), 6 : 2 unsaturated fluorotelomer acid (6 : 2 FTUCA) and 5 : 3 unsaturated fluorotelomer acid (5 : 3 Uacid). Given that the molecular and biochemical basis for the microbial metabolism of poly- and per fluorinated compounds has yet to be examined, we undertook to investigate 6 : 2 FTS metabolism in NB4-1Y. To this end, a whole-genome shotgun sequence was prepared and two-dimensional differential in-gel electrophoresis was used to compare proteomes of MgSO4- and 6 : 2 FTS-grown cells. Of the three putative alkanesulfonate monooxygenases, four nitrilotriacetate monooxygenases and one taurine dioxygenase located in the draft genome, two nitrilotriacetate monooxygenases were differentially expressed in the presence of 6 : 2 FTS. It is hypothesized that these two enzymes may be responsible for 6 : 2 FTS desulfonation. In addition, a differentially expressed putative double bond reductase may be involved in the reduction of 5 : 3 Uacid to 5 : 3 acid. Other proteins differentially expressed during 6 : 2 FTS metabolism included a sulfate ABC transporter ATP-binding protein and two alkyl hydroperoxide reductases. This work establishes a foundation for future studies on the molecular biology and biochemistry of poly- and per-fluorinated compound metabolism in bacteria. PMID- 23744906 TI - Use of a fluoroscopic overlay to assist arthroscopic anterior cruciate ligament reconstruction. AB - BACKGROUND: A growing body of evidence supports the importance of anatomic tunnel positioning in the success of anterior cruciate ligament (ACL) reconstruction, which stimulates the need for technologies to aid surgeons in achieving accurate anatomic tunnel placement. Intraoperative fluoroscopy is potentially one such technology, while its efficacy and usability have yet to be established. PURPOSE: To investigate the performance of an intraoperative fluoroscopic overlay in guiding tunnel placement during ACL reconstruction. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty cadaveric knees underwent computed tomography (CT) scans and arthroscopic digitization of ACL insertion sites. The outlines of the digitized insertion sites were mapped to the corresponding CT-acquired bone models through a co-registration procedure. Twenty orthopaedic surgeons performed simulated ACL reconstructions, each on a randomly assigned cadaveric knee, first without and then with the aid of a fluoroscopic overlay system. The overlay system displayed on a lateral fluoroscopic image targets points representing the locations of the ACL insertion sites estimated from the literature data. Surgeons were allowed to adjust their tunnel positions under the guidance of the fluoroscopic image. Their initial, intermediate, and final positions were documented and compared with the target points as well as the native insertion sites. RESULTS: Surgeons demonstrated significant (P < .01) improvements in femoral and tibial tunnel placements relative to the target points from an average distance of 3.9 mm to 1.6 mm on the femur and 2.1 mm to 0.9 mm on the tibia. The improvements toward the knee-specific actual insertion sites were significant on the tibial side but not on the femoral side. CONCLUSION: Surgeons can be successfully guided with fluoroscopy to create more consistent femoral and tibial tunnels during ACL reconstruction. More research is warranted to develop better population representations of the locations of natural insertion sites. CLINICAL RELEVANCE: Intraoperative fluoroscopy can be an effective, easy, and safe method for improving tunnel positioning during ACL reconstruction. PMID- 23744907 TI - A prospective study of the association between bone contusion and intra-articular injuries associated with acute anterior cruciate ligament tear. AB - BACKGROUND: Bone bruising, commonly found on magnetic resonance imaging (MRI) after anterior cruciate ligament (ACL) injury, may be associated with intra articular injuries, but little is known about this association. PURPOSE: To examine demographic factors and intra-articular injuries associated with bone bruising in patients undergoing ACL reconstruction. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Patients with ACL injury who had an MRI within 6 weeks and arthroscopy within 3 months of injury were included in this prospective study (N = 171). Presence and severity of bone bruising were determined from preoperative MRIs for each anatomic site: lateral femoral condyle (LFC), lateral tibial plateau (LTP), medial femoral condyle (MFC), and medial tibial plateau (MTP). Multiple logistic regression was used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for predictors of bruising and associations between bruising and intra-articular injuries found during arthroscopy. Outcomes included the presence of bruising and severity of lateral bruising (mild, moderate, severe vs none/minimal bruising). RESULTS: Frequencies of bone bruising were as follows: 85% LTP, 77% LFC, 26% MTP, and 6% MFC. Patient age between 18 and 28 years (OR, 0.27; 95% CI, 0.09-0.82) and 29 years and older (OR, 0.18; 95% CI, 0.05-0.61) predicted less LFC bruising compared with patients aged 17 years and younger. Age (18-28 years: OR, 0.15; 95% CI, 0.03-0.66; >=29 years: OR, 0.10; 95% CI, 0.02-0.68) and contact injuries (OR, 0.17; 95% CI, 0.04 0.78) predicted less moderate LFC bruising. Male sex predicted mild (OR, 6.16; 95% CI, 1.44-26.43), moderate (OR, 8.98; 95% CI, 1.96-41.19), and severe (OR, 15.66; 95% CI, 3.19-76.92) LFC bruising. Male sex also predicted mild LTP bruising (OR, 0.19; 95% CI, 0.05-0.83), and contact injuries predicted severe LTP bruising (OR, 5.01; 95% CI, 1.21-20.67). LFC bruising (OR, 2.57; 95% CI, 1.04 6.32) and LTP bruising (OR, 3.13; 95% CI, 1.06-9.23) were associated with lateral meniscal tears. Moderate (OR, 8.14; 95% CI, 1.93-34.27) and severe (OR, 15.30; 95% CI, 2.34-100.10) LTP bruising was associated with medial meniscal tears. MFC bruising and MTP bruising were not associated with any predictors or intra articular injuries. CONCLUSION: Bone bruising is more common and severe in young men, and lateral bone bruising is associated with lateral meniscal tears. Medial meniscal tears are associated with increased severity of LTP bruising. PMID- 23744909 TI - Passing the baton. PMID- 23744914 TI - Particle physics. Europe opens door to global approach on megaprojects. PMID- 23744908 TI - Genome-wide analysis reveals origin of transfer RNA genes from tRNA halves. AB - Transfer RNAs (tRNAs) play an important role linking mitochondrial RNA and amino acids during protein biogenesis. Four types of tRNA genes have been identified in living organisms. However, the evolutionary origin of tRNAs remains largely unknown. In this article, we conduct a deep sequence analysis of diverse genomes that cover all three domains of life to unveil the evolutionary history of tRNA genes from tRNA halves. tRNA half homologs were detected in diverse organisms, and some of them were expressed in mouse tissues. Continuous tRNA genes have a conserved pattern similar to indels, which is, more closely flanking regions have higher single nucleotide substitution rates, whereas tRNA half homologs do not have this pattern. In addition, tRNAs tend to break into tRNA halves when tissues are incubated in vitro, the tendency of tRNA to break into tRNA halves may be a "side-effect" of tRNA genes evolving from tRNA halves. These results suggest that modern tRNAs originated from tRNA halves through a repeat element-mediated mechanism. These findings provide insight into the evolutionary origin of tRNA genes. PMID- 23744915 TI - Russia. Fading academy stakes future on reforming president. PMID- 23744916 TI - Paleontology. Authenticity of China's fabulous fossils gets new scrutiny. PMID- 23744917 TI - Radiation safety. Accelerator leak halts Japanese physics experiments. PMID- 23744918 TI - Mysteries of development. PMID- 23744919 TI - Mysteries of development. How do organs know when they have reached the right size? PMID- 23744920 TI - Mysteries of development. Why do so many neurons commit suicide during brain development? PMID- 23744921 TI - Mysteries of development. How do microbes shape animal development? PMID- 23744923 TI - Mysteries of development. Under development. PMID- 23744922 TI - Mysteries of development. How does fetal environment influence later health? PMID- 23744924 TI - Bioelectronics. The cyborg era begins. PMID- 23744925 TI - Rhino poaching: supply and demand uncertain. PMID- 23744926 TI - Rhino poaching: unique challenges. PMID- 23744927 TI - Rhino poaching: apply conservation psychology. PMID- 23744928 TI - Rhino poaching: supply and demand uncertain--response. PMID- 23744930 TI - Science and regulation. Uncapping conflict of interest? PMID- 23744931 TI - Neuroscience. Illuminating the neural circuitry of compulsive behaviors. PMID- 23744932 TI - Physics. Interfacing atoms and light--the smaller the stronger. PMID- 23744933 TI - Microbiology. Seas of superoxide. PMID- 23744934 TI - Mathematics. Bayes' theorem in the 21st century. PMID- 23744935 TI - Astronomy. A trap for planet formation. PMID- 23744936 TI - Neuroscience. What the bomb said about the brain. PMID- 23744937 TI - Developmental biology. Deserts and waves in gene expression. PMID- 23744938 TI - Morphogenesis. Getting into shape. Introduction. PMID- 23744939 TI - Mechanics of epithelial tissue homeostasis and morphogenesis. AB - Epithelia are robust tissues that support the structure of embryos and organs and serve as effective barriers against pathogens. Epithelia also chemically separate different physiological environments. These vital functions require tight association between cells through the assembly of junctions that mechanically stabilize the tissue. Remarkably, epithelia are also dynamic and can display a fluid behavior. Cells continuously die or divide, thereby allowing functional tissue homeostasis. Epithelial cells can change shape or intercalate as tissues deform during morphogenesis. We review the mechanical basis of tissue robustness and fluidity, with an emphasis on the pivotal role of junction dynamics. Tissue fluidity emerges from local active stresses acting at cell interfaces and allows the maintenance of epithelial organization during morphogenesis and tissue renewal. PMID- 23744940 TI - Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. AB - Recent examples have highlighted how stem cells have the capability to initiate morphogenesis in vitro; that is, to generate complex structures in culture that closely parallel their in vivo counterparts. Lgr5, the receptor for the Wnt agonistic R-spondins, marks stem cells in multiple adult organs of mice and humans. In R-spondin-based three-dimensional cultures, these Lgr5 stem cells can grow into ever-expanding epithelial organoids that retain their original organ identity. Single Lgr5 stem cells derived from the intestine can be cultured to build epithelial structures that retain hallmarks of the in vivo epithelium. Here, we review the mechanisms that support this notable example of self organization and discuss applications of this technology for stem cell research, disease modeling (e.g., for colorectal cancer and cystic fibrosis), and regenerative medicine. PMID- 23744941 TI - Probing the solar magnetic field with a Sun-grazing comet. AB - On 15 and 16 December 2011, Sun-grazing comet C/2011 W3 (Lovejoy) passed deep within the solar corona, effectively probing a region that has never been visited by spacecraft. Imaged from multiple perspectives, extreme ultraviolet observations of Lovejoy's tail showed substantial changes in direction, intensity, magnitude, and persistence. To understand this unique signature, we combined a state-of-the-art magnetohydrodynamic model of the solar corona and a model for the motion of emitting cometary tail ions in an embedded plasma. The observed tail motions reveal the inhomogeneous magnetic field of the solar corona. We show how these motions constrain field and plasma properties along the trajectory, and how they can be used to meaningfully distinguish between two classes of magnetic field models. PMID- 23744942 TI - A major asymmetric dust trap in a transition disk. AB - The statistics of discovered exoplanets suggest that planets form efficiently. However, there are fundamental unsolved problems, such as excessive inward drift of particles in protoplanetary disks during planet formation. Recent theories invoke dust traps to overcome this problem. We report the detection of a dust trap in the disk around the star Oph IRS 48 using observations from the Atacama Large Millimeter/submillimeter Array (ALMA). The 0.44-millimeter-wavelength continuum map shows high-contrast crescent-shaped emission on one side of the star, originating from millimeter-sized grains, whereas both the mid-infrared image (micrometer-sized dust) and the gas traced by the carbon monoxide 6-5 rotational line suggest rings centered on the star. The difference in distribution of big grains versus small grains/gas can be modeled with a vortex shaped dust trap triggered by a companion. PMID- 23744943 TI - Entanglement polytopes: multiparticle entanglement from single-particle information. AB - Entangled many-body states are an essential resource for quantum computing and interferometry. Determining the type of entanglement present in a system usually requires access to an exponential number of parameters. We show that in the case of pure, multiparticle quantum states, features of the global entanglement can already be extracted from local information alone. This is achieved by associating any given class of entanglement with an entanglement polytope-a geometric object that characterizes the single-particle states compatible with that class. Our results, applicable to systems of arbitrary size and statistics, give rise to local witnesses for global pure-state entanglement and can be generalized to states affected by low levels of noise. PMID- 23744944 TI - From sub-Rayleigh to supershear ruptures during stick-slip experiments on crustal rocks. AB - Supershear earthquake ruptures propagate faster than the shear wave velocity. Although there is evidence that this occurs in nature, it has not been experimentally demonstrated with the use of crustal rocks. We performed stick slip experiments with Westerly granite under controlled upper-crustal stress conditions. Supershear ruptures systematically occur when the normal stress exceeds 43 megapascals (MPa) with resulting stress drops on the order of 3 to 25 MPa, comparable to the stress drops inferred by seismology for crustal earthquakes. In our experiments, the sub-Rayleigh-to-supershear transition length is a few centimeters at most, suggesting that the rupture of asperities along a fault may propagate locally at supershear velocities. In turn, these sudden accelerations and decelerations could play an important role in the generation of high-frequency radiation and the overall rupture-energy budget. PMID- 23744945 TI - Stepwise evolution of essential centromere function in a Drosophila neogene. AB - Evolutionarily young genes that serve essential functions represent a paradox; they must perform a function that either was not required until after their birth or was redundant with another gene. How young genes rapidly acquire essential function is largely unknown. We traced the evolutionary steps by which the Drosophila gene Umbrea acquired an essential role in chromosome segregation in D. melanogaster since the gene's origin less than 15 million years ago. Umbrea neofunctionalization occurred via loss of an ancestral heterochromatin-localizing domain, followed by alterations that rewired its protein interaction network and led to species-specific centromere localization. Our evolutionary cell biology approach provides temporal and mechanistic detail about how young genes gain essential function. Such innovations may constantly alter the repertoire of centromeric proteins in eukaryotes. PMID- 23744946 TI - Structural systems biology evaluation of metabolic thermotolerance in Escherichia coli. AB - Genome-scale network reconstruction has enabled predictive modeling of metabolism for many systems. Traditionally, protein structural information has not been represented in such reconstructions. Expansion of a genome-scale model of Escherichia coli metabolism by including experimental and predicted protein structures enabled the analysis of protein thermostability in a network context. This analysis allowed the prediction of protein activities that limit network function at superoptimal temperatures and mechanistic interpretations of mutations found in strains adapted to heat. Predicted growth-limiting factors for thermotolerance were validated through nutrient supplementation experiments and defined metabolic sensitivities to heat stress, providing evidence that metabolic enzyme thermostability is rate-limiting at superoptimal temperatures. Inclusion of structural information expanded the content and predictive capability of genome-scale metabolic networks that enable structural systems biology of metabolism. PMID- 23744947 TI - Structural basis for effector control and redox partner recognition in cytochrome P450. AB - Cytochromes P450 catalyze a variety of monooxygenase reactions that require electron transfer from redox partners. Although the structure of many P450s and a small handful of redox partners are known, there is very little structural information available on redox complexes, thus leaving a gap in our understanding on the control of P450-redox partner interactions. We have solved the crystal structure of oxidized and reduced P450cam complexed with its redox partner, putidaredoxin (Pdx), to 2.2 and 2.09 angstroms, respectively. It was anticipated that Pdx would favor closed substrate-bound P450cam, which differs substantially from the open conformer, but instead we found that Pdx favors the open state. These new structures indicate that the effector role of Pdx is to shift P450cam toward the open conformation, which enables the establishment of a water-mediated H-bonded network, which is required for proton-coupled electron transfer. PMID- 23744948 TI - Repeated cortico-striatal stimulation generates persistent OCD-like behavior. AB - Although cortico-striato-thalamo-cortical (CSTC) circuit dysregulation is correlated with obsessive compulsive disorder (OCD), causation cannot be tested in humans. We used optogenetics in mice to simulate CSTC hyperactivation observed in OCD patients. Whereas acute orbitofrontal cortex (OFC)-ventromedial striatum (VMS) stimulation did not produce repetitive behaviors, repeated hyperactivation over multiple days generated a progressive increase in grooming, a mouse behavior related to OCD. Increased grooming persisted for 2 weeks after stimulation cessation. The grooming increase was temporally coupled with a progressive increase in light-evoked firing of postsynaptic VMS cells. Both increased grooming and evoked firing were reversed by chronic fluoxetine, a first-line OCD treatment. Brief but repeated episodes of abnormal circuit activity may thus set the stage for the development of persistent psychopathology. PMID- 23744949 TI - Geniculocortical input drives genetic distinctions between primary and higher order visual areas. AB - Studies of area patterning of the neocortex have focused on primary areas, concluding that the primary visual area, V1, is specified by transcription factors (TFs) expressed by progenitors. Mechanisms that determine higher-order visual areas (V(HO)) and distinguish them from V1 are unknown. We demonstrated a requirement for thalamocortical axon (TCA) input by genetically deleting geniculocortical TCAs and showed that they drive differentiation of patterned gene expression that distinguishes V1 and V(HO). Our findings suggest a multistage process for area patterning: TFs expressed by progenitors specify an occipital visual cortical field that differentiates into V1 and V(HO); this latter phase requires geniculocortical TCA input to the nascent V1 that determines genetic distinctions between V1 and V(HO) for all layers and ultimately determines their area-specific functional properties. PMID- 23744950 TI - Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors. AB - Dysfunctions in frontostriatal brain circuits have been implicated in neuropsychiatric disorders, including those characterized by the presence of repetitive behaviors. We developed an optogenetic approach to block repetitive, compulsive behavior in a mouse model in which deletion of the synaptic scaffolding gene, Sapap3, results in excessive grooming. With a delay conditioning task, we identified in the mutants a selective deficit in behavioral response inhibition and found this to be associated with defective down regulation of striatal projection neuron activity. Focused optogenetic stimulation of the lateral orbitofrontal cortex and its terminals in the striatum restored the behavioral response inhibition, restored the defective down regulation, and compensated for impaired fast-spiking neuron striatal microcircuits. These findings raise promising potential for the design of targeted therapy for disorders involving excessive repetitive behavior. PMID- 23744951 TI - A switch between topological domains underlies HoxD genes collinearity in mouse limbs. AB - Hox genes are major determinants of the animal body plan, where they organize structures along both the trunk and appendicular axes. During mouse limb development, Hoxd genes are transcribed in two waves: early on, when the arm and forearm are specified, and later, when digits form. The transition between early and late regulations involves a functional switch between two opposite topological domains. This switch is reflected by a subset of Hoxd genes mapping centrally into the cluster, which initially interact with the telomeric domain and subsequently swing toward the centromeric domain, where they establish new contacts. This transition between independent regulatory landscapes illustrates both the modularity of the limbs and the distinct evolutionary histories of its various pieces. It also allows the formation of an intermediate area of low HOX proteins content, which develops into the wrist, the transition between our arms and our hands. This regulatory strategy accounts for collinear Hox gene regulation in land vertebrate appendages. PMID- 23744952 TI - Imaging morphogenesis: technological advances and biological insights. AB - Morphogenesis, the development of the shape of an organism, is a dynamic process on a multitude of scales, from fast subcellular rearrangements and cell movements to slow structural changes at the whole-organism level. Live-imaging approaches based on light microscopy reveal the intricate dynamics of this process and are thus indispensable for investigating the underlying mechanisms. This Review discusses emerging imaging techniques that can record morphogenesis at temporal scales from seconds to days and at spatial scales from hundreds of nanometers to several millimeters. To unlock their full potential, these methods need to be matched with new computational approaches and physical models that help convert highly complex image data sets into biological insights. PMID- 23744953 TI - The analgesic efficacy of subcostal transversus abdominis plane block compared with thoracic epidural analgesia and intravenous opioid analgesia after radical gastrectomy. AB - BACKGROUND: The transversus abdominis plane (TAP) block has been shown to provide effective postoperative analgesia in lower abdominal surgery. Subcostal TAP block has also been proposed as a new technique to provide analgesia for the supraumbilical abdomen. We compared the analgesic and opioid-sparing effects of a single-injection subcostal TAP block with continuous thoracic epidural analgesia and IV opioid analgesia. METHODS: Ninety patients undergoing elective radical gastrectomy were randomized to receive either combined general-subcostal TAP anesthesia (group TAP), combined general-epidural anesthesia (group EA), or general anesthesia (group GA), and were analyzed on an intention-to-treat basis. In group TAP, a bilateral subcostal TAP block was performed after induction of general anesthesia using 20 mL of 0.375% ropivacaine. In group EA, a thoracic epidural was placed between T8 and T9 and bolused with 8 mL of 0.25% ropivacaine before induction of general anesthesia. The epidural was maintained with 5 mL/h of 0.25% ropivacaine during the surgery. Group GA received standard general anesthesia. In the postanesthesia care unit (PACU), all groups received IV morphine titration for visual analog scale (VAS) pain scores >3. All patients were started on IV patient-controlled analgesia with morphine after morphine titration in the PACU, while group EA also had their epidural maintained with 5 mL/h of 0.125% bupivacaine with 8 MUg/mL morphine. Patients were assessed in the PACU and at 1, 3, 6, 24, 48, and 72 hours postoperatively. Primary outcomes measured were morphine consumption at 24 hours and all VAS pain scores. RESULTS: Data from 82 of 90 (91.1%) patients were included in the study. Group TAP demonstrated decreased cumulative morphine consumption at 24 hours (98.75% confidence intervals, -29 to -9 mg) and noninferiority on VAS pain scores at all measurement times, as compared with group GA with standard opioid analgesia. However, group EA was superior to group TAP regarding cumulative morphine consumption at 24 hours (98.75% confidence intervals, -23 to -4 mg) and noninferior to group TAP on VAS pain scores at all comparison points. Group TAP had reduced morphine consumption from PACU admission to 6 hours as compared with group GA, but increased morphine consumption for 6 to 24 hours as compared with group EA. CONCLUSION: Single-injection subcostal TAP block was more effective than IV opioid analgesia, while continuous thoracic epidural analgesia was more effective than the single-injection subcostal TAP block. PMID- 23744955 TI - What is the accuracy of the high-fidelity METI Human Patient Simulator physiological models during oxygen administration and apnea maneuvers? AB - BACKGROUND: A widely used physiological simulator is generally accepted to give valid predictions of oxygenation status during disturbances in breathing associated with anesthesia. We compared predicted measures with physiological measurements available in the literature, or derived from other models. METHODS: Five studies were selected from the literature which explored arterial oxygenation, with or without preoxygenation, in clinical situations or through mathematical modeling as well as the evolution of the fraction of expired oxygen (Feo2) during preoxygenation maneuvers. Scenarios from these studies were simulated on the METI-Human Patient SimulatorTM simulator, and the data were compared with the results in the literature. RESULTS: Crash-induction anesthesia without preoxygenation induces an O2 pulse saturation (Spo2) decrease that is not observed on the METI simulator. In humans, after 8 minutes of apnea, Spo2 decreased below 90% while the worst value was 95% during the simulation. The apnea time to reach 85% was less with obese patients than with healthy simulated patients and was shortened in the absence of preoxygenation. However, the data in the literature include METI simulator confidence interval 95% values only for healthy humans receiving preoxygenation. The decrease in Pao2 during 35-second apnea started at end-expiration was slower on the METI simulator than the values reported in the literature. Feo2 evolution during preoxygenation maneuvers on the METI simulator with various inspired oxygen fractions (100%, 92%, 84%, and 68%) was very close to those reported in humans when perfect mask seal is provided. In practice, this seal is impossible to obtain on the METI simulator. CONCLUSIONS: Spo2 decreased much later during apnea on the METI simulator than in a clinical situation, whether preoxygenation was performed or not. The debriefing after simulation of critical situations or the use of the METI simulator to test a new equipment must consider these results. PMID- 23744954 TI - Perioperative torsade de pointes: a systematic review of published case reports. AB - BACKGROUND: Torsade de pointes is a rare but potentially fatal arrhythmia. More than 40 cases of perioperative torsade de pointes have been reported in the literature; however, the current evidence regarding this complication is very limited. To improve our understanding, we performed a systematic review and meta analysis of all published case reports of perioperative torsade de pointes. METHODS: MEDLINE was systematically searched for cases of perioperative torsade de pointes. We included patients of all age groups and cases that occurred from the immediate preoperative period to the third postoperative day. Patient and case characteristics as well as QT interval data were extracted. RESULTS: Forty six cases of perioperative torsade de pointes were identified; 29 occurred in women (67%), and 2 episodes were fatal (case fatality rate: 4%). Craniotomies and cardiac surgery accounted for 40% of all cases. Preceding events identified by the authors were hypokalemia (12/46, 26%; 99% confidence interval [CI], 9%-43%) and bradycardia (7/46, 15%; 99% CI, 2%-28%). Drugs were implicated in approximately one third of the events (14/46, 30%; 99% CI, 13%-48%). The mean corrected QT (QTc) at baseline was 457 +/- 67 milliseconds (minimum 320 milliseconds; maximum 647 milliseconds; data available in 27/46 patients). At the time of the event, the mean QTc increased to 575 +/- 77 milliseconds (minimum 413 milliseconds; maximum 766 milliseconds; data available in 33/46 patients). On average, QTc increased by +118 milliseconds (99% CI, 70-166 milliseconds; P < 0.001) between baseline and after the torsade de pointes event. All patients, except for 2, had a substantial prolongation of their QTc interval at the time of the event. CONCLUSIONS: This systematic review identified several common risk factors for perioperative torsade de pointes. Given the nearly uniform presence of a substantial QTc interval prolongation at the time of a torsade de pointes episode, increased vigilance for perioperative QTc interval prolongation may be warranted. PMID- 23744956 TI - The surgical Apgar score is strongly associated with intensive care unit admission after high-risk intraabdominal surgery. AB - BACKGROUND: Understanding intensive care unit (ICU) triage decisions for high risk surgical patients may ultimately facilitate resource allocation and improve outcomes. The surgical Apgar score (SAS) is a simple score that uses intraoperative information on hemodynamics and blood loss to predict postoperative morbidity and mortality, with lower scores associated with worse outcomes. We hypothesized that the SAS would be associated with the decision to admit a patient to the ICU postoperatively. METHODS: We performed a retrospective cohort study of adults undergoing major intraabdominal surgery from 2003 to 2010 at an academic medical center. We calculated the SAS (0-10) for each patient based on intraoperative heart rate, mean arterial blood pressure, and estimated blood loss. Using logistic regression, we assessed the association of the SAS with the decision to admit a patient directly to the ICU after surgery. RESULTS: The cohort consisted of 8501 patients, with 72.7% having an SAS of 7 to 10 and <5% an SAS of 0 to 4. A total of 8.7% of patients were transferred immediately to the ICU postoperatively. After multivariate adjustment, there was a strong association between the SAS and the decision to admit a patient to the ICU (adjusted odds ratio 14.41 [95% confidence interval {CI}, 6.88-30.19, P < 0.001] for SAS 0-2, 4.42 [95% CI, 3.19-6.13, P < 0.001] for SAS 3-4, and 2.60 [95% CI, 2.08-3.24, P < 0.001] for SAS 5-6 compared with SAS 7-8). CONCLUSIONS: The SAS is strongly associated with clinical decisions regarding immediate ICU admission after high-risk intraabdominal surgery. These results provide an initial step toward understanding whether intraoperative hemodynamics and blood loss influence ICU triage for postsurgical patients. PMID- 23744957 TI - Formulation and evaluation of lidocaine base ethosomes for transdermal delivery. AB - BACKGROUND: Although transdermal preparations of local anesthetics have been used to reduce pain caused by skin surgery, these preparations cannot effectively penetrate through the epidermis because of the barrier formed by the stratum corneum and the thick epidermis. Ethosomes can effectively transport drugs across the skin because of their thermodynamic stability, small size, high encapsulation efficiency, and percutaneous penetration. We evaluated lidocaine base ethosomes by measuring their loading efficiency, encapsulation efficiency, thermodynamic stability, and percutaneous penetration capability in vitro, and their effectiveness and cutaneous irritation in vivo. METHODS: Lidocaine base ethosomes were prepared using the injection-sonication-filter method. Size, loading efficiency, encapsulation efficiency, and stability were evaluated using a Zetasizer and high performance liquid chromatography. Formulation was determined by measuring the maximum encapsulation efficiency in the orthogonal test. Percutaneous penetration efficiency in vitro was analyzed using a Franz-type diffusion cell experiment. In vivo effectiveness was analyzed using the pinprick test. Cutaneous irritancy tests were performed on white guinea pigs, followed by histopathologic analysis. The results were compared with lidocaine liposomes as well as lidocaine delivered in a hydroethanolic solution. RESULTS: Lidocaine base ethosomes composed of 5% (w/w) egg phosphatidyl choline, 35% (w/w) ethanol, 0.2% (w/w) cholesterol, 5% (w/w) lidocaine base, and ultrapure water had a mean maximum encapsulation of 51% +/- 4%, a mean particle size of 31 +/- 3 nm, and a mean loading efficiency of 95.0% +/- 0.1%. The encapsulation efficiency of lidocaine base ethosomes remained stable for 60 days at 25 degrees C +/- 1 degrees C (95% confidence interval [CI], -1.12% to 1.34%; P = 0.833). The transdermal flux of lidocaine base differed significantly for the 3 preparations (F = 120, P < 0.001), being significantly greater from ethosomes than from liposomes (95% corrected CI, 1129-1818 ug/(cm(2).h); P < 0.001), and from hydroethanolic solution (95% corrected CI, 1468-2157 ug/(cm(2).h); P < 0.001). Lidocaine base ethosomes had a shorter onset time and longer duration in vivo than did lidocaine base liposomes or lidocaine delivered in a hydroethanolic solution. Lidocaine base ethosomes showed no evidence of dermal irritation in guinea pigs. CONCLUSIONS: Ethosomes are potential carriers of local anesthetics across the skin and may have applicability for other percutaneous drugs that require rapid onset. PMID- 23744958 TI - Endotracheal tube cuff leaks: causes, consequences, and management. AB - The consequences of endotracheal tube (ETT) cuff leak may range from a bubbling noise to a life-threatening ventilatory failure. Although the definitive solution is ETT replacement, this is often neither needed nor safe to perform. Frequently, the leak is not caused by a structural defect in the ETT. Cuff underinflation, cephalad migration of the ETT (partial tracheal extubation), misplaced orogastric or nasogastric tubes, wide discrepancy between ETT and tracheal diameters, or increased peak airway pressure can cause leaks around intact cuffs. Correction of these problems will stop the leak without ETT replacement. Alternatively, ETT cuff, pilot balloon, and inflation system damage due to inadvertent trauma or manufacturing defects may be responsible. Conservative management ideas (management without ETT replacement) were previously published to solve the problem. However, when a large structural defect is identified or conservative measures fail, ETT replacement becomes necessary. This can be performed with direct laryngoscopy if laryngeal visualization is adequate. A difficult exchange with possible airway loss should be anticipated, and prepared for, when there are signs and/or history of difficult intubation. A risk/benefit analysis of each individual situation is warranted before decisions are made on how best to proceed. Alternative back-up ventilation plans should be preformulated and the necessary equipment ready before the exchange. In this review, various management concerns and plans are discussed, and a simple algorithm to manage leaky ETT cuff situations is presented. PMID- 23744959 TI - The effect of a bolus dose of intravenous lidocaine on the minimum alveolar concentration of sevoflurane: a prospective, randomized, double-blinded, placebo controlled trial. AB - BACKGROUND: The anesthetic effect of volatile anesthetics can be quantified by the minimum alveolar concentration (MAC) of the drug that prevents movement in response to a noxious stimulus in 50% of patients. The underlying mechanism regarding how immobilization is achieved by volatile anesthetics is not thoroughly understood, but several drugs affect MAC. In this study, we investigated the effect of a single IV bolus dose of lidocaine on the MAC of sevoflurane in humans. METHODS: We determined the MAC for sevoflurane using the Dixon "up-and-down" method in 3 groups of patients, aged 30 to 65 years, who underwent elective surgery (30 patients per group). Study medication (placebo, 0.75 mg.kg(-1) lidocaine or 1.5 mg.kg(-1) lidocaine) was administered 3 minutes before skin incision after a 15-minute equilibration period and the response to skin incision was recorded (movement versus no movement). RESULTS: MAC was 1.86% +/- 0.40% in the placebo and 1.87% +/- 0.45% in the 0.75 mg.kg(-1) lidocaine group (P = 1.00). MAC was 1.63% +/- 0.24% in the 1.5 mg.kg(-1) lidocaine group, which was significantly lower than that of the placebo group (mean difference of 0.23% sevoflurane [95% adjusted confidence interval {CI}, 0.03-0.43]; P = 0.022). No significant difference was observed between the 0.75 mg.kg(-1) lidocaine and the placebo groups (mean difference of -0.01% sevoflurane [95% adjusted CI, -0.27 to 0.25]; P = 1). CONCLUSIONS: IV 1.5 mg.kg(-1) lidocaine decreased the MAC by at least 0.03% sevoflurane (mean difference 0.23% sevoflurane [95% adjusted CI, 0.03 0.43]). We did not observe a significant reduction in the MAC of sevoflurane with the IV administration of 0.75 mg.kg(-1) lidocaine. PMID- 23744960 TI - Global epidemiology of Trichomonas vaginalis. AB - Despite having the highest prevalence of any sexually transmitted infection (STI) globally, there is a dearth of data describing Trichomonas vaginalis (TV) incidence and prevalence in the general population. The lack of basic epidemiological data is an obstacle to addressing the epidemic. Once considered a nuisance infection, the morbidities associated with TV have been increasingly recognised over the past decade, highlighting the importance of this pathogen as a public health problem. Recent developments in TV diagnostics and molecular biology have improved our understanding of TV epidemiology. Improved characterisation of the natural history of TV infection has allowed us to hypothesise possible explanations for observed variations in TV prevalence with age. Direct and indirect hormonal effects on the female genital tract provide a likely explanation for the greater burden of persistent TV infection among women compared with men. Further characterisation of the global epidemiology of TV could enhance our ability to respond to the TV epidemic. PMID- 23744961 TI - Comparison of the performance of STI screening services for gay and bisexual men across 40 European cities: results from the European MSM Internet Survey. AB - OBJECTIVES: Sexually transmitted infections (STIs) such as anal/genital warts, syphilis and genital/rectal gonorrhoeal/chlamydial infections compromise the health of men who have sex with men (MSM). Rectal bacterial STIs increase the per contact risk of HIV infection. Early detection of asymptomatic STIs requires regular screening including collection of clinical specimens (or, for warts: physical examinations) that allow for the detection of infections at sites common to men's same sex practices. METHODS: From June to August 2010, the European MSM Internet Survey recruited 174,209 men from 38 European countries to an anonymous online questionnaire in 25 languages. As sexual healthcare for MSM in most countries is organised locally, we chose cities for comparison. Multivariable regression models were used to compare accessibility of services and applied diagnostic procedures across 40 cities. RESULTS: The proportion of respondents tested for STIs in the last 12 months in the absence of symptoms ranged from 8.9% in Istanbul to 48.0% in Amsterdam. At city level, low STI screening correlated with inaccessible services (R2=44.1%). At individual level, anal/penile inspection and anal swabbing was most common in U.K. cities, Amsterdam, Dublin and Stockholm. Compared to London, MSM in 30 cities had an adjusted OR (AOR) of (0.02 to 0.18) for anal swabbing; and (0.06 to 0.25) for anal/penile inspection (p<0.001). CONCLUSIONS: Anal/genital warts and rectal infections are likely to be profoundly underdiagnosed among MSM in most European cities. This has implications for the sexual health of MSM, HIV prevention and comparing national surveillance data. There is an urgent need to improve sexual healthcare tailored to MSM at risk for STIs. PMID- 23744962 TI - Introduction: The use of animals models to advance epigenetic science. PMID- 23744963 TI - Recruitment and biological consequences of histone modification of H3K27me3 and H3K9me3. AB - Two histone marks, H3K27me3 and H3K9me3, are well known for their repressive roles in the genic and nongenic regions of metazoan genomes. Several protein complexes are known to be responsible for generating these marks, including polycomb repression complex 2 and several H3K9 methylases. Recent studies have shown that the targeting of these histone-modifying complexes within mammalian genomes may be mediated through several DNA-binding proteins, including AEBP2, JARID2, and YY1. In this review, we discuss the potential targeting mechanisms in light of the recent results that have been derived from genome-wide chromatin immunoprecipitation sequencing data and the in vivo functions of these two histone marks in light of the results derived from mouse and human genetic studies. PMID- 23744966 TI - Nutritional epigenetics. AB - Within the last two decades, significant progress has been made in understanding the importance of epigenetic mechanisms in the regulation of gene expression as a consequence of gene-environment interactions. Nutrition, among many other environmental factors, is a key player that can induce epigenetic changes not only in the directly exposed organisms but also in subsequent generations through the transgenerational inheritance of epigenetic traits. This article aims to provide insights into the usefulness of the mouse model for epigenetic studies involving nutrition as well as the inherent limitations when compared with epigenetic phenomena in humans. Mice are one of the most versatile models for nutrition and epigenetic studies because of several features, such as short life span, relative low cost for generating samples, the existence of well characterized genetically engineered lines, the detailed sequencing of genomes, and the relative similarity of their metabolic processes to human metabolism. However, several limitations have to be acknowledged, such as the different location of genes on the chromosomes (and hence possibly different consequences of some epigenetic alterations), differences in the epigenetic patterns established during late embryogenesis, and possible epigenetic differences associated with cellular senescence caused by the different structure of telomeres when compared with humans. All these aspects have to be carefully analyzed when deciding whether a mouse model should be considered for a study in nutrition and epigenetics. Consequently, the results obtained from mouse studies should be carefully interpreted regarding their relevance to humans. PMID- 23744964 TI - Developmental epigenetics of the murine secondary palate. AB - Orofacial clefts occur with a frequency of 1 to 2 per 1000 live births. Cleft palate, which accounts for 30% of orofacial clefts, is caused by the failure of the secondary palatal processes--medially directed, oral projections of the paired embryonic maxillary processes--to fuse. Both gene mutations and environmental effects contribute to the complex etiology of this disorder. Although much progress has been made in identifying genes whose mutations are associated with cleft palate, little is known about the mechanisms by which the environment adversely influences gene expression during secondary palate development. An increasing body of evidence, however, implicates epigenetic processes as playing a role in adversely influencing orofacial development. Epigenetics refers to inherited changes in phenotype or gene expression caused by processes other than changes in the underlying DNA sequence. Such processes include, but are not limited to, DNA methylation, microRNA effects, and histone modifications that alter chromatin conformation. In this review, we describe our current understanding of the possible role epigenetics may play during development of the secondary palate. Specifically, we present the salient features of the embryonic palatal methylome and profile the expression of numerous microRNAs that regulate protein-encoding genes crucial to normal orofacial ontogeny. PMID- 23744965 TI - Sexually selected traits: a fundamental framework for studies on behavioral epigenetics. AB - Emerging evidence suggests that epigenetic-based mechanisms contribute to various aspects of sex differences in brain and behavior. The major obstacle in establishing and fully understanding this linkage is identifying the traits that are most susceptible to epigenetic modification. We have proposed that sexual selection provides a conceptual framework for identifying such traits. These are traits involved in intrasexual competition for mates and intersexual choice of mating partners and generally entail a combination of male-male competition and female choice. These behaviors are programmed during early embryonic and postnatal development, particularly during the transition from the juvenile to adult periods, by exposure of the brain to steroid hormones, including estradiol and testosterone. We evaluate the evidence that endocrine-disrupting compounds, including bisphenol A, can interfere with the vital epigenetic and gene expression pathways and with the elaboration of sexually selected traits with epigenetic mechanisms presumably governing the expression of these traits. Finally, we review the evidence to suggest that these steroid hormones can induce a variety of epigenetic changes in the brain, including the extent of DNA methylation, histone protein alterations, and even alterations of noncoding RNA, and that many of the changes differ between males and females. Although much previous attention has focused on primary sex differences in reproductive behaviors, such as male mounting and female lordosis, we outline why secondary sex differences related to competition and mate choice might also trace their origins back to steroid-induced epigenetic programming in disparate regions of the brain. PMID- 23744967 TI - Epigenetic influence of stress and the social environment. AB - Animal models of early-life stress and variation in social experience across the lifespan have contributed significantly to our understanding of the environmental regulation of the developing brain. Plasticity in neurobiological pathways regulating stress responsivity, cognition, and reproductive behavior is apparent during the prenatal period and continues into adulthood, suggesting a lifelong sensitivity to environmental cues. Recent evidence suggests that dynamic epigenetic changes--molecular modifications that alter gene expression without altering the underlying DNA sequence--account for this plasticity. In this review, we highlight studies of laboratory rodents that illustrate the association between the experience of prenatal stress, maternal separation, maternal care, abusive caregiving in infancy, juvenile social housing, and adult social stress and variation in DNA methylation and histone modification. Moreover, we discuss emerging evidence for the transgenerational impact of these experiences. These experimental paradigms have yielded insights into the potential role of epigenetic mechanisms in mediating the effects of the environment on human development and also indicate that consideration of the sensitivity of laboratory animals to environmental cues may be an important factor in predicting long-term health and welfare. PMID- 23744970 TI - Gene-environment interactions and epigenetic pathways in autism: the importance of one-carbon metabolism. AB - Both genetic and epigenetic factors play important roles in the rate and severity of classic autism and autism spectrum disorders (ASDs). This review focuses on DNA methylation as a key epigenetic mechanism in autism. The critical role that one-carbon (C1) metabolism plays in establishing and maintaining DNA methylation patterns makes it a likely candidate pathway to regulate epigenetic processes in ASDs. This review is the first, to our knowledge, to examine how altering C1 metabolic function through genetic and environmental factors (focusing on diet) may lead to aberrant DNA methylation and increase susceptibility to ASDs. Additionally, the critical time windows for sensitivity to genetic and dietary factors both during the development of cortical networks implicated in ASDs and in regard to potential treatments are discussed. One thing is clear, if C1 metabolism plays a critical role in ASDs, it provides a potential avenue for treatment and perhaps, ultimately, prevention. PMID- 23744968 TI - Environmental epigenetics and its implication on disease risk and health outcomes. AB - This review focuses on how environmental factors through epigenetics modify disease risk and health outcomes. Major epigenetic events, such as histone modifications, DNA methylation, and microRNA expression, are described. The function of dose, duration, composition, and window of exposure in remodeling the individual's epigenetic terrain and disease susceptibility are addressed. The ideas of lifelong editing of early-life epigenetic memories, transgenerational effects through germline transmission, and the potential role of hydroxylmethylation of cytosine in developmental reprogramming are discussed. Finally, the epigenetic effects of several major classes of environmental factors are reviewed in the context of pathogenesis of disease. These include endocrine disruptors, tobacco smoke, polycyclic aromatic hydrocarbons, infectious pathogens, particulate matter, diesel exhaust particles, dust mites, fungi, heavy metals, and other indoor and outdoor pollutants. We conclude that the summation of epigenetic modifications induced by multiple environmental exposures, accumulated over time, represented as broad or narrow, acute or chronic, developmental or lifelong, may provide a more precise assessment of risk and consequences. Future investigations may focus on their use as readouts or biomarkers of the totality of past exposure for the prediction of future disease risk and the prescription of effective countermeasures. PMID- 23744969 TI - Early origins of adult disease: approaches for investigating the programmable epigenome in humans, nonhuman primates, and rodents. AB - According to the developmental origins of health and disease hypothesis, in utero experiences reprogram an individual for immediate adaptation to gestational perturbations, with the sequelae of later-in-life risk of metabolic disease. An altered gestational milieu with resultant adult metabolic disease has been observed in instances of both in utero constraint (e.g., from famine or uteroplacental insufficiency) and overt caloric abundance (e.g., from a maternal high-fat, caloric-dense diet). The commonality of the adult metabolic phenotype begs the question of how diverse in utero experiences (i.e., reprogramming events) converge on common metabolic pathways and how the memory of these events is maintained across the lifespan. We and others have investigated the molecular mechanisms underlying fetal programming and observed that epigenetic modifications to the fetal and placental epigenome accompany these reprogramming events. Based on several lines of emerging data in human and nonhuman primates, it is now felt that modified epigenetic signature--and the histone code in particular--underlies alterations in postnatal gene expression and metabolic pathways central to accurate functioning and maintenance of health. Because of the tissue lineage specificity of many of these modifications, nonhuman primates serve as an apt model system for the capacity to recapitulate human gene expression and regulation during development. This review summarizes recent epigenetic advances using rodent and primate (both human and nonhuman) models during in utero development and contributing to adult diseases later in life. PMID- 23744973 TI - Animal models in epigenetic research: institutional animal care and use committee considerations across the lifespan. AB - The rapid expansion and evolution of epigenetics as a core scientific discipline have raised new questions about how endogenous and environmental factors can inform the mechanisms through which biological form and function are regulated. Existing and proposed animal models used for epigenetic research have targeted a myriad of health and disease endpoints that may be acute, chronic, and transgenerational in nature. Initiating events and outcomes may extend across the entire lifespan to elicit unanticipated phenotypes that are of particular concern to institutional animal care and use committees (IACUCs). The dynamics and plasticity of epigenetic mechanisms produce effects and consequences that are manifest differentially within discreet spatial and temporal contexts, including prenatal development, stem cells, assisted reproductive technologies, production of sexual dimorphisms, senescence, and others. Many dietary and nutritional interventions have also been shown to have a significant impact on biological functions and disease susceptibilities through altered epigenetic programming. The environmental, chemical, toxic, therapeutic, and psychosocial stressors used in animal studies to elicit epigenetic changes can become extreme and should raise IACUC concerns for the well-being and proper care of all research animals involved. Epigenetics research is rapidly becoming an integral part of the search for mechanisms in every major area of biomedical and behavioral research and will foster the continued development of new animal models. From the IACUC perspective, care must be taken to acknowledge the particular needs and concerns created by superimposition of epigenetic mechanisms over diverse fields of investigation to ensure the proper care and use of animals without impeding scientific progress. PMID- 23744971 TI - The human imprintome: regulatory mechanisms, methods of ascertainment, and roles in disease susceptibility. AB - Imprinted genes form a special subset of the genome, exhibiting monoallelic expression in a parent-of-origin-dependent fashion. This monoallelic expression is controlled by parental-specific epigenetic marks, which are established in gametogenesis and early embryonic development and are persistent in all somatic cells throughout life. We define this specific set of cis-acting epigenetic regulatory elements as the imprintome, a distinct and specially tasked subset of the epigenome. Imprintome elements contain DNA methylation and histone modifications that regulate monoallelic expression by affecting promoter accessibility, chromatin structure, and chromatin configuration. Understanding their regulation is critical because a significant proportion of human imprinted genes are implicated in complex diseases. Significant species variation in the repertoire of imprinted genes and their epigenetic regulation, however, will not allow model organisms solely to be used for this crucial purpose. Ultimately, only the human will suffice to accurately define the human imprintome. PMID- 23744974 TI - Management of postblepharoplasty chemosis. AB - Clinically significant chemosis occasionally complicates lower eyelid blepharoplasty. In this report, the etiologic components of postblepharoplasty chemosis are discussed. The time course and duration of chemosis vary according to the underlying cause. Early, late, and prolonged chemosis are managed with different strategies. Diagnostic and therapeutic algorithms for chemosis assessment and management are presented. PMID- 23744972 TI - Cancer epigenetics: a brief review. AB - Cancer is a disease that results from the successive accumulation of genetic and epigenetic alterations. Despite intense study, many unanswered questions about the nature of the contribution of epigenetic changes to carcinogenesis remain. In this review, we describe principles of epigenetics as they relate to our current understanding of carcinogenesis. There are a number of in vivo models of specific pathways of carcinogenesis that are very useful for the characterization of epigenetic mechanisms that link environmental exposures or genetic susceptibility and cancer progression. Because epigenetic alterations are thought to be reversible, they offer great promise for treatment of cancer. The use of animal models to evaluate the effects of decitabine and zebularine has elucidated the mechanisms of action and indicated the potential for these types of treatment. Ultimately, the greatest challenge lies in the integration of laboratory and epidemiologic data to best prevent and treat this deadly disease. PMID- 23744975 TI - Retrospective assessment of objective prognostic score in terminally ill Korean patients with cancer. AB - We conducted a retrospective study by reviewing the medical records of 104 patients to assess the usefulness of the objective prognostic score (OPS) in an independent population of Korea. The median survival time (+/-standard error) of the high OPS group (>=3) was 9.0 +/- 1.31 days and that of the low OPS group (<3) was 26.0 +/- 3.3 days. The former was significantly shorter than the latter (P < .001). Only delirium (hazard ratio 1.751, P = .032) was related to shorter survival time independent of the OPS. This study demonstrates that the OPS is a valid and useful prognostic tool for predicting survival in terminally ill Korean patients with cancer, and that inclusion of delirium into the OPS may improve its prognostic value. PMID- 23744976 TI - Trends in length of hospice care from 1996 to 2007 and the factors associated with length of hospice care in 2007: findings from the National Home and Hospice Care Surveys. AB - Using the National Home and Hospice Care Surveys, we examined trends in length of hospice care from 1996 to 2007 and the factors associated with length of care in 2007. Results suggest that the increasing average lengths of care over time reflect the increase in the longest duration of care. For-profit ownership is associated with hospice care received for over a year. PMID- 23744977 TI - Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints. AB - OBJECTIVES: Data on the incidence of symptomatic osteoarthritis (OA) are scarce. We estimated incidence of clinical hip, knee and hand OA, and studied the effect of prevalent OA on joint-specific incident OA. METHODS: SIDIAP contains primary care records for>5 million people from Catalonia (Spain). Participants aged >=40 years with an incident diagnosis of knee, hip or hand OA between 2006 and 2010 were identified using International Classification of Diseases (ICD)-10 codes. Incidence rates and female-to-male rate ratios (RRs) for each joint site were calculated. Age, gender and body mass index-adjusted HR for future joint-specific OA according to prevalent OA at other sites were estimated using Cox regression. RESULTS: 3 266 826 participants were studied for a median of 4.45 years. Knee and hip OA rates increased continuously with age, and female-to-male RRs were highest at age 70-75 years. In contrast, female hand OA risk peaked at age 60-64 years, and corresponding female-to-male RR was highest at age 50-55 years. Adjusted HR for prevalent knee OA on risk of hip OA was 1.35 (99% CI 1.28 to 1.43); prevalent hip OA on incident knee OA: HR 1.15 (1.08 to 1.23). Prevalent hand OA predicted incident knee and hip OA: HR 1.20 (1.14 to 1.26) and 1.23 (1.13 to 1.34), respectively. CONCLUSIONS: The effect of age is greatest in the elderly for knee and hip OA, but around the menopause for hand OA. OA clusters within individuals, with higher risk of incident knee and hip disease from prevalent lower limb and hand OA. PMID- 23744978 TI - The longitudinal relationship between changes in body weight and changes in medial tibial cartilage, and pain among community-based adults with and without meniscal tears. AB - INTRODUCTION: Meniscal tears are commonly found on MRI and increase the risk for radiographic knee osteoarthritis (OA). While meniscectomy is recommended when knee pain is severe or functionally disabling, it is unclear how to best treat meniscal tears without these symptoms. The aim of this longitudinal study was to examine the effect of weight change on knee cartilage and pain in a cohort of community-based adults with and without meniscal tears detected by MRI. METHODS: 250 adults with no history of knee OA or knee injury were recruited from the general community and weight-loss clinics. MRI of the knee, Western Ontario and McMaster University Osteoarthritis Index (WOMAC), weight and height were measured at baseline and again at follow-up approximately 2 years later. RESULTS: Medial meniscal tears were present in 36 (18%) of the cohort. In those with medial meniscal tears, after adjustment for confounders, percentage weight change was significantly associated with percentage change in medial tibial cartilage volume (beta 0.2% 95% CI 0.08% to 0.3% p=0.002) and knee pain (beta 11.6% 95% CI 2.1% to 21.1% p=0.02). That is, for every 1% gain in weight, there was an associated 0.2% increased loss of medial tibial cartilage volume and 11.6% increase in pain. In those with no medial meniscal tear, neither change in medial tibial cartilage volume (beta 0.02% 95% CI -0.01% to 0.10% p=0.53) or pain (beta 1.9% 95% CI -2.2% to 6.1% p=0.36) were significantly associated with change in weight. CONCLUSIONS: This study demonstrated that among adults with medial meniscal tears, weight gain is associated with increased cartilage loss and pain, while weight loss is associated with the converse. This suggests attention to weight is particularly important in the management of people with medial meniscal tears. PMID- 23744979 TI - Drug therapy in undifferentiated arthritis: a systematic literature review. AB - Undifferentiated arthritis (UA) is defined as an inflammatory oligoarthritis or polyarthritis in which no definitive diagnosis can be made. We performed a literature review to assess the efficacy of various drug therapies in patients with UA. The literature search was conducted using electronic databases Pubmed, EMBASE and MEDLINE in adults with UA or early arthritis (not fulfilling the American College of Rheumatology (ACR) 1987 or ACR/European League Against Rheumatism (EULAR) 2010 criteria for rheumatoid arthritis). Drug therapy consisted of disease modifying antirheumatic drugs (DMARDs), biological agents and oral, intramuscular or intra-articular corticosteroids. Nine publications on eight randomised controlled trials (RCTs), two publications on two uncontrolled open-label trials and seven publications on three cohort studies were included. Temporary treatment with methotrexate (MTX), abatacept and intramuscular corticosteroids were demonstrated in RCTs with 12 months to 5 years follow-up to be more effective than placebo in suppressing disease activity or radiological progression. One study suggests that DMARD combination therapy is, at least after 4 months, superior to MTX monotherapy in patients with UA at high risk of developing persistent arthritis. The open-label uncontrolled trials and cohort studies also suggested that early treatment may provide immediate suppression of inflammation. The long-term benefit of early treatment in UA remains unclear. In conclusion, patients with UA benefit from early treatment with MTX. Combining multiple DMARDs or DMARDs with corticosteroids and biological agents may be even more beneficial. However, which treatment may provide the best results or may alter the disease course has still to be determined. More RCTs with longer follow up time are needed. PMID- 23744982 TI - Development of scales to assess mental health literacy relating to recognition of and interventions for depression, anxiety disorders and schizophrenia/psychosis. AB - OBJECTIVE: The aim of this study was to develop scales to assess mental health literacy relating to affective disorders, anxiety disorders and schizophrenia/psychosis. METHOD: Scales were created to assess mental health literacy in relation to depression, depression with suicidal thoughts, early schizophrenia, chronic schizophrenia, social phobia and post-traumatic stress disorder using data from a survey of 1536 health professionals (general practitioners, clinical psychologists and psychiatrists), assessing recognition of these disorders and beliefs about the helpfulness of interventions. This was done by using the consensus of experts about the helpfulness and harmfulness of treatments for each disorder as a criterion. Data from a general population survey of 6019 Australians aged >= 15 was used to examine associations between scale scores, exposure to mental disorders and sociodemographic variables, to assess scale validity. RESULTS: Those with a close friend or family member with a mental disorder had significantly higher mean scores on all mental health literacy scales, providing support for scale validity. Personal experience of the problem and working with people with a similar problem was linked to higher scores on some scales. Male sex, a lower level of education and age > 60 were linked to lower levels of mental health literacy. Higher scores were also linked to a greater belief that people with mental disorders are sick rather than weak. CONCLUSIONS: The scales developed in this study allow for the assessment of mental health literacy in relation to depression, depression with suicidal thoughts, early schizophrenia, chronic schizophrenia, social phobia and PTSD. Those with exposure to mental disorders had higher scores on the scales, and analyses of the links between scale scores and sociodemographic variables of age, gender and level of education were in line with those seen in other studies, providing support for scale validity. PMID- 23744981 TI - Breast cancer metastasis suppressor-1 promoter methylation in primary breast tumors and corresponding circulating tumor cells. AB - Breast cancer metastasis suppressor-1 (BRMS1) differentially regulates the expression of multiple genes, leading to metastasis suppression without affecting orthotopic tumor growth. For the first time, BRMS1 promoter methylation was evaluated as a prognostic biomarker in primary breast tumors and a subset of corresponding circulating tumor cells (CTC). Formalin-fixed paraffin embedded samples were analyzed for BRMS1 methylation status using methylation-specific PCR in a human specimen cohort consisting of noncancerous tissues, benign fibroadenomas, and primary breast tumors, including some with adjacent noncancerous tissues. Peripheral blood mononuclear cells from a large subset of these patients were fixed in cytospins and analyzed. In addition, BRMS1 expression in cytospins was examined by double-immunofluorescence using anti BRMS1 and pan-cytokeratin antibodies. BRMS1 promoter methylation was not detected in noncancerous breast tissues or benign fibroadenomas; however, methylation was observed in more than a third of primary breast tumors. Critically, BRMS1 promoter methylation in primary tumors was significantly associated with reduced disease-free survival with a trend toward reduced overall survival. Similarly, a third of cytospin samples were positive for the presence of CTCs, and the total number of detected CTCs was 41. Although a large fraction of CTCs were negative or maintained low expression of BRSM1, promoter methylation was observed in a small fraction of samples, implying that BRSM1 expression in CTCs was either downregulated or heterogeneous. In summary, these data define BRMS1 promoter methylation in primary breast tumors and associated CTCs. IMPLICATIONS: This study indicates that BRSM1 promoter methylation status has biomarker potential in breast cancer. PMID- 23744983 TI - Towards a framework for increasing help-seeking for social anxiety disorder. PMID- 23744984 TI - Treatment to reduce risk of psychosis: the need to consider the potential harms as well as the benefits. PMID- 23744989 TI - Adventitial stem cells in vein grafts display multilineage potential that contributes to neointimal formation. AB - OBJECTIVE: This study was designed to carry out the characterization of stem cells within the adventitia and to elucidate their functional role in the pathogenesis of vein graft atherosclerosis. APPROACH AND RESULTS: A mouse vein graft model was used to investigate the functional role of adventitial stem/progenitor cells on atherosclerosis. The adventitia of vein grafts underwent significant remodeling during early stages of vessel grafting and displayed markedly heterogeneous cell compositions. Immunofluorescence staining indicated a significant number of stem cell antigen-1-positive cells that were closely located to vasa vasorum. In vitro clonogenic assays demonstrated 1% to 11% of growing rates from adventitial cell cultures, most of which could be differentiated into smooth muscle cells (SMCs). These stem cell antigen-1 positive cells also displayed a potential to differentiate into adipogenic, osteogenic, or chondrogenic lineages in vitro. In light of the proatherogenic roles of SMCs in atherosclerosis, we focused on the functional roles of progenitor-SMC differentiation, in which we subsequently demonstrated that it was driven by direct interaction of the integrin/collagen IV axis. The ex vivo bioreactor system revealed the migratory capacity of stem cell antigen-1-positive progenitor cells into the vessel wall in response to stromal cell-derived factor 1. Stem cell antigen-1-positive cells that were applied to the outer layer of vein grafts showed enhanced atherosclerosis in apolipoprotein E-deficient mice, which contributed to ~ 30% of neointimal SMCs. CONCLUSIONS: We demonstrate that during pathological conditions in vein grafting, the adventitia harbors stem/progenitor cells that can actively participate in the pathogenesis of vascular disease via differentiation into SMCs. PMID- 23744990 TI - Scavenger receptor-AI-targeted iron oxide nanoparticles for in vivo MRI detection of atherosclerotic lesions. AB - OBJECTIVE: In search of molecular imaging modalities for specific detection of inflammatory atherosclerotic plaques, we explored the potential of targeting scavenger receptor-AI (SR-AI), which is highly expressed by lesional macrophages and linked to effective internalization machinery. APPROACH AND RESULTS: Ultrasmall superparamagnetic iron oxide particles were conjugated to a peptidic SR-AI ligand (0.371 mol Fe/L and 0.018 mol PP1/L). In vitro incubation of human or murine macrophages with SR-AI-targeted USPIO led to significantly higher iron uptake in vitro than with nontargeted USPIO, as judged by quantitative atomic absorption spectroscopy and Perl's staining. Incremental uptake was strictly mediated by SRs. SR-AI-targeted USPIO displayed accelerated plasma decay and a 3.5-fold increase (P=0.01) in atherosclerotic plaque accumulation on intravenous injection into apolipoprotein E-deficient mice compared with nontargeted USPIO. In addition, atherosclerotic humanized LDLr(-/-) chimeras with leukocyte expression of human SR-AI showed a significant improvement in contrast-to-noise ratio (2.7-fold; P=0.003) in the atherosclerotic aortic arch plaques 24 hours after injection of SR-AI-targeted USPIO compared with chimeras with leukocyte SR AI deficiency. CONCLUSIONS: Collectively, our data provide several lines of evidence that SR-AI-targeted molecular imaging of USPIO-based contrast agents holds great promise for in situ detection of inflammatory plaques in manifest atherosclerosis. PMID- 23744991 TI - Rapid estrogen receptor signaling mediates estrogen-induced inhibition of vascular smooth muscle cell proliferation. AB - OBJECTIVE: The proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in vascular diseases, such as atherosclerosis and restenosis, after percutaneous coronary intervention. Many studies have shown that estrogen inhibits VSMC proliferation in response to vascular injury in the mouse carotid injury model. However, the mechanisms that mediate these effects remain unclear. Here, we investigated the mechanisms by which estrogen inhibits VSMC proliferation. APPROACH AND RESULTS: We established a novel transgenic mouse line, referred to as the disrupting peptide mice, in which rapid estrogen receptor (ER)-mediated signaling is abolished by overexpression of a peptide that prevents the ER from forming a signaling complex necessary for rapid signaling. Carotid artery VSMCs from disrupting peptide mice or littermate wild-type female mice were obtained by the explant method. In VSMCs derived from wild-type mice, estrogen significantly inhibited VSMC proliferation. Phosphorylation levels of Akt and extracellular regulated kinase induced by platelet derived growth factor were significantly inhibited by estrogen pretreatment. Estrogen enhanced complex formation between ERalpha and protein phosphatase 2A (PP2), and enhanced PP2A activity. The blockade of PP2A activity abolished the estrogen-induced antiproliferative effect on VSMCs. In contrast, none of these effects of estrogen observed in the wild-type VSMCs were observed in VSMCs derived from disrupting peptide mice. These results support that rapid, non-nuclear ER signaling is required for estrogen-induced inhibition of VSMC proliferation, and further that PP2A activation by estrogen mediates estrogen-induced antiproliferative effects. CONCLUSIONS: These findings support that PP2A activation via rapid, non-nuclear ER signaling may be a novel target for therapeutic approaches to inhibit VSMC proliferation, which plays a central role in atherosclerosis and restenosis. PMID- 23744992 TI - Liver-specific cholesteryl ester hydrolase deficiency attenuates sterol elimination in the feces and increases atherosclerosis in ldlr-/- mice. AB - OBJECTIVE: Liver is the major organ responsible for the final elimination of cholesterol from the body either as biliary cholesterol or as bile acids. Intracellular hydrolysis of lipoprotein-derived cholesteryl esters (CEs) is essential to generate the free cholesterol required for this process. Earlier, we demonstrated that overexpression of human CE hydrolase (Gene symbol CES1) increased bile acid synthesis in human hepatocytes and enhanced reverse cholesterol transport in mice. The objective of the present study was to demonstrate that liver-specific deletion of its murine ortholog, Ces3, would decrease cholesterol elimination from the body and increase atherosclerosis. APPROACH AND RESULTS: Liver-specific Ces3 knockout mice (Ces3-LKO) were generated, and Ces3 deficiency did not affect the expression of genes involved in cholesterol homeostasis and free cholesterol or bile acid transport. The effects of Ces3 deficiency on the development of Western diet-induced atherosclerosis were examined in low density lipoprotein receptor knock out(-/-) mice. Despite similar plasma lipoprotein profiles, there was increased lesion development in low density lipoprotein receptor knock out(-/-)Ces3-LKO mice along with a significant decrease in the bile acid content of bile. Ces3 deficiency significantly reduced the flux of cholesterol from [(3)H]-CE-labeled high-density lipoproteins to feces (as free cholesterol and bile acids) and decreased total fecal sterol elimination. CONCLUSIONS: Our results demonstrate that hepatic Ces3 modulates the hydrolysis of lipoprotein-delivered CEs and thereby regulates free cholesterol and bile acid secretion into the feces. Therefore, its deficiency results in reduced cholesterol elimination from the body, leading to significant increase in atherosclerosis. Collectively, these data establish the antiatherogenic role of hepatic CE hydrolysis. PMID- 23744993 TI - Flt-1 (vascular endothelial growth factor receptor-1) is essential for the vascular endothelial growth factor-Notch feedback loop during angiogenesis. AB - OBJECTIVE: Vascular endothelial growth factor (VEGF) signaling induces Notch signaling during angiogenesis. Flt-1/VEGF receptor-1 negatively modulates VEGF signaling. Therefore, we tested the hypothesis that disrupted Flt-1 regulation of VEGF signaling causes Notch pathway defects that contribute to dysmorphogenesis of Flt-1 mutant vessels. APPROACH AND RESULTS: Wild-type and flt-1(-/-) mouse embryonic stem cell-derived vessels were exposed to pharmacological and protein based Notch inhibitors with and without added VEGF. Vessel morphology, endothelial cell proliferation, and Notch target gene expression levels were assessed. Similar pathway manipulations were performed in developing vessels of zebrafish embryos. Notch inhibition reduced flt-1(-/-) embryonic stem cell derived vessel branching dysmorphogenesis and endothelial hyperproliferation, and rescue of flt-1(-/-) vessels was accompanied by a reduction in elevated Notch targets. Surprisingly, wild-type vessel morphogenesis and proliferation were unaffected by Notch suppression, Notch targets in wild-type endothelium were unchanged, and Notch suppression perturbed zebrafish intersegmental vessels but not caudal vein plexuses. In contrast, exogenous VEGF caused wild-type embryonic stem cell-derived vessel and zebrafish intersegmental vessel dysmorphogenesis that was rescued by Notch blockade. CONCLUSIONS: Elevated Notch signaling downstream of perturbed VEGF signaling contributes to aberrant flt-1(-/-) blood vessel formation. Notch signaling may be dispensable for blood vessel formation when VEGF signaling is below a critical threshold. PMID- 23744994 TI - The contributions of risk factor trends to cardiometabolic mortality decline in 26 industrialized countries. AB - BACKGROUND: Cardiovascular disease mortality has declined and diabetes mortality has increased in high-income countries. We estimated the potential role of trends in population body mass index, systolic blood pressure, serum total cholesterol and smoking in cardiometabolic mortality decline in 26 industrialized countries. METHODS: Mortality data were from national vital statistics. Body mass index, systolic blood pressure and serum total cholesterol were from a systematic analysis of population-based data. We estimated the associations between change in cardiometabolic mortality and changes in risk factors, adjusted for change in per-capita gross domestic product. We calculated the potential contribution of risk factor trends to mortality decline. RESULTS: Between 1980 and 2009, age standardized cardiometabolic mortality declined in all 26 countries, with the annual decline between <1% in Mexico to ~ 5% in Australia. Across the 26 countries together, risk factor trends may have accounted for ~ 48% (men) and ~ 40% (women) of cardiometabolic mortality decline. Risk factor trends may have accounted for >60% of decline among men and women in Finland and Switzerland, men in New Zealand and France, and women in Italy; their benefits were smallest in Mexican, Portuguese, and Japanese men and Mexican women. Risk factor trends may have slowed down mortality decline in Chilean men and women and had virtually no effect in Argentinean women. The contributions of risk factors to mortality decline seemed substantially larger among men than among women in the USA, Canada and The Netherlands. CONCLUSIONS: Industrialized countries have varied widely in the extent of risk factor prevention, and its likely benefits for cardiometabolic mortality. PMID- 23744995 TI - Missed medication doses in hospitalised patients: a descriptive account of quality improvement measures and time series analysis. AB - OBJECTIVE: To investigate the changes in overdue doses rates over a 4-year period in an National Health Service (NHS) teaching hospital, following the implementation of interventions associated with an electronic prescribing system used within the hospital. DESIGN: Retrospective time-series analysis of weekly dose administration data. SETTING: University teaching hospital using a locally developed electronic prescribing and administration system (Prescribing, Information and Communication System or PICS) with an audit database containing details on every drug prescription and dose administration. PARTICIPANTS: Prescription data extracted from the PICS database. INTERVENTION(S): Four interventions were implemented in the Trust: (i) the ability for doctors to pause medication doses; (ii) clinical dashboards; (iii) visual indicators for overdue doses and (iv) overdue doses Root Cause ANALYSIS: (RCA) meetings and a National Patient Safety Agency (NPSA) Rapid Response Alert. Main outcome measure(s) The percentage of missed medication doses. RESULTS: Rates of both missed antibiotic and non-antibiotic doses decreased significantly upon the introduction of clinical dashboards (reductions of 0.60 and 0.41 percentage points, respectively), as well as following the instigation of executive-led overdue doses RCA meetings (reductions of 0.83 and 0.97 percentage points, respectively) and the publication of an associated NPSA Rapid Response Alert. Implementing a visual indicator for overdue doses was not associated with significant decreases in the rates of missed antibiotic or non-antibiotic doses. CONCLUSIONS: Electronic prescribing systems can facilitate data collection relating to missed medication doses. INTERVENTIONS: providing hospital staff with information about overdue doses at a ward level can help promote reductions in overdue doses rates. PMID- 23744996 TI - Autologous transplantation of simple retinal pigment epithelium sheet for massive submacular hemorrhage associated with pigment epithelium detachment. AB - PURPOSE: To evaluate the long-term outcome of autologous simple RPE sheet transplantation in patients with simultaneous massive submacular hemorrhage and pigment epithelium detachment (PED). METHODS: Fourteen patients with 10 occult AMD eyes and 4 PCV eyes underwent a surgical procedure including a 180 degrees peripheral temporal retinotomy, choroidal neovascular membrane (CNVM) excision, and transplantation of an autologous simple RPE sheet developed from the PED region outside the CNVM lesion. Best-corrected visual acuity, multifocal ERG, and microperimetry were recorded to evaluate macular function. Optical coherence tomography, fundus fluorescein angiography, and an RPE autofluorescence test were performed to observe the status of the transplanted simple RPE sheet. RESULTS: Mean follow-up duration was 24 +/- 6 months. Mean ETDRS score increased from 14.0 +/- 23.4 preoperatively to 31.9 +/- 23.8 at 18 months postoperatively (P < 0.05). Of 14 eyes, 5 (36%) presented with central fixation postoperatively, whereas only 3 (21%) eyes presented with central fixation preoperatively. Ten grafts (71%) showed normal RPE color. Postoperative complications included one (7%) retinal detachment due to proliferative vitreoretinopathy and one (7%) delayed recurrent submacular hemorrhage. CONCLUSIONS: Transplantation of an autologous simple RPE sheet for eyes with massive submacular hemorrhage associated with PED was achieved with a simplified surgical procedure, resulting in increased postoperative visual acuity. PMID- 23744997 TI - Identification of cell surface markers glypican-4 and CD200 that differentiate human corneal endothelium from stromal fibroblasts. AB - PURPOSE: There is a lack of definitive cell surface markers to differentiate cultured human corneal endothelial cells (HCECs) from stromal fibroblasts, which could contaminate HCEC cultures. The aim of our study is to discover cell surface antigens on HCECs that can be used to identify and purify HCECs from stromal fibroblasts. METHODS: RNA sequencing (RNA-seq) was used to find differentially overexpressed genes in HCECs and commercial antibodies against these overexpressed antigens were screened by immunofluorescence assay. Similarly, 242 commercial antibodies against cell-surface antigens also were screened. Selected antibodies were used to sort HCECs from stromal fibroblasts by fluorescence activated cell sorting (FACS). RESULTS: Two monoclonal antibodies, anti-GPC4 and anti-CD200, were identified to stain HCECs specifically. FACS was used successfully to sort HCECs away from stromal fibroblasts. Recovery efficiency of HCECs after sorting using anti-GPC4 antibody was higher compared to anti-CD200 antibody, but purity of HCECs culture using either antibody was comparable. CONCLUSIONS: Taken together, the anti-GPC4 and anti-CD200 antibodies can be useful for purification and identification of HCECs in cultures containing stromal fibroblasts. PMID- 23744998 TI - Cone photoreceptor neuroprotection conferred by CNTF in a novel in vivo model of battlefield retinal laser injury. AB - PURPOSE: To develop a reproducible laboratory model to simulate a battlefield foveal laser injury and to test potential neuroprotective effects of a single injection treatment that might be administered in a military setting. METHODS: Frequency-doubled 532-nm Nd:YAG laser was used to induce a threshold retinal injury bilaterally in transgenic reporter mice that have fluorescent cones. Intravitreal injection of ciliary neurotrophic factor (CNTF) was then administered to the lasered eye and compared with a contralateral sham injection of saline. The effect on fluorescent cone cell survival was quantified using a confocal scanning laser ophthalmoscope (cSLO), TUNEL assays, and quantitative real-time PCR (qPCR). RESULTS: At 3 weeks post-laser, cSLO imaging showed that the proportion of surviving cones expressing green fluorescent protein (GFP) was greater in CNTF-treated (54.1 +/- 5.15% of baseline count) than in sham-injected eyes (28.7 +/- 4.4%), which was accompanied by a reduction in TUNEL-positive cells. This difference in cone survival persisted at the 6-week point (treated, 39.6 +/- 3.2% versus sham, 18.0 +/- 3.8%). These changes were accompanied by a reduction in TUNEL-positive cells. The Bcl-2/Bax ratio was increased in CNTF treated eyes at 1 week postlaser exposure relative to controls. CONCLUSIONS: A single intravitreal injection of CNTF protein was shown to improve cone survival when administered immediately after laser exposure. Similar treatments with CNTF might also have a role in attenuating retinal laser damage sustained by combat personnel in the military setting. PMID- 23744999 TI - Bulbar conjunctival thickness measurements with optical coherence tomography in healthy chinese subjects. AB - PURPOSE: To conduct in vivo measurements of the bulbar conjunctiva epithelial, stromal, and total thicknesses in healthy Chinese subjects using optical coherence tomography (OCT) and to compare the conjunctival thickness differences between sex and age. METHODS: From January to July 2012, healthy Chinese subjects were recruited to undergo a Cirrus HD-OCT examination using the Anterior Segment 5 Line Raster scanning protocol. Ophthalmoscopy and slit-lamp examinations were performed on all eyes, along with the determination of visual acuity. The bulbar conjunctiva epithelial thickness, stromal thickness, and full thickness were measured on cross-sectional conjunctiva images. The average values of each parameter were compared between males and females and among eight age groups (<20, 21-30, 31-40, 41-50, 51-60, 61-70, 71-80, and >80 years). RESULTS: A total of 711 eyes in 711 subjects (average age 46.5 years) were included. The average conjunctiva epithelial, stromal, and full thickness measurements were 42.4 +/- 7.4 MUm, 197.7 +/- 32.5 MUm, and 240.1 +/- 29.8 MUm, respectively. No significant difference was found for any of the three parameters between sexes. The conjunctiva epithelial thickness values decreased significantly after age 20 and were then maintained at relatively low levels, followed by a sharp increase at 60 years of age. The conjunctiva stromal thickness decreased throughout the entire lifetime, and the full thickness decreased from the teenage to the elderly periods. CONCLUSIONS: None of the Chinese conjunctiva epithelial, stromal, and full thickness was sex-related, but all of them were age-related. PMID- 23745000 TI - Sources of structural autofluorescence in the human trabecular meshwork. AB - PURPOSE: In situ 2-photon excitation fluorescence (TPEF) of the human trabecular meshwork (TM) reveals beams of heterogeneous autofluorescence (AF) comprising high intensity fluorescent fibers (AF-high) on a background of lower intensity fluorescence (AF-low). To determine the sources of this AF heterogeneity, we imaged human TM to characterize AF, second harmonic generation (SHG) for collagen, and eosin-labeled fluorescence identifying elastin. METHODS: Corneoscleral rims retained after corneal transplantation were incubated with and without eosin, and imaged by TPEF. TPEF was collected through multiphoton bandpass filters to obtain AF, SHG (collagen bandwidth), and eosin-labeled fluorescence images. For qualitative comparisons, near-simultaneous image acquisition pairs of AF-SHG (+/-eosin coincubation), AF-eosin, and SHG-eosin were captured. For quantitative comparisons, multiple regions of interest (ROI) were defined in separate TM beam regions within the uveal and corneoscleral meshwork for image acquisition pairs of AF-SHG (without eosin coincubation) and SHG-eosin. We defined 18 ROI within each acquisition pair as the basis for Manders colocalization analysis. Perfect colocalization was defined as a Manders coefficient (Mcoeff) of 1. RESULTS: Qualitatively and quantitatively, AF-low colocalized with SHG (Mcoeff=1), but not SHG signal-voids. AF-high colocalized with SHG signal-voids (Mcoeff=1), but not the SHG signal. Like AF-high, eosin labeled fluorescence qualitatively and quantitatively colocalized (Mcoeff=1) with SHG signal-voids, but not the SHG signal. CONCLUSIONS: Heterogeneous AF in human TM is comprised of high intensity signal originating from elastin fibers in beam cores and lower intensity signal originating from collagen. These findings are relevant to interpreting structural extracellular matrix signals in AF images of the TM. PMID- 23745001 TI - Clinical and genetic characteristics of Korean occult macular dystrophy patients. AB - PURPOSE: We investigated the genetic characteristics of retinitis pigmentosa 1 like 1 (RP1L1) gene in patients with occult macular dystrophy (OMD) and identified genotype-phenotype correlations. METHODS: We sequenced the entire exons and flanking regions of the RP1L1 gene in 19 Korean OMD patients. Detailed retinal morphologic abnormalities were evaluated using spectral domain optical coherence tomography and infrared reflectance imaging. Clinical features, retinal morphologic abnormalities, and disease progression were compared among the subtypes separated on the basis of genotypes. RESULTS: Ten of 19 (52.6%) patients had RP1L1 mutations: 7 (36.8%) had the previously reported mutation, p.Arg45Trp, and the other 3 (15.8%) had novel variants (p.Gln2311Pro, p.Ser676Cys, and p.Asp1425His). p.Gln2311Pro, p.Asp1425His, and p.Ser676Cys were predicted as pathogenic in 3, 2, and none of 5 computational assessment tools, respectively. Photoreceptor disruption across the fovea was symmetric in all eyes with RP1L1 mutations, but asymmetric in 3 eyes without the mutations. Symmetric round hyporeflectance centered on the fovea in infrared reflectance images was seen in all patients with the p.Arg45Trp mutation, but in only 2 of 12 patients without the mutation. The patients with p.Arg45Trp showed greater extent of photoreceptor disruption than those without the mutation. Progression of photoreceptor disruption was remarkable in patients with RP1L1 mutations, but insignificant in those without. CONCLUSIONS: OMD is clinically and genetically heterogeneous, with different morphologic features and progression in outer retinal pathology according to RP1L1 gene mutations, indicating the genotype-phenotype correlation in patients with OMD. PMID- 23745002 TI - Extralenticular and lenticular aspects of accommodation and presbyopia in human versus monkey eyes. AB - PURPOSE: To determine if the accommodative forward movements of the vitreous zonule and lens equator occur in the human eye, as they do in the rhesus monkey eye; to investigate the connection between the vitreous zonule posterior insertion zone and the posterior lens equator; and to determine which components muscle apex width, lens thickness, lens equator position, vitreous zonule, circumlental space, and/or other intraocular dimensions, including those stated in the objectives above-are most important in predicting accommodative amplitude and presbyopia. METHODS: Accommodation was induced pharmacologically in 12 visually normal human subjects (ages 19-65 years) and by midbrain electrical stimulation in 11 rhesus monkeys (ages 6-27 years). Ultrasound biomicroscopy imaged the entire ciliary body, anterior and posterior lens surfaces, and the zonule. Relevant distances were measured in the resting and accommodated eyes. Stepwise regression analysis determined which variables were the most important predictors. RESULTS: The human vitreous zonule and lens equator move forward (anteriorly) during accommodation, and their movements decline with age, as in the monkey. Over all ages studied, age could explain accommodative amplitude, but not as well as accommodative lens thickening and resting muscle apex thickness did together. Accommodative change in distances between the vitreous zonule insertion zone and the posterior lens equator or muscle apex were important for predicting accommodative lens thickening. CONCLUSIONS: Our findings quantify the movements of the zonule and ciliary muscle during accommodation, and identify their age-related changes that could impact the optical change that occurs during accommodation and IOL function. PMID- 23745004 TI - A prospective study of spherical refractive error and ocular components among Northern Irish schoolchildren (the NICER study). AB - PURPOSE: To explore 3-year change in spherical refractive error and ocular components among white Northern Irish schoolchildren. METHODS: Baseline data were collected among 6- to 7-year-old and 12- to 13-year-old children. Three years after baseline, follow-up data were collected. Cycloplegic refractive error and ocular components measurements (axial length [AL], anterior chamber depth [ACD], corneal radius of curvature [CRC]) were determined using binocular open-field autorefraction and ocular biometry. Change in spherical equivalent refractive error (SER) and ocular components were calculated. RESULTS: A statistically significantly greater change in SER was found between 6 to 7 years and 9 to 10 years (younger cohort) compared to between 12 to 13 years and 15 to 16 years (older cohort) (-0.38 diopter [D] and -0.13 D, respectively) (P<0.001). A statistically significantly greater change in AL was found among the younger compared to the older cohort (0.48 mm and 0.14 mm, respectively) (P<0.001). Change in ACD was minimal across both groups (0.12 mm younger and 0.05 mm older cohort) as were changes in CRC. Change in SER was associated with change in AL in both age groups (both P<0.01). CONCLUSIONS: There is a greater change in both spherical refractive error and axial length in younger children when compared with teenagers. Although increase in axial length drives refractive change during childhood and teenage years, lens compensation continues to occur in an attempt to maintain emmetropia. White children living in Northern Europe demonstrate dramatically less change in spherical refractive error over a fixed period of time than their East Asian counterparts. In contrast, they appear to exhibit more rapid myopic progression than UK children studied in the mid-20th century. PMID- 23745003 TI - Ion transport function of SLC4A11 in corneal endothelium. AB - PURPOSE: Mutations in SLC4A11, a member of the SLC4 superfamily of bicarbonate transporters, give rise to corneal endothelial cell dystrophies. SLC4A11 is a putative Na+ borate and Na+:OH- transporter. Therefore we ask whether SLC4A11 in corneal endothelium transports borate (B[OH]4-), bicarbonate (HCO3-), or hydroxyl (OH-) anions coupled to Na+. METHODS: SLC4A11 expression in cultured primary bovine corneal endothelial cells (BCECs) was determined by semiquantitative PCR, SDS-PAGE/Western blotting, and immunofluorescence staining. Ion transport function was examined by measuring intracellular pH (pHi) or Na+ ([Na+](i)) in response to Ringer solutions with/without B(OH)4- or HCO3- after overexpressing or small interfering RNA (siRNA) silencing of SLC4A11. RESULTS: SLC4A11 is localized to the basolateral membrane in BCEC. B(OH)4- (2.5-10 mM) in bicarbonate free Ringer induced a rapid small acidification (0.01 pH unit) followed by alkalinization (0.05-0.1 pH unit), consistent with diffusion of boric acid into the cell followed by B(OH)4-. However, the rate of B(OH)4--induced pHi change was unaffected by overexpression of SLC4A11. B(OH)4- did not induce significant changes in resting [Na+(i)] or the amplitude and rate of acidification caused by Na+ removal. siRNA-mediated knockdown of SLC4A11 (~70%) did not alter pHi responses to CO2/HCO3--rich Ringer, Na+-free induced acidification, or the rate of Na+ influx in the presence of bicarbonate. However, in the absence of bicarbonate, siSLC4A11 knockdown significantly decreased the rate (43%) and amplitude (48%) of acidification due to Na+ removal and recovery (53%) upon add back. Additionally, the rate of acid recovery following NH4+ prepulse was decreased significantly (27%) by SLC4A11 silencing. CONCLUSIONS: In corneal endothelium, SLC4A11 displays robust Na+-coupled OH- transport, but does not transport B(OH)4- or HCO3-. PMID- 23745006 TI - Three different phenotypes of mild nonproliferative diabetic retinopathy with different risks for development of clinically significant macular edema. AB - PURPOSE: To identify different phenotypes of nonproliferative diabetic retinopathy (NPDR) and their progression to clinically significant macular edema (CSME). METHODS: A prospective observational study was designed to follow eyes/patients with diabetes type 2 and NPDR with no prior laser treatment for 2 years or until development of CSME. A total of 410 patients, one eye per patient, fulfilled the inclusion/exclusion criteria and were included in the study. Ophthalmological examinations, including BCVA, fundus photography with Retmarker analysis, and optical coherence tomography (OCT), were performed at baseline, month 6 and month 24, or before laser treatment. Hierarchical cluster analysis was used to identify homogeneous subgroups and clinically significant thresholds of the data collected. RESULTS: A total of 376 eyes/patients performed the 6 month visit and were considered for cluster analysis. This mathematical method identified three different phenotypes based on statistically significant differences for the microaneurysm (MA) turnover and for the central retinal thickness (RT): phenotype A (low MA turnover and normal RT, 48.1%); phenotype B (low MA turnover and increased central RT, 23.2%); and phenotype C (high MA turnover, 28.7%). From the 348 eyes/patients that reached the study end point or completed the 24-month visit, 26 developed CSME: 3 from phenotype A (1.8%), 7 from phenotype B (8.5%), and 16 from phenotype C (16.2%). Eyes/patients from phenotype C showed a higher risk for CSME development (OR = 3.536; P < 0.001). CONCLUSIONS: Hierarchical cluster analysis identifies three different phenotypes of NPDR based on MA turnover and central macular thickness. Eyes/patients from phenotype C show a higher risk for the development of CSME. (ClinicalTrials.gov number, NCT00763802.) PMID- 23745005 TI - Accommodative movements of the vitreous membrane, choroid, and sclera in young and presbyopic human and nonhuman primate eyes. AB - PURPOSE: We report, for the first time to our knowledge, dynamic movements of the vitreous membrane and peripheral choroid during accommodation, and age-related changes in the anterior sclera. METHODS: We studied 11 rhesus monkeys (ages 6-27 years) and 12 human subjects (ages 19-65 years). Accommodation was induced pharmacologically in human subjects and by central electrical stimulation in the monkeys. Ultrasound biomicroscopy, endoscopy, and contrast agents were used to image various intraocular structures. RESULTS: In the monkey, the anterior hyaloid membrane bows backward during accommodation in proportion to accommodative amplitude and lens thickening. A cleft exists between the pars plicata region and the anterior hyaloid membrane, and the cleft width increases during accommodation from 0.79 +/- 0.01 mm to 1.01 +/- 0.02 mm in young eyes (n = 2, P < 0.005), as fluid from the anterior chamber flows around the lens equator toward the cleft. In the older eyes the cleft width was 0.30 +/- 0.19 mm, which during accommodation increased to 0.45 +/- 0.20 mm (n = 2). During accommodation the ciliary muscle moved forward by approximately 1.0 mm, pulling forward the choroid, retina, vitreous zonule, and the neighboring vitreous interconnected with the vitreous zonule. Among the humans, in the older eyes the scleral contour bowed inward in the region of the limbus, compared to the young eyes. CONCLUSIONS: The monkey anterior hyaloid bends posteriorly during accommodation in proportion to accommodative amplitude and the sclera bows inward with increasing age in both species. Future descriptions of the accommodative mechanism, and approaches to presbyopia therapy, may need to incorporate these findings. PMID- 23745007 TI - Ablation of the X-linked retinitis pigmentosa 2 (Rp2) gene in mice results in opsin mislocalization and photoreceptor degeneration. AB - PURPOSE: Mutations in the RP2 gene are associated with 10% to 15% of X-linked retinitis pigmentosa (XLRP), a debilitating disorder characterized by the degeneration of retinal rod and cone photoreceptors. The molecular mechanism of pathogenesis of photoreceptor degeneration in XLRP-RP2 has not been elucidated, and no treatment is currently available. This study was undertaken to investigate the pathogenesis of RP2-associated retinal degeneration. METHODS: We introduced loxP sites that flank exon 2, a mutational hotspot in XLRP-RP2, in the mouse Rp2 gene. We then produced Rp2-null allele using transgenic mice that expressed Cre recombinase under control of the ubiquitous CAG promoter. Electroretinography (ERG), histology, light microscopy, transmission electron microscopy, and immunofluorescence microscopy were performed to ascertain the effect of ablation of Rp2 on photoreceptor development, function, and protein trafficking. RESULTS: Although no gross abnormalities were detected in the Rp2(null) mice, photopic (cone) and scotopic (rod) function as measured by ERG showed a gradual decline starting as early as 1 month of age. We also detected slow progressive degeneration of the photoreceptor membrane discs in the mutant retina. These defects were associated with mislocalization of cone opsins to the nuclear and synaptic layers and reduced rhodopsin content in the outer segment of mutant retina prior to the onset of photoreceptor degeneration. CONCLUSIONS: Our studies suggest that RP2 contributes to the maintenance of photoreceptor function and that cone opsin mislocalization represents an early step in XLRP caused by RP2 mutations. The Rp2(null) mice should serve as a useful preclinical model for testing gene- and cell-based therapies. PMID- 23745008 TI - Development of standardized methods for assessing biocidal efficacy of contact lens care solutions against Acanthamoeba trophozoites and cysts. AB - PURPOSE: To investigate experimental variables in the development of standardized methods to assess the efficacy of contact lens disinfection systems against the trophozoite and cysts of Acanthamoeba spp. METHODS: A. castellanii (ATCC 50370), A. polyphaga (ATCC 30461), and A. hatchetti (CDC: V573) were adapted to axenic culture and used to produce cysts either with Neff's encystment medium (NEM) or starvation on nonnutrient agar (NNA). Challenge test assays and a most probable number approach were used to compare the trophozoite and cysticidal efficacy of four multipurpose disinfectant solutions (MPDSs) and a one-step hydrogen peroxide system (with and without the neutralizing step). RESULTS: With trophozoites, four of four MPDSs and the one-step peroxide system gave >=3 log10 kill for all strains 6 hours, regardless of culture medium used. Greater resistance was found against cysts, with results for MPDSs varying by species and method of cyst production. Here, 1-3 log10 kill was found with NEM cysts for three of four MPDSs compared with one of four for the NNA cysts at 6 hours (A. castellanii and A. polyphaga, only). The one-step peroxide system gave 1-1.9 log10 kill with NEM cysts and 0.8-1.1 for NNA cysts. Only 3% hydrogen peroxide gave total kill (>3 log10) of NNA cysts at 6 hours. CONCLUSIONS: A reproducible method for determining the susceptibility of Acanthamoeba trophozoites and cysts to contact lens care systems has been developed. This will facilitate assay standardization for assessing the efficacy of such products against the organism and aid development of improved disinfectant and therapeutic agents. PMID- 23745009 TI - The prevalence and types of glaucoma in an urban Indian population: the Singapore Indian Eye Study. AB - PURPOSE: To determine the prevalence and types of glaucoma in an urban Singaporean Indian population. METHODS: The Singapore Indian Eye Study (SINDI) was a population-based, cross-sectional survey that examined 3400 (75.6% response) persons aged 40 to 80 years. Participants underwent a standardized examination including slit-lamp biomicroscopy, Goldmann applanation tonometry, and dilated optic disc assessment. Participants suspected to have glaucoma also underwent visual field examination (24-2 SITA standard, Humphrey Visual Field Analyzer II), gonioscopy, and repeat applanation tonometry. Glaucoma was defined according to International Society for Geographical and Epidemiologic Ophthalmology criteria. RESULTS: Of the 3400 participants, 78 (2.29%) had diagnosed glaucoma, giving an age-standardized prevalence of 1.95% (95% confidence interval [CI], 1.5%-2.5%). The age-standardized prevalence of primary open-angle glaucoma (POAG) was 1.25% (95% CI, 0.89%-1.73%), primary angle-closure glaucoma (PACG) 0.12% (95% CI, 0.04%-0.33%), and secondary glaucoma 0.55% (95% CI, 0.35%-0.86%). The mean IOP among the participants in the normal group in the study population was 15.6 +/- 2.6 mm Hg and 17.7 +/- 6.1 mm Hg in subjects with glaucoma (P = 0.003). The mean central corneal thickness (CCT) in the normal study population was 540.31 +/- 33.79; the mean CCT in subjects with POAG (529.8 +/- 30.8 MUm) was statistically different from the normal study group (P = 0.003). CONCLUSIONS: The prevalence of glaucoma among Singaporean Indians 40 years of age and older in Singapore was 1.95%, approximately half that of the Chinese and the Malay persons in Singapore. As in other Asian studies, POAG was the main form of glaucoma accounting for nearly 60% of cases. PMID- 23745010 TI - Crystallization studies on rare-earth co-doped fluorozirconate-based glasses. AB - This work focuses on the structural changes of barium chloride (BaCl2) nanoparticles in fluorochlorozirconate-based glass ceramics when doped with two different luminescent activators, in this case rare-earth (RE) ions, and thermally processed using a differential scanning calorimeter. In a first step, only europium in its divalent and trivalent oxidation states, Eu2+ and Eu3+, is investigated, which shows no significant influence on the crystallization of hexagonal phase BaCl2. However, higher amounts of Eu2+ increase the activation energy of the phase transition to an orthorhombic crystal structure. In a second step, nucleation and nanocrystal growth are influenced by changing the structural environment of the glasses by co-doping with Eu2+ and trivalent Gd3+, Nd3+, Yb3+, or Tb3+, due to the different atomic radii and electro-negativity of the co dopants. PMID- 23745012 TI - ADOLESCENTS' SEXUAL BEHAVIOR AND ACADEMIC ATTAINMENT. AB - High school students today have high ambitions but do not always make choices that maximize their likelihood of educational success. This is the motivation for investigating relationships between high school sexual behavior and two important academic attainment milestones: earning a high school diploma and enrollment in distinct postsecondary programs. Analysis of data from 7,915 National Education Longitudinal Study of 1988-1994 participants indicates that timing of sexual initiation, contraceptive nonuse, and parenthood all predict female and male students' academic attainment. Furthermore, sexual behavior has more ramifications as attainment milestones become more competitive. These findings point to the importance of considering how students' choices across multiple life domains influence academic attainment, an important predictor of adult socioeconomic opportunity. PMID- 23745011 TI - Fast Analytical Methods for Macroscopic Electrostatic Models in Biomolecular Simulations. AB - We review recent developments of fast analytical methods for macroscopic electrostatic calculations in biological applications, including the Poisson Boltzmann (PB) and the generalized Born models for electrostatic solvation energy. The focus is on analytical approaches for hybrid solvation models, especially the image charge method for a spherical cavity, and also the generalized Born theory as an approximation to the PB model. This review places much emphasis on the mathematical details behind these methods. PMID- 23745013 TI - Attitudes about Children and Fertility Limitation Behavior. AB - The relationship between attitudes and individual behavior is at the core of virtually all demographic theories of fertility. This paper extends our understanding of fertility behavior by exploring how psychic costs of childbearing and contraceptive use, conceptualized as attitudes about children and contraception, are related to the transition from high fertility and little contraceptive use to lower fertility and wide spread contraceptive use. Using data from rural Nepal I examine models of the relationship between multiple, setting-specific attitudes about children and contraception and the hazard of contraceptive use to limit childbearing. Specific attitude measures attempt to capture the relative value of children versus consumer goods, the religiously based value of children, and the acceptability of contraceptive use. Findings demonstrate that multiple measures of women's attitudes about children and contraception were all independently related to their fertility limitation behavior. PMID- 23745014 TI - The Synthesis and Characterization of a Group of Transition Metal Octabutoxynaphthalocyanines and the Absorption and Emission Properties of the Co, Rh, Ir, Ni, Pd and Pt Members of This Group. AB - The synthesis and photophysical properties of new metallo octabutoxynaphthalocyanines with Rh(III), Ir(III), and Pt(II) are reported. Various metals were inserted into the metal-free octabutoxynaphthalocyanine and the resultant metal complexes were fully characterized by NMR, UV-vis spectroscopy, and mass spectrometry. The absorption and emission properties of these new complexes were also examined and compared to those of Co(II), Ni(II), and Pd(II) octabutoxynaphthalocyanines. The results provide useful information to understand the effect of these transition metals on the properties of this macrocyclic ring. PMID- 23745016 TI - Mesoscale phase distribution in single particles of LiFePO4 following lithium deintercalation. AB - The chemical phase distribution in hydrothermally grown micrometric single crystals LiFePO4 following partial chemical delithiation was investigated. Full field and scanning X-ray microscopy were combined with X-ray absorption spectroscopy at the Fe K- and O K-edges, respectively, to produce maps with high chemical and spatial resolution. The resulting information was compared to morphological insight into the mechanics of the transformation by scanning transmission electron microscopy. This study revealed the interplay at the mesocale between microstructure and phase distribution during the redox process, as morphological defects were found to kinetically determine the progress of the reaction. Lithium deintercalation was also found to induce severe mechanical damage in the crystals, presumably due to the lattice mismatch between LiFePO4 and FePO4. Our results lead to the conclusion that rational design of intercalation-based electrode materials, such as LiFePO4, with optimized utilization and life requires the tailoring of particles that minimize kinetic barriers and mechanical strain. Coupling TXM-XANES with TEM can provide unique insight into the behavior of electrode materials during operation, at scales spanning from nanoparticles to ensembles and complex architectures. PMID- 23745017 TI - Molecule of the month: miRNA and proteins DARPP-32, DRD1, SLC6A3, and CK2. PMID- 23745018 TI - The evolutionary significance of certain amino acid substitutions and their consequences for HIV-1 immunogenicity toward HLA's A*0201 and B*27. AB - In silico tools are employed to examine the evolutionary relationship to possible vaccine peptide candidates' development. This perspective sheds light on the proteomic changes affecting the creation of HLA specific T-cell stimulating peptide vaccines for HIV. Full-length sequences of the envelope protein of the HIV subtypes A, B, C and D were obtained through the NCBI Protein database were aligned using CLUSTALW. They were then analyzed using RANKPEP specific to Human Leukocyte Antigen A*02 and B*27. Geneious was used to catalogue the collected gp160 sequences and to construct a phylogenic tree. Mesquite was employed for ancestral state reconstruction to infer the order of amino acid substitutions in the epitopes examined. The results showed that consensus peptide identified SLAEKNITI had changes that indicated predicted escape mutation in strains of HIV responding to pressure exerted by CD8+ cells expressing HLA A*02. The predominating 9-mers IRIGPGQAF of gp120 are significantly less immunogenic toward HLA B*27 than to HLA A*02. The data confirms previous findings on the importance for efficacious binding, of an arginine residue at the 2(nd) position of the gag SL9 epitope, and extends this principle to other epitopes which interacts with HLA B*27. This study shows that the understanding of viral evolution relating T cell peptide vaccine design is a development that has much relevance for the creation of personalized therapeutics for HIV treatment. PMID- 23745019 TI - Fortuitously discovered liver lesions. AB - The fortuitously discovered liver lesion is a common problem. Consensus might be expected in terms of its work-up, and yet there is none. This stems in part from the fact that there is no preventive campaign involving the early detection of liver tumors other than for patients with known liver cirrhosis and oncological patients. The work-up (detection and differential diagnosis) of liver tumors comprises theoretical considerations, history, physical examination, laboratory tests, standard ultrasound, Doppler ultrasound techniques, contrast-enhanced ultrasound (CEUS), computed tomography and magnetic resonance imaging, as well as image-guided biopsy. CEUS techniques have proved to be the most pertinent method; these techniques became part of the clinical routine about 10 years ago in Europe and Asia and are used for a variety of indications in daily clinical practice. CEUS is in many cases the first and also decisive technical intervention for detecting and characterizing liver tumors. This development is reflected in many CEUS guidelines, e.g., in the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines 2004, 2008 and 2012 as well as the recently published World Federation for Ultrasound in Medicine and Biology-EFSUMB guidelines 2012. This article sets out considerations for making a structured work-up of incidental liver tumors feasible. PMID- 23745021 TI - Sofosbuvir and ABT-450: terminator of hepatitis C virus? AB - Combination therapy with peginterferon (pegIFN)-alpha and ribavirin (RBV) has been the standard of care (SOC) for chronic hepatitis C. Unfortunately, not all patients can achieve a sustained virologic response (SVR) with this regimen. SVR rates are approximately 80% in patients with hepatitis C virus (HCV) genotype 2, 3, 5 and 6 and 40%-50% in patients with genotype 1 and 4. Therefore, strategies to improve SVR rates have been an important issue for clinical physicians. Several direct acting antiviral agents (DAAs) have significantly higher SVR rates when combined with pegIFN-alpha and RBV than pegIFN-alpha and RBV alone. Treatments containing DAAs have several advantages over the previous SOC, including higher specificity and efficacy, shorter treatment durations, fewer side effects, and oral administration. Based on these advantages, treatment with pegIFN-alpha and RBV plus telaprevir or boceprevir has become the current SOC for patients with genotype 1 HCV infection. However, many patients are either not eligible for therapy or decline treatment due to coexisting relative or absolute contraindications as well as an inability to tolerate the hematological side effects and adverse events caused by the new SOC. These factors have contributed to the advent of pegIFN-alpha-free regimens. The newest therapeutic regimens containing sofosbuvir and ABT-450 have shown promising results. In this review, we summarize the development of anti-HCV agents and the clinical efficacy of sofosbuvir and ABT-450-based therapies as well as the potential for future HCV studies. PMID- 23745020 TI - E2F transcription factors and digestive system malignancies: how much do we know? AB - E2F family of transcription factors regulates various cellular functions related to cell cycle and apoptosis. Its individual members have traditionally been classified into activators and repressors, based on in vitro studies. However their contribution in human cancer is more complicated and difficult to predict. We review current knowledge on the expression of E2Fs in digestive system malignancies and its clinical implications for patient prognosis and treatment. E2F1, the most extensively studied member and the only one with prognostic value, exhibits a tumor-suppressing activity in esophageal, gastric and colorectal adenocarcinoma, and in hepatocellular carcinoma (HCC), whereas in pancreatic ductal adenocarcinoma and esophageal squamous cell carcinoma may function as a tumor-promoter. In the latter malignancies, E2F1 immunohistochemical expression has been correlated with higher tumor grade and worse patient survival, whereas in esophageal, gastric and colorectal adenocarcinomas is a marker of increased patient survival. E2F2 has only been studied in colorectal cancer, where its role is not considered significant. E2F4's role in colorectal, gastric and hepatic carcinogenesis is tumor-promoting. E2F8 is strongly upregulated in human HCC, thus possibly contributing to hepatocarcinogenesis. Adenoviral transfer of E2F as gene therapy to sensitize pancreatic cancer cells for chemotherapeutic agents has been used in experimental studies. Other therapeutic strategies are yet to be developed, but it appears that targeted approaches using E2F-agonists or antagonists should take into account the tissue-dependent function of each E2F member. Further understanding of E2Fs' contribution in cellular functions in vivo would help clarify their role in carcinogenesis. PMID- 23745022 TI - Epidemiology, clinical-treatment patterns and outcome in 256 hepatocellular carcinoma cases. AB - AIM: To analyze the epidemiology, clinical characteristics, treatment patterns and outcome in hepatocellular carcinoma (HCC) patients. METHODS: We analyzed clinical, pathological and therapeutic data from 256 consecutive patients, examined at S. Croce Hospital in Cuneo-Piedmont, with a diagnosis of HCC between 30(th) June 2000 and 1(st) July 2010. We analyzed the hospital imaging database and examined all medical records, including the diagnosis code for HCC (155.0 according to the ICD-9M classification system), both for inpatients and outpatients, and discovered 576 relevant clinical records. After the exclusion of reports relating to multiple admissions for the same patient, we identified 282 HCC patients. Moreover, from this HCC series, we excluded 26 patients: 1 patient because of an alternative final diagnosis, 8 patients because of a lack of complete clinical data in the medical record and 17 patients because they were admitted to different health care facilities, leaving 256 HCC patients. To highlight possible changes in HCC patterns over the ten-year period, we split the population into two five-year groups, according to the diagnosis period: 30(th) June 2000-30(th) June 2005 and 1(st) July 2005-1(st) July 2010. Patients underwent a 6-mo follow up. RESULTS: Two hundred and fifty-six HCC patients were included (male/female 182/74; mean age 70 years), 133 in the first period and 123 in the second. Hepatitis C virus (HCV) infection was the most common HCC risk factor (54.1% in the first period, 50.4% in the second; P = 0.63); in the first period, 21.8% of patients were alcoholics and 15.5% were alcoholics in the second period (P > 0.05); the non-viral/non-alcoholic etiology rate was 3.7% in the first period and 20.3% in the second period (P < 0.001). Child class A patients increased significantly in the second period (P < 0.001). Adjusting for age, gender and etiology, there was a significant increase in HCC surveillance during the second period (P = 0.01). Differences between the two periods were seen in tumor parameters: there was an increase in the number of unifocal HCC patients, from 53 to 69 (P = 0.01), as well as an increase in the number of cases where the HCC was < 3 cm [from 22 to 37 (P = 0.01)]. The combined incidence of stage Barcelona Clinic Liver Cancer 0 (very-early) and A (early) HCC was 46 (34.6%) between 2000-2005, increasing to 62 (50.4%) between 2005-2010 (P = 0.01). Of the patients, 62.4% underwent specific treatment in the first group, which increased to 90.2% in the second group (P < 0.001). Diagnosis period (P < 0.01), Barcelona Clinic Liver Cancer stage (P < 0.01) and treatment per se (P < 0.05) were predictors of better prognosis; surveillance was not related to survival (P = 0.20). CONCLUSION: This study showed that, between 2000-2005 and 2005-2010, the number of HCV-related HCC decreased, non-viral/non alcoholic etiologies increased and of surveillance programs were more frequently applied. PMID- 23745023 TI - CT/99mTc-GSA SPECT fusion images demonstrate functional differences between the liver lobes. AB - AIM: To evaluate the functional differences between the 2 liver lobes in non cirrhotic patients by using computed tomography/(99m)Tc-galactosyl human serum albumin (CT/(99m)Tc-GSA) single-photon emission computed tomography (SPECT) fusion images. METHODS: Between December 2008 and March 2012, 264 non-cirrhotic patients underwent preoperative liver function assessment using CT/(99m)Tc-GSA SPECT fusion images. Of these, 30 patients, in whom the influence of a tumor on the liver parenchyma was estimated to be negligible, were selected. Specifically, the selected patients were required to meet either of the following criteria: (1) the presence of an extrahepatic tumor; or (2) presence of a single small intrahepatic tumor. These 30 patients were retrospectively analyzed to calculate the percentage volume (%Volume) and the percentage function (%Function) of each lobe. The ratio between the %Function and %Volume (function-to-volume ratio) of each lobe was also calculated, and the ratios were compared between the 2 lobes. Furthermore, the correlations between the function-to-volume ratio and each of 2 liver parameters [lobe volume and diameter ratio of the left portal vein to the right portal vein (LPV-to-RPV diameter ratio)] were investigated. RESULTS: The median values of %Volume and %Function were 62.6% and 67.1% in the right lobe, with %Function being significantly higher than %Volume (P < 0.01). The median values of %Volume and %Function were 31.0% and 28.7% in the left lobe, with %Function being significantly lower than %Volume (P < 0.01). The function-to volume ratios of the right lobe (1.04-1.14) were significantly higher than those of the left lobe (0.74-0.99) (P < 0.01). The function-to-volume ratio showed no significant correlation between the lobe volume in either lobe. In contrast, the function-to-volume ratio showed significant correlations with the LPV-to-RPV diameter ratio in both lobes (right lobe: negative correlation, r s = -0.37, P = 0.048; left lobe: positive correlation, r s = 0.71, P < 0.001). The function-to volume ratio in the left lobe tended to be higher, and that in the right lobe tended to be lower, in accordance with the increase in the LPV-to-RPV diameter ratio. CONCLUSION: CT/(99m)Tc-GSA SPECT fusion images demonstrated that the function of the left lobe was significantly decreased compared with that of the right lobe in non-cirrhotic livers. PMID- 23745024 TI - Mechanisms of trichostatin A inhibiting AGS proliferation and identification of lysine-acetylated proteins. AB - AIM: To explore the effect of lysine acetylation in related proteins on regulation of the proliferation of gastric cancer cells, and determine the lysine acetylated proteins and the acetylated modified sites in AGS gastric cancer cells. METHODS: The CCK-8 experiment and flow cytometry were used to observe the changes in proliferation and cycle of AGS cells treated with trichostatin A (TSA). Real time polymerase chain reaction and Western blotting were used to observe expression changes in p21, p53, Bax, Bcl-2, CDK2, and CyclinD1 in gastric cancer cells exposed to TSA. Cytoplasmic proteins in gastric cancer cells before and after TSA treatment were immunoprecipitated with anti-acetylated lysine antibodies, separated using sodium dodecyl sulfate polyacrylamide gel electrophoresis gel and silver-stained to detect the proteins by mass spectrometry after removal of the gel. The acetylated proteins in AGS cells were enriched with lysine-acetylated antibodies, and a high-resolution mass spectrometer was used to detect the acetylated proteins and modified sites. RESULTS: TSA significantly inhibited AGS cell proliferation, and promoted cell apoptosis, leading to AGS cell cycle arrest in G0/G1 and G2/M phases, especially G0/G1 phase. p21, p53 and Bax gene expression levels in AGS cells were increased with TSA treatment duration; Bcl-2, CDK2, and CyclinD1 gene expression levels were decreased with TSA treatment duration. Two unknown protein bands, 72 kDa (before exposure to TSA) and 28 kDa (after exposure to TSA), were identified by silver-staining after immunoprecipitation of AGS cells with the lysine-acetylated monoclonal antibodies. Mass spectrometry showed that the 72 kDa protein band may be PKM2 and the 28 kDa protein band may be ATP5O. The acetylated proteins and modified sites in AGS cells were determined. CONCLUSION: TSA can inhibit gastric cancer cell proliferation, which possibly activated signaling pathways in a variety of tumor-associated factors. ATP5O was obviously acetylated in AGS cells following TSA treatment. PMID- 23745025 TI - Survival after inflammatory bowel disease-associated colorectal cancer in the Colon Cancer Family Registry. AB - AIM: To investigate the survival of individuals with colorectal cancer (CRC) with inflammatory bowel disease (IBD-associated CRC) compared to that of individuals without IBD diagnosed with CRC. METHODS: Epidemiologic, clinical, and follow-up data were obtained from the Colon Cancer Family Registry (Colon CFR). IBD associated cases were identified from self-report of physician diagnosis. For a subset of participants, medical records were examined to confirm self-report of IBD. Cox proportional hazards regression was applied to estimate adjusted hazard ratios (aHR) and 95%CI of mortality, comparing IBD-associated to non-IBD associated CRC, adjusted for age at CRC diagnosis, sex, Colon CFR phase, and number of prior endoscopies. Following imputation to complete CRC stage information, adjustment for CRC stage was examined. RESULTS: A total of 7202 CRC cases, including 250 cases of IBD-associated CRC, were analyzed. Over a twelve year follow-up period following CRC diagnosis, 2013 and 74 deaths occurred among non-IBD associated CRC and IBD-associated CRC patients, respectively. The difference in survival between IBD-associated and non-IBD CRC cases was not statistically significant (aHR = 1.08; 95%CI: 0.85-1.36). However, the assumption of proportional hazards necessary for valid inference from Cox regression was not met over the entire follow-up period, and we therefore limited analyses to within five years after CRC diagnosis when the assumption of proportional hazards was met. Over this period, there was evidence of worse prognosis for IBD-associated CRC (aHR = 1.36; 95%CI: 1.05-1.76). Results were similar when adjusted for CRC stage, or restricted to IBD confirmed in medical records. CONCLUSION: These results support the hypothesis that IBD-associated CRC has a worse prognosis than non-IBD-associated CRC. PMID- 23745026 TI - Early dynamic transcriptomic changes during preoperative radiotherapy in patients with rectal cancer: a feasibility study. AB - AIM: To develop novel biomarkers of rectal radiotherapy, we measured gene expression profiles on biopsies taken before and during preoperative radiotherapy. METHODS: Six patients presenting with a locally advanced rectal cancer (T>T2, N0/Nx, M0) eligible for preoperative radiotherapy (45 Gy in 25 fractions) were selected in a pilot study. Six tumor and 3 normal tissues biopsies were taken before and during radiotherapy, after a dose of 7.2 Gy at a median time of 1 h following irradiation (0:27-2:12). Tumor or normal tissue purity was assessed by a pathologist prior to RNA extraction. Mean RNA content was 23 MUg/biopsy (14-37) before radiotherapy and 22.7 MUg/biopsy (12-35) during radiotherapy. After RNA amplification, biopsies were analysed with 54K HG-U133A Plus 2.0 Affymetrix expression micro-arrays. Data were normalized according to MAS5 algorithm. A gene expression ratio was calculated as: (gene expression during radiotherapy - gene expression before radiotherapy)/gene expression before radiotherapy. Were selected genes that showed a ratio higher than +/- 0.5 in all 6 patients. RESULTS: Microarray analysis showed that preoperative radiotherapy significantly up-regulated 31 genes and down-regulated 6 genes. According to the Gene Ontology project classification, these genes are involved in protein metabolism (ADAMDEC1; AKAP7; CAPN5; CLIC5; CPE; CREB3L1; NEDD4L; RAB27A), ion transport (AKAP7; ATP2A3; CCL28; CLIC5; F2RL2; NEDD4L; SLC6A8), transcription (AKAP7; CREB3L1; ISX; PABPC1L; TXNIP), signal transduction (CAPN5; F2RL2; RAB27A; TNFRSF11A), cell adhesion (ADAMDEC1; PXDN; SPON1; S100A2), immune response (CCL28; PXDN; TNFRSF11A) and apoptosis (ITM2C; PDCD4; PVT1). Up-regulation of 3 genes (CCL28; CLIC5; PDCD4) was detected by 2 different probes and up-regulation of 2 genes (RAB27A; TXNIP) by 3 probes. CONCLUSION: Micro-arrays can efficiently assess early transcriptomic changes during preoperative radiotherapy for rectal cancer, and may help better understand tumor radioresistance. PMID- 23745027 TI - Treatment of hepatitis C in compensated cirrhotic patients is equally effective before and after liver transplantation. AB - AIM: To investigate differences in tolerability and response to treatment in compensated cirrhotic patients affected by hepatitis C virus (HCV) infection before and after liver transplantation. METHODS: Forty-three HCV non-liver transplanted (LT) cirrhotics (mean age 55 +/- 8 years, 65.1% male, Child-Pugh-A, genotype 1-4: 65.1%, 2-3: 34.9%) and 17 LT recipients with recurrent HCV-related cirrhosis (mean age 57 +/- 9 years, 88.2% male, Child-Pugh-A, genotype 1-4: 76.5%, 2-3: 23.5%) were included in the analysis from retrospective series. All patients received recombinant or pegylated interferon plus ribavirin at a standard dose and duration. Adverse events were recorded and classified according to the Common Terminology Criteria for Adverse Events. The mean duration of follow-up was of 4.3 +/- 1.8 years after the end of the treatment. RESULTS: An early virological response (EVR) was achieved in 30/43 (69.8%) non-LT and in 8/17 (47.1%) LT cirrhotics, a sustained virological response (SVR) in 18/43 (41.9%) and 5/17 (29.4 %), respectively. No statistical difference was observed in EVR and SVR rates between the two groups. Among HCV non-LT cirrhotics, 6/43 (13.9%) discontinued the treatment prematurely, 11.6% of them receiving <= 80% of treatment; 8/17 (47%) LT cirrhotics withdrew the treatment, 35.2% of them receiving <= 80% of treatment. If compared with LT-ones (P = 0.015), an higher risk of treatment discontinuation could affect LT cirrhotics, who undergo more frequently <= 80% of treatment (P = 0.05). None of the non-LT cirrhotics died after the end of the treatment. With no regards to the achievement of SVR, LT cirrhotic patients showed a reduced survival in respect to non-LT ones (87% at 1 year, 76% at 3 and 5 years after the end of treatment). CONCLUSION: HCV antiviral treatment is equally effective in compensated cirrhotics both before and after LT, which patients show a higher risk of premature treatment withdrawal and a reduced survival, independently of the achievement of SVR. PMID- 23745028 TI - Stage and size using magnetic resonance imaging and endosonography in neoadjuvantly-treated rectal cancer. AB - AIM: To assess the stage and size of rectal tumours using 1.5 Tesla (1.5T) magnetic resonance imaging (MRI) and three-dimensional (3D) endosonography (ERUS). METHODS: In this study, patients were recruited in a phase I/II trial of neoadjuvant chemotherapy for biopsy-proven rectal cancer planned for surgical resection with or without preoperative radiotherapy. The feasibility and accuracy of 1.5T MRI and 3D ERUS were compared with the histopathology of the fixed surgical specimen (pathology) to determine the stage and size of the rectal cancer before and after neoadjuvant chemotherapy. A Philips Intera 1.5T with a cardiac 5-channel synergy surface coil was used for the MRI, and a B-K Medical Falcon 2101 EXL 3D-Probe was used at 13 MHz for the ERUS. Our hypothesis was that the staging accuracy would be the same when using MRI, ERUS and a combination of MRI and ERUS. For the combination, MRI was chosen for the assessment of the lymph nodes, and ERUS was chosen for the assessment of perirectal tissue penetration. The stage was dichotomised into stage I and stage II or greater. The size was measured as the supero-inferior length and the maximal transaxial area of the tumour. RESULTS: The staging feasibility was 37 of 37 for the MRI and 29 of 36 for the ERUS, with stenosis as a limiting factor. Complete sets of investigations were available in 18 patients for size and 23 patients for stage. The stage accuracy by MRI, ERUS and the combination of MRI and ERUS was 0.65, 0.70 and 0.74, respectively, before chemotherapy and 0.65, 0.78 and 0.83, respectively, after chemotherapy. The improvement of the post-chemotherapy staging using the combination of MRI and ERUS compared with the staging using MRI alone was significant (P = 0.046). The post-chemotherapy understaging frequency by MRI, ERUS and the combination of MRI and ERUS was 0.18, 0.14 and 0.045, respectively, and these differences were non-significant. The measurements of the supero inferior length by ERUS compared with MRI were within 1.96 standard deviations of the difference between the methods (18 mm) for tumours smaller than 50 mm. The agreement with pathology was within 1.96 standard deviations of the difference between imaging and pathology for all tumours with MRI (15 mm) and for tumours that did not exceed 50 mm with ERUS (22 mm). Tumours exceeding 50 mm in length could not be reliably measured by ERUS due to the limit in the length of each recording. CONCLUSION: MRI is preferable to use when assessing the size of large or stenotic rectal tumours. However, staging accuracy is improved by combining MRI with ERUS. PMID- 23745029 TI - Low trypsinogen-1 expression in pediatric ulcerative colitis patients who undergo surgery. AB - AIM: To investigate whether matrix metalloproteinases-9 (MMP-9) or trypsinogens could serve as histological markers for an aggressive disease course in pediatric ulcerative colitis (UC). METHODS: We identified 24 patients with pediatric onset (<= 16 years) UC who had undergone surgery during childhood/adolescence a median of 2.1 years (range 0.1-7.4 years) after the diagnosis (between 1990 and 2008) in Children's Hospital, Helsinki, Finland. We also identified 27 conservatively treated UC patients and matched them based on their age at the time of diagnosis and follow-up at a median of 6 years (range 3-11 years) to serve as disease controls. Twenty children for whom inflammatory bowel disease (IBD) had been excluded as a result of endoscopy served as non-IBD controls. Colon biopsies taken by diagnostic endoscopy before the onset of therapy were stained using immunohistochemistry to study the expression of MMP-9, trypsinogen-1 (Tryp-1), Tryp-2, and a trypsin inhibitor (TATI). The profiles of these proteases and inhibitor at diagnosis were compared between the surgery group, the conservatively treated UC patients and the non-IBD controls. RESULTS: The proportions of Tryp-1 and Tryp-2 positive samples in the colon epithelium and in the inflammatory cells of the colon stroma were comparable between the studied groups at diagnosis. Interestingly, the immunopositivity of Tryp-1 (median 1; range 0-3) was significantly lower in the epithelium of the colon in the pediatric UC patients undergoing surgery when compared to that of the conservatively treated UC patients (median 2; range 0-3; P = 0.03) and non-IBD controls (median 2; range 0-3; P = 0.04). For Tryp-2, there was no such difference. In the inflammatory cells of the colon stroma, the immunopositivities of Tryp-1 and Tryp-2 were comparable between the studied groups at diagnosis. Also, the proportion of samples positive for TATI, as well as the immunopositivity, was comparable between the studied groups in the colon epithelium. In the stromal inflammatory cells of the colon, TATI was not detected. In UC patients, there were significantly more MMP-9 positive samples and a higher immunopositivity in the stromal inflammatory cells of the colon when compared to the samples from the non-IBD patients (P = 0.006 and P = 0.002, respectively); the immunopositivity correlated with the histological grade of inflammation (95%CI: 0.22-0.62; P = 0.0002), but not with the other markers of active disease. There were no differences in the immunopositivity or in the proportions of MMP-9 positive samples when examined by epithelial staining. The staining profiles in the ileal biopsies were comparable between the studied groups for all of the studied markers. CONCLUSION: For pediatric UC patients who require surgery, the immunopositivity of Tryp-1 at diagnosis is lower when compared to that of patients with a more benign disease course. PMID- 23745030 TI - Possible ameliorative effect of breastfeeding and the uptake of human colostrum against coeliac disease in autistic rats. AB - AIM: To examine the possible ameliorative effect of breastfeeding and the uptake of human colostrum against coeliac disease in autistic rats. METHODS: Female rats were fed a standard diet and received a single intraperitoneal injection of 600 mg/kg sodium valproate on day 12.5 after conception. In study 1, neonatal rats were randomly subjected to blood tests to investigate autism. In study 2, the 1(st) group was fed by the mother after an injection of interferon-gamma (IFN gamma) and administration of gliadin. The pups in the 2(nd) group were prevented from accessing maternal milk, injected IFN-gamma, administered gliadin, and hand fed human colostrum. The normal littermates fed by the table mothers were injected with physiological saline and served as normal controls in this study. RESULTS: The protein concentration was higher in group 2 than in group 1 in the duodenum (161.6 +/- 9 and 135.4 +/- 7 mg/g of tissue, respectively, P < 0.01). A significant increase (P < 0.001) in body weight was detected in human colostrum treated pups on post natal day (PND) 7 and 21 vs suckling pups in group 1. A delay in eye opening was noticed in the treated rats in group 1 on PND 13 compared with the control group and group 2. Administration of a single intraperitoneal injection of 600 mg/kg sodium valproate on day 12.5 after conception resulted in significantly reduced calcium and vitamin D levels in study 1 compared with the control groups (P < 0.001). However, human colostrum uptake inhibited increases in the level of transglutaminase antibody in autistic pups with coeliac disease. CONCLUSION: The effects of early-life nutrition and human colostrum on the functional maturation of the duodenal villi in autistic rats with coeliac disease that might limit or prevent the coeliac risk with autism. PMID- 23745031 TI - Gastric antisecretory and antiulcer activity of bovine hemoglobin. AB - AIM: To investigate gastric antisecretory and gastroprotective activity of bovine hemoglobin (B-Hb) in rats. METHODS: Adult Albino-Wistar rats were divided into groups of 6 animals each. B-Hb in doses of 100, 300 and 900 mg/kg body weight was tested for gastric acid secretion and antiulcer activity. Gastric secretions were measured 6 h after pylorus ligation in rats pretreated with B-Hb. The acidity was measured by titrating gastric contents against 0.01 mol/L NaOH to pH 7. Indomethacin ulcers were produced by oral administration of 30 mg/kg bw in the rats pretreated with B-Hb one hour before indomethacin. Six hours after indomethacin stomach removed and ulcer index was recorded. Ethanol ulcer were produced by 1 mL of ethanol in the rats pretreated with B-Hb 30 min before the ethanol. One hour after ethanol stomach were cut open to score ulcers. Histological examination and analysis of gastric wall mucus, non-protein sulfhydryl groups (NP-SH), and myeloperoxidase (MPO) were carried in gastric tissue following ethanol administration. RESULTS: In control rats pylorus ligation for 6 h resulted in the accumulation of 8.1 +/- 0.61 mL of gastric secretion. The treatment of the rats with 100, 300 and 900 mg/kg of B-Hb produced a significant decrease in the volume of gastric secretion 5.6 +/- 0.63, 5.5 +/- 0.75 and 4.7 +/- 0.58 mL respectively as compared to the control group [analysis of variance (ANOVA) F = 4.77, P < 0.05]. The lesion area in the control group was found to be 22.4 +/- 3.2 mm(2) six hours after the administration of indomethacin. Treatment of rats with B-Hb at doses of 100 mg/kg (24.3 +/- 3.29 mm(2)), 300 mg/kg (16.2 +/- 1.45 mm(2)) and 900 mg/kg (12.6 +/- 1.85 mm(2)) produced a dose dependent decreased the lesion scores (ANOVA F = 4.50, P < 0.05). The ulcer index following one hour after 1 mL ethanol was 7.1 +/- 0.31. Pretreatment of rats with B-Hb at the doses of 100 mg/kg (2.5 +/- 0.42), 300 mg/kg (2.1 +/- 0.4) and 900 mg/kg (0.7 +/- 0.21) significantly inhibited the formation of gastric lesions (ANOVA F = 63.26, P < 0.0001). Histological examination of gastric mucosa following ethanol showed significant lesions in the form of gastric pits with detachment of the surface epithelium; vacuolation of epithelial cells and elongation of microvessels. The changes were dose dependently attenuated by B-Hb. The treatment of rats with ethanol significantly decreased the Alcian blue binding capacity of gastric wall mucus (480 +/- 25.6 MUg Alcian blue/g of tissue) as compared to control rats (667 +/- 25.8 MUg). Pretreatment of rats with B-Hb at the doses of 100 mg/kg (516 +/- 31.6 MUg/g), 300 mg/kg (558 +/- 28.8 MUg/g) and 900 mg/kg (654 +/- 33.8 MUg/g) significantly attenuated ethanol induced depletion of gastric wall mucus (ANOVA F = 8.05, P < 0.005). A significant and dose dependent increase of gastric mucosal NP-SH (ANOVA F = 19.62, P < 0.001) and decrease in MPO activity (ANOVA F = 3.1, P < 0.05) was observed in B-Hb treated rats. CONCLUSION: B-Hb possesses significant gastric antisecretory and gastroprotective activity against experimentally induced gastric lesion. The gastroprotective effects of B-Hb are accompanied by inhibition of neutrophils activity, reduction of oxidative stress and maintenance of mucosal integrity. PMID- 23745032 TI - Anticancer effects of sweet potato protein on human colorectal cancer cells. AB - AIM: To investigate the effects of proteins purified from sweet potato storage roots on human colorectal cancer cell lines. METHODS: 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Hoechst 33258 nuclear staining and Boyden transwell chamber methods were used to determine whether purified sweet potato protein (SPP) from fresh sweet potato roots affected proliferation, migration and invasion, respectively, of human colorectal cancer SW480 cells in vitro. The inhibitory effects of SPP on growth of human colorectal cancer HCT-8 cells intraperitoneally xenografted in nude mice and spontaneous lung metastasis of murine Lewis lung carcinoma 3LL cells subcutaneously transplanted in C57 BL/6 mice were also investigated in vivo. RESULTS: SPP inhibited the proliferation of SW480 cells in a dose-dependent manner, with an IC50 value of 38.732 MUmol/L (r (2) = 0.980, P = 0.003) in the MTT assay. Hoechst 33258 nuclear staining further revealed inhibition of cell viability and induction of apoptosis by SPP. The transwell assay disclosed significant reduction in migrated cells/field by 8 MUmol/L SPP (8.4 +/- 2.6 vs 23.3 +/- 5.4, P = 0.031) and invaded cells/field through the ECMatrix by 0.8 MUmol/L SPP, compared with the control (25.2 +/- 5.2 vs 34.8 +/- 6.1, P = 0.038). Both intraperitoneal (ip) and intragastric (ig) administration of SPP led to significant suppression of growth of intraperitoneally inoculated HCT-8 cells in nude mice to 58.0% +/- 5.9% (P = 0.037) and 43.5% +/- 7.1% (P = 0.004) of the controls, respectively, after 9 d treatment. Bloody ascites additionally disappeared after ip injection of trypsin inhibitor. Notably, ig and ip administration of SPP induced a significant decrease in spontaneous pulmonary metastatic nodule formation in C57 BL/6 mice (21.0 +/- 12.3 and 27.3 +/- 12.7 nodules/lung vs 42.5 +/- 4.5 nodules/lung in controls, respectively, P < 0.05) after 25 d treatment. Moreover, the average weight of primary tumor nodules in the hind leg of mice decreased from 8.2 +/- 1.3 g/mice in the control to 6.1 +/- 1.4 g/mice in the ip group (P = 0.035). CONCLUSION: SPP exerts significant antiproliferative and antimetastatic effects on human colorectal cancer cell lines, both in vitro and in vivo. PMID- 23745033 TI - Efficacy of adjuvant XELOX and FOLFOX6 chemotherapy after D2 dissection for gastric cancer. AB - AIM: To compare the efficacy of capecitabine and oxaliplatin (XELOX) with 5 fluorouracil, folinic acid and oxaliplatin (FOLFOX6) in gastric cancer patients after D2 dissection. METHODS: Between May 2004 and June 2010, patients in our gastric cancer database who underwent D2 dissection for gastric cancer at the First Affiliated Hospital of Sun Yat-Sen University were retrospectively analyzed. A total of 896 patients were enrolled into this study according to the established inclusion and exclusion criteria. Of these patients, 214 received the XELOX regimen, 48 received FOLFOX6 therapy and 634 patients underwent surgery only without chemotherapy. Overall survival was compared among the three groups using Cox regression and propensity score matched-pair analyses. RESULTS: Patients in the XELOX and FOLFOX6 groups were younger at the time of treatment (median age 55.2 years; 51.2 years vs 58.9 years), had more undifferentiated tumors (70.1%; 70.8% vs 61.4%), and more lymph node metastases (80.8%; 83.3% vs 57.7%), respectively. Overall 5-year survival was 57.3% in the XELOX group which was higher than that (47.5%) in the surgery only group (P = 0.062) and that (34.5%) in the FOLFOX6 group (P = 0.022). Multivariate analysis showed that XELOX therapy was an independent prognostic factor (hazard ratio = 0.564, P < 0.001). After propensity score adjustment, XELOX significantly increased overall 5-year survival compared to surgery only (58.2% vs 44.2%, P = 0.025) but not compared to FOLFOX6 therapy (48.5% vs 42.7%, P = 0.685). The incidence of grade 3/4 adverse reactions was similar between the XELOX and FOLFOX6 groups, and more patients suffered from hand-foot syndrome in the XELOX group (P = 0.018). CONCLUSION: Adjuvant XELOX therapy is associated with better survival in patients after D2 dissection, but does not result in a greater survival benefit compared with FOLFOX6 therapy. PMID- 23745034 TI - Differences in HER2 over-expression between proximal and distal gastric cancers in the Chinese population. AB - AIM: To investigate HER2 expression and its correlation with clinicopathological variables between proximal and distal gastric cancers (GC) in the Chinese population. METHODS: Immunostaining of HER2 was performed and scored on a scale of 0-3 in 957 consecutive GC cases, according to the revised scoring criteria of HercepTest(TM) as used in the ToGA trial. Correlations between HER2 expression and clinicopathologic variables of proximal (n = 513) and distal (n = 444) GC were investigated. RESULTS: Our results showed that HER2 expression was significantly higher in the proximal than in distal GC (P < 0.05). Overall, HER2 expression was significantly higher in male patients (P < 0.01), the Lauren intestinal type (P < 0.001), low-grade (P < 0.001) and pM1 (P < 0.01) diseases, respectively. There was a significant difference in HER2 expression among some pTNM stages (P < 0.05). In contrast, HER2 expression in the distal GC was significantly higher in male patients (P < 0.001), low-grade histology (P < 0.001), the Lauren intestinal type (P < 0.001), and pM1 (P < 0.001). In the proximal GC, however, higher HER2 expression scores were observed only in tumors with low-grade histology (P < 0.001) and the Lauren intestinal type (P < 0.001). CONCLUSION: HER2 over-expression in GC of Chinese patients was significantly more common in proximal than in distal GC, and significantly correlated with the Lauren intestinal type and low-grade histology in both proximal and distal GC, and with pM1 disease and male gender in distal GC. PMID- 23745035 TI - Effect of endogenous insulin-like growth factor and stem cell factor on diabetic colonic dysmotility. AB - AIM: To investigate whether the reduction of stem cell factor (SCF) is mediated by decreased endogenous insulin-like growth factor (IGF)-1 in diabetic rat colon smooth muscle. METHODS: Sixteen Sprague-Dawley rats were randomly divided into two groups: control group and streptozotocin-induced diabetic group. After 8 wk of streptozotocin administration, colonic motility function and contractility of circular muscle strips were measured. The expression of endogenous IGF-1 and SCF was tested in colonic tissues. Colonic smooth muscle cells were cultured from normal adult rats. IGF-1 siRNA transfection was used to investigate whether SCF expression was affected by endogenous IGF-1 expression in smooth muscle cells, and IGF-1 induced SCF expression effects were studied. The effect of high glucose on the expression of endogenous IGF-1 and SCF was also investigated. RESULTS: Diabetic rats showed prolonged colonic transit time (252 +/- 16 min vs 168 +/- 9 min, P < 0.01) and weakness of circular muscle contraction (0.81 +/- 0.09 g vs 2.48 +/- 0.23 g, P < 0.01) compared with the control group. Endogenous IGF-1 and SCF protein expression was significantly reduced in the diabetic colonic muscle tissues. IGF-1 and SCF mRNA expression also showed a paralleled reduction in diabetic rats. In the IGF-1 siRNA transfected smooth muscle cells, SCF mRNA and protein expression was significantly decreased. IGF-1 could induce SCF expression in a concentration and time-dependent manner, mainly through the extracellular signal-regulated kinase 1/2 signal pathway. High glucose inhibited endogenous IGF 1 and SCF expression and the addition of IGF-1 to the medium reversed the SCF expression. CONCLUSION: Myopathy may resolve in colonic motility dysfunction in diabetic rats. Deficiency of endogenous IGF-1 in colonic smooth muscle cells leads to reduction of SCF expression. PMID- 23745036 TI - PRSS1_p.Leu81Met mutation results in autoimmune pancreatitis. AB - AIM: To describe protease serine 1 (PRSS1) gene mutations in patients with autoimmune pancreatitis (AIP) and the clinical features of AIP. METHODS: Fourteen patients with AIP, 56 with other chronic pancreatitis, 254 with pancreatic cancer and 120 normal controls were studied. The mutations and polymorphisms of four genes involved with pancreatitis or pancreatic cancer, PRSS1, SPINK1, CFTR and MEN1, were sequenced. The pathogenic mechanism of AIP was investigated by comparing the wild-type expression system with the p.81Leu->Met mutant expression system. RESULTS: Two novel mutations (p.81Leu->Met and p.91Ala->Ala) were found in PRSS1 gene from four patients with AIP. PRSS1_p.81Leu->Met mutation led to a trypsin display reduction (76.2%) combined with phenyl agarose (Ca(2+) induced failure). Moreover, the ratio of trypsin/amylase in patients with AIP was higher than in the patients with pancreatic cancer and other pancreatitis. A large number of lymphocytes and plasma cells were found in the bile ducts accompanied by hyperplasia of myofibroblasts. CONCLUSION: Autoimmune pancreatitis may be related to PRSS1 gene mutations. PMID- 23745037 TI - Gene expression profiles in peripheral blood mononuclear cells of ulcerative colitis patients. AB - AIM: To identify peripheral blood mononuclear cell (PBMC) gene expression profiles of ulcerative colitis (UC) patients, using oligonucleotide microarrays, to gain insights into UC molecular mechanisms. METHODS: The Human OneArray microarrays were used for a complete genome-wide transcript profiling of PBMCs from 12 UC patients and 6 controls. Differential analysis per gene was performed with a random variance model; t test and P values were adjusted to control the false discovery rate (5%). Gene ontology (GO) was deployed to analyze differentially expressed genes at significant levels between patients and controls to identify the biological processes involved in UC. RESULTS: Comparative analysis revealed that 4438 probes (4188 genes) were differentially expressed between the two groups, of which 3689 probes (3590 genes) were down regulated whereas 749 probes (598 genes) were up-regulated. Many disregulated genes in our data have been reported by previous microarray studies carried out on intestinal mucosa samples, such as S100A8, CEACAM1 and S100A9. GO enrichment analysis revealed 67 high enrichment up-regulated categories and one significant down-regulated category. The up-regulated genes were mainly involved in immune and inflammatory response, cell cycle and proliferation, DNA metabolism and repair. CONCLUSION: Gene expression profiling of PBMCs from patients with UC has highlighted several novel gene categories that could contribute to the pathogenesis of UC. PMID- 23745038 TI - Varicella zoster meningitis complicating combined anti-tumor necrosis factor and corticosteroid therapy in Crohn's disease. AB - Opportunistic viral infections are a well-recognized complication of anti-tumor necrosis factor (TNF) therapy for inflammatory bowel disease (IBD). Cases of severe or atypical varicella zoster virus infection, both primary and latent reactivation, have been described in association with immunosuppression of Crohn's disease (CD) patients. However, central nervous system varicella zoster virus infections have been rarely described, and there are no previous reports of varicella zoster virus meningitis associated with anti-TNF therapy among the CD population. Here, we present the case of a 40-year-old male with severe ileocecal CD who developed a reactivation of dermatomal herpes zoster after treatment with prednisone and adalimumab. The reactivation presented as debilitating varicella zoster virus meningitis, which was not completely resolved despite aggressive antiviral therapy with prolonged intravenous acyclovir and subsequent oral valacyclovir. This is the first reported case of opportunistic central nervous system varicella zoster infection complicating anti-TNF therapy in the CD population. This paper also reviews the literature on varicella zoster virus infections of immunosuppressed IBD patients and the importance of vaccination prior to initiation of anti-TNF therapy. PMID- 23745039 TI - Endoscopic management of an esophagopericardial fistula after radiofrequency ablation for atrial fibrillation. AB - A case is reported of a 76-year-old man with a past history of atrial fibrillation. A radiofrequency ablation procedure was suggested following several failed cardioversion attempts. However, an esophagopericardial fistula complicated the procedure. This life-threatening complication was successfully managed using both the placement of a covered esophageal stent and surgical pericardial and mediastinal drainage. In fact, no persisting fistula could be detected when the esophageal stent was removed seven weeks later. Atrioesophageal and esophagopericardial fistulas are two of the most severe complications associated with cardiological radiofrequency ablation procedures. They are responsible for majority of the deaths associated with this procedure. Despite the extremely high morbimortality associated with cardiothoracic surgery in such conditions, this treatment is the gold-standard for the management of such complications. This case report emphasizes the importance and efficacy of the endoscopic approach as part of a multidisciplinary management approach to this serious adverse event following radiofrequency ablation for atrial fibrillation. PMID- 23745040 TI - Malignant solitary fibrous tumor involving the liver. AB - Solitary fibrous tumors are predominantly benign and are most commonly found in the thoracic cavity and pleura; while reports exist in the literature of malignant solitary fibrous tumors and those located in extrathoracic organs, these cases are considered extremely rare. Herein, a case is reported of a malignant solitary fibrous tumor involving the liver that was diagnosed and treated in a 62-year-old woman. The patient presented with complaints of upper abdominal pain and unintentional weight loss. Computed tomography scan of the abdomen revealed a remarkably large mass, measuring 15 cm * 10 cm * 20 cm, which appeared to be unrelated to any particular organ. The intraoperative finding of a wide communication with the left liver suggested hepatic origin, and served as an indicator for tumor resection via left hemihepatectomy. The diagnosis of solitary fibrous tumor and its malignant nature was confirmed by histological and immunohistochemical examination of the resected tissues. Hepatic solitary fibrous tumor is very rare, and surgery remains the mainstay of treatment. Due to limited reports of such tumors in the literature, little can be said about the benefit of adjuvant therapy and prognosis for the rare cases with malignant histological findings. PMID- 23745041 TI - Synchronous pancreatic solid pseudopapillary neoplasm and intraductal papillary mucinous neoplasm. AB - Solid pseudopapillary neoplasm (SPN) is a rare and low-grade malignant pancreatic neoplasm composed of poorly cohesive monomorphic neoplastic cells forming solid and pseudopapillary structures with frequent hemorrhagic-cystic degeneration. Intraductal papillary mucinous neoplasm (IPMN) is a pancreatic exocrine tumor composed of intraductal papillary growth of mucin containing neoplastic cells in the main pancreatic duct or its major branches. In the case presented here, a 53 year-old, Japanese man was found to have multiple cystic lesions and dilatation of the main pancreatic duct in the neck of the pancreas. Histological examination revealed a main-duct and branch-duct type IPMN, of the gastric-type, involving the neck of the pancreas, associated with a 0.5 cm SPN in the caudal side of the IPMN. We diagnosed this case as synchronous SPN and IPMN. As far as we know, only one other case of synchronous SPN and IPMN has been reported. Both the present case and the previously reported case showed abnormal nuclear expression of beta catenin in SPN, whereas IPMN showed no abnormal nuclear expression. These results suggest that beta-catenin abnormality is not a common pathogenetic factor of synchronous SPN and IPMN. PMID- 23745042 TI - Foreign body retained in liver long after gauze packing. AB - This case report describes a foreign body retained in the liver long after perihepatic gauze packing. A 64-year-old female patient had suffered a rib fracture and liver rupture during a traffic accident in 1973. She discovered a mass in her right hypochondrium. Her hepatic ultrasonography showed a round mass (20.3 cm * 17.3 cm * 16.0 cm in size) with fluid echogenicity in the right lobe of her liver, and a hepatic cystic-solid mass (19.7 cm * 18.5 cm * 15.6 cm in size) was identified in an abdominal computerized tomography scan. Several pieces of gauze were extracted, and brown pus from the hepatic mass was suctioned during her exploratory laparotomy. Histology documented gauze remnants with necrotic material inclusions and fibrotic capsules. To our knowledge, this patient's case represents the longest time for which a foreign body has been retained in the liver. In addition, we conducted a comprehensive literature review of foreign bodies retained in the liver. Foreign bodies may be introduced into the liver via penetrating trauma, surgical procedures or the ingestion of foreign bodies (which then migrate from the gut). Thus, they can be classified into the following three categories: penetrating, medical and migrated foreign bodies. The details of the case are thoroughly described. PMID- 23745043 TI - Is the American Association for the Study of Liver Diseases recommendation for hepatocellular carcinoma screening a cul-de-sac? AB - The American Association for the Study of Liver Diseases just confirmed a grade I recommendation for hepatocellular carcinoma (HCC) screening despite growing controversy. Why should HCC be an exception in the long list of other cancers where the feasibility and the efficacy of screening were investigated by randomized trials? Only 12.0% of United States patients are screened, a fact that precludes efficacy, and there are no relevant figures on the benefit-risk ratio. The ethics of belief is a treacherous reef. Screening is not just performing a test, but is a public health issue: a national program is needed to ensure minimal participation, quality controls and evaluation of the results to improve the process. There are also serious concerns regarding undisclosed potential conflicts of interest. PMID- 23745044 TI - An investigation of the influence of cell topography on epithelial mechanical stresses during pulmonary airway reopening. AB - The goal of this study is to assess the local mechanical environment of the pulmonary epithelium in a computational model of airway reopening. To this end, the boundary element method (BEM) in conjunction with lubrication theory is implemented to assess the stationary-state behavior of a semi-infinite bubble traveling through a liquid-occluded parallel plate flow chamber lined with epithelial cells. The fluid occlusion is assumed to be Newtonian and inertia is neglected. The interactions between the microgeometry of the model airway's walls and the interfacial kinematics surrounding the bubble's tip result in a complex, spatially and temporally dependent stress distribution. The walls' nonplanar topography magnifies the normal and shear stresses and stress gradients. We find that decreasing the bubble's speed serves to increase the maximum normal stress and stress gradient but decrease the maximum shear stress and stress gradient. Our results give credence to the pressure-gradient-induced epithelial damage theory recently proposed by Bilek et al. [J. Appl. Physiol. 94, 770 (2003)] and Kay et al. [J. Appl. Physiol. 97, 269 (2004)]. We conclude that the amplified pressure gradients found in this study may be even more detrimental to the airway's cellular epithelium during airway reopening. PMID- 23745045 TI - Pentablock copolymers of pluronic F127 and modified poly(2-dimethyl amino)ethyl methacrylate for internalization mechanism and gene transfection studies. AB - Cationic polymers are one of the major nonviral gene delivery vectors investigated in the past decade. In this study, we synthesized several cationic copolymers using atom transfer radical polymerization (ATRP) for gene delivery vectors: pluronic F127-poly(dimethylaminoethyl methacrylate) (PF127-pDMAEMA), pluronic F127-poly (dimethylaminoethyl methacrylate-tert-butyl acrylate) (PF127 p(DMAEMA-tBA)), and pluronic F127-poly(dimethylaminoethyl methacrylate-acrylic acid) (PF127-p(DMAEMA-AA)). The copolymers showed high buffering capacity and efficiently complexed with plasmid deoxyribonucleic acid (pDNA) to form nanoparticles 80-180 nm in diameter and with positive zeta potentials. In the absence of 10% fetal bovine serum, PF127-p(DMAEMA-AA) showed the highest gene expression and the lowest cytotoxicity in 293T cells. After acrylic acid groups had been linked with a fluorescent dye, the confocal laser scanning microscopic image showed that PF127-p(DMAEMA-AA)/pDNA could efficiently enter the cells. Both clathrin-mediated and caveolae-mediated endocytosis mechanisms were involved. Our results showed that PF127-p(DMAEMA-AA) has great potential to be a gene delivery vector. PMID- 23745046 TI - Psychomotor retardation and externally oriented thinking in major depression. AB - OBJECTIVE: To investigate possible correlations between the tendency towards alexithymia and the depressive state, globally and with regard to the Toronto Alexithymia scale (TAS-20) subscales and the Hamilton rating scale for depression (HAM-D) subscales. METHODS: 75 patients, suffering from Unipolar Depression, were assessed through the HAM-D and the TAS-20 and compared to the control group (n = 63). Both groups were divided into two subgroups (30-60 years old; 61-80 years old). Correlations between the tendency towards alexithymia and depressive symptoms, globally and with regard to the TAS-20 subscales and the HAM-D subscales, were investigated. RESULTS: WITH REGARD TO PATIENTS, A POSITIVE CORRELATION WAS FOUND BETWEEN: the HAM-D total score and the TAS-20 total score; the HAM-D factor V (psychomotor retardation) and the TAS-20 total score; the TAS 20 subscale III (externally oriented thinking) and the HAM-D total score. In addition a positive correlation between the HAM-D factor V and the TAS-20 subscales I and III was found and confirmed among females. In patients aged 30-60 years, the HAM-D factor V was correlated with all the TAS-20 subscales. As to the control group, a positive correlation was found between: the HAM-D factor I (anxiety/somatization) and the TAS-20 total score; the TAS-20 subscale I and the HAM-D total score; the HAM-D factor I and the TAS-20 subscale. The latter was confirmed in the control group aged 30-60 years. CONCLUSION: The link between alexithymia and affective symptoms has been confirmed in the patients and in the control group. An interesting data is the correlation between psychomotor retardation and externally oriented thinking among the patients. According to cognitive theories, psychomotor retardation could be related to feelings of incapacity perceived by an individual. A patient, with an externally oriented thinking, might run into a distorted perception of his own ability to function, thus causing a psychomotor "fattening". PMID- 23745047 TI - Door-to-door survey of major neurological disorders (project) in Al Quseir City, Red Sea Governorate, Egypt. AB - A door-to-door survey, including every household, was conducted for all inhabitants of Al Quseir City (33,283), Red Sea Governorate, Egypt by three specialists of neurology as well as nine senior staff members of neurology and 15 female social workers to assess the epidemiology of major neurological disorders. Over six phases, from July 1, 2009 to January 31, 2012, screening of all eligible people in the population was carried out, by which case ascertainment of all major neurological disorders included in the study was done according to the accepted definitions and diagnostic criteria of the World Health Organization. The order of frequency of prevalence of the studied neurological disorders was dementia (3.83% for those aged > 60 years), migraine (2.8% for those aged > 8 years), stroke (6.2/1000 for those aged > 20 years), epilepsy (5.5/1000), Parkinson's disease (452.1/100,000 for those aged > 40 years), cerebral palsy (3.6/1000 among children < 18 years), spinal cord disorders (63/100,000) dystonia (39.11/100,000), cerebellar ataxia (30.01/100,000), trigeminal neuralgia (28/100,000 for those aged > 37 years), chorea (21.03/100,000), athetosis (15/100,000), and multiple sclerosis (13.74/100,000). The incidence rates of stroke, epilepsy, and Bell's palsy were 181/100,000, 48/100,000, and 98.9/100,000 per year, respectively. PMID- 23745048 TI - Pharmacokinetic drug interaction profile of omeprazole with adverse consequences and clinical risk management. AB - BACKGROUND: Omeprazole, a proton pump inhibitor (PPI), is widely used for the treatment of dyspepsia, peptic ulcer, gastroesophageal reflux disease, and functional dyspepsia. Polypharmacy is common in patients receiving omeprazole. Drug toxicity and treatment failure resulting from inappropriate combination therapy with omeprazole have been reported sporadically. Systematic review has not been available to address the pharmacokinetic drug-drug interaction (DDI) profile of omeprazole with adverse consequences, the factors determining the degree of DDI between omeprazole and comedication, and the corresponding clinical risk management. METHODS: Literature was identified by performing a PubMed search covering the period from January 1988 to March 2013. The full text of each article was critically reviewed, and data interpretation was performed. RESULTS: Omeprazole has actual adverse influences on the pharmacokinetics of medications such as diazepam, carbamazepine, clozapine, indinavir, nelfinavir, atazanavir, rilpivirine, methotrexate, tacrolimus, mycophenolate mofetil, clopidogrel, digoxin, itraconazole, posaconazole, and oral iron supplementation. Meanwhile, low efficacy of omeprazole treatment would be anticipated, as omeprazole elimination could be significantly induced by comedicated efavirenz and herb medicines such as St John's wort, Ginkgo biloba, and yin zhi huang. The mechanism for DDI involves induction or inhibition of cytochrome P450, inhibition of P glycoprotein or breast cancer resistance protein-mediated drug transport, and inhibition of oral absorption by gastric acid suppression. Sometimes, DDIs of omeprazole do not exhibit a PPI class effect. Other suitable PPIs or histamine 2 antagonists may be therapeutic alternatives that can be used to avoid adverse consequences. The degree of DDIs associated with omeprazole and clinical outcomes depend on factors such as genotype status of CYP2C19 and CYP1A2, ethnicity, dose and treatment course of precipitant omeprazole, pharmaceutical formulation of object drug (eg, mycophenolate mofetil versus enteric-coated mycophenolate sodium), other concomitant medication (eg, omeprazole-indinavir versus omeprazole indinavir-ritonavir), and administration schedule (eg, intensified dosing of mycophenolate mofetil versus standard dosing). CONCLUSION: Despite the fact that omeprazole is one of the most widely prescribed drugs internationally, clinical professionals should enhance clinical risk management on adverse DDIs associated with omeprazole and ensure safe combination use of omeprazole by rationally prescribing alternatives, checking the appropriateness of physician orders before dispensing, and performing therapeutic drug monitoring. PMID- 23745049 TI - Current and future initiatives for vascular health management in clinical practice. AB - Central arterial structure and function comprise a primary determinant of vascular health, and are integral to the important concept of ventriculo-vascular coupling or interaction. Central aortic stiffening is a major influence on central blood pressure, and directly relates to coronary perfusion. The joint session of the International Society of Vascular Health (Eastern Region) and the Ukrainian Congress of Cardiology was held in Kiev, Ukraine, on September 23, 2011; it provided an expert forum to discuss arterial evaluations, clinical applications, and progress toward translating arterial protection into cardiovascular benefits. The conclusions of the expert panel were: 1. Aortic stiffness is not presently a treatment target but may be useful for substratifying cardiovascular risk in individuals in order to better target the intensity of conventional therapy, and it may be useful in assessing response to treatment. 2. Crosstalk between macro- and microcirculation in hypertension has important implications for pharmacological treatment. An antihypertensive regimen should abolish the vicious cycle between the increased resistance in the microcirculation and the increased stiffness of the larger arteries. Such treatment should be based on drugs with multiple actions on the vascular tree, or on drug combinations that target the various segments of the arterial system. 3. Several blood pressure-independent mechanisms of large artery stiffness exist. Future considerations for clinical understanding of large artery stiffness should involve new drugs and new evaluation methods - with a focus on vascular health, for the initiation of cardiovascular prevention, for newly designed studies for treatment evaluation, and for new studies of drug combinations. 4. Arterial stiffening is a sign of cardiovascular aging and is a major factor affecting the biomechanics of large arteries. Arterial stiffness is an attractive therapeutic target in terms of vascular aging. Healthy lifestyle, physical exercise, and smoking cessation are the most effective ways of preventing and treating early vascular aging. Long-term effects of cardiovascular drugs on arterial stiffness need to be further investigated. 5. The emerging clinical data on the cardio ankle vascular index (CAVI) technique of arterial health assessment is presented, showing that the CAVI is elevated in aging, coronary artery diseases, chronic kidney disease, hypertension, diabetes mellitus, smoking, and stress. The CAVI decreased with the administration of statins, angiotensin II receptor blocking agents, and calcium channel blockers. The CAVI is suggested as an important predictor of cardiovascular diseases. Future development of a clinical understanding of large artery stiffness is important and should include consideration of new drugs and new evaluation methods, with a focus on vascular health aimed at cardiovascular prevention. PMID- 23745050 TI - Validation of Omron RS8, RS6, and RS3 home blood pressure monitoring devices, in accordance with the European Society of Hypertension International Protocol revision 2010. AB - BACKGROUND: Allowing patients to measure their blood pressure at home is recognized as being of clinical value. However, it is not known how often these measurements are taken correctly. Blood pressure monitors for home use fall into two types based on the position of the cuff, ie, at the upper arm or the wrist. The latter is particularly convenient, as measurements can be taken fully clothed. This study aimed to evaluate the performance of the wrist-type blood pressure monitors Omron RS8 (HEM-6310F-E), Omron RS6 (HEM-6221-E), and Omron RS3 (HEM-6130-E). METHODS: A team of three trained doctors validated the performance of these devices by comparing the measurements obtained from these devices with those taken using a standard mercury sphygmomanometer. All the devices met the validation requirements of the European Society of Hypertension International Protocol revision 2010. RESULTS: The difference in blood pressure readings between the tested device and the standard mercury sphygmomanometer was within 3 mmHg, which is acceptable according to the European Society of Hypertension guidelines. CONCLUSION: All the home devices tested were found to be suitable for measuring blood pressure at home because their performance fulfilled the requirement of the guidelines. PMID- 23745051 TI - Telangiectatic osteosarcoma: a review of literature. AB - Telangiectatic osteosarcoma is a rare variant of osteosarcoma and hence its occurrence, presentation, and prognosis are poorly understood. With advancements in technology and available treatment options, the scenario of its diagnosis, management, and outcome has changed. Chemotherapy with surgery was challenged previously, but has now been proved to be beneficial. We reviewed the available literature and compared results to define the characteristics of the disease, its presentation, radiographic and pathologic features, optimal treatment, and prognosis. PMID- 23745052 TI - The different radiosensitivity when combining erlotinib with radiation at different administration schedules might be related to activity variations in c MET-PI3K-AKT signal transduction. AB - OBJECTIVES: The aim of this paper was to investigate the efficacy and activity variation associated with phosphoinositide 3-kinase (PI3K) signal transduction when combining erlotinib with radiation, using different administration schedules. MATERIALS AND METHODS: Erlotinib was delivered to A973 cancer cells in the following three ways: (1) irradiation after administration, (2) irradiation upon administration, and, (3) irradiation before administration. The cell survival rates were detected using colony-forming assays, while cell apoptosis was detected with flow cytometry. The expression levels of C-MET, p-C-MET, AKT, and p-AKT were determined via Western blotting analysis, under 6 Gy irradiation with/ without erlotinib. RESULTS: The sensitizer enhancement ratios (SERs) of erlotinib irradiation after administration, irradiation upon administration, and irradiation before administration groups were 2.19, 1.53, and 1.38, respectively. A higher apoptosis rate was observed when irradiation was delivered after erlotinib. In addition, changes in cell apoptosis were found to be related to concurrent changes in C-MET, p-C-MET, AKT, and p-AKT expression. Protein expression increased in the combination groups, with trends showing a negative relationship with cell apoptosis. CONCLUSION: The radiosensitive effect of erlotinib varied because of the different administration schedules; this variation may be related to PI3K signal transduction and its associated regulating effect. PMID- 23745053 TI - Herpes zoster in the T1 dermatome presenting with Horner's syndrome, radicular weakness, and postherpetic neuralgia. AB - Herpes zoster is caused by varicella zoster virus infection involving the dorsal root ganglia of spinal nerve roots. This common problem can be associated with multiple neurological abnormalities. We present a case of Herpes zoster affecting the T1 dermatome associated with ipsilateral Horner's syndrome and radicular weakness. PMID- 23745054 TI - Hypoglycemia associated with off-label sitagliptin use. AB - PURPOSE: To describe a case of hypoglycemia induced by off-label use of sitagliptin in an adult patient with type 2 diabetes. CASE SUMMARY: Addition of sitagliptin to metformin, glimepiride, and NovoLog((r)) 70/30 Mix induced hypoglycemia in a 55-year-old Caucasian female. Hypoglycemia improved, although still occurred periodically, following sulfonylurea discontinuation and a 28% insulin dose reduction. Hypoglycemic symptoms were absent during a 3-day dechallange but occurred again upon sitagliptin reinitiation. DISCUSSION: Although the mechanism of action of sitagliptin does not predispose patients to hypoglycemic events, when combined with hypoglycemia-inducing medications, eg, sulfonylureas or insulin, and possibly meglitinides, the incidence likely increases. CONCLUSIONS: Caution should be used when combining sitagliptin with either sulfonylureas or insulin, and possibly meglitinides, for the treatment of type 2 diabetes as hypoglycemia may ensue. Hypoglycemia due to off-label combinations with insulin and sitagliptin may be prevented by reducing meal-time insulin doses. Prescribers and patients should vigilantly monitor for hypoglycemic events when using sitagliptin off-label with similar pharmacologic combinations such as meglitinides and other rapid-acting insulin products. Additionally, clinicians may encounter resistance from insurance companies to cover such off-label combinations. PMID- 23745055 TI - Combined cutaneous findings with segmental odontomaxillary dysplasia: Review of the literature and proposal of a new clinical classification. AB - Segmental odontomaxillary dysplasia is characterized by variability of its clinical and radiological features, and may mimic other fibro-osseous lesions. We describe the case of a segmental odontomaxillary dysplasia in a 12-year-old male comprising of dermal, gingival, bony, and dental abnormalities. He presented with left midfacial diffuse hyperkeratotic erythematous lesion, ipsilateral hypopigmentation of upper lip with indistinct vermilion border, left-sided facial swelling, unilateral maxillary enlargement and ipsilateral failure of eruption of permanent teeth. Radiographic imaging showed abnormal bony trabeculation, impacted and missing teeth. Histopathologic findings showed characteristic features of segmental odontomaxillary dysplasia. We herein report a case of this rare unusual anomaly, review the literature, and propose a new clinical classification based on the limited number of previously reported cases in an attempt to categorize the clinical variants of the condition which might be helpful when treatment options are to be considered. Clinicians should be aware of its presence when encountering patients presenting with a facial cutaneous lesion especially when it is associated with facial asymmetry and unresponsive to treatment. PMID- 23745056 TI - Development and implementation of an online hybrid model for teaching evidence based practice to health professions: processes and outcomes from an Australian experience. AB - Evidence-based practice is now considered to be a vital element of health care service delivery. The call to use evidence to inform other areas, such as teaching and learning, is growing. This paper reports on the processes used to integrate best evidence into teaching practices within an undergraduate health science program. An existing course within this program at an Australian tertiary institution was remodeled by a newly appointed course coordinator in response to critical feedback from student cohorts. A systematic, iterative, five-step approach was used in the development of the new course. The process of development was influenced by current research evidence, an audit of the existing course, and critical feedback from students. The new course was evaluated using quantitative and qualitative research methods for five study periods. In 2005, prior to implementing the changes, the overall student satisfaction rating for the course was zero (representing the lowest possible score). In 2006, the overall student satisfaction rating was 62.07, in 2007 it was 65.8, and in 2008 it was 55.7. Qualitative findings also supported these quantitative findings, indicating improvements in the structure and process of the new course. The outcomes from the evaluation of the remodeled course provide evidence of a consistent quality learning experience for students, and support the concept of using research evidence to guide the development of teaching and learning practices in the training of health professionals. PMID- 23745057 TI - PowerPoint or chalk and talk: Perceptions of medical students versus dental students in a medical college in India. AB - PURPOSE: To assess students' perceptions of the impact of PowerPoint (PPT) presentations in lectures in comparison to the traditional chalk and talk method and lectures using transparencies and overhead projector (TOHP). The study analyzes the preferences for teaching aids of medical students versus dental students. METHODS: Second year medical and dental undergraduates were asked to fill in a nine-item questionnaire about their perceptions of the three lecture delivery methods. Following analysis of the questionnaire the students were interviewed further. The results were analyzed separately for medical and dental students to see if there was any difference in their perceptions. RESULTS: The majority of the medical students (65.33%) preferred PPT presentations, while 15.16% of students preferred the lectures using chalkboard, and 19.51% preferred TOHP for teaching (P < 0.001). Of the dental students: 41.84% preferred chalkboard, 31.21% preferred TOHP, and 25.85% students preferred PPT presentations in the lectures (P < 0.05). Some important comments of the students were also recorded on interview which could be valuable for the medical teachers. CONCLUSION: The medical students clearly preferred the use of PPT presentations while the dental students did not. The study does not bring out evidence based superiority of any lecture delivery method. It appears that in the hands of a trained teacher any teaching aid would be appropriate and effective. This highlights the need for formal training in teaching technologies to develop good presentation skills and thus motivate the students. PMID- 23745058 TI - Station-based deconstructed training model for teaching procedural skills to medical students: a quasi-experimental study. AB - BACKGROUND: Every procedural skill consists of some microskills. One of the effective techniques for teaching a main procedural skill is to deconstruct the skill into a series of microskills and train students on each microskill separately. When we learn microskills, we will learn the main skill also. This model can be beneficial for tuition on procedural skills. OBJECTIVE: In this study, we propose a stationed-based deconstructed training model for tuition of each microskill, and then we assessed the medical students' self-perceived abilities. METHODS: This quasi-experimental study was conducted in 268 medical students (536 matched pre- and post-questionnaires) at the surgical clerkship stage during five consecutive years in three teaching and learning groups. In this study, we taught each skill in 10 steps (proposed model) to the students. We then evaluated the students' self-perceived abilities using a pre- and post-self assessment technique. SPSS v13 software with one-way analysis of variance and paired t-tests were used for data collection and analysis. RESULTS: Assessment of medical students' perceived abilities before and after training showed a significant improvement (P < 0.001) in both cognitive and practical domains. There were also significant differences between the three teaching and learning groups (P < 0.001). There were no significant differences for the different years of training regarding the observed improvement. CONCLUSION: This study suggests that deconstructing the practical skills into microskills and tuition of those microskills via the separated structured educational stations is effective according to the students' self-ratings. PMID- 23745059 TI - Doctors or technicians: assessing quality of medical education. AB - Medical education institutions usually adapt industrial quality management models that measure the quality of the process of a program but not the quality of the product. The purpose of this paper is to analyze the impact of industrial quality management models on medical education and students, and to highlight the importance of introducing a proper educational quality management model. Industrial quality management models can measure the training component in terms of competencies, but they lack the educational component measurement. These models use performance indicators to assess their process improvement efforts. Researchers suggest that the performance indicators used in educational institutions may only measure their fiscal efficiency without measuring the quality of the educational experience of the students. In most of the institutions, where industrial models are used for quality assurance, students are considered as customers and are provided with the maximum services and facilities possible. Institutions are required to fulfill a list of recommendations from the quality control agencies in order to enhance student satisfaction and to guarantee standard services. Quality of medical education should be assessed by measuring the impact of the educational program and quality improvement procedures in terms of knowledge base development, behavioral change, and patient care. Industrial quality models may focus on academic support services and processes, but educational quality models should be introduced in parallel to focus on educational standards and products. PMID- 23745061 TI - Occupational safety among dental health-care workers. AB - Compared to other health-care workers, dental health-care workers come in close contact with patients and use a variety of sharp and high-speed rotating instruments. It is important to understand the characteristics of the occupational accidents that occur. We reviewed incident reports from April 1, 2005, to March 31, 2010, at Matsumoto Dental University Hospital. In addition, questionnaires dealing with identification of occupational safety issues, especially splash exposures, were conducted for dentists, dental hygienists, and nurses. Thirty-two occupational injuries were reported during the study period, including 23 sharp instrument injuries (71.9%), 6 splash exposures (18.8%), and 3 others. Of the six splash exposures, only two cases involved potential contamination with blood or other potentially infectious patient material. Of the 66 workers who experienced sharps injuries, 20 workers (30.3%, 20/66) reported them to the hospital work safety team. The questionnaire revealed high incident of splash exposures and conjunctiva exposures: 87.9% (51/58) and 60.3% (35/58) in dentists and 88.6% (39/44) and 61.4% (27/44) in dental hygienists. The compliance rate for routine use of protective eyewear was 60.3% (35/58) for dentists and 34.1% (15/44) for hygienists. Of the presented informational items included in the questionnaire, those that strongly persuaded respondents to use protective eyewear were 'splatters from the patient's mouth contain blood' (90%, 99/110) and 'dental operations at our clinic are performed based only on a questionnaire without serious examinations for HBV, HCV, and HIV' (71.8%, 79/110). The reason of low compliance of protective eyewear among dentists might relate to fine dental procedures. Appropriate information is important for the motive of wearing personal protective equipment, and an early educational program may have a potential to increase compliance with the use of that equipment. PMID- 23745060 TI - Supporting medical students with learning disabilities in Asian medical schools. AB - Learning disabilities (LDs) represent the largest group of disabilities in higher education (HE) institutes, including medical schools, and the numbers are continuing to rise. The worrying concern is that two-thirds to half of these students with LDs remain undiagnosed when they start their undergraduate education and may even graduate without having their disabilities diagnosed. These students struggle with their academic abilities, receive poor grades and, as a result, develop lower perceptions of their intellectual abilities than do those students without LDs. All these ultimately hamper their professional practice, employment, and career progression. Appropriate and adequate educational policies, provisions, and practices help students to progress satisfactorily. In Asian countries, public and professional awareness about LDs is low, supportive provisions are limited, legislations are inadequate, data are scarce, and equal-opportunity/widening-participation policies are not implemented effectively in the HE sector. This article discusses the issues related to LDs in medical education and draws policy, provision, and practice implications to identify, assess, and support students with LDs in medical schools, particularly in an Asian context. PMID- 23745062 TI - Peer review practicalities in clinical medicine. AB - Peer review processes in teaching requires a reviewer to observe a teacher's practice in a planned manner. Conversation between the two enables the teacher to reflect on their own teaching, promoting self-improvement. Although a central part of the teaching process, and despite its crucial role in continuing professional development, peer review is not widely practiced in hospital settings. This article explains the process and its benefits. Practical implementations of the process in busy clinical settings are suggested. Its evaluation and incorporation into undergraduate learning and postgraduate clinical practice are described. With enthusiastic support for colleagues and allowances for its implementation, it should become part of the regular teaching practice, improving the quality of teaching delivered. PMID- 23745063 TI - Five-year survey of medical student attrition in a medical school in Nigeria: a pilot study. AB - BACKGROUND: Student attrition represents a waste of career opportunity and, at times, results in a holistic loss of sense of self-worth for the students involved. The aim of this study was to evaluate the nature, causes, and impact of medical student attrition in Nigeria. METHOD: A pilot analysis was undertaken using the records of students who failed at medical school as a result of inability to pass the second MBBS examination at Ebonyi State University, Abakaliki, Nigeria, between 2002 and 2007. Some of these students were interviewed using a structured questionnaire. RESULTS: Data analysis showed that 58 (7.8%) of the students admitted into preclinical class withdrew from their study. Thirty-six (62.1%) were males and the rest were females. Thirteen of those withdrawn were interviewed, and 53.8% of them believed they had poor academic ability, while 15.4% attributed their withdrawal to family pressure. No record of guidance or counseling session programs was noted for these students either at the point of withdrawal from the faculty and on the choice of a new career path. CONCLUSION: As a result of the high attrition rate due to low academic ability, efforts should be made to check students for evidence of this at the point of admission to medicine training. Also, more accommodating teaching programs should be encouraged in faculties to accommodate students with such challenges. Good guidance and counseling programs should be encouraged to handle these inevitable cases of attrition when they occur, to avoid the demoralizing low self-esteem that plagues these individuals for the rest of their lives. PMID- 23745064 TI - Evaluating an undergraduate interprofessional simulation-based educational module: communication, teamwork, and confidence performing cardiac resuscitation skills. AB - PURPOSE: Interprofessional (IP) collaboration during cardiac resuscitation is essential and contributes to patient wellbeing. The purpose of this study is to evaluate an innovative simulation-based IP educational module for undergraduate nursing and medical students on cardiac resuscitation skills. METHODS: Nursing and medical trainees participated in a new cardiac resuscitation curriculum involving a 2-hour IP foundational cardiac resuscitation skills lab, followed by three 2-hour IP simulation sessions. Control group participants attended the existing two 2-hour IP simulation sessions. Study respondents (N = 71) completed a survey regarding their confidence performing cardiac resuscitation skills and their perceptions of IP collaboration. RESULTS: Despite a consistent positive trend, only one out of 17 quantitative survey items were significantly improved for learners in the new curriculum. They were more likely to report feeling confident managing the airway during cardiac resuscitation (P = 0.001). Overall, quantitative results suggest that senior nursing and medical students were comfortable with IP communication and teamwork and confident with cardiac resuscitation skills. There were no significant differences between nursing students' and medical students' results. Through qualitative feedback, participants reported feeling comfortable learning with students from other professions and found value in the IP simulation sessions. CONCLUSION: Results from this study will inform ongoing restructuring of the IP cardiac resuscitation skills simulation module as defined by the action research process. Specific improvements that are suggested by these findings include strengthening the team leader component of the resuscitation skills lab and identifying learners who may benefit from additional practice in the role of team leader and with other skills where they lack confidence. PMID- 23745065 TI - Using systematically observed clinical encounters (SOCEs) to assess medical students' skills in clinical settings. AB - INTRODUCTION: The Objective Structured Clinical Examination (OSCE) is widely used to assess the clinical performance of medical students. However, concerns related to cost, availability, and validity, have led educators to investigate alternatives to the OSCE. Some alternatives involve assessing students while they provide care to patients - the mini-CEX (mini-Clinical Evaluation Exercise) and the Long Case are examples. We investigated the psychometrics of systematically observed clinical encounters (SOCEs), in which physicians are supplemented by lay trained observers, as a means of assessing the clinical performances of medical students. METHODS: During the pediatrics clerkship at the University of Iowa, trained lay observers assessed the communication skills of third-year medical students using a communication checklist while the students interviewed and examined pediatric patients. Students then verbally presented their findings to faculty, who assessed students' clinical skills using a standardized form. The reliability of the combined communication and clinical skills scores was calculated using generalizability theory. RESULTS: Fifty-one medical students completed 199 observed patient encounters. The mean combined clinical and communication skills score (out of a maximum 45 points) was 40.8 (standard deviation 3.3). The calculated reliability of the SOCE scores, using generalizability theory, from 10 observed patient encounters was 0.81. Students reported receiving helpful feedback from faculty after 97% of their observed clinical encounters. CONCLUSION: The SOCE can reliably assess the clinical performances of third-year medical students on their pediatrics clerkship. The SOCE is an attractive addition to the other methods utilizing real patient encounters for assessing the skills of learners. PMID- 23745066 TI - Interprofessional education: a concept analysis. AB - Interprofessional education is broadly defined as a teaching and learning process that fosters collaborative work between two or more health care professions. Interprofessional education, as a proven, beneficial approach to collaborative learning that addresses the problems of fragmentation in health care delivery and separation among health care professionals, is frequently promulgated but not always successfully implemented. Furthermore, there are several different interpretations, overlapping terminologies, interchangeable terms, and a lack of uniformity of a definition for interprofessional education. This concept analysis determines the attributes and characteristics of interprofessional education, develops an operational definition that fits all health-related disciplines, defines common goals, and improves overall clarity, consensus, consistency, and understanding of interprofessional education among educators, professionals, and researchers. Through effective incorporation of interprofessional education into curricular and practice settings, optimal patient-centered outcomes can potentially result as effective and highly integrated teams facilitate and optimize collaborative patient care and safety. PMID- 23745067 TI - Teaching surgical skills in obstetrics using a cesarean section simulator - bringing simulation to life. AB - PURPOSE: Cesarean section is the most common surgery performed in obstetrics. Incorporating a simulation model into training provides a safe, low-stress environment in which students can gain skills and receive feedback. The purpose of this study was to determine the effectiveness of obstetrics simulator training for medical students doing their internship. METHODS: Twenty-five students posted in the Department of Obstetrics and Gynecology received a formal lecture on cesarean section and demonstration of the procedure on a mannequin in the first week of their internship, The study group (n = 12) practiced their skills on an obstetrics simulator under the direct supervision of a faculty member. The control group received no simulator-based training (n = 13) or further instruction. All students were asked to complete a prevalidated questionnaire to assess their level of confidence in performing the procedure after the educational session. RESULTS: Compared with their peers in the study, students in the simulator group were significantly more likely to define the steps of cesarean section (91% vs 61.5%), and were comfortable in assisting cesarean section (100% vs 46.15%) as they were able to identify the layers of abdomen opened during cesarean section. All 12 students reported this as an excellent experience. CONCLUSION: We were able to construct an inexpensive cesarean section trainer that facilitates instruction in cesarean section technique in a low stress environment. PMID- 23745070 TI - Narrative reflective practice in medical education for residents: composing shifting identities. AB - As researchers note, medical educators need to create situations to work with physicians in training to help them attend to the development of their professional identities. While there is a call for such changes to be included in medical education, educational approaches that facilitate attention to the development of medical students' professional identities, that is, who they are and who they are becoming as physicians, are still under development. One pedagogical strategy involves narrative reflective practice as a way to develop physician identity. Using this approach, medical residents first write narrative accounts of their experiences with patients in what are called "parallel charts". They then engage in a collaborative narrative inquiry within a sustained inquiry group of other residents and two researcher/facilitators (one physician, one narrative researcher). Preliminary studies of this approach are underway. Drawing on the experiences of one medical resident in one such inquiry group, we show how this pedagogical strategy enables attending to physician identity making. PMID- 23745069 TI - Introducing students to patient safety through an online interprofessional course. AB - Interprofessional education (IPE) is increasingly called upon to improve health care systems and patient safety. Our institution is engaged in a campus-wide IPE initiative. As a component of this initiative, a required online interprofessional patient-safety-focused course for a large group (300) of first year medical, dental, and nursing students was developed and implemented. We describe our efforts with developing the course, including the use of constructivist and adult learning theories and IPE competencies to structure students' learning in a meaningful fashion. The course was conducted online to address obstacles of academic calendars and provide flexibility for faculty participation. Students worked in small groups online with a faculty facilitator. Thematic modules were created with associated objectives, online learning materials, and assignments. Students posted completed assignments online and responded to group members' assignments for purposes of group discussion. Students worked in interprofessional groups on a project requiring them to complete a root cause analysis and develop recommendations based on a fictional sentinel event case. Through project work, students applied concepts learned in the course related to improving patient safety and demonstrated interprofessional collaboration skills. Projects were presented during a final in-class session. Student course evaluation results suggest that learning objectives and content goals were achieved. Faculty course evaluation results indicate that the course was perceived to be a worthwhile learning experience for students. We offer the following recommendations to others interested in developing an in-depth interprofessional learning experience for a large group of learners: 1) consider a hybrid format (inclusion of some face-to-face sessions), 2) address IPE and broader curricular needs, 3) create interactive opportunities for shared learning and working together, 4) provide support to faculty facilitators, and 5) recognize your learners' educational level. The course has expanded to include students from additional programs for the current academic year. PMID- 23745068 TI - Innoversity in knowledge-for-action and adaptation to climate change: the first steps of an 'evidence-based climatic health' transfrontier training program. AB - It has become increasingly clear to the international scientific community that climate change is real and has important consequences for human health. To meet these new challenges, the World Health Organization recommends reinforcing the adaptive capacity of health systems. One of the possible avenues in this respect is to promote awareness and knowledge translation in climatic health, at both the local and global scales. Within such perspective, two major themes have emerged in the field of public health research: 1) the development of advanced training adapted to 'global environment' change and to the specific needs of various groups of actors (doctors, nurses, public health practitioners, health care managers, public service managers, local communities, etc) and 2) the development of strategies for implementing research results and applying various types of evidence to the management of public health issues affected by climate change. Progress on these two fronts will depend on maximum innovation in transdisciplinary and transsectoral collaborations. The general purpose of this article is to present the program of a new research and learning chair designed for this double set of developmental objectives - a chair that emphasizes 'innoversity' (the dynamic relationship between innovation and diversity) and 'transfrontier ecolearning for adaptive actions'. The Ecoapprentissages, sante mentale et climat collaborative research chair (University of Montreal and Quebec National Public Health Institute) based in Montreal is a center for 'transdisciplinary research' on the transfrontier knowledge-for-action that can aid adaptation of the public health sector, the public mental health sector, and the public service sector to climate change, as well as a center for complex collaborations on evidence-based climatic health 'training'. This program-focused article comprises two main sections. The first section presents the 'general' and 'specific contexts' in which the chair emerged. The 'general context' pertains to the health-related challenge of finding ways to integrate, transfer, and implement knowledge, a particularly pointed challenge in Canada. The 'specific context' refers to the emerging research field of adaptation of public health to climate change. In the second section, the characteristics of the research chair are more extensively detailed (the vision of 'innoversity' and ' transfrontier knowledge-for-action,' the approach of shared responsibility and complex collaboration, objectives, and major axes of research). We conclude with a call for complex collaboration toward knowledge-for-action in public health services/mental health services/public services' adaptation to climate change: this call is aimed at individual and institutional actors in the North and South/West and East concerned by these issues. PMID- 23745071 TI - Student performance and their perception of a patient-oriented problem-solving approach with audiovisual aids in teaching pathology: a comparison with traditional lectures. AB - PURPOSE: We use different methods to train our undergraduates. The patient oriented problem-solving (POPS) system is an innovative teaching-learning method that imparts knowledge, enhances intrinsic motivation, promotes self learning, encourages clinical reasoning, and develops long-lasting memory. The aim of this study was to develop POPS in teaching pathology, assess its effectiveness, and assess students' preference for POPS over didactic lectures. METHOD: One hundred fifty second-year MBBS students were divided into two groups: A and B. Group A was taught by POPS while group B was taught by traditional lectures. Pre- and posttest numerical scores of both groups were evaluated and compared. Students then completed a self-structured feedback questionnaire for analysis. RESULTS: The mean (SD) difference in pre- and post-test scores of groups A and B was 15.98 (3.18) and 7.79 (2.52), respectively. The significance of the difference between scores of group A and group B teaching methods was 16.62 (P < 0.0001), as determined by the z-test. Improvement in post-test performance of group A was significantly greater than of group B, demonstrating the effectiveness of POPS. Students responded that POPS facilitates self-learning, helps in understanding topics, creates interest, and is a scientific approach to teaching. Feedback response on POPS was strong in 57.52% of students, moderate in 35.67%, and negative in only 6.81%, showing that 93.19% students favored POPS over simple lectures. CONCLUSION: It is not feasible to enforce the PBL method of teaching throughout the entire curriculum; However, POPS can be incorporated along with audiovisual aids to break the monotony of dialectic lectures and as alternative to PBL. PMID- 23745072 TI - A regional model of interprofessional education. AB - This paper describes the innovative features of the first regional model of interprofessional education (IPE) in the US, developed by The Commonwealth Medical College, Scranton, PA, USA, as a new, independent, community-based medical school in northeastern Pennsylvania. Essential educational components include collaborative care seminars, interprofessional sessions, simulations, live web-based seminars and newly innovative virtual environment interactive exercises. All of these elements are being integrated into the curricula of 14 undergraduate and allied professional schools, and three graduate medical education programs located in the region. Activities incorporate simulation, standardized patients, student leadership, and faculty and student facilitation. As this new regional model of interprofessional education is fully implemented, its impact will be assessed using both quantitative and qualitative outcomes measurements. Appropriate ongoing modifications to the model will be made to ensure improvement and further applicability to collaborative learning. PMID- 23745073 TI - Current status of advanced gastrointestinal endoscopy training fellowships in the United States. AB - Rapid growth in the field of advanced gastrointestinal endoscopy has led to an increase in specialized therapeutic endoscopy fellowships. The cornerstones of these programs are training in endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound. These procedures are more complex and challenging to master than routine colonoscopy and upper endoscopy, and in the case of ERCP, higher risk. The concentration of the educational experience in the hands of relatively fewer trainees with specialized interest in advanced endoscopy has resulted in providing a focused cohort of graduating fellows with higher case volumes in training, which likely enhances diagnostic and therapeutic success and safer performance of these procedures. Endoscopic simulators, although not currently in widespread use, have the potential to improve advanced procedural training without jeopardizing patient safety. PMID- 23745074 TI - Interprofessional Resource Centre: a knowledge translation strategy. AB - The Interprofessional Resource Centre (IRC) was based on an extensive literature search and a provincial consultative process that involved administrators, health care providers, educators, preceptors, and alternative and complementary health care providers from different disciplines. Information from the literature review was synthesized into a logic model that served as a preliminary outline for the IRC to be further developed during the stakeholder consultation. The findings from the literature were triangulated with the opinions of different groups of key stakeholders who participated in three different methods of data collection: 1) a large-scale deliberative survey, 2) an in-person dialogue, and 3) targeted questionnaires. The result of this process was an online tool that presents information on what needs to be considered when planning interprofessional practice and education within an organization with the purpose of: 1) building capacity within agencies for interprofessional, collaborative practice; 2) providing preceptors with educational strategies to develop interprofessional competencies in their students; 3) promoting the use of technology as a strategy for knowledge transfer within the agencies and between educational institutions; and 4) developing an evaluation plan to measure interprofessional practice and education. PMID- 23745075 TI - Community engagement in US and Canadian medical schools. AB - INTRODUCTION: This study examines the integration of community engagement and community-engaged scholarship at all accredited US and Canadian medical schools in order to better understand and assess their current state of engagement. METHODS: A 32-question data abstraction instrument measured the role of community engagement and community-engaged scholarship as represented on the Web sites of all accredited US and Canadian medical schools. The instrument targeted a medical school's mission and vision statements, institutional structure, student and faculty awards and honors, and faculty tenure and promotion guidelines. RESULTS: Medical school Web sites demonstrate little evidence that schools incorporate community engagement in their mission or vision statements or their promotion and tenure guidelines. The majority of medical schools do not include community service terms and/or descriptive language in their mission statements, and only 8.5% of medical schools incorporate community service and engagement as a primary or major criterion in promotion and tenure guidelines. DISCUSSION: This research highlights significant gaps in the integration of community engagement or community-engaged scholarship into medical school mission and vision statements, promotion and tenure guidelines, and service administrative structures. PMID- 23745076 TI - Career choices among medical students in Bangladesh. AB - INTRODUCTION: Information regarding career choices of medical students is important to plan human resources for health, design need-based educational programs, and ensure equitable and quality health care services in a country. AIM: The aim of the study is to identify career choices, nature of career, intended practice locations, and reasons for career choices of Bangladesh medical students. METHOD: First-, third-, and fifth-year students of Bangladesh Medical College and Uttara Adhunik Medical College completed a self-report questionnaire on career choices, nature of career, intended practice locations, and reasons for career choices. The students were requested to choose three long-term choices from the given specialties. RESULTS: A total of 132 students responded (46 males and 86 females) and response rate was 75%. The popular choices (first choice) among males and females were medical specialty, surgical specialty, obstetrics and gynecology, and general practice. For first, second, and third choices altogether, male students chose surgical specialties and female students preferred medical specialties. The leading reasons for selecting a specialty were personal interest and wide job opportunity. More than 67% of respondents wanted to join private services and about 90% chose major cities as practice locations. About 43% of respondents expressed willingness to practice medicine in Bangladesh, whereas 51% of total respondents wanted to practice abroad. DISCUSSION: Majority of students intended to specialize in established clinical specialties and subsequently practice in major cities, and more than half wanted to immigrate to other countries. Basic medical subjects and service-oriented (lifestyle-related) and preventive/social medical specialties were found to be less attractive. If this pattern continues, Bangladesh will suffer a chronic shortage of health personnel in certain specialties and in rural areas. CONCLUSIONS: Reorientation of health care and medical education is needed along with policy settings to attract doctors to the scarcity and high-priority disciplines so that imbalances encountered would be minimal in future. PMID- 23745077 TI - Simple heuristics in over-the-counter drug choices: a new hint for medical education and practice. AB - INTRODUCTION: Over-the-counter (OTC) drugs are widely available and often purchased by consumers without advice from a health care provider. Many people rely on self-management of medications to treat common medical conditions. Although OTC medications are regulated by the National and the International Health and Drug Administration, many people are unaware of proper dosing, side effects, adverse drug reactions, and possible medication interactions. PURPOSE: This study examined how subjects make their decisions to select an OTC drug, evaluating the role of cognitive heuristics which are simple and adaptive rules that help the decision-making process of people in everyday contexts. SUBJECTS AND METHODS: By analyzing 70 subjects' information-search and decision-making behavior when selecting OTC drugs, we examined the heuristics they applied in order to assess whether simple decision-making processes were also accurate and relevant. Subjects were tested with a sequence of two experimental tests based on a computerized Java system devised to analyze participants' choices in a virtual environment. RESULTS: We found that subjects' information-search behavior reflected the use of fast and frugal heuristics. In addition, although the heuristics which correctly predicted subjects' decisions implied significantly fewer cues on average than the subjects did in the information-search task, they were accurate in describing order of information search. A simple combination of a fast and frugal tree and a tallying rule predicted more than 78% of subjects' decisions. CONCLUSION: The current emphasis in health care is to shift some responsibility onto the consumer through expansion of self medication. To know which cognitive mechanisms are behind the choice of OTC drugs is becoming a relevant purpose of current medical education. These findings have implications both for the validity of simple heuristics describing information searches in the field of OTC drug choices and for current medical education, which has to prepare competent health specialists to orientate and support the choices of their patients. PMID- 23745078 TI - Introduction of virtual patients onto a final year anesthesia course: Hong Kong experience. AB - e-Learning has revolutionized the way in which undergraduate medical education is delivered. One e-learning tool of note is the virtual patient (VP), a type of computer software that simulates real-life clinical scenarios, in which the learner emulates the role of health care provider to obtain the history, conduct examination, and make diagnoses and management decisions. VPs have been in use since 1993. Early designs were based on serial screen-cards of patient history, examination, investigations, diagnoses, treatment, and outcome, which the learner explored. With the development of web technology, VPs can now be accessed via the Internet and are more versatile, supporting different structural designs to suit a variety of learning objectives, and they can branch via different routes through a case. Using VPs has a number of advantages: 1) VPs improve access to learning material, 2) VPs help learners to acquire higher order cognitive skills like strategic thinking and decision making, 3) VPs provide a safe environment to practice, 4) VPs help to teach interdisciplinary care, and 5) VPs can be used instead of patients for examination. A number of well-known VP player systems are in use today: CASUS, CAMPUS, web-based Simulation of Patients, OpenLabyrinth, and vpSim. At the Chinese University of Hong Kong, we have also developed a web-based VP authoring and player system called Formative Assessment Case Studies (FACS), which is run by our Teaching and Learning Resources Centre. FACS has been integrated into Year-5 Anesthesia teaching since 2006. Three VP products have been developed: Anaesthesia FACS (six cases) that teaches preoperative assessment, Acute Pain Management FACS, and an eight-part longitudinal VP which tells the story of a patient's stay, and anesthesia care, for routine gynecological surgery. Students spend about 3 hours on each during a 2-week clinical attachment. Our VPs have been well received and have overcome problems of providing adequate clinical exposure. PMID- 23745080 TI - Medical students' assessment preferences at King Faisal University, Saudi Arabia. AB - OBJECTIVE: To assess the preferred methods for assessment among medical students at both preclinical and clinical stages of medical education and the possible correlates that promote these preferences. SUBJECTS AND METHODS: All medical students from the third year onwards were surveyed. A self-administered anonymous questionnaire was designed to gather information on the preferred assessment method for course achievement. The preferred methods were also evaluated in relation to cognitive functions. Preference for specific exam format, in the form of multiple choices, short essay questions, or both, and the stated reasons for that preference, was also included in the questionnaire. RESULTS: Out of 310 questionnaires distributed, 238 were returned. Written tests, projects, portfolios, and take home exams were the preferred modes for assessing students' achievements in a course; oral tests including a viva voce were the least preferred type of assessment. Questions that tested the domains of 'understanding' and 'application' were the most preferred type while those entailing 'analysis' were the least preferred. Multiple choice question format was the most preferred type of question (68.7%) at both pre- and clinical stages. CONCLUSION: Students' assessments at the College of Medicine, King Faisal University, Saudi Arabia, do not use the full range of cognitive domains. The emphasis on higher domains for medical students' assessment incorporating critical thinking should increase as the students' progress through their medical courses. PMID- 23745079 TI - Physician participation in clinical research and trials: issues and approaches. AB - The rapid development of new drugs, therapies, and devices has created a dramatic increase in the number of clinical research studies that highlights the need for greater participation in research by physicians as well as patients. Furthermore, the potential of clinical research is unlikely to be reached without greater participation of physicians in research. Physicians face a variety of barriers with regard to participation in clinical research. These barriers are system-or organization-related as well as research-and physician-related. To encourage physician participation, appropriate organizational and operational infrastructures are needed in health care institutes to support research planning and management. All physicians should receive education and training in the fundamentals of research design and methodology, which need to be incorporated into undergraduate medical education and postgraduate training curricula and then reinforced through continuing medical education. Medical schools need to analyze current practices of teaching-learning and research, and reflect upon possible changes needed to develop a 'student-focused teaching-learning and research culture'. This article examines the barriers to and benefits of physician participation in clinical research as well as interventions needed to increase their participation, including the specific role of undergraduate medical education. The main challenge is the unwillingness of many physicians and patients to participate in clinical trials. Barriers to participation include lack of time, lack of resources, trial-specific issues, communication difficulties, conflicts between the role of clinician and scientist, inadequate research experience and training for physicians, lack of rewards and recognition for physicians, and sometimes a scientifically uninteresting research question, among others. Strategies to encourage physician participation in clinical research include financial and nonfinancial incentives, adequate training, research questions that are in line with physician interests and have clear potential to improve patient care, and regular feedback. Finally, encouraging research culture and fostering the development of inquiry and research-based learning among medical students is now a high priority in order to develop more and better clinician-researchers. PMID- 23745081 TI - Complex interventions required to comprehensively educate allied health practitioners on evidence-based practice. AB - There is currently no strong evidence regarding the most effective training approach for allied health professionals that will support them to consistently apply the best research evidence in daily practice. Current evidence-based practice training tends to be 'one size fits all', and is unlikely to be appropriate for all allied health disciplines because of the variability in their tasks and scope of practice. The scant body of evidence regarding the effectiveness of evidence-based practice training for allied health practitioners provides some support for improving knowledge and skills, but equivocal evidence about influencing behaviors and attitudes. We propose a new model of evidence based practice training, based on the concept of complex interventions reported in the literature. We believe that by offering training in evidence-based practice based on complex interventions relevant to the needs of the attendees, using fixed and variable components, there may be greater success in significantly influencing knowledge skills, attitudes, and behaviors. PMID- 23745082 TI - Transforming nursing education: a review of stressors and strategies that support students' professional socialization. AB - Nurse educators are facing the challenge of creating new ways of teaching and facilitating enhanced learning experiences in clinical practice environments that are inherently complex, highly demanding, and unpredictable. The literature consistently reports the negative effects of excess stress and unsupportive relationships on wellbeing, self-efficacy, self-esteem, learning, persistence, and success. However, understanding contributing factors of stress, such as the student's experiences of uncaring and oppressive interactions, is clearly not adequate. The transformation of nursing education requires a paradigm shift that embraces collegiality, collaboration, caring, and competence for students and the faculty. This paper reviews the literature on stress and its effects on nursing students. Grounded in theory related to stress and human caring, this paper focuses on the clinical environment and faculty-student relationships as major sources of students' stress and offers strategies for mitigating stress while fostering learning and professional socialization of future nurses. PMID- 23745083 TI - Interface between problem-based learning and a learner-centered paradigm. AB - BACKGROUND: Problem-based learning (PBL) has made a major shift in support of student learning for many medical school curricula around the world. Since curricular development of PBL in the early 1970s and its growth in the 1980s and 1990s, there have been growing numbers of publications providing positive and negative data in regard to the curricular effectiveness of PBL. The purpose of this study was to explore supportive data for the four core objectives of PBL and to identify an interface between the objectives of PBL and a learner-centered paradigm. METHODS: The four core PBL objectives, ie, structuring of knowledge and clinical context, clinical reasoning, self-directed learning, and intrinsic motivation, were used to search MEDLINE, the Education Resources Information Center, the Educator's Reference Complete, and PsycINFO from January 1969 to January 2011. The literature search was facilitated and narrowed if the published study included the following terms: "problem-based learning", "medical education", "traditional curriculum", and one of the above four PBL objectives. RESULTS: Through a comprehensive search analysis, one can find supportive data for the effectiveness of a PBL curriculum in achieving the four core objectives of PBL. A further analysis of these four objectives suggests that there is an interface between PBL objectives and criteria from a learner-centered paradigm. In addition, this review indicates that promotion of teamwork among students is another interface that exists between PBL and a learner-centered paradigm. CONCLUSION: The desire of medical schools to enhance student learning and a need to provide an environment where students construct knowledge rather than receive knowledge have encouraged many medical schools to move into a learner-centered paradigm. Implementation of a PBL curriculum can be used as a prevailing starting point to develop not only a learner-centered paradigm, but also to facilitate a smooth curricular transition from a teacher-centered paradigm to a learner centered paradigm. PMID- 23745084 TI - Comprehensiveness of care by family physicians in Edmonton. AB - INTRODUCTION: The scope of practice by general practitioners and family physicians in North America has been changing over time. Are academic practices providing residents the same scope of practice as the urban practices into which they are going? METHODS: A survey describing the activities and scope of general practice/family practice was constructed from the literature and checked with general practitioners/family physicians for face validity. It was administered by mail to academic family physicians at the University of Alberta Department of Family Medicine in Edmonton and to all practicing general practitioners/family physicians in the city and Capital Region around Edmonton. There was a response rate of 78% and 50.9%, respectively. RESULTS: Academic physicians' practices differed from those of their urban colleagues. The former were all certified by the College of Family Physicians of Canada, worked in group practices, and included more males and fewer immigrants. They worked as many hours, but did less clinical work than their urban colleagues. Even so, 25% did more than 40 hours of clinical work each week compared with 68% of urban physicians. There was a wide scope of services and procedures provided by both groups and other services that were different from group to group. There was no difference between groups in intention to add or remove services in the next two years, but academic physicians had removed more services in the last two years. CONCLUSION: General practitioners/family physicians still provide a wide range of services. Although both academic and urban general practitioners/family physicians have reduced some services in the last two years, they have both added others to their repertoire. Although the teaching and urban general practitioners/family physicians practices have many similarities, they also have differences, which may have implications for the training of future urban family physicians. PMID- 23745085 TI - Predicting performance at medical school: can we identify at-risk students? AB - BACKGROUND: The purpose of this study was to examine the predictive potential of multiple indicators (eg, preadmission scores, unit, module and clerkship grades, course and examination scores) on academic performance at medical school, with a view to identifying students at risk. METHODS: An analysis was undertaken of medical student grades in a 6-year medical school program at the Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates, over the past 14 years. RESULTS: While high school scores were significantly (P < 0.001) correlated with the final integrated examination, predictability was only 6.8%. Scores for the United Arab Emirates university placement assessment (Common Educational Proficiency Assessment) were only slightly more promising as predictors with 14.9% predictability for the final integrated examination. Each unit or module in the first four years was highly correlated with the next unit or module, with 25%-60% predictability. Course examination scores (end of years 2, 4, and 6) were significantly correlated (P < 0.001) with the average scores in that 2-year period (59.3%, 64.8%, and 55.8% predictability, respectively). Final integrated examination scores were significantly correlated (P < 0.001) with National Board of Medical Examiners scores (35% predictability). Multivariate linear regression identified key grades with the greatest predictability of the final integrated examination score at three stages in the program. CONCLUSION: This study has demonstrated that it may be possible to identify "at-risk" students relatively early in their studies through continuous data archiving and regular analysis. The data analysis techniques used in this study are not unique to this institution. PMID- 23745086 TI - High-fidelity simulation in the nonmedical domain: practices and potential transferable competencies for the medical field. AB - Simulation is a promising pedagogical tool in the area of medical education. High fidelity simulators can reproduce realistic environments or clinical situations. This allows for the practice of teamwork and communication skills, thereby enhancing reflective reasoning and experiential learning. Use of high-fidelity simulators is not limited to the medical and aeronautical fields, but has developed in a large number of nonmedical organizations as well. The techniques and pedagogical tools which have evolved through the use of nonmedical simulations serve not only as teaching examples but also as avenues which can help further the evolution of the concept of high-fidelity simulation in the field of medicine. This paper presents examples of high-fidelity simulations in the military, maritime, and aeronautical fields. We compare the implementation of high-fidelity simulation in the medical and nonmedical domains, and discuss the possibilities and limitations of simulators in medicine, based on recent nonmedical applications. PMID- 23745087 TI - Medical students-as-teachers: a systematic review of peer-assisted teaching during medical school. AB - INTRODUCTION: International interest in peer-teaching and peer-assisted learning (PAL) during undergraduate medical programs has grown in recent years, reflected both in literature and in practice. There, remains however, a distinct lack of objective clarity and consensus on the true effectiveness of peer-teaching and its short- and long-term impacts on learning outcomes and clinical practice. OBJECTIVE: To summarize and critically appraise evidence presented on peer teaching effectiveness and its impact on objective learning outcomes of medical students. METHOD: A literature search was conducted in four electronic databases. Titles and abstracts were screened and selection was based on strict eligibility criteria after examining full-texts. Two reviewers used a standard review and analysis framework to independently extract data from each study. Discrepancies in opinions were resolved by discussion in consultation with other reviewers. Adapted models of "Kirkpatrick's Levels of Learning" were used to grade the impact size of study outcomes. RESULTS: From 127 potential titles, 41 were obtained as full-texts, and 19 selected after close examination and group deliberation. Fifteen studies focused on student-learner outcomes and four on student-teacher learning outcomes. Ten studies utilized randomized allocation and the majority of study participants were self-selected volunteers. Written examinations and observed clinical evaluations were common study outcome assessments. Eleven studies provided student-teachers with formal teacher training. Overall, results suggest that peer-teaching, in highly selective contexts, achieves short-term learner outcomes that are comparable with those produced by faculty-based teaching. Furthermore, peer-teaching has beneficial effects on student-teacher learning outcomes. CONCLUSIONS: Peer-teaching in undergraduate medical programs is comparable to conventional teaching when utilized in selected contexts. There is evidence to suggest that participating student-teachers benefit academically and professionally. Long-term effects of peer-teaching during medical school remain poorly understood and future research should aim to address this. PMID- 23745088 TI - Impact of an educational program on nursing students' caring and self-perception in intensive clinical training in Jordan. AB - BACKGROUND: Framing and development of clinical skills in nursing students during their clinical practice is critical because this can shape their future caring skills. Professional caring empowers patients and contributes to their well-being and health. Education may enhance the capacity of nurses to be effective caring practitioners. Their study program encourages caring behavior in nursing students, consequently affecting their professional self-perception. METHODS: The present study investigated the effect of an educational program on caring behavior and professional self-perception in nursing students using a controlled pre/post test study design. The study sample consisted of 50 nursing students undertaking their final year in 2010-2011. Subjects were randomly assigned to either an experimental or a control group. The study was conducted in two critical care units affiliated to the Ma'an and Queen Rania hospitals in the south of Jordan. The instruments utilized were the Caring Dimensions Inventory, Nursing Students Attitude Observational Checklist, and Professional Self-Concept of Nurses Instrument. RESULTS: The study findings favor the effect of the educational program because there was increased knowledge and understanding of caring theory and related concepts, a more holistic approach to care, enhanced caring practices, and improved self-perception in the study group compared with the control group during different periods of assessment. The study group showed significantly better caring perception in psychological, technical, and professional terms than the control group during different periods of assessment. There was a significant positive trend of overall professional self-perception for the study group compared with the control group. CONCLUSION: Nursing curricula should incorporate concepts and principles that guide students in developing caring, safe, competent, and professional behavior. Nursing students must seek educational opportunities to acquire knowledge for role preparation, to participate in knowledge generation, and for personal and professional development. PMID- 23745089 TI - Comparison of peer-led versus professional-led training in basic life support for medical students. AB - BACKGROUND: The effect of peer-led training in basic life support (BLS) in the education of medical students has not been assessed. SUBJECTS AND METHODS: This study was a randomized controlled trial with a blinded outcome assessor. A total of 74 fourth-year medical students at Ehime University School of Medicine, Japan were randomly assigned to BLS training conducted by either a senior medical student (peer-led group) or a health professional (professional-led group). The primary outcome measure was the percentage of chest compressions with adequate depth (38-51 mm) by means of a training mannequin evaluated 20 weeks after BLS training. Secondary outcome measures were compression depth, compression rate, proportion of participants who could ensure adequate compression depth (38-51 mm) and adequate compression rate (90-110/minute), and retention of BLS knowledge as assessed by 22-point questionnaire. RESULTS: Percentage chest compressions with adequate depth (mean +/- SD) was 54.5% +/- 31.8% in the peer-led group and 52.4% +/- 35.6% in the professional-led group. The 95% confidence interval (CI) of difference of the means was -18.7% to 22.8%. The proportion of participants who could ensure an adequate mean compression rate was 17/23 (73.9%) in the peer-led group but only 8/22 (36.4%) in the professional-led group (P = 0.011). On the 22 point questionnaire administered 20 weeks after training, the peer-led group scored 17.2 +/- 2.3 whereas the professional-led group scored 17.8 +/- 2.0. The 95% CI of difference of the means was -1.72 to 0.57. CONCLUSION: Peer-led training in BLS by medical students is feasible and as effective as health professional-led training. PMID- 23745090 TI - Effectiveness of an infant oral health care educational intervention on knowledge of dental students. AB - BACKGROUND: This study evaluated the effectiveness of an infant oral health care educational intervention on the knowledge of female dental students at King Saud University in Riyadh city. METHODS: One hundred and twenty-eight students participated in the study. The participants were from different levels in the dental college, ie, second year (D2), third year (D3), fourth year (D4), and fifth year (D5). Assessment by questionnaire was completed immediately before and after a 14-minute educational intervention, in the form of a PowerPoint presentation and video on oral health of infants for dental students. The 18-item multiple-choice questionnaire was based on information presented in the presentation. RESULTS: A significant difference (P < 0.001) was found between average pretest scores (9.30 +/- 2.24), and average post-test scores (12.56 +/- 2.05). The highest percentage of improvement in the post-test as compared with the pretest was recorded for group D2 (50.6%) followed by D3 (40%), D4 (35%), and D5 (23%). One hundred and twenty-six (98.4%) study participants found the presentation helpful in improving their understanding of infant oral health, and 77 (60.2%) were very satisfied with the presentation. Sixty-six participants (51.6%) reported that the presentation was very effective in teaching them about infant oral health, and 83 (65%) were very likely to incorporate this information into their daily practice. CONCLUSION: A 14-minute PowerPoint and video educational intervention was effective in teaching basic information about infant oral health to dental students. PMID- 23745091 TI - Promises and hurdles of undergraduate medical development in Greece. AB - AIM: In this paper we sought to explore undergraduate medical students' views about their professional development during their studies that are considered to be related to medical professionalism. METHOD: A descriptive cross-sectional study using interpretative analysis of anonymous 10-item questionnaires was conducted at the University of Patras Medical School (UPMS), Greece. The study sample consisted of 134 undergraduate students in their fifth and sixth year of study at UPMS. RESULTS: Undergraduate students emphasized the great significance of daily clinically-oriented practice in the wards in the group of behaviors consistent with medical professionalism. The integrated curriculum and informal discussions with members of the academic staff in the form of role models were also regarded as valuable approaches strongly enhancing professionalism. Students' personal statements contained attributes regarding premium professional skills, including constancy and perfectionism throughout a lifelong learning process, so as to be able to provide high quality medical care to patients. CONCLUSION: According to our undergraduate medical students themselves, the last 2 years of their studies are important to understand the essence of professionalism and develop their professional medical attitudes. Clinically oriented teaching activities together with the informal curriculum of enhanced role modeling promote medical professional behaviors and increase standards of health care provided to patients. PMID- 23745092 TI - Inadequate awareness of hepatitis C among nonspecialist physicians in China. AB - BACKGROUNDPURPOSE: Hepatitis C virus (HCV) is a major public health problem and can cause severe liver disease. The public has little understanding of hepatitis C. Therefore, a survey was performed to investigate the awareness of nonspecialists in China of hepatitis C. METHODS: A questionnaire on hepatitis C was publicized on the medical community site DXY.cn from April 15 to July 15, 2009. The questionnaire included ten questions and covered the etiology, epidemiology, diagnosis, treatment, and prevention of hepatitis C. RESULTS: About 1362 physicians from various regions, hospitals, and departments in China took part in the survey. Eleven percent mistakenly believed that the disease was not transmitted from mother to infant, by sharing a needle or syringe, by sharing a razor or toothbrush, or by having sex with a partner with HCV infection. Sixty two percent did not regard anti-HCV antibody detection as a routine procedure for hospitals. Forty-four percent of respondents indicated that they would not advise a patient who tested positive for anti-HCV antibody to consult a specialist. Seventy-one percent thought that hepatitis C was incurable or had a very low cure rate. Nearly 50% thought that there were no effective treatments for hepatitis C. CONCLUSION: Chinese nonspecialists have a little understanding of hepatitis C, which may have a negative effect on the prevention and treatment of hepatitis C. PMID- 23745093 TI - Introduction to Evidence-Based Medicine: a student-selected component at the Faculty of Medicine, King Abdulaziz University. AB - BACKGROUND: Evidence-based medicine (EBM) involves approaching a clinical problem using a four-step method: (1) formulate a clear clinical question from a patient's problem, (2) search the literature for relevant clinical articles, (3) evaluate (critically appraise) the evidence for its validity and usefulness, (4) implement useful findings into clinical practice. EBM has now been incorporated as an integral part of the medical curriculum in many faculties of medicine around the world. The Faculty of Medicine, King Abdulaziz University, started its process of curriculum reform and introduction of the new curriculum 4 years ago. One of the most characteristic aspects of this curriculum is the introduction of special study modules and electives as a student-selected component in the fourth year of study; the Introduction to Evidence-Based Medicine course was included as one of these special study modules. The purpose of this article is to evaluate the EBM skills of medical students after completing the course and their perceptions of the faculty member delivering the course and organization of the course. MATERIALS AND METHODS: The EBM course was held for the first time as a special study module for fourth-year medical students in the first semester of the academic year 2009-2010. Fifteen students were enrolled in this course. At the end of the course, students anonymously evaluated aspects of the course regarding their EBM skills and course organization using a five- point Likert scale in response to an online course evaluation questionnaire. In addition, students' achievement was evaluated with regard to the skills and competencies taught in the course. RESULTS: Medical students generally gave high scores to all aspects of the EBM course, including course organization, course delivery, methods of assessment, and overall. Scores were also high for students' self evaluation of skill level and EBM experience. The results of a faculty member's evaluation of the students' achievement showed an average total percentage (92.2%) for all EBM steps. CONCLUSION: The EBM course at the Faculty of Medicine, King Abdulaziz University, is useful for familiarizing medical students with the basic principles of EBM and to help them in answering routine questions of clinical interest in a systematic way. In light of the results obtained from implementing this course with a small number of students, and as a student selected component, the author believes integrating EBM longitudinally throughout the curriculum would be beneficial for King Abdulaziz University medical students. It would provide a foundation of knowledge, offer easy access to resources, promote point-of-care and team learning, help students to develop applicable skills for lifelong learning, and help the faculty to achieve its goals of becoming more student-centered and encouraging students to employ more self-directed learning strategies. PMID- 23745094 TI - Human factors perspective on the prescribing behavior of recent medical graduates: implications for educators. AB - BACKGROUND: Junior doctors are at high risk of involvement in medication errors. Educational interventions to enhance human factors and specifically nontechnical skills in health care are increasingly reported, but there is no work in the context of prescribing improvement to guide such education. We set out to determine the elements that influence prescribing from a human factors perspective by recent medical graduates and use this to guide education in this area. METHODS: A total of 206 recent medical graduates of the North Western Foundation School were asked to describe their views on safety practices and behaviors. Free text data regarding prescribing behaviors were collected 1, 2, and 4 months after starting their posts. A 94.1% response rate was achieved. Qualitative analysis of data was completed using the constant comparison method. Five initial categories were developed, and the researchers subsequently developed thematic indices according to their understanding of the emerging content of the data. Further data were collected through group interviews 8-9 months into the placement to ensure thematic saturation. RESULTS: Six themes were established at the axial coding level, ie, contributors to inappropriate prescribing, contributors to appropriate prescribing, professional responsibility, prescribing error, current practices, and methods for improvement of prescribing. Utilizing appropriate theoretical elements, we describe how recent medical graduates employ situational and error awareness to guide risk assessment. CONCLUSION: We have modeled the human factors of prescribing behavior by recent medical graduates. As these factors are related to a number of recognized elements of nontechnical skills training within health care, educators should consider design elements from such existing interventions to support prescribing improvement programs. Future research should seek to assess the effectiveness of prescribing focused nontechnical skills training. PMID- 23745095 TI - Problem-solving strategies in psychiatry: differences between experts and novices in diagnostic accuracy and reasoning. AB - BACKGROUND: The purpose of this study was to examine and compare diagnostic success and its relationship with the diagnostic reasoning process between novices and experts in psychiatry. METHODS: Nine volunteers, comprising five expert psychiatrists and four clinical clerks, completed a think-aloud protocol while attempting to make a DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnosis of a selected case with both Axis I and Axis III diagnoses. RESULTS: Expert psychiatrists made significantly more successful diagnoses for both the primary psychiatric and medical diagnoses than clinical clerks. Expert psychiatrists also gave fewer differential options. Analyzing the think-aloud protocols, expert psychiatrists were much more organized, made fewer mistakes, and utilized significantly less time to access their knowledge than clinical clerks. Both novices and experts seemed to use the hypothetic-deductive and scheme-inductive approaches to diagnosis. However, experts utilized hypothetic-deductive approaches significantly more often than novices. CONCLUSION: The hypothetic-deductive diagnostic strategy was utilized more than the scheme-inductive approach by both expert psychiatrists and clinical clerks. However, a specific relationship between diagnostic reasoning and diagnostic success could not be identified in this small pilot study. The author recommends a larger study that would include a detailed analysis of the think-aloud protocols. PMID- 23745096 TI - Online research article discussion board to increase knowledge translation during emergency medicine residency. AB - BACKGROUND: Many clinicians have difficulties reading current best practice journal articles on a regular basis. Discussion boards are one method of online asynchronous learning that facilitates active learning and participation. We hypothesized that an online repository of best practice articles with a discussion board would increase journal article reading by emergency medicine residents. METHODS: PARTICIPANTS ANSWERED THREE QUESTIONS WEEKLY ON A DISCUSSION BOARD: What question does this study address? What does this study add to our knowledge? How might this change clinical practice? A survey regarding perceived barriers to participating was then distributed. RESULTS: Most participants completed an article summary once or twice in total (23/32, 71.9%). Only three were involved most weeks (3/32, 9.4%) whereas 5/32 (15.6%) participated monthly. The most common barriers were lack of time (20/32, 62.5%), difficulty logging on (7/32, 21.9%), and forgetting (6/32, 18.8%). CONCLUSION: Although subjects were provided weekly with an article link, email, and feedback, journal article reading frequency did not increase. PMID- 23745097 TI - Validation study of a computer-based open surgical trainer: SimPraxis((r)) simulation platform. AB - BACKGROUND: Technological advances have dramatically changed medical education, particularly in the era of work-hour restrictions, which increasingly highlights a need for novel methods to teach surgical skills. The purpose of this study was to evaluate the validity of a novel, computer-based, interactive, cognitive simulator for training surgeons to perform pelvic lymph node dissection (PLND). METHODS: Eight prostate cancer experts evaluated the content of the simulator. Contextual aspects of the simulator were rated on a five-point Likert scale. The experts and nine first-year residents completed a simulated PLND. Time and deviations were logged, and the results were compared between experts and novices using the Mann-Whitney test. RESULTS: Before training, 88% of the experts felt that a validated simulator would be useful for PLND training. After testing, 100% of the experts felt that it would be more useful than standard video training. Eighty-eight percent stated that they would like to see the simulator in the curriculum of residency programs and 56% thought it would be useful for accreditation purposes. The experts felt that the simulator aided in overall understanding, training indications, concepts and steps of the procedure, training how to use an assistant, and enhanced the knowledge of anatomy. Median performance times taken by experts and interns to complete a PLND procedure on the simulator were 12.62 and 23.97 minutes, respectively. Median deviation from the incorporated procedure pathway for experts was 24.5 and was 89 for novices. CONCLUSION: We describe an interactive, computer-based simulator designed to assist in mastery of the cognitive steps of an open surgical procedure. This platform is intuitive and flexible, and could be applied to any stepwise medical procedure. Overall, experts outperformed novices in their performance on the trainer. Experts agreed that the content was acceptable, accurate, and representative. PMID- 23745098 TI - Undergraduate radiology education in private and public teaching hospitals in Karachi, Pakistan: teaching duties, methodologies, and rewards. AB - BACKGROUND: In an integrated method of education, medical students are introduced to radiology in their preclinical years. However, no study has been conducted in Pakistan to demonstrate an academic framework of medical radiology education at an undergraduate level. Therefore, we aimed to document and compare the current level of teaching duties, teaching methodologies, and teaching rewards among radiologists and residents in private and public teaching hospitals in Karachi, Pakistan. METHODS: A survey was conducted among 121 radiologists and residents in two private and two public teaching hospitals in Karachi, Pakistan. Radiologists who were nationally registered with the Pakistan Medical and Dental Council either part-time or full-time were included. Radiology residents and fellows who were nationally registered with the Pakistan Medical and Dental Council were also included. Self-administered questionnaires addressing teaching duties, methods, and rewards were collected from 95 participants. RESULTS: The overall response rate was 78.51% (95/121). All of the radiologists were involved in teaching residents and medical students, but only 36% reported formal training in teaching skills. Although most of the respondents (76%) agreed that medical students appeared enthusiastic about learning radiology, the time spent on teaching medical students was less than five hours per week annually (82%). Only 37% of the respondents preferred dedicated clerkships over distributed clerkships (41%). The most common preferred teaching methodology overall was one-on-one interaction. Tutorials, teaching rounds, and problem-based learning sessions were less favored by radiologists than by residents. Teaching via radiology films (86%) was the most frequent mode of instruction. Salary (59%) was the most commonly cited teaching reward. The majority of respondents (88%) were not satisfied with their current level of teaching rewards. CONCLUSION: All radiologists and residents working in an academic radiology department are involved in teaching undergraduate students at multiple levels. The most valued teaching methodology involves use of images, with one-on-one interaction between the trainer and trainee. The monetary reward for teaching is inbuilt into the salary. The methodology adopted for teaching purposes was significantly different between respondents from private hospitals and those from public teaching hospitals. Because of low satisfaction among the respondents, efforts should be made to provide satisfying teaching rewards. PMID- 23745099 TI - Increasing numbers of medical undergraduates from lower socioeconomic backgrounds: positive for health care? PMID- 23745100 TI - Exploring the individual determinants of evidence uptake in allied health using a journal club as a medium. AB - PURPOSE: A recent trial which examined the impact of a structured model of journal club (JC) demonstrated variability in evidence-based practice (EBP) outcomes across allied health disciplines. The aim of the current study was to determine if there are individual practitioner characteristics that could explain this variability and identify potential predictors of EBP outcomes. METHOD: This exploratory study used the data obtained from the JC trial. The predictive value of practitioner-related variables including academic degree, previous exposure to EBP training, and previous research involvement was analyzed using univariate logistic regression models. The dose of intervention was also included in the exploratory analysis. RESULTS: The change in self-reported knowledge, evidence uptake, and attitude following participation in a JC was influenced by individual practitioner characteristics including their discipline, academic background, previous EBP training, previous research involvement, and JC attendance. Improvement in objective knowledge did not seem to be affected by any of these variables. Whether these individual characteristics have the ability to predict who will achieve less than, or greater than, 50% change in knowledge, attitude, and evidence uptake, is not known, except for academic background which predicted physiotherapists' improvement in attitude. CONCLUSION: Participation in a structured JC can lead to significant improvements in EBP knowledge irrespective of the characteristics of individual practitioners. The change in attitude and evidence uptake, however, may be influenced by individual characteristics which will therefore require careful consideration when designing EBP interventions. An EBP intervention is likely to be successful if a systematic assessment of the barriers at different levels (ie, individual, organizational, and contextual) informs the choice of evidence implementation strategy. PMID- 23745101 TI - A needs assessment for a master's program in dental public health in Jeddah Saudi Arabia. AB - OBJECTIVES: The Faculty of Dentistry at King Abdulaziz University in Jeddah, Saudi Arabia, is planning a master's program in dental public health (DPH) to address the lack of adequate DPH professionals in the country. A needs assessment survey or situational analysis is typically recommended as the foundation of any curriculum development process. We conducted this survey to understand the level of DPH expertise existing in the country, to identify needs and gaps, and to explore perceptions in the area of DPH. METHODS: A DPH competency based survey was emailed to all onsite Saudi faculty members, all DPH practitioners in Jeddah city, and a random sample of dental interns (n = 122). The questionnaire collected information about participants' demographics, knowledge of DPH, preferred method for gaining knowledge about DPH, perceptions about a new master's program in DPH, preferred teaching and delivery methods, prerequisite education, and self-assessment of participants' own DPH competency levels. Descriptive statistics, chi-square or Fisher's exact statistics, and proportional odds ratios were calculated to analyze data. RESULTS: There was a total of 105 respondents (86.1%). About 98% had some knowledge of DPH. The most preferred method to gain knowledge on DPH was seminar series (47.6%). The most preferred methods for teaching instruction were using a "list of discussion topics" and "providing examples," and the most preferred method for delivery of coursework was "face-to-face classroom activities with online readings and assignments." The most preferred prerequisite education was having a bachelor's degree in dentistry. Most participants considered themselves as having moderate experience and basic range of knowledge of DPH practices and competencies. CONCLUSION: The survey has helped assess the participants' views on the need for a graduate program in DPH. It is a preliminary step in designing a well-structured program, which will address the needs and gaps in oral public health in the country and inform the development of course content. PMID- 23745102 TI - Abrupt changes in the patterns and complexity of anterior cingulate cortex activity when food is introduced into an environment. AB - Foraging typically involves two distinct phases, an exploration phase where an organism explores its local environment in search of needed resources and an exploitation phase where a discovered resource is consumed. The behavior and cognitive requirements of exploration and exploitation are quite different and yet organisms can quickly and efficiently switch between them many times during a foraging bout. The present study investigated neural activity state dynamics in the anterior cingulate sub-region of the rat medial prefrontal cortex (mPFC) when a reliable food source was introduced into an environment. Distinct and largely independent states were detected using a Hidden Markov Model (HMM) when food was present or absent in the environment. Measures of neural entropy or complexity decreased when rats went from exploring the environment to exploiting a reliable food source. Exploration in the absence of food was associated with many weak activity states, while bouts of food consumption were characterized by fewer stronger states. Widespread activity state changes in the mPFC may help to inform foraging decisions and focus behavior on what is currently most prominent or valuable in the environment. PMID- 23745103 TI - Benefit of the doubt: a new view of the role of the prefrontal cortex in executive functioning and decision making. AB - The False Tagging Theory (FTT) is a neuroanatomical model of belief and doubt processes that proposes a single, unique function for the prefrontal cortex. Here, we review evidence pertaining to the FTT, the implications of the FTT regarding fractionation of the prefrontal cortex, and the potential benefits of the FTT for new neuroanatomical conceptualizations of executive functions. The FTT provides a parsimonious account that may help overcome theoretical problems with prefrontal cortex mediated executive control such as the homunculus critique. Control in the FTT is examined via the "heuristics and biases" psychological framework for human judgment. The evidence indicates that prefrontal cortex mediated doubting is at the core of executive functioning and may explain some biases of intuitive judgments. PMID- 23745104 TI - Optogenetic inhibition of D1R containing nucleus accumbens neurons alters cocaine mediated regulation of Tiam1. AB - Exposure to psychostimulants results in structural and synaptic plasticity in striatal medium spiny neurons (MSNs). These cellular adaptations arise from alterations in genes that are highly implicated in the rearrangement of the actin cytoskeleton, such as T-lymphoma invasion and metastasis 1 (Tiam1). Previous studies have demonstrated a crucial role for dopamine receptor 1 (D1)-containing striatal MSNs in mediating psychostimulant induced plasticity changes. These D1 MSNs in the nucleus accumbens (NAc) positively regulate drug seeking, reward, and locomotor behavioral effects as well as the morphological adaptations of psychostimulant drugs. Here, we demonstrate that rats that actively self administer cocaine display reduced levels of Tiam1 in the NAc. To further examine the cell type-specific contribution to these changes in Tiam1 we used optogenetics to selectively manipulate NAc D1-MSNs or dopamine receptor 2 (D2) expressing MSNs. We find that repeated channelrhodopsin-2 activation of D1-MSNs but not D2-MSNs caused a down-regulation of Tiam1 levels similar to the effects of cocaine. Further, activation of D2-MSNs, which caused a late blunted cocaine mediated locomotor behavioral response, did not alter Tiam1 levels. We then examined the contribution of D1-MSNs to the cocaine-mediated decrease of Tiam1. Using the light activated chloride pump, eNpHR3.0 (enhanced Natronomonas pharaonis halorhodopsin 3.0), we selectively inhibited D1-MSNs during cocaine exposure, which resulted in a behavioral blockade of cocaine-induced locomotor sensitization. Moreover, inhibiting these NAc D1-MSNs during cocaine exposure reversed the down-regulation of Tiam1 gene expression and protein levels. These data demonstrate that altering activity in specific neural circuits with optogenetics can impact the underlying molecular substrates of psychostimulant mediated behavior and function. PMID- 23745105 TI - Adaptive enhancement of learning protocol in hippocampal cultured networks grown on multielectrode arrays. AB - Learning in neuronal networks can be investigated using dissociated cultures on multielectrode arrays supplied with appropriate closed-loop stimulation. It was shown in previous studies that weakly respondent neurons on the electrodes can be trained to increase their evoked spiking rate within a predefined time window after the stimulus. Such neurons can be associated with weak synaptic connections in nearby culture network. The stimulation leads to the increase in the connectivity and in the response. However, it was not possible to perform the learning protocol for the neurons on electrodes with relatively strong synaptic inputs and responding at higher rates. We proposed an adaptive closed-loop stimulation protocol capable to achieve learning even for the highly respondent electrodes. It means that the culture network can reorganize appropriately its synaptic connectivity to generate a desired response. We introduced an adaptive reinforcement condition accounting for the response variability in control stimulation. It significantly enhanced the learning protocol to a large number of responding electrodes independently on its base response level. We also found that learning effect preserved after 4-6 h after training. PMID- 23745106 TI - Antecedent occipital alpha band activity predicts the impact of oculomotor events in perceptual switching. AB - Oculomotor events such as blinks and saccades transiently interrupt the visual input and, even though this mostly goes undetected, these brief interruptions could still influence the percept. In particular, both blinking and saccades facilitate switching in ambiguous figures such as the Necker cube. To investigate the neural state antecedent to these oculomotor events during the perception of an ambiguous figure, we measured the human scalp electroencephalogram (EEG). When blinking led to perceptual switching, antecedent occipital alpha band activity exhibited a transient increase in amplitude. When a saccade led to switching, a series of transient increases and decreases in amplitude was observed in the antecedent occipital alpha band activity. Our results suggest that the state of occipital alpha band activity predicts the impact of oculomotor events on the percept. PMID- 23745107 TI - Empathizing with sensory and movement differences: moving toward sensitive understanding of autism. PMID- 23745108 TI - Computational studies of the role of serotonin in the basal ganglia. AB - It has been well established that serotonin (5-HT) plays an important role in the striatum. For example, during levodopa therapy for Parkinson's disease (PD), the serotonergic projections from the dorsal raphe nucleus (DRN) release dopamine as a false transmitter, and there are strong indications that this pulsatile release is connected to dyskinesias that reduce the effectiveness of the therapy. Here we present hypotheses about the functional role of 5-HT in the normal striatum and present computational studies showing the feasibility of these hypotheses. Dopaminergic projections to the striatum inhibit the medium spiny neurons (MSN) in the striatopalladal (indirect) pathway and excite MSNs in the striatonigral (direct) pathway. It has long been hypothesized that the effect of dopamine (DA) depletion caused by the loss of SNc cells in PD is to change the "balance" between the pathways to favor the indirect pathway. Originally, "balance" was understood to mean equal firing rates, but now it is understood that the level of DA affects the patterns of firing in the two pathways too. There are dense 5-HT projections to the striatum from the dorsal raphe nucleus and it is known that increased 5-HT in the striatum facilitates DA release from DA terminals. The direct pathway excites various cortical nuclei and some of these nuclei send inhibitory projections to the DRN. Our hypothesis is that this feedback circuit from the striatum to the cortex to the DRN to the striatum serves to stabilize the balance between the direct and indirect pathways, and this is confirmed by our model calculations. Our calculations also show that this circuit contributes to the stability of the dopamine concentration in the striatum as SNc cells die during Parkinson's disease progression (until late phase). There may be situations in which there are physiological reasons to "unbalance" the direct and indirect pathways, and we show that projections to the DRN from the cortex or other brain regions could accomplish this task. PMID- 23745109 TI - c-Fos immunoreactivity in prefrontal, basal ganglia and limbic areas of the rat brain after central and peripheral administration of ethanol and its metabolite acetaldehyde. AB - Considerable evidence indicates that the metabolite of ethanol (EtOH), acetaldehyde, is biologically active. Acetaldehyde can be formed from EtOH peripherally mainly by alcohol dehydrogenase (ADH), and also centrally by catalase. EtOH and acetaldehyde show differences in their behavioral effects depending upon the route of administration. In terms of their effects on motor activity and motivated behaviors, when administered peripherally acetaldehyde tends to be more potent than EtOH but shows very similar potency administered centrally. Since dopamine (DA) rich areas have an important role in regulating both motor activity and motivation, the present studies were undertaken to compare the effects of central (intraventricular, ICV) and peripheral (intraperitoneal, IP) administration of EtOH and acetaldehyde on a cellular marker of brain activity, c-Fos immunoreactivity, in DA innervated areas. Male Sprague-Dawley rats received an IP injection of vehicle, EtOH (0.5 or 2.5 g/kg) or acetaldehyde (0.1 or 0.5 g/kg) or an ICV injection of vehicle, EtOH or acetaldehyde (2.8 or 14.0 MUmoles). IP administration of EtOH minimally induced c Fos in some regions of the prefrontal cortex and basal ganglia, mainly at the low dose (0.5 g/kg), while IP acetaldehyde induced c-Fos in virtually all the structures studied at both doses. Acetaldehyde administered centrally increased c Fos in all areas studied, a pattern that was very similar to EtOH. Thus, IP administered acetaldehyde was more efficacious than EtOH at inducing c-Fos expression. However, the general pattern of c-Fos induction promoted by ICV EtOH and acetaldehyde was similar. These results are consistent with the pattern observed in behavioral studies in which both substances produced the same magnitude of effect when injected centrally, and produced differences in potency after peripheral administration. PMID- 23745111 TI - Cerebral responses to vocal attractiveness and auditory hallucinations in schizophrenia: a functional MRI study. AB - Impaired self-monitoring and abnormalities of cognitive bias have been implicated as cognitive mechanisms of hallucination; regions fundamental to these processes including inferior frontal gyrus (IFG) and superior temporal gyrus (STG) are abnormally activated in individuals that hallucinate. A recent study showed activation in IFG-STG to be modulated by auditory attractiveness, but no study has investigated whether these IFG-STG activations are impaired in schizophrenia. We aimed to clarify the cerebral function underlying the perception of auditory attractiveness in schizophrenia patients. Cerebral activation was examined in 18 schizophrenia patients and 18 controls when performing Favorability Judgment Task (FJT) and Gender Differentiation Task (GDT) for pairs of greetings using event related functional MRI. A full-factorial analysis revealed that the main effect of task was associated with activation of left IFG and STG. The main effect of Group revealed less activation of left STG in schizophrenia compared with controls, whereas significantly greater activation in schizophrenia than in controls was revealed at the left middle frontal gyrus (MFG), right temporo parietal junction (TPJ), right occipital lobe, and right amygdala (p < 0.05, FDR corrected). A significant positive correlation was observed at the right TPJ and right MFG between cerebral activation under FJT minus GDT contrast and the score of hallucinatory behavior on the Positive and Negative Symptom Scale. Findings of hypo-activation in the left STG could designate brain dysfunction in accessing vocal attractiveness in schizophrenia, whereas hyper-activation in the right TPJ and MFG may reflect the process of mentalizing other person's behavior by auditory hallucination by abnormality of cognitive bias. PMID- 23745112 TI - Absence of chronic traumatic encephalopathy in retired football players with multiple concussions and neurological symptomatology. AB - BACKGROUND: Chronic traumatic encephalopathy (CTE) is the term coined for the neurodegenerative disease often suspected in athletes with histories of repeated concussion and progressive dementia. Histologically, CTE is defined as a tauopathy with a distribution of tau-positive neurofibrillary tangles (NFTs) that is distinct from other tauopathies, and usually shows an absence of beta-amyloid deposits, in contrast to Alzheimer's disease (AD). Although the connection between repeated concussions and CTE-type neurodegeneration has been recently proposed, this causal relationship has not yet been firmly established. Also, the prevalence of CTE among athletes with multiple concussions is unknown. METHODS: We performed a consecutive case series brain autopsy study on six retired professional football players from the Canadian Football League (CFL) with histories of multiple concussions and significant neurological decline. RESULTS: All participants had progressive neurocognitive decline prior to death; however, only 3 cases had post-mortem neuropathological findings consistent with CTE. The other 3 participants had pathological diagnoses of AD, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Moreover, the CTE cases showed co morbid pathology of cancer, vascular disease, and AD. DISCUSSION: Our case studies highlight that not all athletes with history of repeated concussions and neurological symptomology present neuropathological changes of CTE. These preliminary findings support the need for further research into the link between concussion and CTE as well as the need to expand the research to other possible causes of taupathy in athletes. They point to a critical need for prospective studies with good sampling methods to allow us to understand the relationship between multiple concussions and the development of CTE. PMID- 23745110 TI - Salsolinol modulation of dopamine neurons. AB - Salsolinol, a tetrahydroisoquinoline present in the human and rat brains, is the condensation product of dopamine and acetaldehyde, the first metabolite of ethanol. Previous evidence obtained in vivo links salsolinol with the mesolimbic dopaminergic (DA) system: salsolinol is self-administered into the posterior of the ventral tegmental area (pVTA) of rats; intra-VTA administration of salsolinol induces a strong conditional place preference and increases dopamine release in the nucleus accumbens (NAc). However, the underlying neuronal mechanisms are unclear. Here we present an overview of some of the recent research on this topic. Electrophysiological studies reveal that DA neurons in the pVTA are a target of salsolinol. In acute brain slices from rats, salsolinol increases the excitability and accelerates the ongoing firing of dopamine neurons in the pVTA. Intriguingly, this action of salsolinol involves multiple pre- and post-synaptic mechanisms, including: (1) depolarizing dopamine neurons; (2) by activating MU opioid receptors on the GABAergic inputs to dopamine neurons - which decreases GABAergic activity - dopamine neurons are disinhibited; and (3) enhancing presynaptic glutamatergic transmission onto dopamine neurons via activation of dopamine type 1 receptors, probably situated on the glutamatergic terminals. These novel mechanisms may contribute to the rewarding/reinforcing properties of salsolinol observed in vivo. PMID- 23745114 TI - Maintaining a Sense of Control in the Context of Cognitive Challenge: Greater Stability in Control Beliefs Benefits Working Memory. AB - We considered the functional role of control beliefs for cognitive performance by focusing on patterns of stability across multiple trials increasing in level of difficulty. We assessed 56 adults aged 18-88 on working memory tasks. We examined stability vs. lability (intraindividual variability, IIV) in control beliefs and the relationships with anxiety, distraction, and performance. Age was positively associated with IIV in control and performance, and IIV increased with task difficulty. Those maintaining stable control beliefs had better performance, and showed less anxiety and distraction. Those with lower stability and less control showed steeper declines in performance and increases in distraction. The findings suggest that stability of control beliefs may serve a protective function in the context of cognitively challenging tasks. PMID- 23745113 TI - Kinematic decomposition and classification of octopus arm movements. AB - The octopus arm is a muscular hydrostat and due to its deformable and highly flexible structure it is capable of a rich repertoire of motor behaviors. Its motor control system uses planning principles and control strategies unique to muscular hydrostats. We previously reconstructed a data set of octopus arm movements from records of natural movements using a sequence of 3D curves describing the virtual backbone of arm configurations. Here we describe a novel representation of octopus arm movements in which a movement is characterized by a pair of surfaces that represent the curvature and torsion values of points along the arm as a function of time. This representation allowed us to explore whether the movements are built up of elementary kinematic units by decomposing each surface into a weighted combination of 2D Gaussian functions. The resulting Gaussian functions can be considered as motion primitives at the kinematic level of octopus arm movements. These can be used to examine underlying principles of movement generation. Here we used combination of such kinematic primitives to decompose different octopus arm movements and characterize several movement prototypes according to their composition. The representation and methodology can be applied to the movement of any organ which can be modeled by means of a continuous 3D curve. PMID- 23745115 TI - Blood group determinates incidence for pancreatic cancer in Germany. AB - BACKGROUND: Genetic risk factors for sporadic pancreatic cancer are largely unknown but actually under high exposure. Findings of correlations between the AB0 blood group system (Chromosome 9q34,1-q34,2) and the risk of pancreatic cancer (PC) in patients from Asia, America and south Europe have already been published. So far it is unclear, whether this correlation between blood group an PC incidence can be found in German patients as well. METHODS: One hundred and sixty-six patients who underwent a resection of PC were evaluated in a period between 2000 and 2010. Blood group reference distribution for the German population is given as: 0: 41%; A: 43%; B: 11%; AB: 5%; Rhesus positive: 85%; Rhesus negative: 15%. Analyses were done using the non-parametric Chi(2)-test (p value two sided; SPSS 19.0). RESULTS: Median age was 62 (34-82) years. Gender: female 73/44%; male: 93/56%. Observed blood group proportions: 0: 43 (25.9%)/A: 94 (56.6%)/B: 16 (9.6%)/AB: 13 (7.8%)/Rhesus positive: 131 (78.9%)/negative: 35 (21.1%). We detected a significant difference to the German reference distribution of the AB0 system (Chi(2) 19.34, df 3, p < 0.001). Rhesus factor has no impact on AB0-distribution (Chi(2) 4.13, df 3, p = 0.25), but differs significantly from reference distribution-probably due to initial AB0-variation (Chi(2) 4.82, df 1, p = 0.028). The odds ratio for blood group A is 2.01 and for blood group 0 is 0.5. CONCLUSIONS: The incidence of PC in the German cohort is highly associated with the AB0-system as well. More patients with blood group A suffer from PC (p < 0.001) whereas blood group 0 was less frequent in patients with PC (p < 0.001). Thus, our findings support the results from other non-German surveys. The causal trigger points of this carcinogenesis correlation are still not known. PMID- 23745118 TI - Girl in the cellar: a repeated cross-sectional investigation of belief in conspiracy theories about the kidnapping of Natascha Kampusch. AB - The present study utilized a repeated cross-sectional survey design to examine belief in conspiracy theories about the abduction of Natascha Kampusch. At two time points (October 2009 and October 2011), participants drawn from independent cross-sections of the Austrian population (Time Point 1, N = 281; Time Point 2, N = 277) completed a novel measure of belief in conspiracy theories concerning the abduction of Kampusch, as well as measures of general conspiracist ideation, self esteem, paranormal and superstitious beliefs, cognitive ability, and media exposure to the Kampusch case. Results indicated that although belief in the Kampusch conspiracy theory declined between testing periods, the effect size of the difference was small. In addition, belief in the Kampusch conspiracy theory was significantly predicted by general conspiracist ideation at both time points. The need to conduct further longitudinal tests of conspiracist ideation is emphasized in conclusion. PMID- 23745116 TI - Automatic neural processing of disorder-related stimuli in social anxiety disorder: faces and more. AB - It has been proposed that social anxiety disorder (SAD) is associated with automatic information processing biases resulting in hypersensitivity to signals of social threat such as negative facial expressions. However, the nature and extent of automatic processes in SAD on the behavioral and neural level is not entirely clear yet. The present review summarizes neuroscientific findings on automatic processing of facial threat but also other disorder-related stimuli such as emotional prosody or negative words in SAD. We review initial evidence for automatic activation of the amygdala, insula, and sensory cortices as well as for automatic early electrophysiological components. However, findings vary depending on tasks, stimuli, and neuroscientific methods. Only few studies set out to examine automatic neural processes directly and systematic attempts are as yet lacking. We suggest that future studies should: (1) use different stimulus modalities, (2) examine different emotional expressions, (3) compare findings in SAD with other anxiety disorders, (4) use more sophisticated experimental designs to investigate features of automaticity systematically, and (5) combine different neuroscientific methods (such as functional neuroimaging and electrophysiology). Finally, the understanding of neural automatic processes could also provide hints for therapeutic approaches. PMID- 23745117 TI - The neurobiology of imagination: possible role of interaction-dominant dynamics and default mode network. AB - This work aims at presenting some hypotheses about the potential neurobiological substrate of imagery and imagination. For the present purposes, we will define imagery as the production of mental images associated with previous percepts, and imagination as the faculty of forming mental images of a novel character relating to something that has never been actually experienced by the subject but at a great extent emerges from his inner world. The two processes appear intimately related and imagery can arguably be considered as one of the main components of imagination. In this proposal, we argue that exaptation and redeployment, two basic concepts capturing important aspects of the evolution of biological structures and functions (Anderson, 2007), could also be useful in explaining imagery and imagination. As far as imagery is concerned it is proposed that neural structures originally implicated in performing certain functions, e.g., motor actions, can be reused for the imagery of the virtual execution of that function. As far as imagination is concerned we speculate that it can be the result of a "tinkering" that combines and modifies stored perceptual information and concepts leading to the creation of novel "mental objects" that are shaped by the subject peculiar inner world. Hence it is related to his self-awareness. The neurobiological substrate of the tinkering process could be found in a hierarchical model of the brain characterized by a multiplicity of functional modules (FMs) that can be assembled according to different spatial and temporal scales. Thus, it is surmised that a possible mechanism for the emergence of imagination could be represented by modulatory mechanisms controlling the perviousness of "modifiers" along the communication channels within and between FMs leading to their dynamically reassembling into novel configurations. PMID- 23745119 TI - An extension of the localist representation theory: grandmother cells are also widely used in the brain. PMID- 23745120 TI - Fluoroquinolone resistance mechanisms in an Escherichia coli isolate, HUE1, without quinolone resistance-determining region mutations. AB - Fluoroquinolone resistance can cause major clinical problems. Here, we investigated fluoroquinolone resistance mechanisms in a clinical Escherichia coli isolate, HUE1, which had no mutations quinolone resistance-determining regions (QRDRs) of DNA gyrase and topoisomerase IV. HUE1 demonstrated MICs that exceeded the breakpoints for ciprofloxacin, levofloxacin, and norfloxacin. HUE1 harbored oqxAB and qnrS1 on distinct plasmids. In addition, it exhibited lower intracellular ciprofloxacin concentrations and higher mRNA expression levels of efflux pumps and their global activators than did reference strains. The genes encoding AcrR (local AcrAB repressor) and MarR (MarA repressor) were disrupted by insertion of the transposon IS3-IS629 and a frameshift mutation, respectively. A series of mutants derived from HUE1 were obtained by plasmid curing and gene knockout using homologous recombination. Compared to the MICs of the parent strain HUE1, the fluoroquinolone MICs of these mutants indicated that qnrS1, oqxAB, acrAB, acrF, acrD, mdtK, mdfA, and tolC contributed to the reduced susceptibility to fluoroquinolone in HUE1. Therefore, fluoroquinolone resistance in HUE1 is caused by concomitant acquisition of QnrS1 and OqxAB and overexpression of AcrAB-TolC and other chromosome-encoded efflux pumps. Thus, we have demonstrated that QRDR mutations are not absolutely necessary for acquiring fluoroquinolone resistance in E. coli. PMID- 23745121 TI - Structural Modifications of Bacterial Lipopolysaccharide that Facilitate Gram Negative Bacteria Evasion of Host Innate Immunity. AB - Bacterial lipopolysaccharide (LPS), a cell wall component characteristic of Gram negative bacteria, is a representative pathogen-associated molecular pattern that allows mammalian cells to recognize bacterial invasion and trigger innate immune responses. The polysaccharide moiety of LPS primary plays protective roles for bacteria such as prevention from complement attacks or camouflage with common host carbohydrate residues. The lipid moiety, termed lipid A, is recognized by the Toll-like receptor 4 (TLR4)/MD-2 complex, which transduces signals for activation of host innate immunity. The basic structure of lipid A is a glucosamine disaccharide substituted by phosphate groups and acyl groups. Lipid A with six acyl groups (hexa-acylated form) has been indicated to be a strong stimulator of the TLR4/MD-2 complex. This type of lipid A is conserved among a wide variety of Gram-negative bacteria, and those bacteria are easily recognized by host cells for activation of defensive innate immune responses. Modifications of the lipid A structure to less-acylated forms have been observed in some bacterial species, and those forms are poor stimulators of the TLR4/MD-2 complex. Such modifications are thought to facilitate bacterial evasion of host innate immunity, thereby enhancing pathogenicity. This hypothesis is supported by studies of Yersinia pestis LPS, which contains hexa-acylated lipid A when the bacterium grows at 27 degrees C (the temperature of the vector flea), and shifts to contain less-acylated forms when grown at the human body temperature of 37 degrees C. This alteration of lipid A forms following transmission of Y. pestis from fleas to humans contributes predominantly to the virulence of this bacterium over other virulence factors. A similar role for less-acylated lipid A forms has been indicated in some other bacterial species, such as Francisella tularensis, Helicobacter pylori, and Porphyromonas gingivalis, and further studies to explore this concept are expected. PMID- 23745122 TI - The role of the innate immune system in granulomatous disorders. AB - The dynamic structure of the granuloma serves to protect the body from microbiological challenge. This organized aggregate of immune cells seeks to contain this challenge and protect against dissemination, giving host immune cells a chance to eradicate the threat. A number of systemic diseases are characterized by this specialized inflammatory process and granulomas have been shown to develop at multiple body sites and in various tissues. Central to this process is the macrophage and the arms of the innate immune response. This review seeks to explore how the innate immune response drives this inflammatory process in a contrast of diseases, particularly those with a component of immunodeficiency. By understanding the genes and inflammatory mechanisms behind this specialized immune response, will guide research in the development of novel therapeutics to combat granulomatous diseases. PMID- 23745123 TI - Different Members of the IL-1 Family Come Out in Different Ways: DAMPs vs. Cytokines? AB - Intercellular communications control fundamental biological processes required for the survival of multicellular organisms. Secretory proteins are among the most important messengers in this network of information. Proteins destined to the extracellular environment contain a signal sequence with the necessary information to target them to the Endoplasmic Reticulum, and are released by a "classical" pathway of secretion. However, in the early 1990s it became evident that non-classical mechanisms must exist for the secretion of some proteins, which in spite of their extracellular localization and function, lack a signal peptide. Indeed, the group of leaderless secretory proteins rapidly grew and is still growing. Many of them are implicated in the regulation of the inflammatory response. Interestingly, most members of the IL-1 family (IL-1F), including the master pro-inflammatory cytokine IL-1beta, are leaderless proteins and find their way out of the cells in different manners. In this article, we will review current hypotheses on the mechanisms of externalization of IL-1F members and discuss their relevance with respect to the different functions (as cytokines or as DAMPs) played by the different IL-1 proteins. PMID- 23745124 TI - Defective pulmonary innate immune responses post-stem cell transplantation; review and results from one model system. AB - Infectious pulmonary complications limit the success of hematopoietic stem cell transplantation (HSCT) as a therapy for malignant and non-malignant disorders. Susceptibility to pathogens in both autologous and allogeneic HSCT recipients persists despite successful immune reconstitution. As studying the causal effects of these immune defects in the human population can be limiting, a bone marrow transplant (BMT) mouse model can be used to understand the defect in mounting a productive innate immune response post-transplantation. When syngeneic BMT is performed, this system allows the study of BMT-induced alterations in innate immune cell function that are independent of the confounding effects of immunosuppressive therapy and graft-versus-host disease. Studies from several laboratories, including our own show that pulmonary susceptibility to bacterial infections post-BMT are largely due to alterations in the lung alveolar macrophages. Changes in these cells post-BMT include cytokine and eicosanoid dysregulations, scavenger receptor alterations, changes in micro RNA profiles, and alterations in intracellular signaling molecules that limit bacterial phagocytosis and killing. The changes that occur highlight mechanisms that promote susceptibility to infections commonly afflicting HSCT recipients and provide insight into therapeutic targets that may improve patient outcomes post HSCT. PMID- 23745127 TI - The Impact of Hemolysis on Cell-Free microRNA Biomarkers. AB - Cell-free microRNAs in plasma and serum have become a promising source of biomarkers for various diseases. Despite rapid progress in this field, there remains a lack of consensus regarding optimal quantification methods, reference genes, and quality control of samples. Recent studies have shown that hemolysis occurring during blood collection has substantial impact on the microRNA content in plasma/serum. To date, the impact of hemolysis has only been investigated for a limited number of microRNAs, mainly the red blood cell (RBC)-enriched miRs-16 and -451. In contrast, the effect of hemolysis on other microRNAs - in particular those proposed as biomarkers - has not been addressed. In this study we profiled the microRNA content of hemolyzed and non-hemolyzed plasma as well as RBCs to obtain a profile of microRNAs in the circulation affected or unaffected by hemolysis. Profiling by TaqMan Array Microfluidic Cards was used to compare three pairs of hemolyzed and non-hemolyzed plasma (with varying degrees of hemolysis) and one RBC sample. A total of 136 microRNAs were detectable in at least two of the samples, and of those 15 were at least twofold elevated in all three hemolyzed samples. This number increased to 88 microRNAs for the sample with the highest level of hemolysis, with all of these also detected in the RBC profile. Thus these microRNAs represent a large proportion of detectable microRNAs and those most likely to be affected by hemolysis. Several of the hemolysis susceptible microRNAs (e.g., miRs-21, -106a, -92a, -17, -16) have also been previously proposed as plasma/serum biomarkers of disease, highlighting the importance of rigorous quality control of plasma/serum samples used for measurement of circulating microRNAs. As low-level hemolysis is a frequent occurrence during plasma/serum collection it is critical that this is taken into account in the measurement of any candidate circulating microRNA. PMID- 23745128 TI - The prevalence of hepatitis C virus in mashhad, iran: a population-based study. AB - BACKGROUND: Hepatitis C virus (HCV) infection is a significant health problem throughout the world. Chronic form of the disease is found in about 75% to 85% of the newly infected individuals. The chronic infection may lead to severe forms including chronic liver disease, cirrhosis and with a higher mortality rate, hepatocellular carcinoma. Since no vaccine has yet been developed against HCV, there is an increasing need to take measures to control the spread of the infection. Therefore, epidemiologic study of the virus is important to manage and monitor the spread of the virus in the community. OBJECTIVES: The aim of this study was to determine the prevalence of hepatitis C seropositivity in the general population of Mashhad, northeast of Iran. PATIENTS AND METHODS: Three thousand, eight hundred and seventy (3870) individuals living in the city of Mashhad were recruited using cluster sampling method. HCV seropositivity was determined with HCV antibody detection ELISA kit and was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) method. RESULTS: In this study the overall seroprevalence of hepatitis C was founded to be 0.2% by using ELISA method. However, the overall Hepatitis C virus infection prevalence was found to be 0.13% with RT-PCR method. CONCLUSIONS: Our study suggested that the prevalence rate of Hepatitis C virus is below 1% in the general population of Mashhad. PMID- 23745126 TI - Disease resistance or growth: the role of plant hormones in balancing immune responses and fitness costs. AB - Plant growth and response to environmental cues are largely governed by phytohormones. The plant hormones ethylene, jasmonic acid, and salicylic acid (SA) play a central role in the regulation of plant immune responses. In addition, other plant hormones, such as auxins, abscisic acid (ABA), cytokinins, gibberellins, and brassinosteroids, that have been thoroughly described to regulate plant development and growth, have recently emerged as key regulators of plant immunity. Plant hormones interact in complex networks to balance the response to developmental and environmental cues and thus limiting defense associated fitness costs. The molecular mechanisms that govern these hormonal networks are largely unknown. Moreover, hormone signaling pathways are targeted by pathogens to disturb and evade plant defense responses. In this review, we address novel insights on the regulatory roles of the ABA, SA, and auxin in plant resistance to pathogens and we describe the complex interactions among their signal transduction pathways. The strategies developed by pathogens to evade hormone-mediated defensive responses are also described. Based on these data we discuss how hormone signaling could be manipulated to improve the resistance of crops to pathogens. PMID- 23745125 TI - Viral and cellular factors involved in Phloem transport of plant viruses. AB - Phloem transport of plant viruses is an essential step in the setting-up of a complete infection of a host plant. After an initial replication step in the first cells, viruses spread from cell-to-cell through mesophyll cells, until they reach the vasculature where they rapidly move to distant sites in order to establish the infection of the whole plant. This last step is referred to as systemic transport, or long-distance movement, and involves virus crossings through several cellular barriers: bundle sheath, vascular parenchyma, and companion cells for virus loading into sieve elements (SE). Viruses are then passively transported within the source-to-sink flow of photoassimilates and are unloaded from SE into sink tissues. However, the molecular mechanisms governing virus long-distance movement are far from being understood. While most viruses seem to move systemically as virus particles, some viruses are transported in SE as viral ribonucleoprotein complexes (RNP). The nature of the cellular and viral factors constituting these RNPs is still poorly known. The topic of this review will mainly focus on the host and viral factors that facilitate or restrict virus long-distance movement. PMID- 23745129 TI - Paediatric non-alcoholic Fatty liver disease: impact on patients and mothers' quality of life. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the causes of fatty liver in adults and is currently the primary form of chronic liver disease in children and adolescents. However, the psychological outcome (i.e. the behavioural problems that can in turn be related to psychiatric conditions, like anxiety and mood disorders, or lower quality of life) in children and adolescents suffering of NAFLD has not been extensively explored in the literature. OBJECTIVES: The present study aims at evaluating the emotional and behavioural profile in children suffering from NAFLD and the quality of life in their mothers. PATIENTS AND METHODS: A total of 57 children (18 females/39 males) with NAFLD were compared to 39 age-matched control children (25 females/14 males). All participants were submitted to the following psychological tools to assess behavior, mood, and anxiety: the Multidimensional Anxiety Scale for Children (MASC), the Child Behavior Checklist (CBCL), and the Children's Depression Inventory (CDI). Moreover, the mothers of 40 NAFLD and 39 control children completed the World Health Organization Quality of Life-BREF (WHOQOL-BREF) questionnaire. RESULTS: NAFLD children scored significantly higher as compared to control children in MASC (P = 0.001) and CDI total (P < 0.001) scales. The CBCL also revealed significantly higher scores for NAFLD children in total problems (P = 0.046), internalizing symptoms (P = 0.000) and somatic complaints (P < 0.001). The WHOQOL-BREF revealed significantly lower scores for the mothers of NAFLD children in the overall perception of the quality of life (P < 0.001), and in the "relationships" domain (P = 0.023). CONCLUSIONS: Increased emotional and behavioural problems were detected in children with NAFLD as compared to healthy control children, together with an overall decrease in their mothers' quality of life. These results support the idea that these patients may benefit from a psychological intervention, ideally involving both children and parents, whose quality of life is likely negatively affected by this disease. PMID- 23745130 TI - Don't throw the bathwater in with the baby. AB - The Presidential Address of the European Association of Developmental Psychology this year concerned how genes and environments interplay to shape loneliness and other developmental psychological relevant outcomes. This is a very welcome. However, when developmental psychology now is ready to integrate recent genetic and neuroscience knowledge and methods, I think it would be very wise to not uncritical go through the mistakes that have be done in other disciplines and instead learn from their hard lessons. I discuss some problems (genes versus environments, identifying gene for a phenotype, environments cause of developmental outcomes, and gene X environment interaction and epigenetics) and some suggestions for solutions which can be used to avoid throwing in the bathwater with the baby. PMID- 23745131 TI - The role of dynamic infrared imaging in melanoma diagnosis. AB - Melanoma incidence and the lifetime risk are increasing at an alarming rate in the United States and worldwide. In order to improve survival rates, the goal is to detect melanoma at an early stage of the disease. Accurate, sensitive and reliable quantitative diagnostic tools can reduce the number of unnecessary biopsies, the associated morbidity as well as the costs of care in addition to improving survival rates. The recently introduced quantitative dynamic infrared imaging system QUAINT measures differences in the infrared emission between healthy tissue and the lesion during the thermal recovery process after the removal of a cooling stress. Results from a clinical study suggest that the temperature of cancerous lesions is higher during the first 45-60 seconds of thermal recovery than the temperature of benign pigmented lesions. This small temperature difference can be measured by modern infrared cameras and serve as an indicator for melanoma in modern quantitative melanoma detectors. PMID- 23745133 TI - New feature: themed sections. PMID- 23745132 TI - Differences in Social Vulnerability among Individuals with Autism Spectrum Disorder, Williams Syndrome, and Down Syndrome. AB - Although individuals with disabilities are at increased risk of victimization, few studies examine persons with different disability conditions to determine whether distinctive cognitive-behavioral profiles are associated with different levels of social vulnerability. To determine the differences in social vulnerability and experiences of victimization, caregiver responses to a Social Vulnerability Questionnaire were examined for 103 caregivers of individuals with autism spectrum disorder (ASD), Williams syndrome (WS), and Down syndrome (DS). Although all three groups experienced similar rates and types of victimization, the specific correlates of social vulnerability differed by disability. Individuals with ASD displayed less risk awareness and had less social protection; those with WS were rated higher on risk factors related to perceived vulnerability and parental independence; and those with DS had less risk awareness and were perceived to be more vulnerable. Safety interventions should be tailored to address each group's specific correlates of social vulnerability. PMID- 23745134 TI - A phylomedicine approach to understanding the evolution of auditory sensory perception and disease in mammals. AB - Hereditary deafness affects 0.1% of individuals globally and is considered as one of the most debilitating diseases of man. Despite recent advances, the molecular basis of normal auditory function is not fully understood and little is known about the contribution of single-nucleotide variations to the disease. Using cross-species comparisons of 11 'deafness' genes (Myo15, Ush1 g, Strc, Tecta, Tectb, Otog, Col11a2, Gjb2, Cldn14, Kcnq4, Pou3f4) across 69 evolutionary and ecologically divergent mammals, we elucidated whether there was evidence for: (i) adaptive evolution acting on these genes across mammals with similar hearing capabilities; and, (ii) regions of long-term evolutionary conservation within which we predict disease-associated mutations should occur. We find evidence of adaptive evolution acting on the eutherian mammals in Myo15, Otog and Tecta. Examination of selection pressures in Tecta and Pou3f4 across a taxonomic sample that included a wide representation of auditory specialists, the bats, did not uncover any evidence for a role in echolocation. We generated 'conservation indices' based on selection estimates at nucleotide sites and found that known disease mutations fall within sites of high evolutionary conservation. We suggest that methods such as this, derived from estimates of evolutionary conservation using phylogenetically divergent taxa, will help to differentiate between deleterious and benign mutations. PMID- 23745135 TI - Structural dynamics flexibility informs function and evolution at a proteome scale. AB - Protein structures are dynamic entities with a myriad of atomic fluctuations, side-chain rotations, and collective domain movements. Although the importance of these dynamics to proper functioning of proteins is emerging in the studies of many protein families, there is a lack of broad evidence for the critical role of protein dynamics in shaping the biological functions of a substantial fraction of residues for a large number of proteins in the human proteome. Here, we propose a novel dynamic flexibility index (dfi) to quantify the dynamic properties of individual residues in any protein and use it to assess the importance of protein dynamics in 100 human proteins. Our analyses involving functionally critical positions, disease-associated and putatively neutral population variations, and the rate of interspecific substitutions per residue produce concordant patterns at a proteome scale. They establish that the preservation of dynamic properties of residues in a protein structure is critical for maintaining the protein/biological function. Therefore, structural dynamics needs to become a major component of the analysis of protein function and evolution. Such analyses will be facilitated by the dfi, which will also enable the integrative use of structural dynamics with evolutionary conservation in genomic medicine as well as functional genomics investigations. PMID- 23745136 TI - Structural and functional insight into the universal stress protein family. AB - We present the crystal structures of two universal stress proteins (USP) from Archaeoglobus fulgidus and Nitrosomonas europaea in both apo- and ligand-bound forms. This work is the first complete synthesis of the structural properties of 26 USP available in the Protein Data Bank, over 75% of which were determined by structure genomics centers with no additional information provided. The results of bioinformatic analyses of all available USP structures and their sequence homologs revealed that these two new USP structures share overall structural similarity with structures of USPs previously determined. Clustering and cladogram analyses, however, show how they diverge from other members of the USP superfamily and show greater similarity to USPs from organisms inhabiting extreme environments. We compared them with other archaeal and bacterial USPs and discuss their similarities and differences in context of structure, sequential motifs, and potential function. We also attempted to group all analyzed USPs into families, so that assignment of the potential function to those with no experimental data available would be possible by extrapolation. PMID- 23745137 TI - Genomic islands of divergence and their consequences for the resolution of spatial structure in an exploited marine fish. AB - As populations diverge, genomic regions associated with adaptation display elevated differentiation. These genomic islands of adaptive divergence can inform conservation efforts in exploited species, by refining the delineation of management units, and providing genomic tools for more precise and effective population monitoring and the successful assignment of individuals and products. We explored heterogeneity in genomic divergence and its impact on the resolution of spatial population structure in exploited populations of Atlantic cod, Gadus morhua, using genome wide expressed sequence derived single nucleotide polymorphisms in 466 individuals sampled across the range. Outlier tests identified elevated divergence at 5.2% of SNPs, consistent with directional selection in one-third of linkage groups. Genomic regions of elevated divergence ranged in size from a single position to several cM. Structuring at neutral loci was associated with geographic features, whereas outlier SNPs revealed genetic discontinuities in both the eastern and western Atlantic. This fine-scale geographic differentiation enhanced assignment to region of origin, and through the identification of adaptive diversity, fundamentally changes how these populations should be conserved. This work demonstrates the utility of genome scans for adaptive divergence in the delineation of stock structure, the traceability of individuals and products, and ultimately a role for population genomics in fisheries conservation. PMID- 23745138 TI - Hybrid watermilfoil lineages are more invasive and less sensitive to a commonly used herbicide than their exotic parent (Eurasian watermilfoil). AB - Hybridization may stimulate the evolution of invasiveness in human-impacted habitats if unique hybrid genotypes have higher fitness than parental genotypes. Human efforts to control invasive taxa frequently involve the intentional alteration of habitats, but few studies have considered whether hybridization can result in decreased sensitivity to control measures. Here, we investigate whether interspecific hybrids between introduced Eurasian watermilfoil (Myriophyllum spicatum) and native northern watermilfoil (M. sibiricum) are more invasive than parental Eurasian watermilfoil, especially in regard to their relative responses to an herbicide commonly applied for their control (2,4-dichlorophenoxyacetic acid; 2,4-D). In two separate laboratory experiments, hybrids on average grew faster and were less sensitive to 2,4-D compared with parental Eurasian watermilfoil. These two invasive traits appear to be common in hybrid watermilfoils, as opposed to being restricted to a few unique lineages, because they were found in a diversity of hybrid genotypes from several independent hybridization events. In addition, we found that hybrids occurred more frequently than parental species in natural lakes previously treated with 2,4-D. Our results provide compelling empirical evidence that hybridization is associated with the evolution of increased invasiveness in watermilfoils, and have important implications for their management. PMID- 23745139 TI - Reduced fitness of Atlantic salmon released in the wild after one generation of captive breeding. AB - Salmonids rank among the most socioeconomically valuable fishes and the most targeted species by stocking with hatchery-reared individuals. Here, we used molecular parentage analysis to assess the reproductive success of wild- and hatchery-born Atlantic salmon over three consecutive years in a small river in Quebec. Yearly restocking in this river follows a single generation of captive breeding. Among the adults returning to the river to spawn, between 11% and 41% each year were born in hatchery. Their relative reproductive success (RRS) was nearly half that of wild-born fish (0.55). RRS varied with life stage, being 0.71 for fish released at the fry stage and 0.42 for fish released as smolt. The lower reproductive success of salmon released as smolt was partly mediated by the modification of the proportion of single-sea-winter/multi-sea-winter fish. Overall, our results suggest that modifications in survival and growth rates alter the life-history strategies of these fish at the cost of their reproductive success. Our results underline the potential fitness decrease, warn on long-term evolutionary consequences for the population of repeated stocking and support the adoption of more natural rearing conditions for captive juveniles and their release at a younger stage, such as unfed fry. PMID- 23745140 TI - The sexually dimorphic on the Y-chromosome gene (sdY) is a conserved male specific Y-chromosome sequence in many salmonids. AB - All salmonid species investigated to date have been characterized with a male heterogametic sex-determination system. However, as these species do not share any Y-chromosome conserved synteny, there remains a debate on whether they share a common master sex-determining gene. In this study, we investigated the extent of conservation and evolution of the rainbow trout (Oncorhynchus mykiss) master sex-determining gene, sdY (sexually dimorphic on the Y-chromosome), in 15 different species of salmonids. We found that the sdY sequence is highly conserved in all salmonids and that sdY is a male-specific Y-chromosome gene in the majority of these species. These findings demonstrate that most salmonids share a conserved sex-determining locus and also strongly suggest that sdY may be this conserved master sex-determining gene. However, in two whitefish species (subfamily Coregoninae), sdY was found both in males and females, suggesting that alternative sex-determination systems may have also evolved in this family. Based on the wide conservation of sdY as a male-specific Y-chromosome gene, efficient and easy molecular sexing techniques can now be developed that will be of great interest for studying these economically and environmentally important species. PMID- 23745141 TI - The impact of insecticide resistance on Culex pipiens immunity. AB - Because of their role as vectors of diseases, the evolution of insecticide resistance in mosquitoes has been intensively investigated. Insecticide resistance is associated to a wide range of pleiotropic effects on several key life-history traits of mosquitoes such as longevity and behavior. However, despite its potential implications in pathogen transmission, the effects of insecticide resistance on mosquito immunity have received little, if any, attention. Here, we investigate the impact of insecticide resistance in Culex pipiens, an epidemiologically important vector of a wide array of pathogens. Using both isogenic laboratory strains and field-caught mosquitoes, we investigate the impact of two main insecticide resistance mechanisms (metabolic detoxification and target site modification) on the relative transcription of several genes involved in the immune response to pathogens, at both their constitutive and inducible levels. Our results show a discrepancy between the isogenic laboratory lines and field-collected mosquitoes: While in the isogenic strains, insecticide-resistant mosquitoes show a drastic increase in immune gene expression, no such effect appears in the field. We speculate on the different mechanisms that may underlie this discrepancy and discuss the risks of making inferences on the pleiotropic effects of insecticide-resistant genes by using laboratory-selected insecticide-resistant lines. PMID- 23745142 TI - Strong natural selection during plant restoration favors an unexpected suite of plant traits. AB - RESTORATION IS AN OPPORTUNITY TO STUDY NATURAL SELECTION: One can measure the distribution of traits in source propagules used to found populations, compare this with the distribution of traits in successful recruits, and determine the strength and direction of selection on potentially adaptive traits. We investigated whether natural selection influenced seedling establishment during postfire restoration in the Great Basin, an area where large-scale restoration occurs with a few widely available cultivars planted over a large range of environmental conditions. We collected seeds from established plants of the perennial grass Elymus elymoides ssp. californicus (squirreltail) at two restoration sites and compared the distribution of phenotypic traits of surviving plants with the original pool of restoration seeds. Seeds were planted in common gardens for two generations. Plants grown from seeds that established in the field were a nonrandom subset of the original seeds, with directional selection consistently favoring a correlated suite of traits in both field sites: small plant and seed size, and earlier flowering phenology. These results demonstrate that natural selection can affect restoration establishment in strong and predictable ways and that adaptive traits in these sites were opposite of the current criteria used for selection of restoration material in this system. PMID- 23745143 TI - Local adaptation and evolutionary potential along a temperature gradient in the fungal pathogen Rhynchosporium commune. AB - To predict the response of plant pathogens to climate warming, data are needed on current thermal adaptation, the pathogen's evolutionary potential, and the link between them. We conducted a common garden experiment using isolates of the fungal pathogen Rhynchosporium commune from nine barley populations representing climatically diverse locations. Clonal replicates of 126 genetically distinct isolates were assessed for their growth rate at 12 degrees C, 18 degrees C, and 22 degrees C. Populations originating from climates with higher monthly temperature variation had higher growth rate at all three temperatures compared with populations from climates with less temperature fluctuation. Population differentiation in growth rate (Q ST) was significantly higher at 22 degrees C than population differentiation for neutral microsatellite loci (G ST), consistent with local adaptation for growth at higher temperatures. At 18 degrees C, we found evidence for stabilizing selection for growth rate as Q ST was significantly lower than G ST. Heritability of growth rate under the three temperatures was substantial in all populations (0.58-0.76). Genetic variation was lower in populations with higher growth rate at the three temperatures and evolvability increased under heat stress in seven of nine populations. Our findings imply that the distribution of this pathogen is unlikely to be genetically limited under climate warming, due to its high genetic variation and plasticity for thermal tolerance. PMID- 23745145 TI - Oceanographic connectivity and environmental correlates of genetic structuring in Atlantic herring in the Baltic Sea. AB - Marine fish often show little genetic structuring in neutral marker genes, and Atlantic herring (Clupea harengus) in the Baltic Sea are no exception; historically, very low levels of population differentiation (F ST ? 0.002) have been found, despite a high degree of interpopulation environmental heterogeneity in salinity and temperature. Recent exome sequencing and SNP studies have however shown that many loci are under selection in this system. Here, we combined population genetic analyses of a large number of transcriptome-derived microsatellite markers with oceanographic modelling to investigate genetic differentiation and connectivity in Atlantic herring at a relatively fine scale within the Baltic Sea. We found evidence for weak but robust and significant genetic structuring (F ST = 0.008) explainable by oceanographic connectivity. Genetic differentiation was also associated with site differences in temperature and salinity, with the result driven by the locus Her14 which appears to be under directional selection (F ST = 0.08). The results show that Baltic herring are genetically structured within the Baltic Sea, and highlight the role of oceanography and environmental factors in explaining this structuring. The results also have implications for the management of herring fisheries, the most economically important fishery in the Baltic Sea, suggesting that the current fisheries management units may be in need of revision. PMID- 23745144 TI - First steps in experimental cancer evolution. AB - Evolutionary processes play a central role in the development, progression and response to treatment of cancers. The current challenge facing researchers is to harness evolutionary theory to further our understanding of the clinical progression of cancers. Central to this endeavour will be the development of experimental systems and approaches by which theories of cancer evolution can be effectively tested. We argue here that the experimental evolution approach - whereby evolution is observed in real time and which has typically employed microorganisms - can be usefully applied to cancer. This approach allows us to disentangle the ecological causes of natural selection, identify the genetic basis of evolutionary changes and determine their repeatability. Cell cultures used in cancer research share many of the desirable traits that make microorganisms ideal for studying evolution. As such, experimental cancer evolution is feasible and likely to give great insight into the selective pressures driving the evolution of clinically destructive cancer traits. We highlight three areas of evolutionary theory with importance to cancer biology that are amenable to experimental evolution: drug resistance, social evolution and resource competition. Understanding the diversity, persistence and evolution of cancers is vital for treatment and drug development, and an experimental evolution approach could provide strategic directions and focus for future research. PMID- 23745148 TI - Incorporating feature ranking and evolutionary methods for the classification of high-dimensional DNA microarray gene expression data. AB - BACKGROUND: DNA microarray gene expression classification poses a challenging task to the machine learning domain. Typically, the dimensionality of gene expression data sets could go from several thousands to over 10,000 genes. A potential solution to this issue is using feature selection to reduce the dimensionality. AIMS: The aim of this paper is to investigate how we can use feature quality information to improve the precision of microarray gene expression classification tasks. METHOD: We propose two evolutionary machine learning models based on the eXtended Classifier System (XCS) and a typical feature selection methodology. The first one, which we call FS-XCS, uses feature selection for feature reduction purposes. The second model is GRD-XCS, which uses feature ranking to bias the rule discovery process of XCS. RESULTS: The results indicate that the use of feature selection/ranking methods is essential for tackling highdimensional classification tasks, such as microarray gene expression classification. However, the results also suggest that using feature ranking to bias the rule discovery process performs significantly better than using the feature reduction method. In other words, using feature quality information to develop a smarter learning procedure is more efficient than reducing the feature set. CONCLUSION: Our findings have shown that extracting feature quality information can assist the learning process and improve classification accuracy. On the other hand, relying exclusively on the feature quality information might potentially decrease the classification performance (e.g., using feature reduction). Therefore, we recommend a hybrid approach that uses feature quality information to direct the learning process by highlighting the more informative features, but at the same time not restricting the learning process to explore other features. PMID- 23745147 TI - CHOP THERAPY INDUCED MITOCHONDRIAL REDOX STATE ALTERATION IN NON-HODGKIN'S LYMPHOMA XENOGRAFTS. AB - We are interested in investigating whether cancer therapy may alter the mitochondrial redox state in cancer cells to inhibit their growth and survival. The redox state can be imaged by the redox scanner that collects the fluorescence signals from both the oxidized-flavoproteins (Fp) and the reduced form of nicotinamide adenine dinucleotide (NADH) in snap-frozen tissues and has been previously employed to study tumor aggressiveness and treatment responses. Here, with the redox scanner we investigated the effects of chemotherapy on mouse xenografts of a human diffuse large B-cell lymphoma cell line (DLCL2). The mice were treated with CHOP therapy, i.e., cyclophosphamide (C) + hydroxydoxorubicin (H) + Oncovin (O) + prednisone (P) with CHO administration on day 1 and prednisone administration on days 1-5. The Fp content of the treated group was significantly decreased (p = 0.033) on day 5, and the mitochondrial redox state of the treated group was slightly more reduced than that of the control group (p = 0.048). The decrease of the Fp heterogeneity (measured by the mean standard deviation) had a border-line statistical significance (p = 0.071). The result suggests that the mitochondrial metabolism of lymphoma cells was slightly suppressed and the lymphomas became less aggressive after the CHOP therapy. PMID- 23745149 TI - Acute ischaemic stroke prediction from physiological time series patterns. AB - BACKGROUND: Stroke is one of the major diseases with human mortality. Recent clinical research has indicated that early changes in common physiological variables represent a potential therapeutic target, thus the manipulation of these variables may eventually yield an effective way to optimise stroke recovery. AIMS: We examined correlations between physiological parameters of patients during the first 48 hours after a stroke, and their stroke outcomes after three months. We wanted to discover physiological determinants that could be used to improve health outcomes by supporting the medical decisions that need to be made early on a patient's stroke experience. METHOD: We applied regression based machine learning techniques to build a prediction algorithm that can forecast threemonth outcomes from initial physiological time series data during the first 48 hours after stroke. In our method, not only did we use statistical characteristics as traditional prediction features, but we also adopted trend patterns of time series data as new key features. RESULTS: We tested our prediction method on a real physiological data set of stroke patients. The experiment results revealed an average high precision rate: 90%. We also tested prediction methods only considering statistical characteristics of physiological data, and concluded an average precision rate: 71%. CONCLUSION: We demonstrated that using trend pattern features in prediction methods improved the accuracy of stroke outcome prediction. Therefore, trend patterns of physiological time series data have an important role in the early treatment of patients with acute ischaemic stroke. PMID- 23745150 TI - Using prediction to improve elective surgery scheduling. AB - BACKGROUND: An ageing population and higher rates of chronic disease increase the demand on health services. The Australian Institute of Health and Welfare reports a 3.6% per year increase in total elective surgery admissions over the past four years.1 The newly introduced National Elective Surgery Target (NEST) stresses the need for efficiency and necessitates the development of improved planning and scheduling systems in hospitals. AIMS: To provide an overview of the challenges of elective surgery scheduling and develop a prediction based methodology to drive optimal management of scheduling processes. METHOD: Our proposed two stage methodology initially employs historic utilisation data and current waiting list information to manage case mix distribution. A novel algorithm uses current and past perioperative information to accurately predict surgery duration. A NEST compliance guided optimisation algorithm is then used to drive allocation of patients to the theatre schedule. RESULTS: It is expected that the resulting improvement in scheduling processes will lead to more efficient use of surgical suites, higher productivity, and lower labour costs, and ultimately improve patient outcomes. CONCLUSION: Accurate prediction of workload and surgery duration, retrospective and current waitlist as well as perioperative information, and NEST-compliance driven allocation of patients are employed by our proposed methodology in order to deliver further improvement to hospital operating facilities. PMID- 23745151 TI - Classification of cancer-related death certificates using machine learning. AB - BACKGROUND: Cancer monitoring and prevention relies on the critical aspect of timely notification of cancer cases. However, the abstraction and classification of cancer from the free-text of pathology reports and other relevant documents, such as death certificates, exist as complex and time-consuming activities. AIMS: In this paper, approaches for the automatic detection of notifiable cancer cases as the cause of death from free-text death certificates supplied to Cancer Registries are investigated. METHOD: A number of machine learning classifiers were studied. Features were extracted using natural language techniques and the Medtex toolkit. The numerous features encompassed stemmed words, bi-grams, and concepts from the SNOMED CT medical terminology. The baseline consisted of a keyword spotter using keywords extracted from the long description of ICD-10 cancer related codes. RESULTS: Death certificates with notifiable cancer listed as the cause of death can be effectively identified with the methods studied in this paper. A Support Vector Machine (SVM) classifier achieved best performance with an overall Fmeasure of 0.9866 when evaluated on a set of 5,000 freetext death certificates using the token stem feature set. The SNOMED CT concept plus token stem feature set reached the lowest variance (0.0032) and false negative rate (0.0297) while achieving an F-measure of 0.9864. The SVM classifier accounts for the first 18 of the top 40 evaluated runs, and entails the most robust classifier with a variance of 0.001141, half the variance of the other classifiers. CONCLUSION: The selection of features significantly produced the most influences on the performance of the classifiers, although the type of classifier employed also affects performance. In contrast, the feature weighting schema created a negligible effect on performance. Specifically, it is found that stemmed tokens with or without SNOMED CT concepts create the most effective feature when combined with an SVM classifier. PMID- 23745152 TI - Automated classification of limb fractures from free-text radiology reports using a clinician-informed gazetteer methodology. AB - BACKGROUND: Timely diagnosis and reporting of patient symptoms in hospital emergency departments (ED) is a critical component of health services delivery. However, due to dispersed information resources and a vast amount of manual processing of unstructured information, accurate point-of-care diagnosis is often difficult. AIMS: The aim of this research is to report initial experimental evaluation of a clinician-informed automated method for the issue of initial misdiagnoses associated with delayed receipt of unstructured radiology reports. METHOD: A method was developed that resembles clinical reasoning for identifying limb abnormalities. The method consists of a gazetteer of keywords related to radiological findings; the method classifies an X-ray report as abnormal if it contains evidence contained in the gazetteer. A set of 99 narrative reports of radiological findings was sourced from a tertiary hospital. Reports were manually assessed by two clinicians and discrepancies were validated by a third expert ED clinician; the final manual classification generated by the expert ED clinician was used as ground truth to empirically evaluate the approach. RESULTS: The automated method that attempts to individuate limb abnormalities by searching for keywords expressed by clinicians achieved an F-measure of 0.80 and an accuracy of 0.80. CONCLUSION: While the automated clinician-driven method achieved promising performances, a number of avenues for improvement were identified using advanced natural language processing (NLP) and machine learning techniques. PMID- 23745153 TI - Reliable epileptic seizure detection using an improved wavelet neural network. AB - BACKGROUND: Electroencephalogram (EEG) signal analysis is indispensable in epilepsy diagnosis as it offers valuable insights for locating the abnormal distortions in the brain wave. However, visual interpretation of the massive amounts of EEG signals is time-consuming, and there is often inconsistent judgment between experts. AIMS: This study proposes a novel and reliable seizure detection system, where the statistical features extracted from the discrete wavelet transform are used in conjunction with an improved wavelet neural network (WNN) to identify the occurrence of seizures. METHOD: Experimental simulations were carried out on a well-known publicly available dataset, which was kindly provided by the Epilepsy Center, University of Bonn, Germany. The normal and epileptic EEG signals were first pre-processed using the discrete wavelet transform. Subsequently, a set of statistical features was extracted to train a WNNs-based classifier. RESULTS: The study has two key findings. First, simulation results showed that the proposed improved WNNs-based classifier gave excellent predictive ability, where an overall classification accuracy of 98.87% was obtained. Second, by using the 10th and 90th percentiles of the absolute values of the wavelet coefficients, a better set of EEG features can be identified from the data, as the outliers are removed before any further downstream analysis. CONCLUSION: The obtained high prediction accuracy demonstrated the feasibility of the proposed seizure detection scheme. It suggested the prospective implementation of the proposed method in developing a real time automated epileptic diagnostic system with fast and accurate response that could assist neurologists in the decision making process. PMID- 23745154 TI - Artificial intelligence in health - the three big challenges. PMID- 23745155 TI - JOCB Bulletin. PMID- 23745156 TI - JOINT AND INDIVIDUAL VARIATION EXPLAINED (JIVE) FOR INTEGRATED ANALYSIS OF MULTIPLE DATA TYPES. AB - Research in several fields now requires the analysis of datasets in which multiple high-dimensional types of data are available for a common set of objects. In particular, The Cancer Genome Atlas (TCGA) includes data from several diverse genomic technologies on the same cancerous tumor samples. In this paper we introduce Joint and Individual Variation Explained (JIVE), a general decomposition of variation for the integrated analysis of such datasets. The decomposition consists of three terms: a low-rank approximation capturing joint variation across data types, low-rank approximations for structured variation individual to each data type, and residual noise. JIVE quantifies the amount of joint variation between data types, reduces the dimensionality of the data, and provides new directions for the visual exploration of joint and individual structure. The proposed method represents an extension of Principal Component Analysis and has clear advantages over popular two-block methods such as Canonical Correlation Analysis and Partial Least Squares. A JIVE analysis of gene expression and miRNA data on Glioblastoma Multiforme tumor samples reveals gene miRNA associations and provides better characterization of tumor types. PMID- 23745157 TI - Tenth Annual ISGIO Meeting. PMID- 23745158 TI - Intensity-Modulated Radiation Therapy vs. 3D Conformal Radiation Therapy for Squamous Cell Carcinoma of the Anal Canal. AB - PURPOSE: We compared our institutional experience using 3D conformal radiation therapy (3DCRT) vs. IMRT (intensity-modulated radiation therapy) for anal cancer. METHODS: We performed a single-institution retrospective review of all patients with squamous cell carcinoma anal cancer treated from September 2000 through September 2011, using definitive chemoradiation with curative intent. RESULTS: This study included 89 consecutive patients (37 3DCRT, 52 IMRT). Median follow-up for all patients, IMRT patients alone, and CRT patients alone was 26.5 months (range, 3.5-133.6), 20 months (range, 3.5-125.5), and 61.9 months (range, 7.6 133.6), respectively. Three-year overall survival (OS), progression-free survival (PFS), locoregional control (LRC), and colostomy-free survival (CFS) were 91.1%, 82.3%, 90.8%, and 91.3% in the IMRT cohort and 86.1%, 72.5%, 91.9%, and 93.7% in the 3DCRT group (all P > .1). More patients in the 3DCRT group required a treatment break (11 vs. 4; P = .006), although the difference in median treatment break duration was not significant (12.2 vs. 8.0 days; P = .35). Survival did not differ based on whether a treatment break was needed (all P > .1). Acute grade >=3 nonhematologic toxicity was decreased in the IMRT cohort (21.1 vs. 59.5%; P < .0001). Acute grade >=3 skin toxicity was worse in the 3DCRT group (P < .0001), whereas an improvement in late grade >=3 gastrointestinal (GI) toxicity was observed in the IMRT patients (P = .012). CONCLUSIONS: This study is the largest thus far to compare 3DCRT and IMRT for definitive treatment of anal cancer. Although long-term outcomes did not significantly differ based on RT technique, a marked decrease in adverse effects and the need for a treatment break was achieved with IMRT. PMID- 23745159 TI - Alternate dosing of cetuximab for patients with metastatic colorectal cancer. AB - BACKGROUND: Many chemotherapeutic regimens used to treat colorectal cancer (CRC), including 5-fluorouracil plus leucovorin in combination with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX), are administered on an every-other-week (q2w) dosing schedule. Chemotherapy in combination with a monoclonal antibody (mAb) directed toward the epidermal growth factor receptor (EGFR) has emerged as an effective treatment option. There are currently 2 anti-EGFR mAbs approved by the United States Food and Drug Administration: cetuximab and panitumumab. Mutations of KRAS, a downstream protein in the EGFR pathway, predict resistance to EGFR mAbs. Thus, cetuximab and panitumumab are indicated for patients without a KRAS mutation (KRAS wild-type). Whereas panitumumab is approved on a q2w dosing schedule, cetuximab is approved as a weekly dose. However, only cetuximab is approved with FOLFIRI for frontline metastatic CRC, whereas panitumumab is approved for third-line. Because concomitant therapies are often administered q2w, the weekly dosing of cetuximab results in additional medical office visits. DESIGN: Several studies have assessed the safety and efficacy of cetuximab q2w. For this review, a comprehensive literature search of studies evaluating cetuximab q2w dosing was conducted. Safety and efficacy results of these trials and retrospective analyses were summarized and reviewed. RESULTS: In general, results with cetuximab q2w were comparable to those obtained with the weekly regimen. CONCLUSION: These data suggest that for patients for whom weekly treatment with cetuximab presents a substantial burden to their quality of life, q2w dosing of cetuximab is a viable treatment option with a benefit:risk profile similar to that of the weekly regimen. PMID- 23745160 TI - Management of a patient diagnosed with pancreatic cancer and myelodysplastic syndrome. PMID- 23745161 TI - Cutaneous metastasis of pancreatic adenocarcinoma as a first clinical manifestation: a case report and review of the literature. PMID- 23745164 TI - Upcoming articles. PMID- 23745162 TI - Metastatic appendiceal carcinoma diagnosed in an asymptomatic patient with incidental thyroid mass on routine examination. PMID- 23745165 TI - DNA-Templated Molecular Silver Fluorophores. AB - Conductive and plasmon-supporting noble metals exhibit an especially wide range of size-dependent properties, with discrete electronic levels, strong optical absorption, and efficient radiative relaxation dominating optical behavior at the ~10-atom cluster scale. In this Perspective, we describe the formation and stabilization of silver clusters using DNA templates and highlight the distinct spectroscopic and photophysical properties of the resulting hybrid fluorophores. Strong visible to near-IR emission from DNA-encapsulated silver clusters ranging in size from 5-11 atoms has been produced and characterized. Importantly, this strong Ag cluster fluorescence can be directly modulated and selectively recovered by optically controlling the dark state residence, even when faced with an overwhelming background. The strength and sequence sensitivity of the oligonucleotide-Ag interaction suggests strategies for fine tuning and stabilizing cluster-based emitters in a host of sensing and biolabeling applications that would benefit from brighter, more photostable, and quantifiable emitters in high background environments. PMID- 23745166 TI - Advances in the prevention of heterosexual transmission of HIV/AIDS among women in the United States. AB - Despite recent advances in testing and treatment, the incidence of HIV/AIDS in the United States has remained stagnant with an estimated 56,300 new infections every year. Women account for an increasing proportion of the epidemic. The vulnerability of women to HIV stems from both increased biologic susceptibility to heterosexual transmission and also the social, economic, and structural disadvantages they often confront. This review describes the main reasons for the increased vulnerability of U.S. women to HIV transmission with particular emphasis on specific high-risk groups including: non-Hispanic blacks, women who use drugs, women with a history of incarceration, and victims of intimate partner violence. Although behavioral approaches to HIV prevention may be effective, pragmatic implementation is often difficult, especially for women who lack sociocultural capital to negotiate condoms with their male partners. Recent advances in HIV prevention show promise in terms of female-initiated interventions. These notably include female condoms, non-specific vaginal microbicides, and antiretroviral oral and vaginal pre-exposure prophylaxis. In this review, we will present evidence in support of these new female-initiated interventions while also emphasizing the importance of advocacy and the political support for these scientific advances to be successful. PMID- 23745167 TI - Cancer Stem Cells and the Bone Marrow Microenvironment. AB - "Cancer" is a disease that can spread to the other organs over time. The prognosis of cancer patients with metastasis is generally poor. Accordingly, there is an urgent need to establish a greater understanding of metastatic processes. It is highly likely that cancer stem cells (CSCs) are the key cells that mediate metastases, even while the cellular origin of CSCs remains unknown. Growing evidence has also revealed that the microenvironment has profound effects on the regulation of CSCs. Recently, it has been shown that bone metastatic cancer cells target the microenvironment or 'niche' which houses hematopoietic stem cells (HSCs). The major function of the HSC niche is to maintain 'stemness' of HSCs. These findings suggest that by targeting the HSC niche metastatic cells parasitize the very foundation of hematopoiesis to maintain their stemness. These observations suggest that there will be a need to target the HSC niche to provide effective therapies to eradicate metastatic CSCs. PMID- 23745168 TI - Characterizing protein domain associations by Small-molecule ligand binding. AB - BACKGROUND: Protein domains are evolutionarily conserved building blocks for protein structure and function, which are conventionally identified based on protein sequence or structure similarity. Small molecule binding domains are of great importance for the recognition of small molecules in biological systems and drug development. Many small molecules, including drugs, have been increasingly identified to bind to multiple targets, leading to promiscuous interactions with protein domains. Thus, a large scale characterization of the protein domains and their associations with respect to small-molecule binding is of particular interest to system biology research, drug target identification, as well as drug repurposing. METHODS: We compiled a collection of 13,822 physical interactions of small molecules and protein domains derived from the Protein Data Bank (PDB) structures. Based on the chemical similarity of these small molecules, we characterized pairwise associations of the protein domains and further investigated their global associations from a network point of view. RESULTS: We found that protein domains, despite lack of similarity in sequence and structure, were comprehensively associated through binding the same or similar small molecule ligands. Moreover, we identified modules in the domain network that consisted of closely related protein domains by sharing similar biochemical mechanisms, being involved in relevant biological pathways, or being regulated by the same cognate cofactors. CONCLUSIONS: A novel protein domain relationship was identified in the context of small-molecule binding, which is complementary to those identified by traditional sequence-based or structure-based approaches. The protein domain network constructed in the present study provides a novel perspective for chemogenomic study and network pharmacology, as well as target identification for drug repurposing. PMID- 23745169 TI - Stress response pathways in ameloblasts: implications for amelogenesis and dental fluorosis. AB - Human enamel development of the permanent teeth takes place during childhood and stresses encountered during this period can have lasting effects on the appearance and structural integrity of the enamel. One of the most common examples of this is the development of dental fluorosis after childhood exposure to excess fluoride, an elemental agent used to increase enamel hardness and prevent dental caries. Currently the molecular mechanism responsible for dental fluorosis remains unknown; however, recent work suggests dental fluorosis may be the result of activated stress response pathways in ameloblasts during the development of permanent teeth. Using fluorosis as an example, the role of stress response pathways during enamel maturation is discussed. PMID- 23745170 TI - Views of IRBs Concerning their Local Ecologies: Perceptions of Relationships, Systems, and Tensions between IRBs and their Institutions. AB - BACKGROUND: Research has generally examined institutional review boards (IRBs) in isolation, but critical questions arise of how these entities fit into the larger institutional contexts in which they operate and what the implications may be. METHODS: Semi-structured interviews were conducted with leaders of IRBs from among the top 240 institutions receiving funding from the National Institutes of Health. RESULTS: Interviewees felt that institutions may affect IRBs through both broad, indirect features (e.g., size, type of research, and culture of the institution), and more direct, IRB-related factors (e.g., amount of leadership and resource support for the IRB). Interviewees thought that institutional support of IRBs ranged from financial to non-financial, direct and indirect, and that these institutional factors can mold amounts of IRB staff and education, audits, and education of principal investigators (PIs), and tensions IRBs had to address. Respondents felt that these factors can in turn potentially affect IRB reviews of protocols and interactions with principle investigators (PIs). Within the complex systems of an institution, IRBs felt that PIs' experiences and complaints about the IRB to institutional leaders may also shape how the institution related to the IRB. CONCLUSIONS: These data are the first to show how IRBs perceive themselves as working within the contexts of dynamic local institutional relationships and systems that pose challenges and tensions that can potentially affect critical aspects of IRB functioning. The findings have implications for practice, future research, and policy. PMID- 23745172 TI - Housing, the Neighborhood Environment, and Physical Activity among Older African Americans. AB - This study examines the association of neighborhood environment, as measured by housing factors, with physical activity among older African Americans. Context is provided on the effects of structural inequality as an inhibitor of health enhancing neighborhood environments. The study population included African Americans participating in the UAB Study of Aging (n=433). Participants demonstrated the ability to walk during a baseline in-home assessment. The strength and independence of housing factors were assessed using neighborhood walking for exercise as the outcome variable. Sociodemographic data, co-morbid medical conditions, and rural/urban residence were included as independent control factors. Homeownership, occupancy, and length of residency maintained positive associations with neighborhood walking independent of control factors. Housing factors appear to be predictive of resident engagement in neighborhood walking. Housing factors, specifically high rates of homeownership, reflect functional and positive neighborhood environments conducive for physical activity. Future interventions seeking to promote health-enhancing behavior should focus on developing housing and built-environment assets within the neighborhood environment. PMID- 23745173 TI - Evaluation of Tumor Cell Response to Hyperthermia with Bioluminescent Imaging. AB - BACKGROUND: Hyperthermia is used in combination with radiotherapy and/or chemotherapy in the treatment of various types of cancer. Currently, the tumor cell response to hyperthermia is determined largely based on the size reduction of tumor mass, which is insensitive. METHODS: We tested the feasibility of bioluminescent imaging (BLI) in evaluation of the tumor cell response to hyperthermia by exposing luciferase-expressing MDA-MB-231-luc human breast cancer cells to high temperature (43 degrees C) for 10 minutes to 2 hours. The tumor cells were the imaged and the light signal generated by the tumor cells was quantified with BLI. To validate its usefulness, the light signal intensity was comparatively analyzed with the tumor cell clonogenicity and cell viability, which were measured with classic clonogenic and MTT assays. RESULTS: The light signal intensity determined by BLI was closely correlated with the absolute number of viable cells as well as the cell viability measured with the traditional MTT assay under normal culture condition. Relative to the clonogenicity of tumor cells after exposure to hyperthermia, however, BLI underestimated, while MTT assay overestimated the cell viability. Difference in the interpretation of tumor cell clonogenic ability following hyperthermia with BLI, MTT dye, and clonogenic assay may be due to the different mechanisms of the three measurements as well as the fact that hyperthermia can induce cell damage at levels of both transient and permanent. CONCLUSIONS: BLI is sensitive, convenient, and potentially valuable in the evaluation and monitoring of tumor cell response to treatments including hyperthermia. PMID- 23745171 TI - Comorbidity in Atopic Dermatitis. AB - The negative impact of atopic dermatitis (AD) often extends beyond the skin. Children with AD experience increased rates of infectious, mental health, and allergic diseases compared to their non-atopic peers. The mechanisms underlying these associations remain elusive. New insights from genetic and epidermal research pinpoint the skin barrier as a primary initiator of AD. Epicutaneous sensitization represents an intriguing new model which links a disrupted skin barrier to the later development of IgE-mediated diseases in patients with AD. Recent epidemiological studies have identified new comorbidities linked to AD as well, including several mental health disorders and obesity. This manuscript reviews the recent literature regarding both classic and newly described AD comorbidities. PMID- 23745174 TI - Water Detoxification by a Substrate-Bound Catecholamine Adsorbent. PMID- 23745175 TI - Hypoxamirs in Pulmonary Hypertension: Breathing New Life into Pulmonary Vascular Research. AB - In mammalian cells, hypoxia, or inadequate oxygen availability, regulates the expression of a specific set of microRNA, which have been previously termed "hypoxamirs." Over the past five years, the appreciation of the importance of hypoxamirs in regulating the cellular adaptation to hypoxia has grown dramatically. At a cellular level, each hypoxamir can simultaneously regulate expression of multiple (>100) target genes in order to control fundamental biological processes, including survival, proliferation, angiogenesis, migration, and metabolism, among others. A maladaptive imbalance of these hypoxic phenotypes often drives many ischemic cardiovascular diseases, such as pulmonary hypertension -- an enigmatic vascular disorder characterized by pronounced and severe panvasculopathy secondary to diverse upstream etiologies, notably including hypoxia. Yet, despite this pathogenic relationship between hypoxic cell phenotypes and disease, the mechanistic roles of hypoxamirs in modulating pulmonary hypertension remain largely unrecognized. Some advances have been made to explore the known contributions of specific hypoxamirs in the development and progression of pulmonary hypertension as well as discuss potential methods to more comprehensively study their roles in this complex disease. As a result, a more sophisticated understanding of their pervasive roles in pathogenesis could set the stage for unique diagnostic and therapeutic strategies in pulmonary hypertension. PMID- 23745177 TI - Integrating formative assessment and participatory research: Building healthier communities in the CHILE Project. AB - BACKGROUND: The need to conduct formative assessment to inform the development of interventional studies has been increasingly recognized in community-based health research. While this purpose alone may provide sufficient justification to conduct formative assessment, researchers are also recognizing the importance of such efforts with regard to partnership building. PURPOSE: This article reports a formative assessment process in a large scale randomized controlled trial in New Mexico aimed at preventing obesity in rural American Indian and Hispanic children in Head Start programs. METHODS: We interviewed Head Start staff and conducted observations to understand the context of food service and physical activity in these sites. We also collected data from other community partners, including grocery store managers and primary care providers, to assess appropriate strategies regarding their engagement in the study. RESULTS: Formative assessment findings helped modify the planned intervention while allowing for variation relevant to cultural and Head Start organizational conditions in each community. Rather than view formative assessment only as a planning phase of the research, our experience illustrates the need to conceptualize these activities more broadly. DISCUSSION: Integrating formative assessment and participatory research raises the need to address the challenge of ensuring standardization and consistency across varied community settings, the evolving nature of initial formative relationships and the need to build trust in academic/community partnerships. TRANSLATION TO HEALTH EDUCATION PRACTICE: In our work with American Indian and Hispanic communities in New Mexico, formative assessment represents a partnership building opportunity. PMID- 23745176 TI - Increased Intragenic IGF2 Methylation is Associated with Repression of Insulator Activity and Elevated Expression in Serous Ovarian Carcinoma. AB - Overexpression of insulin-like growth factor-II (IGF2) is a prominent characteristic of many epithelial ovarian malignancies. IGF2 imprinting and transcription are regulated in part through DNA methylation, which in turn regulates binding of the insulator protein CTCF within the IGF2/H19 imprint center. We have shown that IGF2 overexpression in ovarian cancer is associated with hypermethylation of CTCF binding sites within the IGF2/H19 imprint center. The aim of this study was to investigate the methylation and binding capacity of a novel putative CTCF binding motif located intragenic to IGF2 and determine how this relates to IGF2 expression. Among 35 primary serous epithelial ovarian cancer specimens, methylation of two CpGs, including one within the core binding motif and another adjacent to this motif, was higher in the 18 cancers with elevated IGF2 expression versus 10 with low expression (average 68.2 versus 38.5%; p < 0.0001). We also found that the CpG site within the CTCF binding motif is hypermethylated in male gametes (>92%; average 93.2%; N = 16). We confirmed binding of CTCF to this region in ovarian cancer cells, as well as the paralog of CTCF, Brother Of the Regulator of Imprinted Sites (BORIS), which is frequently overexpressed in cancers. The unmethylated CTCF binding motif has insulator activity in cells that express CTCF or BORIS, but not in cells that express both CTCF and BORIS. These intragenic CpG dinucleotides therefore comprise a novel paternal germline imprint mark and are located in a binding motif for the insulator protein CTCF. Methylation of the CpG dinucleotides is positively correlated with IGF2 transcription, indicating that increased methylation represses insulator function. These combined results suggest that methylation and CTCF binding at this region play important roles in regulating the level of IGF2 transcription. Our data have revealed a novel epigenetic regulatory element within the IGF2/H19 imprinted domain that is highly relevant to aberrant IGF2 expression in ovarian malignancies. PMID- 23745178 TI - Effects of the polyhistidine tag on kinetics and other properties of trehalose synthase from Deinococcus geothermalis. AB - Two recombinant trehalose synthases from Deinococcus geothermalis (DSMZ 11300) were compared. A significant influence of the artificial polyhistidine tag was observed in protein constitution. The recombinant trehalose synthase from D. geothermalis with His6-tag has a higher Km value of 254 mM, in comparison with the wild-type trehalose synthase (Km 170 mM), and displayed a lower activity of maltose conversion when compared to the wild type. Moreover, differences in properties like temperature, pH, thermal- and pH-stability were observed. Presence of the histidine tag caused a decrease of thermal resistance in case of trehalose synthase with His6-tag. These data confirmed a suggestion that the introduction of the histidine domain produces in some seldom cases undesirable changes in the protein. PMID- 23745179 TI - Fourier transform infrared microspectroscopy reveals that tissue culture conditions affect the macromolecular phenotype of human embryonic stem cells. AB - We employed Fourier transform infrared (FTIR) microspectroscopy to investigate the effects of different tissue culture environments on the FTIR spectra of undifferentiated human embryonic stem cells (hESCs) and their differentiated progeny. First we tested whether there were any possible spectral artifacts resulting from the use of transflectance measurements by comparing them with transmission measurements and found no evidence of these concluding that the lack of any differences resulted from the homogeneity of the dried cytospun cellular monolayers. We found that hESCs that were enzymatically passaged onto mouse embryonic fibroblasts (MEFs) in KOSR based hESC medium, hESCs enzymatically passaged onto Matrigel in mTESR medium and hESCs mechanically passaged onto MEFs in KOSR-based hESC medium, possessed unique FTIR spectroscopic signatures that reflect differences in their macromolecular chemistry. Further, these spectroscopic differences persisted even upon differentiation towards mesendodermal lineages. Our results suggest that FTIR microspectroscopy is a powerful, objective, measurement modality that complements existing methods for studying the phenotype of hESCs and their progeny, particularly changes induced by the cellular environment. PMID- 23745180 TI - An aptasensor for electrochemical detection of tumor necrosis factor in human blood. AB - Electrochemical aptasensors can detect disease markers such as cytokines to provide point-of-care diagnosis that is low-cost, rapid, specific and sensitive. Herein, we describe the development of an aptamer-based electrochemical sensor for detection and analysis of tumor necrosis factor-alpha (TNF-alpha) - a key inflammatory cytokine - in whole human blood. When testing spiked blood, a TNF alpha detection limit of 58 pM (10 ng mL(-1)) and a linear range of 6 nM (100 ng mL(-1)) could be achieved. Furthermore, detection of TNF-alpha in mitogen stimulated whole blood was demonstrated. PMID- 23745181 TI - Abrupt spin crossover in an iron(III) quinolylsalicylaldimine complex: structural insights and solvent effects. AB - The first Fe(III) qsal-X complex exhibiting abrupt complete spin crossover at 228 K with a hysteresis of 8 K, [Fe(qsal-I)2]OTf is reported. Structural studies of the MeOH solvate in the LS and HS state and at the spin transition are described. PMID- 23745182 TI - Direct growth of flower-like manganese oxide on reduced graphene oxide towards efficient oxygen reduction reaction. AB - Three-dimensional manganese oxide is directly grown on reduced graphene oxide (RGO) sheets, exhibiting comparable catalytic activity, higher selectivity and better stability towards oxygen reduction reaction than those of the commercial Pt/XC-72 catalyst. PMID- 23745183 TI - [Viral etiology in lower respiratory tract infection in children]. PMID- 23745184 TI - [In memory of Jurgen Koebke]. PMID- 23745185 TI - Reply to Stone et al.: Human-made role in local temperature extremes. PMID- 23745186 TI - [20th anniversary of the Cochrane Collaboration]. PMID- 23745187 TI - Chinese orthopaedic surgeons doing clinical research for international publication. PMID- 23745188 TI - High-frequency oscillation for ARDS. PMID- 23745189 TI - Biotechnology: Virtual reality. PMID- 23745191 TI - Retraction: The serine protease inhibitor neuroserpin regulates the growth and maturation of hippocampal neurons through a non-inhibitory mechanism. J. Neurochem. 121, 561-74. PMID- 23745190 TI - From the archives. Hepato-lenticular degeneration. By Stanley Barnes and E Weston Hurst. Brain 1925; 48: 279-333. With a further note on hepato-lenticular degeneration. By Stanley Barnes and E Weston Hurst. Brain 1926; 49: 36-60. With hepatolenticular degeneration: a final note. By Stanley Barnes and E Weston Hurst. Brain 1929; 52: 1-5. PMID- 23745192 TI - [Coronary stent restenosis--better viewed with CCTA than with ICA]. PMID- 23745193 TI - [Pulmonary embolism--confident exclusion by Wells-Score and the D-dimer-test]. PMID- 23745194 TI - The paper trail. PMID- 23745195 TI - Moral authority. PMID- 23745196 TI - Treatment of recurrent breast cancer following breast conserving surgery. AB - Patients with isolated ipsilateral breast cancer recurrence face completion mastectomy in the majority of cases. Selected patients may derive good outcomes from repeat breast conservation surgery and indeed repeat irradiation may be employed using one of many different modalities. Tumor biology rather than salvage surgery method is likely to influence outcome. Patients with isolated breast tumor recurrence are treated in the majority of cases with completion mastectomy, when for selected patients there exists little evidence that more radical surgery provides better outcomes in terms of further recurrence and overall survival, than repeated breast conserving surgery. Literature search identifying articles addressing the issue of repeat breast conserving surgery for ipsilateral breast tumor recurrence, and repeat radiotherapy(search terms include: repeat breast conserving surgery, salvage mastectomy, salvage breast conserving surgery,salvage radiotherapy, reirradiation). Thirty-five articles discussed the outcomes of repeat breast conserving surgery versus salvage mastectomy, methods of repeat breast irradiation, repeat sentinel lymph node biopsy and related factors. Repeat breast conserving surgery may represent a safe and feasible treatment method for isolated ipsilateral breast tumor recurrence. PMID- 23745198 TI - Device may increase HIV testing in remote areas. PMID- 23745197 TI - "Create the right conditions for staff to deliver quality care". PMID- 23745199 TI - Personalized support, satisfaction affect HIV treatment outcomes. PMID- 23745200 TI - Education. School programming can have big impact on HIV prevention. PMID- 23745201 TI - Social networking encourages testing in high-risk groups. PMID- 23745202 TI - Talk with patients about their use of alternative therapies. PMID- 23745203 TI - Prisons. HIV-positive inmate fails to show deliberate indifference. PMID- 23745204 TI - Women charge spa with negligence over unsterilized needle. PMID- 23745205 TI - SSI. HIV-positive woman failed to show she was unable to work. PMID- 23745206 TI - ADA. Question of whether employer failed to accommodate exists. PMID- 23745207 TI - Treatment. Bee venom destroyed HIV without damaging cells. PMID- 23745208 TI - Testing high-risk individuals every 3 months most cost-effective. PMID- 23745209 TI - Prevention. Community focus on HIV reduces transmission, stigma. PMID- 23745210 TI - Mistrust of government deters elderly from HIV testing. PMID- 23745211 TI - SSI. ALJ failed to explain denial of benefits to man with AIDS. PMID- 23745212 TI - Prisons. Inmate cannot proceed with violation of privacy claims. PMID- 23745213 TI - Prisons. Insufficient treatment did not amount to serious indifference. PMID- 23745214 TI - Immigration. Court affirms denial of asylum for Brazilian man with HIV. PMID- 23745215 TI - Final priority--National Institute on Disability and Rehabilitation Research- Rehabilitation Research and Training Centers. Final priority. AB - The Assistant Secretary for Special Education and Rehabilitative Services announces a priority for the Disability and Rehabilitation Research Projects and Centers Program administered by the National Institute on Disability and Rehabilitation Research (NIDRR). Specifically, we announce a priority for a Rehabilitation Research and Training Center (RRTC) on Promoting Healthy Aging for Individuals with Long-Term Physical Disabilities. The Assistant Secretary may use this priority for competitions in fiscal year (FY) 2013 and later years. We take this action to focus research attention on areas of national need. We intend this priority to improve health and function outcomes for individuals aging with long term physical disabilities. PMID- 23745216 TI - Author's replay. PMID- 23745217 TI - Clinical and therapeutic features of pulmonary nontuberculous mycobacterial disease, Brazil, 1993-2011. AB - To identify clinical and therapeutic features of pulmonary nontuberculous mycobacterial (PNTM) disease, we conducted a retrospective analysis of patients referred to the Brazilian reference center, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, who received a diagnosis of PNTM during 1993-2011 with at least 1 respiratory culture positive for NTM. Associated conditions included bronchiectasis (21.8%), chronic obstructive pulmonary disease (20.7%), cardiovascular disease (15.5%), AIDS (9.8%), diabetes (9.8%), and hepatitis C (4.6%).Two patients had Hansen disease; 1 had Marfan syndrome. Four mycobacterial species comprised 85.6% of NTM infections: Mycobacterium kansasii, 59 cases (33.9%); M. avium complex, 53 (30.4%); M. abscessus, 23 (13.2%); and M. fortuitum, 14 (8.0%). A total of 42 (24.1%) cases were associated with rapidly growing mycobacteria. In countries with a high prevalence of tuberculosis, PNTM is likely misdiagnosed as tuberculosis, thus showing the need for improved capacity to diagnose mycobacterial disease as well as greater awareness of PNTM disease prevalence. PMID- 23745219 TI - [Aspects of yeast biodiversity]. AB - Yeast biodiversity represents a dynamic scientific domain characterized by permanent emerging theories and accumulation of new data. Identification of genome structure for a number of yeast species and elucidation of regulatory pathways for species-specific metabolic networks, lead to development of numerous applications of yeasts in industry, biotechnology, therapeutics and bioremediation. The studies of the scientific community were long time focused on Saccharomyces cerevisae due mainly to its use in food production. Therefore, the species belonging to Saccharomyces genus became reference points for genomics and biodiversity studies. During last decades there is a growing interest for yeast species able to produce biomass by assimilating or degrading various compounds such as methanol, hydrocarbons, wood hydrolisates and other residues or by products from different industries. PMID- 23745218 TI - Tuberculosis and HIV co-infection, California, USA, 1993-2008. AB - To understand the epidemiology of tuberculosis (TB) and HIV co-infection in California, we cross-matched incident TB cases reported to state surveillance systems during 1993-2008 with cases in the state HIV/AIDS registry. Of 57,527 TB case-patients, 3,904 (7%) had known HIV infection. TB rates for persons with HIV declined from 437 to 126 cases/100,000 persons during 1993-2008; rates were highest for Hispanics (225/100,000) and Blacks (148/100,000). Patients co infected with TB-HIV during 2001-2008 were significantly more likely than those infected before highly active antiretroviral therapy became available to be foreign born, Hispanic, or Asian/Pacific Islander and to have pyrazinamide monoresistant TB. Death rates decreased after highly active antiretroviral therapy became available but remained twice that for TB patients without HIV infection and higher for women. In California, HIV-associated TB has concentrated among persons from low- and middle-income countries who often acquire HIV infection in the peri-immigration period. PMID- 23745220 TI - [Antibiotic resistance of bacterial strains isolated from bacteremias in immuno compromised patients]. AB - Immunocompromised hosts are subjects of predilection to bloodstream infections. The global mortality is high. Bacterial strains are frequently multiresistant; fungemias are almost always deadly, in spite of the susceptibility of the fungus. OBJECTIVE: to evaluate the positive blood cultures in patients with malignant and non-malignant diseases and to determine the resistance mechanisms with the Vitek2. MATERIAL AND METHOD: a 29 months study--181 episodes of invasive infections--168 patients. The blood culture vials were Bactec Plus. The isolates were identified using Api galleries and with the Vitek 2. The susceptibility was tested by the disk-diffusion method (Oxoid Ltd.). Minimal inhibitory concentrations: Vitek2. INTERPRETATION: EUCAST 2008 standard. RESULTS: overall mortality: 27%. Gram-negative bacilli: 59.4% and 48.5% Gram-positive cocci. Klebsiella pneumoniae and Escherichia coli isolates accounted for 16.43% and 71.23%respectively; 25% of E. coli strains and 33% of K. pneumoniae respectively, produced extended-spectrum beta-lactamases. Oxacillin resistance: 54.4% of S. aureus isolates. No resistance to carbapenems in enterobacteria. CONCLUSIONS: Bacterial resistance is not likely to decrease, if at all; Death produced by infections is an event that can be prevented. Molecular determinations should be performed to assess the role of the virulence genes and of the resistance mechanisms and to help the better understanding of the interractions between bacteria and the human organism. PMID- 23745221 TI - [Current state of the epidemiology of malaria in Romania]. AB - Malaria is the most common disease in the tropical areas and the most common imported disease in the non endemic areas, being considered by WHO a public health issue. About half of the world population lives in zones where there is a malaria risk, and in 2008 were reported 243 million malaria cases and 863.000 deaths. Europe was declared "malaria-free" by WHO in 1975. However there are still cases, most of them imported due to migration and travelling to high risk zones. In 2008 in Europe were reported 5848 imported cases in 25 countries. In recent years there were sporadic indigenous cases in Spain (2009) and Greece (2009, 2011), but the risk of malaria transmission in Europe is considered low in present. In Romania since 1961 indigenous transmission was interrupted, and starting with 1963 we are in the maintenance phase of malaria eradication. in the period 2007-2010 were reported 68 cases of malaria, all imported (24 cases in 2007, 13 cases in 2008, 12 cases in 2009 and 19 cases in 2010) and one death in 2007 (to a man aged 40 years infected in Uganda and who developed a toxic form of malaria with Plasmodium falciparum). Most cases of malaria (94.1%) were recorded in men who have traveled for work in Africa (83.8%), and who were infected with Plasmodium falciparum (67.7% of cases). Occurrence of malaria cases in non endemic areas is possible by the increasing number of people who travel in the risk areas and/ or ignoring and not following prevention measures, respectively chemoprophylaxis and personal protective measures against mosquito's bites. PMID- 23745222 TI - [Rapid methods for the diagnostic of food-borne infections determined by bacteria pertaining to genus Salmonella]. AB - For a long period of time, microbiological analysis of samples gathered from individuals, food and environment was based on culture techniques which were considered "gold standard". These conventional methods are yet time-consuming (with respect to germ identification and characterization), cumulative costs are huge, which made research focus on obtaining methods with a rapidity / cost ratio higher than that of classical methods. Rapid diagnostic became as well a priority in the case of food-borne diseases determined by Salmonella spp. These methods of rapid diagnostic are based on phenotypic or molecular techniques for identification and typing, as well as on tests using biosensors and DNA chips, which are under development, and which use the capacity of real-time monitoring of the presence of multiple pathogens in food. With the continuous development of new molecular technologies allowing the rapid detection of food pathogens, the future of conventional microbiological methods looks rather insecure, the more so as there is continuous interest in improving the performances of genotypic methods regarding easy handling, reliability and low costs. The work reviews the panoply of Salmonella identification and typing tests available in the present. PMID- 23745223 TI - [Measuring the control and decrease in prevalence of Listeria monocytogenes species in foods of animal origin]. AB - A large distributed bacterium, Listeria monocytogenes has been isolated from water and fresh vegetables, raw meat and processed meat (all types), and raw, salted and smoked fish. L. monocytogenes grows at low oxygen concentrations and at low temperatures, surviving for a long time in the environment, in the processing plant, as well as on the equipment, instruments and during storage at the refrigeration temperature. L. monocytogenes causes invasive listeriosis, often affecting immunocompromised individuals. Epidemiologically, listeriosis appears as sporadic cases and outbreaks, with an incidence of 3-8 cases/1000000 inhabitants, run-down in most countries, reflecting the measures compulsory in food processing industry. The purpose of this review is to describe the measures regarding the implementation of Current Good Manufacturing Practice (CGMP), to protrude the integrity of cold chain through preparing, packing and holding food, including household refrigerating, and to increase a good communication, particularly for consumers at increased risk of listeriosis. PMID- 23745224 TI - Pyogenic granuloma: an enigma within a paradox or a solution in search of a problem. PMID- 23745225 TI - Muckle-Wells syndrome: individualized, reflare-guided dosing of the orphan drug canakinumab. PMID- 23745226 TI - Assessment of the antidandruff activity of a new shampoo: a randomized, double blind, controlled study by clinical and instrumental evaluations. AB - The aim of this randomized, double-blind, controlled study was to evaluate the antidandruff activity exerted by a new shampoo on patients affected by dandruff and/or mild seborrheic dermatitis by means of both D-squame technique coupled with image analysis and clinical assessments. Thirty-four patients were enrolled and 1:1 randomly assigned to either a test shampoo or a comparative shampoo group. Treatment schedule was twice a week for 4 weeks. The D-squame technique was shown to be able to objectively record variations in scalp desquamation both between test and comparative groups and within the same group over time. The results obtained with this instrumental approach showed a statistically significant reduction by 52% vs baseline after 2 weeks of treatment. There was an even greater reduction after 4 weeks (-66%). This reduction was statistically significant compared with the comparative group at the same time points. The analysis of all the other parameters (except Wood's lamp) confirmed the superiority of the test vs the comparative shampoo. The test shampoo proved to be safe, well tolerated, and accepted by the patients for cosmetic acceptability and efficacy. The study confirmed the antidandruff efficacy of the test shampoo and its superiority vs the comparative shampoo. PMID- 23745227 TI - Persistent serpentine supravenous hyperpigmentation--a possible cutaneous manifestation of HIV infection or a normal racial variant: a report of 3 cases. AB - Persistent serpentine supravenous hyperpigmentation (PSSH) describes a hyperpigmentation of the skin overlying peripheral veins. This cutaneous finding is typically seen in association with systemic chemotherapy or collagen vascular diseases such as progressive systemic sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Three dark-skinned patients with idiopathic serpentine supravenous hyperpigmentation (ISSH) without collagen vascular disease or prior intravenous cytotoxic treatments were reported. All 3 patients were dark-skinned men with symmetric, uniform hyperpigmentation of the supravenous network of the bilateral lower extremities that had been present for years. The serpentine supravenous hyperpigmentation on the lower extremities was uniform in width and color, which contrasts with the darker discoloration near the site of infusion seen with PSSH associated with chemotherapy. Interestingly, 2 of the patients had advanced human immunodeficiency virus (HIV) disease in association with their ISSH while the HIV status of the third patient was unknown. Thus, we contend that ISSH be considered a normal racial variant or a possible cutaneous manifestation of HIV disease. PMID- 23745228 TI - Lichen planus pigmentosus. AB - Lichen planus pigmentosus, a variant of lichen planus, is a disorder with conflicting taxonomy. Its worldwide recognition is still not fully understood because of insufficient contemporary evidence of the disease in the literature. The authors review the historical background, etiopathogenesis, clinical connotation, atypical variants, and histopathology to highlight its diversity. PMID- 23745229 TI - ONMEL (itraconazole) 200-mg tablet. PMID- 23745230 TI - PICATO (ingenol mebutate 0.015% and 0.05% gels): a novel treatment for actinic keratosis. PMID- 23745231 TI - ABSORICA (isotretinoin): a new form. PMID- 23745232 TI - Treatment of necrobiotic xanthogranuloma with 2-chlorodeoxyadenosine. AB - A 71-year-old man presented with ulcerating yellow-red plaques of the back, chest, face, and extremities (Figure 1). He had a 10-year history of these lesions. The initial plaque appeared on the back followed by rapid progression of multiple similar lesions involving the face, chest, abdomen, and extremities. The plaques on his face were predominately in the periorbital and eyelid regions. Skin biopsy revealed an ulcerated epidermis. Dense sheets of foamy histiocytes were present in the dermis and contained foci of necrobiosis. Numerous Touton giant cells were present and cholesterol clefts were prominent. Special stains for organisms were negative. On further laboratory evaluation, serum protein electrophoresis revealed a monoclonal spike of 0.5 g/dL IgG lambda. Results from bone marrow biopsy were negative. Other significant laboratory findings included an elevated sedimentation rate and low serum complement. Clinical findings, histopathology, and laboratory evaluations were consistent with the diagnosis of necrobiotic xanthogranuloma (NXG). PMID- 23745233 TI - Phacomatosis pigmentokeratotica--a patient with hypophosphatemic rickets. AB - The epidermal naevus syndrome (ENS) is a sporadic condition characterized by congenital epidermal naevi associated with anomalies in other organ systems, most commonly the central nervous system and skeleton. We report a case of ENS presenting hypophosphataemic rickets resistant to traditional therapeutic agents. PMID- 23745234 TI - [Prescribing family medicine]. PMID- 23745235 TI - [Hospital's discharge prescription: a challenge for continuity of care and the interprofessional collaboration]. AB - The transition between hospital and community is an interface at high risk for medication. "The Association of Family Doctors" committee in the canton of Vaud (MFVaud), together with community pharmacists' and Homecare representatives, have begun to consider the following improvements: fast and co-ordinated care providers' information; arrangements for family doctors appointments as soon as possible; awareness and education for interprofessional collaboration; more secured preparation of pill boxes; development of interprofessional means such as medication use reviews and reconciliations. In the opinion of all the experts, there is an urgent public health need to act in an interprofessional manner, even if the solutions required (especially change in professional culture and technologies) are not immediate. PMID- 23745236 TI - [Polypharmacy and the elderly: neither too much nor too little]. AB - Elderly persons are at high risk of polypharmacy. Polypharmacy has been associated with numerous adverse outcomes, such as poorer quality of life, higher morbidity and mortality. However, deciding to stop or to continue a treatment is a difficult task, which confronts the physician to complex clinical and ethical choices. Such a decision requires a geriatric multidimensional assessment of the patient, an estimation of his or her prognosis, the definition of the goals of care and a careful assessment of the time to benefit of each drug. Diverse methods and tools to support the physician in this process are discussed in this article. However these can not replace a reflexive approach of the physician that integrates the values and representations of the patient with regard to his or her health and end of life, as well as his or her needs, fears and choices. PMID- 23745237 TI - [Medication adherence in chronic patients: from its concepts to its management in primary care]. AB - Medication nonadherence is common and its determinants are diverse. Adherence is influenced by many parameters, such as patient's self-efficacy, knowledge of health risk, outcome expectations, benefits of change, and barriers and facilitators. The sociocognitive theory helps professionals to structure their approach and to support patients in managing their treatment. Professionals need skills and time, and benefit from coordination in care, in particular between physicians and pharmacists. This article presents the key elements of a medication adherence program as well as tools and some useful questions. PMID- 23745238 TI - [Prescribing monitoring in clinical practice: from enlightened empiricism to rational strategies]. AB - Monitoring of a medical condition is the periodic measurement of one or several physiological or biological variables to detect a signal regarding its clinical progression or its response to treatment. We distinguish different medical situations between diagnostic, clinical and therapeutic process to apply monitoring. Many clinical, variables can be used for monitoring, once their intrinsic properties (normal range, critical difference, kinetics, reactivity) and external validity (pathophysiological importance, predictive power for clinical outcomes) are established. A formal conceptualization of monitoring is being developed and should support the rational development of monitoring strategies and their validation through appropriate clinical trials. PMID- 23745239 TI - [Prescribing physical activity to reluctant adolescents: why, how and for what benefits?]. AB - Family doctors often face requests to exempt adolescents from physical education classes. Knowledge of the goals of physical education in compulsory and post compulsory education can help the practitioner discuss this important subject and its physical and mental health implications. In Geneva, an innovative programme called "EPI" (individualised physical activity at the secondary school level) has been developed and doctors can refer adolescents who otherwise would not be able to participate in conventional gym classes. Motivational interviewing techniques the "motivational interviewing pyramid for young people" are useful to help the practitioner during these consultations. PMID- 23745240 TI - [Teaching students guidelines: prescription in the practice setting]. AB - The aim of this article is to help primary care teachers to instruct students' recommendations for drug prescription. Teaching drug prescription covers many aspects of primary care physicians' profession: establishing the correct diagnosis, choosing the appropriate treatment for any individual patient, negotiating with the patient concrete ways of taking the treatment, handling the necessary pharmacologic knowledge or existing tools that help treatment choice and communicating efficiently with the patient. The WHO 6-step method is presented. It helps to clarify the complexity of medical prescription so as to make it understandable for the student. PMID- 23745241 TI - [Protecting vulnerable persons: an ethical requirement in need of clarification]. AB - Protecting vulnerable persons is important. But who is vulnerable and what protections are required? This article outlines versions of vulnerability found in the literature: vulnerability as human finitude, as a lesser ability to protect one's interests, as fragility, as a hindrance to health. It then proposes a definition of vulnerability as an increased risk of incurring a wrong and examines how this definition could be applied to clear-cut as well as controversial cases of vulnerability. Protecting vulnerable persons requires a diagnostic approach: identifying the wrong involved, the source of vulnerability, adequate protections, as well as the persons who participate in the duty of protection. PMID- 23745242 TI - [Methoxetamine: the emergence of neodrugs]. PMID- 23745243 TI - [The other side of family physicians shortage]. PMID- 23745244 TI - [AIDS. Thirty years already (1)]. PMID- 23745245 TI - [The story of Osphena and dyspareunia]. PMID- 23745246 TI - [Overwhelmed by the events... regarding PMA]. PMID- 23745247 TI - [Allogenic BMSCs reverse chimerism inducing the tolerance of xeno-skin graft in mouse model]. AB - OBJECTIVE: To investigate the feasibility of bone marrow mesenchymal stem cells (BMSCs) in inducing immune tolerance and to establish the mouse model of reverse chimerism in xeno-skin transplantation. METHODS: The mouse model of bone marrow chimerism was established with immuncompromised BALB/C-nu/nu female mice by receiving the transplantation of BMSCs from green fluorescent protein (GFP) C57BL/10 male mice, the optimized chimeric time was identified by RT-PCR testing of SRY gene and immunohistochemistry measurement of GFP expression. In the experiment group, GFP-C57BL/10 male mice received the transplantation of the skin from immuncompromised BALB/C-nu/nu female mice with BMSCs bone marrow-chimerism. In the rejection group, GFP-C57BL/10 male mice received the transplantation of the skin from immuncompromised BALB/C-nu/nu female mice without BMSCs bone marrow chimerism. In the control group, allo-transplantation of skin was performed in GFP-C57BL/10 male mice. Histological study was performed to investigate the survival rate and angiogenesis of the transplanted skin. RESULTS: The bone marrow chimeric model was established, the expressions of SRY gene and GFP protein reached the highest level at four weeks (1.22 +/- 0.10; 458.0 +/- 3.4) post transplanted with BMSCs (10(6)), which was significantly different in comparison with those at one week, two weeks and six weeks posttransplantation(P < 0.05). Four-weeks after transplantation was further confirmed as the optimized chimeric time. The mean survival time of donor skin graft > 14 d in the experimental group, while it only was 5 d in the rejection group. CONCLUSION: The bone marrow chimerism can be formed in the recipient by donor BMSCs transplantation, which can further induce tolerance of mice xeno-skin transplantation by reverse chimerism. PMID- 23745248 TI - [Construction and expression of the eukaryotic expression vector containing AIF gene]. AB - OBJECTIVE: To construct the eukaryotic express vector containing apoptosis inducing factor (AIF) gene and to study its expression in A549 cells. METHODS: According to the GenBank AIF mRNA sequence, specific primers to amplify AIF gene from lung carcinoma cell line A549 by RT-PCR was designed. The amplified AIF gene fragment was cloned into plasmid pUC-T by TA cloning, then double enzyme digestion and DNA sequencing were used to identifying the positive recombinant AIF-pUC-T. The target fragment was retrieved and cloned into the eukaryotic express vector pcDNA3.1(+). The positive recombinant AIF-pcDNA3.1(+) was transfected into A549 cells, and expression of AIF gene was verified by RT-PCR and Western blot. RESULTS: AIF target gene was successfully amplified and cloned into the pUC-T. The target fragment was retrieved and cloned into the eukaryotic express vector pcDNA3.1(+), and it was completely coincided with the AIF sequence in GenBank suggested by cells transfected with AIF-pcDNA3. 1(+) was much higher than that of control cells which was not transfected with AIF-pcDNA3.1(+). CONCLUSION: The AIF eukaryotic expression vector AIF-pcDNA3.1(+) is successfully constructed in A549 cells and it could be experimental foundations for further study of AIF gene. PMID- 23745249 TI - [Gene sequence and antigenic epitope variation within the F protein of respiratory syncytial virus in Sichuan, China]. AB - OBJECTIVE: To investigate the variation of cytotoxic T-lymphocyte (CTL) and neutralizing epitopes in F protein of respiratory syncytial virus (RSV) isolated in Sichuan. METHODS: Nearly full-length of F protein gene of 10 strains of RSV isolated in Sichuan was amplified by RT-PCR and sequenced. The genetic variations, especially the CTL and neutralizing antibody epitopes within different subtypes and genotypes were analyzed and compared. RESULTS: The F protein of RSV is highly conserved within the two subtypes, with the P-distances of nucleotide and amino acids were 0.102 +/- 0.005 and 0.058 +/- 0.006, respectively. Neutralizing epitopes 47F and L4 were conserved between the subtypes, but RS-348 and 7C2 were only conserved within the subtypes. CTL epitopes HLA B * 57, HLA A * 01 and HLA Cw * 12 were conserved only within subtype A. There were specific different sites between the subtypes. CONCLUSION: The sequences of F protein from Sichuan RSV isolates were highly conserved, so as the epitopes on F-protein within subtypes, the identified CLT epitopes in subtype A may not be recognized in subtype B virus. PMID- 23745250 TI - [The mechanism of PINK1 localization on the outer membrane of mitochondria]. AB - OBJECTIVE: To study the specific mechanism of PTEM-induced putative kinase 1(PINK1) located to the outer membrane of damaged mitochondria. METHODS: Cultured HEK293T cells were transfected with plasmids expressing different proteins, following with DMSO or CCCP treatment. Western blot and coimmuoprecipitation were used to detect the expression and interaction of proteins. RESULTS: Full length PINK1, but not its mitochondria targeting sequence (MTS) & trans-membrane (TM) deleted forms or other outer mitochondria outer membrane proteins, could interact with Tom40 upon CCCP treatment and the interaction ability was more than 20 times stronger than that of DMSO control. When the added CCCP is washed out, the interaction between full length PINK1 and Tom40 declined rapidly. PINK1 with removed or mutated TM can interact with Tom40 even in the absence of CCCP. CONCLUSION: The accumulated PINK1 on the outer membrane of damaged mitochondria is just stuck on the TOM complex instead of integrated into the lipid bilayer. PMID- 23745251 TI - [Correlation between IDH1 mutation and prognosis in supratentorial high-grade astrocytomas]. AB - OBJECTIVE: To study the correlation between isoeitratedehydrogenasel 1 (IDH1) mutation and prognosis in supratentorial high-grade astrocytomas. METHODS: There were 217 samples of supratentorial high-grade astrocytomas specimens collected for DNA extraction, IDH1 mutation of each patient was determined by PCR and direct sequencing. The differences of clinical features were compared between mutant group and wild type group. The relationship between IDH1 mutation and overall survival of the patients was studied with Kaplan-Meier survival curve, while multiple factors analysis was carried out by COX regression model. RESULTS: There were 43 (19.3%) IDH1 mutations in 217 specimens, of which 9 (24.3%) in WHO grade III, 34 (18.9%) in WHO grade IV. The mean age of primary glioblastoma multiforme (GBM) in mutant type group and wild type group were 39.17 and 47.66 years old respectively (P < 0.05). The median survival time was 64 weeks for the patients in IDH1 mutation group and 50 weeks for those in wild type group, and the difference was statistically significant (P < 0.001). The median survival time was 51 weeks for the wild type group of WHO grade III cases and 58 weeks for the mutant group of WHO grade IV cases (P < 0.001). COX multiple variable analysis showed that IDH1 mutation, surgical resection, preoperative Karnofsky performance, radiotherapy and chemotherapy were statistically significant in prognosis (P < 0.05). CONCLUSION: IDH1 mutation can be found in supratentorial high-grade astrocytomas, the patients with IDH1 mutation may have a better prognosis. PMID- 23745252 TI - [Analysis of Y chromosome microdeletion in non-obstructive male infertile patients with azoospermia and severe oligozoospermia]. AB - OBJECTIVE: To investigate the frequency and types of the major Y chromosome microdeletions in non-obstructive infertile males with azoospermia and severe oligozoospermia in Chinese. METHODS: Multiplex polymerise chain reaction (PCR) amplification was used to detect Y chromosome microdeletion in 203 nonobstructive infertile men, including 125 patients with azoospermia and 78 with severe oligozoospermia, as well as 100 fertile men in the control group. RESULTS: Among the 203 non-obstructive infertile cases, 22 (10.8%) carried a Y chromosome microdeletion and the frequencies of such microdeletions were 9.6% in azoospermia and 12.8% in oligozoospermia. The most frequent microdeletions were in the AZFc, and all the severe oligospermia were found microdeletions in the AZFc. No Y chromosome microdeletion was detected in the control group. CONCLUSION: It is necessary to offer genetic screening and counseling to infertility men prior to intracytoplasmic sperm injection (ICSI) or in-vitro fertilization (IVF). PMID- 23745253 TI - [The effect of nicotinamide N-methytransferase overexpression on biological behaviors of SMMC7721 hepatocellar carcinoma cell line]. AB - OBJECTIVE: To study the effect of over expressed nicotinamide N-methytransferase (NNMT) on the malignant biological behaviors of hepatocellular carcinoma cell line SMMC7721. METHODS: The cells transfected with SMMC/NNMT abbreviated as S/NNMT, parental cells including the negative control which transfected with SMMC/pcDNA3. 1 abbreviated as S/P and parental group which abbreviated S. MTT assay and Plate Clone Formation Assay, cell adhension assay and invasion assay were applied to evaluate the effect of NNMT overexpression on the malignant biological behaviors of hepatocellular carcinoma cell line SMMC7721. RESULTS: Compared with the negative control and parental group, MTT assay and Plate Clone Formation Assay demonstrated that over expression of NNMT in SMMC7721 cells could not influence the proliferation clone formation of SMMC7721 cells (P > 0.05). Over expression of NNMT in SMMC7721 cells significantly enhanced the ability of invasion and adhension (P < 0.001). CONCLUSION: NNMT gene can partially influence the malignant behaviors of hepatocellular carcinoma cellline SMMC7721 and increased the ability of invasion and adhension. PMID- 23745254 TI - [Preliminary evaluation of biodegradable scaffold of polyethylene (PEGPU) glycol polyurethane in bladder tissue engineering]. AB - OBJECTIVE: To evaluate the ability of growth and proliferation of bladder urothelial cell and smooth muscle cell in 3-dimension (3-D) polyethylene glycol polyurethane (PEGPU) porous scaffolds. METHODS: The PEGPU scaffolds with 4 different pore size (90.8, 76.7, 40.9 and 39.6 microm) were prepared. Mouse fibroblasts, human bladder smooth muscle cells and human urothelial cells were implanted into the scaffolds and cultured respectively. The cell growth appearance on the outer and inner surface of 3-D scaffold was observed by FITC and DAPI dying, and the ability of growth and proliferation of implanted cells in 3-D scaffold was evaluated by CCK-8 method. RESULTS: All the three types of cell adhered on the surface and proliferated in the four different pore size 3-D scaffolds. Mouse fibroblasts, human bladder smooth muscle cells and human bladder urothelial cells achieved the optimum condition of growth and proliferation in the 3-D scaffold with mean pore size of 40.9 microm, 90.8 microm and 39.6 microm, respectively. CONCLUSION: 3-D PEGPU scaffold shows the potential to be used in bladder tissue engineering. PMID- 23745255 TI - [Effect of Rhodiola Sacra on left ventricular remodeling and its mechanism in spontaneously hypertensive rats]. AB - OBJECTIVE: To investigate the effect of Rhodiola Sacra on left ventricular remodeling in spontaneously hypertensive rats (SHRs). METHODS: 30 male SHRs were randomly allocated into a treatment and a control group, which were intragastric administered with Rhodiola Sacra 500 mg/(kg x d) and water respectively. Tail systolic blood pressure (SBP) was monitored every two weeks. After 8 weeks, the body mass (BM) and left ventricle mass (LVM) of the rats were measured for computing the left ventricle mass index (LVMI). Plasma and myocardial homogenate angiotensin II (Ang II), aldosterone (ALD) and the protein of myocardial homogenate were detected respectively by radioimmunoassay, and then the quantity of Ang II and ALD per gram protein was calculated. Myocardial specimen slides were stained with method of Masson staining, and myocardial collagen volume fraction (CVF) was calculated by a Computer Image System. Protein expression of Ang II type 1 receptor (AT1) in left ventricular myocardium were detected by immunohistochemistry technique, and calculated by a Computer Image System. RESULTS: Compared with the control group, there was a obvious decrease in SBP (P < 0.05), LVMI (mg/g, 2.84 +/- 0.13 vs. 2.97 +/- 0.12, P = 0.044), myocardial CVF (%, 4.41 +/- 0.53 vs. 4.89 +/- 0.53, P = 0.021), plasma Ang II (ng/L, 77.61 +/- 14.12 vs. 92.59 +/- 16.64, P = 0.042), plasma ALD (ng/L, 73.52 +/- 18.61 vs. 90.11 +/- 19.67, P = 0.005), myocardial Ang II (ng/g x protein, 40.03 +/- 5.36 vs. 46.02 +/- 6.78, P = 0.005) or myocardial ALD (ng/g x protein, 37.61 +/- 6.25 vs. 43.70 +/- 5.09, P = 0.049), whereas no significant difference was observed in the protein expression of AT1 in left ventricular myocytes between the two groups. CONCLUSION: Rhodiola Sacra may prevent left ventricular remodeling in SHRs, which is probably attributed to blood pressure lowering and inhibition of RAS, especially myocardial RAS. PMID- 23745256 TI - [Effect of Heshouwuyin on the expression of Cox7a2 protein in testis tissue of exercised-induced fatigue rat]. AB - OBJECTIVE: To explore the effect of Heshouwuyin on the expression of cytochrome C oxidase7a2 (Cox7a2) in testis tissue of rats with exercised-induced fatigue. METHODS: Fifty SD rats were divided into normal control group (A group), Heshouwuyin administered normal group (B group), model control group (C group), Heshouwuyin treated group (D group) and Heshouwuyin prevented group (E group) randomly with 10 rats for each. The exercise-induced fatigue models in rats of C, D, E groups were established. The rats in D group were treated with Heshouwuyin [20 g/(kg x d), contained crude drug 9.6 g/mL] for 60 days (during the 42 days of modeling and after the 18 days of modeling). The rats in E group were also treated with Heshouwuyin for 60 days (but before the 18 days of modeling and during the 42 days of modeling). Beckmancoulter Unicel Dxl 800 was used to detect the level of serum testosterone, according to the manufacture's instructions. Western blot and RT-PCR were used to observe the differential expression of Cox7a2. RESULTS: The level of serum testosterone in C group was decreased compared with A group (P < 0.05), which implied the success of modeling. Compared with group A, the level of serum testosterone in B, D, E groups were increased (P < 0.05). Cox7a2 protein was expressed mainly in leydig cell and spermatocyte. Compared with A,B, D, E groups, the expression of Cox7a2 protein and mRNA in C group increased (P < 0.05), and there no significant difference was observed between group A and B, as well as group D and E. CONCLUSION: The expression of Cox7a2 was down-regulated by Heshouwuyin. PMID- 23745257 TI - [Mechanical hyperalgesia induced by chronic morphine administration in young rats]. AB - OBJECTIVE: To investigate the effects of chronic morphine administration on pain behaviors in young rats and to explore the mechanisms involved. METHODS: Sixteen SD young rats of 3-4 weeks were randomly divided into control and morphine administration groups. Young rats received saline (1 mL/kg) or morphine (10 mg/kg) subcutaneously. Each regimen was given once daily for 14 days. Pain behaviors were examined on day 1, 3, 5, 7, and 14 before the daily drug administration. Western blot was used to examine the expression of glutamate decarboxylase 65 (GAD65) in the spinal cord dorsal horn on day 14 after the last drug administration. RESULTS: Following 14 days of morphine administration, mechanical hyperalgesia was induced in young rats. Compared with control group, the mechanical withdrawal threshold of morphine group significantly decreased on days 3, 5,7 and 14. Chronic administration of morphine downregulated the expression of GAD65 in the spinal cord dorsal horn of young rats. CONCLUSION: Chronic morphine administration could induce mechanical hyperalgesia in young rats, and the downregulation of GAD65 in the spinal cord dorsal horn might play a critical role in the molecular mechanisms of morphine-induced hyperalgesia. PMID- 23745258 TI - [The effect of surfentanyl and fentanyl at rhythmic spontaneous contraction on isolated rabbits uterine smooth muscles]. AB - OBJECTIVE: To investigate the effects of surfentanyl and fentanyl on spontaneous contractions of isolated uterine smooth muscles of rabbits. METHODS: Thirty isolated uterine smooth muscles strips of rabbits with rhythmic spontaneous contraction were randomly divided into three groups: control group (n = 10) fentanyl group (n = 10) and surfentanyl group (n = 10). The effects of fentanyl and surfentanyl on spontaneous contractions intensity, frequency and duration of isolated uterine smooth muscles of rabbits in different concentrationswere monitored. RESULTS: There were no effect on the spontaneous contraction of isolated uterine muscles of rabbits at the concentration of 1 x 10(-8) mol/L in fentanyl group. The spontaneous contraction intensity was decreased significantly when the concentration of fentanyl more than 3 x 10(-8) mol/L (P < 0.05). The spontaneous contraction intensity, frequency and duration was inhibited more than 50% when the concentration of fentanyl more than 3 x 10(-7) mol/L (P < 0.05). And the spontaneous contraction duration was inhibited more than 50% when the concentration of surfentanyl more than 1 x 10(-7) mol/L (P < 0.05). Compared with surfentanyl group, there were significant difference on spontaneous contraction intensity when the concentration of fentanyl more than 3 x 10(-8) mol/L (P < 0.05). Difference on frequency, more than 3 x 10(-8) mol/L (P < 0.05) and difference on duration, at the concentration of 1 x 10(-7) and 1 x 10(-7) mol/L (P < 0.05). CONCLUSION: Fentanyl restrained the spontaneous contractions of isolated uterine smooth muscles of rabbits in concentration-dependent manner. Surfentanyl could reduce the spontaneous contractions duration on isolated uterine smooth muscles of rabbits. But there were no effect on frequency and duration. PMID- 23745259 TI - [Clinical efficacy and serum cobalt, chromium metal ion concentrations after total hip arthroplasty with three different hard-on-hard bearings]. AB - OBJECTIVE: To compare the clinical efficacy and serum concentrations of cobalt, chromium metal ion in three different hard-on-hard bearings after total hip arthroplasty at 2-years postoperatively. METHODS: Ninety (90) THA patients were divided into ceramic-on-ceramic (COC), ceramic-on-metal (COM), metal-on-metal (MOM) group (n = 30 in each group). At preoperative and 3, 6, 12, 24 months postoperative 5 time points, serum concentrations of cobalt and chromium metal ion were measured, Harris hip score was evaluated, X-rays and color doppler ultrasound examination of the ipsilateral hip also were observed. RESULTS: The excellent rates of Harris hip score were 100% in three groups. Continuous X-rays showed no radiolucent line around the acetabular component, no osteolysis, and no inflammatory pseudotumor. After the THA operation, the metal ion levels in COM and MOM groups increased rapidly, and stabilized at 12 months, then showed a downward trend, but the chromium ion level of MOM continued to rise at 24 months, with a significant difference when compared with that at 12 months (an increase of 0.48 microg/L, P = 0.021). The serum concentrations of metal ion in COC group were relatively constant at all time points, and the cobalt, chromium ion levels of MOM group were significantly higher than those of COC and COM group. CONCLUSION: The postoperative functional recovery of the three hard-on-hard bearings all were good, and no inflammatory pseudotumor and osteolysis were found. The serum levels of cobalt, chromium ion of COM were lower than those of MOM, but higher than those of COC. PMID- 23745260 TI - [Comparison between allogeneic tendon fixation and screw fixation in ligamentous Lisfranc injury: a biomechanical analysis]. AB - OBJECTIVE: To compare the stability provided by a allogeneic tendon with a screw for the treatment of ligamentous Lisfranc injury. METHODS: Six fresh-frozen, paired cadaveric feet were loaded in the condition of Lisfranc ligament-intact, injury and fixation models. With axial or abduction stress, the distance between medial cuneiform and second metatarsal was recorded. RESULTS: With both two types of stress, there were statistically significant differences in motion detected between the intact and post-injury conditions (all P = 0.000), and the magnitudes were greater with abduction [(4.14 +/- 1.02) mm] than axial load [(1.60 +/- 0.64) mm]. In screw fixation group, the mean position changes under axial load and abduction load were (1.53 +/- 0.62) mm and (4.06 +/- 1.05) mm in post-injury model respectively, while the changes were (0.76 +/- 0.35) mm and (1.20 +/- 0.53) mm in the fixation model (all P = 0.000) which were not statistical different to that in the intact model. In allogeneic tendon fixation group, the mean position changes were (1.66 +/- 0.65) mm and (4.21 +/- 1.00) mm in the post-injury model, while were (0.90 +/- 0.41) mm and (1.33 +/- 0.61) mm in the fixation model (all P = 0.000) which also were not statistical different to that in the intact model. CONCLUSION: Under abduction stress, a significantly greater difference was found between pre- and post-injury, which may be valuable for diagnosing and testing ligamentous Lisfranc injury. Allogeneic tendon fixation can provide similar stability as screw fixation in ligamentous Lisfranc injury. PMID- 23745261 TI - [A biomechanical comparison of Acutrak headless compression screw and AO cannulated lag screw for the fixation of Hoffa fracture]. AB - OBJECTIVE: To compare the stability, strength of Letenneur type I Hoffa fractures fixed by Acutrak headless compression screws and AO cannulated lag screws. METHODS: 12 models of Letenneur type I Hoffa fractures were randomly divided into 4 groups, which were fixed with two AO cannulated lag screws or Acutrak headless compression screws anteroposteriorly or posteroanteriorly. The stress between two fragments of all specimens was tested. Axial compression test, the cycle load test and the limit load test were successively performed in every specimen. RESULTS: In axial compression test, displacement of Acutrak headless compression screw groups was lower than that of AO cannulated lag screw anteroposteriorly (P < 0.05). The load to failure for Acutrak headless compression screw groups was higher than that of AO cannulated lag screws (P < 0.05), no matter in anteroposterior or posteroanterior direction. CONCLUSION: The strength and stability of Letenneur type I Hoffa fractures fixeded with Acutrak headless compression screw were superior to those provided by AO cannulated lag screw. The direction of screw affects the initial stability for AO cannulated lag screw, other than Acutrak headless compression screw. PMID- 23745262 TI - [The relationship between centric relation-maximum intercuspation disharmony and temporomandibular dysfunction in class II patients]. AB - OBJECTIVE: To investigate the relationship between the degree of displacement of centric relation-maximum intercuspation (CR-MI) and temporomandibular dysfunction (TMD) in Class II patients. METHODS: The questionnaire and clinical examination were administered in 107 Class II patients and students, using the Helkimo index (Di and Ai). The differences in condylar position between CR and MI in all three spatial planes were measured using the Condyle Position Indication (CPI). RESULTS: Di positively correlated with degree of CR-MI displacement in all five displacement (P < 0.05), while Ai positively correlated with degree of CR-MI displacement except horizontal displacement. Di and Ai significantly correlated with degree of CR-MI discrepancy in all five displacement (P < 0.05); With the increasing of Di and Ai rank, the degree of CR-MI displacement and CR-MI discrepancy increased. Also, symptoms of TMD were significantly correlated with the degree of CR-MI displacement and CR-MI discrepancy except horizontal displacement (P < 0.05). Severer CR-MI displacement and CR-MI discrepancy were observed in patients who had TMD symptoms. CONCLUSION: In Class II patients, degree of CR-MI displacement is an important factor of TMD, and correlated with the severity of TMD. PMID- 23745263 TI - [Relationship between early serum albumin variation and prognosis in patients with severe acute pancreatitis treated in ICU]. AB - OBJECTIVE: To investigate the relationship between serum albumin variation within 24 hours of ICU admission and prognosis in critically ill patients with sever acute pancreatitis (SAP). METHODS: We retrospectively analyzed all the clinical data of the patients with SAP treated in ICU from Jul. 2005 to Jun. 2010. The patients were divided into two groups, survival group (n = 131) and death group (n = 108). Clinical and laboratory data, outcomes, and serum albumin within 24 hours after admission to ICU of those patients were evaluated respectively, and Logistic regression analysis was performed. RESULTS: Significant differences were existed between two groups (P < 0.01) in average age, the score of acute physiology and chronic health evaluation II (APACHE II), Ranson criteria, the score of sequential organ failure assessment (SOFA), and albumin variation within 24 hours (Serum albumin descent degree and ratio in early stage). However, sex ratio, mean serum albumin concentration within 24 hours, and onset time did not have significant differences (P > 0.05). The area under ROC curve for albumin variation within 24 hours were 0. 728 and 0. 742, the best cut-off values were 4.25 g/L (sensitivity 61.45%, specificity 81.67%) and 13.5% (sensitivity 62.65%, specificity 78.33%), respectively. Multiple logistic regression analysis showed that albumin variation within 24 hours was associated with death. CONCLUSION: The albumin variation within 24 hours was the risk factors for poor prognosis of critically ill SAP in early stage. PMID- 23745264 TI - [A study on carbapenem resistance in klebsiella pneumoniae]. AB - OBJECTIVE: To investigate the molecular mechanisms of reduced carbapenem susceptibility in Klebsiella pneumonia. METHODS: One reduced carbapenem susceptible Klebsiella pneumonia clinical isolate was investigated. Kirby-Bauer disc test was applied to determine the antibiotic susceptibility of the isolate. Modified Hodge Test and EDTA-disk synergy test were used to confirm whether this Klebsiella pneumonia strain could produce metallo-beta-lactamase. The genotype of the beta-lactamase was confirmed by PCR and DNA sequence analysis. Plasmid DNA preparations and conjugation experiment were used to determine the location of the resistant gene. RESULTS: Antibacterial circle of imipenem, meropenem for Klebsiella pneumonia isolate were 16 cm and 17 cm implied that the isolated strain producing carbapenemas. Modified Hodge Test and EDTA-disk synergy test confirmed that this Klebsiella pneumonia isolate produced metallo-beta-lactamase. IMP-4 gene was amplified by PCR and confirmed with sequence analysis. A reduced carbapenem susceptibility in obtained conjugants was observed when evaluated with Kirby-Bauer disc test and conjugation experiment also revealed that blalMP-4 were carried on one plasmid with a size of approximately 73 000 bp. CONCLUSION: Production of plasmid-mediated metallo-beta lactamase IMP-4 might lead to the reduced susceptibility of Klebsiella pneumonia spp. to carbapenems. PMID- 23745265 TI - [Pharmacokinetics study of amoxicillin sodium clavulanate potassium (10:1) injection in healthy volunteers]. AB - OBJECTIVE: To study the pharmacokinetics of amoxicillin sodium clavulanate potassium (10:1) injection with different single doses intravenous infusion and one dose repeated intravenous injection in healthy volunteers for guiding the rational clinical regimen. METHODS: Using infusion pump constantly intravenous dripping in 30 min, 4 mL blood samples were collected before and after the administration at 10 min, 20 min, 30 min, 45 min, and 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 10 h. The plasma concentrations of amoxicillin and clavulanate were detected by high performance liquid chromatography- mass spectrometry/mass spectrometry method. The pharmacokinetic parameters were calculated by DAS2.0.1 software. RESULTS: The dispositions of amoxicillin and clavulanate matched three or two compartment model with the weight coefficient 1/cc. To avoid the biases caused by compartment model fitting, the pharmacokinetic parameters were statistical moment parameters of non-compartment model. The peak concentrations, the areas under curve, the half-lifes and the clearances after single injections of 0. 55 g, 1.1 g and 2.2 g indicated that both amoxillin and clavulanate had linear dynamics characteristics. After 1.1 g single dose and multiple doses infusion, the pharmacokinetic parameters of amoxicillin and clavulanate were close respectively, and the trough concentrations before the 7th to 13th administration were lower than the detection limitation, which implied that the previous administration had cleared out before the next administration, and no accumulation happened after multiple doses. CONCLUSIONS: The amoxicillin sodium clavulanate potassium (10:1) injection possesses the linear kinetics. The dosage regimen of 1.1 g Q8h intravenous infusion could meet the needs of clinical therapy. PMID- 23745266 TI - [The relationship between refractive error and influencing factors in children]. AB - OBJECTIVE: To investigate the influence of refractive factors, including axial length, cornea power and astigmatism, and total astigmatism to refractive errors. METHODS: Axial length (AL) and cornea power (K) of 295 children (590 eyes) aged 8. 43 years old (4-14 years old) were obtained through IOL-Master, refractive error was measured by retinoscope after cycloplegia. The eyes were divided into 7 groups according to their spherical equivalence (SE). The 7 groups were high myopia, moderate myopia, low myopia, emmetropia, low hyperopia, moderate hyperopia and high hyperopia. AL and cornea parameters of different groups were compared using ANOVA and Pearson's correlation was used to analyze the relationship between SE, AL and cornea astigmatism and total astigmatism respectively. RESULTS: (1) Of the 7 groups, AL was longest in the high myopia group and shortest in the high hyperopia group. There was a statistically significant difference (P < 0.05) in AL among the 7 groups. (2) High and moderate myopes had the greatest K values and though there was no difference between the 2 groups, they had greater K values compared to other groups (P < 0.05). Moderate hyperopes had the smallest K values which were smaller than any other group except high hyperopia group. (3) SE was negatively correlated with K (r = -0.242, P < 0.001) and positively correlated with cornea astigmatism (r = 0.131, P = 0.001) but had no correlation with total astigmatism. AL was negatively correlated with cornea astigmatism (r = -0.218, P < 0.001) and had no correlation with K and total astigmatism. (4) Multiple linear regression using AL, K and age as independent variable and SE as dependent variable was applied to analyze the relationship of these variables, and the equation was. CONCLUSION: The bigger the cornea K value and the longer the AL were, the more myopia the eye was. The study showed that cornea K value of high hyperopes became steeper, indicating that the corneas of high hyperopes tried to compensate for the hyperopic refractive error due to short AL so that the eye can grow toward emmetropization; but the corneas of other groups had the same trend as the AL, which caused myopia or hyperopia together. However, generally speaking, the cornea became steeper as myopia got more severe and flatter as hyperopia more severe. PMID- 23745267 TI - [Impact of urbanization on the residents' health service needs and utilization based on the urban and rural integration development]. AB - OBJECTIVE: To explore the impact of urbanization on the residents' health service needs and utilization for the purpose of providing references for health making decision by analyzing the difference of health service needs and utilization in semi-urban residents, urban residents and rural residents. METHODS: The residents in the three economic zones of Chengdu were selected by stratified ration sampling and interviewed with the questionnaire. RESULTS: The two-week morbidity rate, hospitalization rate, and non clinical visit rate of semi-urban residents were higher than those of other people, and the chronic disease prevalence rate of urban residents was higher. Age, employment status, and the urban-rural identification were the main influential factors of two-week morbidity rate and chronic illness prevalence. After the related factors were controlled, the urban rural identification was not the impact factor of the health service utilization. CONCLUSION: The urban-rural integration development has promoted the health service accessibility and narrowed the disparity of health to some extent between urban and rural residents. However, the semi-urban residents should be caught a great deal of attention as a special group, and given more employment assistance. PMID- 23745268 TI - [Relationship between social-psycological factors and quality of life in old women with coronary heart disease]. AB - OBJECTIVE: To investigate the influence of depression, social supports and quality of sleep and quality of life on old women who were 60 years or older and postmenopause with coronary heart disease. METHODS: 125 old women with coronary heart disease completed questionnaires of Seattle Angina Questionnaire (SAQ), Social Support Scale (SSRS) and Self-rating Depression Scale (SDS). Logistic regression analysis and Spearman correlation analysis were performed to evaluate the relationship between social-psycological factors and quality of life. RESULTS: 120 of questionnaires wereeffective (representing 96% of all collected questionnaires). Regression analysis showed that marital status (OR = 2.450), education (OR = 0.520), income (OR = 19.541) and course of disease (OR = 0.309) were associated with QOL in CHD (P < 0.05). Spearman analysis demonstrated that there were negative correlations between SQA score and PSQI and depression scores (r = -0.771, P < 0.01; r = -0.703, P < 0.05); and positive correlation between SQA score and Social support score (r = 0.565, P < 0.05). CONCLUSION: Social psychological factors might influence the quality of life in old women with coronary heart disease, it is important that physicians pay attention to these factors when they treat old women with coronary heart disease. PMID- 23745269 TI - [Developing early intervention and follow-up system for premature infants of brain injury ]. AB - As the increasing trend of survival rate for premature birth, especially in early preterm infants, it calls more and more attention to neurologic sequelae of premature birth. Besides cerebral palsy, there are high incidences of neuropsychological disorders in premature infants, such as learning and social communication problems, which sometimes remain a challenge for the quality of life even in their adulthood. In order to solve these difficult situation and problems, more and more medical research and clinical efforts have being focused on the mechanism of brain injury, neurological sequelae of premature birth, early intervention and follow-up for premature. Hereby we are discussing our works for brain injury in preterm the mechanism of neurological sequelae, assessment methods and early intervention, to provide rationale for the establishment of early intervention and follow-up system for premature infants with brain injury. PMID- 23745270 TI - [Influence of neonatal diseases and treatments on the development of cerebral palsy in preterm infant]. AB - OBJECTIVE: To investigated the risk factors of cerebral palsy development in preterm infants. METHODS: This study included 203 preterm infants (gestation age < 37 weeks) diagnosed with cerebral palsy (CP) and 220 preterm infants without cerebral palsy or any other severe neurological disorders during April 2005 to August 2011. The risk factors in the development of cerebral palsy, including the diseases of premature infants and the treatments in neonatal period, were analyzed by multiple logistic regression analysis. RESULTS: Multivariate logistic analysis for the risk factors associated with cerebral palsy in neonatal period found significant differences in the occurrence of periventricular leukomalacia (PVL, OR = 39.87, P < 0.05), hypoxia-ischemic encephalopathy (HIE, OR = 4.24, P < 0.05), hypoglycemia of neonatal (OR = 2.18, P < 0.05), neonatal hyperbilirubinemia (OR = 1.72, P < 0.05), continuous positive airway pressure (CPAP, OR = 0.21, P < 0.05). CONCLUSION: The factors including PLV, HIE, hypoglycemia, and neonatal jaundice may increase the risk in the development of CP in preterm infant, while CPAP may decrease the risk of cerebral palsy. PMID- 23745271 TI - [The regulation of Akt signaling on axonal density after hypoxic-ischemic brain injury in neonatal rat]. AB - OBJECTIVE: To investigate the activity of protein kinase B (Akt) and its downstream protein, glycogen synthase kinase-3beta (GSK-3beta) under hypoxia ischemia (HI), and the possible regulation for axonal density. METHODS: Postnatal day 10 SD rats were suffered the right common carotid artery ligation and 8% mixture of oxygen and nitrogen hypoxia 2.5 h to produce HI model. The expression of total and phosphorylated Akt and GSK-3beta was detected by western blot after HI. After pretreatment of Akt inhibitor, wortmannin or LY294002, Western blot detect the expression of total and phosphorylated of Akt, GSK-3beta at 4 h and 24 h after HI. After pretreatment of wortmannin, axonal density was determined by Bielschowsky silver impregnation, and histological injury was evaluated by hematoxylin and eosin (HE) staining. RESULTS: The expression of total Akt and GSK 3beta remained unchanged after HI. p-Akt protein significantly decreased at 0.5 h, increased at 2 h and reached the highest at 4 h, returned to baseline at 8 h, declined at 24 and 48 h after HI, and finally returned to baseline again at 72 h compared with that of sham controls, p-GSK-3beta protein decreased at 0. 5 h, increased at 2 h, reached the highest at 4 h, returned to baseline at 8 and decreased at 24 h, reached the lowest at 48 h, and returned to baseline at 72 h. Wortmannin or LY294002 intervention didn't change the expression of total Akt and GSK-3beta, while decrease the p-Akt and p-GSK-3beta expression. HI cause decreased axonal density, and the histological injury of brain. Wortmannin pretreatment could aggravate the histological injury and decrease axonal density after HI. CONCLUSION: The Akt pathway is involved in axonal density and histological brain injury after HI in neonatal rat. PMID- 23745272 TI - [Application of amplitutude integrated electroencephalography for early diagnosis of brain injury in premature infants]. AB - OBJECTIVE: To study the characteristics of amplitude integrated electroencephalography (aEEG) in preterm infants with brain injury. METHODS: This study included 62 cerebral damage infants with 28-36 weeks gestational age (GA), and another 51 normal infants in control group, aEEG recording was performed to each infant during the first 48 h of life, the duration of each recording was at least 2 h. The features of aEEG, such as continuity(Co), sleep-wake cycling (Cy) and amplitude of the lower border (LB), were evaluated by semiquantitative analysis and compared between the two groups. RESULTS: All the aEEG features were found having significantly lower values in brain injuries group (P < 0.05). Logistic regression of aEEG features to the presence of brain injury revealed that only Cy was significantly correlated to the outcome (OR = 0.217, P < 0.05). ROC curve demonstrated Cy of the best sensitivity and specificity with 0.769 AUC. Co, LB yielded 0.677, 0.602 AUC respectively. Correlation analysis of GA to Co, Cy, LB and total score showed significantly correlated, the correlation coefficient for Co, Cy, LB and total scores were 0.546, 0.488, 0.536, 0.588 respectively (P < 0.05). CONCLUSION: The Cy in the initial aEEG is predictive for brain injury in premature infants with 28-36 weeks GA. The older the GA at birth, the more mature the aEEG pattern in premature neonates. PMID- 23745273 TI - [Analysis of brainstem auditory evoked potential in premature infants after perinatal hypoxia]. AB - OBJECTIVE: To examine brainstem auditory evoked potential (BAEP) in preterm infants after perinatal hypoxia within 3 days and 1 month after birth. METHODS: BAEP was studied in 42 preterm infants after perinatal hypoxia within 3 days and 1 month after birth, and was compared with those in preterm without any major perinatal problems. RESULTS: The latencies of wave V and the interpeak intervals of III-V and I-V in BAEP of hypoxia preterm infants differed significantly from those in the control with 3 days after birth. One month later, the latencies of wave and the interpeak intervals in BAEP of hypoxia infants were improved, and there were no significant differences between two groups. CONCLUSION: Central auditory function in preterm infants will be damaged by perinatal hypoxia, which must be taken into account even the damage could be improved in 1 month after birth. PMID- 23745274 TI - [Effects of early neurodevelopmental treatment on motor and cognitive development of critically ill premature infants]. AB - OBJECTIVE: To study the effects of neurodevelopmental treatment (NDT) on motor and cognitive development of critically ill premature infants. METHODS: There were 203 infants, who were less than 32 week gestational age (GA), with very-low birth weight, were included in the study. The infants were assigned to NDT group (n = 96) or control group (n = 107) according to the parent's decision. The infants in NDT group received NDT intervention once per week from corrected age (CA) 1 month to 3 months, and 3 to 5 times per week in the following 9 months. NDT intervention included elongation, establishing alignment, optimizing base of support, facilitation and inhibition, stimulation for activating muscle activity. Both groups received family intervention, such as massage and exercise based on early education. Bayley Scales of Infant Development-II (BSID-II) score was assessed at 3,6,9,12 months CA for all the infants. RESULTS: NDT intervention achieved significant effects on motor and cognitive development. Mental development index (MDI) and psychomotor development index (PDI) of BSID-II were significant higher in NDT group (P < 0.05). Cerebral palsy was finally diagnosed in 15 children in NDT group (16.67%) and 12 (12.12%) in control group at 12 months CA, there was no significant difference between the two groups (P > 0.05). CONCLUSION: NDT intervention can improve motor and cognitive development in critically ill premature infants within 12 months CA. PMID- 23745275 TI - [Investigation on pharmacokinetics of aminophylline in very low birth weight infants]. AB - OBJECTIVE: To investigate the pharmacokinetics of aminophylline in very low birth weight infant. METHODS: This study investigated 104 very low birth weight infants using aminophylline 5 mg/kg treating apnea who were hospitalized in our department during 2011-2012. The blood concentration of aminophylline was measured in 30 min before, 8 h and 5 d after first time loading dose, and was counterchecked every week before aminophylline withdrawal. The pharmacokinetic parameters of aminophylline were calculated and population pharmacokinetic model was established by MW/Pharm3.6 statistical analysis. RESULTS: The average birth weight of these 104 very low birth weight infants was (1.15 +/- 0.23) kg, average gestational age was (31.19 +/- 2.50) weeks. The results of aminophylline pharmacokinetics showed: the plasma clearance was (17.88 +/- 5.61) mL/(kg x h), the apparent volume of distribution was (0.93 +/- 0.18) L/kg, the half life time was (28.6 +/- 7.59) h. The aminophylline plasma clearance was related to creatinine clearance, gestational age and days of age after birth (related coefficient was 0.68, 0.62, 0.56 respectively, P < 0.05),the apparent volume of distribution was related to birth weight (related coefficient was 0.82, P < 0.05). The population pharmacokinetics model established can predict the concentration-time curve of the patients. CONCLUSION: The pharmacokinetics of aminophylline in very low birth weight infant was quite different from adult, which suggest blood concentration monitoring and dose adjustment for the clinical use of aminophylline in low birth weight infants. PMID- 23745276 TI - [The methodology and influential factors of real-time elastography in liver examination]. AB - OBJECTIVE: To investigate the methodology and influential factors of real-time elastography (RTE) in liver examination. METHODS: Forty normal volunteers received the examination of liver with RTE. All strain images were analyzed by the Strain Histogram Measurement and the liver fibrosis index (LFI) values were recorded. Two-tailed t-test was used to evaluate the significance of the potential influence factors of RTE, including inter-lobar variations, respiratory phase, different sections and gender. A paired two-tailed t-test and Bland-Altman test were used in the analysis of the inter- and intra-observer consistency. RESULTS: There were significant differences between the LFI values in the left lobe and those in the right lobe (2.52 +/- 0.47 vs. 1.58 +/- 0.41), also between right intercostal and right sub-costal approach (1.58 +/- 0.41 vs. 1. 59 +/- 0.45). There were no significant differences either between the LFI values of end expiration and those of end-inspiration (2.61 +/- 0.54 vs. 1.58 +/- 0.41) or between male and female (1.57 +/- 0.37 vs. 1.60 +/- 0.46). RTE showed goodness of fit between the inter- and intra-observer consistency. CONCLUSION: Liver stiffness measurement performed by RTE at end-inspiration in the right lobe with inter-costal approach may reveal liver elasticity more accurately. PMID- 23745277 TI - [Feasibility and accuracy of ultrasound-guided methodology in the examination of lumbar spine facet joints]. AB - OBJECTIVE: To investigate the feasibility, accuracy of B ultrasound in the examination of joint space of lumbar spine facet joints compared with CT scan. METHODS: Ten healthy adult volunteers were enrolled. The joint space of lumbar facet joints was measured by ultrasound. To identify the spinal levels, the posterior parasagittal sonograms were obtained at levels L1 to S1. The lumbar facet joints were delineated with the help of transverse sonograms at each level. Meanwhile, the lumbar facet joints were evaluated by spiral CT on the same plane, reformatted to 1-mm axial slices. RESULTS: A total of 88 lumbar facet joints from L1 to S1 were clearly visualized in the 10 volunteers. Both ultrasound and CT measurements showed the same average depth and lateral distance of lumbar facet joint space (P > 0.05). CONCLUSION: The lumbar facet joint space can be accurately demonstrated by ultrasound. PMID- 23745278 TI - [Optimization and characterization of SalB-pC loaded self-emulsifying drug delivery system]. AB - OBJECTIVE: To prepare self-emulsifying delivery system (SEDDS) of Salvianolic acid B phospholipid complex (SalB-PC) and evaluate its quality. METHODS: The best formulation was optimized using single-factor and pseudo-ternary phase diagrams, according to the emulsifying efficiency, the characteristics and partical size of the emulsion and other indicators. The morphology, particle size, zeta-potential and the release in artificial intestinal fluid of self-emulsifying formulation were evaluated. RESULTS: The weight ratio of SalB-PC: Lauroglycol FCC:Cremophor EL:Transcutol P in the best formulation was 9:45:40:15. SalB-PC loaded self emulsifying formulation is yellow and transparent solution, with partical size about (187.2 +/- 7.1) nm, polydispersity index (PDI) about 0.267 +/- 0.008 and zeta-potential about (-35.6 +/- 2.7) mV after diluted about 100-fold. The self emulsifying formulation released slower than the solution with only SalB or SalB PC. CONCLUSION: Water-soluble drug Salvianolic acid B can be prepared to SEDDS, and this formulation can slow down the release of SalB in artificial intestinal fluid. PMID- 23745279 TI - [Establishment of in vitro co-cultue system for tumor vascular endothelial cells]. AB - OBJECTIVE: To establish a in vitro culture model of tumor vascular endothelial cells (TECs). METHODS: We established in vitro culture model of TECs, named A549 HUVECs, through the co-culutre system culturing primary human umbilical vein endothelial cells (HUVECs) and human lung adenocarcinoma epithelial cell line A549 cells in indirect co-cultures, six-well Transwell-clear dishes (0.4 microm porous filter, Costar). We then observed TECs' cell morphology, growth characteristics, proliferation and karyotype, telomerase activity, etc. RESULTS: In the indirect co-culture system, A549-HUVECs showed migration cell-type appearance, more active cellular metabolism, increasing cell permeability, augmenting cell proliferation, which indicated A549-HUVECs being in a state of the regulation of homeostasis imbalance for cell proliferation and apoptosis. Besides, the analysis of A549-HUVECs genetic characteristics showed that the chromosome karyotype of A549-HUVECs was sub-triploid, and its telomerase activity increased, phenotypic change occurred, which possessed the similar pathological features of precancerous lesion. CONCLUSION: A549-HUVECs co-culture system could be feasible for tumor vascular research. PMID- 23745280 TI - [Mid-long-term clinical results and hemodynamic evaluation of aortic valve replacement with 17 mm St. Jude medical regent valve]. AB - OBJECTIVE: To investigate the mid-long-term clinical results of aortic valve replacement with 17 mm St. Jude medical regent valve with hemodynamic evaluation including the measurement of effective orifice area, the occurrence of prosthesis patient mismatch (PPM) and its affect on heart function. METHODS: There were 44 patients accepted aortic valve replacement with 17 mm St. Jude medical regent valve because of small aortic annulus. Before the operation and during the postoperative follow-up, color doppler echocardiography was used to measure the hemodynamic parameters, such as left ventricular mass (LVmass), effective orifice area (EOA) and effective orifice area index (EOAI), etc. RESULTS: Transthoracic echocardiographic data were obtained from 39 of 44 patients (88.6%) at 12-55 months after surgery. One (2.27%) died of heart failure in 1 year. According to the current standard of PPM (EOAI < or = 0.85 cm2/m2), 33 cases (82.1%) had PPM, 13 cases (30.8%) had severe PPM with an EOAI < or = 0.65 cm2/m2. After the operation, there were significant decreases in LVAo-PG (19 +/- 8) mmHg and left ventricular mass index (LVmass I) (86.6 +/- 23.3) g/m2 (P < 0.05). The assessment for physical capacity according to NYHA classification: 41 patients improved to class II or better and 2 patients improved to class III (P < 0.05). CONCLUSION: The patients with small aortic annulus may obtain satisfactory clinical results after AVR with 17 mm St. Jude medical regent valve, PPM seems not affect the mid long-term results. PMID- 23745281 TI - [The value of chest CT features evaluating the severity and prognosis for acute pancreatitis]. AB - OBJECTIVE: To analyze the chest CT imaging features of AP and explore the clinical value of diagnosis and prognosis for acute pancreatitis. METHODS: Using the new standard of Atlanta for Acute Pancreatitis, 130 cases AP were divided into two groups, mild acute pancreatitis (MAP, 80 cases) and severe acute pancreatitis (SAP, 50 cases). The patients of clinical and CT features were analyzed. Explore bilateral pleural effusion thickness and lung consolidation thickness at mediastinum window of chest transvers CT and investigate results with the scores of CTSI, EPIC, BISAP and APACHE-II. RESULTS: The chest CT of SAP manifested: The percentage of bilateral pleural effusion, pulmonary consolidation in SAP was more than in MAP, while the percentage of single pleural effusion, pulmonary consolidation and negative damage in SAP was less than in MAP. There was no significant difference between two groups (P > 0.05). The ratios among left pleural effusion/chest thickness, left pulmonary consolidation/chest thickness and right pulmonary consolidation/chest thickness in SAP were more than in MAP, There were significant differences between two groups (P < 0.05). There were significant differences among different groups about CTSI score, EPIC score, BISAP score and APACHE-II score (P < 0.05). After comparison each two groups, there were significant differences among some groups for all scores, especially in the EPIC score and BISAP score. There was middle-grade positive correlation among bilateral pleural effusion and pulmonary consolidation with EPIC score, BISAP score (P < 0.05); there low-grade positive correlation with CTSI score, APACHE-II score (P < 0.05). About the hospital stays, there was no significant differences among all groups, but there were significant differences between group 1 and group 5. AP with double pleural effusion or pulmonary consolidation died each one, the mortality were 1.5% and 1.1% respectively, while single pleural effusion or pulmonary consolidation died no one. There was no significant difference between them (P = 1.000). CONCLUSION: Bilateral pleural effusion/pulmonary consolidation suggest SAP to some extent. Measuring the values of pleural effusion/pulmonary consolidation has some clinic cost for assessing the severity and the prognosis of Acute Pancreatitis. PMID- 23745282 TI - Lung volumes, pulmonary ventilation, and hypoxia following rapid decompression to 60,000 ft (18,288 m). AB - INTRODUCTION: Rapid decompressions (RD) to 60,000 ft (18,288 m) were undertaken by six subjects to provide evidence of satisfactory performance of a contemporary, partial pressure assembly life support system for the purposes of flight clearance. METHODS: A total of 12 3-s RDs were conducted with subjects breathing 56% oxygen (balance nitrogen) at the base (simulated cabin) altitude of 22,500 ft (6858 m), switching to 100% oxygen under 72 mmHg (9.6 kPa) of positive pressure at the final (simulated aircraft) altitude. Respiratory pressures, flows, and gas compositions were monitored continuously throughout. RESULTS: All RDs were completed safely, but one subject experienced significant hypoxia during the minute at final altitude, associated with severe hemoglobin desaturation to a low of 53%. Accurate data on subjects' lung volumes were obtained and individual responses post-RD were reviewed in relation to patterns of pulmonary ventilation. The occurrence of severe hypoxia is explained by hypoventilation in conjunction with unusually large lung volumes (total lung capacity 10.18 L). CONCLUSIONS: Subjects' lung volumes and patterns of pulmonary ventilation are critical, but idiosyncratic, determinants of alveolar oxygenation and severity of hypoxia following RD to 60,000 ft (18,288 m). At such extreme altitudes even vaporization of water condensate in the oxygen mask may compromise oxygen delivery. An altitude ceiling of 60,000 ft (18,288 m) is the likely threshold for reliable protection using partial pressure assemblies and aircrew should be instructed to take two deep 'clearing' breaths immediately following RD at such extreme pressure breathing altitudes. PMID- 23745283 TI - Auditory, visual, and bimodal data link displays and how they support pilot performance. AB - BACKGROUND: The design of data link messaging systems to ensure optimal pilot performance requires empirical guidance. The current study examined the effects of display format (auditory, visual, or bimodal) and visual display position (adjacent to instrument panel or mounted on console) on pilot performance. METHODS: Subjects performed five 20-min simulated single-pilot flights. During each flight, subjects received messages from a simulated air traffic controller. Messages were delivered visually, auditorily, or bimodally. Subjects were asked to read back each message aloud and then perform the instructed maneuver. RESULTS: Visual and bimodal displays engendered lower subjective workload and better altitude tracking than auditory displays. Readback times were shorter with the two unimodal visual formats than with any of the other three formats. Advantages for the unimodal visual format ranged in size from 2.8 s to 3.8 s relative to the bimodal upper left and auditory formats, respectively. Auditory displays allowed slightly more head-up time (3 to 3.5 seconds per minute) than either visual or bimodal displays. Position of the visual display had only modest effects on any measure. DISCUSSION: Combined with the results from previous studies by Helleberg and Wickens and Lancaster and Casali the current data favor visual and bimodal displays over auditory displays; unimodal auditory displays were favored by only one measure, head-up time, and only very modestly. Data evinced no statistically significant effects of visual display position on performance, suggesting that, contrary to expectations, the placement of a visual data link display may be of relatively little consequence to performance. PMID- 23745284 TI - Adaptation in locomotor stability, cognition, and metabolic cost during sensory discordance. AB - BACKGROUND: Locomotor instability may affect planetary extravehicular activities during the initial adaptation to the new gravitational environment. The goal of this study was to quantify the locomotor, cognitive, and metabolic effects of exposure to a discordant sensory environment. METHODS: A treadmill mounted on a 6 degree-of-freedom motion base was used to present 15 healthy subjects with a destabilizing support surface while they walked. Dependent measures of locomotor stability, cognitive load, and metabolic cost were stride frequency (SF), reaction time (RT), and the volume of oxygen consumed (Vo2), respectively. Subjects completed an 8-min baseline walk followed by 20 min of walking with a continuous, sinusoidal, laterally oscillating support-surface perturbation. Data for minutes 1, 7, 13, and 20 of the support-surface perturbation period were compared with the baseline. RESULTS: SF, RT, and Vo2 were significantly greater during support-surface motion than during the baseline walking condition and showed a trend toward recovery to baseline levels during the perturbation period. Results demonstrated that adaptation to walking in a discordant sensory environment has quantifiable and significant costs in SF, RT, and Vo2 as shown by mean increases of 9%, 20%, and 4%, respectively, collected during the first minute of exposure. By the fourth minute of exposure, mean Vo2 consumption had increased to 20% over its baseline. DISCUSSION: We believe that preflight sensorimotor adaptation training paradigms will impart gains in stability and the ability to multitask, and might increase productive mission time by extending work time in extravehicular activity suits where metabolic expenditure is a limiting factor. PMID- 23745285 TI - Cardiovascular and ventilatory responses to dorsal, facial, and whole-head water immersion in eupnea. AB - OBJECTIVE: Facial cooling can regulate reflexes of the dive response whereas further body cooling generally induces the cold-shock response. We examined the cardiovascular and ventilatory parameters of these responses during 3-min immersions of the head dorsum, face, and whole head in 17 degrees C water while breathing was maintained. METHODS: From a horizontal position, the head was inserted into a temperature controlled immersion tank in which the water level could be changed rapidly. On four occasions, either the head dorsum, face or whole head (prone and supine) were exposed to water. RESULTS: Mean decrease in heart rate (14%) and increases in systolic (9%) and diastolic (5%) blood pressures were seen during immersion. Relative mean finger skin blood flow had an early transient decrease (31%) for 90 s and then returned to baseline values. A strong transient increase was seen in minute ventilation (92%) at 20 s of immersion via tidal volume (85%). There were no consistent differences between the head dorsum, face, and whole head for all variables in response to immersion. CONCLUSIONS: The cold-shock response (increased minute ventilation and tidal volume) predominated over the dive response in the initial moments of immersion only. The order of emergence of these responses provides further recommendation to avoid head submersion upon cold water entry. It is important to protect the face, with a facemask, and the head dorsum, with an insulative hood, in cold water. PMID- 23745286 TI - Evaluation of aircrew candidate blood testing. AB - BACKGROUND: The medical assessment of Royal Air Force (RAF) aircrew candidates includes the measurement of 39 individual blood parameters, grouped into 9 blood test panels, to detect disqualifying medical condition(s) (DMC). Although this program has run for over 20 yr, its contribution to the assessment of fitness to fly remains unquantified. METHODS: To determine whether blood testing independently identified DMC, the medical records of 589 male and female aircrew candidates, assessed at the RAF Officer and Aircrew Selection Centre during 2009 and 2010, were scrutinized for DMC while blinded to blood results. DMC identified through blood testing were then recorded and the sensitivity, specificity, and predictive values were calculated. The costs for the financial year 2009-2010 were estimated. RESULTS: For all candidates ages < or = 32 yr, specificity and positive predictive value for all blood test panels combined were 79% and < 1%, respectively. There were 8 DMC identified by blood testing while 994 (21%) of all panels contained an abnormality. For older candidates, three DMC were detected through blood testing that were not recorded elsewhere. The direct cost of the program, based on monetary charges levied for blood testing, was over pound 10,900 (c. US$16,350) but the total costs, including indirect costs to the RAF and individuals, were considerably higher. CONCLUSION: Blood testing at the initial medical assessment identified few DMC, but the organizational and individual burden associated with the program was substantial. Consideration should be given to the curtailment of blood testing in RAF aircrew candidates. PMID- 23745287 TI - Stress reactivity and cognitive performance in a simulated firefighting emergency. AB - BACKGROUND: During emergencies maladaptive behavior can reduce survival. This study compared the effects of a basic firefighter training course on 21 volunteers (with no firefighting experience) with age and gender-matched controls. METHODS: Stress reactivity (salivary cortisol and anxiety) were monitored across the course: day 1 (classroom), day 2 (physical equipment training), and day 3 (simulated fire emergency). Cognitive performance (visual attention, declarative and working memory) considered important in surviving a fire emergency were measured immediately post-training or after a 20-min delay. RESULTS: Prior to threat subjects showed an anticipatory cortisol increase but no corresponding increase in self-reported anxiety. On day 3 cortisol was higher in firefighters tested immediately after (10.37 nmol x L(-1) and 20 min after training (7.20 nmol L(-1)) compared to controls (3.13 nmol x L(-1)). Differences in cognitive performance were observed post-threat, with impairments in visual declarative memory in the firefighting subjects tested immediately, and working memory impairments observed in those tested after a 20-min delay. CONCLUSIONS: Cognitive impairments were found following a simulated emergency and could explain maladaptive responses observed during real fires. Moreover, the results suggest the type of cognitive impairments observed may be time dependent, with different cognitive difficulties becoming evident at different times following an emergency. PMID- 23745288 TI - Garment fit and protection from sustained +Gz acceleration with 'full-coverage' anti-G trousers. AB - INTRODUCTION: Garment fit may influence the effectiveness with which Full Coverage Anti-G Trousers (FCAGT) transmit pressure to the skin surface, and hence provide protection from sustained +Gz acceleration. A search of the available literature, however, did not reveal any prior work quantifying this effect. METHODS: Three related studies were performed. In Study I, using a mannequin, garment-to-surface pressure transmission ratios were measured at various locations under normally fitted (NF) and loosely fitted (LF) FCAGT. In Study II, garment pressure-volume ratios and lung volumes were measured at +1 Gz in six men wearing FCAGT in three conditions: NF, LF, or NF with inflatable socks at 13 kPa differential pressure (NF+SOCKS). In Study III, relaxed +Gz tolerance (RGT) and ratings of perceived exertion (RPE) at +7, +8, and +9 Gz were measured in eight men wearing FCAGT in four experimental conditions: NF; LF; abdomen LF, legs NF; or abdomen NF, legs LF. RESULTS: LF did not affect pressure transmission over the lower limbs or lower abdomen, but transmission over the upper abdomen was significantly compromised. Lung volumes were reduced with FCAGT inflation, but LF was associated with greater expiratory reserve volumes and increased FCAGT volume. Under +Gz acceleration, LF over the abdomen (with or without lower limb LF) decreased RGT and increased RPE, but not with lower limb LF when abdominal fit was normal. DISCUSSION: Care should be taken to achieve and maintain a snug FCAGT fit, especially of the abdominal portion of the FCAGT, to ensure optimal anti-G protection during sustained acceleration. PMID- 23745289 TI - Cardiovascular investigations of airline pilots with excessive cardiovascular risk. AB - BACKGROUND: This study examined the prevalence of airline pilots who have an excessive cardiovascular disease (CVD) risk score according to the New Zealand Guideline Group (NZGG) Framingham-based Risk Chart and describes their cardiovascular risk assessment and investigations. METHODS: A cross-sectional study was performed among 856 pilots employed in an Oceania based airline. Pilots with elevated CVD risk that had been previously evaluated at various times over the previous 19 yr were reviewed retrospectively from the airline's medical records, and the subsequent cardiovascular investigations were then described. RESULTS: There were 30 (3.5%) pilots who were found to have 5-yr CVD risk score of 10-15% or higher. Of the 29 pilots who had complete cardiac investigations data, 26 pilots underwent exercise electrocardiography (ECG), 2 pilots progressed directly to coronary angiograms and 1 pilot with abnormal echocardiogram was not examined further. Of the 26 pilots, 7 had positive or borderline exercise tests, all of whom subsequently had angiograms. One patient with a negative exercise test also had a coronary angiogram. Of the 9 patients who had coronary angiograms as a consequence of screening, 5 had significant disease that required treatment and 4 had either trivial disease or normal coronary arteries. CONCLUSION: The current approach to investigate excessive cardiovascular risk in pilots relies heavily on exercise electrocardiograms as a diagnostic test, and may not be optimal either to detect disease or to protect pilots from unnecessary invasive procedures. A more comprehensive and accurate cardiac investigation algorithm to assess excessive CVD risk in pilots is required. PMID- 23745290 TI - Twin studies in altitude and hypoxia research. AB - Humans exhibit high individual variation in response to acute hypoxia exposure. A number of published studies have used a classic 'twin study' model, comparing responses within pairs of monozygotic and dizygotic twins, to separate genetic from environmental contributions to the variation in altitude acclimatization. Available data suggest that some aspects of acclimatization have a heritable component. Most prominent is the hypoxic ventilatory response (HVR), which was repeatedly shown to be heritable in a number of age groups spanning infancy to adulthood (F-ratio range: 2.03 to 5.26). The ventilatory response to hypercapnia appears to only be heritable when tested in hypoxic conditions, providing additional evidence for a genetic component to the HVR (F-ratio range: 0.31, 6.92). A number of studies reported an estimate of heritability for more general hypoxic responses, such as heart rate, blood pressure, and blood gases; however, many of these studies relied on relatively small sample sizes and used inaccurate estimates of heritability and thus provided inconclusive evidence to elucidate the source of variation. Future genetic inquiries into the basis of variation in altitude acclimatization might benefit from further use of the classic twin study model: these experiments could identify the specific endophenotypes of altitude acclimatization that are heritable and therefore promising candidates for subsequent molecular studies, such as candidate-gene or genome-wide association studies. PMID- 23745291 TI - Flight physiology training experiences and perspectives: survey of 117 pilots. AB - INTRODUCTION: Human factors and awareness of flight physiology play a crucial role in flight safety. Even so, international legislation is vague relative to training requirements in hypoxia and altitude physiology. METHODS: Based on a previously developed survey, an adapted questionnaire was formulated and released online for Portuguese pilots. Specific questions regarding the need for pilot attention monitoring systems were added to the original survey. There were 117 pilots, 2 of whom were women, who completed the survey. RESULTS: Most of the pilots had a light aviation license and flew in unpressurized cabins at a maximum ceiling of 10,000 ft (3048 m). The majority of the respondents never experienced hypoxic symptoms. In general, most of the individuals agreed with the importance of an introductory hypoxia course without altitude chamber training (ACT) for all pilot populations, and with a pilot monitoring system in order to increase flight safety. DISCUSSION: Generally, most of the pilots felt that hypoxia education and training for unpressurized aircraft is not extensive enough. However, almost all the respondents were willing to use a flight physiology monitoring system in order to improve flight safety. PMID- 23745292 TI - An epidemiological study of reproductive health in female civil aviation employees. AB - OBJECTIVE: To investigate the correlations between occupational risk factors and reproductive health and to provide targeted healthcare services to female civil aviation employees based on surveys about menstrual and reproductive health status. METHODS: Subjects were selected from flight attendants working for China Southern Airlines, Air China, and other airlines; employees of China Aviation Oil Limited, China TravelSky, and China Aviation Supplies Holding Company; and airport ground service crews. Data were collected using anonymous questionnaires. A total of 1175 valid questionnaires were recovered. The subjects were categorized into a flight attendant group and a ground service group, which contained 563 and 612 women, respectively. RESULTS: The prevalence of irregular menstruation, including abnormal cycles, severe dysmenorrhea, and hypomenorrhea or menorrhagia, was significantly higher in the flight attendant group (30.55%) than in the ground service group (13.40%); in concordance, the fertility rate was significantly lower in the flight attendant group (36.59%) than in the ground service group (43.95%). The spontaneous abortion rate in the flight attendant group (6.80%) was significantly higher than in the ground service group (2.97%). The rate of life-threatening abortions, preterm births, and low birth weight was significantly lower in the flight attendant group than in the ground service group. CONCLUSION: The impact of occupational risk factors on the reproductive health of female aviation workers should be evaluated and examined more thoroughly. Additional healthcare services such as routine menstruation healthcare and policies for workers planning to have a pregnancy are beneficial in monitoring reproductive health, reducing harmful exposures during early pregnancy, and preventing incapacitating gynecologic events. PMID- 23745293 TI - Non-barotraumatic tooth fracture during scuba diving. AB - BACKGROUND: When dental pain or tooth fracture occurs during diving, variations in atmospheric pressure are usually considered as etiology. CASE REPORT: We present a case of a military diver referred for dental pain which appeared during diving. Diagnoses suggested by the diving medical specialist were barodontalgia and dental barotrauma. The dental exam, however, highlighted a tooth fracture due to the in-diving use of an inappropriate mouth regulator which yielded excessive occlusal pressure on a tooth with pre-existing extensive dental restoration. DISCUSSION: This case highlights the importance of the use of an adapted mouthpiece by divers, and the need for awareness of physicians and dentists who treat divers of the implications of scuba diving on dental and oral medicine. PMID- 23745294 TI - Space suit glove design with advanced metacarpal phalangeal joints and robotic hand evaluation. AB - BACKGROUND: One area of space suits that is ripe for innovation is the glove. Existing models allow for some fine motor control, but the power grip--the act of grasping a bar--is cumbersome due to high torque requirements at the knuckle or metacarpal phalangeal joint (MCP). This area in particular is also a major source of complaints of pain and injury as reported by astronauts. METHOD: This paper explores a novel fabrication and patterning technique that allows for more freedom of movement and less pain at this crucial joint in the manned space suit glove. The improvements are evaluated through unmanned testing, manned testing while depressurized in a vacuum glove box, and pressurized testing with a robotic hand. RESULTS: MCP joint flex score improved from 6 to 6.75 (out of 10) in the final glove relative to the baseline glove, and torque required for flexion decreased an average of 17% across all fingers. Qualitative assessments during unpressurized and depressurized manned testing also indicated the final glove was more comfortable than the baseline glove. DISCUSSION: The quantitative results from both human subject questionnaires and robotic torque evaluation suggest that the final iteration of the glove design enables flexion at the MCP joint with less torque and more comfort than the baseline glove. PMID- 23745295 TI - Readership survey 2013: what you think about our journal. AB - A readership survey was sent via email link to all current members of the Aerospace Medical Association for whom email addresses were available. This is necessary to pulse readership, to answer certain questions about the direction of the journal, and to provide advertisers with demographic information to help them make an informed decision about advertising in the journal. The overall response rate was excellent: approximately 25% of the reachable active membership responded. There were 2,037 possible respondents and only 37 bounces, with 535 responses, of which 491 were complete. The survey was conducted using Survey Monkey and a total of 36 questions were asked. The overall impression of the journal ranged from good to excellent with a few exceptions, as did the ratings for the writing and mix of articles. One item that has been asked and answered in every readership survey I have been a part of over the years is that you would like us to publish more clinical articles. This is an area where the journal will strive to improve, with the help of readers and authors. PMID- 23745296 TI - Investigating the "white spot" in aviation medicine and aircraft accident analysis. PMID- 23745297 TI - Author's reply: To PMID 23447851. PMID- 23745298 TI - An endoscopically placed duodenal-jejunal bypass sleeve. PMID- 23745299 TI - You're the flight surgeon: nephrolithiasis. PMID- 23745300 TI - Your're the flight surgeon: contact dermatitis. PMID- 23745301 TI - The month in aerospace medicine history. PMID- 23745302 TI - Endometrial carcinoma: clinical characteristic and survival rates by the new compared to the prior FIGO staging systems. AB - OBJECTIVE: To compare clinical characteristic features and survival rates of endometrial cancer (EMC) patients according to the new 2009 and prior 1988 FIGO staging systems. MATERIAL AND METHOD: Clinico-pathological data of EMC patients who had primary surgical treatment between 1992 and 2008 were collected. The new FIGO staging was compared to the prior assigned staging. Survivals of patients according to prior and new staging were compared RESULTS: Data from 259 patients was reviewed. Mean age was 55.4 +/- 9.9 years. Radiation was the most common adjuvant therapy after surgery, 95/106 patients (89.6%). Progression and recurrences occurred in 34 patients (16 with progression and 18 with recurrence) while 47 died (18.1%). Comparing the prior and current staging, early stage I-II was commonly found in both systems. Stages were the same in 81 patients (31.3%), lower in 177 (68.3%), and higher in one (0.4%). After a median follow-up of 57.5 months, 5-year progression-free, cancer-specific and overall survivals according to the prior and new systems were similar in stage III-IV. Survivals of new stage IA (from 16-prior stage IA, 124-IB, 12-IIA, and 1-IIIA) and stage IB (from 32-IC and 8-IIA) were worse than those of prior stage IA or IB. Survivals of the new stage II patients (11-IIB) were the same as prior stage IIB. CONCLUSION: The "new" FIGO staging system for endometrial cancer patients resulted in lower stage in a large number of patients. Survival trends were worse in the new stage I and remained similar in the other stages. PMID- 23745303 TI - Intraperitoneal sub-diaphragmatic instillation of bupivacaine plus morphine for reducing postoperative shoulder pain after gynecologic endoscopy. AB - BACKGROUND: Gynecologic endoscopic surgery is a minimally invasive surgical technique for treatment of various gynecologic diseases. When compared to conventional laparotomy, this procedure has advantages in many aspects such as reduced postoperative pain, short hospital stay, and decreased morbidity associated with laparotomy. However 15 to 30% of the patients experienced moderate or severe postoperative shoulder pain. Methods to minimize postoperative shoulder pain after gynecologic endoscopy are essential to maximize the quality of life of the patients. OBJECTIVE: To evaluate the benefit of intraperitoneal instillation of bupivacaine plus morphine for reducing postoperative shoulder pain incidence after gynecologic endoscopy. MATERIAL AND METHOD: A randomized clinical trial was conducted in 158 patients undergoing laparoscopic procedures. The patients were randomly assigned to receive either 0.5% bupivacaine hydrochloride 20 mL mixed with morphine 3 mg (study group) or normal saline (control group) instillation to subdiaphragmatic area before finishing the procedure. Shoulder pain was evaluated at immediate post-operative time, and at 12 and 24 hours from the termination of surgery. The data of requested analgesic drugs after surgery was also recorded. RESULTS: Baseline characteristics were comparable between the two groups. Diagnosis, laparoscopic procedures, and duration of operation were also comparable. There were comparable proportions of patients reporting shoulder pain at 12 and 24 hours between the study and control group (30.4% and 30.4% at 12 hours, and 11.3% and 21.5% at 24 hours, respectively). Median pain scores at 12 and 24 hours were comparable between the study and control group (3 and 2 at 12 hours, and 4 and 4 at 24 hours, respectively). Requirement of analgesics was slightly greater among control than study group, but without statistical significance (17.7% and 24.1% respectively). CONCLUSION: Intraperitoneal instillation of bupivacaine plus morphine had no efficiency for reducing postoperative shoulder pain incidence after gynecologic endoscopy. PMID- 23745304 TI - Prevalence of lactobacilli in normal women and women with bacterial vaginosis. AB - OBJECTIVE: To study the prevalence and the number of lactobacilli in normal subjects and in women with bacterial vaginosis (BV). MATERIAL AND METHOD: The studied subjects consisted of 60 normal and 60 BV women. The diagnosis of BV was based on at least three of five indicators of Chandeying criteria. The vaginal specimens were collected and cultured on MRS plates for determination of lactobacilli counts. RESULTS: The number of lactobacilli was highly significant (p < 0.001) in the women with diagnosis of BK and the mean count of lactobacilli in BV was markedly decreased (5.3 +/- 1.8 log colony-forming unit--CFU/ml), compared with normal women (8.8 +/- 2.9 log CFU/ml). Among the treated BV group, follow-up vaginal specimen was encountered in 47 of 60 cases (78.3%). The proportion of lactobacilli isolation was slightly increased from 12 (25.5%) to 15 (31.9%) in 47 cases. Concordance with quantitative settlement of lactobacilli in BV was increased from 1.4 +/- 2.6 log CFU/ml, to 1.8 +/- 2.9 log CFU/ml in treated BV. Treated BV the lactobacilli had not restored significance (p = 0.5831), as well as the total bacteria. CONCLUSION: Lactobacilli dominantly occur in healthy women, and markedly decline in BV. However, the vaginal ecosystem is dynamically changed in the lactobacilli of either normal or BV women. PMID- 23745305 TI - Aspirin non-responder in Thai ischemic stroke patients. AB - BACKGROUND: An important cause of recurrent ischemic stroke is failure to prevent secondary stroke due to poor control of important stroke risk factors. One of the proposed important risk factor is aspirin resistance. The prevalence of aspirin resistance varied widely. It depended on heterogeneity in studied populations and methods of platelet functional assessment. OBJECTIVE: To describe the prevalence of aspirin resistance based on optical platelet aggregometry in stroke patients who attended the Neurological Institute and investigate the clinical risk factors associated with aspirin resistance. MATERIAL AND METHOD: Three hundred stable ischemic stroke patients, whose aspirin dosage varied between 60 to 325 mg/day for at least 14 days before enrollment were recruited in the present study. Demographic data, modifiable risk factors, and treatment were collected by interview and from medical records. Aspirin resistance was determined by optical platelet aggregation technique, using arachidonicacid (AA) and adenosine diphosphate (ADP) as agonists. RESULTS: The patients were classified into two groups based on their platelet aggregatometry tests (PAT). The cases group (n = 40, 13.3%) included both patients with aspirin resistance (n = 2, 0.6%) and aspirin semi-responsiveness (n = 38, 12.7%). The control group was aspirin non resistance (n = 260, 86.7%). The cases were older (64.8 year vs. 61.26 year, p = 0.049), higher proportion of females (60% vs. 41.5%, p = 0.029), and shorter in height (159.9 CM vs. 164.1 CM, p = 0.007) than the control group. Dosage and duration of the aspirin therapy were the same in both groups. The multivariate analysis showed old age was associated with aspirin resistance. CONCLUSION: The prevalence of aspirin resistance in the present study is 0.6% (95% CI, 0.18% 1.38%). The risk factor for aspirin resistance in post stroke patients is aging. No association between duration and aspirin dosage with aspirin resistance was found. The proportion of aspirin resistance was similar to a previous study done in post myocardial infarction patients. PMID- 23745306 TI - Clinical features and prognostic factors for liver cancer from a referral center in northern Thailand. AB - BACKGROUND: Primary liver cancer included hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is the leading cancer with high mortality in Thailand. We aim to evaluate the overall survival and predictor of mortality in patients with HCC and CCA. MATERIAL AND METHOD: We reviewed medical records of 786 patients with liver mass between July 2007 and June 2010, 287 patients were HCC and 449 patients were CCA. The overall survival and prognostic variables for survival were analyzed. RESULTS: The mean age of HCC patients and CCA patient were 53.8 years and 59.2 years. Male was predominant, 85% and 74% in HCC and CCA. By BCLC staging for HCC, patients at early stage (A), intermediate stage (B), advanced stage (C), and terminal stage (D) were 40 (13.9%), 105 (36.6%), 95 (33.1%), and 43 (15.0%). Among 449 CCA patients, 143 (31.8%) were intrahepatic type and 306 (68.2%) were ductal type. The mean follow-up time for HCC and CCA patients were 20.1 and 16.7 months. The 1-year, 2-year, and 3-year survival of HCC and CCA were 55%, 34%, 31.3% and 54%, 21.2%, 19.1%, respectively. Predictor of death in HCC patients included portal vein thrombosis and did not receive any treatment (p < 0.05). Meanwhile, the predictor of death in CCA patient included intrahepatic type, total bilirubin > 2 mg/dl, CA 19-9 > 100, and unresectable tumor (p< 0.05). CONCLUSION: The survival of patients who received any type of treatment was much better than in the past. Still, in patients with advanced disease whom only supportive treatments were provided, the prognosis is grave. PMID- 23745307 TI - High on-clopidogrel treatment platelet reactivity in Thai patients with chronic stable angina scheduled for percutaneous coronary intervention. AB - OBJECTIVE: To determine the prevalence, clinical profile, and risk factors of high on-clopidogrel treatment platelet reactivity in Thai patients with chronic stable angina scheduled for percutaneous coronary intervention. MATERIAL AND METHOD: The patients were prospectively recruited from the consecutive patients undergoing coronary angiography and planned for elective percutaneous coronary intervention (PCI). Ten ml of blood samples were cautiously drawn from the antecubital vein of the patients to determine the hemoglobin and platelet count. Platelet aggregation test was performed by light transmittance aggregometry using platelet-rich plasma. Platelets were stimulated with 5 microM adenosine diphosphate (ADP). Platelet aggregation was expressed as the maximal percent change in light transmittance from baseline. High on-clopidogrel treatment platelet reactivity was defined as post treatment maximal platelet aggregation > 46% with 5 micromol/l ADP used as agonist. RESULTS: The present study consecutively enrolled two hundred four patients diagnosed with chronic stable angina planned for PCI. Seventy-nine patients demonstrated the high on clopidogrel treatment platelet reactivity (38.7%). Among these patients, 48% were men with a mean age of 66 years. Diabetes mellitus and chronic kidney disease were detected in 34.2%. Original clopidogrel (Plavix) was prescribed in 72% of the patients and 28% received generic clopidogrel (Apolets). The prevalence of high on-clopidogrel treatment platelet reactivity increased in the older patients, patients with CKD and patients receiving angiotensin receptor blockers (ARB). However from multivariate analysis, none of the risk factors, including age, BMl, diabetes mellitus, smoking, CKD, ARB use, and type of clopidogrel (Plavix versus Apolets) had a statistically significant association with the high on-clopidogrel treatment platelet reactivity. CONCLUSION: The prevalence of high on-clopidogrel treatment platelet reactivity in the present study was 38.7%. No significant association was demonstrated between age, BMI, diabetes mellitus, smoking, CKD, ARB use, type of clopidogrel, and high on-clopidogrel treatment platelet reactivity. PMID- 23745308 TI - Left atrial coagulation activity in patient with mitral stenosis in sinus rhythm. AB - OBJECTIVE: Anticoagulation therapy is strongly recommended in all patients with mitral stenosis (MS) in atrial fibrillation (AF) but this treatment is controversial in patients in sinus rhythm (SR). The objective of the present study was to investigate the coagulation activity in patients with MS in sinus rhythm compared to those in atrial fibrillation. MATERIAL AND METHOD: The authors studied the levels of biochemical markers of thrombin generation (thrombin-anti thrombin [TAT] complex,fibrinogen, and factor XIII) and fibrinolysis (D-dimer) in specimens of blood from the atria in 35 consecutive patients with moderate to severe MS (18 in sinus rhythm and 17 in AF) who underwent percutaneous balloon mitral valvotomy. RESULTS: The levels coagulation factors in left atrium in patients with MS in SR and AF were thrombin-anti-thrombin complex = 77.21 +/- 8.87 mg/L vs. 73.48 +/- 7.78 mg/L, p = 0.755, fibrinogen = 356.57 +/- 41.86 mg/L vs. 271.62 +/- 22.47 mg/L, p = 0.089, factor XIII = 139.88 +/- 8.96 mg/L vs. 123.42 +/- 6.24 mg/L, p = 0.152, and D-dimer = 846.14 +/- 137.84 mg/L vs. 693.88 +/- 164.67 mg/L, p = 0.481. Levels of coagulation activities did not correlate with the left atrial size. CONCLUSION: This present study demonstrates that coagulation activity is not different whether they are in SR or in AF and suggests that anticoagulation therapy should be considered in these patients. PMID- 23745309 TI - Pharmacodynamics of imipenem in critically ill patients with ventilator associated pneumonia. AB - BACKGROUND: Drug dispositions are altered in critically ill patients, including ventilator-associated pneumonia (VAP) when compared with healthy subjects leading to fluctuations of plasma concentrations. OBJECTIVE: To compare the probability of target attainment (PTA) and cumulative fraction of response (CFR) for imipenem between administration by 0.5-hour and 2-hour infusions. MATERIAL AND METHOD: The present study was a randomized three-way crossover in nine patients with VAP Each patient received imipenem in three regimens consecutively: (i) a 0.5-hour infusion of 0.5 g every six hours for 24 hours; (ii) a 2-hour infusion of 0.5 g every six hours for 24 hours; and (iii) a 2-hour infusion of 1 g every six hours for 24 hours. Monte Carlo simulation was performed to determine the PTA at various regimens and the study used susceptibility patterns obtained from EUCAST and MYSTIC for assessment of CFR. RESULTS: For an MIC of 2 microg/ml, the PTAs achieving 40% T > MIC following a 0.5-hour infusion of 0.5 g, a 2-hour infusion of 0.5 g, and a 2-hour infusion of 1 g were 90.93%, 98.97%, and 100%, respectively. Only a 2-hour infusion of 1 g achieved 98.75% of the PTA of 40% T > MGC for an MIC of 4 microg/ml. All regimens were predicted to achieve CFR > 99% against E. coli and Klebsiella spp. CONCLUSION: A 2-hour infusion of 1 g regimen was predicted to have the highest PTA rates. All regimens achieved a high CFR against E. coli and Klebsiella spp. PMID- 23745310 TI - Role of routine bronchial washing culture for TB in Maharat Nakhon Ratchasima Hospital, Thailand. AB - OBJECTIVE: To evaluate the role of routine bronchial washings (BW) culture for diagnostic sputum smear negative pulmonary case of tuberculosis (TB) at Maharat Nahkon Ratchasima Hospital. MATERIAL AND METHOD: A retrospective, observational study of performed bronchial washing (BW) specimens from 93 patients who met presumptive criteria of smear negative case of pulmonary TB was done. The culture of BW for TB was done by conventional technique. All of the BW specimens were not centrifuged before AFB stain. Pathological reports were included in the study. Statistical analysis was described as percentage. RESULTS: Ninety-three patients were included in the presented study. Eighty-seven patients had a diagnosis of smear-negative pulmonary case of TB (93.5%). The un-centrifuged BW smear for AFB was positive in 17 (18.3%) patients while conventional culture of BW for TB was positive in 34 (36.6%) patients. The MDRTB and NTM were positive in one (1.1%) and five (5.4%) patients respectively The positive un-centrifuged BW smear for AFB in the MDRTB and NTM patients were 0 and 2/5 (40%) respectively. The pathological reported granulomatous disease was found in 18 (19.4%) patients. Five (5.4%) patients had all positive of any methods while 45 (48.4%) patients had all negative tests. CONCLUSION: The routine culture BW for TB should be done in every case of presumptive diagnosis of sputum smear negative pulmonary case of TB. Furthermore, it can establish that MDRTB and NTM cannot be identified with only AFB stain. PMID- 23745311 TI - Open-assisted laparoscopic radical cystectomy using an ileal neobladder with intracorporeal urethra-neobladder anastomosis: technique and early experiences. AB - OBJECTIVE: Laparoscopic radical cystectomy is now widely performed in cases of muscle-invasive bladder cancer. The present study experience with laparoscopic radical cystectomy using an ileal neobladder in which urethra-neobladder anastomosis was successfully performed intracorporeally MATERIAL AND METHOD: Between March and November 2009, five patients underwent laparoscopic radical cystectomy using an ileal neobladder with urethra-neobladder anastomosis. Preoperative characteristics, operative data, and results were analyzed. RESULTS: The operation was successful for all patients. The mean operative time was 6 hours and 30 minutes. Mean estimated blood loss was 560 ml. No intraoperative complications occurred. Mean hospital stay was 19.6 days. Mean Foley catheter indwelled time was 18 days. Return of bowel function took 4.8 days. Mean time to remove silastic drain was 14.2 days. After Foley catheter removal, all patients spontaneously voided without difficulty. CONCLUSION: Laparoscopic radical cystectomy of ileal neobladders using intracorporeal urethra-neobladder anastomosis is technically feasible. This technique takes advantage of laparoscopic surgery, good visualization, additional stitches, and more secure anastomosis. PMID- 23745312 TI - Predicting factors for biochemical recurrence and oncological outcomes following laparoscopic radical prostatectomy in Rajavithi Hospital, Thailand. AB - OBJECTIVE: To determine the predicting factor of biochemical recurrence and analysis of pathological and oncological outcomes following laparoscopic radical prostatectomy (LRP) at Rajavithi Hospital in Thailand. MATERIAL AND METHOD: One hundred twenty men underwent laparoscopic radical prostatectomy between October 2006 and December 2011. Four men were excluded due to open surgical conversions and fourteen men were excluded due to lacking of follow-up. The remaining 102 men had a mean preoperative prostate specific antigen of 21.4 ng/ml (ranging from 0.4 to 185) and Gleason score of 6.2 (ranging from 6 to 10). Stage was cT1b in one case (1%), cT1c in 66 (64.7%), cT2 in 28 (27. 5%), and cT3 in seven (6.9%). Immediate postoperative adjuvant therapy of twenty-six men was excluded from biochemical recurrence analysis. RESULTS: Mean follow-up period was 19.7 months (median 16, ranging from 2 to 54.8). Pathological stage was pT0N0 in two men (2%), pT2N0 in 78 (76.5%), pT3N0 in 11 (10.8%), and pT2-3N1 in 11 (10.8%). Positive surgical margin (SM) rates increased with higher stage (23.1% in pT2, 63.6% in pT3 and 81.8% in pT2-3N1, p < 0.0001). Three-year biochemical recurrence free survival was 87.1% for pT2N0 and 50% for pT3N0/N1 disease (p = 0.025), and 84.2% overall. Univariate analysis for age, preoperative PSA, postoperative Gleason score, pathological stage, and margin status showed that only margin status could be used as a predictor for biochemical recurrence. CONCLUSION: Predicting factor for biochemical recurrence after LRP was positive SM status. From the oncological result, LRP in our experience is a safe and efficacious therapy for localized prostate cancer with acceptable and was consistent with results of previous studies. PMID- 23745313 TI - The best calyceal tract approach for treating renal stones with percutaneous nephrolithotomy. AB - OBJECTIVE: To compare the perioperative outcomes of percutaneous nephrolithotomy (PCNL) performed via the upper middle, and lower calyces. MATERIAL AND METHOD: The authors retrospectively reviewed 92 renal units in 92 patients who required PCNL at our institution between 2006 and 2010. Patients with partial and full staghorn stones with total stone size > or = 2 cm were included in the present study. Patients were excluded if they had multiple small stones or a single stone < 2 cm. The present study analyzed 92 renal units in 92 patients. The authors divided the patients into three groups (groups 1, 2, and 3) based on the surgical approach, which was the upper middle, and lower calyceal approaches. PCNL was performed using a standard ultrasonic lithotriptor with a rigid nephroscope, and holmium: YAG laser lithotripsy was carried out with a flexible nephroscope, with simultaneous nitinol tipless basket extraction of fragments. Procedures were repeated until the patients were rendered stone-free (confirmed visually or by nephrostogram). Estimated blood loss, length of hospital stay, operative time, and the number of procedures (to achieve stone-free status) were analyzed and compared among the groups, and complications were reported. RESULTS: The present study showed that the length of hospital stay, estimated blood loss, number of procedures, and operative time were not significantly different between the three groups. In Group 1, four patients had complications and included two patients with mid-ureteral stone, and one patient each with renal pelvic perforation and urinary tract infection with sepsis. One patient from Group 2 contracted a urinary tract infection. In Group 3, five patients exhibited complications and included one with mid-ureteral stone, two with renal hemorrhage, and two with urinary tract infection. CONCLUSION: The estimated blood loss, duration of hospital stay, operative time, number of procedures (to achieve stone-free status), and complications did not statistically differ between the three groups. Moreover very few complications occurred in the different surgical approaches. Therefore, PCNL via all the three approaches were deemed safe and effective. PMID- 23745314 TI - Combination of intra-articular autologous activated peripheral blood stem cells with growth factor addition/ preservation and hyaluronic acid in conjunction with arthroscopic microdrilling mesenchymal cell stimulation Improves quality of life and regenerates articular cartilage in early osteoarthritic knee disease. AB - BACKGROUND: Trauma or osteoarthritis (OA) create articular cartilage defects that cannot efficiently heal, thus leading to significant long-term disability. Failed conservative treatment in cartilage diseases is a known condition that necessitates repair attempts but current methods are inadequate. Recent studies in OA animal models and humans, showed articular cartilage regeneration following combinations of drilling, adult stem cells, and intra-articular hyaluronic acid. OBJECTIVE: In the present series, the authors evaluated the combination of repeated intra-articular (IA) autologous activated peripheral blood stem cells (AAPBSC) with growth factor addition/preservation (GFAP) along with hyaluronic acid (HA) in conjunction with arthroscopic microdrilling mesenchymal cell stimulation (MCS) in early osteoarthritic knee disease that failed conservative treatment. MATERIAL AND METHOD: Four women and one man (median age 56, range 52 59 years) that failed conservative treatment were enrolled. Arthroscopic MCS was performed once in all patients with subsequent IA injection of AAPBSC with GFAP along with IA-HA intra-operatively, repeated at days 7 and 14. The patients were evaluated by WOMAC and KOO scores at baseline, one, and six months. Cancellous bone biopsies were performed to investigate cell attachment, proliferation, and differentiation by electron microscopy and histological staining. RESULTS: All patients improved significantly in WOMAC and KOO scores at one and six months compared to baseline. No adverse effects were seen during the AAPBSC harvesting, arthroscopy and/or IA injections. One month post-surgery, all pain medications could be withdrawn. Electron microscopy scanning revealed cell attachment and proliferation while histological analysis demonstrated that the cell layer on the cancellous scaffold showed increased proteoglycan and glycosaminoglycan content indicating hyaline cartilage presence. CONCLUSION: The combination of intra articular (IA) autologous activated peripheral blood stem cells (AAPBSC) with growth factor addition/preservation (GFAP) along with hyaluronic acid (HA) in conjunction with arthroscopic microdrilling mesenchymal cell stimulation (MCS) resulted in Quality of Life improvements measured by WOMAC and KOO scores and succeeded in regenerating articular cartilage in early osteoarthritic knee disease that failed conservative treatment. Further controlled studies are warranted to confirm the above results in larger groups. PMID- 23745315 TI - Nausea, vomiting and pruritus induced by intrathecal morphine. AB - BACKGROUND: Presently, in Siriraj Hospital, intrathecal morphine is routinely used in spinal anesthesia for postoperative pain control in more than 600 cases per month with doses lower than 0.3 mg. However, the incidence of side effects is high. This retrospective data review was performed to identify incidence and risk factors of postoperative nausea, vomiting, and pruritus. MATERIAL AND METHOD: One thousand three hundred six anesthetic records were analyzed for incidence of nausea, vomiting, and pruritus after spinal anesthesia with intrathecal morphine in Siriraj Hospital between October 2010 and April 2011. Data extracted were age, gender, type of operations, dosage of spinal morphine, and frequency, and severity of adverse effects (nausea, vomiting, and pruritus). Odd ratios and multiple logistic regression analysis were used. RESULTS: Incidence of nausea, vomiting, and pruritus were 21.5, 14.8, and 59.5% respectively. No respiratory depression and urinary retention was reported There was statistically significant correlation in the incidence of nausea, vomiting, and pruritus with female gender, cesarean section, and intrathecal morphine dose (p < 0.001). Intrathecal morphine more than 0.2 mg resulted in an increase in severity of side effects. CONCLUSION: The intrathecal morphine is effective in postoperative pain control. However it induces high incidence of nausea, vomiting, and pruritus. Prevention of side effects and alternatives to intrathecal morphine need further research. PMID- 23745316 TI - The correlation of parathyroid hormone and heart rate variability in CAPD patients. AB - OBJECTIVE: To investigate the correlation of parathyroid hormone (PTH) and cardiac autonomic nervous system (ANS) measured by heart rate variability (HRV) method in continuous ambulatory peritoneal dialysis (CAPD) patients. MATERIAL AND METHOD: Healthy subjects (HS) and two groups of CAPD patients classified by the PTH concentration: high PTH group (H-PTH; PTH = 150-300 pg/ml) and ultra-high PTH group (UH-PTH; PTH > 300 pg/ml) were studied. Time and frequency domains of HRV were analyzed. For the frequency domain, the fast Fourier transform of the total power (TP), low frequency (LF), high frequency (HF), and LF/HF ratio were transformed by natural logarithm (ln). The Pearson's correlation was used to analyze the correlation between lnPTH and the parameters of HRV RESULTS: Time and frequency domains of HS were at highest values whilst LF/HF ratio was the lowest. For UH-PTH CAPD patients, the values of standard deviation of R-R interval (SDNN), root mean square of the difference of R-R interval (RMSSD), lnTP and lnHF were significantly lower whereas lnLF was not significantly different compared to H-PTH. In addition, lnHF was found to have the highest negative correlation value with lnPTH concentration (r = -0.53). CONCLUSION: PTH, a serious uremic toxin, influences the initiation of ANS dysfunction. According to decreased lnHF a decrease in parasympathetic activity was demonstrated in UH-PTH. Consequently, the modality that can stimulate the parasympathetic activity should be considered in CAPD patients who were hyperparathyroidism. PMID- 23745317 TI - Preliminary experience of CyberKnife treatment of lung metastasis: the question about real clinical benefit. AB - OBJECTIVE: Evaluate the effectiveness of radiotherapy plan and physical parameters including local tumor response and clinical outcome of lung metastasis in patients who received CyberKnife treatment at Ramathibodi Hospital. MATERIAL AND METHOD: Six cases with twenty lesions of lung metastasis patients were evaluated for tumor response after having received CyberKnife treatment. The prescribed radiation dose was calculated approximately to biological equivalent dose (BED) around 60 to 100 gray (Gyz). The response of each lesion to treatment was evaluated from roentgenographic study during follow-up period along with adverse event, status of patients, and disease. RESULTS: At the third month after treatment, roentgenographic partial response (PR, 50% decrease in size) was demonstrated in eight lesions and stable disease (SD, unchanged size) in eight lesions with no complete response (CR, disappearance of tumor) detected. Progressive disease (PD, 25% increase in size) of six treated lesions was detected during the follow-up period. At the time of report, two patients were alive and still received palliative chemotherapy, two patients died from uncontrolled progressive metastases and failed palliative chemotherapy, and two patients lost follow-up after progressive metastases with unknown surviving status. No severe adverse event was observed. The treatment planning parameters demonstrated borderline of radiation dose homogeneity, and conformality coverage of the target volume. CONCLUSION: This preliminary report aimed to provide the idea of choosing the appropriate lung metastasis patient to receive CyberKnife treatment that must strictly clarify the real clinical benefit of each selected case to achieve the best outcome from this special treatment procedure. PMID- 23745318 TI - Radioiodine remnant ablation in low-risk differentiated thyroid cancer. AB - OBJECTIVE: Evaluate the success rate of first high dose 100 mCi (3.7 GBq) radioiodine remnant ablation (RRA) in low-risk differentiated thyroid cancer (DTC) patients after surgery and determine factors influencing the success. MATERIAL AND METHOD: Between 1994 and 2011, a retrospective analysis was performed of 166 low-risk DTC patients after surgery (age range 18-76 years, mean age 38 years, 147 women and 19 men) with primary tumor > 1 cm of diameter stage 52 pT1pN0, 85 pT2pN0, 12 pT3pN0, and 17 pTxN0 underwent high dose 100 mCi (3.7 GBq) RRA. Successful RRA was defined as visually undetectable thyroid bed activity or elsewhere on the first follow-up whole body scan (WBS) six to 12 months after RRA and the stimulated thyroglobulin (st-Tg) levels < 2 ng/mL at the same time of follow-up WBS and without interfering thyroglobulin antibodies (TgAb). Additional 1-131 treatment was individualized depending on clinical characteristics with 100 to 150 mCi (3.7-5.5 GBq) 1-131 six to 12 months intervals to achieve no thyroid bed uptake. RESULTS: Successful RRA was achieved in 122 of the 166 patients (73.5%). Failure by both criteria was seen in nine patients (5.4%). Of the 44 patients with ablation failure, additional I-131 treatment was individualized in 26 patients (59.1%). St-Tg levels at time of ablation and tumor size had significance influences on the success of RRA. The st Tg levels at time of ablation were 7.5 +/- 11.5 ng/mL (0.1-80.3) in the ablation success group as compared with the ablation failure group of 24.1 +/- 24.9 ng/mL (1.3-97), p-value < 0.001. Patients with ablation failure group had statistical significance of average tumor size greater than patients with ablation success group (3.2 +/- 1.1 and 2.7 +/- 1.1 cm), p-value = 0.012. CONCLUSION: The efficacy of first high dose RRA in low-risk DTC after surgery shows comparable rates with those reported in the literature. The two factors influencing ablation success are st-Tg levels at time of ablation and tumor size. PMID- 23745319 TI - Cognitive enhancement effects of Bacopa monnieri (Brahmi) on novel object recognition and VGLUT1 density in the prefrontal cortex, striatum, and hippocampus of sub-chronic phencyclidine rat model of schizophrenia. AB - BACKGROUND: Decreased vesicular glutamate transporter type 1 (VGLUT1) in schizophrenic brain indicates the deficit of glutamatergic function, which may produce cognitive impairment in the patients. Brahmi might be a novel therapeutic agent for the cognitive deficit treatment in schizophrenia by changing cerebral VGLUT1 density. OBJECTIVE: To study effects of Brahmi on attenuation at cognitive deficit and cerebral VGLUT1 density in sub-chronic phencyclidine (PCP) rat model of schizophrenia. MATERIAL AND METHOD: Rats were administered PCP or vehicle. Half of the PCP-group was treated with Brahmi. Discrimination ratio (DR) representing cognitive ability was obtained from novel object recognition test. VGLUT1 density was measured in prefrontal cortex, striatum, cornu ammonis fields 1 (CA1) and 2/3 (CA2/3) of hippocampus and dentate gyrus (DG) using western blot and immunohistochemistry. RESULTS: DR in PCP-group was significantly decreased compared with control. This occurred alongside reduced VGLUT1 in prefrontal cortex, striatum, CA1 and CA2/3. PCP with Brahmi showed a significant increase in DR score compared with PCP alone. This occurred alongside significant increase in VGLUT1 in CA1 and CA2/3. CONCLUSION: Cognitive deficit observed in PCP administered rats was mediated by VGLUT1 reduction in prefrontal cortex, striatum, CA1 and CA2/3. Interestingly, Brahmi could recover this cognitive deficit by increasing VGLUT1 in CA1 and CA2/3 to normal. PMID- 23745320 TI - Laparoscopic radical prostatectomy in a cadaveric renal transplant patient: first case in Thailand and the authors first experience--a case report. AB - OBJECTIVE: To report the authors' experience in laparoscopic radical prostatectomy for the treatment of localized prostate carcinoma in a cadaveric renal transplant recipient. MATERIAL AND METHOD: A 64-year-old man with chronic renal failure unknown cause had a transplant cadaveric donor kidney about nine years ago. Creatinine clearance was estimated about 68.61 ml/min. He was presented with lower urinary tract symptoms in 2008. He was diagnosed and was treated as benign prostatic hyperplasia. Digital rectal examination was normal and prostate specific antigen (PSA) was 10.84 ng/ml when he was followed-up in 2010. The authors did a prostate gland biopsy, one of four cores from right lobe of prostate gland revealed prostatic adenoma with Gleason score of 6 (3 + 3). Bone scan did not show any sign of metastases. The authors performed a Laparoscopic radical prostatectomy, extraperitoneal technique. RESULTS: The patient underwent successful laparoscopic radical prostatectomy without any complications. The operative time was 210 minutes, the estimated blood loss of 300 ml. Pathological analyses revealed negative surgical margins with focal extraprostatic extension, and no seminal vesical, lymphatic, and perineural invasion. The patient tolerated the procedure well and was discharged on day 4. At fourth months, the patient was continent, PSA was 0.003, and renal function stable. At one year, PSA was 0.011 ng/ml and the creatinine was 1.15 mg/dl. CONCLUSION: The authors experience suggests that extraperitoneal laparoscopic radical prostatectomy is a technically feasible and safe treatment of localized prostate cancer in renal transplant recipients. PMID- 23745321 TI - [Amiodarone administered orally or intravenously - the same or different drug?]. AB - Amiodarone is used to manage virtually all forms of supraventricular and ventricular tachycardia and has therefore become one of the most frequently used antiarrhythmic drugs in clinical practice. Amiodarone has a variable oral bioavailability. After absorption, the drug undergoes extensive enterohepatic circulation. A large first pass effect results in desethylamiodarone, which is active and has similar electrophysiologic effects as the parent compound. Peak amiodarone serum levels, after oral dosing, are achieved within 3-7 hours. Acute amiodarone therapy results in a use-dependent inhibition of inward sodium and inward calcium currents, as well as a non-competitive alpha- and beta-blockade effect. Acute amiodarone therapy has no consistent effects on the repolarization phase of action potentials. The major effect of chronic amiodarone therapy is an inhibition of outward potassium currents resulting in a prolongation of action potential duration, not only in atrial and ventricular muscles but also in the sinoatrial node and atrioventricular nodes. A basic understanding of the pharmacokinetics is important for the clinician to understand the antiarrhythmic properties of both the oral and intravenous preparation. PMID- 23745322 TI - [Soluble selectins in myocardial infarction]. AB - In myocardial infarction, the endothelial activation which induces leukocytes migration into the myocardial tissues, may play an important role in ischemic injury. Selectins, shedding from the surface of activated cells into bloodstream, maybe suggested as markers of endothelial activation and leukocytes stimulation. The aim of the study was evaluation. To evaluate serum soluble E- and P-selectin levels as endothelial activation marker and serum soluble L-selectin level as leukocytes stimulation marker in myocardial infarction. MATERIAL AND METHODS: We examined 27 patients with acute myocardial infarction (AMI) The control group (K) consisted of 23 healthy subjects without symptoms of coronary artery disease. The concentration of soluble selectins (sE-, sP-, sL-selectin) were analyzed in venous blood serum. Results of routine laboratory tests: lipid levels, leukocyte count, prothrombin time were also included into statistical analysis. RESULTS: A significant decrease in serum sL-selectin level was observed in patients with acute myocardial infarction compared to the control group. However, no difference was found in sE- and sP-selectin levels between the patient group and the control group. The sE-selectin level correlated positively with triglicerides level and inversely with HDL cholesterol level. There were a positive correlation between sP-selectin level and leukocyte count as well as inverse correlation between sP selectin level and prothrombin time. The sL-selectin level correlated positively with leukocyte count. There were also a positive correlation between sP-selectin level and sE-selectin as well as sL-selectin levels. CONCLUSIONS: The sE-selectin level increases with the severity of atherogenic changes in serum lipid profil, and sP-selectin level increases due to inflammatory and prothrombotic processes. The sL-selectin level is influenced by inflamamatory processes in the vascular wall. The sE- and sP-selectin levels, unchanged compared to the control group, do not reflect adequately the degree of endothelial activation. An decreased sL selectin level may indicate functional depletion of leukocytes in patients with myocardial infarction and make it difficult to assess the degree of leukocytes stimulation. PMID- 23745323 TI - [GOLD 2011 - COPD from a new perspective]. AB - The GOLD 2011 recommendations for chronic obstructive pulmonary disease (COPD) introduce a new classification system to optimize treatment in individual patients. Except for FEV,, this classification incorporates breathlessness measurement using modified medical research council questionnaire (mMRC) or the COPD assessment Test (CAT) and the number of exacerbations. The aim of our study was to compare the GOLD 2010 and GOLD 2011 COPD. MATERIAL AND METHODS: The study group consisted of 143 patients. Based on the post-bronchodilator FEV, only, as recommended in the GOLD 2010 report, there were 24 patients in stage I, 57patients in II, 43 in Ill and 19 in IV, respectively. In all patients, the number of exacerbations per year was noted and dyspnea was assessed with the modified MRC scale. The patients were subsequently graded to group A,B,C,D as proposed in the combined COPD assessment in GOLD 2011. RESULTS: Grading of 51 (35,7%) patients according to the GOLD 2011 criteria was difficult; there were 22 patients in GOLD stage I/II with > or =2 exacerbations per year and 29 patients in GOLD stage Ill/IV with < 2 exacerbations per year. They were grading to more risk group. CONCLUSION: The new classification according to GOLD 2011 lets on optimizations of the treatment, in most cases of COPD patients but in clinical practice, there may be problems with the classification of the patients with severe airway obstruction without frequent exacerbations and especially those with mild/moderate airflow limitation and frequent exacerbations. PMID- 23745324 TI - [Galbladder contractility in children with functional dyspepsia]. AB - Disturbances of the gallbladder and biliary tract in children, contrary to those in adults, were not included in Ill Rome Criteria of functional disorders of the alimentary tract. The aim of the work was sonographic assessment of gallbladder function in functional dyspepsia in children. MATERIAL AND METHODS: The study included 45 children, aged 6 to 18 years (28 girls and 17 boys) with functional dyspepsia and 32 healthy children without symptoms form the alimentary tract of the same age, who were regarded as the control group. Diagnosis of functional dyspepsia was made based on Ill Rome Criteria. Anatomy and contractility of the gallbladder were assessed sonographically taking into consideration its volume in fasting state, than 30 and 60 minutes after the test meal. In anatomy assessment the presence of septum, thickness of the wall and the presence of thickened bile were taken into account. RESULTS: Anatomical anomalies and wall thickness changes were observed statistically significantly more frequently in children with functional dyspepsia. There was no statistical difference in the volume of the gallbladder in fasting state and its contractility after test meal. CONCLUSIONS: Anatomical anomalies of the gallbladder were more frequent in children with functional dyspepsia in comparison to healthy children, however, there were no statistical differences in its volume in fasting state and contractility after test meal. PMID- 23745325 TI - [Iodine supply and thyroid function in the group of healthy pregnant women living in Warsaw]. AB - Iodine deficiency and thyroid gland disorders are especially harmful for pregnant women and normal fetal development. After initiation in 1997 of obligatory iodine prophylaxis, Poland has been found since 2003 a country with sufficient delivery of this microelement. However, in the population of pregnant women, slight deficiency of this element still exists. Insufficient iodine supply results in abnormalities of thyroid hormones'biosynthesis. Simultaneously, adaptive changes, occurring in pregnancy, make the proper interpretation of hormone's assays difficult. Lack of normative data for the thyroid hormones concentration in the each pregnancy trimester for Polish population cause additional difficulties in the interpretation of these results. The aim of the study was prospective observation of iodine intake and thyroid function in healthy pregnant women supplemented with 150 pg of iodine daily MATERIALS AND METHODS: 62 healthy pregnant women living in Warsaw in the early weeks of pregnancy, confirmed by ultrasonographic examination, were included to this study. Pregnancies were singleton resulting in birth of healthy neonates. Urinary iodine concentrations (UIC), serum TSH, fT4, fT3, antyTPO, thyroid volume and morphology by the ultrasonography examination were assessed in consecutive trimesters of pregnancy. TSH level was measured in the each newborn. RESULTS: Low urinary iodine concentrations (UIC)-median 96 microg/l was found at the beginning of pregnancy Only in 14% of pregnant women UIC exceeded 150 microg/l. In spite of intended supplementation of at least 150 microg of extra iodine per day, medians of UIC in the next trimesters were 122 microg/l and 129 microg/l, respectively. TSH levels kept reference values for the 1st trimester of pregnancy in 86% of participants and in the next trimesters in 85% and 95%, respectively. Levels of fT4 were within reference range for the women in the 1st trimester. In 2nd trimester 12% and in 3rd trimester 33% of pregnant women had fT4 level below the reference value. Concentrations of fT3 were within reference values during whole pregnancy. Median thyroid volume was respectively 11.12 ml; 13.0 ml and 15.75 ml (range: 6.8 26.8 ml) in subsequent trimesters.Median neonatal' TSH level on the 3rd day of life, as a screening of thyroid insufficiency, was 1.34 mlU/l (range: 0.01-6.6 mlU/l) and in 4.41 % of newborns TSH concentrations were higher than 5 mlU/I. CONCLUSION: Despite the sufficient supply of iodine in the whole population, iodine consumption among the pregnant women is still not satisfactory. The increase of TSH values above the upper reference level for pregnant women in 15% of patients may be related to iodine deficiency. It is important to educate pregnancy planning women about this problem. Our observations confirm the importance of the recommendations that during the pregnancy every woman should receive supplementation of iodine at the minimal amount of 150 microg daily. PMID- 23745326 TI - [Evaluation of the arterial blood flow parameters in the eye of myopic patients]. AB - Myopia is a common refractive defect. Has a good vision from near and deterioration of vision with increasing distance. The main reason for its occurrence is too long axis of the eyeball. The consequence of elongation of the eyeball is the development of degenerative changes in the retina. Despite much research has failed to clearly identify the causes of degenerative changes in those short-sighted. The aim of the study was to evaluate the maximum and minimum speed in arterial blood vessels of the eye in people with myopia. MATERIAL AND METHODS: The study included 70 patients (138 eyes), 53 women and 17 men, aged from 18 to 79 years, with myopia of -0.25 to -18.0 Dsph and length of the eyeball from 22.61 to 33.36 mm. Depending on the kind and the degree of the progress of degenerative changes, patients were divided in 4 groups: I - without degenerative changes on the fundus (n=32; K-23, M-9); II- with the short-sighted sickle (n=20; K-14, M-6); Ill - with the structure thinned down of the retina, accompanying the short-sighted sickle (n = 8; K-6, M-2); IV - with extensive choroidal-retina disappearances in the fundus (n = 10; K-7, M-3). In all individuals enrolled underwent Color Doppler ultrasound with apparatus SSA 770A Toshiba Aplio with linear probe frequency 12 MHz, judging maximum (Vmax) and minimum (Vmin) speed in the arteries of the eye: ophthalmic artery (OA), central retinal artery (CRA) and short posterior ciliary arteries (SPCA) located on the nasal and temporal side of the optic disc. The results were statistically analyzed. RESULTS: No statistically significant relationship between the nature of degenerative changes of the eye, and blood velocity in the OA. There was a increase in Vmax and Vmin blood in OA in Group IV, but these changes were not statistically significant. Statistically significant correlation was observed while in the CRA. With a decrease in Vmax and Vmin of blood flowing through a vessel exacerbation of retinal degeneration. Vmax and Vmin changes in the blood did not correlate significantly SPCA with retinal degeneration, although the results were much worse in the temporal vessels. CONCLUSIONS: With the deterioration of blood flow parameters of the central retinal artery and short posterior ciliary arteries comes to the severity of the retinal degeneration in myopic patients. More severe impairment of blood circulation in the temporal ciliary explain higher incidence of degenerative changes in the temporal side of the optic disc. PMID- 23745327 TI - [Refractive errors in patients with cerebral palsy]. AB - Ocular changes are common in patients with cerebral palsy (CP) and they exist in about 50% of cases. The most common are refractive errors and strabismus disease. The aim of the paper was to estimate the relativeness between refractive errors and neurological pathologies in patients with selected types of CP. MATERIAL AND METHODS. The subject of the analysis was showing refractive errors in patients within two groups of CP: diplegia spastica and tetraparesis, with nervous system pathologies taken into account. Results. This study was proven some correlations between refractive errors and type of CP and severity of the CP classified in GMFCS scale. CONCLUSIONS: Refractive errors were more common in patients with tetraparesis than with diplegia spastica. In the group with diplegia spastica more common were myopia and astigmatism, however in tetraparesis - hyperopia. PMID- 23745328 TI - [Surgical treatment of malignant eyelid tumors]. AB - Eyelid tumors constitute 5 to 10% of all skin malignancies. They mostly affect the elderly, chronically exposed to sunlight. The primary treatment is radical surgical excision of the tumor. The aim of this study was the clinical and microscopical analysis of malignant eyelid tumors in treated patients, the presentation of selected reconstructive methods and the evaluation of long-term results of surgical treatment of eyelid tumors. MATERIAL AND METHODS: The study involved 92 patients treated in 2000-2007 for malignant tumors of the eyelids. All patients underwent surgical excision of the tumor with concurrent eyelid reconstruction. The choice of reconstructive method depended on the size and location of the tumor. Histopathological evaluation was carried out specifying the type of cancer and radical surgery. The long-term results were rated on the basis of medical records and patients' examinations. RESULTS: Tumors were located mostly within the lower eyelid 67 (70.5%) and the medial canthus 17 (17.9%). Basal cell carcinoma was found in 83 (87.3%) cases, while in 12 (12.7%) diagnosed with other, less common cancers. Histopathological verification of tumor margins revealed incomplete excision in 14 specimens (14.7%). Reoperations due to recurrent tumor was performed in 11 (15.6%) cases. Good long-term results of functionally-aesthetic reconstruction of the eyelids was observed in 84 (91.3%) patients. CONCLUSIONS: 1. Basal cell carcinoma is the most common malignant tumor of the oculopalpebral region and originate mainly in the lower eyelid. 2. Significantly higher risk of recurrence exists in a more aggressive form of BCC (infiltrative basal-cell carcinoma) and tumors located in medial canthus. 3. The knowledge of multiple reconstruction methods allows the surgeon to choose the most appropriate one, depending on the size and location of the defect formed after excision of the tumor. PMID- 23745329 TI - [Reversible dilated cardiomyopathy as an atypical form of takotsubo cardiomyopathy]. AB - Stress-induced cardiomyopathy is characterized by transient regional left ventricular (LV) dysfunction that may involve, in different forms, midventricular, apical or basal segments. The authors describe a case of a 41 year-old woman with reversible, but global LV systolic dysfunction, complicated with apical thrombi. Clinical symptoms of dilated cardiomyopathy were preceded by persistent stressful workplace conditions. Ischemic, inflammatory, metabolic and endocrine causes of the disease were excluded. After 6 weeks, complete recovery of LV function in echocardiography and normal cardiac magnetic resonance imaging were observed, despite only modest doses of ramipril, carvedilol and diuretics. Six months later, as a result of another episode of emotional stress, she was hospitalized for typical takotsubo cardiomyopathy. Reversible global LV hypokinesis may be an atypical variant of stress-induced cardiomyopathy. PMID- 23745330 TI - [Influence of suitable home care on convalescence of the patient in heavy general condition - case report]. AB - The case of 78 year-old patient with diseases of cardio-vascular system and cancer of prostate gland in anamnesis has been described below. The reason for surgery and pharmacological treatment was a hemorrhagic shock in the course of aneurysm rupture of the left common iliac artery. The following complications appeared while saving his life: heavy failure of cardio-respiratory system, kidneys failure, generalized infection, tracheoesophageal fistula, bedsores of the body and in the nose, pareses and the rigor of auriculars. After stabilizing his general condition, the patient with efficient respiratory and circulatory system was released home. The aim of this work is to prove a positive influence of suitable care on his convalescence. PMID- 23745331 TI - [Chronic inflammation and metabolic syndrome in comparison with other signs belonging to the image of polycystic ovary syndrome]. AB - Polycystic ovary syndrome (PCOS) is a disorder which concern even 5-10% of women in reproductive age. PCOS is a cause of hyperandrogenism and menstrual disorders with chronic anovulation. The most common clinical symptoms observed in PCOS are hirsutism, acne and obesity. Patients with PCOS often suffer from metabolic disorders like insulin resistance, hyperinsulinemia, dyslipidemia, arteriosclerosis and other abnormalities of the metabolic syndrome. 35 to 60% of women with PCOS are obese and about 50% of them have insulin resistance and hyperinsulinemia. The pathogenesis of atherosclerosis emphasizes the role of inflammatory processes. There are a number of markers of the inflammation process. They are also observed in PCOS and may indicate an increased risk of cardiovascular disease in women. More than 46% of women with PCOS can be diagnosed with metabolic syndrome. Because of the fact that patients with PCOS are at higher risk group of the earlier development of complications such as diabetes t 2, atherosclerosis, hypertension and cardiovascular system diseases, it is important to carry out metabolic disorders diagnosis in every patient with PCOS. It will help to estimate the risk of complications and allow for the implementation of prevention or treatment of metabolic diseases belonging to the image of PCOS. PMID- 23745332 TI - [The usefulness of natriuretic peptides measurements in the diagnostics of chosen cardiovascular diseases]. AB - Natriuretic peptides compose the group of neurohormones produced by the myocardium in response to its walls stretching caused by the volume or pressure overload. They restrain the sodium kidney reabsorbtion, thus increasing the diuresis and natriuresis. They also participate in blood pressure, initial load as well as the water-mineral balance regulation. The main representatives of this group are ANP (atrial natriuretic peptide) and BNP (brain netriuretic peptide). With regard to slow dynamics of the serum levels changes, the measurements of BNP play an important role in cardiological diagnotics. Its serum concentration raises in these cardiovascular diseases that are connected with the left ventricle overload. So it can be treated as a specific left ventricle dysfunction marker, whereas its high concentrations correlate with the functional class according to NYHA. It also can be used in risk stratification in patients with the acute coronary syndrome and pulmonary embolism, as well as helping to differentiate the pulmonary and cardiac causes of acute dyspnoea. The serum level of NT-proBNP (N-terminal propeptide of brain natriuretic peptide) is also the independent predictive factor of the recurrence of atrial fibrillation after the restoring the sinus rhythm. PMID- 23745333 TI - [FGF-23 and Klotho protein - new markers in chronic kidney disease?]. AB - Disorders of calcium and phosphate metabolism are among the major problems in patients with chronic kidney disease (CKD), especially undergoing chronic dialysis. Besides the classic parathyroid-kidney axis, in recent years the existence of an endocrinological bone-kidney axis has been established, which allows better explanation of calcium and phosphate metabolism pathophysiology and secondary hyperparathyroidism in CKD. Fibroblast growth factor 23 (FGF-23) and its co-factor alpha-Klotho protein are the most important factors in the axis. The role of FGF-23 and Klotho protein, their mechanisms of action and significance in CKD have been presented. In ealy stages of CKD the increase of FGF-23 level precedes the decline in vitamin 1.25 (OH)2D3 and the increase of PTH level. Some studies showed correlation between the elevated FGF-23 level and increased mortality from cardiovascular disease in patients with chronic kidney disease. Clinical usefulness of determinations of FGF-23 and Klotho protein in chronic kidney disease is currently investigated. PMID- 23745334 TI - [Glycoxidative modification of albumin in medical research]. AB - Human albumin is a major, multi-functional serum protein. As the other protein is subjected to many modifications, including glycation and oxidation, which occurs physiologically in low intensity, however, are significantly increased in various pathological conditions. They often co-occur with each other, reinforcing its negative effects, and therefore are referred to common name - glycoxidative processes. Glycation, increased especially in diabetes, causes structural and functional changes of many proteins, both short-and long-lived, and it may result in increased oxidative stress and protein oxidation, which secondarily may increase their susceptibility to glycation. Studies in vivo and in vitro processes of oxidation and glycation of albumin and other proteins allowed us to identify biochemical markers that are routinely used in the diagnosis and monitoring of diseases (ischemia modified albumin, fructosamine) and those commonly used in research (e.g. AGE, CML, SH and CO groups, AOPP), which in perspective could be used in clinical trials (especially AGEs and AOPP). The study presents current state of knowledge on the mechanisms, the importance and the possibility of using glycoxidative modified albumin in medical science. PMID- 23745335 TI - Comparative analysis of the animal model and results of the clinical research of the aneurysm inclination angle as the predisposing factor for the occurrence of rupture. AB - INTRODUCTION: Natural course of aneurysms that occur on blood vessels of the brain singles out the need for understanding the mechanism of the occurrence of aneurysm wall rupture and identification of anatomic characteristics as predictive factors for hemorrhage to occur. OBJECTIVE: In this study we comparatively present results of our researches and experimental models on animals. METHODS: We made a comparative analysis of anatomical characteristics of blood vessels of the brain and aneurysms obtained on the basis of digital subtraction angiography and intraoperative finding. In this article we review recent research in the anatomic characteristics of intracranial aneurysms and parent blood vessels. We present a series of 185 aneurysms (ruptured and unruptured) dissected at the Neurosurgical Clinic of Clinical Center of Serbia in Belgrade. RESULTS: Inclination angle may be considered as the vital predesposing factor for intracranial aneurysm rupture. In aneurysms that ruptured it was 139.748+/-27.242 degrees, while in unruptured aneurysms it was considerably smaller and amounted to 100.882+/-22.001 degrees (p<0.01). CONCLUSION: Inclination angle may be regarded as the vital predisposing factor since it differs considerably in unruptured and ruptured aneurysms. Aneurysms with blood stream angle smaller than 115 degrees have very small probability of rupture, while blood stream angle bigger than 150 degrees presents a high risk of rupture. PMID- 23745336 TI - [Analysis of antimicrobial effect of MTAD solution in infected root canal system using PCR technique]. AB - INTRODUCTION: Clinically acceptable antiseptic should possess organolithic mineralolithic properties and antimicrobial efficacy, and should be non-toxic. OBJECTIVE: The aim of the paper was to assess the presence of genomes of the most common microorganisms (Porphyromonas gingivalis, Agregatibacter actinomycetemcomitans, Tanerella forsythensis, Prevotella intermedia, Treponema denticola and Enterococcus faecalis) in infected tooth root canals before and after rinsing with solution of doxycycline, citric acid and detergent Tween-80 (MTAD) in patients with clinically diagnosed primary apex periodontitis. METHODS: The content of primarily infected canals before and after using the MTAD solution was used as a biological material in which the presence of microorganisms DNA was proved. For the detection of bacterial genome the multiplex PCR technique was applied. RESULTS: The percentage of positive samples before canal treatment was 100%. In infected root canals E. faecalis was most dominant (37%). In a relatively high percentage we detected P. intermedia (25%), A. actinomycetemcomitans (20%), T. denticola (17%), T. forsythensis (15%) and P. gingivalis (10%). After rinsing the canal system using MTAD solution, there was a statistically significant decrease in E. faecalis (12%), P. intermedia (0%), T forsythensis (0%) and P. gingivalis (0%). The presence of other bacteria was also diminished but not statistically significantly. CONCLUSION: With the application of multiplex PCR technique which provided a simultaneous amplification of various genomic sequences, using several pairs of primers, the most dominant in infected root canals were E. faecalis. P. intermedia, A. actinomycetemcomitans, T. denticola, T. forsythensis and P. gingivalis. After mechanic treatment and irrigation of root canals with MTAD solution, P. intermedia, P. gingivalis and T forsythensis were not found. The presence of E. faecalis, A. actinomycetemcomitans and T. denticola was diminished, however, not statistically significantly. PMID- 23745337 TI - Antioxidative status of saliva before and after non-surgical periodontal treatment. AB - INTRODUCTION: Oxidative stress and antioxidants play an important role in the pathogenesis of inflammatory disease, including chronic periodontitis (CP). Saliva contains enzymatic (glutathione peroxidase - GPx, superoxide dismutase - SOD, etc.) and non-enzymatic (albumin - ALB, uric acid - UA, glutathione, etc.) antioxidants. OBJECTIVE: The aims of this study were to investigate: a) level of SOD, GPx, UA, ALB and total antioxidative status (TAS) of saliva in CP patients before and after non-surgical treatment, and b) correlations between clinical periodontal parameters and levels of salivary antioxidants. METHODS: Saliva was collected from 21 CP patients before and after non-surgical treatment. The condition of periodontium was assessed by plaque index, gingival index, bleeding on probing, probing depth and clinical attachment loss. Level of investigated antioxidants (except GPx) and TAS was determined using colorimetric method and commercial kits. GPx activity was determined using UV method and commercial kits. RESULTS: After the treatment significant increase of UA, ALB, Gpx, TAS was detected (p<0.01) and decrease of SOD activity (p>0.05). A significant correlation was observed between GPx and PI (r=0.575, p=0.008), SOD and GI (r=0.525, p=0.017) before therapy, and SOD and bleeding on probing (BP) (r=0.59, p=0.006), TAS and BP (r=0.453, p=0.045) after therapy. CONCLUSION: These data suggest that levels of salivary antioxidants generally increase after non surgical periodontal treatment. Correlation between some clinical periodontal parameters and level of salivary antioxidants was found. PMID- 23745338 TI - Tumor necrosis factor alpha gene polymorphism in serbian patients with sarcoidosis. AB - INTRODUCTION: Sarcoidosis is a multisystemic disease of unknown etiology. Genetic factors play a considerable role in the onset of the disease. Tumor necrosis factor alpha (TNF-a) is a proinflammatory cytokine which plays an important role in the pathogenesis of the disease and the formation of granuloma by regulating cellular proliferation and apoptosis. OBJECTIVE: The aim of this study was to investigate the role of TNF-alpha-308 G/A polymorphism in the development of sarcoidosis and to evaluate the association between the aforementioned type of polymorphism and the clinical course of the disease. METHODS: Seventy patients with sarcoidosis and 50 healthy volunteers were genotyped for the TNF-alpha 308G/A polymorphism. Polymorphism variants were examined by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) on the DNA isolated from blood leukocytes. RESULTS: There were no significant differences in TNF-alpha 308A allele frequency distribution between sarcoidosis patients and the control group, but the TNF-alpha-308A allele was observed significantly more frequently in the sarcoidosis patients with Lofgren's syndrome when compared with non Lofgren's patients. CONCLUSION: We have found that the TNF-alpha-308A variant is associated with Lofgren's syndrome in Serbian patients with sarcoidosis. PMID- 23745339 TI - [Mucinous cystadenomas of the liver]. AB - INTRODUCTION: Biliary cystadenomas of the liver are rare benign tumors prone to malignant alteration so that a total excision is recommended. OBJECTIVE: The aim of the paper is to present our experience in treatment and to evaluate whether a simple ablation represents the appropriate treatment. METHODS: Over a 10-year period 25 patients (24 women) of the average age of 58 years suffering from cystadenomas of the liver, 18 in the right, 4 in the left and 3 in both lobes of the liver were operated. Twenty-three patients had a single lesion, while two patients had 3 and 6 lesions, respectively. Pain was present in 20, occasional vomiting in 4, discomfort in 2 and a sense of fullness in 2 patients.Three patients were jaundiced, 1 due to cystadenoma of the liver, 2 due to concomitant tumors of the head of the pancreas, while 5 patients had concomitant diseases. RESULTS: A total ablation was performed in 22 patients, left lateral bisegmentectomy in 1 and partial excision in 2 patients. Six additional procedures were performed. Five cystadenomas of the liver had,,ovarian like" stroma, all in women. A focal malignant alteration was found in 2 patients aged 66 and 79 years, respectively. Recurrence was registered in 1 female patient in whom a partial excision had been done. Two patients with concomitant malignancy and 1 patient who developed malignant histiocytosis six months after surgery, died after 1, 2 and 3 years, respectively. CONCLUSION: Biliary cystadenomas of the liver may be misdiagnosed as simple liver cysts, so that ,,frozen section" histology is highly recommended. In most cases the tumor may be successfully treated by ablation up to the healthy liver tissue. Major liver resections are rarely necessary. PMID- 23745340 TI - Mesenchymal stem cells isolated from peripheral blood and umbilical cord Wharton's jelly. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) are a promising tool for regenerative medicine, but due to the heterogeneity of their populations, different sources and isolation techniques, the characteristics defining MSCs are inconsistent. OBJECTIVE: The aim of this study was to compare the characteristics of MSCs derived from two different human tissues: peripheral blood (PB-MSCs) and umbilical cord Wharton's Jelly (UC-MSCs). METHODS: The PB-MSC and UC-MSC were isolated by adherence to plastic after gradient-density separation or an explant culture method, respectively, and compared regarding their morphology, clonogenic efficiency, proliferating rates, immunophenotype and differentiation potential. RESULTS: MSCs derived from both sources exhibit similar morphology, proliferation capacity and multilineage (osteogenic, chondrogenic, adipogenic and myogenic) differentiation potential. Differences were observed in the clonogenic capacity and the immunophenotype, since UC-MSCs showed higher CFU-F (colony-forming units fibroblastic) cloning efficiency, as well as higher embryonic markers (Na-nog, Sox2, SSEA4) expression. When additional surface antigens were analyzed by flow cytometry (CD44, CD90, CD105, CD33, CD34, CD45, CD11b, CD235a) or immunofluorescent labeling (vimentin, STRO-1 and alpha-smooth muscle actin), most appeared to have similar epitope profiles irrespective of MSC source. CONCLUSION: The results obtained demonstrated that both MSCs represent good alternative sources of adult MSCs that could be used in cell therapy applications. PMID- 23745341 TI - [The diagnosis of Chlamydia trachomatis cervical infection among students by using classical and molecular methods]. AB - INTRODUCTION: Chlamydia trachomatis is the most common cause of sexually transmitted disease. The possibility of serious complications may be prevented by early detection of the bacteria on the uterine cervix by the application of sensitive and reliable tests such as up-to-date molecular tests. OBJECTIVE: The aim of the study was the comparison of sensitivity and specificity of three different methods in the diagnosis of Chlamydia trachomatis infection. METHODS: The study included 69 female students referred to the gynecological outpatient unit at the Students' Polyclinic for colposcopic examination of the uterine cervix. Cervical Chlamydia trachomatis was diagnosed by using three different methods: direct immunofluorescence (DIF), nucleic acid hybridization assay (hc2), and polymerase chain reaction (PCR). RESULTS: By using DIF Chlamydia trachomatis was identified in four students (5.80%), by using hc2 also in four (5.80%), while by using PCR test in six students (8.70%). Comparative analysis of the obtained results evidenced sensitivity and specificity rates of DIF in comparison to PCR method of 46% and 95%, respectively. Sensitivity and specificity of DIF method in comparison to hc2 was 62% and 97%. Sensitivity and specificity of hc2 method in comparison to PCR was 76% and 100%. CONCLUSION: Contemporary molecular methods, such as PCR, are methods of choice for the identification of endocervical Chlamydia trachomatis in the population of university students without symptoms of the disease. PMID- 23745342 TI - [Assessment of the natural course and treatment of premalignant uterine cervical lesions in pregnancy]. AB - INTRODUCTION: Premalignant changes of the uterine cervix occur with similar frequency during pregnancy and in non-pregnant women. Due to the fact that any surgery on the cervix can jeopardize pregnancy, it is important to define the protocol of procedures for the treatment of these changes during pregnancy. OBJECTIVE: The aim of the study was to investigate the natural course of premalignant cervical changes during pregnancy and the impact of their treatment on the pregnancy course. METHODS: Study involved all patients with colposcopically, cytologically and hystopathologically diagnosed premalignant cervical changes during pregnancy from 2002 to 2008. Patients were divided into two groups according to the applied treatment during pregnancy: surgery or monitoring by regular colposcopic and cytological examinations. The two groups were compared concerning treatment outcome, persistence or regression of changes and pregnancy duration. RESULTS: Study involved 58 patients. Spontaneous remission of lesions occurred after pregnancy in 63.79% of cases. High-grade squamous intraepithelial lesion (H-SIL) demonstrated a higher rate of persistency in comparison with low-grade squamous intraepithelial lesion (L-SIL) (X2=25.115; p<0.05). Only one finding of L-SIL progressed into H-SIL in the monitored group. Patients who underwent conization during pregnancy had a significantly more frequent preterm deliveries (X2=14.369; p<0.05). CONCLUSION: The obtained high rate of spontaneous regression of cervical changes after pregnancy as well as the lower incidence of preterm births in patients who were not treated by conization during pregnancy, confirm that patients with premalignant cervical changes should be, if invasion is excluded, under follow-up throughout pregnancy by regular colposcopic and cytological examinations. Therapeutic conization, due to numerous complications, should be performed only when there is a suspected presence of a more severe form of the disease (micro invasive and invasive carcinoma). PMID- 23745343 TI - Behavioral response of people in Belgrade to the bombing campaign during 1999. AB - INTRODUCTION: In contrast to numerous reports on long-term psychological consequences of disasters, the literature addressing the acute impact of intentional collective disaster is limited. OBJECTIVE: This research aimed to examine the impact of the bombing campaign on the behavior of people living in Belgrade during the air attacks in 1999. METHODS: The questionnaire was designed and administered to 231 participants. Psychological distress symptoms were assessed using the Symptom Checklist-Revised (SCL-90-R). RESULTS: Participants reported fear and anger as dominant feelings, and the majority of them complained about sleep disturbance, body weight change, and loss of interest for sexual activity. Regression analysis of the scores of the SCL-90-R revealed significant effects of the duration of living under the stress of air attacks, age and gender of the participants and living in the risky areas of the city, upon the scores on Anxiety and Depression dimension. CONCLUSION: The results of the study contributed to our understanding of the processes through which individuals pass during a long lasting bombardment. It can be beneficial for mental health services in evaluating which actions of care and support could be most suitable. PMID- 23745344 TI - Forensic aspects of postmortem serum carbohydrate-deficient transferrin analysis as a marker of alcohol abuse. AB - INTRODUCTION: Carbohydrate-deficient transferrin (CDT) has been suggested as one of alcohol abuse indicators having produced good results in forensic medicine for years. OBJECTIVE: The aim of the study was to identify correlation between present methodology of alcohol abuse diagnosis at autopsy (macroscopic and microscopic findings) and CDT examination using the method of isoelectrofocusing (IEF) in polyacrylamide gel electrophoresis (PAGE). We also analyzed if the time interval between the moment of death and blood sample collection influences CDT findings. METHODS: The method used for CDTanalysis was IEF-PAGE. Sera of 49 males and 11 females aged 14-87 years, average age 46.85+/-18.53, were used in this study. Control group consisted of five patients who died after medical treatment that lasted longer than 15 days, and five patients who started Disulfiram therapy in controlled hospital environment. RESULTS: The results obtained in CDT examination in dead bodies' sera showed sensitivity 59% and specificity 71%. A high incidence of falsely positive CDT result was noticed in liver failure and cirrhosis of non-alcoholic origin. CDT analysis is also possible to be done in samples collected postmortem up to 76 hours. CONCLUSION: In forensic medicine, the method of CDT determination is reliable for the diagnosis of alcohol abuse. PMID- 23745345 TI - [Alcohol use among adolescents in Serbia]. AB - INTRODUCTION: European School Survey Project on Alcohol and Other Drugs (ESPAD), the largest international research project, was conducted for the first time in Serbia in 2008. OBJECTIVE: The objective was to analyze data obtained by ESPAD research on alcohol use among secondary school first grade students, and particularly the difference in the use of alcohol by gender, type of school students attend, their place of residence and the territory among secondary school students in Serbia in 2008. METHODS: Attitudes and practice related to alcohol use of 6,553 secondary school first grade students were analyzed. A standardized, internationally approved questionnaire, structured and designed for self-filling was used on a stratified, one-stage sample of students. The data received from the ESPAD research were processed by X2 test to test the significance of differences between the observed characteristics, with the conclusion level of p<0.01. RESULTS: Over three-quarters of students can easily buy beer or wine. More than one half can buy spirits and alcopops. 89.1% of students drank alcoholic beverages at least once in a lifetime and 78.2% in the last year. At least once in a lifetime 42.2% of students were drunk and 29.7% in the last year. At least once in the last month 32.0% of students had five or more drinks in a row. Boys consumed alcohol more frequently and got drunk more often than girls (p<0.01). CONCLUSION: This research emphasizes the need for creating a prevention of alcohol use and alcohol abuse program among adolescents and more consistent application of the existing regulations aiming to decrease alcohol use among adolescents in Serbia. PMID- 23745346 TI - [Financial sustainability of home care in the health system of the Republic of Serbia]. AB - INTRODUCTION: Over the last several years, during the economic crisis, the Ministry of Health and the Republican Health Insurance Fund (RHIF) have been faced with new challenges in the sphere of healthcare services financing both in the primary as well as other types of health insurance in the Republic of Serbia (RS). OBJECTIVE: Analysis of cost-effectiveness of two models of organization of home treatment and healthcare in the primary insurance, with evaluation of the cost sustainability of a single visit by the in-home therapy team. METHODS: Economic evaluation of the cost of home treatment and healthcare provision in 2011 was performed. In statistical analysis, the methods of descriptive statistics were employed. The structure of fixed costs of home healthcare was developed according to the RS official norms, as well as fixed costs of providing services of home therapy by the Healthcare Centre "New Belgrade". The statement of account for provided home therapy services was made utilizing the RHIF price list. RESULTS: The results showed that the cost of home healthcare and therapy of the heterogeneous population of patients in the Healthcare Centre "New Belgrade" was more cost-effective in relation to the cost of providing home therapy services according to the RS official norms. CONCLUSION: Approved costs utilized when making a contract for services of home therapy and healthcare with the RHIF are not financially sustainable. It was shown that the price of 10 EUR for each home visit by the in-home therapy team enables sustainability of this form of providing healthcare services in RS. PMID- 23745347 TI - [Superficial siderosis: case report and literature review]. AB - INTRODUCTION: Superficial siderosis (SS) is caused by chronic subarachnoid bleeding and is characterized by free iron and hemosiderin deposition along the pial and subpial structures of central nervous system. SS leads to progressive and irreversible CNS damage. The most common causes of chronic subarachnoidal bleeding are tumors, head and spinal cord trauma, arteriovenous malformations and aneurysms. SS is characterized by clinical triad: sensorineural hearing loss, cerebellar ataxia and piramydal signs. Brain MR imaging is the investigation of choice for the diagnosis of SS.Typical findings include hypointensities seen on T2-weighted MR imaging around the brain, cerebellum, brain stem, spinal cord, VIII cranial nerve and atrophy of cerebellum and medulla. CASE OUTLINE: A 71-year old female patient noticed hand tremor in the middle of the third decade of life, and later slowly progressive bilateral hearing loss. At the age of 64 she developed unsteady gate, hand clumsiness and dysarthria, to became incapable of independent walking and standing five years later. Clinical course and brain MRI findings were typical for SS, but additional investigation did not reveal the couse of subarahnoidal bleeding. CONCLUSION: SS represents a rare and under recognized condition that must be considered in all patients with cerebellar syndrome of unknown cause. Early diagnosis of SS in some cases with identified cause of chronic bleeding allowes therapeutic interventions that may prevent further progression of the disease. PMID- 23745348 TI - Primary percutaneous coronary intervention in a patient with right internal mammary artery graft originating from arteria lusoria dextra. AB - INTRODUCTION: Congenital aomalies of the aortic arch, although numerous and heterogeneous, occur in less than 1% of individuals at autopsies. Left aortic arch with an aberrant right subclavian artery, also called arteria lusoria dextra, is the most common anomaly of the aortic arch, occurring in 0.5-2.5% of individuals. CASE OUTLINE: We report the case of a 48-year-old man suffering from acute inferoposterior-wall ST elevation myocardial infarction successfully treated by primary percutaneous coronary intervention.Ten years ago, the patient had undergone coronary artery bypass graft surgery with the implantation of two arterial grafts- left and right internal mammary arteries on both left anterior descending and right coronary artery. After several attempts to canulate truncus brachiocephalicus, angiogram revealed the left aortic arch with the aberrant right subclavian artery. To our knowledge, this is the first described case of primary percutaneous coronary intervention via the aberrant right subclavian artery and right internal mammary artery graft with stent implantation in the infarct related lesion of the distal segment of right coronary artery. Subsequent 64-multidetector computed tomography confirmed the angiographic findings. CONCLUSION: Early recognition of congenital anomalies of the aortic arch and its great vessels, even before coronary artery bypass graft surgery, could be crucial for the urgent and successful treatment of patients with life-threatening conditions, such as ST segment elevation myocardial infarction. PMID- 23745349 TI - [Juvenile Sjogren's syndrome: case report]. AB - INTRODUCTION: Sjogren's syndrome (SS) is an autoimmune disease of unknown etiology, clinically manifested by dry eyes (xerophthalmia) and dry mouth (xerostomia). In childhood SS is a rare disease, clinically atypically or asymptomatic and is often unrecognized. We report a girl with asymptomatic, juvenile form of primary Sjogren's syndrome (JSS). CASE OUTLINE: A 13-year-old girl was initially observed for several months due to elevated sedimentation rate (ESR 75-90 mm/h) without signs of inflammation or other symptoms and disease signs. Subjective symptoms of dryness of the eyes and mouth were absent at the beginning. Ophthalmologic examination demonstrated hypolacrimia although the patients had no subjective signs of xerophthalmia. Ultrasonography (US) revealed mild enlargement and heterogeneity of large salivary glands parenchyma. Increased rheumatoid factor (RF), anti SS-A/Ro, anti SS-B/La antibodies were found in serum. Ophthalmologic examination demonstrated decreased lacrimation.JSS was confirmed on the basis of ophthalmologic examination, immunological tests, histological findings of biopsy of small and US of major salivary glands. During a 12-years follow-up period systemic or extraglandular manifestations of JSS and other autoimmune diseases were not observed. CONCLUSION: Our experience suggests that in the differential diagnosis of unexplained elevated ESR the primary form of JSS should be also taken into consideration. Ultrasonographic changes of major salivary glands in the absence of symptoms of xerostomia point out that this noninvasive method has an important role in the diagnosis and management of patients with JSS. PMID- 23745350 TI - Small bowel adenocarcinoma mimicking a large adrenal tumor. AB - INTRODUCTION: Adenocarcinoma of the small bowel is a rare gastrointestinal neoplasm usually affecting the distal duodenum and proximal jejunum. Because of their rarity and poorly defined abdominal symptoms, a correct diagnosis is often delayed. CASE OUTLINE: We present a 43-year-old woman admitted at the Clinic for Endocrinology due to a large tumor (over 7 cm) of the left adrenal gland.The tumor was detected by ultrasound and confirmed by CT scan.The patient complained of abdominal pain in the left upper quadrant, fatigue and septic fever. Normal urinary catecholamines excluded pheochromocytoma. The endocrine evaluations revealed laboratory signs of subclinical hypercorticism: midnight cortisol 235 nmol/L, post 1 mg - overnight Dexamethasone suppression test for cortisol 95.5 nmol/L and basal ACTH 4.2 pg/mL. Plasma rennin activity and aldosterone were within the normal range. Surgery was performed. Intraoperative findings showed signs of acute peritonitis and a small ulceration of the jejunum below at 70 cm on the anal side from the Treitz's ligament. Adrenal glands were not enlarged. Patohistology and immunochemistry identified adenocarcinoma of the jejunum without infiltration of the lymphatic nodules. The extensive jejunal resection and lavage of the peritoneum were performed. Due to complications of massive peritonitis, the patient died seven days after surgery. CONCLUSION: Poorly defined symptoms and a low incidence make the diagnosis of small bowel carcinoma, particularly of the jejunal region, very difficult in spite of the new endoscopic techniques. PMID- 23745351 TI - [Treatment of the femoral neck pseudoarthrosis in childhood: case report]. AB - INTRODUCTION: Femoral neck fractures in children and adolescents are rare. However, their complications are frequent - avascular necrosis, femoral neck pseudoarthrosis, premature physeal closure with consequent growth disturbance and coxa vara deformity. CASE OUTLINE: A 9.5-year-old boy was injured in a car accident, and femoral neck fracture was diagnosed. Prior to admission at our hospital he was surgically treated several times. He was admitted at our hospital eight months following the accident. On the X-ray transcervical pseudoarthrosis of the femoral neck was found, as well as coxa vara deformity and metaphyseal avascular necrosis. He was operated at our hospital; all previously placed ostefixation material was removed, valgus osteotomy of 30 degrees was done as well as additional local osteoplasty using the commercial osteoindactive agent (Osteovit). Postoperatively, we applied skin traction, bed rest and physical therapy. At the final follow-up, the patient was recovered completely. He is now painless, the legs are of equal length, range of movements in the left hip is full, life activity is normal.The X-ray shows that the femoral neck pseudoarthrosis is fully healed. CONCLUSION: This case is presented in order to encourage other colleagues to challenge the problematic situation such as this one. Also, we would like to remind them what one should think about and what should be taken into consideration in the primary treatment of femoral neck fractures in children. Valgus femoral osteotomy, as a part of the primary treatment of femoral neck fracture in children (identically as in the adults) can prevent the occurrence of femoral neck pseudoarthrosis. PMID- 23745352 TI - [Bullet embolism in a case of homicide: case report]. AB - INTRODUCTION: Bullet embolism is a special form of embolism, where embolus is either a bullet or its fragment. Bullet penetrates through the injured part of the body into circulation and then travels to a distant part of the body, until it gets blocked in a vessel of the same diameter as the bullet. CASE OUTLINE: We are presenting a case of gunshot injury in a 26-year-old male, found unconscious on the passenger seat, with the gunshot injury of the right hand and hemithorax, who died two hours after admission to hospital. Post-mortem X-ray revealed the presence of a metallic foreign body - a bullet, in the level of the left femoral neck. The autopsy revealed entrance and exit gunshot wounds of the upper third of the right upper arm.There was a second entrance gunshot wound, and the bullet passed through the right hemithorax and the right lung, and then through the intervertebral disc between the eighth and ninth thoracic vertebrae, and also making a complete laceration of the wall of the thoracic aorta, in the right posterior semicircumference. The slightly deformed bullet, caliber 7.65 mm, was found embedded in the lumen of the vessel at the bifurcation of the deep femoral artery from the left femoral artery. CONCLUSION: Bullet embolism is a rare complication of gunshot wounds. It should be suspected in any gunshot wound victim without an exit wound, or the lack of a missile in the bullet pathway, or if there are premortem signs or symptoms unexpected for the presumed pathway of the bullet, such as distant ischemia or infection. In these cases, some of postmortem imaging techniques should be used to save time in diagnosis, treatment and at autopsy. PMID- 23745353 TI - [Vascular dementia: facts and controversies]. AB - Vascular dementia (VaD) is the second most frequent dementia after Alzheimer's disease, and is diagnosed during lifetime in 20% of demented patients. Five-year survival rate in VaD is 39%, while it is estimated to be 75% in healthy persons of the same age. It is therefore important to make correct diagnosis of VaD early in the course of the disease. Risk factors forVaD are identical to stroke risk factors, and there are significant possibilities for the prevention of vascular cognitive decline. Cognitive decline develops acutely or step-by-step within three months after stroke, but more gradual progression of intellectual decline is also possible. Neurological examination can reveal pyramidal and extrapyramidal signs, pseudobulbar palsy, gait disturbance and urinary incontinence. Neuropsychological profile comprises the loss of cognitive set shifting, decline in word fluency, verbal learning difficulties, perseverations, difficulties in complex figure copying, and in patients with cortically located lesions also problems with speech and praxia. The basis of the diagnosis is, besides history, neurological examination and neuropsychological assessment, computed tomography and/ or magnetic resonance brain imaging. Vascular risk factors control is the most important measure in VaD prevention. Modern guidelines for the treatment of cognitive decline in VaD emphasize that donepezil can be useful in the improvement of cognitive status at the level of Class Ila recommendation at the level of evidence A, while memantine may be useful in patients with mixed VaD and Alzheimer's disease dementia. PMID- 23745354 TI - [Idiopathic short stature]. AB - Growth is a complex process and the basic characteristic of childhood growth monitoring provides insight into the physiological and pathological events in the body. Statistically, the short stature means departure from the values of height for age and sex (in a particular environment), which is below -2 standard deviation score, or less than -2 standard deviation, i.e. below the third percentile. Advances in molecular genetics have contributed to the improvement of diagnostics in endocrinology. Analysis of patients' genotypes should not be performed before taking a classical history, detailed clinical examination and appropriate tests. In patients with idiopathic short stature specific causes are excluded, such as growth hormone deficiency,Turner syndrome, short stature due to low birth weight, intrauterine growth retardation, small for gestational age, dysmorphology syndromes and chronic childhood diseases. The exclusion of abovementioned conditions leaves a large number of children with short stature whose etiology includes patients with genetic short stature or familial short stature and those who are low in relation to genetic potential, and who could also have some unrecognized endocrine defect. Idiopathic short stature represents a short stature of unknown cause of heterogeneous etiology, and is characterized by a normal response of growth hormone during stimulation tests (>10 ng/ml or 20 mJ/I), without other disorders, of normal body mass and length at birth. In idiopathic short stature standard deviation score rates <-2.25 (-2 to -3) or <1.2 percentile. These are also criteria for the initiation of growth hormone therapy. In children with short stature there is also the presence of psychological and social suffering. Goals of treatment with growth hormone involve achieving normal height and normal growth rate during childhood. PMID- 23745355 TI - [The role of regulatory T cells in the modulation of anti-tumor immune response]. AB - Regulatory T cells (Treg) represent a subset of CD4+T cells whose function is to suppress immune responses. Treg lymphocytes can be divided into two subsets: natural nTreg lymphocytes that are developed in the thymus and inducible iTreg lymphocytes, which originate from conventional T lymphocytes on the periphery.The majority of Treg lymphocytes express high levels of interleukin-2 (IL-2) receptor a chain (CD25) and transcription factor FoxP3 (critical for the development and suppressor activity of iTreg lymphocytes). Cancer cells can modulate anti-tumor immune response indirectly, through the activation of Treg lymphocytes. It has been shown that the loss of regulatory function by depletion of tumor-induced Treg lymphocytes may enhance effectors response, resulting in tumor rejection, while the increased number of Treg lymphocytes effectively prevents tumor destruction. nTreg lymphocytes express increasingly CTLA-4 and membrane-bound TGF beta, which inhibits cytokine production and responses of effectors lymphocytes.iTreg lymphocytes secrete immunosuppressive cytokines such as ILreg 10 and TGF-beta.Treg lymphocytes represent one of important obstruction in anti tumor immunity. PMID- 23745356 TI - The evolution of the female sexual response concept: treatment implications. AB - Sexual dysfunctions have been the most prevalent group of sexual disorders and include a large number of populations of both sexes.The research of sexual behavior and treatment of women with sexual distress arises many questions related to differences in sexual response of men and women. The conceptualization of this response in modern sexology has changed over time.The objective of our paper was to present the changes and evolution of the female's sexual response concept in a summarized and integrated way, to analyze the expanded and revised definitions of the female sexual response as well as implications and recommendations of new approaches to diagnostics and treatment according to the established changes.The lack of adequate empirical basis of the female sexual response model is a critical question in the literature dealing with this issue. Some articles report that linear models demonstrate more correctly and precisely the sexual response of women with normal sexual functions in relation to women with sexual dysfunction. Modification of this model later resulted in a circular model which more adequately presented the sexual response of women with sexual function disorder than of women with normal sexual function.The nonlinear model of female sexual response constructed by Basson incorporates the value of emotional intimacy, sexual stimulus and satisfaction with the relationship. Female functioning is significantly affected by multiple psychosocial factors such as satisfaction with the relationship, self-image, earlier negative sexual experience, etc. Newly revised, expanded definitions of female sexual dysfunction try to contribute to new knowledge about a highly contextual nature of woman's sexuality so as to enhance clinical treatment of dysfunctions.The definitions emphasize the evaluation of the context of women's problematic sexual experiences. PMID- 23745357 TI - [Reference citation]. AB - Scientific and professional papers represent the information basis for scientific research and professional work. References important for the paper should be cited within the text, and listed at the end of the paper. This paper deals with different styles of reference citation. Special emphasis was placed on the Vancouver Style for reference citation in biomedical journals established by the International Committee of Medical Journal Editors. It includes original samples for citing various types of articles, both printed and electronic, as well as recommendations related to reference citation in accordance with the methodology and ethics of scientific research and guidelines for preparing manuscripts for publication. PMID- 23745358 TI - [Genetic transformation of flax (Linum usitatissimum L.) with chimeric GFP-TUA6 gene for visualisation of microtubules]. AB - The data of Agrobacterium-mediated transformation of some Linum usitatissimum cultivars zoned on the territories of Belarus and Ukraine with the plasmid carrying chimeric GFP-TUA6 gene and nptII gene as selectable marker conferring resistance to kanamycin are presented in this study. Transformation was affected by a number of factors including optical density (OD600), time of inoculation of explants with Agrobacterium and co-culture conditions. Transgenic nature of obtained lines was confirmed by PCR analysis. Expression of GFP-TUA6 gene was detected with confocal laser scanning microscopy. The obtained transgenic lines can be used for further functional studies the role of microtubules in the processes of building the flax fibres and resistance to wind. PMID- 23745359 TI - [Clarification of Rht8 and Ppd-D1 gene linkage on the 2D chromosome of winter bread wheat]. AB - In the south part of Ukraine the haplotype of Rht8c and Ppd-D1a genes is highly distributed among modern bread wheat varieties. During the time of breeding program it has been selected as one of the most important adaptive complex for plants of this region. Genetic distance between Rht8c and Ppd-D1a was clarified. PMID- 23745360 TI - [Phenotypic variability of Arabidopsis thaliana seedlings as a result of inhibition of Hsp90 chaperones]. AB - The influence of geldanamycin (GDA)--an inhibitor of Hsp90 chaperones--on growth and morphogenesis of Arabidopsis thaliana seedlings was studied. It was shown that treatment of seeds Col with the inhibitor resulted in a dose-dependent increase in variability of seedling's rates of growth and phenotypes. GDA treatment of genetic polymorphic seeds of natural A. thaliana populations and UV B irradiated seeds Col resulted in a significant rise in the amount of seedlings with morphological alterations and the amount of non-germinated seeds. The obtained data testify that Hsp90 may restrict stochastic processes, thereby participating in the plant development canalization, conceal genetic variations and maintain cell vitality. PMID- 23745361 TI - [Differentiation of haploid and diploid rape plants at the cytological and morphological levels]. AB - Some cytological and morphological characteristics of haploid and dihaploid plants of winter rape obtained via anther culture were studied. It was shown that in haploid plants the number of chloroplasts in stomata guard cells and the size of the stomata guard cells themselves were much smaller, and the number of stomata per unit area was greater than in doubled haploids and diploids. Haploids were also characterized by a smaller size of petals and anthers, and in general, a smaller flower compared to dihaploids and diploids. PMID- 23745362 TI - Cytomorphological studies in some members of tribe Paniceae (Poaceae) from district Kangra of Himachal Pradesh (Western Himalayas). AB - The present paper deals with cytological studies on the population basis of 21 species belonging to 9 genera of tribe Paniceae of family Poaceae from cytologically unexplored area of Western Himalayas i.e. district Kangra of Himachal Pradesh for the assessment of genetic diversity of grass flora. On world wide basis, the chromosome counts have been made for the first time for three species such as Brachiaria remota (n = 16), Digitaria granularis (n = 36) and Isachne albens (n = 5). Similarly, on India basis, altogether new records are made for two species such as Echinochloa cruspavonis (n = 27) and Paspalum distichum (2n = 50). A comparison of the different euploid cytotypes studied at present for Digitaria adscendens, D. setigera and Oplismenus compositus revealed significant variations in their morphology, depicting increase in some of the characters of polyploid cytotypes. The course of meiosis has been observed to be normal in all the studied populations with high pollen fertility except for two species such as Paspalum dilatatum and P. distichum marked with abnormal meiosis and reduced pollen fertility. PMID- 23745363 TI - Chromosome number and secondary chromosomal associations in wild populations of Geranium pratense L. from the cold deserts of Lahaul-Spiti (India). AB - In this work we studied the meiotic chromosome number and details of secondary chromosomal associations recorded for the first time in Geranium pratense L. from the alpine environments in the cold deserts of Lahaul-Spiti (India). All the presently studied individuals of the species existed at 4x level (x = 14). The present chromosome count of n = 28 in the species adds a new cytotype to the already existing diploid chromosome count of 2n = 28 from the Eastern Himalayas and outside of India. Out of the six accessions scored presently four showed normal meiotic course. However, two accessions investigated from Mud, 3800 m and Koksar, 3140 m depicted abnormal meiotic course due to the presence of multivalents and univalents, and secondary associations of bivalents/chromosomes. The secondary chromosomal associations in the species existed among bivalents/chromosomes were noticed in the PMCs at prophase-1 (diakinesis) and persisted till the separation of sister chromatids at M-II. The variation in the number of bivalents/chromosomes involved in the secondary associations at M-I (2 8) and A-I/M-II (2-12) has also been recorded. The occurrence of such secondary associations of bivalents/chromosomes in G. pratense which existed at 4x level indicated the secondary polyploid nature of the species. PMID- 23745364 TI - [Correlation of the spermatozoa morphological anomaly with the presence of aneuploidies in its nuclei in the patients with astheno-, oligo- and teratozoospermia]. AB - Examination of the numerous anomalies of the chromosomes 13, 18, 21, X, Y was carried out using FISH method before the IVF attempt in the patients with astheno , oligo- and teratozoospermia. The percentage of aneuploid spermatozoa was magnificently higher (p < 0.05) in patients with oligozoospermia comparing with the ones with astheno- and teratozoospermia. There is a significant difference in content of spermatozoa with cytoplasmic drop depending on the FISH result. PMID- 23745365 TI - Comparison of micronuclei frequency in bone marrow cells of three rat lines. AB - The aim of this paper is to compare the spontaneous and induced with cyclophosphamide micronucleus indexes in bone marrow cells of the Sprague Dawley, Lewis and Wistar rat lines. Five experimental groups were formed (10 animals of each sex and of each line, in every group). The first group was used as the negative control (intact animals), the second one was exposed to oral administration of drugs; other conditions were the same as for the other groups. The third group was treated with 2% Tween 65 and the fourth group was treated with 0.9% NaCl. Both substances were administered by oral way to 2 ml/kg during 14 days. The fifth group was treated intraperitoneally with strong mutagen cyclophosphamide in the dose of 50 mg/kg (10 ml/kg in solution), on 48th and 24th hours before euthanasia. The Sprague Dawley line (both sexes) was significantly different from the other lines. Rats of this line had lower index of spontaneous formation of micronuclei, higher index of cyclophosphamide-induced micronucle formation, percent of micronucleated erythrocytes in bone marrow and the index of cytotoxicity. The results obtained make it possible to identify the most appropriate line of rats as model animals for studies of genotoxicity. It will allow also to obtain more accurate estimates of genotoxicity of various substances. PMID- 23745366 TI - The downregulation of the miniature gene does not replicate miniature loss-of function phenotypes in Drosophila melanogaster wing to the full extent. AB - During maturation Drosophila wing epithelial cells undergo number of changes due to processes, which take place in the wing of the newly emerged fly, among which epithelial-to-mesenchymal transition (EMT) and apoptosis are pivotal. It is considered that neurohormone bursicon is responsible for their triggering. In turn, extracellular matrix protein Miniature is also essential for proper progress of apoptosis and, presumably, EMT. In accordance with our previously proposed hypothesis, Miniature and bursicon form stabilizing/accumulative complexes, which are able to diffuse freely within Drosophila wing, in such a way constitutively promoting enough concentrations of the maturation triggering signal. Here we tried to come to confirmation of our hypothesis from the other side, using UAS/GAL4 system and RNAi-silencing techniques. PMID- 23745367 TI - "Health 2020"--new framework for health policy. Part I. AB - The paper presents the new framework for health policy adopted in September 2012 during the 62nd session of World Health Organization (WHO) Regional Committee for Europe as the strategy "Health 2020". Four priority areas for policy action as well as prerequisites for achieving two interlinked strategic objectives; improving health for all and reducing health inequalities as well as improving leadership and participatory governance for health are presented and discussed. PMID- 23745368 TI - Results of liver transplantation in the Department of General, Transplant and Liver Surgery at the Medical University of Warsaw in patients with chronic hepatitis B and C viruses infection. AB - INTRODUCTION: Cirrhosis related to hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is the most frequent indication for liver transplantation worldwide. Progress in prophylaxis of posttransplant HBV recurrence has led to major improvements in long-term outcomes of patients after liver transplantation. Conversely, impaired posttransplant survival of patients with HCV infection was reported in several studies, mainly due to recurrence of viral infection. The purpose of this study was to compare long-term results of liver transplantation between patients with HBV monoinfection, HCV monoinfection and HBV/HCV coinfection. MATERIAL AND METHODS: A total of 1090 liver transplantations were performed in the Department of General, Transplant and Liver Surgery in cooperation with the Department of Immunology, Internal Medicine, and Transplantology at the Transplantation Institute Medical University of Warsaw between December 1994 and May 2012. After exclusion of patients with cirrhosis of non-viral etiology, patients with malignant tumors, and patients with acute liver failure, the final study cohort comprised 209 patients with HBV (HBV+/HCV- subgroup; n = 56) or HCV (HBV-/HCV+ subgroup; n = 119) monoinfection or HBV/HCV coinfection (HBV+/HCV+; n = 34). These subgroups of patients were compared in terms of long-term results of transplantations, defined by 5-year patient and 5 year graft survival estimates. RESULTS: Overall and graft survival rates after 5 years for the whole study cohort were 74.5% and 72.6%, respectively. Five-year overall survival was 70.4% for patients within the HBV+/HCV- subgroup, 77.8% for patients within the HBV-/HCV+ subgroup, and 68.5% for patients within the HBV+/HCV+ subgroup. The corresponding rates of graft survival were 67.0%, 76.3%, and 68.5% for patients within the HBV+/HCV-, HBV-/ HCV+, and HBV+/HCV+ subgroups, respectively. Observed differences were non-significant, both in terms of overall (p = 0.472) and graft (p = 0.461) survival rates. CONCLUSIONS: Both overall and graft survival rates after liver transplantations performed in the Department of General, Transplant and Liver Surgery in cooperation with the Department of Immunology, Internal Medicine, and Transplantology at the Transplantation Institute Medical University of Warsaw in patients with HBV and HCV infection are comparable to those reported by other European and American centers. In contrast to other studies, obtained results do not confirm the negative impact of HCV infection on long-term outcomes of patients. PMID- 23745369 TI - Distribution of HCV genotypes in Poland. AB - Available data on prevalence of HCV genotypes in Poland are insufficient. The aim of the study was the analysis of distribution of HCV genotypes in Poland over the period of recent 10 years regarding the age of patients and the regions of the country. MATERIAL AND METHODS: Analysis of HCV genotypes in Poland was carried out between 2003 and 2012, and included 14 651 patients from 22 centers where patients with chronic viral hepatitis C are diagnosed and treated. Genotypes were analyzed in age groups (< 20 years of age, 20-40 years of age, > 40 years of age) as well as in populations of HBV and HIV co-infections. RESULTS: Genotype (G) 1 infection was demonstrated in 79.4%, G2 -0.1%, G3- 13.8%, G4- 4.9%, G6-0.09% and mixed infections in 1.6%. There was no infection with genotype 5. The highest prevalence of G1 was observed in the Lodzkie voivodship (89.2%) and the Slaskie voivodship (86.7%) while the lowest one in the Warminsko-mazurskie (62.0%) and the Podlaskie voivodships (68.2%). Genotype 3 most commonly occurs in the Warminsko-mazurskie (28.1%), and the Podlaskie voivodships (23.0%) and is least common in the Malopolskie (7.9%) and the Lodzkie voivodships (9.0%). Genotype 4 is more common in the Kujawsko-pomorskie (11.7%) and the Podlaskie voivodships (8.6%) and relatively less common in the Lubelskie (1.1%) and the Lodzkie voivodships (1.8%). Prevalence of G1 infection in 2003-2004 was 72% and increased up to 85.6% in 2011-2012, that was accompanied by decrease of G3 prevalence from 17% to 8% in this period. In HBV co-infected (n = 83), G1 infection was demonstrated in 85.5%, G3 - in 7.2%, G4 -4.8%, and mixed genotypes in 6%. Among HIV co-infected (n = 391), a much lower prevalence of G1 (33.0%) and a high of G3 (40.4%) as well as G4 (24.0%) were observed. CONCLUSIONS: There is a geographic variability of HCV genotypes prevalence in Poland. Increase of HCV G1 infections and decrease of G3 and G4 were observed in the last 10 years. Genotypes G3 and G4 occur more often in HCV/HIV co-infected than in HCV mono-infected patients. PMID- 23745370 TI - RSV respiratory infection in children under 5 y.o.--dynamics of the immune response Th1/Th2 and IgE. AB - INTRODUCTION: The imbalance of Th1/Th2 cytokine concentrations and increased level of IgE might be useful tool for prediction of severity of RSV infection among young children and possibility of sequels. The ratio of cytokines Th1/Th2 varied during the disease. THE AIM of our studies was the assessment of immunological response by dynamics of Th1 and Th2 cytokines and IgE in RSV infections. MATERIAL AND METHODS: Study was done on sera collected from 36 young children hospitalized because of RSV infection and from 16 children with other respiratory tract infection (HMPV, EV, HPIV1-3). Assaying of the serum levels of cytokine Th1 (IL-2, IFN-g, TNF), Th2 (IL-4, IL-6, IL-10) and concentration of IgE has been done. Paired sera (48 patients) were collected in the interval 4-14 days. Reference group consist of 18 children (< 6 months of life) hospitalised because other than respiratory diseases with negative results for viruses tested by PCR. RESULTS: Among children with respiratory infection the Th1/Th2 ratio was shifted towards Th2, level of IgE increased in comparison to the reference group. Changes in concentration of IL-6, IFN-g, IL-10 were related to RSV infection, mainly bronchitis and bronchiolitis, while the dynamic of TNF concentration was independent on aetiological agent. It was found that the risk factors (prematurity, artificial nutrition) correlated with RSV bronchitis and the levels of cytokines and IgE. Increased level of IL-6 and IL-10 were shown in prematures, and increased concentration of IgE--among artificial nourished children. The time of serum collection affected the level of cytokines and IgE and the effect was depended on the aetiological agent. In RSV infections was observed significant decrease with time of IL-6, IL-10 and IFN-gamma but not IgE (still significantly higher than in the reference group). While the significant decrease of IgE was determined only in other than RSV infections. CONCLUSIONS: Determined level of cytokines and IgE varied depending on the time of serum collection. Observed dynamics in paired sera and IgE might have prognostic value in disease and sequels of RSV infections. Prevention RSV infection in premature infants should be done in any possible way. Breastfeeding is one of the critical elements of prevention of RSV infection. PMID- 23745371 TI - Tuberculoma of the central nervous system--a case report. AB - Tuberculoma of the brain is a rare form of central nervous system (CNS) tuberculosis with non-specific clinical manifestation. Due to its similarity with many other infectious and non-infectious lesions, diagnosis is difficult. The study presents the case of a patient who developed CNS tuberculoma during the course of tuberculous meningitis. PMID- 23745372 TI - Prevalence of Toxoplasma gondii parasite infection among people who died due to sudden death in the capital city of Warsaw and its vicinity. AB - BACKGROUND: It has recently been shown that the behavioural effects resulting from latent T. gondii infection in immunocompetent people could pose as a threat to their welfare. AIM. The aim of the study was to evaluate the prevalence of T. gondii infection in a group of people who died suddenly in Warsaw and its vicinity. MATERIAL AND METHODS: The studied group (n = 169 people) included 42 road traffic accident victims who were driving a vehicle (bicycle (n = 6), a motorbike (n = 3), a motorcycle (n = 13), a car (n = 20)) prior to sudden death and 41 people whose death resulted from suicide. Blood samples were collected post-mortem and examined for the presence of T. gondii, IgG antibodies and ethyl alcohol. RESULTS: Of the 169 people tested, T. gondii IgG antibodies were found in the serum of 93 (55%) of which 25 (59.5%) were drivers and 26 (63.4%) people who died as a result of suicide. With respect to the prevalence of T. gondii infection no statistically significant differences were found between the study (61.4%) and control group (49.4%); (p = 0.09). A statistically significant result was recorded in the 38-58 age group between suicide and control groups (71.4% vs. 44.4%; p < 0.05). Positive test results for the presence of ethyl alcohol in the blood were reported among 49.7% of the studied population: 25.7% among drivers, 67.6% among suicides and 51.8% in the control group. To a statisctically siginificant degree, IgG T. gondii antibodies were found to occur more frequently in people with positive blood alcohol test results among suicides (72% vs. 50%; p < 0.05) and among the control group (60% vs. 40%; p < 0.05) than in their equivalents with negative test results. CONCLUSIONS: Our work confirmed the usefulness of serologically testing samples collected post-mortem for epidemiological purposes. The small size of the study group made it impossible to evaluate the potential associations between exposure to T. gondii infection and the probability of sudden death. The significance of Toxoplasma gondii infection as a risk factor for self-destructive behaviour merits further study. PMID- 23745373 TI - The role of PCR in diagnostics of Lyme borreliosis. AB - Molecular biology techniques play a significant role in diagnostics of many infectious diseases. Polymerase chain reaction (PCR) is used to confirm tick borne diseases e.g. Borrelia burgdorferi infection. Extension of PCR method in laboratory diagnostics of Lyme disease (LD) gives a possibility of confirmation of spirochete infection before patient body managed to produce antibodies. Diversity of material, which may be tested (blood, cerebrospinal fluid, skin biopsies, synovial fluid) and possibility of using several conservative genes for Borrelia genospecies additionally widen a diagnostic utility of PCR tests. Though high divergence of PCR results obtained in various laboratories is still a significant issue. Hence, standardization of molecular diagnostic in LD is so important. PMID- 23745374 TI - Recurrent meningitis--a review of current literature. AB - The paper discusses epidemiology, aetiology and the most important predisposing factors associated with recurrent meningitis, as well as the possibilities to prevent this particularly challenging clinical problem. The frequency of recurrent meningitis is estimated to be 2-9%. However, the case fatality is lower compared to a single episode of meningitis. The main causes of recurrent meningitis are considered to be: head injury, congenital or acquired (post traumatic or post-surgical) cranial or spinal defects, chronic intracranial inflammation, complement system dysfunction, as well as congenital and acquired humoral or cellular immunodeficiency. PMID- 23745375 TI - Trichomoniasis--an important cofactor of human immunodeficiency virus infection. AB - Trichomonas (T.) vaginalis is the most common non-viral sexually transmitted infection worldwide. The estimated number of new T. vaginalis infections accounts for 276.4 million cases globally. The pathogen induces local inflammation of the lower genitourinary tract, can be involved in premature labour, low birth weight and facilitates HIV-1 transmission via sexual intercourse. In the paper, we present basic epidemiological data on T. vaginalis infection, biologic mechanisms by which the pathogen enhances HIV-1 acquisition, principles of modern diagnosis and treatment of the infection. PMID- 23745376 TI - Looking for the new preparations for antibacterial therapy. II. Clinical trials; new beta-lactam antibiotics and beta-lactamase inhibitors. AB - To obtain a status of a medicinal product, a compound possessing potential antimicrobial activity and displaying no cytotoxicity, must undergo three phases of clinical trials to prove its therapeutic efficacy, safety and quality. Properties of the compound should be based on the results of studies meeting specific criteria. Studies should be: randomized, double-blind, involving sufficient number of volunteers, concerning the infections localized in strictly defined area and caused by identified microorganisms. After the medicinal product is authorized to be on the market, clinical trials of the fourth phase are carried out to detect adverse effects, overdose symptoms, interactions of the new drug with other medicinal products and to establish characteristic of activity among groups such as children, elderly, women in pregnancy and patients suffering from other diseases, but only if the benefits of receiving treatment outweigh the risks. This article is a second part of the series associated with searching for new antibacterial agents and it relates to performance of clinical trials and the new compounds belonging to the class of beta-lactams. Among the 9 presented compounds, candidates to become medicinal products, two belong to the cephalosporins (CXA-101, S-649266), one to carbapenems (razupenem), three to monobactams (BAL30072, BAL30376, MC-1) and three to beta-lactamase inhibitors (NXL-104, MK-7655, ME1071). PMID- 23745377 TI - Fall related hospital admissions among seniors in Poland in 2010. AB - BACKGROUND: Falls among elderly people causing hospitalization are considered one of the most important public health problems. Our objective was to analyse fall related hospital admissions among seniors (> or = 65 years old) in Poland in 2010. The analyses were conducted with regard to gender, place of residence and age. Additionally, the health consequences of falls among elderly people were studied. Injuries and other consequences of external causes, were expressed in the form of three-character ICD-10 codes representing the underlying disease (S00 T98). METHODS: Data on hospital admissions resulting from falls among seniors were obtained from the database held at the Department - Centre for Monitoring and Analyses of Population Health Status and Health Care System by the National Institute of Public Health - National Institute of Hygiene. RESULTS: Analysis has shown that the hospitalization ratio due to falls is much higher for women than for men. On average, 1 024 per 100 000 women are hospitalized due to a fall, while the number for men is 649. For every analysed age group women are at a higher risk of hospitalization due to a fall than men. In 2010 nearly 70% of hospital admissions of elderly people due to a fall were caused by a fall on the same level as a result of tripping or slipping (31 712 hospitalizations). No differences in relation to gender were observed. Risk of hospitalization due to a fall increases with age. For people over 80 years of age it is 2.5 times higher than for people in the 65-69 age group (1 459 and 570 per 100 000 respectively). It was observed that the length of hospital stay increases with age. There were no significant differences between the number of hospitalizations depending on the place of residence. The analysis showed that differences in the length of stay for women and men are statistically significant. However, there was no statistically significant difference between the lengths of stay depending on a place of residence. Almost one-third of hospitalizations (31.4%) resulted from femur fracture (14 356 hospitalizations). Women are more likely to suffer from a femur fracture. CONCLUSIONS: A comparison of results of research conducted, among other countries, in the United States, The Netherlands, and Denmark, as well as Polish demographic prognosis, has shown that an increase of fall related hospital admissions among senior citizens is to be expected in Poland in oncoming years. PMID- 23745378 TI - Associations and foundations in the field of health care and their role in the health system of Poland. AB - The article presents data on associations and foundations active in health care field in Poland, on the basis of a review of research done by Klon/Jawor Association and the Central Statistical Office. The article also applies to the issue of cooperation between NGOs and governmental adminstration in the health area and identifies lacking information that is necessary for better planning of national health policy. In Poland there are about three thousand associations and foundations whose main focus is the health care. In 2010, they accounted for about 7% of all non-governmental organizations. Results of representative nationwide surveys from 2008 and 2010 indicate that the NGO's active in the field of health care have, in most cases, legal form of associations. Almost half of the organizations declared national or international scope of action. Headquarters of most organizations were mainly in the cities, and only, one in twenty in the village. Most organizations were located in the mazowieckie province and a significant fraction of them was in Warsaw itself. Organizations were stood out by a relatively large number of personnel on the background of the entire NGO sector. Half of the organizations employed paid workers, the majority also collaborated with volunteers who were not members of the organization. More than a third of organizations dealt with the rehabilitation, therapy and long term care, and about 1/3 dealt with prevention, health promotion and education, and blood donations. World Health Organization indicates the need for systematic collection of data about the role of the nongovernmental sector in health. In Poland, legal regulations require the public institutions and organizations to cooperate with NGOs to achieve health objectives. In spite of relevant data on NGOs in the field of health care in Poland, the necessary information to assess their potential are still lacking. Recognition of the capacity and limitations ofNGOs could enable better planning of national health policy. PMID- 23745379 TI - The role of non-governmental organizations in the social and the health system. AB - The article presents the definitions, objectives, fields and tasks of non governmental organizations in social life, health system and health policy. In addition, the article addresses the issue of effectiveness and quality of NGOs' activity. The term "NGOs" (Non-governmental Organizations) includes different categories of entities that operate not to obtain financial gain, and also do not belong to the government sector. Non-governmental Organizations' fields of activity were described in the International Classification of Non-Profit Organizations (ICNPO). NGOs are an integral part of a democratic society. Sociological sciences emphasize their importance in enhancing social integration, implementation of the principle of subsidiarity, building civil society, social dialogue and participatory democracy. The main tasks of NGOs in the health system are providing services and health advocacy. Provision of services includes medical, social and psychological services as well as, integration activities, care and nursing, material and financial support, educational and information services and training. Health advocacy is a combination of individual and social actions designed to gain political commitment, policy support, social acceptance and systems support for a particular health goal or program. An important task carried out by NGOs is participation in the formation of health policy. The increasing role of NGOs in providing social services and the participation in political processes, result in the need to confirm the validity and credibility of their operation. One of the ways could be to introduce the mechanisms to assess quality and efficiency, such as registration as a part of a legal system, self-regulatory activities (card rules, codes of ethics), certification, participation in networks, monitoring and audit. PMID- 23745380 TI - How much is the cost of multiple sclerosis--systematic literature review. AB - In Poland, a data on MS costs is lacking. AIM: The systematic review of cost of illness studies was conducted to estimate the average annual cost of MS patient and its breakdown. MATERIAL AND METHODS: The PubMed database was searched for relevant literature. Following search criteria were used: "multiple sclerosis", "costs", "cost of illness" and "disease burden". Articles written in English including total costs published 2002-2012 were included. In total 17 studies were classified. The costs were re-calculated into USD Purchasing Power Parity (PPP). The available approach from the literature was used for the cost breakdown presentation. RESULTS: The average patient was 47 years old with EDSS equals 4 and 13 years from the date of diagnosis. The average annual cost was 41 133 US$ PPP. The direct costs did not exceed 70% of total costs in any study. The pharmaceutical expenses were one of the most important contributors to the direct costs. Only 40% of patients were active on the labor market what translated into the loss of productivity and consequently an increase in total costs. CONCLUSIONS: The preformed systematic review revealed that multiple sclerosis imposes a huge economic burden on the healthcare system and society. It happens due to productivity loss and caregiver burden. PMID- 23745381 TI - Brief comment on publication "First chemical mass attack in history of wars, Bolimow, January 31, 1915". PMID- 23745382 TI - [Estimation of PM2.5 over eastern China from MODIS aerosol optical depth using the back propagation neural network]. AB - With the fast economic development in China in recent years, air pollutions are becoming increasingly serious. It is, therefore, imperative to develop new technology to solve this issue. Due to the wide spatial coverage of satellite remote sensing, along with the relatively lower cost compared to ground-based in situ aerosol measurements, satellite retrieved aerosol optical depth (AOD) is widely recognized as a good surrogate of surface PM2.5 concentrations. In this study, two years (2007-2008) of AOD data from moderate resolution imaging spectroradiometer (MODIS) onboard Terra at five observational sites of China (Benxi, Zhengzhou, Lushan, Nanning, Guilin), combined with five meteorological factors such as wind speed, wind direction, temperature humidity and planetary boundary height, were used as important input to establish the Back Propagation (BP) neural networks model, which was applied to estimate PM2.5. Afterwards, the model estimated PM2.5 was validated by in situ PM2.5 measurements from the five sites. Specially, scatter analysis showed that the linear correlation coefficient (R) between ground PM2.5 observation and model estimated PM2.5 at Lushan was the highest (R = 0.6), whereas the R values at the four other sites were lower, ranging from 0.43 to 0.49. Time series validations were performed as well, indicating that the R value significantly varied from day to day. However, the R value could be significantly improved by fitting the five-day moving average ground observation values against the model estimated PM2.5 data. Also, the R value at Lushan was the highest (R = 0.83), suggesting that MODIS AOD can be used to monitor PM2.5 by the BP networks model developed in this study. PMID- 23745383 TI - [Comparison of atmospheric particulate matter and aerosol optical depth in Beijing City]. AB - The pollution of particulate matter was serious in Beijing City from the synchronous observation of particulate matter mass concentration and aerosol optical characteristics in 2009. The annual mean concentrations of PM2.5 and PM10 were (65 +/- 14) microg x m(-3) and (117 +/- 31) microg x m(-3), respectively, which exceeded the national ambient air quality annual standards to be implemented in 2016. There were 35% and 26% days of 2009 that the daily standards were exceeded. There was a significant correlation between fine particulate (PM2.5) and inhalable particle (PM10), with a correlation coefficient (R) of approximately 0.90 (P < 0.001). PM10 contained a large percentage of PM2.5, with an annual percentage of about 61%. The percentage became much higher from spring to winter, while the correlation between PM2.5 and PM10 became much stronger. The annual mean of AOD (500 nm) and Angstrom exponent were (0.55 +/- 0.1) and (1.12 +/- 0.08), respectively. There were significant correlations between PM2.5, PM10 and AOD in the four seasons and the whole year, and the correlation coefficients were greater than or equal to 0.50. Furthermore, the correlation functions and coefficients had seasonal variations. The correlations were more significant in summer and autumn than in spring and winter. The annual correlation could cover up the seasonal systematic differences. The correlations between AOD revised by Mixed Layer Height and PM2.5 PM10 revised by Relative Humidity became stronger, and the exponential correlations were superior to the linear correlations. PMID- 23745384 TI - [Impacts of meteorological factors on atmospheric methane mole fractions in the background area of Yangtze River delta]. AB - Impacts of surface wind direction, surface wind speed, surface air temperature and sunshine hours on the CH4 concentration at Lin'an regional atmospheric background station were studied based on the results from Jan. 2009 to Dec. 2011. The results revealed that the diurnal variation of atmospheric CH4 concentration presented a single-peak curve at Lin'an regional background station. The diurnal amplitude varied from 19.0 x 10(-9) to 74.7 x 10(-9), with the lowest value observed in the afternoon and the highest at dawn. The monthly mean CH4 concentrations varied from 1955.7 x 10(-9) to 2036.2 x 10(-9), with the highest concentration observed in autumn and the lowest in spring. The wind directions NE SSE could induce higher CH4 concentrations while SW-NNW wind directions had negative effects on the observed results. The CH4 concentration turned out to be lower with higher surface wind speed. With the increase of surface air temperature or sunshine hours, the CH4 concentration went up first till reaching a peak, and then decreased. PMID- 23745385 TI - [Dispersion and analysis of odor pollution in landfill area under the enclosed operation condition]. AB - Odor pollution of landfill site is a serious problem accompanied with the urbanization process that influences city life. Generally, odor emission points in landfill boundary are detected by experience, but the pollution intensity, distribution and variation in the scope of landfill boundary are difficulty to describe. In this research, odor emission points were disclosed with equal odor concentration curves that were delineated using electric nose and GPS instrument. The leakage of landfill gas and exhaust emission from biogas incineration torch was the main cause of the odor pollution in landfill area. Gas production evaluation suggested that the improvement of landfill gas consumption is the key point to control the odor pollution at the landfill site. PMID- 23745386 TI - [Distribution characteristics and sea-air fluxes of volatile halocarbons in the East China Sea in winter]. AB - Volatile halocarbons (VHCs) are important greenhouse gases, which play significant roles in the global warming and the chemistry of the atmosphere. The concentrations of four kinds of volatile halocarbons including CHCl3, C2 HCl3, C2 Cl4 and CHBr3 in seawater were determined by Purge and Trap-Chromatography in the East China Sea during the period of 23 December 2009-5 January 2010, and the sources of the VHCs were studied. The result showed that the means (ranges) of the CHCl3, C2 HCl3, C2 Cl4 and CHBr3 concentrations in the surface waters were 23.04 (6.04-107.81), 18.81 (10.67-32.35), 3.72 (0.39-9.77) and 24.33 (13.44 33.01) pmol x L(-1), respectively. The concentrations of VHCs near shore were higher than those in the open sea. In the PN section the vertical distribution of VHCs had a common feature that the maxima appeared in the upper mixed layer. The distributions of the four kinds of VHCs were significantly influenced by the Yangtze River effluent, the Kuroshio water and biological activities. A marked positive correlation between the C2 HCl3 and C2Cl4 concentrations was observed in the surface waters, suggesting that they might have some common sources. Besides, a positive correlation was found between chlorophyll a (Chl-a) and CHBr3 concentrations in the surface seawater, indicating that phytoplankton biomass might play an important role in the distribution of CHBr3 in the study area. Our data indicated that the entire ECS shelf acted as a source for atmospheric CHCl3, C2 HCl3 and CHBr3 during the study period. PMID- 23745387 TI - [Intra- and inter-annual variabilities of particulate organic matter in the Mirs Bay from 2000 to 2010]. AB - Based on the data obtained from monthly cruises from 2000 to 2010, temporal and spatial distributions of the particulate organic matter (POM) in the Mirs Bay were briefly presented and discussed. The POM composition and residence time were approached by combining with the chlorophyll a (Chl-a) measurements. It has been shown that the hydrodynamics in the Mirs Bay only pose a weak impact on the POM distributions. The POM concentration was (1.1 +/- 0.8) mg x L(-1), which was not much different from those in both the Pearl River Estuary and the Daya Bay, but higher than that in the northern South China Sea. A notably positive correlation was found between the POM and Chl-a in the surface-water. The ratio of the phytoplankton POM (PPOM): Chl-a was about 70 g x g(-1), based on which the PPOM concentration was calculated to be (0.31 +/- 0.39) mg x L(-1), accounting for about 28% of the POM. The primary productivity (PP) and integrated POM (IPOM) were used for estimating the POM residence time, which was found to be about 6.5 days in the Mirs Bay, close to that for POC in the coastal continental shelf waters in the southern East China Sea. During the 11-year investigation, the PP inter-annual variability showed a decreasing trend, but both the POM and IPOM underwent a trend of increase, which suggested that the refractory detritus POM had been gradually acumulated in the Mirs Bay. PMID- 23745388 TI - [Phytoplankton assemblages and their relation to environmental factors by multivariate statistic analysis in Bohai Bay]. AB - A detailed field survey of hydrological, chemical and biological resources was conducted in the Bohai Bay in spring and summer 2007. The distributions of phytoplankton and their relations to environmental factors were investigated with multivariate analysis techniques. Totally 17 and 23 taxa were identified in spring and summer, respectively. The abundance of phytoplankton in spring was 115 x 10(4) cells x m(-3), which was significantly higher than that in summer (3.1 x 10(4) cells x m(-3)). Characteristics of phytoplankton assemblages in the two seasons were identified using principal component analysis (PCA), while redundancy analysis (RDA) was used to examine the environmental variables that may explain the patterns of variation of the phytoplankton community. Based on PCA results, in the spring, the phytoplankton was mainly distributed in the center and northern water zone, where the nitrate nitrogen concentration was higher. However, in summer, phytoplankton was found distributed in all zones of Bohai Bay, while the dominant species was mainly distributed in the estuary. RDA indicated that the key environmental factors that influenced phytoplankton assemblages in the spring were nitrate nitrogen (NO3(-) -N), nitrite nitrogen (NO2(-) -N) and soluble reactive phosphorus (SRP), while ammonium nitrogen (NH4(+) -N) and water temperature (WT) played key roles in summer. PMID- 23745389 TI - [Characteristics and evolution of hydrochemical compositions of freshwater lake in Tibetan plateau]. AB - Freshwater lake of the Tibetan plateau has great ecological value and extreme vulnerability. The water samples have been collected in Daggyaima Co at an altitude of 5 080 m +/- 10 m. This study has investigated the sources, the major controlling factors of the major ions, and hydrochemical evolution trend according to the hydrochemical composition of water samples. The results showed that the major cations and anion of lake water were Ca(2+), Na(+) and HCO3(-), respectively, and the hydrochemical type was HCO3 -Ca, The total dissolved solid (TDS) was in the range of 71.2-199.8 mg x L(-1). The concentrations of EC, Ca(2+) and HCO3(-) in water samples from Southeast areas were relatively low resulted from the rich aluminum and poor calcium of geological background and the dilution effect of surface runoff. The Na(+)/(Na(+) + Ca(2+)) of water samples was 0.08 0.75, Cl(-) /(Cl(-) + HCO3(-)) was 0.11-0.35, Ca/Na was 0.58, Mg/Ca was 0.12, and HCO3/Na was 1.46, which suggested that the hydrochemical composition of the lake water was mainly controlled by silicate rock weathering based on Gibbs model and analysis of elemental stoichiometry. The minerals participated in weathering processes included plagioclase (anorthite, albite), potassium feldspar, biotite, calcite, dolomite, gypsum, rock salt, etc. The average value of K/Na was 0.059, indicating the weathering level of potassium feldspar was relatively low. The saturation index (SI) of calcite, dolomite, gypsum, quartz and hematite contained in the lake was higher than zero, while the SI of rock salt was lower than 0, revealing the trend that the freshwater lake is turning into salt water lake in Tibetan Plateau. PMID- 23745390 TI - [Estimation of nonpoint source pollutant loads and optimization of the best management practices (BMPs) in the Zhangweinan River basin]. AB - One of the key techniques in establishing and implementing TMDL (total maximum daily load) is to utilize hydrological model to quantify non-point source pollutant loads, establish BMPs scenarios, reduce non-point source pollutant loads. Non-point source pollutant loads under different years (wet, normal and dry year) were estimated by using SWAT model in the Zhangweinan River basin, spatial distribution characteristics of non-point source pollutant loads were analyzed on the basis of the simulation result. During wet years, total nitrogen (TN) and total phosphorus (TP) accounted for 0.07% and 27.24% of the total non point source pollutant loads, respectively. Spatially, agricultural and residential land with steep slope are the regions that contribute more non-point source pollutant loads in the basin. Compared to non-point source pollutant loads with those during the baseline period, 47 BMPs scenarios were set to simulate the reduction efficiency of different BMPs scenarios for 5 kinds of pollutants (organic nitrogen, organic phosphorus, nitrate nitrogen, dissolved phosphorus and mineral phosphorus) in 8 prior controlled subbasins. Constructing vegetation type ditch was optimized as the best measure to reduce TN and TP by comparing cost effective relationship among different BMPs scenarios, and the costs of unit pollutant reduction are 16.11-151.28 yuan x kg(-1) for TN, and 100-862.77 yuan x kg(-1) for TP, which is the most cost-effective measure among the 47 BMPs scenarios. The results could provide a scientific basis and technical support for environmental protection and sustainable utilization of water resources in the Zhangweinan River basin. PMID- 23745391 TI - [An object-oriented intelligent engineering design approach for lake pollution control]. AB - Regarding the shortage and deficiency of traditional lake pollution control engineering techniques, a new lake pollution control engineering approach was proposed in this study, based on object-oriented intelligent design (OOID) from the perspective of intelligence. It can provide a new methodology and framework for effectively controlling lake pollution and improving water quality. The differences between the traditional engineering techniques and the OOID approach were compared. The key points for OOID were described as object perspective, cause and effect foundation, set points into surface, and temporal and spatial optimization. The blue algae control in lake was taken as an example in this study. The effect of algae control and water quality improvement were analyzed in details from the perspective of object-oriented intelligent design based on two engineering techniques (vertical hydrodynamic mixer and pumping algaecide recharge). The modeling results showed that the traditional engineering design paradigm cannot provide scientific and effective guidance for engineering design and decision-making regarding lake pollution. Intelligent design approach is based on the object perspective and quantitative causal analysis in this case. This approach identified that the efficiency of mixers was much higher than pumps in achieving the goal of low to moderate water quality improvement. However, when the objective of water quality exceeded a certain value (such as the control objective of peak Chla concentration exceeded 100 microg x L(-1) in this experimental water), the mixer cannot achieve this goal. The pump technique can achieve the goal but with higher cost. The efficiency of combining the two techniques was higher than using one of the two techniques alone. Moreover, the quantitative scale control of the two engineering techniques has a significant impact on the actual project benefits and costs. PMID- 23745392 TI - [Contribution of plant litters to sediments organic matter in Jiulong river estuary wetland]. AB - The purpose of this study was to characterize the decomposition process of different plant litters and its controlling factors, and to quantify the different contribution rates to sediments organic matter throughout the decomposition of different plant litters. Results showed that the decomposition rates of plant litters buried at medium tidal level were 0.655 a(-1) for mangrove and 1.723 a(-1) for Spartina, which were greater than those with 0.651 a(-1) for mangrove and 1.586 a(-1) for Spartina at high tidal level. The reduction of carbon concentration in plant litters at high tidal level was lower than that at medium tidal level, while the increment of nitrogen and sulfur concentrations in plant litters at high tidal level was greater than those at medium tidal. And the isotope abundance of carbon (delta13C) in plant litters at medium tidal level reduced much more significantly than that at high tidal level. The contribution rates of plant litters carbon to sediments organic matter differed among tidal levels, plant species and decomposition duration. Specifically, the decomposition of mangrove litters contributed 5.96% to the sediment organic matter at medium tidal level, which was greater than that (3.03%) at high tidal level. Similarly, the decomposition of Spartina litters contributed 14.81% to the sediment organic matter at medium tidal level, which was also greater than that (13.97%) at high tidal level. The contribution of the decomposition of Spartina litters organic matter (average with 14.39%) was greater than that of mangrove litters (4.50%). The decomposition of plant litters requires a long process. The contribution of plant litters to sediments organic matter throughout one year decomposition was lower than that in complete decomposition, in particular, mangrove litters. Our study showed that the quantitative differences in plant litters-derived sediment organic matter would improve the proper estimation of the contribution of litters to wetland organic matter. PMID- 23745393 TI - [Application of tiered approach to assess the impact of backfilling remediated soil on groundwater]. AB - The tiered approach for assessing the impact of backfilling treated contaminated soil on groundwater was presented in details with a case study. The soil was contaminated by 1,2-dicholorenthane and 9 other organic pollutants and had been remediated before backfilling to meet the pre-set remediation goals based on health risk assessment. The results from tiered I assessment indicate that the concentrations of 8 contaminants in the leachate of the backfilling soil layer would exceed the assessment standards probably leading to groundwater contamination. However, the results from tiered II assessment, in which the adsorption and retardation of vadose zone soil was taken into account and the concentrations of pollutants reaching the groundwater table were predicated, reveal that only the concentrations of 6 contaminants would exceed the assessment standards. Further, taking the dilution and mixing of the groundwater into consideration, tiered III assessment was adopted and the results reveal that only 4 contaminants were beyond the standards. Finally, tiered IV assessment, aiming at predicting the concentration at the target well downstream, was carried out by considering the retardation of contaminants in saturated layer, and the results indicate only 1 pollutant was above the assessment standard. Therefore, it can be seen that the predicted concentrations of the target pollutants at advanced assessment levels will be closer to those at the target drinking water well and the amount of contaminants whose initially-set remediation goals need to be modified will decrease correspondingly, indicating the reduction in pollution prevention cost, although more efforts should be made and more field data should be collected to implement the advance assessment level. PMID- 23745394 TI - [Removal of nitrate from groundwater using permeable reactive barrier]. AB - To provide a cost-effective method for the remediation of nitrate-polluted groundwater, column experiments were performed to study the removal of nitrate by permeable reactive barrier filled with fermented mulch and sand (biowall), and the mechanisms and influence factors were explored. The experimental results showed that the environmental condition in the simulated biowall became highly reduced after three days of operation (oxidation-reduction potential was below - 100 mV), which was favorable for the reduction of nitrate. During the 15 days of operation, the removal rate of nitrate nitrogen (NO3(-) -N) by the simulated biowall was 80%-90% (NO3(-)-N was reduced from 20 mg x L(-1) in the inlet water to 1.6 mg x L(-1) in the outlet water); the concentration of nitrite nitrogen (NO2(-) -N) in the outlet water was below 2.5 mg x L(-1); the concentration of ammonium nitrogen (NH4(+) -N) was low in the first two days but increased to about 12 mg x L(-1) since day three. The major mechanisms involved in the removal of nitrate nitrogen were adsorption and biodegradation. When increasing the water flow velocity in the simulated biowall, the removal rate of NO3(-) -N was reduced and the concentration of NH4(+) -N in the outlet water was significantly reduced. A simulated zeolite wall was set up following the simulated biowall and 98% of the NH4(+) -N could be removed from the water. PMID- 23745395 TI - [Research on pollution load of sediments in storm sewer in Beijing district]. AB - Based on the investigation of sewer sediments in Xi Cheng district in Beijing, scour-release pollution load in one rainfall from sewer sediments was studied by monitoring the pollutants in the run-off of manhole's section. It was shown that the contribution of scour-release pollutants from sewer sediments to sewer outflow was obvious. The contribution rate of the sediments pollution load to runoff outflow in the 84 m pipeline in one rainfall (9 Jul., 2010) was as follows: TN 8.5%, TP 8.2%, COD 18.3%, SS 7.7%, respectively. And the pollutant contribution rate in the 295 m pipeline in another rainfall (4 Aug., 2010) was TN 23.12%, TP 60.01%, COD 33.78%, SS 31.89%. Therefore, it is important to control the pollution from sewer sediments for the improvement of water environment. PMID- 23745396 TI - [Occurrence and risk assessment of five selected PPCPs in municipal wastewater treatment plant and the receiving water]. AB - Five PPCPs, including clofibric acid (CA), diclofenac (DFC), ibuprofen (IBP), ketoprofen (KEP), and naproxen (NPX) were selected as target compounds to investigate their occurrence and removal efficiency in a wastewater treatment plant (WWTP) of Shanghai. Furthermore, their distribution and potential toxicological risk in the WWTP receiving river water were investigated. The results showed that all targets were detected in WWTP influent, suggesting that domestic sewage discharge is an important source of PPCPs to the WWTP. Lower removal efficiency of these PPCPs was found in the WWTP and the main mechanism of elimination was biodegradation. The pattern of five selected PPCPs in the river was similar to that in WWTP effluent, indicating that WWTP effluent was a main source of PPCPs to the receiving water. Risk assessment showed that diclofenac posed a high risk, while ketoprofen, naproxen, clofibric acid and ibuprofen showed low risks to biota in the receiving river. PMID- 23745397 TI - [Microbial risk assessment of urban water bodies for aesthetical and recreational uses]. AB - With the increasing public access to urban water bodies for aesthetical and recreational purposes, it is of critical importance for densely populated urban areas to conduct microbial risk assessment and accordingly implement effective risk management. Based on the methodology of quantitative microbial risk assessment, a case study was conducted on three typical urban water bodies for aesthetical and recreational uses in a southern city in China. Exposure assessment was carried out through water quality monitoring, field survey and literature review, and accordingly human health risk was assessed with different dose-response equations based on fecal coliforms (FC), Escherichia coli (EC) and Enterococci (ENT). Microbial risk estimated by different dose-response equations was found consistent with and comparable to each other. Stream B located in a residential area was not suitable for primary- or secondary-contact recreational uses, and its microbial risk to the public mainly came from water abstraction for household miscellaneous uses. Stream C and Lake E, located in a public open space and a scenic area respectively, could meet the current recreational requirements, and their microbial risk to the public was generally attributed to various recreational activities. It was necessary to address the public health risk associated with the unauthorized or inappropriate water uses (e.g. abstraction for household miscellaneous uses) of urban aesthetical and recreational water bodies. PMID- 23745398 TI - [Study on removal of di-(2-ethylhcxyl) phthalate by using of small-scale biological aerated filter]. AB - Ceramsite medium biological aerated filter (BAF) was used to treat the sewage containing di-(2-ethylhcxyl) phthalate (DEHP). The treatment efficiency under different empty bed contact time (EBCT) and temperatures was investigated and the major intermediate products of biodegradation of DEHP were analyzed via GC-MS. Results show that the removal rate of DEHP can be highly achieved at 90.3% under the conditions of 25 degrees C and 8 hours of empty bed contact time. The removal efficiency will be increased after raising temperature or EBCT. The EBCT plays the main role between two influencing factors. The biodegradation of DEHP in BAF is expressed in the first-order kinetics. The major intermediate products of biodegradation of DEHP are made up of mono-2-ethylhexyl phthalate( MEHP), bisethylhexyl phthalate (BEHP), dibutyl phthalate (DBP), dimethyl phthalate (DMP) and phthalic acid (PA). It is supposed that the possible pathway of the biodegradation of di-(2-ethylhcxyl) phthalate is that the long alkyl side-chain of DEHP may be cleavaged into a shorter and more straight one, then PA is formed after cleavaging the two ester bonds, and finally being oxidized into CO2 and H2O. PMID- 23745399 TI - [Mechanism of membrane fouling and filtration characteristics in a membrane bioreactor for industrial wastewater treatment]. AB - The influence of mixed liquor suspended solids (MLSS), soluble microbial product (SMP), extracellular polymeric substance (EPS), colloidal particles and other factors contributed to membrane fouling was analyzed in this pilot test by membrane bioreactor (MBR) process for the leather printing and dyeing industrial park mixed wastewater treatment. The results showed that slight membrane fouling occurred after 120-day experiment with an observable increase in membrane resistance R20 from 1.5 x 10(12) m(-1) to 1.8 x 10(12) m(-1). Also, a linear correlation was found between the proportion of colloidal particles concentration in TOC of MBR former solution and membrane filtration resistance change. However, the change of MLSS, SMP, EPS and other factors was not correlated with the membrane filtration resistance change. Therefore, the colloidal particle was considered to be the main factor causing membrane fouling, which attached to the membrane surface and deposited to block the membrane pore. PMID- 23745400 TI - [Enhanced electro-chemical oxidation of Acid Red 3R solution with phosphotungstic acid supported on gamma-Al2O3]. AB - Supported phosphotungstic acid catalysts on gamma-Al2O3 (HPW/gamma-Al2O3) were prepared by solution impregnation and characterized by FTIR, XRD, TG-DTA and SEM. The heteropolyanion shows a Keggin structure. Electro-chemical oxidation of Acid Red 3R was investigated in the presence of HPW supported on gamma-Al2O3 as packing materials in the reactor. The results show that HPW/gamma-Al2O3 has a good catalytic activity for decolorization of Acid Red 3R. When HPW loading was 4.6%, pH value of Acid Red 3R was 3, the voltage was 25.0 V, air-flow was 0.04 m3 x h(-1), and electrode span was 3.0 cm, the decolorization efficiency of Acid Red 3R can reach 97.6%. The removal rate of color had still about 80% in this electro chemical oxidation system, after HPW/gamma-Al2O3 was used for 10 times, but active component loss existed. The interim product was analyzed by means of Vis UV absorption spectrum. It shows that the conjugated structure of dye is destroyed primarily. PMID- 23745401 TI - [Degradation kinetics of activated carbon catalyzed persulfate oxidation orange G]. AB - The oxidation degradation of orange G (OG) in aqueous solutions by the activated carbon catalyzed peroxydisulfate (PDS) has been kinetically investigated. These processes are based on the generation of sulfate radicals, which are powerful oxidizing species found in nature. The results demonstrated that OG could be degraded by GAC/PDS reagent effectively. Moreover, the dosage of PDS and GAC, temperature and initial concentration of OG had an impact on OG oxidation, higher temperature and GAC dosage resulted in higher OG degrading rates. In addition, the empirical kinetic equation for OG oxidation by GAC/PDS combined system under the conditions of 0.050-0.125 mmol x L(-1) of OG, 5.0 of pH, 10/1-160/1 of n(PDS)/n(OG), 0.1-1.6 g x L(-1) of GAC, 298-338 K of temperature, could be reasonably represented by the first order kinetics, which was fitted very well with the experimental data. In addition, the catalytic properties of reused GAC have been investigated. PMID- 23745402 TI - [Study on the start-up of the anaerobic baffled reactor for treating alkali deweighting and dyeing-printing wastewater]. AB - The start-up of treating alkali-deweighting and dyeing-printing wastewater by anaerobic baffled reactor (ABR) was investigated. Through seeding with the anaerobic granular sludge, the start-up with low organic loading was started by using artificial alkali-deweighing and dyeing wastewater as influent with the condition of temperature 32 degrees C-35 degrees C and pH 7.8-8.3. After continuously running 70 days, the start-up had been completed to reach the stabilization. The results showed that the pH of effluent kept stable around 7.3 and the average COD removal rate was up to 78% while the average volume loading rate was 1.93 kg x (mm3 x d)(-1). After the start-up, a separating function of each compartment was observed and meanwhile the anaerobic granular sludge with good properties was achieved. Relative to the start, the size of granular sludge particle was increased and the sludge sedimentation performance became better and the value of f (MLVSS/MLSS) was up to 0.65 at the end of the experiment. In addition, high activity of the microorganism was observed that the average value of dehydrogenase activity (DHA) with TF expression and the coenzyme F420 concentration were x (g x h)(-1) and 0.18 micromol x g(-1), respectively. PMID- 23745403 TI - [Study on the pollutants removal performance along the advanced treatment in tannery wastewater by O3-BAF]. AB - A pilot-scale hybrid process of ozone and biological aerated filters (BAF) with the capacity of 36 t x d(-1) was applied for advanced treatment of the secondary biologically effluent from a dyeing and tannery park wastewater treatment plant. The pollutants removal performance along the height of different medias BAFs were investigated. The results showed that the average COD and color were 55.4 mg x L( 1) and 12.6 times at the height of 1500 mm in activated carbon BAF, and were 55.6 mg x L(-1) and 9.4 times at the height of 1 800 mm in composite BAF, both of the effluent at each height met the first level B criteria specified in the Discharge Standard of Pollutants for Municipal Wastewater Treatment Plant (GB 18918-2002). Along the height of ceramist BAF, the COD and color were seldom removed. In activated carbon BAF and composite BAF, COD and ammonia nitrogen were both greatly decreased at the height of 1 200 mm, then decreased slowly. The biomasses simultaneously reached the maximum at the height of 900 mm in activated carbon, composite and ceramist BAF, with the maxims of 30.69, 28.87 and 15.94 nmol x g( 1), respectively. PMID- 23745404 TI - [Effect of pilot UASB-SFSBR-MAP process for the large scale swine wastewater treatment]. AB - In this paper, a treatment process consisted of UASB, step-fed sequencing batch reactor (SFSBR) and magnesium ammonium phosphate precipitation reactor (MAP) was built to treat the large scale swine wastewater, which aimed at overcoming drawbacks of conventional anaerobic-aerobic treatment process and SBR treatment process, such as the low denitrification efficiency, high operating costs and high nutrient losses and so on. Based on the treatment process, a pilot engineering was constructed. It was concluded from the experiment results that the removal efficiency of COD, NH4(+) -N and TP reached 95.1%, 92.7% and 88.8%, the recovery rate of NH4(+) -N and TP by MAP process reached 23.9% and 83.8%, the effluent quality was superior to the discharge standard of pollutants for livestock and poultry breeding (GB 18596-2001), mass concentration of COD, TN, NH4(+) -N, TP and SS were not higher than 135, 116, 43, 7.3 and 50 mg x L(-1) respectively. The process developed was reliable, kept self-balance of carbon source and alkalinity, reached high nutrient recovery efficiency. And the operating cost was equal to that of the traditional anaerobic-aerobic treatment process. So the treatment process could provide a high value of application and dissemination and be fit for the treatment pf the large scale swine wastewater in China. PMID- 23745405 TI - [Cultivation of aerobic granular sludge with municipal wastewater and studies on its characteristics under the continuous flow]. AB - The aerobic granular sludge was cultivated successfully in a continuous-flow airlift aerobic granular sludge fluidized bed (CAFB), with low-concentration municipal sewage as the influent and flocculent activated sludge as the seeding sludge. The formation, characteristics and the biological diversity of the aerobic granules in the CAFB were investigated and analyzed. Experimental results showed that many dense and compact granules with diameter of 800-1 000 microm were formed as early as the 6th days operation. At the start-up stage, sludge volume index (SVI) decreased to 35 mL x g(-1), the mixed liquor suspended solid (MLSS) concentration increased to 6000 mg x L(-1), and the mass fraction of extracellular polymeric substances increased significantly. The granules presented a good biological diversity and high biomass contents at the steady running stage. The aerobic granules were basically composed of coccid and bacillus as observed by the scanning electron microscope. A large number of voids and channels were found to be located on the surface of the granules. The removal rate of COD maintained at 70% -75% at the steady stage of CAFB running, and the effluent COD concentrations were 70 mg x L(-1). At the 32nd day of operation, filamentous bacteria grew apparently and sludge bulking happened. Above results showed the CAFB aerobic granules formed rapidly, and performed a good ability on the pollutant removal. However, more work is necessary on the steady running of this novel bioreactor in the future. PMID- 23745406 TI - [Kinetic model of enhanced biological phosphorus removal with mixed acetic and propionic acids as carbon sources. (I): Model constitution]. AB - Based on activated sludge model No. 2 (ASM2), the anaerobic/aerobic kinetic model of phosphorus-accumulating organisms (PAO) was established with mixed short-chain fatty acids (SCFAs) as the base substance in enhanced biological phosphorus removal process. The characteristic of the PAO model was that the anaerobic metabolism rates of glycogen degradation, poly-beta-hydroxyalkanoates synthesis and polyphosphate hydrolysis were expressed by SCFAs uptake equation, and the effects of anaerobic maintenance on kinetics and stoichiometry were considered. The PAO kinetic model was composed of 3 soluble components, 4 particulate components and a pH parameter, which constituted the matrix of stoichiometric coefficients. On the basis of PAO model, the GAO kinetic model was established, which included 7 processes, and phosphorus content influenced the aerobic metabolism only. PMID- 23745407 TI - [Kinetic model of enhanced biological phosphorus removal with mixed acetic and propionic acids as carbon sources. (II): Process simulation]. AB - Two groups of sequencing batch reactors were used to study the metabolism substrate transformation of phosphorus-accumulating organisms (PAO) and glycogen accumulating organisms (GAO) fed with mixed acetic and propionic acids. Seven stoichiometry parameters and 24 kinetic parameters were contained in the PAO and GAO kinetic model, and stoichiometry parameters were deduced from the stoichiometry models, while kinetic parameters were determined by experimental results. The kinetic model parameters of stoichiometry and kinetics were determined according the experiments and the literature. Subsequently, the substrate transformations of PAO and GAO were calculated by the Matlab software. The model curves matched the SBR experimental data well, indicating that the kinetic model based on SCFAs metabolism could be used to simulate PAO and GAO in anaerobic-aerobic conditions. PMID- 23745408 TI - [Kinetic model of enhanced biological phosphorus removal with mixed acetic and propionic acids as carbon sources. (III): Model application]. AB - The kinetic model based on SCFAs metabolism was applied for the prediction of phosphorus-and glycogen-accumulating organisms (PAO and GAO) competition with different carbon sources and m(P)/m(COD) ratios. When acetic acid was used as the sole carbon source, the biomass compositions were almost the same as those before cultivation, and neither PAO nor GAO could be out-competed from EBPR. However, increasing propionic acid in the influent helped PAO to be the predominance organism, and EBPR performance kept excellent when the ratio of propionate to mixed acids (acetate + propionate) was higher than 0.33. It also found that the m(P)/m(COD) ratio should be kept at 0.04-0.10 to avoid phosphorus became a limiting factor for PAO growth. This was because at low m(P)/m(COD) ratios, such as 0.01, GAO would take up 95% of the total (PAO + GAO) biomass. PMID- 23745409 TI - [Comparative study on water-air CO2, CH4 flux in two tributaries in the Three Gorges Reservoir, China]. AB - The Three Gorges Reservoir (TGR) is a huge reservoir under the subtropical climate condition. It shows great spatio-temporal heterogeneity on biogeochemical cycling of carbon in the TGR's aquatic ecosystem. 1 a field monitoring on water air CO2 and CH4 fluxes was conducted from June, 2010 to May, 2011 in Longxi River and Pengxi River, the 2 typical tributaries in the Three Gorges Reservoir. Comparative study showed that annual CO2 diffusive fluxes in the Longxi River and Pengxi River were (7.30 +/- 1.89) mmol x (m2 x h)(-1) and (0.71 +/- 0.46) mmol x (m2 x h)(-1), respectively, and the CH4 diffusive fluxes were (0.11 +/- 0.095) mmol x (m2 x h)(-1) and (0.007 4 +/- 0.001 7) mmol x (m2 x h)(-1). Higher intensities and seasonal variance of CO2 and CH4 fluxes were observed in Longxi River compared to those in Pengxi River. Through a comparative analysis of the environmental and watershed parameters in both rivers, it was found that the unstable hydraulic conditions and habitat of Longxi River prohibited the growth of phytoplankton, reducing its capability of carbon assimilation. The higher pollution load in the basin and the higher organic matters and total nitrogen in the impounding soil of Longxi River also resulted in the higher level of greenhouse gas fluxes compared to those in the Pengxi River. More studies shall be conducted to elucidate the variance of CH4 flux and its controlling factors in both rivers. PMID- 23745410 TI - [Factors influencing the spatial variability in soil respiration under different land use regimes]. AB - In order to investigate the factors influencing the spatial variability in soil respiration under different land use regimes, field experiments were performed. Soil respiration and relevant environment, vegetation and soil factors were measured. The spatial variability in soil respiration and the relationship between soil respiration and these measured factors were investigated. Results indicated that land use regimes had significant effects on soil respiration. Soil respiration varied significantly (P < 0.001) among different land use regimes. Soil respiration rates ranged from 1.82 to 7.46 micromol x (m2 x s)(-1), with a difference of 5.62 micromol x (m2 x s)(-1) between the highest and lowest respiration rates. Soil organic carbon was a key factor controlling the spatial variability in soil respiration. In all, ecosystems studied, the relationship between soil respiration and soil organic carbon content can be described by a power function. Soil respiration increased with the increase of soil organic carbon. In forest ecosystem, the relationship between soil respiration and diameter at breast height (DBH) of trees can be explained by a natural logarithmic function. A model composed of soil organic carbon (C, %), available phosphorous (AP, g x kg(-1)) and diameter at breast height (DBH, cm) explained 92.8% spatial variability in soil respiration for forest ecosystems. PMID- 23745411 TI - [Differences in soil respiration between cropland and grassland ecosystems and factors influencing soil respiration on the Loess Plateau]. AB - Understanding the effect of land-use change on soil respiration rates becomes critical in predicting soil carbon cycling under conversion of arable into grassland on the Loess Plateau. From July 2010 to December 2011, CO2 efflux from the soil surface was measured between 08:00 to 10:00 am in clear days by a Licor 8100 closed chamber system (Li-COR, Lincoln, NE, US). Also, soil temperature and soil moisture at the 5-cm depth was measured using a Li-Cor thermocouple and a hand-held frequency-domain reflectometer (ML2x, Delta-T Devices Ltd, UK) at each PVC collar, respectively. We found marked differences (P < 0.05) in soil respiration related to different land-use: the mean cropland soil respiration [1.35 micromol x (m2 x s)(-1)] was 24% (P < 0.05) less than the paired grassland soil respiration [1.67 micromol x (m2 x s)(-1)] (P < 0.05) during the period of experiment and the cumulative CO2-C emissions in grassland (856 g x m(-2)) was 23% (P < 0.05) higher than that in cropland (694 g x m(-2)). Soil moisture from 0 5 cm depth was much drier in cropland and significantly different between cropland and grassland except for winter. However, there were no clear relationships between soil moisture and soil respiration. Soil temperature at 5 cm depth was 2.5 degress C higher in grassland during the period of experiment (P < 0.05). Regression of soil temperature vs. soil respiration indicated significant exponential relationships both in grassland and cropland. Besides, there were intrinsic differences in response of soil respiration to temperature between the cropland and grassland ecosystems: grassland and cropland respiration response was significantly different at the alpha = 0.05 level, also expressed by a higher temperature sensitivity of soil respiration (Q10) in cropland (2.30) relative to grassland (1.74). Soil temperature of cropland and grassland can explain 79% of the variation in the soil respiration in grassland, compared to 82% in cropland. Therefore, land-use change can alter soil CO2 efflux under similar edaphic and climate conditions in the gully region of the Loess Plateau. The soil temperature difference between cropland and grassland can explain the soil respiration difference caused by land-use change, which was confirmed by the validation results. PMID- 23745412 TI - [Application and benefit evaluation of tiered health risk assessment approach on site contaminated by benzene]. AB - The procedures of implementing tiered health risk assessment approach were introduced in detail, and took a large-scale site polluted by benzene in Beijing as an example, the difference on the remediation target of benzene in soil, as well as the corresponding soil remediation volume and costs, were compared. The results indicate that the benzene concentration in soil within 1.5 m in depth and the one below should be remediated to 0.26 mg x kg(-1) and 0.15 mg x kg(-1), respectively, in order to keep the cumulative carcinogenic health risk below 1 x 10(-6) based on tiered II assessment. However, according to tiered III assessment result, which is based on the benzene in soil gas within the contaminated areas in the investigated site, the soil in the corresponding depth should only be remediated to 2.6 mg x kg(-1) and 1.5 mg x kg(-1), respectively. That means the soil remediation volume delimited on tiered III assessment result is less than the one on tiered II by 139 537 m3 and the corresponding remediation costs will be reduced by 57 million Yuan, meaning the enormous economic benefits compared to the costs (around 100 thousands Yuan) spent to carry out tiered III assessment in the site. PMID- 23745413 TI - [History of heavy metal pollution from tidal flat in Haizhou Bay]. AB - Coastal zone could be considered as an important sink of regional source to sink and preserve historical records of environmental evolution. Four sediment cores, collected from tidal flat at Haizhou Bay near Lianyungang City, were examined for concentrations of heavy metals including Cd, Cr, Cu, Mn, Pb and Zn in core sediments to investigate the historical input of trace metals. In addition, sediment rates of cores LH3 and LH4 were determined based on radionuclide 210Pb. The results showed that grain size control effect was not the main factor that influenced the distribution of heavy metals. Heavy metals concentrations in the surface sediments were higher than these regional background values. Furthermore, Al element as a proxy of grain size was selected for normalization and calculation of metal enrichment factor (EF) and anthropogenic heavy metal fluxes. The results revealed that heavy metals in tidal flats were continuously enriched in the past decades, meanwhile, tidal flats have been significantly subjected to contaminations due to anthropogenic activities. Moreover, the depth profiles of heavy metals fluxes correspond to scenario of social-economy development of Lianyungang, which is an important urban area near Haizhou Bay. From 1950s to 2005, anthropogenic fluxes of metals increased with fluctuations, whereas, since 2005 anthropogenic fluxes declined, which may be correlated to the adjustment of industrial structure as well as the strengthened environmental regulation. PMID- 23745414 TI - [Accumulation, distribution and pollution assessment of heavy metals in surface sediment of Caohai plateau wetland, Guizhou province]. AB - The objective of this paper is to investigate the concentrations and distribution characteristics of heavy metals in surface sediments of different areas in the Caohai plateau wetland. 16 samples of surface sediments were collected and 7 heavy metals were analyzed. Heavy metal pollution in surface sediments of different areas in the Caohai plateau wetland was estimated by the Tomlinson Pollution Load Index (PLI) method. The analyzed results indicated that the average contents of Cd, Hg, As, Pb, Cr, Cu, Zn were 0.985, 0.345, 15.8, 38.9, 38.6, 22.8 and 384 mg x kg(-1), respectively. The heavy metal distributions varied with regional environment changes, the order of average contents of Cd and Hg in different regions was E (the eastern region) > S (the southern region) > N (the northern region), the order of the average content of Pb was N > E > S, and that of Zn was S > E > N. The results also suggested a medium heavy metal pollution level in the surface sediment of the Caohai plateau wetland with the PLI(zone) reaching 1.17. The order of pollution level in surface sediments of different regions was E > S > N. The results showed medium pollution levels in E and Hg which reached the extreme intensity pollution level were also the major polluted elements in surface sediments of the Caohai plateau wetland. And also, results showed medium pollution levels of Cd and Pb in surface sediments of Caohai plateau wetland. Cluster analysis results showed similar pollution sources of Cd, Zn, Pb and Hg, which should be attached great importance in terms of the prevention of the Caohai plateau wetland. PMID- 23745415 TI - [Assessment and correlation analysis of heavy metals pollution in soil of Dajinshan Island]. AB - The Dajinshan Island is the highest altitude point in the nature land of Shanghai. In order to find out the status of soil heavy metals pollution of the Dajinshan Island and its correlation, this paper used the methods of grid and serpents sampling to collect samples, and applied the single factor pollution index method and potential ecological harm index method to assess the pollutions status. The results showed that the main contributor of soil heavy metal pollution in Dajinshan Island was Cd, with an over-standard rate of 85.4%, followed by Pb, with an over-standard rate of 26.8%, whereas Zn and Cu were not excessive. In addition, there was significant positive correlation between Pb-Cu, Pb-Zn and Cu-Zn at the level of P = 0.05, suggesting that they had high homology and were easily influenced by the soil forming materials. This was an indirect evidence that the Dajinshan Island was well protected and not much affected by human activities. PMID- 23745416 TI - [Fraction distribution and risk assessment of heavy metals in stream sediments from a typical nonferrous metals mining city]. AB - A modified Tessier's sequential extraction procedure was used to investigate the fraction of seven types of heavy metals (Cd, Cr, Cu, Zn, Ni, Pb, As) in the surface sediments from Huixi Stream in Tongling City, a typical nonferrous metals mining city, China. Based on speciation distribution analysis of these metals, contamination degree and ecological risk assessment of heavy metals were conducted by means of risk assessment code (RAC) and mean sediment quality guideline quotient (SQG-Q). The results show that: (1) Cr and As are major composed with residual fractions, Zn, Ni and Pb are mainly constituted of residual and bound to iron and manganese oxides fractions, and Cu is dominated by bounding to organic matter, while Cd exists in approximate mass fractions of exchangeable, bound to carbonates, bound to iron and manganese oxides, and residue. (2) Carbonate and exchangeable mass fractions of Cd, Cr, Cu, Zn, Ni, Pb and As reach 46.48%, 4.62%, 4.05%, 4.12%, 9.17%, 0.97% and 0.03%, respectively. According to the RAC, Cd is of high risk to the environment, Cr, Cu, Zn and Ni are of low risk to the environment, while Pb and As pose extreme low risk to the environment. (3) The SQG index, calculated with SQG-Q, is 10.42, which is far higher than the threshold value 1.0, indicating that the sediment in Huixi Stream has a very high potential for biological toxicity effect. The PEL-Q indexes corresponding to Cd, Cr, Cu, Zn, Ni, Pb and As approach 4.23, 1.14, 20.75, 6.04, 2.33, 4.58 and 41.71, respectively, suggesting that all these metals have great potentials for biological toxicity and the adverse effects will frequently occur. PMID- 23745417 TI - [Contamination and health risk for heavy metals via consumption of vegetables grown in fragmentary vegetable plots from a typical nonferrous metals mine city]. AB - A systematic survey of As, Ni, Cu, Pb, Cd and Zn concentrations in eight kinds of vegetables (involving 226 samples) and their corresponding soils at 35 sampling sites in the fragmentary vegetable plots of a typical nonferrous metals mine city, Tongling, was carried out for assessing heavy metal pollution, bio accumulation ability and potential health risk to local inhabitants due to exposure via consumption of vegetables. The results showed that: (1) The soils of the studied vegetable plots were seriously contaminated by heavy metals and the mean concentrations of As, Ni, Cu, Pb, Cd and Zn reached 96.96, 56.64, 1 247.82, 313.59, 6.743 and 600.96 mg x kg(-1), respectively, all significantly exceeding the soil background value of Tongling city; (2) The mean values of integrated pollution index corresponding to eight varieties of vegetables were all higher than the threshold value (i. e. 3.0) of heavy pollution; (3) In general, the largest bioaccumulation factor of heavy metals in vegetables was As, followed by Ni and Cu, and the order of pollution degree of heavy metals in vegetables was Ni > Zn > Cu > Pb > As > Cd; (4) The target hazard quotients (THQs) of As, Ni, Cu, Pb, Cd and Zn were 17.92, 1.01, 10.14, 0.73, 0.21 and 1.93, respectively. Arsenic and copper were the major risk contributors for inhabitants since the THQs of them respectively mounted to 56.10% and 31.75% of the total THQ value according to the average vegetable consumption; (5) The estimated daily intake (DI) of As, Ni, Cu, Pb, Cd and Zn from vegetables was 324.38, 1 211.25, 24 326.25, 176.25, 12.75 and 34 800 microg x d(-1) for adult residents, respectively; and (6) The target cancer risk (TR) of vegetables polluted by As to individual human health was 8.06 x 10(-3), significantly higher than the management standard (i. e. 10( 6) - 10(-4)) of United States Environmental Protection Agency (US EPA) and the standard (i. e. 5.0 x 10(-5)) of International Commission on Radiological Protection (ICRP), indicating that it was quite unsafe for the general population to consume vegetables from the studied fragmentary plots. PMID- 23745418 TI - [Correlativity study of the distribution of soil magnetic susceptibility and the heavy metal contents in Xi'an City]. AB - The magnetic susceptibility and the concentrations of Co, Cr, Cu, Pb, Sn, Sr and Ba in topsoil samples from Xi'an City were measured to study their spatial distribution and their correlation in this study. The results show that the concentrations of all measured heavy metals are higher than their background values in Cinnamon topsoil, which is the main soil type of Xi'an City. The heavy metals concentrations and the magnetic susceptibility of the studied samples display moderate variance. Co, Cr, Cu, Pb, Sn, Sr and Ba are significantly positively correlated with low-frequency magnetic susceptibility, while are significantly negatively correlated with frequency susceptibility. The spatial distribution of low-frequency magnetic susceptibility is identical with the concentrations of Pb and Cu. However, the spatial variation of frequency magnetic susceptibility is different from the concentrations of Co, Cr and Ba. The pollution assessment results show that the heavy metal pollution in topsoil of Xi'an City is moderate. The spatial contribution of the pollution load index was significantly correlated with the magnetic susceptibility of topsoil in Xi'an City. Therefore, soil magnetic susceptibility can be used as an effective monitoring means for heavy metal pollution in urban soil. PMID- 23745419 TI - [Distribution characteristics and environmental significance of heavy metals in soil particle size fractions from tropical forests in China]. AB - Three tropical forest soils were collected from Haikou, Qionghai and Tunchang in Hainan Island. Soil particle size fractionations were conducted using the standard dry-sieving procedure. Distribution of heavy metals in bulk samples and particle size fractions was determined by ICP-MS. The distribution characteristics and the response to organic carbon and iron were discussed. The results showed that the distribution of heavy metals was highly associated with the particle size fractions and variable patterns were found, which decreased with the increasing size. The accumulation of Cr, Ni, Cu, Zn, Cd and Cd was predominantly contributed by the particles finer than < 53 microm in diameter, whereas As mainly accumulated in particle size of 53-1 000 microm. Generally, the microaggregate (< 250 microm) contributed 14.38%-65.04% of heavy metals to the contents in bulk soil and the silt-clay aggregates (< 53 microm) contributed 2.61% -32.01%. The content of heavy metals except for As and Cd and Pb in Haikou soil in these different size fractions were controlled by the organic carbon and iron contents, which increased with the decreasing particle size. PMID- 23745420 TI - [Study on phosphorus adsorption characteristic of sediments in an ecological ditch]. AB - Sediments properties and phosphorus (P) adsorption capacities were compared among the samples of 0-5 cm and 5-15 cm layers from the ecological ditch vegetated with Cenetlla asiatica, Sparganium stoloniferum and a natural agricultural ditch with weeds. The results showed the 0-5 cm sediment vegetated with Cenetlla asiatica had higher concentrations of oxalate extracted Fe, Al and P than those vegetated with Sparganium stoloniferum or weeds. The parameters calculated from the Freudlich and Langmiur isotherms showed the equilibrium phosphate concentration (EPC0) ranged from 0.009 to 0.031 mg x L(-1). Cenetlla asiatica in the 0-5 cm layer had the maximum values of 352.2 L x kg(-1) and 562.7 mg x kg(-1) for Freundlich adsorption constant (K(f)) and Langmuir sorption maximum (S(max)), respectively, which proved it had the highest P adsorption capacity. The regression analysis showed P sorption parameters had significant relationship to oxalate-extracted Fe, clay content and DPS (P < 0.05). It was thus clear that aquatic plants influenced sediment properties and P adsorption capacity, and the practice of growing proper plants in ecological ditch could reduce the risk of P loss in non-point source pollution. PMID- 23745421 TI - [Fractions and adsorption characteristics of phosphorus on sediments and soils in water level fluctuating zone of the Pengxi River, a tributary of the Three Gorges Reservoir]. AB - The sediment, one of the key factors leading to the eutrophication of water bodies, is an important ecological component of natural water body. In order to investigate the morphological characteristics and moving-transiting rule of phosphorus in the sediments of the Pengxi River, a tributary of the Three Gorges Reservoir, the distributions of different phosphorus forms on the three cross section in the sediments and three soil types of riparian zone were investigated using the sequential extraction method. The characteristics of phosphorus adsorption on the sediments were also investigated by batch experiments. The equilibrium phosphorus concentrations at zero adsorption (EPC0) on those sediments were estimated using the Henry linear models. The results show that the total phosphorus (TP) contents of these sediments and soils of riparian zone were 0.80-1.45 g x kg(-1) and 0.65-1.16 g x kg(-1), respectively. Phosphorus in sediments and soils were divided into inorganic phosphorus (IP) and organic phosphorus (Or-P), and the inorganic phosphorus was the dominant component of TP. Of the inorganic phosphorus fractions, the percentages of phosphorus bounded to calcium (Ca-P) and occluded phosphorus (O-P) from sediments were higher than 80%, implying that the contents of phosphorus were mainly influenced by their bedrocks and the sedimentary environmental conditions, not by the activities of human beings. The fractions of Ca-P and O-P were the dominant components of inorganic phosphorus in alluvial soil and purple soil, while the fraction of O-P was the highest in the paddy soil. The EPC0 values of the sediments from the sections of Huangshi, Shuangjiang and Gaoyang were 0.08, 0.13 and 0.11 mg x L(-1) respectively, but the EPC0 values of the alluvial soil, purple soil and paddy soil located in riparian zone were 0.08, 0.09 and 0.04 mg x L(-1), respectively. Correlation analysis shows that the values of EPC0 positively related to the contents of total phosphorus and clay content, and significantly related to the content of Ca-P and pH values. According to the phosphorus concentration in the water of Pengxi River, it concludes that sediments and soils in the zone of fluctuating water level of the Pengxi river can be the sink of phosphorus in summer and autumn, while can be the source of phosphorus in the spring and winter. Therefore, the inherent phosphorus present in sediments and soils would be a major threat to the water quality and ecosystem reservation in the watershed of the Pengxi River. PMID- 23745422 TI - [Sorption behavior of Triton X-100 on loess and affecting factors]. AB - Batch experiments involving soil-aqueous systems were conducted to determine sorption of Triton X-100 onto natural loess as a function of equilibrium time, Triton X-100 concentration, ionic strength, and pH value. The results showed that the equilibration time for sorption of Triton X-100 onto loess was about 30 min. The sorption kinetics of Triton X-100 fitted well to the pseudo-first-order kinetic model and the corresponding parameters Q(e), k1, and r2 were 3.041 mg x g(-1), 0.102 min(-1), and 0.9934, respectively. Sorption isotherm was found to be distinctly nonlinear. The Sips model provided the best fitting to the experimental data among the four isothermal models tested. Q(max) and r2 of Sips model were 3.202 mg x g(-1) and 0.998 7, respectively. It was found that the ionic strength and the pH of the solution had a significant influence on the sorption of Triton X-100 onto loess. The amount of Triton X-100 sorbed onto the loess increased significantly with increasing concentration of NaCl. Sorption of Triton X-100 onto loess was influenced greatly by pH, the amount of Triton X-100 sorbed decreased as the pH increased. PMID- 23745423 TI - [Residual levels in air, soil and soil-air exchange of organochlorine pesticides in Hami region of Xinjiang and its potential ecological risk]. AB - The concentrations of HCHs and DDTs in soil and air of urban/rural/forestry centre locations in the Hami region of Xinjiang were monitored for a year by passive atmospheric sampling in order to study the residual levels and air-soil exchange and evaluate ecological risk. The study results showed that the annual average concentrations of HCHs and DDTs in the air of Hami were 107.1 pg x m(-3) and 43.9 pg x m(-3), respectively, and the concentrations of HCHs and DDTs in summer and autumn were generally higher than those in winter and spring. It was deduced that the HCHs and DDTs tended to evaporate into the air because of the higher temperatures in summer and autumn. For OCPs in the air of study area, HCHs were dominanted the main pollution compared with DDTs. Meanwhile, alpha-HCH contributed the largest portion among all HCHs isomers, and p,p'-DDE dominated the residual levels of DDTs. Moreover, the values of alpha-HCH/gamma-HCH were in the range of 3 to 7, which indicated that the use of technical HCHs or the long distance atmosphere transport of HCHs may play a significant role for HCHs in the air of Hami region. Furthermore, ratios of (DDD + DDE)/DDTs were in the range of 0.4-0.9, 71.4% of which were higher than 0.5, indicating that DDTs in the air were mainly from historical usage and no new DDTs sources emerged in Hami recently. The concentrations of HCHs and DDTs in soil were between 0.344-6.954 ng x g(-1) and 0.104-26.397 ng x g(-1), respectively, which did not exceed the National Soil Quality Standard Level I. In addition, DDTs predominated in soil OCPs, in which beta-HCH accounting for a huge percentage in HCHs isomers, while o,p'-DDT predominated in pollution caused by DDTs isomers. From study results, it was also suggested that the important cause of DDTs residues in soil of Hami area could be the recent inputs of new sources since the value of (DDD + DDE)/DDTs were lower than 0.5. The sources of HCHs and DDTs in soil and atmosphere were not consistent, which was mainly caused by the different characteristics of soil and atmosphere and the complex geographical environment and climatic conditions in Hami region. The study on air-soil exchange showed that the escaping tendency of the various isomers of HCHs and p, p'-DDE was mainly from the soil to the air, on the contrary, the escaping tendency of o,p'-DDE,o,p'-DDD,p,p'-DDD,o,p'-DDT,p,p' DDT was mainly from the air to the soil in Hami, which indicated that the soil was the sink of most of DDTs, and the air was the source of most of DDTs; while the air was the sink of HCHs and p,p'-DDE, and the soil was the source of HCHs and p,p'-DDE. There were potential risks of DDTs to birds and soil organisms in urban soil and forestry centre soil of Hami region, while the ecological risk of HCHs was light in Hami surface soil. PMID- 23745424 TI - [Levels and sources of decabromodiphenyl ether and dechlorane plus in Xining and Tianjun, Qinghai Province, China]. AB - Decabromodiphenyl ether (BDE-209) and dechlorane plus (DP), two common additive flame retardants, are widely used in electronic products. Since they are widely spread in both abiotic and biotic environmental samples, they have attracted worldwide attention. This study reported the measurement of the levels of BDE-209 and DP in the atmosphere of Xining City and Tianjun County in Qinghai Province. Compared with other areas, the average levels of BDE-209 in Xining City were higher, 370 pg x m(-3) in summer and 470 pg x m(-3) in winter, and that in Tianjun County were 220 pg x m(-3) and 390 pg x m(-3), respectively. Meanwhile, the average level of DP was at a low level both in Xining (0.85 pg x m (-3) and 0.25 pg x m(-3) in summer and winter) and Tianjun (0.24 pgx m(-3) and 0.16 pg x m(-3) in summer and winter), which showed that the level of DP in Xining was higher than that in Tianjun and the level of DP in summer was higher than that in winter. The anti-DP fractional abundances (f(anti)) in Xining City and Tianjun County were 0.66 +/- 0.04 and 0.68 +/- 0.06, respectively. Neither seasonal variation nor spatial variation of f (anti) was found at the sampling sites. A weak inverse correlation was found between the level of BDE-209 and DP in Qinghai,suggesting that the local sources of the two pollutants may be different. PMID- 23745425 TI - [Vertical distribution of PBDEs and DL-PCBs in sediments of Taihu Lake]. AB - Sediment core samples collected from the Zhushan Bay, Meiliang Bay, South Taihu of Taihu Lake were analyzed for 8 polybrominated diphenylethers (PBDEs) and 12 dioxin-like PCBs (DL-PCBs). The results revealed that the PBDEs levels were highest in the Zhushan Bay, followed by Meiliang Bay and South Taihu; and the DL PCB levels were highest in the Meiliang Bay, followed Zhushan Bay and South Taihu. The vertical distribution of PBDEs level showed an exponential growth trend in Taihu Lake sediments, BDE-209 was the most abundant PBDEs congeners; and the vertical distribution of the DL-PCBs level in the sediments revealed that the contamination caused by DL-PCBs continued to increase in recent years, indicating that there were PCBs sources in the Taihu Lake region. There was significant difference in the composition of PBDEs congeners at different depths in the sediments of Meiliang Bay, however, the detailed causes remain to be investigated in further studies. The vertical distribution pattern of PCBs congeners revealed that PCB-77, -118, -105 levels significantly decreased with increasing depth in 0 15 cm upper sediments and there chang in the lower sediments. PMID- 23745426 TI - [Characteristics of organic pollutants in the sediments from a typical electronics industrial zone]. AB - In order to investigate the contamination status of organic pollutants in a river of a typical electrical equipment industrial area, Ronggui, Foshan, the sediments were sampled for the composition, concentration and occurrence analysis of organic pollutants. The polar and non-polar fractionation methods were employed for the fingerprint establishment of organic pollutants. One hundred and seventy one of organic chemicals including ten categories of alkanes, alkenes, polycyclic aromatic hydrocarbons, benzene, heterocyclic compounds, phthalate esters, aldehydes, ketones, polar compounds, silicon-containing material as well as alkyl esters were examined. The number of different categories of the detected organic pollutants in a descending order was: alkanes > polar compounds > polycyclic aromatic hydrocarbons > aldehydes and ketones > heterocyclic compounds > benzene homologues, phthalate ester > alkyl esters > silicon material > olefins. The abundance of detected organic pollutants in a descending order was: alkanes > polar compounds > alkyl esters > olefins > polycyclic aromatic hydrocarbons > phthalates > silicon material > aldehydes and ketones > heterocyclic compounds > benzene homologues. Among the 51 kinds of alkanes detected, nonadecane accounted for 14.83%, and the persistent organic pollutants accounted for 2.33% of the total organic matter. Compared to similar studies, there were 51 kinds of alkanes and they accounted for 55.5% of the total organic chemicals, showing high diversity and abundance. In addition, some electronics industry-related organic pollutants such as silicone materials were also detected in high frequency. PMID- 23745427 TI - [Emission characteristics of polycyclic aromatic hydrocarbons in exhaust particles from a diesel car]. AB - The emission characteristics of polycyclic aromatic hydrocarbons (PAHs) in exhaust particles from a diesel car were studied. In the experiment, pure diesel fuel and B10 fuel with a biodiesel blend ratio of 10% were chosen. The gaseous emissions of HC, CO and NO(x) under New European Driving Cycle (NEDC) were measured, and exhaust particulate matter (PM) samples were analyzed by gas chromatography-mass spectrometry. The emission characteristics of PAHs in exhaust particles were highlighted. The results show that the emission concentrations of HC, CO, NO(x), and PM decreased when the diesel car used B10 fuel. Fluoranthene and pyrene were dominant in PAHs of PM emissions when the diesel car used pure diesel or B10 fuel. Compared to pure diesel, there was a slight increase in low ring PAHs emissions when the diesel car used B10 fuel. On the contrary, PAHs emissions in middle and high-ring declined significantly. Besides, Benzo [ a] pyrene equivalent toxicity analysis results show that the BEQs of B10 fuel decreased by 21.6% compared to pure diesel. That means the toxicity of PAHs in exhaust particles declined when the diesel car used biodiesel fuel. PMID- 23745428 TI - [Characterization of PAHs in fly ashes from coke production]. AB - In order to investigate the characteristics of polycyclic aromatic hydrocarbons (PAHs) in ashes from coking, PAHs in ashes from three coke production plants were analyzed with GC-MS, and the distribution characteristics of PAHs and potential toxicity risk were discussed. The sum of 16 EPA prior PAHs varied from 8.17 x 10(2) to 5.17 x 10(3) microg x g(-1). PAH contents from the coke oven (stamp charging) with the height of 3.2 m were two times higher than those from the one (top charging) with the height of 6.0 m, and PAHs in ashes from coal charging were significantly higher than those from coke pushing in the same plant. Four ring and five-ring PAHs were the dominant species in ashes from coking and the sum of them accounted for more than 80.00% of total PAHs. Chrysene (Chr), benzo [a] anthracene (BaA) and benzo [b] fluoranthene (BbF) were abundant in all ash samples. The content of total BaP-based toxic equivalency (BaPeq) ranged from 1.64 x 10(2) to 9.57 x 10(2) microg x g(-1). From the carcinogenic point of view, besides benzo [a] pyrene (BaP), dibenz [a,h] anthracene (DbA) contributed most to the overall toxicity of PAHs, followed by BaA and BbF. BaPeq concentration from coal charging was 5.21-fold higher than that from coke pushing, indicating that different reuse ways should be considered based on their specific toxicity profiles of PAHs. PMID- 23745429 TI - [Comparison of PAHs distribution in stabilized sludge by sludge drying bed and reed bed]. AB - The difference in the removal efficiencies of polycyclic aromatic hydrocarbons (PAHs) in planted and unplanted sludge drying bed was investigated. Pilot-scale sludge drying bed and reed bed had the same size of 3.0 m x 1.0 m x 1.3 m (L x W x H), and the bed height consisted of a 65 cm media layer and a 65 cm super height. Both beds had a ventilation pipe which was mounted on the drainage pipes. The experiment lasted for three years, and the first two years was the sludge loading period, and the third year was the natural stabilization period. In the first two years, a total thickness of 8.4 m of sludge was loaded and the average sludge loading rate was 41.3 kg x (m2 x a)(-1). After the three-year stabilization, the contents of the sixteen PAHs decreased with time in both the sludge drying bed and the reed bed. The total PAHs contents in the surface, middle and bottom sludge layers in the sludge drying bed were 4.161, 3.543 and 3.118 mg x kg(-1) (DW), corresponding to 26.91%, 37.77% and 45.23% of removal; and the values in the reed bed were 2.722, 1.648 and 1.218 mg x kg(-1) (DW), corresponding to 52.18%, 71.05% and 78.60% of removal. The average PAHs removal in the reed bed was 29.86% higher than that in the sludge drying bed. In the stabilized sludge, the removal of low-molecular-weight PAHs predominated. The results suggested that reed played a positive role in the removal of PAHs. PMID- 23745430 TI - [Effects of adsorbents on partitioning and fixation of heavy metals in the incineration process of sewage sludge]. AB - Experiments were carried out on laboratory-scale electrically heated tube furnace sewage sludge combustion with different adsorbents. Four solid adsorbents (calcium oxide, Alumina, fly ash and kaolin) were used to control the emission of heavy metals (Pb, Cd, Cu, Cr, Ni, Zn) during the sewage sludge incineration. The results showed that the heavy metals tended to be fixed and left over in the incineration bottom ash with the addition of calcium oxide, Alumina, fly ash and kaolin. With the increase of the solid adsorbent ratio, the residual rate of heavy metals in the bottom ash also increased. Incineration temperature had a great influence on the heavy metal adsorption effect of the solid adsorbent. The forms, melting point and boiling point of the heavy metals were found to be important factors that determined its volatility. There was huge difference in the inhibitory effect of different adsorbents on heavy metals migration. From the view of controlling heavy metal evaporation, the adsorbents kaolin and CaO were superior to the other adsorbents. The interaction between the active center of the solid adsorbent and the molecules of the heavy metal compounds depended on the distribution of these active sites and the chemical properties of the heavy metals. PMID- 23745431 TI - [Environmental toxicity of waste foundry sand]. AB - The metal leaching characteristics and volatile organic compounds (VOCs) of five different types of waste foundry sands were analyzed with the toxicity characteristic leaching procedure (TCLP) and head space-gas chromatography (HS GC). Microtox and soil dehydrogenase activity (DHA) tests were then used to evaluate the bio-effects of these waste sands. The results showed that due to the different metals poured and casting materials used to make the sand molds, there was significant difference among the five waste foundry sands in the compositions and concentrations of metal and organic pollutants. The concentrations of Fe in the leachates of iron and steel casting waste foundry sand exceeded the maximal allowable concentrations specified in the National Standard of Drinking Water Quality, whereas the As concentration in the leachate of aluminum casting waste foundry sand exceeded the standard. The five waste foundry sands had quite different compositions and levels of VOCs, which resulted in different levels of inhibition effects on the luminescent bacteria (30% and 95%). Additionally, the soil DHA tests suggested that metal pollutants in waste foundry sands may inhibit the soil microbial activity, whereas organics in the sands may slightly promote the microbial activity. The results of this study indicated that the waste foundry sands may pose considerable threat to the environment when improperly disposed. PMID- 23745432 TI - [Construction and properties of a microbial whole-cell sensor CB10 for the bioavailability detection of Cr6+]. AB - A microbial whole-cell biosensor CB10 for the bioavailability assessing of Cr6+ was constructed by molecular biotechnology. The regulatory gene and promoter of CB10 was from the chromium resistance system of plasmid pMOL28 from Cupriavidus metallidurans CH34, and the reporter gene of CB10 was luc which was derived from Photinus pyralis. Finally, its response characteristic was discussed under different incubation conditions e. g. pH and temperature. The results showed that a microbial whole-cell biosensor CB10 had been successfully constructed which could respond to Cr6+ within 30 min, with a LOD for Cr6+ of 2 micromol x L(-1). When the incubation concentration of Cr6+ was between 20 micromol x L(-1) and 200 micromol x L(-1), the luc activity of the CB10 biosensor was in linear correlation with the concentration of Cr6+. When the concentration of heavy metal was in the range of 10-50 micromol x L(-1), the response of CB10 was relatively more specific. Moreover, high concentrations of Pb2+, Mn2+ and Sb2+ could also induce CB10. By analyzing the response characteristic of CB10 biosensor, we could draw the conclusion that 15-30 degrees C and pH 4-7 were appropriate for CB10, and 30 degrees C and pH 7 were the optimal conditions for the incubation of the CB10 biosensor. The microbial whole-cell biosensor CB10 for the detection of Cr6+ was fast-responding, specific, sensitive and stable under various conditions. In prospective, it could be used in the fast detection of Cr6+ in water and assessment of the bioavailability of Cr6+ in soil. PMID- 23745433 TI - [Structure and dynamics of microbial community in the denitrifying sulfide removal process]. AB - In order to investigate the relationship between the structure of microbial community and the operational efficiency of the denitrifying sulfide removal (DSR) process, whole genomic DNA was extracted from sludge samples at each operational stage. Functional gene arrays (FGAs), a high throughput metagenomic technology, was employed to characterize the change of microbial community structure in DSR process. The results of diversity indices (Simpson and Shannon indices) and clustering showed that the microbial community structure changed greatly with stages according to the operational conditions. In stage I and II, diversity indices and richness decreased due to acclimation of the microbial community to the environment, whereas they increased notably according to the maturing of sludge which may indicate that the bioreactor entered the steady stage. Analysis of key functional genes showed that the abundance of genes did not only reflect the activities of functional bacteria but also had a close relationship with the reactor performance. PMID- 23745434 TI - [Effects of physico-chemical parameters on the abundance of the denitrification associated genes nirK, nirS and nosZ during agricultural waste composting]. AB - The abundance variation of the functional genes (nirK, nirS and nosZ) involved in denitrification was investigated using the real-time polymerase chain reaction (real-time PCR) at different locations (top, center and bottom) of the compost pile during the agricultural waste composting. The changes in pile temperature, pH, moisture content, soluble NH4(+) -N, NO3(-) -N and water soluble carbon (WSC) were measured. The results showed that the abundance of those genes varied among the samples collected in different zones. Redundancy analysis (RDA) was applied to explore the correlations between the abundance of nirK, nirS and nosZ and the composting physic-chemical parameters. The results suggested that water soluble carbon (WSC), pile temperature and nitrate had the most significant impacts on the abundance of the three genes. The t-value biplots for each environmental variable indicated that nirK was positively related with temperature and pH (P < 0.05), nirS was positively related with temperature (P < 0.05), and nosZ was positively related with NH4(+) -N while negatively with WSC. PMID- 23745435 TI - [Impact of PAHs on the expression of PRDX in earthworm (Eisenia fetida)]. AB - A peroxiredoxin6 (PRDX6)-like gene segment has been found in up-regulated cDNA libraries of earthworm Eisenia fetida exposed to benzo[a]pyrene(BaP). Analysis with basic local alignment search tool (BLAST) and phylogenetic analysis revealed that the gene segment contains a characteristic motif which was encoded by Cys, illustrating that this gene segment belongs to PRDX. To verify the response of PRDX in E. feitida exposed to poly aromatic hydrocarbons (PAHs), four-week pollution experiments were conducted following the methods recommended by the Organization for Economic Co-operation and Development (OECD). The results showed that the expression of PRDX was up-regulated in earthworm exposed to 1.0 mg x kg( 1) Pyrene and BaP. It was indicated that PRDX in E. fetida was the potential molecular biomarkers of antioxidative stress caused by soil contamination. PMID- 23745436 TI - [Preparation of OMC-Au/L-Lysine/Au modified glassy carbon electrode and the study on its detection response to hydroquinone and catechol]. AB - Ordered mesoporous carbon-Au nanoparticles (OMC-Au) nanocomposites were synthesized by a one-step chemical reduction route, and an OMC-Au/L-Lysine/Au composite film-modified glassy carbon electrode (GCE) was constructed. The microstructure of OMC and OMC-Au/L-Lysine/Au composite films were characterized by SEM, and the preparation process of OMC-Au/L-Lysine/Au modified glassy carbon electrode was investigated using cyclic voltammetry and electrochemical impedance spectroscopy. The electrocatalytic oxidation of hydroquinone and catechol on the modified electrode was discussed by differential pulse voltammetry in this study, and a sensor for separate determination of hydroquinone and catechol based on OMC Au/L-Lysine/Au modified glassy carbon electrode was developed. Under the optimal conditions, the cathodic peak current was linearly related to hydroquinone concentration over ranges from 1.0 x 10(-6) mol x L(-1) to 8.0 x 10(-4) mol x L( 1) with a detection limit of 3.0 x 10(-7) mol x L(-1), and linearly related to catechol concentration from 1.0 x 10(-7) mol x L(-1) to 8.0 x 10(-5) mol x L(-1) with a detection limit of 8.0 x 10(-7) mol x L(-1). PMID- 23745437 TI - [Risk communication in construction of new nuclear power plant]. AB - Accompanied by construction of new nuclear power plants in the coming decades in China, risk management has become increasingly politicized and contentious. Nuclear risk communication is a critical component in helping individuals prepare for, respond to, and recover from nuclear power emergencies. It was discussed that awareness of trust and public attitudes are important determinants in nuclear power risk communication and management. However, there is limited knowledge about how to best communicate with at-risk populations around nuclear power plant in China. To bridge this gap, this study presented the attitudinal data from a field survey in under-building Haiyang nuclear power plant, Shandong Province to measure public support for and opposition to the local construction of nuclear power plant. The paper discussed the structure of the communication process from a descriptive point of view, recognizing the importance of trust and understanding the information openness. The results showed that decision-making on nuclear power was dominated by a closed "iron nuclear triangle" of national governmental agencies, state-owned nuclear enterprises and scientific experts. Public participation and public access to information on nuclear constructions and assessments have been marginal and media was a key information source. As information on nuclear power and related risks is very restricted in China, Chinese citizens (51%) tend to choose the government as the most trustworthy source. More respondents took the negative attitudes toward nuclear power plant construction around home. It drew on studies about risk communication to develop some guidelines for successful risk communication. The conclusions have vast implications for how we approach risk management in the future. The findings should be of interest to state and local emergency managers, community-based organizations, public health researchers, and policy makers. PMID- 23745438 TI - [National Arts and Sciences Prize]. PMID- 23745439 TI - [Long-term renal function in patients with renal-cell carcinoma treated surgically: comparison between radical and partial nephrectomy]. AB - PURPOSE: To compare the renal function (RF) in patients with renal-cell carcinoma (RCC) treated by radical (RN) or partial nephrectomy (PN) and to assess the impact of the two surgical techniques in the glomerular filtration rate (GFR). MATERIAL AND METHODS: We retrospectively analyzed the database of patients with renal tumors treated surgically. RF was assessed preoperatively and postoperatively and compared between both techniques. GFR was estimated using CKD EPI formula. Statistical analysis included X2, Student's t and Friedman tests and a method of logistic regression (multivariate analysis). RESULTS: 223 patients with RCC, who underwent surgery between 1981 and 2010, had complete information. The mean follow-up was 67.6 +/- 49.6 months. There were no significant differences in baseline characteristics between the RN (n = 196) and PN (N = 27) groups. After 6 months a GFR < 60 mL/min/1.73 m2 was detected in 63% vs. 29% (p = 0.0007), after 12 months in 64% vs. 33% (p = 0.002) and after 60 months in 53% vs. 40% (p = 0.2) of the patients in RN and PN groups, respectively. The absolute decrease in GFR was 22% after RN and 17% after PN. In the multivariate analysis, preoperative GFR and type of surgery were associated with an impairment of RF after 6 and 12 months. CONCLUSION: RN results in a more important impairment of RF after 6 and 12 months. At 60 months, patients treated with PN maintain a mean GFR > 60 mL/min/1.73 m2. PMID- 23745440 TI - [An index internal diameter ductus arteriosus/body surface area as a need for closure of duct in the preterm newborn]. AB - OBJECTIVE: To determine a rate of internal diameter (ID), the narrowest of ductus arteriosus (DA)/body surface area (BSA) in preterm newborns (PTNB) for need for closure of DA either medically or surgically. MATERIAL AND METHODS: Prospective (cohort), held in a Neonatology Service in February 2010 to January 2011. Inclusion criteria were PTNB from 28 to 36 weeks of gestation from 0 to 28 days after birth, which confirmed diagnosis of patent ductus arteriosus (PDA) by echocardiogram, taking the narrowest ID, who did not present heart complex congenital or other major malformations in other systems without pulmonary arterial hypertension, that had not received drug treatment with prostaglandin inhibitors to close the DA. The exclusion criteria for complications of mechanical ventilation (air leaks, atelectasis, etc.) before measurements. BSA was determined based on their weight and height. There were two comparison groups during its evolution, those who finally merited either closure medical or surgical closure or was indicated but the poor conditions of the patient by the same PDA mainly, the procedure was not carried out (Group A) and Group B, those that are not operated or not medically closed DA not being hemodynamically significant [corrected]. Statistical analysis was performed using descriptive statistics and inferential. Significance levels were set at p < 0.05. RESULTS: The study population consisted of 32 patients who were divided into two groups: group A of 13 patients and group B with 19 patients. The study population characteristics between the two groups showed significant difference only in the Apgar Score for the Group B. In multivariate analysis found statistically significant as need for closure of DA only a index ID DA/ BSA when it was > 14. CONCLUSIONS: It is important to take into account a number of known ways to assess whether the DA is hemodynamically significant and therefore should be closed medically or surgically and according to this study, a parameter to requiring its closure is an index ID DA/BSA with a value > 14. PMID- 23745441 TI - [Predicting risk of caries in schoolchildren from northwestern Mexico: longitudinal study]. AB - OBJECTIVE: To analyze the caries risk through the Bratthall's Cariogram (BC) and the frequency of dental caries in a Mexican northwest children population for 12 months period. MATERIAL AND METHODS: A cohort of 583 scholar children between 6 and 10 years old from Sinaloa state was involved for 12 months period (2007 2008). The Bratthall's Cariogram was used to predict caries risk and the. WHO's criteria were used to obtain the caries index. The caries risk association with clinical variables was analyzed by logistic regression analysis and Sperman's Rho rank correlation test was used to evaluate the correlation between DMFT index and BC. RESULTS: The caries risk increased with respect to age (p < 0.05), the CB identified correctly children for high risk (85%) and low risk (65%) caries for a 12 months period. The baseline values of BC showed a positive correlation with DMFT index (0.86 and p = 0.0001); the diagnostic test evaluation showed the following values: positive predictive value of 87%, negative predictive value of 63%, sensitivity of 93% and specificity of 63%. CONCLUSIONS: The caries risk increased with the age in the studied population. The Bratthall's Cariogram is a useful screening test to evaluate the risk for dental caries at individual and population levels. PMID- 23745442 TI - [Concurrent validity in Mexican college population of the adult ADHD self report scale]. AB - INTRODUCTION: In order to make a valid adult ADHD diagnostic, the clinician must overcome a series of difficulties, the main of which may be the fact that the current DSM-IV diagnostic criteria for ADHD were designed for children, hence having valid and reliable instruments in order to screen for possible patients be very helpful. OBJECTIVE: To validate the ASRS for its use on Mexican college population through concurrent validity with the FASCT scale. MATERIAL AND METHODS: We evaluated 447 (287 women, average age 23.59 years) undergraduate students from 4 universities in Mexico City. All participants answered the ASRS and FASCT scales. RESULTS: Positive and statistically significant correlations were found between the ASRS and FASCT (r = 0.79) and the agreement in diagnostic was moderate (k = 0.58). CONCLUSIONS: ASRS seems to have adequate concurrent validity with the FASCT, nevertheless further research comparing it with a semi structured or highly structured interview is needed. PMID- 23745443 TI - [Operational mechanism modification of bone mechanostat in an animal model of nutritional stress: effect of propranolol]. AB - INTRODUCTION: Propranolol (P) treatment exerts a preventive effect against the detrimental consequences to bone status in mildly chronically food-restricted growing rats (NGR) by an increment in cortical bone and by improving its spatial distribution. OBJECTIVE: To study the effect of beta-blocker on operational mechanism of bone mechanostat in an animal model of nutritional stress. MATERIAL AND METHODS: Weanling male Wistar rats were randomly assigned to four groups: control (C), C + P (CP), NGR and NGR + P (NGRP). C and CP rats were fed freely with the standard diet. NGR and NGRP rats received, for 4 weeks, 80% of the amount of food consumed by C and CP respectively, the previous day, corrected by body weight. Propranolol (7 mg/kg/day) was injected ip 5 days per week, for four weeks in CP and NGRP rats. C and NGR received saline injections at an identical dosage regimen. Body weight and length were determined during the experimental period. Dietary intake was registered daily. Animals were sacrificed after 4 weeks of food restriction. Immediately, cuadriceps, femur and tibiae from each animal were dissected and weighed, and histomorphometric and mechanical studies were performed. Serum a-CTX, osteocalcin, intact PTH, calcium and phosphorous were determined. Body protein (% prot) was measured in all groups. RESULTS: Food restriction induced detrimental effects on body and femoral growth, load-bearing capacity (Wf), % prot and cuadriceps weight in NGR us. C (p < 0.01). beta-blocker did not modify anthropometric and bone morphometric parameters in NGRP and CP us. NGR and C, respectively (p > 0.05). However, Wf NGRP vs. NGR was significantly higher (p < 0.01). alpha-CTX was significantly higher in NGR vs. C (p < 0.01). No significant differences were observed in alpha-CTX levels between CP, NGRP and C (p > 0.05). Serum osteocalcin, intact PTH, calcium and phospho- rous showed no significant difference between groups (p > 0.05). CONCLUSION: These results suggest that modeling increase in bone mass and strength in NGRP rats could be due to an anticatabolic interaction of the beta-blocker propranolol on operational mechanism of bone mechanostat in an animal model of nutritional stress. PMID- 23745444 TI - [Absolute power of cortical oscillations and their topographical distribution in a sample of young adults during resting wakefulness and unspecific attention]. AB - INTRODUCTION: The EEG records neuronal membrane potential oscillations that depend on the morpho-functional characteristics of the membrane and of modifications by postsynaptic excitatory (PSEP) and inhibitory (PSIP) potentials. The quantitative EEG (qEEG) measures the absolute power (AP) of oscillations separated in frequencies, resulting from the interaction among subcortical cortical-subcortical ensembles. The hypothesis is that neuronal networks function at a given frequency and that their APs are codes that, by becoming synchronized in diverse ensembles, generate behavior. OBJECTIVE: To establish the spectral power of cortical oscillations under diverse study paradigms and in different populations. In particular, to identify the AP and topographical distribution of four cerebral frequency bands under resting wakefulness and activation, and to integrate results into a database to establish comparison standards. MATERIAL AND METHODS: Undergraduate students, average age of 20.6 +/- 2.6 years, who participated voluntarily in the study. Recordings were made with a Nicolet EEG. We chose, in the first stage, closed eyes (CE) three samples of 12 s each. In the second stage, we chose pairs of 6 s samples, first with CE and then with OE. For their analysis, we applied the Welch periodogram and we plotted the average AP (AAP) and standard deviation (SD) of delta, theta, alpha, and beta per lead. Differences were compared through non-parametric tests (Wilcoxon and Dunnett T3); setting statistical significance at a = 0.05. RESULTS: Average APs of each frequency band differ significantly in intensity and topographic distribution generating a profile of each rhythm. When opening the eyes, rhythms desynchronized significantly at different intensities in the diverse leads, except for beta in the left fronto-frontal lead. DISCUSSION: Results indicate the existence of cortical ensembles that synchronize at a determined frequency and are modified by visual stimulation, indicating the effects of the subcortico cortical circuits. The integrated database provides comparison standards to support diagnoses and treatments. PMID- 23745445 TI - [Therapeutic intervention alternatives in cancer, using attenuated live bacterial vectors: Salmonella enterica as a carrier of heterologous molecules]. AB - Salmonella enterica is a facultative anaerobic bacteria, whose ability to colonize antigen-presenting cells (APCs) such as dendritic cells and macrophages, has allowed its successful use as an alive, attenuated bacterial vector for vaccination. Salmonella enterica elicits efficient cellular, humoral and mucosal immune responses, against heterologous antigens including viruses, parasites, other bacterial species and tumor-associated antigens, since it is capable of delivering these antigens to cells of the immune system. The extracellular expression of heterologous antigens on the surface of Salmonella enterica via its type I, III and V secretion systems, and their delivery into infected cells is essential for its stimulation of immune responses against these antigens. Moreover, Salmonella enterica is a promising therapeutic agent against cancer, as demonstrated by reports of pre-clinical and clinical studies indicating that, after systemic administration, Salmonella enterica preferentially localizes in solid tumors and metastases as compared to normal tissues. In this review, we focus on novel prophylactic and therapeutic anti-cancer approaches using Salmonella enterica as a delivery system of heterologous molecules with the aim of inhibiting tumor growth. PMID- 23745446 TI - [Hyponatremia]. PMID- 23745447 TI - [Factors relating to falls in hospitalized patients]. AB - Falls are one indicator of quality, and are classified as an adverse event, where the consequences of these can range from mild to severe and even fatal; the Joint Commission International (JCI) reports them as the sixth most frequently reported event in the database Sentinel Events. A challenge for health institutions is to maintain a risk-free environment, ensuring users to achieve the expected improvement; however each hospital is extremely complex due to the constant interaction of the person with their environment, making it necessary to have clear understanding of the variables that can influence the situation. To consider a risk-free environment must be considered preventive actions to minimize risk factors, which can be both intrinsic and extrinsic, first includes the particular characteristics of the person, and the latter refers to the hospital environment. It is important to consider that within the intrinsic factors, although they cannot be completely modified, is necessary to make an assessment and identify risks to promote preventive measures, respect to the extrinsic; is responsibility of the multidisciplinary health team to identify and eliminate the causes that contribute to the presence of falls. PMID- 23745448 TI - [Tuberculosis in Mexico: contributions of the Museum of Anatomopathology, 1895 1899]. AB - In 1895, Rafael Lavista founded the Museum of Anatomopathology at the Hospital de San Andrds in Mexico City, for the purpose of preparing and preserving anatomical pieces useful for the study of different diseases. Porfirio Diaz officially inaugurated the Museum in March 1896, but in June 1899 it was renamed as the Instituto Patologico Nacional. During its four years of activity, a variety of illnesses were studied, including tuberculosis, which spurred great interest among Museum personnel because of its high incidence. This text examines the labors developed at the Museum of Anatomopathology in relation to tuberculosis, discusses the researchers involved, and reviews the articles published in the Museum's journal: Revista quincenal de anatomia patologica. PMID- 23745449 TI - [Fatty tissue and bone]. AB - Obesity is one of leading public health issues. Along with genetic predisposition it is the main risk factor for osteoarthritis and it also has an influence on rheumatoid arthritis. Fatty tissue acts on arthritic joints through a biomechanical and humoral mechanisms. The humoral mechanism is complex and the role of adipokines in the pathogenesis of arthritis is still not entirely clear. It is assumed that no adipokine can cause joint damage on its own, but only a dysfunction in a relationship between leptine and other adipokines can cause inflammatory-destructive processes. It remains unclear whether the involvement of adipokines is primary or secondary in the process ofjoint inflammation. The relative influence of visceral fatty tissue adipokines as compared to that of locally synthesised adipokines from various joint structures is unclear. Adipokines have a predominantly pro-inflammatory action and destroy the cartilage, although they can also have a protective action. A better knowledge of the role adipokines play not only allows for a better knowledge of pathophysiological processes in osteoarthritis and rheumatoid arthritis, but it also opens possibilities for development of new therapies. PMID- 23745450 TI - [Pathogenesis of polymyositis and dermatomyositis]. AB - The idiopathic inflammatory myopathies, collectively called myositis, are a heterogeneous group of diseases of which polymyositis and dermatomyositis are the best known. These heterogeneous group of chronic disordes sharing the clinical symptom of muscle weakness and, in typical cases, inflammatory cell infiltrates in muscle tissue. There are four major types of idiopathic inflammatory myopathies: dermatomyositis, polymyositis, inclusion body myositis and immune mediated necrotizing myopathies (autoimmune necrotizing myopathies). Clinical and histopatological distinctions between these conditions suggest that different pathogenic processes underline each of the inflammatory myopathies. PMID- 23745451 TI - [Laboratory diagnostics of polymyositis/dermatomyositis]. AB - Polymyositis/dermatomyositis is chronic systemic inflammatory disease that usually affects the skin and muscle tissue. The diagnosis of polymyositis/dermatomyositis isn't simple, and represents challenge for clinicians, it is based on the integration of results: medical history and clinical presentation, laboratory findings enzymes more or less specific to muscle tissue, myositis-specific autoantibodies and autoantibodies associated with myositis which can be found at other inflammatory connective tissue diseases without myositis, electromyography findings, and biopsy of muscle and skin. Laboratory tests contribute and assist in the diagnosis of polymyositis/dermatomyositis but they should always be evaluated in context with clinical picture and other tests and decisions about diagnosis and/or treatment are based on the integration of the results. PMID- 23745452 TI - [Electromyoneurographic study in inflammatory and noninflammatory myopathies]. AB - Electromyoneurographic (EMNG) study is very useful in diagnosis of myopathy. Motor unit action potentials are low-amplitude, polyphasic and short duration and can be present to variable degree in different type of myopathies. Four components of needle EMG provide important information; morphology of motor unit action potentials, spontaneus activity, insertional activity and recruitment. Myopathy associtaed with fibrillations ussualy have components of inflammation and necrosis. Although there are no EMG findings for a specific disorders or couse, the combined patterns of findings may be characteristic of certain types of myopathy. PMID- 23745453 TI - [Pathology diagnosis of idiopathic inflammatory myopathies]. AB - The idiopathic inflammatory myopathies represent a group ofimmunologically mediated diseases characterized by inflammation of skeletal muscle potentially leading to irreversible damage. On the basis of clinical, histological and immunological features dermatomyositis, polymyositis and sporadic inclusion-body myositis are recognized as separate entities. A definitive diagnosis of idiopathic inflammatory myopathies requires detailed histological, histochemical, immunohistochemical and electron-microscopic analysis of adequate muscle biopsy sample. However, in spite of thorough morphological analysis distinction of these disorders is not always straightforward and a close clinicopathological correlation is often essential to reach a correct diagnosis. Detailed morphological features ofidiopathic inflammatory myopathies and their relationship to pathogenesis is outlined. PMID- 23745454 TI - [Non-invasive imaging of chronic inflammatory myopathies]. AB - In patients with chronic inflammatory myositis noninvasive diagnostic modalities, such as magnetic resonance (MR) imaging, and ultrasonography (US), are able to demonstrate muscular edema, fluid collections, fatty infiltration, atrophy, fibrosis, and calcifications. Because MR imaging is sensitive to the presence of edema and offers better tissue differentiation, current MR imaging with fat suppressed T2-weighted techniques or STIR images appears to be more efficient than US in the diagnosis and management of inflammatory myopathies. MR imaging has also been proposed as a means to guide biopsy in an area of active disease, thereby reducing the problem of sampling error. These changes in signal intensity, however, are not specific for myositis. Although MR imaging is now the imaging modality of choice in this issue, reduced availability, patient discomfort, and exclusion of certain patients with indwelling metal objects, such as pacemakers, are disadvantages. The availability and ease of use of US makes it preferable to MR imaging. Real-time sonoelastography can be used for various musculoskeletal applications, but the clinical utility in diagnosis of myositis is yet to be established. On the other hand, the contrast-enhanced US is a feasible method for noninvasively demonstrating increased perfusion in the involved muscle groups, and most likely, will soon become preferable, noninvasive imaging method in patients with myositis. PMID- 23745455 TI - [Polymyositis/dermatomyositis--clinical picture and treatment]. AB - The clinical presentation ofmyositis ranges from a painless muscle weakness to significant myalgia with muscle weakness and constitutional symptoms. Along with muscle and skin affection and constitutional symptoms, the disease can affect lungs, joints, heart and gastrointestinal system. It is important to note that the clinical presentation ofmyositis syndrome may overlap with symptoms of other connective tissue disease in overlap syndromes (SLE, SSCL, RA, SSjo). Common manifestations of the disease are weakness and muscle fatigue, which is the result of skeletal muscles inflammation (usually the proximal group of muscles, bilaterally and symmetrical). Severe forms of the disease with affection of the throat and respiratory muscles can vitally endan- ger patients. Among constitutional (general) symptoms, fever, malaise and weight loss are usually expressed. Skin affection in dermatomyositis can be localized or generalized like vesiculobullous erythroderma. Pathognomonic cutaneous manifestations of dermatomyositis are Gottron's papules and heliotrope erythema. Lungs are most commonly affected organs (with exception of muscles and skin) in polymyositis and dermatomyositis. The affection of lung can sometimes result in fatal outcome (interstitial lung disease, secondary pulmonary hypertension). Cardiac affection is usually subclinical, but can also be expressed as heart failure, acute coronary syndrome or conduction disturbances. Infrequent manifestations of the disease are gastroesophageal reflux, malabsorption, gastrointestinal mucosal ulceration, soft tissue calcification, Raynaud's syndrome, arthralgia/arthritis and some other less common clinical manifestations of the disease. Treatment of polymyositis/dermatomyositis includes immunosuppressive/immunomodulatory therapy and supportive, symptomatic treatment. The basis for myositis treatment are glucocorticoids, which are applied orally in a daily dosage regimen of 0.75 to 1 mg/kg/day, and in severe forms of the disease in the i.v. pulse doses of 1 g/day. Immunosuppressants/immunomodulators are added in the therapy along with glucocorticoids for better control of the disease and to reduce the required dose of glucocorticoids (side effects of longterm high doses glucocorticoide use). The most commonly used immunosuppressive drug is methotrexate at a dose of up to 25 mg/week. Hydroxychloroquine has a good effect on the cutaneous manifestations of the disease. Among other immunosuppressants which are used in the treatment of myositis are azathioprine, cyclosporine (in patients with pulmonary affection), mycophenolate mofetil and tacrolimus. Intravenous immunoglobulins applied parenterally in a dose of 2 g/kg divided into multiple doses showed an excellent clinical effect in patients with affection of the esophagus and throat muscles, in patients with pulmonary affection and in patients with resistant disease. The experience with the biologics is limited to a small number of patients. Physiotherapy is a necessary form of treatment for the recovery of muscle strength in the remission phase of the disease. A prompt treatment of infections and heart failure is sometimes life-saving in patients with myositis. Symptomatic treatment of pain with analgesics and NSAIDs reduces pain, speeds up recovery and improves the quality of life in patients with myositis. PMID- 23745456 TI - [Polymyositis, dematomyositis: overlap syndromes with connective tissue diseases and malignancies]. AB - Polymyositis and Dermatomyositis are often connected with autoimmune diseases and are closely linked with specific autoantibodies. Clinical manifestations are mild in correlation with clinical picture ofmyositis related to malignancy. Pulmonary complications are main cause of mortality in overlap syndromes with autoimmune diseases. Infection, cardiovascular complications and underlying malignancy provide greater mortality risk. PMID- 23745457 TI - [Anti-synthetase syndrome]. AB - Antysynthetase syndrome is considered as a group ofidiopathic inflammatory myositis with charcteristic serologic hallmark--antibodies which recognise the aminoacyl-tRNA synthetasses (ARS). Clinical picture of those patients contains myositis and/or intersticial lung disease (ILD) and/or arthritis and/or fever and/or Raynaud phenomenon and sometimes characteristic look of mechanic's hands. Myositis can be overt, sometimes even absent, while IBP is major cause of morbidity and determines the outcome of the disease. Untill now eight different any-synthetase autoantibodies are recognised, and most frequent are findings of anti-histidyl-tRNa synthetase antibodies. Patients with other ARS autoantibodies usually have severe ILD. Drug of choice are steroids in dosage of 1 mg/kg with immunosupresive agent (azatioprin or methotrexate) while in severe IBP cyclophosphamide is needed. Recently succsesful treatment with rituximab in combination with cyclophosphamide is reported. PMID- 23745458 TI - [Rare myositides and myopathies]. AB - Inflammatory myopathies comprise dermatomyositis, polymyositis, inclusion body myositis, secondary myopathies associated with connective tissue diseases, malignancies, sarcoidosis and Behcet's disease. In the article the inclusion body myositis is presented. Differential diagnosis ofproximal muscle weakness also includes certain non-inflammatory myopathies The statin myopathy, as an example of the drug-induced myotoxicity, is elaborated. The infectious myopathies are described with the emphasis on parasitic myopathy. The endocrine myopathies are overviewed. PMID- 23745459 TI - [Juvenile dermatomyositis]. AB - Juvenile dermatomyositis is the most common idiopathic inflammatory myopathy in children, and presents a heterogeneous group of subacute, chronic and acute diseases of skeletal muscles. Its unique presentation is marked with characteristic skin rushes and progressive muscle weakness. JDM is clinically distinct from adult dermatomyositis, because it is a systemic vasculopathy not associated with malignancy and it often overlaps with other chronic childhood inflammatory diseases. Although immunopathology of JDM is complex, new studies are completing our knowledge of disease pathogenesis. Corticosteroids represent the first line therapy, afterwards combined with immunomodulatory drugs and biological agents. Better knowledge of the disease combined with modem treatment modalities resulted in reduced mortality rates and in much improved quality of life in patients with JDM. PMID- 23745460 TI - [Exercises in patients with myositis--active treatment intervention?]. AB - Polymyositis, dermatomyositis and inclusion body myositis are rare inflammatory myopathies characterized by muscle weakness. Regardless of pharmacological treatment in most patients remain muscle weakness and inability to perform daily activities. Until recently, the prevailing opinion was that active exercises can exacerbate the inflammatory activity in the muscles and is now known that active exercise and exercise with resistance improve strength and endurance of muscles, aerobic capacity and overall functional ability. Exercises are prescribed according to the disease activity, manual muscle test or dynamometer measurements, range of motion, cardiorespiratory capacity and clinical status of the locomotor system. Each of the components can be influenced by targeted exercises and should be a integral part of myositis therapy. PMID- 23745461 TI - [Uric arthritis--a historical view]. AB - This paper gives a historical review of uric arthritis in the world and in Croatia. PMID- 23745462 TI - [Epidemiology and risk factors for gout]. AB - Gout is the most prevalent form of inflammatory arthropathy, and affecting more than 2% of the population in industrialized countries. The development and expression of gout depends on three key steps:chronic hyperuricemia, the growth ofmonosodium urate crystals and interaction between this cristals and inflammatory system. Prevalence and incidence of gout have risen in recent decades. Numerous risk factors for the development of gout have been established, including hyperuricaemia, genetic factors, dietary factors, alcohol consumption, metabolic syndrome, hypertension, obesity, diuretic use and chronic renal disease. PMID- 23745463 TI - [Pathophysiology of gout]. AB - Hyperuricemia is rather often metabolic disorder in general population. It is multifactorial disorder influenced by purine rich diet, alcohol consumption, diuretics use and renal deterioration. In the presence of local urate superasturation and lower solubility, monosodium crystals are deposited in joints, kidneys and soft tissue leading to clinical manifestations, such as gout, tophaceus deposits, nephrolithiasis and uric nephropathy. Major advances in understanding the pathogenesis of hyperuricemia and gout have been made recently, including genetic studies of urate transporters in kidneys as well as innate immune inflammatory responses and cytokine production which will be discussed thoroughly in this paper. PMID- 23745464 TI - [Clinical features and laboratory diagnostics of uric arthritis]. AB - Uric arthritis (gout) is a metabolic rheumatic diseases, which is as old as human race, with the characteristic epidemiological data, which differ with respect to climate, socio-economic life conditions and each population habits. Regardless the difference, clinical and laboratory parameters are always very similar and specific, so that their cognition and understanding, are the key criterion for the diagnosis of the disease. PMID- 23745465 TI - [Radiologic imaging of crystalline arthritides]. AB - Gout is a group of diseases characterized by arthritis and is a result of urate metabolism disturbance with the deposition of monosodium urate crystals in the joint and soft tissues. Clinical manifestations include acute and chronic arthritis, tophaceous deposits, interstitial renal disease and uric acid nephrolithiasis. The diagnosis is based on the identification of uric acid crystals in joint or body fluids. PMID- 23745466 TI - [Conventional treatment of gout]. AB - Gout is a severely disabling disorder, leading to poor quality of life, functional impairment with repercussion on physical activity, social functioning and emotional health. On the other hand, gout is probably the best understood and most manageable of all common systemic rheumatic diseases. The treatment of gout is appropriately divided into treatment of the acute attack and prevention of further attacks and of joint damage. Standard management of acute attacks of gout consists of rest, application of ice to the affected joint, and prescription of non-steroidal anti-inflammatory drugs, or glucocorticoids which should be started immediately to be most effective. Colchicin and interleukin-1 inhibitors can be used as alternative, when are indicated and available. Urate lowering therapy (usually alopurinol) is indicated to treat recurrent gout attacks, chronic arthropathy, tophi and uric acid renal lithiasis. PMID- 23745467 TI - [New and emerging drugs for uric arthritis]. AB - Gout is one of the most common forms of arthritis in the developed countries. Nevertheless, it is poorly managed mainly due to limited options in drug treatment, lack of widely accepted treatment strategies and underestimation of the importance of the disease. A significant proportion of especially elderly patients with gout are either unresponsive to or intolerant of the use of currently available medications. In the past decade we are witnessing the rise in gout prevalence and improvement in our understanding of its pathophysiology which both leaded to resurgence in scientist and clinician interest. Herewith are presented new medications for gout that act through different mechanism: anti interleukin (IL)-1 drugs (anakinra, canakinumab, rilonacept) terminate the symptoms of acute gouty arthritis, febuxostat is a new selective xanthine oxidase inhibitor, poly(ethylene) glycol-uricase is a recently developed uricolytic as well as some new uricosuric agents. These innovatory drugs alongside with the concept of treat-to-target, with clear serum urate cut off, will help in the management of patients with gout. PMID- 23745468 TI - [Gout as a systemic disease: systemic manifestations and comorbidities of hyperuricaemia]. AB - Gout is a recurrent inflammation of one or more joints that occurs because of disposal monosodium urate crystals in joints and other structures in soft tissues. Gout is a common metabolic disorder characterized by chronic hyperuricemia, serum urate levels > or = 360 mmol/1 (> 6.8 mg/ dl), which exceeds the physiological threshold of saturation. Well known complications of gout are tophi, deforming arthropathy, urolithiasis, chronic urate nephropathy, acute uric nephropathy (usually secondary due to chemotherapy), avascular necrosis of the femoral head. The risk of developing gout is directly linked to the development of hyperuricemia. Numerous evidence-based clinical and epidemiological study of urinary acid as an independent risk factor for developing hypertension, cardiovascular disease, chronic kidney disease, stroke and metabolic syndrome revalued the role of uric acid in human health and disease. In gout, as in other rheumatic disease, extraarticular manifestations are of utmost importance for morbidity and mortality. PMID- 23745469 TI - [Pseudo-gout]. AB - Pseudo-gout or calcium pyrophosphate crystal deposition disease (CPPD) is mainly a disease of the elderly. Diagnosis is obtained by identyfication of calcium pyrophosphate (CPP) crystals in the synovial fluid. Typical X-ray result is chondrocalcinosis (CC) mostly of the knee. CPPD is most frequently asymptomatic and not requires medical therapy. Treatment of acute form of desease is usualy joint aspiration and intra-articular injection. PMID- 23745470 TI - [Musculoskeletal ultrasound in rheumatology--current status and future perspectives]. AB - In the last ten years we are whitnesses of fast development of ultrasound in rheumatology clinical practice and research. The main problem is general perception that US can be highly subjective. Since 2004 an international collaborative group of ultrasound experts known as the OMERACT Ultrasound Task Force has worked to address the metric qualities of ultrasound in RA and other arthritides, according to criteria specified by the OMERACT filter. The same group has worked since 2000 in the EULAR setting for promoting training and educational issues. Part of this group is now promoting the standardized use of ultrasound at a practical international level: the TUI initiative (Targeted ultrasound initiative). One of the main goals of TUI initiative is standardisation and formal assessment of musculoskeletal ultrasound. PMID- 23745471 TI - [Role of diagnostic ultrasound in assessment of disease activity in rheumatoid arthritis]. AB - Since biologics have been introduced for the treatment of rheumatoid arthritis a need for reliable imaging modality to assess treatment efficacy have been opened. In the last years through technological advances diagnostic ultrasound has become highly sensitive and specific method for detection of inflammatory and destructive changes in rheumatoid arthritis. Thus, high resolution ultrasound enhanced by power Doppler has been recognized in clinical studies and in every day work as useful method for assessment of disease activity. Here we give special interest in application of diagnostic ultrasound enhanced by power Doppler for assessment of inflammatory activity, therapeutic decision and monitoring to attain remission in rheumatoid arthritis patients. PMID- 23745472 TI - Transformation--it's up to us. PMID- 23745473 TI - The knowledge and resources you need. PMID- 23745474 TI - Accelerating major gifts. PMID- 23745475 TI - Maximizing social media in multichannel campaigns. PMID- 23745476 TI - Gift planning without GPS. PMID- 23745477 TI - Institutional sustainability. PMID- 23745478 TI - Using lean to improve medication administration safety: in search of the "perfect dose". AB - BACKGROUND: At Virginia Mason Medical Center (Seattle), the Collaborative Alliance for Nursing Outcomes (CALNOC) Medication Administration Accuracy Quality Study was used in combination with Lean quality improvement efforts to address medication administration safety. METHODS: Lean interventions were targeted at improving the medication room layout, applying visual controls, and implementing nursing standard work. The interventions were designed to prevent medication administration errors through improving six safe practices: (1) comparing medication with medication administration record, (2) labeling medication, (3) checking two forms of patient identification, (4) explaining medication to patient, (5) charting medication immediately, and (6) protecting the process from distractions/interruptions. RESULTS: Trained nurse auditors observed 9,244 doses for 2,139 patients. Following the intervention, the number of safe-practice violations decreased from 83 violations/100 doses at baseline (January 2010-March 2010) to 42 violations/100 doses at final follow-up (July 2011-September 2011), resulting in an absolute risk reduction of 42 violations/100 doses (95% confidence interval [CI]: 35-48), p < .001). The number of medication administration errors decreased from 10.3 errors/100 doses at baseline to 2.8 errors/100 doses at final follow-up (absolute risk reduction: 7 violations/100 doses [95% CI: 5-10, p < .001]). The "perfect dose" score, reflecting compliance with all six safe practices and absence of any of the eight medication administration errors, improved from 37 in compliance/100 doses at baseline to 68 in compliance/100 doses at the final follow-up. CONCLUSION: Lean process improvements coupled with direct observation can contribute to substantial decreases in errors in nursing medication administration. PMID- 23745479 TI - A multicenter, multidisciplinary, high-alert medication collaborative to improve patient safety: the Singapore experience. AB - BACKGROUND: High-alert medications can cause significant patient harm when used in error. A multicenter, multidisciplinary, high-alert medication collaborative was established in Singapore in 2009 to identify and maintain a current list of high-alert medications and to create systematic approaches for preventing and reducing the risk of medication errors and adverse drug events (ADEs) for high alert medications. METHODS: The collaborative was led by a core multidisciplinary team consisting of pharmacists, nurses, and physicians, as well as clinical services and quality personnel, from six primary and acute care institutions. Multidisciplinary work groups were formed to drive the improvement efforts using the Plan-Do-Study-Act (PDSA) cycles. Tracking of improvement work was conducted with an adaptation of the Institute for Healthcare Improvement Trigger Tool method. RESULTS: A localized high-alert medication list was developed through local ADE reports, literature review, an online survey of health care professionals, and expert opinion. Some 130 interventions were proposed to prevent, detect, and mitigate harm from the use of high-alert medications for 10 drug classes/drugs. A significant number of these interventions were tested and revised during the PDSA cycles before implementation throughout the institution and subsequent spread to other institutions. Outcome audits identified areas for improvement. The interventions, which were subsequently incorporated into the change packages, led to a 50% and 67% decline in the ADE rates for radiocontrast agents and heparin, respectively. CONCLUSION: The collaborative has provided a sound framework for ongoing development and refinement of high-alert medication change packages and for sharing of ADE data and best practices across the participating institutions. PMID- 23745480 TI - Measuring handoff quality in labor and delivery: development, validation, and application of the Coordination of Handoff Effectiveness Questionnaire (CHEQ). AB - BACKGROUND: A prospective, nonblinded intervention study was conducted (1) to evaluate the psychometric properties of a new questionnaire, the CHEQ (Coordination of Handoff Effectiveness Questionnaire) for measuring the quality of handoff interactions in labor and delivery (L&D) and (2) to demonstrate the utility of the CHEQ in evaluating the effectiveness of a previously described intervention, the tangible handoff, for standardizing handoffs in L&D. METHODS: The CHEQ incorporates three existing handoff-related scales: teamwork climate, job satisfaction, and burnout. Two new scales--information quality and process quality--were developed, refined, and evaluated. The CHEQ was administered to 56 eligible L&D nurses pre- and post-implementation of the tangible handoff intervention. RESULTS: Baseline and postintervention response rates for the CHEQ were 98% and 84%, respectively. Overall, the teamwork climate scale significantly improved from 57.17% to 68.35% (t = -2.84, p = .006), and the burnout scale significantly decreased from 49.70% to 36.21% (t = -2.56, p = .012) following implementation of the tangible handoff. Job satisfaction improved, although not at a statistically significant level. Cronbach's alpha results ranged from .68 to .96 for all scales, both pre- and post-intervention. CONCLUSIONS: The CHEQ is psychometrically sound for evaluating handoffquality, is practical to administer, achieves high response rates, and is amenable to straightforward statistical analysis. The CHEQ is useful for evaluating handoff quality and gauging the responsiveness to a unit-level intervention in the scope of unit-level climate. The CHEQ may be replicated or adapted for other clinical areas to investigate handoffs and inform the design and evaluation of handoff interventions. PMID- 23745481 TI - Enhancing the effectiveness of follow-up phone calls to improve transitions in care: three decision points. AB - BACKGROUND: Unavoidable rehospitalizations are frequent, costly, and burdensome for patients and families. The incidence of rehospitalizations within 30 days of discharge can be reduced by improving communication and coordination of care, including enhancing communication with patients and families. Postdischarge follow-up calls are often cited as a cost-effective intervention, yet there is little standardization on how they should be conducted. METHODS: A nonsystematic review of the literature focused on the use of telephone follow-up (TFU) to improve postdischarge processes and reduce avoidable readmissions. Its use was also examined as a component of postdischarge processes among hospitals and organizations participating in the STate Action on Avoidable Rehospitalizations (STAAR) initiative. THE THREE DECISION POINTS: (1) Who Should Make the Call? The decision about who should initiate telephone contact will involve multiple considerations, such as available staff time, level of clinical knowledge required, and financial and practical sustainability. (2) Which Information Is Essential? Care teams should define the follow-up calls' short- and long-term goals and then identify the information needed to achieve them. A standardized assessment sheet may help ensure that patients are always asked the appropriate questions to ascertain whether they require advice and/or intervention, changes in medication, or a visit to their physician or emergency department. (3) What is the Optimal Timing, Frequency, and Duration of Follow-up Calls? The frequency of calls should depend on the patient population, and the duration on the length of the standardized assessment or telephone script and on patient need. CONCLUSION: TFU should continue to be explored as a cost-effective option to reduce readmissions. PMID- 23745482 TI - Using an assessment tool to identify risk of osteopenia in infants and prevent fractures. PMID- 23745483 TI - A framework for patient safety: a defense nuclear industry--based high reliability model. PMID- 23745484 TI - [Rol in Mexico]. PMID- 23745485 TI - [Profile of women with breast disease wich does self-exploration. Which are the factors associated with this practice?]. AB - BACKGROUND/AIMS: In recent decades the fight against breast cancer has focused primarily on the treatment and secondary prevention (early detection mainly). In the case of breast self-examination, althought it has not been prove to reduce mortality, it is important in cases detected by women themselves (it is estimated 90% of total), mainly in the interval cancers. OBJECTIVES: To identify within women with breast cancer, how many do self-examination and identify associated factors. Describe the clinical and pathological features of cancers in women who do perform self-examination. METHODOLOGY: In women diagnosed with breast cancer during 2007 in a hospital in the province of Cadiz, Spain, is reconstructed in retrospect the story related the cancer process: symptoms, psychosocial factors that determine the contact with the health system, preventive practices (self examination, mammography screening). A description of the pathological tumor: presenting symptom, tumor size, node negative, grade of differentiation. RESULTS: We studied 149 women with breast cancer, from whom 52% did self-exploration. Women who performed self-examination were younger (54.78 years) against the women who did not (65.63 years), married (66.2%), active workers and have a higher educational level. The assessment of the first symptoms in these women as "important" is positively correlated with those women who practice self examination. For other preventive practices, women who does self-examination are also the most actives in early detection programs (74.4% against 29.5% which didn't do self-examination). For the pathologic characteristics of tumor in women who did self-examination: the tumor size was 2.5 cm, 50.7/are well differentiated, and 59.1% of cases the nodes are negative. CONCLUSIONS: Women who does self-examination are younger, have higher educational level, are married, are active workers and are often involved in other preventive practices. On them, the tumors diagnosed have a smaller size, are diagnosed at earlier stages and usually present better degree of differentiation. PMID- 23745486 TI - [Breast self-examination as main technique for breast cancer prevention]. AB - Breast cancer is the most common malignancy in women. Breast self-examination stands out as the main preventive measure, since almost 95% of breast tumours are detected by the woman herself through this technique. Nursing is the group most closely related to health education appropriate guidelines to perform the technique correctly: monthly technical realization, recognition of abnormalities in the breast, go to the doctor for possible doubt about changes in them, etc. PMID- 23745487 TI - [A lump in the breast]. AB - The statistics seem to indicate that at some point in their lives, one in nine women must face breast cancer. The author recounts hi personal way of moving forward and sharing the questions and answers that have been found in this way. She is the author of the book with the same title that his article. PMID- 23745488 TI - [Pulsing the rhythm of life. Interview by Maria Jesus Nadal Nadal]. PMID- 23745489 TI - [Spanish nursing, 1977-1978]. PMID- 23745490 TI - [Patients with oral anticoagulant therapy]. AB - INTRODUCTION: patients with ACO treatment must have some knowledge about the risks it causes. For this, that medical personnel must give and proper education in quality and quantity both the patient and the family. OBJECTIVES: determine the knowledge level in relation with the treatment ACO that the patients treated have in an AP query in a rural healthy area like is Plasencia. MATERIAL AND METHOD: an observational descriptive retrospective study was conducted with 34 patients who was being treated with ACO. Data about pathologies, biometrics parameters about the clinical historical and interviews with the patients in the nurse query were picked up. RESULTS: when the data were analyzed, the number of the patients according to the sex was equaled. Not according to the ages: people between 80-90 years old were the 26.5% from the total. About the pathologies causatives of the treatment, the FA is the most frequent with the 50%, followed by the pulmonary thromboembolism with the 23%. The control of the results was distributed controlling the youngest people at the hospital, the oldest people in AP. In relation with the tracing of the treatment, people with FA and valve prosthesis were the people most fulfilled. DISCUSSION: To the medical personnel it is necessary to know the patient ACO profile, as the risk associated treatment. Young patients with cardiovascular pathologies are controlled at the hospital for they most variation in results, controlled in older primary care patients (AP) and rural residents have greater grip and better control. With this knowledge, medical personnel would make interventions for help adherence, monitoring control, treatment as well as the collaboration of family. PMID- 23745491 TI - [Rol, awarded as a scientific periodical with the largest trajectory and exemplary dedication to nursing]. PMID- 23745492 TI - [Continuous monitoring systems of glucose]. AB - The possibility of obtaining a continuous reading of glucose may represent a breakthrough and a useful tool for the management of diabetes. Technological advances can improve the quality of life and people with diabetes metabolic control, even if this means having to learn and incorporate new technical concepts, new algorithms for pattern modification and new challenges in Therapeutic Education. PMID- 23745493 TI - [Factors influencing research activity of Andalusian nurses and improvement strategies]. AB - OBJECTIVES: To identify factors influencing research activity of Andalusian nurses and to find improvement strategies. METHODS: Qualitative research using SWOT analysis (weaknesses, threats, strengths, opportunities). Nurses were selected deliberately in eight groups according to predetermined criteria. Analysis included categorization and relationship of factors and strategies. RESULTS: 81 participants were included in groups of 7-12 range. 45 categories were identified with 212 factors: 12 weaknesses (50 factors), 10 strengths (44 factors), 12 threats (68 factors) and 11 opportunities (50 factors). In addition, 32 categories were identified with 53 strategies: 14 categories of W-T strategies (42 strategies), 3 categories of S-T strategies (11 strategies), 5 categories of W-O strategies (13 strategies) and 10 categories of S-O strategies (41 strategies). CONCLUSION: Nurses identified numerous factors, mainly threats. The strategies are focused on W-T but they also suggest many but weak 5-0 strategies due to the low potential of the opportunities and strengths perceived. PMID- 23745494 TI - [Promoting active aging]. PMID- 23745495 TI - [A great encounter of community nursing and primary care]. PMID- 23745496 TI - [Is HbA1c 40 mmol/mol a sign of good diabetes care?]. PMID- 23745497 TI - [Let the county councils take over the occupational health services]. PMID- 23745498 TI - [Propranolol first choice in infantile hemangiomas. Large randomized trials are needed to determine the dosage and duration of treatment]. PMID- 23745499 TI - [Hemangioma can be effectively treated with propranolol. Experiences from twelve cases, with promising results and few side effects]. PMID- 23745500 TI - [Propanolol effective treatment for laryngo-tracheal hemangioma]. PMID- 23745501 TI - [MRSA in primary health care facilities]. PMID- 23745502 TI - [Pharmacogenetic analysis can predict adverse effects of statins]. PMID- 23745503 TI - [QTc-prolongation in acute drug-poisoning. Guidelines for management from the Swedish Poisons Information Centre]. PMID- 23745505 TI - [Let forensic physicians work on weekends]. PMID- 23745504 TI - [Niemann-Pick type C disease. Rare but possible diagnosis in adult neurology and psychiatry]. PMID- 23745506 TI - [More defibrillators needed in society]. PMID- 23745507 TI - [The patient information act should be supplemented with guidelines on medical record procedures]. PMID- 23745508 TI - Mechanism of copper incorporation in subunit II of cytochrome C oxidase from Thermus thermophilus: identification of intermediate species. AB - Detailed spectroscopic and kinetic studies of incorporation of copper ion in the wild type (WT) and the D111AA (AA = K, N, or E) mutants of the metal ion binding site of the soluble fragment of subunit II of cytochrome c oxidase from Thermus thermophilus (TtCuA) showed the formation of at least two distinct intermediates. The global analyses of the multiwavelength kinetic results suggested a four-step reaction scheme involving two distinct intermediates in the pathway of incorporation of copper ions into the apoprotein forming the purple dinuclear CuA. An early intermediate similar to the red copper binding proteins was detected in the WT as well as in all the mutants. The second intermediate was a green copper species in the case of WT TtCuA. Mutation of Asp111, however, formed a second intermediate that is distinctly different from that formed in the case of the WT protein, suggesting that mutants follow pathways of copper ion incorporation different from that in the WT protein. The electrostatic interaction between Asp111 and the coordinating His114 possibly plays a subtle role in the mechanism of incorporation of metal ion into the protein. The overall Kd for WT TtCuA was found to be ~8 nM, which changed with mutation of the Asp111 residue. The activation and thermodynamic parameters were also determined from the temperature- and pH-dependent multiwavelength kinetics, and the results are discussed to unravel the role of Asp111 in the mechanism of formation of the dinuclear CuA center in cytochrome c oxidase. PMID- 23745509 TI - Conductive PVDF-HFP nanofibers with embedded TTF-TCNQ charge transfer complex. AB - Tetrathiafulvalene-tetracyanoquinodimethane charge-transfer complex (TTF-TCNQ CTC) represents a promising organic conductive system. However, application of this donor-acceptor pair is highly limited, because of its ultrafast crystallization kinetics and very low solubility. In this work, conductive organic nanofibers were generated via a coelectrospinning process of poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) with embedded TTF and TCNQ in the shell and core solutions, respectively. Upon supply of the polymer solutions, a core-shell droplet was formed at the exit of the spinneret. The electron donor TTF and the electron acceptor TCNQ migrated toward each other, within the compound droplet, to produce conductive CTC crystals. In the presence of a sufficiently strong electric field, jetting set in at the droplet tip, which yielded solidified PVDF-HFP nanofibers embedded with aligned CTC. Fiber diameters ranged between 100 and 500 nm. X-ray analysis showed strong equatorial reflections (110,200) of oriented copolymer PVDF-HFP crystals (beta-phase) with copolymer chains oriented along the fiber axis, and of CTC (001), indicating that the CTC molecular planes were aligned parallel to the nanofiber axis. In addition, reflections of unreacted TCNQ (120,220) and TTF (110) crystals were observed. The electrospun nanofibers were collected to form a fiber mat, which was evaluated as a working electrode in a three-electrode cell system, exhibiting differential conductance of 5.23 MUmho. PMID- 23745511 TI - Biological responses to activated carbon amendments in sediment remediation. AB - Sorbent amendment with activated carbon (AC) is a novel in situ management strategy for addressing human and ecological health risks posed by hydrophobic organic chemicals (HOCs) in sediments and soils. A large body of literature shows that AC amendments can reduce bioavailability of sediment-associated HOCs by more than 60-90%. Empirically derived biodynamic models can predict bioaccumulation in benthic invertebrates within a factor of 2, allowing for future scenarios under AC amendment to be estimated. Higher AC dose and smaller AC particle size further reduce bioaccumulation of HOCs but may induce stress in some organisms. Adverse ecotoxicity response to AC exposure was observed in one-fifth of 82 tests, including changes in growth, lipid content, behavior, and survival. Negative effects on individual species and benthic communities appear to depend on the characteristics of the sedimentary environment and the AC amendment strategy (e.g., dose and particle size). More research is needed to evaluate reproductive end points, bacterial communities, and plants, and to link species- and community level responses to amendment. In general, the ability of AC to effectively limit the mobility of HOCs in aquatic environments may outshine potential negative secondary effects, and these outcomes must be held in comparison to traditional remediation approaches. PMID- 23745510 TI - A ratiometric two-photon fluorescent probe reveals reduction in mitochondrial H2S production in Parkinson's disease gene knockout astrocytes. AB - Hydrogen sulfide (H2S) is a multifunctional signaling molecule that exerts neuroprotective effects in oxidative stress. In this article, we report a mitochondria-localized two-photon probe, SHS-M2, that can be excited by 750 nm femtosecond pulses and employed for ratiometric detection of H2S in live astrocytes and living brain slices using two-photon microscopy (TPM). SHS-M2 shows bright two-photon-excited fluorescence and a marked change in emission color from blue to yellow in response to H2S, low cytotoxicity, easy loading, and minimum interference from other biologically relevant species including reactive sulfur, oxygen, and nitrogen species, thereby allowing quantitative analysis of H2S levels. Molecular TPM imaging with SHS-M2 in astrocytes revealed that there is a correlation between the ratiometric analysis and expression levels of cystathionine beta-synthase (CBS), the major enzyme that catalyzes H2S production. In studies involving DJ-1, a Parkinson's disease (PD) gene, attenuated H2S production in comparison with wild-type controls was observed in DJ-1-knockout astrocytes and brain slices, where CBS expression was decreased. These findings demonstrate that reduced H2S levels in astrocytes may contribute to the development of PD and that SHS-M2 may be useful as a marker to detect a risk of neurodegenerative diseases, including PD. PMID- 23745512 TI - A novel approach of periodate oxidation coupled with HPLC-FLD for the quantitative determination of 3-chloro-1,2-propanediol in water and vegetable oil. AB - A novel approach of periodate oxidation coupled with high-performance liquid chromatography (HPLC)-fluorescence detection (FLD) for the quantitative determination of 3-chloro-1,2-propanediol (3-MCPD) has been established. The essence of this approach lies in the production of chloroacetaldehyde by the oxidization cleavage of 3-MCPD with sodium periodate and the HPLC analysis of chloroacetaldehyde monitored by an FLD detector after fluorescence derivatization with adenine. The experimental parameters relating to the efficiency of the derivative reaction such as concentration of adenine, chloroacetaldehyde reaction temperature, and time were studied. Under the optimized conditions, the proposed method can provide high sensitivity, good linearity (r(2) = 0.999), and repeatability (percent relative standard deviations between 2.57% and 3.44%), the limits of detection and quantification were 0.36 and 1.20 ng/mL, respectively, and the recoveries obtained for water samples were in the range 93.39-97.39%. This method has been successfully applied to the analysis of real water samples. Also this method has been successfully used for the analysis of vegetable oil samples after pretreatment with liquid-liquid extraction; the recoveries obtained by a spiking experiment with soybean oil ranged from 96.27% to 102.42%. In comparison with gas chromatography or gas chromatography-mass spectrometry, the proposed method can provide the advantages of simple instrumental requirement, easy operation, low cost, and high efficiency, thus making this approach another good choice for the sensitive determination of 3-MCPD. PMID- 23745513 TI - Biliary epithelial cells play an essential role in the reconstruction of hepatic tissue with a functional bile ductular network. AB - One of the most challenging issues in liver tissue engineering is the incorporation of a functional bile duct (BD) network in the hepatic tissue. In this study, we investigated the feasibility of a three-dimensional (3D) coculture of adult rat primary biliary epithelial cells (ABECs) and rat fetal liver cells (FLCs) to form functional BD structures. 3D hetero-spheroids containing various ratios of the two cell types were successfully obtained in low-adherence, round bottom, 96-well plates. Histological analyses and functional analysis using fluorescein diacetate demonstrated that the ABECs critically contributed to the reconstruction of continuous ductular networks. Metabolized fluorescein was transported toward cystic structures in a time- and ABEC ratio-dependent manner. In particular, the duct-like structures containing fluorescein accumulations interlinked the large cystic accumulations. Furthermore, transplantation experiments demonstrated that ABECs, but not FLCs, enabled the establishment of BD networks in vivo. This study provided important insights into the development of transplantable liver tissues with bile excretion functionality. PMID- 23745514 TI - Adipocytokines in childhood cancer survivors and correlation with metabolic syndrome components. AB - BACKGROUND: Although there are several studies on the prevalence of metabolic syndrome (MetS) in childhood cancer survivors (CCS), the association between MetS components and serum adipocytokine level has not been elucidated. METHODS: The charts of 49 patients (27 male, 22 female) who had attended the CCS clinic of the Department of Pediatrics, Kyoto University Hospital, between April 2009 and March 2010 were retrospectively reviewed. Median age was 10.7 years, and the median interval since the completion of chemotherapy was 5.1 years. The diagnosis of MetS was made based on the Japanese criteria for either children or adults. RESULTS: Three (6.1%) of 49 patients fulfilled the criteria for MetS, and 28 (57.1%) had at least one component of MetS. High leptin level was seen in 18 patients (36.7%), and low total adiponectin level was seen in 20 (40.8%). The number of patients with high leptin was correlated with body mass index z-score (>2.0), abdominal circumference/height (>=0.5), diastolic blood pressure and fasting blood sugar. The number of patients with low total adiponectin was correlated with systolic blood pressure and triglyceride. When the patients were divided into three groups based on the number of positive MetS components (0, 1 and 2-4), leptin and adiponectin tended to be higher and lower in the third group, respectively. CONCLUSIONS: Adipocytokines may play a role in the pathogenesis of MetS occurring in CCS. It is recommended that adipocytokines be evaluated together with MetS components at the CCS follow-up clinics. PMID- 23745515 TI - Hydrophobic segment of dengue virus C protein. Interaction with model membranes. AB - Dengue virus (DENV) C protein is essential for viral assembly. DENV C protein associates with intracellular membranes through a conserved hydrophobic domain and accumulates around endoplasmic reticulum-derived lipid droplets which could provide a platform for capsid formation during assembly. In a previous work we described a region in DENV C protein which induced a nearly complete membrane rupture of several membrane model systems, which was coincident with the theoretically predicted highly hydrophobic region of the protein. In this work we have carried out a study of the binding to and interaction with model biomembranes of a peptide corresponding to this DENV C region, DENV2C6. We show that DENV2C6 partitions into phospholipid membranes, is capable of rupturing membranes even at very low peptide-to-lipid ratios and its membrane-activity is modulated by lipid composition. These results identify an important region in the DENV C protein which might be directly implicated in the DENV life cycle through the modulation of membrane structure. PMID- 23745516 TI - Mixed treatment comparison of efficacy and tolerability of biologic agents in patients with rheumatoid arthritis. AB - OBJECTIVE: To determine the comparative efficacy and tolerability of abatacept and tumor necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA) and inadequate response to conventional disease modifying anti-rheumatic drugs (DMARDs). RESEARCH DESIGN AND METHODS: A systematic review identified RCTs in RA patients who responded inadequately to conventional DMARDs and were treated with one of the following biologic agents: abatacept, adalimumab, etanercept, infliximab, certolizumab pegol, or golimumab. Bayesian hierarchical models were used to compare efficacy and tolerability outcomes of abatacept and combined TNFi at 6 months and 1 year. RESULTS: In this mixed treatment comparison (MTC), the likelihood of achieving ACR response was comparable between abatacept and combined TNFi at 6 months for ACR20, 50, and 70: (odds ratio [OR] = 0.98 [95% confidence interval (CI): 0.73, 1.27], 0.99 [0.73, 1.31], and 0.91 [0.62, 1.27], respectively); and at 12 months for ACR20 (OR = 1.27 [0.92, 1.71]) and ACR50 (1.21 [0.82, 1.68]), with a higher likelihood of achieving an ACR70 response at 12 months (1.41 [1.02, 1.82]). Odds of DAS28 remission at 12 months was greater for abatacept than the combined TNFi (OR = 2.03 [1.04, 3.58]). Abatacept had better tolerability, defined as a lower likelihood of withdrawal due to adverse events, at both 6 and 12 months (OR = 0.38 [0.10, 0.88] and 0.51 [0.27, 0.86], respectively). These analyses include indirect comparisons across clinical trials and are not a replacement for head-to-head data. While all TNFi have been grouped into one class, there may be some differences between the individual TNFi that are not captured in our study. CONCLUSIONS: In this MTC, abatacept demonstrated similar efficacy at 6 months, a higher likelihood of achieving ACR70 response and DAS28 remission at 12 months and better tolerability relative to the combined TNFi in patients with RA who had an inadequate response to conventional DMARDs. PMID- 23745517 TI - Hypertension and vascular dementia in the elderly: the potential role of anti hypertensive agents. AB - BACKGROUND: Vascular dementia (VaD) - a severe form of vascular cognitive impairment - and cognitive decline are associated with hypertension and therefore it seems logical to consider that reducing BP with anti-hypertensive therapy may protect against the development/onset of cognitive function impairment or dementia. SCOPE: This narrative, non-systematic review discusses the available evidence on the potential correlation between the use of anti-hypertensive agents and the risk of VaD and cognitive decline. METHODS: MEDLINE was searched for inclusion of relevant studies. No limitations in time were considered. RESULTS: A consensus on the potential effects of anti-hypertensive treatment in the reduction of VaD and associated cognitive decline has not been reached. A protective effect of anti-hypertensive agents has been observed in a number of studies although it is still unclear whether different classes of anti hypertensive agents have a different effect on the development of VaD. CONCLUSIONS: The protective effect of anti-hypertensive agents appears to depend on the specific drug used - positive effects have been observed with calcium channel blockers (CCBs), such as lercanidipine and nitrendipine, the combination perindopril-indapamide and telmisartan. PMID- 23745518 TI - Incidence and risk of denosumab-related hypocalcemia in cancer patients: a systematic review and pooled analysis of randomized controlled studies. AB - PURPOSE: The aim of this study is to evaluate the frequency and relative risk of hypocalcemia in cancer patients receiving denosumab. METHODS: We searched the PubMed (data from 1966 to October 2012), Embase (data from 1980 to October 2012) and Cochrane Library (up to October 2012) electronic databases for relevant randomized controlled trials (RCTs). Abstracts presented at conferences were also searched. Phase II and III trials of denosumab in patients with any type of cancer that reported occurrence of hypocalcemia were eligible. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models depending on the heterogeneity among included trials. RESULTS: A total of 8990 patients with a variety of solid tumors from seven RCTs were included for the meta-analysis. The overall incidences of all-grade and high-grade hypocalcemia in cancer patients were 5.2% (95% confidence interval [CI]: 2.8-9.3%) and 2.0% (95% CI: 0.7-5.5%), respectively. The use of denosumab was associated with significantly increased risk of developing all-grade (RR 1.932, 95% CI: 1.590-2.347, p < 0.001) and high-grade hypocalcemia (RR 4.027, 95% CI: 2.346-6.912, p < 0.001) in comparison with controls. CONCLUSIONS: The use of denosumab is associated with a significantly increased risk of developing hypocalcemia (p < 0.001). Physicians should be aware of this adverse effect and should monitor cancer patients receiving denosumab. PMID- 23745519 TI - Variations in blood pressure and lipid goal attainment in primary care. AB - BACKGROUND: Hypertension and dyslipidemia are the most prevalent cardiovascular risk factors. Blood pressure (BP) and lipid levels are modifiable and yet most patients fail to achieve their recommended target goals. The objective of this review was to examine the variations in achievement of optimal BP and lipid levels in individuals with cardiovascular risk factors or cardiovascular disease at a primary care level. SCOPE: A comprehensive literature review and evaluation was conducted from January 2000 to June 2012 using electronic databases. The search was limited to studies reported in English language, published between January 2000 to June 2012 and those conducted in the US adult population (>=18 years). The inclusion of articles was limited to populations with cardiovascular risk factors or any cardiovascular disease. FINDINGS: The review identified a total of 32 studies that assessed variations in attainment of BP or lipid goals. The demographic factors (age, sex, and race) and clinical factors (obesity, presence of diabetes, and history of cardiovascular conditions) were most commonly evaluated by the studies. However, modifiable factors such as diet, physical exercise, adherence to medication, or smoking habit were least commonly evaluated by the studies documented in this review. CONCLUSION: The studies, conducted in a range of settings, reflect disparities in attainment of recommended BP or lipid goals. Given such disparities, future research is required to better understand the complexity of different factors underlying the failure of patients to achieve BP and lipid goals. This can help to identify appropriate treatment strategies or interventions that can address patient specific needs at a primary care level. PMID- 23745520 TI - Robust and flexible free-standing films for unidirectional drug delivery. AB - Robust and flexible free-standing polymer films for unidirectional drug delivery are fabricated by sandwiching drug-containing polyelectrolyte multilayer films between poly(lactic-co-glycolic acid) (PLGA) barrier and capping layers. The drug containing films are fabricated by layer-by-layer (LbL) assembly of chemically cross-linked poly(allylamine hydrochloride)-dextran (PAH-D) microgel and hyaluronic acid (HA), which can load negatively charged cancer-inhibiting drug, methotrexate (MTX). Because the PLGA barrier layer effectively blocks MTX release, MTX can be predominantly released from the PLGA capping layer of the free-standing film. This increases the efficacy of released MTX to cancer cells while minimizing its side effects on the normal tissues. We believe that the unidirectional drug delivery free-standing films can open a new avenue to design of highly efficient drug delivery systems for biomedical application. PMID- 23745521 TI - Moving forward to 2014: global IHR (2005) implementation. PMID- 23745522 TI - Health and national security: a contemporary collision of cultures. PMID- 23745523 TI - Implementation of a personnel reliability program as a facilitator of biosafety and biosecurity culture in BSL-3 and BSL-4 laboratories. AB - In late 2010, the National Biodefense Analysis and Countermeasures Center (NBACC) implemented a Personnel Reliability Program (PRP) with the goal of enabling active participation by its staff to drive and improve the biosafety and biosecurity culture at the organization. A philosophical keystone for accomplishment of NBACC's scientific mission is simultaneous excellence in operations and outreach. Its personnel reliability program builds on this approach to: (1) enable and support a culture of responsibility based on human performance principles, (2) maintain compliance with regulations, and (3) address the risk associated with the insider threat. Recently, the Code of Federal Regulations (CFR) governing use and possession of biological select agents and toxins (BSAT) was amended to require a pre-access suitability assessment and ongoing evaluation for staff accessing Tier 1 BSAT. These 2 new requirements are in addition to the already required Federal Bureau of Investigation (FBI) Security Risk Assessment (SRA). Two years prior to the release of these guidelines, NBACC developed its PRP to supplement the SRA requirement as a means to empower personnel and foster an operational environment where any and all work with BSAT is conducted in a safe, secure, and reliable manner. PMID- 23745524 TI - Brine shrimp lethality assay 'an effective prescreen': microwave-assisted synthesis, BSL toxicity and 3DQSAR studies-based designing, docking and antitumor evaluation of potent chalcones. AB - CONTEXT: In the course of searching potential antitumor agents from a library of chalcones synthesized under microwave irradiations, the brine shrimp lethality (BSL) assay and a 3D structure-activity relationship (3DQSAR) studies were followed by the antitumor evaluation of most potent analogues. OBJECTIVE: The objective of the current study was to effectively use the BSL assay for the identification of potential cytotoxic analogues from a set of compounds. METHODS: We applied the comparative molecular field analysis (CoMFA) and devised 3DQSAR on 33 synthesized chalcones leading to prediction of five related compounds with improved activity. The scope of BSL assay for the prediction of antitumor potency was tested through the in vitro antitumor studies against six human tumor cell lines, docking studies and the tubulin-polymerization assay. RESULTS: The newly designed compounds 34-38 displayed very promising cytotoxic potency. From our results, the BSL toxicity, antitumor efficacy and docking outcomes could be easily co-related. CONCLUSION: The study draws a very good relationship between a simple, inexpensive, and bench-top BSL assay and the antitumor potential of the cytotoxic compounds. Devising the CoMFA analysis helped in designing chalcones with improved cytotoxic potential as displayed through their BSL and cytotoxic activity against human tumor cell lines. The studies are noteworthy as such comprehensive studies were never performed before on the BSL assay. The present studies widen the scope of the BSL model that may prove quite helpful as a preliminary screen in the antitumor drug designing and synthesis expeditions. PMID- 23745525 TI - Hyaluronic acid improves the tolerability of hypertonic saline in the chronic treatment of cystic fibrosis patients: a multicenter, randomized, controlled clinical trial. AB - TRIAL DESIGN AND METHODS: Between December 2009 and July 2011, four cystic fibrosis (CF) centers in Italy participated in a randomized, double-blind, controlled clinical trial to test whether 7% hypertonic saline (HS) administered together with 0.1% hyaluronic acid (HA) was better tolerated by patients who previously did not tolerate HS well on its own. Participants were CF patients at least 8 years old, in clinically stable conditions, with forced expiratory volume in 1 sec (FEV1) at least 50% predicted. Forty patients were recruited and randomized to receive either HS or HS plus HA (5 mL to be inhaled over 15 min, twice daily for 28 days). Primary endpoints were cough, throat irritation, salty taste, and overall acceptability, as assessed by each patient on a semiquantitative scale on a diary card. Secondary endpoint was FEV1 change at the end of treatment. Patients were randomized into randomly permuted blocks. The first and last doses were administered in hospital. In between, patients were treated at home. Patients, all caregivers, and the statistician who conducted the analysis (different from the one who generated the random list) were blinded to group assignment. RESULTS: Severity of cough, throat irritation, and saltiness were more severe in patients treated with HS alone, both after the first inhalation and over the entire treatment period. Overall pleasantness was rated higher by patients treated with the combination product. All differences were highly significant. There were no changes in FEV1 between the first and last administrations. Five patients did not complete the study. Four patients (two from each group) withdrew because of cough or throat irritation. One more patient from the HS group withdrew because of a respiratory exacerbation at week 3. CONCLUSIONS: HS is currently a cornerstone in the treatment of CF patients. The addition of HA to HS reduces the prevalence and severity of cough, throat irritation, and saltiness and may improve compliance in patients who previously did not tolerate HS well on its own. Longer-term studies could further assess the benefit of chronic treatment. PMID- 23745526 TI - Comparison of dry powder versus nebulized beta-agonist in patients with COPD who have suboptimal peak inspiratory flow rate. AB - BACKGROUND: A peak inspiratory flow rate (PIFR) of <60 L/min against the internal resistance (resist) of a dry powder inhaler (DPI) may limit the ability of a patient with chronic obstructive pulmonary disease (COPD) to achieve bronchodilation. The hypothesis was that lung function would be higher with a beta-agonist inhaled via nebulization compared with dry powder in patients with COPD who exhibit a PIFRresist of <60 L/min against the Diskus((r)). METHODS: This study was randomized, single-blind, and crossover with spirometry and inspiratory capacity (IC) measured at 15, 30, and 120 min post treatment. The efficacy of arformoterol aerosol solution (15 MUg/2 mL) via nebulizer was compared with salmeterol dry powder (50 MUg) via Diskus. The primary outcome was the change in lung function from baseline at 2 hr as these two inhaled beta-agonists have the similar peak bronchodilator effect as measured by forced expiratory volume in 1 sec (FEV1). RESULTS: Twenty patients (15 females/5 males) with postalbuterol FEV1 of 0.83+/-0.31 L (38+/-12% predicted) and PIFRresist of 53+/-5 L/min completed the study. At 15 min, improvements in FEV1, forced vital capacity (FVC), and IC were significantly higher with arformoterol than with salmeterol. At 2 hr, changes in FVC and IC, but not FEV1, were significantly higher with arformoterol. At visit 3, patient preference was similar for salmeterol Diskus (n=8) and arformoterol solution (n=7), whereas five patients reported no preference. CONCLUSIONS: At peak effect (2 hr), volume responses were greater with arfomoterol via nebulizer compared with dry powder salmeterol in patients with COPD who had a PIFRresist of <60 L/min. Bronchodilator therapy via nebulization should be considered in patients with COPD who have a suboptimal PIFRresist against a particular DPI. PMID- 23745527 TI - An expedient and divergent tandem one-pot synthesis of pyrimidin-2,4-diones using the Blaise reaction intermediate. AB - A novel divergent tandem one-pot method for the synthesis of 3,5,6-trisubstituted 1H-pyrimidin-2,4-dione derivatives is developed. In the presence of 10 mol % of Cu(OAc)2, the alpha-substituted Blaise reaction intermediates (R(2) ? H) reacted with isocyanates chemoselectively to afford pyrimidin-2,4-diones, whereas the alpha-unsubstituted Blaise reaction intermediate (R(2) = H) showed a propensity to be a C-nucleophile toward electrophiles, permitting the installation of different functionalities at the 5-position through sequential tandem reactions. PMID- 23745528 TI - FRAX score in acromegaly: does it tell the whole story? PMID- 23745529 TI - Cross-reaction and co-sensitization among related and unrelated allergens in canine intradermal tests. AB - BACKGROUND: Intradermal tests are used to identify allergens for avoidance and immunotherapy in atopic dogs. HYPOTHESIS/OBJECTIVES: To evaluate cross-reaction or co-sensitization among 53 intradermal test allergens. ANIMALS: Six hundred and fifty-one client-owned dogs with atopic dermatitis. METHODS: Intradermal tests were performed with 53 house dust/storage mite, epidermal, insect, tree, weed and grass pollen and mould allergens. Pairwise comparisons were used to calculate the odds ratios (ORs), 95% confidence intervals (CIs) and statistical significance for the results of each allergen pair, with significance at P < 0.0006 (Holm Bonferroni correction to reduce the false-detection rate). RESULTS: Apart from cotton, cockroach, red clover, grain smut and Penicillium, the results for the allergens within each group were statistically associated [ORs from 4.7 (CI 2.5 8.9) to 1229.4 (CI 166.5-1795.1); P = 0.0005 to P < 0.0001]. Excluding red clover and cotton, 94% of results between tree, weed and grass pollens were also statistically associated [ORs from 8.3 (CI 3.6-24.7) to 117 (CI 29.1-341); P = 0.0005 to P < 0.0001]. In contrast, few allergens from unrelated groups were statistically associated [ORs from 0.12 (CI 0.03-1.1) to 27.7 (CI 0.2-93); P = 1.0 to P < 0.0001]. The mean (SD) of the log e transformed ORs for the related and statistically associated allergens [5.3 (1.3)] was significantly greater than those for related but nonstatistically associated [1.7 (1.6)] or unrelated allergens [1.4 (1.4); P < 0.0001]. CONCLUSIONS AND CLINICAL IMPORTANCE: This suggests that there is cross-reaction or co-sensitization between related allergens. This could have implications for allergen selection in testing and immunotherapy, but further studies are required to differentiate cross-reaction from co-sensitization. PMID- 23745532 TI - The button graft technique for perforations affecting less than 25% of the tympanic membrane: a non-randomised comparison of a new modification to cartilage tympanoplasty with underlay and overlay grafts. AB - OBJECTIVES: To evaluate a new composite cartilage-perichondrium graft (button graft) for repair of small-sized tympanic membrane perforations and to compare its success rate with that of the underlay and overlay techniques with temporal fascia or tragal perichondrium. DESIGN: Prospective, sequential allocation of surgical technique study. SETTING: Tertiary care university hospital. PATIENTS: One hundred 95 patients aged 14-42 years with central, uncomplicated tympanic membrane perforations with completely visualised margins affecting less than 25% of the tympanic membrane, distributed in three groups: 1 (underlay), 2 (overlay) and 3 (button graft). INTERVENTIONS: Patients were allocated in sequence to: 1 underlay graft, 2 overlay graft and 3 cartilage tympanoplasty with button graft technique. Patients were operated on under local anaesthesia. MAIN OUTCOME MEASURES: Postoperative status of the tympanic membrane, hearing improvement, duration of surgery and incidence of complications at 12 months postoperative. RESULTS: Group 1 (underlay) had 66 patients; group 2 (overlay), 65; and group 3 (cartilage), 66. Success was defined as the complete closure of the tympanic membrane one year after the operation. The success rates were 98.5% (65 of 66), 97% (63 of 65) and 98.5% (65 of 66) cases, and the mean air-bone gap gains were 10.18 (+/-5.4) dB, 8.5 (+6.5) dB and 9.1 (+5.1) dB for groups 1, 2 and 3, respectively. No bone conduction threshold or speech discrimination score worsening was noted. The mean durations of the operative procedure were 35 +/- 8.4 (range 22,63), 42 +/- 6.8 (range 33,75) and 23 +/- 6.3 (range 15,41) min for groups 1, 2 and 3, respectively (P = 0.02). Tympanic membrane retraction occurred in three cases in underlay group 1, and tympanic membrane cholesteatoma pearls occurred in two cases in overlay group 2. CONCLUSIONS: The button graft technique is an effective and fast alternative for the repair of small tympanic membrane perforations if complete visualisation of the margin is possible. The shorter time taken with the button grafts is mainly due to the non-requirement for a skin incision. The results are comparable to those of the underlay and overlay techniques. PMID- 23745533 TI - Anti-adhesive effect of a thermosensitive poloxamer applied after the removal of nasal packing in endoscopic sinus surgery: a randomised multicentre clinical trial. AB - OBJECTIVE: To compare the efficacies of a thermosensitive poloxamer (TPX) and Merogel in preventing adhesion applied after the removal of nasal packing in endoscopic sinus surgery as a non-inferiority trial. DESIGN: Randomised, multicentre, single-blind, active-controlled, matched-pair study. SETTING: Yonsei University Gangnam Severance Hospital, Korea University Guro Hospital. PARTICIPANTS: A total of 70 patients were enroled and underwent endoscopic sinus surgeries. Four of the patients did not complete their follow-up. Analysis of the 66 enroled patients having completed postoperative assessment was performed. The severity of rhinosinusitis was graded with a Lund-McKay CT score, and only those with bilateral disease and a CT score difference <=2 between sinuses were included. MAIN OUTCOME MEASURES: An independent rhinologist from a third institution through a blinded assessment with digital photoendoscopy of the middle meati bilaterally taken postoperatively. RESULTS: In the blinded assessment, thermosensitive poloxamer (anti-adhesion rate: 92%) was similar to Merogel (anti-adhesion rate: 89%). Evaluation of the presence and grade of adhesion, oedema, and infection in the middle meatus revealed no significant differences between the thermosensitive poloxamer group and the Merogel group at all postoperative periods. CONCLUSION: Anti-adhesive effects of thermosensitive poloxamer are similar to those of Merogel. Therefore, thermosensitive poloxamer can be considered a safe alternative to Merogel for preventing adhesion in patients undergoing endoscopic sinus surgeries, and further evaluation of thermosensitive poloxamer as an anti-adhesive and primary packing material compared with the control using no packing is needed. PMID- 23745534 TI - 12-minute consultation: an evidence-based approach to the management of dysphagia. AB - BACKGROUND: Dysphagia is frequently encountered by the otolaryngologist and due to its diverse aetiologies often poses a diagnostic challenge. Of particular importance in diagnosis is to distinguish between oropharyngeal and oesophageal dysphagia. This article aims to provide a systematic, concise and evidence-based method of managing the patient with dysphagia. METHOD: This review was based on a literature search last undertaken on 15 January 2013. The MEDLINE, EMBASE and Cochrane databases were searched using the subject heading dysphagia in combination with classification, diagnosis, investigations, management, treatment and surgery. Results were limited to English language articles including case series, clinical trials, randomised controlled trials, meta-analyses, systematic reviews and review articles. Relevant references from selected articles were also reviewed. RESULTS: The majority of published literature for dysphagia is of level II/III evidence, with 16 relevant randomised controlled trials identified. The clinical history is of paramount importance in delineating the cause of dysphagia. There is no significant difference regarding the diagnostic efficacy of fibreoptic endoscopic evaluation of swallowing compared to videofluoroscopy, and where indicated and practicable, these investigations complement each other. In general, structural causes of dysphagia are managed surgically, whereas swallowing therapy is efficacious in managing dysphagia due to neuromyogenic disorders. CONCLUSIONS: A structured history of dysphagia and its associated symptoms, flexible laryngoscopy and endoscopic assessment of swallowing where relevant in addition to targeted investigations should lead to the correct diagnosis and appropriate management. PMID- 23745536 TI - A randomised trial comparing intraoral ultrasound to landmark-based needle aspiration in patients with suspected peritonsillar abscess. PMID- 23745537 TI - Re: Reducing treatment delay by improving information flow within the multidisciplinary team: a multi cycle audit spiral in head and neck cancer. PMID- 23745538 TI - Intra-operative methylene blue for leak identification during total laryngectomy. PMID- 23745539 TI - Pinnaplasty using the three blade scorer. PMID- 23745540 TI - Removing an endosheath. PMID- 23745541 TI - Tonsillectomy and residents: a safe match? PMID- 23745542 TI - Earplugs presenting as an impacted foreign body in the ear canal. PMID- 23745543 TI - How well is ISCP performing? - an otolaryngologist's overview of the official evaluation report and its executive summary by JCST. PMID- 23745544 TI - Pericyte loss in diabetic retinopathy: mechanisms and consequences. AB - The onset of diabetic retinopathy is characterized by morphologic alterations of the microvessels, with thickening of the basement membrane, loss of inter endothelial tight junctions and early and selective loss of pericytes, together with increased vascular permeability, capillary occlusions, microaneurysms and, later, loss of endothelial cells (EC). A key role in the evolution of the disease is played by pericytes, specialized contractile mesenchymal cells of mesodermal origin, that, in capillaries, exert a function similar to smooth muscle cells in larger vessels, regulating vascular tone and perfusion pressure. Thickening of the basement membrane, together with systemic and local hypertension, hyperglycaemia, advanced glycation end-product formation and hypoxia, may disrupt the tight link between pericytes and EC causing pericyte apoptosis, while endothelium, deprived of proliferation control, can give rise to new vessels. Pericyte dropout has great consequences on capillary remodelling and may cause the first abnormalities of the diabetic eye which can be observed clinically. Hyperglycaemia and local hypertension are known to be a direct cause of pericyte apoptosis and dropout, and intracellular biochemical pathways of the glucose metabolites have been explored. However, the exact mechanisms are not yet fully understood and need further clarification in order to develop new effective drugs for the prevention of retinopathy. PMID- 23745545 TI - Traditional and novel risk factors of diabetic retinopathy and research challenges. AB - Diabetic retinopathy affects one-third of people with diabetes and is the most frequent cause of blindness in working aged adults. Although diabetic retinopathy blindness appears to have fallen in the developed world, the rapidly increasing number of persons with diabetes worldwide has resulted in a continuous increase in the global burden of this disease. The major risk factors for diabetic retinopathy include duration of diabetes, hyperglycemia, and hypertension, but this is accountable for only a small amount of the variation in the risk of diabetic retinopathy. Research into new markers for retinopathy including genetics, blood biomarkers and retinal imaging will further improve our understanding of the risk factors and pathogenesis of diabetic retinopathy. PMID- 23745546 TI - Somatostatin replacement: a new strategy for treating diabetic retinopathy. AB - Diabetic retinopathy (DR) has been classically considered to be a microcirculatory disease of the retina. However, there is growing evidence to suggest that retinal neurodegeneration is an early event in the pathogenesis of DR which participates in the microcirculatory abnormalities that occur in DR. Among the neuroprotective factors synthesized by the retina, somatostatin (SST) is one of the most relevant. In DR there is a downregulation of retinal expression of SST that is associated with retinal neurodegeneration. There is growing evidence suggesting that SST could play a key role in the main pathogenic mechanisms involved in the development of DR (neurodegeneration, neovascularization and vascular leackage). Recently, first evidence that the topical administration of SST prevents retinal neurodegeneration in streptozotozin- induced diabetic rats has been reported. Indeed, SST eye drops prevented b-wave abnormalities in the ERG which are considered sensitive indicators of DR. In addition, SST eye drops prevented, glial activation, apoptosis and the misbalance between proapoptotic and survival signalling caused by diabetes. Furthermore, SST eye drops reduce glutamate- induced excitotoxicity. Therefore, topical administration of SST could be contemplated as an appropriate therapeutic approach for DR. However, clinical trials will be needed to establish its exact position in the treatment of this devastating complication of diabetes. Diabetic retinopathy (DR) has been classically considered to be a microcirculatory disease of the retina. However, there is growing evidence to suggest that retinal neurodegeneration is an early event in the pathogenesis of DR which participates in the microcirculatory abnormalities that occur in DR [1]. The retina synthesizes neuroprotective factors which counteract the deleterious effects of neurotoxic factors involved in neurodegeneration. The loss of these neuroprotective factors or the reduction of their effectiveness is essential for the development of retinal neurodegeneration. Among the neuroprotective and neurotrophic factors somatostatin (SST) is one of the most relevant. The main aim of the present review is to provide experimental evidence supporting the promising therapeutical use of SST to prevent or arrest DR. PMID- 23745547 TI - Advanced glycation end products and diabetic retinopathy. AB - Diabetic retinopathy (DR) has a complex pathogenesis which is impacted by a raft of systemic abnormalities and tissue-specific alterations occurring in response to the diabetes milieu. Many pathogenic processes play key roles in retinal damage in diabetic patients. One such pathway is the formation and accumulation of advanced glycation endproducts (AGEs) and advanced lipoxidation end products (ALEs) which are relevant modifications with roles in the initiation and progression of pathology. In this review, AGE/ALE formation in the diabetic retina is discussed alongside their impact on retinal cell function. In addition, various inhibitors of the AGE-RAGE system and their therapeutic utility for DR will also be evaluated. PMID- 23745548 TI - Fenofibrate: a new treatment for diabetic retinopathy. Molecular mechanisms and future perspectives. AB - Despite improving standards of care, people with diabetes remain at risk of development and progression of diabetic retinopathy (DR) and visual impairment. Identifying novel therapeutic approaches, preferably targeting more than one pathogenic pathway in DR, and at an earlier stage of disease, is attractive. There is now consistent evidence from two major trials, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study and the Action to Control Cardiovascular Risk in Diabetes Eye (ACCORD-Eye) study, totalling 11,388 people with type 2 diabetes (5,701 treated with fenofibrate) that fenofibrate reduces the risk of development and progression of DR. Therefore, fenofibrate may be considered a preventive strategy for patients without DR or early intervention strategy for those with mild DR. A number of putative therapeutic mechanisms for fenofibrate, both dependent and independent of lipids, have been proposed. A deeper understanding of the mode of action of fenofibrate will further help to define how best to use fenofibrate clinically as an adjunct to current management of DR. PMID- 23745550 TI - Mimicking microvascular alterations of human diabetic retinopathy: a challenge for the mouse models. AB - Although it has become acceptable that neuroretinal cells are also affected in diabetes, vascular lesions continue to be considered as the hallmarks of diabetic retinopathy. Animal models are essential for the understanding and treatment of human diabetic retinopathy, and the mouse is intensively used as a model because of its similarity to human and the possibility to be genetically modified. However, until today not all retinal vascular lesions developed in diabetic patients have been reproduced in diabetic mice, and the reasons for this are not completely understood. In this review, we will summarize retinal vascular lesions found in diabetic and diabetic-like mouse models and its comparison to human lesions. The goal is to provide insights to better understand human and mice differences and thus, to facilitate the development of new mouse models that mimic better human diabetic retinopathy. PMID- 23745551 TI - Mitochondria damage in the pathogenesis of diabetic retinopathy and in the metabolic memory associated with its continued progression. AB - Diabetic retinopathy is the leading cause of blindness in young adults, and with the incidence of diabetes increasing at a frightening rate, retinopathy is estimated to threaten vision for almost 51 million patients worldwide. In diabetes, mitochondria structure, function and DNA (mtDNA) are damaged in the retina and its vasculature, and the mtDNA repair machinery and biogenesis are compromised. Proteins encoded by mtDNA become subnormal contributing to dysfunctional electron transport system, and the transport of proteins that are important in mtDNA biogenesis and function, but are encoded by nuclear DNA, is impaired. These diabetes-induced abnormalities in mitochondria continue even when hyperglycemic insult is terminated, and are implicated in the metabolic memory phenomenon associated with the continued progression of diabetic retinopathy. Diabetes also facilitates epigenetic modifications-the changes in histones and DNA methylation in response to cells changing environmental stimuli, which the cell can memorize and pass to the next generation. Epigenetic modifications contribute to the mitochondria damage, and are postulated in the development of diabetic retinopathy, and also to the metabolic memory phenomenon. Thus, strategies targeting mitochondria homeostasis and/or enzymes important for histone and DNA methylation could serve as potential therapies to halt the development and progression of diabetic retinopathy. PMID- 23745549 TI - Neurodegeneration in the pathogenesis of diabetic retinopathy: molecular mechanisms and therapeutic implications. AB - Diabetic retinopathy (DR), commonly classified as a microvascular complication of diabetes, is now recognized as a neurovascular complication or sensory neuropathy resulting from disruption of the neurovascular unit. Current therapies for DR target the vascular complication of the disease process, including neovascularization and diabetic macular edema. Since neurodegeneration is an early event in the pathogenesis of DR, it will be important to unravel the mechanisms that contribute to neuroretinal cell death in order to develop novel treatments for the early stages of DR. In this review we comment on how inflammation, the metabolic derangements associated with diabetes, loss of neuroprotective factors, and dysregulated glutamate metabolism may contribute to retinal neurodegeneration during diabetes. Promising potential therapies based on these specific aspects of DR pathophysiology are also discussed. Finally, we stress the importance of developing and validating new markers of visual function that can be used to shorten the duration of clinical trials and accelerate the delivery of novel treatments for DR to the public. PMID- 23745552 TI - Subthreshold laser therapy for diabetic macular edema: metabolic and safety issues. AB - PURPOSE: To review the most important metabolic effects and clinical safety data of subthreshold micropulse diode laser (D-MPL) in diabetic macular edema (DME). METHODS: Review of the literature about the mechanisms of action and role of D MPL in DME. RESULTS: The MPL treatment does not damage the retina and is selectively absorbed by the retinal pigment epithelium (RPE). MPL stimulates secretion of different protective cytokines by the RPE. No visible laser spots on the retina were noted on any fundus image modality in different studies, and there were no changes of the outer retina integrity. Mean central retinal sensitivity (RS) increased in subthreshold micropulse diode laser group compared to standard ETDRS photocoagulation group. CONCLUSIONS: MPL is a new, promising treatment option in DME, with both infrared and yellow wavelengths using the less aggressive duty cycle (5%) and fixed power parameters. It appears to be safe from morphologic and functional point of view in mild center involving DME. PMID- 23745553 TI - Therapeutic potential of nucleic acid-based drugs in coronary hyper- proliferative vascular diseases. AB - The thickening of the vessel wall (intimal hyperplasia) is a pathological process which often follows revascularization approaches such as transluminal angioplasty and artery bypass graft, procedures used to re-vascularize stenotic artery. Despite the significant improvements in the treatment of intimal hyperplasia obtained in the last years, the problem has not completely solved. Nucleic acid based-drugs (NABDs) represent an emergent class of molecules with potential therapeutic value for the treatment of intimal hyperplasia. NABDs of interest in the field of intimal hyperplasia are: ribozymes, DNAzymes, antisense oligonucleotides, decoy oligonucleotides, small interfering RNAs and micro interfering RNAs. These molecules can recognize, in a sequencespecific fashion, a target which, depending on the different NABDs, can be represented by a nucleic acid or a protein. Upon binding, NABDs can down-modulate the functions of the target (mRNA/proteins) and thus they are used to impair the functions of disease causing biological molecules.In spite of the great therapeutic potential demonstrated by NABDs in many experimental model of intima hyperplasia, their practical use is hindered by the necessity to identify optimal delivery systems to the vasculature. In the first part of this review a brief description of the clinical problem related to intima hyperplasia formation after revascularization procedures is reported. In the second part, the attention is focused on the experimental evidences of NABD therapeutic potential in the prevention of intimal hyperplasia. Finally, in the third part, we will describe the strategies developed to optimize NABD delivery to the diseased vessel. PMID- 23745555 TI - DNAzyme delivery approaches in biological settings. AB - DNAzymes are DNA-based catalytic molecules that have potential use in a range of disorders where the targeted gene plays an important role in disease pathogenesis. DNAzymes are at a comparatively early developmental stage as alternatives to conventional therapies. The biological action of DNAzymes on target mRNA requires efficient delivery into target cells and this hurdle has hampered their broader use, particularly in systemic settings. DNAzymes have been delivered in naked form without a carrier or combined with agents such as polymers and liposomes. This article reviews these and other delivery approaches and offers perspectives on future methodologies for improved DNAzyme delivery and utility as novel drugs. PMID- 23745554 TI - Adult stem cells and biocompatible scaffolds as smart drug delivery tools for cardiac tissue repair. AB - The contribution of adult stem cells to cardiac repair is mostly ascribed to an indirect paracrine effect, rather than to their actual engraftment and differentiation into new contractile and vascular cells. This effect consists in a direct reduction of host cell death, promotion of neovascularization, and in a "bystander effect" on local inflammation. A number of cytokines secreted by adult stem/progenitor cells has been proposed to be responsible for the consistent beneficial effect reported in the early attempts to deliver different stem cell subsets to the injured myocardium. Aiming to maximize their beneficial activity on the diseased myocardium, the genetic modification of adult stem cells to enhance and/or control the secretion of specific cytokines would turn them into active drug delivery vectors. On the other hand, engineering biocompatible scaffolds as to release paracrine factors could result in multiple advantages: (1) achieve a local controlled release of the drug of interest, thus minimizing off-target effects, (2) enhance stem cell retention in the injured area and (3) boost the beneficial paracrine effects exerted by adult stem cells on the host tissue. In the present review, a critical overview of the state-of-the-art in the modification of stem cells and the functionalization of biocompatible scaffolds to deliver beneficial soluble factors to the injured myocardium is offered. Besides the number of concerns to be addressed before a clinical application can be foreseen for such concepts, this path could translate into the generation of active scaffolds as smart cell and drug delivery systems for cardiac repair. PMID- 23745556 TI - Nucleic acid carrier systems based on polyethylenimine conjugates for the treatment of metastatic tumors. AB - Nucleic acid (NA) based drugs offer the potential of highly selective treatments for malignant diseases. They act as an initially inactive pro-drug being activated at the intended site of action, either by translation into a protein in case of plasmid DNA or through expression shutdown by interfering specifically with messenger RNA (RNAi technology). In case of already metastasized cancer, systemic treatment via the blood stream is often inevitable to reach the lesion. This makes it necessary to protect NAs from enzymatic degradation, but also to target them to the tumor with appropriate ligands. Polycationic molecules can provide such functions by condensing NAs into virus sized particles by virtue of charge interaction with the negatively charged phosphate backbone of NAs. Here we review the application of NA carrier systems based on the polycation polyethylenimine (PEI), where peptide based ligands are attached to the polycation via heterobifunctional polyethylene glycol linker molecules. Conjugate synthesis, in vitro testing and in vivo application in subcutaneous and disseminated cancer models in rodents are discussed. PMID- 23745557 TI - Nanoparticles in biomedicine: new insights from plant viruses. AB - In recent years there has been an outburst of interest regarding the employment of nanoparticles for biomedical applications. Among the different types, such as metallic, organic, biological and hybrid systems, virus based nanoparticles have become a popular field of research. Viruses are able to form organized structures by molecular self assembly of repetitive building blocks, which implies non covalent interactions of protein monomers to form the quaternary structure of viral capsids. Plant virus based systems, in particular, are among the most advanced and exploited for their potential use as bioinspired structured nanomaterials and nanovectors. Plant viruses have a size particularly suitable for nanoscale applications and can offer several advantages. In fact, they are structurally uniform, robust, biodegradable and easy to produce. Moreover, many are the examples regarding functionalization of plant virus based nanoparticles by means of modification of their external surface and by loading cargo molecules into their internal cavity. This plasticity in terms of nanoparticles engineering is the ground on which multivalency, payload containment and targeted delivery can be fully exploited. This review aims primarily to summarize the most important plant virus based nanoparticles systems through their recent applications in biomedicine, such as epitope display for vaccine development and targeted delivery for diagnosis or therapy. In addition, their production in the most commonly used plant propagation and expression systems will be also reviewed. PMID- 23745558 TI - Pluronic-based core/shell nanoparticles for drug delivery and diagnosis. AB - Pluronic-based core/shell nanoparticles (NPs) were formed using various strategies such as self-assembly and temperature induced-phase transition. To improve their functionality as a nanomedicine for diagnosis and therapy, the vesicle fusion and layer by layer approach were employed. Because of the hydrophilic nature of the Pluronic shell and the relatively small size, Pluronic based core/shell NPs were used in order to improve their pharmacokinetic behaviors in drugs and in imaging agents. This review will introduce various types of Pluronic-based core/shell NPs according to their preparation method and formation mechanism. The focus will be on the Pluronic-based core/shell NPs for tumor targeting, stimulated release of proteins, and cancer imaging capabilities. PMID- 23745559 TI - New insights in the pathogenesis and treatment of diabetic retinopathy. PMID- 23745560 TI - Development of RNA aptamer-based therapeutic agents. AB - RNA aptamers are non-coding small RNAs that bind to their cognate targets with high specificity and affinity. They are generally identified by iterative rounds of in vitro selection termed SELEX (Systemic Evolution of Ligands by Exponential Enrichment). Similar to antibodies, they can inhibit, modulate and disrupt the functions of target proteins effectively, making them promising therapeutic agents for the treatment of various diseases and targeted drug delivery. Herein we summarize the recent progress of RNA aptamers as potential therapeutics, and highlight a few pioneer examples in the stage of both clinical trials and pre clinical developments. PMID- 23745561 TI - Advances in chemical synthesis of structurally modified bioactive RNAs. AB - Methods for the chemical synthesis of RNA have been available for almost half century, and presently, RNA could be chemically synthesized by automated synthesizers, using protected ribonucleosides preactivated as phosphoramidites, which has already been covered by many reviews. In addition to advancement on synthetic methods, a variety of modifications have also been made on the synthesized oligonucleotides, and previous reviews on the general synthesis of RNAs have not covered this area. In this tutorial review, three types of modifications have been summarized standing at the viewpoint of medicinal chemistry: (1) modifications on nucleobase, comprising substituent introduction and replacement with pseudobase; (2) modifications on ribose, consisting of modifications on the 2', 3' or 5'-position, alternation of configuration, and conformational restriction on ribose; (3) modifications on internucleoside linkages, including amide, formacetal, sulfide, sulfone, ether, phosphorothiolate and phosphorothioate linkages. Synthetic methods achieving these modifications along with the functions or values of these modifications have also been discussed and commented on. PMID- 23745562 TI - MicroRNA miR-122 as a therapeutic target for oligonucleotides and small molecules. AB - The most abundant microRNA (miRNA) in the liver, miR-122, is regulated by specific, liver-enriched transcription factors and is responsible for proper proliferation and differentiation of hepatocytes and for the regulation of lipid and cholesterol metabolisms. miR-122 is also involved in several hepatic disorders, as downregulation of miR-122 is often associated with hepatocellular carcinoma (HCC) and miR-122 is a required component for the replication and proliferation of the hepatitis C virus (HCV). Various probes have been developed to promote a better understanding of the involvement of miR-122 in liver diseases, including modified antisense agents and small molecule inhibitors. These agents, capable of specifically modifying miR-122 activity, provide excellent tools to investigate the function and regulation of miR-122 and offer potential new lead compounds for drug discovery. Especially small molecule modifiers can display numerous advantages over nucleotide analogs, as discussed in this review. PMID- 23745565 TI - Small molecules modulating biogenesis or processing of microRNAs with therapeutic potentials. AB - MicroRNAs (miRNAs) are single-stranded non-coding RNAs with the ability to regulate gene expression at post-transcriptional level. Typically, miRNAs function by binding to the 3' untranslated regions (UTR) of target mRNAs, leading to the degradation or repressed expression of target genes. It is estimated that miRNAs are involved in almost every genetic pathway and the regulation of miRNAs plays important roles in physiological and pathological processes. Small molecules that can regulate miRNAs have great potential as probes to explore miRNAs-mediated regulatory network. Small-molecule regulators of disease-related miRNAs also hold the potential as novel therapeutic agents. Based on the screening systems developed in recent years, several small-molecule regulators have been identified as specific or universal regulators of miRNAs. Therapeutic potentials of these small molecules have also been demonstrated. A general review on the reported small molecules modulating the biogenesis or function of miRNAs will be presented in this paper, with emphasis on the screening methods, proposed mechanism of action and the therapeutic potentials of these small molecules. PMID- 23745563 TI - Canonical and non-canonical barriers facing antimiR cancer therapeutics. AB - Once considered genetic "oddities", microRNAs (miRNAs) are now recognized as key epigenetic regulators of numerous biological processes, including some with a causal link to the pathogenesis, maintenance, and treatment of cancer. The crux of small RNA-based therapeutics lies in the antagonism of potent cellular targets; the main shortcoming of the field in general, lies in ineffective delivery. Inhibition of oncogenic miRNAs is a relatively nascent therapeutic concept, but as with predecessor RNA-based therapies, success hinges on delivery efficacy. This review will describes the canonical (e.g. pharmacokinetics and clearance, cellular uptake, endosome escape, etc.) and non-canonical (e.g. spatial localization and accessibility of miRNA, technical limitations of miRNA inhibition, off-target impacts, etc.) challenges to the delivery of antisense based anti-miRNA therapeutics (i.e. antimiRs) for the treatment of cancer. Emphasis will be placed on how the current leading antimiR platforms-ranging from naked chemically modified oligonucleotides to nanoscale delivery vehicles-are affected by and overcome these barriers. The perplexity of antimiR delivery presents both engineering and biological hurdles that must be overcome in order to capitalize on the extensive pharmacological benefits of antagonizing tumor associated miRNAs. PMID- 23745564 TI - Molecular imaging strategies for in vivo tracking of microRNAs: a comprehensive review. AB - MicroRNAs (miRNAs) are single-stranded non-coding RNAs of ~22 nucleotides, which can negatively regulate gene expression through induction of mRNA degradation and/or post-transcriptional gene silencing. MiRNAs are key factors in the regulation of many biological processes such as cell proliferation, differentiation, and death. Since miRNAs are known to be in close association with cancer development, non-invasive imaging of miRNA expression and/or activity is of critical importance, for which conventional molecular biology techniques are not suitable or applicable. Over the last several years, various molecular imaging techniques have been investigated for imaging of miRNAs. In this review article, we summarize the current state-of-the-art imaging of miRNAs, which are typically based on fluorescent proteins, bioluminescent enzymes, molecular beacons, and/or various nanoparticles. Non-invasive imaging of miRNA expression and/or biological activity is still at its infancy. Future research on more clinically relevant, non-toxic techniques is required to move the field of miRNA imaging into clinical applications. Non-invasive imaging of miRNA is an invaluable method that can not only significantly advance our understandings of a wide range of human diseases, but also lead to new and more effective treatment strategies for these diseases. PMID- 23745566 TI - Roles of miRNA in cardiovascular development and dysfunction. AB - Non-coding RNAs, especially microRNAs (miRNAs), have been recently found to play a major role in the post-transcriptional regulation of both development and dysfunction of the cardiovascular system. Mechanistically, the induction or repression of miRNAs occurring in cardiovascular dysfunction triggers downstream cardiac events in a celltype- specific manner. More importantly, the endogenous microRNAs' disturbance can be modified to rescue cardiac function through exogenous overexpressing or neutralizing strategy. In this paper, we summarizes the current knowledge about miRNAs functions as well as their role in cardiac development and disease, and reports novel miRNAs-based therapeutic approaches to counteract maladaptive remodeling upon cardiac dysfunction. PMID- 23745568 TI - Severity of hydronephrosis correlates with tumour invasiveness and urinary bladder recurrence of ureteric cancer. AB - OBJECTIVES: To explore the prognostic role of hydronephrosis grade in patients with pure ureteric cancer. PATIENTS AND METHODS: The study included 162 patients with pure ureteric cancer who were treated between January 2005 and December 2010 at a single tertiary referral centre. The association between hydronephrosis grade with pathological findings and oncological outcomes was assessed using multivariate Cox regression analysis. RESULTS: Hydronephrosis grade >2 was independently associated with non-organ-confined ureteric cancer (P = 0.003). Hydronephrosis grade <2 was highly prevalent in organ-confined disease. Hydronephrosis grade >2 and bladder cancer history independently predict bladder cancer recurrence (P = 0.021 and P = 0.002, respectively) Hydronephrosis of grade >2 was found to be associated with local and distant recurrence only in univariate analysis; non-organ-confined pathology independently predicted local and distant oncological failure (P <= 0.001 and P = 0.002, respectively). CONCLUSIONS: Hydronephrosis grade >2 is associated with non-organ-confined ureteric cancer and with bladder cancer recurrence. Non-organ-confined pathology is still the most important predictor for local and distant oncological failure. PMID- 23745567 TI - Multimodality imaging of RNA interference. AB - The discovery of small interfering RNAs (siRNAs) and their potential to knock down virtually any gene of interest has ushered in a new era of RNA interference (RNAi). Clinical use of RNAi faces severe limitations due to inefficiency delivery of siRNA or short hairpin RNA (shRNA). Many molecular imaging techniques have been adopted in RNAi-related research for evaluation of siRNA/shRNA delivery, biodistribution, pharmacokinetics, and the therapeutic effect. In this review article, we summarize the current status of in vivo imaging of RNAi. The molecular imaging techniques that have been employed include bioluminescence/fluorescence imaging, magnetic resonance imaging/ spectroscopy, positron emission tomography, single-photon emission computed tomography, and various combinations of these techniques. Further development of non-invasive imaging strategies for RNAi, not only focusing on the delivery of siRNA/shRNA but also the therapeutic efficacy, is critical for future clinical translation. Rigorous validation will be needed to confirm that biodistribution of the carrier is correlated with that of siRNA/shRNA, since imaging only detects the label (e.g. radioisotopes) but not the gene or carrier themselves. It is also essential to develop multimodality imaging approaches for realizing the full potential of therapeutic RNAi, as no single imaging modality may be sufficient to simultaneously monitor both the gene delivery and silencing effect of RNAi. PMID- 23745569 TI - Role of major histocompatibility complex class II expression by non-hematopoietic cells in autoimmune and inflammatory disorders: facts and fiction. AB - It is well established that interactions between CD4(+) T cells and major histocompatibility complex class II (MHCII) positive antigen-presenting cells (APCs) of hematopoietic origin play key roles in both the maintenance of tolerance and the initiation and development of autoimmune and inflammatory disorders. In sharp contrast, despite nearly three decades of intensive research, the functional relevance of MHCII expression by non-hematopoietic tissue-resident cells has remained obscure. The widespread assumption that MHCII expression by non-hematopoietic APCs has an impact on autoimmune and inflammatory diseases has in most instances neither been confirmed nor excluded by indisputable in vivo data. Here we review and put into perspective conflicting in vitro and in vivo results on the putative impact of MHCII expression by non-hematopoietic APCs--in both target organs and secondary lymphoid tissues--on the initiation and development of representative autoimmune and inflammatory disorders. Emphasis will be placed on the lacunar status of our knowledge in this field. We also discuss new mouse models--developed on the basis of our understanding of the molecular mechanisms that regulate MHCII expression--that constitute valuable tools for filling the severe gaps in our knowledge on the functions of non hematopoietic APCs in inflammatory conditions. PMID- 23745570 TI - Association of IFNAR2 and IL10RB genes in chronic hepatitis B virus infection. AB - In this study, we investigated the effects of two functional polymorphisms, type I interferon receptor 2 gene (IFNAR2)-F8S and interleukin-10 receptor subunit beta gene (IL10RB)-K47E, on chronic hepatitis B virus (HBV) infection. We included 227 Thai patients with chronic HBV infection [100 with hepatocellular carcinoma (HCC) and 127 non-HCC], 170 individuals with self-limited HBV infection and 150 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to analyze these two single nucleotide polymorphisms (SNPs). In this study, the C allele of IFNAR2-F8S was found to be significantly increased in chronic HBV patients when compared with healthy controls [odds ratio, OR (95% confidence interval, CI)= 3.31 (2.11-5.21), P = 6.214 * 10(-9) and corrected P-value, P(c)= 1.864 * 10(-8)]. The effect of this allele was similar to that of an autosomal dominant gene in the presence of CC and CT genotype, when compared to TT with an OR of 4.02 (P = 4.631 * 10(-9) and P(c)= 1.389 * 10(-8)). Furthermore, AA genotype of IL10RB-K47E was found to be significantly decreased in chronic HBV patients compared with individuals with self-limited HBV infection (P = 0.006, P(c)= 0.018 and OR = 0.45). For haplotype analysis, we found CA and CG haplotypes were associated with susceptibility to chronic HBV (P = 0.014, OR = 6.84 and P = 0.002, OR = 3.75, respectively) when compared with healthy individuals. This study suggests that IFNAR2-F8S polymorphisms might be involved in the susceptibility to chronic HBV infection. Moreover, AA genotype of IL10RB-K47E may provide a protective effect in this disease. However, an association study using a larger sample size should be performed to confirm these findings. PMID- 23745571 TI - Transmission disequilibrium analysis of 31 type 1 diabetes susceptibility loci in Finnish families. AB - Currently more than 50 type 1 diabetes (T1D) loci outside the human leukocyte antigen (HLA)-region have been established in large European and/or North American populations. Our aim was to attempt to replicate these findings in the less heterogenic Finnish population and to explore evidence for genetic heterogeneity. We analyzed 1761 Finnish T1D trio families for association in 31 T1D loci (25 confirmed and 6 have inconsistent prior evidence). Families were categorized into nine different subgroups according to potential features that reflect underlying genetic heterogeneity in patients (age at diagnosis, sex and HLA genotypes). Seventeen confirmed loci and one nonconfirmed locus (1p31.1) presented significant evidence for association in the full data set. Magnitude and direction of effect was consistent with prior evidence. The strongest effects were seen at the insulin gene, PTPN22 and IL2RA regions. Tentative evidence of odds ratio (OR) heterogeneity within subgroups was seen in eight loci. Our findings were well in line with those reported in the latest meta-analyses using large admixed Caucasian populations, which concurs with the notion that the currently confirmed T1D loci, that have been discovered and replicated mostly in diverse populations, are common to all European populations. The observed effect modifications by subgrouping require validation in later studies with more statistical power. PMID- 23745572 TI - Association of HLA-G 3' untranslated region polymorphisms with antibody response against Plasmodium falciparum antigens: preliminary results. AB - Host and Plasmodium interactions result in highly variable clinical phenotypes, partly explained by the nature and level of anti-malarial antibody response. Human leukocyte antigen (HLA)-G can create a tolerogenic environment, allowing parasites to escape from anti-malarial immunity. We performed a family-based association study encompassing 483 Sereer individuals (261 children and their parents), and reported two independent signals at the HLA-G 3' untranslated region associated with antibody response to specific Plasmodium falciparum blood stage antigens, previously associated with malaria protection: (i) +3010G together with +3142C with total IgG and IgG1 against GLURP and (ii) +3196G with IgG3 against MSP2. While these results require further investigation, they suggest for the first time a role of HLA-G in the regulation of humoral immune response in malaria. PMID- 23745573 TI - Identification of a new HLA-C allele, HLA-C*08:75 in a Caucasian individual. AB - HLA-C*08:75 differs from C*08:02:01 by a non-synonymous mutation at codon 229 (GAG to AAG) in exon 4. PMID- 23745574 TI - Imaging of Xenopus laevis oocyte plasma membrane in physiological-like conditions by atomic force microscopy. AB - Xenopus laevis oocytes are an interesting model for the study of many developmental mechanisms because of their dimensions and the ease with which they can be manipulated. In addition, they are widely employed systems for the expression and functional study of heterologous proteins, which can be expressed with high efficiency on their plasma membrane. Here we applied atomic force microscopy (AFM) to the study of the plasma membrane of X. laevis oocytes. In particular, we developed and optimized a new sample preparation protocol, based on the purification of plasma membranes by ultracentrifugation on a sucrose gradient, to perform a high-resolution AFM imaging of X. laevis oocyte plasma membrane in physiological-like conditions. Reproducible AFM topographs allowed visualization and dimensional characterization of membrane patches, whose height corresponds to a single lipid bilayer, as well as the presence of nanometer structures embedded in the plasma membrane and identified as native membrane proteins. The described method appears to be an applicable tool for performing high-resolution AFM imaging of X. laevis oocyte plasma membrane in a physiological-like environment, thus opening promising perspectives for studying in situ cloned membrane proteins of relevant biomedical/pharmacological interest expressed in this biological system. PMID- 23745575 TI - A fluorogenic TMP-tag for high signal-to-background intracellular live cell imaging. AB - Developed to complement the use of fluorescent proteins in live cell imaging, chemical tags enjoy the benefit of modular incorporation of organic fluorophores, opening the possibility of high photon output and special photophysical properties. However, the theoretical challenge in using chemical tags as opposed to fluorescent proteins for high-resolution imaging is background noise from unbound and/or nonspecifically bound ligand-fluorophore. We envisioned we could overcome this limit by engineering fluorogenic trimethoprim-based chemical tags (TMP-tags) in which the fluorophore is quenched until binding with E. coli dihydrofolate reductase (eDHFR)-tagged protein displaces the quencher. Thus, we began by building a nonfluorogenic, covalent TMP-tag based on a proximity-induced reaction known to achieve rapid and specific labeling both in vitro and inside of living cells. Here we take the final step and render the covalent TMP-tag fluorogenic. In brief, we designed a trimeric TMP-fluorophore-quencher molecule (TMP-Q-Atto520) with the quencher attached to a leaving group that, upon TMP binding to eDHFR, would be cleaved by a cysteine residue (Cys) installed just outside the binding pocket of eDHFR. We present the in vitro experiments showing that the eDHFR:L28C nucleophile cleaves the TMP-Q-Atto520 rapidly and efficiently, resulting in covalent labeling and remarkable fluorescence enhancement. Most significantly, while only our initial design, TMP-Q-Atto520 achieved the demanding goal of not only labeling highly abundant, localized intracellular proteins but also less abundant, more dynamic cytoplasmic proteins. These results suggest that the fluorogenic TMP-tag can significantly impact high resolution live cell imaging and further establish the potential of proximity induced reactivity and organic chemistry more broadly as part of the growing toolbox for synthetic biology and cell engineering. PMID- 23745576 TI - Conformational differences between the methoxy groups of QA and QB site ubisemiquinones in bacterial reaction centers: a key role for methoxy group orientation in modulating ubiquinone redox potential. AB - Ubiquinone is an almost universal, membrane-associated redox mediator. Its ability to accept either one or two electrons allows it to function in critical roles in biological electron transport. The redox properties of ubiquinone in vivo are determined by its environment in the binding sites of proteins and by the dihedral angle of each methoxy group relative to the ring plane. This is an attribute unique to ubiquinone among natural quinones and could account for its widespread function with many different redox complexes. In this work, we use the photosynthetic reaction center as a model system for understanding the role of methoxy conformations in determining the redox potential of the ubiquinone/semiquinone couple. Despite the abundance of X-ray crystal structures for the reaction center, quinone site resolution has thus far been too low to provide a reliable measure of the methoxy dihedral angles of the primary and secondary quinones, QA and QB. We performed 2D ESEEM (HYSCORE) on isolated reaction centers with ubiquinones (13)C-labeled at the headgroup methyl and methoxy substituents, and have measured the (13)C isotropic and anisotropic components of the hyperfine tensors. Hyperfine couplings were compared to those derived by DFT calculations as a function of methoxy torsional angle allowing estimation of the methoxy dihedral angles for the semiquinones in the QA and QB sites. Based on this analysis, the orientation of the 2-methoxy groups are distinct in the two sites, with QB more out of plane by 20-25 degrees . This corresponds to an ~50 meV larger electron affinity for the QB quinone, indicating a substantial contribution to the experimental difference in redox potentials (60 75 mV) of the two quinones. The methods developed here can be readily extended to ubiquinone-binding sites in other protein complexes. PMID- 23745577 TI - In silico design of supramolecules from their precursors: odd-even effects in cage-forming reactions. AB - We synthesize a series of imine cage molecules where increasing the chain length of the alkanediamine precursor results in an odd-even alternation between [2 + 3] and [4 + 6] cage macrocycles. A computational procedure is developed to predict the thermodynamically preferred product and the lowest energy conformer, hence rationalizing the observed alternation and the 3D cage structures, based on knowledge of the precursors alone. PMID- 23745578 TI - Cell behavior on gallium nitride surfaces: peptide affinity attachment versus covalent functionalization. AB - Gallium nitride is a wide band gap semiconductor that demonstrates a unique set of optical and electrical properties as well as aqueous stability and biocompatibility. This combination of properties makes gallium nitride a strong candidate for use in chemical and biological applications such as sensors and neural interfaces. Molecular modification can be used to enhance the functionality and properties of the gallium nitride surface. Here, gallium nitride surfaces were functionalized with a PC12 cell adhesion promoting peptide using covalent and affinity driven attachment methods. The covalent scheme proceeded by Grignard reaction and olefin metathesis while the affinity driven scheme utilized the recognition peptide isolated through phage display. This study shows that the method of attaching the adhesion peptide influences PC12 cell adhesion and differentiation as measured by cell density and morphological analysis. Covalent attachment promoted monolayer and dispersed cell adhesion while affinity driven attachment promoted multilayer cell agglomeration. Higher cell density was observed on surfaces modified using the recognition peptide. The results suggest that the covalent and affinity driven attachment methods are both suitable for promoting PC12 cell adhesion to the gallium nitride surface, though each method may be preferentially suited for distinct applications. PMID- 23745579 TI - Micranthanone A, a new diterpene with an unprecedented carbon skeleton from Rhododendron micranthum. AB - A new diterpene with an unprecedented carbon skeleton, micranthanone A (1), two new grayanane diterpenoids bearing an unusual 5,6-(3,4-dihydroxylbenzylidene acetal) motif, rhodomicranols A (2) and B (3), and three known grayanane diterpenoids (4-6) were isolated from Rhododendron micranthum. Their structures were elucidated by spectroscopic analyses, calculated ECD, and single-crystal X ray diffraction. The in vitro immunomodulatory activities of 1-6 were evaluated, and a plausible biogenetic pathway for 1 is proposed. PMID- 23745580 TI - Metabolomic profiling and sensorial quality of 'Golden Delicious', 'Liberty', 'Santana', and 'Topaz' apples grown using organic and integrated production systems. AB - Apple quality was investigated in the scab-resistant 'Liberty', 'Santana', and 'Topaz' cultivars and the scab-susceptible 'Golden Delicious' cultivar. Trees subjected to the same crop load were cultivated using either an organic (ORG) or an integrated production (IP) system. Physicochemical properties, phenolic content, and sensorial quality of fruit from both systems were compared. There were no significant differences in fruit mass, starch, and total soluble solid content (the latter was higher in ORG 'Liberty') between ORG and IP fruit, whereas significantly higher flesh firmness was found in ORG fruit (except no difference in 'Golden Delicious'). Significantly higher total phenolic content in ORG fruit was found in 'Golden Delicious', whereas differences in other cultivars were not significant. Targeted metabolomic profiling of multiple classes of phenolics confirmed the impact of the production system on the 'Golden Delicious' phenolic profile as higher levels of 4-hydroxybenzoic acid, neo- and chlorogenic acids, phloridzin, procyanidin B2+B4, -3-O-glucoside and -3-O-galactoside of quercetin, kaempferol-3-O-rutinoside, and rutin being found in ORG fruit. The results obtained suggested that scab resistance influenced the phenolic biosynthesis in relation to the agricultural system. Sensorial evaluation indicated significantly better flavor (except for 'Topaz') and better appearance of IP fruit. PMID- 23745581 TI - Common variant in VEGFA and response to anti-VEGF therapy for neovascular age related macular degeneration. AB - Age-related macular degeneration (AMD) is a leading cause of visual impairment in aging populations in industrialized countries. Here we investigated whether the genotype of vascular endothelial growth factor A (VEGFA) gene is associated with response to anti-VEGF therapy. 223 eyes with neovascular AMD were treated with intravitreal anti-VEGF therapy. Responders were defined as patients who had an improvement in best corrected visual acuity (BCVA) of at least 5 letters or one line on the EDTRS visual acuity chart along with resolution of intraretinal or subretinal fluid over 12 months. Patients who did not meet the definition of responders were classified as poor-responders. The vision of responders (n = 148) improved while the vision of poor-responders (n = 75) worsened (P<0.001). Responders on average had a decrease in central foveal thickness (CFT), while poor-responders had an increase in CFT (P <0.001). Compared with the responder group, the poor-responder group had a higher frequency of the risk (T) allele (Allelic P = 0.019) and TT genotype (P = 0.002 under a recessive model) for the VEGFA-rs943080 polymorphism. VEGFA expression was 1.8-fold higher in cells with the VEGFA rs943080 TT genotype than in cells with the VEGFA rs943080 CC genotype (P = 0.012). Age, gender, smoking, diabetes mellitus, and hypertension did not play a significant role in treatment response, but BMI was found to be significantly different between responders and poorresponders (P = 0.033). In conclusion, we demonstrated a potential pharmacogenetic relationship between the VEGFA gene and treatment response to anti-VEGF therapy.The studies are registered at ClinicalTrials.gov under the identifiers NCT00474695 (http://clinicaltrials. gov/ct2/show/NCT00474695) and NCT01464723 (http://clinicaltrials.gov/ct2/show/NCT01464723). PMID- 23745582 TI - Mitochondria-targeted antioxidant peptide SS31 protects the retinas of diabetic rats. AB - Oxidative stress is one of the main contributors in the pathogenesis of diabetic retinopathy. The aim of this study is to investigate the effects of SS31 which is a mitochondria-targeted antioxidant peptide on the retinas of streptozotocin (STZ)-induced diabetic rats. Two weeks after induction of diabetes, SS31 (3 mg/kg) or the same volume of normal saline (N.S) was injected subcutaneously into the back of diabetic rats every day. Four months later, the integrity of inner blood retinal barrier (iBRB) was measured by Evans blue perfusion. The expression and distribution of claudin-5, occludin, acrolein, 8-OHdG and nitrotyrosine in the rat retinas were detected by immunofluorescent staining. Retinal ultrastructures were observed by transmission electron microscopy. The protein level of VEGFR2, Trx-2, Bcl-2, Bax, caspase-3, p53, and NF-kappaB in the rat retinas were assayed by western blot. Four months after subcutaneous injection, the diabetic rats treated with SS31 had better structures of retinal ganglion cells, thinner capillary basement membrane, less iBRB leakage, more uniform staining of claudin-5 and occludin in the retinal vessels, lower levels of acrolein, 8-OHdG, nitrotyrosine, Bax, caspase-3, p53, and NF-kappaB, and higher levels of Trx-2 and Bcl-2 in the retinas than those treated with N.S. In conclusion, SS31 could protect the retinal structures and inhibit the breakdown of iBRB by reducing oxidative damage, increasing Trx-2 and Bcl-2 expression, and decreasing p53, NF-kappaB, Bax, caspase-3, and VEGFR2 expression in the retinas of diabetic rats. SS31 could be a potential new treatment for diabetic retinopathy and other oxidative stress-related diseases. PMID- 23745583 TI - Triamcinolone acetonide inhibits p38MAPK activation and neuronal apoptosis in early diabetic retinopathy. AB - OBJECTIVE: Intravitreal glucocorticoids and anti-vascular endothelial growth factor (VEGF) therapies are novel strategies for the treatment of advanced diabetic retinopathy, a condition with inflammatory and neuropathic elements. In contrast with anti-VEGF therapy, glucocorticoids may also exert neuroprotective effects. How glucocorticoids protect retinal neurons is unknown. The aims of the study are to investigate the anti-apoptotic actions of glucocorticoids on diabetic retinal neurons, and characterize the signalling pathways involved. RESEARCH DESIGN AND METHODS: The regulation of gene expression of the four p38 mitogen-activated protein kinase (MAPK) isoforms (alpha, beta, delta and gamma) and the glucocorticoid receptor (GR) in the retinas was evaluated using quantitative RT-PCR, Western blot and immunohistochemistry. Phosphorylation of all isoforms p38MAPK (Thr180/Tyr182) and GR (S-211) was further evaluated. Apoptosis was confirmed by immunolocalization of active CASPASE-3 and the subsequent cleavage of poly (ADP-ribose) polymerase (PARP) following intravitreal injection of triamcinolone acetonide (IVTA), in an early diabetic rat model (26 days after induction of diabetes. RESULTS: IVTA significantly down-regulated mRNA expression of Caspase 3. Activation of CASPASE-3, the subsequent cleavage of PARP 1 and phosphorylation of p38MAPK induced by diabetes were attenuated by IVTA treatment, concomitantly with activation by phosphorylation of the glucocorticoid receptor (GR S-211). CONCLUSIONS: IVTA activates the GR and exerts neural protective effects on retinal neurons. Inhibition of the p38MAPK pathway and activation of GR play a critical anti-apoptotic role in retinal neurons of diabetes following IVTA treatment. Both the anti-inflammatory and anti-apoptotic effects of glucocorticoids may be mediated through inhibition of the p38MAPK pathway in diabetic retinopathy. PMID- 23745584 TI - ERK signaling pathway regulates embryonic survival and eye development in goldfish, Carassius auratus. AB - The extracellular signal-regulated kinase (ERK) is one of the three major types of mitogen-activated protein kinases. Previous studies showed that ERKs mediate various signaling pathways for cell proliferation, differentiation, survival and transformation in mammals. In the present study, we use goldfish as a model system and demonstrate that ERK kinases play important roles in promoting embryonic survival and regulate development of eye and trunk in vertebrates. ERKs are highly expressed in multiple tissues including lens epithelial cells, lens fiber cells, retina, brain, muscle and heart of adult goldfish. Injection of the dominant negative ERK mutant (DNM-ERK) into the fertilized eggs of goldfish significantly inhibited ERK activity at blastula stage, and completely blocked ERK activity at gastrula and later stages. As a result, the blastula cells were induced into apoptosis, and majority of the injected embryos were lethal at embryonic stages. At the molecular level, inhibition of ERK activity by DNM-ERKs suppressed phosphorylation of Bad at Ser-112 to promote apoptosis. Similar results were observed when MEK activity was inhibited by U0126 treatment. The survived embryos display significant abnormality in the phenotypes of both eye and trunk. Associated with the abnormality in the eye development, phosphorylation in Pax-6 and expression of HSF4 were significantly decreased and expression of the beta-crystallin gene was also downregulated. These results provide novel information regarding the roles of ERKs in regulating vertebrate development. PMID- 23745586 TI - Mutation p.S335X in GATA4 reduces its DNA binding affinity and enhances cell apoptosis associated with ventricular septal defect. AB - Genetic mutations in GATA4, a transcriptional factor, have been found to cause congenital heart diseases. The underlying mechanism, however, remains largely unknown. We previously reported 7 heterozygous variants in patients with ventricular septal defects (VSD). Here we functionally characterized a de novo mutation p.S335X and demonstrated that this mutation led to the pre-termination of its translation, producing a truncated GATA4 lacking a conservative region at C-terminus. Truncated GATA4 did not disturb its subcellular localization; however, it delayed the cardiomyocyte differentiation in P19cl6 model and prohibited Bcl2 expression that led to apoptosis proved by fragmented genomic DNA and positive TUNEL staining in H9C2 cells. By ChIP assay, we showed that GATA4 without C-terminus reduced its DNA binding affinity and suppressed the expressions of its target genes. These findings suggest that C-terminus of GATA4 is critical to maintain DNA binding, and genetic mutations in this region may affect genes important for myocyte apoptosis and differentiation associated with congenital heart defects. PMID- 23745585 TI - p53 directly regulates alphaA- and betaA3/A1-crystallin genes to modulate lens differentiation. AB - It is well established that the tumor suppressor p53 plays major roles in regulating apoptosis and cell cycle progression. In addition, recent studies have demonstrated that p53 is actively involved in regulating cell differentiation in muscle, the circulatory system and various carcinoma tissues. We have recently shown that p53 also controls lens differentiation. Regarding the mechanism, we reveal that p53 directly regulates c-Maf and Prox1, two important transcription factors to control cell differentiation in the ocular lens. In the present study, we present further evidence to show that p53 can regulate lens differentiation by controlling expression of the differentiation genes coding for the lens crystallins. First, the alphaA and betaA3/A1 gene promoters or introns all contain putative p53 binding sites. Second, gel mobility shifting assays revealed that the p53 protein in nuclear extracts from lens epithelial cells directly binds to the p53 binding sites found in these crystallin gene promoters or introns. Third, exogenous wild type p53 induces dose-dependent expression of the luciferase reporter gene driven by different crystallin gene promoters and the exogenous dominant negative mutant p53 causes dose-dependent inhibition of the same crystallin genes. Fourth, ChIP assays revealed that p53 binds to crystallin gene promoters in vivo. Finally, in the p53 knockout mouse lenses, expression levels of various crystallins were found down-regulated in comparison with those from the wild type mouse lenses. Together, our results reveal that p53 directly regulates expression of different sets of genes to control lens differentiation. PMID- 23745587 TI - Suicidal inactivation of methemoglobin by generation of thiyl radical: insight into NAC mediated protection in RBC. AB - N-acetyl-L-cysteine (NAC) improves antioxidant potentials of RBCs to provide protection against oxidative stress induced hemolysis. The antioxidant mechanism of NAC to reduce oxidative stress in RBC, studied through inactivation of pro oxidant MetHb. NAC causes irreversible inactivation of the MetHb in an H2O2 dependent manner, and the inactivation follows the pseudo- first- order kinetics. The kinetic constants are ki = 8.5MUM, kinact = 0.706 min(-1) and t1/2 = 0.9 min. Spectroscopic studies indicate that MetHb accepts NAC as a substrate and oxidizes through a single electron transfer mechanism to the NACox. The single e- oxidation product of NAC has been identified as the 5, 5'- dimethyl-1- pyrroline N- oxide (DMPO) adduct of the sulfur centered radical (a(N) = 15.2 G and a(H)=16.78 G). Binding studies indicate that NACox interacts at the heme moiety and NAC oxidation through MetHb is essential for NAC binding. Heme-NAC adduct dissociated from MetHb and identified (m/z 1011.19) as 2:1 ratio of NAC/heme in the adduct. TEMPO and PBN treatment reduces NAC binding to MetHb and protects against inactivation confirms the role of thiyl radical in the inactivation process. Furthermore, scavenging thiyl radicals by TEMPO abolish the protective effect of NAC in hemolysis. Current work highlights antioxidant mechanism of NAC through NAC thiyl radical generation, and MetHb inactivation to exhibit protection in RBC against oxidative stress induced hemolysis. PMID- 23745589 TI - Towards better understanding on psychiatric disorder, ocular diseases, heart disease and cancer. PMID- 23745590 TI - The confounding effect of nitrite on N2O production by an enriched ammonia oxidizing culture. AB - The effect of nitrite (NO2(-)) on the nitrous oxide (N2O) production rate of an enriched ammonia-oxidizing bacteria (AOB) culture was characterized over a concentration range of 0-1000 mg N/L. The AOB culture was enriched in a nitritation system fed with synthetic anaerobic digester liquor. The N2O production rate was highest at NO2(-) concentrations of less than 50 mg N/L. At dissolved oxygen (DO) concentration of 0.55 mg O2/L, further increases in NO2(-) concentration from 50 to 500 mg N/L resulted in a gradual decrease in N2O production rate, which maintained at its lowest level of 0.20 mg N2O-N/h/g VSS in the NO2(-) concentration range of 500-1000 mg N/L. The observed NO2(-)-induced decrease in N2O production was even more apparent at increased DO concentration. At DO concentrations of 1.30 and 2.30 mg O2/L, the lowest N2O production rate (0.25 mg N2O-N/h/g VSS) was attained at a lower NO2(-) concentration of 200-250 mg N/L. These observations suggest that N2O production by the culture is diminished by both high NO2(-) and high DO concentrations. Collectively, the findings show that exceedingly high NO2(-) concentrations in nitritation systems could lead to decreased N2O production. Further studies are required to determine the extent to which the same response to NO2(-) is observed across different AOB cultures. PMID- 23745588 TI - beta2-AR-HIF-1alpha: a novel regulatory axis for stress-induced pancreatic tumor growth and angiogenesis. AB - The purpose of this study was to test the hypothesis that chronic stress in a negative social and psychological state plays a critical role in pancreatic cancer development and progression. In this study, we created a new stress model system to determine the effects of chronic stress on pancreatic cancer progression. Here, we show that chronic stress not only causes depression in mice, most likely attributed to an elevated level of epinephrine, but also induces pancreatic cancer progression. We provide evidence that the pancreatic cancer progression induced by chronic stress could be blocked to a significant degree by beta2-AR inhibitor ICI118 551 or HIF-1alpha inhibitor 2 methoxyestradiol. Moreover, establishment of pancreatic cancer in mice exposed to chronic stress was accompanied by up-regulation of the expression of MMP-2, MMP 9, and VEGF, mediated by a HIF- 1alpha-dependent beta-AR signaling pathway. Our data suggest that the beta2-AR-HIF-1alpha axis regulates stress-induced pancreatic tumor growth and angiogenesis. This study may have a therapeutic or preventive potential for the patients with pancreatic cancer who are especially prone to psychosocial stress challenges. PMID- 23745591 TI - Multiple morphologies of gold-magnetite heterostructure nanoparticles are effectively functionalized with protein for cell targeting. AB - Nanoparticles composed of a magnetic iron oxide core surrounded by a metal shell have utility in a broad range of biomedical applications. However, the presence of surface energy differences between the two components makes wetting of oxide with metal unfavorable, precluding a "core-shell" structure of an oxide core completely surrounded by a thin metal shell. Three-dimensional island growth followed by island coalescence into thick shells is favored over the two dimensional layer-by-layer growth of a thin, continuous metal coating of a true core-shell. Aqueous synthesis of gold-coated magnetite nanoparticles with analysis by infrared, energy-dispersive X-ray, and electron energy loss spectroscopies; high-resolution transmission electron microscopy; selected area electron diffraction; and high-angle annular dark-field scanning transmission electron microscopy showed two distinct morphologies that are inconsistent with an idealized core-shell. The majority were isolated ~16-22-nm-diameter nanoparticles consisting of ~7-nm-diameter magnetite and a thick deposition of gold, most often discontinuous, with some potentially "sandwiched" morphologies. A minority were aggregates of agglomerated magnetite decorated with gold but displaying significant bare magnetite. Both populations were successfully conjugated to fibrinogen and targeted to surface-activated platelets, demonstrating that iron oxide-gold nanoparticles produced by aqueous synthesis do not require an ideal core-shell structure for biological activity in cell labeling and targeting applications. PMID- 23745592 TI - Measurement of total and free malondialdehyde by gas-chromatography mass spectrometry--comparison with high-performance liquid chromatography methology. AB - Malondialdehyde (MDA) is considered to be a biomarker for enzymatic degradation and lipid peroxidation of polyunsaturated fatty acids. Usually, MDA determination from different biological materials is performed by reaction with thiobarbituric acid (TBA) followed by high-performance liquid chromatography (HPLC) analysis and fluorometric detection. As this method lacks specificity and sensitivity, we developed a gas chromatography-mass spectrometry (GC-MS) method based on derivatization of MDA with 2,4-dinitrophenylhydrazine. Representative ions in negative ion chemical ionization (NICI) mode were recorded at m/z 204 for MDA and at m/z 206 for the deuterated analogon (MDA-d2) as internal standard. This stable and precise GC-MS method showed good linearity (r2 = 0.999) and higher specificity and sensitivity than the HPLC method and was validated for both total MDA (t-MDA) and free MDA (f-MDA). Within-day precisions were 1.8-5.4%, between day precisions were 4.8-9.2%; and accuracies were between 99% and 101% for the whole calibration range (0.156-5.0 MUmol/L for t-MDA and 0.039-0.625 MUmol/L for f-MDA). Although comparison of t-MDA levels from GC-MS and HPLC results using Passing-Bablok regression analysis as well as Bland-Altman plot showed a correlation of the data, a tendency to increased results for the HPLC values was detectable, due to possible formation of unspecific products of the TBA reaction. PMID- 23745593 TI - Protective effect of artichoke (Cynara scolymus) leaf extract against lead toxicity in rat. AB - CONTEXT: Artichoke, Cynara scolymus L. (Asteraceae), has many natural antioxidants and multiple pharmacological actions. Recent studies have shown that it has antitoxic activity. OBJECTIVE: Lead (Pb) is a dangerous environmental toxicant that induces a broad range of dysfunctions in human. This study evaluated the protective effect of the hydroethanolic extract of artichoke against altered biochemical parameters in rats fed with lead-containing diet. MATERIALS AND METHODS: Thirty-two rats were randomly divided into four groups. The first (control) group received standard diet. The second, third and fourth groups received 500 mg lead/kg diet, 500 mg lead/kg diet plus 300 mg/kg b.w. artichoke extract daily, and 500 mg lead/kg diet plus 1 mg vitamin C/100 g b.w. daily for 6 weeks, respectively. Serum lead, lipoprotein profile, ALT (alanine transaminase), AST (aspartate transaminase), ALP (alkaline phosphatase), malondialdehyde (MDA) and liver histopathology assessments were conducted. RESULTS: Serum lead, triglyceride (TG), VLDL, ALT, AST, ALP and MDA levels decreased significantly (p < 0.05) in the artichoke-treated group (35.85, 38.26, 38.38, 21.90, 12.81, 26.86 and 46.91%, respectively) compared to lead-intoxicated rats without treatment. No significant change was observed in serum lead, ALP and ALT between artichoke and vitamin C-treated groups (p > 0.05). Furthermore, the liver histopathology in rats treated with artichoke showed a mild degree of lymphocyte infiltration that was relatively comparable to the control and vitamin C-treated groups. DISCUSSION AND CONCLUSION: These results clearly show that the artichoke extract in lead-poisoned rats has suitable chelating properties for the reduction of blood lead levels. PMID- 23745594 TI - A multifaceted community-based asthma intervention in Chicago: effects of trigger reduction and self-management education on asthma morbidity. AB - OBJECTIVES: Home-based, multifaceted interventions have been effective in reducing asthma morbidity in children. However, identification of independent components that contribute to outcomes and delineating effectiveness by level of asthma symptoms would help to refine the intervention and target appropriate populations. METHODS: A community health educator led asthma intervention implemented in a low-income African-American neighborhood included asthma management education, individually tailored low-cost asthma home trigger remediation, and referrals to social and medical agencies, when appropriate. Changes in asthma morbidity measures were assessed in relation to implementation of individual intervention components using multivariable logistic regression. RESULTS: Among the 218 children who completed the year-long program, there were significant reductions in measures of asthma morbidity, including symptoms, urgent care visits, emergency department (ED) visits, hospitalizations, missed school days, and missed work days for caretakers. We also found significant decreases in the prevalence of many home asthma triggers and improvements in asthma management practices. Improvement in caretaker's ability to manage the child's asthma was associated with reduction in ED visits for asthma and uncontrolled asthma. Specific home interventions, such as repair of water leaks and reduced exposure to plants, dust, clutter and stuffed toys, may be related to reduction in asthma morbidity. CONCLUSIONS: This program was effective in reducing asthma morbidity in low-income African-American children and identified specific interventions as possible areas to target in future projects. Furthermore, the intervention was useful in children with persistent asthma symptoms as well as those with less frequent asthma exacerbations. PMID- 23745595 TI - The pandemic and all-hazards preparedness act: its contributions and new potential to increase public health preparedness. PMID- 23745596 TI - Multifunctionality of organometallic quinonoid metal complexes: surface chemistry, coordination polymers, and catalysts. AB - Quinonoid metal complexes have potential applications in surface chemistry, coordination polymers, and catalysts. Although quinonoid manganese tricarbonyl complexes have been used as secondary building units (SBUs) in the formation of novel metal-organometallic coordination networks and polymers, the potentially wider applications of these versatile linkers have not yet been recognized. In this Account, we focus on these diverse new applications of quinonoid metal complexes, and report on the variety of quinonoid metal complexes that we have synthesized. Through the use of [(eta(6)-hydroquinone)Mn(CO)3](+), we are able to modify the surface of Fe3O4 and FePt nanoparticles (NPs). This process occurs either by the replacement of oleylamine with neutral [(eta(5) semiquinone)Mn(CO)3] at the NP surface, or by the binding of anionic [(eta(4) quinone)Mn(CO)3](-) upon further deprotonation of [(eta(5)-semiquinone)Mn(CO)3] at the NP surface. We have demonstrated chemistry at the intersection of surface modified NPs and coordination polymers through the growth of organometallic coordination polymers onto the surface modified Fe3O4 NPs. The resulting magnetic NP/organometallic coordination polymer hybrid material exhibited both the unique superparamagnetic behavior associated with Fe3O4 NPs and the paramagnetism attributable to the metal nodes, depending upon the magnetic range examined. By the use of functionalized [(eta(5)-semiquinone)Mn(CO)3] complexes, we attained the formation of an organometallic monolayer on the surface of highly ordered pyrolitic graphite (HOPG). The resulting organometallic monolayer was not simply a random array of manganese atoms on the surface, but rather consisted of an alternating "up and down" spatial arrangement of Mn atoms extending from the HOPG surface due to hydrogen bonding of the quinonoid complexes. We also showed that the topology of metal atoms on the surface could be controlled through the use of quinonoid metal complexes. A quinonoid rhodium complex showed catalytic activity in Suzuki-Miyaura type reaction. As a result of the excellent stability of the homogeneous catalyst [(quinone)Rh(COD)](-) in water, we also successfully demonstrated catalyst recycling in 1,2- and 1,4-addition reactions. The compound [(quinone)Ir(COD)](-) showed significantly poorer catalytic activity in 1,4 addition reactions. Following upon the excellent coordination ability of the quinonoid rhodium complexes to metal centers, we synthesized organometallic coordination polymer nanocatalysts and silica gel-supported quinonoid rhodium catalysts, the latter using a surface sol-gel technique. The resulting heterogeneous catalysts showed activity in the stereospecific polymerization of phenylacetylene. PMID- 23745597 TI - High-level secretion of a recombinant protein to the culture medium with a Bacillus subtilis twin-arginine translocation system in Escherichia coli. AB - The twin-arginine translocation (Tat) system transports folded proteins across the plasma membrane in bacteria, and heterologous proteins can be exported by this pathway if a Tat-type signal peptide is present at the N-terminus. The system thus has potential for biopharmaceutical production in Escherichia coli, where export to the periplasm is often a favoured approach. Previous studies have shown that E. coli cells can export high levels of protein by the Tat pathway, and the protein product accummulates almost exclusively in the periplasm. In this study, we analysed E. coli cells that express the Bacillus subtilis TatAdCd system in place of the native TatABC system. We show that a heterologous model protein, comprising the TorA signal peptide linked to green fluorescent protein (TorA-GFP), is efficiently exported by the TatAdCd system. However, whereas the GFP is exported initially to the periplasm during batch fermentation, the mature protein is increasingly found in the extracellular culture medium. By the end of a 16-h fermentation, ~ 90% of exported GFP is present in the medium as active mature protein. The total protein profiles of the medium and periplasm are essentially identical, confirming that the outer membrane becomes leaky during the fermentation process. The cells are otherwise intact, and there is no large scale release of cytoplasmic contents. Export levels are relatively high, with ~ 0.35 g GFP.L-1 culture present in the medium. This system thus offers a means of producing recombinant protein in E. coli and harvesting directly from the medium, with potential advantages in terms of ease of purification and downstream processing. PMID- 23745598 TI - The PH domain of phosphoinositide-dependent kinase-1 exhibits a novel, phospho regulated monomer-dimer equilibrium with important implications for kinase domain activation: single-molecule and ensemble studies. AB - Phosphoinositide-dependent kinase-1 (PDK1) is an essential master kinase recruited to the plasma membrane by the binding of its C-terminal PH domain to the signaling lipid phosphatidylinositol-3,4,5-trisphosphate (PIP3). Membrane binding leads to PDK1 phospho-activation, but despite the central role of PDK1 in signaling and cancer biology, this activation mechanism remains poorly understood. PDK1 has been shown to exist as a dimer in cells, and one crystal structure of its isolated PH domain exhibits a putative dimer interface. It has been proposed that phosphorylation of PH domain residue T513 (or the phospho mimetic T513E mutation) may regulate a novel PH domain dimer-monomer equilibrium, thereby converting an inactive PDK1 dimer to an active monomer. However, the oligomeric states of the PH domain on the membrane have not yet been determined, nor whether a negative charge at position 513 is sufficient to regulate its oligomeric state. This study investigates the binding of purified wild-type (WT) and T513E PDK1 PH domains to lipid bilayers containing the PIP3 target lipid, using both single-molecule and ensemble measurements. Single-molecule analysis of the brightness of the fluorescent PH domain shows that the PIP3-bound WT PH domain on membranes is predominantly dimeric while the PIP3-bound T513E PH domain is monomeric, demonstrating that negative charge at the T513 position is sufficient to dissociate the PH domain dimer and is thus likely to play a central role in PDK1 monomerization and activation. Single-molecule analysis of two dimensional (2D) diffusion of PH domain-PIP3 complexes reveals that the dimeric WT PH domain diffuses at the same rate as a single lipid molecule, indicating that only one of its two PIP3 binding sites is occupied and there is little penetration of the protein into the bilayer as observed for other PH domains. The 2D diffusion of T513E PH domain is slower, suggesting the negative charge disrupts local structure in a way that allows deeper insertion of the protein into the viscous bilayer, thereby increasing the diffusional friction. Ensemble measurements of PH domain affinity for PIP3 on plasma membrane-like bilayers reveal that the dimeric WT PH domain possesses a one order of magnitude higher target membrane affinity than the previously characterized monomeric PH domains, consistent with a dimerization-triggered, allosterically enhanced affinity for one PIP3 molecule (a much larger affinity enhancement would be expected for dimerization-triggered binding to two PIP3 molecules). The monomeric T513E PDK1 PH domain, like other monomeric PH domains, exhibits a PIP3 affinity and bound state lifetime that are each 1 order of magnitude lower than those of the dimeric WT PH domain, which is predicted to facilitate release of activated, monomeric PDK1 to the cytoplasm. Overall, the study yields the first molecular picture of PH domain regulation via electrostatic control of dimer-monomer conversion. PMID- 23745599 TI - Melatonin synthesis in human colostrum mononuclear cells enhances dectin-1 mediated phagocytosis by mononuclear cells. AB - Many cells in the organism besides pinealocytes, synthesize melatonin. Here, we evaluate both the mechanism of zymosan-induced melatonin synthesis and its autocrine effect in human colostral mononuclear cells. The synthesis of melatonin was induced by activation of the transcription factor nuclear factor kappa B (NF kappaB), as either the blockade of the proteasome or the binding of NF-kappaB to DNA inhibits zymosan-induced melatonin synthesis. As observed in RAW 264.7 lineage cells, the dimer involved is RelA/c-Rel. Melatonin plays a direct role in mononuclear cell activity, increasing zymosan-induced phagocytosis by stimulating MT2 melatonin receptors and increasing the expression of dectin-1. This role was confirmed by the blockade of melatonin receptors using the competitive antagonist luzindole and the MT2 -selective partial agonist 4P-PDOT. In summary, we show that melatonin produced by immune-competent cells acts in an autocrine manner, enhancing the clearance of pathogens by increasing phagocyte efficiency. Given that these cells are present in human colostrum for 4 or 5 days after birth, this mechanism may be relevant for the protection of infant health. PMID- 23745600 TI - Identification and characterization of the major histocompatibility complex class II DQB (MhcMath-DQB1) alleles in Tibetan macaques (Macaca thibetana). AB - Tibetan macaque (Macaca thibetana), an endangered primate species endemic to China, have been used as experimental animal model for various human diseases. Major histocompatibility complex (MHC) genes play a crucial role in the susceptibility and/or resistance to many human diseases, but little is known about Tibetan macaques. To gain an insight into the MHC background and to facilitate the experimental use of Tibetan macaques, the second exon of Mhc-DQB1 gene was sequenced in a cohort of wild Tibetan macaques living in the Sichuan province of China. A total of 23 MhcMath-DQB1 alleles were identified for the first time, illustrating a marked allelic polymorphism at the DQB1 locus for these macaques. Most of the sequences (74%) observed in this study belong to DQB1*06 (9 alleles) and DQB1*18 (8 alleles) lineages, and the rest (26%) belong to DQB1*15 (3 alleles) and DQB1*17 (3 alleles) lineages. The most frequent alleles detected among these macaques were MhcMath-DQB1*15:02:02 (17.9%), followed by Math-DQB1*06:06, 17:03 and 18:01, which were detected in 9 (16.1%) of the monkeys, respectively. Non-synonymous substitutions occurred at a significantly higher frequency than synonymous substitutions in the peptide binding region, suggesting balancing selection for maintaining polymorphisms at the MHC class II DQB1 locus. Phylogenetic analyses confirms the trans-species model of evolution of the Mhc-DQB1 genes in non-human primates, and in particular, the extensive allele sharing is observed between Tibetan and other macaque species. PMID- 23745601 TI - The relationship between bone mass and body composition in children with hypothalamic and simple obesity. AB - INTRODUCTION: Obesity has been associated with a positive influence on bone mass. This is thought to be due to a mechanical load exerted on the skeleton, together with various hormones and adipocytokines that control appetite and weight, such as leptin, some of which directly affect bone mass. However, there are conflicting reports of the association between fat mass and bone mass in children. Animal studies demonstrate increased bone mass where there is impaired central leptin signalling. Hypothalamic damage can cause abnormal central leptin action, which contributes to the development of obesity. OBJECTIVE: The objective of this study was to investigate the relationship between body composition and bone mass in hypothalamic and simple childhood obesity, in conjunction with the effect of the adipocytokines, leptin and adiponectin. DESIGN: This was a cross sectional study of three groups of children, those with hypothalamic obesity (HO), those with congenital hypopituitarism (CH) and those with simple obesity (SO). RESULTS: A total of 65 children (HO = 26 [11 males], CH = 17 [eight males] and SO = 22 [15 males]) had body composition assessed using dual-energy X-ray absorptiometry together with measurement of serum leptin and adiponectin. No significant differences were seen in bone mass once bone density (BMD) was adjusted for differences in body size between groups. Significantly elevated levels of leptin and adiponectin were seen in the HO group compared with the SO group (P < 0.01, P < 0.05, respectively). CONCLUSION: Adiposity is associated with increased bone mass; however, this relationship is complex. Despite the presence of hyperleptinaemia, increased bone mass in the HO group was not seen. This may be due to the effects of other factors such as adiponectin, abnormal hypothalamic signalling, pituitary hormone deficiencies and disruption of normal homoeostatic mechanisms within the hypothalamus. PMID- 23745602 TI - Acid-promoted cascade cyclization to produce fused-polycyclic indole derivatives. AB - An acid-promoted novel cascade cyclization is described. Using 8 equiv of trifluoroacetic acid or a catalytic amount of Lewis acid as the promoter, structurally diverse polycyclic cyclopenta[b]indoles were obtained in moderate to excellent yield. This cascade process was extremely effective for the synthesis of 8-membered ring-fused cyclopenta[b]indole derivatives. PMID- 23745604 TI - Latex migration in battery slurries during drying. AB - We used real-time fluorescence microscopy to investigate the migration of latex particles in drying battery slurries. The time evolution of the fluorescence signals revealed that the migration of the latex particles was suppressed above the entanglement concentration of carboxymethyl cellulose (CMC), while it was significantly enhanced when CMC fully covered the surfaces of the graphite particles. In particular, a two-step migration was observed when the graphite particles flocculated by depletion attraction at high CMC/graphite mass ratios. The transient states of the nonadsorbing CMC and graphite particles in a medium were discussed, and the uses of this novel measurement technique to monitor the complex drying processes of films were demonstrated. PMID- 23745603 TI - Role of the transcription factor ChAP1 in cytoplasmic redox homeostasis: imaging with a genetically encoded sensor in the maize pathogen Cochliobolus heterostrophus. AB - The redox-sensitive transcription factor ChAP1 [Cochliobolus heterostrophus YAP1 (Yeast Activator Protein 1) orthologue] of C. heterostrophus is required for oxidative stress tolerance. It is not known, however, to what extent the intracellular redox state changes on exposure of the fungus to oxidants, and whether ChAP1 is involved in the return of the cell to redox homeostasis. In order to answer these questions, we expressed a ratiometric redox-sensitive fluorescent protein sensor, pHyper, in C. heterostrophus. The fluorescence ratio was sensitive to extracellular hydrogen peroxide (H2O2) concentrations that had been shown previously to inhibit the germination of conidia and growth of the pathogen in culture. chap1 mutants showed a slower return to redox homeostasis than the wild-type on exposure to H2O2. Plant extracts that mimic oxidants in their ability to promote nuclear retention of ChAP1 reduced, rather than oxidized, the fungal cells. This result is consistent with other data suggesting that ChAP1 responds to plant-derived signals other than oxidants. pHyper should be a useful reporter of the intracellular redox state in filamentous fungi. PMID- 23745605 TI - Counting pandemic deaths: comparing reported numbers of deaths from influenza A(H1N1)pdm09 with estimated excess mortality. AB - BACKGROUND: During the wave 1 of the influenza A(H1N1)pdm09 virus, Norway appeared to be suffering from high mortality rates. However, by the end of the pandemic, it was widely reported that the number of deaths were much lower than previous years. OBJECTIVES: The mortality burden from influenza is often assessed by two different approaches: counting influenza-certified deaths and estimating the mortality burden using models. The purpose of this study is to compare the number of reported deaths with results from two different models for estimating excess mortality during the pandemic in Norway. Additionally, mortality estimates for the pandemic season are compared with non-pandemic influenza seasons. METHODS: Numbers on reported influenza A(N1h1)pdm09 deaths are gived by the Cause of Death Registry at Statistics Norway and an ad hoc registry at the Norwegian Institute of Public Health. Overall and Pnemumonia and Influenza certified mortality is modeled using Poission regression, adjusting for levels of reported influenza-like illness and seasonal and year-to-year variation. RESULTS AND CONCLUSIONS: Modelling results suggest that the excess mortality in older age groups is considerably lower during the pandemic than non-pandemic seasons, but there are indications of an excess beyond what was reported during the pandemic. This highlights the benefits of both methods and the importance of explaining where these numbers come from. PMID- 23745606 TI - Determination of the alkylpyrazine composition of coffee using stable isotope dilution-gas chromatography-mass spectrometry (SIDA-GC-MS). AB - A stable isotope dilution analysis based on gas chromatography-mass spectrometry analysis (SIDA-GC-MS) was developed for the quantitative analysis of 12 alkylpyrazines found in commercially available coffee samples. These compounds contribute to coffee flavor. The accuracy of this method was tested by analyzing model mixtures of alkylpyrazines. Comparisons of alkylpyrazine-concentrations suggested that water as extraction solvent was superior to dichloromethane. The distribution patterns of alkylpyrazines in different roasted coffees were quite similar. The most abundant alkylpyrazine in each coffee sample was 2 methylpyrazine, followed by 2,6-dimethylpyrazine, 2,5-dimethylpyrazine, 2 ethylpyrazine, 2-ethyl-6-methylpyrazine, 2-ethyl-5-methylpyrazine, and 2,3,5 trimethylpyrazine, respectively. Among the alkylpyrazines tested, 2,3 dimethylpyrazine, 2-ethyl-3-methylpyrazine, 2-ethyl-3,6-dimethylpyrazine, and 2 ethyl-3,5-dimethylpyrazine revealed the lowest concentrations in roasted coffee. By the use of isotope dilution analysis, the total concentrations of alkylpyrazines in commercially available ground coffee ranged between 82.1 and 211.6 mg/kg, respectively. Decaffeinated coffee samples were found to contain lower amounts of alkylpyrazines than regular coffee samples by a factor of 0.3 0.7, which might be a result of the decaffeination procedure. PMID- 23745607 TI - Supersaturation-dependent surface structure evolution: from ionic, molecular to metallic micro/nanocrystals. AB - Deduced from thermodynamics and the Thomson-Gibbs equation that the surface energy of crystal face is in proportion to the supersaturation of crystal growth units during the crystal growth, we propose that the exposed crystal faces can be simply tuned by controlling the supersaturation, and higher supersaturation will result in the formation of crystallites with higher surface-energy faces. We have successfully applied it for the growth of ionic (NaCl), molecular (TBPe), and metallic (Au, Pd) micro/nanocrystals with high-surface-energy faces. The above proposed strategy can be rationally designed to synthesize micro/nanocrystals with specific crystal faces and functionality toward specific applications. PMID- 23745609 TI - Structural diversity of Aspergillus (section nigri) spores. AB - The taxonomy of fungal species, similar to that of many other microorganisms, suffers frequent revisions due to the discovery of new species and to the development and gathering of characterization data and morphological information. Morpho-taxonomy helps in the identification of many species. This work presents the macro, micro-morphological, and spectral mass analyses for phenotypic characterization of 13 species of Aspergillus section Nigri, showing that the characterization of spores (conidia) by scanning electron microscopy can be used as a tool to discriminate key morphological characteristics and separate closely related fungi. These results were corroborated by colony plates, stereomicroscopy, light microscopy, and spectral mass data. PMID- 23745608 TI - Laypersons' views of material incentives for enhancing colorectal cancer screening. AB - BACKGROUND: Colorectal cancer (CRC) early detection improves health outcomes; screening programmes invest efforts in initiating invitations to target populations to be tested. Enhanced adherence is essential for reduction of morbidity and mortality. Participation rates in Israel are still relatively low. OBJECTIVE: To explore lay views regarding the concept of receiving material incentives in exchange for enhanced adherence to CRC screening. RESEARCH DESIGN: Qualitative study. Between November 2009 and February 2010 six focus group discussions were carried out in two urban, middle and low socio-economic status primary care clinics in a Northern city in Israel. Participants were eligible individuals for CRC screening, aged 50-68 (N = 24). Data analysis followed the principles of grounded theory, supported by qualitative software. RESULTS: Participants found administering incentives in exchange for CRC screening inappropriate on rational and moral grounds. They valued their relations with the medical team and the health system more than the potential gain expected. Individuals eligible for CRC screening perceived themselves as responsible for their health, admitting difficulties in realizing this responsibility. Incentives were reported unsuitable for solving reported screening difficulties and a potential harm to the doctor-patient relationship. CONCLUSIONS: Focus group participants expressed an unconventional voice towards the use of material incentives. They pointed to the need for focused support of health behaviour change and valued their autonomy. While a proportion of the invitees in the target population see the importance of screening and appreciate the HMO's initiative to invite them for testing, they also expressed their need for support from the HMO in realizing the recommended health behaviour. PMID- 23745610 TI - A facile method to fabricate hydrogels with microchannel-like porosity for tissue engineering. AB - Hydrogels are widely used as three-dimensional (3D) tissue engineering scaffolds due to their tissue-like water content, as well as their tunable physical and chemical properties. Hydrogel-based scaffolds are generally associated with nanoscale porosity, whereas macroporosity is highly desirable to facilitate nutrient transfer, vascularization, cell proliferation and matrix deposition. Diverse techniques have been developed for introducing macroporosity into hydrogel-based scaffolds. However, most of these methods involve harsh fabrication conditions that are not cell friendly, result in spherical pore structure, and are not amenable for dynamic pore formation. Human tissues contain abundant microchannel-like structures, such as microvascular network and nerve bundles, yet fabricating hydrogels containing microchannel-like pore structures remains a great challenge. To overcome these limitations, here we aim to develop a facile, cell-friendly method for engineering hydrogels with microchannel-like porosity using stimuli-responsive microfibers as porogens. Microfibers with sizes ranging 150-200 MUm were fabricated using a coaxial flow of alginate and calcium chloride solution. Microfibers containing human embryonic kidney (HEK) cells were encapsulated within a 3D gelatin hydrogel, and then exposed to ethylenediaminetetraacetic acid (EDTA) solution at varying doses and duration. Scanning electron microscopy confirmed effective dissolution of alginate microfibers after EDTA treatment, leaving well-defined, interconnected microchannel structures within the 3D hydrogels. Upon release from the alginate fibers, HEK cells showed high viability and enhanced colony formation along the luminal surfaces of the microchannels. In contrast, HEK cells in non-EDTA treated control exhibited isolated cells, which remained entrapped in alginate microfibers. Together, our results showed a facile, cell-friendly process for dynamic microchannel formation within hydrogels, which may simultaneously release cells in 3D hydrogels in a spatiotemporally controlled manner. This platform may be adapted to include other cell-friendly stimuli for porogen removal, such as Matrix metalloproteinase-sensitive peptides or photodegradable gels. While we used HEK cells in this study as proof of principle, the concept described in this study may also be used for releasing clinically relevant cell types, such as smooth muscle and endothelial cells that are useful for repairing tissues involving tubular structures. PMID- 23745611 TI - Co-location of air capture, subseafloor CO2 sequestration, and energy production on the Kerguelen plateau. AB - Reducing atmospheric CO2 using a combination of air capture and offshore geological storage can address technical and policy concerns with climate mitigation. Because CO2 mixes rapidly in the atmosphere, air capture could operate anywhere and in principle reduce CO2 to preindustrial levels. We investigate the Kerguelen plateau in the Indian Ocean, which offers steady wind resources, vast subseafloor storage capacities, and minimal risk of economic damages or human inconvenience and harm. The efficiency of humidity swing driven air capture under humid and windy conditions is tested in the laboratory. Powered by wind, we estimate ~75 Mt CO2/yr could be collected using air capture and sequestered below seafloor or partially used for synfuel. Our analysis suggests that Kerguelen offers a remote and environmentally secure location for CO2 sequestration using renewable energy. Regional reservoirs could hold over 1500 Gt CO2, sequestering a large fraction of 21st century emissions. PMID- 23745612 TI - Syringic acid from Tamarix aucheriana possesses antimitogenic and chemo sensitizing activities in human colorectal cancer cells. AB - CONTEXT: For its variety of biological activities, Tamarix aucheriana (Decne.) Baum. (Tamaricaceae) has an extensive history as a traditional Arab medicine. OBJECTIVES: Antimitogenic and chemo-sensitizing activities of syringic acid (SA) were studied against human colorectal cancer. MATERIALS AND METHODS: Chromatographic and spectral data were used for the isolation and identification of SA. MTT, flow cytometry, in vitro invasion and angiogenesis assays, fluoremetry, ELISA and Real Time qPCR were used to test antimitogenic and chemo sensitizing activities of SA, cell cycle, apoptosis, proteasome and NFkappaB-DNA binding activities, cancer cell invasion and angiogenesis, and expression of cell cycle/apoptosis-related genes. RESULTS: SA showed a time- and dose-dependent (IC50 = 0.95-1.2 mg mL-1) antimitogenic effect against cancer cells with little cytotoxicity on normal fibroblasts (<=20%). SA-altered cell cycle (S/G2-M or G1/G2-M phases) in a time-dependent manner, induced apoptosis, inhibited DNA binding activity of NFkappaB (p <= 0.0001), chymotrypsin-like/PGPH (peptidyl glutamyl peptide-hydrolyzing) (p <= 0.0001) and the trypsin-like (p <= 0.002) activities of 26S proteasome and angiogenesis. SA also differentially sensitized cancer cells to standard chemotherapies with a marked increase in their sensitivity to camptothecin (500-fold), 5FU (20,000-fold), doxorubicin (210 fold), taxol (3134-fold), vinblastine (1000-fold), vincristine (130-fold) and amsacrine (107-fold) compared to standard drugs alone. DISCUSSION: SA exerted its chemotherapeutic and chemo-sensitizing effects through an array of mechanisms including cell-cycle arrest, apoptosis induction, inhibition of cell proliferation, cell migration, angiogenesis, NFkappaB DNA-binding and proteasome activities. CONCLUSION: These results demonstrate the potential of SA as an antimitogenic and chemo-sensitizing agent for human colorectal cancer. PMID- 23745613 TI - Formation of radicals during heating lysine and glucose in solution with an intermediate water activity. AB - Heating glucose with lysine under alkaline conditions (pH 7.0-10.0) was found to take place with consumption of oxygen together with formation of brown-colored compounds. Highly reactive intermediary radicals were detected when lysine and glucose were heated at intermediate water activity at pH 7.0 and 8.0. The detection was based on initial trapping of highly reactive radicals by ethanol followed by spin trapping of 1-hydroxyethylradicals with alpha-(4-pyridyl N oxide)-N-tert-butylnitrone (POBN) and Electron Spin Resonance (ESR) spectroscopy. The generation of reactive intermediary radicals from the Maillard reactions was favored by enhancing alkaline conditions (pH 8.0) and stimulated by presence of the transition metal ion Fe2+. The stability of the nitrone spin traps, N-tert butyl-alpha-phenylnitrone and POBN was examined in buffered aqueous solutions within the pH range 1-12, and found to be less temperature dependent at acidic pH compared to alkaline conditions. A low rate (kobs) of hydrolysis of POBN was found at the used experimental conditions of 70 degrees C and pH 7.0 and 8.0, which made this spin trap method suitable for the detection of radicals in the Maillard reaction system. PMID- 23745614 TI - Sharing, liking, commenting, and distressed? The pathway between Facebook interaction and psychological distress. AB - Studies on the mental health implications of social media have generated mixed results. Drawing on a survey of college students (N=513), this research uses structural equation modeling to assess the relationship between Facebook interaction and psychological distress and two underlying mechanisms: communication overload and self-esteem. It is the first study, to our knowledge, that examines how communication overload mediates the mental health implications of social media. Frequent Facebook interaction is associated with greater distress directly and indirectly via a two-step pathway that increases communication overload and reduces self-esteem. The research sheds light on new directions for understanding psychological well-being in an increasingly mediated social world as users share, like, and comment more and more. PMID- 23745615 TI - Cheating, breakup, and divorce: is Facebook use to blame? AB - The purpose of the present study was to investigate the relationship between using the social networking site known as Facebook and negative interpersonal relationship outcomes. A survey of 205 Facebook users aged 18-82 was conducted using a 16-question online survey to examine whether high levels of Facebook use predicted negative relationship outcomes (breakup/divorce, emotional cheating, and physical cheating). It was hypothesized that those with higher levels of Facebook use would demonstrate more negative relationship outcomes than those with lower use. The study then examined whether these relationships were mediated by Facebook-related conflict. Furthermore, the researchers examined length of relationship as a moderator variable in the aforementioned model. The results indicate that a high level of Facebook usage is associated with negative relationship outcomes, and that these relationships are indeed mediated by Facebook-related conflict. This series of relationships only holds for those who are, or have been, in relatively newer relationships of 3 years or less. The current study adds to the growing body of literature investigating Internet use and relationship outcomes, and may be a precursor to further research investigating whether Facebook use attributes to the divorce rate, emotional cheating, and physical cheating. PMID- 23745616 TI - Superman vs. BAD man? The effects of empathy and game character in violent video games. AB - Recent findings indicate that events in video games, as well as players' perceptions of game characters, moderate well-established video game effects. This includes the level of identification with game characters, and players' interpretation of whether or not the actions of the characters are conceived as moral. In the present study, it was tested whether manipulating empathy for well known game characters influences video game effects in a violent beat-'em-up game. As was expected, playing the comic hero Superman led to more prosocial behavior (i.e., returning a lost letter) than playing the evil villain Joker. A similar positive effect was observed for inducing game characters as warm and empathic before playing. Compared to a neutral text, participants in the empathy text condition judged the violence in the game as less justified, irrespective of game character. When looking at hostile perception, an interaction was found between empathy and game character. For Superman, empathy led participants to interpret neutral faces as less aggressive. When playing the evil Joker, however, empathy even increased hostile perception. This is in line with previous findings that empathy may not be positive per se. In fact, it may backfire depending on the interaction of game characters and the empathy players feel for them. PMID- 23745617 TI - Communication, opponents, and clan performance in online games: a social network approach. AB - Online gamers form clans voluntarily to play together and to discuss their real and virtual lives. Although these clans have diverse goals, they seek to increase their rank in the game community by winning more battles. Communications among clan members and battles with other clans may influence the performance of a clan. In this study, we compared the effects of communication structure inside a clan, and battle networks among clans, with the performance of the clans. We collected battle histories, posts, and comments on clan pages from a Korean online game, and measured social network indices for communication and battle networks. Communication structures in terms of density and group degree centralization index had no significant association with clan performance. However, the centrality of clans in the battle network was positively related to the performance of the clan. If a clan had many battle opponents, the performance of the clan improved. PMID- 23745618 TI - "It's common sense that it's wrong": young people's perceptions and experiences of cyberbullying. AB - The use of the Internet, mobile phones, and social networking sites by some young people to harass and intimidate each other has led cyberbullying to become a significant concern for parents, educators, and policy makers. The existing literature on this behavior is largely quantitative, with only a small number of qualitative studies addressing this issue. This study examined perceptions and experiences of cyberbullying in a series of 18 focus groups conducted with young people aged 9-19 in the UK. The results suggest that cyberbullying is perceived to be problematic and serious but relatively routine part of young people's online lives and interactions. The results also highlighted the influence of the characteristics of technologically mediated communication on the dynamics of the behavior. The role of anonymity in determining victim-perpetrator relationships and the seriousness of the behavior was discussed by participants, though the influence of disinhibition and inability to view the direct impact of victimization were perceived to be of greater importance. The implications of the results are discussed, and areas for future research suggested. PMID- 23745619 TI - Nonalcoholic fatty liver disease and reduced serum vitamin D(3) levels. AB - Nonalcoholic fatty liver disease (NAFLD) and vitamin D3 deficiency are two highly prevalent pathologic conditions worldwide that share several cardiometabolic risk factors. In addition to its traditional calcium-related effects on the skeleton, vitamin D3 deficiency has now been recognized to exert nonskeletal adverse effects on several other organ systems. Accumulating epidemiological evidence suggests that low levels of serum 25-hydroxyvitamin D3 are associated with the presence and severity of NAFLD, independently of several potential confounders, including features of the metabolic syndrome. The molecular mechanisms of this association remain incompletely understood. A variety of biologically plausible mechanisms may mediate a hepato-protective role for the active metabolite of vitamin D3. 1alpha,25-dihydroxyvitamin D3 modulates the insulin signaling pathway/insulin resistance, suppresses fibroblast proliferation and collagen production, exerts anticoagulant and profibrinolytic effects, and modulates macrophage activity and inflammatory cytokine generation. Overall, the high prevalence of vitamin D3 deficiency and the plausible biological mechanisms linking this to NAFLD suggest that treatment of vitamin D3 deficiency to prevent and/or treat NAFLD is a promising field to explore. Large placebo-controlled randomized clinical trials are urgently needed to determine whether vitamin D3 supplementation could have any potential benefit in reducing the development and progression of NAFLD. PMID- 23745620 TI - Postprandial adiponectin levels are associated with improvements in postprandial triglycerides after Roux-en-Y gastric bypass in type 2 diabetic patients. AB - BACKGROUND: Postprandial hypertrygliceridemia is a known factor for cardiovascular disease and is often observed in patients with type 2 diabetes mellitus (T2DM) and visceral adiposity. Adiponectin is a hormone with antiatherogenic and anti-inflammatory effects, which decreases in obesity and T2DM subjects. The weight loss induced by diet or bariatric surgery could be restoring adiponectin levels. OBJECTIVE: The aim of the study was to evaluate the impact of weight loss induced by bariatric surgery, which could restore adiponectin and triglycerides (TG) levels in obese and diabetic patients. METHODS: Ten patients with T2DM (BMI 39.3+2.44) were evaluated before and at 7 and 90 days after Roux-en-Y gastric bypass (RYGB). A meal test was performed and plasma insulin, glucagon-like peptide-1 (GLP-1), glucose, TG, and adiponectin levels were measured at fasting and at 30, 60, 90, and 120 min postprandial. RESULTS: Seven days after surgery, significant reductions in the insulin resistance were observed, while TG and adiponectin levels remained unchanged during the meal test. Ninety days after surgery, TG and glucose levels decreased significantly at fasting, and postprandial, adiponectin, GLP-1, and insulin curves increased significantly after meal ingestion. Both changes in the area under the curve (AUC) of adiponectin correlated with changes in the AUC of TG (R= 0.64, P=0.003) and changes in AUC of adiponectin correlated with changes in total fat mass. No correlation was found between changes in insulin, GLP-1, and TG levels. CONCLUSIONS: The adiponectin levels may be involved in the mechanism responsible for high TG levels in obese and diabetic patients. These abnormalities can be reversed by RYGB. PMID- 23745621 TI - AsthmaWise - a field of dreams? The results of an online education program targeting older adults with asthma. AB - OBJECTIVES: The aim of this study was to establish the feasibility and acceptability of an online asthma self-management program developed for older Australians with asthma. METHODS: AsthmaWise, an internet education self management program, was piloted for a 3-month period at the beginning of 2012. Participants were recruited using both online and offline strategies and were required to complete surveys, both pre- and post-intervention, in a repeated measures design. RESULTS: Matched data were collected from 51 participants; the results showed AsthmaWise to be a feasible and acceptable method of delivering asthma education to the target population. Self-reported measures showed an increase in participants' asthma knowledge, asthma control and quality of life. Results from the Perceived Health Web Site Usability Questionnaire (PHWSUQ) showed improvements between usability testing and implementation. CONCLUSION: The need for asthma self-management education will continue to increase as the population ages and a greater number of older adults are living with asthma. This small pilot study indicates that an online asthma self-management education program can result in improved outcome measures in a target group not normally considered technologically literate. PMID- 23745622 TI - Mechlorethamine-based drug structures for intervention of central nervous system tumors. AB - Tumors of the central nervous system are the third most common type of childhood cancers. Brain tumors occur in children and adults; however pediatric patients require a different treatment process. Thirteen drugs similar to mechlorethamine are analyzed in this study. These drugs possess molecular properties enabling substantial and successful access to tumors of the central nervous system. All drugs exhibit zero violations of the Rule of 5, which indicate favorable bioavailability. Ranges in Log P, formula weight, and polar surface area for these drugs are: 1.554 to 3.52, 156.06 to 460.45, and 3.238 Angstroms(2) to 45.471 Angstroms(2), respectively. Hierarchical cluster analysis determined that agents 7 and 12 are most similar to the parent compound mechlorethamine. The mean values of Log P, formula weight, polar surface area, and molecular volume are 2.25, 268.51, 16.57 Angstroms(2), and 227.01 Angstroms(3), respectively. Principal component analysis indicates that agents 7 and 12 are most similar to mechlorethamine and multiple regression analysis of molecular properties produced a model to enable the design of similar alkylating agents. Values of Log (Cbrain/Cblood) indicate these agents will have very high permeation into the central nervous system. PMID- 23745623 TI - World Bank: harnessing civil society expertise in undertaking and disseminating research findings. AB - The UK Consortium on AIDS and International Development was an essential partner to the evaluation leaders in harnessing the contribution and expertise of civil society. This article describes what the partnership entailed, the additional value it brought and how civil society might use the evaluation findings both as a tool for advocacy and a means for improving its own engagement with the individuals directly affected by HIV and with those who care for them. PMID- 23745624 TI - Socioeconomic determinants of stigmatization and HIV testing in Lesotho. AB - HIV/AIDS stigmatizing attitudes and their consequences on preventative behaviors are among the most poorly understood aspects of the AIDS epidemic. This paper analyzes the socioeconomic determinants of discriminating attitudes toward people living with HIV and their implications on the likelihood of HIV testing. These effects are tested using the 2004 and 2009 Demographic and Health Surveys conducted in Lesotho, where HIV/AIDS is a pervasive problem. We find that HIV/AIDS stigmatizing attitudes are negatively associated with education and wealth and positively correlated with Catholic religion for women and traditional circumcision for men. The analysis also shows a negative association between stigmatizing beliefs and the probability of being tested for HIV. PMID- 23745625 TI - Social capital and HIV competent communities: the role of community groups in managing HIV/AIDS in rural Zimbabwe. AB - Community involvement is increasingly identified as a "critical enabler" of an effective HIV/AIDS response. We explore pathways between community participation and HIV prevention, treatment and impact mitigation in Zimbabwe, reviewing six qualitative studies in Manicaland. These find that community group membership is often (not always) associated with decreased HIV incidence, reduced stigma and improved access to some services, particularly amongst women. Participation in formal community groups (e.g., church or women's groups) and informal local networks (e.g., neighbours, families) provides opportunities for critical dialogue about HIV/AIDS, often facilitating renegotiation of harmful social norms, sharing of previously hidden personal experiences of HIV/AIDS, formulation of positive action plans and solidarity to action them. However, implementation of new plans and insights is constrained by poverty, social uncertainty and poor service delivery. Furthermore, dialogue may have negative effects, spreading false information and entrenching negative norms. The extent that formal groups and informal networks facilitate externally imposed HIV/AIDS interventions varies. They potentially provide vital practical and emotional support, facilitating service access, treatment adherence and AIDS care. However, they may sometimes play a negative role in prevention activities, challenging stereotypes about sexuality or gender. There is an urgent need for greater recognition of the role of indigenous community groups and networks, and the inclusion of "strengthening local responses" as a key element of interventions and policy. Such efforts require great sensitivity. Heavy-handed external interference in complex indigenous relationships risks undermining the localism and bottom-up initiative and activism that might be central to their effectiveness. Cautious efforts might seek to enhance the potentially beneficial effects of groups, especially for women, and limit potentially damaging ones, especially for men. Efforts should be made to facilitate contexts that enable groups to have beneficial effects, through nesting them within wider comprehensive responses, and supporting them through strong partnerships with service providers. PMID- 23745626 TI - Funding and expenditure of a sample of community-based organizations in Kenya, Nigeria, and Zimbabwe. AB - Over the last decade, international donors, technical specialists, and governments have come to recognize the potential of community-based organizations (CBOs) in the fight against HIV/AIDS. Recent empirical studies suggest that community engagement, including the involvement of CBOs, adds value to the national response to HIV/AIDS. With the emerging evidence of the effectiveness of engaging communities in the fight against AIDS, it is crucial to understand the economic dimension of community engagement. This article provides an analysis of funding and expenditure data collected from CBOs in three African countries: Kenya, Nigeria, and Zimbabwe. It presents descriptive information regarding CBO funding and expenditure and examines the factors associated with the total amount of funds received and with the proportions of the funds allocated to programmatic activities and program management and administration. An average CBO in the sample received US$29,800 annually or about US$2480 per month. The highest percentage of CBO funding (37%) came from multilateral organizations. CBOs in the sample spent most of their funds (71%) on programmatic activities including provision of treatment, support, care, impact mitigation, and treatment services. PMID- 23745627 TI - Implementing for results: program analysis of the HIV/STI interventions for sex workers in Benin. AB - HIV response has entered a new era shaped by evidence that the combination of interventions impacts the trajectory of the epidemic. Even proven interventions, however, can be ineffective if not to scale, appropriately implemented, and with the right combination. Benin is among the pioneering countries that prioritized HIV prevention for sex workers and clients early on. Effective implementation up to 2006 resulted in consistent condom use among sex workers increasing from 39% to 86.2% and a decline in prevalence of gonorrhea from 5.4% to 1.6%. This study responds to the growing concern that, although proven interventions for female sex workers (FSWs) were expanded in Benin since 2008, indicators of coverage and behaviors are far from satisfactory. The quest to better understand implementation and how to render service delivery efficient and effective resonates with increased emphasis in the international arena on return for investments. Quantitative and qualitative methods were utilized to collect data. The output measured is the number of sex workers seeking Sexually Transmitted Infection (STI) care at user-friendly STI Clinics (SCs). Data were collected for 2010-2011 in nine regions of Benin. While recognizing that commitment to scale up is commendable, the study revealed deficiencies in program design and implementation that undermine outcomes. The selected mix of interventions is not optimal. Allocation of funds is not proportionate to the needs of FSW across regions. Only 5 of 41 SCs were fully functional at time of study. Free distribution of condoms covers only 10% of needs of FSWs. Funding and financing gaps resulted in extended interruptions of services. Successful HIV prevention in Benin will depend on the effective and efficient implementation of well-funded programs in sex work setting. Resources should be aligned to local sex work typology and presence in communities. A national framework defining an appropriate mix of interventions, management structure, referral mechanisms, and operational standards is required to guide rigorous implementation. Health services, in particular functional and user-friendly SCs coupled with mechanisms that link community-based work and health facilities should be strengthened to ensure STI care/anti-retroviral treatment expansion. Without leadership of sex workers, any attempt to end HIV will be unsuccessful. PMID- 23745628 TI - DFID commentary on the evaluation of the community response to HIV and AIDS. AB - The UK Department for International Development (DFID) has funded communities involved in the HIV response for many years. The critical importance of this response, the ownership by and empowerment of communities that has emerged, is to be celebrated. But there is still much we do not know about the complex inter relationship between community engagement and impact on HIV outcomes. We need a much clearer understanding of how best to support and sustain effective and efficient responses. The DFID funded World Bank evaluation of the community response to HIV and AIDS reflects a broader commitment to more and better evaluation, as a key instrument for learning what works most effectively for poor people. The real proof of sustained value of this evaluation is in the longer term translation of evidence into policy and practice, and through shaping future evaluation and research priorities. In particular more evidence needs to be generated on the complex pathways to achieving health impacts, and more systematic effort is required to quantify the benefits and costs of interventions. PMID- 23745629 TI - Exploring impacts of multi-year, community-based care programs for orphans and vulnerable children: a case study from Kenya. AB - The Community-Based Care for Orphans and Vulnerable Children (CBCO) program operated in Kenya during 2006-2010. In Eastern Province, the program provided support to approximately 3000 orphans and vulnerable children (OVC) living in 1500 households. A primary focus of the program was to support savings and loan associations composed of OVC caregivers (typically elderly women) to improve household and OVC welfare. Cross-sectional data were collected in 2011 from 1500 randomly selected households from 3 populations: program participants (CBCO group, n=500), households in the same villages as program participants but not in the program (the local-community-group = Group L, n=300), and households living in nearby villages where the program did not operate (the adjacent-community group, Group A, n=700). Primary welfare outcomes evaluated are household food security, as measured by the Household Food Insecurity Access instrument, and OVC educational attainment. We compared outcomes between the CBCO and the subset of Group L not meeting program eligibility criteria (L-N) to investigate disparities within local communities. We compared outcomes between the CBCO group and the subset of Group A meeting eligibility criteria (A-E) to consider program impact. We compared outcomes between households not eligible for the program in the local and adjacent community groups (L-N and A-N) to consider if the adjacent communities are similar to the local communities. In May-June 2011, at the end of the OVC program, the majority of CBCO households continued to be severely food insecure, with rates similar to other households living in nearby communities. Participation rates in primary school are high, reflecting free primary education. Among the 18-22 year olds who were "children" during the program years, relatively few children completed secondary school across all study groups. Although the CBCO program likely provided useful services and benefits to program participants, disparities continued to exist in food security and educational outcomes between program participants and their non-OVC peers in the local community. Outcomes for CBCO households were similar to those observed for OVC households in adjacent communities. PMID- 23745630 TI - Understanding the role of peer group membership in reducing HIV-related risk and vulnerability among female sex workers in Karnataka, India. AB - In Karnataka state, South India, we analyzed the role of membership in peer groups in reducing HIV-related risk and vulnerability among female sex workers (FSWs). Data from three surveys conducted in Karnataka, a behavioral tracking survey and two rounds of integrated biological and behavioral assessments (IBBAs), were analyzed. Using propensity score matching, we examined the impact of group membership on selected outcomes, including condom use, experience of violence, access to entitlements, and the prevalence of sexually transmitted infections, including HIV infection. Focus group discussions were conducted with the FSWs to better understand their perceptions regarding membership in peer groups. Peer group members participating in the IBBAs had a lower prevalence of gonorrhea and/or chlamydia (5.2 vs 9.6%, p<0.001), and of syphilis (8.2 vs 10.3%, p<0.05), compared to non-members. The average treatment effect for selected outcome measures, from the propensity score matching, showed that FSWs who were members of any peer group reported significantly less experience of violence in the past six months, were less likely to have bribed police to avoid trouble in the past six months, and were more likely to have obtained at least one formal identification document in the past five years, compared to non-members. In focus group discussions, group members indicated that they had more confidence in dealing with situations of forced sex and violence. Including community mobilization and peer group formation in the context of HIV prevention programing can reduce HIV-related risk and vulnerability among FSWs. PMID- 23745631 TI - Community collectivization and its association with consistent condom use and STI treatment-seeking behaviors among female sex workers and high-risk men who have sex with men/transgenders in Andhra Pradesh, India. AB - We examine community collectivization among female sex workers (FSWs) and high risk men who have sex with men and transgenders (HR-MSM) following several years of HIV prevention programming with these populations, and its association with selected outcome indicators measuring individual behaviors (condom use with different partners and sexually transmitted infection [STI] treatment-seeking from government health facilities). Data for this study were collected from a large-scale cross-sectional survey conducted in 2010-2011 among FSWs (sample size: 3557) and HR-MSM (sample size: 2399) in Andhra Pradesh, India. We measured collectivization among FSWs in terms of three binary (low, high) indices of collective efficacy, collective agency, and collective action. Collectivization among HR-MSM was measured by participation in a public event (no, yes), and a binary (low, high) index of collective efficacy. Adjusted odds ratios (adjusted OR) and their 95% confidence intervals (CI) were computed to assess the relationships between collectivization and outcome indicators directly and through mediation of variables such as self-efficacy for condom use and utilization of government health facilities. Results show that among FSWs, high levels of collective efficacy (adjusted OR: 1.3, 95% CI: 1.1-1.7) and collective action (adjusted OR:1.3, 95% CI: 1.1-1.8) were associated with consistent condom use (CCU) with regular clients. Among HR-MSM, participation in a public event (adjusted OR: 2.7, 95% CI: 2.0-3.6) and collective efficacy (adjusted OR: 1.9, 95% CI: 1.5-2.3) were correlated with condom use with paying partners. The association between collectivization and outcome indicators continued to be significant in most cases even after adjusting for the potential mediators. Indicators of collectivization exhibited significant positive association with self-efficacy for condom use and service utilization from government health facilities among both FSWs and HR-MSM. The association of high levels of collectivization with CCU, STI treatment-seeking from government health facilities, ability to negotiate for condom use, and self-efficacy in utilizing government health facilities is relevant to effort to improve the effectiveness and sustainability of HIV prevention programs in India and beyond. PMID- 23745632 TI - Evaluating the effects of community-based organization engagement on HIV and AIDS related risk behavior in Kenya. AB - International donors have increasingly shifted AIDS funding directly to community based organizations (CBOs) with the assumption that responding to the epidemic is best achieved at the community level. The World Bank, ICF Macro, and the National Council for Population and Development in Kenya, conducted a study to evaluate the community response in Kenya. The study used a quasi-experimental design comparing seven study communities and seven comparison communities in Nyanza Province and Western Province. We examined the impact of CBO activity on individual and community-level outcomes, including HIV knowledge, awareness and perceptions, sexual risk behavior, and social transformation (gender ideology and social capital). The study consisted of two components: a household survey conducted in all 14 communities, and qualitative data collected in a subset of communities. Individuals in communities with higher CBO engagement were significantly more likely to have reported consistent condom use. Higher CBO engagement was associated with some measures of social capital, including participation in local and national elections, and participation in electoral campaigns. CBOs provide added value in addressing the HIV and AIDS epidemic in very targeted and specific ways that are closely tied to the services they provide (e.g., prevention education); thus, increasing CBO engagement can be an effective measure in scaling up prevention efforts in those areas. PMID- 23745633 TI - Evaluation of the community response to HIV and AIDS: learning from a portfolio approach. AB - While communities have played a large role in the HIV/AIDS response, their contributions and innovative approaches to HIV prevention, treatment, care and support have not always been the focus of systematic and rigorous evaluations. To address this gap, the World Bank led an evaluation of the impact of the community response to HIV, including country studies in Burkina Faso, India, Kenya, Lesotho, Nigeria, Senegal, South Africa and Zimbabwe over a three-year period. Due to the complexity and varied nature of community responses, the evaluation attempted to determine the results that investments have produced at the community level by applying a mixed method approach: Randomized Controlled Trials, quasi-experimental studies, qualitative studies and analytical studies including financial data. Specifically, the studies examined a typology of community response and the flow of funds to community-based organizations, while investigating the impact of the community responses on (1) knowledge and behavior, (2) use of services, (3) social transformation, and (4) HIV incidence. This editorial summarizes the results of this evaluation portfolio, finding that investments in communities have produced significant results, including, improved knowledge and behavior, and increased use of health services, and even decreased HIV incidence. Evidence on social transformation was more mixed, with community groups found to be effective only in some settings. Each study in the evaluation provides a partial view of how communities shape the local response; however, taken together they corroborate the common wisdom that communities can be a vital part of the global HIV/AIDS response. PMID- 23745634 TI - It takes a village: community-based organizations and the availability and utilization of HIV/AIDS-related services in Nigeria. AB - Community-based organizations (CBOs) have emerged as a vital part of the response to HIV/AIDs in Nigeria. The evaluation, on which this article is based, conducted in 28 communities in 6 states and the Federal capital Territory in Nigeria, assessed the effects of the CBO engagement on a set of outcomes related to HIV/AIDS knowledge, attitudes, beliefs, and practices, stigma, service availably and utilization and social capital. It consisted of three components: a household survey conducted in all 28 communities, qualitative data collected from CBO staff and key informants (KIs), and a funding allocation study (qualitative interviews and the funding allocation study were conducted in a subset of 14 communities). This article focuses on the association between CBO engagement and reported availability and utilization of HIV/AIDS-related services. It shows that CBO engagement has a potential to add value to the national response to HIV/AIDS by increasing the awareness, availability, and utilization of HIV/AIDS-related services, especially in the area of prevention, care and support. The CBOs in the evaluation communities focused on prevention activities as well as on providing support for people living with HIV/AIDS (PLWHA) and prevention and care and support were the highest expenditure categories reported by CBOs. Respondents in communities with a stronger CBO engagement were more likely to: (1) be aware of any HIV/AIDs-related services, (2) report that prevention and care services were available in their communities, and (3) have used any HIV/AIDS related services, prevention-related and care-related services than respondents in communities where CBO engagement was weaker. The association between service awareness and service use and CBO engagement was stronger in rural than in urban areas. PMID- 23745635 TI - Evidence for a contribution of the community response to HIV decline in eastern Zimbabwe? AB - Membership of indigenous local community groups was protective against HIV for women, but not for men, in eastern Zimbabwe during the period of greatest risk reduction (1999-2004). We use four rounds of data from a population cohort to investigate: (1) the effects of membership of multiple community groups during this period; (2) the effects of group membership in the following five years; and (3) the effects of characteristics of groups hypothesised to determine their effect on HIV risk. HIV incidence from 1998 to 2003 was 1.18% (95% CI: 0.78 1.79%), 0.48% (0.20-1.16%) and 1.13% (0.57-2.27%), in women participating in one, two and three or more community groups at baseline versus 2.19% (1.75-2.75%) in other women. In 2003-2005, 36.5% (versus 43% in 1998-2000) of women were members of community groups, 50% and 56% of which discussed HIV prevention and met with other groups, respectively; the corresponding figures for men were 24% (versus 28% in 1998-2000), 51% and 58%. From 2003 to 2008, prior membership of community groups was no longer protective against HIV for women (1.13% versus 1.29%, aIRR = 1.25; p = 0.23). However, membership of groups that provided social spaces for dialogue about HIV prevention (0.62% versus 1.01%, aIRR = 0.54; p = 0.28) and groups that interacted with other groups (0.65% versus 1.01%, aIRR = 0.51; p = 0.19) showed non-significant protective effects. For women, membership of a group with external sponsorship showed a non-significant increase in HIV risk compared to membership of unsponsored groups (adjusted odds ratio = 1.63, p = 0.48). Between 2003 and 2008, membership of community groups showed a non-significant tendency towards higher HIV risk for men (1.47% versus 0.94%, p = 0.23). Community responses contributed to HIV decline in eastern Zimbabwe. Sensitive engagement and support for local groups (including non-AIDS groups) to encourage dialogue on positive local responses to HIV and to challenge harmful social norms and incorrect information could enhance HIV prevention. PMID- 23745636 TI - The effects of home-based HIV counseling and testing on HIV/AIDS stigma among individuals and community leaders in western Kenya: evidence from a cluster randomized trial. AB - HIV counseling and testing services play an important role in HIV treatment and prevention efforts in developing countries. Community-wide testing campaigns to detect HIV earlier may additionally impact community knowledge and beliefs about HIV. We conducted a cluster-randomized evaluation of a home-based HIV testing campaign in western Kenya and evaluated the effects of the campaign on community leaders' and members' stigma toward people living with HIV/AIDS. We find that this type of large-scale HIV testing can be implemented successfully in the presence of stigma, perhaps due to its "whole community" approach. The home-based HIV testing intervention resulted in community leaders reporting lower levels of stigma. However, stigma among community members reacted in mixed ways, and there is little evidence that the program affected beliefs about HIV prevalence and prevention. PMID- 23745638 TI - Proton-detected solid-state NMR spectroscopy at aliphatic sites: application to crystalline systems. AB - When applied to biomolecules, solid-state NMR suffers from low sensitivity and resolution. The major obstacle to applying proton detection in the solid state is the proton dipolar network, and deuteration can help avoid this problem. In the past, researchers had primarily focused on the investigation of exchangeable protons in these systems. In this Account, we review NMR spectroscopic strategies that allow researchers to observe aliphatic non-exchangeable proton resonances in proteins with high sensitivity and resolution. Our labeling scheme is based on u [(2)H,(13)C]-glucose and 5-25% H2O (95-75% D2O) in the M9 bacterial growth medium, known as RAP (reduced adjoining protonation). We highlight spectroscopic approaches for obtaining resonance assignments, a prerequisite for any study of structure and dynamics of a protein by NMR spectroscopy. Because of the dilution of the proton spin system in the solid state, solution-state NMR (1)HCC(1)H type strategies cannot easily be transferred to these experiments. Instead, we needed to pursue ((1)H)CC(1)H, CC(1)H, (1)HCC or ((2)H)CC(1)H type experiments. In protonated samples, we obtained distance restraints for structure calculations from samples grown in bacteria in media containing [1,3]-(13)C-glycerol, [2] (13)C-glycerol, or selectively enriched glucose to dilute the (13)C spin system. In RAP-labeled samples, we obtained a similar dilution effect by randomly introducing protons into an otherwise deuterated matrix. This isotopic labeling scheme allows us to measure the long-range contacts among aliphatic protons, which can then serve as restraints for the three-dimensional structure calculation of a protein. Due to the high gyromagnetic ratio of protons, longer range contacts are more easily accessible for these nuclei than for carbon nuclei in homologous experiments. Finally, the RAP labeling scheme allows access to dynamic parameters, such as longitudinal relaxation times T1, and order parameters S(2) for backbone and side chain carbon resonances. We expect that these measurements will open up new opportunities to obtain a more detailed description of protein backbone and side chain dynamics. PMID- 23745637 TI - S100A11 is involved in the regulation of the stability of cell cycle regulator p21(CIP1/WAF1) in human keratinocyte HaCaT cells. AB - The cyclin-dependent kinase inhibitor p21(CIP1/WAF1) is a regulatory factor of the cell cycle. Its transcriptional activation and protein stability are tightly controlled by several distinct mechanisms. S100A11 is a member of the S100 family of Ca2+-binding proteins involved in several biological processes, including cell cycle progression and signal transduction. In the present study, we show that down-regulation of S100A11 results in the reduction of p21 protein in human HaCaT keratinocytes. It appears that a ubiquitin-independent proteasomal degradation process is involved in p21 degradation in S100A11 down-regulated cells. The application of a proteasome inhibitor stabilized p21 protein in these cells. Analysis of distinct signal transduction pathways revealed a disturbed phosphatidylinositol-3-kinase/Akt pathway after S100A11 knockdown. We determined that the glycogen synthase kinase-3, which is negatively regulated by phosphatidylinositol 3-kinase/Akt, was activated in cells possessing knocked-down S100A11 and appears to be involved in p21 protein destabilization. The application of a specific inhibitor of glycogen synthase kinase 3 resulted in an increase of the p21 protein level in S100A11 down-regulated HaCaT cells. Glycogen synthase kinase 3 is able to phosphorylate p21 at T57, which induces p21 proteasomal turnover. Mutation of the glycogen synthase kinase 3 site threonine 57 into alanine (T57A) stabilizes p21 in HaCaT cells lacking S100A11. Beside decreased p21 protein, down-regulation of S100A11 triggered the induction of apoptosis in HaCaT cells. These observations suggest that S100A11 is involved in the maintenance of p21 protein stability and appears to function as an inhibitor of apoptosis in human HaCaT keratinocyte cells. Thus, the data shed light on a novel pathway regulating p21 protein stability. PMID- 23745639 TI - Antibodies bound to Abeta oligomers potentiate the neurotoxicity of Abeta by activating microglia. AB - Beta amyloid (Abeta) oligomers are thought to contribute to the pathogenesis of Alzheimer's disease. However, clinical trials using Abeta immunization were unsuccessful due to strong brain inflammation, the mechanisms of which are poorly understood. In this study we tested whether monoclonal antibodies to oligomeric Abeta would prevent the neurotoxicity of Abeta oligomers in primary neuronal glial cultures. However, surprisingly,the antibodies dramatically increased the neurotoxicity of Abeta. Antibodies bound to monomeric Abeta fragments were non toxic to cultured neurons, while antibodies to other oligomeric proteins: hamster polyomavirus major capsid protein, human metapneumovirus nucleocapsid protein, and measles virus nucleocapsid protein, strongly potentiated the neurotoxicity of their antigens. The neurotoxicity of antibody-antibody oligomeric antigen complexes was abolished by removal of the Fc region from the antibodies or by removal of microglia from cultures, and was accompanied by inflammatory activation and proliferation of the microglia in culture. In conclusion, we find that immune complexes formed by Abeta oligomers or other oligomeric/multimeric antigens and their specific antibodies can cause death and loss of neurons in primary neuronal-glial cultures via Fc-dependent microglial activation. The results suggest that therapies resulting in antibodies to oligomeric Abeta or oligomeric brain virus proteins should be used with caution or with suppression of microglial activation. PMID- 23745640 TI - Editorial: Towards a future nursing education landscape. PMID- 23745641 TI - Certified nursing assistants' perception of pain in people with dementia: a hermeneutic enquiry in dementia care practice. AB - AIMS AND OBJECTIVES: To interpret certified nursing assistants' perception of pain in people with dementia in nursing care practice. BACKGROUND: Detection and understanding of pain in people with dementia remains a challenge due to their difficulty in verbalising their pain. Nursing assistants provide daily nursing care and therefore play a vital role in pain detection. Nevertheless, pain research from the nursing assistants' perspective is sparse. DESIGN: A qualitative approach within the interpretive tradition was adopted. METHODS: Individual interviews with twelve certified nursing assistants, all working in dementia care, were conducted and interpreted using philosophical hermeneutics. RESULTS: Nursing assistants' perception of pain is on three levels. Each level consists of a theme. The first theme 'Being in the facing phase' refers to the initial perception of the person's expressions. The second theme 'Being in the reflecting phase' means ability to reflect more deeply on one's perception, together with other colleagues and next of kins. The third theme 'Being in the acting phase' means perception arising from preventive and protective care focusing on contributing to well-being. The themes served as a basis for comprehensive understanding, where perception of pain arises from closeness, compassion and dialogue based on personhood, accompanied by professional knowledge of pain and dementia. CONCLUSION: Nursing assistants' perception of pain is based on ethical concerns and on their own subjective pain experiences rather than on medical skills. Their perception derives from fundamental values that are important aspects of nursing care. Interdisciplinary solidarity may strengthen cooperation amongst CNAs and RNs to achieve best pain management practice. RELEVANCE TO CLINICAL PRACTICE: Attention to nursing assistants' perception of pain needs to be highlighted when they are front-line staff and have developed important pain detection skills. Their skills are essential complements and must be used in the development of pain management in dementia care practice. PMID- 23745642 TI - Religion and self-management of Thai Buddhist and Muslim women with type 2 diabetes. AB - AIMS AND OBJECTIVES: To report of a qualitative study of how religion affects the self-management of Thai Buddhist and Muslim women with type 2 diabetes. BACKGROUND: The importance of diabetes self-management is well recognised. However, research on such self-management in Thailand is scarce, in particular on the influence of religion on the self-management of Thai Buddhist and Muslim women with type 2 diabetes. DESIGN: A descriptive qualitative study was conducted. METHODS: Purposive convenience sampling was used, and 48 women, 19 Buddhist and 29 Muslim, aged from 28-80 years, participated. Data were collected in 2008-09 and analysed by use of manifest and latent content analysis. RESULTS: Four themes of the influence of religion on the self-management among Thai women with type 2 diabetes emerged: religion - a way of coping with diabetes, spiritual practice - a help for disease control, spiritual practice - an effort to struggle with everyday life, and support from family - a cultural practice. CONCLUSIONS: The Buddhist and Muslim women had self-management capabilities that were often related to their religions. However, many of them had poor control of their blood sugar levels and needed assistance. RELEVANCE TO CLINICAL PRACTICE: Reference to religion and spiritual practice can be an effective means of helping diabetes patients better manage their disease and change their lifestyles. Furthermore, family and economic and social environments should be taken into account both in care and in interventions aimed at helping patients cope and empowering them to control their disease. PMID- 23745643 TI - Exploring staff diabetes medication knowledge and practices in regional residential care: triangulation study. AB - AIMS AND OBJECTIVES: This study is drawn from a larger project that aimed to identify the staffing and organisational factors influencing the quality of diabetes care for older people living in residential care in regional Victoria, Australia. The focus of the current study is on medication management for residents with diabetes. BACKGROUND: With a continuous rise in diabetes in the population, there is an associated increase in the prevalence of diabetes in aged care residential settings. However, there is little specific guidance on how to manage diabetes in older people living in institutional settings who experience multiple concurrent chronic conditions. DESIGN: A triangulation strategy consisting of three phases. METHODS: A one-shot cross-sectional survey (n = 68) focus group interviews and a case file audit (n = 20). Data were collected between May 2009-January 2010. FINDINGS: Staff knowledge of diabetes and its contemporary medication management was found to be suboptimal. Challenges to managing residents with diabetes included limited time, resident characteristics and communication systems. Additionally, the variability in medical support available to residents and a high level of polypharmacy added to the complexity of medication management of resident. CONCLUSIONS: The current study suggests administering medicine to residents in aged care settings is difficult and has potentially serious medical, professional and economic consequences. Limitations to staff knowledge of contemporary diabetes care and medications potentially place residents with diabetes at risk of receiving less than optimal diabetes care. RELEVANCE TO CLINICAL PRACTICE: Providing evidence-based guidelines about diabetes care in residential care settings is essential to achieve acceptable outcomes and increase the quality of life for residents in public aged care. Continuing education programs in diabetes care specifically related to medication must be provided to all health professionals and encompass scope of practice. PMID- 23745644 TI - A qualitative study on non-verbal sensitivity in nursing students. AB - AIMS AND OBJECTIVES: To explore nursing students' perception of the meanings and roles of non-verbal communication and sensitivity. It also attempts to understand how different factors influence their non-verbal communication style. BACKGROUND: The importance of non-verbal communication in the health arena lies in the need for good communication for efficient healthcare delivery. Understanding nursing students' non-verbal communication with patients and the influential factors is essential to prepare them for field work in the future. DESIGN: Qualitative approach based on 16 in-depth interviews. METHODS: Sixteen nursing students from the Master of Nursing and the Year 3 Bachelor of Nursing program were interviewed. Major points in the recorded interviews were marked down for content analysis. RESULTS: Three main themes were developed: (1) understanding students' non-verbal communication, which shows how nursing students value and experience non-verbal communication in the nursing context; (2) factors that influence the expression of non-verbal cues, which reveals the effect of patients' demographic background (gender, age, social status and educational level) and participants' characteristics (character, age, voice and appearance); and (3) metaphors of non verbal communication, which is further divided into four subthemes: providing assistance, individualisation, dropping hints and promoting interaction. CONCLUSIONS: Learning about students' non-verbal communication experiences in the clinical setting allowed us to understand their use of non-verbal communication and sensitivity, as well as to understand areas that may need further improvement. RELEVANCE TO CLINICAL PRACTICE: The experiences and perceptions revealed by the nursing students could provoke nurses to reconsider the effects of the different factors suggested in this study. The results might also help students and nurses to learn and ponder their missing gap, leading them to rethink, train and pay more attention to their non-verbal communication style and sensitivity. PMID- 23745645 TI - Nursing informatics competencies: assessment of undergraduate and graduate nursing students. AB - AIMS AND OBJECTIVES: To report the informatics competencies of students in selected undergraduate and graduate nursing programmes, to examine whether informatics competencies differed between the different programmes and to suggest competency-based applications that will strengthen informatics courses and informatics-related content throughout the curricula. BACKGROUND: Nursing students in undergraduate and graduate nursing programmes have different educational backgrounds and different practice experience. Thus, their informatics preparation is apt to be varied, and nursing curricula must reflect this variation while advancing students towards informatics proficiency. However, studies on informatics competency assessment in these nursing students are scarce. DESIGN: A descriptive survey design. METHODS: Data were collected from 289 nursing students using a 30-item Self-Assessment of Nursing Informatics Competencies Scale via an email sent to students using a LISTSERV mailing list. The email embedded link to the Internet survey package, SurveyMonkey, which included the Self-Assessment of Nursing Informatics Competencies Scale and demographic questions along with an online consent form. RESULTS: Students in both programmes were competent in three subscale areas: basic computer knowledge and skills, clinical informatics attitude, and wireless device skills. Graduate students reported slightly higher mean competency scores than did undergraduate students in three subscales: clinical informatics role, clinical informatics attitude and wireless device skills. CONCLUSIONS: Findings indicate specific topics for nurse educators to consider when designing informatics curricula. The comparison of undergraduate and graduate students indicates similarities in informatics competencies in terms of areas where students were competent and small mean score differences. Further studies are suggested to examine whether there are differences in informatics competencies between undergraduate and graduate students. RELEVANCE TO CLINICAL PRACTICE: These results assist nurse educators in determining specific areas of informatics content that need greater focus and inclusion in the design of better nursing educational programmes. Examples of integrating competencies into existing curriculum or informatics courses are suggested. PMID- 23745646 TI - Implications for school nursing through interprofessional education and practice. AB - AIMS AND OBJECTIVES: To explore the interprofessional collaboration between nursing and social work professionals in their delivery of health services for schoolchildren. BACKGROUND: Interprofessional education has long been recommended as a way to meet the need for effective collaboration in school health service with a view to improving the quality of health care. No local study in Hong Kong has looked specifically at how nursing and social work professionals carry out school health services through interprofessional education and practice. Therefore, an examination was conducted of collaboration on a community-based school caring project. DESIGN: A qualitative design was employed, using semi structured interviews, field observation and field debriefing. METHODS: Seven nursing students and five social work students were recruited and interviewed in 2011. The transcripts were analysed using qualitative content analysis. RESULTS: Three themes were identified: (1) early identification of children's needs through interprofessional collaboration for health promotion, (2) prompt referral for schoolchildren in need, and (3) comprehensive planning and implementation of school health service. CONCLUSION: The strength of collaborative work between nursing and social work professionals is that it helps to identify and address these complex health needs of children. Healthcare providers are hence able to develop a fuller understanding of children's problems, which in turn enables them to provide appropriate and effective health promotion interventions. RELEVANCE TO CLINICAL PRACTICE: The development of interprofessional education for school health services should be envisaged by the local higher educational institute and policy makers to reduce children's risk-taking behaviours and promote their health and well-being. Health educators and health policy makers can better understand how interprofessional education and collaboration can promote children health service for regional and national policy and practice. PMID- 23745647 TI - Factors helping adolescents to stop self-cutting: descriptions of 347 adolescents aged 13-18 years. AB - AIMS AND OBJECTIVES: To describe the factors contributing to the stopping of self cutting among 13-18-year-old Finnish adolescents from the personal perspective of the adolescents. BACKGROUND: Self-cutting is quite common among adolescents. However, adolescents' personal descriptions of what helped them to stop self cutting have not previously been investigated. DESIGN: Qualitative descriptive design with quantification. METHODS: The data were collected from 347 participants using structured self-rating questionnaires as a part of a larger research project focusing on the mental well-being of adolescents aged between 13 18 years in Finland. The participants were asked to write their own descriptions of how they had been able to stop self-cutting, if they had done so. The data were analysed using qualitative content analysis. Frequencies and percentages were calculated in relation to the total number of identified references to factors contributing to the stopping of self-cutting. This enabled the determination of the most important factors helping adolescents to stop self cutting from their own perspective. RESULTS: Six main themes emerged: factors associated with self-cutting and meanings related to it (n = 173); personal factors (n = 126); factors associated with other people (n = 104); factors associated with care or therapy (n = 18); meanings related to the instruments used to cut (n = 1) and unidentified factors (n = 18). CONCLUSIONS: Factors associated with self-cutting and meanings related to it were the most important factors contributing to the stopping of self-cutting. Personal factors and those associated with other people were also important, while factors associated with care were of less importance in this study. RELEVANCE TO CLINICAL PRACTICE: The factors identified in this study could potentially be used in clinical practice to assist other adolescents in stopping their self-cutting. PMID- 23745648 TI - Dealing with the devil: weight loss concerns in young adult women with type 1 diabetes. AB - AIMS AND OBJECTIVES: To examine the weight loss concerns of young adults with type 1 diabetes. BACKGROUND: Eating disorders are prevalent in young women with type 1 diabetes. DESIGN: Qualitative. METHODS: Interviews with 35 young adults (23-30 years of age) with type 1 diabetes and 13 healthcare professionals. RESULTS: Most female interviewees were concerned about the difficulties of losing weight when having diabetes. Six female interviewees developed severe eating disturbances when they were younger. These women initially regarded their disturbed eating behaviour positively and engaged in weight loss activities intermittently. However, over time, they lost control of their behaviour, and it came to dominate their lives. Family conflict often intensified disordered eating behaviours. Eventually all of these women managed to transition away from their behaviour, although this process took, for some of them, several years. Several of them (now in their early to late twenties), however, continued to struggle with weight loss impulses. Healthcare professionals felt that eating- and weight related issues often went undiagnosed and undocumented in young adult women with type 1 diabetes. CONCLUSION: Many young women with type 1 diabetes are worried about their weight, but will not engage in risky weight loss activities because of concerns about their health. A minority of young adult women will develop more severe eating-related disturbances. These eating disturbances may last a significant amount of time before clinicians become aware of them. These women may also experience disordered weight loss impulses for sometime after clinical interventions. RELEVANCE TO CLINICAL PRACTICE: Clinicians should screen young adult women with type 1 diabetes for eating disorders and monitor young adult women who have developed eating disorders over the longer term. There may be a need to provide asymptomatic young women with diabetes with information about the potential risks of insulin omission. PMID- 23745649 TI - The prescribing practices of nurses who care for patients with skin conditions: a questionnaire survey. AB - AIMS AND OBJECTIVES: To explore the practice of nurses who prescribe medication for patients with skin conditions. BACKGROUND: Nurses have lead roles in dermatology services. In the United Kingdom, nurses in primary care frequently prescribe medicines for skin conditions, but there are concerns about role preparation and access to continuing professional development. The prescribing practices of nurse independent supplementary prescribers who care for patients with skin conditions are under-researched. DESIGN: Cross-sectional survey. METHODS: An online questionnaire was used to survey 186 nurses who prescribed for skin conditions from May-July 2010. Data were analysed using descriptive statistics and nonparametric tests. RESULTS: The majority worked in primary care (78%) and general practice (111, 59.7%). Twenty (10.8%) had specialist modules (at diploma, degree or master's level), 104 (55.9%) had dermatology training (e.g. study days), 44 (23.7%) had no training, and a further 18 (9.6%) did not respond. Oral antibiotics, topical antifungal and antibacterial drugs were frequently prescribed. Nurses with specialist dermatology training used their qualification in a greater number of ways, prescribed the broadest range of products and prescribed more items per week. Over 70% reporting on continuing professional development had been able to access it. CONCLUSIONS: A large number of nurses in primary care prescribe medicines for skin conditions and are involved in medicines management activities. Lack of specialist dermatology training is a concern and associated with lower prescribing-related activities. Access to dermatology training and continuing professional development are required to support nurse development in this area of practice and maximise benefits. RELEVANCE TO CLINICAL PRACTICE: Nurse prescribers' involvement in medicines management activities has important implications in terms of improving access to services, efficiency and cost savings. To maximise their contribution, improved provision of specialist dermatology training is required. This will be of interest to education providers and service planners in the UK and countries around the world. PMID- 23745650 TI - A ten-year clinical update of a large RET p.Gly533Cys kindred with medullary thyroid carcinoma emphasizes the need for an individualized assessment of affected relatives. AB - OBJECTIVE: Reviewing the clinical outcomes of a large kindred with a RET p.Gly533Cys mutation, 10 years after the first description of this kindred, has provided an important set of clinical data for healthcare decision-making. DESIGN AND PATIENTS: We identified 728 RET533 Brazilian relatives, spread out over 7 generations. We performed clinical examination, biochemical and imaging analyses in the proband and in 103 carriers. MEASUREMENT AND RESULTS: The proband has been followed without evidence of structural disease in the last 10 years but with elevated calcitonin. The clinical and surgical features of 60 thyroidectomized RET533 relatives were also described. Forty-six patients had MTC (21-72 years), and 11 patients had C-cell hyperplasia (CCH) (5-42 years). Twelve MTC patients with lymph node metastases had a tumour size of 0.7-2.8 cm. Calcitonin level and CEA were correlated with disease stage, and none of the patients presented with an altered PTH or metanephrine. A 63-year-old woman developed pheochromocytoma and breast cancer. Two other RET533 relatives developed lung squamous cell carcinoma and melanoma. CONCLUSIONS: A vast clinical variability in RET533 presentation was observed, ranging from only an elevated calcitonin level (3%) to local metastatic disease (25%). Many individuals were cured (42%) and the majority had controlled chronic disease (56%), reinforcing the need for individualized ongoing risk stratification assessment. The importance of this update relies on the fact that it allows us to delineate the natural history of RET 533 MEN2A 10 years after its first description. PMID- 23745651 TI - Photochromism of a naphthalene-bridged imidazole dimer constrained to the "anti" conformation. AB - Anti-1,8-bisTPI-naphthalene in which two imidazole rings are constrained to an anti-conformation leading to the first-formed 1,4'-isomer of the bridged imidazole dimer has been synthesized. The color of the radicals is different from that of the previously reported bridged-imidazolyl radicals because the intramolecular interaction between the radicals becomes weak due to the anti conformation. This molecular design would be a profitable strategy to control the color of the radicals of the bridged imidazole dimer for application in ophthalmic lenses. PMID- 23745653 TI - Intensive care units and the oldest-old: are we doing good, too little, or too much? PMID- 23745652 TI - Structure and properties of tethered bilayer lipid membranes with unsaturated anchor molecules. AB - The self-assembled monolayers (SAMs) of new lipidic anchor molecule HC18 [Z-20-(Z octadec-9-enyloxy)-3,6,9,12,15,18,22-heptaoxatetracont-31-ene-1-thiol] and mixed HC18/beta-mercaptoethanol (betaME) SAMs were studied by spectroscopic ellipsometry, contact angle measurements, reflection-absorption infrared spectroscopy, and electrochemical impedance spectroscopy (EIS) and were evaluated in tethered bilayer lipid membranes (tBLMs). Our data indicate that HC18, containing a double bond in the alkyl segments, forms highly disordered SAMs up to anchor/betaME molar fraction ratios of 80/20 and result in tBLMs that exhibit higher lipid diffusion coefficients relative to those of previous anchor compounds with saturated alkyl chains, as determined by fluorescence correlation spectroscopy. EIS data shows the HC18 tBLMs, completed by rapid solvent exchange or vesicle fusion, form more easily than with saturated lipidic anchors, exhibit excellent electrical insulating properties indicating low defect densities, and readily incorporate the pore-forming toxin alpha-hemolysin. Neutron reflectivity measurements on HC18 tBLMs confirm the formation of complete tBLMs, even at low tether compositions and high ionic lipid compositions. Our data indicate that HC18 results in tBLMs with improved physical properties for the incorporation of integral membrane proteins (IMPs) and that 80% HC18 tBLMs appear to be optimal for practical applications such as biosensors where high electrical insulation and IMP/peptide reconstitution are imperative. PMID- 23745656 TI - Analysing and reflecting on limits. PMID- 23745657 TI - Nursing as 'disobedient' practice: care of the nurse's self, parrhesia, and the dismantling of a baseless paradox. AB - In this paper, I discuss nurses' ongoing difficulty in engaging with politics and address the persistent belief that political positioning is antithetical to quality nursing care. I suggest that nurses are not faced with choosing either caring for their patients or engaging with politics. I base my discussion on the assumption that such dichotomy is meaningless and that engaging with issues of relationships firmly grounds nursing in the realm of politics. I argue that the ethical merit of nursing care relies instead on positioning nurses squarely at the centre of care activities, experiences, and functions. Such positioning makes possible what Foucault called 'practices of self-formation', that is, micro-level processes that balance out the ubiquitous economic, cultural, legal, and scientific technologies that steadily constitute subjects in this era of modernity. Nurses, then, become not a group that needs to be controlled and governed, but individuals who must care for their self before they may care for anyone else. PMID- 23745658 TI - The politics of corruption, inequality, and the socially excluded. AB - In this article, the production of knowledge in the context of socially excluded people exposed to inequality, oppression, and exploitation is problematized. The analysis follows Enrique Dussel's philosophical exegesis of the politics of power and corruption and his vision of a critical transformation of the social political order. The argument is also informed by the work of critical educator Paulo Freire, who elucidates the conditions of oppression and marginalization and highlights the importance of conscientization to develop a critical awareness of these conditions. Hannah Arendt's work on the politics of understanding totalitarianism also assists in the elucidation of the machinery that operates behind oppression to sustain power and inequality. The article emphasizes the need to recognize the inequality of conditions that exists between the producer of knowledge and those who live through inequality and oppression in their lived corporality. A critical transformation of the process of production of knowledge is needed to both acknowledge the conditions that sustain this endeavour in the first place and avoid the corruption of knowledge. A work of conscientization is also necessary among knowledge producers to undertake a critical analysis of inequality that exposes the corruption of power. This analysis needs to examine and unmask the hidden mechanisms that perpetuate inequality and oppression and serve only the interests of a few. The abysmal gaps between the wealthy and the poor within and among countries bespeak a degree of human indifference that reflects a most serious and complex phenomenon that perverts something profoundly human in our societies. PMID- 23745659 TI - Expanding our understanding of sovereign power: on the creation of zones of exception in forensic psychiatry. AB - The purpose of this paper is to engage with the readers in a theoretical reflection on nursing practices in forensic psychiatric settings. In this paper, we argue that practices of exclusion in forensic psychiatric settings share some common ground with Agamben's description of sovereign power and, consequently, the possible creation of zones of exception in this environment. The concept of exception is, therefore, purposely used to shift our thinking, highlight the political forces surrounding exclusionary practices in forensic psychiatric nursing, and explore the ethical tensions that arise for nurses who become entangled in the control of these zones of exception. We argue that ethical and political discussions regarding this phenomenon are necessary if we wish to further understand the complexities of this field of practice and promote constructive change. PMID- 23745660 TI - Washing the patient: dignity and aesthetic values in nursing care. AB - Dignity is a fundamental concept, but its meaning is not clear. This paper attempts to clarify the term by analysing and reconnecting two meanings of dignity: humanitas and dignitas. Humanitas refers to citizen values that protect individuals as equal to one another. Dignitas refers to aesthetic values embedded in genres of sociality that relate to differences between people. The paper explores these values by way of an empirical ethical analysis of practices of washing psychiatric patients in nursing care. Nurses legitimate the washing of reluctant patients with reference to dignity. The analysis shows the intertwinement of humanitas and dignitas that gives dignity its fundamental meaning. PMID- 23745661 TI - Desiring productivity: nary a wasted moment, never a missed step! AB - The purpose of this paper is to explore how nurses are enrolled into and take part in programmes of efficiency and effectiveness. Using the philosophical theorizing about desire as a force or power, I focus specifically on what is understood as relations between desire and productivity in current Westernized health-care systems. Use is made of the idea from Spinoza that human emotions consist only of pleasure, pain, and desire as these act as a motive force. This is then linked with more contemporary work on the politics and discourses of desire. A report on the implementation of a productivity programme in the United Kingdom, The Productive Ward: Releasing time to careTM, is explored for the ways its developers set about motivating nurses to endorse and enact the programme. In exploring the mechanics of desire in these processes, a view of desire as productive is promoted. Looking at desire as assembling actions, and an assemblage, moves the analysis to an interrogation of actions and practices used to enable and bring nurses to the process. Moreover, in working through the various modalities and operations of desire, the potential and limits of such projects are abstracted. Such potentials and limits are necessarily set by the intensification of power and desire in the capitalist economy, saturating areas of nursing, and health-care provision. PMID- 23745662 TI - Image, measure, figure: a critical discourse analysis of nursing practices that develop children. AB - Motivated by discourses that link early child development and health, nurses engage in seemingly benign surveillance of children. These practices are based on knowledge claims and technologies of developmental science, which remain anchored in assumptions of the child body as an incomplete form with a universal developmental trajectory and inherent potentiality. This paper engages in a critical discursive analysis, drawing on Donna Haraway's conceptualizations of technoscience and figuration. Using a contemporary developmental screening tool from nursing practice, this analysis traces the effects of this tool through production, transformation, distribution, and consumption. It reveals how the techniques of imaging, abstraction, and measurement collide to fix the open, transformative child body in a figuration of the developing child. This analysis also demonstrates how technobiopower infuses nurses' understandings of children and structures developmentally appropriate expectations for children, parents, and nurses. Furthermore, it describes how practices that claim to facilitate healthy child development may inversely deprive children of agency and foster the production of normal or ideal children. An alternative ontological perspective is offered as a challenge to the individualism of developmental models and other dominant ideologies of development, as well as practices associated with these ideologies. In summary, this analysis argues that nurses must pay closer attention to how technobiopower infuses practices that monitor and promote child development. Fostering a critical understanding of the harmful implications of these practices is warranted and offers the space to conceive of human development in alternate and exciting ways. PMID- 23745663 TI - Beat the clock! Wait times and the production of 'quality' in emergency departments. AB - Emergency care in large urban hospitals across the country is in the midst of major redesign intended to deliver quality care through improved access, decreased wait times, and maximum efficiency. The central argument in this paper is that the conceptualization of quality including the documentary facts and figures produced to substantiate quality emergency care is socially organized within a powerful ruling discourse that inserts the interests of politics and economics into nurses' work. The Canadian Triage and Acuity Scale figures prominently in the analysis as a high-level organizer of triage work and knowledge production that underpins the way those who administer the system define, measure and evaluate emergency care processes, and then use this information for restructuring. Managerial targets and thinking not only dominate the way emergency work is understood, determined, and controlled but also subsume the actual work of health-care providers in spaces called 'wait times', where it is systematically rendered 'unknowable'. The analysis is supported with evidence from an extensive institutional ethnography that shows what nurses actually do to manage the safe passage of patients through their emergency care process starting with the work of triage nurses. PMID- 23745664 TI - Philosophy in the nurse's world: politics of nursing practice II. PMID- 23745665 TI - Phenotypic variability of a likely FA2H founder mutation in a family with complicated hereditary spastic paraplegia. PMID- 23745666 TI - Distribution of influenza and other acute respiratory viruses during the first year after the 2009-2010 influenza pandemic in the English- and Dutch-speaking Caribbean countries. AB - BACKGROUND: Limited specimen collection and testing for influenza occurred in the English and Dutch-speaking Caribbean countries prior to the 2009/2010 influenza pandemic. Caribbean Epidemiology Centre (CAREC) member countries rapidly mobilized to collect specimens during the pandemic and a vast majority of confirmed cases during the pandemic period were influenza A(H1N1)pdm09. OBJECTIVES: To describe the aetiology and distribution of acute respiratory illness (ARI) among laboratory confirmed cases during the first year after the 2009/2010 influenza pandemic in the English- and Dutch-speaking Caribbean. RESULTS: In total, 774 specimens were tested and 394 (52.7%) cases had positive laboratory confirmation. Respiratory syncytial virus (RSV) (28.4%) and influenza A(H3N2) (23.1%) were most frequently detected. RSV activity peaked in July 2011 while influenza A(H3N2) peaked in October 2010. Influenza was responsible for illness in greater numbers in persons 15-64 years while RSV was seen in primarily in children<5 years and adults>65 years. Other agents confirmed include rhinovirus (12.9%), influenza B (10.9%) and influenza A(H1N1)pdm09 (9.4%). CONCLUSIONS: RSV and influenza A(H3N2) were the most common viruses identified during the first year after the influenza A(H1N1)pdm09 pandemic. Influenza was detected every month with peak activity corresponding to that typically seen in North America (October to March). In order to determine the seasonality of influenza and RSV, laboratory data from subsequent years and increased specimen submission is needed. PMID- 23745667 TI - Selective nucleic acid capture with shielded covalent probes. AB - Nucleic acid probes are used for diverse applications in vitro, in situ, and in vivo. In any setting, their power is limited by imperfect selectivity (binding of undesired targets) and incomplete affinity (binding is reversible, and not all desired targets bound). These difficulties are fundamental, stemming from reliance on base pairing to provide both selectivity and affinity. Shielded covalent (SC) probes eliminate the longstanding trade-off between selectivity and durable target capture, achieving selectivity via programmable base pairing and molecular conformation change, and durable target capture via activatable covalent cross-linking. In pure and mixed samples, SC probes covalently capture complementary DNA or RNA oligo targets and reject two-nucleotide mismatched targets with near-quantitative yields at room temperature, achieving discrimination ratios of 2-3 orders of magnitude. Semiquantitative studies with full-length mRNA targets demonstrate selective covalent capture comparable to that for RNA oligo targets. Single-nucleotide DNA or RNA mismatches, including nearly isoenergetic RNA wobble pairs, can be efficiently rejected with discrimination ratios of 1-2 orders of magnitude. Covalent capture yields appear consistent with the thermodynamics of probe/target hybridization, facilitating rational probe design. If desired, cross-links can be reversed to release the target after capture. In contrast to existing probe chemistries, SC probes achieve the high sequence selectivity of a structured probe, yet durably retain their targets even under denaturing conditions. This previously incompatible combination of properties suggests diverse applications based on selective and stable binding of nucleic acid targets under conditions where base-pairing is disrupted (e.g., by stringent washes in vitro or in situ, or by enzymes in vivo). PMID- 23745668 TI - Dual-index evaluation of character changes in Panax ginseng C. A. Mey stored in different conditions. AB - Panax ginseng C. A. Mey has been used as a traditional medicine and functional food in Asia for thousands of years for its improvement of human immunity and metabolism and its antitumor and antifatigue activities. This study reports the impact of storage conditions and storage period on the quality of P. ginseng. The contents of four major ginsenosides in P. ginseng and phosphorylation activities of Akt of ginseng extracts were affected by both storage conditions and storage period. In contrast, the ATP generation capacity of ginseng extracts was affected by storage conditions, but not by storage period. The results showed that the quality of P. ginseng could be well maintained at a relative humidity between 70% and 90%, and dry conditions might decrease the quality of P. ginseng. Through dual-index evaluation, the present study extended our knowledge on the changes of ginsenosides and bioactivities in P. ginseng with respect to different storage conditions and storage periods. PMID- 23745669 TI - Surugamides A-E, cyclic octapeptides with four D-amino acid residues, from a marine Streptomyces sp.: LC-MS-aided inspection of partial hydrolysates for the distinction of D- and L-amino acid residues in the sequence. AB - Surugamides A-E (1-5), cyclic octapeptides with four D-amino acid residues, were isolated from the broth of marine-derived Streptomyces sp. Their planar structures were determined by analyses of spectroscopic data, and the absolute configuration of constituent amino acid residues was determined by the Marfey's method. Differentiation of D-Ile and L-Ile in the sequence was established by chiral analysis of fragment peptides obtained from the partial hydrolysate, whose identification was conducted by LC-MS/MS. PMID- 23745670 TI - Rational site-directed pharmacotherapy for major depressive disorder. AB - It is now accepted that major depressive disorder (MDD) is not a single pathophysiological entity. It is therefore not surprising that remission rates to a first antidepressant trial are low. In addition, antidepressants may target various neuronal elements for which there are gene polymorphisms, such as the serotonin (5-HT) reuptake transporter, which may modulate response. Acting on a single monoaminergic target, such as inhibiting the 5-HT transporter, may confer efficacy in MDD, but other targets may be used and/or combined in treatment resistant patients. These include the blockade of norepinephrine transporters, monoamine oxidase, 5-HT(2A), 5-HT(1B) and 5-HT7 receptors, and the activation of 5-HT(1A) and dopamine 2 receptors. While antidepressants may have more than one of these properties, so do atypical antipsychotics. When using the latter medications, however, their regimens should be below those effective in treating psychosis to avoid dopamine 2 antagonism, which could be counter-productive in MDD. In some patients, combining medications from treatment initiation may also provide additional therapeutic benefits. PMID- 23745671 TI - Prognostic factors in papillary microcarcinoma with emphasis on histologic subtyping: a clinicopathologic study of 148 cases. AB - BACKGROUND: There continues to be controversy regarding which clinicopathological features confer a higher risk of adverse outcome in papillary microcarcinomas (PMC). The aim of this study was to assess the prognostic value of a meticulous histologic examination in PMC. METHOD: All papillary thyroid carcinoma <1 cm in size without associated larger thyroid carcinomas, identified between 1977 and 2002, were categorized as PMC and subjected to a meticulous histopathologic examination by 2 thyroid pathologists. RESULTS: 148 PMC patients fulfilled the inclusion criteria. Within PMC, young age, male sex, tumor multicentricity, extrathyroidal extension, and infiltrative and larger tumor (>=0.5 cm) correlated with the presence of >1 cm metastatic node (MN) or >3 MN at presentation (p<0.05). With a median follow-up of 9.9 years, only 1 (0.7%) of 134 PMC patients died of thyroid carcinomas and 3 (2.2%) had recurrences in the neck. The patient who died had harbored a poorly differentiated carcinoma in his MN. The presence of MN and especially a large MN (>1 cm) correlated with worse recurrence-free survival (p=0.005 and p<0.0001, respectively). Except for one, all individuals with clinically adverse outcomes had >1 cm MN. Patients whose MNs were predominantly composed of poorly differentiated carcinoma or tall cell variant papillary thyroid carcinoma had a significant shorter recurrence-free survival (p<0.0001). Only 1 of 80 radioactive iodine-naive PMC patients with absent or small MN (<=1 cm) had recurrence with a median follow-up of 9.2 years. CONCLUSIONS: (i) The size and histotype of the MN are predictors of outcome in PMC and should be recorded. (ii) The very rare PMC patients who suffer recurrence or even die of disease have usually aggressive histopathologic features at presentation. (iii) PMC patients with nodal disease that is small or absent at presentation are at a very low risk of recurrence and may be spared radioactive iodine therapy. PMID- 23745672 TI - Population dynamics of aerial and terrestrial populations of Phytophthora ramorum in a California forest under different climatic conditions. AB - Limited information is available on how soil and leaf populations of the sudden oak death pathogen, Phytophthora ramorum, may differ in their response to changing weather conditions, and their corresponding role in initiating the next disease cycle after unfavorable weather conditions. We sampled and cultured from 425 trees in six sites, three times at the end of a 3-year-long drought and twice during a wet year that followed. Soil was also sampled twice with similar frequency and design used for sampling leaves. Ten microsatellites were used for genetic analyses on cultures from successful isolations. Results demonstrated that incidence of leaf infection tripled at the onset of the first wet period in 3 years in spring 2010, while that of soil populations remained unchanged. Migration of genotypes among sites was low and spatially limited under dry periods but intensity and range of migration of genotypes significantly increased for leaf populations during wet periods. Only leaf genotypes persisted significantly between years, and genotypes present in different substrates distributed differently in soil and leaves. We conclude that epidemics start rapidly at the onset of favorable climatic conditions through highly transmissible leaf genotypes, and that soil populations are transient and may be less epidemiologically relevant than previously thought. PMID- 23745673 TI - Allergic bronchopulmonary aspergillosis: a clinico-serological correlation with radiologic profile. AB - OBJECTIVE: To study the different types of radiological presentations of ABPA in a tertiary clinic in Northern India and analyze them with respect to serological profile and clinical characteristics. METHODS: We performed a retrospective analysis of clinical, serological and radiological characteristics of ABPA patients registered at a unit of tertiary pulmonary care center in North India. The patients were classified based on radiological presentation into ABPA-S, ABPA CB and ABPA-CB-ORF and the differences in these groups were studied. RESULTS: There were 112 patients with ABPA between age 6 and 75 years. About 8.9% (n = 10) of patients had a history of smoking and 38.4% (n = 43) had a history of prior anti-tuberculosis treatment. The median duration of symptoms was longest in the ABPA-CB-ORF group (15 years) followed by ABPA-CB (7 years) and ABPA-S (5 years). Mean serum total IgE level in the ABPA-CB-ORF group was 14 330 IU/mL followed by the APBA-CB (3700 IU/mL) and ABPA-S (1020 IU/mL) groups (p < 0.0001). The ABPA-CB ORF group had the highest median specific anti-Aspergillus fumigatus IgE followed by ABPA-CB and ABPA-S groups (42.24 kU/L, 20.65 kU/L and 3.44 kU/L, respectively) (p < 0.0001). ABPA-CB-ORF group had the highest percentage of positive serum precipitins against Aspergillus spp. (92%) followed by ABPA-CB (79.6%) and ABPA-S (68%) (p < 0.05). CONCLUSIONS: The patients with more pronounced lung damage in the form of ABPA-CB and ABPA-CB-ORF had higher serological parameters suggestive of increased systemic inflammation. Hence, ABPA may be categorized as mild (ABPA S), moderate (ABPA-CB) and severe (ABPA-CB-ORF) categories which oscillate between remission and exacerbation phases. PMID- 23745674 TI - Detection and identification of 1-methylethyl and methyl radicals generated by irradiating tea tree (Melaleuca alternifolia) oil with visible light (436 nm) in the presence of flavin mononucleotide and ferrous ion. AB - Here, we determined the electron spin resonance (ESR) spectra of standard reaction mixtures (I) containing 25 MUM flavin mononucleotide (FMN), 0.018% tea tree (Melaleuca alternifolia) oil, 1.9 M acetonitrile, 20 mM phosphate buffer (pH 7.4), 0.1 M alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (4-POBN), and 1.0 mM FeSO4(NH4)2SO4 irradiated with 436 nm visible light (7.8 J/cm2). Prominent ESR signals (alphaN = 1.58 mT and alphaHbeta = 0.26 mT) were detected, suggesting that free radicals form in the standard reaction. In order to know whether singlet oxygen (1O2) is involved in the radical formation or not, ESR measurement was performed for the standard D2O reaction mixture (I) which contained 25 MUM FMN, 0.0036% tea tree oil, 1.9 M acetonitrile-d3, 20 mM phosphate buffer (pH 7.4), 0.1 M 4-POBN and 1.0 mM FeSO4 in D2O. The ESR peak height of the standard D2O reaction increased to 169 +/- 24% of the control. Thus, 1O2 seems to be involved in the formation of the radicals because D2O increases the lifetime of singlet oxygen. High-performance liquid chromatography-ESR-mass spectrometry analyses detected 1-methylethyl and methyl radicals in the standard reaction. The radicals appear to form through the reaction of ferrous ion with alpha-terpinene endoperoxide (ascaridole), which generated from the reaction of alpha-terpinene with 1O2. The 1-methylethyl and methyl radicals may exert a pro-oxidant effect under these conditions. PMID- 23745675 TI - Global regulatory networks control the hrp regulon of the gall-forming bacterium Pantoea agglomerans pv. gypsophilae. AB - Gall formation by Pantoea agglomerans pv. gypsophilae is dependent on the hypersensitive response and pathogenicity (hrp) system. Previous studies demonstrated that PagR and PagI, regulators of the quorum-sensing system, induce expression of the hrp regulatory cascade (i.e., hrpXY, hrpS, and hrpL) that activates the HrpL regulon. Here, we isolated the genes of the Gac/Rsm global regulatory pathway (i.e., gacS, gacA, rsmB, and csrD) and of the post transcriptional regulator rsmA. Our results demonstrate that PagR and PagI also upregulate expression of the Gac/Rsm pathway. PagR acts as a transcriptional activator of each of the hrp regulatory genes and gacA in a N-butanoyl-L homoserine lactone-dependent manner as shown by gel shift experiments. Mutants of the Gac/Rsm genes or overexpression of rsmA significantly reduced Pantoea agglomerans virulence and colonization of gypsophila. Overexpression of rsmB sRNA abolished gall formation, colonization, and hypersensitive reaction on nonhost plants and prevented transcription of the hrp regulatory cascade, indicating a lack of functional type III secretion system. Expression of rsmB sRNA in the background of the csrD null mutant suggests that CsrD may act as a safeguard for preventing excessive production of rsmB sRNA. Results presented indicate that the hrp regulatory cascade is controlled directly by PagR and indirectly by RsmA, whereas deficiency in RsmA activity is epistatic to PagR induction. PMID- 23745676 TI - Arabidopsis thaliana FLOWERING LOCUS D is required for systemic acquired resistance. AB - Localized infection in plants often induces systemic acquired resistance (SAR), which provides long-term protection against subsequent infections. A signal originating in the SAR-inducing organ is transported to the distal organs, where it stimulates salicylic acid (SA) accumulation and priming, a mechanism that results in more robust activation of defenses in response to subsequent pathogen infection. In recent years, several metabolites that promote long-distance SAR signaling have been identified. However, the mechanism or mechanisms by which plants perceive and respond to the SAR signals are largely obscure. Here, we show that, in Arabidopsis thaliana, the FLOWERING LOCUS D (FLD) is required for responding to the SAR signals leading to the systemic accumulation of SA and enhancement of disease resistance. Although the fld mutant was competent in accumulating the SAR-inducing signal, it was unable to respond to the SAR signal that accumulates in petiole exudates of wild-type leaves inoculated with a SAR inducing pathogen. Supporting FLD's role in systemic SAR signaling, we observed that dehydroabietinal and azelaic acid, two metabolites that, in wild-type plants, promote SAR-associated systemic accumulation of SA and priming, respectively, were unable to promote SAR in the fld mutant. FLD also participates in flowering, where it functions to repress expression of the flowering repressor FLOWERING LOCUS C (FLC). However, epistasis analysis indicates that FLD's function in SAR is independent of FLC. PMID- 23745677 TI - Diverse amino acid changes at specific positions in the N-terminal region of the coat protein allow Plum pox virus to adapt to new hosts. AB - Plum pox virus (PPV)-D and PPV-R are two isolates from strain D of PPV that differ in host specificity. Previous analyses of chimeras originating from PPV-R and PPV-D suggested that the N terminus of the coat protein (CP) includes host specific pathogenicity determinants. Here, these determinants were mapped precisely by analyzing the infectivity in herbaceous and woody species of chimeras containing a fragment of the 3' region of PPV-D (including the region coding for the CP) in a PPV-R backbone. These chimeras were not infectious in Prunus persica, but systemically infected Nicotiana clevelandii and N. benthamiana when specific amino acids were modified or deleted in a short 30 amino-acid region of the N terminus of the CP. Most of these mutations did not reduce PPV fitness in Prunus spp. although others impaired systemic infection in this host. We propose a model in which the N terminus of the CP, highly relevant for virus systemic movement, is targeted by a host defense mechanism in Nicotiana spp. Mutations in this short region allow PPV to overcome the defense response in this host but can compromise the efficiency of PPV systemic movement in other hosts such as Prunus spp. PMID- 23745678 TI - Harpins, multifunctional proteins secreted by gram-negative plant-pathogenic bacteria. AB - Harpins are glycine-rich and heat-stable proteins that are secreted through type III secretion system in gram-negative plant-pathogenic bacteria. Many studies show that these proteins are mostly targeted to the extracellular space of plant tissues, unlike bacterial effector proteins that act inside the plant cells. Over the two decades since the first harpin of pathogen origin, HrpN of Erwinia amylovora, was reported in 1992 as a cell-free elicitor of hypersensitive response (HR), diverse functional aspects of harpins have been determined. Some harpins were shown to have virulence activity, probably because of their involvement in the translocation of effector proteins into plant cytoplasm. Based on this function, harpins are now considered to be translocators. Their abilities of pore formation in the artificial membrane, binding to lipid components, and oligomerization are consistent with this idea. When harpins are applied to plants directly or expressed in plant cells, these proteins trigger diverse beneficial responses such as induction of defense responses against diverse pathogens and insects and enhancement of plant growth. Therefore, in this review, we will summarize the functions of harpins as virulence factors (or translocators) of bacterial pathogens, elicitors of HR and immune responses, and plant growth enhancers. PMID- 23745679 TI - Life in the "plastisphere": microbial communities on plastic marine debris. AB - Plastics are the most abundant form of marine debris, with global production rising and documented impacts in some marine environments, but the influence of plastic on open ocean ecosystems is poorly understood, particularly for microbial communities. Plastic marine debris (PMD) collected at multiple locations in the North Atlantic was analyzed with scanning electron microscopy (SEM) and next generation sequencing to characterize the attached microbial communities. We unveiled a diverse microbial community of heterotrophs, autotrophs, predators, and symbionts, a community we refer to as the "Plastisphere". Pits visualized in the PMD surface conformed to bacterial shapes suggesting active hydrolysis of the hydrocarbon polymer. Small-subunit rRNA gene surveys identified several hydrocarbon-degrading bacteria, supporting the possibility that microbes play a role in degrading PMD. Some Plastisphere members may be opportunistic pathogens (the authors, unpublished data) such as specific members of the genus Vibrio that dominated one of our plastic samples. Plastisphere communities are distinct from surrounding surface water, implying that plastic serves as a novel ecological habitat in the open ocean. Plastic has a longer half-life than most natural floating marine substrates, and a hydrophobic surface that promotes microbial colonization and biofilm formation, differing from autochthonous substrates in the upper layers of the ocean. PMID- 23745680 TI - Association of angiotensin-converting enzyme and angiotensin II type I receptor gene polymorphisms with extreme obesity in Polish individuals. AB - There is strong evidence for the presence of a functional renin-angiotensin system in human adipose tissue. The aim of our study was to investigate the association of polymorphic variants of angiotensin-converting enzyme gene (ACE I/D) and angiotensin II type I receptor gene (AGTR1 A1166C) with extreme obesity and obesity-associated type 2 diabetes mellitus (T2DM) and to examine their combined effect on extremely obese patients. Overall, no significant associations were detected between ACE and AGTR1 gene polymorphisms and extreme obesity. However, extremely obese patients with T2DM showed an increased frequency of ACE II genotype compared with controls (p<0.05) and with non-diabetic extremely obese patients (p<0.01). The results suggest that II genotype of ACE was a significant contributor to extreme obesity in AA homozygotes of AGTR1 gene, regardless of the presence of T2DM. Moreover, the analysis of genetic polymorphisms demonstrated that ACE II and AGTR1 AC genotypes were most frequently observed in patients with extreme obesity and T2DM. On the basis of our results, we suggest that ACE II homozygosity may be a significant predictor of extreme obesity and T2DM and that the interaction between ACE and AGTR1 genes may be considered a predisposing factor for extreme obesity and extreme obesity-associated T2DM development. PMID- 23745681 TI - Nucleofection of expression vectors induces a robust interferon response and inhibition of cell proliferation. AB - The interferon (IFN) response, induced as a side effect after transfection of nucleic acids into mammalian cells, is known but inadequately described. We followed the IFN response, the fate of cells, and the possible mechanisms leading to this response in NIH3T3 mouse fibroblasts after DNA nucleofection. The gateway destination vector, phGf, and its derivatives encoding toxic and non-toxic variants of the minor structural proteins of polyomaviruses, VP2 and VP3, were used. DNA vector sequences induced in cells the production of high levels of IFN and the upregulation of the IFN-inducible genes, Mx-1, STAT1, IRF1, and IRF7. The IFN response was not restricted to phGf-derived plasmids. In nucleofected cells, upregulation of the modified gamma-histone 2A.X indicating DNA damage and inhibition of cell proliferation were also observed. Although 3T3 cells expressed the Toll-like receptor-9 (TLR9) and vectors used for nucleofection contained unmethylated CpGs, signaling leading to IFN induction was found to be TLR9 independent. However, the early activation of nuclear factor-kappa B suggested the participation of this transcription factor in IFN induction. Surprisingly, in contrast to nucleofection, transfection using a cationic polymer induced only a poor IFN response. Together, the results point to a strong side effect of nucleofection. PMID- 23745682 TI - Genetic variations in MDM2 and P53 genes confer risk for adult acute lymphoblastic leukemia in a Chinese population. AB - The tumor suppressor P53 and its negative regulator mouse double minute 2 (MDM2) play crucial roles in carcinogenesis. Previous case-control studies also revealed that P53 72Arg>Pro and MDM2 309T>G polymorphisms contribute to the risk of common cancers. However, the relationship between these two functional polymorphisms and adult acute lymphoblastic leukemia (ALL) susceptibility has not been explored. In this study, we performed a case-control study to explore the association between MDM2 and P53 gene polymorphisms and ALL risk in a Chinese population. We found an increased adult ALL risk associated with the MDM2 GG (odds ratio [OR]=2.79, 95% confidence interval [95% CI]=1.67-4.68) and TG (OR=1.49, 95% CI=0.95-2.53) genotypes. An increased risk associated with the P53 Pro/Pro genotype (OR=2.22, 95% CI=1.30-3.79) compared with the Arg/Arg genotype was also observed. Furthermore, the gene-gene interaction of MDM2 and P53 polymorphisms increased the adult ALL risk in a super-multiplicative manner (OR for the presence of both MDM2 GG and P53 Pro/Pro genotypes=8.05, 95% CI=2.53-25.58). These findings suggest that polymorphisms of MDM2 and P53 genes may be genetic modifiers for developing adult ALL. PMID- 23745683 TI - Ultra-wideline solid-state NMR spectroscopy. AB - Although solid-state NMR (SSNMR) provides rich information about molecular structure and dynamics, the small spin population differences between pairs of spin states that give rise to NMR transitions make it an inherently insensitive spectroscopic technique in terms of signal acquisition. Scientists have continuously addressed this issue via improvements in NMR hardware and probes, increases in the strength of the magnetic field, and the development of innovative pulse sequences and acquisition methodologies. As a result, researchers can now study NMR-active nuclides previously thought to be unobservable or too unreceptive for routine examination via SSNMR. Several factors can make it extremely challenging to detect signal or acquire spectra using SSNMR: (i) low gyromagnetic ratios (i.e., low Larmor frequencies), (ii) low natural abundances or dilution of the nuclide of interest (e.g., metal nuclides in proteins or in organometallic catalysts supported on silica), (iii) inconvenient relaxation characteristics (e.g., very long longitudinal or very short transverse relaxation times), and/or (iv) extremely broad powder patterns arising from large anisotropic NMR interactions. Our research group has been particularly interested in efficient acquisition of broad NMR powder patterns for a variety of spin-1/2 and quadrupolar (spin > 1/2) nuclides. Traditionally, researchers have used the term "wideline" NMR to refer to experiments yielding broad (1)H and (2)H SSNMR spectra ranging from tens of kHz to ~250 kHz in breadth. With modern FT NMR hardware, uniform excitation in these spectral ranges is relatively easy, allowing for the acquisition of high quality spectra. However, spectra that range in breadth from ca. 250 kHz to tens of MHz cannot be uniformly excited with conventional, high-power rectangular pulses. Rather, researchers must apply special methodologies to acquire such spectra, which have inherently low S/N because the signal intensity is spread across such large spectral breadths. We have suggested the term ultra-wideline NMR (UWNMR) spectroscopy to describe this set of methodologies. This Account describes recent developments in pulse sequences and strategies for the efficient acquisition of UWNMR spectra. After an introduction to anisotropically broadened NMR patterns, we give a brief history of methods used to acquire UWNMR spectra. We then discuss new acquisition methodologies, including the acquisition of CPMG echo trains and the application of pulses capable of broadband excitation and refocusing. Finally, we present several applications of UWNMR methods that use these broadband pulses. PMID- 23745684 TI - Glutamatergic and GABAergic energy metabolism measured in the rat brain by (13) C NMR spectroscopy at 14.1 T. AB - Energy metabolism supports both inhibitory and excitatory neurotransmission processes. This study investigated the specific contribution of astrocytic metabolism to gamma-aminobutyric acid (GABA) synthesis and inhibitory GABAergic neurotransmission that remained to be ilucidated in vivo. Therefore, we measured (13)C incorporation into brain metabolites by dynamic (13)C nuclear magnetic resonance spectroscopy at 14.1 T in rats under alpha-chloralose anaesthesia during infusion of [1,6-(13)C]glucose. The enhanced sensitivity at 14.1 T allowed to quantify incorporation of (13) C into the three aliphatic carbons of GABA non invasively. Metabolic fluxes were determined with a mathematical model of brain metabolism comprising glial, glutamatergic and GABAergic compartments. GABA synthesis rate was 0.11 +/- 0.01 MUmol/g/min. GABA-glutamine cycle was 0.053 +/- 0.003 MUmol/g/min and accounted for 22 +/- 1% of total neurotransmitter cycling between neurons and glia. Cerebral glucose oxidation was 0.47 +/- 0.02 MUmol/g/min, of which 35 +/- 1% and 7 +/- 1% was diverted to the glutamatergic and GABAergic tricarboxylic acid cycles, respectively. The remaining fraction of glucose oxidation was in glia, where 12 +/- 1% of the TCA cycle flux was dedicated to oxidation of GABA. 16 +/- 2% of glutamine synthesis was provided to GABAergic neurons. We conclude that substantial metabolic activity occurs in GABAergic neurons and that glial metabolism supports both glutamatergic and GABAergic neurons in the living rat brain. PMID- 23745686 TI - Long-term evaluation of 'BARC 68Ge/68Ga generator' based on the nanoceria polyacrylonitrile composite sorbent. AB - This article describes the long-term evaluation of a nanoceria-polyacrylonitrile (CeO2-PAN) composite sorbent-based (68)Ge/(68)Ga generator reported. This generator used the new CeO2-PAN composite sorbent for preparation of the (68)Ge/(68)Ga generator. Since this sorbent has not been previously evaluated, a thorough long-term evaluation of the performance of the generator is necessary to ensure its applicability for clinical practice. The performance of the generator was evaluated in terms of (68)Ga yield, (68)Ge breakthrough, radioactive concentration of the (68)Ga solution, and suitability of the (68)Ga for the preparation of (68)Ga-labeled tracers. The (68)Ge/(68)Ga generator was able to provide a (68)Ga activity with consistent yields (>70%) and having acceptable radionuclidic (<10(-4)% of (68)Ge breakthrough), radiochemical, and chemical purities for an extended period of time. The eluted (68)GaCl3 is useful for the majority of the (68)Ga complexation chemistry. PMID- 23745685 TI - Epigenetic control of skeletal muscle regeneration: Integrating genetic determinants and environmental changes. AB - During embryonic development, pluripotent cells are genetically committed to specific lineages by the expression of cell-type-specific transcriptional activators that direct the formation of specialized tissues and organs in response to developmental cues. Chromatin-modifying proteins are emerging as essential components of the epigenetic machinery, which establishes the nuclear landscape that ultimately determines the final identity and functional specialization of adult cells. Recent evidence has revealed that discrete populations of adult cells can retain the ability to adopt alternative cell fates in response to environmental cues. These cells include conventional adult stem cells and a still poorly defined collection of cell types endowed with facultative phenotype and functional plasticity. Under physiological conditions or adaptive states, these cells cooperate to support tissue and organ homeostasis, and to promote growth or compensatory regeneration. However, during chronic diseases and aging these cells can adopt a pathological phenotype and mediate maladaptive responses, such as the formation of fibrotic scars and fat deposition that progressively replaces structural and functional units of tissues and organs. The molecular determinants of these phenotypic transitions are only emerging from recent studies that reveal how dynamic chromatin states can generate flexible epigenetic landscapes, which confer on cells the ability to retain partial pluripotency and adapt to environmental changes. This review summarizes our current knowledge on the role of the epigenetic machinery as a 'filter' between genetic commitment and environmental signals in cell types that can alternatively promote skeletal muscle regeneration or fibro-adipogenic degeneration. PMID- 23745687 TI - CD146 protein as a marker to predict postoperative liver metastasis in colorectal cancer. AB - OBJECTIVE: To study the expression and regulatory effects of CD146 protein in colorectal cancer and the correlation between CD146 protein expression and the prognosis of colorectal cancer. MATERIALS AND METHODS: The CD146 protein level was detected by immunohistochemistry staining. The relationship between CD146 expression and clinicopathological parameters of colorectal cancer was determined. RESULTS: It was observed that 216 (20.00%) of the 1080 cases positively expressed CD146 protein. Univariate analyses indicated that CD146 expression was related to histological grade, Duke's stage, and liver metastasis (p=0.001, 0.001, and 0.001, respectively). Spearman correlation analysis showed that CD146 expression has line correlation to histological grade, Duke's stage, and liver metastasis (p=0.02, 0.01 and 0.001, respectively). After multivariate analysis, Duke's stage and CD146 were related to liver metastasis (p=0.01 and 0.001, respectively). In the Cox regression test, histological grade, Duke's stage, and CD146 were detected as the independent prognostic factors (p=0.045, 0.01, and 0.001, respectively). CONCLUSIONS: CD146 protein may be a potential biomarker for the postoperative liver metastasis of colorectal cancer. PMID- 23745688 TI - Synthesis of tetrasubstituted pyrroles from terminal alkynes and imines. AB - Tetrasubstituted pyrroles can be obtained via the reaction of terminal alkynes and imines using (n)BuLi as the base in one step with high chemoselectivity (method 1). Alternatively, the intermediate propargylamines can also react with imines to afford tetrasubstituted pyrroles when using LiHMDS as the base (method 2), which provides a complementary method to construct the pyrroles with different substituents. PMID- 23745689 TI - Isolated hypermethylation of GRB10 (7p12.2) in a Silver-Russell syndrome patient carrying a 20p13 microdeletion. PMID- 23745690 TI - Isolation and enzymatic properties of a nonspecific acid phosphatase from Vigna aconitifolia seeds. AB - Acid phosphatase (EC 3.1.3.2) from Vigna aconitifolia seeds was purified to apparent homogeneity by using ammonium sulfate fractionation and cation-exchange chromatography [carboxymethyl (CM) cellulose]. The enzyme was 228-fold purified with 14.6% recovery. Analytical gel filtration chromatography on Sephadex G-200 column showed that Mr of native enzyme was 58 kDa and denaturing PAGE demonstrated that it was made up of two subunits of 24 and 27 kDa. The enzyme showed its optimum activity at pH 5.0 and 60 degrees C. It exhibited broad substrate specificity and showed a higher specificity constant for para nitrophenyl phosphate, Na beta-naphthyl phosphate, and adenosine monophosphate (AMP). Cu2+, Mo6+, Fe3+, phosphate, and fluoride ions were reported as strong inhibitors for the enzyme. Active site study for the enzyme demonstrated that tryptophan and aspartic acid may be important for the catalysis. PMID- 23745691 TI - Chrysanthemum expressing a linalool synthase gene 'smells good', but 'tastes bad' to western flower thrips. AB - Herbivore-induced plant volatiles are often involved in direct and indirect plant defence against herbivores. Linalool is a common floral scent and found to be released from leaves by many plants after herbivore attack. In this study, a linalool/nerolidol synthase, FaNES1, was overexpressed in the plastids of chrysanthemum plants (Chrysanthemum morifolium). The volatiles of FaNES1 chrysanthemum leaves were strongly dominated by linalool, but they also emitted small amount of the C11-homoterpene, (3E)-4,8-dimethyl-1,3,7-nonatriene, a derivative of nerolidol. Four nonvolatile linalool glycosides in methanolic extracts were found to be significantly increased in the leaves of FaNES1 plants compared to wild-type plants. They were putatively identified by LC-MS-MS as two linalool-malonyl-hexoses, a linalool-pentose-hexose and a glycoside of hydroxy linalool. A leaf-disc dual-choice assay with western flower thrips (WFT, Frankliniella occidentalis) showed, initially during the first 15 min of WFT release, that FaNES1 plants were significantly preferred. This gradually reversed into significant preference for the control, however, at 20-28 h after WFT release. The initial preference was shown to be based on the linalool odour of FaNES1 plants by olfactory dual-choice assays using paper discs emitting pure linalool at similar rates as leaf discs. The reversal of preference into deterrence could be explained by the initial nonvolatile composition of the FaNES1 plants, as methanolic extracts were less preferred by WFT. Considering the common occurrence of linalool and its glycosides in plant tissues, it suggests that plants may balance attractive fragrance with 'poor taste' using the same precursor compound. PMID- 23745692 TI - Engineering hydrophobic protein-carbohydrate interactions to fine-tune monoclonal antibodies. AB - Biologically active conformations of the IgG1 Fc homodimer are maintained by multiple hydrophobic interactions between the protein surface and the N-glycan. The Fc glycan modulates biological effector functions, including antibody dependent cellular cytotoxicity (ADCC) which is mediated in part through the activatory Fc receptor, FcgammaRIIIA. Consistent with previous reports, we found that site-directed mutations disrupting the protein-carbohydrate interface (F241A, F243A, V262E, and V264E) increased galactosylation and sialylation of the Fc and, concomitantly, reduced the affinity for FcgammaRIIIA. We rationalized this effect by crystallographic analysis of the IgG1 Fc F241A mutant, determined here to a resolution of 1.9 A, which revealed localized destabilization of this glycan-protein interface. Given that sialylation of Fc glycans decreases ADCC, one explanation for the effect of these mutants on FcgammaRIIIA binding is their increased sialylation. However, a glycan-engineered IgG1 with hypergalactosylated and hypersialylated glycans exhibited unchanged binding affinity to FcgammaRIIIA. Moreover, when we expressed these mutants as a chemically uniform (Man5GlcNAc2) glycoform, the individual effect of each mutation on FcgammaRIIIA affinity was preserved. This effect was broadly recapitulated for other Fc receptors (FcgammaRI, FcgammaRIIA, FcgammaRIIB, and FcgammaRIIIB). These data indicate that destabilization of the glycan-protein interactions, rather than increased galactosylation and sialylation, modifies the Fc conformation(s) relevant for FcgammaR binding. Engineering of the protein-carbohydrate interface thus provides an independent parameter in the engineering of Fc effector functions and a route to the synthesis of new classes of Fc domain with novel combinations of affinities for activatory and inhibitory Fc receptors. PMID- 23745693 TI - Adrenomedullin as a potential therapeutic agent for inflammatory bowel disease. AB - Adrenomedullin (AM) was originally isolated from human pheochromocytoma as a biologically active peptide with potent vasodilating action but is now known to exert a wide range of physiological effects, including cardiovascular protection, neovascularization, and apoptosis suppression. A variety of tissues, including the gastrointestinal tract, have been shown to constitutively produce AM. Pro inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-1, and lipopolysaccharides, induce the production and secretion of AM. Conversely, AM induces the downregulation of inflammatory cytokines in cultured cells. Furthermore, AM downregulates inflammatory processes in a variety of different colitis models, including acetic acid-induced colitis and dextran sulfate sodium induced colitis. AM exerts antiinflammatory and antibacterial effects and stimulates mucosal regeneration for the maintenance of the colonic epithelial barrier. Here, we describe the first use of AM to treat patients with refractory ulcerative colitis. The results strongly suggest that AM has potential as a new therapeutic agent for the treatment of refractory ulcerative colitis. PMID- 23745694 TI - Adrenomedullin in cardiovascular disease: a useful biomarker, its pathological roles and therapeutic application. AB - Many neurohumoral factors play important roles in the regulation of the cardiovascular system and in the pathophysiology of cardiovascular disease. Adrenomedullin (AM) is a potent vasodilatory peptide originally discovered in the acid extract of human pheochromocytoma tissue but now known to exert a variety of effects within the cardiovascular system. AM expression is widely distributed throughout the cardiovascular system and has been identified in the heart, lungs, blood vessels and kidneys. In addition, the co-localization of AM and its receptor components suggest AM acts as an autocrine and/or paracrine factor to play a key role in the regulation of cardiovascular function. Evidence also strongly suggests that cardiovascular disease is associated with elevated levels of AM in plasma and tissue. In this review, we describe the pathophysiological changes in plasma and local AM associated with myocardial infarction, heart failure and pulmonary hypertension. We also describe the clinical application of AM in cardiovascular disease from the viewpoints of diagnosis and treatment. PMID- 23745695 TI - Antiinflammatory activities of CGRP modulating innate immune responses in health and disease. AB - Sensory nerves are abundant in lymphoid organs and rapidly release the neuropeptide calcitonin gene-related peptide (CGRP) in response to injury or infection. CGRP directly acts on macrophages and dendritic cells and inhibits the capacity of these cells to produce inflammatory cytokines and to present antigens to T cells. Effector mechanisms, by which CGRP acts on innate immune cells, include upregulation of IL-10, IL-10-independent induction of the inducible cAMP early repressor (ICER) and inhibition of NF-kappaB activity. Engagement of the CGRP receptor, which is composed of receptor activity modifying protein-1 (RAMP1) and calcitonin receptor-like receptor (CLR), increases cellular cAMP levels leading to the activation of protein kinase A (PKA). PKA appears crucial for mediating the antiinflammatory effects of CGRP. Available evidence therefore indicates that CGRP acts as a negative regulator of innate immune responses and contributes to limiting tissue damage in inflammatory disorders. In sepsis caused by mixed-bacterial infection, however, antiinflammatory activities of CGRP may exaggerate leading to immunosuppression and impaired host defense. PMID- 23745696 TI - Protective effects of intermedin on cardiovascular, pulmonary and renal diseases: comparison with adrenomedullin and CGRP. AB - Intermedin/adrenomedullin-2 (IMD/AM2) belongs to the calcitonin gene-related peptide (CGRP) / adrenomedullin (AM) family. The biological actions of this family are attributed to their actions at three receptor subtypes comprising the calcitonin receptor-like receptor (CLR) complexed with one of three receptor activity modifying proteins. In contrast to AM and CGRP, IMD binds non selectively to all three receptor subtypes: CGRP, AM1, AM2. The peptide displays an overlapping but differential and more restricted distribution across the healthy systemic and pulmonary vasculature, heart and kidney relative to CGRP and AM. This, combined with tissue, regional and cell-type specific receptor expression, underpins differences in regard to magnitude, potency and duration of haemodynamic, cardiac and renal effects of IMD relative to those of AM and CGRP, and receptor-subtype involvement. In common with other family members, IMD protects the mammalian vasculature, myocardium and kidney from acute ischaemia reperfusion injury, chronic oxidative stress and pressure-loading; IMD inhibits apoptosis, attenuates maladaptive tissue remodelling and preserves cardiac and renal function. Robust upregulation of IMD expression in rodent models of cardiovascular and renal disease argues strongly for the pathophysiological relevance of this particular counter-regulatory peptide. Such findings are likely to translate well to the clinic: early reports indicate that IMD is expressed in and protects cultured human vascular and cardiac non-vascular cells from simulated ischaemia-reperfusion injury, primarily via the AM1 receptor, and may have utility as a plasma biomarker in cardiovascular disease. These observations should provide the rationale for short-term administration of the peptide in acute disease, including myocardial infarction, cerebrovascular insult, cardiac and renal failure. PMID- 23745698 TI - Role of amylin and its receptors in neurodegeneration. AB - Amylin (islet amyloid polypeptide) and amyloid beta protein (Abeta), identified as proteinaceous deposits within the pancreas of diabetics and the brain of Alzheimer's patients respectively, share many biophysical, physiological and neurotoxic properties. Although no specific beta receptor" has been identified, emerging evidence suggests that the amylin receptor serves a putative target receptor for the actions of Abeta in the brain. The amylin receptor consists of a calcitonin receptor dimerized with receptor activity-modifying proteins and is widely distributed within central nervous system. Abeta can directly activate this G protein-coupled receptor and trigger multiple intracellular signal transduction messengers and pathways that include calcium, cAMP, ERK1/2 and Fos. Growing evidence suggests that amylin and amylin receptors are involved in many aspects of neurodegenerative pathophysiology. Developing therapeutic strategies aimed at modulating amylin receptor function may prove useful for treatment of neurodegenerative diseases such as Alzheimer's disease. PMID- 23745697 TI - Islet amyloid polypeptide and diabetes. AB - Islet amyloid polypeptide (IAPP, amylin) is a 37 amino acid residue hormone expressed mainly by pancreatic islet beta cells and to less extent by some gastrointestinal endocrine cells and by certain regions in central nervous system. In experimental systems a number of different effects have been ascribed to IAPP but the in vivo importance of many of them is still unknown. At least effects on the central nervous system and on endocrine pancreatic cells are likely to be physiologically relevant. In these tissues calcitonin receptors and receptor activity-modifying proteins (RAMPs) 1 and 3, creating high affinity IAPP receptors have been identified. How expression of the components of these complexes are regulated and how further signaling is conducted are more or less unknown. IAPP is most well-known for its ability to aggregate into amyloid fibrils in islets of Langerhans in association with type 2 diabetes leading to loss of beta cells. In addition, amyloid is deposited between endocrine cells and between such cells and capillaries and most likely disturbs important interactions between the cells. How IAPP receptor complexes are affected by the amyloid formation process or by amyloid itself, or vice versa, are completely unknown. PMID- 23745699 TI - Regulation of adrenomedullin and its family peptide by RAMP system--lessons from genetically engineered mice. AB - Adrenomedullin (ADM), originally identified as a vasodilating peptide, is now recognized to be a pleiotropic molecule involved in both the pathogenesis of cardiovascular diseases and circulatory homeostasis. Homozygotes of ADM knockout mice (ADM-/-) were lethal at mid-gestation with abnormalities of vascular development and this finding clarified the angiogenic potency of ADM. Calcitonin gene-related peptide (CGRP), which has a structure and function similar to that of ADM, has been identified as a family peptide of ADM. Unlike ADM-/-, CGRP-/- were apparently normal. Therefore, the study of knockout mice first clarified the distinctly different physiological roles between ADM and CGRP. In contrast, heterozygotes of ADM knockout mice (ADM+/-) were alive but showed blood pressure elevation, reduced neovascularization, and enhanced neointimal formation by arterial injury. Based on these observations, there was hope ADM would have a therapeutic use. However, ADM has a short half-life in the blood stream and its application in chronic disease has limitations. Therefore, we focused on the ADM receptor system. The calcitonin-receptor-like receptor (CLR), which is the ADM receptor, associates with one of the accessory proteins, called receptor activity modifying proteins (RAMPs). By interacting with RAMP1, CLR exhibits a high affinity for CGRP, whereas by interacting with either RAMP2 or -3, CLR exhibits a high affinity for ADM. We generated RAMP knockout mice and found that vascular phenotypes similar to ADM-/- were reproduced only in RAMP2-/-. This shows that RAMP2 is the key determinant of the vascular functions of ADM. RAMP2 could be an attractive therapeutic target in cardiovascular diseases. PMID- 23745700 TI - Comparing the molecular pharmacology of CGRP and adrenomedullin. AB - CGRP and adrenomedullin [AM] are peptides that have a number of physiological effects, including vasodilation, through the activation of a shared GPCR, the family B calcitonin receptor-like receptor [CLR]. Specificity to each ligand is conferred through the unusual association of CLR with a single transmembrane accessory protein. For CGRP this is receptor activity-modifying protein 1 [RAMP1] and for AM acting at the AM1 receptor this is RAMP2. Receptor signalling by two specific peptide ligands through a common GPCR provides researchers with vital and unique information into similarities and differences of GPCR activation. Understanding the structure and function of these receptors will also provide a platform for future drug design for a number of cardiovascular and metabolic diseases in which CGRP and AM have been implicated. This review summarises the latest information and data concerning ligand binding, receptor activation and structural studies for both the CGRP and AM receptors. PMID- 23745701 TI - Ectodomain structures of the CGRP and AM receptors. AB - Receptor activity-modifying proteins (RAMPs) 1-3, which are classified as type I transmembrane proteins, serve as the partner proteins of several family B GPCRs for physiologically active peptides, including the calcitonin receptor- like receptor (CLR). The properties of the GPCRs are defined by the RAMP and peptide ligand combination. The CLR*RAMP1 heterodimer functions mainly as the calcitonin gene-related peptide (CGRP) receptor, while the CLR*RAMP2 and CLR*RAMP3 heterodimers primarily function as the adrenomedullin 1 and adrenomedullin 2 (AM1 and AM2) receptors, respectively. The crystal structures of the RAMP1 and RAMP2 ectodomains exhibited three-helix bundles, and those of their complexes with the N-terminal extracellular domain of CLR revealed how the two ectodomains associate to form the CGRP and AM1 receptors, respectively. On this structural framework, the various intermolecular interactions of CLR with RAMP1 and RAMP2 result in the distinct shapes of the putative ligand-binding sites, where several residues are uniquely presented. Therefore, the differences in the shapes and the presented residues of the binding sites determine the specificities of the receptors to either CGRP or AM. These structural features of the ectodomains are consistent with mutagenesis results, and are useful to further examine the binding modes of the peptide ligands to the full-length CGRP and AM1 receptors. PMID- 23745702 TI - CGRP receptor antagonism and migraine therapy. AB - Migraine is the most prevalent of the neurological disorders and can affect the patient throughout the lifetime. Calcitonin gene-related peptide (CGRP) is a neuropeptide that is expressed in the central and peripheral nervous systems. It is now 2 decades since it was proposed to be involved in migraine pathophysiology. The cranial sensory system contains C-fibers storing CGRP and trigeminal nerve activation and acute migraine attacks result in release of CGRP. The CGRP receptor consists of a complex of calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1) and receptor component protein (RCP). At the central synapses in the trigeminal nucleus caudalis, CGRP acts postjunctionally on second-order neurons to transmit pain signals centrally via brainstem and midbrain to thalamus and higher cortical pain regions. CLR and RAMPs are widely expressed throughout the brain, in the trigeminal ganglion and in intracranial arteries. CGRP does not induce neurogenic inflammation or sensitization at peripheral meningeal sites but relays nociceptive information from trigeminal primary afferent neurons to the second-order neurons in the spinal trigeminal nucleus neurons. CGRP receptor antagonists have been developed as novel antimigraine drugs and found to be effective in the treatment of acute migraine attacks. Other ways to stop CGRP activity has been introduced recently through antibodies against CGRP and the CGRP receptor. While the CGRP receptors are expressed both in the CNS and at various places related to the trigeminal system the exact site of action for their therapy effect is still unresolved but the new approaches may resolve this. PMID- 23745705 TI - Functions of third extracellular loop and helix 8 of Family B GPCRs complexed with RAMPs and characteristics of their receptor trafficking. AB - At least one of three receptor activity-modifying proteins (RAMP1, RAMP2 and RAMP3) can interact with 10 G protein-coupled receptors (GPCRs; nine Family B GPCRs and a Family C GPCR). All three RAMPs interact with the calcitonin (CT) receptor (CTR), the CTR-like receptor (CLR), the vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) 1 (VPAC1) and the VPAC2 receptor, which are all Family B GPCRs. Three RAMPs enable CTR to function as three heterodimeric receptors for amylin, which is a feeding suppression peptide. These RAMPs also transport the CLR to the cell surface, where they function as a CT gene-related peptide (CGRP) receptor (CLR/RAMP1 heterodimer) and two adrenomedullin (AM) receptors (CLR/RAMP2 and CLR/RAMP3 heterodimers). CGRP and AM are potent hypotensive peptides that exert powerful protective effects against multi-organ damage. We recently reported that the third extracellular loop (ECL3) of CLR governs the activation of AM, but not CGRP, signaling in the three CLR/RAMP heterodimers. Furthermore, we showed that in the presence of RAMP2, the eighth helix (helix 8) in the proximal portion of the cytoplasmic C-terminal tail of the CLR, which is thought to be present in all family B GPCRs, participates in receptor signaling. In addition, we demonstrated that overexpression of GPCR kinase (GRK) 2, GRK3 and GRK4 enhances the AM-induced internalization of the CLR/RAMP2 heterodimer. In this review, we describe these studies and consider their implications for other Family B GPCRs that can interact with RAMPs. PMID- 23745704 TI - Role of CGRP-receptor component protein (RCP) in CLR/RAMP function. AB - The receptor for calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) requires an intracellular peripheral membrane protein named CGRP-receptor component protein (RCP) for signaling. RCP is required for CGRP and AM receptor signaling, and it has recently been discovered that RCP enables signaling by binding directly to the receptor. RCP is present in most immortalized cell lines, but in vivo RCP expression is limited to specific subsets of cells, usually co localizing with CGRP-containing neurons. RCP protein expression correlates with CGRP efficacy in vivo, suggesting that RCP regulates CGRP signaling in vivo as it does in cell culture. RCP is usually identified in cytoplasm or membranes of cells, but recently has been observed in nucleus of neurons, suggesting an additional transcriptional role for RCP in cell function. Together, these data support an essential role for RCP in CGRP and AM receptor function, in which RCP expression enhances signaling of the CGRP or AM receptor, and therefore increases the efficacy of CGRP and AM in vivo. PMID- 23745706 TI - Is the cytoskeleton an intracellular receptor for adrenomedullin and PAMP? AB - Classical transmembrane receptors have been described for both adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP). Through interactions with these membrane receptors, AM and PAMP exert a variety of endocrine, paracrine, and autocrine functions. In addition to these better known activities, recent publications have shown that both peptides can bind directly to the cytoskeleton resulting in important cellular physiological responses. In vitro and in vivo experiments show that the peptides bind to major components of the cytoskeleton: tubulin and kinesin for PAMP and a number of microtubule-associated proteins (MAPs) in the case of AM. Physiological experiments show that PAMP contributes to microtubule fluidity and increases kinesin speed. Lack of AM and PAMP results in hyperpolymerization of the cytoskeleton and a reduced motility of intracellular organelles. These data suggest that the cytoskeleton may have a novel function as an intracellular receptor, acting as the binding site and the signal transducer for specific peptide hormones such as PAMP. PMID- 23745703 TI - Roles of CLR/RAMP receptor signaling in reproduction and development. AB - Adrenomedullin (ADM), calcitonin gene-related peptides (alpha- and beta-CGRPs), and intermedin/adrenomedullin 2 (IMD/ADM2) are major regulators of vascular tone and cardiovascular development in vertebrates. Recent research into their functions in reproduction has illuminated the role of these peptides and their cognate receptors (calcitonin receptor-like receptor/receptor activity-modifying protein (CLR/RAMP) receptors) in fetal-maternal blood circulation, fetoplacental development, female gamete development, and gamete movement in the oviduct. Although ADM family peptides function in a temporally and spatially specific manner in various reproductive processes, they appear to act via a similar set of second messengers, including nitric oxide, cyclic GMP, cyclic AMP, and calcium activated potassium channels in different tissues. These discoveries supported the view that CLR/RAMP receptors were recruited to perform a variety of newly evolved reproductive functions during the evolution of internal reproduction in mammals. These advances also provided insight into how CLR/RAMP receptor signaling pathways coordinate with other physiological adaptions to accommodate the extra metabolic needs during pregnancy, and captured some important details as to how fetal-maternal vascular communications are generated in the first place. Furthermore, these findings have revealed novel, promising opportunities for the prevention and treatment of aberrant pregnancies such as pregnancy induced hypertension, preeclampsia, and tubal ectopic pregnancy. However, significant efforts are still needed to clarify the relationships between certain components of the CLR/RAMP signaling pathway and aberrant pregnancies before CLR/RAMP receptors can become targets for clinical management. With this understanding, this review summarizes recent progresses with particular focus on clinical implications. PMID- 23745707 TI - The RAMP-interacting Family B G Protein-Coupled Receptors and Their Specific Bioactive Peptides. PMID- 23745710 TI - High age predicts low referral of hyperthyroid patients to specialized hospital departments: evidence for referral bias. AB - BACKGROUND: Hospital-based studies may be hampered by referral bias. We investigated how the phenomenon may influence studies of hyperthyroid patients. METHODS: By means of a computer-based linkage to the laboratory database and subsequent detailed evaluation of subjects with abnormal test results, we prospectively identified all 1148 patients diagnosed with overt hyperthyroidism in a four-year period in and around Aalborg City, Denmark. Each patient was classified according to nosological type of hyperthyroidism. We studied the referral pattern of patients to local hospital units, and analyzed how referral depended on subtype of disease, sex, age, and degree of biochemical hyperthyroidism. RESULTS: In a 4-year period, 1032 hyperthyroid patients were diagnosed at primary care offices, and 435 of these (42.2%) were referred to specialized units, 92 patients had hyperthyroidism diagnosed in other hospital departments (referral: 43, 46.7%), and 24 patients had hyperthyroidism diagnosed at the specialized unit after referral for other diseases. Patients suffering from Graves' disease (GD; n=474, median age=65.8 years) were referred more often (odds ratio=1.7 [95% confidence interval 1.3-2.2]) than those diagnosed with multinodular toxic goiter (MNTG; n=525, median age=74.6 years). Higher age was associated with less referral of patients suffering from MNTG (referred vs. nonreferred patients, 64.0 vs. 77.4 years, p<0.001) and GD (43.9 vs. 56.4 years, p<0.001), whereas GD patients referred to a hospital had more severe biochemical hyperthyroidism (serum total triiodothyronine, 4.86 vs. 3.79 nmol/L; serum total thyroxine, 204 vs. 180 nmol/L; both p<0.001). Findings were confirmed in multivariate models reporting age as a significant predictor for referral in both GD and MNTG patients (both p<0.001). Among referred hyperthyroid patients (all combined), those aged up to 40 years (referral rate, 66.8%) were represented 11.6 (6.6-20.6) times more often than those aged 80 years and above (referral rate, 14.8%). CONCLUSIONS: Hyperthyroid patients referred to a specialized hospital unit were younger (GD+MNTG) and had more severe biochemical hyperthyroidism (GD) compared to nonreferred patients. Thus, referral bias may influence hospital based studies of hyperthyroid patients, and may hamper external generalization of such studies. Whether the referral bias of hyperthyroid patients in Denmark can be generalized to other countries or cultures remains unknown. PMID- 23745711 TI - Synthesis and bioactivity of beta-(1->4)-linked oligomannoses and partially acetylated derivatives. AB - The synthesis of beta-(1->4)-linked hexa- to octamannoses and their partially acetylated derivatives was efficiently carried out by assembly of appropriate oligomeric fragments using beta-selective glucosylation followed by gluco to manno epimerization at a late stage of the synthetic pathway. In the course of this study, we also observed that 2-O-acetylated oligomannoses coexisted in equilibrium with the 3-O-acetylated isomers due to intramolecular migration of the acetyl group. Bioactivity of the synthetic oligomannoses and partially acetylated derivatives was investigated in order to identify the possible smallest oligomer for induction of cytokines as that shown in the polysaccharides extracted from Dendrobium huoshanense. PMID- 23745709 TI - Multiple silk coatings on biphasic calcium phosphate scaffolds: effect on physical and mechanical properties and in vitro osteogenic response of human mesenchymal stem cells. AB - Ceramic scaffolds such as biphasic calcium phosphate (BCP) have been widely studied and used for bone regeneration, but their brittleness and low mechanical strength are major drawbacks. We report the first systematic study on the effect of silk coating in improving the mechanical and biological properties of BCP scaffolds, including (1) optimization of the silk coating process by investigating multiple coatings, and (2) in vitro evaluation of the osteogenic response of human mesenchymal stem cells (hMSCs) on the coated scaffolds. Our results show that multiple silk coatings on BCP ceramic scaffolds can achieve a significant coating effect to approach the mechanical properties of native bone tissue and positively influence osteogenesis by hMSCs over an extended period. The silk coating method developed in this study represents a simple yet effective means of reinforcement that can be applied to other types of ceramic scaffolds with similar microstructure to improve osteogenic outcomes. PMID- 23745713 TI - In situ growth of metal-organic framework thin films with gas sensing and molecule storage properties. AB - New porous metal-organic framework (MOF) films based on the flexible ligand 1,3,5 tris[4-(carboxyphenyl)oxamethyl]-2,4,6-trimethylbenzene (H3TBTC) were fabricated on alpha-Al2O3 substrates under solvent thermal conditions. The factors affecting the fabrication of films, such as the temperature of pre-activation and the dosage of the reagents, were investigated. Tuning the subtle factors on film fabrications, a series of MOF thin films with different morphologies and grain sizes were prepared. The morphology and grain size of the films are monitored by scanning electron microscopy (SEM). X-ray diffraction (XRD) and attenuated total reflection infrared (ATR-IR) were also used to characterize the MOF films. The results indicate that the temperature of pre-activation and the dosage of the reagents are the key parameters during the process of film formation. The properties of the films, especially the sensing and sorption behavior, have been studied by an optical digital cameral and ultraviolet-visible (UV-vis) spectra. The evidence shows that the films are sensitive to small organic molecules, such as methanol and pyridine. Meanwhile, the films can adsorb small dye molecules. Thus, the films may have potential applications in either organic vapor sensing or storage of small dye molecules. PMID- 23745714 TI - Relationships between hand laterality and verbal and spatial skills in 436 healthy adults balanced for handedness. AB - The relationship between manual laterality and cognitive skills remains highly controversial. Some studies have reported that strongly lateralised participants had higher cognitive performance in verbal and visuo-spatial domains compared to non-lateralised participants; however, others found the opposite. Moreover, some have suggested that familial sinistrality and sex might interact with individual laterality factors to alter cognitive skills. The present study addressed these issues in 237 right-handed and 199 left-handed individuals. Performance tests covered various aspects of verbal and spatial cognition. A principal component analysis yielded two verbal and one spatial factor scores. Participant laterality assessments included handedness, manual preference strength, asymmetry of motor performance, and familial sinistrality. Age, sex, education level, and brain volume were also considered. No effect of handedness was found, but the mean factor scores in verbal and spatial domains increased with right asymmetry in motor performance. Performance was reduced in participants with a familial history of left-handedness combined with a non-maximal preference strength in the dominant hand. These results elucidated some discrepancies among previous findings in laterality factors and cognitive skills. Laterality factors had small effects compared to the adverse effects of age for spatial cognition and verbal memory, the positive effects of education for all three domains, and the effect of sex for spatial cognition. PMID- 23745715 TI - Contrast-enhanced ultrasound in the preoperative, intraoperative and postoperative assessment of liver lesions. AB - The use of contrast agents (CA) with liver ultrasound (US) has gained recently an established role for the diagnosis of various hepatic diseases due to their safety, high versatility and low costs (contrast-enhanced ultrasound: CEUS). The purpose of this review is to provide a state-of-the-art summary of the available evidence for their use in the characterization of focal liver lesions. A published work search was conducted for all preclinical and clinical studies involving CA on hepatic US imaging. CEUS increases the sensitivity for lesion detection and the specificity to differentiate between benign and malignant diseases due to the enhanced visualization of the tumor microcirculation. Results achieved seem at least equivalent to those of spiral computed tomography or magnetic resonance imaging. The association of CA with intraoperative ultrasound has changed the surgical approach in 25% of patients and guarantees complete ablations by a single session in most of them. CEUS provides detailed information about tumor vasculature, improves the preoperative characterization and therefore the therapeutic strategy, and can evaluate the intraoperative completeness of the ablation. PMID- 23745712 TI - Characterization of neuraminidase inhibitor-resistant influenza A(H1N1)pdm09 viruses isolated in four seasons during pandemic and post-pandemic periods in Japan. AB - BACKGROUND/OBJECTIVES: Japan has the highest frequency of neuraminidase (NA) inhibitor use against influenza in the world. Therefore, Japan could be at high risk of the emergence and spread of NA inhibitor-resistant viruses. The aim of this study was to monitor the emergence of NA inhibitor-resistant viruses and the possibility of human-to-human transmission during four influenza seasons in Japan. METHODS: To monitor antiviral-resistant A(H1N1)pdm09 viruses, we examined viruses isolated in four seasons from the 2008-2009 season through the 2011-2012 season in Japan by allelic discrimination, NA gene sequencing, and NA inhibitor susceptibility. RESULTS: We found that 157 (1.3%) of 12 026 A(H1N1)pdm09 isolates possessed an H275Y substitution in the NA protein that confers about 400- and 140 fold decreased susceptibility to oseltamivir and peramivir, respectively, compared with 275H wild-type viruses. The detection rate of resistant viruses increased from 1.0% during the pandemic period to 2.0% during the post-pandemic period. The highest detection rate of the resistant viruses was found in patients who were 0-9 years old. Furthermore, among the cases with resistant viruses, the percentage of no known exposure to antiviral drugs increased from 16% during the pandemic period to 44% during the post-pandemic period, implying that suspected human-to-human transmission of the resistant viruses gradually increased in the post-pandemic period. CONCLUSIONS: A(H1N1)pdm09 viruses resistant to oseltamivir and peramivir were sporadically detected in Japan, but they did not spread throughout the community. No viruses resistant to zanamivir and laninamivir were detected. PMID- 23745716 TI - Brain stress system response after morphine-conditioned place preference. AB - This study examined the involvement of the brain stress system in the reinforcing effects of morphine. One group of mice was conditioned to morphine using the conditioned place preference (CPP) paradigm and the other group received morphine in a home-cage (non-conditioned). Adrenocorticotropic hormone and corticosterone levels were measured by radioimmunoassay; phospho (p) CREB expression and the number of corticotropin-releasing factor (CRF) neurons and fibres were measured by immunohistochemistry in different brain areas. We observed that the number of CRF neurons in the paraventricular nucleus (PVN) was increased after morphine induced CPP, which was paralleled with enhanced CRF-immunoreactivity fibres in the nucleus tractus solitarius (NTS) and ventral tegmental area (VTA) vs. home cage group injected with morphine. Morphine exposure induced an increase in CREB phosphorylated at Ser133 in the PVN and central amygdale (CeA), whereas mice exhibiting morphine CPP had higher levels of pCREB in the PVN, CeA and bed nucleus of the stria terminalis (BNST). We also found that most of the CRF positive neurons in the PVN, CeA and BNST co-express pCREB after morphine CPP expression, suggesting that the drug-associated environmental contexts can elicit neuronal activity in the brain stress system. From the present results it is clear that exposure to a drug-associated context remains a potent activator of signalling pathways leading to CRF activation in the brain stress system. PMID- 23745717 TI - A new steroidal glycoside from the seeds of Hyoscyamus niger. AB - A new steroidal glycoside hyoscyamoside G (1), together with two known analogues hyoscyamoside E (2) and hyoscyamoside F1 (3), was isolated from the seeds of Hyoscyamus niger. The structure of 1 was established as (22R,24Z) 1alpha,3beta,7beta,22,26-pentakishydroxylergost-22-O-beta-d-gulcopyranosyl-5,24 diene-26-O-beta-d-glucopyranoside, by means of chemical and spectroscopic methods including HRESI-MS, 1D and 2D NMR. In vitro, compound 2 showed cytotoxicity against human lung cancer cell H460 with IC50 value of 66 MUg/mL. PMID- 23745719 TI - Perspectives in enzymology of membrane proteins by solid-state NMR. AB - Membrane proteins catalyze reactions at the cell membrane and facilitate thetransport of molecules or signals across the membrane. Recently researchers have made great progress in understanding the structural biology of membrane proteins, mainly based on X-ray crystallography. In addition, the application of complementary spectroscopic techniques has allowed researchers to develop a functional understanding of these proteins. Solid-state NMR has become an indispensable tool for the structure-function analysis of insoluble proteins and protein complexes. It offers the possibility of investigating membrane proteins directly in their environment, which provides essential information about the intrinsic coupling of protein structure and functional dynamics within the lipid bilayer. However, to date, researchers have hardly explored the enzymology of mem brane proteins. In this Account, we review the perspectives for investigating membrane-bound enzymes by solid-state NMR. Understanding enzyme mechanisms requires access to kinetic parameters, structural analysis of the catalytic center, knowledge of the 3D structure and methods to follow the structural dynamics of the enzyme during the catalytic cycle. In principle, solid-state NMR can address all of these issues. Researchers can characterize the enzyme kinetics by observing substrate turnover within the membrane or at the membrane interphase in a time-resolved fashion as shown for diacylglycerol kinase. Solid-state NMR has also provided a mechanistic understanding of soluble enzymes including triosephosphate isomerase (TIM) and different metal-binding proteins, which demonstrates a promising perspective also for membrane proteins. The increasing availability of high magnetic fields and the development of new experimental schemes and computational protocols have made it easier to determine 3D structure using solid-state NMR. Dynamic nuclear polarization, a key technique to boost sensitivity of solid-state NMR at low temperatures, can help with the analysis of thermally trapped catalytic intermediates, while methods to improve signal-to noise per time unit enable the real-time measurement of kinetics of conformational changes during the catalytic cycle. PMID- 23745718 TI - Bacterial communities established in bauxite residues with different restoration histories. AB - Bauxite residue is the alkaline byproduct generated when alumina is extracted from bauxite ores and is commonly deposited in impoundments. These sites represent hostile environments with increased salinity and alkalinity and little prospect of revegetation when left untreated. This study reports the establishment of bacterial communities in bauxite residues with and without restoration amendments (compost and gypsum addition, revegetation) in samples taken in 2009 and 2011 from 0 to 10 cm depth. DNA fingerprint analysis of bacterial communities based on 16S rRNA gene fragments revealed a significant separation of the untreated site and the amended sites in both sampling years. 16S amplicon analysis (454 FLX pyrosequencing) revealed significantly lower alpha diversities in the unamended in comparison to the amended sites and hierarchical clustering separated the unamended site from the amended sites. The taxonomic analysis revealed that the restoration resulted in the accumulation of bacterial populations typical for soils including Acidobacteriaceae, Nitrosomonadaceae, and Caulobacteraceae. In contrast, the unamended site was dominated by taxonomic groups including Beijerinckiaceae, Xanthomonadaceae, Acetobacteraceae, and Chitinophagaceae, repeatedly associated with alkaline salt lakes and sediments. While bacterial communities developed in the initially sterile bauxite residue, only the restoration treatments created diverse soil-like bacterial communities alongside diverse vegetation on the surface. PMID- 23745720 TI - PLA/PEG-PPG-PEG/dexamethasone implant prepared by hot-melt extrusion for controlled release of immunosuppressive drug to implantable medical devices, Part 2: in vivo evaluation. AB - Hot-melt extrusion (HME) plays an important role in preparing implants as local drug delivery systems in pharmaceutical fields. Here, a new PLA/PEG-PPG PEG/Dexamethasone (PLA/F68/Dex) implant prepared by HME has been developed. Importantly, the implant was successfully achieved to control release of immunosuppressive drug to an implanted device. In particular, this implant has not been reported previously in pharmaceutical fields. FTIR and XRD were adopted to investigate the properties of the samples. The in vivo release study showed that the maximum value of Dex release from the implants was approximately 50% at 1 month. The in vivo degradation behavior was determined by UV spectrophotometer and scanning electron microscopy studies, and the weight loss rate of the implants were up to 25% at 1 month. Furthermore, complete blood count (CBC) test, serum chemistry and major organs were performed, and there is no significant lesion and side effects observed in these results. Therefore, the results elucidated that the new PLA/F68/Dex implant prepared by HME could deliver an immunosuppressive drug to control the inflammatory reaction at the implant site. PMID- 23745721 TI - Can we predict sleep-disordered breathing in pregnancy? The clinical utility of symptoms. AB - Sleep-disordered breathing (SDB) is reported commonly during pregnancy and is associated with an increased risk of adverse maternal and fetal outcomes, but the majority of these data are based upon self-report measures not validated for pregnancy. This study examined the predictive value of screening questionnaires for SDB administered at two time-points in pregnancy, and attempted to develop an 'optimized predictive model' for detecting SDB in pregnancy. A total of 380 women were recruited from an antenatal clinic in the second trimester of pregnancy. All participants completed the Berlin Questionnaire and the Multivariable Apnea Risk Index (MAP Index) at recruitment, with a subset of 43 women repeating the questionnaires at the time of polysomnography at 37 weeks' gestation. Fifteen of 43 (35%) women were confirmed to have a respiratory disturbance index (RDI) > 5 h(-1) . Prediction of an RDI > 5 h(-1) was most accurate during the second trimester for both the Berlin Questionnaire (sensitivity 0.93, specificity 0.50, positive predictive value 0.50 and negative predictive value 0.93), and the MAP Index [area under the receiver operating characteristic (ROC) curve of 0.768]. A stepwise selection model identified snoring volume, a body mass index (BMI)>=32 kg m(-2) and tiredness upon awakening as the strongest independent predictors of SDB during pregnancy; this model had an area under the ROC curve of 0.952. We conclude that existing clinical prediction models for SDB perform inadequately as a screening tool in pregnancy. The development of a highly predictive model from our data shows promise for a quick and easy screening tool to be validated for future use in pregnancy. PMID- 23745723 TI - Palladium-catalyzed oxidative cross-coupling of N-tosylhydrazones with indoles: synthesis of N-vinylindoles. AB - A general and efficient palladium-catalyzed oxidative cross-coupling reaction of N-tosylhydrazones with indoles providing N-vinylindoles has been developed. The reaction proceeds smoothly with various indoles and N-tosylhydrazones in a stereocontrolled manner, and a wide variety of N-vinylindoles were obtained up to 99% yields for 26 examples. PMID- 23745722 TI - Endothelial nitric oxide deficiency promotes Alzheimer's disease pathology. AB - Aging and the presence of cerebrovascular disease are associated with increased incidence of Alzheimer's disease. A common feature of aging and cerebrovascular disease is decreased endothelial nitric oxide (NO). We studied the effect of a loss of endothelium derived NO on amyloid precursor protein (APP) related phenotype in late middle aged (LMA) (14-15 month) endothelial nitric oxide synthase deficient (eNOS(-/-) ) mice. APP, beta-site APP cleaving enzyme (BACE) 1, and amyloid beta (Abeta) levels were significantly higher in the brains of LMA eNOS(-/-) mice as compared with LMA wild-type controls. APP and Abeta1-40 were increased in hippocampal tissue of eNOS(-/-) mice as compared with wild-type mice. LMA eNOS(-/-) mice displayed an increased inflammatory phenotype as compared with LMA wild-type mice. Importantly, LMA eNOS(-/-) mice performed worse in a radial arm maze test of spatial learning and memory as compared with LMA wild-type mice. These data suggest that chronic loss of endothelial NO may be an important contributor to both Abeta related pathology and cognitive decline. Cardiovascular risk factors are associated with increased incidence of Alzheimer's disease (AD). A common feature of these risk factors is decreased endothelial nitric oxide (NO). We observed, in mice deficient in endothelial nitric oxide synthase, increased amyloid precursor protein (APP), beta-site APP cleaving enzyme 1, amyloid beta levels, microglial activation, and impaired spatial memory. This suggests chronic loss of endothelial NO may be an important contributor to the pathogenesis of sporadic AD. PMID- 23745724 TI - AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. PMID- 23745725 TI - Five-year results of a prospective randomised controlled clinical trial of posterior computer-aided design-computer-aided manufacturing ZrSiO4 -ceramic crowns. AB - The aim of this prospective randomised controlled clinical trial was to evaluate the clinical outcome of shrinkage-free ZrSiO4 -ceramic full-coverage crowns on premolars and molars in comparison with conventional gold crowns over a 5-year period. Two hundred and twenty-three patients were included and randomly divided into two treatment groups. One hundred and twenty-three patients were restored with 123 ZrSiO4 -ceramic crowns, and 100 patients received 100 gold crowns, which served as the control. All crowns were conventionally cemented with glass-ionomer cement. After an observation period of 6, 12, 24, 36, 48 and 60 months, the survival probability (Kaplan-Meier) for the shrinkage-free ZrSiO4 -ceramic crowns was 98.3%, 92.0%, 84.7%, 79% and 73.2% and for the gold crowns, 99%, 97.9%, 95.7%, 94.6% and 92.3%, respectively. The difference between the test and control group was statistically significant (P = 0.0027). The gold crowns showed a better marginal integrity with less marginal discoloration than the ceramic crowns. The most common failure in the ceramic crown group was fracture of the crown. The 60 month results of this prospective randomised controlled clinical trial suggest that the use of these shrinkage-free ZrSiO4 -ceramic crowns in posterior tooth restorations cannot be recommended. PMID- 23745727 TI - Perinatal risk factors for adverse long-term pulmonary outcome in premature infants: comparison of different definitions of bronchopulmonary dysplasia/chronic lung disease. AB - BACKGROUND: The aim of the study was to determine factors that affect adverse long-term pulmonary outcome in premature infants. METHODS: This retrospective analysis was done using 306 clinical records of preterm singleton neonates at <32 weeks of gestation. Two definitions of adverse pulmonary outcome were used: chronic lung disease (CLD), defined as a need for supplemental oxygen for at least 28 days after birth; and bronchopulmonary dysplasia (BPD), defined as oxygen dependency for at least 28 days after birth plus at 36 weeks postmenstrual age and/or a need for positive-pressure ventilatory support. Selected perinatal variables were compared between these definitions, and factors related to disease development were identified on multivariate analysis. RESULTS: The incidence of CLD and of BPD were 42% and 17%, respectively. Regardless of the definitions, the incidence of patent ductus arteriosus and of neonatal infection were significantly higher in the patients who met the disease criteria, but that of chorioamnionitis and of small for gestational age (SGA) were significantly higher in the patients only when the BPD definition was applied. Multivariate analysis identified SGA as an independent risk factor for the development of BPD after controlling for gestational age. CONCLUSIONS: Among selected perinatal variables, prenatal risk factors, particularly SGA, contributed to prolonged dependency on oxygen and/or positive-pressure ventilatory support, in combination with neonatal risk factors. PMID- 23745726 TI - Structural and functional diversity in the activity and regulation of DAPK related protein kinases. AB - Within the large group of calcium/calmodulin-dependent protein kinases (CAMKs) of the human kinome, there is a distinct branch of highly related kinases that includes three families: death-associated protein-related kinases, myosin light chain-related kinases and triple functional domain protein-related kinases. In this review, we refer to these collectively as DMT kinases. There are several functional features that span the three families, such as a broad involvement in apoptotic processes, cytoskeletal association and cellular plasticity. Other CAMKs contain a highly conserved HRD motif, which is a prerequisite for kinase regulation through activation-loop phosphorylation, but in all 16 members of the DMT branch, this is replaced by an HF/LD motif. This DMT kinase signature motif substitutes phosphorylation-dependent active-site interactions with a local hydrophobic core that maintains an active kinase conformation. Only about half of the DMT kinases have an additional autoregulatory domain, C-terminal to the kinase domain that binds calcium/calmodulin in order to regulate kinase activity. Protein substrates have been identified for some of the DMT kinases, but little is known about the mechanism of recognition. Substrate conformation could be an equally important parameter in substrate recognition as specific preferences in sequence position. Taking the data together, this kinase branch encapsulates a treasure trove of features that renders it distinct from many other protein kinases and calls for future research activities in this field. PMID- 23745729 TI - Fetal growth in relation to maternal and fetal IGF-axes: a systematic review and meta-analysis. AB - Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are key regulators of fetal growth. However, the literature is inconsistent. Our objective was to systematically and objectively evaluate the available literature and to develop a balanced opinion on the relation between maternal and fetal IGF axes and birthweight. A systematic review and a meta-analysis were conducted according to the published Moose (Meta-analysis of Observational Studies in Epidemiology) guidelines. A robust recognized systematic methodology was used in the literature search and analysis to avoid bias. Weighted mean difference and 95% confidence intervals of cord/maternal IGFs and IGFBP-1 and -3 were calculated. Eleven observational studies were included. Cord IGF-I (p < 0.0001) and IGFBP-3 (p = 0.003) were significantly higher in large-for-gestational age (LGA) than appropriate-for-gestational age (AGA) babies. Cord IGFBP-1 was significantly higher in small-for-gestational age (SGA) than AGA babies (p < 0.0001). LGA and AGA babies had similar IGF-II levels, whereas SGA and AGA babies had comparable IGF-I levels. IGF-I was significantly higher in mothers of AGA than SGA babies (p < 0.0001). The assay methods and background population marginally affect the overall homogeneity and the direction of the primary analysis. Fetal IGFs and their binding proteins play different roles in fetal growth at either end of the growth spectrum. Fetal IGF-I and IGFBP-3 may be influential in LGA. However, fetal IGFBP-1 has a more prominent role in SGA. PMID- 23745728 TI - Enantioselective intramolecular aldehyde alpha-alkylation with simple olefins: direct access to homo-ene products. AB - A highly selective method for the synthesis of asymmetrically substituted carbocycles and heterocycles from unactivated aldehyde-olefin precursors has been achieved via enantioselective SOMO-catalysis. Addition of a catalytically generated enamine radical cation across a pendent olefin serves to establish a general asymmetric strategy toward the production of a wide range of formyl substituted rings with alkene transposition. Conceptually, this novel mechanism allows direct access to "homo-ene"-type products. PMID- 23745730 TI - Accurate method for the determination of intramolecular 13C isotope composition of ethanol from aqueous solutions. AB - A new method, combining headspace solid phase microextraction (HS-SPME) with an online pyrolysis system coupled with isotope ratio mass spectrometry (IRMS), is developed for the determination of the intramolecular (13)C isotope composition of ethanol in aqueous solutions. The delta(13)C values of the pyrolytic fragments (CO, CH4, C2H4) are shown to be highly reproducible (sd <0.40/00). Furthermore, using 14 ethanol samples of known intramolecular isotope distribution, the CO and CH4 fragments are shown to arise solely from the methylene (CH2OH) and methyl (CH3) carbon atom positions of the original ethanol, respectively. Although the different steps (extraction and pyrolysis) fractionate between (12)C and (13)C, the isotopic fractionation is reproducible (sd <0.40/00), allowing correcting factors to be applied in order to back-calculate the original delta(13)CCH2OH and delta(13)CCH3 values of ethanol. The method thus allows the determination of the isotope composition of ethanol at the intramolecular and molecular levels, within a single run and a short experimental time (30 min), and with a very easy sample preparation. The method is then applied to alcoholic beverages to show its potential for authentication purposes. PMID- 23745732 TI - The aryl hydrocarbon receptor and food allergy. AB - The immune system is important for protection against pathogens and malignant cells. However, malfunction of the immune system can also result in detrimental auto-immune diseases, inflammatory diseases, cancers and allergies. The aryl hydrocarbon receptor (AhR), present in numerous tissues and cell subsets, including cells of the immune system, plays an important role in the functioning of the immune system. Activation of the AhR is for example associated with various effects on dendritic cells (DCs), regulatory T cells and the Th1/Th2 cell balance. These cells play a major role in the development of food allergy. Food allergy is an increasing health problem in both humans and animals. Despite the knowledge in risk factors and cellular mechanisms for food allergy, no approved treatments are available yet. Recently, it has been shown that activation of the AhR by dioxin-like compounds suppresses allergic sensitization by suppressing the absolute number of precursor and effector T cells, by preserving CD4(+)CD25(+)Foxp3(+) Treg cells and by affecting DCs and their interaction with effector T cells. Future research should elucidate whether and how AhR activation can be used to interfere in food allergic responses in humans and in animals. This may lead to new prevention strategies and therapeutic possibilities for food allergy. PMID- 23745731 TI - Integrated analysis of seed proteome and mRNA oxidation reveals distinct post transcriptional features regulating dormancy in wheat (Triticum aestivum L.). AB - Wheat seeds can be released from a dormant state by after-ripening; however, the underlying molecular mechanisms are still mostly unknown. We previously identified transcriptional programmes involved in the regulation of after ripening-mediated seed dormancy decay in wheat (Triticum aestivum L.). Here, we show that seed dormancy maintenance and its release by dry after-ripening in wheat is associated with oxidative modification of distinct seed-stored mRNAs that mainly correspond to oxidative phosphorylation, ribosome biogenesis, nutrient reservoir and alpha-amylase inhibitor activities, suggesting the significance of post-transcriptional repression of these biological processes in regulating seed dormancy. We further show that after-ripening induced seed dormancy release in wheat is mediated by differential expression of specific proteins in both dry and hydrated states, including those involved in proteolysis, cellular signalling, translation and energy metabolism. Among the genes corresponding to these proteins, the expression of those encoding alpha amylase/trypsin inhibitor and starch synthase appears to be regulated by mRNA oxidation. Co-expression analysis of the probesets differentially expressed and oxidized during dry after-ripening along with those corresponding to proteins differentially regulated between dormant and after-ripened seeds produced three co-expressed gene clusters containing more candidate genes potentially involved in the regulation of seed dormancy in wheat. Two of the three clusters are enriched with elements that are either abscisic acid (ABA) responsive or recognized by ABA-regulated transcription factors, indicating the association between wheat seed dormancy and ABA sensitivity. PMID- 23745733 TI - Synthesis of 4-membered carbasugars by way of stereoselective SmI2-mediated aldehyde-alkene cyclization. AB - A stereodivergent synthesis of the first examples of 4-membered carbasugars has been achieved from vitamin C by way of an efficient intramolecular SmI2-mediated aldehyde-alkene coupling. In this key step, cylobutanes with four contiguous asymmetric centers are generated with a high level of stereocontrol. PMID- 23745734 TI - Mucopolysaccharidosis Type IIIA presents as a variant of Kluver-Bucy syndrome. AB - Mucopolysaccharidosis Type IIIA (MPS IIIA) is a neurodegenerative disease with behavioral symptoms unique among the mucopolysaccharidoses. Children with MPS IIIA reportedly mouth things, explore novel environments almost continuously, disregard danger, and empathize/socialize and comply less with parents. These characteristics resemble Kluver-Bucy syndrome (K-Bs). To test the K-Bs hypothesis, 30 children with MPS IIIA were compared to 8 "posttransplant" mucopolysaccharidosis Type IH patients in an experimental "risk room." The room contained attractive and mildly frightening objects, exposure to a 92-dB startle noise triggered by contact with an attractive toy, mother's return after a brief absence, and compliance with her cleanup directive. Children with MPS IIIA: (a) left mother sooner, (b) wandered more, (c) were more likely to approach frightening objects, (d) were less likely to respond to loud noise with whole body startle, (e) were less likely to avoid the toy associated with the startle noise, (f) interacted less with mother upon her return, and (g) complied less with her cleanup command. K-Bs is associated with loss of amygdala function. Brain magnetic resonance imaging (MRI) of a subset of the children with MPS IIIA showed volume loss that was greater in the amygdala than in the hippocampus; only amygdala loss correlated with reduced fearfulness. MPS IIIA may be the first identified pediatric disease presenting systematically as a K-Bs variant. If validated by further studies, the K-Bs hypothesis of MPS IIIA would provide important clinical and theoretical information for the guidance of families as well as markers for natural disease progression and treatment effects. PMID- 23745735 TI - Percutaneous transvenous embolization for portosystemic shunts associated with encephalopathy: Long-term outcomes in 14 patients. AB - AIM: To evaluate the clinical outcomes of percutaneous transvenous embolization (PTE) for portosystemic shunt (PSS) associated with encephalopathy METHODS: Fourteen patients with portosystemic encephalopathy (PSE) were enrolled in this retrospective cohort study. We evaluated technical success, clinical success, complication and outcomes. RESULTS: In cases in which PSS was one of main causes of PSE, three also had splenorenal shunts, four gastrorenal shunts, four superior mesenteric vein systemic shunts, one inferior mesenteric vein systemic shunt and two main trunk of portal vein inferior vena cava shunts. We used only ethanolamine oleate (EO) in five; EO and coils in five; EO, coils and n-butyl 2 cyanoacrylate (NBCA) in two; and coils and NBCA in two patients as embolic materials. The rate of primary and secondary technical success was 93% (13/14 patients) and 100%, respectively. No major complications were encountered related to PTE. Follow-up period was a median of 27 months (range, 12-79). All patients had sustained disappearance of PSE. PSE recurred in one patient because of another PSS development. Thus, clinical success was achieved in 93% (13/14 patients). The ammonia levels 1 year after PTE were significantly improved compared with pre-PTE (median, 102 vs 41 MUmol/L) and maintained lower levels 2 and 3 years later. Child-Pugh scores did not change significantly. Esophageal varices were aggravated in 29% (4/14 patients). Five patients died, but no death of hepatic failure related to PTE was encountered. CONCLUSION: PTE could be one of the useful treatment options for PSE. PMID- 23745736 TI - Why is working memory related to intelligence? Different contributions from storage and processing. AB - Domain-specific contributions of working memory (WM), short-term memory (STM), and executive functioning (EF) to individual differences in intelligence were analysed using a latent variable approach. A sample of 345 participants completed a battery of 24 tests tapping the constructs of interests as comprehensively as possible. Visuospatial and verbal STM and WM tasks were administered along with three subcomponents of EF, namely inhibition, planning, and shifting. Intelligence was assessed by non-verbal/abstract/fluid intelligence (Gf) and verbal/crystallised intelligence (Gc) standardised tests. Structural equation modelling results show that EF is the main predictor of Gf, whereas verbal STM is the main predictor of Gc. Storage and processing providing different contributions to the prediction of Gf and Gc supports the view that both short term storage and executive functioning account for the relationship between WM and intelligence. This main conclusion stresses the importance of acknowledging core cognitive constructs as being hierarchical systems with general and domain specific mechanisms. PMID- 23745737 TI - In silico design and construction of metal-binding hybrid proteins for specific removal of cadmium based on CS3 pili display on the surface of Escherichia coli. AB - In this study, through a combination of bioinformatics and genetic engineering procedures, high-affinity metal-binding peptides were designed and expressed on the surface of Escherichia coli for selective Cd(2+) adsorption. Putative cadmium binding motifs were identified by searches against the Prosite database and permissive sites in the major subunit (CstH) of the enterotoxigenic E. coli pili were predicted based on the data derived from modeling of 3D structures, secondary structure prediction and assignment, inspection of protein hydropathy and exposed regions, and also protein interaction sites. The metal-binding motifs were inserted into one permissive site of the CstH (amino acid 38) with the aid of the SOEing PCR technique. The capacity and selectivity of the recombinant bacteria displaying hybrid pili to adsorb cadmium were evaluated with the atomic absorption procedure. The levels of Cd(2+) accumulation in the recombinant E. coli strains were 13.9- and 11.33-fold higher than those in the control strain. Cd(2+) was selectively absorbed from a solution containing equal concentrations of four metals, resulting in more than 90% of the total adsorbed metals being Cd(2+) , showing a relatively high affinity for Cd(2+) over other coexisting metal ions. PMID- 23745739 TI - Anatase nanoparticle surface reactivity in NaCl media: a CD-MUSIC model interpretation of combined experimental and density functional theory studies. AB - The effect of particle size on the primary charging behavior of a suite of monodisperse nanometer diameter (4, 20, and 40 nm) anatase samples has been quantitatively examined with macroscopic experimental studies. The experimental results were evaluated using surface complexation modeling, which explicitly incorporated corresponding molecular-scale information from density functional theory (DFT) simulation studies. Potentiometric titrations were completed in NaCl media, at five ionic strengths (from 0.005 to 0.3 m), and over a wide pH range (3 11), at a temperature of 25 degrees C. From the experimental results, the pH of zero net proton charge (pHznpc) for the 4 and 20 nm diameter samples was 6.42, whereas the pHznpc was 6.22 for the 40 nm sample. The slopes of the net proton charge curves increased with an increase in particle size. Multisite surface complexation and charge distribution (CD) models, with a Basic Stern layer description of the electric double layer, were developed to describe all experimental data. Fits to the experimental data included an inner-sphere Na bidentate species, an outer-sphere Na-monodentate species, and outer-sphere Cl monodentate species. DFT simulations found the Na-bidentate species to be the most stable species on the (101) anatase surface (the predominant crystal face). The CD value for the Na-bidentate species was calculated using a bond valence interpretation of the DFT-optimized geometry. The Stern layer capacitance value varied systematically with particle size. The collective experimental and modeling studies show that subtle differences exist in the interface reactivity of nanometer diameter anatase samples. These results should help to further elucidate an understanding of the solid-aqueous solution interface reactivity of nanosized particles. PMID- 23745740 TI - Sigma-1 receptor knockout impairs neurogenesis in dentate gyrus of adult hippocampus via down-regulation of NMDA receptors. AB - AIMS: This study investigated the influence of sigma-1 receptor (sigma1 R) deficiency on adult neurogenesis. METHODS: We employed 8-week-old male sigma1 R knockout (sigma1 R(-/-) ) mice to examine the proliferation and differentiation of progenitor cells, and the survival and neurite growth of newborn neurons in hippocampal dentate gyrus (DG). RESULTS: In comparison with wild-type (WT) littermates, the numbers of 24-h-old BrdU(+) cells and Ki67(+) cells in sigma1 R( /-) mice increased, while the number of 28-day-old BrdU(+) cells decreased without changes in proportion of BrdU(+) /NeuN(+) cells and BrdU(+) /GFAP(+) cells. The neurite density of newborn neurons was slightly reduced in sigma1 R(-/ ) mice. In DG granular cells, N-methyl-d-aspartate (NMDA)-activated current (INMDA ) and phosphorylation of NMDA receptor (NMDAr) NR2B were reduced in sigma1 R(-/-) mice without the alteration of NR2B expression and membrane properties compared to WT mice. The NR2B antagonist abolished the difference in INMDA between sigma1 R(-/-) mice and WT mice. The application of NMDAr agonist in sigma1 R(-/-) mice prevented the over-proliferation of cells and reduction in newborn neurons, but it had no effects on the hypoplastic neurite. The administration of NMDAr antagonist in WT mice enhanced the cell proliferation and depressed the survival of newborn neurons. CONCLUSION: The sigma1 R deficiency impairs neurogenesis in DG through down-regulation of NMDArs. PMID- 23745741 TI - A non-pathogenic live vector as an efficient delivery system in vaccine design for the prevention of HPV16 E7-overexpressing cancers. AB - The attenuated or non-pathogenic live vectors have been evolved specifically to deliver DNA into cells as efficient delivery tools in gene therapy. Recently, a non-pathogenic protozoan, Leishmania tarentolae (L.tar) has attracted a great attention. In current study, we used Leishmania expression system (LEXSY) for stable expression of HPV16 E7 linked to different mini-chaperones [N-/C-terminal of gp96] and compared their immunogenicity and protective effects in C57BL/6 mice against TC-1 challenge. TC-1 murine model is primary C57BL/6 mice lung epithelial cells co-transformed with HPV16 E6, HPV16 E7 and ras oncogenes. Our results showed that subcutaneous administration of mice with both the recombinant L.tar E7-NT (gp96) and L.tar-E7-CT (gp96) led to enhance the levels of IFN-gamma and also IgG2a before and after challenge with TC-1. Furthermore, L.tar-E7-CT (gp96) live vaccine indicated significant protective effects as compared to control groups as well as group vaccinated with L.tar-E7. Indeed, the recombinant live vector is capable of eliciting effective humoral and cellular immune responses in mice, but however, further studies are required to increase their efficacy. PMID- 23745742 TI - Effects of surface charge and hydrophobicity on anodic biofilm formation, community composition, and current generation in bioelectrochemical systems. AB - The focus of this study was to investigate the effects of surface charge and surface hydrophobicity on anodic biofilm formation, biofilm community composition, and current generation in bioelectrochemical systems (BESs). Glassy carbon surfaces were modified with -OH, -CH3, -SO3(-), or -N(+)(CH3)3 functional groups by electrochemical reduction of aryl diazonium salts and then used as anodes with poised potential of -0.2 V (vs Ag/AgCl). The average startup times and final current densities for the -N(+)(CH3)3, -OH, -SO3(-), and -CH3, electrodes were (23 d, 0.204 mA/cm(2)), (25.4 d, 0.149 mA/cm(2)), (25.9 d, 0.114 mA/cm(2)), and (37.2 d, 0.048 mA/cm(2)), respectively. Biofilms on different surfaces were analyzed by nonturnover cyclic voltammetry (CV), fluorescence in situ hybridization (FISH), and 16S rRNA gene amplicon pyrosequencing. The results demonstrated that 1) differences in the maximum current output between surface modifications was correlated with biomass quantity, and 2) all biofilms were dominated by Geobacter populations, but the composition of -CH3-associated biofilms differed from those formed on surfaces with different chemical modification. This study shows that anode surface charge and hydrophobicity influences biofilm development and can lead to significant differences in BESs performance. Positively charged and hydrophilic surfaces were more selective to electroactive microbes (e.g. Geobacter) and more conducive for electroactive biofilm formation. PMID- 23745738 TI - Preclinical models of antipsychotic drug action. AB - One of the main obstacles faced by translational neuroscience is the development of animal models of psychiatric disorders. Behavioural pharmacology studies indicate that psychedelic drugs, such as lysergic acid diethylamide (LSD) and dissociative drugs, such as phencyclidine (PCP), induce in healthy human volunteers psychotic and cognitive symptoms that resemble some of those observed in schizophrenia patients. Serotonin 5-HT2A and metabotropic glutamate 2 receptors have been involved in the mechanism of action of psychedelic and dissociative drugs. Here we review recent advances using LSD-like and PCP-like drugs in rodent models that implicate these receptors in the neurobiology of schizophrenia and its treatment. PMID- 23745743 TI - Early therapy with neuraminidase inhibitors for influenza A (H1N1) pdm 2009 infection. AB - BACKGROUND: Neuraminidase inhibitors have been reported to decrease mortality in patients infected with influenza A (H1N1) pdm 2009 (H1N1 pdm09), but it is not clear whether they are effective against H1N1pdm09 in apparently healthy children. METHODS: The effect of early treatment with neuraminidase inhibitors on 70 otherwise healthy children with possible H1N1 pdm09 (pH1N1pdm09) infection was investigated. The children were simultaneously treated with a neuraminidase inhibitor (oseltamivir or zanamivir) and maoto, a Japanese traditional herbal medicine, which had been reported to be effective against seasonal influenza. Clinical severity was assessed using patient history, namely the worst values for clinical vital signs and laboratory data on admission. After refining these parameters with univariate, decision tree and multiple regression analysis, mean covariance structure equation analysis was used to investigate the association of estimated clinical severity to the selected parameters. RESULTS: Total path analysis using a Bayesian method indicated that the estimated clinical severity of pH1N1pdm09 was positively associated with maximum body temperature, pulse rate, respiration rate, duration necessary for defervescence, admission duration and log urinary beta2-microglobulin/creatinine level, and negatively associated with age and the presence and duration of treatment with the neuraminidase inhibitor in the outpatient clinic. CONCLUSIONS: This study provides the first clinical evidence that early treatment with neuraminidase inhibitors in outpatient clinic decreased the estimated clinical severity of pH1N1pdm09 in apparently otherwise healthy pediatric inpatients. PMID- 23745744 TI - Insulin resistance-induced hypertension and a role of perivascular CGRPergic nerves. AB - Insulin resistance is defined as a preliminary step of type 2 diabetes mellitus with decreased insulin action evoked by continuous postprandial hyperglycemia, which is provoked by high fat and calories dieting, a lack of physical activity and obesity. In the early phase of type 2 diabetes mellitus, patients have a hyperinsulinemia to compensate deficient insulin action by increased secretion from the pancreas to maintain euglycemia. Then, pancreatic beta cells progressively decrease secretion function, resulting in the development of diabetes mellitus with decreased serum insulin levels. Accumulating evidences show that insulin resistance is associated with hypertension. However, the mechanisms underlying hypertension associated with type 2 diabetes mellitus have still unknown. Therefore, to elucidate the mechanisms of insulin resistance induced hypertension, we investigated that the effects of hyperinsulinemia or hyperglycemia on vascular responses mediated by perivascular nerves including sympathetic adrenergic nerves and calcitonin gene-related peptide (CGRP) containing nerves (CGRPergic nerves). In this article, we show evidence that insulin resistance-induced hypertension could be resulted from increased density and function of sympathetic nerve, and decreased density and function of CGRPergic nerves. Furthermore, our findings provide a new insight into the research of therapeutic drugs for insulin resistance-induced hypertension. PMID- 23745745 TI - Letter to the editor. Second thoughts on the sidedness of P. PMID- 23745746 TI - Biocidal packaging for pharmaceuticals, foods, and other perishables. AB - Many consumer goods must be protected from bacterial and fungal colonization to ensure their integrity and safety. By making these items' packaging biocidal, the interior environment can be preserved from microbial spoilage without altering the products themselves. Herein we briefly review this concept, referred to as active packaging, and discuss existing methods for constructing active packaging systems. They are based on either packaging materials that release biocides or those that are themselves intrinsically biocidal (or biostatic), with numerous variations within each category. PMID- 23745747 TI - Commentary on Kim et al. (2013): drink driving in Hong Kong--a response. PMID- 23745748 TI - Commentary on Kerr et al. (2013): advertising high-potency heroin. PMID- 23745749 TI - Commentary on Lindstrom et al. (2013): does economic stress lead to tobacco smoking and does it matter if it does? PMID- 23745750 TI - Formation of trivalent zirconocene complexes from ansa-zirconocene-based olefin polymerization precatalysts: an EPR- and NMR-spectroscopic study. AB - Reduction of Zr(IV) metallocenium cations with sodium amalgam (NaHg) produces EPR signals assignable to Zr(III) metallocene complexes. The chloro-bridged heterodinuclear ansa-zirconocenium cation [(SBI)Zr(MU-Cl)2AlMe2](+) (SBI = rac dimethylsilylbis(1-indenyl)), present in toluene solution as its B(C6F5)4(-) salt, thus gives rise to an EPR signal assignable to the complex (SBI)Zr(III)(MU Cl)2AlMe2, while (SBI)Zr(III)-Me and (SBI)Zr(III)(MU-H)2Al(i)Bu2 are formed by reduction of [(SBI)Zr(MU-Me)2AlMe2](+) B(C6F5)4(-) and [(SBI)Zr(MU H)3(Al(i)Bu2)2](+) B(C6F5)4(-), respectively. These products can also be accessed, along with (SBI)Zr(III)-(i)Bu and [(SBI)Zr(III)](+) AlR4(-), when (SBI)ZrMe2 is allowed to react with HAl(i)Bu2, eliminating isobutane en route to the Zr(III) complex. Further studies concern interconversion reactions between these and other (SBI)Zr(III) complexes and reaction mechanisms involved in their formation. PMID- 23745752 TI - Are different subtypes of autism spectrum disorders associated with different factors? PMID- 23745753 TI - The importance of investigating alcohol use among people with schizophrenia. PMID- 23745751 TI - The nucleotide cycle of spastin correlates with its microtubule-binding properties. AB - Spastin is an AAA (ATPase associated with diverse cellular activities) protein with microtubule (MT)-severing activity. The spastin-encoding gene was identified as the most often mutated gene in the human neurodegenerative disease hereditary spastic paraplegia. Although the structure of the AAA domain of spastin has been determined, the mechanism by which spastin severs MTs remains elusive. Here, we studied the MT-binding and nucleotide-binding properties of spastin, as well as their interplay. The results suggest that ATP-bound spastin interacts strongly and cooperatively with MTs; this interaction stimulates ATP hydrolysis by spastin. After ATP hydrolysis, spastin dissociates from MTs, and then exchanges ADP for ATP in solution for the next round of work. In particular, spastin in the ternary complex of MT-spastin-ATP is the most cooperative state during the working cycle, and is probably the force-generating state that is responsible for MT severing. The results presented in this study establish the nucleotide cycle of spastin in correlation with its MT-binding properties, and provide a biochemical framework for further studies of the working mechanism of spastin. PMID- 23745755 TI - Interfacial micropore defect formation in PEDOT:PSS-Si hybrid solar cells probed by TOF-SIMS 3D chemical imaging. AB - Conducting p-type polymer layers on n-type Si have been widely studied for the fabrication of cost-effective hybrid solar cells. In this work, time-of-flight secondary ion mass spectrometry (TOF-SIMS) is used to provide three-dimensional chemical imaging of the interface between poly(3,4-ethylene dioxythiophene):polystyrenesulfonate (PEDOT:PSS) and SiOx/Si in a hybrid solar cell. To minimize structural damage to the polymer layer, an Ar cluster sputtering source is used for depth profiling. The present result shows the formation of micropore defects in the interface region of the PEDOT:PSS layer on the SiOx/Si substrate. This interfacial micropore defect formation becomes more prominent with increasing thickness of the native oxide layer, which is a key device parameter that greatly affects the hybrid solar cell performance. Three dimensional chemical imaging coupled with Ar cluster ion sputtering has therefore been demonstrated as an emerging technique for probing the interface of this and other polymer-inorganic systems. PMID- 23745754 TI - Identification of coronin-1a as a novel antibody target for clinically isolated syndrome and multiple sclerosis. AB - Recently, we identified the mimotope UH-CIS6 as a novel candidate antibody target for clinically isolated syndrome (CIS) and relapsing-remitting (RR) multiple sclerosis (MS). The purpose of this study was to further validate UH-CIS6 as an antibody target for CIS and MS and to identify the in vivo antibody target of UH CIS6. First, a UH-CIS6 peptide ELISA was optimized. Next, we investigated the antibody response toward UH-CIS6 in cerebrospinal fluid (CSF) from patients with CIS (n = 20), MS (n = 43) and other neurological diseases (n = 42). Immunoprecipitation of anti-UH-CIS6 antibodies on a normal human brain lysate was performed to identify the in vivo antibody target of UH-CIS6. The cellular expression of an in vivo candidate target was investigated by immunohistochemistry using MS brain tissue sections. Antibody reactivity toward UH-CIS6 was detected in a significantly increased proportion of CSF samples from CIS and RR-MS patients as compared with neurological controls (p = 0.046). We identified and confirmed coronin-1a as the in vivo antibody target for UH-CIS6. Furthermore, coronin-1a was expressed by T cells and macrophages in an active MS lesion. Together, these results demonstrate that coronin-1a is a novel antibody target for CIS and MS. PMID- 23745756 TI - Dual-mode operation of a bistable [1]rotaxane with a fluorescence signal. AB - We report the operation of a ferrocene-based bistable [1]rotaxane that can work in two parallel platforms. In an "active" signal mode, the relative mechanical movement of its ring and thread in response to external acid-base-stimuli can result in a remarkable fluorescence signal output observed by the naked eye, whereas no obvious fluorescence change occurred in a "silent" signal mode after oxidation. Its fluorescence responses to the different combinations of DBU and/or Fe(ClO4)3 corresponds to an INHIBIT logic gate. PMID- 23745757 TI - Chemoselective benzylation of unprotected anthranilic acids with benzhydryl alcohols by water-soluble Au(III)/TPPMS in water. AB - A novel and efficient method for the benzylation of unprotected anthranilic acids with benzhydryl alcohols using water-soluble Au(III)/TPPMS in water is developed. Water plays an important role in our catalytic system. This new protocol could be used for not only N-benzylation, but also chemoselective C-benzylation by the Friedel-Crafts reaction. PMID- 23745758 TI - Indices of initial hepatitis C virus RNA reduction rate to predict efficacy of interferon-beta followed by peginterferon plus ribavirin for genotype 1b high viral load. AB - AIM: Initial hepatitis C virus (HCV) RNA reduction was investigated as a potential index for sustained virological response (SVR) in the treatment of interferon (IFN)-beta followed by peginterferon plus ribavirin (PEG IFN/RBV). METHODS: The treatment course was retrospectively analyzed in 64 genotype 1b patients with a HCV RNA level of 5.0 logIU/mL or higher. IFN-beta was administrated twice a day for 2 weeks followed by 24 or 48 weeks of PEG IFN/RBV. The serum HCV RNA level was measured by real-time polymerase chain reaction before administration and at 1, 2 and 4 weeks of therapy. RESULTS: By the duration of PEG IFN administration, the SVR rates were 11% (2/18, <19 weeks), 64% (23/36, 20-24 weeks) and 40% (4/10, 25-72 weeks) (P = 0.0011, chi(2) -test). The SVR rate was high in patients in whom the HCV RNA level had decreased by 2.5 logIU/mL or greater at 1 week of IFN-beta (29/55 [53%] vs 0/9 [0%], P = 0.0029, chi(2) -test). Among these patients, the SVR rate was even higher in those with continuous reduction in the first 2 weeks after the switch to PEG IFN/RBV (27/45 [60%] vs 2/10 [20%], P = 0.0048). Age below 65 years, no previous IFN course and good initial HCV RNA reduction were significantly associated with SVR on multivariate analysis, and the SVR rate was 95% (18/19) among these patients. CONCLUSION: The 2.5 logIU/mL reduction in HCV RNA at 1 week of IFN-beta and the continuous reduction just after the switch to PEG IFN/RBV are important SVR predictive indices. PMID- 23745759 TI - The relationship between language production and verbal short-term memory: the role of stress grouping. AB - This study investigates the influence of stress grouping on verbal short-term memory (STM). English speakers show a preference to combine syllables into trochaic groups, both lexically and in continuous speech. In two serial recall experiments, auditory lists of nonsense syllables were presented with either trochaic (STRONG-weak) or iambic (weak-STRONG) stress patterns, or in monotone. The acoustic correlates that carry stress were also manipulated in order to examine the relationship between input and output processes during recall. In Experiment 1, stressed and unstressed syllables differed in intensity and pitch but were matched for spoken duration. Significantly more syllables were recalled in the trochaic stress pattern condition than in the iambic and monotone conditions, which did not differ. In Experiment 2, spoken duration and pitch were manipulated but intensity was held constant. No effects of stress grouping were observed, suggesting that intensity is a critical acoustic factor for trochaic grouping. Acoustic analyses demonstrated that speech output was not identical to the auditory input, but that participants generated correct stress patterns by manipulating acoustic correlates in the same way in both experiments. These data challenge the idea of a language-independent STM store and support the notion of separable phonological input and output processes. PMID- 23745760 TI - Assessing the accuracy of the WISC-IV seven-subtest short form and the child and adolescent intellectual disability screening questionnaire in identifying intellectual disability in children. AB - Little research has been conducted into the accuracy of abbreviated assessments in identifying children and young people with an intellectual disability (ID). The present study compared two such methods in a clinical population of individuals with (n = 106) and without (n = 170) ID: a 7-subtest short form of the Wechsler Adult Intelligence Scales for Children--fourth edition (WISC-IV) proposed by Crawford and colleagues and the Child and Adolescent Intellectual Disability Screening Questionnaire (CAIDS-Q). Both the CAIDS-Q and the WISC-IV short form had high and comparable levels of predicting group classification (88% and 91% correct classification, respectively). Both methods would appear to offer clinicians and researchers an efficient and accurate means of identifying those who are likely to have ID. The WISC-IV short form was slightly more accurate, but the CAIDS-Q may offer the advantages of being shorter to administer and having no requirement for the user to have a particular qualification or training. PMID- 23745761 TI - Transgenic banana plants overexpressing a native plasma membrane aquaporin MusaPIP1;2 display high tolerance levels to different abiotic stresses. AB - Water transport across cellular membranes is regulated by a family of water channel proteins known as aquaporins (AQPs). As most abiotic stresses like suboptimal temperatures, drought or salinity result in cellular dehydration, it is imperative to study the cause-effect relationship between AQPs and the cellular consequences of abiotic stress stimuli. Although plant cells have a high isoform diversity of AQPs, the individual and integrated roles of individual AQPs in optimal and suboptimal physiological conditions remain unclear. Herein, we have identified a plasma membrane intrinsic protein gene (MusaPIP1;2) from banana and characterized it by overexpression in transgenic banana plants. Cellular localization assay performed using MusaPIP1;2::GFP fusion protein indicated that MusaPIP1;2 translocated to plasma membrane in transformed banana cells. Transgenic banana plants overexpressing MusaPIP1;2 constitutively displayed better abiotic stress survival characteristics. The transgenic lines had lower malondialdehyde levels, elevated proline and relative water content and higher photosynthetic efficiency as compared to equivalent controls under different abiotic stress conditions. Greenhouse-maintained hardened transgenic plants showed faster recovery towards normal growth and development after cessation of abiotic stress stimuli, thereby underlining the importance of these plants in actual environmental conditions wherein the stress stimuli is often transient but severe. Further, transgenic plants where the overexpression of MusaPIP1;2 was made conditional by tagging it with a stress-inducible native dehydrin promoter also showed similar stress tolerance characteristics in in vitro and in vivo assays. Plants developed in this study could potentially enable banana cultivation in areas where adverse environmental conditions hitherto preclude commercial banana cultivation. PMID- 23745762 TI - Zebrafish genomics comes of age. AB - The ZF-HEALTH/EuFishBiomed workshop on "Genomics and High-throughput Sequencing Technologies with the Zebrafish Model" took place in December 2012 in Cambridge, United Kingdom. The organisers, Fiona Wardle and Ferenc Muller, brought together developmental biologists, geneticists, and bioinformaticians from Europe and the rest of the world to share findings and insights about the latest genomic capabilities and applications in this popular model organism. PMID- 23745763 TI - Influence of hormone replacement therapy on osteoprotegerin and receptor activator of nuclear factor kappa-B ligand concentrations in menopausal women. AB - The study was designed to compare the levels of the receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) in the serum and saliva of menopausal women and verify whether there is a correlation between concentrations of these cytokines and bone mineral density (BMD) of the femur and mandible. Blood and saliva samples were collected from a group of 60 women during menopause--30 untreated (control group) and 30 treated with hormone replacement therapy (HRT) (research group). Densitometry was conducted on the femoral bone and mandible. BMD in the research group was significantly higher than in the control group. The OPG concentration was slightly higher in the research group. The concentration of RANKL was slightly higher in the control group. Differences in RANKL/OPG between groups were not high enough to be statistically significant. Analysis of the RANKL in saliva revealed a significantly higher concentration of this factor in the control group. Observed beneficial effects of HRT on bone tissue may be exerted through the RANKL/OPG ratio, but further research is required to clearly confirm this thesis. PMID- 23745765 TI - Experimental characterization of next-generation expanded-bed adsorbents for capture of a recombinant protein expressed in high-cell-density yeast fermentation. AB - Expanded-bed adsorption (EBA) can be particularly useful in protein recovery from high-cell-density fermentation broth where conventional methods for harvest and clarification, such as continuous centrifugation and depth filtration, demand long processing times and are associated with high costs. In this work, the use of next-generation high-particle-density EBA adsorbents, including two mixed-mode resins, for the direct capture of a recombinant protein expressed in yeast at high cell densities is evaluated. Using classical experimental approaches and under different conditions (pH, salt, etc.), Langmuir isotherm parameters for these resins are obtained along with pore diffusivity values. Additional batch adsorption studies with Fastline(r) MabDirect, the resin that demonstrated the highest static binding capacity for the recombinant protein of interest under the conditions evaluated in this study, indicate competitive binding of nontarget proteins and approximately a 30% reduction in equilibrium binding capacity to 50 mg/mL settled bed in the presence of a 5%-10% cell concentration. Packed-bed (PB) dynamic binding capacities for the MabDirect resin (25-40 mg/mL PB) were significantly higher than for the Fastline(r) HSA resin and for the MabDirect MM resin in expanded-bed mode (5-10 mg/mL settled bed). Bed expansion behavior for the mMabDirect MM resin along with process yield and eluate purity are identified as a function of linear velocity and cell density, demonstrating process feasibility for pilot scale use. PMID- 23745764 TI - Differential effects of acute and repeated stress on hippocampus and amygdala inputs to the nucleus accumbens shell. AB - The basolateral amygdala (BLA) and ventral subiculum (vSub) of the hippocampus convey emotion and context information, respectively, to the nucleus accumbens (NAc). Using in vivo extracellular recordings from NAc neurons, we examined how acute and repeated restraint stress alters the plasticity of the vSub and BLA afferent pathways. High-frequency (HFS) and low-frequency (LFS) stimulation was applied to the vSub to assess the impact on NAc responses to vSub and BLA inputs. In addition, iontophoretic application of the dopamine D2-antagonist sulpiride was used to explore the role of dopamine in the NAc in mediating the effects of stress on plasticity. Acute and repeated restraint caused disparate effects on BLA- and vSub-evoked responses in the NAc. Following repeated restraint, but not after acute restraint, HFS of the vSub failed to potentiate the vSub-NAc pathway while instead promoting a long-lasting reduction of the BLA-NAc pathway and these effects were independent of D2-receptor activity. In contrast, LFS to the vSub pathway after acute restraint resulted in potentiation in the vSub-NAc pathway while BLA-evoked responses were unchanged. When sulpiride was applied prior to LFS of the vSub after acute stress, there was a pronounced decrease in vSub evoked responses similar to control animals. This work provides new insight into the impact of acute and repeated stress on the integration of context and emotion inputs in the NAc. These data support a model of stress whereby the hippocampus is inappropriately activated and dominates the information processing within this circuit via a dopaminergic mechanism after acute bouts of stress. PMID- 23745766 TI - Association between the XRCC6 Promoter rs2267437 polymorphism and cancer risk: evidence based on the current literature. AB - BACKGROUND: Increasing evidence suggests that the DNA repair gene XRCC6 (Ku70) may be critically involved in the aetiology of the human carcinogenesis. Many studies have investigated the association between the rs2267437 polymorphism and cancer susceptibility. However, the results of these studies have been controversial. This meta-analysis was conducted to quantitatively summarize the evidence for a relationship between the rs2267437 polymorphism and cancer risk. METHODS: Electronic databases, including PUBMED and EMBASE, were searched for publications that met the inclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate the strength of the association between the XRCC6 promoter rs2267437 polymorphism and cancer risk in a fixed-effects model (the Mantel-Haenszel method) or a random-effects model (the DerSimonian and Laird method), as appropriate. RESULTS: A total of 13 case control studies, involving 3675 cases and 4247 controls, investigating the XRCC6 rs2267437 polymorphism and cancer susceptibility were identified for the meta analysis. The pooled analysis showed that there is a significant relationship between the XRCC6 rs2267437 polymorphism and cancer susceptibility (GG vs. CC: OR=1.28, 95% CI=1.03-1.60). Subgroup analyses based on the cancer type, ethnicity, and source of the controls were also performed, and these results indicated that the XRCC6 promoter rs2267437 polymorphism was associated with cancer risk in breast cancer studies (GG vs. CC: OR=1.79, 95% CI=1.25-2.56; GG vs. CG+CC: OR=1.40, 95% CI=1.01-1.95), in Asian populations (GG vs. CC: OR=1.33, 95% CI=1.01-1.74) and in population-based studies (GG vs. CC: OR=1.57, 95% CI=1.12-2.22; CG vs. CC: OR=1.35, 95% CI=1.11-1.64; GG+CG vs. CC: OR=1.37, 95% CI=1.14-1.65). CONCLUSION: This meta-analysis suggests that the XRCC6 rs2267437 polymorphism may affect breast cancer susceptibility and increase the risk of cancer in Asian populations and in the general population. It is critical that further large-scale and well-designed studies be conducted to confirm the association between the rs2267437 genotype and cancer risk. PMID- 23745767 TI - Designing a photoresponsive molecularly imprinted system on a silicon wafer substrate surface. AB - A photoresponsive molecularly imprinted system was prepared on a silicon wafer substrate surface via the host-guest complex of grafted 4-(3 triethoxysilylpropyiureido)azobenzene (TSUA) and mono-6-deoxy-6-((p chlorosulfonyl)-benzoic acid)-beta-cyclodextrin (CBA-beta-CD), and the acid-base pair interactions/hydrogen bonds between CBA-beta-CD and the template molecules, including theophylline (TPE) and 4-hydroxybenzoic acid (4-HA). A molecular imprinting cycle "imprinting -> extracting -> uptaking -> shuffling" was also defined in the study, the processes of uptaking and shuffling were investigated in detail by equilibrium binding experiments, and the Langmuir adsorption isotherm and Scatchard equation were used to evaluate the binding affinity and the theoretical binding sites of the molecularly imprinted (MIS), nonimprinted (NIS), and pure (PS) silicon wafer substrates. Compared with the NISs and PSs, the MISs showed a significantly higher adsorption capacity for the template molecules. More importantly, the MISs showed a reimprinted ability; after the process of shuffling, the molecularly imprinted systems on the substrate surface were destroyed, and new imprinted systems could be fabricated for the recognition of other template molecules after washing the substrates under irradiation at 450 nm. Moreover, the selective adsorption for the MISs was investigated, which indicated that the MISs showed specific affinity to the template molecules (TPE or 4-HA). PMID- 23745768 TI - Transmission of Streptococcus dysgalactiae subsp. equisimilis between child and dog in an Aboriginal Australian community. AB - Streptococcus dysgalactiae subsp. equisimilis (SDSE), also known as group G and C streptococci, is becoming increasingly recognized as a pathogen in humans. We report here the finding of an identical strain of SDSE in the throat of a child and their dog in an Aboriginal Australian community. The strain was identified using the API 20Strep system, 16S rRNA gene sequencing, emm sequence typing (emmST) and multilocus sequence typing (MLST) as a group C SDSE, stC839.5 and ST 3. Carriage of this strain by a human and dog in the same household justifies detailed epidemiological studies using molecular typing to clarify the extent of cross-species transmission and sharing of SDSE and other group G and C streptococci, and its impact in these communities. PMID- 23745769 TI - Computational study on the drug resistance mechanism against HCV NS3/4A protease inhibitors vaniprevir and MK-5172 by the combination use of molecular dynamics simulation, residue interaction network, and substrate envelope analysis. AB - Hepatitis C virus (HCV) NS3/4A protease is an important and attractive target for anti-HCV drug development and discovery. Vaniprevir (phase III clinical trials) and MK-5172 (phase II clinical trials) are two potent antiviral compounds that target NS3/4A protease. However, the emergence of resistance to these two inhibitors reduced the effectiveness of vaniprevir and MK-5172 against viral replication. Among the drug resistance mutations, three single-site mutations at residues Arg155, Ala156, and Asp168 in NS3/4A protease are especially important due to their resistance to nearly all inhibitors in clinical development. A detailed understanding of drug resistance mechanism to vaniprevir and MK-5172 is therefore very crucial for the design of novel potent agents targeting viral variants. In this work, molecular dynamics (MD) simulation, binding free energy calculation, free energy decomposition, residue interaction network (RIN), and substrate envelope analysis were used to study the detailed drug resistance mechanism of the three mutants R155K, A156T, and D168A to vaniprevir and MK-5172. MD simulation was used to investigate the binding mode for these two inhibitors to wild-type and resistant mutants of HCV NS3/4A protease. Binding free energy calculation and free energy decomposition analysis reveal that drug resistance mutations reduced the interactions between the active site residues and substituent in the P2 to P4 linker of vaniprevir and MK-5172. Furthermore, RIN and substrate envelope analysis indicate that the studied mutations of the residues are located outside the substrate (4B5A) binding site and selectively decrease the affinity of inhibitors but not the activity of the enzyme and consequently help NS3/4A protease escape from the effect of the inhibitors without influencing the affinity of substrate binding. These findings can provide useful information for understanding the drug resistance mechanism against vaniprevir and MK-5172. The results can also provide some potential clues for further design of novel inhibitors that are less susceptible to drug resistance. PMID- 23745770 TI - Disability and health: exploring the disablement experience of young adult African Americans. AB - PURPOSE: The objective of this study was to examine disablement as experienced by young adult African American men and women with permanent mobility impairment. METHOD: This study included a sample of 5 male and 5 female participants ranging in age from 22 to 39. An exploratory descriptive design and qualitative methods, including interviews and fieldnotes, were used. Interview data was analyzed using the process of inductive qualitative content analysis. RESULTS: Basic desires for independence, shared intimacy, and psychological and physical health were not diminished by physical limitations. The disablement experience of this group is reflected in the themes of "Cumulative Losses" and "Sustained Desires". The findings of this study describe the high level of motivation that young adult African American men and women with disabilities have to improve levels of health and well-being within the context of their impairments. CONCLUSION: This study provides a better understanding of the contextual factors and experiences that may contribute to the development of further disability and subsequent health related problems over time. Increased knowledge of the disablement experience of these young men and women may assist health care entities and social service providers in improving health care and rehabilitation efforts targeting this group. Implications for Rehabilitation Disablement among African American Young Adults This study's findings describe the high level of motivation that young adult African American men and women with disabilities have to improve levels of health and well-being. The two primary themes, "Cumulative Losses" and "Sustained Desires", suggest that despite a number of significant losses, several innate desires remained intact in the context of impairment. Understanding the disablement experience of young African Americans may assist health care entities and social service providers in improving health care targeting this group. PMID- 23745771 TI - Dose-response relationships of polycyclic aromatic hydrocarbons exposure and oxidative damage to DNA and lipid in coke oven workers. AB - Polycyclic aromatic hydrocarbons (PAHs) are known to induce reactive oxygen species and oxidative stress, but the dose-response relationships between exposure to PAHs and oxidative stress levels have not been established. In this study, we recruited 1333 male coke oven workers, monitored the levels of environmental PAHs, and measured internal PAH exposure biomarkers including 12 urinary PAH metabolites and plasma benzo[a]pyrene-r-7,t-8,t-9,c-10 tetrahydotetrol-albumin (BPDE-Alb) adducts, as well as the two oxidative biomarkers urinary 8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha). We found that the total concentration of urinary PAH metabolites and plasma BPDE-Alb adducts were both significantly associated with increased 8-OHdG and 8-iso-PGF2alpha in both smokers and nonsmokers (all p < 0.05). This exposure-response effect was also observed for most PAH metabolites (all p(trend) < 0.01), except for 4-hydroxyphenanthrene and 8-OHdG (p(trend) = 0.108). Furthermore, it was shown that only urinary 1-hydroxypyrene has a significant positive association with both 8-OHdG and 8-iso-PGF2alpha after a Bonferroni correction (p < 0.005). Our results indicated that urinary SigmaOH PAHs and plasma BPDE-Alb adducts can result in significant dose-related increases in oxidative damage to DNA and lipids. Furthermore, when a multianalyte method is unavailable, our findings demonstrate that urinary 1-hydroxypyrene is a useful biomarker for evaluating total PAHs exposure and assessing oxidative damage in coke oven workers. PMID- 23745772 TI - Ganglioside influence on phospholipid films investigated with single molecule fluorescence measurements. AB - Single molecule fluorescence measurements are used to probe the effects of GM1 in DPPC monolayers. Langmuir-Blodgett films of GM1 and DPPC were doped with ~10(-8) mol % of the fluorescent lipid probe, BODIPY-PC, and transferred onto glass substrates at 23 mN/m. As shown previously, the individual orientation of each BODIPY-PC probe in the membrane can be measured using defocused polarized total internal reflection fluorescence microscopy, revealing changes in film properties at the molecular level. Here, BODIPY-PC tilt angle histograms are used to characterize the effects of GM1 in DPPC films from 0.05 to 100 mol % GM1. At high GM1 levels (>5 mol % GM1), trends in the single molecule measurements agree with previous bulk measurements showing the turnover from condensing to expanding influence of GM1 at 15-20 mol %, thus validating the single molecule approach. At biologically relevant, low concentrations of GM1 (<5 mol % GM1), where bulk fluorescence measurements are less informative, the single molecule measurements reveal a marked influence of GM1 on film properties. The addition of trace amounts of GM1 to DPPC films leads to an expansion of the film which continues to 0.10 mol % GM1, above which the trend reverses and the condensing effect previously noted is observed. PMID- 23745773 TI - Food as medicine. PMID- 23745774 TI - Letter to the editor. PMID- 23745775 TI - What is currently the best radiopharmaceutical for the hybrid PET/CT detection of recurrent medullary thyroid carcinoma? AB - Among thyroid malignancies, medullary thyroid carcinoma (MTC) has some very specific features. Production and secretion of large amounts of peptides occur in malignant transformed C cells with few exceptions, leading to high serum levels of calcitonin (Ctn) and carcinoembryonic antigen (CEA), that act after thyroidectomy as tumour markers warning for the presence of persistent or metastatic MTC. The availability of those serum biomarkers with an excellent sensitivity challenges medical imaging to localise the recurrent cancer tissue, since surgery is a major therapeutic option. The aims of this article are (i) to review literature evidence about the efficacy and tolerance of radiopharmaceuticals for 3 targets of PET/CT imaging (glucose metabolism, bioamines metabolism and somatostatin receptors) and also bone scintigraphy which is recommended in the Guidelines of European Society for Medical Oncology (ESMO; (ii) to compare the availability and the costs in relation with those radiopharmaceuticals, (iii) and to discuss a possible sequence of those examinations, in order to optimise spending and to minimise the overall radiation dose. In this context of recurrent MTC suspected on rising tumour markers levels after thyroidectomy, this survey of literature confirms that FDOPA is the best radiopharmaceutical for PET/CT with significant diagnostic performance if Ctn>150 pg/mL; an early image acquisition starting during the first 15 min is advised. In negative cases, FDG should be the next PET radiopharmaceutical, in particular if Ctn and CEA levels are rapidly rising, and PET with a somatostatin analogue labelled with gallium-68 when neither FDOPA nor FDG PET are conclusive. Bone scintigraphy could complement FDG-PET/CT if FDOPA is not available. PMID- 23745776 TI - Gadolinium-deferasirox-D-glucosamine: novel anti-tumor and MR molecular (theranostic) imaging agent. AB - TARGET AND PURPOSE: Cancer and heart disease are hard maladies in human communities. To recognize these kinds of diseases in primary states can help for remission and decreasing the expenses. One of the best techniques for recognizing is imaging of the tissue. METHODS: The main reason of this study is to survey the design of molecules Gd3+ -Defrasirox-DG as a type of glucose labeled with gadolinium to capture more specific cancer tissue and heart by MRI instrument as a technique extremely accurate and sensitive not too costly and lack of radioactive half-life compared with radioactive 18FDG as competing compound. RESULT: In this research, glucose is combined with Deferasirox for making complexes with gadolinium. With replacing the new compound of advanced imaging technology, it transferred from nuclear medicine to Radiology and the results were evaluated in vitro and in vivo that indicated the success in imaging of the heart and cancer in animal tumor model. CONCLUSION: The mechanism of cancer cells death is through activation of TNF-alpha system. At present, due to the lack of radiation and radioactive half-life and low production cost and high access to MRI compared with PET, this compound can be considered as 18FDG opponent in the near future as the new MRI successor agent. PMID- 23745777 TI - At the crossroads: HIV prevention and treatment for people who inject drugs in Ukraine. PMID- 23745778 TI - Catalyzing pyramidal inversion: configurational lability of P-stereogenic phosphines via single electron oxidation. AB - We report that pyramidal inversion of trivalent phosphines may be catalyzed by single electron oxidation. Specifically, a series of P-stereogenic (aryl)methylphenyl phosphines are shown to undergo rapid racemization at ambient temperature when exposed to catalytic quantities of a single electron oxidant in solution. Under these conditions, transient phosphoniumyl radical cations (R3P(*+)) are formed, and computational models indicate that the pyramidal inversion barriers for these open-shell intermediates are on the order of ~5 kcal/mol. The observed 10(20)-fold rate enhancement over uncatalyzed pyramidal inversion opens new opportunities for the dynamic stereochemistry of phosphines and may hold additional implications for the configurational stability of P stereogenic phosphine ligands on high-valent oxidizing transition metals. PMID- 23745779 TI - Desensitization in delayed drug hypersensitivity reactions -- an EAACI position paper of the Drug Allergy Interest Group. AB - Drug hypersensitivity may deprive patients of drug therapy, and occasionally no effective alternative treatment is available. Successful desensitization has been well documented in delayed drug hypersensitivity reactions. In certain situations, such as sulfonamide hypersensitivity in HIV-positive patients or hypersensitivity to antibiotics in patients with cystic fibrosis, published success rates reach 80%, and this procedure appears helpful for the patient management. A state of clinical tolerance may be achieved by the administration of increasing doses of the previously offending drug. However, in most cases, a pre-existent sensitization has not been proven by positive skin tests. Successful re-administration may have occurred in nonsensitized patients. A better understanding of the underlying mechanisms of desensitization is needed. Currently, desensitization in delayed hypersensitivity reactions is restricted to mild, uncomplicated exanthems and fixed drug eruptions. The published success rates vary depending on clinical manifestations, drugs, and applied protocols. Slower protocols tend to be more effective than rush protocols; however, underreporting of unsuccessful procedures is very probable. The decision to desensitize a patient must always be made on an individual basis, balancing risks and benefits. This paper reviews the literature and presents the expert experience of the Drug Hypersensitivity Interest Group of the European Academy of Allergy and Clinical Immunology. PMID- 23745780 TI - Hippocampal volume in relation to clinical and cognitive outcome after electroconvulsive therapy in depression. AB - OBJECTIVE: In a previous magnetic resonance imaging (MRI) study, we found a significant increase in hippocampal volume immediately after electroconvulsive therapy (ECT) in patients with depression. The aim of this study was to evaluate hippocampal volume up to 1 year after ECT and investigate its possible relation to clinical and cognitive outcome. METHOD: Clinical and cognitive outcome in 12 in-patients with depression receiving antidepressive pharmacological treatment referred for ECT were investigated with the Montgomery-Asberg Depression Rating Scale (MADRS) and a broad neuropsychological test battery within 1 week before and after ECT. The assessments were repeated 6 and 12 months after baseline in 10 and seven of these patients, respectively. Hippocampal volumes were measured on all four occasions with 3 Tesla MRI. RESULTS: Hippocampal volume returned to baseline during the follow-up period of 6 months. Neither the significant antidepressant effect nor the significant transient decrease in executive and verbal episodic memory tests after ECT could be related to changes in hippocampal volume. No persistent cognitive side effects were observed 1 year after ECT. CONCLUSION: The immediate increase in hippocampal volume after ECT is reversible and is not related to clinical or cognitive outcome. PMID- 23745781 TI - A possible explanation for the high frequency of contact sensitisation in chronic venous ulcers. PMID- 23745782 TI - Efficient ratiometric fluorescence probe based on dual-emission quantum dots hybrid for on-site determination of copper ions. AB - Of various chemosensory protocols, the color change observed by the naked eye is considered to be a conceivable and on-site way to indicate the presence of an analyte. We herein designed a ratiometric fluorescence probe by hybridizing dual emission quantum dots (QDs) and demonstrated its efficiency for on-site visual determination of copper ions. The hybrid probe comprises two sizes of cadmium telluride QDs emitting red and green fluorescence, respectively, in which the red emitting ones are embedded in silica nanoparticles and the green-emitting ones are covalently linked onto the surface. The fluorescence of the embedded QDs is insensitive to the analyte, whereas the green emissive QDs are functionalized to be selectively quenched by the analyte. Upon exposure to different amounts of copper ions, the variations of the dual emission intensity ratios display continuous color changes from green to red, which can be clearly observed by the naked eye. The limit of detection for copper is estimated to be 1.1 nM, much lower than the allowable level of copper (~20 MUM) in drinking water set by U.S. Environmental Protection Agency. The probe is demonstrated for the determination of copper ions in lake water and mineral water samples, especially for visually monitoring copper residues on herb leaves. This prototype ratiometric probe is simple, fully self-contained, and thus potentially attractive for visual identification without the need for elaborate equipment. PMID- 23745783 TI - Transjugular intrahepatic portosystemic shunt for a wait list patient is not a contraindication for orthotopic liver transplant outcomes. AB - OBJECTIVES: A transjugular intrahepatic portosystemic shunt for treating recurrent variceal bleeding or refractory ascites can be used as bridge therapy in patients awaiting a liver transplant. However, incorrect placement of the transjugular intrahepatic portosystemic shunt may complicate surgery during a liver transplant. This study sought to analyze a cohort of transplanted recipients to underscore whether transjugular intrahepatic portosystemic shunts can negatively affect liver transplant outcomes. MATERIALS AND METHODS: We retrospectively analyzed 207 patients who had undergone a liver transplant between January 2001 and December 2009 in the Rome "La Sapienza" center. Transjugular intrahepatic portosystemic shunt was performed before the liver transplant in 36 cases (17%). The analyzed population was stratified into 2 groups (no transjugular intrahepatic portosystemic shunt [n=171 ] and transjugular intrahepatic portosystemic shunt [n=36 ]), and patient survival outcomes were compared. RESULTS: In the no-transjugular intrahepatic portosystemic shunt group, 60 of 171 deaths (35%) were reported, 20 of which were seen in the first 3 months after the liver transplant. In the same group, 61 graft losses (36%) were observed, with 19 of which were seen in the first 3 months after the liver transplant. In transjugular intrahepatic portosystemic shunt group, 12 of the 36 deaths (33%) were seen; 5 patients died within 3 months of the liver transplant. In this latter group, 12 grafts (33%) were lost, 4 of which were reported during the first 3 months after surgery. The median patient survival was 64 months and 69 months in the 2 groups. On survival analysis, no significant differences were found between the 2 groups. CONCLUSIONS: Transjugular intrahepatic portosystemic shunt does not seem to affect outcomes after a liver transplant. We suggest that clinicians recognized the location of the stent to prevent any difficulty during surgery. PMID- 23745784 TI - Preovulatory progesterone rise during ovarian stimulation for IVF. AB - The aim of this review is to analyze the relationship between the preovulatory progesterone (P) rise and the in vitro fertilization (IVF) pregnancy outcome. It also investigates the sources and effects of P level increase, including the underlying mechanisms and potential strategies in preventing its elevation during ovarian stimulation. The origin of production of P in the early follicular phase is adrenal which shifts toward the ovaries prior to the ovulation. Several factors contribute to the etiology of P level increase including the number of multiple follicles, the overdose of gonadotropins and poor ovarian response. Nowadays, the influence of the preovulatory P rise on IVF outcome remains controversial. Several authors have failed to demonstrate any negative impact, while others reported a detrimental effect associated with the rise of P. It seems that P rise (<= 1.5 ng/ml or 4.77 nmol/l) may have deleterious effects on endometrial receptivity, namely, accelerating the endometrial maturation process that subsequently narrows the time-frame for implantation and thus decreases pregnancy rates. To prevent a P rise, it might be preferable to use milder stimulation protocols, earlier trigger of ovulation, cryopreservation of all embryos and transfer in the natural cycle. PMID- 23745786 TI - Optical biopsy of benign and malignant tissue by time resolved spectroscopy. AB - Pathological condition of malignant tissue could be analyzed by spectral domain or time domain spectroscopy, the two being the complementary to each other in optical biopsy (OB) of cancer. This paper reports results of time resolved emission spectroscopy (TRS) of 24 excised tissue samples of breast and prostate (normal control = 12; benign = 4; malignant = 8), employing a 390 nm, 100 fs, Ti Sapphire laser pulses.The fluorescence decay times were measured using streak camera and the resultant data were fitted for single and bi-exponential decays with reliability of 97%. Our results show the distinct difference between normal, benign and malignant tissues mostly due to the emission spectra of Nicotinamide Adenine Dinucleotide (NADH), Flavin Mononucleotide (FAD) and also due to the heterogeneity of micro environments associated with the diseased tissues. In this short report, fit is also shown that TRS of breast tissues are similar to those of prostate tissues. PMID- 23745785 TI - Robotic radiosurgery for the treatment of 1-3 brain metastases: a pragmatic application of cost-benefit analysis using willingness-to-pay. AB - With the emergence of radiosurgery as a new radiotherapeutic technique, health care decision makers are required to incorporate community need, cost and patient preferences when allocating radiosurgery resources. Conventional patient utility measures would not reflect short term preferences and would therefore not inform decision makers when allocating radiosurgery treatment units. The goal of this article is to demonstrate the feasibility of cost-benefit analysis to elicit the yearly net monetary benefit of robotic radiosurgery. To calculate the yearly incremental cost of robotic radiosurgery as compared to fixed gantry radiosurgery we used direct local cost data. We assumed a standard 10 year replacement and 5% amortization rate. Decision boards summarizing the clinical scenario of brain metastases and the difference between robotic and fixed gantry radiosurgery in terms of immobilization, comfort and treatment time were then presented to a sample of 18 participants. Participants who preferred robotic radiosurgery were randomly assigned to either a low ($1) or high ($5) starting point taxation based willingness-to-pay algorithm. The yearly incremental cost of providing robotic radiosurgery was $99,177 CAD. The mean community yearly willingness-to-pay for robotic radiosurgery was $2,300,000 CAD, p = 0.03. The calculated yearly net societal benefit for robotic radiosurgery was $2,200,823 CAD. Among participants who preferred robotic radiosurgery there was no evidence of starting point bias, p = 0.8. We have shown through this pilot study that it is feasible to perform cost-benefit analysis to evaluate new technologies in Radiation Oncology. Cost benefit analysis offers an analytic method to evaluate local preferences and provide accountability when allocating limited healthcare resources. PMID- 23745787 TI - Prostate tissue characterization/classification in 144 patient population using wavelet and higher order spectra features from transrectal ultrasound images. AB - In this work, we have proposed an on-line computer-aided diagnostic system called "UroImage" that classifies a Transrectal Ultrasound (TRUS) image into cancerous or non-cancerous with the help of non-linear Higher Order Spectra (HOS) features and Discrete Wavelet Transform (DWT) coefficients. The UroImage system consists of an on-line system where five significant features (one DWT-based feature and four HOS-based features) are extracted from the test image. These on-line features are transformed by the classifier parameters obtained using the training dataset to determine the class. We trained and tested six classifiers. The dataset used for evaluation had 144 TRUS images which were split into training and testing sets. Three-fold and ten-fold cross-validation protocols were adopted for training and estimating the accuracy of the classifiers. The ground truth used for training was obtained using the biopsy results. Among the six classifiers, using 10-fold cross-validation technique, Support Vector Machine and Fuzzy Sugeno classifiers presented the best classification accuracy of 97.9% with equally high values for sensitivity, specificity and positive predictive value. Our proposed automated system, which achieved more than 95% values for all the performance measures, can be an adjunct tool to provide an initial diagnosis for the identification of patients with prostate cancer. The technique, however, is limited by the limitations of 2D ultrasound guided biopsy, and we intend to improve our technique by using 3D TRUS images in the future. PMID- 23745789 TI - Radiotherapy for esophageal cancer using simultaneous integrated boost techniques: dosimetric comparison of helical TomoTherapy, Volumetric-modulated Arc Therapy (RapidArc) and dynamic intensity-modulated radiotherapy. AB - This study compared TomoTherapy (TM), with Volumetric-Modulated Arc Therapy (RapidArc, RA), and dynamic intensity-modulated radiotherapy (dIMRT) for locally advanced esophageal cancer (LAEC) with a simultaneous integrated boost (SIB) technique with regard to the target coverage and sparing of organs at risk (OARs). Twelve patients receiving four-dimensional computed tomography simulation were enrolled for dosimetric comparison. Gross tumor volume was contoured with the maximum intensity projection method. Using an SIB method, Planning target volume low (PTVL) and planning target volume high (PTVH) were prescribed as 54 Gy and 60 Gy, respectively, each administered in 30 fractions. We compared the results of statistical analysis for target coverage, homogeneity index (HI) and conformity index (CI) of PTVs, parameters of OARs and monitor unit (MU) were compared for analysis. The HI for PTVH varied significantly for the 3 techniques of TM, RA, and dIMRT (4.38 +/- 0.86, 6.40 +/- 0.86, and 6.11 +/- 0.68, respectively; P , 0.001). The CI scores for PTVH also differed across TM, RA, and dIMRT (0.64 6 0.06, 0.53 6 0.06, and 0.59 +/- 0.05, respectively; P < 0.001). The HI for PTVL showed a significant difference among TM, RA, and dIMRT (15.44 +/- 0.88, 20.88 +/- 1.03 and 18.65 +/- 1.42, respectively; P < 0.001). The percentage of lung volume receiving 5 Gy (V5) and 20 Gy (V20) (for V5: TM 54.4 +/- 8.0%; RA 67.5 +/- 14.5%, P < 0.01; dIMRT 44.8 +/- 8.2%; for V20: 13.6 6 3.3%, 12.2 +/- 3.6%, 18.1 6 3.4%, P = 0.001, respectively). For RA, the lung V5 >= 65% was observed in 6 patients and the V10 >= 50 % in one patient. TM, RA and dIMRT provided comparable coverage of the target and sparing of OARs. TM demonstrated superior CI and HI for tumor coverage and lowered the specified dose parameters for lung. RA provided an advantage in terms of the lowest MU and V20 of the lung, but its higher lung V5 was of some concern about lung toxicity. PMID- 23745788 TI - Validation of automatic contour propagation for 4D treatment planning using multiple metrics. AB - The aim of this work is to provide insights into multiple metrics clinical validation of deformable image registration and contour propagation methods in 4D lung radiotherapy planning. The following indices were analyzed and compared: Volume Difference (VD), Dice Similarity Coefficient (DSC), Positive Predictive Value (PPV) and Surface Distances (SD). The analysis was performed on three patient datasets, using as reference a ground-truth volume generated by means of Simultaneous Truth And Performance Level Estimation (STAPLE) algorithm from the outlines of five experts. Significant discrepancies in the quality assessment provided by the different metrics in all the examined cases were found. Metrics sensitivity was more evident in presence of image artifacts and particularly for tubular anatomical structures, such as esophagus or spinal cord. Volume Differences did not account for position and DSC exhibited criticalities due to its intrinsic symmetry (i.e. over- and under-estimation of the reference contours cannot be discriminated) and dependency on the total volume of the structure. PPV analysis showed more robust performance, as each voxel concurs to the classification of the propagation, but was not able to detect inclusion of propagated and ground-truth volumes. Mesh distances could interpret the actual shape of the structures, but might report higher mismatches in case of large local differences in the contour surfaces. According to our study, the combination of VD and SD for the validation of contour propagation algorithms in 4D could provide the necessary failure detection accuracy. PMID- 23745790 TI - Knockdown of protein phosphatase magnesium-dependent 1 (PPM1D) through lentivirus mediated RNA silencing inhibits colorectal carcinoma cell proliferation. AB - Colorectal cancer is one of the most common cancers in the world. Protein phosphatase magnesium-dependent 1 d (PPM1D) is aberrantly upregulated in many human carcinoma cells, and recent research has suggested that it could be a potential therapeutic target of cancer. However, the function of PPM1D in colorectal carcinoma cells is not well studied. To investigate the function of PPM1D in colorectal carcinoma, we used lentivirus-based RNA silencing to knock down the expression of PPM1D in RKO cells. We found that the lentivirus-mediated RNAi system efficiently decreased the expression level of endogenous PPM1D. Inhibiting PPM1D expression efficiently inhibited the proliferation and colony formation of RKO cells. Moreover, we found that PPM1D silencing led to G0/G1 cell cycle arrest and the accumulation of cells at the sub-G1 phase. Furthermore, we found that PPM1D knockdown reduced the expression level of cyclinB1, inhibited ERK phosphorylation and activated the AKT signaling pathway. We found that PPM1D plays a crucial role in colorectal carcinoma cell proliferation and colony formation. Our work provides strong evidence suggesting that PPM1D is a potential therapeutic target of human colorectal cancers. Lentivirus-mediated PPM1D silencing is a promising gene therapeutic method to treat colorectal cancers. PMID- 23745791 TI - Lack of association between cytotoxic T-lymphocyte antigen-4 -318C/T polymorphism and cancer risk: a meta-analysis of case-control studies. AB - Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is important for the down regulation of T-cell activation. Number of studies assessed the association between CTLA-4 318C/T polymorphisms and cancer in different populations. However, the studies have provided conflicting results. We performed a meta-analysis to examine the association between CTLA-4 -318C/T polymorphisms and cancer susceptibility. Eligible studies were identified by searching several databases for relevant reports published up to September 30, 2012. Sixteen eligible studies with a total of 6190 patients and 6560 controls were included to summarize the association between CTLA-4 -318C/T polymorphisms and the risk of cancer. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Overall, no significant associations were found in all genetic models when all studies were pooled into the meta-analysis (for -318C/T polymorphisms as estimated using a fixed effect model: TT vs. (CC + CT), OR = 1.02, 95% CI = 0.83-1.24; (TT + CT) vs. CC, OR = 1.20, 95% CI = 1.00-1.44; TT vs. CC, OR = 1.09, 95% CI = 0.74-1.59; CT vs. CC, OR = 1.21, 95% CI = 1.00-1.46). In further subgroup analyses for the -318C/T polymorphisms, stratified by design of ethnicity, cancer types, solid tumors to non-solid tumors, epithelial tumors to non-epithelial tumors, no significant associations were found in any subgroup of the population. This meta-analysis strongly suggests that -318C/T polymorphisms in CTLA-4 are not associated with an increased risk of cancer. PMID- 23745792 TI - Sources of variation in nutrient intake and the number of days to assess usual intake among men and women in the Seoul metropolitan area, Korea. AB - Sources of variation in nutrient intake have been examined for Western diets, but little is known about the sources of variation and their differences by age and sex among Koreans. We examined sources of variation in nutrient intake and calculated the number of days needed to estimate usual intake using 12 d of dietary records (DR). To this end, four 3 d DR including two weekdays and one weekend day were collected throughout four seasons of 1 year from 178 male and 236 female adults aged 20-65 years residing in Seoul, Korea. The sources of variation were estimated using the random-effects model, and the variation ratio (within-individual:between-individual) was calculated to determine a desirable number of days. Variations attributable to the day of the week, recording sequence and seasonality were generally small, although the degree of variation differed by sex and age (20-45 years and 46-65 years). The correlation coefficient between the true intake and the observed intake (r) increased with additional DR days, reaching 0.7 at 3-4 d and 0.8 at 6-7 d. However, the degree of increase became attenuated with additional days: r increased by 13.0-26.9 % from 2 to 4 d, by 6.5-16.4 % from 4 to 7 d and by 4.0-11.6 % from 7 to 12 d for energy and fifteen nutrients. In conclusion, the present study suggests that the day of the week, recording sequence and seasonality minimally contribute to the variation in nutrient intake. To measure Korean usual dietary intake using open ended dietary instruments, 3-4 d may be needed to achieve modest precision (r>0.7) and 6-7 d for high precision (r>0.8). PMID- 23745793 TI - Gene expression signature-based prognostic risk score in patients with glioblastoma. AB - The present study aimed to identify genes associated with patient survival to improve our understanding of the underlying biology of gliomas. We investigated whether the expression of genes selected using random survival forests models could be used to define glioma subgroups more objectively than standard pathology. The RNA from 32 non-treated grade 4 gliomas were analyzed using the GeneChip Human Genome U133 Plus 2.0 Expression array (which contains approximately 47 000 genes). Twenty-five genes whose expressions were strongly and consistently related to patient survival were identified. The prognosis prediction score of these genes was most significant among several variables and survival analyses. The prognosis prediction score of three genes and age classifiers also revealed a strong prognostic value among grade 4 gliomas. These results were validated in an independent samples set (n = 488). Our method was effective for objectively classifying grade 4 gliomas and was a more accurate prognosis predictor than histological grading. PMID- 23745794 TI - Comparative analysis of MAPK and PI3K/AKT pathway activation and inhibition in human and canine melanoma. AB - The lack of advanced animal models of human cancers is considered a barrier to developing effective therapeutics. Canine and human melanomas are histologically disparate but show similar disease progression and response to therapies. The purpose of these studies was to compare human and canine melanoma tumours and cell lines regarding MAPK and PI3K/AKT signalling dysregulation, and response to select molecularly targeted agents. Pathway activation was investigated via microarray and mutational analysis. Growth inhibition and cell cycle effects were assessed for pathway inhibitors AZD6244 (MAPK) and rapamycin (PI3K/AKT) in human and canine melanoma cells. Human and canine melanoma share similar differential gene expression patterns within the MAPK and PI3K/AKT pathways. Constitutive pathway activation and similar sensitivity to AZD6244 and rapamycin was observed in human and canine cells. These results show that human and canine melanoma share activation and sensitivity to inhibition of cancer-related signalling pathways despite differences in activating mutations. PMID- 23745795 TI - Evolutionary development of neural systems in vertebrates and beyond. AB - The emerging field of "neuro-evo-devo" is beginning to reveal how the molecular and neural substrates that underlie brain function are based on variations in evolutionarily ancient and conserved neurochemical and neural circuit themes. Comparative work across bilaterians is reviewed to highlight how early neural patterning specifies modularity of the embryonic brain, which lays a foundation on which manipulation of neurogenesis creates adjustments in brain size. Small variation within these developmental mechanisms contributes to the evolution of brain diversity. Comparing the specification and spatial distribution of neural phenotypes across bilaterians has also suggested some major brain evolution trends, although much more work on profiling neural connections with neurochemical specificity across a wide diversity of organisms is needed. These comparative approaches investigating the evolution of brain form and function hold great promise for facilitating a mechanistic understanding of how variation in brain morphology, neural phenotypes, and neural networks influences brain function and behavioral diversity across organisms. PMID- 23745796 TI - Interactions and stabilities of the UV RESISTANCE LOCUS8 (UVR8) protein dimer and its key mutants. AB - The dimeric UVR8 protein is an ultraviolet-B radiation (280-315 nm) photoreceptor responsible for the first step in UV-B regulation of gene expression in plants. Its action comprises the actual absorption of the UV quanta by a tryptophan array at the protein-protein interface, followed by monomerization and subsequent aggregation with downstream signaling components. A crystal structure of the Arabidopsis thaliana tryptophan-rich wild type UVR8 protein dimer was recently published, showing the presence of several salt bridges involving arginines R146, R286, R338, and R354. In this work, molecular dynamics simulations in conjunction with umbrella sampling were used to calculate the binding free energy for the wild type UVR8 dimer and three of its mutants (R286A, R338A, and R286A/R338A), in order to verify whether the key mutants are able to disrupt the dimeric structure as indicated experimentally. PMID- 23745797 TI - Demonstrating the appropriateness of developing sediment quality guidelines based on sediment geochemical properties. AB - The pool of bioavailable metals in sediments is typically much smaller than the total metal concentration and is strongly influenced by metal-binding with acid volatile sulfide (AVS), particulate organic carbon (OC), and iron and manganese oxide solid phases. We have investigated how the properties of relatively oxidized sediments influence the exposure and effects of copper on the survival and growth rate of the deposit-feeding benthic bivalve Tellina deltoidalis. Growth rate was a much more sensitive end point than survival. Toxic effects to growth were consistently observed in sediment where both pore water and overlying water copper concentrations were below the effect threshold for dissolved copper. Decreases in growth of the bivalve were largely attributable to dietary exposure to sediment-bound copper, as the organism was observed to actively feed on fine materials from the sediment surface. For sediments with the same total copper concentrations, effects were less for sediments with greater concentrations of fine particles (<63 MUm sediment) or particulate organic carbon (OC). Based on the concentration-response relationship, a no-effect value of 5.5 mg <63 MUm Cu g(-1) OC for growth of T. deltoidalis was calculated. The results confirm the appropriateness of using OC-normalized copper concentration in the <63 MUm sediment fraction to develop sediment quality guidelines (SQGs) that vary with sediment properties. For sediments where the amount of AVS is not sufficient to bind metals in non bioavailable forms, the metal-binding capacity provided by OC and iron and manganese oxyhydroxides associated with the fine sediments considerably reduced metal bioavailability. These sediment properties should be considered when assessing the risks posed by metal-contaminated sediments. PMID- 23745798 TI - The hardest butter to button: immediate context effects in spoken word identification. AB - According to some theories, the context in which a spoken word is heard has no impact on the earliest stages of word identification. This view has been challenged by recent studies indicating an interactive effect of context and acoustic similarity on language-mediated eye movements. However, an alternative explanation for these results is that participants looked less at acoustically similar objects in constraining contexts simply because they were looking more at other objects that were cued by the context. The current study addressed this concern whilst providing a much finer grained analysis of the temporal evolution of context effects. Thirty-two adults listened to sentences while viewing a computer display showing four objects. As expected, shortly after the onset of a target word (e.g., "button") in a neutral context, participants saccaded preferentially towards a cohort competitor of the word (e.g., butter). This effect was significantly reduced when the preceding verb made the competitor an unlikely referent (e.g., "Sam fastened the button"), even though there were no other contextually congruent objects in the display. Moreover, the time-course of these two effects was identical to within approximately 30 ms, indicating that certain forms of contextual information can have a near-immediate effect on word identification. PMID- 23745799 TI - Gender differences in intimate partner violence and psychiatric disorders in England: results from the 2007 adult psychiatric morbidity survey. AB - Aims. To assess the extent to which being a victim of intimate partner violence (IPV) is associated with psychiatric disorders in men and women. Methods. A stratified multistage random sample was used in the third English psychiatric morbidity survey. Psychiatric disorders were measured by the Clinical Interview Schedule (Revised) and screening questionnaires. IPV was measured using British Crime Survey questions. Results. 18.7% (95% CI 17.1-20.4; n = 595 of 3197) of men had experienced some form of IPV compared with 27.8% of women (95% CI 26.2-29.4; n = 1227 of 4206; p < 0.001). IPV was associated with all disorders measured (except eating disorders in men). Physical IPV was significantly linked to psychosis and with substance and alcohol disorders in men and women, but significant associations with common mental disorders (CMDs), post-traumatic stress disorder (PTSD) and eating disorders were restricted to women. Emotional IPV was associated with CMDs in men and women. Conclusions. The high prevalence of experiences of partner violence, and strength of the association with every disorder assessed, suggests enquiry about partner violence is important in identifying a potential risk and maintenance factor for psychiatric disorders, and to ascertain safety, particularly in women as they are at greatest risk of being victims of violence. PMID- 23745800 TI - Novel biomarkers in the prognosis, progression and treatment of cardiovascular disease: the role of microRNAs. PMID- 23745801 TI - Insights in microRNAs biology. AB - MicroRNAs (miRNAs) are small, non-coding RNAs, that function as post transcriptional regulators of gene expression. Recent studies now predict that numerous miRNA molecules regulate a large proportion of the human transcriptome, thus creating a whole new research field that utilizes their potential impact on gene expression in favor of diagnosis, prognosis and drug development. MiRNAs are generated from transcription of respective genes into primary structures that usually follow a two-step maturation process in the cell nucleus and cytoplasm. Active miRNA folds downregulate protein expression either via direct repression of targeted messenger RNA (mRNA) or mRNA cleavage. They are critical factors that control human development and organogenesis and reemerge as key-molecules that profoundly influence adult cells and tissues under stress-responsive conditions. Therefore, several miRNAs exhibit dysregulated functions in almost all aspects of human pathology such as cancer, cardiovascular diseases, metabolic disorders, genetic and neurodegenerative diseases, forming tissue-specific molecular profiles that further define salient pathologic features. The present article offers an overview on miRNAs biogenesis and functional processes, major aspects of their participation in human development and milestones regarding their contribution in human diseases. Furthermore, their utility as extracellular biomarkers and the rationale behind miRNA inhibition or miRNA delivery are being discussed. PMID- 23745802 TI - MicroRNAs: Novel diagnostic and prognostic biomarkers in atherosclerosis. AB - MicroRNAs (miRNAs) are an emerging class of highly conserved, non-coding small RNAs that regulate gene expression on the post-transcriptional level by inhibiting the translation of protein from mRNA or by promoting the degradation of mRNA. The involvement of miRNAs in the regulation of lipid metabolism, inflammatory response, cell cycle progression and proliferation, oxidative stress, platelet activation, endothelial function, angiogenesis and plaque formation and rapture indicates important roles in the initiation and progression of atherosclerosis. In the light of this evidence we will review the role of miRNAs in atherosclerosis. PMID- 23745803 TI - Novel biomarkers assessing endothelial dysfunction: role of microRNAs. AB - Endothelial dysfunction reflected by reduced nitric oxide availability is nowadays considered as a causative factor of atherosclerosis. A variety of biomarkers has been used as indicators of endothelial dysfunction in cardiovascular disease. Discovered just over a decade ago, microRNAs have evoked a great deal of interest, due to their importance for many aspects of homeostasis and disease. miRNAs comprise a novel class of endogenous, single-stranded, short RNA sequences able to regulate gene expression by binding to complementary sequences on mRNAs According to a growing body of evidence, they have been implicated in the regulation of several human physiological processes. They have been shown to participate in cardiovascular disease pathogenesis including atherosclerosis and endothelial dysfunction and this may have important clinical implications. PMID- 23745804 TI - MicroRNAs in arterial hypertension. AB - Arterial hypertension is an epidemic currently affecting almost a billion people worldwide. The consequences from high blood pressure vary, from peripheral arterial disease and chronic kidney failure to acute myocardial infarction and stroke. MicroRNAs (miRNAs) are small non-coding RNA molecules comprised of 22-26 nucleotides and provide posttranscriptional protein expression regulation. The many biological processes in which they are implicated, such as cell proliferation, apoptosis, metabolism, cell differentiation and morphogenesis confirms the functional significance of miRNAs. It has been found that miRNAs are expressed in cardiovascular disorders and seem to be important players in the pathogenesis of arterial hypertension. The elucidation of which miRNAs are key players and at what level is of high value since it is necessary in order to better understand the mechanisms underlying hypertension, thus leading to better diagnostic modalities and therapeutic regimes. PMID- 23745805 TI - MicroRNAs: Biomarkers for cardiovascular disease in patients with diabetes mellitus. AB - Diabetes mellitus (DM) is a complex metabolic disorder characterized by low insulin production/secretion by pancreatic beta cells and/or low responsiveness by insulin target tissues MicroRNAs have been associated with DM, but it is not clear whether this is a cause or an effect of metabolic abnormalities related to DM. In the hyperglycemic environment miRNAs are in involved in multiple stages of cardiovascular disease development and progression. In diabetic patients with cardiovascular disease miRNAs could potentially serve as early biomarkers for diagnosis and as therapeutic agents. The current review focuses on the involvement of miRNAs in molecular mechanisms underlying the pathogenesis of DM and its cardiovascular complications. PMID- 23745806 TI - Prognostic role of miRNAs in coronary artery disease. AB - The increasing prevalence of coronary artery disease (CAD) as well as its' monitoring remain crucial problems and fields of long debate. Thus, several circulating biomarkers have been found during the last decade and examined in terms of their potential to assist in the prognosis of CAD. Of great interest, are small non-coding RNAs (microRNAs or miRNAS or miRs), due to their association with many aspects of CAD. microRNAs circulate in the bloodstream, while they exist in tissues and affect plaque initiation and progression. In addition, they have been found to contribute to the pathophysiology of CAD and to the CAD related manifestations such as myocardial infarction, heart failure and cardiac arrhythmias. Therefore, evaluating the role of these molecules may be of great importance in the understanding of atherogenesis providing new evidence for diagnosis and prognosis of CAD. PMID- 23745807 TI - Diagnostic and therapeutic potentials of microRNAs in heart failure. AB - MicroRNAs are a class of evolutionarily small non-coding RNAs of 19 to 25 nucleotides in length, that represent one of the most exciting areas of current medical science as they can regulate a complex regulatory network of gene expression and physiologic processes including differentiation, proliferation and apoptosis in a highly context dependent fashion. Recently, their role in cardiovascular disease and in the regulation of cardiomyocyte size and function, in the action potential, in angiogenesis and in mitochondrial function was recognized. Importantly, they have been evaluated for their prognostic and diagnostic role in heart failure and modification of specific microRNAs levels has been tested as a therapeutic option in experimental heart failure models. In this review article we refer the most emerging evidence, concerning the role of microRNAs in myocardial development in heart failure pathophysiology and prognosis, and their therapeutic implications. PMID- 23745808 TI - MicroRNAs in aortic disease. AB - MicroRNAs (miRNAs) are non-coding RNAs of ~22 nucleotides which act as down regulators of gene expression in the post-transcription level and/or in the translation level. Several studies have shown that the process of their maturation is rather crucial for the development of cardiovascular system thus their regulation (up-,down-) is implicated with many cardiac pathologies. This is evaluated through their circulating levels which are reliable, stable and the changes in their serum profiles are representative of tissue alterations serum levels. Furthermore, they have been shown to participate in cardiovascular disease pathogenesis including atherosclerosis, coronary artery disease, myocardial infarction, heart failure cardiac arrhythmias and aortic stenosis. In the present review, we will first describe i) the process of miRNAs' maturation ii) their role in the cardiovascular development, iii) their role as biomarkers of cardiac diseases, iv) the cardiac myo-miR families and the v) their role in cardiac remodeling and the development of cardiac diseases. Second we will review the miRNA families that participate in aortic stenosis separated according to its main pathways (imflammation, fibrosis, calcification). Finally, we will describe the miRNAs that participate in the development of aortic aneurysm and aortic dissection according to their serum levels. PMID- 23745809 TI - The emerging role of microRNA in stroke. AB - MicroRNAs (miRNAs) are small non-coding RNAs approximately 22 nucleotides in length that play a pivotal role in post-transcriptional gene regulation by binding to complementary sites in the 3'-untranslated region of messenger RNAs. In the past decade, their role in several human diseases, from cancer to cardiovascular disease, has been established by a wealth of evidence. Stroke is responsible for 10% of deaths worldwide and is one of the leading causes of disability. MiRNAs are involved in stroke risk factors including hypertension, atherosclerosis, atrial fibrillation, diabetes and dyslipidemia. The role of miRNAs in the pathophysiology of stroke has been the subject of more recent investigations. Animal studies, which dominate the field, have demonstrated the differential expression of miRNAs in brain and blood following ischemic or hemorrhagic insult and the potential use of miRNA antagonists to reduce focal cerebral damage. In particular, antagomirs to miR-145, -497, -181a, -1 and let-7f have been found to be neuroprotective in vivo. The discovery of circulating miRNAs in peripheral blood, which are unexpectedly stable, has allowed the recent completion of several studies in human stroke patients that have confirmed the differential expression of specific miRNAs following stroke and have addressed their potential use as diagnostic and prognostic markers. With miRNA research in stroke still in its infancy, it is anticipated that in the next few years significant discoveries that may have important therapeutic implications will emerge. PMID- 23745810 TI - MicroRNAs in peripheral artery disease. AB - Peripheral arterial disease (PAD) is due to diffuse atherosclerosis. The pathological process is characterized mainly by the aberrant proliferation of vascular smooth muscle cells and the formation of neointimal lesions. MicroRNAs (miRNAs) are highly conserved non-coding small RNA molecules that regulate a large fraction of the genome by binding to complementary mRNA sequences, resulting in post-transcriptional gene silencing. Recent evidence has demonstrated that specific miRNAs are involved in the pathological development of PAD. In this review, the roles of specific miRNAs in PAD are summarized. PMID- 23745811 TI - MicroRNAs in the diagnosis and treatment of unstable angina. AB - During the last decade, a growing body of evidence has shown an interplay of genetics and inflammation which leads to a greater understanding of the complex pathophysiology of atherosclerotic vascular disease. Of great interest are non coding RNAs, called microRNAs due to their importance for many aspects of homeostasis and disease. According significant data, they have been implicated in the regulation of several human physiological processes, while they seem to participate in cardiovascular disease pathogenesis including atherosclerosis and acute coronary syndromes. Accordingly, other biomarkers beyond troponins such as microRNAs, could be proved very useful in the aim of enhancing diagnostic or therapeutic effectiveness. Notably, there is evidence that patients with unstable angina pectoris could be discriminated from stable patients, given higher expression levels of several microRNAs, suggesting that they could be used to identify patients at risk for acute coronary syndromes. Also, they may have a substantial therapeutic impact in the management of athero-thrombotic vascular disorders, even though there are still obstacles in their use for that purposes, such as the delivery of the drug to target cells. Thus, it will be necessary to further explore their complications, before their use as therapeutic option. PMID- 23745812 TI - MicroRNAs in cardiovascular therapeutics. AB - Recent research reveals the crucial role microRNAs (miRNAs) in the pathogenesis and progression of many pathological conditions, including cardiovascular diseases. It is widely documented that miRNAs represent critical regulators of cardiovascular function and participate in almost all aspects of cardiovascular biology. In particular, they are involved in several pathophysiological pathways of various manifestations of cardiovascular disease, such as coronary artery disease, heart failure, stroke, diabetes mellitus, arterial hypertension and cardiac arrhythmias. In the present article we review the available literature regarding to the role of miRNAs in certain cardiovascular conditions. Moreover, we discuss the therapeutic potential of miRNAs for treating cardiovascular diseases and we attempt to highlight future directions. PMID- 23745813 TI - Case report of skull metastasis from hepatocellular carcinoma after a liver transplant. AB - A solitary skull metastasis from hepatocellular carcinoma is rare. A 38-year-old man with hepatocellular carcinoma presented to our institution with a palpable temporal scalp mass. We took a magnetic resonance image, and discovered an enhanced and osteolytic skull tumor. The tumor was removed by an occipital craniectomy, and the histologic diagnosis was a cranial metastasis owing to hepatocellular carcinoma. A skull metastasis owing to hepatocellular carcinoma should be considered in the differential diagnosis in patients with a subcutaneous scalp mass. Although a distant metastasis can affect the prognosis of the patient, early treatment may improve survival. PMID- 23745815 TI - [What is personalistic bioethics? An analysys of its specificity and its theoretical foundations]. AB - This article try to analyze why, although personalistic bioethics is expanding, there are so few theoretical studies on its characteristics and identity, and concludes it is due to a problem of lack of specificity. Personalistic bioethicists rely either on movements or institutions that have a weak theoretical foundation or in the realist philosophy taken in a very broad sense, which generates a problem of internal inconsistency due to its great diversity. To solve this problem the author proposes: 1) be aware of the existence of this theoretical problem; 2) solve it through the use of personalistic philosophy understood as a particular philosophical school of the XX century. In this sense, the author proposes: 1) a detailed description of personalistic philosophy; 2) states that a particular version, the modern ontological personalism, developed from an anthropological point of view by Wojtyla, from a bioethical point of view by Sgreccia and from the theory of personalism by Burgos is the best choice to put the foundations of personalistic bioethics. The author concludes exposing the contributions and limits of this theory for personalistic bioethics, and the steps that should be followed to promote it and develop it. PMID- 23745814 TI - Triplet formation by charge recombination in thin film blends of perylene red and pyrene: developing a target model for the photophysics of organic photovoltaic materials. AB - Photoinduced charge separation in a mixture of Perylene Red (N,N'-bis(2,6-di isopropylphenyl)-1,6,7,12-tetraphenoxyperylene-3,4:9,10-tetracarboxylic acid bis imide) and pyrene, organized in thin solid film on quartz, was studied by means of steady-state absorption and emission spectroscopy and by femtosecond transient absorption spectroscopy. Steady state spectroscopy shows substantial interaction between the two chromophores in the ground and excited states. Luminescence quenching indicates charge transfer interaction. Global and target analysis of the transient absorption data indicates a complex photophysical behavior with the formation of long-lived charges (free charge carriers) and of a triplet excited state species (with rates of ~10.4 * 10(9) and 72.1 * 10(6) s(-1)) via charge recombination pathways from charged states. A generally applicable target model for the analysis of photophysical data of photovoltaic blends is developed. PMID- 23745816 TI - [The meaning behind some personalist bioethical principles]. AB - The article focuses on the anthropological bases of the personalist bioethical principles of unitotality and solidarity. In the first sense person is an unity, not a external compound of body and soul. Following Zubiri her dynamic unity goes through diverse phases, according to whether the actionally, dispositional or in passivity active notes predominate. Personal temporality is studied as a progressive concentration of the person in herself starting from a given beginning. But if the person distends temporally, it is because she is not identical with herself, but she is constitutively open or in coexistence. What leads us to broach the suppositions of the seconde principle of solidarity, as a form of donation from her opened interiority. PMID- 23745818 TI - [From virtue bioethics to bioethics personalistic: is integration possible?]. AB - In this article we analyze how the idea of virtue as an important element of human ethical action is slowly being lost. There are proposals both in ethics and in bioethics to rehabilitate virtue and to consider it as a very important element of human morality. In particular, in the health sector the rehabilitation of virtue, would imply greater focus on the ethical character of professionals and personal improvement rather than on training for the resolution of ethical cases. Such guidance would also improve the health professional-patient relationship with an increase not only in the technical quality but also in human dimension of health sciences. However, this orientation or tendency in bioethics suffers from a deficit in reasoning due to lack of a complete theory of human action that covers the good and also norms. The second part of the article looks at the relation between of virtue and personalistic bioethics. Virtue is considered as an important element of human action and is integrated with the good and norms. After analyzing and distinguishing between what is today considered personalistic bioethics and the contributions of personalism to bioethics, the paper concludes that the integration of virtue in personalistic bioethics is not only possible but desirable to overcome the ethical minimalism that has resulted from modern day principlism driven bioethics. PMID- 23745817 TI - [Bioethics and rationality. Personalism at the service of expanding the horizon of reason at the foundation of bioethics]. AB - Personalism not only provides a valuable contribution to those interested in bioethics by allowing contrasts with other schools and currents of thought, but its ethical and anthropological features can serve to widen the horizon of reason. Bioethics today needs to expand the horizon of rationality in which it is animated through: 1) An ontologically ground personalism thanks to which the personal being emerges with all its evidence as being in the most proper sense of being. 2) The overcoming of subjectivism-objectivism antinomy through the claim that human subjectivity is an objective fact. 3) The recognition of the personalistic norm of action as a fundamental precept of natural law. When bioethics is built with openness to the objective datum of subjectivity it becomes easy to appreciate the human person as a real aim that should not be used as mere means. 4) The discovery of the normative basis of the moral life, because determining the ultimate end of human action is not the same as obtaining an ultimate justification of the norms of human action. When this distinction is deeply assimilated, it can show that the precepts of natural law must be respected regardless the acceptance of God's existence. PMID- 23745819 TI - [Personalist bioethics and utilitarian bioethics]. AB - This paper shows the insufficiency of a bioethics which would intend to derive its proposals from Utilitarianism, identifying some inadequacies in the ethics of John Stuart Mill, e.g., the difficulties of the utilitarian commitment with instrumentalism, the deficiency of an utilitarian moral psychology and the naivete of the forensic dimension of the utilitarian submission. PMID- 23745820 TI - [Principialistic and personalistic bioethics. Some perspectives]. AB - Bioethics is a rapidly growing discipline. It needs clear philosophical and theological foundations to remain a sure guide in promoting and defending the gift of life. In this paper it is not our task to perform a detailed analysis about the rich tenets of personalist bioethics. Instead, we make a comparative table between two bioethical models or proposals, Principialism and Personalism, similar in some respects, but different in others. So, the criteria that will guide us in deciding on biomedical practice will become clearer. PMID- 23745821 TI - [Personalist bioethics in the university curriculum]. AB - Growing awareness of the importance of Bioethics has meant that this subject has taken on an increasingly important role in higher education. However, its incorporation into the educational syllabus at different levels has been slower than might have been expected, particularly at pre-university and undergraduate level. This article reviews the current situation of personalist Bioethics in the university curriculum. Starting from an analysis of the way Bioethics has been included at undergraduate and graduate level, it goes on to explore the factors that may aid or hinder the development of this subject. The conclusion explains how teaching and learning about Bioethics in the university curriculum requires rigorous research with a sound theoretical basis in personalist philosophy, as understood by the 20th century personalist school of philosophers. PMID- 23745822 TI - [The genetics and the dignity of the human being]. AB - The biological elements of man are not sufficient to confront the bioethical questions around the person concept, but are necessary to accurately define the properties of the human beings and the theological, philosophical and legal aspects that are attributable to each person. The human being is a singular being. Indeed, the coexistence of two dimensions of different nature, material and spiritual, is the most important difference between the man and the rest of living beings. Moreover, in man appears a new characteristic, unique between the living beings, the ethical component. The values and guidelines of the moral and ethical behavior of the human being must be considered of natural origin since they have contributed to the success and survival of the species. The man is not only Homo sapiens but also Homo moralis. The recognition of fault, self-control, solidarity, love, generosity, altruism and honesty, among others, are innate qualities in the human beings. The unit of the human species demands the respect and the consideration of the same dignity for all its members, but only for its members. The philosophical anthropology emphasizes the singularity of each human being, each person. This agrees totally with the data of the science, which emphasize the individual and singular genetic identity of each human being. PMID- 23745823 TI - [Psychotherapy and rehumanization from addictions. A model for personalist bioethics]. AB - If we agree that there is any chance of overcoming addictions, however remote, and that man would not be man if he did not have that opportunity, we conclude that there must be a model or theory to back it up. Our proposal in this paper is to approach the addictive phenomenon from the perspective of re-humanization, an anthropological and therapeutic model corroborated by Re-humanizing Therapeutic Communities as a healing therapy that helps the most dehumanized persons in society. This valuable theoretical and practical model, which we have come to call "re-humanization Philosophy" for more than ten years, may be of help for the epistemology of present-day Personalist Bioethics. PMID- 23745824 TI - [Human person and personalism]. AB - The first part of this article is an analysis of the historical and philosophical evolution of the concept of human person, from antiquity to present times, including an outline of its major developments. The second part deals critically with reductionist and empiricist positions -particularly Engelhardt's and of utilitarianism- exposing some of its practical implications in the realm of Bioethics. Finally the author concludes with an enunciation of what would constitute a conceptual basis for the ontological foundation of Personal Bioethics derived from the initial framework of intuitive ideas first outlined by Sgreccia in the eighties. PMID- 23745826 TI - Female crickets assess relatedness during mate guarding and bias storage of sperm towards unrelated males. AB - Recent evidence shows that females exert a post-copulatory fertilization bias in favour of unrelated males to avoid the genetic incompatibilities derived from inbreeding. One of the mechanisms suggested for fertilization biases in insects is female control over transport of sperm to the sperm-storage organs. We investigated post-copulatory inbreeding-avoidance mechanisms in females of the cricket Teleogryllus oceanicus. We assessed the relative contribution of related and unrelated males to the sperm stores of double-mated females. To demonstrate unequivocally that biased sperm storage results from female control rather than cryptic male choice, we manipulated the relatedness of mated males and of males performing post-copulatory mate guarding. Our results show that when guarded by a related male, females store less sperm from their actual mate, irrespective of the relatedness of the mating male. Our data support the notion that inhibition of sperm storage by female crickets can act as a form of cryptic female choice to avoid the severe negative effects of inbreeding. PMID- 23745825 TI - Endothelial caveolar subcellular domain regulation of endothelial nitric oxide synthase. AB - Complex regulatory processes alter the activity of endothelial nitric oxide synthase (eNOS) leading to nitric oxide (NO) production by endothelial cells under various physiological states. These complex processes require specific subcellular eNOS partitioning between plasma membrane caveolar domains and non caveolar compartments. Translocation of eNOS from the plasma membrane to intracellular compartments is important for eNOS activation and subsequent NO biosynthesis. We present data reviewing and interpreting information regarding: (i) the coupling of endothelial plasma membrane receptor systems in the caveolar structure relative to eNOS trafficking; (ii) how eNOS trafficking relates to specific protein-protein interactions for inactivation and activation of eNOS; and (iii) how these complex mechanisms confer specific subcellular location relative to eNOS multisite phosphorylation and signalling. Dysfunction in the regulation of eNOS activation may contribute to several disease states, in particular gestational endothelial abnormalities (pre-eclampsia, gestational diabetes etc.), that have life-long deleterious health consequences that predispose the offspring to develop hypertensive disease, Type 2 diabetes and adiposity. PMID- 23745827 TI - Sensitization of p-GaP with CdSe quantum dots: light-stimulated hole injection. AB - The sensitization of p-GaP by adsorbed CdSe quantum dots has been observed. Nondegenerately doped, planar p-GaP(100) photoelectrodes consistently showed sub band-gap (>550 nm) photoresponsivity in an aqueous electrolyte containing Eu(3+/2+) when CdSe quantum dots (diameters ranging from 3.1 to 4.5 nm) were purposely adsorbed on the surface. Both time-resolved photoluminescence decays and steady-state photoelectrochemical responses supported sensitized hole injection from the CdSe quantum dots into p-GaP. The observation of hole injection in this system stands in contrast to sensitized electron injection seen in other metal oxide/quantum dot material combinations and therefore widens the possible designs for photoelectrochemical energy conversion systems that utilize quantum dots as light-harvesting components. PMID- 23745828 TI - Post-abortion care services for youth and adult clients in Kenya: a comparison of services, client satisfaction and provider attitudes. AB - Unsafe abortion accounts for 35% of maternal mortality in Kenya. Post-abortion care (PAC) reduces maternal death and provides an opportunity to prevent unwanted pregnancies. Few studies have documented how the receipt of PAC services varies by client age. In this study, descriptive data were collected from clients, providers and eight health facilities in Kenya's Central and Nairobi provinces to examine receipt of PAC services by client age, client satisfaction and provider attitudes. Delivery of PAC treatment, pain management, HIV and STI services and violence screening did not vary by age. However, fewer youth between the ages of 15 and 24 received a contraceptive method compared with adult clients (35% versus 48%; p=0.02). Forty-nine per cent of youth reported not using a family planning method due to fears of infertility, side-effects or lack of knowledge compared with 22% of adults. Additional efforts are needed in Kenya to bolster the family planning services that young PAC clients receive and increase the uptake of contraception. PMID- 23745830 TI - Functional foods and nutraceuticals as therapeutic tools for the treatment of diet-related diseases. AB - In Western societies, the incidence of diet-related diseases is progressively increasing due to greater availability of hypercaloric food and a sedentary lifestyle. Obesity, diabetes, atherosclerosis, and neurodegeneration are major diet-related pathologies that share a common pathogenic denominator of low-grade inflammation. Functional foods and nutraceuticals may represent a novel therapeutic approach to prevent or attenuate diet-related disease in view of their ability to exert anti-inflammatory responses. In particular, activation of intestinal T regulatory cells and homeostatic regulation of the gut microbiota have the potential to reduce low-grade inflammation in diet-related diseases. In this review, clinical applications of polyphenol-rich functional foods and nutraceuticals in postprandial inflammation, obesity, and ageing will be discussed. We have placed special emphasis on polyphenols since they are broadly distributed in plants. PMID- 23745829 TI - Hospital mortality of cirrhosis: better, but still room for improvement! PMID- 23745831 TI - Scanning electrochemical microscopy of DNA hybridization on DNA microarrays enhanced by HRP-modified SiO2 nanoparticles. AB - Imaging of localized hybridization of nucleic acids immobilized on a glass DNA microarray was performed by means of generation collection (GC) mode scanning electrochemical microscopy (SECM). Amine-tethered oligodeoxynucleotide probes, spotted on the glass surface, were hybridized with an unmodified target sequence and a biotinylated indicator probe via sandwich hybridization. Spots where sequence-specific hybridization had occurred were modified by streptavidin horseradish-peroxidase-(HRP)-wrapped SiO2 nanoparticles through the biotin streptavidin interaction. In the presence of H2O2, hydroquinone (H2Q) was oxidized to benzoquinone (BQ) at the modified spot surface through the HRP catalytic reaction, and the generated BQ corresponding to the amount of target DNA was reduced in solution by an SECM tip. With this DNA microarray, a number of genes could be detected simultaneously and selectively enough to discriminate between complementary sequences and those containing base mismatches. The DNA targets at prepared spots could be imaged in SECM GC mode over a wide concentration range (10(-7)-10(-12) M). This technique may find applications in genomic sequencing. PMID- 23745833 TI - Understanding human papillomavirus vaccination intentions: comparative utility of the theory of reasoned action and the theory of planned behavior in vaccine target age women and men. AB - INTRODUCTION: Human papillomavirus (HPV) is an exceedingly prevalent sexually transmitted infection with serious medical, sexual, and relationship consequences. HPV vaccine protection is available but vaccine uptake is very inconsistent. AIMS: This research applies two major theories of health behavior uptake, the Theory of Reasoned Action and the Theory of Planned Behavior, in an effort to understand intentions to receive HPV vaccine among vaccine target age women and men. The Theory of Reasoned Action asserts that attitudes toward HPV vaccination and perceptions of social support for HPV vaccination are the determinants of intentions to be vaccinated, whereas the Theory of Planned Behavior holds that attitudes toward vaccination, perceptions of social support for vaccination, and perceived ability to get vaccinated are the determinants of intentions to be vaccinated. METHODS: Canadian university men (N=118) and women (N=146) in the HPV vaccine target age range took part in this correlational study online. MAIN OUTCOME MEASURES: Participants completed standard measures of attitudes toward HPV vaccination, perceptions of social support for vaccination, perceived ability to get vaccinated, beliefs about vaccination, and intentions to be vaccinated in the coming semester. RESULTS: Findings confirmed the propositions of the Theory of Reasoned Action and indicated that attitudes toward undergoing HPV vaccination and perceptions of social support for undergoing HPV vaccination contributed uniquely to the prediction of women's (R2=0.53) and men's (R2=0.44) intentions to be vaccinated in the coming semester. CONCLUSION: Clinical and public health education should focus on strengthening attitudes and perceptions of social support for HPV vaccination, and on the basic beliefs that appear to underlie attitudes and perceptions of social support for HPV vaccination, in efforts to promote HPV vaccine uptake. PMID- 23745832 TI - Receptor tyrosine kinases MET and RON as prognostic factors in diffuse large B cell lymphoma patients receiving R-CHOP. AB - Receptor tyrosine kinases MET and RON (MST1R) form non-covalent complexes on the cell surface, a critical step in tumor progression. A recent study suggested a prognostic role for MET expression in diffuse large B-cell lymphoma (DLBCL). The aim of this study was to examine the impact of MET and RON expression in uniformly treated DLBCL patients. The expression of MET and RON was retrospectively examined by immunohistochemistry in 120 DLBCL patients treated with rituximab combined with a CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone). The median follow-up time was 42.5 months (range, 1 89 months). Thirty-two (26%) and 30 patients (25%) expressed MET or RON, respectively. Seventy-five patients (62.5%) were negative for both MET and RON (MET(-) RON(-) ). MET negativity was associated with worse overall survival (P = 0.029). In multivariate analysis, negativity for both MET and RON (MET(-) RON(-) ) was strongly associated with inferior overall survival (P = 0.008). Interestingly, the MET(-) RON(-) phenotype retained its prognostic impact after subgroup analysis according to the international prognostic index or by the cell of origin by immunohistochemical algorithm by Choi et al. This study suggests that the MET(-) RON(-) phenotype is an independent prognostic factor in DLBCL patients receiving R-CHOP, and may identify a subgroup of DLBCL patients who require more intensive therapy. PMID- 23745834 TI - Morphological changes in eosinophils are reliable markers of the severity of an acute asthma exacerbation in children. AB - BACKGROUND: Early identification of the severity of asthma exacerbation would be helpful for the management of patients. We aimed to evaluate the correlation of morphological change in activated eosinophils and the severity of an asthma exacerbation. METHODS: Blood was collected from 55 asthmatic children: 40 of whom were having an exacerbation, 15 symptom-free, and 15 healthy controls. The percentage of eosinophils with morphological changes (emission of single or multiple pseudopods, presence of cytoplasmic vacuoles, releasing a small, moderate, or large quantity of granules, spreading, eosinophil death, and presence of cluster of free eosinophil granules) was quantified after the adherence to a slide and compared using the Mann-Whitney test. The correlation between the severity of the asthma exacerbation and the percentage changed eosinophils was tested with Spearman's correlation. RESULTS: The proportion of activated eosinophils was higher in asthmatic symptom-free children than in the control group, and acute asthma exacerbation produced an additional increase in eosinophil activation (P < 0.01). More significantly increased morphological changes were emissions of multiple pseudopods, presence of cytoplasmic vacuoles, spreading, and presence of a cluster of free eosinophil granules (P < 0.001). The following were correlated with the severity of an asthma exacerbation: >=14% of eosinophils emitting single pseudopod, 8% emitting multiple pseudopods, 17% with vacuoles, 28% eosinophils releasing a large quantity of granules, and 66% of spread eosinophils. CONCLUSIONS: Quantifying the morphological changes in eosinophils is a feasible, easy, and reliable manner to identify the severity of an asthma exacerbation and therefore might improve the clinical management of asthmatic children. PMID- 23745835 TI - Impact of urea on detergent micelle properties. AB - Co-solvents, such as urea, can entail drastic changes in the micellization behavior of detergents. We present a systematic quantification of the impact of urea on the critical micellar concentration, the micellization thermodynamics, and the micelle size in three homologous series of commonly used non-ionic alkyl detergents. To this end, we performed demicellization experiments by isothermal titration calorimetry and hydrodynamic size measurements by dynamic light scattering on alkyl maltopyranosides, cyclohexyl alkyl maltopyranosides, and alkyl glucopyranosides at urea concentrations of 0-8 M. For all detergents studied, we found that the critical micellar concentration increases exponentially because the absolute Gibbs free energy of micellization decreases linearly over the entire urea concentration range, as does the micelle size. In contrast, the enthalpic and entropic contributions to micellization reveal more complex, nonlinear dependences on urea concentration. Both free energy and size changes are more pronounced for long-chain detergents, which bury more apolar surface area upon micelle formation. The Gibbs free energy increments per methylene group within each detergent series depend on urea concentration in a linear fashion, although they result from the entropic term for alkyl maltosides but are of enthalpic origin for cyclohexyl alkyl maltosides. We compare our results to transfer free energies of amino acid side chains, relate them to protein-folding data, and discuss how urea-induced changes in detergent micelle properties affect in vitro investigations on membrane proteins. PMID- 23745836 TI - Novel approaches for the identification of inhibitors of leishmanial dipeptidylcarboxypeptidase. AB - INTRODUCTION: Leishmaniasis imposes a substantial burden of mortality and morbidity affecting 12 million globally and continues to be a neglected tropical disease. Control of the disease is mainly based on chemotherapy, which relies on a handful of drugs with serious limitations. Over the last decade, target-based drug discovery is also being employed in addition to the random screening of compounds. Leishmanial dipeptidylcarboxypeptidase (LDCP), an angiotensin converting enzyme (ACE) related metallopeptidase, has been recently identified as a novel drug target for antileishmanial chemotherapy. AREAS COVERED: This article examines dipeptidylcarboxypeptidase (DCP) of Leishmania donovani and of other sources from the international literature regarding their biochemical and structural characterization in comparison to mammalian ACE. Furthermore, the author discusses the identification of LdDCP specific inhibitors by virtual screening and their effect on parasite multiplication. Finally, the review looks ahead at areas for further exploration of DCP inhibitors in Leishmania chemotherapy. EXPERT OPINION: The first step in targeted screening is to identify a suitable drug target and its validation followed by its use in high throughput screening of compounds. Limited studies on LDCP inhibitors have established a good correlation between parasite enzyme inhibition and their biological activity. This suggests that there is a potential for LDCP inhibitors as new antileishmanial drugs. PMID- 23745837 TI - Executive functions and cerebellar development in children. AB - This article examines the role of the cerebellum in processing executive functions in developmental age. The areas implicated in its elaboration are interconnected in a network that includes the prefrontal cortex, the basal ganglia, and the cerebellum. Implementation of the capacities to plan and to control corresponds to the development of the network and its structures. The development, from an evolutionary point of view, of the most recent parts of the cerebellum and of its connections with the prefrontal cortex is tied to the crucial role that it plays in an inexorable way in action execution with implicit mechanisms of anticipation and control. Deficits in executive functions are present in many cerebellar pathologies and there is also an important link between motor development and the development of many higher-order cognitive and functional domains. Further studies are needed to clarify the role of the cerebellum in executive functions both in pathological or normal conditions in the developmental age. PMID- 23745838 TI - Thermal reversal of polyvalent choline phosphate, a multivalent universal biomembrane adhesive. AB - Multivalent macromolecular associations are widely observed in biological systems and are increasingly being utilized in bioengineering, nanomedicine, and biomaterial applications. Control over such associations usually demands an ability to reverse the multivalent binding. While in principle this can be done with binding site competitive inhibitors, dissociation is difficult in practice due to limited site accessibility when the macromolecule is bound. We demonstrate here efficient binding reversal of multivalent linear copolymers that adhere to any mammalian cell via the universal mechanism based on choline phosphate (CP) groups binding to phosphatidyl choline (PC)-containing biomembranes. Using a smart linear polymer exhibiting a lower critical solution temperature (LCST), we take advantage of the thermal contraction of the polymer above the LCST, which reduces accessibility of the CP groups to cell membrane PC lipids. The polymer construct can then desorb from the cell surface, reversing all effects of multivalent polymer adhesion on the cell. PMID- 23745840 TI - Comment on "Common mental disorders and long-term sickness absence in a general working population". PMID- 23745839 TI - Copper-induced deregulation of microRNA expression in the zebrafish olfactory system. AB - Although environmental trace metals, such as copper (Cu), can disrupt normal olfactory function in fish, the underlying molecular mechanisms of metal-induced olfactory injury have not been elucidated. Current research has suggested the involvement of epigenetic modifications. To address this hypothesis, we analyzed microRNA (miRNA) profiles in the olfactory system of Cu-exposed zebrafish. Our data revealed 2, 10, and 28 differentially expressed miRNAs in a dose-response manner corresponding to three increasing Cu concentrations. Numerous deregulated miRNAs were involved in neurogenesis (e.g., let-7, miR-7a, miR-128, and miR-138), indicating a role for Cu-mediated toxicity via interference with neurogenesis processes. Putative gene targets of deregulated miRNAs were identified when interrogating our previously published microarray database, including those involved in cell growth and proliferation, cell death, and cell morphology. Moreover, several miRNAs (e.g., miR-203a, miR-199*, miR-16a, miR-16c, and miR-25) may contribute to decreased mRNA levels of their host genes involved in olfactory signal transduction pathways and other critical neurological processes via a post transcriptional mechanism. Our findings provide novel insight into the epigenetic regulatory mechanisms of metal-induced neurotoxicity of the fish olfactory system and identify novel miRNA biomarkers of metal exposures. PMID- 23745841 TI - Number representation: a question of look? The distance effect in comparison of English and Turkish number words. AB - Cohen Kadosh found that Hebrew number words and Arabic digits elicited different distance effects. The numerical distance effect (i.e., faster reaction times and smaller error rates for numbers with larger distance to a standard number, e.g., 5) was smaller for number words than for digits. The author suggested that the result indicated a notation-dependent (i.e., nonabstract) numerical representation. Alternatively, however, it is possible that the distance effect was decreased by perceptual features of the Hebrew number words used as stimuli. To test this hypothesis, we replicated the study of Cohen Kadosh, but with English and Turkish number words compared to Arabic digits. The perceptual features of Turkish number words lead to the hypothesis that the opposite effect should be present: an increased distance effect for number words compared to Arabic digits. On the other hand, English number words show features similar to those of Hebrew number words, thus leading to the expectation of a decreased distance effect for them. Our results confirmed our hypotheses. We conclude that the distance effect can be influenced also by perceptual features in addition to the impact of numerical representations. PMID- 23745842 TI - Amyloidogenic peptide/single-walled carbon nanotube composites based on tau protein-related peptides derived from AcPHF6: preparation and dispersive properties. AB - We investigated the abilities of a family of tau-protein-related amphiphilic peptides with predictable self-association characteristics (N-acetyl-VQIVXK-NH2 (X = F, L, V, W, Y, A, K)) to disperse single-walled carbon nanotubes (SWCNTs). The dispersion abilities of these peptides could be explained by a linear combination of their hydrophobic and amyloidogenic properties in a 60/40 ratio. Circular dichroism (CD) spectra of one of the peptides having a high propensity to form an amyloid (N-acetyl-VQIVYK-NH2 (AcPHF6)) showed that this peptide exists as a random coil in water but assumes a beta-sheet conformation when sonicated with SWCNTs. Electron microscopy results, changes in near-infrared spectra, and changes in the Raman spectra upon formation of composites suggest that AcPHF6 intercalates, coats, and exfoliates SWCNT bundles. N-terminal truncation of AcPHF6 greatly reduced its ability to disperse SWCNTs. Taken together, our results suggest that amyloidogenic peptides wrap SWCNTs, forming an extensive beta-sheet network. To date, peptides based on the AcVQIVXK framework are structurally the simplest peptides that have been found to disperse CNTs, and an understanding of those properties that determine their efficiency may be used to design even more efficient peptides for these purposes. We believe that due to the structural simplicity, this family of peptides will have clear synthetic advantages over peptides now known to disperse CNTs. PMID- 23745843 TI - Light-wave mixing and scattering with quantum gases. AB - We present a semiclassical theoretical framework on light-wave mixing and scattering with single-component quantum gases. We show that these optical processes originating from elementary excitations with dominant collective atomic recoil motion are stimulated Raman or hyper-Raman in nature. In the forward direction the wave-mixing process, which is the most efficient process in normal gases, is strongly reduced by the condensate structure factor even though the Bogoliubov dispersion relation automatically compensates the optical-wave phase mismatch. In the backward direction, however, the free-particle-like condensate structure factor and Bogoliubov dispersion result in highly efficient light-wave mixing and collective atomic recoil motion that are enhanced by a stimulated hyper-Raman gain and a very narrow two-photon motional state resonance. PMID- 23745844 TI - Quantum information causality. AB - How much information can a transmitted physical system fundamentally communicate? We introduce the principle of quantum information causality, which states the maximum amount of quantum information that a quantum system can communicate as a function of its dimension, independently of any previously shared quantum physical resources. We present a new quantum information task, whose success probability is upper bounded by the new principle, and show that an optimal strategy to perform it combines the quantum teleportation and superdense coding protocols with a task that has classical inputs. PMID- 23745845 TI - Entanglement swapping between photons that have never coexisted. AB - The role of the timing and order of quantum measurements is not just a fundamental question of quantum mechanics, but also a puzzling one. Any part of a quantum system that has finished evolving can be measured immediately or saved for later, without affecting the final results, regardless of the continued evolution of the rest of the system. In addition, the nonlocality of quantum mechanics, as manifested by entanglement, does not apply only to particles with spacelike separation, but also to particles with timelike separation. In order to demonstrate these principles, we generated and fully characterized an entangled pair of photons that have never coexisted. Using entanglement swapping between two temporally separated photon pairs, we entangle one photon from the first pair with another photon from the second pair. The first photon was detected even before the other was created. The observed two-photon state demonstrates that entanglement can be shared between timelike separated quantum systems. PMID- 23745846 TI - Catch-disperse-release readout for superconducting qubits. AB - We analyze a single-shot readout for superconducting qubits via the controlled catch, dispersion, and release of a microwave field. A tunable coupler is used to decouple the microwave resonator from the transmission line during the dispersive qubit-resonator interaction, thus circumventing damping from the Purcell effect. We show that, if the qubit frequency tuning is sufficiently adiabatic, a fast high-fidelity qubit readout is possible, even in the strongly nonlinear dispersive regime. Interestingly, the Jaynes-Cummings nonlinearity leads to the quadrature squeezing of the resonator field below the standard quantum limit, resulting in a significant decrease of the measurement error. PMID- 23745848 TI - Feedback control of trapped coherent atomic ensembles. AB - We demonstrate how to use feedback to control the internal states of trapped coherent ensembles of two-level atoms, and to protect a superposition state against the decoherence induced by a collective noise. Our feedback scheme is based on weak optical measurements with negligible backaction followed by coherent microwave manipulations. The efficiency of the feedback system is studied for a simple binary noise model and characterized in terms of the trade off between information retrieval and destructivity from the optical probe. We also demonstrate the correction of more general types of collective noise. This technique can be used for the operation of atomic interferometers beyond the standard Ramsey scheme, opening the way towards improved atomic sensors. PMID- 23745847 TI - Reliable entanglement detection under coarse-grained measurements. AB - We derive reliable entanglement witnesses for coarse-grained measurements on continuous variable systems. These witnesses never return a "false positive" for identification of entanglement, under any degree of coarse graining. We show that even in the case of Gaussian states, entanglement witnesses based on the Shannon entropy can outperform those based on variances. We apply our results to experimental identification of spatial entanglement of photon pairs. PMID- 23745849 TI - Nondemolition measurement of the vacuum state or its complement. AB - Measurement is integral to quantum information processing and communication; it is how information encoded in the state of a system is transformed into classical signals for further use. In quantum optics, measurements are typically destructive, so that the state is not available afterwards for further steps. Here we show how to measure the presence or absence of the vacuum in a quantum optical field without destroying the state, implementing the ideal projections onto the respective subspaces. This not only enables sequential measurements, useful for quantum communication, but it can also be adapted to create novel states of light via bare raising and lowering operators. PMID- 23745850 TI - Maximum likelihood reconstruction for Ising models with asynchronous updates. AB - We describe how the couplings in an asynchronous kinetic Ising model can be inferred. We consider two cases: one in which we know both the spin history and the update times and one in which we know only the spin history. For the first case, we show that one can average over all possible choices of update times to obtain a learning rule that depends only on spin correlations and can also be derived from the equations of motion for the correlations. For the second case, the same rule can be derived within a further decoupling approximation. We study all methods numerically for fully asymmetric Sherrington-Kirkpatrick models, varying the data length, system size, temperature, and external field. Good convergence is observed in accordance with the theoretical expectations. PMID- 23745851 TI - Local response of topological order to an external perturbation. AB - We study the behavior of the Renyi entropies for the toric code subject to a variety of different perturbations, by means of 2D density matrix renormalization group and analytical methods. We find that Renyi entropies of different index alpha display derivatives with opposite sign, as opposed to typical symmetry breaking states, and can be detected on a very small subsystem regardless of the correlation length. This phenomenon is due to the presence in the phase of a point with flat entanglement spectrum, zero correlation length, and area law for the entanglement entropy. We argue that this kind of splitting is common to all the phases with a certain group theoretic structure, including quantum double models, cluster states, and other quantum spin liquids. The fact that the size of the subsystem does not need to scale with the correlation length makes it possible for this effect to be accessed experimentally. PMID- 23745853 TI - Crossover from growing to stationary interfaces in the Kardar-Parisi-Zhang class. AB - This Letter reports on how the interfaces in the (1+1)-dimensional Kardar-Parisi Zhang (KPZ) class undergo, in the course of time, a transition from the flat, growing regime to the stationary one. Simulations of the polynuclear growth model and experiments on turbulent liquid crystal reveal universal functions of the KPZ class governing this transition, which connect the distribution and correlation functions for the growing and stationary regimes. This in particular shows how interfaces realized in experiments and simulations actually approach the stationary regime, which is never attained unless a stationary interface is artificially given as an initial condition. PMID- 23745852 TI - Generic, hierarchical framework for massively parallel Wang-Landau sampling. AB - We introduce a parallel Wang-Landau method based on the replica-exchange framework for Monte Carlo simulations. To demonstrate its advantages and general applicability for simulations of complex systems, we apply it to different spin models including spin glasses, the Ising model, and the Potts model, lattice protein adsorption, and the self-assembly process in amphiphilic solutions. Without loss of accuracy, the method gives significant speed-up and potentially scales up to petaflop machines. PMID- 23745854 TI - Applications of an 88Y/Be photoneutron calibration source to dark matter and neutrino experiments. AB - The low-energy monochromatic neutron emission from an (88)Y/Be source can be exploited to mimic the few keV(nr) nuclear recoils expected from low-mass weakly interacting massive particles and coherent scattering of neutrinos off nuclei. Using this source, a MU(+)MU(-)MU(+)MU(-) decays. AB - A search for the decays B(0)((s))->MU(+)MU(-)MU(+)MU(-) and B(0)->MU(+)MU( )MU(+)MU(-) is performed using data, corresponding to an integrated luminosity of 1.0 fb(-1), collected with the LHCb detector in 2011. The number of candidates observed is consistent with the expected background and, assuming phase-space models of the decays, limits on the branching fractions are set: B(B(s)(0) >MU(+)MU(-)MU(+)MU(-))<1.6(1.2)*10(-8) and B(B(0)->MU(+)MU(-)MU(+)MU( ))<6.6(5.3)*10(-9) at 95% (90%) confidence level. In addition, limits are set in the context of a supersymmetric model which allows for the B((s))(0) meson to decay into a scalar (S) and pseudoscalar particle (P), where S and P have masses of 2.5 GeV/c and 214.3 MeV/c, respectively, both resonances decay into MU(+)MU( ). The branching fraction limits for these decays are B(B(s)(0)->SP)<1.6(1.2)*10( 8) and B(B(0)->SP)<6.3(5.1)*10(-9) at 95% (90%) confidence level. PMID- 23745879 TI - Finite-time transport in volume-preserving flows. AB - Finite-time transport between distinct flow regions is of great relevance to many scientific applications, yet quantitative studies remain scarce to date. The primary obstacle is computing the evolution of material volumes, which is often infeasible due to extreme interfacial stretching. We present a framework for describing and computing finite-time transport in n-dimensional (chaotic) volume preserving flows that relies on the reduced dynamics of an (n-2)-dimensional "minimal set" of fundamental trajectories. This approach has essential advantages over existing methods: the regions between which transport is investigated can be arbitrarily specified; no knowledge of the flow outside the finite transport interval is needed; and computational effort is substantially reduced. We demonstrate our framework in 2D for an industrial mixing device. PMID- 23745880 TI - Many-body contact repulsion of deformable disks. AB - We use a spring-and-plaquette network model to analyze the repulsion between elastic disks in contact. By studying various 2D geometries, we find that as disks approach the incompressibility limit the many-body effects become dominant and the disk-disk interaction is not pairwise additive. Upon compression, the disks undergo a transition from the localized to the distributed deformation regime accompanied by a steep increase of energy consistent with the onset of a hard core. These results shed new light on the structures formed by deformable objects such as soft nanocolloids. PMID- 23745881 TI - Probing small-scale intermittency with a fluctuation theorem. AB - We characterize statistical properties of the flow field in developed turbulence using concepts from stochastic thermodynamics. On the basis of data from a free air-jet experiment, we demonstrate how the dynamic fluctuations induced by small scale intermittency generate analogs of entropy-consuming trajectories with sufficient weight to make fluctuation theorems observable at the macroscopic scale. We propose an integral fluctuation theorem for the entropy production associated with the stochastic evolution of velocity increments along the eddy hierarchy and demonstrate its extreme sensitivity to the accurate description of the tails of the velocity distributions. PMID- 23745882 TI - Single flow snapshot reveals the future and the past of pairs of particles in turbulence. AB - We develop an analytic formalism and derive new exact relations that express the short-time dispersion of fluid particles via the single-time velocity correlation functions in homogeneous isotropic and incompressible turbulence. The formalism establishes a bridge between single-time Eulerian and long-time Lagrangian pictures of turbulent flows. In particular, we derive an exact formula for a short-term counterpart of the long-time Richardson law, and we identify a conservation law of turbulent dispersion which is true even in nonstationary turbulence. PMID- 23745883 TI - Ship wakes: Kelvin or Mach angle? AB - From the analysis of a set of airborne images of ship wakes, we show that the wake angles decrease as U(-1) at large velocities, in a way similar to the Mach cone for supersonic airplanes. This previously unnoticed Mach-like regime is in contradiction with the celebrated Kelvin prediction of a constant angle of 19.47 degrees independent of the ship's speed. We propose here a model, confirmed by numerical simulations, in which the finite size of the disturbance explains this transition between the Kelvin and Mach regimes at a Froude number Fr=U/?[gL]~/=0.5, where L is the hull ship length. PMID- 23745884 TI - Pore-scale mixing and transverse dispersivity of randomly packed monodisperse spheres. AB - We show that transverse dispersion in flow through randomly packed monodisperse spheres (sphere diameter d) is a velocity-dependent superposition of three separable random processes-diffusion with coefficient D(r), intrinsic mechanical dispersion with dispersivity l(m)=d/33 caused by advection on streamlines, and a newly identified coupled mechanical dispersion with dispersivity l(c)=d/11, which arises by coupled advection and transverse diffusion at the pore scale. The velocity dependence of the transverse dispersivity is derived from first principles. Our analysis is insensitive to details of the pore geometry and is verified by pulsed field gradient NMR experiments which covered 4.5 orders of magnitude in reduced velocity. PMID- 23745885 TI - Cascade of kinetic energy in three-dimensional compressible turbulence. AB - The conservative cascade of kinetic energy is established using both Fourier analysis and a new exact physical-space flux relation in a simulated compressible turbulence. The subgrid scale (SGS) kinetic energy flux of the compressive mode is found to be significantly larger than that of the solenoidal mode in the inertial range, which is the main physical origin for the occurrence of Kolmogorov's -5/3 scaling of the energy spectrum in compressible turbulence. The perfect antiparallel alignment between the large-scale strain and the SGS stress leads to highly efficient kinetic energy transfer in shock regions, which is a distinctive feature of shock structures in comparison with vortex structures. The rescaled probability distribution functions of SGS kinetic energy flux collapse in the inertial range, indicating a statistical self-similarity of kinetic energy cascades. PMID- 23745886 TI - Measurement of a structured backflow in an open small channel induced by surface tension gradients. AB - We present experiments in which the laterally confined flow of a surfactant film driven by controlled surface tension gradients causes the subtended liquid layer to self-organize into an inner upstream microduct surrounded by the downstream flow. The anomalous interfacial flow profiles and the concomitant backflow are a result of the feedback between two-dimensional and three-dimensional microfluidics realized during flow in open microchannels. Bulk and surface particle image velocimetry data combined with an interfacial hydrodynamics model explain the dependence of the observed phenomena on channel geometry. PMID- 23745887 TI - Magnetospheric energy principle for spherically symmetric monopolar magnetospheres. AB - A new magnetospheric energy principle is developed for spherically symmetric monopolar magnetospheres with open straight field lines. The principle is based on the self-adjointness of the force operator, which ensures energy conservation in the unperturbed magnetospheric plasma volume. A Neuman-type boundary condition for the perpendicular displacement at the ionosphere yields a negative contribution to the potential energy variation. This contribution makes high-mode number incompressible field-line-bending modes unstable owing to the plasma displacement over the spherical ionospheric surface. PMID- 23745888 TI - Wave-breaking phenomena in a relativistic magnetized plasma. AB - We study the wave-breaking phenomenon of relativistic upper-hybrid (UH) oscillations in a cold magnetoplasma. For our purposes, we use the electron continuity and relativistic electron momentum equations, together with Maxwell's equations, as well as introduce Lagrangian coordinates to obtain an exact nonstationary solution of the governing nonlinear equations. It is found that bursts in the electron density appear in a finite time as a result of relativistic electron mass variations in the UH electric field, indicating a phase mixing or breaking of relativistic UH oscillations. We highlight the relevance of our investigation of the UH wave phase-mixing or UH wave-breaking process to electron energization and plasma particle heating. PMID- 23745889 TI - Influence of ion mass on laser-energy absorption and synchrotron radiation at ultrahigh laser intensities. AB - The role of ions in the energy absorption of a short and ultraintense laser pulse and in the synchrotron radiation generated by accelerated electrons is revisited. For laser intensities above 10(22) W/cm(2) and plasma densities more than 10 times the critical density, the ion-to-electron mass ratio strongly affects the energy repartition between the electrons, ions, and radiation. This phenomenon is studied with a one-dimensional relativistic particle-in-cell code, taking into account the radiation reaction force. The choice of the ion mass strongly affects the energy and angular distribution of the photon emission and the electron energy distribution. This effect may be important for laboratory modeling of radiation dominated relativistic astrophysical events. It can be verified in experiments with solid hydrogen targets. PMID- 23745890 TI - Enhanced proton acceleration by an ultrashort laser interaction with structured dynamic plasma targets. AB - We experimentally demonstrate a notably enhanced acceleration of protons to high energy by relatively modest ultrashort laser pulses and structured dynamical plasma targets. Realized by special deposition of snow targets on sapphire substrates and using carefully planned prepulses, high proton yields emitted in a narrow solid angle with energy above 21 MeV were detected from a 5 TW laser. Our simulations predict that using the proposed scheme protons can be accelerated to energies above 150 MeV by 100 TW laser systems. PMID- 23745891 TI - Negative-mass instability in nonlinear plasma waves. AB - The negative-mass instability, previously found in ion traps, appears as a distinct regime of the sideband instability in nonlinear plasma waves with trapped particles. As the bounce frequency of these particles decreases with the bounce action, bunching can occur if the action distribution is inverted in trapping islands. In contrast to existing theories that also infer instabilities from the anharmonicity of bounce oscillations, spatial periodicity of the islands turns out to be unimportant, and the particle distribution can be unstable even if it is flat at the resonance. An analytical model is proposed that describes both single traps and periodic nonlinear waves and concisely generalizes the conventional description of the sideband instability in plasma waves. The theoretical results are supported by particle-in-cell simulations carried out for a regime accentuating the negative-mass instability. PMID- 23745892 TI - Observation of ion acceleration and heating during collisionless magnetic reconnection in a laboratory plasma. AB - The ion dynamics in a collisionless magnetic reconnection layer are studied in a laboratory plasma. The measured in-plane plasma potential profile, which is established by electrons accelerated around the electron diffusion region, shows a saddle-shaped structure that is wider and deeper towards the outflow direction. This potential structure ballistically accelerates ions near the separatrices toward the outflow direction. Ions are heated as they travel into the high pressure downstream region. PMID- 23745893 TI - Fractional topological states of dipolar fermions in one-dimensional optical superlattices. AB - We study the properties of dipolar fermions trapped in one-dimensional bichromatic optical lattices and show the existence of fractional topological states in the presence of strong dipole-dipole interactions. We find some interesting connections between fractional topological states in one-dimensional superlattices and the fractional quantum Hall states: (i) the one-dimensional fractional topological states for systems at filling factor nu=1/p have p-fold degeneracy, (ii) the quasihole excitations fulfill the same counting rule as that of fractional quantum Hall states, and (iii) the total Chern number of p-fold degenerate states is a nonzero integer. The existence of crystalline order in our system is also consistent with the thin-torus limit of the fractional quantum Hall state on a torus. The possible experimental realization in cold atomic systems offers a new platform for the study of fractional topological phases in one-dimensional superlattice systems. PMID- 23745894 TI - Kibble-Zurek scaling and its breakdown for spontaneous generation of Josephson vortices in Bose-Einstein condensates. AB - Atomic Bose-Einstein condensates confined to a dual-ring trap support Josephson vortices as topologically stable defects in the relative phase. We propose a test of the scaling laws for defect formation by quenching a Bose gas to degeneracy in this geometry. Stochastic Gross-Pitaevskii simulations reveal a -1/4 power-law scaling of defect number with quench time for fast quenches, consistent with the Kibble-Zurek mechanism. Slow quenches show stronger quench-time dependence that is explained by the stability properties of Josephson vortices, revealing the boundary of the Kibble-Zurek regime. Interference of the two atomic fields enables clear long-time measurement of stable defects and a direct test of the Kibble-Zurek mechanism in Bose-Einstein condensation. PMID- 23745895 TI - Geometric mechanics of periodic pleated origami. AB - Origami structures are mechanical metamaterials with properties that arise almost exclusively from the geometry of the constituent folds and the constraint of piecewise isometric deformations. Here we characterize the geometry and planar and nonplanar effective elastic response of a simple periodically folded Miura ori structure, which is composed of identical unit cells of mountain and valley folds with four-coordinated ridges, defined completely by two angles and two lengths. We show that the in-plane and out-of-plane Poisson's ratios are equal in magnitude, but opposite in sign, independent of material properties. Furthermore, we show that effective bending stiffness of the unit cell is singular, allowing us to characterize the two-dimensional deformation of a plate in terms of a one dimensional theory. Finally, we solve the inverse design problem of determining the geometric parameters for the optimal geometric and mechanical response of these extreme structures. PMID- 23745896 TI - Residual stresses in glasses. AB - The history dependence of glasses formed from flow-melted steady states by a sudden cessation of the shear rate gamma[over ] is studied in colloidal suspensions, by molecular dynamics simulations and by mode-coupling theory. In an ideal glass, stresses relax only partially, leaving behind a finite persistent residual stress. For intermediate times, relaxation curves scale as a function of gamma[over ]t, even though no flow is present. The macroscopic stress evolution is connected to a length scale of residual liquefaction displayed by microscopic mean-squared displacements. The theory describes this history dependence of glasses sharing the same thermodynamic state variables but differing static properties. PMID- 23745897 TI - Nanostripe pattern of NaCl layers on Cu(110). AB - A sodium chloride monolayer on a Cu(110) surface gives rise to a highly corrugated periodic nanostripe pattern of the (100) lattice as observed by scanning tunneling microscopy and low-energy electron diffraction. As revealed by density-functional calculations, this pattern is a consequence of the frustration of the overlayer-substrate chemical bonding produced by epitaxial mismatch. The coexistence of regions of strong Cu-Cl covalent and weak nonbonding interactions leads to a chemically induced topographic modulation here realized in a two dimensional dielectric. The carpetlike growth of the NaCl layer across Cu step edges induces a distinct contrast inversion in the stripe pattern as a result of the change in epitaxial relationship due to the stacking sequence of the (110) Cu layers. It is demonstrated that the competition between local substrate-overlayer and intraoverlayer interactions can support a well-defined heteroepitaxial relationship of a ionic dielectric film and a metal surface, with important consequences for the nanoscale morphology and related properties. PMID- 23745898 TI - Layer-by-layer entangled spin-orbital texture of the topological surface state in Bi2Se3. AB - We study Bi(2)Se(3) by polarization-dependent angle-resolved photoemission spectroscopy and density-functional theory slab calculations. We find that the surface state Dirac fermions are characterized by a layer-dependent entangled spin-orbital texture, which becomes apparent through quantum interference effects. This explains the discrepancy between the spin polarization obtained in spin and angle-resolved photoemission spectroscopy-ranging from 20% to 85%-and the 100% value assumed in phenomenological models. It also suggests a way to probe the intrinsic spin texture of topological insulators, and to continuously manipulate the spin polarization of photoelectrons and photocurrents all the way from 0 to +/-100% by an appropriate choice of photon energy, linear polarization, and angle of incidence. PMID- 23745899 TI - Helical edge resistance introduced by charge puddles. AB - We study the influence of electron puddles created by doping of a 2D topological insulator on its helical edge conductance. A single puddle is modeled by a quantum dot tunnel coupled to the helical edge. It may lead to significant inelastic backscattering within the edge because of the long electron dwelling time in the dot. We find the resulting correction to the perfect edge conductance. Generalizing to multiple puddles, we assess the dependence of the helical edge resistance on the temperature and doping level and compare it with recent experimental data. PMID- 23745900 TI - Absence of metallicity in K-doped picene: importance of electronic correlations. AB - Potassium-doped picene (K(x)picene) has recently been reported to be a superconductor at x=3 with critical temperatures up to 18 K. Here we study the electronic structure of K-doped picene films by photoelectron spectroscopy and ab initio density functional theory combined with dynamical mean-field theory (DFT+DMFT). Experimentally we observe that, except for spurious spectral weight due to the lack of a homogeneous chemical potential at low K concentrations (x~1), the spectra always display a finite energy gap. This result is supported by our DFT+DMFT calculations which provide clear evidence that K(x)picene is a Mott insulator for integer doping concentrations x=1, 2, and 3. We discuss various scenarios to understand the discrepancies with previous reports of superconductivity and metallic behavior. PMID- 23745901 TI - Correlations in nonequilibrium Luttinger liquid and singular Fredholm determinants. AB - We study interaction-induced correlations in Luttinger liquid with multiple Fermi edges. Many-particle correlation functions are expressed in terms of Fredholm determinants det(1+AB[over ^]), where A(epsilon) and B(t) have multiple discontinuities in energy and time spaces. We propose a general asymptotic formula for this class of determinants and provide analytical and numerical support to this conjecture. This allows us to establish nonequilibrium Fermi-edge singularities of many-particle correlation functions. As an example, we calculate a two-particle distribution function characterizing genuinely nonequilibrium quantum correlations between left- and right-moving fermions that have left the interaction region. PMID- 23745902 TI - Superconductivity and the pseudogap in the two-dimensional Hubbard model. AB - Recently developed numerical methods have enabled the explicit construction of the superconducting state of the Hubbard model of strongly correlated electrons in parameter regimes where the model also exhibits a pseudogap and a Mott insulating phase. d(x(2)-y(2)) symmetry superconductivity is found to occur in proximity to the Mott insulator, but separated from it by a pseudogapped nonsuperconducting phase. The superconducting transition temperature and order parameter amplitude are found to be maximal at the onset of the normal-state pseudogap. The emergence of superconductivity from the normal state pseudogap leads to a decrease in the excitation gap. All of these features are consistent with the observed behavior of the copper-oxide superconductors. PMID- 23745903 TI - Magnetic structure of phase II in U(Ru(0.96)Rh(0.04))2Si2 determined by neutron diffraction under pulsed high magnetic fields. AB - We report neutron diffraction measurements on U(Ru(0.96)Rh(0.04))(2)Si(2) single crystal under pulsed high magnetic fields up to 30 T applied along the tetragonal c axis. The high-field experiments revealed that the field-induced phase II above 26 T corresponds to a commensurate up-up-down ferrimagnetic structure characterized by the wave vector q=(2/3,0,0) with the magnetic moments parallel to the c axis, which naturally explains the one-third magnetization plateau and the substantially changed Fermi surface in phase II. This a-axis modulated magnetic structure indicates that the phase II near the hidden order phase is closely related to the characteristic incommensurate magnetic fluctuations at Q(1)=(0.6,0,0) in the pure system URu(2)Si(2), in contrast to the pressure induced antiferromagnetic order at Q(0)=(1,0,0). PMID- 23745904 TI - Excitons and biexcitons in symmetric electron-hole bilayers. AB - Symmetric electron-hole bilayer systems have been studied at zero temperature using the diffusion quantum Monte Carlo method. A flexible trial wave function is used that can describe fluid, excitonic, and biexcitonic phases. We calculate condensate fractions and pair correlation functions for a large number of densities r(s) and layer separations d. At small d we find a one-component fluid phase, an excitonic fluid phase, and a biexcitonic fluid phase, and the transitions among them appear to be continuous. At d=0, excitons appear to survive down to about r(s)=0.5 a.u., and biexcitons form at r(s)>2.5 a.u. PMID- 23745905 TI - Nernst effect: evidence of local Kondo scattering in heavy fermions. AB - A distinctly temperature-dependent Nernst coefficient, nu, which is strongly enhanced over that of LaCu(2)Si(2), is observed between T=2 and 300 K for CeCu(2)Si(2) and Ce(0.8)La(0.2)Cu(2)Si(2). The enhanced nu(T) is determined by the asymmetry of the on-site Kondo (conduction electron -4f electron) scattering rate. Taking into account the measured Hall mobility, MU(H), the highly unusual thermopower, S, of these systems can be semiquantitatively described by S(T)= nu(T)/MU(H)(T), which explicitly demonstrates that the thermopower originates from the local Kondo scattering process over a wide temperature range from far above to well below the coherence temperature (~20 K for CeCu(2)Si(2)). Our results suggest that the Nernst effect can act as a proper probe of local charge carrier scattering. This promises to impact on exploring the unconventional enhancement of the thermopower in correlated materials suited for potential applications. PMID- 23745906 TI - Insulating behavior at the neutrality point in single-layer graphene. AB - The fate of the low-temperature conductance at the charge-neutrality (Dirac) point in a single sheet of graphene on boron nitride is investigated down to 20 mK. As the temperature is lowered, the peak resistivity diverges with a power-law behavior and becomes as high as several megohms per square at the lowest temperature, in contrast with the commonly observed saturation of the conductivity. As a perpendicular magnetic field is applied, our device remains insulating and directly transitions to the broken-valley-symmetry, nu=0 quantum Hall state, indicating that the insulating behavior we observe at zero magnetic field is a result of broken valley symmetry. Finally we discuss the possible origins of this effect. PMID- 23745907 TI - Importance of spin-orbit interaction for the electron spin relaxation in organic semiconductors. AB - Despite the great interest organic spintronics has recently attracted, there is only a partial understanding of the fundamental physics behind electron spin relaxation in organic semiconductors. Mechanisms based on hyperfine interaction have been demonstrated, but the role of the spin-orbit interaction remains elusive. Here, we report muon spin spectroscopy and time-resolved photoluminescence measurements on two series of molecular semiconductors in which the strength of the spin-orbit interaction has been systematically modified with a targeted chemical substitution of different atoms at a particular molecular site. We find that the spin-orbit interaction is a significant source of electron spin relaxation in these materials. PMID- 23745909 TI - High-dimensional topological insulators with quaternionic analytic Landau levels. AB - We study the three-dimensional topological insulators in the continuum by coupling spin-1/2 fermions to the Aharonov-Casher SU(2) gauge field. They exhibit flat Landau levels in which orbital angular momentum and spin are coupled with a fixed helicity. The three-dimensional lowest Landau level wave functions exhibit the quaternionic analyticity as a generalization of the complex analyticity of the two-dimensional case. Each Landau level contributes one branch of gapless helical Dirac modes to the surface spectra, whose topological properties belong to the Z(2) class. The flat Landau levels can be generalized to an arbitrary dimension. Interaction effects and experimental realizations are also studied. PMID- 23745908 TI - Reversal of the circular dichroism in angle-resolved photoemission from Bi2Te3. AB - The helical Dirac fermions at the surface of topological insulators show a strong circular dichroism which has been explained as being due to either the initial state spin angular momentum, the initial-state orbital angular momentum, or the handedness of the experimental setup. All of these interpretations conflict with our data from Bi(2)Te(3) which depend on the photon energy and show several sign changes. Our one-step photoemission calculations coupled to ab initio theory confirm the sign change and assign the dichroism to a final-state effect. Instead, the spin polarization of the photoelectrons excited with linearly polarized light remains a reliable probe for the spin in the initial state. PMID- 23745910 TI - Majorana-Klein hybridization in topological superconductor junctions. AB - We present a powerful and general approach to describe the coupling of Majorana fermions to external leads, of interacting or noninteracting electrons. Our picture has the Klein factors of bosonization appearing as extra Majorana fermions hybridizing with the physical ones. We demonstrate the power of this approach, analyzing a highly nontrivial SO(M) Kondo problem arising in topological superconductors with M Majorana-lead couplings, allowing for arbitrary M and for conduction electron interactions. Mapping the problem on a quantum Brownian motion model we find robust non-Fermi liquid behavior, even for Fermi liquid leads, and a quantum phase transition between insulating and Kondo regimes when the leads form Luttinger liquids. In particular, for M=4 we find a stable realization of the two-channel Kondo fixed point. Obtaining the linear conductance at low temperatures, we predict transport signatures of this Majorana Kondo-Luttinger physics. PMID- 23745911 TI - Electronic and magnetic properties of zigzag graphene nanoribbons on the (111) surface of Cu, Ag, and Au. AB - We carry out an ab initio study of the structural, electronic, and magnetic properties of zigzag graphene nanoribbons on Cu(111), Ag(111), and Au(111). Both, H-free and H-terminated nanoribbons are considered revealing that the nanoribbons invariably possess edge states when deposited on these surfaces. In spite of this, they do not exhibit a significant magnetization at the edge, with the exception of H-terminated nanoribbons on Au(111), whose zero-temperature magnetic properties are comparable to those of free-standing nanoribbons. These results are explained by the different hybridization between the graphene 2p orbitals and those of the substrates and, for some models, also by the charge transfer between the surface and the nanoribbon. Interestingly, H-free nanoribbons on Au(111) and Ag(111) exhibit two main peaks in the local density of states around the Fermi energy, which originate from different states and, thus, do not indicate edge magnetism. PMID- 23745912 TI - Dissipation and supercurrent fluctuations in a diffusive normal-metal superconductor ring. AB - A mesoscopic hybrid normal-metal-superconductor ring is characterized by a dense Andreev spectrum with a flux dependent minigap. To probe the dynamics of such a ring, we measure its linear response to a high frequency flux, in a wide frequency range, with a multimode superconducting resonator. We find that the current response contains, besides the well-known dissipationless Josephson contribution, a large dissipative component. At high frequency compared to the minigap and low temperature, we find that the dissipation is due to transitions across the minigap. In contrast, at lower frequency there is a range of temperature for which dissipation is caused predominantly by the relaxation of the Andreev states' population. This dissipative response, related via the fluctuation dissipation theorem to a nonintuitive zero frequency thermal noise of supercurrent, is characterized by a phase dependence dominated by its second harmonic, as predicted long ago but never observed thus far. PMID- 23745913 TI - Time-resolved optical reflectivity of the electron-doped Nd(2-x)Ce(x)CuO(4+delta) cuprate superconductor: evidence for an interplay between competing orders. AB - We use pump-probe spectroscopy to measure the photoinduced reflectivity DeltaR of the electron-doped cuprate superconductor Nd(2-x)Ce(x)CuO(4+delta) at a value of x near optimal doping, as a function of time, temperature, and laser fluence. We observe the onset of a negative DeltaR signal at T(*)~75 K, above the superconducting transition temperature, T(c), of 23 K. The relatively slow decay of DeltaR, compared to the analogous signal in hole doped compounds, allows us to resolve time-temperature scaling consistent with critical fluctuations. A positive DeltaR signal onsets at T(c) that we associate with superconducting order. We find that the two signals are strongly coupled below T(c), in a manner that suggests a repulsive interaction between superconductivity and another fluctuating order. PMID- 23745914 TI - Self-consistent dynamics of a Josephson junction in the presence of an arbitrary environment. AB - We derive microscopically the dynamics associated with the dc Josephson effect in a superconducting tunnel junction interacting with an arbitrary electromagnetic environment. To do so, we extend to superconducting junctions the so-called P(E) theory (see, e.g., Ingold and Nazarov, arXiv:cond-mat/0508728) that accurately describes the interaction of a nonsuperconducting tunnel junction with its environment. We show the dynamics of this system is described by a small set of coupled correlation functions that take into account both Cooper pair and quasiparticle tunneling. When the phase fluctuations are small the problem is fully solved self-consistently, using and providing the exact linear admittance Y(omega) of the interacting junction. PMID- 23745915 TI - Superharmonic long-range triplet current in a diffusive Josephson junction. AB - We study the Josephson current through a long ferromagnetic bilayer in the diffusive regime. For noncollinear magnetizations, we find that the current-phase relation is dominated by its second harmonic, which corresponds to the long-range coherent propagation of two triplet pairs of electrons. PMID- 23745916 TI - Tunneling spectroscopy of quasiparticle bound states in a spinful Josephson junction. AB - The spectrum of a segment of InAs nanowire, confined between two superconducting leads, was measured as function of gate voltage and superconducting phase difference using a third normal-metal tunnel probe. Subgap resonances for odd electron occupancy-interpreted as bound states involving a confined electron and a quasiparticle from the superconducting leads, reminiscent of Yu-Shiba-Rusinov states-evolve into Kondo-related resonances at higher magnetic fields. An additional zero-bias peak of unknown origin is observed to coexist with the quasiparticle bound states. PMID- 23745917 TI - Anomalous doping variation of the nodal low-energy feature of superconducting (Bi,Pb)2(Sr,La)2CuO(6+delta) crystals revealed by laser-based angle-resolved photoemission spectroscopy. AB - The nodal band dispersion in (Bi,Pb)(2)(Sr,La)(2)CuO(6+delta) (Bi2201) is investigated over a wide range of doping by using 7-eV laser-based angle-resolved photoemission spectroscopy. We find that the low-energy band renormalization ("kink"), recently discovered in Bi(2)Sr(2)CaCu(2)O(8+delta) (Bi2212), also occurs in Bi2201, but at a binding energy around half that in Bi2212. Surprisingly, the coupling energy dramatically increases with a decrease of carrier concentration, showing a sharp enhancement across the optimal doping. These properties (material and doping dependence of the coupling energy) demonstrate the significant correlation among the mode coupling, the energy gap close to the node, and the strong electron correlation. Our results suggest forward scattering arising from the interplay between the electrons and in-plane polarized acoustic phonon branch as the origin of the low-energy renormalization. PMID- 23745918 TI - Jamming behavior of domains in a spiral antiferromagnetic system. AB - Using resonant magnetic x-ray photon correlation spectroscopy, we show that the domains of a spiral antiferromagnet enter a jammed state at the onset of long range order. We find that the slow thermal fluctuations of the domain walls exhibit a compressed exponential relaxation with an exponent of 1.5 found in a wide variety of solidlike jammed systems and can be qualitatively explained in terms of stress release in a stressed network. As the temperature decreases, the energy barrier for fluctuations becomes large enough to arrest further domain wall fluctuations, and the domains freeze into a spatial configuration within 10 K of the Neel temperature. The relaxation times can be fitted with the Vogel Fulcher law as observed in polymers, glasses, and colloids, thereby indicating that the dynamics of domain walls in an ordered antiferromagnet exhibit some of the universal features associated with jamming behavior. PMID- 23745919 TI - Observation of electronic inhomogeneity and charge density waves in a bilayer La(2-2x)Sr(1+2x)Mn2O7 single crystal. AB - We employed a scanning tunneling microscope to image the (001) surface topography and local density of states (LDOS) in La(2-2x)Sr(1+2x)Mn(2)O(7) (x=0.32, LSMO) single crystals below the Curie temperature (T(C)~120 K). The LDOS maps revealed a stripelike modulation propagating along the tetragonal a axis with a wavelength of about 16 A, which is indicative of a charge density wave (CDW). The observed CDW in the x=0.32 sample is far from the Fermi surface nesting instability as compared with the data of angle resolved photoemission spectroscopy in an x=0.40 sample. The stripe model developed previously for cuprates can explain the observed CDW in our LSMO sample, indicating that competing interactions between localized and itinerant phases are the origin of the spatial modulations present intrinsically in cuprates and manganites. PMID- 23745920 TI - Comparing ultrafast demagnetization rates between competing models for finite temperature magnetism. AB - We investigate a recent controversy in ultrafast magnetization dynamics by comparing the demagnetization rates from two frequently used but competing descriptions for finite temperature magnetism, namely a rigid band structure Stoner-like approach and a system of localized spins. The calculations on the localized spin system show a demagnetization rate and time comparable to experimentally obtained values, whereas the rigid band approach yields negligible demagnetization, even when the microscopic spin-flip process is assumed to be instantaneous. This shows that rigid band structure calculations will never be in quantitative agreement with experiments, irrespective of the investigated microscopic scattering mechanism. PMID- 23745921 TI - Giant molecular magnetocapacitance. AB - Through investigating the spin-dependent charging energy of nanoscale systems, we introduce a new concept of intrinsic molecular magnetocapacitance (MC). In molecules and nanosize quantum dots that undergo a spin state transition, the MC can be as high as 12%. First-principles calculations demonstrate that in a number of nanoscale systems, the quantum capacitance is highly sensitive to the system spin and charge states. In single molecule junctions, one can exploit molecular MC through the Coulomb blockade effect by modulating the bias voltage and applying an external magnetic field, which turns electron conductance on or off. Detailed analysis on molecular nanomagnet Mn(3)O(sao)(3)( )(O(2)CMe)(H(2)O)(py)(3) shows a 6% MC with a switching field of ~40 T. Its MC can be further enhanced to 9.6% by placing the molecule above a dielectric surface, opening up new avenues for novel nanoscale materials design. Under current experimental conditions, the predicted molecular MC effect can be probed without substantial difficulties. PMID- 23745922 TI - X-ray imaging and multiferroic coupling of cycloidal magnetic domains in ferroelectric monodomain BiFeO3. AB - Magnetic domains at the surface of a ferroelectric monodomain BiFeO(3) single crystal have been imaged by hard x-ray magnetic scattering. Magnetic domains up to several hundred microns in size have been observed, corresponding to cycloidal modulations of the magnetization along the wave vector k=(delta,delta,0) and symmetry equivalent directions. The rotation direction of the magnetization in all magnetic domains, determined by diffraction of circularly polarized light, was found to be unique and in agreement with predictions of a combined approach based on a spin-model complemented by relativistic density-functional simulations. Imaging of the surface shows that the largest adjacent domains display a 120 degrees vortex structure. PMID- 23745923 TI - Possibility of direct observation of edge Majorana modes in quantum chains. AB - Several scenarios for the realization of edge Majorana modes in quantum chain systems, spin chains, chains of Josephson junctions, and chains of coupled cavities in quantum optics, are considered. For all these systems excitations can be presented as superpositions of a spinless fermion and a hole, characteristic of a Majorana fermion. We discuss the features of our exact solution with respect to possible experiments, in which edge Majorana fermions can be directly observed when studying magnetic, superconducting, and optical characteristics of such systems. PMID- 23745924 TI - Spatially homogeneous ferromagnetism below the enhanced Curie temperature in EuO(1-x) thin films. AB - We have used low-energy implanted muons as a volume sensitive probe of the magnetic properties of EuO(1-x) thin films. We find that static and homogeneous magnetic order persists up to the elevated T(C) in the doped samples, and the muon signal displays the double dome feature also observed in the sample magnetization. Our results appear incompatible with either the magnetic phase separation or bound magnetic polaron descriptions previously suggested to explain the elevated T(C), but are compatible with an RKKY-like interaction mediating magnetic interactions above 69 K. PMID- 23745925 TI - Thermal conductivity of Ho2Ti2O7 along the [111] direction. AB - Thermal transport measurements have been made on the spin-ice material Ho(2)Ti(2)O(7) in an applied magnetic field with both the heat current and the field parallel to the [111] direction for temperatures from 50 mK to 1.2 K. A large magnetic field >6 T is applied to suppress the magnetic contribution to the thermal conductivity in order to extract the lattice conductivity. The low field thermal conductivity thus reveals a magnetic field dependent contribution to the conductivity which both transfers heat and scatters phonons. We interpret these magnetic excitations as monopolelike excitations and describe their behavior via existing Debye-Huckel theory. PMID- 23745926 TI - Spin-current order in anisotropic triangular antiferromagnets. AB - We analyze instabilities of the collinear up-up-down state of a two-dimensional quantum spin-S spatially anisotropic triangular lattice antiferromagnet in a magnetic field. We find, within the large-S approximation, that near the end point of the plateau, the collinear state becomes unstable due to the condensation of two-magnon bound pairs rather than single magnons. The two-magnon instability leads to a novel two-dimensional vector chiral phase with alternating spin currents but no magnetic order in the direction transverse to the field. This phase breaks a discrete Z(2) symmetry but preserves a continuous U(1) one of rotations about the field axis. It possesses orbital antiferromagnetism and displays a magnetoelectric effect. PMID- 23745927 TI - Driving magnetostructural transitions in layered intermetallic compounds. AB - We report the dramatic effect of applied pressure and magnetic field on the layered intermetallic compound Pr(0.5)Y(0.5)Mn(2)Ge(2). In the absence of pressure or magnetic field this compound displays interplanar ferromagnetism at room temperature and undergoes an isostructural first order magnetic transition (FOMT) to an antiferromagnetic state below 158 K, followed by another FOMT at 50 K due to the reemergence of ferromagnetism as praseodymium orders (T(C)(Pr)). The application of a magnetic field drives these two transitions towards each other, whereas the application of pressure drives them apart. Pressure also produces a giant magnetocaloric effect such that a threefold increase of the entropy change associated with the lower FOMT (at T(C)(Pr)) is seen under a pressure of 7.5 kbar. First principles calculations, using density functional theory, show that this remarkable magnetic behavior derives from the strong magnetoelastic coupling of the manganese layers in this compound. PMID- 23745928 TI - Resonant x-ray diffraction study of the strongly spin-orbit-coupled mott insulator CaIrO3. AB - We performed resonant x-ray diffraction experiments at the L absorption edges for the post-perovskite-type compound CaIrO(3) with a (t(2g))^{5} electronic configuration. By observing the magnetic signals, we could clearly see that the magnetic structure was a striped ordering with an antiferromagnetic moment along the c axis and that the wave function of a t(2g) hole is strongly spin-orbit entangled, the J(eff)=1/2 state. The observed spin arrangement is consistent with theoretical work predicting a unique superexchange interaction in the J(eff)=1/2 state and points to the universal importance of the spin-orbit coupling in Ir oxides, independent of the octahedral connectivity and lattice topology. We also propose that nonmagnetic resonant scattering is a powerful tool for unraveling an orbital state even in a metallic iridate. PMID- 23745929 TI - Confinement and deconfinement of spinons in two dimensions. AB - We use Monte Carlo methods to study spinons in two-dimensional quantum spin systems, characterizing their intrinsic size lambda and confinement length Lambda. We confirm that spinons are deconfined, Lambda->infinity and lambda finite, in a resonating valence-bond spin-liquid state. In a valence-bond solid, we find finite lambda and Lambda, with lambda of a single spinon significantly larger than the bound state-the spinon is soft and shrinks as the bound state is formed. Both lambda and Lambda diverge upon approaching the critical point separating valence-bond solid and Neel ground states. We conclude that the spinon deconfinement is marginal in the lowest-energy state in the spin-1 sector, due to weak attractive spinon interactions. Deconfinement in the vicinity of the critical point should occur at higher energies. PMID- 23745930 TI - Model of the optical emission of a driven semiconductor quantum dot: phonon enhanced coherent scattering and off-resonant sideband narrowing. AB - We study the crucial role played by the solid-state environment in determining the photon emission characteristics of a driven quantum dot. For resonant driving, we predict a phonon enhancement of the coherently emitted radiation field with increasing driving strength, in stark contrast to the conventional expectation of a rapidly decreasing fraction of coherent emission with stronger driving. This surprising behavior results from thermalization of the dot with respect to the phonon bath and leads to a nonstandard regime of resonance fluorescence in which significant coherent scattering and the Mollow triplet coexist. Off resonance, we show that despite the phonon influence, narrowing of dot spectral sideband widths can occur in certain regimes, consistent with an experimental trend. PMID- 23745931 TI - High-pressure measurements of hydrogen phase IV using synchrotron infrared spectroscopy. AB - Phase IV of dense solid hydrogen has been identified by its infrared spectrum using high-pressure synchrotron radiation techniques. The spectrum exhibits a sharp vibron band at higher frequency and lower intensity than that for phase III, indicating the stability of molecular H(2) with decreased intermolecular interactions and charge transfer between molecules. A low-frequency vibron having a strong negative pressure shift indicative of strongly interacting molecules is also observed. The character of the spectrum is consistent with an anisotropic, mixed layer structure related to those recently predicted theoretically. Phase IV was found to be stable from 220 GPa (300 K) to at least 340 GPa (near 200 K), with the I-III-IV triple point located. Infrared transmission observed to the lowest photon energies measured places constraints on the electronic properties of the phase. PMID- 23745932 TI - Origin of efficiency roll-off in colloidal quantum-dot light-emitting diodes. AB - We study the origin of efficiency roll-off (also called "efficiency droop") in colloidal quantum-dot light-emitting diodes through the comparison of quantum-dot (QD) electroluminescence and photoluminescence. We find that an electric-field induced decrease in QD luminescence efficiency-and not charge leakage or QD charging (Auger recombination)-is responsible for the roll-off behavior, and use the quantum confined Stark effect to accurately predict the external quantum efficiency roll-off of QD light-emitting diodes. PMID- 23745933 TI - Nonlinear terahertz metamaterials via field-enhanced carrier dynamics in GaAs. AB - We demonstrate nonlinear metamaterial split ring resonators (SRRs) on GaAs at terahertz frequencies. For SRRs on doped GaAs films, incident terahertz radiation with peak fields of ~20-160 kV/cm drives intervalley scattering. This reduces the carrier mobility and enhances the SRR LC response due to a conductivity decrease in the doped thin film. Above ~160 kV/cm, electric field enhancement within the SRR gaps leads to efficient impact ionization, increasing the carrier density and the conductivity which, in turn, suppresses the SRR resonance. We demonstrate an increase of up to 10 orders of magnitude in the carrier density in the SRR gaps on semi-insulating GaAs. Furthermore, we show that the effective permittivity can be swept from negative to positive values with an increasing terahertz field strength in the impact ionization regime, enabling new possibilities for nonlinear metamaterials. PMID- 23745934 TI - Spontaneous emission control in a tunable hybrid photonic system. AB - We experimentally demonstrate control of the rate of spontaneous emission in a tunable hybrid photonic system that consists of two canonical building blocks for spontaneous emission control, an optical antenna and a mirror, each providing a modification of the local density of optical states (LDOS). We couple fluorophores to a plasmonic antenna to create a superemitter with an enhanced decay rate. In a superemitter analog of the seminal Drexhage experiment we probe the LDOS of a nanomechanically approached mirror. Because of the electrodynamic interaction of the antenna with its own mirror image, the superemitter traces the inverse of the LDOS enhancement provided by the mirror, in stark contrast to a bare source, whose decay rate is proportional to the mirror LDOS. PMID- 23745935 TI - Carrier lifetime in exfoliated few-layer graphene determined from intersubband optical transitions. AB - We report a femtosecond transient spectroscopy study in the near to middle infrared range, 0.8-0.35 eV photon energy, on graphene and few layer graphene single flakes. The spectra show an evolving structure of photoinduced absorption bands superimposed on the bleaching caused by Pauli blocking of the interband optically coupled states. Supported by tight-binding model calculations, we assign the photoinduced absorption features to intersubband transitions as the number of layers is increased. Interestingly, the intersubband photoinduced resonances show a longer dynamics than the interband bleaching, because of their independence from the absolute energy of the carriers with respect to the Dirac point. The dynamic of these intersubband transitions reflects the lifetime of the hot carriers and provides an elegant method to access it in this important class of semimetals. PMID- 23745936 TI - Anomalous dressing of Dirac fermions in the topological surface state of Bi2Se3, Bi2Te3, and Cu-doped Bi2Se3. AB - Quasiparticle dynamics on the topological surface state of Bi(2(3), Bi(2)Te(3), and superconducting Cu(x)Bi(2)Se(3) are studied by 7 eV laser-based angle resolved photoemission spectroscopy. We find strong mode couplings in the Dirac cone surface states at energies of ~3 and ~15-20 meV associated with an exceptionally large coupling constant lambda of ~3, which is one of the strongest ever reported for any material. This result is compatible with the recent observation of a strong Kohn anomaly in the surface phonon dispersion of Bi(2)Se(3), but it appears that the theoretically proposed "spin-plasmon" excitations realized in helical metals are also playing an important role. Intriguingly, the ~3 meV mode coupling is found to be enhanced in the superconducting state of Cu(x)Bi(2)Se(3). PMID- 23745937 TI - Spin backflow and ac voltage generation by spin pumping and the inverse spin Hall effect. AB - The spin current pumped by a precessing ferromagnet into an adjacent normal metal has a constant polarization component parallel to the precession axis and a rotating one normal to the magnetization. The former is now routinely detected as a dc voltage induced by the inverse spin Hall effect (ISHE). Here we compute ac ISHE voltages much larger than the dc signals for various material combinations and discuss optimal conditions to observe the effect. The backflow of spin is shown to be essential to distill parameters from measured ISHE voltages for both dc and ac configurations. PMID- 23745938 TI - Highly efficient noise-assisted energy transport in classical oscillator systems. AB - Photosynthesis is a biological process that involves the highly efficient transport of energy captured from the Sun to a reaction center, where conversion into useful biochemical energy takes place. Using a quantum description, Rebentrost et al. [New J. Phys. 11, 033003 (2009)] and Plenio and Huelga [New J. Phys. 10, 113019 (2008)] have explained this high efficiency as the result of the interplay between the quantum coherent evolution of the photosynthetic system and noise introduced by its surrounding environment. Even though one can always use a quantum perspective to describe any physical process, since everything follows the laws of quantum mechanics, is the use of quantum theory imperative to explain this high efficiency? Recently, it has been shown by Eisfeld and Briggs [Phys. Rev. E 85, 046118 (2012)] that a purely classical model can be used to explain main aspects of the energy transfer in photosynthetic systems. Using this approach, we demonstrate explicitly here that highly efficient noise-assisted energy transport can be found as well in purely classical systems. The wider scope of applicability of the enhancement of energy transfer assisted by noise might open new ways for developing new technologies aimed at enhancing the efficiency of a myriad of energy transfer systems, from information channels in microelectronic circuits to long-distance high-voltage electrical lines. PMID- 23745939 TI - Principles of adaptive sorting revealed by in silico evolution. AB - Many biological networks have to filter out useful information from a vast excess of spurious interactions. In this Letter, we use computational evolution to predict design features of networks processing ligand categorization. The important problem of early immune response is considered as a case study. Rounds of evolution with different constraints uncover elaborations of the same network motif we name "adaptive sorting." Corresponding network substructures can be identified in current models of immune recognition. Our work draws a deep analogy between immune recognition and biochemical adaptation. PMID- 23745940 TI - Cluster explosive synchronization in complex networks. AB - The emergence of explosive synchronization has been reported as an abrupt transition in complex networks of first-order Kuramoto oscillators. In this Letter we demonstrate that the nodes in a second-order Kuramoto model perform a cascade of transitions toward a synchronous macroscopic state, which is a novel phenomenon that we call cluster explosive synchronization. We provide a rigorous analytical treatment using a mean-field analysis in uncorrelated networks. Our findings are in good agreement with numerical simulations and fundamentally deepen the understanding of microscopic mechanisms toward synchronization. PMID- 23745941 TI - Comment on "Evidence of non-mean-field-like low-temperature behavior in the Edwards-Anderson spin-glass model". PMID- 23745942 TI - Yucesoy, Katzgraber, and Machta reply:. PMID- 23745944 TI - Multiscale measurement of cardiac energetics. AB - Herein we describe our laboratories' experimental methods for interrogating cardiac energetics at the organ (whole heart), tissue (trabecula) and perforated fibre (mitochondrial) levels. In whole heart and trabecula experiments, we focus on measuring pressure-volume (force-length) work and oxygen consumption (heat production) from which mechanical efficiency is derived. In both preparations (i.e. across scales differing by three orders of magnitude) we find efficiency values of 10%-15%. Mitochondrial experiments invoke a trio of titration protocols to yield information on oxygen consumption, ATP flux, membrane potential, electron leak and reactive oxygen species production, the latter two of which index energy transfer inefficiencies. PMID- 23745943 TI - Systematic review of duration and choice of systemic antibiotic therapy for acute haematogenous bacterial osteomyelitis in children. AB - AIM: Historically, children with acute osteomyelitis received 4-6 weeks of parenteral antibiotics; however, evidence to guide optimal duration of therapy is limited. This study aims to summarise the available evidence on the duration and choice of antimicrobial therapy for acute haematogenous osteomyelitis in children. METHODS: We systematically reviewed the literature on children with acute osteomyelitis to determine if shorter durations of antibiotic treatment compared with protracted treatment gave different cure rates. We also analysed studies for choice of antibiotics to determine differences in success rates. Randomised controlled trials, cohort studies, case-control studies and case series were eligible for inclusion. RESULTS: We identified six randomised controlled trials, three of which addressed duration of antibiotic use and three choice of antibiotic for acute osteomyelitis in children. We found 28 observational studies, 20 of which focused on duration and 22 of which allowed analysis of choice of antibiotic. A range of therapy durations and types of antibiotics were assessed. Only one small study looked at treatment of neonates. CONCLUSIONS: The quality of evidence on antibiotic treatment for acute osteomyelitis is limited, allowing only weak (GRADE 2B) recommendations. Our review suggests that early transition from intravenous to oral therapy, after 3-4 days in patients responding well, followed by oral therapy to a total of 3 weeks may be as effective as longer courses for uncomplicated acute osteomyelitis. This recommendation does not apply to neonates. PMID- 23745945 TI - Phytochemicals targeting genes relevant for type 2 diabetes. AB - Nutrigenomic approaches based on ethnopharmacology and phytotherapy concepts have revealed that type 2 diabetes mellitus (T2DM) may be susceptible to dietary intervention. Interaction between bioactive food components and the genome may influence cell processes and modulate the onset and progression of the disease. T2DM, characterized by insulin resistance and beta cell dysfunction, is one of the leading causes of death and disability. Despite the great advances that have been made in the understanding and management of this complex, multifactorial disease, T2DM has become a worldwide epidemic in the 21st century. Population and family studies have revealed a strong genetic component of T2DM, and a number of candidate genes have been identified in humans. Variations in the gene sequences such as single nucleotide polymorphisms, explain the individual differences in traits like disease susceptibility and response to treatment. A clear understanding of how nutrients affect the expression of genes should facilitate the development of individualized intervention and, eventually, treatment strategies for T2DM. Review of the literature identified many phytochemicals/extracts from traditional medicinal plants that can target diabetogenic genes. This review focuses on the genetic aspects of T2DM, nutrient modification of genes relevant for diabetes, and future prospects of nutritional therapy of T2DM. PMID- 23745946 TI - Identification of a Bacteriovorax sp. isolate as a potential biocontrol bacterium against snakehead fish-pathogenic Aeromonas veronii. PMID- 23745947 TI - Assessment of pharmacodynamic effects following oral administration of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules compared with crushed morphine sulfate controlled-release tablets and placebo in nondependent recreational opioid users. AB - OBJECTIVES: To compare the pharmacodynamic effects, including self-reports of "drug liking" and "high," of crushed morphine sulfate and naltrexone hydrochloride extended-release capsules (MSN), crushed morphine sulfate controlled-release (CR) tablets, and placebo in an abuse potential study. DESIGN: Randomized, double-blind, placebo-controlled, three-way crossover study. SETTING: Single-center. SUBJECTS: Nondependent recreational opioid users. INTERVENTIONS: Orally administered crushed MSN (120-mg morphine sulfate and 4.8-mg naltrexone hydrochloride), crushed 120-mg morphine sulfate CR, and placebo. OUTCOME MEASURES: Subjective ratings (100-point visual analog scales) of positive drug effects (drug liking, high, good effects, take drug again, and overall drug liking), any effects, and negative effects (bad effects, feel sick, nausea, sleepy, and dizzy), along with pupillometry, pharmacokinetic (PK), and safety assessments. RESULTS: Crushed morphine sulfate CR significantly increased ratings of all positive subjective measures relative to placebo (P < 0.0001). Crushed MSN significantly decreased all positive subjective ratings compared with morphine sulfate CR (P <= 0.005), but significantly increased ratings compared with placebo (P < 0.03). Peak pupil diameter was significantly larger for MSN than morphine sulfate (P < 0.0001). PK analysis of morphine plasma concentrations indicated that Cmax was significantly lower and tmax significantly longer for crushed MSN compared with crushed morphine sulfate CR. Plasma concentrations of naltrexone and 6-beta-naltrexol were present following crushed MSN. CONCLUSIONS: This study demonstrated that when crushed and administered orally to nondependent recreational opioid users, MSN was associated with significantly lower scores on all positive subjective measures including drug liking and high, and significantly less pupil constriction compared with crushed morphine sulfate CR. PMID- 23745948 TI - Formation/fate of reactive metabolites from general anesthetics and a comparison of toxic and non-toxic analogues: a DFT study. AB - Chloroform and Halothane are well known hepatotoxic anesthetics for which toxicity is attributed to their reactive metabolites. The molecular level details of reactions leading to the formation of reactive metabolites from chloroform and halothane have not been explored. Potential energy surface (PES) for the formation of phosgene (a toxic intermediate) from Chloroform has been studied using quantum chemical methods. The HOOH mediated reaction of chloroform to give phosgene has been found to be exothermic by 81.24 kcal/mol with a barrier of ~ 3 kcal/mol through the water catalyzed transition sate. The quantum chemical studies on the reactivity profile of phosgene indicated that urea derivatives need to be considered on the mechanism leading to toxicity. Similarly, metabolic pathways of Halothane oxidation have been studied. The C-H bond dissociation energies (BDE) and radical stabilization energies (RSE) for Chloroform and Halothane (< 95 kcal/mol and > 10 kcal/mol) were found to be significantly different for these toxic anesthetics in comparison to their safer analogues (> 100 kcal/mol and < 5 kcal/mol) respectively; thus these parameters can be employed to distinguish toxic and non-toxic general anesthetics. Enthalpy for the Cpd I, a widely used model for CYP450 enzymes, mediated reactions also agreed well with these results. PMID- 23745949 TI - Renal and hepatic kinetics of Tc-99m-labelled hexakis-methoxy-isobutyl Isonitrile. AB - OBJECTIVE: Technetium-99m-labelled hexakis-methoxy-isobutyl isonitrile (Tc-99m MIBI) is a substrate for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter protein, and can be used to image P-gp expression. The aim was to study normal kinetics of Tc-99m-MIBI in the kidney and liver to help understand physiological studies of P-gp expression in these organs. METHODS: Thirty healthy kidney transplant donors received intravenous Tc-99m-MIBI followed by dynamic scintigraphy for 20 min and static imaging at 30 and 120 min. Time-activity curves were generated from parenchymal ROI. An assumed mono-exponential Tc-99m MIBI blood clearance with rate constant of 0.3 min-1 was used to predict the Tc 99m- MIBI that would have accumulated in the organs had none left. The activities leaving were then calculated by subtraction and expressed as percentages of the predicted total accumulated activities. RESULTS: Kidney time-activity curves peaked at 2-4 min then declined to a plateau from ~15-16 min equal to 31 [SD 5]% of the total activity accumulated (corresponding to 69 [5]% rapidly eliminated) (phase 1). Bladder activity followed a similar but opposite time course. Between 30 and 120 min (phase 2), activity left at 0.36 (0.13) %.min-1. Liver curves peaked at 8-10 min. Differentiation of the elimination curve revealed that a variable proportion of tracer (5-56%; mean 30 [14]%) was rapidly excreted over ~11 min. From 30 min, activity left at 1.02 (0.23) %.min-1. There was no correlation between renal and hepatic elimination rates in either phase or between early and late phase elimination rates in either organ. CONCLUSIONS: Early renal elimination is predominantly via glomerular filtration and urinary excretion. The liver rapidly excretes a more variable and lower proportion of Tc 99m-MIBI than the kidney. P-gp located at the urine/tubule and bile/hepatocyte boundaries prevents Tc-99m-MIBI re-entering cells and thereby influences elimination and retention in both phases, although other ABC transporters are probably also involved. PMID- 23745950 TI - Attenuated total reflectance-FT-IR spectroscopy for gunshot residue analysis: potential for ammunition determination. AB - The ability to link a suspect to a particular shooting incident is a principal task for many forensic investigators. Here, we attempt to achieve this goal by analysis of gunshot residue (GSR) through the use of attenuated total reflectance (ATR) Fourier transform infrared spectroscopy (FT-IR) combined with statistical analysis. The firearm discharge process is analogous to a complex chemical process. Therefore, the products of this process (GSR) will vary based upon numerous factors, including the specific combination of the firearm and ammunition which was discharged. Differentiation of FT-IR data, collected from GSR particles originating from three different firearm-ammunition combinations (0.38 in., 0.40 in., and 9 mm calibers), was achieved using projection to latent structures discriminant analysis (PLS-DA). The technique was cross (leave-one out), both internally and externally, validated. External validation was achieved via assignment (caliber identification) of unknown FT-IR spectra from unknown GSR particles. The results demonstrate great potential for ATR-FT-IR spectroscopic analysis of GSR for forensic purposes. PMID- 23745951 TI - Genetic connections among Turkic-speaking Iranian ethnic groups based on HLA class II gene diversity. AB - Iran is a linguistically heterogeneous nation where Persian, Turkic and Arabic are the three main language families spoken. Based on their linguistic properties, Qashqais, Turkmens and Azeris are Turkic-speaking people. The purpose of this study was to investigate whether any genetic relationship exists among the Turkic-speaking Iranian subpopulations based on HLA class II gene diversity. HLA-DRB1, DQA1 and DQB1 alleles were identified by PCR-based methods in 100 Qashqais and 66 Turkmens, and the results were compared with our previously published HLA data for Azeris. Despite a number of allelic and haplotypic similarities, Qashqais, Turkmens and Azeris were not in the same clade of the phylogenetic tree. However, based on the results of principal coordinates analysis, they are grouped together with Kurds and Bakhtiaris. Contrary to their common linguistic features, the Turkic-speaking people of Iran are closer to other Iranian subpopulations than to the people of Turkey and central Asia. Overall, it seems that linguistic criteria alone are not able to determine the relationships among these populations, and a combination of different kinds of anthropological information should be used to determine their actual phylogenetic relationships. PMID- 23745952 TI - Motor assessment in pediatric neuropsychology: relationships to executive function. AB - Executive function often refers to control behaviors such as "initiating," "sustaining," "inhibiting," and "switching." These mechanisms contribute to regulation of thinking and emotion but can be observed most clearly in the motor system. Neuropsychology has been influenced by "top-down" models of cognitive control that emerged from information-processing theories of cognition. In fact, neural models provide evidence that control processes are highly interactive within the cortico-striatal-cerebellar circuits. Cognition unfolds in response to motor-driven adaptation, and evidence exists for similar firing of brain cells and circuits during "imagined action" as in actual motor behavior. The motor system develops early and yet is not routinely assessed in neuropsychological evaluation of children with neurodevelopmental disorders. This article reviews some of the approaches to motor assessment that have sensitivity to neurodevelopmental disorders, and advocates for inclusion of motor assessment, particularly in evaluating control processes independent of culture, language, and other confounders. PMID- 23745953 TI - Emergency room access for recurring seizures: when and why. AB - BACKGROUND AND PURPOSE: To develop a hypothetical model identifying potentially modifiable predictive factors of Emergency Room (ER) visits by patients suffering from drug resistant epilepsy. METHODS: During a 1-year period, all adult drug resistant patients followed by the same epileptologist were recruited after the occurrence of one or more epileptic attacks. They were divided into two groups based on whether they went to the ER after seizures. A prospective comparative analysis of the clinical and social characteristics of the two groups was performed in order to identify independent predictors of ER visits. Logistic regression analysis was used to confirm the potential predictive role of the evaluated variables. RESULTS: Logistic regression analysis confirmed the potential role in predicting ER visits for these variables: foreign nationality, current psychiatric therapy, current antiepileptic drug polytherapy, comorbidities, more than one episode in the same day and changes in usual seizure pattern. A relevant association was also found between the frequency of ER neuroimaging use and the following variables: occurrence of episodes on holidays or weekends, current antiepileptic drug monotherapy, multiple comorbidities and brain injury after seizure. CONCLUSIONS: The present study evaluated factors, some potentially amenable to change, related to drug resistant epileptic patients' ER visits following a seizure. This information may serve to improve the clinical and therapeutic management of patients, decrease the need for urgent care and reduce subsequent patient stress and related costs. PMID- 23745954 TI - Preference, satisfaction and errors with two dry powder inhalers in patients with COPD. AB - OBJECTIVE: To assess preference, satisfaction and critical errors with a novel, breath-actuated, multi-dose dry powder inhaler (DPI; Genuair(r)/PressairTM), versus a widely used, single-dose DPI (HandiHaler(r)) in patients with moderate to-severe chronic obstructive pulmonary disease. METHODS: In this randomised, open-label, multicentre, cross-over study, patients (aged >= 40 years) inhaled placebo once daily through both inhalers for 2 weeks in addition to current medication. The primary end point was percentage of patients who preferred Genuair to HandiHaler. Overall patient satisfaction (5-point scale: 1 = very dissatisfied; 5 = very satisfied), critical errors and willingness to continue using each inhaler (0 = not willing; 100 = definitely willing) were assessed. RESULTS: Of 130 patients randomised, 105 were included in the intent-to-treat population (71.4% male; mean age 65.7 years). After 2 weeks, significantly more patients preferred Genuair than HandiHaler (79.1 vs 20.9%; p < 0.0001). Overall satisfaction scores (4.6 vs 3.8; p < 0.0001) and willingness to continue use scores (84.0 vs 62.5; p < 0.0001) were significantly higher with Genuair versus HandiHaler. Significantly fewer patients made >= 1 critical error with Genuair only compared with HandiHaler only (2.9 vs 19.0%; p < 0.0001). CONCLUSION: After 2 weeks' practice, patients preferred and were more willing to continue using Genuair than HandiHaler. Genuair was associated with higher patient satisfaction and fewer critical errors than HandiHaler. PMID- 23745955 TI - Effect of mycophenolic acid and bortezomib on purified human B cells: an in vitro study of long-term functionally stable MICA-sensitized renal recipients. AB - OBJECTIVES: We sought to develop a B-cell in vitro culture system and test B cells isolated from sensitized kidney recipients and healthy controls, and assess the effectiveness of proteasome inhibitors and mycophenolic acid on antibody secretion and cell apoptosis. MATERIALS AND METHODS: CD19(+) B cells and CD19(+)CD27(+) memory B-cell subsets were detected from peripheral blood mononuclear cells obtained from 6 MICA-sensitized kidney recipients and 6 healthy controls. Peripheral blood B cells were isolated and cultured with CpG2006, PMA, MICA antigen, B-cell activating factor, CD40 ligand (CD40L), human recombinant IL 2 (rhuIL-2), rhuIL-10, rhuIL-4, and rhuIL-21. After culturing for 7 days, we tested several variables of B-cell activity including differentiation, apoptosis, and IgM production. We also assessed the effects of 2 immunosuppressive drugs (mycophenolic acid and bortezomib) on antibody secretion and cellular apoptosis. RESULTS: Kidney recipients had a lower ratio of CD19+ B cells in peripheral blood mononuclear cells than did healthy controls. However, the percentage of CD19(+)CD27(+) B cells was higher in kidney recipients than in healthy controls. In the cell stimulation culture system, the ratio of CD19(+) B cells, CD19(+)CD27(+) B cells, and CD19(+)CD138(+) B cells increased after culturing for 7 days compared with unstimulated controls. In addition, the percentage of apoptotic B cells decreased, and antibody production increased in sensitized transplant patients and healthy controls. Treatment with bortezomib or mycophenolic acid induced B-cell apoptosis and inhibited secretion of antibodies. CONCLUSIONS: This study describes establishment of a B-cell in vitro culture system, showing that B cells may be stimulated to secrete antibodies. The study also provides an assay for studying B cells in vitro. This study provides information suggesting that bortezomib and mycophenolic acid can inhibit B-cell antibody secretion. PMID- 23745956 TI - Alarms are still a problem! PMID- 23745957 TI - Insight into the effects of biochar on manure composting: evidence supporting the relationship between N2O emission and denitrifying community. AB - Although nitrous oxide (N2O) emissions from composting contribute to the accelerated greenhouse effect, it is difficult to implement practical methods to mitigate these emissions. In this study, the effects of biochar amendment during pig manure composting were investigated to evaluate the inter-relationships between N2O emission and the abundance of denitrifying bacteria. Analytical results from two pilot composting treatments with (PWSB, pig manure + wood chips + sawdust + biochar) or without (PWS, pig manure + wood chips + sawdust) biochar (3% w/w) demonstrated that biochar amendment not only lowered NO2(-)-N concentrations but also lowered the total N2O emissions from pig manure composting, especially during the later stages. Quantification of functional genes involved in denitrification and Spearman rank correlations matrix revealed that the N2O emission rates correlated with the abundance of nosZ, nirK, and nirS genes. Biochar-amended pig manure had a higher pH and a lower moisture content. Biochar amendment altered the abundance of denitrifying bacteria significantly; less N2O-producing and more N2O-consuming bacteria were present in the PWSB, and this significantly lowered N2O emissions in the maturation phase. Together, the results demonstrate that biochar amendment could be a novel greenhouse gas mitigation strategy during pig manure composting. PMID- 23745958 TI - Hydrogeologic controls on induced seismicity in crystalline basement rocks due to fluid injection into basal reservoirs. AB - A series of Mb 3.8-5.5 induced seismic events in the midcontinent region, United States, resulted from injection of fluid either into a basal sedimentary reservoir with no underlying confining unit or directly into the underlying crystalline basement complex. The earthquakes probably occurred along faults that were likely critically stressed within the crystalline basement. These faults were located at a considerable distance (up to 10 km) from the injection wells and head increases at the hypocenters were likely relatively small (~70-150 m). We present a suite of simulations that use a simple hydrogeologic-geomechanical model to assess what hydrogeologic conditions promote or deter induced seismic events within the crystalline basement across the midcontinent. The presence of a confining unit beneath the injection reservoir horizon had the single largest effect in preventing induced seismicity within the underlying crystalline basement. For a crystalline basement having a permeability of 2 * 10(-17) m(2) and specific storage coefficient of 10(-7) /m, injection at a rate of 5455 m(3) /d into the basal aquifer with no underlying basal seal over 10 years resulted in probable brittle failure to depths of about 0.6 km below the injection reservoir. Including a permeable (kz = 10(-13) m(2) ) Precambrian normal fault, located 20 m from the injection well, increased the depth of the failure region below the reservoir to 3 km. For a large permeability contrast between a Precambrian thrust fault (10(-12) m(2) ) and the surrounding crystalline basement (10(-18) m(2) ), the failure region can extend laterally 10 km away from the injection well. PMID- 23745959 TI - Longitudinal ultradeep characterization of HIV type 1 R5 and X4 subpopulations in patients followed from primary infection to coreceptor switch. AB - In early infection HIV-1 generally uses the CCR5 coreceptor. During disease progression the coreceptor use switches to include CXCR4 in approximately 70% of infected individuals. The primary determinant for coreceptor use is located in the V3 loop of the viral envelope. Here, ultradeep pyrosequencing (UDPS) of the V3 loop was used to investigate if CXCR4-using (X4) virus may be present as a minority population during primary HIV infection (PHI). Three patients with HIV populations that switched coreceptor use, as determined by the MT-2 cell culture assay, were investigated. Longitudinally collected plasma samples (four to nine samples per patient) obtained from PHI until after coreceptor switch were analyzed by UDPS of the V3 loop. From each sample between 279 and 32,094 reads were generated based on template molecule availability. UDPS analysis showed that the X4 virus that emerged after switch was not present during PHI or prior to overt phenotypic switch. In addition, the phylogenetic analyses indicated that the X4 populations originated from R5 variants that had evolved after the previous R5-only sample was obtained. Finally, one to three major variants were found during PHI, supporting the idea that infection is established with one or just a few viral particles. PMID- 23745960 TI - Relationships between sleep disruptions, health and care responsibilities among mothers of school-aged children with disabilities. AB - AIM: Sleep problems are more common among children with disabilities. Mothers are likely to provide night-time care. Mothers of children with disabilities are known to experience high levels of stress and mental health issues compared with other mothers. Relationships between a child's sleep problems, and chronic maternal sleep interruption and subjective health have not been researched. METHOD: Cross-sectional mail-out survey with follow-up phone call was used. Instruments included the Short Form 36 version 2 and instruments that measured maternal, child and sleep characteristics. Descriptive statistics examined characteristics of participants and correlation, and Kruskal-Wallis test was used to determine important maternal and child characteristics around sleep issues. RESULTS: All mothers (n = 152) cared for a school-aged child with a developmental disability including autism spectrum disorder (n = 94) and cerebral palsy (n = 29). Nearly half (49%) of the mothers were awoken more than 4 nights/week. Three distinct sleep groups were identified: no sleep interruption; sleep interruption once/night, 4 nights/week; and more frequent interruption. Mothers experiencing the most sleep interruptions reported significantly poorer health on six Short Form 36 version 2 dimensions. Night-time caregiving was associated with higher child care needs rather than children's diagnoses. Mothers who experienced more sleep interruption also participated less in health-promoting activities (active leisure, time with socially supportive others) during the day. CONCLUSION: This study identifies a group of mothers with chronic sleep interruption and demonstrates related poor maternal subjective health and lower participation in health activities that may service to support maternal health. Mothers with children with the highest daytime care needs also experienced high night-time care responsibilities. Changes to service provision are recommended to identify mothers in need of additional supports and services. PMID- 23745961 TI - Kinetic study of the inhibition mechanism of dehaloperoxidase-hemoglobin a by 4 bromophenol. AB - The mechanism of dehaloperoxidase-hemoglobin (DHP) inhibition by 4-bromophenol (4 BP) was investigated using Michealis-Menten and transient-state kinetic analyses. Transient-state kinetics using the stopped-flow technique to mix DHP and H2O2 in the presence of inhibitor concentrations less than 10-fold greater than the enzyme concentration show that 4-BP does not fully impede H2O2 entering the distal pocket to activate DHP. It is not clear whether an oxoferryl intermediate is formed under these conditions and there may be alternative pathways for H2O2 reaction in the 4-BP bound form of DHP. Two new species have been identified during the reaction of 4-BP bound form of DHP in the transient-state kinetic experiment by using Singular Value Decomposition (SVD) and global-fitting analysis. Rather than forming Compound ES in the unbound form, an inhibitor bound intermediate that possesses blue-shifted Soret band and a double peaked Q-band is observed. This intermediate is subsequently converted to the end-point species that is distinguished from Compound RH formed in the uninhibited enzyme. Bench top mixing kinetics of DHP were conducted in order to determine the inhibitor binding constant and to understand the enzyme inhibition mechanism from a thermodynamic perspective. It was found that the inhibition constant, Ki, decreased from 2.56 mM to 0.15 mM over the temperature range from 283 to 298 K, which permits determination of the enthalpy and entropy for inhibitor binding as 135.5 +/- 20.9 kJ/mol and 526.1 +/- 71.9 J/(mol.K), respectively, leading to the conclusion that inhibitor binding is entropically driven. PMID- 23745962 TI - Maternal dietary intake during pregnancy has longstanding consequences for the health of her offspring. AB - Over the past 100 years, advances in pharmaceutical and medical technology have reduced the burden of communicable disease, and our appreciation of the mechanisms underlying the development of noncommunicable disease has broadened. During this time, a number of studies, both in humans and animal models, have highlighted the importance of maintaining an optimal diet during pregnancy. In particular, a number of studies support the hypothesis that suboptimal maternal protein and fat intake during pregnancy can have long-term effects on the growing fetus, and increase the likelihood of these offspring developing cardiovascular, renal, or metabolic diseases in adulthood. More recently, it has been shown that dietary intake of a number of micronutrients may offset or reverse the deleterious effects of macronutrient imbalance. Furthermore, maternal fat intake has also been identified as a major contributor to a healthy fetal environment, with a beneficial role for unsaturated fats during development as well as a beneficial impact on cell membrane physiology. Together these studies indicate that attempts to optimise maternal nutrition may prove to be an efficient and cost-effective strategy for preventing the development of cardiovascular, renal, or metabolic diseases. PMID- 23745963 TI - Diffuse scalp alopecia in a middle-aged patient. PMID- 23745965 TI - Long-term safety of ustekinumab for psoriasis. AB - INTRODUCTION: The biologic, Ustekinumab (Stelara(r), Centocor, Inc., Malvern, PA, USA), is a fully human monoclonal antibody with a high affinity for the shared p40 subunit of interleukins 12 and 23 (IL-12 and IL-23). Approved for use in treating moderate-to-severe psoriasis in 2009, there has been considerable interest in the long-term safety of ustekinumab. AREAS COVERED: This review discusses the use of ustekinumab in the treatment of psoriasis and its potential to be an effective and well-tolerated therapy. A literature search was performed for articles published through April 2013 to identify any safety concerns. EXPERT OPINION: Our results indicate that ustekinumab has demonstrated higher efficacy rates as compared to traditional therapies; and with a favorable dosing schedule and stable safety profile, patients with recalcitrant disease will now have another option for treatment. PMID- 23745964 TI - Clinical evaluation of salivary periodontal pathogen levels by real-time polymerase chain reaction in patients before dental implant treatment. AB - OBJECTIVE: Periodontal pathogens in dental plaque are the main causative agents of periodontitis and peri-implantitis. Detection of the presence of such periodontal pathogens early would serve as a useful tool in the diagnosis and treatment of this disease. Therefore, the purpose of this study was to investigate whether the periodontal pathogen levels in saliva were correlated with the periodontal status of patients receiving implant treatment. MATERIALS AND METHODS: A total of 291 patients visiting Tokyo Dental College Chiba Hospital were divided into four groups: a no-periodontitis (np) group, a mild periodontitis (mip) group, a moderate-periodontitis (mop) group, and a severe periodontitis (sp) group. The levels of the following five periodontal pathogens in saliva were evaluated using real-time polymerase chain reaction: Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Treponema denticola, and Prevotella intermedia. RESULTS: The levels of P. gingivalis and T. forsythia were significantly higher in mop group than in np group (P < 0.05). The levels of all periodontal pathogens tested except A. actinomycetemcomitans were significantly higher in sp group than in np group (P < 0.05). CONCLUSION: The detection levels of the periodontal pathogens targeted in saliva samples were correlated with the periodontal status. This suggests that using saliva to screen for periodontopathic bacteria offers an easier-to-use clinical tool than the paper point method in the diagnosis and treatment of periodontitis and peri-implantitis. PMID- 23745966 TI - Preptin analogues: chemical synthesis, secondary structure and biological studies. AB - Peptide hormones that modulate insulin secretion have been recognized to have therapeutic potential, with peptides such as amylin (pramlintide acetate, Symlin) and exendin-4 (exenatide, Byetta) now commercially available. Preptin is a peptide that has been shown to increase insulin secretion in vitro and in vivo. Here, we describe the first chemical synthesis and analysis of a short series of preptin analogues based on the rat preptin sequence. Phe 21 in the preptin sequence was substituted with the non-protein amino acids D-Phe, D-Hphe, 3 aminobenzoic acid and 1-aminocyclooctane-1-carboxylic acid, which rendered the preptin analogues resistant to chymotryptic protease hydrolysis at this position. Substitution of Phe 21 with these non-protein amino acids did not abrogate the insulin secretory effect of preptin, with analogues showing a similar dose dependent effect on insulin secretion from betaTC6-F7 mouse beta-cells in both the presence and absence of glucose as unmodified rat preptin. Further studies on the stability of the preptin analogues and their effect on insulin secretion are in progress. PMID- 23745967 TI - Determination of fructooligosaccharides in burdock using HPLC and microwave assisted extraction. AB - The root of burdock ( Arctium lappa L.) is a commonly used vegetable in Asia. Fructooligosaccharides (FOS) are usually considered as its main bioactive components. Thus, quantitative analysis of these components is very important for the quality control of burdock. In this study, an HPLC-ELSD and microwave assisted extraction method was developed for the simultaneous determination of seven FOS with degrees of polymerization (DP) between 3 and 9, as well as fructose, glucose, and sucrose in burdock from different regions. The separation was performed on a Waters XBridge Amide column (4.6 * 250 mm i.d., 3.5 MUm) with gradient elution. All calibration curves for investigated analytes showed good linear regression (r > 0.9990). Their LODs and LOQs were lower than 3.63 and 24.82 MUg/mL, respectively. The recoveries ranged from 99.2 to 102.6%. The developed method was successfully applied to determination of ten sugars in burdock from different locations of Asia. The results showed that the contents of FOS in different samples of burdock collected at appropriate times were similar, and the developed HPLC-ELSD with microwave-assisted extraction method is helpful to control the quality of burdock. PMID- 23745968 TI - Intra-operative monitoring--many alarms with minor impact. AB - Alarms are key components of peri-operative monitoring devices, but a high false alarm rate may lead to desensitisation and neglect. The objective of this study was to quantify the number of alarms and assess the value of these alarms during moderate-risk surgery. For this purpose, we analysed documentation of anaesthesia workstations during 38 surgical procedures. Alarms were classified on technical validity and clinical relevance. The median (IQR [range]) alarm density per procedure was 20.8 (14.5-34.2 [3.7-85.6]) alarms.h-1 (1 alarm every 2.9 min) and increased during induction and emergence of anaesthesia, with up to one alarm per 0.99 min during these periods (p < 0.001). Sixty-four per cent of all alarms were clinically irrelevant, whereas 5% of all alarms required immediate intervention. The positive predictive value of an alarm during induction and emergence was 20% (95% CI 16-24%) and 11% (95% CI 8-14%), respectively. This study shows that peri operative alarms are frequently irrelevant, with a low predictive value for an emerging event requiring clinical intervention. PMID- 23745969 TI - Advancing pain care--core competencies for pain management. PMID- 23745970 TI - Life cycle assessment of hemp cultivation and use of hemp-based thermal insulator materials in buildings. AB - The aim of this research is to assess the sustainability of a natural fiber, such as hemp (Cannabis sativa), and its use as thermal insulator for building applications. The sustainability of hemp was quantified by life cycle assessment (LCA) and particular attention was given to the amount of CO2eq of the whole process, and the indicator greenhouse gas protocol (GGP) was selected to quantify CO2eq emissions. In this study also CO2 uptake of hemp was considered. Two different allocation procedures (i.e., mass and economic) were adopted. Other indicators, such as Cumulative Energy Demand (CED) and EcoIndicator99 H were calculated. The production of 1 ha yielded 15 ton of hemp, whose global warming potential (GWP100) was equal to about -26.01 ton CO2eq: the amount allocated to the technical fiber (20% of the total amount of hemp biomass) was -5.52 ton CO2eq when mass allocation was used, and -5.54 ton CO2eq when economic allocation was applied. The sustainability for building applications was quantified by considering an insulation panel made by hemp fiber (85%) and polyester fiber (15%) in 1 m(2) of wall having a thermal transmittance (U) equal to 0.2 W/m(2)_K. The environmental performances of the hemp-based panel were compared to those of a rockwool-based one. PMID- 23745971 TI - Volume measurement of crowns in mandibular primary central incisors by micro computed tomography. AB - OBJECTIVE: To determine sex differences in the tissue proportions of crowns of mandibular primary central incisors in Chinese children and to quantify the volume of crown components in three dimensions using micro-computed tomography (micro-CT). MATERIALS AND METHODS: The specimens used in this study were 41 mandibular first deciduous incisor teeth with intact crowns (21 males and 20 females) obtained from patients between 5-6 years of age. Each specimen was scanned using micro-CT at a resolution of 0.05 mm and 3D-rendered images were created. The volume of each component of the crown was measured and examined for differences in different sex and ages. RESULTS: The pulp chamber volume decreased with age and the volume ratio of the pulp chamber to the whole crown was significantly smaller in 6-year-olds than in 5-year-olds (p < 0.05). CONCLUSIONS: Males had significantly larger tooth crown volumes and dentin volumes than females did (p < 0.001), while the volume of enamel showed no sexual dimorphism. PMID- 23745973 TI - 'It's a curse!': coprolalia in Tourette syndrome. AB - BACKGROUND AND PURPOSE: Coprolalia is a complex socially inappropriate vocal tic most frequently reported in the context of Tourette syndrome (TS) and widely portrayed as a cardinal characteristic of this condition throughout popular culture. This study investigated which clinical factors may predispose some patients with TS to experience coprolalia and the impact of this symptom on quality of life. METHODS: Participants were 60 patients with TS (39 males, mean age 32.15, SD 14.1 years) of whom 50% reported mental coprolalia (urges) and 33% reported actual involuntary swearing as a tic. Relationships between the presence of coprolalia and a range of clinical variables including severity of tics, obsessive-compulsive symptoms, attention problems, anxiety, depression, premonitory urges for tics and quality of life were investigated. RESULTS: The presence of urges to utter obscene language was significantly related to non obscene socially inappropriate symptoms and self-reported tic severity. Although experiencing socially inappropriate urges in general was correlated with the presence of mental coprolalia, only the presence of more severe tics was a good indicator of outbursts of obscene vocal tics. Having coprolalia was related to significantly poorer quality of life in TS. CONCLUSIONS: As outbursts of coprolalia exert a specific negative impact on quality of life clinicians should consider improvement in this symptom during evaluation of treatment efficacy. PMID- 23745974 TI - Nonlinear analysis: the intermodulated differential immittance spectroscopy. AB - Intermodulation is used for the analysis of the nonlinear behavior of electrochemical and electronic systems. As a matter of fact, different than the passive elements, electrochemical systems have a highly nonlinear character, which can be used to obtain information on the reaction mechanism and structure of the double layer. The setup for measuring and analyzing the intermodulated sidebands is discussed in detail, using a commercial Schottky diode as the ideal system. A general intermodulated differential immitance spectroscopy technique was consequently defined as the analysis of the variation of the immittance elements as a function of the stimulus frequency, and its transfer function was called differential immittance spectrum. Through a simple model, it was possible to precisely calculate the flat band voltage and the doping level of the Schottky diode from a single differential immittance spectrum. The differential immitance spectra of a dummy cell containing passive elements demonstrated the resolution limits of the technique. PMID- 23745972 TI - Groundwater protection and unconventional gas extraction: the critical need for field-based hydrogeological research. AB - Unconventional natural gas extraction from tight sandstones, shales, and some coal-beds is typically accomplished by horizontal drilling and hydraulic fracturing that is necessary for economic development of these new hydrocarbon resources. Concerns have been raised regarding the potential for contamination of shallow groundwater by stray gases, formation waters, and fracturing chemicals associated with unconventional gas exploration. A lack of sound scientific hydrogeological field observations and a scarcity of published peer-reviewed articles on the effects of both conventional and unconventional oil and gas activities on shallow groundwater make it difficult to address these issues. Here, we discuss several case studies related to both conventional and unconventional oil and gas activities illustrating how under some circumstances stray or fugitive gas from deep gas-rich formations has migrated from the subsurface into shallow aquifers and how it has affected groundwater quality. Examples include impacts of uncemented well annuli in areas of historic drilling operations, effects related to poor cement bonding in both new and old hydrocarbon wells, and ineffective cementing practices. We also summarize studies describing how structural features influence the role of natural and induced fractures as contaminant fluid migration pathways. On the basis of these studies, we identify two areas where field-focused research is urgently needed to fill current science gaps related to unconventional gas extraction: (1) baseline geochemical mapping (with time series sampling from a sufficient network of groundwater monitoring wells) and (2) field testing of potential mechanisms and pathways by which hydrocarbon gases, reservoir fluids, and fracturing chemicals might potentially invade and contaminate useable groundwater. PMID- 23745975 TI - Pulmonary resection for bronchial polyp after lung transplant in a cystic fibrosis patient. AB - Many clinical conditions should be considered in the differential diagnosis of life-threatening events in cystic fibrosis patients after a lung graft transplant. We report on a 17-year-old boy who underwent a lobectomy owing to an inflammatory endobronchial polyp complicated by massive airways bleeding 12 months after having had a bilateral sequential lung graft for cystic fibrosis. This unusual complication underscores the requirement for flexible bronchoscopy in patients with recurrent infection at any stage after transplant. Early diagnosis may prevent life-threatening complications. PMID- 23745977 TI - Microleakage under orthodontic bands cemented with nano-hydroxyapatite-modified glass ionomer. AB - OBJECTIVES: To estimate the in vivo effect of nano-hydroxyapatite (HA) modification of banding glass-ionomer cement on microleakage under orthodontic bands. MATERIALS AND METHODS: Eighty noncarious premolars scheduled for extraction in 20 orthodontic patients were randomly divided into four groups. Grouping was based on the ratio of nano-HA (0%, 5%, 10%, 15% by weight) added to the luting glass-ionomer cement (GIC) Ketac-Cem, which was used for cementation of prefabricated micro-etched orthodontic bands. Dye penetration method was used for microleakage evaluation at the cement-band and cement-enamel interfaces. Statistical evaluation was performed with a Kruskal-Wallis test and a Mann Whitney U-test, and a Bonferroni-adjusted significance level was calculated. RESULTS: Bands cemented with conventional GIC showed the highest microleakage scores in comparison to those cemented with nano-HA-modified GIC. No significant difference was found between teeth banded with 10% and 15% modified GIC. CONCLUSIONS: Modification of the banding GIC with 15% nano-HA revealed a positive effect on reducing microleakage around orthodontic bands. PMID- 23745976 TI - Three-dimensional analysis of effects of rapid maxillary expansion on facial sutures and bones. AB - OBJECTIVE: To evaluate the evidence on three-dimensional immediate effects of rapid maxillary expansion (RME) treatment on growing patients as assessed by computed tomography/cone beam computed tomography (CT/CBCT) imaging. MATERIALS AND METHODS: The published literature was searched through the PubMed, Embase, and Cochrane Library electronic databases from January 1966 to December 2012. The inclusion criteria consisted of randomized controlled trials, prospective controlled studies, and prospective case-series. Two reviewers extracted the data independently and assessed the quality of the studies. RESULTS: The search strategy resulted in 73 abstracts or full-text articles, of which 10 met the inclusion criteria. When treating posterior crossbites with a RME device, the existing evidence points out that the midpalatal suture opening is around 20%-50% of the total screw expansion. There seems to be no consistent evidence on whether the midpalatal sutural opening is parallel or triangular. The effect on the nasal cavity dimensions after RME seems to be apparent and indicates an enlargement between 17% and 33% of the total screw expansion. Circummaxillary sutures, particularly the zygomaticomaxillary and frontomaxillary sutures and also spheno occipital synchondrosis, appear to be affected by the maxillary expansion. Overall, however, the changes were small and the evidence not conclusive. CONCLUSIONS: CT imaging proved to be a useful tool for assessment of treatment effects in all three dimensions. The majority of the articles were judged to be of low quality, and therefore, no evidence-based conclusions could to be drawn from these studies. PMID- 23745978 TI - Gingival recession--can orthodontics be a cure? AB - Does orthodontic treatment help or hinder a patient's periodontal status? What factors affect the periodontium? Can those factors be managed in a way that remedies existing periodontal issues? A 35-year-old woman presented with severe gingival recession and a unilateral Class II malocclusion. The treatment plan was to correct the malocclusion in a way that torques the roots more onto bone and to change her dental hygiene methods. With an extensive review of the literature, this case review attempts to make sense of the enigma of gingival recession and demonstrates an excellent treatment solution to concomitant orthodontic and periodontal problems. PMID- 23745979 TI - Characteristics of Down syndrome subjects in a Saudi sample. AB - OBJECTIVE: To compare the cephalometric characteristics of Down syndrome (DS) subjects with those of normal subjects. MATERIALS AND METHODS: Cephalometric radiographs of 60 Saudi DS subjects and 60 controls with specific inclusion criteria were used. Descriptive statistics were used to describe the quantitative and categorical variables, and the Student's t-test for two independent samples was used to compare the mean values of quantitative variables. RESULTS: SBa and SN were higher in controls than in DS subjects, whereas the NSBa was significantly higher in DS subjects than in controls. SNA, Co-A, ANB, and A-Na perp of controls were higher than the DS subjects. However, SN-MP, PP-MP, ANS Me/N-Me, Y-axis, and Ar-Go-Me of the DS subjects were higher than those of the controls. In addition, U1-NA, U1-NA mm, L1-NB, and L1-NB mm of the DS subjects were also higher than the controls with a more acute U1-L1 angle in DS. NLA was larger in controls than in DS, whereas LL-E and UL-E of the DS subjects were higher than the controls. CONCLUSIONS: Differences between DS subjects and controls can be found when examining cephalometric radiographs. Anterior and posterior cranial base lengths are shorter with a backward inclination of the posterior cranial base in DS subjects. DS subjects present with a retrognathic maxilla and shorter effective length, with an increased LFH and a hyperdivergent mandible. Bimaxillary dental protrusion can also be expected in DS subjects with prominent lips and a reduced nasolabial angle. PMID- 23745980 TI - A comparative anchorage control study between conventional and self-ligating bracket systems using differential moments. AB - OBJECTIVE: To compare the efficiency in anchorage preservation of conventional and self-ligating brackets after the extraction of first maxillary premolars using differential moment mechanics. MATERIALS AND METHODS: Thirty-eight patients requiring extraction of maxillary first premolars and maximum anchorage during space closure were evaluated based on bracket type. Group 1, comprising 23 patients, was bonded with preadjusted conventional brackets (CBs) with a slot of 0.022-inch * 0.030-inch. Group 2 comprised 15 patients who were bonded with 0.022 inch preadjusted self-ligating brackets (SLBs). Patients in both groups received a nickel titanium (NiTi) intrusion arch and a 150 g NiTi closing coil spring for separate canine retraction, followed by a continuous mushroom loop archwire to retract the incisors. Lateral cephalograms were available at the start of treatment (T1) and at the completion of space closure (T2). Statistical comparisons were performed with paired and unpaired Student's t-tests. RESULTS: No significant differences were found between the groups in maxillary molars anchorage loss (3.87 +/- 1.35 mm and 3.65 +/- 1.73 mm for the CB and SLB groups, respectively). Only the mean vertical movement of the tip of the incisor was significantly different between the groups (CB = -0.92 +/- 1.46 mm; SLB = 0.56 +/- 1.65 mm). CONCLUSION: There were no significant differences in the amount of anchorage loss of the maxillary first molars between SLB and CB systems during space closure using differential moments. PMID- 23745981 TI - Fasciola hepatica: an unusual development of redial generations in an isolate of Lymnaea truncatula. AB - Single-miracidium infections of Lymnaea truncatula by Fasciola hepatica were experimentally carried out to identify the redial generations of this trematode when the larval development was unusual (when the first-appearing mother redia, or R1a redia, died after its exit from the sporocyst). Four parameters were measured in the body and pharyngeal region at weekly intervals. At day 49 post exposure at 20 degrees C, the body of the second mother rediae (R1b) was significantly longer than that of the subsequent generations, R2a and R2b/R3a (a mean of 3.0 mm instead of 1.0 and 0.9 mm, respectively). The body was significantly wider in the R1b and R2a groups than in the R2b/R3a rediae. The pharyngeal lumen was significantly wider in the R1b group than in the R2a and R2b/R3a rediae (a mean of 48.6 MUm instead of 10.8 and 3.3 MUm at day 49). The thickness of the pharyngeal wall did not differ in the R1b and R2b/R3a groups, but was significantly lower in the R2a group (19.5 MUm instead of 23.0-23.6 at day 49). There was better development of R1b and R2b/R3a rediae in the snails when the R1a redia died, compared with normal larval development (with a living R1a redia). PMID- 23745982 TI - Perinatal outcomes of Australian buprenorphine-exposed mothers and their newborn infants. AB - AIM: To determine the short-term outcomes of Australian buprenorphine-exposed mother/infant dyads. METHODS: Retrospective record review of drug-exposed mothers and infants in Australia. Groups were based on drug exposure: buprenorphine (55, 3.8%), non-buprenorphine opiates (O, 686, 48.6%) and non-opiates (NO, 671, 47.5%). RESULTS: More than 30% of buprenorphine mothers continued to use heroin (21, 38%) and benzodiazepines (16, 29%). They were more likely to have child at risk concerns (29, 52.7%, P = 0.019) and have previous children placed in out-of home care (9, 16.3%, P = 049). Buprenorphine babies were less likely to be preterm (16% vs. 25% (O), P = 0.001 and 23% (NO), P = 0.004) and had higher birthweights (median: 3165 g vs. 2842.5 g (O), P < 0.001 and 2900 g (NO), P = 0.004). Buprenorphine and non-buprenorphine opioid babies had similar maximum Finnegan scores (median 10 vs. 11(O), P = 0.144). The number of babies needing abstinence treatment (45% vs. 51% (O), P = 0.411) and length of hospital stay (median days 9 vs. 11(O), P = 0.067) were similar, but buprenorphine infants required lower maximum morphine doses (mg/kg/day) (median 0.4 mg vs. 0.5 mg (O), P = 0.009). CONCLUSIONS: Short-term medical outcomes of infants of buprenorphine using mothers are similar to those of non-buprenorphine opiate-using mothers, but interpretation of these results is confounded by the high rates of polydrug exposure in the buprenorphine group. This and other social concerns noted in buprenorphine mothers and infants warrant further study. PMID- 23745983 TI - Improved N(alpha)-acetylated peptide enrichment following dimethyl labeling and SCX. AB - Protein N-terminal acetylation is one of the most common modifications occurring co- and post-translationally on either eukaryote or prokaryote proteins. However, compared to other protein modifications, the physiological role of protein N terminal acetylation is relatively unclear. To explore the biological functions of protein N-terminal acetylation, a robust and large-scale method for qualitative and quantitative analysis of this modification is required. Enrichment of N(alpha)-acetylated peptides or depletion of the free N-terminal and internal tryptic peptides prior to analysis by mass spectrometry are necessary based on current technologies. This study demonstrated a simple strong cation exchange (SCX) fractionation method to selectively enrich N(alpha) acetylated tryptic peptides via dimethyl labeling without the need for tedious protective labeling and depleting procedures. This method was introduced for the comprehensive analysis of N-terminal acetylated proteins from HepG2 cells. Several hundred N-terminal acetylation sites were readily identified in a single SCX flow-through fraction. Moreover, the N(alpha)-acetylated peptides of some protein isoforms were simultaneously observed in the SCX flow-through fraction, which indicated that this approach can be utilized to discriminate protein isoforms with very similar full sequences but different N-terminal sequences, such as beta-actin/gamma-actin, ERK1/ERK2, alpha-centractin/beta-centractin, and ADP/ATP translocase 2 and 3. Compared to other methods, this method is relatively simple and can be directly implemented in a two-dimensional separation (SCX-RP) mass spectrometry scheme for quantitative N-terminal proteomics using stable isotope dimethyl labeling. PMID- 23745984 TI - Where do parents sleep best when children are hospitalized? A pilot comparison study. AB - This pilot study compared the sleep quality and quantity of parents who slept at their hospitalized child's bedside with parents who slept at the hospital's onsite Ronald McDonald House(r) (RMH). Wrist actigraphy and questionnaires were used to estimate parent sleep quality and quantity. Parents who slept at their hospitalized child's bedside (n = 27) experienced more sleep disruption (wake after sleep onset) and reported poorer sleep quality and feeling less rested than parents who slept at RMH (n = 11). Bedside accommodation was associated with poorer parent sleep even when controlling for the covariates of child age and parent gender. Nearby family accommodations, such as RMH, may facilitate parent child proximity during a child's hospitalization while also providing parents with opportunities for essential sleep. PMID- 23745985 TI - Caspase-3-dependent apoptosis of citreamicin epsilon-induced HeLa cells is associated with reactive oxygen species generation. AB - Citreamicins, members of the polycyclic xanthone family, are promising antitumor agents that are produced by Streptomyces species. Two diastereomers, citreamicin epsilon A (1) and B (2), were isolated from a marine-derived Streptomyces species. The relative configurations of these two diastereomers were determined using NMR spectroscopy and successful crystallization of citreamicin epsilon A (1). Both diastereomers showed potent cytotoxic activity against HeLa (cervical cancer) and HepG2 (hepatic carcinoma) cells with IC50 values ranging from 30 to 100 nM. The terminal deoxynucleotidyl transferase dUTP nick-end labeling assay confirmed that citreamicin epsilon A (1) induced cellular apoptosis, and Western blot analysis showed that apoptosis occurred via activation of caspase-3. The 2,7 dichlorofluorescein diacetate assay indicated that citreamicin epsilon substantially increased the intracellular concentration of reactive oxygen species (ROS). To confirm the hypothesis that citreamicin epsilon induced apoptosis through an increase in the intracellular ROS concentration, the oxidized products, oxicitreamicin epsilon A (3) and B (4), were obtained from a one-step reaction catalyzed by Ag2O. These products, with a reduced capacity to increase the intracellular ROS concentration, exhibited a significantly weakened cytotoxicity in both HeLa and HepG2 cells compared with that of citreamicin epsilon A (1) and B (2). PMID- 23745986 TI - Liposomes as potential carrier system for targeted delivery of polyene antibiotics. AB - The development of new therapeutic modalities involves the use of drug carrier, such as liposomes, which can modify pharmacokinetic and bio-distribution of drug profile. Polyene antibiotics incorporation into liposomes improves its availability at the site, bio-distribution and therapeutic index mainly through the engulfment of liposomes by circulating monocytes/macrophages and transportation to the site of infection. Polyene antibiotics (AmB, SJA-95, HA-1 92) and other antibiotics (streptomycin, tobramycin, quinolones, anti-tubercular and anti-cancer drugs), liposomal preparations are described with possible advantages from therapeutic efficacy and toxicity point of view. The polyene macrolide antibiotics liposomal preparations proved to be more effective in the treatment of systemic mycosis. The AmB-cyclodextrin derivatives inclusion complex is a major breakthrough in liposomal preparation which can be converted into aqueous phase of liposome. Liposomal drug incorporated preparation has been one of the important areas of research for developing the existing polyene antibiotics into useful chemotherapeutic agents in clinical medicine. In recent past other antibiotics have also been incorporated into liposomes using wide variety of materials, phosphatidylethanolamine derivatives (pegylated liposomes, enzyme sensitive conjugates, fluidosomes of anti-cancer drugs and poly lactic/glycolic acid microspheres for anti-tuberculosis drugs). In addition, attempts were also made to extend the receptor mediated drug targeting and to review some relevant patents. PMID- 23745987 TI - Nutritional approaches to breaking the intergenerational cycle of obesity. AB - The link between poor maternal nutrition and an increased burden of disease in subsequent generations has been widely demonstrated in both human and animal studies. Historically, the nutritional challenges experienced by pregnant and lactating women were largely those of insufficient calories and severe micronutrient deficiencies. More recently, however, Western societies have been confronted with a new nutritional challenge; that of maternal obesity and excessive maternal intake of calories, fat, and sugar. Exposure of the developing fetus and infant to this obesogenic environment results in an increased risk of obesity and metabolic disease later in life. Furthermore, increased caloric, fat, and sugar intake can occur in conjunction with micronutrient deficiency, which may further exacerbate these programming effects. In light of the current epidemic of obesity and metabolic disease, attention has now turned to identifying nutritional interventions for breaking this intergenerational obesity cycle. In this review, we discuss the approaches that have been explored to date and highlight the need for further research. PMID- 23745988 TI - Quantitative analysis of titanium-induced artifacts and correlated factors during micro-CT scanning. AB - OBJECTIVES: To investigate the impact of cover screw, resin embedment, and implant angulation on artifact of microcomputed tomography (micro-CT) scanning for implant. MATERIALS AND METHODS: A total of twelve implants were randomly divided into 4 groups: (i) implant only; (ii) implant with cover screw; (iii) implant with resin embedment; and (iv) implants with cover screw and resin embedment. Implants angulation at 0 degrees , 45 degrees , and 90 degrees were scanned by micro-CT. Images were assessed, and the ratio of artifact volume to total volume (AV/TV) was calculated. A multiple regression analysis in stepwise model was used to determine the significance of different factors. One-way ANOVA was performed to identify which combination of factors could minimize the artifact. RESULTS: In the regression analysis, implant angulation was identified as the best predictor for artifact among the factors (P < 0.001). Resin embedment also had significant effect on artifact volume (P = 0.028), while cover screw had not (P > 0.05). Non-embedded implants with the axis parallel to X-ray source of micro-CT produced minimal artifact. CONCLUSIONS: Implant angulation and resin embedment affected the artifact volume of micro-CT scanning for implant, while cover screw did not. PMID- 23745989 TI - Neurotropin inhibits the increase in intraepidermal nerve density in the acetone treated dry-skin mouse model. AB - Epidermal hyperinnervation is considered one cause of sensitization to itch, and is thought to regulated by keratinocyte-derived axonal guidance molecules, including nerve growth factor (NGF) and semaphorin (Sema)3A. Neurotropin (NTP) shows antipruritic effects in allergic disease and is also used for pain relief. Using cultured rat dorsal root ganglion neurones, we previously found that NTP inhibited NGF-induced neurite outgrowth. However, no such inhibitory effect has been shown in vivo. We therefore assessed the effects of intraperitoneal administration of NTP on nerve density and expression of NGF and Sema3A mRNAs in the epidermis of acetone-treated mice showing epidermal hyperinnervation. We found that NTP significantly reduced intraepidermal nerve growth in these acetone treated mice. NTP significantly upregulated epidermal Sema3A mRNA, but had no effect on expression of epidermal NGF mRNA. These findings indicate that NTP may reduce intraepidermal nerve density by inducing expression of Sema3A in the epidermis. PMID- 23745990 TI - TAK1 inhibition in the DFG-out conformation. AB - The first example of an inhibitor of the kinase TAK1 that binds in the DFG-out conformation is disclosed. These preliminary studies used kinase-targeted screening and structure-based drug design to create a molecule with dual pharmacological inhibition of p38 and TAK1 that demonstrated significant activity in a cell-based, anti-inflammatory assay. PMID- 23745992 TI - Bioresorbable vascular scaffolds: the promise of transience. PMID- 23745991 TI - Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients. AB - Radiation dermatitis occurs in approximately 95% of patients receiving radiotherapy (RT) for breast cancer. We conducted a randomized, double-blind, placebo-controlled clinical trial to assess the ability of curcumin to reduce radiation dermatitis severity in 30 breast cancer patients. Eligible patients were adult females with noninflammatory breast cancer or carcinoma in situ prescribed RT without concurrent chemotherapy. Randomized patients took 2.0 grams of curcumin or placebo orally three times per day (i.e., 6.0 grams daily) throughout their course of RT. Weekly assessments included Radiation Dermatitis Severity (RDS) score, presence of moist desquamation, redness measurement, McGill Pain Questionnaire-Short Form and Symptom Inventory questionnaire. The 30 evaluable patients were primarily white (90%) and had a mean age of 58.1 years. Standard pooled variances t test showed that curcumin reduced RDS at end of treatment compared to placebo (mean RDS = 2.6 vs. 3.4; P = 0.008). Fisher's exact test revealed that fewer curcumin-treated patients had moist desquamation (28.6% vs. 87.5%; P = 0.002). No significant differences were observed between arms for demographics, compliance, radiation skin dose, redness, pain or symptoms. In conclusion, oral curcumin, 6.0 g daily during radiotherapy, reduced the severity of radiation dermatitis in breast cancer patients. PMID- 23745993 TI - Driving, dementia and Australian physicians: primum non nocere? AB - Older Australians are increasingly reliant on automobiles as their sole form of transport. As our population is ageing and the prevalence of dementia is increasing, it is anticipated that the number of drivers with dementia will rise over time. Much of the literature relating to driving and dementia focuses on safety rather than mobility. The objective of this paper is to highlight several topical ethical issues that pertain to Australian drivers with dementia. It is recommended that future research, policy and practice should centre on the crucial mobility and transport needs of our senior citizens. PMID- 23745994 TI - Hours of work and rest in the rail industry. AB - Currently, the National Transport Commission is considering four options to form the regulatory framework for rail safety within Australia with respect to fatigue. While the National Transport Commission currently recommends no limitations around hours of work or rest, we provide evidence which suggests regulatory frameworks should incorporate a traditional hours of service regulation over more flexible policies. Our review highlights: Shift durations >12 h are associated with a doubling of risk for accident and injury. Fatigue builds cumulatively with each successive shift where rest in between is inadequate (<12 h). A regulatory framework for fatigue management within the rail industry should prescribe limits on hours of work and rest, including maximum shift duration and successive number of shifts. Appropriately, validated biomathematical models and technologies may be used as a part of a fatigue management system, to augment the protection afforded by limits on hours of work and rest. A comprehensive sleep disorder screening and management programme should form an essential component of any regulatory framework. PMID- 23745995 TI - Relationship between glycaemia and length of hospital stay during an acute exacerbation of chronic obstructive pulmonary disease. AB - We have assessed whether glucose concentration and patient outcome are related in hospitalised patients when glycaemia is quantified in detail. Continuous glucose monitoring was performed on 47 consecutive subjects with an acute exacerbation of chronic obstructive pulmonary disease. Length of hospital stay increased by 10% for each mmol/L increase in mean glucose (P = 0.01). In a multivariable analysis, mean glucose was independently associated with length of hospital stay (P = 0.02). These data add weight to evidence that hyperglycaemia may adversely affect patient outcomes in hospitalised patients. PMID- 23745996 TI - Expanding spectrum of TNFRSF1A gene mutations among patients with idiopathic recurrent acute pericarditis. AB - Although idiopathic recurrent acute pericarditis (IRAP) is generally presumed to derive from an autoimmune process, increasing interest is currently being devoted to autoinflammatory diseases, a group of disorders of the innate immune system caused by mutations of genes involved in the regulation or activation of the inflammatory response, without any apparent involvement of autoimmunity. The tumour necrosis factor receptor-1-associated periodic syndrome is the most common autosomal dominant autoinflammatory disorder and is caused by mutations in the TNFRSF1A gene encoding the 55-kD receptor for tumour necrosis factor-alpha. IRAP patients carrying TNFRSF1A gene mutations have been recently described. We report herein the first IRAP patients carrying the rare R104Q and D12E TNFRSF1A gene mutations, thus expanding the spectrum of tumour necrosis factor receptor-1 associated periodic syndrome mutations in IRAP patients. PMID- 23745997 TI - A complex case of bilateral Lemierre syndrome with suggestions on anticoagulation management. PMID- 23745998 TI - Lumiracoxib-induced cholestatic liver injury. PMID- 23745999 TI - Late diagnosis of human immunodeficiency virus infection in patients with viral hepatitis. PMID- 23746000 TI - HLA-haploidentical bone marrow transplantation for haematologic malignancies. PMID- 23746001 TI - An ironic effect of monitoring closeness. AB - Most theories of goal pursuit underscore the beneficial consequences of monitoring progress towards goals. However, effects of affect labelling and dissociations between experience and meta-consciousness suggest that monitoring may not always facilitate goal pursuit. We predicted that in the case of pursuing interpersonal closeness, intense monitoring of progress would have a detrimental effect. We tested this hypothesis with the intimate conversation procedure, adapted from Aron, Melinat, Aron, Vallone, and Bator (1997). Participants in the closeness-monitoring condition asked themselves every five minutes in the course of a 45-minute interaction with a partner whether they felt any closer to their partner, whereas participants in the control condition monitored the room temperature. As predicted, intense monitoring interfered with achieving a feeling of closeness, as measured by sitting distance between pair members following the intimate conversation procedure. We discuss the possibility that monitoring would also be detrimental for achieving other goals that are internal states. PMID- 23746002 TI - Groundwater recharge rate and zone structure estimation using PSOLVER algorithm. AB - The quantification of groundwater recharge is an important but challenging task in groundwater flow modeling because recharge varies spatially and temporally. The goal of this study is to present an innovative methodology to estimate groundwater recharge rates and zone structures for regional groundwater flow models. Here, the unknown recharge field is partitioned into a number of zones using Voronoi Tessellation (VT). The identified zone structure with the recharge rates is associated through a simulation-optimization model that couples MODFLOW 2000 and the hybrid PSOLVER optimization algorithm. Applicability of this procedure is tested on a previously developed groundwater flow model of the Tahtali Watershed. Successive zone structure solutions are obtained in an additive manner and penalty functions are used in the procedure to obtain realistic and plausible solutions. One of these functions constrains the optimization by forcing the sum of recharge rates for the grid cells that coincide with the Tahtali Watershed area to be equal to the areal recharge rate determined in the previous modeling by a separate precipitation-runoff model. As a result, a six-zone structure is selected as the best zone structure that represents the areal recharge distribution. Comparison to results of a previous model for the same study area reveals that the proposed procedure significantly improves model performance with respect to calibration statistics. The proposed identification procedure can be thought of as an effective way to determine the recharge zone structure for groundwater flow models, in particular for situations where tangible information about groundwater recharge distribution does not exist. PMID- 23746003 TI - Laboratory testing of rivaroxaban in routine clinical practice: when, how, and which assays. AB - A number of target-specific oral anticoagulants (TSOAs) have been developed in recent years, and some have shown considerable promise in large-scale, randomized clinical trials in the prevention and treatment of thromboembolism. Unlike traditional anticoagulants, such as vitamin K antagonists, these TSOAs exhibit predictable pharmacokinetics and pharmacodynamics. Among these agents, rivaroxaban, a direct Factor Xa inhibitor, has been approved for clinical use in many countries for the management of several thromboembolic disorders. As with the other TSOAs, rivaroxaban is given at fixed doses without routine coagulation monitoring. However, in certain patient populations or special clinical circumstances, measurement of drug exposure may be useful, such as in suspected overdose, in patients with a haemorrhagic or thromboembolic event during treatment with an anticoagulant, in those with acute renal failure, or in patients who require urgent surgery. This article summarizes the influence of rivaroxaban on commonly used coagulation assays and provides practical guidance on laboratory testing of rivaroxaban in routine practice. Both quantitative measurement (using the anti-Factor Xa method) and qualitative measurement (using prothrombin time, expressed in seconds) are discussed, together with some practical considerations when performing these tests and interpreting the test results. PMID- 23746004 TI - Radiologic case study. Diskovertebral fracture of the spine in ankylosing spondylitis. PMID- 23746006 TI - Periosteal tension band fixation of a pronation external rotation type fracture of the ankle in a child. AB - Interposed soft tissues can block the anatomical reduction of displaced physeal fractures in children and may necessitate surgical removal. The authors describe a new technique in which they surgically freed the interposed distal-based periosteal flap in an irreducible Salter-Harris type II fracture in a 6-year-old boy and then used this flap in a tension band mode to stabilize the fracture. The thick periosteal flap was held under tension and was reattached to the tibial metaphysis using a 3.5-mm cortical screw and a multi-spiked soft tissue washer. The fracture healed satisfactorily, and the patient regained his ankle function and range of motion by 2 months. Periosteal tension band fixation achieves good skeletal stabilization and avoids more than 1 surgical incision. PMID- 23746005 TI - CT-guided biopsy for musculoskeletal lesions. PMID- 23746007 TI - Anatomic anterior cruciate ligament reconstruction using distally inserted doubled hamstrings tendons. AB - Many surgical techniques aimed to obtain an anatomical anterior cruciate ligament reconstruction using the hamstrings tendons are described in the literature. All of these techniques encompass the detachment of the tibial insertion of the hamstrings tendons, thus damaging the neurovascular supply of the tendons and resulting in lower residual proprioceptivity and worse ligamentization of the graft. This article describes a new technique that permits an anatomic single bundle ACL reconstruction using distally inserted doubled hamstrings tendons fixed at the femoral level with a second-generation cortical suspensory device. PMID- 23746008 TI - Metastatic carcinoma and orthopedists. PMID- 23746010 TI - Volar ligament repair for radiocarpal fracture-dislocation. AB - Radiocarpal fracture-dislocations are uncommon injuries, comprising a spectrum of trauma to the capsuloligamentous complex and osseous structures of the radiocarpal joint along with the adjacent structures. Management guidelines are derived from limited case series and expert opinions. An understanding of the relevant anatomy suggests that restoration of an anatomically reduced joint in conjunction with repair or reconstruction of the osseous and soft tissue structures optimizes outcome. Special consideration should be given to repair of the radial styloid, intercarpal ligaments, and radiocarpal capsuloligamentous complex. The authors report 2 patients with radiocarpal fracture-dislocations in which reduction and stabilization of the carpus was achieved using suture anchor fixation of the volar extrinsic radiocarpal ligaments. PMID- 23746009 TI - Peripheral compartment as the initial access for hip arthroscopy in complex cases: technical note. AB - When performing arthroscopic procedures, the hip joint is divided into central and peripheral compartments. Currently, both compartments are evaluated in most of the procedures, but the procedures are usually started by accessing the central compartment. When a direct approach to the central compartment is significantly impeded, it is necessary to perform the initial arthroscopic approach to the hip from the peripheral compartment using either an intracapsular technique or an extracapsular technique. The technical pearls that might be required in these patients are discussed, and typical clinical cases are presented. PMID- 23746011 TI - Driving after orthopedic surgery. AB - EDUCATIONAL OBJECTIVES: As a result of reading this article, physicians should be able to: (1) Identify preoperative factors that may contribute to a patient's ability to return to driving after orthopedic surgery. (2) Understand the role of upper-extremity immobilization and how it may impair a patient's ability to operate a motor vehicle. (3) Recognize how various forms of lower-extremity immobilization (e.g., controlled ankle-motion boot, cast, and Aircast Walker) affect braking reaction times and total braking times. (4) Be aware of current guidelines about when it is appropriate to return to driving following arthroscopy, lower-extremity fracture, and hip and knee arthroplasty. Few guidelines are available to assist orthopedic surgeons in advising patients about when to return to driving after orthopedic surgery. A patient's surgical procedure, postoperative weight-bearing restrictions, immobilization, and other factors influence a patient's ability to drive after orthopedic surgery. Multiple studies have used driving simulators to predict when it may be safe to return to driving after orthopedic surgery. However, study conclusions and recommendations vary significantly. This article reviews the factors contributing to a patient's ability to return to driving after orthopedic surgery and reviews recommendations based on the available literature following fracture, arthroscopy, and arthroplasty. PMID- 23746012 TI - One-year mortality after isolated pelvic fractures with posterior ring involvement in elderly patients. AB - Previous 1-year mortality studies of pelvic fractures in elderly patients have focused on pubic rami fractures, in elderly patients with multiple injuries, or both. Baseline information on the 1-year mortality of isolated pelvic fractures in elderly patients is unavailable. The purpose of this study was to evaluate the 1-year mortality of elderly patients (aged 60 years or older) after isolated pelvic fractures with posterior ring involvement (Orthopaedic Trauma Association type 61-B and C). All patients aged 60 years or older treated for pelvic injuries at a single Level I trauma center over a 12-year period were retrospectively reviewed (N=1223). Exclusion criteria were associated injuries to other body systems (Abbreviated Injury Scale greater than 2), ballistic injuries, long bone fractures, concurrent acetabular fractures, and type 61-A fractures or isolated pubic rami fractures without posterior involvement. Mortality data were obtained from the Social Security Death Index. Seventy patients met the inclusion criteria. Patients treated nonoperatively were significantly older compared with those treated operatively. However, the Charlson Comorbidity Index did not significantly differ between treatment groups. A significantly higher percentage of type-B fractures (83.0%) were treated nonoperatively compared with type-C fractures, which were treated operatively 88.2% of the time. Mortality rates at 3 and 6 months and 1 year postoperatively were 7.1%, 11.4%, and 12.9%, respectively. These results suggest that the 1-year mortality rates of isolated pelvic fractures in elderly patients are lower than those reported previously for hip fractures and pelvic fractures with concurrent injuries. Although age was identified as a significant variable differing between patients treated operatively vs nonoperatively, comorbidities were not. PMID- 23746013 TI - Predictive value of inflammatory markers for irrigation and debridement of acute TKA infection. AB - The roles of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are well established in the diagnosis of total joint infection. However, it is not entirely clear what value preoperative CRP and ESR have in predicting outcomes following irrigation and debridement with insert exchange for acute hematogenous total knee arthroplasty infection. The total joint registry at the authors' institution was reviewed to identify all patients who underwent irrigation and debridement with insert exchange for a diagnosis of acute hematogenous infection of a primary total knee arthroplasty. Patient medical records were then reviewed for preoperative white blood cell count and CRP and ESR levels; interval from symptom onset to surgery; infecting organism; and any additional surgery for infection. Average patient age was 72 years (range, 51-91 years). Forty-four patients were men and 26 were women. Mean follow-up was 54 months (range, 12-176 months). Seventy-two procedures (69 patients) met the inclusion criteria. Of these, 20 (28%) additional procedures for infection were performed and were classified as treatment failures. Average CRP was 173.7 mg/L in the successful group and 159.0 mg/L in the failed group (P=.31). Mean ESR at the time of irrigation and debridement with insert exchange was 61.3 mm/hr in both groups (P=.49). Although CRP and ESR are well established in the diagnosis of infection, no role currently exists for them in predicting the outcomes of irrigation and debridement with insert exchange for the treatment of acute hematogenous total knee arthroplasty infection. PMID- 23746014 TI - Partial articular-sided rotator cuff tears: in situ repair versus tear completion prior to repair. AB - Uncertainty exists over the ideal surgical treatment method for partial articular sided rotator cuff tears, with options ranging from debridement to in situ repair to tear completion prior to repair. The purpose of this study was to determine whether in situ repair was a viable biomechanical treatment option compared with tear completion prior to repair of partial articular-sided rotator cuff tears. Fourteen fresh-frozen cadaveric shoulders were dissected. Partial articular-sided tears were created and repaired using in situ repair or tear completion prior to the repair. Strain and displacement were measured at 45 degrees , 60 degrees , and 90 degrees of glenohumeral abduction. Testing was performed with a load of 100 N applied for 30 cycles. Data from the biomechanical testing displayed 4 conditions that showed improved characteristics of in situ repair over completion and repair: bursal-sided strain anteriorly at 45 degrees , bursal-sided strain anteriorly at 90 degrees , bursal-sided displacement anteriorly at 45 degrees , and bursal-sided displacement anteriorly at 90 degrees . The data indicate that in situ repair is a viable biomechanical treatment option compared with tear completion prior to repair of partial articular-sided rotator cuff tears. When clinically appropriate, the in situ repair may offer some biomechanical advantages, with lower strain and displacement observed on the bursal side compared with tear completion prior to repair. PMID- 23746015 TI - Emergent surgical reduction and fixation for Pipkin type I femoral fractures. AB - The purpose of this study was to assess the effect of timing of large fragment fixation in patients with Pipkin type-I fractures. Patients with Pipkin type-I fractures from the authors' trauma center were prospectively observed between July 2007 and July 2010. Fragments that constituted more than one-fourth of the femoral head were included. Thirty-six patients were equally randomized to undergo emergent surgical reduction and fixation or secondary operative fixation after emergent closed reduction. No significant differences existed between the 2 groups with regard to the baseline characteristics, operating time, and blood loss (P>.05). However, the emergent surgical reduction and fixation group had a shorter hospital stay (P<.05). The results after more than 2-year follow-up showed that the complication and avascular necrosis rates were higher in the secondary operative fixation after emergent closed reduction group compared with the emergent surgical reduction and fixation group (P<.05). It was difficult to achieve an anatomically reduced femoral head when the fragments constituted more than one-fourth of the femoral head. Patients who underwent secondary operative fixation after emergent closed reduction had a high avascular necrosis rate and a relatively poor outcome. Emergent surgical reduction and fixation should be performed shortly after injury to enhance the treatment outcome. PMID- 23746016 TI - Intrafocal pinning for distal radius metaphyseal fractures in children. AB - The purpose of this retrospective case control study was to evaluate the results of intrafocal pinning for distal radius metaphyseal fractures in children and to compare these results with conventional pinning. Data were collected from medical records and radiographs from patients who underwent closed reduction and percutaneous pinning for distal radius fracture in a Level I trauma center at the authors' institution between 2008 and 2010. Inclusion criteria included a dorsally angulated metaphyseal fracture without physeal involvement, an open distal radius physis, and a follow-up to radiographic union. A total of 10 patients with intrafocal pinning were compared to 26 patients with conventional pinning. Preoperatively, angulation was greater in patients who received intrafocal pinning than conventional pinning based on anteroposterior radiographs. Postoperatively, the 2 groups did not differ in angulation on either anteroposterior or lateral radiographs. One malunion and 2 pin-related complications occurred in the conventional pinning group, and 1 pin-related complication occurred in the intrafocal pinning group. The 2 groups did not differ by age, sex, side of injury, days to surgery, or initial shortening. This study affirms that the intrafocal pinning technique is an alternative to the conventional pinning technique for the stabilization of displaced metaphyseal distal radius fractures in children. Intrafocal pinning can also be used as a reduction tool for fractures that cannot be reduced by closed manipulation. The complications are comparable between the 2 techniques. PMID- 23746017 TI - Tantalum rod implantation and vascularized iliac grafting for osteonecrosis of the femoral head. AB - Osteonecrosis of the femoral head is a progressive disease. Without operative intervention, it most often results in collapse and deterioration of the joint. Many joint-preserving surgeries have been implemented, but no uniform treatment exists. The authors report a modified technique of tantalum rod implantation combined with vascularized iliac grafting for the treatment of osteonecrosis of the femoral head. Fifty-two patients (56 hips) with osteonecrosis of the femoral head (Association Research Circulation Osseous classification stage II-IV) treated with this technique were retrospectively reviewed. The major steps of this technique included vascularized iliac graft harvested, necrotic lesion excised, and combined interventions implantation. All patients were followed for a mean of 60 months. Seven hips had to be converted to a total hip arthroplasty. The 5-year joint-preserving success rate of entire group was 87.5%, with 95% for Association Research Circulation Osseous stage II hips, 92% for Association Research Circulation Osseous stage III hips, and 63.6% for Association Research Circulation Osseous stage IV hips. The success rate was lower for stage IV hips compared with stage II and III hips. Mean Harris Hip score of the 49 hips improved significantly from 50 to 91 points. Forty-three (76.8%) of 56 hips remained stable on radiographs. The technique of tantalum rod implantation combined with vascularized iliac grafting may be an effective joint-preserving method for the treatment of intermediate-stage osteonecrosis of the femoral head. A larger group of patients that is compared with a control group is necessary to further research. PMID- 23746018 TI - Evolving incidence of MRSA in urban hand infections. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is the most commonly cultured bacteria in hand infections. Understanding the most common bacteria involved in hand infections allows appropriate and efficient administration of antibiotics. Delay in treatment may lead to increased morbidity, including stiffness, contracture, and amputation. The purposes of this study are to determine whether the incidence of MRSA in culture-positive hand infections continues to increase and whether MRSA is a risk factor for increased length of stay. Electronic medical records were queried to identify patients admitted to a large, academic urban medical center with the diagnosis of a hand infection between January 1, 2005, and December 31, 2009. Methicillin-resistant S aureus accounted for 220 of the positive cultures over the 5-year study period. Polymicrobial infection represented 81 positive cultures, and MRSA was only present in 10 of these cases. Patients with MRSA were found to have a mean length of hospital stay of 4.1 days compared with 4.5 days in non-MRSA infections. Understanding the most common bacteria involved in hand infections allows appropriate and efficient administration of antibiotics. Methicillin-resistant S aureus is the most commonly cultured bacteria in the hand. However, polymicrobial infections have become increasingly more common. Although incidences of polymicrobial infections increased over the study period in this series, clinical judgment should be exercised before initiating broad-spectrum antibiotic coverage. PMID- 23746019 TI - Precontoured locking plate fixation for displaced lateral clavicle fractures. AB - Displaced fractures of the lateral end of the clavicle are associated with an increased risk of nonunion with conservative treatment; therefore, operative treatment is recommended. Various operative treatments have been suggested, but no consensus exists regarding a gold standard for the surgical treatment of this type of fracture. The purpose of this study was to evaluate clinical and radiological outcomes using a precontoured locking compressive distal clavicular plate for Neer type II distal clavicle fractures. Thirty-five patients with Neer type II distal clavicle fractures underwent surgery between March 2009 and January 2012. All patients were evaluated for function using the Constant-Murley Shoulder Outcome Score and University of California, Los Angeles shoulder rating scale, active shoulder range of motion, time to bone union, and coracoclavicular distance. Mean follow-up was 24.2 months (range, 12-35 months). No significant difference existed between the injured and contralateral sides in mean Constant Murley scores (P=.13) or mean University of California, Los Angeles shoulder rating (P=.27). All patients obtained bony union over a mean of 4.1 months (range, 3.5-6.0 months).The coracoclavicular distance was not significantly different between the injured and contralateral shoulders in the immediate postoperative period (P=.28) or at final follow-up (P=.35). One superficial wound infection occurred, but no major complications, such as nonunion, plate failure, secondary fracture, or deep infection, occurred. Precontoured locking compressive distal clavicular plate fixation for the treatment of displaced fractures of the lateral end of the clavicle is an acceptable surgical method with good results. PMID- 23746020 TI - Correlation of subjective and objective measures before and after shoulder arthroplasty. AB - The degree to which subjective patient-reported measures reflects objective findings or how well subjective and objective measures reflect patient satisfaction is not well established. The purpose of this study was to determine the correlation between such measures before and after shoulder arthroplasty. A group of 174 patients (93 total shoulder arthroplasty and 81 reverse shoulder arthroplasty) were prospectively evaluated pre- and postoperatively (mean follow up, 49 months) with the following subjective measures: American Shoulder and Elbow Surgeons score, Simple Shoulder Test, Short Form 36 (SF-36) summary scores, and patient satisfaction. Objective measures included Biodex isometric strength and videotaped range of motion. The objective measures were combined to derive 1 number representative of the overall shoulder function. All measures improved from their preoperative statuses except the SF-36 physical component summary in patients undergoing revision and the SF-36 mental component summary in patients undergoing primary reverse shoulder arthroplasty. A patient satisfaction score of 5 or more was seen in 89% of patients. Preoperatively, a significant (P<.05) correlation existed between the American Shoulder and Elbow Surgeons and the Simple Shoulder Test (rho=0.546), American Shoulder and Elbow Surgeons score and SF-36 physical component summary (rho=0.407), and Simple Shoulder Test and SF-36 physical component summary (rho=0.479). Objective measures had lower correlations (rho<0.4) with subjective scores. Postoperatively, the correlation improved among all measures. Patient satisfaction correlated more with subjective than objective measures. Subjective measures had relatively low correlations with objective measures. Improvements in the current measures are necessary to provide evidence based comparisons of the effectiveness of shoulder arthroplasty. PMID- 23746021 TI - Opinions regarding the management of hand and wrist injuries in elite athletes. AB - Injuries to the hand and wrist are commonly encountered in athletes. Decisions regarding the most appropriate treatment, the timing of treatment, and return to play are made while balancing desires to resume athletic activities and sound orthopedic principles. Little recognition in the literature exists regarding the need for a different approach when treating these injuries in elite athletes and the timing to return to play. This study explored the complexities of treating hand and wrist injuries in the elite athlete. Thirty-seven consultant hand surgeons for teams in the National Football League, National Basketball Association, and Major League Baseball completed a brief electronic survey about the management of 10 common hand injuries. Notable variability existed in responses for initial management, return to protected play, and return to unprotected play for all injuries, aside from near consensus agreement (94%) that elite athletes with stable proximal interphalangeal dislocations could immediately return to protected play. Basketball surgeons were less likely to recommend early return to protected play than non-basketball surgeons. Baseball surgeons were more likely to recommend early unprotected play after scaphoid fixation. Football surgeons were more likely to recommend earlier return to protected play after thumb ulnar collateral ligament injuries, whereas basketball surgeons were less likely to recommend earlier return to protected play. This study demonstrated wide variability in how consultant hand surgeons approach the treatment of hand and wrist injuries. The findings emphasize the need to individually tailor treatment decisions to the patient's desires and demands, particularly in high-performance athletes. PMID- 23746022 TI - Reunderstanding of garden type I femoral neck fractures by 3-dimensional reconstruction. AB - Garden type I fractures include incomplete fractures and impacted fractures. With advances in scientific technology and medical treatment, certain deficiencies of the Garden classification have become apparent. The authors hypothesized that the incidence of incomplete femoral neck fractures was low and that impacted femoral neck fractures were not undisplaced and stable fractures. A new method was developed to precisely measure the spatial displacement of the femoral head in impacted femoral neck fractures. Between 2008 and 2011, nine hundred sixty-six patients with femoral neck fractures were treated, 48 of whom had Garden type I fractures, as seen on anteroposterior radiographs. Seven fractures were classified as incomplete on radiographs; however, after 3-dimensional reconstruction, 3 were classified as incomplete and 4 as complete fractures. Furthermore, the remaining 41 Garden I fractures that were classified as impacted on radiographs showed large spatial displacement on 3-dimensional reconstruction. The average rotational displacement of the femoral head was 19.29 degrees +/ 10.51 degrees , and the average displacements of the femoral head center and the lowest point of the fovea capitis were 8.76+/-4.45 and 14.39+/-8.08 mm, respectively. This study showed that the incidence of incomplete femoral neck fractures was low. Impacted femoral neck fractures showed variable degrees of displacement and were not undisplaced, stable fractures. Garden classification for impacted femoral neck fractures has certain limitations. Impacted femoral neck fractures should be differentiated from Garden type I fractures so clinicians can select appropriate treatments for these fractures. PMID- 23746023 TI - Factors influencing resident participation in the AAOS Political Action Committee. AB - Resident participation in the political action committee (PAC) is important for professional advocacy and for ensuring access to quality musculoskeletal care. The following questions were asked: Would faculty contribution-matching increase donation rates and amounts among orthopedic surgery residents at a single institution? What barriers do residents self-identify that prevent or delay PAC participation? How do residents perceive a faculty contribution-matching program? Residents at 1 institution were encouraged to participate in the PAC before and after the introduction of a faculty contribution-matching program. In addition, telephone follow-up was performed and resident perceptions were assessed regarding the program and barriers to participation. Rates of participation, amounts donated, and perceptions are reported. Resident participation in the PAC increased from 10% to 95% following the introduction of a faculty contribution matching program. The second group of residents contributed 67 cents for every dollar given by the first group. Significant barriers identified included time constraints and an inability to access the PAC Web portal. Ninety-four percent of the initial nonresponders said that they made joining the PAC a priority after learning about the faculty contribution-matching program. They specifically cite giving greater attention to an issue that the faculty value. Four months after the initial e-mail, 100% of residents had contributed. Residents believe that professional activism is important but ascribe it a lower priority than other professional duties. Residency programs might facilitate resident involvement in the PAC by instituting faculty contribution-matching and by assisting junior residents with their American Association of Orthopaedic Surgeons login information. PMID- 23746024 TI - Anterior versus posterior fixation for the treatment of lumbar pyogenic vertebral osteomyelitis. AB - This study was designed to observe the clinical outcome of anterior versus posterior instrumentation in the treatment of Pyogenic vertebral osteomyelitis of the lumbar spine. Twenty-three patients underwent either anterior (anterior fixation group) or posterior fixation (posterior fixation group) combined with a single-stage anterior radical debridement and had an average follow-up of 38 months. Clinical evaluation was performed using the Oswestry Disability Index and visual analog scale. Serial tests of the erythrocyte sedimentation rate and C reactive protein levels were used to monitor for infection recurrence. Radiography was performed pre- and postoperatively to assess the deformity correction and for bony fusion. Serial erythrocyte sedimentation rate and C reactive protein levels reflect the active state of infection and can guide postoperative treatment. Patients in the anterior fixation group showed significantly better results on the Oswestry Disability Index than those in the posterior fixation group 2 years postoperatively. The visual analog scale values demonstrated a significant difference between the 2 groups at 1 and 2 years postoperatively, with pain significantly improved in the anterior fixation group. Radiological results showed no significant difference in fusion time, deformity correction, and cage subsidence. Both anterior and posterior fixation had satisfactory outcomes and were reliable and safe for the treatment of Pyogenic vertebral osteomyelitis of the lumbar spine. Patients with anterior fixation may achieve better postoperative results, such as better well being and less pain. PMID- 23746025 TI - Successful treatment of concomitant ipsilateral intracapsular and extracapsular hip fractures. AB - Femoral neck fractures and intertrochanteric fractures often occur in elderly patients, but simultaneous ipsilateral intra- and extracapsular hip fractures are rare. Either osteosynthesis or femoral head prosthesis is performed, but careful rehabilitation is necessary because of the instability of the fracture, even postoperatively. This article describes a 76-year-old man who fell and sustained concomitant ipsilateral intra- and extracapsular hip fractures. The patient was treated with a femoral head prosthesis with a polished cemented stem combined with locking plate osteosynthesis. Weight-bearing gait was possible 1 day postoperatively, and bone union was achieved at postoperative week 8. The locking plate had excellent angular stability, even when the screw fixation was monocortical, leading to a reduced risk of intraoperative redislocation without disturbing stem insertion. Sufficient fixation was obtained as a result of the molding effect of the cement stem and the tension band function of the plate. These effects collectively made it possible to achieve full weight-bearing gait immediately postoperatively. Although the intramedullary blood circulation was disturbed by the cement, periosteal blood circulation was retained by the virtue of the locking plate, which facilitated early bone union. PMID- 23746026 TI - Patellar dislocation with genu valgum treated by DFO. AB - Congenital habitual patellar dislocation is a rare condition of the knee where the patella dislocates during flexion and relocates during extension. The congenital form is permanent, irreducible, and presents at birth. It is characterized by a short quadriceps and a major patellofemoral dysplasia and short height. This article presents a rare case of a 27-year-old woman with recurring bilateral habitual dislocation of the patella after a failed previous proximal and distal realignment procedure. Clinical examinations of both knees revealed genu valgus knees and lateral joint pain that recurred after several previous operations. Radiographs of both knees showed patellar dislocation and genu valgum associated with patellofemoral dysplasia and osteoarthritis of the lateral compartment. Long-leg standing radiographs showed an anatomic tibiofemoral angle of right 13 degrees and left 6 degrees valgus and a mechanical tibiofemoral angle of right 8 degrees and left 2 degrees valgus and weight-bearing line of 65% on the right and 48% on the left. The authors performed a distal femoral closing wedging osteotomy to correct the valgus deformity, and then percutaneous lateral release and medial reefing were performed to stabilize the patellas of both knees simultaneously. PMID- 23746027 TI - Subpectoral biceps tenodesis for failed type II SLAP repair. AB - Superior labrum anterior-posterior lesions are a common cause of shoulder pain. The diagnosis, classification, and indications for surgical intervention remain controversial, and mixed outcomes are associated with primary repair. Given the increasing prevalence of primary superior labrum anterior-posterior repairs in the United States, more surgeons will need to treat patients with poor primary results. A retrospective review of prospectively collected data was performed on patients who underwent subpectoral biceps tenodesis for failed type II superior labrum anterior-posterior repair by a single surgeon between January 2008 and December 2011. Primary outcome variables included pain via the visual analog scale, American Shoulder and Elbow Surgeons score, and Short Form 12 score. Secondary outcome variables included the Simple Shoulder Test and Single Assessment Numeric Evaluation scores. Demographic and intraoperative information was recorded for each patient. A paired t test statistical analysis was performed with a P value less than .05 considered statistically significant. A total of 11 patients met the inclusion criteria. Of these patients, 9 (82%) completed postoperative surveys at a mean 26-month follow-up. Mean visual analog scale scores improved from 4.1 to 2.5 (P=.03), Simple Shoulder Test scores from 5.4 to 9.3 (P=.005), American Shoulder and Elbow Surgeons scores from 54.5 to 78.0 (P=.002), and Single Assessment Numeric Evaluation scores from 42.5 to 70.4 (P=.001). Mean SF-12 (physical component) improved from 35.5 to 47.9 (P=.018). No failures or peri- or postoperative complications occurred. No patients required additional surgery. The findings suggest that subpectoral biceps tenodesis as a salvage for failed type II superior labrum anterior-posterior repair demonstrates improved results. Larger scale comparative studies are required to justify this technique. PMID- 23746028 TI - Platelet-rich plasma promotes healing of osteoporotic fractures. AB - With an aging population worldwide, the frequency of osteoporotic fractures is increasing. Therefore, biological methods to enhance the internal fixation of osteoporotic fractures becomes more important to reduce the societal burden of care. The purposes of this study were to evaluate the role of platelet-rich plasma (PRP) in the treatment of osteoporotic fractures and to clarify the best concentration of PRP. Bone marrow mesenchymal stem cells isolated from osteoporotic rats were cultured in high- (8.21+/-0.4*10(9)/mL), medium-(2.65+/ 0.2*10(9)/mL), and low-concentration (0.85+/-0.16*10(9)/mL) PRP and in platelet poor plasma (8+/-0.5*10(6) platelet/mL). The capacities of cell proliferation and osteogenic and adipogenic differentiation were compared. A transverse osteotomy was performed in the middle of the left femoral diaphysis followed by K-wire fixation, and various concentrations of PRP were transplanted into the fracture zone. Radiologic, mechanical, and histologic evaluations were performed at 2, 4, and 8 weeks, respectively. The results indicated that PRP could inhibit adipogenic differentiation and that medium-concentration PRP was effective in inducing the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells derived from osteoporotic bone marrow and in promoting fracture healing, whereas high-concentration PRP inhibited osteogenic differentiation and callus remodeling. Certain concentrations of PRP can effectively enhance the healing of osteoporotic fractures. Medium-concentration PRP is a suitable concentration to use in practice. PMID- 23746029 TI - Febrile response following megaprosthesis replacement for primary bone sarcoma. AB - The presence of early postoperative fever after megaprosthesis replacement surgery is a concern for orthopedic oncologists due to the possibility of infection. The aims of the current study were to determine the incidences and patterns of fever and factors associated with its development and to determine the clinical significance of fever after megaprosthesis replacement surgery. Seventy-one patients who had undergone megaprosthesis reconstruction for previously unoperated localized lower-extremity osteosarcoma were reviewed. No patient had evidence of infection preoperatively. Mean patient age was 23.72+/ 16.84 years (range, 6.7-74 years), and average follow-up was 59.5 months (range, 4-240 months). Five postoperative surgical wound infections (4 deep, 1 superficial) occurred on postoperative days 5, 13, 14, 20, and 21. Fevers (body temperature of 38 degrees C or higher) were present in 62 patients (87.3%) at some point during the first 2 postoperative weeks. Peak body temperature was observed on postoperative day 1 in 62% of the febrile patients. Of the 62 febrile patients, 94% were relieved of fever by postoperative day 5. No significant association was observed between the presence of fever and surgical wound infection. Body temperature curves in patients with infection showed that several atypical patterns, such as multiple fever peaks and persistent fever, were accompanied by physical findings within the normalization period. Fever during the first 5 postoperative days is common after megaprosthesis replacement for bone sarcomas and seems to be a normal physiologic response to surgery. However, atypical fever patterns or additional physical findings require investigation. PMID- 23746030 TI - Patient demographics and risk factors in pediatric distal humeral supracondylar fractures. AB - The literature on distal humeral supracondylar fractures does not systematically define relationships between patient characteristics and the severity or complications of these injuries. This study evaluated age, sex, height, and body mass index (BMI) in relation to fracture severity and posttreatment complications in a pediatric population. The medical records of 382 pediatric patients treated for distal humeral supracondylar fractures over a 5-year period at 1 institution were included. Variables included age, sex, height, weight, injury mechanism, fracture severity (Gartland Classification), treatment, follow-up duration, and treatment complications. Body mass index and BMI-for-age percentile were calculated. Descriptive statistics with univariate analyses and logistic regression analysis with odds ratios and 95% confidence intervals were used. Children sustaining Gartland type 3 fractures were significantly older and taller than those sustaining Gartland type 1 and 2 fractures. No significant difference existed in fracture occurrence between boys and girls. Fracture severity did not differ significantly due to sex, BMI, or BMI-for-age percentile. Severe fractures were associated with increased posttreatment complications. Complication rates did not vary significantly by age, sex, height, BMI, or BMI-for-age. Taller children aged 5 to 6 years were at the greatest risk for Gartland type 3 distal humeral supracondylar fractures. Severe fractures are associated with an increased complication risk. Sex, BMI, and BMI-for-age percentile had no effect on fracture severity or complication rates. PMID- 23746031 TI - Predictive factors of recovery in long thoracic mononeuropathy. AB - The aim of the study was to identify specific factors that affect the outcome in patients with long thoracic mononeuropathy. The authors reviewed all medical records of patients with long thoracic mononeuropathy from the archive of the electromyography service over the past 16 years. Age, sex, occupation, pain at onset, symptom duration, neuropathy causes and side, and electromyography findings were collected. The outcome was evaluated by performing standard telephone interviews consisting of 9 queries about use limitations in the affected upper limb. If no limitation existed, the recovery was considered complete. If partial limitations only affected the upper limb in performing 5 or fewer of 9 specific activities, the outcome was considered good; if limitations affected more than 5 activities, the outcome was considered poor. The authors performed a multivariate logistic regression to calculate the association between good outcome or full recovery and poor outcome with demographic, clinical, and electromyography findings. Forty-one patients were included (mean+/-SD age, 39+/ 14 years; 68.3% men). Causes were shoulder-arm overuse or trauma in 19 patients, iatrogenic in 5, idiopathic in 9, and inflammatory in 8. Twenty-seven patients had a good outcome and full recovery and 14 had a poor outcome. No patient underwent surgery. Age, sex, occupation, pain at onset, symptom duration, neuropathy side, and electromyography findings were not predictive of the outcome. The probability of full recovery and good outcome was 7.5 times greater in long thoracic mononeuropathy secondary to idiopathic or inflammatory causes compared with other etiologies. PMID- 23746032 TI - Functional outcomes following locking plate fixation of complex proximal humeral fractures. AB - The purpose of this study was to evaluate the functional outcome of patients with complex proximal humeral fractures fixated by locking plate technology. Eighty nine patients (27 men, 62 women) older than 50 years with 3- and 4-part proximal humeral fractures were treated using locking plate fixation and followed up for more than 1 year. Functional outcomes were assessed by using the Disabilities of the Arm, Shoulder, and Hand (DASH) and Constant scores, and the complications were evaluated through physical and radiographic examinations. Mean DASH and Constant scores for all 89 patients were 19.6 and 66.6 points, respectively. No significant differences existed in the 2 scores between patients with 3- and 4 part fractures. Of the 71 patients without complications, 68 had an excellent functional outcome according to the DASH score, whereas 2 patients had an excellent outcome on the Constant score. For the 18 patients with complications, the functional outcomes were significantly poorer compared with patients without complications. According to the Constant score, all patients with complications were classified into a moderate or poor functional outcome, but the rate was 12% with the DASH score. In patients with 3- and 4-part proximal humeral fractures fixed with locking plate fixation, complications were the major cause of compromised functional outcomes. Based on these results, different conclusions would be reached when the functional outcome was assessed by using the DASH and Constant scores separately. Because the clinician-based Constant score may bias the results, patient-based assessments, such as the DASH score, are required for the evaluation of functional outcome after shoulder surgery. PMID- 23746033 TI - Complications in minimally invasive percutaneous fixation of thoracic and lumbar spine fractures. AB - Minimally invasive stabilization of thoracic and lumbar fractures without neurologic involvement is becoming a more frequent alternative to open fusion and conservative treatment. The authors analyzed the complication rate and limits of this technique in a consecutive series of 99 patients (127 thoracolumbar vertebral fractures) who underwent this technique between May 2005 and November 2009. Eighty-three patients had only spine injuries, whereas 16 had polytrauma injuries (mean Injury Severity Score, 25.2). In these 16 patients, percutaneous fixation was performed as a damage control procedure. The most frequent construct was monosegmental: 1 level above and 1 level below the fractured vertebra. In the remaining 21 patients, multilevel construction was performed for multiple injuries. Complications were analyzed according to the period of onset (intra- and postoperative) and the severity (major and minor). Twelve (12%) complications were recorded: 4 (4%) were intraoperative, 6 (6%) were early postoperative, and 2 (2%) were late postoperative; 4 (4%) were minor and 8 (8%) were major. Mean follow-up was 52 months (range; 36-90 months). All patients except 1 were considered healed after 6-month follow-up. The failed patient had an initial kyphosis greater than 20 degrees , and a posterior open reduction and fusion would have been more appropriate. Minimally invasive stabilization of selected spine injuries is a safe technique with a low complication rate. The main goal of this approach is a fast recovery time, so any complication leading to an extended length of stay should be considered severe. An adequate learning curve is important to minimize complications. PMID- 23746034 TI - Health care subsidy and outcomes of total knee arthroplasty in Asians. AB - Singapore has a nonmodified universal health care system in which the government ensures affordable health care in the public health system, largely through a system of compulsory savings, subsidies, and price controls. Patients seeking treatment via the public health system may also choose for nonsubsidized options, with the benefits of being able to choose a surgeon, better privacy, and shorter time to surgery. To the authors' knowledge, few studies have reported the effect of health care subsidies on total knee arthroplasty outcomes. The purpose of this study was to assess whether patients receiving a health care subsidy had good outcomes or fared worse than their paying counterparts after undergoing conventional total knee arthroplasty. The authors retrospectively reviewed 369 patients who underwent total knee arthroplasty between 2006 and 2010. Patients were stratified into 2 groups: nonsubsidized (n=95) and subsidized patients (n=274). Outcome measures, such as range of motion, function score, knee score, Oxford Knee Questionnaire, and the Short Form 36 questionnaire, were compared between the groups at 6-month and 2-year follow-up. Subsidized patients had good postoperative outcomes, and no significance differences existed in outcome scores and range of motion between the 2 groups at 6-month and 2-year follow-up except in the mean function score, where patients in the nonsubsidized group did better (P=.019). Subsidized patients had good outcomes and did not fare worse than nonsubsidized patients after conventional total knee arthroplasty, except for their knee function score. PMID- 23746035 TI - Necrotizing fasciitis in a pediatric orthopedic population. AB - Few studies have analyzed necrotizing fasciitis in children, and all have relied on cases of necrotizing fasciitis in the abdomen, head, and neck region. The authors sought to correlate the preoperative values of several laboratory tests previously validated in the adult literature, such as the Laboratory Risk Indicator for Necrotizing Fasciitis, with surgically confirmed necrotizing fasciitis in children to provide clinical guidance for the preoperative laboratory workup of necrotizing fasciitis. A retrospective chart review was performed on consecutive patients younger than 18 years with a diagnosis of necrotizing fasciitis. A total of 13 patients with an average age of 7.9 years (range, 9 months-16 years) were included. Ten (76.9%) infections were found in the lower extremity and 3 (23.1%) in the upper extremity. Seven (53.8%) patients had ecchymosis on examination. All patients presented with an elevated white blood cell count. No amputations were performed, and no mortality occurred. All patients underwent surgery within 24 hours of presentation. Elevated temperature, white blood count, erythrocyte sedimentation rate, and C-reactive protein values are typically seen in pediatric patients with necrotizing fasciitis; however, no correlation existed between other the preoperative laboratory values with the previously described scoring systems, such as the Laboratory Risk Indicator for Necrotizing Fasciitis. Aggressive monitoring of signs and symptoms is suggested, even if a patient does not meet all conventional diagnostic criteria. The authors recommend prompt surgical debridement and early administration of antibiotics, which should include clindamycin. PMID- 23746036 TI - Results with 98 Endo-Modell rotating hinge prostheses for primary knee arthroplasty. AB - Rotating hinge knee prostheses have been developed as an advancement of the fixed hinge models. Some authors suggest that this type of prosthesis is associated with a greater risk of aseptic loosening because of the increased stresses to the bone-prosthesis interface; therefore, they are scarcely used as primary implants. The current authors evaluated of a series of 98 rotating hinge knee arthroplasties Endo-Modell (Waldemar LINK GmbH and Co, Hamburg, Germany) implanted for knee osteoarthritis. The Hospital for Special Surgery Knee Score and the Knee Society Score were used for the clinical and radiographic evaluation. Log-rank or Wilcoxon tests were used to test the statistical significances, and the Kaplan-Maier method was used to calculate the implant survival probability. After a medium follow-up of approximately 174 months, the clinical scores showed a statistically significant improvement from the pre- to postoperative period. The complication rate was high, and the cumulative implants survival rate was 88.7% at 1 year, 85.9% at 5 years, 79.8% at 10 years, and 75.8% at 15 years. The Endo-Modell rotating hinge implants demonstrated no significant risk of aseptic loosening, and the hinge was not a primary cause of failure. However, the overall failure rate was higher than that of unhinged implants; therefore, this prosthesis is recommended for cases of instability and revision rather than primary knee arthroplasty. PMID- 23746037 TI - Factors predicting change in pelvic posterior tilt after THA. AB - In total hip arthroplasty, steep cup inclination should be avoided because it increases the risk of edge loading. Pelvic posterior tilt should be carefully monitored because it increases cup inclination and anteversion, leading to edge loading or impingement. The authors evaluated how much the pelvic tilt angle changes from the supine position referenced in planning for cup orientation preoperatively to the standing position 1 year after total hip arthroplasty (Deltaref). The pelvic tilt angle was measured in 124 patients who underwent total hip arthroplasty due to osteoarthritis, and the mean Deltaref was -9.5 degrees +/-5.3 degrees (range, -23 degrees to 5 degrees ). Preoperative compression fractures, spondylolisthesis, and disk-space narrowing were predictive of increased pelvic posterior tilt after total hip arthroplasty. The authors mathematically calculated how much change in pelvic posterior tilt was clinically possible with the original cup alignment, which ranged from 40 degrees to 45 degrees of radiographic inclination and 0 degrees to 30 degrees radiographic anteversion to more than 50 degrees of inclination. Even if the maximum posterior tilt (23 degrees ) occurred, no edge loading would occur in almost half of those original cups. Surgeons should aim for 40 degrees of inclination. When the original cup inclination was 40 degrees , edge loading was prevented. Edge loading caused by steep cup inclination can be prevented by adjusting the cup orientation to account for predicted pelvic tilting, but spinal alignment must also be considered because lumbar kyphosis can increase postoperative pelvic posterior tilt. PMID- 23746039 TI - Differential lead component pulling as a possible mechanism of inside-out abrasion and conductor cable externalization. AB - BACKGROUND: Conductor cable externalization with protrusion (CCE*) is highly prevalent among the Riata 8F and ST 7F defibrillation (DF) leads and infrequently present in the QuickSite and the QuickFlex coronary sinus (CS) leads (St. Jude Medical, Sylmar, CA, USA). A model for CCE* based on differential lead component pulling and conjugate extension with reciprocal compression-bending was developed. Extension of a proximal lead body segment by pectoral or cardiac movements causes reciprocal compression-bending of a distal lead body segment mediated by inextensible conductor cables running down a lead body fixed at various points by fibrous adhesions. The "sawing" action of these cables under tension causes inside-out abrasion of insulation leading to CCE*. METHODS: DF leads from different manufacturers and the QuickFlex and QuickFlex MU CS leads were subjected to simulated differential pulling. RESULTS: Restitution from differential pulling followed three patterns: complete, partial without escalation, and incomplete with escalation. Only the last pattern (only shown by the Riata 8F and ST 7F leads) was associated with an increased risk to CCE*. For CS leads, deformation concentrated on the more flexible segment when the lead body did not have a uniform construction. CONCLUSIONS: The Durata, Riata ST Optim, QuickFlex MU, and Quartet leads should be relatively immune to CCE*. The Durata leads are extremely resistant to longitudinal deformation and probably cause mediastinal displacement rather than differential pulling in response to pectoral movements in vivo. Implantation techniques and lead designs can be used to minimize the risk of CCE*. A bench test for CCE* can be constructed. PMID- 23746038 TI - Energy-saving lamps and their impact on photosensitive and normal individuals. AB - BACKGROUND: A preliminary investigation showed that ultraviolet radiation (UVR) emissions from compact fluorescent lamps (CFLs) can pose a risk to the skin of photosensitive individuals. OBJECTIVES: To carry out a larger-scale study, in patients with a range of photodermatoses, to assess this risk. To determine a safe alternative light source for photosensitive individuals. To investigate if CFL emissions have the potential to induce skin responses in normal individuals. METHODS: Two hundred patients were directly exposed to a single-envelope CFL as part of their routine management. Irradiation was carried out on the inner forearm with lamps positioned at 5 cm. Skin assessments were made immediately and 24 h postirradiation. Eleven of these patients were further tested to a double envelope CFL. One hundred and one patients were tested to emissions from a light emitting diode (LED). A study involving 20 healthy individuals was carried out with exposure to the single-envelope CFL. RESULTS: Skin erythema was induced by the single-envelope CFL in the following cases: 16 of 53 chronic actinic dermatitis, seven of 52 polymorphic light eruption, five of nine solar urticaria, one of two actinic prurigo, one of one erythropoietic protoporphyria and two of 20 healthy subjects. The double-envelope CFL eliminated or reduced the skin response in all 11 patients tested. The LED did not induce any UVR-provoked skin responses. CONCLUSIONS: UVR from CFLs can aggravate the skin of photosensitive and healthy individuals when situated in close proximity. Double-envelope lamps reduce this risk. LEDs offer a safer alternative light source that eliminates the risk of UVR-induced skin erythema. PMID- 23746040 TI - Germinated grains: a superior whole grain functional food? AB - Grains are global dietary staples that when consumed in whole grain form, offer considerable health benefits compared with milled grain foods, including reduced body weight gain and reduced cardiovascular and diabetes risks. Dietary patterns, functional foods, and other lifestyle factors play a fundamental role in the development and management of epidemic lifestyle diseases that share risks of developing adverse metabolic outcomes, including hyperglycaemia, hypertension, dyslipidaemia, oxidative stress, and inflammation. Whole grains provide energy, nutrients, fibres, and bioactive compounds that may synergistically contribute to their protective effects. Despite their benefits, the intake of grains appears to be lower than recommended in many countries. Of emerging interest is the application of germination processes, which may significantly enhance the nutritional and bioactive content of grains, as well as improve palatability. Enhancing grain foods in a natural way using germination techniques may therefore offer a practical, natural, dietary intervention to increase the health benefits and acceptability of whole grains, with potentially widespread effects across populations in attenuating adverse lifestyle disease outcomes. Continuing to build on the growing body of in-vitro studies requires substantiation with extended in-vivo trials so that we may further develop our understanding of the potential of germinated grains as a functional food. PMID- 23746041 TI - Biological baseline of joint self-repair procedures. AB - Gel-Repairer is a biomaterial composed of Polydeoxyribonucleotides (Pdrn), Heat Shock Proteins (Hsps) and a thickening substance. It works as a local mesenchymal stem cells (MSCs) stimulator, finally generating connective tissue renewal. Our research is within the field of regenerative medicine and has historically built its foundation from the studies carried out on non-vital amnion and placental membranes. Our end point is the activation and stimulation of the local mesenchymal stem cells (MSCs) for the structural recovery of the joint involved in the degenerative process. Since 2003, we have been applying the Gel Repairer over more than 1200 patients, most of them elderly, affected by Degenerative Joint Disease (DJD). After 10 years of clinical experience, the results are really impressive, including the absence of toxicity, adverse reactions or side effects. Our clinical findings allowed the presentation of a clinical preliminary study performed on a large group of patients from 2003 to 2009 and recently published [1]. The following article is aimed at looking into the mechanism of action of the Joint Self-Repair procedure; furthermore some new technical opportunities are presented on tissue engineering advances in this fast evolving sector. PMID- 23746043 TI - Treatment of comorbid pain and PTSD in returning veterans: a collaborative approach utilizing behavioral activation. AB - OBJECTIVE: We explore preliminary clinical effectiveness and feasibility of an intervention utilizing collaborative care components and behavioral activation (BA) to treat comorbid chronic pain and posttraumatic stress disorder (PTSD). DESIGN: Descriptive, including pre- and posttreatment assessment results. SETTING: Portland Veterans Affairs Medical Center. PARTICIPANTS: Fifty-eight Iraq and Afghanistan veterans with chronic pain and PTSD symptoms. INTERVENTIONS: Veterans participated in a biopsychosocial evaluation and up to eight BA sessions using a collaborative approach involving primary care, mental health, and other clinicians. A physiatrist assisted the psychologist in providing recommendations to primary care providers. OUTCOME MEASURES: Participants were administered pre- and posttreatment measures of PTSD, pain severity, pain interference, mental health, quality of life, satisfaction, and global ratings of change with the purpose of assessing progress and improving quality. RESULTS: Of the 58 participants, 30 completed treatment. Common recommendations included physical therapy and exercise programs, pain medication or pain medication adjustments, and additional diagnostic workups, such as imaging. Participants who completed the program showed significant improvements on measures of PTSD, pain severity, and pain interference. Improvements were also evident on measures of mental health and quality of life. Overall, participants were satisfied with the program, and on average reported feeling "somewhat better." CONCLUSIONS: These findings suggest that a collaborative approach that includes BA is feasible and a potentially effective treatment for comorbid chronic pain and PTSD. PMID- 23746042 TI - Effect of bisphenol A on rat metabolic profiling studied by using capillary electrophoresis time-of-flight mass spectrometry. AB - Bisphenol A (BPA), a chemical widely used in the manufacture of polycarbonate plastics, has raised considerable concern in recent decades because of its hormone-like properties. Whether BPA exposure is a health risk remains controversial in many countries. A metabolomics study based on capillary electrophoresis time-of-flight mass spectrometry (CE-TOF/MS) was performed to study the urine metabolic profiles of Sprague-Dawley rats fed with four dose levels of BPA (0, 1, 10, and 100 MUg/kg body weight) for 45 days. Multivariate pattern recognition directly reflected the metabolic perturbations caused by BPA. On the basis of univariate analysis, 42 metabolites including amino acids, polyamines, nucleosides, organic acids, carbohydrates, pterins, polyphenols, and sugar phosphates were found as the most significantly differential metabolites. The marked perturbations were related with valine, leucine and isoleucine biosynthesis, D-glutamine and D-glutamate metabolism, etc. Significant alterations of neurotransmitters (glutamate, gamma-aminobutyric acid, and noradrenaline) and neurotransmitter-related metabolites (tyrosine, histamine, valine, and taurine) suggested that the toxic effects of small-dose BPA (below 50 mg/kg/day) may contribute to its interactions with the neuromediating system. Our study demonstrated that metabolomics may offer more specific insights into the molecular changes underlying the physiological effects of BPA. PMID- 23746044 TI - Review of the management of childhood asthma in Tasmania. AB - AIM: To review the supply of medications to children with asthma and parent reported management of childhood asthma in Tasmania and highlight evidence practice gaps for future interventions. METHODS: Participating pharmacies ran a software application that extracted data from dispensing records and helped to identify children with asthma. Parents of identified children were mailed a survey evaluating components of asthma management. Dispensing and survey data were analysed. RESULTS: A total of 939 children from 23 pharmacies were identified by the software and deemed eligible for inclusion. Surveys were received from 353 (37.6%) parents. In the past year, short-acting beta-2 agonists were supplied to 56.1% of the cohort, preventers to 76.5% (inhaled corticosteroids 52.3%; leukotriene receptor antagonists 31.3%; inhaled cromones 0.6%), long-acting beta-2 agonists (LABAs) to 25.7% and oral corticosteroids to 21.5%. Approximately half of the children receiving inhaled corticosteroids were concurrently receiving a LABA. Among children with indicators of inadequately controlled asthma, up to 73.7% of their parents reported that their asthma was adequately controlled, up to 38.2% did not possess an Asthma Action Plan, up to 36.8% were not regularly using a spacer and up to 22.8% had not received a preventer. CONCLUSION: These results indicate gaps in childhood asthma management, in particular, undersupply of preventers in high-risk patient groups, high supply of LABAs and insufficient spacer and asthma action plan usage. These areas should be targeted for interventions to improve childhood asthma management. PMID- 23746045 TI - High-fat diet induces dynamic metabolic alterations in multiple biological matrices of rats. AB - Obesity is a condition resulting from the interactions of individual biology and environmental factors causing multiple complications. To understand the system's metabolic changes associated with the obesity development and progression, we systematically analyzed the dynamic metabonomic changes induced by a high-fat diet (HFD) in multiple biological matrices of rats using NMR and GC-FID/MS techniques. Clinical chemistry and histopathological data were obtained as complementary information. We found that HFD intakes caused systematic metabolic changes in blood plasma, liver, and urine samples involving multiple metabolic pathways including glycolysis, TCA cycle, and gut microbiota functions together with the metabolisms of fatty acids, amino acids, choline, B-vitamins, purines, and pyrimidines. The HFD-induced metabolic variations were detectable in rat urine a week after HFD intake and showed clear dependence on the intake duration. B-vitamins and gut microbiota played important roles in the obesity development and progression together with changes in TCA cycle intermediates (citrate, alpha ketoglutarate, succinate, and fumarate). 83-day HFD intakes caused significant metabolic alterations in rat liver highlighted with the enhancements in lipogenesis, lipid accumulation and lipid oxidation, suppression of glycolysis, up-regulation of gluconeogenesis and glycogenesis together with altered metabolisms of choline, amino acids and nucleotides. HFD intakes reduced the PUFA to-MUFA ratio in both plasma and liver, indicating the HFD-induced oxidative stress. These findings provided essential biochemistry information about the dynamic metabolic responses to the development and progression of HFD-induced obesity. This study also demonstrated the combined metabonomic analysis of multiple biological matrices as a powerful approach for understanding the molecular basis of pathogenesis and disease progression. PMID- 23746046 TI - Ankle-brachial index long-term outcome after first-ever ischaemic stroke. AB - BACKGROUND AND PURPOSE: Ankle-brachial blood pressure index (ABI) is a clinical tool to identify the presence of peripheral artery disease. There is a scarcity of data associating ABI with long-term outcome in patients with IS. The association between ABI and long-term outcome in patients with first-ever acute IS was assessed. METHODS: Ankle-brachial blood pressure index was assessed in all consecutive patients with a first-ever acute IS admitted at Alexandra University hospital (Athens, Greece) between January 2005 and December 2010. ABI was considered normal when > 0.90 and <= 1.30. The Kaplan-Meier product limit method was used to estimate the probability of 5-year composite cardiovascular event free (defined as recurrent stroke, myocardial infarction or cardiovascular death) and overall survival. A multivariate analysis was performed to assess whether ABI is an independent predictor of 5-year mortality and dependence. RESULTS: Amongst 653 patients, 129 (19.8%) with ABI <= 0.9 were identified. Five-year cumulative composite cardiovascular event-free and overall survival rates were better in normal ABI stroke patients (log-rank test: 7.22, P = 0.007 and 23.40, P < 0.001, respectively). There was no difference in 5-year risk of stroke recurrence between low and normal ABI groups (hazard ratio, HR = 1.23, 95% CI 0.68-2.23). In multivariate Cox regression analysis, independent predictors of 5-year mortality included age (HR = 2.55 per 10 years, 95% CI 1.86-3.48, P < 0.001), the National Institutes of Health Stroke Scale (per point increase HR = 1.12, 95% CI 1.08 1.16, P < 0.001), and low ABI (HR = 2.22, 95% CI 1.22-4.03, P = 0.009). Age (HR = 1.21 per 10 years, 95% CI 1.01-1.45, P = 0.04) and low ABI (HR = 1.72, 95% CI 1.11-2.67, P = 0.01) were independent predictors of the composite cardiovascular end-point. CONCLUSIONS: Low ABI in patients with acute IS is associated with increased 5-year cardiovascular event risk and mortality. However, ABI does not appear to predict long-term stroke recurrence. PMID- 23746047 TI - A prospective randomized comparative study of monopolar and bipolar transurethral resection of the prostate and photoselective vaporization of the prostate in patients who present with benign prostatic obstruction: a single center experience. AB - PURPOSE: The first prospective randomized study to compare the safety and short term efficacy of monopolar transurethral resection of the prostate (TURP), bipolar TURP, and photoselective vaporization of the prostate (PVP) using GreenLight high-performance system 120W laser in patients who presented with benign prostatic obstruction (BPO). PATIENTS AND METHODS: The 186 consecutive patients who presented with BPO and who were planned for surgery were randomized into three groups: Group A, patients who underwent monopolar TURP; group B, patients who underwent bipolar TURP; and group C, patients who underwent PVP. All three groups were subdivided into two subgroups based on prostate volume: Subgroup 1 >20 cc and <50 cc, and subgroup 2, between 50 and 80 cc. Patients preoperative, perioperative, and follow-up data were recorded and analyzed. RESULTS: The baseline characteristics of the three groups and subgroups 1 and 2 were comparable. The number of patients in whom postoperative irrigation was instituted, amount of fluid used for postoperative irrigation, duration of postoperative irrigation, postoperative hemoglobin concentration, and duration of catheterization were significantly in favor of group C patients except for the mean operative time, which was significantly longer among them. All three groups demonstrated an increase in International Prostate Symptom Score, quality of life score, and maximum flow rate and decrease in prostate volume and postvoid residual urine at 12-month follow-up. The mean Intgernational Index of Erectile Function-5 score did not show improvement in any group. The need for blood transfusion and clot retention necessitating intervention were significantly lower among group C patients compared with group A, whereas these values for group B patients did not reach significant level compared with either group A or C. These complications were comparable among subgroup 1 patients, whereas subgroup 2 patients had shown results in favor of subgroup C2. CONCLUSION: Monopolar TURP, bipolar TURP, and PVP are equally efficacious at 12-month follow up. PVP has added advantages of lesser blood loss, lesser need for blood transfusion (especially for prostate volume 50-80 cc), and shorter catheterization time. PMID- 23746048 TI - Progressing the global antimalarial portfolio: finding drugs which target multiple Plasmodium life stages. AB - The number of novel antimalarial candidates entering preclinical development has seen an increase over the last several years. Most of these drug candidates were originally identified as hits coming from screening large chemical libraries specifically targeting the asexual blood stages of Plasmodium falciparum. Indeed, a large proportion of the current antimalarial arsenal has mainly targeted the asexual blood stage which is responsible for clinical symptoms of the disease. However, as part of the eradication agenda and to address resistance, any next generation antimalarial should have additional activity on at least one other parasite life stage, i.e. gametocytocidal and/or tissue schizonticidal activity. We have applied this approach by screening compounds with intrinsic activity on asexual blood stages in assays against sexual and liver stages and identified two new antimalarial chemotypes with activity on multiple parasite life stages. This strategy can be expanded to identify other chemical classes of molecules with similar activity profiles for the next generation antimalarials. The following review summarizes the discovery of the spiroindolones and imidazolopiperazine classes of antimalarials developed by the NGBS consortium (Novartis Institute for Tropical Diseases, Genomic Institute of the Novartis Research Foundation, Biomedical Primate Research Center, and the Swiss Tropical and Public Health Institute) currently in clinical trials. PMID- 23746049 TI - Tailoring n-ZnO/p-Si branched nanowire heterostructures for selective photoelectrochemical water oxidation or reduction. AB - We report the fabrication of three-dimensional (3D) branched nanowire (NW) heterostructures, consisting of periodically ordered vertical Si NW trunks and ZnO NW branches, and their application for solar water splitting. The branched NW photoelectrodes show orders of magnitudes higher photocurrent compared to the bare Si NW electrodes. More interestingly, selective photoelectrochemical cathodic or anodic behavior resulting in either solar water oxidation or reduction was achieved by tuning the doping concentration of the p-type Si NW core. Specifically, n-ZnO/p-Si branched NW array electrodes with lightly doped core show broadband absorption from UV to near IR region and photocathodic water reduction, while n-ZnO/p(+)-Si branched NW arrays show photoanodic water oxidation with photoresponse only to UV light. The photoelectrochemical stability for over 24 h under constant light illumination and fixed biasing potential was achieved by coating the branched NW array with thin layers of TiO2 and Pt. These studies not only reveal the promise of 3D branched NW photoelectrodes for high efficiency solar energy harvesting and conversion to clean chemical fuels, but also developing understanding enabling rational design of high efficiency robust photocathodes and photoanodes from low-cost and earth-abundant materials allowing practical applications in clean renewable energy. PMID- 23746050 TI - Scalloping is a reliable endoscopic marker for celiac disease. AB - BACKGROUND: Scalloping of duodenal folds noted on esophagogastroduodenoscopy (EGD) has been associated with various illnesses including celiac disease (CD). The aim of the present study was to examine the frequency of scalloping in pediatric patients undergoing EGD and to assess its significance in the diagnosis of CD. We also evaluated the association of scalloping with the histopathology and celiac serology in the subgroup of celiac patients. PATIENTS AND METHODS: All children (0-18 years) who underwent EGD at Shaare Zedek Medical Center for any reason during a 2.5-year period were retrospectively included, yielding a consecutive cohort without selection bias. Relevant data were obtained from the patient files. RESULTS: During the study period, 623 children underwent EGD of whom 149 (24%) were eventually diagnosed with CD. In 74/623children (12%), scalloping was seen and had a sensitivity of 48% (95% CI 0.40-0.57), specificity of 99% (0.98-0.99) and positive predictive value of 97% (0.9-0.99) to diagnose CD. The prevalence of scalloping increased with advancing stage of the Marsh classification from 33% (7/21) in Marsh 1 to 63% (34/54) in Marsh 3c (P < 0.001). Scalloping was associated with a significantly higher median tissue transglutaminase level (153 [IQR 98-168] versus 49 [IQR 11-143]; P = 0.011). CONCLUSION: The results suggest that the diagnosis of CD is almost certain if isolated scalloping is observed during EGD done to rule out CD. Thus, attention to this finding may serve as an additional tool in the diagnosis of CD. PMID- 23746051 TI - An unusual cause of widespread umbilicated papules and nodules. PMID- 23746052 TI - Evaluating the predictivity of virtual screening for ABL kinase inhibitors to hinder drug resistance. AB - Virtual screening methods are now widely used in early stages of drug discovery, aiming to rank potential inhibitors. However, any practical ligand set (of active or inactive compounds) chosen for deriving new virtual screening approaches cannot fully represent all relevant chemical space for potential new compounds. In this study, we have taken a retrospective approach to evaluate virtual screening methods for the leukemia target kinase ABL1 and its drug-resistant mutant ABL1-T315I. 'Dual active' inhibitors against both targets were grouped together with inactive ligands chosen from different decoy sets and tested with virtual screening approaches with and without explicit use of target structures (docking). We show how various scoring functions and choice of inactive ligand sets influence overall and early enrichment of the libraries. Although ligand based methods, for example principal component analyses of chemical properties, can distinguish some decoy sets from active compounds, the addition of target structural information via docking improves enrichment, and explicit consideration of multiple target conformations (i.e. types I and II) achieves best enrichment of active versus inactive ligands, even without assuming knowledge of the binding mode. We believe that this study can be extended to other therapeutically important kinases in prospective virtual screening studies. PMID- 23746053 TI - Age differences in the role of cognitive versus somatic arousal in sleep outcomes. AB - The purpose of this study is twofold: (a) to determine whether daily or overall cognitive and somatic arousal better predict sleep and (b) to investigate age differences in the arousal-sleep relation. Fifty younger and 50 older adults completed the Pre-Sleep Arousal Scale and sleep diaries for 14 consecutive days. Analyses revealed mean arousal may better predict sleep regardless of age. However, daily arousal represents an important avenue of research as it may uncover lagged or coupling effects in the arousal-sleep relation. Significant age differences in the arousal-sleep relation suggest age-dependent associations between the type of arousal and sleep. Implications for assessment of sleep in older and younger adults are discussed. PMID- 23746055 TI - Molecular evidence of type 2 mosaicism in Gorlin syndrome. AB - We present a 12-year-old girl with a family history of Gorlin syndrome who had unilateral, segmentally arranged basaloid skin tumours present since birth, ipsilateral, palmoplantar pits of rather large size distributed along Blaschko lines, and an ipsilateral odontogenic keratocyst. The patient and her father were heterozygous for a germline mutation in the form of a single-base substitution in exon 18 of the PTCH1 gene. In the patient's lesional skin, a microdeletion in exon 3 of PTCH1 was detected, giving rise to a truncated protein. This additional mutation was ruled out in the contralateral skin and in blood lymphocytes, thus confirming its mosaic state. In this way we provide for the first time molecular proof of a type 2 segmental involvement of this autosomal dominant trait. PMID- 23746054 TI - Dynamics of immune effector mechanisms during infection with Mycobacterium avium in C57BL/6 mice. AB - Opportunistic infections with non-tuberculous mycobacteria such as Mycobacterium avium are receiving renewed attention because of increased incidence and difficulties in treatment. As for other mycobacterial infections, a still poorly understood collaboration of different immune effector mechanisms is required to confer protective immunity. Here we have characterized the interplay of innate and adaptive immune effector mechanisms contributing to containment in a mouse infection model using virulent M. avium strain 104 in C57BL/6 mice. M. avium caused chronic infection in mice, as shown by sustained organ bacterial load. In the liver, bacteria were contained in granuloma-like structures that could be defined morphologically by expression of the antibacterial innate effector protein Lipocalin 2 in the adjoining hepatocytes and infiltrating neutrophils, possibly contributing to containment. Circulatory anti-mycobacterial antibodies steadily increased throughout infection and were primarily of the IgM isotype. Highest levels of interferon-gamma were found in infected liver, spleen and serum of mice approximately 2 weeks post infection and coincided with a halt in organ bacterial growth. In contrast, expression of tumour necrosis factor was surprisingly low in spleen compared with liver. We did not detect interleukin-17 in infected organs or M. avium-specific T helper 17 cells, suggesting a minor role for T helper 17 cells in this model. A transient and relative decrease in regulatory T cell numbers was seen in spleens. This detailed characterization of M. avium infection in C57BL/6 mice may provide a basis for future studies aimed at gaining better insight into mechanisms leading to containment of infections with non-tuberculous mycobacteria. PMID- 23746056 TI - The nitrogen cycle in anaerobic methanotrophic mats of the Black Sea is linked to sulfate reduction and biomass decomposition. AB - Anaerobic methanotrophic (ANME) mats host methane-oxidizing archaea and sulfate reducing prokaryotes. Little is known about the nitrogen cycle in these communities. Here, we link the anaerobic oxidation of methane (AOM) to the nitrogen cycle in microbial mats of the Black Sea by using stable isotope probing. We used four different (15)N-labeled sources of nitrogen: dinitrogen, nitrate, nitrite and ammonium. We estimated the nitrogen incorporation rates into the total biomass and the methyl coenzyme M reductase (MCR). Dinitrogen played an insignificant role as nitrogen source. Assimilatory and dissimilatory nitrate reduction occurred. High rates of nitrate reduction to dinitrogen were stimulated by methane and sulfate, suggesting that oxidation of reduced sulfur compounds such as sulfides was necessary for AOM with nitrate as electron acceptor. Nitrate reduction to dinitrogen occurred also in the absence of methane as electron donor but at six times slower rates. Dissimilatory nitrate reduction to ammonium was independent of AOM. Ammonium was used for biomass synthesis under all conditions. The pivotal enzyme in AOM coupled to sulfate reduction, MCR, was synthesized from nitrate and ammonium. Results show that AOM coupled to sulfate reduction along with biomass decomposition drive the nitrogen cycle in the ANME mats of the Black Sea and that MCR enzymes are involved in this process. PMID- 23746057 TI - A decade of Plasmodium falciparum metabolic pathways of therapeutic interest to develop new selective antimalarial drugs. AB - Plasmodium falciparum has a specific metabolism of particular interest because several of its features, with respect to the host human ones, are potential pharmacological targets. Such features have been more intensely investigated since 2002, thanks to the full sequencing of the genome of P. falciparum. In this review, we are interested in the potential metabolic targets of therapeutic interest identified and investigated over the past decade in terms of lead-to drug development. PMID- 23746058 TI - Novel anticancer agents and targets: recent advances and future perspectives. AB - An urgent need for the discovery of novel anticancer agents is required for the long term therapy of cancer. Large number of novel bio-active and potential anticancer agents are being used in clinical and pre-clinical trials. Although many heterocyclic compounds are already available commercially as anticancer agents, great efforts have been put to identify novel anticancer targets. This review provides an insight of the novel anticancer targets and molecules of the first and final stage of clinical and pre-clinical trials. PMID- 23746059 TI - Smart drug release systems based on stimuli-responsive polymers. AB - Stimuli-responsive polymers could respond to external stimuli, such as temperature, pH, photo-irradiation, electric field, biomolecules in solution, etc., which further induce reversible transformations in the structures and conformations of polymers, providing an excellent platform for controllable drug release, while the accuracy of drug delivery could obtain obvious improvement in this system. In this review, recent progresses in the drug release systems based on stimuli-responsive polymers are summarized, in which drugs can be released in an intelligent mode with high accuracy and efficiency, while potential damages to normal cells and tissues can also be effectively prevented owing to the unique characteristics of materials. Moreover, we introduce some smart nanoparticles polymers conjugates and drug release devices, which are especially suitable for the long-term sustained drug release. PMID- 23746060 TI - Recent advances in the synthesis of tubulysins. AB - Tubulysins are a family of natural tetrapeptides in clinical development as a consequence of their potent anticancer activity, even for multi-drug resistant carcinoma. Tubulysins inhibit tubulin polymerization by binding to the peptide binding site located near the vinca alkaloid binding site of tubulin. The limited availability and pharmacological profile of the tubulysins attracted synthetic and medicinal chemists to initiate programs towards their total synthesis. This paper reviews efforts toward the total synthesis of tubulysins and selected structure-activity relationship studies of tubulysin analogs. PMID- 23746061 TI - Near-field mediated plexcitonic coupling and giant Rabi splitting in individual metallic dimers. AB - Strong coupling between resonantly matched localized surface plasmons and molecular excitons results in the formation of new hybridized energy states called plexcitons. Understanding the nature and tunability of these hybrid nanostructures is important for both fundamental studies and the development of new applications. We investigate the interactions between J-aggregate excitons and single plasmonic dimers and report for the first time a unique strong coupling regime in individual plexcitonic nanostructures. Dark-field scattering measurements and finite-difference time-domain simulations of the hybrid nanostructures show strong plexcitonic coupling mediated by the near-field inside each dimer gap, which can be actively controlled by rotating the polarization of the optical excitation. The plexciton dispersion curves, obtained from coupled harmonic oscillator models, show anticrossing behavior at the exciton transition energy and giant Rabi splitting ranging between 230 and 400 meV. These energies are, to the best of our knowledge, the largest obtained on individual hybrid nanostructures. PMID- 23746062 TI - An analysis of the duplicate testing strategy of an Irish immunochemical faecal occult blood test colorectal cancer screening programme. AB - AIM: This study examined the relevance of using a two-sample quantitative immunochemical faecal occult blood test (FIT) at a high cut-off stringency by the first population-based colorectal cancer (CRC) pilot screening programme in Ireland. METHOD: Approximately 10,000 individuals between the ages of 50 and 74 years were invited to perform two consecutive FITs. These were analysed in tandem using the OC Sensor and participants with at least one positive result with a haemoglobin cut-off for positivity at 100 ng/ml were offered colonoscopy. RESULTS: A total of 5023 (52%) [2177 (43%) male, 2846 (57%) female] individuals with a median age of 64 years participated. At least one positive FIT was detected from 514 (10%) individuals. From the 419 (82%) patients who proceeded to colonoscopy 17 (4%) had CRC and 132 (33%) had an advanced adenoma. The detection rate for these screen-relevant lesions was 3% (95% CI 2.5-3.5) and the FIT positive colonoscopy detection rate was 36% (95% CI 31-40). The number needed to undergo colonoscopy to find an advanced lesion was 2.8. The two-test system detected four (23.5%) additional patients with CRC and 37 (28%) with an advanced adenoma compared with a single test. CONCLUSION: The CRC miss rate estimated for a single test (23.5%) was unacceptably high when the goal was to maximize the discovery of advanced lesions in the initial screening round. We conclude that the two-test protocol at a high cut-off threshold is suitable for optimizing FIT screening in Ireland. PMID- 23746063 TI - Peptidomic profiling of secreted products from pancreatic islet culture results in a higher yield of full-length peptide hormones than found using cell lysis procedures. AB - Peptide Hormone Acquisition through Smart Sampling Technique-Mass Spectrometry (PHASST-MS) is a peptidomics platform that employs high resolution liquid chromatography-mass spectrometry (LC-MS) techniques to identify peptide hormones secreted from in vitro or ex vivo cultures enriched in endocrine cells. Application of the methodology to the study of murine pancreatic islets has permitted evaluation of the strengths and weaknesses of the approach, as well as comparison of our results with published islet studies that employed traditional cellular lysis procedures. We found that, while our PHASST-MS approach identified fewer peptides in total, we had greater representation of intact peptide hormones. The technique was further refined to improve coverage of hydrophilic as well as hydrophobic peptides and subsequently applied to human pancreatic islet cultures derived from normal donors or donors with type 2 diabetes. Interestingly, in addition to the expected islet hormones, we identified alpha cell-derived bioactive GLP-1, consistent with recent reports of paracrine effects of this hormone on beta-cell function. We also identified many novel peptides derived from neurohormonal precursors and proteins related to the cell secretory system. Taken together, these results suggest the PHASST-MS strategy of focusing on cellular secreted products rather than the total tissue peptidome may improve the probability of discovering novel bioactive peptides and also has the potential to offer important new insights into the secretion and function of known hormones. PMID- 23746064 TI - Multi-sensor esophageal temperature probe used during radiofrequency ablation for atrial fibrillation is associated with increased intraluminal temperature detection and increased risk of esophageal injury compared to single-sensor probe. AB - BACKGROUND: Radiofrequency (RF) ablation in the posterior left atrium has risk of thermal injury to the adjacent esophagus. Increased intraluminal esophageal temperature has been correlated with risk of esophageal injury. The objective of this study was to compare esophageal temperature monitoring (ETM) using a multi sensor temperature probe with 12 sensors to a single-sensor probe during catheter ablation for atrial fibrillation (AF). METHODS AND RESULTS: We compared the detection of intraluminal esophageal temperature rises in 543 patients undergoing RF ablation for AF with ETM. Esophageal endoscopy (EGD) was performed on all patients with maximum esophageal temperature >= 39 degrees C. Esophageal lesions were classified by severity as mild or severe ulcerations. Four hundred fifty five patients underwent RF ablation with single-sensor ETM and 88 patients with multi-sensor ETM. Thirty-nine percent of patients with single-sensor versus 75% with multi-sensor ETM reached a maximum detected esophageal temperature >= 39 degrees C (P < 0.0001). Esophageal injury was detected by EGD in 29% of patients with maximum temperature >= 39 degrees C by single-sensor versus 46% of patients with multi-sensor ETM (P = 0.021). Thirty-nine percent of patients with lesions in the single-sensor probe group had severe ulcerations compared to 33% of patients in the multi-sensor probe group (P = 0.641). CONCLUSIONS: Intraluminal esophageal temperature >= 39 degrees C is detected more frequently by the multi sensor temperature probe versus the single-sensor probe, with more frequent esophageal injury and with comparable severity of injury. Despite detecting esophageal temperature rises in more patients, the multi-sensor probe may not have any measurable benefit compared to a single-sensor probe. PMID- 23746065 TI - Studies on the impact of onsite evaluation must account for the per-pass success rate. PMID- 23746066 TI - Parent-child conflict as an etiological moderator of childhood conduct problems: an example of a 'bioecological' gene-environment interaction. AB - BACKGROUND: Prior research has suggested that, consistent with the diathesis stress model of gene-environment interaction (G * E), parent-child conflict activates genetic influences on antisocial/externalizing behaviors during adolescence. It remains unclear, however, whether this model is also important during childhood, or whether the moderation of child conduct problems by negative/conflictive parenting is better characterized as a bioecological interaction, in which environmental influences are enhanced in the presence of environmental risk whereas genetic influences are expressed most strongly in their absence. The current study sought to distinguish between these possibilities, evaluating how the parent-child relationship moderates the etiology of childhood-onset conduct problems. METHOD: We conducted a series of 'latent G by measured E' interaction analyses, in which a measured environmental variable was allowed to moderate both genetic and environmental influences on child conduct problems. Participants included 500 child twin pairs from the Michigan State University Twin Registry (MSUTR). RESULTS: Shared environmental influences on conduct problems were found to be several-fold larger in those with high levels of parent-child conflict as compared with those with low levels. Genetic influences, by contrast, were proportionally more influential at lower levels of conflict than at higher levels. CONCLUSIONS: Our findings suggest that, although the diathesis-stress form of G * E appears to underlie the relationship between parenting and conduct problems during adolescence, this pattern of moderation does not extend to childhood. Instead, results were more consistent with the bioecological form of G * E which postulates that, in some cases, genetic influences may be most fully manifested in the absence of environmental risk. PMID- 23746068 TI - Kiwifruit: our daily prescription for health. AB - Kiwifruit are unequalled, compared with other commonly consumed fruit, for their nutrient density, health benefits, and consumer appeal. Research into their health benefits has focussed on the cultivars Actinidia deliciosa 'Hayward' (green kiwifruit) and Actinidia chinensis 'Hort 16A', ZESPRI((r)) (gold kiwifruit). Compared with other commonly consumed fruit, both green and gold kiwifruit are exceptionally high in vitamins C, E, K, folate, carotenoids, potassium, fibre, and phytochemicals acting in synergy to achieve multiple health benefits. Kiwifruit, as part of a healthy diet, may increase high-density lipoprotein cholesterol, and decrease triglycerides, platelet aggregation, and elevated blood pressure. Consuming gold kiwifruit with iron-rich meals improves poor iron status, and green kiwifruit aids digestion and laxation. As a rich source of antioxidants, they may protect the body from endogenous oxidative damage. Kiwifruit may support immune function and reduce the incidence and severity of cold or flu-like illness in at-risk groups such as older adults and children. However, kiwifruit are allergenic, and although symptoms in most susceptible individuals are mild, severe reactions have been reported. While many research gaps remain, kiwifruit with their multiple health benefits have the potential to become part of our "daily prescription for health." PMID- 23746069 TI - A novel nonsense mutation in the CDSN gene underlying hypotrichosis simplex of the scalp in a Chinese family. PMID- 23746070 TI - Spontaneously differentiated GATA6-positive human embryonic stem cells represent an important cellular step in human embryonic development; they are not just an artifact of in vitro culture. AB - In this study, we isolated and characterized spontaneously differentiated human embryonic stem cells (SD-hESCs) found in hESC colonies in comparison to the morphologically premature ESCs in the colonies to investigate the potential role of SD-hESCs in embryogenesis. SD-hESCs were distinguished from undifferentiated hESCs by their higher expression of GATA6, a marker for primitive endoderm and transthyretin, a marker visceral endoderm in embryoid bodies (EBs). SD-hESCs expressed OCT4 and NANOG, markers for pluripotent stem cells, at significantly lower levels than undifferentiated hESCs. EBs derived from isolated SD-hESCs were morphologically distinct from cells directly derived from the undifferentiated hESCs; they contained higher number of cysts compared to EBs from undifferentiated hESC-derived EBs (42% vs. 20%). Furthermore, the extracellular signal molecule, BMP2/4, induced a higher GATA4/6 expression and cystic EB formation than control and noggin-treated EBs. Since cystic formation in EBs play a role in primitive endoderm formation during embryogenesis, the SD-hESC may be a relevant cell type equipped to differentiate into primitive endoderm. Our results suggest that SD-ESCs generated during routine hESC culture are not just an artifact of in vitro culture and these cells could serve as a useful model to study the process of embryogenesis. PMID- 23746071 TI - Does anxiety sensitivity correlate with startle habituation? An examination in two independent samples. AB - Individuals with anxiety disorders have previously demonstrated abnormal habituation to aversiveness over time. As anxiety sensitivity (AS), or an individuals' propensity to fear of anxiety-related sensations, has been shown to be a risk factor for anxiety disorders (particularly panic disorder), the present study examined whether AS was also associated with abnormal habituation. This association was examined in two independent samples of undergraduates (Ntotal=178). Habituation was operationalised as the reduction in startle response to multiple startle probes presented over 2.5 minutes and three definitions of this reduction were employed. Results indicated that individuals with higher levels of AS evidenced deficits in startle habituation, but the strength of this relationship was somewhat dependent on the definition of startle habituation, with the most robust definition being an analysis of participants' individual slopes across all nine blinks. The present findings suggest that startle habituation is a key mechanism underlying AS, and may help elucidate the role this risk factor plays in the pathogenesis of anxiety disorders. PMID- 23746073 TI - Prevalence and risk factors of asymptomatic intracranial arterial stenosis in a community-based population of Chinese adults. AB - BACKGROUND AND PURPOSE: Intracranial arterial stenosis (ICAS) is one of the most common causes of ischaemic stroke in Asia. Knowledge of the prevalence and risk factors of asymptomatic ICAS is limited. The prevalence of ICAS was therefore investigated and its risk factors in a Chinese community-based population were explored. METHODS: From 2010 to 2011, a stratified (by sex and age) random sample of 5440 participants aged 40 years or older were enrolled in the study. ICAS was assessed using transcranial Doppler. Logistic regression was used to evaluate potential risk factors associated with ICAS in participants. RESULTS: In total, 13.2% (95% CI 12.3-14.1) of the subjects had ICAS, and women were more likely than men to have ICAS in the 40-49 year age group. Hypertension [odds ratio (OR) = 2.23, 95% CI 1.87-2.66], diabetes (OR = 1.99, 95% CI 1.62-2.45), left ventricular hypertrophy (OR = 1.66, 95% CI 1.18-2.34) and elevated high sensitivity C-reactive protein (OR = 1.55, 95% CI 1.19-2.02) were independently associated with higher prevalence of ICAS after adjusting for age, gender, body mass index, smoking status and other covariates. Of the 716 ICAS individuals, 90.6% had one or more of these risk factors. Amongst the subjects who had at least one risk factor, 15.2% had ICAS. CONCLUSIONS: Intracranial artery stenosis is common in the Chinese population. Individuals who had one or more risk factors were more likely to have ICAS, suggesting more aggressive risk factor management. PMID- 23746072 TI - Sleep and aging: examining the effect of psychological symptoms and risk of sleep disordered breathing. AB - Controversy exists as to whether self-reported sleep quality declines with age, despite changes in sleep being accepted as part of normal aging. This study sought to investigate age-related differences in self-reported sleep quality, after controlling for conditions that are common with age, such as psychological symptoms and increased risk of sleep-disordered breathing (SDB). The Pittsburgh Sleep Quality Index (PSQI) was administered to a sample of 582 community adults (aged 18-89 years), and the association between age and 3 factors of the PSQI (sleep efficiency, perceived sleep quality, and daily disturbance), and global scores, was examined controlling for depression, anxiety, stress, gender, and SDB risk. Results indicate that (a) before controlling for covariates, there was no significant relation between age and all indexes of self-reported sleep quality, with the exception of sleep efficiency. However, once depression, gender, and SDB risk were controlled for, a significant, yet small, relation was revealed between older age and poorer global sleep quality; (b) there was no association between age and perceived sleep quality or daily disturbances before or after controlling for relevant covariates; and (c) depression, gender, and SDB risk were significant predictors of poorer sleep quality across the indexes but, in general, did not have a marked impact on the relation between age and sleep quality. In conclusion, results suggest that sleep problems are common across the lifespan, and that there were modest age-related differences in self-reported sleep quality, which were not due to depressed mood, gender, or risk of SDB. PMID- 23746074 TI - Multi-functional plasmacytoid dendritic cells redistribute to gut tissues during simian immunodeficiency virus infection. AB - The objective of this study was to determine the systemic effects of chronic simian immunodeficiency virus (SIV) infection on plasmacytoid dendritic cells (pDCs). pDCs play a critical role in antiviral immunity, but current data are conflicting on whether pDCs inhibit HIV/SIV replication, or, alternatively, contribute to chronic immune activation and disease. Furthermore, previous pDC studies have been complicated by incomplete descriptions of generalized depletion during HIV/SIV infection, and the effects of infection on pDCs outside peripheral blood remain unclear. In scheduled-sacrifice studies of naive and chronically SIV infected rhesus macaques we evaluated the distribution and functionality of pDCs in multiple tissues using surface and intracellular polychromatic flow cytometry. As previously observed, pDCs were reduced in peripheral blood and spleens, but were also depleted in non-lymphoid organs such as the liver. Interestingly, pDCs accumulated up to fourfold in jejunum, colon and gut-draining lymph nodes, but not in peripheral lymph nodes. Most unexpectedly, SIV infection induced a multi functional interferon-alpha, tumour necrosis factor-alpha, and macrophage inflammatory protein-1beta cytokine secretion phenotype, whereas in normal animals these were generally distinct and separate functions. Herein we show a systemic redistribution of pDCs to gut tissues and gut-draining lymph nodes during chronic SIV infection, coupled to a novel multi-functional cytokine producing phenotype. While pDC accumulation in the mucosa could aid in virus control, over-production of cytokines from these cells could also contribute to the increased immune activation in the gut mucosa commonly associated with progressive lentivirus infections. PMID- 23746075 TI - Management of advanced and/or metastatic carcinoid tumors: historical perspectives and emerging therapies. AB - INTRODUCTION: Carcinoid tumors are uncommon neoplasms that offer unique therapeutic challenges to practicing physicians. Several chemotherapy combinations and IFN-alpha have been used for the treatment of unresectable carcinoid tumors over the last decades, but they have shown variable clinical results. Given the heterogeneity of these tumors, there is no clear therapeutic agent or combination that confers a significant advantage over others. AREAS COVERED: The authors provide a comprehensive evaluation of the existing therapies for advanced carcinoid tumors such as traditional agents, combination therapies and newer drugs. EXPERT OPINION: Somatostatin analogs are known to provide symptomatic relief in patients with carcinoid syndrome, but their antiproliferative effect has not been proven beyond the reasonable doubt. Traditional streptozocin-based regimens may offer a survival benefit in patients with advanced carcinoids, yet their toxicity is not negligible. Temozolomide has shown efficacy alone and in combination with other agents, and its further testing in advanced carcinoid tumors appears warranted. Efficacy of various tyrosine kinase inhibitors, VEGF inhibitors and mTOR inhibitors appears promising, and should be explored in patients with metastatic carcinoid tumors. In addition, use of these agents in combination with traditional chemotherapeutic agents should also be investigated. PMID- 23746076 TI - The effect of endoscopic mucosal resection and transanal endoscopic microsurgery on anorectal function. AB - AIM: The study assessed the impact on anorectal function of endoscopic mucosal resection (EMR) and transanal endoscopic microsurgery (TEM) of large rectal adenomas. METHOD: Patients with a large (>= 3 cm) rectal adenoma undergoing EMR or TEM were included. Self-reported faecal incontinence was assessed using the Colorectal Functional Outcome (COREFO) questionnaire and the Wexner Incontinence Grading Scale. Anorectal manometry was performed before and at 6 months after treatment to measure anal resting (ARP) and squeeze pressure (SP), squeeze endurance (SE), the rectoanal inhibitory reflex (RAIR), rectal volumetry of first sensation (FS), first urge (FU), maximum tolerable volume (MTV) and rectal compliance (RC). RESULTS: Twenty-four patients were included in the study, of whom 11 underwent EMR and 13 underwent TEM. The mean adenoma size was 51 +/- 19 mm and the median distance from the anal verge was 3 cm (interquartile range 1-10 cm). Follow-up data were available from 20 patients; one patient had died and three had undergone total mesorectal excision. Incontinence for liquid stool and Wexner score decreased significantly after treatment. In contrast, none of the measured parameters of anorectal motility (ARP, SP, SE, RAIR, RC) and perception (FS, FU, MTV) was affected by adenoma resection. No differences were found in baseline and follow-up incontinence and functional parameters between intervention groups, except for postprocedural ARP, which was lower after TEM than after EMR. CONCLUSION: Continence in patients with a large rectal adenoma improved after EMR or TEM, probably due to decreased rectal mucus production. Anal sphincter pressure, rectoanal reflexes, rectal sensation and compliance were not affected by adenoma resection. PMID- 23746077 TI - Facile one-step synthesis of inorganic-framework molecularly imprinted TiO2/WO3 nanocomposite and its molecular recognitive photocatalytic degradation of target contaminant. AB - Inorganic-framework molecularly imprinted TiO2/WO3 nanocomposites with molecular recognitive photocatalytic activity were first prepared successfully by a facile one-step sol-gel method using 2-nitrophenol and 4-nitrophenol as template molecules, and tetrabutyl orthotitanate as titanium source as well as the precursor of functional monomer which could complex with template molecules. The template molecules could be completely removed by means of high-temperature calcination, avoiding the traditional extraction procedures that are time- as well as solvent-consuming. Compared to nonimprinted TiO2/WO3, the molecularly imprinted TiO2/WO3 shows a much higher adsorption capacity and selectivity toward the template molecules. The enhancement in terms of adsorption capacity and selectivity can be attributed to the chemical interaction between target molecules and imprinted cavities, as well as size matching between imprinted cavities and target molecules. The photocatalytic activity of molecularly imprinted TiO2/WO3 toward the target molecules is more than two times that of non imprinted TiO2/WO3, a result of selective adsorption of target molecules on molecularly imprinted TiO2/WO3. The formation pathway of intermediate products in 2-nitrophenol and 4-nitrophenol degradation process was provided. Moreover, molecularly imprinted TiO2/WO3 exhibits high stability. The results indicate that inorganic-framework molecularly imprinted TiO2/WO3 nanocomposites have a promising prospect in the treatment of wastewater for irrigation. PMID- 23746079 TI - Surface electromyography findings in unilateral myofascial pain patients: comparison of painful vs. non painful sides. AB - OBJECTIVES: To answer the clinical research question: in patients with myofascial pain, are there any differences in the surface electromyography (sEMG) activity of muscles of the painful and nonpainful sides that can be detected by commercially available devices? METHODS: The study sample (N = 39; 64% F, mean age 35.7 +/- 15 years) consisted of patients seeking for temporomandibular disorders Temporomandibular Disorders (TMD) treatment and meeting Research Diagnostic Criteria for TMD (RDC/TMD) diagnosis of myofascial pain, with pain referred only in muscles on one side. They underwent sEMG of jaw muscles to record levels of standardized sEMG activity at rest, as well as during maximum clenching on teeth for the four investigated muscles, viz., bilateral masseter and temporalis. The existence of differences between sEMG values of muscles of the painful and nonpainful sides during the standardization test (i.e., clenching on cotton rolls) at rest and during clenching on teeth was assessed. RESULTS: At the study population level, differences between the sEMG values of muscles of the painful and nonpainful sides were not significant in any conditions, viz., either at rest or during clenching tasks. At the individual level, the difference between the sEMG activity of painful and nonpainful sides was very variable. CONCLUSIONS: The above findings were not supportive of the existence of any detectable difference in sEMG activity between jaw muscles of the painful and nonpainful sides in patients with unilateral myofascial pain. Centrally mediated mechanism for pain adaptation may explain these findings, and the role of sEMG as a diagnostic tool for muscle pain needs to be carefully reconceptualized. PMID- 23746080 TI - Age-related differences revealed in Australian fur seal Arctocephalus pusillus doriferus gut microbiota. AB - The gut microbiota of Australian fur seals (Arctocephalus pusillus doriferus) was examined at different age classes using fluorescent in situ hybridisation (FISH) and 16S rRNA gene pyrosequencing. The FISH results indicated that in the fur seal groups, the predominant phyla are Firmicutes (22.14-67.33%) followed by Bacteroidetes (3.11-15.45%) and then Actinobacteria (1.4-5.9%) consistent with other mammals. Phylum Proteobacteria had an initial abundance of 1.8% in the 2 month-old pups, but < 1% of bacterial numbers for the other fur seal age groups. Significant differences did occur in the abundance of Clostridia, Lactobacilli and Bifidobacteria between 2 months pups and 9 months pups and adult fur seals. Results from the 16S rRNA gene pyrosequencing supported the FISH data and identified significant differences in the composition of Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Verrucomicrobia and Fusobacteria at all ages. Class Clostridia in phylum Firmicutes dominates the microbiota of the 2 months and 9 months seal pups, whilst class Bacilli dominates the 6 months pups. In addition, a high level of dissimilarity was observed between all age classes. This study provides novel insight into the gut microbiota of Australian fur seals at different age classes. PMID- 23746081 TI - Targeting peroxisome proliferator-activated receptor gamma for generation of antidiabetic drug. AB - The incidence of Diabetes Mellitus (DM) has increased to alarming levels not only in developed countries but also in developing and underdeveloped countries. Scientific data have made it clear by now that patients with DM are predisposed to many other diseases. One of the worst associations of DM is with obesity and the number of DM patients with obesity is increasing at a very fast pace due to dramatic change in life style around the world in last few decades. This necessitates the discovery of new drugs to treat increasing numbers of people with both DM and obesity. Peroxisome Proliferator activated receptor gamma (PPARgamma) is a well known target for DM and thiazolidiniones (TZDs; a common class of antidiabetic drug) which includes rosiglitazone and pioglitazone act through PPARgamma. Recent studies have demonstrated that PPARgamma apart from being important in glucose utilization also plays a critical role in lipid metabolism and energy homeostasis affecting long-term metabolic status. The possibility of selective modulation of PPARgamma has opened up a whole new avenue of research and has the potential of producing some drug which can simultaneously fight both DM and obesity, without the side-effects of the currently available PPARgamma modulators. Here, we discuss various aspects of selective modulation of PPARgamma action. PMID- 23746082 TI - Left atrial massive thrombus formation on the transseptal sheath despite adequate anticoagulation with warfarin and heparin during pulmonary vein isolation. PMID- 23746078 TI - Engineering of switchable aptamer micelle flares for molecular imaging in living cells. AB - Simultaneous monitoring of the expression, distribution, and dynamics of biological molecules in living cells is one of the most challenging tasks in the analytical sciences. The key to effective and successful intracellular imaging is the development of delivery platforms with high efficiency and ultrasensitive molecular probes for specific targets of interest. To achieve these goals, many nanomaterials are widely used as carriers to introduce nucleic acid probes into living cells for real-time imaging of biomolecules. However, limitations on their use include issues of cytotoxicity and delivery efficiency. Herein, we propose a switchable aptamer micelle flare (SAMF), formed by self-assembly of an aptamer switch probe-diacyllipid chimera, to monitor ATP molecules inside living cells. Similarity of hydrophobic composition between diacyllipids in the micelle flares and phospholipid bilayers in the dynamic membranes of living cells allows SAMFs to be uptaken by living cells more efficiently than aptamer switch probes without external auxiliary. Switchable aptamers were found to bind target ATP molecules with high selectivity and specificity, resulting in restoration of the fluorescence signal from "OFF" to "ON" state, thus indicating the presence of the analyte. These switchable aptamer micelle flares, which exhibit cell permeability and nanoscale controllability, show exceptional promise for molecular imaging in bioanalysis, disease diagnosis, and drug delivery. PMID- 23746083 TI - Comparative digestibility of low-quality grass hay by two breeds of cattle differing in mature live weight. AB - The digestive capacity of the Portuguese native breed of Barrosao cattle and the Holstein-Friesian breed was measured when fed meadow hay (72-74 g CP and 641-671 g NDF/kg dry matter), offered either alone or supplemented with soya bean meal (150 g/kg dry matter), at maintenance level. Four mature cows of each breed were used. Average initial live weight (LW) was 457 and 635 kg for the Barrosao and the Holstein-Friesian cows respectively. The organic matter digestibility (OMD) of the meadow hay was higher in Holstein-Friesian than in Barrosao cows (p < 0.08) whether supplemented or not. The neutral detergent fibre digestibility of the hay was also higher in Holstein-Frisian when the hay was fed alone (p < 0.08). The soya bean meal supplementation increased the OMD and the NDFD digestibility of the total diet (p < 0.05), but not the OMD digestibility of the hay (p > 0.05). The results obtained in this study suggest a higher ability to digest fibre in the large dairy breed than in the small native breed. This suggestion is also supported by previous findings with sheep breeds largely differing in mature live weight. PMID- 23746085 TI - Control of Schottky barriers in single layer MoS2 transistors with ferromagnetic contacts. AB - MoS2 and related metal dichalcogenides (MoSe2, WS2, WSe2) are layered two dimensional materials that are promising for nanoelectronics and spintronics. For instance, large spin-orbit coupling and spin splitting in the valence band of single layer (SL) MoS2 could lead to enhanced spin lifetimes and large spin Hall angles. Understanding the nature of the contacts is a critical first step for realizing spin injection and spin transport in MoS2. Here, we have investigated Co contacts to SL MoS2 and find that the Schottky barrier height can be significantly decreased with the addition of a thin oxide barrier (MgO). Further, we show that the barrier height can be reduced to zero by tuning the carrier density with back gate. Therefore, the MgO could simultaneously provide a tunnel barrier to alleviate conductance mismatch while minimizing carrier depletion near the contacts. Such control over the barrier height should allow for careful engineering of the contacts to realize spin injection in these materials. PMID- 23746084 TI - Design, synthesis, and biological evaluation of pyrazolo[3,4-d]pyrimidines active in vivo on the Bcr-Abl T315I mutant. AB - Starting from our in-house library of pyrazolo[3,4-d]pyrimidines, a cross-docking simulation was conducted on Bcr-Abl T315I mutant. Among the selected compounds (2a-e), the 4-bromo derivative 2b showed the best activity against the Bcr-Abl T315I mutant. Deeper computational studies highlighted the importance of the bromine atom in the para position of the N1 side chain phenyl ring for the interaction with the T315I mutant. A series of 4-bromo derivatives was thus synthesized and biologically evaluated. Compound 2j showed a good balance of different ADME properties, high activity in cell-free assays, and a submicromolar potency against T315I Bcr-Abl expressing cells. In addition, it was converted into a water-soluble formulation by liposome encapsulation, preserving a good activity on leukemic T315I cells and avoiding the use of DMSO as solubilizing agent. In vivo studies on mice inoculated with 32D-T315I cells and treated with 2j showed a more than 50% reduction in tumor volumes. PMID- 23746086 TI - Epidermolysis bullosa simplex: greater penetrance due to a keratin 5 gene variant. PMID- 23746087 TI - Spectral analysis based on fast Fourier transformation (FFT) of surveillance data: the case of scarlet fever in China. AB - Many infectious diseases exhibit repetitive or regular behaviour over time. Time domain approaches, such as the seasonal autoregressive integrated moving average model, are often utilized to examine the cyclical behaviour of such diseases. The limitations for time-domain approaches include over-differencing and over fitting; furthermore, the use of these approaches is inappropriate when the assumption of linearity may not hold. In this study, we implemented a simple and efficient procedure based on the fast Fourier transformation (FFT) approach to evaluate the epidemic dynamic of scarlet fever incidence (2004-2010) in China. This method demonstrated good internal and external validities and overcame some shortcomings of time-domain approaches. The procedure also elucidated the cycling behaviour in terms of environmental factors. We concluded that, under appropriate circumstances of data structure, spectral analysis based on the FFT approach may be applicable for the study of oscillating diseases. PMID- 23746088 TI - Sun-induced frowning fosters aggressive feelings. AB - We tested whether aggressiveness can be triggered by the involuntary frowning that occurs when people face the sun, due to the fact that sun-induced frowning involves the same pattern of facial muscle activation as in the expression of anger (interestingly, Charles Darwin remarked on the sunshade-like nature of frowning). In line with data showing that experimentally and unobtrusively induced facial and body displays facilitate congruent feelings, we found that participants walking against the sun without sunglasses scored higher in a self report measure of anger and aggression compared to those walking with the sun behind and/or wearing sunglasses. We also suggest that frowning at the sun affects mood very quickly, because we did not find any effect of walking time on self-reported aggressiveness. Our results provide the first evidence of the ecological validity of the facial feedback hypothesis. PMID- 23746089 TI - Adult acute calcific discitis confined to the nucleus pulposus in the cervical spine: case report. AB - Acute calcific discitis is a rare condition in the pediatric population and has been reported in only 2 instances in the adult population. This report describes a case of acute calcific discitis that uniquely presented in the adult cervical spine. A 22-year-old woman presented with the chief complaint of sudden-onset neck pain. Nonsurgical management, including nonsteroidal antiinflammatory drugs, provided moderate symptom relief. Radiography revealed nucleus pulposus calcification at the C2-3 level. Contrast-enhanced MRI did not reveal any additional abnormalities. Further nonsurgical management, including physical therapy and nonsteroidal antiinflammatory drugs, led to complete symptom relief within 6 months. Follow-up imaging demonstrated that the calcification had nearly resolved. Acute calcific discitis should be managed conservatively; the prognosis for a complete recovery is excellent. The pathophysiology of the disorder is yet to be elucidated, and the disorder is not exclusive to the pediatric population. PMID- 23746090 TI - Changes in pain behavior and glial activation in the spinal dorsal horn after pulsed radiofrequency current administration to the dorsal root ganglion in a rat model of lumbar disc herniation: laboratory investigation. AB - OBJECT: Herniated discs can induce sciatica by mechanical compression and/or chemical irritation caused by proinflammatory cytokines. Using immunohistochemistry methods in the dorsal horn of a rat model of lumbar disc herniation, the authors investigated the effects of pulsed radiofrequency (PRF) current administration to the dorsal root ganglion (DRG) on pain-related behavior and activation of microglia, astrocytes, and mitogen-activated protein kinase. METHODS: A total of 33 Sprague-Dawley rats were randomly assigned to either a sham-operated group (n = 10) or a nucleus pulposus (NP)-exposed group (n = 23). Rats in the NP-exposed group were further subdivided into NP exposed with sham stimulation (NP+sham stimulation, n = 10), NP exposed with PRF (NP+PRF, n = 10), or euthanasia 10 days after NP exposure (n = 3). The DRGs in the NP+PRF rats were exposed to PRF waves (2 Hz) for 120 seconds at 45 V on postoperative Day 10. Rats were tested for mechanical allodynia 10 days after surgery and at 8 hours, 1 day, 3 days, 10 days, 20 days, and 40 days after PRF administration. Immunohistochemical staining of astrocytes (glial fibrillary acidic protein), microglia (OX-42), and phosphorylated extracellular signal-regulated kinases (pERKs) in the spinal dorsal horn was performed at 41 days after PRF administration. RESULTS: Starting at 8 hours after PRF administration, mechanical withdrawal thresholds dramatically increased; this response persisted for 40 days (p < 0.05). After PRF administration, immunohistochemical expressions of OX-42 and pERK in the spinal dorsal horn were quantitatively reduced (p < 0.05). CONCLUSIONS: Pulsed radiofrequency administration to the DRG reduced mechanical allodynia and downregulated microglia activity and pERK expression in the spinal dorsal horn of a rat model of lumbar disc herniation. PMID- 23746091 TI - Arthroplasty. PMID- 23746092 TI - Risk to the vertebral artery during C-2 translaminar screw placement: a thin-cut computerized tomography angiogram-based morphometric analysis: clinical article. AB - OBJECT: The goal of this study was to characterize the anatomy relevant to placement of crossing C-2 translaminar screws, including morphometric data, and to evaluate the risk of violating the vertebral artery (VA) during the screw placement. Placement of bilateral crossing C-2 translaminar screws has become an increasingly popular method for dorsal C-2 instrumentation as it is felt to avoid the known risk of VA injury associated with C1-2 transarticular screw fixation and C-1 lateral mass-C-2 pars screw fixation. METHODS: The source images from 50 CT angiograms of the neck obtained from October to November 2007 were studied. Digital imaging software was used to measure lamina thickness and maximum screw length, perform angulation of screw trajectories in the axial plane, and evaluate the potential for VA injury. In cases where the VA could be injured, the distance between the maximal screw length and artery was measured. Logistic regression was performed to evaluate lamina width, axial angle, and screw length for predicting the potential for VA injury. RESULTS: Mean lamina thickness, axial angle, and maximal screw length were determined for 100 laminae, and a potential for VA injury was noted in 55 laminae. The anatomically defined ideal screw length was longer in laminae with potential for VA injury than in laminae with no apparent risk (35.2 vs 33.6 mm, p = 0.0131). Only increasing optimal screw length was noted to be a statistically significant predictor of potential VA injury (p = 0.0159). The "buffer zone" (the distance between an optimally placed screw and the VA) was 5.6 +/- 1.9 mm (mean +/- SD, range 1.8-11.4 mm). A screw limited to 28 mm in length appeared to be safe in all laminae studied. CONCLUSIONS: Crossing C-2 translaminar screws have been reported to be safe and effective. In addition to morphometric characteristics, the authors have found that screws placed in this trajectory could jeopardize the vertebral arteries in the foramen transversarium or the C1-2 interval. A C-2 translaminar screw limited to 28 mm in length appeared to be safe in all 100 screw trajectories studied in this series. PMID- 23746093 TI - Midbrain atrophy is not a biomarker of progressive supranuclear palsy pathology. AB - BACKGROUND AND PURPOSE: Midbrain atrophy is a characteristic feature of progressive supranuclear palsy (PSP), although it is unclear whether it is associated with the PSP syndrome (PSPS) or PSP pathology. The aim of the present study was to determine whether midbrain atrophy is a useful biomarker of PSP pathology, or whether it is only associated with typical PSPS. METHODS: All autopsy-confirmed subjects were identified with the PSP clinical phenotype (i.e. PSPS) or PSP pathology and a volumetric MRI. Of 24 subjects with PSP pathology, 11 had a clinical diagnosis of PSPS (PSP-PSPS), and 13 had a non-PSPS clinical diagnosis (PSP-other). Three subjects had PSPS and corticobasal degeneration pathology (CBD-PSPS). Healthy control and disease control groups (i.e. a group without PSPS or PSP pathology) and a group with CBD pathology and corticobasal syndrome (CBD-CBS) were selected. The midbrain area was measured in all subjects. [Correction added on 21 June 2013, after first online publication: the abbreviation of corticobasal degeneration pathology was changed from CBD-PSP to CBD-PSPS.] RESULTS: The midbrain area was reduced in each group with clinical PSPS (with and without PSP pathology). The group with PSP pathology and non-PSPS clinical syndromes did not show reduced midbrain area. Midbrain area was smaller in the subjects with PSPS than in those without PSPS (P < 0.0001), with an area under the receiver operator curve of 0.99 (0.88, 0.99). A midbrain area cut-point of 92 mm(2) provided optimum sensitivity (93%) and specificity (89%) for differentiation. CONCLUSION: Midbrain atrophy is associated with the clinical presentation of PSPS, but not with the pathological diagnosis of PSP in the absence of clinical PSPS. This finding has important implications for the utility of midbrain measurements as diagnostic biomarkers for PSP pathology. PMID- 23746094 TI - Hair in newborns and infants: clinical and dermoscopic evaluation of 45 cases. AB - BACKGROUND: The literature still lacks comprehensive assessments on the features of neonatal hair and scalp characteristics. OBJECTIVES: To evaluate the clinical and dermoscopic features of scalp hair in newborns, including measurement of hair density, length and diameter. METHODS: Forty-five newborns were recruited for the study. For each patient, data regarding sex, age at consultation, delivery method, gestational age and maternal age at delivery were collected. A clinical score of hair density was created by investigators in order to divide the neonates into two groups: group 1 included neonates with poor and slightly poor hair density and group 2 included neonates with quite good and good hair density. Each patient underwent scalp videodermatoscopy. RESULTS: Based on their clinical score, 15 newborns had good hair density, while 30 had poor hair density. Among the parameters evaluated by the investigators, only weight at birth significantly correlated with neonatal hair density. Two neonates presented a frontal-temporal pattern of hair loss. Videodermatoscopy revealed that nine neonates, all in the poor hair density group, had a particular hair shaft dermoscopic feature, characterized by the presence of widespread thin hair. CONCLUSION: On the basis of the results obtained from our study, we propose a new classification of transient neonatal hair loss. We have found two different hair types: 'neonatal type', rarely observed, that appears in the first 4 weeks of life with a frontal temporal pattern; and 'classic type', more frequently observed, appearing at 8-12 weeks of life with a predominant occipital pattern. PMID- 23746095 TI - Diffuse glioma detection. PMID- 23746096 TI - Obsessive-compulsive disorder and cingulotomy. PMID- 23746097 TI - Deep brain stimulation and aggression. PMID- 23746098 TI - Prevalence of patient safety indicators and hospital-acquired conditions in those treated for unruptured cerebral aneurysms: establishing standard performance measures using the Nationwide Inpatient Sample database. AB - OBJECT: The Agency for Healthcare Research and Quality (AHRQ) patient safety indicators (PSIs) and the Centers for Medicare and Medicaid Services hospital acquired conditions (HACs) are metrics used to gauge the quality of health care provided by health care institutions. The PSIs and HACs are publicly reported metrics and are directly linked to reimbursement for services. To better understand the prevalence of these adverse events in hospitalized patients treated for unruptured cerebral aneurysms, the authors determined the incidence rates of PSIs and HACs among patients with a diagnosis of unruptured aneurysm in the Nationwide Inpatient Sample (NIS) database. METHODS: The NIS, part of the AHRQ's Healthcare Cost and Utilization Project, was queried for all hospitalizations between 2002 and 2010 involving coiling or clipping of unruptured cerebral aneurysms. The incidence rate for each PSI and HAC was determined by searching the hospital records for ICD-9 codes. The SAS statistical software package was used to calculate incidences and perform multivariate analyses to determine the effects of patient variables on the probability of each indicator developing. RESULTS: There were 54,589 hospitalizations involving unruptured cerebral aneurysms in the NIS database for the years 2002-2010; 8314 patients (15.2%) underwent surgical clipping and 9916 (18.2%) were treated with endovascular coiling. One thousand four hundred ninety-two PSI and HAC events occurred among the 8314 patients treated with clipping; at least 1 PSI or HAC occurred in 14.6% of these patients. There were 1353 PSI and HAC events among the 9916 patients treated with coiling; at least 1 PSI or HAC occurred in 10.9% of these patients. Age, sex, and comorbidities had statistically significant associations with an adverse event. Compared with the patients having no adverse event, those having at least 1 PSI during their hospitalizations had significantly longer hospital stays (p < 0.0001), higher hospital costs (p < 0.0001), and higher mortality rates (p < 0.0001). CONCLUSIONS: These results estimate baseline national rates of PSIs and HACs in patients with unruptured cerebral aneurysms. These data may be used to gauge individual institutional quality of care and patient safety metrics in comparison with national data. PMID- 23746099 TI - Contralateral L-6 nerve root transfer to repair lumbosacral plexus root avulsion: experimental study in rhesus monkeys. AB - OBJECT: Nerve transfer is used for brachial plexus injuries but has rarely been applied to repairs in the lower extremities. The aim of this study was to evaluate the feasibility and effectiveness of using the contralateral L-6 nerve root to repair lumbosacral plexus root avulsions. METHODS: Eighteen rhesus monkeys were randomized into 3 groups. In the experimental group, the left L4-7 and S-1 nerve roots were avulsed and the right L-6 nerve root was transferred to the left inferior gluteal nerve and the sciatic nerve branch innervating the hamstrings. In the control group, the left L4-7 and S-1 nerve roots were avulsed and nerve transfer was not performed. In the sham operation group, the animals underwent a procedure that did not involve nerve avulsion and nerve transfer. Functional outcomes were measured by electrophysiological study, muscle mass investigation, and histological study. RESULTS: The mean amplitudes of the compound muscle action potentials from the gluteus maximus and biceps femoris in the experimental group were higher than those in the control group but lower than those in the sham group (p < 0.05). The muscle mass and myofiber cross-sectional area of these muscles were heavier and larger than those in the control group (p < 0.05). The number of myelinated nerve fibers of the inferior gluteal nerve and the branch of the sciatic nerve innervating the hamstrings in the control group was significantly smaller than the number in the experimental and sham groups (p < 0.01). CONCLUSIONS: In this animal model, the contralateral L-6 (analogous to S 1 in humans) nerve root can be used to repair lumbosacral plexus root avulsion. PMID- 23746100 TI - Limitations of nerve repair of segmental defects using acellular conduits. AB - The authors present the case of a 20-year-old man who, 3 months after his initial injury, underwent repair of a 1.7-cm defect of the ulnar nerve at the wrist; repair was performed with an acellular nerve allograft. Given the absence of clinical or electrophysiological recovery at 8 months postrepair, the patient underwent reexploration, excision of the "regenerated cable," and rerepair of the ulnar nerve with sural nerve autografts. Histology of the cable demonstrated minimal axonal regeneration at the midpoint of the repair. At the 6- and 12-month follow-ups of the sural nerve graft repair, clinical and electrophysiological evidence of both sensory and motor reinnervation of the ulnar nerve and associated hand muscles was demonstrated. In this report, the authors describe a single case of failed acellular nerve allograft and correlate the results with basic science and human studies reporting length and diameter limitations in human nerve repair utilizing grafts or conduits devoid of viable Schwann cells. PMID- 23746101 TI - Pure arterial malformation of the posterior cerebral artery: importance of its recognition. AB - The finding of dilated, elongated, and tortuous vessels on brain imaging should prompt clinicians to determine what vascular anomaly is present. Importantly, not all suspicious serpentine flow voids are manifestations of arteriovenous malformations or arteriovenous fistulas. Other types of intracranial vasculopathies should also be considered. The authors report a rare case of dilated, tortuous, and redundant left posterior communicating artery and left P2 segment of the posterior cerebral artery identified in a young healthy adult that remained stable over a 30-year period. Dynamic and 3D images were critical for determining the type of vascular anomaly and for guiding appropriate management. The authors propose that this case represents a pure arterial malformation and discuss its distinguishing features. PMID- 23746102 TI - Long-term results of posteromedial hypothalamic deep brain stimulation for patients with resistant aggressiveness. AB - OBJECT: Erethism describes severe cases of unprovoked aggressive behavior, usually associated with some degree of mental impairment and gross brain damage. The etiology can be epileptic, postencephalitic, or posttraumatic, or the condition can be caused by brain malformations or perinatal insults. Erethism is often refractory to medication, and patients must often be interned in institutions, where they are managed with major restraining measures. The hypothalamus is a crucial group of nuclei that coordinate behavioral and autonomic responses and play a central role in the control of aggressive behavior. Deep brain stimulation (DBS) of the posteromedial hypothalamus (PMH) has been proposed as a treatment for resistant erethism, although experience with this treatment around the world is scarce. The objective of this study was to examine the long-term outcome of PMH DBS in 6 patients with severe erethism treated at the authors' institution. METHODS: Medical records of 6 patients treated with PMH DBS for intractable aggressiveness were reviewed. The therapeutic effect on behavior was assessed by the Inventory for Client and Agency Planning preoperatively and at the last follow-up visit. RESULTS: Two patients died during the follow-up period due to causes unrelated to the neurosurgical treatment. Five of 6 patients experienced a significant reduction in aggressiveness (the mean Inventory for Client and Agency Planning general aggressiveness score was -47 at baseline and -25 at the last follow-up; mean follow-up 3.5 years). Similar responses were obtained with low- and high frequency stimulation. In 4 cases, the patients' sleep patterns became more regular, and in 1 case, binge eating and polydipsia ceased. One of the 3 patients who had epilepsy noticed a 30% reduction in seizure frequency. Another patient experienced a marked sympathetic response with high-frequency stimulation during the first stimulation trial, but this subsided when stimulation was set at low frequency. A worsening of a previous headache was noted by 1 patient. There were no other side effects. CONCLUSIONS: In this case series, 5 of 6 patients with pathological aggressiveness had a reduction of their outbursts of violence after PMH DBS, without significant adverse effects. Prospective controlled studies with a larger number of patients are needed to confirm these results. PMID- 23746103 TI - Predictors of mortality in nontraumatic subdural hematoma. AB - OBJECT: Subdural hematoma (SDH) is a common diagnosis in neurosurgical and neurocritical practice. Comprehensive outcome data are lacking for nontraumatic SDH. The authors determined which factors are associated with in-hospital mortality in a large sample of patients with nontraumatic SDH. METHODS: Using the Nationwide Inpatient Sample, the authors selected adults who had been hospitalized in the US between 2007 and 2009 and in whom a primary diagnosis of nontraumatic SDH (ICD-9-CM code 432.1) had been made. Demographics, comorbidities, surgical treatment, and discharge outcomes were identified. Univariate and multivariate analyses were performed to identify predictors of in hospital mortality. RESULTS: Among 14,093 patients with acute nontraumatic SDH, the mean age was 71.4 +/- 14.8 (mean +/- standard deviation). In addition, 22.2% of the patients were admitted during the weekend. Surgical evacuation was performed in 51.4% of the patients, and 11.8% of all patients died during hospitalization. In multivariate analyses, patient age (adjusted OR 1.02, 95% CI 1.012-1.022), congestive heart failure (adjusted OR 1.42, 95% CI 1.19-1.71), warfarin use (adjusted OR 1.41, 95% CI 1.17-1.70), coagulopathy (adjusted OR 2.14, 95% CI 1.75-2.61), mechanical ventilation (adjusted OR 16.85, 95% CI 14.29 19.86), and weekend admission (adjusted OR 1.19, 95% CI 1.02-1.38) were independent predictors of in-hospital mortality. Race (Hispanic: adjusted OR 0.65, 95% CI 0.51-0.83; black: adjusted OR 0.78, 95% CI 0.63-0.96), urban hospital location (adjusted OR 0.69, 95% CI 0.54-0.89), and surgical SDH evacuation (adjusted OR 0.52, 95% CI 0.45-0.60) were strong independent predictors for decreased mortality. CONCLUSIONS: One in 9 patients with nontraumatic SDH dies during hospitalization. Among the several predictors of in hospital mortality, the weekend effect and treatment with surgical evacuation are potentially modifiable factors. Further investigation may lead to improvements in management and outcomes. PMID- 23746104 TI - Transplantation of Schwann cells in a collagen tube for the repair of large, segmental peripheral nerve defects in rats. AB - OBJECT: Segmental nerve defects pose a daunting clinical challenge, as peripheral nerve injury studies have established that there is a critical nerve gap length for which the distance cannot be successfully bridged with current techniques. Construction of a neural prosthesis filled with Schwann cells (SCs) could provide an alternative treatment to successfully repair these long segmental gaps in the peripheral nervous system. The object of this study was to evaluate the ability of autologous SCs to increase the length at which segmental nerve defects can be bridged using a collagen tube. METHODS: The authors studied the use of absorbable collagen conduits in combination with autologous SCs (200,000 cells/MUl) to promote axonal growth across a critical size defect (13 mm) in the sciatic nerve of male Fischer rats. Control groups were treated with serum only-filled conduits of reversed sciatic nerve autografts. Animals were assessed for survival of the transplanted SCs as well as the quantity of myelinated axons in the proximal, middle, and distal portions of the channel. RESULTS: Schwann cell survival was confirmed at 4 and 16 weeks postsurgery by the presence of prelabeled green fluorescent protein-positive SCs within the regenerated cable. The addition of SCs to the nerve guide significantly enhanced the regeneration of myelinated axons from the nerve stump into the proximal (p < 0.001) and middle points (p < 0.01) of the tube at 4 weeks. The regeneration of myelinated axons at 16 weeks was significantly enhanced throughout the entire length of the nerve guide (p < 0.001) as compared with their number in a serum-only filled tube and was similar in number compared with the reversed autograft. Autotomy scores were significantly lower in the animals whose sciatic nerve was repaired with a collagen conduit either without (p < 0.01) or with SCs (p < 0.001) when compared with a reversed autograft. CONCLUSIONS: The technique of adding SCs to a guidance channel significantly enhanced the gap distance that can be repaired after peripheral nerve injury with long segmental defects and holds promise in humans. Most importantly, this study represents some of the first essential steps in bringing autologous SC-based therapies to the domain of peripheral nerve injuries with long segmental defects. PMID- 23746106 TI - Petroclival tumors. PMID- 23746105 TI - A magnetic resonance imaging, histological, and dose modeling comparison of focused ultrasound, radiofrequency, and Gamma Knife radiosurgery lesions in swine thalamus. AB - OBJECT: The purpose of this study was to use MRI and histology to compare stereotactic lesioning modalities in a large brain model of thalamotomy. METHODS: A unilateral thalamotomy was performed in piglets utilizing one of 3 stereotactic lesioning modalities: focused ultrasound (FUS), radiofrequency, and radiosurgery. Standard clinical lesioning parameters were used for each treatment; and clinical, MRI, and histological assessments were made at early (< 72 hours), subacute (1 week), and later (1-3 months) time intervals. RESULTS: Histological and MRI assessment showed similar development for FUS and radiofrequency lesions. T2-weighted MRI revealed 3 concentric lesional zones at 48 hours with resolution of perilesional edema by 1 week. Acute ischemic infarction with macrophage infiltration was most prominent at 72 hours, with subsequent resolution of the inflammatory reaction and coalescence of the necrotic zone. There was no apparent difference in ischemic penumbra or "sharpness" between FUS or radiofrequency lesions. The radiosurgery lesions presented differently, with latent effects, less circumscribed lesions at 3 months, and apparent histological changes seen in white matter beyond the thalamic target. Additionally, thermal and radiation lesioning gradients were compared with modeling by dose to examine the theoretical penumbra. CONCLUSIONS: In swine thalamus, FUS and radiosurgery lesions evolve similarly as determined by MRI, histological examination, and theoretical modeling. Radiosurgery produces lesions with more delayed effects and seemed to result in changes in the white matter beyond the thalamic target. PMID- 23746107 TI - Garlic and cardioprotection: insights into the molecular mechanisms. AB - Garlic is widely recognized for its immense therapeutic potential. Garlic has been shown to exert its beneficial effects against a wide spectrum of diseases, including cancer, diabetes, and microbial infections, as well as immunological and cardiovascular disorders. Most of the research on garlic has indicated that garlic and its active compounds are effective in reducing cardiovascular and metabolic risk by normalizing abnormal plasma lipids, oxidized low density lipoproteins, abnormal platelet aggregation, high blood pressure, and cardiac injury. Some of the beneficial effects of dietary garlic against cardiovascular disorders are mediated via the generation of hydrogen sulfide and nitric oxide in cardiomyocytes and endothelial cells. Garlic has the potential to protect the heart against myocardial infarction, doxorubicin-induced cardiotoxicity, arrhythmia, hypertrophy, and ischemia-reperfusion injury. The induction of cardiac endogenous antioxidants and the reduction of lipid peroxidation by garlic has been reported by several different groups. Other mechanisms, such as regulating ion channels, modulating Akt signaling pathways, histone deacetylase inhibition, and cytochrome P450 inhibition, could be responsible for the cardioprotective effect of garlic. Although several mechanisms have been identified for the cardioprotective effect of garlic, there is a need for further research to identify the specific molecular mechanism of cardioprotection in different cardiac diseases. PMID- 23746108 TI - Use of latent profile analysis to assess the validity of a peer-rejected group of children. AB - The goal of this article was to validate the existence and qualities of a peer rejected group of children using latent profile analysis (LPA). Two separate racially/ethnically diverse samples (Study 1: N = 2,052 second graders; Study 2: N = 594 fourth and fifth graders) completed peer nominations of liking and disliking, from which we calculated Social Preference and Social Impact scores. These scores served as indicators in the LPAs to form LPA groups. In addition, we collected self-, teacher-, and peer-report report data on aggression, depressive symptoms, peer victimization, and social competence. In each sample, an LPA group emerged in which most children were classified as rejected using the Coie, Dodge, and Coppotelli ( 1982 ; CDC) approach (Study 1: 95%; Study 2: 86%). However, in both samples, only a minority of children classified as rejected using the CDC approach fell into this LPA group (Study 1: 46%; Study 2: 36%). The LPA group that mirrored the CDC rejected group received more maladjusted scores than all other LPA groups on aggression, depressive symptoms, peer victimization, and social competence. Furthermore, when compared to children classified as rejected using only the CDC approach, children classified as rejected under both the LPA and CDC approaches were more maladjusted in terms of all sociometric and socioemotional variables. LPA analyses across two developmental levels validated the existence of an empirically derived group of children who overlapped closely with the CDC rejected group. However, this group was considerably smaller and more maladjusted than the CDC rejected group. PMID- 23746109 TI - Macroscopic vertical alignment of nanodomains in thin films of semiconductor amphiphilic block copolymers. AB - Though several techniques have been reported on the alignment of conventional block copolymers, the macroscopic vertical orientation of semiconductor block copolymer microdomains in thin films has still not been accomplished. Here, we report the control on the alignment of nanostructures in a semiconductor amphiphilic block copolymer comprising an amorphous triphenyldiamine hole conductor block and a hydrophilic poly(styrene sulfonate) segment. Three different compositions with a hole conductor content of 57, 72, and 79 wt % were synthesized using a combination of controlled reversible addition/fragmentation transfer polymerization and "click" chemistry. All polymers feature a narrow molecular weight distribution. Cryo-TEM reveals the formation of micelles in DMF solutions of the amphiphilic copolymer having nanoscopic dimensions. The micelle size correlates well with the X-ray analysis of dried bulk samples. Atomic force microscopy (AFM) confirms the micellar structure in the as-cast films. Thermal annealing causes an aggregation of micelles but did not lead to morphologies known for conventional block copolymers. However, annealing in saturated DMF vapor induces a morphology transition and a vertical orientation of the microdomains which was determined by grazing incidence small-angle X-ray scattering and AFM. The morphology varies from lamella to cylinders with increasing content of the hole-conductor block. The orientation arises from the controlled evaporation of the solvent, a mechanism that is similar to that observed for conventional block copolymers. Our approach demonstrates the macroscopic vertical alignment of nanodomains in semiconductor block copolymers which is a key requirement for applications in hybrid devices. PMID- 23746110 TI - Effect of sacrum-perineum heat therapy on active phase labor pain and client satisfaction: a randomized, controlled trial study. AB - AIM: Reduction of labor pain is one of the most important aspects of obstetric care. Heat therapy, typically applied to the woman's back, lower abdomen, groin, and/or perineum during last stage of labor, is an easy pain relief method that does not require highly skilled care. The effectiveness of heat therapy applied to the perineum during the first stage of labor has not been evaluated. This study aimed to evaluate the effectiveness of heat therapy for pain and woman's satisfaction during physiological labor. SUBJECTS AND METHODS: Sixty primiparous women aged 18-35 years old were randomly assigned to heat therapy and control groups. Pain and satisfaction scores were measured by visual analog scale. The measurements of satisfaction were accomplished after birth. Data were analyzed by using the t-test and chi-square RESULTS: Mean pain scores in the heat therapy group were significantly lower than the control group (P < 0.05). The mean satisfaction score in the heat therapy group was significantly higher than in the control group (P < 0.05). CONCLUSION: Heat therapy, an inexpensive complementary treatment with low risk, can reduce the intensity of pain and increase mothers' satisfaction with care during the active phase of labor. PMID- 23746111 TI - The influence of isoleucine and arginine on biological activity and peptide membrane interactions of antimicrobial peptides from the bactericidal domain of AvBD4. AB - In this study, the influence of isoleucine and arginine on the biological activity and peptide-membrane interactions of linear avian beta-defensin-4 (RL38) analogs was investigated. Results of biological activities showed that the antimicrobial activities of AvBD-4 analogs were closely related to hydrophobicity and amphipathicity. The peptide GLI19 with high hydrophobicity value and amphipathicity displayed broad spectrum antimicrobial activity against both gram negative and gram-positive, whereas GLR19 with increasing multiple charges only exhibited activity against gram-negative. The interaction between peptides and the liposome membrane demonstrated that the peptides preferentially bound to negatively charged phospholipids over zwitterionic phospholipids, which supported the antimicrobial activity data. The outer membranes assay further demonstrated that GLI19 had a greater capacity than the other tested peptides to penetrate the cell membrane at a low concentration. Collectively, the peptides derived from the bactericidal domain of linear beta- defensins by truncation and hydrophobic amino acid substitution may be effective high-potential antibacterial agents. PMID- 23746112 TI - Evaluation of cell-free expression system for the production of soluble and functional human GPCR N-formyl peptide receptors. AB - Human N-formyl peptide receptors (FPRs) belong to the G protein-coupled receptors (GPCRs) superfamily, the most frequently addressed drug targets in the pharmaceutical industry, and are considered to play important roles in innate immunity and host defense mechanisms. Although still a highly challenging task, the availability of soluble and functional GPCRs including FPRs in milligram quantities is essential to spur the advancement of protein-based structural and functional studies for drug discovery. In this report, the applicability of E. coli extracts-based cell-free expression system to producing soluble and active human FPRs and hence to FPRs protein-based research was evaluated, during which human FPR3 was selected as our prototype receptor. To better solubilize the freshly expressed human FPR3, a panel of different detergents (mostly nonionic detergents) were selected and evaluated in the cell-free system devoid of natural membrane. After one-step immunoaffinity purification, the secondary structure and biological function of purified FPR3 were characterized. A final yield of 0.6 mg functional human FPR3 per ml reaction volume was obtained. The demonstrated proper folding and functionality of the cell-free produced human FPR3 opens a new avenue for the fast and efficient generation of human FPRs (and even other GPCRs) for structural and functional analysis. PMID- 23746113 TI - Signal transducer and activator of transcription 3 (Stat3) contributes to T-cell homeostasis by regulating pro-survival Bcl-2 family genes. AB - The naive T-cell pool in peripheral lymphoid tissues is fairly stable in terms of number, diversity and functional capabilities in spite of the absence of prominent stimuli. This stability is attributed to continuous tuning of the composition of the T-cell pool by various homeostatic signals. Despite extensive research into the link between signal transducer and activator of transcription 3 (Stat3) and T-cell survival, little is known about how Stat3 regulates homeostasis by maintaining the required naive T-cell population in peripheral lymphoid organs. We assessed whether the elimination of Stat3 in T cells limits T cell survival. We demonstrated that the proportion and number of single-positive thymocytes as well as T cells in the spleen and lymph nodes were significantly decreased in the Stat3-deficient group as a result of the enhanced susceptibility of Stat3-deleted T lymphocytes to apoptosis. Importantly, expression of the anti apoptotic Bcl-2 and Bcl-xL was markedly decreased in Stat3-deleted single positive thymocytes and T lymphocytes, suggesting that Stat3 helps to maintain the T-cell pool in the resting condition by promoting the expression of Bcl-2 family genes. These findings suggest the importance of Stat3 in the integration of homeostatic cues for the maintenance and functional tuning of the T-cell pool. PMID- 23746114 TI - Tools of our trade. PMID- 23746116 TI - Phantom rectum following abdominoperineal excision for rectal neoplasm: appearance and disappearance. AB - AIM: The sensation that the rectum remains or is functioning after abdominoperineal excision (APE) is called phantom rectum (PR). Its postoperative and long-term morbidity are not well documented. Informed consent may not include the risk and consequences of this condition. We assessed the incidence and morbidity of PR after APE and compared those with vs those without vertical rectus abdominis myocutaneous flaps. METHOD: Patients who underwent APE between 1 January 2004 and 31 December 2008 were identified. Preoperative radiation and operative reconstruction by vertical rectus abdominis myocutaneous (VRAM) flaps were noted. Patients were interviewed by telephone to assess the presence and timing of PR symptoms and their effect on quality of life. RESULTS: Thirty-six of 80 patients who underwent APE were available for follow-up. Twenty-three (64%) described PR symptoms including urgency to evacuate [22 (61%)], sensation of faeces in the rectum [19 (52%)] and sensation of passing flatus [17 (48%)]. Eleven (47%) who had VRAM vs 25 who did not, reported having symptoms of PR at < 3 months after APE. Patients described their symptoms as 'unchanged over time' [20 (56%)], 'gradually decreasing and ultimately disappearing' [13 (35%)] or 'worsening' [3 (9%)]. Preoperative radiation and laparoscopic approach were not associated with PR symptoms. Significantly more patients having a VRAM flap reported early PR symptoms [7/11 (64%) vs 4/25 (16%)] (P = 0.008). CONCLUSION: PR sensations were experienced by 23 (64%) patients who underwent APE for rectal cancer. VRAM reconstruction was associated with early PR presentation. The possibility of PR should be discussed preoperatively in patients undergoing APE for anorectal neoplasm. PMID- 23746117 TI - Zirconium-mediated synthesis of arsaalkene compounds from arsines and isocyanides. AB - An atom-economical synthesis of arsaalkenes via a net coupling of aryl arsines with aryl or alkyl isocyanides at zirconium is presented. Reaction of zirconium arsenido complexes (N3N)ZrAsHAr [N3N = N(CH2CH2NSiMe3)3(3-); Ar = Ph, (2) Mes (3)] with aryl and alkyl isocyanides yields arsaalkene products of the general form (N3N)Zr[NRC(H)?As(Ar)]. Two examples (5: R = Mes, Ar = Ph; 6: R = CH2Ph, Ar = Mes) were structurally characterized. Observation of intermediates in the reaction and structural characterization of the previously reported 1,1-insertion product benzylisocyanide with (N3N)ZrAsPh2 (8), (N3N)Zr[eta(2)-C(PPh2)=NCH2Ph] (9), support the mechanistic hypothesis that these reactions occur via 1,1 insertion followed by rearrangement. PMID- 23746118 TI - Living donor versus deceased donor liver transplantation: a surgeon-matched comparison of recipient morbidity and outcomes. AB - Informed consent for living donor liver transplantation (LDLT) requires that patients are provided with accurate information on the relative benefits and risks of this procedure compared with deceased donor liver transplantation (DDLT). There is strong evidence to suggest that LDLT facilitates timely transplantation to patients; however, information on the relative morbidity and death risks after LDLT as compared with DDLT is limited. A matched cohort comparison was performed matching recipients for age, MELD, date of transplant, gender, primary diagnosis, and recipient surgeon. A total of 145 LDLT were matched with 145 DDLT. LDLT had a higher overall rate of perioperative surgical complications (P = 0.009). Most of this difference was caused by a higher rate of biliary complications. However, the complications that occurred in the DDLT group tended to be more serious (P = 0.037), and these complications were strongly associated with graft loss in multivariate analysis. The 3- and 5-year graft and patient survivals were similar. In conclusion, DDLT and LDLT have different complication profiles, but comparable hospital stays and survival rates. In areas of deceased donor organ shortages, LDLT offers an excellent alternative to DDLT because it facilitates access to a liver transplant without compromising short- or medium-term recipient outcomes. PMID- 23746119 TI - Multimodality evaluation of dural arteriovenous fistula with CT angiography, MR with arterial spin labeling, and digital subtraction angiography: case report. AB - Dural arteriovenous fistulae (DAVF) are cerebrovascular lesions with pathologic shunting into the venous system from arterial feeders. Digital subtraction angiography (DSA) has long been considered the gold standard for diagnosis, but advances in noninvasive imaging techniques now play a role in the diagnosis of these complex lesions. Herein, we describe the case of a patient with right-side pulsatile tinnitus and DAVF diagnosed using computed tomography angiography, magnetic resonance with arterial spin labeling, and DSA. Implications for imaging analysis of DAVFs and further research are discussed. PMID- 23746120 TI - The mitogen-inducible gene-6 is involved in regulation of cellular senescence in normal diploid fibroblasts. AB - BACKGROUND INFORMATION: The mitogen-inducible gene-6 (Mig-6) is a non-kinase scaffolding adaptor protein. It has been shown that Mig-6 may play important roles in regulating stress response, maintaining homeostasis and functioning as a tumour suppressor. In this study, we investigated the role of Mig-6 in cellular senescence. RESULTS: Our results showed that Mig-6 is up-regulated during the senescence process. Functional analysis indicated that cells over-expressing Mig 6 have reduced DNA synthesis and showed the signs of senescence. Knockdown of Mig 6 delayed the initiation of Ras-induced cellular senescence. These results suggest that the increase of Mig-6 expression contributes to establishment of cellular senescence. Furthermore, our results showed that Mig-6 induction of senescence is related to its inhibition of EGF receptor (EGFR)/Erb B signalling. Subsequent analysis of the mechanism responsible for the up-regulation of its expression showed that FOXO3A transcriptionally up-regulates Mig-6 expression via directly binding to the FOXO response element in Mig-6 5'-flanking regulatory sequences. CONCLUSIONS: Mig-6 induces premature senescence via functioning in regulation of cellular senescence in normal diploid fibroblasts. PMID- 23746121 TI - Aminoglycoside therapy in infectious diseases. AB - INTRODUCTION: Aminoglycosides are of the oldest antibiotics. Even though representatives of the class are used in various applications, the use that has established aminoglycosides in medicine is their antimicrobial activity. AREAS COVERED: Current knowledge on mechanism of action, adverse events, strategies to overcome toxicity and increase efficacy of aminoglycosides, as well as therapeutic uses and future perspectives of this class of antibiotics. EXPERT OPINION: Aminoglycosides are still the treatment of choice for diseases such as brucellosis and plague. Toxicity, along with the discovery of equally potent and less toxic antibiotics, has shelved aminoglycosides the past 30 years. However, this has largely saved them from resistance development. Apart from retaining efficacy, strategies to overcome toxicity, especially once daily administration, has made aminoglycosides a safer choice. Further, plazomicin is a very promising synthetic aminoglycoside that escapes all clinically significant aminoglycoside modifying enzymes and has completed a clinical Phase II trial. Despite being in clinical practice for > 60 years, issues such as the synergistic role of aminoglycosides in Gram-positive endocarditis remain controversial. Prospective randomized trials are needed to clarify the benefit of aminoglycosides in this setting. Nonetheless, in an era of emerging resistance, aminoglycosides are valuable weapons against multidrug-resistant pathogens. PMID- 23746122 TI - Serum malondialdehyde levels, myeloperoxidase and catalase activities in patients with nephrotic syndrome. AB - OBJECTIVES: Some studies have indicated the pathophysiological importance of reactive oxygen species (ROS) in patients with nephrotic syndrome. Myeloperoxidase (MPO) is a leukocyte-derived enzyme-generating ROS that has been proposed to exert a wide array of pro-atherogenic effects throughout all stages of the atherosclerotic process. The aim of this study was to investigate the serum malondialdehyde (MDA) levels, MPO and catalase activities in patients with adult nephrotic syndrome. PATIENTS AND METHOD: s Twenty-four patients with nephrotic syndrome and 24 healthy controls were enrolled. Serum MPO activity, catalase activity, and MDA levels were assessed. RESULTS: Serum MPO activity and MDA levels were significantly higher in patients with nephrotic syndrome than controls (both, P<0.001), while catalase activity was significantly lower (P<0.001). Serum catalase activity was found to be significantly correlated with MPO activity (r=-0.417, P=0.003) and MDA levels (r=-0.532, P=0.007). The serum MDA levels were also found to be significantly correlated with MPO activity (r=0.419, P=0.003). CONCLUSIONS: We concluded that serum MPO activity and oxidative stress were increased and that serum catalase activity was decreased in patients with adult nephrotic syndrome. In addition, these results indicate that increased MPO activity is associated with an oxidant-antioxidant imbalance that may contribute to atherosclerosis in patients with adult nephrotic syndrome. PMID- 23746123 TI - Effect of induced mild hypothermia on two pro-inflammatory cytokines and oxidative parameters during experimental acute sepsis. AB - This study aimed to determine the effect of induced mild hypothermia (34 degrees C) on the production of two cytokines (interleukin (IL-6) and tumor necrosis factor (TNF)alpha) and reactive nitrogen and oxygen species in plasma and the heart of acutely septic rats. After anesthesia and in conditions of normothermia (38 degrees C) or mild hypothermia (34 degrees C), acute sepsis was induced by cecal ligation and perforation. For each temperature three groups were formed: (1) baseline (blood sample collected at T0 hour), (2) sham (blood sample at T4 hours) and (3) septic (blood sample at T4 hours). At either temperature sepsis induced a significant increase in plasma IL-6, TNF-alpha and HO* concentration, compared with the sham groups (P<=0.016). Compared with the normothermic septic group, septic rats exposed to mild hypothermia showed a mild decrease in TNF alpha concentration (104+/-50 pg/ml vs. 215+/-114 pg/ml; P>0.05) and a significant decrease in IL-6 (1131+/-402 pg/ml vs. 2494+/-691 pg/ml, P=0.038). At either temperature sepsis induced no enhancement within the heart of lipoperoxidation (malondialdehyde content) or antioxidant activities (superoxide dismutase and catalase). In conclusion, during acute sepsis, induced mild hypothermia appears to reduce some pro-inflammatory and oxidative responses. This may, in part, explain the beneficial effect of hypothermia on survival duration of septic rats. PMID- 23746124 TI - Electrical performance and scalability of Pt dispersed SiO2 nanometallic resistance switch. AB - Highly reproducible bipolar resistance switching was recently demonstrated in a composite material of Pt nanoparticles dispersed in silicon dioxide. Here, we examine the electrical performance and scalability of this system and demonstrate devices with ultrafast (<100 ps) switching, long state retention (no measurable relaxation after 6 months), and high endurance (>3 * 10(7) cycles). A possible switching mechanism based on ion motion in the film is discussed based on these observations. PMID- 23746125 TI - Characteristic findings of handprint and dermoscopy in reticulate acropigmentation of Kitamura. PMID- 23746126 TI - Surgical treatment of hypothalamic hamartoma causing central precocious puberty: long-term follow-up. AB - Hypothalamic hamartoma (HH) is a rare condition that often manifests as central precocious puberty (CPP). There is a lack of information available concerning the long-term effectiveness of surgery for the treatment of CPP due to HH. Here the authors describe 3 cases of CPP due to HH, with a follow-up ranging from 9 to 11 years after surgery. Three girls experienced breast growth and menses at 5-18 months of age and 5-36 months of age, respectively. Serum concentrations of luteinizing hormone, follicle-stimulating hormone, and estradiol concentrations ranged from 2.5 to 6.5 mIU/ml, 4.8-5.9 mIU/ml, and 47.9-133.0 pg/ml, respectively. Magnetic resonance imaging confirmed that CPP was caused by HH. Lesions were resected using a right pterional approach. After surgery, endocrine hormone concentrations were normalized, breasts shrunk, and menses ceased in each patient. Moreover, all of them subsequently developed normally and experienced age-appropriate onset of puberty. Each patient's height and weight were normal at the most recent follow-up (9-11 years after surgery), and none had experienced learning difficulties. Central precocious puberty due to HH can be successfully treated with resection. In the 3 cases presented, this approach was associated with both short- and long-term efficacy. PMID- 23746127 TI - Postoperative epidural hematoma covering the galeal flap in pediatric patients with moyamoya disease: clinical manifestation, risk factors, and outcomes. AB - OBJECT: Postoperative epidural hematoma (EDH), a blood collection between the inserted galeal flap and the overlying skull flap (epigaleal flap hematoma), is a frustrating complication of the surgical treatment of moyamoya disease (MMD) in pediatric patients. The symptoms of postoperative EDH are often similar to those of postoperative cerebral ischemia, and may cause confusion during clinical decision making. The authors designed this study to evaluate the incidence, clinical presentation, risk factors, and treatment outcomes of postoperative EDH in pediatric patients with MMD. METHODS: A retrospective review of 148 pediatric patients with 250 craniotomies who underwent indirect bypass revascularization surgery between January 2002 and December 2006 was performed. This group consisted of 60 male and 88 female patients, and the mean age at surgery was 7.5 years (range 1-18 years). RESULTS: Of the 250 craniotomies, postoperative EDH was detected in 32 cases. In 12 cases of EDH, surgical treatment was necessary (4.8% of 250 craniotomies). During the same period, 743 non-MMD craniotomy operations were performed. In 6 of these 743 operations, patients developed postoperative EDH that required surgical treatment, significantly less than the percentage of EDH requiring postoperative treatment in patients with MMD (0.8%, p < 0.001). The average interval between craniotomy surgery and the detection of EDH was 1.8 days (range 0-5 days) in patients with MMD and 0.5 days (range 0-2 days; p = 0.018) in the non-MMD craniotomy group. Postoperative EDH was observed in significantly fewer cases (17 of 191) when a subcutaneous drain (SCD) was inserted over the bone flap than in cases in which an SCD was not inserted (14 of 55; p = 0.001). The mean international normalized ratio of prothrombin time in the immediate postoperative blood test was 1.27 +/- 0.17 in the EDH group and 1.20 +/- 0.11 in the non-EDH group (values are expressed as the mean +/- SD; p = 0.008). Central galeal flap tenting suture and immediate postoperative platelet count were not related to the incidence of postoperative EDH following pediatric MMD surgery. CONCLUSIONS: Postoperative EDH is more likely to be found following craniotomy in patients with MMD than in those without MMD, and may occur in a delayed fashion. Insertion of an SCD and immediate correction of an abnormal value for international normalized ratio of prothrombin time can decrease the incidence of postoperative EDH following surgery for pediatric MMD. PMID- 23746128 TI - Differences in the epidemiology between paediatric and adult invasive Streptococcus pyogenes infections. AB - In order to investigate for possible differences between paediatric and adult invasive Streptococcus pyogenes (iGAS) infections, a total of 142 cases were identified in 17 Greek hospitals during 2003-2007, of which 96 were children and 46 adults. Bacteraemia, soft tissue infections, streptococcal toxic shock syndrome (STSS), and necrotizing fasciitis were the main clinical presentations (67.6%, 45.1%, 13.4%, and 12.0% of cases, respectively). Bacteraemia and lymphadenitis were significantly more frequent in children (P=0.019 and 0.021, respectively), whereas STSS was more frequent in adults (P=0.017). The main predisposing factors in children were varicella and streptococcal pharyngotonsillitis (25% and 19.8%, respectively), as opposed to malignancy, intravenous drug abuse and diabetes mellitus in adults (19.6%, 15.2% and 10.9%, respectively). Of the two dominant emm-types, 1 and 12 (28.2% and 8.5%, respectively), the proportion of emm-type 12 remained stable during the study period, whereas emm-type 1 rates fluctuated considerably. Strains of emm-type 1 from children were associated with erythromycin susceptibility, STSS and intensive-care-unit admission, whereas emm-type 12 isolates from adults were associated with erythromycin and clindamycin resistance. Finally, specific emm types were detected exclusively in adults or in children. In conclusion, several clinical and epidemiological differences were detected, that could prove useful in designing age-focused strategies for prevention and treatment of iGAS infections. PMID- 23746129 TI - Construction of an intermediate-resolution lattice model and re-examination of the helix-coil transition: a dynamic Monte Carlo simulation. AB - In protein modeling, spatial resolution and computational efficiency are always incompatible. As a compromise, an intermediate-resolution lattice model has been constructed in the present work. Each residue is decomposed into four basic units, i.e. the alpha-carbon group, the carboxyl group, the imino group, and the side-chain group, and each basic coarse-grained unit is represented by a minimum cubic box with eight lattice sites. The spacing of the lattice is about 0.56 A, holding the highest spatial resolution for the present lattice protein models. As the first report of this new model, the helix-coil transition of a polyalanine chain was examined via dynamic Monte Carlo simulation. The period of formed alpha helix was about 3.68 residues, close to that of a natural alpha-helix. The resultant backbone motion was found to be in the realistic regions of the conformational space in the Ramachandran plot. Helix propagation constant and nucleation constant were further determined through the dynamic hydrogen bonding process and torsional angle variation, and the results were used to make comparison between classical Zimm-Bragg theory and Lifson-Roig theory based on the Qian-Schellman relationship. The simulation results confirmed that our lattice model can reproduce the helix-coil transition of polypeptide and construct a moderately fine alpha-helix conformation without significantly weakening the priority in efficiency for a lattice model. PMID- 23746130 TI - Bevacizumab for macular edema secondary to retinal vein occlusion: a systematic review and meta-analysis. AB - PURPOSE: To assess the effect and safety of using single intravitreal bevacizumab (IVB) versus intravitreal triamcinolone acetonide (IVTA) and grid laser photocoagulation (GLP), or a combination of IVB and IVTA for treatment of retinal vein occlusion (RVO)-associated macular edema, mainly exploring its effects on visual acuity (VA) and central macular thickness (CMT). METHODS: Eligible studies were identified via searching databases, including Medline (PubMed), Web of Science, and the Cochrane Library, without status or other limits up to June 2012. SELECTION CRITERIA: We include randomized clinical control trials comparing 1.25 mg IVB injection with other treatment strategies, including a 4 mg IVTA injection or GLP or a combination of 1.25 mg IVB and 2 mg IVTA injection, for patients with RVO-associated macular edema. Eligible studies should report both VA and CMT outcomes, and with a minimum follow-up of 4 weeks. Results: Two authors assessed the trial quality and extracted data independently. MAIN RESULTS: Four studies were included in this study. Comparing to IVTA and GLP, IVB was more effective in improving VA at 1 month (weighted mean difference [WMD], 0.07; 95% confidence interval [CI], -0.10 to -0.05; P<0.00001), 3 months (WMD, 0.24; 95% CI, -0.28 to -0.20; P<0.00001), and 6 months during the follow-up (WMD, -0.17; 95% CI, -0.21 to -0.13; P<0.00001) in patients with RVO-associated macular edema. There was no statistical significance in reducing CMT values throughout the periods. Compared with IVB/IVTA combination, VA improvement became statistically significant at 3 months of follow-up (WMD, -0.26; 95% CI, -0.29 to 0.23; P<0.00001), while no statistical significance was found in both VA values at 1 month of follow-up and CMT values throughout the periods. The occurrence of intraocular pressure (IOP) was much lower in IVB groups. CONCLUSIONS: IVB is effective in treating patients with RVO-associated macular edema; especially if it has distinct effects, of which, VA could be improved to the utmost extent as well as by the earliest of time. IVB is also effective in decreasing CMT, but without any significant advantages over IVTA or GLP. Furthermore, IVB seems to be safer than IVTA in consideration of IOP increase. PMID- 23746131 TI - Regional melanoma incidence in England, 1996-2006: reversal of north-south latitude trends among the young female population. AB - BACKGROUND: Melanoma incidence often shows an increasing latitudinal gradient from north to south among white European populations. OBJECTIVES: To assess emerging regional melanoma incidence patterns in England. METHODS: All primary invasive cutaneous melanomas diagnosed in England in people aged 10-89 years, in 1996-2006, were ascertained. Age-standardized incidence rates by sex, age and Government Office Region were calculated for the entire population and for the white population only. Rates according to socioeconomic deprivation were further calculated among those aged under 30 years. Regional heterogeneity and latitude and deprivation trends were assessed by Poisson regression and tests for trend. RESULTS: Overall, melanoma incidence in England was highest in the South West (overall, 18.75; white, 19.03 per 100,000) and lowest in London (overall, 8.85; white, 11.22 per 100,000). Incidence significantly increased with more southerly latitudes in all white adults aged over 30 years (P < 0.0001), except women aged 30-49 years (1.8%, P = 0.10). However, these north-south latitude trends were reversed in white 10-29 year olds, with sex-specific analyses showing an absence of trend in male subjects (2.7%, P = 0.41) and a strong decreasing trend (-9.8%, P < 0.0001) in female subjects. The highest rates in the young female population occurred in the North West (5.46 per 100,000), and specifically in the second most deprived (5.69 per 100,000) and the second most affluent (6.48 per 100,000) groups. CONCLUSIONS: Melanoma incidence is high in young people in northern England, including among the moderately deprived, reversing the expected north south incidence gradients. Prevalent sunbed use in northern England and holiday sun exposure abroad may explain these emerging trends. PMID- 23746132 TI - Orthogonal chemistry for the synthesis of thiocoraline-triostin hybrids. Exploring their structure-activity relationship. AB - The natural compounds triostin and thiocoraline are potent antitumor agents that act as DNA bisintercalators. From a pharmaceutical point of view, these compounds are highly attractive although they present a low pharmacokinetic profile, in part due to their low solubility. Synthetically, they represent a tour de force because no robust strategies have been developed to access a broad range of these bicyclic (depsi)peptides in a straightforward manner. Here we describe solid phase strategies to synthesize new bisintercalators, such as thiocoraline triostin hybrids, as well as analogues bearing soluble tags. Orthogonal protection schemes (up to five from: Fmoc, Boc Alloc, pNZ, o-NBS, and Troc), together with the right concourse of the coupling reagents (HOSu, HOBt, HOAt, Oxyma, EDC, DIPCDI, PyAOP, PyBOP, HATU, COMU), were crucial to establish the synthetic plan. In vitro studies and structure-activity relationships have been shown trends in the structure-activity relationship that will facilitate the design of new bisintercalators. PMID- 23746134 TI - A Toll road to Alzheimer disease? PMID- 23746135 TI - Alzheimer's disease and frail syndrome: features overlap predictive of poor outcome. PMID- 23746133 TI - The risk of elective orthopaedic surgery for haemophilia patients: Japanese single-centre experience. AB - Haemophilic arthropathy causes pain and a severely restricted range of motion, and results in a significant reduction in quality of life. When conservative treatments have failed, orthopaedic surgery is recommended for these patients with severe haemophilic arthropathy. However, surgery for haemophilia patients is challenging due to high complication rate such as infection, delayed wound healing and mortality. The aim of this study was to evaluate the incidence of early complications and identify preoperative risk factors of surgery for haemophilia patients. We report a series of haemophilia patients undergoing elective orthopaedic surgery between 2006 and 2012. During this period, 119 surgeries in 81 patients were prepared and 118 surgeries in 80 patients were actually performed. Four deep bacterial infections and four delayed wound healings occurred within 6 months postoperatively. One patient died preoperatively and four patients died postoperatively. Only the presence of inhibitor was a significant risk factor for infection. We found no risk factor related to delayed wound healing. Our data revealed alkaline phosphatase, albumin, platelet, alpha-fetoprotein, presence of ascites and child classification C as predictors of perioperative mortality following elective orthopaedic surgery. Our role is to identify potential patients who present with risk factors for complications and attempt to seek the best determination of treatment strategy for these people. PMID- 23746136 TI - Annual advances in neurorestoratology: a summary of IANR VI and 10th GCNN conference, Bucharest, Romania, April 4-7, 2013. PMID- 23746137 TI - Brilliant Blue G: what a little more colour can be. PMID- 23746138 TI - Evidence base update for psychosocial treatments for pediatric obsessive compulsive disorder. AB - Pediatric obsessive-compulsive disorder (OCD) is a chronic and impairing condition that often persists into adulthood. Barrett, Farrell, Pina, Peris, and Piacentini (2008), in this journal, provided a detailed review of evidence-based psychosocial treatments for youth with OCD. The current review provides an evidence base update of the pediatric OCD psychosocial treatment literature with particular attention to advances in the field as well as to the methodological challenges inherent in evaluating such findings. Psychosocial treatment studies conducted since the last review are described and evaluated according to methodological rigor and evidence-based classification using the JCCAP evidence based treatment evaluation criteria (Southam-Gerow & Prinstein, this issue). Findings from this review clearly converge in support of cognitive-behavioral therapy as an effective and appropriate first line treatment for youth with OCD (either alone or in combination with medication). Although no treatment for pediatric OCD has yet to be designated as "well-established," both individual and individual family-based treatments have been shown to be "probably efficacious." Moderators and predictors of treatment outcome are discussed as are the areas where we have advanced the field and the areas where we have room to grow. The methodological and clinical challenges inherent in a review of the evidence base are reviewed. Finally, future research directions are outlined. PMID- 23746141 TI - Tuning the band gap of graphene nanoribbons synthesized from molecular precursors. AB - A prerequisite for future graphene nanoribbon (GNR) applications is the ability to fine-tune the electronic band gap of GNRs. Such control requires the development of fabrication tools capable of precisely controlling width and edge geometry of GNRs at the atomic scale. Here we report a technique for modifying GNR band gaps via covalent self-assembly of a new species of molecular precursors that yields n = 13 armchair GNRs, a wider GNR than those previously synthesized using bottom-up molecular techniques. Scanning tunneling microscopy and spectroscopy reveal that these n = 13 armchair GNRs have a band gap of 1.4 eV, 1.2 eV smaller than the gap determined previously for n = 7 armchair GNRs. Furthermore, we observe a localized electronic state near the end of n = 13 armchair GNRs that is associated with hydrogen-terminated sp(2)-hybridized carbon atoms at the zigzag termini. PMID- 23746140 TI - Omega-3 fatty acids and changes in LBM: alone or in synergy for better muscle health? AB - Myopenia or muscle wasting due to ageing, chronic disease, and various medical interventions has been associated with increased mortality, morbidity, and poorer physical function. Attempts through nutrient and exercise interventions have been made to prevent this deterioration. In addition, while a measure of lean body mass (LBM) is associated with health outcomes, LBM function may be a better prognostic tool. Long-chain omega-3 fatty acids (LCn-3s) are nutrients that may mitigate LBM losses in noncancer populations. The purpose of this review is to determine whether LCn-3s have a role in LBM sparing in noncancer populations, to establish a minimum dose and duration of LCn-3s that will result in LBM change, and to summarise the potential effects of LCn-3s on LBM function when combined with an anabolic stimulus. Overall, in noncancer populations, LCn-3s have limited utility in sparing LBM during energy balance, energy restriction, or in conjunction with aerobic exercise. Further investigations are required to determine the appropriate dose and duration of LCn-3s for optimal LBM function. Finally, compelling evidence exists for LCn-3s in conjunction with an anabolic stimulus to improve LBM function and quality. Functionality of LBM tissue is an important outcome for population health, and LCn-3s show some promise, albeit pending further study. PMID- 23746142 TI - Cytoreductive radiofrequency ablation in patients with metastatic renal cell carcinoma (RCC) with small primary tumours treated with sunitinib or interferon alpha. AB - OBJECTIVES: To evaluate the role of cytoreductive radiofrequency ablation (cRFA) in patients with metastatic renal cell carcinoma (RCC) with small primary tumours treated with immuno- or targeted therapy. To assess the efficacy of sunitinib in patients with metastatic RCC with unresected small primary tumours. PATIENTS AND METHODS: Three parallel single-arm prospective studies were conducted. Eligibility criteria were nearly identical for all trials and included: histopathologically confirmed RCC; metastatic measurable disease; size of primary tumour <5 cm; good or intermediate prognosis according to the Memorial Sloan Kettering Cancer Center model; and no previous therapy. Study 1: Patients were treated with percutaneous cRFA under computed tomography guidance followed by interferon (IFN)-alpha, 9 MIU, s.c., three times per week. Study 2: Patients received cRFA followed by sunitinib in repeated 6-week cycles of 50 mg/day orally for 4 weeks, then 2 weeks off treatment. Study 3: Patients with unresected primary RCC received sunitinib alone. The primary endpoint was progression-free survival (PFS). RESULTS: Baseline patient characteristics (age, gender, histology, Eastern Cooperative Oncology Group performance status, metastatic sites, primary tumour size) were similar in all three studies. Efficacy data for 114 evaluable patients showed an objective response rate of 8% (95% confidence interval [CI] 4.5, 10.5) for study 1, 28.9% (95% CI 15.2, 34) for study 2, and 31.6% (95% CI 20.3, 38.9) for study 3. The median (95% CI) PFS times were 9.1 (6.9, 10.2), 13.4 (9.8, 14.4) and 12.7 (11.3, 13.5) months for studies 1, 2 and 3, respectively. Objective response rate was significantly higher and PFS significantly longer in the sunitinib trials than in study 1 (P < 0.01 all differences); no differences were found between studies 2 and 3 (objective response rate, P = 0.1; PFS, P = 0.6). Study 1 met its primary endpoint, showing that PFS was significantly longer than the expected 5 months (P = 0.02). The median (95% CI) objective survival (OS) times were greater in study 2 (cRFA/sunitinib) and study 3 (sunitinib-alone) than in study 1 (IFN-alpha) at 27.2 (22.6, 31.8) and 22.5 (20.7, 24.3) vs 19.5 (16.3, 22.7) months, respectively. Differences were significant (study 1 vs 2, hazard ratio [HR] = 0.55; P = 0.003; study 1 vs study 3 HR = 0.6, P = 0.01). OS was significantly longer in the cRFA/sunitinib group compared with the sunitinib-alone group (HR = 0.71; P = 0.04). There were no unexpected toxicities of medical treatment or complications of cRFA. CONCLUSIONS: cRFA is a safe and effective approach for select patients with metastatic RCC treated with immunotherapy. The cRFA technique did not improve PFS in patients treated with sunitinib; cRFA probably has impact on OS in these patients. This needs to be tested in a larger trial. Sunitinib was effective in patients with metastatic RCC with unresected small primary tumours. PMID- 23746143 TI - Electronic structure and biologically relevant reactivity of low-spin {FeNO}8 porphyrin model complexes: new insight from a bis-picket fence porphyrin. AB - Because of HNO's emerging role as an important effector molecule in biology, there is great current interest in the coordination chemistry of HNO and its deprotonated form, the nitroxyl anion (NO(-)), with hemes. Here we report the preparation of four new ferrous heme-nitroxyl model complexes, {FeNO}(8) in the Enemark-Feltham notation, using three electron-poor porphyrin ligands and the bis picket fence porphyrin H2[3,5-Me-BAFP] (3,5-Me-BAFP(2-) = 3,5-methyl-bis(aryloxy) fence porphyrin dianion). Electrochemical reduction of [Fe(3,5-Me-BAFP)(NO)] (1 NO) induces a shift of nu(N-O) from 1684 to 1466 cm(-1), indicative of formation of [Fe(3,5-Me-BAFP)(NO)](-) (1-NO(-)), and similar results are obtained with the electron-poor hemes. These results provide the basis to analyze general trends in the properties of ferrous heme-nitroxyl complexes for the first time. In particular, we found a strong correlation between the electronic structures of analogous {FeNO}(7) and {FeNO}(8) complexes, which we analyzed using density functional theory (DFT) calculations. To further study their reactivity, we have developed a new method for the preparation of bulk material of pure heme {FeNO}(8) complexes via corresponding [Fe(porphyrin)](-) species. Reaction of [Fe(To-F2PP)(NO)](-) (To-F2PP(2-) = tetra(ortho-difluorophenyl)porphyrin dianion) prepared this way with acetic acid generates the corresponding {FeNO}(7) complex along with the release of H2. Importantly, this disproportionation can be suppressed when the bis-picket fence porphyrin complex [Fe(3,5-Me-BAFP)(NO)](-) is used, and excitingly, with this system we were able to generate the first ferrous heme-NHO model complex reported to date. The picket fence of the porphyrin renders this HNO complex very stable, with a half-life of ~5 h at room temperature in solution. Finally, with analogous {FeNO}(8) and {FeNHO}(8) complexes in hand, their biologically relevant reactivity toward NO was then explored. PMID- 23746145 TI - Alterations of naive and memory B-cell subsets are associated with risk of rejection and infection in heart recipients. AB - Rejection and infection are relevant causes of mortality in heart recipients. We evaluated the kinetics of the maturation status of B lymphocytes and its relationship with acute cellular rejection and severe infection in heart recipients. We analyzed B-cell subsets using 4-color flow cytometry in a prospective follow-up study of 46 heart recipients. Lymphocyte subsets were evaluated at specific times before and up to 1 year after transplantation. Higher percentages of pretransplant class-switched memory B cells (CD19+CD27+IgM-IgD- >14%) were associated with a 74% decrease in the risk of severe infection [Cox regression relative hazard (RH) 0.26, 95% confidence interval (CI), 0.07-0.86; P = 0.027]. Patients with higher percentages of naive B cells at day 7 after transplantation (CD19+CD27-IgM+IgD+ >58%) had a 91% decrease in the risk of developing acute cellular rejection (RH 0.09; 95% CI, 0.01-0.80; P = 0.02). Patients with infections showed a strong negative correlation between baseline serum B-cell-activating factor (BAFF) concentration and absolute counts of memory class-switched B cells (R = -0.81, P = 0.01). The evaluation of the immunophenotypic maturation status of B lymphocytes could prove to be a useful marker for identifying patients at risk of developing rejection or infection after heart transplantation. PMID- 23746146 TI - Analysis of the germination kinetics of individual Bacillus subtilis spores treated with hydrogen peroxide or sodium hypochlorite. AB - More than 95% of individuals in populations of Bacillus subtilis spores killed approximately 95% by hydrogen peroxide or hypochlorite germinated with a nutrient, although the germination of the treated spores was slower than that of untreated spores. The slow germination of individual oxidizing agent-treated spores was due to: (i) 3- to 5-fold longer lag times (Tlag ) between germinant addition and initiation of fast release of spores' large dipicolinic acid (DPA) depot (ii) 2- to 10-fold longer times (DeltaTrelease ) for rapid DPA release, once this process had been initiated; and (iii) 3- to 7-fold longer times needed for lysis of spores' peptidoglycan cortex. These results indicate that effects of oxidizing agent treatment on subsequent spore germination are on: (i) nutrient germinant receptors in spores' inner membrane (ii) components of the DPA release process, possibly SpoVA proteins also in spores' inner membrane, or the cortex lytic enzyme CwlJ; and (iii) the cortex-lytic enzyme SleB, also largely in spores' inner membrane. This study further indicates that rapid assays of spore viability based on measurement of DPA release in spore germination can give false positive readings. SIGNIFICANCE AND IMPACT OF THE STUDY: This work shows that with Bacillus subtilis spore populations in which approximately 95% of individual spores were killed by several oxidizing agents, >95% of the spores in these populations germinated with nutrients, albeit slowly. This is important, as assay of an early germination event, release of dipicolinic acid, has been suggested as a rapid assay for spore viability and would give false-positive readings for the level of the killing of oxidizing agent-treated spore populations. Analysis of the germination kinetics of multiple individual untreated or oxidizing agent treated spores also provides new information on proteins damaged by oxidizing agent treatment, and at least some of which are in spores' inner membrane. PMID- 23746147 TI - Swim training restores glucagon-like peptide-1 insulinotropic action in pancreatic islets from monosodium glutamate-obese rats. AB - AIMS: Glucagon-like peptide-1 (GLP-1) is an important modulator of insulin secretion by endocrine pancreas. In the present study, we investigated the effect of swim training on GLP-1 insulinotropic action in pancreatic islets from monosodium glutamate (MSG)-obese rats. METHODS: Obesity was induced by neonatal MSG administration. MSG-obese and control (CON) exercised rats swam for 30 min (3 times week(-1) ) for 10 weeks. Pancreatic islets were isolated by colagenase technique and incubated with low (5.6 mM) or high (16.7 mM) glucose concentrations in the presence or absence of GLP-1 (10 nM). In addition, GLP-1 gene expression in ileum was quantified in fasting and glucose conditions. RESULTS: Exercise reduced obesity and hyperinsulinemia in MSG-obese rats. Swim training also inhibited glucose-induced insulin secretion in islets from both groups. Islets from MSG-obese rats maintained GLP-1 insulinotropic response in low glucose concentration. In contrast, in the presence of high glucose concentration, GLP-1 insulinotropic action was absent in islets from MSG-obese rats. Islets from MSG-exercised rats showed reduced GLP-1 insulinotropic action in the presence of low glucose. However, in high glucose concentration swim training restored GLP-1 insulinotropic response in islets from MSG-obese rats. In all groups, glucose intake increased GLP-1 immunoreactivity and gene expression in ileum cells in relation to fasting conditions. Swim training reduced these parameters only in ileum cells from CON-exercised rats. Neither MSG treatment nor exercise affected GLP-1 expression in the ileum. CONCLUSIONS: Exercise avoids insulin hypersecretion restoring GLP-1's insulinotropic action in pancreatic islets from MSG-obese rats. PMID- 23746148 TI - Exchange bias in Fe@Cr core-shell nanoparticles. AB - We have used X-ray magnetic circular dichroism and magnetometry to study isolated Fe@Cr core-shell nanoparticles with an Fe core diameter of 2.7 nm (850 atoms) and a Cr shell thickness varying between 1 and 2 monolayers. The addition of Cr shells significantly reduces the spin moment but does not change the orbital moment. At least two Cr atomic layers are required to stabilize a ferromagnetic/antiferromagnetic interface and generate the associated exchange bias and increase in coercivity. PMID- 23746149 TI - Compliance with opioid treatment guidelines for chronic non-cancer pain (CNCP) in primary care at a Veterans Affairs Medical Center (VAMC). AB - OBJECTIVE: The primary objective of this study was to measure prescribing compliance with the Veterans Affairs/Department of Defense treatment guidelines for chronic non-cancer pain (CNCP) in the primary care setting. We also determined the proportion of subjects who demonstrated aberrant drug-related behaviors (ADRBs) and the patient characteristics associated with them. DESIGN: This is a retrospective chart review. SETTING: Primary care setting in Veterans Affairs Medical Center. SUBJECTS: All patients with CNCP between the ages of 18 and 87 years who received opioid prescriptions for 3 or more consecutive months during a 1-year period (July 2009 to August 2010) were eligible for inclusion. A random sample of 800 patients was selected using pharmacy prescription database. Chi-square test was utilized to analyze associations between ADRB and patient characteristics. RESULTS: About half the patients in our sample had a signed opioid pain care agreement (OPCA), and at least one urine drug test (UDT) was obtained. UDT was positive for an illicit drug/unreported opioid in 19.5% of the patients, and negative for the prescribed drug in 25.2% of the sample. About 10% of the sample population had morphine equivalent dose equal to or greater than 200 mg/day. ADRBs were identified in 22.9% of the patients. Younger age, psychiatric comorbidities, history of substance abuse, and high opioid dose were associated with high risk of ADRB, but the presence of OPCA lowered the risk of ADRB. CONCLUSION: This article studied the prescribing practices of opioids in a primary care setting and can be used to enhance provider education regarding chronic pain guidelines. PMID- 23746151 TI - Research fraud and its combat: what can a journal do? PMID- 23746152 TI - Back to basics: keeping students cognitively active between the classroom and the examination. PMID- 23746153 TI - On showing all the ripples in the growth analysis pond. PMID- 23746154 TI - Choosing study outcomes: keeping an eye on the big picture. PMID- 23746155 TI - Tools for the direct observation and assessment of psychomotor skills in medical trainees: a systematic review. AB - CONTEXT: The Accreditation Council for Graduate Medical Education (ACGME) Milestone Project mandates programmes to assess the attainment of training outcomes, including the psychomotor (surgical or procedural) skills of medical trainees. The objectives of this study were to determine which tools exist to directly assess psychomotor skills in medical trainees on live patients and to identify the data indicating their psychometric and edumetric properties. METHODS: An electronic search was conducted for papers published from January 1948 to May 2011 using the PubMed, Education Resource Information Center (ERIC), Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Web of Science electronic databases and the review of references in article bibliographies. A study was included if it described a tool or instrument designed for the direct observation of psychomotor skills in patient care settings by supervisors. Studies were excluded if they referred to tools that assessed only clinical or non-technical skills, involved non-medical health professionals, or assessed skills performed on a simulator. Overall, 4114 citations were screened, 168 (4.1%) articles were reviewed for eligibility and 51 (1.2%) manuscripts were identified as meeting the study inclusion criteria. Three authors abstracted and reviewed studies using a standardised form for the presence of key psychometric and edumetric elements as per ACGME and American Psychological Association (APA) recommendations, and also assigned an overall grade based on the ACGME Committee on Educational Outcome Assessment grading system. RESULTS: A total of 30 tools were identified. Construct validity based on associations between scores and training level was identified in 24 tools, internal consistency in 14, test-retest reliability in five and inter-rater reliability in 20. The modification of attitudes, knowledge or skills was reported using five tools. The seven-item Global Rating Scale and the Procedure Based Assessment received an overall Class 1 ACGME grade and are recommended based on Level A ACGME evidence. CONCLUSIONS: Numerous tools are available for the assessment of psychomotor skills in medical trainees, but evidence supporting their psychometric and edumetric properties is limited. PMID- 23746156 TI - Comparative effects of test-enhanced learning and self-explanation on long-term retention. AB - CONTEXT: Educators often encourage students to engage in active learning by generating explanations for the material being learned, a method called self explanation. Studies have also demonstrated that repeated testing improves retention. However, no studies have directly compared the two learning methods. METHODS: Forty-seven Year 1 medical students completed the study. All students participated in a teaching session that covered four clinical topics and was followed by four weekly learning sessions. In the learning sessions, students were randomised to perform one of four learning activities for each topic: testing with self-generated explanations (TE); testing without explanations (T); studying a review sheet with self-generated explanations (SE), and studying a review sheet without explanations (S). Students repeated the same activity for each topic in all four sessions. Six months later, they took a free-recall clinical application test on all four topics. RESULTS: Repeated testing led to better long-term retention and application than repeatedly studying the material (p < 0.0001, eta(2) = 0.33). Repeated generation of self-explanations also improved long-term retention and application, but the effect was smaller (p < 0.0001, eta(2) = 0.08). When data were collapsed across topics, both testing conditions produced better final test performance than studying with self explanation (TE = 40% > SE = 29% [p = 0.001, d = 0.70]; T = 36% > SE = 29% [p = 0.02, d = 0.48]). Studying with self-explanation led to better retention and application than studying without self-explanation (SE = 29% > S = 20%; p = 0.001, d = 0.68). Our analyses showed significant interaction by topic (p = 0.001, eta(2) = 0.06), indicating some variation in the effectiveness of the interventions among topics. CONCLUSIONS: Testing and generating self-explanations are both learning activities that can be used to produce superior long-term retention and application of knowledge, but testing is generally more effective than self-explanation alone. PMID- 23746157 TI - How students deal with inconsistencies in health knowledge. AB - OBJECTIVES: In their work, health care professionals have to deal daily with inconsistent health information and are confronted with differing therapeutic health concepts. Medical education should prepare students to handle these challenges adequately. The aim of this study was to contribute to a better understanding of how students deal with inconsistencies in health knowledge when they are presented with either a therapeutic concept they accept or one they reject. METHODS: Seventy-six students of physiotherapy participated in this 2 * 2 experiment with health information (consistent versus inconsistent information) and therapeutic concept (congruent versus contradictory therapeutic concept) as between-group factors. The participants' task was to improve the quality of a text about the effectiveness of stretching; participants were randomly assigned to one of four texts. Knowledge acquisition and text modification were measured as dependent variables. RESULTS: Students acquired more knowledge when they worked with a text containing inconsistent information. Medical information that was presented in agreement with a student's therapeutic concept was also more readily acquired than the same information presented posing a contradictory therapeutic concept. Participants modified the contradictory text in order to adapt it to their own point of view. Disagreement resulted in a disregard or devaluation of the information itself, which in turn was detrimental to learning. CONCLUSIONS: It is a problem when prospective health care professionals turn a blind eye to discrepancies that do not fit their view of the world. It may be useful for educational purposes to include a knowledge conflict caused by a combination of conviction and inconsistent information to facilitate learning processes. PMID- 23746158 TI - Differential growth in doctor-patient communications skills. AB - CONTEXT: Although doctor-patient communication is considered a core competency for medical doctors, the effect of training has not been unequivocally established. Moreover, knowledge about the variance in the growth of different skills and whether certain patterns in growth can be detected could help us to develop more efficient programmes. We therefore investigated the growth in general practitioner (GP) trainees' doctor-patient communication skills in their first year and whether the growth was different for distinct categories of skills. METHODS: Seventy-one first-year GP trainees were invited to participate in a study aimed at measuring their consultation skills at the beginning (baseline) and at the end of their first year (follow-up). Consultation skills were assessed with the MAAS-Global rating list for consultation skills. RESULTS: Data on 29 general practitioner trainees were collected. MAAS-Global scores showed a significant growth on all items but one. Patient-oriented skills showed significantly more growth than task-oriented skills. Empathy as a separate skill seems to be mastered predominantly before the start of training. CONCLUSIONS: Three patterns in the growth in skills were distinguished: (i) low baseline, relatively high follow-up, (ii) moderate baseline, moderate growth and (iii) high baseline, hardly any growth. Patient-oriented skills follow either pattern (i) or (iii), whereas task-oriented skills follow pattern (ii). These findings may help to define where the focus should lie in the training of doctor-patient communication skills. PMID- 23746159 TI - Effects of reviewing routine practices on learning outcomes in continuing education. AB - CONTEXT: Conventional continuing medical education (CME) has been shown to have modest effects on doctor performance. New educational approaches based on the review of routine practices have brought better results. Little is known about factors that affect the outcomes of these approaches, especially in middle-income countries. This study aimed to investigate factors that influence the learning and quality of clinical performance in CME based on reflection upon experiences. METHODS: A questionnaire and a clinical performance test were administered to 165 general practitioners engaged in a CME programme in Brazil. The questionnaire assessed behaviours related to four input variables (individual reflection on practices, peer review of experiences, self-regulated learning and learning skills) and two mediating variables (identification of learning needs and engagement in learning activities, the latter consisting of self-study of scientific literature, consultations about patient problems, and attendance at courses). Structural equation modelling was used to test a hypothesised model of relationships between these variables and the outcome variable of clinical performance, measured by the clinical performance test. RESULTS: After minor adjustments, the hypothesised model fit the empirical data well. Individual reflection fostered identification of learning needs, but also directly positively influenced the quality of clinical performance. Peer review did not affect identification of learning needs, but directly positively affected clinical performance. Learning skills and self-regulation did not help in identifying learning needs, but self-regulation enhanced study of the scientific literature, the learning activity that most positively influenced clinical performance. Consultation with colleagues, the activity most frequently triggered by the identification of learning needs, did not affect performance, and attendance of courses had only limited effect. CONCLUSIONS: This study shed light on the factors that influence learning and performance improvement in continuing education based on the review of routine practices in middle-income settings. The findings support the importance of reflection on practices as an instrument for enhancing clinical performance. PMID- 23746160 TI - Effects of morning report case presentation on length of stay and hospitalisation costs. AB - CONTEXT: The primary goal of discussing patient cases during the morning report is to teach appropriate clinical decision making. In addition, the selection of the best diagnostic strategy and application of evidence-based patient care are important. Reducing hospital costs is fundamental to controlling inflation in health care costs, especially in university hospitals that are subject to budget constraints in developing countries. The goal of this study was to explore the effect of morning report case presentation on length of stay (LoS) and hospitalisation costs in a university teaching hospital. METHODS: A total of 54 patients whose cases had been presented at morning report sessions in the department of internal medicine during a 3-month period (presented group) were selected and their medical records reviewed for data on final diagnosis, hospital LoS and detailed hospital costs. A control group of 104 patients, whose cases had not been presented, were selected on the basis that their final diagnoses matched with those of the presented group. In addition, the groups were matched for age, sex, occupation, comorbidities and insurance coverage. Final diagnoses were based on International Classification of Disease 10 (ICD-10) diagnostic code criteria. RESULTS: The mean +/- standard deviation (SD) hospital LoS was 8.32 +/- 4.11 days in the presented group and 10.46 +/- 4.92 days in the control group (p = 0.045). Mean +/- SD hospitalisation costs per patient were significantly lower in the presented group (US$553.43 +/- 92.16) than the control group (US$1621.93 +/- 353.14) (p = 0.004). Although costs for paraclinical services were similar, there were very significant reductions in costs for medications used during hospitalisation and bed-days (p = 0.002). CONCLUSIONS: Discussing clinical aspects of patient cases in morning report sessions facilitates the management process and has a significant effect on LoS and hospitalisation costs in patients admitted to hospital. PMID- 23746161 TI - Predictive validity of the Dundee multiple mini-interview. AB - CONTEXT: The multiple mini-interview (MMI) is the primary admissions tool used to assess non-cognitive skills at Dundee Medical School. Although the MMI shows promise, more research is required to demonstrate its transferability and predictive validity, for instance, relative to other UK pre-admissions measures. METHODS: Applicants were selected for interview based on a combination of measures derived from the Universities and Colleges Admissions Service (UCAS) form (academic achievement, medical experience, non-academic achievement and references) and the UK Clinical Aptitude Test (UKCAT) in 2009 and 2010. Candidates were selected into medical school according to a weighted combination of the UKCAT, the UCAS form and MMI scores. Examination scores were matched for 140 and 128 first- and second-year students, respectively, who took the 2009 MMIs, and 150 first-year students who took the 2010 MMIs. Pearson's correlations were used to test the relationships between pre-admission variables, examination scores and demographic variables, namely gender and age. Statistically significant correlations were adjusted for range restrictions and were used to select variables for multiple linear regression analysis to predict examination scores. RESULTS: Statistically significant correlations ranged from 0.18 to 0.34 and 0.23 to 0.50 unrestricted. Multiple regression confirmed that MMIs remained the most consistent predictor of medical school assessments. No scores derived from the UCAS form correlated significantly with examination scores. CONCLUSIONS: This study reports positive findings from the largest undergraduate sample to date. The MMI was the most consistent predictor of success in early years at medical school across two separate cohorts. UKCAT and UCAS forms showed minimal or no predictive ability. Further research in this area appears worthwhile, with longitudinal studies, replication of results from other medical schools and more detailed analysis of knowledge, skills and attitudinal outcome markers. PMID- 23746162 TI - Evaluating the quality of medical multiple-choice items created with automated processes. AB - OBJECTIVES: Computerised assessment raises formidable challenges because it requires large numbers of test items. Automatic item generation (AIG) can help address this test development problem because it yields large numbers of new items both quickly and efficiently. To date, however, the quality of the items produced using a generative approach has not been evaluated. The purpose of this study was to determine whether automatic processes yield items that meet standards of quality that are appropriate for medical testing. Quality was evaluated firstly by subjecting items created using both AIG and traditional processes to rating by a four-member expert medical panel using indicators of multiple-choice item quality, and secondly by asking the panellists to identify which items were developed using AIG in a blind review. METHODS: Fifteen items from the domain of therapeutics were created in three different experimental test development conditions. The first 15 items were created by content specialists using traditional test development methods (Group 1 Traditional). The second 15 items were created by the same content specialists using AIG methods (Group 1 AIG). The third 15 items were created by a new group of content specialists using traditional methods (Group 2 Traditional). These 45 items were then evaluated for quality by a four-member panel of medical experts and were subsequently categorised as either Traditional or AIG items. RESULTS: Three outcomes were reported: (i) the items produced using traditional and AIG processes were comparable on seven of eight indicators of multiple-choice item quality; (ii) AIG items can be differentiated from Traditional items by the quality of their distractors, and (iii) the overall predictive accuracy of the four expert medical panellists was 42%. CONCLUSIONS: Items generated by AIG methods are, for the most part, equivalent to traditionally developed items from the perspective of expert medical reviewers. While the AIG method produced comparatively fewer plausible distractors than the traditional method, medical experts cannot consistently distinguish AIG items from traditionally developed items in a blind review. PMID- 23746163 TI - Web-based feedback after summative assessment: how do students engage? AB - CONTEXT: There is little research into how to deliver summative assessment student feedback effectively. The main aims of this study were to clarify how students engage with feedback in this context and to explore the roles of learning-related characteristics and previous and current performance. METHODS: A website was developed to deliver feedback about the objective structural clinical examination (OSCE) in various formats: station by station or on skills across stations. In total, 138 students (in the third year out of five) completed a questionnaire about goal orientation, motivation, self-efficacy, control of learning beliefs and attitudes to feedback. Individual website usage was analysed over an 8-week period. Latent class analyses were used to identify profiles of students, based on their use of different aspects of the feedback website. Differences in learning-related student characteristics between profiles were assessed using analyses of variance (anovas). Individual website usage was related to OSCE performance. RESULTS: In total, 132 students (95.7%) viewed the website. The number of pages viewed ranged from two to 377 (median 102). Fifty per cent of students engaged comprehensively with the feedback, 27% used it in a minimal manner, whereas a further 23% used it in a more selective way. Students who were comprehensive users of the website scored higher on the value of feedback scale, whereas students who were minimal users scored higher on extrinsic motivation. Higher performing students viewed significantly more web pages showing comparisons with peers than weaker students did. Students who just passed the assessment made least use of the feedback. CONCLUSIONS: Higher performing students appeared to use the feedback more for positive affirmation than for diagnostic information. Those arguably most in need engaged least. We need to construct feedback after summative assessment in a way that will more effectively engage those students who need the most help. PMID- 23746164 TI - Tubulin inhibitors: a patent survey. AB - Tubulin is one of the most useful and strategic molecular targets for anticancer drugs. The dynamic process of microtubule assembly and disassembly can be blocked by various agents that bind to distinct sites in the beta-tubulin subunit. By interfering with microtubule function in vitro, these agents arrest cells in mitosis, eventually leading to cell death, by both apoptosis and necrosis. So far, three binding domains have been identified a) the colchicine site close to the alpha/beta interface, b) the area where the vinca alkaloids bind, and c) the taxane-binding pocket. This review compiles the patent literature up to 2013 and offers a detailed account of all the advances on Tubulin inhibitors (lead molecules) along with in depth knowledge about the number of novel scaffolds, modified analogs and derivatives of the lead molecules. Colchicine binding site remains the most explored site indicated by the patent survey as majority of the patents revolves around phenstatin and combretastatin based molecules where the key structural feature for tubulin inhibition is an appropriate arrangement of the two aromatic rings at an appropriate distance and optimal dihedral angle maximizing interactions with tubulin. A brief account of promising tubulin inhibitors in stages of clinical development and some strategies for the development of potent molecules overcoming the problem of drug resistance have also been discussed. PMID- 23746165 TI - Perchlorate radiolysis on Mars and the origin of martian soil reactivity. AB - Results from the Viking biology experiments indicate the presence of reactive oxidants in martian soils that have previously been attributed to peroxide and superoxide. Instruments on the Mars Phoenix Lander and the Mars Science Laboratory detected perchlorate in martian soil, which is nonreactive under the conditions of the Viking biology experiments. We show that calcium perchlorate exposed to gamma rays decomposes in a CO2 atmosphere to form hypochlorite (ClO( )), trapped oxygen (O2), and chlorine dioxide (ClO2). Our results show that the release of trapped O2 (g) from radiation-damaged perchlorate salts and the reaction of ClO(-) with amino acids that were added to the martian soils can explain the results of the Viking biology experiments. We conclude that neither hydrogen peroxide nor superoxide is required to explain the results of the Viking biology experiments. PMID- 23746166 TI - Angiographic lumen changes associated with oversized intracranial stent implantation for aneurysm treatment. AB - BACKGROUND: The effect of oversized intracranial stent implantation, and potential excessive neointimal hyperplasia from the chronic outward radial force, has not been reported. We sought to compare the angiographic narrowing associated with implantation of oversized stents. METHODS: We reviewed an aneurysm database and identified patients treated with stent-assisted embolization involving a vessel size transition. Demographics and lesion characteristics were extracted. The relationship between lumen diameter and stent oversizing was compared. RESULTS: Twenty vessels were identified in 18 patients, providing 80 paired data points. Mean follow-up time was 8 months (SD 6). The average oversizing in the smaller diameter parent vessel landing-zone was 1.75 mm. Mean change in lumen size from pre-stent implantation was not significantly different for any of the four sites. There was a significant difference in change of lumen size at the stent tines when compared with the respective mid-stent segment for both the proximal (P = 0.02) and distal (P = 0.0004) landing zones. CONCLUSIONS: A small significant lumen loss occurs at stent tines when compared to midstent struts. However, there is no overall significant stenosis from highly oversized stents. Persistent luminal gain from the oversized stent radial force likely predominates over any neointimal hyperplasia. PMID- 23746167 TI - Formation and characterization of a molecule-metal-molecule bridge in real space. AB - Metal-organic complexes were formed by means of inelastic excitations in a scanning tunneling microscope (STM). The electronic structure of the complex was characterized using STM imaging and spectroscopy. By exploiting the symmetry of the complex, its electronic structure can be rationalized from linear combinations of molecular orbitals. The actual bonding geometry, which cannot be inferred from STM alone, was determined from atomic force microscopy images with atomic resolution. Our study demonstrates that the combination of these techniques enables a direct quantification of the interplay of geometry and electronic coupling in metal-organic complexes in real space. PMID- 23746168 TI - Structure prediction of gBP21 protein of L. donovani and its molecular interaction. AB - Visceral leishmaniasis (Kala-azar) is a fatal disease caused by the obligate intracellular parasite Leishmania donovani and the available drugs for the treatment are few, and are frequently associated with side effects and toxicity. RNA editing is one of the essential metabolic processes in the kinetoplastids, where the pre-mRNAs are edited post-transcriptionally by the guide RNAs with the addition or deletion of uridine residues. The aim is to block the gBP21 protein involved in RNA editing process thereby other direct and indirect protein activity is reduced and ultimately the editing process in L. donovani is disturbed and it will inhibit the growth. RNA editing factors are RNA-linked proteins essential for in vivo editing i.e. mitochondrial RNA binding protein1 (MRP 1) originally called as gBP21. The model of L. donovani gBP21 (gBP21Ldv) showed that this protein bears an anti-parallel beta sheet (segregated alpha and beta regions) with beta-beta-beta-beta-alpha-beta-beta-beta-beta-alpha-type topology ("whirly" transcription-factor fold). Each of the four beta strands within a given beta-beta-beta-beta-alpha repeats and form a curved anti-parallel beta-sheet that packs perpendicularly against the sheet from the other repeat. Among all of the computationally screened compounds by the GLIDE program (Schrodinger) and GOLD program hyperoside1a, posaconazole, quercetin, and pentanediol, 427 exhibited higher binding affinities with the modeled gBP21 protein of L. donovani. Ligandfit program (DSv2.5) revealed that DNA, RNA polymerase inhibitors acyclovir, mitomycin C, and daunorubicin have better binding affinity towards gBP21Ldv. These compounds may be given in combination with miltefosine (first line therapy) against patients with VL and other associated disorders like anemia. PMID- 23746169 TI - Ephrins and pain. AB - INTRODUCTION: The ephrin receptor family is the largest family of receptor tyrosine kinases, which comprises 14 members that are divided into A and B subclasses. The ephrin receptor (Eph-receptor) ligands are named ephrins. Ephrins/Eph receptors interact with a variety of membrane receptors that respond to chemokines, neurotransmitters or growth factors. A growing body of evidence indicates that ephrins/Eph receptors are involved in the modulation of different types of pain. AREAS COVERED: A literature review summarizing the most recent data in terms of ephrins and their ligands and their association with different types of pain. Moreover, the latest knowledge regarding the involvement of ephrins/Eph receptors in pain modulation as well as its possible therapeutic perspectives are presented. EXPERT OPINION: The ephrins/Eph receptors system seems to be an emerging target for pain drug discovery, because it is involved in the pathophysiology of many types of pain. The modulation of different types of pain by selective agonists or antagonists may hold tremendous therapeutic potential in various pain conditions mentioned in this review. However, the current limited but promising data, merit consideration and further investigation. PMID- 23746171 TI - Transfer factor: an overlooked potential for the prevention and treatment of infectious diseases. AB - Transfer factor (TF) is a low-molecular-weight lymphocyte extract capable of transferring antigen-specific cell-mediated immunity (CMI) to T lymphocytes. It has been used successfully as an adjuvant or primary therapy for viral, parasitic, fungal, and some bacterial infections, as well as immunodeficiencies, neoplasias, allergies and autoimmune diseases. From the list of infections that seem to respond noticeably to transfer factor, those due to viruses of the herpes family are particularly remarkable. Indeed, for these viruses it was shown that TF can prevent infection or relapse, acting as a CMI vaccine. Data also suggest its possible use for adjuvant treatment and probably prevention of two currently widespread infections: tuberculosis and AIDS. Furthermore, TF has an interesting potential: answering the challenge from unknown pathogenic agents, a black box effect permitting production of antigen-specific TF to a new pathogen, even before its identification. It thus seems that the preventative potential of transfer factor is as important as its therapeutic one, both discussed in this review. PMID- 23746170 TI - The safety profile of ustekinumab in the treatment of patients with psoriasis and concurrent hepatitis B or C. AB - BACKGROUND: Ustekinumab, an interleukin (IL)-12 and IL-23 blocker, has emerged as a new therapeutic option for patients with psoriasis. It is generally well tolerated but safety data on the use of ustekinumab in patients with viral hepatitis are limited. OBJECTIVE: To assess the safety profile of ustekinumab in the treatment of patients with psoriasis who have concomitant hepatitis B or hepatitis C. METHODS: This study included 18 patients with concurrent psoriasis and hepatitis B virus (HBV) infection (14 patients) or hepatitis C virus (HCV) infection (four patients) who were treated with at least two ustekinumab injections. Viral loads were measured at baseline and each time before the administration of ustekinumab. Relevant clinical data were recorded. RESULTS: Among 11 patients positive for hepatitis B surface antigen (HBsAg), two out of the seven (29%) patients who did not receive antiviral prophylaxis exhibited HBV reactivation during ustekinumab treatment. No viral reactivation was observed in the three occult HBV-infected patients (HBsAg-negative/hepatitis B core antibody positive patients). One patient with HCV, liver cirrhosis and treated hepatocellular carcinoma (HCC) experienced HCV reactivation and recurrent HCC during the ustekinumab treatment. No significant increase in aminotransferase levels was observed in any patient. CONCLUSIONS: Antiviral prophylaxis appears to minimize the risk of viral reactivation in patients with concurrent psoriasis and HBV infection. Without effective anti-viral prophylaxis, the risk/benefit of ustekinumab treatment should be carefully assessed in patients with psoriasis and HBV or HCV infection and/or HCC. Close monitoring for HBV and HCV viral load is recommended, particularly for patients with high-risk factors. Serum aminotransferase determination may not be useful for early detection of viral reactivation. PMID- 23746172 TI - Anticancer efficiency of reovirus in normoxia and hypoxia. AB - Oncolytic viruses infect, replicate in, and lyse tumour cells but spare the normal ones. One of oncolytic viruses is a naturally occurring replication competent reovirus (RV), which preferentially kills tumour cells with activated Ras signaling pathways. The aim of this study was to survey effects of RV on brain tumour-derived cells in vitro under hypoxic conditions since hypoxia causes resistance to radio- and chemotherapy. This study demonstrates that RV replicates preferentially in tumour cells and that the virus is able to overcome cellular adaptation to hypoxia and infect and kill hypoxic tumour cells. RV can both replicate in hypoxic tumour microenvironment and cause the cytopathic effect, subsequently inducing cell death. We found that a large proportion of cells are killed in hypoxia (1% O2) by caspase-independent mechanisms. Furthermore, we learned that the cell death induced by RV in hypoxic conditions is not caused by autophagy. PMID- 23746173 TI - ADAM10/17-dependent release of soluble c-Met correlates with hepatocellular damage. AB - The signalling pathway elicited by hepatocyte growth factor (HGF) and its receptor c-Met is indispensable for liver development and regeneration. It has been described that c-Met is released from the cell surface by a disintegrin and metalloprotease 10 (ADAM10) resulting in a soluble c-Met form known as sMet. Using the human hepatocellular HepG2 and hepatic stellate cell LX2 lines we show that sMet is released from the cell surface of liver cells by both ADAM17 and ADAM10, with ADAM17 appearing to be the major proteinase. Moreover, using a mouse model of 3,5-diethoxycarbonyl- 1,4-dihydroxycollidine (DDC)-induced hepatobiliary obstruction we show that serum levels of sMet correlate well with the liver damage state and consecutive regeneration as well as with established markers of liver damage such as alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and total bilirubin. However, sMet exhibited remarkably better correlation with liver damage and inflammation than did serum tumour necrosis factor alpha (TNF-alpha), whose shedding is also mediated by ADAM proteolytic activity. Our results indicate that the proteolytic activity of ADAM10/17 is essential for regulating HGF/c-Met signalling during acute liver damage and following regeneration and that the differential serum levels of sMet together with expression of c-Met/HGF might be a useful indicator not only for damage, but also for ongoing liver regeneration. PMID- 23746174 TI - Promoter methylation of GATA4, WIF1, NTRK1 and other selected tumour suppressor genes in ovarian cancer. AB - Ovarian cancer is the leading cause of death from gynaecologic tumours, but the molecular and especially epigenetic events underlying the transformation are poorly understood. Various methylation changes have been identified and show promise as potential cancer biomarkers. The aim of this study was to investigate promoter methylation of selected tumour suppressor genes in ovarian cancer by comparison with normal ovarian tissue. To search for epigenetic events we used methylation-specific multiplex ligation-dependent probe amplification to compare the methylation status of 44 tissue samples of ovarian cancer with 30 control samples. Using a 20% cut-off for methylation, we observed significantly higher methylation in genes NTKR1, GATA4 and WIF1 in the ovarian cancer group compared with the control group. These findings could potentially be used in screening of ovarian cancer, and may have implications for future chemotherapy based on epigenetic changes. PMID- 23746176 TI - Salivary levels of TNF-alpha and IL-6 in patients with oral premalignant and malignant lesions. AB - The aim of this study was to determine the salivary concentrations of tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) in patients with premalignant and malignant lesions. The study involved 57 patients who were examined between 2008 and 2010 at the Department of Oral Medicine and Department of Oral and Maxillofacial Surgery of the Medical Faculty, University of Rijeka, Croatia. They were divided into three groups: 19 patients with oral premalignant lesions, 19 with oral squamous cell carcinoma and 19 healthy control volunteers. Whole saliva was collected and investigated for the presence of TNF-alpha and IL 6 by enzyme immunoassay at the Department of Dentistry and Maxillofacial Surgery, Medical Faculty, University of Graz, Austria. All groups had statistically significant differences in values of TNF-alpha and IL-6 (P < 0.001). The results suggest that these proinflammatory cytokines are elevated in the saliva of patients with oral squamous cell carcinoma and oral premalignant lesions as compared to controls, which may have diagnostic and/or prognostic significance. PMID- 23746175 TI - Sequence analysis of the foot and mouth disease virus type O/IRN/2007 VP1 gene from Iranian isolate. AB - The foot and mouth disease virus (FMDV) causes a vesicular and contagious disease of cloven-hoofed animals. In this study, the virus was isolated from vesicles of the infected cattle using cell culture and serotyped by ELISA test. The extracted RNA from the infected cells was reverse transcribed and amplified using VP1 gene specific primer pairs by means of one-step RT-PCR. The purified VP1 gene was sub cloned into the uniqe KpnI and BamHI cloning sites of the pcDNA3.1+ vector. The DH5alpha strain of E. coli was transformed by the vector. The sequences of sub cloned FMDV type O/IRN/2007 VP1 were aligned with FMDV type O/UKG/2001 VP1 using MegAlign software. Nucleotide sequence comparisons were made using the BLAST software available from the NCBI website. The amino acid sequences of three sub cloned FMDV type O/IRN/2007 VP1 were also aligned with three other similar sequences using MegAlign software. Nineteen of the most similar VP1 nucleotide sequences (by BLASTN program), FMDV O/IRN/2007 VP1 sequence, twenty isolates of FMDV-O VP1 in Iran and eight topotypes of FMDV type O were aligned by Mega5 to create a FMDV-O VP1-based sequence similarity tree. The nucleotide sequence comparison indicated that FMDV O/ IRN/2007 VP1 had the greatest nucleotide sequence similarity to the VP1 gene of FMDV O1/Manisa/Turkey/69 (99%), FMDV O1/Manisa/Netherlands (98%) and FMDV O1/Manisa/iso87/Turkey (98%). It was also observed that the highest identity between FMDV O/IRN/2007 VP1 sequence and other nucleotide sequences of FMDV type O VP1 genes isolated in Iran during 1997-2004 was about 91%. PMID- 23746177 TI - SLC2A4gene: a promising target for pharmacogenomics of insulin resistance. PMID- 23746181 TI - Institutional profile: the Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, UK. AB - The Wolfson Centre for Personalised Medicine is part of the Institute of Translational Medicine at the University of Liverpool (Liverpool, UK). It houses a multidisciplinary team of personalized medicine researchers engaged in collaborative research with partners across the globe. The primary focus of the centre is the identification of predictive biomarkers of drug safety and efficacy with the aim of translation from 'bench-to-bedside'. Studies utilizing the latest genotyping and phenotyping, and point-of-care technologies, are undertaken with the ultimate aim of developing easy access for patients to truly personalized medicine. In addition to translation into clinical practice, the Centre puts significant emphasis into education of clinicians and scientists alike, as well as public engagement activities to promote personalized medicine. PMID- 23746178 TI - Practical limitations to estimating heritability in pharmacogenetic studies. PMID- 23746182 TI - Cost-effectiveness of pharmacogenetic-guided dosing of phenprocoumon in atrial fibrillation. AB - AIM: To investigate the cost-effectiveness of pharmacogenetic-guided phenprocoumon dosing versus standard anticoagulation care in Dutch patients with atrial fibrillation. MATERIALS & METHODS: Using a decision-analytic Markov model, cost-effectiveness of pharmacogenetic-guided therapy versus standard care was estimated. RESULTS: Compared with standard care, the pharmacogenetic-guided dosing strategy increased quality-adjusted life-years (QALYs) only very slightly and increased costs by ?15. The incremental cost-effectiveness ratio was ?2658 per QALY gained. In sensitivity analyses, the cost of genotyping had the largest influence on the cost-effectiveness ratio. In a probabilistic sensitivity analysis, the incremental costs of genotype-guided dosing were less than ?20,000 per QALY gained in 75.6% of the simulations. CONCLUSION: Pharmacogenetic-guided dosing of phenprocoumon has the potential to increase health slightly and may be able to achieve this in a cost-effective way. Owing to the many uncertainties it is too early to conclude whether or not patients starting phenprocoumon should be genotyped. PMID- 23746183 TI - Implementation and outcomes of a live continuing education program on pharmacogenomics. AB - AIM: This study evaluated the implementation and outcomes of a pharmacogenomics education program among pharmacists. MATERIALS & METHODS: Continuing education lectures were presented at local, state and national pharmacy conferences. RESULTS: Six hundred and seventy three pharmacist participants (mean +/- standard deviation: 45 +/- 14 years of age with 19 +/- 13 years of practice experience) completed program evaluations. Participants' knowledge and overall ability to address pharmacogenomics testing significantly improved (p < 0.001). More than 50% rated self-efficacy for putting pharmacogenomics knowledge into clinical practice to be likely or very likely. Attitudes toward increasing the number of patients to educate, updating pharmacogenomics knowledge, and providing advice were 39, 76 and 64%, respectively. Participants rated program components to be useful or very useful, and the quality of the program format, program content and audience response system as good, very good or excellent. CONCLUSION: Through live continuing education presentations at pharmacy conferences, participants showed significant increases in knowledge and their overall ability to address pharmacogenomics testing with patients. PMID- 23746184 TI - Association of ABCB1 genetic polymorphisms with susceptibility to colorectal cancer and therapeutic prognosis. AB - AIM: To evaluate the association of ABCB1 gene polymorphisms with susceptibility to colorectal cancer (CRC) and clinical outcomes of CRC patients with chemotherapy. PATIENTS & METHODS: A case-control study was performed on the C3435T, C1236T and G2677T/A polymorphisms in the ABCB1 gene in 1028 CRC patients and 1230 controls. RESULTS: We observed that the ABCB1 C3435T and G2677T/A variants as well as the 3435T-1236T-2677T haplotype significantly increased the risk of CRC. The ABCB1 C3435T CT genotype had a significant effect on the time to recurrence (adjusted hazard ratio [HR; 95% CI]: 0.560 [0.355-0.882]; p = 0.012). Moreover, ABCB1 C1236T variant carriers displayed a longer overall survival after postoperative oxaliplatin-based chemotherapy (adjusted HR [95% CI]: 0.354 [0.182 0.692], 0.646 [0.458-0.910], respectively). In addition, 1236TT-2677TT-3435TT haplotype carriers showed a worse progression-free survival (adjusted HR [95% CI]: 1.477 [1.012-3.802]; p = 0.043) and recurrence-free survival (adjusted HR [95% CI]: 2.183 [1.253-3.802]; p = 0.006). CONCLUSION: The ABCB1 polymorphisms might be a candidate pharmacogenomic factor to assess susceptibility and prognosis after oxaliplatin-based chemotherapy for CRC patients. PMID- 23746185 TI - High-resolution melt analysis to detect sequence variations in highly homologous gene regions: application to CYP2B6. AB - High-resolution melt (HRM) analysis using 'release-on-demand' dyes, such as EvaGreen((r)) has the potential to resolve complex genotypes in situations where genotype interpretation is complicated by the presence of pseudogenes or allelic variants in close proximity to the locus of interest. We explored the utility of HRM to genotype a SNP (785A>G, K262R, rs2279343) that is located within exon 5 of the CYP2B6 gene, which contributes to the metabolism of a number of clinically used drugs. Testing of 785A>G is challenging, but crucial for accurate genotype determination. This SNP is part of multiple known CYP2B6 haplotypes and located in a region that is identical to CYP2B7, a nonfunctional pseudogene. Because small CYP2B6-specific PCR amplicons bracketing 785A>G cannot be generated, we simultaneously amplified both genes. A panel of 235 liver tissue DNAs and five Coriell samples were assessed. Eight CYP2B6/CYP2B7 diplotype combinations were found and a novel variant 769G>A (D257N) was discovered. The frequency of 785G corresponded to those reported for Caucasians and African-Americans. Assay performance was confirmed by CYP2B6 and/or CYP2B7 sequence analysis in a subset of samples, using a preamplified CYP2B6-specific long-range-PCR amplicon as HRM template. Inclusion rather than exclusion of a homologous pseudogene allowed us to devise a sensitive, reliable and affordable assay to test this CYP2B6 SNP. This assay design may be utilized to overcome the challenges and limitations of other methods. Owing to the flexibility of HRM, this assay design can easily be adapted to other gene loci of interest. PMID- 23746187 TI - Personalized medicine in oncology: where have we come from and where are we going? AB - Current advances in the biology of cancer and emergence of new tools for genome analysis have opened clinical perspectives in oncology, generally termed as 'personalized medicine'. This broad term must encompass previous well-proven strategies, such as pharmacogenetics- and pharmacokinetics-based dosing, with more recently introduced pharmacogenomics approaches, all applied as a means to tailor treatment to a given patient presenting with a given tumor. Despite outstanding results in lung cancer, colorectal cancer and melanoma, only a few predictive biomarkers are currently justified in routine clinical practice. Overall, there is a persistent gap between the growing number of identified deregulated pathways or genetic mutations, both at the tumor and the constitutional levels, and their actual implementation at the bedside as part of clinical routine. This article underlines these limitations and covers several issues that may explain the discrepancy between the plethora of published data about emerging biomarkers, and the relative scarcity of tests eventually reaching a clinically validated application. The main identified difficulties concern invasive and costly prospective biomarker studies and the issue of tumor heterogeneity. Finally, early trial designs for targeted therapies as well as those for conventional cytotoxics may not necessarily address the right questions by skipping critical end points. Proposed solutions point out the use of liquid biopsies and systems biology approaches, for an easier implementation of personalized medicine at the bedside. PMID- 23746186 TI - Role of interactions in pharmacogenetic studies: leukotrienes in asthma. AB - Researchers have identified thousands of loci involved in complex traits and drug response. However, in most cases they only explain a small proportion of the heritability of the trait. Among different strategies conducted to identify this 'missing heritability', here we illustrate the importance of complex gene environment interactions using findings regarding the role of leukotrienes on the bronchodilator response to albuterol in Latino asthmatics. Patients managing their asthma with leukotriene-modifying medication presented higher increases in the bronchodilator response to albuterol. Moreover, interactions between genes responsible for leukotriene production were associated with a decreased risk of asthma. Combining genetic and pharmacologic effects, leukotriene-modifying users carrying certain combinations of alleles presented higher improvements in lung function after bronchodilator administration. Genes and drugs act at different orders of interaction (from individual effects to gene-gene-drug-drug interactions) and population-specific effects have to be considered. These results may be extrapolated to other complex phenotypes. PMID- 23746188 TI - Clinical relevance of pharmacogenetics in gastrointestinal stromal tumor treatment in the era of personalized therapy. AB - Gastrointestinal stromal tumor (GIST) is a well-recognized and now relatively well-understood mesenchymal tumor. Before the imatinib era, the treatment of metastatic GIST was frustrating owing to its refractoriness to conventional chemotherapy and radiotherapy. After a metastatic GIST patient was granted compassionate use of imatinib in 2000, the treatment of this disease has emerged as a model for the development of other molecularly targeted therapies. In this article the authors review how tumor genotypes, in particular KIT and PDGFRA mutational analysis, have been integrated in the optimal clinical management of GIST patients. The authors also discuss the potential practical relevance of pharmacogenetics, which, integrated with therapeutic drug monitoring, should receive greater consideration, with the aim of personalized therapy. PMID- 23746190 TI - Pharmacogenomic biomarkers for personalized medicine. AB - Pharmacogenomics examines how the benefits and adverse effects of a drug vary among patients in a target population by analyzing genomic profiles of individual patients. Personalized medicine prescribes specific therapeutics that best suit an individual patient. Much current research focuses on developing genomic biomarkers to identify patients, to identify which patients would benefit from a treatment, have an adverse response, or no response at all, prior to treatment according to relevant differences in risk factors, disease types and/or responses to therapy. This review describes the use of the two personalized medicine biomarkers, prognostic and predictive, to classify patients into subgroups for treatment recommendation. PMID- 23746189 TI - Clinical delivery of pharmacogenetic testing services: a proposed partnership between genetic counselors and pharmacists. AB - One of the basic questions in the early uses of pharmacogenetic (PGx) testing revolves around the clinical delivery of testing. Because multiple health professionals may play a role in the delivery of PGx testing, various clinical delivery models have begun to be studied. We propose that a partnership between genetic counselors and pharmacists can assist clinicians in the delivery of comprehensive PGx services. Based on their expert knowledge of pharmacokinetics and pharmacodynamics, pharmacists can facilitate the appropriate application of PGx test results to adjust medication use as warranted and act as a liaison to the healthcare team recommending changes in medication based on test results and patient input. Genetic counselors are well-trained in genetics as well as risk communication and counseling methodology, but have limited knowledge of pharmaceuticals. The complementary knowledge and skill set supports the partnership between genetic counselors and pharmacists to provide effective PGx testing services. PMID- 23746191 TI - Pharmacogenomics of lipid-lowering therapies. AB - Statins are the most widely used group of lipid-lowering drugs and they have been shown to be effective in the prevention of cardiovascular disease, primarily by reducing plasma low-density lipoprotein cholesterol concentrations and possibly through other pleiotropic effects. However, there are large variations in lipid responses to statins and some patients have intolerable muscle adverse drug reactions, which may in part be related to genetic factors. In the last decade, pharmacogenetic studies on statins ranging from the candidate gene approach to the more recent genome-wide association studies have provided evidence that genetic variations play an important role in determining statin responses. This review summarizes the current understanding on the pharmacogenomics of statins and other lipid-lowering drugs in current use. PMID- 23746194 TI - Oils rich in alpha-linolenic acid independently protect against characteristics of fatty liver disease in the Delta6-desaturase null mouse. AB - Alpha-linolenic acid's (ALA) biological activity is poorly understood and primarily associated with its conversion to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Delta-6 desaturase (D6D) initiates the metabolism of linoleic acid (LA) and ALA to arachidonic acid, EPA, and DHA, respectively. In this study, D6D knock-out (D6KO) mice were used to evaluate the effects of ALA rich oils in preventing hepatic steatosis and inflammation. D6KO and wild-type mice were fed 1 of 4 high-fat (14% w/w) diets: (i) lard (LD, 0% n-3 PUFA), (ii) canola oil + ARASCO (CD, 8% ALA), (iii) flax seed oil + ARASCO (FD, 55% ALA), (iv) menhaden oil (MD, 30% EPA/DHA) for 8 or 20 weeks. Livers of D6KO mice consuming CD and FD were depleted of EPA/DHA, and enriched in ALA. Markers of fat accumulation and inflammation were lowest in the MD-fed mice, at 8 and 20 weeks, regardless of genotype. CD- and FD-fed D6KO groups were found to have lower liver lipid accumulation and lower hepatic inflammation relative to the LD-fed mice at 8 weeks. In conclusion, while MD was the most protective, this study shows that ALA can act independently on risk factors associated with the development of fatty liver disease. PMID- 23746193 TI - Future directions in the study of social relationships as regulators of the HPA axis across development. AB - Many promising findings support the notion that social relationships can dampen hypothalamic-pituitary-adrenocortical (HPA) axis stress responses and protect individuals from maladaptive psychological and physical disease states. Despite the public health relevance of this topic, little is known about developmental changes in the social regulation of the HPA system, with most prior research having focused on early childhood and adulthood. This gap is particularly striking with regards to adolescence, an age period when it seems likely that reliance on parents as sources of stress-buffering decreases, even as the security of friends and relationship partners as stress buffers may not yet be certain. Furthermore, we speculate that early life stress or abnormal social experiences may impact the propensity to draw mental and physical health benefits from social relationships, but more empirical support for these ideas is needed. Last, research linking social support to cumulative life stress has mostly relied on self-report measures of stress, making it difficult to show that social support impacts the type of chronic stress exposure that is associated with increased allostatic load or "wear and tear" on the body and on psychological functioning. Recent advancements in methodology (e.g., assessing hair cortisol levels) as well as composite measures of allostatic load using biomarkers that capture the activity of multiple neuroendocrine, cardiovascular, immune, and metabolic systems will allow us to ask new questions about the extent to which social relationships can impact cumulative life stress and health. PMID- 23746195 TI - Successful delivery in patients with severe congenital factor V deficiency: a study of five homozygous patients. PMID- 23746196 TI - Novel nitrogen-enriched oridonin analogues with thiazole-fused A-ring: protecting group-free synthesis, enhanced anticancer profile, and improved aqueous solubility. AB - Oridonin (1), a complex ent-kaurane diterpenoid isolated from the traditional Chinese herb Isodon rubescens , has demonstrated great potential in the treatment of various human cancers due to its unique and safe anticancer pharmacological profile. Nevertheless, the clinical development of oridonin for cancer therapy has been hampered by its relatively moderate potency, limited aqueous solubility, and poor bioavailability. Herein, we report the concise synthesis of a series of novel nitrogen-enriched oridonin derivatives with thiazole-fused A-ring through an efficient protecting group-free synthetic strategy. Most of them, including compounds 7-11, 13, and 14, exhibited potent antiproliferative effects against breast, pancreatic, and prostate cancer cells with low micromolar to submicromolar IC50 values as well as markedly enhanced aqueous solubility. These new analogues obtained by rationally modifying the natural product have been demonstrated not only to significantly induce the apoptosis and suppress growth of triple-negative MDA-MB-231 breast cancer both in vitro and in vivo but also effective against drug-resistant ER-positive MCF-7 clones. PMID- 23746197 TI - Methylnaltrexone use in a seventeen-month-old female with progressive cancer and rectal prolapse. AB - BACKGROUND: Opioid-induced constipation is commonly seen in pediatrics, especially at the end of life. As patients clinically decline, constipation often leads to increased pain and distress, while its enteral treatment becomes more challenging. METHOD: There is little information about the safety and use of methylnaltrexone in children. We present the case of a 17-month-old girl with progressive leukemia who was at the end of her life and whose severe opioid induced constipation and rectal prolapse was successfully treated with the MU opioid-receptor antagonist methylnaltrexone. We selected a lower dose based on our lack of experience with methylnaltrexone in this age group and concern for potential complications given her rectal prolapse. DISCUSSION: Opioid-induced constipation, abdominal distention, and rectal prolapse caused our patient's most distressing symptoms, even in the context of advanced cancer. A single dose of subcutaneous methylnaltrexone (0.12 mg/kg) resolved her constipation and rectal prolapse within one hour. Although evidence is limited, the drug has successfully been used in pediatric patients with no reported side effects to date. We recommend its use earlier in the course of severe opioid-induced constipation in children unable to tolerate an oral laxation regimen. Prospective research is needed to establish the parameters for use of this effective agent in children who cannot tolerate other regimens. PMID- 23746199 TI - Anti-IL-13 in inflammatory bowel disease: from the bench to the bedside. AB - Much work has been done to understand the molecular mechanisms underlying the inflammatory bowel diseases (IBD). IL-13 has emerged as an important cytokine effective in ulcerative colitis (UC) and fistulizing Crohn's disease (CD). IL-13 is a T helper 2-type cytokine with pleiotropic effects, involved in parasite expulsion, asthma pathophysiology, natural history of cancer and other human pathologies. Great interest has therefore been developed in inhibiting its function as a therapeutic intervention in these diseases. The multifunctional properties of IL-13, with particular emphasis on its role in both CD and UC, as well as current developing pharmacologic agents inhibiting the IL-13 signaling pathway have been reviewed. Anti-IL-13 agents seem to be promising therapeutic strategies for the future management of IBD and other human diseases. PMID- 23746201 TI - Evaluation of colorimetric loop-mediated isothermal amplification assay for visual detection of Streptococcus agalactiae and Streptococcus iniae in tilapia. AB - Streptococcus agalactiae and Strep. iniae are bacterial pathogens that cause streptococcosis in many fish species. An accelerated colorimetric loop-mediated isothermal amplification (LAMP) assay with pre-addition of calcein was established, and the transmission and detection of Strep. agalactiae and Strep. iniae in tilapia under natural aquatic environment were investigated. A positive reaction was observed by a colour change from orange to green through the naked eyes after completion at 63 degrees C for 30 min with 10 times higher sensitivity than that of nested PCR assays and without cross-amplification with other fish bacterial pathogens. All sample types of Nile and red tilapia (broodstock, fertilized egg, fry) were Strep. agalactiae- and Strep. iniae positive by this new method, implying that they could be vertically transmitted. With its application for screening broodstock and fry before stocking and for monitoring fish health in grow-out ponds, the method would become very useful in fish farming industry. SIGNIFICANCE AND IMPACT OF THE STUDY: The application of colorimetric LAMP with pre-addition of calcein offers simple, rapid and sensitive technique with applicability for small field laboratories. This technique explored the possible vertical transmission mode of Strep. agalactiae and Strep. iniae under natural aquatic environment. It could be such preliminary data provided for the screening broodstock before breeding and/or the specific pathogen-free production. PMID- 23746198 TI - Magnetic resonance imaging (MRI)-guided transurethral ultrasound therapy of the prostate: a preclinical study with radiological and pathological correlation using customised MRI-based moulds. AB - OBJECTIVE: To characterise the feasibility and safety of a novel transurethral ultrasound (US)-therapy device combined with real-time multi-plane magnetic resonance imaging (MRI)-based temperature monitoring and temperature feedback control, to enable spatiotemporally precise regional ablation of simulated prostate gland lesions in a preclinical canine model. To correlate ablation volumes measured with intra-procedural cumulative thermal damage estimates, post procedural MRI, and histopathology. MATERIALS AND METHODS: Three dogs were treated with three targeted ablations each, using a prototype MRI-guided transurethral US-therapy system (Philips Healthcare, Vantaa, Finland). MRI provided images for treatment planning, guidance, real-time multi-planar thermometry, as well as post-treatment evaluation of efficacy. After treatment, specimens underwent histopathological analysis to determine the extent of necrosis and cell viability. Statistical analyses (Pearson's correlation, Student's t-test) were used to evaluate the correlation between ablation volumes measured with intra-procedural cumulative thermal damage estimates, post procedural MRI, and histopathology. RESULTS: MRI combined with a transurethral US therapy device enabled multi-planar temperature monitoring at the target as well as in surrounding tissues, allowing for safe, targeted, and controlled ablations of prescribed lesions. Ablated volumes measured by cumulative thermal dose positively correlated with volumes determined by histopathological analysis (r(2) 0.83, P < 0.001). Post-procedural contrast-enhanced and diffusion-weighted MRI showed a positive correlation with non-viable areas on histopathological analysis (r(2) 0.89, P < 0.001, and r(2) 0.91, P = 0.003, respectively). Additionally, there was a positive correlation between ablated volumes according to cumulative thermal dose and volumes identified on post-procedural contrast-enhanced MRI (r(2) 0.77, P < 0.01). There was no difference in mean ablation volumes assessed with the various analysis methods (P > 0.05, Student's t-test). CONCLUSIONS: MRI guided transurethral US therapy enabled safe and targeted ablations of prescribed lesions in a preclinical canine prostate model. Ablation volumes were reliably predicted by intra- and post-procedural imaging. Clinical studies are needed to confirm the feasibility, safety, oncological control, and functional outcomes of this therapy in patients in whom focal therapy is indicated. PMID- 23746202 TI - Reasons for dose reduction of mycophenolate mofetil during the first year after renal transplantation and its impact on graft outcome. AB - Mycophenolate mofetil (MMF) decreases the risk of acute rejection and is associated with improved graft survival in renal transplant recipients. However, MMF-related side effects often necessitate dose reduction, which may expose patients to a higher risk of acute rejection and graft loss. This study's aim was to examine the reasons for MMF dose reduction during the first post-transplant year and its impact on acute rejection, overall and death-censored graft loss. METHODS: Single-center retrospective analysis of 749 renal transplant recipients treated with MMF in their initial maintenance immunosuppressive protocol. RESULTS: In 365 patients (48.7%) a total of 530 MMF dose reductions were done. Reasons for reduction were hematologic toxicity (46.5%), infection (16.1%), gastrointestinal side effects (12.3%), malignancy (2.1%), study protocol (14.6%), and unknown (13.5%). MMF dose reduction as such was not an independent predictor of acute rejection or graft survival, although reductions in >= 50% of initial dose were significantly associated with acute rejection. CONCLUSIONS: In this retrospective cohort, by far the most important reason for MMF dose reduction during the first post-transplantation year was hematologic. MMF dose reductions in >= 50% increased the risk of acute rejection but did not compromise graft survival. PMID- 23746203 TI - Commentary: To intervene or not? Appreciating or treating individual differences in childhood temperament--remarks on Rapee (2013). PMID- 23746205 TI - A randomized, double-blind, placebo-controlled trial of the effect of dried purple carrot on body mass, lipids, blood pressure, body composition, and inflammatory markers in overweight and obese adults: the QUENCH trial. AB - Obesity is a significant health issue worldwide and is associated with chronic, low-grade inflammation predisposing the individual to cardiovascular disease and impaired blood glucose homeostasis. Anthocyanins and phenolic acids from purple carrots are effective at reversing inflammation and metabolic alterations in animal models, potentially through inhibition of inflammatory pathways. The effects of dried purple carrot on body mass, body composition, blood pressure, lipids, inflammatory markers, liver function tests, and appetite were investigated in 16 males (aged 53.1 +/- 7.6 years and with a mean BMI of 32.8 +/- 4.6 kg/m(2)) with normal lipid and inflammatory markers. There was no evidence that 118.5 mg/day of anthocyanins and 259.2 mg/day of phenolic acids for 4 weeks resulted in statistically significant changes in body mass, body composition, appetite, dietary intake, low density lipoprotein, total cholesterol, blood pressure, or C-reactive protein in these obese participants at the dose and length of intervention used in this trial. High density lipoprotein cholesterol was lower in the intervention group (p < 0.05). Aspartate amino transferase and alanine amino transferase did not change, indicating that the intervention was safe. More studies are required to establish the bioavailability and pharmacokinetic effects of purple carrot anthocyanins and phenolic acids prior to further trials of efficacy with respect to treating inflammation and metabolic alterations. PMID- 23746204 TI - Protein partners of dynamin-1 in the retina. AB - Dynamin proteins are involved in vesicle generation, providing mechanical force to excise newly formed vesicles from membranes of cellular compartments. In the brain, dynamin-1, dynamin-2, and dynamin-3 have been well studied; however, their function in the retina remains elusive. A retina-specific splice variant of dynamin-1 interacts with the photoreceptor-specific protein Tubby-like protein 1 (Tulp1), which when mutated causes an early onset form of autosomal recessive retinitis pigmentosa. Here, we investigated the role of the dynamins in the retina, using immunohistochemistry to localize dynamin-1, dynamin-2, and dynamin 3 and immunoprecipitation followed by mass spectrometry to explore dynamin-1 interacting proteins in mouse retina. Dynamin-2 is primarily confined to the inner segment compartment of photoreceptors, suggesting a role in outer segment protein transport. Dynamin-3 is present in the terminals of photoreceptors and dendrites of second-order neurons but is most pronounced in the inner plexiform layer where second-order neurons relay signals from photoreceptors. Dynamin-1 appears to be the dominant isoform in the retina and is present throughout the retina and in multiple compartments of the photoreceptor cell. This suggests that it may function in multiple cellular pathways. Surprisingly, dynamin-1 expression and localization did not appear to be disrupted in tulp1-/- mice. Immunoprecipitation experiments reveal that dynamin-1 associates primarily with proteins involved in cytoskeletal-based membrane dynamics. This finding is confirmed by western blot analysis. Results further implicate dynamin-1 in vesicular protein transport processes relevant to synaptic and post-Golgi pathways and indicate a possible role in photoreceptor stability. PMID- 23746206 TI - Chromosomal excision of a new pathogenicity island modulates Salmonella virulence in vivo. AB - Although the excision of unstable pathogenicity islands is a phenomenon that has been described for several virulent bacteria, whether this process directly affects the capacity of these microorganisms to cause disease in their hosts remains unknown. Salmonella enterica serovar Enteritidis (S. Enteritidis) is an enterobacterium that harbors several unstable pathogenicity islands that can excise from the main bacterial chromosome. Here we have evaluated whether excision of one of these pathogenicity islands, denominated as Region of Difference 21 (ROD21), is required for S. Enteritidis to cause disease in the host. By means of genetic targeting of the integrase encoded by the ROD21 we have generated S. Enteritidis strains unable to excise ROD21. The failure to excise ROD21 significantly reduced the capacity to cause a lethal disease and to colonize the spleen and liver of mice, as compared to wild type S. Enteritidis. On the contrary, S. Enteritidis strains overexpressing an excisionase protein increased the frequency of ROD21 excision and showed an improved capacity to cause lethal disease in mice. Accordingly, strains unable to excise ROD21 showed an altered expression of genes located in this pathogenicity island. Our results suggest that the genetic excision of the pathogenicity island ROD21 in S. Enteritidis modulates the capacity of this bacterium to cause disease in mice due to a change in the expression of virulence genes. PMID- 23746208 TI - Effectiveness of human milk-based fortifiers for preventing necrotizing enterocolitis in preterm infants: case not proven. PMID- 23746207 TI - Breastfeeding with epilepsy: mothers' experiences and the role of professionals, family, and friends. PMID- 23746210 TI - Venous air embolism from Tisseel use during endoscopic cranial vault remodeling for craniosynostosis repair: a case report. AB - Venous air embolism (VAE) is a potential complication during cranial vault remodeling requiring early detection and prompt therapeutic intervention. The incidence of VAE has been reported to be as high as 82.6% during open craniectomy for craniosynostosis repair. On the other hand, two separate studies reported a much lower incidence of VAE (8% and 2%) during endoscopic strip craniectomy. As surgical advancements progress, minimally invasive neurosurgical procedures are increasing in the pediatric population with reported benefits of decreased blood loss and need for transfusion, shorter hospital stay, decreased cost, lower morbidity, and mortality. In addition, there is a heightened emphasis on achieving hemostasis, which has led to the use of products such as antifibrinolytics and fibrin sealants. We present a case where a VAE causing significant hemodynamic instability (grade III) ensued immediately following aerosolized fibrin sealant application. Exploration of the potential source of VAE pointed to the high pressure and close proximity (between spray device and tissue) during application of the sealant, likely forcing air into the vascular system. PMID- 23746209 TI - Potent cardioprotection from ischemia-reperfusion injury by a two-domain fusion protein comprising annexin V and Kunitz protease inhibitor. AB - BACKGROUND: Considerable evidence suggests that coagulation proteases (tissue factor [TF]/activated factor VII [FVIIa]/FXa/thrombin) and their target protease activated receptors (PAR-1/PAR-2) play important roles in myocardial ischemia reperfusion (I-R) injury. We hypothesized that localized inhibition of TF/FVIIa on the membrane surfaces of ischemic cells could effectively block coagulation cascade and subsequent PAR-1/PAR-2 cell signaling, thereby protecting the myocardium from I-R injury. OBJECTIVES: We recently developed an annexin V-Kunitz inhibitor fusion protein (ANV-6L15) that could specifically bind to anionic phospholipids on the membrane surfaces of apoptotic cells and efficiently inhibit the membrane-anchored TF/FVIIa. In this study, we investigated the cardioprotective effect of ANV-6L15 in a rat cardiac I-R model in comparison with that of hirudin. METHODS: Left coronary artery occlusion was maintained for 45 min followed by 4 h of reperfusion in anesthetized Sprague-Dawley rats. One minute before or 2 min after coronary ligation, rats received an intravenous bolus injection of ANV-6L15 (2.5-250 MUg kg(-1) ), vehicle, or hirudin via bolus injection and continuous infusion. RESULTS AND CONCLUSIONS: ANV-6L15 dose dependently reduced infarct size by up to 87% and decreased plasma levels of cardiac troponin I, tumor necrosis factor-alpha, and soluble intercellular adhesion molecule-1, by up to 97%, 96%, and 66%, respectively, with little impact on the coagulation parameters. ANV-6L15 also ameliorated hemodynamic derangements, attenuated neutrophil infiltration and reduced Terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic cardiomyocytes. Hirudin was less efficacious even at supraclinical dose. ANV-6L15 confers exceptionally potent cardioprotection and is a promising drug candidate for the prevention of myocardial I-R injury. PMID- 23746211 TI - HIV-1 Nef mediates Pak phosphorylation of Mek1 serine298 and elicits an active phospho-state of Pak2. AB - The HIV-1 Nef protein brings about increased T cell activity and viral titers through mechanisms that are poorly understood. Nef activity has been described as an enhancer, but not an inducer, of certain signaling pathways that lead to T cell activation and viral production, particularly from resting T cells. The protein has also been found to associate with and promote autophosphorylation of a serine kinase, Pak2, but the Nef-associated kinase level is very low and difficult to study. Here we demonstrate that Nef expression mediates phosphorylation of Mek1 serine298 in T cell lines as well as primary human T cells, thus directly affecting the Erk cascade. This phosphorylation is through a Pak and Rac activity. We also find that Pak2 in Nef expressing cells is phosphorylated on serine192/197, the first biochemical description of the Nef mediated activation state for this kinase. PMID- 23746212 TI - Plasmon nanomechanical coupling for nanoscale transduction. AB - We demonstrate plasmon-mechanical coupling in a metalized nanomechanical oscillator. A coupled surface plasmon is excited in the 25 nm wide gap between two metalized silicon nitride beams. The strong plasmonic dispersion allows the nanomechanical beams' thermal motion at a frequency of 4.4 MHz to be efficiently transduced to the optical transmission, with a measured displacement spectral density of 1.11 * 10(-13) m/Hz(1/2). When exciting the second-order plasmonic mode at lambda = 780 nm we observe optical-power-induced frequency shifts of the mechanical oscillator. Our results show that novel functionality of plasmonic nanostructures can be achieved through coupling to engineered nanoscale mechanical oscillators. PMID- 23746213 TI - Rotational spectrum of paracetamol. AB - In this paper we report the first rotational spectrum of isolated paracetamol. Solid samples of paracetamol were vaporized by laser ablation, expanded in a supersonic jet and characterized by Fourier transform microwave spectroscopy in the 4-10 GHz frequency range. The spectra of a total of four conformers, two with a trans peptidic -CO-NH- functional group arrangement and two with a cis peptidic group arrangement have been observed for the first time. The identification of all the conformers was based on the comparison of the experimental rotational and (14)N quadrupole coupling constants with those predicted by ab initio calculations, and relative values of their electrical dipole moment components. PMID- 23746214 TI - A comparison of cardiovascular risk indices in patients with polycystic ovary syndrome with and without coexisting nonalcoholic fatty liver disease. AB - BACKGROUND: Women with polycystic ovary syndrome (PCOS) have an adverse cardiovascular risk profile and an increased prevalence of nonalcoholic fatty liver disease (NAFLD), which is also associated with an adverse cardiovascular risk profile. OBJECTIVE: To compare the cardiovascular risk profile of women with PCOS alone and women with PCOS and NAFLD. DESIGN, SETTING AND PARTICIPANTS: Twenty-five oligoanovulatory women with PCOS were screened for NAFLD (including liver biopsy if appropriate) and had their cardiovascular risk factors measured which included the inflammatory marker C-reactive protein (CRP), endothelial function {measured using endoPAT 2000 and serum markers [intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin and P selectin]}, clot structure and function [maximum absorbance (MA) and lysis potential (LT)]. RESULTS: Twelve patients had confirmed PCOS without evidence of NAFLD, and 13 patients had confirmed PCOS with evidence of NAFLD. The PCOS and NAFLD group were heavier (BMI 43.9 +/- 2.2 kg/m(2) ) compared with the PCOS alone group (BMI 37.6 +/- 1.4 kg/m(2) P = 0.03). There was no difference in CRP (7.57 +/- 0.95 vs 6.59 +/- 1.87 mm P = 0.62) or endothelial function (RH-PAT 1.96 +/- 0.1 vs 1.74 +/- 0.16 P = 0.25), ICAM-1 (221 +/- 48 vs 250 +/- 60 ng/ml P = 0.19), VCAM-1 (2124 +/- 78 vs 2314 +/- 91 ng/ml P = 0.13), E-selectin (33.9 +/- 3.3 vs 39.5 +/- 15.5 ng/ml P = 0.31) and P-selectin (101.0 +/- 6.6 vs 95.9 +/- 10.2 ng/ml P = 0.69). There was no difference in clot formation or lysis. CONCLUSION: The patients with PCOS and NAFLD were heavier compared with patients with PCOS alone. Despite this, we were unable to demonstrate differences in inflammatory markers, endothelial function or clot structure and function, suggesting that severity of steatosis is not the most important determinant of cardiovascular risk in PCOS. PMID- 23746216 TI - A magnetoplasmonic imaging agent for copper(I) with dual response by MRI and dark field microscopy. AB - We present the design and synthesis of a responsive magnetoplasmonic assembly for copper(I) which allows monitoring of the concentration of the metal both in three dimensions by magnetic resonance imaging and with high spatial resolution by dark field microscopy. The probe consists of azide-functionalized iron oxide nanoparticles 11.6 nm in diameter and acetylene-terminated gold nanoparticles 44 nm in diameter that form three-dimensional networks of intermingled magnetic and plasmonic nanoparticles in the presence of copper. This aggregation results in a decrease in longitudinal relaxivity, and an initial increase followed by a sharp decrease in transverse relaxivity, a change observable both by T1- and T2 weighted images, concomitantly with a decrease of surface plasmon resonance intensity. PMID- 23746215 TI - Short-fiber protein of ad40 confers enteric tropism and protection against acidic gastrointestinal conditions. AB - The lack of vectors for selective gene delivery to the intestine has hampered the development of gene therapy strategies for intestinal diseases. We hypothesized that chimeric adenoviruses of Ad5 (species C) displaying proteins of the naturally enteric Ad40 (species F) might hold the intestinal tropism of the species F and thus be useful for gene delivery to the intestine. As oral-fecal dissemination of enteric adenovirus must withstand the conditions encountered in the gastrointestinal tract, we studied the resistance of chimeric Ad5 carrying the short-fiber protein of Ad40 to acid milieu and proteases and found that the Ad40 short fiber confers resistance to inactivation in acidic conditions and that AdF/40S was further activated upon exposure to low pH. In contrast, the chimeric AdF/40S exhibited only a slightly higher protease resistance compared with Ad5 to proteases present in simulated gastric juice. Then, the biodistribution of different chimeric adenoviruses by oral, rectal, and intravenous routes was tested. Expression of reporter beta-galactosidase was measured in extracts of 15 different organs 3 days after administration. Our results indicate that among the chimeric viruses, only intrarectally given AdF/40S infected the colon (preferentially enteroendocrine cells and macrophages) and to a lesser extent, the small intestine, whereas Ad5 infectivity was very poor in all tissues. Additional in vitro experiments showed improved infectivity of AdF/40S also in different human epithelial cell lines. Therefore, our results point at the chimeric adenovirus AdF/40S as an interesting vector for selective gene delivery to treat intestinal diseases. PMID- 23746217 TI - Late gestation over- and undernutrition predispose for visceral adiposity in response to a post-natal obesogenic diet, but with differential impacts on glucose-insulin adaptations during fasting in lambs. AB - AIM: To investigate if late gestation under- or overnutrition has similar adverse impacts on visceral adiposity, metabolic and endocrine function in sheep, and if subsequent exposure to a high-fat diet in early post-natal life exaggerates the prenatal programming outcomes later in life. METHODS: Thirty-six twin-pregnant ewes were fed a NORM (fulfilling 100% of daily requirements for energy and protein), LOW (50% of NORM) or HIGH diet (150% of energy and 110% of protein requirements) during the last 6 weeks of gestation (term = 147 days). Post natally, the twin lambs were subjected to a high-fat or a moderate diet until 6 months of age (around puberty), where metabolic and endocrine adaptability to fasting was examined, and subgroups of animals were killed. RESULTS: Animals exposed to either prenatal under- or overnutrition had reduced subcutaneous fat deposition when fed a high-fat diet, resulting in higher ratios of mesenteric and peri-renal fat relative to subcutaneous fat compared to controls. This was not related to prenatal influences on plasma glucose or insulin. Irrespective of the prenatal diet, high-fat-fed lambs underwent changes resembling the metabolic syndrome with higher plasma glucose, cholesterol, non-esterified fatty acids, triglyceride and lactate combined with abdominal obesity. Peri-renal fat appeared to be a particular target of a high-fat diet post-natally. CONCLUSION: Both prenatal under- and overnutrition predisposed for abdominal adiposity, apparently by reducing the expandability of subcutaneous adipose tissue and induced differential physiological adaptations to fasting. This study does not suggest that exposure to gestational overnutrition will provide a protective effect against development of hyperglycaemia later in life. PMID- 23746218 TI - Syntheses, structures, and magnetic and luminescence properties of a new Dy(III) based single-ion magnet. AB - Three new Ln(III) complexes based on 2,2'-bipyridine [Ln(hfac)3(bpy)] (Ln = Dy (1), Tb (2), or Ho (3); hfac = hexafluoroacetylacetonate; and bpy = 2,2' bipyridine) have been synthesized and characterized structurally and magnetically. Single-crystal X-ray analysis shows that all these complexes contain one [Ln(hfac)3(bpy)] unit in which a center Ln(III) ion is surrounded with a slightly distorted square-antiprismatic LnO6N2 coordination sphere formed by three bischelate hfac anions and one bpy ligand. Both static and dynamic magnetic properties were studied for complex 1, which is proved to be a new single-ion magnet. The luminescence characterizations of complexes 1 and 2 are also studied in this paper. PMID- 23746219 TI - The effects of different disease-resistant cultivars of banana on rhizosphere microbial communities and enzyme activities. AB - To understand the mechanism of soil microbial ecosystem and biochemical properties in suppressing soilborne plant diseases, the relationship between the soil rhizosphere microbial communities, hydrolase activities, and different disease-resistant cultivars was investigated. There were statistically significant differences in microbial diversity in the rhizosphere soil between the disease-tolerant cultivar Fj01 and susceptible cultivar Baxi. The rhizosphere soil of Fj01 showed a trend of higher microbial diversity than that of Baxi. At the same growth stage, the similar trends of variation in microbial community diversity between the two different cultivars were observed. The bacterial community abundance in rhizosphere soil from the two banana cultivars was quantified by real-time PCR assays. The size of the rhizosphere bacterial population from the Fj01 was significantly larger than that from the Baxi during the growing stage from July to September. The activities of urease and phosphatase were analyzed to study the effects of the two banana cultivars to soil ecosystem functioning. Urease activity was significantly higher in the rhizosphere soil of Fj01 than that of Baxi in the period from July to September. However, phosphatase activity showed no significant difference between the two different rhizosphere soils. PMID- 23746220 TI - A mechanistic rationale for the 9-amino(9-deoxy)epi cinchona alkaloids catalyzed asymmetric reactions via iminium ion activation of enones. AB - The 9-amino(9-deoxy)epi cinchona alkaloids have expanded the synthetic potential of asymmetric aminocatalysis, enabling the highly stereoselective functionalization of a variety of sterically hindered carbonyl compounds. However, there is a lack of basic understanding of the mechanisms of cinchona based primary aminocatalysis. Herein, we describe how a combination of experimental and theoretical mechanistic studies has revealed the origin of the stereoselectivity of the Friedel-Crafts alkylation of indoles with alpha,beta unsaturated ketones catalyzed by 9-amino(9-deoxy)epi quinine. An essential role for the achiral acid cocatalyst is uncovered: upon condensation of the cinchona catalyst with the enone, the resulting covalent imine intermediate and the acid interact to build-up a well-structured ion-pair supramolecular catalytic assembly, which is stabilized by multiple attractive noncovalent interactions. All the components of the assembly cooperatively participate in the stereocontrolling event, with the anion of the achiral acid being the structural element responsible for the pi-facial discrimination of the iminium ion intermediate. PMID- 23746221 TI - Methanol extract of the aerial parts of barley (Hordeum vulgare) suppresses lipopolysaccharide-induced inflammatory responses in vitro and in vivo. AB - CONTEXT: Recently, there has been renewed interest in barley (Hordeum vulgare L. Poaceae) as a functional food and for its medicinal properties. OBJECTIVE: This study examines the anti-inflammatory potential of the active fractions of barley and the mechanisms involved. MATERIALS AND METHODS: The macrophages were exposed to 100 MUg/mL of each of the barley extracts in the presence of 1 MUg/mL lipopolysaccharide (LPS) and after 24 or 48 h of incubation, cells or culture supernatants were analyzed by various assays. The anti-inflammatory potential of barley fractions was also investigated using the LPS-injected septic mouse model. The active constituents in the fractions were identified using gas chromatography mass spectrometry (GC-MS). RESULTS: The active fractions, named F4, F7, F9 and F12, inhibited almost completely the LPS-induced production of nitric oxide (NO) and inducible NO synthase. Pre-treatment with these fractions at 100 MUg/mL diminished the tumor necrosis factor-alpha (TNF-alpha) levels to 19.8, 3.5, 1.2 and 1.7 ng/mL, respectively, compared to LPS treatment alone (41.5 ng/mL). These fractions at 100 MUg/mL also suppressed apparently the secretion of interleukin (IL)-6 and IL-1beta and the DNA-binding activity of nuclear factor-kappaB in LPS stimulated cells. Mice injected intraperitoneally with LPS (30 mg/kg BW) showed 20% survival at 48 h after injection, whereas oral administration of the fractions improved the survival rates to 80%. GC-MS analysis revealed the presence of the derivatives of benzoic and cinnamic acids and fatty acids in the fractions. DISCUSSION AND CONCLUSION: The aerial parts of barley are useful as functional food to prevent acute inflammatory responses. PMID- 23746222 TI - Targeting membrane androgen receptors in tumors. AB - INTRODUCTION: In the last decade androgen actions that are originated from non genomic, rapid signaling have been described in a large number of cell models and tissues. These effects are initiated through the stimulation of membrane androgen binding sites or receptors (mAR). Although the molecular identity of mARs remains elusive, their activation is known to trigger multiple non-genomic signaling cascades and to regulate numerous cell responses. In recent years specific interest is being paid to the role of mARs in tumors. Specifically, it was demonstrated that mAR activation by non-permeable testosterone conjugates induced potent anti-tumorigenic responses in prostate, breast, colon and glial tumors. In addition, in vivo animal studies further emphasized the potential clinical importance of these receptors. AREAS COVERED: This review will summarize the current knowledge on the mAR-induced non-genomic, rapid androgen actions. It will focus on the molecular signaling pathways governed by mAR activation, discuss latest attempts to elucidate the molecular identity of mAR, address the plethora of cell responses initiated by mAR and evaluate the potential role of mAR and mAR specific signaling as possible therapeutic targets in tumors. EXPERT OPINION: mAR and mAR-induced specific signaling may represent novel therapeutic targets in tumors through the development of specific testosterone analogs. PMID- 23746223 TI - Paediatric pseudoxanthoma elasticum with cardiovascular involvement. AB - BACKGROUND: Pseudoxanthoma elasticum (PXE) is characterized by aberrant mineralization of connective tissues, causing considerable morbidity and mortality. The disease is typically of late onset, the skin manifestations first being noted in the teens or later. Another aberrant mineralization disorder, generalized arterial calcification of infancy (GACI), is present at birth and can demonstrate a phenotypic overlap with PXE. OBJECTIVES: A patient with PXE was noted to have skin findings as early as at 6 years of age, with cardiovascular involvement. The purpose of this study was to examine the genetic basis of this phenotypic presentation in the spectrum of PXE/GACI. METHODS: The patient's genotype was studied by sequencing ABCC6 and ENPP1, genes known to be associated with PXE and/or GACI. RESULTS: Screening of the ABCC6 gene revealed two pathogenetic mutations, p.R1141X and g.del23-29. Analysis of the ENPP1 gene failed to demonstrate the presence of mutations. CONCLUSIONS: This study demonstrates the presence of cutaneous findings of PXE in an 8-year-old paediatric patient, with cardiovascular involvement, illustrating the phenotypic spectrum of PXE. PMID- 23746224 TI - Development and anti-microbial potential of topical formulations containing Cocos nucifera Linn. AB - In order to achieve better treatment for local wounds and bacterial infections, topical formulations containing Cocos nucifera Linn. were developed. These formulations were evaluated for their physicochemical properties and antimicrobial efficacy against various strains of microorganisms. Semisolid formulations containing 5% w/w of Cocos nucifera Linn. were prepared by employing different dermatological bases and were evaluated for their physical appearance, pH, rheological properties, FTIR-spectroscopic analysis, thermodynamic stability and stability studies. The antimicrobial activity of each prepared formulation was determined using disk-diffusion method against various strains of microorganisms. All the prepared formulations were found to be stable and exhibited suitable physicochemical characteristics including pH, viscosity and spreadability which are necessary for an ideal topical preparation, in addition to strong antimicrobial activity. Carbopol gel base was found to be the most suitable dermatological base for Cocos nucifera Linn. in comparsion to other bases. Cocos nucifera Linn. formulations showed great potential for wounds and local bacterial infections. Moreover, carbopol gel base with its aesthetic appeal was found to be a suitable dermatological base for Cocos nucifera Linn. semisolid formulation as it had demonstrated significant physicochemical properties and greater diffusion when assessed using disk- diffusion method. PMID- 23746225 TI - Development and evaluation of transdermal organogels containing nicorandil. AB - The objective of the study was to formulate a transdermal product containing Nicorandil as a model drug, because it has been first drug of choice to treat angina and hypertension. A further objective was to reduce its side effects. The transdermal product was prepared using various synthetic and natural gelling agents such as Carbopol 934p, Carbopol 974p, HPMC K15M and HPMC K100M. Various penetration enhancers were incorporated to enhance the diffusion across the rat skin. A further objective was to formulate organogels and minimize the concentration of penetration enhancer to 50% of the concentration used in gels and yet to achieve the maximum drug release. The prepared formulations were evaluated for their physical appearance, viscosity, spreadability, drug content and freeze thaw cycle. Based on in vitro studies across rat skin and human cadaver skin it was concluded that Nicrorandil transdermal organogel formulation using HPMC K100M with 2% w/w Transcutol-P shows increase in cumulative diffusion of Nicorandil amongst all other formulations. PMID- 23746226 TI - Botulinum neurotoxin: unique folding of enzyme domain of the most-poisonous poison. AB - Botulinum neurotoxin (BoNT), the most toxic substance known to mankind, is the first example of the fully active molten globule state. To understand its folding mechanism, we performed urea denaturation experiments and theoretical modeling using BoNT serotype A (BoNT/A). We found that the extent of BoNT/A denaturation from the native state (N) shows a nonmonotonic dependence on urea concentration indicating a unique multistep denaturation process, N -> I1 [Formula: see text] I2 [Formula: see text] U, with two intermediate states I1 and I2. BoNT/A loses almost all its secondary structure in 3.75 M urea (I1), yet it displays a native like secondary structure in 5 M urea (I2). This agrees with the results of theoretical modeling, which helped to determine the molecular basis of unique behavior of BoNT/A in solution. Except for I2, all the states revert back to full enzymatic activity for SNAP-25 including the unfolded state U stable in 7 M urea. Our results stress the importance of structural flexibility in the toxin's mechanism of survival and action, an unmatched evolutionary trait from billion year-old bacteria, which also correlates with the long-lasting enzymatic activity of BoNT inside neuronal cells. BoNT/A provides a rich model to explore protein folding in relation to functional activity. PMID- 23746227 TI - End-of-life management of patients who have been established on oral methadone for pain control. PMID- 23746228 TI - The use of role play for interdisciplinary teaching of palliative care communication skills. PMID- 23746229 TI - The effect of palliative care on the assistance of terminally ill cancer patients. PMID- 23746230 TI - Reduction in symptoms for homebound patients receiving home-based primary and palliative care. AB - BACKGROUND: Increasing numbers of patients are living with multiple, chronic medical conditions and functional impairments that leave them homebound. Home based primary and palliative care (HBPC) programs provide access to health care services for this vulnerable population. Homebound patients have high symptom burden upon program enrollment. Yet little is known as to how individual symptoms are managed at home, especially over longer time periods. OBJECTIVES: The purpose of this study was to determine whether high symptom burden decreases following HBPC enrollment. METHODS: All patients newly enrolled in an HBPC program who reported at least one symptom on the Edmonton Symptom Assessment Scale (ESAS) were eligible for telephone ESAS follow-up. Patients received a comprehensive initial home visit and assessment by a physician with subsequent follow-up care, interdisciplinary care management including social work, and urgent in-home care as necessary. Multivariate linear mixed models with repeated measures were used to assess the impact of HBPC on pain, depression, anxiety, tiredness, and loss of appetite among patients with moderate to severe symptom levels at baseline. RESULTS: One hundred forty patients were followed. Patient pain, anxiety, depression, and tiredness significantly decreased following intervention with symptom reductions seen at 3 weeks and maintained at 12 weeks. (p<0.01) Loss of appetite trended toward an overall significant decrease and showed significant reductions at 12 week follow-up. CONCLUSION: In a chronically ill population of urban homebound, patient symptoms can be successfully managed in the home. Future work should continue to explore symptom assessment and management over time for the chronically ill homebound. PMID- 23746231 TI - The longitudinal pattern of response when morphine is used to treat chronic refractory dyspnea. AB - BACKGROUND: While evidence supports using sustained release morphine for chronic refractory breathlessness, little is known about the longitudinal pattern of breathlessness intensity as people achieve symptomatic benefit. The aim of this study is to describe this pattern. METHODS: This secondary analysis used breathlessness intensity scores (100 mm visual analogue scale (VAS)) from a prospective, dose increment study of once daily (morning) sustained release morphine for chronic refractory breathlessness. Participants who achieved <10% improvement over their own baseline at one week (10 mg) were titrated to 20 mg and if no response, another week later to 30 mg for one week. Time was standardized at the first day of the week in which participants responded generating twice daily data one week either side of symptomatic benefit. Analysis used random effect mixed modeling. RESULTS: Of the 83 participants, 17/52 responders required >10 mg: 13 participants (20 mg) and 4 (30 mg), contributing 634 VAS observations. In the week leading to a response, average VAS scores worsened by 0.3 mm/day (p=0.16); the average improvement in the first 24 hours of response was 10.9 mm (7.0 to 14.7; p<0.0001), with continued improvement of 2.2 mm/day (p<0.001) for six more days. CONCLUSION: When treating chronic refractory breathlessness with once daily sustained release morphine, titrate to effect, since inadequate dose may generate no response; and following an initial response, further dose increases should not occur for at least one week. Whether further benefit would be derived beyond day six on the dose to which people respond, and what net effect a further dose increase would have are questions yet to be answered. PMID- 23746232 TI - Perinatal and postweaning exposure to galactooligosaccharides/inulin prebiotics induced biomarkers linked to tolerance mechanism in a mouse model of strong allergic sensitization. AB - Food allergies are increasing, and no treatment exists, thus enhancing interest in prebiotic strategies. This study aimed to analyze the preventive effects of prebiotic feeding during perinatal and postweaning periods in a mouse model of allergy by studying biomarkers related to tolerance (IgG2a, IgA, IFN-gamma, TGF beta, and IL-10), to allergy (IgE, IgG1, IL-4, IL-17, symptoms), and to microbiota (propionate and MyD88). Balb/c mice, both dams and their pups, were fed a diet supplemented with (+Prb) or without (-Prb) GOS/inulin prebiotics. Mice were then sensitized with allergens. Regardless of diet, sensitized mice exhibited similar levels of IgE, IgG1, CD-23, IL-4, IL-17, and symptoms. However, in comparison to -Prb-sensitized mice, +Prb-sensitized mice displayed higher concentrations of total IgG2a (6669 +/- 1788 vs 3696 +/- 1326 fluorescence units, p < 0.005), specific IgA (285 +/- 26 vs 156 +/- 9 fluorescence units, p < 0.01), IFN-gamma (3194 +/- 424 vs 1853 +/- 434 pg/mL, p < 0.01), IL-10 (777 +/- 87 vs 95 +/- 136 pg/mL, p < 0.005), TGF-beta (4853 +/- 1959 vs 243 +/- 444 pg/mL, p < 0.01), MyD88 (0.033 +/- 0.019 vs 0.009 +/- 0.004 relative expression, p < 0.01), and propionate (4.15 +/- 0.8 vs 2.9 +/- 1.15 MUmol, p < 0.05). In a mouse model of allergy, prebiotic exposure during perinatal and postweaning periods induced the highest expression of biomarkers related to tolerance without affecting biomarkers related to allergy. PMID- 23746234 TI - Systemic use of non-biologic corticosteroids in orofacial diseases. AB - Systemic non-biologic agents have long been in clinical use in medicine - often with considerable efficacy, albeit with some adverse effects--as with all medications. With the advent of biologic agents, all of which currently are restricted to systemic use, there is a growing need to ensure which agents have the better therapeutic ratio. The non-biologic agents (NBAs) include a range of agents, most especially the corticosteroids (corticosteroids). This study reviews the corticosteroids in systemic use in management of orofacial mucocutaneous diseases; subsequent studies discuss corticosteroid-sparing agents used in the management of orofacial diseases, such as calcineurin inhibitors used to produce immunosuppression; purine synthetase inhibitors; and cytotoxic and other immunomodulatory agents. PMID- 23746235 TI - [Effects of dexamethasone on expressions of IL-21 and its receptor in lungs of experimental asthma mice]. AB - OBJECTIVE: To observe the expressions of IL-21 and its receptor (IL-21R) in the lungs of chronic asthmatic mice, and investigate the effects of dexamethasone (Dex) on their expressions. METHODS: Thirty-three specific pathogen free (SPF) BALB/c female mice were randomly divided into control group, asthmatic group and Dex treated group, 11 mice each group. The asthma model mice were induced by ovalbumin (OVA) with the classic method. The airway inflammation was evaluated by HE staining. The thicknesses of bronchial wall (Wat/Pbm) and airway smooth muscle (Wam/Pbm) were measured. The expressions of IL-21 and IL-21R proteins were detected by immunohistochemistry and Western blotting. RESULTS: Compared with the control group, the Wat/Pbm and Wam/Pbm in the asthmatic group significantly increased (P<0.01). The indexes in the Dex group were significantly reduced as compared with those in the asthmatic group (P<0.01). The expressions of IL-21 and IL-21R proteins in the asthmatic group were higher than those in the control group (P<0.05), but they were lower in the Dex group than in the asthmatic group (P<0.05). CONCLUSION: The enhanced expressions of IL-21 and IL-21R in the asthmatic mice are found, and Dex can inhibit the expressions of IL-21 and IL-21R in the lung tissues of asthmatic mice. PMID- 23746233 TI - Serum prostate-specific antigen (PSA) concentration is positively associated with rate of disease reclassification on subsequent active surveillance prostate biopsy in men with low PSA density. AB - OBJECTIVE: To investigate the association between serum prostate-specific antigen (PSA) concentration at active surveillance (AS) entry and disease reclassification on subsequent AS biopsy ('biopsy reclassification') in men with low PSA density (PSAD). To investigate whether a clinically meaningful PSA threshold for AS eligibility/ineligibility for men with low PSAD can be identified based on risk of subsequent biopsy reclassification. PATIENTS AND METHODS: We included men enrolled in the Johns Hopkins AS Study (JHAS) who had a PSAD of <0.15 ng/mL/g (640 men). We estimated the incidence rates (IRs; per 100 person years) and hazard ratios (HR) of biopsy reclassification (Gleason score >= 7, any Gleason pattern 4 or 5, >=3 positive cores, or >=50% cancer involvement/biopsy core) for categories of serum PSA concentration at the time of entry into AS. We generated predicted IRs using Poisson regression to adjust for age and prostate volume, mean percentage free PSA (ratio of free to total PSA) and maximum percentage biopsy core involvement with cancer. RESULTS: The unadjusted IRs (per 100 person years) of biopsy reclassification across serum PSA concentration at entry into JHAS showed, in general, an increase; however, the pattern was not linear with higher IRs in the group >= 4 to <6 ng/mL (14.2, 95% confidence interval [CI] 11.8-17.2%) when compared with >=6 to <8 ng/mL (8.4, 95% CI 5.7-12.3%) but almost similar IRs when compared with the group >= 8 to <10 ng/mL (14.8, 95% CI 8.4-26.1%). The adjusted predicted IRs of reclassification showed a similar non-linear increase in IRs, whereby the rates around 4 ng/mL were similar to the rates around 10 ng/mL. CONCLUSION: Risk for biopsy reclassification increased non-linearly across PSA concentration in men with low PSAD, whereby no obvious clinically meaningful threshold could be identified. This information could be incorporated into decision-making for AS. However, longer follow-up times are needed to warrant final conclusions. PMID- 23746236 TI - [Localization and function of CD59 and Cbp in T lymphocytes]. AB - OBJECTIVE: To investigate the distributions of GPI-anchored protein CD59 and C terminal Src kinase-binding protein (Cbp) in cell membrane of T lymphocytes and the roles in cell activation and proliferation. METHODS: The locations of CD59 and Cbp were observed under a fluorescence microscope with the immunofluorescence cytochemistry. The Jurkat cells were transfected with the recombinant plasmid pSUPER-siCD59 using the electric transfection method. Using RT-PCR and Western blotting, we detected the expression of CD59 and the phosphorylation level of protein-tyrosine kinase oncogene family (fyn) in different groups. Moreover, the cell proliferation activity was measured by MTT assay. RESULTS: The immunofluorescence cytochemistry showed that CD59 and Cbp were mainly distributed in cell membrane. Compared with other groups, the quantitative RT-PCR and Western blotting showed that the expression of CD59 was reduced, and along with it the phosphorylation level of fyn decreased in pSUPER-siCD59 group, and MTT assay revealed that its cell proliferation was inhibited (P<0.05). CONCLUSION: CD59 was a type of membrane-bound protein, CD59 and Cbp played synergistic roles in cell activation and proliferation. PMID- 23746237 TI - [Anti-phagocytosis mechanism of SalK/SalR, a two-component regulatory system of Streptococcus suis serotype 2]. AB - OBJECTIVE: To determine the role of the two-component regulatory system (TCS) SalK/SalR in the resistance of Streptococcus suis serotype 2 (SS2) phagocytosed by THP-1-derived macrophages (THP-Mphi). METHODS: Using transmission electron microscopy (TEM), the capsular differences between the wild-type strain 05ZYH33 and the mutant deltasalKR were observed. The interactions of SS2 with THP-Mphi were monitored by Gram staining and immunofluorescence cytochemistry. The anti phagocytic activity of SS2 was evaluated by the construction of phagocytosis model of THP-Mphi. RESULTS: The TEM showed that in the mutant deltasalKR, the capsule was lost; the Gram staining and immunofluorescence imaging revealed that the absence of salKR caused more SS2 were engulfed by THP-Mphi. The phagocytosis model of THP-Mphi cells further demonstrated that the mutant deltasalKR was easier to be phagocytosed by THP-1 cells than the wild-type strain. CONCLUSION: The SalK/SalR regulatory system resists the phagocytosis by THP- Mphi through the capsular formation, but the mechanism of how it regulates the formation of the capsule needs further elucidation. PMID- 23746238 TI - [Monoclonal antibody against laminin receptor 1 inhibits the pulmonary fibrosis induced by bleomycin in rats]. AB - OBJECTIVE: To investigate the effect of the anti-laminin receptor 1 (anti-LAMR1) monoclonal antibody (mAb) on rat pulmonary fibrosis induced by bleomycin. METHODS: Seventy-two male Wistar rats were randomly divided into 3 groups: LAMR1 mAb group (group L), control group (group C) and model group (group M). All rats were injected with bleomycin via tracheal instillation (5 mg/kg body mass) to induce pulmonary fibrosis. Then, the rats were treated with anti-LAMR1 mAb (group L), dexamethasone (group C), normal saline (group M), three times each week via intraperitoneal injection. Eight rats in each group were sacrificed at the 7, 14, 28 days. Histological changes of the lungs were evaluated by HE staining. The expression of surfactant protein A (SP-A) in the lung tissue was measured by immunohistochemistry. The expression of hydroxyproline (Hyp) in serum was measured by ELISA. The expressions of MMP-9 and TGF-beta1 mRNA were evaluated by PCR. RESULTS: Compared with the other two groups, group M presented more apparent alveolitis and the higher expression of hydroxyproline in serum, the lower expression of SP-A, and the higher expressions of MMP-9 and TGF-beta1 mRNA in the lung tissue. CONCLUSION: LAMR1 mAb can evidently alleviate pulmonary fibrosis induced by bleomycin in rats. PMID- 23746239 TI - [Expression and purification of Legionella pneumophila MIP protein and its application in serological diagnosis]. AB - OBJECTIVE: To express and purify macrophage infectivity potentiator (MIP) protein of Legionella pneumophila(Lp), and explore its value in the serological diagnosis of Lp. METHODS: The recombinant plasmid pET-mip was transformed into E.coli BL21 competent cells. The expression of MIP protein was induced, and then analyzed by SDS-PAGE electrophoresis, purified by affinity chromatography. We screened out 40 positive blood serum and 30 negative blood serum using the DRG (Germany, IgG/IgM/IgA) Lp kit. The blood serum samples were detected for IgG, IgM, IgA antibody levels by indirect ELISA that we had established with the purified MIP protein as the coating antigen, as well as by R&D (USA, IgG/IgM/IgA) Lp kit. The two methods were compared in the sensitivity, specificity and consistency of the test results. RESULTS: The recombinant MIP protein was successfully expressed and purified with Mr; being 40 000 in E.coli BL21. In comparison of the indirect ELISA we developed with the R&D Lp kit for detecting Lp antibody IgG, IgM and IgA in blood serum, the specificity of IgG was 88.5% and the sensitivity was 95.5%, the Kappa value was 0.846 (P<0.05), the area under the ROC curve was 0.927; the specificity of IgM was 89.3% and the sensitivity was 97.6%, the Kappa value was 0.88 (P<0.05), the area under the ROC curve was 0.947; the specificity of IgA was 90% and the sensitivity was 95.2%, the Kappa value was 0.856 (P<0.05), the area under the ROC curve was 0.931. CONCLUSION: MIP proteins of L.pneumophila was expressed and purified successfully, and MIP protein can be used as a coating antigen in serological diagnosis of L.pneumophila. PMID- 23746241 TI - [Protective immune responses induced by intranasal immunization with Mycoplasma pneumoniae P1C-IL-2 fusion DNA vaccine in mice]. AB - OBJECTIVE: To investigate the immune responses and immune protections of a DNA vaccine constructed by fusing Mycoplasma pneumoniae (M. pneumoniae) p1 gene car boxy terminal region (p1c gene) with interleukin-2 (IL-2) gene. METHODS: BALB/c mice were immunized by intranasal inoculation of P1C-IL-2 fusion DNA vaccine. Levels of serum IgG, IgG isotypes, BAL fluids IgA, IFN-gamma and IL-4 were detected by ELISA. We established the mouse models infected with M. pneumoniae, and then observed the histopathological changes in lungs and counted colonies in bronchoalveolar lavage fluid (BALF) after challenged intranasally with M. pneumoniae. RESULTS: Serum total IgG, IgG1 and IgG2a isotypes, levels of IFN gamma and IL-4 in BALF increased significantly in the group inoculated with P1C IL-2 fusion DNA vaccine as compared with the one with P1C DNA vaccine (P<0.05), while there was no significant difference in BALF IgA between the two groups (P>0.05). The lung tissue inflammation was aggravated and the histopathologic score (HPS) of P1C-IL-2 DNA vaccine immunized mice significantly increased as compared with those in P1C DNA vaccine immunized mice at 1, 3, 6 d after challenged intranasally with M. pneumoniae (P<0.05). The P1C-IL-2 fusion DNA vaccine did not show significant difference from P1C DNA vaccine in the detectable number of M. pneumoniae strain in BALF(P>0.05). CONCLUSION: IL-2 can enhance the systemic immune responses of P1C DNA vaccine, but it also can develop a severe histopathological change in early days after infection of M. pneumoniae. PMID- 23746240 TI - [Expression of endoglin in human non-small cell lung cancer and its clinical significance]. AB - OBJECTIVE: To investigate the expression of endoglin (ENG) in human non small cell lung cancer (NSCLC) cell lines, cancer and adjacent non-cancer tissues, and its role in NSCLC development, progression, metastasis and recurrence. METHODS: Five strains of NSCLC cells and one strain of normal human bronchial epithelial (HBE) cells were cultured in vitro. Human NSCLC tissues and their corresponding adjacent lung tissues were taken from 22 NSCLC cases to detect the mRNA and protein levels of ENG using real-time PCR and Western blotting, respectively. Chi square test was performed to analyze the correlations between the ENG expression and clinical data. RESULTS: The mRNA and protein levels of ENG were up-regulated in 3 NSCLC cell strains of high metastasis. However, the expression of ENG was missing in the other low-metastatic NSCLC cell strains and the HBE cell strain. Besides, the mRNA and protein levels of ENG were up-regulated in the 19 out of 22 lung cancer tissues (86.36%), which were significantly higher than those in the adjacent non-cancer tissues (P<0.01). The over-expression of ENG was significantly correlated positively with lymph node metastasis (P<0.01), but not with age, sex, tumor size, clinical stage, pathological grade or histopathological type. CONCLUSION: The expression of ENG in NSCLC is significantly correlated positively with lymph node metastasis, and it might be a biomarker for the metastasis and prognosis of NSCLC. PMID- 23746242 TI - [Construction and expression of recombinant lentivirus encoding miR-203 and its inhibitory effect on proliferation and migration of human umbilical vein endothelial cells]. AB - OBJECTIVE: To construct a recombinant lentivirus harboring human-derived microRNA 203 (miR-203), and investigate its biological effect on proliferation and migration of human umbilical vein endothelial cells (HUVEC-12). METHODS: The precursor miR-203 DNA fragment was obtained by PCR and inserted into pLenti-6.3 lentivirus vector, and then was stably transfected into HUVEC-12 cells (HUVEC-Lv miR-203). Overexpression of exogenous pre-miR-203 was determined using real-time quantitative PCR (qRT-PCR). Subsequently, to investigate its effects on proliferation and migration of HUVEC-12 cells, MTT assay and wound healing assay were respectively performed. RESULTS: We successfully constructed a lentivirus based delivery system to stably express exogenous pre-miR-203 in HUVEC-12 cells. MTT assay and wound healing assay showed that miR-203 could significantly suppress cell proliferation and migration of HUVEC-12. CONCLUSION: MiR-203 has the inhibitory effect on the proliferation and migration of HUVEC-12 cells. PMID- 23746244 TI - [Role of BPIFB1 in regulating inflammatory response of RAW264.7 cells infected by P.aeruginosa]. AB - OBJECTIVE: To demonstrate the mechanisms and regulation pathways of BPIFB1 against P.aeruginosa infection. METHODS: After treated with 10 ng/mL LPS and 1.28 mg/mL BPIFB1, RAW 246.7 cells were detected for the expression levels of CD14 receptor, TLR4 and MyD88 by ELISA and Western blotting. In addition, using RNAi and specific protease inhibitor blockade respectively, we observed the changes in the expressions of MyD88, TRAF6, NF-kappaB and different signaling pathway molecules in RAW 246.7 cells after BPIFB1 and LPS treatment. RESULTS: The expression levels of CD14, TLR4 and MyD88 significantly decreased after the RAW264.7 cells were treated with BPIFB1 and LPS. When the expressions of MyD88, TRAF6 and NF-kappaB were blocked by specific siRNA respectively, there was a significant reduction of TNF-alpha over-expression induced by BPIFB1 and LPS. And when the cells were treated with BPIFB1, LPS and related protease inhibitors, the phosphorylation levels of ERK1/2, p38 and Akt1 were evidently inhibited by kinase inhibitors. CONCLUSION: The combination of BPIFB1 and LPS can reduce the degree of cell inflammatory responses induced by P.aeruginosa by inhibiting the expressions of relative intracellular cytokines. PMID- 23746245 TI - [Construction and biological function of eukaryotic expression vector for myc tagged HER2]. AB - OBJECTIVE: To construct eukaryotic expression vector of myc-tagged human HER2 and investigate its role in breast cancer cell proliferation and drug resistance. METHODS: Human HER2 gene was amplified by PCR and cloned into the pXJ-40-myc vector. The recombinant myc-HER2 was identified by enzyme digestion and sequencing, transfected into breast cancer cell line ZR75-1, and then was detected by Western blotting. Next, CCK8 assay was performed to investigate myc Her2 transfected cell proliferation. Trastuzumab, anti-Her2 antibody, was added to determine the sensitivity of cells transfected with myc-Her2. RESULTS: Enzyme digestion and sequencing confirmed the myc-HER2 vector was constructed successfully. Western blotting showed the expression of myc-HER2 in the ZR75-1 cells. The result of cell growth curve showed that cells transfected with myc her2 grew significantly faster than the control cells. Moreover, trastuzumab obviously suppressed the growth of ZR75-1 cells transfected with myc-HER2. CONCLUSION: The myc-HER2 vector was successfully constructed which lays an experimental foundation for the study of HER2 drug resistance to trastuzumab. PMID- 23746243 TI - [Angiotensin-(1-7) inhibits hypoxia-induced renal tubular epithelial-to mesenchymal transition in rats]. AB - OBJECTIVE: To investigate the effect of angiotensin-(1-7) [Ang(1-7)] on the transdifferentiation of normal rat kidney proximal tubular epithelia cells (NRK52E) under hypoxic condition induced by cobaltous chloride (Co) and the underlying mechanism. METHODS: NRK52E cells were divided into control group, Co group, Co+Ang-(1-7) group and Ang-(1-7) group and cultured for 6 d. Expression levels of hypoxia-inducible factor-1alpha (HIF-lalpha) and alpha-smooth muscle actin (alpha-SMA) were detected by immunocytochemistry. Immunohistochemistry and Western blotting were used to determine the expression of p-ERK1/2 and ELISA to measure the content of collagen type 1 (Col I) in the culture supernatant. RESULTS: Compared with the control group, the expressions of HIF-lalpha, alpha SMA, Col Iand p-ERK1/2 in the Co group and the Co+Ang-(1-7) group increased significantly (P<0.05) 6 d later. Compared with the Co group, the expressions of HIF-lalpha, alpha-SMA, Col Iand p-ERK1/2 in the Co+Ang-(1-7) group decreased significantly (P<0.05). CONCLUSION: Ang-(1-7) can inhibit Co-induced rats' tubular epithelial-to-mesenchymal transition and reduce the production of extracellular matrix. Inhibition of ERK1/2 pathway may play an important role in this process. PMID- 23746246 TI - [Preparation, epitope analysis and clinical application of monoclonal antibodies against heart-type fatty acid binding protein]. AB - OBJECTIVE: To prepare and characterize the monoclonal antibody (mAb) against recombinant human heart-type fatty acid binding protein (H-FABP) and apply it to the clinical analysis. METHODS: BALB/c mice were immunized with recombinant H FABP (rH-FABP) from prokaryotic expression or synthesized peptide fragment. After common fusion and screening, the subtypes, titer and affinity of mAbs were detected respectively. After purification, the specificity of mAbs was tested by indirect ELISA and Western blotting. ELISA system was established by pair mapping and applied in the detection of clinical samples. Two epitope peptides were designed by bioinformatics and used to detect the epitope of 1-F10 through Western blotting. RESULTS: Four different hybridoma clones secreting anti-H-FABP antibodies were developed, with high titres of 1:51 200-1:1024 000. Immunoglobulin types of these mAbs were found to be IgG2a or IgG2b, respectively. The affinity of the mAb 1-F10 even reached 9.02*10(9); mol/L. ELISA and Western blotting showed that these mAbs could identify H-FABP specifically. In addition, the pair mapping of monoclonal antibodies 3-H5-1-F10 could recognize H-FABP in human serum samples. Furthermore, the specific target recognized by 1-F10 mAb was located within amino acid 86-133 of H-FABP. CONCLUSION: Four highly specific mAbs against H-FABP were successfully obtained and the established ELISA system could be used to detect the H-FABP in clinical serum samples, and the epitope of 1-F10 mAb was also verified. PMID- 23746247 TI - [Cloning and expression of the prokaryotic expression vectors of phytoplasma immunodominant membrane protein A and preparation of its antiserum]. AB - OBJECTIVE: To construct the prokaryotic expression vector of phytoplasma immunodominant membrane protein A (IdpA) in prokaryotic cell, express and purify the IdpA and prepare its antiserum. METHODS: With the recombinant plasmid pMD18-T IdpA as templates, IdpA gene was amplified by PCR and cloned into prokaryotic expression vector pET-28a(+) by endonuclease reaction and T4 DNA ligase reaction. Then the recombinant plasmid pET-28a(+)-IdpA was transformed into E.coli BL21 (DE3). After confirmed by PCR and double enzyme digestion, the recombinant protein IdpA was expressed under IPTG induction and purified. The purified product was used to immunize BALB/c mice to prepare its antiserum. IdpA-specific mouse antiserum was identified by ELISA and Westerrn blotting. RESULTS: The prokaryotic vectors of pET-28a(+)-IdpA were constructed successfully and the recombinant protein IdpA was induced to express stably in the E.coli BL21. The purity of IdpA was up to over 90%. In the BALB/c mice immunized by the purified IdpA, the titre of IdpA-specific antiserum was as high as 1:320 000. CONCLUSION: The recombinant protein IdpA was expressed successfully in E.coli and the IdpA specific antiserum was prepared. PMID- 23746249 TI - [Expression Wnt2 in breast cancer tissues and sera of the patients]. AB - OBJECTIVE: To observe the expression of Wnt2 in the breast cancer cells (MDA-MB 231, ZR-75-30 and MCF-7) and tissues, and analyze the correlation of Wnt2 expression with CA-153 in the sera of patients with breast cancer. METHODS: The expression of Wnt2 at both mRNA and protein levels was measured respectively by real-time fluorescent quantitative PCR and Western blotting in the three human breast cancer cell lines. In addition, the immunohistochemistry (IHC) was applied to detect the expression of Wnt2 in 5 corresponding tissues adjacent to cancer, 9 breast carcinoma in situ and 9 invasive breast cancer; ELISA was used to detect Wnt2 and electrochemiluminescence immunoassay was used to detect CA-153 in the sera of 15 normal women and 30 patients with breast cancer. Furthermore, we collected complete clinicopathological data from the participating subjects, and analyzed their relationships with serum Wnt2 levels. RESULTS: The mRNA and protein of Wnt2 were negative in the three human breast cancer cells, while Wnt2 in the epithelial and interstitial cells of breast cancer tissues was significantly higher than that in normal tissues (P<0.05). The expression levels of Wnt2 and CA-153 in the sera of patients with breast cancer were higher than those in normal women (P<0.05), and Wnt2 levels in the sera of breast cancer patients were positively correlated with serum CA-153 levels. CONCLUSION: Simultaneous tests of Wnt2 and CA-153 levels in the serum may help the diagnostic screening of breast cancer. PMID- 23746248 TI - [Expression and clinical significance of soluble B7-H3 in sera of patients with primary hepatocellular carcinoma]. AB - OBJECTIVE: To detect the expression and clinical significance of co-stimulatory molecule B7-H3 in sera and tissues of patients with hepatocellular carcinoma (HCC). METHODS: We collected 63 samples of sera and liver tissue from HCC patients, 5 adjacent normal tissues of hepatic hemangioma as controls, and the other 50 sera samples of healthy people in the same time. The expression of soluble B7-H3 (sB7-H3) in sera from HCC patients and healthy people was detected by ELISA. Immunohistochemistry was performed to analyze the expression of B7-H3 on normal liver and HCC tissues. RESULTS: The level of sB7-H3 from HCC patients was significantly higher than that from healthy people [(4143.47+/-976.27) pg/mL vs (2076.18+/-605.42) pg/mL, P<0.05]; and sB7-H3 level was related to clinical stage, distant metastasis and the positive expression of B7-H3 in HCC tissues (P<0.05), while there was no significant difference between its expression and the other clinical pathological parameters, such as the patients' age, gender, histological type, lymphatic metastasis and size of tumor. Furthermore, a positive correlation was found between the level of sB7-H3 and CA19-9 in HCC patients (P<0.05), but it was not associated with AFP and CEA. CONCLUSION: The level of sB7-H3 in HCC patients was significantly higher than that in healthy people, and B7-H3 expression was correlated with clinical pathological indexes, which implicated that detecting the expression of sB7- H3 might be helpful for the diagnosis of primary HCC. PMID- 23746250 TI - [Role of T lymphocyte activation in the development of severe fever accompanied by thrombocytopenia syndrome]. AB - OBJECTIVE: To explore the effect of peripheral blood T lymphocyte activation on the blood cells, tissue injury and the development of disease in patients with severe fever with thrombocytopenia syndrome (SFTS). METHODS: The expressions of CD69, HLA-DR, CD28 and CTLA-4 on peripheral blood T lymphocytes were determined dynamically by flow cytometry and the relationships between the above immune molecules and ALT, AST, leukocytes, platelets were analyzed respectively. RESULTS: The expressions of CD69 and HLA-DR on peripheral blood T lymphocytes in patients with SFTS were elevated significantly during the whole course of disease (P<0.05). CD28 expression on CD4(+); lymphocyte subset decreased in the early stage and gradually increased to the normal range. Meanwhile, CTLA-4 expression on T lymphocytes went up in the late stage of viral infection. The levels of serum ALT, AST, LDH and CK were significantly higher than the upper limit of the normal and the counts of WBC and PLT dropped to the lowest at the outset. But all of them returned back to the normal range gradually with the down-regulation of CD69 and HLA-DR and the up-regulation of CTLA-4 on T lymphocyte. CONCLUSION: The overactivation of T lymphocytes may contribute to tissue injury and the high expression of CTLA-4 may be a negative feedback regulation to the overactivation of T lymphocytes, which plays an important role in immunoregulation of SFTS patients. PMID- 23746251 TI - [Construction and immunogenicity analysis of tumor peptide vaccine P64k-EGFR(262 328); targeting the dimmerization interface of EGFR]. AB - OBJECTIVE: To construct a tumor-specific peptide vaccine P64k-EGFR(262-328); targeting the dimerization interface of EGFR and analyze its immunogenicity in BALB/c mice. METHODS: The fusion gene of P64k-EGFR(262-328); was amplified by splicing overlap extension-PCR (SOE-PCR) and cloned into the pMD18-T vector. After double-enzyme cleavage and sequence analysis, the fusion gene was cloned into the expression vector pET-21b by digestion with Nde I and Hind III and then transformed into the BL21(DE3). After induced by IPTG to express, the fusion protein P64k-EGFR(262-328); was purified by source Q and Ni-NTA chromatography. BALB/c mice were immunized with the purified protein dissolved in double distilled water emulsified (1:1) in Freuds' adjuvant, and their sera were tested for antibody titers by ELISA. RESULTS: The P64k-EGFR(262-328); gene of 2031 bp was acquired. SDS-PAGE showed that the recombinant protein was 70 kDa, expressed mainly in a soluble form. After two steps of column chromatography, the purity was over 95%. The peptide vaccine could elicit a high titer of more than 1:16 000 in BALB/c mice. CONCLUSION: The tumor-specific peptied vaccine P64k-EGFR(262 328); was constructed successfully, which could pay a good foundation for the further study on its function and application. PMID- 23746252 TI - Neurological and Cardiovascular Potential of Pharmacologically Active Hydrazonone Derivatives. AB - Hydrazone derivatives possess an azomethine group and are considered as an important class of pharmacological active compounds and also created interest of researchers to synthesized variety of hydrazones derivatives having biological activities for new drug development. Hydrazones moieties are present in many pharmacological active molecules. which have been showed high interest because of their various types of diverse pharmacological, biological and clinical applications. Hydrazonones possess wide variety of biological activities such as antimicrobial, analgesic, anti-inflammatory, antiplatelet, antitubercular, anticancer, antiviral, antimalarial, anthelmintic, antifungal and antiparasitic etc. Various hydrazones possess neurological and cardiovascular activities. This is review focus on the neurological and cardiovascular activities of hydrazones compounds. PMID- 23746254 TI - Arrest peptides: cis-acting modulators of translation. AB - Each peptide bond of a protein is generated at the peptidyl transferase center (PTC) of the ribosome and then moves through the exit tunnel, which accommodates ever-changing segments of ~ 40 amino acids of newly translated polypeptide. A class of proteins, called ribosome arrest peptides, contains specific sequences of amino acids (arrest sequences) that interact with distinct components of the PTC-exit tunnel region of the ribosome and arrest their own translation continuation, often in a manner regulated by environmental cues. Thus, the ribosome that has translated an arrest sequence is inactivated for peptidyl transfer, translocation, or termination. The stalled ribosome then changes the configuration or localization of mRNA, resulting in specific biological outputs, including regulation of the target gene expression and downstream events of mRNA/polypeptide maturation or localization. Living organisms thus seem to have integrated potentially harmful arrest sequences into elaborate regulatory mechanisms to express genetic information in productive directions. PMID- 23746255 TI - Structural basis of the translational elongation cycle. AB - The sequential addition of amino acids to a growing polypeptide chain is carried out by the ribosome in a complicated multistep process called the elongation cycle. It involves accurate selection of each aminoacyl tRNA as dictated by the mRNA codon, catalysis of peptide bond formation, and movement of the tRNAs and mRNA through the ribosome. The process requires the GTPase factors elongation factor Tu (EF-Tu) and EF-G. Not surprisingly, large conformational changes in both the ribosome and its tRNA substrates occur throughout protein elongation. Major advances in our understanding of the elongation cycle have been made in the past few years as a result of high-resolution crystal structures that capture various states of the process, as well as biochemical and computational studies. PMID- 23746256 TI - Correlating structure and energetics in protein-ligand interactions: paradigms and paradoxes. AB - Predicting protein-binding affinities of small molecules, even closely related ones, is a formidable challenge in biomolecular recognition and medicinal chemistry. A thermodynamic approach to optimizing affinity in protein-ligand interactions requires knowledge and understanding of how altering the structure of a small molecule will be manifested in protein-binding enthalpy and entropy changes; however, there is a relative paucity of such detailed information. In this review, we examine two strategies commonly used to increase ligand potency. The first of these involves introducing a cyclic constraint to preorganize a small molecule in its biologically active conformation, and the second entails adding nonpolar groups to a molecule to increase the amount of hydrophobic surface that is buried upon binding. Both of these approaches are motivated by paradigms suggesting that protein-binding entropy changes should become more favorable, but paradoxes can emerge that defy conventional wisdom. PMID- 23746253 TI - Mechanisms for initiating cellular DNA replication. AB - The initiation of DNA replication represents a committing step to cell proliferation. Appropriate replication onset depends on multiprotein complexes that help properly distinguish origin regions, generate nascent replication bubbles, and promote replisome formation. This review describes initiation systems employed by bacteria, archaea, and eukaryotes, with a focus on comparing and contrasting molecular mechanisms among organisms. Although commonalities can be found in the functional domains and strategies used to carry out and regulate initiation, many key participants have markedly different activities and appear to have evolved convergently. Despite significant advances in the field, major questions still persist in understanding how initiation programs are executed at the molecular level. PMID- 23746257 TI - Molecular chaperone functions in protein folding and proteostasis. AB - The biological functions of proteins are governed by their three-dimensional fold. Protein folding, maintenance of proteome integrity, and protein homeostasis (proteostasis) critically depend on a complex network of molecular chaperones. Disruption of proteostasis is implicated in aging and the pathogenesis of numerous degenerative diseases. In the cytosol, different classes of molecular chaperones cooperate in evolutionarily conserved folding pathways. Nascent polypeptides interact cotranslationally with a first set of chaperones, including trigger factor and the Hsp70 system, which prevent premature (mis)folding. Folding occurs upon controlled release of newly synthesized proteins from these factors or after transfer to downstream chaperones such as the chaperonins. Chaperonins are large, cylindrical complexes that provide a central compartment for a single protein chain to fold unimpaired by aggregation. This review focuses on recent advances in understanding the mechanisms of chaperone action in promoting and regulating protein folding and on the pathological consequences of protein misfolding and aggregation. PMID- 23746258 TI - Sumoylation: a regulatory protein modification in health and disease. AB - Posttranslational modification with small ubiquitin-related modifier (SUMO) proteins is now established as one of the key regulatory protein modifications in eukaryotic cells. Hundreds of proteins involved in processes such as chromatin organization, transcription, DNA repair, macromolecular assembly, protein homeostasis, trafficking, and signal transduction are subject to reversible sumoylation. Hence, it is not surprising that disease links are beginning to emerge and that interference with sumoylation is being considered for intervention. Here, we summarize basic mechanisms and highlight recent developments in the physiology of sumoylation. PMID- 23746259 TI - Design of protein catalysts. AB - Diverse engineering strategies have been developed to create enzymes with novel catalytic activities. Among these, computational approaches hold particular promise. Enzymes have been computationally designed to promote several nonbiological reactions, including a Diels-Alder cycloaddition, proton transfer, multistep retroaldol transformations, and metal-dependent hydrolysis of phosphotriesters. Although their efficiencies (kcat/KM = 0.1-100 M(-1) s(-1)) are typically low compared with those of the best natural enzymes (10(6)-10(8) M(-1) s(-1)), these catalysts are excellent starting points for laboratory evolution. This review surveys recent progress in combining computational and evolutionary approaches to enzyme design, together with insights into enzyme function gained from studies of the engineered catalysts. PMID- 23746260 TI - Hydrogen tunneling links protein dynamics to enzyme catalysis. AB - The relationship between protein dynamics and function is a subject of considerable contemporary interest. Although protein motions are frequently observed during ligand binding and release steps, the contribution of protein motions to the catalysis of bond making/breaking processes is more difficult to probe and verify. Here, we show how the quantum mechanical hydrogen tunneling associated with enzymatic C-H bond cleavage provides a unique window into the necessity of protein dynamics for achieving optimal catalysis. Experimental findings support a hierarchy of thermodynamically equilibrated motions that control the H-donor and -acceptor distance and active-site electrostatics, creating an ensemble of conformations suitable for H-tunneling. A possible extension of this view to methyl transfer and other catalyzed reactions is also presented. The impact of understanding these dynamics on the conceptual framework for enzyme activity, inhibitor/drug design, and biomimetic catalyst design is likely to be substantial. PMID- 23746262 TI - Posttranslational biosynthesis of the protein-derived cofactor tryptophan tryptophylquinone. AB - Methylamine dehydrogenase (MADH) catalyzes the oxidative deamination of methylamine to formaldehyde and ammonia. Tryptophan tryptophylquinone (TTQ) is the protein-derived cofactor of MADH required for this catalytic activity. TTQ is biosynthesized through the posttranslational modification of two tryptophan residues within MADH, during which the indole rings of two tryptophan side chains are cross-linked and two oxygen atoms are inserted into one of the indole rings. MauG is a c-type diheme enzyme that catalyzes the final three reactions in TTQ formation. In total, this is a six-electron oxidation process requiring three cycles of MauG-dependent two-electron oxidation events using either H2O2 or O2. The MauG redox form responsible for the catalytic activity is an unprecedented bis-Fe(IV) species. The amino acids of MADH that are modified are ~ 40 A from the site where MauG binds oxygen, and the reaction proceeds by a hole hopping electron transfer mechanism. This review addresses these highly unusual aspects of the long-range catalytic reaction mediated by MauG. PMID- 23746261 TI - Methylerythritol phosphate pathway of isoprenoid biosynthesis. AB - Isoprenoids are a class of natural products with more than 55,000 members. All isoprenoids are constructed from two precursors, isopentenyl diphosphate and its isomer dimethylallyl diphosphate. Two of the most important discoveries in isoprenoid biosynthetic studies in recent years are the elucidation of a second isoprenoid biosynthetic pathway [the methylerythritol phosphate (MEP) pathway] and a modified mevalonic acid (MVA) pathway. In this review, we summarize mechanistic insights on the MEP pathway enzymes. Because many isoprenoids have important biological activities, the need to produce them in sufficient quantities for downstream research efforts or commercial application is apparent. Recent advances in both MVA and MEP pathway-based synthetic biology are also illustrated by reviewing the landmark work of artemisinic acid and taxadien 5alpha-ol production through microbial fermentations. PMID- 23746263 TI - Barriers to nutritional intake in patients with acute hip fracture: time to treat malnutrition as a disease and food as a medicine? AB - Inadequate energy and protein intake leads to malnutrition; a clinical disease not without consequence post acute hip fracture. Data detailing malnutrition prevalence, incidence, and intake adequacy varies widely in this patient population. The limited success of reported interventional strategies may result from poorly defined diagnostic criteria, failure to address root causes of inadequate intake, or errors associated with selection bias. This pragmatic study used a sequential, explanatory mixed methods design to identify malnutrition aetiology, prevalence, incidence, intake adequacy, and barriers to intake in a representative sample of 44 acute hip fracture patients (73% female; mean age, 81.7 +/- 10.8 years). On admission, malnutrition prevalence was 52.2%. Energy and protein requirements were only met twice in 58 weighed 24 h food records. Mean daily patient energy intake was 2957 kJ (50.9 +/- 36.1 kJ.kg(-1)) and mean protein intake was 22.8 g (0.6 +/- 0.46 g.kg(-1)). This contributed to a further in-patient malnutrition incidence of 11%. Barriers to intake included patient perceptions that malnutrition and (or) inadequate intake were not a problem, as well as patient and clinician perceptions that treatment for malnutrition was not a priority. Malnutrition needs to be treated as a disease not without consequence, and food should be considered as a medicine after acute hip fracture. PMID- 23746265 TI - Assessing quality of life of nursing home residents with dementia: feasibility and limitations in patients with severe cognitive impairment. AB - BACKGROUND: The Quality of Life-Alzheimer's Disease Scale (QOL-AD) is a reliable and valid self-report measure for assessing quality of life (QoL) in people with dementia in long-term care settings, but little is known yet about the number of patients with severe cognitive impairment who are able to complete this measure, and the characteristics of those unable to do so. The aim of the study is to advance knowledge of these issues. METHODS: Data on residents with dementia were collected from 11 nursing homes. The QOL-AD residential version was directly applied to residents with dementia diagnosis and Mini-Mental State Examination scores under 27, randomly selected in each center. Residents' QoL was further assessed from the perspective of some close relative and some staff member. Altogether, 102 data sets from residents, 184 from relatives, and 197 from staff members were collected. An analysis of the characteristics of completers versus non-completers regarding levels of cognitive impairment was carried out. RESULTS: People with dementia in long-term care are able to report their QoL. The QOL-AD completion rate decreases as the cognitive impairment level increases; non completion is associated with greater overall impairment. About 30% of residents with severe cognitive impairment could self-report on their QoL with acceptable reliability. CONCLUSIONS: QoL self-rating should be the first-line option when assessing residents with severe cognitive impairment. For those that are not able to complete self-report measures, proxies' report could be an alternative, although the development of other assessment procedures (e.g. observational) should be considered. PMID- 23746266 TI - Lymphomatoid papulosis type D: an aggressive histology for an indolent disease. PMID- 23746264 TI - High variability in baseline urinary free cortisol values in patients with Cushing's disease. AB - OBJECTIVE: Twenty-four-hour urinary free cortisol (UFC) sampling is commonly used to evaluate Cushing's syndrome. Because there are few data on UFC variability in patients with active Cushing's disease, we analysed baseline UFC in a large patient cohort with moderate-to-severe Cushing's disease and assessed whether variability correlates with hypercortisolism severity. These data will help clinicians establish the minimum number of UFC samples required to obtain reliable data. DESIGN: Observational study (enrolment phase of Phase III study). METHODS: Patients (n = 152) with persistent/recurrent or de novo Cushing's disease and mean UFC (mUFC) >=1.5*ULN (normal: 30-145 nmol/24 h) were included. Mean UFC level was calculated from four 24-h urine samples collected over 2 weeks. RESULTS: Over 600 24-h UFC samples were analysed. The mUFC levels of samples 1 and 2 and samples 3 and 4 were 1000 nmol/24 h (SD 1872) and 940 nmol/24 h (SD 2148), respectively; intrapatient coefficient of variation (CV) was 38% for mUFC. The intrapatient CV using all four samples was 52% (95% CI: 48-56). The intrapatient CV was 51% (95% CI: 44-58) for samples 1 and 2, 49% (95% CI: 43-56) for samples 3 and 4 and 54% (95% CI: 49-59) for samples 1, 2 and 3. Variability in mUFC increased as UFC levels increased. There were no correlations between UFC and clinical features of hypercortisolism. CONCLUSIONS: There is intrapatient variability of approximately 50% in 24-h UFC measurements, which is relevant to targets set to estimate any treatment effect. Analysing more than two 24-h collection periods in individual patients does not result in a relevant decrease in variability. Interestingly, UFC levels did not correlate with hypercortisolism severity. PMID- 23746268 TI - Molecular-scale perspective of water-catalyzed methanol dehydrogenation to formaldehyde. AB - Methanol steam reforming is a promising reaction for on-demand hydrogen production. Copper catalysts have excellent activity and selectivity for methanol conversion to hydrogen and carbon dioxide. This product balance is dictated by the formation and weak binding of formaldehyde, the key reaction intermediate. It is widely accepted that oxygen adatoms or oxidized copper are required to activate methanol. However, we show herein by studying a well-defined metallic copper surface that water alone is capable of catalyzing the conversion of methanol to formaldehyde. Our results indicate that six or more water molecules act in concert to deprotonate methanol to methoxy. Isolated palladium atoms in the copper surface further promote this reaction. This work reveals an unexpected role of water, which is typically considered a bystander in this key chemical transformation. PMID- 23746267 TI - Physical activity text messaging interventions in adults: a systematic review. AB - BACKGROUND: Physical inactivity is a leading health risk factor for mortality worldwide. Researchers are examining innovative techniques including the use of mobile technology to promote physical activity. One such technology, text messaging, is emerging internationally as a method to communicate with and motivate individuals to engage in healthy behaviors, including physical activity. AIM: Review the existing scientific literature on adult physical activity text messaging interventions. METHODS: This systematic review examined research papers that addressed physical activity text messaging intervention studies in adults. Using multiple databases, the search strategy included published English language studies through October 1, 2011. An author-developed data collection tool was used independently by two reviewers to extract and examine the selected study variables. RESULTS: The initial search resulted in the identification of 200 publications. Eleven publications representing 10 studies were included in the final review. Studies were conducted in seven countries with over half the studies being randomized controlled trials. Participants of the studies were predominantly young to middle aged women. Physical activity data were mainly obtained by self-report although three studies used pedometers or accelerometers. Interventions ranged from only sending out text messages to combining text messages with educational materials, staff support, and/or Internet technology. Minimal information was given regarding development or number of text messages used. The median effect size for the studies was 0.50. CONCLUSIONS: To date, using text messaging as a method to promote physical activity has only been studied by a small group of researchers. Current physical activity text messaging literature is characterized by small sample sizes, heterogeneous but positive effect sizes, and a lack of specificity as to the development of the text messages used in these studies. Further research in this area is imperative to facilitate the expansion of mobile technology to promote physical activity. PMID- 23746269 TI - Analysis of putative nonulosonic acid biosynthesis pathways in Archaea reveals a complex evolutionary history. AB - Sialic acids and the other nonulosonic acid sugars, legionaminic acid and pseudaminic acid, are nine carbon-containing sugars that can be detected as components of the glycans decorating proteins and other molecules in Eukarya and Bacteria. Yet, despite the prevalence of N-glycosylation in Archaea and the variety of sugars recruited for the archaeal version of this post-translational modification, only a single report of a nonulosonic acid sugar in an archaeal N linked glycan has appeared. Hence, to obtain a clearer picture of nonulosonic acid sugar biosynthesis capability in Archaea, 122 sequenced genomes were scanned for the presence of genes involved in the biogenesis of these sugars. The results reveal that while Archaea and Bacteria share a common route of sialic acid biosynthesis, numerous archaeal nonulosonic acid sugar biosynthesis pathway components were acquired from elsewhere via various routes. Still, the limited number of Archaea encoding components involved in the synthesis of nonulosonic acid sugars implies that such saccharides are not major components of glycans in this domain. PMID- 23746270 TI - Targeting the BH3 domain of Bcl-2 family proteins. A brief history from natural products to foldamers as promising cancer therapeutic avenues. AB - For many years the spotlight in drug discovery has been on a relatively small number of validated therapeutic target classes, such as G-protein coupled receptors and enzymes such as protein kinases, with well characterized enzymatic and cellular activities. However, with recent progress in genomics and proteomics, protein-protein interactions (PPIs) provide new way of finding novel bioactive molecules acting on their interfaces. This review addresses the current case studies and state of the art in the development of small chemical modulators controlling interactions of proteins that have pathological implications in various human diseases and in particular in cancer. The attention is focused on Bcl-2 family protein modulators ranging from natural products to synthetic ones with particular interest in foldamers as BH3 alpha helix mimetics. PMID- 23746271 TI - Heterocyclic HIV-protease inhibitors. AB - In the panorama of HIV protease inhibitors (HIV PIs), many efforts have been devoted to the development of new compounds with reduced peptidic nature in order to improve pharmacokinetics and pharmacodynamics features. The introduction of cyclic scaffolds in the design of new chemical entities reduces flexibility and affords more rigid inhibitors. Specifically, common dipeptide isosteres are replaced by a central cyclic scaffold designed to address the key interactions with catalytic aspartic acids and residues belonging to the flap region of the active site. The current interest in cyclic chemotypes addressing key interactions of HIV protease is motivated by the different nature of interactions formed with the enzyme, although maintaining key structural resemblance to a peptide substrate, hopefully giving rise to novel HIV-1 PIs displaying an improved profile towards multidrug resistant strains. This approach has been demonstrated for Tipranavir, which is a potent FDA approved HIV-1 PI representing the most famous example of heterocyclic aspartic protease inhibitors. PMID- 23746272 TI - Hepatic PPARs: their role in liver physiology, fibrosis and treatment. AB - Complex molecular and cellular mechanisms are involved in the pathway of liver fibrosis. Activation and transformation of hepatic stellate cells (HSCs) are considered the two main reasons for the cause and development of liver fibrosis. The peroxisome proliferator-activated receptors (PPARs) belonging to the family of ligand-activated transcription factors play a key role in liver homeostasis, regulating adipogenesis and inhibiting fibrogenesis in HSCs. Normal transcriptional function of PPARs contributes to maintain HSCs in quiescent phase. A reduced expression of PPARs in HSCs greatly induces a progression of liver fibrosis and an increased production of collagen. Here, we discuss role and function of PPARs and we take into consideration molecular factors able to reduce PPARs activity in HSCs. Finally, although further validations are needed, we illustrate novel strategies available from in vitro and animal studies on how some PPARs-agonists have been proved effective as antifibrotic substances in liver disease. PMID- 23746273 TI - Medicinal chemistry of antimigraine drugs. AB - Migraine is one of the most frequent neurological disorder with high impact on the quality of life. Primary headaches such as migraine are pathophysiologically complex disorders. The concept of the trigeminovascular system dysfunction in migraine has led to a number of drug discoveries dramatically changing the treatment options. Acute and prophylactic therapy targeting either the trigeminovascular system or central structures involve several groups of drugs with peculiar medicinal chemistry. In the proposed review up to date concept of treatment strategy, medicinal chemistry data of the drugs used will be summarized. The present review gives detailed information on drugs effective in aborting migraine attacks (by inhibiting prostanoid synthesis, are agonists of serotonin 5-HT1B/D receptors, on the recently introduced CGRP-receptor antagonists) and the drugs recommended for prophylactic treatment (selected beta adrenergic receptor antagonists, Ca-channel inhibitors, antiepileptics, antidepressants). The pharmacokinetics, fate in the body (absorption, distribution, metabolism, excretion) and significant pharmacological effects as well as the recent bioanalytical methods for their determination are presented. PMID- 23746274 TI - Drug-induced liver injury: mechanisms, types and biomarkers. AB - Drug-induced liver injury is a ubiquitous issue in clinical settings and pharmaceutical industry. Hepatotoxicity elicited by drugs may be intrinsic or idiosyncratic, both which are driven by different molecular mechanisms. Recently, a unifying mechanistic model of drug-induced liver injury has been introduced. According to this model, drug-induced hepatotoxicity relies on 3 consecutive steps, namely an initial cellular insult that leads to the occurrence of mitochondrial permeability transition, which in turn ultimately burgeons into the onset of cell death. Clinically, drug-induced liver injury can be manifested in a number of acute and chronic conditions, including hepatitis, cholestasis, steatosis and fibrosis. These pathologies can be diagnosed and monitored by addressing well-established physical, clinical chemistry and histopathological biomarkers. In the last few years, several novel read-outs of drug-induced liver injury have been proposed, involving genetic, epigenetic, transcriptomic, proteomic and metabolomic parameters. These new concepts and recent developments in the field of drug-induced liver injury are revised in the current paper. PMID- 23746275 TI - Leptin in joint and bone diseases: new insights. AB - Leptin is an adipokine with pleiotropic actions that regulates food intake, energy metabolism, inflammation and immunity, and also participates in the complex mechanism that regulates skeleton biology, both at bone and cartilage level. Leptin is increased in obesity and contributes to the "low-grade inflammatory state" of obese subjects causing a cluster of metabolic aberrations that affects joints and bone. In this review, we report the most recent research advances about the role of leptin in bone and cartilage function and its implication in inflammatory and degenerative joint diseases, such as osteoarthritis, rheumatoid arthritis and osteoporosis. PMID- 23746276 TI - n-3 fatty acids: role in neurogenesis and neuroplasticity. AB - Omega-3 polyunsaturated fatty acids (PUFA) are essential unsaturated fatty acids with a double bond (C=C) starting after the third carbon atom from the end of the carbon chain. They are important nutrients but, unfortunately, mammals cannot synthesize them, whereby they must be obtained from food sources or from supplements. Amongst nutritionally important polyunsaturated n-3 fatty acids, alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are highly concentrated in the brain and have anti-oxidative stress, anti inflammatory and antiapoptotic effects. They are involved in many bodily processes and may reportedly lead to neuron protection in neurological diseases. aged or damaged neurons and in Alzheimer's disease. Their effect in cognitive and behavioral functions and in several neurological and psychiatric disorders has been also proven. The dentate gyrus (DG), a sub-region of hippocampus, is implicated in cognition and mood regulation. The hippocampus represents one of the two areas in the mammalian brain in which adult neurogenesis occurs. This process is associated with beneficial effects on cognition, mood and chronic pharmacological treatment. The exposure to n-3 fatty acids enhances adult hippocampal neurogenesis associated with cognitive and behavioral processes, promotes synaptic plasticity by increasing long-term potentiation and modulates synaptic protein expression to stimulate the dendritic arborization and new spines formation. On this basis we review the effect of n-3 fatty acids on adult hippocampal neurogenesis and neuroplasticity. Moreover their possible use as a new therapeutic approach for neurodegenerative diseases is pointed out. PMID- 23746278 TI - A peptide microarray fabricated on a non-fouling phosphatidylcholine-polymer coated surface for a high-fidelity analysis of a cellular kinome. AB - Phosphatidylcholine-polymer-coated plastic slides were utilized for the fabrication of peptide microarrays for cellular kinome analysis. According to the non-fouling features of the surface, the signal-to-noise ratio of the detection of phosphorylated peptides improved by about 100-fold from that of a peptide microarray fabricated on a glass slide blocked by a commercial BSA-based reagent. When the phosphatidylcholine-polymer-coated peptide microarray was applied to the analysis of the kinome of HCC827 cells, hyperactivation of c-Src and EGFR were successfully detected. PMID- 23746277 TI - A focus on heme oxygenase-1 (HO-1) inhibitors. AB - The aim of this review is to highlight the advances in the field of heme oxygenase-1 (HO-1) inhibitors over the past years, particularly from a medicinal chemistry point of view; progresses made in the field strongly helped to clarify physiological roles of the heme oxygenase (HO) system. HO is a family of ubiquitously expressed enzymes which regulate the regiospecific catabolism of heme leading to the formation of equimolar amounts of carbon monoxide (CO), ferrous iron (Fe++), and biliverdin. HO exists in two distinct, catalytically active isoforms: HO-1 and HO-2. HO-1 is an inducible 32-kDa protein, while HO-2 is a constitutively synthesized 36-kDa protein and generally is unresponsive to any of the inducers of HO-1. A third isoform, HO-3, is still an elusive protein. The HO system, along with its catabolism products, is involved in a variety of crucial physiological functions, including cytoprotection, inflammation, anti oxidative effects, apoptosis, neuro-modulation, immune-modulation, angiogenesis, and vascular regulation. The use of selective HO inhibitors is a very important tool to clarify the role of the HO system and the mechanisms underlying its physiological effects and pathological involvement; due to the inducible nature of HO-1, selective inhibition of HO-1 isoform is generally preferable. Notably, HO-1 inhibitors may be also beneficial in therapeutic applications and have been mainly studied for treatment of hyperbilirubinemia and certain types of cancer. Historically, the first molecules used as non selective HO-1 inhibitors were metalloporphyrins (Mps). The subsequent development of the imidazole-dioxolane derivatives afforded the first generation of non-porphyrin based, isozyme selective HO-1 inhibitors. PMID- 23746279 TI - Neurotrophin-3 stimulates migration of mesenchymal stem cells overexpressing TrkC. AB - BACKGROUND AND PURPOSE: Transplantation/infusion of mesenchymal stem cells (MSCs) is a promising new approach for treatment of spinal cord injury (SCI). Considering some defined chemokines of MSCs that may have adverse side effects in SCI repair, it is therefore desirable to search for a new chemokine, which should not only be harmless to the host, but also would attract more MSCs to the injury area of spinal cord. This study sought to demonstrate if neurotrophin- 3 (NT-3) would attract migration of MSCs with overexpressing tyrosine kinase C (TrkC) a NT 3 receptor. EXPERIMENTAL APPROACH: A micropipette containing NT-3 was placed in cell culture dish. After this, movement of TrkC gene modified MSCs was monitored for 240 min under an inverted microscope equipped with an imaging system. In vivo, a gelatin sponge scaffold containing TrkC gene modified MSCs was transplanted into the injury area of transected rat spinal cord. Following this, replication-deficient recombinant adenoviral vectors carrying human NT-3 gene (Ad NT-3) was injected 1 mm caudal to the transplantation site to create an NT-3 enriched area. KEY RESULTS: The results showed that TrkC overexpressing MSCs migrated actively towards the source of NT-3 in the NT-3+TrkC-GFP-MSCs group in vitro. A similar phenomenon was not observed in the control groups. In vivo, transplanted MSCs overexpressing TrkC migrated into the NT-3 enriched area. The incidence of migrating MSCs as well as migration distance was significantly higher than the control groups. CONCLUSION AND IMPLICATIONS: The present results suggest that NT-3 may play a role in attracting MSCs with its high affinity for TrkC as a chemokine receptor. PMID- 23746280 TI - Body fat distribution after menopause and cardiovascular disease risk factors: Korean National Health and Nutrition Examination Survey 2010. AB - BACKGROUND: The prevalence of cardiovascular disease in women increases sharply after menopause. The purpose of this study was to clarify the relationship between menopause and body fat distribution and to investigate their association with cardiovascular disease risk factors. METHODS: We analyzed 2035 women 20-79 years of age using the National Health and Nutrition Examination Survey (KNHANES) 2010 database. Body fat was measured using dual-energy X-ray absorptiometry. RESULTS: The percentage of total body fat and the body fat distribution (BFD) index (the ratio of the trunk fat mass to leg fat mass) are significantly higher in postmenopausal women than in premenopausal women (all p<0.001). When adjusted for age, menopause was associated with higher total body fat percentage (adjusted beta=1.082, 95% confidence interval [CI] 0.074-2.090, p=0.035). In women with a body mass index<25 kg/m(2), the higher BFD index was also independently associated with menopause (adjusted beta=14.408, 95% CI 1.672-27.145, p=0.027). After adjusting for age and body fat percentage, the BFD index showed significant and independent associations with systolic and diastolic blood pressure (adjusted beta=0.060 and 0.042, all p<0.001, respectively), fasting glucose (adjusted beta=0.007, p<0.001), total and high density lipoprotein cholesterol (adjusted beta=0.001 and -0.002, p<0.05 and p<0.001, respectively), and triglyceride levels (adjusted beta=0.007, p<0.001- except for low density lipoprotein cholesterol. CONCLUSIONS: After menopause, women have not only higher total body fat percentage but also its different distribution, which independently correlates with cardiovascular disease risk factors. Therefore, this change in body fat may cause the sharp increase in cardiovascular disease incidence in middle-aged women, especially after menopause. PMID- 23746282 TI - Chlorodifluoroacetyl isothiocyanate, ClF2CC(O)NCS: preparation and structural and spectroscopic studies. AB - Chlorodifluoroacetyl isothiocyanate, ClF2CC(O)NCS, was synthesized by the reaction of ClF2CC(O)Cl with an excess of AgNCS. The colorless product melts at 85 degrees C, and its vapor pressure follows the equation ln p = -4471.1 (1/T) + 11.35 (p [atm], T [K]) in the range -38 to 22 degrees C. The compound has been characterized by IR (gas phase, Ar matrix, and matrix photochemistry), by liquid Raman, by (19)F and (13)C NMR, gas UV-vis, and photoelectron spectroscopy (PES), by photoionization mass spectrometry (PIMS), and by gas electron diffraction (GED). The conformational properties of ClF2CC(O)NCS have been analyzed by joint application of vibrational spectroscopy, GED and quantum chemical calculations. The existence of two conformers has been detected in the gas and liquid phases, in which the C-Cl bond adopts a gauche orientation with respect to the C?O group; the C?O group is in syn- or anti-position with respect to the N?C double bond of the NCS group. The computed DeltaG degrees difference between these two gauche syn and gauche-anti forms is DeltaG degrees = 0.63 kcal mol(-1) in the B3LYP/6 31G(d) approximation. The most significant gas-phase structural parameters for gauche-syn ClF2CC(O)NCS are re(NC?S) 1.559(2) A, re(N?CS) 1.213(2) A, re(N-C) 1.399(7) A, re(C?O) 1.199(2) A, and ?e(CNC) 134.7(13) degrees . Photolysis of ClF2CC(O)NCS using an ArF excimer laser (193 nm) mainly yields ClF2CNCS, CO, and ClC(O)CF2NCS. The valence electronic properties of the title compound were studied using PES and PIMS. The experimental first vertical ionization energy of 10.43 eV corresponds to the ejection primarily of the sulfur lone-pair electrons of the in-plane nonbonding orbital on the NCS group. PMID- 23746283 TI - Direct laryngoscopy after potential difficult intubation in children only predicts standard Cormack and Lehane view to within one grade. AB - BACKGROUND: Some techniques used to achieve intubation in children predicted to have a difficult airway do not involve direct laryngoscopy or assessment of the laryngeal grade. Direct laryngoscopy may therefore be performed immediately after intubation to provide a record for future anesthetics. It is unknown whether this postintubation grade accurately reflects the standard laryngeal grade in this group. AIM: The aim of the study was to identify those children who were predicted to be a difficult intubation and to perform direct laryngoscopy before and after intubation. We set out to ascertain if direct laryngoscopy performed after intubation could accurately predict the standard un-intubated laryngeal grade in this group. METHODS: All children presenting for general anesthesia who were clinically predicted to be a difficult intubation were considered for this study and prospectively recruited. After induction of anesthesia, one study anesthetist performed direct laryngoscopy before and another study anesthetist then performed direct laryngoscopy after intubation. These laryngeal grades were then compared. RESULTS: A total of 21 children were successfully recruited and studied, and all patients were successfully intubated. Overall, the postintubation grade did not reliably reflect the standard grade, but did not differ by more than one grade in any patient. In one-third of subjects, the postintubation grade was equal to the standard grade, in one-third it was a grade 'easier' and in one-third a grade 'harder'. CONCLUSION: Assessment and documentation of a postintubation laryngeal grade does not appear to provide reliable information for future anesthetics and may even have the potential to be misleading. Any such documentation should always refer to the presence of an endotracheal tube and be interpreted with caution. PMID- 23746281 TI - Health disparities among sexual minority women veterans. AB - BACKGROUND: Lesbian and bisexual (i.e., sexual minority) identity is more common among women veterans than among male veterans. Unique health issues have been identified among women veterans and among sexual minority women, but little is known about women who are both sexual minorities and veterans. This study aimed to compare demographic and health information from sexual minority women veterans with sexual minority women non-veterans and heterosexual women veterans. METHODS: Behavioral Risk Factor Surveillance Survey data were pooled from ten U.S. states that elected to ask sexual identity during 2010. The analytic sample was comprised of women who identified both their sexual identity and veteran status (n=1,908). Mental health indicators were frequent mental distress, sleep problems, low social/emotional support, and low satisfaction with life. Health risk indicators included current smoking, overweight, and obesity. Physical health status was defined by three components: disability requiring assistive equipment, >14 days of poor physical health in the past 30 days, and activity limitations. RESULTS: Compared with heterosexual women veterans, sexual minority women veterans had higher odds of mental distress (odds ratio [OR]=3.03, 95% confidence interval [CI]: 1.61-5.70) and smoking (OR=2.31, 95%CI: 1.19-4.48). After adjusting for demographic correlates, sexual minority women veterans had three times the odds of poor physical health (OR=3.01, 95%CI: 1.51-5.99) than their sexual minority non-veteran peers. CONCLUSIONS: Results suggest sexual minority women veterans may experience unique health disparities relevant to provision of care in both Veterans Affairs (VA) and non-VA healthcare systems. Future research requires availability of data that include sexual minority status. PMID- 23746284 TI - Increased production of plumbagin in Plumbago indica root cultures by gamma ray irradiation. AB - CONTEXT: Plumbagin is a major active constituent of Plumbago indica L. (Plumbaginaceae). It possesses various pharmacological activities that have been shown to assist in the treatment of various diseases. OBJECTIVES: This work is focused on increasing the production of plumbagin in P. indica root cultures using low doses of gamma ray irradiation as an elicitor. MATERIALS AND METHODS: The effect of low doses of gamma ray irradiation (0, 5, 10, 15, 20, 25 Gy) and ages of the root cultures (0, 5, 10, 15, 20 days) for elicitation of plumbagin production was determined. The stability of the elicited root cultures to produce plumbagin was also determined during three cycles of subculture. RESULTS AND DISCUSSION: Treatment of the root cultures with a low dose of gamma ray at 20 Gy gave the highest level of plumbagin production (1.04 mg/g DW) when compared to all other treated groups. The appropriate age of the root cultures for maximum production of plumbagin was found to be 10 days. However, treatment of 5-day-old root cultures resulted in a significant increase of dried root biomass that also had a high plumbagin production. Based on the total biomass per culture flask, the amounts of plumbagin produced by the 5- and 10-day-old treated roots were 0.59 and 0.37 mg/250 mL flask, respectively, which were 4.2- and 2.6-fold higher than the level in the control. Subculturing the root cultures until the third generation still showed an increase in plumbagin production without any effects on their growth. PMID- 23746285 TI - Effect of temporally patterned TNF-alpha delivery on in vitro osteogenic differentiation of mesenchymal stem cells cultured on biodegradable polymer scaffolds. AB - Recent insight into the critical role of pro-inflammatory cytokines, particularly tumor necrosis factor-alpha (TNF-alpha), in bone regeneration has heralded a new direction in the design of tissue engineering constructs. Previous studies have demonstrated that continuous delivery of 50 ng/ml TNF-alpha to mesenchymal stem cells (MSCs) cultured on three-dimensional (3D) biodegradable electrospun poly(epsilon-caprolactone) (PCL) microfiber meshes stimulates mineralized matrix deposition, a marker of osteogenic differentiation. Since TNF-alpha exhibits a biphasic pattern of expression following bone fracture in vivo, this study aimed to investigate the effects of temporal patterns of TNF-alpha delivery on in vitro osteogenic differentiation of MSCs cultured on 3D electrospun PCL scaffolds. MSCs were cultured for 16 days and exposed to continuous, early, intermediate, or late TNF-alpha delivery. To further elucidate the effects of TNF-alpha on osteogenic differentiation, the study design included MSCs precultured both in the presence and absence of typically required osteogenic supplement dexamethasone. Mineralized matrix deposition was not observed in constructs with dexamethasone naive MSCs, suggesting that TNF-alpha is not sufficient to trigger in vitro osteogenic differentiation of MSCs. For MSCs precultured with dexamethasone, TNF alpha suppressed alkaline phosphatase activity, an early marker of osteogenic differentiation, and stimulated mineralized matrix deposition, a late stage marker of MSC osteogenic differentiation. By elucidating the impact of temporal variations in TNF-alpha delivery on MSC osteogenic differentiation, our results offer insight into the regenerative mechanism of TNF-alpha and provide the design parameters for a novel tissue engineering strategy that rationally controls TNF alpha signaling to stimulate bone regeneration. PMID- 23746286 TI - A maternal diet of fatty fish reduces body fat of offspring compared with a maternal diet of beef and a post-weaning diet of fish improves insulin sensitivity and lipid profile in adult C57BL/6 male mice. AB - AIM: The maternal diet during pregnancy and lactation may affect the long-term health of the offspring. Our aim was to study how a fish or meat diet perinatal and after weaning affects body composition, insulin sensitivity and the profile of n-3 and n-6 polyunsaturated fatty acids (PUFAs) in breast milk, fat depots, skeletal muscle and liver in male adult mice offspring. METHODS: During gestation and lactation, C57BL/6 dams were fed a herring- or beef-based diet. Half of the pups in each group changed diets after weaning. In offspring, body composition measured by DEXA, plasma lipid profile and insulin sensitivity measured by euglycemic clamp or QUICKI were monitored to adulthood. Analysis of total FAs by GC-MS were performed in the diet, breast milk and in different tissues. RESULTS: At 9 week of age, offspring of herring-fed dams had less body fat than offspring of beef-fed dams. Mice fed herring after weaning had increased insulin sensitivity at 15 week of age, reduced total plasma cholesterol and triglyceride levels, and compared with beef-fed mice, larger interscapular brown adipose tissue depots. The FA composition of the maternal diet was mirrored in breast milk, and the herring diet significantly affected the FA profile of different tissues, leading to an increased content of n-3 PUFAs. CONCLUSION: A herring based maternal diet reduces body fat in the offspring, but the insulin sensitivity, plasma lipids and amount of brown adipose tissue are affected by the offspring's own diet; the herring diet is more beneficial than the beef diet. PMID- 23746287 TI - Application of higher order cumulant features for cardiac health diagnosis using ECG signals. AB - Electrocardiogram (ECG) is the electrical activity of the heart indicated by P, Q R-S and T wave. The minute changes in the amplitude and duration of ECG depicts a particular type of cardiac abnormality. It is very difficult to decipher the hidden information present in this nonlinear and nonstationary signal. An automatic diagnostic system that characterizes cardiac activities in ECG signals would provide more insight into these phenomena thereby revealing important clinical information. Various methods have been proposed to detect cardiac abnormalities in ECG recordings. Application of higher order spectra (HOS) features is a seemingly promising approach because it can capture the nonlinear and dynamic nature of the ECG signals. In this paper, we have automatically classified five types of beats using HOS features (higher order cumulants) using two different approaches. The five types of ECG beats are normal (N), right bundle branch block (RBBB), left bundle branch block (LBBB), atrial premature contraction (APC) and ventricular premature contraction (VPC). In the first approach, cumulant features of segmented ECG signal were used for classification; whereas in the second approach cumulants of discrete wavelet transform (DWT) coefficients were used as features for classifiers. In both approaches, the cumulant features were subjected to data reduction using principal component analysis (PCA) and classified using three layer feed-forward neural network (NN) and least square-support vector machine (LS-SVM) classifiers. In this study, we obtained the highest average accuracy of 94.52%, sensitivity of 98.61% and specificity of 98.41% using first approach with NN classifier. The developed system is ready clinically to run on large datasets. PMID- 23746288 TI - Efficient automatic selection and combination of EEG features in least squares classifiers for motor imagery brain-computer interfaces. AB - Discriminative features have to be properly extracted and selected from the electroencephalographic (EEG) signals of each specific subject in order to achieve an adaptive brain-computer interface (BCI) system. This work presents an efficient wrapper-based methodology for feature selection and least squares discrimination of high-dimensional EEG data with low computational complexity. Features are computed in different time segments using three widely used methods for motor imagery tasks and, then, they are concatenated or averaged in order to take into account the time course variability of the EEG signals. Once EEG features have been extracted, proposed framework comprises two stages. The first stage entails feature ranking and, in this work, two different procedures have been considered, the least angle regression (LARS) and the Wilcoxon rank sum test, to compare the performance of each one. The second stage selects the most relevant features using an efficient leave-one-out (LOO) estimation based on the Allen's PRESS statistic. Experimental comparisons with the state-of-the-art BCI methods shows that this approach gives better results than current state-of-the art approaches in terms of recognition rates and computational requirements and, also with respect to the first ranking stage, it is confirmed that the LARS algorithm provides better results than the Wilcoxon rank sum test for these experiments. PMID- 23746289 TI - A binary phase-shift keying receiver for the detection of attention to human speech. AB - Synthetic sounds, tone-beeps, vowels or syllables are typically used in the assessment of attention to auditory stimuli because they evoke a set of well known event-related potentials, whose characteristics can be statistically contrasted. Such approach rules out the use of stimuli with non-predictable response, such as human speech. In this study we present a procedure based on the robust binary phase-shift keying (BPSK) receiver that permits the real-time detection of selective attention to human speeches in dichotic listening tasks. The goal was achieved by tagging the speeches with two barely-audible tags whose joined EEG response constitutes a reliable BPSK constellation, which can be detected by means of a BPSK receiver. The results confirmed the expected generation of the BPSK constellation by the human auditory system. Also, the bit error rate and the information transmission rate achieved in the detection of attention fairly followed the expected curves and equations of the standard BPSK receiver. Actually, it was possible to detect attention as well as the estimation a priori of its accuracy based on the signal-to-noise ratio of the BPSK signals. This procedure, which permits the detection of the attention to human speeches, can be of interest for new potential applications, such as brain-computer interfaces, clinical assessment of the attention in real time or for entertainment. PMID- 23746290 TI - Closed-loop control of the thalamocortical relay neuron's Parkinsonian state based on slow variable. AB - A novel closed-loop control strategy is proposed to control Parkinsonian state based on a computational model. By modeling thalamocortical relay neurons under external electric field, a slow variable feedback control is applied to restore its relay functionality. Qualitative and quantitative analysis demonstrates the performance of feedback controller based on slow variable is more efficient compared with traditional feedback control based on fast variable. These findings point to the potential value of model-based design of feedback controllers for Parkinson's disease. PMID- 23746292 TI - Behind the magical numbers: hierarchical chunking and the human working memory capacity. AB - To explore the influence of chunking on the capacity limits of working memory, a model for chunking in sequential working memory is proposed, using hierarchical bidirectional inhibition-connected neural networks with winnerless competition. With the assumption of the existence of an upper bound to the inhibitory weights in neurobiological networks, it is shown that chunking increases the number of memorized items in working memory from the "magical number 7" to 16 items. The optimal number of chunks and the number of the memorized items in each chunk are the "magical number 4". PMID- 23746291 TI - Robust neonatal EEG seizure detection through adaptive background modeling. AB - Adaptive probabilistic modeling of the EEG background is proposed for seizure detection in neonates with hypoxic ischemic encephalopathy. The decision is made based on the temporal derivative of the seizure probability with respect to the adaptively modeled level of background activity. The robustness of the system to long duration "seizure-like" artifacts, in particular those due to respiration, is improved. The system was developed using statistical leave-one-patient-out performance assessment, on a large clinical dataset, comprising 38 patients of 1479 h total duration. The developed technique was then validated by a single test on a separate totally unseen randomized prospective dataset of 51 neonates totaling 2540 h of duration. By exploiting the proposed adaptation, the ROC area is increased from 93.4% to 96.1% (41% relative improvement). The number of false detections per hour is decreased from 0.42 to 0.24, while maintaining the correct detection of seizure burden at 70%. These results on the unseen data were predicted from the rigorous leave-one-patient-out validation and confirm the validity of our algorithm development process. PMID- 23746293 TI - ETEA: a Euclidean minimum spanning tree-based evolutionary algorithm for multi objective optimization. AB - The Euclidean minimum spanning tree (EMST), widely used in a variety of domains, is a minimum spanning tree of a set of points in space where the edge weight between each pair of points is their Euclidean distance. Since the generation of an EMST is entirely determined by the Euclidean distance between solutions (points), the properties of EMSTs have a close relation with the distribution and position information of solutions. This paper explores the properties of EMSTs and proposes an EMST-based evolutionary algorithm (ETEA) to solve multi-objective optimization problems (MOPs). Unlike most EMO algorithms that focus on the Pareto dominance relation, the proposed algorithm mainly considers distance-based measures to evaluate and compare individuals during the evolutionary search. Specifically, in ETEA, four strategies are introduced: (1) An EMST-based crowding distance (ETCD) is presented to estimate the density of individuals in the population; (2) A distance comparison approach incorporating ETCD is used to assign the fitness value for individuals; (3) A fitness adjustment technique is designed to avoid the partial overcrowding in environmental selection; (4) Three diversity indicators-the minimum edge, degree, and ETCD-with regard to EMSTs are applied to determine the survival of individuals in archive truncation. From a series of extensive experiments on 32 test instances with different characteristics, ETEA is found to be competitive against five state-of-the-art algorithms and its predecessor in providing a good balance among convergence, uniformity, and spread. PMID- 23746294 TI - A model for analysing the collective dynamic behaviour and characterising the exploitation of population-based algorithms. AB - Several previous studies have focused on modelling and analysing the collective dynamic behaviour of population-based algorithms. However, an empirical approach for identifying and characterising such a behaviour is surprisingly lacking. In this paper, we present a new model to capture this collective behaviour, and to extract and quantify features associated with it. The proposed model studies the topological distribution of an algorithm's activity from both a genotypic and a phenotypic perspective, and represents population dynamics using multiple levels of abstraction. The model can have different instantiations. Here it has been implemented using a modified version of self-organising maps. These are used to represent and track the population motion in the fitness landscape as the algorithm operates on solving a problem. Based on this model, we developed a set of features that characterise the population's collective dynamic behaviour. By analysing them and revealing their dependency on fitness distributions, we were then able to define an indicator of the exploitation behaviour of an algorithm. This is an entropy-based measure that assesses the dependency on fitness distributions of different features of population dynamics. To test the proposed measures, evolutionary algorithms with different crossover operators, selection pressure levels and population handling techniques have been examined, which lead populations to exhibit a wide range of exploitation-exploration behaviours. PMID- 23746295 TI - Filtering sensory information with XCSF: improving learning robustness and robot arm control performance. AB - It has been shown previously that the control of a robot arm can be efficiently learned using the XCSF learning classifier system, which is a nonlinear regression system based on evolutionary computation. So far, however, the predictive knowledge about how actual motor activity changes the state of the arm system has not been exploited. In this paper, we utilize the forward velocity kinematics knowledge of XCSF to alleviate the negative effect of noisy sensors for successful learning and control. We incorporate Kalman filtering for estimating successive arm positions, iteratively combining sensory readings with XCSF-based predictions of hand position changes over time. The filtered arm position is used to improve both trajectory planning and further learning of the forward velocity kinematics. We test the approach on a simulated kinematic robot arm model. The results show that the combination can improve learning and control performance significantly. However, it also shows that variance estimates of XCSF prediction may be underestimated, in which case self-delusional spiraling effects can hinder effective learning. Thus, we introduce a heuristic parameter, which can be motivated by theory, and which limits the influence of XCSF's predictions on its own further learning input. As a result, we obtain drastic improvements in noise tolerance, allowing the system to cope with more than 10 times higher noise levels. PMID- 23746296 TI - Palladium-catalyzed Catellani aminocyclopropanation reactions with vinyl halides. AB - Palladium is shown to catalyze an intramolecular aminocyclopropanation of norbornenes with aliphatic vinyl halides in good yields. The reaction tolerates a variety of amine substituents and gives good results with a variety of carbocyclic and oxabicyclic [2.2.1] alkene acceptors. Notably, stabilized enolate nucleophiles were also employed in cyclopropanation reactions. PMID- 23746297 TI - Spatial distribution of positive cores improves the selection of patients with low-risk prostate cancer as candidates for active surveillance. AB - OBJECTIVE: To test the hypothesis that spatial distribution of positive cores at biopsy is a predictor of unfavourable prostate cancer characteristics at radical prostatectomy (RP) in active surveillance (AS) candidates. PATIENTS AND METHODS: We examined the data of 524 patients treated with RP, between 2000 and 2012. All fulfilled at least one of four commonly used AS criteria. Regression models tested the relationship between positive cores spatial distribution, defined as the number of positive zones at biopsy (PBxZ) and tumour laterality at biopsy and two endpoints: (i) unfavourable prostate cancer at RP (Gleason score >= 4 + 3, and/or pT3 disease), and (ii) clinically significant prostate cancer (tumour volume >= 2.5 mL). RESULTS: Unfavourable prostate cancer and clinically significant prostate cancer rates were 8 and 25%, respectively. Patients with more than one PBxZ had a 3.2-fold higher risk of harbouring unfavourable prostate cancer, and a 2.3-fold higher risk of harbouring clinically significant prostate cancer compared with their counterparts with one PBxZ (both P = 0.01). Patients with bilateral tumour at biopsy had a 3.3-fold higher risk of harbouring unfavourable prostate cancer and a 1.7-fold higher risk of harbouring clinically significant prostate cancer compared with their counterparts with unilateral tumour at biopsy (both P <= 0.04). Some of these results did not reach a statistically significant level, when the analyses were restricted to patients that fulfilled the most stringent AS criteria. CONCLUSIONS: Positive cores spatial distribution at biopsy should be considered, when advising patients about AS. The addition of this predictor to AS inclusion criteria can help identifying patients at a higher risk of progression, and reduce the rate of inappropriate surveillance of aggressive tumours. However, the most stringent AS criteria (namely John-Hopkins criteria and Prostate Cancer Research International: Active Surveillance criteria) might not benefit from the addition of this predictor. This point warrants further investigation in future studies. PMID- 23746298 TI - Near-infrared quantum cutting platform in thermally stable phosphate phosphors for solar cells. AB - This study investigated the photoluminescent properties of Tb(3+)-Yb(3+)-, Ce(3+) Tb(3+)-Yb(3+)-, and Eu(2+)-Yb(3+)-doped KSrPO4. The samples were prepared by a solid-state reaction with various doping concentrations. Emission at near infrared range was focused on the application of luminescent solar concentrator for solar cells. Quantum cutting (QC) energy transfer was confirmed by the lifetimes of the donor. Near-infrared QC involved emission of Yb(3+) ions was achieved by excitation of Ce(3+), Tb(3+), and Eu(2+) ions, where the energy transfer processes occurred from Ce(3+) to Tb(3+) to Yb(3+), Tb(3+) to Yb(3+), and Eu(2+) to Yb(3+), respectively. In addition, the concentration quenching effect of Yb(3+) ions was avoided by low doping concentrations. The overall quantum efficiencies were calculated, and the maximum efficiency reaches 139%. The energy diagrams for divalent and trivalent rare-earth ions in KSrPO4 host lattice were analyzed. Results of this study demonstrate that heat-stable phosphate phosphors are promising candidates for increasing the efficiency of silicon-based solar cells. PMID- 23746299 TI - Histopathological assessment of tumour regression, nodal stage and status of resection margins determines prognosis in patients with oral squamous cell carcinoma treated with neoadjuvant radiochemotherapy. AB - OBJECTIVES: In advanced oral squamous cell carcinoma (OSCC), tumour regression after neoadjuvant radiochemotherapy seems to be an important prognostic factor. In this study, we intended to compare regression grading according to two previously described regression models and to analyse the association of tumour regression and other tumour characteristics with patients' characteristics and overall survival. METHODS: The retrospective study included 63 treatment-naive patients with primary OSCC of stages II-IV, who were treated with a concomitant neoadjuvant radiochemotherapy followed by radical surgery. Assessment of histopathological features was performed, there under regression grading according to two previously described regression models. RESULTS: Both tumour regression models provided comparable results in terms of distribution of different regression grades. In univariate analysis regression gradings (P = 0.003 and P = 0.007), ypT-stage, ypN-stage and status of resection margins (P < 0.001) were significantly associated with the 5-year overall survival (OS). None of the pretreatment clinicopathological parameters showed association with histopathological tumour regression. Multivariate analysis revealed the status of resection margins and of lymph node metastasis as statistically significant features for OS (P = 0.020 and P = 0.003, respectively). CONCLUSION: Tumour regression grading, nodal stage and status of resection margins predict prognosis in patients after neoadjuvant treatment. Currently, there are no pretreatment clinicopathological parameters, which predicting good tumour response to therapy. Thus, identifying non-responding patients, which might benefit from an intensified systemic therapy, requires surgical resection and consecutive histopathological assessment. Therefore, further investigation and validation of new, especially, molecular predictors of tumour response to radiochemotherapy remains an unmet, future clinical need. PMID- 23746301 TI - Hsp104 as a key modulator of prion-mediated oxidative stress in Saccharomyces cerevisiae. AB - Maintenance of cellular redox homoeostasis forms an important part of the cellular defence mechanism and continued cell viability. Despite extensive studies, the role of the chaperone Hsp104 (heat-shock protein of 102 kDa) in propagation of misfolded protein aggregates in the cell and generation of oxidative stress remains poorly understood. Expression of RNQ1-RFP in Saccharomyces cerevisiae cells led to the generation of the prion form of the protein and increased oxidative stress. In the present study, we show that disruption of Hsp104 in an isogenic yeast strain led to solubilization of RNQ1 RFP. This reduced the oxidative stress generated in the cell. The higher level of oxidative stress in the Hsp104-containing (parental) strain correlated with lower activity of almost all of the intracellular antioxidant enzymes assayed. Surprisingly, this did not correspond with the gene expression analysis data. To compensate for the decrease in protein translation induced by a high level of reactive oxygen species, transcriptional up-regulation takes place. This explains the discrepancy observed between the transcription level and functional enzymatic product. Our results show that in a DeltaHsp104 strain, due to lower oxidative stress, no such mismatch is observed, corresponding with higher cell viability. Thus Hsp104 is indirectly responsible for enhancing the oxidative stress in a prion-rich environment. PMID- 23746300 TI - Dissecting cytochrome P450 3A4-ligand interactions using ritonavir analogues. AB - Cytochrome P450 3A4 (CYP3A4) inhibitors ritonavir and cobicistat, currently administered to HIV patients as pharmacoenhancers, were designed on the basis of the chemical structure/activity relationships rather than the CYP3A4 crystal structure. To better understand the structural basis for CYP3A4 inhibition and the ligand binding process, we investigated five desoxyritonavir analogues to elucidate how substitution/elimination of the phenyl side groups (Phe-1 and Phe 2) and removal of the isopropyl-thiazole (IPT) moiety affect affinity, inhibitory potency, and the ligand binding mode. Our experimental and structural data indicate that the side group size reduction not only drastically lowers affinity and inhibitory potency for CYP3A4 but also leads to multiple binding modes. Regardless of the side group chemical nature and the number of molecules bound, the space adjacent to the 369-371 peptide and Arg105 (Phe-2 site) is always occupied and, hence, must be a critically important binding site. When possible, the ligands also try to fill the pocket near the I-helix (Phe-1 site), even if it causes steric hindrance. Extensive hydrophobic interactions established at the Phe-1 site improve inhibitory potency, whereas contacts provided by IPT might strengthen the Fe-N bond. Overall, however, the end group contributes less to the ligand association process, which, in contrast, is greatly facilitated by the polar interactions mediated by the active site Ser119. PMID- 23746303 TI - Compositional analysis of genetically modified (GM) crops: key issues and future needs. AB - Effective symposia need two strong legs to stand upon: informative presentations of recent research paired with lively discussion of these topics. Although it is easy for the organizers of a symposium to predict the usefulness of the former, as they select the speakers and their topic areas, guaranteeing productive discussion is a far more difficult task. For the Crop Composition Workshop sponsored by the International Life Sciences Institute's Committee on Food and Biotechnology (ILSI IFBIC), the organizers scheduled four roundtable discussions with preselected questions and with rapporteurs drawn from governmental organizations and public-sector research institutes (the authors). It was also the organizers' intent to let these discussions flow on the basis of the experiences of the participants and pressing issues within the overall debate on the role of crop compositional analysis within safety assessment of biotechnology as it exists now and in the future. The goal of this perspective is to summarize the issues raised, providing references when possible, and to describe the consensus statements reached through the course of these discussions. PMID- 23746302 TI - Low frequency of male circumcision and unwillingness to be circumcised among MSM in Buenos Aires, Argentina: association with sexually transmitted infections. AB - OBJECTIVE: The aims of this study were to investigate the frequency of male circumcision among men who have sex with men (MSM) in Buenos Aires, Argentina; the association between circumcision and sexually transmitted infections (STIs); and, among those uncircumcised, the willingness to be circumcised. METHODS: A cross-sectional study was conducted among 500 MSM recruited through the respondent-driven sampling (RDS) technique. Participants underwent a consent process, responded to a Web-based survey that included questions on demographic information, sexual behaviour, and circumcision and provided biological samples. HIV, hepatitis B virus (HBV), hepatitis C virus (CV), Treponema pallidum, and human papiloma virus (HPV) diagnoses were performed using standard methodologies. For all analyses, data were weighted based on participants' network size. RESULTS: Only 64 (13%) of the 500 MSM in our study reported being circumcised. Among uncircumcised men (n=418), 302 (70.4%) said that they would not be willing to get circumcised even if the procedure could reduce the risk of HIV infection. When considering all participants, circumcision status was not significantly associated with HIV, HBV, HCV, T. pallidum or HPV infections. However, when we restricted the sample to men who do not practice receptive anal intercourse (RAI) and compared circumcised to uncircumcised men, the former (N=33) had no cases of HIV infection, while 34 of 231 (14.8%) uncircumcised men were HIV positive (p=0.020). Regarding HPV, uncircumcised men had a significantly larger number of different HPV types compared with circumcised men (mean 1.83 vs. 1.09, p<0.001) and a higher frequency of high-risk-HPV genotypes (47.6% vs. 12.5%, p=0.012). CONCLUSIONS: Consistent with international evidence, male circumcision appears to have a partial protective effect among MSM. The efficacy of circumcision in reducing risk of HIV infection among MSM appears to be correlated with sexual practices. Given the lack of motivation among MSM with regard to circumcision, proper awareness on the risks and benefits of circumcision needs to be created, if circumcision has to be introduced as a prevention strategy. PMID- 23746304 TI - The effect of 25-hydroxyvitamin D on insulin sensitivity in obesity: is it mediated via adiponectin? AB - There has been substantial recent interest in using vitamin D to improve insulin sensitivity and preventing/delaying diabetes in those at risk. There is little consensus on the physiological mechanisms and whether the association is direct or indirect through enhanced production of insulin-sensitising chemicals, including adiponectin. We examined cross-sectional associations between serum 25 hydroxyvitamin D (25(OH)D) and insulin sensitivity (Matsuda index), parathyroid hormone (PTH), waist circumference, body mass index (BMI), triglycerides (TG), total and high molecular weight (HMW) adiponectin, HMW : total adiponectin ratio (HMW : total adiponectin), and total cholesterol : HDL cholesterol ratio (TC:HDL cholesterol) in 137 Caucasian adults of mean age 43.3 +/- 8.3 years and BMI 38.8 +/- 6.9 kg/m(2). Total adiponectin (standardised beta = 0.446; p < 0.001), waist circumference (standardised beta = -0.216; p < 0.05), BMI (standardised beta = 0.212; p < 0.05), and age (standardised beta = -0.298; p < 0.001) were independently associated with insulin sensitivity. Serum 25(OH)D (standardised beta = 0.114; p = 0.164) was not associated with insulin sensitivity, total or HMW adiponectin, HMW : total adiponectin, or lipids. Our results provide the novel finding that 25(OH)D is not associated with HMW adiponectin or HMW : total adiponectin in nondiabetic, obese adults and support the lack of association between 25(OH)D and lipids noted by others in similar groups of patients. PMID- 23746305 TI - Detection of leukemia associated antigen-specific cytotoxic T cells in a patient with Philadelphia chromosome-positive leukemia during treatment with dasatinib. PMID- 23746306 TI - Rapid assessments of metal bioavailability in marine sediments using coelomic fluid of sipunculan worms. AB - A suitable test organism for assessing the bioavailability of sediment-bound metals should accumulate metals mainly from the sediment instead of other sources such as water. The deposit-feeding sipunculan worms, which indiscriminately ingest sediment particles and have a very low uptake rate of dissolved metals, appear to be such good candidates. The worms have additional advantage due to simple anatomy and are like little sacs full of liquid, that is, coelomic fluid, which can be easily collected for metal analysis after simple sample treatment. We measured the metal concentrations in a sipunculan worm, Phascolosoma arcuatum and in sediments collected from intertidal zones of Xiamen City, China. Significant correlations were found for the concentrations of chromium, nickel, copper, zinc, cadmium, and lead in sediments and their concentrations in both somatic tissue and coelomic fluid of the worms. Analyzing the metals in coelomic fluid led to similar results as the somatic-tissue metals for assessing the bioavailability of sediment-bound metals and the spatial pattern of sediment bound metal contamination. Therefore, measuring coelomic-fluid metal concentrations can be used to provide a rapid assessment of metal bioavailability in marine sediments. PMID- 23746307 TI - Resonances in the Ne + H2(+) -> NeH(+) + H proton-transfer reaction. AB - We investigated the oscillations found in the integral cross section of the title reaction, which are particularly evident for Ne + H2(+)(v0 = 2,j0 = 1) [essentially isoenergetic with NeH(+)(v' = 0,j' = 0) + H] at low collision energy (Ecol < 0.30 eV). We employed mainly an exact time-independent (TI) quantum dynamics method and used the best potential energy surface available. From analysis of TI initial state selected to all integral cross sections, state-to state integral cross sections, and the corresponding differential cross sections (DCSs), we showed that the oscillations correspond to resonances. They arise from the influence of the global [Ne-H-H](+) (collinear) minimum on dynamics and probably correspond to Feshbach resonances. Besides, the forward-backward peaking DCS (which oscillates with Ecol) behavior observed could be a signature for this type of resonances. Finally, as most data on resonances in bimolecular reactions correspond to neutral systems, we hope that the present results will encourage experimentalists to re-examine this benchmark system. PMID- 23746308 TI - Pretreatment of donor islets with the Na(+) /Ca(2+) exchanger inhibitor improves the efficiency of islet transplantation. AB - Pancreatic islet transplantation is an attractive therapy for the treatment of insulin-dependent diabetes mellitus. However, the low efficiency of this procedure necessitating sequential transplantations of islets with the use of 2-3 donors for a single recipient, mainly due to the early loss of transplanted islets, hampers its clinical application. Previously, we have shown in mice that a large amount of HMGB1 is released from islets soon after their transplantation and that this triggers innate immune rejection with activation of DC, NKT cells and neutrophils to produce IFN-gamma, ultimately leading to the early loss of transplanted islets. Thus, HMGB1 release plays an initial pivotal role in this process; however, its mechanism remains unclear. Here we demonstrate that release of HMGB1 from transplanted islets is due to hypoxic damage resulting from Ca(2+) influx into beta cells through the Na(+) /Ca(2+) exchanger (NCX). Moreover, the hypoxia-induced beta cell damage was prevented by pretreatment with an NCX specific inhibitor prior to transplantation, resulting in protection and long term survival of transplanted mouse and human islets when grafted into mice. These findings suggest a novel strategy with potentially great impact to improve the efficiency of islet transplantation in clinical settings by targeting donor islets rather than recipients. PMID- 23746309 TI - The heritability of circulating testosterone, oestradiol, oestrone and sex hormone binding globulin concentrations in men: the Framingham Heart Study. AB - OBJECTIVE: Circulating testosterone, oestradiol and oestrone concentrations vary considerably between men. Although a substantial proportion of this variation may be attributed to morbidity and behavioural factors, these cannot account for its entirety, suggesting genetic inheritance as a potential additional determinant. The analysis described here was intended to estimate the heritability of male circulating total testosterone (TT), calculated free testosterone (cFT), oestrone (E1), oestradiol (E2) and sex hormone binding globulin (SHBG), along with the genetic correlation between these factors. DESIGN: Cross-sectional, observational analysis of data from male members of the Offspring and Generation 3 cohorts of the Framingham Heart Study. Data were collected in the years 1998-2005. PARTICIPANTS: A total of 3367 community-dwelling men contributed to the analysis, including 1066 father/son and 1284 brother pairs among other family relationships. MEASUREMENTS: Levels of serum sex steroids (TT, E1 and E2) were measured by liquid chromatography-tandem mass spectrometry, SHBG by immunofluorometric assay and cFT by mass action equation. Heritability was obtained using variance components analysis with adjustment for covariates including age, diabetes mellitus, body mass index and smoking status. RESULTS: Age-adjusted heritability estimates were 0.19, 0.40, 0.40, 0.30 and 0.41 for cFT, TT, E1, E2 and SHBG, respectively. Adjustment for covariates did not substantially attenuate these estimates; SHBG-adjusted TT results were similar to those obtained for cFT. Genetic correlation coefficients (rhoG ) indicated substantial genetic association between TT and cFT (rhoG = 0.68), between TT and SHBG (pG = 0.87), between E1 and E2 (rhoG = 0.46) and between TT and E2 (rhoG = 0.48). CONCLUSION: Circulating testosterone, oestradiol and oestrone concentrations exhibit substantial heritability in adult men. Significant genetic association between testosterone and oestrogen levels suggests shared genetic pathways. PMID- 23746310 TI - Re: Digital compression of facial arteries facilitates cutaneous nasal surgery. PMID- 23746311 TI - Saponin and non-saponin fractions of red ginseng ameliorate cisplatin-induced pica in rats. AB - CONTEXT: Nausea and vomiting are considered as the foremost unpleasant side effects of chemotherapy experienced by 20-90% of cancer patients. OBJECTIVE: In the present study, the effects of Korean Panax ginseng C.A. Meyer (Araliaceae) (RG), ginseng saponin (GS) and non-saponin (GNS) on cisplatin (CP)-induced pica and gastric damage in rats were investigated. MATERIAL AND METHODS: Rats were treated with RG (25, 50, 100 mg/kg b.wt.), GS (5 and 10 mg/kg 100 mg/kg b.wt.) and GNS (50 and 100 mg/kg b.wt.) before or after a single intraperitoneal injection of CP (6 mg/kg b.wt.). Kaolin together with normal food intake, normal food alone, body weight, histological examination of stomach and small intestine were used as indices of CP-induced pica in rats. RESULTS: Pre-treatment with RG (50 and 100 mg/kg b.wt.) attenuated CP-induced kaolin intake at 24 h. CP-induced kaolin intake decreased upon post-treatment of rats with RG (50 and 100 mg/kg b.wt.) at 48 h. The incidence of body weight reduction at 48 and 72 h diminished in rats post-treated with RG (50 mg/kg b.wt.). Pre-treatment with GS (5 and 10 mg/kg b.wt.) and GNS (50 and 100 mg/kg b.wt.) attenuated CP-induced kaolin intake while normal food intake was not improved in 24 and 48 h. DISCUSSION AND CONCLUSION: The gastro-protective effects of RG, GS and GNS were further confirmed by histopathological (damage in glandular portion and villi with dilated appearance) findings. The study indicates that both the red GS and GNS improve feeding behavior against CP-induced pica in rats. PMID- 23746312 TI - The challenge of constructing, classifying, and representing metabolic pathways. AB - Scientists, educators, and students benefit from having free and centralized access to the wealth of metabolic information that has been gathered over the decades. Curators of the MetaCyc database work to present this information in an easily understandable pathway-based framework. MetaCyc is used not only as an encyclopedic resource for metabolic information but also as a template for the pathway prediction software that generates pathway/genome databases for thousands of organisms with sequenced genomes (available at www.biocyc.org). Curators need to define pathway boundaries and classify pathways within a broader pathway ontology to maximize the utility of the pathways to both users and the pathway prediction software. These seemingly simple tasks pose several challenges. This review describes these challenges as well as the criteria that need to be considered, and the rules that have been developed by MetaCyc curators as they make decisions regarding the representation and classification of metabolic pathway information in MetaCyc. The functional consequences of these decisions in regard to pathway prediction in new species are also discussed. PMID- 23746314 TI - Immunomodulation and lymphoma in humans. AB - Observational and clinical studies have associated increased cancer risks with primary or acquired immunodeficiencies, autoimmunity, and use of immunotherapies to treat chronic inflammation (e.g. autoimmunity) or support organ engraftment. Understanding of the relationship between immune status and cancer risk is generally grounded in two juxtaposing paradigms: that the immune system protects the host via surveillance of tumors and oncogenic viruses (e.g. immunosurveillance model) and that chronic inflammation can augment tumor growth and metastasis (inflammation model). Whereas these models support a role of immune status in many cancers, they are insufficient to explain the disproportionate increase in B-cell lymphoma risk observed across patient populations with either chronic immunosuppression or inflammation. Evaluation for the presence of Epstein-Barr virus (EBV) in lymphomas obtained from various populations demonstrates a variable role for the virus in lymphomagenesis across patient populations. An evaluation of the DNA alterations found in lymphomas and an understanding of B-cell ontogeny help to provide insight into the unique susceptibility of lymphocytes, primarily B-cells, to oncogenic transformation. EBV-independent B-cell oncogenic transformation is driven by chronic antigenic stimulation due to either inflammation (as seen in patients with autoimmune disease or a tissue allograft) or to unresolved infection (as seen in immunosuppressed patients), and the transformation arises as a result of DNA damage from genomic recombination and mutation during class switching and somatic hypermutation. This model explains the increased background rate of lymphoma in some patients with autoimmunity, and highlights the challenge of resolving the confounding that occurs between disease severity and use of targeted immunotherapies to treat chronic inflammation. The ability to distinguish between disease- and treatment-related risk of lymphoma and an appreciation of the etiology of B-cell transformation is central to an improved risk assessment by scientists, clinicians and regulators, including the approval, labeling, and chronic use of immunotherapies. PMID- 23746313 TI - Immune alterations induced by chronic noise exposure: comparison with restraint stress in BALB/c and C57Bl/6 mice. AB - Exposure to loud noise levels represents a problem in all regions of the world. Noise exposure is known to affect auditory structures in living organisms. However, it should not be ignored that many of the effects of noise are extra auditory. In particular, it has been proposed that noise could affect immune system similarly to other stressors. Nevertheless, only a few studies so far have investigated the effects of noise on the immune function. The aim of the present work was to investigate the effect of chronic (2 weeks) noise (95-97 dBA) exposure on immune responses in BALB/c and C57 mice. To ascertain if the effect of noise is similar to other psychological stressors, the effect of chronic restraint--applied for the same time--on immune response was also analyzed. It was found that chronic noise impaired immune-related end-points in vivo and ex vivo depending on the strain used. Noise, but not restraint, affected C57Bl/6 mouse T-cell-dependent antibody production and ex vivo stimulated T-cell proliferation, but had no effect on these parameters in BALB/c mice or their cells. In fact, none of the stressors altered T-cell responses associated with the BALB/c mice. Further, noise exposure induced a decrease in corticosterone and catecholamines levels in BALB/c mice. In contrast, no differences were seen in these parameters for those BALB/c mice under restraint or for that matter C57Bl/6 mice exposed to restraint or noise. The results of these studies indicate that noise could seriously affect immune responses in susceptible individuals. In addition, it may also be concluded that noise possibility should not be considered a classic stressor. PMID- 23746316 TI - Corrigendum. PMID- 23746315 TI - Activation and trafficking of peritoneal B1a B-cells in response to amphibole asbestos. AB - B1a B-cells are concentrated in peritoneal and pleural cavities, are producers of 'natural auto-antibodies', and have been implicated in autoimmune responses. Their numbers are increased in humans and mice with systemic autoimmune diseases, but their role in the immune pathology is not known. Asbestos causes pulmonary, pleural, and peritoneal pathologies by accessing these tissues after inhalation. Amphibole asbestos has been shown to elicit immune dysfunction, including chronic inflammation, fibrosis, and autoantibody production. This study tested the hypothesis that asbestos affects immune dysfunction by activating B1a B-cells to traffic to secondary lymphatic tissue. C57Bl/6 mice were exposed to amphibole asbestos (Libby 6-Mix) either endotracheally or intraperitoneally, and the B1a B cells in pleural or peritoneal compartments were tested by multi-parameter flow cytometry. Adoptive transfer of peritoneal lymphocytes from CD45.1 transgenic to wild-type mice was used to track the migration. The percentage and numbers of B1a B-cells in pleural and peritoneal cavities decreased 3-6 days following exposure. During that time, asbestos exposure led to a decrease in cells expressing alpha-4 (alpha4) integrin and MHC II antigen. Peritoneal cells treated in vitro showed decreased alpha4 integrin with no change in CD5, IgM, or MHC II antigen. Therefore, B1a cells (IgM(+), CD5(+), MHC II(+)) traffic from the peritoneal cavity following loss of alpha4 integrin expression. Following adoptive transfer into the peritoneum of asbestos-exposed mice, CD45.1(+) B1a cells were detected in the spleen and mesenteric lymph nodes after 3 days, peaking at 6 days. Interestingly, the percentage of splenic suppressor B-cells (IgM(+), CD5(+), CD11b(+), CD1d(+)) decreased following amphibole exposure, demonstrating that the B1a cells did not contribute to an increased pool of suppressive B-cells. These results show that B1a B-cells respond to asbestos exposure by trafficking to secondary lymphatic tissue where they may affect ultimate immune dysfunction. PMID- 23746317 TI - Genome-wide association study of degenerative bony changes of the temporomandibular joint. AB - OBJECTIVES: To identify susceptibility genes underlying degenerative bony changes of the temporomandibular joint (TMJ). MATERIALS AND METHODS: Bony changes of the TMJ condylar head were diagnosed by examination of panoramic radiographs and/or magnetic resonance images and/or computed tomography images. We conducted a genome-wide association study (GWAS) of 146 cases with TMJ degeneration and 374 controls from East Asian populations using an Illumina HumanOmniExpress BeadChip. After rigorous quality-control filtering, approximately 550,000 single nucleotide polymorphisms (SNPs) were used for tests of associations with disease status. RESULTS: Forty-one SNPs at 22 independent loci showed association signals at P < 1 * 10(-4). The SNP rs878962, which maps on an intron of TSPAN9 on chromosome 12, showed the strongest association (combined OR = 1.89, 95% confidence interval = 1.43-2.50, P = 8.1 * 10(-6)). According to in silico predictions of the 41 SNPs, two intronic SNPs of APOL3 (rs80575) and MRC2 (rs2460300) may fall within regulatory elements and affect DNA-protein interactions. We could not replicate SNPs located on genes that have been reported to be associated with temporomandibular disorder or temporomandibular osteoarthritis in previous studies at P < 1 * 10(-4). CONCLUSIONS: Our GWAS identified 22 independent loci showing suggestive association signals with degenerative bony changes of the TMJ. These loci provide good candidates for future follow-up studies. PMID- 23746318 TI - Words of wisdom. Re: dutasteride in localised prostate cancer management: the REDEEM randomised, double-blind, placebo-controlled trial. PMID- 23746319 TI - Words of wisdom. Re: intermittent androgen suppression for rising PSA level after radiotherapy. PMID- 23746320 TI - Words of wisdom. Re: androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. PMID- 23746321 TI - Re: intratumor heterogeneity and branched evolution revealed by multiregion sequencing. PMID- 23746322 TI - Words of wisdom. Re: long-term endoscopic management of upper tract urothelial carcinoma: 20-year single-centre experience. PMID- 23746323 TI - Words of wisdom. Re: final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. PMID- 23746324 TI - Determination of mycotoxins in milk-based products and infant formula using stable isotope dilution assay and liquid chromatography tandem mass spectrometry. AB - A stable isotope dilution assay and liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed and validated for the determination of 12 mycotoxins, aflatoxins B1, B2, G1, G2, and M1, deoxynivalenol, fumonisins B1, B2, and B3, ochratoxin A, T-2 toxin, and zearalenone, in milk-based infant formula and foods. Samples were fortified with 12 13C uniformly labeled mycotoxins ([13C]-mycotoxins) that correspond to the 12 target mycotoxins and prepared by dilution and filtration, followed by LC-MS/MS analysis. Quantitation was achieved using the relative response factors of [13C]-mycotoxins and target mycotoxins. The average recoveries in fortified milk, milk-based infant formula, milk powder, and baby yogurt of aflatoxins B1, B2, G1, and G2 (2, 10, and 50 MUg/kg), aflatoxin M1 (0.5, 2.5, and 12.5 MUg/kg), deoxynivalenol, fumonisins B1, B2, and B3 (40, 200, and 1000 MUg/kg), ochratoxin A, T-2 toxin, and zearalenone (20, 100, and 500 MUg/kg), range from 89 to 126% with RSDs of <20%. The individual recoveries in the four fortified matrices range from 72% (fumonisin B3, 20 MUg/kg, milk-based infant formula) to 136% (T-2 toxin, 20 MUg/kg, milk powder), with RSDs ranging from 2 to 25%. The limits of quantitation (LOQs) were from 0.01 MUg/kg (aflatoxin M1) to 2 (fumonisin B1) MUg/kg. Aflatoxin M1 was detected in two European Reference materials at 0.127 +/- 0.013 MUg/kg (certified value = 0.111 +/- 0.018 MUg/kg) and 0.46 +/- 0.04 MUg/kg (certified value = 0.44 +/- 0.06 MUg/kg), respectively. In 60 local market samples, aflatoxins B1 (1.14 +/- 0.10 MUg/kg) and B2 (0.20 +/- 0.03 MUg/kg) were detected in one milk powder sample. Aflatoxin M1 was detected in three imported samples (condensed milk, milk based infant formula, and table cream), ranging from 0.10 to 0.40 MUg/kg. The validated method provides sufficient selectivity, sensitivity, accuracy, and reproducibility to screen for aflatoxin M1 at nanograms per kilogram concentrations and other mycotoxins, without using standard addition or matrix matched calibration to compensate for matrix effects. PMID- 23746325 TI - Synthesis of quaternary alpha-methyl alpha-amino acids by asymmetric alkylation of pseudoephenamine alaninamide pivaldimine. AB - The utility of pseudoephenamine as a chiral auxiliary for the alkylative construction of quaternary alpha-methyl alpha-amino acids is demonstrated. The method is notable for the high diastereoselectivities of the alkylation reactions, for its versatility with respect to electrophilic substrate partners, and for its mild hydrolysis conditions, which provide alpha-amino acids without salt contaminants. Alternatively, alpha-amino esters can be obtained by direct alcoholysis. PMID- 23746327 TI - The CPVT-associated RyR2 mutation G230C enhances store overload-induced Ca2+ release and destabilizes the N-terminal domains. AB - CPVT (catecholaminergic polymorphic ventricular tachycardia) is an inherited life threatening arrhythmogenic disorder. CPVT is caused by DADs (delayed after depolarizations) that are induced by spontaneous Ca2+ release during SR (sarcoplasmic reticulum) Ca2+ overload, a process also known as SOICR (store overload-induced Ca2+ release). A number of mutations in the cardiac ryanodine receptor RyR2 are linked to CPVT. Many of these CPVT-associated RyR2 mutations enhance the propensity for SOICR and DADs by sensitizing RyR2 to luminal or luminal/cytosolic Ca2+ activation. Recently, a novel CPVT RyR2 mutation, G230C, was found to increase the cytosolic, but not the luminal, Ca2+ sensitivity of single RyR2 channels in lipid bilayers. This observation led to the suggestion of a SOICR-independent disease mechanism for the G230C mutation. However, the cellular impact of this mutation on SOICR is yet to be determined. To this end, we generated stable inducible HEK (human embryonic kidney)-293 cell lines expressing the RyR2 WT (wild-type) and the G230C mutant. Using single-cell Ca2+ imaging, we found that the G230C mutation markedly enhanced the propensity for SOICR and reduced the SOICR threshold. Furthermore, the G230C mutation increased the sensitivity of single RyR2 channels to both luminal and cytosolic Ca2+ activation and the Ca2+-dependent activation of [3H]ryanodine binding. In addition, the G230C mutation decreased the thermal stability of the N-terminal region (amino acids 1-547) of RyR2. These data suggest that the G230C mutation enhances the propensity for SOICR by sensitizing the channel to luminal and cytosolic Ca2+ activation, and that G230C has an intrinsic structural impact on the N-terminal domains of RyR2. PMID- 23746328 TI - A ferrimagnetic Zintl phase Pr4MnSb9: synthesis, structure, and physical properties. AB - A new valence precise Zintl phase, Pr4MnSb9, has been successfully synthesized by solid-state reaction at high temperature. The single-crystal X-ray diffraction data reveal its monoclinic symmetry in the space group C2/m (No. 12) with a = 24.12(2) A, b = 4.203(3) A, c = 15.67(2) A, beta = 98.05(1) degrees , and Z = 4. The structure is characterized by the covalent three-dimensional network constructed by two types of five-atom-wide Sb5(7-) ribbons that are joined by 6 fold coordinated Mn(3+) cations, through which the narrower three-atom-wide Sb3(5 ) ribbons are attached as a tag, and interstitial Pr(3+) cations and single Sb(3 ) anions locate within the tunnels. Its magnetic susceptibility and isothermal hysteresis suggest ferrimagnetic behavior. The electrical conductivity and Seebeck coefficient of the cold-pressed pellet suggest a semimetal feature that agrees with the spin-polarized calculation results using the tight-binding linear muffin-tin orbital (TB-LMTO) method. PMID- 23746326 TI - Conservation of dark recovery kinetic parameters and structural features in the pseudomonadaceae "short" light, oxygen, voltage (LOV) protein family: implications for the design of LOV-based optogenetic tools. AB - In bacteria and fungi, various light, oxygen, voltage (LOV) sensory systems that lack a fused effector domain but instead contain only short N- and C-terminal extensions flanking the LOV core exist. In the prokaryotic kingdom, this so called "short" LOV protein family represents the third largest LOV photoreceptor family. This observation prompted us to study their distribution and phylogeny as well as their photochemical and structural properties in more detail. We recently described the slow and fast reverting "short" LOV proteins PpSB1-LOV and PpSB2 LOV from Pseudomonas putida KT2440 whose adduct state lifetimes varied by 3 orders of magnitude [Jentzsch, K., Wirtz, A., Circolone, F., Drepper, T., Losi, A., Gartner, W., Jaeger, K. E., and Krauss, U. (2009) Biochemistry 48, 10321 10333]. We now present evidence of the conservation of similar fast and slow reverting "short" LOV proteins in different Pseudomonas species. Truncation studies conducted with PpSB1-LOV and PpSB2-LOV suggested that the short N- and C terminal extensions outside of the LOV core domain are essential for the structural integrity and folding of the two proteins. While circular dichroism and solution nuclear magnetic resonance experiments verify that the two short C terminal extensions of PpSB1-LOV and PpSB2-LOV form independently folding helical structures in solution, bioinformatic analyses imply the formation of coiled coils of the respective structural elements in the context of the dimeric full length proteins. Given their prototypic architecture, conserved in most more complex LOV photoreceptor systems, "short" LOV proteins could represent ideally suited building blocks for the design of genetically encoded photoswitches (i.e., LOV-based optogenetic tools). PMID- 23746329 TI - Consuming a low-fat diet from weaning to adulthood reverses the programming of food preferences in male, but not in female, offspring of 'junk food'-fed rat dams. AB - AIM: This study aimed to determine whether the negative effects of maternal 'junk food' feeding on food preferences and gene expression in the mesolimbic reward system could be reversed by weaning the offspring onto a low-fat diet. METHODS: Offspring of control (n = 11) and junk food-fed (JF, n = 12) dams were weaned onto a standard rodent chow until 6 weeks (juvenile) or 3 months (adult). They were then given free access to both chow and junk food for 3 weeks and food preferences determined. mRNA expression of key components of the mesolimbic reward system was determined by qRT-PCR at 6 weeks, 3 and 6 months of age. RESULTS: In the juvenile group, both male and female JF offspring consumed more energy and carbohydrate during the junk food exposure at 6 weeks of age and had a higher body fat mass at 3 months (P < 0.05). Female juvenile JF offspring had higher tyrosine hydroxylase, dopamine receptors and dopamine active transporter expression in the ventral tegmental area (P < 0.05). In the adult group, there was no difference between control and JF offspring in energy and macronutrient intakes during exposure to junk food; however, female JF offspring had a higher body fat mass at 6 months (P < 0.05). CONCLUSION: These results suggest that the effects of perinatal junk food exposure on food preferences and fat mass can be reversed by consuming a low-fat diet from weaning to adulthood in males. Females, however, retain a higher propensity for diet-induced obesity even after consuming a low-fat diet for an extended period after weaning. PMID- 23746331 TI - F127/Calcium phosphate hybrid nanoparticles: a promising vector for improving siRNA delivery and gene silencing. AB - Calcium phosphate-based transfection method had been used to transfer DNA into living cells. However, it had so far not been studied in detail to what extend siRNA delivery system. In this study, Pluronic F127/calcium phosphate hybrid nanoparticles (F127/CaP) were prepared by a facile room temperature method and employed as carriers to deliver siRNA to silence tumor cell. The morphology of the F127/CaP hybrid nanoparticles was investigated with TEM. In order to determine the ratio of F127 to CaP in the hybrid nanoparticles, TGA (the thermogravimetric analysis) was applied. MTT assays confirmed that the F127/CaP hybrid nanoparticles were quite safe. The hybrid F127/CaP nanoparticles obtained were 120-210 nm in diameter, and they were applied as siRNA carriers for siRNA loading and in vitro transfection. The siRNA encapsulating efficiency was 91.5 wt.% with a loading content of 6.5 wt.%. Compared to traditional CaP transfection method, the siRNA-loaded F127/CaP exhibited higher gene inhibition efficiency, and this was supported by fluorescence microscopy. Quantitative analysis of GFP silencing efficiency of various siRNA formulations was measured by using FACS flow cytometry analysis. Additionally, both custom CaP and F127/CaP are biocompatible and biodegradable, thus the as-prepared F127/CaP hybrid nanoparticles are promising for siRNA delivery. PMID- 23746330 TI - Functional health status in children and adolescents after Fontan: comparison of generic and disease-specific assessments. AB - PURPOSE: The aim of this study was to compare associations between generic versus disease-specific functional health status assessments and patient and clinical characteristics for patients with severe congenital heart disease. METHODS: This was a cross-sectional observational study involving 325 single ventricle patients, aged 10-18 years, after Fontan procedure. Enrolled patients underwent a medical history review, laboratory testing, and assessment of the functional health status by completion of the generic Child Report Child Health Questionnaire and the disease-specific Congenital Heart Adolescent and Teenage questionnaire. Correlated conceptually equivalent domains from both questionnaires were identified and their associations with patient and clinical variables were compared. RESULTS: From the generic assessment, patients perceived marginally lower physical functioning (p = 0.05) but greater freedom from bodily pain compared with a normal population (p < 0.001). The equivalent physical functioning/limitations domain of the generic instrument, compared with the disease-specific instrument, had similar associations (higher multi-variable model R2) with medical history variables (R2 = 0.14 versus R2 = 0.12, respectively) and stronger associations with exercise testing variables (R2 = 0.22 versus R2 = 0.06). Similarly, the corresponding freedom from bodily pain/symptoms domains from both questionnaires showed a greater association for the generic instrument with medical history variables (R2 = 0.15 versus R2 = 0.09, respectively) and non-cardiac conditions (R2 = 0.13 versus R2 = 0.06). The associations of each questionnaire with echocardiographic results, cardiac magnetic resonance imaging results, and serum brain natriuretic peptide levels were uniformly weak (R2 range <0.01 to 0.04). CONCLUSIONS: Assessment of the physical functional health status using generic and disease-specific instruments yields few differences with regard to associations between conceptually similar domains and patient and clinical characteristics for adolescents after Fontan procedure. PMID- 23746332 TI - Histological inflammation and risk of subsequent prostate cancer among men with initially elevated serum prostate-specific antigen (PSA) concentration in the Finnish prostate cancer screening trial. AB - OBJECTIVE: To assess whether histological signs of inflammation are associated with an increased risk of subsequent prostate cancer (PCa) in men with elevated serum prostate-specific antigen (PSA) concentrations and benign initial biopsy. MATERIALS AND METHODS: Study subjects were men aged 54-67 years with an elevated PSA (>=4 ng/mL or 3-4 ng/mL and free to total PSA ratio <=0.16 or positive digital rectal examination), but a benign biopsy result within the Finnish population-based randomised screening trial for PCa, which started in 1996. A total of 293 prostate biopsies without PCa or suspicion of malignancy from the first screening round in the Tampere centre were re-evaluated by a uropathologist to assess histological inflammation. Results of the subsequent screening rounds were obtained from the trial database and PCa diagnoses made outside the screening were obtained from the Finnish Cancer Registry. The median length of follow-up was 10.5 years. Cox regression analysis was used to assess PCa risk after the initial benign biopsy. RESULTS: Histological inflammation was found in 66% of the biopsies. Subjects with inflammation at the biopsy had a slightly lower PCa risk in the second screening round (18 vs 27%, rate ratio 0.69, 95% confidence interval [CI] 0.35-1.34) relative to men without inflammation. In further follow-up, the PCa risk remained nonsignificantly lower (hazard ratio [HR] 0.71, CI 0.46-1.10; P = 0.13). The risk was not appreciably affected by adjustment for age, PSA, prostate volume and family history of PCa (HR 0.67, CI 0.42-1.07; P = 0.092). CONCLUSIONS: Histological inflammation in a prostate biopsy among men with an initial false-positive screening test was not associated with an increased risk of subsequent PCa, but instead with a decreased risk which was of borderline significance. Inflammation in prostate biopsy is not a useful risk indicator in PCa screening. PMID- 23746334 TI - Integrating ultrasound technology into teaching gross anatomy: point of order! PMID- 23746335 TI - Herbal medicinal oils in traditional Persian medicine. AB - CONTEXT: In Iran, conventional production methods of herbal oils are widely used by local practitioners. Administration of oils is rooted in traditional knowledge with a history of more than 3000 years. Scientific evaluation of these historical documents can be valuable for finding new potential use in current medicine. OBJECTIVE: The current study (i) compiled an inventory of herbal oils used in ancient and medieval Persia and (ii) compared the preparation methods and therapeutic applications of ancient times to current findings of medicinal properties in the same plant species. MATERIALS AND METHODS: Information on oils, preparation methods and related clinical administration was obtained from ancient Persian documents and selected manuscripts describing traditional Persian medicine. Moreover, we investigated the efficacy of medicinal plant species used for herbal oils through a search of the PubMed, Scopus and Google Scholar databases. RESULTS: In Iran, the application of medicinal oils date back to ancient times. In medieval Persian documents, 51 medicinal oils produced from 31 plant species, along with specific preparation methods, were identified. Flowers, fruits and leaves were most often used. Herbal oils have been traditionally administered via oral, topical and nasal routes for gastrointestinal, musculoskeletal, and neural diseases, respectively. According to current investigations, most of the cited medicinal plant species were used for their anti-inflammatory and analgesic properties. CONCLUSIONS: Medicinal oils are currently available in Iranian medicinal plant markets and are prepared using traditional procedures for desirable clinical outcomes. Other than historical clarification, the present study provides data on clinical applications of the oils that should lead to future opportunities to investigate their potential medicinal use. PMID- 23746336 TI - Assessment of 30-day all-cause mortality in metronidazole-treated patients with Clostridium difficile infection. AB - The Society for Healthcare Epidemiology (SHEA) and the Infectious Diseases Society of America (IDSA) clinical practice guidelines for Clostridium difficile infection (CDI) help to define and make recommendations for the treatment of mild to moderate disease with metronidazole and severe disease with vancomycin. We retrospectively evaluated 285 patients who were initially treated with metronidazole and stratified them by severity of illness using the guideline criteria. We compared the outcomes in the 2 groups including the need to change therapy, recurrences, and 30-day all-cause mortality. There were no differences in recurrence rates based on severity of disease. From the multivariate analysis, severe CDI was predictive of 30-day all-cause mortality (odds ratio (OR) 1.98, 95% confidence interval (CI) 1.07-3.67, p = 0.03), after controlling for ICU stay prior to diagnosis (OR 2.94, 95% CI 1.60-5.41. p = 0.001), age (OR 1.02, 95% CI 1.004-1.05, p = 0.02), and the modified Charlson score (OR 1.31, 95% CI 1.14 1.49, p < 0.0001). PMID- 23746333 TI - Regioselective covalent immobilization of recombinant antibody-binding proteins A, G, and L for construction of antibody arrays. AB - Immobilized antibodies are useful for the detection of antigens in highly sensitive microarray diagnostic applications. Arrays with the antibodies attached regioselectively in a uniform orientation are typically more sensitive than those with random orientations. Direct regioselective immobilization of antibodies on a solid support typically requires a modified form of the protein. We now report a general approach for the regioselective attachment of antibodies to a surface using truncated forms of antibody-binding proteins A, G, and L that retain the structural motifs required for antibody binding. The recombinant proteins have a C-terminal CVIX protein farnesyltransferase recognition motif that allows us to append a bioorthogonal azide or alkyne moiety and use the Cu(I)-catalyzed Huisgen cycloaddition to attach the binding proteins to a suitably modified glass surface. This approach offers several advantages. The recombinant antibody binding proteins are produced in Escherichia coli, chemoselectively modified posttranslationally in the cell-free homogenate, and directly attached to the glass surface without the need for purification at any stage of the process. Complexes between immobilized recombinant proteins A, G, and L and their respective strongly bound antibodies were stable to repeated washing with PBST buffer at pH 7.2. However, the antibodies could be stripped from the slides by treatment with 0.1 M glycine.HCl buffer, pH 2.6, for 30 min and regenerated by shaking with PBS buffer, pH 7.2, at 4 degrees C overnight. The recombinant forms of proteins A, G, and L can be used separately or in combination to give glass surfaces capable of binding a wide variety of antibodies. PMID- 23746337 TI - The association of interleukin-18 promoter polymorphisms and serum levels with duodenal ulcer, and their correlations with bacterial CagA and VacA virulence factors. AB - BACKGROUND: We analyzed the impact of interleukin (IL)-18 promoter polymorphisms on IL-18 serum levels in Helicobacter pylori-infected duodenal ulcer (DU) patients and healthy asymptomatic (AS) carriers. We also aimed to determine the association of the H. pylori virulence factors CagA and VacA antibodies with serum concentrations of IL-18 in order to elucidate any correlation between them. METHODS: Three groups of patients were enrolled: DU patients (67 individuals), AS carriers (48 individuals), and H. pylori-negative subjects (26 individuals). Serum concentrations of IL-18 were determined by ELISA. Patient sera were tested by Western blot method to determine the presence of serum antibodies to bacterial CagA and VacA. Genotyping of IL-18 promoter polymorphisms at positions - 137G/C and - 607C/A were performed by allele-specific primer PCR protocol. RESULTS: Our study revealed that serum IL-18 levels are positively influenced by CagA-positive H. pylori strains, so that maximum levels of IL-18 were detected in DU patients with the CagA(+) phenotype, regardless of the presence of the anti-VacA antibody. Regarding IL-18 promoter polymorphisms, the AA genotype and A allele at position 607C/A were found to be significantly lower in DU patients than in AS carriers and H. pylori-negative subjects (p = 0.032 and 0.043, respectively). CONCLUSIONS: The IL-18 - 607C variant was associated with higher levels of serum IL-18 and an increased risk of DU. Moreover, our findings indicated that serum concentrations of IL-18 were influenced by CagA factor, irrespective of the VacA status, suggesting that high levels of IL-18 in CagA-positive subjects predisposes to susceptibility to DU. PMID- 23746338 TI - Clinical role of serum pre-B cell colony-enhancing factor in ventilated patients with sepsis and acute respiratory distress syndrome. AB - BACKGROUND: We measured serum levels of pre-B cell colony-enhancing factor (PBEF), which has been suggested as a novel biomarker of sepsis and acute respiratory distress syndrome (ARDS), and evaluated its use as a prognostic biomarker. METHODS: PBEF was measured in 104 adult ventilated patients who were diagnosed with sepsis upon admission using an enzyme-linked immunosorbent assay. RESULTS: The mean age of our patients was 62.9 +/- 12.1 y, and 62 (59.6%) patients were male. The median PBEF level was 5.4 ng/ml (range 1.1-150.7 ng/ml). Non-survivors (n = 57) demonstrated significantly higher PBEF levels than survivors (18.7 +/- 34.5 vs 6.9 +/- 6.1 ng/ml; p = 0.022). Most particularly, patients with PBEF levels >= 10.4 ng/ml (n = 27) demonstrated higher hospital mortality than patients with PBEF levels < 10.4 ng/ml (n = 77) (74.1% vs. 48.1%; p = 0.025). Univariate logistic analysis determined PBEF >= 10.4 ng/ml to be an independent factor associated with hospital survival (hazard ratio = 0.324, 95% confidence interval = 0.123-0.854; p = 0.023). Among patients with sepsis-induced ARDS (n = 59), non-survivors (n = 35) demonstrated significantly higher PBEF levels than survivors (n = 24), but not interleukin-6 (IL-6) levels. CONCLUSIONS: Our findings indicate that high PBEF is associated with poor clinical outcomes in ventilated patients with sepsis and sepsis-induced ARDS. Serum PBEF might be a better predictor of mortality than IL-6 in patients with sepsis-induced ARDS. PMID- 23746339 TI - Neonatal transfusion-transmitted hepatitis C virus infection following a pre seroconversion window-phase donation in Sweden. AB - A 9-day-old child developed a transfusion-transmitted hepatitis C virus (HCV) infection following a pre-seroconversion window-phase donation. Retrospective analysis of donor plasma revealed detectable HCV core antigen (154 fmol/l), as well as HCV RNA (87,000 IU/ml). Of 5.24 million Swedish plasma samples from December 1998 to September 2012, 5 additional window-phase donations were identified. PMID- 23746340 TI - A case of oculoglandular tularemia resistant to medical treatment. AB - Tularemia is a zoonotic disease of the northern hemisphere. Oculoglandular tularemia is the rarest form, comprising 1.4-4.2% of all cases. We present a patient with oculoglandular tularemia that did not respond to gentamicin to demonstrate the need for prolonged antimicrobial treatment and surgical intervention. PMID- 23746341 TI - Antimicrobial resistance among respiratory Haemophilus influenzae isolates from pulmonology services over a six-year period. AB - BACKGROUND: Respiratory tract infections (RTI) are frequently caused by Haemophilus influenzae. Widespread antibacterial resistance among respiratory microorganisms complicates empirical RTI treatment. Therefore, national data on antibiotic resistance for H. influenzae are important for guiding optimal antibiotic choice. METHODS: The antibiotic susceptibility of H. influenzae strains isolated from respiratory specimens of patients admitted to the pulmonology services between 2005 and 2010 was assessed. Isolates were collected annually from 13 hospitals in the Netherlands as part of the national intramural antimicrobial resistance surveillance performed by the Dutch Working Group on Antibiotic Policy (SWAB). Breakpoints for resistance were in accordance with the criteria of the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Trend analysis was performed using logistic regression analysis. RESULTS: In total, 1606 H. influenzae strains were analyzed. The prevalence of antibiotic resistance to amoxicillin, co-amoxiclav, doxycycline, co-trimoxazole, and clarithromycin was stable over the 6-y period, and there was a trend towards a decrease in the prevalence of beta-lactamase-producing isolates. Regarding prevalences, no significant trends were observed. CONCLUSIONS: Our study showed no significant changes in antibiotic resistance for H. influenzae isolated at different hospitals in the Netherlands over a 6-y period. Regular surveillance remains important in controlling the prevalence of resistance, since actual resistance data should be taken into account when the choice of an empiric antibiotic is made. PMID- 23746342 TI - An uncommon cause of Staphylococcus aureus sepsis. AB - We describe a case of Staphylococcus aureus sepsis after acupuncture for chronic fatigue syndrome (CFS). Sepsis is a rare, but potentially fatal complication of acupuncture. The most common cause of bacterial infection after acupuncture is S. aureus. The effectiveness of acupuncture for the treatment of CFS is not proven, therefore the potential benefits should be weighed against the risks. PMID- 23746343 TI - Prevalence of quinolone resistance determinant qnrA6 among broad- and extended spectrum beta-lactam-resistant Proteus mirabilis and Morganella morganii clinical isolates with sul1-type class 1 integron association in a Tunisian Hospital. AB - OBJECTIVES: The aim of this study was to investigate the prevalence and the emergence of plasmid-mediated quinolone resistance among broad-spectrum beta lactam-resistant Proteus mirabilis and Morganella morganii clinical isolates recovered in the Military Hospital in Tunisia. METHODS: Of 200 strains examined, 50 exhibited resistance to quinolones. Quinolone resistance determinants (qnr and aac(6')-Ib-cr) were characterized by multiplex PCR and sequencing. Chromosomal quinolone resistance mutations in the quinolone resistance-determining region (QRDR) and class 1 integron characterization were analysed by PCR and sequencing. The clonal relationship between the isolates was studied by pulsed-field gel electrophoresis (PFGE). RESULTS: Fourteen isolates harboured qnrA6 and among them 8 (57%) were extended-spectrum beta-lactamase (ESBL) producers, whilst 12 (85%) isolates harboured blaDHA-1. Mutations in the QRDR were detected in gyrA (Ser83Ile, Glu87Lys), gyrB (Ser464Phe), and parC (Ser80Ile). qnrA6 and blaDHA-1 genes were found embedded in complex sul1-type class 1 integrons. A gene cassette carrying aac(6')-Ib-cr was found located in the class 1 integron upstream of the qacEDelta1 gene. According to the PFGE analysis, the isolates were clonally unrelated. CONCLUSIONS: This is the first description in North Africa of class 1 integrons carrying blaDHA-1, qnrA6 gene, and aac(6')-Ib-cr determinants in clinical strains of Proteus mirabilis and Morganella morganii. PMID- 23746344 TI - Aspergillus sp. isolated in critically ill patients with extracorporeal membrane oxygenation support. AB - This study reports Aspergillus isolation in critically ill patients who underwent extracorporeal membrane oxygenation (ECMO) and highlights the difficulty in establishing a diagnosis of aspergillosis in this population. The diagnosis of Aspergillus infection or colonization was retrospectively performed using the proposed modified criteria of the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSG) adapted to critically ill patients. Between 2005 and 2011, 11 of 151 patients (7.2%) who underwent ECMO had Aspergillus sp. isolates, 10 in a pulmonary sample and 1 in a mediastinal wound sample. Five patients did not have any classical risk factors for aspergillosis. One patient had a proven invasive pulmonary aspergillosis (IPA), 2 had a putative IPA, and 1 patient had a possible Aspergillus mediastinitis, whilst in 7 patients this was considered colonization. However, the clinical relevance of Aspergillus isolation was based on an algorithm not validated in patients undergoing ECMO. Our data support the need to implement non-invasive diagnostic procedures for aspergillosis in this population. PMID- 23746345 TI - Pathways to prevention: improving nonresident African American fathers' parenting skills and behaviors to reduce sons' aggression. AB - This study describes a test of the Fathers and Sons Program for increasing intentions to avoid violence and reducing aggressive behaviors in 8- to 12-year old African American boys by enhancing the parenting skills satisfaction and parenting behaviors of their nonresident fathers. The study included 158 intervention and 129 comparison group families. Structural equation model results indicated that the intervention was effective for improving fathers' parenting skills satisfaction, which was positively associated with sons' satisfaction with paternal engagement. Sons' paternal engagement satisfaction was positively associated with their intentions to avoid violence. Although aggressive behaviors were lower for comparison group sons, the intervention effectively reduced sons' aggressive behaviors indirectly by enhancing fathers' parenting behaviors. Support for family-centered youth violence prevention efforts is discussed. PMID- 23746346 TI - Metabolic syndrome is strictly associated with parental obesity beginning from childhood. AB - OBJECTIVE: We aimed to identify potential correlates or risk factors for metabolic syndrome (MetS) in a cohort of schoolchildren. We quantified the prevalence of MetS, analysed the clustering of MetS components and described the distribution of metabolic parameters not included in MetS definition. DESIGN: Population-based, cross-sectional study. PATIENTS AND MEASUREMENTS: A total of 489 children (6.7-13 years) representing the 92.6% of the whole school population between the 1st year of primary school and the 2nd year of junior high school living in a centre of southern Italy. Weight, height, waist circumference, blood pressure (BP), laboratory parameters (indexes of glucose metabolism, lipid profile and uric acid), anamnestic and parental information, lifestyle and dietary habits were collected. Dietary habits data were available only for 353 children. RESULTS: MetS prevalence was 9.8%. Of 48 children with MetS, 38 (79.2%) were simultaneously positive for abdominal obesity and elevated BP. In children with MetS, the prevalence of insulin resistance, high insulin, high non-HDL(high density lipoprotein) cholesterol and high uric acid was higher than in children without MetS. In 6.7-10-year-old children, only the presence of parental history of obesity [odds ratio (OR) = 4.3, 95% CI = 1.8-10.2] was higher in those with MetS than in those without. In 10.1-13-year-old children, the presence of parental history of obesity, the habits of no walking/cycling to school, long screen time and no breakfast consumption were higher in children with MetS than in those without, but only parental history of obesity (adjusted OR = 3.8, 95% CI = 1.7-8.4) remained significantly related to MetS in multivariate logistic regression. CONCLUSIONS: Parental obesity was strictly associated with MetS in all children and should be considered in clinical practice. In older children, wrong lifestyle and dietary habits were related to parental obesity. PMID- 23746347 TI - The D box meets its match. AB - In this issue of Molecular Cell, He and colleagues (2013) unveil a high resolution structure of a key regulatory interface in cell-cycle control: the destruction box sequence bound to the anaphase-promoting complex. PMID- 23746348 TI - The Rs of biology: R-loops and the regulation of regulators. AB - Work by Sun et al. (2013) in Arabidopsis reveals an additional function for R loops in suppressing the expression of a long noncoding RNA and sheds light on the single-stranded DNA binding protein AtNDX that promotes persistence of the R loop. PMID- 23746349 TI - Defining the RGG/RG motif. AB - Motifs rich in arginines and glycines were recognized several decades ago to play functional roles and were termed glycine-arginine-rich (GAR) domains and/or RGG boxes. We review here the evolving functions of the RGG box along with several sequence variations that we collectively term the RGG/RG motif. Greater than 1,000 human proteins harbor the RGG/RG motif, and these proteins influence numerous physiological processes such as transcription, pre-mRNA splicing, DNA damage signaling, mRNA translation, and the regulation of apoptosis. In particular, we discuss the role of the RGG/RG motif in mediating nucleic acid and protein interactions, a function that is often regulated by arginine methylation and partner-binding proteins. The physiological relevance of the RGG/RG motif is highlighted by its association with several diseases including neurological and neuromuscular diseases and cancer. Herein, we discuss the evidence for the emerging diverse functionality of this important motif. PMID- 23746350 TI - Kinetochores coordinate pericentromeric cohesion and early DNA replication by Cdc7-Dbf4 kinase recruitment. AB - Centromeres play several important roles in ensuring proper chromosome segregation. Not only do they promote kinetochore assembly for microtubule attachment, but they also support robust sister chromatid cohesion at pericentromeres and facilitate replication of centromeric DNA early in S phase. However, it is still elusive how centromeres orchestrate all these functions at the same site. Here, we show that the budding yeast Dbf4-dependent kinase (DDK) accumulates at kinetochores in telophase, facilitated by the Ctf19 kinetochore complex. This promptly recruits Sld3-Sld7 replication initiator proteins to pericentromeric replication origins so that they initiate replication early in S phase. Furthermore, DDK at kinetochores independently recruits the Scc2-Scc4 cohesin loader to centromeres in G1 phase. This enhances cohesin loading and facilitates robust pericentromeric cohesion in S phase. Thus, we have found the central mechanism by which kinetochores orchestrate early S phase DNA replication and robust sister chromatid cohesion at microtubule attachment sites. PMID- 23746351 TI - Structural definition is important for the propagation of the yeast [PSI+] prion. AB - Prions are propagated in Saccharomyces cerevisiae with remarkable efficiency, yet we know little about the structural basis of sequence variations in the prion protein that support or prohibit propagation of the prion conformation. We show that certain single-amino-acid substitutions in the prion protein Sup35 impact negatively on the maintenance of the associated prion-based [PSI(+)] trait by combining in vivo phenotypic analysis with solution NMR structural studies. A clear correlation is observed between mutationally induced conformational differences in one of the oligopeptide repeats (R2) in the N terminus of Sup35 and the relative ability to propagate [PSI(+)]. Strikingly, substitution of one of a Gly-Gly pair with highly charged residues that significantly increase structural definition of R2 lead to a severe [PSI(+)] propagation defect. These findings offer a molecular explanation for the dominant-negative effects of such psi-no-more (PNM) mutations and demonstrate directly the importance of localized structural definition in prion propagation. PMID- 23746352 TI - SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase. AB - Lipid metabolism is tightly controlled by the nutritional state of the organism. Nutrient-rich conditions increase lipogenesis, whereas nutrient deprivation promotes fat oxidation. In this study, we identify the mitochondrial sirtuin, SIRT4, as a regulator of lipid homeostasis. SIRT4 is active in nutrient-replete conditions to repress fatty acid oxidation while promoting lipid anabolism. SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD), an enzyme that produces acetyl CoA from malonyl CoA. Malonyl CoA provides the carbon skeleton for lipogenesis and also inhibits fat oxidation. Mice lacking SIRT4 display elevated MCD activity and decreased malonyl CoA in skeletal muscle and white adipose tissue. Consequently, SIRT4 KO mice display deregulated lipid metabolism, leading to increased exercise tolerance and protection against diet-induced obesity. In sum, this work elucidates SIRT4 as an important regulator of lipid homeostasis, identifies MCD as a SIRT4 target, and deepens our understanding of the malonyl CoA regulatory axis. PMID- 23746353 TI - Kinetic competition between elongation rate and binding of NELF controls promoter proximal pausing. AB - Pausing of RNA polymerase II (Pol II) 20-60 bp downstream of transcription start sites is a major checkpoint during transcription in animal cells. Mechanisms that control pausing are largely unknown. We developed permanganate-ChIP-seq to evaluate the state of Pol II at promoters throughout the Drosophila genome, and a biochemical system that reconstitutes promoter-proximal pausing to define pausing mechanisms. Stable open complexes of Pol II are largely absent from the transcription start sites of most mRNA genes but are present at snRNA genes and the highly transcribed heat shock genes following their induction. The location of the pause is influenced by the timing between when NELF loads onto Pol II and how fast Pol II escapes the promoter region. Our biochemical analysis reveals that the sequence-specific transcription factor, GAF, orchestrates efficient pausing by recruiting NELF to promoters before transcription initiation and by assisting in loading NELF onto Pol II after initiation. PMID- 23746355 TI - Liquid-liquid extraction of uranyl by an amide ligand: interfacial features studied by MD and PMF simulations. AB - We report a molecular dynamics study of biphasic systems involved in the liquid liquid extraction of uranyl nitrate by a monoamide ligand (L = N,N-di(2 ethylhexyl)isobutyramide, DEHiBA) to hexane, from pH neutral or acidic (3 M nitric acid) aqueous solutions. We first describe the neat interfaces simulated with three electrostatic models, one of which including atomic polarizabilities. The free energy profiles for crossing the water/hexane interface by L or its UO2(NO3)2L2 complex are then investigated by PMF (potential of mean force) calculations. They indicate that the free ligand and its complex are surface active. With the polarizable force field, however, the complexes have a lower affinity for the interface than without polarization. When DEHiBA gets more concentrated and in acidic conditions, their surface activity diminishes. Surface activity of UO2(NO3)2L2 complexes is further demonstrated by demixing simulations of randomly mixed DEHiBA, hexane, and neutral or acidic water. Furthermore, demixing of randomly mixed solvents, L molecules, UO2(NO3)2 salts, and nitric acid shows in some cases complexation of L to form UO2(NO3)2L2 and UO2(NO3)2L complexes that adsorb at the aqueous interfaces. These features suggest that uranyl complexation by amide ligands occurs "right at the interface", displaying marked analogies with the liquid-liquid extraction of uranyl by TBP (tri-n-butyl phosphate). Regarding the positive effect of nitric acid on extraction, the simulations point to several facets involving enhanced ion pairing of uranyl nitrate, decreased affinity of the complex for the interface, and finally, stabilization of the complex in the organic phase. PMID- 23746354 TI - Amoebicidal activity of phytosynthesized silver nanoparticles and their in vitro cytotoxicity to human cells. AB - Acanthamoeba causes infections in humans and other animals and it is important to develop treatment therapies. Jatropha curcas, Jatropha gossypifolia and Euphorbia milii plant extracts synthesized stable silver nanoparticles (AgNPs) that were relatively stable. Amoebicidal activity of J. gossypifolia, J. curcas and E. milii leaf extracts showed little effect on viability of Acanthamoeba castellanii trophozoites. Plant-synthesized AgNPs showed higher amoebicidal activity. AgNPs synthesized by J. gossypifolia extract were able to kill 74-27% of the trophozoites at concentrations of 25-1.56 MUg mL(-1) . AgNPs were nontoxic at minimum inhibitory concentration with peripheral blood mononuclear cells. These results suggest biologically synthesized nanoparticles as an alternative candidate for treatment of Acanthamoeba infections. PMID- 23746356 TI - Further characterization of three Yersinia enterocolitica strains with a nalidixic acid-resistant phenotype isolated from humans with diarrhea. AB - Antimicrobial-resistant bacteria pose a threat to public health. Three Yersinia enterocolitica strains cultured from patients presenting with diarrhea and resistant to nalidixic acid were studied. Target gene mutations in gyrA alone were identified as part of the genetic basis for this phenotype. Efflux activity was also noted, since the presence of the efflux pump inhibitor, phenylalanine arginine-beta-naphthylamide, increased susceptibility to nalidixic acid. PMID- 23746357 TI - A three-loci variable number of tandem repeats analysis for molecular subtyping of Vibrio cholerae O1 and O139. AB - Rapid and easy-to-use molecular subtyping methods are being explored and used for the surveillance of bacterial diseases, including multiple-loci variable number of tandem repeats (VNTR) analysis (MLVA). In this study, we assessed different VNTR combinations for the subtyping of Vibrio cholerae serogroups O1 and O139 with strain panels selected from a long-term nationwide cholera survey. By only using three highly variable loci (VC0147, VCA0171, and VCA0283), we acquired a high discriminatory power, which equals that found after using a combination of all nine loci and that of a pulsed-field gel electrophoresis analysis. Evaluation using the outbreak strains showed a good clustering of the three-loci MLVA (VC0147, VCA0171, and VCA0283). In addition, a six-loci MLVA (VC0147, VC0437, VC1457, VC1650, VCA0171, and VCA0283) protocol allowed for the clustering of O1/O139 V. cholerae strains, which have different serogroups/biotypes and toxigenic/nontoxigenic characteristics. Here, we propose that the three-loci MLVA can be utilized as a molecular subtyping protocol in cholera epidemiological investigations, and the six-loci MLVA can be used in phylogenetic and population structure analyses of V. cholerae O1/O139. PMID- 23746358 TI - Transmission and persistence of methicillin-resistant Staphylococcus aureus in milk, environment, and workers in dairy cattle farms. AB - The aim of this study was to determine the presence and persistence of methicillin-resistant Staphylococcus aureus (MRSA) in milk, farm environment, and farmers on 22 dairy cattle farms in Korea during 2008-2009. Genetic relatedness among the MRSA isolates was also investigated. Of 1146 samples examined, 35 of 559 (6.3%) quarter milk samples from 371 cows, four of 86 (4.7%) hand and nose samples from 43 farmers, and 6 of 501 (1.2%) farm environment samples were MRSA positive. Except for three isolates, all MRSA were classified into ST72-spa t324 SCCmec IV with PVL negative, the most predominant clonal type among community associated MRSA in South Korea. All 35 MRSA-positive milk samples from 19 cows were obtained from a single farm (Farm G) out of 22 (4.5%) farms tested. The farm G was revisited 1 year later and milk samples were collected for examination of MRSA again. Two of six previous MRSA-positive cattle that had been kept on the farm still harbored MRSA genetically identical to MRSA strains, which were isolated from the same farm a year ago. The results of this study provide the evidence of transmission of MRSA among cattle, farm environment, and farmers and also long-term persistence of MRSA in animals. PMID- 23746359 TI - Examining the role of intersubunit contacts in catalysis by 3-deoxy-d-manno octulosonate 8-phosphate synthase. AB - 3-Deoxy-d-manno-octulosonate 8-phosphate synthase (KDO8PS) catalyzes the reaction between phosphoenolpyruvate and arabinose 5-phosphate (A5P) in the first committed step in the pathway to 3-deoxy-d-manno-octulosonate, a component in the cell wall of Gram-negative bacteria. KDO8PS is evolutionarily and structurally related to the first enzyme of the shikimate pathway, 3-deoxy-d-arabino heptulosonate 7-phosphate synthase (DAH7PS), which uses erythrose 4-phosphate in place of A5P. Both KDO8PS and type Ibeta DAH7PS enzymes adopt similar homotetrameric associations with their active sites close to one of the interfaces. The conserved PAFLxR motif in KDO8PS and the corresponding GARNxQ motif in type Ibeta DAH7PS, both on the short beta4-alpha4 loop of the (beta/alpha)8 barrel, form part of this interface and provide key contacts with substrates. This (112)PAFLxR(117) motif was mutated in Neisseria meningitidis KDO8PS in order to assess its role in enzyme function. Arg117 extends across the interface to provide guanidinium functionality in the A5P binding site of the adjacent subunit. Substitution Arg117Ala severely hampered catalysis, whereas substitution to Lys was tolerated better. Mutation of Phe114 to either Arg or Ala results in active proteins, but with substantially elevated Km(A5P) values. Mutant proteins that combine substitutions in this motif demonstrate poor catalytic function, and, although these mutated residues now structurally resemble their counterparts in the GARNxQ motif of type Ibeta DAH7PS, no DAH7PS like activity was observed. Analysis of the structures reveals that small changes in relative orientation of the subunits are important for the differences in active-site construction. Quaternary structure is therefore tightly linked to substrate specificity. PMID- 23746360 TI - Cu-catalyzed synthesis of tryptanthrin derivatives from substituted indoles. AB - A concise method for the preparation of tryptanthrins from indoles via the copper catalyzed aerobic oxidation is described. The reactions can be carried out under mild reaction conditions with varying functional group tolerance. PMID- 23746361 TI - Risk factors for injuries in landslide- and flood-affected populations in Uganda. AB - INTRODUCTION: The frequency of occurrence of natural disasters has increased over the past several decades, which necessitates a better understanding of human vulnerability, particularly in low-resource settings. This paper assesses risk factors for injury in the March 2010 floods and landslides in Eastern Uganda, and compares the effects of location, injury type, and severity. METHODS: A stratified cluster survey of the disaster-affected populations was conducted five months after onset of the disasters. Probability proportional to size sampling was used to sample 800 households, including 400 affected by floods in Butaleja District and 400 affected by landslides in Bududa District. RESULTS: Flood- and landslide-affected populations were surveyed in July 2010 using a stratified cluster design. The odds of injury were 65% higher in the flood-affected groups than the landslide-affected groups in a logistic regression (OR = 0.35; 95% CI, 0.24-0.52; P < .001). The injury rate was greater in individuals under 42 years of age, and location of injury was a contributing factor. More people were injured in the flood-affected population as compared with the landslide-affected population, and injuries were more severe. CONCLUSIONS: This study illustrates differences between populations injured by flood and landslide disasters that occurred simultaneously in Eastern Uganda in 2010. In areas where landslides are prone to occur due to massive rainfalls or floods, preventative measures, such as early warning systems and evacuation, are more likely to increase the likelihood of people surviving, while for areas with massive floods, immediate and effective medical attention can save lives and improve injury outcomes. PMID- 23746362 TI - End-on azido-bridged 3d-4f complexes showing single-molecule-magnet property. AB - Four tetranuclear 3d-4f complexes with the 4f centers bridged solely by end-on azide bridges were reported. The [CuTb]2 compound displays single-molecule-magnet behavior with hysteresis loops observed at up to 2.4 K. PMID- 23746363 TI - Formation of perfluorinated surfactants from precursors by indigenous microorganisms in groundwater. AB - The formation of perfluorinated surfactants (PFSs) from their precursors in waters is of concern. In this study, the formation of PFSs through biodegradation of precursors was measured in incubation tests. Indigenous microorganisms in groundwater were able to biodegrade perfluorooctane sulfonamide (FOSA) to yield perfluorooctane sulfonate (PFOS). The addition of nutrients and soil promoted the formation. A 42-d incubation test using sources of groundwater recharge showed that PFOS, perfluorooctanoate, and perfluorononanoate were significantly and remarkably (?1.5*) formed from precursors in street runoff through biodegradation, but not in rainwater or wastewater effluent. Significant formation of PFSs from precursors in street runoff was observed. PMID- 23746364 TI - Detection of polybrominated diphenyl ethers in culture media and protein sources used for human in vitro fertilization. AB - The concentrations of 10 polybrominated diphenyl ethers (PBDEs) in commercial culture media and protein sources (PSs) for in vitro fertilization (IVF) of human ova were investigated. Samples of 15 IVF media (IVFM), nine sperm preparation media (SPM), and six PSs were analyzed. PBDEs were detected in 10 IVFM, seven SPM, and all PS samples in ranges of 0.6-35, 0.9-31, and 7.5-385pgg(-1), respectively. A dominant PBDE congener BDE-47 was detected in the PS and PS supplemented samples. Our findings suggested that PS supplementation was the potential cause of PBDE-contamination of IVFM and SPM. PMID- 23746365 TI - Degradation of pesticide mixture on modified matrix of a biopurification system with alternatives lignocellulosic wastes. AB - The biobed systems were designed to retain and to degrade pesticides through the properties of a biomixture composed of straw (ST), topsoil and peat (PT) 2:1:1 v/v. The ST is the main substrate in the biomixture, as it allows the proliferation of fungi that promotes pesticide degradation. The use of readily available components in the biomixture is an important aspect to build a biobed. Therefore, potential use of readily available wastes as barley husk (BH), sawdust (SW) and oat husk (OH), as total or partial substitutes of ST were tested in pesticide degradation studies. Metabolite formation and the biological activities were also evaluated. Biomixture composed of OH was highly efficient in pesticide degradation, with t1/2 values of 28.6, 58.9 and 26.8 d for atrazine (ATZ), chlorpyrifos (CHL) and isoproturon (ISP). On the other hand, comparable for degrading capacities with the ST based biomixture were obtained with SW and BH, but only as partial replacement. Contrarily, high t1/2 values (more than 100 d) were obtained in biomixtures with total substitution of ST by SW or BH. Metabolite formation was observed in all biomixtures tested, but without clear formation patterns. Moreover, high and stable biological activity was observed in the biomixtures composed of OH. Therefore, our results demonstrated that ST can be partial or totally replaced by OH in the biomixture allowing an efficient degradation of pesticide mixture. However, it is recommended that ST can be only partially replaced by BH and SW in the biomixture to allow efficient pesticide degradation. PMID- 23746366 TI - Multimedia fate modeling and comparative impact on freshwater ecosystems of pharmaceuticals from biosolids-amended soils. AB - This study modeled the impact on freshwater ecosystems of pharmaceuticals detected in biosolids following application on agricultural soils. The detected sulfonamides and hydrochlorothiazide displayed comparatively moderate retention in solid matrices and, therefore, higher transfer fractions from biosolids to the freshwater compartment. However, the residence times of these pharmaceuticals in freshwater were estimated to be short due to abiotic degradation processes. The non-steroidal anti-inflammatory mefenamic acid had the highest environmental impact on aquatic ecosystems and warrants further investigation. The estimation of the solid-water partitioning coefficient was generally the most influential parameter of the probabilistic comparative impact assessment. These results and the modeling approach used in this study serve to prioritize pharmaceuticals in the research effort to assess the risks and the environmental impacts on aquatic biota of these emerging pollutants. PMID- 23746367 TI - Risk assessment of xenoestrogens in a typical domestic sewage-holding lake in China. AB - Release of domestic sewage leads to accumulation of xenoestrogens in holding waters, especially in closed or semi-enclosed waters such as lakes. In the study, the occurrence, distribution, estrogenic activity and risk of eight xenoestreogens were evaluated in Lake Donghu, China. Nonylphenol (NP), octylphenol (OP), and bisphenol A (BPA) were identified as the main xenoestrogens ranging from tens of ngL(-1) (in the surface water) or ng g(-1)dw (in the suspended particles and sediment) to tens of MUgL(-1) or MUg g(-1)dw. The sum of 17beta-estradiol equivalents (?EEQs) ranged from 0.32 to 45.02 ngL(-1) in the surface water, 0.53 to 71.86 ng g(-1)dw in the suspended particles, and 0.09 to 24.73 ng g(-1)dw in the sediment. Diethylstilbestrol (DES) was determined as the main contributor to ?EEQs followed by NP. The risk assessment showed a higher risk in the surface water than in the suspended particles and sediment in such domestic sewage-holding lake. PMID- 23746368 TI - Breastfeeding and bigger brains. What comes first? PMID- 23746369 TI - Response to: Breastfeeding and bigger brains. What comes first? PMID- 23746370 TI - Human muscle fatigue, eccentric damage and coherence in the EMG. PMID- 23746371 TI - Enantioseparation of alpha-amino acids by means of Cinchona alkaloids as selectors in chiral ligand-exchange chromatography. AB - A conventional nonchiral column was used for the enantioseparation of several racemic alpha-amino acids (native and derivatized) through the use of Cinchona alkaloids as chiral selectors along with Cu(II) ions in chiral ligand-exchange chromatography. The mobile phase composition (i.e., the organic modifier content and pH) was studied in order to modulate retention and enantioselectivity. Good enantioseparation of many amino acids was obtained using equimolar amounts of Cu(II) and either cinchonidine, quinine or quinidine as chiral selectors in the mobile phase. The molecular geometry of the diastereomeric complexes formed was modeled and energetic differences between both compounds were calculated by methods based on semi-empirical force-field. Good correlations were obtained between experimental enantioselectivity factors and calculated energetic differences. PMID- 23746372 TI - An high-performance liquid chromatographic method for the simultaneous analysis of acetylcarnitine taurinate, carnosine, asparagine and potassium aspartate and for the analysis of phosphoserine in alimentary supplements. AB - A RP-HPLC method with pre-column derivatization was developed and validated for the simultaneous quantification of carnosine (Carn), acetylcarnitine taurinate (AC-Tau), asparagine (Asn), potassium aspartate (Asp) and for the determination of phosphoserine (p-Ser) in new and commercial alimentary supplements. The effect of complex matrices was evaluated by the study of the amino acid derivatization reaction with 2,4-dinitrofluorobenzene (DNFB) both in standard and placebo solutions. The reaction was carried out for 20 min at 70 degrees C in alkaline medium (pH10) for p-Ser analysis, whereas for 60 min in the case of Carn, AC-Tau, Asn and Asp analysis. The adducts have been separated on a Discovery RP Amide C16 (250 mm*4.6mm, i.d.) column using a mobile phase consisting of acetonitrile (ACN) and triethylammonium (TEA) phosphate buffer (pH 3, 0.05 M) under gradient elution conditions at a flow-rate of 0.8 mL/min. Detection was set at lambda=360 nm. The validation parameters such as linearity, sensitivity, accuracy, precision and specificity were found to be highly satisfactory. Linear responses were observed by placebo solutions (determination coefficient <=0.9996). Intra-day precision (relative standard deviation, RSD) was <=1.06% for corrected peak area and <=0.99% for retention times (tR) without significant differences between intra- and inter-day data. Recovery studies showed good results for all examined compounds (from 97.7% to 101.5%) with RSD ranging from 0.5% to 1.3%). The high stability of derivatized compound solutions at room temperature means an undoubted advantage of the method allowing the simultaneous preparation of a large number of samples and consecutive chromatographic analyses by the use of an autosampler. The developed method can be considered suitable for the quality control of new and commercial products. PMID- 23746373 TI - Autoantigen induced clonal expansion in immortalized B cells from the peripheral blood of multiple sclerosis patients. AB - We studied Ig heavy chain (VDJ) sequences and antigen reactivity of 412 immortalized B cell lines from the peripheral blood of 10 multiple sclerosis (MS) patients, 4 clinically isolated syndrome (CIS) patients and 6 healthy controls (HCs). 78/238 (32.8%) MS and CIS B cell lines were part of 9 clonally expanded B cell populations, of which 5 were present in multiple patients. Increased VH1 gene family usage was evidenced for MS B cells, with 29.2% expressing VH1-69. Affinity maturation in MS and CIS was indicated by increased Ig VDJ mutations. Autoantibody producing B cells reactive to intracellular antigens were significantly higher in MS (25%) and CIS (28%) patients than in HCs (5%), including 3/9 expanded B cell clones. Specificity for phosphatidylcholine was observed for 1/9 B cell clones. These findings indicate clonally expanded autoreactive B cells with affinity maturation in the peripheral blood in MS and CIS. PMID- 23746374 TI - Sex and gender differences in control of blood pressure. AB - In recent years, the interest in studying the impact of sex steroids and gender on the regulation of blood pressure and cardiovascular disease has been growing. Women are protected from most cardiovascular events compared with men until after menopause, and postmenopausal women are at increased risk of cardiovascular complications compared with premenopausal women. The pathophysiological mechanisms have not been elucidated, but are not likely to be as simple as the presence or absence of oestrogens, since hormone replacement therapy in elderly women in the Women's Health Initiative or HERS (Heart and Estrogen/progestin Replacement Study) did not provide primary or secondary prevention against cardiovascular events. Men are also thought to be at risk of cardiovascular disease at earlier ages than women, and these mechanisms too are not likely to be as simple as the presence of testosterone, since androgen levels fall in men with cardiovascular and other chronic diseases. In fact, many investigators now believe that it is the reduction in androgen levels that frequently accompanies chronic disease and may exacerbate cardiovascular disease in men. In the present review, the roles of sex steroids and gender in mediating or protecting against hypertension and cardiovascular disease will be discussed. PMID- 23746375 TI - Potential of cardiac stem/progenitor cells and induced pluripotent stem cells for cardiac repair in ischaemic heart disease. AB - Stem cell therapy has emerged as a promising strategy for cardiac and vascular repair. The ultimate goal is to rebuild functional myocardium by transplanting exogenous stem cells or by activating native stem cells to induce endogenous repair. CS/PCs (cardiac stem/progenitor cells) are one type of adult stem cell with the potential to differentiate into cardiac lineages (cardiomyocytes, smooth muscle cells and endothelial cells). iPSCs (induced pluripotent stem cells) also have the capacity to differentiate into necessary cells to rebuild injured cardiac tissue. Both types of stem cells have brought promise for cardiac repair. The present review summarizes recent advances in cardiac cell therapy based on these two cell sources and discusses the advantages and limitations of each candidate. We conclude that, although both types of stem cells can be considered for autologous transplantation with promising outcomes in animal models, CS/PCs have advanced more in their clinical application because iPSCs and their derivatives possess inherent obstacles for clinical use. Further studies are needed to move cell therapy forward for the treatment of heart disease. PMID- 23746376 TI - Association between estimated GFR, health-related quality of life, and depression among older adults with diabetes: the Diabetes and Aging Study. AB - BACKGROUND: Although chronic kidney disease (CKD) is a highly prevalent condition among older adults with diabetes, the associations between health-related quality of life (HRQoL) and severity of CKD in this population are not well understood. The objective of this study was to assess HRQoL and depressive symptoms across estimated glomerular filtration rate (eGFR) stages. STUDY DESIGN: Cross sectional. SETTING & PARTICIPANTS: 5,805 members of Kaiser Permanente Northern California, 60 years or older with diabetes, from the 2005-2006 Diabetes Study of Northern California (DISTANCE) survey. PREDICTOR: eGFR categories were defined as >=90 (referent category), 75-89, 60-74, 45-59, 30-44, or <=29 mL/min/1.73 m(2). OUTCOMES: HRQoL was measured using the modified Short Form-8 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. Depressive symptoms were measured using the Patient Health Questionnaire-8. RESULTS: In unadjusted linear regression analyses, physical (PCS) and mental (MCS) HRQoL scores were significantly lower with worsening eGFR level. However, after adjustment for sociodemographics, diabetes duration, obesity, and cardiovascular comorbid conditions and taking into account interactions with proteinuria, none of the eGFR categories was significantly or substantively associated with PCS or MCS score. In both unadjusted and adjusted analyses, higher risk of depressive symptoms was observed in respondents with eGFR <=29 mL/min/1.73 m(2) (relative risk, 2.02; 95% CI, 1.10-3.71; P < 0.05) compared with the referent group. However, this eGFR-depression relationship was no longer significant after adjusting for hemoglobin level. LIMITATIONS: Participants are part of a single health care delivery system. CONCLUSIONS: Our findings suggest the need for greater attention to and potential interventions for depression in patients with reduced eGFR. PMID- 23746377 TI - Efficacy and safety of pegylated interferon alfa-2b and ribavirin combination therapy versus pegylated interferon monotherapy in hemodialysis patients: a comparison of 2 sequentially treated cohorts. AB - BACKGROUND: Pegylated interferon (peginterferon; interferon with an attached polyethylene glycol molecule) monotherapy is the recommended treatment for chronic hepatitis C virus (HCV) infection in hemodialysis patients. Limited data concerning peginterferon alfa-2b and ribavirin treatment in this population are available. STUDY DESIGN: 2 prospective observational cohort studies. SETTING & PARTICIPANTS: From 2007-2009, a total of 26 patients received peginterferon alfa 2b monotherapy. From 2009-2012, an additional 26 patients were treated with peginterferon alfa-2b and ribavirin. PREDICTORS: Peginterferon alfa-2b monotherapy, 1.0 MUg/kg/wk, versus peginterferon alfa-2b, 1.0 MUg/kg/wk, and ribavirin, 200 mg, 3 times per week. Treatment durations were 24 and 48 weeks for HCV genotypes non-1 and 1, respectively. OUTCOMES & MEASUREMENTS: End-of treatment virologic response and sustained virologic response (SVR) were undetectable HCV RNA at the end of treatment and 24 weeks after treatment ended, respectively. SVR and treatment-related withdrawal rate were evaluated by intention-to-treat (ITT) and per-protocol (PP) analyses. Severe anemia was defined as nadir hemoglobin level <8 g/dL. RESULTS: Patients who received combination therapy had a higher end-of-treatment virologic response than patients who received monotherapy (85% vs 62% in ITT [P = 0.03] and 100% vs 80% in PP [P = 0.03]). The SVR rate was higher in the combination-treatment cohort than in the monotherapy cohort (62% vs 27% in ITT [P = 0.01] and 73% vs 35% in PP [P = 0.01]). Patients who received combination therapy had a significantly higher rate of severe anemia than those who received monotherapy (58% vs 27%; P = 0.03). However, treatment withdrawal rates were similar between the combination (15%) and monotherapy (23%) groups. LIMITATIONS: Comparison of 2 sequential cohorts rather than a randomized control study. CONCLUSIONS: Peginterferon alfa-2b and ribavirin combination therapy provided a higher SVR rate than peginterferon alfa 2b monotherapy for treatment-naive dialysis patients with chronic HCV infection through careful monitoring of hematologic parameters and ribavirin dose modification. Severe anemia was significantly higher in patients receiving combination therapy than patients treated with monotherapy. PMID- 23746378 TI - Atrial fibrillation in CKD: balancing the risks and benefits of anticoagulation. AB - Chronic kidney disease (CKD) and atrial fibrillation are common conditions that often coexist and are associated with increased risk of stroke. Despite the wealth of evidence for optimal management of atrial fibrillation in the general population, the role of anticoagulation with warfarin in individuals with CKD with atrial fibrillation is far less well defined. Current recommendations for anticoagulation in patients treated with dialysis and those with an earlier stage of CKD are based on clinical trials in the general atrial fibrillation population that have largely excluded individuals with CKD. Observational studies of anticoagulation in dialysis patients have produced conflicting results, mainly because of increased risk of bleeding. This, together with warfarin's potential adverse effects on ectopic/vascular calcification and progression of CKD, may result in negating the benefits associated with anticoagulation in the general population. With the recent emergence of novel oral anticoagulants, there is an urgent need for a better understanding of the complex inter-relationship among CKD, atrial fibrillation, stroke, and bleeding risk. This knowledge is paramount to optimize the potential benefits of treatment and minimize the potential harms in this very high-risk and growing population. PMID- 23746379 TI - Correlation of pre-existing vascular pathology with arteriovenous graft outcomes in hemodialysis patients. AB - BACKGROUND: Arteriovenous grafts (AVGs) are prone to neointimal hyperplasia leading to AVG failure. We hypothesized that pre-existing pathologic abnormalities of the vessels used to create AVGs (including venous intimal hyperplasia, arterial intimal hyperplasia, arterial medial fibrosis, and arterial calcification) are associated with inferior AVG survival. STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: Patients with chronic kidney disease undergoing placement of a new AVG at a large medical center who had vascular specimens obtained at the time of surgery (n = 76). PREDICTOR: Maximal intimal thickness of the arterial and venous intima, arterial medial fibrosis, and arterial medial calcification. OUTCOME & MEASUREMENTS: Unassisted primary AVG survival (time to first intervention) and frequency of AVG interventions. RESULTS: 55 patients (72%) underwent interventions and 148 graft interventions occurred during 89.9 years of follow-up (1.65 interventions per graft-year). Unassisted primary AVG survival was not associated significantly with arterial intimal thickness (HR, 0.72; 95% CI, 0.40-1.27; P = 0.3), venous intimal thickness (HR, 0.64; 95% CI, 0.37-1.10; P = 0.1), severe arterial medial fibrosis (HR, 0.58; 95% CI, 0.32-1.06; P = 0.6), or severe arterial calcification (HR, 0.68; 95% CI, 0.37-1.31; P = 0.3). The frequency of AVG interventions per year was associated inversely with arterial intimal thickness (relative risk [RR], 1.99; 95% CI, 1.16-3.42; P < 0.001 for thickness <10 vs. >25 MUm), venous intimal thickness (RR, 2.11; 95% CI, 1.39-3.20; P < 0.001 for thickness <5 vs. >10 MUm), arterial medial fibrosis (RR, 3.17; 95% CI, 1.96-5.13; P < 0.001 for fibrosis <70% vs. >=70%), and arterial calcification (RR, 2.12; 95% CI, 1.31 3.43; P = 0.001 for <10% vs. >=10% calcification). LIMITATIONS: Single-center study. Study may be underpowered to demonstrate differences in unassisted primary AVG survival. CONCLUSIONS: Pre-existing vascular pathologic abnormalities in patients with chronic kidney disease may not be associated significantly with unassisted primary AVG survival. However, vascular intimal hyperplasia, arterial medial fibrosis, and arterial calcification may be associated with a decreased frequency of AVG interventions. PMID- 23746381 TI - Effect of glycemic index and glycemic load on energy intake in children. AB - OBJECTIVE: Several studies assessed the effect of glycemic index (GI) and glycemic load (GL) on energy intake in children but findings are not consistent in this regard. The aim of this study is to summarize and assess the evidence for the effect of GI and GL on energy intake by conducting a meta-analysis on published randomized clinical trials. METHOD: Our search process was conducted in PUBMED, Web of Science, and Google Scholar databases. The following keywords were searched in any part of published articles: "glycemic index" OR "glycaemic index" OR "glycemic load" OR "glycaemic load" OR "energy intake" AND "child" OR "children" OR "adolescent" OR "youth." RESULTS: We gathered 5099 articles. Non clinical trial studies that did not intervene by GI or GL or those not assessing energy intake as a dependent variable and those that were conducted on patients over age 18 y were excluded. Each included study was evaluated three times and the exclusion criteria was checked. Eventually, six studies from 1999 to 2012 met the criteria (213 participants ages 4-17.5 y). There is heterogeneity in the study's participants in the present paper. Children with type 2 diabetes, obesity, or normal-weight children were recruited in different studies. Overall effect of consuming low GI (LGI) and low GL (LGL) meals on energy intake was not significant. Subgroup analysis showed that LGI (not LGL) meals decreased subsequent energy intake, whereas heterogeneity was significant in the LGI group of studies. Although a slight asymmetry was shown by Begg's funnel plot, the Egger's asymmetry was not significant. We did not find any evidence of publication bias for studies assessing the effect of low GI or GL meals on energy intake. CONCLUSION: Consuming LGI diet (not LGL) has favorable effect on reducing energy intake and obesity, subsequently. PMID- 23746382 TI - Patient selection and pathological outcomes using currently available active surveillance criteria. AB - OBJECTIVES: To establish the rate of higher risk criteria in various definitions of an active surveillance population. PATIENTS AND METHODS: Over a period of 10 years, 1161 patients were diagnosed with prostate cancer and underwent radical prostatectomy at our institution. Statistical analysis was performed comparing the rates of upgrading, extracapsular extension, seminal vesical involvment and unfavourable disease (Gleason score upgrading >6 and/or T3 disease) for six groups of patients eligible for the University of Toronto, Royal Marsden, John Hopkins, University of California San Francisco, Memorial Sloan Kettering Cancer Center and Prospective Randomized International Active Surveillance. RESULTS: Active surveillance protocols including patients with biopsy Gleason score 3+4 (Royal Marsden) had significantly higher rates of extracapsular extension (P = 0.009), upgrading to pathological Gleason >3+4 (P = 0.004) and unfavourable disease (P = 0.001) compared to the most stringent John Hopkins criteria. Unfavourable disease was found in more than 40% of patients in all series with no significant difference between the Gleason 6 protocols. Biochemical recurrence free survival at 5 and 10 years was 76.7% and 63.3% for the entire cohort. Positive margins (P < 0.001), pT3 tumours (P = 0.006) and unfavourable disease (P < 0.001) were significant predictors of biochemical recurrence. CONCLUSIONS: Active surveillance in patients with Gleason 3+4 presents a risk of missing unfavourable disease and should be limited to older patients with comorbidities. The differences in inclusion criteria between Gleason 6 protocols did not have a significant impact on the pathological results. PMID- 23746380 TI - Recent evidence for rapid synthesis and action of oestrogens during auditory processing in a songbird. AB - It is now clear that oestrogens are not only circulating reproductive hormones, but that they also have neurotransmitter-like properties in a wide range of brain circuits. The view of oestrogens as intrinsic neuromodulators that shape behaviour has been bolstered by a series of recent developments from multiple vertebrate model systems. Here, we review several recent findings from studies of songbirds showing how the identified neural circuits that govern auditory processing and sensorimotor integration are modulated by the local and acute production of oestrogens. First, studies using in vivo microdialysis demonstrate that oestrogens fluctuate in the auditory cortex (30-min time bin resolution) when songbirds are hearing song and interacting with conspecifics. Second, oestrogens rapidly boost the auditory-evoked activity of neurones in the same auditory cortical region, enhancing auditory processing. Third, local pharmacological blockade of oestrogen signalling in this region impairs auditory neuronal responsiveness, as well as behavioural song preferences. Fourth, the rapid actions of oestrogens that occur within the auditory cortex can propagate downstream (trans-synaptically) to sensorimotor circuits to enhance the neural representation of song. Lastly, we present new evidence showing that the receptor for the rapid actions of oestradiol is likely in neuronal membranes, and that traditional nuclear oestrogen receptor agonists do not mimic these rapid actions. Broadly speaking, many of these findings are observed in both males and females, emphasising the fundamental importance of oestrogens in neural circuit function. Together, these and other emergent studies provide support for rapid, brain derived oestrogen signalling in regulating sensorimotor integration, learning and perception. PMID- 23746383 TI - Automated subtraction CT angiography for visualization of the whole brain vasculature: a feasibility study. AB - RATIONALE AND OBJECTIVES: To develop an automated computed tomography angiography (CTA) imaging protocol that allows visualization of the whole brain vasculature and evaluate the clinical usefulness of the technique for delineation of intracranial vessels in patients with cerebrovascular disorders. MATERIALS AND METHODS: We prospectively included 100 patients who underwent automated subtraction CTA for suspected cerebrovascular disorders. The nonenhanced and contrast enhanced scans were obtained with the same table feeding speed. The x ray tube start angles of the two scans were matched to enable accurate registration and subtraction of the CTA datasets. Subtracted CTA datasets were reformatted as three-dimensional volume rendering and maximum intensity projection images for further review. Two independent readers assessed the quality of subtraction and delineation of intracranial vessels. The visibility of ophthalmic arteries was also assessed. RESULTS: Subtraction was successful in all patients. The image quality of bone removal was rated excellent in 95 patients, with no or minimal bone remnants. Incomplete bone removal was observed in five patients because of severe motions between the scans. In 97 of 100 patients, arterial segments at the circle of Willis could be clearly visualized. Excellent delineation of bilateral ophthalmic arteries was possible in 81 of 100 patients. CONCLUSIONS: The whole brain vasculature would be clearly visualized by using the optimized automated CTA protocol. Our automated, single-source, dual-energy subtraction CTA protocol is a fully automated subtraction method that is capable of delineating major intracranial vessels as well as very small arteries. PMID- 23746384 TI - Clinical value of T2-weighted imaging combined with diffusion-weighted imaging in preoperative T staging of urinary bladder cancer: a large-scale, multiobserver prospective study on 3.0-T MRI. AB - RATIONALE AND OBJECTIVES: To prospectively assess the incremental value of diffusion-weighted imaging (DWI) combined with T2-weighted images (T2WI) in determining the T stage of bladder cancer by using pathologic findings as the reference standard. MATERIALS AND METHODS: This study is approved by the institutional review board; informed consent was waived. The study includes 362 patients (age range, 48-87 years; mean, 71 years) who underwent 3.0-T magnetic resonance imaging and histologic examination. Three observers with varying experience levels reviewed the T2WI data alone, DWI data alone, and combined T2WI and DWI data. Sensitivity, specificity, accuracy, and area under curve (AUC) were determined with the Z test after adjusting for data clustering. RESULTS: For differentiating Tis to T1 tumors from T2 to T4 tumors, the AUCs for T2WI and DWI (0.97 for observer 1 and 0.96 for observer 2) were greater than those for the DWI alone (0.92 for observer 1 and 0.90 for observer 2) (P < .05). Observer 3 had similar AUCs for T2WI and DWI compared to DWI alone. The accuracy of T2WI and DWI (observer 1, 98%; observer 2, 96%; observer 3, 92%) was greater than that of DWI alone (observer 1, 92%; observer 2, 90%; observer 3, 87%) for all observers (P < .05). The specificity of T2WI and DWI (observer 1, 100%; observer 2, 98%; observer 3, 93%) was greater than that of DWI alone (observer 1, 92%; observer 2, 90%; observer 3, 87%) for all observers (P < .05). Sensitivity was not improved even when T2WI and DWI were used. For differentiating Tis to T2 Tumors from T3 to T4 Tumors, the overall accuracy, specificity, and AUC for diagnosing T2 or higher stages were not significantly improved by combiningT2WI and DWI. CONCLUSIONS: T2WI combined with DWI can be a reliable sequence for preoperative evaluation of T stage urinary bladder cancer. It is particularly more useful in differentiating T1 or lower tumors from T2 or higher tumors compared to DWI alone. PMID- 23746385 TI - SiOC glasses produced from silsesquioxanes by the aerosol-assisted vapor synthesis method. AB - In this paper, we describe a new method based on aerosol-assisted vapor synthesis for making glass materials by pyrolysis of readily available silsesquioxanes CH3Si(OCH3)3 and CH3Si(OC2H5)3. Combined powder X-ray diffraction (XRD) and spectroscopic studies in the far infrared region (FIR) showed that under applied conditions the method yielded amorphous materials. Subsequent structural studies with the application of the (29)Si and (13)C MAS NMR, Raman, and middle infrared (MIR) techniques led to the conclusion that the pyrolysis of the silsesquioxane precursors resulted in glass materials with a structure of amorphous silica v SiO2. In the case of certain glasses prepared from CH3Si(OCH3)3, they were also shown to possess in the structure some Si-C bonds (black glasses), whereas those originated from CH3Si(OC2H5)3 were composites that in addition to the silica glass phase contained domains of free/unbound carbon. PMID- 23746386 TI - Disseminated sporotrichosis with cutaneous and testicular involvement. PMID- 23746387 TI - Myochondromucosal rotation flap combined with a melolabial transposition flap for the reconstruction of full-thickness defects of the ala nasi. PMID- 23746388 TI - Growth and photosynthetic responses to copper in wild grapevine. AB - The present study evaluates the tolerance and accumulation potential of Vitis vinifera ssp. sylvestris under moderate and high external Cu levels. A greenhouse experiment was conducted in order to investigate the effects of a range of external Cu concentrations (0-23mmolL(-1)) on growth and photosynthetic performance by measuring gas exchange, chlorophyll fluorescence parameters and photosynthetic pigments. We also measured the total copper, nitrogen, phosphorus, sulphur, calcium, magnesium, iron, potassium and sodium concentrations in the plant tissues. All the experimental plants survived even with external Cu concentrations as high as 23mmolL(-1) (1500mg Cu L(-1)), although the excess of metal resulted in a biomass reduction of 35%. The effects of Cu on growth were linked to a reduction in net photosynthesis, which may be related to the effect of the high concentration of the metal on photosynthetic electron transport. V. vinifera ssp. sylvestris survived with leaf Cu concentrations as high as 80mgkg( 1) DW and growth parameters were unaffected by leaf tissue concentrations of 35mg Cu kg(-1) DW. The results of our study indicate that plants of V. vinifera ssp. sylvestris from the studied population are more tolerant to Cu than the commercial varieties of grapevine that have been studied in the literature, and could constitute a basis for the genetic improvement of Cu tolerance in grapevine. PMID- 23746389 TI - Influence of oxidation on fulvic acids composition and biodegradability. AB - Oxidation is well-known process of transforming natural organic matter during the treatment of drinking water. Chlorine, ozone, and chlorine dioxide are common oxidants used in water treatment technologies for this purpose. We studied the influence of different doses of these oxidants on by-products formation and changes in biodegradable dissolved organic carbon (BDOC) and molecular weight distribution (MWD) of fulvic acids (FA) with different BDOC content. Chlorination did not significantly change the MWD of FA and disinfection by-products formation. However, higher molecular weight compounds, than those in the initial FA, were formed. It could be a result of chlorine substitution into the FA structure. Chlorine dioxide oxidized FA stronger than chlorine. During ozonation of FA, we found the highest increase of BDOD due to the formation of a high amount of organic acids and aldehydes. FA molecules were transformed into a more biodegradable form. Ozonation is the most preferable process among those observed for pre-treatment of FA before biofiltration. PMID- 23746390 TI - The effect of oil sands process-affected water and naphthenic acids on the germination and development of Arabidopsis. AB - Oil sands mining in the Athabasca region of northern Alberta results in the production of large volumes of oil sands process-affected water (OSPW). We have evaluated the effects of OSPW, the acid extractable organic (AEO) fraction of OSPW, and individual naphthenic acids (NAs) on the germination and development of the model plant, Arabidopsis thaliana (Arabidopsis). The surrogate NAs that were selected for this study were petroleum NAs that have been used in previous toxicology studies and may not represent OSPW NAs. A tricyclic diamondoid NA that was recently identified as a component of OSPW served as a model NA in this study. Germination of Arabidopsis seeds was not inhibited when grown on medium containing up to 75% OSPW or by 50mgL(-1) AEO. However, simultaneous exposure to three simple, single-ringed surrogate NAs or a double-ringed surrogate NA had an inhibitory effect on germination at a concentration of 10mgL(-1), whereas inhibition of germination by the diamondoid model NA was observed only at 50mgL( 1). Seedling root growth was impaired by treatment with low concentrations of OSPW, and exposure to higher concentrations of OSPW resulted in increased growth inhibition of roots and primary leaves, and caused bleaching of cotyledons. Treatment with single- or double-ringed surrogate NAs at 10mgL(-1) severely impaired seedling growth. AEO or diamondoid NA treatment was less toxic, but resulted in severely impaired growth at 50mgL(-1). At low NA concentrations there was occasionally a stimulatory effect on root and shoot growth, possibly owing to the broad structural similarity of some NAs to known plant growth regulators such as auxins. This report provides a foundation for future studies aimed at using Arabidopsis as a biosensor for toxicity and to identify genes with possible roles in NA phytoremediation. PMID- 23746391 TI - Effects of antagonists of glutamate receptors on pro-inflammatory cytokines in the brain cortex of rats subjected to experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Inflammatory cytokines and glutamate neurotoxicity have been proposed as major determinants accompanying the demyelination and axonal degeneration observed during the course of MS. The present study using the animal model of MS known as experimental autoimmune encephalomyelitis (EAE) demonstrates that pharmacological inhibition of ionotropic NMDA glutamate receptors by their antagonists (amantadine and memantine) suppresses neurological symptoms of disease in EAE rats and reduces expression of pro-inflammatory cytokines in the brain. Conversely, antagonists of group I metabotropic glutamate receptors, mGluRs (LY 367385 and MPEP), do not affect the inflammatory process and the neurological condition of EAE rats. PMID- 23746392 TI - Long backboard versus vacuum mattress splint to immobilize whole spine in trauma victims in the field: a randomized clinical trial. AB - INTRODUCTION: Patients with possible spinal injury must be immobilized properly during transport to medical facilities. The aim of this research was comparing spinal immobilization using a long backboard (LBB) with using a vacuum mattress splint (VMS) in trauma victims transported by an Emergency Medical Services (EMS) system. METHODS: In this randomized clinical trial, 60 trauma victims with possible spinal trauma were divided to two groups, each group immobilized with one of the two instruments. Speed and ease of application, immobilization rate, and the patients' comfort were recorded. RESULTS: In this survey, LBB was faster to apply: 211.66 (SD = 28.53) seconds vs 654.00 (SD = 16.61) seconds. Various measures of immobilization were better by LBB. Also, LBB offered a significant improvement in comfort over a VMS for the patient with possible spinal injury. All of the results were statistically significant. CONCLUSION: The results of this study showed that immobilization using LBB was easier, faster, and more comfortable for the patient, and provided additional decrease in spinal movement when compared with a VMS. PMID- 23746394 TI - Sleep, its regulation and possible mechanisms of sleep disturbances. AB - The state of sleep consists of different phases that proceed in successive, tightly regulated order through the night forming a physiological program, which for each individual is different but stabile from one night to another. Failure to accomplish this program results in feeling of unrefreshing sleep and tiredness in the morning. The program core is constructed by genetic factors but regulated by circadian rhythm and duration and intensity of day time brain activity. Many environmental factors modulate sleep, including stress, health status and ingestion of vigilance-affecting nutrients or medicines (e.g. caffeine). Acute sleep loss results in compromised cognitive performance, memory deficits, depressive mood and involuntary sleep episodes during the day. Moreover, prolonged sleep curtailment has many adverse health effects, as evidenced by both epidemiological and experimental studies. These effects include increased risk for depression, type II diabetes, obesity and cardiovascular diseases. In addition to voluntary restriction of sleep, shift work, irregular working hours, jet lag and stress are important factors that induce curtailed or bad quality sleep and/or insomnia. This review covers the current theories on the function of normal sleep and describes current knowledge on the physiologic effects of sleep loss. It provides insights into the basic mechanisms of the regulation of wakefulness and sleep creating a theoretical background for understanding different disturbances of sleep. PMID- 23746393 TI - [Adaptation and validation of the Spanish version of the Pain Evaluation Scale in patients with advanced dementia: PAINAD-Sp]. AB - INTRODUCTION: Pain in elderly people is considered a major concern in nursing home facilities affecting between 49% and 83% of the residents. Progression of Alzheimer's Disease causes more communication difficulties in patients with advanced dementia and therefore more problems to understand even the most simple pain evaluation scales. Identification and implementation of appropriate pain management strategies depends on an adequate pain assessment. MATERIAL AND METHODS: The main objective of the study was to validate the Spanish version of the PAINAD Scale (PAINAD-Sp) and to assess its applicability in Spanish Geriatric Nursing Homes. The 20 patients diagnosed with severe dementia from a Geriatric Centre in Spain were observed by five observers with different professional profiles for 5 minutes to each participant, and PAINAD-Sp Scale was administered simultaneously to a Visual Analogical Scale-VAS. Three different observational conditions were established: resting condition, during presumably pleasant activity and during presumable painful activity. RESULTS: Cronbach's alpha ranged between 0.467 and 0.827 (average 0.692), and rose if Breathing item was deleted. Inter-rater reliability ranged between 0.587 and 0.956. Correlation between PAINAD-Sp Scale total measures and VAS was statistically significant (P<.05) in all measures and ranged from 0.517 to 0.868. CONCLUSIONS: Findings in the study showed that the scale is useful to measure pain in non communicative patients suffering from dementia. The scale maintains good levels of reliability for different healthcare professionals even when they have little training. PMID- 23746395 TI - Giant pseudoaneurysm of the left ventricular outflow tract: a rare disease. AB - Pseudoaneurysm of the left ventricular outflow tract (LVOT) is a rare disease with high morbidity and mortality, resulting from left ventricular damage due to myocardial infarction, infective endocarditis or surgical trauma. A case of giant pseudoaneurysm of the LVOT, even more rarely reported in the literature, is described. The lesion was detected 12 years after aortic valve replacement for infective endocarditis in a young patient, a former intravenous drug user. As it is an uncommon disease, little is known about its clinical presentation and treatment. PMID- 23746396 TI - Diagnostic yield of current referral strategies for elective coronary angiography in suspected coronary artery disease-an analysis of the ACROSS registry. AB - INTRODUCTION AND OBJECTIVES: The purpose of this study was to assess the diagnostic yield of current referral strategies for elective invasive coronary angiography (ICA). METHODS: We performed a cross-sectional observational study of consecutive patients without known coronary artery disease (CAD) undergoing elective ICA due to chest pain symptoms. The proportion of patients with obstructive CAD (defined as the presence of at least one >=50% stenosis on ICA) was determined according to the use of noninvasive testing. RESULTS: The study population consisted of 1892 individuals (60% male, mean age 64+/-11 years), of whom 1548 (82%) had a positive noninvasive test: exercise stress test (41%), stress myocardial perfusion imaging (36%), stress echocardiogram (3%) or coronary computed tomography angiography (3%). Referral without testing occurred in 18% of patients. The overall prevalence of obstructive CAD was 57%, higher among those with previous testing (58% vs. 51% without previous testing, p=0.026) and when anatomic rather than functional tests were used (81.3% vs. 57.1%, p=0.001). A positive test and conventional risk factors were all independent predictors of obstructive CAD, with adjusted odds ratios (95% confidence interval) of 1.34 (1.03-1.74) for noninvasive testing, 1.05 (1.04-1.06) for age, 3.48 (2.81-4.29) for male gender, 1.86 (1.32-2.62) for current smoking, 1.74 (1.38-2.20) for diabetes, 1.30 (1.04-1.62) for hypercholesterolemia, and 1.39 (1.08-1.80) for hypertension. CONCLUSIONS: More than 40% of patients without known CAD undergoing elective ICA did not have obstructive lesions, even though four out of five had a positive noninvasive test. These exams were relatively weak gatekeepers; functional tests were more often used but appeared to be outperformed by the anatomic test. PMID- 23746397 TI - Semiconstrained total elbow arthroplasty for posttraumatic arthritis or deformities of the elbow: a prospective study. AB - PURPOSE: To report the short-term results for posttraumatic total elbow arthroplasty. METHODS: We included patients presenting to our hospital with symptomatic chronic posttraumatic arthritis or deformities of the elbow, aged 55 to 90 years. All patients had reconstruction with a Coonrad-Morrey prosthesis. We performed clinical follow-up after 2, 6, 12, 24, and 36 months, consisting of physical examination, standard radiographs, and calculation of the Mayo elbow performance index. RESULTS: A total of 17 patients were enrolled in this study and had a mean follow-up of 32 months. Mean preoperative flexion arc was 67 degrees and 105 degrees postoperatively. The mean preoperative Mayo elbow performance index score was 54 (range, 30-80) and improved to a postoperative score of 93 (range, 60-100). We encountered 6 complications in 5 patients. Four complications required surgical intervention and 2 minor complications were treated noninvasively. CONCLUSIONS: Short-term functional outcomes after total elbow arthroplasty in this prospective cohort of patients with posttraumatic arthritis or deformities of the elbow were good according to mean postoperative measurements. PMID- 23746398 TI - Effect of capitate morphology on contact biomechanics after proximal row carpectomy. AB - PURPOSE: Proximal row carpectomy (PRC) is used as a treatment for a variety of wrist pathologies to maintain motion and to improve strength and decrease pain. Several studies have looked at how PRC alters wrist characteristics, although they did not provide an explanation for the variability observed in outcomes. Studies have classified the capitate into 3 unique types: round, V-shaped, or flat. We hypothesized that these differences in morphology could affect the contact biomechanics between the radius and the capitate after PRC. METHODS: A total of 14 cadaveric wrists underwent PRC. They were classified by capitate morphology and then loaded to 200 N in a neutral position, flexion, and extension. We measured contact area, contact pressure, and location using pressure-sensitive film in all 3 positions and compared their morphology types. RESULTS: Nine wrists had a round-type capitate, 4 had a V-shaped capitate, and 1 had a flat capitate, which we excluded from statistical analysis. Comparing round and V-shaped types, we found no differences in contact area, pressure, or location in any wrist position For the V-shaped capitates, there was increased contact pressure in flexion and extension compared with the wrist in neutral. Center of pressure translated dorsal and radial in flexion to volar and ulnar in extension for all types. CONCLUSIONS: When we compared V-shaped and round-type capitates, we found no significant differences in contact characteristics of the wrist after PRC. There were some differences in contact pressure for V-shaped capitates in various wrist positions. CLINICAL RELEVANCE: Differences between round and V-shaped capitates do not appear to affect contact biomechanics after PRC. Thus, these 2 capitate shapes may not necessarily be a factor in the decision-making process to perform PRC. PMID- 23746399 TI - Enhanced OH radical generation by dual-frequency ultrasound with TiO2 nanoparticles: its application to targeted sonodynamic therapy. AB - The present study demonstrated the enhanced hydroxyl (OH) radical generation by combined use of dual-frequency (0.5 MHz and 1 MHz) ultrasound (US) and titanium dioxide (TiO2) nanoparticles (NPs) as sonocatalyst. The OH radical generation became the maximum, when 0.5 MHz US was irradiated at an intensity of 0.8 W/cm(2) and 1 MHz US was irradiated at intensities at 0.4 W/cm(2) in the presence of TiO2 NPs under the examined conditions. After incorporation of TiO2 NPs modified with targeting protein pre-S1/S2, HepG2 cancer cells were subjected to the dual frequency US at optimum irradiation intensities ("targeted-TiO2/dual-US treatment"). Growth of the HepG2 cells was reduced by 46% compared with the control condition after irradiation of dual-frequency US for 60s with TiO2 NPs incorporation. In contrast, HepG2 cell growth was almost the same as that in the control condition when cells were irradiated with either 0.5 MHz or 1 MHz ultrasound alone without TiO2 NP incorporation. PMID- 23746400 TI - Hydatid cyst. PMID- 23746401 TI - Increase in PI3K signalling mimics mutated-Kras induction of pancreatic cancer. PMID- 23746402 TI - Application of carbon-based nanomaterials in sample preparation: a review. AB - In this paper, a broad overview on the applications of different carbon-based nanomaterials, including nanodiamonds, fullerenes, carbon nanotubes, graphene, carbon nanofibers, carbon nanocones-disks and nanohorns, as well as their functionalized forms, in sample preparation is provided. Particular attention has been paid to graphene because many papers regarding its application in this research field are becoming available. The distinctive properties, derivatization methods and application techniques of these materials were summarized and compared. According to their research status and perspective, these nanomaterials were classified in four groups (I: graphene and carbon nanotubes; II: carbon nanofibers; III: fullerenes; and IV: nanodiamonds, carbon nanocones/disks and carbon nanohorns) and characteristics and future trends of every group were discussed. PMID- 23746403 TI - Disposable amperometric magnetoimmunosensor for the sensitive detection of the cardiac biomarker amino-terminal pro-B-type natriuretic peptide in human serum. AB - A novel amperometric magnetoimmunosensor using an indirect competitive format is developed for the sensitive detection of the amino-terminal pro-B-type natriuretic peptide (NT-proBNP). The immunosensor design involves the covalent immobilization of the antigen onto carboxylic-modified magnetic beads (HOOC-MBs) activated with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) and N hydroxysulfosuccinimide (sulfo-NHS), and further incubation in a mixture solution containing variable concentrations of the antigen and a fixed concentration of an HRP-labeled detection antibody. Accordingly, the target NT-proBNP in the sample and that immobilized on the MBs compete for binding to a fixed amount of the specific HRP-labeled secondary antibody. The immunoconjugate-bearing MBs are captured by a magnet placed under the surface of a disposable gold screen-printed electrode (Au/SPE). The amperometric responses measured at -0.10 V (vs. a Ag pseudo-reference electrode), upon addition of 3,3',5,5'-tetramethylbenzidine (TMB) as electron transfer mediator and H2O2 as the enzyme substrate, are used to monitor the affinity reaction. The developed magnetoimmunosensor provides attractive analytical characteristics in 10-times diluted human serum samples, exhibiting a linear range of clinical usefulness (0.12-42.9 ng mL(-1)) and a detection limit of 0.02 ng mL(-1), which can be used in clinical diagnosis of chronic heart failure in the elderly and for classifying patients at risk of death after heart transplantation. The magnetoimmunosensor was successfully applied to the analysis of spiked human serum samples. PMID- 23746404 TI - Direct tandem mass spectrometry for the simultaneous assay of opioids, cocaine and metabolites in dried urine spots. AB - A micro-analytical method based on spotting urine samples (20MUL) onto blood/urine spot collection cards followed by air-drying and extraction (dried urine spot, DUS) was developed and validated for the screening/confirmation assay of morphine, 6-methylacetylmorphine (6-MAM), codeine, cocaine and benzoylecgonine (BZE). Acetonitrile (3 mL) was found to be a useful solvent for target extraction from DUSs under an orbital-horizontal stirring at 180 rpm for 10 min. Determinations were performed by direct electrospray ionization tandem mass spectrometry (ESI-MS/MS) under positive electrospray ionization conditions, and by using multiple reaction monitoring (MRM) with one precursor ion/product ion transition for the identification and quantification (deuterated analogs of each target as internal standards) of each analyte. The limits of detection of the method were 0.26, 0.94, 1.5, 1.1, and 2.0 ng mL(-1), for cocaine, BZE, codeine, morphine and 6-MAM, respectively; whereas, relative standard deviations of intra- and inter-day precision were lower than 8 and 11%, respectively, and intra- and inter-day analytical recoveries ranged from 94+/-4 to 105+/-3%. The small volume of urine required (20 MUL), combined with the simplicity of the analytical technique makes it a useful procedure for screening/quantifying drugs of abuse. The method was successfully applied to the analysis of urine from polydrug abusers. PMID- 23746405 TI - Determination of isotopic composition of dissolved copper in seawater by multi collector inductively coupled plasma mass spectrometry after pre-concentration using an ethylenediaminetriacetic acid chelating resin. AB - Copper is an essential trace metal that shows a vertical recycled-scavenged profile in the ocean. To help elucidate the biogeochemical cycling of Cu in the present and past oceans, it is important to determine the distribution of Cu isotopes in seawater. However, precise isotopic analysis of Cu has been impaired by the low concentrations of Cu as well as co-existing elements that interfere with measurements by multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). The objective of this study is to develop a simple Cu pre concentration method using Nobias-chelate PA1 resin (Hitachi High Technologies). This extraction followed by anion exchange, allows precise analysis of the Cu isotopic composition in seawater. Using this method, Cu was quantitatively concentrated from seawater and >99.9999% of the alkali and alkaline earth metals were removed. The technique has a low procedural blank of 0.70 ng for Cu for a 2L sample and the precision of the Cu isotopic analysis was +/-0.070/00 (+/-2SD, n=6). We applied this method to seawater reference materials (i.e., CASS-5 and NASS-6) and seawater samples obtained from the northwestern Pacific Ocean. The range of dissolved delta(65)Cu was 0.40-0.680/00. PMID- 23746406 TI - Innovative method for carbon dioxide determination in human postmortem cardiac gas samples using headspace-gas chromatography-mass spectrometry and stable labeled isotope as internal standard. AB - A novel approach to measure carbon dioxide (CO2) in gaseous samples, based on a precise and accurate quantification by (13)CO2 internal standard generated in situ is presented. The main goal of this study was to provide an innovative headspace-gas chromatography-mass spectrometry (HS-GC-MS) method applicable in the routine determination of CO2. The main drawback of the GC methods discussed in the literature for CO2 measurement is the lack of a specific internal standard necessary to perform quantification. CO2 measurement is still quantified by external calibration without taking into account analytical problems which can often occur considering gaseous samples. To avoid the manipulation of a stable isotope-labeled gas, we have chosen to generate in situ an internal labeled standard gas ((13)CO2) on the basis of the stoichiometric formation of CO2 by the reaction of hydrochloric acid (HCl) with sodium hydrogen carbonate (NaH(13)CO3). This method allows a precise measurement of CO2 concentration and was validated on various human postmortem gas samples in order to study its efficiency. PMID- 23746407 TI - Determination of fructose 1,6-bisphosphate using a double-receptor sandwich type fluorescence sensing method based on uranyl-salophen complexes. AB - In this paper, we report a double-receptor sandwich type fluorescence sensing method for the determination of fructose bisphosphates (FBPs) using fructose 1,6 bisphosphate (F-1,6-BP) as a model analyte based on uranyl-salophen complexes. The solid phase receptor is an immobilized uranyl-salophen (IUS) complex which is bound on the surface of glass slides by covalent bonds. The labeled receptor is another uranyl-salophen complex containing a fluorescence group, or uranyl salophen-fluorescein (USF). In the procedure of determining F-1,6-BP in sample solution, F-1,6-BP is first adsorbed on the surface of the glass slide through the coordination reaction of F-1,6-BP with IUS. It then binds USF through another coordination reaction to form a sandwich-type structure of IUS-F-1,6-BP-USF. The amount of F-1,6-BP is detected by the determination of the fluorescence intensity of IUS-F-1,6-BP-USF bound on the glass slide. Under optimal conditions, the linear range for the detection of F-1,6-BP is 0.05-5.0 nmol mL(-1) with a detection limit of 0.027 nmol mL(-1). The proposed method has been successfully applied for the determination of F-1,6-BP in real samples with satisfactory results. PMID- 23746408 TI - Novel high-sensitive fluorescent detection of deoxyribonuclease I based on DNA templated gold/silver nanoclusters. AB - Herein, fluorescent DNA-templated gold/silver nanoclusters (DNA-Au/Ag NCs) are presented as a novel probe for sensitive detection of deoxyribonuclease I (DNase I). The procedure is based on quenching fluorescence of DNA-Au/Ag NCs by DNase I digestion of the DNA (5'-CCCTTAATCCCC-3') template. This decrease in fluorescence intensity permitted sensitive detection of DNase I in a linear range of 0.013-60 MUg mL(-1), with a detection limit of 3 ng mL(-1) at a signal-to-noise ratio of 3. Furthermore, the practicality of this probe for detection of DNase I in human serum and saliva samples was validated, demonstrating its advantages of simplicity, selectivity, sensitivity and low cost. Importantly, satisfactory agreement between results obtained by the fluorescent method described here and high performance liquid chromatography (HPLC) further confirmed the reliability and accuracy of this approach. PMID- 23746409 TI - Arrays on disc for screening and quantification of pollutants. AB - A rapid compact disc based methodology for screening and quantification of organic pollutants in mandarin juices is presented. The assay is established on the coating conjugate indirect competitive principle and developed under disc array configuration. The detection is based on the acquisition of attenuated reflective signals that were proportional to optical density of the immunoreaction product. The competitive assay is applied to quantify simultaneously, in a selective manner, non-systemic insecticides in mandarin juices. The detection limits were 0.2 and 0.1 MUg L(-1) and the sensitivity 2.1 and 1.5 MUg L(-1), for chlorpyrifos and fenthion, respectively. Pollutants were directly quantified after sample dilution in a total time of 40 min. Also, the implementation of positive and negative controls into the array configuration served as an automatic quality control test. The effect of thermal treatment on pesticide dissipation was studied and found that it was insignificant under the studied conditions. Recovery intervals ranged from 96-105% to 94-103%, for chlorpyrifos and fenthion, respectively and were similar to those obtained with gas chromatography coupled to mass spectrometry. In the current configuration, 64 samples can be simultaneously analyzed on a disc at a very competitive value, demonstrating its potential for high-throughput multiplexed screening applications for controlled monitoring programs in low-level labs or outside the lab setting. PMID- 23746410 TI - Determination of fluoroquinolone antibiotics through the fluorescent response of Eu(III) based nanoparticles fabricated by layer-by-layer technique. AB - The present work introduces the determination of fluoroquinolone antibiotics (FQs) in aqueous solutions through the fluorescent response of Eu(TTA)3 and [Eu(TTA)(3)1] (TTA(-) and 1 are thenoyltrifluoroacetonate and phosphine oxide derivative) complexes encapsulated into the polyelectrolyte capsules fabricated through layer-by-layer deposition of poly(sodium 4-styrenesulfonate) (PSS) and polyethyleneimine (PEI). The variation of luminescent core, polyelectrolyte deposition and concentration conditions reveals two modes of fluorescent response on FQs of diverse structure namely the sensitization and quenching of Eu(III) centered luminescence. The obtained regularities reveal the ternary complex formation and the ligand exchange occurring at the interface of polyelectrolyte coated [Eu(TTA)(3)1] based colloids as the reasons of the diverse fluorescent response of Eu(III) centered luminescence on FQs. The factors affecting the fluorescent response have been revealed, which are: the content of luminescent core, the mode of polyelectrolyte deposition, concentration and structure of FQs. The discrimination of moxifloxacin and lomefloxacin from levofloxacin, ofloxacin, difloxacin, perfloxacin through the quenching of Eu(III) luminescence in PSS [Eu(TTA)(3)1] colloids has been revealed. PMID- 23746411 TI - A fluorescence turn-on method for real-time monitoring of protease activity based on the electron transfer between a fluorophore labeled oligonucleotide and cytochrome c. AB - A new continuous fluorescence turn-on assay for protease activity and inhibitor screening has been developed. A fluorophore labeled single stranded DNA (FAM-DNA) and cytochrome c (cyt c) were employed. The fluorescence of the FAM-DNA was efficiently quenched when binding to cyt c, through the electron transfer between the FAM fluorophore and the heme cofactor of cyt c. In the presence of a protease, such as trypsin, cyt c was digested into small peptide fragments. The FAM-DNA was released, which resulted in the recovery of the FAM fluorescence. The rate of the cyt c digestion could be reduced via the addition of an inhibitor. As a result, reduced degree of the fluorescence recovery was obtained. The limit of detection of our assay is 1 nM trypsin and the IC50 values are 3.23 MUg mL(-1) and 0.303 MUg mL(-1) for the inhibitor from egg white and the inhibitor from soybean, respectively. Our method could be used for the sensing of protease activity for various biochemical applications, and for the screening of protease inhibitors as drugs for the treatment of various related diseases. PMID- 23746412 TI - Development of an environment-friendly microextraction method for the determination of aliphatic and aromatic aldehydes in water. AB - Aldehydes are produced in water disinfected primarily by ozone treatment, and are generally present in treated water below the limit of detection (<5 MUg L(-1)) of commonly proposed methods. Formaldehyde is the most studied along with acetaldehyde due to their mutagenic character, and because it causes chromosomal aberrations. This paper reports the first miniaturised system for the simultaneous determination of thirteen aldehydes (aliphatic and aromatic) which are selected based on their frequent or suspected presence in water, mainly as disinfection by-products (DBPs). The micro liquid-liquid extraction (MLLE) method is a miniaturisation of EPA Method 556.1 for carbonyl compounds that includes some innovations, such as performing the derivatising reaction in a strong acidic medium (pH 1.1), and the addition of magnesium sulphate to the aqueous layer as the heating agent, which allows to carry out the whole simultaneous derivatisation/microextraction process in only 1 min. Large-volume sample injection (50 MUL) coupled to programmed temperature vaporiser-gas chromatography mass spectrometry is also used to improve both sensitivity and selectivity. The MLLE method demonstrated high extraction efficiency (96%) with low limits of detection, between 0.7 and 80 ng L(-1), and good precision (RSD below 10%, n=11). The proposed method was evaluated by determining aldehydes in water. Our study demonstrated that the selection of the target aldehydes was appropriate since all were found (at average concentrations from 8.0 to 1.4 MUg L(-1) for aliphatic and aromatic aldehydes, respectively) in swimming pool waters as DBPs. PMID- 23746413 TI - Social connectedness and predictors of successful ageing. AB - OBJECTIVES: As populations age it is important to minimize the time people live in a less than successful state of ageing. Our aim was to identify predictors of successful ageing. STUDY DESIGN: At baseline (1990-1994), demographic, anthropometric, health, social connectedness and behavioural data were collected for 41,514 men and women participating in the Melbourne Collaborative Cohort Study. Only those born in Australia, New Zealand and UK were included in this analysis. At follow-up in 2003-2007 data on health conditions, physical disability and psychological stress were collected and used to define successful ageing. A total of 5512 eligible participants with full data who were aged 70 and over, were included in this longitudinal analysis. OUTCOME MEASURES: Successful ageing at follow-up was defined as aged 70 years or over and absence of diabetes, heart attack, coronary artery bypass graft surgery, angioplasty, stroke, cancer; impairment, perceived major difficulty with physical functioning; and low risk of psychological distress. RESULTS: A body mass index in the healthy range, low waist/hip ratio, not smoking, being physically active, and not having arthritis, asthma, hypertension, or gallstones were associated prospectively with successful ageing. There was no evidence for an association of social connectedness with successful ageing. CONCLUSIONS: A healthy lifestyle and maintenance of healthy weight, but not social connectedness, may improve the chances of ageing successfully by our definition. Social connectedness may be related to a perception of ageing well, but it does not appear to help avoid the usual conditions associated with ageing. PMID- 23746415 TI - Very young age at implantation and eight nerve deficiency: two important and controversial issues in pediatric cochlear implantation. PMID- 23746414 TI - Microbiology of bacteria causing recurrent acute otitis media (AOM) and AOM treatment failure in young children in Spain: shifting pathogens in the post pneumococcal conjugate vaccination era. AB - OBJECTIVE: To prospectively identify the bacterial aetiology and antimicrobial susceptibility of problematic (recurrent and treatment failure) acute otitis media in Spanish children several years after the introduction of 7-valent pneumococcal conjugate vaccine. METHODS: Tympanocentesis or careful sampling of spontaneous otorrhoea was performed on children aged 3 to <36 months with recurrent acute otitis media, acute otitis media treatment failure or unresolved acute otitis media. RESULTS: 105 acute otitis media episodes (77 sampled by tympanocentesis, 28 otorrhoea samples) were evaluated: 46 recurrent, 35 treatment failures, 24 unresolved acute otitis media. 74 episodes (70.4%) had at least one bacterium identified on culture: Streptococcus pneumoniae was identified in 21 episodes, Haemophilus influenzae (all non-typeable) in 44, Streptococcus pyogenes in 2, Moraxella catarrhalis in 2. No statistically significant difference in bacterial aetiology by episode type was detected. Non-typeable H. influenzae was the most commonly isolated pathogen in all acute otitis media types and in all age sub-groups. Forty percent of S. pneumoniae isolates were multi-drug resistant. Pneumococcal serotype 19A was the most frequently identified serotype (7/21 episodes). Multi-drug resistance was found in 56% of 19A isolates. Of non typeable H. influenzae isolates, 15% were ampicillin resistant and 13% were amoxicillin/clavulanate resistant. S. pneumoniae and non-typeable H. influenzae DNA were each detected in 57% of samples culture negative for these pathogens, including 12 co-infections. CONCLUSION: Combining culture and polymerase chain reaction results, H. influenzae and S. pneumoniae may be implicated in 70% and 43% of clinically problematic bacterial acute otitis media episodes, respectively. The impact of new vaccines to prevent both S. pneumoniae and non typeable H. influenzae acute otitis media may be substantial in this population and is worth investigating. PMID- 23746416 TI - Epithelial salivary gland tumors in children: a twenty-five-year experience of 122 patients. AB - OBJECTIVE: The purpose of this study was to evaluate our 25-year experience of pediatric salivary tumors. METHODS: Patients less than 19 years old with a diagnosis of salivary tumor were identified at Oral-maxillofacial Head and Neck Tumor Center, China Medical University from 1987 to 2011. RESULTS: 122 patients were included in our study, 105 tumors were benign and 17 were malignant. The most common involved site was parotid gland, pleomorphic adenoma represented 91.4% in benign group, and mucoepidermoid carcinoma represented 47.1% in malignant group. All tumors in submandibular gland were benign. Warthin's tumor was diagnosed in one patient. In our follow-up, no regional recurrences occurred in patients without neck dissection. The 5- and 10-year overall survival rates of patients with malignant salivary tumors were 81.8% and 66.7% respectively. CONCLUSIONS: Epithelial salivary tumor was rare, parotid gland was most common involved site, pleomorphic adenoma and mucoepidermoid carcinoma were the most common benign and malignant tumor respectively. The prognosis of patients with malignant salivary tumors was not very favorable. PMID- 23746417 TI - Exhaled biomarker pattern is altered in children with obstructive sleep apnoea syndrome. AB - OBJECTIVES: Obstructive sleep apnoea syndrome (OSAS) is a common disorder in children, which is associated with enhanced inflammatory status. Inflammation associated changes could be monitored by the assessment of exhaled biomarker profile. This study aimed to compare the exhaled biomarker profile in children with OSAS and habitual snorers. METHODS: Eighteen children with OSAS (8 +/- 2 years, mean +/- SD) and ten non-OSAS subjects with habitual snoring (9 +/- 2 years) were recruited. Exhaled breath was collected from the lower airways, processed using an electronic nose (E-nose) and analyzed off-line using principal component analysis, followed by discrimination analysis and logistic regression to build a receiver operating characteristic (ROC) curve. RESULTS: Exhaled biomarker pattern of OSAS patients was discriminated from that of control subjects (p = 0.03, cross-validation accuracy: 64%), ROC curve analysis (area: 0.83) showed 78% sensitivity and 70% specificity. CONCLUSIONS: The altered exhaled biomarker pattern in OSAS might reflect accelerated airway and/or systemic inflammation in diseased state. Breath pattern analysis by an E-nose can serve as a new tool to monitor inflammation in children with OSAS. PMID- 23746418 TI - Standardising reporting of cervical lymphadenopathy in paediatric neck ultrasound: a pilot study using an evidence-based reporting protocol. AB - OBJECTIVES: Cervical lymphadenopathy is common in children and can arise from a wide range of aetiologies. Ultrasound can be a useful imaging tool for initial investigation but is known to be operator dependent. We aimed to compare the content of ultrasound reporting in this clinical scenario before and after the introduction of an evidence-based reporting protocol. METHODS: We performed a prospective 8-month pilot study assessing the content of ultrasound reports generated from scans to investigate suspected cervical lymphadenopathy in children referred to our tertiary referral otolaryngology service. We found wide variation in report content and inconsistent reporting of certain radiological features. In response to this we performed a literature search to identify key, clinically relevant ultrasonographic features for cervical lymphadenopathy and then in consultation with our radiology colleagues, devised a protocol to facilitate the reporting of these key features. Content of reports was then prospectively re-audited over a further 8-month period. RESULTS: 23 reports were assessed before and 26 after introduction of the reporting protocol. Fisher's exact test was used to analyse the data. We found a statistically significant (p < 0.05) improvement in the frequency of reporting of various key features such as nodal distribution, shape, echogenicity, calcification, necrosis and vascular pattern. CONCLUSIONS: The introduction of a standardised protocol has helped to streamline the reporting of ultrasounds to investigate cervical lymphadenopathy within our department. In the absence of any national guidelines on the reporting of paediatric neck ultrasound in this scenario, we propose that our protocol could be used by other departments to improve standardisation and as a teaching aid. PMID- 23746419 TI - Tasks in the pending tray for obstructive sleep apnea. Are we waiting for inspiration? PMID- 23746420 TI - Expert panel assessment of acute liver injury identification in observational data. AB - BACKGROUND: Observational data are useful for studying drug safety; however, to be effective, accurate outcome measurement is paramount. OBJECTIVES: This study compared alternative outcome definitions for acute liver injury (ALI) and explored opportunities for improving ALI identification in observational data. METHODS: The Truven MarketScan(r) Lab Database (MSLR) was used to identify patients meeting at least 1 of 4 ALI definitions, including definitions based on diagnosis codes, laboratory measures, or combinations of diagnoses, procedures, and/or laboratory measures. Expert panelists reviewed patient data using a Web dashboard. Panelists determined whether they believed the patient had ALI and identified factors influencing their decision. Logistic regression models explored which factors were influential in case determination. RESULTS: Overall, only 37 of 208 reviewed patients (17.8%) were classified as cases. The diagnosis based definition yielded no positive cases and the laboratory-based definition yielded the most positive cases (31 of 60). The most influential factors in case classification were occurrence of procedures after the index date (OR = 13.2, 95% CI = 5.3-32.9), no occurrence of drug treatments before the index date (OR = 4.6; 95% CI = 1.6-13.2), occurrence of drug treatments before the index date (OR = 0.3; 95% CI = 0.1-0.6), and no drug treatments after the index date (OR = 0.2; 95% CI = 0.0-0.5). CONCLUSIONS: Comparing ALI definitions illustrated tradeoffs between the number of plausible cases identified and the likelihood of cases being classified as positive. Future research should refine ALI case definitions, considering the import of laboratory results, procedures, and drugs in defining a case. PMID- 23746422 TI - The effects of adjunctive parathyroid hormone injection on bisphosphonate-related osteonecrosis of the jaws: an animal study. AB - Bisphosphonate (BP)-related osteonecrosis of the jaw (BRONJ) is a serious and challenging complication of chronic BP uptake in patients with osteoporosis who require management of skeletal-related events. The efficiency of adjunctive parathyroid hormone (PTH) injection was evaluated after chronic BP administration that was followed by tooth extraction. BRONJ was not observed in any of the subjects in the control groups, while BRONJ was observed in 66% and 22% of the subjects in the tooth extraction group and the tooth extraction with PTH injection group, respectively. In addition the presence and severity of inflammation was lower in the PTH injected group than in the tooth extraction group, but the difference was not statistically significant (P>0.01). In conclusion, the administration of 30MUg/kg/day PTH during a period of 8 weeks had positive effects on the resolution of BRONJ, but further studies are required to verify the effectiveness of PTH in the treatment of BRONJ. PMID- 23746421 TI - A survey on mortality from non-variceal upper gastrointestinal bleeding: Is the emergency referral system adequate? AB - BACKGROUND: Non-variceal upper gastrointestinal bleeding (NVUGIB) is an important cause of mortality and morbidity worldwide. Little information is available on the clinical management of non-variceal upper gastrointestinal bleeding in Italy in relation to the current organization of the Italian Emergency Health Services into Level-I and Level-II Emergency Departments (ED), the latter being more complex structures with greater resources. METHODS: A retrospective survey on clinical, endoscopic, and survival data was conducted by the regional sections of the 3 main Italian gastroenterological societies, AIGO, SIED and SIGE, recording all consecutive episodes of non-variceal upper gastrointestinal bleeding referred to 7 centres (4 of which were Level-II Emergency Departments) in Rome, Italy, during a one-year period. A total of 624 consecutive patients (64% males, mean age 67.6 +/- 16.2 years) were included. Thirty-day mortality was 4.6%. Main factors associated with survival at both univariate and multivariate analysis were the presence of full Rockall score <5 and the admission to a Level-II Emergency Departments (p<0.001). Level-I Emergency Departments admitted patients with a full Rockall score >= 5 (p=0.02) more frequently than patients with negative endoscopic findings (p<0.001). CONCLUSIONS: Referral of non-variceal upper gastrointestinal bleeding patients to Emergency Departments with more resources (Level-II) is associated with reduced mortality. Yet, unfortunately, high-risk patients were more often admitted to Level-I Emergency Departments, which suggests the need for a better organization of the emergency referral system. PMID- 23746423 TI - ATR-FTIR: a "rejuvenated" tool to investigate amyloid proteins. AB - Amyloid refers to insoluble protein aggregates that are responsible for amyloid diseases but are also implicated in important physiological functions (functional amyloids). The widespread presence of protein aggregates but also, in most of the cases, their deleterious effects explain worldwide efforts made to understand their formation, structure and biological functions. We emphasized the role of FTIR and especially ATR-FTIR techniques in amyloid protein and/or peptide studies. The multiple advantages provided by ATR-FTIR allow an almost continuous structural view of protein/peptide conversion during the aggregation process. Moreover, it is now well-established that infrared can differentiate oligomers from fibrils simply on their spectral features. ATR-FTIR is certainly the fastest and easiest method to obtain this information. ATR-FTIR occupies a key position in the analysis and comprehension of the complex aggregation mechanism(s) at the oligomer and/or fibril level. These mechanism(s) seem to present strong similarities between different amyloid proteins and might therefore be extremely important to understand for both disease-associated and functional amyloid proteins. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies. PMID- 23746424 TI - Unexpected death of a ventilator-dependent amyotrophic lateral sclerosis patient. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal, progressive, neurodegenerative disease and most patients affected die of respiratory compromise and/or pneumonia within 2-3 years of diagnosis. As ALS progresses, ventilator assistance is required. In the end stages of the disease, patients suffer from respiratory failure and may become ventilator-dependent. Deaths due to malfunction of mechanical ventilators are reported but there are very few forensic autopsy records. We report the case of a 69-year-old ALS female ventilator-dependent, trachostomised patient who was found dead by her husband, with the ventilator in "stand-by" mode. METHOD: A forensic autopsy was performed. Samples of internal organs were taken for histological and toxicological examination. The ventilator internal memory was also analysed and tested in order to find possible malfunction. RESULTS: Gross examination did not reveal any sign of trauma but showed brain and lung congestion. Pulmonary histological examination revealed thickening of peribronchial interstitial space, alveolar over-distension, break of inter-alveolar walls and diffuse alveolar haemorrhages. Focal microhemorrhages were also detected in other organs. Analysis of the ventilator internal memory showed that during the night of death, there had been several voltage drops. Specific tests revealed malfunction of the internal battery which was unable to provide the necessary voltage, as a consequence the ventilator switched off, stopping ventilation. Battery malfunction reduced the volume of the ventilator alarm, which was not heard by the caregiver. CONCLUSION: Histological pattern, with acute pulmonary emphysema and focal polivisceral haemorrhages, is strongly suggestive of a death due to "acute" asphyxia. The authors also discuss the need for strict supervision and follow up of these ventilatory dependent patients and their devices. PMID- 23746425 TI - [Correlation between pulmonary function, posture, and body composition in patients with asthma]. AB - AIM: Asthma may result in postural disorders due to increased activity of accessory respiratory muscles and hyperinflation. Our primary objective was to assess the correlation between pulmonary function and posture in adult patients with asthma. Secondarily, we aimed to study the correlation between body composition and body posture in this group of patients. METHOD: This was a cross sectional study including 34 patients with asthma who were subjected to postural assessment (photogrammetry), pulmonary function testing (spirometry, whole-body plethysmography, diffusing capacity for carbon monoxide, and respiratory muscle strength), and body composition estimation by means of bioelectrical impedance. RESULTS: Most patients were female (70.6%) with a median age of 32.5 years (range: 23-42 years old). We found a significant correlation between horizontal alignment of head (anterior view) and the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC; rho=-0,37; P=.03), total lung capacity (TLC; rho=0,42; P=.01), and residual volume (RV; rho=0,45; P<.001). Bronchial obstruction and respiratory muscle strength variables also correlated with postural assessment measures on the right and left lateral views. Both body mass index and the percentage of fat mass correlated with horizontal alignment of head, horizontal alignment of the pelvis, and the frontal angle of the lower limbs. CONCLUSION: Adult patients with asthma exhibit specific postural disorders that correlate with pulmonary function and body composition. The assessment of postural variables may provide a better pulmonary rehabilitation approach for these patients. PMID- 23746426 TI - Establishment of monoclonal antibodies against the extracellular domain that block binding of NMO-IgG to AQP4. AB - Neuromyelitis optica is a demyelinating disease characterized by a disease specific autoantibody designated as NMO-IgG that specifically recognizes aquaporin-4, and the binding of NMO-IgG to AQP4 causes the progress of the disease. Prevention of the binding of NMO-IgG, therefore, may alleviate the disease. Here we have developed monoclonal antibodies against AQP4 with a baculovirus display system in order to obtain high affinity monoclonal antibodies against the extracellular domains of AQP4. Our monoclonal antibodies can block the binding of NMO-IgG in spite of their heterogeneity. Taken together, we propose that our monoclonal antibodies can be applied in clinical therapy for NMO patients. PMID- 23746427 TI - Patterns from drying drops. AB - The objective of this review is to investigate different deposition patterns from dried droplets of a range of fluids: paints, polymers and biological fluids. This includes looking at mechanisms controlling the patterns and how they can be manipulated for use in certain applications such as medical diagnostics and nanotechnology. This review introduces the fundamental properties of droplets during evaporation. These include profile evolution (constant contact angle regime (CCAR) and constant radius regime (CRR)) and the internal flow (Marangoni and Capillary flow (Deegan et al. [22])). The understanding of these processes and the basic physics behind the phenomenon are crucial to the understanding of the factors influencing the deposition patterns. It concludes with the applications that each of these fluids can be used in and how the manipulation of the deposition pattern is useful. The most commonly seen pattern is the coffee ring deposit which can be seen frequently in real life from tea/coffee stains and in water colour painting. This is caused by an outward flow known as capillary flow which carries suspended particles out to the edge of the wetted area. Other patterns that were found were uniform, central deposits and concentric rings which are caused by inward Marangoni flow. Complex biological fluids displayed an array of different patterns which can be used to diagnose patients. PMID- 23746428 TI - Impulsivity and substance-related attentional bias: a meta-analytic review. AB - BACKGROUND: Previous research demonstrates the role of attentional bias in addictive behaviors. Impulsivity is thought to affect the strength of attentional biases, and thus, attentional biases might be one mechanism by which impulsivity affects addictive behaviors. However, whether or not impulsivity is related to attentional biases across different conceptualizations of impulsivity and attentional biases has yet to be examined as an initial test of such causal models. METHODS: The authors completed a meta-analysis of 13 published research studies examining the relationship between substance-related attentional bias and different conceptualizations of impulsivity. RESULTS: There was a small and significant effect size between impulsivity and substance-related attentional bias (r=0.20), which was moderated by impulsivity measurement type (Qb=5.91, df=1, p<0.05): there was a stronger relationship between behavioral impulsivity and substance-related attentional bias (r=0.22) than trait impulsivity and substance-related attentional bias (r=0.10). Different components of behavioral impulsivity and trait impulsivity did not affect the relationship. CONCLUSIONS: This study is the first systematic and empirical demonstration of the relationship between substance-related attentional bias and impulsivity and suggests viability of future examinations of casual models relating these constructs. Since trait and behavioral conceptualizations differentially relate to substance-related attentional bias, the current review further supports research suggesting how disaggregation of multidimensional constructs can lead to more robust relationships. PMID- 23746429 TI - Electronic cigarette use by college students. AB - BACKGROUND: Electronic cigarettes, or e-cigarettes, are battery operated devices that deliver nicotine via inhaled vapor. There is considerable controversy about the disease risk and toxicity of e-cigarettes and empirical evidence on short- and long-term health effects is minimal. Limited data on e-cigarette use and correlates exist, and to our knowledge, no prevalence rates among U.S. college students have been reported. This study aimed to estimate the prevalence of e cigarette use and identify correlates of use among a large, multi-institution, random sample of college students. METHODS: 4444 students from 8 colleges in North Carolina completed a Web-based survey in fall 2009. RESULTS: Ever use of e cigarettes was reported by 4.9% of students, with 1.5% reporting past month use. Correlates of ever use included male gender, Hispanic or "Other race" (compared to non-Hispanic Whites), Greek affiliation, conventional cigarette smoking and e cigarette harm perceptions. Although e-cigarette use was more common among conventional cigarette smokers, 12% of ever e-cigarette users had never smoked a conventional cigarette. Among current cigarette smokers, e-cigarette use was negatively associated with lack of knowledge about e-cigarette harm, but was not associated with intentions to quit. CONCLUSIONS: Although e-cigarette use was more common among conventional cigarette smokers, it was not exclusive to them. E cigarette use was not associated with intentions to quit smoking among a sub sample of conventional cigarette smokers. Unlike older, more established cigarette smokers, e-cigarette use by college students does not appear to be motivated by the desire to quit cigarette smoking. PMID- 23746430 TI - Emerging pharmacotherapies for alcohol dependence: a systematic review focusing on reduction in consumption. AB - BACKGROUND: European Medicines Agency guidelines recognize two different treatment goals for alcohol dependence: abstinence and reduction in alcohol consumption. All currently approved agents are indicated for abstinence. This systematic review aimed to identify drugs in development for alcohol dependence treatment and to establish, based upon trial design, if any are seeking market authorization for reduction in consumption. METHODS: We searched PubMed and Embase (December 2001-November 2011) to identify agents in development for alcohol dependence treatment. Additional studies were identified by searching ClinicalTrials.gov and the R&D Insight and Clinical Trials Insight databases. Studies in which the primary focus was treatment of comorbidity, or n<=20, were excluded. Studies were then classified as 'abstinence' if they: described a detoxification/alcohol withdrawal period; enrolled patients who had undergone detoxification previously; or presented relapse/abstinence rates as the primary outcome. Studies in patients actively drinking at baseline were classified as 'reduction in consumption'. RESULTS: Of 602 abstracts identified, 45 full-text articles were eligible. Five monotherapies were in development for alcohol dependence treatment: topiramate, fluvoxamine, aripiprazole, flupenthixol and nalmefene. Nalmefene was the only agent whose sponsor was clearly seeking definitive approval for reduction in consumption. Development status was unclear for topiramate, fluvoxamine, aripiprazole and flupenthixol. Fifteen agents were examined in published exploratory investigator-initiated trials; the majority focused on abstinence. Ongoing (unpublished) trials tended to focus on reduction in consumption. CONCLUSIONS: While published studies generally focused on abstinence, ongoing trials focused on reduction in consumption, suggesting a change in emphasis in the approach to treating alcohol dependence. PMID- 23746431 TI - Instant messaging at the hospital: supporting articulation work? AB - INTRODUCTION: Clinical work is increasingly fragmented and requires extensive articulation and coordination. Computer systems may support such work. In this study, we investigate how instant messaging functions as a tool for supporting articulation work at the hospital. PURPOSE: This paper aims to describe the characteristics of instant messaging communication in terms of number and length of messages, distribution over time, and the number of participants included in conversations. We also aim to determine what kind of articulation work is supported by analysing message content. METHODS: Analysis of one month's worth of instant messages sent through the perioperative coordination and communication system at a Danish hospital. RESULTS: Instant messaging was found to be used extensively for articulation work, mostly through short, simple conversational exchanges. It is used particularly often for communication concerning the patient, specifically, the coordination and logistics of patient care. Instant messaging is used by all actors involved in the perioperative domain. CONCLUSION: Articulation work and clinical work are hard to separate in a real clinical setting. Predefined messages and strict workflow design do not suffice when supporting communication in the context of collaborative clinical work. Flexibility is of vital importance, and this needs to be reflected in the design of supportive communication systems. PMID- 23746432 TI - Application of a model based on fuzzy logic for evaluating nursing diagnostic accuracy of students. AB - PURPOSE: To describe a model for assessing nursing diagnostic accuracy and its application to undergraduate students, comparing students' performance according to the course year. METHODS: This model, based on the theory of fuzzy sets, guides a student through three steps: (a) the student must parameterize the model by establishing relationship values between defining characteristic/risk factors and nursing diagnoses; (b) presentation of a clinical case; (c) the student must define the presence of each defining characteristic/risk factors for the clinical case. Subsequently, the model computes the most plausible diagnoses by taking into account the values indicated by the student. This gives the student a performance score in comparison with parameters and diagnoses that were previously provided by nursing experts. These nursing experts collaborated with the construction of the model indicating the strength of the relationship between the concepts, meaning, they parameterized the model to compare the student's choice with the expert's choice (gold standard), thus generating performance scores for the student. The model was tested using three clinical cases presented to 38 students in their third and fourth years of the undergraduate nursing course. RESULTS: Third year students showed superior performance in identifying the presence of defining characteristic/risk factors, while fourth year students showed superior performance in the diagnoses by the model. CONCLUSIONS: The Model for Evaluation of Diagnostic Accuracy Based on Fuzzy Logic applied in this study is feasible and can be used to evaluate students' performance. In this regard, it will open a broad variety of applications for learning and nursing research. LIMITATIONS: Despite the ease in filling the printed questionnaires out, the number of steps and fields to fill in may explain the considerable number of questionnaires with incorrect or missing data. This was solved in the digital version of the questionnaire. In addition, in more complex cases, it is possible that an expert opinion can lead to a wrong decision due to the subjectivity of the diagnostic process. PMID- 23746433 TI - Generativity, hierarchical action and recursion in the technology of the Acheulean to Middle Palaeolithic transition: a perspective from Patpara, the Son Valley, India. AB - The Acheulean to Middle Palaeolithic transition is one of the most important technological changes that occurs over the course of human evolution. Here we examine stone artefact assemblages from Patpara and two other excavated sites in the Middle Son Valley, India, which show a mosaic of attributes associated with Acheulean and Middle Palaeolithic industries. The bifaces from these sites are very refined and generally small, but also highly variable in size. A strong relationship between flake scar density and biface size indicates extensive differential resharpening. There are relatively low proportions of bifaces at these sites, with more emphasis on small flake tools struck from recurrent Levallois cores. The eventual demise of large bifaces may be attributed to the curation of small prepared cores from which sharper, or more task-specific flakes were struck. Levallois technology appears to have arisen out of adapting aspects of handaxe knapping, including shaping of surfaces, the utilization of two inter dependent surfaces, and the striking of invasive thinning flakes. The generativity, hierarchical organization of action, and recursion evident in recurrent Levallois technology may be attributed to improvements in working memory. PMID- 23746434 TI - Enhanced photo-reduction and removal of Cr(VI) on reduced graphene oxide decorated with TiO2 nanoparticles. AB - Reduced graphene oxide decorated with TiO2 nanoparticles (TiO2-RGO) was synthesized and characterized by scanning and transmission electron microscopy, powder X-ray diffraction, ultraviolet-visible spectroscopy, photoluminescence excitation and emission spectroscopy, and X-ray photoelectron spectroscopy. Photo reduction and removal of Cr(VI) from an aqueous solution using the material were investigated under visible light irradiation. Compared to pure TiO2, the TiO2-RGO exhibited an improved photocatalytic performance in the reduction of Cr(VI) under visible light irradiation, with a maximum removal of 86.5% vs 54.2% due to the increased light absorption intensity and wavelength range as well as the reduction in electron-hole pair recombination in TiO2 with the addition of RGO. The adsorption and photocatalytic reduction of Cr(VI) decreased with increasing pH, due to the decrease in the electrostatic attraction between anionic Cr(VI) and TiO2-RGO and the decrease in the thermodynamic driving force of Cr(VI) reduction to Cr(III). PMID- 23746435 TI - Durability and restoring of superhydrophobic properties in silica-based coatings. AB - The durability and restorable properties of superhydrophobicity are a most important issue essential for utilization of superhydrophobic materials in industrial and domestic fields. In this work, we have focused on the sol-gel dip coating synthesis, durability, and restoring properties of a superhydrophobic surface composed of spherical silica particles with low energy free surface successfully achieved on the surface of glass substrates. The water contact angle (WCA) of the as-prepared superhydrophobic coatings reached as high as 170+/-1 degrees (WCA=170+/-1 degrees ) and the sliding angle was 3+/-1 degrees (WSA=3+/ 1 degrees ). The behavior of wettability on superhydrophobic coating surface under various external disturbances including outdoor environments, heat, and mild acidic condition is investigated. It is shown in particular that degradation and repairing of surface methyl groups between two such surfaces leads to a fully restorable coating surface by the surface modification with trimethylchlorosilane (TMCS) at room temperature. The coating also holds good thermal stability; it holds superhydrophobicity up to 550 degrees C and gets degrade into superhydrophilicity above 600 degrees C without deforming surface morphology. The results confirm the durability of the silica coating under different external disturbances and sol-gel dip coating method and restoring property provide the best solution to fabricate superhydrophobic silica coating surface with extended durability at low cost. PMID- 23746436 TI - On the hysteresis of argon adsorption in a uniform closed end slit pore. AB - We present a molecular simulation study of adsorption and desorption in slit mesopores of uniform width with one end closed and explore the effects of pore dimensions (width and length), temperature and surface affinity on the hysteresis loop: its position, lower and upper closure points, area and shape. Our results show that the metastability, brought about by structural change in the adsorbate, is the reason for the existence of hysteresis, and contrast with reports suggesting that reversibility invariably prevails for adsorption in closed end pores. The shape, area and position of the hysteresis loop are complex functions of pore width, length and temperature. We establish a parametric map of the boundary separating reversible and hysteretic regions. Our simulation results also show a number of interesting observations that have not been previously reported or generally recognised: (1) the fluid within the core of the pore behaves like a bulk liquid as the pore is progressively filled, via the movement of the meniscus from the closed end to the pore mouth, but as the pore fills, the fluid in the core becomes structured, (2) the shape of the meniscus changes as adsorption progresses but is constant during desorption because of the constant thickness of the adsorbed layer in the two-phase region, (3) the hysteresis loop is larger for a longer pore, (4) the area of the hysteresis loop increases with pore width up to a certain width, beyond which it decreases and finally disappears, (5) as temperature approaches the critical hysteresis temperature, the hysteresis loop area decreases, but it retains its Type H1 character. PMID- 23746437 TI - Peroxidase-like activity of amino-functionalized magnetic nanoparticles and their applications in immunoassay. AB - Amino-functionalized Fe3O4 magnetic nanoparticles with high peroxidase-like activity (MNPs-NH2) are reported in this work. The peroxidase-like activity is approximately the same as naked Fe3O4 magnetic nanoparticles (MNPs). MNPs-NH2 displayed much better thermal stability and pH tolerance than horseradish peroxidase (HRP). The optimal pH and temperature are approximately pH 4 and 40 degrees C, respectively. We showed that the MNPs-NH2 were successfully applied in a double-antibody sandwich "enzyme"-linked immunosorbent assay to replace of HRP, in which MNPs-NH2 were not only separation carriers, but also detection indicator. PMID- 23746438 TI - Formation of polyelectrolyte-gold nanoparticle necklaces on paper. AB - This work reports a simple method to form and visualize individual polyelectrolyte-nanoparticle necklace-like structures on paper, which is applicable to other porous surfaces. In this work, one-dimensional necklaces of negatively charged gold nanoparticles (AuNPs) have been electrostatically assembled along the backbone of a cationic polyacrylamide (CPAM) chain adsorbed on paper. The process involves rapidly passing a dilute CPAM solution through filter paper, adsorbing the polyelectrolyte on the surface, followed by the immediate filtration of an AuNP suspension through the same filter paper. The nanoparticles used were negatively charged, citrate ion capped AuNPs with an average diameter of 20 nm. Scanning electron microscopy images of the dried paper sample showed that the AuNP necklaces were adsorbed in a perpendicular direction to that of the cellulose fibers and along the length of the CPAM molecules which were draped over the fibers. The effects of CPAM polymer concentration, charge density, and molecular weight on such assembly of AuNPs were studied. This technique enables the visualization of polyelectrolyte molecules and the formation of very well organized and reproducible polyelectrolyte-nanoparticle necklaces on a porous, three-dimensional substrate. PMID- 23746439 TI - Enhanced azo dye removal through anode biofilm acclimation to toxicity in single chamber biocatalyzed electrolysis system. AB - Azo dye is widely used in printing and dyeing process as one of refractory wastewaters for its high chroma, stable chemical property and toxicity for aquatic organism. Biocatalyzed electrolysis system (BES) is a new developed technology to degrade organic waste in bioanode and recover recalcitrant contaminants in cathode with effective decoloration. The ion exchange membrane (IEM) separate anode and cathode for biofilm formation protection. Azo removal efficiency was up to 60.8%, but decreased to 20.5% when IEM was removed. However, expensive ion exchange membrane (IEM) not suitable for further practical application, bioelectrochemical activity of bioanode is sensitive to the toxicity of azo dye. A gradient increase of azo dye concentration was used to acclimate anode biofilm to pollutant toxicity. The azo removal efficiency can be enhanced to 73.3% in 10h reaction period after acclimation. The highest removal efficiency reached 83.7% and removal rates were increased to 8.37 from 3.04 g/h/L of dual chamber. That indicated the feasibility for azo dye removal by single-chamber BES. The IEM cancellation not only decreased the internal resistance, but increased the current density and azo dye removal. PMID- 23746440 TI - Interventional patient hygiene: discussion of the issues and a proposed model for implementation of the nursing care basics. AB - More than 140 years ago, Florence Nightingale wrote "It may seem a strange principal to enunciate as the very first requirement in a Hospital that it should do the sick no harm." Data suggests that 63% of all preventable errors are related to clinical problems that are within nursing's independent scope of practice. Many of these fall in the category of "interventional hygiene" activities and include prevention of skin injury, post-operative respiratory complications and failure to rescue. As nurses we are called upon to assure higher levels of safety and quality for our patients by our governments, professional organisations and hospital administrations. It is essential that we implement evidence based nursing care strategies to reduce avoidable errors in care so that clinical outcomes improve. The author of this paper, who coined the team "interventional patient hygiene", discusses the science related to many of these care issues and proposes an Interventional Care Model for use by nurses in redesigning how we approach nurse sensitive care practices in the future. Additionally, a change framework called "Sustaining Nursing Clinical Practice" is described to ensure reintroduction and valuing of evidence basic nursing care in conjunction with the right resources and systems to sustain the new practice. PMID- 23746441 TI - Evaluation of the nursing workload through the Nine Equivalents for Nursing Manpower Use Scale and the Nursing Activities Score: a prospective correlation study. AB - OBJECTIVE: To determine the relationship between nursing workload measured through the nine equivalents of nursing manpower use (NEMS) scale and that measured through the nursing activities score (NAS) scale and to analyse staff needs as determined through each of the scales. METHODS: The study used a descriptive prospective correlational design to collect data between October 2007 and July 2009. Nursing workload data for 730 ICU patients were collected daily using the NAS and NEMS scales. Both scales were then correlated and used to estimate staff needs. FINDINGS: 6815 score pairs were collected, which reflected the nursing workload for each patient as calculated daily using both scales. Pearson's correlation coefficient for individual measurements obtained through the NAS and the NEMS corresponded to .672, and to .932 for the daily total workload in the unit. The staffing requirements based on the NAS scale scores were significantly higher than those based on the NEMS scale. A high correlation existed for individual measurements using both scales and for the total workload measurement in the unit. The main difference was found when analysing staffing requirements, with higher staff numbers needed for the NAS scale. CONCLUSION: Both NAS and NEMS can be used to measure the nursing workload in the ICU. Staffing requirements using NAS were higher than those using NEMS. PMID- 23746442 TI - [Sensitivity of ultrasonographic diagnosis in hand malformations. About 80 cases]. AB - During pregnancy, the Haute Autorite de sante (HAS) recommends to realize three ultrasonographic evaluations, notably for the early detection of congenital malformations. Yet, in our experience, ultrasonographic antenatal diagnoses of hand malformations are rare. This is both a retrospective (years 2003-2008) and a prospective study (2009-2012). It quantifies the sensibility of hand malformations ultrasonographic diagnosis. Questionnaires have been sent or given during consultations to parents of children with upper limb malformation. The parents' acceptance of diagnosis and their anxiety have been evaluated. Eighty eight malformations have been recruited for our series. Only 11 antenatal diagnoses have been made. Thus, sonographic diagnosis sensibility is 12.5% in our series. Thirty-nine percent of the parents have been shocked by the absence of diagnosis at birth. The sensibility of hand malformation ultrasonographic diagnosis is rarely documented in literature. It is generally low. This diagnosis may raise concerns about eugenism and legal issues. However, congenital malformations, even in the absence of a diagnosis, must be taken care of by a clearly determined network. Our results highlight difficulties of prenatal diagnosis of upper limb malformations. A lot of questions arise: what information should be delivered to the parents? Should antenatal ultrasonographic diagnosis be legislated? "Minor" malformations are often well managed by the parents, but "major" malformations ignored often raise legal issues. PMID- 23746444 TI - Sequential and multistep substrate interrogation provides the scaffold for specificity in human flap endonuclease 1. AB - Human flap endonuclease 1 (FEN1), one of the structure-specific 5' nucleases, is integral in replication, repair, and recombination of cellular DNA. The 5' nucleases share significant unifying features yet cleave diverse substrates at similar positions relative to 5' end junctions. Using single-molecule Forster resonance energy transfer, we find a multistep mechanism that verifies all substrate features before inducing the intermediary-DNA bending step that is believed to unify 5' nuclease mechanisms. This is achieved by coordinating threading of the 5' flap of a nick junction into the conserved capped-helical gateway, overseeing the active site, and bending by binding at the base of the junction. We propose that this sequential and multistep substrate recognition process allows different 5' nucleases to recognize different substrates and restrict the induction of DNA bending to the last common step. Such mechanisms would also ensure the protection of DNA junctions from nonspecific bending and cleavage. PMID- 23746443 TI - Totipotent embryonic stem cells arise in ground-state culture conditions. AB - Embryonic stem cells (ESCs) are derived from mammalian embryos during the transition from totipotency, when individual blastomeres can make all lineages, to pluripotency, when they are competent to make only embryonic lineages. ESCs maintained with inhibitors of MEK and GSK3 (2i) are thought to represent an embryonically restricted ground state. However, we observed heterogeneous expression of the extraembryonic endoderm marker Hex in 2i-cultured embryos, suggesting that 2i blocked development prior to epiblast commitment. Similarly, 2i ESC cultures were heterogeneous and contained a Hex-positive fraction primed to differentiate into trophoblast and extraembryonic endoderm. Single Hex positive ESCs coexpressed epiblast and extraembryonic genes and contributed to all lineages in chimeras. The cytokine LIF, necessary for ESC self-renewal, supported the expansion of this population but did not directly support Nanog positive epiblast-like ESCs. Thus, 2i and LIF support a totipotent state comparable to early embryonic cells that coexpress embryonic and extraembryonic determinants. PMID- 23746445 TI - Tyrosine phosphorylation regulates the activity of phytochrome photoreceptors. AB - Phytochromes are red/far-red light receptors that function in photomorphogenesis of plants. Photoisomerization of phytochrome by red light leads to its translocation to the nucleus, where it regulates gene expression. We examined whether phytochrome is phosphorylated in response to light, and we report that phytochrome B (phyB)'s N terminus contains a region with a number of phosphoserines, threonines, and tyrosines. The light-dependent phosphorylation of tyrosine 104 (Y104) appears to play a negative role in phyB's activity, because a phosphomimic mutant, phyBY104E, is unable to complement any phyB-related phenotype, is defective in binding to its signaling partner PIF3, and fails to form stable nuclear bodies even though it retains normal photochemistry in vitro. In contrast, plants stably expressing a nonphosphorylatable mutant, phyBY104F, are hypersensitive to light. The proper response to changes in the light environment is crucial for plant survival, and our study brings tyrosine phosphorylation to the forefront of light-signaling mechanisms. PMID- 23746446 TI - The making of a slicer: activation of human Argonaute-1. AB - Argonautes are the central protein component in small RNA silencing pathways. Of the four human Argonautes (hAgo1-hAgo4) only hAgo2 is an active slicer. We determined the structure of hAgo1 bound to endogenous copurified RNAs to 1.75 A resolution and hAgo1 loaded with let-7 microRNA to 2.1 A. Both structures are strikingly similar to the structures of hAgo2. A conserved catalytic tetrad within the PIWI domain of hAgo2 is required for its slicing activity. Completion of the tetrad, combined with a mutation on a loop adjacent to the active site of hAgo1, results in slicer activity that is substantially enhanced by swapping in the N domain of hAgo2. hAgo3, with an intact tetrad, becomes an active slicer by swapping the N domain of hAgo2 without additional mutations. Intriguingly, the elements that make Argonaute an active slicer involve a sophisticated interplay between the active site and more distant regions of the enzyme. PMID- 23746447 TI - NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological disease. AB - The molecular basis of cytochrome c oxidase (COX, complex IV) deficiency remains genetically undetermined in many cases. Homozygosity mapping and whole-exome sequencing were performed in a consanguineous pedigree with isolated COX deficiency linked to a Leigh syndrome neurological phenotype. Unexpectedly, affected individuals harbored homozygous splice donor site mutations in NDUFA4, a gene previously assigned to encode a mitochondrial respiratory chain complex I (NADH:ubiquinone oxidoreductase) subunit. Western blot analysis of denaturing gels and immunocytochemistry revealed undetectable steady-state NDUFA4 protein levels, indicating that the mutation causes a loss-of-function effect in the homozygous state. Analysis of one- and two-dimensional blue-native polyacrylamide gels confirmed an interaction between NDUFA4 and the COX enzyme complex in control muscle, whereas the COX enzyme complex without NDUFA4 was detectable with no abnormal subassemblies in patient muscle. These observations support recent work in cell lines suggesting that NDUFA4 is an additional COX subunit and demonstrate that NDUFA4 mutations cause human disease. Our findings support reassignment of the NDUFA4 protein to complex IV and suggest that patients with unexplained COX deficiency should be screened for NDUFA4 mutations. PMID- 23746448 TI - A systematic approach for the genetic dissection of protein complexes in living cells. AB - Cells contain many important protein complexes involved in performing and regulating structural, metabolic, and signaling functions. One major challenge in cell biology is to elucidate the organization and mechanisms of robustness of these complexes in vivo. We developed a systematic approach to study structural dependencies within complexes in living cells by deleting subunits and measuring pairwise interactions among other components. We used our methodology to perturb two conserved eukaryotic complexes: the retromer and the nuclear pore complex. Our results identify subunits that are critical for the assembly of these complexes, reveal their structural architecture, and uncover mechanisms by which protein interactions are modulated. Our results also show that paralogous proteins play a key role in the robustness of protein complexes and shape their assembly landscape. Our approach paves the way for studying the response of protein interactomes to mutations and enhances our understanding of genotype phenotype maps. PMID- 23746450 TI - The genomic landscape of the somatic linker histone subtypes H1.1 to H1.5 in human cells. AB - Human cells contain five canonical, replication-dependent somatic histone H1 subtypes (H1.1, H1.2, H1.3, H1.4, and H1.5). Although they are key chromatin components, the genomic distribution of the H1 subtypes is still unknown, and their role in chromatin processes has thus far remained elusive. Here, we map the genomic localization of all somatic replication-dependent H1 subtypes in human lung fibroblasts using an integrative DNA adenine methyltransferase identification (DamID) analysis. We find in general that H1.2 to H1.5 are depleted from CpG-dense regions and active regulatory regions. H1.1 shows a DamID binding profile distinct from the other subtypes, suggesting a unique function. H1 subtypes can mark specific domains and repressive regions, pointing toward a role for H1 in three-dimensional genome organization. Our work integrates H1 subtypes into the epigenome maps of human cells and provides a valuable resource to refine our understanding of the significance of H1 and its heterogeneity in the control of genome function. PMID- 23746449 TI - Systematic triple-mutant analysis uncovers functional connectivity between pathways involved in chromosome regulation. AB - Genetic interactions reveal the functional relationships between pairs of genes. In this study, we describe a method for the systematic generation and quantitation of triple mutants, termed triple-mutant analysis (TMA). We have used this approach to interrogate partially redundant pairs of genes in S. cerevisiae, including ASF1 and CAC1, two histone chaperones. After subjecting asf1Delta cac1Delta to TMA, we found that the Swi/Snf Rdh54 protein compensates for the absence of Asf1 and Cac1. Rdh54 more strongly associates with the chromatin apparatus and the pericentromeric region in the double mutant. Moreover, Asf1 is responsible for the synthetic lethality observed in cac1Delta strains lacking the HIRA-like proteins. A similar TMA was carried out after deleting both CLB5 and CLB6, cyclins that regulate DNA replication, revealing a strong functional connection to chromosome segregation. This approach can reveal functional redundancies that cannot be uncovered through traditional double-mutant analyses. PMID- 23746451 TI - TGF-beta signaling is associated with endocytosis at the pocket region of the primary cilium. AB - Transforming growth factor beta (TGF-beta) signaling is regulated by clathrin dependent endocytosis (CDE) for the control of cellular processes during development and in tissue homeostasis. The primary cilium coordinates several signaling pathways, and the pocket surrounding the base and proximal part of the cilium is a site for CDE. We report here that TGF-beta receptors localize to the ciliary tip and endocytic vesicles at the ciliary base in fibroblasts and that TGF-beta stimulation increases receptor localization and activation of SMAD2/3 and ERK1/2 at the ciliary base. Inhibition of CDE reduced TGF-beta-mediated signaling at the cilium, and TGF-beta signaling and CDE activity are reduced at stunted primary cilia in Tg737orpk fibroblasts. Similarly, TGF-beta signaling during cardiomyogenesis correlated with accumulation of TGF-beta receptors and activation of SMAD2/3 at the ciliary base. Our results indicate that the primary cilium regulates TGF-beta signaling and that the ciliary pocket is a compartment for CDE-dependent regulation of signal transduction. PMID- 23746452 TI - Substrate-selective repair and restart of replication forks by DNA translocases. AB - Stalled replication forks are sources of genetic instability. Multiple fork remodeling enzymes are recruited to stalled forks, but how they work to promote fork restart is poorly understood. By combining ensemble biochemical assays and single-molecule studies with magnetic tweezers, we show that SMARCAL1 branch migration and DNA-annealing activities are directed by the single-stranded DNA binding protein RPA to selectively regress stalled replication forks caused by blockage to the leading-strand polymerase and to restore normal replication forks with a lagging-strand gap. We unveil the molecular mechanisms by which RPA enforces SMARCAL1 substrate preference. E. coli RecG acts similarly to SMARCAL1 in the presence of E. coli SSB, whereas the highly related human protein ZRANB3 has different substrate preferences. Our findings identify the important substrates of SMARCAL1 in fork repair, suggest that RecG and SMARCAL1 are functional orthologs, and provide a comprehensive model of fork repair by these DNA translocases. PMID- 23746453 TI - Markedly asymmetric presentation in multiple system atrophy. AB - BACKGROUND: Multiple system atrophy (MSA) presents with fairly symmetrical, levodopa unresponsive parkinsonism and additional features like autonomic dysfunction, cerebellar and corticospinal tract involvement. Marked asymmetry in atypical parkinsonism suggests alternative diagnosis like Corticobasal syndrome (CBS). METHODS: We describe five unusual cases, who presented initially with markedly asymmetric parkinsonism, rigid dystonic abnormal limb posturing and subsequently developed clinical and/or radiological features consistent with probable MSA-P. RESULTS: Using the internationally accepted diagnostic criteria, the patients fulfilled the diagnostic criteria for probable MSA-P after 5 years from disease onset. Case 4 and 5 had characteristic MRI features and Case 2 was pathologically confirmed. CONCLUSIONS: We use these cases to highlight that MSA-P MSA-P can present rarely with very marked asymmetry, dystonic limb and myoclonic jerks leading to a diagnosis of CBS at onset. PMID- 23746455 TI - Utilizing poxviral vectored vaccines for antibody induction-progress and prospects. AB - Over the last decade, poxviral vectors emerged as a mainstay approach for the induction of T cell-mediated immunity by vaccination, and their suitability for human use has led to widespread clinical testing of candidate vectors against infectious intracellular pathogens and cancer. In contrast, poxviruses have been widely perceived in the vaccine field as a poor choice of vector for the induction of humoral immunity. However, a growing body of data, from both animal models and recent clinical trials, now suggests that these vectors can be successfully utilized to prime and boost B cells and effective antibody responses. Significant progress has been made in the context of heterologous prime-boost immunization regimes, whereby poxviruses are able to boost responses primed by other vectors, leading to the induction of high-titre antigen-specific antibody responses. In other cases, poxviral vectors have been shown to stimulate humoral immunity against both themselves and encoded transgenes, in particular viral surface proteins such as influenza haemagglutinin. In the veterinary field, recombinant poxviral vectors have made a significant impact with numerous vectors licensed for use against a variety of animal viruses. On-going studies continue to explore the potential of poxviral vectors to modulate qualitative aspects of the humoral response, as well as their amenability to adjuvantation seeking to improve quantitative antibody immunogenicity. Nevertheless, the underlying mechanisms of B cell induction by recombinant poxviruses remain poorly defined, and further work is necessary to help guide the rational optimization of future poxviral vaccine candidates aiming to induce antibodies. PMID- 23746454 TI - Neuropathology of dementia in a large cohort of patients with Parkinson's disease. AB - The aim of our study was to establish the contribution of distinct pathological aggregates (cortical Lewy bodies (LB), neuronal tau-inclusions and beta-amyloid plaque (Abeta) deposition) in dementia related to Parkinson's disease (PD) in a large autopsy cohort. We studied the brains of 155 PD patients, 109 of whom were clinically demented. The total LB score, the Braak stages for neurofibrillary tangles (NFT) and the Thal phases for Abeta deposition were assessed in each case, according to previously published guidelines. All the three lesion types were more abundant in the demented PD group, compared to the non-demented PD group, but neocortical LB pathology was the most important substrate of dementia. A significant correlation was found between the severity of Abeta phases, NFT stages and cortical LB scores. In a subgroup of severely demented PD patients, cortical tau burden was much higher than in the rest of the group. Extensive cortical NFTs associate unavoidably with dementia. Some patients remain cognitively intact despite high cortical LB score. In conclusion, our data strongly support a combining, yet distinct role of neocortical LBs and tau deposits. PMID- 23746456 TI - Rotavirus vaccines WHO position paper: January 2013 - Recommendations. AB - This article presents the World Health Organizations (WHO) evidence and recommendations for the use of rotavirus vaccination from the WHO position paper on rotavirus vaccines - January 2013 recently published in the Weekly Epidemiological Record [1]. This position paper summarizes the WHO position on the inclusion of rotavirus vaccines in all national immunization programmes and recent developments in the field, in particular the potential of rotavirus vaccines to further reduce mortality by employing more flexible immunization schedules. The current document replaces the position paper on the use of rotavirus vaccines published in 2007 [2]. Footnotes to this paper provide a number of core references. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This paper reflects the recommendations of WHO's Strategic Advisory Group of Experts (SAGE) on immunization. These recommendations were discussed by SAGE at its April 2012 meeting. Evidence presented at the meeting can be accessed at http://www.who.int/immunization/sage/previous/en/index.html. PMID- 23746457 TI - Transplacental transmission of BTV-8 in sheep: BTV viraemia, antibody responses and vaccine efficacy in lambs infected in utero. AB - Bluetongue virus (BTV) is an insect vector transmitted virus which causes an economically important disease in ruminants. BTV infection during pregnancy can result in infection of the foetus, which may lead to the birth of persistently infected or immunotolerant offspring. Since persistently infected animals continuously produce large amounts of virus they could be a source of infection for the insect vector. This could significantly influence the epidemiology of the virus and hence might require additional measures to control a BTV outbreak. Therefore, we investigated the potential of BTV-8 to induce persistent infection or immunotolerance in lambs in an experimental setting. Infection of eighteen 70 75 days pregnant ewes with wild type BTV-8 led to the birth of 25 out of 44 BTV RNA positive lambs (foetal infected, FI). All 23 FI lambs born alive also had anti BTV antibodies at birth; infectious virus could be recovered from 5 out of 25 FI lambs. Viral RNA loads decreased rapidly after birth; 19 out of 20 FI lambs that remained in the experiment until week 14 after birth, were RNA negative at that time. Since persistence of BTV-8 infection could not be demonstrated, we investigated whether foetal infection had an effect on protection against a field virus infection and on efficacy of vaccination. To this end, 5 FI lambs and 5 foetal non-infected (FNI) lambs were vaccinated with the inactivated Bovilis((r)) BTV-8 vaccine, five months after birth. Three weeks after the vaccination, all lambs were infected with wild type BTV-8. The foetal infection did not interfere with vaccination efficacy. In contrast, foetal BTV-8 infection induced an immune response which afforded protection against BTV challenge comparable to the level of protection induced by vaccination. PMID- 23746458 TI - Influenza vaccine: development of a novel intranasal and subcutaneous recombinant adjuvant. AB - The synthetic peptide GK-1, derived from Taenia crassiceps, enhances the protection induced by human influenza vaccine in both young and aged mice. Herein, the adjuvant properties of GK-1 fused to the pVIII protein of a heat inactivated phagemid vector (FGK1) when co-administered with the influenza vaccine were assessed, to evaluate its feasibility as a low-cost adjuvant. In mice, FGK1 significantly increased the expected IgG and IgA anti-influenza antibody levels both in sera and in bronchoalveolar fluids when intranasally or subcutaneously co-administered with influenza vaccine. Single-dose pig co immunization with FGK1 and influenza vaccine induced serum levels of IgG anti influenza antibodies similar to those elicited by a two-dose immunization with the influenza vaccine alone. Preclinical evaluation of FGK1 with the influenza vaccine is currently in progress, in order to recommend its use for veterinary purposes. PMID- 23746459 TI - Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. AB - An expanded G4C2 hexanucleotide repeat in the proximal regulatory region of C9orf72 is a frequent cause of neurodegenerative diseases in the frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND) spectrum. Although primarily characterized by variably abundant pathological inclusions of TDP-43 protein, the lesion load was extended to TDP-43-negative, p62-positive neuronal and glial inclusions in extended regions of the central nervous system (CNS), particularly in cerebellum, where they may be characteristic of a C9orf72 repeat expansion. Disease mechanisms associated with repeat expansion disorders, including haploinsufficiency, RNA toxicity, and abnormal translation of expanded repeat sequences, are beginning to emerge. We review genetic, clinical, and pathological highlights and discuss current insights into the biology of this novel type of repeat expansion disease. PMID- 23746460 TI - Toward a cross-species understanding of empathy. AB - Although signs of empathy have now been well documented in non-human primates, only during the past few years have systematic observations suggested that a primal form of empathy exists in rodents. Thus, the study of empathy in animals has started in earnest. Here we review recent studies indicating that rodents are able to share states of fear, and highlight how affective neuroscience approaches to the study of primary-process emotional systems can help to delineate how primal empathy is constituted in mammalian brains. Cross-species evolutionary approaches to understanding the neural circuitry of emotional 'contagion' or 'resonance' between nearby animals, together with the underlying neurochemistries, may help to clarify the origins of human empathy. PMID- 23746461 TI - [Priorization of facilitators for the implementation of medication review with follow-up service in Spanish community pharmacies through exploratory factor analysis]. AB - OBJECTIVE: to prioritize previously identified in Spain facilitators for the implementation of new Pharmaceutical Services that allow designing strategies for the implementation of Medication Review with follow-up (MRFup) service. DESIGN, SETTING AND PARTICIPANTS: Exploratory factor analysis (EFA). A draft of a questionnaire was performed based on a previous literature review and following the RAND/UCLA methodology. An expert panel worked with it and generated a definitive questionnaire which, after piloting, was used with a representative sample of pharmacists, owners or staff members, who were working in community pharmacy, using computer-assisted telephone interviewing (CATI) methodology. To understand underlying constructs in the questionnaire an EFA was performed. Different approaches were tested such as principal components factor analysis and principal axis factoring method. The best interpretability was achieved using the Factorization of Principal axis method with Direct Oblimin rotation, which explained the 40.0% of total variance. RESULTS: This produced four factors defined as: "Incentives", "External campaigns", "Expert in MRFup" and "Professionalism of the pharmacist". CONCLUSIONS: It can be stated that for implementation and sustainability of MRFup Service it is necessary being paid; also it must be explained to health professional and society in general. Practice of MRFup service demands pharmacists receiving a more clinical education and assuming more responsibilities as health professionals. PMID- 23746462 TI - On-target antihypertensive treatment in Italy: the ISPIT (Indagine Sicoa Paziente Iperteso a Target) survey study. PMID- 23746463 TI - [Early molecular adsorbent recirculating system (MARS) treatment in two severe mushroom poisonings]. PMID- 23746464 TI - [Natural evolution of excess body weight (overweight and obesity) in children]. AB - OBJECTIVE: To analyze the chronological evolution of excess body weight (overweight and obesity) in order to raise public awareness within the different areas of intervention (family, school, business environment, health services) and to take effective actions. MATERIAL AND METHODS: Weight, height and body mass index (BMI) of 604 healthy subjects (307 males and 297 females) have been recorded at birth and at the age of 1, 2, 3, 4, 6, 8, 10, 12 and 14 years. The excess body weight has been calculated according to national references from Ferrandez et al. RESULTS: Prevalence of excess body weight at age 14 years was significantly higher (P<.05) in males (29%) than in females (12.8%). BMI (kg/m2) was significantly higher (P<.05) for both sexes in every age period, except for birth and age 1 year, in those patients with excess body weight at age 14, with respect to patients with normal nutritional status of the same age. Those groups with excess body weight at age 14 showed a BMI (Z-score) reaching overweight or obesity levels at age 4, and progressively increasing. CONCLUSIONS: Excess body weight probably starts at early stages in life, when dietary habits of the child depends almost exclusively on family habits, and may be aggravated during school attendance. Finally, a disproportionate weight increase occurs in adolescence that is probably related to unhealthy dietary habits and way of life. PMID- 23746465 TI - [Importance of muscle biopsy in the diagnosis of juvenile dermatomyositis]. PMID- 23746466 TI - [Giant pilomatrixoma: a benign tumour with a rare presentation]. PMID- 23746467 TI - [Micropapular rash in an 8 year-old girl]. PMID- 23746468 TI - [Multiplex ligation-dependent probe amplification detection of spinal muscular atrophy type I in a 3 months' patient and wide detection of healthy carriers in the family]. PMID- 23746469 TI - [Ureteral valves: literature review and description of 4 new cases]. AB - Ureteral valves are a rare malformation, with an incidence of 1 in 5000-8000 live births. Urological malformations are associated with 50% of cases according to the current literature. We report 4 cases treated in our hospital from 2004 to 2012. Three of the patients had renal dysgenesis, one case associated with complete urethral duplication, and another case associated with a ureteral atresia. PMID- 23746470 TI - Inferring cardiovascular control from spontaneous variability. PMID- 23746471 TI - The economic costs of routine INR monitoring in infants and children--examining point-of-care devices used within the home setting compared to traditional anticoagulation clinic monitoring. AB - INTRODUCTION: The use of point-of-care (POC) devices within the home for routine INR monitoring has demonstrated reliability, safety and effectiveness in the management of infants and children requiring long-term warfarin therapy. However, a comprehensive cost-analysis of using this method of management, compared to attending anticoagulation clinics has not been reported. The aim of this study was to compare the estimated societal costs of attending anticoagulation clinics for routine INR monitoring to using a POC test in the home. MATERIALS AND METHODS: This study used a comparative before-and-after design that included 60 infants and children managed via the Haematology department at a tertiary paediatric centre. Each participant was exposed to both modes of management at various times for a period of >=3 months. A questionnaire, consisting of 25 questions was sent to families to complete and return. Data collected included: the frequency of monitoring, mode of travel to and from clinics, total time consumed, and primary carer's income level. RESULTS: The home monitoring cohort saved a total of 1 hour 19 minutes per INR test compared to attending anticoagulation clinics and had a cost saving to society of $66.83 (AUD) per INR test compared to traditional care; incorporating health sector costs, travel expenses and lost time. CONCLUSIONS: The traditional model of care requires a considerable investment of time per test from both child and carer. Home INR monitoring in infants and children provides greater societal economic benefits compared to traditional models. PMID- 23746472 TI - Synthesis and acrosin inhibitory activities of 5-phenyl-1H-pyrazole-3-carboxylic acid amide derivatives. AB - A series of novel 5-phenyl-1H-pyrazole-3-carboxylic acid amide derivatives were designed, synthesized, and their acrosin inhibitory activities in vitro were evaluated. The results of the acrosin inhibitory activity showed that all target compounds were more potent than control TLCK. Compounds AQ-A1, AQ-D3, AQ-D4, AQ E4 and AQ-E5 exhibited stronger acrosin inhibitory activities than control ISO-1. Especially, compound AQ-E5 displayed the most potent acrosin inhibitory activity in all the compounds, with an IC50 of 0.01MUmol/mL. This study provided a new structural class for the development of novel acrosin inhibitory agents. PMID- 23746473 TI - Optimization of the electrophile of chloronitrobenzamide leads active against Trypanosoma brucei. AB - We previously reported the phenylchloronitrobenzamides (PCNBs), a novel class of compounds active against the species of trypanosomes that cause Human African Trypanosomiasis (HAT). Herein, we explored the potential to adjust the reactivity of the electrophilic chloronitrobenzamide core. These studies identified compound 7d that potently inhibited the growth of trypanosomes (EC50=120nM for Trypanosoma b. brucei, 18nM for Trypanosoma b. rhodesiense, and 38nM for Trypanosoma b. gambiense) without significant cytotoxicity against mammalian cell lines (EC50>25MUM for HepG2, HEK293, Raji, and BJ cell lines) and also had good stability in microsomal models (t1/2>4h in both human and mouse). Overall these properties indicate the compound 7d and its analogs are worth further exploration as potential leads for HAT. PMID- 23746474 TI - Notable difference in anti-HIV activity of integrase inhibitors as a consequence of geometric and enantiomeric configurations. AB - While some examples are known of integrase inhibitors that exhibit potent anti HIV activity, there are very few cases reported of integrase inhibitors that show significant differences in anti-HIV activity that result from distinctions in cis and trans-configurations as well as enantiomeric stereostructure. We describe here the design and synthesis of two enantiomeric trans-hydroxycyclopentyl carboxamides which exhibit notable difference in anti-HIV activity. This difference is explained through their binding interactions within the active site of the HIV-1 integrase intasome. The more active enantiomer 3 (EC50 25nM) was relatively stable in human liver microsomes. Kinetic data revealed that its impact on key cytochrome P450 isozymes, as either an inhibitor or an activator, was minor, suggesting a favorable CYP profile. PMID- 23746475 TI - The identification of novel p38alpha isoform selective kinase inhibitors having an unprecedented p38alpha binding mode. AB - A novel series of p38 MAP kinase inhibitors with high selectivity for the p38alpha isoform over the other family members including the highly homologous p38beta isoform has been identified. X-ray co-crystallographic studies have revealed an unprecedented kinase binding mode in p38alpha for representative analogs, 5c and 9d, in which a Leu108/Met109 peptide flip occurs within the p38alpha hinge region. Based on these findings, a general strategy for the rational design of additional promising p38alpha isoform selective inhibitors by targeting this novel binding mode is proposed. PMID- 23746476 TI - Synthesis and evaluation of a conditionally-silent agonist for the alpha7 nicotinic acetylcholine receptor. AB - We introduce the term 'silent agonists' to describe ligands that can place the alpha7 nicotinic acetylcholine receptor (nAChR) into a desensitized state with little or no apparent activation of the ion channel, forming a complex that can subsequently generate currents when treated with an allosteric modulator. KC-1 (5'-phenylanabaseine) was synthesized and identified as a new silent agonist for the alpha7 nAChR; it binds to the receptor but does not activate alpha7 nAChR channel opening when applied alone, and its agonism is revealed by co-application with the type II positive allosteric modulator PNU-120596 in the Xenopus oocyte system. The concise synthesis was accomplished in three steps with the C-C bonds formed via Pd-catalyzed mono-arylation and organolithium coupling with N-Boc piperidinone. Comparative structural analyses indicate that a positive charge, an H-bond acceptor, and an aryl ring in a proper arrangement are needed to constitute one class of silent agonist for the alpha7 nAChR. Because silent agonists may act on signaling pathways not involving ion channel opening, this class of alpha7 nAChR ligands may constitute a new alternative for the development of alpha7 nAChR therapeutics. PMID- 23746477 TI - New bioactive dihydrofuranocoumarins from the roots of the Tunisian Ferula lutea (Poir.) Maire. AB - A phytochemical investigation of the roots of Ferula lutea (Poir.) Maire led to the isolation of new dihydrofuranocoumarins as two inseparable isomers, (-)-5 hydroxyprantschimgin 1 and (-)-5-hydroxydeltoin 2, together with eight known compounds, (-)-prantschimgin 3, (-)-deltoin 4, psoralen 5, xanthotoxin 6, umbelliferone 7, caffeic acid 8, beta-sitosterol 9 and stigmasterol 10. Their structures were elucidated on the basis of extensive spectroscopic methods, including 1D and 2D NMR experiments and mass spectroscopy analysis, as well as by comparison with literature data. The anti-acetylcholinesterase and cytotoxic effects of the isolates and antioxidant activities of the mixture (1+2) were also evaluated in this work. Results showed that the mixture (1+2) has the most cytotoxic activity with IC50 values 0.29+/-0.05 and 1.61+/-0.57MUM against the cell lines HT-29 and HCT 116, respectively. The greatest acetylcholinesterase inhibitory activity (IC50=0.76+/-0.03) was exhibited by the xanthotoxin 6. In addition, the mixture (1+2) was investigated for its antioxidant activity and showed IC50 values 18.56, 13.06, 7.59, and 4.81MUM towards DPPH free radical scavenging, ABTS radical monocation, singlet oxygen and hydrogen peroxide, respectively. PMID- 23746478 TI - Preliminary genetic analyses of important musculoskeletal conditions of Thoroughbred racehorses in Hong Kong. AB - A retrospective cohort study of important musculoskeletal conditions of Thoroughbred racehorses was conducted using health records generated over a 15 year period (n=5062, 1296 sires). The prevalence of each condition in the study population was: fracture, 13%; osteoarthritis, 10%; suspensory ligament injury, 10%; and tendon injury, 19%. Linear and logistic sire and animal regression models were built to describe the binary occurrence of these musculoskeletal conditions, and to evaluate the significance of possible environmental risk factors. The heritability of each condition was estimated using residual maximum likelihood (REML). Bivariate mixed models were used to generate estimates of genetic correlations between each pair of conditions. Heritability estimates of fracture, osteoarthritis, suspensory ligament and tendon injury were small to moderate (range: 0.01-0.20). Fracture was found to be positively genetically correlated with both osteoarthritis and suspensory ligament injury. These results suggest that there is a significant genetic component involved in the risk of the studied conditions. Due to positive genetic correlations, a reduction in prevalence of one of the correlated conditions may effect a reduction in risk of the other condition. PMID- 23746479 TI - Impact of bivalirudin and paclitaxel-eluting stents on outcomes in patients undergoing primary percutaneous coronary intervention of the left anterior descending artery. AB - Patients with ST elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) of the left anterior descending artery (LAD) are at increased risk for cardiovascular events compared with patients undergoing non-LAD PCI. We assessed the impact of bivalirudin and paclitaxel eluting stenting (PES) in patients with STEMI who underwent LAD PCI. In the HORIZONS-AMI trial, 1,445 patients had LAD PCI and 1,884 patients had non-LAD PCI. The 3-year composite rates of death, reinfarction, stroke, or ischemia driven target vessel revascularization were significantly higher in patients who underwent LAD PCI compared with non-LAD PCI (24.0% vs 20.6%, hazard ratio [HR] 1.20, 95% confidence interval [CI] 1.04 to 1.39, p = 0.013), driven by a statistically significant increase in cardiac death (5.4% vs 2.7%, HR 2.00, 95% CI 1.40 to 2.86, p = 0.001). For patients who underwent LAD PCI, treatment with bivalirudin resulted in significantly lower rates of cardiac death (3.8% vs 6.8%, HR 0.55, 95% CI 0.34 to 0.89, p = 0.01), reinfarction (5.3% vs 9.5%, HR 0.55, 95% CI 0.37 to 0.83, p = 0.004), and major bleeding events (7.3% vs 11.8%, HR 0.60, 95% CI 0.43 to 0.86, p = 0.004) compared with unfractionated heparin plus glycoprotein IIb/IIIa inhibitor. Randomization to PES compared with bare-metal stenting resulted in a significant lower rate of target vessel revascularization (13.2% vs 19.8%, HR 0.64, 95% CI 0.47 to 0.86, p = 0.003) with no significant differences in stent thrombosis, reinfarction, or death. In conclusion, in patients with STEMI who underwent primary PCI of LAD, the use of bivalirudin was associated with a reduction in mortality and bleeding rates at 3 years. PES reduced revascularization rates in this population but did not have a significant impact on mortality. PMID- 23746480 TI - Usefulness of high-sensitivity cardiac troponin T and brain natriuretic peptide as biomarkers of myocardial fibrosis in patients with hypertrophic cardiomyopathy. AB - Myocardial fibrosis assessed by late gadolinium enhancement cardiac magnetic resonance imaging is associated with cardiovascular events in patients with hypertrophic cardiomyopathy (HC), but few data are available regarding the utility of biomarkers for detecting late gadolinium enhancement. The aim of this study was to examine serum levels of myoglobin, cardiac myosin light chain I, high-sensitivity cardiac troponin T (hs-cTnT), and creatine kinase-MB isoenzyme and plasma levels of brain natriuretic peptide (BNP) in relation to late gadolinium enhancement in 53 patients with HC. Levels of hs-cTnT and BNP were higher in 23 patients with late gadolinium enhancement than in 30 patients without it (p <0.01 for both). An hs-cTnT level >=0.007 ng/ml or a BNP level >=70 pg/ml had good diagnostic value for detecting late gadolinium enhancement, with sensitivity of 96% or specificity of 90% with the combination of these 2 biomarkers. The extent of late gadolinium enhancement was correlated with BNP level (p <0.01) but not with hs-cTnT level in 23 patients with HC with late gadolinium enhancement. The increase in the extent of late gadolinium enhancement was related to hs-cTnT level in 8 patients during 22 months of follow-up (p = 0.02). In conclusion, the combination of hs-cTnT and BNP is useful in detecting myocardial fibrosis in patients with HC. The findings of this study indicate that hs-cTnT is a direct marker of ongoing myocardial fibrosis and that BNP is a marker of left ventricular overload partially associated with myocardial fibrosis. PMID- 23746481 TI - Endothelial progenitor cells, microvascular obstruction, and left ventricular remodeling in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - Endothelial progenitor cells (EPCs) are released from the bone marrow during cardiac ischemic events, potentially influencing vascular and myocardial repair. We assessed the clinical and angiographic correlates of EPC mobilization at the time of primary percutaneous coronary intervention in 78 patients with ST elevation myocardial infarction and the impact of both baseline and follow-up EPC levels on left ventricular (LV) remodeling. Blood samples were drawn from the aorta and the culprit coronary artery for cytofluorimetric EPC detection (CD34+CD45dimKDR+ cells, in percentage of cytofluorimetric counts). Area at risk was assessed by Bypass Angioplasty Revascularization Investigation myocardial jeopardy index, thrombotic burden as thrombus score and microvascular obstruction (MVO) as a combination of ST segment resolution and myocardial blush grade. Echocardiographic evaluation of LV remodeling was performed at 1-year follow-up in 54 patients, whereas peripheral EPC levels were reassessed in 40 patients. EPC levels during primary percutaneous coronary intervention were significantly higher in intracoronary than in aortic blood (0.043% vs 0.0006%, p <0.001). Both intracoronary and aortic EPC were related to area at risk extent, to intracoronary thrombus score (p <0.001), and inversely to MVO (p = 0.001). Peripheral EPC levels at 1-year follow-up were lower in patients with LV remodeling than in those without (0.001% [0.001 to 0.002] vs 0.003% [0.002 to 0.010]; p = 0.01) and independently predicted absence of remodeling at multivariate analysis. In conclusion, a rapid intracoronary EPC recruitment takes place in the early phases of ST elevation myocardial infarction, possibly reflecting an attempted reparative response. The extent of this mobilization seems to be correlated to the area at risk and to the amount of MVO. Persistently low levels of EPC are associated to LV remodeling. PMID- 23746482 TI - Differential chemokine responses in the murine brain following lyssavirus infection. AB - The hallmark of lyssavirus infection is lethal encephalomyelitis. Previous studies have reported distinct lyssavirus isolate-related differences in severity of cellular recruitment into the encephalon in a murine model of infection following peripheral inoculation with rabies virus (RABV) and European bat lyssavirus (EBLV)-1 and -2. In order to understand the role of chemokines in this process, comparative studies of the chemokine pattern, distribution and production in response to infection with these lyssaviruses were undertaken. Expression of CCL2, CCL5 and CXCL10 was observed throughout the murine brain with a distinct caudal bias in distribution, similar to both inflammatory changes and virus antigen distribution. CCL2 immunolabelling was localized to neuronal and astroglial populations. CCL5 immunolabelling was only detected in the astroglia, while CXCL10 labelling, although present in the astroglia, was more prominent in neurons. Isolate-dependent differences in the amount of chemokine immunolabelling in specific brain regions and chemokine production by neurons in vitro were observed, with a greater expression of CCL5 in vivo and CXCL10 production in vitro after EBLV infection. Additionally, strong positive associations between chemokine immunolabelling and perivascular cuffing and, to a lesser extent, virus antigen score were also observed. These differences in chemokine expression may explain the variation in severity of encephalitic changes observed in animals infected with different lyssavirus isolates. PMID- 23746483 TI - Oncocytic adrenocortical carcinoma in a putty-nosed monkey (Cercopithecus nictitans) with hyperadrenocorticism. AB - Oncocytic adrenocortical tumours are rare in man and have never been described in non-human primates. An oncocytic adrenocortical carcinoma was identified in an 18 year-old female putty-nosed monkey (Cercopithecus nictitans) with hyperadrenocorticism and invasive aspergillosis. Microscopically, the tumour consisted of large cells with abundant eosinophilic, granular cytoplasm containing numerous mitochondria as identified by electron microscopy. Tumour cells had large nuclei with occasional intranuclear cytoplasmic pseudoinclusions. Immunohistochemically, tumour cells expressed vimentin, synaptophysin and neuron specific enolase, while they were negative for cytokeratin, chromogranin-A, melan A and S100. PMID- 23746485 TI - Prenatal vitamin D status and risk of psychotic experiences at age 18years-a longitudinal birth cohort. AB - BACKGROUND: Low early life vitamin D status is associated with an increased risk of schizophrenia and psychotic experiences. Here we examine if maternal pregnancy vitamin D concentrations are associated with offspring psychotic experiences as young adults. METHODS: A community sample of 2047 participants was investigated. Maternal prenatal 25 hydroxyvitamin D (25(OH)D) concentrations were assessed with tandem mass spectroscopy. Psychotic experiences were assessed at age 18years using a semi-structured clinical interview. RESULTS: 177 cohort members reported suspected or definite psychotic experiences, There was no evidence of an association between maternal 25(OH)D concentrations as quartiles (p=0.85 hypothesis test of general association versus no association across the quartiles) or as a continuous variable (p=0.89) versus experience of suspected and definite psychotic experiences at 18years. Within the cohort, only 29 subjects met criteria for a psychotic disorder at age 18. Based on this sample, there was no significant association between maternal 25(OH)D and psychotic disorder at 18years. DISCUSSION: Maternal vitamin D levels were not associated with risk of psychotic experiences nor psychotic disorders in this birth cohort. PMID- 23746484 TI - Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia. AB - The origin of inflammation in psychiatric disorders is not well understood. The translocation of commensal microbiota across the gastrointestinal barrier can result in a persistent state of low-grade immune activation and/or inflammation. We measured serological surrogate markers of bacterial translocation (soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP)) in two psychiatric cohorts and compared these levels to C-reactive protein (CRP), body mass index (BMI), and food-related and autoimmune antibodies. The two cohorts were composed of the following: (1) n=141 schizophrenia, n=75 bipolar disorder, n=78 controls; (2) n=78 antipsychotic-naive first-episode schizophrenia, n=38 medicated first episode schizophrenia. sCD14 seropositivity conferred a 3.1-fold increased odds of association with schizophrenia (multivariate regressions, OR=3.09, p<0.0001) compared to controls. Case-control differences in sCD14 were not matched by LBP. Quantitative levels of LBP, but not sCD14, correlated with BMI in schizophrenia (R(2)=0.21, p<0.0001). sCD14 and LBP also exhibited some congruency in schizophrenia with both significantly correlated with CRP (R(2)=0.26-0.27, p<0.0001) and elevated in females compared to males (p<0.01). Antipsychotic treatment generally did not impact sCD14 or LBP levels except for significant correlations, especially sCD14, with gluten antibodies in antipsychotic-naive schizophrenia (R(2)=0.27, p<0.0001). In bipolar disorder, sCD14 levels were significantly correlated with anti-tissue transglutaminase IgG (R(2)=0.37, p<0.001). In conclusion, these bacterial translocation markers produced discordant and complex patterns of activity, a finding that may reflect an imbalanced, activated innate immune state. Whereas both markers may upregulate following systemic exposure to Gram-negative bacteria, non-lipopolysaccharide based monocyte activation, autoimmunity and metabolic dysfunction may also contribute to the observed marker profiles. PMID- 23746486 TI - Demographic, socio-environmental, and substance-related predictors of duration of untreated psychosis (DUP). AB - OBJECTIVE: Longer duration of untreated psychosis (DUP) is associated with poorer early-course and long-term outcomes, and is a target of early detection and intervention efforts. Given the paucity of research on childhood and adolescent stressors (e.g., maltreatment and neighborhood disorder) as potential predictors of DUP, limited research on premorbid substance use as a determinant of DUP, and inconclusive findings on the association between DUP and neurocognition, we conducted three sets of analyses to address these issues. Mode of onset of psychosis was also considered, given its established role as an illness-level correlate of DUP. METHODS: We rigorously assessed DUP and other pertinent variables in 180 predominantly African American, low-income, and socially disadvantaged first-episode psychosis patients hospitalized in five psychiatric units. RESULTS: Mode of onset of psychosis, prior incarceration, and the level of childhood/adolescent maltreatment were all significant independent predictors of DUP. Regarding premorbid substance use, having ever used cannabis and the amount of premorbid alcohol use were significantly associated with DUP. None of the seven neurocognitive domains assessed were even modestly, or clinically meaningfully, associated with DUP. CONCLUSIONS: These and other findings on DUP may be informative for early detection and intervention services. For example, such services might benefit from special outreach to criminal justice settings and disadvantaged neighborhoods, and to young people likely to have a history of childhood/adolescent maltreatment and gradually developing psychotic symptoms. PMID- 23746487 TI - Effect of overground vs treadmill running on plantar pressure: influence of fatigue. AB - The differences produced when running on a treadmill vs overground may call into question the use and validity of the treadmill as a piece of equipment commonly used in research, training, and rehabilitation. The aim of the present study was to analyze under pre/post fatigue conditions the effect of treadmill vs overground on plantar pressures. Twenty-seven recreational runners (17 men and 10 women) ran on a treadmill and overground at two speeds: S1=3.33 m/s and S2=4.00 m/s, before and after a fatigue protocol consisting of a 30-min run at 85% of their individual maximal aerobic speed (MAS). Contact time (CT in seconds), peak pressure (PP in kPa), and relative load (RL in %) were analyzed under nine foot zones of the left foot using an in-shoe plantar pressure device. A two-way repeated measures ANOVA showed that running on a treadmill increases CT (7.70% S1 and 9.91% S2), modifies the pressure distribution and reduces PP (25.98% S1 and 31.76% S2), especially under the heel, medial metatarsals, and hallux, compared to running overground. Moreover, on both surfaces, fatigue (S2) led to a reduced stride frequency (2.78%) and reduced PP on the lateral heel and hallux (15.96% and 16.35%, respectively), and (S1) increased relative load on the medial arch (9.53%). There was no significant interaction between the two factors analyzed (surface and fatigue). Therefore, the aforementioned surface effect, which occurs independently of the fatigue state, should be taken into account when interpreting the results of studies that use the treadmill in their experimental protocols, and when prescribing physical exercise on a treadmill. PMID- 23746488 TI - Localizing target structures in ultrasound video - a phantom study. AB - The problem of localizing specific anatomic structures using ultrasound (US) video is considered. This involves automatically determining when an US probe is acquiring images of a previously defined object of interest, during the course of an US examination. Localization using US is motivated by the increased availability of portable, low-cost US probes, which inspire applications where inexperienced personnel and even first-time users acquire US data that is then sent to experts for further assessment. This process is of particular interest for routine examinations in underserved populations as well as for patient triage after natural disasters and large-scale accidents, where experts may be in short supply. The proposed localization approach is motivated by research in the area of dynamic texture analysis and leverages several recent advances in the field of activity recognition. For evaluation, we introduce an annotated and publicly available database of US video, acquired on three phantoms. Several experiments reveal the challenges of applying video analysis approaches to US images and demonstrate that good localization performance is possible with the proposed solution. PMID- 23746490 TI - Do conversations with virtual avatars increase feelings of social anxiety? AB - Virtual reality (VR) technology provides a way to conduct exposure therapy with patients with social anxiety. However, the primary limitation of current technology is that the operator is limited to pre-programed avatars that cannot be controlled to interact/converse with the patient in real time. The current study piloted new technology allowing the operator to directly control the avatar (including speaking) during VR conversations. Using an incomplete repeated measures (VR vs. in vivo conversation) design and random starting order with rotation counterbalancing, participants (N = 26) provided ratings of fear and presence during both VR and in vivo conversations. Results showed that VR conversation successfully elevated fear ratings relative to baseline (d = 2.29). Participants also rated their fear higher during VR conversation than during in vivo conversation (d = 0.85). However, in vivo conversation was rated as more realistic than VR conversation (d = 0.74). No participants dropped out and 100% completed both VR and in vivo conversations. Qualitative participant comments suggested that the VR conversations would be more realistic if they did not meet the actor/operator and if they were not in the same room as the participant. Overall, the data suggest that the novel technology allowing real time interaction/conversation in VR may prove useful for the treatment of social anxiety in future studies. PMID- 23746489 TI - Voxel-based morphometric gray matter correlates of posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) is associated with functional abnormalities within a neurocircuitry that includes the hippocampus, amygdala, and medial prefrontal cortex. Evidence of structural abnormalities within these regions, and their association with PTSD severity and symptom burden is, however, sparse. The present study evaluated the relation between indices of gray matter volume and PTSD symptom severity using voxel-based morphometry. Fifteen individuals meeting DSM-IV criteria for PTSD completed the Clinician Administered PTSD Scale and underwent structural magnetic resonance imaging. Greater PTSD severity and avoidance/numbing were correlated with increased gray matter volume of the right amygdala-hippocampal complex. Greater hyper-arousal was associated with reduced gray matter volume in the left superior medial frontal gyrus. Findings are consistent with current neurocircuitry models of PTSD, which posit that the disorder is associated with structural and functional variance within this distributed network. PMID- 23746491 TI - Association study between MAO-A gene promoter VNTR polymorphisms and obsessive compulsive disorder. AB - A functional variant in the mono-amine oxidase-A (MAO-A) gene has been shown to affect neural function related to several mental disorders. Therefore, we would like to ascertain if MAO-A could be a candidate gene for obsessive-compulsive disorder (OCD). We genotyped 414 healthy subjects and 240 OCD patients and found no significant difference not only in allele frequencies in male patients (chi(2) = 0.365, DF = 1, P = 0.545, odds ratio (OR) = 1.139, confidence interval (CI) = 0.75-1.74) but also in allele frequencies (chi(2) = 0.698, DF = 1, P = 0.404, OR = 0.849, CI = 0.579-1.246) or genotypic frequencies (chi(2)=0.933, DF = 2, P = 0.627) in female patients between OCD patients and controls. Given that this is the first investigation of this gene in OCD in a Chinese Han population, further studies are required to obtain more definitive conclusions in a larger number of subjects. PMID- 23746492 TI - Infant distress to novelty is associated with maternal anxiety disorder and especially with maternal avoidance behavior. AB - Research suggested that maternal anxiety disorders might be related to infants' behavioral inhibition. This study investigated whether maternal postpartum anxiety disorder is associated with infant temperament, more precisely, infant distress to novelty, an early predictor of behavioral inhibition. Differences in the latter were analyzed in a German sample by comparing n = 38 healthy mother infant dyads to n=44 dyads comprised of mothers diagnosed with a DSM-IV anxiety disorders. Infant age ranged from 2.83 to 7.97 months. Infant temperament was measured by means of the Infant Behavior Questionnaire. Mothers were screened for postpartum anxiety disorder using the Structured Clinical Interview for DSM-IV Disorders. Severity of anxiety was measured by self-reported questionnaires (Anxiety Cognition Questionnaire, Body Sensations Questionnaire and Mobility Inventory). Infant salivary cortisol reaction when being confronted with a socio emotional stressor (Face-to-Face-Still-Face paradigm) was assessed to validate infant distress. A Mann-Whitney-U analysis suggested that infants of mothers with an anxiety disorder show more distress to novelty than infants of healthy mothers. Furthermore, data reveal a positive Spearman's rho-correlation between infant distress to novelty and maternal avoidance behavior (Mobility Inventory). A strong correlation between infant cortisol reactivity and reported distress to novelty validated the maternal evaluation of infant temperament in our sample. Results suggest a possible approach to promote infant development by encouraging mothers with anxiety symptoms to encounter feared stimuli. PMID- 23746493 TI - The role of social isolation in social anxiety disorder: a systematic review and meta-analysis. AB - INTRODUCTION: Social isolation in the context of social anxiety disorder has not been closely examined. This study aimed to describe the role and measurement of social isolation in those with social anxiety disorder. METHOD: A systematic review and meta-analyses were conducted using a prospectively prepared protocol for search strategy, selection criteria, and data extraction. DerSimonian-Laird random effects models were used to calculate pooled estimates of effect. RESULTS: Thirty-four studies, containing 20 formal instruments and four other measures of social isolation, were included. Most formal instruments were utilized in single studies, whereas simple structural measures (e.g., living alone) were used most frequently. The pooled score was 38.1 on the Loneliness and Social Dissatisfaction Questionnaire, 33.1 on the Liebowitz Social Anxiety Scale (avoidance subscale), and 21.1 on the Social Avoidance and Distress Scale. CONCLUSIONS: Social isolation is common in social anxiety disorder but assessed by a heterogeneous mix of measures. PMID- 23746494 TI - A critical review of approaches to the treatment of dental anxiety in adults. AB - Dental anxiety and specific phobia of dental procedures are prevalent conditions that can result in substantial distress and oral health impairment. This paper critically reviews 22 randomized treatment trials aimed at reducing dental anxiety and avoidance in adults, published in peer-reviewed journals between 1974 and 2012. The following treatment techniques are reviewed: various forms of cognitive-behavioral therapy (CBT), relaxation training, benzodiazepine premedication, music distraction, hypnotherapy, acupuncture, nitrous oxide sedation, and the use of lavender oil scent. CBT delivered in a variety of formats, including one-session treatment, has the most evidence for its efficacy. Cognitive techniques, relaxation, and techniques to increase patients' sense of control over dental care are also efficacious but perform best when combined with repeated, graduated exposure. Other interventions require further study in randomized trials before conclusions about their efficacy are warranted. Limitations of the extant outcome research and implications for future treatment and research are discussed. PMID- 23746495 TI - Posttraumatic stress disorder in OEF/OIF veterans with and without traumatic brain injury. AB - Veterans of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF) are presenting with high rates of co-occurring posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI). The purpose of this study was to compare the clinical presentations of combat-veterans with PTSD and TBI (N = 40) to those with PTSD only (N = 56). Results suggest that the groups present two distinct clinical profiles, with the PTSD + TBI group endorsing significantly higher PTSD scores, higher overall anxiety, and more functional limitations. The higher PTSD scores found for the PTSD + TBI group appeared to be due to higher symptom intensity, but not higher frequency, across PTSD clusters and symptoms. Groups did not differ on additional psychopathology or self-report of PTSD symptoms or executive functioning. Further analysis indicated PTSD severity, and not TBI, was responsible for group differences, suggesting that treatments implicated for PTSD would likely be effective for this population. PMID- 23746496 TI - Comparison of quantitative EEG between patients with Alzheimer's disease and those with Parkinson's disease dementia. AB - OBJECTIVE: Dementia frequently occurs in Parkinson's disease (PD) but its pathophysiological basis is little known. Comparative EEG studies of Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) are still rare, but could provide knowledge on the different pathophysiological mechanisms involved. The objective of the present study was to comparatively evaluate the absolute power and coherence on the EEG for patients with AD and PDD. METHODS: This study assessed 38 adults with AD, 12 with PDD, 31 with Parkinson's disease without dementia, and 37 controls (CG) by a neurological evaluation, CERAD neuropsychological battery, executive functions tests and qEEG, calculating global absolute powers for the delta, theta, alpha and beta bands and inter- and intra-hemispheric coherences. RESULTS: The delta and theta powers were highest in PDD and lowest in CG (p<0.05). The beta frontal-occipital inter-hemispheric coherence was highest in PDD (p<0.05). Whereas, alpha and beta frontal inter hemispheric coherence was highest in PDD and lowest in AD (p<0.05). CONCLUSION: These results suggest that qEEG power and coherence measures are different in AD and PDD. SIGNIFICANCE: These qEEG differences must be related to the distinct mechanisms of cortical neural connections in AD and PDD. PMID- 23746497 TI - Reproducibility of contact heat evoked potentials (CHEPs) over a 6 months interval. AB - OBJECTIVE: Contact heat evoked potentials (CHEPs) mediated by primary afferent Adelta-fibers can be recorded at the vertex. CHEPs are reduced in small fibre neuropathy and considered as a noninvasive measure of small fibre function. As long-term stability of CHEPs has not been examined, it is presently not clear if CHEPs may also be useful for following the course of small fibre neuropathy. METHODS: Here, we analyzed CHEPs from 60 healthy subjects recorded at two occasions separated by 6 months. RESULTS: There was a systematic shift towards larger amplitudes (from 40.2 +/- 13.8 MUV to 53.3 +/- 17.5 MUV, p<0.001) and towards shorter latencies (from 425.0 +/- 28.8 ms to 387.2 +/- 30.3 ms, p<0.001) after six months, while CHEP areas were more constant over time. CONCLUSIONS: The present results show that systematic changes of CHEP amplitudes and latencies may occur over time. Possible reasons include seasonal differences in skin conductivity for heat and psychological effects. SIGNIFICANCE: CHEP areas seem to be more stable over time than amplitudes or latencies, however, it remains to be determined if CHEP areas differentiate between subjects with lesions of the nociceptive system and healthy controls as reliably as CHEP amplitudes. PMID- 23746498 TI - Vestibular evoked myogenic potentials: the fuzzy picture of different stimulation types is beginning to come into focus. PMID- 23746500 TI - [Acute confusional syndrome due to levofloxacin]. PMID- 23746499 TI - Forward and inverse electroencephalographic modeling in health and in acute traumatic brain injury. AB - OBJECTIVE: EEG source localization is demonstrated in three cases of acute traumatic brain injury (TBI) with progressive lesion loads using anatomically faithful models of the head which account for pathology. METHODS: Multimodal magnetic resonance imaging (MRI) volumes were used to generate head models via the finite element method (FEM). A total of 25 tissue types-including 6 types accounting for pathology-were included. To determine the effects of TBI upon source localization accuracy, a minimum-norm operator was used to perform inverse localization and to determine the accuracy of the latter. RESULTS: The importance of using a more comprehensive number of tissue types is confirmed in both health and in TBI. Pathology omission is found to cause substantial inaccuracies in EEG forward matrix calculations, with lead field sensitivity being underestimated by as much as ~ 200% in (peri-) contusional regions when TBI-related changes are ignored. Failing to account for such conductivity changes is found to misestimate substantial localization error by up to 35 mm. CONCLUSIONS: Changes in head conductivity profiles should be accounted for when performing EEG modeling in acute TBI. SIGNIFICANCE: Given the challenges of inverse localization in TBI, this framework can benefit neurotrauma patients by providing useful insights on pathophysiology. PMID- 23746501 TI - Superresolution imaging--caveolae, caveolins, mitochondria, and function in heart. PMID- 23746502 TI - A slippery walk to the microtubule-end. PMID- 23746503 TI - Another disordered chameleon: the Micro-Exon Gene 14 protein from Schistosomiasis. PMID- 23746504 TI - Queueing up for translation. PMID- 23746505 TI - Modeling stochastic kinetics of molecular machines at multiple levels: from molecules to modules. AB - A molecular machine is either a single macromolecule or a macromolecular complex. In spite of the striking superficial similarities between these natural nanomachines and their man-made macroscopic counterparts, there are crucial differences. Molecular machines in a living cell operate stochastically in an isothermal environment far from thermodynamic equilibrium. In this mini-review we present a catalog of the molecular machines and an inventory of the essential toolbox for theoretically modeling these machines. The tool kits include 1), nonequilibrium statistical-physics techniques for modeling machines and machine driven processes; and 2), statistical-inference methods for reverse engineering a functional machine from the empirical data. The cell is often likened to a microfactory in which the machineries are organized in modular fashion; each module consists of strongly coupled multiple machines, but different modules interact weakly with each other. This microfactory has its own automated supply chain and delivery system. Buoyed by the success achieved in modeling individual molecular machines, we advocate integration of these models in the near future to develop models of functional modules. A system-level description of the cell from the perspective of molecular machinery (the mechanome) is likely to emerge from further integrations that we envisage here. PMID- 23746507 TI - Mitochondrial free Ca2+ levels and their effects on energy metabolism in Drosophila motor nerve terminals. AB - Mitochondrial Ca2+ uptake exerts dual effects on mitochondria. Ca2+ accumulation in the mitochondrial matrix dissipates membrane potential (DeltaPsim), but Ca2+ binding of the intramitochondrial enzymes accelerates oxidative phosphorylation, leading to mitochondrial hyperpolarization. The levels of matrix free Ca2+ ([Ca2+]m) that trigger these metabolic responses in mitochondria in nerve terminals have not been determined. Here, we estimated [Ca2+]m in motor neuron terminals of Drosophila larvae using two methods: the relative responses of two chemical Ca2+ indicators with a 20-fold difference in Ca2+ affinity (rhod-FF and rhod-5N), and the response of a low-affinity, genetically encoded ratiometric Ca2+ indicator (D4cpv) calibrated against known Ca2+ levels. Matrix pH (pHm) and DeltaPsim were monitored using ratiometric pericam and tetramethylrhodamine ethyl ester probe, respectively, to determine when mitochondrial energy metabolism was elevated. At rest, [Ca2+]m was 0.22 +/- 0.04 MUM, but it rose to ~26 MUM (24.3 +/ 3.4 MUM with rhod-FF/rhod-5N and 27.0 +/- 2.6 MUM with D4cpv) when the axon fired close to its endogenous frequency for only 2 s. This elevation in [Ca2+]m coincided with a rapid elevation in pHm and was followed by an after-stimulus DeltaPsim hyperpolarization. However, pHm decreased and no DeltaPsim hyperpolarization was observed in response to lower levels of [Ca2+]m, up to 13.1 MUM. These data indicate that surprisingly high levels of [Ca2+]m are required to stimulate presynaptic mitochondrial energy metabolism. PMID- 23746506 TI - Mechanical consequences of cell-wall turnover in the elongation of a Gram positive bacterium. AB - A common feature of walled organisms is their exposure to osmotic forces that challenge the mechanical integrity of cells while driving elongation. Most bacteria rely on their cell wall to bear osmotic stress and determine cell shape. Wall thickness can vary greatly among species, with Gram-positive bacteria having a thicker wall than Gram-negative bacteria. How wall dimensions and mechanical properties are regulated and how they affect growth have not yet been elucidated. To investigate the regulation of wall thickness in the rod-shaped Gram-positive bacterium Bacillus subtilis, we analyzed exponentially growing cells in different media. Using transmission electron and epifluorescence microscopy, we found that wall thickness and strain were maintained even between media that yielded a threefold change in growth rate. To probe mechanisms of elongation, we developed a biophysical model of the Gram-positive wall that balances the mechanical effects of synthesis of new material and removal of old material through hydrolysis. Our results suggest that cells can vary their growth rate without changing wall thickness or strain by maintaining a constant ratio of synthesis and hydrolysis rates. Our model also indicates that steady growth requires wall turnover on the same timescale as elongation, which can be driven primarily by hydrolysis rather than insertion. This perspective of turnover-driven elongation provides mechanistic insight into previous experiments involving mutants whose growth rate was accelerated by the addition of lysozyme or autolysin. Our approach provides a general framework for deconstructing shape maintenance in cells with thick walls by integrating wall mechanics with the kinetics and regulation of synthesis and turnover. PMID- 23746508 TI - A random motility assay based on image correlation spectroscopy. AB - We demonstrate the random motility (RAMOT) assay based on image correlation spectroscopy for the automated, label-free, high-throughput characterization of random cell migration. The approach is complementary to traditional migration assays, which determine only the collective net motility in a particular direction. The RAMOT assay is less demanding on image quality compared to single cell tracking, does not require cell identification or trajectory reconstruction, and performs well on live-cell, time-lapse, phase contrast video microscopy of hundreds of cells in parallel. Effective diffusion coefficients derived from the RAMOT analysis are in quantitative agreement with Monte Carlo simulations and allowed for the detection of pharmacological effects on macrophage-like cells migrating on a planar collagen matrix. These results expand the application range of image correlation spectroscopy to multicellular systems and demonstrate a novel, to our knowledge, migration assay with little preparative effort. PMID- 23746509 TI - Tracking image correlation: combining single-particle tracking and image correlation. AB - The interactions and coordination of biomolecules are crucial for most cellular functions. The observation of protein interactions in live cells may provide a better understanding of the underlying mechanisms. After fluorescent labeling of the interacting partners and live-cell microscopy, the colocalization is generally analyzed by quantitative global methods. Recent studies have addressed questions regarding the individual colocalization of moving biomolecules, usually by using single-particle tracking (SPT) and comparing the fluorescent intensities in both color channels. Here, we introduce a new method that combines SPT and correlation methods to obtain a dynamical 3D colocalization analysis along single trajectories of dual-colored particles. After 3D tracking, the colocalization is computed at each particle's position via the local 3D image cross correlation of the two detection channels. For every particle analyzed, the output consists of the 3D trajectory, the time-resolved 3D colocalization information, and the fluorescence intensity in both channels. In addition, the cross-correlation analysis shows the 3D relative movement of the two fluorescent labels with an accuracy of 30 nm. We apply this method to the tracking of viral fusion events in live cells and demonstrate its capacity to obtain the time-resolved colocalization status of single particles in dense and noisy environments. PMID- 23746510 TI - Exponential sum-fitting of dwell-time distributions without specifying starting parameters. AB - Fitting dwell-time distributions with sums of exponentials is widely used to characterize histograms of open- and closed-interval durations recorded from single ion channels, as well as for other physical phenomena. However, it can be difficult to identify the contributing exponential components. Here we extend previous methods of exponential sum-fitting to present a maximum-likelihood approach that consistently detects all significant exponentials without the need for user-specified starting parameters. Instead of searching for exponentials, the fitting starts with a very large number of initial exponentials with logarithmically spaced time constants, so that none are missed. Maximum likelihood fitting then determines the areas of all the initial exponentials keeping the time constants fixed. In an iterative manner, with refitting after each step, the analysis then removes exponentials with negligible area and combines closely spaced adjacent exponentials, until only those exponentials that make significant contributions to the dwell-time distribution remain. There is no limit on the number of significant exponentials and no starting parameters need be specified. We demonstrate fully automated detection for both experimental and simulated data, as well as for classical exponential-sum-fitting problems. PMID- 23746511 TI - Structural flexibility of CaV1.2 and CaV2.2 I-II proximal linker fragments in solution. AB - Voltage-dependent calcium channels (CaV) enable the inward flow of calcium currents for a wide range of cells. CaV1 and CaV2 subtype alpha1 subunits form the conducting pore using four repeated membrane domains connected by intracellular linkers. The domain I-II linker connects to the membrane gate (IS6), forming an alpha-helix, and is bound to the CaVbeta subunit. Previous studies indicated that this region may or may not form a continuous helix depending on the CaV subtype, thereby modulating channel activation and inactivation properties. Here, we used small-angle x-ray scattering and ensemble modeling analysis to investigate the solution structure of these linkers, extending from the membrane domain and including the CaVbeta-binding site, called the proximal linker (PL). The results demonstrate that the CaV1.2 PL is more flexible than the CaV2.2 PL, the flexibility is intrinsic and not dependent on CaVbeta binding, and the flexibility can be most easily explained by the presence of conserved glycines. Our analysis also provides a robust example of investigating protein domains in which flexibility plays an essential role. PMID- 23746512 TI - The mechanism of Na+/K+ selectivity in mammalian voltage-gated sodium channels based on molecular dynamics simulation. AB - Voltage-gated sodium (Nav) channels and their Na+/K+ selectivity are of great importance in the mammalian neuronal signaling. According to mutational analysis, the Na+/K+ selectivity in mammalian Nav channels is mainly determined by the Lys and Asp/Glu residues located at the constriction site within the selectivity filter. Despite successful molecular dynamics simulations conducted on the prokaryotic Nav channels, the lack of Lys at the constriction site of prokaryotic Nav channels limits how much can be learned about the Na+/K+ selectivity in mammalian Nav channels. In this work, we modeled the mammalian Nav channel by mutating the key residues at the constriction site in a prokaryotic Nav channel (NavRh) to its mammalian counterpart. By simulating the mutant structure, we found that the Na+ preference in mammalian Nav channels is collaboratively achieved by the deselection from Lys and the selection from Asp/Glu within the constriction site. PMID- 23746513 TI - Small-molecule photostabilizing agents are modifiers of lipid bilayer properties. AB - Small-molecule photostabilizing or protective agents (PAs) provide essential support for the stability demands on fluorescent dyes in single-molecule spectroscopy and fluorescence microscopy. These agents are employed also in studies of cell membranes and model systems mimicking lipid bilayer environments, but there is little information about their possible effects on membrane structure and physical properties. Given the impact of amphipathic small molecules on bilayer properties such as elasticity and intrinsic curvature, we investigated the effects of six commonly used PAs--cyclooctatetraene (COT), para nitrobenzyl alcohol (NBA), Trolox (TX), 1,4-diazabicyclo[2.2.2]octane (DABCO), para-nitrobenzoic acid (pNBA), and n-propyl gallate (nPG)--on bilayer properties using a gramicidin A (gA)-based fluorescence quench assay to probe for PA-induced changes in the gramicidin monomer<->dimer equilibrium. The experiments were done using fluorophore-loaded large unilamellar vesicles that had been doped with gA, and changes in the gA monomer<->dimer equilibrium were assayed using a gA channel permeable fluorescence quencher (Tl+). Changes in bilayer properties caused by, e.g., PA adsorption at the bilayer/solution interface that alter the equilibrium constant for gA channel formation, and thus the number of conducting gA channels in the large unilamellar vesicle membrane, will be detectable as changes in the rate of Tl+ influx-the fluorescence quench rate. Over the experimentally relevant millimolar concentration range, TX, NBA, and pNBA, caused comparable increases in gA channel activity. COT, also in the millimolar range, caused a slight decrease in gA channel activity. nPG increased channel activity at submillimolar concentrations. DABCO did not alter gA activity. Five of the six tested PAs thus alter lipid bilayer properties at experimentally relevant concentrations, which becomes important for the design and analysis of fluorescence studies in cells and model membrane systems. We therefore tested combinations of COT, NBA, and TX; the combinations altered the fluorescence quench rate less than would be predicted assuming their effects on bilayer properties were additive. The combination of equimolar concentrations of COT and NBA caused minimal changes in the fluorescence quench rate. PMID- 23746515 TI - Cholesterol translocation in a phospholipid membrane. AB - Cholesterol (CHOL) molecules play a key role in modulating the rigidity of cell membranes and controlling intracellular transport and signal transduction. Using an all-atom molecular dynamics approach, we study the process of CHOL interleaflet transport (flip-flop) in a dipalmitoylphosphatidycholine (DPPC)-CHOL bilayer over a time period of 15 MUs. We investigate the effect of the flip-flop process on mechanical stress across the bilayer and the role of CHOL in inducing molecular order in bilayer leaflets. The simulations are carried out at physiologically relevant CHOL concentration (30%), temperature (323 K), and pressure (1 bar). CHOL flip-flop events are observed with a rate constant of 3 * 104s-1. Once a flip-flop event is triggered, a CHOL molecule takes an average of 73 nanoseconds to migrate from one bilayer leaflet to the other. PMID- 23746514 TI - A membrane-translocating peptide penetrates into bilayers without significant bilayer perturbations. AB - Using a high throughput screen, we have identified a family of 12-residue long peptides that spontaneously translocate across membranes. These peptides function by a poorly understood mechanism that is very different from that of the well known, highly cationic cell penetrating peptides such as the tat peptide from HIV. The newly discovered translocating peptides can carry polar cargoes across synthetic bilayers and across cellular membranes quickly and spontaneously without disrupting the membrane. Here we report on the biophysical characterization of a representative translocating peptide from the selected family, TP2, as well as a negative control peptide, ONEG, from the same library. We measured the binding of the two peptides to lipid bilayers, their secondary structure propensities, their dispositions in bilayers by neutron diffraction, and the response of the bilayer to the peptides. Compared to the negative control, TP2 has a greater propensity for membrane partitioning, although it still binds only weakly, and a higher propensity for secondary structure. Perhaps most revealing, TP2 has the ability to penetrate deep into the bilayer without causing significant bilayer perturbations, a property that may help explain its ability to translocate without bilayer permeabilization. PMID- 23746516 TI - Membrane modulates affinity for calcium ion to create an apparent cooperative binding response by annexin a5. AB - Isothermal titration calorimetry was used to characterize the binding of calcium ion (Ca2+) and phospholipid to the peripheral membrane-binding protein annexin a5. The phospholipid was a binary mixture of a neutral and an acidic phospholipid, specifically phosphatidylcholine and phosphatidylserine in the form of large unilamellar vesicles. To stringently define the mode of binding, a global fit of data collected in the presence and absence of membrane concentrations exceeding protein saturation was performed. A partition function defined the contribution of all heat-evolving or heat-absorbing binding states. We find that annexin a5 binds Ca2+ in solution according to a simple independent site model (solution-state affinity). In the presence of phosphatidylserine containing liposomes, binding of Ca2+ differentiates into two classes of sites, both of which have higher affinity compared with the solution-state affinity. As in the solution-state scenario, the sites within each class were described with an independent-site model. Transitioning from a solution state with lower Ca2+ affinity to a membrane-associated, higher Ca2+ affinity state, results in cooperative binding. We discuss how weak membrane association of annexin a5 prior to Ca2+ influx is the basis for the cooperative response of annexin a5 toward Ca2+, and the role of membrane organization in this response. PMID- 23746517 TI - Series of concentration-induced phase transitions in cholesterol/phosphatidylcholine mixtures. AB - In lipid membranes, temperature-induced transition from gel-to-fluid phase increases the lateral diffusion of the lipid molecules by three orders of magnitude. In cell membranes, a similar phase change may trigger the communication between the membrane components. Here concentration-induced phase transition properties of our recently developed statistical mechanical model of cholesterol/phospholipid mixtures are investigated. A slight (<1%) decrease in the model parameter values, controlling the lateral interaction energies, reveals the existence of a series of first- or second-order phase transitions. By weakening the lateral interactions first, the proportion of the ordered (i.e., superlattice) phase (Areg) is slightly and continuously decreasing at every cholesterol mole fraction. Then sudden decreases in Areg appear at the 0.18-0.26 range of cholesterol mole fractions. We point out that the sudden changes in Areg represent first- or second-order concentration-induced phase transitions from fluid to superlattice and from superlattice to fluid phase. Sudden changes like these were detected in our previous experiments at 0.2, 0.222, and 0.25 sterol mole fractions in ergosterol/DMPC mixtures. By further decreasing the lateral interactions, the fluid phase will dominate throughout the 0.18-0.26 interval, whereas outside this interval sudden increases in Areg may appear. Lipid composition-induced phase transitions as specified here should have far more important biological implications than temperature- or pressure-induced phase transitions. This is the case because temperature and pressure in cell membranes are largely invariant under physiological conditions. PMID- 23746518 TI - Kinesin-8 is a low-force motor protein with a weakly bound slip state. AB - During the cell cycle, kinesin-8s control the length of microtubules by interacting with their plus ends. To reach these ends, the motors have to be able to take many steps without dissociating. However, the underlying mechanism for this high processivity and how stepping is affected by force are unclear. Here, we tracked the motion of yeast (Kip3) and human (Kif18A) kinesin-8s with high precision under varying loads using optical tweezers. Surprisingly, both kinesin 8 motors were much weaker compared with other kinesins. Furthermore, we discovered a force-induced stick-slip motion: the motor frequently slipped, recovered from this state, and then resumed normal stepping motility without detaching from the microtubule. The low forces are consistent with kinesin-8s being regulators of microtubule dynamics rather than cargo transporters. The weakly bound slip state, reminiscent of a molecular safety leash, may be an adaptation for high processivity. PMID- 23746520 TI - Fracture mechanics of collagen fibrils: influence of natural cross-links. AB - Tendons are important load-bearing structures, which are frequently injured in both sports and work. Type I collagen fibrils are the primary components of tendons and carry most of the mechanical loads experienced by the tissue, however, knowledge of how load is transmitted between and within fibrils is limited. The presence of covalent enzymatic cross-links between collagen molecules is an important factor that has been shown to influence mechanical behavior of the tendons. To improve our understanding of how molecular bonds translate into tendon mechanics, we used an atomic force microscopy technique to measure the mechanical behavior of individual collagen fibrils loaded to failure. Fibrils from human patellar tendons, rat-tail tendons (RTTs), NaBH4 reduced RTTs, and tail tendons of Zucker diabetic fat rats were tested. We found a characteristic three-phase stress-strain behavior in the human collagen fibrils. There was an initial rise in modulus followed by a plateau with reduced modulus, which was finally followed by an even greater increase in stress and modulus before failure. The RTTs also displayed the initial increase and plateau phase, but the third region was virtually absent and the plateau continued until failure. The importance of cross-link lability was investigated by NaBH4 reduction of the rat-tail fibrils, which did not alter their behavior. These findings shed light on the function of cross-links at the fibril level, but further studies will be required to establish the underlying mechanisms. PMID- 23746519 TI - Cross-species mechanical fingerprinting of cardiac myosin binding protein-C. AB - Cardiac myosin binding protein-C (cMyBP-C) is a member of the immunoglobulin (Ig) superfamily of proteins and consists of 8 Ig- and 3 fibronectin III (FNIII)-like domains along with a unique regulatory sequence referred to as the MyBP-C motif or M-domain. We previously used atomic force microscopy to investigate the mechanical properties of murine cMyBP-C expressed using a baculovirus/insect cell expression system. Here, we investigate whether the mechanical properties of cMyBP-C are conserved across species by using atomic force microscopy to manipulate recombinant human cMyBP-C and native cMyBP-C purified from bovine heart. Force versus extension data obtained in velocity-clamp experiments showed that the mechanical response of the human recombinant protein was remarkably similar to that of the bovine native cMyBP-C. Ig/Fn-like domain unfolding events occurred in a hierarchical fashion across a threefold range of forces starting at relatively low forces of ~50 pN and ending with the unfolding of the highest stability domains at ~180 pN. Force-extension traces were also frequently marked by the appearance of anomalous force drops suggestive of additional mechanical complexity such as structural coupling among domains. Both recombinant and native cMyBP-C exhibited a prominent segment ~100 nm-long that could be stretched by forces <50 pN before the unfolding of Ig- and FN-like domains. Combined with our previous observations of mouse cMyBP-C, these results establish that although the response of cMyBP-C to mechanical load displays a complex pattern, it is highly conserved across species. PMID- 23746521 TI - Sequence and temperature dependence of the end-to-end collision dynamics of single-stranded DNA. AB - Intramolecular collision dynamics play an essential role in biomolecular folding and function and, increasingly, in the performance of biomimetic technologies. To date, however, the quantitative studies of dynamics of single-stranded nucleic acids have been limited. Thus motivated, here we investigate the sequence composition, chain-length, viscosity, and temperature dependencies of the end-to end collision dynamics of single-stranded DNAs. We find that both the absolute collision rate and the temperature dependencies of these dynamics are base composition dependent, suggesting that base stacking interactions are a significant contributor. For example, whereas the end-to-end collision dynamics of poly-thymine exhibit simple, linear Arrhenius behavior, the behavior of longer poly-adenine constructs is more complicated. Specifically, 20- and 25-adenine constructs exhibit biphasic temperature dependencies, with their temperature dependences becoming effectively indistinguishable from that of poly-thymine above 335 K for 20-adenines and 328 K for 25-adenines. The differing Arrhenius behaviors of poly-thymine and poly-adenine and the chain-length dependence of the temperature at which poly-adenine crosses over to behave like poly-thymine can be explained by a barrier friction mechanism in which, at low temperatures, the energy barrier for the local rearrangement of poly-adenine becomes the dominant contributor to its end-to-end collision dynamics. PMID- 23746522 TI - Early bacteriopheophytin reduction in charge separation in reaction centers of Rhodobacter sphaeroides. AB - A question at the forefront of biophysical sciences is, to what extent do quantum effects and protein conformational changes play a role in processes such as biological sensing and energy conversion? At the heart of photosynthetic energy transduction lie processes involving ultrafast energy and electron transfers among a small number of tetrapyrrole pigments embedded in the interior of a protein. In the purple bacterial reaction center (RC), a highly efficient ultrafast charge separation takes place between a pair of bacteriochlorophylls: an accessory bacteriochlorophyll (B) and bacteriopheophytin (H). In this work, we applied ultrafast spectroscopy in the visible and near-infrared spectral region to Rhodobacter sphaeroides RCs to accurately track the timing of the electron on BA and HA via the appearance of the BA and HA anion bands. We observed an unexpectedly early rise of the HA- band that challenges the accepted simple picture of stepwise electron transfer with 3 ps and 1 ps time constants. The implications for the mechanism of initial charge separation in bacterial RCs are discussed in terms of a possible adiabatic electron transfer step between BA and HA, and the effect of protein conformation on the electron transfer rate. PMID- 23746523 TI - Conformational determinants for the recruitment of ERCC1 by XPA in the nucleotide excision repair (NER) Pathway: structure and dynamics of the XPA binding motif. AB - XPA is an essential protein in the nucleotide excision repair (NER) pathway, in charge of recruiting the ERCC1-XPF endonuclease complex to the DNA damage site. The only currently available structural insight into the binding of XPA to ERCC1 derives from the solution NMR structure of a complex between the ERCC1 central fragment and a 14-residue peptide, corresponding to the highly conserved binding motif of the XPA N-terminus, XPA67-80. The extensive all-atom molecular-dynamics simulation study of the XPA67-80 peptide both bound to the ERCC1 central fragment and free in solution presented here completes the profile of the structural determinants responsible for the ERCC1/XPA67-80 complex stability. In addition to the wild-type, this study also looks at specific XPA67-80 mutants in complex with the ERCC1 central domain and thus contributes to defining the conformational determinants for binding, as well as all of the essential structural elements necessary for the rational design of an XPA-based, ERCC1-specific inhibitor. PMID- 23746524 TI - Folding factors and partners for the intrinsically disordered protein micro-exon gene 14 (MEG-14). AB - The micro-exon genes (MEG) of Schistosoma mansoni, a parasite responsible for the second most widely spread tropical disease, code for small secreted proteins with sequences unique to the Schistosoma genera. Bioinformatics analyses suggest the soluble domain of the MEG-14 protein will be largely disordered, and using synchrotron radiation circular dichroism spectroscopy, its secondary structure was shown to be essentially completely unfolded in aqueous solution. It does, however, show a strong propensity to fold into more ordered structures under a wide range of conditions. Partial folding was produced by increasing temperature (in a reversible process), contrary to the behavior of most soluble proteins. Furthermore, significant folding was observed in the presence of negatively charged lipids and detergents, but not in zwitterionic or neutral lipids or detergents. Absorption onto a surface followed by dehydration stimulated it to fold into a helical structure, as it did when the aqueous solution was replaced by nonaqueous solvents. Hydration of the dehydrated folded protein was accompanied by complete unfolding. These results support the identification of MEG-14 as a classic intrinsically disordered protein, and open the possibility of its interaction/folding with different partners and factors being related to multifunctional roles and states within the host. PMID- 23746525 TI - Multiple steps to activate FAK's kinase domain: adaptation to confined environments? AB - Protein kinases regulate cell signaling by phosphorylating their substrates in response to environment-specific stimuli. Using molecular dynamics, we studied the catalytically active and inactive conformations of the kinase domain of the focal adhesion kinase (FAK), which are distinguished by displaying a structured or unstructured activation loop, respectively. Upon removal of an ATP analog, we show that the nucleotide-binding pocket in the catalytically active conformation is structurally unstable and fluctuates between an open and closed configuration. In contrast, the pocket remains open in the catalytically inactive form upon removal of an inhibitor from the pocket. Because temporal pocket closures will slow the ATP on-rate, these simulations suggest a multistep process in which the kinase domain is more likely to bind ATP in the catalytically inactive than in the active form. Transient closures of the ATP-binding pocket might allow FAK to slow down its catalytic cycle. These short cat naps could be adaptions to crowded or confined environments by giving the substrate sufficient time to diffuse away. The simulations show further how either the phosphorylation of the activation loop or the activating mutations of the so-called SuperFAK influence the electrostatic switch that controls kinase activity. PMID- 23746526 TI - Carbohydrate recognition by RpfB from Mycobacterium tuberculosis unveiled by crystallographic and molecular dynamics analyses. AB - Resuscitation of Mtb is crucial to the etiology of Tuberculosis, because latent tuberculosis is estimated to affect one-third of the world population. The resuscitation-promoting factor RpfB is mainly responsible for Mtb resuscitation from dormancy. Given the impact of latent Tuberculosis, RpfB represents an interesting target for tuberculosis drug discovery. However, no molecular models of substrate binding and catalysis are hitherto available for this enzyme. Here, we identified key interactions involved in substrate binding to RpfB by combining x-ray diffraction studies and computational approaches. The crystal structure of RpfB catalytic domain in complex with N,N',N"-triacetyl-chitotriose, as described here, provides the first, to our knowledge, atomic representation of ligand recognition by RpfB and demonstrates that the strongest interactions are established by the N-acetylglucosamine moiety in the central region of the enzyme binding cleft. Molecular dynamics analyses provided information on the dynamic behavior of protein-substrate interactions and on the role played by the solvent in RpfB function. These data combined with sequence conservation analysis suggest that Glu-292 is the sole residue crucial for catalysis, implying that RpfB acts via the formation of an oxocarbenium ion rather than a covalent intermediate. Present data represent a solid base for the design of effective drug inhibitors of RpfB. Moreover, homology models were generated for the catalytic domains of all members of the Mtb Rpf family (RpfA-E). The analysis of these models unveiled analogies and differences among the different members of the Rpf protein family. PMID- 23746527 TI - An inverse power-law distribution of molecular bond lifetimes predicts fractional derivative viscoelasticity in biological tissue. AB - Viscoelastic characteristics of many materials falling under the category of soft glassy substances, including biological tissue, often exhibit a mechanical complex modulus Y(omega) well described by a fractional derivative model: Y(omega) = E(iomega/phi)k, where E = a generalized viscoelastic stiffness; i = ( 1)1/2; omega = angular frequency; phi = scaling factor; and k = an exponent valued between 0 and 1. The term "fractional derivative" refers to the value of k: when k = 0 the viscoelastic response is purely elastic, and when k = 1 the response is purely viscous. We provide an analytical derivation of the fractional derivative complex modulus based on the hypothesis that the viscoelastic response arises from many intermittent molecular crosslinks, whose lifetimes longer than a critical threshold lifetime, tcrit, are distributed with an inverse power law proportional to t-(k+2). We demonstrate that E is proportional to the number and stiffness of crosslinks formed at any moment; the scaling factor phi is equivalent to reciprocal of tcrit; and the relative mean lifetime of the attached crosslinks is inversely proportional to the parameter k. To test whether electrostatic molecular bonds could be responsible for the fractional derivative viscoelasticity, we used chemically skinned human skeletal muscle as a one dimensional model of a soft glassy substance. A reduction in ionic strength from 175 to 110 mEq resulted in a larger E with no change in k, consistent with a higher probability of interfilament molecular interactions. Thick to thin filament spacing was reduced by applying 4% w/v of the osmolyte Dextran T500, which also resulted in a larger E, indicating a greater probability of crosslink formation in proportion to proximity. A 10 degrees C increase in temperature resulted in an increase in k, which corresponded to a decrease in cross-bridge attachment lifetime expected with higher temperatures. These theoretical and experimental results suggest that the fractional derivative viscoelasticity observed in some biological tissue arises as a mechanical consequence of electrostatic interactions, whose longest lifetimes are distributed with an inverse power law. PMID- 23746528 TI - New organelles by gene duplication in a biophysical model of eukaryote endomembrane evolution. AB - Extant eukaryotic cells have a dynamic traffic network that consists of diverse membrane-bound organelles exchanging matter via vesicles. This endomembrane system arose and diversified during a period characterized by massive expansions of gene families involved in trafficking after the acquisition of a mitochondrial endosymbiont by a prokaryotic host cell >1.8 billion years ago. Here we investigate the mechanistic link between gene duplication and the emergence of new nonendosymbiotic organelles, using a minimal biophysical model of traffic. Our model incorporates membrane-bound compartments, coat proteins and adaptors that drive vesicles to bud and segregate cargo from source compartments, and SNARE proteins and associated factors that cause vesicles to fuse into specific destination compartments. In simulations, arbitrary numbers of compartments with heterogeneous initial compositions segregate into a few compositionally distinct subsets that we term organelles. The global structure of the traffic system (i.e., the number, composition, and connectivity of organelles) is determined completely by local molecular interactions. On evolutionary timescales, duplication of the budding and fusion machinery followed by loss of cross interactions leads to the emergence of new organelles, with increased molecular specificity being necessary to maintain larger organellar repertoires. These results clarify potential modes of early eukaryotic evolution as well as more recent eukaryotic diversification. PMID- 23746529 TI - Translational cross talk in gene networks. AB - It has been shown experimentally that competition for limited translational resources by upstream mRNAs can lead to an anticorrelation between protein counts. Here, we investigate a stochastic model for this phenomenon, in which gene transcripts of different types compete for a finite pool of ribosomes. Throughout, we utilize concepts from the theory of multiclass queues to describe a qualitative shift in protein count statistics as the system transitions from being underloaded (ribosomes exceed transcripts in number) to being overloaded (transcripts exceed ribosomes in number). The exact analytical solution of a simplified stochastic model, in which the numbers of competing mRNAs and ribosomes are fixed, exhibits weak positive correlations between steady-state protein counts when total transcript count slightly exceeds ribosome count, whereas the solution can exhibit strong negative correlations when total transcript count significantly exceeds ribosome count. Extending this analysis, we find approximate but reasonably accurate solutions for a more realistic model, in which abundances of mRNAs and ribosomes are allowed to fluctuate randomly. Here, ribosomal fluctuations contribute positively and mRNA fluctuations contribute negatively to correlations, and when mRNA fluctuations dominate ribosomal fluctuations, a strong anticorrelation extremum reliably occurs near the transition from the underloaded to the overloaded regime. PMID- 23746530 TI - Examination of the subsarcolemmal tubular system of mammalian skeletal muscle fibers. AB - A subsarcolemmal tubular system network (SSTN) has been detected in skeletal muscle fibers by confocal imaging after the removal of the sarcolemma. Here we confirm the existence and resolve the fine architecture and the localization of the SSTN at an unprecedented level of detail by examining extracellularly applied tubular system markers in skeletal muscle fiber preparations with a combination of three imaging modalities: confocal fluorescence microscopy, direct stochastic optical reconstruction microscopy, and tomographic electron microscopy. Three dimensional reconstructions showed that the SSTN was a dense two-dimensional network within the subsarcolemmal space around the fiber, running ~500-600 nm underneath and parallel to the sarcolemma. The SSTN is composed of tubules ~95 nm in width with ~60% of the tubules directed transversely and >30% directed longitudinally. The deeper regular transverse tubules located at each A-I boundary of the sarcomeres branched from the SSTN, indicating individual transverse tubules that form triads are continuous with, but do not directly contact the sarcolemma. This suggests that the SSTN plays an important role in affecting the exchange of deeper tubule lumina with the extracellular space. PMID- 23746531 TI - Nanoscale distribution of ryanodine receptors and caveolin-3 in mouse ventricular myocytes: dilation of t-tubules near junctions. AB - We conducted super-resolution light microscopy (LM) imaging of the distribution of ryanodine receptors (RyRs) and caveolin-3 (CAV3) in mouse ventricular myocytes. Quantitative analysis of data at the surface sarcolemma showed that 4.8% of RyR labeling colocalized with CAV3 whereas 3.5% of CAV3 was in areas with RyR labeling. These values increased to 9.2 and 9.0%, respectively, in the interior of myocytes where CAV3 was widely expressed in the t-system but reduced in regions associated with junctional couplings. Electron microscopic (EM) tomography independently showed only few couplings with caveolae and little evidence for caveolar shapes on the t-system. Unexpectedly, both super-resolution LM and three-dimensional EM data (including serial block-face scanning EM) revealed significant increases in local t-system diameters in many regions associated with junctions. We suggest that this regional specialization helps reduce ionic accumulation and depletion in t-system lumen during excitation contraction coupling to ensure effective local Ca2+ release. Our data demonstrate that super-resolution LM and volume EM techniques complementarily enhance information on subcellular structure at the nanoscale. PMID- 23746532 TI - Assessing liver dysfunction in cirrhosis: role of the model for end-stage liver disease and its derived systems. AB - The model for end-stage liver disease (MELD) has replaced the role of the Child Turcotte-Pugh system as a more commonly used system in evaluating the severity of liver dysfunction in patients with chronic liver disease, owing to its superior ability to predict survival. The United Network of Organ Sharing (UNOS) in the USA has used the MELD system for prioritizing donor grafts in advanced cirrhotic patients awaiting liver transplantation since 2002. Serum sodium level is another important prognostic predictor in cirrhosis. Consequently, by incorporating serum sodium into the original MELD, the MELD-Na, MELDNa, the MELD-to-sodium ratio (MESO) index, and the ReFit MELDNa were proposed in an attempt to improve the predictive ability of the original MELD. Nevertheless, there are some limitations of the MELD-based systems that need to be refined. The MELD-based systems merely use laboratory data as parameters for the equation, therefore, any lack in unification and standardization of laboratory methods will result in inconsistent data that affect the prioritization of liver transplantation. Furthermore, the MELD system includes creatinine as a parameter, and serum creatinine level may represent different degrees of renal dysfunction in men and women. Therefore, these limitations may compromise the fair process of organ allocation for female cirrhotic patients. Currently, the application of the MELD system has been extended to tumor staging of hepatocellular carcinoma. Several studies have replaced the Child-Turcotte-Pugh system with the MELD as a parameter, indicating that the use of different criteria of liver dysfunction in cancer staging may enhance prognostic accuracy. Although the outcome data of the modified staging systems need to be confirmed, the concept of using the MELD as a reference system for evaluating the severity of liver dysfunction has globally become an important issue. PMID- 23746533 TI - The utilization of hospice care among patients with motor neuron diseases: the experience in Taiwan from 2005 to 2010. AB - BACKGROUND: The nature and extent of how patients with motor neuron diseases (MNDs) utilize hospice care in Taiwan remains unclear. This study aims to investigate the use of hospice care in Taiwan by patients with MND, and those factors that affect the extent, the cost, and the quality of their hospice treatment and care. METHODS: We analyzed data from hospice care inpatient claims of MNDs, using the National Health Insurance Research Database of Taiwan during 2005-2010. RESULTS: Thirty patients and 58 related discharges were enrolled into our study, which consisted of 13 males and 17 females, with a mean age 58.3 years. Of that total, 27 of them (90%) had amyotrophic lateral sclerosis, and four (13.3%) had comorbid cancers; 17 died during hospice care. Acute low respiratory conditions (31.0%) accounted for the most common acute comorbidity. Noninvasive ventilation care was performed in only 13 (22.4%) of the discharges. In contrast to nasogastric intubation (40 discharges, 69.0%), no gastrostomy/jejunostomy was noted. These procedures bore no relationship to results observed in the discharges. Family physicians provided most inpatient hospice services (74.1%). Respiratory problems were the major causes of death (70.6% of decedents). The mean inpatient costs of hospice care were noticeably reduced from previously established nationwide mean costs. CONCLUSION: Hospice care can save costs for patients with terminal MNDs, and family physicians play a valuable role in caring for these patients. However, respiratory and feeding problems are prevalent, yet there are proven benefits when noninvasive ventilation care and gastrostomy/jejunostomy are promoted. PMID- 23746534 TI - An 11-year experience with ovarian surgery during pregnancy. AB - BACKGROUND: The management of ovarian tumors during pregnancy can be challenging because of the risk of fetal wastage and the possibility of surgery-related complications, or a delayed diagnosis of a possibly lethal disease or malignancy. The aim of this study was to study the characteristics and outcomes of pregnant women undergoing surgical intervention for ovarian tumors during pregnancy. METHODS: We reviewed the data of 102 pregnant women who underwent ovarian surgery between 2000 and 2010 at Taipei Veterans General Hospital, Taiwan. Data subject to analysis included gestational age at the time of surgery, complications, surgical and pathological findings, and the outcome of pregnancy. RESULTS: Fifty two women who underwent surgery were excluded, whether by cesarean section, during the postpartum period or during simultaneous abortion surgery. Ultimately, the data of 50 patients were analyzed. Almost all patients (n = 46, 92%) were asymptomatic and underwent elective surgery. Frequently, this surgery was done in the second trimester (n = 35, 70%). We determined that teratoma (26%), mucinous cystadenomas (20%), and endometriomas (16%) were the three most common pathological findings. Nonspecific ovarian tumors were common (28%), including seven corpus luteum cysts, six simple cysts, and one paratubal cyst. Two women were diagnosed with malignant ovarian tumors, but both were metastatic and the primary site was the colon. Ten women underwent laparoscopic surgery. General anesthesia was used in four patients, and all underwent emergency exploratory laparotomy. There was no surgery-related complication or instance of preterm labor. CONCLUSION: In our study cohort, surgical intervention during pregnancy was safe, since neither surgical approach, such as exploratory laparotomy or laparoscopic surgery, nor anesthesia methods, for example general anesthesia or spinal anesthesia showed negative impact on the pregnancy outcomes. Reported cases of malignant ovarian tumor are still rare, thus, the possibility of metastatic tumor should be considered first. PMID- 23746535 TI - Ovarian surgery during pregnancy. PMID- 23746536 TI - Remote cerebellar hemorrhage after cervical spinal surgery. AB - Remote cerebellar hemorrhage (RCH) is an unpredictable and rare complication of spinal surgery. We report five cases of RCH following cervical spinal surgery, and summarize another seven similar cases from the literature. Dural opening with cerebrospinal fluid (CSF) hypovolemia seems to be an important factor contributing to RCH following cervical spinal surgery. As other authors have proposed, surgical positioning may be another factor contributing to RCH. RCH is thought to be hemorrhagic venous infarction, resulting from the stretching occlusion of the superior cerebellar vein by the cerebellar sag effect. Either intraoperative CSF loss or a postoperative CSF leak from drainage may cause cerebellar sag, further resulting in RCH. RCH is usually self-limiting, and most patients with RCH have an optimal outcome after conservative treatment. Severe cases that involved surgical intervention because of evidence of brainstem compression or hydrocephalus also had acceptable outcomes, compared to spontaneous CH. It has been suggested that one way to prevent RCH is to avoid extensive perioperative loss of CSF, by paying attention to surgical positioning during spinal surgery. We also underline the importance of early diagnosis and CSF expansion in the early treatment of RCH. PMID- 23746537 TI - Pro-atherogenic lipid changes and decreased hepatic LDL receptor expression by tocilizumab in rheumatoid arthritis. AB - OBJECTIVES: Blocking the interleukin-6 pathway by tocilizumab (TCZ) has been associated with changes in the lipoprotein profile, which could adversely impact cardiovascular (CV) risk in patients with rheumatoid arthritis (RA). In the present study, we addressed the effect of TCZ on lipoproteins in both fasting and non-fasting state in RA patients and tested the effect of TCZ on LDL receptor (LDLr) expression in vitro. METHODS: Twenty patients with active RA and an inadequate response to TNF blockers received monthly TCZ intravenously. On week 0, 1 and 6 blood was drawn before and after an oral fat load, the lipid profiles and HDL antioxidative capacity were measured. Effects of TCZ on LDLr expression in transfected HepG2 cells were subjected. RESULTS: After 6 weeks of TCZ, total cholesterol increased by 22% (4.8 +/- 0.9 to 5.9 +/- 1.3 mmol/L; p < 0.001), LDLc by 22% (3.0 +/- 0.6 to 3.6 +/- 0.8 mmol/L; p < 0.001) and HDLc by 17% (1.4 +/- 0.4 to 1.7 +/- 0.7 mmol/L; p < 0.016). Fasting triglycerides (TG) increased by 48% (1.0 +/- 0.4 to 1.4 +/- 0.8 mmol/L; p = 0.011), whereas postprandial incremental area under the curve TG increased by 62% (p = 0.002). Lipid changes were unrelated to the change in disease activity or inflammatory markers. No difference in HDL antioxidative capacity was found. In vitro, LDLr expression in cultured liver cells was significantly decreased following TCZ incubation (P < 0.001). CONCLUSIONS: TCZ adversely impacts on both LDLc as well as fasting and postprandial TG in patients with RA. The changes in hepatic LDLr expression following TCZ imply that adverse lipid changes may be a direct hepatic effect of TCZ. The net effect of TCZ on CV-morbidity has to be confirmed in future clinical trials. PMID- 23746538 TI - Stroke in sickle cell anemia patients: a need for multidisciplinary approaches. AB - Sickle cell anemia (SCA) is an autosomal recessive disorder, with Mendelian inheritance pattern, caused by a missense mutation in the beta-polypeptide chain of the hemoglobin B. SCA preferentially affects populations in countries where malaria was/is present (e.g. Africa, USA, Brazil). Thereby, in USA, the incidence of SCA is relatively high, around 1/500, and the prevalence is about 1/1000. In Brazil, SCA represents a major public health problem with an incidence ranging from 1/2000 to 1/600 depending on the regions. Homozygotic patients present more severe medical conditions and reduced life expectancy than heterozygous individuals who generally are asymptomatic. Eventually, this life-threatening disease displays a complex etiology owing to heterogeneous phenotypes and clinical outcomes, subsequently affecting the management of the patients. One of the most critical complications associated with SCA is stroke, a leading neurologic cause of death and disability. About 24% of SCA patients have a stroke by the age of 45 and 11% by the age of 20. From the general population, twin and familial aggregation studies as well as genome-wide association studies (GWAS), mostly in pediatric populations with ischemic stroke, showed that the risk of stroke has a substantial genetic component. Nevertheless, to fully characterize genomic contributors of stroke and permit reliable personalized medicine, multidisciplinary studies incorporating knowledge from clinical medicine, epidemiology, genetics, and molecular biology, are required. In this manuscript, stroke in SCA patients is extensively reviewed with emphasis to the US and Brazilian populations. Recent advances in genomics analysis of stroke in SCA patients are highlighted. PMID- 23746539 TI - Is aberrant functional connectivity a psychosis endophenotype? A resting state functional magnetic resonance imaging study. AB - BACKGROUND: Schizophrenia and bipolar disorder share overlapping symptoms and risk genes. Shared aberrant functional connectivity is hypothesized in both disorders and in relatives. METHODS: We investigated resting state functional magnetic resonance imaging in 70 schizophrenia and 64 psychotic bipolar probands, their respective first-degree relatives (n = 70 and 52), and 118 healthy subjects. We used independent component analysis to identify components representing various resting state networks and assessed spatial aspects of functional connectivity within all networks. We first investigated group differences using five-level, one-way analysis of covariance (ANCOVA), followed by post hoc t tests within regions displaying ANCOVA group differences and correlation of such functional connectivity measures with symptom ratings to examine clinical relationships. RESULTS: Seven networks revealed abnormalities (five-level one-way ANCOVA, family-wise error correction p < .05): A) fronto occipital, B) midbrain/cerebellum, C) frontal/thalamic/basal ganglia, D) meso/paralimbic, E) posterior default mode network, F) fronto-temporal/paralimbic and G) sensorimotor networks. Abnormalities in networks B and F were unique to schizophrenia probands. Furthermore, abnormalities in networks D and E were common to both patient groups. Finally, networks A, C, and G showed abnormalities shared by probands and their relative groups. Negative correlation with Positive and Negative Syndrome Scale negative and positive scores were found in regions within network C and F respectively, and positive correlation with Positive and Negative Syndrome Scale negative scores was found in regions in network D among schizophrenia probands only. CONCLUSIONS: Schizophrenia, psychotic bipolar probands, and their relatives share both unique and overlapping within-network brain connectivity abnormalities, revealing potential psychosis endophenotypes. PMID- 23746541 TI - Orexin 1 receptor in the seminiferous tubules of boar testis: an immunohistochemical study. AB - Orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R) are two G-protein-coupled receptors that bind their ligands, orexin A (OXA) and B (OXB), with different affinities. The male genital system represents an important target for OXA, which appears to play a role in the control of steroidogenesis and germ cell development in the testis. It is known that among domestic breeding animals, in the boar the number of Leydig cells is very high and OXA appears to have stimulatory activity on testosterone production. In this study, we aimed to evaluate the presence of OX1R in the boar testis in order to extend our knowledge concerning the distribution and a potential functional role of the orexinergic system in the male reproductive tract of farm animals. The presence of OX1R immunopositive cells in seminiferous tubules of the boar testis enables us to hypothesize a possible role of OXA on male germ cells cycle in pig. Further investigations, involving functional and ultrastructural analysis, may contribute to our understanding of the role of orexins in the boar genital system. PMID- 23746540 TI - Neural mechanisms of attention-deficit/hyperactivity disorder symptoms are stratified by MAOA genotype. AB - BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is characterized by deficits in reward sensitivity and response inhibition. The relative contribution of these frontostriatal mechanisms to ADHD symptoms and their genetic determinants is largely unexplored. METHODS: Using functional magnetic resonance imaging and genetic analysis of the monoamine oxidase A (MAOA) gene, we investigated how striatal and inferior frontal activation patterns contribute to ADHD symptoms depending on MAOA genotype in a sample of adolescent boys (n = 190). RESULTS: We demonstrate an association of ADHD symptoms with distinct blood oxygen level-dependent (BOLD) responses depending on MAOA genotype. In A hemizygotes of the expression single nucleotide polymorphism rs12843268, which express lower levels of MAOA, ADHD symptoms are associated with lower ventral striatal BOLD response during the monetary incentive delay task and lower inferior frontal gyrus BOLD response during the stop signal task. In G hemizygotes, ADHD symptoms are associated with increased inferior frontal gyrus BOLD response during the stop signal task in the presence of increased ventral striatal BOLD response during the monetary incentive delay task. CONCLUSIONS: Depending on MAOA genotype, ADHD symptoms in adolescent boys are associated with either reward deficiency or insufficient response inhibition. Apart from its mechanistic interest, our finding may aid in developing pharmacogenetic markers for ADHD. PMID- 23746542 TI - Best practice for PTEN gene and protein assessment in anatomic pathology. AB - There is a lack of standardization of a best practice protocol for Phosphatase and Tensin Homolog (PTEN) assessment by immunohistochemistry in anatomic pathology routine practice. We performed immunohistochemistry for 19 antibodies against PTEN, eleven of which were excluded during the standardization step. Immunohistochemistry of the remaining eight antibodies was performed on a Tissue Microarray containing 55 prostate and 40 renal carcinoma samples. Fluorescent in situ hybridization (FISH) was used as reference standard for immunohistochemistry specificity evaluation. Concerning nuclear staining, polyclonal (Cat#22034-1-AP); 6H2.1 mMAb (Cat#ABM-2052), Y184 RabMAb (Cat#NB110-57441) and 217702 mMAb antibodies presented the highest agreement with fluorescent in situ hybridization (p<0.001 for all) and with regard to cytoplasmic staining, Y184 RabMAb (Cat#NB110 57441); polyclonal (Cat#22034-1-AP) and 217702 mMAb presented the highest agreement (p<0.001 for all). Our results indicate that several commercially available antibodies do not show reliability of sensitivity and specificity for PTEN evaluation and we propose 6H2.1 mMAb (Cat#ABM-2052) as the antibody of choice for laboratory standardization and best practice in clinical routine, which demonstrated excellent sensitivity for both nuclear and cytoplasmic staining, specificity for PTEN by Western blot and good correlation with PTEN status by FISH with regard to nuclear staining. PMID- 23746543 TI - Scoliosis in Duchenne muscular dystrophy (DMD). AB - Scoliosis is a frequent complication in the non-ambulant patient with Duchenne muscular dystrophy (DMD). Weakness of the paraspinal muscles leads to trunk and body positional changes facilitating the development of a progressive collapsing scoliosis which inevitably interferes with comfortable sitting and may exacerbate deteriorating respiratory function. The recommended international standard of care for management of DMD includes strategies to prolong ambulation which may delay the onset of scoliosis. In the non-ambulant child there should be regular monitoring for scoliosis and, when present, surgical treatment should undertaken at an early stage. Careful multi-disciplinary pre-operative assessment and peri operative care are essential. PMID- 23746544 TI - A new mutation of the fukutin gene causing late-onset limb girdle muscular dystrophy. AB - Defects in glycosylations of alpha-dystroglycan are associated with mutations in several genes, including the fukutin gene (FKTN). Hypoglycosylation of alpha dystroglycan results in several forms of muscular dystrophy with variable phenotype. Outside Japan, the prevalence of muscular dystrophies related to aberrations of FKTN is rare, with only eight reported cases of limb girdle phenotype (LGMD2M). We describe the mildest affected patient outside Japan with genetically confirmed LGMD2M and onset of symptoms at age 14. She was brought to medical attention at age 12, not because of muscle weakness, but due to episodes of tachycardia caused by Wolff-Parkinson-White syndrome. On examination, she had rigid spine syndrome, a typical limb girdle dystrophy pattern of muscle weakness, cardiomyopathy, and serum CK levels >2000 IU/L (normal <150 IU/L). A homozygous, novel c.917A>G; p.Y306C mutation in the FKTN gene was found. The case confirms FKTN mutations as a cause of LGMD2M without mental retardation and expands the phenotypic spectrum for LGMD2M to include cardiomyopathy and rigid spine syndrome in the mildest affected non-Japanese patient reported so far. PMID- 23746545 TI - Multisystem disorder and limb girdle muscular dystrophy caused by LMNA p.R28W mutation. AB - Primary laminopathies caused by mutations in the LMNA gene typically display an extremely pleiotropic clinical presentation including cardiac, muscular and metabolic phenotypes. Additionally, many atypical laminopathies have been described combining features of two or more of the distinctive disorders or syndromes associated with LMNA mutations. We report on a 46-year-old female patient with a heterozygous p.R28W LMNA mutation, who presented with a novel clinical phenotype comprising severe limb-girdle muscular dystrophy, pronounced partial lipodystrophy, cardiac conduction defect, polycystic ovary disease and a metabolic syndrome with insulin-resistant diabetes mellitus and hypertriglyceridemia. On examination, her 23-year old daughter solely showed early signs of a LGMD phenotype. PMID- 23746546 TI - Mutations in RAB28, encoding a farnesylated small GTPase, are associated with autosomal-recessive cone-rod dystrophy. AB - The majority of the genetic causes of autosomal-recessive (ar) cone-rod dystrophy (CRD) are currently unknown. A combined approach of homozygosity mapping and exome sequencing revealed a homozygous nonsense mutation (c.565C>T [p.Glu189*]) in RAB28 in a German family with three siblings with arCRD. Another homozygous nonsense mutation (c.409C>T [p.Arg137*]) was identified in a family of Moroccan Jewish descent with two siblings affected by arCRD. All five affected individuals presented with hyperpigmentation in the macula, progressive loss of the visual acuity, atrophy of the retinal pigment epithelium, and severely reduced cone and rod responses on the electroretinogram. RAB28 encodes a member of the Rab subfamily of the RAS-related small GTPases. Alternative RNA splicing yields three predicted protein isoforms with alternative C-termini, which are all truncated by the nonsense mutations identified in the arCRD families in this report. Opposed to other Rab GTPases that are generally geranylgeranylated, RAB28 is predicted to be farnesylated. Staining of rat retina showed localization of RAB28 to the basal body and the ciliary rootlet of the photoreceptors. Analogous to the function of other RAB family members, RAB28 might be involved in ciliary transport in photoreceptor cells. This study reveals a crucial role for RAB28 in photoreceptor function and suggests that mutations in other Rab proteins may also be associated with retinal dystrophies. PMID- 23746547 TI - Long runs of homozygosity are enriched for deleterious variation. AB - Exome sequencing offers the potential to study the population-genomic variables that underlie patterns of deleterious variation. Runs of homozygosity (ROH) are long stretches of consecutive homozygous genotypes probably reflecting segments shared identically by descent as the result of processes such as consanguinity, population size reduction, and natural selection. The relationship between ROH and patterns of predicted deleterious variation can provide insight into the way in which these processes contribute to the maintenance of deleterious variants. Here, we use exome sequencing to examine ROH in relation to the distribution of deleterious variation in 27 individuals of varying levels of apparent inbreeding from 6 human populations. A significantly greater fraction of all genome-wide predicted damaging homozygotes fall in ROH than would be expected from the corresponding fraction of nondamaging homozygotes in ROH (p < 0.001). This pattern is strongest for long ROH (p < 0.05). ROH, and especially long ROH, harbor disproportionately more deleterious homozygotes than would be expected on the basis of the total ROH coverage of the genome and the genomic distribution of nondamaging homozygotes. The results accord with a hypothesis that recent inbreeding, which generates long ROH, enables rare deleterious variants to exist in homozygous form. Thus, just as inbreeding can elevate the occurrence of rare recessive diseases that represent homozygotes for strongly deleterious mutations, inbreeding magnifies the occurrence of mildly deleterious variants as well. PMID- 23746548 TI - Alleles of a polymorphic ETV6 binding site in DCDC2 confer risk of reading and language impairment. AB - Reading disability (RD) and language impairment (LI) are common learning disabilities that make acquisition and utilization of reading and verbal language skills, respectively, difficult for affected individuals. Both disorders have a substantial genetic component with complex inheritance. Despite decades of study, reading and language, like many other complex traits, consistently evade identification of causative and functional variants. We previously identified a putative functional risk variant, named BV677278 for its GenBank accession number, for RD in DCDC2. This variant consists of an intronic microdeletion and a highly polymorphic short tandem repeat (STR) within its breakpoints. We have also shown this STR to bind to an unknown nuclear protein with high specificity. Here, we replicate BV677278's association with RD, expand its association to LI, identify the BV677278-binding protein as the transcription factor ETV6, and provide compelling genetic evidence that BV677278 is a regulatory element that influences reading and language skills. We also provide evidence that BV677278 interacts nonadditively with KIAA0319, an RD-associated gene, to adversely affect several reading and cognitive phenotypes. On the basis of these data, we propose a new name for BV677278: "READ1" or "regulatory element associated with dyslexia 1." PMID- 23746549 TI - Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy. AB - Nemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal recessive fetal akinesia sequence. We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targeted gene sequencing of additional families. We identified 19 mutations in KLHL40 (kelch-like family member 40) in 28 apparently unrelated NEM kindreds of various ethnicities. Accounting for up to 28% of the tested individuals in the Japanese cohort, KLHL40 mutations were found to be the most common cause of this severe form of NEM. Clinical features of affected individuals were severe and distinctive and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties at birth. Molecular modeling suggested that the missense substitutions would destabilize the protein. Protein studies showed that KLHL40 is a striated-muscle-specific protein that is absent in KLHL40-associated NEM skeletal muscle. In zebrafish, klhl40a and klhl40b expression is largely confined to the myotome and skeletal muscle, and knockdown of these isoforms results in disruption of muscle structure and loss of movement. We identified KLHL40 mutations as a frequent cause of severe autosomal-recessive NEM and showed that it plays a key role in muscle development and function. Screening of KLHL40 should be a priority in individuals who are affected by autosomal-recessive NEM and who present with prenatal symptoms and/or contractures and in all Japanese individuals with severe NEM. PMID- 23746550 TI - De novo mutations in the genome organizer CTCF cause intellectual disability. AB - An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in CTCF in individuals with intellectual disability, microcephaly, and growth retardation. Furthermore, an individual with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. Transcriptome analyses in all three individuals with point mutations revealed deregulation of genes involved in signal transduction and emphasized the role of CTCF in enhancer-driven expression of genes. Our findings indicate that haploinsufficiency of CTCF affects genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition. PMID- 23746552 TI - Clinical and biochemical outcome after hydroxocobalamin dose escalation in a series of patients with cobalamin C deficiency. AB - BACKGROUND: CblC deficiency produces a combination of methylmalonic aciduria (MMA) and homocystinuria (HCU), and is the most common error of cobalamin metabolism. Patients present a wide spectrum of symptoms, ranging from early severe multisystemic forms, to milder late-onset phenotypes. Cognitive and visual impairment are nearly constant. Hydroxocobalamin (OHCbl), betaine, folinic acid, levocarnitine and eventually dietary protein restriction are the main therapeutic approaches. Although early introduction of OHCbl is crucial, no standardized protocols regarding dose adaptation exist. No reports on long-term outcomes after high doses of this vitamin have been published. METHODS: In this study five patients with CblC deficiency (early severe forms) were treated with high doses of OHCbl for 18 to 30months. Clinical examinations, neurological assessment, and biochemical studies (plasma total homocysteine (tHcy), amino acids, hydroxocobalamin, and methylmalonic acid in urine) were periodically performed. RESULTS: Variable clinical and biochemical outcomes were observed in patients treated with high doses of OHCbl. The best biochemical response was observed in those children with the worse metabolic control. By contrast, those patients with a concentration of tHcy around 50MUmol/l or less showed only minor changes. Clinically, a considerable improvement was observed in those patients with severe problems in communication, expressive language and behavior. CONCLUSIONS: According to our study, high OHCbl doses in CblC deficiency could have a greater benefit in those children with a prior history of suboptimal metabolic control, and also in those with severe neurological phenotypes. More specifically, we observed improvements in communication skills and behavior. These results should encourage further prospective trials to determine the optimal OHCbl regimen and to generate protocols and guidelines in this rare disorder. PMID- 23746551 TI - Alteration of ganglioside biosynthesis responsible for complex hereditary spastic paraplegia. AB - Hereditary spastic paraplegias (HSPs) form a heterogeneous group of neurological disorders. A whole-genome linkage mapping effort was made with three HSP-affected families from Spain, Portugal, and Tunisia and it allowed us to reduce the SPG26 locus interval from 34 to 9 Mb. Subsequently, a targeted capture was made to sequence the entire exome of affected individuals from these three families, as well as from two additional autosomal-recessive HSP-affected families of German and Brazilian origins. Five homozygous truncating (n = 3) and missense (n = 2) mutations were identified in B4GALNT1. After this finding, we analyzed the entire coding region of this gene in 65 additional cases, and three mutations were identified in two subjects. All mutated cases presented an early-onset spastic paraplegia, with frequent intellectual disability, cerebellar ataxia, and peripheral neuropathy as well as cortical atrophy and white matter hyperintensities on brain imaging. B4GALNT1 encodes beta-1,4-N-acetyl galactosaminyl transferase 1 (B4GALNT1), involved in ganglioside biosynthesis. These findings confirm the increasing interest of lipid metabolism in HSPs. Interestingly, although the catabolism of gangliosides is implicated in a variety of neurological diseases, SPG26 is only the second human disease involving defects of their biosynthesis. PMID- 23746553 TI - Improving surveillance for hyperammonemia in the newborn. AB - OBJECTIVE: Prompt ascertainment is crucial for the management of hyperammonemic infants. Because these patients are rare and recognition of hyperammonemia is often delayed, we designed and implemented an electronic medical record (EMR) based tool to assist physicians in the detection of hyperammonemia. METHODS: We retrospectively evaluated the hospitalizations of prior hyperammonemic infants to identify codable elements that could trigger an EMR-based warning. An alert was designed and implemented and its utilization was prospectively analyzed. RESULTS: Blood gas studies were obtained universally and early in the retrospectively evaluated infants (x-=26h before ammonia level). Prompting physicians to evaluate ammonia after ordering blood gas studies would have accelerated the initial ammonia order in 89% of retrospective cases. The alert has activated 184 times over the first six months of operation leading to 63 laboratory evaluations and detection of one hyperammonemic infant. CONCLUSION: Implementation of an EMR based warning system can improve surveillance for hyperammonemia in a susceptible population. PMID- 23746554 TI - An exon 53 frameshift mutation in CUBN abrogates cubam function and causes Imerslund-Grasbeck syndrome in dogs. AB - Cobalamin malabsorption accompanied by selective proteinuria is an autosomal recessive disorder known as Imerslund-Grasbeck syndrome in humans and was previously described in dogs due to amnionless (AMN) mutations. The resultant vitamin B12 deficiency causes dyshematopoiesis, lethargy, failure to thrive, and life-threatening metabolic disruption in the juvenile period. We studied 3 kindreds of border collies with cobalamin malabsorption and mapped the disease locus in affected dogs to a 2.9Mb region of homozygosity on canine chromosome 2. The region included CUBN, the locus encoding cubilin, a peripheral membrane protein that in concert with AMN forms the functional intrinsic factor-cobalamin receptor expressed in ileum and a multi-ligand receptor in renal proximal tubules. Cobalamin malabsorption and proteinuria comprising CUBN ligands were demonstrated by radiolabeled cobalamin uptake studies and SDS-PAGE, respectively. CUBN mRNA and protein expression were reduced ~10 fold and ~20 fold, respectively, in both ileum and kidney of affected dogs. DNA sequencing demonstrated a single base deletion in exon 53 predicting a translational frameshift and early termination codon likely triggering nonsense mediated mRNA decay. The mutant allele segregated with the disease in the border collie kindred. The border collie disorder indicates that a CUBN mutation far C-terminal from the intrinsic factor-cobalamin binding site can abrogate receptor expression and cause Imerslund-Grasbeck syndrome. PMID- 23746555 TI - One-year sustained glycemic control and weight reduction in type 2 diabetes after addition of liraglutide to metformin followed by insulin detemir according to HbA1c target. AB - AIM: To investigate durability of efficacy and safety over 1 year of the sequence of liraglutide added to metformin followed by add-on insulin detemir if glycated hemoglobin (HbA1c) remains >=7.0%. METHODS: Patients previously uncontrolled on metformin+/-sulfonylurea with HbA1c >=7.0% after 12 weeks of adding liraglutide 1.8mg to metformin (run-in; sulfonylurea discontinued) were randomized 1:1 to 52 weeks' open-label add-on detemir (randomized treatment [RT] group; n=162) or continuation without detemir (randomized control [RC] group; n=161). Patients with HbA1c <7.0% continued 52 weeks' unchanged treatment (observational group; n=498). RESULTS: Run-in HbA1c improvement from 8.3% to 7.6% (-0.6%) was further enhanced in the RT group (-0.50%) and maintained in the RC group (+0.01%) over 52 weeks; estimated treatment difference (ETD)[95%CI]: -0.51 [-0.70;-0.31]; P<0.0001. More RT (52%) than RC patients (22%) achieved HbA1c <7.0% at 52 weeks (P<0.0001). Run-in weight loss (-3.5kg) was maintained in the RT (-0.05kg) and enhanced in the RC group (-1.02kg) after 52 weeks; ETD [95%CI]: 0.97 [0.04;1.91]; P=0.04. No major hypoglycemia occurred; minor hypoglycemia rates were low across groups (0.034-0.228 events/patient-year). CONCLUSIONS: Supplementing metformin+liraglutide with detemir for 52 weeks improved glycemic control with sustained weight loss and low hypoglycemia rate. PMID- 23746556 TI - Impact of diabetes on costs before and after major lower extremity amputations in Germany. AB - AIMS: To compare direct medical costs 1 year before up to 3 years after first major lower extremity amputation (LEA) between patients with and without diabetes. METHODS: We used health insurance claims data and included patients with a first major LEA between 2005 and 2009. Costs for hospitalization, rehabilitation, outpatient care, outpatient drug prescriptions, non-physician services, durable medical equipment and long-term care were assessed. We estimated cost ratios (CR) for diabetes status using generalized linear models adjusted for age, sex, amputation level, care dependency as well as observation time and mortality within the corresponding period and costs before LEA. RESULTS: We included 444 patients with first major LEA (58.3% had diabetes), 71.8% were male and the average age was 69.1 years. Total mean costs for 1 year before LEA were higher in patients with diabetes (24,504 vs. 18,961 Euros), which was also confirmed by the multivariate analysis (CR: 1.27; 95% CI: 1.06-1.52). Costs up to 24 weeks after LEA were virtually the same in both groups (36,686 vs. 35,858 Euros), but thereafter differences increase again with higher costs for diabetics. Costs for 3 years after LEA were 115,676 vs. 92,862 Euros, respectively (CR: 1.26; 95% CI: 1.12-1.42). Hospitalizations accounted for more than 50% of total costs irrespective of diabetes status and period. CONCLUSIONS: Costs up to 24 weeks after first major LEA are mainly driven by the amputation itself irrespective of diabetes. Thereafter, costs for diabetic patients were higher again, which underlines the importance of studying long-term costs. PMID- 23746557 TI - [It was not my usual visit]. PMID- 23746558 TI - Change in postprandial substrate oxidation after a high-fructose meal is related to body mass index in healthy men. AB - Oral fructose decreases fat oxidation and increases carbohydrate oxidation in obese subjects, but the metabolic response to fructose in lean individuals is less well understood. The purpose of this study was to assess the effects of a single fructose-rich mixed meal on substrate oxidation in young healthy nonobese men. We hypothesized that a decrease in fat oxidation and an increase in carbohydrate oxidation would be observed after a fructose-rich mixed meal compared with a glucose-rich mixed meal. Twelve healthy, normal weight to overweight, aged 23 to 31 years participated in a double-blind, crossover study. Each participant completed 2 study visits, eating a mixed meal containing 30% of the calories from either fructose or glucose. Blood samples for glucose, insulin, triglycerides, and leptin as well as gas exchange by indirect calorimetry were measured intermittently for 7 hours. Serum insulin was higher after a fructose mixed meal, but plasma glucose, plasma leptin, and serum triglycerides were not different. Mean postprandial respiratory quotient and estimated fat oxidation did not differ between the fructose and glucose meals. The change in fat oxidation between the fructose- and glucose-rich meals negatively correlated with body mass index (BMI; r = -0.59 [P = .04] and r = -0.59 [P = .04] at the 4- and 7-hour time points, respectively). In healthy nonobese men, BMI correlates with altered postprandial fat oxidation after a high-fructose mixed meal. The metabolic response to a high-fructose meal may be modulated by BMI. PMID- 23746559 TI - Pomegranate juice intake attenuates the increase in oxidative stress induced by intravenous iron during hemodialysis. AB - The hemodialysis (HD) procedure induces oxidative stress (OS), which is further aggravated by intravenous (IV) iron administration, aimed at correcting anemia of patients with HD. We have recently shown that 1 year of pomegranate juice (PJ) intake attenuated OS and inflammation in patients with HD. In the current study, we hypothesized that a single dose of PJ can attenuate the enhanced OS and inflammation induced by both the dialysis procedure and IV iron administration during HD session. Twenty-seven patients with HD were randomized to receive PJ or placebo during 1 dialysis session with IV iron. Blood samples were drawn before and after the session to asses OS biomarkers such as advanced oxidation protein products and myeloperoxidase (MPO), whereas polymorphonuclear leukocyte (PMNL) counts served as an indirect measure of inflammation. At the end of the dialysis session, an increase in advanced oxidation protein products and MPO levels as well as a decrease in PMNLs counts were observed in the placebo group, whereas no significant changes occurred in the PJ group. The postdialysis increase in MPO levels in the placebo group is a direct result of PMNL degranulation, associated with postdialysis decrease in PMNL counts. Degranulation of PMNLs leads to the release of other cell moieties, such as inflammatory mediators and proteases that enhance inflammation. We conclude that PJ intake attenuated the increase in systemic OS and inflammation induced by IV iron administration during the dialysis session. These beneficial effects illuminate the previously observed attenuation in OS and inflammation in patients with HD on prolonged PJ intake. PMID- 23746560 TI - High proportion of 6 to 18-year-old children and adolescents in the United Arab Emirates are not meeting dietary recommendations. AB - In the United Arab Emirates (UAE), overweight, obesity, and associated chronic diseases have recently emerged as major public health concerns among all age groups, including children and adolescents. We hypothesized that although energy needs might be met by the majority of Emirati children and adolescents, their diet quality and intakes of certain micronutrients may not meet recommendations. A cross-sectional design was used to assess dietary intakes of 253 children (6-10 years of age) and 276 adolescents (11-18 years of age) in the UAE. Trained dietitians collected a 24-hour food recall in the homes of the participants. Nutrient intakes were compared with the Dietary Reference Intakes, and food group consumption was compared with MyPyramid recommendations. Results showed that 9 to 13-year-old females consumed 206 kcal/d from candy and sweets and nearly 264 cal/d from sugar-sweetened beverages. The proportion of participants with percentage energy from saturated fat greater than the recommendation ranged from 27.6% (males 9-13 years) to 45.9% (males 6-8 years). Mean intakes of vitamins A, D, and E were lower than the Estimated Average Requirements for all the subgroups. Mean calcium intake was lower than recommendations for all age and sex subgroups. The proportions of participants whose intakes were less than the recommended number of servings from the food groups were substantial: more than 90% of each of the 6 subgroups for the milk group and 100% among 9 to 18-year-old males for vegetables. In conclusion, the results of this study indicate the need for interventions targeting 6 to 18-year-old children and adolescents in the UAE to improve their diet quality. PMID- 23746561 TI - Acute and chronic caffeine administration increases physical activity in sedentary adults. AB - Caffeine is a commonly used stimulant thought to have ergogenic properties. Most studies on the ergogenic effects of caffeine have been conducted in athletes. The purpose of this study was to test the hypothesis that caffeine reduces ratings of perceived exertion and increases liking of physical activity in sedentary adults. Participants completed treadmill walking at 60% to 70% of their maximal heart rate at baseline and for 6 subsequent visits, during which half of the participants were given caffeine (3 mg/kg) and half given placebo in a sports drink vehicle. To investigate the potential synergistic effects of acute and chronic caffeine on self-determined exercise duration, participants were rerandomized to either the same or different condition for the last visit, creating 4 chronic/acute treatment groups (placebo/placebo, placebo/caffeine, caffeine/placebo, caffeine/caffeine). Participants rated how much they liked the activity and perceived exertion at each visit. There was a main effect of time on liking of physical activity, with liking increasing over time and an interaction of sex and caffeine treatment on liking, with liking of activity increasing in female participants treated with caffeine, but not with placebo. There was no effect of caffeine on ratings of perceived exertion. Individuals who received caffeine on the final test day exercised for significantly longer than those who received placebo. These data suggest that repeated exposure to physical activity significantly increases liking of exercise and reduces ratings of perceived exertion and that caffeine does little to further modify these effects. PMID- 23746562 TI - Phosphatidylserine and caffeine attenuate postexercise mood disturbance and perception of fatigue in humans. AB - Phosphatidylserine (PS) may attenuate the adverse effects of physical fatigue. Therefore, we investigated the effects of a multi-ingredient supplement containing 400 mg/d PS and 100 mg/d caffeine (supplement [SUP]) for 2 weeks on measures of cognitive function (CF), reaction time (RT), and mood (MD) following an acute exercise stress. It is hypothesized that PS will maintain preexercise CF and RT scores, while attenuating postexercise fatigue. Participants completed 2 acute bouts of resistance exercise (T1 and T2) separated by 2-week ingestion of SUP or control (CON). Outcome measures were assessed pre- and postexercise. When collapsed across groups, a significant decrease in RT performance was seen in the 60-second reaction drill from pre- to postexercise at T1. All other RT tests were similar from pre- to postexercise at T1. Reaction time was not significantly changed by PS. When collapsed across groups, a significant increase in performance of the serial subtraction test was seen. A significant increase (8.9% and 7.1%) in the number of correct answers and a significant decrease (8.0% and 7.5%) in time to answer were seen from pre- to postworkout at T1 and T2, respectively. A significant increase in total MD score from pre- to postworkout was observed for CON but not for PS at T2. Phosphatidylserine significantly attenuated pre- to postexercise perception of fatigue compared to CON. Ingestion of SUP for 14 days appears to attenuate postexercise MD scores and perception of fatigue, but does not affect CF or RT, in recreationally trained individuals. PMID- 23746563 TI - Estimation of eicosapentaenoic acid and docosahexaenoic acid intakes in pregnant Japanese women without nausea by using a self-administered diet history questionnaire. AB - Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intakes during pregnancy affect fetal development and maternal mental health; therefore, an accurate assessment of EPA and DHA intakes is required. We hypothesized that a self-administered diet history questionnaire (DHQ) that was developed for non pregnant adults could be used for estimating EPA and DHA intakes in pregnant Japanese women; thus, we evaluated the validity and reproducibility of the DHQ during pregnancy. We recruited 262 healthy participants with singleton pregnancies during their second trimester at a university hospital in Tokyo between June 2010 and July 2011. Plasma concentrations of EPA and DHA were measured as reference values. Fifty-eight women completed the DHQ twice, within a 4- to 5-week period to assess the reproducibility of the results. Among the participants without pregnancy-associated nausea (n = 180), significantly positive correlations were observed between energy-adjusted intakes and plasma concentrations of EPA (r(s) = 0.388), DHA (r(s) = 0.264), and EPA + DHA (r(s) = 0.328). More than 60% of the participants without nausea fell into the same or adjacent quintiles according to energy-adjusted intakes and plasma concentrations of EPA, DHA, and EPA + DHA. Meanwhile, among the participants with nausea, a low correlation for EPA and no correlation for DHA and EPA + DHA were found. Intraclass correlation coefficients for the 2-time DHQ measurements were 0.691 (EPA) and 0.663 (DHA). The results indicate that the DHQ has an acceptable level of validity and reproducibility for assessing EPA, DHA, and EPA + DHA intakes in pregnant Japanese women without nausea. PMID- 23746565 TI - Exercise prevents hyperhomocysteinemia in a dietary folate-restricted mouse model. AB - Hyperhomocysteinemia is a condition that results from altered methyl group metabolism and is associated with numerous pathological conditions. A number of nutritional and hormonal factors have been shown to influence circulating homocysteine concentrations; however, the impact of exercise on homocysteine and methyl group balance is not well understood. Our hypothesis was that exercise represents an effective means to prevent hyperhomocysteinemia in a folate independent manner. The purpose of this study was to determine the influence of exercise on homocysteine metabolism in a dietary folate-restricted mouse model characterized by moderate hyperhomocysteinemia. Female outbred mice (12 weeks old) were assigned to either a sedentary or free-access wheel exercise group. Following a 4-week acclimation period, half of the mice in each group were provided a folate-restricted diet for 7-weeks prior to euthanasia and tissue collection. As expected, folate-restricted sedentary mice exhibited a 2-fold increase in plasma total homocysteine concentrations; however, exercise completely prevented the increase in circulating homocysteine concentrations. Moreover, exercise reduced plasma homocysteine concentrations 36% within the group fed only the control diet. The prevention of hyperhomocysteinemia by exercise appears, at least in part, to be the result of increased folate independent homocysteine remethylation owing to a 2-fold increase in renal betaine homocysteine S-methyltransferase. To our knowledge, this is the first report demonstrating the prevention of hyperhomocysteinemia by exercise in a dietary folate-restriction model. Future research will be directed at determining if exercise can have a positive impact on other nutritional, hormonal, and genetic models of hyperhomocysteinemia relevant to humans. PMID- 23746564 TI - Acute sodium bicarbonate loading has negligible effects on resting and exercise blood pressure but causes gastrointestinal distress. AB - Oral ingestion of sodium bicarbonate (bicarbonate loading) has acute ergogenic effects on short-duration, high-intensity exercise. Because sodium bicarbonate is 27% sodium, ergogenic doses (ie, 300 mg?kg-1) result in sodium intakes well above the Dietary Reference Intakes upper limit of 2300 mg/day. Therefore, it is conceivable that bicarbonate loading could have hypertensive effects. Therefore, we performed a double-blind crossover trial to evaluate the hypothesis that bicarbonate loading increases resting and exercise blood pressure (BP). A secondary hypothesis was that bicarbonate loading causes gastrointestinal distress. Eleven endurance-trained men and women (exercise frequency, 4.6 +/- 0.4 sessions/wk; duration, 65 +/- 6 min/session) underwent testing on two occasions in random sequence: once after bicarbonate loading (300 mg?kg-1) and once after placebo ingestion. BP and heart rate were measured before bicarbonate or placebo consumption, 30 minutes after consumption, during 20 min of steady state submaximal cycling exercise, and during recovery. Bicarbonate loading did not affect systolic BP during rest, exercise, or recovery (P = .38 for main treatment effect). However, it resulted in modestly higher diastolic BP (main treatment effect, +3.3 +/- 1.1 mmHg, P = .01) and higher heart rate (main treatment effect, +10.1 +/- 2.4 beats per minute, P = .002). Global ratings of gastrointestinal distress severity (0-10 scale) were greater after bicarbonate ingestion (5.1 +/- 0.5 vs 0.5 +/- 0.2, P < .0001). Furthermore, 10 of the 11 subjects (91%) experienced diarrhea, 64% experience bloating and thirst, and 45% experienced nausea after bicarbonate loading. In conclusion, although a single, ergogenic dose of sodium bicarbonate does not appear to have acute, clinically important effects on resting or exercise BP, it does cause substantial gastrointestinal distress. PMID- 23746566 TI - A low-protein, high-carbohydrate diet increases de novo fatty acid synthesis from glycerol and glycerokinase content in the liver of growing rats. AB - We had previously shown that adipose tissue increased in rats fed a low-protein, high-carbohydrate (LPHC) diet (6% protein, 74% carbohydrate) without a simultaneous increase in the de novo fatty acids (FA) synthesis. In addition, impairment in insulin signaling in adipose tissues was observed in these rats. For this study, we hypothesized that the insulin signaling pathway is preserved in the livers from these rats, which contributes to an increase in liver lipogenesis and, consequently, an increase in the weight of the adipose tissue. We also hypothesized that glycerol from triacylglycerol is an important substrate for FA synthesis. Our results showed that administration of the LPHC diet induced an increase in the in vivo rate of total FA synthesis (150%) as well as FA synthesis from glucose (270%) in the liver. There were also increased rates of [U 14C]glycerol incorporation into glyceride-FA (15-fold), accompanied by increased glycerokinase content (30%) compared with livers of rats fed the control diet. The LPHC diet did not change the glycerol-3-phosphate generation from either glucose or glyceroneogenesis. There was an increase in the insulin sensitivity in liver from LPHC-fed rats, as evidenced by increases in IR(beta) (35%) levels and serine/threonine protein kinase (AKT) levels (75%), and basal (95%) and insulin stimulated AKT phosphorylation (105%) levels. The LPHC diet also induced an increase in the liver sterol regulatory element-binding protein-1c content (50%). In summary, these data confirmed the hypothesis that lipogenesis and insulin signaling are increased in the livers of LPHC-fed rats and that glycerol is important not only for FA esterification but also for FA synthesis. PMID- 23746568 TI - The role of IL-22 and Th22 cells in human skin diseases. AB - Interleukin (IL)-22 is a cytokine that is involved in the modulation of tissue responses during inflammation. It is produced by immune cell subsets such as T cells, while the expression of its receptor is restricted to cells of non hematopoietic origin, particularly epithelial cells. In the skin, IL-22 induces keratinocyte proliferation and epidermal hyperplasia, inhibits terminal differentiation of keratinocytes, and promotes the production of antimicrobial proteins. Although IL-22 was initially thought to be produced by T helper (Th)17 cells, IL-22 production can also occur in an apparently unique subset of cells, Th22 cells, which lack the ability to produce IL-17 and interferon-gamma. Of note, Th22 cells, which express the skin homing chemokine receptors CCR4 and CCR10, reside in the normal skin and are enriched in the lesional skin of inflammatory skin diseases, indicating the importance of IL-22 in skin homeostasis and pathogenesis of skin diseases. Although a critical role of IL-22 was initially highlighted in psoriasis, a growing body of evidence indicates that this cytokine also plays a role in atopic dermatitis and other inflammatory skin diseases. Moreover, emerging experimental data suggest that IL-22 also participates in the pathophysiology of malignancies of the skin. In this review, recent findings regarding the expression, regulation, and function of the IL-22 pathway in various human skin diseases will be discussed. Considering the strong association between excess activation of the IL-22/Th22 pathway and human skin diseases, targeting this pathway may provide promising new therapeutic approaches. PMID- 23746567 TI - Citrus aurantium and Rhodiola rosea in combination reduce visceral white adipose tissue and increase hypothalamic norepinephrine in a rat model of diet-induced obesity. AB - Extracts from the immature fruit of Citrus aurantium are often used for weight loss but are reported to produce adverse cardiovascular effects. Root extracts of Rhodiola rosea have notable antistress properties. The hypothesis of these studies was that C aurantium (6% synephrine) and R rosea (3% rosavins, 1% salidroside) in combination would improve diet-induced obesity alterations in adult male Sprague-Dawley rats. In normal-weight animals fed standard chow, acute administration of C aurantium (1-10 mg/kg) or R rosea (2-20 mg/kg) alone did not reduce deprivation-induced food intake, but C aurantium (5.6 mg/kg) + R rosea (20 mg/kg) produced a 10.5% feeding suppression. Animals maintained (13 weeks) on a high-fat diet (60% fat) were exposed to 10-day treatments of C aurantium (5.6 mg/kg) or R rosea (20 mg/kg) alone or in combination. Additional groups received vehicle (2% ethanol) or were pair fed to the C aurantium + R rosea group. Although high-fat diet intake and weight loss were not influenced, C aurantium + R rosea had a 30% decrease in visceral fat weight compared with the other treatments. Only the C aurantium group had an increased heart rate (+7%) compared with vehicle. In addition, C aurantium + R rosea administration resulted in an elevation (+15%) in hypothalamic norepinephrine and an elevation (+150%) in frontal cortex dopamine compared with the pair-fed group. These initial findings suggest that treatments of C aurantium + R rosea have actions on central monoamine pathways and have the potential to be beneficial for the treatment of obesity. PMID- 23746569 TI - Contribution of flagellin subunit FliC to piglet epithelial cells invasion by F18ab E. coli. AB - Flagellar structures contribute to the virulence of multiple gastrointestinal pathogens either as the effectors of motility, as adhesins, or as a secretion apparatus for virulence factors. Escherichia coli F18ab variant strains are associated with edema disease (ED) in pig industries worldwide. These strains use flagella to increase the efficiency of epithelial cell invasion. In this study, we aimed to elucidate the mechanism by which flagella contribute to F18ab E. coli invasion. To explore the role of flagella in the invasion process, we performed invasion assays with either flagellated and motile, flagellated but non-motile, or non-flagellated non-motile bacteria. We observed that flagellated but non motile bacteria invade piglet epithelial cells even more efficiently than the parent wild-type (WT) strain in vitro. By contrast, the non-flagellated bacteria have significantly reduced invasion as compared with the parent strain. These results demonstrate that flagella function mainly as adhesins to enhance the ability of F18ab E. coli to target piglet epithelial cells. PMID- 23746570 TI - High-grade intracranial chondrosarcoma presenting with haemorrhage. AB - Chondrosarcomas are rare sarcomas that produce malignant cartilage, infrequently arising as a primary intracranial tumour. We present a patient with intracranial chondrosarcoma with intratumoural haemorrhage arising in an unusual location and with unusual imaging findings. A 46-year-old man presented with headache, nausea, and vomiting over the previous 24 hours. Physical and neurological examinations were normal. Cranial CT scans and MRI revealed a large right pre-frontal (subdural) and interhemispheric heterogeneous density associated with a frontal, partially calcified mass and midline shift. An awake craniotomy was performed. With the intra-operative quick section favouring subdural hematoma, the lesion was subtotally resected. Follow-up imaging confirmed residual mass. Pathology examination revealed a high-grade malignant neoplasm with chondroid differentiation, diagnosed as conventional Grade III chondrosarcoma. The patient was referred to oncology for follow-up and radiation therapy. Intracranial chondrosarcoma was first reported in 1899, and since then continues to be an extremely rare malignancy of the brain. These tumours commonly present as extra axial masses, originating from the skull base, and produce symptoms due to progressive enlargement and compression of local structures. Unusual presentations of these tumours, such as vascularity, intratumoural haemorrhage, and intra-axial location, may complicate pre-surgical decision making by altering the provisional diagnosis prior to intervention. This patient emphasises the importance of careful analysis and incorporation of imaging findings into surgical decision making. Specific imaging characteristics that, in such unusual situations, are suggestive of chondrosarcoma should motivate an aggressive surgical approach to optimise adjuvant interventions. PMID- 23746571 TI - Outcomes for unruptured ophthalmic segment aneurysm surgery. AB - Ophthalmic segment aneurysms present unique technical challenges because of their proximity to the optic nerve and the anterior clinoid process. The current study was performed to examine whether surgery for unruptured ophthalmic segment aneurysms is an effective treatment modality with acceptable complication rates. A consecutive case series (prospectively collected data) was retrospective reviewed for the period between April 1992 and August 2012. Clinical results, operative complications, angiographic outcomes and prognostic factors associated with surgery are presented. Of the 169 patients with 182 unruptured ophthalmic segment aneurysms that were surgically repaired, 11 (6.4%) experienced new permanent neurological deficits, including six instances of complete visual loss. There was one postoperative death (0.6%) related to a middle cerebral artery infarction. Transient morbidity occurred in 18 patients (10.4%), including cerebrospinal fluid rhinorhea (10 patients), oculomotor nerve palsy (four patients) and transient dysphasia (four patients). A total of 142 aneurysms (78.0%) had documented postoperative angiography. Surgical treatment resulted in 135 (95.1%) complete obliterations and seven (4.9%) neck remnants. Retreatment was performed in three patients (1.7%). Logistic regression analysis of risk factors revealed that age (p < 0.02), aneurysm size (p < 0.01) and the use of temporary clipping (p < 0.01) were significant negative predictors of outcome. The risk associated with surgical repairs for unruptured ophthalmic segment aneurysms is no greater than aneurysms in other locations (6.4% morbidity; 0.6% mortality) and no more hazardous than outcomes achieved by alternative therapies. The robustness of aneurysm repair achieved by open microsurgery is an important consideration. PMID- 23746572 TI - Comparison of bovine tuberculosis recurrence in Irish herds between 1998 and 2008. AB - During the last several decades in Ireland, there has been substantial scientific progress in our understanding and related policy changes in the bovine tuberculosis (bTB) eradication programme. A range of performance measurements are routinely available, each highlighting a steadily improving situation in Ireland. However, recent research has highlighted an on-going problem of residual infection, contributing to recurrent breakdowns. In light of this general improvement, but also cognisant of residual infection, a critical evaluation of changes in effectiveness of managing recurrence is particularly valuable. Therefore, the objective of the study was to compare the herd-level risk of recurrence of bTB in Ireland between 1998 and 2008. A retrospective cohort study was carried out, using a Cox proportional-hazards model, to compare the risk of restriction recurrence in herds derestricted during 1998 and 2008. These herds were observed for up to 3 years from the end of the 'index restriction'. At the univariable level, 46.4% and 34.8% of study herds derestricted in 1998 and 2008, respectively, had a subsequent breakdown during the study period (chi(2)=70.6, P<0.001). In the multivariable analysis, there has been a significant reduction in bTB recurrence in Ireland, with 2008-derestricted herds being 0.74 times (95% confidence interval: 0.68-0.81) as likely to be restricted during the subsequent study period compared with 1998-derestricted herds. In the final Cox model, the rate of a future breakdown increased with increasing herd size, increasing number of standard reactors in the index restriction, increasing percentage of newly restricted herds within the District Electoral Division (DED) and if the herd had a previous bTB episode in the previous 5 years. The risk varied across herd type. The results from the current study provide further reassurance of an improved national situation, both in terms of limiting the establishment of new infection (bTB incidence) and in effectively clearing infection once detected (recurrence following derestriction). Recurrence of bTB requires effective implementation of multiple control strategies, focusing on identifying and removing residually infected cattle, and limiting environmental sources of infection, which in Ireland primarily relates to badgers. PMID- 23746573 TI - Seroprevalence of Toxoplasma gondii infection in domestic rabbits in Durango State, Mexico. AB - There is a lack of information concerning the seroprevalence of Toxoplasma gondii infection in rabbits in northern Mexico. Through a cross sectional study, antibodies to T. gondii were determined in 429 domestic rabbits in Durango State, Mexico using the modified agglutination test. Rabbits were raised in 29 properties in 6 municipalities. Overall, antibodies to T. gondii were found in 70 (16.3%) of 429 rabbits, with titers of 1:25 in 42, 1:50 in 19, 1:100 in 5, 1:200 in 3, and 1:800 in 1. Seropositive rabbits were found in 21 (72.4%) of 29 properties, including 16 of 21 homes, 4 of 5 farms, and 1 of 3 pet shops. This is the first study of T. gondii infection in rabbits in Durango, Mexico. Results indicate that infected rabbits are a potential source of T. gondii infection in humans in Durango State. PMID- 23746574 TI - Crossmodal and action-specific: neuroimaging the human mirror neuron system. AB - The notion of a frontoparietal human mirror neuron system (HMNS) has been used to explain a range of social phenomena. However, most human neuroimaging studies of this system do not address critical 'mirror' properties: neural representations should be action specific and should generalise across visual and motor modalities. Studies using repetition suppression (RS) and, particularly, multivariate pattern analysis (MVPA) highlight the contribution to action perception of anterior parietal regions. Further, these studies add to mounting evidence that suggests the lateral occipitotemporal cortex plays a role in the HMNS, but they offer less support for the involvement of the premotor cortex. Neuroimaging, particularly through application of MVPA, has the potential to reveal the properties of the HMNS in further detail, which could challenge prevailing views about its neuroanatomical organisation. PMID- 23746575 TI - Xbox KinectTM represents high intensity exercise for adults with cystic fibrosis. AB - BACKGROUND: Exercise is important for patients with cystic fibrosis (CF). Interactive gaming consoles are a new trend in exercise. This study sought to determine the exercise intensity of training using the Xbox Kinect(TM). METHODS: Participants with CF completed two sessions separated by <=10 days. The first session involved a cardiopulmonary exercise test (CPET) to measure peak exercise capacity. The second session involved 20 min of exercise using the Xbox KinectTM. RESULTS: Ten participants (median [interquartile range] FEV1 58 [46]%, 29 [6] years, 6 males) completed the study. The average heart rate over the final 10 min of exercise using the Xbox KinectTM, expressed as a percentage of the peak heart rate achieved on the CPET, was 86% (95% confidence interval, 81 to 92%). CONCLUSIONS: Training using the Xbox KinectTM represents high intensity exercise for adults with CF and may be a suitable alternative to conventional exercise modalities. PMID- 23746576 TI - Using diatoms to monitor stream biological integrity in Eastern Canada: an overview of 10 years of index development and ongoing challenges. AB - An improved version of the Eastern Canadian Diatom Index (IDEC: Indice Diatomees de l'Est du Canada) was developed, incorporating modifications to optimize diatom based monitoring in Eastern Canada. The most significant improvement with this version of the IDEC is the extended coverage area including additional reference sites. This new version of the IDEC also incorporated a simplified list of diatom taxa to reduce the variability among analysts as it gains in popularity. Rare taxa (<2%) were excluded and various morphotypes were grouped. The index was created based on three sub-indices that were adapted to cover the range of natural pH and conductivity values allowing us to partial out the strong influence of natural pH and conductivity from the general pollution gradient. The index was created using 648 diatom assemblages including those from nearly 150 reference (or least-disturbed) sites. The reference sites covered a large range of natural characteristics. The diatom assemblages collected in these environments constitute "biotype class A" in each sub-index and represent a realistic goal for restoration. Associated total phosphorus and total nitrogen showed that class A generally reflects conditions that are considered oligotrophic (<0.025 mg L(-1)) or oligo-mesotrophic, while class D at the opposite end of the pollution gradient reflects eutrophic or hyper-eutrophic environments. There is a good correspondence between IDEC values and nutrient criteria, water quality indices based on physico-chemistry measurements, the presence of agricultural activities, and urban areas. The IDEC has a great potential to assist water quality monitoring, particularly when the objective is to assess the trophic status of a watercourse. PMID- 23746577 TI - Association of home care needs and functional recovery among community-dwelling elderly hip fracture patients. AB - The aim of this study was to assess the home care needs and task difficulty of community-dwelling aged hip fracture and the association of functional recovery with care received. A cohort of hip fracture patients admitted to orthopedic wards for surgery was collected from August 2009 to December 2010. Patients transferred to long-term care facilities after surgery were excluded. Functional status (feeding, clothing, grooming, bathing, getting in/out of bed, walking, toileting, standing up/sitting down, and walking up/down stairs) and task difficulty for caregivers were recorded at discharge, one week and one month after discharge. In total, 116 patients (mean age: 79.4 +/- 8.5 years, 51.7% males) were enrolled. The mean age of primary caregivers was 53.4 +/- 14.2 years, and most were daughters or sons (54.3%), spouses (34.5%) or foreign workers (11.0%). The most common care needs were wound care (95.7%), medical visits (94.8%), cleaning and maintaining living quarters (92.2%) and vigilance to ensure patient safety (92.2%). The care needs and task difficulty significantly correlated with physical function before, one week and one month after discharge (r=-0.530, p<0.001; r=-0.326, p=0.001; r=-0.432, p<0.001; r=-0.684, p<0.001; and r=-0.475, p<0.001, respectively). The complex and taxing home care needs of community-dwelling elderly hip fracture patients were significantly associated with functional recovery. Comprehensive geriatric assessment and related special medical services may greatly help caregivers and promote the practice of aging in place. Further study is needed to develop appropriate caregiver education to promote the functional recovery of elderly hip fracture patients at home. PMID- 23746578 TI - Epidemiology and aetiology of neonatal seizures. AB - Neonatal seizures constitute the most frequent and distinctive neurological symptom in the neonatal period. Seizures in the neonatal period differ considerably from those observed later in life with respect to their aetiological profile and clinical presentation. In addition, the aetiological profile in preterm infants is different from that seen in term infants. Hypoxic-ischaemic encephalopathy is the most frequent cause of neonatal seizures in term babies followed by focal ischaemia (stroke), cerebral malformations and metabolic disturbances. In preterm neonates, intraventricular haemorrhage and infections cause most of the seizures reported in this group. Better neuroimaging techniques have reduced the number of undiagnosed cases, and the institution of newer neuroprotective strategies has influenced the outcome. PMID- 23746579 TI - Short communication: Accounting for new mutations in genomic prediction models. AB - Genomic evaluation models so far do not allow for accounting of newly generated genetic variation due to mutation. The main target of this research was to extend current genomic BLUP models with mutational relationships (model AM), and compare them against standard genomic BLUP models (model A) by analyzing simulated data. Model performance and precision of the predicted breeding values were evaluated under different population structures and heritabilities. The deviance information criterion (DIC) clearly favored the mutational relationship model under large heritabilities or populations with moderate-to-deep pedigrees contributing phenotypic data (i.e., differences equal or larger than 10 DIC units); this model provided slightly higher correlation coefficients between simulated and predicted genomic breeding values. On the other hand, null DIC differences, or even relevant advantages for the standard genomic BLUP model, were reported under small heritabilities and shallow pedigrees, although precision of the genomic breeding values did not differ across models at a significant level. This method allows for slightly more accurate genomic predictions and handling of newly created variation; moreover, this approach does not require additional genotyping or phenotyping efforts, but a more accurate handing of available data. PMID- 23746580 TI - Effect of gum tragacanth on rheological and physical properties of a flavored milk drink made with date syrup. AB - Date syrup as a nutritional additive and safe alternative to added sugar is one of the best choices for milk flavoring. In this study, a flavored milk beverage was formulated using date syrup for flavoring the product and gum tragacanth to obtain an acceptable mouth feel. Steady shear and dynamic oscillatory rheological properties of the samples contained 3 concentrations (0, 0.1, 0.2, and 0.3%, wt/wt) of 2 types of gum tragacanth (Astragalus gossypinus and Astragalus rahensis) which at 3 degrees C, were studied. Particle size distribution and colorimetric assays were determined by laser diffractometry and using reflection spectrometer, respectively. Sensory analysis was performed with 25 semitrained panelists, using a 5-point hedonic scale. The results showed that viscoelastic properties, flow behavior parameters, particle size, and color parameters (L*, a*, and b*, where L* represents lightness, a* represents the redness/greenness quality of the color, and b* represents the yellowness and blueness quality of the colors) were significantly affected by the concentration of the gum tragacanth and the severity of this effect was influenced by the type of gum. The use of appropriate type and concentration of gum tragacanth in date milk formulation can improve the texture and mouth feel by affecting on particle size and the flow behavior of this product. PMID- 23746581 TI - Short communication: Supplementing lysine and methionine in a lactation diet containing a high concentration of wet corn gluten feed did not alter milk protein yield. AB - Primiparous (n=33) and multiparous (n=63) lactating Holstein cows (186+/-51 d in milk) were used to evaluate the effects of supplementing metabolizable amino acids using lysine in a matrix of Ca salts of fatty acids (Megamine-L, Arm & Hammer Animal Nutrition, Princeton, NJ) and the isopropyl ester of 2-hydroxy-4 (methylthio) butanoic acid (MetaSmart, Adisseo Inc., Antony, France) in diets containing >26% wet corn gluten feed (dry matter basis). Cows were blocked by production level, parity, and pregnancy status, then randomly assigned to 1 of 8 pens and allowed a 7-d adaption period before receiving dietary treatments for 28 d. Pens were assigned randomly to either of 2 diets formulated to differ by metabolizable amino acid supply. Dry matter intake and production were monitored daily and milk components analyzed 3d/wk. Data were analyzed using mixed models with repeated measures. The original design of the study consisted of a control diet predicted to be deficient in lysine and methionine; however, after ingredient nutrients were analyzed and modeled with animal requirements at dry matter intake [26.6+/-0.35 kg/d (mean +/- SEM)] and milk production levels achieved during the study (40.1+/-0.46 kg/d), only marginal deficiencies were predicted for the control (-8.1g/d for lysine; -1g/d for methionine) according to the National Research Council method, whereas the Cornell Net Carbohydrate and Protein System 5.0 and 6.1 models indicated positive balances for these amino acids (25.9 and 21.8 g/d for lysine, 14.7 and 18.9 g/d for methionine, respectively). Supplementing 30 g/d of metabolizable lysine in a Ca soap matrix and 2.4 g/d of metabolizable methionine as 2-hydroxy-4-(methylthio) butanoic acid led to positive predicted lysine and methionine balances by all 3 models, and predicted metabolizable lysine-to-methionine ratios ranging from 2.9 to 3.1. No treatment effects were observed for dry matter intake, milk yield, milk component concentrations or yields, or energy-corrected milk yield. Despite the negative lysine balance and low lysine-to-methionine ratio predicted by the National Research Council model, results provided no evidence of a lysine deficiency in the control diet. PMID- 23746582 TI - Application of a posteriori granddaughter and modified granddaughter designs to determine Holstein haplotype effects. AB - A posteriori and modified granddaughter designs were applied to determine haplotype effects for Holstein bulls and cows with BovineSNP50 [~50,000 single nucleotide polymorphisms (SNP); Illumina Inc., San Diego, CA] genotypes. The a posteriori granddaughter design was applied to 52 sire families, each with >=100 genotyped sons with genetic evaluations based on progeny tests. For 33 traits (milk, fat, and protein yields; fat and protein percentages; somatic cell score; productive life; daughter pregnancy rate; heifer and cow conception rates; service-sire and daughter calving ease; service-sire and daughter stillbirth; 18 conformation traits; and net merit), the analysis was applied to the autosomal segment with the SNP with the greatest effect in the genomic evaluation of each trait. All traits except 2 had a within-family haplotype effect. The same design was applied with the genetic evaluations of sons corrected for SNP effects associated with chromosomes besides the one under analysis. The number of within family contrasts was 166 without adjustment and 211 with adjustment. Of the 52 bulls analyzed, 36 had BovineHD (high density; Illumina Inc.) genotypes that were used to test for concordance between sire quantitative trait loci and SNP genotypes; complete concordance was not obtained for any effects. Of the 31 traits with effects from the a posteriori granddaughter design, 21 were analyzed with the modified granddaughter design. Only sires with a contrast for the a posteriori granddaughter design and >=200 granddaughters with a record usable for genetic evaluation were included. Calving traits could not be analyzed because individual cow evaluations were not computed. Eight traits had within-family haplotype effects. With respect to milk and fat yields and fat percentage, the results on Bos taurus autosome (BTA) 14 corresponded to the hypothesis that a missense mutation in the diacylglycerol O-acyltransferase 1 (DGAT1) gene is the main causative mutation, although other polymorphisms in that gene also modify fat yield and percentage. The positive allele for protein concentration was less frequent, which indicated that selection on that locus could be effective. Although the results can be used to determine causative polymorphisms for most of the analyzed traits, complete DNA sequencing of most of the analyzed sires probably will be required. PMID- 23746583 TI - Immunomodulatory and hypoallergenic properties of milk protein hydrolysates in ICR mice. AB - Approximately 2.5% of young children are allergic to cow milk. In this study, milk protein hydrolysates made from full-cream milk via enzymatic hydrolysis played a positive role in regulating the immune system of ICR mice. Milk protein hydrolysates enhanced immunity in mice by stimulating host immunity, probably by increasing the weight of certain immune system organs, improving the level of hemolysin in serum, and enhancing the phagocytosis of macrophages. Milk protein hydrolysates have the capability to reduce type I hypersensitivity by decreasing IgE levels, IL-4 in serum, and the release of histamine and bicarbonate in peritoneal mast cells, as well as enhancing transforming growth factor-beta levels in the serum of ovalbumin-sensitized mice. PMID- 23746584 TI - Liver fat content and lipid metabolism in dairy cows during early lactation and during a mid-lactation feed restriction. AB - During the transition period, the lipid metabolism of dairy cows is markedly affected by energy status. Fatty liver is one of the main health disorders after parturition. The aim of this study was to evaluate the effects of a negative energy balance (NEB) at 2 stages in lactation [NEB at the onset of lactation postpartum (p.p.) and a deliberately induced NEB by feed restriction near 100 d in milk] on liver triglyceride content and parameters of lipid metabolism in plasma and liver based on mRNA abundance of associated genes. Fifty multiparous dairy cows were studied from wk 3 antepartum to approximately wk 17 p.p. in 2 periods. According to their energy balance in period 1 (parturition to wk 12 p.p.), cows were allocated to a control (CON; n=25) or a restriction group (RES; 70% of energy requirements; n=25) for 3 wk in mid lactation starting at around 100 d in milk (period 2). Liver triglyceride (TG) content, plasma nonesterified fatty acids (NEFA), and beta-hydroxybutyrate were highest in wk 1 p.p. and decreased thereafter. During period 2, feed restriction did not affect liver TG and beta-hydroxybutyrate concentration, whereas NEFA concentration was increased in RES cows as compared with CON cows. Hepatic mRNA abundances of tumor necrosis factor alpha, ATP citrate lyase, mitochondrial glycerol-3-phosphate acyltransferase, and glycerol-3-phosphate dehydrogenase 2 were not altered by lactational and energy status during both experimental periods. The expression of fatty acid synthase was higher in period 2 compared with period 1, but did not differ between RES and CON groups. The mRNA abundance of acetyl-coenzyme A carboxylase showed a tendency toward higher expression during period 2 compared with period 1. The solute carrier family 27 (fatty acid transporter), member 1 (SLC27A1) was upregulated in wk 1 p.p. and also during feed restriction in RES cows. In conclusion, the present study shows that a NEB has different effects on hepatic lipid metabolism and TG concentration in the liver of dairy cows at early and later lactation. Therefore, the homeorhetic adaptations during the periparturient period trigger excessive responses in metabolism, whereas during the homeostatic control of endocrine and metabolic systems after established lactation, as during the period of feed restriction in the present study, organs are well adapted to metabolic and environmental changes. PMID- 23746585 TI - Comparison of updates to the Molly cow model to predict methane production from dairy cows fed pasture. AB - Molly is a deterministic, mechanistic, dynamic model representing the digestion, metabolism, and production of a dairy cow. This study compared the predictions of enteric methane production from the original version of Molly (MollyOrigin) and 2 new versions of Molly. Updated versions included new ruminal fiber digestive parameters and animal hormonal parameters (Molly84) and a revised version of digestive and ruminal parameters (Molly85), using 3 different ruminal volatile fatty acid (VFA) stoichiometry constructs to describe the VFA pattern and methane (CH4) production (g of CH4/d). The VFA stoichiometry constructs were the original forage and mixed-diet VFA constructs and a new VFA stoichiometry based on a more recent and larger set of data that includes lactate and valerate production, amylolytic and cellulolytic bacteria, as well as protozoal pools. The models' outputs were challenged using data from 16 dairy cattle 26 mo old [standard error of the mean (SEM)=1.7], 82 (SEM=8.7) d in milk, producing 17 (SEM=0.2) kg of milk/d, and fed fresh-cut ryegrass [dry matter intake=12.3 (SEM=0.3) kg of DM/d] in respiration chambers. Mean observed CH4 production was 266+/-5.6 SEM (g/d). Mean predicted values for CH4 production were 287 and 258 g/d for MollyOrigin without and with the new VFA construct. Model Molly84 predicted 295 and 288 g of CH4/d with and without the new VFA settings. Model Molly85 predicted the same CH4 production (276 g/d) with or without the new VFA construct. The incorporation of the new VFA construct did not consistently reduce the low prediction error across the versions of Molly evaluated in the present study. The improvements in the Molly versions from MollyOrigin to Molly84 to Molly85 resulted in a decrease in mean square prediction error from 8.6 to 8.3 to 4.3% using the forage diet setting. The majority of the mean square prediction error was apportioned to random bias (e.g., 43, 65, and 70% in MollyOrigin, Molly84, and Molly85, respectively, on the forage setting, showing that with the updated versions a greater proportion of error was random). The slope bias was less than 2% in all cases. We concluded that, of the versions of Molly used for pastoral systems, Molly85 has the capability to predict CH4 production from grass-fed dairy cows with the highest accuracy. PMID- 23746586 TI - Genomic architecture of bovine kappa-casein and beta-lactoglobulin. AB - The objective of this study was to characterize the genetic architecture underlying the absolute concentrations of 2 important milk proteins, kappa-casein (kappa-CN) and beta-lactoglobulin (beta-LG), in a backcross population of (Holstein * Jersey) * Holstein cattle. A genome-wide association analysis was performed using a selective DNA pooling strategy and the Illumina BovineHD BeadChip assay [777,000 (777K) SNP markers; Illumina Inc., San Diego, CA]. After correction for multiple testing, 25 single nucleotide polymorphisms were found to be associated with kappa-CN and 36 single nucleotide polymorphisms were associated with beta-LG. A pathway association analysis revealed 15 Gene Ontology (GO) terms associated with the kappa-CN trait and 28 GO terms associated with beta-LG. In addition, several GO terms were associated with both milk proteins. Further analysis revealed that kappa-CN and beta-LG production is regulated by both kinase and phosphatase activity, including mechanisms regulating the extracellular matrix. These results are in concordance with the complex multihormonal process controlling the expression of milk proteins and interactions between mammary epithelial cells and extracellular matrix components. Although kappa-CN and beta-LG milk proteins are expressed by single genes, the results from this study showed that many loci are involved in the regulation of the concentration of these 2 proteins. PMID- 23746587 TI - The occurrence of noncoagulating milk and the association of bovine milk coagulation properties with genetic variants of the caseins in 3 Scandinavian dairy breeds. AB - Substantial variation in milk coagulation properties has been observed among dairy cows. Consequently, raw milk from individual cows and breeds exhibits distinct coagulation capacities that potentially affect the technological properties and milk processing into cheese. This variation is largely influenced by protein composition, which is in turn affected by underlying genetic polymorphisms in the major milk proteins. In this study, we conducted a large screening on 3 major Scandinavian breeds to resolve the variation in milk coagulation traits and the frequency of milk with impaired coagulation properties (noncoagulation). In total, individual coagulation properties were measured on morning milk collected from 1,299 Danish Holstein (DH), Danish Jersey (DJ), and Swedish Red (SR) cows. The 3 breeds demonstrated notable interbreed differences in coagulation properties, with DJ cows exhibiting superior coagulation compared with the other 2 breeds. In addition, milk samples from 2% of DH and 16% of SR cows were classified as noncoagulating. Furthermore, the cows were genotyped for major genetic variants in the alphaS1- (CSN1S1), beta- (CSN2), and kappa-casein (CSN3) genes, revealing distinct differences in variant frequencies among breeds. Allele I of CSN2, which had not formerly been screened in such a high number of cows in these Scandinavian breeds, showed a frequency around 7% in DH and DJ, but was not detected in SR. Genetic polymorphisms were significantly associated with curd firming rate and rennet coagulation time. Thus, CSN1S1 C, CSN2 B, and CSN3 B positively affected milk coagulation, whereas CSN2 A(2), in particular, had a negative effect. In addition to the influence of individual casein genes, the effects of CSN1S1-CSN2-CSN3 composite genotypes were also examined, and revealed strong associations in all breeds, which more or less reflected the single gene results. Overall, milk coagulation is under the influence of additive genetic variation. Optimal milk for future cheese production can be ensured by monitoring the frequency of unfavorable variants and thus preventing an increase in the number of cows producing milk with impaired coagulation. Selective breeding for variants associated with superior milk coagulation can potentially increase raw milk quality and cheese yield in all 3 Scandinavian breeds. PMID- 23746588 TI - Accuracy of genomic prediction for milk production traits in the Chinese Holstein population using a reference population consisting of cows. AB - Genomic selection using dense markers covering the whole genome is a tool for the genetic improvement of livestock and is revolutionizing the breeding system in dairy cattle. Progeny-tested bulls have been used to form reference populations in almost all countries where genomic selection has been implemented. In this study, the accuracy of genomic prediction when cows are used to form the reference population was investigated. The reference population consisted of 3,087 cows. All individuals were genotyped with Illumina BovineSNP50. After genotype imputation and editing, 48,676 single nucleotide polymorphisms were available for analysis. Two methods, genomic BLUP (GBLUP) and BayesB, were used to render genomic estimated breeding values (GEBV) for 5 milk production traits. Accuracies of GEBV were assessed in 3 ways: r(GEBV,EBV) (the correlation between GEBV and conventional EBV) in 67 progeny-tested bulls, rGEBV,EBV from a 5-fold cross validation in the 3,087 cow reference population, and the theoretical accuracy (for GBLUP) calculated in the same way as for conventional BLUP. The results showed that using GBLUP, the r(GEBV,EBV) and theoretical accuracy of genomic prediction in Chinese Holstein ranged from 0.59 to 0.76 and 0.70 to 0.80, respectively, which was 0.13 to 0.30 and 0.23 to 0.33 higher than the accuracies of conventional pedigree index, respectively. The results indicate that, as an alternative, genomic selection using cows in the reference population is feasible. PMID- 23746589 TI - The microbial content of raw and pasteurized cow milk as determined by molecular approaches. AB - The microbial composition of raw and pasteurized milk is assessed on a daily basis. However, many such tests are culture-dependent, and, thus, bacteria that are present at subdominant levels, or that cannot be easily grown in the laboratory, may be overlooked. To address this potential bias, we have used several culture-independent techniques, including flow cytometry, real-time quantitative PCR, and high-throughput DNA sequencing, to assess the microbial population of milk from a selection of commercial milk producers, pre- and postpasteurization. The combination of techniques employed reveals the presence of a previously unrecognized and diverse bacterial population in unpasteurized cow milk. Most notably, the use of high-throughput DNA sequencing resulted in several bacterial genera being identified in milk samples for the first time. These included Bacteroides, Faecalibacterium, Prevotella, and Catenibacterium. Our culture-independent analyses also indicate that the bacterial population of pasteurized milk is more diverse than previously appreciated, and that nonthermoduric bacteria within these populations are likely to be in a damaged, nonculturable form. It is thus apparent that the application of state-of-the-art approaches can provide a detailed insight into the bacterial composition of milk and could potentially be employed in the future to investigate the factors that influence the composition of these populations. PMID- 23746590 TI - The effect of timing of oral meloxicam administration on physiological responses in calves after cautery dehorning with local anesthesia. AB - Dehorning is a painful husbandry procedure that is commonly performed in dairy calves. Parenteral meloxicam combined with local anesthesia mitigates the physiological and behavioral effects of dehorning in calves. The purpose of this study was to determine the influence of timing of oral meloxicam administration on physiological responses in calves after dehorning. Thirty Holstein bull calves, 8 to 10 wk of age (28-70 kg), were randomly assigned to 1 of 3 treatment groups: placebo-treated control group (n=10), calves receiving meloxicam administered orally (1 mg/kg) in powdered milk replacer 12h before cautery dehorning (MEL-PRE; n=10), and calves receiving meloxicam administered as an oral bolus (1 mg/kg) at the time of dehorning (MEL-POST; n=10). Following cautery dehorning, blood samples were collected to measure cortisol, substance P (SP), haptoglobin, ex vivo prostaglandin E2 (PgE2) production after lipopolysaccharide stimulation and meloxicam concentrations. Maximum ocular temperature and mechanical nociceptive threshold (MNT) were also assessed. Data were analyzed using noncompartmental pharmacokinetic analysis and repeated measures ANOVA models. Mean peak meloxicam concentrations were 3.61+/-0 0.21 and 3.27+/-0.14 MUg/mL with average elimination half-lives of 38.62+/-5.87 and 35.81+/-6.26 h for MEL-PRE and MEL-POST, respectively. Serum cortisol concentrations were lower in meloxicam-treated calves compared with control calves at 4 h postdehorning. Substance P concentrations were significantly higher in control calves compared with meloxicam-treated calves at 120 h after dehorning. Prostaglandin E2 concentrations were lower in meloxicam-treated calves compared with control calves. Mechanical nociceptive threshold was higher in control calves at 1h after dehorning, but meloxicam-treated calves tended to have a higher MNT at 6h after dehorning. No effect of timing of meloxicam administration on serum cortisol concentrations, SP concentrations, haptoglobin concentrations, maximum ocular temperature, or MNT was observed. However, PgE2 concentrations in MEL-PRE calves were similar to control calves after 12h postdehorning, whereas MEL-POST calves had lower PgE2 concentrations for 3 d postdehorning. These findings support that meloxicam reduced cortisol, SP, and PgE2 after dehorning, but only PgE2 production was significantly affected by the timing of meloxicam administration. PMID- 23746591 TI - Short communication: Evaluation of acid-insoluble ash and indigestible neutral detergent fiber as total-tract digestibility markers in dairy cows fed corn silage-based diets. AB - The objective of this experiment was to evaluate acid-insoluble ash (AIA) and indigestible NDF (iNDF) as intrinsic digestibility markers in comparison with total fecal collection (TC) in dairy cows fed corn silage- and alfalfa haylage based diets. The experiment was part of a larger experiment, which involved 8 Holstein cows [102+/-28.4 d in milk, 26.4+/-0.27 kg/d of dry matter (DM) intake, and 43+/-5.3 kg/d milk yield]. The experimental design was a replicated 4*4 Latin square with the following treatments: metabolizable protein (MP)-adequate diet [15.6% crude protein (CP); high-CP], MP-deficient diet (14.0% CP; low-CP), and 2 other low-CP diets supplemented (top-dressed) with ruminally protected Lys or Lys and Met. Data for the 3 low-CP diets were combined for this analysis. Total feces were collected for 5 consecutive days during each period to estimate total-tract apparent digestibility. Digestibility was also estimated using AIA (digestion with 2 N HCl) and iNDF (12-d ruminal incubation in 25-MUm-pore-size bags). Significant diet * digestibility method interactions were observed for fecal output of nutrients and digestibility. Fecal output of nutrients estimated using AIA or iNDF was lower compared with TC and fecal output of DM, organic matter, and CP tended to be higher for iNDF compared with AIA for the high-CP diet. For the low-CP diet, however, fecal output of all nutrients was lower for AIA compared with TC and was higher for iNDF compared with TC. Data from this experiment showed that, compared with TC, AIA underestimated fecal output and overestimated digestibility, particularly evident with the fiber fractions and the protein-deficient diet. Compared with TC, fecal output was overestimated and digestibility of the low-CP diet was underestimated when iNDF was used as a marker, although the magnitude of the difference was smaller compared with that for AIA. In the conditions of the current study, iNDF appeared to be a more reliable digestibility marker than AIA in terms of detecting dietary differences in apparent digestibility of some nutrients, but significant diet * marker interactions existed that need to be considered when estimating total-tract digestibility using intrinsic markers. PMID- 23746592 TI - Short communication: Circulating serotonin (5-HT) concentrations on day 1 of lactation as a potential predictor of transition-related disorders. AB - The monoamine serotonin (5-hydroxytryptamine; 5-HT) has been described as a homeostatic regulator of lactation. Recently, our laboratory determined that 5-HT is involved in the regulation of calcium and glucose homeostasis during the transition period in rodents. More specifically, we demonstrate that 5-HT is responsible for calcium mobilization from bone and upregulation of hepatic gluconeogenic enzymes and mammary gland glucose transporters. Our objective was to investigate the correlation between circulating 5-HT concentrations and circulating ionized calcium, parathyroid hormone-related protein (PTHrP), and glucose concentrations on d 1 postpartum. We also investigated the correlation between circulating 5-HT and milk fever and ketosis incidence and severity in multiparous Holstein cows at the onset of lactation. Blood samples were collected from 42 multiparous cows on d 1 of lactation and analyzed for 5-HT, calcium, glucose, and PTHrP. Milk fever (determined subjectively for each cow on d 1 postpartum) and ketosis incidence and severity (scale 1 to 4, determined objectively for each cow during the first 10 d postpartum) were recorded for all animals. Serum 5-HT was positively correlated with serum calcium and with plasma PTHrP (r>0.37). Serum 5-HT was negatively correlated with milk fever incidence and with ketosis severity (most severe ketosis incidence recorded during the first 10 d postpartum; r<-0.33). Serum calcium and plasma glucose concentrations were negatively correlated with milk fever and ketosis severity, respectively (r< 0.39). These data indicate that 5-HT potentially plays a role in the regulation of calcium and glucose homeostasis during the transition period in cattle, which we previously demonstrated in rodents. Increased circulating concentrations of 5 HT might decrease milk fever at the onset of lactation and ketosis severity during the first 10 d postpartum in dairy cows. Understanding this physiological axis could help describe the underlying mechanisms associated with these periparturient metabolic disorders in dairy cows. PMID- 23746593 TI - Preventive ethics for cesarean delivery: the time has come. PMID- 23746594 TI - Fertility preservation: we are in this for a long haul. PMID- 23746595 TI - Improving microaneurysm detection in color fundus images by using context-aware approaches. AB - In this paper, we present two approaches to improve microaneurysm detector ensembles. First, we provide an approach to select a set of preprocessing methods for a microaneurysm candidate extractor to enhance its detection performance in color fundus images. The performance of the candidate extractor with each preprocessing method is measured in six microaneurysm categories. The best performing preprocessing method for each category is selected and organized into an ensemble-based method. We tested our approach on the publicly available DiaretDB1 database, where the proposed approach led to an improvement regarding the individual approaches. Second, an adaptive weighting approach for microaneurysm detector ensembles is presented.The basis of the adaptive weighting approach is the spatial location and contrast of the detected microaneurysm. During training, the performance of ensemble members is measured with respect to these contextual information, which serves as a basis for the optimal weights assigned to the detectors. We have tested this approach on two publicly available datasets, where it showed its competitiveness compared without previously published ensemble-based approach for microaneurysm detection. Moreover, the proposed approach outperformed all the investigated individual detectors. PMID- 23746596 TI - Numerical and experimental assessment of turbulent kinetic energy in an aortic coarctation. AB - The turbulent blood flow through an aortic coarctation in a 63-year old female patient was studied experimentally using magnetic resonance imaging (MRI), and numerically using computational fluid dynamics (CFD), before and after catheter intervention. Turbulent kinetic energy (TKE) was computed in the numerical model using large eddy simulation and compared with direct in vivo MRI measurements. Despite the two totally different methods to obtain TKE values, both quantitative and qualitative results agreed very well. The results showed that even though both blood flow rate and Reynolds number increased after intervention, total turbulent kinetic energy levels decreased in the coarctation. Therefore, the use of the Reynolds number alone as a measure of turbulence in cardiovascular flows should be used with caution. Furthermore, the change in flow field and kinetic energy were assessed, and it was found that before intervention a jet formed in the throat of the coarctation, which impacted the arterial wall just downstream the constriction. After intervention the jet was significantly weaker and broke up almost immediately, presumably resulting in less stress on the wall. As there was a good agreement between measurements and numerical results (the increase and decrease of integrated TKE matched measurements almost perfectly while peak values differed by approximately 1mJ), the CFD results confirmed the MRI measurements while at the same time providing high-resolution details about the flow. Thus, this preliminary study indicates that MR-based TKE measurements might be useful as a diagnostic tool when evaluating intervention outcome, while the detailed numerical results might be useful for further understanding of the flow for treatment planning. PMID- 23746597 TI - Determination of local and global elastic moduli of valve interstitial cells cultured on soft substrates. AB - The elasticity of the extracellular matrix profoundly affects biological responses of cells, but also their mechanical properties. Single cell mechanical properties are often measured by atomic force microscopy (AFM), but technical guidelines for AFM measurement of cells grown on soft substrates are not well established. In this study, the local and global elastic moduli of aortic valve interstitial cells (VICs) cultured on soft polyacrylamide substrates (3-144kPa) were characterized via AFM force mapping using pyramidal and spherical tips, respectively. Local and global VIC modulus values both increased with substrate stiffness (p<0.05), with the average local cell modulus being consistently two to three times greater than the global modulus (p<0.05). For local measurements, a minimum of four measurements was required to observe the trend of increasing cell modulus with substrate stiffness, but there was no advantage to testing additional spots. The Hertz model was relatively accurate in estimating the global cell elastic modulus (<12% error, based on validated finite element analyses), despite the cells being of finite thickness and grown on deformable substrates, neither of which are accounted for in the Hertz model. The results of this study provide practical guidelines for efficient AFM-based measurement of the mechanical properties of cells on gels. They also provide new physiologically relevant data on VIC mechanical properties and their correlation with substrate stiffness-dependent cytoskeletal changes, with relevance to heart valve mechanobiology and disease. PMID- 23746598 TI - Regarding "Proximal humeral fracture fixation: a biomechanical comparison of two constructs". PMID- 23746599 TI - [Acquired von Willebrand syndrome: a case series of nine patients and literature review]. AB - PURPOSE: Whereas von Willebrand disease is the most common constitutional bleeding disorder, acquired von Willebrand syndrome is rare. METHODS: Retrospective, monocentric descriptive study of consecutive cases of acquired von Willebrand syndrome diagnosed between 2000 and 2012. Diagnostic criteria included: absence of a past history of mucocutaneous bleeding, with low plasma levels of factor VIII (FVIII) and von Willebrand factor (VWF), ristocetine cofactor activity (RCo) and antigen (Ag). RESULTS: Nine men were diagnosed with von Willebrand syndrome. Six of them presented with recent mucocutaneous bleeding. In eight cases, the biological phenotype was a type 2 von Willebrand disease, with decreased VWF:RCo/VWF:Ag ratio. A lymphoproliferative disease with circulating paraprotein was identified in all patients, including one chronic lymphoid leukemia, three Waldenstrom and one marginal zone lymphomas, four monoclonal gammapathies of unknown significance. Screening for an anti-VWF inhibitor was negative. Symptomatic treatment using infusion of VWF concentrates was administrated in the presence of severe mucocutaneaous bleeding. Five patients received intravenous immunoglobulins with a good response only in patients with G isotype paraprotein. A chemotherapy was initiated if indicated for the underlying disorder. Three of the four patients who achieved remission of the associated lymphoma had a subsequent improvement of plasma VWF levels, while all other patients remained deficient. CONCLUSION: Acquired von Willebrand syndrome is a rare but potentially serious disease. The diagnostic should be suspected in adults with unusual mucocutaneous bleeding, with or without prolonged partial thromboplastin time (PTT), and confirmed with a decreased plasma level of VWF (Ag and RCo). An associated haematological, neoplastic or cardiac valvular disease must be searched. PMID- 23746600 TI - Minimum duration of actigraphy-defined nocturnal awakenings necessary for morning recall. AB - BACKGROUND: Healthy adults awaken between each sleep cycle approximately 5 times each night but generally do not remember all of these awakenings in the morning. A rule of thumb has arisen in the sleep field that approximately 5 min of continuous wakefulness are required to form a memory for an awakening. However, few studies have examined memory for these sleep-wake transitions and none have done so in the home, while participants follow their normal routine. METHODS: Self-report and actigraphy were used in the participant's home environment to determine the minimum duration of an awakening necessary for morning recall for each of the 39 healthy adults. RESULTS: Recall thresholds ranged from 30 to 600 s with a mean of 259 s (4 min 19 s) and were negatively associated with sleep efficiency but not significantly associated with total sleep time, age, income, or education. There also was a sex by cohabitation interaction, with single men having lower thresholds than single women and cohabiting participants, which was explained by higher sleep efficiency in noncohabitating men. Large individual differences suggest that many factors may influence recall threshold. CONCLUSIONS: Our preliminary study is the first to calculate the duration of wakefulness necessary for morning recall of nocturnal awakenings and the first to use a field-based design, allowing for the study of habitual sleep patterns at the participant's home. Further study is needed to explore if recall thresholds calculated using actigraphy can be validated against polysomnography (PSG) or be used to guide potential treatments. PMID- 23746601 TI - Elevated glial fibrillary acidic protein levels in the cerebrospinal fluid of patients with narcolepsy. AB - Glial fibrillary acidic protein (GFAP) is an established indicator of astrogliosis. Therefore, variable cerebrospinal fluid (CSF) concentrations of this protein might reflect disease-specific pathologic profiles. In patients with narcolepsy, a loss of hypocretin-1 (hcrt-1) neurons in the brain and low concentrations of hcrt-1 in CSF have been reported. We performed a commercially available enzyme-linked immunosorbent assay to investigate if GFAP also is altered in the CSF of these patients. Here we detected significantly higher CSF levels of GFAP in patients with low hcrt-1 levels, of which the majority had a diagnosis of narcolepsy and cataplexy (NC); however, this finding was not observed in patients with hcrt-1 levels that were within reference range. In conclusion, GFAP may be useful as an additional disease biomarker in patients with narcolepsy, and this hypothesis should be investigated in larger studies. PMID- 23746602 TI - Nocturnal frontal lobe epilepsy: a sleep disorder rather than an epileptic syndrome? PMID- 23746603 TI - Health insurance coverage within sibships: prevalence of mixed coverage and associations with health care utilization. AB - An increasing proportion of children in the United States lives in families with complicated family structures and a mix of immigrant and US-born family members. Eligibility rules for health insurance coverage, however, were not designed with these families in mind. The result can be complicated insurance patterns among siblings within families, with some "sibships" only being partially-insured, and other sibships having both private and public coverage. We hypothesize that mixed coverage among siblings causes confusion and logistical difficulties for parents and may lead to less access to appropriate health care for their children. In this article, we use data from the 2009-2011 National Health Interview Survey (n = 51,418 children in 20,478 sibships) to present estimates of the prevalence of mixed health insurance coverage among siblings and describe the predictors of such coverage. We also use linked data from the 2001-2005 National Health Interview Survey and 2002-2007 Medical Expenditure Panel Survey (n = 17,871) to show how mixed coverage is related to health care utilization. We find that although few sibships are characterized by different health insurance coverage types, mixed coverage among siblings is far more common among families with mixed nativity status, and blended families with step- and half-siblings. In terms of outcomes, children living in sibships with mixed coverage have significantly lower odds of having a usual source of health care. We also consider whether the association between mixed insurance coverage and health care outcomes differs across particular combinations of insurance coverage. We find that both publicly insured children who have uninsured siblings and privately-insured children with publicly-insured siblings are less likely to have a usual source of care than similar children with uniformly-insured siblings. Because a usual source of care is associated with better health care outcomes, we argue that policymakers should consider ways to reduce mixed coverage among children and families. PMID- 23746604 TI - A spatial analysis of community disadvantage and access to healthcare services in the U.S. AB - Ongoing socioeconomic and racial and ethnic gaps in access to healthcare make it vital to examine the relationship between characteristics of communities and their impact on the availability of healthcare services. This study investigates how community-based resource constraints influence the provision of healthcare services in the United States. Drawing on several theoretical frameworks including research in the spatial distribution of healthcare, we compile data on 3141 U.S. counties in order to investigate the argument that gaps in the provision of substance abuse treatment are a function of resource constraints experienced by disadvantaged communities. Our principal aim is to demonstrate that socioeconomic privation, racial and ethnic isolation and limited healthcare infrastructure constrain the provision of substance abuse treatment services. Since prior research shows spatial clustering of socioeconomic privation, racial and ethnic isolation, and healthcare resources, we explicitly model the spatial dimensions of community-based resource disadvantage. Central findings support our chief expectations: counties with greater socioeconomic privation and diminished healthcare infrastructure experienced limited access to substance abuse treatment. Moreover, treatment clusters themselves were significantly related to socioeconomic privation and diminished healthcare infrastructure. Counties with a higher proportion of racial and ethnic minority members, however, did not experience less access to substance abuse treatment, with one exception, although post hoc analyses showed poverty had a moderating effect on race and ethnicity. Study limitations and implications for the organization of treatment resources are discussed. PMID- 23746605 TI - Socioeconomic inequalities and mental health problems in children and adolescents: a systematic review. AB - Socioeconomic inequalities in health are an important topic in social sciences and public health research. However, little is known about socioeconomic disparities and mental health problems in childhood and adolescence. This study systematically reviews publications on the relationships between various commonly used indicators of socioeconomic status (SES) and mental health outcomes for children and adolescents aged four to 18 years. Studies published in English or German between 1990 and 2011 were included if they reported at least one marker of socioeconomic status (an index or indicators, e.g., household income, poverty, parental education, parental occupation status, or family affluence) and identified mental health problems using validated instruments. In total, 55 published studies met the inclusion criteria, and 52 studies indicated an inverse relationship between socioeconomic status and mental health problems in children and adolescents. Socioeconomically disadvantaged children and adolescents were two to three times more likely to develop mental health problems. Low socioeconomic status that persisted over time was strongly related to higher rates of mental health problems. A decrease in socioeconomic status was associated with increasing mental health problems. The strength of the correlation varied with age and with different indicators of socioeconomic status, whereas heterogeneous findings were reported for gender and types of mental health problems. The included studies indicated that the theoretical approaches of social causation and classical selection are not mutually exclusive across generations and specific mental health problems; these processes create a cycle of deprivation and mental health problems. The review draws attention to the diversity of measures used to evaluate socioeconomic status, which might have influenced the comparability of international epidemiological studies. Furthermore, the review highlights the need for individual-level early childhood interventions as well as a reduction in socioeconomic inequalities at a societal level to improve mental health in childhood and adolescence. PMID- 23746606 TI - How healthcare provider talk with parents of children following severe traumatic brain injury is perceived in early acute care. AB - Healthcare provider talk with parents in early acute care following children's severe traumatic brain injury (TBI) affects parents' orientations to these locales, but this connection has been minimally studied. This lack of attention to this topic in previous research may reflect providers' and researchers' views that these locales are generally neutral or supportive to parents' subsequent needs. This secondary analysis used data from a larger descriptive phenomenological study (2005-2007) with parents of children following moderate to severe TBI recruited from across the United States. Parents of children with severe TBI consistently had strong negative responses to the early acute care talk processes they experienced with providers, while parents of children with moderate TBI did not. Transcript data were independently coded using discourse analysis in the framework of ethnography of speaking. The purpose was to understand the linguistic and paralinguistic talk factors parents used in their meta-communications that could give a preliminary understanding of their cultural expectations for early acute care talk in these settings. Final participants included 27 parents of children with severe TBI from 23 families. We found the human constructed talk factors that parents reacted to were: a) access to the child, which is where information was; b) regular discussions with key personnel; c) updated information that is explained; d) differing expectations for talk in this context; and, e) perceived parental involvement in decisions. We found that the organization and nature of providers' talk with parents was perceived by parents to positively or negatively shape their early acute care identities in these locales, which influenced how they viewed these locales as places that either supported them and decreased their workload or discounted them and increased their workload for getting what they needed. PMID- 23746607 TI - Contextual factors and weight change over time: a comparison between U.S. Hispanics and other population sub-groups. AB - In recent decades there has been an increasing interest in understanding the role of social and physical contexts in influencing health behaviors and outcomes. This is especially true for weight, which is considered to be highly dependent on environmental factors. The evidence linking neighborhood characteristics to weight in the United States, however, is mixed. Many studies in this area are hampered by cross sectional designs and a limited scope, insofar as they investigate only one dimension of neighborhood context. It is also unclear to what extent neighborhood characteristics account for racial/ethnic disparities in weight. Using longitudinal data from the Los Angeles Family and Neighborhood Survey (L.A. FANS), we compare patterns of weight change between Hispanics and other racial and ethnic groups in order to evaluate whether we observe a pattern of unhealthy assimilation in weight among Hispanic immigrants and to identify differences in the rate at which different groups gain weight over time. We also explore the extent to which patterns of weight change are related to a wider range of community characteristics. We find that weight increases across all groups between the two study waves of L.A. FANS and that the increases are significant except for Asians/Pacific Islanders. With respect to differences in the pace of weight change, second and higher generation Hispanic women and black men gain weight more rapidly than their first generation Hispanic counterparts. Although the evidence presented indicates that first generation Hispanics gain weight, we do not find evidence for convergence in weight since the U.S.-born gain weight at a more rapid rate. The inclusion of community-level variables does not alter the relationships between the race, ethnicity, and immigrant generation categories and weight change. Of the six types of community characteristics considered, only collective efficacy is consistently and significantly associated with weight change, although the protective effect of neighborhood collective efficacy is seen only among women. PMID- 23746609 TI - 'It can do no harm': Body maintenance and modification in alternative medicine acknowledged as a non risk health regimen. AB - This article proposes the notion of a non-risk health regimen as a mode of recognising more dynamic aspects of risk-awareness in health care, in this case alternative medicine in Denmark. Danish users of alternative medicine are in an ambivalent position. They are responsible citizens who care about their own health. On the other hand, they are doing this by paying out of their own pockets for attending non-authorised treatments with very limited scientific evidence for their effects. This article draws on 138 qualitative in-depth interviews conducted in 2006-07 with 46 Danish users of different forms of session-based alternative medicine. A recurring theme throughout users' accounts is found to be that the treatments 'at least can do no harm'. Many of the users regard pharmaceuticals or surgery as an artificial impediment and a threat to overall health, whereas the energy-stimulating processes initiated by the alternative practitioner are not considered risky. The no harm discourse constitutes a sophisticated lay-explanation that brings together a wide range of explanations within which three themes are identified: responsibility; optimization; desperation. By informing these findings with the concept of reflexive body techniques, it is shown that use of alternative medicine is a process of working on the self and body in a spectrum between transition (i.e., pain relief or self development) and continuity (i.e. well-being or prevention of illness) and not only a quest for cure. In this process 'non-risk' emerges as a lay explanation in the efforts of users to construct coherent self-narratives as agents in a risk aware environment. The development of the notion of a non-risk health regimen invites and facilitates further studies on various lay motives within health care in general and contributes to explaining the popularity of alternative medicine in particular. PMID- 23746608 TI - Parsing the peanut panic: the social life of a contested food allergy epidemic. AB - As medical reports over the last decade indicate that food allergies among children are on the rise, peanut allergies in particular have become a topic of intense social debate. While peanut allergies are potentially fatal, they affect very few children at the population level. Yet, peanut allergies are characterized in medical and popular literature as a rising "epidemic," and myriad and broad-based social responses have emerged to address peanut allergy risk in public spaces. This analysis compares medical literature to other textual sources, including media reports, legislation, and advocacy between 1980 and 2010 in order to examine how peanut allergies transformed from a rare medical malady into a contemporary public health problem. I argue that the peanut allergy epidemic was co-constructed through interactions between experts, publics, biomedical categories, and institutions, while social reactions to the putative epidemic expanded the sphere of surveillance and awareness of peanut allergy risk. The characterization of the peanut allergy problem as an epidemic was shaped by mobility across social sites, with both discursive and material effects. PMID- 23746610 TI - "Your body is your business card": Bodily capital and health authority in the fitness industry. AB - Although scholars have noted the connection between appearance and assumptions of health, the degree to which these assumptions matter for establishing authority in social interaction remains less clear. Using a theoretical framework involving "bodily capital"--that is, the value generated from appearance, attractiveness, and physical ability--I investigate the role of appearance in the U.S. fitness industry. Drawing on data from interviews with 26 personal trainers and 25 clients between 2010 and 2011, I find that a trainer's fit-appearing physique imbues their interactions with a degree of moral and health authority. This corporeal credibility engenders trust among clients and allows exercise to be understood as a form of health work. The implications for academics and medical practitioners reach beyond the gym setting and extend recent research linking appearance to health, authority, and medical credibility. PMID- 23746611 TI - Detection of subclinical keratoconus using an automated decision tree classification. AB - PURPOSE: To develop a method for automatizing the detection of subclinical keratoconus based on a tree classification. DESIGN: Retrospective case-control study. METHODS: setting: University Hospital of Bordeaux. participants: A total of 372 eyes of 197 patients were enrolled: 177 normal eyes of 95 subjects, 47 eyes of 47 patients with forme fruste keratoconus, and 148 eyes of 102 patients with keratoconus. observation procedure: All eyes were imaged with a dual Scheimpflug analyzer. Fifty-five parameters derived from anterior and posterior corneal measurements were analyzed for each eye and a machine learning algorithm, the classification and regression tree, was used to classify the eyes into the 3 above-mentioned conditions. main outcome measures: The performance of the machine learning algorithm for classifying eye conditions was evaluated, and the curvature, elevation, pachymetric, and wavefront parameters were analyzed in each group and compared. RESULTS: The discriminating rules generated with the automated decision tree classifier allowed for discrimination between normal and keratoconus with 100% sensitivity and 99.5% specificity, and between normal and forme fruste keratoconus with 93.6% sensitivity and 97.2% specificity. The algorithm selected as the most discriminant variables parameters related to posterior surface asymmetry and thickness spatial distribution. CONCLUSION: The machine learning classifier showed very good performance for discriminating between normal corneas and forme fruste keratoconus and provided a tool that is closer to an automated medical reasoning. This might help in the surgical decision before refractive surgery by providing a good sensitivity in detecting ectasia-susceptible corneas. PMID- 23746613 TI - Neural mechanisms underlying ecstasy-related attentional bias. AB - Conditioned responses to cues associated with drug taking play a pivotal role in a number of theories of drug addiction. This study examined whether attentional biases towards drug-related cues exist in recreational drug users who predominantly used ecstasy (3,4-methylenedioxymethamphetamine). Experiment 1 compared 30 ecstasy users, 25 cannabis users, and 30 controls in an attentional distraction task in which neutral, evocative, and ecstasy-related pictures were presented within a coloured border, requiring participants to respond as quickly as possible to the border colour. Experiment 2 employed functional magnetic resonance imaging (fMRI) and the attentional distraction task and tested 20 ecstasy users and 20 controls. Experiment 1 revealed significant response speed interference by the ecstasy-related pictures in the ecstasy users only. Experiment 2 revealed increased prefrontal and occipital activity in ecstasy users in all conditions. Activations in response to the ecstasy stimuli in these regions showed an apparent antagonism whereby ecstasy users, relative to controls, showed increased occipital but decreased right prefrontal activation. These results are interpreted to reflect increased visual processing of, and decreased prefrontal control over, the irrelevant but salient ecstasy-related stimuli. These results suggest that right inferior frontal cortex may play an important role in controlling drug-related attentional biases and may thus play an important role in mediating control over drug usage. PMID- 23746612 TI - Estimated retinal ganglion cell counts in glaucomatous eyes with localized retinal nerve fiber layer defects. AB - PURPOSE: To estimate retinal ganglion cell (RGC) losses associated with visible glaucomatous localized retinal nerve fiber layer (RNFL) defects. DESIGN: Observational cross-sectional study. METHODS: A multicenter study of 198 normal eyes (138 subjects) and 66 glaucomatous eyes (55 subjects) recruited from the Diagnostic Innovations in Glaucoma Study and the African Descent and Glaucoma Evaluation Study. All eyes underwent standard automated perimetry (SAP), spectral domain optical coherence tomography, and fundus stereophotography within 6 months. Glaucomatous eyes were included if localized RNFL defects were detected by masked grading of stereophotographs. The number of RGCs in each sector of a structure-function map was estimated using a previously published model combining RGC estimates from SAP and spectral-domain optical coherence tomography. The estimated percentage loss of RGCs (combined structure-function index) was calculated. RESULTS: In glaucomatous eyes, there were 136 sectors with visible RNFL defects and 524 sectors without visible RNFL defects. The most common sectors with visible RNFL defects were inferior and inferotemporal sectors, followed by superior and supertemporal sectors. Eyes with visible RNFL defects had a mean estimated RGC count of 657,172 cells versus 968 883 cells in healthy eyes (P < .001). The average combined structure-function index in sectors with a visible RNFL defect (59 +/- 21%) was significantly higher than in sectors without a visible RNFL defect in glaucomatous eyes (15 +/- 29%; P < .001) and higher than in healthy eyes (1 +/- 13%; P < .001). CONCLUSIONS: Although visible localized RNFL defects often are considered an early sign of glaucoma, this study indicates that they are likely to be associated with large neuronal losses. PMID- 23746614 TI - White matter abnormalities in pediatric obsessive-compulsive disorder. AB - Diffusion tensor imaging (DTI) has been useful in allowing us to examine the nature and extent of neuronal disruption associated with obsessive-compulsive disorder (OCD). However, little is known about the underlying brain structure in OCD. Diffusion-weighted magnetic resonance imaging was performed in 16 children with OCD and 22 typically developing children. Tract-based spatial statistics (TBSS) was used to compare the microstructure of white-matter tracts of OCD children with those of typically developing children. Correlation/regression analyses were also performed on each diffusion measure in order to detect any correlation of white-matter microstructure with scales of symptom severity. Analysis revealed significantly greater axial diffusivity in both the genu and the splenium of the corpus callosum in the control compared to the OCD group; these regions consecutively connect bilateral medial frontal regions and bilateral parietal regions. Secondly, correlation and voxel-based regression analysis revealed that lower axial diffusion correlated with greater severity of symptoms within the OCD group, as measured by the Child Behaviour Checklist Obsessive Compulsive Scale (CBCL-OCS). The findings demonstrated a correlation of axial diffusivity with severity of symptoms in children with OCD. DTI may provide novel ways to help reveal the relationships between clinical symptoms and altered brain regions. PMID- 23746615 TI - The influence of combined cognitive plus social-cognitive training on amygdala response during face emotion recognition in schizophrenia. AB - Both cognitive and social-cognitive deficits impact functional outcome in schizophrenia. Cognitive remediation studies indicate that targeted cognitive and/or social-cognitive training improves behavioral performance on trained skills. However, the neural effects of training in schizophrenia and their relation to behavioral gains are largely unknown. This study tested whether a 50 h intervention which included both cognitive and social-cognitive training would influence neural mechanisms that support social ccognition. Schizophrenia participants completed a computer-based intervention of either auditory-based cognitive training (AT) plus social-cognition training (SCT) (N=11) or non specific computer games (CG) (N=11). Assessments included a functional magnetic resonance imaging (fMRI) task of facial emotion recognition, and behavioral measures of cognition, social cognition, and functional outcome. The fMRI results showed the predicted group-by-time interaction. Results were strongest for emotion recognition of happy, surprise and fear: relative to CG participants, AT+SCT participants showed a neural activity increase in bilateral amygdala, right putamen and right medial prefrontal cortex. Across all participants, pre-to post intervention neural activity increase in these regions predicted behavioral improvement on an independent emotion perception measure (MSCEIT: Perceiving Emotions). Among AT+SCT participants alone, neural activity increase in right amygdala predicted behavioral improvement in emotion perception. The findings indicate that combined cognition and social-cognition training improves neural systems that support social-cognition skills. PMID- 23746616 TI - Analysis and reduction of thermal dose errors in MRgFUS treatment. AB - ExAblate 2000 MRgFUS system (InSightec) installed in Ospedale Maggiore Niguarda Ca' Granda (Milano, Italy) is currently used to treat uterine fibroids. Through the magnetic resonance thermometry (PRF method), it is possible to monitor the temperature in the target in real-time and compute the treated region calculating the thermal dose. The purpose of this work is to investigate the errors in the temperature measurements and their effect on thermal dose. A low pass filtering of temperature maps is proposed to reduce the errors and therefore to improve the reliability of the treated regions calculated. The PRF method was studied through a calibration experiment on ex vivo pig muscle. The outcome resulted to be a very good linearity (p value 0.03) between phase and temperature in the range of interest, and an alpha value of -0.0109 +/- 0.0002 ppm/ degrees C. Temperature statistical uncertainty was evaluated by analyzing the temperature readout variability in specific gel provided by InSightec for daily quality assurance control. It resulted to be 1.89 +/- 0.32 degrees C. A Monte Carlo simulation of the MRI temperature measurement and thermal dose calculations in our specific conditions of geometry and statistical uncertainty revealed that a low-pass filtering process on each temperature map can strongly reduce systematic errors in thermal dose evaluations (1.11 overestimation factor instead of 2.62 without filter); consequently the systematic errors on the size of the predicted ablated area are reduced as well. PMID- 23746617 TI - Mechanisms of heterochromatin subnuclear localization. AB - Transcriptionally repressed heterochromatin becomes the dominant form of chromatin in most terminally differentiated cells. Moreover, in most cells, at least one class of heterochromatin is positioned adjacent to the nuclear lamina. Recent approaches have addressed the mechanism of heterochromatin localization, in order to determine whether spatial segregation contributes to gene repression. Findings in worms and human cells confirm a role for histone H3K9 methylation in heterochromatin positioning, identifying a modification that is also necessary for gene repression of worm transgenic arrays. These pathways appear to be conserved, although mutations in mammalian cells have weaker effects, possibly due to redundancy in positioning mechanisms. We propose a general model in which perinuclear anchoring is linked to an epigenetic propagation of the heterochromatic state, through histone modification. PMID- 23746618 TI - New approaches for sensing metabolites and proteins in live cells using RNA. AB - Tools to study the abundance, distribution, and flux of intracellular molecules are crucial for understanding cellular signaling and physiology. Although powerful, the current FRET-based technology for imaging cellular metabolites is not easily generalizable. Thus, new platforms for generating genetically encoded sensors are needed. We recently developed a new class of biosensors on the basis of Spinach, an RNA mimic of GFP. In this case, RNA aptamers against a target ligand are modularly fused to Spinach that substantially induce Spinach fluorescence in the presence of ligand. We have used this approach to detect metabolites and proteins both in vitro and in living bacteria, thus providing an alternative to FRET-based sensors and a generalizable approach for generating fluorescent sensors to any ligand of interest. PMID- 23746619 TI - The time-dependent effects of prostate granules and seminal plasma on the capacitation, acrosome reaction, and motility of rabbit sperm. AB - The present study investigated the role of rabbit seminal plasma and prostate granules on capacitation, the acrosomal reaction (AR), and sperm motility. Semen ejaculates obtained from five mature New Zealand White rabbit bucks in three collection series were used in the study. Raw semen, Percoll-selected sperm alone and in presence of either seminal plasma or prostate granules were incubated for 120min in capacitation medium. Chlortetracycline fluorescence (reflecting capacitation and the acrosome reaction) and sperm kinetic traits were analysed in each sample. All traits were observed from 0 to 120min of incubation at 37 degrees C in 5% CO2. Both seminal plasma and prostatic granules markedly improved the sperm motility but seminal plasma mainly inhibited the capacitation progress whereas prostatic granules inhibited the AR. In conclusion, prostatic granules and seminal plasma have specific roles in synchronising sperm capacitation and the AR with egg availability. PMID- 23746620 TI - Integration of a local into a regional primary angioplasty action plan (the Catalan Codi Infart network) reduces time to reperfusion. PMID- 23746621 TI - Systematic review of the effects of physical exercise training programmes in children and young adults with congenital heart disease. AB - BACKGROUND: Most patients with congenital heart disease (ConHD) do not perform regular physical exercise. Consensus reports have stated that exercise should be encouraged and regularly performed in these patients, but this is not common practise. We reviewed the literature on actual evidence for either negative or positive effects of physical exercise training programmes in children and young adults with ConHD. METHODS: Using the Medline database, we systematically searched for articles on physical exercise training programmes in ConHD. RESULTS: A total of 31 articles met all inclusion criteria; in total, 621 subjects (age range 4 to 45 years) were included. Most studies used training programmes with a duration of 12 weeks. On average, the number of training sessions was 3 times per week. In 12 studies, training intensity was set at a percentage of peak heart rate. Outcome measures reported were PeakVO2, activity levels and muscle strength. Twenty-three studies (72%) found a significant positive change in the main outcome measure after the physical exercise training period. None of the studies reported negative findings related to physical exercise training in ConHD. Cardiac effects have hardly been studied. CONCLUSION: In most studies, participation in a physical exercise training programme was safe and improved fitness in children and young adults with ConHD. We recommend that patients with ConHD participate in physical exercise training. Cardiac effects need to be studied more extensively. PMID- 23746622 TI - Learn the game but don't play it: nurses' perspectives on learning and applying statistics in practice. AB - BACKGROUND: An integrative review regarding undergraduate level statistics pedagogy for nurses revealed a paucity of research to inform curricula development and delivery. OBJECTIVE: The aim of the study was to explore alumni nurses' perspectives about statistics education and its application to practice. DESIGN: A mixed-method approach was used whereby a quantitative approach was used to complement and develop the qualitative aspect. SETTING: This study was conducted in Toronto, Ontario, Canada. PARTICIPANTS: Participants were nursing alumni who graduated from four types of nursing degree programs (BScN) in two Ontario universities between the years 2005-2009. METHODS: Data were collected via surveys (n=232) followed by interviews (n=36). RESULTS: Participants reported that they did not fear statistics and that they thought their math skills were very good or excellent. They felt that statistics courses were important to their nursing practice but they were not required to use statistics. Qualitative findings emerged in the two major themes: 1) nurses value statistics and 2) nurses do not feel comfortable using statistics. CONCLUSIONS: Nurses recognize the inherent value of statistics to improve their professional image and interprofessional communication; yet they feel denied of full participation in application to their practice. Our findings have major implications for changes in pedagogy and practice. PMID- 23746623 TI - Heart rate variability remains reduced and sympathetic tone elevated after temporal lobe epilepsy surgery. AB - PURPOSE: There is evidence of autonomic dysregulation in temporal lobe epilepsy. The structures removed during temporal lobectomy are important centers of central cardiovascular control; therefore surgery may conceivably alter the cardiovascular autonomic function. The effects of temporal lobectomy on autonomic cardiac control are controversial. We investigated the effects of temporal lobectomy on heart rate variability (HRV) in the early and late postoperative periods. METHODS: We used 1-h ECG recordings to assess heart rate variability by spectral analysis in 24 consecutive patients who underwent temporal lobectomy due to intractable temporal lobe epilepsy. ECG recordings were performed before and twice (early and late) after surgery. The results were compared with age and sex matched controls. RESULTS: When compared with controls, all the time and frequency domain indices (SDRR, RMSSD, TP, LF and HF) were significantly lower in the patient group before surgery. Findings were similar in the early and late post-operative periods except that the LF/HF ratio increased in the patient group after the late post-operative period. Within the patient group, compared to pre operative results, normalized HF was increased in the early post-operative period; however in the late post-operative period, LF/HF ratio was increased. CONCLUSIONS: These findings show that in patients with intractable temporal lobe epilepsy, HRV is decreased globally in both sympathetic and parasympathetic domains. While the total HRV remains reduced throughout the postoperative periods, the LF/HF ratio, i.e., sympathovagal balance is altered, in favor of parasympathetic side early after surgery, but towards the sympathetic side after the first postoperative month. PMID- 23746624 TI - Cortical excitability in drug naive juvenile myoclonic epilepsy. AB - PURPOSE: To evaluate the effect of diurnal variability on cortical excitability using single pulse transcranial magnetic stimulation (TMS), in drug naive patients with juvenile myoclonic epilepsy (JME) and to look for any differences in cortical excitability between males and females. METHODS: Thirty drug-naive patients with JME and 10 healthy controls were studied. Resting motor threshold (RMT), motor evoked potential (MEP), the duration of central motor conduction time (CMCT) and cortical silent period (CSP) were measured, twice, first early in the morning and again in the afternoon of the same day. RESULTS: Diurnal variation with higher evening values of CMCT and CSP were observed in the control group. In the study group, diurnal variation in RMT, CMCT and CSP was found with higher values in the morning than in control group. However, only the raised values of CSP [mean, 110.7ms, morning and 96.44ms, evening] were of statistical significance [p=0.005, morning and 0.039, evening] as compared to controls. In the study group, males had higher values of RMT, CMCT and CSP than in females. However, the CMCT in males was lower in the evening study than in females. Further, RMT and morning CMCT was lower in females than in controls. In females, the morning CSP [mean, 100.91ms, morning versus 87.86ms, evening] was significantly prolonged [p=0.017, morning versus 0.221, evening] as compared to controls. CONCLUSION: The study is suggestive of the existence of impaired supraspinal/intracortical inhibitory circuits which may account for the hyperexcitability of the motor system being prominent in the morning among drug naive patients with JME. In this study, increased activity of cortical inhibitory networks, as evidenced by prolonged cortical silent period existed among drug naive JME patients, but was found to be significant only in female patients. This may explain the increased seizure susceptibility in this cohort, at this time of the day and an increased manifestation of JME in females. PMID- 23746625 TI - Children and physical activity. PMID- 23746626 TI - Lipoprotein-associated phospholipase A2 and venous thromboembolism: a prospective study. AB - INTRODUCTION: Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory marker associated positively with atherothrombotic risk. Whether Lp PLA2 is related to risk of venous thromboembolism (VTE) is incompletely studied. METHODS: We assessed Lp-PLA2 activity in 10,687 Atherosclerosis Risk in Communities (ARIC) Study participants and followed them a median of 8.3 years (from 1996-98 through 2005) for VTE occurrence (n=226). RESULTS: There was no significant association between baseline Lp-PLA2 quartiles and risk of VTE, neither overall nor stratified as provoked or unprovoked. Adjusted for other risk factors, the hazard ratios (95% confidence interval) of total VTE across quartiles of Lp-PLA2 were 1.0 (reference), 0.95 (0.64, 1.42), 1.03 (0.69, 1.56), and 1.26 (0.83, 1.91). In the subset of participants with LDL-cholesterol >=130 mg/dL, hazard ratios of total VTE were 1.00, 1.39 (0.44, 4.44), 2.45 (0.84, 7.11), and 2.84 (0.99, 8.14). CONCLUSION: Our study does not support the overall hypothesis that elevated Lp-PLA2 contributes to VTE occurrence in the general population. However, in the presence of high LDL-cholesterol there was some evidence that Lp-PLA2 may increase VTE risk. PMID- 23746627 TI - Management of cardiovascular disease in haemophilia. AB - Improvements in the management of haemophilia have led to a significant increase in the life expectancy of haemophilia patients, which is now close to the life expectancy in the general male population. Therefore, age-related conditions, especially cardiovascular disease (CVD), have become increasingly common in these patients. The management of CVD, especially that of coronary artery disease (CAD), acute coronary syndrome (ACS) and atrial fibrillation (AF), is particularly challenging in patients with haemophilia due to the need to find an adequate balance between bleeding and ischemic risk, requiring close coordination between cardiologists and haemophilia specialists. However, specific recommendations and relevant literature and data are scarce. Therefore, we propose pragmatic and practical therapeutic suggestions, based on the available literature and our own experience, for the management of ACS, stable angina and AF in patients with haemophilia. Overall, evidence and experience suggest that they should be treated much in the same way as the general CVD population, following standard guidelines, while choosing available treatment options known to be associated with low rates of bleeding complications. Treatments advocated for patient with haemophilia include antiplatelet therapy (aspirin and P2Y12 inhibitors), antithrombin therapy such as heparin or bivalirudin, glycoprotein IIb/IIIa inhibitors (GPIIb/IIIa inhibitors), transradial cardiac catheterization, and use of bare metal (BMS) or drug-eluting stents (DES). Antithrombotic agents with shorter half-lives that are reversible or have an antidote offer a safer choice in this setting. In addition, optimal clotting factor replacement therapy should be tailored to the increased risk of bleeding associated with invasive procedures and antithrombotic therapies, particularly during the acute phase of ACS. PMID- 23746628 TI - Activation of the contact system in patients with a first acute myocardial infarction. AB - INTRODUCTION: The contribution of the contact system to arterial thrombosis is unclear, results of clinical studies are conflicting. Particularly, little is known about the involvement of the contact system in the progression of arterial thrombosis. Therefore, we investigated the activation of the contact system during an acute myocardial infarction (AMI) and 3 and 6 months following the acute event. METHODS: Plasma of patients with a first AMI was collected on admission and 3 and 6 months after the AMI. The levels of complexes of activated factor XI (FXIa), FXIIa and kallikrein with C1 esterase inhibitor (C1INH) and the levels of complexes of FXIa with alpha1-antitrypsin (AT) were measured in these plasmas. Recurrent cardiovascular events were recorded during a one year period after the AMI. RESULTS: We observed that the levels of FXIa-C1INH were elevated during the acute phase compared to the steady-phase 3 and 6 months after the AMI. The levels of FXIa-AT, FXIIa-C1INH and kallikrein-C1INH did not change over time. The levels of FXIa-C1INH, FXIa-AT, FXIIa-C1INH and kallikrein-C1INH were not predictive for a recurrent event. CONCLUSION: We observed that during an AMI, the activation of FXI was increased. The levels of FXIIa-C1INH were not elevated, suggesting that activation of FXI during the acute phase did not result from contact activation. The levels of the enzyme inhibitor complexes were not predictive for a recurrent event one year after the first AMI. PMID- 23746629 TI - A prestin motor in chicken auditory hair cells: active force generation in a nonmammalian species. AB - Active force generation by outer hair cells (OHCs) underlies amplification and frequency tuning in the mammalian cochlea but whether such a process exists in nonmammals is unclear. Here, we demonstrate that hair cells of the chicken auditory papilla possess an electromechanical force generator in addition to active hair bundle motion due to mechanotransducer channel gating. The properties of the force generator, its voltage dependence and susceptibility to salicylate, as well as an associated chloride-sensitive nonlinear capacitance, suggest involvement of the chicken homolog of prestin, the OHC motor protein. The presence of chicken prestin in the hair cell lateral membrane was confirmed by immunolabeling studies. The hair bundle and prestin motors together create sufficient force to produce fast lateral displacements of the tectorial membrane. Our results imply that the first use of prestin as a motor protein occurred early in amniote evolution and was not a mammalian invention as is usually supposed. PMID- 23746631 TI - In vitro antiviral activity of phlorotannins isolated from Ecklonia cava against porcine epidemic diarrhea coronavirus infection and hemagglutination. AB - Despite the prepdominat agent causing severe entero-pathogenic diarrhea in swine, there are no effective therapeutical treatment of porcine epidemic diarrhea virus (PEDV). In this study, we evaluated the antiviral activity of five phlorotannins isolated from Ecklonia cava (E. cava) against PEDV. In vitro antiviral activity was tested using two different assay strategies: (1) blockage of the binding of virus to cells (simultaneous-treatment assay) and (2) inhibition of viral replication (post-treatment assay). In simultaneous-treatment assay, compounds 2 5 except compound 1 exhibited antiviral activities of a 50% inhibitory concentration (IC50) with the ranging from 10.8 +/- 1.4 to 22.5 +/- 2.2 MUM against PEDV. Compounds 1-5 were completely blocked binding of viral spike protein to sialic acids at less than 36.6 MUM concentrations by hemagglutination inhibition. Moreover, compounds 4 and 5 of five phlorotannins inhibited viral replication with IC50 values of 12.2 +/- 2.8 and 14.6 +/- 1.3 MUM in the post treatment assay, respectively. During virus replication steps, compounds 4 and 5 exhibited stronger inhibition of viral RNA and viral protein synthesis in late stages (18 and 24 h) than in early stages (6 and 12 h). Interestingly, compounds 4 and 5 inhibited both viral entry by hemagglutination inhibition and viral replication by inhibition of viral RNA and viral protein synthesis, but not viral protease. These results suggest that compounds isolated from E. cava have strong antiviral activity against PEDV, inhibiting viral entry and/or viral replication, and may be developed into natural therapeutic drugs against coronavirus infection. PMID- 23746630 TI - Abnormal visual motion processing is not a cause of dyslexia. AB - Developmental dyslexia is a reading disorder, yet deficits also manifest in the magnocellular-dominated dorsal visual system. Uncertainty about whether visual deficits are causal or consequential to reading disability encumbers accurate identification and appropriate treatment of this common learning disability. Using fMRI, we demonstrate in typical readers a relationship between reading ability and activity in area V5/MT during visual motion processing and, as expected, also found lower V5/MT activity for dyslexic children compared to age matched controls. However, when dyslexics were matched to younger controls on reading ability, no differences emerged, suggesting that weakness in V5/MT may not be causal to dyslexia. To further test for causality, dyslexics underwent a phonological-based reading intervention. Surprisingly, V5/MT activity increased along with intervention-driven reading gains, demonstrating that activity here is mobilized through reading. Our results provide strong evidence that visual magnocellular dysfunction is not causal to dyslexia but may instead be consequential to impoverished reading. VIDEO ABSTRACT: PMID- 23746632 TI - Effects of apolipoprotein E genotypes on metabolic profile and oxidative stress in southwest Chinese women with polycystic ovary syndrome. AB - OBJECTIVE: Apolipoprotein (APO) E genetic polymorphism plays an important role in lipid and lipoprotein metabolism, and has been shown to be associated with the risk of metabolic and cardio-cerebrovascular diseases and late-onset Alzheimer's disease. It is not clear, however, whether there are any relationships between the APOE genotypes and PCOS in Chinese women. The aim of this study was to investigate the relationship between APOE genotypes and the risk of polycystic ovary syndrome (PCOS) and to evaluate the effects of the genotypes on metabolic profile and oxidative stress in south-west Chinese women. STUDY DESIGN: A total of 625 patients with PCOS based on the Rotterdam consensus criteria and 514 control women from a population of Chinese Han nationality in the Chengdu area were studied during 2006-2012. APOE genotypes were determined by PCR and restriction fragment length polymorphism analysis. Clinical and metabolic parameters, serum malondialdehyde concentration, and total antioxidant capacity were analyzed. RESULTS: No significant differences were found in the frequencies of APOE genotypes (E2/2, E2/3, E2/4, E3/3, E3/4, E4/4) and alleles (epsilon2, epsilon3, epsilon4) between PCOS and control groups. Compared with epsilon3 homozygotes (APOE3/3), however, epsilon2 carriers (APOE2/2+APOE2/3+APOE2/4) had significantly higher body mass index, waist circumference and waist-to-hip ratio, a more adverse glucose and insulin metabolic profile, lower high density lipoprotein (HDL)-cholesterol (C) and APOA1 levels, higher triglyceride (TG)/HDL C ratio and prevalence of metabolic syndrome (MS), whereas epsilon4 carriers (APOE3/4+APOE4/4) had higher total cholesterol (TC) and low density lipoprotein (LDL)-C levels in patients with PCOS. CONCLUSIONS: In a cohort of south-west Chinese women, there were no significant associations between any APOE genotype and PCOS. The APOE epsilon2 allele seems to be related to abdominal obesity, insulin resistance and MS in PCOS women. PMID- 23746633 TI - Gasless laparoscopic surgery during pregnancy: evaluation of its role and usefulness. AB - The minimally invasive laparoscopic approach in the surgical treatment of diseases during pregnancy has become progressively more accepted and applied. In an attempt to overcome the potential adverse effects of pneumoperitoneum on the fetus, gasless laparoscopic surgery (GLS) has been developed. This article reviews the evidence available for the role and effectiveness of GLS in pregnancy. A computerized literature search was conducted on Medline, Science Citation Index, Current Contents, Embase, and PubMed databases for English language publications from the first report of GLS in pregnancy in 1995 to June 2012. Eleven case reports or retrospective series were identified. A total of 44 pregnant women underwent GLS for various surgical indications. In all cases, the procedures were carried out without complication, and the women were discharged from hospital with a continuing pregnancy. GLS in pregnancy has comparable outcomes to conventional CO2 laparoscopy, but it is associated with some advantages. Hypercarbia and increased intraperitoneal pressure due to CO2 insufflation are avoided. The use of high-pressure continuous suction may prevent the problems that are potentially associated with intra-abdominal smoke generated by electrosurgery, which can increase the risk of fetal exposure to elevated levels of toxic gases. Because this procedure may be performed under regional anesthesia, avoiding general anesthesia, there is a minimal transplacental passage of anesthetic drugs to the fetus. The surgeon must be expert in advanced laparoscopic procedures. PMID- 23746634 TI - Cloning and characterization of four novel coral acid-rich proteins that precipitate carbonates in vitro. AB - Biomineralization is a widely dispersed and highly regulated but poorly understood process by which organisms precipitate minerals from a wide variety of elements [1]. For many years, it has been hypothesized that the biological precipitation of carbonates is catalyzed by and organized on an extracellular organic matrix containing a suite of proteins, lipids, and polysaccharides [2, 3]. The structures of these molecules, their evolutionary history, and the biophysical mechanisms responsible for calcification remain enigmatic. Despite the recognition that mineralized tissues contain proteins that are unusually rich in aspartic and glutamic acids [4-6], the role of these proteins in biomineralization remains elusive [5, 6]. Here we report, for the first time, the identification, cloning, amino acid sequence, and characterization of four highly acidic proteins, derived from expression of genes obtained from the common stony coral, Stylophora pistillata. Each of these four proteins can spontaneously catalyze the precipitation of calcium carbonate in vitro. Our results demonstrate that coral acid-rich proteins (CARPs) not only bind Ca(2+) stoichiometrically but also precipitate aragonite in vitro in seawater at pH 8.2 and 7.6, via an electrostatic interaction with protons on bicarbonate anions. Phylogenetic analysis suggests that at least one of the CARPs arose from a gene fusion. Similar, highly acidic proteins appear to have evolved several times independently in metazoans through convergence. Based purely on thermodynamic grounds, the predicted change in surface ocean pH in the next decades would appear to have minimal effect on the capacity of these acid-rich proteins to precipitate carbonates. PMID- 23746635 TI - Theta oscillations at encoding mediate the context-dependent nature of human episodic memory. AB - Human episodic memory is highly context dependent. Therefore, retrieval benefits when a memory is recalled in the same context compared to a different context. This implies that items and contexts are bound together during encoding, such that the reinstatement of the initial context at test improves retrieval. Animal studies suggest that theta oscillations and theta-to-gamma cross-frequency coupling modulate such item-context binding, but direct evidence from humans is scarce. We investigated this issue by manipulating the overlap of contextual features between encoding and retrieval. Participants studied words superimposed on movie clips and were later tested by presenting the word with either the same or a different movie. The results show that memory performance and the oscillatory correlates of memory formation crucially depend on the overlap of the context between encoding and test. When the context matched, high theta power during encoding was related to successful recognition, whereas the opposite pattern emerged in the context-mismatch condition. In addition, cross-frequency coupling analysis revealed a context-dependent theta-to-gamma memory effect specifically in the left hippocampus. These results reveal for the first time that context-dependent episodic memory effects are mediated by theta oscillatory activity. PMID- 23746636 TI - Developmental basis of phallus reduction during bird evolution. AB - BACKGROUND: One of the most puzzling events in evolution is the reduction and loss of the phallus in birds. All birds reproduce by internal fertilization, but only ~3% of birds have retained a phallus capable of intromission. A number of hypotheses have been proposed for the evolutionary mechanisms that drove phallus reduction; however, the underlying developmental mechanisms are unknown. RESULTS: We investigated genital development in two sister clades of birds, Galliformes (land fowl), most of which lack an intromittent phallus, and Anseriformes (waterfowl), which have well developed phalluses; and in two outgroups, Paleognathae (emus) and Crocodilia (alligators). Galliform embryos undergo cryptic development of a genital tubercle, the precursor of the phallus, but this later undergoes apoptosis, leading to regression of the tubercle. At the molecular level, a derived pattern of Bmp4 expression was identified in chick (a galliform) genital tubercles. Inhibition of Bmp signaling in chick genitalia rescues cells from apoptosis and prevents phallus regression, whereas activation of Bmp signaling in duck (an anseriform) genitalia induces a galliform-like pattern of apoptosis. Thus, distal Bmp activity is necessary and sufficient to induce apoptosis in Galloanserae genital tubercles. CONCLUSIONS: Our results indicate that evolutionary reduction of the intromittent phallus in galliform birds occurred not by disruption of outgrowth signals but by de novo activation of cell death by Bmp4 in the genital tubercle. These findings, together with discoveries implicating Bmps in evolution of beak shape, feathers, and toothlessness, suggest that modulation of Bmp gene regulation played a major role in the evolution of avian morphology. PMID- 23746637 TI - Dance choreography is coordinated with song repertoire in a complex avian display. AB - All human cultures have music and dance, and the two activities are so closely integrated that many languages use just one word to describe both. Recent research points to a deep cognitive connection between music and dance-like movements in humans, fueling speculation that music and dance have coevolved and prompting the need for studies of audiovisual displays in other animals. However, little is known about how nonhuman animals integrate acoustic and movement display components. One striking property of human displays is that performers coordinate dance with music by matching types of dance movements with types of music, as when dancers waltz to waltz music. Here, we show that a bird also temporally coordinates a repertoire of song types with a repertoire of dance-like movements. During displays, male superb lyrebirds (Menura novaehollandiae) sing four different song types, matching each with a unique set of movements and delivering song and dance types in a predictable sequence. Crucially, display movements are both unnecessary for the production of sound and voluntary, because males sometimes sing without dancing. Thus, the coordination of independently produced repertoires of acoustic and movement signals is not a uniquely human trait. PMID- 23746638 TI - A cytokinin-activating enzyme promotes tuber formation in tomato. AB - BACKGROUND: Dedicated storage organs in the form of tubers are evolutionary novelties that share a common function but originate in diverse species from different organs. Tubers in potato, Solanum tuberosum, are derived from the swollen tips of specialized basal lateral juvenile shoots, called stolons. Lateral buds of tomato, Solanum lycopersicum, a potato sibling species, only form regular shoots. The evo-devo mechanisms restricting tuber formation to basal juvenile axillary meristems of potato while completely inhibiting it in tomato meristems are not currently understood. RESULTS: Ectopic expression of tomato LONELY GUY (LOG1), a cytokinin (CK) biosynthesis gene, imparts potential to the outgrowing juvenile tomato buds to generate, de novo, aerial minitubers (TMTs). TMTs are morphologically, developmentally, and metabolically homologous to aerial potato tubers and display a unique transcriptome with altered hormonal signaling networks. The new hormonal balance stimulates ectopic branching of dormant axillary meristems and loss of apical dominance without disruption of polar auxin transport and obviates the need for specific branching genes. miR156, a master regulator of juvenility, extends tuber-forming potential to distal axillary buds in both wild-type potato and tomato primed by LOG1 signaling. CONCLUSIONS: Ubiquitous activation of TLOG1 uncovered a developmentally suppressed tuber forming potential within tomato axillary meristems. Other meristems in other plants may also carry hidden, suppressed organogenesis potentials. The unlocking of this potential by the activity of a single gene represents a prime example of an evolutionary novelty in the making and suggests that CKs may function as universal regulators of storage-organ formation in plants. PMID- 23746639 TI - Group formation, relatedness, and the evolution of multicellularity. AB - The evolution of multicellular organisms represents one of approximately eight major evolutionary transitions that have occurred on earth. The major challenge raised by this transition is to explain why single cells should join together and become mutually dependent, in a way that leads to a more complex multicellular life form that can only replicate as a whole. It has been argued that a high genetic relatedness (r) between cells played a pivotal role in the evolutionary transition from single-celled to multicellular organisms, because it leads to reduced conflict and an alignment of interests between cells. We tested this hypothesis with a comparative study, comparing the form of multicellularity in species where groups are clonal (r = 1) to species where groups are potentially nonclonal (r <= 1). We found that species with clonal group formation were more likely to have undergone the major evolutionary transition to obligate multicellularity and had more cell types, a higher likelihood of sterile cells, and a trend toward higher numbers of cells in a group. More generally, our results unify the role of group formation and genetic relatedness across multiple evolutionary transitions and provide an unmistakable footprint of how natural selection has shaped the evolution of life. PMID- 23746640 TI - Aurora B defines its own chromosomal targeting by opposing the recruitment of the phosphatase scaffold Repo-Man. AB - Aurora B is the catalytic subunit of the chromosomal passenger complex (CPC), which coordinates mitotic processes through phosphorylation of key regulatory proteins. In prometaphase, the CPC is enriched at the centromeres to regulate the spindle checkpoint and kinetochore-microtubule interactions. Centromeric CPC binds to histone H3 that is phosphorylated at T3 (H3T3ph) by Aurora B-stimulated Haspin. PP1/Repo-Man acts antagonistically to Haspin and dephosphorylates H3T3ph at the chromosome arms but is somehow prevented from causing a net dephosphorylation of centromeric H3T3ph during prometaphase. Here, we show that Aurora B phosphorylates Repo-Man at S893, preventing its recruitment by histones. We also identify PP2A as a mitotic interactor of Repo-Man that dephosphorylates S893 and thereby promotes the targeting of Repo-Man to chromosomes and the dephosphorylation of H3T3ph by PP1. Thus, Repo-Man-associated PP1 and PP2A collaborate to oppose the chromosomal targeting of Aurora B. We propose that the reciprocal feedback regulation of Haspin and Repo-Man by Aurora B generates a robust bistable response that culminates in the centromeric targeting of the CPC during prometaphase. PMID- 23746642 TI - Chromatographic and adsorption properties of poly(1-trimethylsilyl-1-propyne) and their stabilization by adding poly(1-phenyl-1-propyne). AB - The chromatographic and adsorption properties of poly(1-trimethylsilyl-1-propyne) (PTMSP), a high permeable glassy polymer, were studied in the course of long-term usage of the Chromosorb P NAW+10wt% PTMSP adsorbent on a packed column in the temperature range of 30-180 degrees C. The structural changes in PTMSP related to a decrease in free volume and partial oxidation of the polymer were shown to substantially affect the adsorbent's properties. After the first 1.5 years (7000 h) of the column operation, the elution order of compounds changed, peak symmetry and efficiency of the column increased, the retention parameters as well as heats of adsorption of light hydrocarbons showed considerable changes. In order to stabilize the chromatographic properties of PTMSP, another disubstituted polyacetylene, poly(1-phenyl-1-propyne) (PPP), was added to the initial polymer, and a new mixed stationary phase, 97% PTMSP+3% PPP, was obtained and characterized. The resulting adsorbent, Chromosorb P NAW+10 wt% (97% PTMSP+3% PPP), is effective for solving a wide range of chromatographic problems, such as simultaneous detection of hydrocarbons and sulfur-containing inorganic gases, analysis of chlorine-substituted methanes in CCl4 and thiophene in benzene, separation of hydrocarbons and aromatic compounds. The chromatographic properties of the Chromosorb P NAW+10 wt% PTMSP (97% PTMSP+3% PPP) adsorbent were shown to remain stable in the course of its long-term operation (for at least 1.5 years, or 7000 h) on a packed column in the temperature range of 30-180 degrees C. PMID- 23746641 TI - Dynamic localization of G-actin during membrane protrusion in neuronal motility. AB - BACKGROUND: Actin-based cell motility is fundamental for development, function, and malignant events in eukaryotic organisms. During neural development, axonal growth cones depend on rapid assembly and disassembly of actin filaments (F actin) for their guided extension to specific targets for wiring. Monomeric globular actin (G-actin) is the building block for F-actin but is not considered to play a direct role in spatiotemporal control of actin dynamics in cell motility. RESULTS: Here we report that a pool of G-actin dynamically localizes to the leading edge of growth cones and neuroblastoma cells to spatially elevate the G-/F-actin ratio that drives membrane protrusion and cell movement. Loss of G actin localization leads to the cessation and retraction of membrane protrusions. Moreover, G-actin localization occurs asymmetrically in growth cones during attractive turning. Finally, we identify the actin monomer-binding proteins profilin and thymosin beta4 as key molecules that localize actin monomers to the leading edge of lamellipodia for their motility. CONCLUSIONS: Our results suggest that dynamic localization of G-actin provides a novel mechanism to regulate the spatiotemporal actin dynamics underlying membrane protrusion in cell locomotion and growth cone chemotaxis. PMID- 23746643 TI - Hollow-fiber liquid-phase microextraction for the determination of natural and synthetic estrogens in milk samples. AB - In this work, a group of nine estrogens, four of them being natural (estriol, 17beta-estradiol, 17alpha-estradiol and estrone), four being synthetic (17alpha ethynylestradiol, diethylstibestrol, dienestrol and hexestrol) and one metabolite (2-hydroxyestradiol) have been extracted and preconcentrated from milk samples with different fat content (whole, semi-skimmed and skimmed). After protein precipitation with acetonitrile containing acetic acid, evaporation of the supernatant and reconstitution of the residue in water, hollow-fiber liquid-phase microextraction (HF-LPME) using 1-octanol as extraction solvent was applied to further preconcentrate the analytes. Separation, determination and quantification were achieved by high-performance liquid chromatography coupled to a diode array detector and a fluorescence detector set in series. Deproteinization conditions, as well as parameters affecting the extraction efficiency in HF-LPME (pH of the sample, ionic strength, extraction time, stirring speed, temperature and desorption conditions) were investigated and optimized. Calibration, precision and accuracy studies were carried out to validate the methodology in different types of milk providing LODs in the low MUg/L range. PMID- 23746644 TI - Identification of sympathomimetic alkylamine agents in urine using liquid chromatography-mass spectrometry and comparison of derivatization methods for confirmation analyses by gas chromatography-mass spectrometry. AB - The detection of 11 sympathomimetic alkylamines in urine was presented with a focus on human doping control is proposed using liquid chromatography tandem mass spectrometry (LC-QqQ) and high resolution mass spectrometry (LC-HRMS) as a screening tool after a dilute-and-shoot (DS) approach. For the LC-HRMS analyses, several compounds exhibited better limits of detection (L.O.D.) than the LC-QqQ. However, due to their small differences in structure, co-elution among the alkylamines was observed. Therefore, the chemical conversion of the alkylamines into an appropriate derivative for the confirmation analyses using gas chromatography-mass spectrometry (GC-MS) was evaluated. Five derivatization approaches were evaluated in an attempt to increase the analytical response and the confidence of the identification. The choice of the appropriated derivative for each alkylamine makes their spectra more easily interpretable, fulfills the WADA's rather strict identification criteria and enables the unequivocal identification of alkylamines in urine. PMID- 23746645 TI - Insight into the extraction mechanism of polymeric ionic liquid sorbent coatings in solid-phase microextraction. AB - An investigation into the mechanism of extraction for polymeric ionic liquid (PIL)-based solid phase microextraction sorbent coatings is described. Four PIL based coatings, namely, a poly(1-4-vinylbenzyl)-3-hexadecylimidazolium bis[(trifluoromethyl)sulfonyl] imide (poly([VBHDIM][NTf2])) PIL produced through 2,2'-azo-bis(isobutyronitrile) (AIBN) initiated free-radical polymerization, a UV initiated poly(1-vinyl-3-hexylimidazolium) chloride (poly([VHIM][Cl])) PIL, and two crosslinked PILs containing the same IL monomers copolymerized with dicationic IL crosslinkers, were investigated. Calibration curves of 1-octanol were plotted in the presence of naphthalene, a model interfering compound, to observe changes in the linear range, sensitivity, and amount of analytes extracted. Results were compared with a polydimethylsiloxane/divinylbenzene (PDMS/DVB) coating and a polyacrylate (PA) coating which are known to extract analytes primarily through adsorption and partitioning mechanisms, respectively. All PIL-based coatings extracted analytes via a non-competitive partitioning mechanism regardless of the extent of crosslinking. PMID- 23746646 TI - Spectroscopic and chromatographic characterisation of a pentafluorophenylpropyl silica phase end-capped in supercritical carbon dioxide as a reaction solvent. AB - This research uses solid-state nuclear magnetic resonance (NMR) spectroscopy to characterise the nature and amount of different surface species, and chromatography to evaluate phase properties of a pentafluorophenylpropyl (PFPP) bonded silica phase prepared and end-capped using supercritical carbon dioxide (sc-CO2) as a reaction solvent. Under sc-CO2 reaction conditions (at temperature of 100 degrees C and pressure of 414 bar), a PFPP silica phase was prepared using 3-[(pentafluorophenyl)propyldimethylchlorosilane] within 1h. The bonded PFPP phase was subsequently end-capped with bis-N,O-trimethylsilylacetamide (BSA), hexamethyldisilazane (HMDS) and trimethylchlorosilane (TMCS) within 1h under the same sc-CO2 reaction conditions (100 degrees C/4141 bar). Elemental microanalysis, thermogravimetric analysis (TGA), and scanning electron microscopy (SEM) were used to provide support data to solid-state NMR and chromatographic evaluation. Results revealed a surface coverage of 2.2 MUmol/m(2) for the non-end capped PFPP silica phase while the PFPP phase end-capped with BSA gave a higher surface coverage (3.9 MUmol/m(2)) compared to HMDS (2.9 MUmol/m(2)) and TMCS (2.8 MUmol/m(2)). (29)Si CP/MAS NMR analysis of the PFPP end-capped with BSA shows a significant decrease in the amount of Q(3) (free silanols) and Q(4) (siloxane groups) species, coupled with the absence of the most reactive Q(2) (geminal silanols) in addition to increased amount of a single resonance peak centred at +13 ppm (MH) corresponding to -Si-O-*Si-CH3 bond. (13)C CP/MAS NMR shows the resonance corresponding to the propyl linkage (CH3CH2CH2-) and methyl groups (Si(CH3)n) confirming successful silanisation and endcapping reactions in sc-CO2. Chromatographic evaluation of the BSA end-capped PFPP phase with Neue text mixture revealed improved chromatographic separation as evidenced in the enhanced retention of hydrophobic markers and decreased retention for basic solutes. Moreover, chromatography revealed a change in column selectivity for the BSA end capped PFPP phase with dipropylphthalate eluting before naphthalene, indicating decreased silanol groups and increased hydrophobicity. The extend of BSA end capping as measured by the increase in column efficiency (67,260 N/m vs. 60,480 N/m) on a 2.1 i.d.*50 mm column, methylene group selectivity (alpha(CH(2)) = 2.27 vs. 2.14) and decreased silanophilic interactions (S=3.7 vs. 4.10) indicate that the increase in carbon loading (3.9 MUmol/m(2) vs. 2.2 MUmol/m(2)) and improvement in chromatography in good peak shape and symmetry is attributed to end-capping with trimethylsilyl groups. PMID- 23746647 TI - Fast methodology for the reliable determination of nonylphenol in water samples by minimal labeling isotope dilution mass spectrometry. AB - In this work we have developed and validated an accurate and fast methodology for the determination of 4-nonylphenol (technical mixture) in complex matrix water samples by UHPLC-ESI-MS/MS. The procedure is based on isotope dilution mass spectrometry (IDMS) in combination with isotope pattern deconvolution (IPD), which provides the concentration of the analyte directly from the spiked sample without requiring any methodological calibration graph. To avoid any possible isotopic effect during the analytical procedure the in-house synthesized (13)C1-4 (3,6-dimethyl-3-heptyl)phenol was used as labeled compound. This proposed surrogate was able to compensate the matrix effect even from wastewater samples. A SPE pre-concentration step together with exhaustive efforts to avoid contamination were included to reach the signal-to-noise ratio necessary to detect the endogenous concentrations present in environmental samples. Calculations were performed acquiring only three transitions, achieving limits of detection lower than 100ng/g for all water matrix assayed. Recoveries within 83 108% and coefficients of variation ranging from 1.5% to 9% were obtained. On the contrary a considerable overestimation was obtained with the most usual classical calibration procedure using 4-n-nonylphenol as internal standard, demonstrating the suitability of the minimal labeling approach. PMID- 23746648 TI - Quantitative assessment of iron deposition in the midbrain using 3D-enhanced T2 star weighted angiography (ESWAN): a preliminary cross-sectional study of 20 Parkinson's disease patients. AB - Conventional magnetic resonance imaging (MRI) assesses neurodegenerative structural changes in the cerebral anatomy of Parkinson's disease (PD) patients but cannot detect non-structural abnormalities; however, enhanced T2 star weighted angiography (ESWAN) can precisely indicate PD-related substantia nigra (SN) iron deposition. The differences in ESWAN-based parameters between different PD stages were assessed using midbrain iron deposits of 20 PD patients aged 64.3+/-12.7 (41-85) years grouped by Hoehn and Yahr staging into minimal (stages <=2.5) or moderate to severe (stages >=3.0) motor impairment groups and 14 healthy control subjects. Conventional MRI and ESWAN measurements of mean phase value (MPV) and midbrain dimensions (width and diameter) revealed similar anatomical characteristics; however, ESWAN revealed the presence of smaller MPVs and SN pars compacta (SNc) (P<0.01) and a negative correlation between reduction extent and motor impairment (P<0.01). SNc width to midbrain diameter was reduced in moderate to severe impairment patients versus control and minimal impairment patients (both P<0.01). A positive correlation was found between MPV and width or SNc width to midbrain diameter ratio (P<0.01 and P<0.05, respectively). Minimal impairment group mean MPV and substantia nigra pars reticulata (SNr) width evidenced no significant reduction, unlike significant reductions in the moderate to severe impairment group (P<0.01). No significant changes were observed in MPV or width in the RN region (P>0.05). ESWAN allows for early and accurate iron deposition determination in PD patients, particularly useful as a supplement to conventional MRI in early-stage PD patients. PMID- 23746649 TI - Synthesis of a trisaccharide repeat of the zwitterionic Sp1 capsular polysaccharide utilizing 2-Azido-4-benzylamino-4N,3-O-carbonyl-2,4,6-trideoxy-d galactopyranosyl trichloroacetimidate. AB - 2-Azido-4-benzylamino-4N,3-O-carbonyl-2,4,6-trideoxy-d-galactopyranosyl trichloroacetimidate 2 conveniently prepared in six steps from 6-deoxy-d-glucal glycosylated a selectively protected alpha1,3 linked methyl galabioside to afford the trisaccharide skeleton of a repeating unit of the Sp1 zwitterionic capsular polysaccharide. Lithium hydroxide hydrolysis of the 3,4-cyclic carbamate permitted the creation of a 2-acetamido-4-amino-2,4,6-trideoxygalactose residue. Selective cleavage of p-methoxybenzyl ethers by trifluoroacetic acid gave a selectively deprotected trisaccharide with two hydroxymethyl groups that were oxidized by the TEMPO reagent to afford access to trisaccharide glycoside 1 containing 2-acetamido-4-amino-2,4,6-trideoxygalactose and two galacturonic acid residues. PMID- 23746650 TI - Structure, biosynthesis, and function of bacterial capsular polysaccharides synthesized by ABC transporter-dependent pathways. AB - Bacterial capsules are formed primarily from long-chain polysaccharides with repeat-unit structures. A given bacterial species can produce a range of capsular polysaccharides (CPSs) with different structures and these help distinguish isolates by serotyping, as is the case with Escherichia coli K antigens. Capsules are important virulence factors for many pathogens and this review focuses on CPSs synthesized via ATP-binding cassette (ABC) transporter-dependent processes in Gram-negative bacteria. Bacteria utilizing this pathway are often associated with urinary tract infections, septicemia, and meningitis, and E. coli and Neisseria meningitidis provide well-studied examples. CPSs from ABC transporter dependent pathways are synthesized at the cytoplasmic face of the inner membrane through the concerted action of glycosyltransferases before being exported across the inner membrane and translocated to the cell surface. A hallmark of these CPSs is a conserved reducing terminal glycolipid composed of phosphatidylglycerol and a poly-3-deoxy-d-manno-oct-2-ulosonic acid (Kdo) linker. Recent discovery of the structure of this conserved lipid terminus provides new insights into the early steps in CPS biosynthesis. PMID- 23746651 TI - Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. AB - Immune tolerance requires regulatory T (Treg) cells to prevent autoimmune disease, with the transcription factor Foxp3 functioning as the critical regulator of Treg cell development and function. We report here that Foxp3 was lethal to developing Treg cells in the thymus because it induced a unique proapoptotic protein signature (Puma+++p-Bim++p-JNK++DUSP6-) and repressed expression of prosurvival Bcl-2 molecules. However, Foxp3 lethality was prevented by common gamma chain (gammac)-dependent cytokine signals that were present in the thymus in limiting amounts sufficient to support only ~1 million Treg cells. Consequently, most newly arising Treg cells in the thymus were deprived of this signal and underwent Foxp3-induced death, with Foxp3+CD25- Treg precursor cells being the most susceptible. Thus, we identify Foxp3 as a proapoptotic protein that requires developing Treg cells to compete with one another for limiting amounts of gammac-dependent survival signals in the thymus. PMID- 23746652 TI - Effector-like CD8+ T cells in the memory population mediate potent protective immunity. AB - The CD8+ memory T cell population is heterogeneous, and it is unclear which subset(s) optimally mediate the central goal of the immune system-protection against infection. Here we investigate the protective capacities of CD8+ T cell subsets present at the memory stage of the immune response. We show that a population of CD8+ T cells bearing markers associated with effector cells (KLRG1(hi), CD27(lo), T-bet(hi), Eomes(lo)) persisted to the memory phase and provided optimal control of Listeria monocytogenes and vaccinia virus, despite weak recall proliferative responses. After antigen-specific boosting, this population formed the predominant secondary memory subset and maintained superior pathogen control. The effector-like memory subset displayed a distinct pattern of tissue distribution and localization within the spleen, and their enhanced capacity to eliminate Listeria involved specialized utilization of cytolysis. Together, these data suggest that long-lived effector CD8+ T cells are optimal for protective immunity against certain pathogens. PMID- 23746653 TI - Oligodendrocyte progenitor cell susceptibility to injury in multiple sclerosis. AB - Remyelination in multiple sclerosis (MS) is often incomplete. In experimental models, oligodendrocyte progenitor cells (OPCs) rather than previously myelinating oligodendrocytes (OLs) are responsible for remyelination. This study compares the relative susceptibility of adult human OPCs and mature OLs to injury in actively demyelinating MS lesions and under in vitro stress conditions. In all lesions (n = 20), the number of OLs (Olig2 weak/NogoA positive) was reduced compared to control white matter (mean 38 +/- 4% of control value). In 11 cases, OPC numbers (Olig2 strong; NogoA negative) were also decreased; in eight of these, the reduction was greater for OPCs than for OLs. In the other nine samples, OPC numbers were greater than control white matter, indicating ongoing OPC migration and/or proliferation. Analysis of co-cultures with rat dorsal root ganglia neurons confirmed that OPCs were more capable of contacting and ensheathing axons than OLs. In isolated culture under stress conditions (withdrawal of serum/glucose and/or antioxidants), OPCs showed increased cell death and reduced process extension compared to OLs. Under all culture conditions, OPCs up-regulated expression of genes in the extrinsic proapoptotic pathway, and had increased susceptibility to tumor necrosis factor-induced cell death as compared to OLs. Our data suggest that susceptibility of OPCs to injury within the MS lesion environment contributes to the limited remyelination in MS. PMID- 23746654 TI - Regulatory T cells improve nephrocalcinosis but not dystrophic cardiac calcinosis in DBA/2 mice. AB - Nephrocalcinosis is characterized by aberrant deposition of calcium in the kidneys and is seen in phosphate nephropathy, primary hyperparathyroidism, and distal renal tubular acidosis. To further evaluate the specific pathophysiologic role of T cells in ectopic calcification, we used DBA/2 mice that are prone to develop nephrocalcinosis and dystrophic cardiac calcinosis. Female DBA/2 mice were depleted of T cells (n = 10) or regulatory T cells (Tregs) (n = 15) using either an anti-CD3E or an anti-CD25 monoclonal antibody and compared with isotype treated controls (n = 9; n = 15), respectively. After this immunomodulation, the DBA/2 mice were given a high-phosphate diet for 9 days and the degree of calcification was assessed by microcomputed tomography. Successful depletion was confirmed by flow cytometry of splenocytes. In DBA/2 mice, the high-phosphate diet induced a phenotype of nephrocalcinosis and dystrophic cardiac calcinosis. T cell depletion significantly increased renal calcification in microcomputed tomography (P = 0.022). Concordantly, Treg depletion significantly deteriorated acute phosphate nephropathy (P = 0.039) and was associated with a significantly increased mortality rate (P = 0.004). Immunomodulation had no impact on the amount of cardiac calcification. Semiquantitative histopathologic evaluations with Alizarin Red staining independently confirmed the respective radiologic measurements. In summary, our data suggest a pivotal role of T cells, particularly Tregs, in the progression of nephrocalcinosis and emphasize the fact that inflammation deteriorates the outcome in acute phosphate nephropathy. PMID- 23746655 TI - Anti-proliferative actions of T-type calcium channel inhibition in Thy1 nephritis. AB - Aberrant proliferation of mesangial cells (MCs) is a key finding in progressive glomerular disease. TH1177 is a small molecule that has been shown to inhibit low voltage activated T-type Ca(2+) channels (TCCs). The current study investigates the effect of TH1177 on MC proliferation in vitro and in vivo. The effect of Ca(2+) channel inhibition on primary rat MC proliferation in vitro was studied using the microculture tetrazolium assay and by measuring bromodeoxyuridine incorporation. In vivo, rats with Thy1 nephritis were treated with TH1177 or vehicle. Glomerular injury and average glomerular cell number were determined in a blinded fashion. Immunostaining for Ki-67 and phosphorylated ERK were also performed. The expression of TCC isoforms in healthy and diseased tissue was investigated using quantitative real-time PCR. TCC blockade caused a significant reduction in rat MC proliferation in vitro, whereas L-type inhibition had no effect. Treatment of Thy1 nephritis with TH1177 significantly reduced glomerular injury (P < 0.005) and caused a 49% reduction in glomerular cell number (P < 0.005) compared to the placebo. TH1177 also reduced Ki-67-positive and pERK positive cells per glomerulus by 52% (P < 0.01 and P < 0.005, respectively). These results demonstrate that TH1177 inhibits MC proliferation in vitro and in vivo, supporting the hypothesis that TCC inhibition may be a useful strategy for studying and modifying MC proliferative responses to injury. PMID- 23746657 TI - A survey of current policy and practice of surgical exposure for preclerkship medical students at American medical institutions. AB - BACKGROUND: The goals of this study were to (1) determine the extent of preclerkship surgical participation in American medical colleges; (2) examine policies regarding such surgical participation; and (3) elicit medical school administrators' perceptions about such exposure. METHODS: Surveys were sent to 128 accredited medical schools (1 administrator each). The 54 (42%) replies were analyzed using descriptive statistics and Student's t tests, with significance defined as a P value of <= .05. RESULTS: Of the respondents, 55.6% did not permit student surgical participation. Only 22.2% of responding institutions offered preclerkship surgical skills electives. Administrators from the former group of schools perceived significantly greater risk (P = .001) to patient safety with student surgical participation than did administrators at schools permitting such participation, even though no respondents reported malpractice or worker's compensation cases arising from student participation. CONCLUSIONS: Medical students have limited opportunities for preclerkship surgical participation at most American medical institutions, possibly because of unsubstantiated concerns for patient safety. PMID- 23746656 TI - Cross-regulation of T regulatory-cell response after coxsackievirus B3 infection by NKT and gammadelta T cells in the mouse. AB - Coxsackievirus B3 (CVB3) variants H3 and H310A1 differ by a single nonconserved amino acid in the VP2 capsid region. C57Bl/6 mice infected with the H3 virus develop myocarditis correlating with activation of T cells expressing the Vgamma4 T cell receptor chain. Infecting mice with H310A1 activates natural killer T (NKT; mCD1d-tetramer(+) TCRbeta(+)) cells, but not Vgamma4 T cells, and fails to induce myocarditis. H310A1 infection preferentially activates M2 alternatively activated macrophage and CD4(+)FoxP3 (T regulatory) cells, whereas CD4(+)Th1 (IFN gamma(+)) cells are suppressed. By contrast, H3 virus infection activates M1 proinflammatory and CD4(+)Th1 cells, but not T regulatory cells. The M1 macrophage show significantly increased CD1d expression compared to M2 macrophage. The ability of NKT cells to suppress myocarditis was shown by adoptive transfer of purified NKT cells into H3-infected NKT knockout (Jalpha18 knockout) mice, which inhibited cardiac inflammation and increased T regulatory cell response. Cardiac virus titers were equivalent in all mouse strains indicating that neither Vgamma4 nor NKT cells participate in control of virus infection. These data show that NKT and Vgamma4 cells cross-regulate T regulatory cell responses during CVB3 infections and are the primary factor determining viral pathogenesis in this mouse model. PMID- 23746659 TI - Overview of clinical flow cytometry data analysis: recent advances and future challenges. AB - Major technological advances in flow cytometry (FC), both for instrumentation and reagents, have emerged over the past few decades. These advances facilitate simultaneous evaluation of more parameters in single cells analyzed at higher speed. Consequently, larger and more complex data files that contain information about tens of parameters for millions of cells are generated. This increasing complexity has challenged pre-existing data analysis tools and promoted the development of new algorithms and tools for data analysis and visualization. Here, we review the currently available (conventional and newly developed) data analysis and visualization strategies that aim for easier, more objective, and robust interpretation of FC data both in biomedical research and clinical diagnostic laboratories. PMID- 23746660 TI - Pneumothorax following extended latissimus dorsi flap breast reconstruction: rare complication or coincidence? PMID- 23746658 TI - Correlation of staging systems to survival in patients with resected hilar cholangiocarcinoma. AB - BACKGROUND: We aimed to identify staging parameters associated with survival in patients with hilar cholangiocarcinoma. METHODS: Clinicopathologic characteristics were obtained retrospectively for all resected patients with Bismuth-Corlette III cholangiocarcinoma between 1993 and 2011. Patients were stratified by the American Joint Commission on Cancer (AJCC) (7th edition) and Memorial Sloan-Kettering Cancer Center (MSKCC) staging systems. Survival analyses tested the effects of clinicopathologic factors and staging covariates on recurrence-free and overall survival. RESULTS: Eighty patients (mean age 63 +/- 11 years, 63% male) underwent anatomic hepatectomy with bile duct resection/reconstruction for Bismuth-Corlette IIIa (53%) and IIIb (47%) cholangiocarcinoma. The median follow-up was 26 months (interquartile range = 12 to 50 months), and the median time to recurrence was 15 months (interquartile range = 6 to 38 months). Neither AJCC nor MSKCC staging systems were associated with recurrence-free survival (all P >= .059). MSKCC T-stage but not the AJCC staging system was associated with overall survival (P <= .026). CONCLUSIONS: MSKCC T-stage classification but not AJCC staging is independently associated with overall survival for patients after resection of hilar cholangiocarcinoma. PMID- 23746661 TI - Does plastic surgery have an image problem?: the perception of plastic surgery in an era of general practitioner commissioning. PMID- 23746662 TI - Training for hand fractures: the breadstick model. PMID- 23746663 TI - Physicians' responses to clinical decision support on an intensive care unit- comparison of four different alerting methods. AB - BACKGROUND: In intensive care environments, technology is omnipresent whereby ensuring constant monitoring and the administration of critical drugs to unstable patients. A clinical decision support system (CDSS), with its widespread possibilities, can be a valuable tool in supporting adequate patient care. However, it is still unclear how decision support alerts should be presented to physicians and other medical staff to ensure that they are used most effectively. OBJECTIVE: To determine the effect of four different alert presentation methods on alert compliance after the implementation of an advanced CDSS on the intensive care unit (ICU) in our hospital. METHODS: A randomized clinical trial was executed from August 2010 till December 2011, which included all patients admitted to the ICU of our hospital. The CDSS applied contained a set of thirteen locally developed clinical rules. The percentage of alert compliance was compared for four alert presentation methods: pharmacy intervention, physician alert list, electronic health record (EHR) section and pop-up alerts. Additionally, surveys were held to determine the method most preferred by users of the CDSS. RESULTS: In the study period, the CDSS generated 902 unique alerts, primarily due to drug dosing during decreased renal function and potassium disturbances. Alert compliance was highest for recommendations offered in pop-up alerts (41%, n=68/166), followed by pharmacy intervention (33%, n=80/244), the physician alert list (20%, n=40/199) and the EHR section (19%, n=55/293). The method most preferred by clinicians was pharmacy intervention, and pop-up alerts were found suitable as well if applied correctly. The physician alert list and EHR section were not considered suitable for CDSSs in the process of this study. CONCLUSION: The alert presentation method used for CDSSs is crucial for the compliance with alerts for the clinical rules and, consequently, for the efficacy of these systems. Active alerts such as pop-ups and pharmacy intervention were more effective than passive alerts, which do not automatically appear within the clinical workflow. In this pilot study, ICU clinicians also preferred pharmacy intervention and pop-up alerts. More research is required to expand these results to other departments and other hospitals, as well as to other types of CDSSs and different alert presentation methods. PMID- 23746664 TI - Optimizing sleep in older adults: treating insomnia. AB - As the world's population ages, the elevated prevalence of insomnia in older adults is a growing concern. Insomnia is characterized by difficulty falling or remaining asleep, or by non-restorative sleep, and resultant daytime dysfunction. In addition to being at elevated risk for primary insomnia, older adults are at greater risk for comorbid insomnia, which results from, or occurs in conjunction with another medical or psychiatric condition. In this review, we discuss normal changes in sleep that accompany aging, circadian rhythm changes and other factors that can contribute to late-life insomnia, useful tools for the assessment of insomnia and related problems in older people, and both non-pharmacological and pharmacological strategies for the management of insomnia and optimization of sleep in later life. PMID- 23746665 TI - [Nursing care in males with spinal cord injury and sexual dysfunction]. AB - The impact of spinal cord injury and its sequels requires important efforts of adaptation. In several studies, people with spinal cord injury claim to have covered most of their needs at physical, emotional and social level, but they are not yet fully satisfied with their sexual life. Sexual function is usually impaired in men with spinal cord injuries, and is sometimes related to problems of erection, ejaculation and/or orgasm. This issue is not a priority in the first phase, but it appears over the subsequent periods when patients often ask for a solution to this problem. A case-study is presented of a 25 year old male with chronic complete spinal cord injury (ASIA A), L4-L5 level, who reported sexual dysfunction and attended an annual review in the National Hospital for Paraplegics. After performing a nursing assessment using the functional health patterns of Gordon, the team proposed a nursing care plan according to the taxonomy of NANDA (North American Nursing Association), NOC (Nursing Outcome Classification) and NIC (Nursing Intervention Classification). Nurses are the healthcare professionals who have more direct and continuous contact with these patients. Specific programs need to be designed to provide them with the sexual education, which should contain adequate emotional and sexual information. We believe that an appropriate and systematic assessment of patient's sexuality, as well as the application of the (NANDA, NOC, NIC) nurse methodology, may be very helpful in improving the outcomes of these specific interventions. PMID- 23746667 TI - EGFR-directed treatments in SCCHN. PMID- 23746666 TI - Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open label phase 3 randomised trial. AB - BACKGROUND: Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients. METHODS: This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m(2) on day 1 of each cycle) and fluorouracil (1000 mg/m(2) on days 1-4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with ClinicalTrials.gov, number NCT00460265. FINDINGS: Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11.1 months (95% CI 9.8-12.2) in the panitumumab group and 9.0 months (8.1-11.2) in the control group (hazard ratio [HR] 0.873, 95% CI 0.729-1.046; p=0.1403). Median progression-free survival was 5.8 months (95% CI 5.6-6.6) in the panitumumab group and 4.6 months (4.1-5.4) in the control group (HR 0.780, 95% CI 0.659-0.922; p=0.0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11.7 months [95% CI 9.7-13.7] vs 8.6 months [6.9-11.1]; HR 0.73 [95% CI 0.58-0.93]; p=0.0115), but this difference was not shown for p16-positive patients (11.0 months [7.3-12.9] vs 12.6 months [7.7-17.4]; 1.00 [0.62-1.61]; p=0.998). In the control group, p16 positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0.70 [95% CI 0.47-1.04]). INTERPRETATION: Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings. FUNDING: Amgen Inc. PMID- 23746668 TI - Genes, communities & invasive species: understanding the ecological and evolutionary dynamics of host-pathogen interactions. AB - Reciprocal interactions between hosts and pathogens drive ecological, epidemiological and co-evolutionary trajectories, resulting in complex patterns of diversity at population, species and community levels. Recent results confirm the importance of negative frequency-dependent rather than 'arms-race' processes in the evolution of individual host-pathogen associations. At the community level, complex relationships between species abundance and diversity dampen or alter pathogen impacts. Invasive pathogens challenge these controls reflecting the earliest stages of evolutionary associations (akin to arms-race) where disease effects may be so great that they overwhelm the host's and community's ability to respond. Viewing these different stabilization/destabilization phases as a continuum provides a valuable perspective to assessment of the role of genetics and ecology in the dynamics of both natural and invasive host-pathogen associations. PMID- 23746669 TI - Nociception originating from the crural fascia in rats. AB - Little is documented in the literature as to the function of muscle fascia in nociception and pain. The aim of this study was to examine the distribution of presumptive nociceptive nerve fibers, to characterize fascial thin-fiber sensory receptors, and to examine the spinal projection of nociceptive input from the rat crural fascia (CF). Nerve fibers labeled with specific antibodies to calcitonin gene-related peptide (CGRP) and peripherin were found to be densely distributed in the distal third of the CF. Thin-fiber receptors (Adelta- and C-fibers) responding to pinching stimuli to the CF with sharpened watchmaker's forceps, identified in vivo with the teased fiber technique from the common peroneal nerve, exist in the CF. Forty-three percent of the mechano-responsive fascial C fibers were polymodal receptors (nociceptors) responding to mechanical, chemical (bradykinin), and heat stimuli, whereas almost all Adelta-fibers were responsive only to mechanical stimuli. Repetitive pinching stimulus to the CF induced c-Fos protein expression in the middle to medial part of superficial layers ie, laminae I-II of the spinal dorsal horn at segments L2 to L4, peaking at L3. These results clearly demonstrate the following: 1) peptidergic and non-peptidergic axons of unmyelinated C-fibers with nerve terminals are distributed in the CF; 2) peripheral afferents responding to noxious stimuli exist in the fascia, and 3) nociceptive information from the CF is mainly processed in the spinal dorsal horn at the segments L2 to L4. These results together indicate that the "muscle fascia," a tissue often overlooked in pain research, can be an important source of nociception under normal conditions. PMID- 23746670 TI - Influences of calcination temperature on growth and superconducting properties of GdBa2Cu3O7-delta films fabricated by fluorine-free metal organic deposition method. AB - GdBa2Cu3O7-delta is one of the best candidates for the superconducting coated conductors because it has high critical temperature and high critical current density under high magnetic fields. In this study, superconducting GdBa2Cu3O7 delta films were fabricated by fluorine-free metal organic deposition method via two different calcination temperatures, 723K and 873K, to examine the influence of calcination temperature on film growth and superconducting characteristics. Critical temperatures and critical current densities of the sample calcined at 873K were superior to the sample calcined at 723K. In the case of the sample calcined at 723K, the mixture of amorphous and crystalline phases was observed, and that of a- and c-axis oriented grains after the crystallization. In the case of the sample calcined at 873K, the randomly oriented crystalline phases were observed, and the mixture of c-axis oriented grains and (Gd, Al)2BaO4 phase after the crystallization. These microstructural changes caused the differences in superconducting characteristics. PMID- 23746671 TI - Chard (Beta vulgaris L. var. cicla) extract ameliorates hyperglycemia by increasing GLUT2 through Akt2 and antioxidant defense in the liver of rats. AB - Chard is a plant used as an alternative hypoglycemic agent by diabetic people in Turkey. The aim of this study was to examine the molecular mechanism of hypoglycemic effects of chard extract. Male Sprague-Dawley rats (6-7 months old) were divided into five groups for this investigation: (1) control, (2) hyperglycemic, (3) hyperglycemic+chard, (4) hyperglycemic+insulin, (5) hyperglycemic+chard+insulin. Fourteen days after animals were rendered hyperglycemic by intraperitoneal injection of 60 mg/kg streptozotocin, the chard water extract (2 g/kg/day) or/and insulin (6 U/kg/day) was administered for 45 days. Hypoglycemic effect of chard extract was demonstrated by a significant reduction in the fasting blood glucose and increased glycogen levels in liver of chard extract-treated hyperglycemic rats. Moreover, activity of adenosine deaminase, which is suggested as an important enzyme for modulating the bioactivity of insulin, was decreased by chard treatment. Immunostaining analysis showed increased nuclear translocation of Akt2 and synthesis of GLUT2 in the hepatocytes of chard or/and insulin-treated hyperglycemic rats. The oxidative stress was decreased and antioxidant defense was increased by chard extract or/and insulin treatment to hyperglycemic rats according to the decreased malondialdehyde formation, the activities of catalase, superoxide dismutase, myeloperoxidase and increased glutathione levels. These findings suggest that chard extract might improve glucose response by increasing GLUT2 through Akt2 and antioxidant defense in the liver. PMID- 23746673 TI - Tomographic evaluation of iliac crest bone grafting and the use of immediate temporary implants to the atrophic maxilla. AB - Sixteen consecutive patients with atrophic maxillae, who had been referred for bone augmentation using iliac bone grafting before the placement of dental implants, received a full clinical examination and underwent a CT scan before and after surgery. Linear vertical and horizontal measurements were made before and 6 months after surgery. Differences in mean bone gain or loss for each area were compared between a group that received an immediate total provisional prosthesis on temporary immediate implants (test group, 12 patients) and a control group (four patients). Both groups showed significant horizontal bone gain in all regions and vertical bone augmentation in the posterior regions. The test group showed no significant difference for bone gain compared to the control group, but half the test group had problems during treatment. Bone augmentation of the atrophic maxilla with iliac crest bone grafting resulted in sufficient vertical and horizontal bone augmentation to install six or eight implants in all patients and successfully rehabilitate them. The results suggest that the use of total provisional prostheses on temporary immediate implants meets the aesthetic demands required, but should be used with care and in special cases. PMID- 23746672 TI - The evaluation of lateral pterygoid muscle pathologic changes and insertion patterns in temporomandibular joints with or without disc displacement using magnetic resonance imaging. AB - Temporomandibular joint (TMJ) disc displacement is a common disorder in patients with internal derangement. Certain anatomic features of TMJ may make the patient prone to this condition, namely lateral pterygoid muscle (LPM) insertion variations. The aim of this study was to investigate LPM attachments and their relationships with disc displacement and subsequent pathologic changes. A total of 26 patients with clinical temporomandibular disorders (TMDs) and a control group of 14 unaffected individuals were studied. Magnetic resonance images (MRIs) were taken to evaluate LPM insertion patterns, superior LPM head pathologic changes, and relative disc to condyle position. Data registration and analysis were done using SPSS v. 16.0. The most common variation (type I) was shown to be the superior head with two bundles, one attached to the disc and another to the condyle. No significant relationship between LPM insertion type and disc displacement or pathologic changes of the muscle was found. However, a link between disc displacement and muscle pathologic changes was established (P=0.001). PMID- 23746674 TI - Comparison of concomitant boost radiotherapy against concurrent chemoradiation in locally advanced oropharyngeal cancers: a phase III randomised trial. AB - PURPOSE: To test the toxicity and efficacy of concomitant boost radiotherapy alone against concurrent chemoradiation (conventional fractionation) in locally advanced oropharyngeal cancer in our patient population. METHODS AND MATERIALS: In this open-label, randomised trial, 216 patients with histologically proven Stage III-IVA oropharyngeal cancer were randomly assigned between June 2006 and December 2010 to receive either chemoradiation (CRT) to a dose of 66 Gy in 33 fractions over 6.5 weeks with concurrent cisplatin (100 mg/m(2) on days 1, 22 and 43) or accelerated radiotherapy with concomitant boost (CBRT) to a dose of 67.5 Gy in 40 fractions over 5 weeks. The compliance, toxicity and quality of life were investigated. Disease-free survival (DFS) and overall survival (OS) curves were estimated with the Kaplan-Meier method and compared using log rank test. RESULTS: The compliance to radiotherapy was superior in concomitant boost with lesser treatment interruptions (p=0.004). Expected acute toxicities were significantly higher in CRT, except for grade 3/4 mucositis which was seen more in CBRT arm (39% and 55% in CRT and CBRT, respectively; p=0.02). Late toxicities like Grade 3 xerostomia were significantly high in CRT arm than CBRT arm (33% versus 18%; p<0.0001). The quality of life was significantly poor in CRT arm at all follow up visits (p<0.0001). The rates of 2 year disease-free survival were similar with 56% in the chemoradiotherapy group and 61% in CBRT group (p=0.2; HR 0.81, 95%CI-0.53-1.2). Subgroup analysis revealed that patients with nodal size >2 cm had significantly better DFS with CRT (p=0.05; HR-1.59, 95%CI-0.93-2.7). CONCLUSION: In selected patients of locally advanced oropharyngeal cancer, concomitant boost offers a better compliance, toxicity profile and quality of life with similar disease control, than chemoradiation. PMID- 23746675 TI - Treatment of multiple primary lung cancers using stereotactic radiotherapy, either with or without surgery. AB - BACKGROUND AND PURPOSE: Multiple primary lung cancers (MPLC) are not an uncommon presentation. Current guidelines recommend a curative approach when early-stage MPLC is diagnosed as favorable outcomes have been reported after surgery. We studied outcomes following stereotactic ablative radiotherapy (SABR). MATERIALS AND METHODS: Following review of imaging and pathology at a multi-disciplinary tumor board, a total of 62 patients were referred for SABR with a diagnosis of synchronous MPLC. SABR was performed for both lesions in 56 patients, while another 6 underwent SABR for only one lesion and surgery for the other lesion. A total dose of 54-60 Gy was delivered in 3-8 fractions. RESULTS: Median follow-up was 44 months (95% CI: 29-59). Overall survival of all patients was 31 months (95% CI: 17-44), with an actuarial 2-year survival of 56%. No grade 4 or 5 post SABR toxicity was observed. Local control rates calculated per lesion, were 84% at 2 years, and 78% at 3 years. The two-year actuarial regional control rate was 87%. CONCLUSIONS: SABR for synchronous MPLC achieves a lesion control rate of 84% after 2 years, with limited toxicity. SABR should be considered when patients with lung cancer present with a synchronous second lesion and no nodal involvement. PMID- 23746676 TI - Patient photographs--a landmark for the ICU staff: a descriptive study. AB - OBJECTIVES: The purpose of this study was to investigate ICU staff's perceptions of photographs displayed at the bedsides of unconscious patients and whether profession, years in ICU and work status had any influence on these perceptions. RESEARCH METHODOLOGY: A cross-sectional study was used comprising a questionnaire with statements and one open-ended question. All registered nurses, enrolled nurses and anaesthetists working in one ICU in Sweden were included. A total of 85 participants returned a questionnaire (response rate=77%). RESULTS: The findings of the study revealed that a photograph of the patient helped the ICU staff to relate to the patient as a person. Profession, years in ICU and work status had influence on the ICU staff's perceptions. From the content analysis two categories emerged: "getting closer and see the person" and "a landmark bringing hope". CONCLUSION: The ICU staff need to consider how close to the patient they want to be and why the patient's recovery is worth striving for. Keeping a professional approach is one of the challenges of working in ICU. A photograph can be an inexpensive and easy way of preventing the loss of identity of the patient as an individual within the technocratic environments of the ICU. PMID- 23746677 TI - Risk of bias in research in oral and maxillofacial surgery. AB - The risk of bias is important in the interpretation of the results of research. The aim of this review was to evaluate the risk of bias in randomised controlled trials (RCTs) in oral and maxillofacial surgery (OMFS) over a 10-year period. We searched databases of publications for RCTs published between January 2000 and January 2010. Papers were assessed with 2 up-to-date logical quality lists, the Delphi list and the Jadad scale. Those papers with a low risk of bias were given a Jadad score >=4 (range 0-5) and a Delphi score >=6 (range 0-9). A total of 230 papers met the inclusion criteria, and only 41 (18%) were assessed as being at low risk. Most of those included did not correctly describe such important items for risk of bias as method of randomisation (n=124, 54%), concealment of allocation (n=143, 62%), blinding (n=175, 76%), and intention-to-treat analyses (n=182, 79%). In the fields of implantology, traumatology, obstructive sleep apnoea syndrome, and extractions, no paper had a low risk of bias. This systematic review has shown a shortage of research in OMFS with a low risk of bias published over a 10-year period. Further research should concentrate on better describing items at important risk of bias. PMID- 23746678 TI - Extreme mandibular dentobasal discrepancy in orthognathic surgery: a proposal for a definitive solution. AB - Some cases in orthognathic surgery present with large discrepancies between the skeletal pattern and the occlusion. If there is little or no sagittal dental discrepancy, but the mandibular basal bone is prognathic, surgical correction can be critical. We describe a two-step procedure to treat these patients. The first step is to adapt the lower alveolar bone to the position of the chin. Distraction osteogenesis in the anterior dentoalveolar mandibular region carries the lower incisors to the same level as the chin. A one-tooth space is opened in the distraction area to obtain a full negative over-jet. Bimaxillary osteotomy can be used to correct class III dentoskeletal malocclusion. Five patients aged 20-40 years have been operated on during the last 2 years. The first step creates harmony between the chin and lower lip, together with a negative over-jet and a true prognathic profile. The class III malocclusion is corrected with a bimaxillary osteotomy. Our two-step plan achieves good occlusion and profile in patients with severe discrepancies between their occlusion and the position of the chin. Dental implants can then be inserted into the gaps left by distraction, which results in a third bicuspid on each side of the mandible. PMID- 23746679 TI - Step-by-step deposition of synthetic dopamine-eumelanin and metal cations. AB - The photoprotection of skin depends mostly on a balance between two natural pigments: the black-brown eumelanin and the yellow-reddish pheomelanin. These pigments as well as their counterpart in the central nervous system, neuromelanin, interact strongly with metal cations like Fe(3+). In the mussel foot proteins, the coordination between catechol groups and these ions is also responsible for the strong hardness the mussel's cuticle. These examples are suggestive that coatings and materials can be made based on such materials, for instance, synthetic eumelanin colloids and metal cations. Herein, we demonstrate that films made from synthetic dopamine-eumelanin colloids and metal cations can be deposited on surfaces in a step-by-step manner. As typical metal cations, we used Cu(2+), Fe(3+), and La(3+) which are known to interact with eumelanins. In all cases, step-by-step deposition is only possible in the absence of water rinse between two deposition steps. It was found that trivalent cations allow for a faster increase in film deposition than Cu(2+). Complementary in PDADMAC (eumelanin-Fe(3+))m films, iron III was found not to be reduced. PMID- 23746680 TI - Efficient photocatalytic degradation of rhodamine B over CdS sensitized SiO2 HNb3O8 under visible light. AB - CdS/SiO2-HNb3O8 and CdS-HNb3O8 composite photocatalysts were developed for rhodamine B photodegradation under visible light. The characteristics of samples were investigated by XRD, SEM, TEM, PL, and UV-visible absorption spectroscopy. A liquid phase deposition method and an impregnation-gas phase deposition method were adopted for the loading of CdS onto SiO2-HNb3O8. All the composite materials show improved photocatalytic activities than the component materials for rhodamine B photodegradation under visible light. With better CdS dispersion and expanded interlayer distance of HNb3O8, the CdS/SiO2-HNb3O8 sample prepared by the novel impregnation-gas phase deposition method showed better activity than the counterpart prepared by conventional liquid phase deposition, CdS-pillared HNb3O8, and some reference samples such as P25, nitrogen-doped TiO2, and Bi2WO6. The enhanced photocatalytic activity of the CdS/SiO2-HNb3O8 composite is ascribed to the interface charge transfer between the two component materials, as well as the layered structure and the intercalation properties of SiO2-HNb3O8. PMID- 23746681 TI - Thermosensitive hybrid hydrogels with silica nanoparticle-cross-linked polymer networks. AB - A simple methodology for the preparation of thermosensitive organic-inorganic hybrid hydrogels using silica nanoparticle-mediated polymer networks is described. A thermosensitive copolymer poly[N-isopropylacrylamide-co-(3 methacryloxypropyltrimethoxysilane)], (pNS), with reactive side chains (Si-O-CH3) was first synthesized by free radical polymerization using N-isopropylacrylamide (NIPAAm) and 3-methacryloxypropyltrimethoxysilane (MAPTS). Then, simple mixing of the aqueous solution of this copolymer with silica nanoparticle (SiP) suspensions at room temperature led to the formation of thermosensitive hybrid hydrogels cross-linked with silica nanoparticles (SiP) which did not require any other processing like washing for the removal of unreacted monomers and initiators. The effects of SiP content on gelation abilities, temperature-responsive behaviors, swelling and deswelling kinetics, and mechanical properties of the hydrogels were investigated. The results showed that transparent hybrid hydrogels with adjustable network structures were obtained within a few minutes to a couple of hours depending on the concentration of the copolymers and the silica nanoparticles. The hybrid hydrogels exhibited a lower critical solution temperature (LCST) of around 33 degrees C with no significant deviation from conventional poly(N-isopropylacrylamide) hydrogels; the LCST was not significantly affected by the concentration of silica nanoparticles (which in these systems serve as the cross-linkers). In addition, the hydrogels showed significantly large equilibrium swelling ratios, improved mechanical strength, and suitable deswelling behavior, which can easily be tuned by varying the composition of the hybrid hydrogels. PMID- 23746682 TI - Electrorheological and dielectric behavior of new ionic liquid/silica systems. AB - New phosphonium-based ionic liquids, denoted, 11 carboxyundecyltriphenylphosphonium bromide (IL1) and octadecyltriphenylphosphonium iodide (IL2), were employed on the sol-gel synthesis to prepare new silica-based matrices. The fastest gelation during the sol-gel process was observed in hydrolysis/condensation of tetraethoxysilane in the presence of IL1. The confinement of ionic liquids (especially IL1) inside the silica networks was suggested by thermogravimetric analysis and Fourier transform infrared spectroscopy. The resulting ionogels present higher permittivity than pure silica and were used as the solid component for the development of new electrorheological fluids, presenting good ER behavior, mainly those prepared with IL1. PMID- 23746683 TI - Disassembly of redox responsive poly(ferrocenylsilane) multilayers: the effect of blocking layers, supporting electrolyte and polyion molar mass. AB - Layer by layer (LbL) organometallic multilayers, composed of poly(ferrocenylsilane) (PFS) polycations and polyanions, were fabricated and characterized. Disassembly of redox responsive PFS(-)/PFS(+) films as well as multilayers consisting of PFS(-)/PFS(+) combined with redox inert bilayers was studied. The influence of parameters on disassembly kinetics and mechanism, such as distance between redox PFS multilayers and the electrode, effect of the top inert layer, the choice of the supporting electrolyte, the ionic strength of the solution, and the molar mass of polymers, was investigated. The results elucidate the details of the disassembly mechanism and provide design criteria for preparing templates with highly controllable disassembly kinetics. PMID- 23746684 TI - Micelle growth of cationic gemini surfactants studied by NMR and by time-resolved fluorescence quenching. AB - The micelle growth of a series of five cationic gemini surfactants has been investigated by time-resolved fluorescence quenching (TRFQ) and by two NMR techniques, line width analysis and diffusometry. The surfactant series was designed such that the effect of a number of variables could be assessed: length of the spacer unit, presence of ester bonds in the tails close to the head groups, and presence of a hydroxyl group in the spacer. For the gemini with long spacer, the micelles remained relatively small in size upon an increase of the concentration. The gemini surfactants with short spacer, on the other hand, showed a considerable micellar growth as the concentration was raised. It is of particular interest that the relatively simple line width analysis of one dimensional (1)H NMR spectra gave qualitatively the same results as the more sophisticated TRFQ and NMR diffusometry techniques. PMID- 23746685 TI - [Effect of coronary risk and of hypertension on renal risk in the general population]. AB - INTRODUCTION: Abnormal albuminuria (>= 30 mg/g) and low estimated glomerular filtration rate (eGFR<60 mL/min/1.73 m(2)) not only are renal risk factors, but also cardiovascular and coronarian risk factors. Though, the relation between coronary risk and renal risk, and its interaction with insufficiently controlled brachial pressure (BP) is poorly described in the literature. SUBJECTS AND METHODS: We realised a cross-sectional study on subjects 40 and older, having attended a medical exam in 11 IRSA centers between 2006 and 2010. Every subject filled a questionnaire, underwent biological analysis, and a clinical examination. eGFR and albuminuria were measured, and the 10-year risk of coronarian event was calculated (Laurier's equation) RESULTS: We analysed 118,314 subjects, amongst whom 96,400 had no personal cardiovascular history. Amongst those, 9.1% had a 10-year coronary risk over 10%. There was a continuous relationship between coronary risk and renal risk: subjects with a risk above 15% had a significative risk of pathological albuminuria (OR: 6.87 [5.58-8.44]), and of low eGFR (2.26 [1.82-2.78]) compared to those with a risk under 5%. There was a continuous relationship between BP and renal risk, with a significative risk of pathological albuminuria (OR=7.75 [6.69-8.96]) and of low eGFR (OR: 1.33 [1.09 1.60]) in subjects with BP greater than or equal to 180/110 mmHg, compared to those with normal BP. CONCLUSION: In the French population, 9.1% of subjects have a 10-year coronary risk above 10%. This risk is associated to abnormalities of the renal function. The relation between coronary risk and renal risk is continuous and dose-dependent, as is the relation between BP and renal risk. PMID- 23746686 TI - [Unilateral renal denervation and the renal kallikrein-bradykinin system in the rat]. AB - AIM: The antihypertensive effect of renal denervation in hypertensive patients is partially explained by increased tubular natriuresis. To study the possible contribution of the kallikrein-kinin system (KKS) to this natriuretic effect in rats, we measured kallikrein activity (KA) and bradykinin concentrations (BK) in plasma and tissues. METHODS: To measure KA, we adapted and validated an enzymatic assay that cleaves para-nitroaniline (pNA) from the tripeptide H-D-Pro-Phe-Arg pNA. The coefficients of variation (CV) within- and between-assays were less than 8% for plasma and tissue KA (plasma n=6 and 13; tissue n=4). Linear results for serially diluted samples confirmed the assay specificity. Tissue BK determinations were based on an established assay for plasma BK: tissue was homogenized and kinins extracted in ethanol, and BK was isolated by high performance (HPLC) liquid chromatography and quantitated by radioimmunassay. Within- and between-assay CV for plasma BK were 18% (n=8 and n=35, respectively) and for BK in various tissues less than 16% (n=5-8). RESULTS: In male Wistar rats (n=3), plasma BK was 8.2 +/- 6.6 fmol/mL (mean +/- SD), and tissue BK (fmol/g) in 14 tested organs varied between brain (14 +/- 3) and submaxillary gland (521 +/- 315). Six days after left-sided unilateral renal denervation, left renal tissue BK (89 +/- 9) was not different from right renal BK (75 +/- 23). Similarly, KA was comparable in the two kidneys (left 18.0 +/- 1.5, right 15.8 +/- 1.4 MUkat/g). CONCLUSION: Any possible effect of unilateral renal denervation on the kidney's KKS would have to be bilateral. PMID- 23746687 TI - [Television viewing and cardiovascular risk behaviors in the adult population of the French West Indies]. AB - OBJECTIVE: Recent studies have shown a link between prolonged television viewing and cardiovascular (CV) morbidity and mortality. We aimed to estimate the relationship between television viewing and CV risk behaviors and in the adult population of the French West Indies. PATIENTS AND METHODS: We used data from Consant, a cross-sectional study carried out in 2007 on a representative sample of the adult Guadeloupean population (1005 subjects aged 25-74 years selected by stratified random sampling and interviewed at home by trained investigators working in pairs). RESULTS: Among respondents who reported watching television for 2 hours or more per day, 46.5% stated practicing no leisure time physical activity, compared with 35.6% among those who reported watching television for less than 2 hours per day. Adjusting for age, sex, education, income, family status, and perceived CV benefits of physical activity, the odds ratio of physical inactivity was estimated at 1.75 (P<10(-3)) among subjects who reported watching television for 2 hours or more per day, compared with other subjects. A similar relationship was observed when considering dieting to prevent weight gain. CONCLUSION: In this representative sample of a French Caribbean population, a strong and very significant relationship was observed between prolonged television viewing and CV risk behaviors. Prolonged television viewing seems common to a lifestyle that is characterized by little physical activity and unhealthy eating habits. This may play a role in social inequalities observed in CV diseases. PMID- 23746688 TI - Impact of iodine delivery rate with varying flow rates on image quality in dual energy CT of patients with suspected pulmonary embolism. AB - RATIONALE AND OBJECTIVES: To prospectively compare four contrast material injection protocols for dual-energy computed tomography (CT) pulmonary angiography (DE-CTPA) in patients with suspected pulmonary embolism (PE). MATERIALS AND METHODS: One hundred twenty consecutive patients were randomized to contrast material injection protocols defined by different iodine concentrations and iodine delivery rates (IDRs): (A) 80 mL iopromide 370/4 mL/sec = IDR 1.4 gI/sec; (B) 80 mL iopromide 370 at 3 mL/sec = IDR 1.1 gI/sec; (C) 98 mL iopromide 300 at 4.9 mL/sec = IDR 1.4 gI/sec; and (D) 98 mL iopromide 300 at 3.7 mL/sec = IDR 1.1 gI/sec. Attenuation values were measured in the inflow tract (subclavian vein-superior vena cava-right atrium), target tract (right ventricle-pulmonary trunk-pulmonary arteries), and outflow tract (left atrium-left ventricle ascending aorta). Two readers assessed subjective image quality of CTPA images and iodine perfusion maps. The number of artifacts due to hyperdense contrast material on iodine perfusion maps was recorded. RESULTS: Target tract attenuation was highest for protocol A with 374 +/- 98 Hounsfield units (HU) (highly concentrated contrast material/high IDR). This was significant compared to protocols B and D (P = .0118, P = .0427) but not compared to protocol C (P = .3395). No significant difference in target tract attenuation was found between protocols B (309 +/- 80 HU), protocol C (352 +/- 119 HU), and D (325 +/- 74 HU). CTPA and iodine perfusion map image quality for protocol A was rated significantly higher compared to all other protocols (median score = 5/4; P < .0001 for both) with moderate interreader agreement (kappa = 0.58/0.47). Protocols A and B displayed increased artifacts on iodine perfusion maps compared to protocols C and D (3 versus 2). CONCLUSION: Despite increased artifacts on iodine perfusion maps, highly concentrated iodinated contrast material combined with high flow rates provides improved diagnostic image quality and has the highest target-tract attenuation for DE-CTPA protocols. PMID- 23746689 TI - Theoretical image performance with customized aspheric and spherical IOLs - when do we get a benefit from customized aspheric design? AB - BACKGROUND & PURPOSE: Implantation of an artificial intraocular lens (IOL) during cataract surgery significantly changes the balance of aberrations in the eye. We demonstrate the theoretical superiority of customized aspheric IOL designs over standard spherical IOLs for different values of corneal curvature, asphericity and axial length. METHODS: For a selected set of corneal surfaces we calculated a best-fit equiconvex spherical IOL. In a second step we customized the IOL back surface to correct the wavefront aberrations of the cornea. Then we calculated a quadric approximation of the IOL back surface to retrieve the aspheric parameters of the customized lens in terms of radius of curvature and asphericity/conic constant. The optical performance of the three IOL models was monitored in terms of lateral ray spread (LRS) at retinal plane for variations of corneal curvatures, asphericity and axial lengths of the pseudophakic eye. RESULTS: The LRS of customized aspheric IOLs was significantly smaller compared to that of spherical IOLs (typically between 10 and 25 dB). For high aspheric coefficients the LRS increased with spherical IOLs. With aspheric IOLs LRS was higher for steep corneas paired with high aspheric coefficients, mostly due to the fitting error of the quadratic function. For several combinations of corneal curvature and aspheric coefficients the focal point of the aspheric IOL was up to 400 times smaller than the spherical one. CONCLUSION: This study appeals to the reader for the potential benefit of customized aspheric IOL design instead of the principle of a 'one size fits all' aspheric coefficient as used currently in clinical practice. A benefit with customized IOLs is less depending from the axial length and can be achieved with corneas of a moderate prolate aspheric shape with an equal or more negative Q value than the average of -0.22. Longer eyes seem to benefit less than short eyes. PMID- 23746691 TI - AY9944 A-7 promotes meiotic resumption and preimplantation development of prepubertal sheep oocytes maturing in vitro. AB - Follicular fluid meiosis-activating sterol (FF-MAS), an intermediate in the cholesterol biosynthetic pathway, has been identified as a compound that induces the resumption of meiosis in mammalian oocyte. FF-MAS is converted to testis meiosis-activating sterol by a sterol Delta14-reductase. An inhibitor of Delta14 reductase and Delta7-reductase, AY9944 A-7, causes accumulation of FF-MAS by inhibiting its metabolism. The objective of this study was to determine the effects of AY9944 A-7 supplementation to oocyte maturation media on prepubertal sheep oocyte meiotic resumption and subsequent preimplantation development of embryos. Prepubertal sheep oocytes isolated at the germinal vesicle stage from their follicles were cultured with 0, 10, 20, 30, and 40 MUM AY9944 A-7 for 24 hours in media with or without a meiotic inhibitor hypoxanthine (Hx, 4 mM). The resumption of meiosis was assessed by the frequency of germinal vesicle breakdown and the first polar body (PBI) extrusion. After maturation for 24 hours, oocytes with PBI were inseminated in vitro, and the percentages developing to the two cell stage and blastocyst stage were measured as indicators of early embryonic developmental competence. AY9944 A-7 induced maturation of sheep cumulus-oocyte complexes with optimal concentrations of 10 and 20 MUM both in Hx-inhibited meiotic maturation and spontaneous maturation, whereas AY9944 A-7 with any concentrations had no significant effect on that of denuded oocytes and split cumulus-oocyte complexes. Furthermore, maturing oocytes treated with either 10 or 20 MUM AY9944 A-7 dramatically increased the percentages of ovine embryos developing to the two-cell stage and blastocyst stage. Higher concentrations of AY9944 A-7, 30 and 40 MUM, were detrimental to oocytes and led to their degeneration. The present findings indicated for the first time that AY9944 A-7 was not only able to promote meiotic maturation, both Hx-inhibited and spontaneous, but also enhanced preimplantation developmental competence of prepubertal sheep oocytes maturing in vitro. PMID- 23746692 TI - Cryosurvival and pregnancy rates after exposure of IVF-derived Bos indicus embryos to forskolin before vitrification. AB - In vitro-produced (IVP) bovine embryos are more sensitive to cryopreservation than their in vivo counterparts due to their higher lipid concentrations, whereas Bos indicus IVP embryos are even more sensitive than Bos taurus IVP embryos. To examine the effects of a lipolytic agent, before vitrification of Bos indicus IVP embryos, on embryo survival, viability, and pregnancy rates, two experiments were conducted. In experiment 1, Bos indicus (Nelore) embryos were produced from abattoir-derived ovaries and allocated into two groups. In the treatment group, 10 MUM of forskolin was added to the in vitro culture medium on Day 5 and incubated for 48 hours. On Day 7 of culture, IVP-expanded blastocysts from both the control (n = 101) and treatment (n = 112) groups were vitrified with ethylene glycol and DMSO via the Cryotop procedure. Although there was no significant difference between the rates of blastocoel reexpansion and hatching of the embryos exposed to forskolin (87.5% and 70.5%, respectively) compared with the control embryos (79.2% and 63.3%, respectively), the numerically superior rates of the embryos exposed to forskolin led to another experiment. In experiment 2, blastocysts produced from the ovum pick up were exposed or not exposed to the lipolytic agent and vitrified as in experiment 1. Embryos treated with forskolin had higher pregnancy rates than the control group (48.8% vs. 18.5%). In view of these results, 1908 Bos indicus embryos were produced from ovum pick up, exposed to the lipolytic agent, and blastocysts were transferred to recipients, and the pregnancy rates of the embryos of various breeds were compared. The mean pregnancy rate obtained was 43.2%. All data were analyzed by chi-square or by binary logistic regression (P <= 0.05). In conclusion, treatment with forskolin before vitrification improved cryotolerance of Bos indicus IVP embryos, resulting in good post-transfer pregnancy rates. PMID- 23746694 TI - Efficacy of transvaginal ultrasound-guided twin reduction in the mare by embryonic or fetal stabbing compared with yolk sac or allantoic fluid aspiration. AB - Transvaginal ultrasound-guided pregnancy reduction (TUGR) is a procedure described for the management of twins post-fixation in the horse. Success rates are often disappointing but are reported to be more favorable for bilaterally situated twins and when intervention takes place before day 35 of gestation. This study aimed to determine whether stabbing the embryo/fetus rather than aspirating conceptus fluids improved the likelihood of success, measured as the birth of a normal live singleton foal. Data from 103 TUGR interventions were analyzed by logistic regression analysis; method of treatment, relative conceptus location (i.e., uni- vs. bilateral), and stage of gestation were included as interdependent factors that potentially influence the outcome. Overall, 34/103 (33%) TUGR interventions resulted in a single live foal. There was no significant difference (P = 0.14) in the outcome between TUGR based on fetal stabbing (12/28: 42.9%) versus fluid aspiration (22/75: 29.3%). There was also no significant influence (P = 0.11) of the conceptuses being located unilaterally (19/65: 29.2%) versus bilaterally (15/38: 39.5%). However, TUGR was numerically more successful (P = 0.05) when performed <= Day 35 of gestation (21/53: 39.6%), as opposed to > Day 35 (13/50: 26%). Day 45 may represent an even more critical time point because only 2 out of 15 TUGRs (13.3%) performed beyond this day resulted in the birth of a live foal, compared with 11/35 (31.4%) performed between Days 36 and 45. Although the numbers are low, this suggests that TUGR is not the method of choice for reducing > Day 45 twins. Four pregnancy losses were recorded 1 to 7 months post-TUGR (4/38: 10.5%), and although it is tempting to attribute the losses to TUGR, this rate of late gestation pregnancy loss is normal. We conclude that TUGR by fetal stabbing does not offer significant advantages over fluid aspiration. However, TUGR should be performed before Day 35 of gestation and is considered primarily a salvage procedure to be used when re-breeding is not a viable alternative. PMID- 23746695 TI - Interaction of EGFR with the tumour microenvironment: implications for radiation treatment. AB - Treatment failure through radioresistance of tumours is associated with activation of the epidermal growth factor receptor (EGFR). Tumour cell proliferation, DNA-repair, hypoxia and metastases-formation are four mechanisms in which EGFR signalling has an important role. In clinical trials, a correlation has been demonstrated between high EGFR expression in tumours and poor outcome after radiotherapy. Inhibition of EGFR signalling pathways improves the effectiveness of radiotherapy of head and neck cancers by overcoming these main mechanisms of radioresistance. The fact that only a minority of the patients respond to EGFR inhibitors reflects the complexity of interactions between EGFR dependent signalling pathways and the tumour microenvironment. Furthermore, many components of the microenvironment are potential targets for therapeutic interventions. Characterisation of the interaction of EGFR signalling and the tumour microenvironment is therefore necessary to improve the effectiveness of combined modality treatment with radiotherapy and targeted agents. Here, the current status of knowledge is reviewed and directions for future research are discussed. PMID- 23746693 TI - Efficiency of ciprofloxacin for bacterial control, post-thaw quality, and in vivo fertility of buffalo spermatozoa. AB - Ciprofloxacin (CP) was evaluated for bacterial control, post-thaw quality, and fertility of buffalo semen. Pseudomonas aeruginosa, Escherichia coli, Proteus sp., Corynebacterium sp., Micrococcus sp., and Staphylococcus sp. were isolated from buffalo semen. Pseudomonas aeruginosa, Corynebacterium sp., and Micrococcus sp. were resistant to streptomycin, whereas P. aeruginosa and Proteus sp. were resistant to penicillin. All bacteria were susceptible to CP. In vitro dose toxicity was assessed in sodium citrate buffer containing 0, 200 to 2000 MUg/mL of CP. CP up to 1000 MUg/mL was found nontoxic to motility and viability of buffalo sperm. For post-thaw quality, buffalo semen was frozen in Tris-citric acid extender containing streptomycin-penicillin (SP; 1000 MUg/mL-1000 IU/mL) or CP 600 MUg/mL and was assessed for total aerobic bacterial count (post-thaw), motility, plasma membrane integrity, viability at 0, 2, and 4 hours post-thaw. At 4 hours post-thaw, plasma membrane integrity (%) was higher (P < 0.05) in extender containing CP than SP. Total aerobic bacterial count was 0.00 in extender containing CP compared with 0.07 * 10(4) cfu/mL with SP. To assess the in vivo fertility rate, semen (two bulls) frozen in Tris-citric acid extender containing SP or CP was used to inseminate, and 400 inseminations (200/group) were recorded. Higher (P <= 0.05) fertility rate was recorded with CP (55%) compared with SP (41%). In conclusion, use of CP in extender was efficient to control the bacterial contamination without compromising the post-thaw quality and fertility of cryopreserved water buffalo bull semen. PMID- 23746696 TI - Homologous recombination mediates cellular resistance and fraction size sensitivity to radiation therapy. AB - PURPOSE: Cellular sensitivity to radiotherapy total dose and fraction size is strongly influenced by DNA double strand break (DSB) repair. Here, we investigate response to radiotherapy fraction size using CHO cell lines deficient in specific DNA repair pathways in response to radiation induced DNA double strand breaks (DSB). EXPERIMENTAL DESIGN: We irradiated CHO cell lines, AA8 (WT), irs1SF (XRCC3 ), V3-3 (DNA-PKcs-) and EM9 (XRCC1-) with 16 Gy in 1 Gy daily fractions over 3 weeks or 16 Gy in 4 Gy daily fractions over 4 days, and studied clonogenic survival, DNA DSB repair kinetics (RAD51 and 53BP1 foci staining) and cell cycle profiles (flow cytometry). RESULTS: In response to fractionated radiotherapy, wild-type and DNA repair defective cells accumulated in late S/G2 phase. In cells proficient in homologous recombination (HR), accumulation in S/G2 resulted in reduced sensitivity to fraction size and increased cellular resistance (clonogenic survival). Sensitivity to fraction size was also lost in NHEJ defective V3-3 cells, which likely rely on functional HR. By contrast, HR defective irs1SF cells, with functional NHEJ, remained equally sensitive to fractionation throughout the 3-week treatment. CONCLUSIONS: The high fidelity of HR, which is independent of induced DNA damage level, is postulated to explain the low fractionation sensitivity and cellular resistance of cells in S/G2 phase. In conclusion, our results suggest that HR mediates resistance to fractionated radiotherapy, an observation that may help future efforts to improve radiotherapy outcome. PMID- 23746697 TI - Chronic adipose tissue inflammation: all immune cells on the stage. AB - Inflammation is indispensable for host homeostasis against invading pathogens and efficient wound healing upon tissue malfunction and has to be tightly controlled by various mechanisms to limit excess responses harmful to host tissues. A myriad of disease conditions ranging from type 2 diabetes (T2D) to neurodegenerative and cardiovascular disorders are now shown to progress due to persistent, unresolved inflammation in metabolic tissues such as adipose, liver, pancreas, muscle, and brain. However, their underlying mechanisms are incompletely understood. The actions of innate and adaptive immune cells in these ailments are increasingly appreciated so much so that a new research area called 'immunometabolism' has emerged. In this review, we will highlight the fundamental roles of various immune cells in adipose tissue during the initiation and progression of obesity induced inflammation and discuss potential anti-inflammatory therapies from different mechanistic points of view. PMID- 23746698 TI - Air-particle abrasion on zirconia ceramic using different protocols: effects on biaxial flexural strength after cyclic loading, phase transformation and surface topography. AB - This study evaluated the effect of different air-particle abrasion protocols on the biaxial flexural strength and structural stability of zirconia ceramics. Zirconia ceramic specimens (ISO 6872) (Lava, 3M ESPE) were obtained (N=336). The specimens (N=118, n=20 per group) were randomly assigned to one of the air abrasion protocols: Gr1: Control (as-sintered); Gr2: 50 um Al2O3 (2.5 bar); Gr3: 50 um Al2O3 (3.5 bar); Gr4: 110 um Al2O3(2.5 bar); Gr5: 110 um Al2O3 (3.5 bar); Gr6: 30 um SiO2 (2.5 bar) (CoJet); Gr7: 30 um SiO2(3.5 bar); Gr8: 110 um SiO2 (2.5 bar) (Rocatec Plus); and Gr9: 110 um SiO2 (3.5 bar) (duration: 20 s, distance: 10 mm). While half of the specimens were tested immediately, the other half was subjected to cyclic loading in water (100,000 cycles; 50 N, 4 Hz, 37 degrees degrees C) prior to biaxial flexural strength test (ISO 6872). Phase transformation (t->m), relative amount of transformed monoclinic zirconia (FM), transformed zone depth (TZD) and surface roughness were measured. Particle type (p=0.2746), pressure (p=0.5084) and cyclic loading (p=0.1610) did not influence the flexural strength. Except for the air-abraded group with 110 um Al2O3 at 3.5 bar, all air-abrasion protocols increased the biaxial flexural strength (MPa) (Controlnon-aged: 1,030 +/- 153, Controlaged: 1,138 +/- 138; Experimentalnon aged: 1,307 +/- 184-1,554 +/- 124; Experimentalaged: 1,308 +/- 118-1,451 +/- 135) in both non-aged and aged conditions, respectively. Surface roughness (Ra) was the highest with 110 um Al2O3(0.84 um. FM values ranged from 0% to 27.21%, higher value for the Rocatec Plus (110 um SiO2) and 110 um Al2O3 groups at 3.5 bar pressure. TZD ranged between 0 and 1.43 um, with the highest values for Rocatec Plus and 110 um Al2O3 groups at 3.5 bar pressure. PMID- 23746699 TI - Shock absorbing ability of articular cartilage and subchondral bone under impact compression. AB - Despite the important role of subchondral bone in maintaining the integrity of the overlying articular cartilage, little research has focused on measuring its mechanical behavior, particularly under injurious load conditions such as impact compression. In this study, the stiffness and the absorbed energy of subchondral bone were compared to that of its overlying cartilage by applying impact compression to equine cartilage-bone specimens. Deformations of the cartilage and subchondral bone were examined independently within the cartilage-bone unit by analyzing real-time images of cartilage-bone explants. Peak subchondral bone and cartilage stiffness (mean +/- SD) were 800.7 +/- 250.0 MPa and 119.9 +/- 50.8 MPa respectively. The maximum absorbed energy per unit volume of subchondral bone was approximately 4 times lower than that of cartilage. Micro-computed tomography (MUCT) images at 9 MUm resolution revealed oblique fissures at the cartilage articular surface. At the cartilage-bone interface, micro-cracks as thin as 30 MUm in width and micro-fractures of width 200 MUm could be seen in the MUCT images. The relative energy loss in bone was 76.5 +/- 6.8% in specimens with bone fracture and 23.0 +/- 20.4% in specimens without bone fracture. Our results indicate that both articular cartilage and subchondral bone absorb shock under impact compression, but the energy absorption of bone is much higher in specimens that fracture. This may spare the overlying cartilage from immediate injury, but is a potential risk for subsequent post-traumatic osteoarthritis (PTOA). PMID- 23746700 TI - Finite Element simulation of buckling-induced vein tortuosity and influence of the wall constitutive properties. AB - The mechanisms giving rise to vein tortuosity, which is often associated with varicosis, are poorly understood. Recent works suggest that significant biological changes in the wall of varicose veins may precede the mechanical aspects of the disease. To test the hypothesis of tortuosity being a consequence of these changes, a Finite Element model was developed based on previous experimental work on vein buckling. The model was then used to evaluate the effect of alterations of the mechanical behavior of the wall on tortuosity onset and severity. The results showed that increasing anisotropy toward the circumferential direction promotes tortuosity. An increase in wall stiffness tends to decrease the level of tortuosity but interestingly, if the vein segment is little or not pre-stretched such increase will not prevent, or it will even promote, the onset of tortuosity. These results provide additional arguments supporting the hypothesis of tortuosity being the consequence of biologically induced changes in the varicose vein wall. Based on a 3D model of the leg and in vivo identification of the material properties of varicose veins, a clinical validation of these findings is being developed. PMID- 23746701 TI - [To be or not to be. Reflections of a tutor]. PMID- 23746702 TI - [Anaemia as a cause of haemodynamic angina in a patient with chronic ischaemic heart disease]. AB - Ischaemic heart disease is the leading cause of mortality and morbidity and one of the primary causes of morbidity in Spain. The variability in the clinical presentation of this condition at both primary care and emergency services level requires a careful history and a thorough physical examination. In the case presented, the main symptoms of angina and dyspnea reported in the anamnesis, and the obvious pallor in the physical examination, were the key data to identify anaemia as a cause of angina. PMID- 23746703 TI - [Acral acanthosis nigricans associated with taking growth hormone]. AB - Acanthosis nigricans is a skin lesion characterized by the presence of a hyperpigmented, velvety cutaneous thickening that usually appears in flexural areas. Less frequently, it can occur in other locations, such as the dorsum of hands and feet. In this case it is called acral acanthosis nigricans. It is a dermatological manifestation of systemic disease. It is often associated with insulin resistance-mediated endocrine diseases. A case is presented on a patient with acanthosis nigricans secondary to the use of growth hormone. PMID- 23746704 TI - [Sharing experiences: rotation in primary care in Posadas, Argentina]. AB - Primary care should be the cornerstone of any health system. It is the first contact with the community health system of any country. The Declaration of Alma Ata, 1978, seeks to provide the basis for the construction of a new health system that will allow the full exercise of the right to health. Carrying out an external rotation in Primary Care in Posadas, Misiones Province, Argentina, during medical training, in family medicine, offers an insight into how other health systems work, provide health care to the community in a Primary Care Center in a country with its similarities and differences like ours, follow the implementation of programs, working with family medicine residents in another country, and living a rewarding personal and professional experience. PMID- 23746705 TI - [Enalapril and inappropriate antidiuretic hormone secretion]. PMID- 23746706 TI - [Candidaemia by Candida glabrata in a young patient with no previous symptoms]. PMID- 23746707 TI - [Massive alveolar haemorrhage in Wegener's granulomatosis]. AB - Wegener's granulomatosis is a systemic vasculitis with involvement of primary granulomatous upper and lower respiratory tract, glomerulonephritis and vasculitis of small vessels. The lung disease ranges from asymptomatic pulmonary nodules to pulmonary infiltrates and fulminant alveolar haemorrhage. The prognosis is poor due to kidney and respiratory failure, although the data are changing due to new treatments with glucocorticoids and cyclophosphamide. We report a case with severe lung disease, which after appropriate anamnesis, multiple tests, and optimal sequential action, the patient was diagnosed with Wegener's granulomatosis. This disease has a low incidence in the Emergency Department, where the patient history supported by the appropriate additional provides a diagnostic suspicion. It is important that the Emergency Department has the skills to manage the stability in these patients in order to resolve their symptoms. PMID- 23746708 TI - Neutron spectra at two beam ports of a TRIGA Mark III reactor loaded with HEU fuel. AB - The neutron spectra have been measured in two beam ports, one radial and another tangential, of the TRIGA Mark III nuclear reactor from the National Institute of Nuclear Research in Mexico. Measurements were carried out with the reactor core loaded with high enriched uranium fuel. Two reactor powers, 5 and 10 W, were used during neutron spectra measurements using a Bonner sphere spectrometer with a (6)LiI(Eu) scintillator and 2, 3, 5, 8, 10 and 12 in.-diameter high-density polyethylene spheres. The neutron spectra were unfolded using the NSDUAZ unfolding code. For each spectrum total flux, mean energy and ambient dose equivalent were determined. Measured spectra show fission, epithermal and thermal neutrons, being harder in the radial beam port. PMID- 23746709 TI - Dispersion of Fukushima radionuclides in the global atmosphere and the ocean. AB - Large quantities of radionuclides were released in March-April 2011 during the accident of the Fukushima Dai-ichi Nuclear Power Plant to the atmosphere and the ocean. Atmospheric and marine modeling has been carried out to predict the dispersion of radionuclides worldwide, to compare the predicted and measured radionuclide concentrations, and to assess the impact of the accident on the environment. Atmospheric Lagrangian dispersion modeling was used to simulate the dispersion of (137)Cs over America and Europe. Global ocean circulation model was applied to predict the dispersion of (137)Cs in the Pacific Ocean. The measured and simulated (137)Cs concentrations in atmospheric aerosols and in seawater are compared with global fallout and the Chernobyl accident, which represent the main sources of the pre-Fukushima radionuclide background in the environment. The radionuclide concentrations in the atmosphere have been negligible when compared with the Chernobyl levels. The maximum (137)Cs concentration in surface waters of the open Pacific Ocean will be around 20 Bq/m(3). The plume will reach the US coast 4-5 y after the accident, however, the levels will be below 3 Bq/m(3). All the North Pacific Ocean will be labeled with Fukushima (137)Cs 10 y after the accident with concentration bellow 1 Bq/m(3). PMID- 23746710 TI - Clinical features of pure obsessive-compulsive disorder. AB - OBJECTIVE: Psychiatric comorbidity is the rule in obsessive-compulsive disorder (OCD); however, very few studies have evaluated the clinical characteristics of patients with no co-occurring disorders (non-comorbid or "pure" OCD). The aim of this study was to estimate the prevalence of pure cases in a large multicenter sample of OCD patients and compare the sociodemographic and clinical characteristics of individuals with and without any lifetime axis I comorbidity. METHOD: A cross-sectional study with 955 adult patients of the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders (C-TOC). Assessment instruments included the Yale-Brown Obsessive-Compulsive Scale, the Dimensional Yale-Brown Obsessive-Compulsive Scale, The USP-Sensory Phenomena Scale and the Brown Assessment of Beliefs Scale. Comorbidities were evaluated using the Structured Clinical Interview for DSM-IV Axis I Disorders. Bivariate analyses were followed by logistic regression. RESULTS: Only 74 patients (7.7%) presented pure OCD. Compared with those presenting at least one lifetime comorbidity (881, 92.3%), non-comorbid patients were more likely to be female and to be working, reported less traumatic experiences and presented lower scores in the Y-BOCS obsession subscale and in total DY-BOCS scores. All symptom dimensions except contamination-cleaning and hoarding were less severe in non-comorbid patients. They also presented less severe depression and anxiety, lower suicidality and less previous treatments. In the logistic regression, the following variables predicted pure OCD: sex, severity of depressive and anxious symptoms, previous suicidal thoughts and psychotherapy. CONCLUSIONS: Pure OCD patients were the minority in this large sample and were characterized by female sex, less severe depressive and anxious symptoms, less suicidal thoughts and less use of psychotherapy as a treatment modality. The implications of these findings for clinical practice are discussed. PMID- 23746711 TI - Impulsivity in patients with panic disorder-agoraphobia: the role of cyclothymia. AB - The relationship between Panic Disorder (PD) and impulsivity is not well explored. The present investigation aims to compare impulsivity, measured by different rating tools, in PD patients vs. healthy controls and to explore the influence of co-morbid Cyclothymic Disorder (CD) on the relationship between PD and impulsivity. Sixty-four subjects with PD and 44 matched controls underwent a diagnostic and symptomatological evaluations by the Mini Neuropsychiatric Interview (M.I.N.I) Plus 5.0; the Bech-Rafaelsen Depression and Mania Scale (BRDMS), the State-Trait Anxiety Inventory (STAI), the Hypomania Check List (HCL 32) and the Clinical Global Impression (CGI); the Questionnaire for the Affective and Anxious Temperament Evaluation of Memphis, Pisa, Paris and San Diego-Modified (TEMPS-M), the Separation Anxiety Sensitivity Index (SASI), the Interpersonal Sensitivity Symptoms Inventory (ISSI). Finally, psychometric and neurocognitive evaluations of impulsivity was carried out using the Barratt Impulsiveness Scale (BIS-11) and the Immediate and Delayed Memory Task (IMT/DMT). Subjects with PD were more impulsive than the controls in all the explored measures, reporting higher scores in symptomatological and temperamental scales. The comparison between PD patients with (Cyclo+) and without (Cyclo-) comorbid CD and controls showed that Cyclo+ are the most impulsive subjects in all the investigated measures and are characterized by the greatest symptomatological impairment, the highest scores in temperamental scales, and the highest levels of interpersonal sensitivity and separation anxiety. In our patients with PD, without lifetime comorbidity with major mood episodes, trait and state impulsivity may be related to the presence of comorbid cyclothymic mood instability. PMID- 23746712 TI - Editorial comment. PMID- 23746713 TI - Validating a claims-based method for assessing severe rectal and urinary adverse effects of radiotherapy. AB - OBJECTIVE: To validate a claims-based algorithm for detecting severe rectal and urinary adverse effects (AEs) of radiotherapy (RT) to inform the design and interpretation of outcomes studies, using administrative datasets to detect such RT AEs. METHODS: An institutional billing analysis was performed to identify patients managed with RT for prostate or cervical cancer at the University of Minnesota, between 2000 and 2006. A priori, we identified Current Procedural Terminology procedural codes consistent with treatment for severe RT AEs. A retrospective chart review and a billing (ie "claims") analysis were performed to detect the procedures used to treat RT AEs. The accuracy of the claims-based algorithm was compared with chart review (the reference standard). RESULTS: On chart review, 31 patients (7.6%) with severe rectal and urinary RT AEs were detected among 406 patients with nonmetastatic cancer at diagnosis. The most common AE was ureteral stenosis (25% of all AEs). The sensitivity and specificity of the claims-based analysis were 75% and 100% respectively for urethral stricture, 100% and 99% respectively for ureteral stricture, 60% and 100% respectively for radiation cystitis, 88% and 100% respectively for rectal or urinary fistula, and 88% and 100% respectively for radiation proctitis. CONCLUSION: We demonstrated an excellent specificity and yet fairly good sensitivity of our claims-based algorithm for detecting treatment of urethral stricture, rectal or urinary fistulas, radiation proctitis, and ureteral stricture. These data might inform the design and interpretation of studies using claims-based methods for the detection of severe urinary AEs of pelvic RT. PMID- 23746715 TI - ERG protein expression and gene rearrangements are present at lower rates in metastatic and locally advanced castration-resistant prostate cancer compared to localized disease. AB - OBJECTIVE: To compare ERG expression and gene rearrangements rates in metastatic and castration-resistant prostate cancer (CRPC) to localized disease as ERG is the most common genetic event in early prostate cancer (PCa) with potential prognostic and therapeutic implications. METHODS: We evaluated ERG protein expression in 344 patients with PCa in 3 cohorts including localized, metastatic, and castration-resistant disease using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). RESULTS: ERG protein expression was detected exclusively in the neoplastic epithelium and was found in 6.8% and 46.3% of high-grade prostatic intraepithelial neoplasia (HGPIN) and localized PCa, respectively. In metastatic and locally advanced CRPC, ERG expression was significantly lower, occurring at 36.1% and 37.2%, respectively. In PCa with foamy gland morphology, ERG protein expression was detected in only 18.6% compared with reported rates of about 42%-48% in acinar PCa. Moreover, ERG protein expression and gene rearrangements showed an overall consistency rate of 90.6% (P <.0001). The consistency rate was 100% both in benign glands and HGPIN, and 96.1% in localized PCa. However, it was significantly lower at 76.9% and 85% in node metastatic and CRPC, respectively (P <.0001). CONCLUSION: ERG protein expression is restricted to neoplastic prostatic epithelium and is present at lower rates in metastatic and CRPC compared to localized PCa. IHC and FISH concordance rates were significantly lower in node metastatic and CRPC compared to localized PCa, which may suggest different biological and therapeutic implications. The lower rate of ERG protein expression in foamy gland PCa may suggest potential differences for this pattern of PCa at the molecular level. PMID- 23746716 TI - Teleconsultation in geriatrics: impact on professional practice. AB - Teleconsultations in medicine are encouraged by authorities and decision-makers to improve access to specialty services for isolated patients. For elderly patients in geriatric hospitals, they thus avoid trips to consult with specialists. However, teleconsultation can modify clinical practice and it may be abandoned for reasons not related to technical issues. Qualitative research on the impact of teleconsultation on medical practice and organisation are thus crucial for an understanding of the changes it can generate. METHODS: We used qualitative methods to analyse the impact on professional work practices and care organisation of an initially experimental and then permanent teleconsultation system using a video conference system set up between a geriatric hospital and a tertiary care hospital. Sixty-six teleconsultations (56 during the experimental phase and 10 when the system was in routine use) were observed and ten semi structured interviews were carried out with the actors in the teleconsultations. RESULTS: Our study shows that the uses of teleconsultation affected work practices of both the consulted specialist and the geriatrician who participated in the consultation alongside the patient. The interactions of specialists with the patient were more difficult than in a face-to-face setting and delegation of the clinical examination of the patient depended on a specific form of cooperation and on trust in the person doing the examination. New kinds of relationships between health professionals contributed to sharing and transmission of knowledge between practitioners. While teleconsultations established alliances between geriatricians and specialists, they none-the-less called for a certain humility on the part of geriatricians. In order for these relationships to become routine and to facilitate interaction among participants, the project manager carried out important work during the experimental phase of the teleconsultations by organising these interactions. Finally, the teleconsultations went through several local reorganisations, especially within the geriatric hospital. These included changes in the geriatrician's schedule and the added presence of an assistant knowledgeable in telemedicine. CONCLUSIONS: Specialists found the system used for teleconsultation between a geriatric hospital and a tertiary care hospital to be suitable for their consultations. The main advantage brought about by the teleconsultation system studied resulted from its collaborative nature, which created relationships between health professionals. This resulted in improved care for elderly patients. However, using the system required effort on the part of both the specialists and the geriatricians. Adapting to the system was facilitated by coordination work carried out by the project manager during the experimental phase that created a favourable context for cooperation between actors, allowing diagnoses to be made at a distance. Finally, teleconsultations do not appear suitable for all specialties, by reason of the limits imposed on the delegation of tasks, or to all situations. They require setting up new forms of organisation that must be encouraged by decision-makers. PMID- 23746717 TI - The tetA gene decreases tigecycline sensitivity of Salmonella enterica isolates. AB - To determine the association of tetracycline resistance determinants with tigecycline sensitivity, tetracycline-resistant Salmonella spp. isolated from clinical and food samples were tested for the presence of tetracycline resistance determinants, tigecycline sensitivity, and the impact of tetA on tigecycline resistance. In addition, the impacts of multiple resistance mechanisms on tigecycline resistance were determined using an isolate with ramR mutation. Of the 49 tetracycline-resistant Salmonella isolates screened, 32 were positive for tetA, 13 were positive for tetB, 2 were positive for tetC and 1 isolate was positive for both tetA and tetB. The minimum inhibitory concentration (MIC) of tigecycline for tetA-carrying isolates ranged from 0.19 mg/L to 3mg/L (mode 0.75 mg/L), whereas the MIC of tigecycline for tetB-carrying isolates ranged from 0.064 mg/L to 0.5mg/L (modes 0.25mg/L and 0.38 mg/L, excluding the isolate with both tetA and tetB). Double frameshift mutations in codons 201, 202 and 203 were observed in partial sequences of the tetA genes in these strains and the majority of published tetA gene sequences. Curing of the tetA genes from three isolates reduced the tigecycline MICs, whilst deletion of ramR increased tigecycline MICs. This study indicates that the tetA gene decreases sensitivity to tigecycline in Salmonella spp. at a low level. With additional resistance mechanisms, tetA carrying strains can reach the breakpoint for tigecycline resistance. PMID- 23746718 TI - Screening for elderly patients admitted to the emergency department requiring specialized geriatric care. AB - BACKGROUND: There is a need for a brief geriatric assessment (BGA) tool to screen elderly patients admitted to the Emergency Department (ED) for their risk of a long hospital stay. OBJECTIVE: To examine whether a BGA administered to elderly patients admitted to the ED may predict the risk of a long hospital stay in the geriatric acute care unit. METHODS: This study had a prospective cohort study design, enrolling 424 elderly patients (mean age 84.0 +/- 6.5 years, 31.6% male) who were evaluated in the ED using a BGA composed of the following items: age, gender, number of medications taken daily, history of falls during the past 6 months, Mini-Mental State Examination (MMSE) score, and non-use of home-help services (i.e., living alone without using any formal or informal home services or social help). The length of stay (LOS) was calculated in days. Patients were separated into three groups based on LOS: low (<8 days), intermediate (8-13 days), and high (>13 days). RESULTS: The prevalence of male gender was higher among patients with the longest LOS compared to those with intermediate LOS (p = 0.002). There were more patients with a history of falls in the high LOS group compared to the intermediate LOS group (p = 0.001) and the low LOS group (p < 0.001). The classification tree showed that male patients with an MMSE score <20 who fell with age under 85 years formed the end node with the greatest relative risk (RR) of a long hospital stay (RR = 14.3 with p < 0.001). CONCLUSIONS: The combination of a history of falls, male gender, cognitive impairment, and age under 85 years identified elderly ED patients at high risk of a long hospital stay. PMID- 23746719 TI - Improved survival with surgery in prostate cancer patients without medical comorbidity: a self-fulfilling prophecy? PMID- 23746720 TI - Re: Steven Joniau, Laura Van den Bergh, Evelyne Lerut, et al. Mapping of pelvic lymph node metastases in prostate cancer. Eur Urol 2013;63:450-8. PMID- 23746721 TI - Feature extraction and recognition of ictal EEG using EMD and SVM. AB - Automatic seizure detection is significant for long-term monitoring of epilepsy, as well as for diagnostics and rehabilitation, and can decrease the duration of work required when inspecting the EEG signals. In this study we propose a novel method for feature extraction and pattern recognition of ictal EEG, based upon empirical mode decomposition (EMD) and support vector machine (SVM). First the EEG signal is decomposed into Intrinsic Mode Functions (IMFs) using EMD, and then the coefficient of variation and fluctuation index of IMFs are extracted as features. SVM is then used as the classifier for recognition of ictal EEG. The experimental results show that this algorithm can achieve the sensitivity of 97.00% and specificity of 96.25% for interictal and ictal EEGs, and the sensitivity of 98.00% and specificity of 99.40% for normal and ictal EEGs on Bonn data sets. Besides, the experiment with interictal and ictal EEGs from Qilu Hospital dataset also yields a satisfactory sensitivity of 98.05% and specificity of 100%. PMID- 23746722 TI - An insight into the molecular basis for convergent evolution in fish antifreeze Proteins. AB - Antifreeze proteins (AFPs) prevent the growth of ice-crystals in order to enable certain organisms to survive under sub-zero temperature surroundings. These AFPs have evolved from different types of proteins without having any significant structural and sequence similarities among them. However, all the AFPs perform the same function of anti-freeze activity and are a classical example of convergent evolution. We have analyzed fish AFPs at the sequence level, the residue level and the physicochemical property group composition to discover molecular basis for this convergent evolution. Our study on amino acid distribution does not reveal any distinctive feature among AFPs, but comparative study of the AFPs with their close non-AFP homologs based on the physicochemical property group residues revealed some useful information. In particular (a) there is a similar pattern of avoidance and preference of amino acids in Fish AFP subtypes II, III and IV-Aromatic residues are avoided whereas small residues are preferred, (b) like other psychrophilic proteins, AFPs have a similar pattern of preference/avoidance for most of the residues except for Ile, Leu and Arg, and (c) most of the computed amino acids in preferred list are the key functional residues as obtained in previous predicted model of Doxey et al. For the first time this study revealed common patterns of avoidance/preference in fish AFP subtypes II, III and IV. These avoidance/preference lists can further facilitate the identification of key functional residues and can shed more light into the mechanism of antifreeze function. PMID- 23746723 TI - An ontology of cancer therapies supporting interoperability and data consistency in EPRs. AB - Ontologies can formally describe the semantics of the medical domain in an unambiguous and machine processable form, acting as a conceptual interface between different applications that must interoperate. In this paper we present an ontology of cancer therapies originally developed to bridge the gap between an oncologic Electronic Patient Record (EPR) and a guideline-based decision support system. We show an application of the ontology complemented by rules to classify therapies recorded in the EPR. The results show how such an ontology can be used also to discover possible problems of data consistency in the EPR. PMID- 23746724 TI - Automatic sleep staging from ventilator signals in non-invasive ventilation. AB - Non-invasive ventilation (NIV), a recognized treatment for chronic hypercapnic respiratory failure, is predominantly applied at night. Nevertheless, the quality of sleep is rarely evaluated due to the required technological complexity. A new technique for automatic sleep staging is here proposed for patients treated by NIV. This new technique only requires signals (airflow and hemoglobin oxygen saturation) available in domiciliary ventilators plus a photo-plethysmogram, a signal already managed by some ventilators. Consequently, electroencephalogram, electrooculogram, electromyogram, and electrocardiogram recordings are not needed. Cardiorespiratory features are extracted from the three selected signals and used as input to a Support Vector Machine (SVM) multi-class classifier. Two different types of sleep scoring were investigated: the first type was used to distinguish three stages (wake, REM sleep and nonREM sleep), and the second type was used to evaluate five stages (wake, REM sleep, N1, N2 and N3 stages). Patient dependent and patient-independent classifiers were tested comparing the resulting hypnograms with those obtained from visual/manual scoring by a sleep specialist. An average accuracy of 91% (84%) was obtained with three-stage (five-stage) patient-dependent classifiers. With patient-independent classifiers, an average accuracy of 78% (62%) was obtained when three (five) sleep stages were scored. Also if the PPG-based and flow features are left out, a reduction of 4.5% (resp. 5%) in accuracy is observed for the three-stage (resp. five-stage) cases. Our results suggest that long-term sleep evaluation and nocturnal monitoring at home is feasible in patients treated by NIV. Our technique could even be integrated into ventilators. PMID- 23746725 TI - A femur fracture reduction method based on anatomy of the contralateral side. AB - Femoral fractures may result in loss of the original femur anatomy, without leaving a direct source of reference for femur reduction procedures. Femoral configuration renders it feasible to redesign the original femur based on the information obtained from the contralateral femur. In this report, we describe a method to rebuild the original femur based on the contralateral side as the reference after ascertaining the bilateral symmetry of the body. The method was tested on animals using the spine model and the experimental results are discussed briefly. PMID- 23746726 TI - MREJ: MRE elasticity reconstruction on ImageJ. AB - Magnetic resonance elastography (MRE) is a promising method for health evaluation and disease diagnosis. It makes use of elastic waves as a virtual probe to quantify soft tissue elasticity. The wave actuator, imaging modality and elasticity interpreter are all essential components for an MRE system. Efforts have been made to develop more effective actuating mechanisms, imaging protocols and reconstructing algorithms. However, translating MRE wave images into soft tissue elasticity is a nontrivial issue for health professionals. This study contributes an open-source platform - MREJ - for MRE image processing and elasticity reconstruction. It is established on the widespread image-processing program ImageJ. Two algorithms for elasticity reconstruction were implemented with spatiotemporal directional filtering. The usability of the method is shown through virtual palpation on different phantoms and patients. Based on the results, we conclude that MREJ offers the MRE community a convenient and well functioning program for image processing and elasticity interpretation. PMID- 23746727 TI - Mathematica program: its use to simulate metabolic irreversible pathways and inhibition of the first enzyme of a pathway by its end product as visualized with the reservoir model. AB - The main objective of this report is to show the usefulness and versatility of the Mathematica program to simulate enzyme linear pathways and to depict the effect of changing the Vmax and/or Km values of one or more enzymes on the course of the reaction. In addition, analysis of the different types of inhibition of the first enzyme of the pathway by its end product is viewed with the reservoir model for enzyme kinetics. All the data shown here are quantitatively related to the kinetic constants of the implicated enzymes. Particular attention has been paid to calculate the time needed to achieve half of the possible total synthesis of the final product of a metabolic pathway. PMID- 23746729 TI - Evaluating the sleep quality of obstructive sleep apnea patients after continuous positive airway pressure treatment. AB - Continuous positive airway pressure treatment (CPAP) is administered to treat the common disorder of obstructive sleep apnea. However, patients receiving CPAP treatment without a sleep assessment and clinical diagnosis often do not feel or understand the improvement in their condition, necessitating a sleep quality improvement index for physicians to analyze improvements in patient treatment rapidly. This work presents a novel sleep quality evaluation system that calculates the improvement value for sleep quality using electroencephalogram and electrocardiogram signal features, as well as fuzzy inferences. Experimental results indicate that the sleep quality improvement rating of the proposed system and that of the apnea-hyponea index correlate with each other. Importantly, the proposed system can identify considerable levels of improvement in the physiological signals of patients having undergone CPAP treatment. PMID- 23746728 TI - A feasibility study of diagnosing cardiovascular diseases based on blood/urine element analysis and consensus models. AB - The classification of normal and cardiovascular disease groups with consensus models according to metal concentration in blood/urine samples is discussed in this study. The concentrations of nine elements (i.e., chromium, iron, manganese, aluminum, cadmium, copper, zinc, nickel and selenium) were analyzed using three types of chemometric methods including fisher linear discriminant analysis (FLDA), support vector machine (SVM) and decision tree (DTree). Data from 60 healthy individuals and 24 cardiovascular patients were collected and analyzed. Principal component analysis (PCA) was initially used in a preliminary analysis; however, it proved a difficult task to distinguish normal samples from cardiovascular ones using this method. Then, based on the consensus strategy, a series of classifiers were constructed and compared. In terms of three performance indices, i.e., accuracy, sensitivity and specificity, the DTree classifier exhibited the best overall performance, followed by SVM and FLDA is the poorest. In addition, analysis of blood samples was superior to urine samples. In conclusion, the combination of a consensus DTree classifier and elemental analysis of blood samples can serve as an aid for diagnosis of cardiovascular diseases, especially in routine physical examination. PMID- 23746730 TI - Mesh quality oriented 3D geometric vascular modeling based on parallel transport frame. AB - While a number of methods have been proposed to reconstruct geometrically and topologically accurate 3D vascular models from medical images, little attention has been paid to constantly maintain high mesh quality of these models during the reconstruction procedure, which is essential for many subsequent applications such as simulation-based surgical training and planning. We propose a set of methods to bridge this gap based on parallel transport frame. An improved bifurcation modeling method and two novel trifurcation modeling methods are developed based on 3D Bezier curve segments in order to ensure the continuous surface transition at furcations. In addition, a frame blending scheme is implemented to solve the twisting problem caused by frame mismatch of two successive furcations. A curvature based adaptive sampling scheme combined with a mesh quality guided frame tilting algorithm is developed to construct an evenly distributed, non-concave and self-intersection free surface mesh for vessels with distinct radius and high curvature. Extensive experiments demonstrate that our methodology can generate vascular models with better mesh quality than previous methods in terms of surface mesh quality criteria. PMID- 23746732 TI - The precision of resting blood pressure measurement. AB - By analysis of timed series of blood pressure(BP) measurements from a single individual, it was shown that data-averaging did not usually give a true value of resting systolic or diastolic pressure. Such measurements fitted a pattern of first order decay from an initial pressure towards a resting systolic or diastolic pressure, P. Using non-linear regression analysis it was possible to approach a standard error of 1mmHg/1mmHg for P values on a single day; the between-day dispersion, over a period of months, was found to be about 2mmHg/2mmHg. Computer analysis is required to give values of resting systolic and diastolic BP accompanied by error estimates. PMID- 23746731 TI - Keratin protein property based classification of mammals and non-mammals using machine learning techniques. AB - Keratin protein is ubiquitous in most vertebrates and invertebrates, and has several important cellular and extracellular functions that are related to survival and protection. Keratin function has played a significant role in the natural selection of an organism. Hence, it acts as a marker of evolution. Much information about an organism and its evolution can therefore be obtained by investigating this important protein. In the present study, Keratin sequences were extracted from public data repositories and various important sequential, structural and physicochemical properties were computed and used for preparing the dataset. The dataset containing two classes, namely mammals (Class-1) and non mammals (Class-0), was prepared, and rigorous classification analysis was performed. To reduce the complexity of the dataset containing 56 parameters and to achieve improved accuracy, feature selection was done using the t-statistic. The 20 best features (parameters) were selected for further classification analysis using computational algorithms which included SVM, KNN, Neural Network, Logistic regression, Meta-modeling, Tree Induction, Rule Induction, Discriminant analysis and Bayesian Modeling. Statistical methods were used to evaluate the output. Logistic regression was found to be the most effective algorithm for classification, with greater than 96% accuracy using a 10-fold cross validation analysis. KNN, SVM and Rule Induction algorithms also were found to be efficacious for classification. PMID- 23746733 TI - A general model for continuous noninvasive pulmonary artery pressure estimation. AB - Elevated pulmonary artery pressure (PAP) is a significant healthcare risk. Continuous monitoring for patients with elevated PAP is crucial for effective treatment, yet the most accurate method is invasive and expensive, and cannot be performed repeatedly. Noninvasive methods exist but are somewhat inaccurate, expensive, and cannot be used for continuous monitoring. We present a machine learning model based on heart sounds that estimates pulmonary artery pressure with enough accuracy to exclude an invasive diagnostic operation, allowing for consistent monitoring of heart condition in suspect patients without the cost and risk of invasive monitoring. We conduct a greedy search through 38 possible features using a 109-patient cross-validation to find the most predictive features. Our best general model has a standard estimate of error (SEE) of 8.3mmHg, which outperforms the previous best performance in the literature on a general set of unseen patient data. PMID- 23746734 TI - Computerized analysis of respiratory sounds during COPD exacerbations. AB - Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a major event in the natural course of the disease, and is associated with significant mortality and socioeconomic impact. Abnormal respiratory sounds are commonly present in patients with AECOPD. Computerized analysis of these sounds can assist in diagnosis and in evaluation during follow-up. Exploratory data analysis methods were applied to respiratory sounds in these patients when they were hospitalized because of exacerbation. Two different patterns of presentation and evolution of respiratory sounds in AECOPD were found and described from the method of computerized respiratory sound analysis and unsupervised clustering that was devised. Based on the findings of the study, remote monitoring of respiratory sounds may be useful for the detection and/or follow-up of COPD exacerbation. PMID- 23746735 TI - An ant colony optimization based algorithm for identifying gene regulatory elements. AB - It is one of the most important tasks in bioinformatics to identify the regulatory elements in gene sequences. Most of the existing algorithms for identifying regulatory elements are inclined to converge into a local optimum, and have high time complexity. Ant Colony Optimization (ACO) is a meta-heuristic method based on swarm intelligence and is derived from a model inspired by the collective foraging behavior of real ants. Taking advantage of the ACO in traits such as self-organization and robustness, this paper designs and implements an ACO based algorithm named ACRI (ant-colony-regulatory-identification) for identifying all possible binding sites of transcription factor from the upstream of co-expressed genes. To accelerate the ants' searching process, a strategy of local optimization is presented to adjust the ants' start positions on the searched sequences. By exploiting the powerful optimization ability of ACO, the algorithm ACRI can not only improve precision of the results, but also achieve a very high speed. Experimental results on real world datasets show that ACRI can outperform other traditional algorithms in the respects of speed and quality of solutions. PMID- 23746736 TI - Sparse maximum margin discriminant analysis for feature extraction and gene selection on gene expression data. AB - Dimensionality reduction is necessary for gene expression data classification. In this paper, we propose a new method for reducing the dimensionality of gene expression data. First, based on a sparse representation, we developed a new criterion for characterizing the margin, which is called sparse maximum margin discriminant analysis (SMMDA); this approach can be used to find an optimal transform matrix such that the sparse margin is maximal in the transformed space. Second, using SMMDA, we present a new feature extraction method for gene expression data. Third, based on SMMDA, we propose a new discriminant gene selection method. During gene selection, we first found the one-dimensional projection of the gene expression data in the most separable direction using SMMDA. Then, we applied the sparse representation technique to regress the projection, and we obtained the relevance vector for the gene set. Discriminant genes were then selected according to this vector. Compared with the conventional method of maximum margin discriminant analysis, the proposed SMMDA method successfully avoids the difficulty of parameter selection. Extensive experiments using publicly available gene expression datasets showed that SMMDA is efficient for feature extraction and gene selection. PMID- 23746739 TI - Computed tomography imaging features and classification of isolated dissection of the superior mesenteric artery. AB - OBJECTIVES: To analyze computed tomography (CT) imaging features of isolated dissection of the superior mesenteric artery (SMA). METHODS: The imaging findings of 20 consecutive patients with isolated dissection of the SMA were retrospectively evaluated and categorized according to a new imaging classification: Type A, dissections localized at the curved part of the SMA and extended proximally; Type B, dissections limited to the curved part; Type C or D, dissections localized at the curved part and extended distally without or with involved ileocolic or distal ileal arteries. The relationship between classification and symptoms and treatment effect is discussed, and prior reported cases where CT images were available were classified and analyzed. RESULTS: The dissections were around the curved part of the SMA in all 20 patients. In symptomatic patients, the true lumen was more stenosed, the dissection started nearer the SMA ostium, and the dissection was longer. The best effect of conservative treatment was achieved in Type B cases. When dissection extended distally, the effect progressively worsened from Type B to Type D. CONCLUSIONS: The new classification is useful for describing the imaging features of isolated dissection of the SMA. PMID- 23746737 TI - Gender differences in the prospective associations of self-reported sleep quality with biomarkers of systemic inflammation and coagulation: findings from the Heart and Soul Study. AB - Systemic inflammation is proposed as a putative mechanism underlying the link between poor sleep and cardiovascular disease. The aim of present study was to investigate the cross-sectional and prospective associations of self-reported sleep quality with biomarkers of inflammation and coagulation implicated in coronary heart disease (CHD) and to explore whether these associations differed between men and women. To this end, measures of sleep quality and markers of inflammation, including circulating levels of interleukin-6 (IL-6), high sensitivity C-reactive protein (CRP), and fibrinogen were assessed at baseline in 980 participants with established CHD and 626 at 5-year follow-up. In the sample as a whole, subjective sleep quality was unrelated to inflammatory markers in cross-sectional and prospective analyses. However, in gender stratified analyses, adjusting for age, ethnicity, education, body mass index, and regular snoring, poorer subjective sleep quality at baseline was prospectively associated with 5 year increases in IL-6 (b = 0.14, SE = 0.05, p = 0.003), CRP (b = 0.21, SE = 0.09, p = 0.02), and fibrinogen (b = 18.02, SE = 7.62, p = 0.02) in women but not men. These associations remained independent of lifestyle/psychosocial factors, medical comorbidities, medication use, and cardiac function. Women who reported baseline sleep disturbances characterized by a tendency to wake up too early in the morning also showed significant 5-year increases in circulating IL-6 that withstood covariate adjustment. Further research is necessary to elucidate the pathways that underlie gender-specific associations between subjective sleep quality and markers of inflammation and coagulation as this may help clarify gender disparities in CHD. PMID- 23746741 TI - ["Stroke-like" episodes in Sturge-Weber syndrome]. PMID- 23746742 TI - [Hepatopulmonary syndrome--a rare cause of hypoxaemia]. PMID- 23746740 TI - [A model list of high risk drugs]. AB - INTRODUCTION: "High-risk drugs" are those that have a very high "risk" of causing death or serious injury if an error occurs during its use. The Institute for Safe Medication Practices (ISMP) has prepared a high-risk drugs list applicable to the general population (with no differences between the pediatric and adult population). Thus, there is a lack of information for the pediatric population. The main objective of this work is to develop a high-risk drug list adapted to the neonatal or pediatric population as a reference model for the pediatric hospital health workforce. MATERIAL AND METHODS: We made a literature search in May 2012 to identify any published lists or references in relation to pediatric and/or neonatal high-risk drugs. RESULTS: A total of 15 studies were found, from which 9 were selected. A model list was developed mainly based on the ISMP one, adding strongly perceived pediatric risk drugs and removing those where the pediatric use was anecdotal. CONCLUSIONS: There is no published list that suits pediatric risk management. The list of pediatric and neonatal high-risk drugs presented here could be a "reference list of high-risk drugs " for pediatric hospitals. Using this list and training will help to prevent medication errors in each drug supply chain (prescribing, transcribing, dispensing and administration). PMID- 23746743 TI - [How should we treat patients with ulcerative colitis and cytomegalovirus infection?]. PMID- 23746744 TI - [Estimated prevalence of autism spectrum disorders in the Canary Islands]. AB - AIMS: To make an initial estimate of the prevalence of autism spectrum disorders (ASDs) among children in the province of Las Palmas (Spain). MATERIAL AND METHODS: Descriptive study was conducted on 1,796 children between the ages of 18 and 30 months of age, all part of the Child Health Surveillance of the Canary Islands, more specifically the province of Las Palmas, with a population of 1,090,605. The parents of children involved completed the Spanish version of the Modified Checklist for Autism in Toddlers (M-CHAT/ES) in the paediatric clinic. The positive cases were then diagnosed by experts by means of the Autism Diagnostic Interview-Revised (ADIR) and the Autism Diagnostic Observation Schedule (ADOS). RESULTS: A 0.61% prevalence of ASDs was determined, similar to that reported in previous studies using the same tools. The ratio was six girls for every five boys. This was contrary to the results of previous studies which suggested more boys than girls were affected. This may have been due to the sample size, which will have to be increased in future studies to confirm this outcome. CONCLUSIONS: An increased sample size and also spread to other age ranges should be used in order to obtain a more reliable estimate of prevalence. As regards the gender ratio, this could be a result of the small size of the sample researched, and should therefore be confirmed by further studies. PMID- 23746745 TI - Disseminated intravascular coagulation in a novel porcine model of severe Staphylococcus aureus sepsis fulfills human clinical criteria. AB - Sepsis is a common and often fatal complication in human patients in intensive care units. Relevant and well characterized animal models of sepsis may provide valuable information on pathophysiological mechanisms and be a mean of testing new therapeutic strategies. Large animal models of Staphylococcus aureus sepsis are rare, even though S. aureus increasingly affects human patients. Sepsis changes the haemostatic balance and leads to endothelial cell (EC) activation, coagulopathy and, in severe cases, disseminated intravascular coagulation (DIC). The aim of this study was to characterize the haemostatic and vascular alterations in a novel porcine model of severe S. aureus sepsis, investigating whether the changes fulfill the human clinical criteria for DIC. Five pigs were inoculated intravenously with S. aureus and two control animals were sham inoculated. Blood samples were collected for thromboelastography (TEG) and assessment of plasma-based haemostatic parameters. Tissue was collected for histopathology and reverse transcriptase quantitative real-time polymerase chain reaction for measurement of mRNA encoding EC markers. All infected animals developed DIC; including procoagulant activation represented by hypercoagulable TEG profiles and prolonged clotting time. Histologically, numerous pulmonary thrombi were present in one pig. Inhibitor consumption was represented by decreasing antithrombin levels in infected pigs. Hyaline globules were found in three infected pigs, confirming fibrinolytic activation. EC activation was identified by expression of von Willebrand factor in small vessels together with elevated mRNA encoding activated EC markers. Severe haemostatic and vascular changes fulfilling the human criteria for DIC were therefore seen in all infected pigs. A tendency towards uncompensated DIC was seen in two animals. PMID- 23746746 TI - Determining optimum flash patterns for emergency service vehicles: an experimental investigation using high definition film. AB - An investigation of how emergency vehicle lighting (EVL) can be improved is reported with reference to an analysis of police vehicle road traffic accidents (Study 1). In Study 2, 37 regular drivers were shown film clips of a marked police vehicle, in which flash rate (1 Hz, 4 Hz) and pattern (single, triple pulse) were varied on the blue Light Emitting Diode (LED) roofbar. Results indicate a 4 Hz flash rate conveys greater urgency than a 1 Hz rate, while a 1 Hz, single flash combination was ranked the least urgent of all combinations. Participants claimed they would leave significantly more space before pulling out in front of an approaching police car (gap acceptance) in the 4 Hz single pulse condition in comparison to other EVL combinations. The preliminary implications for which flash characteristics could prove most optimal for emergency service use are discussed with regard to effects on driver perception and expected driving behaviour. PMID- 23746747 TI - The prevention of canine leishmaniasis and its impact on public health. AB - Canine leishmaniasis (CanL) caused by Leishmania infantum is a vector-borne disease of great veterinary and medical significance. Prevention of CanL requires a combined approach including measures focused on dogs and the environment where the vectors perpetuate. Over past decades, considerable effort has been put towards developing novel and cost-effective strategies against CanL. Vaccination is considered among the most promising tools for controlling CanL, and synthetic pyrethroids are useful and cost-effective in reducing risk of L. infantum infection in dogs. The effectiveness of the use of vaccines plus repellents in preventing L. infantum infection and subsequent disease development should be assessed by means of large-scale, randomized controlled field trials because this combined strategy may become the next frontier in the control of CanL. PMID- 23746749 TI - Wear of two denture teeth materials in vivo-2-year results. AB - OBJECTIVE: (1) To quantify wear of two different denture tooth materials in vivo with two study designs, (2) to relate tooth variables to vertical loss. METHODS: Two different denture tooth materials had been used (experimental material=test; DCL=control). In study 1 (split-mouth, 6 test centers) 60 subjects received complete dentures, in study 2 (two-arm, 1 test center) 29 subjects. In study 1 the mandibular dentures were supported by implants in 33% of the subjects, in study 2 only in 3% of the subjects. Impressions of the dentures were taken and poured with improved stone at baseline and after 6, 12, 18 and 24 months. Each operator evaluated the wear subjectively. Wear analysis was carried out with a laser scanning device. Maximal vertical loss of the attrition zones was calculated for each tooth cusp and tooth. A mixed linear model was used to statistically analyse the logarithmically transformed wear data. RESULTS: Due to drop-outs and unmatchable casts, only 47 subjects of study 1 and 14 of study 2 completed the 2-year recall. Overall, 75% of all teeth present could be analysed. There was no statistically difference in the overall wear between the test and control material for either study 1 or study 2. The relative increase in wear over time was similar in both study designs. However, a strong subject effect and center effect were observed. The fixed factors included in the model (time, tooth, center, etc.) accounted for 43% of the variability, whereas the random subject effect accounted for another 30% of the variability, leaving about 28% of unexplained variability. More wear was consistently recorded in the maxillary teeth compared to the mandibular teeth and in the first molar teeth compared to the premolar teeth and the second molars. Likewise, the supporting cusps showed more wear than the non-supporting cusps. The amount of wear did not depend on whether or not the lower dentures were supported by implants. The subjective wear was correct in about 67% of the cases if it is postulated that a wear difference of 100MUm should be subjectively detectable. SIGNIFICANCE: The clinical wear of denture teeth is highly variable with a strong patient effect. More wear can be expected in maxillary denture teeth compared to mandibular teeth, first molars compared to premolars and supported cusps compared to non-supported cusps. Laboratory data on the wear of denture tooth materials may not be confirmed in well-structured clinical trials probably due to the large inter-individual variability. PMID- 23746748 TI - Ahead of the curve: next generation estimators of drug resistance in malaria infections. AB - Drug resistance is a major obstacle to controlling infectious diseases. A key challenge is detecting the early signs of drug resistance when little is known about its genetic basis. Focusing on malaria parasites, we propose a way to do this. Newly developing or low level resistance at low frequency in patients can be detected through a phenotypic signature: individual parasite variants clearing more slowly following drug treatment. Harnessing the abundance and resolution of deep sequencing data, our 'selection differential' approach addresses some limitations of extant methods of resistance detection, should allow for the earliest detection of resistance in malaria or other multi-clone infections, and has the power to uncover the true scale of the drug resistance problem. PMID- 23746750 TI - Clinically relevant fracture testing of all-ceramic crowns. AB - OBJECTIVES: Fracture strength measured in vitro indicates that most all-ceramic crowns should be able to withstand mastication forces. Nevertheless, fractures are one of the major clinical problems with all-ceramic restorations. Furthermore, the fracture mode of all-ceramic crowns observed in clinical use differs from that found in conventional fracture strength tests. The aim of the present study was to develop and investigate a method that simulates clinical fracture behavior in vitro. METHODS: 30 crowns with alumina cores were made to fit a cylindrical model with a molar-like preparation design. These crowns were randomly allocated to 3 tests groups (n=10). The crowns in group 1 were cemented to abutment models of epoxy and subsequently fractured by occlusal loading without contact damage. The crowns in group 2 were fractured by cementation with expanding cement. The crowns in group 3 were cemented on an abutment model of epoxy split almost in two and fractured by increasing the diameter of the model in the bucco-lingual direction. The fractured crowns were analyzed by fractographic methods and compared to a reference group of 10 crowns fractured in clinical use. RESULTS: The fracture modes of all the in vitro crowns were similar to clinical fracture modes. The fracture modes in group 1 were most closely matched to the clinical fractures. These crowns also fractured at clinically relevant loads. CONCLUSION: Laboratory tests that induce a distortion of the abutment model during occlusal loading without occlusal contact damage can simulate clinical fractures of all-ceramic crowns. PMID- 23746751 TI - Barriers to D&E practice among family planning subspecialists. AB - OBJECTIVE: Over 95% of all second-trimester abortions are managed by dilation and evacuation procedures (D&E) and account for nearly 9% of all abortions in the United States annually. The Fellowship in Family Planning (FFP) offers subspecialty training in abortion and contraception to obstetrician-gynecologists and family medicine physicians. Twenty years after the FFP founding, we report on the abortion practice characteristics and specific barriers these subspecialists face. STUDY DESIGN: We surveyed obstetrician-gynecologist family planning (FP) subspecialists by email regarding second-trimester abortion training and practice barriers with a focus on D&E. RESULTS: Our response rate was 62% (105/169) of all fellowship-affiliated physicians. Respondents were composed primarily of young women working in academic settings in the West and Northeast regions. Nearly all FP subspecialists have been trained to 24 weeks' gestation and currently provide D&Es, with an average of nearly 200 per year. D&E practice barriers vary by geographical location and degree of "regional restrictiveness." FP subspecialists practicing in more abortion-restrictive regions were four times more likely to report a personal main barrier (such as concern for safety) than other types of main barriers (p=.05). Providing D&Es in a hospital operating room was associated with 2.8 times higher odds of reporting an institutional or coworker main barrier (p=.02). High-volume D&E practice was associated with three times lower odds of reporting an institutional/coworker main barrier (p=.02). CONCLUSIONS: By identifying the barriers to D&E practice experienced by FP subspecialists, we can begin to develop a coordinated approach to eradicating modifiable barriers and, ultimately, improve access for women seeking D&E services. PMID- 23746752 TI - Maximum flow access in heat exchangers, heat generating bodies and inanimate flow systems: constructal law and the emergence of shapes and structures in thermo fluid mechanics: comment on "The emergence of design in pedestrian dynamics: locomotion, self-organization, walking paths and constructal law" by Antonio F. Miguel. PMID- 23746753 TI - Incorporation of extruded coils into the third nerve in association with third nerve palsy. AB - The extrusion of the coil complex outside of the aneurysmal dome is thought to be an important mechanism by which the aneurysm neck and fundus recanalize, but the migration of the coil loops and their incorporation inside vital nervous structures has not been clearly described. We reviewed the medical literature on coil extrusion and migration and report a rare case of third nerve palsy due to direct damage caused by coil loop migration that resolved after surgery. A 25 year-old woman presented with subarachnoid hemorrhage and painful left third nerve palsy. The angiogram revealed a supraclinoid internal carotid aneurysm incorporating the origin of the left posterior communicating artery. Her aneurysm was coiled. The 8 month follow-up angiogram revealed a major recurrence of her aneurysm. It was decided to surgically clip the aneurysm. At surgery, coil loops were found in the subarachnoid space and embedded into the third nerve. At 1 month follow-up she had recovered well, and only had very subtle diplopia upon fatigue. Coil extrusion is a fairly common phenomenon that should be suspected in instances of major aneurysmal recurrence. Surgical treatment is recommended, and special care should be taken when mobilizing the extruded coil mass. PMID- 23746754 TI - Identification of potential anticancer compounds from Oplopanax horridus. AB - Oplopanax horridus is a plant native to North America. Previous reports have demonstrated that this herb has antiproliferative effects on cancer cells but study mostly focused on its extract or fractions. Because there has been limited phytochemical study on this herb, its bioactive compounds are largely unknown. We recently isolated and identified 13 compounds, including six polyynes, three sesquiterpenes, two steroids, and two phenolic acids, of which five are novel compounds. In this study, we systemically evaluated the anticancer effects of compounds isolated from O. horridus. Their antiproliferative effects on a panel of human colorectal and breast cancer cells were determined using the MTS assay. Cell cycle distribution and apoptotic effects were analyzed by flow cytometry. The in vivo antitumor effect was examined using a xenograft tumor model. Among the 13 compounds, strong antiproliferative effects were observed from falcarindiol and a novel compound oplopantriol A. Falcarindiol showed the most potent antiproliferative effects, significantly inducing pro-apoptosis and cell cycle arrest in the S and G2/M phases. The anticancer potential of falcarindiol was further verified in vivo, significantly inhibiting HCT-116 tumor growth in an athymic nude mouse model at 15 mg/kg. We also analyzed the relationship between polyyne structures and their pharmacological activities. We observed that both the terminal hydroxyl group and double bond obviously affected their anticancer potential. Results from this study supplied valuable information for future semi synthesis of polyyne derivatives to develop novel cancer chemopreventive agents. PMID- 23746755 TI - Effect of catalpol on diabetic nephropathy in rats. AB - PURPOSE: To investigate the effect of catalpol on diabetic nephropathy in rats. METHODS: Male Sprague-Dawley rats were randomly divided into two groups and fed with normal pallet diet (NPD) or high-fat diet (HFD) for 4 weeks respectively. Then the HFD-fed rats were injected with 35 mg/kg streptozotocin (STZ) for establishing diabetic model. The diabetic rats were randomly divided into five groups: model group, model plus catalpol 30, 60, 120 mg/kg groups and model plus metformin 200 mg/kg group. The NPD-fed rats were randomly divided into two groups: normal control group and normal plus catalpol 60 mg/kg control group. After administration for 10 weeks, random blood glucose (RBG), glycated serum protein (GSP), 24h urinary protein excretion (UPE), serum creatinine (Scr), blood urea nitrogen (BUN), and kidney weight index (KWI) were determined. The kidney pathological changes were evaluated by periodic acid-Schiff (PAS) staining. The concentrations of angiotensin II (Ang II), transforming growth factor-beta1 (TGF beta1), connective tissue growth factor (CTGF), fibronectin (FN), collagen type IV (Col IV) in renal cortex were determined. Real time RT-PCR was used to detect the mRNA expressions of TGF-beta1 and CTGF. RESULTS: Catalpol could significantly reduce the KWI, improve the kidney function and pathological change, decrease the tissue level of Ang II, TGF-beta1, CTGF, FN, Col IV. Catalpol could also down regulate the mRNA expressions of TGF-beta1 and CTGF in renal cortex. CONCLUSION: Catalpol may have beneficial effects against diabetic nephropathy. The mechanisms may be related to reducing the extracellular matrix accumulation by restraining the expression of TGF-beta1, CTGF and Ang II. PMID- 23746757 TI - Promising effects on ameliorating mitochondrial function and enhancing Akt signaling in SH-SY5Y cells by (M)-bicelaphanol A, a novel dimeric podocarpane type trinorditerpene isolated from Celastrus orbiculatus. AB - Oxidative stress plays an important role in the pathological processes of various neurodegenerative diseases. In this study, we investigated the neuroprotective effects of (M)-bicelaphanol A, which has been the first dimeric podocarpane type trinorditerpene isolated from Celastrus orbiculatus, against hydrogen peroxide (H2O2)-induced injury in human SH-SY5Y neuroblastoma cells. Our study showed that cells pretreated with (M)-bicelaphanol A significantly attenuated H2O2-induced cell viability reduction and cell apoptosis. These neuroprotective effects of (M) bicelaphanol A were associated with a reduction of reactive oxygen species and an increase in the level of adenosine triphosphate. In addition, (M)-bicelaphanol A pretreatment markedly increased the phosphorylation level of Akt in SH-SY5Y cells. In conclusion, our results for the first time demonstrate that the protection of (M)-bicelaphanol A on SH-SY5Y cells against H2O2-induced oxidative stress may attribute, at least partially, to its attenuation of mitochondrial dysfunction and activation of Akt signaling pathway. Above results shed more light on the molecular mechanisms involved in the neuroprotective effects of (M) bicelaphanol A, which could be a potential drug candidate for the treatment of oxidative stress-associated neurodegenerative diseases. PMID- 23746758 TI - Antipathogenic potential of Rhizophora spp. against the quorum sensing mediated virulence factors production in drug resistant Pseudomonas aeruginosa. AB - Quorum sensing (QS) is a process of cell-cell communication mechanism occurs between the bacterial cells through the secretary signal molecules. This QS mechanism has been shown to control over the expression of various genes responsible for the production of virulence factors in several bacterial pathogens. Hence, the present study was intended to evaluate the antipathogenic potential of mangrove trees of the genus Rhizophora against the QS dependent virulence factors production in Pseudomonas aeruginosa PAO1, clinical isolates CI I (GU447237) and CI-II (GU447238). The methanol extract of Rhizophora apiculata and R. mucronata (1 mg/ml) showed significant inhibition against QS dependent virulence factors production such as LasA protease, LasB elastase, total protease, pyocyanin pigment production and biofilm formation in P. aeruginosa PAO1, CI-I and CI-II. This study for the first time, reports the quorum sensing inhibitory (QSI) potential of Rhizophora spp. against P. aeruginosa infections. PMID- 23746756 TI - Antinociceptive effects of oxymatrine from Sophora flavescens, through regulation of NR2B-containing NMDA receptor-ERK/CREB signaling in a mice model of neuropathic pain. AB - PURPOSE: In this study we investigated antinociceptive effects of oxymatrine through regulation of NR2B-containing NMDA receptor-ERK/CREB signaling in a chronic neuropathic pain model induced by chronic constrictive injury (CCI) of the sciatic nerve. METHODS: The von Frey and plantar tests were performed to assess the degree of mechanical and thermal changes respectively. Immunohistochemistry assay was used to evaluate the expressions of NR2B. Western blotting assay were used to evaluate the expressions of NR2B, tERK, p-ERK, tCREB and p-CREB. RESULTS: The intraperitoneal administration of OMT (160, 80 mg/kg) could prevent the development of mechanical allodynia, thermal hyperalgesia induced by CCI. Intraperitoneal administration of OMT decreased the mean IOD of NR2B in the dorsal horn and expression of NR2B, p-ERK and p-CREB protein. CONCLUSION: Regulation of NMDA NR2B receptor-ERK/CREB signaling maybe the targets for the antinociceptive effects of OMT on a chronic neuropathic pain model induced by chronic constrictive injury of the sciatic nerve. PMID- 23746759 TI - The cognitive neuropsychology of recollection. PMID- 23746760 TI - Chest computed tomography imaging for blunt pediatric trauma: not worth the radiation risk. AB - INTRODUCTION: A child's risk of developing cancer from radiation exposure associated with computed tomography (CT) imaging is estimated to be as high as 1/500. Chest CT (CCT), often as part of a "pan-scan," is increasingly performed after blunt trauma in children. We hypothesized that routine CCT for the initial evaluation of blunt injured children does not add clinically useful information beyond chest radiograph (CXR) and rarely changes management. METHODS: Pediatric (<15 y) trauma team evaluations over 6 y at an academic Level I trauma center were reviewed. Demographic data, injuries, imaging, and management were identified for all patients undergoing CT. Effective radiation dose in milliSieverts (mSv) was calculated using age-adjusted scales. RESULTS: Fifty seven of 174 children (33%) undergoing CT imaging had a CCT; 55 (97%) of these had a CXR. Pathology was identified in significantly fewer CXRs compared with CCTs (51% versus 83%, P < 0.001). All 7/57 (12%) emergent or urgent chest interventions were based on information from CXR. In 53 children (93%), the CCT was ordered as part of a pan-scan, resulting in a radiation dose of 37.69 +/- 7.80 mSv from initial CT scans. Radiation dose was significantly greater from CCT than from CXR (8.7 +/- 1.1 mSv versus 0.017 +/- 0.002 mSv, P < 0.001). CONCLUSIONS: Clinically useful information found on CCT had good correlation to information obtained from CXR and did not change patient management, however, did add significantly to the radiation exposure of initial imaging. We recommend selective use of CCT, particularly in the presence of an abnormal mediastinal silhouette on CXR after a significant deceleration injury. PMID- 23746761 TI - Minimizing unnecessary parenteral nutrition after appendectomy in children. AB - BACKGROUND: Consensus guidelines have indicated that postoperative parenteral nutrition (PN) might provide benefit when patients are expected to be nil per os (NPO) >=7 d and when PN is administered >=5 d. We hypothesized that most children receiving PN after appendectomy do not satisfy these criteria. METHODS: The medical records of the patients who had undergone appendectomy for perforated appendicitis from 2006-2011 were analyzed, and the proportion meeting the criteria for beneficial PN was determined. The clinical parameters independently associated with the criteria for beneficial PN (PN therapy >=5 d, ileus >=5 d, NPO >=7 d) were identified using multiple regression analysis. RESULTS: A total of 1612 patients were treated for appendicitis. Of these, 587 met the inclusion criteria (age <16 y, perforated appendicitis, appendectomy within 24 h, no previous indication for PN). Of the 587 patients, 12.1% received PN; 43.8% of these received PN for >=5 d. The predictors of PN duration of >=5 d included preoperative symptoms for >=3 d (P < 0.01) and initiation of PN by postoperative day 3 (P = 0.047). Preoperative symptoms for >=3 d, imaging showing a discrete abscess or bowel obstruction, and operative findings of diffuse peritonitis predicted ileus of >=5 d and NPO of >=7 d (P < 0.01 for all). Major complications were more common in patients with ileus lasting >=5 d. CONCLUSIONS: Fewer than one-half of patients receiving PN in the present cohort met the consensus-based guidelines for postoperative PN. The preoperative symptom duration, preoperative imaging findings demonstrating abscess and/or bowel obstruction, and intraoperative findings of diffuse peritonitis might predict prolonged ileus and longer recovery periods for children undergoing surgery for perforated appendicitis. PMID- 23746762 TI - 5-Aminolevulinic acid-mediated photodynamic therapy using light-emitting diodes of different wavelengths in a mouse model of peritoneally disseminated gastric cancer. AB - BACKGROUND: 5-Aminolevulinic acid (5-ALA) is a precursor of the strong photosensitizer, protoporphyrin IX, in cancer cells. The efficacy of 5-ALA mediated photodynamic therapy (ALA-PDT) using light-emitting diodes (LEDs) was evaluated in a mouse model of peritoneally disseminated gastric cancer. MATERIALS AND METHODS: The effects of violet (peak wavelength 410 nm), green (peak wavelength 525 nm), and red (peak wavelength 635 nm) LEDs on reactive oxygen species generation and ALA-PDT cytotoxicity were measured in vitro. 5-ALA was intraperitoneally injected into a mouse xenograft model of peritoneally disseminated enhanced green fluorescent protein-expressing MKN-45 cells, followed by irradiation of micrometastatic nodules on the omentum and evaluation of the necrotic areas of these nodules. RESULTS: ROS generation and the cytotoxic effects of ALA-PDT were highest for the violet and lowest for the red LEDs. The necrotic areas of nodules were significantly larger after irradiation with each LED than in the control mice. The violet and green LEDs had the same anticancer effects, which were significantly greater than those of the red LED. CONCLUSIONS: ALA-PDT using LEDs was effective in treating peritoneally disseminated gastric cancer. The differences in the anticancer effects among the three light sources indicate the necessity of selecting the light source with the optimal wavelength most effective for in vivo clinical applications. PMID- 23746763 TI - Specialization and utilization after hepatectomy in academic medical centers. AB - BACKGROUND: Specialized procedures such as hepatectomy are performed by a variety of specialties in surgery. We aimed to determine whether variation exists among utilization of resources, cost, and patient outcomes by specialty, surgeon case volume, and center case volume for hepatectomy. METHODS: We queried centers (n = 50) in the University Health Consortium database from 2007-2010 for patients who underwent elective hepatectomy in which specialty was designated general surgeon (n = 2685; 30%) or specialist surgeon (n = 6277; 70%), surgeon volume was designated high volume (>38 cases annually) and center volume was designated high volume (>100 cases annually). We then stratified our cohort by primary diagnosis, defined as primary tumor (n = 2241; 25%), secondary tumor (n = 5466; 61%), and benign (n = 1255; 14%). RESULTS: Specialist surgeons performed more cases for primary malignancy (primary 26% versus 15%) while general surgeons operated more for secondary malignancies (67% versus 61%) and benign disease (18% versus 13%). Specialists were associated with a shorter total length of stay (LOS) (5 d versus 6 d; P < 0.01) and lower in-hospital morbidity (7% versus 11%; P < 0.01). Patients treated by high volume surgeons or at high volume centers were less likely to die than those treated by low volume surgeons or at low volume centers, (OR 0.55; 95% CI 0.33-0.89) and (OR 0.44; 95% CI 0.13-0.56). CONCLUSIONS: Surgical specialization, surgeon volume and center volume may be important metrics for quality and utilization in complex procedures like hepatectomy. Further studies are necessary to link direct factors related to hospital performance in the changing healthcare environment. PMID- 23746764 TI - Predicting lymph node metastasis in early colorectal cancer using the CITED1 expression. AB - BACKGROUND: The identification of molecular markers that are useful for predicting lymph node metastasis is urgently needed to determine treatment strategies for T1 colorectal cancer (CRC). We previously showed that 10 candidate genes are correlated with de-differentiation at the invasion front of CRC using a gene expression analysis. These 10 genes are potential markers that may predict lymph node metastasis by CRC. MATERIALS AND METHODS: Samples were obtained from 161 patients with CRC. Quantitative real-time reverse transcription-polymerase chain reaction assays were performed using 66 T3 samples in order to extract genes correlated with lymph node metastasis. Immunohistochemical studies of the extracted genes were performed on 66 T3 and 95 T1 samples. A univariate analysis followed by a multivariate logistic regression model was used to examine independent risk factors for lymph node metastasis. RESULTS: The CITED1 messenger RNA expression was found to be an independent risk factor for lymph node metastasis in T3 CRC patients (P = 0.040). A high CITED1 protein expression, as detected with immunohistochemistry, was also an independent risk factor in T3 CRC patients (P = 0.035). In T1 colorectal cancer patients, a high CITED1 protein expression was found to be an independent risk factor for lymph node metastasis (P = 0.010). The positive predictive and negative predictive values in the T1 colorectal cancer patients were 27.5% and 95.5%, respectively. CONCLUSIONS: The CITED1 expression is correlated with lymph node metastasis in patients with CRC. In T1 colorectal cancer patients, CITED1 has the potential ability to predict the presence of lymph node metastasis. PMID- 23746765 TI - Implications of Foley catheterization in children with perforated appendicitis. AB - BACKGROUND: We treat patients after appendectomy for perforated appendicitis with patient controlled analgesia (PCA) using a background continuous dose. We usually place urinary catheters in these patients because of concerns of urinary retention. The objective of the present study was to determine the rate of urinary retention in this patient population when a catheter was not used or was removed before the continuous PCA infusion was discontinued. METHODS: We performed a retrospective review of all patients who had received PCA postoperatively for perforated appendicitis from December 2008 to May 2011. The demographics, need for replacement of a Foley catheter, number of recorded nursing calls to physicians, and the incidence of urinary tract infection was recorded. Patients who had received a urinary catheter intraoperatively were compared with those who had not. Subgroups were also created according to whether the patients with a Foley catheter had undergone removal of their catheter before or after cessation of the continuous PCA infusion. RESULTS: Of 242 patients, 20 (8.3%) did not have a catheter postoperatively, 1 of whom required a catheter because of retention. Of the 222 patients who started with a catheter, 2 required reinsertion for retention (P = 0.59). Age, gender, and body mass index were similar for patients with and without a catheter. In the subgroup analysis, of the patients with a catheter, 48 (21.6%) had their catheter removed before discontinuation of the continuous PCA infusion and none required Foley catheter replacement. Of the 174 patients whose catheters were removed after discontinuation of the continuous PCA dose, 2 required catheter replacement (P = 0.46). A significantly higher percentage of telephone calls was generated for patients with a catheter than for patients without a Foley catheter (41.4% versus 10%, P = 0.007). No patients with a catheter developed a urinary tract infection. CONCLUSIONS: Patients with a perforated appendicitis who receive a continuous PCA have a low rate of urinary retention whether or not a catheter has been placed intraoperatively. PMID- 23746766 TI - CHD1L promotes tumor progression and predicts survival in colorectal carcinoma. AB - BACKGROUND: To evaluate the expression of chromodomain helicase/adenosine triphosphatase DNA binding protein 1-like gene (CHD1L) in colorectal carcinoma (CRC) and its clinical significance. Its oncogenic ability was also investigated. MATERIALS AND METHODS: CHD1L amplification and overexpression were detected by fluorescence in situ hybridization, real-time reverse transcriptase-polymerase chain reaction, and immunohistochemistry in 86 patients with CRC. The correlation between the clinical characteristics and prognosis was also determined. To evaluate the tumorigenic ability of CHD1L, it was cloned into expression vector pcDNA3.1(+) and transfected into CRC cell line SW1116. Next, the changes in the biologic behavior of the CRC cells, including cell proliferation, adhesion, migration, and invasion, were examined. Apoptosis and the cell cycle of the CRC cells were detected using flow cytometry. RESULTS: We have demonstrated that CHD1L is frequently amplified and overexpressed in CRC. Overexpression of CHD1L correlated with a large tumor size, deep tumor invasion, and a high histologic grade. It also conferred worse disease-free survival. CHD1L-transfected cells possessed a strong oncogenic ability, increasing the tumorigenicity in nude mice, which could be effectively suppressed by small interfering RNA against CHD1L. Functional studies showed that overexpression of CHD1L could promote G1/S-phase cells and inhibit apoptosis. CONCLUSIONS: Our results suggest that CHD1L is the target oncogene within the 1q21 amplicon and plays a pivotal role in CRC pathogenesis. PMID- 23746767 TI - Epidermal growth factor receptor overexpression is a marker for adverse pathologic features in papillary thyroid carcinoma. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) overexpression (EGFR-H) is implicated in thyroid carcinoma disease progression; however, the clinicopathologic significance of EGFR-H in tumors that harbor EGFR and/or v-Raf murine sarcoma viral oncogene homolog B1 (BRAF)(V600E) mutations is unknown. METHODS: Tissue microarrays from 81 patients who had undergone thyroidectomy for carcinoma from 2002-2011 were scored for EGFR expression using immunohistochemistry. Somatic mutations in EGFR exons 19 and 21 and BRAF were analyzed. Correlations between the EGFR immunohistochemistry, EGFR, and BRAF(V600E) mutations and the clinicopathologic features were assessed. RESULTS: EGFR-H was detected in 39.5% of carcinomas (n = 32) from patients with papillary (PTC, 46.2%, n = 18), follicular (29.6%, n = 8), and anaplastic (100.0%, n = 6) but not medullary (0.0%, n = 9) thyroid carcinoma. BRAF(V600E) mutations were identified in 22.2% of the carcinoma cases (n = 18, 15 PTCs and 3 anaplastic thyroid carcinomas). No somatic EGFR mutations were detected in any subtype. On PTC univariate analysis, EGFR-H correlated with increasing stage, extrathyroid extension, tumor capsule invasion, adverse pathologic features (any demonstration of extrathyroid extension, tumor capsule invasion, lymphovascular invasion, lymph node metastasis, and/or distant metastasis), and BRAF(V600E) mutations. On multivariate analysis, EGFR-H correlated with BRAF(V600E) mutations. In BRAF wild type PTCs, the correlation between EGFR-H and adverse pathologic features approached statistical significance (P = 0.065). CONCLUSIONS: EGFR-H could be an important biomarker for aggressive PTCs, particularly in BRAF wild-type PTCs. Despite EGFR-H in PTC, follicular thyroid carcinoma, and anaplastic thyroid carcinoma by immunohistochemistry, somatic EGFR mutations were absent. Therefore, future investigations of EGFR should consider histologic and immunohistochemical methods, in addition to molecular profiling of thyroid carcinomas. This multimodal approach is particularly important for future clinical trials testing anti-EGFR therapy. PMID- 23746768 TI - What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications. AB - BACKGROUND: At the time of writing only dopamine agonists are licensed for the treatment of restless legs syndrome (RLS) in various countries, but randomized controlled trials (RCTs) have been performed with other treatments. We performed comprehensive meta-analyses and indirect comparisons of RCTs for all currently recommended treatments of RLS. METHODS: We searched the Central, Medline, Embase, PsycINFO and CINAHL databases. Outcome measures were the international RLS study group severity scale (IRLS), clinical global impression-improvement, (CGI-I), periodic limb movement index (PLMI), and psychosocial parameters such as quality of life (QoL). We also conducted indirect comparisons by testing for heterogeneity between the substance groups. RESULTS: Placebo (58 trials) and actively (4 trials) controlled RCTs with dopamine agonists (38 trials), levodopa (4 trials), anticonvulsants (13 trials), most of them with alpha2delta ligands (11 trials), opioids (1 trial), and iron treatments (6 trials) were included (9596 patients). Although treatment effects showed large variations, changes in the IRLS in the substance groups were comparable (P = 0.78), with a mean reduction in the IRLS of -5.47 points for dopamine agonists, -5.12 points for anticonvulsants (alpha2delta ligands and levetiracetam), and -4.59 points for iron treatments. The CGI-I indicated slightly different treatment effects between the substance groups, while PLMI changes during treatment differed (P = 0.002), showing a marked decrease with dopamine agonists (-22.50/h), levodopa (-26.01/h), and oxycodone (-34.46/h) compared with a slight decrease for anticonvulsants (alpha2delta ligands and levetiracetam; -8.48/h) and iron treatments (-13.10/h). Quality of sleep and QoL improved moderately in most of the RCTs investigating these parameters (standardized mean difference, SMD) 0.40 and 0.33, respectively). In the few studies evaluating the change of depressive (n = 4) or anxiety symptoms (n = 3), these symptoms improved slightly (SMD -0.24, and 0.21). Adverse effects and dropouts were comparable in number across all substance groups. In meta-regressions, the treatment effect was predicted by the design of the trial (the more sites involved in a trial the lower the effect) and by the duration of action of a medication (the longer the duration of action, expressed as the half-life time of a substance, the greater the improvement), the latter indicating potential superiority of treatments with stable blood concentration. CONCLUSION: This first meta-analysis of all RCTs for the pharmacological treatment of RLS provides evidence that, besides the well-defined efficacy of dopaminergic treatment, other treatments with different pharmacological principles show efficacy in small samples and may be well tolerated alternatives for the treatment of RLS. In the group of anticonvulsants, only the trials performed with alpha2delta ligands such as gabapentin, gabapentin enacarbil, and pregabalin showed good efficacy. This indicates a specific mechanism of action of these substances in RLS. The group of iron treatments consisted of a few trials with different compounds in oral and intravenous application form, respectively. For a more differentiated evaluation of the efficacy of iron treatments further studies are necessary. The large efficacy of one opioid RCT in RLS has to be confirmed in further studies. PMID- 23746769 TI - How clinician-patient communication contributes to health improvement: modeling pathways from talk to outcome. AB - OBJECTIVE: Although researchers have long investigated relationships between clinician-patient communication and health outcomes, much of the research has produced null, inconsistent, or contradictory findings. This essay examines challenges in the study of how clinician-patient communication contributes to a patient's health and offers recommendations for future research. DISCUSSION: Communication may directly impact outcomes, but more often it will have an indirect effect through its influence on intervening variables (e.g., patient understanding, clinician-patient agreement on treatment, adherence to treatment). For example, a patient communication skills intervention may not directly improve pain control for cancer patients. However, it may do so indirectly by activating patients to talk about cancer pain, which prompts the physician to change pain medication, which leads to better pain control. Additionally, communication measurement is complicated because relationships among communication behavior, meaning, and evaluation are complex. CONCLUSION: Researchers must do more to model pathways linking clinician-patient communication to the outcomes of interest, particularly pathways in which the communication effects are indirect or mediated through other variables. To better explicate how communication contributes to health outcomes, researchers must critically reflect on the assumptions they are making about communication process and choose measures consistent with those assumptions. PMID- 23746770 TI - Data-to-text summarisation of patient records: using computer-generated summaries to access patient histories. AB - OBJECTIVE: We assess the efficacy and utility of automatically generated textual summaries of patients' medical histories at the point of care. METHOD: Twenty-one clinicians were presented with information about two cancer patients and asked to answer key questions. For each clinician, the information on one of the patients comprised their official hospital records, and for the other patient it comprised summaries that were computer-generated by a natural language generation system from data extracted from the official records. We measured the accuracy of the clinicians' responses to the questions, the time they took to complete them, and recorded their attitude to the computer-generated summaries. RESULTS: Results showed no significant difference in the accuracy of responses to the computer generated records over the official records, but a significant difference in the time taken to assess the patients' condition from the computer-generated records. Clinicians expressed a positive attitude towards the computer-generated records. CONCLUSION: AI-based computer-generated textual summaries of patient histories can be as accurate as, and more efficient than, human-produced patient records for clinicians seeking to accurately identify key information about a patients overall history. PRACTICE IMPLICATIONS: Computer-generated textual summaries of patient histories can contribute to the management of patients at the point-of care. PMID- 23746771 TI - World Health Assembly adopts Comprehensive Mental Health Action Plan 2013-2020. PMID- 23746773 TI - Global child and maternal nutrition--the SUN rises. PMID- 23746772 TI - Maternal and child undernutrition and overweight in low-income and middle-income countries. AB - Maternal and child malnutrition in low-income and middle-income countries encompasses both undernutrition and a growing problem with overweight and obesity. Low body-mass index, indicative of maternal undernutrition, has declined somewhat in the past two decades but continues to be prevalent in Asia and Africa. Prevalence of maternal overweight has had a steady increase since 1980 and exceeds that of underweight in all regions. Prevalence of stunting of linear growth of children younger than 5 years has decreased during the past two decades, but is higher in south Asia and sub-Saharan Africa than elsewhere and globally affected at least 165 million children in 2011; wasting affected at least 52 million children. Deficiencies of vitamin A and zinc result in deaths; deficiencies of iodine and iron, together with stunting, can contribute to children not reaching their developmental potential. Maternal undernutrition contributes to fetal growth restriction, which increases the risk of neonatal deaths and, for survivors, of stunting by 2 years of age. Suboptimum breastfeeding results in an increased risk for mortality in the first 2 years of life. We estimate that undernutrition in the aggregate--including fetal growth restriction, stunting, wasting, and deficiencies of vitamin A and zinc along with suboptimum breastfeeding--is a cause of 3.1 million child deaths annually or 45% of all child deaths in 2011. Maternal overweight and obesity result in increased maternal morbidity and infant mortality. Childhood overweight is becoming an increasingly important contributor to adult obesity, diabetes, and non communicable diseases. The high present and future disease burden caused by malnutrition in women of reproductive age, pregnancy, and children in the first 2 years of life should lead to interventions focused on these groups. PMID- 23746774 TI - Delivery platforms for sustained nutrition in Ethiopia. PMID- 23746777 TI - Only collective action will end undernutrition. PMID- 23746776 TI - Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost? AB - Maternal undernutrition contributes to 800,000 neonatal deaths annually through small for gestational age births; stunting, wasting, and micronutrient deficiencies are estimated to underlie nearly 3.1 million child deaths annually. Progress has been made with many interventions implemented at scale and the evidence for effectiveness of nutrition interventions and delivery strategies has grown since The Lancet Series on Maternal and Child Undernutrition in 2008. We did a comprehensive update of interventions to address undernutrition and micronutrient deficiencies in women and children and used standard methods to assess emerging new evidence for delivery platforms. We modelled the effect on lives saved and cost of these interventions in the 34 countries that have 90% of the world's children with stunted growth. We also examined the effect of various delivery platforms and delivery options using community health workers to engage poor populations and promote behaviour change, access and uptake of interventions. Our analysis suggests the current total of deaths in children younger than 5 years can be reduced by 15% if populations can access ten evidence based nutrition interventions at 90% coverage. Additionally, access to and uptake of iodised salt can alleviate iodine deficiency and improve health outcomes. Accelerated gains are possible and about a fifth of the existing burden of stunting can be averted using these approaches, if access is improved in this way. The estimated total additional annual cost involved for scaling up access to these ten direct nutrition interventions in the 34 focus countries is Int$9.6 billion per year. Continued investments in nutrition-specific interventions to avert maternal and child undernutrition and micronutrient deficiencies through community engagement and delivery strategies that can reach poor segments of the population at greatest risk can make a great difference. If this improved access is linked to nutrition-sensitive approaches--ie, women's empowerment, agriculture, food systems, education, employment, social protection, and safety nets--they can greatly accelerate progress in countries with the highest burden of maternal and child undernutrition and mortality. PMID- 23746775 TI - Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis. AB - BACKGROUND: Babies with low birthweight (<2500 g) are at increased risk of early mortality. However, low birthweight includes babies born preterm and with fetal growth restriction, and not all these infants have a birthweight less than 2500 g. We estimated the neonatal and infant mortality associated with these two characteristics in low-income and middle-income countries. METHODS: For this pooled analysis, we searched all available studies and identified 20 cohorts (providing data for 2,015,019 livebirths) from Asia, Africa, and Latin America that recorded data for birthweight, gestational age, and vital statistics through 28 days of life. Study dates ranged from 1982 through to 2010. We calculated relative risks (RR) and risk differences (RD) for mortality associated with preterm birth (<32 weeks, 32 weeks to <34 weeks, 34 weeks to <37 weeks), small for-gestational-age (SGA; babies with birthweight in the lowest third percentile and between the third and tenth percentile of a US reference population), and preterm and SGA combinations. FINDINGS: Pooled overall RRs for preterm were 6.82 (95% CI 3.56-13.07) for neonatal mortality and 2.50 (1.48-4.22) for post-neonatal mortality. Pooled RRs for babies who were SGA (with birthweight in the lowest tenth percentile of the reference population) were 1.83 (95% CI 1.34-2.50) for neonatal mortality and 1.90 (1.32-2.73) for post-neonatal mortality. The neonatal mortality risk of babies who were both preterm and SGA was higher than that of babies with either characteristic alone (15.42; 9.11-26.12). INTERPRETATION: Many babies in low-income and middle-income countries are SGA. Preterm birth affects a smaller number of neonates than does SGA, but is associated with a higher mortality risk. The mortality risks associated with both characteristics extend beyond the neonatal period. Differentiation of the burden and risk of babies born preterm and SGA rather than with low birthweight could guide prevention and management strategies to speed progress towards Millennium Development Goal 4- the reduction of child mortality. FUNDING: Bill & Melinda Gates Foundation. PMID- 23746778 TI - Maternal and child nutrition: building momentum for impact. PMID- 23746779 TI - Nutrition-sensitive food systems: from rhetoric to action. PMID- 23746780 TI - Nutrition-sensitive interventions and programmes: how can they help to accelerate progress in improving maternal and child nutrition? AB - Acceleration of progress in nutrition will require effective, large-scale nutrition-sensitive programmes that address key underlying determinants of nutrition and enhance the coverage and effectiveness of nutrition-specific interventions. We reviewed evidence of nutritional effects of programmes in four sectors--agriculture, social safety nets, early child development, and schooling. The need for investments to boost agricultural production, keep prices low, and increase incomes is undisputable; targeted agricultural programmes can complement these investments by supporting livelihoods, enhancing access to diverse diets in poor populations, and fostering women's empowerment. However, evidence of the nutritional effect of agricultural programmes is inconclusive--except for vitamin A from biofortification of orange sweet potatoes--largely because of poor quality evaluations. Social safety nets currently provide cash or food transfers to a billion poor people and victims of shocks (eg, natural disasters). Individual studies show some effects on younger children exposed for longer durations, but weaknesses in nutrition goals and actions, and poor service quality probably explain the scarcity of overall nutritional benefits. Combined early child development and nutrition interventions show promising additive or synergistic effects on child development--and in some cases nutrition--and could lead to substantial gains in cost, efficiency, and effectiveness, but these programmes have yet to be tested at scale. Parental schooling is strongly associated with child nutrition, and the effectiveness of emerging school nutrition education programmes needs to be tested. Many of the programmes reviewed were not originally designed to improve nutrition yet have great potential to do so. Ways to enhance programme nutrition-sensitivity include: improve targeting; use conditions to stimulate participation; strengthen nutrition goals and actions; and optimise women's nutrition, time, physical and mental health, and empowerment. Nutrition-sensitive programmes can help scale up nutrition-specific interventions and create a stimulating environment in which young children can grow and develop to their full potential. PMID- 23746781 TI - The politics of reducing malnutrition: building commitment and accelerating progress. AB - In the past 5 years, political discourse about the challenge of undernutrition has increased substantially at national and international levels and has led to stated commitments from many national governments, international organisations, and donors. The Scaling Up Nutrition movement has both driven, and been driven by, this developing momentum. Harmonisation has increased among stakeholders, with regard to their understanding of the main causes of malnutrition and to the various options for addressing it. The main challenges are to enhance and expand the quality and coverage of nutrition-specific interventions, and to maximise the nutrition sensitivity of more distal interventions, such as agriculture, social protection, and water and sanitation. But a crucial third level of action exists, which relates to the environments and processes that underpin and shape political and policy processes. We focus on this neglected level. We address several fundamental questions: how can enabling environments and processes be cultivated, sustained, and ultimately translated into results on the ground? How has high level political momentum been generated? What needs to happen to turn this momentum into results? How can we ensure that high-quality, well-resourced interventions for nutrition are available to those who need them, and that agriculture, social protection, and water and sanitation systems and programmes are proactively reoriented to support nutrition goals? We use a six-cell framework to discuss the ways in which three domains (knowledge and evidence, politics and governance, and capacity and resources) are pivotal to create and sustain political momentum, and to translate momentum into results in high-burden countries. PMID- 23746782 TI - Nutrition: a quintessential sustainable development goal. PMID- 23746783 TI - Pregnancy care and birth outcomes for women with moderate to super-extreme obesity. AB - PURPOSE: To describe the health service utilisation and birth outcomes of pregnant women with moderate to super-extreme obesity. BACKGROUND: Maternal obesity is increasingly recognised as a key risk factor for adverse outcomes for both women and their babies. Little is known about the service utilisation and perinatal outcomes of women with obesity beyond a body mass index of 40. METHOD: Women with a self-reported pre-pregnancy BMI of 40 or more, who had received care and birthed a baby at the study site between 1 January 2009 and 31 December 2010. Clinical audit was used to identify the health service utilisation and birth outcomes of these women. RESULTS: 153 women had a BMI of 40 or more. Women saw 6 different health professionals during pregnancy (1-16). Most of their visits were with a medical practitioner, often with limited experience, and almost all women only saw a midwife once at their booking visit (n=150, 98.0%). While the majority of women experienced a normal pregnancy, free from any complications, almost half the women in this study experienced a caesarean section (n=74, 48.4%). CONCLUSION: Clinical audit has been useful in providing additional information which suggests current maternity care provision is not meeting the needs of this group of women. The model of antenatal care provision may be a mediating factor in the birth outcomes experienced by obese women. The development of effective, targeted antenatal care, designed to meet the needs of these women is recommended. PMID- 23746784 TI - Novel chlorinated dibenzofurans isolated from the cellular slime mold, Polysphondylium filamentosum, and their biological activities. AB - Cellular slime molds are expected to have the huge potential for producing secondary metabolites including polyketides, and we have studied the diversity of secondary metabolites of cellular slime molds for their potential utilization as new biological resources for natural product chemistry. From the methanol extract of fruiting bodies of Polysphondylium filamentosum, we obtained new chlorinated benzofurans Pf-1 (4) and Pf-2 (5) which display multiple biological activities; these include stalk cell differentiation-inducing activity in the well-studied cellular slime mold, Dictyostelium discoideum, and inhibitory activities on cell proliferation in mammalian cells and gene expression in Drosophila melanogaster. PMID- 23746785 TI - Primary vertebral osteosarcoma: five cases. AB - Primary vertebral osteosarcoma is a rare type of osteosarcoma, differing from the appendicular forms by an incidence peak occurring at a higher age and a poorer prognosis, due to the difficulties of the surgical treatment. We present five cases of histologically proven primary vertebral osteosarcomas followed in our institution between 2004 and 2012. They allow to illustrate some essential radiologic features, useful to evoke this rare entity. PMID- 23746786 TI - Reply to: "understanding the immunogenicity concept". PMID- 23746787 TI - Reply to Balsa et al. relative with the review "Understanding the concept of immunogenicity". PMID- 23746788 TI - Neuropsychiatric manifestations in systemic lupus erythematosus: physiopathogenic and therapeutic basis. PMID- 23746789 TI - Acute effect of callosotomy on cortical temporal coupling in humans: intraoperative electrocorticographic recording. AB - OBJECTIVE: To investigate the acute role of the corpus callosum in inter- and intrahemispheric temporal coupling. METHODS: Intraoperative electrocorticography (ECoG) makes it possible to investigate the acute role of the corpus callosum in cortical temporal coupling, or synchrony, without additional surgical intervention, thus avoiding the confounding effects of scalp recordings and the long-term reorganization of functional connectivity. ECoGs were recorded in three patients during callosotomies. Bilateral electrode grids were placed over the frontal cortex. ECoGs were recorded immediately before and after performing the anterior two-thirds callosal transection, were digitalized at a sampling rate of 512Hz, inspected for artifacts, and later analyzed offline. Cross-correlation between inter- and intrahemispheric electrode pairs were obtained for 1Hz bins and special broad bands obtained by principal component analysis for each patient pre- and post-callosotomy. RESULTS: A statistically significant change was observed in intrahemispheric temporal coupling between electrode pairs that exceeded the confidence limit of correlation. CONCLUSIONS: Present results show that interrupting the influence of the corpus callosum has an acute effect on intrahemispheric activity by decreasing temporal coupling between cortical areas. SIGNIFICANCE: Intrahemispheric temporal coupling does not depend exclusively on ipsilateral cortico-cortical pathways or on subcortical influences, but also on callosal pathways. PMID- 23746790 TI - New insights into lymphocyte activation and differentiation. PMID- 23746791 TI - Distinct resident and recirculating memory T cell subsets in non-lymphoid tissues. AB - Antigen experienced or memory T cells make a critical contribution to immunity against infection. Many pathogens colonise non-lymphoid tissues and memory T cells in these compartments can deal with such localised infections. Emerging data show that there are at least two phenotypically distinct peripheral T cell subsets, one permanently resident and one recirculating between tissues and blood. A full appreciation of the T cells in the non-lymphoid memory pool and their relationship to those in the circulation is an important step in understanding how to generate and exploit effective peripheral immunity for the purpose of infection control. PMID- 23746792 TI - Leucine modulates the effect of Walker factor, a proteolysis-inducing factor-like protein from Walker tumours, on gene expression and cellular activity in C2C12 myotubes. AB - Cancer-cachexia causes severe weight loss, particularly from the wasting of skeletal muscle, which occurs due to increased protein catabolism and/or decreased protein synthesis. The muscle protein degradation observed in cancer patients is mediated by a specific cytokine, proteolysis-inducing factor (PIF), which is produced by the tumour. This protein increases the ubiquitin-proteasome pathway activity, and the synthesis of muscle protein in these patients can be affected by several factors, including nutrient-related signalling. Some nutrients, such as leucine, can decrease the ubiquitin-proteasome pathway activity and increase the skeletal muscle protein content in cachectic animals. In this study, we investigated the effects of leucine on cell viability, morphology, functional proteasome activity, enzymatic activity, and protein synthesis and degradation in C2C12 myotubes exposed to the proteolysis-inducing factor (PIF)-like protein purified from Walker tumour-bearing rats. Walker factor (WF) had no cytotoxic effects on myotube cells and morphological characteristics were not altered in the presence of WF and/or leucine. However, increased alkaline phosphatase activity was observed. At higher WF concentrations, chymotrypsin-like activity, cathepsin B activity and 20S proteasome gene expression increased. Treating myotubes with leucine before exposure to WF causes leads to a decrease in proteasome activity as well as the activity of chymotrypsin and cathepsin enzymes. Total protein synthesis decreased in WF treated cells concomitantly as protein degradation increased. After leucine exposure, the observed effects of WF were minimal or even reverted in some cases. Taken together, these results suggest an important modulatory effect for leucine on the effects of WF in C2C12 myotube cells. PMID- 23746793 TI - Asymmetries of knowledge in patient-provider encounters: three studies adopting conversation analysis. PMID- 23746794 TI - Multiple endocrine neoplasia type I presenting as recurrent stroke like episodes. PMID- 23746795 TI - Association of ALOX5AP1 SG13S114T/A variant with ischemic stroke, stroke subtypes and aspirin resistance. AB - The important role of genetic variants in the etiology and pathophysiology of stroke is being increasingly recognized. Simultaneously, the influence of genetic factors in the clinical outcome of drug therapy cannot be ignored. 5-lipoxygenase activating (ALOX5AP) gene involved in the synthesis of leukotrienes, has been recognized as an important gene contributing towards susceptibility of stroke risk. Leukotrienes are involved in the physiological mechanism of atherosclerotic events and inflammation. The present study was designed to identify the association of SG13S114T/A polymorphism in ALOX5AP1 gene with risk of stroke, its subtypes and aspirin resistance. We studied six hundred and ten patients with ischemic stroke and six hundred and ten age and sex matched healthy controls. The ischemic stroke was classified according to Trial of Org 10172 in Acute stroke Treatment. ALOX5AP1 SG13S114T/A polymorphism was determined using PCR RFLP methods. Follow-up was done for all the patients for a period of 3 months, 6 months and 12 months. The patients were classified into two groups responders and non-responders. The non-responders were identified to have a poor clinical outcome defined as a score of more than 2 on modified Rankin Scale Score and less than 5 on extended Glassgow Outcome Scale from stroke onset. We found statistically significant difference in the genotypic distribution between patients and controls (for AA vs TT, chi2=9.894; p=0.001, odds ratio=1.68 (95% confidence interval (CI); 1.215, 2.326). Significant difference was observed in the frequency of A and T alleles in patients and controls (A vs T chi(2)=10.23; p=0.001, odds ratio=1.301 (95% CI; 1.107, 1.528). Multiple logistic regression analysis revealed, the most predictive risk factor for stroke was AA genotype [adjusted odds ratio=1.660 (95% CI; 1.167-2.361) and p=0.005], hypertension, smoking and diabetes (p<0.001 in each case). We also found a significant association of AA genotype with intracranial large artery atherosclerosis (p=0.002, odds ratio=2.04, (95%CI; 1.279-3.275) and cardioembolism (p<0.001, odds ratio=4.73 (95% CI; 2.661-8.439). The risk of aspirin resistance was significantly higher among patients with AA genotype in comparison to carriers of homozygous TT genotype (AA vs TT, chi2=22.25, odds ratio=2.983, 95% CI; 1.884- 4.723, p<0.001). The frequency of recurrence and death events was more in non responders. We didn't find a significant association of the aspirin dose with outcome. Our results indicate that the individuals bearing AA genotype of ALOX5AP1 SG13S114T/A polymorphism are more prone to stroke and bad outcome as well as with aspirin resistance than TA and TT genotypes. PMID- 23746796 TI - Global and regional estimates of preeclampsia and eclampsia: a systematic review. AB - Reduction of maternal mortality is a target within the Millennium Development Goals. Data on the incidence of preeclampsia and eclampsia, one of the main causes of maternal deaths, are required at both national and regional levels to inform policies. We conducted a systematic review of the incidence of hypertensive disorders of pregnancy (HDP) with the objective of evaluating its magnitude globally and in different regions and settings. We selected studies using pre-specified criteria, recorded database characteristics and assessed methodological quality of the eligible studies reporting incidence of any HDP during the period 2002-2010. A logistic model was then developed to estimate the global and regional incidence of HDP using pre-specified predictor variables where empiric data were not available. We found 129 studies meeting the inclusion criteria, from which 74 reports with 78 datasets reporting HDP were analysed. This represents nearly 39 million women from 40 countries. When the model was applied, the overall estimates are 4.6% (95% uncertainty range 2.7-8.2), and 1.4% (95% uncertainty range 1.0-2.0) of all deliveries for preeclampsia and eclampsia respectively, with a wide variation across regions. The figures we obtained give a general idea of the magnitude of the problem and suggest that some regional variations might exist. The absence of data in many countries is of concern, however, and efforts should be made to implement data collection and reporting for substantial statistics. The implementation of large scale surveys conducted during a short period of time could provide more reliable and up-to-date estimations to inform policy. PMID- 23746798 TI - Fetal growth in women with homozygous sickle cell disease: an observational study. AB - OBJECTIVES: To assess fetal growth and whether lower birthweight to mothers with homozygous sickle cell (SS) disease is related to maternal body composition or to clinical events in pregnancy. STUDY DESIGN: A prospective study of 41 pregnant women with SS disease and 41 women with a normal (AA) phenotype attending the antenatal clinic, University Hospital of the West Indies, Kingston, Jamaica. Maternal anthropometry, body composition and fetal sonographic measurements were assessed at 15, 25, and 35 weeks' gestation from December 2005 to April 2008. Birth measurements were performed within 24h of delivery. Differences between maternal genotypes and between their offspring were assessed using 2-sample t tests. Multiple linear regression was used to control for baby's gender and gestational age at delivery. Fetal growth was compared in SS mothers with and without admission for sickle-related complications including bone pain crisis, acute chest syndrome, pregnancy-induced hypertension and urinary tract infection. RESULTS: Mothers with SS disease had lower weight, body fat, fat mass and lean body mass throughout pregnancy but correlation with birth size did not reach statistical significance. Sonographically, babies of SS mothers had smaller abdominal circumference, femoral length and a lower estimated fetal weight at 35 weeks. Birth measurements confirm lower birthweight, crown-heel length and head circumference but the differences were no longer significant after adjustment for baby gender and gestational age at delivery. Bone pain crisis in pregnancy was associated with a significantly reduced crown-heel length at birth. CONCLUSION: Lower birthweight in babies of mothers with SS disease is largely the result of the lower gestational age. Fetal sonography showed no growth differences by maternal genotype until 35 weeks' gestation and a reduced crown-heel length in offspring of SS mothers was associated with bone pain crises in pregnancy. PMID- 23746797 TI - Rupture of a pseudoaneurysm as a rare cause of severe postpartum hemorrhage: analysis of 11 cases and a review of the literature. AB - OBJECTIVE: To clarify the clinical features of severe postpartum hemorrhage (PPH) resulting from a ruptured pseudoaneurysm and to determine the efficacy of selective arterial embolization as a method of management. STUDY DESIGN: Eleven women who underwent selective arterial embolization for treatment of severe hemorrhage due to a ruptured pseudoaneurysm were identified from 2 hospitals within the past 5 years. A retrospective analysis was performed to identify the clinical characteristics of the hemorrhage and to evaluate the efficacy of arterial embolization. RESULTS: Nine women delivered by cesarean delivery. Eight of the 11 women had late PPH with onset of bleeding occurring 6-100 days (median, 11.5) after delivery. The average volume of transfusion was 3196 ml of packed red blood cells (range, 1600-8980 ml). Uterine atony occurred in only one patient and was accompanied by an intrauterine abscess. Administration of uterotonic agents did not diminish the bleeding. Only one patient out of 11 underwent re embolization. CONCLUSION: If late PPH without uterine infection or retained placenta occurs after cesarean delivery, one should suspect the possibility of a ruptured pseudoaneurysm. Selective arterial embolization may be considered as a primary means of treatment. PMID- 23746799 TI - Implications of within-farm transmission for network dynamics: consequences for the spread of avian influenza. AB - The importance of considering coupled interactions across multiple population scales has not previously been studied for highly pathogenic avian influenza (HPAI) in the British commercial poultry industry. By simulating the within-flock transmission of HPAI using a deterministic S-E-I-R model, and by incorporating an additional environmental class representing infectious faeces, we tracked the build-up of infectious faeces within a poultry house over time. A measure of the transmission risk (TR) was computed for each farm by linking the amount of infectious faeces present each day of an outbreak with data describing the daily on-farm visit schedules for a major British catching company. Larger flocks tended to have greater levels of these catching-team visits. However, where density-dependent contact was assumed, faster outbreak detection (according to an assumed mortality threshold) led to a decreased opportunity for catching-team visits to coincide with an outbreak. For this reason, maximum TR-levels were found for mid-range flock sizes (~25,000-35,000 birds). When assessing all factors simultaneously using multivariable linear regression on the simulated outputs, those related to the pattern of catching-team visits had the largest effect on TR, with the most important movement-related factor depending on the mode of transmission. Using social network analysis on a further database to inform a measure of between-farm connectivity, we identified a large fraction of farms (28%) that had both a high TR and a high potential impact at the between farm level. Our results have counter-intuitive implications for between-farm spread that could not be predicted based on flock size alone, and together with further knowledge of the relative importance of transmission risk and impact, could have implications for improved targeting of control measures. PMID- 23746800 TI - Food- and water-borne disease: using case control studies to estimate the force of infection that accounts for primary, sporadic cases. AB - Disease models which take explicit account of heterogeneities in the risk of infection offer significant advantages over models in which the risk of infection is assumed to be uniform across all hosts. However, estimating the incidence rate (force of infection) in the different at-risk (exposure) groups is no easy matter. Classically, epidemiologists differentiate groups of hosts with different infection-risks according to their exposure to putative explanatory risk factors. The importance of these risk factors is assessed by case-control studies, in which the measure of effect (the difference in disease occurrence between one population and another) is the odds ratio. This paper describes for the first time how - and under what circumstances - the incidence in these different exposure groups can be estimated from odds ratios derived from case control studies in which controls have been selected by density sampling. This new estimation technique can be applied to any transmission modality but is especially useful in the case of models of food- and water-borne disease for which the case control literature represents a vast and, as yet, untapped resource. The paper finishes with a worked example using one of the most common of all food- and water-borne pathogens, Toxoplasma gondii. PMID- 23746801 TI - Modeling of bovine spongiform encephalopathy in a two-species feedback loop. AB - Bovine spongiform encephalopathy, otherwise known as mad cow disease, can spread when an individual cow consumes feed containing the infected tissues of another individual, forming a one-species feedback loop. Such feedback is the primary means of transmission for BSE during epidemic conditions. Following outbreaks in the European Union and elsewhere, many governments enacted legislation designed to limit the spread of such diseases via elimination or reduction of one-species feedback loops in agricultural systems. However, two-species feedback loops-those in which infectious material from one-species is consumed by a secondary species whose tissue is then consumed by the first species-were not universally prohibited and have not been studied before. Here we present a basic ecological disease model which examines the role feedback loops may play in the spread of BSE and related diseases. Our model shows that there are critical thresholds between the infection's expansion and decrease related to the lifespan of the hosts, the growth rate of the prions, and the amount of prions circulating between hosts. The ecological disease dynamics can be intrinsically oscillatory, having outbreaks as well as refractory periods which can make it appear that the disease is under control while it is still increasing. We show that non susceptible species that have been intentionally inserted into a feedback loop to stop the spread of disease do not, strictly by themselves, guarantee its control, though they may give that appearance by increasing the refractory period of an epidemic's oscillations. We suggest ways in which age-related dynamics and cross species coupling should be considered in continuing evaluations aimed at maintaining a safe food supply. PMID- 23746802 TI - Antiviral stockpiles for influenza pandemics from the household perspective: treatment alone versus treatment with prophylaxis. AB - Model-based studies of antiviral use to mitigate the impact of moderate and severe influenza pandemics implicitly take the viewpoint of a central public health authority. However, it seems likely that the key decision of when to use antivirals will be made at the household level. We used a stochastic compartmental model of the transmission of influenza within and between households to evaluate the expected mortality under two strategies: households saving available antivirals for treatment only and households implementing prophylaxis as well as treatment. Given that every individual in the population was allocated a single course of antivirals, we investigated the impact of these two strategies for a wide range of AVED, the efficacy of antivirals in preventing death in severe cases (AVED=1 for complete protection). We found a cross-over point for our baseline parameter values in a regime where antivirals were still highly effective in reducing the chance of death: below AVED=0.9 the optimal strategy was for households to use both treatment and prophylaxis. We also considered the possibility that a small number of households might "cheat" by choosing to follow the treatment-only strategy when other households were following treatment with prophylaxis. The cross-over point for cheating households was considerably lower, at AVED=0.6, but substantially above 0. These results suggest that unless antivirals are almost completely effective in reducing the chance of death in serious cases, households will likely be better served implementing prophylaxis as well as treatment. More generally, our study illustrates the potential value of considering viewpoints other than a central authority when conducting model-based analysis of interventions against infectious disease. PMID- 23746803 TI - Infectivity of GI and GII noroviruses established from oyster related outbreaks. AB - Noroviruses (NoVs) are the major cause of acute epidemic gastroenteritis in industrialized countries. Outbreak strains are predominantly genogroup II (GII) NoV, but genogroup I (GI) strains are regularly found in oyster related outbreaks. The prototype Norwalk virus (GI), has been shown to have high infectivity in a human challenge study. Whether other NoVs are equally infectious via natural exposure remains to be established. Human susceptibility to NoV is partly determined by the secretor status (Se+/-). Data from five published oyster related outbreaks were analyzed in a Bayesian framework. Infectivity estimates where high and consistent with NV(GI) infectivity, for both GII and GI strains. The median and CI95 probability of infection and illness, in Se+ subjects, associated with exposure to a mean of one single NoV genome copy were around 0.29[0.015-0.61] for GI and 0.4[0.04-0.61] for GII, and for illness 0.13[0.007 0.39] for GI and 0.18[0.017-0.42] for GII. Se- subjects were strongly protected against infection. The high infectivity estimates for Norwalk virus GI and GII, makes NoVs critical target for food safety regulations. PMID- 23746804 TI - Indirect transmission and the effect of seasonal pathogen inactivation on infectious disease periodicity. AB - The annual occurrence of many infectious diseases remains a constant burden to public health systems. The seasonal patterns in respiratory disease incidence observed in temperate regions have been attributed to the impact of environmental conditions on pathogen survival. A model describing the transmission of an infectious disease by means of a pathogenic state capable of surviving in an environmental reservoir outside of its host organism is presented in this paper. The ratio of pathogen lifespan to the duration of the infectious disease state is found to be a critical parameter in determining disease dynamics. The introduction of a seasonally forced pathogen inactivation rate identifies a time delay between peak pathogen survival and peak disease incidence. The delay is dependent on specific disease parameters and, for influenza, decreases with increasing reproduction number. The observed seasonal oscillations are found to have a period identical to that of the seasonally forced inactivation rate and which is independent of the duration of infection acquired immunity. PMID- 23746805 TI - A noncanonical mechanism of carboxypeptidase inhibition revealed by the crystal structure of the Tri-Kunitz SmCI in complex with human CPA4. AB - The crystal structure of SmCI (Sabellastarte magnifica carboxypeptidase inhibitor) has been determined in complex with human carboxypeptidase A4 (hCPA4). SmCI is composed by three BPTI/Kunitz domains, each one displaying high structural homology and functionality with serine protease inhibitors. Moreover, SmCI possesses a distinctive capability to inhibit metallo-carboxypeptidases, constituting a bifunctional metallocarboxy- and serine protease inhibitor. The structure of the 1:1 complex of SmCI with hCPA4 reveals a noncanonical mechanism of carboxypeptidase inhibition, which surprisingly occurs mainly via the N terminal segment, which penetrates into the active site groove of the enzyme. Mutagenesis and biochemical analysis confirm the major role of the N-terminal segment in the inhibition of carboxypeptidases. SmCI represents a tri-Kunitz serine protease inhibitor adapted to inhibit metallo-carboxypeptidases and discloses an unusual mechanism of inhibition by the N-terminal segment, emulating the "classical" C-terminal substrate-like inhibition. PMID- 23746806 TI - Full-length structure of a sensor histidine kinase pinpoints coaxial coiled coils as signal transducers and modulators. AB - Two-component systems (TCSs), which comprise sensor histidine kinases (SHK) and response-regulator proteins, represent the predominant strategy by which prokaryotes sense and respond to a changing environment. Despite paramount biological importance, a dearth exists of intact SHK structures containing both sensor and effector modules. Here, we report the full-length crystal structure of the engineered, dimeric, blue-light-regulated SHK YF1 at 2.3 A resolution, in which two N-terminal light-oxygen-voltage (LOV) photosensors are connected by a coiled coil to the C-terminal effector modules. A second coaxial coiled coil derived from the N-termini of the LOV photosensors and inserted between them crucially modulates light regulation: single mutations within this coiled coil attenuate or even invert the signal response of the TCS. Structural motifs identified in YF1 recur in signal receptors, and the underlying signaling principles and mechanisms may be widely shared between soluble and transmembrane, prokaryotic, and eukaryotic signal receptors of diverse biological activity. PMID- 23746808 TI - Structure and conformational variability of the mycobacterium tuberculosis fatty acid synthase multienzyme complex. AB - Antibiotic therapy in response to Mycobacterium tuberculosis infections targets de novo fatty acid biosynthesis, which is orchestrated by a 1.9 MDa type I fatty acid synthase (FAS). Here, we characterize M. tuberculosis FAS by single-particle cryo-electron microscopy and interpret the data by docking the molecular models of yeast and Mycobacterium smegmatis FAS. Our analysis reveals a porous barrel like structure of considerable conformational variability that is illustrated by the identification of several conformational states with altered topology in the multienzymatic assembly. This demonstrates that the barrel-like structure of M. tuberculosis FAS is not just a static scaffold for the catalytic domains, but may play an active role in coordinating fatty acid synthesis. The conception of M. tuberculosis FAS as a highly dynamic assembly of domains revises the view on bacterial type I fatty acid synthesis and might inspire new strategies for inhibition of de novo fatty acid synthesis in M. tuberculosis. PMID- 23746807 TI - Structural insights into the functions of TBK1 in innate antimicrobial immunity. AB - Tank-binding kinase 1 (TBK1) is a serine/threonine protein-kinase mediating innate antimicrobial immunity. TBK1 is involved in the signaling of TLRs, RLRs, and STING-mediated sensing of cytosolic DNA. Stimulation of these receptors results in the activation of TBK1, which phosphorylates interferon regulatory factor (IRF)-3. Phosphorylated IRF-3 translocates into the nucleus to initiate the transcription of the interferon (IFN)-beta gene. Here, we show that TBK1 is activated by autophosphorylation at residue Ser172. Structures of TBK1 bound to two inhibitors showed that TBK1 has the IkappaB kinase fold with three distinct domains: the kinase domain, the ubiquitin-like domain, and the scaffold and dimerization domain. However, the overall structures of the TBK1 monomer and its dimer are different from IKKbeta in the arrangements of the three domains and in dimer formation. Phosphorylation of IRF-3 by TBK1 in vitro results in its oligomerization, and phosphorylation of residue Ser386 plays a key role in IRF-3 activation. PMID- 23746809 TI - [Alteration in quality of life in anorexia nervosa and improvement under treatment: validation of a new questionnaire, the QUAVIAM]. AB - Anorexia nervosa (AN) is a chronic and often severe eating disorder, which could have a serious impact on various life domains. AN may lead to physical, mental, behavioural and socioprofessional impairment. Thus, one could expect a poor quality of life (QoL) in AN patients. QoL is certainly a key factor to provide quantitative measurement of treatment efficacy that will facilitate clinical decision-making and treatment planning. Despite that QoL was rarely prospectively analyzed in AN patients, one could conclude that AN patients showed reduced QoL, as compared to normal controls and other psychiatric-disordered patients. It seems that mental health components of QoL are more impaired than the physical ones in AN patients, who showed a modest impact in the physical domain. Thus, our aim was to analyse the QoL using a new, French, questionnaire, the QUAVIAM (qualite de vie dans l'anorexie mentale). After a bibliography research (including EDE, EDI, SF-36, QOL.ED), the choice of 12 themes, regrouped in six scores, was made by three eating disorder specialists and two recovered patients. For each score, 10 to 15 questions were written by the experts, and then corrections and validation were made by the five experts and 21 patients. After this, we prospectively determined the reproducibility (3 days interval), the specificity, and the sensitivity for short-term change in patients exhibiting an "active" AN (n=54, mean age: 31 +/- 9 yrs, mean BMI: 14.1 +/- 2.8 kg/m(2), AN duration: 2.6 +/- 1.9 yrs), and again after cognitive behavioral therapy (CBT). We also analyzed the QUAVIAM score and subscores in 48 recovering patients and in 56 subjects without eating disorder. The QUAVIAM final version (61 questions) was collected in 76 patients and the 56 healthy controls matched for sex and age. Its reproducibility was 91% (intra-questionnaire) and 94% (inter-questionnaire), its specificity 98% (versus controls; P<0.0001) and its sensitivity 99%. The QUAVIAM global score of the AN patients was more impaired (389 +/- 87) than that of the recovering patients (157 +/- 82) and the normal controls (89 +/- 49; P<0.0001). Each of the six subscores was higher (more altered) in active AN than in recovering AN patients and in normal subjects: the somatic, the psychological, the hedonic, the socioprofessional, the affective and the TCA-related ones (P<0.001 for each comparison). The QUAVIAM global score and its subscores were significantly improved (decreased) by the 3-month CBT: 385 +/- 25 before and 189 +/- 30 after CBT (P<0.0001). The changes were observed for all the subscales (P<0.0001). The somatic subscore did not decrease less than the other subscores. Thus, the present study permits proposing the QUAVIAM for analysis of physical, mental, behavioural and socioprofessional impairment or improvements in AN patients. PMID- 23746810 TI - [Is it possible to use molecular biology techniques on endobronchial ultrasound guided transbronchial needle aspirations (EBUS-PTBA)? A challenge]. PMID- 23746811 TI - [Feasibility of assessing EGFR mutation and others using samples obtained by EBUS transbronchial needle aspiration]. AB - INTRODUCTION: Assessment of mutation status in patients with non-small cell lung cancer (NSCLC) is often required. The aim of this study was to confirm the feasibility of molecular mutation analysis in cytologic specimens obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). METHODS: Patients with an EBUS-TBNA positive for adenocarcinoma or NSCLC (squamous cell carcinoma excluded) were included retrospectively from January to December 2010, and prospectively from January to August 2011. Specimens were collected on liquid based preparation and processed on paraffin-embedded cell blocks after ThinPrepO procedure. Molecular analysis was performed by a SnaPshot assay for EGFR and by pyrosequencing for KRAS on suitable samples (>5% tumor cells). RESULTS: Eighty-two patients were included (63 adenocarcinoma). Molecular analysis for EGFR was feasible in 80 (97.6%) patients and for KRAS in 78 (95.1%) patients. Molecular analysis identified EGFR and KRAS mutations in tumor samples from four (5%) and 18 (23%) patients respectively. All EGFR mutations were found in women. CONCLUSIONS: Molecular analysis mutations can be performed routinely in cytologic specimens obtained by EBUS-TBNA. PMID- 23746812 TI - [Surgery for bronchial carcinoma after treatment of a previous cancer]. AB - INTRODUCTION: The increase in the number of cancer survivors, together with the improvement of their follow-up, lead to the frequent diagnosis of resectable non small cell lung cancer (NSCLC) in patients with history of previous malignancy. We sought to analyse the outcomes of these patients. METHODS: Patients undergoing surgical resection for NSCLC between January 1980 and December 2009 were retrospectively reviewed. For each patient, the presence of previous malignancy was noted, and classified into five groups: oro-pharyngeal cancer, lung cancer, haematopoietic malignancy, other organ malignancy, and more than two cancers. RESULTS: The overall population included 5846 patients. Among them, 1243 (21%) had a history of previous malignancy, of whom 383 (31%) presented with synchronous cancer. Patients with history of previous malignancy were more often female, older, with more adenocarcinomas, more limited disease, less pneumonectomies, but higher postoperative morbidity and mortality. Overall survival was worse in patients with a history of previous malignancy than in patients without (median, 5 and 10 year: 33 months, 34.3%, 17.8% versus 47 months, 44.6%, 28.8%). CONCLUSION: A history of previous malignancy impacted significantly the prognosis of patients operated on for limited NSCLC. However, only surgical resection led to improved long-term survival at 5 years. PMID- 23746813 TI - [Attitudes and behavior in relation to smoking among medical students in Casablanca in 2010]. AB - OBJECTIVE: Smoking is a major public health problem. The doctor should be at the forefront in the fight against tobacco. Our study aims to determine the prevalence of smoking among medical students and to evaluate their attitudes towards this problem. PATIENTS AND METHODS: A cross-sectional survey was conducted among 736 medical students enrolled in the faculty of medicine and pharmacy of Casablanca in the academic year 2009/2010. RESULTS: The prevalence of smoking was 7.9%. It was significantly higher in men (16% against 3% in women) and varied little from one age group to another (7-8%). The average number of cigarettes smoked per day was eight. More than half of the students (58%) had attempted to quit smoking. The main motivation was the occurrence of certain symptoms (66%). Ex-smokers accounted for 10% of the total. Moroccan anti-smoking law was poorly understood by more than half of our students (72%). The majority was in favor of prohibition of tobacco sales to children (92%) and the training of health professionals to help patients who want to quit smoking (86%). CONCLUSION: Compared with previous years this study shows a marked decrease in the prevalence of smoking among medical students in Casablanca as well as a better understanding of its ill effects. This is due not only to greater awareness of this problem among medical students but also to the introduction of the teaching of the pathologies related to tobacco. PMID- 23746815 TI - [Pulmonary rehabilitation and non-invasive ventilation before lung surgery in very high-risk patients]. AB - INTRODUCTION: The benefits of a rehabilitation program before surgical lung cancer resection remain to be defined. The purpose of this prospective observational study was to assess the effects of rehabilitation together with the use of noninvasive ventilation (NIV) in patients who were at a high operative risk. METHODS: Between January 2010 and June 2011, 20 consecutive patients (16 males, four females, mean age: 66 years [44-79]) with a clinical N0 non-small cell lung cancer were included. Eligibility criteria were predicted post operative respiratory function (FEV1, VO2 max) below the guideline thresholds for eligibility for surgical resection and/or associated with severe co-morbidities. The protocol included a cardiorespiratory rehabilitation program and 3 hours of NIV each day. Functional tests were repeated after 3 weeks of therapy. RESULTS: Participants displayed a significant increase in their FEV1 and VO2 max, which allowed surgical resection to go ahead in all patients (lobectomy, n=15; pneumonectomy, n=3; bilobectomy, n=2). The morbidity rate was 20% (acute renal failure, n=2; pneumonia, n=1; haemothorax, n=1). The mortality rate was 5% (myocardial infarction, n=1). Further postoperative rehabilitation allowed a return at home in 19 patients after a mean hospital stay of 11 days. CONCLUSION: Pulmonary rehabilitation associated with a period of preoperative NIV allows surgery to be performed in patients who are not initially eligible for resection. An evaluation of long-term outcomes survival in comparison to non-surgical therapies is necessary. PMID- 23746816 TI - [Right upper lobe pulmonary agenesis]. AB - INTRODUCTION: Pulmonary agenesis is a rare congenital anomaly. Other cardiovascular, gastrointestinal, musculoskeletal, and urogenital system anomalies can be observed in association with it. CASE REPORT: A 24-year-old female patient presented to our clinic with a history of cough and chest pain with an abnormal chest X-ray. Physical examination was normal. Chest X-ray, CT Scan and endoscopy led to the diagnosis of right upper lobe pulmonary agenesis. CONCLUSION: The diagnosis of pulmonary malformations like agenesis or hypoplasia can be delayed and may not occur until adulthood. Once the diagnosis has been established medical follow up is mandatory. PMID- 23746814 TI - [Indoor air quality and adult asthma]. AB - INTRODUCTION: Asthma is a chronic inflammatory disease of the airways. The recent increase in its global prevalence suggests a possible role of environmental factors such as indoor air pollution. In 2000, according to the Institute Of Medicine, there was insufficient evidence to determine whether or not an association existed between high priority indoor air pollutants, listed by the French Indoor Air Quality Observatory, and asthma. The objective of this paper is to describe the current state of knowledge on the links between exposure to high priority indoor air pollutants and exacerbations of adult asthma. METHOD: A review of the Medline database has been undertaken of the following pollutants: formaldehyde, benzene, acetaldehyde, volatile organic compounds, particles (PM2.5, PM10) and diethylhexyl-phthalate. The studies were classified by type and source of pollutant. RESULTS: Twenty-three studies were included in the analysis. Most of the observational studies have shown an association between pollutants (by type and source) and adult asthma. The best documented pollutants were formaldehyde and volatile organic compounds. No studies were found on acetaldehyde and diethylhexyl-phthalate. CONCLUSION: The analysis of the literature is complicated on account of the difficulty of comparing different studies. However, since the synthesis performed in 2000, the existence of a link between chemical indoor air pollutants and increased respiratory symptoms appears to be reinforced. It seems necessary to adopt preventive health measures while pursuing scientific research on this topic. PMID- 23746817 TI - [Mediastinal mature teratoma with spontaneous malignant transformation]. AB - INTRODUCTION: Malignant teratomas can be either immature teratomas or they can develop after treatment of other malignant germ cell tumors with chemotherapy or radiotherapy. Spontaneous malignant transformation of mature teratomas is very rare. OBSERVATION: We report the case of a patient complaining of atypical chest pain. Chest plain radiography showed a right anterior mediastinal mass. Computed tomography revealed a heterogeneous mediastinal mass with fat areas and calcification. There were hilar and mediastinal lymph nodes as well as lung parenchymal nodules. CT-guided and then surgical biopsies confirmed the diagnosis of a mature teratoma, which had degenerated into a digestive adenocarcinoma. CONCLUSION: Spontaneous malignant transformation of mature mediastinal teratoma is very rare. The diagnosis of malignant transformation is based on radiological examinations, laboratory tests and histological studies. PMID- 23746818 TI - [Bronchopericardial fistula treatment by a metallic stent]. AB - INTRODUCTION: Bronchopericardial fistula is a rare condition leading to pneumopericardium. This medical condition is often related to neoplastic disease, or a complication of surgical interventions. The treatment approach depends on both the etiology and the clinical presentation. In stable patients, pericardial drain insertion and/or surgical resection of the fistula are considered options for persistent cases. We present the case of a bronchopericardial fistula treated by placement of an endobronchial stent. CASE PRESENTATION: A 64-year-old man operated on for lung cancer had a recurrence treated with radiation and chemotherapy. A pneumopericadium was discovered when he presented with a new onset of atrial fibrillation. Bronchoscopy revealed a fistula tract. Pericardial drainage was persistent and did not improve the clinical situation. The poor health status of the patient contraindicated surgery and an alternative therapeutic approach with endobronchial stent placement was undertaken. The fistula sealed immediately, the pericardial drain could be removed removed and the patient was able to be discharged from hospital. CONCLUSION: Endobronchial stenting should be considered as a potential treatment option in patients with pneumopericardium secondary to bronchopericadial fistula, particularly where a non-surgical is required. PMID- 23746819 TI - [Multiple lung abscesses]. PMID- 23746820 TI - [Pulmonary nodules describing the radiological sign of the galaxy]. PMID- 23746821 TI - [Impact of facial versus nose mask on the length of use of CPAP in patients with Sleep Apnea Syndrome?]. PMID- 23746823 TI - Incomplete sleep paralysis as the first symptom of narcolepsy. PMID- 23746822 TI - Effects of antiepileptic treatment on sleep and seizures in nocturnal frontal lobe epilepsy. AB - OBJECTIVE: To study the effects of antiepileptic treatment on sleep parameters and video-polysomnography (VPSG) seizures in nocturnal frontal lobe epilepsy (NFLE). METHODS: Twenty patients with a clinical and VPSG diagnosis of NFLE (baseline polysomnography [PSG]) underwent a clinical follow-up and performed a second VPSG after effective antiepileptic treatment lasting for at least 6 months. Conventional sleep measures, cyclic alternating pattern (CAP) parameters, and objective VPSG seizures were assessed in NFLE patients before and after treatment and were compared with the results of 20 age- and gender-matched control subjects. RESULTS: Antiepileptic treatment determined a partial reduction of objective VPSG seizures of approximately 25% compared to baseline condition. Alterations of most conventional sleep measures recovered normal values, but nonrapid eye movement (NREM) sleep instability remained pathologically enhanced (CAP rate, +26% compared to controls) and was associated with persistence of daytime sleepiness. CONCLUSIONS: Residual epileptic events and high levels of unstable NREM sleep can define a sort of objective resistance of both seizures and disturbed arousal system to the therapeutic purpose of the antiepileptic drugs in NFLE. This finding could determine the need for new therapeutic options in this particular form of epilepsy. PMID- 23746824 TI - I don't sleep because I can't breathe. PMID- 23746825 TI - Reduced plastic brain responses to repetitive transcranial magnetic stimulation in severe obstructive sleep apnea syndrome. AB - OBJECTIVES: Abnormalities in cortical excitability have been proposed to underlie the pathophysiology of various neurocognitive manifestations of obstructive sleep apnea syndrome (OSAS). Transcranial magnetic stimulation (TMS) provides a noninvasive method for study and modulation of cortical excitability in the human brain, and repetitive TMS (rTMS) has been proven useful for neurophysiologic investigation in various neurologic conditions. We aimed to investigate cortical excitability in patients with OSAS during wakefulness and to determine if rTMS would change the abnormal excitability patterns. METHODS: Measures of motor cortical and corticospinal excitability (resting motor threshold [RMT], motor evoked potential [MEP] amplitude, and cortical silent period [CSP]) were taken before and after a session of 10-Hz rTMS applied to the motor cortex in 13 individuals with untreated severe OSAS (apnea-hypopnea index [AHI]>30) and 12 age and sex-matched healthy controls (HC). RESULTS: OSAS subjects had a significantly higher RMT (P<.003) and a longer CSP duration (P<.002) compared to HC. No difference was observed between MEP values of OSAS subjects and HC (P>.05). In response to rTMS, the HC group had a significant increase in CSP and MEP values from baseline, which were absent in OSAS subjects. CONCLUSIONS: Individuals with OSAS demonstrated increased motor cortex inhibition, which did not respond to 10-Hz rTMS. As rTMS-induced changes in MEP and CSP involve a separate neurotransmitter system (N-methyl-d-aspartate [NMDA] and gamma aminobutyric acid [GABA], respectively), these findings suggest a widespread alteration in cortical neurophysiology in severe OSAS subjects that requires clarification with further exploration. PMID- 23746826 TI - Mole gun injury. AB - A mole gun is a weapon, which is used to trap and kill moles. This report provides an overview of the state of knowledge of mole gun injuries, comparable to blast injuries caused by fireworks, explosive or gunshot. Over a 2-year period, the authors reported their experience with ten hand injuries caused by mole gun. Radial side of the hand was often concerned, particularly the thumb. The authors explain their choices in the management of such lesions. Surgery was performed primarily and a large debridement currently seemed to offer the best outcome for the patient. Blast, crush, burns and lacerations may explain the higher rate of amputation to the digits. A long period of physiotherapy, specifically of the hand, was needed before the patient could return to work. This ballistic hand trauma encountered by surgeons requires knowledge and understanding of these injuries. It should be in accordance with firearms law because of severe injuries encountered and possible lethal wounds. PMID- 23746827 TI - [Carpal injuries in children]. AB - Carpal injuries in children are uncommon. Radiographic diagnosis can be difficult because of late ossification of carpal bones. Scaphoid fracture occurs in 3% of hand and wrist fractures. Fractures in the distal third or at the waist are the most frequent fracture sites. In case of clinical and X-rays presumption, CT-scan and MRI often diagnose scaphoid fractures. Orthopaedic treatment with closed cast for 8 weeks, or more for adolescents, gives a high rate of union in non-displaced or minimally-displaced fractures. Non-union is the most frequent complication. Closed cast can be the treatment of non-union in absence of humpback or DISI deformity. Other carpal bone fractures or ligament injuries of the wrist in children are uncommon and CT-scan, MRI or arthroscopy can be useful in case of clinical suspicion. PMID- 23746828 TI - Endoscopic correction of vesicoureteral reflux in children with a solitary kidney: the risk of obstruction. AB - PURPOSE: We aimed to review patients with a solitary kidney and ipsilateral vesicoureteral reflux (VUR) who underwent endoscopic correction of VUR (ECVUR) and to evaluate the prevalence of obstruction in this group of patients. MATERIALS AND METHODS: We retrospectively reviewed the files of all patients who underwent ECVUR at our center between January 2000 and June 2011. Only patients with a solitary kidney and ipsilateral VUR were included. RESULTS: Thirteen patients met our criteria. Two patients (15.38%) developed obstruction post ECVUR. Both patients developed anuria in the first 24 h after surgery and required intervention. Two patients (15.38%) had increasing hydroureteronephrosis that was discovered on follow-up ultrasound, with no symptoms or signs of obstruction. Both were managed conservatively. CONCLUSION: Our results showed a higher percentage of obstruction post-ECVUR in patients with a solitary kidney (15.38%), who required immediate intervention. Thus, we recommend giving clear instructions to parents of patients with VUR and a solitary kidney post-ECVUR before discharge from the hospital regarding decreased urine output and loin pain. We recommend a follow-up ultrasound to rule out obstruction and detect new onset hydronephrosis. PMID- 23746829 TI - Structural determinants for naturally evolving H5N1 hemagglutinin to switch its receptor specificity. AB - Of the factors governing human-to-human transmission of the highly pathogenic avian-adapted H5N1 virus, the most critical is the acquisition of mutations on the viral hemagglutinin (HA) to "quantitatively switch" its binding from avian to human glycan receptors. Here, we describe a structural framework that outlines a necessary set of H5 HA receptor-binding site (RBS) features required for the H5 HA to quantitatively switch its preference to human receptors. We show here that the same RBS HA mutations that lead to aerosol transmission of A/Vietnam/1203/04 and A/Indonesia/5/05 viruses, when introduced in currently circulating H5N1, do not lead to a quantitative switch in receptor preference. We demonstrate that HAs from circulating clades require as few as a single base pair mutation to quantitatively switch their binding to human receptors. The mutations identified by this study can be used to monitor the emergence of strains having human-to human transmission potential. PMID- 23746831 TI - Identification and characterization of microRNAs in vascular smooth muscle cells from patients with abdominal aortic aneurysms. AB - BACKGROUND: The role of microRNAs (miRs) in the development of various cardiovascular diseases was recently highlighted in several studies. However, the biological role of miRs in the pathogenesis of abdominal aortic aneurysms (AAAs) is still not well defined. The present study aims to identify and characterize miR expression in the aortic explant cultures of AAA patients. METHODS: A new microarray platform (miChip) using locked nucleic acid-modified capture probes with increased sensitivity and specificity was employed to detect the miR expression profile in human vascular smooth muscle cell cultures from AAA surgical samples. The array data were further validated by real-time quantitative reverse transcription polymerase chain reaction (qPCR) experiments with additional AAA and control aorta samples. Potential target genes of the differentially expressed miRs were predicted by bioinformatics analysis. Some of the results were confirmed by enzyme immunosorbent assay and Western blot analysis. RESULTS: Total RNA extracted from the explant of six AAAs and six normal aortas exhibited notably different miR profiles. A twofold difference of miR-516a-5p and miR-1260 was expressed in AAAs compared with normal aortic cultures (P < .05). The expression of miR-516a-5p was more than three times higher in AAAs, and miR-1260 expression was almost four times lower, as validated by qPCR. Additional qPCR performing on an extra 10 AAAs and 10 control aortas showed similar results. The expression of three predicted targets--secretory interleukin-3, vascular endothelial growth factor A, and collagen type 1, alpha 1 proteins--was significantly elevated in aneurysmal cultures compared with normal aortic cultures (P < .05). CONCLUSIONS: This miR microarray study displayed an altered expression of miR-516a-5p and miR-1260 in AAAs compared with control aortas. Functional annotations of the two miRs via bioinformatics approaches revealed that both are highly involved in some predefined mechanisms of AAA formation. Three of their target genes were also upregulated in AAAs. The results may be critical to elucidate the functional role of miRs in diseased aorta. PMID- 23746832 TI - In situ laser fenestration during emergent thoracic endovascular aortic repair is an effective method for left subclavian artery revascularization. AB - BACKGROUND: Retrograde laser fenestration of the left subclavian artery (LSA) during emergent thoracic endovascular aortic repair (TEVAR) uses a relatively simple intraoperative method of endograft modification to revascularize aortic branches for a variety of acute thoracic aortic pathologies. This study presents our expanded experience and midterm outcomes of TEVAR with laser fenestration to revascularize the LSA as an alternative to debranching. METHODS: Patients who underwent TEVAR with LSA revascularization by laser graft fenestration from September 2009 through August 2012 were retrospectively reviewed. TEVAR was performed with deployment of a Dacron (DuPont, Wilmington, Del) endograft over the LSA orifice. Laser catheter fenestration of the graft was performed through retrograde brachial access, followed by balloon-expandable covered stent deployment through the fenestration to traverse the endograft and LSA. Routine postoperative follow-up imaging with computed tomography angiography was performed to assess TEVAR and LSA fenestration patency, endoleak, and aneurysm/dissection exclusion. RESULTS: TEVAR with laser fenestration was successfully performed in 22 patients (12 men; mean age, 57 years) in an urgent or emergent setting secondary to unremitting symptoms or rupture. Twelve patients had large symptomatic thoracic aortic aneurysms (eight secondary to chronic dissection); four patients had acute symptomatic type B aortic dissection, and six patients had an intramural hematoma or penetrating aortic ulcer, or both. An average of two endografts (range, 1-4) were deployed. LSA-covered stents were 8 to 10 mm in diameter. Mean operative time was 154 +/- 65 minutes. Average hospital length of stay was 12 +/- 7 days. No major fenestration-related complications occurred. One patient developed postoperative paraplegia. One patient died in the postoperative period, for an in-hospital mortality rate of 4.5%. Two patients died of non-TEVAR-related causes at a mean follow-up of 10 months (range, 1-40 months). Follow-up computed tomography angiography imaging demonstrated a 100% primary patency for the LSA stents. One patient had an asymptomatic LSA stent stenosis. Type II endoleaks from the LSA in two patients required endovascular coil embolization. No fenestration-related type I or III endoleaks were noted. CONCLUSIONS: In situ retrograde laser fenestration is a feasible and effective option for LSA revascularization during TEVAR involving a spectrum of acute thoracic aortic pathology. Laser fenestration provides a rapid, reproducible method of fenestrating the endograft material. The high technical success, low fenestration-related morbidity, and excellent midterm patency support this technique of intraoperative endograft modification. PMID- 23746830 TI - Glycan receptor binding of the influenza A virus H7N9 hemagglutinin. AB - The advent of H7N9 in early 2013 is of concern for a number of reasons, including its capability to infect humans, the lack of clarity in the etiology of infection, and because the human population does not have pre-existing immunity to the H7 subtype. Earlier sequence analyses of H7N9 hemagglutinin (HA) point to amino acid changes that predicted human receptor binding and impinge on the antigenic characteristics of the HA. Here, we report that the H7N9 HA shows limited binding to human receptors; however, should a single amino acid mutation occur, this would result in structural changes within the receptor binding site that allow for extensive binding to human receptors present in the upper respiratory tract. Furthermore, a subset of the H7N9 HA sequences demarcating coevolving amino acids appears to be in the antigenic regions of H7, which, in turn, could impact effectiveness of the current WHO-recommended prepandemic H7 vaccines. PMID- 23746833 TI - (Radio)active neurogenesis in the human hippocampus. AB - Fifteen years ago, the generation of new neurons in adulthood was documented in the human hippocampus, but lingering questions have remained about the extent of this process. In this issue of Cell, Spalding et al. provide elegant evidence for continued neurogenesis into adulthood at rates that suggest it may play a significant role in human behavior. PMID- 23746834 TI - This message will self-destruct: NMD regulates axon guidance. AB - The navigation of axons to their final destination can involve a sequence of steps that require different sets of guidance receptors. In this issue, Colak et al. show that regulated intra-axonal protein synthesis coupled to nonsense mediated mRNA decay (NMD) controls a switch in Robo3.2 expression that is critical for navigation. PMID- 23746835 TI - Chromatin meets its organizers. AB - Chromatin organization and gene-gene interactions are critical components of carrying out developmental programs. Phillips-Cremins et al. identify a series of unexpected architectural proteins that work in a combinatorial manner to functionally organize chromatin in a cell-type-specific manner at the submegabase length scale. PMID- 23746836 TI - A new DUB makes linear ubiquitin a party to its own destruction. AB - Linear ubiquitin (Ub) plays a role in nuclear factor kappaB signaling, but the deubiquitinating enzyme that disassembles these chains was unknown. In this issue of Cell, Keusekotten et al. identify a new enzyme that disassembles linear chains with the use of a mechanism that relies on Ub itself to help catalyze peptide bond cleavage. PMID- 23746837 TI - Fixing a hole where the Ras gets in. AB - A clinically efficacious Ras inhibitor has eluded drug-discovery efforts for decades. In a paper in Nature, Zimmermann and et al. show that blocking a hole in PDEdelta that normally engages the lipid tail of Ras disrupts downstream signaling, pointing to a potentially promising route to develop Ras inhibitors for cancer treatment. PMID- 23746839 TI - Dynamics of hippocampal neurogenesis in adult humans. AB - Adult-born hippocampal neurons are important for cognitive plasticity in rodents. There is evidence for hippocampal neurogenesis in adult humans, although whether its extent is sufficient to have functional significance has been questioned. We have assessed the generation of hippocampal cells in humans by measuring the concentration of nuclear-bomb-test-derived 14C in genomic DNA, and we present an integrated model of the cell turnover dynamics. We found that a large subpopulation of hippocampal neurons constituting one-third of the neurons is subject to exchange. In adult humans, 700 new neurons are added in each hippocampus per day, corresponding to an annual turnover of 1.75% of the neurons within the renewing fraction, with a modest decline during aging. We conclude that neurons are generated throughout adulthood and that the rates are comparable in middle-aged humans and mice, suggesting that adult hippocampal neurogenesis may contribute to human brain function. PMID- 23746840 TI - Posttranscriptional control of T cell effector function by aerobic glycolysis. AB - A "switch" from oxidative phosphorylation (OXPHOS) to aerobic glycolysis is a hallmark of T cell activation and is thought to be required to meet the metabolic demands of proliferation. However, why proliferating cells adopt this less efficient metabolism, especially in an oxygen-replete environment, remains incompletely understood. We show here that aerobic glycolysis is specifically required for effector function in T cells but that this pathway is not necessary for proliferation or survival. When activated T cells are provided with costimulation and growth factors but are blocked from engaging glycolysis, their ability to produce IFN-gamma is markedly compromised. This defect is translational and is regulated by the binding of the glycolysis enzyme GAPDH to AU-rich elements within the 3' UTR of IFN-gamma mRNA. GAPDH, by engaging/disengaging glycolysis and through fluctuations in its expression, controls effector cytokine production. Thus, aerobic glycolysis is a metabolically regulated signaling mechanism needed to control cellular function. PMID- 23746841 TI - Regulation of axon guidance by compartmentalized nonsense-mediated mRNA decay. AB - Growth cones enable axons to navigate toward their targets by responding to extracellular signaling molecules. Growth-cone responses are mediated in part by the local translation of axonal messenger RNAs (mRNAs). However, the mechanisms that regulate local translation are poorly understood. Here we show that Robo3.2, a receptor for the Slit family of guidance cues, is synthesized locally within axons of commissural neurons. Robo3.2 translation is induced by floor-plate derived signals as axons cross the spinal cord midline. Robo3.2 is also a predicted target of the nonsense-mediated mRNA decay (NMD) pathway. We find that NMD regulates Robo3.2 synthesis by inducing the degradation of Robo3.2 transcripts in axons that encounter the floor plate. Commissural neurons deficient in NMD proteins exhibit aberrant axonal trajectories after crossing the midline, consistent with misregulation of Robo3.2 expression. These data show that local translation is regulated by mRNA stability and that NMD acts locally to influence axonal pathfinding. PMID- 23746842 TI - Scaling of dorsal-ventral patterning by embryo size-dependent degradation of Spemann's organizer signals. AB - Spemann's organizer plays a key role in dorsal-ventral (DV) patterning in the amphibian embryo by secreting diffusible proteins such as Chordin, an antagonist to ventralizing bone morphogenetic proteins (BMPs). The DV patterning is so robust that an amphibian embryo with its ventral half surgically removed can develop into a smaller but proportionally patterned larva. Here, we show that this robust patterning depends on facilitated Chordin degradation and requires the expression of the Chordin-proteinase inhibitor Sizzled on the opposite side. Sizzled, which is stable and diffuses widely along the DV axis, stabilizes Chordin and expands its distribution in the ventral direction. This expanded Chordin distribution, in turn, limits BMP-dependent Sizzled production, forming an axis-wide feedback loop for shaping Chordin's activity. Using bisection assays, we demonstrate that Chordin degradation is dynamically controlled by embryo-size-coupled Sizzled accumulation. We propose a scaling model that enables the DV pattern to adjust proportionally to embryonic axis size. PMID- 23746838 TI - The hallmarks of aging. AB - Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects. PMID- 23746843 TI - OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. AB - The linear ubiquitin (Ub) chain assembly complex (LUBAC) is an E3 ligase that specifically assembles Met1-linked (also known as linear) Ub chains that regulate nuclear factor kappaB (NF-kappaB) signaling. Deubiquitinases (DUBs) are key regulators of Ub signaling, but a dedicated DUB for Met1 linkages has not been identified. Here, we reveal a previously unannotated human DUB, OTULIN (also known as FAM105B), which is exquisitely specific for Met1 linkages. Crystal structures of the OTULIN catalytic domain in complex with diubiquitin reveal Met1 specific Ub-binding sites and a mechanism of substrate-assisted catalysis in which the proximal Ub activates the catalytic triad of the protease. Mutation of Ub Glu16 inhibits OTULIN activity by reducing kcat 240-fold. OTULIN overexpression or knockdown affects NF-kappaB responses to LUBAC, TNFalpha, and poly(I:C) and sensitizes cells to TNFalpha-induced cell death. We show that OTULIN binds LUBAC and that overexpression of OTULIN prevents TNFalpha-induced NEMO association with ubiquitinated RIPK1. Our data suggest that OTULIN regulates Met1-polyUb signaling. PMID- 23746844 TI - HIF1A employs CDK8-mediator to stimulate RNAPII elongation in response to hypoxia. AB - The transcription factor HIF1A is a key mediator of the cellular response to hypoxia. Despite the importance of HIF1A in homeostasis and various pathologies, little is known about how it regulates RNA polymerase II (RNAPII). We report here that HIF1A employs a specific variant of the Mediator complex to stimulate RNAPII elongation. The Mediator-associated kinase CDK8, but not the paralog CDK19, is required for induction of many HIF1A target genes. HIF1A induces binding of CDK8 Mediator and the super elongation complex (SEC), containing AFF4 and CDK9, to alleviate RNAPII pausing. CDK8 is dispensable for HIF1A chromatin binding and histone acetylation, but it is essential for binding of SEC and RNAPII elongation. Global analysis of active RNAPII reveals that hypoxia-inducible genes are paused and active prior to their induction. Our results provide a mechanistic link between HIF1A and CDK8, two potent oncogenes, in the cellular response to hypoxia. PMID- 23746845 TI - Rif1 and Rif2 shape telomere function and architecture through multivalent Rap1 interactions. AB - Yeast telomeres comprise irregular TG1-3 DNA repeats bound by the general transcription factor Rap1. Rif1 and Rif2, along with Rap1, form the telosome, a protective cap that inhibits telomerase, counteracts SIR-mediated transcriptional silencing, and prevents inadvertent recognition of telomeres as DNA double-strand breaks. We provide a molecular, biochemical, and functional dissection of the protein backbone at the core of the yeast telosome. The X-ray structures of Rif1 and Rif2 bound to the Rap1 C-terminal domain and that of the Rif1 C terminus are presented. Both Rif1 and Rif2 have separable and independent Rap1-binding epitopes, allowing Rap1 binding over large distances (42-110 A). We identify tetramerization (Rif1) and polymerization (Rif2) modules that, in conjunction with the long-range binding, give rise to a higher-order architecture that interlinks Rap1 units. This molecular Velcro relies on Rif1 and Rif2 to recruit and stabilize Rap1 on telomeric arrays and is required for telomere homeostasis in vivo. PMID- 23746846 TI - Visualizing GroEL/ES in the act of encapsulating a folding protein. AB - The GroEL/ES chaperonin system is required for the assisted folding of many proteins. How these substrate proteins are encapsulated within the GroEL-GroES cavity is poorly understood. Using symmetry-free, single-particle cryo-electron microscopy, we have characterized a chemically modified mutant of GroEL (EL43Py) that is trapped at a normally transient stage of substrate protein encapsulation. We show that the symmetric pattern of the GroEL subunits is broken as the GroEL cis-ring apical domains reorient to accommodate the simultaneous binding of GroES and an incompletely folded substrate protein (RuBisCO). The collapsed RuBisCO folding intermediate binds to the lower segment of two apical domains, as well as to the normally unstructured GroEL C-terminal tails. A comparative structural analysis suggests that the allosteric transitions leading to substrate protein release and folding involve concerted shifts of GroES and the GroEL apical domains and C-terminal tails. PMID- 23746848 TI - Reshaping antibody diversity. AB - Some species mount a robust antibody response despite having limited genome encoded combinatorial diversity potential. Cows are unusual in having exceptionally long CDR H3 loops and few V regions, but the mechanism for creating diversity is not understood. Deep sequencing reveals that ultralong CDR H3s contain a remarkable complexity of cysteines, suggesting that disulfide-bonded minidomains may arise during repertoire development. Indeed, crystal structures of two cow antibodies reveal that these CDR H3s form a very unusual architecture composed of a beta strand "stalk" that supports a structurally diverse, disulfide bonded "knob" domain. Diversity arises from somatic hypermutation of an ultralong DH with a severe codon bias toward mutation to cysteine. These unusual antibodies can be elicited to recognize defined antigens through the knob domain. Thus, the bovine immune system produces an antibody repertoire composed of ultralong CDR H3s that fold into a diversity of minidomains generated through combinations of somatically generated disulfides. PMID- 23746850 TI - SnapShot: single-molecule fluorescence. PMID- 23746849 TI - Structures of Drosophila cryptochrome and mouse cryptochrome1 provide insight into circadian function. AB - Drosophila cryptochrome (dCRY) is a FAD-dependent circadian photoreceptor, whereas mammalian cryptochromes (CRY1/2) are integral clock components that repress mCLOCK/mBMAL1-dependent transcription. We report crystal structures of full-length dCRY, a dCRY loop deletion construct, and the photolyase homology region of mouse CRY1 (mCRY1). Our dCRY structures depict Phe534 of the regulatory tail in the same location as the photolesion in DNA-repairing photolyases and reveal that the sulfur loop and tail residue Cys523 plays key roles in the dCRY photoreaction. Our mCRY1 structure visualizes previously characterized mutations, an NLS, and MAPK and AMPK phosphorylation sites. We show that the FAD and antenna chromophore-binding regions, a predicted coiled-coil helix, the C-terminal lid, and charged surfaces are involved in FAD-independent mPER2 and FBXL3 binding and mCLOCK/mBMAL1 transcriptional repression. The structure of a mammalian cryptochrome1 protein may catalyze the development of CRY chemical probes and the design of therapeutic metabolic modulators. PMID- 23746847 TI - Regulation of organismal proteostasis by transcellular chaperone signaling. AB - A major challenge for metazoans is to ensure that different tissues, each expressing distinctive proteomes, are nevertheless well protected at an organismal level from proteotoxic stress. We show that expression of endogenous metastable proteins in muscle cells, which rely on chaperones for proper folding, induces a systemic stress response throughout multiple tissues of C. elegans. Suppression of misfolding in muscle cells can be achieved not only by enhanced expression of HSP90 in muscle cells but as effectively by elevated expression of HSP90 in intestine or neuronal cells. This cell-nonautonomous control of HSP90 expression relies upon transcriptional feedback between somatic tissues that is regulated by the FoxA transcription factor PHA-4. This transcellular chaperone signaling response maintains organismal proteostasis when challenged by a local tissue imbalance in folding and provides the basis for organismal stress-sensing surveillance. PMID- 23746851 TI - Gender difference and economic gradients in the secular trend of population systolic blood pressure. AB - To a large extent population blood pressure (PBP) affects morbidity and mortality in the society. Reports indicated that PBP decreased in many western countries. The associations between the main cardiovascular risk factors and the changing PBP have been described. The aim of this study was to investigate association between income factors and trends in population BP and hypertension. Copenhagen City Heart Study is a prospective longitudinal epidemiological study on almost 20000 individuals through four surveys from 1976 to 2003. The BP measurement was fully standardised. Questionnaires on household income and CV risk factors were completed by the participants. After adjustment for cardiovascular risk factors there were no significant differences in systolic BP (SBP) trend associated to income among men. Among women, however, there was a reverse relationship between SBP and income. In addition, there was a trend towards a lowering of risk-factor adjusted SBP in the high income women with time. The mechanism that lies behind the associations between trend in SBP and income is not known but data suggest that poor lifestyle may explain some of the differences. The treated hypertensives are treated without income associated treatment differences. IN CONCLUSION: Women in higher income groups have lower SBP than women in low-income groups and the gap between SBP in high-income women and low-income women increased with time. There were no significant differences in SBP-trend associated to income among men. Results in treating hypertension did not differ between the income groups. PMID- 23746852 TI - Intensity of peri-operative glycemic control and postoperative outcomes in patients with diabetes: a meta-analysis. AB - AIMS: Peri-operative hyperglycemia is a risk factor for postoperative morbidity and mortality. However, the role of specific glycemic targets in reducing this risk has not been defined, particularly among patients with diabetes. Thus, our objective was to conduct a meta-analysis relating distinct peri-operative glycemic targets and postoperative outcomes in patients with diabetes. METHODS: A systematic review was performed by two authors utilizing pre-specified terms: "diabetes mellitus" and "perioperative" and "mortality" and "blood glucose" or "strict glucose control" or "intensive insulin therapy" in PUBMED, CENTRAL and EMBASE. Glycemic control was considered strict when perioperative targets ranged between 100 and 150mg/dL (5.6-8.3mmol/l), moderate when the targets ranged between 150 and 200mg/dL 8.3-11.1mmol/l), and liberal when the target was >200mg/dL (11.1mmol/l). The data were combined utilizing the Dersimoan-Laird random-effects method. The primary endpoint was postoperative mortality with secondary endpoints of postoperative atrial fibrillation, wound infection, and stroke. RESULTS: The literature search yielded 760 studies, of which only 6 met inclusion criteria. When compared with a liberal target, pooled data showed that a moderate glycemic target was associated with reduced postoperative mortality (OR=0.48, 95% CI 0.24-0.76) and stroke (OR=0.61, 95% CI 0.38-0.98), but no differences in atrial fibrillation or wound infection were found. There were no significant differences in postoperative outcomes between moderate versus strict perioperative glycemic target. CONCLUSIONS: Pooled results suggest that in patients with diabetes, a moderate peri-operative glycemic target (150-200mg/dl [5.6-8.3mmol/l]) is associated with reduction in postoperative mortality and stroke compared with a liberal target (>200mg/dl [11.1mmol/l]), whereas no significant additional benefit was found with more strict glycemic control (<150mg/dl [5.6mmol/l]). PMID- 23746853 TI - Predictive significance of confirmation biopsies in patients on active surveillance. PMID- 23746854 TI - Antibiotic stewardship: a call for action by the urologic community. AB - Increasing antibiotic resistance and lack of new antibiotics in the near future calls for a variety of coordinated strategies called "Antibiotic stewardship", to improve antibiotic use with the goal of enhancing patient health outcomes and reducing emergence of resistance to antibiotics. PMID- 23746855 TI - A rare case of paediatric pelvic ring injury with lower urinary tract obstruction secondary to a combat blast mechanism. AB - Paediatric pelvic ring fractures are rare, and typically the result of high energy mechanisms that yield other potentially fatal visceral and solid organ injuries. Specific pelvic fracture patterns have been associated with injury to the lower urinary tract, with the most severe involving laceration of the bladder or transection of the urethra. We report a unique case of paediatric pelvic ring disruption causing an isolated obstruction of the lower urinary tract without laceration or discontinuity. Although most paediatric pelvic fractures are managed non-operatively, we postulate that significant ring deformity contributing to urinary retention be considered an indication for open surgical treatment. PMID- 23746856 TI - Pullulan-histone antibody nanoconjugates for the removal of chromatin fragments from systemic circulation. AB - The billions of cells that die in the adult human body daily release considerable amounts of fragmented chromatin in the form of mono- and oligonucleosomes into the circulation in normal individuals, and in higher quantities in many disease conditions. Recent results suggest that circulating chromatin fragments (Cfs) especially from abnormal cells can spontaneously enter into healthy cells to damage their DNA and induce genomic instability. Furthermore, Cfs isolated from cancer patients may induce oncogenic transformation in the recipients' cells. Thus, it follows that if such Cfs emanating from apoptotic cells could be prevented from reaching other cells, it could potentially inhibit pathological conditions, including cancer. Here we have developed pullulan based histone antibody nanoconjugates for the removal of Cfs. Nanoconjugates were developed and various physico-chemical characterizations were carried out. The efficacy of these nanoconjugates on removing Cfs was evaluated both in vitro and in vivo. Our results indicate that nanoconjugates may have therapeutic value in the efficient removal of Cfs, reducing inflammation and fatality in a mouse model of sepsis, and in preventing neutropenia following treatment with Adriamycin. PMID- 23746857 TI - Long-term results of cell-free biodegradable scaffolds for in situ tissue engineering of pulmonary artery in a canine model. AB - We previously developed a cell-free, biodegradable scaffold for in-situ tissue engineering vasculature (iTEV) in a canine inferior vena cava (IVC) model. In this study, we investigated application of this scaffold for iTEV of the pulmonary artery (iTEV-PA) in a canine model. In vivo experiments were conducted to determine scaffold characteristics and long-term efficacy. Biodegradable scaffolds comprised polyglycolide knitted fibers and an l-lactide and epsilon caprolactone copolymer sponge, with an outer glycolide and epsilon-caprolactone copolymer monofilament reinforcement. Tubular scaffolds (8 mm diameter) were implanted into the left pulmonary artery of experimental animals (n = 7) and evaluated up to 12 months postoperatively. Angiography of iTEV-PA after 12 months showed a well-formed vasculature without marked stenosis, aneurysmal change or thrombosis of iTEV-PA. Histological analysis revealed a vessel-like vasculature without calcification. However, vascular smooth muscle cells were not well developed 12 months post-implantation. Biochemical analyses showed no significant difference in hydroxyproline and elastin content compared with native PA. Our long-term results of cell-free tissue-engineering of PAs have revealed the acceptable qualities and characteristics of iTEV-PAs. The strategy of using this cell-free biodegradable scaffold to create relatively small PAs could be applicable in pediatric cardiovascular surgery requiring materials. PMID- 23746858 TI - Neuroglial differentiation of adult enteric neuronal progenitor cells as a function of extracellular matrix composition. AB - Enteric neuronal progenitor cells are neural crest-derived stem cells that can be isolated from fetal, post-natal and adult gut. Neural stem cell transplantation is an emerging therapeutic paradigm to replace dysfunctional or lost enteric neurons in several aganglionic disorders of the GI tract. The impetus to identify an appropriate microenvironment for enteric neuronal progenitor cells derives from the need to improve survival and phenotypic stability following implantation. Extracellular matrix composition can modulate stem cell fate and direct differentiation. Adult mammalian myenteric ganglia in vivo are surrounded by a matrix composed primarily of Collagen IV, Laminin and a Heparan sulfate proteoglycan. In these studies, adult mammalian enteric neuronal progenitor cells isolated from full thickness rabbit intestines were induced to differentiate when cultured on various combinations of neural ECM substrates. Neuronal and glial differentiation was studied as a function of ECM composition on coated glass coverslips. Poly-lysine coated coverslips (control) supported extensive glial differentiation but very minimal neuronal differentiation. Individual culture substrata (Laminin, Collagen I and Collagen IV) were conducive for both neuronal and glial differentiation. The addition of laminin or heparan sulfate to collagen substrates improved neuronal differentiation, significantly increased neurite lengths, branching and initiation of neuronal network formation. Glial differentiation was extensive on control poly lysine coated coverslips. Addition of laminin or heparan sulfate to composite collagen substrates significantly reduced glial immunofluorescence. Various neural ECM components were evaluated individually and in combination to study their effect of neuroglial differentiation of adult enteric neuronal progenitor cells. Our results indicate that specific ECM substrates that include type IV Collagen, laminin and heparan sulfate support and maintain neuronal and glial differentiation to different extents. Here, we identify a matrix composition optimized to tissue engineer transplantable innervated GI smooth muscle constructs to remedy aganglionic disorders. PMID- 23746859 TI - Intracellular micro-rheology probed by micron-sized wires. AB - In the last decade, rapid advances have been made in the field of micro-rheology of cells and tissues. Given the complexity of living systems, there is a need for the development of new types of nano- and micron-sized probes, and in particular of probes with controlled interactions with the surrounding medium. In the present paper, we evaluate the use of micron-sized wires as potential probes of the mechanical properties of cells. The wire-based micro-rheology technique is applied to living cells such as murine fibroblasts and canine kidney epithelial cells. The mean-squared angular displacement of wires associated to their rotational dynamics is obtained as a function of the time using optical microscopy and image processing. It reveals a Brownian-like diffusive regime of the form Deltapsi(2)(t,L) ~ t/L(3), where L denotes the wire length. This scaling suggests that an effective viscosity of the intracellular medium can be determined, and that in the range 1-10 MUm it does not depend on the length scale over which it is measured. PMID- 23746861 TI - New technique using an energy-based device versus conventional technique in open thyroidectomy. AB - OBJECTIVE: Thyroid surgery is a common basic procedure in otorhinolaryngology. The purpose of this study was to assess the efficiency of using a new LigaSure((r)) vessel sealing system (LigaSure((r)) Small Jaw Instrument; Covidien, Boulder, CO, USA). METHODS: We evaluated 83 patients who underwent thyroid surgery between July 2009 and June 2012. The patients were allocated to two groups, which underwent thyroid surgery using either the LigaSure((r)) Small Jaw Instrument or conventional techniques. We investigated the duration of operation, estimated blood loss, pathological characteristics, postoperative complications, and length of hospital stay. As for duration of operation and estimated blood loss, we also performed analyses by subgroups according to the extent of thyroid resection, as either total thyroidectomy or hemithyroidectomy. RESULTS: The study groups showed no significant differences in age, sex, indications, extent of operation and estimated blood loss. Complication rates for recurrent laryngeal nerve palsy, hypoparathyroidism, hematoma, and wound infection did not differ between groups, except for temporary hypoparathyroidism. Operation time was significantly shorter in the LigaSure((r)) Small Jaw Instrument group than in the conventional group for all extents of thyroid resection. CONCLUSION: Use of the LigaSure((r)) Small Jaw Instrument seems likely to reduce the operating time for thyroid surgery without increasing estimated blood loss or the frequency of postoperative complications compared to conventional techniques. PMID- 23746860 TI - The promotion of bone healing by progranulin, a downstream molecule of BMP-2, through interacting with TNF/TNFR signaling. AB - Endochondral ossification plays a key role in the bone healing process, which requires normal cartilage callus formation. Progranulin (PGRN) growth factor is known to enhance chondrocyte differentiation and endochondral ossification during development, yet whether PGRN also plays a role in bone regeneration remains unknown. In this study we established surgically-induced bone defect and ectopic bone formation models based on genetically-modified mice. Thereafter, the bone healing process of those mice was analyzed through radiological assays including X-ray and micro CT, and morphological analysis including histology and immunohistochemistry. PGRN deficiency delayed bone healing, while recombinant PGRN enhanced bone regeneration. Moreover, PGRN was required for BMP-2 induction of osteoblastogenesis and ectopic bone formation. Furthermore, the role of PGRN in bone repair was mediated, at least in part, through interacting with TNF-alpha signaling pathway. PGRN-mediated bone formation depends on TNFR2 but not TNFR1, as PGRN promoted bone regeneration in deficiency of TNFR1 but lost such effect in TNFR2 deficient mice. PGRN blocked TNF-alpha-induced inflammatory osteoclastogenesis and protected BMP-2-mediated ectopic bone formation in TNF alpha transgenic mice. Collectively, PGRN acts as a critical mediator of the bone healing process by constituting an interplay network with BMP-2 and TNF-alpha signaling, and this represents a potential molecular target for treatment of fractures, especially under inflammatory conditions. PMID- 23746862 TI - Sinus tract identification by Methylene Blue gel. PMID- 23746863 TI - Anatomy of the superficial lymphatics of the abdominal wall and the upper thigh and its implications in lymphatic microsurgery. AB - BACKGROUND: The recent advent in the surgical treatment of lymphedema necessitates a more detailed understanding of the anatomy of the lymphatic system. Lymphovenous anastomosis (LVA) requires a precise knowledge of the anatomy of the superficial lymphatic collectors in relation to the superficial veins. In vascularized lymph node transfer (VLNT), donor site lymphatic function must be preserved. METHODS: Using the previously described technique, the superficial lymphatic drainage of 8 anterior hemi-abdomen/upper thigh specimens from 4 fresh human cadavers was investigated. RESULTS: The upper and lower abdominal collectors were found above Scarpa's fascia immediately below the subdermal venules. They were thin-walled and translucent and their diameter ranged between 0.2 and 0.8 mm. In the upper thigh two distinct groups of superficial collectors were found. The collectors of the ventromedial bundle constituted the majority of the superficial collectors, were deep in the subcutaneous fat, measured 0.6-1 mm in diameter, had thick walls, and consistently drained into two large nodes inferolateral to the saphenous bulb. The local collectors of the thigh were immediately deep to the subdermal venules, measured 0.3-0.5 mm, had thin walls, and drained into the superolateral group of the superficial inguinal nodes which also drained the lower abdomen, the lower back and the upper gluteal region. CONCLUSIONS: When raising the groin lymphatic flap for VLNT, the medial extent of the dissection should be limited to the lateral border of femoral artery. When following up patients after VLNT with a groin donor site, circumference measurements must include the upper thigh. PMID- 23746865 TI - [Toward an improvement in ultrasound learning of residents in gynaecology and obstetrics]. PMID- 23746864 TI - Determinants of health-related quality of life in Crohn's disease: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Understanding the determinants of Crohn's disease (CD) patients' health-related quality of life (HRQOL) may facilitate interventions that improve HRQOL. Therefore, we systematically assessed determinants of HRQOL in adult CD patients. METHODS: The databases PubMed, EMBASE, the Cochrane Library, PsycINFO and CINAHL were searched for English abstracts, related to socio-demographic, psychological, clinical and treatment-related determinants of HRQOL in CD disease. Two independent reviewers extracted study characteristics and assessed the methodological quality according the criteria of Hayden et al. The main outcome was the number of studies showing a statistically significant association between the above-mentioned determinants and HRQOL. A meta-analysis was performed to quantify the relationship between disease activity and HRQOL. RESULTS: Of the 2060 articles identified, 29 eligible studies were included. The majority of studies were cross-sectional and had a moderate to high quality. Data on psychological determinants were scarce. Work disability, increased disease activity, number of relapses, corticosteroid treatment and hospitalization rate were significantly associated with a lower HRQOL in the majority of included studies. Biological treatment positively influenced HRQOL. The pooled data on the association between disease activity and HRQOL resulted in a weighed mean correlation coefficient of -0.61 (CI -0.65 to -0.57). CONCLUSIONS: HRQOL of adult CD patients is consistently determined by markers of active disease, including work disability, increased disease activity, number of relapses, biological treatment and hospitalization rate. As disease activity contributed to only 37% of HRQOL, there remains a need for additional, possibly modifiable, determinants. These determinants may refine possibilities to improve HRQOL. PMID- 23746868 TI - Surgical versus conservative management of osteochondrosis. AB - The paper reviews current knowledge on conservative versus surgical options for the treatment of osteochondrosis entities in the horse. Clinical and radiographic signs of each significant osteochondrosis entity in the horse are presented, followed by the value of conservative treatment versus arthroscopic surgery options as well as the results for each option with the various entities. The entities presented in detail include, osteochondritis dissecans (OCD) of the femoropatellar, tarsocrural, metacarpophalangeal and metatarsophalangeal, and glenohumural articulations. The various treatment options for subchondral cystic lesions of the medial femoral condyle are detailed with evidence for the value of various treatments and subchondral cystic lesions in other locations are briefly reviewed. PMID- 23746869 TI - Agreement between the cell culture titrations of canine minute virus determined by two susceptibility-testing methods. AB - The correct diagnosis of canine minute virus is critical in dog breeding. In this study, the Bland Altman test was used to compare the performance of two susceptibility-testing methods, namely polymerase chain reaction (PCR) and indirect immunofluorescence assay (IFA). The agreement between IFA and PCR in monocytes revealed a mean difference of -1752.16 with 95% confidence and an interval ranging from -3229.80 to -274.53 (SD=2325.62). The agreement between IFA and PCR in Walter Reed canine cells (WRCC) revealed a mean difference of -2396.55 with 95% confidence and an interval ranging from -3774.63 to -1018.48 (SD=2168.93). The Bland Altman test confirmed the overall accuracy of PCR vs IFA and the plot showed that all points were not randomly arranged in the range of average +/- 1.96 * SD of the differences. PMID- 23746867 TI - Metabolic safety of growth hormone in type 1 diabetes and idiopathic growth hormone deficiency. AB - OBJECTIVE: To evaluate metabolic consequences of growth hormone (GH) treatment in children with type 1 diabetes. STUDY DESIGN: This study is an analysis of metabolic changes in 37 patients with childhood-onset GH deficiency and type 1 diabetes, documented in the Diabetes Patienten Verlaufsdocumentationsystem database. Main outcome measures were changes in hemoglobin A1c and daily insulin requirements during GH therapy in children with GH deficiency and type 1 diabetes compared with a large cohort of adolescents with type 1 diabetes. RESULTS: Thirty seven patients with type 1 diabetes and a diagnosis of idiopathic GH deficiency after onset of diabetes were compared with 48856 patients with type 1 diabetes. After adjustment for age, sex, duration of diabetes, and migration background, a significant difference in mean daily insulin requirement was seen between the 2 groups (1.0 IU/kg/day in subjects with GH deficiency and type 1 diabetes vs 0.85 IU/kg/day in controls; P < .01) and height-SDS (-2.0 in subjects with GH deficiency and diabetes vs +0.03 in controls; P < .0001). There was no significant between-group difference in hemoglobin A1 concentration, however (8.1% +/- 1.4% in patients with GH deficiency and type 1 diabetes vs 8.2% +/- 1.7% in those with type 1 diabetes only; P > .05). CONCLUSION: An increased daily insulin requirement should be considered in patients with type 1 diabetes treated with GH. With adequate adaptation of insulin dosage, metabolic control is not impaired during GH treatment. PMID- 23746870 TI - Delayed endochondral ossification in early medial coronoid disease (MCD): a morphological and immunohistochemical evaluation in growing Labrador retrievers. AB - Medial coronoid disease (MCD) is a common joint disease of dogs. It has a multifactorial aetiology, but the relationship between known causal factors and the disease has yet to be elucidated. As most of the published literature is clinical and it reports changes associated with advanced disease, it is not known whether the changes reflect the cause or consequences of the condition. The aim of this study was to investigate early micromorphological changes occurring in articular cartilage and to describe the postnatal development of the medial coronoid process (MCP) before MCD develops. Three litters of MCD-prone young Labrador retrievers were purpose-bred from a dam and two sires with MCD. Comparisons of the micromorphological appearance of the MCP in MCD-negative and MCD-positive joints demonstrated that MCD was initially associated with a disturbance of endochondral ossification, namely a delay in the calcification of the calcifying zone, without concurrent abnormalities in the superficial layers of the joint cartilage. Cartilage canals containing patent blood vessels were only detected in dogs <12 weeks old, but the role of these channels in impaired ossification requires further investigation. Retained hyaline cartilage might ossify as the disease progresses, but weak areas can develop into cracks between the retained cartilage and the subchondral bone, leading to cleft formation and fragmentation of the MCP. PMID- 23746871 TI - Characterization of anal double balloon endoscopy in the dog. AB - Retrograde (anal) exploration of the canine small intestine by conventional endoscopy is restricted to the ileum, but double balloon endoscopy (DBE) has recently been validated using the oral approach. In this study, anal DBE was performed on nine healthy dogs to characterize the efficiency, exploration dynamics and safety of the technique. DBE was successful in all dogs; the average estimated insertion depth of the endoscope was about 2m and took approximately 1h to achieve. No complications or related adverse clinical effects were observed, and pancreatitis did not occur following the procedure. Anal DBE is viable and safe in the dog within the limits of the study, and has the potential to facilitate the diagnosis and treatment of gastrointestinal diseases, not only in portions of the colon and ileum, but also in portions of the distal jejunum. PMID- 23746872 TI - Prednisolone inclusion in a first-line multidrug cytostatic protocol for the treatment of canine lymphoma does not affect therapy results. AB - Chemotherapy protocols for canine lymphoma include the routine use of glucocorticoids for their lympholytic effect. However, glucocorticoids are associated with side effects (e.g. polyphagia, polyuria, and weight gain), limit the use of non-steroidal anti-inflammatory drugs, and can induce drug transporter expression that could lead to drug resistance. Despite these negative effects, there are no data to support the use of glucocorticoids as part of a multidrug chemotherapy protocol for the treatment of canine lymphoma. A prospective, randomized clinical trial was conducted in 81 dogs with multicentric lymphoma and no history of recent glucocorticoid use. All dogs were staged and treated with the same chemotherapy protocol (L-asparaginase, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with half of the dogs receiving prednisolone. Both treatment groups were similar with respect to demographics, immunophenotype, and clinical stage, except for a higher number of substage b patients in the prednisolone group (5 vs. 14; P=0.015). Treatment results obtained with the initial treatment (complete response rate 75%, disease-free period 176 days) and rescue treatment (complete response rate 45%, disease-free period 133 days), overall survival (283 days) and adverse events (number and grade) were similar for both groups. In conclusion, prednisolone, as part of a multidrug chemotherapy protocol, has no additional effect on treatment results and can be omitted from first-line multidrug protocols used for the treatment of canine lymphoma. PMID- 23746873 TI - Nursing time study for the administration of a PRN oral analgesic on an orthopedic postoperative unit. AB - As needed (PRN) oral opioid analgesics are an integral part of many orthopedic postoperative multimodal pain management regimens. However, the unpredictable nature of this dosing method can lead to disruptions in the process of administering the medication, as well as be an interruption to regular nursing activities. This IRB approved quantitative time study tested the hypothesis that a significant amount of nursing time is required in the administration of PRN oral opioid analgesics on a postoperative orthopedic nursing unit. The purpose of this study is to evaluate the time necessary to complete the required steps related to the administration of PRN oral analgesics. Nurses from 28 nursing shifts used a personal digital assistant (PDA) to record the time needed to complete these steps. We determined that 10.9 minutes is the mean time required to administer PRN oral analgesics on this unit. Other time studies have evaluated the medication administration process as a whole. No time studies related to PRN oral analgesic administration have been reported. In phase I of our project, the data were summarized and will be used as a baseline comparison for phase II, in which we will evaluate an oral PCA medication administration system. PMID- 23746866 TI - Health related quality of life in patients with biliary atresia surviving with their native liver. AB - OBJECTIVES: To quantify health related quality of life (HRQOL) of patients with biliary atresia with their native livers and compare them with healthy children and patients with biliary atresia post-liver transplant (LT) and to examine the relationship between HRQOL and medical variables. STUDY DESIGN: A cross-sectional HRQOL study of patients with biliary atresia with their native livers (ages 2-25 years) was conducted and compared with healthy and post-LT biliary atresia samples using Pediatric Quality of Life Inventory 4.0 child self and parent proxy reports, a validated measure of physical/psychosocial functioning. RESULTS: 221 patients with biliary atresia with native livers (54% female, 67% white) were studied. Patient self and parent proxy reports showed significantly poorer HRQOL than healthy children across all domains (P < .001), particularly in emotional and psychosocial functioning. Child self and parent proxy HRQOL scores from patients with biliary atresia with their native livers and post-LT biliary atresia were similar across all domains (P = not significant). Child self and parent proxy reports showed moderate agreement across all scales, except social functioning (poor to fair agreement). On multivariate regression analysis, black race and elevated total bilirubin were associated with lower Total and Psychosocial HRQOL summary scores. CONCLUSIONS: HRQOL in patients with biliary atresia with their native livers is significantly poorer than healthy children and similar to children with post-LT biliary atresia. These findings identify significant opportunities to optimize the overall health of patients with biliary atresia. PMID- 23746875 TI - Age-associated changes in gene expression of goat oocytes. AB - Oocyte aging severely decreases the quality of oocytes, which hampers fertilization and subsequent embryo development. In the present study, age dependent molecular changes in goat oocytes were investigated. First, the quality of goat oocytes with various in vitro culture times (24, 30, 36, 48, and 60 hours) was evaluated on the basis of developmental rates of parthenogenetically activated embryos and apoptosis of cumulus cells (CCs). Second, relative gene expression of six genes (mitochondrial genes: PGC-1alpha and NRF-1; epigenetic modification genes: SNRPN and HAT1; mitotic spindle checkpoint protein: SMAD2; and hyaluronan synthase gene: HAS3) were analyzed during oocyte aging. Third, we further studied the changes of seven genes (PGC-1alpha and NRF-1; apoptotic related genes: BAX and BCL2; hyaluronan synthase gene: HAS2; metabolism-related gene: STAR; and superoxide dismutase gene: SOD1) in CCs during oocyte aging. In these studies, the blastocyst rate gradually decreased and the number of apoptotic cells significantly increased as the culture time increased (P < 0.05). Moreover, relative gene expressions of PGC-1alpha, NRF-1 and SMAD2 significantly decreased from 24 to 36 hours (P < 0.05), whereas the levels of HAT1 and HAS3 slowly increased as culture was prolonged. Furthermore, the levels of PGC-1alpha, BCL2, HAS2 and SOD1 quickly reduced, and BAX significantly increased from 24 to 36 hours in aged CCs (P < 0.05). In conclusion, goat oocytes started to age at 30 hours in vitro culture, and gene expression patterns of oocytes and CCs significantly changed as the oocytes aged. Gene expression pattern changes in CCs may provide a convenient and effective way to detect oocyte aging without compromising oocyte integrity. PMID- 23746874 TI - Handling of boar spermatozoa during and after flow cytometric sex-sorting process to improve their in vitro fertilizing ability. AB - The objective of this study was to develop an adequate sperm handling protocol in order to obtain a sex-sorted sperm population with an optimal fertilizing ability. For this purpose, different aspects of the sorting procedure were examined. The effects of the high dilution rates (experiment 1), type of collection medium used (experiment 2), and sheath fluid composition (experiment 3) on sorted boar sperm quality and function were evaluated. Sperm quality was assessed by motility and viability tests, whereas sperm function was evaluated by an in vitro fertilization assay which determined the penetration and polyspermy rates as well as the mean number of sperm penetrating each oocyte. In experiment 1, the results obtained indicated that the high dilution rates did not cause a decrease either in the sperm quality parameters evaluated or the in vitro fertilization ability of spermatozoa. In experiment 2, although sperm quality was not affected, fertilizing ability was compromised after sorting, regardless of the collection medium that was used. In the experiment 3, all groups displayed adequate sperm quality values, but higher in vitro fertility parameters were obtained for spermatozoa sorted in presence of EDTA in the sheath fluid and egg yolk (EY) in the collection media when compared with those sorted in absence of these protective agents. No differences in penetration rates between unsorted highly diluted (control) and sorted sperm in the presence of EDTA and EY were observed. In conclusion, fertilizing ability was compromised in sex-sorted sperm. The addition of EDTA to sheath fluid and EY to collection medium improved boar sperm fertilizing ability, and both agents should be included as essential media components in future studies. PMID- 23746876 TI - Cysteamine supplementation during in vitro maturation of slaughterhouse- and opu derived bovine oocytes improves embryonic development without affecting cryotolerance, pregnancy rate, and calf characteristics. AB - Optimization of ovum pick up (OPU) followed by in vitro embryo production (IVP) is strongly driven by the needs of both beef and dairy cattle breeders to enhance genetic improvement. The rapidly growing use of genomic selection in cattle has increased the interest in using OPU-IVP technology to increase the number of embryos and offspring per donor, thus allowing enhanced selection intensity for the next generation. The aim of this study was to optimize embryo production through supplementation of cysteamine during in vitro maturation (IVM) and in vitro culture (IVC) of both slaughterhouse- and OPU-derived oocytes. The effects on embryo production and on embryo cryotolerance, post-transfer embryo survival, and calf characteristics, including gestation length, birth weight, perinatal mortality, and sex ratio were studied. In study 1, immature slaughterhouse derived cumulus-oocyte complexes (COCs) were matured in IVM medium supplemented with or without 0.1 mM cysteamine, fertilized and cultured for 7 days in 0.5 ml SOFaaBSA. In study 2, cysteamine was present during both IVM (0.1 mM) and IVC (0.01, 0.05, 0.1 mM) from Days 1 to 4. In study 3, OPU-derived COCs were matured in medium supplemented with or without 0.1 mM cysteamine in a 2 * 2 factorial design (OPU week and cysteamine treatment). Embryos were evaluated for stage and grade on Day 7 and, depending on the number of transferable embryos and recipients available, the embryos were transferred either fresh or frozen-thawed at a later date. The presence of cysteamine during IVM significantly increased the embryo production rate with slaughterhouse-derived COCs (24.0% vs. 19.4%). The higher number of embryos at Day 7 was due to an increased number of blastocysts, whereas the distribution of embryos among different quality grades and cryotolerance was not affected. Embryo production rate was negatively affected when cysteamine was present during both the processes of IVM and IVC during Days 1 to 4 of culture (13.2%-19.3% vs. 26.4%). The presence of cysteamine during IVM of OPU-derived COCs also significantly increased the embryo production rate (34.4% vs. 23.4%). The higher number of embryos was again totally due to an increased number of blastocysts, whereas cryotolerance was not affected. The relative increase in embryo production rate was higher with OPU-derived oocytes compared with slaughterhouse-derived COCs (47% vs. 24%). This improvement resulted in a mean of 1.73 transferable embryos per OPU session compared with 1.06 in the absence of cysteamine. The presence of cysteamine did not affect pregnancy rate, gestation length, birth weight, perinatal mortality, and sex of calves born from either fresh or frozen-thawed embryos. This study reported that cysteamine supplementation during IVM greatly improved the efficiency and affectivity of an OPU-IVP program. PMID- 23746877 TI - Oncoplastic breast conservation does not lead to a delay in the commencement of adjuvant chemotherapy in breast cancer patients. AB - INTRODUCTION: There is hardly any evidence that oncoplastic breast conservation surgery (OBCS) does not lead to a delay in the commencement of adjuvant chemotherapy. Although this is an integral part of overall oncological safety, no controlled studies have been published so far. Therefore, our aim was to determine whether OBCS led to a delay when compared to simple wide local excision (WLE), mastectomy (Ms) or mastectomy with immediate reconstruction (MsIR). METHODS: Breast cancer patients who required adjuvant chemotherapy after OBCS, WLE, Ms and MsIR were identified from prospectively maintained institutional databases. Time between multidisciplinary team decision to offer chemotherapy and delivery of first cycle of chemotherapy was measured and compared among the four groups of patients. RESULTS: time to chemotherapy of breast cancer patients (n = 169) treated with OBCS (n = 31) were 29 [16-58] days, while it was 29.5 [15-105] days after WLE (n = 66), 29 [15-57] days after Ms (n = 56) and 31 [15-58] days after MsIR (n = 16). A combined analysis involving all four groups demonstrated no statistically significant difference (p = 0.524). Similarly, inter-group analysis revealed no significant differences in between patients treated with OBCS compared to any of the three control groups (OBCS to WLE: p = 0.433; OBCS to Ms: p = 0.800; OBCS to MsIR: p = 0.405). CONCLUSION: OBCS seems as safe as WLE, Ms or MsIR in terms of delivery of adjuvant chemotherapy, and, therefore, should not adversely affect breast cancer outcome in this respect. PMID- 23746879 TI - Association between vitamin B12 level and anti-parietal cells and anti-intrinsic factor antibodies among adult Jordanian patients with Helicobacter pylori infection. AB - OBJECTIVE: Evaluate the association of Helicobacter pylori infection with anti parietal cell antibodies (APCA) and anti-intrinsic factor antibodies (AIFA) and their impact on vitamin B12 serum level. PATIENTS AND METHODS: One hundred patients (M/F: 43/57; age 46.5+/-17.5 years) who underwent upper gastrointestinal endoscopy at King Abdullah University Hospital, Irbid, Jordan were enrolled in the study. The patients were grouped as H. pylori-infected (n=81) or H. pylori negative (n=19) by histopathological examination. Fasting serum vitamin B12 levels, anti-parietal cell antibodies and anti-intrinsic factor antibodies for patients and controls were determined. RESULTS: Anti-parietal cell antibodies and anti-intrinsic factor antibodies were positive in 9.9% and 18.5% of H. pylori positive patients respectively. None of the H. pylori negative subjects had anti parietal cell antibodies or anti-intrinsic factor antibodies. Serum vitamin B12 level was lower in the H. pylori-infected patients (275+/-70.4pg/mL) than in controls (322.9+/-60.7pg/mL; p<0.05). H. pylori was positive in 94% of the low vitamin B12 group compared with 64.6% of the normal-vitamin B12 group (p<0.5). CONCLUSION: Patients with H. pylori infection are more likely to have anti parietal cell antibodies and anti-intrinsic factor antibodies. There was an association between H. pylori infection and lower vitamin B12 levels. H. pylori infection might be a significant factor in the pathogenesis of autoimmune gastritis. PMID- 23746878 TI - Therapeutic impact of CT-guided percutaneous catheter drainage in treatment of deep tissue abscesses. AB - Combination therapy of CT-guided percutaneous drainage and antibiotics is the first-line treatment for abscesses. Its effectiveness has been demonstrated. However, the therapeutic impact of this procedure for infection treatment has never been reported. We retrospectively analyzed all 47 patients who received CT guided percutaneous drainage for infection treatment. Patients' characteristics, pathogens isolated, antibiotics administered, technical and clinical outcomes, complications related to this procedure and therapeutic impacts were investigated. Patients were 26 males and 21 females. The mean age was 63.5 years (+/-18.7). The diseases targeted were 19 retroperitoneal abscesses, 18 intra abdominal abscesses, three pelvic abscesses, and seven others. As for technical outcomes, all of the 54 procedures (100%) were successful. As for clinical outcomes, 44 (93.6%) were cured and three patients (6.4%) died. No complications related to this procedure were found in this study. A total of 42 patients (88%) had a change in the management of their infection as a result of CT-guided percutaneous drainage, such as selection and discontinuation of antibiotics. In conclusion, CT-guided percutaneous drainage is a safe and favorable procedure in the treatment of deep tissue abscesses. Therapeutic impact of these procedures helped physicians make a rational decision for antibiotics selection. PMID- 23746880 TI - Towards better health for people in China. PMID- 23746881 TI - Ready, set, go for physical activity. PMID- 23746883 TI - Policy dialogue on China's changing burden of disease. PMID- 23746882 TI - MERS-CoV: a global challenge. PMID- 23746884 TI - Towards evidence-based public health policy in China. PMID- 23746885 TI - Can China's new mental health law substantially reduce the burden of illness attributable to mental disorders? PMID- 23746886 TI - Dementia in China: east-west collaboration bears fruit. PMID- 23746888 TI - Xuetao Cao: reforming medical research in China. PMID- 23746889 TI - Obesity, blood pressure, and cardiovascular outcomes. PMID- 23746890 TI - Obesity, blood pressure, and cardiovascular outcomes. PMID- 23746891 TI - Obesity, blood pressure, and cardiovascular outcomes. PMID- 23746892 TI - Obesity, blood pressure, and cardiovascular outcomes - Authors' reply. PMID- 23746893 TI - Obesity, blood pressure, and cardiovascular outcomes. PMID- 23746894 TI - Publications from China in The Lancet, NEJM, and JAMA. PMID- 23746895 TI - Outpatient workload in China. PMID- 23746896 TI - Ya'an earthquake. PMID- 23746897 TI - Internationalisation of Chinese medical schools. PMID- 23746898 TI - Inadequate evaluation of medical doctors in China. PMID- 23746899 TI - Psychiatry for the elderly in the UK. PMID- 23746900 TI - Frailty assessment in elderly people. PMID- 23746901 TI - Rapid health transition in China, 1990-2010: findings from the Global Burden of Disease Study 2010. AB - BACKGROUND: China has undergone rapid demographic and epidemiological changes in the past few decades, including striking declines in fertility and child mortality and increases in life expectancy at birth. Popular discontent with the health system has led to major reforms. To help inform these reforms, we did a comprehensive assessment of disease burden in China, how it changed between 1990 and 2010, and how China's health burden compares with other nations. METHODS: We used results of the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) for 1990 and 2010 for China and 18 other countries in the G20 to assess rates and trends in mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE). We present results for 231 diseases and injuries and for 67 risk factors or clusters of risk factors relevant to China. We assessed relative performance of China against G20 countries (significantly better, worse, or indistinguishable from the G20 mean) with age-standardised rates and 95% uncertainty intervals. FINDINGS: The leading causes of death in China in 2010 were stroke (1.7 million deaths, 95% UI 1.5-1.8 million), ischaemic heart disease (948,700 deaths, 774,500-1,024,600), and chronic obstructive pulmonary disease (934,000 deaths, 846,600-1,032,300). Age-standardised YLLs in China were lower in 2010 than all emerging economies in the G20, and only slightly higher than noted in the USA. China had the lowest age-standardised YLD rate in the G20 in 2010. China also ranked tenth (95% UI eighth to tenth) for HALE and 12th (11th to 13th) for life expectancy. YLLs from neonatal causes, infectious diseases, and injuries in children declined substantially between 1990 and 2010. Mental and behavioural disorders, substance use disorders, and musculoskeletal disorders were responsible for almost half of all YLDs. The fraction of DALYs from YLDs rose from 28.1% (95% UI 24.2-32.5) in 1990 to 39.4% (34.9-43.8) in 2010. Leading causes of DALYs in 2010 were cardiovascular diseases (stroke and ischaemic heart disease), cancers (lung and liver cancer), low back pain, and depression. Dietary risk factors, high blood pressure, and tobacco exposure are the risk factors that constituted the largest number of attributable DALYs in China. Ambient air pollution ranked fourth (third to fifth; the second highest in the G20) and household air pollution ranked fifth (fourth to sixth; the third highest in the G20) in terms of the age-standardised DALY rate in 2010. INTERPRETATION: The rapid rise of non-communicable diseases driven by urbanisation, rising incomes, and ageing poses major challenges for China's health system, as does a shift to chronic disability. Reduction of population exposures from poor diet, high blood pressure, tobacco use, cholesterol, and fasting blood glucose are public policy priorities for China, as are the control of ambient and household air pollution. These changes will require an integrated government response to improve primary care and undertake required multisectoral action to tackle key risks. Analyses of disease burden provide a useful framework to guide policy responses to the changing disease spectrum in China. FUNDING: Bill & Melinda Gates Foundation. PMID- 23746902 TI - Epidemiology of Alzheimer's disease and other forms of dementia in China, 1990 2010: a systematic review and analysis. AB - BACKGROUND: China is increasingly facing the challenge of control of the growing burden of non-communicable diseases. We assessed the epidemiology of Alzheimer's disease and other forms of dementia in China between 1990, and 2010, to improve estimates of the burden of disease, analyse time trends, and inform health policy decisions relevant to China's rapidly ageing population. METHODS: In our systematic review we searched for reports of Alzheimer's disease or dementia in China, published in Chinese and English between 1990 and 2010. We searched China National Knowledge Infrastructure, Wanfang, and PubMed databases. Two investigators independently assessed case definitions of Alzheimer's disease and dementia: we excluded studies that did not use internationally accepted case definitions. We also excluded reviews and viewpoints, studies with no numerical estimates, and studies not done in mainland China. We used Poisson regression and UN demographic data to estimate the prevalence (in nine age groups), incidence, and standardised mortality ratio of dementia and its subtypes in China in 1990, 2000, and 2010. FINDINGS: Our search returned 12,642 reports, of which 89 met the inclusion criteria (75 assessed prevalence, 13 incidence, and nine mortality). In total, the included studies had 340,247 participants, in which 6357 cases of Alzheimer's disease were recorded. 254,367 people were assessed for other forms of dementia, of whom 3543 had vascular dementia, frontotemporal dementia, or Lewy body dementia. In 1990 the prevalence of all forms of dementia was 1.8% (95% CI 0.0-44.4) at 65-69 years, and 42.1% (0.0-88.9) at age 95-99 years. In 2010 prevalence was 2.6% (0.0-28.2) at age 65-69 years and 60.5% (39.7-81.3) at age 95 99 years. The number of people with dementia in China was 3.68 million (95% CI 2.22-5.14) in 1990, 5.62 million (4.42-6.82) in 2000, and 9.19 million (5.92 12.48) in 2010. In the same period, the number of people with Alzheimer's disease was 1.93 million (1.15-2.71) in 1990, 3.71 million (2.84-4.58) people in 2000, and 5.69 million (3.85-7.53) in 2010. The incidence of dementia was 9.87 cases per 1000 person-years, that of Alzheimer's disease was 6.25 cases per 1000 person years, that of vascular dementia was 2.42 cases per 1000 person-years, and that of other rare forms of dementia was 0.46 cases per 1000 person-years. We retrieved mortality data for 1032 people with dementia and 20,157 healthy controls, who were followed up for 3-7 years. The median standardised mortality ratio was 1.94:1 (IQR 1.74-2.45). INTERPRETATION: Our analysis suggests that previous estimates of dementia burden, based on smaller datasets, might have underestimated the burden of dementia in China. The burden of dementia seems to be increasing faster than is generally assumed by the international health community. Rapid and effective government responses are needed to tackle dementia in low-income and middle-income countries. FUNDING: Nossal Institute of Global Health (University of Melbourne, Australia), the National 12th Five-Year Major Projects of China, National Health and Medical Research Council Australia-China Exchange Fellowship, Importation and Development of High-Calibre Talents Project of Beijing Municipal Institutions, and the Bill & Melinda Gates Foundation. PMID- 23746903 TI - Challenges in the management of acute peptic ulcer bleeding. AB - Acute upper gastrointestinal bleeding is a common medical emergency worldwide, a major cause of which are bleeding peptic ulcers. Endoscopic treatment and acid suppression with proton-pump inhibitors are cornerstones in the management of the disease, and both treatments have been shown to reduce mortality. The role of emergency surgery continues to diminish. In specialised centres, radiological intervention is increasingly used in patients with severe and recurrent bleeding who do not respond to endoscopic treatment. Despite these advances, mortality from the disorder has remained at around 10%. The disease often occurs in elderly patients with frequent comorbidities who use antiplatelet agents, non-steroidal anti-inflammatory drugs, and anticoagulants. The management of such patients, especially those at high cardiothrombotic risk who are on anticoagulants, is a challenge for clinicians. We summarise the published scientific literature about the management of patients with bleeding peptic ulcers, identify directions for future clinical research, and suggest how mortality can be reduced. PMID- 23746904 TI - Food supply and food safety issues in China. AB - Food supply and food safety are major global public health issues, and are particularly important in heavily populated countries such as China. Rapid industrialisation and modernisation in China are having profound effects on food supply and food safety. In this Review, we identified important factors limiting agricultural production in China, including conversion of agricultural land to other uses, freshwater deficits, and soil quality issues. Additionally, increased demand for some agricultural products is examined, particularly those needed to satisfy the increased consumption of animal products in the Chinese diet, which threatens to drive production towards crops used as animal feed. Major sources of food poisoning in China include pathogenic microorganisms, toxic animals and plants entering the food supply, and chemical contamination. Meanwhile, two growing food safety issues are illegal additives and contamination of the food supply by toxic industrial waste. China's connections to global agricultural markets are also having important effects on food supply and food safety within the country. Although the Chinese Government has shown determination to reform laws, establish monitoring systems, and strengthen food safety regulation, weak links in implementation remain. PMID- 23746905 TI - Intussusception detected with ultrasound in a resource-limited setting. PMID- 23746906 TI - Cell nucleus. PMID- 23746907 TI - Calculation of melatonin and resveratrol effects on steatosis hepatis using soft computing methods. AB - In this work, beneficial effects of melatonin and resveratrol drugs on liver damage in rats, induced by application of acute and chronic carbon tetrachloride (CCl4) have been examined. The study consists of three main stages: (1) DATA ACQUISITION: light microscopic images were obtained from 60 rats separated into 10 groups after the preparation of liver tissue samples for histological examination. Rats in first five experimental groups for the four-day and the other five groups for twenty-day were examined. (2) Data processing: by the help of histograms of oriented gradient (HOG) method, obtaining low-dimensional image features (color, shape and texture) and classifying five different group characteristics by using these features with artificial neural networks (ANNs), and support vector machines (SVMs) have been provided. (3) Calculation of drug effectiveness: firstly to determine the differences between group characteristics of rats, a pilot group has been selected (diseased group-CCl4), and the responses of ANN and SVM trained by HOG features have been calculated. As a result of ANN, it has been seen that melatonin and resveratrol drugs have %65.62-%75.12 positive effects at the end of the fourth day, %84.12-%98.89 positive effects on healing steatosis hepatis at the end of the twentieth day respectively and as a result of SVM, it has been seen that melatonin and resveratrol drugs have %62.5-%68.75 positive effects at the end of the fourth day, %45.12-%60.89 positive effects on healing steatosis hepatis at the end of the twentieth day respectively. PMID- 23746909 TI - The mandibular symmetry evaluation of total temporomandibular joint replacement on developing sheep. AB - OBJECTIVE: To evaluate the mandibular symmetry effect of temporomandibular joint (TMJ) replacement by surgicase5.0 software. METHODS: Six developing sheep were included in our study. Spiral computed tomography (CT) data of all sheep was obtained and transformed into 3-dimensional model by surgicase5.0 software preoperatively. 3-dimensional resin skull models were obtained and total TMJ prostheses were made. The right sides of all sheep were carried out operation based on preoperative planning as the experimental group, while the left sides were as the control group. CT scanning was performed one, four and twelve weeks after operation. Ramus heights (RH), mandibularbody length (ML), condyle-incisor (CI) and supramental-condyle (BC) of both experimental and control group were measured to be compared by Wilcoxon Signed Rank. Meanwhile those measurements were also compared with preoperative counterpart by Wilcoxon Signed Rank respectively. RESULTS: All animals were alive to the end of this experiment with normal eating. There were significant differences for RH, CI, BC between the experimental and control group after twelve weeks. The comparison before and after operation on experimental group showed that there was significant difference on ML, CI and BC after four and twelve weeks. The comparison on control group showed that there was significant difference on ML, CI, BC after four weeks and RH, ML, CI, BC after twelve weeks. CONCLUSION: In conclusion, we deduce that sheep carried out by custom-made TMJ prosthesis can eat well. However the long term results of total TMJ replacement on developing sheep may not be very good. PMID- 23746908 TI - A revised metric for quantifying body shape in vertebrates. AB - Vertebrates exhibit tremendous diversity in body shape, though quantifying this variation has been challenging. In the past, researchers have used simplified metrics that either describe overall shape but reveal little about its anatomical basis or that characterize only a subset of the morphological features that contribute to shape variation. Here, we present a revised metric of body shape, the vertebrate shape index (VSI), which combines the four primary morphological components that lead to shape diversity in vertebrates: head shape, length of the second major body axis (depth or width), and shape of the precaudal and caudal regions of the vertebral column. We illustrate the usefulness of VSI on a data set of 194 species, primarily representing five major vertebrate clades: Actinopterygii, Lissamphibia, Squamata, Aves, and Mammalia. We quantify VSI diversity within each of these clades and, in the course of doing so, show how measurements of the morphological components of VSI can be obtained from radiographs, articulated skeletons, and cleared and stained specimens. We also demonstrate that head shape, secondary body axis, and vertebral characteristics are important independent contributors to body shape diversity, though their importance varies across vertebrate groups. Finally, we present a functional application of VSI to test a hypothesized relationship between body shape and the degree of axial bending associated with locomotor modes in ray-finned fishes. Altogether, our study highlights the promise VSI holds for identifying the morphological variation underlying body shape diversity as well as the selective factors driving shape evolution. PMID- 23746910 TI - Variation of the impact duration during the in vitro insertion of acetabular cup implants. AB - The acetabular cup (AC) is an implant impacted into a bone cavity and used for hip prosthesis surgery. Initial stability of the AC is an important factor for long term surgical success. The aim of this study is to determine the variations of the impact duration during AC implant insertion. Twenty-two bone samples taken from bovine femurs were prepared ex vivo for the insertion of an acetabular cup implant, following the surgical procedure used in the clinic. For each bone sample, ten impacts were applied using reproducible mass falls (3.5 kg) in order to insert the AC implant. Each impact duration was recorded using a wide bandwidth force sensor. For all bone samples, the impact duration was shown to first decrease as a function of the impact number, then reaching a stationary value equal in average to 4.2+/-0.7 ms after an average number of 4.1+/-1.7 impacts. The impact duration may be related to variations of the bone-implant interface contact rigidity because of an increase the amount of bone tissue in contact with the AC implant. Measurements of impact duration have a good potentiality for clinical application to assist the surgeon during the insertion of the AC implant, providing valuable information on the bone-implant interface contact properties. PMID- 23746911 TI - Rapid geodesic mapping of brain functional connectivity: implementation of a dedicated co-processor in a field-programmable gate array (FPGA) and application to resting state functional MRI. AB - Graph theory-based analyses of brain network topology can be used to model the spatiotemporal correlations in neural activity detected through fMRI, and such approaches have wide-ranging potential, from detection of alterations in preclinical Alzheimer's disease through to command identification in brain machine interfaces. However, due to prohibitive computational costs, graph-based analyses to date have principally focused on measuring connection density rather than mapping the topological architecture in full by exhaustive shortest-path determination. This paper outlines a solution to this problem through parallel implementation of Dijkstra's algorithm in programmable logic. The processor design is optimized for large, sparse graphs and provided in full as synthesizable VHDL code. An acceleration factor between 15 and 18 is obtained on a representative resting-state fMRI dataset, and maps of Euclidean path length reveal the anticipated heterogeneous cortical involvement in long-range integrative processing. These results enable high-resolution geodesic connectivity mapping for resting-state fMRI in patient populations and real-time geodesic mapping to support identification of imagined actions for fMRI-based brain-machine interfaces. PMID- 23746912 TI - [Publishing scientific papers, with what purpose?]. PMID- 23746913 TI - [Regeneration of critical injuries of the peripheral nerve with growth factors]. AB - INTRODUCTION: This project aims to study the regeneration of non-repairable lesions of peripheral nerve by muscle grafts enhanced with growth factors. MATERIAL AND METHODS: The experiment was carried out in two phases. The first one compared direct suture of a critical defect in the sciatic nerve of ten rats, with the interposition of autologous muscle graft, denatured by heat, in another ten. The second phase compared ten rats with nerve repair using an acellular muscle graft, with injection of 2cc of IGF-1 (10mg/ml mecasermin, Injectable solution) into the acellular graft of another ten. A clinical and functional follow-up was carried out including, ambulation, footprint measurement, and "grasping test". . The animals were sacrificed at 90-100 days, and samples obtained for macro- and microscopic studies with toluidine blue, haematoxylin eosin and Masson's trichrome staining. RESULTS: The first experiment showed the characteristic findings of nerve tissue in muscle graft level sections. The second was an enhancement of the results: post-surgical clinical improvement, early ambulation, decrease in the rate of pressure ulcers in toes, recovery of the footprint, and increasing the percentage of nerve endings in distal sciatic regeneration (47-62%). CONCLUSIONS: In this study the experimental and clinical possibilities of nerve defect repair by denatured muscle are demonstrated, confirming the suitability of the technique. Furthermore, it confirms our hypothesis with clinical and cellular determinations enriched by the addition of growth factors that promote nerve regeneration. PMID- 23746914 TI - [Prognostic factors of the crankshaft phenomenon in patients with scoliosis and open triradiate cartilage. Is the double approach the solution?]. AB - OBJECTIVE: To study young patients after scoliosis surgery in order to determine risk and prevention factors for developing a crankshaft phenomenon (CP). MATERIAL AND METHODS: Retrospective study of a cohort of 26 skeletally immature patients. Six were excluded due to progression of various conditions. Crankshaft was defined as an increase in the Cobb angle >10 degrees , or an increase in the Mehta angle (DAVC) >10 degrees , or any decrease in the apex-rib thoracic distance, or increase in the apical vertebral translation (AVT). Patients with and without CP development were compared in order to analyse preoperative, surgical and postoperative risk factors, as well as the influence of different surgical techniques. RESULTS: The mean follow-up was 83.9 months. Nine patients (45%) developed the crankshaft phenomenon. Only immaturity parameters were associated with development of CP. No preoperative or postoperative radiographic parameters appeared to influence its development. The amount of correction may be a protective factor (41.4 vs. 61.4%; P=.06). The double approach was able to prevent the development of CP (0%) compared with single posterior instrumentation (44%), P=.02. DISCUSSION: None of these preoperative factors seemed to predispose to CP: gender or aetiology, T5-T12 kyphosis or apical hypokyphosis, coronal Cobb, vertebral rotation, or DAVC. The residual postoperative Cobb, achieved kyphosis, or wired instrumentation versus hooks, also seemed to have no influence. CONCLUSION: In patients with open triradiate cartilage under 11 years of age, it seems advisable to correct by double approach to avoid the appearance of the crankshaft phenomenon. PMID- 23746915 TI - [Growing rods in early-onset scoliosis. Do they really help to control the deformity and spinal and thoracic growth?]. AB - OBJECTIVE: To determine the efficacy of growing rods in the treatment of early onset scoliosis. MATERIAL AND METHODS: A total of 32 patients were treated using fusion techniques that included double growing rods and Vertical Expandable Prosthetic Titanium Ribs (VEPTR), in our Early Onset Scoliosis Centre between 2004 and 2011. After analysing the clinical histories and x-rays, 20 patients were included due to meeting the inclusion criteria. All patients had previously received conservative treatment with cranial traction and a series of plasters/corsets. The deformity was analysed before and after the initial surgery, and in successive tightenings, using the x-rays of the coronal and sagittal planes by means of the Cobb angle, as well as the longitudinal and coronal growth of the thorax, and the growth of the spinal column. A series of 188 x-rays of 53 patients with cystic fibrosis were studied in order to perform a comparative analysis with the patients with early-onset scoliosis. RESULTS: There was significant improvement in the angle (Cobb and kyphosis) and linear parameters (T1-S1 distance, T1-T12 distance, and coronal width of the thorax) after the initial surgery, but the successive tightenings had a minimal beneficial effect, losing effectiveness over a period of time. The patients with early-onset scoliosis showed a lower growth of the thorax compared to the patients with cystic fibrosis. DISCUSSION: Treatment of early-onset scoliosis with expandable devices is mainly beneficial with the initial procedure and the first tightenings, but shows a loss of efficacy over a period time. PMID- 23746916 TI - [Elective primary total hip arthroplasty in octogenarians. A case-control study]. AB - OBJECTIVE: To evaluate the results and efficacy of cementless total hip arthroplasty (THA) in octogenarians with osteoarthritis. MATERIAL AND METHODS: Matched case-control study with ratio 1:2. Consecutive selection of 54 octogenarians (55 hips), and 106 control patients (110 hips) with age ranging from 70 to 79 years. Mean follow-up of 7 years (range: 5-12). Before 5 postoperative years, 1 and 4 patients, respectively, died and they were excluded. Clinical assessment was performed using ASA grade, comorbidities, and Harris and Merle D'Aubigne hip scores, and radiographic, complications, and mortality evaluations were made. RESULTS: There were no perioperative deaths in either cohort. The rates of postoperative medical complications (P=.601) and survival (P=.360) were similar. The survival at 7 years was 89.8% in octogenarian and 95.3% in controls, with no influence of the preoperative variables. There were no differences in postoperative functional outcomes (P=.761), but improvement respect to the preoperative was higher in octogenarian (P=.002). In octogenarians there were 2 intraoperative fractures, 2 dislocations and 2 unstable stems, and in control patients 1 deep infection, 1 peri-prosthetic femoral fracture, 2 unstable cups and 4 unstable stems. The rates of aseptic complications, the need for revision, and arthroplasty survival (94% at 7 years) were similar in both cohorts. DISCUSSION: Due to improvement in health status, the octogenarian may have a life expectancy of at least 10 years. The cost arguments and an arbitrary age should not influence the selection of candidates for cementless THA. CONCLUSIONS: Cementless THA has been shown to be safe and effective in octogenarian patients with osteoarthritis. The notable increase found in functional outcomes justifies the continued use in these patients. PMID- 23746917 TI - [Hip arthroplasty with conventional stem as rescue treatment after failed treatment of intertrochanteric hip fractures]. AB - OBJECTIVE: The purpose of this study is to evaluate the results and complications of hip arthroplasty with conventional stem performed as a salvage procedure after the failed treatment of an intertrochanteric hip fracture. MATERIAL AND METHODS: Between 1997 and 2011, 17 patients with a mean age of 76 years were treated with hip arthroplasty for failed treatment of intertrochanteric hip fracture. In all cases a conventional stem was used. The mean follow-up was 6 years (range 1-14 years). Pain, range of motion (Merle d'Aubigne) and functional results (Barthel), as well as implant fixation (Harris and Engh), were evaluated during the follow up. RESULTS: Except for one case of death (6%) and one case of infection (Girdlestone arthroplasty), all patients were able to walk independently at 6 months. The majority of the patients (87%) had no or mild pain. After 2 surgeries (osteosynthesis and hip arthroplasty) the mean Barthel Score had decreased from 81 to 66 points. Just one case (6%) of stem loosening has been observed. DISCUSSION: In older patients, prosthetic replacement after failed proximal femoral fixation is a reliable salvage option. Most patients have good pain relief and functional improvement, although the rate of perioperative medical complications is high. Surgery is less demanding and the operating time is shorter when conventional femoral stems are used. PMID- 23746918 TI - [Results and complications of pertrochanteric hip fractures using an intramedullary nail with a helical blade (proximal femoral nail antirotation) in 200 patients]. AB - OBJECTIVES: Evaluation of the surgical management, outcome and complications in patients with pertrochanteric fractures treated with PFNA nail. MATERIAL AND METHOD: A retrospective study was conducted on 200 patients treated consecutively between April 2010 and February 2012. Radiological assessments were performed before and after the surgery, and during the follow-up (fracture reduction, blade position, consolidation or collapse signs). A clinical evaluation was performed as regards walking capabilities. The results were compared with those of a previous study on 700 patients treated with gamma 3 and TFN nails. RESULTS: The blade position was centre-centre in 64% of patients, and decreased to 53% in the mechanical complications group. Tip-apex distance was less than 25mm in 91.5%. The average hospital stay was 9.17 days, with a mean post-surgery stay of 5.95 days. Complications (7.5%): 2 cut out (1%), one cut through (0.5%), 4 cases of helical blade sliding (2%), one failure in distal locking procedure (0.5%), 2 cases with painful fasciae latae (1%), one union delay (0.5%), 2 cases of non union with hardware failure (1%), one case of intense bleeding related to distal locking of the nail (0.5%), and one case of avascular necrosis (0.5%). CONCLUSIONS: The PFNA helical blade system seems to reduce the incidence of cut out and cut through in osteoporotic bone. Blade position was one of the main parameters associated with mechanical complications. PMID- 23746919 TI - [Results of revision after failed surgical treatment for traumatic anterior shoulder instability]. AB - INTRODUCTION AND OBJECTIVES: Persistent or recurrent glenohumeral instability after a previous operative stabilization can be a complex problem. Our aim is to establish the incidence of recurrence and its revision surgery, and to analyse the functional results of the revision instability surgery, as well as to determine surgical protocols to perform it. MATERIALS AND METHODS: A retrospective analysis was conducted on 16 patients with recurrent instability out of 164 patients operated on between 1999 and 2011. The mean follow-up was 57 months and the mean age was 29 years. To evaluate functional outcome we employed Constant, Rowe, UCLA scores and the visual analogue scale. RESULTS: Of the 12 patients who failed the initial arthroscopic surgery, 6 patients underwent an arthroscopic antero-inferior labrum repair technique, 4 using open labrum repair techniques, and 2 coracoid transfer. The two cases of open surgery with recurrences underwent surgery for coracoid transfer. Results of the Constant score were excellent or good in 64% of patients. CONCLUSIONS: Surgical revision of instability is a complex surgery essentially for two reasons: the difficulty in recognising the problem, and the technical demand (greater variety and the increasingly complex techniques). PMID- 23746921 TI - [Arthroscopic treatment of talus osteochondral lesions: study of 73 cases]. AB - BACKGROUND AND AIM: The aim of our study is to analyze the different techniques used in arthroscopic treatment of talus osteochondral lesions. MATERIAL AND METHOD: We retrospectively analyzed 73 patients who underwent surgery between 2000 and 2011. Patients were divided in two groups: group A (51 patients), those treated with osteochondral stimulation techniques, and group B (32 patients), that were treated by repair techniques. The mean age was 32.58 (19-73) years in group A and 36.50 (19-58) in group B. It is identified male predominance and medial lesions in both groups. RESULTS: Were evaluated according to the AOFAS ankle scoring scale, it is observed a statistically significant clinical improvement (P<.001). Preoperative values were 48.77 (31-67) in group A and 58.08 (41-75) in group B. After surgery scores amounted to 85.19 (60-100) in group A and 93.60 (80-100) in group B. CONCLUSIONS: Ankle arthroscopy is an excellent technique for the accurate staging of osteochondral lesions, and diagnosis and treatment of associated injuries. The arthroscopic treatment of lesions grade i, ii and sometimes iii, by stimulation techniques and chondral lesions grade iii and iv by replacement techniques, gives good results with few complications. PMID- 23746920 TI - [Medium term results of unipolar modular radial head arthroplasty]. AB - OBJECTIVE: Analyze the results of unipolar modular radial head arthroplasty in the treatment of complex fractures associated with elbow joint instability. MATERIAL AND METHOD: Retrospective design study of 44 patients, 17 men and 27 women with a mean age of 51 years (17-78) who suffered radial head fractures (Mason III) in the context of an unstable elbow injury. Mean follow-up was 21.2 months (12-60). Radial head replacement was performed with a unipolar modular prosthesis with a fixed stem (Ascension((r)) Modular Radial Head [MRH]), associating repair of concomitant lesions. The Mayo scale Elbow Performance Score (MEPS) was used to perform the functional assessment. A radiological evaluation was performed at the last follow-up and the complications were recorded. RESULTS: Final arc of flexion-extension was 108 degrees with an average of 135 degrees of prono-Supination. At final follow-up, 82% of results were satisfactory according to the MEPS. The 40% of patients (17) had radiographic signs of lucencies around the stem, although most of them were asymptomatic. Two of them needed a second surgical procedure because of painful prosthetic loosening and further surgery was required for a prosthesis dislocation. DISCUSSION: Radial head implants are an adequate treatment option for restoring stability in complex radial head fractures. Modularity allows a wide range of size combination and helps to avoid overstuffing. Periprosthetic osteolysis could be associated with the presence of pain, so it is necessary to perform long-term studies to test the potential complications of this finding. PMID- 23746922 TI - [Intramedullary reaming in Ribbing disease]. AB - Ribbing disease is a rare benign sclerosing bone dysplasia. It presents with an increased bone density at the diaphysis with cortical endosteal/periosteal thickening and affects predominantly the lower extremities. We report a case of a 28 year-old woman with a this condition in her tibia that occluded the medullary cavity, with severe pain that could not be relieved with anti-inflammatory therapy. Several cases have been published on pain relief after intramedullary reaming. We performed this treatment with the surgical steps to avoid complications such as a fracture or false route that may occur due to the difficulty in piercing the closed medullary cavity. Pain improved immediately after surgery, and the patient is asymptomatic after one year. The natural progression of ribbing disease is to stabilise, but there are no data published with long term follow-up after intramedullary reaming. PMID- 23746923 TI - Vanishing ulnae: symmetrical diffuse large B-cell lymphoma. PMID- 23746924 TI - SUDEP and other causes of mortality in childhood-onset epilepsy. AB - BACKGROUND: There are few prospective studies on the causes of mortality in well characterized cohorts with epilepsy and even fewer that have autopsy data that allow for reliable determination of SUDEP. We report causes of mortality and mortality rates in the Finnish cohort with childhood-onset epilepsy. METHODS: A population-based cohort of 245 children with epilepsy in 1964 has been prospectively followed for almost 40 years. Seizure outcomes and mortality were assessed. Autopsy data were available in 70% of the cases. Sudden unexpected death in epilepsy (SUDEP) rates were assessed, and SUDEP was confirmed by autopsy. RESULTS: During the follow-up, 60 subjects died. The major risk factor for mortality was lack of terminal remission (p < 0.0001). Remote symptomatic etiology also increased the risk for death (p < 0.0001) but did not remain significant on multivariate analysis after adjusting for effect of remission. Of the deaths, 33/60 (55%) were epilepsy-related including SUDEP in 23/60 (38%) using the Nashef criteria, status epilepticus in 4/60 (7%), and accidental drowning in 6/60 (10%). The nonepilepsy-related deaths occurred primarily in the remote symptomatic group and were often related to the underlying disorder or to medical comorbidities that developed after the onset of the epilepsy. Risk factors for SUDEP on multivariable analysis included lack of 5-year terminal remission and not having a localization-related epilepsy. In cryptogenic/idiopathic cases, SUDEP did not occur in childhood but begins only in adolescence. CONCLUSION: Childhood-onset epilepsy is associated with a substantial risk of epilepsy-related mortality, primarily SUDEP. In otherwise neurologically normal individuals, the increased SUDEP risk begins in adolescence. The higher mortality rates reported in this cohort are related to duration of follow-up as most of the mortality occurs many years after the onset of the epilepsy. PMID- 23746925 TI - The transfer of pravastatin in the dually perfused human placenta. AB - HMG-CoA reductase inhibitors (statins) are contraindicated during pregnancy. However, it has been suggested that the hydrophilic property of pravastatin prevents its placental transfer to the fetus, explaining neutral effects observed in controlled studies. Using the ex-vivo placental perfusion model, placental transfer of pravastatin (50 ng/ml) was determined. The mean maximum fetal concentration was 4.4 ng/ml. The transfer of pravastatin's across the placenta appears to be limited and slow. Combined with its rapid elimination half-life of 2 h and 50% protein binding, the transfer of pravastatin from maternal to fetal compartments is substantially more limited than observed in the perfusion experiments. PMID- 23746926 TI - Region-specific reduction in brain volume in young adults with perinatal hypoxic ischaemic encephalopathy. AB - BACKGROUND: A severe form of perinatal hypoxic-ischaemic encephalopathy (HIE) carries a high risk of perinatal death and severe neurological sequelae while in mild HIE only discrete cognitive disorders may occur. AIM: To compare total brain volumes and region-specific cortical measurements between young adults with mild moderate perinatal HIE and a healthy control group of the same age. METHODS: MR imaging was performed in a cohort of 14 young adults (9 males, 5 females) with a history of mild or moderate perinatal HIE. The control group consisted of healthy participants, matched with HIE group by age and gender. Volumetric analysis was done after the processing of MR images using a fully automated CIVET pipeline. We measured gyrification indexes, total brain volume, volume of grey and white matter, and of cerebrospinal fluid. We also measured volume, thickness and area of the cerebral cortex in the parietal, occipital, frontal, and temporal lobe, and of the isthmus cinguli, parahippocampal and cingulated gyrus, and insula. RESULTS: The HIE patient group showed smaller absolute volumetric data. Statistically significant (p < 0.05) reductions of gyrification index in the right hemisphere, of cortical areas in the right temporal lobe and parahippocampal gyrus, of cortical volumes in the right temporal lobe and of cortical thickness in the right isthmus of the cingulate gyrus were found. Comparison between the healthy group and the HIE group of the same gender showed statistically significant changes in the male HIE patients, where a significant reduction was found in whole brain volume; left parietal, bilateral temporal, and right parahippocampal gyrus cortical areas; and bilateral temporal lobe cortical volume. CONCLUSIONS: Our analysis of total brain volumes and region-specific corticometric parameters suggests that mild-moderate forms of perinatal HIE lead to reductions in whole brain volumes. In the study reductions were most pronounced in temporal lobe and parahippocampal gyrus. PMID- 23746927 TI - Age-related prevalence and features of migraine headache in Hungarian schoolchildren and adolescents. AB - BACKGROUND: Differences occur in certain features of childhood and adult migraine, such as the duration and location. However, few studies have been reported of the changes in other symptoms during childhood. AIMS: The aims of this study were to establish the prevalence of migraine headache in children in Hungary, and to investigate the changes in prevalence of migraine and migraine symptoms in a wide paediatric age range. METHODS: We conducted a school-based study with the use of a questionnaire. RESULTS: 7361 7-18-year-old students participated. The 1-year prevalence of migraine was 12.5% (9.2% in boys and 15.4% in girls). With the criterion of a headache duration of 4 h for 15-18-year-olds and of 1 h below the age of 15, the overall prevalence decreased to 9.1%. The prevalence of migraine increased steadily from young childhood to late adolescence in both boys and girls. The frequency and duration of headache increased, whereas vomiting and nausea became less prevalent with advancing age in both genders. The prevalence of uni/bilaterality, photophobia and phonophobia increased only in girls, while that of a pulsating character did so only in boys. CONCLUSIONS: The migraine characteristics displayed by the studied population proved similar to those experienced in other countries. The duration of headache applied in the diagnosis of migraine exerts a great impact on the prevalence data. The features of migraine change with advancing age, a situation demanding consideration in studies on migraine in children of different ages. PMID- 23746928 TI - [Localized purpura revealing vascular prosthetic graft infection]. AB - Prosthetic graft infection after vascular reconstruction is a rare but serious complication. We report a case of infection occurring late after implantation of an iliofemoral prosthetic vascular graft. The Staphylococcus aureus infection was revealed by vascular purpura localized on the right leg 7 years after implantation of a vascular prosthesis. This case illustrates an uncommonly late clinical manifestation presenting as an acute infection 7 years after the primary operation. In this situation, the presentation differs from early infection, which generally occurs within the first four postoperative months. Diagnosis and treatment remain a difficult challenge because prosthetic graft infection is a potentially life-threatening complication. Morbidity and mortality rates are high. Here we detail specific aspects of the clinical and radiological presentation. PMID- 23746929 TI - Epithelial mechanobiology, skin wound healing, and the stem cell niche. AB - Skin wound healing is a vital process that is important for re-establishing the epithelial barrier following disease or injury. Aberrant or delayed skin wound healing increases the risk of infection, causes patient morbidity, and may lead to the formation of scar tissue. One of the most important events in wound healing is coverage of the wound with a new epithelial layer. This occurs when keratinocytes at the wound periphery divide and migrate to re-populate the wound bed. Many approaches are under investigation to promote and expedite this process, including the topical application of growth factors and the addition of autologous and allogeneic tissue or cell grafts. The mechanical environment of the wound site is also of fundamental importance for the rate and quality of wound healing. It is known that mechanical stress can influence wound healing by affecting the behaviour of cells within the dermis, but it remains unclear how mechanical forces affect the healing epidermis. Tensile forces are known to affect the behaviour of cells within epithelia, however, and the material properties of extracellular matrices, such as substrate stiffness, have been shown to affect the morphology, proliferation, differentiation and migration of many different cell types. In this review we will introduce the structure of the skin and the process of wound healing. We will then discuss the evidence for the effect of tissue mechanics in re-epithelialisation and, in particular, on stem cell behaviour in the wound microenvironment and in intact skin. We will discuss how the elasticity, mechanical heterogeneity and topography of the wound extracellular matrix impact the rate and quality of wound healing, and how we may exploit this knowledge to expedite wound healing and mitigate scarring. PMID- 23746931 TI - Tackling hospital waiting times: the impact of past and current policies in the Netherlands. AB - This paper reviews the impact of health policies on hospital waiting times in the Netherlands over the last two decades. During the 1990s hospital waiting times increased as a result of the introduction of fixed budgets and capacity constraints for specialists, in addition to the fixed global hospital budgets that were already in place since the 1980s. To tackle these increased waiting times over the years 2000-2011 several policies were implemented, including a change from fixed budgets to activity-based funding--for both hospitals and specialists--and increased competition among hospitals. All together these measures resulted in a strong reduction of waiting times. In 2011 mean expected waiting times for almost all surgical procedures varied from 2 to 6 weeks, well below the broadly accepted specified maximum waiting times. Hence, in the Netherlands hospital waiting times are currently not an important policy concern. Since the waiting time reduction was achieved at the expense of rapidly growing hospital costs, these have become now the primary policy concern. This has triggered the introduction of new powerful supply-side constraints in 2012, which may cause waiting times to increase for the coming years. PMID- 23746932 TI - [Pain assessment in young children, contribution of EVENDOL behavioral pain scale]. PMID- 23746930 TI - Advances in zirconia toughened alumina biomaterials for total joint replacement. AB - The objective of this article is to provide an up-to-date overview of zirconia toughened alumina (ZTA) components used in total hip arthroplasties. The structure, mechanical properties, and available data regarding the clinical performance of ZTA are summarized. The advancements that have been made in understanding the in vivo performance of ZTA are investigated. This article concludes with a discussion of gaps in the literature related to ceramic biomaterials and avenues for future research. PMID- 23746933 TI - Dietary supplementation with resveratrol and/or docosahexaenoic acid alters hippocampal gene expression in adult C57Bl/6 mice. AB - The hippocampus is an important brain structure for multiple cognitive functions, including memory formation. It is particularly sensitive to insults, such as stress, ischemia, and aging; all of these can affect hippocampal and therefore cognitive function. To understand the potential of diet for the preservation of hippocampal function, we investigated the effects of dietary supplementation with resveratrol (RES) or docosahexaenoic acid (DHA), or their combination, on hippocampal gene expression in adult C57BL/6 mice. Animals in the supplemented group received either 50 mg/kg/day of RES or DHA, while the combination group received 50 mg/kg/day of each supplement. Dietary supplements were mixed with the AIN93G diet, and supplementation lasted 6 weeks. The control group received AIN93G diet alone for the same period. At the end of the experiment, the hippocampi were processed for genome-wide gene expression and pathway analyses. Most of the genes that were significantly altered were associated with inflammatory responses as determined by pathway analysis. RES-supplemented animals showed decreased expression of IL-6 (P=.001), MAPKapk2 (P=.015), and increased expression for PI3KR2 (P=.034) and Wnt7a (P=.004) expression. DHA supplemented animals showed a decreased IL-6 (P=.003) and an increased Wnt7a (P=.003) expression. Animals on the combination diet showed a decreased IL-6 (P=.005) and Apolipoprotien E (ApoE) (P=.035) expression. Our findings demonstrate that hippocampal gene expression is significantly altered by all three dietary supplementation regimes. Moreover, our analysis indicates that RES and DHA likely exert their beneficial effects through antiinflammatory mechanisms. PMID- 23746934 TI - Lycopene modulates growth and survival associated genes in prostate cancer. AB - Lycopene is a fat soluble red-orange carotenoid pigment present in tomato that reduces the risk for prostate cancer, a common malignancy among men. However, the mechanism by which lycopene attenuates prostate cancer is not fully defined. In this study we examined the effect of lycopene on proliferation, survival, and biomarker gene expression in prostate cancer (PC-3) cells in culture. WST-1 assay showed that lycopene induces a biphasic effect on PC-3 cells with a modest increase in proliferation at 1-5 MUM, no change at 10-25 MUM and a decrease at 50 100 MUM doses in culture. Interestingly, combination treatment with lycopene induced anti-proliferative effect of Temozolomide on PC-3 cells. Lycopene also augmented the anti-proliferative effect of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, but not Doxorubicin or Taxol, in prostate cancer. Flow cytometry analyses showed that lycopene, in combination with chemotherapeutic agents and PPARgamma agonists, induced modest cell cycle arrest with significant increase in cell death by apoptosis and necrosis on prostate cancer. Gene array and quantitative reverse transcription polymerase chain reaction analyses showed that lycopene alters the expression of growth and apoptosis associated biomarkers in PC-3 cells. These findings highlight that lycopene attenuates prostate cancer by modulating the expression of growth and survival associated genes. PMID- 23746935 TI - Men are stronger than women-also in the hip. PMID- 23746936 TI - Adjusting head circumference for covariates in autism: clinical correlates of a highly heritable continuous trait. AB - BACKGROUND: Brain development follows a different trajectory in children with autism spectrum disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort. METHODS: We used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters. RESULTS: Gender, age, height, weight, genetic ancestry, and ASD status were significant predictors of HC (estimate of the ASD effect = .2 cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC. CONCLUSIONS: Measured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait, and population norms for HC would be far more accurate if covariates including genetic ancestry, height, and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation. PMID- 23746938 TI - Combined effects of global change pressures on animal-mediated pollination. AB - Pollination is an essential process in the sexual reproduction of seed plants and a key ecosystem service to human welfare. Animal pollinators decline as a consequence of five major global change pressures: climate change, landscape alteration, agricultural intensification, non-native species, and spread of pathogens. These pressures, which differ in their biotic or abiotic nature and their spatiotemporal scales, can interact in nonadditive ways (synergistically or antagonistically), but are rarely considered together in studies of pollinator and/or pollination decline. Management actions aimed at buffering the impacts of a particular pressure could thereby prove ineffective if another pressure is present. Here, we focus on empirical evidence of the combined effects of global change pressures on pollination, highlighting gaps in current knowledge and future research needs. PMID- 23746937 TI - Localized targeting of biomaterials following myocardial infarction: a foundation to build on. AB - Acute coronary syndromes can give rise to myocardial injury infarction (MI), which in turn promulgates a series of cellular and extracellular events that result in left ventricular (LV) dilation and dysfunction. Localized strategies focused upon interrupting this inexorable process include delivery of bioactive molecules and stem cell derivatives. These localized treatment strategies are often delivered in a biomaterial complex in order to facilitate elution of the bioactive molecules or stem cell engraftment. However, these biomaterials can impart significant and independent effects upon the MI remodeling process. In addition, significant changes in local cell and interstitial biology within the targeted MI region can occur following injection of certain biomaterials, which may hold important considerations when using these materials as matrices for adjuvant drug/cell therapies. PMID- 23746939 TI - Severe ataxic polyneuropathy associated with chronic levodopa use in Parkinson's disease. PMID- 23746940 TI - Ophthalmologic involvement in Japanese siblings with chorea-acanthocytosis caused by a novel chorein mutation. PMID- 23746942 TI - Temporal distribution of heavy metal concentrations in oysters Crassostrea rhizophorae from the central Venezuelan coast. AB - The oyster Crassostrea rhizophorae is a bivalve abundant in Venezuelan estuaries and consumed by local populations. No known values have been reported on trace metals in oysters from the central Venezuelan coast. We report the concentrations of Al, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Sr, V and Zn in the soft parts of C. rhizophorae, which were collected bimonthly between March 2008 and March 2009, at two sampling areas from the Central Venezuelan Coast: Buche estuary and Mochima estuary. Our results show that for each metal there is a similar temporal variation pattern. The concentrations of the heavy metals reported in this work are useful as reliable baselines and can be used for comparison in future environment studies. Concentrations in C. rhizophorae from the Buche estuary can be interpreted to be high on a global scale for Cd, Cu, Ni and Mn, indicating atypically raised bioavailabilities. PMID- 23746941 TI - Detection of nonylphenol and persistent organic pollutants in fish from the North Pacific Central Gyre. AB - Despite scientific and public concern, research on food web contamination from chemicals in plastic is limited, and distinguishing plastic sources from prey remains a challenge. We analyzed juvenile yellowtail (Seriola lalandi) from the North Pacific Central Gyre for plastic ingestion and tissue concentrations of persistent organic pollutants and nonionic surfactants to investigate potential contamination from plastic exposure. Ingestion of synthetic debris occurred in ~10% of the sample population. PCBs and DDTs were 352+/-240 (mean+/-SD) and 1425+/-1118 ng/g lw, respectively. PBDEs were 9.08+/-10.6 ng/g lw, with BDEs-47, 99, and 209 representing 90% of PBDEs. Nonylphenol (NP) was detected in one-third of the yellowtail with a mean of 52.8+/-88.5 ng/g ww overall and 167+/-72.3 ng/g ww excluding non-detects. Because environmental NP is strongly associated with wastewater treatment effluents, long-range transport is unlikely, and NP was previously measured in gyre plastic, we concluded that plastic-mediated exposure best explained our findings of NP in yellowtail. PMID- 23746943 TI - Recommendations for rotavirus vaccine. AB - Rotavirus infection has been the leading cause of gastroenteritis among children in Taiwan. Studies have shown that 40% of hospitalization for acute gastroenteritis can be prevented through the use of vaccines, including a live, attenuated monovalent rotavirus vaccine and a pentavalent, human-bovine reassortant rotavirus vaccine. In 2009, the World Health Organization suggested that rotavirus vaccine should be included in all national immunization programs. This review summarizes issues and recommendations discussed during an expert meeting in Taiwan. The recommendations included: (1) rotavirus vaccine should be offered to all healthy infants (including those without contraindications, such as immunodeficiency) at an appropriate age; (2) either monovalent or pentavalent vaccine can be administered concurrently with routine injected vaccines; (3) the administration of rotavirus vaccine must be administered at least 2 weeks prior to oral polio vaccination; (4) the first vaccine dose for infants should be administered between age 6 weeks and age 14 weeks 6 days and the course should be completed by age 8 months 0 day; (5) pentavalent vaccines can be administered at 2 months, 4 months, and 6 months while monovalent vaccines can be taken at 2 months and 4 months; (6) a combined use of monovalent and pentavalent vaccine is justified only when the previous dose is unavailable or unknown; and (7) rotavirus vaccines may be given to premature infants, human immunodeficiency virus infected infants and infants who have received or are going to receive blood products. PMID- 23746944 TI - Double peptic perforation: Report of a rare case. AB - Perforation peritonitis is the most common surgery performed in an emergency. Upper gastrointestinal tract perforation is more common than lower gastrointestinal perforation. Multiple peptic perforations in an individual are a relatively rare entity, with fewer than 10 cases reported in the literature. The factor that contributes the most for the occurrence of multiple peptic perforations is analgesic and steroid abuse. Herein, we report a rare case of double peptic perforation in a middle-aged man with history of analgesic use for 18 months. PMID- 23746945 TI - Foreword. An update on transcatheter aortic valve replacement. PMID- 23746947 TI - New strategies for the concurrent strength-, power-, and endurance-training prescription in elderly individuals. PMID- 23746946 TI - An update on transcatheter aortic valve replacement. AB - Before the development of transcatheter aortic valve replacement (TAVR), patients with severe symptomatic aortic stenosis and significant comorbidities who were deemed inoperable were left with no therapeutic option but palliative care. Today, 11 years after Dr Alain Cribier's first transcatheter aortic valve implantation in 2002, more than 50,000 TAVRs have been performed worldwide, majority in Europe. Short-term results from the recently conducted Placement of Aortic Transcatheter Valve (PARTNER) I trial and long-term results from the European/Canadian registry experiences show significant reduction in mortality compared with medical therapy alone (inoperable cohort B) and noninferiority of TAVR versus open aortic valve replacement in high-risk patients (operable high risk cohort A). Technical advances and increasing operator experience will further decrease procedure-related complications and may make TAVR an alternative to open aortic valve replacement in even younger and low- to medium-risk patients with severe symptomatic calcific aortic valve stenosis. PMID- 23746948 TI - Treatment of pain in European nursing homes: results from the Services and Health for Elderly in Long TERm Care (SHELTER) study. AB - OBJECTIVE: To identify pharmacological and nonpharmacological pain management approaches and associated factors in nursing home residents across Europe. SETTING, PARTICIPANTS, AND MEASUREMENTS: Cross-sectional study with 4156 residents who were assessed using the interRAI instrument for Long Term Care Facilities (interRAI LTCF), including pharmacological and nonpharmacological pain management modalities. Those reporting pain were included in the analyses (n = 1900). A deeper analysis was performed for the subsample of residents who reported "current pain," defined as pain at least 1 day within the past 3 days (n = 838), and those who reported "current pain of moderate to severe intensity" (n = 590). RESULTS: Up to 24% of residents who reported pain did not receive any pain medication and up to 11% received it only PRN (as-needed basis), independent of current pain-intensity levels; 61% did not receive any nonpharmacological treatment and 21% received neither pharmacological nor nonpharmacological pain modalities. Considerable differences could be demonstrated across European countries. Factors positively associated with pharmacological pain management were being of female gender, reporting cancer, and having moderate or severe pain. High turnover rates of regular staff and low-to-moderate physicians' availability were negatively associated. Factors positively associated with nonpharmacological treatment were fractures and need of assistance in activities of daily living. Dementia, large nursing home facilities, above-average and high turnover rates of nursing staff, a low physicians' availability, and severe pain intensity were negatively associated. CONCLUSION: Despite some advances in recent years, pain treatment in European nursing home residents remains to be suboptimal and requires further improvement. PMID- 23746949 TI - Double-blind placebo-controlled trial of hydroxytyrosol of Olea europaea on pain in gonarthrosis. AB - Hydroxytyrosol is mainly found in olive leaves after hydrolysis of oleuropein and has anti-oxidant, anti-bacterial, and anti-inflammatory properties. The aim of this study was to investigate the effect of hydroxytyrosol for alleviating the pain in patients with gonarthrosis. We conducted a double-blind clinical trial in which hydroxytyrosol or placebo was administered to adult patients with gonarthrosis for 4 weeks. The group administered hydroxytyrosol showed significant improvement in the Japanese Orthopedic Association score (pain measurement index) and the visual analog scale score compared to the placebo group. PMID- 23746950 TI - Synergistic enhancement of antitumor effect of beta-Lapachone by photodynamic induction of quinone oxidoreductase (NQO1). AB - beta-Lapachone is a phytochemotherapeutic originally isolated from Lapacho tree whose extract has been used medicinally for centuries. It is well known that NAD(P)H:quinone oxidoreductase (NQO1) activity is the principal determinant of beta-Lapachone cytotoxicity. As NQO1 is overexpressed in most common carcinomas, recent investigations suggest its potential application against cancer. Photodynamic therapy (PDT) is a clinically approved and rapidly developing cancer treatment. PDT involves the administration of photosensitizer (PS) followed by local illumination with visible light of specific wavelength. In the presence of oxygen molecules, the light illumination of PS can lead to a series of photochemical reactions and consequently the generation of cytotoxic reactive oxygen species (ROS). It has been reported that beta-Lapachone synergistically interacts with ionizing radiation, hyperthermia and cisplatin and that the sensitivity of cells to beta-Lapachone is closely related to the activity of NQO1. So, the present study aimed to investigate the feasibility of PDT to increase the anticancer effect of beta-Lapachone by up-regulating NQO1 expression on breast cancer MCF-7c3 cells. NQO1 expression was evaluated by Western blot analysis at different times after PDT using ME-ALA as PS. The cytotoxicity of the photodynamic treatment and beta-Lapachone alone or in combination was determined by MTT assay and the combination index (CI)-isobologram method and the dose reduction index (DRI) analysis were used to assess the effect of drug combinations. Our studies for the first time demonstrated that the expression of NQO1 is induced 24h after photodynamic treatment. The sensitivity of cancer cells to beta-Lapachone treatment increased 24h after PDT and a synergistic inhibitory effect on MCF-7c3 cells was showed. Taken together, these results lead us to conclude that the synergistic interaction between beta-Lapachone and PDT in killing cells was consistent with the up-regulation of NQO1. The combination of beta-Lapachone and PDT is a potentially promising modality for the treatment of cancer. PMID- 23746951 TI - 18beta-glycyrrhetinic acid induces immunological adjuvant activity of Th1 against Candida albicans surface mannan extract. AB - The aim of this study was to determine the immunological adjuvant effect of 18beta-glycyrrhetinic acid (GA) isolated from Glycyrrhizae radix. In the experiments, BALB/c mice were immunized on days 1 and 22 intraperitoneally (i.p.) with an emulsion form of Candida albicans surface mannan extract (SM) mixed with either Incomplete Freund's Adjuvant [SM/IFA], or Complete Freund's Adjuvant [SM/CFA] or GA mixed with IFA [SM/GA/IFA]. One week after the second immunization, polyclonal sera were collected from these animals in order to determine IgG isotypes and cytokine profiles in the sera. After the collection, the spleen samples were collected to determine the degree of T cell proliferation. Additionally, the DTH (delayed type hypersensitivity) response was examined by measuring the footpad swelling of immunized mice. Data resulting from the T cell proliferation test showed that SM/GA/IFA enhanced the proliferation the most. The enhancement was about 85% more compared to SM/IFA (p<0.05). IgG isotypes and cytokine profiles displayed that SM/GA/IFA induced the most abundant production of total IgG with the highest IgG2a/IgG1 ratio (1.31) and greatest IFN gamma secretion. In contrast, SM/CFA resulted in an IgG2a/IgG1 ratio less than 1 and SM/IFA produced a dominant induction of IL-4, but almost no IFN-gamma secretion. Together, these observations revealed that GA developed a greater Th1 immune response than Th2 response. The DTH determination confirmed that GA addition induced dominant Th1 immunity - displaying the highest footpad-swelling followed by SM/CFA and BSA/IFA, respectively. All of this data indicates that GA has a Th1-immunological adjuvant activity, which would be beneficial in the treatment of Th1-disordered disease due to C. albicans. PMID- 23746952 TI - Effects of imperatorin, the active component from Radix Angelicae (Baizhi), on the blood pressure and oxidative stress in 2K,1C hypertensive rats. AB - The 2-kidney, 1-clip (2K,1C) model of hypertension was used to investigate the potential antihypertensive and antioxidant effect of imperatorin extracted from the root of radix angelicae. After 10 weeks treatment of imperatorin, mean blood pressure (MBP) of 2K,1C hypertensive rats was obtained, and superoxide dismutase (SOD), nitric oxide (NO) and nitric oxide synthase (NOS) were measured. Malondialdehyde (MDA) and glutathione (GSH) levels, catalase (CATA), xanthine oxidase (XOD), angiotensinII (Ang II) and endothelin (ET) levels of kidney were evaluated with commercial kits. Nicotinamide adenine dinucleotidephosphate (NADPH) oxidase subunits of the renal cortial tissues were determined by RT-PCR and Western blot. 8-Iso-prostaglandin F2alpha (8-iso-PGF2alpha) of 24h urinary excretion was also measured by ELISA. MBP was significantly reduced by treatment with IMP (6.25, 12.5 and 25 mg/kg/day, i.g.) in 2K,1C hypertensive rats. Meanwhile, we found that renal CATA and XOD activities, GSH levels, plasma NO and NOS contents were significantly increased in IMP-treated groups. Plasma ET, renal Ang II levels, MDA and the 24h urinary excretion of 8-iso-PGF2alpha in the IMP treated group were lower than control SD group. After that, we found the mRNA expressions and protein levels of NADPH oxidase subunits in the clipped kidney were markedly reduced after IMP treated in 2K,1C hypertensive rats. IMP showed antihypertensive and antioxidant effects in the renal injury of renovascular hypertensive rats, suggesting that IMP could be of therapeutic use in preventing renal injury related hypertension. PMID- 23746954 TI - Can Hedysari Radix replace Astragali Radix in Danggui Buxue Tang, a Chinese herbal decoction for woman aliment? AB - Astragali Radix (AR) has been used for over 2000 years in China for the enrichment of "Qi". Hedysari Radix (HR), a herb having similar chemical composition with AR, has been commonly used as a substitute of AR in herbal decoction. In order to evaluate the possible replacement of HR for AR in Chinese herbal decoction, systematic comparison of AR and HR was done by chemical and biological assessments. The water extract of AR contained higher levels of calycosin, calycosin-glucoside, ononin, astragaloside III and astragaloside IV, while higher amount of formononetin was found in the HR extract. The estrogenic, erythropoetic and osteogenic effects were compared between the water extracts of AR and HR, and in all cases AR extract showed higher biological activities. Danggui Buxue Tang (DBT) is a very common herbal decoction for woman aliment, and which contains AR and Angelica Sinensis Radix. Here, we generated two forms of DBT having either AR or HR as the major herbs. Chemically, AR-contained DBT showed higher amounts of various active chemicals, except formononetin that was higher in HR-contained DBT. In parallel, the estrogenic, osteogenic and erythropoetic effects of DBT containing AR showed better activities than that of DBT having HR. Thus, AR and HR showed distinct differences in terms of chemical and biological properties. In order to achieve the best therapeutical effect, as well as to guarantee the safety, AR is recommended here to be used for making DBT. PMID- 23746953 TI - Parthenolide from Parthenium integrifolium reduces tumor burden and alleviate cachexia symptoms in the murine CT-26 model of colorectal carcinoma. AB - Excessive elaboration of proinflammatory cytokines are involved in cachexia related hypercatabolism. Parthenolide, as a potential anti-inflammatory active agent, could effectively inhibit nuclear factor-kappa B, and has the potential for the treatment of cancer cachexia. In this study, the cancer cachexia model was established by subcutaneous transplantation CT26 tumor fragment. Parthenolide or placebo was intraperitoneally given daily from the next day. Parthenolide treatment could effectively preserve the body weight, improve the mass of gastrocnemius and tibialis anterior muscles, and alleviate tumor burden. Sizes of muscle fibers and myosin heavy chain were also increasing. The serum proinflammatory cytokine TNF-alpha level was lower than placebo treatment mice measure by ELISA. To investigate the possible mechanism, MuRF1 and Fbx32 was subjected to Western blot analysis and expression of MURF1 was inhibited in gastrocnemius muscle. Collectively, parthenolide treatment could effectively alleviate tumor burden of cachexia, preserve the body weight and improve skeletal muscle characteristics. PMID- 23746955 TI - Inhibitory effects of salidroside and paeonol on tyrosinase activity and melanin synthesis in mouse B16F10 melanoma cells and ultraviolet B-induced pigmentation in guinea pig skin. AB - Salidroside, the major active component of Rhodiola rosea, a herb with antioxidant, free radical scavenging and tyrosinase inhibitory effects, has been recently reported in protecting the kerationcytes from the UV radiation, suggesting the potential of this component in depigmentation. Paeonol is isolated from Moutan Cortex Radicis with anti-inflammation/microbial activities, was reported to induce the down-regulation of microphthalmia-associated transcription factor and subsequently tyrosinase. To testify the potential of these compounds as melanin formation inhibitors for hyperpigmentation therapy, the influence of salidroside and paeonol on pigmentation was investigated. With arbutin as a positive control, salidroside and paeonol were evaluated for their inhibitory effect on the cell viability, tyrosinase activity and melanin synthesis in B16F10 melanoma cells, as well as their effects in UVB-induced hyperpigmentation in brown guinea pig skins. It was demonstrated that the significant inhibition of salidroside (33.0%) and paeonol (22.2-30.9%) on the tyrosinase activity is slightly lower than that of arbutin (18.4-44.7%). However, salidroside exhibited the dose-dependent inhibition (30.6-42.0%) in melanin synthesis at a low concentration of 100 MUM, paeonol and arbutin expressed inhibition rates of 27.4 37.2% and 25.8-45.6% within 500-1000 MUM. The in vivo topical application of these compounds was demonstrated to obviously decrease the hyperpigmentation on UVB stimulated guinea pig skin. This study provided the original evidence for the salidroside and paeonol as therapeutic agents for pigmentation disorder and skin lightening, with further clinical investigation of these compounds in the field of depigmentation was suggested. PMID- 23746956 TI - Protective effect of homonojirimycin from Commelina communis (dayflower) on influenza virus infection in mice. AB - The effects of homonojirimycin (HNJ), one of alkaloids from Commelina communis L., on protection against influenza virus infection in mice were investigated. HNJ was found to improve the survival rate, prolong the mean survival time and reduce virus yields in lungs on days 4 and 6 post-infection (p.i.), after the agent had been orally administered to the mice from 2 days before infection to 6 days p.i. Administration of HNJ (1 mg/kg) significantly increased interferon (IFN)-gamma and interleukin (IL)-10 levels but decreased tumor necrosis factor (TNF)-alpha and IL-6 levels in serum and lungs of influenza-infected mice on days 2, 4 or 6 p.i. These results showed that HNJ exerted protection against influenza virus infection and produced effective immune responses in vivo. PMID- 23746958 TI - An inhibitor of cathepsin K, icariin suppresses cartilage and bone degradation in mice of collagen-induced arthritis. AB - The collagenase cathepsin K has been shown important in the pathogenesis of rheumatoid arthritis (RA). Icariin is the major pharmacologically active flavonol diglycoside of Herba Epimedii, an herb used in Chinese traditional medicine to treat arthritis. We investigated whether icariin can inhibit the protease activity of cathepsin K and its effects on a murine model of collagen-induced arthritis (CIA). Six-week old female BALB/C mice were immunized with type II collagen and treated with vehicle alone icariin (25mg/kg) for 21 days; a control remained untreated. Serum concentrations of type I collagen C-terminal telopeptide (CTX-I) and cartilage oligomeric matrix protein (COMP) and urinary concentrations of deoxypyridinoline (DPD) were measured, and disease severity was assessed. Compared with immunized, untreated mice, immunized icariin-treated mice had significantly lower urinary DPD (~25%, p<0.01) and serum COMP (~11.9%, p<0.01) concentrations, with serum CTX-1 (RatLaps) concentrations being significantly lower in immunized, icariin treated mice than in immunized, vehicle treated (p<0.01) and non-immunized (p<0.005) mice. Icariin also reduced the clinical signs of arthritis. Icariin inhibited cathpesin K activity in vitro and was effective in a mouse model of CIA similar to human RA, suggesting that this agent may have promise in the treatment of patients with RA. PMID- 23746957 TI - Arbortristoside-A and 7-O-trans-cinnamoyl-6beta-hydroxyloganin isolated from Nyctanthes arbortristis possess anti-ulcerogenic and ulcer-healing properties. AB - Nyctanthes arbortristis Linn (Oleaceae) is widely distributed in sub-Himalayan regions and southwards to Godavari, India commonly known as Harsingar and Night Jasmine. In continuation of our drug discovery program on Indian medicinal plants, we isolated arbortristoside-A (AT) and 7-O-trans-cinnamoyl-6beta hydroxyloganin (6-HL) from the seeds of N. arbortristis. AT and 6-HL exhibited anti ulcer activity in experimentally induced ulcer models including cold restraint stress (CRU), alcohol (AL), pylorus ligation-induced gastric ulcer (PL) models and they also showed ulcer healing effect in chronic acetic acid-induced ulcer model (AC). PMID- 23746959 TI - Neferine isolated from Nelumbo nucifera enhances anti-cancer activities in Hep3B cells: molecular mechanisms of cell cycle arrest, ER stress induced apoptosis and anti-angiogenic response. AB - Hepatocellular carcinoma (HCC) is one of the most aggressive malignant diseases and is highly resistant to conventional chemotherapy. Neferine, a major bisbenzylisoquinoline alkaloid derived from the embryos of Nelumbo nucifera, has been reported a few physiological activities. However, the mechanisms of anticancer effects are not well understood and its detailed activities on Hep3B cells have not been determined. Our results suggest that neferine exhibited cytotoxicity against HCC Hep3B cells, but not against HCC Sk-Hep1 and THLE-3, a normal human liver cell line. In addition, consistent with the induction of G1/S phase cell population in flow cytometry, downregulation of c-Myc, cyclin D1, D3, CDK4, E2F-1, as well as dephosphorlyation of cdc2 by western blot analysis, as evidenced by the appearance of cell cycle arrest, were observed in Hep3B cells treated with neferine. Our results demonstrated neferine induced ER stress and apoptosis, acting through multiple signaling cascades by the activation of Bim, Bid, Bax, Bak, Puma, caspases-3, -6, -7, -8 and PARP, and the protein expression levels of Bip, calnexin, PDI, calpain-2 and caspase-12 were also upregulated dramatically by neferine treatment. Overexpression of GFP-LC3B by neferine resulted in a diffuse cytosolic GFP fluorescence and the strong fluorescent spots, representing autophagosomes. The significant reduction of the migration in Hep3B cells and the capillary tube-like formation of HUVECs by neferine were also determined. These observations reveal that the therapeutic potential of neferine in treating HCC Hep3B cells, containing copies of hepatitis B virus (HBV) genomes. PMID- 23746960 TI - Effect of sleeve gastrectomy on body weight, food intake, glucose tolerance, and metabolic hormone level in two different rat models: Goto-Kakizaki and diet induced obese rat. AB - BACKGROUND: It is still an important question whether sleeve gastrectomy (SG) is appropriate only in the context of obesity-the condition for which it was originally developed-or whether lean people with insulin-deficient diabetes might also benefit. The aim of this study is to evaluate the effects of SG in Goto Kakizaki (GK) and diet-induced obese (DIO) rats that have distinct characteristics in beta-cell function and fat mass. MATERIALS AND METHODS: SG was performed in GK and DIO rats. Body weight, food intake, and fasting blood glucose were monitored after surgery. Des-acyl ghrelin in fasting condition and blood glucose, insulin, and glucagon-like peptide-1 levels during meal test were measured. Homeostatic model assessment and insulinogenic index were examined. RESULTS: In both GK and DIO rats, SG improved glucose tolerance with increased glucagon-like peptide-1 and insulin secretion during meal test, and reduced fasting des-acyl ghrelin levels. Insulin sensitivity was enhanced after SG in DIO rats. The improvement in glucose tolerance after SG was shown earlier in DIO rats than in GK rats and weight regain after SG occurred faster and was more prominent in GK rats than in DIO rats. CONCLUSIONS: In both DIO and GK rats, SG could improve glucose tolerance with increased insulin secretion and/or action. The improvement in glucose tolerance was shown earlier in DIO rats than in GK rats. PMID- 23746961 TI - Anoxia inhibits biofilm development and modulates antibiotic activity. AB - BACKGROUND: Many infections involve bacterial biofilms that are notoriously antibiotic resistant. Unfortunately, the mechanism for this resistance is unclear. We tested the effect of oxygen concentration on development of Staphylococcus aureus biofilms, and on the ability of gentamicin and vancomycin to inhibit biofilm development. MATERIALS AND METHODS: To mimic catheter associated biofilms, silastic coupons were inoculated with 10(7)S aureus and incubated either aerobically (~21% O2) or anaerobically (10% CO2, 5% H2, 85% N2) for 16 h at 37 degrees C with varying concentrations of gentamicin and vancomycin. Viable colony-forming units were quantified from sonicated biofilms, and the crystal violet assay quantified biofilm biomass. Metabolomic profiles probed biochemical differences between aerobic and anaerobic biofilms. RESULTS: Control biofilms (no antibiotic) cultivated aerobically contained 8.1-8.6 log10S aureus. Anaerobiasis inhibited biofilm development, quantified by viable bacterial numbers and biomass (P < 0.05). Bactericidal concentrations of gentamicin inhibited biofilm development in normoxia but not anoxia, likely because bacterial uptake of gentamicin is oxygen dependent. The inhibitory effect of vancomycin was more uniform aerobically and anaerobically, although at high bactericidal concentrations, vancomycin effectiveness was decreased under anoxia. There were notable differences in the metabolomic profiles of biofilms cultivated under normoxia versus anoxia. CONCLUSIONS: Compared with aerobic incubation, anaerobiasis resulted in decreased biofilm development, and metabolomics is a promising tool to identify key compounds involved in biofilm formation. The effectiveness of a specific antibiotic depended on its mode of action, as well as on the oxygen concentration in the environment. PMID- 23746962 TI - Functional liver reserve parameters predictive for posthepatectomy complications. AB - BACKGROUND: Posthepatectomy complications have markedly decreased with advances in techniques and management; however, surgical risk to patients with injured livers is still not negligible. We evaluated several preoperative parameters of functional liver reserve tests in patients with various liver diseases as predictors of posthepatectomy complications. A comprehensive evaluation of preoperative liver functions is necessary for the prediction of the risk of posthepatectomy complications. METHODS: Over a 10-y period, we examined 442 patients who underwent hepatectomy for liver and biliary diseases. The patients' background liver diseases included chronic viral liver diseases in 211 patients, obstructive jaundice in 29 patients, and normal liver in 202 patients. Hepatectomy-related postoperative complications (i.e., long-term ascites, intra abdominal infection, and hepatic failure) occurred in 115 (26%) patients. A multivariate logistic analysis was performed to detect the predictive parameters, and a multivariate linear regression analysis was performed to derive a predictive formula for complications. RESULTS: A univariate analysis identified 15 significant parameters associated with hepatectomy-related complications, and eight parameters (i.e., presence of chronic hepatic injury, clearance index by technetium-99 m galactosyl human serum albumin liver scintigraphy of >= 0.60, total bilirubin level of >1 mg/dL, serum hyaluronic acid level of >= 75 ng/mL, major hepatectomy, blood loss of >= 950 mL, operating time of >= 500 min, and combined resection of another organ or major vessel) were independent predictive factors identified in the multivariate analysis. Clearance index by technetium-99 m galactosyl human serum albumin liver, bilirubin level, hyaluronic acid level, and major hepatectomy were the parameters included in the predictive formula. CONCLUSIONS: In the present study, we present a comprehensive formula based on the predictive parameters for hepatic complications for prospective assessment to avoid posthepatectomy morbidity. PMID- 23746963 TI - Incorporating availability/bioavailability in risk assessment and decision making of polluted sites, using Germany as an example. AB - Nearly all publications dealing with availability or bioavailability of soil pollutants start with the following statement: the determination of total pollutant content will lead to an over-estimation of risk. However, an assessment of contaminated sites should be based on the determination of mobile fractions of pollutants, and the fractions with potential for mobilisation that threaten groundwater and surface water, and the actual and potential fractions available for uptake by plants, soil microflora and soil organisms. After reviewing the literature for method proposals concerning the determination of available/bioavailable fractions of contaminants with respect to leaching, plants, microorganisms (biodegradation) and soil organisms, we propose a testing and assessment scheme for contaminated sites. The proposal includes (i) already accepted and used methods, (ii) methods which are under standardisation, and (iii) methods for which development has just started in order to promote urgently needed research. PMID- 23746964 TI - Pleiotropy: what do you mean? Reply to Zhang and Wagner. PMID- 23746965 TI - Combination of YM155, a survivin suppressant with a STAT3 inhibitor: a new strategy to treat diffuse large B-cell lymphoma. AB - Survivin and STAT3 pathway have been reported to be important for the growth of diffuse large B-cell lymphoma (DLBCL) cells. Here we investigated the antitumor activity of sepantronium bromide (YM155), a survivin suppressant, in combination with STAT3 inhibitors in DLBCL cell lines in vitro. YM155 synergistically enhanced STAT3 inhibitors (AG490 and STA-21)-induced apoptosis in DLBCL cell lines. Moreover, rituximab, which shows inhibitory activity against STAT3, also sensitized DLBCL cell lines to YM155 regardless of sensitivity to rituximab. These results suggest that combining the inhibition of survivin with STAT3 pathway is an attractive and potentially effective way for the treatment of DLBCL. PMID- 23746966 TI - A phase I dose-escalation study of MSC1992371A, an oral inhibitor of aurora and other kinases, in advanced hematologic malignancies. AB - A phase I dose-escalation study of MSC1992371A, an oral aurora kinase inhibitor, was carried out in patients with hematologic malignancies. Patients received escalating doses either on days 1-3 and 8-10 (n=36) or on days 1-6 (n=39) of a 21 day cycle. The maximum tolerated doses were 37 and 28 mg/m(2)/day, respectively. Dose-limiting toxicities included severe neutropenia with infection and sepsis, mucositis/stomatitis, and diarrhea. Complete responses occurred in 3 patients. Four disease-specific expansion cohorts then received the dose and schedule dictated by the escalation phase but the study was prematurely discontinued due to hematologic and gastrointestinal toxicity at clinically effective doses. PMID- 23746967 TI - The stem cell experience. PMID- 23746968 TI - Candidate ALS therapeutics motor toward "in vitro clinical trials". AB - Conducting drug discovery efforts in patient- and disease-specific cells can maximize their likelihood of success. In this issue of Cell Stem Cell, Yang et al. (2013) demonstrate the power of lineage-specific cell-based drug screens by identifying a compound that promotes survival of stem-cell-derived ALS mutant motor neurons. PMID- 23746969 TI - The other face of ROS: a driver of stem cell expansion in colorectal cancer. AB - APC mutations causing Wnt activation are commonly found in colorectal cancer, but downstream pathways that facilitate tumorigenesis are unclear. In this issue of Cell Stem Cell, Myant et al. (2013) show that Rac1 activation is required for Wnt driven Lgr5+ intestinal stem cell transformation through ROS production and NF-kB activation. PMID- 23746970 TI - Pluripotent stem cells from cloned human embryos: success at long last. AB - Recently in Cell, Mitalipov and colleagues report an advance that has eluded scientists for over a decade-the successful derivation of embryonic stem cell lines using somatic cell nuclear transfer, or SCNT (Tachibana et al., 2013). PMID- 23746971 TI - Unraveling tumor suppressor networks with in vivo RNAi. AB - BMI1 is a known oncogenic transcriptional repressor in glioblastoma stem-like cells, but its downstream mediators are poorly understood. Recently, in Cancer Cell, Gargiulo et al. (2013) designed a rational in vivo RNAi screen based on BMI1 ChIP-seq from neural progenitors and identified functional tumor suppressor targets, including Atf3 and Cbx7. PMID- 23746972 TI - A sexy spin on nonrandom chromosome segregation. AB - Nonrandom chromosome segregation is an intriguing phenomenon linked to certain asymmetric stem cell divisions. In a recent report in Nature, Yadlapalli and Yamashita (2013) observe nonrandom segregation of X and Y chromosomes in Drosophila germline stem cells and shed light on the complex mechanisms of this fascinating process. PMID- 23746973 TI - Cell therapy companies make strong progress from October 2012 to March 2013 amid mixed stock market sentiment. AB - During Q4 2012 and Q1 2013, the cell therapy industry made strong progress in translation and commercialization. Continued development of the companies included in a dedicated stock market index suggests emergence of this industry as a distinct healthcare sector. PMID- 23746974 TI - Dear student: stem cell scientists' advice to the next generation. AB - For the field of pluripotent stem cell biology to realize its promising future, current researchers will need to pass the torch to new generations. We asked a group of successful scientists in this area, "What advice would you give a young person considering a career in stem cell research?" PMID- 23746975 TI - Modeling human disease with pluripotent stem cells: from genome association to function. AB - Mechanistic insights into human disease may enable the development of treatments that are effective in broad patient populations. The confluence of gene-editing technologies, induced pluripotent stem cells, and genome-wide association as well as DNA sequencing studies is enabling new approaches for illuminating the molecular basis of human disease. We discuss the opportunities and challenges of combining these technologies and provide a workflow for interrogating the contribution of disease-associated candidate genetic variants to disease-relevant phenotypes. Finally, we discuss the potential utility of human pluripotent stem cells for placing disease-associated genetic variants into molecular pathways. PMID- 23746976 TI - Integrating human pluripotent stem cells into drug development. AB - Integration of physiologically relevant in vitro assays at the earliest stages of drug discovery may improve the likelihood of successfully translating preclinical discoveries to the clinic. Assays based on in vitro-differentiated, human pluripotent stem cell (IVD hPSC)-derived cells, which may better model human physiology, are starting to impact the drug discovery process, but their implementation has been slower than originally anticipated. In this Perspective, we discuss imperatives for incorporating IVD hPSCs into drug discovery and the associated challenges. PMID- 23746977 TI - Therapeutic translation of iPSCs for treating neurological disease. AB - Somatic cellular reprogramming is a fast-paced and evolving field that is changing the way scientists approach neurological diseases. For the first time in the history of neuroscience, it is feasible to study the behavior of live neurons from patients with neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, and neuropsychiatric diseases, such as autism and schizophrenia. In this Perspective, we will discuss reprogramming technology in the context of its potential use for modeling and treating neurological and psychiatric diseases and will highlight areas of caution and opportunities for improvement. PMID- 23746978 TI - Cardiac stem cell therapy and the promise of heart regeneration. AB - Stem cell therapy for cardiac disease is an exciting but highly controversial research area. Strategies such as cell transplantation and reprogramming have demonstrated both intriguing and sobering results. Yet as clinical trials proceed, our incomplete understanding of stem cell behavior is made evident by numerous unresolved matters, such as the mechanisms of cardiomyocyte turnover or the optimal therapeutic strategies to achieve clinical efficacy. In this Perspective, we consider how cardiac stem cell biology has led us into clinical trials, and we suggest that achieving true cardiac regeneration in patients may ultimately require resolution of critical controversies in experimental cardiac regeneration. PMID- 23746979 TI - Matrix-embedded osteocytes regulate mobilization of hematopoietic stem/progenitor cells. AB - The bone marrow (BM) niche comprises multiple cell types that regulate hematopoietic stem/progenitor cell (HSPC) migration out of the niche and into the circulation. Here, we demonstrate that osteocytes, the major cellular component of mature bone, are regulators of HSPC egress. Granulocyte colony-stimulating factor (G-CSF), used clinically to mobilize HSPCs, induces changes in the morphology and gene expression of the osteocytic network that precedes changes in osteoblasts. This rapid response is likely under control of the sympathetic nervous system, since osteocytes express the beta2-adrenergic receptor and surgical sympathectomy prevents it. Mice with targeted ablation of osteocytes or a disrupted osteocyte network have comparable numbers of HSPCs in the BM but fail to mobilize HSPCs in response to G-CSF. Taken together, these results indicate that the BM/bone niche interface is critically controlled from inside of the bone matrix and establish an important physiological role for skeletal tissues in hematopoietic function. PMID- 23746980 TI - KDR identifies a conserved human and murine hepatic progenitor and instructs early liver development. AB - Understanding the fetal hepatic niche is essential for optimizing the generation of functional hepatocyte-like cells (hepatic cells) from human embryonic stem cells (hESCs). Here, we show that KDR (VEGFR2/FLK-1), previously assumed to be mostly restricted to mesodermal lineages, marks a hESC-derived hepatic progenitor. hESC-derived endoderm cells do not express KDR but, when cultured in media supporting hepatic differentiation, generate KDR+ hepatic progenitors and KDR- hepatic cells. KDR+ progenitors require active KDR signaling both to instruct their own differentiation into hepatic cells and to non-cell autonomously support the functional maturation of cocultured KDR- hepatic cells. Analysis of human fetal livers suggests that similar progenitors are present in human livers. Lineage tracing in mice provides in vivo evidence of a KDR+ hepatic progenitor for fetal hepatoblasts, adult hepatocytes, and adult cholangiocytes. Altogether, our findings reveal that KDR is a conserved marker for endoderm derived hepatic progenitors and a functional receptor instructing early liver development. PMID- 23746981 TI - ROS are required for mouse spermatogonial stem cell self-renewal. AB - Reactive oxygen species (ROS) generation is implicated in stem cell self-renewal in several tissues but is thought to be detrimental for spermatogenesis as well as spermatogonial stem cells (SSCs). Using cultured SSCs, we show that ROS are generated via the AKT and MEK signaling pathways under conditions where the growth factors glial cell line-derived neurotrophic factor and fibroblast growth factor 2 drive SSC self-renewal and, instead, stimulate self-renewal at physiological levels. SSCs depleted of ROS stopped proliferating, but they showed enhanced self-renewal when ROS levels were increased by the addition of hydrogen peroxide, which induced the phosphorylation of stress kinases p38 mitogen activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK). Moreover, ROS depletion in vivo decreased SSC number in the testis, and NADPH oxidase 1 (Nox1) deficient SSCs exhibited reduced self-renewal division upon serial transplantation. These results suggest that ROS generated by Nox1 play critical roles in SSC self-renewal via the activation of the p38 MAPK and JNK pathways. PMID- 23746982 TI - Sustained mobilization of endogenous neural progenitors delays disease progression in a transgenic model of Huntington's disease. AB - Huntington's disease (HD) is a neurodegenerative disease characterized in part by the loss of striatopallidal medium spiny projection neurons (MSNs). Expression of BDNF and noggin via intracerebroventricular (ICV) delivery in an adenoviral vector triggers the addition of new neurons to the neostriatum. In this study, we found that a single ICV injection of the adeno-associated viruses AAV4-BDNF and AAV4-noggin triggered the sustained recruitment of new MSNs in both wild-type and R6/2 mice, a model of HD. Mice treated with AAV4-BDNF/noggin or with BDNF and noggin proteins actively recruited subependymal progenitor cells to form new MSNs that matured and achieved circuit integration. Importantly, the AAV4-BDNF/noggin treated R6/2 mice showed delayed deterioration of motor function and substantially increased survival. In addition, squirrel monkeys given ICV injections of adenoviral BDNF/noggin showed similar addition of striatal neurons. Induced neuronal addition may therefore represent a promising avenue for disease amelioration in HD. PMID- 23746983 TI - Production, quality and quality assurance of Refuse Derived Fuels (RDFs). AB - This contribution describes characterization, classification, production, application and quality assurance of Refuse Derived Fuels (RDFs) that are increasingly used in a wide range of co-incineration plants. It is shown in this paper, that the fuel-parameter, i.e. net calorific value [MJ/kg(OS)], particle size d(90) or d(95) [mm], impurities [w%], chlorine content [w%], sulfur content [w%], fluorine content [w%], ash content [w%], moisture [w%] and heavy metals content [mg/kg(DM)], can be preferentially used for the classification of different types of RDF applied for co-incineration and substitution of fossil fuel in different industial sectors. Describing the external production of RDF by processing and confectioning of wastes as well as internal processing of waste at the incineration plant, a case study is reported on the application of RDF made out of different household waste fractions in a 120,000t/yr Waste to Energy (WtE) circulating fluidized bed (CFB) incinerator. For that purpose, delivered wastes, as well as incinerator feedstock material (i.e. after internal waste processing) are extensively investigated. Starting with elaboration of sampling plan in accordance with the relevant guidelines and standards, waste from different suppliers was sampled. Moreover, manual sorting analyses and chemical analyses were carried out. Finally, results of investigations are presented and discussed in the paper. PMID- 23746984 TI - Distribution of copper, silver and gold during thermal treatment with brominated flame retardants. AB - The growing consumption of electric and electronic equipment results in creating an increasing amount of electronic waste. The most economically and environmentally advantageous methods for the treatment and recycling of waste electric and electronic equipment (WEEE) are the thermal techniques such as direct combustion, co-combustion with plastic wastes, pyrolysis and gasification. Nowadays, this kind of waste is mainly thermally treated in incinerators (e.g. rotary kilns) to decompose the plastics present, and to concentrate metals in bottom ash. The concentrated metals (e.g. copper, precious metals) can be supplied as a secondary raw material to metal smelters, while the pyrolysis of plastics allows the recovery of fuel gases, volatilising agents and, eventually, energy. Indeed, WEEE, such as a printed circuit boards (PCBs) usually contains brominated flame retardants (BFRs). From these materials, hydrobromic acid (HBr) is formed as a product of their thermal decomposition. In the present work, the bromination was studied of copper, silver and gold by HBr, originating from BFRs, such as Tetrabromobisphenol A (TBBPA) and Tetrabromobisphenol A Tetrabromobisophenol A diglycidyl ether (TTDE) polymer; possible volatilization of the bromides formed was monitored using a thermo-gravimetric analyzer (TGA) and a laboratory-scale furnace for treating samples of metals and BFRs under an inert atmosphere and at a wide range of temperatures. The results obtained indicate that up to about 50% of copper and silver can evolve from sample residues in the form of volatile CuBr and AgBr above 600 and 1000 degrees C, respectively. The reactions occur in the molten resin phase simultaneously with the decomposition of the brominated resin. Gold is resistant to HBr and remains unchanged in the residue. PMID- 23746985 TI - The changing character of household waste in the Czech Republic between 1999 and 2009 as a function of home heating methods. AB - The authors of this paper report on the changing character of household waste, in the Czech Republic between 1999 and 2009 in households differentiated by their heating methods. The data presented are the result of two projects, financed by the Czech Ministry of Environment, which were undertaken during this time period with the aim of focusing on the waste characterisation and complete analysis of the physicochemical properties of the household waste. In the Czech Republic, the composition of household waste varies significantly between different types of households based on the methods of home heating employed. For the purposes of these studies, the types of homes were divided into three categories - urban, mixed and rural. Some of the biggest differences were found in the quantities of certain subsample categories, especially fine residue (matter smaller than 20 mm), between urban households with central heating and rural households that primarily employ solid fuel such coal or wood. The use of these solid fuels increases the fraction of the finer categories because of the higher presence of ash. Heating values of the residual household waste from the three categories varied very significantly, ranging from 6.8 MJ/kg to 14.2 MJ/kg in 1999 and from 6.8 MJ/kg to 10.5 MJ/kg in 2009 depending on the type of household and season. The same factors affect moisture of residual household waste which varied from 23.2% to 33.3%. The chemical parameters also varied significantly, especially in the quantities of Tl, As, Cr, Zn, Fe and Mn, which were higher in rural households. Because knowledge about the properties of household waste, as well as its physicochemical characteristics, is very important not only for future waste management, but also for the prediction of the behaviour and influence of the waste on the environment as the country continues to streamline its legislation to the European Union's solid waste mandates, the results of these studies were employed by the Czech Ministry of Environment to optimise the national waste management strategy. PMID- 23746986 TI - Experimental evidence of colloids and nanoparticles presence from 25 waste leachates. AB - The potential colloids release from a large panel of 25 solid industrial and municipal waste leachates, contaminated soil, contaminated sediments and landfill leachates was studied. Standardized leaching, cascade filtrations and measurement of element concentrations in the microfiltrate (MF) and ultrafiltrate (UF) fraction were used to easily detect colloids potentially released by waste. Precautions against CO(2) capture by alkaline leachates, or bacterial re-growth in leachates from wastes containing organic matter should be taken. Most of the colloidal particles were visible by transmission electron microscopy with energy dispersion spectrometry (TEM-EDS) if their elemental MF concentration is greater than 200 MUgl(-1). If the samples are dried during the preparation for microscopy, neoformation of particles can occur from the soluble part of the element. Size distribution analysis measured by photon correlation spectroscopy (PCS) were frequently unvalid, particularly due to polydispersity and/or too low concentrations in the leachates. A low sensitivity device is required, and further improvement is desirable in that field. For some waste leachates, particles had a zeta potential strong enough to remain in suspension. Mn, As, Co, Pb, Sn, Zn had always a colloidal form (MF concentration/UF concentration>1.5) and total organic carbon (TOC), Fe, P, Ba, Cr, Cu, Ni are partly colloidal for more than half of the samples). Nearly all the micro-pollutants (As, Ba, Co, Cr, Cu, Mo, Ni, Pb, Sb, Sn, V and Zn) were found at least once in colloidal form greater than 100 MUgl(-1). In particular, the colloidal forms of Zn were always by far more concentrated than its dissolved form. The TEM-EDS method showed various particles, including manufactured nanoparticles (organic polymer, TiO(2), particles with Sr, La, Ce, Nd). All the waste had at least one element detected as colloidal. The solid waste leachates contained significant amount of colloids different in elemental composition from natural ones. The majority of the elements were in colloidal form for wastes of packaging (3), a steel slag, a sludge from hydrometallurgy, composts (2), a dredged sediment (#18), an As contaminated soil and two active landfill leachates. These results showed that cascade filtration and ICP elemental analysis seems valid methods in this field, and that electronic microscopy with elemental detection allows to identify particles. Particles can be formed from dissolved elements during TEM sample preparation and cross-checking with MF and UF composition by ICP is useful. The colloidal fraction of leachate of waste seems to be a significant source term, and should be taken into account in studies of emission and transfer of contaminants in the environment. Standardized cross-filtration method could be amended for the presence of colloids in waste leachates. PMID- 23746987 TI - Personalisation of colorectal cancer screening. PMID- 23746989 TI - Pharmaceutical development, composition and quantitative analysis of phthalocyanine as the photosensitizer for cancer photodynamic therapy. AB - Phthalocyanine (Pc) and its related derivatives are a class of functional materials that are easily activated by the light at a special wavelength. As such photosensitizer, Pc has been applied to photodynamic therapy (PDT), in addition to its broad applications in many fields, for both malignant and benign diseases. One of our long-term research focuses is to develop Pc for cancer therapy. Herein we briefly review mechanisms of action of Pc used for photodynamic therapy, its pharmaceutical development and molecular modification to enhance its drugability and improve its intracellular localization. We also describe the current status of the Pc derivatives under clinical investigation, and analyze the methods used for quantitative analysis of those Pc derivatives. PMID- 23746988 TI - Assessment of volumetric growth rates of small colorectal polyps with CT colonography: a longitudinal study of natural history. AB - BACKGROUND: The clinical relevance and in-vivo growth rates of small (6-9 mm) colorectal polyps are not well established. We aimed to assess the behaviour of such polyps with CT colonography assessments. METHODS: In this longitudinal study, we enrolled asymptomatic adults undergoing routine colorectal cancer screening with CT colonography at two medical centres in the USA. Experienced investigators (PJP, DHK, JLH) measured volumes and maximum linear sizes of polyps in vivo with CT colonography scans at baseline and surveillance follow-up. We defined progression, stability, and regression on the basis of a 20% volumetric change per year from baseline (20% or more growth classed as progression, 20% growth to -20% reduction classed as stable, and -20% or more reduction classed as regression). We compared findings with histological subgroups confirmed after colonoscopy when indicated. This study is registered with ClinicalTrials.gov, number NCT00204867. FINDINGS: Between April, 2004, and June, 2012, we screened 22,006 asymptomatic adults and included 243 adults (mean age 57.4 years [SD 7.1] and median age 56 years [IQR 52-61]; 106 [37%] women), with 306 small colorectal polyps. The mean surveillance interval was 2.3 years (SD 1.4; range 1-7 years; median 2.0 years [IQR 1.1-2.3]). 68 (22%) of 306 polyps progressed, 153 (50%) were stable, and 85 (28%) regressed, including an apparent resolution in 32 (10%) polyps. We established immediate histology in 131 lesions on colonoscopy after final CT colonography. 21 (91%) of 23 proven advanced adenomas progressed, compared with 31 (37%) of 84 proven non-advanced adenomas, and 15 (8%) of 198 other lesions (p<0.0001). The odds ratio for a growing polyp at CT colonography surveillance to become an advanced adenoma was 15.6 (95% CI 7.6-31.7) compared with 6-9 mm polyps detected and removed at initial CT colonography screening (without surveillance). Mean polyp volume change was a 77% increase per year for 23 proven advanced adenomas and a 16% increase per year for 84 proven non advanced adenomas, but a 13% decrease per year for all proven non-neoplastic or unresected polyps (p<0.0001). An absolute polyp volume of more than 180 mm(3) at surveillance CT colonography identified proven advanced neoplasia (including one delayed cancer) with a sensitivity of 92% (22 of 24 polyps), specificity of 94% (266 of 282 polyps), positive-predictive value of 58% (22 of 38 polyps), and negative-predictive value of 99% (266 of 268 polyps). Only 16 (6%) of the 6-9 mm polyps exceeded 10 mm at follow-up. INTERPRETATION: Volumetric growth assessment of small colorectal polyps could be a useful biomarker for determination of clinical importance. Advanced adenomas show more rapid growth than non-advanced adenomas, whereas most other small polyps remain stable or regress. Our findings might allow for less invasive surveillance strategies, reserving polypectomy for lesions that show substantial growth. Further research is needed to provide more information regarding the ultimate fate of unresected small polyps without significant growth. FUNDING: US National Institutes of Health, National Cancer Institute. PMID- 23746991 TI - On-line solid phase extraction-liquid chromatography, with emphasis on modern bioanalysis and miniaturized systems. AB - On-line solid phase extraction (SPE)-liquid chromatography (LC) allows for automated, sensitive, precise and selective bioanalysis. It is a common feature in miniaturized- or nano LC systems, which are well suited for applications requiring high sensitivity and/or treatment of limited samples (laser micro dissection samples, rare cancer stem cells, etc.). Traditionally, particles with reversed phase (RP) functional groups are used for the columns in SPE-LC systems. There is however an expanding diversity in SPE-LC combinations applied to meet today's bioanalytical challenges. Current online SPE-LC combinations employ, e.g. porous graphitic carbon (PGC) and hydrophilic interaction liquid chromatography (HILIC) materials for metabolomics and glycomics, restricted access media (RAM) columns coupled with nano LC for peptidomics, immunoaffinity trap columns for targeted proteomics and metal oxide affinity phases for phosphopeptide analysis. However, issues can arise when combining different phases in on-line SPE-LC, e.g. due to solvent incompatibilities between enrichment/separation principles and sample solvent requirements. Consequences can be low recovery and poor resolution, or need for additional instrumentation. On-line SPE-LC with very narrow columns (10-20 MUm inner diameters) can be appropriate to obtain maximum sensitivity and information. In such highly miniaturized systems, non-particulate columns are arguably more suited (e.g. monolithic or porous layer open tubular (PLOT) columns) as e.g. hardware contributions resulting in extra column volumes are reduced. Basic SPE-LC systems can be configured/modified to perform quite complex analytical operations, and certain columns, configurations and hardware can improve robustness. PMID- 23746992 TI - [Acetabular hernia causing intestinal obstruction]. PMID- 23746990 TI - Metabolic differentiations of Pueraria lobata and Pueraria thomsonii using 1H NMR spectroscopy and multivariate statistical analysis. AB - Puerariae Radix was a widely used herbal medicine. Pueraria lobata (PL) and Pueraria thomsonii (PT) were the two authorized sources of Puerariae Radix (gegen) in China. In this study, metabolic differentiations between these two species were investigated using NMR spectroscopy followed by principal components analysis (PCA) and partial least squares-discriminant analysis (PLS-DA). The content of puerarin in PL and PT was also determined using quantitative (1)H NMR spectroscopy. Thirteen isoflavones were tentatively identified based on 1D and 2D NMR spectroscopic data in two species. The (1)H NMR spectra of PL and PT were obviously different. PL and PT could also be markedly discriminated from (1)H NMR spectroscopic data by PCA and PLS-DA. For the crude drug resources, isoflavones, in which puerarin is the most important one, were regarded as the reasonable markers for the discrimination of the two species. The contents of puerarin and total isoflavones in PL were quantitated much higher than those in PT. Above all, (1)H NMR spectroscopy, which can provide comprehensive profiles of the metabolites and achieve convenient determinations of puerarin and total isoflavones in a single run, is an efficient means for evaluating the medicinal samples and achieving a better quality control of Puerariae Radix. PMID- 23746993 TI - [Use of percutaneous needles in the feasability of single-port laparoscopic cholecystectomy]. AB - INTRODUCTION: The usefulness of percutaneous needles (PN) to replace traditional assistance ports in mini-invasive techniques with a single port is analyzed and their feasibility for conducting a single port laparoscopic cholecystectomy (SPLC) is demonstrated. MATERIAL AND METHODS: A retrospective, linear and descriptive study covering 2,431 patients with a diagnosis of acute and non-acute gallbladder disease has been conducted. The patients underwent a single port laparoscopic cholecystectomy using some type of PNs, replacing the assisting ports used in traditional laparoscopic cholecystechtomy (TLC). Based on the progressive use of PNs-reins (R), hooked needles (HN) and passing suture needles (PSN)-to carry out the SPLC technique, 3 groups have been established: A, B and C. The results were compared using a Student T test, odds ratio and CI and were analyzed by means of the SPSS software v. 13.0. RESULTS: The use of PNs showed an increased feasibility for the laparoscopic procedure, as they were included in the surgical technique. The R were useful when carrying out the SPLC in 78% of the cases and when the HK were added, the results increased to 88%. When using the 3 types (R, HN and PSN), the results increased by 96%. Statistical significance was obtained with these values: chi 2=67.13 and P<.001; odds ratio and 95% CI became significant when comparing the B/C, A/C, and A-B/C groups. CONCLUSIONS: The PNs, replacing the assisting ports in laparoscopy, make it possible to attain a feasibility of the process in 96% of the cases. This percentage was similar to what is achieved with the TLC, which places the one port laparoscopy surgery technique as an advantageous and economic alternative. This application of the PNs could be made extensive to other single-port techniques, with a multi-valve platform and natural orifice surgery. PMID- 23746994 TI - Two poplar cellulose synthase-like D genes, PdCSLD5 and PdCSLD6, are functionally conserved with Arabidopsis CSLD3. AB - Root hairs are tip-growing long tubular outgrowths of specialized epidermal cells, and are important for nutrient and water uptake and interaction with the soil microflora. Here we characterized two poplar cellulose synthase-like D (CSLD) genes, PdCSLD5 and PdCSLD6, the most probable orthologs to the Arabidopsis AtCSLD3/KOJAK gene. Both PdCSLD5 and PdCSLD6 are strongly expressed in roots, including in the root hairs. Subcellular localization experiments showed that these two proteins are located not only in the polarized plasma membrane of root hair tips, but also in Golgi apparatus of the root hair and non-hair-forming cells. Overexpression of these two poplar genes in the atcsld3 mutant was able to rescue most of the defects caused by disruption of AtCSLD3, including root hair morphological changes, altered cell wall monosaccharide composition, increased non-crystalline beta-1,4-glucan and decreased crystalline cellulose contents. Taken together, our results provide evidence indicating that PdCSLD5 and PdCSLD6 are functionally conserved with AtCSLD3 and support a role for PdCSLD5 and PdCSL6 specifically in crystalline cellulose production in poplar root hair tips. The results presented here also suggest that at least part of the mechanism of root hair formation is conserved between herbaceous and woody plants. PMID- 23746995 TI - Spatial distribution and expression of intracellular and extracellular acid phosphatases of cluster roots at different developmental stages in white lupin. AB - Acid phosphatases (APases) play a key role in phosphorus (P) acquisition and recycling in plants. White lupin (Lupinus albus L.) forms cluster roots (CRs) and produces large amounts of APases under P deficiency. However, the relationships between the activity of intracellular and extracellular APases (EC 3.1.3.2) and CR development are not fully understood. Here, comparative studies were conducted to examine the spatial variation pattern of APase activity during CR development using the enzyme-labelled fluorescence-97 (ELF-97) and the p-nitrophenyl phosphate methods. The activity of intracellular and extracellular APases was significantly enhanced under P deficiency in the non-CRs and CRs at different developmental stages. These two APases exhibited different spatial distribution patterns during CR development, and these distribution patterns were highly modified by P deficiency. The activity of extracellular APase increased steadily with CR development from meristematic, juvenile, mature to senescent stages under P deficiency. In comparison, P deficiency-induced increase in the activity of intracellular APase remained relatively constant during CR development. Increased activity of intracellular and extracellular APases was associated with enhanced expression of LaSAP1 encoding intracellular APase and LaSAP2 encoding extracellular APase. The expression levels of these two genes were significantly higher at transcriptional level in both mature and senescent CRs. Taken together, these findings demonstrate that both activity and gene expression of intracellular or extracellular APases exhibit a differential response pattern during CR development, depending on root types, CR developmental stages and P supply. Simultaneous in situ determination of intracellular and extracellular APase activity has proved to be an effective approach for studying spatial variation of APases during CR development. PMID- 23746997 TI - The genie. PMID- 23746996 TI - Complications after total thyroidectomy. AB - The two most common early complications of thyroid surgery are hypocalcemia (20 30%) and recurrent laryngeal nerve injury (5-11%). Bilateral recurrent nerve paralysis resulting in adduction of the vocal cords is a rare life-threatening complication (occurring in less than 0.1% of cases that requires emergency management. Prevention of complications depends on careful operative technique and is enhanced for some teams by the use of specific techniques such as intraoperative neuromonitoring. Postsurgical hypocalcemia is managed by the administration of calcium plus vitamin D for at least 10 days. Recurrent laryngeal nerve paralysis recovers in most cases, and no invasive therapy should be performed for at least six months, except for emergency presentations; laryngeal surgery techniques may offer significant improvement if phonation or respiratory sequelae persist beyond six months, but the results are inconsistent. There should be a systematic strategy for detection of complications after thyroidectomy involving a multidisciplinary approach. PMID- 23746998 TI - Nutritional support of the oncology patient. AB - This review focuses on the nutritional support of the non-surgical cancer patient. The following topics are reviewed: cancer cachexia (definition and staging, prevalence and impact on clinical outcome); nutritional screening to identify potential candidates for nutritional support; nutritional requirements in terms of macro-and micro-nutrients of the advanced cancer patient. Finally, the indications and results of nutritional support are presented with a special focus on the following issues: routes of delivering nutritional support, the use of standard or n-3 fatty acids-enriched oral nutritional supplements during radiation therapy and/or chemotherapy, tube feeding during RT (with/without chemotherapy), parenteral nutrition during chemotherapy, nutritional support during hematopoietic stem cell transplantation, (home) enteral or total and supplemental parenteral nutrition in the incurable patient. Lastly, the bioethical aspects of feeding patients with incurable disease are briefly reviewed. PMID- 23746999 TI - Super-resolution microscopy of the immunological synapse. AB - Deciphering the spatial organisation of signalling proteins is the key to understanding the mechanisms underlying immune cell activation. Every advance in imaging technology has led to major breakthroughs in unravelling how receptor and signalling proteins are distributed within the plasma membrane and how membrane signalling is integrated with endosomes and vesicular trafficking. Recently, super-resolution fluorescence microscopy has been applied to immunological synapses, gaining new insights into the nanoscale organisation of signalling processes. Here, we review the advantages and potential of super-resolution microscopy for elucidating the regulation of many aspects of immune signalling. PMID- 23747000 TI - Transcriptional regulation of effector and memory CD8+ T cell fates. AB - Immunity to intracellular pathogens and cancer relies on the generation of robust CD8(+) T cell effector responses as well as the establishment of immunological memory. During a primary immune response CD8(+) T cells experience diverse extracellular environmental cues and cell-cell interactions that trigger downstream transcriptional programs ultimately guiding a CD8(+) T cell to undertake either an effector or a memory cell fate. Here, we discuss our current understanding of the signaling pathways and transcriptional networks that regulate effector and memory commitment in CD8(+) T lymphocytes. PMID- 23747001 TI - Evaluation of the use of pooled fecal samples for the diagnosis of protostrongylid infections in sheep. AB - The Baermann-Wetzel method is the recommended test for the diagnosis of lungworm infections. The objective of this study was to evaluate the use of pooled fecal samples for the diagnosis of protostrongylid infections in sheep flocks and to investigate the sensitivity of the pooled Baermann-Wetzel technique in relation to individual analysis, which is time consuming and expensive. Fecal samples were taken from 10 sheep flocks positive for protostrongylids located in northwestern Spain. Ten pools composed of 6 individual fecal samples, chosen at random from the entire flock sampling, were performed for each flock at the same time as individual analyses. Protostrongylid larvae were detected in 56 pools, with a 56% flock sensitivity. Flock sensitivity was positively associated with the within flock prevalence (P<0.001), but not with the mean larvae output. A high sensitivity (78.3%) has been observed in flocks with medium or high prevalence, so pooled fecal samples can be used in those flocks that require an effective treatment regimen against these nematodes. PMID- 23747002 TI - Prevalence of patient-reported dysphagia in multiple sclerosis patients: an Italian multicenter study (using the DYMUS questionnaire). AB - OBJECTIVE: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with a chronic course. Dysphagia represents one of the current challenges in clinical practice for the management of MS patients. Dysphagia starts to appear in mildly impaired MS subjects (EDSS 2-3) and becomes increasingly common in the most severely disabled subjects (EDSS 8-9). The aim of the present study was to evaluate the frequency and characteristics of patient reported dysphagia in MS patients with a multicenter study using the recently developed DYMUS (DYsphagia in MUltiple Sclerosis) questionnaire. DESIGN: Data were collected in a multi-centre, cross-sectional study using a face-to-face structured questionnaire for clinical characteristics and the DYMUS questionnaire. RESULTS: 1875 patients were interviewed. The current study has shown a correlation between patient-reported dysphagia and EDSS and disease course but not with age, gender and disease duration. Questionnaires were divided into "patient-reported dysphagia-yes" (587, 31.3%) and "patient-reported dysphagia-no" (1288, 68.7%). Compared with the patient-reported dysphagia-no group, patients in patient-reported dysphagia-yes group had higher EDSS score (mean EDSS 4.6 vs. 2.8; p<0.001) and had a longer disease duration (mean duration 13 years vs. 11 years; p<0.001), while there was no significant difference in gender (32.7% vs. 30.5% male and 67.3% vs. 69.5% female) and in age composition (46.18 vs. 42.05). CONCLUSIONS: This study represents the largest, multi-centre sample of MS patients evaluated for patient-reported dysphagia utilizing an ad hoc questionnaire for this condition. PMID- 23747003 TI - Secondary blepharospasm associated with structural lesions of the brain. AB - BACKGROUND: Blepharospasm is a form of focal dystonia that manifests as repetitive involuntary closure of the eyes. The pathogenesis of blepharospasm and the neuroanatomic substrates involved are not fully understood. Dysfunction of the basal ganglia traditionally is presumed to be the main cause of most forms of dystonia, but a growing body of evidence suggests that a network of additional cortical and subcortical structures may be involved. METHODS: The medical records of 1114 patients with blepharospasm seen over past 10 years at Emory University were reviewed to identify potentially contributing brain lesions. A systematic review of the published literature was also conducted to identify potentially contributing brain lesions. RESULTS: Among patients with blepharospasm at Emory University, 18 had focal lesions on imaging studies available for review. The literature review revealed 25 articles describing 30 additional cases of blepharospasm associated with focal lesions. Among all 48 cases, lesions were found in multiple regions including the thalamus (n=12), lower brainstem (n=11), basal ganglia (n=9), cerebellum (n=9), midbrain (n=7), and cortex (n=1). CONCLUSIONS: These data in combination with functional imaging studies of primary blepharospasm support a model in which a network of different regions plays a role in the pathogenesis of blepharospasm. PMID- 23747004 TI - Intramedullary cysticercosis of the spinal cord: a review of patients evaluated with MRI. AB - OBJECTIVE: Review of cases of intramedullary spinal cord cysticercosis diagnosed with MRI to outline the features and outcome of this overlooked form of presentation of neurocysticercosis. METHODS: MEDLINE, LILACS, and manual search of case reports or case series of patients with intramedullary cysticercosis evaluated with MRI. Abstracted data included: demographic profile, clinical manifestations, neuroimaging findings, therapy, and follow-up. RESULTS: Forty three patients were reviewed. Mean age was 36 years, and 65% were men. Most patients (67%) had parasites located at the thoracic spinal cord. All but two patients had a single cyst. The most common form of presentation was a subacute or chronic transverse myelopathy. On MRI, all lesions had signal properties paralleling that of CSF, and most were surrounded by edema and had a "ring-like" pattern of abnormal enhancement. The scolex of the parasite was visualized in 16 (37%) cases. Twenty-nine patients underwent surgical resection of the lesion, and 14 were medically-treated. Follow-up data was available in 20 surgically-treated and 13 medically-treated patients. Twelve (60%) of the 20 surgically-treated patients recovered completely, and the remaining were left with sequelae or did not improve. In contrast, all the 13 medically-treated patients recovered completely after the use of cysticidal drugs plus corticosteroids (11 cases) or corticosteroids alone (two cases). CONCLUSIONS: Intramedullary cysticercosis is rare. Clinical and neuroimaging findings may resemble those of other intramedullary lesions, but the visualization of the scolex or the incidental discovery of intracranial lesions provide helpful diagnostic clues. Prognosis is benign provided the correct diagnosis is suspected and patients receive prompt therapy. PMID- 23747005 TI - Straw men don't get Lyme disease: response to Wood and Lafferty. PMID- 23747006 TI - Recurrent fractures as a new skeletal problem in the course of Angelman syndrome. AB - Angelman syndrome is a genetically inherited syndrome with severe retardation of psychomotor development and speech disturbances, usually accompanied by epilepsy, typical dysmorphic features, and some skeletal symptoms. The aim of the current report is to present new skeletal symptoms which may occur in the course of AS, based on a case report of an 8-year-old girl with confirmed 15q11;12 microdeletion and recurrent low-trauma bone fractures. According to our knowledge it is the first report of such skeletal symptoms in patient with a diagnosis of AS. PMID- 23747007 TI - The effect of amorphous pyrophosphate on calcium phosphate cement resorption and bone generation. AB - Pyrophosphate ions are both inhibitors of HA formation and substrates for phosphatase enzymes. Unlike polyphosphates their hydrolysis results simultaneously in the complete loss of mineral formation inhibition and a localised elevation in orthophosphate ion concentration. Despite recent advances in our knowledge of the role of the pyrophosphate ion, very little is known about the effects of pyrophosphate on bone formation and even less is known about its local delivery. In this work we first developed a self setting pyrophosphate based calcium cement system with appropriate handling properties and then compared its in vivo degradation properties with those of a non-pyrophosphate containing control. Contrary to expectation, the presence of the pyrophosphate phase in the cement matrix did not inhibit mineralisation of the healing bone around the implant, but actually appeared to stimulate it. In vitro evidence suggested that enzymatic action accelerated dissolution of the inorganic pyrophosphate ions, causing a simultaneous loss of their mineralisation inhibition and a localised rise in supersaturation with respect to HA. This is thought to be a rare example of a biologically responsive inorganic material and these materials seem to be worthy of further investigation. Bioceramics to date have mainly been limited to orthophosphate, silicate and carbonate salts of calcium, here we report the successful application of a pyrophosphate material as a degradable osteoconductive bone repair cement. PMID- 23747008 TI - PGS:Gelatin nanofibrous scaffolds with tunable mechanical and structural properties for engineering cardiac tissues. AB - A significant challenge in cardiac tissue engineering is the development of biomimetic grafts that can potentially promote myocardial repair and regeneration. A number of approaches have used engineered scaffolds to mimic the architecture of the native myocardium tissue and precisely regulate cardiac cell functions. However, previous attempts have not been able to simultaneously recapitulate chemical, mechanical, and structural properties of the myocardial extracellular matrix (ECM). In this study, we utilized an electrospinning approach to fabricate elastomeric biodegradable poly(glycerol sebacate) (PGS):gelatin nanofibrous scaffolds with a wide range of chemical composition, stiffness and anisotropy. Our findings demonstrated that through incorporation of PGS, it is possible to create nanofibrous scaffolds with well-defined anisotropy that mimic the left ventricular myocardium architecture. Furthermore, we studied attachment, proliferation, differentiation and alignment of neonatal rat cardiac fibroblast cells (CFs) as well as protein expression, alignment, and contractile function of cardiomyocyte (CMs) on PGS:gelatin scaffolds with variable amount of PGS. Notably, aligned nanofibrous scaffold, consisting of 33 wt. % PGS, induced optimal synchronous contractions of CMs while significantly enhanced cellular alignment. Overall, our study suggests that the aligned nanofibrous PGS:gelatin scaffold support cardiac cell organization, phenotype and contraction and could potentially be used to develop clinically relevant constructs for cardiac tissue engineering. PMID- 23747009 TI - Non-linear elasticity of core/shell spun PGS/PLLA fibres and their effect on cell proliferation. AB - An efficient delivery system is critical for the success of cell therapy. To deliver cells to a dynamic organ, the biomaterial vehicle should mechanically match with the non-linearly elastic host tissue. In this study, non-linearly elastic biomaterials have been fabricated from a chemically crosslinked elastomeric poly(glycerol sebacate) (PGS) and thermoplastic poly(l-lactic acid) (PLLA) using the core/shell electrospinning technique. The spun fibrous materials containing a PGS core and PLLA shell demonstrate J-shaped stress-strain curves, having ultimate tensile strength (UTS), rupture elongation and stiffness constants of 1 +/- 0.2 MPa, 25 +/- 3% and 12 +/- 2, respectively, which are comparable to skin tissue properties reported previously. Our ex vivo and in vivo trials have shown that the elastomeric mesh supports and fosters the growth of enteric neural crest (ENC) progenitor cells, and that the cell-seeded elastomeric fibrous sheet physically remains in intimate contact with guts after grafting, providing the effective delivery of the progenitor cells to an embryonic and post natal gut environment. PMID- 23747010 TI - Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high affinity ligand for STING. AB - The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2'-OH of GMP and 5'-phosphate of AMP, and the other between 3'-OH of AMP and 5' phosphate of GMP. This molecule, termed 2'3'-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2'3'-cGAMP revealed the structural basis of this high-affinity binding and a ligand-induced conformational change in STING that may underlie its activation. PMID- 23747012 TI - Alternative splicing regulates biogenesis of miRNAs located across exon-intron junctions. AB - The initial step in microRNA (miRNA) biogenesis requires processing of the precursor miRNA (pre-miRNA) from a longer primary transcript. Many pre-miRNAs originate from introns, and both a mature miRNA and a spliced RNA can be generated from the same transcription unit. We have identified a mechanism in which RNA splicing negatively regulates the processing of pre-miRNAs that overlap exon-intron junctions. Computational analysis identified dozens of such pre miRNAs, and experimental validation demonstrated competitive interaction between the Microprocessor complex and the splicing machinery. Tissue-specific alternative splicing regulates maturation of one such miRNA, miR-412, resulting in effects on its targets that code a protein network involved in neuronal cell death processes. This mode of regulation specifically controls maturation of splice-site-overlapping pre-miRNAs but not pre-miRNAs located completely within introns or exons of the same transcript. Our data present a biological role of alternative splicing in regulation of miRNA biogenesis. PMID- 23747011 TI - Arginine Methylation Initiates BMP-Induced Smad Signaling. AB - Kinase activation and substrate phosphorylation commonly form the backbone of signaling cascades. Bone morphogenetic proteins (BMPs), a subclass of TGF-beta family ligands, induce activation of their signaling effectors, the Smads, through C-terminal phosphorylation by transmembrane receptor kinases. However, the slow kinetics of Smad activation in response to BMP suggests a preceding step in the initiation of BMP signaling. We now show that arginine methylation, which is known to regulate gene expression, yet also modifies some signaling mediators, initiates BMP-induced Smad signaling. BMP-induced receptor complex formation promotes interaction of the methyltransferase PRMT1 with the inhibitory Smad6, resulting in Smad6 methylation and relocalization at the receptor, leading to activation of effector Smads through phosphorylation. PRMT1 is required for BMP induced biological responses across species, as evidenced by the role of its ortholog Dart1 in BMP signaling during Drosophila wing development. Activation of signaling by arginine methylation may also apply to other signaling pathways. PMID- 23747013 TI - RNA polymerase I stability couples cellular growth to metal availability. AB - Zinc is an essential cofactor of all major eukaryotic RNA polymerases. How the activity of these enzymes is coordinated or regulated according to cellular zinc levels is largely unknown. Here we show that the stability of RNA polymerase I (RNAPI) is tightly coupled to zinc availability in vivo. In zinc deficiency, RNAPI is specifically degraded by proteolysis in the vacuole in a pathway dependent on the export in Xpo1p and deubiquitination of the RNAPI large subunit Rpa190p by Ubp2p and Ubp4p. RNAPII is unaffected, which allows for the expression of genes required in zinc deficiency. RNAPI export to the vacuole is required for survival during zinc starvation, suggesting that degradation of zinc-binding subunits might provide a last resort zinc reservoir. These results reveal a hierarchy of cellular transcriptional activities during zinc starvation and show that degradation of the most active cellular transcriptional machinery couples cellular growth and proliferation to zinc availability. PMID- 23747014 TI - The proto-oncometabolite fumarate binds glutathione to amplify ROS-dependent signaling. AB - The tricarboxylic acid cycle enzyme fumarate hydratase (FH) has been identified as a tumor suppressor in a subset of human renal cell carcinomas. Human FH deficient cancer cells display high fumarate concentration and ROS levels along with activation of HIF-1. The underlying mechanisms by which FH loss increases ROS and HIF-1 are not fully understood. Here, we report that glutamine-dependent oxidative citric acid cycle metabolism is required to generate fumarate and increase ROS and HIF-1 levels. Accumulated fumarate directly bonds the antioxidant glutathione in vitro and in vivo to produce the metabolite succinated glutathione (GSF). GSF acts as an alternative substrate to glutathione reductase to decrease NADPH levels and enhance mitochondrial ROS and HIF-1 activation. Increased ROS also correlates with hypermethylation of histones in these cells. Thus, fumarate serves as a proto-oncometabolite by binding to glutathione which results in the accumulation of ROS. PMID- 23747015 TI - Interaction of p53 with the CCT complex promotes protein folding and wild-type p53 activity. AB - p53 is a transcription factor that mediates tumor suppressor responses. Correct folding of the p53 protein is essential for these activities, and point mutations that induce conformational instability of p53 are frequently found in cancers. These mutant p53s not only lose wild-type activity but can also acquire the ability to promote invasion and metastasis. We show that folding of wild-type p53 is promoted by an interaction with the chaperonin CCT. Depletion of this chaperone in cells results in the accumulation of misfolded p53, leading to a reduction in p53-dependent gene expression. Intriguingly, p53 proteins mutated to prevent the interaction with CCT show conformational instability and acquire an ability to promote invasion and random motility that is similar to the activity of tumor-derived p53 mutants. Our data therefore suggest that both growth suppression and cell invasion may be differentially regulated functions of wild type p53. PMID- 23747017 TI - Adopting the new anticoagulants: all aboard or all in good time? AB - At last there is now more than 1 oral anticoagulant (OAC) available for stroke prevention in atrial fibrillation. Though more choice is a good thing, it does mandate knowing which drug is the most appropriate in a given clinical situation. Three novel OACs--dabigatran, rivaroxaban, and apixaban--are approved for use in atrial fibrillation in Canada. They have each been evaluated in large, randomized controlled trials where they have been shown to be noninferior, or in some cases superior, to warfarin (Coumadin). Prescription coverage for these drugs is increasingly available through third party and government drug plans. The major enhancements of the novel OACs relate to their rapid, consistent anticoagulant effect at fixed dosing and the lack of need for monitoring of anticoagulant effect. Nonetheless, their use is not foolproof and practitioners must be familiar with their limitations. On balance, we favour the use of novel OACs over warfarin in patients who are anticoagulant-naive, given their increased ease of use. However, we advocate switching from warfarin only if international normalized ratio control has been poor or if frequent monitoring is problematic. PMID- 23747016 TI - Differential effects on ARF stability by normal versus oncogenic levels of c-Myc expression. AB - ARF suppresses aberrant cell growth upon c-Myc overexpression by activating p53 responses. Nevertheless, the precise mechanism by which ARF specifically restrains the oncogenic potential of c-Myc without affecting its normal physiological function is not well understood. Here, we show that low levels of c Myc expression stimulate cell proliferation, whereas high levels inhibit by activating the ARF/p53 response. Although the mRNA levels of ARF are induced in both scenarios, the accumulation of ARF protein occurs only when ULF-mediated degradation of ARF is inhibited by c-Myc overexpression. Moreover, the levels of ARF are reduced through ULF-mediated ubiquitination upon DNA damage. Blocking ARF degradation by c-Myc overexpression dramatically stimulates the apoptotic responses. Our study reveals that ARF stability control is crucial for differentiating normal (low) versus oncogenic (high) levels of c-Myc expression and suggests that differential effects on ULF- mediated ARF ubiquitination by c Myc levels act as a barrier in oncogene-induced stress responses. PMID- 23747018 TI - Developmental and contextual factors in the role of severe childhood trauma in geriatric depression: the sample case of former indentured child laborers. AB - The purpose of this study was to quantify the association between childhood traumatic experiences and geriatric depression (GDS) in a population of elderly who were exposed to severe childhood trauma. We aimed to identify the role of childhood maltreatment exposure in geriatric depression and the developmental and contextual factors that exacerbate this relationship. We interviewed 141 former indentured child laborers (58 females) about their experiences as children and their current depressive symptoms (Mage=77, SD=6.8). Participants provided their age, the year they were first indentured, duration indentured, current physical health, completed the Childhood Trauma Questionnaire (CTQ) and the Geriatric Depression Scale (GDS). Child maltreatment, specifically emotional abuse, was strongly associated with geriatric depression symptoms. These effects were specific to individuals who were removed from their biological families between the ages of 3 and 9 years, and for children who were indentured for 6-12 years. Finally, depression partially mediated the association between medical conditions and daily health impairment, but not for individuals "at risk" for depression by virtue of their maltreatment experiences. This study was conducted with a specific subpopulation of elderly and therefore may not generalize to all geriatric depression, nor to all generations or populations with exposure to childhood adversity. This study demonstrates the importance of using a developmental framework to understand how childhood maltreatment facilitates increased risk for the development of depression in late life. PMID- 23747019 TI - Patent foramen ovale and infarct volume in cryptogenic stroke. AB - BACKGROUND: The causal relationship between patent foramen ovale (PFO) and stroke is controversial. We hypothesized that if PFO is a pathway of embolic source, there might be a correlation between PFO characteristics (ie, size or extent of shunt) and ischemic lesion burden (ie, infarct volume and number). METHODS: From ischemic stroke patients admitted to Asan Medical Center between January 2000 and October 2007, we identified those who had (1) acute ischemic lesion on diffusion weighted imaging within 5 days of symptom onset and (2) cryptogenic stroke and only PFO detected by transesophageal echocardiography. PFO characteristics on echocardiographic studies included size, shunt grade, shunt pattern, and the presence of atrial septal aneurysm (ASA). RESULTS: Enrolled were 75 patients (male, 56%; mean age, 45.3+/-13.9 years), including 10 patients (13.3%) with ASA. In univariable analysis, PFO size was positively correlated with log-transformed infarct volume (LIV) (regression coefficient=.469, P=.009). After adjusting for hypertension, stroke history, and migraine (all P<.2), PFO size remained independently associated with LIV (regression coefficient=.481, P=.007). Lesion number was negatively correlated with PFO size (Spearman coefficient rho=-.251, P=.03). The initial National Institutes of Health Stroke Scale scores tended to be positively correlated with PFO size (Spearman coefficient rho=.223, P=.054). CONCLUSIONS: In cryptogenic stroke, PFO size and ischemic lesion burden were positively correlated. These results support that PFO may play a role as a pathway of embolic source in cryptogenic stroke. PMID- 23747020 TI - The aesthetic and cultural pursuits of patients with stroke. AB - BACKGROUND: There has been an increasing interest in the arts in health care, with a suggestion that the arts and aesthetics can augment patient outcomes in stroke and other illnesses. Designing such programmes requires better knowledge of the artistic, aesthetic, and cultural pursuits of people affected by stroke. The aim of this study was to obtain the insights of this group about the profile of art and aesthetic activities in their lives and the influence of stroke on these aspects. METHODS: Patients attending a stroke service were administered questions adapted from the Irish Arts Council's 2006 questionnaire on participation in aesthetics and cultural pursuits. Information was also collected on stroke type and present functional and cognitive status. Thirty-eight patients were interviewed. Of these, 20 were inpatients in hospital at the time of the interview and 18 were interviewed in an outpatient setting. RESULTS: Popular activities included mainstream cinema, listening to music, dancing, attending plays or musicals, and being outdoors. Many patients ceased these activities after their stroke, mostly because of health issues and inaccessibility. Most of the patients valued the importance of the arts in the health-care setting. CONCLUSIONS: This study gives a perspective for the first time on the aesthetic and cultural pursuits of stroke patients before their stroke. It portrays a wide variety of cultural and leisure activities and the cessation of these poststroke. It revealed the restrictions patients felt on gaining access to leisure pursuits both while in hospital and following discharge. PMID- 23747021 TI - Short- and long-term survival after stroke in hospitalized patients in Chile: a nationwide 5-year study. AB - BACKGROUND: Short- and long-term stroke survival is a key indicator of hospital performance in stroke care. Our aim was to estimate short- and long-term survival rates in discharged patients diagnosed with ischemic stroke in Chile in a 5-year period and identify associated variables. MATERIALS AND METHODS: We included all discharged patients from all hospitals in Chile with main diagnosis of ischemic stroke from 2003 to 2007, which were identified through the National Hospital Discharge Registry. To establish survival, discharges were linked to deaths in the Deaths Registry. Kaplan-Meier survival curves were used to estimate the cumulative 7-day, 30-day, 1-year, and 3-year survival rates. Independent predictors of death (sex, age, geographical regions, and status insurance) were assessed by Cox proportional hazard regression model. RESULTS: A total of 51,130 with first-ever ischemic stroke patients were identified. Overall survival rate decreased from 88.9% (95% confidence interval [CI] 88.6-89.2) 7 days after hospital admission to 81.9% (95% CI 81.6-82.3), 69.9% (95% CI 69.5-70.3), and 61.2% (95% CI 60.7-61.6) after 30-day, 1-year, and 3-year, respectively. The multivariable model showed that the elderly patients (>80 years; hazard ratio [HR] 4.07; 95% CI 3.89-4.26) and hospital admission in the North (HR 1.14; 95% CI 1.09-1.20) and South area (HR 1.06; 95% CI 1.03-1.110) were associated with lower survival after stroke. Patients with private health insurance have a higher probability of survival than patients with public insurance (private insurance, HR .53; 95% CI .49-.56). CONCLUSIONS: Short- and long-term survival after ischemic stroke was heterogeneous by geographic regions and type of health insurance, regardless age and sex were the strongest predictors. This suggests an impact of socioeconomic factors and access to acute management of strokes on survival. PMID- 23747022 TI - Resolution phase lipid mediators of inflammation: agonists of resolution. AB - Lipid mediators are appreciated for their roles in leukocyte traffic required in host defense. With identification of novel resolution phase mediators, resolvins, protectins and maresins, these three families and their aspirin-triggered forms, given their potent stereoselective actions with human cells and animal disease models, are coined specialized pro-resolving mediators (SPM). Stereochemistries of key SPM are established and several groups reported organic synthesis. Given increased availability, this two-year-review period expands their potent pro resolving and non-redundant actions. Collectively, they support the concept that return of acute inflammation involves active biosynthesis and SPM signaling toward homeostasis. PMID- 23747023 TI - Changes in macrophage phenotype as the immune response evolves. AB - Mononuclear phagocytic cells (MPCs), including macrophages and dendritic cells (DCs), are widely distributed throughout our organs where they perform important homeostatic, surveillance and regenerative tasks. In response to infection or injury, the composition and number of MPCs change remarkably, in part due to the recruitment of inflammatory monocytes from bone marrow. In infection or injury, macrophages and DCs perform important innate and adaptive immune roles from the initial insult through repair and regeneration of the tissue and resolution of inflammation. Evidence from mouse models of disease has shown increasing complexity and subtlety to the mononuclear phagocytic system, which will be reviewed here. New studies show that in addition to monocytes, the resident populations of mononuclear phagocytes expand in disease states and play distinct but important roles in the immune response. Finally, new insights into these functionally diverse cells are now translating into therapeutics to treat human disease. PMID- 23747024 TI - Treating skin and lung fibrosis in systemic sclerosis: a future filled with promise? AB - Systemic sclerosis (SSc) is a rare autoimmune disorder characterized by immune activation, vascular damage and an excessive accumulation of extracellular matrix proteins in the skin and internal organs. Despite its high morbidity and increased mortality, currently available treatment options for fibrotic manifestations of SSc remain limited and their clinical antifibrotic effects are borderline. In this review, novel insights from recently published clinical trials in SSc on treatment concepts such as mycophenolate mofetil, oral type I collagen, recombinant human relaxin and autologous hematopoietic stem cell transplantation are discussed. In the past decade the most significant progress in this field has been made by the identification of a large number of cellular and molecular key players in the pathogenesis of fibrotic disease manifestations. This has led to the identification of novel candidates as molecular targets for treatment of fibrotic diseases. On the basis of their level of evidence from preclinical studies and based on the availability of first clinical results, the most promising targets are presented including inhibitors of B-cells, tyrosine kinases, 5-hydroxytryptamin receptors, interleukin-6 and Wnt signalling. PMID- 23747025 TI - Reducing blood culture contamination rates: a systematic approach to improving quality of care. AB - Contaminated blood cultures can have a deleterious effect on patient care; they may lead to longer hospital stays, unnecessary antibiotic therapy, needless removal of central lines, and redundant laboratory testing. A multidisciplinary quality improvement team from a western US health care system used an evidence based process to define a system for obtaining blood culture specimens that subsequently decreased contamination rates from 3.7% to 1.7% with an estimated savings close to 2 million dollars in 2 years. PMID- 23747026 TI - The efficacy of minitracheostomy for the management of sputum retention: a systematic review. AB - BACKGROUND: Suction via a minitracheostomy is a safe procedure, but its efficacy in facilitating sputum clearance in individuals with an acute condition has not been systematically reviewed. OBJECTIVES: The aim of this study was to identify and synthesise the efficacy of the insertion of a minitracheostomy and tracheal suction via minitracheostomy for sputum clearance in adults who have undergone surgery or have an acute condition characterised by sputum retention. DATA SOURCES: A systematic literature search using the electronic databases MEDLINE, CINAHL, EMBASE, Cochrane Library and PEDro, with searches limited to English language journal articles published between 1984 and September 2011. DATA EXTRACTION AND DATA SYNTHESIS: All study designs were included. Two independent reviewers used pre-defined inclusion and exclusion criteria to identify all eligible articles. RESULTS: Six studies in six patient groups met the inclusion criteria, with two randomised controlled trials and four case series included. These studies presented the results of 278 patients following surgery and 13 with acute medical conditions. There were a range of criteria that defined the efficacy of minitracheostomy for sputum retention. Studies reporting the adjunctive role found a reduced incidence of complications associated with sputum retention following thoracic surgery. Other studies reported limited benefit in overall respiratory status with minitracheostomy. Heterogeneity among the studies was evident, with major limitations identified. CONCLUSIONS: Limited evidence suggests that minitracheostomy may be a useful adjunct in optimising sputum clearance in adults following thoracic surgery, but the effects in adults with an acute condition and other types of surgery are inconclusive. PMID- 23747027 TI - Affordable clinical gait analysis: an assessment of the marker tracking accuracy of a new low-cost optical 3D motion analysis system. AB - BACKGROUND: 3D motion analysis represents a method of collecting objective, accurate and repeatable gait data, however the high cost of equipment inhibits its widespread use in routine clinical practice. OBJECTIVE: To determine the marker tracking accuracy of a new low-cost optical 3D motion analysis system. DESIGN: Comparative between-system study. SETTING: Clinical motion analysis laboratories. METHODS: A rigid cluster of four reflective markers was used to compare a low-cost Optitrack 3D motion analysis system against two more expensive systems (Vicon 612 and Vicon MX). Accuracy was measured by comparing the mean vector magnitudes (between each combination of markers) for each system, and reliability was measured through the coefficients of variation (CV). Gaps in the marker trajectories, which are considered undesirable, were also counted. RESULTS: In terms of accuracy, the largest disagreement between mean vector magnitudes for Optitrack and Vicon MX was 2.2%. The largest disagreement between Vicon 612 and Vicon MX was 2.1%. Regarding reliability, the mean CV was lowest in Vicon MX (0.3%) and similar in the Vicon 612 (2.5%) and Optitrack (2.3%) systems. The number of trajectory gaps for the Vicon MX, Vicon 612 and Optitrack systems were; zero, six and 11 respectively. CONCLUSIONS: The Optitrack system provides a low-cost 3D motion analysis system that can offer marker tracking accuracy and reliability which is comparable with an older and still widely used system (Vicon 612). Further development work is required before Optitrack can be used for full 3D gait analysis by physiotherapists and other health professionals. PMID- 23747028 TI - Opportunistic microorganisms in individuals with lesions of denture stomatitis. AB - The aim of this study was to isolate, quantify, identify, and compare opportunistic microorganisms (Candida and Staphylococcus genera and Enterobacteriaceae/Pseudomonadaceae families) from prosthesis-fitting surfaces, the hard palate, and mouth rinses of individuals wearing removable maxillary prosthesis with (50) and without (50) lesions of denture stomatitis (DS). The strains were collected and identified using phenotypic, biochemical and molecular tests. The counts of microorganisms were significantly higher in the group of individuals with DS (P < 0.05). C. albicans was the most frequently isolated yeast species in both groups, following by C. tropicalis and C. glabrata. Six isolates were identified as C. dubliniensis. S. aureus and S. epidermidis were the most frequent Staphylococcus species in both groups. Klebsiella pneumoniae was the predominant species in both groups. The association between Candida spp. and bacteria isolated in this study with DS suggests that these microorganisms may play important roles in the establishment and persistence of this disease. PMID- 23747030 TI - Changes in the balance between Treg and Th17 cells in patients with chronic hepatitis B. AB - The purpose of this study was to explore the role of Treg cells, Th17 cells and cytokines associated with Treg/Th17 differentiation in the occurrence, development and outcome of chronic hepatitis B (CHB). To do so, we detected populations of Treg and Th17 cells and their associated cytokines in the peripheral blood of CHB patients. The populations of Treg cells (CD4(+)CD25(high)CD127(low) T cells) and Th17 cells (CD3(+)CD8(-)IL-17(+) T cells) were analyzed in 46 patients with low to moderate chronic hepatitis B (CHB LM), 24 patients with severe chronic hepatitis B (CHB-S) and 20 healthy controls (HC) using flow cytometry. The levels of cytokines associated with Treg/Th17 differentiation, including IL-10, TGF-beta1, IL-17 and IL-23, were measured by enzyme-linked immunosorbent assay (ELISA). Our study showed that the imbalance of Treg and Th17 cells might play an important role in the occurrence, development and outcome of CHB. PMID- 23747029 TI - Molecular diagnosis of microbial aetiologies using SepsiTestTM in the daily routine of a diagnostic laboratory. AB - A universal PCR and sequencing test, SepsiTestTM (Molzym, Germany) was evaluated for its applicability during daily diagnostic routine in a privately operated laboratory. In total, 96 specimens originating from 66 patients under suspect of infectious endocarditis, infections of joints, encephalitis/meningitis, systemic infections and infections of unknown genesis were PCR analysed and compared to culture results. Samples comprised cultured and non-cultured blood, synovial fluid, synovial tissue, heart valves, pacemakers, spinal tissue, cerebrospinal fluid, and swabs. PCR and culture were concordant in 26 negative and 8 positive cases (51.5%). A group of 25 patients was culture-negative but PCR-positive (37.9%). In at least 14 of these, common and/or rare aetiologies were identified, while for 4 patients the results of 16S PCR could not be unequivocally linked with the underlying disease. Benefits and limitations of the molecular test are discussed with special emphasis on technical and economic issues. In conclusion, SepsiTestTM proved to be a valuable tool for the diagnosis of aetiologies, particularly in cases of culture-negative patients who are under strong suspicion for an infection. PMID- 23747031 TI - Evaluation of the diagnostic value of fluorescent in situ hybridization in a rat model of bacterial pneumonia. AB - In severe nosocomial pneumonia, the pathogenic responsibility of bacteria isolated from airways is far from certain, and a lung biopsy is sometimes performed. However, detection and identification of pathogens are frequently unachieved. Here, we developed a protocol for direct visualization of bacteria within the lung tissue using fluorescent in situ hybridization (FISH) in a rat model of Acinetobacter baumannii pneumonia. The reference positive diagnosis of bacterial pneumonia was the presence of pathological signs of pneumonia associated with the proof of bacteria or bacterial PCR products into the parenchyma. By analysis of 122 sets of slices from 26 rats and using the eubacterial probe EUB-338, our results show that FISH reached a sensitivity and a diagnostic accuracy higher than that of optic microscopy (sensitivity: 96% versus 55.4% and diagnostic accuracy: 96.7% versus 66.4%), whereas both approaches had 100% specificity. FISH could be useful especially on negative biopsies from patients with suspected infectious pneumonia. PMID- 23747032 TI - The utility of anaerobic blood culture in detecting facultative anaerobic bacteremia in children. AB - Routine anaerobic blood culture is not recommended in children because obligate anaerobic bacteremia is rare in the pediatric population. However, a number of facultative anaerobic bacteria can cause community and hospital acquired infections in children and the utility of anaerobic blood culture for detection of these organisms is still unclear. We conducted a retrospective analysis of all blood culture samples (n = 24,356) at a children's hospital in Japan from October 2009 to June 2012. Among the samples that had paired aerobic and anaerobic blood cultures, 717 samples were considered clinically significant with 418 (58%) organisms detected from both aerobic and anaerobic cultures, 167 (23%) detected only from aerobic culture and 132 (18%) detected only from anaerobic culture. While most facultative anaerobes were detectable by aerobic culture, over 25% of Enterobacteriaceae and 15% of Staphylococcus sp. were detected from anaerobic cultures bottles only, suggesting its potential role in selected settings. PMID- 23747033 TI - Hedgehog on the move: a precise spatial control of Hedgehog dispersion shapes the gradient. AB - Hedgehog (Hh) as morphogen directs cell differentiation during development activating various target genes in a concentration dependent manner. The mechanisms that permit controlled Hh dispersion and gradient formation remain controversial. New research in the Drosophila wing disc epithelium has revealed a crucial role of Hh recycling for its release and transportation from source cells. Lipid modifications on Hh mediate key interactions with different elements of the pathway, which balance the retention and release of the molecule through the basolateral side of the epithelium, allowing its tight spatial control. Dispersion of Hh is also determined by its hydrophobic nature, and the mechanisms that include membrane-tethered transport of Hh are increasingly proposed. PMID- 23747034 TI - Planar cell polarity in vertebrate limb morphogenesis. AB - Studies of the vertebrate limb development have contributed significantly to understanding the fundamental mechanisms underlying growth, patterning, and morphogenesis of a complex multicellular organism. In the limb, well-defined signaling centers interact to coordinate limb growth and patterning along the three axes. Recent analyses of live imaging and mathematical modeling have provided evidence that polarized cell behaviors governed by morphogen gradients play an important role in shaping the limb bud. Furthermore, the Wnt/planar cell polarity (PCP) pathway that controls uniformly polarized cell behaviors in a field of cells has emerged to be critical for directional morphogenesis in the developing limb. Directional information coded in the morphogen gradient may be interpreted by responding cells through regulating the activities of PCP components in a Wnt morphogen dose-dependent manner. PMID- 23747036 TI - The role of T cell immunity in HIV-1 infection. AB - The interplay between the T cell immune response and human immunodeficiency virus (HIV)-1 largely determines the outcome of infection. Typically, the virus overcomes the immune defences leading to a gradual decline in function that permits the development of disease. In recent years, a concerted effort in comparing T cell responses between 'controllers' and 'progressors' is beginning to identify the T cell subsets and factors that affect disease progression related to the effector functions of both CD4 and CD8 T cells. These efforts are providing opportunities for development of novel therapies and vaccines. PMID- 23747035 TI - Genetic architecture of reciprocal CNVs. AB - Copy number variants (CNVs) represent a frequent type of lesion in human genetic disorders that typically affects numerous genes simultaneously. This has raised the challenge of understanding which genes within a CNV drive clinical phenotypes. Although CNVs can arise by multiple mechanisms, a subset is driven by local genomic architecture permissive to recombination events that can lead to both deletions and duplications. Phenotypic analyses of patients with such reciprocal CNVs have revealed instances in which the phenotype is either identical or mirrored; strikingly, molecular studies have shown that such phenotypes are often driven by reciprocal dosage defects of the same transcript. Here we explore how these observations can help the dissection of CNVs and inform the genetic architecture of CNV-induced disorders. PMID- 23747038 TI - Reply to Stanback et al.'s "Suspect online sellers and contraceptive access". PMID- 23747037 TI - ISG12 is a critical modulator of innate immune responses in murine models of sepsis. AB - Sepsis is still a major burden for our society with high incidence of morbidity and mortality each year. Molecular mechanisms underlying the systemic inflammatory response syndrome (SIRS) associated with sepsis are still ill defined and most therapies developed to target the acute inflammatory component of the disease are insufficient. Recently the role of nuclear receptors (NRs) became a major topic of interest in transcriptional regulation of inflammatory processes. Nuclear receptors, such as the peroxisome proliferators-activated receptors (PPARs), have been demonstrated to exert anti-inflammatory properties by interfering with the NFkappaB pathway. We identified the nuclear envelope protein, interferon stimulated gene 12 (ISG12), which directly interacts with NRs. ISG12 is a co-factor stimulating nuclear export of NRs, thereby reducing the anti-inflammatory potential of NRs such as NR4A1. To examine the role of ISG12 in acute inflammatory processes we used recently generated ISG12 deficient mice. We can clearly demonstrate that lack of ISG12 prolongs survival in experimental sepsis and endotoxemia. Furthermore we can show that several acute inflammatory parameters, such as systemic IL6 cytokine levels, are downregulated in septic ISG12-/- animals. Consistently, similar results were obtained in in vitro experiments in peritoneal macrophages derived from ISG12 deficient mice. In contrast, mice deficient for the nuclear receptor NR4A1 exhibited an exacerbated innate immune response, and showed a significantly higher mortality after lethal endotoxemic challenge. This dramatic phenotype could be restored in ISG12/NR4A1 double deficient mice. We conclude from our data in vitro and in vivo that ISG12 is a novel modulator of innate immune responses regulating anti-inflammatory nuclear receptors such as NR4A1. PMID- 23747039 TI - [Debility after a skin rash in a 66 year-old male]. PMID- 23747040 TI - PTX3 as a paradigm for the interaction of pentraxins with the complement system. AB - Pentraxins are highly conserved components of the humoral arm of innate immunity. They include the short pentraxins C reactive protein (CRP) and serum amyloid P component (SAP), and the long pentraxin PTX3. These are soluble pattern recognition molecules that are present in the blood and body fluids, and share the ability to recognize pathogens and promote their disposal. CRP and SAP are produced systemically in the liver while PTX3 is produced locally in a number of tissues, macrophages and neutrophils being major sources of this long pentraxin. Pentraxins interact with components of the classical and lectin pathways of Complement as well as with Complement regulators. In particular, PTX3 recognizes C1q, factor H, MBL and ficolins, where these interactions amplify the repertoire of microbial recognition and effector functions of the Complement system. The complex interaction of pentraxins with the Complement system at different levels has broad implications for host defence and regulation of inflammation. PMID- 23747041 TI - An epidemiological analysis of paediatric burns in urban and rural areas in south central China. AB - OBJECTIVE: This study aims to analyse the epidemiology of paediatric burns in south central China, illustrate the differences between rural and urban areas, and discern prevention measures to reduce paediatric burns. METHODS: Data were obtained from all paediatric patients admitted to Department of Burns unit of Xiangya Hospital during 2009-2012. A retrospective review was performed, including cause of burn, pre-hospital treatment, place of burn occurrence, anatomical areas involved, extent of burn, date of injury, number of operations, complications, length of hospital stay, hospitalisation cost and cure rate. RESULTS: A total of 278 hospitalised paediatric patients were admitted in this study. The majority (56.47%) were 1-3 years old. Rural patients accounted for 67.99% in total; the ratio of boys to girls was 2.05. Scalding with hot fluids was the most common cause of burns in children (62.59%), followed by flame (17.63), fireworks (9.71%), electricity (5.76%) and other factors such as contact and chemical (4.32%). The living room was the location with the highest frequency of burns in children (53.24%). Burns were more likely to happen in winter and the upper extremities were the most involved anatomic site (53.24%). Total burn surface area (TBSA) ranging from 0% to 9% accounted for 55.4% in total. Rural patients underwent more operations and had longer and costlier hospital stays than urban patients. CONCLUSION: Compared with treatment in urban areas, rural burn patients received less first-aid treatment, underwent more surgery, had more complications and longer and more costly hospital stays. This finding strongly suggests that it is necessary to make more efforts to prevent burns, especially in rural areas. PMID- 23747042 TI - Prognosis of multi-lobar pneumonia in community-acquired pneumonia: a systematic review and meta-analysis. AB - BACKGROUND: Pneumonia is the leading cause of infection related mortality. Multilobar pneumonia (MLP) may have poorer outcomes and is a constituent of some prognostic indices. Our aim was to systematically-review and meta-analyse the impact of multi-lobar involvement in pneumonia. METHODS: We searched PubMed in June 2012 for studies reporting on the association between MLP and clinical outcomes. Potentially relevant studies were cross checked by two independent reviewers before final inclusion. Odds-ratios (OR) for the association between MLP and mortality, unfavourable outcomes, and poor treatment response were pooled using random effects meta-analysis. RESULTS: Twenty-two studies were included in this report. There were a total of 11,456 pneumonia patients including 2897 (25.3%) patients with MLP. As there was substantial clinical and statistical heterogeneity in the overall dataset, we limited the main meta-analysis to patients with community-acquired pneumonia (CAP). This showed that MLP was associated with increased mortality, OR 2.57 (95% CI: 1.83-3.61), with no statistical heterogeneity (I(2)=0%). Evidence from other settings suggests that MLP may also be associated with higher likelihood of other poor outcomes such as worsening clinical/radiological status, delayed resolution, and need for mechanical ventilation. CONCLUSION: MLP appears to be an independent risk factor for mortality in CAP. It may be possible to improve commonly used prognostic indices in CAP by addition of MLP as a criterion. PMID- 23747043 TI - Effect of cardiac resynchronization therapy on pulmonary function in patients with heart failure. AB - Pulmonary congestion due to heart failure causes abnormal lung function. Cardiac resynchronization therapy (CRT) is a proven effective treatment for heart failure. The aim of this study was to test the hypothesis that CRT promotes increased lung volumes, bronchial conductance, and gas diffusion. Forty-four consecutive patients with heart failure were prospectively investigated before and after CRT. Spirometry, gas diffusion (diffusing capacity for carbon monoxide), cardiopulmonary exercise testing, New York Heart Association class, brain natriuretic peptide, the left ventricular ejection fraction, left atrial volume, and right ventricular systolic pressure were assessed before and 4 to 6 months after CRT. Pre- and post-CRT measures were compared using either paired Student's t tests or Wilcoxon's matched-pair test; p values <0.05 were considered significant. Improved New York Heart Association class, left ventricular ejection fraction, left atrial volume, right ventricular systolic pressure, and brain natriuretic peptide were observed after CRT (p <0.05 for all). Spirometry after CRT demonstrated increased percentage predicted total lung capacity (90 +/- 17% vs 96 +/- 15%, p <0.01) and percentage predicted forced vital capacity (80 +/- 19% vs 90 +/- 19%, p <0.01). Increased percentage predicted total lung capacity was significantly correlated with increased peak exercise end-tidal carbon dioxide (r = 0.43, p = 0.05). Increased percentage predicted forced vital capacity was significantly correlated with decreased right ventricular systolic pressure (r = -0.30, p = 0.05), body mass index (r = -0.35, p = 0.02) and creatinine (r = -0.49, p = 0.02), consistent with an association of improved bronchial conductance and decreased congestion. Diffusing capacity for carbon monoxide did not significantly change. In conclusion, increased lung volumes and bronchial conductance due to decreased pulmonary congestion and increased intrathoracic space contribute to an improved breathing pattern and decreased hyperventilation after CRT. Persistent alveolar-capillary membrane remodeling may account for unchanged diffusing capacity for carbon monoxide. PMID- 23747045 TI - Accelerated tau pathology with synaptic and neuronal loss in a novel triple transgenic mouse model of Alzheimer's disease. AB - There is pivotal evidence that tau pathology can be triggered by amyloid-beta (Abeta) pathology in experimental systems. On the other side, studies on human brain specimen have elucidated that tau pathology may occur before amyloid pathology is present indicating that in principle tau pathology could also trigger Abeta aggregation. To address this question, we have crossed 5XFAD mice coexpressing human mutant APP695 with the Swedish, Florida, and London mutations and human mutant presenilin-1 (PS1) with the M146L and L286V mutations with the PS19 model overexpressing human mutant tau with the P301S mutation. The resulting triple transgenic model 5XFAD/PS19 has been characterized at 3 and 9 months of age. A dramatic aggravation of hyperphosphorylated tau pathology together with a dramatically increased inflammatory response and a loss of synapses and hippocampal CA1 neurons in aged 5XFAD/PS19 mice were observed. Extracellular amyloid deposits were unaltered. These data support the assumption of tau pathology being downstream of amyloid pathology, suggesting that both pathologies together trigger the severe neuron loss in the hippocampus in the 5XFAD/PS19 mouse model. PMID- 23747044 TI - Incidence and outcome of high on-treatment platelet reactivity in patients with non-ST elevation acute coronary syndromes undergoing percutaneous coronary intervention (from the VIP [VerifyNow and Inhibition of Platelet Reactivity] study). AB - High residual platelet reactivity (RPR) on clopidogrel treatment has been associated with increased risk for ischemic events during follow-up in patients with acute coronary syndromes. The aim of this study was to assess the incidence, predictors, and clinical consequences of high RPR in a large population of patients with non-ST-segment elevation acute coronary syndromes who underwent percutaneous coronary intervention and stenting. Overall, 833 patients received point-of-care testing of platelet inhibition 30 days after percutaneous coronary intervention. High RPR was diagnosed on the basis of P2Y12 reaction units >230. The incidence and predictors of death, myocardial infarction, stroke, and serious bleeding events were assessed up to 1 year from the day of testing. P2Y12 reaction units were normally distributed, and 264 patients were classified as poor responders (31.7%). Independent predictors of response to clopidogrel were male gender (odds ratio [OR] 1.51), age (OR 0.96), diabetes mellitus (OR 0.51), and use of proton pump inhibitors (OR 0.59). At 1 year, poor responders showed higher rates of death (4.6% vs 1.9%, p = 0.032) and serious bleeding events (4.9% vs 1.8%, p = 0.009) compared with good responders. After adjustment for confounders, high RPR did not emerge as an independent predictor of mortality (OR 0.57, 95% confidence interval [CI] 0.23 to 1.42, p = 0.23) or serious bleeding events (OR 0.61, 95% CI 0.25 to 1.52, p = 0.29). The results did not change using the a cut-off value for P2Y12 reaction units of 208. In conclusion, 1/3 of patients with acute coronary syndromes who underwent percutaneous coronary intervention and stenting showed high on-treatment RPR on bedside monitoring. They had a worse prognosis, but the level of platelet inhibition was not independently associated with the incidence of ischemic or bleeding events. PMID- 23747046 TI - Tissue transglutaminase is not a biochemical marker for Alzheimer's disease. AB - Typical hallmarks of Alzheimer's disease (AD) are pathologic deposits in cortical and subcortical regions consisting of self-aggregated proteins such as amyloid beta (Abeta) or tau. Tissue transglutaminase (tTG) catalyses calcium-dependent cross-linking between proteins (transamidation) resulting in protease-resistant isopeptide bonds. Because of this ability, tTG was suspected to participate in AD pathogenesis. Abeta and tau can be cross-linked by tTG in vitro. In AD neocortex, messenger RNA expression of tTG is increased. However, data on transamidation in AD specimens--activity of not only tTG but also other transglutaminases--are contradictory. The aim of our study was to investigate if tTG is involved in AD development and may be useful as biomarker for AD. We studied human brain samples for tTG concentration, tTG localization, and transamidation activity and cerebrospinal fluid (CSF) for tTG content by novel sensitive and highly specific methods. Neither tTG concentration nor transamidation was increased in AD brain homogenates. Immunohistologically, we found no colocalization of tTG in neocortex sections with tau or Abeta deposits but with blood vessels. Only in rare cases, tTG was detectable in CSF samples. This could be attributed to liberation from erythrocytes. Our data contradict the view that tTG is a potential biochemical marker for AD. PMID- 23747047 TI - Association between PARK16 and Parkinson's disease in the Han Chinese population: a meta-analysis. AB - PARK16 was reported to alter the risk for Parkinson's disease (PD) in the Japanese population. However, its role in Han Chinese PD patients has not been well established. Herein, we investigated the effect of 4 single-nucleotide polymorphisms (SNPs) within the PARK16 locus, including rs823128, rs947211, rs823156, and rs11240572, on the risk of PD by genotyping 497 Taiwanese patients with PD and 500 age-matched control subjects. The results were then meta-analyzed with available genetic association studies in the same population. The meta analysis showed that PD patients demonstrated a lower frequency of the rs823128 G allele (11.93%) than control subjects (14.04%; odds ratio [OR] 0.83, 95% confidence interval [CI] 0.72-0.96, p = 0.010). The frequency of the rs947211 A allele (40.35%) in PD patients was lower than in control subjects (43.01%; OR 0.90, 95% CI 0.80-0.99, p = 0.047). The rs823156 G allele was less frequently seen in PD patients (17.32%) than in control subjects (21.35%; OR 0.77, 95% CI 0.69-0.86, p < 0.001). A lower frequency of the rs11240572 A allele was found in PD patients (14.01%) than in control subjects (17.66%; OR 0.76, 95% CI 0.66-0.88, p < 0.001). Our results indicate a robust protective effect of PARK16 in Han Chinese PD patients. Functional approaches are needed to elucidate the effects of these SNPs on the regulation of gene expression. PMID- 23747048 TI - Drain of the brain: low-affinity p75 neurotrophin receptor affords a molecular sink for clearance of cortical amyloid beta by the cholinergic modulator system. AB - Cholinergic basal forebrain (BF) neurons source one of the largest modulator systems of the brain, supplying acetylcholine to the entire cerebral mantle. Ample evidence suggests a causal link between the depletion of cortical acetylcholine and the selective disruption of cognitive functions in the course of aging and Alzheimer's disease (AD). A distinctive yet underappreciated feature of BF cholinergic neurons is their enrichment with the p75 neurotrophin receptor (p75(NTR)), which is also recognized as a high-affinity acceptor for the amyloid beta (Abeta) peptide. Herein, we critically overview the emerging data, which suggest the relevance of p75(NTR)-mediated uptake of Abeta followed by its degradation in lysosomes of BF cholinergic neurons for the homeostasis and clearance of this peptide from the cerebral cortex. We propose that via such a unique arrangement, cholinergic neurons afford their functional targets with an efficient molecular "drain" for Abeta. This process is suggested as the proximal cause for the greater "wear and tear" of the BF cholinergic system during aging and especially AD. PMID- 23747049 TI - Distinct roles of M1 and M3 muscarinic acetylcholine receptors controlling oscillatory and non-oscillatory [Ca2+]i increase. AB - We examined ACh-induced [Ca2+]i dynamics in pancreatic acinar cells prepared from mAChR subtype-specific knockout (KO) mice. ACh did not induce any [Ca2+]i increase in the cells isolated from M1/M3 double KO mice. In the cells from M3KO mice, ACh (0.3-3 MUM) caused a monotonic [Ca2+]i increase. However, we found characteristic oscillatory [Ca2+]i increases in cells from M1KO mice in lower concentrations of ACh (0.03-0.3 MUM). We investigated the receptor specific pattern of [Ca2+]i increase in COS-7 cells transfected with M1 or M3 receptors. ACh induced the oscillatory [Ca2+]i increase in M3 expressing cells, but not in cells expressing M1, which exhibited monotonic [Ca2+]i increases. IP3 production detected in fluorescent indicator co-transfected cells was higher in M1 than in M3 expressing cells. From the examination of four types of M1/M3 chimera receptors we found that the carboxyl-terminal region of M3 was responsible for the generation of Ca2+ oscillations. The present results suggest that the oscillatory Ca2+ increase in response to M3 stimulation is dependent upon a moderate IP3 increase, which is suitable for causing Ca(2+)-dependent IP3-induced Ca2+ release. The C-terminal domain of M3 may contribute as a regulator of the efficiency of Gq and PLC cooperation. PMID- 23747050 TI - Improving emergency department time to provider, left-without-treatment rates, and average length of stay. AB - BACKGROUND: Emergency Department (ED) overcrowding and ensuing concern about patients who leave without treatment have become a mounting national concern. In addition, the Centers for Medicaid and Medicare Services released regulatory standards for EDs requiring reporting of time from initial triage to decision to admit, as well as actual time of admission. OBJECTIVES: To implement an improved ED patient flow process. METHODS: We performed a comparative, pre- and post intervention ED redesign study evaluating three primary end points between two similar, seasonal time periods. RESULTS: Despite an 11% increase in daily patient volume in 2010, analysis of time to provider pre-ED redesign and post-ED redesign implementation revealed a mean of 126.7 min in 2009 (SD 37.03) vs. a mean of 26.3 min in 2010 (SD 1.17). The p-value was significant at <0.001. Overall ED average length of stay (ALOS) in 2009 was 5.5 h (SD 0.68) and 3.6 h (SD 1.16) in 2010, reflecting a mean reduction in ALOS of 1.9 h. The p-value was significant at <0.01. The proportion of patients who left without treatment (LWOT) also decreased. The proportion of LWOTs during the 2009 study period was 8.7% (95% confidence interval [CI] 6.14-11.26%), compared to 0.2% (95% CI 0.14-0.36%; p < 0.005) in the 2010 study period. Although the overall ED-visit Press Ganey patient-satisfaction scores improved during the 2010 study period, the results were not statistically significant (p < 0.1). CONCLUSION: Our study demonstrated that a tailored ED redesign process can dramatically decrease the time to provider, ALOS, and LWOT rates. PMID- 23747051 TI - Results of docetaxel plus oxaliplatin (DOCOX) +/- cetuximab in patients with metastatic gastric and/or gastroesophageal junction adenocarcinoma: results of a randomised Phase 2 study. AB - BACKGROUND: Patients with advanced adenocarcinoma of the gastroesophageal junction/stomach are treated by combination chemotherapy, with minimal improvements in survival. We evaluated adding cetuximab to combination chemotherapy in these patients. METHODS: The primary objective was progression free survival. Secondary objectives were response rate, time to response, duration of response and safety. Treatment Arm 1: docetaxel+oxaliplatin (DOCOX)=docetaxel 60 mg/m(2) plus oxaliplatin 130 mg/m(2) on Day 1 of each 21-day cycle. Arm 2: docetaxel+oxaliplatin+cetuximab (DOCOX+C)=DOCOX with C 400mg/m(2) first dose then 250 mg/m(2) weekly. The protocol was amended to allow collection of tissue to correlate responses with KRAS status. FINDINGS: One hundred fifty patients were enrolled (75/arm). DOCOX/DOCOX+C: gastric 44%/41%, gastroesophageal junction 51%/55%, both 5%/4%. Response rate/arm: 26.5%/38.0%. Median progression free survival: 4.7/5.1 months (95% confidence interval (CI) 3.0-5.6/4.3-5.9); 1 year survival: 39.1%/33.0%, median overall survival: 8.5/9.4 months; median duration of response: 7.3/5.6months. Grade 3-4 treatment-related adverse events (%) included neutropenia (50%/44%), febrile neutropenia (13%/19%), diarrhoea (12%/17%), fatigue (12%/17%) and leukopenia (7%/14%). Discontinuation was due to progressive disease 39/32 and adverse events 21/34. KRAS was collected on some patients 2 years into the study because of new American Society of Clinical Oncology (ASCO) findings. INTERPRETATION: Cetuximab added to DOCOX may improve response rate minimally; there appears to be no improvement in progression-free survival, overall survival or 1-year survival. Cetuximab added to DOCOX did not produce clinically significant outcomes. Toxicities were consistent with the study drugs' known safety profiles. KRAS mutation was infrequent; no conclusions can be drawn from KRAS response data. ClinicalTrial.gov Identifier: NCT00517829. PMID- 23747052 TI - Incessant slow bundle branch reentrant ventricular tachycardia in a young patient with left ventricular noncompaction. AB - A 15-year-old girl was admitted to the cardiology outpatient clinic due to mild palpitations and documented incessant slow ventricular tachycardia (VT) with left bundle branch block (LBBB) pattern. The baseline electrocardiogram revealed first degree atrioventricular block and intraventricular conduction defect. Transthoracic echocardiography showed prominent trabeculae and intertrabecular recesses suggesting left ventricular noncompaction (LVNC), which was confirmed by cardiac magnetic resonance imaging. During electrophysiological study, a sustained bundle branch reentrant VT with LBBB pattern and cycle length of 480 ms, similar to the clinical tachycardia, was easily and reproducibly inducible. As there was considerable risk of need for chronic ventricular pacing following right bundle ablation, no ablation was attempted and a cardioverter-defibrillator was implanted. To the best of our knowledge, no case reports of BBR-VT as the first manifestation of LVNC have been published. Furthermore, this is an extremely rare presentation of BBR-VT, which is usually a highly malignant arrhythmia. PMID- 23747053 TI - Echocardiographic assessment of the aortic root dilatation in adult patients after tetralogy of Fallot repair. AB - INTRODUCTION: Transthoracic echocardiography is an important tool after tetralogy of Fallot repair, of which aortic root dilatation is a recognized complication. In this study we aimed to assess its prevalence and potential predictors. METHODS: We consecutively assessed adult patients by transthoracic echocardiography after tetralogy of Fallot repair, and divided them into two groups based on the maximum internal aortic diameter at the sinuses of Valsalva in parasternal long-axis view: group 1 with aortic root dilatation (>=38 mm) and group 2 without dilatation (<38 mm). RESULTS: A total of 53 patients were included, mean age 32+/-10 years, with a mean time since surgery of 23+/-7 years. An aortopulmonary shunt had been performed prior to complete repair in 25 patients, and a transannular patch was used in 19 patients. Aortic root measurement was possible in all patients. Aortic root dilatation was identified in eight patients (15%), all male. Male gender (p=0.001), body surface area (1.93+/-0.10 vs. 1.70+/-0.20 m(2), p=0.03) and increased left ventricular end diastolic diameter (p=0.005) were predictors of aortic root dilatation. None of the surgical variables studied were predictors of aortic root dilatation. CONCLUSIONS: The prevalence of aortic root dilatation in this cohort was low and male gender was a predictor of its occurrence. The type of repair and time to surgery did not influence its occurrence. Quantification of aortic root diameter is possible by transthoracic echocardiography; we suggest indexing it to body surface area in clinical practice. PMID- 23747054 TI - Potent anti-inflammatory activity of sesquiterpene lactones from Neurolaena lobata (L.) R. Br. ex Cass., a Q'eqchi' Maya traditional medicine. AB - The widespread use of Neurolaena lobata (L.) R. Br. ex Cass. by Q'eqchi' Maya and indigenous healers throughout the Caribbean for inflammatory conditions prompted the study of the anti-inflammatory activity of this traditional medicine. The objectives of this study were to conduct a detailed ethnobotanical investigation of the uses of N. lobata by the Q'eqchi' Maya of Belize for a variety of inflammatory symptoms and to evaluate the in vitro anti-inflammatory activity of leaf extract and isolated sesquiterpene lactones. The crude 80% EtOH extract of N. lobata leaves administered at 100 MUg/mL reduced LPS-stimulated TNF-alpha production in THP-1 monocytes by 72% relative to the stimulated vehicle control. Isolated sesquiterpene lactones, neurolenins B, C+D, lobatin B and 9alpha-hydroxy 8beta-isovalerianyloxy-calyculatolide were more active (IC50=0.17-2.32 MUM) than the positive control parthenolide (IC50=4.79 MUM). The results provide a pharmacological and phytochemical basis for the traditional use of this leaf for inflammatory conditions. PMID- 23747055 TI - Disparity in European taxation of combustible waste. PMID- 23747059 TI - Involvement of nitrogen and cytokinins in photosynthetic acclimation to elevated CO2 of spring wheat. AB - Acclimation of photosynthetic capacity to elevated CO2 involves a decrease of the leaf Rubisco content. In the present study, it was hypothesized that nitrogen uptake and partitioning within the leaf and among different aboveground organs affects the down-regulation of Rubisco. Given the interdependence of nitrogen and cytokinin signals at the whole plant level, it is also proposed that cytokinins affect the nitrogen economy of plants under elevated CO2, and therefore the acclimatory responses. Spring wheat received varying levels of nitrogen and cytokinin in field chambers with ambient (370 MUmol mol-1) or elevated (700 MUmol mol-1) atmospheric CO2. Gas exchange, Rubisco, soluble protein and nitrogen contents were determined in the top three leaves in the canopy, together with total nitrogen contents per shoot. Growth in elevated CO2 induced decreases in photosynthetic capacity only when nitrogen supply was low. However, the leaf contents of Rubisco, soluble protein and total nitrogen on an area basis declined in elevated CO2 regardless of nitrogen supply. Total nitrogen in the shoot was no lower in elevated than ambient CO2, but the fraction of this nitrogen located in flag and penultimate leaves was lower in elevated CO2. Decreased Rubisco: chlorophyll ratios accompanied losses of leaf Rubisco with CO2 enrichment. Cytokinin applications increased nitrogen content in all leaves and nitrogen allocation to senescing leaves, but decreased Rubisco contents in flag leaves at anthesis and in all leaves 20 days later, together with the amount of Rubisco relative to soluble protein in all leaves at both growth stages. The results suggest that down regulation of Rubisco in leaves at elevated CO2 is linked with decreased allocation of nitrogen to the younger leaves and that cytokinins cause a fractional decrease of Rubisco and therefore do not alleviate acclimation to elevated CO2. PMID- 23747058 TI - Morphing structures and signal transduction in Mimosa pudica L. induced by localized thermal stress. AB - Leaf movements in Mimosa pudica, are in response to thermal stress, touch, and light or darkness, appear to be regulated by electrical, hydrodynamical, and chemical signal transduction. The pulvinus of the M. pudica shows elastic properties. We have found that the movements of the petiole, or pinnules, are accompanied by a change of the pulvinus morphing structures. After brief flaming of a pinna, the volume of the lower part of the pulvinus decreases and the volume of the upper part increases due to the redistribution of electrolytes between these parts of the pulvinus; as a result of these changes the petiole falls. During the relaxation of the petiole, the process goes in the opposite direction. Ion and water channel blockers, uncouplers as well as anesthetic agents diethyl ether or chloroform decrease the speed of alert wave propagation along the plant. Brief flaming of a pinna induces bidirectional propagation of electrical signal in pulvini. Transduction of electrical signals along a pulvinus induces generation of an action potential in perpendicular direction between extensor and flexor sides of a pulvinus. Inhibition of signal transduction and mechanical responses in M. pudica by volatile anesthetic agents chloroform or by blockers of voltage gated ion channels shows that the generation and propagation of electrical signals is a primary effect responsible for turgor change and propagation of an excitation. There is an electrical coupling in a pulvinus similar to the electrical synapse in the animal nerves. PMID- 23747060 TI - Overexpression of the gibberellin 2-oxidase gene from Torenia fournieri induces dwarf phenotypes in the liliaceous monocotyledon Tricyrtis sp. AB - Gibberellins (GAs) are the plant hormones that control many aspects of plant growth and development, including stem elongation. Genes encoding enzymes related to the GA biosynthetic and metabolic pathway have been isolated and characterized in many plant species. Gibberellin 2-oxidase (GA2ox) catalyzes bioactive GAs or their immediate precursors to inactive forms; therefore, playing a direct role in determining the levels of bioactive GAs. In the present study, we produced transgenic plants of the liliaceous monocotyledon Tricyrtis sp. overexpressing the GA2ox gene from the linderniaceous dicotyledon Torenia fournieri (TfGA2ox2). All six transgenic plants exhibited dwarf phenotypes, and they could be classified into two classes according to the degree of dwarfism: three plants were moderately dwarf and three were severely dwarf. All of the transgenic plants had small or no flowers, and smaller, rounder and darker green leaves. Quantitative real-time reverse transcription-polymerase chain reaction (PCR) analysis showed that the TfGA2ox2 expression level generally correlated with the degree of dwarfism. The endogenous levels of bioactive GAs, GA1 and GA4, largely decreased in transgenic plants as shown by liquid chromatography-mass spectrometry (LC-MS) analysis, and the level also correlated with the degree of dwarfism. Exogenous treatment of transgenic plants with gibberellic acid (GA3) resulted in an increased shoot length, indicating that the GA signaling pathway might normally function in transgenic plants. Thus, morphological changes in transgenic plants may result from a decrease in the endogenous levels of bioactive GAs. Finally, a possibility of molecular breeding for plant form alteration in liliaceous ornamental plants by genetically engineering the GA metabolic pathway is discussed. PMID- 23747062 TI - Characterization of PhPRP1, a histidine domain arabinogalactan protein from Petunia hybrida pistils. AB - An arabinogalactan protein, PhPRP1, was purified from Petunia hybrida pistils and shown to be orthologous to TTS-1 and TTS-2 from Nicotiana tabacum and NaTTS from Nicotiana alata. Sequence comparisons among these proteins, and CaPRP1 from Capsicum annuum, reveal a conserved histidine-rich domain and two hypervariable domains. Immunoblots show that TTS-1 and PhPRP1 are also expressed in vegetative tissues of tobacco and petunia respectively. In contrast to the molecular mass heterogeneity displayed by the pistil proteins, the different isoforms found in seedlings, roots, and leaves each has a discrete size (37, 80, 160, and 200 kDa) on SDS-PAGE gels. On the basis of their chemistry, distinctive domain architecture, and the unique pattern of expression, we have named this group of proteins HD-AGPs (histidine domain-arabinogalactan proteins). PMID- 23747061 TI - Antioxidant and phenolic acid profiles of tissue cultured and acclimatized Merwilla plumbea plantlets in relation to the applied cytokinins. AB - Merwilla plumbea (Lindl.) Speta is an important medicinal plant widely used in traditional medicine. We evaluated the effect of five cytokinins [benzyladenine (BA), 2-isopentenyladenine (2iP), meta-topolin (mT), meta-topolin riboside (mTR), and meta-methoxy-9-tetrahydropyran-2-yl-topolin (MemTTHP)] on the level of phenolic acids and antioxidant activity of M. plumbea during the tissue culture and acclimatization stages. Two cytokinins (mT and mTR) significantly improved the antioxidant activity of tissue culture plantlets while the control plantlets were better after acclimatization. Using UPLC-MS/MS, the levels of hydroxybenzoic and hydroxycinnamic acid derivatives (phenolic acids) varied significantly during tissue culture and acclimatization, depending on the cytokinin and plant part analyzed. Vanillic acid (24.9 MUg g-1) detected in underground parts of tissue culture plants supplemented with BA was the most abundant phenolic acid detected. The current findings indicate that the phytochemicals together with the bioactivity during in vitro propagation of M. plumbea is influenced by the cytokinin type used and the stage of plant material collection. PMID- 23747063 TI - How does iron deficiency disrupt the electron flow in photosystem I of lettuce leaves? AB - The changes observed photosystem I activity of lettuce plants exposed to iron deficiency were investigated. Photooxidation/reduction kinetics of P700 monitored as DeltaA820 in the presence and absence of electron transport inhibitors and acceptors demonstrated that deprivation in iron decreased the population of active photo-oxidizable P700. In the complete absence of iron, the addition of plant inhibitors (DCMU and MV) could not recover the full PSI activity owing to the abolition of a part of P700 centers. In leaves with total iron deprivation (0MUM Fe), only 15% of photo-oxidizable P700 remained. In addition, iron deficiency appeared to affect the pool size of NADP(+) as shown by the decline in the magnitude of the first phase of the photooxidation kinetics of P700 by FR light. Concomitantly, chlorophyll content gradually declined with the iron concentration added to culture medium. In addition, pronounced changes were found in chlorophyll fluorescence spectra. Also, the global fluorescence intensity was affected. The above changes led to an increased rate of cyclic electron transport around PSI mainly supported by stromal reductants. PMID- 23747064 TI - Validation of an adapted version of the nutrition environment measurement tool for stores (NEMS-S) in an urban area of Brazil. AB - OBJECTIVE: To validate an adapted instrument that assesses the nutritional environment of food stores in Brazilian urban areas. METHODS: The instrument measured aspects of food environment such as availability, prices, and quality. The Harvard Healthy Eating Pyramid and the degree of processing were used to define healthy foods. The sample included 44 food stores in 3 census tracts in the city of Santos. Inter-rater reliability and stability coefficient were obtained with measurements performed by different individuals at different times. Internal consistency and construct validity were assessed by Cronbach alpha and the known-groups comparison method, respectively. RESULTS: Inter-rater reliability was high. The mean intra-class correlation coefficient was 0.98 and the mean kappa was 0.77. Cronbach alpha values ranged from .68 to .93. CONCLUSIONS AND IMPLICATIONS: The instrument can be useful in the development of interventions to promote healthy eating through actions focused on healthy food availability in Brazilian communities. PMID- 23747065 TI - Prospective, randomized comparison of a prototype endoscope with deflecting working channels versus a conventional double-channel endoscope for rectal endoscopic submucosal dissection in an established experimental simulation model (with video). AB - BACKGROUND: A prototype endoscope was designed to improve visualization and dissection of tissue with the use of 2 working channels with different deflections. OBJECTIVE: To evaluate the efficacy and operability of a prototype endoscope in comparison with a conventional double-channel endoscope for rectal endoscopic submucosal dissection (ESD). DESIGN: Randomized, prospective, controlled, ex vivo study. SETTING: Academic medical center. METHODS: A total of 80 standardized artificial lesions measuring 3 * 3 cm were created approximately 5 cm from the anal verge in fresh ex vivo porcine colorectal specimens. Two endoscopists each completed 20 cases with the prototype endoscope and 20 cases with the conventional endoscope. MAIN OUTCOME MEASUREMENTS: An independent observer recorded procedure time, specimen size, en bloc resection, and perforation rate. RESULTS: For the ESD novice, the mean submucosal dissection time (10.5 +/- 3.8 vs 14.9 +/- 7.3 minutes; P = .024) and total procedure time (18.1 +/- 5.2 vs 23.6 +/- 8.2 minutes; P = .015) were significantly shorter in the prototype group in comparison with the conventional group. For the ESD expert, there was no significant difference between the mean circumferential resection, submucosal dissection, and total procedure time (prototype group 14.2 +/- 6.0 minutes, conventional group 14.2 +/- 8.8 minutes; P = .992). The overall perforation and en bloc resection rates were not significantly different between groups. LIMITATIONS: Ex vivo study. CONCLUSION: In this ex vivo prospective comparison study, there was a technical advantage for the ESD novice with the prototype endoscope that resulted in a shorter procedure time, which was not observed for cases performed by the ESD expert. PMID- 23747066 TI - Combined use of OCT and IVUS in spontaneous coronary artery dissection. PMID- 23747067 TI - Incremental diagnostic value of la strain with leg lifts in heart failure with preserved ejection fraction. AB - OBJECTIVES: The purposes of this study were to examine left atrial (LA) functional reserve in patients with heart failure (HF) with preserved ejection fraction (HFpEF) and to determine whether LA strain has an incremental diagnostic value over clinical and conventional echocardiographic parameters. BACKGROUND: Patients with HFpEF have multiple cardiovascular reserve abnormalities. Although the LA is dysfunctional in HFpEF, the diagnostic value of LA strain remains unknown. METHODS: The LA at rest and during passive leg lifts was echocardiographically assessed in 40 patients with HFpEF and in 46 patients with hypertension without HF (HT controls). Global peak atrial longitudinal strain during ventricular systole (global LAS) and booster strain during atrial contraction (global LAB) were assessed using speckle tracking. RESULTS: Patients with HFpEF had an enlarged LA and reduced LA emptying fraction compared with HT controls at rest, while LA stroke volume (SV) was similar between the groups. During leg lifts, increases in LA reservoir and contractile function (i.e., global LAS and LAB) were blunted in HFpEF patients compared with HT controls, resulting in impaired LASV responses. Global LAS and LAB during leg lifts accurately differentiated HFpEF from HT controls (areas under the curve: 0.95 and 0.92, respectively). Resting global LAS had a significant incremental diagnostic value over clinical (age and sex) and conventional echocardiographic parameters (E/E' ratio, left ventricular mass index, and maximum LA volume index) (global chi-square: 49.6 vs. 30.8; p < 0.0001). The diagnostic value was further improved by adding global LAS during leg lifts (global chi-square: 72.2 vs. 49.6; p < 0.0001). CONCLUSIONS: An enlarged LA compensates for LA dysfunction and maintains LASV at rest in patients with HFpEF. However, depressed LA reserve affects LA performance during leg lifts. Evaluation of LA function, including LA strain using leg lifts, might provide incremental diagnostic value for HFpEF. PMID- 23747068 TI - Response to: Video games: increasing activity in sedentary individuals. PMID- 23747069 TI - The interaction between pseudopods and extracellular signalling during chemotaxis and directed migration. AB - Eukaryotic chemotaxis is extremely complex. Cells can sense a wide range of stimuli, and many intracellular pathways are simultaneously involved. Recent genetic analyses of the steps between receptors and cytoskeleton, and how the cell controls actin and pseudopod behaviour, have yielded exciting new data but still no coherent understanding of chemotaxis. However, concentrating on pseudopods themselves and the physical processes that regulate them, rather than the internal signalling pathways, can simplify the data and help resolve the underlying mechanism. Direct action of electric fields and physical forces on cell migration suggest that mechanical forces and force-generating proteins like actin and myosin are centrally important in steering cells during chemotaxis. PMID- 23747071 TI - Do we need therapeutic trials comparing biotherapies to guide treatment selection in patients with rheumatoid arthritis? PMID- 23747070 TI - Assembling a primary cilium. AB - Cilia are evolutionarily conserved, membrane-bound, microtubular projections emanating from the cell surface. They are assembled on virtually all cell types in the human body, with very few exceptions, and several recent reviews have covered the topic in great detail. The cilium is assembled from mature (mother) centrioles or basal bodies, which serve to nucleate growth of axonemes that give rise to two structurally distinct variants, motile and nonmotile cilia. Whereas motile cilia are typically found in large bundles and beat synchronously to generate fluid flow, primary cilia (with the exception of those found at the embryonic node) are generally immotile and are found as solitary organelles. Remarkably, until recently, the primary cilium was considered a vestigial organelle without apparent biological function. However, research over the past decade has established that the primary cilium is capable of transducing essential signaling information from the extracellular milieu. Defects in the cilium, and the structure from which it arises, the basal body, have been shown to cause a spectrum of diseases, ranging from developmental defects to obesity, diabetes, and cancer. Many of these diseases, or ciliopathies, are manifested as genetic syndromes, such as Joubert syndrome, Bardet-Biedel (BBS), Meckel-Gruber (MKS), and Nephronophthisis (NPHP), illustrating the importance of understanding cilium structure and function and the mechanisms required for its assembly. This review focuses primarily on recent advances in our understanding of the regulatory controls governing the assembly and maintenance of the primary cilium. PMID- 23747072 TI - [Congenital varicella syndrome and neonatal herpes zoster]. PMID- 23747073 TI - Swallow syncope after laparoscopic vertical sleeve gastrectomy. PMID- 23747074 TI - Self-assessment of attractiveness of persons with body decoration. AB - Tattoos and body piercing are forms of body decoration that have been known for ages. The use of such ornamentation is becoming more and more common. Researchers attempt to explain the meaning of this phenomenon within the discipline of behavioural ecology, attributing a sexual selection aspect to body decoration, and thus interpreting it in an evolutionary sense. The hypothesis that superior biological quality of individuals is indicated by body modification is becoming more and more popular. In the present study, this hypothesis is tested on the basis of physical attractiveness as an indicator of genotype quality. The total of 64 males and 52 females with tattoos and body piercings were subjected to tests consisting of the self-assessment of the attractiveness of their bodies. The control group comprised 86 subjects (38 males and 48 females) without body decoration. The results confirm that both women and men with body decoration assess the attractiveness of different parts of their bodies higher (regardless whether the decoration is located there or not) than people without tattoos and body piercing. Thus, the hypothesis has been confirmed that body decoration is a signal of superior biological quality of individuals. PMID- 23747075 TI - Role of the hospitalist in antimicrobial stewardship: a review of work completed and description of a multisite collaborative. AB - BACKGROUND: Historically, antimicrobial stewardship programs have been led by infectious-disease physicians and pharmacists. With the growing presence of hospitalists in health and hospital systems, combined with their focus on quality improvement and patient safety, this emerging medical specialty has the potential to fill essential roles in antimicrobial stewardship programs. OBJECTIVE: The goal of this article was to present the reasons hospitalists are ideally positioned to fill antimicrobial-stewardship roles, a narrative review of previously reported hospitalist-led antibiotic-stewardship projects, and a description of an ongoing multisite collaborative by the Institute for Healthcare Improvement (IHI) and the Centers for Disease Control and Prevention (CDC). METHODS: A review of the published literature was performed, including an extensive review of the abstracts submitted to the Society of Hospital Medicine annual meetings. RESULTS: A number of examples of hospitalists developing and leading antimicrobial-stewardship programs are described. The details of a current multisite IHI/CDC hospitalist-focused initiative are discussed in detail. CONCLUSIONS: Hospitalists are actively involved with, and even lead, a variety of antimicrobial-stewardship programs in several different hospital systems. A large, multisite collaborative focused on hospitalist-led antimicrobial stewardship is currently in progress. PMID- 23747076 TI - Psychometric performance of the incontinence quality-of-life questionnaire among patients with overactive bladder and urinary incontinence. AB - BACKGROUND: The Incontinence Quality-of-Life Instrument (I-QOL) is a condition specific questionnaire that assesses the health-related QOL impact of urinary incontinence, but it has not been validated in patients with overactive bladder (OAB) who have been inadequately managed by anticholinergic therapy. OBJECTIVE: This study assessed the reliability and validity of the I-QOL among patients with OAB with urinary incontinence. METHODS: I-QOL scores were analyzed from a Phase II study that compared the efficacy and tolerability of onabotulinumtoxinA and placebo. Conceptual framework was confirmed via confirmatory factor analysis. Reliability was assessed using Cronbach's alpha and intraclass correlation coefficients (ICCs). Validity was tested by comparing I-QOL scores to tertiles of urinary symptom severity. Effect size statistics estimated the ability of the I QOL to detect change. Responder analysis with cumulative distribution function was plotted to show differentiation between treatment groups with respect to I QOL scores. RESULTS: Comparative fit indices ranged from 0.87 to 0.99 on the confirmatory factor analysis. I-QOL scores showed high internal consistency (0.86 <= Cronbach's alpha <= 0.93), good test-retest reliability (0.68 <= ICC <= 0.84), and good differentiation between tertiles of increasing urinary symptom severity (all, P <= 0.002). Significant differences in I-QOL change scores were noted between responders and nonresponders across all responder definitions (all, P < 0.001) and corresponded with large effect sizes among responders to treatment (1.34 <= effect size <= 2.82). CONCLUSION: This study demonstrated that OAB with urinary incontinence affects health-related QOL and that the I-QOL reliably and validly measures these impacts. PMID- 23747077 TI - Promotion of a healthy public living environment: participatory design of public toilets with visually impaired persons. AB - OBJECTIVES: The principal objective of a healthy living environment is to improve the quality of everyday life. Visually impaired persons (VIPs) encounter many difficulties in everyday life through a series of barriers, particularly in relation to public toilets. This study aimed to explore the concerns of VIPs in accessing public toilets, and identify methods for improvement. Considerations about user participation are also discussed. STUDY DESIGN: Adopting a case study approach, VIPs were invited to participate in the research process. METHODS: In addition to in-depth interviews and field visits, models and a simulated full scale environment were produced to facilitate the VIPs to voice their opinions. RESULTS: The key findings indicate that the design of public toilets for promoting public health should be considered and tackled from a three-level framework: plain, line and point. Governments, professionals and the public need to consider the quality of public toilets in terms of policy, implementation and management. CONCLUSIONS: VIPs have the right to access public toilets. Governments and professionals should respect the particular needs and concerns of VIPs. A three-level framework (plain, line and point) is required to consider the needs of VIPs in accessing public toilets, and user participation is a good way to reveal the actual needs of VIPs. PMID- 23747078 TI - Sequential signs of palpitation, bloody multiple cavity membrane effusion, and myocardial infarction: a case report of multiple myeloma and a literature review. PMID- 23747080 TI - Successful treatment of Bing-Neel syndrome using intrathecal chemotherapy and systemic combination chemotherapy followed by BEAM auto-transplant: a case report and review of literature. PMID- 23747079 TI - Sequential occurrence of a splenic marginal zone lymphoma, extranodal MALT lymphoma, and Hodgkin lymphoma. PMID- 23747081 TI - Clinical significance of serum-soluble interleukin-2 receptor in patients with follicular lymphoma. AB - BACKGROUND: Although sIL-2R level has a prognostic value in patients with diffuse large B-cell lymphoma, its clinical role in patients with follicular lymphoma has not been determined. PATIENTS AND METHODS: We reviewed data on 70 patients diagnosed with follicular lymphoma. RESULTS: Ann Arbor stage was I, II, III, and IV in 6, 9, 17, and 38 patients, respectively, and grade classification according to the World Health Organization criteria was 1, 2, 3A, 3B, and not available in 28, 15, 11, 4, and 12 patients, respectively. sIL-2R at diagnosis was significantly correlated with Ann Arbor stages (P < .001), number of nodal lesions (>= 5 or not) (P = .0050), and Follicular Lymphoma International Prognosis Index risk classification (P = .0015). Furthermore, sIL-2R regressed significantly in patients who achieved complete remission, uncertain complete remission, or partial remission (P < .001), and increased when regrowth of lymphoma was shown (P < .001). Finally, a high level of sIL-2R at diagnosis was correlated with shorter progression-free survival (P = .018) and time to next treatment (P < .001). CONCLUSION: Serum-soluble interleukin-2 receptor is correlated with tumor burden at diagnosis and during the clinical course of therapies in patients with follicular lymphoma, and our data support its usefulness to function as a surrogate marker of tumor progression. PMID- 23747082 TI - Geriatric assessment in older patients with acute myeloid leukemia: a retrospective study of associated treatment and outcomes. AB - We explored whether geriatric assessment variables predicted mortality in addition to known prognostic factors in 101 patients aged >= 65 with newly diagnosed AML. Baseline comorbidity score (HR=1.92; 95%CI 1.18-3.11), difficulty with strenuous activity (HR=2.18; 95%CI 1.19-4.00), and pain (HR=2.17; 95%CI 1.19 3.97) were independent prognostic factors for greater risk of death in a multivariable model that included cytogenetic risk group. They remained independent predictors in the subset of patients with baseline ECOG PS 0-1. Our results support the use of geriatric assessment to better predict prognosis in older patients with AML, even among those with excellent functional status. PMID- 23747083 TI - A brain signature for acute pain. AB - Wager and colleagues developed a functional MRI-based spatial and magnitude pattern for perception of acute pain, which seems to generalize across many task conditions and subjects. This is a strong demonstration of the existence of a pain signature and raises important questions regarding what pain and perception are. PMID- 23747084 TI - Right colectomy: value of the totally laparoscopic approach. AB - The role of laparoscopy for right colectomy remains controversial - largely because of a lack of standardization of the operative procedure, including a diversity of techniques including laparoscopy-assisted cases with extra-corporeal anastomosis and totally laparoscopic procedures with intra-corporeal anastomosis. METHODS: The charts of all patients who underwent right colectomy by a totally laparoscopic approach in our service since 2004 were reviewed and pre-, intra-, and postoperative data were collected. RESULTS: Eighty-two patients underwent totally laparoscopic right colectomy; of these, 32 had a BMI greater than 20 kg/m2 (39%). The mean operative duration was 113 minutes. In most cases, the operative specimen was extracted through a supra-pubic Pfannenstiel incision measuring 4-6 cm in length. Three cases were converted to a laparoscopy-assisted technique (in order to control the ileo-cecal vascular pedicle because of extensive nodal invasion in two cases, and to evaluate a hepatic flexure polyp in the third case). Overall morbidity was 29.3% and parietal morbidity was only 9.8%; there was no difference in morbidity between obese patients (BMI>30 kg/m2) and non-obese patients (BMI<30 kg/m2). The mean duration of hospitalization was 9 days and two patients developed ventral hernia in the extraction incision in long term follow-up. CONCLUSION: These satisfactory results show that the totally laparoscopic approach to right colectomy is technically feasible and safe, even in obese patients. In addition, the very low rate of parietal complications is an argument in favor of this approach. PMID- 23747085 TI - Attentional modulation: target selection, active search and cognitive processing. PMID- 23747086 TI - Treatment with beta-blockers is associated with lower levels of Lp-PLA2 and suPAR in carotid plaques. AB - OBJECTIVES: To determine whether a long-term treatment with beta-blockers influences the inflammatory activity in carotid artery disease by reducing the carotid plaque levels of lipoprotein-associated phospholipase A2 (Lp-PLA2), its enzymatic products lysophosphatidylcholine (lysoPCs), and of soluble urokinase plasminogen activator receptor (suPAR). MATERIALS AND METHODS: One hundred and thirty-four patients with significant symptomatic or asymptomatic carotid stenosis undergoing surgery were prospectively included and divided into two groups (Group A or B) based on the absence or presence of an on-going long-term oral treatment with beta-blockers. The harvested carotid plaques were analyzed for the levels of lysoPCs using mass spectrometry and Lp-PLA2 and suPAR by Enzyme linked immunosorbent assay (ELISA). RESULTS: Plaques of patients on long-term treatment with beta-blockers revealed lower levels of Lp-PLA2 (Group A 0.752 +/- 0.393 ug/g vs. Group B 0.644 +/- 0.445 ug/g, P=.049) as well as suPAR (Group A 0.044 +/- 0.024 MUg/g vs. Group B 0.036 +/- 0.025 MUg/g, P=.028). Levels of Lp PLA2 and suPAR were positively correlated (r=.637, P<.0001). Lp-PLA2 and suPAR levels were also correlated (P<.0001) with the three lysoPC species tested (lysoPC 16:0, lysoPC 18:0. lysoPC 18:1). All the above-mentioned findings were confirmed after correction for age, gender, hypertension, coronary artery disease, and statin usage. CONCLUSIONS: The reduced levels of Lp-PLA2 and suPAR in human carotid plaques of subjects on long-term treatment with beta-blockers suggest their possible protective role in plaque inflammation. Our findings support an even more selective Lp-PLA2 and suPAR inhibition as a possible strategy for the prevention of cardiovascular disease. PMID- 23747087 TI - Information needs of post-menopausal women with hormone receptor positive early stage breast cancer considering adjuvant endocrine therapy. AB - OBJECTIVE: To identify questions that post-menopausal women with receptor positive early-stage breast cancer want answered before their adjuvant-endocrine therapy decision is made. METHODS: We surveyed patients eligible for adjuvant endocrine therapy in the previous 3-18 months. Participants rated the importance of getting each of 95 questions answered before the decision is made (options: essential/desired/not important or no opinion/avoid). For each question rated "essential"/"desired", the participant also identified the purpose(s) for the answer: to help her understand, decide, plan, or other reason(s). RESULTS: The response rate was 55% (188/343). Participants rated a mean of 57 (range: 1-95) questions "essential", 80 (range: 1-95) "essential" or "desired", and 2 (range: 0 27) "avoid". Every question was "essential" to >=31% of participants, and "essential"/"desired" to >=63%. All but eleven questions were rated as "avoid" by >=1 participant. The most frequent purposes for "essential" questions were to: understand their situations (mean 45, range: 0-95), decide (mean 18, range: 0 94), and plan (mean 13, range: 0-95). CONCLUSION: Many patients want a lot of information before this decision is made but there is wide variation within the group in both the number and in which questions they want answered. PRACTICE IMPLICATIONS: Patient education in this setting needs to be tailored to the needs of the individual patient. PMID- 23747088 TI - Critical caring. PMID- 23747089 TI - Evaluation of a treatment and teaching refresher programme for the optimization of intensified insulin therapy in type 1 diabetes. AB - OBJECTIVE: Evaluation of an ambulatory diabetes teaching and treatment refresher programme (DTTP) for the optimization of intensified insulin therapy in patients with type 1 diabetes (refresher course). METHODS: 85 outpatients took part in this prospective multicentre trial. Metabolic and psychosocial data were analyzed at baseline (V1), 6 weeks (V2) and 12 months after DTTP (V3). RESULTS: In patients with baseline HbA1c>7% (88%), HbA1c decreased by 0.36% (p=0.004). The percentage of patients with HbA1c<=7% increased from 21.3 to 34.9% and with HbA1c above 10% decreased from 6.6 to 1.6% at V3. The incidence of hypoglycaemia decreased significantly: non severe hypoglycaemia from 3.31 to 1.39 episodes/pat/week (p=0.001) and severe hypoglycaemia from 0.16 to 0.03 episodes/pat/year (p=0.02). The treatment satisfaction increased by +10 of maximal +/-18 points. The negative influence of diabetes on quality of life decreased from -1.93 to -1.69 points (p=0.031). CONCLUSION: In a group of patients with moderately controlled diabetes type 1 who were already treated with intensified insulin therapy, metabolic control, treatment satisfaction and quality of life were improved after participation in an ambulatory DTTP without increasing insulin dosage, number of injections or insulin species. PRACTICE IMPLICATIONS: This DTTP is effective for the optimization of intensified insulin therapy. PMID- 23747090 TI - The influence of medical students' and doctors' attachment style and emotional intelligence on their patient-provider communication. AB - OBJECTIVE: Attachment style and emotional intelligence (EI) have been highlighted as potential factors influencing the variation in medical students' and doctors' patient-provider communication (PPC), particularly in relation to emotive issues. The objective of this review is to systematically review and synthesise the published literature relating to the influence of medical students' and/or doctors' attachment style and EI on their PPC. METHODS: Electronic and hand searches were conducted to identify all published literature relating to the aim of the review. Data were narratively synthesised. RESULTS: 1597 studies were identified. 14 were included in the review, of which 5 assessed the influence of attachment style and 9 assessed the influence of EI on PPC. No studies assessed the impact of both attachment style and EI on PPC. CONCLUSION: Whilst tentative links were found between both PPC and both attachment style and EI, heterogeneity in study design, predictor variables and outcome measures made drawing conclusions difficult. PRACTICE IMPLICATIONS: More research is needed to assess the influence of both attachment style and EI on PPC. PMID- 23747091 TI - Attachment and biofilm formation by foodborne bacteria in meat processing environments: causes, implications, role of bacterial interactions and control by alternative novel methods. AB - Attachment of potential spoilage and pathogenic bacteria to food contact surfaces and the subsequent biofilm formation represent serious challenges to the meat industry, since these may lead to cross-contamination of the products, resulting in lowered-shelf life and transmission of diseases. In meat processing environments, microorganisms are sometimes associated to surfaces in complex multispecies communities, while bacterial interactions have been shown to play a key role in cell attachment and detachment from biofilms, as well as in the resistance of biofilm community members against antimicrobial treatments. Disinfection of food contact surfaces in such environments is a challenging task, aggravated by the great antimicrobial resistance of biofilm associated bacteria. In recent years, several alternative novel methods, such as essential oils and bacteriophages, have been successfully tested as an alternative means for the disinfection of microbial-contaminated food contact surfaces. In this review, all these aspects of biofilm formation in meat processing environments are discussed from a microbial meat-quality and safety perspective. PMID- 23747092 TI - The development of a new methodology for knowledge sharing in the interface between university and society--an example from the meat sector. AB - Design science research was used for the generation, use and evaluation of a model for knowledge sharing in the user community through open educational resources (OER). The focus of interest was on the development process of a model for knowledge sharing that emphasizes the characteristics and the needs of the user community; the empowerment and democratic issues of openness; the collaboration between institutions and dialog with society; and the consideration of quality and sustainability issues. Initially, the community needs were analyzed through surveys and workshops, and the findings used, through negotiations, to formulate the development process. An open-training platform served as an infrastructure and included a repository with OER, a wiki and a discussion forum. The purpose of this article is an attempt to provide universities with a plan and template for integrated knowledge sharing that responds to societal needs. Usability and usefulness has not been evaluated. PMID- 23747093 TI - Eculizumab in renal transplantation. AB - Antibody-mediated rejection, be it acute, subacute or chronic, is currently recognized as the major cause of graft loss in kidney transplant recipients. Anti HLA donor-specific antibodies are deleterious to the graft fate whether they pre exist to the transplantation or appear in the course of transplantation. The role of complement is therefore prominent in most instances. As well, the role of complement activation is crucial in the recurrence of atypical hemolytic uremic syndrome post-transplantation (aHUS) as well as following ischemia-reperfusion injury leading to delayed graft function. Eculizumab, a fully humanized monoclonal antibody directed against the C5 component of the complement cascade is efficient in chronically and safely blocking complement activation for example in paroxysmal nocturnal hemoglobinuria. In the setting of kidney transplantation, there is convincing but still limited evidence that eculizumab is efficient in preventing both acute and chronic antibody-mediated rejection in highly sensitized recipients requiring desensitization before getting a living donor kidney transplant. Studies are currently ongoing to determine its efficacy and safety in ABO incompatible transplantation, in the prevention of acute and chronic rejection either with a living or a deceased donor kidney as well as in the prevention of delayed graft function. Similar to its efficacy in aHUS on native kidneys, eculizumab prevents or treats recurrence after kidney transplantation. There is still a lot of research to be performed in order to determine precisely the exact indications and the length of treatment with this very active but also very expensive drug that will undoubtedly revolutionize the current management of patients with donor specific antibodies (DSAs) and at risk of HUS recurrence. PMID- 23747094 TI - Characterisation of the FAD2 gene family from Hiptage benghalensis: a ricinoleic acid accumulating plant. AB - We have characterised the FAD2 gene family from Hiptage benghalensis, a tropical plant that accumulates high levels of ricinoleic acid in its seeds. Functional characterisation of six FAD2 gene family members showed that two of them were capable of functioning as Delta12-hydroxylases while the other FAD2 members were confirmed to be Delta12-desaturases. The Delta12-hydroxylation function of these two genes was confirmed in yeast cells, using C16:1(Delta9) and C18:1(Delta9) monounsaturated fatty acids as substrates. These Delta12-hydroxylases, like the other Delta12-hydroxylases previously cloned from plants Ricinus communis (castor), Physaria fendleri and fungus Claviceps purpurea, also showed some Delta12-desaturase activity. The hydroxylation activity of the two Hiptage hydroxylases was further confirmed by their expression in the Arabidopsis fad2/fae1 double mutant where they were able to produce equivalent or higher levels hydroxylated fatty acids in the seed oil when compared with the other known hydroxylases. PMID- 23747095 TI - Characterization of two candidate flavone 8-O-methyltransferases suggests the existence of two potential routes to nevadensin in sweet basil. AB - Regioselective 6-,7-,8-,3'-, and 4'-O-methylations underlie the structural diversity of lipophilic flavones produced in the trichomes of sweet basil (Ocimum basilicum L.). The positions 6, 7, and 4' are methylated by a recently described set of cation-independent enzymes. The roles of cation-dependent O methyltransferases still require elucidation. Here, the basil trichome EST database was used to identify a Mg(2+)-dependent O-methyltransferase that was likely to accept flavonoids as substrates. The recombinant protein was found to be active with a wide range of o-diphenols, and methylated the 8-OH moiety of the flavone backbone with higher catalytic efficiency than the 3'-OH group of candidate substrates. To further investigate flavone 8-O-methylation, the activity of a putative cation-independent flavonoid 8-O-methyltransferase from the same EST collection was assessed with available substrate analogs. Notably, it was strongly inhibited by gardenin B, one of its expected products. The catalytic capacities of the two studied proteins suggest that two alternative routes to nevadensin, a major flavone in some basil cultivars, might exist. Correlating the expression of the underlying genes with the accumulation of 8 substituted flavones in four basil lines did not clarify which is the major operating pathway in vivo, yet the combined data suggested that the biochemical properties of flavone 7-O-demethylase could play a key role in determining the reaction order. PMID- 23747096 TI - Fomentarols A-D, sterols from the polypore macrofungus Fomes fomentarius. AB - Four (1-4) hitherto unknown and seven (5-11) known ergostane-type sterols were isolated from the EtOH extract of the dried fruiting bodies of the polypore macrofungus Fomes fomentarius. On the basis of spectroscopic analysis, the structures of polyhydroxylated sterols 1-4 were elucidated to be (22E,24R) 3beta,5alpha,6beta,14alpha-tetrahydroxyergosta-7,9(11),22-triene (fomentarol A, 1), (22E,24R)-3beta,5beta,6alpha,7alpha-tetrahydroxy-8alpha,9alpha-dihydroergosta 14,22-diene (fomentarol B, 2), (22E,24R)-3beta,5alpha-dihydroxy-6beta ethoxyergosta-7,22-diene (fomentarol C, 3), and (22E,24S)-3beta,25-dihydroxy 15alpha-O-beta-D-glucopyranosylergosta-7,22-dien-6-one (fomentarol D, 4), respectively. Rings A/B and B/C are in turn cis-fused in compound 2, which is uncommon in natural ergostane-type sterols. The potential biogenetic relationship of 2 and other ergostane-type sterols isolated from F. fomentarius was briefly discussed. Moderate cytotoxic effects of the isolated sterols against a small panel of human cancer cell lines were also established. PMID- 23747097 TI - Classification of MRSA cases detected at the time of hospital admission: does the 'look-back' period matter? AB - Limited resources for infection control necessitate efficient local surveillance. Cases of meticillin-resistant Staphylococcus aureus from the authors' hospital surveillance system were examined to determine if attribution of cases as healthcare-associated or non-healthcare-associated differed when using a 12-month vs a four-week 'look-back' period. Two additional cases were reclassified from non-healthcare-associated to healthcare-associated, representing a 2% reclassification rate between four-week and 12-month criteria (P = 0.857). Infection control programmes may save time and resources by minimizing retrospective review of records without compromising data quality due to misclassification. PMID- 23747098 TI - Post-discharge surgical site surveillance - where to from here? PMID- 23747099 TI - The antibacterial activity and stability of acetic acid. AB - Acetic acid has been shown to have good antibacterial activity against micro organisms such as Pseudomonas aeruginosa. This study examined the activity against a range of bacterial pathogens and also assessed any reduction in antibacterial activity due to evaporation or inactivation by organic material in dressings. Acetic acid was active at dilutions as low as 0.166% and the activity was not reduced by evaporation nor by inactivation by cotton swabs. Burn injuries are a major problem in countries with limited resources. Acetic acid is an ideal candidate for use in patients who are treated in those parts of the world. PMID- 23747100 TI - Impact of chlorhexidine washcloths on healthcare-associated infections: do the recent trials add to the evidence? PMID- 23747101 TI - [Compression of the superficial branch of the radial nerve by a synovial ganglion of the elbow (about one case and literature review)]. AB - Compression of the radial nerve at the elbow is quite rare; entrapment of its superficial branch is exceptional. Extrinsic compression is the most frequent etiology. Magnetic resonance imaging plays a major role in the diagnosis, and early surgical excision or echoguided drainage - in case of synovial ganglion - allows a total recovery. The authors report the case of a compression of the superficial branch of radial nerve by an elbow synovial cyst treated by surgical resection. PMID- 23747102 TI - Vaccination with LiESP/QA-21 (CaniLeish(r)) reduces the intensity of infection in Phlebotomus perniciosus fed on Leishmania infantum infected dogs--a preliminary xenodiagnosis study. AB - Ten Beagle dogs at different stages of Leishmania infantum infection, among which 6 had received a full course of LiESP/QA-21 (CaniLeish((r)); Virbac) vaccination, were exposed to the bites of reared Phlebotomus perniciosus to assesses their infectiousness potential. This was found to be negligible/nil in 2 seronegative dogs with subpatent infection. Among the 8 dogs with active infection (=positive serology, bone-marrow qualitative PCR and lymph node culture), 2/5 vaccinated (40.0%) and 2/3 nonvaccinated dogs (66.7%) were infectious to the sand flies (p=0.5). However significantly fewer of the sand flies which fed on the vaccinated dogs were infected when compared to those which fed on the control dogs (10/82 compared to 30/49) (chi-squared test, p<0.0001; mixed binomial model with the dog identity included as a random effect, p=0.03). Furthermore, there was a significant difference in the proportion of sand flies with >500 parasites in their gut (i.e. a higher risk for subsequent transmission): 3.7% for vaccinated dogs compared with 28.6% for nonvaccinated dogs (Fisher's exact test, p<0.0001; binomial mixed model, p=0.006). Although preliminary, these results suggest value in further investigations on L. infantum transmissibility parameters in LiESP/QA-21 vaccinated dogs. PMID- 23747103 TI - Discrimination between ovine Babesia and Theileria species in China based on the ribosomal protein S8 (RPS8) gene. AB - Ovine babesiosis and theileriosis are important hemoprotozoal diseases of sheep and goats in tropical and subtropical regions that lead to economic losses in these animals. PCR-restriction fragment length polymorphism (PCR-RFLP) is a reliable molecular diagnostic tool for discriminating Theileria or Babesia species in the same host. In this study, the DNA sequences of a ribosomal protein S8 (RPS8) gene from four species of piroplasms in China were used to develop a species-specific PCR-RFLP diagnostic tool. The sensitivity of the PCR assays was 0.1 pg DNA for B. motasi and 1 pg DNA for T. uilenbergi and 10 pg DNA for Babesia sp. Xinjiang-2005 and T. luwenshuni. The clear size difference of the PCR products allowed for a direct discrimination for B. motasi, Babesia sp. Xinjiang 2005 and ovine Theileria species (T. uilenbergi and T. luwenshuni), except that the mixed infection between T. uilenbergi and T. luwenshuni may be difficult to distinguish, simply after the electrophoretic separation of the amplification products. Further T. uilenbergi and T. luwenshuni diagnoses were made by digesting the PCR product with SacI. The established method could be applicable for the survey of parasite dynamics, and epidemiological studies as well as prevention and control of the disease. PMID- 23747104 TI - Encephalitozoon cuniculi, Toxoplasma gondii and Neospora caninum infection in invasive Eastern Cottontail Rabbits Sylvilagus floridanus in Northwestern Italy. AB - Sylvilagus floridanus is a lagomorph introduced for hunting purposes from North America to Europe where, in certain areas like Northern Italy, its population reached high densities. Brain, kidney and skeletal muscle of 144 Eastern Cottontail Rabbits S. floridanus were examined by PCR for Encephalitozoon cuniculi, Toxoplasma gondii and Neospora caninum. DNA of E. cuniculi was found with a prevalence of 9.72% (CI 95% 0.058-0.156). T. gondii and N. caninum DNA was detected in 2.08% (CI 95% 0.0071-0.0595) and 2.78% (CI 95% 0.0109-0.0692) of the samples examined, respectively. This is the first report of E. cuniculi infection in a lagomorph species other than in its natural host Oryctolagus cuniculus, and this is also the first time N. caninum is found to naturally infect S. floridanus. E. cuniculi, T. gondii and N. caninum infect S. floridanus at low but relevant prevalences, considered the important role that these pathogens could play in both animal and human health. PMID- 23747105 TI - Recombinant expression of trypanosome surface glycoproteins in Pichia pastoris for the diagnosis of Trypanosoma evansi infection. AB - Serodiagnosis of surra, which causes vast economic losses in livestock, is still based on native antigens purified from bloodstream form Trypanosoma (T.) evansi grown in rodents. To avoid the use of laboratory rodents in antigen preparation we expressed fragments of the invariant surface glycoprotein (ISG) 75, cloned from T. brucei gambiense cDNA, and the variant surface glycoprotein (VSG) RoTat 1.2, cloned from T. evansi gDNA, recombinantly in Pichia (P.) pastoris. The M5 strain of this yeast has an engineered N-glycosylation pathway resulting in homogenous Man5GlcNAc2 N-glycosylation which resembles the predominant Man9 5GlcNAc2 oligomannose structures in T. brucei. The secreted recombinant antigens were affinity purified with yields of up to 10mg and 20mg per liter cell culture of rISG 7529-465-E and rRoTat 1.223-385-H respectively. In ELISA, both recombinant proteins discriminated between pre-immune and immune serum samples of 25 goats experimentally infected with T. evansi. The diagnostic potential of rRoTat 1.223-385-H but not of rISG 7529-465-E was confirmed with sera of naturally infected and control dromedary camels. The results suggest that rRoTat 1.223-385-H expressed in P. pastoris requires further evaluation before it could replace native RoTat 1.2 VSG for serodiagnosis of surra, thus eliminating the use of laboratory animals for antigen production. PMID- 23747106 TI - Humoral immune response and spreading of Encephalitozoon cuniculi infection in experimentally infected ponies. AB - A total of 9 (8 stallions and 1 mare) 1 year old ponies were used for the experimental infection caused by Encephalitozoon cuniculi genotype II (10(7) spores per animal). Subsequently, individual horses were slaughtered 7, 14, 21, 28, 35, 42, 49, 56, and 63 days post infection. Immediately after slaughter, tissues samples of stomach, duodenum, jejunum, ileum, caecum, colon, spleen, liver, kidney, bladder, heart, lungs, and brain were sampled. In addition, urine, feces and blood specimens were collected. Enzyme-linked immunosorbent assay was used for determination of humoral immune response and nested PCR targeting 16S rDNA, whole ITS, and 5.8S rDNA was used for detection of E. cuniculi in collected organs, blood, feces and urine. No clinical signs of microsporidiosis including diarrhea or colic, neurological signs and fever were observed in any horses during whole experiment. Acute microsporidiosis in ponies was characterized by the dissemination of microsporidia into almost all organs and significant increase of concentration of specific antibodies in blood was observed from 28 to 42 DPI. After this acute stage microsporidia disappeared from most organs with the exception of the kidney, which was positive up to 63 DPI when the experiment was terminated. No pathological changes were observed in any organs with exception of one mare's brain, where E. cuniculi-positive cavity measuring 5 cm * 3 cm in diameter formed in the lobus piriformis. PMID- 23747107 TI - Understanding coupling between bone resorption and formation: are reversal cells the missing link? AB - Bone remodeling requires bone resorption by osteoclasts, bone formation by osteoblasts, and a poorly investigated reversal phase coupling resorption to formation. Likely players of the reversal phase are the cells recruited into the lacunae vacated by the osteoclasts and presumably preparing these lacunae for bone formation. These cells, called herein reversal cells, cover >80% of the eroded surfaces, but their nature is not identified, and it is not known whether malfunction of these cells may contribute to bone loss in diseases such as postmenopausal osteoporosis. Herein, we combined histomorphometry and IHC on human iliac biopsy specimens, and showed that reversal cells are immunoreactive for factors typically expressed by osteoblasts, but not for monocytic markers. Furthermore, a subpopulation of reversal cells showed several distinctive characteristics suggestive of an arrested physiological status. Their prevalence correlated with decreased trabecular bone volume and osteoid and osteoblast surfaces in postmenopausal osteoporosis. They were, however, virtually absent in primary hyperparathyroidism, in which the transition between bone resorption and formation occurs optimally. Collectively, our observations suggest that arrested reversal cells reflect aborted remodeling cycles that did not progress to the bone formation step. We, therefore, propose that bone loss in postmenopausal osteoporosis does not only result from a failure of the bone formation step, as commonly believed, but also from a failure at the reversal step. PMID- 23747108 TI - Cryptic no longer: arrays of CLASP1 TOG domains. AB - CLASP proteins play crucial roles in regulating microtubules. In this issue of Structure, Leano and colleagues show that an essential and previously cryptic domain of CLASP is a TOG domain with unusual features that might explain its unique functions. PMID- 23747109 TI - Blocking HIV-1 gp120 at the Phe43 cavity: if the extension fits.... AB - The Phe43 cavity is a mysterious feature in crystallographic structures of HIV-1 gp120-CD4 complexes. In this issue of Structure, Acharya and colleagues provide structural explanations for the potent neutralization by CD4 mimetic miniproteins with chemical extensions that fit into this cavity. PMID- 23747110 TI - HHARI is one HECT of a RING. AB - E3 ubiquitin ligases are the last of an enzyme trio that covalently modifies proteins with ubiquitin, facilitating various cellular functions. In this issue of Structure, Duda and colleagues provide the structural basis for the autoinhibited Ariadne-family of E3-ubiquitin ligases. PMID- 23747111 TI - Report of the wwPDB Small-Angle Scattering Task Force: data requirements for biomolecular modeling and the PDB. AB - This report presents the conclusions of the July 12-13, 2012 meeting of the Small Angle Scattering Task Force of the worldwide Protein Data Bank (wwPDB; Berman et al., 2003) at Rutgers University in New Brunswick, New Jersey. The task force includes experts in small-angle scattering (SAS), crystallography, data archiving, and molecular modeling who met to consider questions regarding the contributions of SAS to modern structural biology. Recognizing there is a rapidly growing community of structural biology researchers acquiring and interpreting SAS data in terms of increasingly sophisticated molecular models, the task force recommends that (1) a global repository is needed that holds standard format X ray and neutron SAS data that is searchable and freely accessible for download; (2) a standard dictionary is required for definitions of terms for data collection and for managing the SAS data repository; (3) options should be provided for including in the repository SAS-derived shape and atomistic models based on rigid-body refinement against SAS data along with specific information regarding the uniqueness and uncertainty of the model, and the protocol used to obtain it; (4) criteria need to be agreed upon for assessment of the quality of deposited SAS data and the accuracy of SAS-derived models, and the extent to which a given model fits the SAS data; (5) with the increasing diversity of structural biology data and models being generated, archiving options for models derived from diverse data will be required; and (6) thought leaders from the various structural biology disciplines should jointly define what to archive in the PDB and what complementary archives might be needed, taking into account both scientific needs and funding. PMID- 23747113 TI - [Why we need a section dedicated to evidence-based radiology]. PMID- 23747114 TI - [Reporting plain films: more than just a legal requirement]. PMID- 23747112 TI - Genome-wide identification and validation of a novel methylation biomarker, SDC2, for blood-based detection of colorectal cancer. AB - Aberrant DNA methylation has shown promise as a biomarker for the early detection of cancer. To discover novel genes frequently methylated at an early stage in colorectal cancer (CRC), DNA microarray analysis coupled with enriched methylated DNA was performed in primary tumors and compared with adjacent nontumor tissues of 12 patients with CRC at stages I to IV. Stepwise filtering for candidate selection in microarray data analysis yielded a set of genes that are highly methylated across all CRC tumors and that can be used as a composite biomarker for CRC detection. Verification assay identified the SDC2 gene as a potential methylation biomarker for early CRC detection. In clinical validation in tissues from 139 CRC patients, a much higher level of aberrant SDC2 methylation was measured in most primary tumors (97.8%), compared with corresponding nontumor tissue of CRC patients, irrespective of clinical stage. Clinical validation of SDC2 methylation in serum DNA from CRC patients (n = 131) at stages I to IV and from healthy individuals (n = 125) by quantitative methylation-specific PCR demonstrated a high sensitivity of 87.0% (95% CI, 80.0% to 92.3%) in detecting cancers, with a specificity of 95.2% (95% CI, 89.8% to 98.2%). Importantly, sensitivity at stage I was 92.3%, indicating the potential of SDC2 methylation as a blood-based DNA test for early detection of CRC. PMID- 23747115 TI - [Critically appraised topics (CATs): a new publishing opportunity in Radiologia]. AB - Physicians need fast access to quality information about the best diagnostic tests and treatments in each case. To meet this need, a new publishing format has emerged. Critically appraised topics (CATs) are elaborated following the five steps of evidence-based medicine. CATs are structured summaries of research articles that deal with a specific clinical query, presenting a critical evaluation of the best evidence available to support the validity of the available options. CATs have proven useful in teaching evidence-based radiology and this publishing format is becoming more common. Radiology CATs can be found on medical websites and in journals, including those dedicated to general medicine as well as those specifically dedicated to radiology. Radiologia encourages the publication of CATs because we consider that they can be useful for daily decision making. PMID- 23747117 TI - The use of modified virtual colonoscopy to structure a descriptive imaging classification with implied severity for rectogenital and disseminated endometriosis. PMID- 23747116 TI - Ergonomic deficits in robotic gynecologic oncology surgery: a need for intervention. AB - STUDY OBJECTIVE: To evaluate surgeon strain using validated ergonomic assessment tools. DESIGN: Observational study (Canadian Task Force classification III). SETTING: Academic medical center. PARTICIPANTS: Robotic surgeons performing gynecologic oncology surgical procedures. INTERVENTIONS: Videotape footage of surgeons performing robotic gynecologic oncology procedures was obtained. A human factors engineer experienced with health care ergonomics analyzed the video recordings and performed ergonomic evaluations of the surgeons. MEASUREMENTS AND MAIN RESULTS: An initial evaluation was conducted using the Rapid Upper Limb Assessment (RULA) survey, an ergonomic assessment and prioritization method for determining posture, force, and frequency concerns with focus on the upper limbs. A more detailed analysis followed using the Strain Index (SI) method, which uses multiplicative interactions to identify jobs that are potentially hazardous. Seventeen hours of video recordings were analyzed, and descriptive data based on RULA/SI analysis were collected. Ergonomic evaluation of surgeon activity resulted in a mean RULA score of 6.46 (maximum possible RULA score, 7), indicating a need for further investigation. The mean SI grand score was 24.34. SI scores >10 suggest a potential for hazard to the operator. Thus, the current use of the surgical robot is potentially dangerous with regards to ergonomic positioning and should be modified. CONCLUSION: At a high-volume robotics center, there are ergonomics deficits that are hazardous to gynecologic surgeons and suggest the need for modification and intervention. A training strategy must be developed to address these ergonomic issues and knowledge deficiencies. PMID- 23747118 TI - [Atherogenic dyslipidemia: a multidisciplinary consensus panel]. AB - The dyslipidaemias are conditions that are still under-diagnosed, under-treated, and poorly controlled. This condition is common to the rest of the risk factors considered fundamental. Within the dyslipidaemias, the data that we have available, generally refer to the hypercholesterolaemias or in particular to the dyslipidaemias not dependent on LDL in patients who are already being treated with statins. However, there is only limited data available on atherogenic dyslipidaemia, characterised by the elevation of triglycerides and/or a decrease in HDL-cholesterol. However, given its profile, to determine the particularities of this atherogenic dyslipidaemia could help to control this anomaly more effectively. The present study, conducted in accordance with the Delphi method, has as its purpose to demonstrate the level of agreement or disagreement of an expert group, made up from different scientific societies, on what atherogenic dyslipidaemia is and represents, as well as what is the most suitable diagnostic and therapeutic approach. It has been concluded that the level of knowledge of the epidemiological aspects, its association with cardiovascular risks, of clinical identification, and specific treatment, has reached a significant level of agreement between the experts consulted. However, some aspects have been detected that, even today, are still subject to controversy: the role of isolated hypertriglyceridaemia as a risk factor, and its consideration as a therapeutic objective both in primary and secondary prevention, the effects linked to HDL cholesterol, and that are strictly associated with the capacity to produce cholesterol efflux, the appropriateness of the therapeutic objectives to individual particularities, as well as the need to employ - frequently - combined treatment to correctly approach the correction of the lipid profile as a whole. PMID- 23747119 TI - Rhesus macaque rhadinovirus-associated disease. AB - Rhesus macaque rhadinovirus (RRV) is a gamma-2 herpesvirus that naturally infects rhesus macaque (RM) monkeys and is closely related to human herpesvirus-8 (HHV 8)/Kaposi's sarcoma-associated herpesvirus (KSHV). Infection of immunodeficient RM induces disease in infected RM that resembles KSHV-associated pathologies. Importantly, RRV possesses homologues of KSHV ORFs that are postulated to play a role in disease development. As such, RRV has emerged as a prominent in vivo model system for examining mechanisms of infection and disease of these pathogenic herpesviruses, and has provided unique insight into how these viruses cause disease. PMID- 23747120 TI - Challenges in the clinical development of a dengue vaccine. AB - Dengue is a potentially fatal viral disease for which treatment is limited to supportive care, and prevention and control are based on mosquito vector control programs. It is the fastest growing arboviral infection and is currently endemic in more than 100 tropical and subtropical countries, placing over 40% of the world's population at risk. At least 50 million infections are thought to occur annually, resulting in approximately 500000 hospitalizations, mainly in children. In the context of an expanding and potentially fatal infectious disease without effective prevention or specific treatment, the public health value of a protective vaccine is clear. This review considers some of the challenges to dengue vaccine development, and in particular the challenges of demonstrating dengue vaccine efficacy. PMID- 23747121 TI - Using epigenetics to define vaccine-induced memory T cells. AB - Memory T cells generated from acute infection or vaccination have the potential to provide the host with life-long immunity against re-infection. Protection by memory T cells is achieved through their acquired ability to persist at anatomical sites of the primary infection as well as maintaining a heightened ability to recall effector functions. The maintenance of CD8 and CD4 T cell function in a state of readiness is key to life-long immunity and manifest through changes in transcriptional regulation. Yet, the ability to identify poised transcriptional programs at the maintenance stage of the response is lacking from most transcriptional profiling studies of memory T cells. Epigenetic profiling allows for the assessment of transcriptionally poised (promoters that are readily accessible for transcription) states of antigen-specific T cells without manipulation of the activation state of the cell. Here we review recent studies that have examined epigenetic programs of effector and memory T cell subsets. These reports demonstrate that acquisition of epigenetic programs during memory T cell differentiation to acute and chronic infections is coupled to, and potentially regulate, the cell's recall response. We discuss the usefulness of epigenetic profiling in characterizing T cell differentiation state and function for preclinical evaluation of vaccines and the current methodologies for single locus versus genome-wide epigenetic profiling. PMID- 23747122 TI - Antibiotic cement nail for the treatment of posttraumatic intramedullary infections of the tibia: midterm results in 10 cases. AB - INTRODUCTION: This is a single, level 1 trauma centre, prospective consecutive patient series with intramedullary infection in the presence of unstable tibial fracture treated using the Kirschner wire-reinforced, antibiotic cement nail. PATIENTS AND METHODS: A total of 10 consecutive patients (eight males and two females) with a mean age of 42 years (range, 20-59) suffering from infection after intramedullary nailing for tibial fracture, admitted during a period of 4 years, were included. An antibiotic cement-coated nail, handmade at the time of surgery, was implanted in all patients. This was followed by a standardised 6 week treatment protocol, extraction of the nail and definitive fixation. RESULTS: At 6 years of follow-up, infection eradication and bony union were possible in all of the patients. No further infection treatment was necessary; however, all of our patients underwent additional procedures (mean: four additional procedures per patient) for cosmetic or other non-infectious reasons (bone grafting, muscle flaps, etc.). CONCLUSIONS: The antibiotic cement-coated nail seems to be an effective treatment for intramedullary infections of the fractured tibia. PMID- 23747123 TI - Factors associated with self-efficacy for managing recovery in the trauma intensive care population: a prospective cohort study. AB - OBJECTIVE: The aim of this paper was to identify factors associated with self efficacy for managing recovery in the trauma intensive care population. INTRODUCTION: Injury accounts for 6.5% of disease burden in Australia, with similar levels being reported in other developed countries. While some studies regarding self-efficacy have identified a relationship to patient recovery post acute injury, others have been inconclusive. This study will identify factors associated with self-efficacy for managing recovery in the trauma intensive care population. METHODS: A prospective cohort study of patients aged >= 18 years, admitted to a metropolitan tertiary hospital in South East Queensland between June 2008 and August 2010 for the acute treatment of injury. Demographic, injury, acute care and psychosocial factors were considered. The primary outcome was self efficacy measured by the 6-item self-efficacy scale (SES) 1 and 6 months post hospital discharge. All factors significant (p<0.10) on univariate analysis were included in multivariable modelling where p<0.05 was considered significant. RESULTS: A total of 88 patients were included. The mean self-efficacy score at 1 and 6 months was similar (6.8 vs 6.9 respectively). Self-efficacy at 1 month, psychological distress (K-10) Score and illness perception (K10) Score accounted for 68.4% (adjusted R(2)) of the variance in 6 month self-efficacy (F3,75)=57.17, p<0.001. Illness perception was the strongest contributor to 6 month self efficacy (beta=-0.516), followed by psychological distress (beta=-0.243) and self efficacy at 1 month (beta=0.205). CONCLUSION: Significant factors associated with self-efficacy for managing recovery at 6 months included 1 month self-efficacy, illness perception and psychological distress. To promote patient recovery, screening patients at 1 month in order to commence relevant interventions could be beneficial. PMID- 23747124 TI - Effect of local administration of insulin-like growth factor I combined with inside-out artery graft on peripheral nerve regeneration. AB - The objective was to assess the effect of topically administered insulin-like growth factor (IGF I) on peripheral nerve regeneration and functional recovery. Eighty male healthy white Wistar rats were divided into four experimental groups (n=20), randomly: in transected group (TC), the left sciatic nerve was transected and stumps were fixed in the adjacent muscle. In treatment group, defect was bridged using an inside-out artery graft (IOAG/IGF) filled with 10 MUL IGF I (100 ng/kg). In artery graft group (IOAG), the graft was filled with phosphate buffered saline alone. In sham-operated group (SHAM), sciatic nerve was exposed and manipulated. Each group was subdivided into five subgroups of five animals each and regenerated nerve fibres were studied 4, 8, 12 and 16 weeks after surgery. Behavioural testing, sciatic nerve functional study, gastrocnemius muscle mass and morphometric indices confirmed faster recovery of regenerated axons in IOAG/IGF than IOAG group (P<0.05). In immunohistochemistry, location of reactions to S-100 in IOAG/IGF was clearly more positive than that in IOAG group. When loaded in an artery graft, IGF I accelerated and improved functional recovery and morphometric indices of sciatic nerve. PMID- 23747125 TI - Clinical course, complication rate and outcome of segmental resection and distraction osteogenesis after chronic tibial osteitis. AB - INTRODUCTION: Radical segmental resection and subsequent distraction osteogenesis are considered the gold standard in the treatment of chronic tibial osteitis. We investigated the clinical course of treatment, particularly with respect to patients' quality of life, and the complication rate associated with this technique. METHODS: In this prospective case series, 25 patients (22 men, 3 women, average age: 46 years) with chronic post-traumatic tibial osteitis were managed operatively from 2006 to 2009. Standardised treatment included bacterial eradication by segmental resection, bone transport using Ilizarov apparatus, and docking manoeuvre. The follow-up rates during bacterial eradication, bone transport, post docking, and complete osseous consolidation were 100% while follow-up two years after completed consolidation was 76%. The main outcome measurements consisted of the quality of life (Medical Outcomes Study 36-Item Short Form Health Survey (SF-36 score)) and the virtual analogue scale (VAS) of pain during the five stages of therapy. Additionally, all complications and difficulties were documented. RESULTS: The average defect size was 5.3 cm (range: 3-13). The healing index was 57 days per cm transport (range: 18-172). The overall treatment time averaged 93 weeks (range: 38-183). Patients suffered 22 minor and 13 major complications including one amputation. The average complication rate per patient consisted of 0.88 minor and 0.52 major complications. After the period of bone transport, the physical and mental component summary scores increased continuously. After completed consolidation, the average mental summary score was comparable to a normal collective. CONCLUSIONS: Distraction osteogenesis is challenging for both the patient and the surgeon. The arduous and demanding nature of the clinical course subjects the patient to considerable mental and physical stress. Thankfully, the average physical and mental status of health continues to improve during the clinical course of treatment. The 2-year success rate of the distraction osteogenesis in an infected tibia is 96%. PMID- 23747126 TI - [Use of restraint in psychiatry: Feelings of caregivers and ethical perspectives]. AB - INTRODUCTION: The return of restraint in psychiatry raises many ethical issues for caregivers. However their experience is little explored in literature. OBJECTIVES: Our objective was to study the feelings of caregivers facing restraint with regard to an ethical perspective and to identify areas for improvement. METHOD: Between November 2011 and February 2012 a descriptive cross sectional epidemiological study was performed in two psychiatric emergency services and two closed units in which doctors and nurses were individually interviewed using semi-structured questionnaires. Five topics were explored: indications and contexts, impact on the patient, caregiver-patient relationship, perspective on the practice and feelings of caregivers on which we insist particularly. Results were presented in tables with percentages and possibly diagrams. The notable responses of caregivers were also cited. RESULTS: Twenty nurses and nine psychiatrists, mostly female, were recruited. They all had participated in experiments of restraint. The self-aggressiveness, the aggressiveness against other persons and agitation were the most frequent indications. In the patients, caregivers identified misunderstanding (79.3%) and anger (75.9%). The majority of nurses (75%) felt that there was an improvement in the caregiver-patient relationship after the episode of restraint compared to what it had been in the moments preceding this measure. The emotional experience of caregivers was rich, intense and predominantly negative type of frustration (35% of nurses; 66.7% of doctors), anger (30 and 33.3%) and lack of feeling (35 and 44.4%). The feelings of doctors and nurses were not completely similar. For caregivers it was "a difficult but necessary experience" (82.75%), "an act of care and safety" (68.9%). All psychiatrists and almost half of the nurses (45%) said they did not feel the same when they used seclusion. In their opinion, seclusion entailed a less painful experience because of its therapeutic properties. More than half of the caregivers thought that there were alternatives to restraint: the strengthening of containing function in the hours before the use of restraint; the use of seclusion at the time of the decision to restrain. They identified contexts (80%) encouraging the use of restraints, not only related to the patient, the lack of resources but also institutional contexts, in particular conflicts or divisions in the health care team. DISCUSSION: The misunderstanding of the patient led us to wonder about the quality of the information he/she received: it was sometimes too formal and did not take into account the uniqueness of the patient. The frustration of caregivers could concern the lack of resources but also be directed towards a patient or caregiver. In addition, there were often cleavages between doctors and nurses that stemmed from a misunderstanding, also with rivalries and power struggles. From the literature and caregivers' reflections we identified three prospects to reduce the use of restraint and modify feelings of caregivers: 1) develop better crisis management upstream through increasing resources and improving training; 2) promote patients support in using ethical principles of autonomy and beneficence by showing them solicitude, inviting them to tell themselves and helping them to regain their own experience; 3) develop an afterthought in setting up institutional reflection time by restoring a central role in clinical team meetings in psychiatry, possibly supplemented by supervision, but also through regional ethical spaces. CONCLUSION: In our investigation, we found that caregivers had a predominantly negative experience with frustration, anger and a lack of feeling. Among caregivers we also identified awareness of ethical issues that may be for the first time for a change. PMID- 23747127 TI - Antioxidant and oxidative stress parameters in brain of Heteropneustes fossilis under air exposure condition; role of mitochondrial electron transport chain. AB - Many fishes are exposed to air in their natural habitat or during their commercial handling. In natural habitat or during commercial handling, the cat fish Heteropneustes fossilis is exposed to air for >24h. Data on its oxidative metabolism in the above condition are not available. Oxidative stress (OS) indices (lipid and protein oxidation), toxic reactive oxygen species (ROS: H2O2) generation, antioxidative status (levels of superoxide dismutase, catalase, glutathione peroxidase and reductase, ascorbic acid and non-protein sulfhydryl) and activities of electron transport chain (ETC) enzymes (complex I-IV) were investigated in brain tissue of H. fossilis under air exposure condition (0, 3, 6, 12 and 18 h at 25 degrees C). Decreased activities of antioxidant (except catalase) and ETC enzymes (except complex II) with increased H2O2 and OS levels were observed in the tissue under water deprivation condition. Positive correlation was observed for complex II activity and non-protein thiol groups with time period of air exposure. The critical time period to induce OS and to reduce most of the studied antioxidant level in brain was found to be 3-6h air exposure. The data can be useful to minimize the stress generated during commercial handling of the live fishes those exposed to air in general and H. fossilis in particular. PMID- 23747128 TI - Comparison of intermittent and continuous exposures to cadmium in the blue mussel, Mytilus edulis: accumulation and sub-lethal physiological effects. AB - Little is known about the bioaccumulation responses of shellfish to metals during intermittent compared to continuous exposure. There is also the concern that the toxicity of intermittent events may not be the same as that from the steady-state continuous exposures. The aim of the present study was to determine whether there was any difference between cadmium (Cd) accumulation, or Cd-dependent biological responses, in tissues of blue mussels (Mytilus edulis) during intermittent compared to continuous Cd exposure. Tissues and hemolymph were collected from M. edulis exposed for 14 days to either control (no added Cd, only seawater), or 50 ug/l Cd as CdCl2 in continuous or intermittent profile (2 day exposure, 2 days in clean seawater alternately); and sub-lethal responses examined using a suite of assays including total glutathione, thiobarbituric acid reactive substances (TBARS), neutral red retention, total hemocyte counts, hemolymph Na(+) and K(+), plasma glucose and histopathology. A time-dependent accumulation of the Cd was observed in tissues of mussels after continuous exposure, while the intermittent exposure showed step-wise changes in the hemolymph and gonad. Tissue Cd concentration in the continuous exposure was significantly increased (>=2 fold) for most tissues compared to the intermittent exposure. No clear differences were seen between the continuous and intermittent exposure for most end points measured apart from a 2 fold significant increase in hemocyte infiltration in the digestive gland of the continuous exposure compared to the intermittent exposure. Overall, the data showed that the Cd accumulation was generally greater in the continuous exposure regime, but despite this, most of the biological responses being similar in both regimes. PMID- 23747129 TI - Trophoblast invasion and oxygenation of the placenta: measurements versus presumptions. AB - Invasion of extravillous trophoblast into maternal tissues has a profound effect on the oxygenation of the placenta and hence the fetus. The main route of trophoblast invasion is interstitial invasion into the tissues of the decidua and myometrium. From this main route side branches reach the spiral arteries (endovascular trophoblast) as well as the uterine glands (endoglandular trophoblast) to open both structures toward the intervillous space. This enables histiotrophic nutrition in the first trimester and hemotrophic nutrition in the second and third trimesters of pregnancy. Failure of endovascular trophoblast invasion has profound effects on the oxygenation of the placenta. Interestingly, this does not lead to hypoxia as has long been presumed. Rather, all measurements available today point to increased oxygen levels within the placenta in patients with a failure of spiral artery transformation. This should lead to a rethink regarding pathological conditions such as intrauterine growth restriction and preeclampsia. PMID- 23747130 TI - A randomized prospective study of glove perforation in orthopaedic surgery: is a thick glove more effective? AB - We compared perforation rates among operative staff who were randomly assigned either thick latex surgical gloves or conventional gloves for use in performing total knee arthroplasty. A total of 1120 gloves were assessed in 70 total knee arthroplasties. Additionally, the degree of tactile sensitivity provided by the gloves was compared using a two-point discrimination (TPD) test. Perforation occurred in 27 surgeries (38.5%) and in 48 gloves (4.29%). Binary logistic regression analysis revealed that the operator was a risk factor for perforation rate (Odds ratio 14.448, P < .0.01) and that the type of glove was not (P = .896). In the TPD test, tactile sensitivity was lower for a thick outer glove than the conventional double glove (P < .001 for each site). Not only did thick surgical gloves lower tactile sensitivity, they also offered no superior protective effect over conventional gloves. PMID- 23747131 TI - Concomitant, sequential, and hybrid therapy for H. pylori eradication: a pilot study. AB - BACKGROUND AND OBJECTIVE: Since the efficacy of the standard triple therapies for Helicobacter pylori eradication has decreased, novel antibiotic regimens have been introduced, including concomitant, sequential, and hybrid therapies. We aimed to compare the cure rates achieved by these new therapy regimens. METHODS: This was a multicenter, open-label, pilot study enrolling consecutive non-ulcer dyspepsia patients with H. pylori infection never previously treated for the infection. Patients were randomized to receive one of the following treatments: (a) concomitant therapy: omeprazole 20mg, amoxicillin 1g, clarithromycin 500 mg, and tinidazole 500 mg for 5 days; (b) sequential therapy: omeprazole 20mg and amoxicillin 1g for 5 days followed by omeprazole 20mg, clarithromycin 500 mg, and tinidazole 500 mg for 5 days; (c) hybrid therapy: omeprazole 20mg, and amoxicillin 1g for 7 days followed by omeprazole 20mg, amoxicillin 1g, clarithromycin 500 mg, and tinidazole 500 mg, for 7 days. All drugs were administered twice daily. Bacterial eradication was checked 6 weeks after treatment by using a (13)C-urea breath test. A 10-day, second-line therapy with omeprazole 20mg, levofloxacin 250 mg, and amoxicillin 1g, all given twice daily, was offered to the eradication failure patients. RESULTS: Overall, 270 patients were enrolled, but 13 patients early interrupted treatment due to side effects. At intention-to-treat (ITT) and per-protocol analysis (PP), the eradication rates were 85.5% and 91.6% with the concomitant regimen, 91.1% and 92.1% with the sequential therapy, and 80% and 85.7% with the hybrid regimen. Differences were not statistically significant. H. pylori infection was cured in 10 (55.6%) patients with the second-line regimen. CONCLUSION: In our study, both concomitant and sequential therapy, but not hybrid therapy, reached high eradication rates. The success rate of second-line levofloxacin-based triple therapy is decreasing. PMID- 23747132 TI - Multimodal treatment and long-term outcome of patients with esthesioneuroblastoma. AB - PURPOSE/OBJECTIVES: To analyze the clinical features, treatment modalities and outcome of patients treated for a localized esthesioneuroblastoma (ENB). MATERIALS AND METHODS: Forty-three consecutive patients with biopsy proven ENB treated at two referral cancer centers between 1998 and 2010 were retrospectively reviewed. RESULTS: Overall, 5 patients had stage A disease, 13 stage B, 16 stage C and 9 stage D according to the modified Kadish classification. Neo-adjuvant chemotherapy was performed in 23 patients leading to a 74 % response rate. Thirty one patients were treated by surgery. Thirty-nine patients (90.6%) underwent radiation therapy. Twelve patients received bilateral cervical lymph node irradiation (LNI). After a median follow-up of 77 months, the 5-year overall and progression free survival were 65% and 57%. Twelve patients (28%) had a locoregional relapse leading to 10 ENB-related deaths. The major prognostic factor was the modified Kadish stage with a 3-year survival for stage A-B, C and D of 100%, 48% and 22% respectively (p < 0.0001). Two (9%) isolated cervical lymph node relapses occurred among staged B and C patients treated without elective LNI and none after elective or adjuvant LNI. CONCLUSION: The high risk of locoregional failure in ENB justifies the use of multimodal therapy. Induction chemotherapy leads to a high response rate. Elective LNI might prevent regional failure in locally advanced disease. PMID- 23747133 TI - Updated strategies to treat acute arterial complications associated with total knee and hip arthroplasty. AB - OBJECTIVE: Traditional treatment of acute arterial complications associated with total knee arthroplasty (TKA) and total hip arthroplasty (THA) has generally included arteriography followed by open surgery. The purpose of this study was to describe our evolution from open surgery to preferential endovascular treatment for acute arterial complications of TKA and THA. METHODS: We analyzed our computerized database registry and patient charts for vascular interventions associated with TKA and THA at a hospital with a large volume of orthopedic surgery to determine changing trends in endovascular intervention for these complications. RESULTS: Between 1989 and 2012, 39,196 TKA (26,374 total: 23,205 primary; 3169 revisions) and THA (12,822 total: 10,293 primary; 2529 revisions) were performed. Vascular surgery consultation was provided for the treatment of acute ischemia, hemorrhage, ischemia with hemorrhage, and pseudoaneurysm formation. All interventions were performed within 30 days of joint replacement. A total of 49 (0.13%) acute arterial complications occurred over the 23-year period: 37 (76%) associated with TKA and 12 (24%) with THA. Arterial injury was detected on the same day as the orthopedic procedure in 28 patients, between postoperative days 1 and 5 in 18 patients, and between postoperative days 5 and 30 in three patients. The arterial complications caused ischemia in 28 patients (58%), hemorrhage in six (12%), ischemia with hemorrhage in six (12%), and pseudoaneurysm in nine (18%). Treatment included solely endovascular intervention in 12 (25%), failed endovascular treatment converted to open surgery in one (2%), and open surgery alone in 36 (73%) patients. Before 2002, only 6% (2/32; 2 TKA) of patients were successfully treated with endovascular intervention compared with 59% (10/17; 9 TKA, 1 THA) after June 2002 (P = .0004). There was no mortality, and limb salvage was achieved in all patients. CONCLUSIONS: Although the majority of acute arterial complications after TKA and THA are diagnosed on the day of surgery, a high clinical awareness for acute arterial injury should also be present in the postoperative period. Although not always feasible, endovascular management is now our preferred treatment for injuries associated with TKA or THA. This offers substantially shorter time to vascular restoration, with less morbidity than open repair, and equivalent satisfactory outcomes. PMID- 23747134 TI - 18FDG PET-CT for detecting gastric cancer recurrence after surgical resection: a meta-analysis. AB - BACKGROUND: We performed a meta-analysis to evaluate the value of (18)FDG PET-CT for the detection of gastric cancer recurrence after surgical resection. METHODS: A systematic literature search was performed in the MEDLINE and EMBASE databases. We calculated the sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio for (18)FDG PET-CT. We also constructed summary receiver operating characteristic curves for (18)FDG PET-CT. RESULTS: Eight studies (500 patients) were included. The sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of (18)FDG PET-CT were 0.86 (95% confidence interval [CI] = 0.71-0.94), 0.88 (95% CI = 0.75-0.94), 17.0 (95% CI = 3.5-14.0), and 0.16 (95% CI = 0.07-0.34), respectively. Overall weighted area under the curve was 0.93 (95% CI = 0.91-0.95). CONCLUSIONS: (18)FDG PET-CT has moderate sensitivity and specificity for detection of gastric cancer recurrence after surgical resection. PMID- 23747135 TI - Investigation of thermal treatment on selective separation of post consumer plastics prior to froth flotation. AB - Plastics have become the widely used materials because of their advantages, such as cheapness, endurance, lightness, and hygiene. However, they cause waste and soil pollution and they do not easily decompose. Many promising technologies are being investigated for separating mixed thermoplastics, but they are still uneconomical and unreliable. Depending on their surface characteristics, these plastics can be separated from each other by flotation method which is useful mineral processing technique with its low cost and simplicity. The main objective of this study is to investigate the flotation characteristics of PET and PVC and determine the effect of plasticizer reagents on efficient plastic separation. For that purpose, various parameters such as pH, plasticizer concentration, plasticizer type, conditioning temperature and thermal conditioning were investigated. As a result, PET particles were floated with 95.1% purity and 65.3% efficiency while PVC particles were obtained with 98.1% purity and 65.3% efficiency. PMID- 23747136 TI - Challenges when performing economic optimization of waste treatment: a review. AB - Strategic and operational decisions in waste management, in particular with respect to investments in new treatment facilities, are needed due to a number of factors, including continuously increasing amounts of waste, political demands for efficient utilization of waste resources, and the decommissioning of existing waste treatment facilities. Optimization models can assist in ensuring that these investment strategies are economically feasible. Various economic optimization models for waste treatment have been developed which focus on different parameters. Models focusing on transport are one example, but models focusing on energy production have also been developed, as well as models which take into account a plant's economies of scale, environmental impact, material recovery and social costs. Finally, models combining different criteria for the selection of waste treatment methods in multi-criteria analysis have been developed. A thorough updated review of the existing models is presented, and the main challenges and crucial parameters that need to be taken into account when assessing the economic performance of waste treatment alternatives are identified. The review article will assist both policy-makers and model developers involved in assessing the economic performance of waste treatment alternatives. PMID- 23747137 TI - Do published ADA studies support the ADA-EASD position statement for the management of hyperglycaemia in type 2 diabetics? AB - The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a position statement in 2012 on the management of hyperglycaemia in patients with type 2 diabetes. The Societe Francophone du Diabete (SFD) adopted it while awaiting future French recommendations. This new care approach individualises the therapeutic choices and objectives for each patient based on their characteristics, through emphasis on the need for mutual cooperation with the patient in decision-making. Glycaemic management should naturally be considered in the context of overall cardiovascular risk reduction, which should remain the primary objective of treatment. The cornerstone of this treatment is based on lifestyle modifications, with the addition of metformin monotherapy if the desired glycaemic control is not attained. There are multiple second- and third-line treatment possibilities, and insulin therapy is an option that can be considered early in the bitherapy stage. On the whole, large published studies at the ADA conference in Philadelphia in June 2012, which are the subject of this article, support this patient-centred position statement. PMID- 23747138 TI - [Breast cancer in woman younger than 35 years in Tunisia: retrospective study about 124 cases]. AB - OBJECTIVES: Our aim was to report the epidemiological and clinical characteristics of breast cancer in young women and to evaluate the therapeutic results in the central part of Tunisia. PATIENTS AND METHODS: We report the results of a retrospective study including 124 patients under 35years old treated for breast cancer between 1995 and 2007 in the Radiotherapy Department of CHU Farhat Hached, Sousse. RESULTS: The mean age of our patients was 31.3years. T2N0, node positive (N+), high grade (SBRII and III) and endocrine responsive tumors were the most frequent. Fourteen patients had metastatic disease. One hundred and fifteen patients underwent a surgical treatment, which was conservative in 35 cases and radical for the others followed by radiotherapy on 114 patients. Chemotherapy, especially based on the FEC protocol, was administrated to 89% of all patients. Forty-five patients received also hormonotherapy. After a median follow-up of 48.5months, 51 patients remained free of disease. The 5years overall survival was 67.7%, the 5years free disease survival was 58.2%. DISCUSSION AND CONCLUSION: The 5years overall survival of breast cancer in young women varies between 55 and 75%, it was 67.7% on our study. These results can be improved by early diagnosis, adapted treatment and nowadays with targeted therapies. PMID- 23747139 TI - Feasibility appraisal of an elastic band exercise program for older adults in wheelchairs. AB - This study appraised the feasibility of an elastic band exercise program for older adults in wheelchairs. A descriptive program review survey was used. A wheelchair-bound senior elastic band (WSEB) exercise program tailored to older adults in wheelchairs was initially developed by a group of 12 experts. A feasibility appraisal survey was administered to 10 older adults in wheelchairs through individual interviews after 4 weeks of the WSEB program. Study participants revealed that the WSEB program was feasible, safe, appropriate, and helpful to them. Participants further suggested practicing the WSEB program 3 times/week for 40 min/session in a group of 15-20 people. The finalized WSEB program has 2 levels: the basic and the advanced WSEB program. It is suggested that the basic level to be taught first with practice until participants are familiar with those exercises before proceeding to the advanced level. PMID- 23747140 TI - Motor readiness and joint torque production in lower limbs of older women fallers and non-fallers. AB - This study aimed to evaluate the motor response time and ability to develop joint torque at the knee and ankle in older women with and without a history of falls, in addition to investigating the effect of aging on these capacities. We assessed 18 young females, 21 older female fallers and 22 older female non-fallers. The peak torque, rate of torque development, rate of electromyography (EMG) rise, reaction time, premotor time and motor time were obtained through a dynamometric assessment and simultaneous electromyography. Surface EMGs of the rectus femoris (RF), vastus lateralis (VL), biceps femoris (BF), gastrocnemius lateralis (GL) and tibialis anterior (TA) muscles were recorded. Knee extension and flexion peak torques were lower in older fallers than in non-fallers. Knee extension and flexion and ankle plantarflexion and dorsiflexion peak torques were lower in both older groups than in the younger group. The rate of EMG rise of the BF and the motor time of the TA were lower and higher, respectively, in older fallers than in the younger adults. The time to reach peak torque in knee extension/flexion and ankle plantarflexion/dorsiflexion and the motor times of the RF, VL, BF and GL were higher in both older groups than in the younger groups. The motor time of the TA during ankle dorsiflexion and the knee extension peak torque were the major predictors of falls in older women, accounting for approximately 28% of the number of falls. Thus, these results further reveal the biomechanical parameters that affect the risk of falls and provide initial findings to support the prescription of exercises in fall prevention programs. PMID- 23747141 TI - Clinical, hematological and biochemical parameters of dairy cows experimentally infected with Vaccinia virus. AB - Vaccinia virus (VACV) is the etiological agent of bovine vaccinia (BV), an important zoonosis that affects dairy cattle. There are many aspects of the disease that remain unknown, and aiming to answer some of these questions, the clinical, hematological, and biochemical parameters of VACV experimentally infected cows were evaluated. In the first part of the study, lactating cows were infected with VACV-GP2 strain. In the second part, animals previously infected with VACV-GP2 were divided into two treatment groups: Group 1, immunosuppressed cows; and Group 2, re-infected cows. In this study, BV could be experimentally reproduced, with similar lesions as observed in natural infections. Moreover, a short incubation period and local lymphadenopathy were also observed. VACV could be detected by PCR and isolated from scabs taken from teat lesions of all inoculated and re-inoculated animals. Lymphocytosis and neutrophilia were observed in all animals from the first part of the experiment, and lymphopenia and relative neutrophilia were observed in the immunosuppressed animals. Detection of viral DNA in oral mucosa lesions suggests that viral reactivation might occur in immunosuppressed animals. Moreover, clinical disease with teat lesions may occur in previously VACV-infected cows under the experimental conditions of the present study. PMID- 23747142 TI - Nonsteroidal anti-inflammatory drug (NSAID) use and sarcopenia in older people: results from the ilSIRENTE study. AB - BACKGROUND: Recently, a great deal of attention has been paid to the role of inflammatory processes in the pathophysiology of sarcopenia. The aim of the present study was to examine the relationship between NSAID use and sarcopenia in a large sample of community-dwelling elderly people aged 80 years or older. METHODS: Data are from the baseline evaluation of 354 individuals enrolled in the ilSIRENTE Study. Following the recommendations of the European Working Group on Sarcopenia in Older People (EWGSOP), the diagnosis of sarcopenia was established on the basis of low muscle mass plus either low muscle strength or low physical performance. The relationship between NSAID use and sarcopenia was estimated by deriving odds ratios (ORs) from multiple logistic regression models considering sarcopenia as the dependent variable. RESULTS: Nearly 12% (n = 44) of the study sample used NSAIDs. Using the EWGSOP-suggested algorithm, 103 individuals (29.1%) with sarcopenia were identified. Ninety-nine (31.9%) participants were affected by sarcopenia among non-NSAID users compared with 4 participants (9.1%) among NSAID users (P < .001). Compared with all nonusers, NSAID users had a nearly 80% lower risk of being affected by sarcopenia (OR 0.21, 95% CI 0.07-0.61). After adjusting for potential confounders, NSAID users had a lower risk of sarcopenia compared with nonusers (OR 0.26, 95% CI: 0.08-0.81). CONCLUSIONS: The results are consistent with the hypothesis that long-term NSAID use might have a protective effect against the loss of muscle mass and function. Interventions able to reduce inflammation-related adverse outcomes at muscle level may be warranted. PMID- 23747143 TI - Bone density in heart or lung transplant recipients--a longitudinal study. AB - BACKGROUND: Osteoporosis is prevalent among heart or lung transplant (HLT) candidates. Bone loss is common posttransplant, with an associated increase in fracture risk. There is a lack of consensus regarding optimal management of bone health in HLT recipients. We report bone health data in a cohort of HLT recipients before and after transplantation and make recommendations for management. METHODS: Patients over the age of 20 who had a heart or lung transplant between 2000 and 2011 were identified from the New Zealand HLT Service database, and demographic data, immunosuppressive regimens, bisphosphonate use, and serial bone mineral density (BMD) data were extracted. RESULTS: Pretransplant BMD was available in 52 heart and 72 lung transplant recipients; 30 and 42, respectively, also had posttransplant BMD data. Pretransplant osteopenia or osteoporosis prevalence were 23% and 8% for heart candidates and 36% and 31% for lung candidates. Posttransplant, BMD decreased significantly at the femoral neck but not at the lumbar spine in the first year, with subsequent stabilization particularly in the presence of bisphosphonate use. Pretransplant BMD was the major predictor for developing osteopenia or osteoporosis after transplantation. CONCLUSION: A significant proportion of HLT recipients have osteopenia or osteoporosis pretransplant, and this persists posttransplant. Pretransplant BMD is an important predictor of subsequent osteopenia or osteoporosis development, allowing risk stratification and targeted intervention. PMID- 23747144 TI - Consequences of the implementation of the Model for End-stage Liver Disease system for liver allocation in Brazil. AB - BACKGROUND: In July 2006, the system for liver allocation in Brazil started to rely on the Model for End-stage Liver Disease (MELD) scale, replacing the previous chronological criteria. Under the new system, the score for listing pediatric patients is obtained by multiplication of the calculated PELD score by 3. The current criteria also features extra points for diseases such as hepatocellular carcinoma (HCC). This study sought to analyze the consequences of implementation of the MELD system on waiting list mortality, posttransplant survival rates and characteristics of the transplanted patients. METHODS: We retrospectively studied data from the State Health Secretariat of Sao Paulo, regarding all patients registered on the waiting list for liver transplantation in the State of Sao Paulo, in two periods: July 2005 to July 2006 (pre-MELD era) and July 2006 to July 2010 (MELD era). Patient survival rates calculated using the Kaplan-Meier method were compared by the log-rank test. P values <.05 were considered statistically relevant. RESULTS: After implementation of the MELD, waiting list registrations decreased by 39.8%; the percentage of transplants in HCC recipients increased from 2.4% to 23.7%; pediatric transplants increased from 6.5% to 9.3%; deaths on the list fell from 599 in the pre-MELD era to 359 in the last year analyzed; recipients with higher MELD displayed significantly lower posttransplant survival rates; HCC patients, better survival after transplantation (P = .002); No difference was observed comparing survival rates between pre-MELD and MELD eras (P = 474) or between adults and children (P = .867). CONCLUSION: Under the MELD system for liver allocation in Brazil, there was a reduction in waiting list mortality and an increased number of transplantations in pediatric and HCC recipients. Survival rates of patients with higher MELD score were inferior. However, this result was offset by the greater survival in HCC recipients, with no difference in patient survival rates between the pre-MELD and MELD eras. PMID- 23747145 TI - Maxillary sinusitis: 1752 cases at the ear-nose-throat department of a teaching hospital in Cotonou, Benin. AB - OBJECTIVE: Maxillary sinusitis is a frequent ear-nose-throat (ENT) infection. The purpose of this study was to determine the prevalence of maxillary sinusitis in the ENT department of a teaching hospital in Cotonou, Benin, and to report the clinical findings, together with the results of complementary examinations and treatment outcomes. PATIENTS AND METHODS: This was a retrospective descriptive analysis of patients seen at our hospital from January 1, 2004 to December 31, 2008 for maxillary sinusitis. RESULTS: Over the 5-year study period, 1752 cases of maxillary sinusitis were treated in the ENT department of the teaching hospital, which works out to 350 or 351 cases per year. The overall prevalence was 19.3%. There were 759 patients (83.1%) aged 16-50 years, and 984 patients (56.2%) were men. Factors favoring maxillary sinusitis were: dry season with dust (n=1051 patients, 60%); and atmospheric pollution (87.6%). Maxillary sinusitis was acute for 528 patients (30.1%) and chronic for 1224 patients (69.9%). A rhinogenic cause was identified for 960 patients (54.8%), an allergic cause for 668 patients (38.1%) and a dental cause for 96 patients (55.5%). In cases of chronic sinusitis, the infection was predominantly staphylococcal (29.3%) and pneumococcal (21.9%). Basically, medical treatment was given by combining local treatments for rhinopharyngeal disinfection or vasoconstriction. In cases with a dental origin, dental care was also delivered. For allergy-related sinusitis, nasal sprays with corticosteroids and antihistamine agents were prescribed. Outcomes were favorable for 89.7% of patients. PMID- 23747146 TI - Prevention and cure of lymphorrhea and lymphocele after cervical lymph-node surgery. PMID- 23747147 TI - Adenoid cystic carcinoma of the paranasal sinuses: retrospective series and review of the literature. AB - OBJECTIVES: Adenoid cystic carcinomas (ACC) are rare malignant tumours arising in the major and minor salivary glands. Involvement of the nasal cavity and paranasal sinuses is rare and poorly described. The purpose of this study was to define the clinical and prognostic criteria of ACC of the paranasal sinuses based on the review of a series of 25 cases. MATERIAL AND METHODS: Single-centre retrospective study of 25 cases of ACC of the paranasal sinuses managed between 1998 and 2011, evaluating epidemiological, clinical, diagnostic and prognostic criteria. Factors influencing survival (Kaplan-Meier/Log Rank test) and the patient's quality of life (EORTC QLQ-C30 questionnaire) were also analysed. RESULTS: Most patients (72%) had a locally-advanced tumour (stage T3 or T4) at diagnosis. Tumour sites, in decreasing order of frequency, were the maxillary sinus, nasal cavities and ethmoid sinus. The most common presenting complaints were maxillary pain or heaviness, unilateral blocked nose, and repeated epistaxis. When the tumour was resectable, treatment comprised a combination of surgery and adjuvant radiotherapy. The 5-year overall survival rate was 63% and the 5-year disease-free survival rate was 43%. The TNM stage at diagnosis (P=0.03), the histological subtype (P=0.023), the possibility of combined surgery and radiotherapy (P=0.03), and local control (P=0.05) were significant factors of improved 5-year overall survival. Positive surgical margins were associated with a trend towards poorer 5-year disease-free survival (ns). CONCLUSIONS: ACC are rare malignant tumours associated with a poor prognosis, characterized by a high recurrence rate. Recommended treatment is a combination of surgery and adjuvant radiotherapy whenever possible. Five-year survival varies as a function of TNM stage, histological subtype, treatment options and local control. PMID- 23747148 TI - Activity of Drill(r) lozenges on the main microorganisms responsible for upper respiratory tract infections. AB - OBJECTIVES: The treatment of sore throat, considered to be essentially due to viral infection, does not require the use of antibiotics. The recommended treatment is therefore based on the use of topical anaesthetics and antiseptics. Throat lozenges play a leading role in topical treatment by allowing immediate, massive and persistent release of the active molecule at the site of infection. The objective of this study was to demonstrate the short-term and long-term in vitro antimicrobial efficacy of Drill((r)) lozenges in relation to the main pathogens responsible for upper respiratory tract infections. MATERIAL AND METHOD: The bactericidal and virucidal activity in relation to the main microorganisms responsible for upper respiratory tract infections, including the H1N1 influenza virus, was evaluated after short (5 minutes) and long (3h) contact times, according to a methodology complying with European standards for the evaluation of chemical antiseptics and disinfectants. In parallel, the global antibacterial activity was determined on 30 strains representative of the resident flora by determination of maximum inhibitory dilutions (MID) and maximum bactericidal dilutions (MBD). RESULTS: Drill((r)) lozenges presented an antibacterial activity inducing significant (>90%) destruction of the main upper respiratory tract pathogens after a 5-minute contact time at high concentration and after a 3-hour contact time after dilution. Drill((r)) lozenges also exerted an antiviral activity inducing 2 log (99%) destruction of the H1N1 virus after a 5-min contact time at high concentration, with maintenance of this activity after dilution (3h). A homogeneous antibacterial activity was observed on the resident flora. CONCLUSION: These in vitro tests confirm the value of chlorhexidine lozenges in the treatment of upper respiratory tract infections such as sore throat. PMID- 23747149 TI - Willingness of pregnant women to participate in a birth cohort study in China. AB - OBJECTIVE: To determine the willingness of pregnant women in Guangzhou, China, to participate in a large-scale birth cohort study. METHODS: A cross-sectional survey was conducted of 526 pregnant women who attended their first prenatal class at Guangzhou Women and Children's Medical Center, Guangzhou, China, between September 21 and November 15, 2011. Information on demographic characteristics, willingness to participate, and preferences regarding collection procedures and incentives were analyzed. RESULTS: In all, 47.9% of the women were willing to participate in a birth cohort study, whereas 23.0% refused and 29.1% were unsure. The majority of the women willing to participate (95.2%-98.4%) accepted the use of non-invasive data collection methods except for stool collection, and 85.9% would allow their offspring to participate in long-term follow-up. Willingness to participate rose to 85.2% when non-monetary incentives were offered. The most popular incentive was assessment of child development. CONCLUSION: The willingness of pregnant Chinese women to participate in long-term observational research was similar to that reported in high-income countries. Non-monetary incentives improved their level of willingness, a finding that might inform future maternal and child health research in low- and middle-income countries. PMID- 23747150 TI - Knowledge of, attitudes toward, and barriers to the practice of emergency contraception among women in Sikkim, India. AB - OBJECTIVE: To assess knowledge, attitudes, and barriers associated with the practice of emergency contraception (EC) among women from the state of Sikkim, India. METHODS: Between November 15, 2011, and June 14, 2012, trained female medical officers and interns used a standard questionnaire to interview 1474 women of reproductive age attending 2 outpatient gynecology clinics. RESULTS: Of those who agreed to participate, 40.6% had ever heard of EC, and EC awareness was particularly low (6.4%) among illiterate women. The most common sources of EC information were electronic media (77.1%), friends and relatives (33.8%), and health personnel (30.4%). Overall, 71.9% of the participants who had heard of EC did not know the timeframe when it should be used. Only 19.6% of the women who had ever heard of EC had adequate knowledge of it, and only 15.1% of these (or 6.1% of the total sample) had ever used EC. The most common barriers to using EC were inadequate knowledge of it, its perceived non-availability, considering it an abortifacient, and religious beliefs. CONCLUSION: Knowledge and practice of EC was low among the women interviewed. There is a need for intensive information EC on the available methods and their correct timing. PMID- 23747151 TI - Receiver operating characteristic analysis: utility, reality, covariates, and the future. PMID- 23747152 TI - Multivariate normally distributed biomarkers subject to limits of detection and receiver operating characteristic curve inference. AB - RATIONALE AND OBJECTIVES: Biomarkers are of ever-increasing importance to clinical practice and epidemiologic research. Multiple biomarkers are often measured per patient. Measurement of true biomarker levels is limited by laboratory precision, specifically measuring relatively low, or high, biomarker levels resulting in undetectable levels below, or above, a limit of detection (LOD). Ignoring these missing observations or replacing them with a constant are methods commonly used although they have been shown to lead to biased estimates of several parameters of interest, including the area under the receiver operating characteristic (ROC) curve and regression coefficients. MATERIALS AND METHODS: We developed asymptotically consistent, efficient estimators, via maximum likelihood techniques, for the mean vector and covariance matrix of multivariate normally distributed biomarkers affected by LOD. We also developed an approximation for the Fisher information and covariance matrix for our maximum likelihood estimations (MLEs). We apply these results to an ROC curve setting, generating an MLE for the area under the curve for the best linear combination of multiple biomarkers and accompanying confidence interval. RESULTS: Point and confidence interval estimates are scrutinized by simulation study, with bias and root mean square error and coverage probability, respectively, displaying behavior consistent with MLEs. An example using three polychlorinated biphenyls to classify women with and without endometriosis illustrates how the underlying distribution of multiple biomarkers with LOD can be assessed and display increased discriminatory ability over naive methods. CONCLUSIONS: Properly addressing LODs can lead to optimal biomarker combinations with increased discriminatory ability that may have been ignored because of measurement obstacles. PMID- 23747153 TI - ROC analysis in biomarker combination with covariate adjustment. AB - RATIONAL AND OBJECTIVES: Receiver operating characteristic (ROC) analysis is often used to find the optimal combination of biomarkers. When the subject level covariates affect the magnitude and/or accuracy of the biomarkers, the combination rule should take into account of the covariate adjustment. The authors propose two new biomarker combination methods that make use of the covariate information. MATERIALS AND METHODS: The first method is to maximize the area under the covariate-adjusted ROC curve (AAUC). To overcome the limitations of the AAUC measure, the authors further proposed the area under covariate standardized ROC curve (SAUC), which is an extension of the covariate-specific ROC curve. With a series of simulation studies, the proposed optimal AAUC and SAUC methods are compared with the optimal AUC method that ignores the covariates. The biomarker combination methods are illustrated by an example from Alzheimer's disease research. RESULTS: The simulation results indicate that the optimal AAUC combination performs well in the current study population. The optimal SAUC method is flexible to choose any reference populations, and allows the results to be generalized to different populations. CONCLUSIONS: The proposed optimal AAUC and SAUC approaches successfully address the covariate adjustment problem in estimating the optimal marker combination. The optimal SAUC method is preferred for practical use, because the biomarker combination rule can be easily evaluated for different population of interest. PMID- 23747154 TI - An examination of data confidentiality and disclosure issues related to publication of empirical ROC curves. AB - RATIONALE AND OBJECTIVES: Grant funding institutions often require organizations to share their collected data as widely as possible while safeguarding the privacy of individuals. Summaries based on these data are often released. Here, the receiver operating characteristic (ROC) curve is explored for potential statistical disclosures in the presence of auxiliary data. MATERIALS AND METHODS: Formulas are introduced for calculating the missing data points from the full data set, given that a user has an empirical ROC curve and a subset of the data used to generate such a curve. Further, a discussion of the plausibility of this scenario is presented. RESULTS: Diagnostic test data were simulated and an ROC curve was produced. Using a subset of the true data and the points on the empirical ROC curve, an attempt was made to reproduce the missing parts of the data. Disease statuses were able to be determined exactly, whereas test scores were solved for up to their rank. CONCLUSIONS: If an individual or organization possessed the points of an empirical ROC curve and a subset of the true data, the true data underlying the ROC curve can be reproduced relatively accurately. As a result, the release of summaries of data, including the ROC curve, must be given careful thought before their release from a statistical disclosure perspective. PMID- 23747155 TI - Validation of Monte Carlo estimates of three-class ideal observer operating points for normal data. AB - RATIONALE AND OBJECTIVES: Traditional two-class receiver operating characteristic (ROC) analysis is inadequate for the complete evaluation of observer performance in tasks with more than two classes. MATERIALS AND METHODS: Here, a Monte Carlo estimation method for operating point coordinates on a three-class ROC surface is developed and compared with analytically calculated coordinates in two special cases: (1) univariate and (2) restricted bivariate trinormal underlying data. RESULTS: In both cases, the statistical estimates were found to be good in the sense that the analytical values lay within the 95% confidence interval of the estimated values about 95% of the time. CONCLUSIONS: The statistical estimation method should be key in the development of a pragmatic performance metric for evaluation of observers in classification tasks with three or more classes. PMID- 23747156 TI - [Autoimmune blistering diseases]. AB - Autoimmune blistering diseases are characterized by the production of pathogenic autoantibodies that are responsible for the formation of epidermal blisters. Major advances in the understanding of the pathogenesis of these disorders have allowed the development of new therapeutic agents. Recent epidemiologic data showed that bullous pemphigoid mainly affects elderly patients. Bullous pemphigoid is often associated with degenerative neurologic disorders. A major increase in the incidence of bullous pemphigoid has been observed in France. Treatment of bullous pemphigoid is mainly based on superpotent topical corticosteroids. The role of desmosomal proteins has been demonstrated in the initiation, propagation and persistence of the autoimmune response in pemphigus. Several studies have shown a correlation between anti-desmoglein antibody titers and disease activity. Pemphigus susceptibility genes have been identified. Oral corticosteroids remain the mainstay of pemphigus treatment. Dramatic and long lasting improvement has been recently obtained with rituximab in recalcitrant types of pemphigus. Other autoimmune junctional blistering diseases are rare entities, whose prognosis can be severe. Their diagnosis has been improved by the use of new immunological assays and immunoelectronic microscopy. Immunosupressants are widely used in severe types in order to prevent mucosal sequelae. PMID- 23747157 TI - Episodes of extremely high concentrations of SO2 and particulate matter in the urban environment of Bor, Serbia. AB - This paper presents the extremely high concentrations of SO2 and particulate matter measured in the urban area of the town Bor (Serbia) during August 2011. Concentrations of SO2 above 125 MUg m(-3) and concentrations of particulate matter above 200 MUg m(-3) recorded over several days indicate significant risk to human health and the ecosystem in this region. PMID- 23747158 TI - The burden of sepsis-a call to action in support of World Sepsis Day 2013. PMID- 23747159 TI - Baseline physical health-related quality of life and subsequent depression outcomes in cardiac patients. AB - Among 137 depressed cardiac patients, lower baseline physical health-related quality of life (HRQoL) was independently associated with greater depression persistence at 6 months among patients randomized to collaborative care, but not usual care. Low physical HRQoL may impact collaborative care effectiveness and indicate a need for alternate depression treatment. PMID- 23747160 TI - No association between AKT1 gene variants and schizophrenia: a Malaysian case control study and meta-analysis. AB - We aim to replicate AKT1 gene variants studies using Malaysian samples. Seven AKT1 single nucleotide polymorphisms (SNPs) were studied in 417 patients and 429 controls. Haplotype showed significant association (p=0.036) with schizophrenia, especially in Malays and Indians. Meta-analysis of rs2494732 showed significant association worldwide (p=0.018) and in Asians (p=0.023). PMID- 23747161 TI - Age-related macular degeneration is associated with increased proportion of CD56(+) T cells in peripheral blood. AB - PURPOSE: To examine the association between age-related changes in the T-cell compartment and prevalence of age-related macular degeneration (AMD). DESIGN: Case-control study. PARTICIPANTS: A total of 117 AMD cases and 106 controls were included prospectively. METHODS: Fresh-drawn peripheral blood samples were processed for flow cytometric analysis of T-cell populations. Plasma samples were analyzed for anti-cytomegalovirus (CMV) immunoglobulin (Ig)G and complement factor H (CFH) Y402H genotype. The diagnosis of AMD was made according to the Clinical Age-Related Maculopathy Staging System. MAIN OUTCOME MEASURES: Association between frequency of aged T cells and prevalence of AMD. RESULTS: The prevalence of AMD was associated with distinct age-related changes in the T-cell compartment. Specifically, the patients with AMD had an increased frequency of CD28(-) T cells that expressed the CD56 surface marker (patients, 34.9% vs. aged controls, 25.8%; P = 0.002). Participants in the highest tertile of CD56(+) CD28( ) T cells had an odds ratio (OR) for the presence of AMD of 3.2 (95% confidence interval [CI], 1.2-8.8) after adjustment for CFH genotype, anti-CMV IgG positivity, age, sex, and smoking history. The adjusted OR of the presence of AMD for persons having at least 1 CFH H402 risk allele increased from 3.5 (95% CI, 1.5-8.1) to 13.3 (95% CI, 3.3-53.6) for persons with at least 1 CFH H402 risk allele and above the median level of CD56(+) CD28(-) T cells. CONCLUSIONS: We found increased levels of circulating aged CD56(+) CD28(-) T cells in patients with AMD. Although this supports the notion of AMD as a systemic disease, it also suggests that the adaptive immune system is implicated in its pathogenesis. PMID- 23747162 TI - Microbial keratitis after Boston type I keratoprosthesis implantation: incidence, organisms, risk factors, and outcomes. AB - PURPOSE: To identify the incidence of and risk factors for microbial keratitis after implantation of the Boston type I keratoprosthesis (Massachusetts Eye and Ear Infirmary, Boston, MA). DESIGN: Retrospective, single-surgeon consecutive case series. PARTICIPANTS: A total of 105 patients (125 keratoprosthesis procedures in 110 eyes) who underwent Boston type I keratoprosthesis implantation at the Jules Stein Eye Institute between May 1, 2004, and April 1, 2012. METHODS: Data regarding ocular history, relevant intraoperative data, postoperative management, and outcomes were collected for each procedure. Risk factor analyses were performed using the Fisher exact test, log-rank test, and hazard ratio (HR). MAIN OUTCOME MEASURES: Incidence of microbial keratitis, organisms responsible, risk factors, and outcomes. RESULTS: During the period under review, 20 presumed infectious infiltrates were diagnosed in 15 eyes (13.6%) of 15 patients (14.3%), for a rate of 0.073 infections per eye-year. The rate of culture-positive bacterial keratitis was 0.022 infections per eye-year, and the rate of culture positive fungal keratitis was 0.015 infections per eye-year. Topical vancomycin use, topical steroid use, and contact lens wear did not increase the incidence of infectious keratitis, but prolonged vancomycin use was associated with an increased risk for fungal keratitis and infectious keratitis overall. Persistent corneal epithelial defect formation also was associated with an increased incidence of fungal keratitis and infectious keratitis overall. There were no cases of endophthalmitis resulting from infectious keratitis. CONCLUSIONS: Infectious keratitis develops in 13.6% of eyes after keratoprosthesis implantation, with a similar rate of culture-positive bacterial and fungal keratitis. The observed rate of microbial keratitis suggests the need for additional topical antimicrobial prophylaxis after keratoprosthesis implantation in eyes at higher risk, such as those with persistent corneal epithelial defect formation or prolonged vancomycin use. PMID- 23747163 TI - Isolated third, fourth, and sixth cranial nerve palsies from presumed microvascular versus other causes: a prospective study. AB - PURPOSE: To estimate the proportion of patients presenting with isolated third, fourth, or sixth cranial nerve palsy of presumed microvascular origin versus other causes. DESIGN: Prospective, multicenter, observational case series. PARTICIPANTS: A total of 109 patients aged 50 years or older with acute isolated ocular motor nerve palsy. TESTING: Magnetic resonance imaging (MRI) of the brain. MAIN OUTCOME MEASURES: Causes of acute isolated ocular motor nerve palsy (presumed microvascular or other) as determined with early MRI and clinical assessment. RESULTS: Among 109 patients enrolled in the study, 22 had cranial nerve III palsy, 25 had cranial nerve IV palsy, and 62 had cranial nerve VI palsy. A cause other than presumed microvascular ischemia was identified in 18 patients (16.5%; 95% confidence interval, 10.7-24.6). The presence of 1 or more vasculopathic risk factors (diabetes, hypertension, hypercholesterolemia, coronary artery disease, myocardial infarction, stroke, and smoking) was significantly associated with a presumed microvascular cause (P = 0.003, Fisher exact test). Vasculopathic risk factors were also present in 61% of patients (11/18) with other causes. In the group of patients who had vasculopathic risk factors only, with no other significant medical condition, 10% of patients (8/80) were found to have other causes, including midbrain infarction, neoplasms, inflammation, pituitary apoplexy, and giant cell arteritis (GCA). By excluding patients with third cranial nerve palsies and those with GCA, the incidence of other causes for isolated fourth and sixth cranial nerve palsies was 4.7% (3/64). CONCLUSIONS: In our series of patients with acute isolated ocular motor nerve palsies, a substantial proportion of patients had other causes, including neoplasm, GCA, and brain stem infarction. Brain MRI and laboratory workup have a role in the initial evaluation of older patients with isolated acute ocular motor nerve palsies regardless of whether vascular risk factors are present. PMID- 23747164 TI - Meibomian gland dysfunction and hypercholesterolemia. AB - OBJECTIVE: Hypercholesterolemia (total cholesterol >= 200 mg/dl) is a significant risk factor for ischemic heart, cerebrovascular, and peripheral vascular disease. Increased cholesterol in the glandular secretion has been postulated to be necessary for the development of meibomian gland dysfunction (MGD), a common form of chronic blepharitis. The purpose of this study was to investigate a possible correlation between MGD and hypercholesterolemia in young and middle-aged patients (aged 18-54 years). DESIGN: Observational, case-control pilot study. PARTICIPANTS AND CONTROLS: Sixty symptomatic patients with MGD with no history of hypercholesterolemia and 63 controls without MGD and with no history of hypercholesterolemia, accrued from January 2011 to June 2012. INTERVENTIONS: Body mass index (BMI), fasting blood triglycerides, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), glucose, and creatinine were measured. Z test or Student t test was used, when appropriate, to calculate differences between groups. Stepwise logistic regression models were used to calculate the estimates of odds ratios (ORs), considering MGD as the dependent variable and including sex, age, BMI, triglycerides, total cholesterol, LDL, HDL, glucose, and creatinine as covariates. MAIN OUTCOME MEASURES: Fasting blood levels of total cholesterol, LDL, and HDL (milligrams/deciliter). RESULTS: Hypercholesterolemia was found in 35 cases (58.3%) and 4 controls (6.3%), a statistically significant difference (P < 0.0001). Mean total cholesterol, LDL, and HDL were 210.8 +/- 4.4, 127.6 +/- 3.9, and 61.6 +/- 1.8 mg/dl, respectively, in cases and 162.9 +/- 3.1, 94.2 +/- 2.6, and 52.5 +/- 1.3 mg/dl, respectively, in controls. All differences were statistically significant (P <= 0.0001). Stepwise logistic regression analysis, including sex, BMI, triglycerides, total cholesterol, and glucose as covariates, revealed that MGD was significantly associated with higher blood levels of total cholesterol (OR, 1.07; 95% confidence interval [CI], 1.04-1.09; P < 0.001). Likewise, MGD was found to be significantly associated with increased blood levels of LDL (OR, 1.07; 95% CI, 1.04-1.09; P < 0.001) and HDL (OR, 1.11; 95% CI, 1.06-1.17; P < 0.001). CONCLUSIONS: The results suggest that young and middle-aged patients with MGD with no history of hypercholesterolemia may have higher blood cholesterol levels than controls of similar age without MGD. If this finding is confirmed by larger studies, MGD may become a marker of previously unknown hypercholesterolemia and ophthalmologists may increase their role in the early detection of an important risk factor for cardiovascular disease. PMID- 23747165 TI - Comparison of in vitro motion and stability between techniques for index metacarpophalangeal joint radial collateral ligament reconstruction. AB - PURPOSE: To evaluate a technique using interference screws to secure a tendon graft for reconstruction of the radial collateral ligament (RCL) of the index finger metacarpophalangeal (MCP) joint. We hypothesized that this technique would provide equivalent stability and flexion as a 4-tunnel reconstruction. METHODS: We isolated the RCL in 17 cadaveric index fingers. A cyclic load was applied to the intact RCL across the MCP joint to assess flexion, ulnar deviation at neutral (UD 0), and ulnar deviation at 90 degrees of MCP joint flexion (UD 90). The RCL was excised from its bony origin and insertion. We performed each reconstruction (4-tunnel and interference screw) sequentially on each specimen in a randomized order using a palmaris longus tendon graft. We repeated testing after each reconstruction and compared differences from the intact state between techniques using paired t-tests for all joint positions (flexion/UD 0/UD 90). RESULTS: There was no statistically significant difference in UD 0 or UD 90 between the intact state and after interference screw reconstruction. Compared with the intact state, there was significantly less UD 0 and significantly more UD 90 after 4 tunnel reconstruction. There was no statistically significant difference between techniques when we compared changes in -UD 0 or UD 90. Change in flexion was statistically significantly different, which indicates that the interference screw technique better replicated intact MCP joint flexion compared with the 4 tunnel technique. CONCLUSIONS: Interference screw reconstruction of the index RCL provides stability comparable to 4-tunnel reconstruction and is less technically challenging. These results substantiate our clinical experience that the interference screw technique provides an optimal combination of stability and flexion at the index MCP joint. CLINICAL RELEVANCE: Using an interference screw to reconstruct the index RCL is less challenging than 4-tunnel reconstruction and provides stability and range of motion that closely resemble the native MCP joint. PMID- 23747166 TI - Traumatic proximal interphalangeal joint reconstruction with an autologous hemi toe osteochondral graft: case report. AB - We report a case of a traumatic proximal interphalangeal joint injury with loss of the middle phalangeal base and articular surface, which was reconstructed with an autologous hemi-toe osteochondral graft. The patient had a 72 degrees improvement in proximal interphalangeal joint motion and excellent functional improvements. Postoperative computed tomography imaging indicated bony union and articular congruence. PMID- 23747167 TI - Soft tissue mallet finger injuries with delayed treatment. PMID- 23747168 TI - Histopathological characteristics of stenosing flexor tenosynovitis in diabetic patients and possible associations with diabetes-related variables. AB - PURPOSE: To compare the histopathological findings of stenosing flexor tenosynovitis (SFTS) in diabetic patients with those in nondiabetic patients and to analyze the predominant characteristics of SFTS in diabetic patients by statistical methods. METHODS: We included 63 patients (63 specimens) who underwent excision of A1 pulleys for SFTS. A total of 38 patients (38 digits) were diabetic and 25 (25 digits) were nondiabetic. We obtained specimens from the proximal one-third of each A1 pulley and analyzed them by histological and immunohistochemical methods. After we identified the predominant histopathological characteristics of SFTS in patients with diabetes, we performed multiple logistic regression analysis to examine the possible associations between the histopathological characteristics and diabetes-related variables. RESULTS: We divided histopathological findings into 3 types in both diabetic and nondiabetic groups. Types 1 and 2 showed fibrocartilage metaplasia including fibrocartilage-like cells surrounded by basophilic extracellular substances. Type 2 was characterized by the presence of granulation tissue in the middle layer, which was not recognized in type 1. The granulation tissue contained newly formed microvessels, stromal cells, a small number of inflammatory cells, and extracellular matrix that showed myxomatous degeneration. Type 3 showed a decrease in fibrocartilage-like cells with surrounding extracellular eosinophilic substances, which was similar to hyaline degeneration. The histopathological features of type 2 were found in 68% of the diabetic group and in 28% of the nondiabetic group. This difference was statistically significant. The findings of type 2 were significantly associated with the severity of diabetic retinopathy and hemoglobin A1c values in the diabetic group. CONCLUSIONS: Type 2 findings were more frequent in the diabetic group than in the nondiabetic group. A pathomechanism to accelerate neovascularization and hypercellularity in the granulation tissue in the middle layer of A1 pulley may exist, especially in diabetic patients with severe retinopathy and poorly controlled hyperglycemia. PMID- 23747169 TI - 3-Dimensional deformity analysis of malunited forearm diaphyseal fractures. AB - PURPOSE: Several biomechanical studies using cadavers have revealed that axial rotation deformity of the forearm bones reduces forearm motion. However, little information is available on the 3-dimensional deformity patterns, including axial rotation deformity in malunited diaphyseal fractures of the forearm. The complex deformity of both forearm bones is difficult to assess on plain radiographs or cross-sectional images. Therefore, we assessed osseous deformity in malunited diaphyseal fractures of the forearm using 3-dimensioinal analysis. METHODS: We examined 21 patients (16 malunions of both forearm bones and 5 isolated radial malunions). Three-dimensional computer models of bilateral radius and ulna were created from computed tomography data. We evaluated deformity by superimposing the mirror-image bone model of the contralateral normal bone onto a model of the affected bone. RESULTS: In 21 radial malunions, extension (n = 17) and pronation (n = 16) deformities were common. This tendency was seen particularly in proximal malunions. Average extension, valgus, and pronation deformities were 18 degrees , 2 degrees , and 16 degrees , respectively. In 16 ulnar malunions, valgus (n = 15) and pronation (n = 12) deformities were common. Average flexion, valgus, and pronation deformities were 1 degrees , 11 degrees , and 6 degrees , respectively. Extension deformity of the radius and valgus deformity of the ulna were correlated with restriction of forearm motion. CONCLUSIONS: Malunited diaphyseal fractures of both forearm bones showed complex deformities, which suggests that 3 dimensional modeling may be a more effective method than standard computed tomography or radiographs. Pronation deformity of the radius may be caused by the supinator and pronator muscles. In addition, the deformity pattern of both bones may indicate that valgus and internal rotation force in the neutral forearm position is applied to both forearm bones after injury. CLINICAL RELEVANCE: Three dimensional forearm osteotomy, including rotational realignment, is necessary to obtain anatomical reduction. PMID- 23747170 TI - Rehabilitation following extensor tendon repair. PMID- 23747171 TI - Reliability of the hospital nutrition environment scan for cafeterias, vending machines, and gift shops. AB - According to ecological models, the physical environment plays a major role in determining individual health behaviors. As such, researchers have started targeting the consumer nutrition environment of large-scale foodservice operations when implementing obesity-prevention programs. In 2010, the American Hospital Association released a call-to-action encouraging health care facilities to join in this movement and improve their facilities' consumer nutrition environments. The Hospital Nutrition Environment Scan (HNES) for Cafeterias, Vending Machines, and Gift Shops was developed in 2011, and the present study evaluated the inter-rater reliability of this instrument. Two trained raters visited 39 hospitals in southern California and completed the HNES. Percent agreement, kappa statistics, and intraclass correlation coefficients were calculated. Percent agreement between raters ranged from 74.4% to 100% and kappa statistics ranged from 0.458 to 1.0. The intraclass correlation coefficient for the overall nutrition composite scores was 0.961. Given these results, the HNES demonstrated acceptable reliability metrics and can now be disseminated to assess the current state of hospital consumer nutrition environments. PMID- 23747172 TI - Inhibition of human immunodeficiency virus type-1 through autophagy. AB - As an obligatory intracellular pathogen, human immunodeficiency virus type-1 (HIV) is dependent upon its ability to exploit host cell machinery for replication and dissemination, and to circumvent cellular processes that prevent its growth. One such intracellular process is autophagy, a component of the host defense against HIV with roles in innate immune signaling, adaptive immunity and intracellular degradation of HIV. During permissive infection, HIV down-modulates autophagy, promoting its own replication. Inducers of autophagy can overcome this suppression and inhibit HIV. This review summarizes recent advances in understanding the antiviral and replicative roles of autophagy during HIV infection. Dissecting the molecular mechanisms by which HIV utilizes autophagy may lead to the identification of novel drug candidates to treat and potentially eradicate HIV infection. PMID- 23747173 TI - Endogenous cannabinoids in amygdala and hippocampus in post-mortem brains of Cloninger type 1 and 2 alcoholics. AB - Accumulating evidence continues to link certain aspects of the endogenous cannabinoid (EC) system with alcohol dependence, negative-reinforcement learning, and the modulation of stress responses. Specific alterations in brain regions that are related to stress and negative-reinforcement learning have been reported to exist in Cloninger type 1 and type 2 alcoholics. To study possible differences in profiles of EC systems between Cloninger type 1 (n = 9) and type 2 (n = 8) alcoholics and non-alcoholic control subjects (n = 10), we analyzed post-mortem amygdala and hippocampus brain samples for several ECs by quantitative liquid chromatography with triple quadrupole mass-spectrometric detection. A significant difference was found between these 3 groups in terms of EC profiles in the amygdala (p = 0.037). In particular, this difference was prominent for variations in docosahexaenoylethanolamide levels, which were significantly higher in type 1 alcoholics (p = 0.022) when compared to controls. There was also a large negative correlation between anandamide concentration and mGlu1/5 receptor density in the hippocampi of Cloninger type 1 alcoholics (R = -0.88, p = 0.002), which was not seen in Cloninger type 2 alcoholics or in controls. Although preliminary, and from relatively small diagnostic groups, these results suggest that the EC system profile may be altered in the hippocampus and amygdala of Cloninger type 1 alcoholics. PMID- 23747174 TI - Internal resistance of microfluidic microbial fuel cell: challenges and potential opportunities. AB - The efficiency of microbial fuel cells (MFCs) is affected by several factors such as activation overpotentials, ohmic losses and concentration polarization. These factors are handled in micro-sized MFCs using special electrodes with physically or chemically modified surfaces constructed with specified materials. Most of the existing MULscale MFCs show great potential in rapid screening of electrochemically-active microbes and electrode performance; although they generate significantly lower volumetric power density compared with their mL counterparts because of their high internal resistance. This review presents the development of microfluidic MFCs, with summarization of their advantages and challenges, and focuses on the efforts done to minimize the adverse effects of internal resistance (ohmic and non-ohmic) on their performance. PMID- 23747175 TI - Tgif1 and SnoN modified chondrocytes or stem cells for tendon-bone insertion regeneration. AB - Tendon-bone insertion injuries are a common occurrence but rarely heal, despite the many strategies that have been employed. The tendon-bone insertion consists of four types of tissues: tendon, fibrocartilage, mineral fibrocartilage and bone, making it hard to regenerate. The key to reconstructing the tendon enthesis is to rebuild the gradations of cell type, collagen type, mineral content and collagen fiber orientation. Chondrocytes were found to be able to differentiate into tendon and bone tissues upon special stimulation, which offers promise for tendon enthesis regeneration. Tgif1 is a key factor that represses the expression of the cartilage master gene Sox9, which is induced by TGFbetas, and changes the expression rate of Sox9 versus Scx, eventually promoting fibrogenesis. SnoN is a key factor that is induced by TGFbetas to inhibit the hypertrophy of chondrocytes and therefore bone formation. It appears that the induction of Tgif1 and the repression of SnoN can cause chondrocytes to differentiate into tendon and bone tissues. Moreover, a gradation of the expression levels of Tgif1 and SnoN in chondrocytes may create a gradation of the tissue from tendon to fibrocartilage to bone. Consequently, we propose that a gradation of gene-modified chondrocytes (Tgif1-inducing cells, primary cells, SnoN-repressing cells) or stem cells that arise from a gradation of stimulation (Tgif1 induction and SnoN repression) will aid in the regeneration of the tendon-bone insertion. PMID- 23747176 TI - Cardiac autonomic nerve stimulation in the treatment of heart failure. AB - Research on the therapeutic modulation of cardiac autonomic tone by electrical stimulation has yielded encouraging early clinical results. Vagus nerve stimulation has reduced the rates of morbidity and sudden death from heart failure, but therapeutic vagus nerve stimulation is limited by side effects of hypotension and bradycardia. Sympathetic nerve stimulation that has been implemented in the experiment may exacerbate the sympathetic-dominated autonomic imbalance. In contrast, concurrent stimulation of both sympathetic and parasympathetic cardiac nerves increases myocardial contractility without increasing heart rate. This review assesses the current state of electrical stimulation of the cardiac autonomic nervous system to treat heart failure. PMID- 23747177 TI - Massive interventricular septal aneurysm and stroke in a healthy young patient: guilt by association? AB - Aneurysm of the membranous interventricular septum is an uncommon cardiac defect that is, on rare occasions, associated with embolic stroke. We describe here the case of an otherwise healthy, 41-year-old man who presented to the hospital with acute-onset confusion and left-sided body weakness attributed to a right middle cerebral artery ischemic stroke. He experienced a nearly complete resolution of deficits following systemic thrombolytic therapy. After an extensive workup, the presumed mechanism of stroke was a thromboembolus that originated in a massive aneurysm of the patient's membranous interventricular septum. Due to a perceived risk of surgical morbidity, the patient was managed conservatively with anticoagulation. He denied further events and reported nearly full function at follow-up. PMID- 23747178 TI - Geometry of saccular cerebral aneurysms not associated with a branch vessel. AB - OBJECTIVE: Saccular cerebral aneurysms located at nonbranching sites are uncommon. Their distribution, morphological features, and presence of a branch vessel or a tiny perforator(s) separate from the aneurysm neck were investigated. METHODS: From a series of 303 microsurgically clipped saccular cerebral aneurysms, 40 aneurysms were identified at sites not related to a branch vessel. RESULTS: The distribution of aneurysms at nonbranching sites was internal carotid: 21 of 40 (52.5%); main stem of the middle cerebral artery/secondary branch of the middle cerebral artery: 6 of 40 (15%); anterior cerebral artery: 1 of 40 (2.5%); pericallosal artery: 1 of 40 (2.5%); pericallosal/callosal marginal: 3 of 40 (7.5%); vertebral artery: 1 of 40 (2.5%); posterior cerebral artery: 1 of 40 (2.5%); posterior cerebral artery/secondary branch of the posterior cerebral artery: 1 of 40 (2.5%); anterior inferior cerebellar artery: 1 of 40 (2.5%); and distal posterior inferior cerebellar artery: 1 of 40 (2.5%). Branch vessels were seen in 5 cases, and small perforating vessels were observed in 2 instances. CONCLUSIONS: Saccular aneurysms occurring at nonbranching sites are uncommon. Their geometry is particularly favorable for flow directed stents and is most amenable to aneurysms located on large-diameter conducting vessels such as the internal carotid, vertebral, and vertebrobasilar vessels. Smaller parent arteries harboring this type of aneurysm will require new technology to maintain patency of these more distal vessels. If endovascular techniques cannot achieve aneurysm sac obliteration, then open craniotomy and aneurysm clipping will provide a satisfactory alternative. PMID- 23747179 TI - Elevated platelet microparticle levels after acute ischemic stroke with concurrent idiopathic thrombocytopenic purpura. AB - We report a 60-year-old woman with idiopathic thrombocytopenic purpura who experienced acute infarction of the middle cerebral artery. She was treated with an antiplatelet agent and prednisolone to limit platelet activation and destruction. In parallel with clinical amelioration, levels of plasma platelet microparticles (PMPs), a procoagulant factor in platelet activation, decreased after treatment but increased after reduction of the prednisolone dose, resulting in progression of vascular stenosis. Immunosuppressive therapy with cyclosporine normalized plasma PMP levels, and no additional vascular events occurred during the 3-month follow-up period. Immunosuppressive therapy to decrease plasma PMP levels is warranted after acute ischemic stroke in the context of idiopathic thrombocytopenic purpura. PMID- 23747180 TI - Factors related to decision delay in acute stroke. AB - BACKGROUND: The time from symptom onset to seeking medical assistance (decision delay) accounts for a proportion of prehospital delay in acute stroke. The aims of this study were to identify factors related to decision delay and calling the emergency medical services (EMS) as the first medical contact. METHODS: Data were prospectively collected from 350 patients with acute stroke or transient ischemic attack. Data on decision delay, prehospital delay, types of first medical contact, and previous stroke knowledge were recorded. Multivariable logistic regression analyses were conducted to identify factors related to decision delay of 1 hour or less and calling the EMS as the first medical contact. RESULTS: The median decision delay was 2.0 hours. Decision delay accounted for 62.3% of prehospital delay (median value). Moderate (National Institutes of Health Stroke Scale [NIHSS] score 8-16; odds ratio [OR] 4.16 [95% confidence interval 1.86 9.30]) or severe symptoms (NIHSS score >= 17; OR 10.38 [2.70-39.90]) and living together (OR 1.84 [1.02-3.43]) were associated with decision delay of 1 hour or less. Moderate (OR 6.31 [2.79-14.29]) or severe symptoms (OR 8.44 [2.64-26.98]) were associated with calling the EMS as the first medical contact. Previous stroke knowledge did not affect an early decision or EMS use. CONCLUSIONS: The decision to seek medical assistance in acute stroke accounts for more than half of the prehospital delay. Severity of symptoms and living together are related to an early decision (<=1 hour). Previous stroke knowledge does not affect decision delay or EMS use. PMID- 23747181 TI - Kidney transplantation in type 2 diabetic patients: a matched survival analysis. AB - BACKGROUND: Diabetes mellitus (DM) is the most prevalent cause of kidney failure. Some concerns have been raised about the kidney transplantation (KT) results in diabetic patients. Therefore, we compared outcomes between diabetic and non diabetic KT patients. METHODS: We included all KT performed in type 2 diabetic patients in our center from July 1983 to December 2009 with graft survivals beyond 3 months. Nondiabetic controls were individually matched with diabetic patients with respect to gender, age, year of transplantation, number of donor HLA mismatches, and dialysis vintage. The two groups were compared concerning patient and graft survivals, delayed graft function (DGF), and prevalence of acute rejection episodes (ARE). RESULTS: The 62 diabetic and 62 nondiabetic patients had a mean follow-up after KT of 102 +/- 64 months. Diabetic patients and controls were similar for the matched variables. Death censored graft survivals of diabetics versus nondiabetics were 70% and 83% at 5 years and 54% and 71% at 10 years, respectively (P = .13). Patient survivals at 5 and 10 years were 69% and 50% for diabetic versus 96% and 84% for nondiabetic patients, respectively (P < .001). The prevalence of ARE and DGF did not differ (chi squared test, P = .12). Multivariate Cox's proportional hazards analysis revealed DM (hazard ratio [HR] 7.72; P = .001) and viral hepatitis (HR = 4.18; P = .02) to correlate with reduced patient survival. CONCLUSION: Survival of diabetic patients after KT was reduced but death-censored graft outcomes were similar compared with matched nondiabetic patients. Concerns about graft survival should not prevent KT for diabetic patients with kidney failure. PMID- 23747182 TI - Cytokine gene polymorphisms in kidney transplantation. AB - BACKGROUND: Acute and chronic rejections remain an important cause of graft loss after renal transplantation. It has been suggested that cytokine genotyping may have a predictive role to identify patients at greater risk of rejection regardless of human leukocyte antigen (HLA) compatibility and/or the presence of anti-HLA antibodies before the renal allograft. OBJECTIVES: We sought to investigate polymorphisms of tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, interleukin (IL)-10, IL-6, and interferon (IFN)-gamma as indices of differential cytokine production in kidney transplantation and to examine their predictive roles for acute or chronic rejection. PATIENTS AND METHODS: TNF-alpha (G/A -308), TGF -beta1 (haplotype codon 10/codon 25), IL-10 (haplotype-1082, -819, -592), IL-6 (C/G -174), and IFN-gamma (T/A +874) single nucleotide polymorphisms (SNPs) were detected using polymerase chain reaction (PCR)-specific sequence primers (SSP) in 231 kidney transplant recipients (KTR) including 106 treated with mycophenolate mofetil (MMF+). RESULTS: We observed no significant associations of any of investigated polymorphism taken alone with acute rejection episodes (ARE) or chronic allograft dysfunction (CAD). Nevertheless, TGF-beta1 Low (L) production was correlated with greater graft survival at 20 years (81.8%) compared with intermediate (L) or high (H) levels (56.1%), affect that the difference was not significant (P = .2). Cytokine haplotype analysis in KTR (MMF-) without HLA-mismatches or presynthesized anti HLA antibodies (n = 32) showed ARE to be significantly more prevalent among the TNF-alpha*H/TGF- beta1*H/IL-10*H production haplotype (75%) compared with the other haplotypes (16%; P = .03). CONCLUSION: The presence of TGF-beta1-H secretion profile may protect the kidney graft. TNF-alpha*H/TGF-beta1*H/IL-10*H haplotype was associated with a higher risk of ARE and with poorer graft survival. PMID- 23747183 TI - Validity of current equations to estimate glomerular filtration rate in kidney transplant recipients. AB - BACKGROUND: Assessing glomerular filtration rate (GFR) is important in surveillance of kidney transplant recipients. This study aimed to determine accuracy of current equations to estimate GFR in Arabic kidney transplant recipients versus measurement of true GFR by 99m technetion diethylene triamine pentaacetic acid ((99m)Tc- DTPA). METHODS: GFR measurements were performed in 158 adult kidney transplant recipients including 91 males (58%), age of overall mean 46 +/- 13 years. There were 82 Egyptians (52%) and 76 from different Arab countries (48%). All grafts were obtained from living related kidney donors. RESULTS: The serum creatinine values range from 0.7 to 8 mg/dL; the true GFR values ranged from 8 to 105 mL/min/1.73 m(2). We estimated GFR using the Modification of Diet in Renal Disease (MDRD), abbreviated MDRD (aMDRD), Walser, Nankivell, Cockcroft-Gault, Mayo Clinic Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and El-Minia equations. All eight estimated eGFRs correlated with (99m)Tc-DTPA clearance (P < .05), but their r(2) was low ranging from 0.66 to 0.53 Their respective r(2) values were: MDRD 0.66, aMDRD 0.60, Walser 0.53, Nankivell 0.58, Cockcroft-Gault 0.59, Mayo Clinic 0.59, CKD-EPI 0.61, and El-Minia equation 0.61. These results were not significantly different when we restricted our analysis to those with body mass indexes < 25 kg/m(2), or to Arabic non-Egyptian subjects. CONCLUSIONS: All eight equations are far from ideal. In an unselected kidney transplantation population in the Arab area, current GFR prediction equations cannot substitute for GFR measurement. PMID- 23747184 TI - Distinguishing characteristics of urothelial carcinoma in kidney transplant recipients between China and Western countries. AB - OBJECTIVE: To identify significant distinctive characteristics of urothelial carcinoma (UC) in kidney transplant recipients between China and Western countries and investigate probable tumor screening and treatment factors contributing to these differences. METHODS: Renal transplant recipients from 1998 to 2011 in our institution diagnosed with UC were included in this study. Our data on tumor incidence, clinical characteristics, and outcomes were compared with literature reports. RESULTS: Among 2572 renal transplant recipients identified, 24 (0.93%) experienced UC, including 10 men and 14 women of overall mean age of 49.3 +/- 11.6 years at transplantation and 53.5 +/- 9.5 years at tumor detection. The Chinese traditional herbal intake mainly focused on 2 preparations: Aristolochic acid and rhubarb (the latter was mainly used in patients with chronic renal impairment) in 20 people. There were 21 (87.5%) cases of upper (UTUC) 5 cases of bilateral, and 13 cases of multifocal urinary tract urothelial carcinoma. Four subjects died owing to tumor progression at 4-63 months postoperatively. CONCLUSIONS: UC in renal transplant recipients shared notable characteristics in China with widespread herb intake: UTUC predominance; multifocal and bilateral organ involvement; high rates of recurrence, progression, and dissemination, in contrast with bladder tumor dominance in Western countries. As a consequence, we suggest that bilateral nephroureterectomy should be performed prophylactically in high-risk patients, especially those with a long history of Chinese herb intake. The relationship of rhubarb consumption to UC in renal transplant recipients should be noted and evaluated. PMID- 23747185 TI - Exploring parenthood in the New Zealand Heart Transplant Program. AB - Heart transplantation is an established treatment for end-stage cardiac disease. This study describes parenthood after heart transplantation in the New Zealand population. An analysis was performed of all heart recipients from the New Zealand program. Exclusion criteria were death within 3 months of transplantation or age <18 years at the time of the survey. Recipients (or next of kin if recipients deceased) were surveyed regarding family status at the time of transplantation and new parenthood after transplantation. A total of 145 of 199 eligible recipients completed the survey ~12.2 years after transplant (119 male, 26 female). Before transplantation, 81% were in a permanent relationship; 72% had children. After transplantation, 19/45 recipients had 27 children (2 female recipients had 3 children), of whom 15 were planned. Complications occurred in 7/27 pregnancies (including one atrial septal defect requiring surgery). Two recipients died after the birth of their children (children aged 2.6 and 14.1 years). This study provides unique data relevant to both female and male recipients regarding new parenthood after heart transplantation and will promote more informed discussion with transplant recipients. PMID- 23747186 TI - Effect of hypogammaglobulinemia on the incidence of community-acquired respiratory viral infections after lung transplantation. AB - BACKGROUND: Hypogammaglobulinemia (HGG) has been associated with an increased risk of infectious complications in lung transplant recipients, but its effect specifically on community-acquired respiratory viruses (CARVs) remains unknown. This study aimed to determine if lung transplant recipients with HGG are at an increased risk of developing CARV infection. Secondary endpoints included the effect of HGG on lung function, incidence of rejection, and mortality. METHODS: A retrospective review of all lung transplant recipients from 2008 to 2011 was performed. Patients were stratified as either having HGG after transplantation or having normal IgG titers according to their nadir IgG level. HGG was defined a serum IgG level of <700 mg/dL. CARVs included human metapneumovirus, influenza A/B, respiratory syncytial virus A/B, parainfluenza 1/2/3, rhinovirus, and adenovirus isolated from bronchoalveolar lavage/wash, sputum, or nasal swab. RESULTS: The cohort consisted of 263 patients with a mean follow-up time of 612 +/- 356 days. The incidence of CARV infection was 27% in patients with normal IgG titers and 23.4% in patients with HGG (P = .62). No difference in rejection, mortality, or lung function was found between the groups. As expected, patients who ever had a CARV infection had a significantly lower 1-second forced expiratory volume % reference on their most recent spirometry than those who had not had a CARV infection (81.6% vs 86.9%; P = .027). CONCLUSIONS: Although CARV infection has been shown to affect lung graft function, these data suggests that HGG is not associated with the incidence of CARV infection. PMID- 23747187 TI - An unusual presentation of a chronic lymphocytic leukemia patient with 17p deletion after reduced-intensity transplantation: Richter syndrome and concomitant graft-versus-host disease--case report. AB - Chronic lymphocytic leukemia (CLL) patients with 17p deletion comprise a challenging subgroup associated with poor overall survival. These patients should be treated with alternative strategies. Reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) can achieve long-term remission in this ultra-high-risk CLL group. Herein, we described a CLL patient with 17p deletion who developed Richter syndrome with extranodal involvement of the liver soon after RIC allo-SCT despite apparent acute graft-versus-host disease. The majority of chronic lymphocytic leukemia (CLL) patients respond well to chemoimmunotherapy. Patients who show ultra-high-risk genetics, such as 17p deletions, comprise a challenging subgroup of patients with poor response to chemoimmunotherapy and median life expectancy <2-3 years at the time of first line treatment. Current treatment approaches for patients with 17p deletion include agents acting independently from the DNA damage pathway, such as alemtuzumab and high-dose corticosteroids. RIC allo-SCT for consolidation can achieve long-term remission in this ultra-high-risk CLL group.(1,2) Richter syndrome (RS) represents the clinicopathologic transformation of CLL to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL).(3) RS appearing after allo-SCT can be managed by tapering of immunosuppression, followed by dose-escalated donor lymphocyte infusion titrated to the degree of leukemia response and graft-versus-host disease (GVHD) encountered.(4) Herein, we describe a CLL patient with 17p deletion who developed RS with extranodal involvement of the liver soon after RIC allo-SCT despite apparent acute GVHD (aGVHD). PMID- 23747188 TI - A preliminary study of a video intervention to inform solid organ transplant recipients about skin cancer. AB - PURPOSE: To obtain preliminary evidence on the effect of a skin cancer prevention video for adult solid organ transplant recipients (SOTR) and informational brochures on outcomes of skin cancer knowledge, beliefs, prevention and detection behaviors, and personal agency (self-confidence/personal control) for behaviors. BACKGROUND: SOTR have a high risk of skin cancer potentiated by life-long immunosuppressive therapy posttransplantation. Skin cancer in SOTR is aggressive and difficult to treat. Prevention and early detection are important for reducing risk and improving skin cancer outcomes, but methods to inform SOTR about their risk are understudied. METHODS: A brief, evidence-based skin cancer informational video tailored to SOTR was evaluated using a quasi-experimental design that compared the outcome variables in two groups of SOTR seen in 4 transplantation clinics within 4-6 weeks posttransplantation. The video/brochure group (VBG) viewed the video once and received skin cancer information brochures. The brochure group (BG) received brochures only. Participants completed a survey on sun protection behavior (6 items; alpha = 0.75), personal agency (6 items; alpha = 0.64), beliefs (6 items; alpha = 0.60), skin cancer knowledge (6 items), and skin self-examination (SSE; 1 item) at baseline and 3 months postintervention. Data were analyzed using descriptive statistics and 2 * 2 analysis of variance. RESULTS: Of 113 participants, 90 completed both surveys (VBG, n = 46; BG, n = 44). Both groups had a significant increase in sun protective behavior (P < .001), skin cancer knowledge (P < .001), beliefs (P = .003), and personal agency (P = .003). There was no effect of either intervention on SSE. CONCLUSION: Both interventions effectively informed SOTR about skin cancer and sun protection, promoted favorable beliefs, and improved personal agency, but were not differentially effective, suggesting that the addition of the video may not be necessary or that the video may need to be viewed more than once. More in-depth SSE teaching strategies may be necessary. PMID- 23747190 TI - Ter94 ATPase complex targets k11-linked ubiquitinated ci to proteasomes for partial degradation. AB - The Cubitus interruptus (Ci)/Gli family of transcription factors can be degraded either completely or partially from a full-length form (Ci155/Gli(FL)) to a truncated repressor (Ci75/Gli(R)) by proteasomes to mediate Hedgehog (Hh) signaling. The mechanism by which proteasomes distinguish ubiquitinated Ci/Gli to carry out complete versus partial degradation is not known. Here, we show that Ter94 ATPase and its mammalian counterpart, p97, are involved in processing Ci and Gli3 into Ci75 and Gli3(R), respectively. Ter94 regulates the partial degradation of ubiquitinated Ci by Cul1-Slimb-based E3 ligase through its adaptors Ufd1-like and dNpl4. We demonstrate that Cul1-Slimb-based E3 ligase, but not Cul3-Rdx-based E3 ligase, modifies Ci by efficient addition of K11-linked ubiquitin chains. Ter94(Ufd1-like/dNpl4) complex interacts directly with Cul1 Slimb, and, intriguingly, it prefers K11-linked ubiquitinated Ci. Thus, Ter94 ATPase and K11-linked ubiquitination in Ci contribute to the selectivity by proteasomes for partial degradation. PMID- 23747191 TI - Oct4 cell-autonomously promotes primitive endoderm development in the mouse blastocyst. AB - In embryonic stem (ES) cells and in early mouse embryos, the transcription factor Oct4 is an essential regulator of pluripotency. Oct4 transcriptional targets have been described in ES cell lines; however, the molecular mechanisms by which Oct4 regulates establishment of pluripotency in the epiblast (EPI) have not been fully elucidated. Here, we show that neither maternal nor zygotic Oct4 is required for the formation of EPI cells in the blastocyst. Rather, Oct4 is first required for development of the primitive endoderm (PE), an extraembryonic lineage. EPI cells promote PE fate in neighboring cells by secreting Fgf4, and Oct4 is required for expression of Fgf4, but we show that Oct4 promotes PE development cell autonomously, downstream of Fgf4 and Mapk. Finally, we show that Oct4 is required for the expression of multiple EPI and PE genes as well as multiple metabolic pathways essential for the continued growth of the preimplantation embryo. PMID- 23747192 TI - Accidental death of elderly persons under the influence of chlorpheniramine. AB - Older individuals are susceptible to accident, such as falls, some of which are fatal. In such cases, autopsies and toxicological analysis may be deemed unnecessary, especially if the critical injuries and manner of death can be determined conclusively based on information at the scene and an external investigation. Here, we report the results of two autopsies performed on elderly individuals who died accidentally under the influence of chlorpheniramine. These autopsies revealed valuable additional information. Case 1: A woman in her 70s, who was living alone, was found dead under the stairs in her house. She had no history of a condition that could have led to sudden death. The autopsy revealed a neck fracture, multiple rib fractures, and a coccyx fracture. The histopathological findings showed fat embolisms in numerous small vessels of the interalveolar septum. Toxicological analysis of blood samples revealed the presence of chlorpheniramine (0.41MUg/ml). Case 2: A woman in her 70s, who was living alone, was found dead in the bathtub in her house. There was no past medical history other than diabetes mellitus and vertigo. The autopsy revealed hyper-inflated lungs and brown-red fluids in the trachea, but there was no evidence of a pathology or injury that could have induced a loss of consciousness. Toxicological analysis of the fluids in the right thoracic cavity revealed the presence of chlorpheniramine (0.57MUg/ml). In both cases, re examination of the scene after the autopsy revealed the presence of common cold medicine containing chlorpheniramine. The victim may have accidentally overdosed on common cold medicine. This overdose would have been compounded by anti histamine-induced drowsiness. The present cases suggest that forensic pathologists should always notify physicians/pharmacists of findings pertaining to unexpected drug side effects. Such intervention would prevent many accidental deaths. In addition, each autopsy must be performed in conjunction with a detailed postmortem investigation. Such efforts would also increase the accuracy of the public health record's mortality statistics. PMID- 23747189 TI - [International multidisciplinary classification of acute pancreatitis severity: the 2013 Spanish edition]. AB - OBJECTIVE: To develop a new classification of acute pancreatitis severity on the basis of a sound conceptual framework, comprehensive review of the published evidence, and worldwide consultation. BACKGROUNDS: The Atlanta definitions of acute pancreatitis severity are ingrained in the lexicon of specialist in pancreatic diseases, but are suboptimal because these definitions are based on the empiric description of events not associated with severity. METHODS: A personal invitation to contribute to the development of a new classification of acute pancreatitis severity was sent to all surgeons, gastroenterologists, internists, intensivists and radiologists currently active in the field of clinical acute pancreatitis. The invitation was not limited to members of certain associations or residents of certain countries. A global web-based survey was conducted, and a dedicated international symposium was organized to bring contributors from different disciplines together and discuss the concept and definitions. RESULTS: The new classification of severity is based on the actual local and systemic determinants of severity, rather than on the description of events that are non-causally associated with severity. The local determinant relates to whether there is (peri) pancreatic necrosis or not, and if present, whether it is sterile or infected. The systemic determinant relates to whether there is organ failure or not, and if present, whether it is transient or persistent. The presence of one determinant can modify the effect of another, whereby the presence of both infected (peri) pancreatic necrosis and persistent organ failure has a greater impact upon severity than either determinant alone. The derivation of a classification based on the above principles results in four categories of severity: mild, moderate, severe, and critical. CONCLUSIONS: This classification is the result of a consultative process among specialists in pancreatic diseases from 49 countries spanning North America, South America, Europe, Asia, Oceania and Africa. It provides a set of concise up to date definitions of all the main entities pertinent to classifying the severity of acute pancreatitis in clinical practice and research. This ensures that the determinant-based classification can be used in a uniform manner throughout the world. PMID- 23747193 TI - Diversity training for signal transduction: leveraging cell-to-cell variability to dissect cellular signaling, differentiation and death. AB - Populations of 'identical' cells are rarely truly identical. Even when in the same state of differentiation, isogenic cells may vary in expression of key signaling regulators, activate signal transduction at different thresholds, and consequently respond heterogeneously to a given stimulus. Here, we review how new experimental and analytical techniques are suited to connect these different levels of variability, quantitatively mapping the effects of cell-to-cell variability on cellular decision-making. In particular, we summarize how this helps classify signaling regulators according to the impact of their variability on biological functions. We further discuss how variability can also be leveraged to shed light on the molecular mechanisms regulating cellular signaling, from the individual cell to the population of cells as a whole. PMID- 23747194 TI - Asymptomatic cervical canal stenosis: is there a risk of spinal cord injury? PMID- 23747195 TI - Long-term kinematic analysis of cervical spine after single-level implantation of Bryan cervical disc prosthesis: a review. PMID- 23747197 TI - Reciprocal functional pseudotyping of HIV-1 and HTLV-1 viral genomes by the heterologous counterpart envelope proteins. AB - HIV-1 and HTLV-1 can infect CD4+ T cells and can co-infect the same individual. In principle, it is possible that both viruses can infect the same CD4+ T cells in dually infected persons. Currently, how efficiently HTLV-1 and HIV-1 co infects the same cell and the full extent of their biological interactions are not well-understood. Here, we report evidence confirming that both viruses can infect the same cells and that HTLV-1 envelope (Env) can pseudotype HIV-1 viral particles and HIV-1 envelope (Env) can pseudotype HTLV-1 virions to mediate subsequent infections of substrate cells. We also show that the construction of a chimeric HTLV-1 molecular clone carrying the HIV-1 Env in place of its HTLV-1 counterpart results in a replication competent moiety. These findings raise new implications of viral complementation and assortment between HIV-1 and HTLV-1 in dually infected persons. PMID- 23747196 TI - Nature, nurture and HIV: The effect of producer cell on viral physiology. AB - Macrophages and CD4-positive T lymphocytes are the major targets and producers of HIV-1. While the molecular details underlying HIV replication in macrophages and T cells become better understood, it remains unclear whether viruses produced by these target cells differ in their biological properties. Recent reports suggest that HIV virions incorporate a large number of producer cell proteins and lipids which have an effect on subsequent viral replication in newly infected cells. The identity and abundance of these incorporated factors varies between different types of producer cells, suggesting that they may influence the replication capacity and pathogenic activity of the virions produced by T cells and macrophages. PMID- 23747198 TI - Essential roles of Leu/Ile/Phe-rich domain of JC virus agnoprotein in dimer/oligomer formation, protein stability and splicing of viral transcripts. AB - Agnoprotein is one of the key regulatory proteins of polyomaviruses, including JCV, BKV and SV40 and is required for a productive viral life cycle. We have recently reported that agnoprotein forms stable dimer/oligomers mediated by a predicted amphipathic alpha-helix, spanning amino acids (aa), 17 to 42. Deletion of the alpha-helix renders a replication incompetent virus. Here, we have further characterized this region by a systematic deletion and substitution mutagenesis and demonstrated that a Leu/Ile/Phe-rich domain, (spanning aa 28-39) within alpha helix is indispensable for agnoprotein structure and function. Deletion of aa 30 37 severely affects the dimer/oligomer formation and stable expression of the protein. Mutagenesis data also indicate that the residues, 34-36, may be involved in regulation of the splicing events of JCV transcripts. Collectively, these data suggest that the Leu/Ile/Phe-rich domain plays critical roles in agnoprotein function and thus represents a potential target for developing novel therapeutics against JCV infections. PMID- 23747199 TI - Interaction of CtBP with adenovirus E1A suppresses immortalization of primary epithelial cells and enhances virus replication during productive infection. AB - Adenovirus E1A induces cell proliferation, oncogenic transformation and promotes viral replication through interaction with p300/CBP, TRRAP/p400 multi-protein complex and the retinoblastoma (pRb) family proteins through distinct domains in the E1A N-terminal region. The C-terminal region of E1A suppresses E1A/Ras co transformation and interacts with FOXK1/K2, DYRK1A/1B/HAN11 and CtBP1/2 (CtBP) protein complexes. To specifically dissect the role of CtBP interaction with E1A, we engineered a mutation (DL->AS) within the CtBP-binding motif, PLDLS, and investigated the effect of the mutation on immortalization and Ras cooperative transformation of primary cells and viral replication. Our results suggest that CtBP-E1A interaction suppresses immortalization and Ras co-operative transformation of primary rodent epithelial cells without significantly influencing the tumorigenic activities of transformed cells in immunodeficient and immunocompetent animals. During productive infection, CtBP-E1A interaction enhances viral replication in human cells. Between the two CtBP family proteins, CtBP2 appears to restrict viral replication more than CtBP1 in human cells. PMID- 23747201 TI - An agenda for clinical decision making and judgement in nursing research and education. AB - Nurses' judgements and decisions have the potential to help healthcare systems allocate resources efficiently, promote health gain and patient benefit and prevent harm. Evidence from healthcare systems throughout the world suggests that judgements and decisions made by clinicians could be improved: around half of all adverse events have some kind of error at their core. For nursing to contribute to raising quality though improved judgements and decisions within health systems we need to know more about the decisions and judgements themselves, the interventions likely to improve judgement and decision processes and outcomes, and where best to target finite intellectual and educational resources. There is a rich heritage of research into decision making and judgement, both from within the discipline of nursing and from other perspectives, but which focus on nurses. Much of this evidence plays only a minor role in the development of educational and technological efforts at decision improvement. This paper presents nine unanswered questions that researchers and educators might like to consider as a potential agenda for the future of research into this important area of nursing practice, training and development. PMID- 23747202 TI - Intrachromosomal looping is required for activation of endogenous pluripotency genes during reprogramming. AB - Generation of induced pluripotent stem cells (iPSCs) by defined factors is an extremely inefficient process, because there is a strong epigenetic block preventing cells from achieving pluripotency. Here we report that virally expressed factors bound to the promoters of their target genes to the same extent in both iPSCs and unreprogrammed cells (URCs). However, expression of endogenous pluripotentcy genes was observed only in iPSCs. Comparison of local chromatin structure of the OCT4 locus revealed that there was a cohesin-complex-mediated intrachromosomal loop that juxtaposes a downstream enhancer to the gene's promoter, enabling activation of endogenous stemness genes. None of these long range interactions were observed in URCs. Knockdown of the cohesin-complex gene SMC1 by RNAi abolished the intrachromosomal interaction and affected pluripotency. These findings highlight the importance of the SMC1-orchestrated intrachromosomal loop as a critical epigenetic barrier to the induction of pluripotency. PMID- 23747203 TI - Klf4 organizes long-range chromosomal interactions with the oct4 locus in reprogramming and pluripotency. AB - Epigenetic mechanisms underlying somatic reprogramming have been extensively studied, but little is known about the nuclear architecture of pluripotent stem cells (PSCs). Using circular chromosome conformation capture with high-throughput sequencing (4C-seq) and fluorescence in situ hybridization (FISH), we identified chromosomal regions that colocalize frequently with the Oct4 locus in PSCs. These PSC-specific long-range interactions are established prior to transcriptional activation of endogenous Oct4 during reprogramming to induced PSCs and are facilitated by Klf4-mediated recruitment of cohesin. Depletion of Klf4 leads to unloading of cohesin at the Oct4 enhancer and disrupts long-range interactions prior to loss of Oct4 transcription and subsequent PSC differentiation, suggesting a causative role for Klf4 in facilitating long-range interactions independent of its transcriptional activity. Taken together, our results delineate the basic nuclear organization at the Oct4 locus in PSCs and suggest a functional role for Klf4-mediated higher-order chromatin structure in maintaining and inducing pluripotency. PMID- 23747204 TI - Phenotypic and genetic parameters of antibody and delayed-type hypersensitivity responses of lactating Holstein cows. AB - Breeding dairy cattle using diverse phenotypic markers has been suggested as a feasible approach to improve health and decrease the deleterious consequences of infectious diseases. Studies conducted in pigs have demonstrated the value of antibody (AMIR)- and cell (CMIR)-mediated immune responses as quantitative traits for improving immune responsiveness by selecting livestock using estimated breeding values (EBV) for immune response (IR) traits. Studies of cattle have tested the possibility of using IR traits as phenotypic markers to classify cows as high (HR), average (AR) and low (LR) responders. Information is scarce or unavailable about either genetic parameters of AMIR and CMIR or their phenotypic and genetic associations with production, conformation, fertility or health traits in lactating dairy cattle. The objectives of the current study were to evaluate phenotypic and genetic parameters of both AMIR and CMIR as quantitative immunological traits (n=6) in comparison with production, fertility and health traits in dairy cattle for their use in a selection index intended to improve bovine health. Results of this study showed significant AMIR and CMIR responses. Most phenotypic correlations between IR traits and production, health or fertility traits were not significant. The highest heritabilities (h(2)) were observed for delayed-type hypersensitivity (DTH) to killed Candida albicans whole cell (CaWC) at 48 h (0.54) and AMIR day 14 (0.42). The highest genetic correlations were observed between AMIR 14 and AMIR 21 (0.99) and between DTH to CaWC 24h and DTH to CaWC 48 h (0.93). Two important and significant sire EBV correlations were noted between AMIR and fat % (0.18), and between CMIR and protein % (-0.15). In conclusion, this study demonstrated that both AMIR and CMIR are heritable traits in cattle and could be considered for their inclusion in a selection index intended to improve health. PMID- 23747205 TI - Corneal approach to hyperopic presbyopia treatment: six-month outcomes of a new multifocal excimer laser in situ keratomileusis procedure. AB - PURPOSE: To report the safety and efficacy of treatment of hyperopic presbyopia with a new multifocal corneal laser in situ keratomileusis (LASIK) procedure, Supracor. SETTING: Mater Private Hospital, Dublin, Ireland. DESIGN: Case series. METHODS: Bilateral LASIK using a multifocal corneal ablation profile was performed on consecutive hyperopic presbyopic patients with a manifest refraction spherical equivalent (MRSE) of +1.00 to +3.25 diopters (D) and a maximum 0.75 D difference between the MRSE and cycloplegic refraction. All patients were followed for a minimum of 6 months postoperatively. The main outcome measures were safety, efficacy in terms of uncorrected distance visual acuity (UDVA) and uncorrected reading ability (Vocational Reading Test), predictability, stability, patient satisfaction, and functioning at 6 months. RESULTS: Forty-six eyes (23 patients) were treated. The mean binocular UDVA was 0.07 logMAR +/- 0.12 (SD) at 6 months, with 91% having a binocular UDVA of 0.2 logMAR or better. Ninety-one percent had an uncorrected reading ability of N8 or better, and 93% were fully independent of reading glasses. Six percent lost 2 or more lines of corrected distance visual acuity (CDVA), with 100% maintaining a CDVA of 0.2 logMAR or better. Five patients (22%) required a retreatment in the dominant eye to enhance UDVA. Ninety-six percent were happy they had the procedure. CONCLUSIONS: The procedure provided a high level of spectacle independence for near vision. The UDVA outcomes must be improved with nomogram adjustment to reduce the retreatment rate. Targeting emmetropia in the dominant eye and 0.50 D myopia in the nondominant eye may be an effective solution. PMID- 23747206 TI - Porcine lens nuclei as a model for comparison of 3 ultrasound modalities regarding efficiency and chatter. AB - PURPOSE: To validate a porcine lens model by comparing density and ultrasound (US) with known human standards using the Infiniti Ozil with Intelligent Phacoemulsification (torsional), Whitestar Signature Micropulse (longitudinal), and Ellips FX (transversal) modalities. SETTING: Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: Lens nuclei were formalin soaked in hour-based intervals and divided into 2.0 mm cubes. Density was characterized by crushing experiments and compared with known human measures. Efficiency and chatter were examined. RESULTS: The mean weight to cut thickness in half ranged from 16.9 g +/- 5.5 (SD) in the 0-hour group to 121.3 +/- 47.5 gm in the 4-hour group. Lenses in the 2-hour group (mean 70.2 +/- 19.1 g) best matched human density (P=.215). The mean efficiency ranged from 0.432 +/- 0.178 seconds to 9.111 +/- 2.925 seconds; chatter ranged from zero to 1.85 +/- 1.927 bounces. No significant difference was detected when comparing the 2-hour formalin group with human lenses in torsional and transversal US. There was no significant difference between transversal and torsional modalities, consistent with human studies. Although longitudinal (6 milliseconds on, 12 milliseconds off) was significantly more efficient at 50% power than at 25%, there was no significant difference compared with transversal or torsional US. CONCLUSIONS: Animal lenses soaked for 2 hours in formalin were most comparable to human lenses. Longitudinal US may be an acceptable alternative to torsional and transversal US. PMID- 23747207 TI - Outcomes of intrastromal corneal ring segments for treatment of keratoconus: five year follow-up analysis. AB - PURPOSE: To report the long-term refractive and optical quality outcomes of patients with intrastromal corneal ring segments (ICRS) to treat keratoconus and to analyze the results according to the patients' age. SETTING: Vissum Instituto Oftalmologico de Alicante, Alicante, Spain. DESIGN: Case series. METHODS: The uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refraction, corneal topography, and aberrometry were evaluated before and after ICRS implantation in eyes with keratoconus. The follow-up was 5 years in all cases. RESULTS: The study comprised 51 eyes (35 patients; age range 15 to 56 years). After 6 months, the improvement in the UDVA, CDVA, spherical equivalent, and mean keratometry (K) value was statistically significant (P<.05). Five years postoperatively, these parameters remained unchanged (P=.31). Slight regression (0.97 diopter [D]) was observed in the mean K between 6 months and 5 years; the regression was not statistically significant (P=.39). Anterior corneal aberrometric values decreased; however, the changes were not statistically significant (P >=.10). Linear regression analysis showed no correlation between the age of the patients and the changes observed in the mean K throughout the follow-up (P>.05, r(2) = 0.001). CONCLUSIONS: Intrastromal corneal ring segment implantation in keratoconus patients provided long-term improvement of the refractive and topographic status. There was no correlation between the amount of individual changes in the mean K reading and patient age. PMID- 23747208 TI - Validation of the telephone-administered PHQ-9 against the in-person administered SCID-I major depression module. AB - BACKGROUND: We assessed item-to-item correspondence between the Patient Health Questionnaire-9 (PHQ-9) and the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) major depression episode portion of the major depressive module. METHOD: Four hundred and ninety-eight soldiers in the Ohio National Guard were administered the PHQ-9 and SCID-I. Data were analyzed using chi-square analyses, logistic regression, receiver operating characteristic (ROC) curve analyses and diagnostic efficiency statistics. RESULTS: To screen for depression effectively, results indicate use of the cardinal first two items, items representing fatigue, appetite and sleep changes with an item level cut-off point of two, and the item representing suicidal ideation with item level cut-off point of one. Further, total PHQ-9 scores significantly predicted SCID-I major depressive episode (MDE) and diagnosis (MDD) with moderate accuracy. Lastly, the cut-off total score of 10 had the optimal balance of sensitivity and specificity compared to other PHQ-9 scoring options. LIMITATIONS: Differences in timeline of administration of the measures, differences in "worst episode" reference between the measures, and use of a specific military population are some of the limitations. CONCLUSIONS: This validation study provides guidelines for the use of the telephone-administered PHQ-9 in assessing the lifetime prevalence of a major depressive episode and diagnosis in non-clinical populations, with implications for clinical use. PMID- 23747209 TI - Valproate as a risk factor for lamotrigine discontinuation. AB - BACKGROUND: Although lamotrigine may be useful for treating bipolar depressive patients, some lamotrigine-associated adverse effects may prevent the continuation of treatment. The purpose of the present study was to identify risk factors for lamotrigine discontinuation after adjustment for several potential interactive factors. METHODS: We examined tolerability in those who discontinued lamotrigine within 2 months of treatment and those who maintained lamotrigine for more than 2 months. Groups were examined separately because 6-8 weeks are necessary to titrate dose and drug eruptions can often occur within 2 months of treatment commencement. RESULTS: Multiple regression analysis revealed that valproate combination was positively and significantly associated with lamotrigine discontinuation after adjustment for other factors. LIMITATIONS: The limitations of the present study were retrospective observation and a relatively small number of subjects. CONCLUSIONS: The present findings reconfirm that lamotrigine and valproate combination treatment may prevent the continuation of lamotrigine in some patients. PMID- 23747210 TI - The utilization of psychopharmacological treatment and medication adherence among Medicaid enrolled children and adolescents with bipolar depression. AB - BACKGROUND: To examine the psychotropic medication utilization and compare adherence to treatment regimens in pediatric bipolar depression patients. METHODS: 2003-2007 MAX data from four geographically diverse states were used. According to the regimen received by the patients (6-18 years) in the first month after the index bipolar depression diagnosis, patients were categorized into six mutually exclusive groups. The month to month change of treatment regimen in each group was then assessed during the 6 month post-index bipolar depression diagnosis. Adherence to each regimen was measured as continuation of the initial regimen, switch to a new regimen, augmentation with medication from a different therapeutic category, and discontinuation of all pharmacotherapies. Repeated measure analysis was conducted to compare the trend of each adherence measure across the study groups. RESULTS: Of the 5,460 subjects identified, 15.39% received antipsychotic monotherapy, 9.43% received mood stabilizer monotherapy, 5.77% received antidepressant monotherapy, 26.48% received mood stabilizer antipsychotic polytherapy, 22.51% received antidepressant polytherapy, and 19.89% received antipsychotic-mood stabilizer-antidepressant polytherapy. At the end of the follow-up period, over 50% of the 1st month polytherapy users and less than 50% of the monotherapy users were continuing their initial regimen. Repeated measure analysis using antipsychotic monotherapy as the reference group suggested differences in trend slopes (p<0.05). LIMITATIONS: In absence of structured clinical evaluation, bipolar disorder diagnoses cannot be ascertained in this study. CONCLUSIONS: Bipolar depression patients were predominantly treated with combinations of psychotropic drugs. Potentially questionable practice, such as antidepressant monotherapy was used only in a small fraction of patients. Combination regimens had better adherence as compared to monotherapies. PMID- 23747211 TI - [Chronic postsurgical pain]. AB - OBJECTIVES: Update reviewing of chronic postsurgical pain. DATA SOURCES: The following review is based on the English and French literature published in PubMed database between January 1998 and 2013. The research articles were made with following keywords alone or in combination: "chronic pain", "surgery", "postsurgical pain". These keywords were combined with "epidemiology", "incidence", "predictive factors" and "prevention". Study selection Publications were deemed relevant if they contained information about CPSP after 8 weeks post surgery. Animal publications were not included. Only randomized controlled studies were taken into consideration for the pharmacological prevention. DATA EXTRACTION: Data extracted were related to epidemiology, impact, predictive factors and prevention of CPSP. DATA SYNTHESIS: Epidemiology of CPSP is more recognized as it is experienced by 10-50% of individuals after classical operations. CPSP can be severe in about 5 to 10% of these patients. CPSP is a major public health problem still rarely diagnosed and treated. Twenty percent of patients consulting in a pain clinic have a CPSP. The frequency of neuropathic pain is important but the difference in the proportion to CPSP falls between 6 68% and depend on the type of surgery. Clinical risk factors and physiopathology of CPSP are subject of wide development. Human studies allowed better understanding of the neurophysiological as well psychological aspect of the development of CPSP. Finally, the possibility of pharmacological prevention of CPSP seems to have increased in the past years. Nevertheless, there are still many questions that need to be answers about the problem. We should clearly define the optimal characteristics of clinical and experimental studies as this will allow the better understanding of the prevention of CPSP. Anesthesiologists play a crucial role in this development. They are involved in all of the stages of the operative care of patients and play a decisive role in the evaluation of the risk, the development of a preventive strategy, and in the early detection and treatment of CPSP. PMID- 23747212 TI - [Guidelines for perioperative haemodynamic optimization. Socie'te' franc aise d'anesthe'sie et de re'animation]. PMID- 23747213 TI - [Chronic postsurgical pain: a clinical reality and a research way to develop]. PMID- 23747214 TI - Novel parameter predicting grade 2 rectal bleeding after iodine-125 prostate brachytherapy combined with external beam radiation therapy. AB - PURPOSE: To propose a novel parameter predicting rectal bleeding on the basis of generalized equivalent uniform doses (gEUD) after (125)I prostate brachytherapy combined with external beam radiation therapy and to assess the predictive value of this parameter. METHODS AND MATERIALS: To account for differences among radiation treatment modalities and fractionation schedules, rectal dose-volume histograms (DVHs) of 369 patients with localized prostate cancer undergoing combined therapy retrieved from corresponding treatment planning systems were converted to equivalent dose-based DVHs. The gEUDs for the rectum were calculated from these converted DVHs. The total gEUD (gEUDsum) was determined by a summation of the brachytherapy and external-beam radiation therapy components. RESULTS: Thirty-eight patients (10.3%) developed grade 2+ rectal bleeding. The grade 2+ rectal bleeding rate increased as the gEUDsum increased: 2.0% (2 of 102 patients) for <70 Gy, 10.3% (15 of 145 patients) for 70-80 Gy, 15.8% (12 of 76 patients) for 80-90 Gy, and 19.6% (9 of 46 patients) for >90 Gy (P=.002). Multivariate analysis identified age (P=.024) and gEUDsum (P=.000) as risk factors for grade 2+ rectal bleeding. CONCLUSIONS: Our results demonstrate gEUD to be a potential predictive factor for grade 2+ late rectal bleeding after combined therapy for prostate cancer. PMID- 23747215 TI - Long-term survival outcomes following internal mammary node irradiation in stage II-III breast cancer: results of a large retrospective study with 12-year follow up. AB - PURPOSE: To examine the effect of internal mammary node irradiation (IMNI) on disease-free survival (DFS) and overall survival (OS) in breast cancer patients treated with modified radical mastectomy and postoperative radiation therapy. METHODS AND MATERIALS: Between 1994 and 2002, 396 patients with stage II-III breast cancer were treated with postmastectomy radiation therapy with (n=197) or without (n=199) IMNI. Patients who received neoadjuvant chemotherapy were excluded. IMNI was administered at the clinical discretion of the treating physician. Median RT dose was 50.4 Gy (range, 45.0-59.4 Gy) in 28 fractions, with inclusion of the supraclavicular fossa in 96% of patients. Adjuvant chemotherapy was administered to 99.7% of the patients and endocrine therapy to 53%. RESULTS: The median follow-up was 149 months (range, 124-202). IMNI patients had more advanced nodal stage and non-high grade tumors than those without IMNI (P<.001). Otherwise, disease and treatment characteristics were well balanced. The 10-year DFS with and without IMNI was 65% and 57%, respectively (P=.05). Multivariate analysis demonstrated that IMNI was an independent, positive predictor of DFS (hazard ratio [HR], 0.70; P=.02). Benefits of IMNI in DFS were seen most apparently in N2 patients (HR, 0.44; 95% confidence interval [CI], 0.26-0.74) and inner/central tumors (HR, 0.55; 95% CI, 0.34-0.90). The 10-year OS with and without IMNI was 72% and 66%, respectively (P=.62). The 10-year DFS and OS were 61%, and 69%, respectively. CONCLUSIONS: Internal mammary node irradiation significantly improved DFS in postmastectomy breast cancer patients. Pending long term results from randomized trials, treatment of internal mammary nodes should be considered in postmastectomy radiation therapy. PMID- 23747216 TI - [Appraisal of the optical diagnostic technique for cervical intra-epithelial neoplasia by polarimetric imaging "Polcolpo". Comparison with colposcopic and histological diagnoses by biopsy]. AB - OBJECTIVES: The main objective of this study was to compare the performances of polarimetric imaging and standard colposcopy for the detection of CIN. MATERIALS AND METHODS: We performed a monocentric prospective clinical study. The standard colposcopic diagnosis obtained during a first consultation was compared to the diagnosis provided by polarimetric imaging in a second consultation. In addition to the biopsies guided by classical or polarimetric colposcopy, a systematic biopsy taken at a predefined location allowed to calculate the specificities and sensitivities of both techniques. RESULTS: One hundred and forty-one patients were included, all of them with anomalous Pap smears. Sixty-seven cone biopsies were taken, 69 % of which were eventually diagnosed with CIN2+ lesions. The sensitivities and specificities were found to be equal for standard and polarimetric colposcopies. CONCLUSION: We could not demonstrate any improvement of the diagnostic performances with polarimetric colposcopy alone. However, for both healthy and pathological cervices, we observed interesting polarimetric responses involving other characteristics than those we initially assumed, and which will be taken into account in a future study. PMID- 23747217 TI - [First-trimester cystic hygroma: prenatal diagnosis and fetal outcome]. AB - OBJECTIVES: To describe the ultrasonographic (US) and fetal karyotyping data of fetuses with cystic hygroma diagnosed in the first trimester. PATIENTS & METHODS: Maternal and fetal data of 69 consecutive fetal cystic hygroma were analysed between 2002 and 2009. RESULTS: The mean size of the cystic hygroma was 6.3 mm +/ 2.4 mm. US abnormalities were present in 54% of cases (37/69) (essentially hydrops fetalis in 45%), with an unfavourable prognosis (P=0.006). Chromosomal abnormalities were present in 53% of cases (36/68) (including 44% of Down syndrome). The rate of unfavourable outcome of pregnancy was 71% of cases (49/69) and was associated with the oldest mothers (P=0.011). In the chromosomally normal pregnancies, there were 59% (19/32) fetus with no apparently abnormalities. Among these 19 children, 13 have been followed up until an average age of 5 years and a half, the infant development was strictly normal. DISCUSSION AND CONCLUSION: The current results suggest to look for the poor prognosis data: nuchal thickness superior to 6 to 6,5 mm, presence of a hydrops fetalis and/or US abnormalities, fetal karyotyping and/or US evolution of cystic hygroma. PMID- 23747218 TI - MAPK mediates inflammatory response and cell death in rat pulmonary microvascular endothelial cells in an ischemia-reperfusion model of lung transplantation. AB - BACKGROUND: Hypoxia-reoxygenation of cultured macrovascular endothelial cells is used to study ischemia-reperfusion (IR)-related cellular and molecular changes; however, these models do not accurately depict events in pulmonary microvascular endothelial cells (PMVECs) during conventional lung retrieval and transplantation. We used rat PMVECs in a new non-hypoxic cell-based lung transplantation model to assess these events. METHODS: To simulate cold storage, rat PMVECs were preserved in 95% O2-5% CO2 at 4 degrees C for 6 hours in low potassium dextran solution. Dishes were warmed for 1 hour to room temperature for simulating implantation. Medium was added at 37 degrees C in 50% O2-5% CO2-45% N2 to simulate reperfusion. Additional PMVECs were transfected with siRNA targeting mitogen-activated protein kinases (MAPKs) and then subjected to simulated IR. RESULTS: MAPKs and NF-kappaB were activated during simulated reperfusion, and AP 1 was activated during ischemia and reperfusion. Increased malondialdehyde levels were found during cold ischemia, and apoptosis and production of IL-1beta, IL-6, and TNF-alpha were observed during reperfusion. Silencing of MAPKs attenuated oxidative stress, inflammation and apoptosis. Silencing of JNK and p38 decreased NF-kappaB phosphorylation and increased inhibitor of NF-kappaB (IkappaB)alpha levels. Knockdown of ERK1/2 increased NF-kappaB phosphorylation but had no effect on IkappaBalpha expression. Silencing of JNK and ERK1/2, but not p38, decreased AP-1 phosphorylation. CONCLUSIONS: Exposing rat PMVECs to simulated non-hypoxic IR caused lipid peroxidation, inflammation and apoptosis, which required MAPK mediated NF-kappaB and AP-1 activation and distinct regulation of MAPKs by these 2 transcription factors. This model could be used to uncouple mechanisms of IR and evaluate potential therapeutics in alleviating IR injury. PMID- 23747219 TI - Radiofrequency perforation may increase the safety of transcatheter Potts shunt creation. PMID- 23747220 TI - Popliteal blocks for foot and ankle surgery: success rate and contributing factors. AB - The purpose of the present study was to evaluate the factors contributing to the success of popliteal nerve blocks performed by podiatric surgical residents in various stages of training. A retrospective review was conducted of 143 consecutively performed blocks during a 2-year period. A total of 29 blocks using a lateral approach and 114 blocks using a modified posterior approach were performed. The intrinsic and extrinsic variables contributing to block outcome were analyzed. A total of 109 successful blocks were performed, for an overall success rate of 76.2%. Significant differences (p < .002) were found between the success and failure groups with respect to the patients body mass index and age. No differences were observed between the success and failure groups with respect to the block approach or months of resident training. In conclusion, podiatric surgical residents in all stages of training can safely and effectively perform popliteal nerve blocks for peri- and postoperative analgesia. Surgeons should be aware of the potential influence of patients body mass index and age on the overall block success rates. PMID- 23747221 TI - Relationship between primary lesion metabolic parameters and clinical stage in lung cancer. AB - OBJECTIVES: The relation of PET-derived parameters as maximum standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV) with clinical stage in lung cancer and correlation of SUVmax of primary tumor and that of metastatic lesion was studied in lung cancer patients. MATERIALS AND METHODS: Patients with lung cancer who were referred for FDG PET/CT were included in the study. RESULTS: PET/CT scans and pathology reports of 168 patients were assessed. A total of 146 (86.9%) of these patients had a diagnosis of non-small cell lung cancer (NSCLC) and 22 (13.1%) had small cell lung cancer (SCLC). Metabolic parameters such as SUVmax, TLG and MTV showed significant differences in all the stages in NSCLC patients (p<0.001). However, after tumors sizes <25 mm were excluded, no significant differences in SUVmax between stages were observed. No significant differences were found between these metabolic parameters and limited or extended disease SCLC. Tumor diameter correlated with primary tumor SUVmax and significant correlations between primary lesion SUVmax and metastatic lesion SUVmax were found. CONCLUSIONS: Although differences were found regarding indices between stages of NSCLC cases, SUVmax differences between stages seem to be caused by underestimation of SUVmax in small lesions. Other glucose metabolism indexes such as MTV and TLG show promising results in terms of prognostic stratification. Future studies are needed for better understanding of their contribution to clinical cases. PMID- 23747222 TI - Use of volumetric-modulated arc therapy for treatment of Hodgkin lymphoma. AB - To evaluate volumetric-modulated arc therapy (VMAT) for treatment of Hodgkin lymphoma (HL) in patients where conventional radiotherapy was not deliverable. A planning computed tomography (CT) scan was acquired for a twelve-year-old boy with Stage IIIB nodular sclerosing HL postchemotherapy with positive positron emission tomography scan. VMAT was used for Phase 1 (19.8Gy in 11 fractions) and Phase 2 (10.8Gy in 6 fractions) treatment plans. Single anticlockwise arc plans were constructed using SmartArc (Philips Radiation Oncology Systems, Fitchburg, WI) with control points spaced at 4 degrees . The inverse-planning objectives were to uniformly irradiate the planning target volume (PTV) with the prescription dose while keeping the volume of lung receiving greater than 20Gy (V20Gy) to less than 30% and minimize the dose to the other adjacent organs at risk (OAR). Pretreatment verification was conducted and the treatment delivery was on an MLCi Synergy linear accelerator (Elekta Ltd, Crawley, UK). The planning results were retrospectively confirmed in a further 4 patients using a single PTV with a prescribed dose of 19.8Gy in 11 fractions. Acceptable dose coverage and homogeneity were achieved for both Phase 1 and 2 plans while keeping the lung V20Gy at 22.5% for the composite plan. The beam-on times for Phase 1 and Phase 2 plans were 109 and 200 seconds, respectively, and the total monitor units were 337.2MU and 292.5MU, respectively. The percentage of measured dose points within 3% and 3mm for Phase 1 and Phase 2 were 92% and 98%, respectively. Both plans were delivered successfully. The retrospective planning study showed that VMAT improved PTV dose uniformity and reduced the irradiated volume of heart and lung, although the volume of lung irradiated to low doses increased. Two-phased VMAT offers an attractive option for large volume sites, such as HL, giving a high level of target coverage and significant OAR sparing together with efficient delivery. PMID- 23747223 TI - Multifield optimization intensity-modulated proton therapy (MFO-IMPT) for prostate cancer: Robustness analysis through simulation of rotational and translational alignment errors. AB - To evaluate the dosimetric consequences of rotational and translational alignment errors in patients receiving intensity-modulated proton therapy with multifield optimization (MFO-IMPT) for prostate cancer. Ten control patients with localized prostate cancer underwent treatment planning for MFO-IMPT. Rotational and translation errors were simulated along each of 3 axes: anterior-posterior (A-P), superior-inferior (S-I), and left-right. Clinical target-volume (CTV) coverage remained high with all alignment errors simulated. Rotational errors did not result in significant rectum or bladder dose perturbations. Translational errors resulted in larger dose perturbations to the bladder and rectum. Perturbations in rectum and bladder doses were minimal for rotational errors and larger for translational errors. Rectum V45 and V70 increased most with A-P misalignment, whereas bladder V45 and V70 changed most with S-I misalignment. The bladder and rectum V45 and V70 remained acceptable even with extreme alignment errors. Even with S-I and A-P translational errors of up to 5mm, the dosimetric profile of MFO IMPT remained favorable. MFO-IMPT for localized prostate cancer results in robust coverage of the CTV without clinically meaningful dose perturbations to normal tissue despite extreme rotational and translational alignment errors. PMID- 23747224 TI - Inhibition of Candida albicans isocitrate lyase activity by cadiolides and synoilides from the ascidian Synoicum sp. AB - Tris-aromatic furanones (1-4) and related bis-aromatic diesters (5 and 6) isolated from the dark red ascidian Synoicum sp., were evaluated for their inhibitory activities toward Candida albicans isocitrate lyase (ICL). These studies led to the identification of compounds 1, 3, and 4 as potent ICL inhibitors, with IC50 values of 7.62, 17.16, and 10.36 MUM, respectively. Growth phenotype of ICL deletion mutants and Northern blot analysis data indicated that compound 1 inhibits the ICL expression in C. albicans under C2 carbon utilizing condition. PMID- 23747225 TI - Design and synthesis of N-alkyldeoxynojirimycin derivatives with improved metabolic stability as inhibitors of BVDV and Tacaribe virus. AB - Novel N-alkyldeoxynojirimycins (NADNJs) based on our previous lead 3 were designed, synthesized and tested in metabolic assays and in virus cultures. NADNJs containing terminal tertiary benzamide, sulfonamide, urea, and oxazolidinone moieties were discovered to have improved metabolic stability compared to 3, while maintaining submicromolar EC50 against BVDV and Tacaribe virus; and low cytotoxicity. PMID- 23747226 TI - Design, synthesis, functional and structural characterization of an inhibitor of N-acetylneuraminate-9-phosphate phosphatase: observation of extensive dynamics in an enzyme/inhibitor complex. AB - The design, synthesis and characterization of a phosphonate inhibitor of N acetylneuraminate-9-phosphate phosphatase (HDHD4) is described. Compound 3, where the substrate C-9 oxygen was replaced with a nonlabile CH2 group, inhibits HDHD4 with a binding affinity (IC50 11MUM) in the range of the native substrate Neu5Ac 9-P (compound 1, Km 47MUM). Combined SAR, modeling and NMR studies are consistent with the phosphonate group in inhibitor 3 forming a stable complex with native Mg(2+). In addition to this key interaction, the C-1 carboxylate of the sugar interacts with a cluster of basic residues, K141, R104 and R72. Comparative NMR studies of compounds 3 and 1 with Ca(2+) and Mg(2+) are indicative of a highly dynamic process in the active site for the HDHD4/Mg(2+)/3 complex. Possible explanations for this observation are discussed. PMID- 23747227 TI - JACR: a necessary, valuable resource for residents and fellows. PMID- 23747228 TI - Combining follow-up and change data is valid in meta-analyses of continuous outcomes: a meta-epidemiological study. AB - OBJECTIVE: To investigate whether it is valid to combine follow-up and change data when conducting meta-analyses of continuous outcomes. STUDY DESIGN AND SETTING: Meta-epidemiological study of randomized controlled trials in patients with osteoarthritis of the knee/hip, which assessed patient-reported pain. We calculated standardized mean differences (SMDs) based on follow-up and change data, and pooled within-trial differences in SMDs. We also derived pooled SMDs indicating the largest treatment effect within a trial (optimistic selection of SMDs) and derived pooled SMDs from the estimate indicating the smallest treatment effect within a trial (pessimistic selection of SMDs). RESULTS: A total of 21 meta-analyses with 189 trials with 292 randomized comparisons in 41,256 patients were included. On average, SMDs were 0.04 standard deviation units more beneficial when follow-up values were used (difference in SMDs: -0.04; 95% confidence interval: -0.13, 0.06; P=0.44). In 13 meta-analyses (62%), there was a relevant difference in clinical and/or significance level between optimistic and pessimistic pooled SMDs. CONCLUSION: On average, there is no relevant difference between follow-up and change data SMDs, and combining these estimates in meta analysis is generally valid. Decision on which type of data to use when both follow-up and change data are available should be prespecified in the meta analysis protocol. PMID- 23747229 TI - [Acute generalized exanthematous pustulosis after spider bite in Maghreb]. PMID- 23747231 TI - Recruitment of exogenous mesenchymal stem cells in mandibular distraction osteogenesis by the stromal cell-derived factor-1/chemokine receptor-4 pathway in rats. AB - Distraction osteogenesis is widely used in orthopaedic and craniofacial surgery. However, its exact mechanism is still poorly understood. The purpose of this study was to find out whether there is systemic recruitment of mesenchymal stem cells (MSC) to the neocallus in the distraction gap by the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis during osteogenesis. We examined the migration of MSC towards a gradient of SDF-1 in vitro. We also transplanted MSC labelled with green fluorescent protein (GFP) intravenously, with or without treatment with CXCR4-blocking antibody, into rats that had had unilateral mandibular distraction osteogenesis, and investigated the distribution of cells labelled with GFP in the soft callus after 24 h. We found that SDF-1 facilitated the migration potency of MSC both in vitro and in vivo, and this migration could be inhibited by AMD3100, an antagonist of CXCR4, and promoted by local infusion of exogenous SDF-1 into the distraction gap. This study provides a new insight into the molecular basis of how new bone is regenerated during distraction osteogenesis. PMID- 23747230 TI - Location of minimum foot clearance on the shoe and with respect to the obstacle changes with locomotor task. AB - Minimum foot clearance (MFC) as it relates to trips and falls has been extensively studied across many locomotor tasks, but examination of this body of research yields several studies with conflicting results and a wide range of MFCs within tasks. While there are several factors that may affect the MFC variability across studies (populations studied, environmental conditions, etc.), one aspect of the discrepancies in the literature may be the result of different placements of shoe markers and/or MFC calculation methods. A marker on the toe is often used, but may only quantify one aspect of how the foot actually clears the trip hazard. The purpose of this study was to determine the location on the shoe where MFC occurs during locomotor tasks with the highest risk of tripping. Ten young adults performed three trials of locomotor tasks which included overground walking, obstacle crossing, level change and stair negotiation. Clearance was calculated for 72 points on each shoe, including those most commonly used in past research. The location of the overall MFC on the shoe sole differed both between limbs and across locomotor tasks. Additionally, the region of the obstacle, step or stair over which the MFC occurred varied both within and across task. Use of this 3D MFC methodology provided further insight into which portions of the shoe may come closest to the tripping hazard. Future research should examine whether the location and value of the MFC changes between different populations, or with environmental modifications. PMID- 23747233 TI - Investigating emotional impairments in adults with autism spectrum disorders and the broader autism phenotype. AB - There is an increasing interest in the socio-affective atypicalities observed in adults with autism spectrum disorder (ASD). The aim of this study was to further explore emotional responsiveness in adults with ASD using well-validated self reports of alexithymia and to determine whether anhedonic features are part of a broader autism phenotype (BAP). Participants comprised 38 adults with ASD, 87 parents of ASD individuals and 47 typical controls. All participants completed the Autism Spectrum Quotient (AQ), the 20-item Toronto Alexithymia Scale, and the Bermond-Vorst Alexithymia Questionnaire, as well as the Chapman Physical and Social Anhedonia Scales. The ASD group differed from controls and parents on most measures, with the exception of physical and social anhedonia, relative to parents. Parents differed from controls on social anhedonia, and a higher proportion of parents were classed as alexithymic, relative to controls. Cluster analysis revealed that some parents share more similarities with ASD participants than with controls. The results suggest that socio-affective impairments characteristic of ASD are part of the BAP. PMID- 23747232 TI - Cholinergic receptor gene (CHRM2) variation and familial loading for alcohol dependence predict childhood developmental trajectories of P300. AB - P300 amplitude in childhood predicts substance use disorders by young adulthood. Trajectories of visual P300 amplitude show an association between low amplitude P300 and familial risk for alcohol dependence (AD). Variation in the cholinergic muscarinic receptor gene (CHRM2) has previously been associated with P300 amplitude and AD. The present study used group based trajectory modeling of auditory P300 data collected longitudinally from offspring in families with and without familial loading for AD to determine if specific trajectories would be associated with familial risk and CHRM2 variation. Trajectory modeling confirms previous reports of an association between the low visual P300 trajectory with high familial risk in male offspring. This association was detected in offspring in the 8-12 age range, but not in 13-18 or 19-29 year olds or in high-risk female offspring. CHRM2 association analysis with P300 finds 8-12 year olds who are homozygous for the T allele of rs1824024 are 2.6 times more likely to follow a P300 trajectory characterized by lower and slower change regardless of familial loading. Combining the odds for being male and having a TT genotype results in odds of 6.5 that individuals will follow the low P300 trajectory. PMID- 23747234 TI - Dizocilpine reduces head diameter of dendritic spines in the hippocampus of adolescent rats. AB - Cognitive deficits are the core symptoms of schizophrenia. Spine deficits have been found in hippocampus of schizophrenia patients, and were associated with cognitive impairments. N-methyl-D-asparate receptors (NMDARs) had been known to play a critical role in synaptic pruning and stabilization during adolescence. In the present study, male adolescent rats were exposed to dizocilpine (MK-801) (0.2mg/kg i.p qd) or 0.9% saline for 14 days. Then spatial memory, spine morphological changes and RhoA, Rac1, Cdc42 mRNA levels in hippocampus were measured. As a result, MK-801 impaired spatial memory in the adolescent rats, as well as reduced the proportion of mushroom spines and increased the proportion of stubby spines in hippocampus. MK-801 also reduced the expression levels of Rac1 and Cdc42 mRNA and upregulated RhoA mRNA in hippocampus. These results imply that subchronic MK-801 administration during adolescence might disturb the expression of RhoA, Rac1 and Cdc42 mRNA, and then lead to the decay of the spines in hippocampus, which could be involved in cognitive impairments in schizophrenia. PMID- 23747235 TI - Predictors of suicide threats in patients with borderline personality disorder over 16 years of prospective follow-up. AB - Despite their impact on interpersonal relationships and health resources, suicide threats are not often studied in those with borderline personality disorder (BPD). The primary aim of this study was to examine clinically relevant predictors of suicide threats in this patient group. Two-hundred and ninety inpatients meeting Revised Diagnostic Interview for Borderlines (DIB-R) and DSM III-R criteria for BPD were assessed during their index admission using a series of semistructured interviews and a self-report measure. These subjects were then reassessed using the same instruments every 2 years for 16 years. All variables in the bivariate analyses were found to be significant. In multivariate analyses, four predictors were found to be significant: feeling abandoned and hopeless, and being demanding and manipulative. The results of this study suggest that suicide threats are often related to emotions connected with interpersonal relationships. Suicide threats may function, albeit maladaptively, to regulate these emotions aroused by interpersonal relationships and bring needed support. PMID- 23747236 TI - Internet and computer based interventions for cannabis use: a meta-analysis. AB - BACKGROUND: Worldwide, cannabis is the most prevalently used illegal drug and creates demand for prevention and treatment services that cannot be fulfilled using conventional approaches. Computer and Internet-based interventions may have the potential to meet this need. Therefore, we systematically reviewed the literature and conducted a meta-analysis on the effectiveness of this approach in reducing the frequency of cannabis use. METHODS: We systematically searched online databases (Medline, PubMed, PsychINFO, Embase) for eligible studies and conducted a meta-analysis. Studies had to use a randomized design, be delivered either via the Internet or computer and report separate outcomes for cannabis use. The principal outcome measure was the frequency of cannabis use. RESULTS: Data were extracted from 10 studies and the meta-analysis involved 10 comparisons with 4,125 participants. The overall effect size was small but significant, g=0.16 (95% confidence interval (CI) 0.09-0.22, P<0.001) at post-treatment. Subgroup analyses did not reveal significant subgroup differences for key factors including type of analysis (intention-to-treat, completers only), type of control (active, waitlist), age group (11-16, 17+ years), gender composition (female only, mixed), type of intervention (prevention, 'treatment'), guided versus unguided programs, mode of delivery (Internet, computer), individual versus family dyad and venue (home, research setting). Also, no significant moderation effects were found for number of sessions and time to follow-up. Finally, there was no evidence of publication bias. CONCLUSIONS: Internet and computer interventions appear to be effective in reducing cannabis use in the short-term albeit based on data from few studies and across diverse samples. PMID- 23747237 TI - Focus on immunometabolism. PMID- 23747238 TI - Does a single nucleotide polymorphism in the FGFR explain the connection between diabetes and cancer? AB - A polymorphism in the fibroblast growth factor receptor 4 gene has been associated with cancer progression and treatment resistance and is now reported to increase insulin secretion, providing a possible genetic link between hyperinsulinemia and cancer (Ezzat et al., 2013). PMID- 23747239 TI - Metformin, microbes, and aging. AB - The mechanisms underlying the biological activity of metformin, a widely prescribed drug to treat type 2 diabetes, remain elusive. In a recent issue of Cell, Cabreiro et al. report that in C. elegans, metformin indirectly impacts lifespan by altering the methionine metabolism of its microbial partner E. coli (Cabreiro et al., 2013). PMID- 23747240 TI - A radical signal activates the epigenetic regulation of longevity. AB - Hormesis is an adaptive stress response implicated in longevity regulation. Schroeder et al. (2013) have now connected stress, epigenetic changes, and aging in yeast by showing that mitochondria-derived reactive oxygen species modulate the chromatin binding capacity of the histone demethylase Rph1p at subtelomeres, resulting in lifespan extension. PMID- 23747241 TI - Agitation by suffocation: how hypoxia activates innate immunity via the Warburg effect. AB - A hypoxic microenvironment can enhance the function of innate immune cells; however, the mechanisms remain unclear. Tannahill et al. (2013) find that in macrophages, the accumulation of succinate, an intermediate metabolite of the tricarboxylic acid cycle, stabilizes the transcription factor HIF-1alpha, leading to activation of the proinflammatory cytokine IL-1beta. PMID- 23747242 TI - Novel regulator of enterohepatic bile acid signaling protects against hypercholesterolemia. AB - Hypercholesterolemia is a major cause of cardiovascular disease and can be treated by targeting bile acid and cholesterol metabolism. Vergnes et al. (2013) now identify Diet1 as a novel regulator of fibroblast growth factor 15/19 production and bile acid biosynthesis. PMID- 23747244 TI - Immunological goings-on in visceral adipose tissue. AB - Chronic, low-grade inflammation of visceral adipose tissue, and systemically, is a critical link between recent strikingly parallel rises in the incidence of obesity and type 2 diabetes. Macrophages have been recognized for some time to be critical participants in obesity-induced inflammation of adipose tissue. Of late, a score of other cell types of the innate and adaptive arms of the immune system have been suggested to play a positive or negative role in adipose tissue infiltrates. This piece reviews the existing data on these new participants; discusses experimental uncertainties, inconsistencies, and complexities; and puts forward a minimalist synthetic scheme. PMID- 23747243 TI - Germline energetics, aging, and female infertility. AB - The role of metabolism in ovarian aging is poorly described, despite the fact that ovaries fail earlier than most other organs. Growing interest in ovarian function is being driven by recent evidence that mammalian females routinely generate new oocytes during adult life through the activity of germline stem cells. In this perspective, we overview the female reproductive system as a powerful and clinically relevant model to understand links between aging and metabolism, and we discuss new concepts for how oocytes and their precursor cells might be altered metabolically to sustain or increase ovarian function and fertility in women. PMID- 23747245 TI - Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity. AB - The role of the immune system is to restore functionality in response to stress. Increasing evidence shows that this function is not limited to insults by infection or injury and plays a role in response to overnutrition. Initially, this metabolic activation of the immune system is a physiological response, but it may become deleterious with time. Therefore, therapeutic interventions should aim at modulating the immune system rather than simply damping it. In this article, we describe the physiology and pathology of the immune system during obesity and diabetes with a focus on islet inflammation, the IL-1beta pathway, and clinical translation. PMID- 23747246 TI - Innate immune receptors: key regulators of metabolic disease progression. AB - The study of the intersection of immunology and metabolism is a growing field fueled by the increased prevalence of obesity-associated pathologies. Importantly, the capacity of the innate immune system to sense metabolic stress induced by nutritional surplus has been linked with the progression of obesity, insulin resistance, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and atherosclerosis. Moreover, it is clear that the innate immune system regulates the composition of the intestinal microbiota, which impacts multiple host metabolic processes. Here we review recent studies in this emerging field with an emphasis on how innate immune receptors determine metabolic disease progression. PMID- 23747247 TI - Pathways in microbe-induced obesity. AB - Diet, host gene composition, and alterations in the intestinal microbiota can contribute to obesity. In microbe-induced obesity, metabolic changes stem from primary perturbation of the microbiota, consequent to modern changes in human biology. Microbiota disruption during early development can result in syndromes of metabolic dysfunction. We focus on the pathways involved in these interactions, particularly related to energy extraction and the role of inflammation in the metabolic phenotypes. Model physiologic systems and perturbations including gastric bypass surgery, pregnancy, and hibernation provide insight into the respective roles of the critical participants. PMID- 23747248 TI - The relationship between metabolism and the autophagy machinery during the innate immune response. AB - The innate immune response is shaped by multiple factors, including both traditional autophagy and LC3-associated phagocytosis (LAP). As the autophagic machinery is engaged during times of nutrient stress, arising from scarcity or pathogens, we examine how autophagy, specifically LAP, and cellular metabolism together influence macrophage function and the innate immune response. PMID- 23747249 TI - Diet1 functions in the FGF15/19 enterohepatic signaling axis to modulate bile acid and lipid levels. AB - We identified a mutation in the Diet1 gene in a mouse strain that is resistant to hyperlipidemia and atherosclerosis. Diet1 encodes a 236 kD protein consisting of tandem low-density lipoprotein receptor and MAM (meprin-A5-protein tyrosine phosphatase mu) domains and is expressed in the enterocytes of the small intestine. Diet1-deficient mice exhibited an elevated bile acid pool size and impaired feedback regulation of hepatic Cyp7a1, which encodes the rate-limiting enzyme in bile acid synthesis. In mouse intestine and in cultured human intestinal cells, Diet1 expression levels influenced the production of fibroblast growth factor 15/19 (FGF15/19), a hormone that signals from the intestine to liver to regulate Cyp7a1. Transgenic expression of Diet1, or adenoviral-mediated Fgf15 expression, restored normal Cyp7a1 regulation in Diet-1-deficient mice. Diet1 and FGF19 proteins exhibited overlapping subcellular localization in cultured intestinal cells. These results establish Diet1 as a control point in enterohepatic bile acid signaling and lipid homeostasis. PMID- 23747250 TI - The cancer-associated FGFR4-G388R polymorphism enhances pancreatic insulin secretion and modifies the risk of diabetes. AB - The fibroblast growth factor receptor 4 (FGFR4)-R388 single-nucleotide polymorphism has been associated with cancer risk and prognosis. Here we show that the FGFR4-R388 allele yields a receptor variant that preferentially promotes STAT3/5 signaling. This STAT activation transcriptionally induces Grb14 in pancreatic endocrine cells to promote insulin secretion. Knockin mice with the FGFR4 variant allele develop pancreatic islets that secrete more insulin, a feature that is reversed through Grb14 deletion and enhanced with FGF19 administration. We also show in humans that the FGFR4-R388 allele enhances islet function and may protect against type 2 diabetes. These data support a common genetic link underlying cancer and hyperinsulinemia. PMID- 23747251 TI - Epigenetic silencing mediates mitochondria stress-induced longevity. AB - Reactive oxygen species (ROS) play complex roles in aging, having both damaging effects and signaling functions. Transiently elevating mitochondrial stress, including mitochondrial ROS (mtROS), elicits beneficial responses that extend lifespan. However, these adaptive, longevity-signaling pathways remain poorly understood. We show here that Tel1p and Rad53p, homologs of the mammalian DNA damage response kinases ATM and Chk2, mediate a hormetic mtROS longevity signal that extends yeast chronological lifespan. This pathway senses mtROS in a manner distinct from the nuclear DNA damage response and ultimately imparts longevity by inactivating the histone demethylase Rph1p specifically at subtelomeric heterochromatin, enhancing binding of the silencing protein Sir3p, and repressing subtelomeric transcription. These results demonstrate the existence of conserved mitochondria-to-nucleus stress-signaling pathways that regulate aging through epigenetic modulation of nuclear gene expression. PMID- 23747252 TI - Mitochondrial Ca2+ uptake induces cyclic AMP generation in the matrix and modulates organelle ATP levels. AB - While the role of mitochondrial Ca2+ homeostasis in cell pathophysiology is widely accepted, the possibility that cAMP regulates mitochondrial functions has only recently received experimental support. The site of cAMP production, its targets, and its functions in the organelles remain uncertain. Using a variety of genetic/pharmacological tools, we here demonstrate that the mitochondrial inner membrane is impermeable to cytosolic cAMP, while an autonomous cAMP signaling toolkit is expressed in the matrix. We demonstrate that rises in matrix Ca2+ powerfully stimulate cAMP increases within mitochondria and that matrix cAMP levels regulate their ATP synthesizing efficiency. In cardiomyocyte cultures, mitochondrial cAMP can be increased by treatments that augment the frequency and amplitude of Ca2+ oscillations within the cytosol and organelles, revealing that mitochondria can integrate an oscillatory Ca2+ signal to increase cAMP in their matrix. The present data reveal the existence, within mitochondria, of a hitherto unknown crosstalk between Ca2+ and cAMP. PMID- 23747253 TI - MICU1 controls both the threshold and cooperative activation of the mitochondrial Ca2+ uniporter. AB - Mitochondrial Ca(2+) uptake via the uniporter is central to cell metabolism, signaling, and survival. Recent studies identified MCU as the uniporter's likely pore and MICU1, an EF-hand protein, as its critical regulator. How this complex decodes dynamic cytoplasmic [Ca(2+)] ([Ca(2+)]c) signals, to tune out small [Ca(2+)]c increases yet permit pulse transmission, remains unknown. We report that loss of MICU1 in mouse liver and cultured cells causes mitochondrial Ca(2+) accumulation during small [Ca(2+)]c elevations but an attenuated response to agonist-induced [Ca(2+)]c pulses. The latter reflects loss of positive cooperativity, likely via the EF-hands. MICU1 faces the intermembrane space and responds to [Ca(2+)]c changes. Prolonged MICU1 loss leads to an adaptive increase in matrix Ca(2+) binding, yet cells show impaired oxidative metabolism and sensitization to Ca(2+) overload. Collectively, the data indicate that MICU1 senses the [Ca(2+)]c to establish the uniporter's threshold and gain, thereby allowing mitochondria to properly decode different inputs. PMID- 23747255 TI - The expression of succinate semialdehyde dehydrogenase in the caudal part of the spinal trigeminal nucleus is down-regulated after electrical stimulation of the dura mater surrounding the superior sagittal sinus in conscious rats. AB - Using two-dimensional gel electrophoresis (2-DE), we examined proteomic changes in the caudal part of the spinal trigeminal nucleus induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus (ES-SSS) in conscious rats. After image analysis of 2-DE gels, nine protein spots of interest were excised from the gels and identified by liquid chromatography-tandem mass spectrometry. Among the nine, succinate semialdehyde dehydrogenase (SSADH) was found to be down-regulated after ES-SSS. This result was validated with Real-time polymerase chain reaction and Western blot analyses. Because SSADH degrades GABA, decreased expression of it increases the local concentration of GABA in the caudal part of the spinal trigeminal nucleus after ES-SSS; this has not been reported before and may participate in the modulation of trigeminovascular headache. PMID- 23747254 TI - The mitochondrial chaperone TRAP1 promotes neoplastic growth by inhibiting succinate dehydrogenase. AB - We report that the mitochondrial chaperone TRAP1, which is induced in most tumor types, is required for neoplastic growth and confers transforming potential to noncancerous cells. TRAP1 binds to and inhibits succinate dehydrogenase (SDH), the complex II of the respiratory chain. The respiratory downregulation elicited by TRAP1 interaction with SDH promotes tumorigenesis by priming the succinate dependent stabilization of the proneoplastic transcription factor HIF1alpha independently of hypoxic conditions. These findings provide a mechanistic clue to explain the switch to aerobic glycolysis of tumors and identify TRAP1 as a promising antineoplastic target. PMID- 23747256 TI - Monitoring of the emergent small animal patient. AB - Monitoring of the emergent patient can be one of the most challenging aspects in veterinary medicine, but can also be one of the most rewarding. Careful monitoring of the emergent patient is crucial in assessment and treatment of potentially life-threatening conditions. While advanced monitoring equipment is becoming increasingly available, triage evaluation and serial assessment can recognize patient changes before clinical deterioration. In addition to hands-on serial patient assessment, valuable monitoring tools include pulse oximetry, blood pressure monitoring, urine output, electrocardiography monitoring, and central venous pressure monitoring. PMID- 23747257 TI - Fluid therapy for the emergent small animal patient: crystalloids, colloids, and albumin products. AB - Fluid therapy is essential in the treatment of emergent veterinary patients. Many different types of intravenous fluids are available, including crystalloids, artificial colloids, and natural colloids. The type, dose, and administration rate can determine the outcome in a critically ill patient. This article discusses the various types of fluids and their indication for use. PMID- 23747258 TI - Transfusion medicine in small animals. AB - This article reviews the use of transfusion medicine in veterinary medicine and discusses current research regarding donor screening and component therapy. Typing and crossmatching methodologies are discussed. Available components, potential uses, and controversies in treatment are also discussed. PMID- 23747259 TI - Emergency management and treatment of the poisoned small animal patient. AB - This article reviews management of the acutely poisoned veterinary patient, including initial telephone triage, appropriate communication and history gathering from the pet owner, decontamination methods (including the use of appropriate emetic agents and dosing of activated charcoal), and general treatment of the poisoned patient. Symptomatic and supportive care of the poisoned patient includes the use of fluid therapy, gastrointestinal support (eg, antacids), central nervous system support (eg, muscle relaxants, anticonvulsants), sedatives/reversal agents (eg, phenothiazines, naloxone, flumazenil), hepatoprotectants, and miscellaneous antidotal therapy. PMID- 23747260 TI - The use of ultrasound for dogs and cats in the emergency room: AFAST and TFAST. AB - Internal injuries are common and often life-threatening conditions that can be challenging to detect based on physical examination, radiographs, and centesis. Recently, ultrasound has been introduced and evaluated in human and veterinary emergency medicine as a point-of-care test for a variety of emergent conditions. This article discusses the indications for point-of-care emergency ultrasound of dogs and cats in the emergency and critical care setting. Techniques for performing focused emergency evaluations are described and the current veterinary and human literature is contrasted, with emphasis on abdominal, pleural, pericardial, and pulmonary evaluation. PMID- 23747261 TI - Management of respiratory emergencies in small animals. AB - Management of respiratory distress involves careful consideration of the history, physical examination, and diagnostic testing. Supplemental oxygen is useful. Urgent procedures, such as intubation, thoracococentesis, or tracheostomy, may be required. The prognosis is dependent on the underlying disease, but is often favorable. This article reviews the approach, differential diagnoses, and the approach to management for dogs and cats with respiratory distress. PMID- 23747262 TI - Management of cardiac emergencies in small animals. AB - Cardiac emergencies are life-threatening conditions that must be diagnosed quickly to avoid delays in therapy. A timely and accurate diagnosis leads to early relief of symptoms and improved survival. This article provides both a comprehensive review and updated management recommendations for common cardiac emergencies in dogs and cats. Specifically, the article confers updates for the efficient clinical recognition of decompensated cardiac patients, including focused echocardiography, cardiac biomarkers, and electrocardiogram interpretation. This article also reviews the latest recommendations for the treatment of heart failure (including the use of pimobendan) and the management of arrhythmias, pericardial effusion, and aortic thromboembolism. PMID- 23747263 TI - Management of urinary tract emergencies in small animals. AB - This article focuses on some of the most commonly seen urinary tract emergencies in dogs and cats, with emphasis on basic pathophysiology, diagnosis, and emergency management of these cases. PMID- 23747264 TI - Endocrine emergencies in dogs and cats. AB - Success in treatment of endocrine emergencies is contingent on early recognition and treatment. Many endocrine diseases presenting emergently have nonspecific signs and symptoms. In addition, these endocrine crises are often precipitated by concurrent disease, further making early identification difficult. This article concentrates on recognition and emergency management of the most common endocrine crises in dogs and cats. PMID- 23747265 TI - Surgical considerations in the emergent small animal patient. AB - To ensure a successful outcome when performing emergency surgery, the clinician must have the knowledge to be able to assess the patient to determine that surgical intervention is necessary, and to determine the urgency of the procedure. The clinician must have the skills to manage common surgical emergency procedures and the equipment necessary to perform the surgery. This article discusses surgical considerations for the emergent patient, including preoperative patient assessment, readiness, surgical instrumentation, and patient preparation. An overview of the trauma triad of death, options for providing effective hemostasis, damage control surgery, peritoneal lavage and drainage, and wound management are reviewed. PMID- 23747266 TI - Updates in the management of the small animal patient with neurologic trauma. AB - Neurologic trauma, encompassing traumatic brain injury (TBI) and acute spinal cord injury (SCI), is a cause of significant morbidity and mortality in veterinary patients. Acute SCIs occurring secondary to trauma are also common. Essential to the management of TBI and SCI is a thorough understanding of the pathophysiology of the primary and secondary injury that occurs following trauma. This article reviews the pathophysiology of this primary and secondary injury, as well as recommendations regarding clinical assessment, diagnostics, pharmacologic and nonpharmacologic therapy, and prognosis. PMID- 23747267 TI - Analgesia, anesthesia, and chemical restraint in the emergent small animal patient. AB - Appropriate stabilization of the critically ill animal before sedation or anesthesia is imperative to minimize anesthetic complications. Problems should be anticipated and an appropriate and efficient therapeutic plan should be formulated before anesthetic induction. Use of a balanced anesthesia technique should be considered to minimize potential deleterious effects of single-use drug therapy. Using a combination of different classes of analgesics may be more effective in treating established pain than using a single agent. The critically ill animal should have drugs titrated to effect to minimize the amount of drug needed and lessen potential side effects. PMID- 23747268 TI - Basics of mechanical ventilation for dogs and cats. AB - Respiratory failure may occur due to hypoventilation or hypoxemia. Regardless of the cause, emergent anesthesia and intubation, accompanied by positive pressure ventilation, may be necessary and life saving. Long-term mechanical ventilation requires some specialized equipment and knowledge; however, short-term ventilation can be accomplished without the use of an intensive care unit ventilator, and can provide oxygen supplementation and carbon dioxide removal in critical patients. PMID- 23747269 TI - Updates in small animal cardiopulmonary resuscitation. AB - For dogs and cats that experience cardiopulmonary arrest, rates of survival to discharge are 6% to 7%, as compared with survival rates of 20% for people. The introduction of standardized cardiopulmonary resuscitation guidelines and training in human medicine has led to substantial improvements in outcome. The Reassessment Campaign on Veterinary Resuscitation initiative recently completed an exhaustive literature review and generated a set of evidence-based, consensus cardiopulmonary resuscitation guidelines in 5 domains: preparedness and prevention, basic life support, advanced life support, monitoring, and postcardiac arrest care. This article reviews some of the most important of these new guidelines. PMID- 23747270 TI - Emergency medicine. Preface. PMID- 23747271 TI - Radiation-induced mitotic cell death and glioblastoma radioresistance: a new regulating pathway controlled by integrin-linked kinase, hypoxia-inducible factor 1 alpha and survivin in U87 cells. AB - We have previously shown that integrin-linked kinase (ILK) regulates U87 glioblastoma cell radioresistance by modulating the main radiation-induced cell death mechanism in solid tumours, the mitotic cell death. To decipher the biological pathways involved in these mechanisms, we constructed a U87 glioblastoma cell model expressing an inducible shRNA directed against ILK (U87shILK). We then demonstrated that silencing ILK enhanced radiation-induced centrosome overduplication, leading to radiation-induced mitotic cell death. In this model, ionising radiations induce hypoxia-inducible factor 1 alpha (HIF 1alpha) stabilisation which is inhibited by silencing ILK. Moreover, silencing HIF-1alpha in U87 cells reduced the surviving fraction after 2 Gy irradiation by increasing cell sensitivity to radiation-induced mitotic cell death and centrosome amplification. Because it is known that HIF-1alpha controls survivin expression, we then looked at the ILK silencing effect on survivin expression. We show that survivin expression is decreased in U87shILK cells. Furthermore, treating U87 cells with the specific survivin suppressor YM155 significantly increased the percentage of giant multinucleated cells, centrosomal overduplication and thus U87 cell radiosensitivity. In consequence, we decipher here a new pathway of glioma radioresistance via the regulation of radiation induced centrosome duplication and therefore mitotic cell death by ILK, HIF 1alpha and survivin. This work identifies new targets in glioblastoma with the intention of radiosensitising these highly radioresistant tumours. PMID- 23747272 TI - Cytotoxic activities of [Ser49]phospholipase A2 from the venom of the saw-scaled vipers Echis ocellatus, Echis pyramidum leakeyi, Echis carinatus sochureki, and Echis coloratus. AB - Fractionation by reversed-phase HPLC of venom from four species of saw-scaled viper: Echis ocellatus, Echis pyramidum leakeyi, Echis carinatus sochureki, and Echis coloratus led to identification in each sample of an abundant protein with cytotoxic activity against human non-small cell lung adenocarcinoma A549 cells. The active component in each case was identified by MALDI-TOF mass fingerprinting of tryptic digests as [Ser49]phospholipase A2 ([Ser49]PLA2). An isoform of [Ser49]PLA2 containing the single Ala18-> Val substitution and a partially characterized [Asp49]PLA2 were also present in the E. coloratus venom. LC50 values against A549 cells for the purified [Ser49]PLA2 proteins from the four species are in the range 2.9-8.5 MUM. This range is not significantly different from the range of LC50 values against human umbilical vein endothelial HUVEC cells (2.5-12.2 MUM) indicating that the [Ser49]PLA2 proteins show no differential anti-tumor activity. The LC50 value for [Ser49]PLA2 from E. ocellatus against human erythrocytes is >100 MUM and the MIC values against Escherichia coli and Staphylococcus aureus are >100 MUM. It is suggested that the [Ser49]PLA2 proteins play a major role in producing local tissue necrosis and hemorrhage at the site of envenomation. PMID- 23747273 TI - Comparison of the localization of tetrodotoxin between wild pufferfish Takifugu rubripes juveniles and hatchery-reared juveniles with tetrodotoxin administration. AB - To reveal the accumulation profile of tetrodotoxin (TTX) in pufferfish Takifugu rubripes juveniles, we compared the localization of TTX in various tissues among wild juveniles and hatchery-reared juveniles with or without TTX administration using immunohistochemical technique with anti-TTX monoclonal antibody. Immuno positive reaction was observed in hepatic tissue, basal cell of skin and olfactory, olfactory epithelium, optic nerve and brain (optic tectum, cerebellum, medulla oblongata) of wild juveniles (body length: BL, 4.7-9.4 cm). TTX was detected in the same tissues as wild juveniles and epithelial cell layer of intestine of hatchery-reared juveniles (BL, 5.0-5.3 cm) to which TTX was orally administrated. No positive reaction was observed from the tissues of hatchery reared juveniles without TTX administration. These results suggest that orally administrated TTX to the non-toxic cultured juveniles is accumulated in the same manner of wild juveniles. In addition, our study revealed that pufferfish accumulates TTX in the central nervous system. PMID- 23747274 TI - Cloning and characterization of a novel Kunitz-type inhibitor from scorpion with unique cysteine framework. AB - Kunitz-type proteins from animal venom are good tools for understanding structure function relationships between serine proteases and their inhibitors. We used a cDNA library to clone and characterize the Buthus martensi Kunitz-type protease inhibitor (BmKPI) present in the venom gland of the scorpion B. martensi. The gene codes for a signal peptide of 19 residues and a mature peptide of 64 residues. The mature BmKPI peptide possesses a unique cysteine framework reticulated by four disulfide bridges, unlike many other Kunitz-type proteins with three disulfide bridges. The recombinant BmKPI peptide was functionally expressed and showed strong inhibitory activity toward trypsin (Ki 1.8 * 10-6 M), chymotrypsin (Ki 3.2 * 10-8 M), and elastase (Ki 1.6 * 10-7 M). Structure functional relationship between elastase and BmKPI was further studied. Cysteine mutagenesis experiment showed that the unique disulfide bridge Cys53-Cys61 had little effect on its inhibiting elastase. Molecular dynamics simulation revealed that BmKPI possesses elastase inhibitory active sites similar to the classical Kunitz-type venom peptides, although their cysteine frameworks were different. These results showed that BmKPI is a new multifunctional serine protease inhibitor. To the best of our knowledge, BmKPI is the first functionally characterized Kunitz-type elastase inhibitor derived from scorpion venoms. PMID- 23747275 TI - Functional analysis of the gene SCO1782 encoding Streptomyces hemolysin (S hemolysin) in Streptomyces coelicolor M145. AB - In the process of evaluating the growth of Streptomyces coelicolor on rich media such as blood agar, we found that S. coelicolor a non-pathogenic, well-known antibiotic producer had the ability to grow and produce a prominent hemolytic zone. By comparing the growth with an agarase gene mutant of S. coelicolor, a similar prominent hemolytic zone was found to develop due to the organism's hemolytic activity. After the confirmation of hemolytic activity from S. coelicolor, the genome was searched for hemolysin-coding genes; consequently, SCO1782, SCO2534, and SCO3882 were identified, whose products were annotated as a putative, membrane, and hypothetical proteins, respectively. Functional characterization of all the recombinant proteins expressed in Escherichia coli BL21(DE3) revealed that only SCO1782 exhibited hemolytic activity. This S. coelicolor protein, designated as S-hemolysin, showed sequence similarity toward hemolysins from Brachyspira hyodysenteriae (35%) and Mycobacterium tuberculosis (62%). Recombinant hemolysin exhibited activity against sheep blood erythrocytes and cytolytic activity against human fibroblast cells. Deletion of SCO1782 resulted in complete loss of hemolysin activity in S. coelicolor. PMID- 23747276 TI - Ventilatory response to hypoxia of the 1-day old chicken hatchling after prenatal cold-induced hypometabolism. AB - Sustained prenatal hypoxia decreases the growth and metabolic rate of the embryo and causes a blunted hypoxic ventilatory response (HVR) in the newborn. The most likely interpretation is that the sustained hypoxic stimulation may interfere with the normal prenatal development of the chemoreceptors. However, we wanted to consider the possibility that the prolonged hypoxic hypometabolism may be a contributing factor. Chicken embryos were incubated at 35 degrees C (Cold group, N=14), which is known to lower the embryonic oxygen consumption (VO2) by ~ 30% throughout incubation, or at 37.5 degrees C (Controls, N=16). Cold incubation delayed hatching by ~ 2 days. The 1-day old hatchlings had normal pulmonary ventilation (VE), measured by the barometric technique, and oxygen consumption (VO2), simultaneously measured by an open flow methodology. During acute hypoxia (~ 15% or ~ 11% O2) the hyperventilation (increase in VO2), the hyperpnea and the hypometabolism were almost identical between the two groups of hatchlings. We conclude that a sustained decrease in metabolic rate during the embryonic period by itself does not carry obvious consequences on the newborn's resting VE and HVR. PMID- 23747277 TI - Characterization of choline uptake in Trypanosoma brucei procyclic and bloodstream forms. AB - Choline is an essential nutrient for eukaryotic cells, where it is used as precursor for the synthesis of choline-containing phospholipids, such as phosphatidylcholine (PC). According to published data, Trypanosoma brucei parasites are unable to take up choline from the environment but instead use lyso phosphatidylcholine as precursor for choline lipid synthesis. We now show that T. brucei procyclic forms in culture readily incorporate [(3)H]-labeled choline into PC, indicating that trypanosomes express a transporter for choline at the plasma membrane. Characterization of the transport system in T. brucei procyclic and bloodstream forms shows that uptake of choline is independent of sodium and potassium ions and occurs with a Km in the low micromolar range. In addition, we demonstrate that choline uptake can be blocked by the known choline transport inhibitor, hemicholinium-3, and by synthetic choline analogs that have been established as anti-malarials. Together, our results show that T. brucei parasites express an uptake system for choline and that exogenous choline is used for PC synthesis. PMID- 23747278 TI - Identification of dihydroorotate dehydrogenase as a relevant drug target for 1 hydroxyquinolones in Toxoplasma gondii. AB - 1-Hydroxyquinolones as for example 1-hydroxy-2-dodecyl-4(1)quinolone (HDQ) are effective growth inhibitors for Toxoplasma gondii. These compounds were shown to interfere with the respiratory chain function by inhibition of type II NADH dehydrogenase activity. With the aid of partial drug resistant mutants we identified in this study the fourth enzyme of the de novo pyrimidine synthesis pathway, the T. gondii dihydroorotate dehydrogenase (TgDHODH), as an additional 1 hydroxyquinolone target. A single point mutation was found in the TgDHODH coding sequence of drug resistant clones that change a conserved Asn into Ser in the vicinity of the dihydroorotate binding site. This mutation is sufficient to confer the partial drug resistance phenotype as shown by allele replacement. Enzyme kinetics revealed that 1-hydroxyquinolones inhibit wild type TgDHODH with IC50s in the nanomolar range, while the IC50s for the N302S mutant were significantly increased. Furthermore, inhibition kinetics revealed that 1 hydroxyquinolones act as competitive inhibitors for the electron acceptor QD, but as uncompetitive inhibitors for dihydroorotate. Moreover, heterologous expression of the ubiquinone independent DHODH from Saccharomyces cerevisiae in T. gondii also leads to partial 1-hydroxyquinolone resistance. Our data suggest that inhibition of TgDHODH activity significantly contributes to the growth inhibiting potential of 1-hydroxyquinolones in T. gondii. PMID- 23747279 TI - Imaging of jasmonic acid binding sites in tissue. AB - Hormones regulate the mechanism of plant growth and development, senescence, and plants' adaptation to the environment; studies of the molecular mechanisms of plant hormone action are necessary for the understanding of these complex phenomena. However, there is no measurable signal for the hormone signal transduction process. We synthesized and applied a quantum dot-based fluorescent probe for the labeling of jasmonic acid (JA) binding sites in plants. This labeling probe was obtained by coupling mercaptoethylamine-modified CdTe quantum dots with JA using N-hydroxysuccinimide (NHS) as a coupling agent. The probe, CdTe-JA, was characterized by transmission electron microscopy, dynamic light scattering, and fluorescent spectrum and applied in labeling JA binding sites in tissue sections of mung bean seedlings and Arabidopsis thaliana root tips. Laser scanning confocal microscopy (LSCM) revealed that the probe selectively labeled JA receptor. The competition assays demonstrated that the CdTe-JA probe retained the original bioactivity of JA. An LSCM three-dimensional reconstruction experiment demonstrated excellent photostability of the probe. PMID- 23747280 TI - Enrichment of cancer cells from whole blood using a microfabricated porous filter. AB - Enrichment of circulating tumor cells (CTCs) from whole blood is very challenging due to its rarity. We have developed a new CTC enrichment method using a microfabricated filter. The filter was designed to fractionate tumor cells by cell size and optimized to have high porosity and proper pore distribution. When cancer cells were spiked in whole blood, the average recovery rate was 82.0 to 86.7% and the limit of detection by filtration process was approximately 2 cancer cells in a testing volume of blood. The results indicate that the microfabricated filter-based enrichment would be useful to retrieve and analyze CTCs in practice. PMID- 23747281 TI - Ink-native electrophoresis: an alternative to blue-native electrophoresis more suitable for in-gel detection of enzymatic activity. AB - Blue-native electrophoresis (BNE) is a useful technique for analyzing protein complexes, but the Coomassie brilliant blue (CBB) dye used in BNE often hampers in-gel detection of enzymatic activity. Here we report an improved method, termed ink-native electrophoresis (INE), in which Pelikan 4001 fountain pen ink is used as a charge-shifting agent instead of CBB. INE is more suitable than BNE for in gel detection of protein kinase activity after polyacrylamide gel electrophoresis (PAGE), and its performance in protein complex separation is comparable to that of conventional BNE. INE may provide a powerful tool to isolate and analyze various protein complexes. PMID- 23747282 TI - Two continuous coupled assays for ornithine-delta-aminotransferase. AB - We have developed two new continuous coupled assays for ornithine-delta aminotransferase (OAT) that are more sensitive than previous methods, measure activity in real time, and can be carried out in multiwell plates for convenience and high throughput. The first assay is based on the reduction of Delta(1) pyrroline-5-carboxylate (P5C), generated from ornithine by OAT, using human pyrroline 5-carboxylate reductase 1 (PYCR1), which results in the concomitant oxidation of NADH (nicotinamide adenine dinucleotide, reduced form) to NAD+ (nicotinamide adenine dinucleotide, oxidized form). This procedure was found to be three times more sensitive than previous methods and is suitable for the study of small molecules as inhibitors or inactivators of OAT or as a method to determine OAT activity in unknown samples. The second method involves the detection of L-glutamate, produced during the regeneration of the cofactor pyridoxal 5'-phosphate (PLP) of OAT by an unamplified modification of the commercially available Amplex Red L-glutamate detection kit (Life Technologies). This assay is recommended for the determination of the substrate activity of small molecules against OAT; measuring the transformation of L-ornithine at high concentrations by this assay is complicated by the fact that it also acts as a substrate for the L-glutamate oxidase (GluOx) reporter enzyme. PMID- 23747283 TI - High-throughput compatible fluorescence resonance energy transfer-based assay to identify small molecule inhibitors of AMSH deubiquitinase activity. AB - Deubiquitinases (DUBs) play an important role in regulating the ubiquitin landscape of proteins. The DUB AMSH (associated molecule with the SH3 domain of STAM) has been shown to be involved in regulating the ubiquitin-dependent down regulation of activated cell surface receptors via the endolysosomal degradative pathway. Therefore, small molecule AMSH inhibitors will be useful chemical probes to study the effect of AMSH DUB activity on cell surface receptor degradation. Currently, there are no known selective inhibitors of AMSH or high-throughput compatible assays for their identification. We report the development and optimization of a novel fluorescence resonance energy transfer (FRET)-based add and-read AMSH DUB assay in a 384-well format. In this format, the optimal temperature for a high-throughput screen (HTS) was determined to be 30 degrees C, the assay tolerates 5% dimethyl sulfoxide (DMSO), and it has a Z-score of 0.71, indicating HTS compatibility. The assay was used to show that AMSH selectively cleaves Lys63-linked diubiquitin over Lys48- and Lys11-linked diubiquitin. The IC50 value of the nonspecific small molecule DUB inhibitor N-ethylmaleimide was 16.2+/-3.2 MUM and can be used as a qualitative positive control for the screen. We conclude that this assay is high-throughput compatible and can be used to identify novel small molecule inhibitors of AMSH. PMID- 23747284 TI - Quality of diabetes and hyperlipidemia screening before a first myocardial infarction. AB - BACKGROUND: There has been significant attention to the quality of care for acute myocardial infarction (MI). However, little is known about the quality of preventive care before a patient's first MI. METHODS: We conducted a retrospective, cohort analysis of 5688 patients admitted with their first MI to 96 acute care hospitals in Ontario, Canada, from April 2004 to March 2005 using the Enhanced Feedback For Effective Cardiac Treatment clinical study database. We calculated rates of screening for diabetes and hyperlipidemia according to guidelines using linkages to the Ontario Health Insurance Plan database. Screening rates were stratified by age, sex, socioeconomic status, and number of primary care visits in the past 5 years. RESULTS: Among the 5688 eligible patients, 27.1% did not receive serum cholesterol screening in the 5 years preceding their MI and 27.5% of patients did not receive a fasting blood glucose or glucose tolerance test in the 3 years before their MI. Women were more likely to be screened than men. Screening rates generally increased with age and were similar across socioeconomic categories. There was a positive association between the number of primary care visits and the likelihood of being screened. CONCLUSIONS: A significant number of patients admitted with their first MI were not screened for important modifiable risk factors. Opportunities for the prevention of coronary disease are being missed. More emphasis is needed on identifying risk factors before the development of acute coronary disease. PMID- 23747285 TI - Time domain functional NIRS imaging for human brain mapping. AB - This review is aimed at presenting the state-of-the-art of time domain (TD) functional near-infrared spectroscopy (fNIRS). We first introduce the physical principles, the basics of modeling and data analysis. Basic instrumentation components (light sources, detection techniques, and delivery and collection systems) of a TD fNIRS system are described. A survey of past, existing and next generation TD fNIRS systems used for research and clinical studies is presented. Performance assessment of TD fNIRS systems and standardization issues are also discussed. Main strengths and weakness of TD fNIRS are highlighted, also in comparison with continuous wave (CW) fNIRS. Issues like quantification of the hemodynamic response, penetration depth, depth selectivity, spatial resolution and contrast-to-noise ratio are critically examined, with the help of experimental results performed on phantoms or in vivo. Finally we give an account on the technological developments that would pave the way for a broader use of TD fNIRS in the neuroimaging community. PMID- 23747286 TI - Multi-site reproducibility of prefrontal-hippocampal connectivity estimates by stochastic DCM. AB - This study examined the reproducibility of prefrontal-hippocampal connectivity estimates obtained by stochastic dynamic causal modeling (sDCM). 180 healthy subjects were measured by functional magnetic resonance imaging (fMRI) during a standard working memory N-Back task at three different sites (Mannheim, Bonn, Berlin; each with 60 participants). The reproducibility of regional activations in key regions for working memory (dorsolateral prefrontal cortex, DLPFC; hippocampal formation, HF) was evaluated using conjunction analyses across locations. These analyses showed consistent activation of right DLPFC and deactivation of left HF across all three different sites. The effective connectivity between DLPFC and HF was analyzed using a simple two-region sDCM. For each subject, we evaluated sixty-seven alternative sDCMs and compared their relative plausibility using Bayesian model selection (BMS). Across all locations, BMS consistently revealed the same winning model, with the 2-Back working memory condition as driving input to both DLPFC and HF and with a connection from DLPFC to HF. Statistical tests on the sDCM parameter estimates did not show any significant differences across the three sites. The consistency of both the BMS results and model parameter estimates indicates the reliability of sDCM in our paradigm. This provides a basis for future genetic and clinical studies using this approach. PMID- 23747288 TI - Network dynamics engaged in the modulation of motor behavior in healthy subjects. AB - Motor skills are mediated by a dynamic and finely regulated interplay of the primary motor cortex (M1) with various cortical and subcortical regions engaged in movement preparation and execution. To date, data elucidating the dynamics in the motor network that enable movements at different levels of behavioral performance remain scarce. We here used functional magnetic resonance imaging (fMRI) and dynamic causal modeling (DCM) to investigate effective connectivity of key motor areas at different movement frequencies performed by right-handed subjects (n=36) with the left or right hand. The network of interest consisted of motor regions in both hemispheres including M1, supplementary motor area (SMA), ventral premotor cortex (PMv), motor putamen, and motor cerebellum. The connectivity analysis showed that performing hand movements at higher frequencies was associated with a linear increase in neural coupling strength from premotor areas (SMA, PMv) contralateral to the moving hand and ipsilateral cerebellum towards contralateral, active M1. In addition, we found hemispheric differences in the amount by which the coupling of premotor areas and M1 was modulated, depending on which hand was moved. Other connections were not modulated by changes in motor performance. The results suggest that a stronger coupling, especially between contralateral premotor areas and M1, enables increased motor performance of simple unilateral hand movements. PMID- 23747287 TI - Estimation of resting-state functional connectivity using random subspace based partial correlation: a novel method for reducing global artifacts. AB - Intrinsic functional connectivity analysis using resting-state functional magnetic resonance imaging (rsfMRI) has become a powerful tool for examining brain functional organization. Global artifacts such as physiological noise pose a significant problem in estimation of intrinsic functional connectivity. Here we develop and test a novel random subspace method for functional connectivity (RSMFC) that effectively removes global artifacts in rsfMRI data. RSMFC estimates the partial correlation between a seed region and each target brain voxel using multiple subsets of voxels sampled randomly across the whole brain. We evaluated RSMFC on both simulated and experimental rsfMRI data and compared its performance with standard methods that rely on global mean regression (GSReg) which are widely used to remove global artifacts. Using extensive simulations we demonstrate that RSMFC is effective in removing global artifacts in rsfMRI data. Critically, using a novel simulated dataset we demonstrate that, unlike GSReg, RSMFC does not artificially introduce anti-correlations between inherently uncorrelated networks, a result of paramount importance for reliably estimating functional connectivity. Furthermore, we show that the overall sensitivity, specificity and accuracy of RSMFC are superior to GSReg. Analysis of posterior cingulate cortex connectivity in experimental rsfMRI data from 22 healthy adults revealed strong functional connectivity in the default mode network, including more reliable identification of connectivity with left and right medial temporal lobe regions that were missed by GSReg. Notably, compared to GSReg, negative correlations with lateral fronto-parietal regions were significantly weaker in RSMFC. Our results suggest that RSMFC is an effective method for minimizing the effects of global artifacts and artificial negative correlations, while accurately recovering intrinsic functional brain networks. PMID- 23747289 TI - Diffusion restriction in the human spinal cord characterized in vivo with high b value STEAM diffusion imaging. AB - Restricted or hindered motion of water across axonal membranes as characterized with diffusion-weighted (DW) imaging may be a potential marker of axonal damage in white matter (WM) injury due to trauma, neurodegeneration, or other causes. This study sought to determine whether high b-value DW imaging with a stimulated echo (STEAM) sequence could improve the spatially resolved assessment of tissue architecture in the human spinal cord in vivo. Diffusion times from 76 ms to 1000 ms and b-values of up to 14,750 s/mm(2) were used to acquire axial DW images in six healthy volunteers, and four additional healthy volunteers were studied with a protocol focused on high b-value, higher-resolution imaging. Mono-exponential, diffusional kurtosis, and mono-exponential with an additive constant (MEC) models were fit individually to diffusion decay curves obtained at different diffusion times. Diffusion restriction, characterized with the diffusional kurtosis and MEC models, was measured more precisely using higher b-value ranges. DW images at high b-value and fitting parameters using the large range of b-values available at the diffusion time of 1000 ms demonstrated signal and restriction differences between gray and white matter and even across white matter regions. These white matter differences may reflect variations in axonal density, diameter, or alignment. We conclude that high b-value DW imaging with a STEAM sequence on a conventional clinical scanner can provide accurate measures of diffusion hindrance and restriction in human spinal cord in vivo. PMID- 23747290 TI - Visualizing oxidative stress-induced depression of cardiac vagal baroreflex by MRI/DTI in a mouse neurogenic hypertension model. AB - A clinical hallmark of hypertension is impairment of the cardiac vagal baroreflex, which maintains stable blood pressure and heart rate under physiological conditions. There is also evidence that oxidative stress in the brain is associated with neurogenic hypertension. We tested the hypothesis that an augmented superoxide level in the nucleus tractus solitarii (NTS), the terminal site of baroreceptor afferents, contributes to the depression of cardiac vagal baroreflex by disrupting the connectivity between the NTS and the nucleus ambiguus (NA), the origin of the vagus nerve, during neurogenic hypertension. An experimental model of neurogenic hypertension that employed intracerebroventricular infusion of angiotensin II in male adult C57BL/6 mice was used. Based on tractographic evaluations using magnetic resonance imaging/diffusion tensor imaging of the medulla oblongata in the brain stem, we found that the connectivity between the NTS and NA was disrupted in neurogenic hypertension, concurrent with impairment of the cardiac vagal baroreflex as detected by radiotelemetry. We further found that the disrupted NTS-NA connectivity was reversible, and was related to oxidative stress induced by augmented levels of NADPH oxidase-generated superoxide in the NTS. We conclude that depression of the cardiac vagal baroreflex induced by oxidative stress in the NTS in the context of neurogenic hypertension may be manifested in the form of dynamic alterations in the connectivity between the NTS and NA. PMID- 23747291 TI - Survival impact of complete cytoreduction to no gross residual disease for advanced-stage ovarian cancer: a meta-analysis. AB - OBJECTIVE: To quantify the impact of complete cytoreduction to no gross residual disease on overall survival among patients with advanced-stage ovarian cancer treated during the platinum-taxane era. METHODS: PubMed and Cochrane Library databases were searched for all articles on primary cytoreductive surgery for advanced-stage ovarian cancer published from 1/1996 to 7/2011. A total of 18 relevant studies (13,257 patients) were identified for analysis. Simple and multiple linear regression analyses, with weighted correlation calculations, were used to assess the effect on median survival time of clinical and treatment related factors. RESULTS: The mean weighted median overall survival time for all cohorts was 44.4 months (range, 27.6-66.9 months). Simple linear regression analysis revealed that residual disease, stage IV disease, and use of intraperitoneal chemotherapy were significantly associated with median survival time. After controlling for other factors on multiple linear regression analysis, each 10% increase in the proportion of patients undergoing complete cytoreduction to no gross residual disease was associated with a significant and independent 2.3-month increase (95%CI = 0.6-4.0, p = 0.011) in cohort median survival compared to a 1.8-month increase (95%CI = 0.6-3.0, p = 0.004) in cohort median survival for optimal cytoreduction (residual disease<=1cm). Each 10% increase in the proportion of patients receiving intraperitoneal chemotherapy was associated with a significant and independent 3.9-month increase (95%CI = 1.1-6.8, p=0.008) in median cohort survival time. CONCLUSIONS: For advanced-stage ovarian cancer treated during the platinum-taxane era, the proportions of patients left with no gross residual disease and receiving intraperitoneal chemotherapy are independently significant factors associated with the most favorable cohort survival time. PMID- 23747292 TI - 'You've got it within you': the political act of keeping a wellness focus in the antenatal time. AB - OBJECTIVE: by exploring midwives' communication techniques intended to promote a wellness focus in the antenatal period, this study identified strategies midwives use to amplify women's own resources and capacities, with the aim of reducing antenatal anxiety. DESIGN: a qualitative design utilising focus groups as a means of generating data. SETTING: two Australian cities: Canberra, ACT and Sydney NSW. PARTICIPANTS: 14 experienced, practising midwives across two states/territories, employed in multiple hospitals and community settings. FINDINGS: three themes emerged from the analysis: calm unhurriedness, speaking in wellness and reassuring bodies. Midwives in these focus groups used strategies in antenatal care that could be co-ordinated into a planned process for wellness focussed care. KEY CONCLUSIONS: individually midwives used a variety of strategies specifically intended to facilitate women's capabilities, to employ worry usefully and to reduce anxiety. Midwives in the study clearly viewed this kind of wellness focussed care as their responsibility and their right. IMPLICATIONS FOR PRACTICE: the midwives' collective wisdom could be shared and developed further into an overall salutogenic antenatal strategy to be used for the good of pregnant women and their infants. PMID- 23747293 TI - Management of type III female genital mutilation in Birmingham, UK: a retrospective audit. AB - OBJECTIVES: to audit clinical management of women with type III female genital mutilation (FGM) according to local guidelines. Secondary objectives were to describe the population that uses the service and compare obstetric outcomes of intrapartum deinfibulation and antenatal deinfibulation. DESIGN: retrospective audit. SETTING: a hospital midwifery-led FGM specialist service in Birmingham, UK. PARTICIPANTS: 253 women with type III FGM who gave birth between January 2008 and December 2009 METHODS: retrospective case analysis using patient records. MAIN OUTCOME MEASURES: proportion of women managed according to locally agreed criteria for the management of FGM; obstetric outcomes including perineal tears, episiotomy rates, estimated blood loss, infant APGAR scores and indications for caesarean section. FINDINGS: 91 (36%) women booked into antenatal care after 16 weeks gestation. Only 26 (10.3%) were managed fully according to guidelines. The area with poorest performance was child protection, where the presence of normal genitalia was documented in only 52 (38.8%) of medical notes following birth of a female infant. The majority of women (214, 84.6%) had been deinfibulated in a previous pregnancy. Of the 39 infibulated at booking, only 9 (23.1%) were deinfibulated antenatally, the rest opted for intrapartum deinfibulation. Women who had intrapartum deinfibulation had a higher average blood loss and more tears than those deinfibulated antenatally, although this was not statistically significant. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: alternative systems should be considered to improve documentation of child protection related information. Further research is needed to confirm or refute the adverse findings among those that delayed deinfibulation. PMID- 23747294 TI - Phase diagram of a 4-component lipid mixture: DSPC/DOPC/POPC/chol. AB - We report the first 4-component phase diagram for the lipid bilayer mixture, DSPC/DOPC/POPC/chol (distearoylphosphatidylcholine/dioleoylphosphatidylcholine/1 palmitoyl, 2-oleoylphosphatidylcholine/cholesterol). This phase diagram, which has macroscopic Ld+Lo phase domains, clearly shows that all phase boundaries determined for the 3-component mixture containing DOPC transition smoothly into the boundaries for the 3-component mixture containing POPC, which has nanoscopic phase domains of Ld+Lo. Our studies start from two published ternary phase diagrams, and show how these can be combined into a quaternary phase diagram by study of a few hundred samples of intermediate compositions. PMID- 23747295 TI - Residues of a proposed gate region in type I ATP-binding cassette import systems are crucial for function as revealed by mutational analysis. AB - The type I ATP-binding cassette (ABC) importer for positively charged amino acids of the thermophilic bacterium Geobacillus stearothermophilus consists of the extracellular solute binding protein, ArtJ, and a homodimer each of the transmembrane subunit, ArtM, and the nucleotide-binding and -hydrolyzing subunit, ArtP. We have investigated the functional consequences of mutations affecting conserved residues from two peptide regions in ArtM, recently proposed to form a 'gate' by which access of a substrate to the translocation path is controlled (Hollenstein et al., 2007 [14]). Transporter variants were reconstituted into proteoliposomes and assayed for ArtJ/arginine-stimulated ATPase activity. Replacement of residues from region 1 (Arg-63, Pro-66) caused no or only moderate reduction in ATPase activity. In contrast, mutating residues from gate region 2 (Lys-159, Leu-163) resulted in a substantial increase in ATPase activity which, however, as demonstrated for variants ArtM(K159I) and ArtM(K159E), is not coupled to transport. Replacing homologous residues in the closely related histidine transporter of Salmonella enterica serovar Typhimurium (HisJ-QMP2) caused different phenotypes. Mutation to isoleucine of HisQ(K163) or HisM(H172), both homologous to ArtM(K159), abolished ATPase activity. The mutations most likely caused a structural change as revealed by limited proteolysis. In contrast, substantial, albeit reduced, enzymatic activity was observed with variants of HisQ(L167->G) or HisM(L176->G), both homologous to ArtM(L163). Our study provides the first experimental evidence in favor of a crucial role of residues from the proposed gate region in type I ABC importer function. PMID- 23747296 TI - Functional properties of cell-free expressed human endothelin A and endothelin B receptors in artificial membrane environments. AB - The human endothelin receptors are members of the rhodopsin class A of G-protein coupled receptors and key modulators of blood pressure regulation. Their functional in vitro characterization has widely been limited by the availability of high quality samples. We have optimized cell-free expression protocols for the human endothelin A and endothelin B receptors by implementing co-translational association approaches of the synthesized proteins with supplied liposomes or nanodiscs. Efficiency of membrane association and ligand binding properties of the receptors have systematically been studied in correlation to different membrane environments and lipid types. Ligand binding was analyzed by a number of complementary assays including radioassays, surface plasmon resonance and fluorescence measurements. High affinity binding of the peptide ligand ET-1 to both endothelin receptors could be obtained with several conditions and the highest Bmax values were measured in association with nanodiscs. We could further obtain the characteristic differential binding pattern of the two endothelin receptors with a panel of selected agonists and antagonists. Two intrinsic properties of the functionally folded endothelin B receptor, the proteolytic processing based on conformational recognition as well as the formation of SDS resistant complexes with the peptide ligand ET-1, were observed with samples obtained from several cell-free expression conditions. High affinity and specific binding of ligands could furthermore be obtained with non-purified receptor samples in crude cell-free reaction mixtures, thus providing new perspectives for fast in vitro screening applications. PMID- 23747297 TI - Clerocidin-mediated DNA footprinting discriminates among different G-quadruplex conformations and detects tetraplex folding in a duplex environment. AB - BACKGROUND: G-quadruplexes are polymorphic non-canonical nucleic acid conformations involved both in physiological and pathological processes. Given the high degree of folding heterogeneity and comparable conformational stabilities, different G-quadruplex forms can occur simultaneously, hence rendering the use of basic instrumental methods for structure determination, like X-ray diffraction or NMR, hardly useful. Footprinting techniques represent valuable and relatively rapid alternative to characterize DNA folding. The natural diterpenoid clerocidin is an alkylating agent that specifically reacts at single-stranded DNA regions, with different mechanisms depending on the exposed nucleotide. METHODS: Clerocidin was used to footprint G-quadruplex structures formed by telomeric and oncogene promoter sequences (c-myc, bcl-2, c-kit2), and by the thrombin binding aptamer. RESULTS: The easy modulability of CL reactivity towards DNA bases permitted to discriminate fully and partially protected sites, highlights stretched portions of the G-quadruplex conformation, and discriminate among topologies adopted by one sequence in different environmental conditions. Importantly, CL displayed the unique property to allow detection of G-quadruplex folding within a duplex context. CONCLUSIONS: CL is a finely performing new tool to unveil G-quadruplex arrangements in DNA sequences under genomically relevant conditions. GENERAL SIGNIFICANCE: Nucleic acid G-quadruplex structures are an emerging research field because of the recent indication of their involvement in a series of key biological functions, in particular in regulation of proliferation-associated gene expression. The use of clerocidin as footprinting agent to identify G-quadruplex structures under genomically relevant conditions may allow detection of new G-quadruplex-based regulatory regions. PMID- 23747298 TI - Molecular basis of ligand recognition by OASS from E. histolytica: insights from structural and molecular dynamics simulation studies. AB - BACKGROUND: O-acetyl serine sulfhydrylase (OASS) is a pyridoxal phosphate (PLP) dependent enzyme catalyzing the last step of the cysteine biosynthetic pathway. Here we analyze and investigate the factors responsible for recognition and different conformational changes accompanying the binding of various ligands to OASS. METHODS: X ray crystallography was used to determine the structures of OASS from Entamoeba histolytica in complex with methionine (substrate analog), isoleucine (inhibitor) and an inhibitory tetra-peptide to 2.00A, 2.03A and 1.87A resolutions, respectively. Molecular dynamics simulations were used to investigate the reasons responsible for the extent of domain movement and cleft closure of the enzyme in presence of different ligands. RESULTS: Here we report for the first time an OASS-methionine structure with an unmutated catalytic lysine at the active site. This is also the first OASS structure with a closed active site lacking external aldimine formation. The OASS-isoleucine structure shows the active site cleft in open state. Molecular dynamics studies indicate that cofactor PLP, N88 and G192 form a triad of energy contributors to close the active site upon ligand binding and orientation of the Schiff base forming nitrogen of the ligand is critical for this interaction. CONCLUSIONS: Methionine proves to be a better binder to OASS than isoleucine. The beta branching of isoleucine does not allow it to reorient itself in suitable conformation near PLP to cause active site closure. GENERAL SIGNIFICANCE: Our findings have important implications in designing better inhibitors against OASS across all pathogenic microbial species. PMID- 23747299 TI - Hofmeister ions control protein dynamics. AB - BACKGROUND: Recently, we have elaborated a thermodynamic theory that could coherently interpret the diverse effects of Hofmeister ions on proteins, based on a single physical parameter, the protein-water interfacial tension (Der et al., Journal of Physical Chemistry B. 2007, 111, 5344-5350). This theory, implying a "liquid drop model", predicts changes in protein conformational fluctuations upon addition of Hofmeister salts (containing either kosmotropic or chaotropic anions) to the medium. METHODS: Here, we report experimental tests of this prediction using a complex approach by applying methods especially suited for the detection of protein fluctuation changes (neutron scattering, micro-calorimetry, and Fourier-transform infrared spectroscopy). RESULTS: It is demonstrated that Hofmeister salts, via setting the hydrophobic/hydrophilic properties of the protein-water interface, control conformational fluctuations even in the interior of the typical membrane transport protein bacteriorhodopsin, around its temperature-induced, unusual alpha(II)->alpha(I) conformational transition between 60 and 90 degrees C. We found that below this transition kosmotropic (COOCH3(-)), while above it chaotropic (ClO4(-)) anions increase structural fluctuations of bR. It was also shown that, in each case, an onset of enhanced equilibrium fluctuations presages this phase transition in the course of the thermotropic response of bR. CONCLUSIONS: These results are in full agreement with the theory, and demonstrate that predictions based on protein-water interfacial tension changes can describe Hofmeister effects and interpret protein dynamics phenomena even in unusual cases. GENERAL SIGNIFICANCE: This approach is expected to provide a useful guide to understand the principles governing the interplay between protein interfacial properties and conformational dynamics, in general. PMID- 23747300 TI - Reverse electron flow-mediated ROS generation in ischemia-damaged mitochondria: role of complex I inhibition vs. depolarization of inner mitochondrial membrane. AB - BACKGROUND: The reverse electron flow-induced ROS generation (RFIR) is decreased in ischemia-damaged mitochondria. Cardiac ischemia leads to decreased complex I activity and depolarized inner mitochondrial membrane potential (DeltaPsi) that are two key factors to affect the RFIR in isolated mitochondria. We asked if a partial inhibition of complex I activity without alteration of the DeltaPsi is able to decrease the RFIR. METHODS: Cardiac mitochondria were isolated from mouse heart (C57BL/6) with and without ischemia. The rate of H2O2 production from mitochondria was determined using amplex red coupled with horseradish peroxidase. Mitochondria were isolated from the mitochondrial-targeted STAT3 overexpressing mouse (MLS-STAT3E) to clarify the role of partial complex I inhibition in RFIR production. RESULTS: The RFIR was decreased in ischemia-damaged mouse heart mitochondria with decreased complex I activity and depolarized DeltaPsi. However, the RFIR was not altered in the MLS-STAT3E heart mitochondria with complex I defect but without depolarization of the DeltaPsi. A slight depolarization of the DeltaPsi in wild type mitochondria completely eliminated the RFIR. CONCLUSIONS: The mild uncoupling but not the partially decreased complex I activity contributes to the observed decrease in RFIR in ischemia-damaged mitochondria. GENERAL SIGNIFICANCE: The RFIR is less likely to be a key source of cardiac injury during reperfusion. PMID- 23747301 TI - ATP interacts with the CPVT mutation-associated central domain of the cardiac ryanodine receptor. AB - BACKGROUND: This study was designed to determine whether the cardiac ryanodine receptor (RyR2) central domain, a region associated with catecholamine polymorphic ventricular tachycardia (CPVT) mutations, interacts with the RyR2 regulators, ATP and the FK506-binding protein 12.6 (FKBP12.6). METHODS: Wild-type (WT) RyR2 central domain constructs (G(2236)to G(2491)) and those containing the CPVT mutations P2328S and N2386I, were expressed as recombinant proteins. Folding and stability of the proteins were examined by circular dichroism (CD) spectroscopy and guanidine hydrochloride chemical denaturation. RESULTS: The far UV CD spectra showed a soluble stably-folded protein with WT and mutant proteins exhibiting a similar secondary structure. Chemical denaturation analysis also confirmed a stable protein for both WT and mutant constructs with similar two state unfolding. ATP and caffeine binding was measured by fluorescence spectroscopy. Both ATP and caffeine bound with an EC50 of ~200-400MUM, and the affinity was the same for WT and mutant constructs. Sequence alignment with other ATP binding proteins indicated the RyR2 central domain contains the signature of an ATP binding pocket. Interaction of the central domain with FKBP12.6 was tested by glutaraldehyde cross-linking and no association was found. CONCLUSIONS: The RyR2 central domain, expressed as a 'correctly' folded recombinant protein, bound ATP in accord with bioinformatics evidence of conserved ATP binding sequence motifs. An interaction with FKBP12.6 was not evident. CPVT mutations did not disrupt the secondary structure nor binding to ATP. GENERAL SIGNIFICANCE: Part of the RyR2 central domain CPVT mutation cluster, can be expressed independently with retention of ATP binding. PMID- 23747302 TI - Vascular targeting to the SST2 receptor improves the therapeutic response to near IR two-photon activated PDT for deep-tissue cancer treatment. AB - BACKGROUND: Broader clinical acceptance of photodynamic therapy is currently hindered by (a) poor depth efficacy, and (b) predisposition towards establishment of an angiogenic environment during the treatment. Improved depth efficacy is being sought by exploiting the NIR tissue transparency window and by photo activation using two-photon absorption (2PA). Here, we use two-photon activation of PDT sensitizers, untargeted and targeted to SST2 receptors or EGF receptors, to achieve deep tissue treatment. METHODS: Human tumor lines, positive or negative for SST2r expression were used, as well as murine 3LL cells and bovine aortic endothelial cells. Expression of SST2 receptors on cancer cells and tumor vasculature was evaluated in vitro and frozen xenograft sections. PDT effects on tumor blood flow were followed using in vivo scanning after intravenous injection of FITC conjugated dextran 150K. Dependence of the PDT efficacy on the laser pulse duration was evaluated. Effectiveness of targeting to vascular SST2 receptors was compared to that of EGF receptors, or no targeting. RESULTS: Tumor vasculature stained for SST2 receptors even in tumors from SST2 receptor negative cell lines, and SST2r targeted PDT led to tumor vascular shutdown. Stretching the pulse from ~120fs to ~3ps led to loss of the PDT efficacy especially at greater depth. PDT targeted to SST2 receptors was much more effective than untargeted PDT or PDT targeted to EGF receptors. GENERAL SIGNIFICANCE: The use of octreotate to target SST2 receptors expressed on tumor vessels is an excellent approach to PDT with few recurrences and some long term cures. PMID- 23747303 TI - Unphosphorylated calponin enhances the binding force of unphosphorylated myosin to actin. AB - BACKGROUND: Smooth muscle has the distinctive ability to maintain force for long periods of time and at low energy costs. While it is generally agreed that this property, called the latch-state, is due to the dephosphorylation of myosin while attached to actin, dephosphorylated-detached myosin can also attach to actin and may contribute to force maintenance. Thus, we investigated the role of calponin in regulating and enhancing the binding force of unphosphorylated tonic muscle myosin to actin. METHODS: To measure the effect of calponin on the binding of unphosphorylated myosin to actin, we used the laser trap assay to quantify the average force of unbinding (Funb) in the absence and presence of calponin or phosphorylated calponin. RESULTS: Funb from F-actin alone (0.12+/-0.01pN; mean+/ SE) was significantly increased in the presence of calponin (0.20+/-0.02pN). This enhancement was lost when calponin was phosphorylated (0.12+/-0.01pN). To further verify that this enhancement of Funb was due to the cross-linking of actin to myosin by calponin, we repeated the measurements at high ionic strength. Indeed, the Funb obtained at a [KCl] of 25mM (0.21+/-0.02pN; mean+/-SE) was significantly decreased at a [KCl] of 150mM, (0.13+/-0.01pN). CONCLUSIONS: This study provides direct molecular level-evidence that calponin enhances the binding force of unphosphorylated myosin to actin by cross-linking them and that this is reversed upon calponin phosphorylation. Thus, calponin might play an important role in the latch-state. GENERAL SIGNIFICANCE: This study suggests a new mechanism that likely contributes to the latch-state, a fundamental and important property of smooth muscle that remains unresolved. PMID- 23747304 TI - Emergent categorical representation of natural, complex sounds resulting from the early post-natal sound environment. AB - Cortical sensory representations can be reorganized by sensory exposure in an epoch of early development. The adaptive role of this type of plasticity for natural sounds in sensory development is, however, unclear. We have reared rats in a naturalistic, complex acoustic environment and examined their auditory representations. We found that cortical neurons became more selective to spectrotemporal features in the experienced sounds. At the neuronal population level, more neurons were involved in representing the whole set of complex sounds, but fewer neurons actually responded to each individual sound, but with greater magnitudes. A comparison of population-temporal responses to the experienced complex sounds revealed that cortical responses to different renderings of the same song motif were more similar, indicating that the cortical neurons became less sensitive to natural acoustic variations associated with stimulus context and sound renderings. By contrast, cortical responses to sounds of different motifs became more distinctive, suggesting that cortical neurons were tuned to the defining features of the experienced sounds. These effects lead to emergent "categorical" representations of the experienced sounds, which presumably facilitate their recognition. PMID- 23747305 TI - A high-fat diet or galanin in the PVN decreases phosphorylation of CREB in the nucleus accumbens. AB - A high-fat diet (HFD) can increase hypothalamic galanin (GAL). GAL has recently been shown to inhibit opiate reward, which in turn, decreases cAMP response element-binding protein (CREB) in the nucleus accumbens (NAc). We hypothesized that injection of GAL into the paraventricular nucleus (PVN), or consumption of a HFD, would be associated with a decrease in NAc CREB. In Exp. 1, GAL in the PVN of naive rats decreased phosphorylated-CREB (pCREB) which is the activated form of CREB, in the NAc compared to saline-injected controls. In Exp. 2, rats fed ad libitum HFD for 4 weeks had reduced NAc pCREB levels compared to rats with sporadic tastes of the HFD. Body weight, serum triglyceride and leptin levels were also raised in the chronic HFD-fed rats. These data suggest that PVN GAL or chronic intake of a HFD can decrease NAc pCREB. The implications of these findings may help to explain the lack of opiate-like withdrawal that has been reported in response to overeating a HFD, thereby providing a potential mechanism underlying behavioral differences seen with addiction-like overconsumption of different types of palatable foods. PMID- 23747306 TI - Protein-protein interactions between intermediate chains and the docking complex of Chlamydomonas flagellar outer arm dynein. AB - Outer arm dynein (OAD) is bound to specific loci on outer-doublet-microtubules by interactions at two sites: via intermediate chain 1 (IC1) and the outer dynein arm docking complex (ODA-DC). Studies using Chlamydomonas mutants have suggested that the individual sites have rather weak affinities for microtubules, and therefore strong OAD attachment to microtubules is achieved by their cooperation. To test this idea, we examined interactions between IC1, IC2 (another intermediate chain) and ODA-DC using recombinant proteins. Recombinant IC1 and IC2 were found to form a 1:1 complex, and this complex associated with ODA-DC in vitro. Binding of IC1 to mutant axonemes revealed that there are specific binding sites for IC1. From these data, we propose a novel model of OAD-outer doublet association. PMID- 23747307 TI - Over-expression of human cytomegalovirus miR-US25-2-3p downregulates eIF4A1 and inhibits HCMV replication. AB - It has been reported that human cytomegalovirus (HCMV) miR-US25-2 reduces DNA viral replication including HCMV. However, the mechanism remains unknown. In our study, eukaryotic translation initiation factor 4A1 (eIF4A1) was identified to be a direct target of miR-US25-2-3p. Small interfering RNA (siRNA) and miR-US25-2-3p mediated eIF4A1 knockdown experiments revealed that high level of miR-US25-2-3p in MRC-5 cells decreased HCMV and host genomic DNA synthesis, and inhibited cap dependent translation and host cell proliferation. However, eIF4A1 up-regulation induced by miR-US25-2-3p inhibitor increased HCMV copy number. Therefore, the over-expression of miR-US25-2-3p and consequent lower expression of eIF4A1 may contribute to the inhibition of HCMV replication. PMID- 23747308 TI - miR-150 promotes the proliferation of lung cancer cells by targeting P53. AB - Lung cancer is one of the most common causes for cancer-related death. Previous studies suggested that uncontrolled cell proliferation induced by activation of pro-cancer genes or inhibition of cancer suppressor genes plays an important role in the pathogenesis of lung cancer. Here, we demonstrate that miR-150 is aberrantly upregulated in lung cancer tissue and negatively correlates with the expression of the proapoptotic gene p53 but not EGR2. We show that miR-150 specifically targets the 3'-UTR of p53 and regulates its expression. Inhibition of miR-150 effectively delays cell proliferation and promotes apoptosis, accompanied by increased p53 protein expression. Our data reveals the mechanisms underlying miR-150 regulated lung cancer pathogenesis, which might be beneficial for lung cancer therapy. PMID- 23747309 TI - Alternative splicing variants of proinsulin mRNA and the effects of excess proinsulin on cardiac morphogenesis. AB - Alternative forms of proinsulin mRNA with differential translational capacities and unknown significance are expressed in several developing tissues and in the adult pancreas. In the chick embryo developing heart, we observed low expression of the translationally active transcript of embryonic proinsulin (Pro1B), and predominant expression of the intron 1-unspliced variant, translationally inactive. In the embryonic mouse heart, intron 1-unspliced isoform appeared after E12.5. This tight regulation is required for normal development, since overexpression of Pro1B resulted in abnormal cardiac morphogenesis in 40% of chick embryos, and was accompanied by changes in gene expression of Amhc1and Vmhc1. PMID- 23747311 TI - Surgical management of chronic fistula after sleeve gastrectomy. AB - BACKGROUND: There is no clear definition of the chronic leak after sleeve gastrectomy. There are several endoscopic approaches, including endoprothese, endoscopic clips, endoscopic sealing glue, or balloon dilation. In case of failure of the endoscopic treatment, a definitive surgical approach can be attempted. The objective was to evaluate the surgical treatment of chronic leak after sleeve gastrectomy. METHODS: From November 2010 through March 2012, 8 patients with chronic gastric fistula after laparoscopic sleeve gastrectomy had definitive surgical repair. The initial intervention, the diagnosis and management of the fistula, and the endoscopic approach were carefully reviewed. RESULTS: Five patients had their original laparoscopic sleeve gastrectomies performed at another hospital, while 3 had laparoscopic sleeve gastrectomy at our institution. The mean period of time from the diagnosis of the fistula to definitive surgical treatment was 14.4 months (range 5-44 months). Seven patients initially had surgical drainage by laparoscopy (5) and by laparotomy (2), with concomitant feeding jejunostomy in 6 patients. The endoscopic treatment consisted of endoprothese in 4 patients, endoscopic sealing glue in 2 patients, and sequential approach with glue and prosthesis in 2 other patients. One patient was treated exclusively by endoscopic approach with no surgical drainage. The surgical procedures performed for chronic fistula were gastrojejunal lateral anastomosis (4), Roux-en-Y gastric bypass (2), and gastrectomy with esojejunal anastomosis (2). Four patients presented with postoperative fistula, with a mean healing time of 32 days (range 22-63 days). No mortality was recorded. CONCLUSION: In chronic forms of fistulas with no improvements by endoscopic approach, the surgical treatment can be a solution. It remains a difficult procedure with a high percentage of leakage, but this type of fistula is more easily tolerated by the patient and heals faster. PMID- 23747310 TI - Divergent alpha-synuclein solubility and aggregation properties in G2019S LRRK2 Parkinson's disease brains with Lewy Body pathology compared to idiopathic cases. AB - Mutations in LRRK2 are the most common genetic cause of Parkinson's disease (PD). The most prevalent LRRK2 mutation is the G2019S coding change, located in the kinase domain of this complex multi-domain protein. The majority of G2019S autopsy cases feature typical Lewy Body pathology with a clinical phenotype almost indistinguishable from idiopathic PD (iPD). Here we have investigated the biochemical characteristics of alpha-synuclein in G2019S LRRK2 PD post-mortem material, in comparison to pathology-matched iPD. Immunohistochemistry with pS129 alpha-synuclein antibody showed that the medulla is heavily affected with pathology in G2019S PD whilst the basal ganglia (BG), limbic and frontal cortical regions demonstrated comparable pathology scores between G2019S PD and iPD. Significantly lower levels of the highly aggregated alpha-synuclein species in urea-SDS fractions were observed in G2019S cases compared to iPD in the BG and limbic cortex. Our data, albeit from a small number of cases, highlight a difference in the biochemical properties of aggregated alpha-synuclein in G2019S linked PD compared to iPD, despite a similar histopathological presentation. This divergence in solubility is most notable in the basal ganglia, a region that is affected preclinically and is damaged before overt dopaminergic cell death. PMID- 23747312 TI - Metabolic syndrome, hypertension, and diabetes mellitus after gastric banding: the role of aging and of duration of obesity. AB - BACKGROUND: Bariatric surgery leads to resolution of arterial hypertension and diabetes mellitus; isolated reports indicate that response to bariatric surgery is lower in aged patients. The aim of this study was to evaluate the role of age and of duration of obesity on the frequency of co-morbidities in morbid obesity, as well as on improvement of co-morbidities. METHODS: A total of 837 consecutive patients with known duration of obesity, undergoing gastric banding, were considered for this study; they were divided into quartiles of age and of duration of obesity. Presence of co-morbidities (diabetes mellitus, arterial hypertension, metabolic syndrome), metabolic variables (cholesterol and HDL-C, triglycerides, blood glucose), anthropometric variables, and loss of weight during 24 months were considered. RESULTS: Older patients had a higher frequency of co-morbidities; duration of obesity only affected frequency of co-morbidities, but not response to surgery. At logistic regression, duration of obesity had a moderate independent effect on the frequency of diabetes. Older patients lost less weight than younger patients, but diabetes mellitus and arterial hypertension improved to the same extent in patients of different ages, and metabolic syndrome disappeared more in older patients, associated with a greater decrease of blood glucose. Frequency of removal of gastric banding and loss to follow-up were not different in different quartiles of age or in different quartiles of duration of obesity. CONCLUSION: Older patients, despite lower weight loss, have a response to bariatric surgery that is similar to that of younger patients; age and duration of obesity should not be considered as limits to indications to bariatric surgery. PMID- 23747314 TI - Totally robotic stapleless vertical sleeve gastrectomy. PMID- 23747313 TI - Longitudinal Assessment of Bariatric Surgery (LABS): retention strategy and results at 24 months. AB - BACKGROUND: Retaining participants in observational longitudinal studies after bariatric surgery is difficult yet critical because the retention rate affects interpretation and generalizability of results. Strategies for keeping participants involved in such studies are not commonly published. The objective of this study was to review LABS retention strategies and present the 24-month retention data. METHODS: The LABS Consortium monitors an observational cohort study of 2458 adults enrolled before bariatric surgery at 10 centers within the United States (LABS-2). To maximize data completeness, the investigators developed retention strategies, including flexible scheduling, a call protocol, reminder letters, abbreviated visit options, honoraria, travel reimbursement, providing research progress reports, laboratory results, newsletters, study website, and retention surveys. Strategies for locating participants included frequent updates of contact information, sending registered letters, and searching medical and public records. RESULTS: At 12 and 24 months, 2426 and 2405 participants remained active, with vital status known for 98.7% and 97.3% and weight obtained for 95.2% and 92.2%, respectively. There were 148 missed visits (6.2%) at 24 months primarily because of inability to contact the participant. Only 15 (0.6%) active participants at 24 months missed all follow-up visits. Although 42 participants could not be located or contacted at 6 months, data were obtained for 23 (54.7%) of them at 12 months, and of the 52 participants who could not be located or contacted at 12 months, data were obtained for 18 (34.6%) at 24 months. CONCLUSION: Longitudinal studies provide the ability to evaluate long-term effects of bariatric surgical procedures. The retention achieved in LABS is superior to that of many published reports but requires extensive effort and resources. This report identifies useful retention strategies. Further research is needed to identify the efficacy and cost-effectiveness of specific retention strategies. PMID- 23747315 TI - Neem leaf glycoprotein is superior than cisplatin and sunitinib malate in restricting melanoma growth by normalization of tumor microenvironment. AB - We have observed earlier that therapeutic treatment with neem leaf glycoprotein (NLGP) inhibits murine B16-melanoma growth in vivo and improves survivability of treated mice. Anti-tumor effect of NLGP is directly associated with enhanced CD8(+) T cell activity and downregulation of suppressive cellular functions. Objective of this present study is to know the efficacy of NLGP in comparison to two popular drugs, Cisplatin and Sunitinib malate (Sutent) in relation to the modulation of tumor microenvironment (TME). Analysis of cytokine milieu within TME revealed IL-10, TGFbeta, IL-6 rich type 2 characters was significantly switched to type 1 microenvironment with dominance of IFNgamma and IL-2 within NLGP-TME, which was not found in other cases; however Cisplatin-TME appeared better in type 2 to type 1 conversion than Sutent-TME as evidenced by RT-PCR, ELISA and immunohistochemical analysis. NLGP-TME educated CD8(+) T cells exhibited greater cytotoxicity to B16 Melanoma cells in vitro and these cells showed comparatively higher expression of cytotoxicity related molecules, perforin and granzyme B than Cisplatin-TME and Sutent-TME educated T cells. Adoptive transfer of NLGP-TME exposed T cells, but not PBS-TME exposed cells in mice, is able to significantly inhibit the growth of melanoma in vivo. Such tumor growth inhibition was in significantly lower extent when therapeutic CD8(+) T cells were exposed to either Cisplatin-TME or Sutent-TME or control-TME. Accumulated evidences strongly suggest that non toxic NLGP normalized TME allows T cells to perform optimally than other TMEs under study to inhibit the melanoma growth. PMID- 23747317 TI - Fibrin improves beta (INS-1) cell function, proliferation and survival through integrin alphavbeta3. AB - Extracellular matrix (ECM)-integrin stimulation can promote beta cell differentiation, proliferation and function. However, beta cells lose their insulin secretion function in response to glucose stimulation, and senesce when cultured with ECM proteins for a long time. Fibrin is a provisional ECM protein that is capable of maintaining beta cell function, yet the mechanisms by which this occurs is unknown. The present study examined how fibrin interacts with integrin receptors to promote beta cell cluster formation, proliferation and function. The rat insulinoma cell line, INS-1, was cultured on tissue-culture polystyrene, or with 2-D or 3-D fibrin gels for up to 4 weeks. Cells cultured with fibrin formed islet-like clusters and showed direct contacts with fibrin determined by scanning electron microscopy. Fibrin-cultured INS-1 cells also had significantly increased glucose-stimulated insulin secretion. A significant increase in integrin alphavbeta3 protein and phosphorylated FAK, Erk1/2 and Akt levels was observed in fibrin-cultured INS-1 cells, which was associated with significantly increased cell proliferation and decreased cell apoptosis. Integrin alphavbeta3 blockade affected INS-1 cell spreading on fibrin gels, and resulted in significantly decreased FAK phosphorylation and increased cleaved caspase-3 levels. These results show that fibrin promotes beta cell function, proliferation and survival via integrin alphavbeta3 interactions. PMID- 23747316 TI - Peptides modeled on the RGG domain of AUF1/hnRNP-D regulate 3' UTR-dependent gene expression. AB - Messenger RNA binding proteins control post-transcriptional gene expression of targeted mRNAs. The RGG (arginine-glycine-glycine) domain of the AUF1/hnRNP-D mRNA binding protein is a regulatory region that is essential for protein function. The AUF1-RGG peptide, modeled on the RGG domain of AUF1, represses expression of the macrophage cytokine, VEGF. This report expands studies on the AUF1-RGG peptide and evaluates the role of post-translational modifications of the AUF1 protein. Results show that a minimal 31-amino acid AUF1-RGG peptide that lacks poly-glutamine and nuclear localization motifs retains suppressive activity on a VEGF-3'UTR reporter. Arginine residues in RGG motifs may be methylated with resulting changes in protein function. Mass spectroscopy analysis was performed on AUF1 expressed in RAW-264.7 cells. In resting cells, arginines in the first and second RGG motifs are monomethylated. Following activation with lipopolysaccharide, the arginines are dimethylated. To evaluate if the arginine residues are essential for AUF1-RGG activity, the methylatable arginines in the AUF1-3RGG peptide were mutated to lysine or alanine. The R->K and R->A mutants lack activity. We also demonstrate that PI3K/AKT inhibitors reduce VEGF gene expression. Although immunoscreening of AUF1 suggests that LPS and PI3K inhibitors alter the phosphorylation status of AUF1-p37, mass spectroscopy results show that the p37 AUF1 isoform is not phosphorylated with or without lipopolysaccharide stimulation. In summary, arginines in the RGG domain of AUF1 are methylated, and AUF1-RGG peptides may be novel reagents that reduce macrophage activation in inflammation. PMID- 23747318 TI - Protein release from dihydroxyacetone-based poly(carbonate ester) matrices. AB - The release of therapeutics from solid polymer matrices is an important field of study in the area of controlled release. Here we report on the hydrolytic degradation of directly compressed discs comprised of statistically random polycarbonate esters based on lactic acid and dihydroxyacetone. The controlled release of two model proteins, bovine serum albumin and lysozyme, was explored using two percentage loadings (5 and 10 wt.%). A first order release pattern and a trend for faster protein release with increasing dihydroxyacetone content were observed over a time period ranging from 2.5 to 70 days. To analyze the effects of the internal polymer matrix environment on protein stability the enzymatic activity of released lysozyme was monitored. The results show a high level of enzyme activity for the polycarbonate ester ratios with more dihydroxyacetone in the backbone and at least 50% activity over the first month of release from the co-polymer ratios with more lactic acid in the backbone. Modeling of the release kinetics using the Korsmeyer-Peppas model showed a high correlation, indicating that the release of protein is a complex mechanism controlled by protein diffusion through, and erosion of, the co-polymer matrix. The outcomes show that these polycarbonate esters may be useful materials for extended controlled release of proteins. PMID- 23747319 TI - Identification of a linear B-cell epitope within the Bluetongue virus serotype 8 NS2 protein using a phage-displayed random peptide library. AB - The NS2 protein of Bluetongue virus (BTV) is an important non-structural protein and plays important roles in viral replication and assembly. In this study, one monoclonal antibody (mAb), 4D4, was raised against BTV8 NS2. Phage display technology was used and identified the consensus binding motif SNYD recognized by mAb 4D4. To define the minimal region required for antibody binding, a panel of synthetic peptides encompassing SNYD derived from the BTV8 NS2 was then used to more specifically define the 4D4 epitope as (149)RSNYDV(154). Furthermore, amino acid sequence alignments of different BTV serotypes and other orbiviruses suggested that this epitope is highly conserved among the BTV serotypes. The mAb reagent generated in this study may be applied to the development of BTV diagnosis and surveillance programs and the epitope defined here can lead to important insights into how BTV might interact with the sheep's immune system. PMID- 23747320 TI - Chemical constituents of Swertia yunnanensis and their anti-hepatitis B virus activity. AB - Four new triterpenoids, sweriyunnangenin A (1), sweriyunnanosides A (2), B (3) and C (4), along with nineteen known compounds (5-23) were isolated from Swertia yunnanensis. Based on extensive spectroscopic analyses (1D- and 2D-NMR, HRESIMS, UV, IR, [alpha]D), the structures of sweriyunnangenin A (1), sweriyunnanosides A (2), B (3) and C (4) were elucidated as taraxer-14-ene-3alpha,6beta-diol, oleanolic acid 28-O-beta-D-glucopyranosyl-(1->2)-O-beta-D-glucopyranoside, 2alpha,3beta-di-hydroxyolean-12-en-28-oic acid 28-O-beta-D-glucopyranosyl(1->6) beta-D-glucopyranosyl (1->6)-beta-D-glucopyranosyl(1->2)-beta-D-glucopyranoside and hederagenin 28-O-beta-D-glucopyranosyl(1->6)-beta-D-glucopyranosyl(1->6)-beta D-glucopyranosyl(1->2)-beta-D-glucopyranoside, respectively. Twenty-two compounds were evaluated for their anti-HBV activities on the HepG 2.2.15 cell line in vitro, of which nine compounds showed potent anti-HBV activities. Compounds 1, 5 6, 14-16 and 19 showed activities against the secretion of HBsAg (IC50 values from 0.10 to 1.76 mM) and HBeAg (IC50 values from 0.04 to 1.41 mM), and compounds 11 and 13-16 exhibited significant inhibition on HBV DNA replication (IC50 values from 0.01 to 0.09 mM). PMID- 23747321 TI - Trilobolide and related sesquiterpene lactones from Laser trilobum possessing immunobiological properties. AB - Three new and five known sesquiterpene lactones were isolated from the roots of Laser trilobum (L.) Borkh. Chemical identity of the known compounds and structural analysis of the new ones were determined by HR MS and NMR spectroscopy. The two new sesquiterpene lactones: 2-acetoxytrilobolide and 2 hydroxy-10-deacetyltrilobolide belong to the guaianolide type, and the third one, eudeslaserolide, to the biogenetically related eudesmanolide type. Both types, together with their biogenetic precursor of germacranolide type (laserolide) are present in L. trilobum, as well as in the related Laserpitium species. Purposefully selected set of these native sesquiterpene lactones was tested for specific immunobiological properties. The obtained results demonstrate that trilobolide and its acetoxy analog are strong activators of cytokine secretion. On the contrary, the other L. trilobum and Laserpitium siler constituents are only very mild activators, or even inhibitors of the cytokine and nitric oxide production. PMID- 23747322 TI - Determination of oxymatrine and its active metabolite matrine in human plasma after administration of oxymatrine oral solution by high-performance liquid chromatography coupled with mass spectrometry. AB - A rapid, sensitive and selective high-performance liquid chromatography mass spectrometric method has been developed and validated for the simultaneous determination of oxymatrine and its active metabolite matrine in human plasma after administration of oxymatrine oral solution. Analytes were extracted from the plasma by liquid-liquid extraction with chloroform. The chromatographic separation was accomplished on a Venusil C18 column (150 mm * 4.6 mm, 5 MUm) protected by a C18 guard column (4.0 mm * 2.0 nm; Phenomenex, Torrance, CA, USA). Analytes were detected on a single quadruple mass spectrometer by selected ion monitoring mode via electrospray ionization source. The assay had a lower limit of quantification of 1.5 ng.mL(-1) for oxymatrine and 3 ng.mL(-1) for matrine in plasma. The calibration curves were linear in the measured range. The overall precision and accuracy for all concentrations of quality controls and standards were within +/-15%. The proposed method enabled unambiguous identification and quantification of oxymatrine and its active metabolite matrine in vivo. The results provided a meaningful basis for evaluating the clinical applications of the oxymatrine oral solution. PMID- 23747323 TI - Mesenchymal stem cell proliferation and differentiation on load-bearing trabecular Nitinol scaffolds. AB - Bone tissue regeneration in load-bearing regions of the body requires high strength porous scaffolds capable of supporting angiogenesis and osteogenesis. 70% porous Nitinol (NiTi) scaffolds with a regular 3-D architecture resembling trabecular bone were produced from Ni foams using an original reactive vapor infiltration technique. The "trabecular Nitinol" scaffolds possessed a high compressive strength of 79 MPa and high permeability of 6.9*10(-6) cm2. The scaffolds were further modified to produce a near Ni-free surface layer and evaluated in terms of Ni ion release and human mesenchymal stem cell (hMSC) proliferation (AlamarBlue), differentiation (alkaline phosphatase activity, ALP) and mineralization (Alizarin Red S staining). Scanning electron microscopy was employed to qualitatively corroborate the results. hMSCs were able to adhere and proliferate on both as-produced and surface-modified trabecular NiTi scaffolds, to acquire an osteoblastic phenotype and produce a mineralized extracellular matrix. Both ALP activity and mineralization were increased on porous scaffolds compared to control polystyrene plates. Experiments in a model coculture system of microvascular endothelial cells and hMSCs demonstrated the formation of prevascular structures in trabecular NiTi scaffolds. These data suggest that load bearing trabecular Nitinol scaffolds could be effective in regenerating damaged or lost bone tissue. PMID- 23747324 TI - Antimicrobial properties and dentin bonding strength of magnesium phosphate cements. AB - The main objective of this work was to assess the antimicrobial properties and the dentin-bonding strength of novel magnesium phosphate cements (MPC). Three formulations of MPC, consisting of magnesium oxide and a phosphate salt, NH4H2PO4, NaH2PO4 or a mixture of both, were evaluated. As a result of the setting reaction, MPC transformed into either struvite (MgNH4PO4.6H2O) when NH4H2PO4 was used or an amorphous magnesium sodium phosphate when NaH2PO4 was used. The MPC had appropriate setting times for hard tissue applications, high early compressive strengths and higher strength of bonding to dentin than commercial mineral trioxide aggregate cement. Bacteriological studies were performed with fresh and aged cements against three bacterial strains, Escherichia coli, Pseudomonas aeruginosa (planktonic and in biofilm) and Aggregatibacter actinomycetemcomitans. These bacteria have been associated with infected implants, as well as other frequent hard tissue related infections. Extracts of different compositions of MPC had bactericidal or bacteriostatic properties against the three bacterial strains tested. This was associated mainly with a synergistic effect between the high osmolarity and alkaline pH of the MPC. These intrinsic antimicrobial properties make MPC preferential candidates for applications in dentistry, such as root fillers, pulp capping agents and cavity liners. PMID- 23747326 TI - Probing the biofunctionality of biotinylated hyaluronan and chondroitin sulfate by hyaluronidase degradation and aggrecan interaction. AB - Molecular interactions involving glycosaminoglycans (GAGs) are important for biological processes in the extracellular matrix (ECM) and at cell surfaces, and also in biotechnological applications. Enzymes in the ECM constantly modulate the molecular structure and the amount of GAGs in our tissues. Specifically, the changeable sulfation patterns of many GAGs are expected to be important in interactions with proteins. Biotinylation is a convenient method for immobilizing molecules to surfaces. When studying interactions at the molecular, cell and tissue level, the native properties of the immobilized molecule, i.e. its biofunctionality, need to be retained upon immobilization. Here, the GAGs hyaluronan (HA) and chondroitin sulfate (CS), and synthetically sulfated derivatives of the two, were immobilized using biotin-streptavidin binding. The degree of biotinylation and the placement of biotin groups (end-on/side-on) were varied. The introduction of biotin groups could have unwanted effects on the studied molecule, but this aspect that is not always straightforward to evaluate. Hyaluronidase, an enzyme that degrades HA and CS in the ECM, was investigated as a probe to evaluate the biofunctionality of the immobilized GAGs, using both quartz crystal microbalance and high-performance liquid chromatography. Our results showed that end-on biotinylated HA was efficiently degraded by hyaluronidase, whereas already a low degree of side-on biotinylation destroyed the degrading ability of the enzyme. Synthetically introduced sulfate groups also had this effect. Hence hyaluronidase degradation is a cheap and easy way to investigate how molecular function is influenced by the introduced functional groups. Binding experiments with the proteoglycan aggrecan emphasized the influence of protein size and surface orientation of the GAGs for in-depth studies of GAG behavior. PMID- 23747325 TI - Hollow hydroxyapatite microspheres: a novel bioactive and osteoconductive carrier for controlled release of bone morphogenetic protein-2 in bone regeneration. AB - The regeneration of large bone defects is a common and significant clinical problem. Limitations associated with existing treatments such as autologous bone grafts and allografts have increased the need for synthetic bone graft substitutes. The objective of this study was to evaluate the capacity of novel hollow hydroxyapatite (HA) microspheres to serve as a carrier for controlled release of bone morphogenetic-2 (BMP2) in bone regeneration. Hollow HA microspheres (106-150 MUm) with a high surface area (>100 m2 g(-1)) and a mesoporous shell wall (pore size 10-20 nm) were created using a glass conversion technique. The release of BMP2 from the microspheres into a medium composed of diluted fetal bovine serum in vitro was slow, but it occurred continuously for over 2 weeks. When implanted in rat calvarial defects for 3 or 6 weeks, the microspheres loaded with BMP2 (1 MUg per defect) showed a significantly better capacity to regenerate bone than those without BMP2. The amount of new bone in the defects implanted with the BMP2-loaded microspheres was 40% and 43%, respectively, at 3 and 6 weeks, compared to 13% and 17%, respectively, for the microspheres without BMP2. Coating the BMP2-loaded microspheres with a biodegradable polymer, poly(lactic-co-glycolic acid), reduced the amount of BMP2 released in vitro and, above a certain coating thickness, significantly reduced bone regeneration in vivo. The results indicate that these hollow HA microspheres could provide a bioactive and osteoconductive carrier for growth factors in bone regeneration. PMID- 23747327 TI - Magnetic susceptibility and hardness of Au-xPt-yNb alloys for biomedical applications. AB - Metal devices in the human body induce serious metal artifacts in magnetic resonance imaging (MRI). Metals artifacts are mainly caused by a volume magnetic susceptibility (chiv) mismatch between a metal device and human tissue. In this research, Au-xPt-yNb alloys were developed for fabricating MRI artifact-free biomedical metal devices. The magnetic properties, hardness and phase constitutions of these alloys were investigated. The Au-xPt-8Nb alloys showed satisfactory chiv values. Heat treatments did not clearly change the chiv values for Au-xPt-8Nb alloys. The Vickers hardness (HV) of these two alloys was much higher than that of high-Pt alloys; moreover, aging at 700 degrees C increased the HV values of these two alloys. A dual phase structure consisting of face centered cubic alpha1 and alpha2 phases was observed and aging at 700 degrees C promoted phase separation. The Au-5Pt-8Nb and Au-10Pt-8Nb alloys showed satisfactory chiv values and high hardness and are thus suggested as candidates for MRI artifact-free alloys for biomedical applications. PMID- 23747328 TI - Evaluating the prognostic significance of preoperative thrombocytosis in epithelial ovarian cancer. AB - OBJECTIVE: Preoperative thrombocytosis has been implicated as a negative prognostic marker for epithelial ovarian cancer (EOC). We assessed whether thrombocytosis is an independent risk factor for EOC recurrence and death. METHODS: Perioperative patient characteristics and process-of-care variables (National Surgical Quality Improvement Program (NSQIP)-defined) were retrospectively abstracted from 587 women who underwent EOC staging between 1/2/03-12/29/08. Thrombocytosis was defined as platelet count > 450 * 10(9)/L. Disease-free survival (DFS) and overall survival (OS) were determined using Kaplan-Meier methods. Associations were evaluated with Cox proportional hazards regression and hazard ratios (HR). RESULTS: The incidence of preoperative thrombocytosis was 22.3%. DFS was 70.8% and 36.0% at 1 and 3 years. OS was 83.3% and 54.3% at 1 and 3 years. Ascites, lower hemoglobin, advanced disease, and receipt of perioperative packed red blood cell transfusion were independently associated with thrombocytosis. Older age and the presence of coronary artery disease were associated with lower likelihood of thrombocytosis. Overall, thrombocytosis was an independent predictor of increased risk of recurrence. Among early stage (I/II) cases, there was a 5-fold increase in the risk of death and nearly 8-fold risk of disease recurrence independently associated with thrombocytosis. CONCLUSION: Preoperative thrombocytosis portends worse DFS in EOC. In early stage disease, thrombocytosis is a potent predictor of worse DFS and OS and further assessment of the impact of circulating platelet-derived factors on EOC survival is warranted. Thrombocytosis is also associated with extensive initial disease burden, measurable residual disease, and postoperative sequelae. Preoperative platelet levels may have value in primary cytoreduction counseling. PMID- 23747329 TI - Patient, treatment and discharge factors associated with hospital readmission within 30 days after surgical cytoreduction for epithelial ovarian carcinoma. AB - OBJECTIVE: Hospital readmissions are common, costly and increasingly viewed as adverse events. In gynecologic oncology, data on readmissions are limited. The goal of this study was to examine the patient, treatment and discharge factors associated with unplanned readmission after cytoreductive surgery. METHODS: We identified all patients with stages II-IV ovarian cancer who underwent surgical cytoreduction at our institution between 2003 and 2011. A retrospective chart review was performed, and clinical variables were extracted. Utilizing linear and logistic regression, these clinical variables were correlated with risk of readmission. RESULTS: A total of 460 patients were included in the analysis, with the majority having a stage IIIC high grade serous cancer. Optimal cytoreduction (<1.0 cm residual disease) was obtained in 368 patients (81%), and 233 patients (50%) underwent at least one radical procedure. Perioperative complications were observed in 148 patients (32%). A large proportion of our cohort was discharged to rehabilitation facilities (12%) or with a visiting nurse (38%). Fifty five patients (12%) were readmitted within 30 days. On multivariate logistic regression, reoperation and perioperative cardiopulmonary event were the only factors associated with readmission (OR=3.2, 95% CI=1.7-6.0). Discharge home with ancillary services was not protective against readmission, even when controlling for perioperative complications (OR=1.18, 95% CI=0.53-2.64). CONCLUSIONS: Readmission after surgical cytoreduction affected 12% of our population. Multivariate analyses suggested perioperative complications, particularly reoperation and cardiopulmonary event, placed the patient at the greatest risk. Age, comorbidities, surgical radicality and discharge with visiting nurse services/rehabilitation facility did not affect the likelihood of readmission. PMID- 23747330 TI - Relationship of margin status and radiation dose to recurrence in post-operative vulvar carcinoma. AB - OBJECTIVE: To evaluate the effect of margin status and radiation dose in patients treated with radiation therapy (RT) for vulvar cancer. Clinical outcomes included vulvar recurrence (VR), relapse-free survival (RFS) and overall survival (OS). METHODS: We retrospectively reviewed the records of 300 patients with Stage I-IVA vulvar cancer treated between 1988 and 2009. Slides were reviewed and margin status was scored as negative (>= 1 cm), close (<1cm) or positive after formalin fixation. Cox proportional hazards models were constructed to determine significant prognostic factors for vulvar relapse. RESULTS: Of 205 eligible patients, 69 (34%) had negative surgical margins, 116 (56%) had close margins and 20 (10%) had positive margins. Median follow-up time was 49 months. The 4-year RFS rate was 53% and OS was 73%. Of 78 recurrences, 62 had the vulva as the first site of recurrence. The 4-year rates of freedom from vulvar recurrence were 82%, 63% and 37% for those with negative, close and positive margins, respectively (p for trend=0.005). On multivariate analysis, close margins (HR=3.03, 95% CI 1.46 6.26) and positive margins (HR=7.02, 95% CI 2.66-18.54) were associated with a significantly increased risk of vulvar relapse. Those who received a dose >= 56 Gy had a lower risk of relapse than those who received <= 50.4 Gy (p<0.05). Though recurrences were noted with margins up to 9 mm, the highest risk of vulvar recurrence was associated with margins <= 5 mm (p=0.002). CONCLUSIONS: Close or positive margins were associated with a significantly increased risk of vulvar recurrence. Radiation with a dose >= 56 Gy may decrease the risk of vulvar recurrence. PMID- 23747331 TI - Risk factors that mitigate the role of paraaortic lymphadenectomy in uterine endometrioid cancer. AB - OBJECTIVE: Paraaortic lymph node (PA) dissemination in endometrial cancer (EC) is uncommon and a systematic infrarenal PA dissection carries morbidity. Our objective was to identify a subgroup of EC patients who may potentially forego PA lymphadenectomy (LND). METHODS: The study endpoint (PA Metastasis or Recurrence; PAMR) was defined as detection of metastasis to PA nodes (among those with any type of PA LND) or PA recurrence within 2 years (among patients without PA LND or those with negative nodes in the context of an inadequate (<5 nodes) PA LND). Patients with non-endometrioid histology, stage IV disease, synchronous cancers, gross extrauterine or gross adnexal disease, neoadjuvant therapy, or insufficient follow-up were excluded. Multivariable logistic regression analysis identified predictors of PAMR. RESULTS: Of the 946 patients, PAMR was observed in 4% (36/946). Multivariable analysis identified positive pelvic nodes (odds ratio (OR) 24.2; p<0.001), >50% MI (OR 5.3; p<0.001) and lymphovascular space invasion (LVSI) (OR 3.7; p=0.005) as the only three independent predictors of PAMR. When all three factors were absent (77% of study cohort), the predicted probability of PAMR was 0.6%. If intraoperative frozen section is not available on pelvic lymph nodes and LVSI, omitting PA LND in all patients with <= 50% MI would affect 84% (792/946) of the total cohort, with a 1.1% risk of PAMR (9/792). CONCLUSION: The majority of patients with endometrioid EC may potentially forgo PA LND with expected reductions in surgical morbidity and cost. This cohort may be identified by a combined absence of: positive pelvic nodes, >50% MI and LVSI. PMID- 23747332 TI - Mapping the reading circuitry for skilled deaf readers: an fMRI study of semantic and phonological processing. AB - We examined word-level reading circuits in skilled deaf readers whose primary language is American Sign Language, and hearing readers matched for reading ability (college level). During fMRI scanning, participants performed a semantic decision (concrete concept?), a phonological decision (two syllables?), and a false-font control task (string underlined?). The groups performed equally well on the semantic task, but hearing readers performed better on the phonological task. Semantic processing engaged similar left frontotemporal language circuits in deaf and hearing readers. However, phonological processing elicited increased neural activity in deaf, relative to hearing readers, in the left precentral gyrus, suggesting greater reliance on articulatory phonological codes, and in bilateral parietal cortex, suggesting increased phonological processing effort. Deaf readers also showed stronger anterior-posterior functional segregation between semantic and phonological processes in left inferior prefrontal cortex. Finally, weaker phonological decoding ability did not alter activation in the visual word form area for deaf readers. PMID- 23747333 TI - Fibroblast growth factor-23 negates 1,25(OH)2D3-induced intestinal calcium transport by reducing the transcellular and paracellular calcium fluxes. AB - The calciotropic hormone 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] has been known to stimulate intestinal calcium transport via both transcellular and paracellular pathways. Recently, we reported that the 1,25(OH)2D3-enhanced calcium transport in the mouse duodenum could be abolished by fibroblast growth factor (FGF)-23, but the targeted calcium transport pathway has been elusive. Herein, the 1,25(OH)2D3-enhanced calcium transport was markedly inhibited by FGF-23 and inhibitors of the basolateral calcium transporters, NCX1 and PMCA1b, suggesting the negative effect of FGF-23 on the transcellular calcium transport. Similar results could be observed in the intestinal epithelium-like Caco-2 monolayer. Although the Arrhenius plot indicated that FGF-23 decreased the potential barrier (e.g., activation energy) of the paracellular calcium movement, FGF-23 was found to modestly decrease the 1,25(OH)2D3-enhanced paracellular calcium transport and calcium permeability. Moreover, FGF-23 affected the 1,25(OH)2D3-induced change in duodenal water permeability as determined by tritiated water, but both 1,25(OH)2D3 and FGF-23 were without effects on the transepithelial fluxes of paracellular markers, (3)H-mannitol and (14)C-polyethylene glycol. It could be concluded that FGF-23 diminished the 1,25(OH)2D3-enhanced calcium absorption through the transcellular and paracellular pathways. Our findings have thus corroborated the presence of a bone-kidney-intestinal axis of FGF-23/vitamin D system in the regulation of calcium homeostasis. PMID- 23747334 TI - How to understand quantum chemical computations on DNA and RNA systems? A practical guide for non-specialists. AB - In this review primarily written for non-experts we explain basic methodological aspects and interpretation of modern quantum chemical (QM) computations applied to nucleic acids. We introduce current reference QM computations on small model systems consisting of dozens of atoms. Then we comment on recent advance of fast and accurate dispersion-corrected density functional theory methods, which will allow computations of small but complete nucleic acids building blocks in the near future. The qualitative difference between QM and molecular mechanics (MM, force field) computations is discussed. We also explain relation of QM and molecular simulation computations to experiments. PMID- 23747335 TI - Translational halt during elongation caused by G-quadruplex formed by mRNA. AB - mRNA forms various secondary and tertiary structures that affect gene expression. Although structures formed in the untranslated regions (UTRs) of mRNAs that inhibit translation have been characterized, stable mRNA structures in open reading frames (ORFs) may also cause translational halt or slow translation elongation. We previously established a method, termed a synchronized translation assay, that enables time course analysis of single turnover translation elongation. In this method, translation initiation, which is a rate determining step of the translation procedure, can be ignored because all ribosomes are synchronized on a specific position of mRNA before translation elongation is restarted from this position. In this paper, we used the synchronized translation assay to evaluate the effects of a G-quadruplex structure located at various positions within the mRNA ORF on translational halt. PMID- 23747336 TI - Self-assembly of DNA-based drug delivery nanocarriers with rolling circle amplification. AB - DNA nanostructures have recently emerged as a type of drug delivery nanocarriers due to their suitable sizes, well-defined structures and low-toxicity. Here, we present a protocol for the assembly of DNA nanoribbon structures with rolling circle amplification (RCA) and delivery of CpG oligonucleotide. DNA nanoribbons with different dimensions and patterns were assembled with long RCA strands and several short staples. Significantly, we demonstrated they exhibited high efficiency cellular uptake and improved immunostimulatory activity compared with ss- or ds- DNA. PMID- 23747337 TI - Isolation and phenotypic characterization of colorectal cancer stem cells with organ-specific metastatic potential. AB - BACKGROUND & AIMS: Migrating cancer stem cells (MCSCs) are believed to form metastases. We sought to identify markers of MCSCs from human colorectal cancers (CRCs) and determine their roles in organ-specific metastasis. METHODS: To identify colorectal MCSCs that contribute to organ-specific metastasis, we developed a model of liver or lung metastasis using primary tumor cells from patients with CRC who had liver and lung metastases. Distinct organ-specific metastatic cells were isolated by 6 cycles of selecting for cells that formed liver and lung tumors after subcutaneous injection into mice. Microarray analysis was used to identify markers of the organ-specific MCSCs. We then measured levels of these markers in CRC cell lines and 128 CRC samples. We characterized the functional roles of these markers in organ-specific metastasis. RESULTS: We identified CD110 and CDCP1 as cell surface markers of MCSCs from human colorectal tumors that metastasized to liver and lung. We observed a distinct pattern of CD110 and CDCP1 in a panel of primary colorectal tumor samples and their matched liver or pulmonary metastases, indicating that these proteins might serve as biomarkers of organ-specific metastasis. Functional studies showed that thrombopoietin attracts CD110(+) CSCs and increases their self-renewal to promote formation of liver metastases. CDCP1 promoted adhesion of CRC cells to the lung endothelium. CONCLUSIONS: We isolated MCSCs from primary human CRCs and found that the CD110(+) and CDCP1(+) subpopulations mediate organ-specific metastasis. These findings might be used to aid in selection of patients for postoperative adjuvant therapy. PMID- 23747338 TI - Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer. AB - The spindle assembly checkpoint controls proper chromosome segregation during mitosis and prevents aneuploidy-an important feature of cancer cells. We performed genome-wide and targeted copy number and mutation analyses of germline DNA from 208 patients with familial or early-onset (40 years of age or younger) colorectal cancer; we identified haploinsufficiency or heterozygous mutations in the spindle assembly checkpoint genes BUB1 and BUB3 in 2.9% of them. Besides colorectal cancer, these patients had variegated aneuploidies in multiple tissues and variable dysmorphic features. These results indicate that mutations in BUB1 and BUB3 cause mosaic variegated aneuploidy and increase the risk of colorectal cancer at a young age. PMID- 23747340 TI - Localized 3D analysis of cartilage composition and morphology in small animal models of joint degeneration. AB - OBJECTIVE: Current histological scoring methods to evaluate efficacy of potential therapeutics for slowing or preventing joint degeneration are time-consuming and semi-quantitative in nature. Hence, there is a need to develop and standardize quantitative outcome measures to define sensitive metrics for studying potential therapeutics. The objectives of this study were to use equilibrium partitioning of an ionic contrast agent via Equilibrium Partitioning of an Ionic Contrast Microcomputed tomography (EPIC-MUCT) to quantitatively characterize morphological and compositional changes in the tibial articular cartilage in two distinct models of joint degeneration and define localized regions of interest to detect degenerative cartilage changes. MATERIALS AND METHODS: The monosodium iodoacetate (MIA) and medial meniscal transection (MMT) rat models were used in this study. Three weeks post-surgery, tibiae were analyzed using EPIC-MUCT and histology. EPIC-MUCT allowed measurement of 3D morphological changes in cartilage thickness, volume and composition. RESULTS: Extensive cartilage degeneration was observed throughout the joint in the MIA model after 3 weeks. In contrast, the MMT model showed more localized degeneration with regional thickening of the medial tibial plateau and a decrease in attenuation consistent with proteoglycan (PG) depletion. Focal lesions were also observed and 3D volume calculated as an additional outcome metric. CONCLUSIONS: EPIC-MUCT was used to quantitatively assess joint degeneration in two distinct preclinical models. The MMT model showed similar features to human Osteoarthritis (OA), including localized lesion formation and PG loss, while the MIA model displayed extensive cartilage degeneration throughout the joint. EPIC-MUCT imaging provides a rapid and quantitative screening tool for preclinical evaluation of OA therapeutics. PMID- 23747339 TI - Post-translational loss of renal TRPV5 calcium channel expression, Ca(2+) wasting, and bone loss in experimental colitis. AB - BACKGROUND & AIMS: Dysregulated Ca(2+) homeostasis likely contributes to the etiology of inflammatory bowel disease-associated loss of bone mineral density. Experimental colitis leads to decreased expression of Klotho, a protein that supports renal Ca(2+) reabsorption by stabilizing the transient receptor potential vanilloid 5 (TRPV5) channel on the apical membrane of distal tubule epithelial cells. METHODS: Colitis was induced in mice via administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS) or transfer of CD4(+)interleukin-10(-/ ) and CD4(+), CD45RB(hi) T cells. We investigated changes in bone metabolism, renal processing of Ca(2+), and expression of TRPV5. RESULTS: Mice with colitis had normal serum levels of Ca(2+) and parathormone. Computed tomography analysis showed a decreased density of cortical and trabecular bone, and there was biochemical evidence for reduced bone formation and increased bone resorption. Increased fractional urinary excretion of Ca(2+) was accompanied by reduced levels of TRPV5 protein in distal convoluted tubules, with a concomitant increase in TRPV5 sialylation. In mouse renal intermedullary collecting duct epithelial (mIMCD3) cells transduced with TRPV5 adenovirus, the inflammatory cytokines tumor necrosis factor, interferon-gamma, and interleukin-1beta reduced levels of TRPV5 on the cell surface, leading to its degradation. Cytomix induced interaction between TRPV5 and UBR4 (Ubiquitin recoginition 4), an E3 ubiquitin ligase; knockdown of UBR4 with small interfering RNAs prevented cytomix-induced degradation of TRPV5. The effects of cytokines on TRPV5 were not observed in cells stably transfected with membrane-bound Klotho; TRPV5 expression was preserved when colitis was induced with TNBS in transgenic mice that overexpressed Klotho or in mice with T-cell transfer colitis injected with soluble recombinant Klotho. CONCLUSIONS: After induction of colitis in mice via TNBS administration or T-cell transfer, tumor necrosis factor and interferon gamma reduced the expression and activity of Klotho, which otherwise would protect TRPV5 from hypersialylation and cytokine-induced TRPV5 endocytosis, UBR4 dependent ubiquitination, degradation, and urinary wasting of Ca(2+). PMID- 23747341 TI - Detection and quantification of endoplasmic reticulum stress in living cells using the fluorescent compound, Thioflavin T. AB - The endoplasmic reticulum (ER) plays a central role in the co- and post translational modification of many proteins. Disruption of these processes can lead to the accumulation of misfolded proteins in the endoplasmic reticulum - a condition known as endoplasmic reticulum stress. In recent years, the association of endoplasmic reticulum stress with a number of disease pathologies has increased interest in the study of this condition. Current methods to detect endoplasmic reticulum stress are indirect and retrospective. Here we describe a new method to detect and quantify endoplasmic reticulum stress in live cells using Thioflavin T (ThT), a small molecule that exhibits enhanced fluorescence when it binds to protein aggregates. We show that enhanced ThT-fluorescence correlates directly with established indicators of unfolded protein response activation. Furthermore, enhanced ThT-fluorescence can be detected in living cells within 20 min of application of an endoplasmic reticulum stress-inducing agent. ThT is capable of detecting endoplasmic reticulum stress induced by distinctly different conditions and compounds, in different cultured cell types as well as in mouse tissue samples. Pre-treatment with a potent endoplasmic reticulum stress-reducing agent, 4-phenylbutyric acid, mitigates the enhanced ThT signal. This new tool will be useful in future research investigating the role of protein misfolding in the development and/or progression of human diseases. PMID- 23747342 TI - Calpain 1 induce lysosomal permeabilization by cleavage of lysosomal associated membrane protein 2. AB - In light induced retinal degeneration (LIRD) photoreceptor cell death is mediated by caspase independent mechanisms. The activation of LEI/L-DNase II pathway in this model, is due to cathepsin D release from lysosomes, although the underlying mechanism remains poorly understood. In this paper we studied the involvement of calpains in lysosomal permeabilization. We investigated, for the first time, the calpain targets at lysosomal membrane level. We found that calpain 1 is responsible for lysosomal permeabilization by cleavage of the lysosomal associated membrane protein 2 (LAMP 2). Moreover, LAMP 2 degradation and lysosomal permeabilization were rescued by calpain inhibition and the use of MEF( /-)lamp 2 cells indicates that the cleavage of LAMP 2A is essential for this permeabilization. Finally, we found that LAMP 2 is cleaved in LIRD, suggesting that the mechanism of calpain induced lysosomal permeabilization is not exclusive of a single cell death model. Overall, these data shed new light on understanding the mechanisms of lysosomal and caspase-independent cell death and point to the original targets for development of the new therapeutic protocols. PMID- 23747343 TI - Estrogen receptor-alpha mediates human multidrug resistance associated protein 3 induction by 17alpha-ethynylestradiol. Role of activator protein-1. AB - Previously, we have demonstrated that 17alpha-ethynylestradiol (EE) induces rat multidrug-resistance associated protein 3 (Mrp3, Abcc3) expression transcriptionally through estrogen receptor-alpha (ER-alpha) activation. We explored the effect of EE on MRP3 expression of human origin. HepG2 cells were transfected with ER-alpha and incubated with EE (1-10-50 MUM) for 48 h. MRP3 protein and mRNA levels were measured by Western blotting and Real time PCR, respectively. EE up-regulated MRP3 protein and mRNA at 50 MUM only in ER-alpha(+) HepG2 cells. The in silico analysis of mrp3 promoter region demonstrated absence of estrogen response elements, but showed several Ap-1 binding sites. We further evaluated the potential involvement of the transcription factors c-JUN and c-FOS (members of Ap-1) in MRP3 up-regulation. ER-alpha(+) HepG2 cells were incubated with EE and c-FOS and c-JUN levels measured by Western blotting in nuclear extracts. EE up-regulated only c-JUN. Experiments of overexpression and knock down of c-JUN by siRNA further demonstrated that this transcription factor is indeed implicated in MRP3 upregulation by EE. Co-immunoprecipitation assay demonstrated that EE induces c-JUN/ER-alpha interaction, and chromatin immunoprecipitation assay showed that this complex is recruited to the AP-1 binding consensus element present at the position (-1300/-1078 bp) of human mrp3 promoter. We conclude that EE induces MRP3 expression through ER-alpha, with recruitment of ER-alpha in complex with c-JUN to the human mrp3 promoter. PMID- 23747345 TI - The antitumor lignan Nortrachelogenin sensitizes prostate cancer cells to TRAIL induced cell death by inhibition of the Akt pathway and growth factor signaling. AB - Prostate cancer cells frequently develop resistance toward androgen-deprivation and chemotherapy. To identify new approaches to treat androgen-dependent prostate cancer, we have performed a structure-activity analysis of lignan polyphenols for cancer cell specific sensitization to tumor necrosis factor-related apoptosis inducing ligand (TRAIL), a death ligand that has ability to induce tumor-specific cell death. In this study, we report that the lignan nortrachelogenin (NTG) is the most efficient of the 27 tested lignan compounds in sensitizing prostate cancer cells to TRAIL-induced apoptosis. Importantly, pretreatment with NTG does not sensitize a non-malignant prostate cell line to TRAIL-induced cell death. The structural comparison of lignans reveals that the dibenzylbutyrolactone skeleton is required for the apoptosis-sensitizing activity, while substitutions at the aromatic rings do not seem to play a critical role in this lignan function. Our study also characterizes the cellular effects and molecular mechanisms involved in NTG anticancer activity. We previously reported that specific lignans inhibit the Akt survival-signaling pathway in concert with TRAIL sensitization. While NTG is also shown to be a effective inhibitor of Akt signaling, in this study we further demonstrate that NTG potently inhibits tyrosine kinase (RTK) activation in response to growth factors, such as insulin and insulin-like growth factor I (IGF-I). Our results identify NTG as a novel agent for prostate cancer therapy with ability to inhibit Akt membrane localization and activity as well as the activation of growth factor receptors (GFRs), thereby efficiently synergizing with TRAIL exposure. PMID- 23747344 TI - Destruxins: fungal-derived cyclohexadepsipeptides with multifaceted anticancer and antiangiogenic activities. AB - Destruxins (Dtx) are secondary metabolites of the entomopathogenic fungus Metarhizium anisopliae. Recently, Dtx came into focus of interest as anticancer therapeutics. However, data on human and especially on cancer cells are fragmentary. In order to successfully establish novel anticancer therapeutics, a broad knowledge on the cellular and molecular mechanisms underlying their activity is essential. Consequently, this study aimed to investigate the impact of the most common Dtx derivatives A, B and E on human cancer cell growth and survival with a focus on colon cancer cell models. Summarizing, the experimental data showed that (i) Dtx A and B exert potent antiproliferative activity in the micromolar and Dtx E in the nanomolar range in KB-3-1, A549, CaCo-2, and especially in HCT116 colon cancer cells, (ii) all three Dtx derivatives cause imbalance of cell cycle distribution, (iii) their cytostatic/cytotoxic effects are widely p53-independent but reduced by p21- and bax-deletion, respectively, (iv) cytotoxicity is based on intrinsic apoptosis induction and associated with phosphoinositide-3-kinase (PI3K)/Akt pathway inhibition, (v) anticancer activity of Dtx E but not Dtx A and B involves disturbance of the intracellular redox balance, (vi) Dtx inhibit the migration and tube formation of human endothelial cells indicating antiangiogenic potential, and (vii) all three Dtx derivatives possess ionophoric properties not differing in conductivity, ion selectivity and single channel kinetics. Thus, Dtx represent feasible, multifunctional anticancer drug candidates for preclinical development especially against colorectal cancer. PMID- 23747346 TI - CXI-benzo-84 reversibly binds to tubulin at colchicine site and induces apoptosis in cancer cells. AB - Here, we have discovered CXI-benzo-84 as a potential anticancer agent from a library of benzimidazole derivatives using cell based screening strategy. CXI benzo-84 inhibited cell cycle progression in metaphase stage of mitosis and accumulated spindle assembly checkpoint proteins Mad2 and BubR1 on kinetochores, which subsequently activated apoptotic cell death in cancer cells. CXI-benzo-84 depolymerized both interphase and mitotic microtubules, perturbed EB1 binding to microtubules and inhibited the assembly and GTPase activity of tubulin in vitro. CXI-benzo-84 bound to tubulin at a single binding site with a dissociation constant of 1.2+/-0.2MUM. Competition experiments and molecular docking suggested that CXI-benzo-84 binds to tubulin at the colchicine-site. Further, computational analysis provided a significant insight on the binding site of CXI-benzo-84 on tubulin. In addition to its potential use in cancer chemotherapy, CXI-benzo-84 may also be useful to screen colchicine-site agents and to understand the colchicine binding site on tubulin. PMID- 23747347 TI - AMP-activated protein kinase: a target for old drugs against diabetes and cancer. AB - The AMP-activated protein kinase (AMPK) is considered a key checkpoint to ensure energy balance in both cells and organisms. AMPK is an alphabetagamma heterotrimer controlled by allosteric regulation by AMP, ADP and ATP, auto inhibitory features and phosphorylation, with the threonine-172 phosphorylation on the catalytic alpha-subunit by LKB1, CaMKKbeta or Tak1 being essential for its fully activation. AMPK acts as a protective response to energy stress in numerous systems, but it is also a key player in diabetes and related metabolic diseases and cancer. Pharmacological activation of AMPK by metformin or other compounds holds a considerable potential to reverse the metabolic abnormalities associated with type 2 diabetes. In cancer, correction of the dysregulated metabolic pathway LKB1/AMPK/mTORC1 can lower the Warburg effect, suggesting AMPK as a potential target for cancer prevention and/or treatment. In this commentary, we review recent findings that support the role and function of AMPK in normal and pathological conditions. We also discuss how the activation of AMPK by naturally occurring compounds could help to prevent the development of numerous chronic diseases contributing in such a way to the well-being of ageing population. PMID- 23747348 TI - Genetic matters: thirty years of progress using mouse models in nicotinic research. AB - This research update summarizes thirty years of studies on genetic influences on responses to the acute or chronic administration of nicotine. Early studies established that various inbred mice are differentially sensitive to the effects of the drug. Classical genetic analyses confirmed that nicotine effects on locomotion, body temperature and seizures are heritable. A significant inverse correlation between the locomotor and hypothermic effects and the density of nicotine binding sites suggested that differential expression alpha4beta2 neuronal nicotinic acetylcholine receptor (nAChR) mediated some of this genetic variability. Subsequent studies with alpha4 and beta2 nAChR null (decreased sensitivity) and gain of function mutants (increased sensitivity) supports the role of the alpha4beta2*nAChR subtype. However, null mutant mice still respond to nicotine, indicating that other nAChR subtypes also mediate these responses. Mice differing in initial sensitivity to nicotine also differ in tolerance development following chronic treatment: those mice that are initially more sensitive to nicotine develop tolerance at lower treatment doses than less sensitive mice, indicating that tolerance is an adaptive response to the effects of nicotine. In contrast, the sensitivity of mice to pre-pulse inhibition of acoustic startle response is correlated with the expression of alpha7-nAChR. While genetic variability in nAChR expression and function is an important factor contributing to differences in response to nicotine, the observations that altered activity of opioid, glutamate, and cannabinoid receptors among others also change nicotine sensitivity reinforces the proposal that the genetics of nicotine response is more complex than differences in nAChRs. PMID- 23747349 TI - Assessment of avoidance behaviors in mouse models of muscle pain. AB - Pain encompasses both a sensory as well as an affective dimension and these are differentially processed in the cortex. Animal models typically use reflexive behaviors to test nociceptive responses; these are thought to reflect the sensory dimension of pain. While several behavioral tests are available for examining the affective dimension of pain it is unclear if these are appropriate in animal models of muscle pain. We therefore tested the utility of existing paradigms as well as new avoidance paradigms in animal models of muscle pain in mice. Specifically we used an escape-avoidance test to noxious mechanical stimuli, a learned avoidance test to noxious mechanical stimuli, and avoidance of physical activity. We used three animal models of muscle pain: carrageenan-induced inflammation, non-inflammatory muscle pain, and exercise-enhanced pain. In the carrageenan model of inflammation mice developed escape-avoidance behaviors to mechanical stimuli, learned avoidance to mechanical stimulation and avoidance of physical activity - these models are associated with unilateral hyperalgesia. When both muscles were inflamed, escape-avoidance behaviors did not develop suggesting that equivalent bilateral pain behaviors cannot be tested with an escape-avoidance test. In the non-inflammatory muscle pain model mice did not show significant changes in escape-avoidance behaviors or learned avoidance, but did avoid physical activity. In the exercise-enhanced pain model, there were no changes in escape-avoidance, learned avoidance of noxious or physical activity In conclusion, we developed several testing protocols that assess supraspinal processing of pain behaviors in models of muscle pain and that are most sensitive in animals with unilateral hyperalgesia. PMID- 23747350 TI - Patch clamp recordings of hair cells isolated from zebrafish auditory and vestibular end organs. AB - The senses of hearing and balance in vertebrates are transduced by hair cells in the inner ear. Hair cells from a wide variety of organisms have been described electrophysiologically but this is the first report of the application of these techniques to the genetically tractable zebrafish model system. Auditory and vestibular hair cells isolated from zebrafish lagenae and utricles were patch clamped and both inward and outward currents under voltage clamp, and changes in membrane potential under current clamp were recorded. Cells displayed substantial diversity in their morphology, constellation of channel types, and level of excitability. While all cells showed evidence of the presence of fast inactivating (A-type) K(+) channels, other K(+) channel types, including delayed rectifier, inward rectifier and large conductance Ca(2+)-activated K(+) (BK) channels were less common. Recorded Ca(2+) currents were identified pharmacologically as L-type. Non-linear regenerative voltage responses were evoked in more than half of the cells studied. PMID- 23747351 TI - The complete mitochondrial genome of the Ailanthus silkmoth, Samia cynthia cynthia (Lepidoptera: Saturniidae). AB - The complete mitochondrial genome (mitogenome) of the Ailanthus silkmoth, Samia cynthia cynthia (Lepidoptera: Saturniidae) was determined. The circular genome is 15,345 bp long, and presents a typical gene organization and order for sequenced mitogenomes of Bombycidea species. The nucleotide composition of the genome is highly A+T biased, accounting for 79.86%. The AT skew of the genome is slightly negative, indicating the occurrence of more Ts than As, as found in other Saturniidae species. All protein-coding genes (PCGs) are initiated by ATN codons, except for COI and COII, which are tentatively designated by CGA and GTG, respectively, as observed in other insects. Four of 13 PCGs, including COI, COII, ATP6, and ND3, harbor the incomplete termination codons, T or TA. With an exception for tRNASer(AGN), all other tRNAs can form a typical clover-leaf structure of mitochondrial tRNA. The 359 bp A+T-rich region of S. c. cynthia contains non-repetitive sequences, but harbors several features common to the Bombycidea insects, including the motif ATAGA followed by a poly-T stretch of 19 bp, a microsatellite-like (AT)7 element preceded by the ATTTA motif, and a poly-A element upstream tRNAMet. The phylogenetic analyses support the morphology-based current hypothesis that Bombycidae and Saturniidae are monophyletic. Our result confirms that Saturniini and Attacini form a reciprocal monophyletic group within Saturniidae. PMID- 23747352 TI - New insights into the melanophilin (MLPH) gene controlling coat color phenotypes in American mink. AB - The mutation causing the Silverblue color type (pp) is one of the most used recessive mutations within American mink (Neovison vison) fur farming, since it is involved in some of the popular color types such as Violet and Saphire which originate from a combination of recessive mutations. In the present study, the genomic and mRNA sequences of the melanophilin (MLPH) gene were studied in Violet, Silverblue and wild-type (wt) mink animals. Although breeding schemes and previous literature indicates that the Violet (aammpp) phenotype is a triple recessive color type involving the same locus as the Silverblue (pp) color type, our findings indicate different genotypes at the MLPH locus. Upon comparison at genomic level, we identified two deletions of the entire intron 7 and of the 5' end of intron 8 in the sequence of the Silverblue MLPH gene. When investigating the mRNA, the Silverblue animals completely lack exon 8, which encodes 65 residues, of which 47 define the Myosin Va (MYO5A) binding domain. This may cause the incorrect anchoring of the MLPH protein to MYO5A in Silverblue animals, resulting in an improper pigmentation as seen in diluted phenotypes. Additionally, in the MLPH mRNA of wt, Violet and Silverblue phenotypes, part of intron 8 is retained resulting in a truncated MLPH protein, which is 359 residues long in wt and Violet and 284 residues long in Silverblue. Subsequently, our findings point out that the missing actin-binding domain, in neither of the 3 analyzed phenotypes affects the transport of melanosomes or the consequent final pigmentation. Moreover, the loss of the major part of the MYO5A domain in the Silverblue MLPH protein seems to be the responsible for the dilute phenotype. Based on our genomic DNA data, genetic tests for selecting Silverblue and Violet carrier animals can be performed in American mink. PMID- 23747353 TI - Prenatal diagnosis and molecular cytogenetic characterization of mosaicism for a small supernumerary marker chromosome derived from chromosome 22 associated with cat eye syndrome. AB - We present prenatal diagnosis of mosaicism for a small supernumerary marker chromosome (sSMC) derived from chromosome 22 associated with cat eye syndrome (CES) using cultured amniocytes in a pregnancy with fetal microcephaly, intrauterine growth restriction, left renal hypoplasia, total anomalous pulmonary venous return with dominant right heart and right ear deformity. The sSMC was bisatellited and dicentric, and was characterized by multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (aCGH). The SALSA MLPA P250-B1 DiGeorge Probemix showed duplication of gene dosage in the CES region. aCGH showed a 1.26-Mb duplication at 22q11.1-q11.21 encompassing CECR1-CECR7. The sSMC was likely inv dup(22) (q11.21). Prenatal diagnosis of an sSMC(22) at amniocentesis should alert CES. MLPA, aCGH and fetal ultrasound are useful for rapid diagnosis of CES in case of prenatally detected sSMC(22). PMID- 23747355 TI - The impact of implementing a public bicycle share program on the likelihood of collisions and near misses in Montreal, Canada. AB - OBJECTIVE: This study aimed to estimate the impact of implementing a public bicycle share program (PBSP) on the likelihood of self-reported collisions and near misses between cyclists and motor vehicles among cyclists living in Montreal. METHODS: A repeated cross sectional design was used. Surveys were conducted at the launch of the PBSP, at the end of the first and second seasons of implementation. Logistic regression estimated changes in the likelihood of reporting collisions or near misses. RESULTS: There was no evidence of a change in likelihood of reporting a collision or near miss after implementing the PBSP. PBSP users were not at a greater risk of reporting a collision (OR=1.53, 95% CI: 0.77-3.02) or near miss (OR=1.37, 95% CI: 0.94-1.98), although confidence intervals were wide. The number of days of cycling per week was associated with collisions (OR=1.27, 95% CI: 1.17-1.39) and near misses (OR=1.34, 95% CI: 1.26 1.42). CONCLUSIONS: There was no evidence of a change in the likelihood of reporting collisions or near misses in Montreal between the implementation of the PBSP and the end of the second season. Time spent cycling was associated with reporting a collision or near miss. PMID- 23747356 TI - Global confluence of infectious and non-communicable diseases -- the case of type 2 diabetes. AB - Globally the prevalence and public health importance of non-communicable diseases (NCD) is increasing in high-, middle-, and low-income countries alike. Concomitant to the NCD burden, control of key infectious diseases (i.e., group B Streptococcus, hepatitis C, tuberculosis, and HIV) in most regions of the world remains elusive. With new epidemiologic trends in disease burden, the allocation of resources and expertise to simultaneously control infectious diseases and NCD becomes increasingly difficult. Using the case of diabetes and three co-occurring infectious diseases, we demonstrate the importance of generating innovative strategies to attack the old (infectious diseases) and new (NCD) disease agendas together. PMID- 23747354 TI - Over-expression of the miRNA cluster at chromosome 14q32 in the alcoholic brain correlates with suppression of predicted target mRNA required for oligodendrocyte proliferation. AB - We examined miRNA expression from RNA isolated from the frontal cortex (Broadman area 9) of 9 alcoholics (6 males, 3 females, mean age 48 years) and 9 matched controls using both the Affymetrix GeneChip miRNA 2.0 and Human Exon 1.0 ST Arrays to further characterize genetic influences in alcoholism and the effects of alcohol consumption on predicted target mRNA expression. A total of 12 human miRNAs were significantly up-regulated in alcohol dependent subjects (fold change>=1.5, false discovery rate (FDR)<=0.3; p<0.05) compared with controls including a cluster of 4 miRNAs (e.g., miR-377, miR-379) from the maternally expressed 14q32 chromosome region. The status of the up-regulated miRNAs was supported using the high-throughput method of exon microarrays showing decreased predicted mRNA gene target expression as anticipated from the same RNA aliquot. Predicted mRNA targets were involved in cellular adhesion (e.g., THBS2), tissue differentiation (e.g., CHN2), neuronal migration (e.g., NDE1), myelination (e.g., UGT8, CNP) and oligodendrocyte proliferation (e.g., ENPP2, SEMA4D1). Our data support an association of alcoholism with up-regulation of a cluster of miRNAs located in the genomic imprinted domain on chromosome 14q32 with their predicted gene targets involved with oligodendrocyte growth, differentiation and signaling. PMID- 23747357 TI - Associations between self-reported weight management methods with diet quality as measured by the Healthy Eating Index-2005. AB - OBJECTIVE: We examine the relationship between weight management practices and diet quality. METHOD: Regressions were used to analyze the associations between self-reported weight management methods and diet quality, as measured by the Healthy Eating Index-2005 (HEI-2005), of 1,933 respondents who tried to lose or not gain weight in the 2003-2004 National Health and Nutrition Examination Survey (NHANES). The regressions controlled for sociodemographics, lifestyle behaviors, and other health-related behaviors and perceptions. RESULTS: Including both switching to foods with lower calories and exercise in weight management was associated with better diet quality, i.e., a higher total HEI-2005 score and higher scores in eight of the twelve HEI-2005 components than including neither method. The eight components included six components on fruit, vegetables and grains, milk, and calories from solid fat, alcohol beverages, and added sugars. Similar but smaller associations were also found among those who reported including either switching to foods with lower calories or exercise. CONCLUSIONS: Based on self-reported data, the findings suggest that including switching to lower calorie foods and exercise in weight management, as recommended by the Dietary Guidelines for Americans (DGA), is associated with diet quality that is more consistent with the key diet-related advice of the DGA. PMID- 23747358 TI - Label-free analysis of prostate acini-like 3D structures by lensfree imaging. AB - We present a lensfree imaging method to analyze polarity in RWPE1 prostate epithelial cells that form polarized acini with lumen under standard tridimensional (3D) culture conditions. The first event in epithelial carcinogenesis is loss of polarity, followed by uncontrolled proliferation leading to metastasis. We demonstrate that it is possible to use optical signatures to discriminate 3D objects with distinct polarities in a large field of view. The three metrics we present here are designed as image processing tools to discriminate acini from spheroids without any 3D reconstruction. To demonstrate that our lensfree imaging platform may be used to study the 3D organization of epithelial cells, we analyzed and quantified the modulation of dynamic processes, e.g., the polarity of acini and the merging of polarized structures, upon transforming growth factor beta-1 (TGF beta-1) addition to the culture media. Hence, coupling lensfree microscopy with 3D cell culture provides an innovative tool to study epithelial tissue morphogenesis in a large field of view and to elucidate the regulation of growth, morphogenesis and differentiation in normal and cancerous human prostate cells. Moreover, such biosensor would be a powerful tool to follow cancer progression and to evaluate anti-cancer drugs. PMID- 23747359 TI - Facile synthesis of hierarchically aloe-like gold micro/nanostructures for ultrasensitive DNA recognition. AB - Well-defined hierarchically aloe-like gold micro/nanostructures (HAG) are one step electrochemically fabricated without introducing any template or surfactant. The formation kinetics of the HAG can be described as a nucleation and three dimensional growth process controlled by the reactant diffusion from the solution side. As the applied electro-deposition potential moved in the negative direction, the gold crystal density increased, and the crystal shape changed from a quasi-spherical to dendritic fractal morphology. Under the optimal potential of -0.1 V and the time of 10 min, well-defined HAG possessing a hydrophilic surface with large effective area (ca. 8 times of its geometrical area) were obtained, which was used as the substrate for fabricating an ultrasensitive DNA biosensor. The DNA biosensor displayed a significantly enhanced detection limit of 12 aM, a wide linear response from 50 aM to 1 pM, as well as good selectivity, stability and reusability. This efficient DNA molecule immobilization platform may have implications in the preparation of many other gold micro/nanostructures (GMNs) with interesting properties and application potentials in many fields, such as biosensing, biocatalysis and biofuel cells. PMID- 23747360 TI - Direct electrochemical determination of Candida albicans activity. AB - Despite advances made in the field, rapid detection methods for the human pathogen Candida albicans are still missing. In this regard, bio-electrochemical systems including electrochemical sensors and biosensors satisfy the increasing demand for rapid, reliable, and direct microbial analyses. In this study, the bioelectrochemical characteristics of C. albicans were investigated for use in an analytical system that determines the viability of the organisms. The electrochemical responses of viable and non-viable cells of C. albicans and Saccharomyces cerevisiae were monitored. Cyclic voltammograms (CV) showed an irreversible oxidation peak at about 750 mV that accounts for viable cells. The peak current increased at viable cell numbers ranging from 3 * 10(5) to 1.6 * 10(7)cells/ml, indicating that the amount of viable cells can be accurately quantified. To elucidate the underlying electron transfer processes, the influence of electron transfer chain (ETC) - inhibitors on the electrochemical behavior of the two organisms were investigated. Inhibition of the function of classical respiratory chain (CRC) led to a decrease in the electrochemical response, whereas the oxidation current increased when the alternative oxidase (AOX) pathway was blocked by salicylhydroxamic acid (SHA). Blocking the AOX pathway improved the electrochemical performance, suggesting an involvement in the CRC, with cytochrome c oxidase (COX) as a relevant protein complex. Mutants, in which components of COX were deleted, showed a lower electro-activity than the wild-type strain. Particularly, deletion of subunit COX5a almost completely abolished the electrochemical signal. We believe that this work can be utilized for the development of early detection assays and opens the door for new technological developments in the field of C. albicans. PMID- 23747361 TI - CNR1 variation is associated with the age at onset in Huntington disease. AB - Huntington disease (HD) is caused by the expansion of a CAG repeat within exon 1 of the HTT gene. Although the variation in age at onset (AO) is partly explained by the length of the expanded repeat blocks, the unexplained variation in AO is highly heritable, emphasizing the role of modifier genes on disease expression. Since down-regulation of type 1 cannabinoid (CB1) receptors is a key pathogenic event in HD, it has been suggested that activation of these receptors in patients may attenuate disease progression. In order to evaluate whether variations in the cannabinoid receptor 1 (CNR1) gene encoding the CB1 receptor protein have modifying effects on the AO of HD, we performed an association study between CNR1 polymorphisms and AO in HD patients. A (AAT)n repeat and a total of nine single nucleotide polymorphisms (SNPs) in the CNR1 gene were selected for genotyping in a cohort of 473 German HD patients recruited in the Huntington Center NRW in Bochum. The AO was significantly associated with the longest alleles (>=17 AAT) of the (AAT)n repeat polymorphism downstream of the CNR1 gene (p = 0.007) as well as with one SNP in the 3'UTR of CNR1 (rs4707436, p = 0.05). Interestingly, the allelic variation of rs4707436 affects different microRNA (miRNA) binding sites which could alter gene regulation and consequently influence protein expression. These findings support the idea that CNR1 variation may have modifying effects on the AO in HD. PMID- 23747362 TI - Isothermal titration calorimetry of membrane proteins - progress and challenges. AB - Integral membrane proteins, including G protein-coupled receptors (GPCR) and ion channels, mediate diverse biological functions that are crucial to all aspects of life. The knowledge of the molecular mechanisms, and in particular, the thermodynamic basis of the binding interactions of the extracellular ligands and intracellular effector proteins is essential to understand the workings of these remarkable nanomachines. In this review, we describe how isothermal titration calorimetry (ITC) can be effectively used to gain valuable insights into the thermodynamic signatures (enthalpy, entropy, affinity, and stoichiometry), which would be most useful for drug discovery studies, considering that more than 30% of the current drugs target membrane proteins. This article is part of a Special Issue entitled: Structural and biophysical characterisation of membrane protein ligand binding. PMID- 23747363 TI - The Protein 4.1 family: hub proteins in animals for organizing membrane proteins. AB - Proteins of the 4.1 family are characteristic of eumetazoan organisms. Invertebrates contain single 4.1 genes and the Drosophila model suggests that 4.1 is essential for animal life. Vertebrates have four paralogues, known as 4.1R, 4.1N, 4.1G and 4.1B, which are additionally duplicated in the ray-finned fish. Protein 4.1R was the first to be discovered: it is a major mammalian erythrocyte cytoskeletal protein, essential to the mechanochemical properties of red cell membranes because it promotes the interaction between spectrin and actin in the membrane cytoskeleton. 4.1R also binds certain phospholipids and is required for the stable cell surface accumulation of a number of erythrocyte transmembrane proteins that span multiple functional classes; these include cell adhesion molecules, transporters and a chemokine receptor. The vertebrate 4.1 proteins are expressed in most tissues, and they are required for the correct cell surface accumulation of a very wide variety of membrane proteins including G-Protein coupled receptors, voltage-gated and ligand-gated channels, as well as the classes identified in erythrocytes. Indeed, such large numbers of protein interactions have been mapped for mammalian 4.1 proteins, most especially 4.1R, that it appears that they can act as hubs for membrane protein organization. The range of critical interactions of 4.1 proteins is reflected in disease relationships that include hereditary anaemias, tumour suppression, control of heartbeat and nervous system function. The 4.1 proteins are defined by their domain structure: apart from the spectrin/actin-binding domain they have FERM and FERM-adjacent domains and a unique C-terminal domain. Both the FERM and C terminal domains can bind transmembrane proteins, thus they have the potential to be cross-linkers for membrane proteins. The activity of the FERM domain is subject to multiple modes of regulation via binding of regulatory ligands, phosphorylation of the FERM associated domain and differential mRNA splicing. Finally, the spectrum of interactions of the 4.1 proteins overlaps with that of another membrane-cytoskeleton linker, ankyrin. Both ankyrin and 4.1 link to the actin cytoskeleton via spectrin, and we hypothesize that differential regulation of 4.1 proteins and ankyrins allows highly selective control of cell surface protein accumulation and, hence, function. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters. Guest Editor: Jean Claude Herve PMID- 23747364 TI - Cytotoxic bile acids, but not cytoprotective species, inhibit the ordering effect of cholesterol in model membranes at physiologically active concentrations. AB - Submillimolar concentrations of cytotoxic bile acids (BAs) induce cell death via apoptosis. On the other hand, several cytoprotective BAs were shown to prevent apoptosis in the same concentration range. Still, the mechanisms by which BAs trigger these opposite signaling effects remain unclear. This study was aimed to determine if cytotoxic and cytoprotective BAs, at physiologically active concentrations, are able to modulate the biophysical properties of lipid membranes, potentially translating into changes in the apoptotic threshold of cells. Binding of BAs to membranes was assessed through the variation of fluorescence parameters of suitable derivatized BAs. These derivatives partitioned with higher affinity to liquid disordered than to the cholesterol enriched liquid ordered domains. Unlabeled BAs were also shown to have a superficial location upon interaction with the lipid membrane. Additionally, the interaction of cytotoxic BAs with membranes resulted in membrane expansion, as concluded from FRET data. Moreover, it was shown that cytotoxic BAs were able to significantly disrupt the ordering of the membrane by cholesterol at physiologically active concentrations of the BA, an effect not associated with cholesterol removal. On the other hand, cytoprotective bile acids had no effect on membrane properties. It was concluded that, given the observed effects on membrane rigidity, the apoptotic activity of cytotoxic BAs could be potentially associated with changes in plasma membrane organization (e.g. modulation of lipid domains) or with an increase in mitochondrial membrane affinity for apoptotic proteins. PMID- 23747365 TI - Membrane selectivity and biophysical studies of the antimicrobial peptide GL13K. AB - GL13K is a short (13 amino acid) antimicrobial peptide derived from the parotid secretory protein. GL13K has been found to exhibit anti-inflammatory and antibacterial activities in physiological salt conditions. We investigated the mechanism of interaction of GL13K, with model membranes comprising 1, 2 dioleoylphosphatidylcholine (DOPC) and 1, 2-dioleoylphosphatidylglycerol (DOPG) using various biophysical and imaging techniques. Circular dichroism studies showed that GL13K adopts a beta-sheet structure in the presence of negatively charged DOPG liposomes while it retains its random coil structure with zwitterionic DOPC liposomes. GL13K did not cause any fusion of these liposomes but was able to selectively disrupt the negatively charged membranes of DOPG leading to vesicular leakage. There was no or minimal evidence of GL13K interaction with DOPC liposomes, however an analysis of supported lipid bilayers (SLBs) using atomic force microscopic (AFM) imaging and dual polarization interferometry (DPI) suggested that GL13K can interact with the surface of a DOPC planar bilayer. In the case of DOPG bilayers, AFM and DPI clearly showed membrane thinned regions where a portion of lipid molecules has been removed. These results suggest that the mechanism of GL13K action on bacterial membranes involves localized removal of lipid from the membrane via peptide-induced micellization. PMID- 23747366 TI - Polystyrene nanoparticle exposure induces ion-selective pores in lipid bilayers. AB - A diverse range of molecular interactions can occur between engineered nanomaterials (ENM) and biomembranes, some of which could lead to toxic outcomes following human exposure to ENM. In this study, we adapted electrophysiology methods to investigate the ability of 20nm polystyrene nanoparticles (PNP) to induce pores in model bilayer lipid membranes (BLM) that mimic biomembranes. PNP charge was varied using PNP decorated with either positive (amidine) groups or negative (carboxyl) groups, and BLM charge was varied using dioleoyl phospholipids having cationic (ethylphosphocholine), zwitterionic (phosphocholine), or anionic (phosphatidic acid) headgroups. Both positive and negative PNP induced BLM pores for all lipid compositions studied, as evidenced by current spikes and integral conductance. Stable PNP-induced pores exhibited ion selectivity, with the highest selectivity for K(+) (PK/PCl~8.3) observed when both the PNP and lipids were negatively charged, and the highest selectivity for Cl(-) (PK/PCl~0.2) observed when both the PNP and lipids were positively charged. This trend is consistent with the finding that selectivity for an ion in channel proteins is imparted by oppositely charged functional groups within the channel's filter region. The PK/PCl value was unaffected by the voltage-ramp method, the pore conductance, or the side of the BLM to which the PNP were applied. These results demonstrate for the first time that PNP can induce ion-selective pores in BLM, and that the degree of ion selectivity is influenced synergistically by the charges of both the lipid headgroups and functional groups on the PNP. PMID- 23747367 TI - AMP-activated kinase, AMPK, is involved in the maintenance of plasma membrane organization in boar spermatozoa. AB - Spermatozoa undergo energy- and metabolism-dependent processes to successfully fertilize the oocyte. AMP-activated protein kinase, AMPK, is a sensor of cell energy. We recently showed that AMPK controls spermatozoa motility. Our aims are i) to investigate the intracellular localization of AMPK in boar spermatozoa by immunofluorescence, ii) to study whether AMPK plays a role in other relevant processes of spermatozoa: mitochondrial membrane potential (?Psim), plasma membrane lipid disorganization, outward phosphatidylserine (PS) exposure, acrosome integrity and induced-acrosome reaction by flow cytometry and iii) to investigate intracellular AMPK pathways by western blot. Spermatozoa were incubated under different conditions in the presence or absence of compound C (CC, 30MUM), an AMPK inhibitor and/or cAMP analog 8Br-cAMP. AMPKalpha protein is expressed at the entire acrosome and at the midpiece of spermatozoa flagellum, whereas phospho-Thr(172)-AMPK is specifically localized at the apical part of acrosome and at flagellum midpiece. CC treatment rapidly confers head-to-head aggregation-promoting property to spermatozoa. Long term AMPK inhibition in spermatozoa incubated in TCM significantly reduces high ?Psim. Moreover, AMPK inhibition significantly induces plasma membrane lipid disorganization and simultaneously reduces outward PS translocation at plasma membrane in a time dependent manner. Acrosomal integrity in TCM is significantly enhanced when AMPK is inhibited. However, neither acrosome reaction nor membrane lipid disorganization induced by ionophore A23187 are affected by CC. AMPK phosphorylation is potently stimulated upon PKA activation in spermatozoa. This work suggests that AMPK, lying downstream of PKA, regulates at different levels mammalian spermatozoa membrane function. PMID- 23747368 TI - Temporal and spatial variability of organotins in an intermittent Mediterranean river. AB - Organotin compounds (OTs) are exclusively anthropogenic and have been widely used for their biocidal properties and as stabilizers in various industrial applications. Hence organotins are common pollutants. Their high toxicity has led to their entry on the EU water framework's priority substances' list. However, few studies are available regarding their behaviour in surface waters, in particular, in intermittent Mediterranean rivers. The Vene is an intermittent river located in Languedoc-Roussillon, southern France. It is the main tributary of an important shellfish farming site: the Thau lagoon. The present study aims at establishing the presence of OTs on a 1.5 km long reach of the river into which a waste water treatment plant (WWTP) discharges. The study is carried out during steady-state flow conditions over two consecutive years and investigates potential OTs sources in everyday domestic activities. Routine field monitoring was carried out over a 5 month period during the springs of 2008 and 2009. The results establish the presence of butyltins and octyltins throughout the 1.5 km long reach at concentrations exceeding the maximum allowable concentration levels imposed by the water framework directive. The WWTP is recognized as an important OTs point source; however, using trace and rare earth elements as tracers, an urban stormwater sewage gutter is identified as a secondary source. Its impact on the river's pollutant loads is however variable in time because of flow intermittency. The paper discusses the need for specific monitoring and management schemes for intermittent rivers. PMID- 23747369 TI - A weight-of-evidence approach to integrate suspended sediment source information. AB - Sediment monitoring, tracing and modelling are widely used to identify suspended sediment sources. Although each method has inherent limitations and uncertainties, their integration provides opportunities to form collective knowledge and encourages robust management strategies. This paper presents a Weight-of-Evidence approach to integrate multiple Lines-of-Evidence for identifying suspended sediment sources. Three sources of evidence were used: i) stream flow and suspended sediment monitoring at river gauges; ii) geochemical sediment tracing at river junctions; and iii) catchment-scale suspended sediment modelling of hillslope, gully, streambank and unsealed road erosion. We applied this approach on two data-poor catchments in Australia. Some reaches were consistently identified as major sources of sediment from all Lines-of-Evidence. However, inconsistencies between the types of evidence in other areas highlighted the high uncertainty in identifying suspended sediment sources in these areas and the need for further investigation. The integration framework maximised the use of scarce information, enabled explicit consideration of uncertainties for catchment management and identified where future monitoring and research should be targeted. PMID- 23747370 TI - Towards the planning and design of disturbance patterns across scales to counter biological invasions. AB - The way in which disturbances from human land use are patterned in space across scales can have important consequences for efforts to govern human/environment with regard to, but not only, invasive spread-dispersal processes. In this context, we explore the potential of disturbance patterns along a continuum of scales as proxies for identifying the geographical regions prone to spread of invasive plant species. To this end, we build on a previous framework of cross scale disturbance patterns, exercising the approach for the Apulia region (South Italy). We first review procedures and results introducing disturbance maps and sliding windows to measure composition (amount) and configuration (contagion) of disturbance patterns both for real and simulated landscapes from random, multifractal and hierarchical neutral models. We introduce cross-scale disturbance profiles obtained by clustering locations from real and simulated landscapes, which are used as foils for comparison to the real landscapes on the same pattern transition space. Critical percolation thresholds derived from landscape observations and theoretical works are discussed in order to identify critical scale domains. With reference to the actual land use and invasive alien flora correlates of disturbance patterns, a cross-scale "invasibility" map of the Apulia region is derived, which shows sub-regions and scale domains with different potentials for the invasive spread of undesirable species. We discuss the potential effect of contagious and non-contagious disturbances like climate change and why multifractal-like disturbance patterns might be more desirable than others to counter biological invasions in a multi-scale and multi-level context of adaptive planning, design and management of disturbance. PMID- 23747371 TI - Casuarina in Africa: distribution, role and importance of arbuscular mycorrhizal, ectomycorrhizal fungi and Frankia on plant development. AB - Exotic trees were introduced in Africa to rehabilitate degraded ecosystems. Introduced species included several Australian species belonging to the Casuarinaceae family. Casuarinas trees grow very fast and are resistant to drought and high salinity. They are particularly well adapted to poor and disturbed soils thanks to their capacity to establish symbiotic associations with mycorrhizal fungi -both arbuscular and ectomycorrhizal- and with the nitrogen fixing bacteria Frankia. These trees are now widely distributed in more than 20 African countries. Casuarina are mainly used in forestation programs to rehabilitate degraded or polluted sites, to stabilise sand dunes and to provide fuelwood and charcoal and thus contribute considerably to improving livelihoods and local economies. In this paper, we describe the geographical distribution of Casuarina in Africa, their economic and ecological value and the role of the symbiotic interactions between Casuarina, mycorrhizal fungi and Frankia. PMID- 23747372 TI - Performance comparison and economics analysis of waste stabilization ponds and horizontal subsurface flow constructed wetlands treating domestic wastewater: a case study of the Juja sewage treatment works. AB - The performance, effluent quality, land area requirement, investment and operation costs of a full-scale waste stabilization pond (WSP) and a pilot scale horizontal subsurface flow constructed wetland (HSSF-CW) at Jomo Kenyatta University of Agriculture and Technology (JKUAT) were investigated between November 2010 to January 2011. Both systems gave comparable medium to high levels of organic matter and suspended solids removal. However, the WSP showed a better removal for Total Phosphorus (TP) and Ammonium (NH4(+)-N). Based on the population equivalent calculations, the land area requirement per person equivalent of the WSP system was 3 times the area that would be required for the HSSF-CW to treat the same amount of wastewater. The total annual cost estimates consisting of capital, operation and maintenance (O&M) costs were comparable for both systems. However, the evaluation of the capital cost of either system showed that it is largely influenced by the size of the population served, local cost of land and the construction materials involved. Hence, one can select either system in terms of treatment efficiency. When land is available other factor including the volume of wastewater or the investment, and O&M costs determine the technology selection. PMID- 23747373 TI - Green synthesis of covellite nanocrystals using biologically generated sulfide: potential for bioremediation systems. AB - This work describes the synthesis of CuS powders in high yield and via an environmentally friendly and straightforward process, under ambient conditions (temperature and pressure), by adding to aqueous copper (II) a nutrient solution containing biologically generated sulfide from sulfate-reducing bacteria (SRB). The powders obtained were composed of CuS (covellite) nanoparticles (NPs) exhibiting a spheroid morphology (<5 nm). The relevance of this method to obtain CuS supported solid substrates has been demonstrated by performing the synthesis in the presence of TiO2 and SiO2 submicron particles. We further extended the work carried out, which substantiates the potential of using biogenic sulfide for the production of covellite nanocrystals and composites, using the effluent of a bioremediation column. Hence, such process results in the synthesis of added value products obtained from metal rich effluents, such as metallurgical and industrial ones, or Acid Mine Drainage (AMD), when associated with bioremediation processes. PMID- 23747374 TI - Impact of co-digestion on existing salt and nutrient mass balances for a full scale dairy energy project. AB - Anaerobic digestion of manure and other agricultural waste streams with subsequent energy production can result in more sustainable dairy operations; however, importation of digester feedstocks onto dairy farms alters previously established carbon, nutrient, and salinity mass balances. Salt and nutrient mass balance must be maintained to avoid groundwater contamination and salination. To better understand salt and nutrient contributions of imported methane-producing substrates, a mass balance for a full-scale dairy biomass energy project was developed for solids, carbon, nitrogen, sulfur, phosphorus, chloride, and potassium. Digester feedstocks, consisting of thickened manure flush-water slurry, screened manure solids, sudan grass silage, and feed-waste, were tracked separately in the mass balance. The error in mass balance closure for most elements was less than 5%. Manure contributed 69.2% of influent dry matter while contributing 77.7% of nitrogen, 90.9% of sulfur, and 73.4% of phosphorus. Sudan grass silage contributed high quantities of chloride and potassium, 33.3% and 43.4%, respectively, relative to the dry matter contribution of 22.3%. Five potential off-site co-digestates (egg waste, grape pomace, milk waste, pasta waste, whey wastewater) were evaluated for anaerobic digestion based on salt and nutrient content in addition to bio-methane potential. Egg waste and wine grape pomace appeared the most promising co-digestates due to their high methane potentials relative to bulk volume. Increasing power production from the current rate of 369 kW to the design value of 710 kW would require co-digestion with either 26800 L d(-1) egg waste or 60900 kg d(-1) grape pomace. However, importation of egg waste would more than double nitrogen loading, resulting in an increase of 172% above the baseline while co-digestion with grape pomace would increase potassium by 279%. Careful selection of imported co-digestates and management of digester effluent is required to manage salt and nutrient mass loadings and reduce groundwater impacts. PMID- 23747375 TI - Composting Phragmites australis Cav. plant material and compost effects on soil and tomato (Lycopersicon esculentum Mill.) growth. AB - Composting organic residues is a friendly to the environment alternative to producing fertilizer. This research was carried out to study the process of composting Phragmites australis Cav. plant material alone or with animal manure on a pilot-scale, to evaluate firstly the quality of the composts produced and secondly, using a pot experiment, the effects of their application on soil physicochemical characteristics and tomato plants development. For the compost production a randomized complete block design was used with five treatments (five compost types) and four replications. For the pot experiment, a completely randomized design was used with 17 treatments (plain soil, soil with synthetic fertilizer and the application of five compost types, at three rates each) and five replications. Compost N increased with composting time, while C/N ratio decreased significantly and by the end it ranged from 43.3 for CM to 22.6 for CY. Compost pH became almost neutral, ranging from 6.73 for CY to 7.21 for CM3Y3AM4 by the end. Compost combinations CY7AM3 and CM7AM3 had a more positive influence on the soil physicochemical characteristics than the others. Soil N, P, Ca and Mg concentrations and the reduction of clay dispersion were the highest when CM7AM3 compost was added. The macro-aggregate stability was the highest for CY7AM3, which also sustained plant growth. The latter compost combination improved most of the soil physicochemical characteristics and plant growth especially, when the application rate was 4% (w/w), which equals to 156 Mg ha(-1). PMID- 23747376 TI - Study of molecular structure, vibrational, electronic and NMR spectra of oncocalyxone A using DFT and quantum chemical calculations. AB - Oncocalyxone A (C17H18O5) is the major secondary metabolite isolated from ethanol extract from the heartwood of Auxemma oncocalyx Taub popularly known as "pau branco". Oncocalyxone A (Onco A) has many pharmaceutical uses such as: antitumor, analgesic, antioxidant and causative of inhibition of platelet activation. We have performed the optimized geometry, total energy, conformational study, molecular electrostatic potential mapping, frontier orbital energy gap and vibrational frequencies of Onco A employing ab initio Hartree-Fock (HF) and density functional theory (DFT/B3LYP) method with 6-311++G(d,p) basis set. Stability of the molecule arising from hyperconjugative interactions and/or charge delocalization has been analyzed using natural bond orbital (NBO) analysis. UV-vis spectrum of the compound was recorded in DMSO and MeOH solvent. The TD-DFT calculations have been performed to explore the influence of electronic absorption spectra in the gas phase, as well as in solution environment using IEF-PCM and 6-31G basis set. The (13)C NMR chemical shifts have been calculated with the B3LYP/6-311++G(d,p) basis set and compared with the experimental values. These methods have been used as tools for structural characterization of Onco A. PMID- 23747377 TI - Synthesis, molecular structure, hydrogen-bonding, NBO and chemical reactivity analysis of a novel 1,9-bis(2-cyano-2-ethoxycarbonylvinyl)-5-(4-hydroxyphenyl) dipyrromethane: a combined experimental and theoretical (DFT and QTAIM) approach. AB - The spectroscopic analysis of a newly synthesized 1,9-bis(2-cyano-2 ethoxycarbonylvinyl)-5-(4-hydroxyphenyl)-dipyrromethane (3) has been carried out using (1)H NMR, UV-Visible, FT-IR and Mass spectroscopic techniques. All the quantum chemical calculations have been carried out using DFT level of theory, B3LYP functional and 6-31G(d,p) as basis set. Thermodynamic parameters (H, G, S) of all the reactants and products have been used to determine the nature of the chemical reaction. The chemical shift of pyrrolic NH in (1)H NMR spectrum appears at 9.4 ppm due to intramolecular hydrogen bonding. TD-DFT calculation shows the nature of electronic transitions as pi->pi(*) within the molecule. A combined experimental and theoretical vibrational analysis designates the existence of H bonding between pyrrole N-H as proton donor and nitrogen of cyanide as proton acceptor, therefore, lowering in stretching vibration of NH and CN. To investigate the strength and nature of H-bonding, topological parameters at bond critical points (BCPs) are analyzed by 'Quantum theory of Atoms in molecules' (QTAIMs). Natural bond orbitals (NBOs) analysis has been carried out to investigate the intramolecular conjugative and hyperconjugative interactions within molecule and their second order stabilization energy (E((2))). Global electrophilicity index (omega=4.528 eV) shows that title molecule (3) is a strong electrophile. The maximum values of local electrophilic reactivity descriptors (fk(+),sk(+),omegak(+)) at vinyl carbon (C6/C22) of (3) indicate that these sites are more prone to nucleophilic attacks. PMID- 23747378 TI - Synthesis of a new N-substituted bis-benzimidazolyl diamide ligand and its trinuclear copper(II) complex: structural and fluorescence studies. AB - The synthesis of a new N-substituted fluorescent probe based on a bis benzimidazole diamide N(2),N(2')-bis[(1-(4-methylbenzyl)-benzimidazol-2 yl)methyl]biphenyl-2,2'-dicarboxamide (L1) with a biphenyl spacer group and its trinuclear copper(II) complex [Cu3(L1)3Cl3].3Cl.3H2O] has been described. X-ray studies shows that the trinuclear complex crystallizes as [{Cu3(L1)3Cl3}2.6Cl.13CH3CN.2H2O] in triclinic space group P-1 with two independent molecules in the asymmetric unit. Each copper(II) adopts a distorted penta-coordinated geometry in each unit. The fluorescence spectra of L1 in methanol show an emission band centered at 300 nm. This band arises due to benzimidazolyl moiety in the ligating system. The diamide L1 in the presence of Fe(3+) show the simultaneous 'quenching' of (300nm) and 'enhancement' of (375 nm) emission band. The new emission band at 375 nm is attributed to intra ligand pi pi(*) transition of the biphenyl moiety. While Cu(2+) and Ag(+) show only the quenching of the 300 nm band. No such behavior was observed with other metal ions like Ni(2+), Co(2+), Mn(2+), Mg(2+), Zn(2+) and Pb(2+). The quenching constant with Fe(3+), Ag(+) and Cu(2+) are calculated by the Stern-Volmer plots. PMID- 23747379 TI - Synthesis, spectral and antimicrobial activity of Zn(II) complexes with Schiff bases derived from 2-hydrazino-5-[substituted phenyl]-1,3,4-thiadiazole and benzaldehyde/2-hydroxyacetophenone/indoline-2,3-dione. AB - Zn(II) complexes have been synthesized by reacting zinc acetate with Schiff bases derived from 2-hydrazino-5-[substituted phenyl]-1,3,4-thiadiazole and 2 hydroxyacetophenone/benzaldehyde/indoline-2,3-dione. All these complexes are soluble in DMF and DMSO; low molar conductance values indicate that they are non electrolytes. Elemental analyses suggest that the complexes have 1:2 metal to ligands stoichiometry of the types [ZnL2(H2O)2](L=monoanionic Schiff bases derived from 2-hydrazino-5-[substituted phenyl]-1,3,4-thiadiazole and 2 hydroxyacetophenone/indoline-2,3-dione) [ZnL2(')(OOCCH3)2(H2O)2](L'=neutral Schiff bases derived from 2-hydrazino-5-[substituted phenyl]-1,3,4-thiadiazole and benzaldehyde), and they were characterized by IR, (1)H NMR, and (13)C NMR. Particle sizes of synthesized compounds were measured with dynamic light scattering (DLS) analyser which indicates that particle diameter are of the range ca. 100-200nm. All these Schiff bases and their complexes have also been screened for their antibacterial (Bacillus subtilis (B. subtilis), Escherichia coli (E. coli) and antifungal activities (Colletotrichum falcatum (C. falcatum), Aspergillus niger (A. niger), Fusarium oxysporium (F. oxysporium) Curvularia pallescence (C. pallescence). The antimicrobial activities have shown that upon complexation the activity increases. PMID- 23747380 TI - Time resolved spectroscopy and gain studies of Fullerenes C60 and C70. AB - The fluorescence decay time of Fullerenes C60 and C70 in pure form as well as in mixture with Coumarin C440 and Quinizarine dyes are studied. Results indicate that the decay of pure fullerenes is constant throughout the solute concentration and it is also independent of excitation wavelength, whereas in the case of mixture with dyes different behavior is noticed. We have also calculated the Stern-Volmer quenching constant and optical gain of both the fullerenes from which it is found that the optical gain is positive for Fullerene C70 only in a very narrow range of concentration. PMID- 23747381 TI - Group 12 dithiocarbamate complexes: synthesis, spectral studies and their use as precursors for metal sulfides nanoparticles and nanocomposites. AB - Zn(II), Cd(II) and Hg(II) dithiocarbamate complexes have been synthesized and characterized by elemental analysis, thermogravimetric analysis, UV-Vis, FTIR, (1)H- and (13)C NMR spectroscopy. The complexes were thermolysed at 180 degrees C and used as single molecule precursors for the synthesis of HDA capped ZnS, CdS and HgS nanoparticles and polymethylmethacrylate (PMMA) nanocomposites. The optical and structural properties of the nanoparticles and nanocomposites were studied by UV-Vis, PL, XRD and SEM. The crystallites sizes of the nanoparticles varied between 3.03 and 23.45 nm. SEM and EDX analyses of the nanocomposites confirmed the presence of the nanoparticles in the polymer matrix. PMID- 23747382 TI - A comparative study on the binding of single and double chain surfactant cobalt(III) complexes with bovine serum albumin. AB - The comparative binding effect of single and double aliphatic chain containing surfactant-cobalt(III) complexes cis-[Co(bpy)2(DA)2](ClO4)3.2H2O (1), cis [Co(bpy)2(DA)Cl](ClO4)2.2H2O (2), cis-[Co(phen)2(CA)2](ClO4)3.2H2O (3), and cis [Co(phen)2(CA)Cl](ClO4)2.2H2O (4) with bovine serum albumin (BSA) under physiological condition was analyzed by steady state, time resolved fluorescence, synchronous, three-dimensional fluorescence, UV-Visible absorption and circular dichroism spectroscopic techniques. The results show that these complexes cause the fluorescence quenching of BSA through a static mechanism. The binding constants (Kb) and the number of binding sites were calculated and binding constant values are found in the range of 10(4)-10(5) M(-1). The results indicate that compared to single chain complex, double chain surfactant-cobalt(III) complex interacts strongly with BSA. Also the sign of thermodynamic parameters (DeltaG degrees , DeltaH degrees , and DeltaS degrees ) indicate that all the complexes interact with BSA through hydrophobic force. The binding distance (r) between complexes and BSA was calculated using Forster non-radiation energy transfer theory and found to be less than 7 nm. The results of synchronous, three dimensional fluorescence and circular dichroism spectroscopic methods indicate that the double chain surfactant-cobalt(III) complexes changed the conformation of the protein considerably than the respective single chain surfactant cobalt(III) complexes. Antimicrobial studies of the complexes showed good activities against pathogenic microorganisms. PMID- 23747383 TI - Determination of trace elements in soil, leaves and fruits of Quercus brantii grown in southwestern Iran by atomic spectroscopy. AB - Quercus brantii acorn is rich of some useful mineral elements such as K, Fe and Zn. The content of these mineral elements in Quercus are dependent on their region and environmental conditions. Q. brantii grown naturally in different regions of Iran especially in Kohgiloye va Boyer Ahmad province (southwestern of Iran). In this study total concentration of Fe, Zn and K elements were determined using atomic absorption and emission spectroscopy in fruits, leaves of Q. brantii and also in the soils where this plant was grown. Statistical evaluation (ANOVA test) was employed for all measurements. Results confirmed that the concentration of elements in fruit and leave depended on area which the plant is growth. The transport factor of elements was also considered. PMID- 23747384 TI - Quantum-chemical investigation of the spin crossover complex [Fe(mbpzbpy)(NCS)2]. AB - The geometries of the spin crossover complex [Fe(mbpzbpy)(NCS)2] were optimized by several density functionals and basis sets. In addition, the vibrational modes and IR spectra, excited states and UV/vis absorption spectra and spin splittings energies were also predicted by DFT/TD-DFT calculations. PMID- 23747385 TI - The coupling of carbon dioxide and epoxides by phenanthroline derivatives containing different Cu(II) complexes as catalyst. AB - A series of the mononuclear Cu(II) metal complexes containing the ligand Bdppz [(9a,13a-dihydro-4,5,9,14-tetraaza-benzo[b]triphenylene-11-yl)-phenyl-methanone] (L1) and Aqphen [(12,17-dihydronaphthol[2,3-h]dipyrido[3,2-a:2',3'-c]-phenazine 12,17-dione)] (L2) were synthesized and used as catalyst for the coupling of carbon dioxide (CO2) and liquid epoxide which served as both reactant and solvent. Dimethylamino pyridine (DMAP) was used as co-catalyst. The yields of epoxides to corresponding cyclic carbonates were determined by comparing the ratio of product to substrate in the (1)H NMR spectrum of an aliquot of the reaction mixture. The mononuclear Cu(II) complexes of these ligands were synthesized by treating an ethanol solvent of the appropriate ligand with a different molar amount of CuCl2.2H2O. The Cu(II) complexes were characterized by FT-IR, UV-Vis, elemental analysis, melting point analysis, mass spectra, molar conductivity measurements and magnetic susceptibility techniques. The reaction of the Bdppz and Aqphen ligands in a 1:1, 1:2 or 1:3 mole ratio with CuCl2.2H2O afforded ionic Cu(II) complexes in the presence of Et3N. PMID- 23747386 TI - Study of structure-activity relationship of enantiomeric, protonated and deprotonated forms of warfarin via vibrational spectroscopy and DFT calculations. AB - The structure-activity relationship of the anticoagulant drug warfarin were studied by studying two enantiomeric forms (S-form and R-form) of warfarin and its protonated as well as deprotonated structures in aqueous media using density functional theory (DFT). Theoretically computed Raman and IR spectra of all the computed structures were compared and their specific vibrational spectroscopic signatures were discussed. The percentage contributions of individual normal modes of warfarin, which provides direct evidence of the different molecular activity due to change in relative atomic position of atoms in molecule, were investigated through potential energy distribution (PED). The optimized energy and molecular electrostatic potential (MEP) maps show that the S-form of the drug molecules warfarin is energetically more stable than R-form and provides higher docking opportunity for the molecular binding with the receptors in the bio systems. PMID- 23747387 TI - Spectroscopic studies on the interaction of carteolol hydrochloride and urea induced bovine serum albumin. AB - The interaction of carteolol hydrochloride, to 0.2 mol L(-1) urea-induced bovine serum albumin in aqueous solution has been first investigated by fluorescence spectra and ultraviolet-visible (UV-vis) spectra at pH 7.40. The quenching mechanism, binding parameter and sites (n), the binding mode (DeltaG, DeltaH, and DeltaS) as well as the binding distance (r) have been obtained according to the experimental results. We also use the synchronous fluorescence method to study the effect of CTL on the conformation change of urea-induced BSA. PMID- 23747388 TI - Photo-physics study of an hydroxy-quinoline derivative as inhibitor of Pim-1 kinase: ultraviolet-visible linear dichroism spectroscopy and quantum chemical calculations. AB - The photophysical properties of the antiviral 7-nicotinoyl-styrylquinoline (MB96) were investigated by means of UV-Vis linear dichroism (LD) spectroscopy on molecular samples aligned in stretched polyvinylalcohol (PVA), supported by time dependent density functional theory (TD-DFT) calculations. Experimentally, the directions of the transitions moments with respect to the long axis of the molecule were deduced from the orientation K factors, determined by means of "trial-and-error" procedure. The absorption spectrum presents two parts. The main transition in the lowest energy part, observed around 365 nm and showing the highest K value 0.8, is longitudinally in-plane polarized. The highest energy part which is extended between 230 and 320 nm, large, diffuse, and of weak intensity, shows estimated K values between 0.2 and 0.5. This complex structure is transversally polarized with some contamination by the longitudinal character of the first strong band. The TD-DFT results agree fairly well with the LD measurements. PMID- 23747389 TI - Amyloid-beta peptide (1-42) aggregation induced by copper ions under acidic conditions. AB - It is well known that the aggregation of amyloid-beta peptide (Abeta) induced by Cu2+ is related to incubation time, solution pH, and temperature. In this work, the aggregation of Abeta1-42 in the presence of Cu2+ under acidic conditions was studied at different incubation time and temperature (e.g. 25 and 37 degrees C). Incubation temperature, pH, and the presence of Cu2+ in Abeta solution were confirmed to alter the morphology of aggregation (fibrils or amorphous aggregates), and the morphology is pivotal for Abeta neurotoxicity and Alzheimer disease (AD) development. The results of atomic force microscopy (AFM) indicated that the formation of Abeta fibrous morphology is preferred at lower pH, but Cu2+ induced the formation of amorphous aggregates. The aggregation rate of Abeta was increased with the elevation of temperature. These results were further confirmed by fluorescence spectroscopy and circular dichroism spectroscopy and it was found that the formation of beta-sheet structure was inhibited by Cu2+ binding to Abeta. The result was consistent with AFM observation and the fibrillation process was restrained. We believe that the local charge state in hydrophilic domain of Abeta may play a dominant role in the aggregate morphology due to the strong steric hindrance. This research will be valuable for understanding of Abeta toxicity in AD. PMID- 23747390 TI - Crystal structures of the ternary complex of APH(4)-Ia/Hph with hygromycin B and an ATP analog using a thermostable mutant. AB - Aminoglycoside 4-phosphotransferase-Ia (APH(4)-Ia)/Hygromycin B phosphotransferase (Hph) inactivates the aminoglycoside antibiotic hygromycin B (hygB) via phosphorylation. The crystal structure of the binary complex of APH(4) Ia with hygB was recently reported. To characterize substrate recognition by the enzyme, we determined the crystal structure of the ternary complex of non hydrolyzable ATP analog AMP-PNP and hygB with wild-type, thermostable Hph mutant Hph5, and apo-mutant enzyme forms. The comparison between the ternary complex and apo structures revealed that Hph undergoes domain movement upon binding of AMP PNP and hygB. This was about half amount of the case of APH(9)-Ia. We also determined the crystal structures of mutants in which the conserved, catalytically important residues Asp198 and Asn203, and the non-conserved Asn202, were converted to Ala, revealing the importance of Asn202 for catalysis. Hph5 contains five amino acid substitutions that alter its thermostability by 16 degrees C; its structure revealed that 4/5 mutations in Hph5 are located in the hydrophobic core and appear to increase thermostability by strengthening hydrophobic interactions. PMID- 23747391 TI - Quantitative analysis of type I collagen fibril regulation by lumican and decorin using AFM. AB - Lumican and decorin, two members of the small leucine-rich repeat proteoglycan (SLRP) family, have been implicated as regulators of collagen I fibril structure in different tissues. Both proteoglycans consist of a core protein and a glycosaminoglycan (GAG) chain, but quantitative information regarding the precise role of the protein and GAG moieties in regulating collagen structure is still limited. In this study, we used AFM imaging and a model system of aligned collagen I nanofibrils to investigate the role of lumican and decorin on collagen I fibril structure with high resolution. When co-assembled with collagen I, recombinant lumican or decorin proteins lacking the GAG chains decreased collagen fibril width to values below <100nm and increased interfibrillar spacing in a dose-dependent manner. At lower concentrations, lumican appeared to have a stabilizing effect on newly-formed collagen fibrils, while at higher concentrations both lumican and decorin inhibited collagen fibrillogenesis. GAG containing decorin also increased interfibrillar spacing, decreased fibril width and ultimately inhibited fibrillogenesis, but these effects required lower concentrations compared to recombinant decorin, indicating that the decorin core protein alone cannot compensate for the full regulatory and structural contribution of the GAG chain during collagen I fibrillogenesis. Using a 2D autocorrelation approach, we furthermore analyzed and compared the effects of recombinant and glycosylated decorin on collagen ultrastructure, providing a quantitative measure for the observed structural differences. AFM analysis of ordered fibrillar collagen arrays in combination with quantitative autocorrelation image analysis thus provides a useful tool for investigating SLRP dependent nanoscale effects on collagen fibril structure. PMID- 23747392 TI - An arm-swapped dimer of the Streptococcus pyogenes pilin specific assembly factor SipA. AB - Streptococcus pyogenes (group A streptococcus [GAS]) is a major human pathogen. Attachment of GAS to host cells depends in large part on pili. These assemblies are built from multiple covalently linked subunits of a backbone protein (FctA), which forms the shaft of the pilus, and two minor pilin proteins, FctB anchoring the pilus to the cell wall and Cpa functioning as the adhesin at the tip. Polymerisation of the pilin subunits is mediated by a specific sortase, which catalyzes the formation of peptide bonds linking successive subunits. An additional gene, SipA, is also essential for GAS pilus polymerisation, but its function remains undefined. Here we report the crystal structure of a truncated SipA protein from GAS, determined at 1.67A resolution. The structure reveals that SipA has the same core fold as the Escherichia coli type-I signal peptidase (SPase-I), but has a much smaller non-catalytic domain. The truncated protein, which lacks 9 N-terminal residues, forms an arm-swapped dimer in which the C terminal beta-strand of each monomer crosses over to interact with an N-terminal strand from the other monomer. In addition, there is no peptide binding cleft and significant differences in the putative membrane association region. PMID- 23747394 TI - Snake venomics of Lachesis muta rhombeata and genus-wide antivenomics assessment of the paraspecific immunoreactivity of two antivenoms evidence the high compositional and immunological conservation across Lachesis. AB - We report the proteomic analysis of the Atlantic bushmaster, Lachesis muta rhombeata, from Brazil. Along with previous characterization of the venom proteomes of L. stenophrys (Costa Rica), L. melanocephala (Costa Rica), L. acrochorda (Colombia), and L. muta muta (Bolivia), the present study provides the first overview of the composition and distribution of venom proteins across this wide-ranging genus, and highlights the remarkable similar compositional and pharmacological profiles across Lachesis venoms. The paraspecificity of two antivenoms, produced at Instituto Vital Brazil (Brazil) and Instituto Clodomiro Picado (Costa Rica) using different conspecific taxa in the immunization mixtures, was assessed using genus-wide comparative antivenomics. This study confirms that the proteomic similarity among Lachesis sp. venoms is mirrored in their high immunological conservation across the genus. The clinical and therapeutic consequences of genus-wide venomics and antivenomics investigations of Lachesis venoms are discussed. BIOLOGICAL SIGNIFICANCE: The proteomics characterization of L. m. rhombeata venom completes the overview of Lachesis venom proteomes and confirms the remarkable toxin profile conservation across the five clades of this wide-ranging genus. Genus-wide antivenomics showed that two antivenoms, produced against L. stenophrys or L. m. rhombeata, exhibit paraspecificity towards all other congeneric venoms. Our venomics study shows that, despite the broad geographic distribution of the genus, monospecific antivenoms may achieve clinical coverage for any Lachesis sp. envenoming. PMID- 23747395 TI - Dropped gallstones: spectrum of imaging findings, complications and diagnostic pitfalls. AB - Spillage of gallstones into the abdominal cavity, referred to as "dropped gallstones" (DGs), occurs commonly during laparoscopic cholecystectomy. The majority of these spilled stones remain clinically silent; however, if uncomplicated DGs are not correctly identified on subsequent imaging, they may mimic peritoneal implants and cause unduly concern. A small percentage of DGs cause complications, including abscess and fistula formation. Recognising the DG within the abscess is critical for definitive treatment. This pictorial review illustrates the imaging appearances and complications of DGs on CT, MRI and ultrasound and emphasises pitfalls in diagnosis. PMID- 23747396 TI - The association of IL1alpha and IL1beta polymorphisms with susceptibility to systemic lupus erythematosus: a meta-analysis. AB - Many epidemiological studies have investigated IL1alpha and IL1beta polymorphisms with SLE risk, but no conclusions are available because of conflicting results. This meta-analysis was performed to more precisely estimate the relationships. The databases of PubMed updated to September 1st, 2012 were retrieved. Odds ratio (OR) and corresponding 95% confidence interval (95% CI) as effect size were calculated by a fixed- or random-effect model. In total, six case-control studies for IL1beta-511C/T, four studies for IL1beta+3953C/T, three studies for IL1alpha 889C/T and three studies for IL1alpha+4845G/T were involved in this analysis. The results indicated that for IL1alpha-889C/T polymorphism T allele was associated with decreased risk of SLE (OR (95% CI)) (T vs. C: 0.802 (0.679-0.949); TT+CT vs. CC: 0.615 (0.380-0.995); TT vs. CC: 0.679 (0.466-0.989)). However, when analysis for TT vs. CT+CC was conducted, the result indicated that IL1alpha-889C/T polymorphism was not associated with SLE (OR (95% CI): 0.847 (0.595-1.205)). Combined analysis indicated that IL1beta-511C/T polymorphism was not overall associated with risk of SLE (OR (95% CI)) (T vs. C: 1.113 (0.954-1.298); TT vs. CT+CC: 1.146 (0.889-1.447); TT+CT vs. CC: 1.145 (0.903-1.452); TT vs. CC: 1.255 (0.928-1.698)). When subgroup analysis for Asian ethnicity was conducted, the results indicated that IL1beta-511C/T polymorphism was associated with SLE only for TT vs. CT+CC (OR (95% CI): 1.468 (1.001-2.152)), but was not associated for T vs. C (OR (95% CI): 1.214 (0.955-1.544)), TT+CT vs. CC (OR (95% CI): 1.112 (0.765 1.615)) and TT vs.CC (OR (95% CI): 1.411 (0.896-2.222)). In addition, overall analyses indicated that IL1beta+3953C/T and IL1alpha+4845G/C polymorphisms were also not associated with risk of SLE (OR (95% CI)) (for IL1beta+3953C/T T vs. C: 0.996 (0.610-1.626), TT vs. CT+CC: 0.658 (0.318-1.358), TT+CT vs. CC: 1.021 (0.618-1.687), TT vs. CC: 0.640 (0.309-1.325); for IL1alpha+4845G/T T vs. G: 1.067 (0.791-1.440), TT+GT vs. GG: 0.934 (0.646-1.351)).This study inferred that IL1alpha-889C/T polymorphism might be moderately associated with SLE, but no sufficient evidence was available to support any associations between IL1beta+3953C/T or IL1alpha+4845G/C polymorphisms and SLE. We could not draw a definite conclusion between IL1beta-511C/T polymorphism and risk of SLE owing to the limited data. Further large sample-sized studies should be required. PMID- 23747397 TI - Functional characterization of the plant ubiquitin regulatory X (UBX) domain containing protein AtPUX7 in Arabidopsis thaliana. AB - p97/CDC48 is a major AAA-ATPase that acts in many cellular events such as ubiquitin-dependent degradation and membrane fusion. Its specificity depends on a set of adaptor proteins, most of them containing the ubiquitin regulatory X (UBX) domain. Using a differential hybridization system, we isolated a UBX-containing protein that is expressed during the early phase of male gametophyte development in the crop Brassica napus and isolated and characterized its closest Arabidopsis thaliana homolog, AtPUX7. The AtPUX7 gene is expressed broadly in both the sporophyte and gametophyte due to regulation inferred by its first intron. The subcellular localization of AtPUX7 was assigned mainly to the nucleus in both the sporophyte and in pollen, mirroring the AAA-ATPase AtCDC48A localization. Furthermore, AtPUX7 interacts specifically with AtCDC48A in yeast as well as in planta in the nucleus. This interaction was mediated through the AtPUX7 UBX domain, which is located at the protein C-terminus, while an N-terminal UBA domain mediated its interaction with ubiquitin. Consistent with those results, a yeast-three hybrid analysis showed that AtPUX7 can act as a bridge between AtCDC48A and ubiquitin, suggesting a role in targeted protein degradation. It is likely that AtPUX7 acts redundantly with other members of the Arabidopsis PUX family because a null Atpux7-1 mutant does not display obvious developmental defects. PMID- 23747398 TI - The genetic polymorphisms of cathepsin S were associated with metabolic disorders in a Chinese Han population. AB - Cathepsin S (CTSS) played an important role in the etiology of cardiovascular disease and metabolic syndrome. Few studies had been reported on the association between the polymorphisms of CTSS and metabolic disorders in Asian population. Therefore we explored the association between the polymorphisms of CTSS and metabolic disorders in a Chinese Han population. The subjects were a Chinese Han cohort with 1160 participants, and the genotyping was performed with PCR-RFLP. Polymorphism rs16827671 was associated with BMI and serum total cholesterol (P=0.001; P=0.02, respectively). Subjects with CT genotype of rs16827671 had a higher risk of hypercholesterolemia (OR=1.64, 95% CI: 1.15-2.33, P=0.006) compared with TT genotype. Subjects with AG genotype of rs11576175 had lower risks of hypertriglyceridemia and borderline hypercholesterolemia (OR=0.52, 95% CI: 0.36-0.73, P=0.0001; OR=0.52, 95% CI: 0.35-0.77, P=0.001, respectively) compared with GG genotype. Compared with the haplotype TG, haplotype TA had a lower risk of hypertriglyceridemia and a higher risk of borderline hypercholesterolemia (OR=0.62, 95% CI: 0.44-0.88, P=0.002; OR=1.59, 95% CI: 1.10 2.31, P=0.008, respectively), and haplotype CA had a lower risk of hypercholesterolemia (OR=0.35, 95% CI: 0.18-0.68, P=0.002). In conclusion, we found that the genetic polymorphisms of CTSS were associated with metabolic disorders in a Chinese Han population, which would enrich the knowledge on genetic mechanisms of the pathogenesis of metabolic disorders. PMID- 23747399 TI - Inventory and general analysis of the ATP-binding cassette (ABC) gene superfamily in maize (Zea mays L.). AB - The metabolic functions of ATP-binding cassette (or ABC) proteins, one of the largest families of proteins presented in all organisms, have been investigated in many protozoan, animal and plant species. To facilitate more systematic and complicated studies on maize ABC proteins in the future, we present the first complete inventory of these proteins, including 130 open reading frames (ORFs), and provide general descriptions of their classifications, basic structures, typical functions, evolution track analysis and expression profiles. The 130 ORFs were assigned to eight subfamilies based on their structures and homological features. Five of these subfamilies consist of 109 proteins, containing transmembrane domains (TM) performing as transporters. The rest three subfamilies contain 21 soluble proteins involved in various functions other than molecular transport. A comparison of ABC proteins among nine selected species revealed either convergence or divergence in each of the ABC subfamilies. Generally, plant genomes contain far more ABC genes than animal genomes. The expression profiles and evolution track of each maize ABC gene were further investigated, the results of which could provide clues for analyzing their functions. Quantitative real time polymerase chain reaction experiments (PCR) were conducted to detect induced expression in select ABC genes under several common stresses. This investigation provides valuable information for future research on stress tolerance in plants and potential strategies for enhancing maize production under stressful conditions. PMID- 23747400 TI - Lack of association of EGR2 variants with bipolar disorder in Japanese population. AB - The early growth response gene 2 (EGR2) has been recently reported to be associated with bipolar disorder in the Korean population. However replication studies in independent cohorts of same and different ethnicities are essential for establishing the credibility of a genotype-phenotype association. With this notion, in the present study we have performed a replication study of the reported association of SNPs in EGR2 in a case-control study comprising of 867 unrelated Japanese bipolar disorder patients and 895 age-, sex- and ethnicity matched controls. Results showed no significant differences in allele and genotype frequencies of EGR2 SNPs between bipolar disorder patients and controls and also in a sex-stratified genetic analysis. The haplotype and meta-analyses also showed no significant association with bipolar disorder. In conclusion, this is the first replication study of the previously reported association of EGR2 with bipolar disorder in a larger sample set and the results showed that the EGR2 gene is unlikely to contribute to the susceptibility of bipolar disorder in a Japanese cohort. PMID- 23747401 TI - XRCC3 Thr241Met polymorphism and risk of acute myeloid leukemia in a Romanian population. AB - BACKGROUND: DNA repair systems have a critical role in maintaining the genome integrity and stability. DNA repair gene polymorphisms may influence the capacity to repair DNA damage, and thus lead to an increased cancer susceptibility. X-ray repair cross-complementing groups 3 (XRCC3), a DNA repair gene, may be involved in acute myeloid leukemia susceptibility. The objective of the current study was to investigate the association of Thr241Met polymorphism of XRCC3 gene with the risk of acute myeloid leukemia (AML). METHODS: This study included 78 AML patients and 121 healthy individuals without cancer. We used polymerase chain reaction-restriction fragment length polymorphism assay to determine XRCC3 genotypes. RESULTS: The XRCC3 variant genotype (Thr/Met+Met/Met) was more frequent in AML patients than in healthy controls (OR=2.76, 95% CI: 1.52-4.98, P=0.001). Our study revealed a statistically significant association between variant genotype (Thr/Met+Met/Met) and AML de novo compared to secondary AML (P=0.007). No significant associations were found between any genotype and age at diagnosis, number of white blood cells and subtype of AML. Overall survival of patients with Thr/Thr genotype was better than those of variant Thr/Met and Met/Met genotypes. CONCLUSIONS: Our findings indicate that the XRCC3 Thr241Met polymorphism may be a genetic risk factor for AML, particularly in male patients with de novo AML from the central part of Romania. PMID- 23747402 TI - Modes of acrosin functioning during fertilization. AB - Mammalian fertilization is a complex process that involves gamete recognition, penetration, and fusion. Biochemical studies that identified the role of acrosome components during sperm-ova interaction especially the zona pellucida (ZP) provided major advances in sperm cell biology. Acrosin (a typical serine protease) functions during fertilization in several significant ways which include: a) activation of acrosome components, b) secondary binding with the ZP, and c) hydrolysis of the ZP. However, studies using knockout (KO) acrosin deficient mice cast doubt on the traditional role of acrosin in fertilization. The KO acrosin-deficient mice exhibit normal fecundity except for delayed fertilization. Despite the doubt cast on the traditional role of acrosin by the KO acrosin-deficient mouse studies, acrosin still remains a major protease involved in multiple processes of fertilization. In this review, we assess the functional profile of acrosin and briefly summarize recent findings on proteases involved in fertilization. We propose a refined scheme for the functional role of acrosin in fertilization. We particularly emphasize the role of acrosin in acrosome exocytosis and activation of other acrosome components based on advanced technology like structural X-ray analysis. PMID- 23747403 TI - Association of glutathione S-transferase polymorphisms (GSTM1 and GSTT1) with primary open-angle glaucoma: an evidence-based meta-analysis. AB - Studies investigating the associations between glutathione S-transferase (GST) genetic polymorphisms and primary open-angle glaucoma (POAG) have reported controversial results. Therefore, a meta-analysis was performed to clarify the effects of GSTM1 and GSTT1 polymorphisms on POAG risk. Published literatures from PubMed, EMBASE, ISI Web of Science and CBM databases were retrieved. All studies evaluating the association between GSTM1/GSTT1 polymorphisms and POAG were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using fixed- or random-effects model. Eleven studies on GSTM1 (1339 cases and 1412 controls) and seven studies on GSTT1 (958 cases, 1003 controls) were included. Overall analysis showed that the association between GSTM1 and GSTT1 null genotype and POAG risk is not statistically significant. Subgroup analyses showed that the null genotype of GSTM1 increased the risk of POAG in Asians. In GSTM1-GSTT1 interaction analysis, individuals with dual null genotype were associated with a significantly increased risk of POAG when compared with the dual present genotype. In conclusion, the present meta-analysis suggested that GSTM1 null genotypes are associated with increased POAG risk in Asian populations but not in Caucasian and mixed populations. Dual null genotype of GSTM1/GSTT1 is associated with increased risk of POAG. Given the limited sample size, the finding on GST polymorphisms needs further investigation. PMID- 23747404 TI - Molecular cloning, expression and antioxidant characterisation of a typical thioredoxin gene (AccTrx2) in Apis cerana cerana. AB - Thioredoxins (Trxs) are a family of small, highly conserved and ubiquitous proteins that are involved in protecting organisms against toxic reactive oxygen species (ROS). In this study, a typical thioredoxin 2 gene was isolated from Apis cerana cerana, AccTrx2. The full-length cDNA sequence of AccTrx2 was composed of 407 bp containing a 318 bp open reading frame (ORF) that encodes a predicted protein of 105 amino acids, 11.974 kDa and an isoelectric point of 4.45. Expression profile of AccTrx2 as determined by a quantitative real-time PCR (qRT PCR) analysis was higher in brain than in other tissues, with its highest transcript occurring on the 15day post-emergence adult and upregulated by such abiotic stresses as 4 degrees C, 16 degrees C, 25 degrees C, H2O2, cyhalothrin, acaricide, paraquat, phoxime and mercury (HgCl2) treatments. However, AccTrx2 was slightly repressed when exposed to 42 degrees C treatment. Characterisation of the recombinant protein showed that the purified AccTrx2 had insulin disulfide reductase activity and could protect DNA from ROS damage. These results indicate that AccTrx2 functions as an antioxidant that plays an important role in response to oxidative stress. PMID- 23747405 TI - DNA methylation status of cyp17-II gene correlated with its expression pattern and reproductive endocrinology during ovarian development stages of Japanese flounder (Paralichthys olivaceus). AB - Cytochrome P450c17-II (cyp17-II, 17alpha-hydroxylase) is responsible for the production of steroid hormones during oocyte maturation in vertebrates. The comparative expression pattern of cyp17-II gene during the gonadal development stages will provide important insights into its function of gonadal development. In addition, epigenetic modification especially DNA methylation plays a vital role in regulation of gene expression. The adult female Japanese flounder at different ovarian development stage (from stages II to V) was obtained in this experiment. The expression of cyp17-II gene in the ovary of Japanese flounder during the gonadal development stages was measured by quantitative PCR. Reproductive traits included gonadosomatic index (GSI), plasma estradiol-17beta (E2) and testosterone (T) were also measured. Moreover, whole CpG dinucleotides methylation status of the two CpG rich regions in cyp17-II coding region was detected by bisulfate sequencing. In the ovary, the cyp17-II gene had the lowest mRNA expression at the early ovarian development stage, but then increased afterward. The variation trends of T and E2 level were consistent with the cyp17 II expression pattern in ovary. In contrast, the whole methylation levels of each CpG rich region (exon 4 and 6) in cyp17-II coding region were declined from stages II to IV, then increased at stage V. The methylation levels of whole CpG sites in each CpG rich region were inversely correlated with the values of ovarian cyp17-II gene expression, T and E2 level, and GSI. Based on the present study, we proposed that cyp17-II may regulate the level of steroid hormone, and then stimulate the oocyte growth and maturation. The cyp17-II gene transcriptional activity was possibly affected by the methylation level of CpG rich regions in coding region. These findings will help in the study of the molecular mechanism of fish reproduction and endocrine physiology. PMID- 23747406 TI - Aza-induced cardiomyocyte differentiation of P19 EC-cells by epigenetic co regulation and ERK signaling. AB - Stem cells in cell based therapy for cardiac injury is being potentially considered. However, genetic regulatory networks involved in cardiac differentiation are not clearly understood. Among stem cell differentiation models, mouse P19 embryonic carcinoma (EC) cells, are employed for studying (epi)genetic regulation of cardiomyocyte differentiation. Here, we comprehensively assessed cardiogenic differentiation potential of 5-azacytidine (Aza) on P19 EC-cells, associated gene expression profiles and the changes in DNA methylation, histone acetylation and activated-ERK signaling status during differentiation. Initial exposure of Aza to cultured EC-cells leads to an efficient (55%) differentiation to cardiomyocyte-rich embryoid bodies with a threefold (16.8%) increase in the cTnI+ cardiomyocytes. Expression levels of cardiac-specific gene markers i.e., Isl-1, BMP-2, GATA-4, and alpha-MHC were up regulated following Aza induction, accompanied by differential changes in their methylation status particularly that of BMP-2 and alpha-MHC. Additionally, increases in the levels of acetylated-H3 and pERK were observed during Aza induced cardiac differentiation. These studies demonstrate that Aza is a potent cardiac inducer when treated during the initial phase of differentiation of mouse P19 EC-cells and its effect is brought about epigenetically and co-ordinatedly by hypo-methylation and histone acetylation-mediated hyper-expression of cardiogenesis-associated genes and involving activation of ERK signaling. PMID- 23747407 TI - Genetic polymorphisms and protein structures in growth hormone, growth hormone receptor, ghrelin, insulin-like growth factor 1 and leptin in Mehraban sheep. AB - The somatotropic axis, the control system for growth hormone (GH) secretion and its endogenous factors involved in the regulation of metabolism and energy partitioning, has promising potentials for producing economically valuable traits in farm animals. Here we investigated single nucleotide polymorphisms (SNPs) of the genes of factors involved in the somatotropic axis for growth hormone (GH1), growth hormone receptor (GHR), ghrelin (GHRL), insulin-like growth factor 1 (IGF I) and leptin (LEP), using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing methods in 452 individual Mehraban sheep. A nonradioactive method to allow SSCP detection was used for genomic DNA and PCR amplification of six fragments: exons 4 and 5 of GH1; exon 10 of GH receptor (GHR); exon 1 of ghrelin (GHRL); exon 1 of insulin-like growth factor-I (IGF-I), and exon 3 of leptin (LEP). Polymorphisms were detected in five of the six PCR products. Two electrophoretic patterns were detected for GH1 exon 4. Five conformational patterns were detected for GH1 exon 5 and LEP exon 3, and three for IGF-I exon 1. Only GHR and GHRL were monomorphic. Changes in protein structures due to variable SNPs were also analyzed. The results suggest that Mehraban sheep, a major breed that is important for the animal industry in Middle East countries, has high genetic variability, opening interesting prospects for future selection programs and preservation strategies. PMID- 23747408 TI - The polymorphism in the promoter region of metallothionein 1 is associated with heat tolerance of scallop Argopecten irradians. AB - Metallothioneins (MTs), a superfamily of cysteine-rich proteins, perform multiple functions, such as maintaining homeostasis of essential metals, detoxification of toxic metals and scavenging of oxyradicals. In this study, the promoter region of a metallothionein (MT) gene from Bay scallop Argopecten irradians (designed as AiMT1) was cloned by the technique of genomic DNA walking, and the polymorphisms in this region were screened to find their association with susceptibility or tolerance to high temperature stress. One insert-deletion (ins-del) polymorphism and sixteen single nucleotide polymorphisms (SNPs) were identified in the amplified promoter region. Two SNPs, -375 T-C and -337 A-C, were selected to analyze their distribution in the two Bay scallop populations collected from southern and northern China coast, which were identified as heat resistant and heat susceptible stocks, respectively. There were three genotypes, T/T, T/C and C/C, at locus -375, and their frequencies were 25%, 61.1% and 13.9% in the heat susceptible stock, while 34.2%, 42.1% and 23.7% in the resistant stock, respectively. There was no significant difference in the frequency distribution of different genotypes between the two stocks (P>0.05). In contrast, at locus 337, three genotypes A/A, A/C and C/C were revealed with the frequencies of 11.6%, 34.9% and 53.5% in the heat susceptible stock, while 45.7%, 32.6% and 21.7% in the heat resistant stock, respectively. The frequency of C/C genotype in the heat susceptible stock was significantly higher (P<0.01) than that in the heat resistant stock, while the frequency of A/A in the heat resistant stock was significantly higher (P<0.01) than that in the heat susceptible stock. Furthermore, the expression of AiMT1 mRNA in scallops with C/C genotype was significantly higher than that with A/A genotype (P<0.05) after an acute heat treatment at 28 degrees C for 120min. These results implied that the polymorphism at locus -337 of AiMT1 was associated with the susceptibility/tolerance of scallops to heat stress, and the -337 A/A genotype could be a potential marker available in future selection of Bay scallop with heat tolerance. PMID- 23747409 TI - Resistin protection against endogenous Abeta neuronal cytotoxicity from mitochondrial pathway. AB - Neurotoxicity of amyloid beta (Abeta) plays an important role in Alzheimer's disease (AD) pathogenesis. In this study, we researched the potential protective effects of resistin against Abeta neurotoxicity in mouse Neuro2a (N2a) cells transfected with the Swedish amyloid precursor protein (Sw-APP) mutant and Presenilin exon 9 deletion mutant (N2a/D9), which overproduced Abeta with abnormal intracellular Abeta accumulation. The results show increased levels of ROS, NO, protein carbonyls, and 4HNE in N2a/D9 cells, which were attenuated by resistin treatment in a dose dependent manner. We also found that resistin could improve mitochondrial function in N2a/D9 cells through increasing the level of ATP and mitochondrial membrane potential. MTT and LDH assay indicated that N2a/D9 cells show increased vulnerability to H2O2-induced insult, which could be ameliorated by resistin. Mechanically, we found that resistin prevented apoptosis signals through reducing the ratio of Bax/Bcl2, the level of cleaved caspase-3, and attenuating cytochrome C release. Finally, the results demonstrated that resistin did not change the production of Abeta1-40 and Abeta1-42 in N2a/D9 cells, which suggests that the protective effects of resistin are independent of APP metabolism. This raises the possibility of novel AD therapies using resistin. PMID- 23747410 TI - Purinergic receptor- and gap junction-mediated intercellular signalling as a mechanism of heterosynaptic metaplasticity. AB - Synaptic plasticity is subject to activity-dependent long-term modification (metaplasticity). We have recently described a novel form of heterosynaptic metaplasticity in hippocampal CA1, whereby 'priming' activity at one set of synapses confers a metaplastic state that inhibits subsequent LTP both within and between dendritic compartments. Here, we investigated the roles of purinergic signalling and gap junctions in mediating this long-distance communication between synapses. We found that the heterosynaptic metaplasticity requires the hydrolysis of extracellular ATP to adenosine, and activation of adenosine A2, but not A1 receptors. The metaplasticity was also blocked by the non-selective gap junction blockers carbenoxolone and meclofenamic acid, and by a connexin43 specific mimetic peptide. These results indicate that an intercellular signalling cascade underlies the long-distance communication required for this form of metaplasticity. PMID- 23747411 TI - LC-MS based assay to measure intracellular compound levels in Mycobacterium smegmatis: linking compound levels to cellular potency. AB - Dihydrofolate reductase (DHFR) plays a central role in maintaining cellular pool of tetrahydrofolic acid, a cofactor necessary for DNA, RNA and protein synthesis. The clinical validation of DHFR as antibacterial target was established by the success of trimethoprim (TMP). DHFR is also an attractive target for identifying anti-tuberculosis molecules however, due to observed weak cellular potency, no DHFR inhibitors have been developed as drugs so far. TMP and its analogs have poor cellular potency on Mycobacterium tuberculosis and Mycobacterium smegmatis cells. We found a mutant strain of M. smegmatis, mc2155 to be sensitive to TMP whereas wild type strain was not inhibited by TMP. We utilized this system to probe if poor or lack of activity of TMP is a consequence of poor intracellular compound levels. An LC-MS based method was developed for measuring TMP and rifampicin (RIF) in M. smegmatis. Using the assay, equivalent RIF levels were observed in both strains however, TMP was detected only in mc2155 cells, hence proving a positive correlation between potency and compound levels. To the best of our knowledge this is the first time LC-MS method has been used to measure compound levels in mycobacterial cells. We propose it to be a valuable tool to understand the lack of potency or resistance mechanisms in antimycobacterial drug development. PMID- 23747412 TI - Identification and characterization of TLR7, TLR8a2, TLR8b1 and TLR8b2 genes in Atlantic salmon (Salmo salar). AB - Mammalian Toll-like receptor (TLR) 7 and 8 are responsible for recognizing viral single-stranded RNA (ssRNA) and are activated by anti-viral imidazoquinoline compounds, leading to a series of defensive mechanisms being launched to protect the host against viruses. In this study, we identified two TLR7 (with one probably a pseudogene) and three TLR8 genes, namely TLR8a2, TLR8b1 and TLR8b2 from Atlantic salmon (Salmo salar) whole-genome shotgun (WGS) contigs. Bioinformatics analysis showed that salmon TLR7 and TLR8a2 are closely related to the corresponding trout orthologs, however, salmon TLR8b1 and TLR8b2 share the highest amino acid sequence similarity to zebrafish TLR8b and formed a subfamily of the piscine TLR8 molecules in phylogenetic tree analysis. A conserved gene synteny was found with the salmon TLR7/8a members as seen in other vertebrate loci. Deduced domain organisation of salmon TLR7 and TLR8 molecules showed similar structural features, with equal numbers of leucine-rich repeats (LRRs) and insertion motifs. Individual TLR molecules were expressed in a similar pattern between parr and post-smolts, with a high expression level in immune tissues. Promoter analysis predicted several transcription factor binding sites in the TLR8a1/2 and TLR8b1 5' flanking regions, namely C/EBP, AP-1, STAT, NFkappaB, and IRF family, suggesting cytokine regulation of the genes. Hence, three recombinant cytokines, type I IFN, IFNgamma and IL-1beta were used to study the regulation of the salmon TLR gene expression levels in primary head kidney cells and the Salmon Head Kidney-1 (SHK-1) cell line. Salmon TLR7 and TLR8a1 gene expression was more sensitive to type I IFN and IFNgamma treatment in primary head kidney cells and SHK-1 cells respectively, with no significant up-regulation of TLR8a2 and TLR8b2 by any of the treatments. On the other hand, salmon TLR8a1 and TLR8b1 were most sensitive to IL-1beta treatment in SHK-1 cells and primary head kidney cells, respectively. TLR8b2 was undetectable in SHK-1 cells under these same conditions. PMID- 23747414 TI - Mechanism study of goldenseal-associated DNA damage. AB - Goldenseal has been used for the treatment of a wide variety of ailments including gastrointestinal disturbances, urinary tract disorders, and inflammation. The five major alkaloid constituents in goldenseal are berberine, palmatine, hydrastine, hydrastinine, and canadine. When goldenseal was evaluated by the National Toxicology Program (NTP) in the standard 2-year bioassay, goldenseal induced an increase in liver tumors in rats and mice; however, the mechanism of goldenseal-associated liver carcinogenicity remains unknown. In this study, the toxicity of the five goldenseal alkaloid constituents was characterized, and their toxic potencies were compared. As measured by the Comet assay and the expression of gamma-H2A.X, berberine, followed by palmatine, appeared to be the most potent DNA damage inducer in human hepatoma HepG2 cells. Berberine and palmatine suppressed the activities of both topoisomerase (Topo) I and II. In berberine-treated cells, DNA damage was shown to be directly associated with the inhibitory effect of Topo II, but not Topo I by silencing gene of Topo I or Topo II. In addition, DNA damage was also observed when cells were treated with commercially available goldenseal extracts and the extent of DNA damage was positively correlated to the berberine content. Our findings suggest that the Topo II inhibitory effect may contribute to berberine- and goldenseal-induced genotoxicity and tumorigenicity. PMID- 23747415 TI - Albumin reduces thrombogenic potential of single-walled carbon nanotubes. AB - Reduction of thrombogenicity of carbon nanotubes is an important prerequisite for their biomedical use. We assessed the thrombogenic activity of carboxylated single-walled carbon nanotubes (c-SWCNTs) and covalently PEGylated c-SWNCTs (PEG SWCNTs) by testing the clotting time of platelet poor plasma and platelet aggregation in whole blood samples, and evaluated the impact of human serum albumin on thrombogenicity of carbon nanotubes. Both types of SWCNTs exhibited considerable thrombogenic activity. SWCNTs accelerated plasma clotting, with a lesser effect seen for PEG-SWCNTs. Treatment of SWCNTs with albumin did not affect the SWCNT-induced shortening of clotting time. In whole blood, no discernible differences in the effect of c-SWCNTs and PEG-SWCNTs on platelets were observed. Upon addition of SWCNTs to blood, dose- and time-dependent formation of agglomerates of nanotubes and platelets was demonstrated. Pretreatment of SWCNTs with albumin reduced the platelet aggregation: the number of single platelets increased, and the size of platelet-SWCNT agglomerates decreased dramatically. Hence, addition of albumin may serve to attenuate the adverse, thrombogenic effect of CNTs. PMID- 23747416 TI - Community-acquired pneumonia during the first post-pandemic influenza season: a prospective, multicentre cohort study. AB - OBJECTIVES: To determine the aetiology, clinical features and prognosis of CAP during the first post-pandemic influenza season. We also assessed the factors associated with severe disease and tested the ability of a scoring system for identifying influenza A (H1N1)pdm09-related pneumonia. METHODS: Prospective cohort study carried out at 10 tertiary hospitals of Spain. All adults hospitalised with CAP from December 01, 2010 to March 31, 2011 were analysed. RESULTS: A total of 747 adults with CAP required hospitalisation. The aetiology was determined in 315 (42.2%) patients, in whom 154 (21.9%) were due to bacteria, 125 (16.7%) were due to viruses and 36 (4.8%) were mixed (due to viruses and bacteria). The most frequently isolated bacteria were Streptococccus pneumoniae. Among patients with viral pneumonia, the most common organism identified were influenza A (H1N1)pdm09. Independent factors associated with severe disease were impaired consciousness, septic shock, tachypnea, hyponatremia, hypoxemia, influenza B, and influenza A (H1N1)pdm09. The scoring system evaluated did not differentiate reliably between patients with influenza A (H1N1)pdm09-related pneumonia and those with other aetiologies. CONCLUSIONS: The frequency of bacterial and viral pneumonia during the first post-pandemic influenza season was similar. The main identified virus was influenza A (H1N1)pdm09, which was associated with severe disease. Although certain presenting clinical features may allow recognition of influenza A (H1N1)pdm09-related pneumonia, it is difficult to express them in a reliable scoring system. PMID- 23747417 TI - Endocytic pathway is indicated for white spot syndrome virus (WSSV) entry in shrimp. AB - The white spot syndrome virus (WSSV) has had a serious economic impact on the global shrimp aquaculture industry in the past two decades. Although research has clarified a lot about its genome and structure, the mechanism of how WSSV enters a cell is still unclear. In this study to determine this mechanism, primary cultured hemocytes were used as an experimental model to observe the process of WSSV entry because the stable shrimp cell lines for WSSV infection are lacking. After labeling virions and endosomes with fluorescent dyes followed by observation with a confocal microscope, the results show that the WSSV colocalizes with early endosomes. Hemocytes are further treated with different endocytic inhibitors, methyl-beta-cyclodextrin (MbetaCD) and chlorpromazine (CPZ). WSSV still can be detected in the hemocytes treated with CPZ, but not in the hemocytes treated with MbetaCD. Thus, we conclude that WSSV adopts the caveolae-mediated endocytosis to enter the shrimp cell. PMID- 23747418 TI - Activation of type 2 cannabinoid receptors (CB2R) promotes fatty acid oxidation through the SIRT1/PGC-1alpha pathway. AB - Abnormal fatty acid oxidation has been associated with obesity and type 2 diabetes. At the transcriptional level, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) has been reported to strongly increase the ability of hormone nuclear receptors PPARalpha and ERRalpha to drive transcription of fatty acid oxidation enzymes. In this study, we report that a specific agonist of the type 2 cannabinoid receptor (CB2R) can lead to fatty acid oxidation through the PGC-1alpha pathway. We have found that CB2R is expressed in differentiated C2C12 myotubes, and that use of the specific agonist trans caryophyllene (TC) stimulates sirtuin 1 (SIRT1) deacetylase activity by increasing the phosphorylation of cAMP response element-binding protein (CREB), thus leading to increased levels of PGC-1alpha deacetylation. This use of TC treatment increases the expression of genes linked to the fatty acid oxidation pathway in a SIRT1/PGC-1alpha-dependent mechanism and also drastically accelerates the rate of complete fatty acid oxidation in C2C12 myotubes, neither of which occur when CB2R mRNA is knocked down using siRNA. These results reveal that activation of CB2R by a selective agonist promotes lipid oxidation through a signaling/transcriptional pathway. Our findings imply that pharmacological manipulation of CB2R may provide therapeutic possibilities to treat metabolic diseases associated with lipid dysregulation. PMID- 23747419 TI - Influenza virus utilizes N-linked sialoglycans as receptors in A549 cells. AB - Influenza viruses (IFVs) recognize sialoglycans expressed on the host cell surface. To understand the mechanisms underlying tissue and host tropisms of IFV, it is essential to elucidate the molecular interaction of the virus with the host sialoglycan receptor. We established and applied a new monoclonal antibody, clone HYB4, which specifically recognizes the Neu5Acalpha2-3 determinant at the non reducing terminal Gal residue of both glycoproteins and gangliosides to investigate the biochemical properties of IFV receptors in A549 cells. HYB4 significantly blocked virus binding to A549 cells in a dose-dependent manner. Virus overlay assay indicated that several glycoproteins with molecular masses of 80-120 kDa of A549 cells were commonly recognized by different subtypes of IFV, such as H1N1 and H3N2. H1N1 virus binding to the glycoproteins was diminished by pretreatment with either sialidase or PNGase F. On TLC-immunostaining experiments with HYB4, GM3 ganglioside was only detected in A549 cells. Interestingly, this antibody bound to GM3 gangliosides on TLC and plastic surfaces, but not on lipid bilayers. In comparison with the recognition of Maackia amurensis lectins, HYB4 exclusively recognized Neu5Acalpha2-3Galbeta1-4GlcNAc residues expressed on glycoproteins. These results strongly suggest that N-linked sialoglycans with the Neu5Acalpha2-3 determinant on several glycoproteins are receptors for influenza virus in A549 cells. PMID- 23747420 TI - Class specific peptide inhibitors for secretory phospholipases A2. AB - Phospholipases A2 (PLA2) catalyze the hydrolytic cleavage of free fatty acids from the sn-2 OH-moiety of glycerophospholipids. These enzymes have a number of functions, from digestion to signaling and toxicity of several venoms. They have also been implicated in inflammation and are connected to diverse diseases, such as cancer, ischemia, atherosclerosis, and schizophrenia. Accordingly, there is a keen interest to develop selective inhibitors for therapeutic use. We recently proposed a novel mechanism for the control of PLA2 activity with highly active protofibrils of PLA2 existing transiently before conversion to inactive amyloid fibrils [19]. In keeping with the above mechanism several algorithms identified (85)KMYFNLI(91) and (17)AALSYGFYG(25) in bee venom (bv) and human lacrimal fluid (Lf) PLA2, respectively, as a regions potentially forming amyloid type aggregates. Interestingly, in keeping with the proposed role of these sequences in the control of the activity of these enzymes, preincubation of 2nM bvPLA2 with (85)KMYFNLI(91) caused complete inhibition of PLA2 activity while the scrambled control peptide YNFLIMK had no effect. Approximately 36% attenuation of the hydrolytic activity of LfPLA2 present in human lacrimal fluid was observed in the presence of 80nM (17)AALSYGFYG(25). PMID- 23747421 TI - Integrated analysis of genomics and proteomics reveals that CKIP-1 is a novel macrophage migration regulator. AB - Casein kinase-2 interacting protein-1 (CKIP-1) has been identified to play an important role in cell morphology, differentiation and apoptosis. However, the role of CKIP-1 in other cellular processes is still unknown. Here we investigated transcriptome profiles of WT and CKIP-1-deficient mouse embryonic fibroblasts (MEFs), and found that innate immunity and cell migration related pathways were significantly correlated with CKIP-1 expression. As macrophage is a key cell type in innate immunity, we then used murine macrophage RAW264.7 cells to discover CKIP-1 interacting proteins by immunoprecipitation/mass spectrometry (IP/MS). Analysis of these proteins revealed migration related pathways were enriched. Further experiments indicated that knockdown of CKIP-1 in RAW264.7 cells resulted in impaired cell migration. Our study suggests that CKIP-1 is a novel regulator of macrophage migration. PMID- 23747422 TI - Cytoplasmic proteasomes are not indispensable for cell growth in Saccharomyces cerevisiae. AB - The 26S proteasome is an essential protease complex responsible for the degradation of ubiquitinated proteins in eukaryotic cells. In rapidly proliferating yeast cells, proteasomes are mainly localized in the nucleus, but the biological significance of the proteasome localization is still unclear. In this study, we investigated the relationship between the proteasome localization and the functions by the anchor-away technique, a ligand-dependent sequestration of a target protein into specific compartment(s). Anchoring of the proteasome to the plasma membrane or the ribosome resulted in conditional depletion of the nuclear proteasomes, whereas anchoring to histone resulted in the proteasome sequestration into the nucleus. We observed that the accumulation of ubiquitinated proteins in all the proteasome-targeted cells, suggesting that both the nuclear and cytoplasmic proteasomes have proteolytic functions and that the ubiquitinated proteins are produced and degraded in each compartment. Consistent with previous studies, the nuclear proteasome-depleted cells exhibited a lethal phenotype. In contrast, the nuclear sequestration of the proteasome resulted only in a mild growth defect, suggesting that the cytoplasmic proteasomes are not basically indispensable for cell growth in rapidly growing yeast cells. PMID- 23747423 TI - Non-toxic conformer of amyloid beta may suppress amyloid beta-induced toxicity in rat primary neurons: implications for a novel therapeutic strategy for Alzheimer's disease. AB - The 42-mer amyloid beta-protein (Abeta42) oligomers cause neurotoxicity and cognitive impairment in Alzheimer's disease (AD). We previously identified the toxic conformer of Abeta42 with a turn at positions 22-23 ("toxic" turn) to form oligomers and to induce toxicity in rat primary neurons, along with the non-toxic conformer with a turn at positions 25-26. G25P-Abeta42 and E22V-Abeta42 are non toxic mutants that disfavor the "toxic" turn. Here we hypothesize that these non toxic mutants of Abeta42 could suppress Abeta42-induced neurotoxicity, and examined their effects on the neurotoxicity, aggregation, and levels of the toxic conformer, which was evaluated by dot blotting using a monoclonal antibody (11A1) against the toxic conformer. G25P-Abeta42 and E22V-Abeta42 suppressed the neurotoxicity and aggregation of Abeta42 as well as the formation of the toxic conformer. The neurotoxicity induced by Abeta42 was also significantly reduced by the treatment of 11A1, but not of Abeta-sequence specific antibodies (6E10 and 4G8). Since recent studies indicate that Abeta oligomers contain parallel beta sheet, the present results suggest that the non-toxic mutants of Abeta42 without the "toxic" turn could prevent the propagation process of the toxic conformer of Abeta42 resulting in suppression of the formation of the toxic oligomers. This could be a promising strategy for AD therapeutics. PMID- 23747424 TI - Determination of deltonin in rat plasma by using HPLC-MS/MS and the application of this method in pharmacokinetic studies. AB - Deltonin is a naturally occurring spirostanol glycoside from Dioscorea zingiberensis C.H. Wright, which is used in traditional Chinese medicine. It exerts strong cytotoxic effect on C26 cells, inhibits C26 derived-tumor growth, and prolongs the survival of tumor-bearing mice after its oral administration, indicating its potential for use as an anti-tumor drug. To investigate the pharmacokinetic profiles of deltonin, a rapid, sensitive, and simplified high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) assay was developed and validated for the determination of deltonin in rat plasma. After acetonitrile-mediated plasma protein precipitation, chromatographic separation of deltonin was achieved using a reversed phase Hypersil Gold column (150mm*2.1mm, 5MUm), with gradient elution using 0.1% formic acid and acetonitrile. Thereafter, deltonin was quantified using MS/MS with electrospray ionization (ESI) in positive multiple reaction monitoring (MRM) mode. The flow rate of the mobile phase was 200MUL/min, and the retention time was 9.03min for deltonin and 6.31min for the internal standard (IS: 20(S)-ginsenoside Rb1). The linear range of the calibration curve was 2-5000ng/mL (r(2)>0.99), and the limit of detection (LOD) was 0.46ng/mL. The intra- and inter-day accuracies ranged from -2.8% to 11.1% and precisions (RSD) were within 13.1%. Deltonin was found to be stable under short term temperature conditions, post-preparative temperature conditions, and after 3 freeze-thaw cycles conditions. The validated method was successfully applied to a pharmacokinetic study in rats after oral administration of deltonin (50 and 100mg/kg). The pharmacokinetics is characterized by high apparent clearance (CL/F) and apparent volume of distribution (Vd/F). PMID- 23747425 TI - Development and validation of an ultra high performance liquid chromatography tandem mass spectrometry method for determination of 10 cephalosporins and desacetylcefapirin in milk. AB - A simple, sensitive and reliable analytical method was developed for the simultaneous determination of 10 cephalosporins and desacetylcefapirin in bovine milk by ultra high performance liquid chromatography-positive electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). Samples were directly purified through HLB cartridge after dilution with 50mM phosphate buffer solution (pH 8.5). Then the eluate was dried under nitrogen and the residue was redissolved in mobile phase. Samples were analyzed by LC-MS/MS on an Acquity UPLC BEH Shield RP18 column with gradient elution. The samples were quantified using ceftiofur-D3 as internal standard. The proposed method was validated according to the European Commission Decision 2002/657/EC. The CCalpha values were 111, 0.04, 140, 55, 55, 67, 23, 23, 68, 0.10 and 113MUg/kg for cefalexin, cefradine, cefacetrile, cefazolin, cefoperazone, cefapirin, cefalonium, cefquinome, desacetylcefapirin, cefotaxime and ceftiofur, respectively. The mean recoveries, repeatability (expressed as coefficient of variation, CVr), and reproducibility (CVR) varied from 94.6% to 117.1%, from 5.6% to 13.6% (CVr), and from 5.9% to 27.9% (CVR), respectively. The method is demonstrated to be suitable for the determination of 10 cephalosporins and desacetylcefapirin in bovine milk. The total time required for the analysis of one sample, including sample preparation, was about 40min. PMID- 23747426 TI - EEG amplitude spectra before near threshold visual presentations differentially predict detection/omission and short-long reaction time outcomes. AB - Performance in simple stimulus detection manifests as both probability of detection and speed of signaling detected stimuli. These two dimensions of performance across trials were examined with respect to brain states just prior to stimulus delivery, using near threshold stimuli targeting the magnocellular or the parvocellular visual streams in an attempt to isolate differential perceptual preparation. The EEG amplitude of 12 university students was analyzed in spectral bands from 2 to 50 Hz at 9 bilateral channel pairs in a window covering -450 ms to +50 ms relative to stimulus onset. A hierarchical statistical procedure was applied to control false positive results. EEG power in the 2, 4, 8 and 10 Hz bands was found significantly lower at the F7-F8 channel pair both before detected compared to omitted stimuli and before the fastest compared to slowest reaction time quartiles, with no stimulus type effect. In addition, the 22 and 24 Hz band activity was lower prior to better performance frontally (F3-F4, F7-F8) in reaction time but not in detection, while it was larger centro-parietally (CP1 CP2, P3-P4) in detection but not in reaction times. Spectral analysis thus shows stimulus detection and response speed to depend partly on common and partly on distinct pre-stimulus brain states. PMID- 23747427 TI - Impairment of reproductive function in a male rat model of non-alcoholic fatty liver disease and beneficial effect of N-3 fatty acid supplementation. AB - Non-alcoholic fatty liver disease (NAFLD) is closely associated with reduced levels of testosterone, which may affect fertility. Herein, we investigated whether NAFLD impairs the reproductive function of male rats. Male Sprague-Dawley rats were fed a high fat diet (HFD) until they developed NAFLD. N-3 polyunsaturated fatty acid (PUFA) was then given for 4 weeks to prevent hepatic steatosis. Testes weight and serum and testicular testosterone were significantly lower in rats with NAFLD compared with healthy controls. Testicular pathological changes in NAFLD rats included markedly reduced sperm number and motility, and the number of apoptotic spermatogenic cells was higher, which was consistent with a reduction in the number of tetraploid cells. Breeding experiments indicated that paternal NAFLD affected neither the sperm morphology nor the development of fetuses and offspring, but did prolong the days required for insemination. However, administration of N-3 PUFA alleviated the impairment of reproductive function. These results suggest that NAFLD impairs reproductive function in male rats by decreasing testicular testosterone synthesis, and N-3 PUFA treatment may have a beneficial therapeutic effect. PMID- 23747428 TI - Vibrational and spectroscopic investigation on the structure of 5H dibenzo[b,f]azipine-5-carboxamide. AB - Fourier transform Raman and Fourier transform infrared spectra of 5H dibenzo[b,f]azepine-5-carboxamide were recorded in the regions 4000-100 cm(-1) and 4000-400 cm(-1) respectively in the solid phase. 5H-dibenzo[b,f]azepine-5 carboxamide is typically used for the treatment of seizure disorders and neuropathic pain. The equilibrium geometry harmonic vibrational frequencies, infrared intensities and Raman scattering activities were calculated by density functional B3LYP/6-31G(d,p) method. A detailed interpretation of the vibrational spectra of this compound has been made on the basis of the calculated Potential energy distribution (PED). The thermodynamic functions of the title compound were also performed at the above methods and basis set. A detailed interpretation of the infrared and Raman spectra of 5H-dibenzo[b,f]azepine-5-carboxamide is reported. Stability of the molecule arising from hyper conjugative interactions, charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The linear polarizability (alpha) and the first order hyperpolarizability (beta) values of the investigated molecule have been computed using DFT quantum mechanical calculations. The calculated HOMO and LUMO energies show that charge transfer occurs within the molecule. The observed and calculated wave numbers are found to be in good agreement. The experimental spectra also coincide satisfactorily with those of theoretically constructed spectra. PMID- 23747429 TI - Inhibition in binding between fullerene and a bisporphyrin in presence of silver nanoparticles in solution: UV-Vis, DLS, SEM and TEM studies. AB - The present paper reports the role of silver nanoparticles, i.e., AgNp (having diameter ~5-15 nm), in non-covalent interaction between fullerenes (C60 and C70) and a designed bisporphyrin (1) in toluene. UV-Vis measurement reveals reduction in binding constant (K) values for both C60-1 (K(C60-1)=18,800 dm(3) mol(-1)) and C70-1 systems (K(C70-1)=27,300 dm(3) mol(-1)) in presence of AgNp, i.e., K(C60-1 AgNp 0=3700 dm(3) mol(-1) and K(C70-1-AgNp 0=1600 dm(3) mol(-1) for C(60)-1-AgNp and C(70)-1-AgNp nanocomposite, respectively. Dynamic light scattering study reveals considerable increase in the particle size of C(70)-1-AgNp nanocomposite, i.e., ~39 nm, compared to C(60)-1-AgNp, e.g., ~22 nm. Scanning electron microscope measurement reveals that the well arranged and composed structure of uncomplexed 1 is perturbed very much in presence of both C60 and C70, and it ultimately results into formation of nanoaggregate in case of C(70)-1-AgNp system. Transmission electron microscope study envisages formation of fibrous structure in presence of C60 and C70. PMID- 23747430 TI - Growth, thermal, dielectric and mechanical properties of L-phenylalanine-benzoic acid: a nonlinear optical single crystal. AB - An efficient amino acid family nonlinear optical single crystal L-phenylalanine benzoic acid (LPB) was conveniently grown by slow evaporation technique at room temperature. The crystal system and the lattice parameters were analyzed by single crystal X-ray diffraction studies. The grown crystal has excellent transmission in the entire visible region and its lower cut-off wavelength was found to be 248 nm. The SHG efficiency of the grown crystal was found to be 1.6 times higher than that of KDP crystal. The Laser damage threshold value of LPB has been found to be 6.5 GW/cm(2). The sample was thermally stable up to 134 degrees C. Microhardness, dielectric and AC/DC conductivity measurements were made along (001) plane and reported for the first time. Microhardness studies revealed that the sample belongs to hard nature. Frequency dependent dielectric constant was measured for different temperatures and found maximum dielectric constant of 14 for 363 K. Photoconductivity studies of LPB divulged its negative photoconducting nature. PMID- 23747431 TI - Vibrational spectroscopy of the mineral meyerhofferite CaB3O3(OH)5.H2O--an assessment of the molecular structure. AB - Meyerhofferite is a calcium hydrated borate mineral with ideal formula: CaB3O3(OH)5.H2O and occurs as white complex acicular to crude crystals with length up to ~4 cm, in fibrous divergent, radiating aggregates or reticulated and is often found in sedimentary or lake-bed borate deposits. The Raman spectrum of meyerhofferite is dominated by intense sharp band at 880 cm(-1) assigned to the symmetric stretching mode of trigonal boron. Broad Raman bands at 1046, 1110, 1135 and 1201 cm(-1) are attributed to BOH in-plane bending modes. Raman bands in the 900-1000 cm(-1) spectral region are assigned to the antisymmetric stretching of tetrahedral boron. Distinct OH stretching Raman bands are observed at 3400, 3483 and 3608 cm(-1). The mineral meyerhofferite has a distinct Raman spectrum which is different from the spectrum of other borate minerals, making Raman spectroscopy a very useful tool for the detection of meyerhofferite in sedimentary and lake bed deposits. PMID- 23747432 TI - Chemiluminescence determination of trimetazidine via inducing the aggregation of gold nanoparticles. AB - A simple, rapid and sensitive chemiluminescence (CL) method combined with flow injection analysis was developed for the determination of trimetazidine. Trimetazidine was found to significantly increase the CL signal arising from N bromosuccinimide-luminol reaction in the presence of gold nanoparticles. The enhanced CL intensity was proportional to trimetazidine concentration in the range of 0.01-5.0 MUg/mL, with a limit of detection (3 sb) of 6.7 ng/mL. The relative standard deviation was 2.8% for 11 repetitive measurements of 0.1 MUg/mL trimetazidine solution. The practicality of the method was evaluated by determining trimetazidine in pharmaceutical formulations and in spiked human serum samples. Moreover, the possible CL reaction mechanism was also discussed. PMID- 23747433 TI - Determination of structural and vibrational spectroscopic features of neutral and anion forms of dinicotinic acid by using NMR, infrared and Raman experimental methods combined with DFT and HF. AB - In this study; the experimental (NMR, infrared and Raman) and theoretical (HF and DFT) analysis of dinicotinic acid were presented. (1)H and (13)C NMR spectra were recorded in DMSO solution and chemical shifts were calculated by using the gauge invariant atomic orbital (GIAO) method. The vibrational spectra of dinicotinic acid were recorded by FT-Raman and FT-IR spectra in the range of 4000-10 cm(-1) and 4000-400 cm(-1), respectively. To determine the most stable neutral conformer of molecule, the selected torsion angle was changed every 10 degrees and molecular energy profile was calculated from 0 degrees to 360 degrees . The geometrical parameters and energies were obtained for all conformers form from density functional theory (DFT/B3LYP) and HF with 6-311++G(d,p) basis set calculations. However, the results of the most stable neutral and two anion forms (anion(-1) and anion(-2) forms) of dinicotinic acid are reported here. The complete assignments were performed on the basis of the total energy distribution (TED) of the vibrational wavenumbers, calculated with scaled quantum mechanics (SQM) method and PQS program. PMID- 23747434 TI - Effectiveness of burr holes for indirect revascularization in patients with moyamoya disease-a review of the literature. AB - OBJECTIVE: Moyamoya disease (MMD) has inspired the development and refinement of numerous surgical techniques to induce revascularization in hypoperfused territories. Over the last 3 decades, the use of burr hole surgery has progressively gained popularity. Used either in combination with another direct or indirect procedure or as the sole method for revascularization, burr hole surgery can be tailored to each patient's specific needs. We reviewed the conceptual progress, the technical evolution, and the clinical and radiological data following burr hole surgery. METHODS: Pubmed and Medline databases were searched for publications from 1970 to 2012 relating to the use of burr holes in the surgical management of MMD. The reference sections of each article were reviewed, and pertinent articles were identified. RESULTS: A review of case reports and case series using burr hole surgery for MMD testifies to the progressive refinement in the decision process and key technical aspects of this procedure. Favorable clinical and angiographic results have been documented in the pediatric and adult MMD population after burr holes, used either in combination with direct or indirect revascularization techniques, or more recently alone in the setting of multiple burr holes. The superficial temporal artery and middle meningeal artery have both been found to contribute to revascularization via burr holes. CONCLUSIONS: Burr hole surgery is an important and versatile tool in the armamentarium of surgeons treating children and adults with MMD, allowing tailoring of the revascularization. Further studies should help to determine factors that may help predict optimal revascularization from this surgical technique. PMID- 23747435 TI - Enhanced transdermal drug delivery of zaltoprofen using a novel formulation. AB - Zaltoprofen is a non-steroidal anti-inflammatory drug (NSAID) belonging to the propionic acid class. It has strong inhibitory effects on acute and chronic inflammation. Although zaltoprofen is well tolerated orally compared to other NSAIDs, it has to be administered in three to four doses per day and was associated with ulcerogenicity, bellyache and indigestion. This makes administration of zaltoprofen unsuitable for patients with gastric ulcer and is also associated with drug interactions. Therefore, it is important to develop an alternative dosage form which is easier to administer and avoids first-pass metabolism. The transdermal route meets all the above advantages. In this study, zaltoprofen gels were prepared using carbomer with mixture solution of polyethylene glycol (PEG) 400, Tween 80 and (2-hydroxypropyl)-beta-cyclodextrin (HPCD) (called as T2), subsequently oleic acid as a penetration enhancer was added. Zaltoprofen gel containing T2 and oleic acid could promote the percutaneous absorption of zaltoprofen and increase AUC by 183% compared to zaltoprofen gel without T2 and oleic acid. Also, there was a finding zaltoprofen gel containing T2 and oleic acid did not cause dermal irritations in an experimental animal. PMID- 23747436 TI - Effect of particle size on the biodistribution of lipid nanocapsules: comparison between nuclear and fluorescence imaging and counting. AB - In vivo biodistribution of nanoparticles depends on several physicochemical parameters such as size. After intravenous injection of 25, 50 and 100 nm lipid nanocapsules (LNC) in nude mice bearing HEK293(beta3) tumour xenografts, biodistribution was evaluated by gamma-scintigraphy and by gamma-counting. The small LNC 25 nm disappeared faster than the larger LNC 50 and 100 nm from the blood circulation due to faster elimination and wider tissue distribution. At 24h, biodistribution profiles of all these LNC were similar. Low LNC quantities were found in this weak EPR (enhanced permeability and retention) tumour regardless the particle size. Co-injected 50 nm fluorescent DiD-LNC and (99m)Tc LNC allowed direct comparison of biodistribution as evaluated by the two methods. Optical imaging underestimated LNC quantity especially in dark-colored organs that were observed to capture extensive quantities of the particles by gamma counting (i.e. liver, spleen, and kidney). PMID- 23747438 TI - Nutritional mode influences lipid accumulation in microalgae with the function of carbon sequestration and nutrient supplementation. AB - Effect of nutritional mode viz., photoautotrophic, photoheterotrophic and photomixotrophic on the biomass growth and lipid productivity of microalgae was studied. Experiments were designed and operated in biphasic mode i.e., growth phase (GP) followed by stress induced starvation phase (SP). Nutritional mode documented marked influence on biomass growth and subsequent lipid productivity. Mixotrophic mode of operation showed higher biomass growth (4.45 mg/ml) during growth phase while higher lipid productivity was observed with nitrogen deprived autotrophic mode (28.2%) followed by heterotrophic (26.1%) and mixotrophic (19.6%) operations. Relative increments in lipid productivities were noticed in SP operation from GP in mixotrophic operation (2.45) followed by autotrophic (2.2) and heterotrophic (2.14) mode of operations. Higher concentrations of chlorophyll b and presence of lipid accumulating species supported the lipid biosynthesis. Algal fatty acid composition varied with function of nutritional modes and depicted eighteen types of saturated (SFA) and unsaturated fatty acids (USFA) with wide fuel and food characteristics. PMID- 23747439 TI - Analysing biomass torrefaction supply chain costs. AB - The objective of the present work was to develop a techno-economic system model to evaluate how logistics and production parameters affect the torrefaction supply chain costs under Swedish conditions. The model consists of four sub models: (1) supply system, (2) a complete energy and mass balance of drying, torrefaction and densification, (3) investment and operating costs of a green field, stand-alone torrefaction pellet plant, and (4) distribution system to the gate of an end user. The results show that the torrefaction supply chain reaps significant economies of scale up to a plant size of about 150-200 kiloton dry substance per year (ktonDS/year), for which the total supply chain costs accounts to 31.8 euro per megawatt hour based on lower heating value (?/MWhLHV). Important parameters affecting total cost are amount of available biomass, biomass premium, logistics equipment, biomass moisture content, drying technology, torrefaction mass yield and torrefaction plant capital expenditures (CAPEX). PMID- 23747440 TI - Nitritation-denitritation in landfill leachate with glycerine as a carbon source. AB - The effects of limited oxygen concentration (0.7 mg O2/L) in the aeration phase of the SBR cycle and glycerine as an additional carbon source on the effectiveness of nitritation-denitritation and sludge production during municipal landfill leachate treatment were examined. As carbon sources, sodium acetate (Ac) and sodium acetate (Ac) with glycerine (Gly) in the proportions of 3:1 (v/v) and 1:1 (v/v) were added. Low dissolved oxygen concentration inhibited the second stage of nitrification and nitrites were the main final products. Nitritation effectiveness was ca. 98-99%. Denitritation efficiency was relatively low (61%) in the reactor fed with Ac, which may be linked with high sludge production (Yobs - 0.6 mgVSS/mg COD). Glycerine addition (Ac:Gly 1:1, v/v) caused an increase in process efficiency to 75.6% with a concurrent significant decrease in biomass production (Yobs - 0.46 mg VSS/mg COD). PMID- 23747441 TI - Effect of temperature and temperature shock on the stability of continuous cellulosic-hydrogen fermentation. AB - Three continuous stirred tank reactors (CSTR) were operated under mesophilic (37 +/- 1 degrees C), thermophilic (55 +/- 1 degrees C) and hyper-thermophilic (80 +/ 1 degrees C) temperatures for 164 days to investigate the effect of temperature and temperature shock on the cellulosic-dark hydrogen fermentation by mixed microflora. During steady state condition, the sudden decreases in the fermentation temperature occurred twice in each condition for 24h. The results show that the 55 +/- 1 and 80 +/- 1 degrees C presented stable hydrogen yields of 12.28 and 9.72 mmol/g cellulose, respectively. However, the 37 +/- 1 degrees C presented low hydrogen yield of 3.56 mmol/g cellulose and methane yield of 5.4 mmol/g cellulose. The reactor performance under 55 +/- 1 or 80 +/- 1 degrees C appeared to be more resilient to the sudden decreases in the fermentation temperature than 37 +/- 1 degrees C. The experimental analysis results indicated that the changing in soluble by-products could explain the effect of temperature and temperature shock, and the thermophilic temperature is expected having a better economic performance for cellulosic-hydrogen fermentation. PMID- 23747442 TI - Dilute sulfuric acid pretreatment of corn stover for enzymatic hydrolysis and efficient ethanol production by recombinant Escherichia coli FBR5 without detoxification. AB - A pretreatment strategy for dilute H2SO4 pretreatment of corn stover was developed for the purpose of reducing the generation of inhibitory substances during pretreatment so that a detoxification step is not required prior to fermentation while maximizing sugar yield. The optimal conditions for pretreatment of corn stover (10%, w/v) were: 0.75% H2SO4, 160 degrees C, and 0-5 min holding time. The conditions were chosen based on maximum glucose release after enzymatic hydrolysis, minimum loss of pentose sugars and minimum formation of sugar degradation products such as furfural and hydroxymethyl furfural. The pretreated corn stover after enzymatic saccharification generated 63.2 +/- 2.2 and 63.7 +/- 2.3 g total sugars per L at 0 and 5 min holding time, respectively. Furfural production was 0.45 +/- 0.1 and 0.87 +/- 0.4 g/L, respectively. The recombinant Escherichia coli strain FBR5 efficiently fermented non-detoxified corn stover hydrolyzate if the furfural content is <0.5 g/L. PMID- 23747443 TI - Nitrile, amide and temperature effects on amidase-kinetics during acrylonitrile bioconversion by nitrile-hydratase/amidase in situ cascade system. AB - In this study the amidase kinetics of an in situ NHase/AMase cascade system was explored as a function of operational parameters such as temperature, substrate concentration and product formation. The results indicated that controlling amidase inactivation, during acrylonitrile bioconversion, makes it possible to recover the intermediate product of the two-step reaction in almost a pure form, without using purified enzyme. It has been demonstrated, in long-term experiments performed in continuous stirred UF-membrane bioreactors, that amidase is kinetically controlled by its proper substrate, depending on the structure, and by acrylonitrile. Using acrylamide, AMase-stability is temperature dependent (5 degrees C, kd=0.008 h(-1); 30 degrees C kd=0.023 h(-1)). Using benzamide, amidase is thermally stable up to 50 degrees C and no substrate inhibition/inactivation occurs. With acrylonitrile, AMase-activity and -stability remain unchanged at concentrations <200 mM but at 200 mM, 35 degrees C, after 70 h process, 90% irreversible inactivation occurs as no AMase-activity on benzamide revives. PMID- 23747444 TI - Industrial wastes as a promising renewable source for production of microbial lipid and direct transesterification of the lipid into biodiesel. AB - Two strategies of converting industrial wastes to microbial lipid and direct transesterification of obtained lipid into biodiesel were attempted. Several oleaginous yeasts were cultivated on industrial wastes. The yeasts grew well on the wastes with low C/N ratio (i.e. serum latex) but accumulated high lipid content only when the wastes had a high C/N ratio (i.e. palm oil mill effluent and crude glycerol). The yeast lipids have similar fatty acid composition to that of plant oil indicating their potential use as biodiesel feedstocks. The combination of these wastes and two-phase cultivation for cell growth and lipid accumulation improved lipid productivity of the selected yeast. The direct transesterification process that eliminates cell drying and lipid extraction steps, gave comparable yield of biodiesel (fatty acid methyl ester >70% within 1h) to that of conventional method. These two successful strategies may contribute greatly to industrializing oil production from microbes and industrial wastes. PMID- 23747445 TI - Heterologous expression and characterization of a novel thermo-halotolerant endoglucanase Cel5H from Dictyoglomus thermophilum. AB - A novel beta-1,4-endoglucanase gene was cloned from Dictyoglomus thermophilum, designated as Cel5H for being a member of glycoside hydrolase family 5. The purified recombinant endoglucanase showed high hydrolytic activities on carboxylmethyl cellulose with a broad optimal temperature of 50-85 degrees C and an optimal pH of 5.0. Furthermore, this enzyme was highly thermostable with a half-life of 336 h at 70 degrees C and retained more than 80% of the initial activity after 135 days incubation at 50 degrees C. To enhance the performance of the thermophilic endoglucanase, chimeric enzymes containing Cel5H and syncretic cellulose binding module (CBM) were constructed. The results showed that all the CBMs were effective. In addition, Cel5H was highly tolerant against high salt concentration and distinguished from salt-tolerant bacteria since it was independent of high salt concentration. Three-dimensional structure of Cel5H was developed by homology modeling methods and surface electrostatic analysis was performed. PMID- 23747446 TI - Co-digestion of solid poultry manure with municipal sewage sludge. AB - The anaerobic digestion was investigated using mixed sewage sludge and poultry manure. The experiments showed that a 30% addition of poultry manure to the sewage sludge did not increase specific gas yield (376 dm(3)/kg VS versus 384 dm(3)/kg VS), however gas production rate as calculated per unit volume was 1.5 higher for sludge and manure mixture. The anaerobic digestion turned out to be inefficient in terms of pathogen treatment, since the reduction of Enterobacteriaceae reached only two logarithmic units. In the course of the digestion processes, nutrients were released to the supernatant, and longer SRT favored that phenomenon. The liquor after the digestion of sludge alone was rich in phosphates (348-358 gP/m(3)) and contained a lot of organic carbon (COD of 2705-6034 gO2/m(3)). Conversely, more ammonium nitrogen was found in the supernatant after co-digestion of sludge with manure (2094-2221 gN/m(3)). However, there was no evidence of ammonia inhibition. PMID- 23747447 TI - Conversion of lignocellulosic biomass to green fuel oil over sodium based catalysts. AB - Upgrading of biomass pyrolysis vapors over 20 wt.% Na2CO3/gamma-Al2O3 catalyst was studied in a lab-scale fix-bed reactor at 500 degrees C. Characterization of the catalyst using SEM and XRD has shown that sodium carbonate is well-dispersed on the support gamma-Al2O3. TGA and (23)Na MAS NMR suggested the formation of new hydrated sodium phase, which is likely responsible for the high activity of the catalyst. Catalytic oil has much lower oxygen content (12.3 wt.%) compared to non catalytic oil (42.1 wt.%). This comes together with a tremendous increase in the energy density (37 compared to 19 MJ kg(-1)). Decarboxylation of carboxylic acids was favoured on the catalyst, resulting to an oil almost neutral (TAN=3.8mg KOH/g oil and pH=6.5). However, the mentioned decarboxylation resulted in the formation of carbonyls, which correlates to low stability of the oil. Catalytic pyrolysis results in a bio-oil which resembles a fossil fuel oil in its properties. PMID- 23747448 TI - Production of partially phosphorylated myo-inositol phosphates using phytases immobilised on magnetic nanoparticles. AB - Phytases of different origin were covalently bound onto Fe3O4 magnetic nanoparticles (12 nm). Binding efficiencies of all three phytases were well above 70% relative to the number of aldehyde groups available on the surface of the magnetic nanoparticles. Temperature stability for all three phytases was enhanced as a consequence of immobilisation, whereas pH dependence of enzyme activity was not affected. Maximum catalytic activity of the immobilised phytases was found at 60 degrees C (rye), 65 degrees C (Aspergillus niger) and 70 degrees C (Escherichia albertii). The immobilised enzymes exhibited the same excellent substrate specificities and unique myo-inositol phosphate phosphatase activities as their soluble counterparts. However, the catalytic turnover number dropped drastically for the immobilised phytases. The amount of the desired partially phosphorylated myo-inositol phosphate isomer could be easily controlled by the contact time of substrate solution and immobilised enzymes. The immobilised phytases showed a high operational stability by retaining almost full activity even after fifty uses. PMID- 23747449 TI - Improvement of docosahexaenoic acid production on glycerol by Schizochytrium sp. S31 with constantly high oxygen transfer coefficient. AB - Volumetric mass transfer coefficient (kLa) is a key fermentation parameter for the production of docosahexaenoic acid (DHA) from glycerol by Schizochytrium sp. S31. In order to elucidate the effects of kLa on the fermentations, both baffled and unbaffled flask cultures and fed-batch cultures were developed in present work. The results showed that high kLa could effectively increase the DHA concentration, DHA productivity and conversion yield (Yx/s, g/g). When kLa was set at 1802 +/- 105 h(-1) in the fed-batch culture, DHA concentration was achieved at 28.93 g/L, DHA productivity at 301 mg/L/h and Yx/s at 0.44 +/- 0.02 g/g, all of which were significantly higher than those in the previous similar studies. PMID- 23747450 TI - Reproducibility of combinatorial peptide ligand libraries for proteome capture evaluated by selected reaction monitoring. AB - Systems biology studies require the capability to quantify with high precision proteins spanning a broad range of abundances across multiple samples. However, the broad range of protein expression in cells often precludes the detection of low-abundance proteins. Different sample processing techniques can be applied to increase proteome coverage. Among these, combinatorial (hexa)peptide ligand libraries (CPLLs) bound to solid matrices have been used to specifically capture and detect low-abundance proteins in complex samples. To assess whether CPLL capture can be applied in systems biology studies involving the precise quantitation of proteins across a multitude of samples, we evaluated its performance across the whole range of protein abundances in Saccharomyces cerevisiae. We used selected reaction monitoring assays for a set of target proteins covering a broad abundance range to quantitatively evaluate the precision of the approach and its capability to detect low-abundance proteins. Replicated CPLL-isolates showed an average variability of ~10% in the amount of the isolated proteins. The high reproducibility of the technique was not dependent on the abundance of the protein or the amount of beads used for the capture. However, the protein-to-bead ratio affected the enrichment of specific proteins. We did not observe a normalization effect of CPLL beads on protein abundances. However, CPLLs enriched for and depleted specific sets of proteins and thus changed the abundances of proteins from a whole proteome extract. This allowed the identification of ~400 proteins otherwise undetected in an untreated sample, under the experimental conditions used. CPLL capture is thus a useful tool to increase protein identifications in proteomic experiments, but it should be coupled to the analysis of untreated samples, to maximize proteome coverage. Our data also confirms that CPLL capture is reproducible and can be confidently used in quantitative proteomic experiments. SIGNIFICANCE: Combinatorial hexapeptide ligand libraries (CPLLs) bound to solid matrices have been proposed to specifically capture and detect low-abundance proteins in complex samples. To assess whether the CPLL capture can be confidently applied in systems biology studies involving the precise quantitation of proteins across a broad range of abundances and a multitude of samples, we evaluated its reproducibility and performance features. Using selected reaction monitoring assays for proteins covering the whole range of abundances we show that the technique is reproducible and compatible with quantitative proteomic studies. However, the protein-to-bead ratio affects the enrichment of specific proteins and CPLLs depleted specific sets of proteins from a whole proteome extract. Our results suggest that CPLL based analyses should be coupled to the analysis of untreated samples, to maximize proteome coverage. Overall, our data confirms the applicability of CPLLs in systems biology research and guides the correct use of this technique. PMID- 23747451 TI - The effect of intramuscular progesterone on the rate of cervical shortening. AB - OBJECTIVE: The purpose of the study was to evaluate whether 17-alpha hydroxyprogesterone caproate (17-OHPC) exposure is associated with the rate of cervical shortening. STUDY DESIGN: Women with a history of spontaneous preterm delivery (PTD) at <37 weeks' gestation who had serial cervical length measurements (2009-2012) were identified. 17-OHPC administration and outcome data were collected. We excluded patients with multiple gestations, indicated PTDs, major fetal anomalies, cerclage, and vaginal progesterone use. The rate of cervical shortening was modeled in relation to 17-OHPC status with the use of methods for longitudinal data analysis. RESULTS: Two hundred thirty-seven patients with 1171 cervical length measurements were included, of whom 184 patients (77.6%) were exposed to 17-OHPC. Gestational age, number of previous PTDs, gestational age at initiation, and interval between cervical length examinations were similar between the 2 groups, although women who were not exposed to 17-OHPC were more likely to have delivered multiples in their previous PTD (24.5% vs 4.4%; P < .01). In the entire cohort, the rate of cervical shortening was identical, regardless of 17-OHPC exposure (0.85 mm per week). Among term deliveries, the rates of cervical shortening per week, on average, were 0.9 and 0.8 mm per week among women with and without 17-OHPC, respectively (P = .76). Among preterm deliveries, the corresponding rates were 0.8 and 1.2 mm, respectively, among women with and without 17-OHPC (P = .67). CONCLUSION: Cervical shortening among women with previous preterm delivery occurs at a similar rate, regardless of exposure to 17-OHPC. PMID- 23747452 TI - The marginal willingness-to-pay for attributes of a hypothetical HIV vaccine. AB - This paper estimates the marginal willingness-to-pay for attributes of a hypothetical HIV vaccine using discrete choice modeling. We use primary data from 326 respondents from Bangkok and Chiang Mai, Thailand, in 2008-2009, selected using purposive, venue-based sampling across two strata. Participants completed a structured questionnaire and full rank discrete choice modeling task administered using computer-assisted personal interviewing. The choice experiment was used to rank eight hypothetical HIV vaccine scenarios, with each scenario comprising seven attributes (including cost) each of which had two levels. The data were analyzed in two alternative specifications: (1) best-worst; and (2) full-rank, using logit likelihood functions estimated with custom routines in Gauss matrix programming language. In the full-rank specification, all vaccine attributes are significant predictors of probability of vaccine choice. The biomedical attributes of the hypothetical HIV vaccine (efficacy, absence of VISP, absence of side effects, and duration of effect) are the most important attributes for HIV vaccine choice. On average respondents are more than twice as likely to accept a vaccine with 99% efficacy, than a vaccine with 50% efficacy. This translates to a willingness to pay US$383 more for a high efficacy vaccine compared with the low efficacy vaccine. Knowledge of the relative importance of determinants of HIV vaccine acceptability is important to ensure the success of future vaccination programs. Future acceptability studies of hypothetical HIV vaccines should use more finely grained biomedical attributes, and could also improve the external validity of results by including more levels of the cost attribute. PMID- 23747453 TI - Regulation of poxvirus vectored vaccines. PMID- 23747454 TI - Serotype distribution of Streptococcus pneumoniae isolated from patients with invasive pneumococcal disease in Brazil before and after ten-pneumococcal conjugate vaccine implementation. AB - The ten-pneumococcal conjugate vaccine (PCV10) was introduced into the national immunization program for childhood vaccination schedules by the Brazilian Health Public Service in March 2010. The aim of this study was to compare Streptococcus pneumoniae serotype distribution, antibiotic resistance patterns, and potential coverage before (January 2006-June 2010) and after (July 2010-September 2012) PCV10 introduction. The incidence of invasive pneumococcal disease (IPD), patient demographics, and disease characteristics were recorded. This study was conducted at the University Hospital of Sao Paulo University in Brazil from January 2006 to September 2012. Serotyping was performed using multiplex PCR typing, and antimicrobial sensitivity by Clinical and Laboratory Standards Institute (CLSI). A total of 259 S. pneumoniae strains were isolated from patients with IPD. The ages of the patients ranged from 3 months to 95 years old. The strains were isolated from cerebrospinal fluid, pleural fluid, and blood. The incidence of IPD among patients at HU-USP changed after the introduction of PCV10. The overall incidence of IPD was 3.42 cases per 1000 admissions in the vaccine pre- implementation period and of 2.99 cases per 1000 admissions in the vaccine post implementation period. The incidence of IPD among children<2 y.o. attended at HU USP changed significantly after the introduction of PCV10, from 20.30 to 3.97 of incidence. The incidence of PCV10- serotypes decrease from 16.47 to 0.44 in the same age, before and after PC10 implementation, respectively. Moreover, it was possible to realize the sensitivity to penicillin among isolates increased significantly in the post-vaccine period. Data from this study suggest that PCV10 contributed to decrease with PID rate among children less than 2 y.o. The resistance rate among pneumococcal isolates also could be observed since serotypes with greater resistance to beta lactam antibiotics were not easily isolated after vaccination. PMID- 23747455 TI - Estimating vaccination coverage against tick-borne encephalitis: comment on: Kosnik IG, Lah AK. A campaign to increase the vaccination rate in a highly endemic tick-borne encephalitis region of Slovenia. Vaccine 2013;31(5):732-4. PMID- 23747456 TI - Time-on-task and sleep deprivation effects are evidenced in overlapping brain areas. AB - Both sleep deprivation and extended task engagement (time-on-task) have been shown to degrade performance in tasks evaluating sustained attention. Here we used pulsed arterial spin labeling (pASL) to study participants engaged in a demanding selective attention task. The participants were imaged twice, once after a normal night of sleep and once after approximately 24h of total sleep deprivation. We compared task-related changes in BOLD signal alongside ASL-based cerebral blood flow (CBF) changes. We also collected resting baseline CBF data prior to and following task performance. Both BOLD fMRI and ASL identified spatially congruent task activation in ventral visual cortex and fronto-parietal regions. Sleep deprivation and time-on-task caused a decline of both measures in ventral visual cortex. BOLD fMRI also revealed such declines in fronto-parietal cortex. Only early visual cortex showed a significant upward shift in resting baseline CBF following sleep deprivation, suggesting that the neural consequences of both SD and ToT are primarily evident in task-evoked signals. We conclude that BOLD fMRI is preferable to pASL in studies evaluating sleep deprivation given its better signal to noise characteristics and the relative paucity of state differences in baseline CBF. PMID- 23747457 TI - The nuisance of nuisance regression: spectral misspecification in a common approach to resting-state fMRI preprocessing reintroduces noise and obscures functional connectivity. AB - Recent resting-state functional connectivity fMRI (RS-fcMRI) research has demonstrated that head motion during fMRI acquisition systematically influences connectivity estimates despite bandpass filtering and nuisance regression, which are intended to reduce such nuisance variability. We provide evidence that the effects of head motion and other nuisance signals are poorly controlled when the fMRI time series are bandpass-filtered but the regressors are unfiltered, resulting in the inadvertent reintroduction of nuisance-related variation into frequencies previously suppressed by the bandpass filter, as well as suboptimal correction for noise signals in the frequencies of interest. This is important because many RS-fcMRI studies, including some focusing on motion-related artifacts, have applied this approach. In two cohorts of individuals (n=117 and 22) who completed resting-state fMRI scans, we found that the bandpass-regress approach consistently overestimated functional connectivity across the brain, typically on the order of r=.10-.35, relative to a simultaneous bandpass filtering and nuisance regression approach. Inflated correlations under the bandpass-regress approach were associated with head motion and cardiac artifacts. Furthermore, distance-related differences in the association of head motion and connectivity estimates were much weaker for the simultaneous filtering approach. We recommend that future RS-fcMRI studies ensure that the frequencies of nuisance regressors and fMRI data match prior to nuisance regression, and we advocate a simultaneous bandpass filtering and nuisance regression strategy that better controls nuisance-related variability. PMID- 23747459 TI - Risk factors for invasive fungal disease after allogeneic hematopoietic stem cell transplantation: a single center experience. AB - Invasive fungal disease (IFD) is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HCT). We performed a retrospective review of 271 adults with a hematologic malignancy undergoing allogeneic HCT to determine the incidence of and risk factors for IFD and to examine the impact of IFD on nonrelapse mortality and overall survival. We defined IFD using standard criteria and selected proven and probable cases for analysis. Diagnoses in the study group included acute leukemia (42%), non-Hodgkin lymphoma (24%), myelodysplastic syndrome (15%), chronic lymphocytic leukemia (5%), and other hematologic disorders (14%). Conditioning included reduced-intensity (64%) and myeloablative (36%) regimens. Donor sources were HLA-matched sibling (60%), matched unrelated (20%), haploidentical (12%), and cord blood (8%). A total of 51 episodes of IFD were observed in 42 subjects (15%). Aspergillus spp (47%) was the most frequent causative organism, followed by Candida spp (43%). The majority of IFD cases (67%) were reported after day +100 post-HCT. In multivariate analysis, haploidentical donor transplantation (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.49-9.77; P = .005) and grade II-IV acute graft-versus-host disease (HR, 2.55; 95% CI, 1.07-6.10; P = .03) were risk factors for the development of IFD. Conversely, higher infused CD34(+) cell dose was associated with a lower risk of IFD (HR, 0.80; 95% CI, 0.68-0.94; P = .006, per 1 * 10(6) cells/kg increase in CD34(+) cell infusion). IFD-related mortality was 33.3%. Nonrelapse mortality was significantly higher in patients who developed IFD compared with those without IFD (P < .001, log-rank test). Patients with IFD had lower overall survival (5.8 months versus 76.1 months; P < .001, log-rank test). Further studies exploring strategies to increase the infused cell dose and determine adequate prophylaxis, especially against aspergillus, beyond day +100 are needed. PMID- 23747458 TI - The effect of scan length on the reliability of resting-state fMRI connectivity estimates. AB - There has been an increasing use of functional magnetic resonance imaging (fMRI) by the neuroscience community to examine differences in functional connectivity between normal control groups and populations of interest. Understanding the reliability of these functional connections is essential to the study of neurological development and degenerate neuropathological conditions. To date, most research assessing the reliability with which resting-state functional connectivity characterizes the brain's functional networks has been on scans between 3 and 11 min in length. In our present study, we examine the test-retest reliability and similarity of resting-state functional connectivity for scans ranging in length from 3 to 27 min as well as for time series acquired during the same length of time but excluding half the time points via sampling every second image. Our results show that reliability and similarity can be greatly improved by increasing the scan lengths from 5 min up to 13 min, and that both the increase in the number of volumes as well as the increase in the length of time over which these volumes was acquired drove this increase in reliability. This improvement in reliability due to scan length is much greater for scans acquired during the same session. Gains in intersession reliability began to diminish after 9-12 min, while improvements in intrasession reliability plateaued around 12-16 min. Consequently, new techniques that improve reliability across sessions will be important for the interpretation of longitudinal fMRI studies. PMID- 23747460 TI - Photodegradation of Dechlorane Plus in n-nonane under the irradiation of xenon lamp. AB - Photodegradation has been regarded as the main mechanism for the removal of many halogenated organic pollutants in the environment. The photodegradation of Dechlorane Plus (DP), an emerging contaminant taken worldwide concerns in recent years, was investigated under the irradiation of a xenon lamp. Rapid photodegradation was found under the irradiation of 200-750 nm light, while the degradation became much slower when the range of light wavelength changed to 280 750 nm. DP degradation followed the pseudo first-order kinetics. The quantum yields of 200-280 nm (UV-C) were about 2-3 orders of magnitude higher than 280 320 nm, and no yields can be detected in 320-750 nm range, in an agreement with the changing photodegradation rates with wavelength. The photodegradation products were identified as lower chlorinated DPs, implicating a mechanism of reductive dechlorination. No photoisomerization or solvent adducts were observed, and the difference of photodegradation rate between syn- and anti-DP isomers was negligible. PMID- 23747461 TI - A simplified analysis of dimethylarsinic acid by wavelength dispersive X-ray fluorescence spectrometry combined with a strong cation exchange disk. AB - Dimethylarsinic acid (DMA(V)) was pre-concentrated from water samples using a strong cation exchange (SCX) disk functionalized with sulfonic groups, before being analyzed by wavelength dispersive X-ray fluorescence spectrometry (WDXRF). The adsorption of DMA(V) occurred preferentially on the surface of the SCX disk, regardless of pH levels, probably due to interactions with the sulfonic functional groups. However, no other arsenic species, such as arsenate (iAs(V)), arsenite (iAs(III)), and monomethylarsonic acid (MMA(V)), were retained. The SCX WDXRF method produced a strongly linear calibration curve (R(2)=0.9996) with its limit of detection at 0.218 MUgL(-1) when a one-liter water sample was used for pre-concentration. The As intensity of the system was sensitive to the Pb content retained on the SCX disk owing to the proximity of the As-Kalpha and Pb-Lalpha lines. To compensate for this interference, a correction factor was developed by considering the calibration slope ratio between the X-ray intensity measured at a Bragg angle of 48.781 degrees and the Pb content of the SCX disks. The results of spike tests for iAs(V), iAs(III), MMA(V), and DMA(V) with and without the addition of Pb in synthetic landfill leachate exhibited reasonable recoveries (i.e., 98-105%) after the spectral adjustment for the Pb interference. PMID- 23747462 TI - Thin extractive membrane for monitoring actinides in aqueous streams. AB - Alpha spectrometry and solid state nuclear track detectors (SSNTDs) are used for monitoring ultra-trace amount of alpha emitting actinides in different aqueous streams. However, these techniques have limitations i.e. alpha spectrometry requires a preconcentration step and SSNTDs are not chemically selective. Therefore, a thin polymer inclusion membrane (PIM) supported on silanized glass was developed for preconcentraion and determination of ultra-trace concentration of actinides by alpha-spectrometry and SSNTDs. PIMs were formed by spin coating on hydrophobic glass slide or solvent casting to form thin and self-supported membranes, respectively. Sorption experiments indicated that uptakes of actinides in the PIM were highly dependent on acidity of solution i.e. Am(III) sorbed up to 0.1 molL(-1) HNO3, U(VI) up to 0.5 molL(-1) HNO3 and Pu(IV) from HNO3 concentration as high as 4 molL(-1). A scheme was developed for selective sorption of target actinide in the PIM by adjusting acidity and oxidation state of actinide. The actinides sorbed in PIMs were quantified by alpha spectrometry and SSNTDs. For SSNTDs, neutron induced fission-fragment tracks and alpha particle tracks were registered in Garware polyester and CR-39 for quantifications of natural uranium and alpha-emitting actinides ((241)Am/(239)Pu/(233)U), respectively. Finally, the membranes were tested to quantify Pu in 4 molL(-1) HNO3 solutions and synthetic urine samples. PMID- 23747463 TI - Carbon isotope fractionation of 1,1,1-trichloroethane during base-catalyzed persulfate treatment. AB - The extent of carbon isotope fractionation during degradation of 1,1,1 trichloroethane (1,1,1-TCA) by a base-catalyzed persulfate (S2O8(2-)) treatment system was investigated. Significant destruction of 1,1,1-TCA was observed at a pH of ~12. An increase in the NaOH:S2O8(2-) molar ratio from 0.2:1 to 8:1 enhanced the reaction rate of 1,1,1-TCA by a factor of ~5 to yield complete (>99.9%) destruction. An average carbon isotope enrichment fractionation factor which was independent of the NaOH:S2O8(2-) molar ratio of -7.0 +/- 0.20/00 was obtained. This significant carbon isotope fractionation and the lack of dependence on changes in the NaOH:S2O8(2-) molar ratio demonstrates that carbon isotope analysis can potentially be used in situ as a performance assessment tool to estimate the degradation effectiveness of 1,1,1-TCA by a base-catalyzed persulfate system. PMID- 23747464 TI - Effects of simulated weathering on the toxicity of selected crude oils and their components to sea urchin embryos. AB - Artificial weathering of Angolan crude and a Heavy Fuel Oil (HFO) was performed by evaporation and photooxidation. The aliphatic, aromatic, polar and asphaltene fractions of the fresh and weathered oils were isolated. The toxicity of the water accommodated fraction or an oil/fraction dissolved in DMSO was assessed using the sea urchin embryo test. Photooxidation was observed to decrease the aromatics content and increase polar compounds. A slight reduction in the toxicity of Angolan crude was observed following weathering for the water accommodated fraction and the extract in DMSO, but no effect was seen for the Heavy Fuel Oil. For aliphatic compounds, the toxicity decreased in the order fresh>evaporated>photooxidated for both Angolan crude and HFO. Weathering slightly increased the toxicity of the aromatic and polar fractions of the oil. The aromatic fractions were responsible for most of the toxicity and the polar compounds were the second most important toxic components, despite having less or similar abundance than the aliphatic fraction. The toxic contribution of the aromatic compounds was higher for the HFO than for the Angolan crude. A decrease in the toxicity of Angolan crude following weathering correlated with a reduction in the toxicity of the aliphatic fraction. PMID- 23747465 TI - Stabilization of heavy metals in lightweight aggregate made from sewage sludge and river sediment. AB - The primary goal of this research is to investigate the stabilization of heavy metals in lightweight aggregate (LWA) made from sewage sludge and river sediment. The effects of the sintering temperature, the (Fe2O3+CaO+MgO)/(SiO2+Al2O3) ratio (K ratio), SiO2/Al2O3 and Fe2O3/CaO/MgO (at fixed K ratio), pH, and oxidative conditions on the stabilization of heavy metals were studied. Sintering at temperatures above 1100 degrees C effectively binds Cd, Cr, Cu and Pb in the LWA, because the stable forms of the heavy metals are strongly bound to the aluminosilicate or silicate frameworks. Minimum leachabilities of Cd, Cr, Cu and Pb were obtained at K ratios between 0.175 and 0.2. When the LWA was subjected to rigorous leaching conditions, the heavy metals remained in the solid even when the LWA bulk structure was broken. LWA made with sewage sludge and river sediment can therefore be used as an environmentally safe material for civil engineering and other construction applications. PMID- 23747466 TI - Toward an effective adsorbent for polar pollutants: formaldehyde adsorption by activated carbon. AB - Due to increasing concerns about environmental pollutants, the development of an effective adsorbent or sensitive sensor has been pursued in recent years. Diverse porous materials have been selected as promising candidates for detecting and removing harmful materials, but the most appropriate pore structure and surface functional groups, both important factors for effective adsorbency, have not yet been fully elucidated. In particular, there is limited information relating to the use of activated carbon materials for effective adsorbent of specific pollutants. Here, the pore structure and surface functionality of polyacrylonitrile-based activated carbon fibers were investigated to develop an efficient adsorbent for polar pollutants. The effect of pore structure and surface functional groups on removal capability was investigated. The activated carbons with higher nitrogen content show a great ability to absorb formaldehyde because of their increased affinity with polar pollutants. In particular, nitrogen functional groups that neighbor oxygen atoms play an important role in maximizing adsorption capability. However, because there is also a similar increase in water affinity in adsorbents with polar functional groups, there is a considerable decrease in adsorption ability under humid conditions because of preferential adsorption of water to adsorbents. Therefore, it can be concluded that pore structures, surface functional groups and the water affinity of any adsorbent should be considered together to develop an effective and practical adsorbent for polar pollutants. These studies can provide vital information for developing porous materials for efficient adsorbents, especially for polar pollutants. PMID- 23747467 TI - Solidification/stabilization of toxic metals in calcium aluminate cement matrices. AB - The ability of calcium aluminate cement (CAC) to encapsulate toxic metals (Pb, Zn and Cu) was assessed under two curing conditions. Changes in the consistency and in the setting time were found upon the addition of the nitrates of the target metals. Both Pb and Cu caused a delay in CAC hydration, while Zn accelerated the stiffening of the mortar. Compressive strengths of the metal-doped mortars, when initially cured at 60 degrees C/100% RH, were comparable with that of the free metal mortar. Three different pore size distribution patterns were identified and related to the compounds identified by XRD and SEM. Sorbent capacities of CAC for the toxic metals were excellent: a total uptake was achieved for up to 3 wt.% loading of the three metals. In this way, CAC mortars were perfectly able to encapsulate the toxic metals, allowing the use of CAC for waste management as proved by the leaching tests. PMID- 23747468 TI - Selective catalytic oxidation of H2S over iron oxide supported on alumina intercalated Laponite clay catalysts. AB - A series of iron oxide supported on alumina-intercalated clay catalysts (named Fe/Al-Lap catalysts) with mesoporous structure and high specific surface area were prepared. The structural and chemical properties were studied by nitrogen sorption isotherms, X-ray diffraction (XRD), UV-vis diffuse reflectance spectra (UV-vis DRS), X-ray photoelectron spectra (XPS), Fourier transform infrared spectroscopy (FTIR), H2 temperature-programmed reduction (H2-TPR) and NH3 temperature-programmed desorption (NH3-TPD) techniques. It was realized that iron oxide mainly existed in the form of isolated Fe(3+) in an oxidic environment. Fe/Al-Lap catalysts showed high catalytic activities in the temperature range of 120-200 degrees C without the presence of excessive O2. This can be attributed to the interaction between iron oxide and alumina, which improve the redox property of Fe(3+) efficiently. In addition, the strong acidity of catalysts and good dispersion of iron oxide were also beneficial to oxidation reaction. Among them, 7% Fe/Al-Lap catalyst presented the best catalytic performance at 180 degrees C. Finally, the catalytic and deactivation mechanisms were explored. PMID- 23747469 TI - New insights on degradation of methylene blue using thermocatalytic reactions catalyzed by low-temperature excitation. AB - Although photocatalysis has been actively surveyed on removing organic pollutants in ultraviolet (UV) environment, because of lacking UV in solar exposure, photodegradation is difficult to be considerably degraded in conventional exposure condition. In this work, an innovative approach was proposed to compensate for it, which was developed in model wastewater using thermal sensitizer at room temperature. At the optimal component condition, the removal rate of adsorption and thermocatalytic degradation processes can reach the highest level of 82.07% solely response to temperature in the dark. Moreover, the kinetics of degradation rate was modeled considering that it was found similarly to Langmuir-Hinshelwood behavior, and a tentative mechanism was objectively established, describing reasonably well in line with the experimental results. On the other hand, it was found that high amount of methylene blue (MB) adsorbed onto thermal sensitizer was of unambiguous importance to subsequent thermocatalytic performance. Briefly, all above suggest that the feasibility to the thermodegradation route has been successfully verified under room temperature excitation. Herein the insight into degradation pattern of dye over thermal excitation may further enlarge applications for wastewater treatment. PMID- 23747470 TI - Elimination of TiO2 nanoparticles with the assist of humic acid: influence of agglomeration in the dissolved air flotation process. AB - With recent advances in nanotechnology, environmental and health consequences of nanomaterial disposal merit close attention. In the search for environmentally friendly reagent, this study investigates the use of humic acid (HA) as an assist of dissolved air flotation (DAF) in the TiO2 nanoparticle (TNP) elimination. To determine mechanisms of TNPs interacting with HA, surface modification experiments were firstly carried out; thereafter, laboratory scaled DAF tests were applied to remove TNPs with HA assisting. Results of surface modification experiments showed that the zeta potential of TNP suspension system had a reversal trend due to counter ions of TNP and anions offered by the HA stock solution. The surface modified suspension was not easy to restabilize because of the close combination of TNPs and HA through sphere linkages or hydrogen-bonded surface complexes. Agglomeration took place more readily along with increasing HA concentration in the optimum dosage range (7.8-9.15 mg/L DOC). The flotation performance revealed that HA could improve the DAF efficiency in the optimum dosage range of HA. The interaction between TNPs and HA (Na(+)-humate), including surface charge neutralization (electrostatic interactions), sphere linkages or hydrogen-bonded surface complexes, hydrophobic interactions, and van der Waals interactions, played dominant roles. PMID- 23747471 TI - Integrated risk reduction framework to improve railway hazardous materials transportation safety. AB - Rail transportation plays a critical role to safely and efficiently transport hazardous materials. A number of strategies have been implemented or are being developed to reduce the risk of hazardous materials release from train accidents. Each of these risk reduction strategies has its safety benefit and corresponding implementation cost. However, the cost effectiveness of the integration of different risk reduction strategies is not well understood. Meanwhile, there has been growing interest in the U.S. rail industry and government to best allocate resources for improving hazardous materials transportation safety. This paper presents an optimization model that considers the combination of two types of risk reduction strategies, broken rail prevention and tank car safety design enhancement. A Pareto-optimality technique is used to maximize risk reduction at a given level of investment. The framework presented in this paper can be adapted to address a broader set of risk reduction strategies and is intended to assist decision makers for local, regional and system-wide risk management of rail hazardous materials transportation. PMID- 23747472 TI - Characterizing toxic Cr(VI) contamination in chromite mine overburden dump and its bacterial remediation. AB - Cr(VI) generated due to natural oxidation of chromite mineral present in chromite mine overburden (COB) dumps of Sukinda, India, has been characterized by different physico-chemical methods. The Cr(VI) was found to be associated with goethite matrix at a contamination level of 500 mg Cr(VI)kg(-1) of COB. Bacillus sp. isolated from the overburden sample exhibiting high tolerance to the hexavalent chromium, was used for the remediation of Cr(VI) in the overburden. The process was optimized while varying the parameters such as pH (2-9), pulp density (10-60%) and temperature (25-40 degrees C). Optimal reduction of more than 98% of Cr(VI) in the COB sample was achieved in 16 h at pH~7.0 and 60% pulp density with the Bacillus sp. (4.05 * 10(7)cells mL(-1)) in absence of media. The exponential rate equation yielded rate constant value of 2.14 * 10(-1)h(-1) at 60% pulp density. The mode of bio-reduction of Cr(VI) in the overburden sample was established by FT-IR, XRD, EPMA and SEM-EDS studies. PMID- 23747473 TI - Reduction of Cr (VI) by organic acids in the presence of Al (III). AB - The effects of Al (III) on the reduction of Cr (VI) by three alpha-hydroxy acids, tartaric, malic and citric acids, were investigated through batch experiments at pH from 2.5 to 4.0 and temperatures from 25 degrees C to 35 degrees C. These reactions could be described as pseudo-zero-order with respect to Cr (VI) when the concentrations of alpha-hydroxy acids were greatly in excess. The transformation rates of Cr (VI) to Cr (III) in the presence of Al (III) without light were in the decreasing order of tartaric acid>malic acid>citric acid. This order suggested that the two alpha-hydroxyl groups in tartaric acid could play an important role in the reduction of Cr (VI) by organic acids. The possible mechanism was that the formed complex between organic acids and Al (III) significantly enhanced the reductivity of alpha-hydroxy acids and further led to the more complicated Cr (VI)-tartaric acid-Al (III) cyclic ester which greatly accelerated the reduction rate. The Cr (VI) reduction reaction rate increased with the decrease of pH but with the increase of Al (III) concentration, tartaric acid concentration, and temperature. As the pH decreased, the increase of [H(+)] led to an increase in {Al(III)H2Tar2}(+), the most active species, and thus the enhanced reduction rate. PMID- 23747474 TI - Hazardous waste characterization among various thermal processes in South Korea: a comparative analysis. AB - Ministry of Environment, Republic of Korea (South Korea) is in progress of converting its current hazardous waste classification system to harmonize it with the international standard and to set-up the regulatory standards for toxic substances present in the hazardous waste. In the present work, the concentrations along with the trend of 13 heavy metals, F(-), CN(-) and 19 PAH present in the hazardous waste generated among various thermal processes (11 processes) in South Korea were analyzed along with their leaching characteristics. In all thermal processes, the median concentrations of Cu (3.58 209,000 mg/kg), Ni (BDL-1560 mg/kg), Pb (7.22-5132.25mg/kg) and Zn (83.02-31419 mg/kg) were comparatively higher than the other heavy metals. Iron & Steel thermal process showed the highest median value of the heavy metals Cd (14.76 mg/kg), Cr (166.15 mg/kg) and Hg (2.38 mg/kg). Low molecular weight PAH (BDL 37.59 mg/kg) was predominant in sludge & filter cake samples present in most of the thermal processes. Comparatively flue gas dust present in most of the thermal processing units resulted in the higher leaching of the heavy metals. PMID- 23747475 TI - Gas phase catalytic hydrodechlorination of chlorobenzene over cobalt phosphide catalysts with different P contents. AB - The gas phase catalytic hydrodechlorination (HDC) of chlorobenzene (CB) at atmospheric pressure was investigated over silica-supported cobalt and cobalt phosphide catalysts containing different P loading and a fixed amount of cobalt (5 wt.%). The effect of the initial P/Co molar ratio on the stoichiometry of the cobalt phosphide phase, the acidity and the hydrogen activation capability were discussed and these properties correlated with the catalytic activity. Catalytic results indicated that the cobalt phosphide phase is much more active than the monometallic cobalt one. The activity raised with the P content present in the sample due to the formation of the CoP phase instead of the Co2P one, which favored the formation of hydrogen spillover species, increased the amount of weak acid sites and the number of exposed superficial cobalt atoms probably related to a better dispersion of the active phase. All the catalysts gave rise benzene as the main reaction product. PMID- 23747476 TI - Foliar sorption of emerging and priority contaminants under controlled conditions. AB - Agricultural irrigation water contains a variety of contaminants that can be introduced into the food chain through intake by irrigated crops. This paper describes an experiment under controlled conditions designed to simulate sprinkle irrigation with polluted water at two different relative humidities (40 and 90%). Specifically, shed lettuce-heart leaves were spiked with an aqueous solution containing organic microcontaminants, including pharmaceuticals (ibuprofen, diclofenac, clofibric acid, and carbamazepine), fragrances (tonalide), biocides (triclosan), insecticides (lindane), herbicides (atrazine), phenolic estrogen (bisphenol A), and polycyclic aromatic hydrocarbons (phenanthrene and pyrene). Following an incubation period (48 h), the treated leaves were rinsed with water, and both the solution used to rinse them and the leaves themselves were independently analyzed to investigate the foliar sorption and uptake of the spiked organic contaminants through cuticle. The results showed that the foliar sorption of emerging and priority microcontaminants in leaves wetted by irrigation practices is related to their polarity (logD(ow)) and volatility (logk(H)), regardless of their compound class and the relative humidity. The results thus underscore the need to improve the quality of reclaimed water in crop irrigation, particularly when sprinkle irrigation is used. PMID- 23747478 TI - Comments on the "Nitrate contamination in ground water of some rural areas of Rajasthan, India" by Suthar et al. [J. Hazard. Mater. 171 (2009)]. PMID- 23747477 TI - Chemical constituents of fine particulate air pollution and pulmonary function in healthy adults: the Healthy Volunteer Natural Relocation study. AB - The study examined the associations of 32 chemical constituents of particulate matter with an aerodynamic diameter <=2.5 MUm (PM2.5) with pulmonary function in a panel of 21 college students. Study subjects relocated from a suburban area to an urban area with changing ambient air pollution levels and contents in Beijing, China, and provided daily morning/evening peak expiratory flow (PEF) and forced expiratory volume in 1s (FEV21) measurements over 6 months in three study periods. There were significant reductions in evening PEF and morning/evening FEV21 associated with various air pollutants and PM2.5 constituents. Four PM2.5 constituents (copper, cadmium, arsenic and stannum) were found to be most consistently associated with the reductions in these pulmonary function measures. These findings provide clues for the respiratory effects of specific particulate chemical constituents in the context of urban air pollution. PMID- 23747479 TI - TEMPO-oxidized cellulose hydrogel as a high-capacity and reusable heavy metal ion adsorbent. AB - Nitroxy radical catalyzed oxidation with hypochlorite/bromide (TEMPO-mediated oxidation) was performed on a cellulose hydrogel prepared using LiOH/urea solvent. TEMPO oxidation successfully introduced carboxyl groups onto the surface of the cellulose hydrogel with retention of the gel structure and its nanoporous property. The equilibrium measurement of Cu(2+) adsorption showed favorable interaction with Cu(2+) and high maximum adsorption capacity. In addition, over 98% of the adsorbed Cu(2+) was recovered using acid treatment, and the subsequent washing allowed the TEMPO-oxidized gels to be used repeatedly. Furthermore, the TEMPO-oxidized cellulose hydrogel showed high adsorption capacity for other toxic metal ions such as Zn(2+), Fe(3+), Cd(2+), and Cs(+). PMID- 23747480 TI - Preparation of triethylene-tetramine grafted magnetic chitosan for adsorption of Pb(II) ion from aqueous solutions. AB - In this paper, a novel triethylene-tetramine grafted magnetic chitosan was synthesized. The chemical structure and the percentage content of each element of chitosan and its derivatives were characterized by elemental analysis, infrared spectroscopy, solid state (13)C NMR, X-ray diffraction analysis and thermogravimetric analysis, respectively. Their surface topography was observed by the transmission electron microscope. The results of adsorption kinetics and adsorption thermodynamics showed the adsorption mechanism could be better described by the pseudo-second-order equation (R>0.999). The adsorption isotherm was well fitted by the Langmuir equation (R>0.999), and 010(6)IU/ml were randomized to receive placebo or vaniprevir at doses of 125 mg qd, 600 mg qd, 25mg bid, 75 mg bid, 250 mg bid, 500 mg bid, and 700 mg bid for 8 days. Forty patients (82.5% male, 75% genotype 1a) received at least one dose of placebo or vaniprevir. After 1 week of vaniprevir, the decrease in HCV RNA from baseline ranged from 1.8 to 4.6 log10IU/ml across all treatment groups, and there was a greater than dose-proportional increase in vaniprevir exposure at doses above 75 mg bid. The most commonly reported drug related adverse events (AEs) were diarrhea (n=5) and nausea (n=5). No pattern of laboratory or ECG abnormalities was observed, all AEs resolved during the study, and there were no discontinuations due to AEs. No serious AEs were reported. Resistance-associated amino acid variants were identified at positions R155 and D168 in patients infected with genotype 1a virus. Vaniprevir monotherapy demonstrated potent antiviral activity in patients with chronic genotype 1 HCV infection, and was generally well tolerated with no serious AEs or discontinuations due to AEs. Further development of vaniprevir, including studies in combination with other anti-HCV agents, is ongoing. PMID- 23747482 TI - High-throughput optogenetic functional magnetic resonance imaging with parallel computations. AB - Optogenetic functional magnetic resonance imaging (of MRI) technology enables cell-type-specific, temporally precise neuronal control and the accurate, in vivo readout of the resulting activity across the entire brain. With the ability to precisely control excitation and inhibition parameters and accurately record the resulting activity, there is an increased need for a high-throughput method to bring the of MRI studies to their full potential. In this paper, an advanced system facilitating real-time fMRI with interactive control and analysis in a fraction of the MRI acquisition repetition time (TR) is proposed. With high processing speed, sufficient time will be available for the integration of future developments that further enhance of MRI data or streamline the study. We designed and implemented a highly optimised, massively parallel system using graphics processing units (GPUs), which achieves the reconstruction, motion correction, and analysis of 3D volume data in approximately 12.80 ms. As a result, with a 750 ms TR and 4 interleaf fMRI acquisition, we can now conduct sliding window reconstruction, motion correction, analysis and display in approximately 1.7% of the TR. Therefore, a significant amount of time can now be allocated to integrating advanced but computationally intensive methods that improve image quality and enhance the analysis results within a TR. Utilising the proposed high-throughput imaging platform with sliding window reconstruction, we were also able to observe the much-debated initial dips in our of MRI data. Combined with methods to further improve SNR, the proposed system will enable efficient real-time, interactive, high-throughput of MRI studies. PMID- 23747483 TI - Insights into Notch3 activation and inhibition mediated by antibodies directed against its negative regulatory region. AB - Notch receptors are single-pass transmembrane proteins that regulate development and tissue homeostasis in all metazoan organisms. Prior to ligand-induced signaling, Notch receptors adopt a proteolytic resistant conformation maintained by a critical interdomain interface within a negative regulatory region (NRR), which sits immediately external to the plasma membrane. Signaling is initiated when ligand binding induces exposure of the proteolytic cleavage site, termed S2, within the NRR. Here, we use hydrogen exchange in conjunction with mass spectrometry to study the dynamics of the human Notch3 NRR in four distinct biochemical states: in its unmodified quiescent form, in a proteolytically "on" state induced by ethylenediaminetetraacetic acid, and in complex with either agonist or inhibitory antibodies. Induction of the on state by either ethylenediaminetetraacetic acid or the agonist monoclonal antibody leads to accelerated deuteration in the region of the S2 cleavage site, reflecting an increase in S2 dynamics. In contrast, complexation of the Notch3 NRR with an inhibitory antibody retards deuteration not only across its discontinuous binding epitope but also around the S2 site, stabilizing the NRR in its "off" state. Together with previous work investigating the dynamics of the Notch1 NRR, these studies show that key features of autoinhibition and activation are shared among different Notch receptors and provide additional insights into mechanisms of Notch activation and inhibition by modulatory antibodies. PMID- 23747484 TI - Stop-and-move of a marginally hydrophobic segment translocating across the endoplasmic reticulum membrane. AB - Many membrane proteins are cotranslationally integrated into the endoplasmic reticulum membrane via the protein-conducting channel, the so-called translocon. The hydrophobic transmembrane segment of the translocating nascent polypeptide chain stops at the translocon and then moves laterally into the membrane. Partitioning of the hydrophobic segment into the membrane is the primary determinant for membrane insertion. Here, we examined the behavior of a marginally hydrophobic segment at the translocon and found that its stop translocation was greatly affected by the C-terminally attached ribosomes. The marginally hydrophobic segment first stops at the membrane and then moves into the lumen as long as the nascent chain is attached to translating ribosomes. When it is released from the ribosome by the termination codon, the marginally hydrophobic segment does not move. Puromycin or RNase treatment also suppressed movement. The movement was reversibly inhibited by high-salt conditions and irreversibly inhibited by ethylenediaminetetraacetic acid. There is an unstable state prior to the stable membrane insertion of the transmembrane segment. This characteristic state is maintained by the synthesizing ribosome. PMID- 23747486 TI - Association of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity. AB - BACKGROUND: Therapeutic drug monitoring (TDM) of voriconazole is important to optimize efficacy and to minimize toxicity and intolerance. In this study, we evaluated the effect of sustained high plasma trough concentration of voriconazole on the incidence of hepatotoxicity in hospitalized Japanese patients. METHODS: Thirty-nine patients were divided into 3 groups according to trough concentrations in two consecutive TDMs: <4 MUg/ml in the first TDM (group A, n=25), >4 MUg/ml in the first and <4 MUg/ml in the second TDM (group B, n=8), and >4 MUg/ml in both first and second TDMs (group C, n=6). RESULTS: Incidences of hepatotoxicity in groups A, B and C were 16.0, 25.0 and 83.3%, and significant differences were observed between groups A and C and groups B and C. Multiple logistic regression analysis identified the classification into groups A, B and C as an independent variable of hepatotoxicity. CONCLUSIONS: These results suggest that sustained high trough concentration of voriconazole may increase the risk of hepatotoxicity, and decreasing trough concentration to <4 MUg/ml by dose adjustment after the initial TDM may reduce the incidence of hepatotoxicity in patients treated with voriconazole. PMID- 23747485 TI - Molecular mechanism of membrane binding of the GRP1 PH domain. AB - The pleckstrin homology (PH) domain of the general receptor of phosphoinositides 1 (GRP1) protein selectively binds to a rare signaling phospholipid, phosphatidylinositol (3,4,5)-trisphosphate (PIP3), in the membrane. The specific PIP3 lipid docking of GRP1 PH domain is essential to protein cellular function and is believed to occur in a stepwise process, electrostatic-driven membrane association followed by the specific PIP3 binding. By a combination of all-atom molecular dynamics (MD) simulations, coarse-grained analysis, electron paramagnetic resonance (EPR) membrane docking geometry, and fluorescence resonance energy transfer (FRET) kinetic studies, we have investigated the search and bind process in the GRP1 PH domain at the molecular scale. We simulated the two membrane binding states of the GRP1 PH domain in the PIP3 search process, before and after the GRP1 PH domain docks with the PIP3 lipid. Our results suggest that the background anionic phosphatidylserine lipids, which constitute around one-fifth of the membrane by composition, play a critical role in the initial stages of recruiting protein to the membrane surface through non-specific electrostatic interactions. Our data also reveal a previously unseen transient membrane association mechanism that is proposed to enable a two-dimensional "hopping" search of the membrane surface for the rare PIP3 target lipid. We further modeled the PIP3-bound membrane-protein system using the EPR membrane docking structure for the MD simulations, quantitatively validating the EPR membrane docking structure and augmenting our understanding of the binding interface with atomic-level detail. Several observations and hypotheses reached from our MD simulations are also supported by experimental kinetic studies. PMID- 23747487 TI - FEM simulation of the die compaction of pharmaceutical products: influence of visco-elastic phenomena and comparison with experiments. AB - This work studies the influence of visco-elastic behavior in the finite element method (FEM) modeling of die compaction of pharmaceutical products and how such a visco-elastic behavior may improve the agreement between experimental and simulated compression curves. The modeling of the process was conducted on a pharmaceutical excipient, microcrystalline cellulose (MCC), by using Drucker Prager cap model coupled with creep behavior in Abaqus((r)) software. The experimental data were obtained on a compaction simulator (STYLCAM 200R). The elastic deformation of the press was determined by performing experimental tests on a calibration disk and was introduced in the simulation. Numerical optimization was performed to characterize creep parameters. The use of creep behavior in the simulations clearly improved the agreement between the numerical and experimental compression curves (stresses, thickness), mainly during the unloading part of the compaction cycle. For the first time, it was possible to reproduce numerically the fact that the minimum tablet thickness is not obtained at the maximum compression stress. This study proves that creep behavior must be taken into account when modeling the compaction of pharmaceutical products using FEM methods. PMID- 23747488 TI - The use and misuse of statistical methodologies in pharmacology research. AB - Descriptive, exploratory, and inferential statistics are necessary components of hypothesis-driven biomedical research. Despite the ubiquitous need for these tools, the emphasis on statistical methods in pharmacology has become dominated by inferential methods often chosen more by the availability of user-friendly software than by any understanding of the data set or the critical assumptions of the statistical tests. Such frank misuse of statistical methodology and the quest to reach the mystical alpha<0.05 criteria has hampered research via the publication of incorrect analysis driven by rudimentary statistical training. Perhaps more critically, a poor understanding of statistical tools limits the conclusions that may be drawn from a study by divorcing the investigator from their own data. The net result is a decrease in quality and confidence in research findings, fueling recent controversies over the reproducibility of high profile findings and effects that appear to diminish over time. The recent development of "omics" approaches leading to the production of massive higher dimensional data sets has amplified these issues making it clear that new approaches are needed to appropriately and effectively mine this type of data. Unfortunately, statistical education in the field has not kept pace. This commentary provides a foundation for an intuitive understanding of statistics that fosters an exploratory approach and an appreciation for the assumptions of various statistical tests that hopefully will increase the correct use of statistics, the application of exploratory data analysis, and the use of statistical study design, with the goal of increasing reproducibility and confidence in the literature. PMID- 23747489 TI - A bioengineered metastatic pancreatic tumor model for mechanistic investigation of chemotherapeutic drugs. AB - Here we bioengineered a metastatic pancreatic tumor model with homogenous human CD133(+)CXCR4(+) cancer stem cells (CSC) and a polyglyconate/gelatin electrospun scaffold. The scaffold sported a highly porous microstructure with the majority of fibers possessing a diameter between 500MUm and 1500MUm. The scaffold supported the growth of tumor cells without provoking apoptosis. The homogeneous CD133(+)CXCR4(+) CSC was transplanted with the scaffold into the pancreas of nude mice to establish a metastatic pancreatic tumor. After 8 weeks, the tumor volume and weight in the scaffold model were 40.52% and 51.49% greater than the traditional model, respectively. The scaffold also increased the incidence of tumor formation and readily induced a hepatic metastasis. In this model we found that FOLFIRINOX possessed a superior capability of preventing the hepatic metastasis of pancreatic tumor cells than gemcitabine. A mechanistic study attributed this superiority to the fact that FOLFIRINOX could induce a greater apoptosis of CD133(+)CXCR4(+) CSC, thus depriving the driving force of hepatic metastasis. This metastatic tumor model showed an increased incidence of tumor formation, an accelerated tumorigenesis and a significant hepatic metastasis, therefore offering scientists a proven platform to study chemotherapeutic drugs. PMID- 23747490 TI - A stability-indicating, ion-pairing, reversed-phase liquid chromatography method for studies of daunorubicin degradation in i.v. infusion fluids. AB - A new stability-indicating method based on high-performance liquid chromatography coupled to ultraviolet and evaporative light scattering detection (HPLC-UV-ELSD) was developed for the quantification of daunorubicin. This is an ion-pairing, reversed-phase method. The column was a Synergi MAX-RP C12 4 MUm (150 mm * 4.6 mm). The mobile phase was 6.2mM nonafluoropentanoic acid in aqueous solution and acetonitrile under isocratic elution mode. The drug was subjected to oxidation, basic and acid hydrolysis to apply stress conditions. Good resolution was achieved between daunorubicin, related products and all degradation products in an overall analytical run time of approximately 16 min with the parent compound daunorubicin eluting at approximately 8 min. The method was fully validated according to ICH guidelines and SFSTP protocols in terms of accuracy, precision, specificity and linearity. For daunorubicin, the decision criteria selected consisted of the acceptability limits (+/-3%) and the proportion of results within the calculated tolerance intervals (95%). In conclusion, the proposed analytical procedures were validated over the selected validation domains daunorubicin (0.25-0.45 mg/mL) and shown to provide a very effective method. Physical and chemical stability study was carried out on daunorubicin preparation in our hospital centralized pharmacy unit. PMID- 23747491 TI - Simultaneous determination of 38 phosphodiestrase-5 inhibitors in illicit erectile dysfunction products by liquid chromatography-electrospray ionization tandem mass spectrometry. AB - This paper describes the development and validation of simultaneous analytical method for 38 compounds, sildenafil, tadalafil, vardenafil and their analogues in illicit erectile dysfunction (ED) products by the liquid chromatography electrospray ionization-tandem mass method (LC-ESI-MS/MS). Chromatographic separation was performed on a C18 reversed-phase column using a gradient of solvent A: aqueous 2 mM ammonium formate solution and solvent B: acetonitrile (ACN). All components were monitored under time-scheduled multiple reaction monitoring (MRM) mode. The limits of detection (LOD) ranged from 0.004 ng/ml to 0.455 ng/ml and the limits of quantification (LOQ) ranged from 0.012 ng/ml to 1.5 ng/ml. Calibration curves were linear with correlation coefficients over 0.9991. Mean recoveries ranged from 73.6% to 111.3%, and relative standard deviation (RSD) was less than 10%. The intra- and inter-day precision ranged from 0.2% to 16.3% and from 0.2% to 17.0%, respectively. The proposed method was applied to investigate the 52 illicit ED products. PMID- 23747492 TI - Finding a niche: Magnetic resonance imaging located an often-overlooked source of uterine bleeding. PMID- 23747493 TI - A novel technique to measure in vivo uterine suspensory ligament stiffness. AB - OBJECTIVE: The purpose of this study was to describe a new computer-controlled research apparatus for measuring in vivo uterine ligament force-displacement behavior and stiffness and to present pilot data for women with and without prolapse. STUDY DESIGN: Seventeen women with varying uterine support underwent testing in the operating room (OR) after anesthetic induction. A tripod-mounted computer-controlled linear servoactuator was used to quantify force-displacement behavior of the cervix and supporting ligaments. The servoactuator applied a caudally directed force to a tenaculum at 4 mm/sec velocity until the traction force reached 17.8 N (4 lbs). Cervix location on Pelvic Organ Prolapse Quantification system (POP-Q) in the clinic, in the OR, at rest, and with minimal force (<1.1 N); maximum force (17.8 N) was recorded. Ligament "stiffness" between minimum and maximum force was calculated. RESULTS: The mean +/- SD subject age was 54.5 +/- 12.7 years; parity was 2.9 +/- 1.1; body mass index was 29.0 +/- 4.3 kg/m(2), and POP-Q point C was -3.1 +/- 3.9 cm. POP-Q point C was correlated most strongly with cervix location at maximum force (r = +0.68; P = .003) and at rest (r = +0.62; P = .009). Associations between cervix location at minimum force (r = +0.46; P = .059) and ligament stiffness (r = -0.44; P = .079) were not statistically significant. Cervix location in the OR with minimal traction lay below the lowest point found on POP-Q for 13 women. CONCLUSION: POP-Q point C was correlated strongly with cervix location at rest and at maximum traction force; however, only 19% of the variation in POP-Q point C location was explained by ligament stiffness. The cervix location in the OR at minimal traction lay below POP-Q point C value in three-fourths of the women. PMID- 23747494 TI - Evidence of the involvement of the monoaminergic systems in the antidepressant like effect of Aloysia gratissima. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aloysia gratissima (Verbenaceae) is an aromatic plant distributed in South America and, employed in folk medicine for the treatment of nervous systems illness, including depression. The neuroprotective and antidepressant-like activities of the aqueous extract of Aloysia gratissima (AE) administered orally has already been demonstrated.In this study the involvement of monoaminergic systems in the antidepressant-like effect of the AE was investigated. MATERIALS AND METHODS: The implication of the monoaminergic systems in the antidepressant-like activity of Aloysia gratissima was evaluated using different pharmacological antagonists that were administered previously to the acute oral administration of AE (10 mg/kg). The antidepressant-like effect was assessed in the TST and locomotor activity was evaluated in the open-field test in mice. RESULTS: The anti-immobility effect elicited by AE in the TST was prevented by the pre-treatment of mice with the antagonists, NAN-190 (5-HT(1A) receptor), ketanserin (5-HT(2A/2C) receptor), prazosin (alpha1-adrenoceptor), yohimbine (alpha2-adrenoceptor), SCH23390 (dopamine D1 receptor), or sulpiride (dopamine D2 receptor). CONCLUSIONS: These results indicate that the antidepressant-like effect of AE in the TST is dependent on its interaction with the serotonergic (5-HT(1A) and 5-HT(2A/2C)), noradrenergic (alpha1 and alpha2 adrenoceptors) and dopaminergic (D1 and D2 receptors) systems, suggesting that this specie might act as a new potential resource for developing antidepressants to treat depressive disorders. PMID- 23747495 TI - Medical comorbidities in patients with psychogenic nonepileptic spells (PNES) referred for video-EEG monitoring. AB - Differentiating between psychogenic nonepileptic spells (PNES) and epileptic seizures without video-EEG monitoring is difficult. The presence of specific medical comorbidities may discriminate the two, helping physicians suspect PNES over epilepsy earlier. A retrospective analysis comparing the medical comorbidities of patients with PNES with those of patients with epilepsy was performed in 280 patients diagnosed with either PNES (N = 158, 74.7% females) or epilepsy (N = 122, 46.7% females) in the Epilepsy Monitoring Unit (EMU) of the University of Pittsburgh Medical Center over a two-year period. Patients with PNES, compared to those with epilepsy, were mostly female, significantly more likely to have a history of abuse, had more functional somatic syndromes (fibromyalgia, chronic fatigue syndrome, chronic pain syndrome, tension headaches, and irritable bowel syndrome), and had more medical illnesses that are chronic with intermittent attacks (migraines, asthma, and GERD). The presence of at least of one these disorders may lead physicians to suspect PNES over epilepsy and expedite appropriate referral for video-EEG monitoring for diagnosis. PMID- 23747496 TI - Everyday memory in children after resective epilepsy surgery. AB - This study investigated parent reports of everyday memory and performance on objective memory tests in children with intractable epilepsy. Participants were 119 children with epilepsy (75 of whom underwent surgery) and 57 healthy controls. The group with epilepsy was examined twice, approximately 2 years apart. Parents reported on their child's memory as manifested in everyday activities and situations, and children with epilepsy completed standardized objective memory tests. At baseline, the children with epilepsy had poorer everyday memory than the healthy control group. Memory did not change significantly over time in the children with epilepsy, and no changes were found related to surgery or to seizure outcome. Intractable epilepsy in childhood is associated with difficulty in using memory in everyday activities. Resective surgery does not result in changes in the parents' observations of their child's memory as manifested in their daily functioning or in the child's performance on objective measures of memory. PMID- 23747497 TI - Is dietary caffeine involved in seizure precipitation? AB - Caffeine acts as a central nervous stimulant by blocking A1 and A2A adenosine receptors. Its effect on seizures is complex. Animal studies and case reports indicate that acute caffeine exposure may induce seizures, whereas chronic exposure might have an opposite effect. Patients acutely hospitalized for seizures (n = 174) were asked for their consumption of caffeinated beverages 24 h prior to admission as well as their habitual caffeine intake. Twenty-four-hour caffeine consumption was also recorded in a later telephone interview on a seizure-free day (n = 154). Thus, the patients served as their own controls. Categorized data were analyzed using the Wilcoxon's signed-ranks test. No difference was found between the intake of caffeine 24 h prior to the seizure and the habitual consumption (p = 0.37) or the consumption on a seizure-free day (p = 0.13). Thus, caffeine does not appear to be a common seizure precipitant. PMID- 23747498 TI - Effects of quercetin on oxidative stress and memory retrieval in kindled rats. AB - Flavonoids are a class of polyphenolic compounds present in fruits and vegetables. Several studies have demonstrated a relationship between the consumption of flavonoid-rich diets and the prevention of human diseases including neurodegenerative disorders. Thus, we assessed the effect of quercetin (3,3',4',5,7-pentahydroxyflavone) on oxidative stress and memory retrieval using a step-through passive avoidance task in kindled rats. Quercetin (25, 50, and 100 mg/kg) was administered intraperitoneally (i.p.) before pentylenetetrazole (PTZ) every other day prior to the training. Retention tests were performed to assess memory in rats. Compared to control, pretreatment with 50 mg/kg of quercetin could attenuate seizure severity from the beginning of the kindling experiment by lowering the mean seizure stages. Moreover, quercetin 50 mg/kg significantly increased the step-through latency of the passive avoidance response compared to the control in the retention test. Malondialdehyde (MDA) levels were significantly increased in the quercetin groups compared to the PTZ group in the hippocampus and cerebral cortex following PTZ kindling. In the quercetin groups, higher sulfhydryl (SH) contents were not observed compared to the PTZ group. These results indicate that quercetin at a specific dose results in decreased seizure severity during kindling and performance improvement in a passive avoidance task in kindled rats. All doses of quercetin led to increased oxidative stress in the hippocampi and cerebral cortices of kindled rats. PMID- 23747499 TI - Cerebellar volume is linked to cognitive function in temporal lobe epilepsy: a quantitative MRI study. AB - INTRODUCTION: Chronic intractable temporal lobe epilepsy (TLE) is associated with certain comorbidities including cognitive impairment. A less common condition among patients with TLE is intermittent explosive disorder (IED), a specific form of aggressive behavior that has been linked to low intelligence and structural pathology in the amygdala. We aimed to identify other neuroanatomical substrates of both cognitive dysfunction and IED in patients with TLE, with special focus on the cerebellum, a brain region known to participate in functional networks involved in neuropsychological and affective processes. METHODS: Magnetic resonance imaging-based volumetric data from 60 patients with temporal lobe epilepsy (36 with and 24 without IED) were evaluated. Cerebellar, hippocampal, and total brain volumes were processed separately. In a total of 50 patients, the relationship between volumetric measurements and clinical and neuropsychological data (full-scale, verbal, and performance intelligence quotients) was analyzed. RESULTS: Intermittent explosive disorder in patients with TLE was not significantly linked to any of the regional volumes analyzed. However, cognitive performance showed a significant association both with total brain volume and cerebellar volume measurements, whereby the left cerebellar volume showed the strongest association. A deviation from normal cerebellar volumes was related to lower intelligence. Of note, left cerebellar volume was influenced by age and duration of epilepsy. Hippocampal volumes had a minor influence on cognitive parameters. CONCLUSION: Our findings suggest that cerebellar volume is not linked to IED in patients with TLE but is significantly associated with cognitive dysfunction. Our findings support recent hypotheses proposing that the cerebellum has a relevant functional topography. PMID- 23747500 TI - Self-perception of stigma in persons with epilepsy in Tehran, Iran. AB - Epilepsy is one of the most stigmatizing medical conditions worldwide. It could be argued that the problem of stigma and discrimination might be different in an Islamic culture. A cross-sectional study of 130 patients with epilepsy was performed using the Internalized Stigma of Mental Illness (ISMI) questionnaire that was adapted for epilepsy. The questionnaire contained 29 items on a 4-point scale in addition to an open-ended question about experience of discrimination. An average score above the midpoint (2.5) is suggested to indicate a high level of stigma. Approximately 23.7% of the patients reported a score above the midpoint. Unemployment and low education were significantly associated with a high level of internalized stigma. Although epilepsy can be effectively treated, patients in Tehran still experience much stigma. For this reason, strategies for reducing self-perception of stigma should be included in a treatment plan. PMID- 23747501 TI - Clinical features of late-onset partial cryptogenic epilepsy: toward an idiopathic temporal epilepsy? AB - Adult-onset epilepsy is commonly thought to be secondary to a brain lesion. However, the etiology of adult-onset epilepsy remains unknown in approximately 25% of patients, despite progress in medical and diagnostic tools. In the present study, we investigated whether late-onset partial cryptogenic epilepsies could be subgrouped based on seizure semiology and clinical characteristics. A total of 41 patients with late-onset cryptogenic epilepsy were included, and the corresponding clinical and electrophysiological data were analyzed. The following three clinical subgroups were identified: 1) a group that fulfilled the diagnostic criteria of transient epileptic amnesia (TEA); 2) a group with late onset cryptogenic epilepsies with a temporal seizure semiology; and 3) a cryptogenic extratemporal group, which was consistent with the categorization of cryptogenic epilepsies, i.e., epilepsies involving unknown lesions. The temporal group showed homogeneous clinical characteristics, especially a rapid evolution and a greater tendency toward generalization and pharmacoresistance compared with the other two groups. Transient epileptic amnesia was associated with a higher frequency of sleep disorders than either of the other groups. Our findings argue for the clinical identification of a subgroup of late-onset temporal epilepsy that might constitute an idiopathic form. The association between TEA and sleep disorders would suggest a possible pathophysiological role of sleep apnea syndromes in TEA. PMID- 23747502 TI - Assessment of a quasi-piezoelectric mattress monitor as a detection system for generalized convulsions. AB - The risk of sudden unexpected death in epilepsy (SUDEP) is highest with nocturnal, unattended generalized convulsions, and basic resuscitation may be able to prevent SUDEP. This study investigates an under-mattress device (ElectroMechanical Film - Emfit(r)) which is triggered by rhythmic motor activity of a specifiable duration, frequency, and intensity using a quasi-piezoelectric material sensitive to changes in mattress pressure. The device was tested during inpatient video-EEG monitoring. Eighteen GTCSs were recorded, 10 out of wakefulness and 8 out of sleep. Sixteen of the 18 seizures (89%) resulted in Emfit(r) activation with both false negative alarms occurring during wakefulness. On average, the device was activated within 9 s of onset of bilateral clonic motor movements (range: -37 to +39 s) and occurred, on average, 45 s before seizure end (range: 19 to 76 s). Only 21 false alarms were encountered, all occurring during wakefulness (PPV: 43%). The data suggest that the Emfit(r) detection device has a high predictive value for generalized convulsions, offers caregivers a reliable and early warning to assist the patient during convulsions, and may be a novel way to prevent SUDEP. PMID- 23747503 TI - Outcome of corpus callosotomy in adults. AB - We present, to our knowledge, the first published series of corpus callosotomy (CC) in adults with medically intractable symptomatic generalized epilepsy (SGE). Fifteen adults were followed for the outcome measures of seizure and antiepileptic drug (AED) burden and quality of life (QoL). Five (33%) patients reported >60%, one (7%) reported between 30 and 60%, and nine (60%) reported <30% reduction in the total number of seizures after CC. Seven (47%) patients reported >60%, three (20%) experienced between 30 and 60%, and five (33%) reported <30% atonic seizure reduction. Twelve patients had no change in AED burden. Nine (60%) patients had no change in QoL, while six (40%) reported some improvement. Corpus callosotomy should be considered as a safe option for adults with medically intractable SGE with demonstrated reduction in the frequency of atonic seizures, and some patients experience a meaningful improvement in quality of life. PMID- 23747504 TI - Degradable and biocompatible nanoparticles decorated with cyclic RGD peptide for efficient drug delivery to hepatoma cells in vitro. AB - Amphiphilic derivatives of poly(benzyl malate) were synthesized and characterized with the aim of being used as degradable and biocompatible building blocks for the design of functional nanoparticles (NPs). An anti-cancer model drug, doxorubicin, has been successfully encapsulated into the prepared NPs and its release profile has been evaluated in water and in culture medium. NPs bearing biotin molecules were prepared either for site-specific drug delivery via the targeting of biotin receptors overexpressed on the surface of several cancer cells, or for grafting biotinylated cyclic RGD peptide onto their surface using the strong and highly specific interactions between biotin and the streptavidin protein. We have shown that this binding did not affect dramatically the physico chemical properties of the corresponding NPs. Cyclic RGD grafted fluorescent NPs were more efficiently uptaken by the HepaRG hepatoma cells than biotinylated fluorescent NPs. Furthermore, the targeting of HepaRG hepatoma cells with NPs bearing cyclic RGD was very efficient and much weaker for HeLa and HT29 cell lines confirming that cyclic RGD is a suitable targeting agent for liver cells. Our results also provide a new mean for rapid screening of short hepatotropic peptides in order to design NPs showing specific liver targeting properties. PMID- 23747505 TI - Optimizing the taste-masked formulation of acetaminophen using sodium caseinate and lecithin by experimental design. AB - In a previous study of ours, the association of sodium caseinate and lecithin was demonstrated to be promising for masking the bitterness of acetaminophen via drug encapsulation. The encapsulating mechanisms were suggested to be based on the segregation of multicomponent droplets occurring during spray-drying. The spray dried particles delayed the drug release within the mouth during the early time upon administration and hence masked the bitterness. Indeed, taste-masking is achieved if, within the frame of 1-2 min, drug substance is either not released or the released amount is below the human threshold for identifying its bad taste. The aim of this work was (i) to evaluate the effect of various processing and formulation parameters on the taste-masking efficiency and (ii) to determine the optimal formulation for optimal taste-masking effect. Four investigated input variables included inlet temperature (X1), spray flow (X2), sodium caseinate amount (X3) and lecithin amount (X4). The percentage of drug release amount during the first 2 min was considered as the response variable (Y). A 2(4)-full factorial design was applied and allowed screening for the most influential variables i.e. sodium caseinate amount and lecithin amount. Optimizing these two variables was therefore conducted by a simplex approach. The SEM and DSC results of spray-dried powder prepared under optimal conditions showed that drug seemed to be well encapsulated. The drug release during the first 2 min significantly decreased, 7-fold less than the unmasked drug particles. Therefore, the optimal formulation that performed the best taste-masking effect was successfully achieved. PMID- 23747506 TI - Toxicity of surface-modified PLGA nanoparticles toward lung alveolar epithelial cells. AB - In vitro cytotoxicity and inflammatory response following exposure to nanoparticles (NPs) made of poly(lactide-co-glycolide) (PLGA) have been investigated on A549 human lung epithelial cells. Three different PLGA NPs (230 nm) were obtained using different stabilizers (polyvinyl alcohol, chitosan, or Pluronic((r)) F68) to form respectively neutral, positively or negatively charged NPs. Polystyrene NPs were used as polymeric but non-biodegradable NPs, and titanium dioxide (anatase and rutile) as inorganic NPs, for comparison. Cytotoxicity was evaluated through mitochondrial activity as well as membrane integrity (lactate dehydrogenase release, trypan blue exclusion, propidium iodide staining). The cytotoxicity of PLGA-based and polystyrene NPs was lower or equivalent to the one observed after exposure to titanium dioxide NPs. The inflammatory response, evaluated through the release of the IL-6, IL-8, MCP-1, TNF-alpha cytokines, was low for all NPs. However, some differences were observed, especially for negative PLGA NPs that led to a higher inflammatory response, which can be correlated to a higher uptake of these NPs. Taken together, these results show that both coating of PLGA NPs and the nature of the core play a key role in cell response. PMID- 23747507 TI - Gaining the upper hand: comparison of alphabetic and keyboard positions as spatial features of letters producing distinct S-R compatibility effects. AB - The present study explored which stimulus feature, alphabetic or keyboard position, primarily influences letter processing in different task settings. In Experiment 1 (alphabetic position judgment) a response side effect (faster responses when the location of letters within the alphabet or on the keyboard maps onto the response hand) could be observed for alphabetic position as task relevant stimulus feature. In Experiments 2 and 3 participants responded to a non spatial stimulus feature (uppercase-lowercase classification) so that both attributes can be characterized as task-irrelevant. The pattern indicated that a keyboard position-hand correspondence effect emerged independent of the time window (after stimulus onset) in which the response was given. However, an alphabetic position-hand correspondence effect only emerged when participants were forced to delay their responses by 450ms. The overall pattern indicated that although both features were processed and translated into a spatial code reflecting their position within the alphabet vs. on the keyboard, the relevance of these features to the task as well as the time that elapsed since stimulus onset determined which attribute of the letters was effective in yielding a stimulus-response compatibility effect. PMID- 23747508 TI - Distractors less salient than targets capture attention rather than producing non spatial filtering costs. AB - Distractors that are less salient than the target evoke reaction time interference in the distractor search paradigm. Here, we investigated whether this interference indeed results from spatial attentional capture or merely from non-spatial filtering costs. Target and distractor salience was manipulated parametrically and the modulation of reaction time interference by the distance between both stimuli was taken as an indicator of attentional capture. For distractors that were less salient than the target, we found distance to be predictive of reaction time interference. Moreover, this relationship was modulated by the difference in relative salience of target and distractor: the less salient the distractor was compared to the target, the weaker was the influence of distance. These results are in accordance with the sequential sampling model of salience-based selection by Zehetleitner et al. (Zehetleitner, M., Koch, A.I., Goschy, H., Muller, H.J., 2013. Salience-based selection: Interference by distractors less salient than the target. PLoS ONE 8: e52595.). This model assumes the salience map to be computed by noisy accumulation of sensory evidence. As a result, the salience map output fluctuates around its true value and less salient locations can be denoted as most salient. A distractor less salient than the target can therefore capture attention with a certain probability. We conclude that reaction time interference by less salient distractors in the distractor search paradigm is a result of attentional capture in a proportion of trials, rather than a result of non-spatial filtering costs. PMID- 23747509 TI - The antiviral cytokines IFN-alpha and IFN-beta modulate parietal epithelial cells and promote podocyte loss: implications for IFN toxicity, viral glomerulonephritis, and glomerular regeneration. AB - Interferon (IFN)-alpha and IFN-beta are the central regulators of antiviral immunity but little is known about their roles in viral glomerulonephritis (eg, HIV nephropathy). We hypothesized that IFN-alpha and IFN-beta would trigger local inflammation and podocyte loss. We found that both IFNs consistently activated human and mouse podocytes and parietal epithelial cells to express numerous IFN stimulated genes. However, only IFN-beta significantly induced podocyte death and increased the permeability of podocyte monolayers. In contrast, only IFN-alpha caused cell-cycle arrest and inhibited the migration of parietal epithelial cells. Both IFNs suppressed renal progenitor differentiation into mature podocytes. In Adriamycin nephropathy, injections with either IFN-alpha or IFN beta aggravated proteinuria, macrophage influx, and glomerulosclerosis. A detailed analysis showed that only IFN-beta induced podocyte mitosis. This did not, however, lead to proliferation, but was associated with podocyte loss via podocyte detachment and/or mitotic podocyte death (mitotic catastrophe). We did not detect TUNEL-positive podocytes. Thus, IFN-alpha and IFN-beta have both common and differential effects on podocytes and parietal epithelial cells, which together promote glomerulosclerosis by enhancing podocyte loss while suppressing podocyte regeneration from local progenitors. PMID- 23747510 TI - Regulation of pathogenic Th17 cell differentiation by IL-10 in the development of glomerulonephritis. AB - Although it is clear that T helper (Th)17 cells play a pathologic role in the pathogenesis of several inflammatory diseases, the contribution and regulation of pathogenic Th17 cells in the development of glomerulonephritis are still not fully understood. Herein, we show that IL-10-deficient mice exhibit exacerbation of glomerulonephritis after induction with anti-glomerular basement membrane globulin, with enhanced pathogenic Th17 immune responses. We further demonstrate that Rag1(-/-) mice reconstituted with IL-10(-/-) CD4(+) T cells develop more severe glomerulonephritis after induction of anti-glomerular basement membrane disease, with more infiltration of inflammatory cells into the kidneys. Finally, IL-17 and interferon gamma double-positive cells were significantly increased in IL-10(-/-) CD4(+) T-cell cultures under pathogenic Th17 conditions compared with wild-type cell cultures. These findings suggest that T-cell-derived IL-10 plays a critical suppressive role in the control of pathogenic Th17 cell differentiation and highlights the importance of IL-10 as protection against glomerulonephritis development. PMID- 23747511 TI - Complement component C3 plays a critical role in protecting the aging retina in a murine model of age-related macular degeneration. AB - Complement component C3 is the central complement component and a key inflammatory protein activated in age-related macular degeneration (AMD). AMD is associated with genetic variation in complement proteins that results in enhanced activation of C3 through the complement alternative pathway. These include complement factor H (CFH), a negative regulator of C3 activation. Both C3 inhibition and/or CFH augmentation are potential therapeutic strategies in AMD. Herein, we examined retinal integrity in aged (12 months) mice deficient in both factors H and C3 (CFH(-/-).C3(-/-)), CFH alone (CFH(-/-)), or C3 alone (C3(-/-)), and wild-type mice (C57BL/6). Retinal function was assessed by electroretinography, and retinal morphological features were analyzed at light and electron microscope levels. Retinas were also stained for amyloid beta (Abeta) deposition, inflammation, and macrophage accumulation. Contrary to expectation, electroretinograms of CFH(-/-).C3(-/-) mice displayed more severely reduced responses than those of other mice. All mutant strains showed significant photoreceptor loss and thickening of Bruch's membrane compared with wild-type C57BL/6, but these changes were greater in CFH(-/-).C3(-/-) mice. CFH(-/-).C3(-/ ) mice had significantly more Abeta on Bruch's membrane, fewer macrophages, and high levels of retinal inflammation than the other groups. Our data show that both uncontrolled C3 activation (CFH(-/-)) and complete absence of C3 (CFH(-/ ).C3(-/-) and C3(-/-)) negatively affect aged retinas. These findings suggest that strategies that inhibit C3 in AMD may be deleterious. PMID- 23747513 TI - Monte Carlo model of HPGe detectors used in routine lung counting. AB - An MCNP model of a pair of planar HPGe detectors (designated as: detector 3 and detector 4), that are used for routine lung counting at AECL, was developed. The model was benchmarked against experimental results, where a multi-line (152)Eu source was counted in several different geometrical arrangements. The best agreement for both detectors was achieved when side and back dead layers (of both detectors) were quadrupled, with respect to the ones quoted by their manufacturer (Canberra). In the case of detector 4, the agreement between simulated and measured spectra was within 4%, throughout the whole gamma-spectrum, spanning 70 1600 keV. The same was true for detector 3 at the lower end of the gamma spectrum. However, at the high end of the gamma-spectrum, the agreement was within 7% and 12% for (152)Eu gamma-lines at 778.9 and 1408.01 keV. PMID- 23747514 TI - Effects of ionizing radiation on Capsicum baccatum var. pendulum (Solanaceae). AB - Cytogenetic and somatic effects of various x-ray treatments were evaluated in pepper, Capsicum baccatum var. pendulum cv. "Cayenne", with the aim to assess optimal conditions for obtaining viable lines. The cytogenetic effects were quantified by counting chromosome aberrations. The level of DNA fragmentation was estimated with TUNEL test (terminal transferase mediated dUTP-fluorescein nick end labeling). Irradiation to 20 Gy with 16-h presoaking can be a suitable treatment of the selected pepper cultivar for a mutagenesis program. PMID- 23747512 TI - Neuronal-specific overexpression of a mutant valosin-containing protein associated with IBMPFD promotes aberrant ubiquitin and TDP-43 accumulation and cognitive dysfunction in transgenic mice. AB - Mutations in valosin-containing protein (VCP) cause a rare, autosomal dominant disease called inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD). One-third of patients with IBMPFD develop frontotemporal dementia, characterized by an extensive neurodegeneration in the frontal and temporal lobes. Neuropathologic hallmarks include nuclear and cytosolic inclusions positive to ubiquitin and transactive response DNA-binding protein 43 (TDP-43) in neurons and glial activation in affected regions. However, the pathogenic mechanisms by which mutant VCP triggers neurodegeneration remain unknown. Herein, we generated a mouse model selectively overexpressing a human mutant VCP in neurons to study pathogenic mechanisms of mutant VCP-mediated neurodegeneration and cognitive impairment. The overexpression of VCPA232E mutation in forebrain regions produced significant progressive impairments of cognitive function, including deficits in spatial memory, object recognition, and fear conditioning. Although overexpressed or endogenous VCP did not seem to focally aggregate inside neurons, TDP-43 and ubiquitin accumulated with age in transgenic mouse brains. TDP-43 was also found to co-localize with stress granules in the cytosolic compartment. Together with the appearance of high molecular-weight TDP-43 in cytosolic fractions, these findings demonstrate the mislocalization and accumulation of abnormal TDP-43 in the cytosol of transgenic mice, which likely lead to an increase in cellular stress and cognitive impairment. Taken together, these results highlight an important pathologic link between VCP and cognition. PMID- 23747515 TI - Identification of tubulin beta chain, thymosin beta-4-like protein 3, and cytochrome b-c1 complex subunit 1 as serological diagnostic biomarkers of gastric cancer. AB - OBJECTIVE: Despite major advances in its diagnosis and treatment, gastric cancer (GC) remains a major life-threatening disease. Treatment of the disease is further aggravated by the lack of diagnostic biomarkers that can aid in the early detection of GC and promote its favorable prognosis. The present work aims to identify novel diagnostic biomarkers for GC. DESIGN AND METHODS: The present work is a case-control study that focuses on proteomic analysis of serum from healthy volunteers and GC patients using ClinProt profiling technology based on mass spectrometry. A pattern of proteins/peptides with the ability to differentiate the studied populations was identified. Deregulated proteins/peptides differentially expressed in the serum of patients compared with healthy volunteers were identified by mass spectroscopy. RESULTS: A pattern of proteins/peptides consisting of four protein/peptide peaks at m/z 1467, 1867, 2701, and 2094 was identified. These protein/peptide peaks were able to differentiate the studied populations with close to 100% sensitivity and specificity. Three of the deregulated proteins/peptides at m/z 1867, 2701, and 2094 were identified by mass spectroscopy (LTQ Orbitrap XL) as tubulin beta chain, thymosin beta-4-like protein 3, and cytochrome b-c1 complex subunit 1, respectively. CONCLUSIONS: The pattern of proteins/peptides identified in the present work shows great potential for GC diagnosis. Deregulated proteins of tubulin beta chain, thymosin beta-4-like protein 3, and cytochrome b-c1 complex subunit 1 may be involved in the pathogenesis of GC and serve as potential serological diagnostic biomarkers. PMID- 23747516 TI - The level of endotoxemia in sepsis varies in relation to the underlying infection: Impact on final outcome. AB - Former studies of our group have shown that the innate and adaptive immune status may differ in relation with the causative infection. To this same end, it was investigated if kinetics of circulating lipopolysaccharide (LPS) leading to inflammatory response may differ. Blood was sampled from 189 patients with sepsis and 206 with severe sepsis/shock starting 24h from advent of sepsis and repeating on day 3. Serum LPS was measured by Limulus Amebocyte Lysate (LAL) assay. From 59 patients, circulating monocytes were isolated and incubated in the absence/presence of LPS. Concentrations of tumor necrosis factor-alpha (TNFalpha) were measured in supernatants by an enzyme immunoassay. In either category of severity, circulating LPS was greater among sufferers from primary Gram-negative bacteremia (BSI) and from community-acquired pneumonia (CAP) than sufferers from other underlying infections. LPS were greater among patients with BSI compared to patients with secondary Gram-negative bacteremia and patients without bacteremia. Greater decrease of circulating LPS over 48h was recorded for survivors compared to non-survivors only within sufferers from BSI and CAP. Significant endotoxemia was considered for patients with serum LPS within the upper quartile of distribution; their monocytes were less potent for release of TNFalpha. It is concluded that endotoxemia in sepsis varies greatly with the underlying infection; this is related with immunoparalysis of monocytes with implications on final outcome. PMID- 23747517 TI - Reduced white matter integrity and cognitive deficit in never-medicated chronic schizophrenia: a diffusion tensor study using TBSS. AB - BACKGROUND: Disrupted white matter (WM) integrity is the pathological hallmark of schizophrenia. Previous studies have reported the cognitive deficits that are associated with WM disruption in schizophrenia with anti-psychiatric treatment. However, no study has yet revealed the correlation between cognition and WM abnormalities in never-medicated chronic schizophrenia. METHODS: We used the diffusion tensor imaging (DTI) with tract-based spatial statistics (TBSS) approach to investigate the whole-brain difference in the WM fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) values between 17 schizophrenia patients and 17 healthy controls matched in age, gender and education level. Patients' cognition was assessed through the MATRICS Consensus Cognitive Battery (MCCB). We explored the association between WM reduction and cognitive, clinical characteristics (severity of clinical symptoms, age, age of onset, illness duration). RESULTS: Voxel-wise statistics revealed that schizophrenia patients showed significant FA reduction in left inferior longitudinal fasciculus (ILF) and left inferior fronto occipital fasciculus (IFOF), and no difference in MD, AD or RD as compared to healthy subjects. Furthermore, in the patients group, lower FA value of the left ILF and left IFOF significantly correlated with worse processing speed, as well as verbal learning and visual learning abilities. There was no correlation between the FA value and the severity of clinical symptoms, age, and age of onset or illness duration. CONCLUSION: Our results provide evidence to support that the disconnection of WM pathways may contribute to the pathophysiology of schizophrenia and suggest that the disturbance of left ILF and left IFOF integrity may contribute to cognitive deficits in schizophrenia, independent of effects of antipsychotic medication. PMID- 23747518 TI - The temporal dynamics of coherent motion processing in autism spectrum disorder: evidence for a deficit in the dorsal pathway. AB - Individuals with autism spectrum disorder (ASD) show impairments in processing coherent motion which have been proposed to be linked to a general deficit in the dorsal visual pathway. However, few studies have investigated the neural mechanisms underlying coherent motion processing in ASD. Thus, the aim of this study was to further test the hypothesis of a dorsal pathway deficit in ASD using visual evoked potentials (VEPs). 16 children and adolescents with ASD and 12 typically developing controls were examined with VEPs elicited by a random dot kinematogram. After an initial experimental sequence, where subjects were presented randomly moving dots, a fraction of the dots moved coherently (dependent on the level of coherence, 20%, 40%, or 60% of the dots) to the left or right side. Subjects were asked to detect the direction of coherent motion via button press. On the behavioural level, no significant group differences emerged. On the neural level, coherently moving dots elicited a N200 followed by a late positive potential (P400). ASD subjects exhibited a reduced N200 amplitude compared to controls. Moreover, in the ASD group, a trend for a negative relationship between N200 amplitude and a measure of autistic pathology was revealed. The present study provides strong support of a dorsal stream deficiency in the disorder and renders alternative explanations for impaired coherent motion processing in ASD less likely. Together with findings from related research fields, our data indicate that deviances in the N200 during coherent motion perception might be fundamental to ASD. PMID- 23747519 TI - PG201 downregulates the production of nitrite by upregulating heme oxygenase-1 expression through the control of phosphatidylinositol 3-kinase and NF-E2-related factor 2. AB - PG201 is an ethanol extract prepared from a specially designed botanical formulation and has previously been shown to contain strong anti-arthritic activities by controlling inflammation and cartilage destruction in two animal models [1,2]. In the present study, we evaluated the effects of PG201 on the expression of heme oxygenase-1 (HO-1). The treatment of Raw264.7 cells (a murine macrophage cell line) and bone marrow-derived macrophages (BMDMs) with PG201 increased the protein and RNA levels of HO-1. The results from a reporter plasmid assay indicated that PG201 induced HO-1 promoter activity through the stress response element present in the two enhancers of the HO-1 promoter. The treatment of cells with PG201 increased the total amount and the nuclear level of NF-E2 related factor 2 (Nrf2). Protein analysis using BMDMs from Nrf2 knockout mice showed that Nrf2 was necessary for the PG201-mediated induction of HO-1 expression. The PG201-mediated induction of these anti-oxidative stress factors was inhibited by a specific inhibitor of phosphatidylinositol 3-kinase (PI3K), but not by inhibitors of p38, ERK and JNK mitogen-activated protein kinases. Furthermore, the results from an experiment involving a specific siRNA and chemical inhibitors for HO-1 showed that the PG201-mediated increase of the HO-1 protein contributed to the suppression of inducible nitric oxide synthase (iNOS) and nitrite production stimulated by lipopolysaccharide. Taken together, these results suggest that PG201 activates Nrf2 through the PI3K signal transduction pathway, increases the expression of HO-1, and subsequently decreases the production of iNOS and nitrite, eventually exerting anti-inflammatory activities. PMID- 23747520 TI - Bioanodes/biocathodes formed at optimal potentials enhance subsequent pentachlorophenol degradation and power generation from microbial fuel cells. AB - Bioanodes formed at an optimal potential of 200 mV vs. SHE and biocathodes developed at -300 mV vs. SHE in bioelectrochemical cells (BECs) enhanced the subsequent performances of microbial fuel cells (MFCs) compared to the un-treated controls. While the startup times were reduced to 320 h (bioanodes) and 420-440 h (biocathodes), PCP degradation rates were improved by 28.5% (bioanodes) and 21.5% (biocathodes), and power production by 41.7% (bioanodes) and 44% (biocathodes). Accordingly, there were less accumulated products of PCP de-chlorination in the biocathodes whereas PCP in the bioanodes was more efficiently de-chlorinated, resulting in the formation of a new product of 3,4,5-trichlorophenol (24.3 +/- 2.2 MUM at 96 h). Charges were diverted to more generation of electricity in the bioanodes at 200 mV while oxygen in the biocathodes at -300 mV acted as a primary electron acceptor. Dominant bacteria known as recalcitrant organic degraders and/or exoelectrogens/electrotrophs included Desulfovibrio carbinoliphilus and Dechlorospirillum sp. on the bioanodes at 200 mV, and Desulfovibrio marrakechensis, Comamonas testosteroni and Comamonas sp. on the biocathodes at 300 mV. These results demonstrated that an optimal potential was a feasible approach for developing both bioanodes and biocathodes for efficient PCP degradation and power generation from MFCs. PMID- 23747521 TI - Activation of intracellular phosphoinositide signaling after a single 600 nanosecond electric pulse. AB - Exposure to nanosecond pulsed electrical fields (nsPEFs) results in a myriad of observable effects in mammalian cells. While these effects are often attributed to the direct permeabilization of both the plasma and organelle membranes, the underlying mechanism(s) are not well understood. We hypothesize that nsPEF induced membrane disturbance will initiate complex intracellular lipid signaling pathways, which ultimately lead to the observed multifarious effects. In this article, we show activation of one of these pathways--phosphoinositide signaling cascade. Here we demonstrate that nsPEF initiates phosphatidylinositol 4,5 bisphosphate (PtdIns(4,5)P2) hydrolysis or depletion from the plasma membrane, accumulation of inositol-1,4,5-trisphosphate (IP3) in the cytoplasm and increase of diacylglycerol (DAG) on the inner surface of the plasma membrane. All of these events are initiated by a single 16.2 kV/cm, 600 ns pulse exposure. To further this claim, we show that the nsPEF-induced activation mirrors the response of M1 acetylcholine Gq/11-coupled metabotropic receptor (hM1). This demonstration of PIP2 hydrolysis by nsPEF exposure is an important step toward understanding the mechanisms underlying this unique stimulus for activation of lipid signaling pathways and is critical for determining the potential for nsPEFs to modulate mammalian cell functions. PMID- 23747522 TI - Growing diversity of trypanosomatid parasites of flies (Diptera: Brachycera): frequent cosmopolitism and moderate host specificity. AB - Widely distributed, highly prevalent and speciose, trypanosomatid flagellates represent a convenient model to address topics such as host specificity, diversity and distribution of parasitic protists. Recent studies dealing with insect parasites of the class Kinetoplastea have been focused mainly on trypanosomatids from true bugs (Heteroptera), even though flies (Diptera, Brachycera) are also known as their frequent hosts. Phylogenetic position, host specificity and geographic distribution of trypanosomatids parasitizing dipteran hosts collected in nine countries on four continents (Bulgaria, Czech Republic, Ecuador, Ghana, Kenya, Madagascar, Mongolia, Papua New Guinea and Turkey) are presented. Spliced leader (SL) RNA gene repeats and small subunit (SSU) rRNA genes were PCR amplified from trypanosomatids infecting the gut of a total of forty fly specimens belonging to nine families. While SL RNA was mainly used for barcoding, SSU rRNA was utilized in phylogenetic analyses. Thirty-six different typing units (TUs) were revealed, of which 24 are described for the first time and represent potential new species. Multiple infections with several TUs are more common among brachyceran hosts than in true bugs, reaching one third of cases. When compared to trypanosomatids from heteropteran bugs, brachyceran flagellates are more host specific on the genus level. From seven previously recognized branches of monoxenous trypanosomatids, the Blastocrithidia and "jaculum" clades accommodate almost solely parasites of Heteroptera; two other clades (Herpetomonas and Angomonas) are formed primarily by flagellates found in dipteran hosts, with the most species-rich Leishmaniinae and the small Strigomonas and "collosoma" clades remaining promiscuous. Furthermore, two new clades of trypanosomatids from brachyceran flies emerged in this study. While flagellates from brachyceran hosts have moderate to higher host specificity, geographic distribution of at least some of them seems to be cosmopolitan. Moreover, the genus Angomonas, so far known only from South America, is present on other continents as well. PMID- 23747523 TI - Snowdrops falling slowly into place: an improved phylogeny for Galanthus (Amaryllidaceae). AB - Snowdrops (Galanthus, 20 spp.; Amaryllidaceae) are cherished garden plants and the world's most traded wild-sourced ornamental bulb genus. Despite their popularity and economic importance, species delimitation is problematic and the infrageneric classification uncertain. We present a molecular phylogenetic study of Galanthus with the aim of resolving these issues and to better understand the evolution within the genus. Sequences of nuclear encoded nrITS, and plastid encoded matK, trnLF, ndhF, and psbK-psbI, for all currently recognised species and two naturally occurring putative hybrids, were analysed using maximum parsimony and Bayesian inference. Phylogenetic analysis of Galanthus, based on nuclear ITS sequences, provides a well-resolved topology, including seven well supported named clades (platyphyllus, trojanus, ikariae, elwesii, nivalis, woronowii, and alpinus), and five major clades (A-E). The recovered ITS topology is in accordance with the geographical distribution of Galanthus species. The combined plastid data set provided far less resolution than that of ITS, with generally lower levels of statistical support, and one case of significant incongruence with the ITS dataset (involving G. gracilis). Phylogenetic network and hybridization analyses identified several possible hybridization events but these are more likely to be due to the result of a lack of resolution in the plastid dataset. The putative natural hybrid, G. *valentinei nothosubsp. subplicatus, is supported by our data and analyses, whereas a hybrid origin for G. *allenii is not. ITS and plastid data indicated that some Galanthus species are in need of taxonomic recircumscription. PMID- 23747524 TI - Modeling bacterial colonization and infection routes in health care settings: analytic and numerical approaches. AB - Health-care associated infections are a major problem in our society, accounting for tens of thousands of patient deaths and millions of dollars in wasted health care expenditures each year. Many of these infections are caused by bacteria that are transmitted from patient to patient either through direct contact or via the hands or clothing of health care workers. Because of the complexity of bacterial transmission routes in health care settings, computational approaches are essential, though often analytically intractable. Here we describe the construction and detailed analysis of a model for bacterial transmission in health care settings. Our model includes both colonization and disease stages for patients and health care workers, as well as an isolation ward and both patient patient and patient-HCW-patient transmission pathways. We explicitly derive the basic reproductive ratio for this complex model, a nine-term expression that contains all nine ways with which a new colonization can occur. Using key parameters found in the medical literature, we use our model to gain insight into the relative importance of various bacterial transmission pathways within health care facilities, and to identify which forms of interventions are likely to prove most effective in hospitals and long-term care settings. We show that analytical and numerical approaches can complement each other as we seek to untangle the complex web of interactions that occur within a health care facility. PMID- 23747525 TI - Decoding synchronized oscillations within the brain: phase-delayed inhibition provides a robust mechanism for creating a sharp synchrony filter. AB - The widespread presence of synchronized neuronal oscillations within the brain suggests that a mechanism must exist that is capable of decoding such activity. Two realistic designs for such a decoder include: (1) a read-out neuron with a high spike threshold, or (2) a phase-delayed inhibition network motif. Despite requiring a more elaborate network architecture, phase-delayed inhibition has been observed in multiple systems, suggesting that it may provide inherent advantages over simply imposing a high spike threshold. In this work, we use a computational and mathematical approach to investigate the efficacy of the phase delayed inhibition motif in detecting synchronized oscillations. We show that phase-delayed inhibition is capable of creating a synchrony detector with sharp synchrony filtering properties that depend critically on the time course of inputs. Additionally, we show that phase-delayed inhibition creates a synchrony filter that is far more robust than that created by a high spike threshold. PMID- 23747526 TI - Immunological effects of Anticarsia gemmatalis multiple nucleopolyhedrovirus (AgMNPV) by stimulation of mice in vivo and in vitro. AB - Baculoviruses are highly specific and only capable of replication in arthropod hosts. The Autographa californica multiple nucleopolyhedrovirus (AcMNPV) is the most studied baculovirus at the molecular level and the Anticarsia gemnatalis multiple nucleopolyhedrovirus (AgMNPV) is the most used viral insecticide worldwide. AcMNPV have also been shown to stimulate the mammalian immune response acting as an adjuvant. In order to evaluate the effects of AgMNPV in modulating macrophage and lymphocyte activation, we have stimulated these cells in vitro and inoculated BALB/c mice intranasally with the two viral phenotypes (PIBs and BVs) and compared with the response induced by the same phenotypes of AcMNPV. Our results showed that baculoviruses are able to modulate mammalian immune response; in vitro they increase phagocytosis, NO2 production and Th1 cells response. In vivo, AgMNPV BVs or PIBs do not induce an inflammatory reaction in normal lung but during a fungal lung infection they can change the type of adaptive response developed. Considering our data, AgMNPV can be considered more useful as a vaccine vector or immune adjuvant than AcMNPV. PMID- 23747527 TI - Ranking TEM cameras by their response to electron shot noise. AB - We demonstrate two ways in which the Fourier transforms of images that consist solely of randomly distributed electrons (shot noise) can be used to compare the relative performance of different electronic cameras. The principle is to determine how closely the Fourier transform of a given image does, or does not, approach that of an image produced by an ideal camera, i.e. one for which single electron events are modeled as Kronecker delta functions located at the same pixels where the electrons were incident on the camera. Experimentally, the average width of the single-electron response is characterized by fitting a single Lorentzian function to the azimuthally averaged amplitude of the Fourier transform. The reciprocal of the spatial frequency at which the Lorentzian function falls to a value of 0.5 provides an estimate of the number of pixels at which the corresponding line-spread function falls to a value of 1/e. In addition, the excess noise due to stochastic variations in the magnitude of the response of the camera (for single-electron events) is characterized by the amount to which the appropriately normalized power spectrum does, or does not, exceed the total number of electrons in the image. These simple measurements provide an easy way to evaluate the relative performance of different cameras. To illustrate this point we present data for three different types of scintillator coupled camera plus a silicon-pixel (direct detection) camera. PMID- 23747528 TI - Thioredoxin inhibits MPK38-induced ASK1, TGF-beta, and p53 function in a phosphorylation-dependent manner. AB - Murine protein serine-threonine kinase 38 (MPK38) is a member of the AMP activated protein kinase-related serine/threonine kinase family. The factors that regulate MPK38 activity and function are not yet elucidated. Here, thioredoxin (Trx) was shown to be a negative regulator of MPK38. The redox-dependent association of MPK38 and Trx was mediated through the C-terminal domain of MPK38. Single and double amino acid substitution mutagenesis of MPK38 (C286S, C339S, C377S, and C339S/C377S) and Trx (C32S, C35S, and C32S/C35S) demonstrated that Cys(339) and Cys(377) of MPK38 and Cys(32) and Cys(35) of Trx are required for MPK38-Trx complex formation. MPK38 directly interacted with and phosphorylated Trx at Thr(76). Expression of wild-type Trx, but not the Trx mutants C32S/C35S and T76A, inhibited MPK38-induced ASK1, TGF-beta, and p53 function by destabilizing MPK38. The E3 ubiquitin-protein ligase Mdm2 played a critical role in the regulation of MPK38 stability by Trx. Treatment of cells with 1-chloro-2,4 dinitrobenzene, a specific inhibitor of Trx reductase, decreased MPK38-Trx complex formation and subsequently increased MPK38 stability and activity, indicating that Trx negatively regulates MPK38 activity in vivo. Finally, we used ASK1-, Smad3-, and p53-null mouse embryonic fibroblasts to demonstrate that ASK1, Smad3, and p53 play important roles in the activity and function of MPK38, suggesting a functional link between MPK38 and ASK1, TGF-beta, and p53 signaling pathways. These results indicate that Trx functions as a physiological inhibitor of MPK38, which plays an important role in inducing ASK1-, TGF-beta-, and p53 mediated activity. PMID- 23747529 TI - Rapid fluorescent visualization of multiple NAD(P)H oxidoreductases in homogenate, permeabilized cells, and tissue slices. AB - Intracellular NAD(P)H oxidoreductases are a class of diverse enzymes that are the key players in a number of vital processes. The method we present and validate here is based on the ability of many NAD(P)H oxidoreductases to reduce the superoxide probe lucigenin, which is structurally similar to flavins, to its highly fluorescent water-insoluble derivative dimethylbiacridene. Two modifications of the method are proposed: (i) an express method for tissue homogenate and permeabilized cells in suspensions and (ii) a standard procedure for cells in culture and acute thin tissue slices. The method allows one to assess, visualize, and localize, using fluorescent markers of cellular compartments, multiple NADH and NADPH oxidoreductase activities. The application of selective inhibitors (e.g., VAS2870, a NOX2 inhibitor; plumbagin, a NOX4 inhibitor) allows one to distinguish and compare specific NAD(P)H oxidoreductase activities in cells and tissues and to attribute them to known enzymes. The method is simple, rapid, and flexible. It can be easily adapted to a variety of tasks. It will be useful for investigations of the role of various NAD(P)H oxidoreductases in a number of physiological and pathophysiological processes. PMID- 23747530 TI - Stain-Free total protein staining is a superior loading control to beta-actin for Western blots. AB - Semi-quantification of proteins using Western blots typically involves normalization against housekeeping genes such as beta-actin. More recently, Ponceau S and Coomassie blue staining have both been shown to be suitable alternatives to housekeeping genes as loading controls. Stain-Free total protein staining offers the advantage of no staining or destaining steps. Evaluation of the use of Stain-Free staining as an alternative to beta-actin or the protein stain Ponceau S showed that Stain-Free staining was superior to beta-actin and as good as or better than Ponceau S staining as a loading control for Western blots. PMID- 23747531 TI - Isopentenyl diphosphate and dimethylallyl diphosphate/isopentenyl diphosphate ratio measured with recombinant isopentenyl diphosphate isomerase and isoprene synthase. AB - Isopentenyl diphosphate (IDP) and its isomer dimethylallyl diphosphate (DMADP) are building units for all isoprenoids; thus, intracellular pool sizes of IDP and DMADP play important roles in living organisms. Several methods have been used to quantify the amount of DMADP or the combined amount of IDP plus DMADP, but measuring the DMADP/IDP ratio has been difficult. In this study, a method was developed to measure the ratio of DMADP/IDP. Catalyzed by a recombinant IDP isomerase (IDI) together with a recombinant isoprene synthase (IspS), IDP was converted to isoprene, which was then detected by chemiluminescence. With this method, the in vitro equilibrium ratio of DMADP/IDP was found to be 2.11:1. IDP and DMADP pools were significantly increased in Escherichia coli transformed with methylerythritol 4-phosphate pathway genes; the ratio of DMADP/IDP was 3.85. An E. coli strain transformed with IspS but no additional IDI had a lower DMADP level and a DMADP/IDP ratio of 1.05. Approximately 90% of the IDP and DMADP pools in light-adapted kudzu leaves were light dependent and so presumably were located in the chloroplasts; the DMADP/IDP ratios in chloroplasts and cytosol were the same as the in vitro ratio (2.04 in the light and 2.32 in the dark). PMID- 23747532 TI - Real-time monitoring of disintegration activity of catalytic core domain of HIV-1 integrase using molecular beacon. AB - HIV-1 integrase, an essential enzyme for retroviral replication, is a validated target for anti-HIV therapy development. The catalytic core domain of integrase (IN-CCD) is capable of catalyzing disintegration reaction. In this work, a hairpin-shaped disintegration substrate was designed and validated by enzyme linked immunosorbent assay; a molecular beacon-based assay was developed for disintegration reaction of IN-CCD. Results showed that the disintegration substrate could be recognized and catalyzed by IN-CCD, and the disintegration reaction can be monitored according to the increase of fluorescent signal. The assay can be applied to real-time detection of disintegration with advantages of simplicity, high sensitivity, and excellent specificity. PMID- 23747533 TI - Dispersive solid phase extraction combined with ion-pair ultra high-performance liquid chromatography tandem mass spectrometry for quantification of nucleotides in Lactococcus lactis. AB - Analysis of intracellular metabolites in bacteria is of utmost importance for systems biology and at the same time analytically challenging due to the large difference in concentrations, multiple negative charges, and high polarity of these compounds. To challenge this, a method based on dispersive solid phase extraction with charcoal and subsequent analysis with ion-pair liquid chromatography coupled with electrospray ionization tandem mass spectrometry was established for quantification of intracellular pools of the 28 most important nucleotides. The method can handle extracts where cells leak during the quenching. Using a Phenyl-Hexyl column and tributylamine as volatile ion-pair reagent, sufficient retention and separation was achieved for mono-, di-, and triphosphorylated nucleotides. Stable isotope labeled nucleotides were used as internal standards for some analytes. The method was validated by determination of the recovery, matrix effects, accuracy, linearity, and limit of detection based on spiking of medium blank as well as standard addition to quenched Lactococcus lactis samples. For standard addition experiments, the isotope labeled standards needed to be added in similar or higher concentrations as the analytes. L. lactis samples had an energy charge of 0.97 +/- 0.001 which was consistent with literature, whereas some differences were observed compared with legacy data based on 33P labeling. PMID- 23747534 TI - Xanthine microsensor based on polypyrrole molecularly imprinted film modified carbon fiber microelectrodes. AB - A molecularly imprinted polymers (MIPs) microsensor was presented as a carbon fiber microelectrode (CFME) coating for specifically recognizing xanthine (Xan). The polymeric film was obtained based on the imprinted procedure of electropolymerization of pyrrole in the presence of the template molecule Xan by cyclic voltammetry, and template was removed by magnetic stirring. Under the optimum conditions, a satisfactory molecularly binding selectivity of Xan was obtained from the MIPs microsensor with an imprinting factor (IF) of 6.63 and a linear response to concentration in certain ranges. The ranges are from 4.0 * 10 6 to 6.0 * 10-5 M and from 8.0 * 10-5 to 2.0 * 10-3 M with a detection limit of 2.5 * 10-7 M. Meanwhile, good stability (relative standard deviation [RSD] = 3.2%, n = 10) and reproducibility (RSD = 2.0%, n = 10) were observed, and recoveries ranging from 96.9 to 102.5% were calculated when applied to Xan determination in real blood serum samples. PMID- 23747535 TI - Fluorescence spectra decomposition by asymmetric functions: Laurdan spectrum revisited. AB - Due to their asymmetric nature, complex fluorescence spectra of molecules can be analyzed much better by log-normal distributions than by Gaussian ones. So far, the log-normal function has been used for deconvolution of emission spectra of different fluorescent molecules, such as Tryptophan and Prodan, but to our knowledge it is far less used for Laurdan (2-dimethylamino-6-lauroylnaphthalene). In this article, we present the decomposition of Laurdan emission spectra in large unilamellar vesicles using a procedure that relies on the log-normal asymmetric function. The procedure was calibrated using Laurdan spectra in homogeneous solutions of various solvents. Comparing our results with the ones obtained from a Gaussian fit, we show that (i) the position of the elementary peaks (~440 and 490 nm) is preserved in a large range of temperatures that include the main phase transition of lipid bilayer and (ii) the bilayer hydration, as reported by Laurdan, increases approximately 8 times from the gel phase to the liquid crystalline one, a result that fits with other reports, providing a more realistic description. In addition, we propose a new parameter to globally evaluate Laurdan emission spectra with the prospect of acquiring a larger range of values than the classical "generalized polarization". PMID- 23747536 TI - Methanol extract of Evodia lepta displays Syk/Src-targeted anti-inflammatory activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Evodia lepta (Spreng.) Merr., in the Rutaceae family, is a medicinal plant traditionally used to treat inflammatory symptoms such as in meningitis and hepatitis. However, no study has systematically investigated its anti-inflammatory activities including its molecular mechanism. MATERIALS AND METHODS: The effects of a methanol extract from the roots Evodia lepta (El-ME) were evaluated using lipopolysaccharide (LPS)-treated RAW264.7 cells producing nitric oxide (NO) and prostaglandin E2 (PGE2), and an HCl/ethanol induced mouse gastritis model. Target molecules were identified by analyzing the activation of transcription factors and their upstream kinases. RESULTS: El-ME reduced the production of NO and PGE2 from LPS-activated RAW264.7 cells in a dose dependent manner. El-ME also ameliorated the gastritis symptoms of EtOH/HCl treated mice. The extract suppressed production of mRNA for the inducible NO synthase (iNOS) and cyclooxygenase (COX)-2; the nuclear translocation of nuclear factor (NF)-kappaB; the phosphorylation of upstream kinases that activate NF kappaB; and the kinase activities of Syk and Src. CONCLUSION: The anti inflammatory effects of El-ME might be due to its suppression of Syk/Src and NF kappaB. Considering the in vitro and in vivo efficacy of El-ME, Evodia lepta could be developed into an anti-inflammatory herbal remedy. PMID- 23747537 TI - Analgesic effects of glycoproteins from Panax ginseng root in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The root of Panax ginseng C.A. Mey has various beneficial pharmacological effects. The present study aimed to evaluate the analgesic activities of glycoproteins from the root of Panax ginseng C.A. Mey in mice. MATERIALS AND METHODS: Glycoproteins were isolated and purified from the root of Panax ginseng C.A. Mey. Physicochemical properties and molecular mass were determined by chemical assay and HPLC. Acetic acid-induced writhing and hot plate tests were employed to study the analgesic effect of glycoproteins and compared with that of aspirin or morphine. The locomotor activity was tested in mice by using actophometer. RESULTS: Four glycoproteins were obtained. The glycoproteins which protein content was the highest (73.04%) displayed dose dependent analgesic effect. In writhing test, the glycoproteins significantly inhibited writhes (P<0.001) at the dose of 20 mg/kg by intraperitoneal injection. In hot-plate test, only at the dose of 20 mg/kg prolong the hot-plate latency (P<0.05, at 30 min). In the locomotor activity test, the glycoproteins were significant decrease of motility counts at the dose of 20 and 40 mg/kg. CONCLUSION: These findings collectively indicate that the glycoproteins from the root of Panax ginseng C.A. Mey exhibited significant analgesic activities and the proteins were the active site, providing evidence for its pharmacal use. PMID- 23747538 TI - Aqueous ethanol extract of the fruit of Xylopia aethiopica (Annonaceae) exhibits anti-anaphylactic and anti-inflammatory actions in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Xylopia aethiopica has been traditionally used in the form of the dried fruit decoction to treat bronchitis, asthma, arthritis and rheumatism in Ghana, Nigeria and Cameroon. Aim of the study is to evaluate the anti-anaphylactic and anti-inflammatory effects of a 70% aqueous ethanol extract of the fruits of Xylopia aethiopica. MATERIALS AND METHODS: Systemic anaphylaxis was induced by the injection of either compound 48/80 or lipopolysaccharide, LPS and survival rates of mice monitored for 1 h or 7 days respectively while IgE mediated anaphylaxis in a local allergic reaction was studied in the pinnal inflammation model in mice. Clonidine-induced catalepsy in mice was used to evaluate the indirect antihistamine effect of Xylopia aethiopica, XAE. The effects of XAE assessed on the maximal and total oedema responses in the carrageenan-induced paw oedema in mice was used to evaluate the anti-inflammatory action of the extract. RESULTS: Administered at 30, 100, 300 and 1000 mg kg(-1) p.o., XAE dose dependently suppressed compound 48/80-induced mouse systemic anaphylactic shock and offered 63% protection to mice against LPS-induced endotoxic shock at a dose of 300 mg kg(-1). In addition, the extract (30-300 mg kg(-1)) in a dose dependent manner significantly inhibited by 23-62% the mouse pinnal inflammation. Clonidine-induced catalepsy in mice was significantly suppressed in a dose and time dependent manner when administered both prophylactically and therapeutically. In the same doses, when administered before the induction of the mouse carrageenan-induced paw oedema, the mean maximal swelling attained during 6 h was reduced to 41.02+/-6.94%, 35.61+/-4.30%, and 29.09+/-4.90% of the inflamed control response respectively and total paw swellings induced over the 6 h were also dose-dependently and significantly suppressed to 74.84+/-14.84%, 63.95+/-9.37%, and 48.13+/-10.90% of the inflamed control response respectively. Administered after the induction of the carrageenan paw oedema the mean maximal swelling attained during 6 h was suppressed to 49.84+/-3.95%, 43.62+/-1.01%, and 35.97+/-1.34% of the inflamed control response respectively while the total paw swellings induced over the 6 h were also dose-dependently and significantly suppressed at 100 and 300 mg kg(-1) to 72.39+/-4.38% and 60.81+/-3.25% of the inflamed control response respectively. CONCLUSION: These findings suggest that XAE inhibits mast cell-dependent immediate allergic reactions and exhibit anti-inflammatory actions through the inhibition of histamine release from mast cells via stabilizing the cell membrane. Our results contribute towards validation of the traditional use of Xylopia aethiopica in the treatment of bronchitis, asthma, arthritis and rheumatism. PMID- 23747539 TI - Photo-bio-synthesis of irregular shaped functionalized gold nanoparticles using edible mushroom Pleurotus florida and its anticancer evaluation. AB - A green chemistry approach to the synthesis of gold nanoparticles using edible mushroom Pleurotus florida (Oyster mushroom) by photo-irradiation method has been attempted. The mixture containing the aqueous gold ions and the mushroom extract was exposed to sunlight; this resulted in the formation of biofunctionalized gold nanoparticles. These nanoparticles were characterized using various techniques like UV-visible spectroscopy; X-ray diffraction studies, Energy dispersive X-ray analysis, Field emission scanning electron microscopy, Atomic force microscopy, Transmission electron microscopy and Fourier transform infrared spectrometry. The obtained biofunctionalized gold nanoparticles showed effective anti-cancer property against four different cancer cell lines A-549 (Human lung carcinoma), K 562 (Human chronic myelogenous leukemia bone marrow), HeLa (Human cervix) and MDA MB (Human adenocarcinoma mammary gland) and no lethal effect is observed in Vero (African green monkey kidney normal cell) cell lines. PMID- 23747540 TI - Cooling rate optimization for zebrafish sperm cryopreservation using a cryomicroscope coupled with SYBR14/PI dual staining. AB - The Zebrafish has gained increased popularity as an aquatic model species in various research fields, and its widespread use has led to numerous mutant strains and transgenic lines. This creates the need to store these important genetic materials as frozen gametes. Sperm cryopreservation in zebrafish has been shown to yield very low post-thaw survival and many protocols suffer from great variability and poor reproducibility. The present study was intended to develop a freezing protocol that can be reliably used to cryopreserve zebrafish sperm with high post-thaw survival. In particular, our study focused on cooling protocol optimization with the aid of cryomicroscopy. Specifically, sperm suspended in 8% DMSO or 4% MeOH were first incubated with live/dead fluorescent dyes (SYBR14/PI) and then cooled at various rates from 4 degrees C to different intermediate stopping temperatures such as -10, -20, -30 and -80 degrees C before rewarming to 35 degrees C at the rate of 100 degrees C/min. %PI-positive (dead) cells were monitored throughout the cooling process and this screening yielded an optimal rate of 25 degrees C/min for this initial phase of freezing. We then tested the optimal cooling rate for the second phase of freezing from various intermediate stopping temperatures to -80 degrees C before plunging into liquid nitrogen. Our finding yielded an optimal intermediate stopping temperature of -30 degrees C and an optimal rate of 5 degrees C/min for this second phase of freezing. When we further applied this two-step cooling protocol to the conventional controlled rate freezer, the average post-thaw motility measured by CASA was 46.8 +/- 6.40% across 11 males, indicating high post-thaw survival and consistent results among different individuals. Our study indicates that cryomiscroscopy is a powerful tool to devise the optimal cooling conditions for species with sperm that are very sensitive to cryodamage. PMID- 23747541 TI - Uptake mechanism of furosemide-loaded pegylated nanoparticles by cochlear cell lines. AB - This study tests the hypothesis that pegylated nanoparticles (NPs) could be taken up by the cochlear cells [House Ear Institute-organ of Corti 1 (HEI-OC1) and Stria vascularis K-1 (SVK-1)], through endocytic pathways. Furthermore, the in vitro drug release and the cytotoxicity of Furosemide (FUR)-loaded NPs on these two cochlear cells are investigated. FUR-loaded pegylated NPs are prepared by the emulsion-solvent diffusion method without surfactant. The NPs are characterized for particle mean diameter, polydispersity index (PDI), morphology, percent drug encapsulation efficiency (EE%), and FUR release kinetics. The methyl tetrazolium salt (MTS) and lactate dehydrogenase (LDH) bioassays are used to evaluate in vitro, the cytotoxicity of FUR-loaded NPs and native FUR. The NPs uptake is investigated using confocal microscopy, microplate reader/fluorimetry, and flow cytometry. Spherical NPs with a mean diameter range of 133-210 nm and PDI values varying from 0.037 to 0.41 are produced. The FUR EE% is 86% and the drug is released from the NPs according to the zero-order and Higuchi models. After treatment with blank NPs, the percentage of cell viability and cell death are 95.96% and 8.95%, in HEI-OC1 cells, respectively. The NPs are internalized by HEI OC1 cells through a clathrin-dependent pathway. In addition, results show that NPs can be taken up via clathrin and cytoskeleton mediated pathways in SVK-1 cells. The internalization of the pegylated NPs can enhance the drug toxicity by necrosis in a dose-dependent and sustained release manner. The formulated NPs provide a promising template for a targeted drug delivery system to the inner ear. PMID- 23747542 TI - Insulinoma-associated 1a (Insm1a) is required for photoreceptor differentiation in the zebrafish retina. AB - The zinc-finger transcription factor insulinoma-associated 1 (Insm1, previously IA-1) is expressed in the developing nervous and neuroendocrine systems, and is required for cell type specific differentiation. Expression of Insm1 is largely absent in the adult, although it is present in neurogenic regions of the adult brain and zebrafish retina. While expression of Insm1 has also been observed in the embryonic retina of numerous vertebrate species, its function during retinal development has remained unexplored. Here, we demonstrate that in the developing zebrafish retina, insm1a is required for photoreceptor differentiation. Insm1a deficient embryos were microphthalmic and displayed defects in rod and cone photoreceptor differentiation. Rod photoreceptor cells were more sensitive to loss of insm1a expression than were cone photoreceptor cells. Additionally, we provide evidence that insm1a regulates cell cycle progression of retinoblasts, and functions upstream of the bHLH transcription factors ath5/atoh7 and neurod, and the photoreceptor specification genes crx and nr2e3. Finally, we show that insm1a is negatively regulated by Notch-Delta signaling. Taken together, our data demonstrate that Insm1 influences neuronal subtype differentiation during retinal development. PMID- 23747544 TI - Loop-mediated isothermal amplification for the rapid detection of Chrysanthemum chlorotic mottle viroid (CChMVd). AB - Loop-mediated isothermal amplification (LAMP) is an established nucleic acid amplification method offering rapid, sensitive, and convenient diagnosis of infectious diseases. Chrysanthemum chlorotic mottle viroid (CChMVd) causes one of the most serious viral diseases in chrysanthemum in Korea. A sensitive LAMP assay was developed for rapidly detecting CChMVd infection. The assay was based on a set of four primers matching the specific region of the CChMVd genome. The CChMVd LAMP primer sets were designed using the sequences from nonsymptomatic and symptomatic CChMVd isolates in Korea. The efficiency and specificity of this method were optimized using Bst DNA polymerase, which allowed for increased viroid detection sensitivity. The reaction was carried out at 65 degrees C for 90 min, and was improved by adding SYBR Green I dye to the inside of the reaction tube lid prior to amplification. The results indicate that this LAMP method will be useful for chrysanthemum viroid disease monitoring and detecting CChMVd infectious disease. PMID- 23747543 TI - The ascl1a and dlx genes have a regulatory role in the development of GABAergic interneurons in the zebrafish diencephalon. AB - During development of the mouse forebrain interneurons, the Dlx genes play a key role in a gene regulatory network (GRN) that leads to the GABAergic phenotype. Here, we have examined the regulatory relationships between the ascl1a, dlx, and gad1b genes in the zebrafish forebrain. Expression of ascl1a overlaps with dlx1a in the telencephalon and diencephalon during early forebrain development. The loss of Ascl1a function results in a loss of dlx expression, and subsequent losses of dlx5a and gad1b expression in the diencephalic prethalamus and hypothalamus. Loss of Dlx1a and Dlx2a function, and, to a lesser extent, of Dlx5a and Dlx6a, impairs gad1b expression in the prethalamus and hypothalamus. We conclude that dlx1a/2a act downstream of ascl1a but upstream of dlx5a/dlx6a and gad1b to activate GABAergic specification. This pathway is conserved in the diencephalon, but has diverged between mammals and teleosts in the telencephalon. PMID- 23747545 TI - Rapid and sensitive detection of varicella zoster virus in saliva of patients with herpes zoster. AB - VZV reactivation produces zoster (shingles) which may be further complicated by meningoencephalitis, myelopathy, vasculopathy and multiple ocular disorders. Importantly, these neurological and ocular complications of VZV reactivation can occur without rash. In such instances, virological verification relies on detection of VZV DNA or anti-VZV IgG antibody in cerebrospinal fluid (CSF), or less often, the presence of VZV DNA in blood mononuclear cells or anti-VZV IgM antibody in serum or CSF. If VZV were readily detected in other tissue samples (e.g., saliva or tears) in patients with neurological disease in the absence of rash and shown to correlate with the standard tests listed above, more invasive tests such as lumbar puncture might be obviated. In patients with acute herpes zoster, the yield of cell DNA was greater in saliva collected by passive drool or synthetic swab than by cotton swab. The time to process saliva from collection to obtaining DNA was 1h. VZV DNA was present exclusively in the pelleted fraction of saliva and was found in 100% of patients before antiviral treatment. This rapid sensitive method can be applied readily to saliva from humans with neurologic and other disease that might be caused by VZV in the absence of rash. PMID- 23747546 TI - Expression of a truncated hepatitis E virus capsid protein in the protozoan organism Leishmania tarentolae and its application in a serological assay. AB - Zoonotic infections with hepatitis E virus (HEV) genotype 3 are presumably transmitted via contaminated pig meat products, which raises the necessity for enhanced serological surveillance of pig herds. The aim of the study was to set up a novel protein expression system to overcome the well-known problems in (HEV ) protein expression using the standard Escherichia coli tools such as inclusion body formation and loss of protein conformation. A recombinant strain of the protozoan organism Leishmania tarentolae (L. tarentolae) was therefore established. A fragment of HEV ORF2 coding for a truncated capsid protein of a porcine HEV strain was cloned and parts of the plasmid DNA were introduced into the Leishmania genome, resulting in stably transformed cells. Via a C-terminal His-tag the recombinant HEVDeltaORF2 protein could be purified and concentrated directly from the medium, resulting in a total protein amount of approximately 1.4 mg/l Leishmania culture. The recombinant protein was coated on ELISA plates and was proven to be highly reactive and well-suited to be applied in a serological assay. By investigating 144 porcine sera, the in-house assay detected specific antibodies in 43.1% of the samples and demonstrated a higher sensitivity than a commercially available antibody test. Taken together, it was shown that L. tarentolae exhibits a remarkable alternative expression strategy for viral antigens with considerable advantages of a eukaryotic protein expression host. PMID- 23747547 TI - Expression and function analysis of metallothionein in the testis of Portunus trituberculatus exposed to cadmium. AB - Metallothioneins (MTs) possess a unique molecular structure that provides metal binding and redox capabilities. These capabilities include the maintenance of metal equilibria that protect against heavy metals (especially cadmium) and oxidative damage. Past studies have focused on the function of MTs in vertebrates. However, the functions of MTs during spermiogenesis in invertebrates remain unclear. In order to investigate the function of MTs during spermiogenesis in Portunus trituberculatus, we used RT-PCR and RACE to identify two MT complete cDNA sequences in the total RNA from the P. trituberculatus testis. The 450 bp MT 1 cDNA consists of a 77 bp 5' untranslated region, a 196 bp 3' untranslated region, and a 177 bp open reading frame that encodes 58 amino acids including 19 cysteines. The 581 bp MT-2 cDNA consists of 73 bp 5' untranslated region, a 328 bp 3' untranslated region, and a 180 bp open reading frame that encodes 59 amino acids including 18 cysteines. MT-1 and MT-2 of P. trituberculatus more closely resemble invertebrate (especially crab) MT homologues than vertebrate MT homologues as indicated by protein alignment comparisons and phylogenetic tree analysis. MT-1 and MT-2 were detected in the heart, testis, muscle, hepatopancreas, and gill of P. trituberculatus by tissue expression analysis. In addition, MT-1 and MT-2 are present during the entire process of spermiogenesis in P. trituberculatus as indicated by H&E staining and in situ hybridization. MT 1 and MT-2 expression levels significantly increase after cadmium (Cd) exposure as measured by real-time quantitative PCR analysis. Therefore, we suggest that MT 1 and MT-2 perform important functions in spermiogenesis and testis detoxification in P. trituberculatus. PMID- 23747548 TI - Oxidative damage and apoptosis induced by microcystin-LR in the liver of Rana nigromaculata in vivo. AB - Microcystins (MCs) are hepatotoxins with potent inhibitor activity of protein phosphatases PP1 and PP2A. The present study shows that MC-LR can induce severe oxidative damage and apoptosis in the livers of frogs (Rana nigromaculata) exposed to 1MUg/L MC-LR for 7 and 14d in vivo. Ultrastructural observation showed the apoptotic morphology of perinuclear chromatin margination and swollen mitochondria, indicating that MC-LR can significantly damage frog liver. Reactive oxygen species (ROS) production and malondialdehyde (MDA) content were positively correlated with exposure time. Meanwhile, reduced glutathione (GSH) content and GSH peroxidase (GPx) activity rapidly decreased after prolonged exposure to 1MUg/L MC-LR in a time-dependent manner. These results imply that the antioxidant defense systems of the liver were damaged. Enhanced apoptosis of cells in the livers of MC-treated frogs was detected by terminal deoxynucleotidyl transferase mediated deoxy-UTP nick end labeling (TUNEL) associated with up-regulation of the mitochondrial system. MC-LR significantly stimulated the livers to release cytochrome c, which improved the protein expressions of Bax, caspase-3, and caspase-9 (p<0.01) and inhibited the protein expression of Bcl-2 with prolonged exposure (p<0.01) via the mitochondrial pathway. These results imply that the mitochondrial pathway has a key function in toxin-induced liver cell apoptosis. The expression of caspase-8 was induced significantly (p<0.01), which illustrates the mechanism that the death receptor pathway is also involved in apoptosis. The present findings show that MC-LR can induce apoptosis in frog liver, which may be related with the decline of amphibian populations. The World Health Organization recommended drinking water limit for MC-LR in water may be not safe for amphibians. PMID- 23747549 TI - No substantial changes in estrogen receptor and estrogen-related receptor orthologue gene transcription in Marisa cornuarietis exposed to estrogenic chemicals. AB - Estrogen receptor orthologues in molluscs may be targets for endocrine disruptors, although mechanistic evidence is lacking. Molluscs are reported to be highly susceptible to effects caused by very low concentrations of environmental estrogens which, if substantiated, would have a major impact on the risk assessment of many chemicals. The present paper describes the most thorough evaluation to-date of the susceptibility of Marisa cornuarietis ER and ERR gene transcription to modulation by vertebrate estrogens in vivo and in vitro. We investigated the effects of estradiol-17beta and 4-tert-Octylphenol exposure on in vivo estrogen receptor (ER) and estrogen-related receptor (ERR) gene transcription in the reproductive and neural tissues of the gastropod snail M. cornuarietis over a 12-week period. There was no significant effect (p>0.05) of treatment on gene transcription levels between exposed and non-exposed snails. Absence of a direct interaction of estradiol-17beta and 4-tert-Octylphenol with mollusc ER and ERR protein was also supported by in vitro studies in transfected HEK-293 cells. Additional in vitro studies with a selection of other potential ligands (including methyl-testosterone, 17alpha-ethinylestradiol, 4 hydroxytamoxifen, diethylstilbestrol, cyproterone acetate and ICI182780) showed no interaction when tested using this assay. In repeated in vitro tests, however, genistein (with mcER-like) and bisphenol-A (with mcERR) increased reporter gene expression at high concentrations only (>10(-6)M for Gen and >10(-5)M for BPA, respectively). Like vertebrate estrogen receptors, the mollusc ER protein bound to the consensus vertebrate estrogen-response element (ERE). Together, these data provide no substantial evidence that mcER-like and mcERR activation and transcript levels in tissues are modulated by the vertebrate estrogen estradiol 17beta or 4-tert-Octylphenol in vivo, or that other ligands of vertebrate ERs and ERRs (with the possible exception of genistein and bisphenol A, respectively) would do otherwise. PMID- 23747550 TI - Effects of nanomolar copper on water plants--comparison of biochemical and biophysical mechanisms of deficiency and sublethal toxicity under environmentally relevant conditions. AB - Toxicity and deficiency of essential trace elements like Cu are major global problems. Here, environmentally relevant sub-micromolar concentrations of Cu (supplied as CuSO4) and simulations of natural light- and temperature cycles were applied to the aquatic macrophyte Ceratophyllum demersum. Growth was optimal at 10nM Cu, while PSII activity (Fv/Fm) was maximal around 2 nM Cu. Damage to the PSII reaction centre was the first target of Cu toxicity, followed by disturbed regulation of heat dissipation (NPQ). Only after that, electron transport through PSII (PhiPSII) was inhibited, and finally chlorophylls decreased. Copper accumulation in the plants was stable until 10nM Cu in solution, but strongly increased at higher concentrations. The vein was the main storage site for Cu up to physiological concentrations (10nM). At toxic levels it was also sequestered to the epidermis and mesophyll until export from the vein became inhibited, accompanied by inhibition of Zn uptake. Copper deficiency led to a complete stop of growth at "0"nM Cu after 6 weeks. This was accompanied by high starch accumulation although electron flow through PSII (PhiPSII) decreased from 2 weeks, followed by decrease in pigments and increase of non photochemical quenching (NPQ). Release of Cu from the plants below 10nM Cu supply in the nutrient solution indicated lack of high-affinity Cu transporters, and on the tissue level copper deficiency led to a re-distribution of zinc. PMID- 23747551 TI - Studying the effects of polycyclic aromatic hydrocarbons on peripheral arterial disease in the United States. AB - PURPOSE: Polycyclic aromatic hydrocarbons are a group of prevalent pollutants which are produced by incomplete combustion of organic materials such as coal, fuel, tobacco smoking and food cooking. The associations between exposures to polycyclic aromatic hydrocarbons (PAHs) and peripheral arterial disease (PAD) have not been well studied. METHODS: We used the 2001-2004 National Health and Nutrition Examination Survey (NHANES) to investigate the associations between eight monohydroxy urinary metabolites of four PAHs and PAD. RESULTS: In a logistic regression model, subjects within the middle and highest tertiles of fluorene metabolites, 2-hydroxyfluorene (2-FLUO) and 3-hydroxyfluorene (3-FLUO), and phenanthrene metabolites, 1-hydroxyphenanthrene (1-PHEN) and 2 hydroxyphenanthrene (2-PHEN), had significantly higher prevalence of PAD as compared to subjects within the lowest tertile after adjusting for cigarette smoking, diabetes mellitus and other covariates (For 2-FLUO, the 3rd tertile: OR=2.22, 95% CI=1.13-4.37, p for trend=0.02; For 3-FLUO, the 3rd tertile: OR=2.36, 95% CI: 1.16-4.77, p for trend=0.02; For 1-PHEN, the 3rd tertile: OR=1.84, 95% CI: 1.01-3.37, p for trend=0.04; For 2-PHEN, the 3rd tertile: OR=1.76, 95% CI: 1.07-2.88, p for trend=0.03). CONCLUSIONS: Our findings suggest that exposure to PAHs may increase the risk of PAD. Further studies are necessary to explore the associations between PAHs and PAD. PMID- 23747552 TI - Variability in operation-based NO(x) emission factors with different test routes, and its effects on the real-driving emissions of light diesel vehicles. AB - The objective of this study is to quantify the differences in NO(x) emissions between standard and non-standard driving and vehicle operating conditions, and to estimate by how much NO(x) emissions exceed the legislative emission limits under typical Korean road traffic conditions. Twelve Euro 3-5 light-duty diesel vehicles (LDDVs) manufactured in Korea were driven on a chassis dynamometer over the standard New European Driving Cycle (NEDC) and a representative Korean on road driving cycle (KDC). NO(x) emissions, average speeds and accelerations were calculated for each 1-km trip segment, so called averaging windows. The results suggest that the NO(x) emissions of the tested vehicles are more susceptible to variations in the driving cycles than to those in the operating conditions. Even under comparable operating conditions, the NO(x) control capabilities of vehicles differ from each other, i.e., NO(x) control is weaker for the KDC than for the NEDC. The NO(x) emissions over the KDC for given vehicle operating conditions exceed those over the NEDC by more than a factor of 8. Consequently, on-road NO(x) emission factors are estimated here to exceed the Euro 5 emission limit by up to a factor of 8, 4 and 3 for typical Korean urban, rural, and motorway road traffic conditions, respectively. Our findings support the development of technical regulations for supplementary real-world emission tests for emission certification and the corresponding research actions taken by automotive industries. PMID- 23747554 TI - Polybrominated diphenyl ethers (PBDEs) in a conventional wastewater treatment plant (WWTP) from Shanghai, the Yangtze River Delta: implication for input source and mass loading. AB - The concentrations of 19 polybrominated diphenyl ethers (PBDEs) congeners in a conventional wastewater treatment plant (WWTP) were determined to investigate the occurrence and fate of PBDEs during wastewater treatment processes. The level of total PBDEs ranged from 1.68 to 4.64 ng/L in wastewater, with BDE209 accounting for the largest proportion, followed by penta- and octa-BDE congeners. PBDEs were found to mainly exist in the particulate phase of wastewater, which rendered sedimentation efficient for the removal of PBDEs, while the removal efficiencies might be varied for congeners with different Br atom numbers. Because of similar congener profiles, in-house dust was considered to be an important source for PBDEs in the WWTP. According to the mass loading estimation, over 60% of total PBDEs entering the WWTP accumulated in the dewatered sludge, resulting in the total PBDE release of 43.8 kg/year via sewage sludge in Shanghai. And the annual release via effluent was estimated to be 5.5 kg, less but shouldn't be neglected. PMID- 23747553 TI - Prenatal urinary phthalate metabolites levels and neurodevelopment in children at two and three years of age. AB - BACKGROUND: Previous studies suggest that prenatal phthalate exposure affects neurodevelopment and behavior during the first years of life. OBJECTIVES: To evaluate the effect of maternal urinary concentrations of phthalate metabolites during pregnancy on mental and psychomotor development in children 24-36 months of age. METHODS: This analysis was conducted on the first three years of life among a subsample of 136 mother-child pairs from the ELEMENT cohort studies conducted in Mexico City. Maternal urine samples collected during the third trimester of pregnancy were analyzed for 9 phthalate metabolites: Mono-ethyl phthalate (MEP), Mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), mono-benzyl phthalate (MBzP), Mono-3-carboxypropyl phthalate (MCPP), and four di 2-ethylhexyl phthalate (DEHP) metabolites [mono-2-ethylhexyl-phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP)]. Among the 136 children, 135 (99.3%) completed the study period. Child neurodevelopment was assessed using mental and psychomotor development indexes (MDI and PDI) from a Bayley (BSID II) test at 24, 30, and 36 months of age. The effect of prenatal phthalate exposure on neurodevelopment was estimated using linear regression models for longitudinal data clustered at the individual level. RESULTS: No significant associations were observed among all children combined, but differential effects by gender were found. Among girls, there was a negative association between MDI and DEHP metabolites MEHP (beta=-2.11 [95% CI: -3.73, 0.49]), MEHHP (beta=-1.89 [95% CI: -3.64, -0.15]), MEOHP (beta=-1.80 [95% CI: 3.58, -0.03]) MECPP (beta=-2.52 [95% CI: -4.44, -0.61]), and SigmaDEHP (beta= 3.41 [95% CI: -5.26, -1.55]); there was no significant effect among boys. Male PDI was positively related to MBzP (beta=1.79 [95% CI: 0.14, 3.45]) and MCPP (beta=1.64 [95% CI: 0.15, 3.12]); there was no significant effect on PDI among girls. CONCLUSION: This study demonstrates that sex plays a role of an effect modifier in the association between prenatal phthalate exposure and neurodevelopment. PMID- 23747555 TI - Inferring wavelength dependence of AOD and Angstrom exponent over a sub-tropical station in South Africa using AERONET data: influence of meteorology, long-range transport and curvature effect. AB - Aerosol optical properties over a southern sub-tropical site Skukuza, South Africa were studied to determine the variability of the aerosol characteristics using CIMEL Sunphotometer data as part of the AErosol RObotic NETwork (AERONET) from December 2005 to November 2006. Aerosol optical depth (AOD), Angstrom exponent (alpha), and columnar water vapor (CWV) data were collected, analyzed, and compiled. Participating in this network provided a unique opportunity for understanding the sources of aerosols affecting the atmosphere of South Africa (SA) and the regional radiation budget. The meteorological patterns significantly (p<0.05) influenced the amount and size distribution of the aerosols. Results showed that seasonal variation of AOD at 500 nm (AOD500) over the observation site were characterized by low values (0.10-0.13) in autumn, moderate values (0.14-0.16) in summer and winter seasons, and high to very high values (0.18 0.40) during the spring, with an overall mean value of 0.18+/-0.12. Angstrom exponent alpha(440-870), varied from 0.5 to 2.89, with significant (p<0.0001) seasonal variability. CWV showed a strong annual cycle with maximum values in the summer and autumn seasons. The relationship between AOD, Angstrom exponent (alpha), and CWV showed a strong dependence (p<0.0001) of alpha on AOD and CWV, while there was no significant correlation between AOD and CWV. Investigation of the adequacy of the simple use of the spectral AOD and Angstrom exponent data was used in deriving the curvature (a2) showed to obtain information for determining the aerosol-particle size. The negative a2 values are characterized by aerosol size dominated by fine-mode (0.1-1 MUm), while the positive curvatures indicate abundance of coarse particles (>1 MUm). Trajectory cluster analyses revealed that the air masses during the autumn and winter seasons have longer advection pathways, passing over the ocean and continent. This is reflected in the aerosol properties that are derived from the ocean, desert, and anthropogenic activities that include biomass burning and industrial pollution. PMID- 23747556 TI - Economic valuation of environmental benefits of removing pharmaceutical and personal care products from WWTP effluents by ozonation. AB - Continuous release of pharmaceutical and personal care products (PPCPs) present in effluents from wastewater treatment plants (WWTPs) is nowadays leading to the adoption of specific measures within the framework of the Directive 2000/60/EC (Water Framework Directive). The ozonation process, normally employed for drinking water production, has also proven its potential to eliminate PPCPs from secondary effluents in spite of their low concentrations. However, there is a significant drawback related with the costs associated with its implementation. This lack of studies is especially pronounced regarding the economic valuation of the environmental benefits associated to avoid the discharge of these pollutants into water bodies. For the first time the shadow prices of 5 PPCPs which are ethynilestradiol, sulfamethoxazole, diclofenac, tonalide and galaxolide from treated effluent using a pilot-scale ozonation reactor have been estimated. From non-sensitive areas their values are -73.73; -34.95; -42.20; -10.98; and -8.67 respectively and expressed in ?/kg. They represent a proxy to the economic value of the environmental benefits arisen from undischarged pollutants. This paper contributes to value the environmental benefits of implementing post-treatment processes aimed to achieve the quality standards required by the Priority Substances Directive. PMID- 23747557 TI - Metal cycling during sediment early diagenesis in a water reservoir affected by acid mine drainage. AB - The discharge of acid mine drainage (AMD) into a reservoir may seriously affect the water quality. To investigate the metal transfer between the water and the sediment, three cores were collected from the Sancho Reservoir (Iberian Pyrite Belt, SW Spain) during different seasons: turnover event; oxic, stratified period; anoxic and under shallow perennially oxic conditions. The cores were sliced in an oxygen-free atmosphere, after which pore water was extracted by centrifugation and analyzed. A sequential extraction was then applied to the sediments to extract the water-soluble, monosulfide, low crystallinity Fe(III) oxyhydroxide, crystalline Fe(III)-oxide, organic, pyrite and residual phases. The results showed that, despite the acidic chemistry of the water column (pH<4), the reservoir accumulated a high amount of autochthonous organic matter (up to 12 wt.%). Oxygen was consumed in 1mm of sediment due to organic matter and sulfide oxidation. Below the oxic layer, Fe(III) and sulfate reduction peaks developed concomitantly and the resulting Fe(II) and S(II) were removed as sulfides and probably as S linked to organic matter. During the oxic season, schwertmannite precipitated in the water column and was redissolved in the organic-rich sediment, after which iron and arsenic diffused upwards again to the water column. The flux of precipitates was found to be two orders of magnitude higher than the aqueous one, and therefore the sediment acted as a sink for As and Fe. Trace metals (Cu, Zn, Cd, Pb, Ni, Co) and Al always diffused from the reservoir water and were incorporated into the sediments as sulfides and oxyhydroxides, respectively. In spite of the fact that the benthic fluxes estimated for trace metal and Al were much higher than those reported for lake and marine sediments, they only accounted for less than 10% of their total inventory dissolved in the column water. PMID- 23747558 TI - Bacteria distribution and dynamics in constructed wetlands based on modelling results. AB - Bacteria communities growing in constructed wetlands play a major role on the removal of pollutants from wastewater and the presence of a stable community is a critical factor affecting their performance. With this work we aimed at finding how long it takes for bacterial communities to stabilise in constructed wetlands and at answering specific questions regarding their abundance, spatial distribution and their relative importance on the treatment processes. To this end the numerical model BIO_PORE was used to simulate the dynamics of 6 functional bacteria groups (heterotrophic, autotrophic nitrifying, fermenting, acetotrophic methanogenic, acetotrophic sulphate reducing and sulphide oxidising bacteria) within a wetland for a period of 3 years. Three indicators of bacterial stabilisation were used: 1) total biomass; b) effluent pollutant concentrations and c) Shannon's diversity index. Results indicate that aerobic bacteria dominated the wetland until the 80th day of operation. Anaerobic bacteria dominated the wetland from that moment and until the end of the studied period. Bacteria stability was reached between 400 and 700 days after starting operation. Once the wetland reached stability, sulphate reducing bacteria accounted for the highest biomass of all bacterial groups (46%). The distribution of bacterial communities obtained after bacterial stability is consistent with available experimental results, and was clearly controlled by dissolved oxygen (SO) concentrations and H2S toxicity. After stability, the progressive accumulation of inert solids pushed the location of the active bacteria zone towards the outlet section. PMID- 23747559 TI - The presence of EU priority substances mercury, hexachlorobenzene, hexachlorobutadiene and PBDEs in wild fish from four English rivers. AB - Since 2007 about 200 to 300 fish per year--generally roach (Rutilus rutilus) also a few bleak (Alburnus alburnus) and eels (Anguilla anguilla)--have been collected from a number of English river sites and stored at -80 degrees C to build up a Fish Tissue Archive as a resource for the monitoring of pollutants. Some of the fish from the Fish Tissue Archive from the years 2007-2011 were analyzed for substances in current and proposed European legislation regarding environmental quality standards (EQS) in biota. It was found that mercury exceeded the EU EQS of 20 MUg/kg in 79% of samples with an average and median of 31 and 29 MUg/kg. The legacy fungicide hexachlorobenzene (HCB) was below the EQS of 10 MUg/kg in all fish analyzed, with a maximum of 6 MUg/kg in some eels. The legacy solvent hexachlorobutadiene (HCBD) was below the EQS of 55 MUg/kg, being <0.2 MUg/kg in all samples where it was measured. The sums of six polybrominated diphenyl ethers (PBDEs) were several orders of magnitude higher than the new proposed 0.0085 MUg/kg biota EQS. This study showed that the regular collection and analysis of whole body homogenate samples of relatively small native pelagic fish is suitable for the monitoring of contaminants capable of bioaccumulation. With regard to current or proposed EQS for EU countries, mercury and potentially PBDE in fish are of some concern in these English rivers. PMID- 23747560 TI - Urban streets functionality as a tool for urban pollution management. AB - Pollution derived from traffic can be considered one of the major problems of modern cities. Although considerable efforts have been devoted to gathering information about pollution and its control, little attention has been paid to the analysis of relationships between pollution distribution and town planning. The existence of these relationships would enable better prediction and prevention of pollution through town planning. In this work, an analysis of one pollutant derived from traffic (urban noise) in 27 cities is presented. Non parametric tests and ROC analyses were employed, using the equivalent sound level (L(eq)) values as the dependent variable. For the characterization of the pollutant, an alternative concept to accessibility is analyzed: the concept of functionality. Results of statistical inferential analysis showed the existence of significant differences between the sound levels of the different category results, confirming that noise is stratified in the studied cities and that the five categories proposed based in the concept of functionality highlight this noise stratification. Moreover, high sensitivity and low non-specificity were obtained by using ROC analysis. Results of this analysis also showed an overall average value of prediction capacity close to 90%. Therefore, because the proposed categories highlight the noise stratification of the studied pollutant in all the towns studied, the functionality concept can be considered an interesting tool for urban planning and for designing pollution prevention policies. Finally, as traffic is a source of other urban pollutants, the concept of functionality may be a new concept for wide environmental pollution management. PMID- 23747561 TI - Gold nanoparticle exposure induces growth and yield enhancement in Arabidopsis thaliana. AB - Nanotechnology has the potential to revolutionize agriculture field. Towards this effort, carbon nanotubes have recently been reported to induce growth enhancement of tobacco cells. In this study, exposure to 24 nm size gold nanoparticles (GNPs) at 10 MUg/ml concentration was found to enhance the total seed yield of Arabidopsis thaliana by 3 times over the control. In addition, 24 nm size GNP exposure at both 10 and 80 MUg/ml concentrations has significantly improved seed germination rate, vegetative growth and free radical scavenging activity. A considerable correlation was found between expression of key plant regulatory molecules, microRNAs (miRs) and seed germination, growth and antioxidant potential of A. thaliana on GNP exposure. This is the first report showing GNPs as a promising tool to enhance seed yield of plants. PMID- 23747562 TI - Microbiological and mycological beach sand quality in a volcanic environment: Madeira archipelago, Portugal. AB - Madeira forms a mid-Atlantic volcanic archipelago, whose economy is largely dependent on tourism. There, one can encounter different types of sand beach: natural basaltic, natural calcareous and artificial calcareous. Microbiological and mycological quality of the sand was analyzed in two different years. Bacterial indicators were detected in higher number in 2010 (36.7% of the samples) than in 2011 (9.1%). Mycological indicators were detected in a similar percentage of samples in 2010 (68.3%) and 2011 (75%), even though the total number of colonies detected in 2010 was much higher (827 in 41 samples) than in 2011 (427 in 66 samples). Enterococci and potentially pathogenic and allergenic fungi (particularly Penicillium sp.) were the most common indicators detected in both years. Candida sp. yeast was also commonly detected in the samples. The analysis of the 3rd quartile and maximum numbers of all indicators in samples showed that artificial beaches tend to be more contaminated than the natural ones. However, a significant difference between the variables was lacking. More monitoring data (number of bathers, sea birds, radiation intensity variation, and a greater number of samples) should be collected in order to confirm if these differences are significant. In general, the sand quality in the archipelago's beaches was good. As the sand may be a vector of diseases, an international common set of indicators and values and a compatible methodologies for assessing sand contamination, should be defined, in order to provide the bather's with an indication of beach sand quality, rather than only the water. PMID- 23747563 TI - Determining the contributions of caspase-2, caspase-8 and effector caspases to intracellular VDVADase activities during apoptosis initiation and execution. AB - Apoptosis signaling crucially depends on caspase activities. Caspase-2 shares features of both initiator and effector caspases. Opinions are divided on whether caspase-2 activity is established during apoptosis initiation or execution in response to DNA damage, death receptor stimulation, or heat shock. So far, approaches towards measuring caspase-2 activity were restricted to analyses in cell homogenates and extracts, yielded inconsistent results, and were often limited in sensitivity, thereby contributing to controversies surrounding the role of caspase-2 during apoptosis. Furthermore, caspases overlap in substrate specificities, and caspase-8 as well as effector caspases may cleave the optimal VDVAD recognition motif as well. We therefore generated a highly sensitive Forster resonance energy transfer (FRET) substrate to determine the relative contribution of these caspases to VDVADase activity non-invasively inside living cells. We observed limited proteolysis of the substrate during apoptosis initiation in response to death receptor stimulation by FasL, TNFalpha and TRAIL. However, this activity was attributable to caspase-8 rather than caspase-2. Likewise, no caspase-2-specific activity was detected during apoptosis initiation in response to genotoxic stress (cisplatin, 5-FU), microtubule destabilization (vincristine), or heat shock. The contribution of caspase-2 to proteolytic activities during apoptosis execution was insignificant. Since even residual, ectopically introduced caspase-2 activity could readily be detected inside living cells in our measurements, we conclude, in contrast to several previous studies, that caspase-2 activity does not contribute to apoptosis in the scenarios investigated, and that instead caspase-8 and effector caspases are the most significant VDVADases during canonical apoptosis signaling. PMID- 23747564 TI - Uptake of advanced glycation end products by proximal tubule epithelial cells via macropinocytosis. AB - Chronic hyperglycaemia during diabetes leads to non-enzymatic glycation of proteins to form advanced glycation end products (AGEs) that contribute to nephropathy. We describe AGE uptake in LLC-PK1 and HK2 proximal tubule cell lines by macropinocytosis, a non-specific, endocytic mechanism. AGE-BSA induced dorsal circular actin ruffles and amiloride-sensitive dextran-TRITC uptake, significantly increased AGE-BSA-FITC uptake (167+/-20% vs BSA control, p<0.01) and was ezrin-dependent. AGE-BSA-FITC uptake was significantly inhibited by amiloride and inhibitors of Arf6, Rac1, racGEF Tiam1, PAK1 and actin polymerisation. AGE-BSA-FITC, Arf6 and PIP2 co-localised within dorsal circular actin ruffles. AGE-BSA increased PAK1 kinase activity (212+/-41% vs control, p<0.05) and protein levels of Tiam1, a Rac1 activator. AGE-BSA significantly increased TGF-beta1 protein levels (160+/-6%, p<0.001 vs BSA), which were significantly inhibited by inhibitors of Arf6 (82+/-19%, p<0.001 vs AGE) and actin polymerisation (107+/-11%, p<0.001 vs AGE), suggesting AGEs partially exert their profibrotic effects via macropinocytosis. PAK1 and PIP5Kgamma siRNA significantly decreased AGE-BSA-FITC uptake (81+/-6% and 64+/-7%, respectively, p<0.05 vs control for both), and AGE-stimulated TGF-beta1 protein release (99+/ 15% and 49+/-8% of control, p<0.05 and p<0.001, respectively). Inhibition of AGE uptake by macropinocytosis inhibitors and a neutralising TGF-beta antibody, reversed the AGE-induced decrease in surface Na(+)K(+)ATPase, suggesting AGE uptake by macropinocytosis may contribute to diabetic kidney fibrosis and/or EMT by modulating this pump. Understanding methods of cellular uptake and signalling by AGEs may lead to novel therapies for diabetic nephropathy. PMID- 23747566 TI - Plasma leptin, glucose and non-esterified fatty acid variations in dromedary camels exposed to prolonged periods of underfeeding or dehydration. AB - The involvement of plasma leptin in the adaptation of dromedary camels to harsh conditions such as food or water shortages was studied through 2 experiments. In experiment 1, fourteen female camels were either fed at 68% of maintenance energy requirements (MER) during 112d (n=4) or overfed at 134% of MER during the first 56d and then underfed at 17% of MER the next 56d (OV-UN, n=5), or underfed and then overfed for the same durations and energy intake levels (UN-OV, n=5). Weekly plasma samples showed that leptin, glucose and non-esterified fatty acid (NEFA) concentrations were significantly modulated by energy intake level. NEFA increased sharply but transiently in underfed camels of the UN-OV or OV-UN groups, whereas glucose and leptin concentrations decreased with underfeeding and increased with overfeeding with more significant effects in camels that were previously overfed or underfed, respectively. In experiment 2 twelve female camels were either normally watered (n=6) or dehydrated (n=6) during 23d and then rehydrated during 4d. Dehydration specifically increased blood hematocrit, plasma NEFA and glucose whereas leptin decreased slightly. For both experiments, leptinemia was positively related to hump adipocyte volume. Taken together these results provide new data for a better understanding of lipid and energy metabolism in camels. PMID- 23747567 TI - Neither time nor number of context-shock pairings affect long-term dependence of memory on hippocampus. AB - There are still basic uncertainties concerning the role of the hippocampus (HPC) in maintaining long-term context memories. All experiments examining the effects of extensive HPC damage on context memory for a single learning episode find that damage soon after learning results in robust retrograde amnesia. Some experiments find that if the learning-to-damage interval is extended, remote context memories are spared. In contrast, other experiments fail to find spared remote context memory. One possible explanation for inconsistency might be the potency of the context memory conditioning procedure, as the experiments showing spared remote memory used a greater number of context-shock pairings, likely creating a stronger context fear memory. We designed an experiment to directly test the question: does increasing the number of context-shock pairings result in sparing of remote context memory after HPC damage? Six independent groups of rats received either 3 or 12 context-shock pairings during a single conditioning session and then either received extensive HPC damage or Control surgery at 1 week, 2-months, or 4-months after conditioning. 10 days after surgery rats were tested for memory of the shock context. Consistent with all relevant studies, HPC damage at the shortest training-surgery interval produced robust retrograde amnesia for both 3- and 12-shock groups whereas the Control rats expressed significantly high levels of memory. At the longer training-surgery interval, HPC damage produced similarly robust retrograde amnesia in the rats in both the 3- and 12-shock groups. These results clearly demonstrate that increasing the number of context-shock pairings within a single learning session does not change the dependence of the memory on the HPC. Current evidence from our group on retrograde amnesia has now shown that partial damage, dorsal vs. ventral damage, discrete cue+context conditioning, time after training, and number of context shock pairings do not affect HPC dependence of context fear memories. When taken together, the evidence strongly supports a permanent role of the HPC in context memory. PMID- 23747565 TI - RING-type E3 ligases: master manipulators of E2 ubiquitin-conjugating enzymes and ubiquitination. AB - RING finger domain and RING finger-like ubiquitin ligases (E3s), such as U-box proteins, constitute the vast majority of known E3s. RING-type E3s function together with ubiquitin-conjugating enzymes (E2s) to mediate ubiquitination and are implicated in numerous cellular processes. In part because of their importance in human physiology and disease, these proteins and their cellular functions represent an intense area of study. Here we review recent advances in RING-type E3 recognition of substrates, their cellular regulation, and their varied architecture. Additionally, recent structural insights into RING-type E3 function, with a focus on important interactions with E2s and ubiquitin, are reviewed. This article is part of a Special Issue entitled: Ubiquitin-Proteasome System. Guest Editors: Thomas Sommer and Dieter H. Wolf. PMID- 23747568 TI - Time course of dorsal and ventral hippocampal involvement in the expression of trace fear conditioning. AB - While a number of early studies demonstrated that hippocampal damage attenuates the expression of recent, but not remotely trained tasks, an emerging body of evidence has shown that damage to, or inactivation of, the hippocampus often impairs recall across a wide range of training-testing intervals. Collectively, these data suggest that the time course of hippocampal involvement in the storage or recall of previously-acquired memories may differ according to hippocampal subregion and the particular learning task under consideration. The present study examined the contributions of dorsal (DH) and ventral (VH) hippocampus to the expression of previously-acquired trace fear conditioning, a form of Pavlovian conditioning in which the offset of an initially neutral cue or cues and the onset of an aversive stimulus is separated by a temporal (trace) interval. Specifically, either saline or the GABA-A agonist muscimol was infused into DH or VH prior to testing either 1, 7, 28, or 42 days after trace fear conditioning. The results revealed a marked dissociation: pre-testing inactivation of DH failed to impair performance at any time-point, while pre-testing inactivation of VH impaired performance at all time-points. Importantly, pre-testing inactivation of VH had no effect on the performance of previously-acquired delay conditioning, suggesting that the deficits observed in trace conditioning cannot be attributed to a deficit in performance of the freezing response. Collectively, these data suggest that VH, but not DH, remains a neuroanatomical locus critical to the recall or expression of trace fear conditioning over an extended period of time. PMID- 23747569 TI - Integer sparse distributed memory: analysis and results. AB - Sparse distributed memory is an auto-associative memory system that stores high dimensional Boolean vectors. Here we present an extension of the original SDM, the Integer SDM that uses modular arithmetic integer vectors rather than binary vectors. This extension preserves many of the desirable properties of the original SDM: auto-associativity, content addressability, distributed storage, and robustness over noisy inputs. In addition, it improves the representation capabilities of the memory and is more robust over normalization. It can also be extended to support forgetting and reliable sequence storage. We performed several simulations that test the noise robustness property and capacity of the memory. Theoretical analyses of the memory's fidelity and capacity are also presented. PMID- 23747570 TI - Synaptic muscarinic response types in hippocampal CA1 interneurons depend on different levels of presynaptic activity and different muscarinic receptor subtypes. AB - Depolarizing, hyperpolarizing and biphasic muscarinic responses have been described in hippocampal inhibitory interneurons, but the receptor subtypes and activity patterns required to synaptically activate muscarinic responses in interneurons have not been completely characterized. Using optogenetics combined with whole cell patch clamp recordings in acute slices, we measured muscarinic responses produced by endogenously released acetylcholine (ACh) from cholinergic medial septum/diagonal bands of Broca inputs in hippocampal CA1. We found that depolarizing responses required more cholinergic terminal stimulation than hyperpolarizing ones. Furthermore, elevating extracellular ACh with the acetylcholinesterase inhibitor physostigmine had a larger effect on depolarizing versus hyperpolarizing responses. Another subpopulation of interneurons responded biphasically, and periodic release of ACh entrained some of these interneurons to rhythmically burst. M4 receptors mediated hyperpolarizing responses by activating inwardly rectifying K(+) channels, whereas the depolarizing responses were inhibited by the nonselective muscarinic antagonist atropine but were unaffected by M1, M4 or M5 receptor modulators. In addition, activation of M4 receptors significantly altered biphasic interneuron firing patterns. Anatomically, interneuron soma location appeared predictive of muscarinic response types but response types did not correlate with interneuron morphological subclasses. Together these observations suggest that the hippocampal CA1 interneuron network will be differentially affected by cholinergic input activity levels. Low levels of cholinergic activity will preferentially suppress some interneurons via hyperpolarization and increased activity will recruit other interneurons to depolarize, possibly because of elevated extracellular ACh concentrations. These data provide important information for understanding how cholinergic therapies will affect hippocampal network function in the treatment of some neurodegenerative diseases. PMID- 23747572 TI - Telmisartan attenuates MPTP induced dopaminergic degeneration and motor dysfunction through regulation of alpha-synuclein and neurotrophic factors (BDNF and GDNF) expression in C57BL/6J mice. AB - Telmisartan (TEL), an angiotensin type 1 receptor (AT1R) antagonist, has been reported to exert neuroprotective effect in animal models of Parkinson's disease (PD). However, its effect on motor functions, mutant protein alpha-synuclein (SYN) and neurotrophic factors (BDNF and GDNF) expression and their interrelation in PD has not yet been elucidated. In the present study, the effect of TEL on 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced motor dysfunctions and dopaminergic degeneration was ascertained through investigating the alterations in protein expression of dopamine transporter (DAT), tyrosine hydroxylase (TH) and SYN in C57BL/6J mouse. Further, the role of TEL on the gene expression of neurotrophic factors such as BDNF and GDNF and protein expression of vesicular monoamine transporter 2 (VMAT2) and Glial fibrillary acidic proteins (GFAP) were studied. In TEL treated mouse, strong negative correlation was observed between motor function and SYN, while a strong positive correlation was noted with BDNF and GDNF expression. TEL caused down-regulation of SYN, GFAP and up-regulation of DAT, TH, VAMT2, BDNF and GDNF expressions. Present data suggest that brain renin angiotensin system (RAS) plays a crucial role in motor function and in the regulation of key proteins such as SYN, BDNF and GDNF, DAT, TH, VMAT2 and GFAP in Parkinsonism. In conclusion, the present study shows that angiotensin type 1 receptor antagonists can ameliorate motor dysfunction and act as potential neuroprotective agent in the management of Parkinsonism. PMID- 23747571 TI - Addiction as a stress surfeit disorder. AB - Drug addiction has been conceptualized as a chronically relapsing disorder of compulsive drug seeking and taking that progresses through three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Drug addiction impacts multiple motivational mechanisms and can be conceptualized as a disorder that progresses from positive reinforcement (binge/intoxication stage) to negative reinforcement (withdrawal/negative affect stage). The construct of negative reinforcement is defined as drug taking that alleviates a negative emotional state. Our hypothesis is that the negative emotional state that drives such negative reinforcement is derived from dysregulation of key neurochemical elements involved in the brain stress systems within the frontal cortex, ventral striatum, and extended amygdala. Specific neurochemical elements in these structures include not only recruitment of the classic stress axis mediated by corticotropin-releasing factor (CRF) in the extended amygdala as previously hypothesized but also recruitment of dynorphin-kappa opioid aversive systems in the ventral striatum and extended amygdala. Additionally, we hypothesized that these brain stress systems may be engaged in the frontal cortex early in the addiction process. Excessive drug taking engages activation of CRF not only in the extended amygdala, accompanied by anxiety-like states, but also in the medial prefrontal cortex, accompanied by deficits in executive function that may facilitate the transition to compulsive-like responding. Excessive activation of the nucleus accumbens via the release of mesocorticolimbic dopamine or activation of opioid receptors has long been hypothesized to subsequently activate the dynorphin-kappa opioid system, which in turn can decrease dopaminergic activity in the mesocorticolimbic dopamine system. Blockade of the kappa opioid system can also block anxiety-like and reward deficits associated with withdrawal from drugs of abuse and block the development of compulsive-like responding during extended access to drugs of abuse, suggesting another powerful brain stress/anti-reward system that contributes to compulsive drug seeking. Thus, brain stress response systems are hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence, and to contribute to the development and persistence of addiction. The recruitment of anti-reward systems provides a powerful neurochemical basis for the negative emotional states that are responsible for the dark side of addiction. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23747573 TI - Agonists and antagonists induce different palonosetron dissociation rates in 5 HT3A and 5-HT3AB receptors. AB - Palonosetron is a potent 5-HT3 receptor antagonist with a unique structure and some unusual properties. Here we explore the properties of palonosetron at heterologously expressed 5-HT3A and 5-HT3AB receptors. We used receptors expressed in HEK293 cells, and functionally analysed them using a membrane potential sensitive dye in a Flexstation, which revealed IC50s of 0.24 nM and 0.18 nM for 5-HT3A and 5-HT3AB receptors respectively. Radioligand binding studies with [(3)H]palonosetron revealed similar Kds: 0.34 nM for 5-HT3A and 0.15 nM for 5-HT3AB receptors. Kinetic studies showed palonosetron association and dissociation rates were slightly faster in 5-HT3AB than 5-HT3A receptors, and for both subtypes dissociation rates were ligand-dependent, with antagonists causing more rapid dissociation than agonists. Similar ligand effects were not observed for [(3)H]granisetron dissociation studies. These data support previous studies which show palonosetron has actions distinct to other 5-HT3 receptor antagonists, and the slow rates observed for agonist induced dissociation (t1/2 > 10 h) could at least partly explain the long duration of palonosetron effects in vivo. PMID- 23747575 TI - A back translation of pregabalin and carbamazepine against evoked and non-evoked endpoints in the rat spared nerve injury model of neuropathic pain. AB - The purpose of the present study was twofold. First to characterize endpoints distinct to the reflexive responses to sensory stimuli typically used in neuropathic pain models. A second aim was to evaluate two clinically approved drugs carbamazepine (Tegretol) and pregabalin (Lyrica) against these endpoints with the purpose to backtranslate from the clinical to preclinical setting. The selected neuropathic pain model was the spared nerve injury (SNI) model and the endpoints were burrowing and measures of paw posture in Sprague Dawley rats. As previously described, SNI surgery produced a robust heightened sensitivity to tactile and thermal (cold) stimuli. SNI surgery also produced robust decreases in burrowing and affected multiple measures of paw position. There was no correlation between magnitude of change in burrowing and sensory allodynia within SNI operated rats. Pregabalin (10-30 mg/kg IP) produced a reliable reversal of both tactile and cold allodynia and also the burrowing deficit, with minimal effect on neurological function evaluated using rotorod, beam walking and open field activity. Pregabalin did not affect any measure of paw position. Pharmacokinetic studies conducted in satellite animals identified plasma levels of pregabalin at the 10 mg/kg IP dose to be equivalent to clinically efficacious levels recorded in neuropathic patients (3-6 MUg/ml). In contrast carbamazepine (10-60 mg/kg IP) had only a very modest effect against a reflexive (tactile) measure, and no effect against the burrowing deficit. Carbamazepine also affected various measures of neurological function, complicating interpretation of the reflexive measure. Measurement of burrowing appears to detect a behavioural deficit associated with the SNI model, that may be attenuated by pregabalin but not carbamazepine. Overall the present findings support an advantage of pregabalin over carbamazepine in terms of both efficacy and tolerability which is consistent with clinical experience. The inclusion of additional endpoints beyond traditional reflexive behaviours further supports the value of rodent neuropathic pain models, such as the SNI, as behavioural assays to detect new chemical entities to treat this pain condition. PMID- 23747577 TI - Suppression of experimental autoimmune encephalomyelitis by 300-315nm ultraviolet light. AB - Multiple sclerosis (MS) is a chronic debilitating disease, with lowest incidence in equatorial regions and highest incidence in temperate regions. This relationship is believed to be related to sunlight or UV light exposure. Recent evidence with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, established that this suppression is not mediated by vitamin D production. UV is comprised of three general wave bands: UVC (100-280nm), UVB (280-320nm) and UVA (320-400nm). In the present study we used four lamps that emit different wavelengths of UV: (1) broad band UVB (BB-UVB: 280-320nm); (2) narrow band UVB (NB-UVB: 300-315nm); (3) broad band UVA (BB-UVA: 300-400nm); and (4) long wavelength UVA (UVA-1: 340-400nm). The effect of these light sources was studied in vitamin D-sufficient C57BL/6 mice. The NB-UVB largely accounted for the suppression and delay of onset of EAE by BB-UVB. In contrast, UVA-1 failed to suppress EAE severity at low (~2.5KJ/m(2)), medium (~5.0KJ/m(2)) and high (~10.0KJ/m(2)) doses. Serum calcium and 25-(OH)D3 levels were unchanged after both NB-UVB and UVA-1 treatments. The results demonstrate that NB-UVB (300-315nm) is largely responsible for light-induced suppression of EAE and its effect is not via production of vitamin D. PMID- 23747576 TI - Stress eating and health. Findings from MIDUS, a national study of US adults. AB - The epidemic of obesity and its related chronic diseases has provoked interest in the predictors of eating behavior. Eating in response to stress has been extensively examined, but currently unclear is whether stress eating is associated with obesity and morbidity. We tested whether self-reported stress eating was associated with worse glucose metabolism among nondiabetic adults as well as with increased odds of prediabetes and diabetes. Further, we investigated whether these relationships were mediated by central fat distribution. Participants were 1138 adults (937 without diabetes) in the Midlife in the US study (MIDUS II). Glucose metabolism was characterized by fasting glucose, insulin, insulin resistance (HOMAIR), glycosylated hemoglobin (HbA1c), prediabetes, and diabetes status. Multivariate-adjusted analyses showed that stress eating was associated with significantly higher nondiabetic levels of glucose, insulin, insulin resistance, and HbA1c as well as higher odds of prediabetes or diabetes. Relationships between stress eating and all outcomes were no longer statistically significant once waist circumference was added to the models, suggesting that it mediates such relationships. Findings add to the growing literature on the relationships among psychosocial factors, obesity, and chronic disease by documenting associations between stress eating and objectively measured health outcomes in a national sample of adults. The findings have important implications for interventive targets related to obesity and chronic disease, namely, strategies to modify the tendency to use food as a coping response to stress. PMID- 23747574 TI - Synaptic regulation of affective behaviors; role of BDNF. AB - Brain derived neurotrophic factor (BDNF), a neurotrophin essential for nervous system development and synaptic plasticity, has been found to have a significant influence on affective behaviors. The notion that an impairment in BDNF signaling might be involved in affective disorders is originated primarily from the opposing effects of antidepressants and stress on BDNF signaling. Antidepressants enhance BDNF signaling and synaptic plasticity. On the other hand, negative environmental factors such as severe stress suppress BDNF signaling, impair synaptic activity and increase susceptibility to affective disorders. Postmortem studies provided strong support for decreased BDNF signaling in depressive disorders. Remarkably, studies in humans with a single nucleotide polymorphism in the BDNF gene, the BDNF Val66Met which affects regulated release of BDNF, showed profound deficits in hippocampal and prefrontal cortical (PFC) plasticity and cognitive behaviors. BDNF regulates synaptic mechanisms responsible for various cognitive processes including attenuation of aversive memories, a key process in the regulation of affective behaviors. The unique role of BDNF in cognitive and affective behaviors suggests that cognitive deficits due to altered BDNF signaling might underlie affective disorders. Understanding how BDNF modulates synapses in neural circuits relevant to affective behaviors, particularly the medial prefrontal cortical (mPFC)-hippocampus-amygdala pathway, and its interaction with development, sex, and environmental risk factors might shed light on potential therapeutic targets for affective disorders. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. PMID- 23747578 TI - Biosynthesis of UDP-N,N'-diacetylbacillosamine in Acinetobacter baumannii: Biochemical characterization and correlation to existing pathways. AB - The Gram-negative, opportunistic pathogen Acinetobacter baumannii has recently captured headlines due to its ability to circumvent current antibiotic therapies. Herein we show that the multi-drug resistant (MDR) AYE strain of A. baumannii contains a gene locus that encodes three enzymes responsible for the biosynthesis of the highly-modified bacterial nucleotide sugar, UDP-N,N'-diacetylbacillosamine (UDP-diNAcBac). Previously, this UDP-sugar has been implicated in the pgl pathway of Campylobacter jejuni. Here we report the overexpression, purification, and biochemical characterization of the A. baumannii enzymes WeeK, WeeJ, and WeeI that are responsible for the production of UDP-diNAcBac. We also demonstrate the function of the phosphoglycosyltransferase (WeeH), which transfers the diNAcBac moiety to undecaprenyl-phosphate. UDP-diNAcBac biosynthesis in A. baumannii is also directly compared to the homologous pathways in the pathogens C. jejuni and Neisseria gonorrhoeae. This work demonstrates for the first time the ability of A. baumannii to generate the highly-modified, UDP-diNAcBac nucleotide sugar found previously in other bacteria adding to the growing list of pathogens that assemble glycoconjugates including bacillosamine. Additionally, characterization of these pathway enzymes highlights the opportunity for investigating the significance of highly-modified sugars in bacterial pathogenesis. PMID- 23747580 TI - Emotion regulation in broadly defined anorexia nervosa: association with negative affective memory bias. AB - Theoretical models in anorexia nervosa (AN) implicate difficulties with emotion regulation as a maintaining factor. To date little is known about how different factors might maintain these difficulties. Forty eight women were recruited, 24 receiving treatment for AN (called broadly defined AN) and 24 healthy controls. Self-report measures of difficulties with emotion regulation and current depression were used in addition to computerized tasks which provided measures of social attentional bias and anger-threat bias, as well negative affective memory and recognition bias. Compared to controls, women with AN had significantly higher levels of difficulties with emotion regulation, depression, and negative affective memory bias, as well as lower bias for anger-threat. Simultaneous examination of the two variables that met pre-conditions for mediation of the relationship between group membership and difficulties with emotion regulation (anger-threat bias and negative affective memory) indicated negative affective memory bias to be a mediator, accounting for around one-third of the total effect a diagnosis of AN has on difficulties with emotion regulation. The association of these variables with AN may indicate shared risk factors with depression, and the variety of therapeutic approaches found to be effective with depression may be useful to further incorporate into treatments for AN. PMID- 23747579 TI - Adipocyte lineages: tracing back the origins of fat. AB - The obesity epidemic has intensified efforts to understand the mechanisms controlling adipose tissue development. Adipose tissue is generally classified as white adipose tissue (WAT), the major energy storing tissue, or brown adipose tissue (BAT), which mediates non-shivering thermogenesis. It is hypothesized that brite adipocytes (brown in white) may represent a third adipocyte class. The recent realization that brown fat exist in adult humans suggests increasing brown fat energy expenditure could be a therapeutic strategy to combat obesity. To understand adipose tissue development, several groups are tracing the origins of mature adipocytes back to their adult precursor and embryonic ancestors. From these studies emerged a model that brown adipocytes originate from a precursor shared with skeletal muscle that expresses Myf5-Cre, while all white adipocytes originate from a Myf5-negative precursors. While this provided a rational explanation to why BAT is more metabolically favorable than WAT, recent work indicates the situation is more complex because subsets of white adipocytes also arise from Myf5-Cre expressing precursors. Lineage tracing studies further suggest that the vasculature may provide a niche supporting both brown and white adipocyte progenitors; however, the identity of the adipocyte progenitor cell is under debate. Differences in origin between adipocytes could explain metabolic heterogeneity between depots and/or influence body fat patterning particularly in lipodystrophy disorders. Here, we discuss recent insights into adipose tissue origins highlighting lineage-tracing studies in mice, how variations in metabolism or signaling between lineages could affect body fat distribution, and the questions that remain unresolved. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease. PMID- 23747582 TI - Which treatment worked better for whom? Moderators of group cognitive behavioral therapy versus adapted mindfulness based stress reduction for anxiety disorders. AB - OBJECTIVE: Identifying treatment moderators facilitates treatment matching and personalized medicine. No previous studies have investigated treatment moderators for a mindfulness-based versus traditional cognitive behavioral therapy (CBT) for anxiety disorders to determine for whom each is most effective. The current study examined three putative moderators of principal anxiety disorder severity outcomes for adapted mindfulness based stress reduction (MBSR) and group CBT - baseline depression symptoms, anxiety sensitivity, and diagnostic severity. METHOD: Seventy-one patients with a DSM-IV anxiety disorder were randomized to adapted MBSR or group CBT and assessed at baseline, post-treatment, and 3-month follow up. RESULTS: CBT outperformed adapted MBSR among those with no to mild depressive symptoms and, at post-treatment only, among those with very high anxiety sensitivity. At follow up, adapted MBSR outperformed CBT among those with moderate to severe depressive symptoms and among those with average anxiety sensitivity (for this sample). Baseline severity affected post-treatment outcomes differently in CBT than in adapted MBSR. CONCLUSION: Baseline levels of depression, anxiety sensitivity, and to some extent diagnostic severity, differentially moderated outcomes in CBT and adapted MBSR for anxiety disorders. Recommendations and clinical implications are discussed. PMID- 23747581 TI - Comparing experiential acceptance and cognitive reappraisal as predictors of functional outcome in individuals with serious mental illness. AB - BACKGROUND: Two psychological regulation strategies to cope with psychotic symptoms proposed by the cognitive behavioral tradition were examined in this study: cognitive reappraisal and experiential acceptance. Although cognitive behavior therapy for psychosis has increasing empirical support, little is known about the role of these two strategies using methods of known ecological validity. METHODS: Intensive longitudinal data was gathered from 25 individuals diagnosed with a psychiatric disorder with psychotic features. During the course of six days we measured contextual factors, psychotic and stressful events, psychological regulation strategies and functional outcome. RESULTS: Positive psychotic symptoms and stressful events had negative associations with quality of life and affect, whereas experiential acceptance had positive associations with them. Cognitive reappraisal had inconsistent associations with quality of life and no association with affect. Social interactions and engagement in activities had a positive association with quality of life. Results were supported by additional and exploratory analyses. CONCLUSIONS: Across measures of functional outcome, experiential acceptance appears to be an effective coping strategy for individuals facing psychotic and stressful experiences, whereas cognitive reappraisal does not. In order to inform treatment development efforts, results suggest the need to further investigate the role of these psychological regulation strategies using ecologically valid methods. PMID- 23747583 TI - Thin slice ratings of client characteristics in intake assessments: predicting symptom change and dropout in cognitive therapy for depression. AB - Thin slice ratings of personality have been shown to predict a number of outcomes, but have yet to be examined in the context of psychotherapy. In a sample of 66 clients participating in cognitive therapy for depression, we examined the predictive utility of thin slice rated pre-treatment client traits. On the basis of short video clip excerpts (i.e., thin slices) of intake assessments, trained observers rated clients on personality characteristics and specific personality disorder (PD) traits. Clients' therapy interest and neuroticism predicted lower odds of dropout. Ratings of extraversion predicted greater symptom change across treatment; ratings of clients' Avoidant and Schizoid PD traits predicted less marked symptom improvement. Ratings of agreeableness and likeability also predicted greater symptom change, but these relations were only significant in one of two analytic approaches used. Evidence for the predictive validity of thin slice ratings was generally stronger than that observed for self-reported PD traits and PD status. Moreover, these self report and diagnostic assessments failed to account for the thin slice-outcome relations identified. Findings support the clinical utility of quick, thin slice impressions of clients, as these ratings could be used to identify clients with a high risk of dropout or poor treatment outcome. PMID- 23747584 TI - Community-based behavioral weight-loss treatment: long-term maintenance of weight loss, physiological, and psychological outcomes. AB - Obesity is a significant public health problem, and sustainable long-term treatments are needed. This study examined a community-based model of weight-loss treatment. Ninety participants were recruited from eight community organizations (mean age: 49.65 years, mean body mass index: 35.80 kg/m(2); 64% female). Treatment groups were randomly assigned to two maintenance conditions: 1) self help continuing care, or 2) assessment-only. Both received the same initial 20 session group behavioral treatment. Those randomized to continuing care were additionally instructed to meet as self-sustaining groups for 18 months post treatment. Weight, physiological, behavioral, and psychological outcomes were assessed at baseline, post-treatment, and at six-month and 18-month follow-up. Eighty-seven percent of participants completed treatment. Participant treatment satisfaction and therapist adherence to treatment protocol were high. No group differences or time by group interaction effects emerged. Participants achieved significant weight losses at post-treatment, with no significant weight regain at six-month or 18-month follow-up. Treatment produced sustained changes in waist circumference, cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, insulin, eating patterns, physical activity, quality of life, and body image. A community-based treatment program may be an effective form of behavioral-weight-loss treatment for overweight/obese adults. Weight losses, along with physiological and psychological benefits, were sustained over time. PMID- 23747585 TI - Cardiovascular activity in blood-injection-injury phobia during exposure: evidence for diphasic response patterns? AB - Exposure to feared stimuli in blood-injection-injury (BII)-phobia is thought to elicit a diphasic response pattern, with an initial fight-flight-like cardiovascular activation followed by a marked deactivation and possible fainting (vasovagal syncope). However, studies have remained equivocal on the importance of such patterns. We therefore sought to determine the prevalence and clinical relevance of diphasic responses using criteria that require a true diphasic response to exceed cardiovascular activation of an emotional episode of a negative valence and to exceed deactivation of an emotionally neutral episode. Sixty BII-phobia participants and 20 healthy controls were exposed to surgery, anger and neutral films while measuring heart rate, blood pressure, respiratory pattern, and end-tidal partial pressure of carbon dioxide (as indicator of hyperventilation). Diphasic response patterns were observed in up to 20% of BII phobia participants and 26.6% of healthy controls for individual cardiovascular parameters. BII-phobia participants with diphasic patterns across multiple parameters showed more fear of injections and blood draws, reported the strongest physical symptoms during the surgery film, and showed the strongest tendency to hyperventilate. Thus, although only a minority of individuals with BII phobia shows diphasic responses, their occurrence indicates significant distress. Respiratory training may add to the treatment of BII phobia patients that show diphasic response patterns. PMID- 23747586 TI - Preparation and evaluation of sinomenine hydrochloride in situ gel for uveitis treatment. AB - PURPOSE: The aim of the present study was to develop and optimize sinomenine hydrochloride (SIN) in situ gel for uveitis treatment. METHODS: Carbopol 940 was used as the gelling agent in combination with hydroxypropyl methylcellulose (HPMC), which acts as a viscosity enhancer. The formulations were prepared using various concentrations of Carbopol 940 and HPMC. The prepared in situ gels were evaluated for gellation, drug release, ocular irritation, elimination time and pharmacokinetic studies. Furthermore, the effect of SIN on the development of experimental autoimmune anterior uveitis (EAAU) was assessed. RESULTS: The optimum concentration of Carbopol was 0.1% (w/v), and that for HPMC was 0.4% (w/v). Which showed a significant enhancement in gel strength in the physiological condition while free flowing at non-physiological condition. Optimum formula F(2-3) consisting of 0.5% SIN was prepared and kept as gel group, and 0.5% SIN solution was prepared and kept as control group. Gel group provided sustained release of the drug over a period of 480 min. No evidence of overt toxicity and irritation was observed in any study. The elimination time of control group and gel group was completed within 10 min and 25 min, respectively. The area under the aqueous humor concentration vs. time curve (AUC(0-t)) and maximum concentration (C(max)) values of gel group was 2.70-fold and 1.79-fold higher than that of control group. Additionally, clinical examination showed that SIN suppressed inflammation in EAAU. CONCLUSIONS: These results support the potential applications of SIN in situ gel for uveitis treatment. PMID- 23747587 TI - Immunomodulatory effects of nanocurcumin in arsenic-exposed rats. AB - We evaluated whether the nanoformulation of curcumin could be more effective than free curcumin against arsenic-induced immune dysfunction in rats. Curcumin was encapsulated in polylactic-co-glycolic acid (PLGA). Nanocurcumin (CUR-NP) exhibited a spherical shape with the mean particle size of 130.8 nm. Rats were randomly divided into five groups of six each. Group I was kept as the control. In Group II, rats were exposed to sodium arsenite (25 ppm) daily through drinking water for 42 days. Groups III, IV and V were treated with arsenic as in Group II, however, they were administered with nanoparticle, curcumin (100 mg/kg bw) and CUR-NP (100 mg/kg bw), respectively, by oral gavage during the last 14 days of arsenic exposure. At term, serum and spleen were collected. Immune dysfunction was evaluated by assessing cellular and humoral immunities. Arsenic significantly decreased the splenic lymphocyte proliferation in response to the antigen -- Keyhole Limpet Hemocyanin (KLH) and mitogen -- concanavalin-A. Arsenic reduced both the delayed type hypersensitivity response and secondary antibody (IgG) response to KLH. It also reduced the lipopolysaccharide-stimulated nitric oxide production in splenic lymphocytes. Free curcumin and CUR-NP treatment significantly attenuated these arsenic-mediated effects. However, the magnitude of the effects indicates that CUR-NP has better ameliorative potential than free curcumin at the equivalent dose level. PMID- 23747588 TI - Redox markers and inflammation are differentially affected by atorvastatin, pravastatin or simvastatin administered before endotoxin-induced acute lung injury. AB - Statins are standard therapy for the treatment of lipid disorders, and the field of redox biology accepts that statins have antioxidant properties. Our aim in this report was to consider the pleiotropic effects of atorvastatin, pravastatin and simvastatin administered prior to endotoxin-induced acute lung injury. Male mice were divided into 5 groups and intraperitoneally injected with LPS (10 mg/kg), LPS plus atorvastatin (10 mg/kg/day; A + LPS group), LPS plus pravastatin (5 mg/kg/day; P + LPS group) or LPS plus simvastatin (20 mg/kg/day; S + LPS group). The control group received saline. All mice were sacrificed one day later. There were fewer leukocytes in the P + LPS and S + LPS groups than in the LPS group. MCP-1 cytokine levels were lower in the P + LPS group, while IL-6 levels were lower in the P + LPS and S + LPS groups. TNF-alpha was lower in all statin-treated groups. Levels of redox markers (superoxide dismutase and catalase) were lower in the A + LPS group (p < 0.01). The extent of lipid peroxidation (malondialdehyde and hydroperoxides) was reduced in all statin treated groups (p < 0.05). Myeloperoxidase was lower in the P + LPS group (p < 0.01). Elastance levels were significantly greater in the LPS group compared to the statin groups. Our results suggest that atorvastatin and pravastatin but not simvastatin exhibit anti-inflammatory and antioxidant activity in endotoxin induced acute lung injury. PMID- 23747589 TI - Lactobacillus acidophilus ATCC 4356 attenuates the atherosclerotic progression through modulation of oxidative stress and inflammatory process. AB - The aim of this study was to investigate the effect of Lactobacillus (L.) acidophilus ATCC 4356 on the progression of atherosclerosis in Apoliprotein-E knockout (ApoE(-/-)) mice and the underlying mechanisms. Eight week-old ApoE(-/-) mice were treated with L. acidophilus ATCC 4356 daily for 12 weeks. The wild type (WT) mice or ApoE(-/-) mice in the vehicle group were treated with saline only. Body weights, serum lipid levels, aortic atherosclerotic lesions, and tissue oxidative and inflammatory statuses were examined among the groups. As compared to ApoE(-/-) mice in the vehicle group, ApoE(-/-) mice treated with L. acidophilus ATCC 4356 had no changes in body weights and serum lipid profiles, but showed decreased atherosclerotic lesion size in en face aorta. In comparison with WT mice, ApoE(-/-) mice in the vehicle group showed higher levels of serum malondialdehyde (MDA), oxidized low density lipoprotein (oxLDL) and tumor necrosis factor-alpha (TNF-alpha), but lower levels of interleukin-10 (IL-10) and superoxide dismutase (SOD) activities in serum. Administration of L. acidophilus ATCC 4356 could reverse these trends in a dose-dependent manner in ApoE(-/-) mice. Furthermore, ApoE(-/-) mice treated with L. acidophilus ATCC 4356 showed an inhibition of translocation of NF-kappaB p65 from cytoplasm to nucleus, suppression of degradation of aortic IkappaB-alpha, and improvements of gut microbiota distribution, as compared to ApoE(-/-) mice in the vehicle group. Our findings suggest that administration of L. acidophilus ATCC 4356 can attenuate the development of atherosclerotic lesions in ApoE(-/-) mice through reducing oxidative stress and inflammatory response. PMID- 23747590 TI - Quantitative real-time PCR approaches for microbial community studies in wastewater treatment systems: applications and considerations. AB - Quantitative real-time PCR (qPCR) has been widely used in recent environmental microbial ecology studies as a tool for detecting and quantifying microorganisms of interest, which aids in better understandings of the complexity of wastewater microbial communities. Although qPCR can be used to provide more specific and accurate quantification than other molecular techniques, it does have limitations that must be considered when applying it in practice. This article reviews the principle of qPCR quantification and its applications to microbial ecology studies in various wastewater treatment environments. Here we also address several limitations of qPCR-based approaches that can affect the validity of quantification data: template nucleic acid quality, nucleic acid extraction efficiency, specificity of group-specific primers and probes, amplification of nonviable DNA, gene copy number variation, and limited number of sequences in the database. Even with such limitations, qPCR is reportedly among the best methods for quantitatively investigating environmental microbial communities. The application of qPCR is and will continue to be increasingly common in studies of wastewater treatment systems. To obtain reliable analyses, however, the limitations that have often been overlooked must be carefully considered when interpreting the results. PMID- 23747591 TI - Regulation of phosphorylation of synaptic and extrasynaptic GluA1 AMPA receptors in the rat forebrain by amphetamine. AB - The AMPA receptor is regulated by phosphorylation. Two major phosphorylation sites (S831 and S845) are located in the intracellular C-terminal tail of GluA1 subunits. The phosphorylation on these sites controls receptor expression and function and is subject to the regulation by psychostimulants. In this study, we further characterized the regulation of S831 and S845 phosphorylation by amphetamine (AMPH) in the adult rat striatum and medial prefrontal cortex (mPFC) in vivo. We focused on the specific fraction of GluA1/AMPA receptors enriched from synaptic and extrasynaptic membranes, using a pre-validated biochemical fractionation procedure. We found that acute AMPH administration elevated GluA1 S845 phosphorylation in the defined synaptic membrane from the striatum in a dose dependent manner. AMPH also induced a comparable increase in S845 phosphorylation in the extrasynaptic fraction of striatal GluA1. Similar increases in S845 phosphorylation in both synaptic and extrasynaptic pools were observed in the mPFC. In contrast, S831 phosphorylation was not altered in synaptic and extrasynaptic GluA1 in striatal neurons and synaptic GluA1 in mPFC neurons in response to AMPH, although a moderate increase in S831 phosphorylation was seen in extrasynaptic GluA1 in the mPFC after an AMPH injection at a high dose. Total synaptic and extrasynaptic GluA1 expression remained stable in the two regions after AMPH administration. Our data demonstrate the differential sensitivity of S845 and S831 phosphorylation to dopamine stimulation. S845 is a primary site where phosphorylation of GluA1 is upregulated by AMPH in striatal and mPFC neurons at both synaptic and extrasynaptic compartments. PMID- 23747592 TI - Effect of azelnidipine and amlodipine on single cell mechanics in mouse cardiomyocytes. AB - Azelnidipine and amlodipine are dihydropyridine-type Ca(2+) channel blockers for the treatment of hypertension. Although these drugs have high vasoselectivity and small negative inotropic effects in vivo, little is known regarding their direct effects on cellular contractility without humoral regulation or the additive effects of these drugs with other antihypertensive drugs on myocardial contractility. To investigate the effects of Ca(2+) channel blockers on single cell mechanics, mouse cardiomyocytes were enzymatically isolated, and a pair of carbon fibers was attached to opposite cell-ends to stretch the cells. Cells were paced at 4 Hz superfused in normal Tyrode solution at 37 degrees C. Cell length and active/passive force calculated from carbon fiber bending were recorded in 6 different preload conditions. Slopes of end-systolic force-length relation curves (maximum elastance) were measured as an index of contractility before and after drugs were administered. Azelnidipine at 10nM and 100 nM did not change maximum elastance, while amlodipine at 100 nM did decrease maximum elastance. The combination of RNH-6270 (active form of angiotensin II receptor blocker, olmesartan, 10nM) and either amlodipine (10nM) or azelnidipine (10nM) did not affect maximum elastance. Although both amlodipine and azelnidipine can be used safely at therapeutically relevant concentrations even in combination with olmesartan, the present results suggest that azelnidipine has a less negative inotropic action compared to amlodipine. PMID- 23747593 TI - Astragaloside IV reduces cerebral edema post-ischemia/reperfusion correlating the suppression of MMP-9 and AQP4. AB - Cerebral edema is a critical complication after intravascular thrombolysis post acute stroke. However, clinical options remained limited for treating cerebral edema after cerebral ischemia/reperfusion (I/R) injury. In the present study, astragaloside IV, a purified extract from astragalus membranaceus, was used in the focal I/R rat model, aimed to investigate its effect on the cerebral edema. We found that astragaloside IV (10 and 20mg/kg) significantly attenuated the cerebral water content (P<0.05) and improved neurological outcomes (P<0.05) in comparison with vehicle group. Moreover, we investigate the effect of astragaloside IV on the (blood-brain barrier) BBB since cerebral edema was closely related to the permeability of the BBB. We found that the permeability of BBB was improved significantly in astragaloside IV groups compared with vehicle group via Evans blue leakage (P<0.05). This was further confirmed under the electron microscope, using lanthanum as a tracer of blood vessel permeability. Lanthanum was usually found within the blood vessel in sham group, rather than in perivascular tissues as shown in vehicle group. In drug groups, lanthanum stain was mainly restricted within the cerebral capillary, indicating the potential BBB protective effect of astragaloside IV. Furthermore, we found that expressions of Matrix metalloproteinase-9 (MMP-9) and aquaporin 4 (AQP4) were increased in vehicle group, which were related to cerebral vasogenic edema or cytotoxic edema. The up-regulations of MMP-9 and AQP4 were inhibited significantly by astragaloside IV administration. We propose that the anti-edema potential of astragaloside IV was correlated with its regulation of MMP-9 and AQP4. PMID- 23747594 TI - Actions of Angeli's salt, a nitroxyl (HNO) donor, on ion transport across mucosa submucosa preparations from rat distal colon. AB - The aim of this study was to investigate whether nitroxyl (HNO), a redox variant of the radical gasotransmitter nitric oxide (NO) with therapeutically promising properties, affects colonic ion transport. Changes in short-circuit current (Isc) induced by the HNO donor Angeli's salt were recorded in Ussing chambers. Cytosolic Ca(2+) concentration was measured with fura-2. The nitroxyl donor induced a concentration-dependent increase in Isc across rat distal colon which was due to a stimulation of chloride secretion. The secretion induced by Angeli's salt (5*10(-4)mol/l) was not altered by the NO scavenger 2-(4-carboxyphenyl)-4,5 dihydro-4,4,5,5-tetramethyl-1H-imidazolyl-1-oxy-3-oxide (carboxy-PTIO), but was abolished by the HNO scavenger l-cysteine. The response was not dependent on the activity of soluble guanylate cyclase or enteric neurons, but was inhibited by indomethacin. Experiments with apically permeabilized epithelia revealed the activation of basolateral K(+) channels and a stimulation of the current carried by the basolateral Na(+)-K(+)-pump by Angeli's salt. The secretion induced by Angeli's salt was reduced in the absence of extracellular Ca(2+). A prominent increase in the cytosolic Ca(2+) concentration was evoked by Angeli's salt predominantly in subepithelial cells within the submucosa, which had the same dependence on extracellular Ca(2+) as the Angeli's salt-induced Cl(-) secretion. Consequently, Angeli's salt induces a soluble guanylate cyclase-independent, Ca(2+)-dependent Cl(-) secretion via activation of the Na(+)-K(+)-ATPase and of basolateral K(+) channels. Cyclooxygenase metabolites produced within the submucosa seem to be involved in this response. PMID- 23747595 TI - The flavanol (-)-epicatechin and its metabolites protect against oxidative stress in primary endothelial cells via a direct antioxidant effect. AB - Accumulating evidence suggests that foods rich in flavanols decrease the risk of developing cardiovascular diseases. Attenuation of oxidative stress was suggested to contribute to the cardiovascular benefit of flavanols. Up to now it was unclear whether flavanol metabolites can also protect cells from oxidative stress. The aim of the present study was to determine the potential contribution of several glucuronidated, methylated and sulfated metabolites of (-)-epicatechin (EC) and (+)-catechin (Cat) to the protection of human vascular endothelial cells (HUVECs) against oxidative stress. The relative potency of the tested compounds to scavenge superoxide anion radicals showed that a free catechol moiety in the molecule is important for the direct antioxidant activity. EC and Cat (0.5, 1, 10uM) were potent radical scavengers and provided protection against intracellular oxidative stress induced by hydrogen peroxide. Although the metabolites provided less intracellular protection compared to EC and Cat, the tested methylated and glucuronidated metabolites reduced oxidative stress significantly in HUVECs. Our results indicate that the metabolites have a relevant contribution in the intracellular protection of EC and Cat against oxidative stress. Also, the direct antioxidant activity plays an important role in this protection. PMID- 23747596 TI - Amelioration of cisplatin-induced mouse renal lesions by a cyclooxygenase (COX)-2 selective inhibitor. AB - In this study, we investigated the effects of the cyclooxygenase (COX)-2 selective inhibitor, meloxicam, on cisplatin-induced inflammation, oxidative stress and renal lesions in BALB/c mice. A single cisplatin injection (13 mg/kg, i.p.) significantly increased plasma creatinine, blood urea nitrogen and urinary glucose accompanied by a concomitant increase in COX-2 mRNA and COX-2 protein levels. These changes in renal lesion parameters were diminished by simultaneous treatment of meloxicam (0.7 mg/kg/day in drinking water). The expression of oxidative stress markers, p47(phox), p67(phox), hemoxygenase-1 (HO-1), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and 4 hydroxy-2-nonenal (4-HNE)-modified protein were increased with cisplatin injection. Simultaneous treatment of meloxicam with cisplatin significantly inhibited the increase in p47(phox), HO-1 and 4-HNE-modified protein. The phosphorylation of extracellular regulated kinase (ERK) and c-jun-N-terminal kinase (JNK) were increased with cisplatin injection, but these changes were inhibited by meloxicam. Moreover, concomitant meloxicam treatment also prevented the cisplatin-induced infiltration of macrophages to the tubulointerstitial area. These results suggest that meloxicam can ameliorate cisplatin-induced mouse renal lesions, potentially through the inhibition of inflammatory and oxidative stress responses. PMID- 23747597 TI - Assessment of the viability of Cryptosporidium parvum oocysts with the induction ratio of hsp70 mRNA production in manure. AB - Determining the presence of viable Cryptosporidium parvum oocysts in complex environmental matrices in hygiene control can prevent the contamination of water resources and food with this pathogen. This study assessed the induction ratio of hsp70 mRNA production by heat shock in different oocysts as a marker of viability. Using different procedures for (m)RNA extraction directly from manure and reverse transcription real-time qPCR, this study found slightly increased hsp70 mRNA contents in viable oocysts that were heat shock induced at 45 degrees C for 20 min compared to not induced oocysts (1.6 fold induction in average). Prolonging the heat shock treatment to 2h did not further increase the copy numbers. Heat shock by consecutive stimuli, such as freezing and then heating, did not yield significantly higher copy numbers than the 45 degrees C treatment. There was a certain background level of hsp70 mRNA in viable oocysts that were not exposed to heat shock, indicating a constitutive production of the transcripts in the oocysts. The production of hsp70 mRNA induced by heat shock in oocysts aged for 9 months that exhibited reduced viability was lower than in fresher oocysts (induction ratio<1.2). No production of hsp70 mRNA by heat shock was detected in 12 months old oocysts that were not viable in the excystation test. Oocysts inactivated at 75 degrees C for 30 min were not able to respond to heat shock, and low amount of copies were occasionally measured only in total RNA extracts, but not in mRNA extracts that were purified directly with an oligo (dT)25 based system. The induction ratio of hsp70 mRNA varied according to the viability of the organisms in a sample. Copy numbers of beta-tubulin mRNA in viable oocysts were lower than hsp70 mRNA, therefore the latter is more suitable to detect low numbers of oocysts by RT-qPCR. PMID- 23747599 TI - CaMK-II activation is essential for zebrafish inner ear development and acts through Delta-Notch signaling. AB - Zebrafish inner ear development is characterized by the crystallization of otoliths onto immotile kinocilia that protrude from sensory "hair" cells. The stereotypical formation of these sensory structures is dependent on the expression of key patterning genes and on Ca2+ signals. One potential target of Ca2+ signaling in the inner ear is the type II Ca2+/calmodulin-dependent protein kinase (CaMK-II), which is preferentially activated in hair cells, with intense activation at the base of kinocilia. In zebrafish, CaMK-II is encoded by seven genes; the expression of one of these genes (camk2g1) is enriched in hair cells. The suppression of camk2g1 expression by antisense morpholino oligonucleotides or inhibition of CaMK-II activation by the pharmacological antagonist, KN-93, results in aberrant otolith formation without preventing cilia formation. In fact, CaMK-II suppression results in additional ciliated hair cells and altered levels of Delta-Notch signaling members. DeltaA and deltaD transcripts are increased and DeltaD protein accumulates in hair cells of CaMK-II morphants, indicative of defective recycling and/or exocytosis. Our findings indicate that CaMK-II plays a critical role in the developing ear, influencing cell differentiation through extranuclear effects on Delta-Notch signaling. Continued expression and activation of CaMK-II in maculae and cristae in older embryos suggests continued roles in auditory sensory maturation and transduction. PMID- 23747598 TI - Cripto is required for mesoderm and endoderm cell allocation during mouse gastrulation. AB - During mouse gastrulation, cells in the primitive streak undergo epithelial mesenchymal transformation and the resulting mesenchymal cells migrate out laterally to form mesoderm and definitive endoderm across the entire embryonic cylinder. The mechanisms underlying mesoderm and endoderm specification, migration, and allocation are poorly understood. In this study, we focused on the function of mouse Cripto, a member of the EGF-CFC gene family that is highly expressed in the primitive streak and migrating mesoderm cells on embryonic day 6.5. Conditional inactivation of Cripto during gastrulation leads to varied defects in mesoderm and endoderm development. Mutant embryos display accumulation of mesenchymal cells around the shortened primitive streak indicating a functional requirement of Cripto during the formation of mesoderm layer in gastrulation. In addition, some mutant embryos showed poor formation and abnormal allocation of definitive endoderm cells on embryonic day 7.5. Consistently, many mutant embryos that survived to embryonic day 8.5 displayed defects in ventral closure of the gut endoderm causing cardia bifida. Detailed analyses revealed that both the Fgf8-Fgfr1 pathway and p38 MAP kinase activation are partially affected by the loss of Cripto function. These results demonstrate a critical role for Cripto during mouse gastrulation, especially in mesoderm and endoderm formation and allocation. PMID- 23747600 TI - Incidence of supraventricular arrhythmias during autologous peripheral blood stem cell transplantation. AB - Arrhythmias, especially supraventricular arrhythmias, often complicate the clinical course during autologous hematopoietic cell transplantation (AHCT). We wanted to determine the incidence and risk factors for cardiac arrhythmias during AHCT. The study included 983 patients (median age, 58 years [range, 19 to 77]; 61% male) who underwent AHCT between August 2006 and December 2010 at a single institution and for whom all relevant medical records were available for review. AHCT was done for plasma cell disorders in 58% patients and for lymphoma or leukemia in the remaining. Overall, 92 patients (9.4%) developed a supraventricular tachyarrhythmia at a median of 9 days posttransplantation (range, 0 to 18) and with a median duration of less than 1 day (range, <1 to 17 days). Atrial fibrillation was the most common and seen in 71 patients (7%), followed by atrial flutter and supraventricular tachycardia in 12 (1%) and 8 (1%) patients, respectively. In multivariate analysis, age older than 63 years, presence of premature supraventricular complexes or atrioventricular conduction delay on pretransplantation electrocardiogram, and history of any prior arrhythmia increased the risk of arrhythmia. Development of arrhythmia resulted in longer outpatient follow-up after AHCT, with the median follow-up for those developing an arrhythmia of 22 days compared with 19 days for the rest; P < .001. In conclusion, 9% of patients undergoing ASCT developed supraventricular arrhythmias posttransplantation, and this risk was elevated among older patients, those with a prior history of arrhythmias, and those with pretransplantation electrocardiographic abnormalities. PMID- 23747602 TI - What dementia reveals about proverb interpretation and its neuroanatomical correlates. AB - OBJECTIVE: Neuropsychologists frequently include proverb interpretation as a measure of executive abilities. A concrete interpretation of proverbs, however, may reflect semantic impairments from anterior temporal lobes, rather than executive dysfunction from frontal lobes. The investigation of proverb interpretation among patients with different dementias with varying degrees of temporal and frontal dysfunction may clarify the underlying brain-behavior mechanisms for abstraction from proverbs. We propose that patients with behavioral variant frontotemporal dementia (bvFTD), who are characteristically more impaired on proverb interpretation than those with Alzheimer's disease (AD), are disproportionately impaired because of anterior temporal-mediated semantic deficits. METHODS: Eleven patients with bvFTD and 10 with AD completed the Delis Kaplan Executive Function System (D-KEFS) Proverbs Test and a series of neuropsychological measures of executive and semantic functions. The analysis included both raw and age-adjusted normed data for multiple choice responses on the D-KEFS Proverbs Test using independent samples t-tests. Tensor-based morphometry (TBM) applied to 3D T1-weighted MRI scans mapped the association between regional brain volume and proverb performance. Computations of mean Jacobian values within select regions of interest provided a numeric summary of regional volume, and voxel-wise regression yielded 3D statistical maps of the association between tissue volume and proverb scores. RESULTS: The patients with bvFTD were significantly worse than those with AD in proverb interpretation. The worse performance of the bvFTD patients involved a greater number of concrete responses to common, familiar proverbs, but not to uncommon, unfamiliar ones. These concrete responses to common proverbs correlated with semantic measures, whereas concrete responses to uncommon proverbs correlated with executive functions. After controlling for dementia diagnosis, TBM analyses indicated significant correlations between impaired proverb interpretation and the anterior temporal lobe region (left>right). CONCLUSIONS: Among two dementia groups, those with bvFTD, demonstrated a greater number of concrete responses to common proverbs compared to those with AD, and this performance correlated with semantic deficits and the volume of the left anterior lobe, the hub of semantic knowledge. The findings of this study suggest that common proverb interpretation is greatly influenced by semantic dysfunction and that the use of proverbs for testing executive functions needs to include the interpretation of unfamiliar proverbs. PMID- 23747601 TI - Significance of ethnicity in the risk of acute graft-versus-host disease and leukemia relapse after unrelated donor hematopoietic stem cell transplantation. AB - The significance of patient and donor ethnicity on risk of acute graft-versus host disease (GVHD) and disease relapse after unrelated donor hematopoietic cell transplantation (HCT) is not known. A total of 4335 patient-donor pairs from the International Histocompatibility Working Group in HCT met the following 3 criteria: (1) HLA-A, -B, -C, -DRB1, and -DQB1 allele matched donor, (2) diagnosis of leukemia, and (3) non-T cell depleted GVHD prophylaxis. Posttransplantation risks of acute GVHD and leukemia relapse were defined in Asian/Pacific Islander, white, African American, Hispanic, and Native American patients that underwent transplantation from donors with the same self-described background. Asian patients had a significantly lower incidence of acute GVHD (Japanese patients: 40.0% grades II to IV and 15.3% grades III to IV; non-Japanese Asian patients: 42.1% grades II to IV and 15.7% grades III to IV) compared with white patients (56.5% grades II to IV and 22.6% grades III to IV) (P < .001). The hazard ratio of acute GVHD for white patients was significantly higher than for Japanese patients. Unexpectedly, the hazard ratio of leukemia relapse in white patients with early disease status was also significantly higher than that in Japanese patients. These results provide a platform for future investigation into the genetic factors for unrelated donor HCT and clinical implications of diverse ethnic background. PMID- 23747603 TI - Cognitive and affective control in a flanker word task: common and dissociable brain mechanisms. AB - In the present study we compared the nature of cognitive and affective conflict modulations at different stages of information processing using electroencephalographic recordings. Participants performed a flanker task in which they had to focus on a central word target and indicate its semantic category (cognitive version) or its valence (affective version). Targets were flanked by congruent or incongruent words in both versions. Although tasks were equivalent at the behavioral level, event-related potentials (ERPs) showed common and dissociable cognitive and emotional conflict modulations. At early stages of information processing, both tasks generated parallel sequential conflict effects in the P1 and N170 potentials. Later, the N2 and the first part of the P3 wave were exclusively modulated by cognitive conflict, whereas the last section of the P3 deflection/Late Positive Component (LPC) was only involved in affective current conflict processing. Therefore, the whole data set suggests the existence of early common mechanisms that are equivalent for cognitive and affective materials and later task-specific conflict processing. PMID- 23747604 TI - Combinational expression of sorbose/sorbosone dehydrogenases and cofactor pyrroloquinoline quinone increases 2-keto-L-gulonic acid production in Ketogulonigenium vulgare-Bacillus cereus consortium. AB - The expression levels of sorbose/sorbosone dehydrogenase genes (sdh and sndh) and the synthesis genes (pqqABCDEN) of the adjoint cofactor pyrroloquinoline quinone (PQQ) were genetically manipulated in Ketogulonigenium vulgare to increase the production of 2-keto-l-gulonic acid (2-KLG), the precursor of vitamin C, in the consortium of K. vulgare and Bacillus cereus. We found that overexpression of sdh sndh alone in K. vulgare could not significantly enhance the production of 2-KLG, revealing the cofactor PQQ was required for the biosynthesis of 2-KLG. Various expression levels of PQQ were achieved by differential expression of pqqA, pqqABCDE and pqqABCDEN, respectively. The combinatorial expression of sdh/sndh and pqqABCDEN in K. vulgare enabled a 20% increase in the production of 2-KLG (79.1+/-0.6gl(-1)) than that of the parental K. vulgare (65.9+/-0.4gl(-1)) in shaking flasks. Our results demonstrated the balanced co-expression of both the key enzymes and the related cofactors was an efficient strategy to increase chemicals' biosynthesis. PMID- 23747605 TI - Metabolic and pathway engineering to influence native and altered erythromycin production through E. coli. AB - The heterologous production of the complex antibiotic erythromycin through Escherichia coli provides a unique challenge in metabolic engineering. In addition to introducing the 19 foreign genes needed for heterologous biosynthesis, E. coli metabolism must be engineered to provide the propionyl-CoA and (2S)-methylmalonyl-CoA substrates required to allow erythromycin formation. In this work, three different pathways to propionyl-CoA were compared in the context of supporting E. coli erythromycin biosynthesis. The comparison revealed that alternative citramalate and threonine metabolic pathways (both starting from exogenous glycerol) were capable of supporting final compound formation equal to a proven pathway reliant upon exogenous propionate. Furthermore, two pathways to (2S)-methylmalonyl-CoA were compared in the production of a novel benzyl erythromycin analog. A pathway dependent upon exogenous methylmalonate improved selectivity and facilitated antibiotic assessment of this new analog. PMID- 23747606 TI - The apelinergic system: sexual dimorphism and tissue-specific modulations by obesity and insulin resistance in female mice. AB - It has been proposed that the apelinergic system (apelin and its receptor APJ) may be a promising therapeutic target in obesity-associated insulin resistance syndrome. However, due to the extended tissue-distribution of this system, the therapeutic use of specific ligands for APJ may target numerous tissues resulting putatively to collateral deleterious effects. To unravel specific tissular dysfunctions of this system under obesity and insulin-resistance conditions, we measured the apelinemia and gene-expression level of both apelin (APL) and APJ in 12-selected tissues of insulin-resistant obese female mice fed with a high fat (HF) diet. In a preliminary study, we compared between adult male and female mice, the circadian plasma apelin variation and the effect of fasting on apelinemia. No significant differences were found for these parameters suggesting that the apelinemia is not affected by the sex. Moreover, plasma apelin level was not modulated during the four days of the estrous cycle in females. In obese and insulin-resistant HF female mice, plasma apelin concentration after fasting was not modified but, the gene-expression level of the APL/APJ system was augmented in the white adipose tissue (WAT) and reduced in the brown adipose tissue (BAT), the liver and in kidneys. BAT apelin content was reduced in HF female mice. Our data suggest that the apelinergic system may be implicated into specific dysfunctions of these tissues under obesity and diabetes and that, pharmacologic modulations of this system may be of interest particularly in the treatment of adipose, liver and renal dysfunctions that occur during these pathologies. PMID- 23747607 TI - Impairment and recovery of hand use after unilateral section of the dorsal columns of the spinal cord in squirrel monkeys. AB - Damage to the ascending forelimb afferents in the dorsal columns (DCs) of the cervical spinal cord in monkeys impairs forelimb use, particularly hand dexterity. Although considerable recovery has been reported, interpretation of the results is complicated by the reproducibility of the lesion and behavioral assessment. Here, we examined the effects of a unilateral DC lesion at the C4-C6 spinal cord level in four adult squirrel monkeys. Behavioral performance was assessed on a reach-to-grasp task over 5-13 weeks after lesion. Retrograde tracers were injected into the skin of the fingertips to determine the distribution of axon terminals in the cuneate nucleus and estimate the effectiveness of lesion at the conclusion of each case. The size and level of DC lesion was reflected in the proportion of spared afferents, which ranged from 1 to 25% across monkeys. The experiments produced two major findings. First, the extent of deafferentation in the DC is directly related to the degree of reaching and grasping impairments, and to the reactivation profile and somatotopic reorganization in contralateral primary somatosensory cortex. Second, considerable behavioral recovery and cortical reorganization occurred even in the monkey with only 1% of axons spared in the DC. Our findings suggest that cutaneous inputs from the hand and forelimb are critical to the integrity of functions such as reaching and grasping. In addition, axon branches from peripheral afferents that terminate on neurons in the dorsal horn of the spinal cord are likely central to the functional recovery. PMID- 23747608 TI - A cognitive map model based on spatial and goal-oriented mental exploration in rodents. AB - The rodent hippocampus has been used to represent the spatial environment as a cognitive map. Classical theories suggest that the cognitive map is a consequence of assignment of different spatial regions to variant cell populations in the framework of rate coding. The current study constructs a novel computational neural model of the cognitive map based on firing rate coding, as widely appears in associative memory, thus providing an explanation for formation and function of the two types of cognitive maps: the spatial vector map, responsible for self localization and simultaneous updating of detailed information; and the goal oriented vector map, important in route finding. A proposed intermediate between these two map types was constructed by combining the spatial vector and goal orientation maps to form an effective and efficient path finding mechanism. Application of such novel cognitive map based path finding methods to a mental exploration model was explored. With adaptation as a driving force, the basic knowledge of the location relationships in the spatial cognitive map was reformed and sent to the goal-oriented cognitive map, thus solving a series of new path problems through mental exploration. This method allows for rapid identification of suitable paths under variant conditions, thus providing a simpler and safer resource for path finding. Additionally, this method also provides an improved basis for potential robotic path finding applications. PMID- 23747609 TI - Rewarding stimulation of the lateral hypothalamus induces a dopamine-dependent suppression of synaptic responses in the entorhinal cortex. AB - The entorhinal cortex receives inputs from sensory and associational cortices, as well as a substantial input from midbrain dopaminergic neurons. Dopamine is likely to modulate the responsiveness of entorhinal cortex neurons to sensory inputs, and excitatory synaptic responses in layers I/II of the entorhinal cortex in vitro can be either facilitated or suppressed by dopamine depending upon the concentration applied. Rewarding stimulation of the lateral hypothalamus leads to activation of dopamine neurons, and the present study evaluated the effect of rewarding stimulation on synaptic responses in the lateral entorhinal cortex evoked by stimulation of the primary olfactory (piriform) cortex in behaving rats. Rewarding brain stimulation reduced the amplitude of synaptic responses in the entorhinal cortex evoked by single pulses delivered to the piriform cortex at intervals of 100-500 ms following the train. Synaptic responses were suppressed when stimulation trains were delivered at a fixed interval, or when trains were initiated by the animal pressing a bar. The suppression depended on the strength of stimulation trains; delivery of higher frequency trains that were sufficient to induce maximal, or 50% of maximal, rates of bar-pressing resulted in significant suppression effects, but lower frequency trains did not. Systemic administration of the dopamine D2 receptor antagonist eticlopride, but not the D1 receptor antagonist SCH23390 or the muscarinic antagonist scopolamine, blocked the suppression of synaptic responses. Results suggest that rewarding brain stimulation leads to a phasic increase in dopamine in the entorhinal cortex resulting in a D2 receptor-dependent suppression of excitatory synaptic responses, and that a similar synaptic modulation may be induced by stimuli associated with appetitive motivation and reward. PMID- 23747610 TI - DSP-4, a noradrenergic neurotoxin, produces sex-specific effects on pairing and courtship behavior in zebra finches. AB - Norepinephrine (NE) is involved in a variety of behaviors across vertebrate species. In songbirds, NE is involved in singing and auditory perception, fundamental components of pair formation. Mechanisms of pairing remain poorly understood in avian species. NE is likely involved given its role in vocal communication and perception. Here, we tested the hypothesis that DSP-4 treatments (a noradrenergic neurotoxin that decreases NE) decreases singing in males, song perception in females and pairing in both sexes using a naturalistic paradigm. Females were tested for preferences of either control or DSP-4 males in a two-choice paradigm using live males. Both sexes were then tested for courtship and pair formation in aviaries. In the two-choice paradigm, control females showed a significant preference for control males over DSP-4 males, whereas DSP-4 females showed no such preference. In the aviary tests, DSP-4 males engaged in less courtship behavior, showed decreased pairing behaviors and increased pair latencies compared to control males. In females, DSP-4 treatments did not alter courtship or pairing behavior. Lower neural densities of noradrenergic fibers in song, auditory, and affiliative regions were observed in DSP-4 animals of both sexes. Furthermore, DBH-ir densities in these regions explained variations in courtship and pairing behaviors, as well as pairing status. Our results extend previous findings to naturalistic contexts, provide evidence that DBH-ir densities in specific regions correlate with pairing-related behaviors, and inform us of sex differences in the role of NE in pairing. PMID- 23747612 TI - Nanomechanical probing of the septum and surrounding substances on Streptococcus mutans cells and biofilms. AB - We report a unique bio-nanomechanical behavior at the septum (Z-ring) of Streptococcus mutans-containing biofilm through in situ measurements obtained by atomic force microscopy. A distinct serrated pattern on the releasing force displacement curves can only be observed with the use of a sharp nanosized probe tip, and this was found at the septum of S. mutans. Further investigations suggested the serrated patterns could be due to the unfolding of some sub-surface divisome proteins. Seismometer measurements were conducted at the septum by placing an ultra-sensitive atomic force microscope probe on the surface. Unique periodic vibrations were observed at the septum under various biofilm conditions. This finding suggests the possibility of remodeling of the cell wall nanostructure at the septum of S. mutans. PMID- 23747611 TI - Effects of stimulus salience on touchscreen serial reversal learning in a mouse model of fragile X syndrome. AB - Fragile X syndrome (FXS) is the most common inherited form of intellectual disability in males and the most common genetic cause of autism. Although executive dysfunction is consistently found in humans with FXS, evidence of executive dysfunction in Fmr1 KO mice, a mouse model of FXS, has been inconsistent. One possible explanation for this is that executive dysfunction in Fmr1 KO mice, similar to humans with FXS, is only evident when cognitive demands are high. Using touchscreen operant conditioning chambers, male Fmr1 KO mice and their male wildtype littermates were tested on the acquisition of a pairwise visual discrimination followed by four serial reversals of the response rule. We assessed reversal learning performance under two different conditions. In the first, the correct stimulus was salient and the incorrect stimulus was non salient. In the second and more challenging condition, the incorrect stimulus was salient and the correct stimulus was non-salient; this increased cognitive load by introducing conflict between sensory-driven (i.e., bottom-up) and task dependent (i.e., top-down) signals. Fmr1 KOs displayed two distinct impairments relative to wildtype littermates. First, Fmr1 KOs committed significantly more learning-type errors during the second reversal stage, but only under high cognitive load. Second, during the first reversal stage, Fmr1 KOs committed significantly more attempts to collect a reward during the timeout following an incorrect response. These findings indicate that Fmr1 KO mice display executive dysfunction that, in some cases, is only evident under high cognitive load. PMID- 23747613 TI - The effect of the change from a herbage- to a concentrate-based diet on the oxidative stability of raw and cooked lamb meat. AB - Over 89 days, 10 lambs (S) were fed concentrates and hay in stall, while 9 lambs (P) grazed at pasture. Two groups of 9 animals grazed at pasture until switching to a concentrate-based diet for 14 or 37 days before slaughter (P-S14 and P-S37). The fat content of longissimus dorsi muscle (LM) increased with increasing duration of concentrate feeding (P=0.05). As a consequence, the concentration of polyunsaturated fatty acids (PUFA) and of the highly peroxidisable (HP) PUFA in the polar lipids was similar between treatments. Lipid oxidation in fresh LM over 8 days of storage was affected by the diet (P<0.0005) with the P-S37 and P treatments producing, respectively, the highest and the lowest TBARS values. The P treatment reduced TBARS in cooked minced LM over 2 days of storage and no difference was found between the P-S14, P-S37 and S treatments. Colour stability of fresh LM was not noticeably affected by the dietary treatment. PMID- 23747614 TI - Interrelationship between measures of collagen, compression, shear force and tenderness. AB - This study examined the relationship between collagen content as determined by hydroxyproline assay with other measures of connective tissue, shear force and tenderness in lamb muscle. Samples were taken from both m. longissimus lumborum (LL, loin) and the m. semimembranosus (SM, topside) of 99 lambs. Sensory tenderness and compression of the LL were not correlated to any measure of collagen or connective tissue, with one exception where compression was correlated (r=-0.28; P<0.05) to the percentage of connective tissue determined by imaging. Intramuscular fat (IMF) was linearly correlated (P<0.05) to sensory tenderness and compression, such that a 1% increase in IMF increased the tenderness score by 2.3+/-0.83 units and reduced compression by 0.73+/-0.21 N. There was no correlation between SM shear force and collagen concentration. The data suggest that measurement of collagen concentration did not explain the variation in shear force and sensory tenderness observed in the meat from lambs. PMID- 23747615 TI - The effects of HNE on ovine oxymyoglobin redox stability in a microsome model. AB - The effect of 4-hydroxy-2-nonenal (HNE), a secondary lipid oxidation product, on ovine myoglobin (Mb) redox stability was investigated. HNE increased oxymyoglobin (OxyMb) oxidation under all pH/temperature conditions studied. Mono-, di- and tri HNE adducts were detected by ESI-Q-TOF MS analysis. Sites of adduction, His 120, His 25 and His 65, were determined by ESI-CID-MS/MS analysis. The relationship between ovine Mb (with/without HNE) and lipid oxidation was also studied in a microsome model in the presence of alpha-tocopherol. Surprisingly, preincubation of Mb with HNE did not affect subsequent Mb redox stability in the microsome model (P<0.05). Microsomes with elevated concentrations of alpha-tocopherol delayed lipid and Mb oxidations relative to controls. HNE-treated ovine Mb caused greater lipid oxidation compared to control ovine Mb in control microsomes (P<0.05). This study demonstrated an interaction between ovine Mb oxidation and lipid oxidation. PMID- 23747616 TI - Meat quality, microbiological status and consumer preference of beef gluteus medius aged in a dry ageing bag or vacuum. AB - This study investigated meat quality and consumer preference after ageing beef gluteus medius in a water vapour-permeable dry-ageing bag or in vacuum for 14 days. Higher ageing and trim losses but lower thawing loss, cooking loss and water content were found in samples aged in dry ageing bags compared to those aged in vacuum. Samples aged in dry ageing bags had higher total bacteria and yeast counts but lower lactic acid bacteria counts than those aged in vacuum, both before and after trimming. Meat aged in dry ageing bag was more tender and juicier and overall preferred by consumers compared with samples aged in vacuum. Female participants outperformed the males in detecting differences in palatability. No differences were found in pH, smell, shear force, colour, Enterobacteriaceae, and mould counts. Thus, by using a dry ageing bag, it is possible to produce dry-aged meat in a more controlled condition without negative effects on sensory or other quality attributes. PMID- 23747617 TI - Effect of the dietary supplementation of essential oils from rosemary and artemisia on muscle fatty acids and volatile compound profiles in Barbarine lambs. AB - Eighteen Barbarine lambs (3 months of age), were assigned for 95 days to 3 treatments: six lambs were fed a barley-based concentrate plus oat hay ad libitum (control group, C); other lambs received the control diet plus essential oil (400 ppm DM) either of Rosmarinus officinalis (R400 group; n=6) or of Artemisia herba alba (A400 group; n=6). At slaughter the muscle longissimus dorsi was sampled and subjected to fatty acid and volatile organic compounds (VOC) analyses. The A400 lambs presented a greater amount of vaccenic, rumenic and linolenic acids and of polyunsaturated fatty acids (PUFA) in meat than the C and R400 animals. Essential oils supplementation did not affect meat VOC profile though the sesquiterpenes copaene and beta-caryophyllene were detected only in the meat of R400 and A400 lambs. It is concluded that the supplementation of rosemary or artemisia essential oils does not produce detrimental effects on lamb meat VOC profile. The supplementation of artemisia can improve meat healthy properties. PMID- 23747618 TI - Effect of tasting and information on consumer opinion about pig castration. AB - Our research explored the relative importance of pig castration amongst other aspects of animal welfare, and the potential impact of information and sensory experiences on European Union (EU) consumers' preferences. The EU is considering a future ban on surgical pig castration by 2018 which may affect markets and consumers' preferences. We carried out an empirical study using consumer-level data obtained from questionnaires completed in a controlled environment by a total of 825 consumers. The experiment was carried out in six EU countries (Spain, United Kingdom, The Netherlands, France, Italy and Germany) which account for 66.0% of the EU-27's and 76.3% of the EU-15's meat production. Results show that consumers do not perceive pig castration to be a relevant aspect of animal welfare nor its relationship with meat quality. Consumers with healthy life styles, concerned about animal welfare and who have had a negative sensory experience with boar meat are willing to accept paying more to avoid boar taint. PMID- 23747619 TI - Feasibility of NIR interactance hyperspectral imaging for on-line measurement of crude composition in vacuum packed dry-cured ham slices. AB - There is a growing market for packaged slices of dry-cured ham. The heterogeneity of the composition of slices between packages is an important drawback when aiming to offer consumers a product with a known and constant composition which fits individual consumer expectations. The aim of this work was to test the feasibility of NIR interactance imaging for on-line analysis of water, fat and salt and their spatial distribution in dry-cured ham slices. PLSR models for predicting water, fat and salt contents with NIR spectra were developed with a calibration set of samples (n=82). The models were validated with an external validation set (n=42). The predictive models were accurate enough for screening purposes. The errors of prediction were 1.34%, 1.36% and 0.71% for water, fat and salt, respectively. The spatial distribution of these components within the slice was also obtained. PMID- 23747620 TI - Risk factors influencing bruising and high muscle pH in Colombian cattle carcasses due to transport and pre-slaughter operations. AB - The aim of this study was investigate risk factors as possible causes for bruising and high muscle pH under commercial operating conditions in Colombia. Data was recorded for 86 journeys referring to 1179 animals. Carcasses were analyzed in terms of muscle pH and bruises (site, size, severity and shape). Our results indicate that truck load density, stops during transportation of cattle and the lairage time at the plant increased the risk of bruises appearing on carcasses. A lairage time of 18 to 24h at the plant increased the prevalence of bruises 2.1 times compared to lairage periods of between 12 and 18 h. Furthermore, intermittent stops during transit are a risk factor for the increase in the incidence of bruises. However, the transport time (up to 4h) was not related to the presence of bruises and high muscle pH. Finally, steers were found to have less risk of presenting a high muscle pH. PMID- 23747621 TI - Influence of storage temperature and duration on lipid and protein oxidation and flavour changes in frozen pork dumpling filler. AB - This study was conducted to evaluate the effect of storage temperature and duration on oxidation and flavour changes in frozen pork dumpling filler. Freshly prepared dumplings were stored for 0, 30, 60, 90, and 180 d at -7 degrees C, -18 degrees C, and an oscillation between -7 degrees C and -18 degrees C. The samples stored at -7 degrees C for 180 d had significantly higher levels of TBARS and protein carbonyls than those stored at -18 degrees C and the fluctuating -7 degrees C/-18 degrees C (P<0.05). The percentage of unsaturated fatty acids in total lipids decreased with extended storage times. The volatile compounds with pleasant odours decreased with time, while the compounds with pungent tastes and smells increased (P<0.05). The sensory results showed that the dumplings stored at higher frozen temperatures for long periods of time had significantly lower acceptability scores (P<0.05). The results suggest that oxidation is a primary cause of quality deterioration in pork dumpling filler during frozen storage. PMID- 23747622 TI - Quality changes during storage of cooked and sliced meat products measured with PTR-MS and HS-GC-MS. AB - The changes in the VOC composition of industrially produced saveloy were measured with Proton-Transfer-Reaction Mass-Spectrometry (PTR-MS) and HeadSpace Gas chromatography-mass spectrometry (HS-GC-MS) during a six weeks storage period. A decrease in the volatile organic compounds contributing to the fresh aroma of saveloy was the main change observed with both PTR-MS and HS-GC-MS. Samples of four other types of cooked and sliced meat product were measured with PTR-MS in the middle and at the end of the four week shelf-life period. These measurements showed an increase in m/z 69, 71, 87 and 89 for the pork loin and in m/z 61 for the herbal saveloy samples. These ions were assigned to the microbial spoilage markers: acetic acid, 2- and 3-methylbutanol, 2- and 3-methylbutanal, diacetyl and acetoin. Overall, this study shows that PTR-MS has potential for quality control of cooked and sliced meat products. PMID- 23747623 TI - Examination of the effect of ageing and temperature at rigor on colour stability of lamb meat. AB - A study of factors (ageing period, rigor temperature and vitamin E level) impacting on the colour stability of lamb m. longissimus thoracis et lumborum (LL) during 3 days of simulated retail display was undertaken. The LL were taken from 84 lambs from 3 slaughters. Slices of LL were measured fresh (24h post mortem) or after ageing for 5 days in vacuum packaging. The oxy/met ratio (630/580 nm), declined with display time, and increased with increasing temperature at pH6.0. Redness (a*) values also declined with display time and a reduction in redness values was observed as LL pH at 24h post-mortem and/or pH at 18 degrees C increased. There was no effect of ageing period or vitamin E level on the oxy/met ratio or a* values when the vitamin E level averaged 3.76 mg/kg LL. These results suggest that maximising vitamin E levels in lambs and achieving a moderate rate of pH decline will optimise colour stability irrespective of ageing period. PMID- 23747624 TI - Effects of cooking methods and chemical tenderizers on survival of Escherichia coli O157:H7 in ground beef patties. AB - This study evaluated chemical tenderizers and cooking methods to inactivate Escherichia coli O157:H7 in ground beef patties (model system for non-intact beef). Ground beef was inoculated with E. coli O157:H7 and mixed with (i) nothing (control), (ii) calcium chloride (CC) and flavoring agents (FA), (iii) CC, FA, and acetic acid (AA), (iv) sodium chloride (SC), sodium tripolyphosphate (ST), and potassium lactate (PL), and (v) the combination of SC, ST, PL, and AA. Patties were stored in aerobic or vacuum bags at -20, 4, and 12 degrees C. Samples were grilled, broiled, or pan-fried to 60 or 65 degrees C. Total bacterial and E. coli O157:H7 populations remained unchanged during storage. Broiling was more effective in reducing E. coli O157:H7 than grilling and pan frying, and acidified tenderizers reduced E. coli O157:H7 more than non-acidified tenderizers in broiling. Higher reductions were observed at 65 degrees C than 60 degrees C in broiled and grilled samples. These results indicate that acidified tenderizers and broiling may be useful in non-intact beef safety. PMID- 23747625 TI - Influence of meat exudates on the quality characteristics of fresh and freeze thawed pork. AB - The influence of the accumulated exudates released from pork loin of itself on the quality characteristics of fresh and freeze-thawed pork during cold storage was investigated. Pork loins were divided into four groups (fresh pork with exudates, fresh pork without exudates, freeze-thawed pork with exudates and freeze-thawed pork without exudates) and stored at 1.0 degrees C for 7 days. Exudate amount increased due to freeze-thawing and with storage, and most quality traits such as drip loss, cooking loss, tenderness, lightness, redness, and moisture content were affected by freeze-thawing (p<0.05). Freeze-thaw increased drip loss but decreased moisture content, cooking loss, tenderness, lightness and redness of meat (p<0.05). Microbial growth was solely affected by exudate removal and the removal of initial exudates decreased microbial growth (p<0.05). Exudates were positively correlated with total protein content and total plate count but negatively correlated with pH and cooking loss. Therefore, removing meat exudates and avoiding freeze can slow down the quality deterioration of pork during cold storage. PMID- 23747626 TI - Influence of fat content on physico-chemical and oxidative stability of foal liver pate. AB - The effect of fat content on physico-chemical properties and lipid and protein stability of foal liver pate was studied. For this purpose, two batches (10 units per batch) of foal liver pate with different pork back fat content [30% (30F) and 40% (40F)] were manufactured. 30F foal liver pate was darker (lower L* value, P>0.05), redder (higher a*, P<0.001) and harder (higher hardness value; P<0.001) compared to those with 40F. Fat level was closely related to the calorific value of foal liver pate, being more calorific in those with higher fat contents (352 kcal/100 g; P<0.001). Regarding total Fe content, 30F foal liver pate showed the higher value (4.19 mg/100 g; P<0.01). Oxidative stability of foal liver pate was influenced by fat level. 40F foal liver pate presented higher TBARS and lower carbonyl contents compared to 30F ones (P<0.001). Finally, foal pates with the two different fat contents had significantly (P<0.001) different n-6/n-3 ratios, foal liver pates with 30F showed the lowest values (9.97) compared to those with 40F content (13.41). PMID- 23747627 TI - Combined heat transfer and kinetic models to predict cooking loss during heat treatment of beef meat. AB - A heat transfer model was used to simulate the temperature in 3 dimensions inside the meat. This model was combined with a first-order kinetic models to predict cooking losses. Identification of the parameters of the kinetic models and first validations were performed in a water bath. Afterwards, the performance of the combined model was determined in a fan-assisted oven under different air/steam conditions. Accurate knowledge of the heat transfer coefficient values and consideration of the retraction of the meat pieces are needed for the prediction of meat temperature. This is important since the temperature at the center of the product is often used to determine the cooking time. The combined model was also able to predict cooking losses from meat pieces of different sizes and subjected to different air/steam conditions. It was found that under the studied conditions, most of the water loss comes from the juice expelled by protein denaturation and contraction and not from evaporation. PMID- 23747628 TI - Effects of tomato pomace supplementation on carcass characteristics and meat quality of fattening rabbits. AB - The aim of this study was to determine how a feeding plan characterized by different levels of tomato pomace (TP) supplementation influences the carcass characteristics, the chemical, physical and sensorial characteristics of rabbit meat. 144 weaned crossbred rabbits were divided into three groups of 48 each. The first group was fed a basal diet without TP, while the other two groups were fed the basal diet after replacing part of the diet with TP at 3% and 6%, respectively. There was a significant difference between the experimental groups in terms of live and carcass weights. The meat of rabbits fed on a 6% TP diet exhibited higher yellowness (b*) and Chroma values when compared to others. The saturated fatty acid content in the longissimus dorsi muscle and perirenal fat decreased significantly with increasing TP inclusion, while polyunsaturated fatty acids increased. Furthermore, our results indicate that a diet integrated with 6% TP could influence positively the overall preference of cooked meat. PMID- 23747629 TI - Stunning and animal welfare from Islamic and scientific perspectives. AB - The transformation of an animal into pieces fit for human consumption is a very important operation. Rather than argue about halal slaughter without stunning being inhumane or stunning being controversial from the Islamic point of view, we discuss slaughter, stunning and animal welfare considering both Islamic and animal welfare legislation requirements. With the world Muslim population close to two billion, the provision of halal meat for the Muslim community is important both ethically and economically. However, from the animal welfare standard point of view, a number of issues have been raised about halal slaughter without stunning, particularly, about stressful methods of restraint and the latency of the onset of unconsciousness. This paper sets out to, discuss the methods of stunning that are acceptable by Islamic authorities, highlight the requirements for stunning to be acceptable in Islam and suggest practical ways to improve the humanness of slaughter. PMID- 23747630 TI - Calibrations between the variables of microbial TTI response and ground pork qualities. AB - A time-temperature indicator (TTI) based on a lactic acid bacterium, Weissella cibaria CIFP009, was applied to ground pork packaging. Calibration curves between TTI response and pork qualities were obtained from storage tests at 2 degrees C, 10 degrees C, and 13 degrees C. The curves of the TTI vs. total cell number at different temperatures coincided to the greatest extent, indicating the highest representativeness of calibration, by showing the least coefficient of variance (CV=11%) of the quality variables at a given TTI response (titratable acidity) on the curves, followed by pH (23%), volatile basic nitrogen (VBN) (25%), and thiobarbituric acid-reactive substances (TBARS) (47%). Similarity of Arrhenius activation energy (Ea) could also reflect the representativeness of calibration. The total cell number (104.9 kJ/mol) was found to be the most similar to that of the TTI response (106.2 kJ/mol), followed by pH (113.6 kJ/mol), VBN (77.4 kJ/mol), and TBARS (55.0 kJ/mol). PMID- 23747631 TI - Association mapping of quantitative trait loci for carcass and meat quality traits at the central part of chromosome 2 in Italian Large White pigs. AB - Association mapping of the central part of porcine chromosome 2 harboring QTLs for carcass and meat quality traits was performed with 17 gene-tagged SNPs located between 44.0 and 77.5 Mb on a physical map (Sscrofa10.2) in Italian Large White pigs. For the analyzed animals records of estimated breeding values for average daily gain, back fat thickness, lean cuts, ham weight, feed conversion ratio, pH1, pHu, CIE L*, CIE a*, CIE b* and drip loss were available. A significant QTL for fat deposition (adjusted P=0.0081) and pH1 (adjusted P=0.0972) to MYOD1 at position 44.4 Mb and a QTL for growth and meatiness (adjusted P=0.0238-0.0601) to UBL5 at position 68.9 Mb were mapped. These results from association mapping are much more accurate than those from linkage mapping and facilitate further search for position candidate genes and causative mutations needed for application of markers through marker assisted selection. PMID- 23747632 TI - Reduction in lipid oxidation by incorporation of encapsulated sodium tripolyphosphate in ground turkey. AB - Ground turkey, with 1% NaCl, was incorporated with no sodium tripolyphosphate (control, nSTP), unencapsulated STP (uSTP; 0.3% or 0.5%), encapsulated STP (eSTP; 0.3% or 0.5% active, phosphate basis), or a blend (0.3% uSTP plus 0.2% eSTP). Encapsulate (hydrogenated vegetable oil) was designed to melt at 74 degrees C. Treatments were stored (4, 24h at 3 degrees C) before being cooked to two different endpoints (EPT; 74, 79 degrees C) followed by post-cooked storage (0, 5, 10days). An improvement of 77% (0.3% eSTP) and 80% (0.5% eSTP) in the reduction of TBARS was found in comparison to corresponding uSTP. The blend produced a 62% improvement compared to uSTP (0.5%) while maintaining cook yield. CIE a* values were highest at both EPT and post-cooked storage times beyond 0 day for eSTP. Meat manufacturing procedures that entail a delayed thermal processing step will benefit by an improvement in lipid oxidation control through the use of encapsulated phosphates. PMID- 23747633 TI - Incidence of Shiga toxin-producing Escherichia coli serogroups in ruminant's meat. AB - To assess the presences of Escherichia coli, its serogroups, virulence factors and antibiotic resistance properties in ruminant's meat, a total of 820 raw meat samples were collected and then evaluated using culture, PCR and disk diffusion methods. Totally, 238 (29.02%) samples were positive for presence of Escherichia coli. All of the isolates had more than one virulence gene including Stx1, Stx2, eaeA and ehly. All investigated serogroups were found in beef and sheep and all except O145, O121 and O128 were found in goat. The O91, O113, O111, O103, O26 and O157 serogroups were found in camel. Totally, aadA1-blaSHV combination was the most predominant antibiotic resistance gene. The highest resistance of STEC strains was seen against penicillin while resistance to nitrofurantoin and ciprofloxacin was minimal. These findings showed that health care and meat inspection should be reconsidered in Iranian slaughterhouses and butchers. PMID- 23747634 TI - Ultrasonic assessment of textural changes in vacuum packaged sliced Iberian ham induced by high pressure treatment or cold storage. AB - Ultrasonic measurements were used to characterize the effect of high pressure treatment (HPT) (600 MPa/6 min) or cold storage (6 degrees C/120 days) on the textural properties of vacuum packaged dry-cured ham. The ultrasonic velocity, textural properties and fat content were determined in the ham packages. The ultrasonic velocity was related to the ham hardness, which depends on the sample composition. HPT induced molecular alterations which resulted in an average increase in the hardness of lean tissue of 0.2N and one of 0.3N in that of fatty tissue. These textural changes give rise to a velocity increase (8m/s for lean and 17 m/s for fatty tissue). The cold storage of the Iberian ham also led to an increase in hardness (average 1.10 N) and ultrasonic velocity (average 70 m/s). Therefore, the non-destructive ultrasonic technique could be a reliable method with which to assess the textural changes induced by HPT or cold storage on packaged dry-cured ham. PMID- 23747635 TI - Preferences for lamb meat: a choice experiment for Spanish consumers. AB - This paper analyzes consumers' preferences for different lamb meat attributes using a choice experiment. In particular, preferences for the type of commercial lamb meat ("Ternasco" and "Suckling") and the origin of production (locally produced "Ojinegra from Teruel") were evaluated. Moreover, we endogenously identify consumers' segments based on consumers' preferences for the analyzed attributes. Data come from a survey administrated in Spain during 2009. A latent class model was used to estimate the effect of the attributes on consumer utility, derive the willingness to pay and determine consumers' segments. Results suggest that consumers' preferences for both attributes are heterogeneous and two homogenous consumers' segments were detected. The largest segment (79%) did not value any of the analyzed attributes while the smaller one (21%) valued both of them positively. In particular, consumers in this second segment are willing to pay an extra premium for the "Ternasco" lamb meat, around double the premium they are willing to pay for the locally produced lamb meat "Ojinegra from Teruel". PMID- 23747636 TI - Mortadella sausage manufactured with Caiman yacare (Caiman crocodilus yacare) meat, pork backfat, and soybean oil. AB - Mortadellas manufactured using Caiman yacare meat (70%) and pork fat (30%) were reformulated by substituting pork fat with increasing amounts of soybean oil (25%, 50%, and 100%) and evaluated 7, 30, and 60 days post-manufacture. The substitutions resulted in an increase in fat content and in the percentage of polyunsaturated fatty acids (total PUFA; 18:2 n-6 and 18:3 n-3), and a reduction in saturated fatty acids (total SFA; 14:0 and 16:0). These alterations reduced (P<0.01) the indices of atherogenicity and thrombogenicity by 4- to 5-fold in the formulation with 100% soybean oil compared to the original formulation. The levels of TBARS obtained at day 7 were positively correlated (P<0.01) with 18:2 n 6 and 18:3 n-3 (r=0.83 and 0.84, respectively) and negatively correlated with 17:0 and 17:1 (r=-0.91 and -0.89, respectively). All formulations received favourable overall acceptability by the sensory panel. PMID- 23747637 TI - Pre rigor processing, ageing and freezing on tenderness and colour stability of lamb loins. AB - Forty eight lamb carcasses with temperature and pH monitored were obtained from two commercial plants. At 24h post mortem both loins (M. longissimus) from each carcass were randomly allocated to a) unaged frozen at -18 degrees C, (b) aged at -1.5 degrees C for 2weeks before freezing, (c) aged for 3 weeks before freezing and (d) aged for 9 weeks without freezing. Shear force, colour stability and proteolysis were analyzed. Carcasses with a slower temperature and more rapid pH decline had more calpain autolysis, slightly higher shear force and less colour stable compared to that counterpart in general (P<0.05). However, the shear force values of the loins were all acceptable (<6 kgF) regardless of different pre rigor processing and ageing/freezing treatments. Furthermore, the loins aged for 2 weeks-then-frozen/thawed had a similar shear force to the loins aged only for 9 weeks suggesting that ageing-then-freezing would result in equivalent tenderness compared to aged only loins for the long-term storage. PMID- 23747638 TI - Microstructural and mechanical properties of camel longissimus dorsi muscle during roasting, braising and microwave heating. AB - This study was conducted to investigate the effects of various heating methods, including roasting, braising and microwave heating, on mechanical properties and microstructure of longissimus dorsi (LD) muscle of the camel. Shear value and compression force increased during microwave heating more than roasting and braising. Results obtained from scanning electron microscopy (SEM) showed more damage from roasting than in either braising or microwave heating. Granulation and fragmentation were clear in muscle fibers after roasting. The perimysium membrane of connective tissue was damaged during braising, while roasting left the perimysium membrane largely intact. The mechanical properties and microstructure of muscle can be affected by changes in water content during cooking. PMID- 23747639 TI - Effects of processing parameters on immersion vacuum cooling time and physico chemical properties of pork hams. AB - The effects of agitation (1002 rpm), different pressure reduction rates (60 and 100 mbar/min), as well as employing cold water with different initial temperatures (IWT: 7 and 20 degrees C) on immersion vacuum cooling (IVC) of cooked pork hams were experimentally investigated. Final pork ham core temperature, cooling time, cooling loss, texture properties, colour and chemical composition were evaluated. The application for the first time of agitation during IVC substantially reduced the cooling time (47.39%) to 4.6 degrees C, compared to IVC without agitation. For the different pressure drop rates, there was a trend that shorter IVC cooling times were achieved with lower cooling rate, although results were not statistically significant (P>0.05). For both IWTs tested, the same trend was observed: shorter cooling time and lower cooling loss were obtained under lower linear pressure drop rate of 60 mbar/min (not statistically significant, P>0.05). Compared to the reference cooling method (air blast cooling), IVC achieved higher cooling rates and better meat quality. PMID- 23747640 TI - The effect of high pressure and residual oxygen on the color stability of minced cured restructured ham at different levels of drying, pH, and NaCl. AB - Color stability of minced cured restructured ham was studied by considering the effects of high pressure (HP) (600 MPa, 13 degrees C, 5 min), raw meat pH24 (low, normal, high), salt content (15, 30 g/kg), drying (20%, 50% weight loss), and residual oxygen level (0.02%-0.30%). Raw hams were selected by pH24 in Semimembranosus, mixed with additives, frozen, sliced, and dried by the Quick-Dry Slice(r) (QDS) process followed by HP treatment or not (control). Packaging and storage simulated industrial packaging: modified atmosphere containing 80% N2, 20% CO2, and residual O2 in one of three intervals: <0.1%, 0.1%-0.2%, or 0.2% 0.3%, and retail storage conditions: chill storage, 12 h light, 12 h darkness. HP improved the stability of the redness of 20% QDS hams, while the stabilizing effect on 50% QDS hams was smaller, concluding that water has the dominating role. Raw meat pH24, salt content, and residual oxygen level had varying effects on the stability of the red color. PMID- 23747642 TI - 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. PMID- 23747643 TI - Total flavonoids of Mosla scabra leaves attenuates lipopolysaccharide-induced acute lung injury via down-regulation of inflammatory signaling in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mosla scabra (Thunb.) C.Y. Wu, belonging to the Labiatae family, is a tomentose and aromatic plant, which is widely used as an antipyretic and antiviral drug for pulmonary diseases and famous for its efficiency in treating colds, fever, pneumonia and chronic bronchitis. To investigate therapeutic effects and possible mechanism of Mosla scabra flavonoids (MF) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. MATERIALS AND METHODS: Mice were orally administrated with MF once (30 mg/kg or 90 mg/kg) 1 h before LPS challenge. Lung specimens and the bronchoalveolar lavage fluid (BALF) were isolated for histopathological examinations and biochemical analyses 6 h after LPS challenge. RESULTS: Pretreatment with MF could decrease significantly lung wet-to-dry weight (W/D) ratio, lower myeloperoxidase (MPO) activity and total protein concentrations in the BALF, reduce serum levels of NO, TNF-alpha, IL-1beta and IL-6 in ALI model. Additionally, MF attenuated lung histopathological changes and significantly inhibited the phosphorylation of p38 MAPK and translocation of NF-kappaB p65. CONCLUSIONS: These results showed MF significantly attenuate LPS-induced acute lung injury and production of inflammatory mediators via inhibiting MAPK and NF-kappaB activation, indicating it as a potential therapeutic agent for ALI. PMID- 23747644 TI - Senecio scandens Buch.-Ham.: a review on its ethnopharmacology, phytochemistry, pharmacology, and toxicity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The aerial parts of Senecio scandens Buch.-Ham. (family Asteraceae) have a long history in traditional Chinese medicine as a treatment for various ailments, such as bacterial diarrhea, enteritis, conjunctivitis, and respiratory tract infections. MATERIALS AND METHODS: A bibliographic investigation of Senecio scandens was accomplished by analyzing secondary sources, including the Chinese Medicinal plantal Classics, the Internet (Google Scholar and Baidu Scholar), and scientific databases accepted worldwide (Pubmed, Scopus, Web of Science, SciFinder, and CNKI). These sources were scrutinized for available information about the uses of Senecio scandens in traditional Chinese medicine, phytochemistry, pharmacology, and toxicology. RESULTS: Senecio scandens is a medicinal plant with a climbing woody stem. Phytochemical studies have shown the presence of numerous valuable compounds, such as flavonoids, alkaloids, phenolic acids, terpenes, volatile oils, carotenoids, and trace elements. Among them, PAs are the characteristic constituents, adonifoline is one of the index ingredients of Senecio scandens. Studies in modern pharmacology have demonstrated that extracts and compounds isolated from Senecio scandens show a wide spectrum of pharmacological activities, including anti-inflammatory, antimicrobial, anti-leptospirosis, hepatoprotective, anti-infusorial, antioxidant, antiviral, antitumoral, analgesic, mutagenic, and toxicological activities. CONCLUSIONS: Phytochemical and pharmacological studies have demonstrated that the extracts of the plant possess various pharmacological activities that can be attributed to the presence of various flavonoids, phenolic acids, and alkaloids. Newer technologies for qualitative and quantitative methods of PAs need to be developed to obtain better accuracy and sensitivity. Due to the toxicity of PAs present in this medicinal plant, the regulations on PAs of Senecio scandens were varied among different countries and regions. In China, the PAs toxicity of Senecio scandens ranking criteria is not well defined in the Chinese Pharmacopoeia 2010, and there is no strict uniform requirement on the PAs in western countries. We propose that the use of Senecio scandens should be reevaluated based on a set of criteria, which includes risk-benefit analysis and severity of the toxic effects, clinical and preclinical data to ensure safe use while continuing to satisfy the need for access to the medicinal plant. PMID- 23747645 TI - Between-limb kinematic asymmetry during gait in unilateral and bilateral mild to moderate knee osteoarthritis. AB - OBJECTIVE: To compare lower-limb kinematic asymmetries during gait in individuals with unilateral and bilateral symptomatic osteoarthritis and controls. DESIGN: Cross-sectional. SETTING: Laboratory. PARTICIPANTS: Participants (N=54) had symptomatic unilateral (n=18) or bilateral (n=18) knee osteoarthritis. Healthy controls were sex- and age-matched and similar in height and weight to osteoarthritis groups (n=18). INTERVENTION: Three-dimensional motion analysis was conducted while participants walked on a treadmill at 1.1m/s. MAIN OUTCOME MEASURES: Maximum joint angles and velocities of the knee and hip during stance, knee flexion, knee adduction, and hip adduction at initial contact, pelvic drop, stride length, and average toe out. RESULTS: There was a significant limb effect for knee flexion at initial contact (P=.01). The bilateral osteoarthritis group demonstrated the largest between-limb asymmetry (2.83 degrees ; 95% confidence interval, .88-4.78; effect size [ES]=.67). The bilateral osteoarthritis group also displayed tendencies toward between-limb asymmetry in hip adduction at initial contact and peak knee adduction during stance; ESs were small (ES=.33 and .48). Lower-limb kinematics was symmetrical in the control and unilateral knee osteoarthritis groups. CONCLUSIONS: Between-limb asymmetries are present even at mild to moderate stages of knee osteoarthritis. During this stage, between-limb asymmetry appears to be more prevalent in patients with bilateral symptomatic disease, suggesting that patients with unilateral disease maintain kinematic symmetry for longer in the knee osteoarthritis process. Further, early treatment strategies should target the restoration of gait symmetry and involve kinematics changes in both lower limbs. Future research is needed to determine the efficacy of such strategies with respect to kinematic asymmetry, pain, and disease progression. PMID- 23747646 TI - Effects of home-based locomotor treadmill training on gross motor function in young children with cerebral palsy: a quasi-randomized controlled trial. AB - OBJECTIVE: To examine the effects of an intensive home-based program of treadmill training on motor skills related to walking in preambulatory children with cerebral palsy (CP). DESIGN: Quasi-randomized controlled trial. SETTING: Homes of the participants. PARTICIPANTS: Children with CP (N=12) with Gross Motor Function Classification System levels I and II were assigned to the intervention group (n=6; mean age +/- SD, 21.76+/-6.50mo) and control group (n=6; 21.25+/-6.07mo). All children were tested preintervention, postintervention, at a 1-month follow up, and at a 4-month follow-up. INTERVENTIONS: All children received their weekly scheduled physical therapy sessions at their homes. In addition, children in the intervention group walked on a portable treadmill in their homes 6 times per week, twice daily for 10- to 20-minute sessions, for 6 weeks. The intervention was carried out by the children's parents with weekly supervision by a physical therapist. MAIN OUTCOME MEASURES: Gross Motor Function Measure-66 Dimensions D/E, Peabody Developmental Motor Scales-2 (PDMS-2), Pediatric Evaluation of Disability Inventory (PEDI), timed 10-m walk test (10MWT), and Functional Mobility Scale (FMS). The Friedman test and Mann-Whitney U test were conducted for within-group and between-group differences, respectively. RESULTS: There was a significant between-group treatment effect for the PDMS-2 at posttest (P=.01) and 1-month postintervention follow-up (P=.09), as well as for the PEDI at posttest (P=.01), the 1-month postintervention follow-up (P=.009), and the 4-month postintervention follow-up (P=.04). The FMS was significant at the posttest (P=.04). CONCLUSIONS: Home-based treadmill training accelerates the attainment of walking skills and decreases the amount of support used for walking in young children with CP. PMID- 23747648 TI - Authority dependence and judgments of utilitarian harm. AB - Three studies tested the conditions under which people judge utilitarian harm to be authority dependent (i.e., whether its right or wrongness depends on the ruling of an authority). In Study 1, participants judged the right or wrongness of physical abuse when used as an interrogation method anticipated to yield useful information for preventing future terrorist attacks. The ruling of the military authority towards the harm was manipulated (prohibited vs. prescribed) and found to significantly influence judgments of the right or wrongness of inflicting harm. Study 2 established a boundary condition with regards to the influence of authority, which was eliminated when the utility of the harm was definitely obtained rather than forecasted. Finally, Study 3 replicated the findings of Studies 1-2 in a completely different context-an expert committee's ruling about the harming of chimpanzees for biomedical research. These results are discussed as they inform ongoing debates regarding the role of authority in moderating judgments of complex and simple harm. PMID- 23747647 TI - Aerobic capacity, orthostatic tolerance, and exercise perceptions at discharge from inpatient spinal cord injury rehabilitation. AB - OBJECTIVE: To describe physical capacity, autonomic function, and perceptions of exercise among adults with subacute spinal cord injury (SCI). DESIGN: Cross sectional. SETTING: Two inpatient SCI rehabilitation programs in Canada. PARTICIPANTS: Participants (N=41; mean age +/- SD, 38.9 +/- 13.7y) with tetraplegia (TP; n=19), high paraplegia (HP; n=8), or low paraplegia (LP; n=14) completing inpatient SCI rehabilitation (mean +/- SD, 112.9 +/- 52.5d postinjury). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Peak exercise capacity was determined by an arm ergometry test. As a measure of autonomic function, orthostatic tolerance was assessed by a passive sit-up test. Self efficacy for exercise postdischarge was evaluated by a questionnaire. RESULTS: There was a significant difference in peak oxygen consumption and heart rate between participants with TP (11.2 +/- 3.4;mL.kg(-1).min(-1) 113.9 +/- 19.7 beats/min) and LP (17.1 +/- 7.5 mL.kg(-1).min(-1); 142.8 +/- 22.7 beats/min). Peak power output was also significantly lower in the TP group (30.0 +/- 6.9W) compared with the HP (55.5 +/- 7.56W) and LP groups (62.5 +/- 12.2W). Systolic blood pressure responses to the postural challenge varied significantly between groups (-3.0 +/- 33.5 mmHg in TP, 17.8 +/- 14.7 mmHg in HP, 21.6 +/- 18.7 mmHg in LP). Orthostatic hypotension was most prevalent among participants with motor complete TP (73%). Results from the questionnaire revealed that although participants value exercise and see benefits to regular participation, they have low confidence in their abilities to perform the task of either aerobic or strengthening exercise. CONCLUSIONS: Exercise is well tolerated in adults with subacute SCI. Exercise interventions at this stage should focus on improving task specific self-efficacy, and attention should be made to blood pressure regulation, particularly in individuals with motor complete TP. PMID- 23747649 TI - Complete unconscious control: using (in)action primes to demonstrate completely unconscious activation of inhibitory control mechanisms. AB - Although robust evidence indicates that action initiation can occur unconsciously and unintentionally, the literature on action inhibition suggests that inhibition requires both conscious thought and intentionality. In prior research demonstrating automatic inhibition in response to unconsciously processed stimuli, the unconscious stimuli had previously been consciously associated with an inhibitory response within the context of the experiment, and participants had consciously formed a goal to activate inhibition processes when presented with the stimuli (because task instructions required participants to engage in inhibition when the stimuli occurred). Therefore, prior work suggests that some amount of conscious thought and intentionality are required for inhibitory control. In the present research, we recorded event-related potentials during two go/no-go experiments in which participants were subliminally primed with general action/inaction concepts that had never been consciously associated with task specific responses. We provide the first demonstration that inhibitory control processes can be modulated completely unconsciously and unintentionally. PMID- 23747650 TI - Sleep restores loss of generalized but not rote learning of synthetic speech. AB - Sleep-dependent consolidation has been demonstrated for declarative and procedural memory but few theories of consolidation distinguish between rote and generalized learning, suggesting similar consolidation should occur for both. However, studies using rote and generalized learning have suggested different patterns of consolidation may occur, although different tasks have been used across studies. Here we directly compared consolidation of rote and generalized learning using a single speech identification task. Training on a large set of novel stimuli resulted in substantial generalized learning, and sleep restored performance that had degraded after 12 waking hours. Training on a small set of repeated stimuli primarily resulted in rote learning and performance also degraded after 12 waking hours but was not restored by sleep. Moreover performance was significantly worse 24-h after rote training. Our results suggest a functional dissociation between the mechanisms of consolidation for rote and generalized learning which has broad implications for memory models. PMID- 23747651 TI - The effect of word predictability on reading time is logarithmic. AB - It is well known that real-time human language processing is highly incremental and context-driven, and that the strength of a comprehender's expectation for each word encountered is a key determinant of the difficulty of integrating that word into the preceding context. In reading, this differential difficulty is largely manifested in the amount of time taken to read each word. While numerous studies over the past thirty years have shown expectation-based effects on reading times driven by lexical, syntactic, semantic, pragmatic, and other information sources, there has been little progress in establishing the quantitative relationship between expectation (or prediction) and reading times. Here, by combining a state-of-the-art computational language model, two large behavioral data-sets, and non-parametric statistical techniques, we establish for the first time the quantitative form of this relationship, finding that it is logarithmic over six orders of magnitude in estimated predictability. This result is problematic for a number of established models of eye movement control in reading, but lends partial support to an optimal perceptual discrimination account of word recognition. We also present a novel model in which language processing is highly incremental well below the level of the individual word, and show that it predicts both the shape and time-course of this effect. At a more general level, this result provides challenges for both anticipatory processing and semantic integration accounts of lexical predictability effects. And finally, this result provides evidence that comprehenders are highly sensitive to relative differences in predictability - even for differences between highly unpredictable words - and thus helps bring theoretical unity to our understanding of the role of prediction at multiple levels of linguistic structure in real-time language comprehension. PMID- 23747652 TI - Can statistical learning bootstrap the integers? AB - This paper examines Piantadosi, Tenenbaum, and Goodman's (2012) model for how children learn the relation between number words ("one" through "ten") and cardinalities (sizes of sets with one through ten elements). This model shows how statistical learning can induce this relation, reorganizing its procedures as it does so in roughly the way children do. We question, however, Piantadosi et al.'s claim that the model performs "Quinian bootstrapping," in the sense of Carey (2009). Unlike bootstrapping, the concept it learns is not discontinuous with the concepts it starts with. Instead, the model learns by recombining its primitives into hypotheses and confirming them statistically. As such, it accords better with earlier claims (Fodor, 1975, 1981) that learning does not increase expressive power. We also question the relevance of the simulation for children's learning. The model starts with a preselected set of15 primitives, and the procedure it learns differs from children's method. Finally, the partial knowledge of the positive integers that the model attains is consistent with an infinite number of nonstandard meanings-for example, that the integers stop after ten or loop from ten back to one. PMID- 23747653 TI - The position of imidazopyridine and metabolic activation are pivotal factors in the antimutagenic activity of novel imidazo[1,2-a]pyridine derivatives. AB - The antimutagenic activity of eight novel imidazo[1,2-a]pyridine derivatives (I VIII) against sodium azide (NaN3) and benzo[a]pyrene (B[a]P) was evaluated using the Salmonella reverse mutation assay. At non-toxic concentrations (12.5-50 uM), imidazopyridines I, II, III, and V with a terminal imidazopyridine group were mutagenic, while derivatives VII and VIII with a central imidazopyridine group were not mutagenic. Compounds IV, VII, and VIII exerted a moderate antimutagenic activity against NaN3 under pre-exposure conditions, and a strong activity (>40%) against B[a]P in the presence of S9 under both pre- and co-exposure conditions and mostly independent on the dose. Imidazopyridines possibly inhibited the microsomal-dependent activation of B[a]P. The demethylated derivative VII was the most active antimutagen. All imidazopyridines had a low to moderate antioxidant activity. The antibacterial activity of imidazopyridines was sporadic and moderate probably due to the failure of bacteria to convert imidazopyridines into active metabolites. The position of imidazopyridine was a pivotal factor in the mutagenic/antimutagenic activity. The strong antimutagenic compounds were dicationic planar compounds with a centered imidazo[1,2-a]pyridine spacer. With LD50 of 60 mg/kg in mice for both derivatives VII and VIII, it is safe to investigate the anticancer activity of these derivatives in animal models. PMID- 23747654 TI - Anti-inflammatory glucocorticoids: changing concepts. AB - Despite being the most effective anti-inflammatory treatment for chronic inflammatory diseases, the mechanisms by which glucocorticoids (corticosteroids) effect repression of inflammatory gene expression remain incompletely understood. Direct interaction of the glucocorticoid receptor (NR3C1) with inflammatory transcription factors to repress transcriptional activity, i.e. transrepression, represents one mechanism of action. However, transcriptional activation, or transactivation, by NR3C1 also represents an important mechanism of glucocorticoid action. Glucocorticoids rapidly and profoundly increase expression of multiple genes, many with properties consistent with the repression of inflammatory gene expression. For example: the dual specificity phosphatase, DUSP1, reduces activation of mitogen-activated protein kinases; glucocorticoid induced leucine zipper (TSC22D3) represses nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) transcriptional responses; inhibitor of kappaBalpha (NFKBIA) inhibits NF-kappaB; tristraprolin (ZFP36) destabilises and translationally represses inflammatory mRNAs; CDKN1C, a cell cycle regulator, may attenuate JUN N-terminal kinase signalling; and regulator of G-protein signalling 2 (RGS2), by reducing signalling from Galphaq-linked G protein-coupled receptors (GPCRs), is bronchoprotective. While glucocorticoid-dependent transrepression can co-exist with transactivation, transactivation may account for the greatest level and most potent repression of inflammatory genes. Equally, NR3C1 transactivation is enhanced by beta2-adrenoceptor agonists and may explain the enhanced clinical efficacy of beta2-adrenoceptor/glucocorticoid combination therapies in asthma and chronic obstructive pulmonary disease. Finally, NR3C1 transactivation is reduced by inflammatory stimuli, including respiratory syncytial virus and human rhinovirus. This provides an explanation for glucocorticoid resistance. Continuing efforts to understand roles for glucocorticoid-dependent transactivation will provide opportunities to improve glucocorticoid therapies. PMID- 23747655 TI - Bafetinib inhibits functional responses of human eosinophils in vitro. AB - Eosinophils play a prominent role in the process of allergic inflammation. Non receptor associated Lyn tyrosine kinases generate key initial signals in eosinophils. Bafetinib, a specific Abl/Lyn tyrosine kinase inhibitor has shown a potent antiproliferative activity in leukemic cells, but its effects on eosinophils have not been reported. Therefore, we studied the effects of bafetinib on functional and mechanistic responses of isolated human eosinophils. Bafetinib was more potent than non-specific tyrosin kinase comparators genistein and tyrphostin inhibiting superoxide anion triggered by N-formyl-Met-Leu-Phe (fMLF; 100 nM) (-log IC50=7.25 +/- 0.04 M; 6.1 +/- 0.04 M; and 6.55 +/- 0.03 M, respectively). Bafetinib, genistein and tyrphostin did not modify the [Ca(2+)]i responses to fMLF. Bafetinib inhibited the release of EPO induced by fMLF with higher potency than genistein and tyrphostin (-log IC50=7.24 +/- 0.09 M; 5.36 +/- 0.28 M; and 5.37 +/- 0.19 M, respectively), and nearly suppressed LTC4, ECP and chemotaxis. Bafetinib, genistein and tyrphostin did not change constitutive apoptosis. However bafetinib inhibited the ability of granulocyte-monocyte colony stimulating factor to prevent apoptosis. The activation of Lyn tyrosine kinase, p ERK1/2 and p-38 induced by fMLF was suppressed by bafetinib and attenuated by genistein and tyrphostin. In conclusion, bafetinib inhibits oxidative burst and generation of inflammatory mediators, and reverses the eosinophil survival. Therefore, future anti-allergic therapies based on bafetinib, could help to suppress excessive inflammatory response of eosinophils at inflammatory sites. PMID- 23747656 TI - Simultaneous species-specific PCR detection and viability testing of poly(vinyl alcohol) cryogel-entrapped Rhodococcus spp. after their exposure to petroleum hydrocarbons. AB - A method of simultaneous species-specific PCR detection and viability testing of poly(vinyl alcohol) cryogel-entrapped Rhodococcus spp. was developed that allowed the estimation of immobilized Rhodococcus opacus and Rhodococcus ruber survival after their exposure to petroleum hydrocarbon mixture. Spectrophotometric INT assay revealed high tolerance of gel-immobilized rhodococci to petroleum hydrocarbons, while among two Rhodococcus strains studied, R. ruber tolerated better to hydrocarbons compared to R. opacus. These findings were confirmed by respirometry results that showed increased respiratory activity of gel immobilized Rhodococcus strains after 10-day incubation with 3% (v/v) petroleum hydrocarbon mixture. Moreover, jointly incubated rhodococcal strains demonstrated higher oxidative activities toward petroleum hydrocarbons than individual strains. Both Rhodococcus species were recovered successfully in cryogel granules using 16S rDNA-targeted PCR, even though the granules were previously stained with INT and extracted with ethanol. The method developed can be used for rapid detection and monitoring of gel-immobilized bacterial inocula in bioreactors or contaminated soil systems. PMID- 23747657 TI - Coalescent theory has many new branches. PMID- 23747658 TI - Thematic Issue on Emerging nanopharmaceuticals for non-parenteral application routes. PMID- 23747659 TI - Antimicrobial assay optimization and validation for HTS in 384-well format using a bioluminescent E. coli K-12 strain. AB - This report describes the optimization and validation of an antimicrobial assay based on the genetically modified bacterial strain Escherichia coli K-12 (pTetlux1). The use of this particular strain enables an inducible cell-based bioluminescent assay for high-throughput screening (HTS) of antimicrobial agents, which shows a pronounced detection of compounds targeting transcriptional and translational events in protein synthesis. The optimizations in 96-well format led to several improvements in assay conditions, such as reduction of the pre incubation time before luminescence induction by half. The threshold for DMSO tolerability was concluded to be up to 1%. Assay protocol was further miniaturized into 384-well format and the liquid handling was automated using a robotic workstation. The use of compound pre-plating into 384-well plates as a part of the process was evaluated, and the total assay volume was further downscaled from 50 MUl to 30 MUl. With this approach, the amount of test compound needed per well was reduced to nanoliter volumes. Using the miniaturized protocol a pilot screen of 2000 known drugs and bioactives was performed. The assay performance was evaluated by calculating known assay quality parameters, the Z' factor having a mean value of 0.8 during the compound library screening indicated an excellent performance. Of the assay positives, 54 compounds showed high inhibitions (60-100%), of which the majority (89%) were known antibacterial agents. Of the actives showing >60% inhibition, 16 compounds were identified as known transcriptional and translational inhibitors. The screening results demonstrated that the miniaturized assay is well suited for identification of antimicrobial compounds in HT screening, and that the assay is specifically sensitive towards bacterial transcription and translation inhibitors. PMID- 23747660 TI - Multilayer laminar co-extrudate as a novel controlled release dosage form. AB - Design of a new dosage form manufactured by laminar extrusion for oral administration of drugs. Different mixtures of materials (microcrystalline cellulose [MCC], hydroxypropyl methylcellulose [HPMC], lactose [LAC], dicalcium phosphate [DCP], coumarin [COU], propranolol hydrochloride [PRO], water [W]) were prepared prior to laminar extrusion. Mono, bi and tri layer extrudates were manufactured and evaluated for extrudability, drying, water uptake and swelling ability and in vitro characterization of the drug release. Good quality extrudates were manufactured with higher HPMC molecular weight and fraction in formulation at an extrusion rate of 400 mm/min and slow drying (forced air stream), otherwise surface roughness, thickness in-homogeneity, bending and shark skin were present in the extrudates. Swelling of extrudates was dependent on HPMC fraction and molecular weight (60% up to 90% weight gain for low and high polymer chains, respectively) and the presence of either MCC or DCP. The release of drug was dependent on its solubility (PRO>COU), the fraction of HPMC (low>high fractions), the type of diluent (DCP>MCC) and number of layers (1>2>3 layers). By designing the number and type of layers, dosage forms with well-defined release kinetics can be tailored. The study has shown the ability of the technology of extrusion to manufacture a controlled release dosage form in a continuous fashion. PMID- 23747661 TI - Sunitinib as an anti-endometriotic agent. AB - Endometriosis is one of the most frequent diseases in gynecology. Currently available medical therapies for this disease are unsatisfactory. Based on current understanding of the pathogenic mechanisms in endometriosis especially the similarity between this disease and cancer, this study was designed to investigate the efficacy of the anticancer drug sunitinib in treating endometriosis. The effect of sunitinib on regression of endometriotic implants was studied in a rat surgical model. Sunitinib reduced cyst cross sectional area by 78.8% and caused complete cyst disappearance in 50% of the animals. Histologically, extensive fibrosis was detected in sunitinib-treated group with positive reaction in TUNEL assay indicating that apoptosis is a mechanism of action. PMID- 23747662 TI - Plasmopara halstedii virus causes hypovirulence in Plasmopara halstedii, the downy mildew pathogen of the sunflower. AB - Plasmopara halstedii virus (PhV) is an isometric virus recently found in the oomycete Plasmopara halstedii. The fully sequenced virus genome consists of two ss(+)RNA strands encoding for the virus polymerase and the coat protein, respectively. Most of previously screened field isolates of P. halstedii were found to harbor PhV, but effects of PhV on the pathogenicity and aggressiveness of the oomycete have not been investigated yet. To assess the influence of PhV on the infectivity of P. halstedii, virus-free isolates of the oomycete were searched for, cultivated on sunflower and used for single zoospore infection. Four genetically homogenous strains belonging to three different pathotypes (710, 730, 750) were established. Subcultures of each strain were successfully infected with PhV. This afforded pairs of isogenic strains with and without virus and allowed assessment of the pathogenicity (susceptibility to specific sunflower genotypes) and aggressiveness (intensity of infection, time scale and density of sporulation) in cultivation of sunflower. While no significant difference was found in the pathogenicity of P. halstedii strains with and without virus towards sunflower seedlings of different resistance (pathotype differentials), the aggressiveness of the oomycete was diminished by PhV. Compared to the virus-free strains, the time required for the first sporulation (latent period) increased by about 1 day post inoculation. Progression of the pathogen from the hypocotyl into the epicotyl of sunflower (systemic infection) was reduced by about one third in the presence of virus. In the virus containing strains, the average density of sporangia produced per cm2 cotyledon reached only 75% of the virus-free controls. In summary, the presence of PhV leads to hypovirulence effects by weakening the aggressiveness of P. halstedii. PMID- 23747663 TI - [Biomonitoring of exposure to chemical products in environmental and workplace toxicology]. AB - Biological monitoring, also called biomonitoring, is a process to prevent and assess health risk for individuals exposed to chemical products present in environment or through workplace exposure. Biomonitoring is most often a monitoring of exposure or of effect. The exposure monitoring is currently the most widespread in toxicology. It involves the determination in biological fluids of different biomarkers, most of which are biomarkers of internal dose. These biological indicators are typically measured in blood and urine, but other biological samples can be analyzed. They are used to assess the penetration of environmental pollutants into the body. Assay results are interpreted in relation to reference values which are adapted either to occupationally exposed populations, or to general population. This interpretation and the choice of appropriate biomarker of exposure are not always obvious. Biomonitoring has some limitations despite its many advantages. It is complementary to another health prevention approach: the monitoring of ambient air. To illustrate in practice the biomonitoring of exposure, several examples of toxics and their associated biomarkers are reviewed: benzene, toluene, styrene, polycyclic aromatic hydrocarbons, chloroform, 2-hexanone and hydrogen cyanide. PMID- 23747664 TI - [Interest and limits of inductively coupled plasma mass spectrometry (ICP-MS) for urinary diagnosis of radionuclide internal contamination]. AB - After a review of radiometric reference methods used in radiotoxicology, analytical performance of inductively coupled plasma mass spectrometry (ICP-MS) for the workplace urinary diagnosis of internal contamination by radionuclides are evaluated. A literature review (covering the period from 2000 to 2012) is performed to identify the different applications of ICP-MS in radiotoxicology for urine analysis. The limits of detection are compared to the recommendations of the International commission on radiological protection (ICRP 78: "Individual monitoring for internal exposure of workers"). Except one publication describing the determination of strontium-90 (beta emitter), all methods using ICP-MS reported in the literature concern actinides (alpha emitters). For radionuclides with a radioactive period higher than 10(4) years, limits of detection are most often in compliance with ICRP publication 78 and frequently lower than radiometric methods. ICP-MS allows the specific determination of plutonium-239 + 240 isotopes which cannot be discriminated by alpha spectrometry. High resolution ICP-MS can also measure uranium isotopic ratios in urine for total uranium concentrations lower than 20 ng/L. The interest of ICP-MS in radiotoxicology concerns essentially the urinary measurement of long radioactive period actinides, particularly for uranium isotope ratio determination and 239 and 240 plutonium isotopes discrimination. Radiometric methods remain the most efficient for the majority of other radionuclides. PMID- 23747665 TI - [Advantages and drawbacks of expectoration decontamination methods for tuberculosis and anti-tuberculosis drug resistance diagnosis]. AB - In the actual context of increasing tuberculosis and anti-tuberculosis drug resistance, the laboratory diagnosis of Mycobacterial infections remain the primordial objective of control and surveillance of human tuberculosis. The diagnosis and following of tuberculosis in resource limited settings are done by microscopy Ziehl-Neelsen method which is poor sensitive (20-53%) and have poor specificity because it's can't distinguish tuberculosis mycobacterium and atypical tuberculoid mycobacterium. Mycobacterium culture on solid media is the gold standard method for tuberculosis and anti-tuberculosis drug resistance diagnosis. Here, the challenge is that expectorations using for culture contain mycobacterium and others contaminating bacteria responsible of culture contamination. Many different methods of homogenization and decontamination of sputum specimens for culturing exist and each laboratory had to do a choice of the better method to optimize isolating of mycobacterium. This review is a summary of homogenization and decontamination methods described in literature and used by certain laboratories for diagnosis of TB by culture. However, it's essential for each laboratory to conduct evaluation of the different methods and do the choice of the appropriate one by taking into account factors such as the feasibility and cost effectively. Nine methods of decontaminations are described in this review taking account of their advantages, drawbacks and their feasibility in resource limited settings. PMID- 23747667 TI - [Investigation of the sudden infant death syndrome: a multidisciplinary approach is required]. AB - The concept of sudden infant death syndrome (SIDS) is defined as the sudden, unexpected death of an infant less than a year old which remains unexplained after in-depth investigations comprising a complete autopsy, biological analyses, and a clinical examination of the circumstances surrounding the death. This definition underlines the importance of finding the cause of this disease in order to improve preventative measures to reduce the number of deaths due to sudden infant death syndrome. Among the causes of SIDS, pediatric infectious diseases may be neglected and must be systematically sought after. We report upon a SIDS death case of a four and a half month-old that occurred during his sleep. Following the absence of an evident cause of death a scientific autopsy was performed. The histological examination of pulmonary tissue revealed broncolitic lesions associated with numerous micro-abscesses. The post mortem microbiological analyses revealed evidence of an infection by the respiratory syncytial virus complicated by a bacterial infection due to Haemophilus influenzae. The case underlines the necessity of a multidisciplinary approach to researching SIDS, involving both clinicians and biologists, in order to determine the causes of these deaths. PMID- 23747666 TI - [Plasma cholinesterase activity in hepatic diseases]. AB - Plasma cholinesterase activity (ChE) may vary in some pathological circumstances. We studied the changes in activity of this enzyme according to the type of liver injury, to assess the interest of this parameter in the diagnosis of liver diseases. Our study was performed on 102 patients with different liver diseases and 53 healthy controls. The ChE activity was lower in patients compared to control group (p < 0.0001), and more pronounced in cirrhotic patients compared to those suffering from hepatitis. Elevated activities of AST, ALT, GGT and ALP and bilirubinemia, and decreased albuminemia were noted in patients compared to controls (p < 0.001). Hypoalbuminemia was significantly important in cirrhotic patients compared to those suffering from cholestasis or hepatitis. A correlation between ChE and bilirubin, albumin and serum protein was found in patients with cirrhosis or those with chronic hepatitis. A significantly lower activity of ChE was found in patients with hepatic insufficiency (HI). In case of suspicion of HI, the prescription of ChE activity could guide or confirm the diagnosis of the impairment. PMID- 23747668 TI - [Evaluation of a new blood gas analysis system: RapidPoint 500((r))]. AB - We present here evaluation of a new blood gas analysis system, RapidPoint 500((r)) (Siemens Healthcare Diagnostics). The aim of this research was to compare the ergonomics and analytical performances of this analyser with those of the RapidLab 1265 for the following parameters: pH, partial oxygen pressure, partial carbon dioxide pressure, sodium, potassium, ionized calcium, lactate and the CO-oximetry parameters: hemoglobin, oxyhemoglobin, carboxyhemoglobin, methemoglobin, reduced hemoglobin, neonatal bilirubin; as well as with the Dimension Vista 500 results for chloride and glucose. The Valtec protocol, recommended by the French Society of Clinical Biology (SFBC), was used to analyze the study results. The experiment was carried out over a period of one month in the Department of medical biochemistry. One hundred sixty five samples from adult patients admitted to the ER or hospitalized in intensive care were tested. The RapidPoint 500((r)) was highly satisfactory from an ergonomic point of view. Intra-and inter- assay coefficients of variation (CV) with the three control levels were below those recommended by the SFBC for all parameters, and the comparative study gave coefficients of determination higher than 0.91. Taken together, the RapidPoint 500((r)) appears fully satisfactory in terms of ergonomics and analytical performance. PMID- 23747669 TI - [Utility of 8-colours multiparameter flow cytometry immunophenotyping of plasma cells for the management of monoclonal gammopathy]. AB - Bone marrow flow cytometric analysis is a powerful and rapid tool for evaluating aberrant plasma cell. In this study, we have examined the utility of multiparameter flow cytometry (MFC) in 52 patients with multiple myeloma (MM) and in 45 patients with monoclonal gammopathy with unknown significance (MGUS) into routine evaluation for the management of patients with plasma cell-related disorders. The plasma cells (PC) were identified by their light scatter distribution and reactivity patterns to CD138, CD38, and CD45. The combination of these parameters was helpful for identifying distinct subpopulations of PCs. Moderate to bright expression of CD56, CD20, CD24, CD28, and CD117 was detected in 67%, 26%, 13%, 27%, and 57% of MM cases and in 58%, 20%, 11%, 43% and 44% of MGUS cases, respectively. In MGUS group, the median percentage abnormal PCs/total PCs was 88% with 37 patients out of 45 (82%) with ratio <95%. The median ratio of the MM group was 98.9% and a ratio >= 95% was observed in 37 samples out of 44 (84%). In conclusion, MFC immunophenotyping of PCs has obvious clinical relevance in differential diagnosis between MM and others monoclonal gammopathies, identification of high-risk MGUS and smouldering MM, and minimal residual disease monitoring of MM. Our results showed that this tool can be easily applied in haematology laboratories. PMID- 23747670 TI - [For an efficient and reasonable accreditation of allergen specific IgE]. AB - French medical laboratories must be accredited before November 2016 according to NF/EN/ISO 15189 standard. However, technical accreditation guidelines cannot be applied literally for the determination of specific IgE for several reasons: more than 600 allergen tests, lack of international gold standard, limited external quality controls. Furthermore, the technique for determination of specific IgE is CE DM-IVD marked, common to all specificities, automatised, standardized according to a single calibration curve. Thus, we propose an efficient but reasonable solution conform to the idea of the accreditation by validating the process. We recommend: a flexible extend type A; choice of only one representative allergen (Dermatophagoides pteronyssinus) for repeatability and precision (20 tests, 2 levels 0.5-1 and 8-12 kUA/L) performed on patients sera, reproducibility (30 consecutive determinations using an Internal Quality Control/IQC), accuracy (IQC and rare External Quality Controls) compared with peers. Sensitivity, specificity, dynamic range, detection threshold are determinated by the provider. Linearity may be checked if the laboratory practices sample dilution for values higher than the upper limit guaranteed by the provider. In the absence of international gold standard, the uncertainty is not measurable. In case of change of instrument, the results obtained by the systems must be compared through 35 tests of different specificities distributed across the range of calibration and including 5 values close to the detection limit. This methodology allows a scientifically effective verification, technically and financially reasonable, to ensure the excellence of the performance of the laboratory with regard to peers and users (allergologists and patients). PMID- 23747671 TI - [Cutaneous pseudolymphoma as an alternative presentation of IgG4 related disease]. AB - Hyper-IgG4 syndrome is a rare entity characterized by fibro-inflammatory lesions of organs, an excess of IgG4 positive plasma cells in histology and high serum level IgG4. Many organs can be affected (pancreas, kidney, salivary glands) and the list continues to grow. The skin damage is rarely reported in the literature and is usually associated with other typical lesions of this syndrome. We report the case of a 53-year-old female followed since 2005 for lymphadenopathy, associated with axillary nodular skin lesions. The assessments made at that time had retained the diagnosis of pseudolymphoma with implementation of multi-line therapy. Six years later, and the persistence of the lesions, plasma cells marked by anti-IgG4 and the serum IgG4 has attached injuries to the syndrome hyper-IgG4. The patient is treated with low dose corticosteroids with a good and protacted response. Cutaneous pseudolymphoma could be a new presentation of the syndrome of hyper-IgG4 in the absence of any other injury usually associated with this entity. This case illustrates the interest for proposing a plasma cell labeling with anti-IgG4 in any case of cutaneous pseudolymphoma. PMID- 23747672 TI - Primary leiomyosarcoma of the inferior vena cava: a case report. AB - Primary leiomyosarcoma of the inferior vena cava (IVC) is a rare malignant tumor originating from the vein smooth muscle. We present one case of primary leiomyosarcoma of the IVC. The patient benefited of surgical exploration at seventh day after admission. Tumor located in the junction of the anterior wall of the IVC and the left and right renal vein. We carried out the tumor resection, vena cava artificial vascular patch prosthetics. The patient did not take anticoagulant drugs after surgery and was discharged at 12 days after surgery. Currently, the patient had survived for nearly six months, repeated abdominal computed tomography examinations showed no clear recurrence. PMID- 23747673 TI - [Signification of Epstein-Barr virus detection in the cerebrospinal fluid of a patient with human immunodeficiency virus related Burkitt lymphoma]. AB - The significance of Epstein-Barr virus detection in the cerebrospinal fluid of patients with Burkitt lymphoma is poorly studied. We report the case of a patient with immunodeficiency associated Burkitt lymphoma in complete remission who presented 5 months after the end of treatment, an isolated optic neuritis. Lumbar puncture found lymphocytic meningitis and the viral load of Epstein-Barr virus was 234,000 copies per milliliter in the cerebrospinal fluid. These symptoms could be explained by Epstein-Barr virus meningoencephalitis but the detection of MYC rearrangements in the cerebrospinal fluid confirms the diagnosis of Burkitt lymphoma cerebral relapse. The detection of the Epstein-Barr virus DNA in the cerebrospinal fluid should be interpreted with caution. PMID- 23747674 TI - [Brain abscess due to Nocardia cyriacigeorgica simulating an ischemic stroke]. AB - Nocardia spp. are bacteria often implicated in pulmonary diseases and central nervous system infections, especially in immunocompromised patients. We report here the case of an immunocompromised woman presenting an insidious brain abcess initially treated as a cerebral stroke. Despite a cotrimoxazole and rifampicin treatment she did not improve. She died 3 month later after she stopped her treatment. PMID- 23747675 TI - [Autochtonous hepatitis E, an emerging infection: case report]. AB - Hepatitis E is rare in France but its increasing frequency makes it an emerging infection. Autochtonous hepatitis E is prevalent, largely confined to older men and currently caused by gentotype 3f. Patients with unexplained hepatitis should be tested by hepatitis E, even in the absence of travel from endemic areas. The diagnosis is based on serological testing (including detection of specific antibodies IgM and IgG, and sometimes by determination of antibody avidity) and nucleic acid amplification techniques which might used first. PMID- 23747676 TI - [Microbiology method validation: illustration with Bact'Alert 3D]. AB - As far as laboratories accreditation according to ISO 15189 is concerned, validation of each method used has to be achieved. Manufacturer's recommendations are not always helpful in this context. That's why each laboratory must proceed systematically to a logical risk analysis. Few publications are available on this subject concerning microbiology. We propose to illustrate it with the example of a blood culture automate: the Bact'Alert 3D commercialised by Biomerieux((r)). PMID- 23747677 TI - [In-house PCR practical knowledge: a sufficient validation according to NF EN ISO 15189?]. AB - As far as molecular biology is concerned, numerous are laboratories using in house method. Used since many years, medical biologists have often a good practical knowledge about them. According to ISO 15189 accreditation, is this knowledge sufficient for the validation of these methods? We have asked this question ourselves about our in-house Leishmaniasis PCR. PMID- 23747678 TI - [Labile or not labile: that is the question...]. PMID- 23747679 TI - Hypermethylation and low transcription of TLR2 gene in chronic periodontitis. AB - Periodontitis is an inflammatory disorder characterized by interactions between periodontal pathogens and host's immune response. Epigenetic may contribute to disease development and outcome by influencing the expression of genes involved in the immune response. It has been shown that Toll-like receptors (TLR) play an important role in the response to periodontopathic bacteria. The aim of study was to evaluate the methylation status and the expression of TLR2 gene in gingival samples from individuals with and without periodontitis. DNA was analyzed using the Methyl Profiler DNA Methylation qPCR assay. DNA methylation and transcript levels were evaluated by real-time polymerase chain reaction. The periodontitis group showed a hypermethylated profile and a low expression of gene. Positive correlation between the TLR2 methylation frequency and probing depth was observed. This study gives the first evidence of methylation frequency in inflamed periodontal tissues and of the possible participation of methylation in the development of periodontitis. PMID- 23747680 TI - The Drosophila DOCK family protein sponge is involved in differentiation of R7 photoreceptor cells. AB - The Drosophila sponge (spg)/CG31048 gene belongs to the dedicator of cytokinesis (DOCK) family genes that are conserved in a wide variety of species. DOCK family members are known as DOCK1-DOCK11 in mammals. Although DOCK1 and DOCK2 involve neurite elongation and immunocyte differentiation, respectively, the functions of other DOCK family members are not fully understood. Spg is a Drosophila homolog of mammalian DOCK3 and DOCK4. Specific knockdown of spg by the GMR-GAL4 driver in eye imaginal discs induced abnormal eye morphology in adults. To mark the photoreceptor cells in eye imaginal discs, we used a set of enhancer trap strains that express lacZ in various sets of photoreceptor cells. Immunostaining with anti-Spg antibodies and anti-lacZ antibodies revealed that Spg is localized mainly in R7 photoreceptor cells. Knockdown of spg by the GMR-GAL4 driver reduced signals of R7 photoreceptor cells, suggesting involvement of Spg in R7 cell differentiation. Furthermore, immunostaining with anti-dpERK antibodies showed the level of activated ERK signal was reduced extensively by knockdown of spg in eye discs, and both the defects in eye morphology and dpERK signals were rescued by over-expression of the Drosophila raf gene, a component of the ERK signaling pathway. Furthermore, the Duolink in situ Proximity Ligation Assay method detected interaction signals between Spg and Rap1 in and around the plasma membrane of the eye disc cells. Together, these results indicate Spg positively regulates the ERK pathway that is required for R7 photoreceptor cell differentiation and the regulation is mediated by interaction with Rap1 during development of the compound eye. PMID- 23747681 TI - The inhibition of COPII trafficking is important for intestinal epithelial tight junction disruption during enteropathogenic Escherichia coli and Citrobacter rodentium infection. AB - Enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) are bacterial pathogens that cause severe illnesses in humans. Citrobacter rodentium is a related mouse pathogen that serves as a small animal model for EPEC and EHEC infections. EPEC, EHEC and C. rodentium translocate bacterial virulence proteins directly into host intestinal cells via a type III secretion system (T3SS). Non LEE-encoded effector A (NleA) is a T3SS effector that is common to EPEC, EHEC and C. rodentium. NleA interacts with and inhibits the mammalian COPII complex, impairing cellular secretion; this interaction is required for bacterial virulence. Although diarrhea is a hallmark of EPEC, EHEC and C. rodentium infections, the underlying mechanisms are not well characterized. One of the essential functions of the intestine is to maintain a barrier between the lumen and submucosa. Tight junctions seal the space between adjacent epithelial cells creating this barrier. Consequently, it is thought that the disruption of intestinal epithelial tight junctions by EPEC, EHEC, and C. rodentium could result in a loss of barrier function. In this study, we demonstrate that NleA mediated COPII inhibition is required for EPEC- and C. rodentium-mediated disruption of tight junction proteins and increases in fecal water content. PMID- 23747683 TI - Extension of Sphingobium sp. BHC-A to a 2,4,5-trichlorophenoxyacetic acid mineralizing strain by metabolic engineering. AB - The gene cassette encoding for TftAB and TftCD proteins was integrated into the 16srDNA gene of the gamma-hexachlorocyclohexane (gamma-HCH) mineralizing strain Sphingobium sp. BHC-A by homologous recombination. The recombinant gamma-HCH mineralizing strain may degrade 2,4,5-trichlorophenoxyacetic acid at a rate of 250nmol mg [protein](-1)h(-1), and the generated intermediate 2,5 dichlorohydroquinone may be further mineralized through gamma-HCH downstream degradation pathway. PMID- 23747682 TI - Short-term caloric restriction, resveratrol, or combined treatment regimens initiated in late-life alter mitochondrial protein expression profiles in a fiber type specific manner in aged animals. AB - Aging is associated with a loss in muscle known as sarcopenia that is partially attributed to apoptosis. In aging rodents, caloric restriction (CR) increases health and longevity by improving mitochondrial function and the polyphenol resveratrol (RSV) has been reported to have similar benefits. In the present study, we investigated the potential efficacy of using short-term (6 weeks) CR (20%), RSV (50 mg/kg/day), or combined CR+ RSV (20% CR and 50 mg/kg/day RSV), initiated at late-life (27 months) to protect muscle against sarcopenia by altering mitochondrial function, biogenesis, content, and apoptotic signaling in both glycolytic white and oxidative red gastrocnemius muscle (WG and RG, respectively) of male Fischer 344 * Brown Norway rats. CR but not RSV attenuated the age-associated loss of muscle mass in both mixed gastrocnemius and soleus muscle, while combined treatment (CR + RSV) paradigms showed a protective effect in the soleus and plantaris muscle (P < 0.05). Sirt1 protein content was increased by 2.6-fold (P < 0.05) in WG but not RG muscle with RSV treatment, while CR or CR + RSV had no effect. PGC-1alpha levels were higher (2-fold) in the WG from CR-treated animals (P < 0.05) when compared to ad-libitum (AL) animals but no differences were observed in the RG with any treatment. Levels of the anti apoptotic protein Bcl-2 were significantly higher (1.6-fold) in the WG muscle of RSV and CR + RSV groups compared to AL (P < 0.05) but tended to occur coincident with elevations in the pro-apoptotic protein Bax so that the apoptotic susceptibility as indicated by the Bax to Bcl-2 ratio was unchanged. There were no alterations in DNA fragmentation with any treatment in muscle from older animals. Additionally, mitochondrial respiration measured in permeabilized muscle fibers was unchanged in any treatment group and this paralleled the lack of change in cytochrome c oxidase (COX) activity. These data suggest that short-term moderate CR, RSV, or CR + RSV tended to modestly alter key mitochondrial regulatory and apoptotic signaling pathways in glycolytic muscle and this might contribute to the moderate protective effects against aging-induced muscle loss observed in this study. PMID- 23747684 TI - Large scale expression and purification of the mouse 5-HT3 receptor. AB - Receptors of the Cys-loop family are central to neurotransmission and primary therapeutic targets. In order to decipher their gating and modulation mechanisms, structural data is essential. However, structural studies require large amounts of pure, functional receptors. Here, we present the expression and purification of the mouse serotonin 5-HT3 receptor to high purity and homogeneity levels. Inducible expression in human embryonic kidney 293 cells in suspension cultures with orbital shaking resulted in yields of 6-8mg receptor per liter of culture. Affinity purification using a strep tag provided pure protein in active form. Further deglycosylation and removal of the purification tag led to a pentameric receptor after size-exclusion chromatography, at the milligram scale. This material is suitable for crystallography, as demonstrated by X-ray diffraction of receptor crystals at low resolution. PMID- 23747685 TI - Direct translocation of staphylococci from the skin surface to deep organs. AB - BACKGROUND: Staphylococcus aureus can invade the bloodstream and cause bacteremic infections, but this organism frequently produces serious deep infections without bacteremia or an identifiable portal of entry. METHODS: We used experimental cutaneous S. aureus infections in mice to determine if the bacteria could reach deep organs without travel through the bloodstream. RESULTS: After skin surface application the bacteria rapidly distributed to lymph nodes, spleen, kidneys and other organs. In these animals, blood cultures were negative, dissemination was more efficient after surface application than injection near dermal blood vessels, and kidney bacterial localization sites were unlike those of bacteremic infections. Whereas normal mice eventually cleared bacteria from the deep sites, those with prolonged immunosuppression became moribund from these infections; they also had negative blood cultures and kidney localization not consistent with hematogenous dissemination. Bacteria were also found in the intervening abdominal wall outside the spleen and kidney sites, suggesting direct movement of the organisms from the skin surface through connecting tissues. CONCLUSIONS: Although capable of hematogenous dissemination, S. aureus can also spread from skin to deep organs by a non-bacteremic process. In this case the bacteria appear to migrate directly from the skin surface to the deep organs below. PMID- 23747686 TI - Identification of in-vivo induced genes of Streptococcus suis serotype 2 specially expressed in infected human. AB - Streptococcus suis (S. suis) serotype 2 usually cause infection in swine. Recently, two large-scale outbreaks in China with severe streptococcal toxic shock syndrome (STSS) and high mortality raised worldwide concern to human S. suis infection. To reveal the molecular pathogenesis of S. suis 2 during human infection, in-vivo induced antigen technology (IVIAT) was applied to identify the in-vivo induced genes (ivi genes) of S. suis 05ZYH33. The ivi genes are specifically expressed or up-regulated in-vivo and always associated with the in vivo survival and pathogenicity of pathogens. In present study, convalescent sera from S. suis 05ZYH33 infected patients were pooled and fully adsorbed with in vitro grown S. suis 05ZYH33 and Escherichia coli BL21 (DE3). Genomic expression library of 05ZYH33 was repeatedly screened with colony immunoblot assay using adsorbed sera. Finally, 19 genes were assessed as ivi genes of 05ZYH33. Fifteen of 19 genes encode proteins with biological functions in substance transport and metabolism, cell structure biogenesis, cell cycle control, replication, translation and other functions. The 4 remaining genes encode proteins with unknown functions. Of the 19 ivi genes, five (SSU05_0247, 0437, 1577, 1664 and 2144) encode proteins with no immunoreactivity to control sera from healthy individuals never exposed to 05ZYH33. The successful identification of ivi genes not only sheds light on understanding the pathogenesis of S. suis 05ZYH33 during its human infection, but also provides potential targets for the developments of new vaccines, therapeutic drugs and diagnostic reagents against human S. suis infection. PMID- 23747687 TI - Isoliquiritigenin induces growth inhibition and apoptosis through downregulating arachidonic acid metabolic network and the deactivation of PI3K/Akt in human breast cancer. AB - Arachidonic acid (AA)-derived eicosanoids and its downstream pathways have been demonstrated to play crucial roles in growth control of breast cancer. Here, we demonstrate that isoliquiritigenin, a flavonoid phytoestrogen from licorice, induces growth inhibition and apoptosis through downregulating multiple key enzymes in AA metabolic network and the deactivation of PI3K/Akt in human breast cancer. Isoliquiritigenin diminished cell viability, 5-bromo-2'-deoxyuridine (BrdU) incorporation, and clonogenic ability in both MCF-7 and MDA-MB-231cells, and induced apoptosis as evidenced by an analysis of cytoplasmic histone associated DNA fragmentation, flow cytometry and hoechst staining. Furthermore, isoliquiritigenin inhibited mRNA expression of multiple forms of AA-metabolizing enzymes, including phospholipase A2 (PLA2), cyclooxygenases (COX)-2 and cytochrome P450 (CYP) 4A, and decreased secretion of their products, including prostaglandin E2 (PGE2) and 20-hydroxyeicosatetraenoic acid (20-HETE), without affecting COX-1, 5-lipoxygenase (5-LOX), 5-lipoxygenase activating protein (FLAP), and leukotriene B4 (LTB4). In addition, it downregulated the levels of phospho-PI3K, phospho-PDK (Ser(241)), phospho-Akt (Thr(308)), phospho-Bad (Ser(136)), and Bcl-xL expression, thereby activating caspase cascades and eventually cleaving poly(ADP-ribose) polymerase (PARP). Conversely, the addition of exogenous eicosanoids, including PGE2, LTB4 and a 20-HETE analog (WIT003), and caspase inhibitors, or overexpression of constitutively active Akt reversed isoliquiritigenin-induced apoptosis. Notably, isoliquiritigenin induced growth inhibition and apoptosis of MDA-MB-231 human breast cancer xenografts in nude mice, together with decreased intratumoral levels of eicosanoids and phospho-Akt (Thr(308)). Collectively, these data suggest that isoliquiritigenin induces growth inhibition and apoptosis through downregulating AA metabolic network and the deactivation of PI3K/Akt in human breast cancer. PMID- 23747688 TI - The red clover necrotic mosaic virus capsid protein N-terminal amino acids possess specific RNA binding activity and are required for stable virion assembly. AB - The red clover necrotic mosaic virus (RCNMV) bipartite RNA genome is packaged into two virion populations containing either RNA-1 and RNA-2 or multiple copies of RNA-2 only. To understand this distinctive packaging scheme, we investigated the RNA-binding properties of the RCNMV capsid protein (CP). Maltose binding protein-CP fusions exhibited the highest binding affinities for RNA probes containing the RNA-2 trans-activator or the 3' non-coding region from RNA-1. Other viral and non-viral RNA probes displayed CP binding but to a much lower degree. Deletion of the highly basic N-terminal 50 residues abolished CP binding to viral RNA transcripts. In planta studies of select CP deletion mutants within this N-terminal region revealed that it was indispensable for stable virion formation and the region spanning CP residues 5-15 is required for systemic movement. Thus, the N-terminal region of the CP is involved in both producing two virion populations due to its RNA binding properties and virion stability. PMID- 23747690 TI - Is penile preservation of distal corporal invasive penile cancer sufficient treatment? PMID- 23747691 TI - Mesh infection of a male sling. PMID- 23747692 TI - Evaluation of the prostaglandin F synthase activity of human and bovine aldo-keto reductases: AKR1A1s complement AKR1B1s as potent PGF synthases. AB - AKR1B1 of the polyol pathway was identified as a prostaglandin F2alpha synthase (PGFS). Using a genomic approach we have identified in the endometrium five bovine and three human AKRs with putative PGFS activity and generated the corresponding recombinant enzymes. The PGFS activity of the recombinant proteins was evaluated using a novel assay based on in situ generation of the precursor of PG biosynthesis PGH2. PGF2alpha was measured by ELISA and the relative potencies of the different enzymes were compared. We identified AKR1A1 and confirmed AKR1B1 as the most potent PGFS expressing characteristic inhibition patterns in presence of methylglyoxal, ponalrestat and glucose. PMID- 23747693 TI - Molecular and biochemical characterization of the beta-1,4-endoglucanase gene Mj eng-3 in the root-knot nematode Meloidogyne javanica. AB - This study describes the molecular and biochemical characterization of the beta 1,4-endoglucanase gene (Mj-eng-3) from the root knot nematode Meloidogyne javanica. A 2156-bp genomic DNA sequence of Mj-eng-3 containing six introns was obtained. Mj-eng-3 was localized in the subventral esophageal glands of M. javanica juveniles by in situ hybridization. Real-time RT-PCR assay showed that the highest transcriptional level of Mj-eng-3 occurred in pre-parasitic second stage juveniles, and this high expression persisted in parasitic second-stage juveniles. Recombinant MJ-ENG-3 degraded carboxymethylcellulose and optimum enzyme activity at 40 degrees C and pH 8.0. EDTA, Mg(2+), Mn(2+), Ca(2+), Co(2+), and Cu(2+) did not affect the activity of MJ-ENG-3; however, Zn(2+) and Fe(2+) inhibited MJ-ENG-3 enzyme activity. In planta Mj-eng-3 RNAi assay displayed a reduction in the number of nematodes and galls in transgenic tobacco roots. These results suggested that MJ-ENG-3 could be secreted by M. javanica to degrade the cellulose of plant cell walls to facilitate its entry and migration during the early stages of parasitism. PMID- 23747694 TI - [Explicative models of cancer biology: an enlarged vision]. AB - The second half of the 20th century has been dominated by genetic models of tumors that provided conceptual tools explaining tumor genesis and its evolution. Other domains--epigenetics, cell metabolism--appeared that generated a more complex landscape of tumor physiopathology. Moreover, the discovery of tumor stem cells and intratumoral heterogeneity are likely to explain recurrence. A major difficulty is that every tumor behaves as an organ that evolves in function of its microenvironment. By integrating all the new data in more and more sophisticated models, the major goals may emerge from the characterisation of new markers for diagnosis and prognosis and from the selection of pertinent and efficient new therapeutic targets. PMID- 23747695 TI - Proposed model for the high rate of rearrangement and rapid migration observed in some IncA/C plasmid lineages. AB - IncA/C plasmids are a class of plasmids from the Enterobacteriaceae that are relatively large (49 to >180 kbp), that are readily transferred by conjugation, and that carry multiple antimicrobial resistance genes. Reconstruction of the phylogeny of these plasmids has been difficult because of the high rate of remodeling by recombination-mediated horizontal gene transfer (HGT). We hypothesized that evaluation of nucleotide polymorphisms relative to the rate of HGT would help to develop a clock to show whether anthropic practices have had significant influences on the lineages of the plasmid. A system was developed to rapidly sequence up to 191 known open reading frames from each of 39 recently isolated IncA/C plasmids from a diverse panel of Salmonella enterica and Escherichia coli strains. With these data plus sequences from GenBank, we were able to distinguish six distinct lineages that had extremely low numbers of polymorphisms within each lineage, especially among the largest group designated as group 1. Two regions, each about half the plasmid in size, could be distinguished with a separate lineal pattern. The distribution of group 1 showed that it has migrated extremely rapidly with fewer polymorphisms than can be expected in 2,000 years. Remodeling by frequent HGT was evident, with a pattern that appeared to have the highest rate just upstream of the putative conjugation origin of transfer (oriT). It seems likely that when an IncA/C plasmid is transferred by conjugation there is an opportunity for plasmid remodeling adjacent to the oriT, which was also adjacent to a multiple antimicrobial resistance gene cassette. PMID- 23747696 TI - PCR characterization suggests that an unusual range of Bartonella species infect the striped field mouse (Apodemus agrarius) in Central Europe. AB - Blood samples from Apodemus agrarius from Poland yielded PCR amplicons of Bartonella species. These included B. grahamii, B. taylorii, and B. birtlesii, as is typical of European Apodemus, as well as B. elizabethae-like forms and a recombinant strain of B. taylorii, most closely related to an American isolate from Tamiasciurus hudsonicus. PMID- 23747697 TI - Longitudinal monitoring of extended-spectrum-beta-lactamase/AmpC-producing Escherichia coli at German broiler chicken fattening farms. AB - Antimicrobial resistance of Escherichia coli to modern beta-lactam antibiotics due to the production of extended-spectrum beta-lactamases (ESBL) and/or plasmid mediated AmpC beta-lactamases (AmpC) represents an emerging and increasing resistance problem that dramatically limits therapeutic options in both human and veterinary medicine. The presence of ESBL/AmpC genes in commensal E. coli from food-producing animals like broilers may pose a human health hazard. However, there are no data available concerning the prevalence of ESBL/AmpC-producing E. coli in German broiler flocks using selective methods. In this longitudinal study, samples were taken from seven conventional broiler fattening farms at three different times within one fattening period. Various samples originating from the animals as well as from their direct environment in the barn were investigated for the occurrence of ESBL/AmpC-producing E. coli. Average detection levels of 51, 75, and 76% in animal samples collected during the three samplings in the course of the fattening period demonstrate a colonization of even 1-day old chicks, as well as a continuous significant (P < 0.001) increase in prevalence thereafter. The detection frequencies in housing environmental samples were relatively high, with an increase over time, and ranged between 54.2 and 100%. A total of 359 E. coli isolates were characterized by PCR and partly via the disc diffusion method. This study shows that prevalence of ESBL/AmpC producing E. coli increases during the fattening period of the broiler flocks examined. Both colonized day-old chicks and contaminated farm environments could represent significant sources of ESBL/AmpC-producing E. coli in German broiler fattening farms. PMID- 23747698 TI - Activating phosphoenolpyruvate carboxylase and phosphoenolpyruvate carboxykinase in combination for improvement of succinate production. AB - Phosphoenolpyruvate (PEP) carboxylation is an important step in the production of succinate by Escherichia coli. Two enzymes, PEP carboxylase (PPC) and PEP carboxykinase (PCK), are responsible for PEP carboxylation. PPC has high substrate affinity and catalytic velocity but wastes the high energy of PEP. PCK has low substrate affinity and catalytic velocity but can conserve the high energy of PEP for ATP formation. In this work, the expression of both the ppc and pck genes was modulated, with multiple regulatory parts of different strengths, in order to investigate the relationship between PPC or PCK activity and succinate production. There was a positive correlation between PCK activity and succinate production. In contrast, there was a positive correlation between PPC activity and succinate production only when PPC activity was within a certain range; excessive PPC activity decreased the rates of both cell growth and succinate formation. These two enzymes were also activated in combination in order to recruit the advantages of each for the improvement of succinate production. It was demonstrated that PPC and PCK had a synergistic effect in improving succinate production. PMID- 23747699 TI - The microcosm mediates the persistence of shiga toxin-producing Escherichia coli in freshwater ecosystems. AB - Water is a major route for infection of humans by exotoxin-producing bacteria, including Shiga toxin-producing Escherichia coli (STEC). While STEC has the potential to be present in nearly every type of water source, its distribution is sporadic, and an understanding of factors that govern its emergence and persistence within water is lacking. In this study, we examined the influence of microbe content on STEC persistence in freshwater. We found that depletion of microbes in the water leads to a considerable increase in the persistence of STEC, an effect that can be mitigated by adding grazing protists to the water. STEC strains appear to be more resistant to the impact of grazing protists than E. coli strains that lack the Shiga toxin (stx) gene. Our results demonstrate that the microcosm can dramatically influence the persistence of STEC in aquatic ecosystems and that the overall impact by microbes on STEC strains is fundamentally different from that of non-STEC strains of bacteria. Overall, these results provide insight into why STEC and possibly other exotoxin-producing bacterial pathogens display such variability in abundance, distribution, and persistence in aquatic ecosystems. PMID- 23747700 TI - Identification and characterization of a novel flagellum-dependent Salmonella infecting bacteriophage, iEPS5. AB - A novel flagellatropic phage of Salmonella enterica serovar Typhimurium, called iEPS5, was isolated and characterized. iEPS5 has an icosahedral head and a long noncontractile tail with a tail fiber. Genome sequencing revealed a double stranded DNA of 59,254 bp having 73 open reading frames (ORFs). To identify the receptor for iEPS5, Tn5 transposon insertion mutants of S. Typhimurium SL1344 that were resistant to the phage were isolated. All of the phage-resistant mutants were found to have mutations in genes involved in flagellar formation, suggesting that the flagellum is the adsorption target of this phage. Analysis of phage infection using the DeltamotA mutant, which is flagellated but nonmotile, demonstrated the requirement of flagellar rotation for iEPS5 infection. Further analysis of phage infection using the DeltacheY mutant revealed that iEPS5 could infect host bacteria only when the flagellum is rotating counterclockwise (CCW). These results suggested that the CCW-rotating flagellar filament is essential for phage adsorption and required for successful infection by iEPS5. In contrast to the well-studied flagellatropic phage Chi, iEPS5 cannot infect the DeltafliK mutant that makes a polyhook without a flagellar filament, suggesting that these two flagellatropic phages utilize different infection mechanisms. Here, we present evidence that iEPS5 injects its DNA into the flagellar filament for infection by assessing DNA transfer from SYBR gold-labeled iEPS5 to the host bacteria. PMID- 23747701 TI - Induction of biofilm formation in the betaproteobacterium Burkholderia unamae CK43B exposed to exogenous indole and gallic acid. AB - Burkholderia unamae CK43B, a member of the Betaproteobacteria that was isolated from the rhizosphere of a Shorea balangeran sapling in a tropical peat swamp forest, produces neither indole nor extracellular polymeric substances associated with biofilm formation. When cultured in a modified Winogradsky's medium supplemented with up to 1.7 mM indole, B. unamae CK43B maintains its planktonic state by cell swelling and effectively degrades exogenous indole. However, in medium supplemented with 1.7 mM exogenous indole and 1.0 mM gallic acid, B. unamae CK43B produced extracellular polymeric substances and formed a biofilm. The concentration indicated above of gallic acid alone had no effect on either the growth or the differentiation of B. unamae CK43B cells above a certain concentration threshold, whereas it inhibited indole degradation by B. unamae CK43B to 3-hydroxyindoxyl. In addition, coculture of B. unamae CK43B with indole producing Escherichia coli in nutrient-rich Luria-Bertani medium supplemented with 1.0 mM gallic acid led to the formation of mixed cell aggregates. The viability and active growth of B. unamae CK43B cells in a coculture system with Escherichia coli were evidenced by fluorescence in situ hybridization. Our data thus suggest that indole facilitates intergenus communication between indole producing gammaproteobacteria and some indole-degrading bacteria, particularly in gallic acid-rich environments. PMID- 23747702 TI - Dispersal and survival of Flavobacterium psychrophilum phages in vivo in rainbow trout and in vitro under laboratory conditions: implications for their use in phage therapy. AB - Attention has been drawn to phage therapy as an alternative approach for controlling pathogenic bacteria such as Flavobacterium psychrophilum in salmonid aquaculture, which can give rise to high mortalities, especially in rainbow trout fry. Recently, phages have been isolated with a broad host range and a strong lytic potential against pathogenic F. psychrophilum under experimental conditions. However, little is known about the fate of phages at environmental conditions. Here, we quantified the dispersal and fate of F. psychrophilum phages and hosts in rainbow trout fry after intraperitoneal injection. Both phages and bacteria were isolated from the fish organs for up to 10 days after injection, and coinjection with both bacteria and phages resulted in a longer persistence of the phage in the fish organs, than when the fish had been injected with the phages only. The occurrence of both phage and bacterium was most prevalent in the kidney and spleen, with only minor occurrence in the brain. The experiment showed that injected phages were rapidly spread in the internal organs of the fish, also in the absence of bacteria. Parallel examination of the regulation of bacteriophage infectivity in controlled laboratory experiments at various environmental conditions showed that pH had only minor effects on long-term (3 months) phage infectivity within a pH range of 4.5 to 7.5, whereas phage infectivity was immediately lost at pH 3. In the absence of host cells, phage infectivity decreased by a factor of 10,000 over 55 days in untreated pond water, while the sterilization and removal of particles caused a 100-fold increase in phage survival relative to the control. In addition, F. psychrophilum-specific phages maintained their infectivity for ~2 months in glycerol at -80 degrees C, whereas infectivity decreased by a factor 10 when kept in a buffer at 20 degrees C. Only a very small degradation in infectivity was seen when bacteriophages were added and dried on fish feed pellets. Together, these results indicate that application of bacteriophages represents a promising approach for the control of F. psychrophilum infections in trout and suggest fish feed as a potential delivery method. PMID- 23747703 TI - Strain/species-specific probe design for microbial identification microarrays. AB - Specific identification of microorganisms in the environment is important but challenging, especially at the species/strain level. Here, we have developed a novel k-mer-based approach to select strain/species-specific probes for microbial identification with diagnostic microarrays. Application of this approach to human microbiome genomes showed that multiple (>=10 probes per strain) strain-specific 50-mer oligonucleotide probes could be designed for 2,012 of 3,421 bacterial strains of the human microbiome, and species-specific probes could be designed for most of the other strains. The method can also be used to select strain/species-specific probes for sequenced genomes in any environments, such as soil and water. PMID- 23747704 TI - Bacterial cell wall synthesis gene uppP is required for Burkholderia colonization of the Stinkbug Gut. AB - To establish a host-bacterium symbiotic association, a number of factors involved in symbiosis must operate in a coordinated manner. In insects, bacterial factors for symbiosis have been poorly characterized at the molecular and biochemical levels, since many symbionts have not yet been cultured or are as yet genetically intractable. Recently, the symbiotic association between a stinkbug, Riptortus pedestris, and its beneficial gut bacterium, Burkholderia sp., has emerged as a promising experimental model system, providing opportunities to study insect symbiosis using genetically manipulated symbiotic bacteria. Here, in search of bacterial symbiotic factors, we targeted cell wall components of the Burkholderia symbiont by disruption of uppP gene, which encodes undecaprenyl pyrophosphate phosphatase involved in biosynthesis of various bacterial cell wall components. Under culture conditions, the DeltauppP mutant showed higher susceptibility to lysozyme than the wild-type strain, indicating impaired integrity of peptidoglycan of the mutant. When administered to the host insect, the DeltauppP mutant failed to establish normal symbiotic association: the bacterial cells reached to the symbiotic midgut but neither proliferated nor persisted there. Transformation of the DeltauppP mutant with uppP-encoding plasmid complemented these phenotypic defects: lysozyme susceptibility in vitro was restored, and normal infection and proliferation in the midgut symbiotic organ were observed in vivo. The DeltauppP mutant also exhibited susceptibility to hypotonic, hypertonic, and centrifugal stresses. These results suggest that peptidoglycan cell wall integrity is a stress resistance factor relevant to the successful colonization of the stinkbug midgut by Burkholderia symbiont. PMID- 23747705 TI - Shiga toxin 2-encoding bacteriophages in human fecal samples from healthy individuals. AB - Shiga toxin-converting bacteriophages (Stx phages) carry the stx gene and convert nonpathogenic bacterial strains into Shiga toxin-producing bacteria. Previous studies have shown that high densities of free and infectious Stx phages are found in environments polluted with feces and also in food samples. Taken together, these two findings suggest that Stx phages could be excreted through feces, but this has not been tested to date. In this study, we purified Stx phages from 100 fecal samples from 100 healthy individuals showing no enteric symptoms. The phages retrieved from each sample were then quantified by quantitative PCR (qPCR). In total, 62% of the samples carried Stx phages, with an average value of 2.6 * 10(4) Stx phages/g. This result confirms the excretion of free Stx phages by healthy humans. Moreover, the Stx phages from feces were able to propagate in enrichment cultures of stx-negative Escherichia coli (strains C600 and O157:H7) and in Shigella sonnei, indicating that at least a fraction of the Stx phages present were infective. Plaque blot hybridization revealed lysis by Stx phages from feces. Our results confirm the presence of infectious free Stx phages in feces from healthy persons, possibly explaining the environmental prevalence observed in previous studies. It cannot be ruled out, therefore, that some positive stx results obtained during the molecular diagnosis of Shiga toxin producing Escherichia coli (STEC)-related diseases using stool samples are due to the presence of Stx phages. PMID- 23747707 TI - Clostridium perfringens is not suitable for the indication of fecal pollution from ruminant wildlife but is associated with excreta from nonherbivorous animals and human sewage. AB - During a 3-year study, Clostridium perfringens was investigated in defined fecal sources from a temperate alluvial backwater area of a large river system. The results reveal that using C. perfringens as a conservative water quality indicator for total fecal pollution monitoring is no longer justified but suggest that it can be used as a tracer for excreta from nonherbivorous wildlife and human sewage. PMID- 23747706 TI - Broad distribution of diverse anaerobic ammonium-oxidizing bacteria in chinese agricultural soils. AB - Anaerobic ammonium-oxidizing (anammox) bacteria have been detected in many marine and freshwater ecosystems. However, little is known about the distribution, diversity, and abundance of anammox bacteria in terrestrial ecosystems. In this study, anammox bacteria were found to be present in various agricultural soils collected from 32 different locations in China. Phylogenetic analysis of the 16S rRNA genes showed "Candidatus Brocadia," "Candidatus Kuenenia," "Candidatus Anammoxoglobus," and "Candidatus Jettenia" in the collected soils, with "Candidatus Brocadia" being the dominant genus. Quantitative PCR showed that the abundance of anammox bacteria ranged from 6.38 * 10(4) +/- 0.42 * 10(4) to 3.69 * 10(6) +/- 0.25 * 10(6) copies per gram of dry weight. Different levels of diversity, composition, and abundance of the anammox bacterial communities were observed, and redundancy analysis indicated that the soil organic content and the distribution of anammox communities were correlated in the soils examined. Furthermore, Pearson correlation analysis showed that the diversity of the anammox bacteria was positively correlated with the soil ammonium content and the organic content, while the anammox bacterial abundance was positively correlated with the soil ammonium content. These results demonstrate the broad distribution of diverse anammox bacteria and its correlation with the soil environmental conditions within an extensive range of Chinese agricultural soils. PMID- 23747709 TI - Diverse synchrony of firing reflects diverse cell-assembly coding in the prefrontal cortex. AB - In the present paper, we focus on the coding by cell assemblies in the prefrontal cortex (PFC) and discuss the diversity of the coding, which results in stable and dynamic representations and the processing of various information in that higher brain region. The key activity that reflects cell-assembly coding is the synchrony of the firing of multiple neurons when animals are performing cognitive and memory tasks. First, we introduce some studies that have shown task-related synchrony of neuronal firing in the monkey PFC. These studies have reported fixed and several types of dynamic synchronous firing during working memory, long-term visual memory, and goal selection. The results of these studies have indicated that cell assemblies in the PFC can contribute to both the stability and the dynamics of various types of information. Second, we refer to rat studies and introduce the findings of cellular interactions that contribute to synchrony in working memory, learning-induced changes in synchrony in spatial tasks, and interactions of the PFC and hippocampus in dynamic synchrony. These studies have proposed neuronal mechanisms of cell-assembly coding in the PFC and its critical role in the learning of task demands in problematic situations. Based on the monkey and rat studies, we conclude that cell-assembly coding in the PFC is diverse and has various facets, which allow multipotentiality in the higher brain region. Finally, we discuss the problem of the sizes of cell assembly, how diverse the sizes are in the PFC, and the technical problems in their investigation. We introduce a unique spike-sorting method that can detect small and local cell assemblies that consist of closely neighboring neurons. Then, we describe the findings of our study that showed that the monkey PFC has both small and large cell assemblies, which have different roles in information coding in the working brain. PMID- 23747708 TI - An improved method for oriT-directed cloning and functionalization of large bacterial genomic regions. AB - We have made significant improvements to a broad-host-range system for the cloning and manipulation of large bacterial genomic regions based on site specific recombination between directly repeated oriT sites during conjugation. Using two suicide capture vectors carrying flanking homology regions, oriT sites are recombined on either side of the target region. Using a broad-host-range conjugation helper plasmid, the region between the oriT sites is conjugated into an Escherichia coli recipient strain, where it is circularized and maintained as a chimeric mini-F vector. The cloned target region is functionalized in multiple ways to accommodate downstream manipulation. The target region is flanked with Gateway attB sites for recombination into other vectors and by rare 18-bp I-SceI restriction sites for subcloning. The Tn7-functionalized target can also be inserted at a naturally occurring chromosomal attTn7 site(s) or maintained as a broad-host-range plasmid for complementation or heterologous expression studies. We have used the oriTn7 capture technique to clone and complement Burkholderia pseudomallei genomic regions up to 140 kb in size and have created isogenic Burkholderia strains with various combinations of genomic islands. We believe this system will greatly aid the cloning and genetic analysis of genomic islands, biosynthetic gene clusters, and large open reading frames. PMID- 23747710 TI - Translating improved quality of care into an improved quality of life for patients with inflammatory bowel disease. AB - The term quality of care has been interpreted in different ways in medicine. Skeptics of the quality movement insist that checkboxes and government and payer oversight will not lead to better patient outcomes. Supporters refer to areas in medicine in which quality improvement efforts have led to improved survival, such as in cystic fibrosis and cardiovascular disease. For quality improvement to be effective, the process demands rigorous documentation, analysis, feedback, and behavioral change. This requires valid metrics and mechanisms to provide dynamic point-of-care (or close to point of care) feedback in a manner that drives improvement. For inflammatory bowel disease, work has been performed in Europe and the United States to develop a framework for how practitioners can improve quality of care. Improve Care Now has created a sophisticated quality improvement program for pediatric patients with inflammatory bowel disease. The American Gastroenterology Association has worked within the National Quality Strategy framework to develop quality measures for patients with inflammatory bowel disease that have been incorporated into Federal programs that are moving Medicare reimbursement from a volume-based to a value-based structure. The Crohn's and Colitis Foundation of America is initiating a quality intervention program that can be implemented in community and academic practices to stimulate continual improvement processes for patients with inflammatory bowel disease. All of this work is intended to make quality improvement programs both feasible and useful, with the ultimate goal of improving quality of life for our patients. PMID- 23747712 TI - Factors affecting the bioaccessibility of fluoride from seafood products. AB - Fluoride is considered important for health because of its beneficial effect on the prevention of dental caries and on bone development in the child population. However, excessive intake has negative effects. The main pathway for exposure is oral, through consumption of drinking water, and some food products. Therefore its bioaccessibility (quantity of the element solubilized during the digestive process) is a parameter to be considered when estimating the risk/benefit associated with this element. The aim of the present study was to evaluate the influence of the digestion phase, gastrointestinal digestion factors (pH, pepsin and bile salt concentrations) and the presence of cations on the bioaccessibility of fluoride from seafood products. The results show that the solubilization of fluoride takes place entirely during the gastric phase. Its bioaccessibility is strongly influenced by conditions that favor the formation of insoluble complexes of fluoride with other elements present in the matrix. The factors that are most influential in reducing its bioaccessibility are the increase in pH in the gastric phase, the presence of cations, especially in the intestinal phase, and a low concentration of bile salts. PMID- 23747713 TI - Modulation of the endogenous antioxidants paraoxonase-1 and urate by pesticide exposure and genetic variants of xenobiotic-metabolizing enzymes. AB - This study evaluated the association between pesticide exposure in farmworkers and plasma levels of the endogenous antioxidants urate and paraoxonase-1 (PON1) enzyme activities (paraoxonase, arylesterase and diazoxonase, three substrate specific assays for measuring PON1 function) by using generalized estimating equations (GEEs). Decreases in plasma and erythrocyte cholinesterases (BChE and AChE, respectively) were used as biomarkers of pesticide exposure. We also assessed the contribution of genetic polymorphisms of the pesticide-metabolising enzymes PON1, glutathione S-transferases (GST) and cholinesterase variants (BCHE) on plasma levels of endogenous antioxidants and potential gene-environment interactions. A dual effect was observed on paraoxonase depending on the pattern of pesticide exposure. Thus, exposure to anticholinesterase pesticides was associated with decreased paraoxonase activity and urate levels whereas long-term pesticide exposure showed an association with increased paraoxonase activity. Significant interactions were observed between BChE activity and PON1 regulatory region polymorphisms on arylesterase and diazoxonase activities, and between AChE activity (a biomarker for long-term pesticide exposure) and PON1192RR genotype on arylesterase activity. These findings suggest that pesticide exposure may affect plasma antioxidant potential and that relevant gene-pesticide interactions may play a mechanistic role in oxidative stress-induced diseases following pesticide exposure. Nonetheless, more studies are needed to better characterise these interactions. PMID- 23747715 TI - A review on ochratoxin A transcriptomic studies. AB - The mycotoxin Ochratoxin A (OTA) is a potent renal carcinogen in male rats. Transcriptomic studies on OTA (4 in vitro, 6 in vivo, 2 in vitro/in vivo) have been reviewed. The aim of 6 of them was mainly mechanistic whereas the rest had mostly predictive (1) or evaluation (5) purposes. An overall tendency towards gene expression downregulation was observed, probably as a result of protein synthesis inhibition. DNA damage response genes were not deregulated in most of the studies. Genes involved in acute renal injury, cell survival and cell proliferation were upregulated in several in vivo studies. Apoptosis genes were deregulated in vitro but less affected in vivo; activation of several MAPKs has been observed. Many genes related to oxidative stress or involved in cell-to-cell interaction pathways (Wnt) or cytoskeleton structure appeared to be deregulated either in vitro or in vivo. Regucalcin was highly downregulated in vivo and other calcium homeostasis genes were significantly deregulated in vitro. Genes related to OTA transport (OATs) and metabolism (CYPs) appeared downregulated in vivo. Overall, the mechanism of action of OTA remains unclear, however transcriptomic data have contributed to new mechanistic hypothesis generation and to in vitro-in vivo comparison. PMID- 23747714 TI - Assessment of the respiratory sensitization potential of proteins using an enhanced mouse intranasal test (MINT). AB - There remains a need for a simple and predictive animal model to identify potential respiratory sensitizers. The mouse intranasal test (MINT) was developed to assess the relative allergic potential of detergent enzymes, however, the experimental endpoints were limited to evaluation of antibody levels. The present study was designed to evaluate additional endpoints (serum and allergic antibody levels, pulmonary inflammation and airway hyperresponsiveness (AHR)) to determine their value in improving the predictive accuracy of the MINT. BDF1 mice were intranasally instilled on days 1, 3, 10, 17 and 24 with subtilisin, ovalbumin, betalactoglobulin, mouse serum albumin or keyhole limpet hemocyanin; challenged with aerosolized methacholine or the sensitizing protein on day 29 to assess AHR, and sacrificed on day 29 or 30. Under the conditions of this study, evaluation of AHR did not improve the predictive power of this experimental model. Allergic antibody responses and IgG isotype characterization proved to be the most sensitive and reliable indicators of the protein allergenic potential with BAL responses providing additional insight. These data highlight that the evaluation of the respiratory sensitization potential of proteins can be best informed when multiple parameters are evaluated and that further improvements and refinements of the assay are necessary. PMID- 23747716 TI - Change in kidney damage biomarkers after 13 weeks of exposing rats to the complex of Paecilomyces sinclairii and its host Bombyx mori larvae. AB - Complex of Paecilomyces sinclairii and host larvae, Bombyx mori, is a well known health food; however, concerns about nephrotoxicity have been raised. Kidney toxicity was investigated after 13 weeks of administering the complex orally to rats with parameters including blood urea nitrogen (BUN), creatinine, and kidney damage biomarkers, beta-2-microglobulin (beta2m), glutathione S-transferase alpha (GST-alpha), kidney injury molecule 1 (KIM-1), tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), vascular endothelial growth factor (VEGF), calbindin, clusterin, cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin. Dose-dependent kidney cell karyomegaly and tubular hypertrophy were observed, with higher severity in males. There was a dose dependent increase in KIM-1 and TIMP-1 levels in kidney and urinary KIM-1, cystatin C, beta2m, and osteopontin levels. KIM-1 and TIMP-1 increased in male kidneys had not recovered by 2 weeks after stopping exposure. Cystatin C in kidney was significantly lowered in all treatment groups at 13 weeks of administration. All the changes were more noticeable in males. These data indicate that the complex damage renal tubule cells with histopathological lesions and changes in biomarker levels. Kidney and urinary KIM-1 and cystatin C were the most markedly affected and early increased indicators among biomarkers tested, whereas BUN and creatinine were not affected. PMID- 23747717 TI - Short-term high-intensity interval exercise training attenuates oxidative stress responses and improves antioxidant status in healthy humans. AB - This study investigated the changes in oxidative stress biomarkers and antioxidant status indices caused by a 3-week high-intensity interval training (HIT) regimen. Eight physically active males performed three HIT sessions/week over 3 weeks. Each session included four to six 30-s bouts of high-intensity cycling separated by 4 min of recovery. Before training, acute exercise elevated protein carbonyls (PC), thiobarbituric acid reactive substances (TBARS), glutathione peroxidase (GPX) activity, total antioxidant capacity (TAC) and creatine kinase (CK), which peaked 24h post-exercise (252 +/- 30%, 135 +/- 17%, 10 +/- 2%, 85 +/- 14% and 36 +/- 13%, above baseline, respectively; p<0.01), while catalase activity (CAT) peaked 30 min post-exercise (56 +/- 18% above baseline; p<0.01). Training attenuated the exercise-induced increase in oxidative stress markers (PC by 13.3 +/- 3.7%; TBARS by 7.2 +/- 2.7%, p<0.01) and CK activity, despite the fact that total work done was 10.9 +/- 3.6% greater in the post- compared with the pre-training exercise test. Training also induced a marked elevation of antioxidant status indices (TAC by 38.4 +/- 7.2%; CAT by 26.2 +/- 10.1%; GPX by 3.0 +/- 0.6%, p<0.01). Short-term HIT attenuates oxidative stress and up-regulates antioxidant activity after only nine training sessions totaling 22 min of high intensity exercise, further supporting its positive effect not only on physical conditioning but also on health promotion. PMID- 23747718 TI - L-Leucine and L-isoleucine enhance growth of BBN-induced urothelial tumors in the rat bladder by modulating expression of amino acid transporters and tumorigenesis associated genes. AB - We investigated the underlying mechanisms of L-leucine and L-isoleucine mediated promotion of bladder carcinogenesis using an initiation-promotion model. Rats were administered N-butyl-N-(4-hydroxybutyl) nitrosamine for 4 weeks and then fed AIN-93G basal diet or diet supplemented with L-leucine or L-isoleucine for 8 weeks followed by the basal diet for another 8 weeks. At the end of the experiment, week 20, there was a significant elevation of papillary and nodular (PN) hyperplasia multiplicity in the amino acid groups. L-Leucine and L isoleucine transporters were up-regulated in PN hyperplasias and/or bladder tumors compared with concomitant normal-appearing bladder urothelium at weeks 12 and/or 20 in all groups. In addition, in normal-appearing bladder urothelium, significantly increased mRNA levels of y+LAT1, LAT2, LAT4, and 4F2hc were observed in the amino acid groups compared with the BBN control group at both weeks 12 and 20, and increased mRNA levels of LAT1 were observed at week 20. Furthermore, up-regulation of TNF-alpha, c-fos, beta-catenin, p53, p21(Cip1/WAF1), cdk4, cyclin D1 and caspase 3 in the amino acid groups was detected in normal-appearing bladder urothelium. Overall, our results indicate that supplementation with l-leucine or l-isoleucine enhanced growth of bladder urothelial tumors by triggering expression of amino acid transporters and tumorigenesis-associated genes. PMID- 23747719 TI - GEP100 regulates epidermal growth factor-induced MDA-MB-231 breast cancer cell invasion through the activation of Arf6/ERK/uPAR signaling pathway. AB - GEP100, a guanine nucleotide exchanging factor (GEF) for Arf6, plays a pivotal role in promoting breast cancer cell invasion both in vitro and in vivo. However, the precise mechanism for GEP100-mediated cell invasion is still poorly understood. In this study, we found that down-regulation of endogenous GEP100 in MDA-MB-231 cells significantly inhibited EGF-induced cell invasion, which was rescued by over-expression of ectopic GEP100. EGF increased Arf6 activity, ERK phosphorylation, and uPAR expression in a time dependent manner. Additionally, blocking Arf6 with Arf6 siRNA largely abolished EGF-induced cell invasion. GEP100 siRNA or Arf6 siRNA suppressed EGF-induced ERK activity and uPAR expression. Furthermore, blocking ERK signaling with U0126, a specific inhibitor for MEK, markedly inhibited EGF-induced uPAR expression and consequently cell invasion. Inhibition of uPAR expression by uPAR siRNA also significantly abolished EGF induced cell invasion. Taken together, this study illustrates that GEP100 regulates an Arf6/ERK/uPAR signaling cascade in EGF-induced breast cancer cell invasion. These findings could provide a rationale for designing new therapies based on inhibition of breast cancer metastasis. PMID- 23747720 TI - eIF4E-Overexpression imparts perillyl alcohol and rapamycin-mediated regulation of telomerase reverse transcriptase. AB - Translation is mediated partly by regulation of free eukaryotic initiation factor 4E (eIF4E) levels through PI3K-Akt-mTOR signaling. Cancer cells treated with the plant-derived perillyl alcohol (POH) or the mechanistic target of rapamycin (mTOR) inhibitor rapamycin dephosphorylate eIF4E-binding protein (4E-BP1) and attenuate cap-dependent translation. We previously showed in cancer cell lines with elevated eIF4E that POH and rapamycin regulate telomerase activity through this pathway. Here, immortalized Chinese hamster ovary (CHO) control cells and CHO cells with forced eIF4E expression (rb4E) were used to elucidate eIF4E's role in telomerase regulation by POH and rapamycin. Despite 5-fold higher eIF4E amounts in rb4E, telomerase activity, telomerase reverse transcriptase (TERT) mRNA, and TERT protein were nearly equivalent in control and rb4E cells. In control cells, telomerase activity, TERT mRNA and protein levels were unaffected by either compound. In contrast, telomerase activity and TERT protein were both attenuated by either agent in rb4E cells, but without corresponding TERT mRNA decreases indicating a translational/post-translational process. S6K, Akt, and 4E BP1 were modulated by mTOR mediators only in the presence of increased eIF4E. Thus, eIF4E-overexpression in rb4E cells enables inhibitory effects of POH and rapamycin on telomerase and TERT protein. Importantly, eIF4E-overexpression modifies cellular protein synthetic processes and gene regulation. PMID- 23747721 TI - CD45RA-Foxp3(high) activated/effector regulatory T cells in the CCR7 + CD45RA CD27 + CD28+central memory subset are decreased in peripheral blood from patients with rheumatoid arthritis. AB - Human CD4+ T cells can be classified as either naive, central memory (TCM), or effector memory (TEM) cells. To identify the CD4+ T cell subsets most important in the pathogenesis of rheumatoid arthritis (RA), we phenotypically defined human CD4+ T cells as functionally distinct subsets, and analyzed the distribution and characteristics of each subset in the peripheral blood. We classified CD4+ T cells into six novel subsets based on the expression of CD45RA, CCR7, CD27, and CD28. The CCR7 + CD45RA-CD27 + CD28+ TCM subset comprised a significantly smaller proportion of CD4+ T cells in RA patients compared to healthy controls. The frequency of TNF-alpha-producing cells in the CCR7-CD45RA-CD27 + CD28+ TEM subset was significantly increased in RA. Furthermore, within the CCR7 + CD45RA-CD27 + CD28+ TCM subset, which was decreased in periperal blood from RA, the proportions of total Foxp3+ Treg cells and CD45RA-Foxp3(high) activated/effector Treg cells were significantly lower in RA patients. Our findings suggest that the increased proportion of TNF-alpha-producing cells and the decreased proportion of CD45RA Foxp3(high) activated/effector Treg cells in particular subsets may have critical roles in the pathogenesis of RA. PMID- 23747722 TI - Human xylosyltransferase-I - a new marker for myofibroblast differentiation in skin fibrosis. AB - Skin fibrosis is a severe type of fibrotic disorder emerging in terms of hypertrophic scars or systemic sclerosis. Key event of fibrogenesis is the transition of fibroblasts to matrix-producing myofibroblasts. In the presence of fibrotic triggers, for instance secretion of profibrotic growth factors like transforming growth factor-beta1 (TGF-beta1) or mechanical strain, myofibroblasts persist. Current research focuses on discovering innovative myofibroblast biomarkers which are regulated in fibrotic development and accessible for antifibrotic inhibition. Here, we consider the suitability of xylosyltransferase I (XT-I) as a myofibroblast biomarker in skin fibrosis. XT-I catalyzes the initial step of glycosaminoglycan biosynthesis. Its increase in enzymatic activity is known to refer only to manifested diseases which are characterized by an abnormal rate of proteoglycan biosynthesis. In this study, treatment of normal human dermal fibroblasts (NHDF) with TGF-beta1 was followed by increased relative XYLT1 mRNA expression. Remarkably, this upregulation was strongly dependent on myofibroblast content, increasing during fibrogenesis. Moreover, XT activity increased time-dependently in response to progressive myofibroblast transformation. XYLT1 expression was inhibited by TGF-beta receptor I (ALK5) inhibitor SB431542. In contrast, XYLT2 expression was only marginally affected by TGF-beta1 as well as ALK5 inhibition. Our results strengthen the significance of XT expression and activity in fibrotic remodeling. Therefore, we propose XT activity, in addition to alpha-SMA expression, as a new biomarker for myofibroblast differentiation and fibrotic development. Further studies are now needed to evaluate the option to control and inhibit fibrotic remodeling by interfering with XT expression. PMID- 23747723 TI - Bone morphogenetic protein-4 contributes to the down-regulation of Kv4.3 K+ channels in pathological cardiac hypertrophy. AB - Kv4.3 K(+) channels contributing to Ito are involved in the repolarization of cardiac action potential. Kv4.3 K(+) channels decrease in pathological cardiac hypertrophy, but the mechanism remains unclear. Our previous study found that the expression of bone morphogenetic protein 4 (BMP4) increased in pressure-overload and Ang II constant infusion induced cardiac hypertrophy. Since the downregulation of Kv4.3 K(+) channels and the upregulation of BMP4 simultaneously occur in pathological cardiac hypertrophy, we hypothesize that the up-regulated BMP4 would contribute to the downregulation of Kv4.3 K(+) channels in cardiac hypertrophy. We found that BMP4 treatment reduced Kv4.3 but not Kv4.2 and Kv1.4 K(+) channel protein expression, and BMP4-induced decrease of Kv4.3 K(+) channel protein expression was reversed by BMP4 inhibitor noggin and DMH1 in cultured cardiomyocytes in vitro. BMP4-induced decrease of Kv4.3 K(+) channel protein expression was also reversed by the NADPH oxidase inhibitor apocynin and the radical scavenger tempol. In in vivo transverse aortic constriction (TAC)-induced cardiac hypertrophy, constant infusion of DMH1 completely rescued TAC-induced down-regulation of Kv4.3 K(+) channel protein expression. We conclude that BMP4 contributes to the downregulation of Kv4.3 K(+) channels in pathological cardiac hypertrophy and the underlying mechanism might be through increasing ROS production. PMID- 23747724 TI - Effects of chemokine (C-C motif) ligand 1 on microglial function. AB - Microglia, which constitute the resident macrophages of the central nervous system (CNS), are generally considered as the primary immune cells in the brain and spinal cord. Microglial cells respond to various factors which are produced following nerve injury of multiple aetiologies and contribute to the development of neuronal disease. Chemokine (C-C motif) ligand 1 (CCL-1), a well-characterized chemokine secreted by activated T cells, has been shown to play an important role in neuropathic pain induced by nerve injury and is also produced in various cell types in the CNS, especially in dorsal root ganglia (DRG). However, the role of CCL-1 in the CNS and the effects on microglia remains unclear. Here we showed the multiple effects of CCL-1 on microglia. We first showed that CCR-8, a specific receptor for CCL-1, was expressed on primary cultured microglia, as well as on astrocytes and neurons, and was upregulated in the presence of CCL-1. CCL-1 at concentration of 1 ng/ml induced chemotaxis, increased motility at a higher concentration (100 ng/ml), and increased proliferation and phagocytosis of cultured microglia. CCL-1 also activated microglia morphologically, promoted mRNA levels for brain-derived neurotrophic factor (BDNF) and IL-6, and increased the release of nitrite from microglia. These indicate that CCL-1 has a role as a mediator in neuron-glia interaction, which may contribute to the development of neurological diseases, especially in neuropathic pain. PMID- 23747725 TI - Generation of mouse models for type 1 diabetes by selective depletion of pancreatic beta cells using toxin receptor-mediated cell knockout. AB - By using the toxin receptor-mediated cell knockout (TRECK) method, we have generated two transgenic (Tg) murine lines that model type 1 (insulin-dependent) diabetes. The first strain, C.B-17/Icr-Prkdc(scid)/Prkdc(scid)-INS-TRECK-Tg, carries the diphtheria toxin receptor (hDTR) driven by the human insulin gene promoter, while the other strain, C57BL/6-ins2(BAC)-TRECK-Tg, expresses hDTR cDNA under the control of the mouse insulin II gene promoter. With regard to the C.B 17/Icr-Prkdc(scid)/Prkdc(scid)-INS-TRECK-Tg strain, only one of three Tg strains exhibited proper expression of hDTR in pancreatic beta cells. By contrast, hDTR was expressed in the pancreatic beta cells of all four of the generated C57BL/6 ins2(BAC)-TRECK-Tg strains. Hyperglycemia, severe ablation of pancreatic beta cells and depletion of serum insulin were observed within 3days after the administration of diphtheria toxin (DT) in these Tg mice. Subcutaneous injection of a suitable dosage of insulin was sufficient for recovery from hyperglycemia in all of the examined strains. Using the C.B-17/Icr-Prkdc(scid)/Prkdc(scid)-INS TRECK-Tg model, we tried to perform regenerative therapeutic approaches: allogeneic transplantation of pancreatic islet cells from C57BL/6 and xenogeneic transplantation of CD34(+) human umbilical cord blood cells. Both approaches successfully rescued C.B-17/Icr-Prkdc(scid)/Prkdc(scid)-INS-TRECK-Tg mice from hyperglycemia caused by DT administration. The high specificity with which DT causes depletion in pancreatic beta cells of these Tg mice is highly useful for diabetogenic research. PMID- 23747726 TI - Identification of HDAC4 as a target of gamma-catenin that regulates the oncogenic K-Ras-mediated malignant phenotype of Rat2 cells. AB - The mechanisms by which activated Ras accelerates malignant transformation of normal cells are not fully understood. Here, we characterized the role and molecular mechanism of gamma-catenin in regulating the malignant phenotype of Rat2 cells induced by codon 12-mutant K-Ras (K-Ras12V). Suppression of gamma catenin signaling by K-Ras12V was an early event and played a crucial role in promoting the acquisition of a highly metastatic phenotype of Rat2 cells. Notably, the gene encoding histone deacetylase 4 (HDAC4) was identified as a target of gamma-catenin during this process. The transcription factor, lymphoid enhancer-binding factor-1 (Lef1), was involved in the modulation of HDAC4 transcription, and disruption of this pathway was a key event in promoting the invasion and migration of K-Ras12V-transduced Rat2 cells. Thus, our findings extend the range of targets for the development of new drugs for the therapy of oncogenic K-Ras-driven cancer. PMID- 23747727 TI - High expression of lysine-specific demethylase 1 correlates with poor prognosis of patients with esophageal squamous cell carcinoma. AB - Recent studies have elucidated the role of lysine-specific demethylase 1 (LSD1), a member of the histone demethylases, in epigenetic regulation of tumor suppressing/promoting genes and neoplastic growth. However, the expression of LSD1 in patients with esophageal squamous cell carcinoma (ESCC) is still unknown. Here, we reported that LSD1 expression was elevated in cancerous tissue and correlated with lymph node metastasis and poorer overall survival in patients with ESCC. Compared to EC109 cells, LSD1 expression was unregulated in aggressive cancer cell lines KYSE450 and KYSE150. Knockdown of LSD1 using lentivirus delivery of LSD1-specific shRNA abrogated the migration and invasion of ESCC cells in vitro. Further, a LSD1 inhibitor, tranylcypromine, suppressed H3K4me2 demethylation and attenuated cellular motility and invasiveness in a dose dependent manner. Taken together, these data suggested that LSD1 was a potential prognostic maker and may be a molecular target for inhibiting invasion and metastasis in ESCC. PMID- 23747728 TI - Generation of priming mesenchymal stem cells with enhanced potential to differentiate into specific cell lineages using extracellular matrix proteins. AB - Poor understanding of the differentiation of mesenchymal stem cells (MSCs) has resulted in a low differentiation yield, and has hindered their application in medicine. As a solution, priming MSCs sensitive to signaling, thus stimulating differentiation into a specific cell lineage, may improve the differentiation yield. To demonstrate this, priming MSCs were produced by using a gelatin matrix for the isolation of primary MSCs from bone-marrow-derived primary cells. Subsequently, cellular characteristics and sensitivity to specific differentiation signals were analyzed at passage five. Compared to non-priming MSCs, priming MSCs showed no significant differences in cellular characteristics, but demonstrated a significant increase in sensitivity to neurogenic differentiation signals. These results demonstrate that generation of priming MSCs by specific extracellular signaling increases the rate of differentiation into a cell-specific lineage. PMID- 23747729 TI - Activin stimulates CYP19A gene expression in human ovarian granulosa cell-like KGN cells via the Smad2 signaling pathway. AB - Activin, a transforming growth factor beta family member, has a wide range of physiological roles during embryonic development and organogenesis. In the ovary, activin, secreted from ovarian granulosa cells, not only acts on the pituitary gland to regulate the gonadotropin secretion from the pituitary gland in an endocrine manner but also acts on granulosa cells in a paracrine/autocrine manner to regulate folliculogenesis. Previously, we showed that activin signals through activin type IB receptor (ActRIB) and up-regulates follicle-stimulating hormone receptor expression and P450 aromatase activity in human ovarian granulose cell like KGN cells. In the current study, we demonstrate the direct involvement of Smad2 as a downstream signal mediator of ActRIB in the transcriptional regulation of the P450 aromatase gene (CYP19A) in KGN cells. Upon activin stimulation, Smad2 activation and an increase in P450 aromatase messenger RNA (mRNA) were observed in KGN cells. Interestingly, Smad2 phosphorylation correlated well with the increase in P450 aromatase mRNA. Reciprocally, knockdown of Smad2 mRNA in KGN cells led to a decrease in the P450 aromatase mRNA expression, suggesting that Smad2 regulates CYP19A gene expression. Further analysis of CYP19A promoter activity revealed that the 5' upstream region between -2069 and -1271bp is required for the activation by Smad2. Finally, we provide compelling evidence that Smad2 shows follicular stage-specific expression, which is high in granulosa cells of preantral or early antral follicles in mice. Our results suggest that activin signaling through the ActRIB-Smad2 pathway plays a pivotal role in CYP19A expression and thus in follicular development. PMID- 23747730 TI - Escherichia coli O157:H7 LPS O-side chains and pO157 are required for killing Caenorhabditis elegans. AB - As a model host, the nematode Caenorhabditis elegans has been used for studying unknown pathogen-host interactions and identifying novel virulence factors in bacterial pathogens. Among the bacterial pathogens that can induce death of C. elegans is enterohemorrhagic Escherichia coli (EHEC) O157:H7, a major serotype of EHEC that causes hemorrhagic colitis and hemolytic uremic syndrome in humans and animals. However, it is unknown which EHEC O157:H7 factors are required for nematode death. In this study, bacterial ability to kill C. elegans was tested for several EHEC O157:H7 wild-type and mutant strains missing one virulence associated factor, including Shiga toxins, enterohemolysin, pO157 (a large virulence plasmid in EHEC O157:H7), Type 3 secretion system, LuxS, and lipopolysaccharide (LPS) O-side chains. Our results demonstrate that only mutants lacking either pO157 or LPS O-side chains cause full attenuation in killing C. elegans. The LPS O-side chain-defective DeltaperA mutant strain was not able to colonize in the intestine even at 24h post-feeding with C. elegans, while the wild-type strain began to accumulate and colonize in the intestine as early as 3h post-feeding. A simple complementation of the mutant strain with the plasmid carrying the intact perA gene in trans completely restored the production of LPS O-side chains, as well as the ability to kill C. elegans. Our results show that pO157 and PerA are required for EHEC O157:H7 to kill C. elegans. PMID- 23747731 TI - Differences in alpha-beta transmembrane domain interactions among integrins enable diverging integrin signaling. AB - Integrins are transmembrane adhesion molecules composed of alpha and beta subunits. In humans, 24 integrins are expressed in a tissue-specific manner. Each integrin plays a specific role within a tissue type to control cell adhesion. We previously found that the degree of transmembrane domain (TMD) interaction between the integrin alphaIIb and beta3 subunits is reversely correlated with the affinity of integrin alphaIIbbeta3 to its ligand. Here, we examined the TMD interactions of various integrins, including alpha4beta1, alphaLbeta2, alpha5beta1, alphaVbeta1, alphaIIbbeta3, and alphaVbeta3. Our findings revealed that the degree of the TMD interactions in integrins alpha4beta1 and alphaLbeta2 expressed in immune cells was low and in integrins alphaIIbbeta3 and alphaVbeta3 expressed in platelets was high, while integrins alpha5beta1 and alphaVbeta1 that are expressed in most adherent cells displayed intermediate TMD interactions. We identified sequence variation within the N-terminal TMD region as a factor responsible for the observed differential degree of TMD interaction among integrins. When the N-terminal interaction that was missing in integrin alpha5beta1 was restored with mutagenesis, the increase in TMD interaction inhibited the outside-in but not inside-out signaling of integrin alpha5beta1 and also accelerated the speed of cell migration. We suggest, therefore, that the degree of TMD interaction is designed to accommodate the specific, desired function of each integrin. PMID- 23747732 TI - Oral delivery of an anti-diabetic peptide drug via conjugation and complexation with low molecular weight chitosan. AB - Despite the therapeutic potential of exendin-4 as a glucagon-like peptide-1 (GLP 1) mimetic for the treatment of type 2 diabetes, its utility has so far been limited because of the low level of patient compliance due to the requirement for frequent injections. In this study, an orally available exendin-4 was produced by conjugating it to low molecular weight chitosan (LMWC). Conjugation between the LMWC and cysteinylated exendin-4 was carried out using a cleavable linker system in order to maximize the availability of the active peptide. The LMWC-exendin-4 conjugate formed a nanoparticle structure with a mean particle size of 101 +/- 41 nm through complexation between the positively charged LMWC backbone and the negatively charged exendin-4 of individual conjugate molecules. The biological activity of the LMWC-exendin-4 conjugate was evaluated in an INS-1 cell line. The LMWC-exendin-4 conjugate stimulated insulin secretion in a dose dependent manner as similar as that of native exendin-4. From the pharmacokinetic study after oral administration of the conjugate, a C(max) value of 344 pg/mL and a T(max) of 6 h were observed, and the bioavailability, relative to the subcutaneous counterpart, was found to be 6.4%. Furthermore, the absorbed exendin-4 demonstrated a significantly enhanced hypoglycemic effect. These results suggest that the LMWC exendin-4 conjugate could be used as a potential oral anti-diabetic agent for the treatment of type 2 diabetes. PMID- 23747733 TI - Complement monitoring of Pluronic 127 gel and micelles: suppression of copolymer mediated complement activation by elevated serum levels of HDL, LDL, and apolipoproteins AI and B-100. AB - Poloxamer 407 is a non-ionic polyethylene oxide (PEO)/polypropylene oxide (PPO) block copolymer, which exhibits reversible thermogelation properties. Poloxamer gel has attracted many applications for controlled release of therapeutic agents as well as in surgical interventions such as controlled vascular occlusion. We show that poloxamer gel can trigger the complement system, which is an integral part of innate immunity and its inadvertent activation can induce clinically significant anaphylaxis. Complement activation by the poloxamer gel is through the alternative pathway, but material transformations from gel to the solution state further incite complement through calcium-sensitive pathways, where a role for C1q and antibodies has been eliminated. Poloxamer addition to plasma/serum (at levels above its critical micelle concentration, cmc) induced formation of large and diffused structures, which may have been responsible for triggering complement. Since poloxamer 407 administration has been reported to cause significant changes in plasma cholesterol and triglyceride levels we further examined the role of lipoproteins in poloxamer-mediated complement activation. Our results show a protective role for elevated serum HDL, LDL and their predominant apolipoproteins (apoAI and apoB-100, respectively) on poloxamer mediated complement activation. Electron microscopy investigations indicated formation of two distinct populations of new structures on mixing of poloxamer (at concentrations above its cmc) with human LDL, which could have played a significant role in regulating complement activation. These observations are in line with the suggested modulatory role of lipoproteins in host defence and inflammatory processes. A better understanding of block copolymer interaction with lipoproteins/apolipoproteins could improve the immune safety of surgical and therapeutic interventions requiring PEO/PPO block copolymers and may provide new insights for combinatorial design of multifunctional copolymers. PMID- 23747734 TI - Capsaicin provokes apoptosis and restricts benzo(a)pyrene induced lung tumorigenesis in Swiss albino mice. AB - Capsaicin (CAP), a constituent of red chilli and red pepper is exposed to exert compelling anticarcinogenic effects. In the present study, we examined the anti tumorigenic potential of CAP on benzo(a)pyrene-induced mice lung tumorigenesis by analyzing the markers of apoptosis. Intraperitoneal administration of CAP (10mg/kg body weight) to Swiss albino mice suppressed the development of lung carcinoma by amending the protein expressions of apoptotic regulators p53, Bcl-2, Bax and caspase-3. The apoptotic-inducing nature of CAP was further confirmed by DNA agarose gel electrophoresis, transmission electron microscopic study and ethidium bromide/acridine orange staining. The results obtained from the present study show that CAP inhibits the development of mice lung carcinogenesis through its ability to induce apoptosis. Our present findings provide the basis for further clinical exploration of CAP as an anti-carcinogenic compound against lung carcinogenesis. PMID- 23747735 TI - A closer look to botulinum neurotoxin type A-induced analgesia. AB - Chronic pain indicates a type of pain that lasts over time and is accompanied by diagnostic and therapeutic difficulties. It follows that treatment failures are common and patients roam from doctor to doctor in search of an effective care program. So there is an urgent need for long-acting and effective therapeutics to alleviate symptoms of the varied forms of chronic pain. During the past few years, a good success has been achieved with a derivative of a neurotoxin. It has been shown that administration of this toxin can block the release of neurotransmitters and pain mediators. Botulinum neurotoxin type A (BoNT/A) is well known as a treatment for neuromuscular conditions such as dystonia and spasticity. However, the clinical application for BoNT/A has continued to expand. Its analgesic effect has been used in clinical practice with satisfactory results. This review provides an introduction of a hypothesis for the mechanism by which BoNT/A eases chronic pain. It also summarizes the clinical therapeutic effects of BoNT/A in different types of chronic pain and its potential prospects. PMID- 23747736 TI - Magnetic separations in biotechnology. AB - Magnetic separations are probably one of the most versatile separation processes in biotechnology as they are able to purify cells, viruses, proteins and nucleic acids directly from crude samples. The fast and gentle process in combination with its easy scale-up and automation provide unique advantages over other separation techniques. In the midst of this process are the magnetic adsorbents tailored for the envisioned target and whose complex synthesis spans over multiple fields of science. In this context, this article reviews both the synthesis and tailoring of magnetic adsorbents for bioseparations as well as their ultimate application. PMID- 23747737 TI - Is there, and should there be, apoptosis in bacteria? AB - Apoptosis is a well-studied form of cell death in metazoans, where it has a clear role during the life of the (multicellular) animal. Some situations of cell death in unicellular eukaryotes (protozoa and yeast) have also been referred to as apoptosis. In recent years apoptosis has further been identified in bacteria several times. As a bacterial response to external stimuli, apoptosis could be important not only for the bacteria but also to the host. Here I will discuss why I believe that the term apoptosis should be avoided for these situations in bacteria, no matter how interesting the molecular background or how biologically important the underlying mechanism may be. PMID- 23747738 TI - A comprehensive analysis of transfection-assisted delivery of iron oxide nanoparticles to dendritic cells. AB - Polylysine (PL) has been used to facilitate dendritic cell (DC) uptake of super paramagnetic iron oxide (SPIO) nanoparticles for use in magnetic resonance imaging (MRI). In this work, we examined the effect of PL on cell toxicity and induction of cell maturation as manifested by the up-regulation of surface molecules. We found that PL became toxic to bone marrow-derived DCs (BMDCs) at the 10 MUg/ml threshold. Incubation of BMDCs with 20 MUg/ml of PL for 1h resulted in approximately 90% cell death. However, addition of SPIO nanoparticles rescued DCs from PL-induced death as the combination of SPIO with PL did not cause cytotoxicity until the PL concentration was 1000 MUg/ml. Prolonged exposure to PL induced BMDC maturation as noted by the expression of surface molecules such as MHC class II, CD40, CCR7 and CD86. However, the combination of SPIO and PL did not induce BMDC maturation at 1h. However prolonged exposure to SPIO nanoparticles induced CD40 expression and protein expression of TNFalpha and KC. The data suggest that the use of PL to enhance the labeling of DCs with SPIO nanoparticles is a dedicated work. Appropriate calibration of the incubation time and concentrations of PL and SPIO nanoparticles is crucial to the development of MRI technology for noninvasive imaging of DCs in vivo. FROM THE CLINICAL EDITOR: The authors of this study present detailed data on toxicity and efficiency of polylysine-facilitated uptake of USPIO-s by dendritic cells for cell-specific MR imaging. PMID- 23747739 TI - Thermo- and pH-sensitive dendrosomes as bi-phase drug delivery systems. AB - Fully supramolecular dendrosomes (FSD) as bi-phase drug delivery systems are reported in this work. For preparation of FSD, amphiphilic linear-dendritic supramolecular systems (ALDSS) have been synthesized by host-guest interactions between hyperbranched polyglycerol having beta-cyclodextrin core and bi-chain polycaprolactone (BPCL) with a fluorescine focal point. Self-assembly of ALDSS in aqueous solutions led to FSD. They were able to encapsulate paclitaxel with a high loading capacity. The dendrosome-based drug delivery systems were highly sensitive to pH and temperature. They were stable at 20-37 degrees C and pH7-8, but dissociated and released drug at temperatures lower than 20 degrees C or higher than 37 degrees C and pH lower than 7 quickly. Dissociation of FSD building blocks by temperature or pH resulted in inclusion complexes between the released drugs and polyglycerol as the secondary drug delivery system. FROM THE CLINICAL EDITOR: This paper reports on the development of a pH- (below 7) and temperature- (below 20 degrees C or above 37 degrees C) sensitive delivery system using supramolecular dendrosomes for more specific delivery and release of drugs using paclitaxel as a model. PMID- 23747740 TI - DermAll nanomedicine for allergen-specific immunotherapy. AB - Allergen-specific immunotherapy (ASIT) the only disease-modifying treatment for IgE-mediated allergies is characterized with long treatment duration and high risk of side effects. We investigated the safety, immunogenicity and efficacy of a novel ASIT, called DermAll, in an experimental allergic rhinitis model. We designed and characterized DermAll-OVA, a synthetic plasmid pDNA/PEIm nanomedicine expressing ovalbumin (OVA) as model allergen. DermAll-OVA was administered topically with DermaPrep device to target Langerhans cells. To detect the clinical efficacy of DermAll ASIT we quantified the nasal symptoms and characterized the immunomodulatory activity of DermAll ASIT by measuring cytokine secretion after OVA-stimulation of splenocytes and antibodies from the sera. In allergic mice DermAll ASIT was as safe as Placebo, balanced the allergen-induced pathogenic TH2-polarized immune responses, and decreased the clinical symptoms by 52% [32%, 70%] compared to Placebo. These studies suggest that DermAll ASIT is safe and should significantly improve the immunopathology and symptoms of allergic diseases. FROM THE CLINICAL EDITOR: A novel allergen-specific immunotherapy for IgE-mediated allergies is presented in this paper, using an experimental allergic rhinitis model and a synthetic plasmid pDNA/PEIm nanomedicine expressing ovalbumin as model allergen. Over 50% reduction of symptoms was found as the immune system's balance was favorably altered toward more TH2-polarized immune responses. PMID- 23747741 TI - Phospholipid micelle-based magneto-plasmonic nanoformulation for magnetic field directed, imaging-guided photo-induced cancer therapy. AB - We present a magnetoplasmonic nanoplatform combining gold nanorods (GNR) and iron oxide nanoparticles within phospholipid-based polymeric nanomicelles (PGRFe). The gold nanorods exhibit plasmon resonance absorbance at near infrared wavelengths to enable photoacoustic imaging and photothermal therapy, while the Fe3O4 nanoparticles enable magnetophoretic control of the nanoformulation. The fabricated nanoformulation can be directed and concentrated by an external magnetic field, which provides enhancement of a photoacoustic signal. Application of an external field also leads to enhanced uptake of the magnetoplasmonic formulation by cancer cells in vitro. Under laser irradiation at the wavelength of the GNR absorption peak, the PGRFe formulation efficiently generates plasmonic nanobubbles within cancer cells, as visualized by confocal microscopy, causing cell destruction. The combined magnetic and plasmonic functionalities of the nanoplatform enable magnetic field-directed, imaging-guided, enhanced photo induced cancer therapy. FROM THE CLINICAL EDITOR: In this study, a nano formulation of gold nanorods and iron oxide nanoparticles is presented using a phospholipid micelle-based delivery system for magnetic field-directed and imaging-guided photo-induced cancer therapy. The gold nanorods enable photoacoustic imaging and photothermal therapy, while the Fe3O4 nanoparticles enable magnetophoretic control of the formulation. This and similar systems could enable more precise and efficient cancer therapy, hopefully in the near future, after additional testing. PMID- 23747742 TI - [Treatment of the leptomeningeal metastases related to solid tumors]. AB - The incidence of metastases of the central nervous system (CNS) is increasing, due to the improvement of the overall survival of cancer patients. Leptomeningeal metastases (LM) are now more often identified, although the criteria used for the diagnosis and monitoring remains inadequate. LM should be diagnosed at an early stage of the disease before the setting of neurological deficits, in order to improve the quality of life of patients. Therapeutic indications remain difficult, though some criteria have been proposed. Prolonged survivals have been reported even in the presence of identified poor prognostic factors at the time of the diagnosis of LM. The median survival of untreated patients is 4 to 6 weeks. Specific treatment may prolong survival by several months. Only six randomized studies are available. All theses studies have limitations due to the difficulty of including these patients in homogeneous trials, with a good methodology and for a time acceptable to the patient enrolment. The treatment requires a combination of chemotherapy and targeted therapies administrated systemically or via intra-cerebrospinal fluid (CSF) route, surgery and radiotherapy. Patient management is specific but requires a multidisciplinary approach, which may vary according to the characteristics of meningeal disease, the characteristics of primary tumors, the general condition of patients and previous lines of treatments. Our objective was to describe the current management of LM of solid tumors. PMID- 23747743 TI - Enhanced survival of transplanted human adipose-derived stem cells by co-delivery with liposomal apoptosome inhibitor in fibrin gel matrix. AB - To improve the survival of transplanted human adipose-derived stem cells (ADSCs), a liposome preparation containing the apoptosome inhibitor, NS3694, was formulated and co-delivered with ADSCs in fibrin gel scaffolds. Liposomes provided enhanced effect on ADSC proliferation in vitro as compared to free drug. Exposure of ADSCs to liposomal NS3694 for 7 days did not affect the surface marker expression profile. NS3694 encapsulated in negatively charged liposomes composed of phosphatidylcholine, phosphatidylglycerol, and cholesterol was evaluated in vivo following subcutaneous transplantation in mice. Survival of ADSCs co-delivered with liposomal NS3694 was significantly higher than that of untreated ADSCs or ADSCs treated with free NS3694 or empty liposomes. An immunohistochemical analysis revealed a higher number of human nucleus-positive cells after treatment with liposomal NS3694 than following treatment with free NS3694. Similarly, liposomal NS3694 significantly enhanced survival of transplanted ADSCs in rabbits compared to other treatments. Taken together, our results indicate the potential of liposomal NS3694 co-delivered with ADSCs using fibrin gel systems as an in vivo-survival enhancer. PMID- 23747744 TI - Bicellar systems as vehicle for the treatment of impaired skin. AB - This study assesses the potential usefulness of bicellar systems to retard the penetration of drugs into damaged skin. The active compound used in this study was diclofenac diethylamine (DDEA). Initially, physicochemical characterisation of the DDEA bicellar systems was performed at different temperatures by small angle X-ray scattering (SAXS), wide-angle X-ray scattering (WAXS) and differential scanning calorimetry (DSC) techniques. Subsequently, in vitro percutaneous absorption of bicellar systems into in vitro damaged skin was studied. SAXS results indicated a slight decrease in the width of their bilayers with increasing temperature, with no apparent stacking in those systems. WAXS patterns were compatible with an orthorhombic lateral packing of the nanoaggregates. The thermogram obtained by DSC indicated a decrease in gel-to liquid crystalline transition temperature (Tm) when the drug was included into bicellar systems. A retardation effect for DDEA was detected by in vitro percutaneous absorption studies when DDEA was vehiculised in the bicellar systems with respect to an aqueous solution of the drug. It seems that the use of bicellar systems as a vehicle for topical application of DDEA on skin with an impaired barrier function may inhibit the penetration of DDEA to the systemic level. Such systems may consequently repair stratum corneum barrier function to some extent. The use of these systems could be considered a new alternative strategy to treat topically pathological skin with different drugs. PMID- 23747745 TI - Formulation development of lyophilized, long-term stable siRNA/oligoaminoamide polyplexes. AB - Polyplexes based on precise oligoaminoamides exhibited promising results in non viral siRNA delivery. However, one serious limitation is insufficient stability of polyplexes in liquid, which raises the demand for lyophilized, long-term stable formulations. Two different siRNA/oligoaminoamide polyplexes were prepared. Freeze-thaw experiments were performed, in order to test various formulations containing sucrose, trehalose, lactosucrose, and hydroxypropyl-beta cyclodextrin for their cryoprotective potential and to investigate the influence of the oligoaminoamide structure on particle stability. Selected formulations were lyophilized and tested for storage stability up to 6 months. Moreover, reconstitution of the lyophilisates in reduced volume as a technique to prepare higher concentration formulations was studied. Samples were analyzed for particle size, gene silencing, cytotoxicity, turbidity, subvisible particles, osmolarity, residual moisture content, glass transition temperature, and morphology. Depending on the oligoaminoamide, siRNA polyplexes maintained particle size and gene silencing efficiency in the absence or presence of low amounts (7%) of stabilizers after freeze-thawing, lyophilization, and reconstitution. Particle stability was highly dependent on the oligoaminoamide used, but independent of the presence of cysteines that form intra-particular disulfide bridges. In contrast to all other excipients, hydroxypropyl-beta-cyclodextrin did not provide sufficient stability. For lyophilized 5%/10% sucrose and 7% lactosucrose formulations, long-term stability was demonstrated at 40 degrees C with retained particle size, retained gene silencing activity, unchanged turbidity values, low numbers of subvisible particles, low residual moisture level, and sufficiently high glass transition temperature. Hence, this work is a promising approach in order to provide long-term stable siRNA polyplex formulations that are ready to use after a simple reconstitution step. PMID- 23747746 TI - PPIevo: protein-protein interaction prediction from PSSM based evolutionary information. AB - Protein-protein interactions regulate a variety of cellular processes. There is a great need for computational methods as a complement to experimental methods with which to predict protein interactions due to the existence of many limitations involved in experimental techniques. Here, we introduce a novel evolutionary based feature extraction algorithm for protein-protein interaction (PPI) prediction. The algorithm is called PPIevo and extracts the evolutionary feature from Position-Specific Scoring Matrix (PSSM) of protein with known sequence. The algorithm does not depend on the protein annotations, and the features are based on the evolutionary history of the proteins. This enables the algorithm to have more power for predicting protein-protein interaction than many sequence based algorithms. Results on the HPRD database show better performance and robustness of the proposed method. They also reveal that the negative dataset selection could lead to an acute performance overestimation which is the principal drawback of the available methods. PMID- 23747748 TI - LC-MS/MS method for the simultaneous quantitation of three active components derived from a novel prodrug against schistosome infection. AB - Schistosomiasis is an infectious disease that has been recognized as a severe health burden for some regions of the world. While praziquantel is the drug of choice, there is an unmet medical need for novel therapies with greater efficacy and resistant profile. DW-3-15 is a novel and promising prodrug possessing both adult and juvenile schistosomes killing capability. Its proposed hydrolytic products, artesunate (ARS), dihydroartemisinin (DHA) and 10-hydroxypraziquantel (10-OHPZQ), are all active in preventing schistosomal infection in relevant disease models. To support pharmacokinetic and PK-PD studies of DW-3-15, a simple, specific and rapid liquid chromatography-tandem mass spectrometry (LC MS/MS) method was developed and validated for the simultaneous determination of the three active components in rat plasma. Using a short C18 column (2.1 mm * 50 mm, 5 MUm) with linear gradient, a baseline resolution of the three analytes and corresponding internal standards was achieved with a total run time of 6 min. Mass detection was carried out by electrospray ionization in positive MRM mode with ion transitions of m/z 402.2->m/z 267.3 for ARS, m/z 302.2->m/z 163.1 for DHA, and m/z 329.2->m/z 219.4 for 10-OHPZQ. The method was linear over concentration ranges of 1.0-500 ng/mL for ARS, 5.0-2500 ng/mL for DHA, and 1.0 500 ng/mL for 10-OHPZQ. The accuracy was within +/-10.0% for ARS, +/-6.4% for DHA, and +/-13.0% for 10-OHPZQ. The within-run and between-run precision of all three analytes at four concentrations tested were less than 15%, except at the LLOQ for DHA which was between 15 and 20%. The method was successfully applied to pharmacokinetic evaluation of DW-3-15 in rats following intravenous administration. PMID- 23747747 TI - Pharmacokinetic characterization of oxymatrine and matrine in rats after oral administration of radix Sophorae tonkinensis extract and oxymatrine by sensitive and robust UPLC-MS/MS method. AB - The purpose of this study is to systematically investigate the pharmacokinetic (PK) behaviors of radix Sophorae tonkinensis (S. tonkinensis) using oxymatrine (OMT) and matrine (MT) as the target markers (2 mg/kg OMT and 1.3 mg/kg MT, oral administration). The PK characteristics in radix S. tonkinensis extracts were also compared with those of pure OMT. A fast ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed. OMT absorption was very fast, and no significant differences were observed (p>0.05) in tmax, CL, and t1/2 for both pure OMT and extracts. Cmax and AUC0->infinity of pure OMT were significantly higher than those of S. tonkinensis extracts (Cmax, 61.64+/-6.65 vs. 43.24+/-10.14 ng/mL; AUC, 9894.48+/-2234.99 vs. 4730.30+/-3503.8 min ng/mL) (p<0.05). However, the absolute OMT bioavailability of pure OMT was higher than that of the compound in radix S. tonkinensis extracts (6.79+/-2.52% vs. 1.87+/-2.66%). By contrast, the bioavailability of total alkaloids (OMT+MT) after pure OMT administration was 81.14+/-8.83%, similar to that of radix S. tonkinensis extracts (69.36+/-17.37%) (p>0.05). It was presumed that OMT absorption has no effect on the bioavailability of the two alkaloids. Other constituents in radix S. tonkinensis extracts can influence the transformation of OMT to MT, which directly leads to variations in the PK behavior of OMT. In addition, the protein binding of OMT and MT in plasma was very low (4.80%-8.95% for OMT, 5.10-10.55% for MT). In conclusion, OMT in radix S. tonkinensis extracts exhibits different PK behaviors with pure OMT through the transformation of OMT to MT due to other complex ingredients. PMID- 23747749 TI - Neonatal expression of amh, sox9 and sf-1 mRNA in Caiman latirostris and effects of in ovo exposure to endocrine disrupting chemicals. AB - Caiman latirostris is a reptilian species that exhibits temperature-dependent sex determination (TSD). Male-to-female sex reversal can be achieved after in ovo estrogen/xenoestrogen exposure. This is known as hormone-dependent sex determination (HSD). The amh, sox9 and sf-1 genes are involved in sex determination, sex differentiation, and steroidogenesis. The aims of this study were: (a) to establish the expression patterns of amh, sox9 and sf-1 mRNA in the gonad-adrenal-mesonephros (GAM) complexes of neonatal TSD-male and TSD-female caimans, (b) to compare the expression of these genes between TSD-females and HSD females (born from E2-exposed eggs incubated at the male-producing temperature) and (c) to evaluate whether in ovo exposure to a low dose of E2 or bisphenol A (BPA) or to a high dose of endosulfan (END) modifies amh, sox9 or sf-1 mRNA expressions in neonatal males. The mRNA expressions of amh, sox9 and sf-1 in GAM complexes from TSD-males and TSD-females and from HSD-females were quantitatively compared by RT-PCR. A sexually dimorphic pattern of amh and sox9 mRNA expression was found, with a higher expression in TSD-males than in TSD-females. sf-1 mRNA did not differ between TSD-males and TSD-females. HSD-females exhibited a higher expression of sox9 than TSD-females. In males, increased mRNA expression of sex determining genes was observed after in ovo exposure to END. E2 decreased sox9 but increased sf-1 mRNA expression. Changes induced by BPA were evident although not significant. These results provide new insights into the potential mechanisms that lead to the gonadal histo-functional alterations observed in caimans exposed to contaminated environments. PMID- 23747750 TI - Added benefits of polio eradication. PMID- 23747751 TI - In vitro drug susceptibility of Leishmania infantum isolated from humans and dogs. AB - Visceral leishmaniasis (VL) caused by parasites of Leishmania donovani complex is a severe human disease which often leads to death if left untreated. Domestic dogs are the main reservoir hosts for zoonotic human visceral infection caused by Leishmania infantum. In the absence of effective human and dog vaccines, the only feasible way to treat and control leishmaniasis is through the use of suitable medications. To know the drug susceptibility of human and canine Leishmania strains from Lisbon-Portugal, a study on a panel of strains was conducted by testing the susceptibility of promastigotes and intracellular amastigotes to the common drugs used in canine leishmaniasis (CanL) and human VL (meglumine antimoniate, amphotericin B, miltefosine and allopurinol). Although a high heterogeneity of susceptibilities was obtained to each drug on both axenic promastigote and intracellular amastigote assays, intracellular amastigotes system correlated better with treatment outcome. Parasites isolated from the refractory human case were the least susceptible to the drugs used highlighting that the emergence of cross-resistance to the drugs available for human therapy should not be neglected. Furthermore, parasites isolated from dogs showed low susceptibility to the main drugs used in CanL treatment. Our results focus the importance of reducing/avoiding the emergence and spread of resistant parasites in the canine and human populations, a factor that requires special consideration when dogs are treated using the same available anti-Leishmania drugs for human VL. In addition, efforts should be made in order to standardize the conditions used to test drug susceptibility (methodologies, drug formulations and media) in order to compare results between laboratories. PMID- 23747752 TI - Roles of 3,4-methylenedioxymethamphetamine (MDMA)-induced alteration of connexin43 and intracellular Ca(2+) oscillation in its cardiotoxicity. AB - Although it is well known that 3,4-methylenedioxymethamphetamine (MDMA) can cause various cardiovascular abnormalities and even sudden death from cardiac arrhythmia, whether it has any effect on myocardial gap junctions, which might be one of the targets mediating MDMA-induced cardiotoxicity, remains unclear. OBJECTIVE: To test the hypothesis that MDMA may affect the myocardial gap junction protein connexin43 (Cx43) and induce cardiac dysrhythmia. METHOD: (1) In vivo study: adult rats were treated with a single dose MDMA administration (20mg/kg, i.p.). Electrocardiogram detection and immunohistochemical analysis were performed to evaluate cardiac function and expression of Cx43, respectively; (2) in vitro study: cultured ventricular myocytes of neonatal rats were treated with MDMA (10, 100, 1000MUmol/L) for 1h. Western blotting and real-time quantitative polymerase chain reaction (RT-qPCR) were performed to investigate the total Cx43 mRNA expression. Immunofluorescent analysis was used to evaluate the amount of junctional Cx43. The phosphorylation status of Cx43 at site Ser368 and intracellular Ca(2+) oscillation were also studied. RESULTS: Obvious changes in electrocardiographic patterns were found in rats following MDMA administration. They were characterized by prolonged QRS duration associated with increased amplitude of QRS complex. The heart rates in treated rats were significantly decreased compared to the rats in the control group. The immunohistochemical findings revealed a significant decrease in Cx43 expression. The in vitro study also showed a marked decline in total Cx43 protein associated with reduction of Cx43 mRNA, whereas the phosphorylated Cx43 at Ser368 was increased. Decrease of junctional Cx43 was found correlated with reduction in N cadherin induced by high concentration of MDMA. Additionally, confocal microscopy findings revealed alteration of intracellular calcium oscillation patterns characterized by high frequency and increasing influx Ca(2+). CONCLUSIONS: MDMA reduces expression of cardiac gap junction protein Cx43. The increase of phosphorylation status of Cx43 at Ser368 induced by MDMA is attributed, at least in part, to the Ca(2+)-dependent regulation of protein kinase C (PKC) activity. Our findings provide first evidence of MDMA-mediated changes in those cardiac gap junctions that may underlie MDMA-induced cardiac arrhythmia. PMID- 23747753 TI - Organic anion-transporting polypeptide 1a4 (Oatp1a4) is important for secondary bile acid metabolism. AB - Organic anion transporting polypeptides (human: OATPs; rodent: Oatps) were thought to have important functions in bile acid (BA) transport. Oatp1a1, 1a4, and 1b2 are the three major Oatp1 family members in rodent liver. Our previous studies have characterized the BA homeostasis in Oatp1a1-null and Oatp1b2-null mice. The present study investigated the physiological role of Oatp1a4 in BA homeostasis by using Oatp1a4-null mice. Oatp1a4 expression is female-predominant in livers of mice, and thereby it was expected that female Oatp1a4-null mice will have more prominent changes than males. Interestingly, the present study demonstrated that female Oatp1a4-null mice had no significant alterations in BA concentrations in serum or liver, though they had increased mRNA of hepatic BA efflux transporters (Mrp4 and Ostalpha/beta) and ileal BA transporters (Asbt and Ostalpha/beta). In contrast, male Oatp1a4-null mice showed significantly altered BA homeostasis, including increased concentrations of deoxycholic acid (DCA) in serum, liver and intestinal contents. After feeding a DCA-supplemented diet, male but not female Oatp1a4-null mice had higher concentrations of DCA in serum and livers than their WT controls. This suggested that Oatp1a4 is important for intestinal absorption of secondary BAs in male mice. Furthermore, loss of Oatp1a4 function did not decrease BA accumulation in serum or livers of bile-duct-ligated mice, suggesting that Oatp1a4 is not likely a BA uptake transporter. In summary, the present study for the first time demonstrates that Oatp1a4 does not appear to mediate the hepatic uptake of BAs, but plays an important male-predominant role in secondary BA metabolism in mice. PMID- 23747754 TI - An illusory distortion of moving form driven by motion deblurring. AB - Many visual processes integrate information over protracted periods, a process known as temporal integration. One consequence of this is that objects that cast images that move across the retinal surfaces can generate blurred form signals, similar to the motion blur that can be captured in photographs taken with slow shutter speeds. Subjectively, retinal motion blur signals are suppressed from awareness, such that moving objects seem sharply defined. One suggestion has been that this subjective impression is due to humans not being able to distinguish between focussed and blurred moving objects. Contrary to this suggestion, here we report a novel illusion, and consequent experiments, that implicate a suppressive mechanism. We find that the apparent shape of circular moving objects can be distorted when their rear edges lag leading edges by ~60 ms. Moreover, we find that sensitivity for detecting blur, and for discriminating between blur intensities, is uniformly worse for physical blurs added behind moving objects, as opposed to in-front. Also, it was easier to differentiate between slight and slightly greater physical blurs than it was to differentiate between slight blur and the absence of blur, both behind and in-front of moving edges. These 'dipper' functions suggest that blur signals must reach a threshold intensity before they can be detected, and that the relevant threshold is effectively elevated for blur signals trailing behind moving contours. In combination, these data suggest moving objects look sharply defined, at least in part, because of a functional adaptation that actively suppresses motion blur signals from awareness. PMID- 23747756 TI - Epigenetic modifications as new targets for liver disease therapies. AB - An important discovery from the human genome mapping project was that it is comprised of a surprisingly low number of genes,with recent estimates suggesting they are as few as 25,000 [1].This supported an alternative hypothesis that our complexity in comparison with lower order species is likely to be determined by regulatory mechanisms operating at levels above the fundamental DNA sequences of the genome [2]. One set of mechanisms that dictate tissue and cellular complexity can be described by the overarching term "epigenetics". In the 1940s, Conrad Waddington described epigenetics as "the branch of biology which studies the causal interactions between genes and their products which bring the phenotype into being". Today we understand epigenetics as a gene regulatory system comprised of 3 major mechanisms including DNA modifications (e.g., methylation), use of histone variants and post-translational modifications of the amino acid tails of histones and non-coding RNAs of which microRNAs are the best characterized [3,4]. Together, these mechanisms orchestrate numerous sets of chemical reactions that switch parts of the genome on and off at specific times and locations.Epigenetic marks, or the epigenome, exhibit a high degree of cellular-specificity and developmental or environmentally driven dynamic plasticity. Due to being at the interface between genome and the environment, the epigenome evolves at a very high rate compared to genetic mutations. Indeed, the differences in the epigenome account for most of the phenotypic uniqueness between closely related species, especially primates. More interestingly,the epigenetic changes, or epimutations, within an individual are not only maintained over cellular generations, but may also be transmitted between generations, such that adaptive epimutations generated in response to a particular environmental cue can influence phenotypes in our children and grandchildren [5]. PMID- 23747755 TI - IFN-gamma inhibits liver progenitor cell proliferation in HBV-infected patients and in 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet-fed mice. AB - BACKGROUND & AIMS: Proliferation of liver progenitor cells (LPCs) is associated with inflammation and fibrosis in chronic liver diseases. However, how inflammation and fibrosis affect LPCs remains obscure. METHODS: We examined the role of interferon (IFN)-gamma, an important pro-inflammatory and anti-fibrotic cytokine, in LPC expansion in HBV-infected patients and in mice challenged with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)- or choline-deficient, ethionine supplemented (CDE) diet as well as in primary LPCs and LPC cell line. RESULTS: The CK19 staining scores correlated with inflammation and fibrosis grades in the livers from 110 HBV-infected patients. Nine-month IFN-gamma treatment decreased LPC numbers, inflammation, and fibrosis in these HBV-infected patients. Similarly, a two-week IFN-gamma treatment also decreased LPC activation in DDC treated mice. Disruption of IFN-gamma or its signaling components (e.g., IFNGR, STAT1, and IRF-1) increased LPC proliferation and liver fibrosis in DDC-fed mice. In contrast, deletion of IFN-gamma did not increase, but rather slightly reduced LPC proliferation in CDE-fed mice. In vitro, IFN-gamma attenuated proliferation of the LPC cell line BMOL and of primary LPCs from wild type mice, but not STAT1( /-) or IRF-1(-/-) mice. Furthermore, co-culture assays suggest that IFN-gamma can indirectly promote LPC proliferation via the activation of macrophages but attenuate it via the inhibition of hepatic stellate cells. CONCLUSIONS: IFN-gamma inhibits LPC expansion via the direct inhibition of LPC proliferation and indirect attenuation of liver fibrosis in the DDC model, but it may also enhance LPC expansion via the promotion of inflammation in the CDE model; thereby playing dual roles in regulating LPC proliferation in vivo. PMID- 23747757 TI - Alkyl protocatechuates as novel urinary biomarkers of exposure to p hydroxybenzoic acid esters (parabens). AB - Human exposure to p-hydroxybenzoic acid esters (parabens) is a concern, owing to adverse health effects of these compounds. Parabens are metabolized and eliminated from the human bodies within a few hours of exposure. In this study, for the first time, methyl- and ethyl-protocatechuates (OH-MeP and OH-EtP) and their parent compounds, methyl- (MeP) and ethyl-parabens (EtP), were determined in urine samples collected from U.S. children and adults. Alkyl protocatechuates were found in almost all urine samples, with median concentrations of 11.8 (OH MeP) and 2.90ng/mL (OH-EtP) in adults, and 5.43 (OH-MeP) and 0.85ng/mL (OH-EtP) in children. In adults, the concentrations of urinary OH-MeP and OH-EtP were higher than the corresponding concentrations of MeP and EtP. Significant correlation between OH-MeP/OH-EtP and MeP/EtP was observed. This is the first report to document hydroxylation of parabens in humans, and to propose hydroxylated metabolites (i.e., alkyl protocatechuates) as alternative biomarkers of exposure to parabens in human biomonitoring studies. The rates of transformation of parabens between children and adults appeared to be different, as evidenced from the slopes of regression between alkyl protocatechuates and parabens. In addition to alkyl protocatechuates, hydroxybenzoic acid (4-HB) and 3,4-dihydroxybenzoic acid (3,4-DHB) were found at considerable levels in the urine samples. The occurrence of a significant proportion of alkyl protocatechuates and 3,4-DHB suggests the need for inclusion of these derivatives in accurate estimation of human exposure to parabens and in epidemiological studies that associate paraben exposure to health outcomes in populations. PMID- 23747758 TI - Reply: all vasodilators are not equal. PMID- 23747759 TI - Prasugrel 5 mg in the very elderly attenuates platelet inhibition but maintains noninferiority to prasugrel 10 mg in nonelderly patients: the GENERATIONS trial, a pharmacodynamic and pharmacokinetic study in stable coronary artery disease patients. AB - OBJECTIVES: This study assessed pharmacodynamic (PD) response to the reduced prasugrel maintenance dose of 5 mg in very elderly (VE) patients (>=75 years of age). BACKGROUND: In the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel Thrombolysis In Myocardial Infarction 38) study prasugrel 10 mg reduced ischemic events versus clopidogrel 75 mg, but increased bleeding in VE patients. METHODS: We examined PD and active metabolite pharmacokinetics (PKs) with prasugrel 5 and 10 mg and clopidogrel 75 mg in a 3-period (12 days each) blinded, crossover study in VE (n = 73; mean: 79 +/- 3 years of age) or (n = 82) nonelderly (NE) (>=45 to <65 years of age; mean: 56 +/- 5 years of age) stable coronary artery disease (CAD) patients receiving background aspirin. Assays included light transmission aggregometry (LTA), VerifyNow P2Y12 (VN-P2Y12), and vasodilator-associated stimulated phosphoprotein (VASP). The primary comparison was noninferiority of maximum platelet aggregation (MPA) comparing the median for prasugrel 5 mg in VE versus the 75th percentile for prasugrel 10 mg in NE, using a pre-specified 1 sided 97.5% confidence interval for the difference <15%. RESULTS: Prasugrel 5 mg in VE met the primary PD noninferiority criterion versus prasugrel 10 mg in NE. For prasugrel 5 mg, MPA was significantly lower (57 +/- 14%) than clopidogrel (63 +/- 14%; p < 0.001) in VE but higher than prasugrel 10 mg in NE (46 +/- 12%; p < 0.001). PD response by LTA, VN-P2Y12, and VASP during all treatments appeared similar between age cohorts. Prasugrel 5 mg resulted in fewer VE poor responders than clopidogrel. Rates of mild bleeding were higher with prasugrel 10 mg but similar for prasugrel 5 mg versus clopidogrel 75 mg. CONCLUSIONS: In aspirin treated stable CAD patients, prasugrel 5 mg in VE attenuated platelet inhibition while meeting pre-specified noninferiority criterion versus prasugrel 10 mg in NE, with significantly better PD response and fewer poor responders compared to clopidogrel 75 mg in VE. (Comparison of Prasugrel and Clopidogrel in Very Elderly and Non-Elderly Patients With Stable Coronary Artery Disease [GENERATIONS]; NCT01107912). PMID- 23747760 TI - Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention. AB - OBJECTIVES: The purpose of this study was to investigate the risk of thrombosis and bleeding according to multiple antithrombotic treatment regimens in atrial fibrillation (AF) patients after myocardial infarction (MI) or percutaneous coronary intervention (PCI). BACKGROUND: The optimal antithrombotic treatment strategy is unresolved in patients with multiple indications. METHODS: A total of 12,165 AF patients hospitalized with MI and/or undergoing PCI between 2001 and 2009 were identified by nationwide registries (60.7% male; mean age 75.6 years). Risk of MI/coronary death, ischemic stroke, and bleeding according to antithrombotic treatment regimen was estimated by Cox regression models. RESULTS: Within 1 year, MI or coronary death, ischemic stroke, and bleeding events occurred in 2,255 patients (18.5%), 680 (5.6%), and 769 (6.3%), respectively. Relative to triple therapy (oral anticoagulation [OAC] plus aspirin plus clopidogrel), no increased risk of recurrent coronary events was seen for OAC plus clopidogrel (hazard ratio [HR]: 0.69, 95% confidence interval [CI]: 0.48 to 1.00), OAC plus aspirin (HR: 0.96, 95% CI: 0.77 to 1.19), or aspirin plus clopidogrel (HR: 1.17, 95% CI: 0.96 to 1.42), but aspirin plus clopidogrel was associated with a higher risk of ischemic stroke (HR: 1.50, 95% CI: 1.03 to 2.20). Also, OAC plus aspirin and aspirin plus clopidogrel were associated with a significant increased risk of all-cause death (HR: 1.52, 95% CI: 1.17 to 1.99 and HR: 1.60, 95% CI: 1.25 to 2.05, respectively). When compared to triple therapy, bleeding risk was nonsignificantly lower for OAC plus clopidogrel (HR: 0.78, 95% CI: 0.55 to 1.12) and significantly lower for OAC plus aspirin and aspirin plus clopidogrel. CONCLUSIONS: In real-life AF patients with indication for multiple antithrombotic drugs after MI/PCI, OAC and clopidogrel was equal or better on both benefit and safety outcomes compared to triple therapy. PMID- 23747761 TI - Currently available versions of genome-wide association studies cannot be used to query the common haptoglobin copy number variant. PMID- 23747762 TI - Cooling the fire of atherosclerosis with heat shock protein 27. PMID- 23747763 TI - An unusual case of saline contrast injected in the anterior cubital vein appearing in the left heart prior to the right heart. PMID- 23747764 TI - Ticagrelor's adenosine-mediated effect and the accuracy of fractional flow reserve. PMID- 23747765 TI - The impact of the environment on diseases and drugs. PMID- 23747766 TI - MicroRNA and myocardial infarction: a mystery turning into glory? PMID- 23747767 TI - Prevalence and prognostic significance of exercise-induced nonsustained ventricular tachycardia in asymptomatic volunteers: BLSA (Baltimore Longitudinal Study of Aging). AB - OBJECTIVES: This study sought to determine the clinical predictors and prognostic significance of exercise-induced nonsustained ventricular tachycardia (NSVT) in a large population of asymptomatic volunteers. BACKGROUND: Prior studies have reported variable risk associated with exercise-induced ventricular arrhythmia. METHODS: Subjects in the BLSA (Baltimore Longitudinal Study of Aging) free of known cardiovascular disease who completed at least 1 symptom-limited exercise treadmill test between 1977 and 2001 were included. NSVT episodes were characterized by QRS morphology, duration, and rate. Subjects underwent follow-up clinical evaluation every 2 years. RESULTS: The 2,099 subjects (mean age: 52 years; 52.2% male) underwent a mean of 2.7 exercise tests, in which 79 (3.7%) developed NSVT with exercise on at least 1 test. The median duration of NSVT was 3 beats (<=5 beats in 84%), and the median rate was 175 beats/min. Subjects with (vs. without) NSVT were older (67 +/- 12 years vs. 51 +/- 17 years, p < 0.0001) and more likely to be male (80% vs. 51%, p < 0.0001) and to have baseline electrocardiographic abnormalities (50% vs. 17%, p < 0.0001) or ischemic ST segment changes with exercise (20% vs. 10%, p = 0.004). Over a mean follow-up of 13.5 +/- 7.7 years, 518 deaths (24.6%) occurred. After multivariable adjustment for age, sex, and coronary risk factors, exercise-induced NSVT was not significantly associated with total mortality (hazard ratio: 1.30; 95% confidence interval: 0.89 to 1.90; p = 0.17). CONCLUSIONS: Exercise-induced NSVT occurred in nearly 4% of this asymptomatic adult cohort. This finding increased with age and was more common in men. After adjustment for clinical variables, exercise-induced NSVT did not independently increase the risk of total mortality. PMID- 23747768 TI - A multicenter, randomized, double-blind, parallel-group, placebo-controlled study of the effects of qili qiangxin capsules in patients with chronic heart failure. AB - OBJECTIVES: The purpose of this study was to assess the effects of qili qiangxin capsules in patients with chronic heart failure (CHF). BACKGROUND: Qili qiangxin capsules are a traditional Chinese medicine that has been approved in China for the treatment of CHF, but the evidence supporting its efficacy remains unclear. METHODS: A total of 512 patients with CHF were enrolled and randomly assigned to receive the placebo or qili qiangxin capsules in addition to their standard medications for the treatment of CHF. The primary endpoint was the reduction or percent change in the plasma N-terminal pro-B-type natriuretic peptide (NT proBNP) level during 12 weeks of treatment. RESULTS: At the 12-week follow-up, a significant reduction in the NT-proBNP level from baseline was observed in both groups, but the qili qiangxin capsule group demonstrated a significantly greater reduction than the placebo group (p = 0.002); 47.95% of patients in the qili qiangxin capsule group demonstrated reductions in NT-proBNP levels of at least 30% compared with 31.98% of patients in the placebo group (p < 0.001). Treatment with qili qiangxin capsules also demonstrated superior performance in comparison to the placebo with respect to New York Heart Association functional classification, left ventricular ejection fraction, 6-min walking distance, and quality of life. CONCLUSIONS: On a background of standard treatment, qili qiangxin capsules further reduced the levels of NT-proBNP. Together, our data suggest that qili qiangxin capsules could be used in combination therapy for CHF. PMID- 23747769 TI - All vasodilators are not equal. PMID- 23747770 TI - Positron emission tomography/computed tomography for diagnosis of prosthetic valve endocarditis. PMID- 23747771 TI - Complete revascularization: a quality-performance metric? PMID- 23747772 TI - Antithrombotic regimens in patients with atrial fibrillation and coronary disease: optimizing efficacy and safety. PMID- 23747773 TI - Timing of hemoconcentration during treatment of acute decompensated heart failure and subsequent survival: importance of sustained decongestion. AB - OBJECTIVES: This study sought to determine if the timing of hemoconcentration influences associated survival. BACKGROUND: Indicating a reduction in intravascular volume, hemoconcentration during the treatment of decompensated heart failure has been associated with reduced mortality. However, it is unclear if this survival advantage stems from the improved intravascular volume or if healthier patients are simply more responsive to diuretics. Rapid diuresis early in the hospitalization should similarly identify diuretic responsiveness, but hemoconcentration this early would not indicate euvolemia if extravascular fluid has not yet equilibrated. METHODS: Consecutive admissions at a single center with a primary discharge diagnosis of heart failure were reviewed (N = 845). Hemoconcentration was defined as an increase in both hemoglobin and hematocrit levels, then further dichotomized into early or late hemoconcentration by using the midway point of the hospitalization. RESULTS: Hemoconcentration occurred in 422 (49.9%) patients (41.5% early and 58.5% late). Patients with late versus early hemoconcentration had similar baseline characteristics, cumulative in hospital loop diuretic administered, and worsening of renal function. However, patients with late hemoconcentration versus early hemoconcentration had higher average daily loop diuretic doses (p = 0.001), greater weight loss (p < 0.001), later transition to oral diuretics (p = 0.03), and shorter length of stay (p < 0.001). Late hemoconcentration conferred a significant survival advantage (hazard ratio: 0.74 [95% confidence interval: 0.59 to 0.93]; p = 0.009), whereas early hemoconcentration offered no significant mortality benefit (hazard ratio: 1.0 [95% confidence interval: 0.80 to 1.3]; p = 0.93) over no hemoconcentration. CONCLUSIONS: Only hemoconcentration occurring late in the hospitalization was associated with improved survival. These results provide further support for the importance of achieving sustained decongestion during treatment of decompensated heart failure. PMID- 23747774 TI - Cardiotonic modulation in heart failure: insights from traditional Chinese medicine. PMID- 23747775 TI - Is the instantaneous wave-free ratio equivalent to fractional flow reserve? PMID- 23747776 TI - Percutaneous transcatheter mitral valve repair: adding life to years. PMID- 23747777 TI - The ATLAS ACS 2-TIMI 51 trial and the burden of missing data: (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2-Thrombolysis In Myocardial Infarction 51). AB - Rivaroxaban is a factor Xa inhibitor that was recently reviewed by the Food and Drug Administration as a potential therapy to reduce the risk of recurrent atherothrombotic events in patients with acute coronary syndromes. Approval of this drug would represent a paradigm shift away from dual antiplatelet therapy toward long-term triple antithrombotic therapy. However, to date, no other experimental anticoagulant agent has demonstrated a favorable risk-benefit profile in this population, in part because of the expected increased risk in major bleeding by combining aspirin, a P2Y12 receptor inhibitor, and an anticoagulant. Approvability of rivaroxaban was considered largely on the basis of the ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2 Thrombolysis In Myocardial Infarction 51) trial, which demonstrated a significant reduction in a composite of cardiovascular death, myocardial infarction, and stroke. Although the primary efficacy endpoint was met, a substantial amount of missing data was observed. We discuss the impact of missing data in this trial, its implications for informative censoring of safety events (major bleeding), and implications for future cardiovascular outcomes trials. PMID- 23747778 TI - Clinical outcomes with drug-eluting and bare-metal stents in patients with ST segment elevation myocardial infarction: evidence from a comprehensive network meta-analysis. AB - OBJECTIVES: The authors investigated the relative safety and efficacy of different drug-eluting stents (DES) and bare metal stents (BMS) in patients with ST-segment elevation myocardial infarction (STEMI) using a network meta-analysis. BACKGROUND: The relative safety of DES and BMS in patients with STEMI continues to be debated, and whether advances have been made in this regard with second generation DES is unknown. METHODS: Randomized controlled trials comparing currently U.S. approved DES or DES with BMS in patients with STEMI were searched using MEDLINE, EMBASE, and Cochrane databases. Information on study design, inclusion and exclusion criteria, sample characteristics, and clinical outcomes was extracted. RESULTS: Twenty-two trials including 12,453 randomized patients were analyzed. At 1-year follow-up, cobalt-chromium everolimus eluting stents (CoCr-EES) were associated with significantly lower rates of cardiac death or myocardial infarction (MI) and stent thrombosis (ST) than BMS. Differences in ST were apparent as early as 30 days and were maintained for 2 years. CoCr-EES were also associated with significantly lower rates of 1-year ST than paclitaxel eluting stents (PES). Sirolimus-eluting stents (SES) were also associated with significantly lower rates of 1-year cardiac death/myocardial infarction than BMS. CoCr-EES, PES, and SES, but not zotarolimus-eluting stents, had significantly lower rates of 1-year target vessel revascularization (TVR) than BMS, with SES also showing lower rates of TVR than PES. CONCLUSIONS: In patients with STEMI, steady improvements in outcomes have been realized with the evolution from BMS to first-generation and now second-generation DES, with the most favorable safety and efficacy profile thus far demonstrated with CoCr-EES. PMID- 23747779 TI - Release kinetics of circulating muscle-enriched microRNAs in patients undergoing transcoronary ablation of septal hypertrophy. AB - OBJECTIVES: This study sought to evaluate exact release kinetics of microRNAs (miRNAs) in acute myocardial infarction (AMI). BACKGROUND: miRNAs may be useful as novel biomarkers in patients with cardiovascular disease, although it is difficult to establish the detailed release kinetics of miRNAs in patients with AMI. METHODS: We analyzed the release kinetics of circulating cardiac-specific (miR-21, miR-208a) and muscle-enriched (miR-1, miR-133a) miRNAs using the TaqMan polymerase chain reaction in patients with hypertrophic obstructive cardiomyopathy who were undergoing transcoronary ablation of septal hypertrophy (TASH), a procedure mimicking AMI. Consecutive patients (n = 21) undergoing TASH were included. Serum samples were collected prior to and at 15, 30, 45, 60, 75, 90, and 105 min and 2, 4, 8, and 24 h after TASH. RESULTS: Circulating concentrations of miR-1 were significantly increased (>3-fold; p = 0.01) after 15 min, with a peak after 75 min (>60-fold; p < 0.001). The miR-21 concentrations were not increased at any time point. Concentrations of miR-133a were significantly increased at 15 min (2.9-fold; p < 0.001) and reached a plateau between 75 and 480 min (>50-fold change). The miR-208a concentrations were elevated at 105 min (>2-fold; p = 0.01), without a further increase. CONCLUSIONS: miR-1, miR-133a, and miR-208a were continuously increased during the first 4 h after the induction of MI. In particular, miR-1 and miR-133a were significantly increased at early time points. These results demonstrate the release kinetics of miRNAs, which are helpful for developing their potential use as biomarkers in patients with acute coronary syndromes. PMID- 23747781 TI - Abdominal contributions to cardiorenal dysfunction in congestive heart failure. AB - Current pathophysiological models of congestive heart failure unsatisfactorily explain the detrimental link between congestion and cardiorenal function. Abdominal congestion (i.e., splanchnic venous and interstitial congestion) manifests in a substantial number of patients with advanced congestive heart failure, yet is poorly defined. Compromised capacitance function of the splanchnic vasculature and deficient abdominal lymph flow resulting in interstitial edema might both be implied in the occurrence of increased cardiac filling pressures and renal dysfunction. Indeed, increased intra-abdominal pressure, as an extreme marker of abdominal congestion, is correlated with renal dysfunction in advanced congestive heart failure. Intriguing findings provide preliminary evidence that alterations in the liver and spleen contribute to systemic congestion in heart failure. Finally, gut-derived hormones might influence sodium homeostasis, whereas entrance of bowel toxins into the circulatory system, as a result of impaired intestinal barrier function secondary to congestion, might further depress cardiac as well as renal function. Those toxins are mainly produced by micro-organisms in the gut lumen, with presumably important alterations in advanced heart failure, especially when renal function is depressed. Therefore, in this state-of-the-art review, we explore the crosstalk between the abdomen, heart, and kidneys in congestive heart failure. This might offer new diagnostic opportunities as well as treatment strategies to achieve decongestion in heart failure, especially when abdominal congestion is present. Among those currently under investigation are paracentesis, ultrafiltration, peritoneal dialysis, oral sodium binders, vasodilator therapy, renal sympathetic denervation and agents targeting the gut microbiota. PMID- 23747780 TI - Double versus standard loading dose of ticagrelor: onset of antiplatelet action in patients with STEMI undergoing primary PCI. PMID- 23747782 TI - Reply: positron emission tomography/computed tomography for diagnosis of prosthetic valve endocarditis. PMID- 23747783 TI - A unique case of a 7-year-old with noonan's syndrome, hypertrophic cardiomyopathy, biventricular outflow tract obstruction, and a right ventricular aneurysm. PMID- 23747784 TI - Reply: To PMID 23312702. PMID- 23747785 TI - Reply: Is the instantaneous wave-free ratio equivalent to fractional flow reserve? PMID- 23747786 TI - Troponin testing for detection of acute myocardial infarction in skeletal muscle disease patients: follow the guidelines. PMID- 23747787 TI - Outcomes after complete versus incomplete revascularization of patients with multivessel coronary artery disease: a meta-analysis of 89,883 patients enrolled in randomized clinical trials and observational studies. AB - OBJECTIVES: This study sought to perform a systematic review and meta-analysis of studies comparing complete revascularization (CR) versus incomplete revascularization (IR) in patients with multivessel coronary artery disease. BACKGROUND: There are conflicting data regarding the benefits of CR in patients with multivessel coronary artery disease. METHODS: We identified observational studies and subgroup analysis of randomized clinical trials (RCT) published in PubMed from 1970 through September 2012 using the following keywords: "percutaneous coronary intervention" (PCI); "coronary artery bypass graft" (CABG); "complete revascularization"; and "incomplete revascularization." Main outcome measures were total mortality, myocardial infarction, and repeat revascularization procedures. RESULTS: We identified 35 studies including 89,883 patients, of whom 45,417 (50.5%) received CR and 44,466 (49.5%) received IR. IR was more common after PCI than after CABG (56% vs. 25%; p < 0.001). Relative to IR, CR was associated with lower long-term mortality (risk ratio [RR]: 0.71, 95% confidence interval [CI]: 0.65 to 0.77; p < 0.001), myocardial infarction (RR: 0.78, 95% CI: 0.68 to 0.90; p = 0.001), and repeat coronary revascularization (RR: 0.74, 95% CI: 0.65 to 0.83; p < 0.001). The mortality benefit associated with CR was consistent across studies irrespective of revascularization modality (CABG: RR: 0.70, 95% CI: 0.61 to 0.80; p < 0.001; and PCI: RR: 0.72, 95% CI: 0.64 to 0.81; p < 0.001) and definition of CR (anatomic definition: RR: 0.73, 95% CI: 0.67 to 0.79; p < 0.001; and nonanatomic definition: RR: 0.57, 95% CI: 0.36 to 0.89; p = 0.014). CONCLUSIONS: CR is achieved more commonly with CABG than with PCI. Among patients with multivessel coronary artery disease, CR may be the optimal revascularization strategy. PMID- 23747788 TI - Increasing diuresis in congestive heart failure: ready for prime time? PMID- 23747789 TI - Percutaneous mitral valve interventions in the real world: early and 1-year results from the ACCESS-EU, a prospective, multicenter, nonrandomized post approval study of the MitraClip therapy in Europe. AB - OBJECTIVES: The purpose of this article is to report early and mid-term outcomes of the ACCESS-EU study (ACCESS-Europe A Two-Phase Observational Study of the MitraClip System in Europe), a European prospective, multicenter, nonrandomized post-approval study of MitraClip therapy (Abbott Vascular, Inc., Santa Clara, California). BACKGROUND: MitraClip has been increasingly performed in Europe after approval; the ACCESS-EU registry provides a snapshot of the real-world clinical demographic data and outcomes. METHODS: A total of 567 patients with significant mitral valve regurgitation (MR) underwent MitraClip therapy at 14 European sites. Mean logistic European System for Cardiac Operative Risk Evaluation at baseline was 23.0 +/- 18.3; 84.9% patients were in New York Heart Association functional class III or IV, and 52.7% of patients had an ejection fraction <=40%. RESULTS: The MitraClip implant rate was 99.6%. A total of 19 patients (3.4%) died within 30 days after the MitraClip procedure. The Kaplan Meier survival at 1 year was 81.8%. Intensive care unit and hospital length of stay was 2.5 +/- 6.5 days and 7.7 +/- 8.2 days, respectively. Single leaflet device attachment was reported in 27 patients (4.8%). There were no MitraClip device embolizations. Thirty-six subjects (6.3%) required mitral valve surgery within 12 months after the MitraClip implant procedure. There was improvement in the severity of MR at 12 months, compared with baseline (p < 0.0001), with 78.9% of patients free from MR, severity of >2+ at 12 months. At 12 months, 71.4% of patients had New York Heart Association functional class II or class I. Six-min walk-test improved 59.5 +/- 112.4 m, and Minnesota-living-with-heart-failure score improved 13.5 +/- 20.5 points. CONCLUSIONS: In the real-world, post approval experience in Europe, patients undergoing the MitraClip therapy are high risk, elderly patients, mainly affected by functional MR. In this patient population, the MitraClip procedure is effective with low rates of hospital mortality and adverse events. PMID- 23747790 TI - Effects of nesiritide and predictors of urine output in acute decompensated heart failure: results from ASCEND-HF (acute study of clinical effectiveness of nesiritide and decompensated heart failure). AB - OBJECTIVES: This study sought to determine if nesiritide increases diuresis in congestive heart failure patients. BACKGROUND: In the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure), 7,141 patients hospitalized with acute decompensated heart failure (ADHF) were randomized to receive nesiritide or placebo for 24 to 168 h, in addition to standard care. There were minimal effects of nesiritide on survival, future hospitalizations, and symptoms. However, whether or not nesiritide increases diuresis in ADHF patients is unknown. METHODS: Urine output was measured in 5,864 subjects; of these, 5,320 received loop diuretics and had dose data recorded. Loop diuretics other than furosemide were converted to furosemide equivalent doses. A total of 4,881 patients had complete data. We used logistic regression models to identify the impact of nesiritide on urine output and the factors associated with high urine output. RESULTS: Median (25th, 75th percentiles) 24-h urine output was 2,280 (1,550, 3,280) ml with nesiritide and 2,200 (1,550, 3,200) ml with placebo (p = NS). Loop diuretic dose (furosemide equivalent) was 80 (40, 140) mg with both nesiritide and placebo. Diuretic dose was a strong predictor of urine output. Other independent predictors included: male sex, greater body mass index, higher diastolic blood pressure, elevated jugular venous pressure, recent weight gain, and lower blood urea nitrogen. The addition of nesiritide did not change urine output. None of the interaction terms between nesiritide and predictors affected the urine output prediction. CONCLUSIONS: Nesiritide did not increase urine output in patients with ADHF. Higher diuretic dose was a strong predictor of higher urine output, but neurohormonal activation (as evidenced by blood urea nitrogen concentration) and lower blood pressure limited diuresis. PMID- 23747791 TI - Electrical storm in idiopathic ventricular fibrillation is associated with early repolarization. AB - OBJECTIVES: This study sought to characterize patients with idiopathic ventricular fibrillation (IVF) who develop electrical storms. BACKGROUND: Some IVF patients develop ventricular fibrillation (VF) storms, but the characteristics of these patients are poorly known. METHODS: Ninety-one IVF patients (86% male) were selected after the exclusion of structural heart diseases, primary electrical diseases, and coronary spasm. Electrocardiogram features were compared between the patients with and without electrical storms. A VF storm was defined as VF occurring >=3 times in 24 h and J waves >0.1 mV above the isoelectric line in contiguous leads. RESULTS: Fourteen (15.4%) patients had VF storms occurring out-of-hospital at night or in the early morning. J waves were more closely associated with VF storms compared to patients without VF storms: 92.9% versus 36.4% (p < 0.0001). VF storms were controlled by intravenous isoproterenol, which attenuated the J-wave amplitude. After the subsidence of VF storms, the J waves decreased to the nondiagnostic level during the entire follow up period. Implantable cardioverter-defibrillator therapy was administered to all patients during follow-up. Quinidine therapy was limited, but the patients on disopyramide (n = 3), bepridil (n = 1), or isoprenaline (n = 1) were free from VF recurrence, while VF recurred in 5 of the 9 patients who were not given antiarrhythmic drugs. CONCLUSIONS: The VF storms in the IVF patients were highly associated with J waves that showed augmentation prior to the VF onset. Isoproterenol was effective in controlling VF and attenuated the J waves, which diminished to below the diagnostic level during follow-up. VF recurred in patients followed up without antiarrhythmic agents. PMID- 23747792 TI - Reply: To PMID 23624205. PMID- 23747793 TI - Radial first: paradox+proficiency=opportunity. PMID- 23747794 TI - Hyperpolarization-activated cyclic nucleotide-gated channels and ventricular arrhythmias in heart failure: a novel target for therapy? PMID- 23747795 TI - First in-human intraoperative imaging of HCC using the fluorescence goggle system and transarterial delivery of near-infrared fluorescent imaging agent: a pilot study. AB - Surgical resections remain the primary curative interventions for hepatocellular carcinoma (HCC). However, lack of real-time intraoperative image guidance confines surgeons to subjective visual assessment of the surgical bed, leading to poor visualization of small positive nodules and the extension of diffuse HCC. To address this problem, we developed a wearable fluorescence imaging and display system (fluorescence goggle) for intraoperative imaging of HCCs in human patients. In this pilot study, both intravenous (IV) and transarterial hepatic (TAH) delivery of indocyanine green (ICG) were explored to facilitate fluorescence goggle-mediated HCC imaging. The results show that all primary tumors in patients (n = 4) who received TAH delivery of ICG were identified successfully by the fluorescence goggle. In addition, 6 satellite tumors were also detected by the goggle, 5 of which were neither identifiable via preoperative magnetic resonance imaging (MRI) and computed tomography (CT) nor by visual inspection and palpation. In the group (n = 5) that received ICG intravenously, only 2 of 6 tumors visible by preoperative MRI or CT were identified with the fluorescence goggle, demonstrating the limitation of this delivery route for a non-tumor-selective imaging agent. Comparative analysis shows that the HCC-to-liver florescence contrast detected by the goggle was significantly greater in patients that received TAH than IV delivery of ICG (P = 0.013). This pilot study demonstrates the feasibility of using the fluorescence goggle to identify multifocal lesions and small tumor deposits using TAH ICG delivery in HCC patients. PMID- 23747797 TI - A novel complex insertion-deletion mutation in the FOXC2 gene in a Japanese patient with lymphedema-distichiasis syndrome. PMID- 23747796 TI - Leucine rich amelogenin peptide alters ameloblast differentiation in vivo. AB - Highly mineralized tooth enamel develops from an extracellular matrix chiefly comprised of amelogenins formed by splicing of 7 (human) or 9 (rodent) exons secreted from specialized epithelial cells known as ameloblasts. Here we examined the role of the 59 amino acid alternatively spliced amelogenin known as leucine rich amelogenin peptide (LRAP) on enamel formation, using transgenic murine models in which LRAP overexpression is driven by an amelogenin promoter (TgLRAP). Beginning in the secretory stage of mouse amelogenesis, we found a reduced thickness of enamel matrix and a loss of Tomes' processes, followed by upregulated amelogenin mRNA expression, inhibited amelogenin secretion and loss of cell polarity. In the presecretory stage (P0) amelogenin m180 mRNA expression was increased 58 fold along with a 203 fold increase in MMP-20 expression and 3.5 and 3.2 fold increased in respectively enamelin and ameloblastin. When LRAP was overexpressed on an amelogenin knockout mouse model, the ameloblasts were not affected. Further, expression of the global chromatin organizer and transcription factor SATB1 was reduced in secretory stage TgLRAP ameloblasts. These findings identify a cellular role for LRAP in enamel formation that is not directly related to directing enamel crystal formation as is reported to be the primary function of full length amelogenins. The effect of LRAP overexpression in upregulating amelogenins, MMP-20 and SATB1, suggests a role in protein regulation critical to ameloblast secretion and matrix processing, to form a mineralized enamel matrix. PMID- 23747798 TI - Human erythrocytes as drug carriers: loading efficiency and side effects of hypotonic dialysis, chlorpromazine treatment and fusion with liposomes. AB - Human red blood cells (RBCs) are emerging as a highly biocompatible microparticulate drug delivery system. So far, drugs have commonly been loaded into freshly isolated RBCs using rather disruptive methods based on hypotonic shock, and assessment of damage was restricted to hemolysis. Here, we investigated loading of RBCs from blood bank units with enzymes of various molecular weights using hypotonic dialysis (HD), pretreatment with chlorpromazine (CPZ) and fusion with liposomes. The latter two techniques have received little attention in RBC loading so far. Along with loading efficiency, all methods were tested for the induction of side effects. Very importantly, next to hemolysis, we also addressed morphological changes and phosphatidyl serine (PS) exposure, which has been recognized as a critical parameter associated with premature RBC removal and induction of transfusion-related pathologies. The efficiency of loading using hypotonic dialysis decreased with the molecular weight of the enzyme. For liposomes and chlorpromazine, loading efficiencies were higher and independent of enzyme molecular weights. While hypotonic dialysis always induced a high degree of hemolysis, irreversible modifications in the morphology of the cells and PS exposure, the side effects that were induced by loading using CPZ and liposomes were limited. In particular, PS exposure, although high immediately after treatment, returned to physiological levels after recovery. Retention and deformability studies using a spleen-mimicking device showed that RBCs treated with CPZ and liposomes behave like physiological RBCs, while HD led to very fragile and poorly deformable RBCs. PMID- 23747799 TI - A cytokine network involving brain-borne IL-1beta, IL-1ra, IL-18, IL-6, and TNFalpha operates during long-term potentiation and learning. AB - We have previously shown that long-term potentiation (LTP) induces hippocampal IL 1beta and IL-6 over-expression, and interfering their signalling either inhibits or supports, respectively, LTP maintenance. Consistently, blockade of endogenous IL-1 or IL-6 restricts or favours hippocampal-dependent memory, effects that were confirmed in genetically manipulated mice. Since cytokines are known for their high degree of mutual crosstalk, here we studied whether a network of cytokines with known neuromodulatory actions is activated during LTP and learning. We found that, besides IL-1beta and IL-6, also IL-1 receptor antagonist (IL-1ra) and IL 18, but not TNFalpha are over-expressed during LTP maintenance in freely moving rats. The increased expression of these cytokines is causally related to an increase in synaptic strength since it was abrogated when LTP was interfered by blockade of NMDA-glutamate receptors. Likewise, IL-1 and IL-6 were found to be over-expressed in defined regions of the hippocampus during learning a hippocampus-dependent task. However, during learning, changes in IL-18 were restricted to the dorsal hippocampus, and no differences in TNFalpha and IL1-ra expression were noticed in the hippocampus. Noticeably, IL-1ra transcripts were significantly reduced in the prefrontal cortex. The relation between cytokine expression and learning was causal because such changes were not observed in animals from a pseudo-trained group that was subject to the same manipulation but could not learn the task. Taken together with previous studies, we conclude that activation of a cytokine network in the brain is a physiologic relevant phenomenon not only for LTP maintenance but also for certain types of learning. PMID- 23747800 TI - Rhipicephalus microplus lipocalins (LRMs): genomic identification and analysis of the bovine immune response using in silico predicted B and T cell epitopes. AB - The attachment to host skin by Rhipicephalus microplus larvae induces a series of physiological events at the attachment site. The host-parasite interaction might induce a rejection of the larvae, as is frequently observed in Bos taurus indicus cattle, and under certain conditions in Bos taurus taurus cattle. Ticks deactivate the host rejection response by secreting specific proteins and lipids that play an essential role in manipulation of the host immune response. The available genomic information on the R. microplus tick was mined using bioinformatics approaches to identify R. microplus lipocalins (LRMs). This in silico examination revealed a total of 12 different putative R. microplus LRMs (LRM1-LRM12). The identity of the LRM family showed high sequence variability: from 6% between LRM7 and LRM8 to 55.9% between LRM2 and LRM6. However, the three dimensional structure of the lipocalin family was conserved in the LRMs. The B and T cell epitopes in these lipocalins were then predicted, and six of the LRMs (5, 6, 9, 10, 11 and 12) were used to examine the host immune interactions with sera and peripheral blood mononuclear cells (PBMCs) collected from tick susceptible and tick-resistant cattle challenged with R. microplus. On days 28-60 after tick infestation, the anti-LRM titres were higher in the resistant group compared with the susceptible cattle. After 60 day, the anti-LRM titres (except LRM9 and LRM11) decreased to zero in the sera of both the tick-resistant and tick susceptible cattle. Using cell proliferation assays, the PBMCs challenged with some of the predicted T cell epitopes (LRM1_T1, T2; LRM_T1, T2 and LRM12_T) exhibited a significantly higher number of IFN-gamma-secreting cells (Th1) in tick-susceptible Holstein-Friesians compared with tick-resistant Brahman cattle. In contrast, expression of the Th2 cytokine (IL-4) was lower in Holstein Friesians cattle compared with Brahman cattle. Moreover, this study found that LRM6, LRM9 and LRM11 play important roles in the mechanism by which R. microplus interferes with the host's haemostasis mechanisms. PMID- 23747801 TI - Spatial variation in the phylogenetic structure of flea assemblages across geographic ranges of small mammalian hosts in the Palearctic. AB - We investigated spatial variation in the phylogenetic structure (measured as a degree of phylogenetic clustering) of flea assemblages across the geographic ranges of 11 Palearctic species of small mammalian hosts and asked whether the phylogenetic structure of the flea assemblage of a host in a locality is affected by (i) distance of this locality from the centre of the host's geographic range, (ii) geographic position of the locality (distance to the equator) and (iii) phylogenetic structure of the entire flea assemblage of the locality. Our results demonstrated that the key factor underlying spatial variation of the phylogenetic structure of the flea assemblage of a host was the distance from the centre of the host's geographic range. However, the pattern of this spatial variation differed between host species and might be explained by their species-specific immunogenetic and/or distributional patterns. Local flea assemblages may also, to some extent, be shaped by environmental filtering coupled with historical events. In addition, the phylogenetic structure of a local within-host flea assemblage may mirror the phylogenetic structure of the entire across-host flea assemblage in that locality and, thus, be affected by the availability of certain phylogenetic lineages. PMID- 23747802 TI - Physical Activity in Pediatric Cancer patients with solid tumors (PAPEC): trial rationale and design. AB - BACKGROUND: This randomized controlled trial on Physical Activity in Pediatric Cancer (PAPEC) was designed to assess the impact of an exercise program on pediatric cancer patients undergoing chemotherapy for solid tumors. METHODS AND DESIGN: 60 pediatric patients of both sexes, aged 4 to 18 years and undergoing treatment for extracranial primary solid tumors will be recruited for this trial. Each participant will be randomly assigned (with blocking on sex) to either an intervention or control (normal care) group. The intervention group will participate in combined inpatient physical training (aerobic + strength) for the duration of neoadjuvant chemotherapy. The intervention will include 3 weekly 60 70 min exercise sessions in the child's room or in a pediatric gym at the hospital, depending on the child's health state. In both groups, determination of several primary (cardio-respiratory fitness, muscle strength, functional capacity, physical activity levels, body weight and quality of life) and secondary outcomes [immune function and inflammatory profile (blood levels of 47 cytokines)] will be made at the following time points: (i) before the exercise intervention (immediately after diagnosis and before treatment onset); (ii) after the exercise intervention (upon termination of neoadjuvant chemotherapy); and (iii) after a detraining period (2 months after the intervention). DISCUSSION: The PAPEC trial will provide relevant new information on biological mechanisms and inform on the potential clinical use of exercise during pediatric cancer treatment as a simple way to prevent future long-term treatment effects and improve the general health state of pediatric cancer patients. PMID- 23747803 TI - Solitary T-cell pseudolymphoma of the breast, treated by PUVA. PMID- 23747804 TI - Design and synthesis of biquinolone-isoniazid hybrids as a new class of antitubercular and antimicrobial agents. AB - Twenty four biquinolone-isoniazid hybrids were designed based on molecular hybridization technique and synthesized via multicomponent cyclocondensation (MCC) approach. All the newly synthesized compounds were screened for their antimicrobial and antitubercular activities. The brine shrimp bioassay was carried out to study the cytotoxicity of the synthesized compounds. Hybrids 7f (MIC = 25 MUg/mL); 7a, 7e and 7m (MIC = 50 MUg/mL); 7g, 7h and 7k (MIC = 62.5 MUg/mL) exhibited excellent antimicrobial activity as compared with standard drugs. Hybrids 7l and 7j displayed 99% inhibition against Mycobacterium tuberculosis bacteria with better LC50 values 35.39 and 34.59 MUg/mL, respectively. These results indicate that the synthesized compounds can act as leads for the development of newer antimicrobial and antitubercular compounds. PMID- 23747805 TI - Synthesis, structure-property relationships and pharmacokinetic evaluation of ethyl 6-aminonicotinate sulfonylureas as antagonists of the P2Y12 receptor. AB - The present paper describes the development of a new series of P2Y12 receptor antagonists based on our previously reported piperazinyl urea series 1 (IC50 binding affinity = 0.33 MUM, aq solubility <0.1 MUM, microsomal CLint (HLM) >=300 MUM/min/mg). By replacement of the urea functionality with a sulfonylurea group we observed increased affinity along with improved stability and solubility as exemplified by 47 (IC50 binding affinity = 0.042 MUM, aq solubility = 90 MUM, microsomal CLint (HLM) = 70 MUM/min/mg). Further improvements in affinity and metabolic stability were achieved by replacing the central piperazine ring with a 3-aminoazetidine as exemplified by 3 (IC50 binding affinity = 0.0062 MUM, aq solubility = 83 MUM, microsomal CLint (HLM) = 28 MUM/min/mg). The improved affinity observed in the in vitro binding assay also translated to the potency observed in the WPA aggregation assay (47: 19 nM and 3: 9.5 nM) and the observed in vitro ADME properties translates to the in vivo PK properties observed in rat. In addition, we found that the chemical stability of the sulfonylureas during prolonged storage in solution was related to the sulfonyl urea linker and depended on the type of solvent and the substitution pattern of the sulfonyl urea functionality. PMID- 23747806 TI - Evaluation of Jatropha isabelli natural products and their synthetic analogs as potential antimalarial therapeutic agents. AB - Protozoal diseases such as malaria are a leading world health concern. We screened a library of fractionated natural products to identify new potential therapeutic leads and discovered that jatrophone (a product of Jatropha isabelli) exerts significant activity against Plasmodium falciparum strains 3D7 and K1. A focused jatrophone-scaffold library was synthesized to evaluate jatrophone's mode of action and identify more selective analogs. Compounds 25 and 32 of this natural product-inspired compound library exhibited micromolar EC50 values against strains 3D7 and K1, thus providing a new antimalarial molecular scaffold. Our report describes an efficient derivatization approach used to evaluate the structure-activity relationship of jatrophone analogs in search of potential new antimalarial agents. PMID- 23747807 TI - An unexpected Dimroth rearrangement leading to annelated thieno[3,2 d][1,2,3]triazolo[1,5-a]pyrimidines with potent antitumor activity. AB - An unusual Dimroth rearrangement occurring in the reaction leading to annelated thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine core allowed the isolation of the linear isomer thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidine. By decorating the linear isomer with the same chains that improved the biological activity of the angular isomers, new annelated thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidines were designed and synthesized. They were selected by the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) for the anticancer screening against a panel of 60 human tumor cell lines. The biological results showed that the new derivatives exhibited strong antiproliferative activity up to nanomolar concentration. In vivo screenings of the most active compound, the N-[2-(1H-imidazol-4-yl)ethyl]-4-(3-phenyl-10-oxo-4,10 dihydrobenzothieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidin-4-yl)butanamide, showed its low toxicity and high potency. PMID- 23747808 TI - Discovery and structure-activity relationships of ent-Kaurene diterpenoids as potent and selective 11beta-HSD1 inhibitors: potential impact in diabetes. AB - The biological screening of a collection of nature occurring diterpenoids against 11beta-HSD1 resulted in the discovery of the lead compound 1b, which pointed to the therapeutic potential for type 2 diabetes. Subsequently, an optimization project was initiated. Starting from compound 1b and its counterpart 2, the hemi synthesis was performed on kaurenic acid scaffolds yielding 36 derivatives. Further evaluations on both human and mouse 11beta-HSD revealed that seven urea derivatives exhibited significant improved potency and selectivity. Especially, the urea 19a has an IC50 (human 11beta-HSD1) = 9.4 nM and selectivity index (human 11beta-HSD) > 10,649. The 2D and 3D binding models of the complex 19a/11beta-HSD1 were generated using docking simulations. Based on the results, the structural-activity relationships (SARs) of compounds 1b and 2 were also discussed. PMID- 23747809 TI - Cytotoxic activity, albumin and DNA binding of new copper(II) complexes with chalcone-derived thiosemicarbazones. AB - [Cu(HL)Cl2] complexes of chalcone-derived thiosemicarbazones were obtained with 3 phenyl-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone (HPyCTPh), complex (1), 3 (4-chlorophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone (HPyCT4ClPh), complex (2), 3-(4-bromophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone (HPyCT4BrPh), complex (3), and 3-(4-nitrophenyl-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone (HPyCT4NO2Ph), complex (4). 1-3 showed interaction with bovine serum albumin (BSA) and deoxyribonucleic acid from calf thymus (CT-DNA). The cytotoxic activities of the thiosemicarbazones and complexes (1-4) were tested against HL60 (wild type human promyelocytic leukemia), Jurkat (human immortalized line of T lymphocyte), MDA-MB 231 (human breast carcinoma) and HCT-116 (human colorectal carcinoma) tumor cell lineages. Upon coordination to copper(II) cytotoxicity significantly increased in Jurkat, MDA-MB 231 and HCT-116 cells. Unlike the free thiosemicarbazones, 1-4 induced DNA fragmentation in solid tumor cells indicating their pro-apoptotic potential. PMID- 23747810 TI - 2-cinnamamido, 2-(3-phenylpropiolamido), and 2-(3-phenylpropanamido)benzamides: synthesis, antiproliferative activity, and mechanism of action. AB - Several new benzamides 4a-q were synthesized by stirring in pyridine the acid chlorides 3a-q with the appropriate anthranilamide derivatives 2a-g. Some of the synthesized compounds were evaluated for their in vitro antiproliferative activity against a panel of 5 human cell lines (K562 human chronic myelogenous leukemia cells, MCF-7 breast cancer cells, HTC-116 and HT26 colon cancer cells and NCI H460 non-small cell lung cancer cells). PMID- 23747811 TI - Design, synthesis, and biological evaluation of novel dipeptide-type SARS-CoV 3CL protease inhibitors: structure-activity relationship study. AB - This work describes the design, synthesis, and evaluation of low-molecular weight peptidic SARS-CoV 3CL protease inhibitors. The inhibitors were designed based on the potent tripeptidic Z-Val-Leu-Ala(pyrrolidone-3-yl)-2-benzothiazole (8; Ki = 4.1 nM), in which the P3 valine unit was substituted with a variety of distinct moieties. The resulting series of dipeptide-type inhibitors displayed moderate to good inhibitory activities against 3CL(pro). In particular, compounds 26m and 26n exhibited good inhibitory activities with Ki values of 0.39 and 0.33 MUM, respectively. These low-molecular weight compounds are attractive leads for the further development of potent peptidomimetic inhibitors with pharmaceutical profiles. Docking studies were performed to model the binding interaction of the compound 26m with the SARS-CoV 3CL protease. The preliminary SAR study of the peptidomimetic compounds with potent inhibitory activities revealed several structural features that boosted the inhibitory activity: (i) a benzothiazole warhead at the S1' position, (ii) a gamma-lactam unit at the S1-position, (iii) an appropriately hydrophobic leucine moiety at the S2-position, and (iv) a hydrogen bond between the N-arylglycine unit and a backbone hydrogen bond donor at the S3-position. PMID- 23747812 TI - PTHrP-induced modifications of the sea bream (Sparus auratus) vertebral bone proteome. AB - Endocrine factors play an essential role in the formation and turnover of the skeleton in vertebrates. In the present study sea bream vertebral bone transcripts for PTH1R and PTH3R were identified and the action of intermittent administration of parathyroid hormone related protein (PTHrP) on the proteome of vertebral bone was analysed. Treatment of immature sea bream (Sparus auratus, n=6) for 5days with homologous recombinant PTHrP(1-125; 150ng/g body weight) modified bone metabolism and caused a significant (p<0.05) reduction in both tartrate resistant acid phosphatase (TRACP) and alkaline phosphatase (ALP) in relation to control fish. However, the ratio of TRACP: ALP in PTHrP treated fish (1.3 to 2.2 cf. control) suggested it had an anabolic response. A sea bream vertebral bone proteome of 157 protein spots was generated and putative identity assigned to 118 (75.2%) proteins of which 72% had homology to proteins/transcripts from teleosts many of which have not previously been reported in teleost bone. Classification of bone proteins using gene ontology revealed those with protein or metal/ion (e.g., calcium, magnesium, zinc) binding (~53%) activities were most abundant. The expression of eight proteins was significantly (p<0.05) modified in the vertebra of PTHrP treated compared to control fish; three were up-regulated, betainehomocystein S-methyltransferase, glial fibrillary acidic protein, parvalbumin beta and five were down-regulated, annexin A5, apolipoprotein A1, myosin light chain 2, fast skeletal myosin light chain 3, troponin C. In conclusion, intermittent administration of PTHrP to sea bream is associated with an anabolic response in vertebral bone metabolism and modifies calcium binding proteins in the proteome. PMID- 23747813 TI - Puerarin attenuates neuronal degeneration in the substantia nigra of 6-OHDA lesioned rats through regulating BDNF expression and activating the Nrf2/ARE signaling pathway. AB - An increasing number of studies suggest that oxidative stress is associated with the Parkinsonian process. This study evaluated the potential neuroprotective role of puerarin (PR) on lesioned substantia nigra (SN) induced by 6-hydroxydopamine (6-OHDA). Data from a rotational test showed that PR treatment significantly decreased apomorphine-induced rotations. Both the dopamine (DA) content in the SN and the endogenous expression of brain-derived neurotrophic factor (BDNF) were also elevated by the treatment. Pathological examination showed that dopaminergic neuronal degeneration in the SN was attenuated by PR treatment. Meanwhile, the contents of gamma-glutamylcysteine synthetase (gamma-GCS), glutathione (GSH) and catalase (CAT) in SN tissue were gradually elevated. Additionally, cytochrome c oxidase (COX) mRNA expression in the SN was markedly up-regulated. At the same time, nuclear factor E2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keapl) levels were progressively increased by the PR treatment. Our findings indicated that puerarin effectively protects against 6-OHDA-mediated oxidative stress injury in SN neurons, in which the underlying mechanisms are involved in modulating BDNF expression and activating the Nrf2/ARE signaling pathway. PMID- 23747815 TI - Screening of Lactobacillus strains for their ability to bind benzo(a)pyrene and the mechanism of the process. AB - In order to investigate the binding ability of Lactobacillus strains to Benzo(a)pyrene (BaP), 15 strains were analysed. L. plantarum CICC 22135 and L. pentosus CICC 23163 exhibited high efficiency in removing BaP from aqueous medium; the binding rates were 66.76% and 64.31%, respectively. This process was affected by temperature, incubation time and pH, and cell viability was not necessary for the binding ability. Additionally, both strains, especially strain CICC 23163 showed high specificity in binding BaP. The cell-BaP complexes were stable in aqueous medium. The mechanism of binding was investigated by examining the binding ability of different components of the microorganism cells. The results revealed that peptidoglycans played an important role in binding BaP and its structural integrity was required. Consequently, we proposed that the mechanism of this process was a physisorption and peptidoglycan was the main binding site. These two strains may be used for dietary detoxification in human diet and animal feed. PMID- 23747814 TI - Changes in splicing factor expression are associated with advancing age in man. AB - Human ageing is associated with decreased cellular plasticity and adaptability. Changes in alternative splicing with advancing age have been reported in man, which may arise from age-related alterations in splicing factor expression. We determined whether the mRNA expression of key splicing factors differed with age, by microarray analysis in blood from two human populations and by qRT-PCR in senescent primary fibroblasts and endothelial cells. Potential regulators of splicing factor expression were investigated by siRNA analysis. Approximately one third of splicing factors demonstrated age-related transcript expression changes in two human populations. Ataxia Telangiectasia Mutated (ATM) transcript expression correlated with splicing factor expression in human microarray data. Senescent primary fibroblasts and endothelial cells also demonstrated alterations in splicing factor expression, and changes in alternative splicing. Targeted knockdown of the ATM gene in primary fibroblasts resulted in up-regulation of some age-responsive splicing factor transcripts. We conclude that isoform ratios and splicing factor expression alters with age in vivo and in vitro, and that ATM may have an inhibitory role on the expression of some splicing factors. These findings suggest for the first time that ATM, a core element in the DNA damage response, is a key regulator of the splicing machinery in man. PMID- 23747816 TI - Escherichia coli-based expression system for the heterologous expression and purification of the elicitin beta-cinnamomin from Phytophthora cinnamomi. AB - Elicitins are sterol carrier proteins from the Oomycete genera Phytophthora and Phytium and elicit a hypersensitive response in many economically important plants, in some cases causing a systemic acquired resistance. Their recombinant expression in bacteria is complicated by the presence of three disulfide bonds in the elicitin structure. In consequence, elicitins have so far only been produced in soluble form by isolation from native Phytophthora or Phytium strains or by recombinant expression in the yeast Pichia pastoris. Here, for the first time, we report the soluble expression of the elicitin beta-cinnamomin from Phytophthora cinnamomi in Escherichia coli by secretion of the protein into the periplasm. beta-Cinnamomin yields have been significantly improved after careful selection of the optimum secretion signal sequence. In total, 17.6 mg beta-cinnamomin per liter cell culture have been obtained in shake flasks with the secretion signal sequence of the maltose-binding protein MalE from E. coli. Furthermore, by making use of a C-terminal His-tag, beta-cinnamomin purification has been significantly simplified with only one step of immobilized metal ion affinity chromatography yielding protein of high purity (>90%). The established protocol has further been successfully applied to the soluble expression of another elicitin. PMID- 23747817 TI - Potentially toxic contamination of sediments, water and two animal species in Lake Kalimanci, FYR Macedonia: relevance to human health. AB - The objectives of the research were: (1) to examine the concentrations of metals in Vimba melanops and Rana temporaria and (2) to evaluate the potential risks of the contaminated organisms to human health in Makedonska Kamenica region. Analyses identified high levels of Cr, Hg, Ni and Pb in studied animals, which also exceeded their permissible levels in food. In sediment and soil samples, levels of Cd, Cu, Cr, Pb, Zn and As were perceived, while Cd, Cu, Ni, Pb, Se and As were increased in water samples. Results of transfer factor revealed that the examined animals had higher bioaccumulation rate from surrounding waters than from sediments or soils. The accomplished Health Risk Index disclosed that studied animals can have considerably high health risks for inhabitants. Conclusively, they could be considered as highly contaminated with metals and can consequently harm human health, especially children in their early development stages. PMID- 23747818 TI - Photochemical trajectory modeling of ozone concentrations in Hong Kong. AB - In this study, tropical cyclones over the East and South China Seas were found to be the most predominant weather conditions associated with the occurrence of high ozone (O3) episodes in Hong Kong in 2005-2009. A photochemical trajectory model coupled with Master Chemical Mechanism (MCM) was adapted to simulate the O3 concentrations during two O3 pollution episodes. The results agreed well with the observed data. A representative backward air mass trajectory was used to determine the contribution of each volatile organic compound (VOC) to the O3 levels. After taking into account both reactivity and mass emission of each VOC, 10 species were found to be the key O3 precursors in Hong Kong. Further analysis identified solvent related products accounting for 70% of the modeled O3 concentration in Hong Kong. The results highlight the importance of considering together reactivity and source sector emissions in developing targeted VOC reduction for O3 abatement strategies. PMID- 23747819 TI - Volatile organic compounds (VOCs) in air from Nisyros Island (Dodecanese Archipelago, Greece): Natural versus anthropogenic sources. AB - This study presents the chemical composition of VOCs in air and gas discharges collected at Nisyros Island (Dodecanese Archipelago, Greece). The main goals are i) to discriminate between natural and anthropogenic VOC sources and ii) to evaluate their impact on local air quality. Up to 63 different VOCs were recognized and quantitatively determined in 6 fumaroles and 19 air samples collected in the Lakki caldera, where fumarolic emissions are located, and the outer ring of the island, including the Mandraki village and the main harbor. Air samples from the crater area show significant concentrations of alkanes, alkenes, cyclic, aromatics, and S- and O-bearing heterocycles directly deriving from the hydrothermal system, as well as secondary O-bearing compounds from oxidation of primary VOCs. At Mandraki village, C6H6/Sigma(methylated aromatics) and Sigma(linear)/Sigma(branched) alkanes ratios <1 allow to distinguish an anthropogenic source related to emissions from outlet pipes of touristic and private boats and buses. PMID- 23747820 TI - Using a toxicokinetics approach to explain the effect of soil pH on cadmium bioavailability to Folsomia candida. AB - The aim of this study was to improve our understanding of metal bioavailability in soil by linking the biotic ligand approach with toxicokinetics modelling. We determined cadmium bioaccumulation kinetics in Folsomia candida (Collembola) as a function of soil pH. Animals were exposed for 21 days to LUFA 2.2 soil at 5 or 20 MUg Cd g(-1) dry soil followed by 21 days elimination in clean soil. Internal cadmium concentrations were modelled using a first-order one-compartment model, relating uptake rate constants (k1) to total soil, water or 0.01 M CaCl2 extractable and porewater concentrations. Based on total soil concentrations, k1 was independent of soil pH while it strongly increased with increasing pH based on porewater concentrations explaining the reduced competition of H(+) ions making cadmium more bioavailable in pore water at high pH. This shows that the principles of biotic ligand modelling are applicable to predict cadmium accumulation kinetics in soil-living invertebrates. PMID- 23747821 TI - Effects of copper on invertebrate-sediment interactions. AB - Toxicants potentially decouple links between biodiversity and ecosystem processes. This study aimed to evaluate how toxicants affect invertebrate bioturbation and decomposition. Effects of copper on functionally distinct macrofaunal species (Asellus aquaticus and Tubifex spp.), decomposition (release of dissolved organic carbon, DOC) and Average Metabolic Response (AMR) and Community Metabolic Diversity (CMD) of bacteria were determined in 5-day microcosm experiments. Bioturbation was assessed as sediment redox potential (Eh) profiles. Concentration-response curves of the functional parameters DOC, and the faunal mediated AMR and CMD in the presence of Tubifex spp. depended on Tubifex spp. survival, i.e. similar EC50 values for both endpoints. In contrast, functional parameters in the presence of A. aquaticus were more sensitive than survival. Sediment Eh-profiles showed that reduced decomposition was caused by reduced sediment reworking by A. aquaticus at sub-lethal copper concentrations. These observations hint at a decoupling of invertebrate community structure and ecosystem functioning upon stress. PMID- 23747822 TI - Overexpression of Ten-m3 in the retina alters ipsilateral retinocollicular projections in the wallaby (Macropus eugenii). AB - Retinal projections to the superior colliculus are organised into retinotopic maps. Binocular vision requires that inputs from the two eyes map in register with each other. Studies in mice lacking Ten-m3, a homophilic transmembrane protein, indicate that it plays a key role in this process by influencing ipsilateral projections. The postnatal, ex utero development of the wallaby allows the targeted manipulation of molecules of interest during development. The distribution of mRNA for Ten-m3 in the retina and superior colliculus of the wallaby, and the effects of its spatiotemporally restricted retinal overexpression was investigated, in particular on the mapping of ipsilateral projections. Quantitative polymerase chain reaction found that Ten-m3 mRNA is expressed at relatively higher levels in the retina and colliculus early in development. Further, it is higher in ventral than dorsal retina, and increased in the retinotopically corresponding medial compared to lateral superior colliculus. In situ hybridisation demonstrated an increasing dorsoventral gradient in retinal ganglion cells was matched to an increasing lateromedial gradient in the superior colliculus. Overexpression of Ten-m3 by in vivo retinal electroporation produced an increase in ipsilateral projections to the binocular rostromedial colliculus, fitting with the proposal that Ten-m3 mediates mapping by attractant homophilic interactions. Retrograde labelling of the projection from this region suggested that overexpression produces a shift in the axons of existing ipsilaterally projecting ganglion cells rather than a rerouting of the axons of contralaterally projecting cells. Retinal manipulation of Ten-m3 levels produces changes in ipsilateral mapping, supporting a role for it in binocular mapping. PMID- 23747823 TI - A structural equation model relating oral condition, denture quality, chewing ability, satisfaction, and oral health-related quality of life in complete denture wearers. AB - OBJECTIVES: To investigate the relationship between mandibular ridge form, stability and retention of mandibular complete denture, accuracy of jaw relation recording, patients' perception of chewing ability, satisfaction with dentures and oral health-related quality of life (OHRQoL) in complete denture wearers. METHODS: A total of 183 edentulous patients, who visited the Dental Hospital of Tokyo Medical and Dental University for new complete dentures, were recruited. Oral examination was performed. Cawood and Howell's method was used to grade the mandibular ridge form. The stability and retention of the mandibular complete denture were assessed using Kapur method. Accuracy of jaw relation recording was evaluated using a newly developed jaw relation index. Patients' perception of chewing ability was rated using a food intake questionnaire. Patients' satisfaction with complete dentures was assessed on a 100-mm visual analogue scale. OHRQoL was measured using the Japanese version of the Oral Health Impact Profile for edentulous subjects. A structural equation model was constructed based on the hypothesis that oral condition and denture quality would be related to chewing ability, satisfaction and OHRQoL. RESULTS: Significant relationships were found between mandibular ridge form, stability of mandibular complete denture, accuracy of jaw relation recording, perceived chewing ability, satisfaction and OHRQoL. Various fit indices were within acceptable limits. CONCLUSIONS: Oral condition and denture quality were related to patients' perception of chewing ability, satisfaction with dentures and OHRQoL in complete denture wearers. CLINICAL SIGNIFICANCE: A favourable oral condition and denture quality are important for successful complete denture therapy. PMID- 23747824 TI - 3-year clinical effectiveness of one-step adhesives in non-carious cervical lesions. AB - OBJECTIVES: Despite representing an important component of current dental adhesives, HEMA has been said to negatively influence the long-term stability of adhesion to dentine and enamel. The aim of this randomised clinical trial was to evaluate the 3-year clinical performance of two one-step self-etch adhesives. METHODS: Thirty patients had 175 non-carious cervical lesions restored with composite (Gradia Direct Anterior, GC) using either the HEMA-rich adhesive Clearfil Tri-S Bond (C3S; Kuraray) or the HEMA-free adhesive G-Bond (GB; GC). The restorations were evaluated by two examiners at baseline, 6, 12, 24 and 36 months regarding retention, caries recurrence, marginal integrity and discoloration and post-operative sensitivity. The data were statistically analysed with GEE and McNemar tests (p<0.05). RESULTS: The recall rate at 6 and 12 months was 100% and decreased to 96.7% at 24 and 36 months. At 3 years, the retention rate was 93.8% for C3S and 98.8% for GB (p=0.14). A pairwise comparison showed no significant differences between the two adhesives for all the parameters evaluated, irrespective of the recall (p>0.05). After 3 years, both adhesives presented an increase in the percentage of clinically acceptable marginal discoloration (C3S: 32.9% and GB: 26.8%) normally associated to clinically acceptable marginal defects (C3S: 35.8% and GB: 26.5%). Only 1 dentine margin of a GB restoration presented a severe marginal defect (1.2%) and 1 C3S restoration presented caries recurrence. The overall 3-year clinical success rate was 92.6% for C3S and 97.6% for GB (p=0.16). CONCLUSION: Both one-step self-etch adhesives presented an equally favourable clinical effectiveness at 3 years. CLINICAL SIGNIFICANCE: HEMA is a monomer frequently present in dental adhesives in order to increase their wettability and hydrophilicity. However, this monomer negatively influences hydrolytic stability and durability of the adhesive interface complex. In this 3 year clinical trial no significant difference in bonding effectiveness was noticed between a HEMA-rich and HEMA-free one-step adhesive. PMID- 23747825 TI - Response of larval Ephestia kuehniella (Lepidoptera: Pyralidae) to individual Bacillus thuringiensis kurstaki toxins mixed with Xenorhabdus nematophila. AB - Bacillus thuringiensis kurstaki strain BNS3 produces parasporal crystals formed by Cry1Aa, Cry1Ac and Cry2Aa delta-endotoxins. In a previous work, we showed that the latter exhibited individually, a weak insecticidal activity against Ephestia kuehniella. In order to improve their toxicities, we studied the combined effect of each delta-endotoxin with X. nematophila cells on E. kuehniella larvae growth. Xenorhabdus cells were used in combination with spore crystal mixture of the wild strain BNS3, known to be active against E. kuehniella, but no improvement in toxicity was observed. This could be due to the high efficiency of BNS3 crystals against this insect. However, when X. nematophila was combined with each of Cry1Aa, Cry1Ac and Cry2Aa, improvement of toxicity was noticed. The best improvements were obtained with Cry1Ac and Cry2Aa, which are more toxic to E. kuehniella than Cry1Aa. The difference in toxicity improvement was attributed to the low affinity of Cry1Aa to BBMV receptors, compared to those of Cry1Ac and Cry2Aa. This synergism between Cry toxins and Xenorhabdus cells could be exploited on control target insect, particularly in case of resistance to Cry toxins. PMID- 23747826 TI - Cross-order and cross-phylum activity of Bacillus thuringiensis pesticidal proteins. AB - The increasing number of Bacillus thuringiensis proteins with pesticidal activities across orders and phyla raises the question how widespread cross activities are and if they are of sufficient biological significance to have implications for ecological safety of those proteins in pest control applications. Cross-activity is reported for 27 proteins and 69 taxa and is substantiated by reasonable evidence (mortality estimates) in 19 cases involving 45 taxa. Cross-activities occur in 13 primary rank families across three classes of pesticidal proteins (Cry, Cyt and Vip), and comprise 13 proteins affecting species across two orders, five proteins affecting three orders and one protein affecting four orders, all within the class Insecta. Cross-activity was quantified (LC50 estimates) for 16 proteins and 25 taxa. Compared to toxicity ranges established for Diptera-, Coleoptera-, Lepidoptera- and Nematoda-active proteins, 13 cross-activities are in the low-toxicity range (10-1000MUg/ml), 12 in the medium - (0.10-10MUg/ml) and two in the high-toxicity range (0.01 0.10MUg/ml). Although cross-activities need to be viewed with caution until they are confirmed through independent testing, current evidence suggests that cross activity of B. thuringiensis pesticidal proteins needs to be taken into consideration when designing and approving their use in pest control applications. PMID- 23747827 TI - Overexpression of stearoyl-coenzyme A desaturase 1 in macrophages promotes reverse cholesterol transport. AB - Stearoyl-coenzyme A desaturase 1 (SCD1) is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids. However, the impact of SCD1 on atherosclerosis remains unclear. The aim of this study was to determine whether SCD1 affects macrophage reverse cholesterol transport (RCT) in mice. Compared to the control, adenoviral-mediated SCD1 overexpression in RAW264.7 macrophages increased cholesterol efflux to HDL, but not to apoA-I, without clear changes in ABCA1, ABCG1 and SR-BI expressions. While knockdown of ABCG1 and SR-BI did not affect the SCD1-induced cholesterol efflux to HDL, SCD1-overexpressing macrophages promoted the formation of both normal- and large-sized HDL in media, accompanying increased apolipoprotein A-I levels in HDL fractions. Transformation to larger particles of HDL was independently confirmed by nuclear magnetic resonance-based lipoprotein analysis. Interestingly, media transfer assays revealed that HDL generated by SCD1 had enhanced cholesterol efflux potential, indicating that SCD1 transformed HDL to a more anti-atherogenic phenotype. To study macrophage RCT in vivo, (3)H-cholesterol-labeled RAW264.7 cells overexpressing SCD1 or the control were intraperitoneally injected into mice. Supporting the in vitro data, injection of SCD1-macrophages resulted in significant increases in (3)H-tracer in plasma, liver, and feces compared to the control. Moreover, there was a shift towards larger particles in the (3)H-tracer distribution of HDL fractions obtained from the mice. In conclusion, macrophage specific SCD1 overexpression promotes overall RCT through increased cholesterol efflux to HDL, suggesting that macrophage SCD1 achieves an anti-atherogenic effect by enhancing RCT. PMID- 23747830 TI - Effects of dopaminergic system activation on feeding behavior and growth performance of the sea bass (Dicentrarchus labrax): a self-feeding approach. AB - Dopamine is synthesized from l-dopa and subsequently processed into norepinephrine and epinephrine. Any excess neurotransmitter can be taken up again by the neurons to be broken down enzymatically into DOPAC. The effect of dopamine on mammalian food intake is controversial. Mice unable to synthesize central dopamine die of starvation. However, studies have also shown that central injection of dopamine inhibits food intake. The effect of dopaminergic system in the fish feeding behavior has been scarcely explored. We report that the inclusion of l-dopa in the diets results in the activation of sea bass central dopaminergic system but also in the significant increase of the hypothalamic serotonin levels. Dietary l-dopa induces a decrease of food intake and feed conversion efficiency that drives a decline of all growth parameters tested. No behavioral effects were observed after l-dopa treatment. l-dopa treatment stimulated central expression of NPY and CRF. It suggests that CRF might mediate l-dopa effects on food intake but also that CRF neurons lie downstream of NPY neurons in the hierarchical forebrain system, thus controlling energy balance. Unexpectedly, dietary administration of haloperidol, a D2-receptor antagonist, cannot block dopamine effects but also induces a decline of the food intake. This decrease seems to be a side effect of haloperidol treatment since fish exhibited a decreased locomotor activity. We conclude that oral l-dopa inhibits sea bass food intake and growth. Mechanism could also involve an increase of hypothalamic serotoninergic tone. PMID- 23747828 TI - High glucose potentiates L-FABP mediated fibrate induction of PPARalpha in mouse hepatocytes. AB - Although liver fatty acid binding protein (L-FABP) binds fibrates and PPARalpha in vitro and enhances fibrate induction of PPARalpha in transformed cells, the functional significance of these findings is unclear, especially in normal hepatocytes. Studies with cultured primary mouse hepatocytes show that: 1) At physiological (6mM) glucose, fibrates (bezafibrate, fenofibrate) only weakly activated PPARalpha transcription of genes in LCFA beta-oxidation; 2) High (11 20mM) glucose, but not maltose (osmotic control), significantly potentiated fibrate-induction of mRNA of these and other PPARalpha target genes to increase LCFA beta-oxidation. These effects were associated with fibrate-mediated redistribution of L-FABP into nuclei-an effect prolonged by high glucose-but not with increased de novo fatty acid synthesis from glucose; 3) Potentiation of bezafibrate action by high glucose required an intact L-FABP/PPARalpha signaling pathway as shown with L-FABP null, PPARalpha null, PPARalpha inhibitor-treated WT, or PPARalpha-specific fenofibrate-treated WT hepatocytes. High glucose alone in the absence of fibrate was ineffective. Thus, high glucose potentiation of PPARalpha occurred through FABP/PPARalpha rather than indirectly through other PPARs or glucose induced signaling pathways. These data indicated L-FABP's importance in fibrate-induction of hepatic PPARalpha LCFA beta-oxidative genes, especially in the context of high glucose levels. PMID- 23747829 TI - Dysregulation of neonatal hippocampal cell genesis in the androgen insensitive Tfm rat. AB - The first two weeks of life are a critical period for hippocampal development. At this time gonadal steroid exposure organizes sex differences in hippocampal sensitivity to activational effects of steroids, hippocampal cell morphology and hippocampus dependent behaviors. Our laboratory has characterized a robust sex difference in neonatal neurogenesis in the hippocampus that is mediated by estradiol. Here, we extend our knowledge of this sex difference by comparing the male and female hippocampus to the androgen insensitive testicular feminized mutant (Tfm) rat. In the neonatal Tfm rat hippocampus, fewer newly generated cells survive compared to males or females. This deficit in cell genesis is partially recovered with the potent androgen DHT, but is more completely recovered following estradiol administration. Tfm rats do not differ from males or females in the level of endogenous estradiol in the neonatal hippocampus, suggesting other mechanisms mediate a differential sensitivity to estradiol in male, female and Tfm hippocampus. We also demonstrate disrupted performance on a hippocampal-dependent contextual fear discrimination task. Tfm rats generalize fear across contexts, and do not exhibit significant loss of fear during extinction exposure. These results extend prior reports of exaggerated response to stress in Tfm rats, and following gonadectomy in normal male rats. PMID- 23747831 TI - Natural selection and population genetic structure of domain-I of Plasmodium falciparum apical membrane antigen-1 in India. AB - Development of a vaccine against Plasmodium falciparum infection is an urgent priority particularly because of widespread resistance to most traditionally used drugs. Multiple evidences point to apical membrane antigen-1(AMA-1) as a prime vaccine candidate directed against P. falciparum asexual blood-stages. To gain understanding of the genetic and demographic forces shaping the parasite sequence diversity in Kolkata, a part of Pfama-1 gene covering domain-I was sequenced from 100 blood samples of malaria patients. Statistical and phylogenetic analyses of the sequences were performed using DnaSP and MEGA. Very high haplotype diversity was detected both at nucleotide (0.998+/-0.002) and amino-acid (0.996+/-0.001) levels. An abundance of low frequency polymorphisms (Tajima's D=-1.190, Fu & Li's D(*) and F(*)=-3.068 and -2.722), unimodal mismatch distribution and a star-like median-joining network of ama-1 haplotypes indicated a recent population expansion among Kolkata parasites. The high minimum number of recombination events (Rm=26) and a significantly high dN/dS of 3.705 (P<0.0001) in Kolkata suggested recombination and positive selection as major forces in the generation and maintenance of ama-1 allelic diversity. To evaluate the impact of observed non-synonymous substitutions in the context of AMA-1 functionality, PatchDock and FireDock protein-protein interaction solutions were mapped between PfAMA-1-PfRON2 and PfAMA-1-host IgNAR. Alterations in the desolvation and global energies of PfAMA-1-PfRON2 interaction complexes at the hotspot contact residues were observed together with redistribution of surface electrostatic potentials at the variant alleles with respect to referent Pf3D7 sequence. Finally, a comparison of P. falciparum subpopulations in five Indian regional isolates retrieved from GenBank revealed a significant level of genetic differentiation (FST=0.084-0.129) with respect to Kolkata sequences. Collectively, our results indicated a very high allelic and haplotype diversity, a high recombination rate and a signature of natural selection favoring accumulation of non-synonymous substitutions that facilitated PfAMA-1-PfRON2 interaction and hence parasite growth in Kolkata clinical isolates. PMID- 23747832 TI - A new approach to synergize academic and guideline-compliant research: the CLARITY-BPA research program. AB - Recently, medical research has seen a strong push toward translational research, or "bench to bedside" collaborations, that strive to enhance the utility of laboratory science for improving medical treatment. The success of that paradigm supports the potential application of the process to other fields, such as risk assessment. Close collaboration among academic, government, and industry scientists may enhance the translation of scientific findings to regulatory decision making. The National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), and U.S. Food and Drug Administration (FDA) developed a consortium-based research program to link more effectively academic and guideline-compliant research. An initial proof-of-concept collaboration, the Consortium Linking Academic and Regulatory Insights on BPA Toxicity (CLARITY-BPA), uses bisphenol A (BPA) as a test chemical. The CLARITY BPA program combines a core perinatal guideline-compliant 2-year chronic toxicity study with mechanistic studies/endpoints conducted by academic investigators. Twelve extramural grantees were selected by NIEHS through an RFA-based initiative to participate in the overall study design and conduct disease-relevant investigations using tissues and animals from the core study. While the study is expected to contribute to our understanding of potential effects of BPA, it also has ramifications beyond this specific focus. Through CLARITY-BPA, NIEHS has established an unprecedented level of collaboration among extramural grantees and regulatory researchers. By drawing upon the strengths of academic and regulatory expertise and research approaches, CLARITY-BPA represents a potential new model for filling knowledge gaps, enhancing quality control, informing chemical risk assessment, and identifying new methods or endpoints for regulatory hazard assessments. PMID- 23747833 TI - Role of heteromeric gap junctions in the cytotoxicity of cisplatin. AB - In several systems, the presence of gap junctions made of a single connexin has been shown to enhance the cytotoxicity of cisplatin. However, most gap junction channels in vivo appear to be heteromeric (composed of more than one connexin isoform). Here we explore in HeLa cells the cytotoxicity to cisplatin that is enhanced by heteromeric gap junctions composed of Cx26 and Cx32, which have been shown to be more selective among biological permeants than the corresponding homomeric channels. We found that survival and subsequent proliferation of cells exposed to cisplatin were substantially reduced when gap junctions were present than when there were no gap junctions. Functional inhibition of gap junctions by oleamide enhanced survival/proliferation, and enhancement of gap junctions by retinoic acid decreased survival/proliferation. These effects occurred only in high density cultures, and the treatments were without effect when there was no opportunity for gap junction formation. The presence of functional gap junctions enhanced apoptosis as reflected in markers of both early-stage and late-stage apoptosis. Furthermore, analysis of caspases 3, 8 and 9 showed that functional gap junctions specifically induced apoptosis by the mitochondrial pathway. These results demonstrate that heteromeric Cx26/Cx32 gap junctions increase the cytotoxicity of cisplatin by induction of apoptosis via the mitochondrial pathway. PMID- 23747834 TI - Transcriptome-wide identification and characterization of the Procambarus clarkii microRNAs potentially related to immunity against Spiroplasma eriocheiris infection. AB - We used the Illumina/Solexa deep sequencing technology to sequence two small RNA libraries prepared from hemocytes of Procambarus clarkii under normal and infection conditions. The high-throughput sequencing approach resulted in approximately 12,801,827 and 8,410,455 raw reads corresponding to 10,949,754 and 6,648,161 high-quality mappable reads for the normal and infected hemocyte samples, respectively. Bioinformatic analyses identified 195 unique miRNAs, including 30 that are conserved in crustaceans, 48 that are novel to crayfish but are present in other arthropods (PN-type), and 117 that are completely new (PC type). Thirty-three miRNAs displayed significant differential expressions between the two hemocyte samples (p < 0.0001). Of these, 15 (45.5%) were significantly up regulated and 18 (54.5%) were significantly down-regulated upon challenge with Spiroplasma eriocheiris. Integrating comparative genomic and bibliomic analysis, of the 33 significant miRNAs identified, 19 were conserved and immune-related in P. clarkii and Eriocheir sinensis infected with S. eriocheiris infection; 24 were conserved and immune-related in P. clarkii and Marsupenaeus japonicus immune response to S. eriocheiris or white spot syndrome virus (WSSV) infection. Function annotation of target genes revealed a broad range of biological processes and signal transduction pathways that regulated by crayfish miRNAs. Thereinto, pcl-miR-34, pcl-miR-7, PN-pcl-let-7, pcl-miR-1, and pcl-miR-2b are highly conserved in vertebrates and invertebrates and function in the similar pathways. To our knowledge, this is the first report of comprehensive identification of P. clarkii miRNAs and of expression analysis of P. clarkii miRNAs after exposure to S. eriocheiris in crayfish, and many miRNAs were differentially regulated under normal and infection conditions. Our results should help develop new control strategies for efficient immune protection against S. eriocheiris infections in crustaceans. PMID- 23747835 TI - HPV vaccine cross-protection: Highlights on additional clinical benefit. AB - Prophylactic human papillomavirus (HPV) vaccines are administered in vaccination programs, targeted at young adolescent girls before sexual exposure, and in catch up programs for young women in some countries. All the data indicate that HPV virus-like particles (VLPs) effectively prevent papillomavirus infections with a high level of antibodies and safety. Since non-vaccine HPV types are responsible for about 30% of cervical cancers, cross-protection would potentially enhance primary cervical cancer prevention efforts. High levels of specific neutralizing antibodies can be generated after immunization with HPV VLPs. Immunity to HPV is type-specific. However, if we consider the phylogenetic tree including the different HPV types, we realize that a certain degree of cross-protection is possible, due to the high homology of some viral types with vaccine ones. The assessment of cross-protective properties of HPV vaccines is an extremely important matter, which has also increased public health implications and could add further value to their preventive potential. The impact of cross-protection is mostly represented by a reduction of cervical intraepithelial neoplasia CIN2-3 more than what expected. In this article we review the mechanisms and the effectiveness of Bivalent (HPV-16/-18) and Quadrivalent (HPV-6/-11/-16/-18) HPV vaccine cross-protection, focusing on the critical aspects and the potential biases in clinical trials, in order to understand how cross-protection could impact on clinical outcomes and on the new perspectives in post-vaccine era. PMID- 23747836 TI - Cost analysis of colposcopy for abnormal cytology in post-treatment surveillance for cervical cancer. AB - OBJECTIVE: The aim of this study was to estimate cost and outcomes associated with colposcopy following abnormal Pap for women with a history of cervical cancer. METHODS: Decision models compared the costs and number of isolated local recurrences (ILR) detected using two strategies, colposcopy and no colposcopy, for women with a history of cervical cancer and low grade or high grade Pap. Clinical data for input were derived from a cohort of women with a history of cervical cancer undergoing surveillance Paps at 2 institutions. Costs were obtained using national reimbursement data. RESULTS: Five hundred fifty-six patients underwent 2900 surveillance Paps. Twenty-seven of 50 women with a low grade Pap underwent colposcopy. One of 3 recurrences in the colposcopy group was an ILR diagnosed colposcopically. Colposcopy following low grade Pap costs $354 more and resulted in a lower rate of diagnosis of ILR compared to no colposcopy (3.7% vs 8.6%). Sixty of 78 women with a high grade Pap underwent colposcopy. Three of 15 recurrences in the colposcopy group were ILR diagnosed colposcopically. Colposcopy following high grade Pap costs $623 more than no colposcopy but resulted in a higher rate of diagnosis of ILR (5% vs 0%; $7481 per additional ILR). CONCLUSIONS: Colposcopy following low or high grade surveillance Pap smear adds substantial cost to the management of women with cervical cancer. Only colposcopy following a high grade Pap is associated with a higher probability that cervical cancer recurrence will be detected when salvageable. These findings support withholding colposcopy for abnormal surveillance Pap tests less than high grade. PMID- 23747837 TI - Distribution and prognosis of molecular breast cancer subtypes defined by immunohistochemical biomarkers in a Spanish population-based study. AB - BACKGROUND: The objective of this study is to analyze the distribution, clinicopathological features, relative survival rate and excess risk of death among females diagnosed with invasive breast cancer and classified by molecular subtype from ten Spanish cancer registries. METHOD: Three thousand four hundred and eighty incident cases of women - mostly diagnosed in 2005 - were classified into five molecular subtypes according to immunohistochemical status of hormonal receptors and HER2 (human epidermal growth factor receptor 2): estrogen receptor (ER) and/or progesterone receptor (PR)+ and HER2-, ER+ and/or PR+ and HER2+, HER2 overexpressed (ER-, PR- and HER2+), triple negative (ER, PR and HER2-) and unclassified (hormonal receptor or/and HER2 unknown). Relative survival rates at 1, 3 and 5years and relative excess risks (RER) of death adjusting for molecular subtype, age, stage and histological grade were estimated. RESULTS: Marked differences in clinicopathological characteristics and relative survival rate were observed between molecular subtypes. Compared with women with ER+ and/or PR+ and HER2-, ER+ and/or PR+ and HER2+ cases had an RER of 1.00 (95% CI: 0.66 to 1.52) after adjusting for age, stage and histological grade, whereas HER2 overexpressed, triple negative and women with unclassified subtypes presented an RER of 1.72 (95% CI: 1.15 to 2.57), 3.16 (95% CI: 2.26 to 4.41) and 2.55 (95% CI: 1.96 to 3.32), respectively. CONCLUSION: The prognostic value of molecular subtype persists when adjusting for age, stage and histological grade. Hormone receptor-positive tumors were associated with a better prognosis when compared with HER2-overexpressed and triple negative subtypes. Further research is required to improve triple negative prognosis. PMID- 23747838 TI - Second-phase validation study of short time exposure test for assessment of eye irritation potency of chemicals. AB - A Short Time Exposure (STE) test is a cytotoxicity test that uses SIRC cells (rabbit corneal cell line) to assess eye irritation potency following a 5-min chemical exposure. This second-phase validation study assessed the predictive capacity of the STE test using 40 coded test substances at three laboratories. A Validation Management Team (VMT) then evaluated the predictivity of the STE test for United Nation (UN) Globally Harmonized System (GHS) categories using 63 test substances including the results of the first-phase validation study. The STE test can assess not only the severe or corrosive ocular irritants (corresponding to the UN GHS Category 1) but also non-irritant (corresponding to UN GHS Non Category) from other toxicity classes, especially for limited types of test substances. The predictivity by STE test, however, was insufficient for identification of UN GHS categories (Category 1, Category 2, or Non Category). These results suggest that the STE test can be recommended as an initial step in a top-down approach to identification of severe irritants and test substances that require classification for eye irritation (UN GHS Category 1) as well as an initial step in a bottom-up approach to identification of test substances that do not require classification for eye irritation (UN GHS Non Category) from other toxicity classes, especially for limited types of test substances. On the other hand, the STE test is not considered adequate for the identification of mild or moderate irritants (i.e., UN GHS Categories 2A and 2B) and severe irritants (UN GHS Category 1). PMID- 23747839 TI - Perioperative characteristics associated with preterm birth in twin-twin transfusion syndrome treated by laser surgery. AB - OBJECTIVE: To identify perioperative risk factors for preterm delivery (PTD) in laser-treated patients with twin-twin transfusion syndrome (TTTS). STUDY DESIGN: Twin-twin transfusion syndrome patients who underwent laser surgery were followed prospectively. Univariate and multivariate analyses were performed to identify gestational and surgical characteristics associated with preterm delivery. RESULTS: Of 318 eligible patients, the mean (SD) gestational age of delivery was 32.8 (4.2) weeks. The number of days from laser surgery to delivery had a bimodal distribution; group I delivered within 21 days and group II delivered after 21 days of surgery. Eighteen patients (5.7%) were in group I and demonstrated the following risk factors for delivery within 21 days: incomplete laser surgery suspected (odds ratio [OR], 11.14; P = .0106), preoperative subchorionic hematoma (OR, 7.92, P = .0361), preoperative cervical length <2.0 cm (OR, 4.71; P = .0117), and recipient's maximum vertical pocket >=14 cm (OR, 3.23; P = .0335). In group II, 92 of 300 patients (30.7%) delivered <32 weeks, and 25 (8.3%) delivered <28 weeks; multivariate logistic regression analyses identified 5 risk factors for delivery <32 weeks: incomplete laser surgery suspected (OR, 10.0; P = .0506); incidental septostomy (OR, 4.4; P = .0009); triplet gestation (OR, 2.6; P = .0689); postoperative membrane detachment (OR, 2.4; P = .0393); and nonposterior placental location (OR, 1.8; P = .0282). CONCLUSION: Timing of delivery after laser for twin-twin transfusion syndrome has a bimodal distribution with distinct gestational and surgical risk factors. This information may be useful in counseling patients and in directing future avenues of research. PMID- 23747840 TI - Beta-amyloid peptides undergo regulated co-secretion with neuropeptide and catecholamine neurotransmitters. AB - Beta-amyloid (Abeta) peptides are secreted from neurons, resulting in extracellular accumulation of Abeta and neurodegeneration of Alzheimer's disease. Because neuronal secretion is fundamental for the release of neurotransmitters, this study assessed the hypothesis that Abeta undergoes co-release with neurotransmitters. Model neuronal-like chromaffin cells were investigated, and results illustrate regulated, co-secretion of Abeta(1-40) and Abeta(1-42) with peptide neurotransmitters (galanin, enkephalin, and NPY) and catecholamine neurotransmitters (dopamine, norepinephrine, and epinephrine). Regulated secretion from chromaffin cells was stimulated by KCl depolarization and nicotine. Forskolin, stimulating cAMP, also induced co-secretion of Abeta peptides with peptide and catecholamine neurotransmitters. These data suggested the co-localization of Abeta with neurotransmitters in dense core secretory vesicles (DCSV) that store and secrete such chemical messengers. Indeed, Abeta was demonstrated to be present in DCSV with neuropeptide and catecholamine transmitters. Furthermore, the DCSV organelle contains APP and its processing proteases, beta- and gamma-secretases, that are necessary for production of Abeta. Thus, Abeta can be generated in neurotransmitter-containing DCSV. Human IMR32 neuroblastoma cells also displayed regulated secretion of Abeta(1-40) and Abeta(1-42) with the galanin neurotransmitter. These findings illustrate that Abeta peptides are present in neurotransmitter-containing DCSV, and undergo co secretion with neuropeptide and catecholamine neurotransmitters that regulate brain functions. PMID- 23747842 TI - Partial least squares and logistic regression random-effects estimates for gene selection in supervised classification of gene expression data. AB - Our main interest in supervised classification of gene expression data is to infer whether the expressions can discriminate biological characteristics of samples. With thousands of gene expressions to consider, a gene selection has been advocated to decrease classification by including only the discriminating genes. We propose to make the gene selection based on partial least squares and logistic regression random-effects (RE) estimates before the selected genes are evaluated in classification models. We compare the selection with that based on the two-sample t-statistics, a current practice, and modified t-statistics. The results indicate that gene selection based on logistic regression RE estimates is recommended in a general situation, while the selection based on the PLS estimates is recommended when the number of samples is low. Gene selection based on the modified t-statistics performs well when the genes exhibit moderate-to high variability with moderate group separation. Respecting the characteristics of the data is a key aspect to consider in gene selection. PMID- 23747843 TI - Application of exogenous mixture of glutathione and stable isotope labeled glutathione for trapping reactive metabolites in cryopreserved human hepatocytes. Detection of the glutathione conjugates using high resolution accurate mass spectrometry. AB - Metabolites (including reactive metabolites) of troglitazone were generated by incubation with cryopreserved human hepatocytes and trapped in the presence of an exogenous mixture of unlabeled and stable isotope labeled (SIL: [1,2-(13)C, (15)N]-glycine) glutathione (GSH/SIL-GSH). The incubation samples were analyzed using liquid chromatography-high resolution accurate mass spectrometry (LC-HRAMS) implemented on a LTQ Orbitrap mass spectrometer. The GSH conjugates of the reactive metabolites were detected via a characteristic mono-isotopic pattern (peaks separated by 3.0037u). Analysis of the incubation samples led to detection of a number of previously described GSH conjugates, as well as two novel methylated GSH conjugates, which were partially characterized based on accurate mass measurements and MS/MS data. The addition of exogenous GSH led to an increase in the apparent level of detected GSH conjugates. Kinetic isotopic measurements showed that the rates of incorporation of exogenous GSH are conjugate-specific. In conclusion, this approach, based on the use of a mixture of GSH/SIL-GSH, allows facile capture and detection of reactive metabolites in human hepatocytes. Moreover, the data suggest that routine addition of glutathione to the assay medium may be advisable for experiments with cryopreserved hepatocytes. PMID- 23747841 TI - Mesenchymal stem cell secretome and regenerative therapy after cancer. AB - Cancer treatment generally relies on tumor ablative techniques that can lead to major functional or disfiguring defects. These post-therapy impairments require the development of safe regenerative therapy strategies during cancer remission. Many current tissue repair approaches exploit paracrine (immunomodulatory, pro angiogenic, anti-apoptotic and pro-survival effects) or restoring (functional or structural tissue repair) properties of mesenchymal stem/stromal cells (MSC). Yet, a major concern in the application of regenerative therapies during cancer remission remains the possible triggering of cancer recurrence. Tumor relapse implies the persistence of rare subsets of tumor-initiating cancer cells which can escape anti-cancer therapies and lie dormant in specific niches awaiting reactivation via unknown stimuli. Many of the components required for successful regenerative therapy (revascularization, immunosuppression, cellular homing, tissue growth promotion) are also critical for tumor progression and metastasis. While bi-directional crosstalk between tumorigenic cells (especially aggressive cancer cell lines) and MSC (including tumor stroma-resident populations) has been demonstrated in a variety of cancers, the effects of local or systemic MSC delivery for regenerative purposes on persisting cancer cells during remission remain controversial. Both pro- and anti-tumorigenic effects of MSC have been reported in the literature. Our own data using breast cancer clinical isolates have suggested that dormant-like tumor-initiating cells do not respond to MSC signals, unlike actively dividing cancer cells which benefited from the presence of supportive MSC. The secretome of MSC isolated from various tissues may partially diverge, but it includes a core of cytokines (i.e. CCL2, CCL5, IL-6, TGFbeta, VEGF), which have been implicated in tumor growth and/or metastasis. This article reviews published models for studying interactions between MSC and cancer cells with a focus on the impact of MSC secretome on cancer cell activity, and discusses the implications for regenerative therapy after cancer. PMID- 23747844 TI - Pregnancy, maternal exposure to hair dyes and hair straightening cosmetics, and early age leukemia. AB - OBJECTIVE: To investigate the association between maternal exposure to hair dyes and hair straightening cosmetics (HDSC) during pregnancy and leukemia at an early age (<2yr., EAL). METHODS: A multicenter hospital-based case-control study was carried out in 13 states in Brazil between 1999 and 2007. Mothers of 176 ALL (acute lymphocytic leukemia) and 55 AML (acute myeloid leukemia) cases and 419 controls were enrolled and interviewed. Data on maternal exposure to HDSC occurring 3months before pregnancy, during pregnancy and during breastfeeding were obtained. Data were also gathered on paternal exposure to HDSC before pregnancy. Unconditional logistic regression was performed and odds ratios (OR) on the association between HDSC use and EAL were obtained after adjustment for hormonal intake during pregnancy, maternal age, education, birth weight, and the child skin color. RESULTS: An adjusted OR of 1.78 (95% C.I. 1.13-2.81) was observed between maternal exposure to HDSC in the first trimester of pregnancy and ALL. Regarding AML, an adjusted OR of 2.43 (95% C.I. 1.13-5.22) was found for maternal exposure to HDSC during breastfeeding. No association between maternal exposure to HDSC during pregnancy and ALL or AML was observed in children with MLL (Mixed Lineage Leukemia) gene rearrangement. CONCLUSIONS: Results in this study seem to support the hypothesis that maternal exposure to HDSC during pregnancy may be involved in the etiology of leukemia in children under 2years of age. PMID- 23747846 TI - Cardiac immune cell remodeling after myocardial infarction. PMID- 23747845 TI - A first principles investigation of aging processes in soman conjugated AChE. AB - We have examined the aging process of soman inhibited AChE using Density functional theory (DFT) calculations. The catalytic serine of AChE can be phosphonylated by the nerve agent soman, and subsequently can undergo an aging process. The consequences of irreversible inhibition of AChE due to the aging process is fatal for mammals. The DFT calculations shed light on some intricate features of aging process of soman inhibited AChE, which has been pondering in the literature. The DFT calculations (M05-2X/6-31G(*) level of theory) performed with the model systems revealed that the dealkylation of pinacolyl group and the methyl migration takes place simultaneously. The role of pre-protonation and electrostatic stabilization by histidine (His440(+)) in catalyzing the aging process of soman inhibited AChE is energetically comparable. The aging process catalyzed by the histidine (His440(+)) residue reduces the free energy of activation by ~14.0kcal/mol, which is in good agreement with the reported experimental results. Further, the calculated results reveal that tryptophan residue (Trp84) of the catalytic anionic subsite (CAS) assists the rearrangement reaction in the rearrangement process via cation-pi interactions. PMID- 23747847 TI - Cancer stem cell in the progression and therapy of pancreatic cancer. AB - Pancreatic cancer (PC) is an aggressive malignancy with a high incidence of distant metastasis and mortality. Emerging evidence has demonstrated that pancreatic cancer stem cells (CSCs), which have the potential to self-renew and are pluripotent, are crucially important in the progression and therapy of PC. The origin of pancreatic CSCs was suggested to be pancreatic acinar cells, centroacinar cells, or acinar-ductal metaplasia. And several CSC-specific markers for pancreatic cancer have been reported, including CD133, CD24, CD44 and CXCR4. Several studies reported the molecular mechanisms regulating human pancreatic CSCs characteristics. In the progression of PC, CSCs are linked with the aggressiveness of PC with association of epithelial to mesenchymal transition (EMT). In the therapy of PC, especially chemotherapy, CSCs offer new insight into PC therapy, especially the mechanism of drug resistance. Therefore, strategies for modulating and treating CSCs can lead to novel targeted therapies for pancreatic cancer. PMID- 23747848 TI - microRNAs in gastric cancer invasion and metastasis. AB - microRNAs (miRNAs) are fundamental gene regulators that can control cell proliferation, differentiation, and apoptosis during tumor development. These molecules can function as oncogenes or tumor suppressors in human cancers. In gastric cancer (GC), miRNAs play a dual role of either promoting or inhibiting cancer invasion and metastasis. In addition, some miRNAs are involved in only the invasion or metastasis, while other miRNAs have multiple functions and participate in invasion, migration and metastasis. In this review, we will discuss the role of miRNAs in the invasion and metastasis of GC. PMID- 23747849 TI - Bone marrow mesenchymal stem cells in hepatocellular carcinoma. AB - Bone marrow mesenchymal stem cells (BMSCs) are non-hematopoietic multipotent stem cells capable of differentiating into mature cells. Studies in animal models have indicated that hepatocellular carcinoma (HCC) may originate from genetically mutated BMSCs. Moreover, it has been shown that BMSCs are influenced by and can modulate their micro-environment via secreted cytokines that promote tumor initiation, growth, and homing to tumor sites. Based on these features, BMSCs have been recognized as a putative target of molecular therapies to treat and prevent HCC. In this review we discuss the role of human BMSCs in HCC pathogenesis and their therapeutic potential. PMID- 23747850 TI - Metachronal propagation of motor activity. AB - A diverse array of biomechanical systems has evolved to satisfy locomotor requirements (reptation, swimming, walking, etc.) and in all cases, successful behabior achievement requires the integrated functioning of various segments, to ensure the appropriate positioning of the different body regions. From comparative studies on a variety of invertebrate and vertebrate organisms, it is now established that the basic motor patterns underlying limb and/or trunk movements during locomotion are driven by central networks of neurons, so-called central pattern generators (CPGs). In limbless animals such as leech, lamprey, snakes... body propulsion is driven by alternate left- right trunk muscle contractions that occur sequentially (or metachronally) along the body length. Here, we highlight some common principles of motor control involving metachronal activity that are shared by multisegmental systems. In a first step we will review systems in which the neural mechanismsthe that underlie modular linear distribution have been extensively studied. Finally, we will review modeling studies that have been performed to better understand the fundamental mechanisms that underlie metachronal propagation. PMID- 23747851 TI - Effects of acute ozone exposure on lung peak allergic inflammation of mice. AB - Asthma exacerbations are often triggered by air pollution, including O3, whereas how patients with asthma exacerbations react to high levels of ambient ozone remain unknown. Here, we investigated the manner in which acute ozone exposure affects the pathophysiological characteristics of an asthma model on the premise of culminated allergic airway inflammation. The asthma model was constructed in mice, and enhanced pause (Penh), total and differential cell number, soluble mediator concentration, histopathology, and Muc5ac mRNA expression in the mice were observed. The results showed that ozone could induce airway hyperresponsiveness (AHR) in controls and an additional enhancement of preexisting AHR in asthmatic mice. When exposed to ozone, the asthmatic mice expressed more neutrophils, TNF-alpha, IL-13, and hyaluronan in bronchoalveolar lavage than controls. The mice with asthma and the controls both showed decreased epithelial cell density in the proximal and distal airways. Ozone aggravated the increased mucus production and mucin gene expression in mice with asthma. These results show that subjects with asthma may react differently to the same high level of ambient ozone, especially for those with asthma exacerbations. PMID- 23747852 TI - Regulation of angiogenesis by phospholipid lysophosphatidic acid. AB - Lysophosphatidic acid (LPA) as a bioactive phospholipid signaling mediator is emerging as an important regulator of endothelial cell functions and angiogenesis. Many studies have shown that LPA is an active player in regulating the processes of endothelial cell migration, proliferation, and differentiation, all essential in angiogenesis. Through modulating angiogenesis associated gene expression, LPA also promotes pathological angiogenesis. Intriguingly, the angiogenic signaling mechanisms mediated by LPA have been linked to specific G protein coupled receptors and down stream MAPK including Erk1/2, p38 and JNK, protein kinase D (PKD-1), Rho kinase (ROCK), and the NF-kappa B signaling pathways. LPA regulates angiogenic responses via a complex signaling network, and LPA signaling is integrated and transduced to the nucleus to coordinate the transcription of different angiogenic genes. Investigation of these mechanisms will provide novel and valuable insights into the understanding of endothelial cell biology and angiogenic programs. This knowledge will facilitate designs for better therapies for the ischemic cardiovascular diseases and malignant tumors. PMID- 23747853 TI - Clathrin, adaptors and disease: insights from the yeast Saccharomyces cerevisiae. AB - Since the identification of clathrin as a vesicular coat protein, numerous studies have contributed to our understanding of the role of clathrin and clathrin-mediated trafficking pathways in cell function. The budding yeast, Saccharomyces cerevisiae, offers a wealth of highly developed approaches that have been applied to study clathrin-mediated trafficking events, most of which are conserved in mammalian cells. Here we review the function of clathrin and clathrin adaptors in yeast. We also discuss the role of these proteins in human disease and how certain pathogens have co-opted trafficking pathways for their own use. These studies highlight the advantages of studying complex trafficking events using yeast as a model. PMID- 23747854 TI - Immunosuppression and the infection caused by gut mucosal barrier dysfunction in patients with early severe acute pancreatitis AB - Few data are available on the relationship between immune response and the infection caused by gut mucosal barrier dysfunction in patients with severe acute pancreatitis (SAP). The aim of this study was to investigate the immune response to gut mucosal barrier dysfunction in patients with early SAP. The results showed that the levels of endotoxin, the lactulose/mannitol (L/M) ratio, the D(-) lactate concentration, the proportion of HLA-DR-positive monocytes, and the expression levels of TNF-alpha, IL-6 and IL-10 all decreased from a high level while the frequency of Tregs increased during the first 14 days. The Th1/Th2 ratio was decreased, with a decreased Th1 and an increased Th2 profile, in the beginning, but it was subsequently increased, with an increased Th1 profile. The data from this study showed that immunosuppression, the shift of the Th1/Th2 balance toward a Th2 response, increased Tregs, and related inflammatory cytokines are involved in the complex process of inflammation and infection caused by gut mucosal barrier dysfunction in patients with early SAP. PMID- 23747855 TI - Decreased saturated fatty acids, total cholesterol and LDL-C in sdd17 mice. AB - SDD17, a delta-15 desaturase from the fungus Saprolegnia can convert arachidonic acid to eicosapentanoic acid in yeast, plant embryos, and mammalian cells. Here, we generated transgenic mice that carried two copies of codon-optimized sdd17 cDNA within a non-coding domain of chromosome 6. RT-PCR analysis revealed that the foreign gene was expressed in the transgenic tissues. Gas chromatography showed that the levels of total unsaturated fatty acids in muscle, liver, and spleen tissues were significantly (p<0.05) increased in transgenic mice compared to non-transgenic mice at 3 or 8 weeks of age. In addition, the serum concentrations of total cholesterol and low-density lipoprotein cholesterol in transgenic females, but not in males, were significantly lower than those in sex matched non-transgenic mice. These results suggest that endogenous sdd17 expression is beneficial for mammalian health and that its effects on fatty acid profiles may differ between sexes. PMID- 23747856 TI - Novel type III interferons produce anti-tumor effects through multiple functions. AB - Type III interferons (IFNs), a new type IFN family consisting of 3 IFN-lambdas, have been identified through a homology search. They include IFN-lambda1, IFN lambda2 and IFN-lambda3, which are also named as interleukin (IL)-29, IL-28A and IL-28B, respectively. The receptor complex of IFN-lambdas is composed of the IL 10 receptor beta (IL-10Rbeta) and a novel IL-28 receptor alpha (IL-28Ralpha). The signal transductions of type III IFNs seem to be similar to those of type I IFNs. Both type I and III IFNs activate Janus activated kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway and transcribe a number of IFN-associated genes. Various types of viruses induce expressions of type III IFNs as well as type I IFNs; however, the biological functions of type III IFNs could be distinct from those of type I IFNs partly because of the tissue restricted expression of the type III receptor complexes. In this review, we encapsulate recent understandings about type III IFNs in particular the anti tumor effects, and discuss possible mechanisms and a potential use for cancer therapy. PMID- 23747857 TI - PPP3CC feedback regulates IP3-Ca2+ pathway through preventing ITPKC degradation. AB - ITPKC, a susceptibility gene of Kawasaki disease, encodes a kinase that negatively regulates intracellular Ca2+ level and inhibits calcineurin-dependent activation of NFAT by phosphorylating IP3. In this study, we identified a novel ITPKC-interacting protein, namely PPP3CC, using yeast two-hybrid. This interaction was further confirmed by GST pull-down and co-immunoprecipitation assays, and fluorescent microscopy showed co-localization of both proteins in the cell cytoplasm. Our functional studies demonstrated that PPP3CC positively influences the protein level of ITPKC, likely by inhibiting phosphorylation of ITPKC and consequently preventing ITPKC from ubiquitin-mediated protein degradation which requires phosphorylation. Importantly, the protein level of PPP3CC negatively correlates with the cellular level of IP3, suggesting a regulatory role of PPP3CC in the IP3-Ca2+ signaling pathway. PMID- 23747858 TI - Cell biology of bacterial sensory modules. AB - Despite their small size, bacterial cells possess very efficient sensory apparatus that allow them to perceive and respond to the external environment with cell movement. In enteric bacteria, these apparatus are complex lattices of different chemoreceptors working in concert and forming clusters positioned at the cell poles. Since the study of chemotaxis has been expanded to other bacterial species, examples of chemosensory systems regulating functions different than taxis have been described and chemoreceptors localizing in ways divergent from the enteric paradigm have been visualized. The scope of this review is to revise and summarize the architecture of different bacterial chemoreceptors. Then, hypotheses will be proposed on how chemoreceptor distribution in cells is coupled to specific functions and life styles in well characterized bacterial model systems, such as Escherichia coli, Rhodobacter sphaeroides, Caulobacter crescentus and Myxococcus xanthus. PMID- 23747859 TI - The shikimate pathway in apicomplexan parasites: implications for drug development. AB - The shikimate pathway provides basic building blocks for a variety of aromatic compounds including aromatic amino acids, ubiquinone, folate and compounds of the secondary metabolism. The seven enzymatic reactions of the pathway lead to the generation of chorismate from simple products of the carbohydrate metabolism, namely erythrose 4-phosphate and phosphoenolpyruvate. The shikimate pathway is present in plants, bacteria, fungi and chromalveolata to which the apicomplexan parasites belong. As it is absent from humans, the enzymes of the shikimate pathway are attractive targets for antimicrobial drug development. Inhibition of the pathway is effective in controlling growth of certain apicomplexan parasites including the malaria parasite Plasmodium falciparum. Yet, despite being an attractive drug target, our knowledge of the shikimate pathway in this parasite group is lacking. The current review summarizes the available information and discusses aspects of the genetic organization of the shikimate pathway in apicomplexan parasites. Compounds acting on shikimate pathway enzymes will be presented and discussed in light of their impact for antiapicomplexan/antiplasmodial drug development. PMID- 23747860 TI - Hematopoietic stem cells improve dopaminergic neuron in the MPTP-mice. AB - Because of their ability for self-renewal and neural differentiation, stem cells are believed to be ideal for cell replacement therapy in Parkinson's disease (PD). Nanofiber-expanded human umbilical cord hematopoietic stem cells (HUHSCs) are advantageous to other stem cells as they provide a source of unlimited stem cell production for clinical application. In this study, we investigated whether 1. nanofiber-expanded HUHSCs are capable of neural differentiation in vitro, and 2. they could improve dopaminergic neuron morphology in the caudate/putamen (CPu) and substantia nigra pars compacta (SNc) of the MPTP-mouse model of PD. When cultured under neural differentiation conditions, nanofiber-expanded HUHSCs were able to undergo neural differentiation in vitro, as determined by gene and protein expression of neural markers such as MAP2, NeuN, HuC, GFAP and Oligo2. Thirty days after a single intracardioventricular injection of HUHSCs to MPTP mice there was a significant recovery of tyrosine hydroxylase (TH) immunostaining in CPu. There was an increase in the size and staining density of TH+ cells in SNc, while their number was unchanged. PMID- 23747861 TI - The apicomplexan inner membrane complex. AB - Dinoflagellates, apicomplexans and ciliates are members of the monophyletic supergroup of Alveolata. The protists of this phylogenetic cluster have adapted to various ecological niches and lifestyles. Dinoflagellates and cilates can be found in any aquatic environment, whereas the phylum Apicomplexa solely comprises intracellular parasites. Despite their diversity all alveolates are united by the presence of membranous vesicles, so called alveoli, located beneath the plasma membrane. In addition to strengthening the cytoskeleton, these vesicles appear to possess taxon-specific functionality. In dinoflagellates and ciliates the alveoli predominantly play a structural role and can function as calcium stores. However, for the Apicomplexa, the alveolar vesicles -here jointly called the inner membrane complex (IMC)- are additionally involved in invasion of the host cell and are important scaffold elements during cytokinesis. Recent studies shed light on the architecture of the apicomplexan IMC and the number and diversity of its constituent proteins. This plethora of proteins and their varying evolutionary origin underlines the versatility of the IMC as a result of the adaption to a parasitic lifestyle. PMID- 23747862 TI - Bactericidal activity of starch-encapsulated gold nanoparticles. AB - We report the bactericidal applications of eco-friendly starch encapsulated gold nanoparticles (St-AuNPs). The mechanism of interaction of the properly characterized St-AuNPs with both Gram negative and Gram positive bacteria were investigated using spread plate assay, transmission electron microscopy (TEM), and fluorescent propidium iodide (PI) exclusion assay. The St-AuNPs were found to possess significant dose dependent antibacterial activity against both types of bacteria. St-AuNPs at 1.2 mg/mL caused 98 % eradication of Gram positive bacteria that was exposed over a period of 12 h. Similarly, 4.8 mg/mL St-AuNPs caused 98 % eradication of Gram negative bacteria over a period of 12h. The St-AuNPs are biocompatible and present a useful solid porous carbohydrate-based polymer vehicle with excellent antimicrobial activity against [Frontiers in Bioscience 18, 982-992, June 1, 2013]. PMID- 23747863 TI - Creation of a suppressive microenvironment by macrophages and cancer-associated fibroblasts. AB - The cancer microenvironment makes up the stroma of the neoplasm and is the tissue that determines tumor growth, progression, and ability to initiate metastases. Because of the role that the cancer microenvironment plays in each stage of tumor development, knowledge about the interactions of the tumor with its microenvironment would seem to be of the utmost importance for developing new treatment strategies. The cancer microenvironment is created by the tissue surrounding the tumor cells and is composed of cells, extracellular matrix, and the proteins of the extracellular matrix. Although tumor cells are capable of penetrating the surrounding stroma, it is the tumor stroma that provides the necessary blood supply and growth factors for the tumor cells that condition tumor growth. In the present review we discuss the role of various cells like tumor-associated macrophages and cancer-associated fibroblasts, expressing RCAS1, B7-H4 molecules, and MT in creating the suppressive profile of the cancer microenvironment and in the cancer microenvironment remodeling that enables both local tumor spread and the creation of metastases. PMID- 23747864 TI - Effects of vitamin C on health: a review of evidence. AB - Vitamin C is an essential dietary nutrient for the biosynthesis of collagen and a co-factor in the biosynthesis of catecholamines, L-carnitine, cholesterol, amino acids, and some peptide hormones. The lack of vitamin C causes scurvy, a pathological condition leading to blood vessel fragility and connective tissue damage due to failure in producing collagen, and, finally, to death as result of a general collapse. Vitamin C is potentially involved also in cancer and cardiovascular diseases prevention. In addition, vitamin C effects on nervous system and chronically ill patients have been also documented. This review attempts to summarize recent and well established advances in vitamin C research and its clinical implications. Since vitamin C has the potential to counteract inflammation and subsequent oxidative damage that play a major role in the initiation and progression of several chronic and acute diseases, it represents a practical tool to administer for the early prevention of these pathologic conditions. PMID- 23747865 TI - Nanoparticles as 'smart' pharmaceutical delivery. AB - Pharmaceuticals in conjunction with nanoparticle delivery systems are growing towards new heights. The aim of this review is to gain a thorough understanding of different types and characteristics of nanoparticle based delivery systems, important properties of delivery systems, pharmaceutical ingredient loading and release in the nanoparticle delivery systems. In this review, we have also highlighted about the promising pharmaceutical deliveries like brain targeted delivery, ocular delivery, oral delivery, dermal and transdermal delivery, cancer chemotherapy, vaccine delivery, nucleic acids delivery and delivery system coupling to implants. A snapshot of the nanoparticle mediated drug deliveries which are commercially available and ongoing clinical trials have been provided. PMID- 23747867 TI - Histone acetylation regulates osteodifferentiation of human dental pulp stem cells via DSPP AB - Dental pulp stem cells (DPSCs) are a unique population of precursor cells isolated from postnatal human dental pulp, with the ability to regenerate a reparative dentin-like complex. We examined the regulation of odontoblast-like differentiation of DPSCs by histone acetylation. Western blot analysis showed that histone H3 acetylation was strongly induced in osteodifferentiation medium. Inhibition of histone acetyltransferase by garcinol reversed osteodifferentiation and mineral formation. Real-time polymerase chain reaction assay indicated that the dentin sialophosphoprotein (DSPP) gene, which is mainly expressed in odontoblasts and preameloblasts in teeth and plays an important role in tooth function, was also down-regulated in garcinol-treated cells. Moreover, lentivirus mediated knockdown of DSPP in human DPSCs was associated with significant inhibition of mineral formation, but not osteoblast differentiation. In conclusion, the results of this study suggest that DSPP positively affects mineral formation, and that odontoblast-like differentiation and maturation of DPSCs can be regulated by histone acetylation of the DSPP gene. PMID- 23747868 TI - Genetic susceptibility to Grave's disease. AB - The variety of clinical presentations of eye changes in patients with Graves' disease (GD) suggests that complex interactions between genetic, environmental, endogenous and local factors influence the severity of Graves' ophthalmopathy (GO). It is thought that the development of GO might be influenced by genetic factors and environmental factors, such as cigarette smoking. At present, however, the role of genetic factors in the development of GO is not known. On the basis of studies with candidate genes and other genetic approaches, several susceptibility loci in GO have been proposed, including immunological genes, human leukocyte antigen (HLA), cytotoxic T-lymphocyte antigen-4 (CTLA-4), regulatory T-cell genes and thyroid-specific genes. This review gives a brief overview of the current range of major susceptibility genes found for GD. PMID- 23747869 TI - New insights into the gene function of osteoporosis. AB - Osteoporosis is a common disease characterized by low bone mass, microarchitectural deterioration of bone tissue and an increased risk of fracture. Population-based and case-control studies have identified polymorphisms in several candidate genes that have been associated with bone mass or osteoporotic fracture, including the vitamin D receptor (VDR), estrogen receptor (ER), oestrogen alpha receptor (ESR), transforming growth factor (TGF)-beta, and type I collagen. The Wnt signaling and receptor activator of nuclear factor kappaB (RANK)/RANK ligand (RANK-L)/osteoprotegerin (OPG) pathways have been shown to play critical roles in determining bone mass and strength. An important aim of future work will be to further clarify the mechanisms involved in the interaction between candidate genes and environmental variables leading to osteoporosis via signaling pathways in individual patients. Hence preventative therapy, particularly gene therapy, could be targeted in patients at greatest risk of osteoporosis. PMID- 23747870 TI - Combined DCE- and DW-MRI in diagnosis of benign and malignant tumors of the tongue. AB - The combination of dynamic contrast-enhanced (DCE) and diffusion-weighted (DW) MRI adds important information to the findings obtained through conventional spin echo MRI. We aimed to determine the value of combined DW- and DCE-MRI in distinguishing benign from malignant tumors of the tongue and mouth floor. The apparent diffusion coefficient (ADC) maps were constructed, and the ADC values of the lesions were calculated from DW-MRI. The slopes were derived from time intensity curves (TICs) from DCE-MRI. The ADC map for malignant tumors was lower compared with the benign lesions. The slope in the malignant tumors was significantly greater compared with the benign lesions. In malignant tumors, the ADC(b=500) threshold of <1.43 10(-3) mm2/s yielded a sensitivity, specificity, and accuracy of 74.6%, 83.3%, and 79.7%, respectively. For benign lesions, a slope threshold of <38.6 yielded a sensitivity, specificity, and accuracy of 80.3%, 74.5%, and 77.9%, respectively. Combined DCE- and DW-MR imaging may provide valuable information that allows for the differentiation between benign lesions and malignant tumors of the tongue and mouth floor. PMID- 23747866 TI - Octamer-binding transcription factors: genomics and functions. AB - The Octamer-binding proteins (Oct) are a group of highly conserved transcription factors that specifically bind to the octamer motif (ATGCAAAT) and closely related sequences in promoters and enhancers of a wide variety of genes. Oct factors belong to the larger family of POU domain factors that are characterized by the presence of an amino-terminal specific subdomain (POUS) and a carboxyl terminal homeo-subdomain (POUH). Eleven Oct proteins have been named (Oct1-11), and currently, eight genes encoding Oct proteins (Oct1, Oct2, Oct3/4, Oct6, Oct7, Oct8, Oct9, and Oct11) have been cloned. Oct1 and Oct2 are widely expressed in adult tissues, while other Oct proteins are much more restricted in their expression patterns. Oct proteins are implicated in crucial and versatile biological events, such as embryogenesis, neurogenesis, immunity, and body glucose and amino acid metabolism. The aberrant expression and null function of Oct proteins have also been linked to various diseases, including deafness, diabetes and cancer. In this review, I will report both the genomic structure and major functions of individual Oct proteins in physiological and pathological processes. PMID- 23747871 TI - Serine racemase: a key player in neuron activity and in neuropathologies. AB - Serine racemase is the pyridoxal 5'-phosphate-dependent enzyme that catalyzes L serine racemisation to D-serine, and L- and D-serine beta-elimination in mammalian brain. D-serine is the essential co-agonist of the N-methyl-D-aspartate receptor, that mediates neurotransmission, synaptic plasticity, cell migration and long term potentiation. High and low D-serine levels have been associated with distinct neuropathologies, aging-related deficits and psychiatric disorders due to either hyper- or hypo-activation of the receptor. Serine racemase dual activity is regulated by ATP, divalent cations, cysteine nitrosylation, post translational modifications, and interactions with proteins that bind either at the N- or C-terminus. A detailed elucidation of the molecular basis of catalysis, regulation and conformational plasticity, as well as enzyme and D-serine localization and neurons and astrocytes cross-talk, opens the way to the development of enzyme inhibitors and effectors for tailored therapeutic treatments. PMID- 23747872 TI - Ligands and receptors of lung surfactant proteins SP-A and SP-D. AB - Surfactant Protein A (SP-A) and D (SP-D) are calcium-dependent collagen containing lectins, also called collectins, which play a significant role in surfactant homeostasis and pulmonary immunity. The role of SP-A and SP-D in immune defence is well- established. They are known to bind to a range of microbial pathogens that invade the lungs and target them for phagocytic clearance by resident alveolar macrophages. They are also involved in the clearance of apoptotic and necrotic cells and subsequent resolution of pulmonary inflammation. To date, the molecular mechanisms by which SP-A and SP-D interact with various immune cells are poorly understood. In spite of overall structural similarity, SP-A and SP-D show a number of functional differences in their interaction with surface molecules of microorganisms and host cells. The aim of this review is to provide an overview of the current knowledge of ligands and receptors that are known to interact with SP-A and SP-D. PMID- 23747873 TI - Mitochondrial dysfunction-related genes in hepatocellular carcinoma. AB - Mitochondria dysfunction is associated with apoptotic resistance and metabolism of tumor cells. Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with multiple genetic aberrations. Certain gene mutations in mitochondria may lead to mitochondrial dysfunction. The p53 family plays a key role in the mitochondrial apoptosis pathway and acts as part of the molecular mechanisms underlying mitochondrial dysfunction in HCC. The novel genes found in the mitochondrial apoptosis signaling pathways, such as mfn2, play a role in the p53 network. In mitochondrial metabolism, expression of certain genes may be associated with apoptosis when they are involved in hepatocarcinogenesis. MicroRNAs have also been found to play a role in this process. Some genes may even exhibit multiple functions in the mitochondrial dysfunction of HCC. In HCC therapy, genes have also been found to influence the chemotherapeutic treatment by killing cells via the apoptosis pathway or autophagy. Investigation of mitochondrial dysfunction-related genes could potentially provide evidence for novel therapies that target HCC. PMID- 23747875 TI - Oxidative stress and neurodegeneration: the yeast model system. AB - In this chapter we are treating yeast cells as a model for oxidative stress response and the consequences of oxidative stress which are one cause for a number of human diseases, including neurodegenerative diseases, which form the main part of this paper. All such model building depends on orthologous relations between highly conserved yeast and human genes, which are easily recognized by sequence comparisons, but much more difficult to prove functionally. Previously we have treated Friedreich's ataxia, while presently we are describing in detail the neuronal ceroid lipofuscinoses, among them Batten disease. A general overview is given how yeast can aid current research in three of the most devastating and at the same time quantitatively most important neurodegenerative diseases of old age: Alzheimer's, Huntington's, and Parkinson's disease. In the ensuing part of the chapter, we describe yeast as model for metabolic regulation and hence as a model for inborn errors of metabolism that are in some instances very faithfully mirrored by introducing the same point mutations into yeast cells which are known from patients. PMID- 23747876 TI - Endothelial progenitor cells and atherosclerosis. AB - Atherosclerosis is due to inflammation and endothelial dysfunction and damage caused by a variety of factors. Dysfunction of endothelial progenitor cells (EPCs) that differentiate into mature endothelial cell contributes to the development of atherosclerosis. Both the number and functionality of EPCs are regulated, particularly in vascular repair. Further elucidation of the role of EPCs in atherosclerosis could potentially enable the development of novel strategies for prevention and treatment of pathological changes in atherosclerosis. PMID- 23747877 TI - Hereditary and sporadic beta-amyloidoses. AB - Cerebral amyloidoses are chronic, progressive neurodegenerative diseases that are caused by the aggregation and deposition of misfolded proteins in the central nervous system, and lead to cognitive deficits, stroke, and focal neurological dysfunction including cerebellar and extrapyramidal signs. Among them, beta amyloidoses are a heterogenous set of conditions characterised by the deposition of beta-amyloid protein in brain parenchyma and/or vessel walls that lead to the development of two main clinico-pathological entities: Alzheimer's disease and cerebral amyloid angiopathy, which may be sporadic or familial, and may also co exist in the same patient. The aim of this review is to describe the most important differences in the pathways leading to parenchymal and cerebrovascular beta-amyloidoses, and the main clinical, neuropathological and biochemical characteristics of the two conditions. It also discusses the phenotypes associated with a series of familial and sporadic beta-amyloidoses in more detail in order to highlight the clinical and neuropathological features that may help to distinguish the different forms of disease. PMID- 23747878 TI - Approaches on genetic polymorphism of Cryptococcus species complex. AB - The Cryptococcus species complex is the significant pathogenic fungi that result in over 1 million cases of cryptococcosis each year in the world. Proper strategy for genetic polymorphism study of the Cryptococcus species complex is crucial to unfold genetic population structure, spread profile and pathogenicity of these pathogenic yeasts worldwide. Currently, an array of approaches, including serotype, PCR fingerprinting, amplified fragment length polymorphisms (AFLP), analysis of DNA sequence, and matrix-assisted laser desorption/ionization time of flight mass spectrometry(MALDI-TOF MS) etc. improved our understanding of genetic diversity or phylogenetic of Cryptococcus species complex. This review synthesizes existing techniques of cryptococcal genetic polymorphism and raises issues that remain to be addressed. PMID- 23747879 TI - BNP and NT-proBNP levels in patients with sepsis. AB - Sepsis is a severe complication of critically ill patients that is characterized by the systemic inflammatory response syndrome (SIRS). The increased levels of B type natriuretic peptide (BNP) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) are related with dysfunction of the cardiovascular system and systemic inflammation. In recent years, BNP and NT-proBNP have been the focus of studies evaluating the severity and prognosis of sepsis. In this study, we will review the role of BNP and NT-proBNP in sepsis. PMID- 23747874 TI - Cerebrospinal fluid biomarkers of Alzheimer's disease in healthy elderly. AB - Numerous studies have shown that Alzheimer's Disease (AD) pathology begins before the onset of clinical symptoms. Because therapies are likely to be more effective if they are implemented early in the disease progression, it is necessary to identify reliable biomarkers to detect AD pathology in the early stages of the disease, ideally in presymptomatic individuals. Recent research has identified three candidate cerebrospinal fluid (CSF) biomarkers that reflect AD pathology: amyloid beta, total tau protein (t-tau), and tau protein phosphorylated at AD specific epitopes (p-tau). They are useful in supporting the AD diagnosis and have predictive value for AD when patients are in the stage of mild cognitive impairment (MCI). However, their predictive utility in cognitively healthy subjects is still being evaluated. We conducted a review of studies published between 1993 and 2011 and summarized their findings on the role of CSF biomarkers for AD in healthy elderly. PMID- 23747880 TI - The role of TLR4 in the pathogenesis of indirect acute lung injury. AB - Indirect acute lung injury (IALI) manifests as rapid-onset respiratory failure following secondary clinical events to the parenchyma or lung vasculature, such as hemorrhage shock, extra-pulmonary sepsis, trauma, ischemia-reperfusion, and burn injury. Accumulating evidence demonstrates the pivotal role of pattern recognition receptors (PRRs) in the innate immune system of lung diseases. Toll like receptor 4 (TLR4), one of the well characterized PRRs, recognizes not only the lipopolysaccharide (LPS) of Gram-negative bacteria, but also the endogenous ligands in IALI. In this review, we summarize a variety of reports concerning the role of TLR4 and IALI pathogenesis. PMID- 23747881 TI - Hepatitis B virus X protein in the proliferation of hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is one of the most common and deadly malignant neoplasms worldwide. Chronic hepatitis B virus (HBV) infection is closely associated with the occurrence of HCC. The HBV genome encodes a ubiquitous transactivator, termed the HBV X protein (HBx), that is essential for HBV replication in vivo. HBx is involved in multiple steps of carcinoma development. Even in the preneoplastic stage, HBx acts as a tumor promoter. HBx participates in several mechanisms that have been linked to cell proliferation, including gene transcription, cell cycle regulation, and several signaling pathways. Moreover, HBx mutants, especially those with mutations in the COOH-terminal end, have been implicated in hepatocarcinogenesis. Therefore, therapeutic strategies targeting HBx could be effective at multiple stages of HCC development, even as early as the preneoplastic stage. PMID- 23747882 TI - Use of the Ussing chamber technique to study nutrient transport by epithelial tissues. AB - The Ussing chamber provides a physiologically relevant system for measuring the transport of ions, nutrients, and drugs across various epithelial tissues. This article outlines the design, structure, principle, and operation of the Ussing chamber, its application in the field of gastrointestinal barrier function and nutrient transport research, as well as its advantages and limitations. This review serves as a practical guide for investigators who are new to the Ussing chamber and should help researchers better understand this valuable method for measuring the transport of electrolytes, organic nutrients, water, and drugs across the small intestine, placenta, and other epithelial tissues. PMID- 23747883 TI - Materials for the onset. A story of necessity and chance. AB - We review the reactions that take place in the HCN/NH2COH/catalysts system. In a vision of origin-of-life as emergence of new properties in complexity, the effectiveness of HCN/NH2COH chemistry is so robust and variegate to look unreasonable. In a logic close to Occamian simplicity, this chemistry embodies necessity. The evolution of the necessary fruits of this chemistry towards organismic level entails Darwinism. The role of chance enters into the process as an answer to evolving environments. PMID- 23747884 TI - Inhibition of ErbB receptors, Hedgehog and NF-kappaB signaling by polyphenols in cancer. AB - Carcinogenesis is a multi-step process triggered by cumulative genetic alterations, which drive the progressive transformation of a normal cell into a cancer cell. Among the signal transduction pathways whose cross-talk plays an important role in neoplastic transformation are those mediated by ErbB receptors, NF-kappaB and the Hedgehog (HH)/glioma-associated oncogene (GLI) cascade. Polyphenols can be employed to inhibit the growth of cancer cells due to their ability to modulate the activity of multiple targets involved in carcinogenesis through simultaneous direct interaction or modulation of gene expression. This review will describe the cross-talk between ErbB receptors, NF-kappaB and the Hedgehog (HH)/glioma-associated oncogene (GLI) signaling pathways and the potential role of polyphenols in inhibiting this dialogue and the growth of cancer cells. PMID- 23747886 TI - Current developments in dural repair: a focused review on new methods and materials. AB - The dura mater, the outermost layer of the meninges covering the brain and spinal cord, is a collagenous connective tissue consisting of numerous collagen fibers, fibroblasts, and few elastic fibers arranged in a parallel form. The dura mater may be damaged by trauma or excising during intracranial or spinal surgery., To date, cerebrospinal fluid leakage followed by dura damage is still an intractable complication due to its various secondary complications , dural repair has recently garnered increased attention with the progress of the spinal surgery and neurosurgery. In this review, we discuss commonly used methods including the addition of sealants, the use of substitutes, and other effective methods and materials. PMID- 23747887 TI - Effects and mechanisms of mechanical stress on secondary fracture healing. AB - Fracture healing is an extremely complex biological reconstruction process, affected by age, hormones, blood supply, degree of injury, mechanical load and many other factors, among which, mechanical stimuli is one of the most important. Bone tissue has a good adaptability to mechanical stress, as biomechanical studies have shown that the local mechanical environment of the fracture site plays a regulatory role in the process of fracture healing. The present article reviews the mechanical mechanisms and effects of mechanical stress on fracture healing. PMID- 23747888 TI - Diagnosis, management, and prevention of prosthetic joint infections. AB - As the number of joint prosthesis replacements worldwide increases exponentially, prosthetic joint infection (PJI), associated with prosthetic implants, has become a devastating complication associated with high morbidity and substantial cost. Patients who develop PJIs typically require extended hospitalization, additional surgical procedures, and long courses of parenteral antimicrobials. Defining the diagnostic criteria is complicated by patient heterogeneity. No single routinely used clinical test has been shown to achieve the ideal sensitivity, specificity, and accuracy for the diagnosis of PJI. Goals of treatment are to eradicate infection, prevent recurrence, and preserve mechanical joint function. Meanwhile, preventive strategies should be used in a timely and appropriate fashion. The present review will discuss the diagnosis, management, and prevention of PJI. PMID- 23747889 TI - Breast cancer genes: beyond BRCA1 and BRCA2. AB - Breast cancer (BC) is a heterogeneous disease. The majority of breast cancer cases (about 70 percent) are considered sporadic. Familial breast cancer (about 30 percent of patients), often seen in families with a high incidence of BC, has been associated with a number of high-, moderate-, and low-penetrance susceptibility genes. Family linkage studies have identified high-penetrance genes, BRCA1, BRCA2, PTEN and TP53, that are responsible for inherited syndromes. Moreover, a combination of family-based and population-based approaches indicated that genes involved in DNA repair, such as CHEK2, ATM, BRIP1 (FANCJ), PALB2 (FANCN) and RAD51C (FANCO), are associated with moderate BC risk. Genome wide association studies (GWAS) in BC revealed a number of common low penetrance alleles associated with a slightly increased or decreased risk of BC. Currently, only high penetrance genes are used in clinical practice on a wide scale. Due to the development of next generation sequencing technologies, it is envisaged that all familial breast cancer genes will be included in the genetic test. However, additional research in clinical management of moderate and low-risk variants is needed before full implementation of multi-gene panel testing into clinical work flows. In this review, we focus on the different components of familial breast cancer risk. PMID- 23747885 TI - Antibody-based therapy of acute myeloid leukemia with gemtuzumab ozogamicin. AB - Antibodies have created high expectations for effective yet tolerated therapeutics in acute myeloid leukemia (AML). Hitherto the most exploited target is CD33, a myeloid differentiation antigen found on AML blasts in most patients and, perhaps, leukemic stem cells in some. Treatment efforts have focused on conjugated antibodies, particularly gemtuzumab ozogamicin (GO), an anti-CD33 antibody carrying a toxic calicheamicin-g 1 derivative that, after intracellular hydrolytic release, induces DNA strand breaks, apoptosis, and cell death. Serving as paradigm for this strategy, GO was the first anti-cancer immunoconjugate to obtain regulatory approval in the U.S. While efficacious as monotherapy in acute promyelocytic leukemia (APL), GO alone induces remissions in less than 25-35% of non-APL AML patients. However, emerging data from well controlled trials now indicate that GO improves survival for many non-APL AML patients, supporting the conclusion that CD33 is a clinically relevant target for some disease subsets. It is thus unfortunate that GO has become unavailable in many parts of the world, and the drug's usefulness should be reconsidered and selected patients granted access to this immunoconjugate. PMID- 23747890 TI - Expression and significance of aquaporins during pregnancy. AB - Outcome of a pregnancy is dependent on high-quality ovulation, successful fertilization, normal embryonic and fetal development, and homeostasis of amniotic fluid. Throughout pregnancy, aquaporins are expressed in the placenta, uterus, adnexa, brain, urinary system, and the lacrimal gland. The regional and temporal regulation of aquaporins play important roles in normal pregnancy, fetal growth, and homeostasis of amniotic fluid volume, and water handling in other organs. The pregnant phenotypes of aquaporin-knockout mice provide direct evidence that aquaporins deficiency results in adverse outcome of pregnancy. Therefore, screening for modulation of aquaporin in abnormal pregnancy becomes desirable. Alteration of aquaporins is seen in preeclampsia, abnormal amniotic fluid volume, chorioamnionitis, and maternal under-nourished pregnancy. Although the functional importance of aquaporins remains to be elucidated, its expression and regulation in abnormal pregnancy suggests potential therapeutic strategies for the treatment of abnormal pregnancy. PMID- 23747891 TI - The canonical Wnt-beta-catenin pathway in development and chemotherapy of osteosarcoma. AB - The canonical Wnt-beta -catenin signaling pathway is a key component of normal skeletal development and disease. Alterations within this signaling pathway have been described in human and canine osteosarcoma (OS); however, debate exists as to whether or not alterations in this pathway contribute to OS development in humans. In metastatic OS, the Wnt-beta-catenin pathway promotes the invasion and migration of OS cells and beta-catenin acts as a biological marker of OS with the potential to metastasize to the lung. The participation of the Wnt-beta-catenin pathway in OS development and metastasis is regulated by several factors, including hormones and alkaline phosphatase (ALP). This pathway is also involved in the resistance of OS to chemotherapy, especially in resistance to all three drugs used in standard chemotherapy, i.e. doxorubicin, cisplatin and methotrexate (MTX). In this review, we will summarize recent findings regarding the Wnt-beta catenin pathway in OS development and chemotherapy. PMID- 23747892 TI - Poly(ADP-ribose) polymerase inhibitors as cancer therapy. AB - Poly(ADP-ribose) polymerase (PARP) inhibitors are pharmacologic agents which primarily inhibit the PARP-1 and PARP-2 enzymes within the cell. Inhibition of PARP results in failure of base-excision repair (BER) to correct single-stranded breaks in DNA. This failure results in double-stranded breaks that are subsequently repaired either by homologous recombination (HR) repair, which is error-free, or by non-homologous end joining (NHEJ), which is an error-prone process. Clinically, PARP inhibitors demonstrate activity in tumors which lack a functional HR system (i.e. BRCA1 and BRCA2 mutations) by forcing NHEJ repair. Known as synthetic lethality, the use of NHEJ in these tumors generates genomic instability and eventual cell death due to rapid development of non-viable genetic errors. In addition due their BER effects, PARP inhibitors are being developed as chemotherapy and radiation sensitizers in a number of tumor types. This review will examine the role of the PARP enzymes in DNA repair, PARP inhibitors in HR-deficient tumors, current results of clinical studies of PARP inhibitors and research efforts to expand the clinical activity of PARP inhibitors beyond HR-deficient tumors. PMID- 23747893 TI - BMP-7 counteracting TGF-beta1 activities in organ fibrosis. AB - Chronic organ injuries are accompanied by a dysregulated scarring process called "Fibrosis" that is characterized by hyperactivity of TGF-beta resulting in an imbalance of extracellular matrix homeostasis and accumulation of fibrosis associated proteins. These changes are due to a specialized matrix-expressing cell type, i.e. the myofibroblast, which is derived from independent cellular sources. Beside resident quiescent fibroblasts that become activated, circulating bone-marrow-derived fibrocytes are attracted by the injured organ. Additionally, epithelial cells transit into mesenchymal cells in a process termed epithelial-to mesenchymal transition. Furthermore, mesothelial cells leave their peripheral location and acquire a fibrogenic phenotype via mesothelial-to-mesenchymal transition. Numerous independent studies have consistently demonstrated that BMP 7 interferes with TGF-betasignaling and a diverse set of matricellular proteins (e.g. CCN proteins), Endoglin, Betaglycan, BAMBI and the members of the repulsive guidance molecule family that modulate cellular proliferation, migration, adhesion and extracellular matrix production. This protein network might therefore depict novel targets for treatment of fibrotic lesions. We here summarize recent knowledge of BMP-7 function and discuss attempts to use this cytokine as a drug to reverse TGF-beta-induced fibrogenesis. PMID- 23747894 TI - Angiogenesis in liver metastasis of colo-rectal carcinoma. AB - In liver metastasis of color-rectal carcinoma, angiogenesis is supported by vascular endothelial growth factor (VEGF) and E-selectin while it is suppressed by Netrin-4 and LK-68. Sinusoidal endothelial cells and the hepatocyte-derived extracellular matrix support growth of microvessels in liver metastases of color rectal cancers. Based on these insights, the new treatment for liver metastasis of color-rectal cancers target diverse pathways and molecules of angiogenesis, especially the VEGF pathway. Additional agents target the cyclooxygenase-2 pathway or follow regimens for inhibiting angiogenesis. In this review, we discuss angiogenesis and treatments avaiable for color-rectal liver metastasis. PMID- 23747895 TI - The role of BRCA1 and BRCA2 in prostate cancer. AB - The familial aggregation of prostate cancer and breast cancer has been observed for almost half a century and about 85% of the inherited breast cancer can be linked to germ-line mutations of BRCA1 (breast cancer 1, early onset) and BRCA2. In this review, we are mainly focusing on the contribution of BRCA1/2 sequence variations to prostate cancer risk and disease progression. We will discuss the biological functions of BRCA1/2 and BRCA1/2-related signaling pathways in prostate cancer biology. The majority of studies supporting the link between BRCA1/2 mutations and prostate cancer are from populations with a high frequency of mutations, such as Ashkenazi Jewish, Icelandic, and U.K. population. BRCA1 can directly interact with the androgen receptor (AR) and Janus kinase (JAK), and can differentially regulate insulin-like growth factor 1 receptor (IGF-IR) expression in an AR-dependent manner. BRCA2 homeostasis in prostate cancer cells has been found to be critical in determining cell fates during prostate cancer progression. This review may be helpful for medical professionals and prostate cancer patients when discussing prostate cancer risks, treatment and prognosis. PMID- 23747896 TI - Estrous activity detection device in mammals. AB - Control of estrus is essential for the efficiency of any breeding program in farm animals, artificial insemination, hand mating and prediction of parturition dates. The present study is providing new evidence about determination of silent estrus in Damascus does. Since many D. does do not show any interest toward the male across seasons compared with spontaneous estrus detected by buck goat (BG). Results revealed that estrus detected by BG has significantly higher in autumn (78 of 86) than spring (3 of 11), while estrus detected by frequent vaginal inspection (FVI) was higher in spring (8 of 11) than autumn (8 of 86). Normal estrous cycles (EC) is significantly higher in D. does detected by BG than by FVI, while short and long EC are higher in D. does detected by FVI than by BG. Moreover, biochemical and hormonal analysis revealed that BG is an effective tool to measure estrus's quality especially in autumn and winter. PMID- 23747897 TI - Frequencies of mtDNA mutations in primary tissues of colorectal adenopolyps. AB - To investigate the potential role of mtDNA alterations during the onset of colorectal cancer, the occurrence of mtDNA variants in colorectal adenomatous (Tubular, Tubulovillous, and Villous) polyps, were studied. High resolution endonucleases and PCR-based sequence were applied to examine mtDNA variants in the ND and ATPase genes of 64 primary tissues of colorectal adeno-polyps and their matched normal controls. Forty-two variants were observed and 57% (24/42) were not previously reported in the MITODAT reference. Fifty-eight percent of these variants were germline and homoplasmic transitions. The distribution of observed mtDNA variants includes: 31% (13/42) tubular, 52% (22/42) tubulovillous, 45% (19/42) villous, and 45% (19/42) cancer (including FAP and JVP). Notably, an unreported germline variant in the ATPase 8 gene at nucleotide position (np) G8573A was observed in tubulovillous adenomas tissues. The results suggest that some specific mtDNA variants may serve as a potential biomarker for colorectal adenomatous polyps. PMID- 23747898 TI - Massive microRNA sequence conservation and prevalence in human and chimpanzee introns. AB - Human and chimpanzee introns contain numerous sequences strongly related to known microRNA hairpin structures. The relative frequency is precisely maintained across all chromosomes, suggesting the possible co-evolution of gene networks dependent upon microRNA regulation and with origins corresponding to the advent of primate transposable elements (TEs). While the motifs are known to be derived from transposable elements, the most common are far more numerous than expected from the number of TEs and their paralogous sequences, and exhibit striking conservation in comparison to the surrounding TE sequence context. Several of these motifs also exhibit structural complimentarity to each other, suggesting a pairing function at the level of DNA or RNA. These "pseudomicroRNAs," in semblance to pseudogenes, include hundreds of thousands of vestigial paralogs of primate microRNAs, many of which may have functioned historically or remain active today. PMID- 23747899 TI - Brown adipose tissue: clinical impact of a re-discovered thermogenic organ. AB - Brown adipose tissue (BAT) is physiologically present and active in adult humans. The stimulation of BAT in man can potentially increase total daily energy expenditure and is seen as a possible target to treat obesity. Altered BAT activity is also related to other diseases and therefore the therapeutic potential of BAT could reach beyond obesity. This is supported by both in vitro and in vivo reports from animal studies, describing the possible role of BAT in both physiology and pathophysiology. In addition, since the discovery of functional BAT several clinically relevant studies have been conducted in adult man. Clinical observations report BAT activity under multiple conditions, suggesting BAT could be important in the onset and/or treatment of diseases related to the metabolic syndrome, thyroid disorders, cancer and immune system dysfunction. This review highlights those diseases or syndromes in which BAT may play a role in relation to prevention, diagnosis or therapy, by translating basic research into clinical relevance. PMID- 23747900 TI - Effects of carnitine supplementation on myocardial function and energy provision in experimental uraemia AB - Cardiovascular complications are the leading cause of death in patients with chronic kidney disease. The uraemic heart undergoes remodelling and changes in metabolic function. Experimental uraemia produces a reduction in the myocardial energy reserve phosphocreatine in parallel with left ventricular hypertrophy and depletion of serum carnitine. This study investigated the effects of chronic L carnitine supplementation on myocardial substrate metabolism and function in the experimental uraemia. Experimental uraemia was induced surgically in male Sprague Dawley rats via a subtotal nephrectomy. Carnitine was administered continuously via subcutaneous mini-osmotic pumps. Cardiac function and substrate oxidation were assessed in vitro by means of isovolumic perfusion using 13C NMR, at 3 and 6 weeks. Uraemic animals exhibited anaemia, kidney dysfunction and systemic carnitine deficiency but no myocardial tissue carnitine deficiency. Myocardial hypertrophy was abolished following carnitine supplementation. This was associated with a reduction in glucose utilisation. In summary carnitine supplementation prevents cardiac hypertrophy, and this effect is amplified with the duration of treatment. This is associated with a reduction in myocardial glucose utilisation but no significant modulation of myocardial function. PMID- 23747902 TI - Hybrid-drug design targeting Pseudomonas aeruginosa dihydropteroate synthase and dihydrofolate reductase AB - In this study, we successfully present the dual-target design hypothesis to inhibit both dihydropteroate synthase (DHPS) and dihydrofolate reductase (DHFR) enzymes using a novel scheme that integrates our previous antibiotic phytochemical interaction data, fragment combination and knowledge-based methods. Both the enzymes are well established antibacterial targets from folate biosynthesis pathway and their synergistic modulation by a single hybrid entity may have profound therapeutic benefits. Evaluation of the designed hybrid compounds based on their physico-chemical properties has indicated them as promising drug candidates with drug-like pharmacotherapeutic profiles. In addition, the stereo-electronic properties such as HOMO, LUMO and MEP maps calculated by quantum chemical methods gave a good correlation with the common pharmacophoric features required for dual-site interactions. Furthermore, docking and dynamics simulation studies reveal that the designed hybrid compounds have favorable binding affinity and stability in both pterin-binding site of DHPS and folate-binding site of DHFR by forming strong hydrogen bonds and hydrophobic interactions with key active-site residues. Looking forward this study could serve as a prospective lead in the process of new natural-product based hybrid drugs development. PMID- 23747903 TI - Relevance of stretch-induced phosphorylation of MAPK and p90rsk in human myocardium. AB - Stretch activates various signal transduction pathways including mitogen activated protein kinases (MAPK). Stretch-induced phosphorylation of MAPK contribution to contractility in human myocardium is unknown. We tested the effects of stretch on p44/42-, p38-MAPK and p90rsk phosphorylation and the functional relevance for force development in failing (F) and non-failing (NF) human myocardium. Trabeculae were stretched to a diastolic tension of 12mN/mm2 for 2.5 to 30 minutes and frozen for Western Blot analysis. Stretch induced a time-dependent increase in phosphorylation of p44/42-, p38-MAPK and p90rsk. For functional analysis, trabeculae from F myocardium were stretched and the immediate (Frank-Starling mechanism; FSM) and delayed (slow force response; SFR) increase in twitch force was assessed before and after blocking the activation of p44/42-MAPK (30 micromol/L U0126) and p38-MAPK (10 micromol/L SB203580). Inhibition of p44/42-MAPK almost completely blocked the SFR (106.7 3.7% vs. 125.4 2.9%), while p38-MAPK-blockade significantly increased the SFR (124.6 1.9% vs. 121.2 2.2%). Stretch induced a time-dependent increase in p44/42-, p38-MAPK and p90rsk phosphorylation in F and NF myocardium. While p44/42-MAPK phosphorylation contributed to the SFR, p38-MAPK activation antagonized the stretch-induced SFR. PMID- 23747904 TI - Can triggered arrhythmias arise from propagation of calcium waves between cardiac myocytes? AB - Intracellular Ca2+ overload can induce regenerative Ca2+ waves that activate inward current in cardiac myocytes, allowing the cell membrane to achieve threshold. The result is a triggered extrasystole that can, under the right conditions, lead to sustained triggered arrhythmias. In this review, we consider the issue of whether or not Ca2+ waves can travel between neighboring myocytes and if this intercellular Ca2+ diffusion can involve enough cells over a short enough period of time to actually induce triggered activity in the heart. This review is not intended to serve as an exhaustive review of the literature summarizing Ca2+ flux through cardiac gap junctions or of how Ca2+ waves move from cell to cell. Rather, it summarizes many of the pertinent experimental studies and considers their results in the theoretical context of whether or not the intercellular propagation of Ca2+ overload can contribute to triggered beats and arrhythmias in the intact heart. PMID- 23747905 TI - Epigenetic aberration of gene expression in endometriosis. AB - Endometriosis is an estrogen-dependent inflammatory disease. In endometriotic tissues, a high-estrogen environment associated with up-regulation of the aromatase gene has been well documented. There is accumulating evidence supporting a concept that endometriosis is a disease associated with an epigenetic disorder. Epigenetics is one of the most expanding fields in the current biomedical research. The word 'epigenetics' refers to the study of mitotically and/or meiotically heritable changes in gene expression that occur without changes in the DNA sequence. The disruption of such changes (epigenetic aberration or disorder) underlies a wide variety of pathologies. Epigenetic regulation includes DNA methylation and histone modifications, and is responsible for a number of gene transcription associated with chromatin modifications that distinguish the states of diseases. In this review, we summarized our studies as well as recent studies from other laboratories using an epigenetic approach focused on DNA methylation. We also summarized studies using advanced technologies including Genome-Wide (GW) methylation profiling analysis and GW Association Study (GWAS). We reviewed recent monozygotic twins studies in relation to environmental factors since they may provide insight into the epigenetic background of endometriosis. Finally, we referred to a new concept of GW DNA methylation. PMID- 23747901 TI - Biomarkers of bipolar disorder: specific or shared with schizophrenia? AB - Kraepelin's observations of the differences in the course and outcome of dementia praecox and manic depression fundamentally influenced thinking about bipolar disorder (BP) and schizophrenia (SZ) for over a century. In modern times, there is increasing awareness that a greater understanding of the similarities between these two highly prevalent and disabling conditions can teach us as many lessons about the pathophysiology of severe mental disorders as does the pursuit of differentiating factors. We review publications on developmental, genetic, epidemiological, and outcome research that challenges the Kraepelian dichotomy. We highlight the increasing evidence of the overlap in genetic susceptibility. Neuro-developmental studies provide evidence of shared early pathological processes, whilst neurophysiological investigations also suggest that different genes may have a role in the development of both phenotypes. There is also evidence of overlapping neurocognitive phenotypes. It has become increasingly clear that a simple binary classification of these disorders represents an oversimplification. It may be more apposite to think in terms of genetic influences on six continuous symptom dimensions: neurobiological, cognitive, positive, negative, depressive and manic symptoms. PMID- 23747906 TI - Use of autologous growth factors in aging tendon and chronic tendinopathy. AB - Aging tendons or chronic tendinopathy are frequent conditions responsible for handicap in middle-aged and aging populations. Current therapies fail to relieve handicap. Medical treatment can sometimes be efficient, but surgical procedures often fail to restore tendon function. Cell therapy with platelets, based on tendon histological modifications and the capacity of such tissue to respond to growth factors, is an ever-expanding field of clinical research. In the current review, we compare the histological properties of normal tendons, aging tendons and chronic tendinopathy. We explain the natural healing process of such tendons and the rationale for using, or not, autologous growth factors. We review current clinical studies exploring the effect of concentrated autologous growth factor injection in chronic lesions and attempt to explain why, to date, all clinical studies have demonstrated no effect of such therapies. PMID- 23747907 TI - Echocardiographic effects of eplerenone and aldosterone in hypertensive rats. AB - The effects of aldosterone receptor blockade on echocardiography in spontaneously hypertensive rats (SHR) are not fully characterized. In this study, multiple echocardiographic parameters were compared for 42 weeks between SHR versus Wistar Kyoto rats (WKY) serving as normotensive controls. In addition, echocardiographic parameters were compared for 28 weeks between the SHR versus SHR treated with eplerenone 100 mg/kg/day or spironolactone 50 mg/kg/day. Compared to normotensive WKY rats, SHRs had significantly increased systolic blood pressure, increased cardiac mass, increased isovolumic relaxation time (IVRT), decreased E/A ratio, increased mitral closure opening time interval (MCO) and increased Tei index. Both eplerenone and spironolactone significantly decreased systolic blood pressure compared to the SHR controls. The spironolactone treatment group demonstrated significant increases in heart rate and cardiac output and a decrease in cardiac index compared to SHR controls. Any aldosterone blockade in SHR protected against the increased cardiac mass. Similar to clinical echocardiographic observations, hypertension in rats results in left ventricular hypertrophy (LVH) and diastolic dysfunction and aldosterone receptor blockade reduces LVH in SHR. PMID- 23747908 TI - Percutaneous absorption of aromatic amines and the risk assessment resulting from the dermal pathway. AB - Aromatic amines (AA) are compounds of different carcinogenic potency causing occupational bladder cancer. The percutaneous absorption of AA is mostly appraised to be high. Many AA are, therefore, assigned with skin notations. However, for the assessment of the dermal exposure route only little data are available. Additionally, in many studies the skin penetration data for AA are provided as absorbed percentage of applied dose or permeability coefficients, which are less useful in risk assessment. In this overview, the toxicological relevance of percutaneous absorption of AA was evaluated and a percutaneous penetration ranking for some AA is proposed. A continuous skin exposure of hands to AA for a few minutes can exceed the inhalative exposure over 8 hours at occupational threshold limit values in the workplace air. The health risk resulting from the percutaneous absorption of AA can be considerable. Also the dermal exposure to azo dyes, which can be metabolized to AA, should be considered with caution. PMID- 23747909 TI - Mouse models of chemically-induced lung carcinogenesis. AB - Primary pulmonary malignancies remain the major source of cancer-related deaths in the Western World. While surgical resection is an efficacious therapy for those with early stage disease, the majority of patients present with advanced malignancies and systemic treatments, such as cytotoxic chemotherapy, have only limited efficacy in lung cancer. Furthermore, chemoprevention for current or former smokers has demonstrated only limited success using available agents. The mouse model of primary lung carcinogenesis represents a very valuable tool for the study of tumor initiation, promotion, and therapy. Here we discuss several models of chemically-induced murine lung cancer with a specific emphasis on translational and clinically-relevant lines of investigation. We emphasize the pros and cons of currently available models in order to facilitate further investigations into the development and treatment of primary pulmonary malignancies. PMID- 23747910 TI - Monitoring molecules in neuroscience: historical overview and current advancements. AB - During the last 50 years, the minimally invasive techniques for monitoring brain chemistry in vivo have significantly contributed to our current understanding of chemical neurotransmission in relation to behavior, as well as, to neuropathology and neuropharmacology of CNS disorders. This article provides a short historical overview of implantable devices including voltammetric electrodes, biosensors, microdialysis and related analytical techniques developed for monitoring and sampling brain chemistry in experimental disease models. A special emphasis is given to dopamine, which besides its important role as a neurotransmitter, could be readily detected by electrochemical techniques. Today, about 70% of all published papers applying voltammetry in the brain refer to dopamine monitoring; the corresponding percentage of brain microdialysis papers referring to dopamine is 41%. PMID- 23747911 TI - Silicon nanotweezers for biomechanical and bioelectrical assays. AB - In modern life, technologies enabling detection of biological molecules at a low threshold, for health and ecological concerns, are in high demand. Directly interrogating the molecules is a promising direction to clarify the noisy response of conventional assays arising from simultaneous different reactions. Besides sophisticated biophysical instrument such as the atomic force microscope, this paper proposes silicon nanotweezers (SNT) as a new microsystem for molecular manipulation. SNT can trap molecules and sense their biomechanical and bioelectrical response in minute operations. In this review SNT characteristics are overviewed; their operation modes are illustrated by molecule and cell trapping, manipulation and characterization in air and in solution. As they are tiny and can be mass produced by highly parallel microsystem technology, SNT can be seen as a potential molecular and cellular probe for routine analysis and bio detection. PMID- 23747912 TI - Prevention of cancer and inflammation by soybean protease inhibitors. AB - Several plant-based nutrients and non-nutrients that can inhibit mutagenesis and cell proliferation have been identified. Some of the most promising compounds identified as chemopreventive and anti-metastatic agents include soybean-derived protease inhibitors (PIs), Bowman-Birk Inhibitor (BBI) and Kunitz-Trypsin Inhibitor (KTI). A growing body of evidence suggests that BBI could act as anti carcinogenic agent and KTI is considered to prevent cancer invasion and metastasis. These inhibitors are non-toxic, are of low cost and can be taken orally or as a part of the daily diet. PIs are undergoing investigation in the clinical setting as potential agents for chemoprevention and anti-metastasis. A complex scenario about the interaction between PIs and cell signaling has been emerging. Soybean PIs are not just anti-proteolytic proteins, but can also be modulators of cell signal transduction. Cancer and inflammatory treatment strategies modulating signal transduction need further investigation. PMID- 23747913 TI - Electroporation as a strategy to promote HtrA1 gene uptake and chemotherapy efficacy in a mouse model of mesothelioma. AB - There is not a consensus on the best therapeutic approach to mesothelioma and the prognosis is still dismal. We have recently demonstrated that HtrA1 is a potential therapeutic target in mesothelioma cells. In this manuscript we describe that electroporation in a mouse mesothelioma xenograft was able to facilitate the expression of exogenous HtrA1 injected intra-lesionally in the tumors and to increase the penetration in the neoplastic cells of cisplatin given intra-peritoneally. Indeed, HtrA1 over-expression caused a significant slowing down of tumor growth; moreover, cisplatin efficacy in reducing tumor mass was amplified by electroporation and this phenomenon was even more significant when combining the electroporation of cisplatin and HtrA1. Considering that a substantial number of mesothelioma patients develop early local recurrence, even with radical resection combined with aggressive chemo- and radiotherapy, this multi-modality approach could be very effective in improving local tumor control after surgery. The identification of effective combination coupled with the development of novel equipments and electrodes will be instrumental in planning the translation of these results to humans as per correct laboratory-clinical interface. PMID- 23747915 TI - Autophagy in epithelial homeostasis and defense. AB - Autophagy delivers protein aggregates, damaged organelles and intracellular microorganisms to the lysosome for degradation. The epidermis and other epithelia show significant levels of autophagy, however, the functions of autophagy in these tissues have remained elusive until recently. Here we review the experimental approaches for the investigation of autophagy in epithelia and discuss the roles of autophagy in epithelial cells with a focus on epidermal keratinocytes and thymic epithelial cells. PMID- 23747916 TI - Evidence for a relation between plasma membrane coenzyme Q and autism. AB - Voltage Dependent Anion Channel (VDAC) in the cell membrane transports important molecules and ions across the cell membrane. It was recently shown that VDAC also acts as a trans membrane NADH dehydrogenase. A recent study showed that autistic children have increased antibodies to VDAC proteins and such a binding inhibits both the transport and dehydrogenase activities of VDAC. The derived function of VDAC, therefore, might underlie the development of autism. It has also recently been shown that the dehydrogenase in erythrocyte membranes requires coenzyme Q. Since the plasma membrane oxidase is not in erythrocyte membranes, the coenzyme Q requirement must be for VDAC. This is consistent with sensitivity of the dehydrogenase to SH inhibitors. This is a novel site for coenzyme Q function but it has an analogy with the Q requirement for the mitochondrial uncoupler protein and the permeability transition pore. PMID- 23747917 TI - Cell development obeys maximum Fisher information. AB - Eukaryotic cell development has been optimized by natural selection to obey maximal intracellular flux of messenger proteins. This, in turn, implies maximum Fisher information on angular position about a target nuclear pore complex (NPR). The cell is simply modeled as spherical, with cell membrane (CM) diameter 10 micrometer and concentric nuclear membrane (NM) diameter 6 micrometer. The NM contains approximately 3000 nuclear pore complexes (NPCs). Development requires messenger ligands to travel from the CM-NPC-DNA target binding sites. Ligands acquire negative charge by phosphorylation, passing through the cytoplasm over Newtonian trajectories toward positively charged NPCs (utilizing positive nuclear localization sequences). The CM-NPC channel obeys maximized mean protein flux F and Fisher information I at the NPC. Therefore the first-order change in I = 0. But also, the 2nd-order change in I is likewise close to zero, indicating significant stability to environmental perturbations. Many predictions are confirmed, including the dominance of protein pathways of from 1-4 proteins, a 4 nm size for the EGFR protein and the flux value F approximately 10(16) proteins/m2-s. After entering the nucleus, each protein ultimately delivers its ligand information to a DNA target site with maximum probability, i.e. maximum Kullback-Liebler entropy H(KL). In a smoothness limit H(KL) --> I(DNA)/2, so that the total CM-NPC-DNA channel obeys maximum Fisher I. It is also shown that such maximum information --> a cell state far from thermodynamic equilibrium, one condition for life. PMID- 23747914 TI - Advances in studying phasic dopamine signaling in brain reward mechanisms. AB - The last sixty years of research has provided extraordinary advances of our knowledge of the reward system. Since its discovery as a neurotransmitter by Carlsson and colleagues (1), dopamine (DA) has emerged as an important mediator of reward processing. As a result, a number of electrochemical techniques have been developed to measure DA in the brain. Together, these techniques have begun to elucidate the complex roles of tonic and phasic DA signaling in reward processing and addiction. In this review, we will first provide a guide for the most commonly used electrochemical methods for DA detection and describe their utility in furthering our knowledge about DA's role in reward and addiction. Second, we will review the value of common in vitro and in vivo preparations and describe their ability to address different types of questions. Last, we will review recent data that has provided new mechanistic insight of in vivo phasic DA signaling and its role in reward processing and reward-mediated behavior. PMID- 23747918 TI - Angiogenesis, lymphangiogenesis and neurogenesis in endometriosis. AB - Endometriosis is a common, benign gynecological disease affecting 10 - 15% of reproductively aged women. It is characterized by the presence of endometrial like tissue at sites outside the uterus. The most widely accepted theory of endometriosis pathogenesis proposes that shed menstrual endometrium can reach the peritoneum, implant and grow as endometriotic lesions. Angiogenesis, lymphangiogenesis and neurogenesis are implicated in successful ectopic establishment and the generation of endometriosis-associated symptoms. This review considers these processes as they occur in the eutopic endometrium and ectopic endometriotic lesions of women with endometriosis. Their regulation is inter-connected and complex. Dysregulation in endometriosis occurs on a background of accumulating evidence that endometriosis is an endometrial disease with underlying genetic influences and cross talk with endometriotic lesions. Understanding the roles of angiogenesis, lymphangiogenesis and neurogenesis in endometriosis pathophysiology is essential for the development of novel therapeutic approaches. PMID- 23747919 TI - Williams' neural stem cells: new model for insight into microRNA dysregulation. AB - Williams syndrome (WS) is a neurodevelopmental genetic disorder, due to a 7q11.23 hemizygous deletion. WS has a characteristic neurocognitive profile that includes intellectual disability (ID). Haploinsufficiency of some of the deleted genes is partially associated with the cognitive phenotype. The aim of this paper is to determine the differences in the microRNA (miRNA) expression in WS patients, using a neural cell model from the patients olfactory neuroepithelium (ONE), and to establish the relationship with those genes involved in neurodevelopment and neural function. To assess these goals, we made a comparative analysis of the miRNAs expression profile between WS patients and controls. Through an in silico analysis, we established potential pathways and targets associated with neural tissue. The expression profile shows 14 dysregulated miRNAs, including nervous system (NS)-rich miRNAs such as miR-125b, let-7c and miR-200. Most of these miRNAs have potential targets associated with NS functions while others have been reported to have specific neuronal functions. These data suggest that miRNAs widely contribute to the regulation of neurodevelopmental intrinsic processes, and that specific miRNAs could participate in WS neurobiology. PMID- 23747920 TI - Wheezing defined. AB - Wheeze is both a symptom to parents (reported as noisy breathing) and a sign to clinical staff - with very differing perspectives between parents and clinicians on what constitutes "wheeze". The purpose of this article is to consider these differences of understanding from the perspective of different stakeholders so that nobody is "lost in translation". Misunderstandings may lead to epidemiologic and treatment faults. Every effort should be made to educate parents and improve their communications with clinicians. PMID- 23747921 TI - Application of metabolomics on diagnosis and treatment of patients with psoriasis in traditional Chinese medicine. AB - Traditional Chinese medicine (TCM) is one of the oldest forms of medical system. With syndrome as the core of diagnosis and therapy in TCM, it has the advantage of collecting macroscopic information of patients for diagnosis. To understand the in vivo mechanism of TCM, a metabolomics approach was used to investigate the global biological characterization of the urine of psoriasis patients with Blood Stasis Syndrome and the therapeutic metabolomics mechanism of the Optimized Yinxieling formula. A total of 41 cases of psoriasis patients with Blood Stasis Syndrome and 19 healthy volunteers were enrolled in this study. Fasting urine samples from patients with consecutive Optimized Yinxieling intake after 0, 4, 8 and 12 weeks and from healthy volunteers were analyzed by Orthogonal Projection on Latent Structures Discriminant Analysis (OPLS-DA), which was utilized for High Performance Liquid Chromatography (HPLC) analysis and temporal metabolic changes identification. For psoriasis group, the scores of PASI of patients decreased after 12 weeks of Optimized Yinxieling treating. The metabolic variations visualized not only in the healthy group and psoriasis group, but also in the psoriasis group before and after Optimized Yinxieling treatment, demonstrated that the metabolic characteristics of the two groups were significantly different. The optimized complex structure of the target proteins from Protein Data Bank was analyzed by software package Discovery Studio. With docking score of original inhibitor and the receptor as the threshold values, two compounds from Chinese medicinal chemical database were predicted to have good interactions with the target proteins. The Metabolomics technique combining molecular docking analysis enhanced our current understanding of the metabolic response to Blood Stasis Syndrome of Psoriasis and the action mechanism of Optimized Yinxieling. This article is part of a Special Issue entitled: Computational Proteomics, Systems Biology & Clinical Implications. Guest Editor: Yudong Cai. PMID- 23747922 TI - Mechanistic features of Salmonella typhimurium propionate kinase (TdcD): insights from kinetic and crystallographic studies. AB - Short-chain fatty acids (SCFAs) play a major role in carbon cycle and can be utilized as a source of carbon and energy by bacteria. Salmonella typhimurium propionate kinase (StTdcD) catalyzes reversible transfer of the gamma-phosphate of ATP to propionate during l-threonine degradation to propionate. Kinetic analysis revealed that StTdcD possesses broad ligand specificity and could be activated by various SCFAs (propionate>acetate~butyrate), nucleotides (ATP~GTP>CTP~TTP; dATP>dGTP>dCTP) and metal ions (Mg(2+)~Mn(2+)>Co(2+)). Inhibition of StTdcD by tricarboxylic acid (TCA) cycle intermediates such as citrate, succinate, alpha-ketoglutarate and malate suggests that the enzyme could be under plausible feedback regulation. Crystal structures of StTdcD bound to PO4 (phosphate), AMP, ATP, Ap4 (adenosine tetraphosphate), GMP, GDP, GTP, CMP and CTP revealed that binding of nucleotide mainly involves hydrophobic interactions with the base moiety and could account for the broad biochemical specificity observed between the enzyme and nucleotides. Modeling and site-directed mutagenesis studies suggest Ala88 to be an important residue involved in determining the rate of catalysis with SCFA substrates. Molecular dynamics simulations on monomeric and dimeric forms of StTdcD revealed plausible open and closed states, and also suggested role for dimerization in stabilizing segment 235-290 involved in interfacial interactions and ligand binding. Observation of an ethylene glycol molecule bound sufficiently close to the gamma-phosphate in StTdcD complexes with triphosphate nucleotides supports direct in-line phosphoryl transfer. PMID- 23747924 TI - Differences in heat-related mortality across four ecological regions with diverse urban, rural, and remote populations in British Columbia, Canada. AB - Temperature-mortality analyses are challenging in rural and remote communities with small populations, but this information is needed for climate change and emergency planning. The geographic health areas of British Columbia, Canada were aggregated into four ecoregions delineated by microclimatic conditions. Time series models were used to estimate the effect of maximum apparent temperature on daily non-traumatic mortality. The population of the coldest ecoregion was most sensitive to hot weather, while the population of the hottest ecoregion was least sensitive. The effects were consistently strongest in decedents aged less than 75 years. A province-wide total of 815 deaths was attributed to hot weather over the 25-year study period, with 735 deaths in the most populous ecoregion. The framework described could be adapted to other climatically variable regions with urban, rural, and remote populations. PMID- 23747923 TI - Neighborhood socioeconomic characteristics and differences in the availability of healthy food stores and restaurants in Sao Paulo, Brazil. AB - Differential access to healthy foods has been hypothesized to contribute to health disparities, but evidence from low and middle-income countries is still scarce. This study examines whether the access of healthy foods varies across store types and neighborhoods of different socioeconomic statuses (SES) in a large Brazilian city. A cross-sectional study was conducted in 2010-2011 across 52 census tracts. Healthy food access was measured by a comprehensive in-store data collection, summarized into two indexes developed for retail food stores (HFSI) and restaurants (HMRI). Descriptive analyses and multilevel models were used to examine associations of store type and neighborhood SES with healthy food access. Fast food restaurants were more likely to be located in low SES neighborhoods whereas supermarkets and full service restaurants were more likely to be found in higher SES neighborhoods. Multilevel analyses showed that both store type and neighborhood SES were independently associated with in-store food measures. We found differences in the availability of healthy food stores and restaurants in Sao Paulo city favoring middle and high SES neighborhoods. PMID- 23747925 TI - Seasonal dynamics of the lungworm, Rhabdias pseudosphaerocephala, in recently colonised cane toad (Rhinella marina) populations in tropical Australia. AB - The impact of parasites on host populations depend upon parasite prevalence and intensity. Understanding how infection dynamics change through time following a host population's initial exposure to the parasite is fundamental to host parasite biology. We studied an invasive host (the cane toad, Rhinella marina) currently undergoing range expansion - a process through which this host's range is expanding faster than that of its lung parasites (the nematode, Rhabdias pseudosphaerocephala), such that hosts at the expanding range edge remain parasite-free for several years. It was predicted that parasite intensity and prevalence would be affected by host characteristics (e.g., size, sex), environmental conditions (e.g., seasons, habitat type), and time since parasite arrival in the newly established invading host population. Over 2,400 cane toads were sampled at 10 sites in recently established toad populations in the highly seasonal monsoonal tropics of northern Australia. The sampling spanned 14 consecutive 3 month seasons commencing in the early stages of lungworm establishment in those toad populations. Both parasite prevalence and intensity increased with host body size but were unaffected by host sex. Prevalence and intensity were highest during drier times of year and in drier habitats (i.e., sites lacking permanent waterbodies). These changes in parasite prevalence may reflect a trend for saturated soil to reduce parasite survival during the free living infective stage, and to allow anuran hosts to disperse widely (thus reducing the transfer of directly transmitted parasites between hosts). Conversely, dry conditions induce toads to aggregate in moist dry-season refugia where conditions may be more conducive to direct transmission of infective parasitic larvae between hosts. PMID- 23747926 TI - Understanding myxozoan infection dynamics in the sea: seasonality and transmission of Ceratomyxa puntazzi. AB - Ceratomyxa puntazzi affects the sharpsnout seabream, Diplodus puntazzo, a recently explored aquaculture species in the Mediterranean. Little is known about the transmission and seasonality of marine myxozoans, although this knowledge is of considerable importance for the design of management strategies for aquaculture. In the present study on C. puntazzi we investigated the potential pathways of transmission as well as the parasite abundance in fish and its density in environmental water samples, throughout a full year. We performed monthly sentinel fish exposures in a C. puntazzi enzootic environment and quantified waterborne stages in seawater. Two novel C. puntazzi-specific PCR and quantitative PCR assays were developed to determine infection levels in fish and water samples. Ceratomyxa puntazzi presents marked seasonal changes in parasite density, with a double-peaked prevalence of infection in sentinel fish in spring and late summer/autumn, at 16-24 degrees C, and a covert infection during the winter months. Invasive blood stages were detected all year round by PCR. The combination of sentinel fish exposure with the quantification of waterborne stages allowed us to attribute this pattern in C. puntazzi density to higher numbers of actinospores in the water, while myxospores are predominant in summer and winter. We demonstrated that temperature increase triggered actinospore production in the invertebrate host in a benthic habitat and we suggest that the life cycle dynamics of the invertebrate host explain the double-peaked infection prevalence in fish. Experimental transmission of different C. puntazzi developmental stages in seawater or by oral and intracoelomic injection was unsuccessful which indicates fish-to-fish transmission is unlikely to occur in aquaculture systems. This is the first model studying seasonality and infection dynamics of a marine myxozoan. PMID- 23747927 TI - Multilocus population genetic analysis of the Southwest Pacific malaria vector Anopheles punctulatus. AB - The population structure and history of the cryptic malaria vector species, Anopheles punctulatus (Doenitz), was investigated throughout Papua New Guinea and the Solomon Islands with the aim of detailing genetic subdivisions and the potential for movement through this biogeographically complex region. We obtained larval collections from over 80 sites and utilised a diverse array of molecular markers that evolve through different processes. Individuals were initially identified to species and genotyped using the ribosomal DNA second internal transcribed spacer. DNA sequencing of a single copy nuclear ribosomal protein S9 and the mitochondrial cytochrome oxidase I loci were then investigated and 12 nuclear microsatellite markers were developed and analysed. Our data revealed three genetically distinct populations--one in Papua New Guinea, the second on Buka Island (Bougainville Province, Papua New Guinea), and the third on Guadalcanal Island (Solomon Islands). Genetic differentiation within Papua New Guinea was much lower than that found in studies of other closely related species in the region. The data does suggest that A. punctulatus has undergone a population bottleneck followed by a recent population and range expansion in Papua New Guinea. Humans and regional economic growth may be facilitating this population expansion, as A. punctulatus is able to rapidly occupy human modified landscapes and traverse unsealed roads. We therefore anticipate extensive movement of this species through New Guinea--particularly into the highlands, with a potential increase in malaria frequency in a warming climate--as well as relatively unrestricted gene flow of advantageous alleles that may confound vector control efforts. PMID- 23747928 TI - Zinc ions as effectors of environmental oxidative lung injury. AB - The redox-inert transition metal Zn is a micronutrient that plays essential roles in protein structure, catalysis, and regulation of function. Inhalational exposure to ZnO or to soluble Zn salts in occupational and environmental settings leads to adverse health effects, the severity of which appears dependent on the flux of Zn(2+) presented to the airway and alveolar cells. The cellular toxicity of exogenous Zn(2+) exposure is characterized by cellular responses that include mitochondrial dysfunction, elevated production of reactive oxygen species, and loss of signaling quiescence leading to cell death and increased expression of adaptive and inflammatory genes. Central to the molecular effects of Zn(2+) are its interactions with cysteinyl thiols, which alters their functionality by modulating their reactivity and participation in redox reactions. Ongoing studies aimed at elucidating the molecular toxicology of Zn(2+) in the lung are contributing valuable information about its role in redox biology and cellular homeostasis in normal and pathophysiology. PMID- 23747929 TI - Tryptophan oxidation photosensitized by pterin. AB - Pterins are normal components of cells and they have been previously identified as good photosensitizers under UV-A irradiation, inducing DNA damage and oxidation of nucleotides. In this work, we have investigated the ability of pterin (Ptr), the parent compound of oxidized pterins, to photosensitize the oxidation of another class of biomolecules, amino acids, using tryptophan (Trp) as a model compound. Irradiation of Ptr in the UV-A spectral range (350 nm) in aerated aqueous solutions containing Trp led to the consumption of the latter, whereas the Ptr concentration remained unchanged. Concomitantly, hydrogen peroxide (H2O2) was produced. Although Ptr is a singlet oxygen ((1)O2) sensitizer, the degradation of Trp was inhibited in O2-saturated solutions, indicating that a (1)O2-mediated process (type II oxidation) was not an important pathway leading to Trp oxidation. By combining different analytical techniques, we could establish that a type I photooxidation was the prevailing mechanism, initiated by an electron transfer from the Trp molecule to the Ptr triplet excited state, yielding the corresponding radical ions (Trp(.+)/Trp(-H). and Ptr(.-)). The Trp reaction products that could be identified by UPLC-mass spectrometry are in agreement with this conclusion. PMID- 23747931 TI - N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes. AB - N-Acetylcysteine (NAC) and allopurinol (ALP) synergistically reduce myocardial ischemia reperfusion (MI/R) injury in diabetes. However, the mechanism is unclear. We postulated that NAC and ALP attenuated diabetic MI/R injury by up regulating phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and Janus kinase 2/signal transducer and activator of transcription-3 (JAK2/STAT3) pathways subsequent to adiponectin (APN) activation. Control (C) or streptozotocin-induced diabetic rats (D) were untreated or treated with NAC and ALP followed by MI/R. D rats displayed larger infarct size accompanied by decreased phosphorylation of Akt, STAT3 and decreased cardiac nitric oxide (NO) and APN levels. NAC and ALP decreased MI/R injury in D rats, enhanced phosphorylation of Akt and STAT3, and increased NO and APN. High glucose and hypoxia/reoxygenation exposure induced cell death and Akt and STAT3 inactivation in cultured cardiomyocytes, which were prevented by NAC and ALP. The PI3K inhibitor wortmannin and Jak2 inhibitor AG490 abolished the protection of NAC and ALP. Similarly, APN restored posthypoxic Akt and STAT3 activation and decreased cell death in cardiomyocytes. Gene silencing with AdipoR2 siRNA or STAT3 siRNA but not AdipoR1 siRNA abolished the protection of NAC and ALP. In conclusion, NAC and ALP prevented diabetic MI/R injury through PI3K/Akt and Jak2/STAT3 and cardiac APN may serve as a mediator via AdipoR2 in this process. PMID- 23747932 TI - Reliable extraction of the circulation component in the thoracic impedance measured by defibrillation pads. AB - AIM: To analyze the feasibility of extracting the circulation component from the thoracic impedance acquired by defibrillation pads. The impedance circulation component (ICC) would permit detection of pulse-generating rhythms (PRs) during the analysis intervals of an automated external defibrillator when a non shockable rhythm with QRS complexes is detected. METHODS: A dataset of 399 segments, 165 associated with PR and 234 with pulseless electrical activity (PEA) rhythms, was extracted from out-of-hospital cardiac arrest episodes by applying a conservative criterion. Records consisted of the electrocardiogram and the thoracic impedance signals free of artifacts due to thoracic compressions and ventilations. The impedance was processed using an adaptive scheme based on a least mean square algorithm to extract the ICC. Waveform features of the ICC signal and its first derivative were used to discriminate PR from PEA rhythms. RESULTS: The segments were split into development (83 PR and 117 PEA rhythms) and testing (82 PR and 117 PEA rhythms) subsets with a mean duration of 10.6s. Three waveform features, peak-to-peak amplitude, mean power, and mean area were defined for the ICC signal and its first derivative. The discriminative power in terms of area under the curve with the testing dataset was 0.968, 0.971, and 0.969, respectively, when applied to the ICC signal, and 0.974, 0.988 and 0.988, respectively, with its first derivative. CONCLUSION: A reliable method to extract the ICC of the thoracic impedance is feasible. Waveform features of the ICC or its first derivative show a high discriminative power to differentiate PR from PEA rhythms (area under the curve higher than 0.96 for any feature). PMID- 23747930 TI - How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo. AB - We present arguments for an evolution in our understanding of how antioxidants in fruits and vegetables exert their health-protective effects. There is much epidemiological evidence for disease prevention by dietary antioxidants and chemical evidence that such compounds react in one-electron reactions with free radicals in vitro. Nonetheless, kinetic constraints indicate that in vivo scavenging of radicals is ineffective in antioxidant defense. Instead, enzymatic removal of nonradical electrophiles, such as hydroperoxides, in two-electron redox reactions is the major antioxidant mechanism. Furthermore, we propose that a major mechanism of action for nutritional antioxidants is the paradoxical oxidative activation of the Nrf2 (NF-E2-related factor 2) signaling pathway, which maintains protective oxidoreductases and their nucleophilic substrates. This maintenance of "nucleophilic tone," by a mechanism that can be called "para hormesis," provides a means for regulating physiological nontoxic concentrations of the nonradical oxidant electrophiles that boost antioxidant enzymes, and damage removal and repair systems (for proteins, lipids, and DNA), at the optimal levels consistent with good health. PMID- 23747933 TI - Peripheral antinociceptive action of mangiferin in mouse models of experimental pain: role of endogenous opioids, K(ATP)-channels and adenosine. AB - This study aimed to assess the possible systemic antinociceptive activity of mangiferin and to clarify the underlying mechanism, using the acute models of chemical (acetic acid, formalin, and capsaicin) and thermal (hot-plate and tail flick) nociception in mice. Mangiferin at oral doses of 10 to 100 mg/kg evidenced significant antinociception against chemogenic pain in the test models of acetic acid-induced visceral pain and in formalin- and capsaicin-induced neuro inflammatory pain, in a naloxone-sensitive manner, suggesting the participation of endogenous opiates in its mechanism. In capsaicin test, the antinociceptive effect of mangiferin (30 mg/kg) was not modified by respective competitive and non-competitive transient receptor potential vanilloid 1 (TRPV1) antagonists, capsazepine and ruthenium red, or by pretreatment with L-NAME, a non-selective nitric oxide synthase inhibitor, or by ODQ, an inhibitor of soluble guanylyl cyclase. However, mangiferin effect was significantly reversed by glibenclamide, a blocker of K(ATP) channels and in animals pretreated with 8-phenyltheophylline, an adenosine receptor antagonist. Mangiferin failed to modify the thermal nociception in hot-plate and tail-flick test models, suggesting that its analgesic effect is only peripheral but not central. The orally administered mangiferin (10-100 mg/kg) was well tolerated and did not impair the ambulation or the motor coordination of mice in respective open-field and rota-rod tests, indicating that the observed antinociception was unrelated to sedation or motor abnormality. The findings of this study suggest that mangiferin has a peripheral antinociceptive action through mechanisms that involve endogenous opioids, K(ATP) channels and adenosine receptors. PMID- 23747934 TI - Handwriting movement analyses comparing first and second graders with normal or dysgraphic characteristics. AB - Dysgraphia of sufficient severity to interfere with the school work has been recognized as representing a distinct deficit; characterization of its movement problem is a necessary step toward offering improved intervention. From among children aged 6-8, 69 children with dysgraphic characteristics (study group) and 69 matched proficient hand-writers (control group) were recruited into this study. Four copying tests of differing complexity levels were administered using a digital tablet. The acquired data included direct measure (axial pen tip force) and derived parameters (stroke velocity, pause time, number of velocity peaks and ratio of In Air to On Paper measures). The major finding is that children with dysgraphic characteristics had increased pause time per stroke and an increased number of directional changes in velocity. Significant differences were also found between students in two different grades, especially in the control group. The parameters extracted and observed in this study can further differentiate and characterize the handwriting problems originating from fine motor deficits. PMID- 23747935 TI - Muscle reaction function of individuals with intellectual disabilities may be improved through therapeutic use of a horse. AB - Reaction time and muscle activation deficits might limit the individual's autonomy in activities of daily living and in participating in recreational activities. The aim of the present study was to assess the effects of a 14-week hippotherapy exercise program on movement reaction time and muscle activation in adolescents with intellectual disability (ID). Nineteen adolescents with moderate ID were assigned either to an experimental group (n=10) or a control group (n=9). The experimental group attended a hippotherapy exercise program, consisting of two 30-min sessions per week for 14 weeks. Reaction time, time of maximum muscle activity and electromyographic activity (EMG) of rectus femoris and biceps femoris when standing up from a chair under three conditions: in response to audio, visual and audio with closed eyes stimuli were measured. Analysis of variance designs showed that hippotherapy intervention program resulted in significant improvements in reaction time and a reduction in time to maximum muscle activity of the intervention group comparing to the control group in all 3 three conditions that were examined (p<0.05). The present findings suggest that the muscle reaction function of individuals with ID can be improved through hippotherapy training. Hippotherapy probably creates a changing environment with a variety of stimuli that enhance deep proprioception as well as other sensory inputs. In conclusion, this study provides evidence that hippotherapy can improve functional task performance by enhancing reaction time. PMID- 23747936 TI - The efficacy of two task-orientated interventions for children with Developmental Coordination Disorder: Neuromotor Task Training and Nintendo Wii Fit Training. AB - Neuromotor Task Training (NTT) and Nintendo Wii Fit Training (Wii training) are both task-based interventions used to improve performance in children with motor coordination problems. The aim of this study was to compare the efficacy of these two interventions on the motor performance, isometric strength and cardiorespiratory fitness (aerobic and anaerobic capacity) of children with Developmental Coordination Disorder (DCD) attending mainstream schools in a low income setting. A pragmatic, quasi-experimental study design was utilized. Children between the ages of 6-10 years, who scored at or below the 16th percentile on the Movement Assessment Battery for Children-2 (MABC-2) and whose teacher reported a functional motor problem, were allocated to either NTT (n=37) or Wii training (n=19) groups depending on school of attendance. The MABC-2, a hand-held dynamometer, the Functional Strength Measure, the Muscle Power Sprint Test and the 20m Shuttle Run Test were used to assess performance at baseline and after the intervention. The main findings show that the mean motor performance scores of both groups improved over the study period. However, significant differences in improvement were detected between groups, with the NTT group showing greater improvement in motor performance, functional strength and cardiorespiratory fitness. No improvements in isometric strength were seen in either group. The Wii training group showed significant improvement in anaerobic performance. This study provides evidence to support the use of both the Wii Training and NTT for children with DCD. However, in comparison to Wii training, the NTT approach yields superior results across measures of motor proficiency, cardiorespiratory fitness and functional strength. The decision to use either approach may be influenced by resources and time constraints. PMID- 23747937 TI - Higher prevalence of autism in Taiwanese children born prematurely: a nationwide population-based study. AB - The reported prevalence of autism in preterm and full-term children varies partially because of small sample sizes. Moreover, little is known about the specific factors that contribute to the risk of autism in preterm children. We aimed to compare the prevalence of autism in preterm and full-term children and to identify neonatal risk factors for autism in preterm children using a large national health system database. We analyzed data from 1078 early preterm (<28 weeks of gestation or birth weight<1000 g), 28,947 later preterm (28-36 weeks), and 1,104,071 full-term (>= 37 weeks) children who were 8-11 years old in 2009. The descending order of prevalence was early preterm (2.2%), later preterm (1.3%), and full-term (0.6%). The prevalence of autism was approximately 2-4 times higher in preterm children than in children born at full-term. The male female ratio (4:1) in preterm and full-term children was not significantly different. Most of the children were first diagnosed with autism between 3 and 6 years old. Preterm children with autism were not diagnosed earlier than were full term children. Regression analysis showed that male gender, a very low birth weight, and neonatal cerebral dysfunction were risk factors for autism in the preterm group. We conclude that autism is more prevalent in preterm children. Preventing extremely preterm birth and significant early brain insults may be helpful in reducing the risk of autism in preterm children. PMID- 23747938 TI - An investigation of self-injurious behaviors in adults with severe intellectual disabilities. AB - Self-injurious behavior (SIB) is commonly observed among individuals with intellectual disability (ID) living in state-run supports and services centers. Specific examples of SIB include poking oneself in the eye; harming oneself by hitting, scratching, or pinching; and pica (i.e., swallowing objects causing bodily harm). Previous research has focused on SIB in individuals with ID more generally without focusing on specific levels of ID or taking into account other important personal variables. This study examined 45 adults with severe ID living in two large state-run facilities in the Southeastern United States who were separated into groups for comparison (ASD and non ASD; verbal and nonverbal). Data was collected on the presence of SIB using the Autism Spectrum Disorder Problem Behavior Adult Version (ASD-PBA). A two-way analysis of variance (ANOVA) was conducted to determine if there were significant differences between groups on rates of SIB. Individuals with ID and ASD exhibited significantly higher rates of SIB than individuals with only ID, F (1,43)=50.84, p<0.05. Furthermore, verbal individuals had significantly higher rates of SIB than nonverbal individuals, F (1,43)=57.612, p<0.05. There was a significant interaction between the effects of ASD diagnosis and verbal ability on rates of SIB, F (1,43)=50.84, p<0.05. The implications of these findings in the context of other research on ID, ASD, SIB, and verbal abilities are discussed. PMID- 23747939 TI - Children with cerebral palsy and periventricular white matter injury: does gestational age affect functional outcome? AB - This study aimed to determine differences in functional profiles and movement disorder patterns in children aged 4-12 years with cerebral palsy (CP) and periventricular white matter injury (PWMI) born >34 weeks gestation compared with those born earlier. Eligible children born between 1999 and 2006 were recruited through the Victorian CP register. Functional profiles were determined using the Gross Motor Function Classification System (GMFCS), Manual Abilities Classification System (MACS), Communication Function Classification System (CFCS), Functional Mobility Scale (FMS) and Bimanual Fine Motor Function (BFMF). Movement disorder and topography were classified using the Surveillance of Cerebral Palsy in Europe (SCPE) classification. 49 children born >34 weeks (65% males, mean age 8 y 9 mo [standard deviation (SD) 2 y 2 mo]) and 60 children born <= 34 weeks (62% males, mean age 8 y 2 mo [SD 2 y 2 mo]) were recruited. There was evidence of differences between the groups for the GMFCS (p=0.003), FMS 5, 50 and 500 (p=0.003, 0.002 and 0.012), MACS (p=0.04) and CFCS (p=0.035), with a greater number of children born <= 34 weeks more severely impaired compared with children born later. Children with CP and PWMI born >34 weeks gestation had milder limitations in gross motor function, mobility, manual ability and communication compared with those born earlier. PMID- 23747940 TI - Comorbid motor deficits in a clinical sample of children with specific language impairment. AB - The aim of the present study was to compare the motor function of a clinical sample of children with specific language impairment (SLI) to a language-matched comparison group that had not been referred for SLI assessment. A typical language comparison group with similar nonverbal IQ was also included. There were approximately 35 children in each group, aged 9- to 10-years-old, and the children completed a range of standardised language, motor and literacy measures. The results showed that the SLI group scored significantly lower than the language-matched and typical language comparison groups on all of the motor and literacy measures. We conclude that language factors alone are insufficient to explain the extensive comorbid motor and literacy deficits shown by the children with SLI in this study. We suggest that the clinical diagnosis of SLI may be influenced by the presence of additional developmental difficulties, which should be made explicit in assessment procedures, and that intervention strategies, which address the broad range of difficulties experienced by children with a clinical diagnosis of SLI, should be prioritised. PMID- 23747942 TI - Pica in persons with developmental disabilities: approaches to treatment. AB - Pica is a very serious problem in which an individual ingests substances without nutrition value, such as paper and paint. As this behavior is often life threatening resulting in surgery, pica has received attention from researchers for several decades. During that time, a number of interventions have been devised, such as behavioral methods (e.g., aversive stimuli, overcorrection, time out, reinforcement) and biological interventions (e.g., pharmacotherapy, nutritional supplements). This paper is a broad review of the research on treatment studies for this problem, with a focus on persons with autism and/or intellectual disability (ID), which constitutes almost all of the published treatment papers. In addition, strengths and weaknesses of different pica treatments are discussed. Upon review, applied behavior analysis (ABA) was found to have the most robust empirical support to treat this behavior. Most clinicians are drifting away from aversive techniques and relying on more positive procedures to guide their treatment plans. The implications of current status and future directions for research are also addressed. PMID- 23747941 TI - Psychopharmacological treatment in children and adolescents with autism spectrum disorders in Germany. AB - Data on psychopharmacological treatment of individuals with autism spectrum disorder (ASD) are scarce, especially for European countries. This study evaluated psychopharmacotherapy utilisation in children and adolescents with a diagnosis of ASD in Germany. Data of a large statutory health insurance company were analysed and outpatients aged 0-24 years with a diagnosis of ASD during a 1 year-period (2009) were identified. For this cohort, the prescription of psychopharmacotherapy was evaluated. Aditionally, we analysed time trends in prescriptions from 2004 to 2009. One thousand one hundred twenty-four patients (75.4% male; mean age: 11.1 years) matched the inclusion criteria. The prevalence of ASD was 0.37% in males and 0.12% in females, respectively. Of all ASD patients, 33.0% were prescribed psychotropic drugs in 2009. 12.5% of ASD patients were treated with stimulants or atomoxetine, 11.7% with antipsychotics, 9.1% with antiepileptics, 6.8% with benzodiazepines, and 3.8% with antidepressants/SSRI. Regarding substances, methylphenidate (24.4% of all psychotropic prescriptions), risperidone (13.3%) and valproate (9.1%) were most frequently prescribed. Psychopharmacologic treatment prevalence was age-related and increased from 16.3% in individuals aged 0-4 years to 55.1% in 20-24 year olds. From 2004 to 2009, the proportion of ASD patients treated with psychotropic drugs rose from 25.9% to 33.0%. This naturalistic study furnishes evidence that the proportion of ASD patients treated with psychotropic drugs has grown considerably in Germany over the least years, with methylphenidate and risperidone being the most frequently prescribed substances. Compared with data from the USA, the proportion of ASD patients with psychopharmacological treatment is noticeably lower in Germany. PMID- 23747943 TI - Experience and outcomes of stepping stones triple P for families of children with autism. AB - This study investigated the experience and perceived outcomes of a behavioural family intervention, standard stepping stones triple P (SSTP), for parents of children with autism. An indepth, prospective, mixed-methods, multiple case-study design was employed. Parent participants and SSTP practitioners took part. Participation in SSTP was consistently associated with improved parental self efficacy, and was also associated with improved parental psychological well-being and decreased perceived need for behavioural services for some families. Three key themes emerged from the qualitative interview data, reflecting changes attributed to participation in SSTP: (1) changes in the "attribution of cause" of misbehaviour, (2) "Who's the boss?" reflecting a change to parents feeling more in charge of their child's behaviour, daily routines and choices, and (3) "Rewarding is rewarding!" reflecting appreciation of a positive approach to behaviour management. Practitioners discussed their impressions of appropriate participants, timing, structure, and session preferences for SSTP, and implications related to the professional qualifications of practitioners delivering SSTP. Clinical implications for the use of SSTP with families of children with autism are discussed. PMID- 23747944 TI - Visuospatial working memory in specific language impairment: a meta-analysis. AB - We conducted a meta-analysis of the data from studies comparing visuospatial working memory (WM) in children with specific language impairment (SLI) and typically developing (TD) children. The effect sizes of 21 studies (including 32 visuospatial storage tasks and 9 visuospatial central executive (CE) tasks) were identified via computerized database searches and the reference sections of the identified studies. Meta-analyses and moderator analyses were conducted to examine the magnitude of the differences in visuospatial storage and CE, and their relation to the inclusion criteria used for SLI and the age of the children. The results showed significant effect sizes for visuospatial storage (d=0.49) and visuospatial CE (d=0.63), indicating deficits in both components of visuospatial WM in children with SLI. The moderator analyses showed that greater impairment in visuospatial storage was associated with more pervasive language impairment, whereas age was not significant associated with visuospatial WM. The finding of deficits in visuospatial WM suggests domain-general impairments in children with SLI. It raises questions about the language-specificity of a diagnosis of SLI. Careful attention should thus be paid to both verbal and visuospatial WM in clinical practice, and especially in those children with pervasive language impairments. PMID- 23747945 TI - Impact of 24-month fluoride tablet program on children with disabilities in a non fluoridated country. AB - The aim of this study was to evaluate the caries preventive effects of a school based fluoride tablet program in children with disabilities. Two hundred and seventeen children with disabilities were divided into two groups: the intervention group (IG) ingested 1.0mg fluoride tablet daily while the control group (CG) ingested a placebo. The initial oral examinations were conducted prior to fluoride intake and 24-month follow-up examinations were conducted to evaluate the effectiveness of fluoride tablet ingestion. The results from this study demonstrated significant reductions in the DMFT index (the sum of decayed, missing, and filled permanent teeth), 0.63, as well as the DMFS index (the sum of decayed, missing, and filled surfaces of the permanent dentition), 1.25, when compared with the CG. A statistically significant reduction in the DMFT index and DMFS index (30.42% and 36.84%, respectively) suggested an anti-cariogenic benefit to fluoride tablet administration. Greater caries reduction occurred on mesio distal and bucco-lingual surfaces (53.27% and 52.57%, respectively). Fluoride tablets should be considered as a caries preventive strategy in school-based caries prevention programs for children with disabilities in fluoride deficient areas. PMID- 23747946 TI - Development of attention networks in deaf children: support for the integrative hypothesis. AB - Early auditory deprivation is known to affect visual attention, yet the early effects of auditory deprivation on visual attention cannot be described simply as deficiencies or enhancements, because selected aspects of visual attention could be modified in various ways along the developmental trajectory. However, few studies have explored the development of these various aspects of visual attention in deaf children. In this paper we study the developmental trajectory of three aspects of visual attention (alerting, orienting and executive control attention networks) in a group of deaf children between 6 and 12 years of age. We used the attention network test to explore the development of the three attention networks and a child-friendly version of the cost-benefit paradigm to characterize the development of the basic operations of orienting. Our results showed a pattern of specific but varied outcomes with respect to the effects of auditory deprivation on these attention networks. First, auditory deprivation can impair development of the alerting network. Second, auditory deprivation can enhance two elementary operations of orienting: moving and engaging. Third, the executive control network showed a developmental trajectory that was neither deficient nor enhanced, but rather similar to that observed with hearing children. Taken together, these results are consistent with the integrative hypothesis of the effects of auditory deprivation on visual attention. PMID- 23747947 TI - Loss of Jak2 impairs endothelial function by attenuating Raf-1/MEK1/Sp-1 signaling along with altered eNOS activities. AB - A number of inhibitors have been used to dissect the functional relevance of Jak2 in endothelial homeostasis, with disparate results. Given that Jak2 deficiency leads to embryonic lethality, the exact role of Jak2 in the regulation of postnatal endothelial function is yet to be fully elucidated. We generated a model in which Jak2 deficiency can be induced by tamoxifen in adult mice. Loss of Jak2 significantly impaired endothelium-dependent response capacity for vasodilators. Matrigel plug assays indicated a notable decrease in endothelial angiogenic function in Jak2-deficient mice. Studies in a hindlimb ischemic model indicated that Jak2 activity is likely to be a prerequisite for prompt perfusion recovery, based on the concordance of temporal changes in Jak2 expression during the course of ischemic injury and perfusion recovery. A remarkable delay in perfusion recovery, along with reduced capillary and arteriole formation, was observed in Jak2-deficient mice. Antibody array studies indicated that loss of Jak2 led to repressed eNOS expression. In mechanistic studies, Jak2 deficiency attenuated Raf-1/MEK1 signaling, which then reduced activity of Sp-1, an essential transcription factor responsible for eNOS expression. These data are important not only for understanding the exact role that Jak2 plays in endothelial homeostasis, but also for assessing Jak2-based therapeutic strategies in a variety of clinical settings. PMID- 23747948 TI - Pyroglutamate-3 amyloid-beta deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models. AB - Amyloid-beta (Abeta) peptides, starting with pyroglutamate at the third residue (pyroGlu-3 Abeta), are a major species deposited in the brain of Alzheimer disease (AD) patients. Recent studies suggest that this isoform shows higher toxicity and amyloidogenecity when compared to full-length Abeta peptides. Here, we report the first comprehensive and comparative IHC evaluation of pyroGlu-3 Abeta deposition in humans and animal models. PyroGlu-3 Abeta immunoreactivity (IR) is abundant in plaques and cerebral amyloid angiopathy of AD and Down syndrome patients, colocalizing with general Abeta IR. PyroGlu-3 Abeta is further present in two nontransgenic mammalian models of cerebral amyloidosis, Caribbean vervets, and beagle canines. In addition, pyroGlu-3 Abeta deposition was analyzed in 12 different AD-like transgenic mouse models. In contrast to humans, all transgenic models showed general Abeta deposition preceding pyroGlu-3 Abeta deposition. The findings varied greatly among the mouse models concerning age of onset and cortical brain region. In summary, pyroGlu-3 Abeta is a major species of beta-amyloid deposited early in diffuse and focal plaques and cerebral amyloid angiopathy in humans and nonhuman primates, whereas it is deposited later in a subset of focal and vascular amyloid in AD-like transgenic mouse models. Given the proposed decisive role of pyroGlu-3 Abeta peptides for the development of human AD pathology, this study provides insights into the usage of animal models in AD studies. PMID- 23747949 TI - Immunogenicity of decellularized porcine liver for bioengineered hepatic tissue. AB - Liver disease affects millions of patients each year. The field of regenerative medicine promises alternative therapeutic approaches, including the potential to bioengineer replacement hepatic tissue. One approach combines cells with acellular scaffolds derived from animal tissue. The goal of this study was to scale up our rodent liver decellularization method to livers of a clinically relevant size. Porcine livers were cannulated via the hepatic artery, then perfused with PBS, followed by successive Triton X-100 and SDS solutions in saline buffer. After several days of rinsing, decellularized liver samples were histologically analyzed. In addition, biopsy specimens of decellularized scaffolds were seeded with hepatoblastoma cells for cytotoxicity testing or implanted s.c. into rodents to investigate scaffold immunogenicity. Histological staining confirmed cellular clearance from pig livers, with removal of nuclei and cytoskeletal components and widespread preservation of structural extracellular molecules. Scanning electron microscopy confirmed preservation of an intact liver capsule, a porous acellular lattice structure with intact vessels and striated basement membrane. Liver scaffolds supported cells over 21 days, and no increased immune response was seen with either allogeneic (rat-into-rat) or xenogeneic (pig into-rat) transplants over 28 days, compared with sham-operated on controls. These studies demonstrate that successful decellularization of the porcine liver could be achieved with protocols developed for rat livers, yielding nonimmunogenic scaffolds for future hepatic bioengineering studies. PMID- 23747950 TI - Compartmentalization of immune responses during Staphylococcus aureus cranial bone flap infection. AB - Decompressive craniectomy is often required after head trauma, stroke, or cranial bleeding to control subsequent brain swelling and prevent death. The infection rate after cranial bone flap replacement ranges from 0.8% to 15%, with an alarming frequency caused by methicillin-resistant Staphylococcus aureus, which is problematic because of recalcitrance to antibiotic therapy. Herein we report the establishment of a novel mouse model of S. aureus cranial bone flap infection that mimics several aspects of human disease. Bacteria colonized bone flaps for up to 4 months after infection, as revealed by scanning electron microscopy and quantitative culture, demonstrating the chronicity of the model. Analysis of a human cranial bone flap with confirmed S. aureus infection by scanning electron microscopy revealed similar structural attributes as the mouse model, demonstrating that it closely parallels structural facets of human disease. Inflammatory indices were most pronounced within the subcutaneous galeal compartment compared with the underlying brain parenchyma. Specifically, neutrophil influx and chemokine expression (CXCL2 and CCL5) were markedly elevated in the galea, which demonstrated substantial edema on magnetic resonance images, whereas the underlying brain parenchyma exhibited minimal involvement. Evaluation of immune mechanisms required for bacterial containment and inflammation revealed critical roles for MyD88-dependent signaling and neutrophils. This novel mouse model of cranial bone flap infection can be used to identify key immunologic and therapeutic mechanisms relevant to persistent bone flap infection in humans. PMID- 23747951 TI - The cigarette smoke constituent benzo[a]pyrene disrupts metabolic enzyme, and apoptosis pathway member gene expression in ovarian follicles. AB - Benzo[a]pyrene (B[a]P) is a prototypical polycyclic aromatic hydrocarbon (PAH) present in cigarette smoke. We previously showed that B[a]P adversely affects follicular development and survival. The objective of this study was to identify the key molecular pathways underlying B[a]P-induced abnormal follicular development. Isolated follicles (100-130 MUm) from ovaries of F1 hybrid (C57BL/6j*CBA/Ca) mice were cultured for 8 (preantral/antral follicles) and 12 (preovulatory follicles) days in increasing concentrations of B[a]P (0 ng/mL [control] to 45 ng/mL). Expression of aryl hydrocarbon receptor (AhR), aryl hydroxylase steroidogenic enzyme, cell-cycle, and apoptotic genes were quantified. B[a]P exposure significantly (P<0.05) increased mRNA expression of Cyp1a1 in preantral/antral follicles and Cyp1b1, Bax and Hsp90ab1 in preovulatory follicles. No significant effect on mRNA expression of StAR, Cyp11a1, aromatase, Cdk4, Cdk2, Ccnd2, cIAP2, and survivin was observed. In conclusion, this study suggests that B[a]P exposure significantly affects the phase I enzymes and cell death genes during preantral/antral and preovulatory growth, and thus highlight the AhR signaling and apoptotis pathways in delayed follicle growth and decreased viability. PMID- 23747952 TI - Ramipril-induced liver injury: case report and review of the literature. AB - BACKGROUND: Ramipril, an inhibitor of the angiotensin-converting enzyme (ACEI), is a drug commonly used in the therapy of hypertension. ACEI-induced hepatotoxicity is rare, and most of the reported cases are associated with captopril. Here, we present the first case of ramipril-induced liver injury proven by positive rechallenge and a review of the literature including the data from the US Food and Drug Administration adverse event reporting system (FAERS). METHODS: Patient data were collected in the Berlin Case-Control Surveillance Study for adverse drug reactions. PubMed research on ACEI-induced hepatotoxicity included all ACEIs except captopril; analysis of the FAERS database focused on ramipril-induced hepatotoxicity in the period 2009-2011. RESULTS: A 40-year-old male patient presented with acute onset jaundice and highly (>20-fold increase of alanine aminotranferase (ALT)) elevated liver enzymes (LEs). Viral or autoimmune hepatitis and biliary etiology were ruled out. Withdrawal of several medications including ramipril resulted in an immediate decrease in LEs, whereas a subsequent re-exposure with ramipril resulted in a striking increase in LEs (>35-fold increase of ALT). After definitely discontinuing ramipril, a rapid decline in LEs was observed, suggesting a certain causal relationship between drug intake and hepatic damage. Analysis of the FAERS database retrieved 65 cases of ramipril associated hepatotoxicity, with jaundice being the most frequent hepatic adverse event. PubMed research detected 23 relevant publications, with enalapril being the ACEI most commonly reported as being associated with liver injury. CONCLUSIONS: ACEI-induced hepatotoxicity is rare. Our case confirms a hepatotoxic potential of ramipril, highlighting the need for alertness among physicians regarding this matter. PMID- 23747953 TI - Reducing oxidative stress in the rostral ventrolateral medulla in renovascular hypertension by peripheral administration of losartan: how and where? PMID- 23747954 TI - Urinary albumin excretion at follow-up predicts cardiovascular outcomes in subjects with resistant hypertension. AB - BACKGROUND: Renal function and albuminuria predict cardiovascular disease (CVD) in general population. However, their prognostic value in patients with resistant hypertension (RH) is somewhat unknown. OBJECTIVE: To determine the ability of renal function and albuminuria to predict CVD in RH patients. METHODS: One hundred and thirty-three RH (blood pressure [BP] >=140/90mmHg despite treatment with >=3 drugs) patients were evaluated. Median follow-up was 73 months. Primary endpoint was a composite of non-fatal cardiovascular events or cardiovascular death. Serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) were determined. Microalbuminuria was defined as a urinary albumin-to-creatinine ratio (UACR) >=30mg/g. RESULTS: Twenty-two patients (16.5%) reached the primary endpoint. Long-term elevated UACR (66 vs. 17mg/g, P=0.045), but not at baseline, was associated with the primary endpoint, after adjusting for age, prior CVD, and both eGFR and office systolic-BP at baseline and during follow-up. Although baseline SCr and eGFR were associated with CVD, significance was lost after baseline risk adjustment. Baseline microalbuminuria prevalence was 45% and 41% in patients with and without CVD (P=0.813), while percentages of patients with microalbuminuria at follow-up were 67% and 28%, respectively (P=0.002). More patients with de novo CVD, compared with those without CVD, developed microalbuminuria at follow-up (28% vs. 6%) or had persistent microalbuminuria (39% vs. 21%), while fewer patients with CVD had microalbuminuria regression (11% vs. 19%) or remained normoalbuminurics (22% vs. 53%; overall P=0.005). CONCLUSION: In RH patients, the inability to microalbuminuria regression, either due to persistence or new appearance, independently predicts CVD. PMID- 23747955 TI - Ambulatory blood pressure monitoring should be used in the primary care setting to diagnose hypertension. PMID- 23747956 TI - Rehabilitation outcome of anoxic-ischaemic encephalopathy survivors with prolonged disorders of consciousness. AB - OBJECTIVES: To examine the natural clinical course of patients admitted to inpatient neurorehabilitation in a coma, vegetative state (VS), or minimally conscious state (MCS) after anoxic-ischaemic encephalopathy (AIE). METHODS: This is a retrospective cohort study of 113 consecutive patients admitted to a German inpatient neurorehabilitation centre with severe disorders of consciousness (DOC) following AIE due to cardiac arrest over a 6-year period. Functional independence was measured with the Glasgow Outcome Scale (GOS) and recovery of consciousness with the Coma Remission Scale (CRS). Separate binary logistic regression models were used to identify independent predictors for functional and behavioural outcomes. RESULTS: Seven patients (6.2%) achieved a good functional outcome (GOS 4-5). Five of these showed significant functional improvement within the first 8 weeks. 22 patients (19.5%) recovered consciousness; the last patient began to make significant improvement between weeks 10 and 12. Logistic regression showed that both increasing age and lower admission CRS predicted unfavourable functional outcome and persistent DOC. A longer stay in the ICU also predicted persistent DOC at the end of neurorehabilitation. However, neither malignant somatosensory evoked potential (SEP) test results nor hypothermia treatment on the ICU were outcome predictors in either outcome category. CONCLUSION: Even among severely affected AIE patients arriving at a neurological rehabilitation centre in a DOC, there remains potential for functional and behavioural improvement. However, significant improvements may not begin for up to 3 months post-injury. This study suggests that recovery of consciousness and even a good neurological outcome are possible despite malignant SEP test results. PMID- 23747957 TI - QR code: use of a novel mobile application to improve performance and perception of CPR in public. PMID- 23747958 TI - Investigation of the inter-observer variability effect on the prognostic value of somatosensory evoked potentials of the median nerve (SSEP) in cardiac arrest survivors using an SSEP classification. AB - BACKGROUND AND PURPOSE: We investigated the inter-observer variability in interpretation of median nerve SSEPs with regard to neurological prognosis in survivors of cardiac arrest (CA). METHODS: Four experienced neurologists analyzed 163 median nerve SSEPs on the basis of a pre-defined classification of SSEPs into five patterns (A-E), with consideration of cortical potentials up to a latency of 150ms. Of these, 133 recordings were from CA survivors and 30 were from healthy volunteers. The experts were blinded to whether a SSEP finding was from a CA survivor or a healthy volunteer. They were also unaware of the neurological outcome for the resuscitated patients. Three categories were defined for decision making. These were "good neurological outcome" represented by patterns A-C, "poor neurological outcome" (patterns D and E), and "not evaluable". Experts' agreement was calculated using the kappa-coefficient. RESULTS: The mean correct prediction by the experts was 81.8% (range 76.3-86.6%) in resuscitated patients with good neurological outcome. In those with poor neurological outcome, however, correct prediction was achieved in only 63% (60.5-66%). All SSEPs from healthy volunteers were classified as "good neurological outcome". The kappa-coefficient (kappa) for all decision-making classifications was 0.75; for patients with poor outcome it was 0.76 and for those with good outcome 0.88. The predictive value for poor neurological outcome of the SSEP pattern D achieved a specificity of 93.5% and that of E a specificity of 98.4%. CONCLUSION: Our study demonstrates good inter observer agreement in the interpretation of median nerve SSEPs in CA survivors on the basis of a pre-defined SSEP evaluation set. The strongest correlation with poor outcome was found for pattern E, bilateral absence of the N20 peak. PMID- 23747959 TI - Comparison between IDMS-traceable Jaffe and enzymatic creatinine assays for estimation of glomerular filtration rate by the CKD-EPI equation in healthy and diabetic subjects. AB - OBJECTIVES: The aim of this paper was to compare the agreement between creatinine measured by Jaffe and enzymatic methods and their putative influence on eGFR as calculated by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation in healthy and diabetic individuals. DESIGN AND METHODS: Cross-sectional study conducted in 123 adult southern Brazilians with GFR>60 mL/min/1.73 m2 (53 patients with type 2 diabetes, 70 healthy volunteers). Mean age was 49+/-16 years (range of 19-86). Most were female (55%) and white (83%). Creatinine was measured by a traceable Jaffe method (Modular P, Roche Diagnostic) and by an enzymatic method (CREA plus, Roche/Hitachi 917). GFR was measured by the 51Cr-EDTA single injection method. RESULTS: Serum creatinine measured by the Jaffe and enzymatic methods was similar in healthy subjects (0.79+/-0.16 vs. 0.79+/-0.15 mg/dL, respectively, P=0.76), and diabetic patients (0.96+/-0.22 vs. 0.92+/-0.29 mg/dL, respectively, P=0.17). However, the correlation between the two methods was higher in the healthy group (r=0.90 vs. 0.76, P<0.001). The difference between Jaffe creatinine and enzymatic creatinine was <10% in 63% of cases in the healthy group and 40% of cases in the diabetes group (P=0.018). In the subset of patients with diabetes, eGFR based on enzymatic assay results showed better agreement with measured GFR than did eGFR based on Jaffe results. CONCLUSION: Jaffe and enzymatic creatinine methods show adequate agreement in healthy subjects, but in the presence of diabetes, the enzymatic method performed slightly better. PMID- 23747960 TI - Plasma neutrophil gelatinase-associated lipocalin as a biomarker for acute kidney injury in critically ill patients with suspected sepsis. AB - OBJECTIVES: The aim of this study was to investigate the diagnostic utility of plasma neutrophil gelatinase-associated lipocalin (NGAL) as an early objective biomarker to predict acute kidney injury (AKI) in critically ill patients with suspected sepsis, for whom procalcitonin (PCT) was used for the diagnosis and staging of sepsis. DESIGN AND METHODS: Plasma NGAL was measured using the Triage NGAL Test (Alere, Inc., San Diego, CA, USA) in 231 samples obtained from patients with suspected sepsis. The results of NGAL were compared with those of Elecsys BRAHMS PCT (Roche Diagnostics, Basel, Switzerland). Renal failure was assessed using the renal subscore of Sepsis-related Organ Failure Assessment (SOFA) score. AKI was defined according to the Acute Kidney Injury Network criteria. RESULTS: The concentrations of plasma NGAL were significantly different according to the five groups of PCT concentration (P<0.0001) and the renal subscore of SOFA score (P<0.0001). Plasma NGAL was significantly increased in the patients with AKI compared with those without AKI (416.5 ng/mL vs. 181.0 ng/mL, P=0.0223). CONCLUSION: Plasma NGAL seems to be a highly sensitive and objective predictor of AKI in patients with sepsis. Plasma NGAL can be added for the diagnosis and staging of renal failure in sepsis. PMID- 23747961 TI - Groupwise whole-brain parcellation from resting-state fMRI data for network node identification. AB - In this paper, we present a groupwise graph-theory-based parcellation approach to define nodes for network analysis. The application of network-theory-based analysis to extend the utility of functional MRI has recently received increased attention. Such analyses require first and foremost a reasonable definition of a set of nodes as input to the network analysis. To date many applications have used existing atlases based on cytoarchitecture, task-based fMRI activations, or anatomic delineations. A potential pitfall in using such atlases is that the mean timecourse of a node may not represent any of the constituent timecourses if different functional areas are included within a single node. The proposed approach involves a groupwise optimization that ensures functional homogeneity within each subunit and that these definitions are consistent at the group level. Parcellation reproducibility of each subunit is computed across multiple groups of healthy volunteers and is demonstrated to be high. Issues related to the selection of appropriate number of nodes in the brain are considered. Within typical parameters of fMRI resolution, parcellation results are shown for a total of 100, 200, and 300 subunits. Such parcellations may ultimately serve as a functional atlas for fMRI and as such three atlases at the 100-, 200- and 300 parcellation levels derived from 79 healthy normal volunteers are made freely available online along with tools to interface this atlas with SPM, BioImage Suite and other analysis packages. PMID- 23747962 TI - Therapeutic effects of non-invasive brain stimulation with direct currents (tDCS) in neuropsychiatric diseases. AB - Neuroplasticity, which is the dynamic structural and functional reorganization of central nervous system connectivity due to environmental and internal demands, is recognized as a major physiological basis for adaption of cognition, and behavior, and thus of utmost importance for normal brain function. Pathological alterations of plasticity are increasingly explored as pathophysiological foundation of diverse neurological and psychiatric diseases. Non-invasive brain stimulation techniques (NIBS), such as repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS), are able to induce and modulate neuroplasticity in humans. Therefore, they have potential to alter pathological plasticity on the one hand, and foster physiological plasticity on the other, in neuropsychiatric diseases to reduce symptoms, and enhance rehabilitation. tDCS is an emerging NIBS tool, which induces glutamatergic plasticity via application of relatively weak currents through the scalp in humans. In the last years its efficacy to treat neuropsychiatric diseases has been explored increasingly. In this review, we will give an overview of pathological alterations of plasticity in neuropsychiatric diseases, gather clinical studies involving tDCS to ameliorate symptoms, and discuss future directions of application, with an emphasis on optimizing stimulation effects. PMID- 23747963 TI - The effects of the Brazilian ant Dinoponera quadriceps venom on chemically induced seizure models. AB - Arthropod venoms are potential sources of neuroactive substances, providing new tools for the design of drugs. The aim of this study was to evaluate the effects of Dinoponera quadriceps venom (DqV) on seizure models in mice induced by pentylenetetrazole (PTZ), pilocarpine, and strychnine. In the PTZ model, intraperitoneal treatment with DqV (0.5mg/kg) increased the time until the first seizure and the percentage of survival (155.4+/-27.7s/12.5%, p<0.05) compared to the control group (79.75+/-3.97s/0%), whereas endovenous treatment (0.1 and 0.5mg/kg) decreased the time until the first seizure (0.1mg/kg: 77.83+/-5.3s versus 101.0+/-3.3s in the control group; 0.5mg/kg: 74.43+/-3.9s versus 101.0+/ 3.3s for the control group, p<0.05). We did not observe significant changes in the pilocarpine- and strychnine-induced seizure models. In assays that measured oxidative parameters in the PTZ model, intraperitoneal treatment with DqV (0.5 and 2.0mg/kg) only decreased the levels of MDA and nitrite in the cortex. However, endovenous treatment with DqV (0.1 and 0.5mg/kg) increased the levels of MDA in the cortex and hippocampus and at a dose of 0.5mg/kg in the striatum. Moreover, increased in nitrite content was observed in all three of the brain regions analyzed. Taken together, the D. quadriceps venom caused both neuroprotective and neurotoxic effects in a PTZ-induced seizure model, and this effect was dependent on the route of administration used. PMID- 23747965 TI - Mechanisms of increased right and left ventricular oxygen uptake during inotropic stimulation. AB - AIMS: Few studies have investigated oxygen supply/demand relations in right ventricle (RV). The current study compared changes in myocardial oxygen uptake (MVO2) and its determinants, myocardial blood flow (MBF) and oxygen extraction (EO2), in RV and left ventricle (LV) during stimulation with inotropic drugs. MAIN METHODS: Twenty-one anesthetized dogs were studied. MBF was measured with radioactive microspheres. A-VO2 difference was determined separately for RV and LV, and used to calculate MVO2 (Fick equation) and EO2. Responses to iv. infusions of isoproterenol (0.1 MUg/kg/min), dobutamine (5 MUg/kg/min), and amrinone (1mg/kg+10 MUg/kg/min) were assessed. KEY FINDINGS: Baseline MVO2 in RV was 50-60% of that in LV. The inotropes increased MVO2 in both RV and LV (range 32-63%; P<0.05). With isoproterenol, the increased MVO2 in the RV was due to increases in both MBF and EO2, whereas in LV it was due only to increases in MBF. With dobutamine and amrinone, the increased MVO2 in RV was due to increased MBF while EO2 was constant (dobutamine) or decreased (amrinone), and that in the LV was due to increased MBF while EO2 decreased. SIGNIFICANCE: RV possesses EO2 reserve that contributed to increased MVO2 during isoproterenol infusion, whereas LV depended on increased MBF alone. Because dobutamine and amrinone caused direct coronary vasodilation, i.e., "luxuriant perfusion," it was not necessary to recruit the EO2 reserve. Thus, it remained available to meet further increases in MVO2 or to maintain MVO2 in the face of reductions in MBF. PMID- 23747964 TI - Selective suppression of endothelial cytokine production by progesterone receptor. AB - Steroid hormones are well-recognized suppressors of the inflammatory response, however, their cell- and tissue-specific effects in the regulation of inflammation are far less understood, particularly for the sex-related steroids. To determine the contribution of progesterone in the endothelium, we have characterized and validated an in vitro culture system in which human umbilical vein endothelial cells constitutively express human progesterone receptor (PR). Using next generation RNA-sequencing, we identified a selective group of cytokines that are suppressed by progesterone both under physiological conditions and during pathological activation by lipopolysaccharide. In particular, IL-6, IL 8, CXCL2/3, and CXCL1 were found to be direct targets of PR, as determined by ChIP-sequencing. Regulation of these cytokines by progesterone was also confirmed by bead-based multiplex cytokine assays and quantitative PCR. These findings provide a novel role for PR in the direct regulation of cytokine levels secreted by the endothelium. They also suggest that progesterone-PR signaling in the endothelium directly impacts leukocyte trafficking in PR-expressing tissues. PMID- 23747966 TI - Investigating microcytic anaemia. PMID- 23747967 TI - Diagnosis related groups in Europe: moving towards transparency, efficiency, and quality in hospitals? PMID- 23747968 TI - Commentary: Nudging hospitals to better quality. PMID- 23747969 TI - Spinal injury. PMID- 23747970 TI - Are accident and emergency attendances increasing? PMID- 23747971 TI - German out of hours locum has conditions placed on practice because of deficient performance. PMID- 23747972 TI - A friendly environmental material: iron oxide dispersed over activated carbon from coffee husk for organic pollutants removal. AB - A friendly environmental material for organic contaminants removal was prepared in this work: small particles of iron oxide dispersed over activated carbon from coffee waste for Fenton-like application. The materials were characterized by means of XRD, N2 physisorption, Mossbauer spectroscopy and H2 pulse titration. The composites showed very good catalytic performances for methylene blue organic dye oxidation. The small goethite particles are the predominant iron oxide phase in the composites. The apparent surface area is quite high and is not very affected after iron impregnation. ESI-MS studies revealed that the dye removal occurs through a Fenton-type system by the composite whereas for the activated carbon the dye removal occurs mainly via adsorption. The iron leaching from the catalysts was negligible, less than 0.5 ppm, which evidences the occurrence of a heterogenous oxidation process. The catalyst was very active for methylene blue oxidation and could be repeatedly used for at least 5 cycles. The catalyst was also active in the oxidation of other organic compounds, such as caffeine and atrazine. PMID- 23747973 TI - Cysteine dioxygenase structures from pH4 to 9: consistent cys-persulfenate formation at intermediate pH and a Cys-bound enzyme at higher pH. AB - Mammalian cysteine dioxygenase (CDO) is a mononuclear non-heme iron protein that catalyzes the conversion of cysteine (Cys) to cysteine sulfinic acid by an unclarified mechanism. One structural study revealed that a Cys-persulfenate (or Cys-persulfenic acid) formed in the active site, but quantum mechanical calculations have been used to support arguments that it is not an energetically feasible reaction intermediate. Here, we report a series of high-resolution structures of CDO soaked with Cys at pH values from 4 to 9. Cys binding is minimal at pH<=5 and persulfenate formation is consistently seen at pH values between 5.5 and 7. Also, a structure determined using laboratory-based X-ray diffraction shows that the persulfenate, with an apparent average O-O separation distance of ~1.8A, is not an artifact of synchrotron radiation. At pH>=8, the active-site iron shifts from 4- to 5-coordinate, and Cys soaks reveal a complex with Cys, but no dioxygen, bound. This 'Cys-only' complex differs in detail from a previously published 'Cys-only' complex, which we reevaluate and conclude is not reliable. The high-resolution structures presented here do not resolve the CDO mechanism but do imply that an iron-bound persulfenate (or persulfenic acid) is energetically accessible in the CDO active site, and that CDO active-site chemistry in the crystals is influenced by protonation/deprotonation events with effective pKa values near ~5.5 and ~7.5 that influence Cys binding and oxygen binding/reactivity, respectively. Furthermore, this work provides reliable ligand bound models for guiding future mechanistic considerations. PMID- 23747974 TI - Structural determinants of oligomerization of delta(1)-pyrroline-5-carboxylate dehydrogenase: identification of a hexamerization hot spot. AB - The aldehyde dehydrogenase (ALDH) superfamily member Delta(1)-pyrroline-5 carboxylate dehydrogenase (P5CDH) catalyzes the NAD(+)-dependent oxidation of glutamate semialdehyde to glutamate, which is the final step of proline catabolism. Defects in P5CDH activity lead to the metabolic disorder type II hyperprolinemia, P5CDH is essential for virulence of the fungal pathogen Cryptococcus neoformans, and bacterial P5CDHs have been targeted for vaccine development. Although the enzyme oligomeric state is known to be important for ALDH function, the oligomerization of P5CDH has remained relatively unstudied. Here we determine the oligomeric states and quaternary structures of four bacterial P5CDHs using a combination of small-angle X-ray scattering, X-ray crystallography, and dynamic light scattering. The P5CDHs from Thermus thermophilus and Deinococcus radiodurans form trimer-of-dimers hexamers in solution, which is the first observation of a hexameric ALDH in solution. In contrast, two Bacillus P5CDHs form dimers in solution but do not assemble into a higher-order oligomer. Site-directed mutagenesis was used to identify a hexamerization hot spot that is centered on an arginine residue in the NAD(+) binding domain. Mutation of this critical Arg residue to Ala in either of the hexameric enzymes prevents hexamer formation in solution. Paradoxically, the dimeric Arg-to-Ala T. thermophilus mutant enzyme packs as a hexamer in the crystal state, which illustrates the challenges associated with predicting the biological assembly in solution from crystal structures. The observation of different oligomeric states among P5CDHs suggests potential differences in cooperativity and protein-protein interactions. PMID- 23747975 TI - NMR mapping of PCNA interaction with translesion synthesis DNA polymerase Rev1 mediated by Rev1-BRCT domain. AB - Rev1 is a Y-family translesion synthesis (TLS) DNA polymerase involved in bypass replication across sites of DNA damage and postreplicational gap filling. In the process of TLS, high-fidelity replicative DNA polymerases stalled by DNA damage are replaced by error-prone TLS enzymes responsible for the majority of mutagenesis in eukaryotic cells. The polymerase exchange that gains low-fidelity TLS polymerases access to DNA is mediated by their interactions with proliferating cell nuclear antigen (PCNA). Rev1 stands alone from other Y-family TLS enzymes since it lacks the consensus PCNA-interacting protein box (PIP-box) motif, instead utilizing other modular domains for PCNA binding. Here we report solution NMR structure of an 11-kDa BRCA1 C-terminus (BRCT) domain from Saccharomyces cerevisiae Rev1 and demonstrate with the use of transverse relaxation optimized spectroscopy (TROSY) NMR methods that Rev1-BRCT domain directly interacts with an 87-kDa PCNA in solution. The domain adopts alpha/beta fold (beta1-alpha1-beta2-beta3-alpha2-beta4-alpha3-alpha4) typical for BRCT domain superfamily. PCNA-binding interface of the Rev1-BRCT domain comprises conserved residues of the outer surface of the alpha1-helix and the alpha1-beta1, beta2-beta3 and beta3-alpha2 loops. On the other hand, Rev1-BRCT binds to the inter-domain region of PCNA that overlaps with the binding site for the PIP-box motif. Furthermore, Rev1-BRCT domain bound to PCNA can be displaced by increasing amounts of the PIP-box peptide from TLS DNA polymerase poleta, suggesting that Rev1-BRCT and poleta PIP-box interactions with the same PCNA monomer are mutually exclusive. These results provide structural insights into PCNA recognition by TLS DNA polymerases that help better understand TLS regulation in eukaryotes. PMID- 23747976 TI - Lymph node ratio is a stronger prognostic factor than microsatellite instability in colorectal cancer patients: results from a 7 years follow-up study. AB - BACKGROUND: The presence of high microsatellite instability (MSI-H) in colorectal cancers has been generally associated with better survival, opposite an increased ratio between metastatic lymph-nodes and nodes sampled in the specimen (LNR) has been associated with a worse outcome. The study aims to detect the incidence and prognostic significance of MSI and LNR in a consecutive series of 119 colorectal cancers. METHODS: 119 consecutive colorectal cancer patients undergone resection at our Department were enrolled from 2000 to 2004. The MSI status has been evaluated by amplification of target sequences. The LNR has been calculated and patients stratified into 4 groups on the basis of the ratio values. Clinical/pathological data were collected and analyzed; the overall, disease free and disease specific survivals were analyzed by the Kaplan-Meier and Cox regression analyses (mean follow-up: 81 months). RESULTS: MSI-H was detected in 11.7% of the cases and patients were compared with the microsatellite stable (MSS) group. We observed a higher prevalence of right colon localizations (p 0.01) and locally advanced tumors (p 0.0012) in the MSI-H subgroup. Kaplan-Meier analysis documented no significant difference comparing MSS patients vs MSI-H, although the latter showed a better survival trend (p ns); worse survivals were observed according with the LNR stratification (p < 0.0001). Multivariate analysis documented a statistical value associated with the LNR sub-groups in relationship with survival. CONCLUSION: According to our results the MSI-H status was associated with particular features (right locations/locally advanced tumors). The results of a long-term follow-up indicate a trend for better survival in MSI-H vs MSS patients. Notably, an increased LNR is associated with worse survivals, both at the univariate and multivariate analysis, displaying this ratio as the strongest prognostic factor of cancer-related survival. PMID- 23747977 TI - Pulmonary function after thoracoplasty and posterior correction for thoracic scoliosis patients. AB - OBJECTIVE: To study the effect of the thoracoplasty on the pulmonary function after the posterior scoliosis correction operation. METHODS: From June 2001 to June 2010, 60 thoracic scoliosis patients (24 males, 36 females) were collected. Their average age was 17.6 +/- 5.0 years. All patients underwent posterior 3 dimensional operation and thoracoplasty. The pulmonary function was examined preoperatively, 3 months, and 24 months after the operation. The correlation between the postoperative decrease ratio of pulmonary function parameters and postoperative recovery time was analyzed by Pearson correlations. RESULTS: The average Cobb's angle in the coronal plane was corrected from 99.1 degrees +/- 17.6 degrees preoperatively to 49.8 degrees +/- 11.8 degrees postoperatively, with the average correction ratio of (44.3 +/- 12.6) %. There were significant decrease in the pulmonary function parameters 3 months after the operation [vital capacity (VC), 14.4%; percentage of the VC with measured/predicted value (VC%), 14.7%; forced vital capacity (FVC), 15.7%; percentage of the FVC with measured/predicted value (FVC%), 16.6%; the first second forced expiratory volume (FEV1), 13.2%; the percentage of FEV1 with measured/predicted value (FEV1%), 12.9%] (P < 0.05). The pulmonary function parameters at the last follow-up were slightly higher than the preoperative parameters, but the statistical difference was not significant (P > 0.05). The decrease ratio of postoperative pulmonary function parameters and the postoperative recovery time was positively correlated. CONCLUSION: The pulmonary function will be decreased obviously after the thoracoplasty and the posterior scoliosis correction operation in the short time, but returns to the normal level after 2 years. PMID- 23747978 TI - Local administration of prostaglandin E1 combined with silicone chamber improves peripheral nerve regeneration. AB - The aim of this study was to assess the effect of locally administered prostaglandin E1 on peripheral nerve regeneration and functional recovery. Sixty male healthy white Wistar rats were divided into four experimental groups (n = 15), randomly: In transected group (TC), left sciatic nerve was transected and stumps were fixed in the adjacent muscle. In treatment group defect was bridged using silicone graft (SIL/PE) filled with 10 MUL prostaglandin E1. In silicone graft group (SIL), the graft was filled with phosphate-buffered saline alone. In sham-operated group (SHAM), sciatic nerve was exposed and manipulated. Each group was subdivided into three subgroups of five animals each and regenerated nerve fibers were studied 4, 8 and 12 weeks after surgery. Behavioral testing, sciatic nerve functional study, gastrocnemius muscle mass and morphometric indices confirmed faster recovery of regenerated axons in SIL/PE than SIL group (p < 0.05). In immunohistochemistry, location of reactions to S-100 in SIL/PE was clearly more positive than that in SIL group. When loaded in a silicone graft, prostaglandin E1 improved functional recovery and morphometric indices of sciatic nerve. Local application of prostaglandin E1 improved functional recovery and morphometric indices of sciatic nerve. PMID- 23747980 TI - Selection bias in cohorts of cases. PMID- 23747979 TI - Pathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease). AB - The neuronal ceroid lipofuscinoses (NCL, Batten disease) are a group of inherited neurodegenerative diseases. Infantile neuronal ceroid lipofuscinosis (INCL, infantile Batten disease, or infantile CLN1 disease) is caused by a deficiency in the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and has the earliest onset and fastest progression of all the NCLs. Several therapeutic strategies including enzyme replacement, gene therapy, stem cell-mediated therapy, and small molecule drugs have resulted in minimal to modest improvements in the murine model of PPT1-deficiency. However, more recent studies using various combinations of these approaches have shown more promising results; in some instances more than doubling the lifespan of PPT1-deficient mice. These combination therapies that target different pathogenic mechanisms may offer the hope of treating this profoundly neurodegenerative disorder. Similar approaches may be useful when treating other forms of NCL caused by deficiencies in soluble lysosomal proteins. Different therapeutic targets will need to be identified and novel strategies developed in order to effectively treat forms of NCL caused by deficiencies in integral membrane proteins such as juvenile neuronal ceroid lipofuscinosis. Finally, the challenge with all of the NCLs will lie in early diagnosis, improving the efficacy of the treatments, and effectively translating them into the clinic. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease. PMID- 23747981 TI - Timing effects of antecedent- and response-focused emotion regulation strategies. AB - Distraction and cognitive reappraisal influence the emotion-generative process at early stages and have been shown to effectively attenuate emotional responding. Inhibiting emotion-expressive behavior is thought to be less beneficial due to later implementation, but empirical results are mixed. Thus, the current study examined the temporal dynamics of these emotion regulation strategies at attenuating the late positive potential (LPP) while participants were shown unpleasant pictures. Results revealed that all strategies successfully reduced the LPP and self-reported negative affect. We confirmed that distraction attenuated the LPP earlier than cognitive reappraisal. Surprisingly, expressive suppression affected emotional responding as early as distraction. This suggests that suppression was used preventively and disrupted the emotion-generative process from the very beginning instead of targeting the emotional response itself. Thus, the obtained results point to the importance of considering the point in time when response-focused emotion regulation strategies are being implemented. PMID- 23747982 TI - The bHLH transcription factor hand is required for proper wing heart formation in Drosophila. AB - The Hand basic helix-loop-helix transcription factors play an important role in the specification and patterning of various tissues in vertebrates and invertebrates. Here, we have investigated the function of Hand in the development of the Drosophila wing hearts which consist of somatic muscle cells as well as a mesodermally derived epithelium. We found that Hand is essential in both tissues for proper organ formation. Loss of Hand leads to a reduced number of cells in the mature organ and loss of wing heart functionality. In wing heart muscles Hand is required for the correct positioning of attachment sites, the parallel alignment of muscle cells, and the proper orientation of myofibrils. At the protein level, alpha-Spectrin and Dystroglycan are misdistributed suggesting a defect in the costameric network. Hand is also required for proper differentiation of the wing heart epithelium. Additionally, the handC-GFP reporter line is not active in the mutant suggesting an autoregulatory role of Hand in wing hearts. Finally, in a candidate-based RNAi mediated knock-down approach we identified Daughterless and Nautilus as potential dimerization partners of Hand in wing hearts. PMID- 23747984 TI - A spontaneous mutation in the nicotinamide nucleotide transhydrogenase gene of C57BL/6J mice results in mitochondrial redox abnormalities. AB - NADPH is the reducing agent for mitochondrial H2O2 detoxification systems. Nicotinamide nucleotide transhydrogenase (NNT), an integral protein located in the inner mitochondrial membrane, contributes to an elevated mitochondrial NADPH/NADP(+) ratio. This enzyme catalyzes the reduction of NADP(+) at the expense of NADH oxidation and H(+) reentry to the mitochondrial matrix. A spontaneous Nnt mutation in C57BL/6J (B6J-Nnt(MUT)) mice arose nearly 3 decades ago but was only discovered in 2005. Here, we characterize the consequences of the Nnt mutation on the mitochondrial redox functions of B6J-Nnt(MUT) mice. Liver mitochondria were isolated both from an Nnt wild-type C57BL/6 substrain (B6JUnib Nnt(W)) and from B6J-Nnt(MUT) mice. The functional evaluation of respiring mitochondria revealed major redox alterations in B6J-Nnt(MUT) mice, including an absence of transhydrogenation between NAD and NADP, higher rates of H2O2 release, the spontaneous oxidation of NADPH, the poor ability to metabolize organic peroxide, and a higher susceptibility to undergo Ca(2+)-induced mitochondrial permeability transition. In addition, the mitochondria of B6J-Nnt(MUT) mice exhibited increased oxidized/reduced glutathione ratios as compared to B6JUnib Nnt(W) mice. Nonetheless, the maximal activity of NADP-dependent isocitrate dehydrogenase, which is a coexisting source of mitochondrial NADPH, was similar between both groups. Altogether, our data suggest that NNT functions as a high capacity source of mitochondrial NADPH and that its functional loss due to the Nnt mutation results in mitochondrial redox abnormalities, most notably a poor ability to sustain NADP and glutathione in their reduced states. In light of these alterations, the potential drawbacks of using B6J-Nnt(MUT) mice in biomedical research should not be overlooked. PMID- 23747983 TI - The thiol pool in human plasma: the central contribution of albumin to redox processes. AB - The plasma compartment has particular features regarding the nature and concentration of low and high molecular weight thiols and oxidized derivatives. Plasma is relatively poor in thiol-based antioxidants; thiols are in lower concentrations than in cells and mostly oxidized. The different thiol-disulfide pairs are not in equilibrium and the steady-state concentrations of total thiols as well as reduced versus oxidized ratios are maintained by kinetic barriers, including the rates of reactions and transport processes. The single thiol of human serum albumin (HSA-SH) is the most abundant plasma thiol. It is an important target for oxidants and electrophiles due to its reactivity with a wide variety of species and its relatively high concentration. A relatively stable sulfenic (HSA-SO3H) acid can be formed in albumin exposed to oxidants. Plasma increases in mixed disulfides (HSA-SSR) or in sulfinic (HSA-SO2H) and sulfonic (HSA-SO3H) acids are associated with different pathologies and may constitute biomarkers of the antioxidant role of the albumin thiol. In this work we provide a critical review of the plasma thiol pool with a focus on human serum albumin. PMID- 23747985 TI - The follicular thyroid cell line PCCL3 responds differently to laminin and to polylaminin, a polymer of laminin assembled in acidic pH. AB - The extracellular-matrix protein laminin forms polymers both in vivo and in vitro. Acidification of pH leads to the formation of an artificial polymer with biomimetic properties, named polylaminin (polyLM). Follicle cells in the thyroid are in close contact with laminin, but their response to this important extracellular signal is still poorly understood. PCCL3 thyroid follicular cells cultured on glass, on regular laminin (LM) or on laminin previously polymerized in acidic pH (polyLM) showed different cell morphologies and propensities to proliferate, as well as differences in the organization of their actin cytoskeleton. On polyLM, cells displayed a typical epithelial morphology and radially organized actin fibers; whereas on LM, they spread irregularly on the substrate, lost cell contacts, and developed thick actin fibers extending through the entire cytoplasm. Iodide uptake decreased similarly in response to both laminin substrates, in comparison to glass. On both the LM and polyLM substrates, the expression of the sodium iodide symporter (NIS) decreased slightly but not significantly. NIS showed dotted immunostaining at the plasma membrane in the cells cultured on glass; on polyLM, NIS was observed mainly in the perinuclear region, and more diffusely throughout the cytoplasm on the LM substrate. Additionally, polyLM specifically favored the maintenance of cell polarity in culture. These findings indicate that PCCL3 cells can discriminate between LM and polyLM and that they respond to the latter by better preserving the phenotype observed in the thyroid tissue. PMID- 23747986 TI - Development and pilot testing of a video-assisted informed consent process. AB - The informed consent process for research has come under scrutiny, as consent documents are increasingly long and difficult to understand. Innovations are needed to improve comprehension in order to make the consent process truly informed. We report on the development and pilot testing of video clips that could be used during the consent process to better explain research procedures to potential participants. Based on input from researchers and community partners, 15 videos of common research procedures/concepts were produced. The utility of the videos was then tested by embedding them in mock-informed consent documents that were presented via an online electronic consent system designed for delivery via iPad. Three mock consents were developed, each containing five videos. All participants (n = 61) read both a paper version and the video-assisted iPad version of the same mock consent and were randomized to which format they reviewed first. Participants were given a competency quiz that posed specific questions about the information in the consent after reviewing the first consent document to which they were exposed. Most participants (78.7%) preferred the video-assisted format compared to paper (12.9%). Nearly all (96.7%) reported that the videos improved their understanding of the procedures described in the consent document; however, the comprehension of material did not significantly differ by consent format. Results suggest videos may be helpful in providing participants with information about study procedures in a way that is easy to understand. Additional testing of video consents for complex protocols and with subjects of lower literacy is warranted. PMID- 23747987 TI - CXCL4L1-fibstatin cooperation inhibits tumor angiogenesis, lymphangiogenesis and metastasis. AB - Anti-angiogenic and anti-lymphangiogenic drugs slow tumor progression and dissemination. However, an important difficulty is that a tumor reacts and compensates to obtain the blood supply needed for tumor growth and lymphatic vessels to escape to distant loci. Therefore, there is a growing consensus on the requirement of multiple anti-(lymph)angiogenic molecules to stop cell invasion efficiently. Here we studied the cooperation between endogenous anti-angiogenic molecules, endostatin and fibstatin, and a chemokine, the Platelet Factor-4 variant 1, CXCL4L1. Anti-angiogenic factors were co-expressed by IRES-based bicistronic vectors and their cooperation was analyzed either by local delivery following transduction of pancreatic adenocarcinoma cells with lentivectors, or by distant delivery resulting from intramuscular administration in vivo of adeno associated virus derived vectors followed by tumor subcutaneous injection. In this study, fibstatin and CXCL4L1 cooperate to inhibit endothelial cell proliferation, migration and tubulogenesis in vitro. No synergistic effect was found for fibstatin-endostatin combination. Importantly, we demonstrated for the first time that fibstatin and CXCL4L1 not only inhibit in vivo angiogenesis, but also lymphangiogenesis and tumor spread to the lymph nodes, whereas no beneficial effect was found on tumor growth inhibition using molecule combinations compared to molecules alone. These data reveal the synergy of CXCL4L1 and fibstatin in inhibition of tumor angiogenesis, lymphangiogenesis and metastasis and highlight the potential of IRES-based vectors to develop anti-metastasis combined gene therapies. PMID- 23747988 TI - Spatial patterns in mesic savannas: the local facilitation limit and the role of demographic stochasticity. AB - We propose a model equation for the dynamics of tree density in mesic savannas which considers long-range competition among trees and the effect of fire indirectly acting as a local facilitation mechanism. Despite the fact that we take short-range facilitation to the local-range limit, the standard full spectrum of spatial structures already obtained in self-organization models of vegetation is recovered. Nonlocal competition, in the limit of infinitesimally short facilitation, promotes the clustering of trees. The long time coexistence between trees and grass, and how fires affect the survival of trees as well as the maintenance of the patterns is studied. The influence of demographic noise is analyzed. The stochastic system, under the parameter constraints typical of mesic savannas, shows non-homogeneous patterns characteristic of realistic situations. The coexistence of trees and grass still remains at reasonable noise intensities. PMID- 23747989 TI - [Scientific level of a journal and our country]. PMID- 23747990 TI - [The meaning and significance of copyright transfer form]. PMID- 23747991 TI - [Open ECG catalogue]. PMID- 23747992 TI - Increased CD45RO+ CD62L+ CD4+ T-cell subpopulation responsible for Th2 response in Kimura's disease. AB - Kimura's disease is characterized by subcutaneous masses, eosinophilia, and markedly elevated serum immunoglobulin E, suggesting that T helper (Th)2 cells may play a role in the pathogenesis. We investigated Th2 cytokine synthesis by mononuclear cells and possible Th1/Th2 subpopulations in Kimura's disease. Peripheral blood samples were obtained from seven patients with Kimura's disease and CD4(+) T-cell subpopulations separated by CD45RO and CD62L were isolated. Purified cells were stimulated with PHA or anti-CD3 mAb, and the cytokine levels were measured by Cytometric Bead Array kit. Peripheral blood mononuclear cells in the majority of the patients produced Th2 cytokines such as interleukin (IL)-3, IL-4, IL-5, IL-13 or GM-CSF higher than those of controls. The ratio of CD45RO(+) CD62L(+) cells in CD4(+) T cells was increased in six out of seven patients compared to age-matched controls. Especially, patient 1 had remarkably increased levels of CD45RO(+) CD62L(+) population in CD4(+) T cells. In addition, IL-4 production levels by CD45RO(+) CD62L(+) CD4(+) T cells of patients 1 and 2 were higher than those of their CD45RO(+) CD62L(-) CD4(+) T cells, in the same manner as those by a normal control. Taken together, the synthesis of Th2 cytokines and CD62L-positive subpopulation in CD45RO(+) CD4(+) T cells, which may represent characteristics of Th2, are increased in patients with Kimura's disease, suggesting that deviation to Th2 may involve in pathogenesis of the disease. PMID- 23747993 TI - CD4+ CD31+ recent thymic emigrants in CHD7 haploinsufficiency (CHARGE syndrome): a case. AB - Lymphocyte counts <2000 cells/MUL are associated with early death in infants with CHARGE (Coloboma, Heart defect, Atresia choanae, Retarded growth and development, Genital hypoplasia, Ear anomalies/deafness) syndrome and CHD7 haploinsufficiency. Absence of recent thymic emigrants is also accompanied by an Omenn-like syndrome and infant death in CHD7 haploinsufficiency. Studies positively identifying recent thymic emigrants, in relation to CHD7 haploinsufficiency, are non existent. Thirty two months of flow-cytometric work-up of an athymic (evaluated by four chest X-rays) infant, with a novel CHD7 deletion, demonstrated sparse (<50 cells/mm(3)) but continuous egress of recent thymic emigrants (CD3(+) CD4(+) CD45RA(+) CD45RO(-) CD31(+)) and homeostatic lymphocyte expansion. Infectious or autoimmune episodes (e.g., Omenn-like syndrome) were not detected (despite lymphocyte counts <2000 cells/MUL) and excellent vaccination (tetanus, Haemophilus influenzae type B and pneumococcal conjugate vaccines) and proliferation (anti-CD3 and anti-CD28 stimulated) responses were recorded. Her CD4(+) T cells displayed Gaussian distributed TCR (CDR3) spectratypes (22 functional Vbeta families). Her CD4(+) T cell profile was also characterized by a slightly increased proportion CD4(+) CD25(+) FoxP3(+) T cells. Since CD3(+) CD4(+) CD45RA(+) CD45RO(-) CD31(+) RTE are reported to be TCR diverse and to contain regulatory T cells, we found it important to report that continuously reduced numbers of CD3(+) CD4(+) CD45RA(+) CD45RO(-) CD31(+) RTE, in the context of CHD7 haploinsufficiency and despite severe lymphopenia, is consistent with an uneventful clinical outcome. PMID- 23747994 TI - Complement factor H gene (CFH) polymorphisms C-257T, G257A and haplotypes are associated with protection against severe dengue phenotype, possible related with high CFH expression. AB - Four genetic polymorphisms located at the promoter (C-257T) and coding regions of CFH gene (exon 2 G257A, exon 14 A2089G and exon 19 G2881T) were investigated in 121 dengue patients (DENV-3) in order to assess the relationship between allele/haplotypes variants and clinical outcomes. A statistical value was found between the CFH-257T allele (TT/TC genotypes) and reduced susceptibility to severe dengue (SD). Statistical associations indicate that individuals bearing a T allele presented significantly higher protein levels in plasma. The -257T variant is located within a NF-kappaB binding site, suggesting that this variant might have effect on the ability of the CFH gene to respond to signals via the NF kappaB pathway. The G257A allelic variant showed significant protection against severe dengue. When CFH haplotypes effect was considered, the ancestral CG/CG promoter-exon 2 SNP genotype showed significant risk to SD either in a general comparison (ancestral * all variant genotypes), as well as in individual genotypes comparison (ancestral * each variant genotype), where the most prevalent effect was observed in the CG/CG * CA/TG comparison. These findings support the involvement of -257T, 257A allele variants and haplotypes on severe dengue phenotype protection, related with high basal CFH expression. PMID- 23747995 TI - Amperometric detection of dopamine in human serum by electrochemical sensor based on gold nanoparticles doped molecularly imprinted polymers. AB - In this work, a highly sensitive and selective biomimetic electrochemical sensor for the amperometric detection of trace dopamine (DA) in human serums was achieved by gold nanoparticles (AuNPs) doped molecularly imprinted polymers (MIPs). Functionalized AuNPs (F-AuNPs), a novel functional monomer bearing aniline moieties on the surface of the AuNPs, were prepared via a direct synthesis method and then used to fabricate the conductive MIPs film on the modified electrode by electropolymerization method in the presence of DA and p aminobenzenethiol (p-ATP). The obtained electrochemical sensor based on the conductive film of AuNPs doped MIPs (AuNPs@MIPs) could effectively minimize the interferences caused by ascorbic acid (AA) and uric acid (UA). The linear range for amperometric detection of DA was from 0.02 MUmol L(-1) to 0.54 MUmol L(-1) with the detection limit of 7.8 nmol L(-1) (S/N=3). Furthermore, the AuNPs@MIPs modified electrode (AuNPs@MIES) was successfully employed to detect trace DA in different human serums. PMID- 23747996 TI - Evaluation of enzyme-based tear glucose electrochemical sensors over a wide range of blood glucose concentrations. AB - Miniature enzyme-based amperometric and coulometric glucose sensors were fabricated and applied to measure tear glucose concentrations in anesthetized rabbits. Without perturbing the eyeball, 3 uL of tear fluid was sampled from the marginal conjunctiva under the lower eyelid of anesthetized rabbits at various time points via a microliter glass capillary tube, and the miniature sensors were then inserted into the volume of collected tear fluids within the capillaries for detection. Intravenous bolus doses of insulin were administrated to the rabbits to lower the elevated blood glucose concentrations caused by anesthesia over the 7h test periods. A significant correlation was found between tear and blood glucose levels for multiple rabbits, suggesting that electrochemical sensor-based tear glucose measurements may be a potential supplementary method for point-of care glucose monitoring. PMID- 23747997 TI - Nonhematopoietic cells represent a more rational target of in vivo hedgehog signaling affecting normal or acute myeloid leukemia progenitors. AB - Recent work has shown that leukemic stem cell self-renewal in chronic myeloid leukemia is dependent on cell-intrinsic hedgehog (Hh) signaling, and early clinical trials suggest that targeting this pathway is also therapeutic in patients with acute myeloid leukemia (AML). In this study, we aimed to better understand Hh signaling in normal hematopoiesis and AML by molecularly and functionally analyzing more than 200 primary human AML patient samples compared with nonleukemic controls. Gene expression analysis indicated that Hh pathway transcripts were similarly regulated in AML and nonleukemic controls, regardless of whether samples were purified based on primitive phenotypes. Consistent with these results, pharmacologic inhibition of Smoothened (SMO) did not preferentially reduce in vitro colony formation of AML versus normal progenitors. Using a unique analytic approach, messenger RNA expression of membrane receptor SMO was found to be unexpectedly rare within all hematopoietic samples analyzed, which is indicative of heterogeneity at the level of Hh signaling machinery. In contrast, abundant SMO expression could be readily detected in the nonhematopoietic fraction of human and murine bone marrow (BM) cells. Our predictions of increased SMO(+) cell frequencies within nonhematopoietic BM fractions were further supported by single-cell protein analyses. Although we did not find support for cell-autonomous sensitivity of AML cells to Hh pathway inhibition, we alternatively suggest that nonhematopoietic BM cells represent an indirect target through which primitive normal and leukemic cells can be modulated. These findings suggest current approaches to applying Hh inhibition should be carefully reevaluated to account for BM niche cell regulation that might be selectively Hh responsive. PMID- 23747999 TI - Pharmaceutical salts: a summary on doses of salt formers from the Orange Book. AB - Over half of the active pharmaceutical ingredients currently approved within the US are pharmaceutical salts. Selection of suitable pharmaceutical salts is carried out during late research or early development phase. Therefore several properties of different pharmaceutical salts of a new chemical entity are assessed during salt screening and salt selection. This typically includes physico-chemical behavior, dissolution rate and pharmacokinetics of a pharmaceutical salt. Beyond these properties also toxicological aspects have to be taken into account. As a starting point for a toxicological assessment we present an overview of the usage of pharmaceutical salts as described in the FDA's Orange Book including maximum daily doses for the most important administration routes. PMID- 23748000 TI - Transmembrane transport of the Galphaq protein carboxyl terminus imitation polypeptide GCIP-27. AB - The Galphaq protein carboxyl terminus imitation polypeptide (GCIP)-27 has been shown to affect cardiac hypertrophy and vascular remodeling in various models both in vitro and in vivo. Transport across the plasma membrane is a critical step in regulating the action of this peptide drug. This study was designed to explore the mechanisms underlying the transmembrane transport of GCIP-27. The peptide drug was labeled with fluorescein isothiocyanate (FITC), and measured in a time- and concentration-dependent manner using laser confocal microscopy. Various transport inhibitors, including energy and endocytosis inhibitors, were used to identify the factors that regulate its transmembrane transport. GCIP-27 transport was examined in cardiomyocytes, cardiac fibroblasts, vascular endothelial cells, vascular smooth muscle cells (VSMCs) and hepatocytes. Atomic force microscopy and scanning electron microscopy were used to determine the ultrastructure of the cardiomyocyte membranes. The results showed that GCIP-27 was transported through the plasmalemma in a time- and concentration-dependent manner. The rate of uptake and the level of GCIP-27 in the cells decreased significantly after treatment with energy inhibitors, methyl-beta-cyclodextrin chlorpromazine or heparin. GCIP-27 levels in VSMCs and cardiomyocytes were significantly greater than the levels observed in hepatocytes, cardiac fibroblasts and vascular endothelial cells. Treatment with GCIP-27 led to a marked increase in the surface roughness of the cellular membrane. In conclusion, the transmembrane transport of GCIP-27 is mediated by endocytosis, which requires energy, and GCIP-27 preferentially enters myocardial cells and VSMCs. PMID- 23748001 TI - Enhanced systemic exposure of saquinavir via the concomitant use of curcumin loaded solid dispersion in rats. AB - The present study aimed to evaluate the effect of curcumin-loaded solid dispersion on the pharmacokinetics of saquinavir in rats. Solid dispersion (SD) formulation was prepared with Solutol(r) HS15 to improve the solubility and bioavailability of curcumin. Subsequently, its inhibition effect on P-gp mediated cellular efflux was examined by using NCI/ADR-RES cells overexpressing P-gp. Compared to the untreated curcumin, SD formulation enhanced the cellular uptake of rhodamine-123, a P-gp substrate by approximately 3 folds in NCI/ADR-RES cells. The oral and intravenous pharmacokinetics of saquinavir were also determined in rats with/without curcumin in the different formulations. Compared to the control given saquinavir alone, curcumin-loaded solid dispersion significantly (p<0.05) increased the oral exposure of saquinavir in rats, while it did not affect the intravenous pharmacokinetics of saquinavir. The AUC and Cmax of oral saquinavir increased by 3.8- and 2.7-folds, respectively in the presence of curcumin-loaded solid dispersion. In contrast, the untreated curcumin did not affect the oral pharmacokinetics of saquinavir. These results suggest that SD formulation of curcumin should be effective to improve the in vivo effectiveness of curcumin as an absorption enhancer, leading to the improved oral exposure of saquinavir. PMID- 23748002 TI - Optimization of polyhydroxybutyrate production by marine Bacillus megaterium MSBN04 under solid state culture. AB - A marine sponge-associated bacterium Bacillus megaterium MSBN04 was used for the production of polyhydroxybutyrate (PHB) under solid state culture (SSC). A central composite design (CCD) was employed to optimize the production medium and to find out the interactive effects of four independent variables, viz. tapioca industry waste, palm jaggery, horse gram flour and trace element solution on PHB production. The maximum yield of PHB 8.637 mg g(-1) of substrate (tapioca industry waste) was achieved from biomass 15.203 mg g(-1) of substrate, using statistically optimized medium. The horse gram flour (nitrogen source) and trace element solution were found to be critical control factors for PHB synthesis. The (1)H NMR analysis revealed that the polymer was a PHB monomer. PHB obtained from this study having high molecular weight (6.7*10(5) Da) with low polydispersity index (PDI) value (1.71) and produced PHB was used to synthesize PHB polymeric nanoparticles using solvent displacement approach. Therefore, B. megaterium MSBN04 is an ideal candidate that can be exploited biotechnologically for the commercial production of PHB under solid state culture. PMID- 23748003 TI - Applying chaperones to protein-misfolding disorders: molecular chaperones against alpha-synuclein in Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of a protein called alpha-synuclein (alpha-syn) into inclusions known as lewy bodies (LB) within neurons. This accumulation is also due to insufficient formation and activity of dopamine produced in certain neurons within the substantia nigra. Lewy bodies are the pathological hallmark of the idiopathic disorder and the cascade that allows alpha-synuclein to misfold, aggregate and form these inclusions has been the subject of intensive research. Targeting these early steps of oligomerization is one of the main therapeutic approaches in order to develop neurodegenerative-modifying agents. Because the folding and refolding of alpha synuclein is the key point of this cascade, we are interested in this review to summarize the role of some molecular chaperones proteins such as Hsp70, Hsp90 and small heat shock proteins (sHsp) and Hsp 104. Hsp70 and its co-chaperone, Hsp70 and small heat shock proteins can prevent neurodegeneration by preventing alpha-syn misfolding, oligomerization and aggregation in vitro and in Parkinson disease animal models. Hsp104 is able to resolve disordered protein aggregates and cross beta amyloid conformers. Together, these chaperones have a complementary effect and can be a target for therapeutic intervention in PD. PMID- 23748004 TI - Synthesis and antibacterial activities of novel nanocomposite films of chitosan/phosphoramide/Fe3O4 NPs. AB - New nanocomposite films of chitosan/phosphoramide/1-5% Fe3O4 NPs were prepared. The Fe3O4 NPs were synthesized as core-shell NPs with starch as a capping agent. The phosphoramide compound was synthesized from the reaction of morpholine with N 4-nitrophenyl phosphoramidic dichloride. The XRD and SEM analysis of Fe3O4 NPs, chitosan (CS), phosphoramide (Ph), CS/Ph and CS/Fe3O4 NPs films as well as the nanocomposite films 1-5 containing CS/Ph/1-5% Fe3O4 NPs were investigated and the results confirmed the formation of the desired films. The in vitro antibacterial activities were evaluated against four bacteria including two Gram-positive Staphylococcus aureus (S. aureus), Bacillus cereus (B. cereus) and two Gram negative Escherchia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa) bacteria. Results indicated greater antibacterial effects for the films against Gram-positive bacteria. In addition, nanocomposite films containing higher percent of Fe3O4 NPs displayed more antibacterial activities. PMID- 23748005 TI - Effects of activating cations and inhibitor on the allosteric regulation of rabbit muscle pyruvate kinase. AB - Rabbit muscle pyruvate kinase (RMPK) requires activating cations for activity, but its activity can be allosterically inhibited. In this study, isothermal titration calorimetry (ITC) was used to examine the different effects of activating cations (K(+) or Mg(2+)) and inhibitor (Phe) on the allosteric regulation of RMPK. The ITC data reveal that the enthalpy change was greater for PEP binding to the active state compared to the inactive state. Meanwhile, the percentage of the active state increased with increasing concentration of K(+) or Mg(2+), whereas increasing Phe concentration had the opposite effect. In addition, we hypothesize that the activation of RMPK involves two processes. First, the interaction of Mg(2+) leads to a more exposed active site of RMPK. The process is rapid and only a small quantity of Mg(2+) can make RMPK transform to the intermediate state. Second, the subsequent binding of K(+) causes a critical orientation of the active site, which plays a more decisive role for PEP binding to RMPK than Mg(2+). PMID- 23748006 TI - Sustained release of Avastin(r) from polysaccharides cross-linked hydrogels for ocular drug delivery. AB - Avastin((r)) was the first choice drug for the treatment of age related macular degeneration (AMD) and proliferative diabetic retinopathy in clinic. Due to its short half-time in intraocular, it was required repeat administration. In this paper, an in situ injectable polysaccharides cross-linked hydrogel was developed for potential ocular drug delivery of avastin. The polysaccharide cross-linked hydrogel was first synthesized by simple mixing of glycol chitosan and oxidized alginate aqueous solution, and then characterized by scanning electron microscopy (SEM) and rheometer. In vitro degradation test indicated that the degradation rate of hydrogels could be controlled by the varying the content of oxidized alginate in hydrogels. In vitro release study showed that the encapsulated avastin had an initial burst release at early stage (within 4 h) followed by a sustained release manner in period of 3 days. With the increase of oxidized alginate concentration in the hydrogel, the release rate of avastin from hydrogels declined accordingly. Meanwhile, the structure stability of avastin released from hydrogels at specific time intervals did not show apparent changes as compared with native avastin based on the analysis of SDS-polyacrylamide gel electrophoresis (SDS-PAEG). As a result, the developed in situ injectable polysaccharides cross-linked hydrogel with controllable degradation rate and drug release might be a versatile carrier for avastin to apply in ocular drug delivery. PMID- 23748007 TI - The effects of R683S (G) genetic mutations on the JAK2 activity, structure and stability. AB - Janus kinase 2 (JAK2) is an important mediator of cytokine receptor signaling and plays key roles in the hematopoietic and immune response. The acquired JAK2 R683S (G) mutations are presumed to be a biomarker for B-cell acute lymphoblastic leukemia (B-ALL). However, how these mutations leading to the B-ALL is still unclear. The crystal structure of JAK2 JH2 domain suggests that the residue R683 locating in the linker between the N and C lobes of JH2 domain is important for keeping the compact structure, activity and structural stability of this domain. Mutations R683S, R683G and R683E significantly increase JAK2 activity and decrease its structural stability. While the R683K and R683H mutations almost have no effects on the JAK2 activity and structural stability. Furthermore, the spectroscopic experiments imply that mutations R683S, R683G and R683E impair the structure of JAK2 JH2 domain, and lead JAK2 to partially unfolded state. It may be this partially unfolded state that caused JAK2 R683S (G) constitutive activation. This study provides clues in understanding the mechanism of JAK2 R683S (G) mutations caused B-ALL. PMID- 23748008 TI - Liposome can improve the adjuvanticity of astragalus polysaccharide on the immune response against ovalbumin. AB - In vitro, the effects of astragalus polysaccharide liposome (APSL) on splenocyte proliferation of mice were determined. The results showed that APSL could significantly promote splenocyte proliferation synergistically with PHA and LPS and the efficacy were superior to those of astragalus polysaccharide (APS) and blank liposome (BL). In immune response experiment, the adjuvant effect of APSL at three doses, APS, BL and aluminum hydroxide (alum) were compared on mice immunized subcutaneously with ovalbumin (OVA). The results showed that APSL could significantly promote splenocyte proliferation, enhance specific IgG, IgG1 and IgG2a antibody responses, promote IFN-gamma and IL-6 secretion, and the efficacy were significantly better than alum at most time points. These results indicated that APSL could significantly improve the adjuvanticity and drug action of APS, and its high and medium doses possessed the best efficacy. Therefore, the liposome would be expected to exploit into a new-type preparation of APS. PMID- 23748009 TI - Acid-thermal dextrin prepared from rice starch: structure and encapsulation properties. AB - In this study, acid-thermal dextrin (ATD) was prepared from rice starch using hydrochloric acid in combination with heat treatment. The structure and encapsulation properties of ATD were examined. The results showed that three fractions (Fraction I, Fraction II, and Fraction III) in ATD were obtained based on the distribution of molecular weight (M(w)) in high-performance size-exclusion chromatographic (HPSEC) spectra. The Fraction II (M(w)~10,000 Da) was identified using high-performance anion exchange chromatography (HPAEC), indicating that it consisted of three major groups: DP=2-5, DP=6-15, and DP=25-36. This distribution in chains led to good encapsulating ability of Fraction II to cinnamaldehyde (CIN) and a maximum encapsulation rate reached 41.2 MUL/g (CIN/Fraction II) with a molar ratio of about 3:1. The encapsulating mechanism was proposed due to a single helical V-conformation (single resonance at 102.7 ppm) of Fraction II present and observed in solid-state NMR spectra. PMID- 23748010 TI - Antitumor activity of polysaccharides from Lepista sordida against laryngocarcinoma in vitro and in vivo. AB - Four water-soluble polysaccharides (LSPa1, LSPb1, LSPb2 and LSPc1) extracted from the fruiting bodies of Lepista sordida were prepared by DEAE cellulose-52 anion exchange and Sepharose 6 Fast Flow gel-permeation chromatography. LSPa1 was composed of Glc, Man and Gal with a molar ratio of 3.2: 1.3: 0.6. LSPb1, LSPb2 and LSPc1 were composed of Glc, Man, Gal, Rha and Ara in the proportions of 2.6: 2.1: 0.9: 0.6: 0.3, 1.2: 1.0: 2.3: 0.6: 0.5, 0.2: 0.3: 2.3: 0.3: 2.0, respectively. The high-performance gel-permeation chromatography (HPGPC) analysis showed that the average molecular weight (Mw) of four polysaccharides were approximately 156, 134, 96 and 57 kDa, respectively. MTT and lactate dehydrogenase (LDH) assays indicated that three acidic polysaccharides, namely LSPb1, LSPb2 and LSPc1, possessed more potent antiproliferative effect on human laryngocarcinoma Hep-2 cells than neutral polysaccharide LSPa1 in a dose- and time-dependent manner and the effect increased in the order of LSPa10.060). At baseline, there were no significant associations between brain anomalies and BDNF genotype. Functional deficits were similar in Met-carrier and Val homozygote patients after 3-year follow-up (X(2) = 0.66; p = 0.564); there was no relationship between significant volume change across time and functional outcome. Otherwise, Met-carrier controls had significant high rates of alcohol-consumption (p = 0.019) compared to Val homozygote controls. CONCLUSION: Our findings do not support the notion that BDNF genotype variations may mediate brain macroscopic morphological changes across time. PMID- 23748017 TI - A trivial role of STAT4 variant in chronic hepatitis B induced hepatocellular carcinoma. AB - Two polymorphisms in the STAT4 and HLA-DQ loci were more recently reported to associate with chronic hepatitis B (CHB) induced hepatocellular carcinoma (HCC). We utilised an independent Vietnamese cohort of clinically classified HBV patients of chronic hepatitis B carriers (n=206), liver cirrhosis (n=222) and hepatocellular carcinoma (n=239) and assessed the influence of the reported variants. The STAT4 variant (rs7574865) was marginally associated with HCC susceptibility in CHB carriers in allelic and recessive genetic models (OR=0.84, 95%CI=0.7-0.99, P=0.048 and OR=0.7, 95%CI=0.5-0.99, P=0.047). No significant association between the studied variant with several clinical parameters such as liver enzymes (ALT, AST), total and direct bilirubin, AFP, HBV genotype and viral loads were observed. Our study highlights the reported variant to be a trivial factor and possibly other confounding factors may regulate STAT4 expression during HCC development. PMID- 23748018 TI - Multiple locus VNTR analysis highlights that geographical clustering and distribution of Dichelobacter nodosus, the causal agent of footrot in sheep, correlates with inter-country movements. AB - Dichelobacter nodosus is a Gram-negative, anaerobic bacterium and the causal agent of footrot in sheep. Multiple locus variable number tandem repeat (VNTR) analysis (MLVA) is a portable technique that involves the identification and enumeration of polymorphic tandem repeats across the genome. The aims of this study were to develop an MLVA scheme for D. nodosus suitable for use as a molecular typing tool, and to apply it to a global collection of isolates. Seventy-seven isolates selected from regions with a long history of footrot (GB, Australia) and regions where footrot has recently been reported (India, Scandinavia), were characterised. From an initial 61 potential VNTR regions, four loci were identified as usable and in combination had the attributes required of a typing method for use in bacterial epidemiology: high discriminatory power (D>0.95), typeability and reproducibility. Results from the analysis indicate that D. nodosus appears to have evolved via recombinational exchanges and clonal diversification. This has resulted in some clonal complexes that contain isolates from multiple countries and continents; and others that contain isolates from a single geographic location (country or region). The distribution of alleles between countries matches historical accounts of sheep movements, suggesting that the MLVA technique is sufficiently specific and sensitive for an epidemiological investigation of the global distribution of D. nodosus. PMID- 23748019 TI - Gamma aminobutyric acid B and 5-hydroxy tryptamine 2A receptors functional regulation during enhanced liver cell proliferation by GABA and 5-HT chitosan nanoparticles treatment. AB - Liver is one of the major organs in vertebrates and hepatocytes are damaged by many factors. The liver cell maintenance and multiplication after injury and treatment gained immense interest. The present study investigated the role of Gamma aminobutyric acid (GABA) and serotonin or 5-hydroxytryptamine (5-HT) coupled with chitosan nanoparticles in the functional regulation of Gamma aminobutyric acid B and 5-hydroxy tryptamine 2A receptors mediated cell signaling mechanisms, extend of DNA methylation and superoxide dismutase activity during enhanced liver cell proliferation. Liver injury was achieved by partial hepatectomy of male Wistar rats and the GABA and 5-HT chitosan nanoparticles treatments were given intraperitoneally. The experimental groups were sham operated control (C), partially hepatectomised rats with no treatment (PHNT), partially hepatectomised rats with GABA chitosan nanoparticle (GCNP), 5-HT chitosan nanoparticle (SCNP) and a combination of GABA and 5-HT chitosan nanoparticle (GSCNP) treatments. In GABA and 5-HT chitosan nanoparticle treated group there was a significant decrease (P<0.001) in the receptor expression of Gamma aminobutyric acid B and a significant increase (P<0.001) in the receptor expression of 5-hydroxy tryptamine 2A when compared to PHNT. The cyclic adenosine monophosphate content and its regulatory protein, presence of methylated DNA and superoxide dismutase activity were decreased in GCNP, SCNP and GSCNP when compared to PHNT. The Gamma aminobutyric acid B and 5-hydroxy tryptamine 2A receptors coupled signaling elements played an important role in GABA and 5-HT chitosan nanoparticles induced liver cell proliferation which has therapeutic significance in liver disease management. PMID- 23748020 TI - Proteomic analysis of Chlorella vulgaris: potential targets for enhanced lipid accumulation. AB - Oleaginous microalgae are capable of producing large quantities of fatty acids and triacylglycerides. As such, they are promising feedstocks for the production of biofuels and bioproducts. Genetic strain-engineering strategies offer a means to accelerate the commercialization of algal biofuels by improving the rate and total accumulation of microalgal lipids. However, the industrial potential of these organisms remains to be met, largely due to the incomplete knowledgebase surrounding the mechanisms governing the induction of algal lipid biosynthesis. Such strategies require further elucidation of genes and gene products controlling algal lipid accumulation. In this study, we have set out to examine these mechanisms and identify novel strain-engineering targets in the oleaginous microalga, Chlorella vulgaris. Comparative shotgun proteomic analyses have identified a number of novel targets, including previously unidentified transcription factors and proteins involved in cell signaling and cell cycle regulation. These results lay the foundation for strain-improvement strategies and demonstrate the power of translational proteomic analysis. BIOLOGICAL SIGNIFICANCE: We have applied label-free, comparative shotgun proteomic analyses, via a transcriptome-to-proteome pipeline, in order to examine the nitrogen deprivation response in the oleaginous microalga, C. vulgaris. Herein, we identify potential targets for strain-engineering strategies targeting enhanced lipid accumulation for algal biofuels applications. Among the identified targets are proteins involved in transcriptional regulation, lipid biosynthesis, cell signaling and cell cycle progression. This article is part of a Special Issue entitled: Translational Plant Proteomics. PMID- 23748021 TI - Site specific identification of endogenous S-nitrosocysteine proteomes. AB - Cysteine S-nitrosylation is a post-translational modification regulating protein function and nitric oxide signaling. Herein the selectivity, reproducibility, and sensitivity of a mass spectrometry-based proteomic method for the identification of endogenous S-nitrosylated proteins are outlined. The method enriches for either S-nitrosylated proteins or peptides through covalent binding of the cysteine sulfur with phenylmercury at pH=6.0. Phenylmercury reacts selectively and efficiently with S-nitrosocysteine since no reactivity can be documented for disulfides, sulfinic or sulfonic acids, S-glutathionylated, S-alkylated or S sulfhydrylated cysteine residues. A specificity of 97+/-1% for the identification of S-nitrosocysteine peptides in mouse liver tissue is achieved by the inclusion of negative controls. The method enables the detection of 36 S-nitrosocysteine peptides starting with 5pmolS-nitrosocysteine/mg of total tissue protein. Both the percentage of protein molecules modified as well as the occupancy by S nitrosylation can be determined. Overall, selective, sensitive and reproducible enrichment of S-nitrosylated proteins and peptides is achieved by the use of phenylmercury. The inclusion of appropriate negative controls secures the precise identification of endogenous S-nitrosylated sites and proteins in biological samples. BIOLOGICAL SIGNIFICANCE: The current study describes a selective, sensitive and reproducible method for the acquisition of endogenously S nitrosylated proteins and peptides. The acquisition of endogenous S nitrosoproteomes provides robust data that is necessary for investigating the mechanism(s) of S-nitrosylation in vivo, the factors that govern its selectivity, the dependency of the modification on different isoforms of nitric oxide synthases (NOS), as well as the physiological functions of this protein modification. This article is part of a Special Issue entitled: Posttranslational Protein modifications in biology and Medicine. PMID- 23748022 TI - Quantitative secretome analysis reveals the interactions between epithelia and tumor cells by in vitro modulating colon cancer microenvironment. AB - In tumor microenvironment, interactions among multiple cell types are critical for cancer progression. Secreted proteins are responsible for crosstalk among these cells within tumor microenvironment. To elucidate the interactions of tumor and epithelia, we co-cultured colon cancer cell line HT29 with normal human colon mucosal epithelial cell line NCM460 to mimic tumor microenvironment in vitro and investigated the differential expression pattern of secretome. A quantitative proteomics approach based on stable isotope labeling by amino acids in cell culture (SILAC) and LC-mass spectrometry was used for secretome analysis. Totally 45 proteins were altered over 2-fold in co-cultured cellular supernatants between equal amounts of NCM460 and HT29 cells, compared with mono-cultured conditions. These differential secreted proteins involve in multiple tumor-associated biological functions. The secretion level and acting pattern of acrogranin, IGFBP6 and vimentin were changed along with different co-cultured cell number ratios between NCM460 and HT29 cells, simulating early, middle or advanced stage of colon cancer. Therefore, a quantitative secretome profiling based on a co culture system can track secreted protein changes and their associated biological roles between tumor and epithelia, which gives a new insight on communications between tumor and epithelia as well as cancer biotherapy by inhibiting cell interactions. BIOLOGICAL SIGNIFICANCE: Tumor microenvironment is a complex system and comprised of cancer cells and host stromal cells. The growth and progression of tumor have been recognized were affected by multidirectional interactions of secreted proteins (secretome), which were produced by the cells within tumor microenvironment. Focus on general secreted molecules of living cells via proteomic tools, is promising for investigating cell communication. Stable isotope labeling by amino acids in cell culture (SILAC) is a metabolic labeling strategy for quantitative analysis, which is gaining popularity because of its ease of implementation, the high quality of quantitative data obtained, robustness and compatibility with existing experimental workflows. Therefore, SILAC-based quantitative secretome analysis was employed for investigating interactions between epithelia and tumor by in vitro modulating colon cancer microenvironment with established co-culture system, which simplified the complexity of cancer microenvironment, also tracked secreted protein changes and their associated biological roles between epithelia and cancer cells. A series of tumor associated secreted proteins was quantitated and investigated in our study. So, the results give a new insight on communications between tumor and epithelia as well as cancer biotherapy by inhibiting interactions of them. PMID- 23748023 TI - Proteomic characterization and cross species comparison of mammalian seminal plasma. AB - Seminal plasma contains a large protein component which has been implicated in the function, transit and survival of spermatozoa within the female reproductive tract. However, the identity of the majority of these proteins remains unknown and a direct comparison between the major domestic mammalian species has yet to be made. As such, the present study characterized and compared the seminal plasma proteomes of cattle, horse, sheep, pig, goat, camel and alpaca. GeLC-MS/MS and shotgun proteomic analysis by 2D-LC-MS/MS identified a total of 302 proteins in the seminal plasma of the chosen mammalian species. Nucleobindin 1 and RSVP14, a member of the BSP (binder of sperm protein) family, were identified in all species. Beta nerve growth factor (bNGF), previously identified as an ovulation inducing factor in alpacas and llamas, was identified in this study in alpaca and camel (induced ovulators), cattle, sheep and horse (spontaneous ovulators) seminal plasma. These findings indicate that while the mammalian species studied have common ancestry as ungulates, their seminal plasma is divergent in protein composition, which may explain variation in reproductive capacity and function. The identification of major specific proteins within seminal plasma facilitates future investigation of the role of each protein in mammalian reproduction. BIOLOGICAL SIGNIFICANCE: This proteomic study is the first study to compare the protein composition of seminal plasma from seven mammalian species including two camelid species. Beta nerve growth factor, previously described as the ovulation inducing factor in camelids is shown to be the major protein in alpaca and camel seminal plasma and also present in small amounts in bull, ram, and horse seminal plasma. PMID- 23748024 TI - Proteomics of model and crop plant species: status, current limitations and strategic advances for crop improvement. AB - In the last decade proteomics studies have gained increasing importance in plant research. The development of proteomics techniques allowing increased proteome coverage and quantitative measurements of proteins have been particularly instrumental to characterize proteomes and their modulation during plant development, biotic and abiotic stresses. Despite important advances, plant proteome analysis, including those of model plant species, remain constrained by limitations inherent to proteomics techniques and data interpretation. Here we review the approaches and achievements of proteomics with model plant and crop species (i.e. Arabidopsis and rice) and discuss the current limitations of crop proteomics. We anticipate future directions that could advance the contribution of plant proteomics to crop improvement. PMID- 23748025 TI - Peptide microarrays to probe for competition for binding sites in a protein interaction network. AB - Cellular protein interaction networks are a result of the binding preferences of a particular protein and the entirety of interactors that mutually compete for binding sites. Therefore, the reconstruction of interaction networks by the accumulation of interaction networks for individual proteins will greatly overestimate connectivity within the network. Here, we addressed the impact of intracellular complexity on signalling networks using microarrays that carried a collection of peptides binding to the GRB2 SH2 and SH3 domains. Binding patterns and affinities for the recombinant adaptor protein GRB2 were compared with the ones for the protein in cell lysates. Peptide microarrays were titrated with the histidine-tagged recombinant protein, cell lysates or mixtures of both. Indeed, for recombinant GRB2, binding was detected for more peptides than for GRB2 in cell lysates. Moreover, binding was also observed for poor binders. It was impossible to define affinity thresholds for the binding of the recombinant protein to enable a discrimination of physiologically relevant interactions. Titrations of recombinant protein with lysate confirmed competition as the basis for fewer interactions. Importantly, the methods presented here enable the description of physiologically relevant binding patterns for proteins of interest and the identification of those peptide motifs, which are most strongly affected by competition. BIOLOGICAL SIGNIFICANCE: The biological significance of protein protein interactions can only be addressed in a physiologically meaningful way in the presence of the endogenous proteome which may contain proteins that compete for binding sites. Using peptide microarrays, we here demonstrate for the adaptor protein GRB2 that this competition strongly reduces the number of interactions with other signalling proteins. PMID- 23748026 TI - Dracula's children: molecular evolution of vampire bat venom. AB - While vampire bat oral secretions have been the subject of intense research, efforts have concentrated only on two components: DSPA (Desmodus rotundus salivary plasminogen activator) and Draculin. The molecular evolutionary history of DSPA has been elucidated, while conversely draculin has long been known from only a very small fragment and thus even the basic protein class was not even established. Despite the fact that vampire bat venom has a multitude of effects unaccounted by the documented bioactivities of DSPA and draculin, efforts have not been made to establish what other bioactive proteins are secreted by their submaxillary gland. In addition, it has remained unclear whether the anatomically distinct anterior and posterior lobes of the submaxillary gland are evolving on separate gene expression trajectories or if they remain under the shared genetic control. Using a combined proteomic and transcriptomic approach, we show that identical proteins are simultaneously expressed in both lobes. In addition to recovering the known structural classes of DSPA, we recovered a novel DSPA isoform as well as obtained a very large sequence stretch of draculin and thus established that it is a mutated version of the lactotransferrin scaffold. This study reveals a much more complex secretion profile than previously recognised. In addition to obtaining novel versions of scaffolds convergently recruited into other venoms (allergen-like, CRiSP, kallikrein, Kunitz, lysozyme), we also documented novel expression of small peptides related to calcitonin, PACAP, and statherin. Other overexpressed protein types included BPI-fold, lacritin, and secretoglobin. Further, we investigate the molecular evolution of various vampire bat venom-components and highlight the dominant role of positive selection in the evolution of these proteins. Conspicuously many of the proteins identified in the proteome were found to be homologous to proteins with known activities affecting vasodilation and platelet aggregation. We show that vampire bat venom proteins possibly evade host immune response by the mutation of the surface chemistry through focal mutagenesis under the guidance of positive Darwinian selection. These results not only contribute to the body of knowledge regarding haematophagous venoms but also provide a rich resource for novel lead compounds for use in drug design and development. BIOLOGICAL SIGNIFICANCE: These results have direct implications in understanding the molecular evolutionary history of vampire bat venom. The unusual peptides discovered reinforce the value of studying such neglected taxon for biodiscovery. PMID- 23748027 TI - Silencing the ecdysone synthesis and signaling pathway genes disrupts nymphal development in the whitefly. AB - Sap-sucking insects are important pests in agriculture and good models to study insect biology. The role of ecdysone pathway genes in the life history of this group of insects is largely unknown likely due to a lack of efficient gene silencing methods allowing functional genetic analyses. Here, we developed a new and high throughput method to silence whitefly genes using a leaf-mediated dsRNA feeding method. We have applied this method to explore the roles of genes within the molting hormone-ecdysone synthesis and signaling pathway for the survival, reproduction and development of whiteflies. Silencing of genes in the ecdysone pathway had a limited effect on the survival and fecundity of adult whiteflies. However, gene silencing reduced survival and delayed development of the whitefly during nymphal stages. These data suggest that the silencing method developed here provides a useful tool for functional gene discovery studies of sap-sucking insects, and further indicate the potential of regulating the ecdysone pathway in whitefly control. PMID- 23748028 TI - The nuclear localization signal is required for nuclear GPER translocation and function in breast Cancer-Associated Fibroblasts (CAFs). AB - Cancer associated fibroblasts (CAFs) actively contribute to the growth and invasion of cancer cells. In recent years, the G protein estrogen receptor (GPER) has been largely involved in the estrogenic signals in diverse types of normal and tumor cells. In CAFs, GPER was localized into the nucleus, however the molecular mechanisms which regulate its nuclear shuttle remain to be clarified. In the present study, we demonstrate that in breast CAFs GPER translocates into the nucleus through an importin-dependent mechanism. Moreover, we show that a nuclear localization signal is involved in the nuclear import of GPER, in the up regulation of its target genes c-fos and CTGF and in the migration of CAFs induced by estrogens. Our data provide novel insights into the nuclear localization and function of GPER in CAFs toward a better understanding of the estrogen action elicited through these key players of the tumor microenvironment. PMID- 23748029 TI - AMPK signaling pathway is rapidly activated by T3 and regulates the cardiomyocyte growth. AB - Previous studies have indicated that AMP-activated protein kinase (AMPK) plays a critical role in the control of cardiac hypertrophy mediated by different stimuli such as thyroid hormone (TH). Although the classical effects of TH mediating cardiac hypertrophy occur by transcriptional mechanisms, recent studies have identified other responses to TH, which are more rapid and take place in seconds or minutes evidencing that TH rapidly modulates distinct signaling pathway, which might contribute to the regulation of cardiomyocyte growth. Here, we evaluated the rapid effects of TH on AMPK signaling pathway in cultured cardiomyocytes and determined the involvement of AMPK in T3-induced cardiomyocyte growth. We found for the first time that T3 rapidly activated AMPK signaling pathway. The use of small interfering RNA against AMPK resulted in increased cardiomyocyte hypertrophy while the pharmacological stimulation of AMPK attenuated this process, demonstrating that AMPK contributes to regulation of T3-induced cardiomyocyte growth. PMID- 23748030 TI - Distinct post-transcriptional regulation of Igfbp1 gene by hypoxia in lowland mouse and Qinghai-Tibet plateau root vole Microtus oeconomus. AB - Our previous study revealed the particular expression patterns of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 1 (IGFBP1) in the Qinghai-Tibet plateau root vole (Microtus oeconomus) under hypoxic challenge. Here we report the molecular mechanisms of Igf gene regulation associated with adaptation to hypoxia. M. oeconomus IGF1 and IGFBP1 were shown to be highly conserved. Hypoxia (8.0% O2, 6h) did not change the liver-derived Igf1 expression in either M. oeconomus or mouse. Hypoxia significantly upregulated hepatic Igfbp1 gene expression and IGFBP1 levels in the liver and plasma of the mouse, but not in M. oeconomus. A functional U-rich element in the 3' untranslated region was found in mouse Igfbp1 mRNA, which was associated with Igfbp1 mRNA stabilization and upregulation under hypoxia, and this U-rich element was eliminated in the M. oeconomus Igfbp1, resulting in blunted Igfbp1 mRNA upregulation, which might be understood as a sequence variation modified during molecular evolution under hypoxia. PMID- 23748031 TI - Telomeres and cardiovascular disease risk: an update 2013. AB - Leukocyte telomere length (LTL) has been regarded as a potential marker of biologic aging because it usually shortens in a predictable way with age. Recently, a growing interest in cardiovascular aging has led to a number of new epidemiologic studies investigating LTL in various disease conditions. Some methodological problems exist because there are different methods available to determine LTL, and standardization is much needed. For example, in the majority of studies, patients with early-onset coronary heart disease have been shown to have shorter LTL. In addition, patients with diabetes mellitus complications tend to have shorter LTL than control subjects. On the other hand, increased left ventricular hypertrophy or mass is associated with longer LTL, and studies investigating hypertension have reported both shorter and longer LTL than found in normotensive control subjects. There is, therefore, a need for longitudinal studies to elucidate these complicated relationships further, to provide estimations of telomere attrition rates, and to overcome analytical problems when only cross-sectional studies are used. The understanding of cardiovascular aging and telomere biology may open up new avenues for interventions, such as stem cell therapy or agents that could retard this aging process over and beyond conventional risk factor control. PMID- 23748032 TI - Upgrading rate of papillary breast lesions diagnosed by core-needle biopsy. AB - PURPOSE: We aimed to estimate the upgrading rate of core-needle biopsy (CNB) diagnosed papillary breast lesions to atypical or malignant papillary lesions on subsequent surgery. MATERIALS AND METHODS: We performed a retrospective review of medical records and imaging findings of patients diagnosed by CNB as having papillary lesions from January 1, 2005 to May 31, 2011. Outcomes were determined by pathology findings from surgical excision or by imaging findings at 12 months follow-up. RESULTS: Of 130 papillary lesions in 127 patients, the upgrading rates were 0% for benign papillary lesion to malignancy, 19% for benign papillary lesion to atypical papillary lesion, and 31% for atypical lesion to malignancy. Most of the malignancies were ductal carcinoma in situ. The presence of malignant lesions was related to specific symptoms (palpable mass or nipple discharge; P = 0.020) and to a higher Breast Imaging Reporting and Data System (BIRADS) category (P = 0.017). CONCLUSION: CNB is accurate in the diagnosis of benign papillary lesions. If no atypical cells are present, no malignancy is found. The presence of atypia on CNB strongly indicates a need for surgical excision. PMID- 23748033 TI - The current role of radiologists in a multidisciplinary team treating breast cancer. AB - In the last decade, advances in the diagnosis and treatment of breast cancer have achieved a significant increase in the general and disease-free survival of affected women but have also increased the complexity of therapeutic decisions. The decision-making process requires agreement between the physicians involved in the management of these patients. Radiologists must understand what other physicians expect and inform them about the usefulness of imaging modalities. This review attempts to provide an update on these subjects. PMID- 23748034 TI - SPECT-CT for characterization of extraosseous uptake of 99mTc-methylene diphosphonate on bone scintigraphy. AB - Bone scintigraphy is a sensitive and popular method for imaging a wide array of benign or malignant skeletal abnormalities. However, the uptake of tracers used for bone scintigraphy may be observed in various extraosseous sites, thereby limiting its specificity. It is difficult to correctly localize such sites of uptake on planar bone scintigraphy alone. The addition of hybrid single-photon emission computed tomography-computed tomography (SPECT-CT) under such circumstances is very useful. The present essay illustrates the commonly encountered extraosseous uptake of 99mTc-methylene diphosphonate (MDP) and the usefulness of hybrid SPECT-CT in clarifying 99mTc-MDP uptake. PMID- 23748035 TI - MRI of bone marrow abnormalities in hematological malignancies. AB - Magnetic resonance imaging (MRI) is essential for evaluating bone marrow. Bone marrow undergoes constant modification and its appearance on MRI changes in response. Knowledge of the types of changes and their origins is essential for analysis of MRI findings of bone marrow infiltration with hematological malignancies. This pictorial review describes the MRI pulse sequences used for imaging of bone marrow, and illustrates bone marrow changes due hematological malignancies, including changes following treatment. PMID- 23748036 TI - CT-based weight assessment of lung lobes: comparison with ex vivo measurements. AB - PURPOSE: We aimed to evaluate the validity of lung lobe weight assessment via computed tomography (CT) by comparing CT-derived and ex vivo measurements. MATERIALS AND METHODS: Unenhanced CT scanning was performed in 30 consecutive patients before lobectomy for lung cancer. The CT images were analyzed using research software after allowing for lobar weight quantitation. The lobar weight estimated by CT was then compared with that measured after surgery using a precision scale (ex vivo measurement). Comparisons as well as assessment of intra and interoperator variability were conducted using the Bland-Altman method and the coefficient of repeatability (CR). Correlations were examined using Pearson's correlation analysis. RESULTS: Comparison analyses were feasible for 28 cases. The ex vivo lobe weight was 186.2+/-57.3 g, whereas the weights measured by the two operators by CT were 190.0+/-55 and 182.4+/-58.2 g, respectively. As compared with ex vivo weights, the CR was 36.4 for operator 1 and 50.4 for operator 2; the mean differences were 3.8 and -3.8 for operators 1 and 2, respectively. The intraoperator and interoperator CR were 20.9 and 36.6, respectively. The mean differences for the intra- and interoperator analysis were -1.5 and -7.5, respectively. The correlation was very high between CT-based and ex vivo measurements (r=0.95 and r=0.90 for operators 1 and 2, respectively; P < 0.001). CONCLUSION: Estimation of lung lobe weight by semi-automated CT analysis is sufficiently reproducible and in agreement with ex vivo measurements. PMID- 23748037 TI - Expressions of transcription factors in goldfish (Carassius auratus L.) macrophages and their progenitors. AB - The development of macrophages is a highly regulated process requiring coordination amongst transcription factors. The presence/absence, relative levels, antagonism, or synergy of all transcription factors involved is critical to directing lineage cell fate and differentiation. While relative levels of many key myeloid transcription factors have been determined in mammalian macrophage differentiation, a similar set of studies have yet to be conducted in a teleost system. In this study, we report on the mRNA levels of transcription factors (cebpa, cjun, cmyb, egr1, gata1, gata2, gata3, lmo2, mafb, pax5, pu.1 and runx1) in sorted goldfish progenitor cells, monocytes, and macrophages from primary kidney macrophage cultures. The mRNA levels of runx1 and pu.1 were significantly higher, gata3 and pax5 mRNA levels were lower, in monocytes compared to progenitors, and the mRNA levels of cjun, egr1, gata2, gata3, mafb and pax5 were significantly decreased in macrophages compared to progenitor cells. The relative mRNA levels of the interferon regulatory factor family of transcription factors, irf1, irf2, irf5, irf7, irf8 and irf9 in sorted progenitors, monocytes and macrophages were also measured. In contrast to other irf family transcription factors examined, irf8 mRNA levels were increased in monocytes compared to progenitors by greater than three-fold, suggesting that irf8 is important for monopoiesis. Lastly, we show the differential regulation of myeloid transcription factor mRNA levels in sorted progenitor cells from 1, 2, or 3-day old cultures in response to the recombinant goldfish growth factors, rgCSF-1 and rgKITLA. PMID- 23748038 TI - Intraperitoneal melatonin is not neuroprotective in the G93ASOD1 transgenic mouse model of familial ALS and may exacerbate neurodegeneration. AB - In amyotrophic lateral sclerosis (ALS) reactive oxygen species and apoptosis are implicated in disease pathogenesis. Melatonin with its anti-oxidant and anti apoptotic properties is expected to ameliorate disease phenotype. The aim of this study was to assess possible neuroprotection of melatonin in the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. Four groups of mice, 14 animals each, were injected intraperitoneally with 0mg/kg, 0.5mg/kg, 2.5mg/kg and 50mg/kg of melatonin from age 40 days. The primary end points were; disease onset, disease duration, survival and rotarod performance. No statistically significant difference in disease onset between the four groups was found. Survival was significantly reduced with the 0.5mg/kg and 50mg/kg doses and tended to be reduced with the 2.5mg/kg dose. Histological analysis of spinal cords revealed increased motoneuron loss in melatonin treated mice. Melatonin treated animals were associated with increased oxidative stress as assessed with 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation. Histochemistry and Western blot data of spinal cord from melatonin treated mice revealed upregulation of human SOD1 compared to untreated mice. In addition, real-time PCR revealed a dose dependent upregulation of human SOD1 in melatonin treated animals. Thus, intraperitoneal melatonin, at the doses used, does not ameliorate and perhaps exacerbates phenotype in the G93ASOD1 mouse ALS model. This is probably due to melatonin's effect on upregulating gene expression of human toxic SOD1. This action presumably overrides any of its direct anti-oxidant and anti apoptotic properties. PMID- 23748039 TI - Mu-opioidergic modulation differs in deep and superficial wide-dynamic range dorsal horn neurons in mice. AB - The spinal cord dorsal horn is an important action site for morphine analgesia. Wide-dynamic range (WDR) neurons in the dorsal horn are essential to spinal pain transmission and show increased excitability after repetitive noxious drive (windup). In light of differences in mu-opioid receptor distribution and neurophysiological properties of WDR neurons between deep and superficial dorsal horn, we recorded extracellular single-unit activity of WDR neurons from deep (350-700 MUm) and superficial (<350 MUm) dorsal horn in C57BL/6 mice and compared their responses to spinal superfusion of morphine (0.5mM, 30 MUl) and naloxone (1mM, 30 MUl). The windup level to repetitive electrical stimulation of 1.0 Hz (16 pulses, suprathreshold for C-fiber activation, 2.0 ms) was significantly decreased by morphine in deep (n=8), but not superficial (n=11), WDR neurons. However, the steady C-component response to graded intra-cutaneous electrical stimuli (0.01-5.0 mA, 2 ms) was significantly depressed by morphine only in superficial neurons. In separate experiments, spinal administration of naloxone facilitated the development of windup to 0.2 Hz stimulation in deep (n=10), but not superficial (n=8), WDR neurons. Accordingly, morphine and naloxone modulation of neuronal activity may be related to a specific effect on neuronal sensitization/plasticity in deep WDR neurons, whereas morphine inhibition may depress acute noxious inputs to superficial WDR neurons. Our study suggests that mu-opioidergic modulation may be different in deep and superficial WDR neurons. PMID- 23748040 TI - An efficient and non-enzymatic method for isolation and culture of endothelial cells from the nidus of human cerebral arteriovenous malformations. AB - In this report, we describe an efficient and non-enzymatic method for isolating and culturing endothelial cells (ECs) from the nidus of surgically resected arteriovenous malformation (AVM) specimens. These cultured cells possessed typical phenotypic markers (i.e. von Willebrand factor and CD34), as well as morphological and ultrastructural characteristics of ECs. However, they had activated Notch-1 signaling, which plays a critical role in the development of AVM. The present study suggests that hypoxic endothelial cells from the nidus of human cerebral arteriovenous malformation (CAVMECs) have angiogenic potentials, as our data showed that VEGF gene expression and cell proliferation were more evident with prolonged hypoxia. In our study, we successfully used the vascular tissue explants adherent method to isolate and culture CAVMECs with high purity. This may prove to be a useful tool for studying the molecular mechanisms that mediate abnormal vessel development and maintenance in AVM. PMID- 23748041 TI - Proteinase 3 induces oxidative stress-mediated neuronal death in rat primary cortical neuron. AB - The recruitment of neutrophils into the cerebral microcirculation occurs, especially, in acute brain diseases like a focal cerebral ischemia and plays important role in pathological processes. Proteinase 3 is one of the three major proteinases expressed in neutrophils but no reports are available whether proteinase 3 can modulate neuronal survival. In this study, treatment of cultured rat primary cortical neuron with proteinase 3 induced overt reactive oxygen species production and decreased total glutathione contents as well as disruption of mitochondrial transmembrane potential. Proteinase 3 induced neuronal cell death as evidenced by MTT analysis as well as propidium iodide staining, which was prevented by pretreatment with an antioxidant, N-acetyl cysteine. Proteinase 3 increased activation of procaspase-3 and altered expression level of apoptotic regulator proteins, such as Bcl-2, Bax, and Bcl-xL. Similar to in vitro data, a direct microinjection of proteinase 3 into striatum of rat brain induced neuronal death, which was mediated by reactive oxygen species. These results suggest that proteinase 3 is new essential regulator of neuronal cell death pathway in a condition of excess neutrophil encounter in neuroinflammatory conditions. PMID- 23748042 TI - CA-074Me, a cathepsin B inhibitor, decreases APP accumulation and protects primary rat cortical neurons treated with okadaic acid. AB - Upregulation of the lysosomal system has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). But the exact role of this system remains unknown. Okadaic acid (OA), a protein phosphatase-2A inhibitor, increases tau phosphorylation, beta-amyloid deposition, and neuronal cell death, which are the pathological hallmarks of AD. To investigate the role of lysosomal activation in AD brain cells, cultured neurons were treated with OA and assessed lysosomal morphology and enzyme activity and the protective effect of cathepsin B, D, or L inhibitors. It was found that although it induced lysosomal swelling and enzyme activation, OA did not induce lysosomal rupture. While inhibition of cathepsin D and L failed to protect neurons from OA-induced cell death, CA074-Me, a cathepsin B inhibitor, conferred a protective effect. Interestingly, CA-074Me reduced amyloid precursor protein (APP) accumulation and alpha-spectrin cleavage, similar to the effect of calpain inhibition. PMID- 23748043 TI - A method for selective ablation of neurons in C. elegans using the phototoxic fluorescent protein, KillerRed. AB - Specific neuron ablation with laser microbeam has been used in behavioral analysis of Caenorhabditis elegans. However, this method is hard to acquire many ablated worms, and is unable to compare behavioral changes just before and after ablation. Here, we developed an ablation method by using genetically encoded photosensitizer protein, KillerRed, which produces reactive oxygen species by green light irradiation. Ablation of AWA sensory neurons abolished the chemotaxis to AWA specific sensitive attractant, diacetyl, and no functional effect on the other sensory neuron, AWC, which senses benzaldehyde. This ablation method can be useful for analyzing neural in situ. PMID- 23748044 TI - Pre-attentive auditory processing of non-scale pitch in absolute pitch possessors. AB - Absolute pitch (AP) refers to the ability to identify the pitch of sound without reference. To clarify the neurophysiological characteristics of AP, we compared mismatch negativity (MMN) elicited by scale and non-scale notes between AP possessors and non-AP individuals. Eight individuals who were able to identify pitch with perfect accuracy were defined as AP possessors. Eighteen participants who failed to achieve perfect accuracy were included in the non-AP group. We presented participants with two tone pairs, in a scale condition and a non-scale condition. The frequency ratios of the two pairs were the same. MMN over the frontal region in the non-scale condition was larger in the AP group than the non AP group. In contrast, no such difference was observed between the two groups in the scale condition. The results suggest that pre-attentive processing of non scale note sounds in the auditory cortex is a salient neurophysiological characteristic of AP. PMID- 23748045 TI - TNF-related weak inducer of apoptosis (TWEAK) promotes kidney fibrosis and Ras dependent proliferation of cultured renal fibroblast. AB - Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) regulates apoptosis, proliferation and inflammation in renal epithelial cells and plays a role in acute kidney injury. However, there is little information on the chronic effects of TWEAK. We hypothesized that TWEAK may influence renal fibrosis and regulate kidney fibroblast biology, in part, through Ras pathway. We studied a chronic model of experimental unilateral ureteral obstruction in wild type and TWEAK deficient mice, and a murine model of systemic TWEAK overexpression. TWEAK actions were also explored in cultured renal and embryonic fibroblasts. TWEAK and TWEAK receptor expression was increased in the obstructed kidneys. The absence of TWEAK decreased early kidney tubular damage, inflammatory infiltrates and myofibroblast number. TWEAK deficient mice had decreased renal fibrosis 21days after obstruction, as assessed by extracellular matrix staining. In mice without prior underlying kidney disease, systemic overexpression of TWEAK induced kidney inflammation and fibrosis. In cultured fibroblasts, TWEAK induced proliferation through activation of the Ras/ERK pathway. TWEAK also activated nuclear factor kappaB (NFkappaB)-dependent inflammatory chemokine production in murine renal fibroblasts. In conclusion, lack of TWEAK reduces renal fibrosis in a model of persistent kidney insult and overexpression of TWEAK led to renal fibrosis. TWEAK actions on renal fibroblasts may contribute to the in vivo observations, as TWEAK promotes inflammatory activity and proliferation in fibroblast cultures. PMID- 23748047 TI - Measures of balance performance are affected by a rested versus fatigued testing condition in people with multiple sclerosis. AB - OBJECTIVE: To investigate the effects of a rested and fatigued testing condition on measures of balance in people with multiple sclerosis (MS). DESIGN: Prospective observational study. SETTING: Academic research laboratory. PARTICIPANTS: Fifteen ambulatory adults with relapsing remitting or secondary progressive MS with moderate disability. METHODS: Measures of postural control, dynamic balance, and fatigue were assessed during a "rested" and "fatigued" testing condition on separate days. MAIN OUTCOME MEASUREMENTS: Static posturography was used to assess postural control. The Mini-Balance Evaluation Systems Test and Dynamic Gait Index were used to assess dynamic balance. The chronic fatigue level was measured by using the Fatigue Severity Scale, and acute fatigue was assessed by using a visual analog scale at multiple time points during testing. RESULTS: During the fatigued condition, the participants reported a significant (P < .05) increase in acute fatigue levels (visual analog scale) and demonstrated a significant (P < .05) decrease in performance on measures of postural control and dynamic balance when compared with the rested condition. However, no significant relationship was identified between the changes in fatigue and changes in balance performance. CONCLUSIONS: Measures of balance performance and acute fatigue may be affected by rested versus fatigued testing conditions in people with MS. However, no significant relationships between changes in balance and fatigue were identified. Therefore, clinicians should use caution when making assumptions about the influence of fatigue on balance performance and should test for individual responses. Clinicians and researchers should also consider controlling for factors such as time of day and prior physical activity when administering standardized measures of balance in people with MS. PMID- 23748046 TI - The rate of spontaneous mutations in human myeloid cells. AB - The mutation rate (MU) is likely to be a key parameter in leukemogenesis, but historically, it has been difficult to measure in humans. The PIG-A gene has some advantages for the detection of spontaneous mutations because it is X-linked, and therefore only one mutation is required to disrupt its function. Furthermore, the PIG-A-null phenotype is readily detected by flow cytometry. Using PIG-A, we have now provided the first in vitro measurement of MU in myeloid cells, using cultures of CD34+ cells that are transduced with either the AML-ETO or the MLL AF9 fusion genes and expanded with cytokines. For the AML-ETO cultures, the median MU value was ~9.4*10(-7) (range ~3.6-23*10(-7)) per cell division. In contrast, few spontaneous mutations were observed in the MLL-AF9 cultures. Knockdown of p53 or introduction of mutant NRAS or FLT3 alleles did not have much of an effect on MU. Based on these data, we provide a model to predict whether hypermutability must occur in the process of leukemogenesis. PMID- 23748048 TI - Optic nerve histopathology in a case of Wolfram Syndrome: a mitochondrial pattern of axonal loss. AB - Mitochondrial dysfunction in Wolfram Syndrome (WS) is controversial and optic neuropathy, a cardinal clinical manifestation, is poorly characterized. We here describe the histopathological features in postmortem retinas and optic nerves (ONs) from one patient with WS, testing the hypothesis that mitochondrial dysfunction underlies the pathology. Eyes and retrobulbar ONs were obtained at autopsy from a WS patient, and compared with those of a Leber hereditary optic neuropathy (LHON) patient and one healthy control. Retinas were stained with hematoxylin & eosin for general morphology and ONs were immunostained for myelin basic protein (MBP). Immunostained ONs were examined in four "quadrants": superior, inferior, nasal, and temporal. The WS retinas displayed a severe loss of retinal ganglion cells in the macular region similar to the LHON retina, but not in the control. The WS ONs, immunostained for MBP, revealed a zone of degeneration in the temporal and inferior quadrants. This pattern was similar to that seen in the LHON ONs but not in the control. Thus, the WS patient displayed a distinct pattern of optic atrophy observed bilaterally in the temporal and inferior quadrants of the ONs. This arrangement of axonal degeneration, involving primarily the papillomacular bundle, closely resembled LHON and other mitochondrial optic neuropathies, supporting that mitochondrial dysfunction underlies its pathogenesis. PMID- 23748049 TI - Severe manifestation of Leber's hereditary optic neuropathy due to 11778G>A mtDNA mutation in a female with hypoestrogenism due to Perrault syndrome. AB - Perrault syndrome (PS) is a rare autosomal recessive condition with ovarian dysgenesis, hearing deficit and neurological abnormalities in female patients. The molecular basis of the syndrome is heterogeneous, mutations in the HSD17B4 gene have been identified in one family and mutations in the HARS2 gene have been found in another one. We have excluded pathogenic changes in the HSD17B4 gene and in the HARS2 gene by a direct sequencing of all coding exons in a female with clinical hallmarks of PS, ataxia and mild mental retardation. In addition, the patient suffers from severe Leber's hereditary optic neuropathy (LHON) due to 11778G>A mtDNA mutation. This case is the first reported patient with PS and LHON. Possible influence of hypoestrogenism on the manifestation of optic neuropathy in this patient is discussed in the context of recent findings concerning the crucial role of estrogens in supporting the vision capacity in LHON-related mtDNA mutation carriers. PMID- 23748050 TI - The Novartis view on emerging drugs and novel targets for the treatment of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterized by airflow limitation and chronic inflammation in the lungs. The mainstay of drug therapy for COPD is represented by long-acting bronchodilators, an important aspect of Novartis' development program. Novel once-daily dosing bronchodilators, such as the long-acting muscarinic antagonist (LAMA) glycopyrronium and the LAMA/long-acting beta2-agonist (LABA) fixed-dose combination QVA149, have been shown to provide significant benefits to patients with COPD in terms of improvement in lung function, exercise tolerance, health related quality of life, symptoms and reduction in the rate of exacerbations. Despite the benefits provided by these new treatment options, prevention of disease progression and control of exacerbations in certain patient phenotypes remain key challenges in the treatment of COPD. In order to address these needs and gain new insights into the complexity of COPD, Novartis is, in addition to bronchodilator-only therapies, developing LABA/inhaled corticosteroids (ICS) combinations to target inflammation, such as QMF149, as well as non-steroid based anti-inflammatory agents against key novel targets. These commitments are central to the Novartis' final goal of improving the standard of care in respiratory medicine and offering a better quality of life to patients with COPD. PMID- 23748052 TI - The synthetic food colouring agent Allura Red AC (E129) is not genotoxic in a flow cytometry-based micronucleus assay in vivo. AB - The safety of several azo colouring agents, used as food additives, has during the years been questioned. Allura Red AC (E129) has in some publications been classified as genotoxic. In fact, in the European Union, Allura Red is permitted as a food additive in human food, but, surprisingly, it was not acceptable as an additive for use in animal feed. In this study we have evaluated whether Allura Red is genotoxic using a flow cytometer-based micronucleus assay in peripheral blood of mice. Male FVB mice were given a single intra-peritoneal injection of various doses of Allura Red and sacrificed at 46 h after treatment. The tested doses were 0, 100, 200, 400, 600, 800, 1000, 1500, and 2000 mg/kg body weight (b.w.). Each dose group constituted three mice, except for in the dose group of 1000 mg/kg b. w., which constituted four mice. Blood samples were collected and the frequency of micronucleated polychromatic erythrocytes (fMNPCE) and the cell proliferation (%PCE) was determined. The analyses did not show any significant difference in the %PCE or in the fMNPCE. Consequently, under the testing circumstances one can conclude that Allura Red is not genotoxic. PMID- 23748051 TI - Effects of non-linearity on cell-ECM interactions. AB - Filamentous biopolymers such as F-actin, vimentin, fibrin and collagen that form networks within the cytoskeleton or the extracellular matrix have unusual rheological properties not present in most synthetic soft materials that are used as cell substrates or scaffolds for tissue engineering. Gels formed by purified filamentous biopolymers are often strain stiffening, with an elastic modulus that can increase an order of magnitude at moderate strains that are relevant to cell and tissue deformation in vivo. This review summarizes some experimental studies of non-linear rheology in biopolymer gels, discusses possible molecular mechanisms that account for strain stiffening, and explores the possible relevance of non-linear rheology to the interactions between cell and extracellular matrices. PMID- 23748053 TI - Antibiotics acting as neuroprotectants via mechanisms independent of their anti infective activities. AB - This review considers available evidence that some antibiotics have ancillary neuroprotective effects. Notably, beta-lactam antibiotics are believed to increase the expression of glutamate transporter GLT1, potentially relieving the neurological excitotoxicity that characterizes disorders like amyotrophic lateral sclerosis. Minocycline has shown promise in reducing the severity of a number of neurological diseases, including multiple sclerosis, most likely by reducing apoptosis and the expression of inflammatory mediators in the brain. Rapamycin inhibits the activity of a serine/threonine protein kinase that has a role in the pathogenesis of numerous neurologic diseases. Herein we examine the unique neuroprotective aspects of these drugs originally developed as anti-infective agents. PMID- 23748055 TI - A combined alpha7 nicotinic acetylcholine receptor agonist and monoamine reuptake inhibitor, NS9775, represents a novel profile with potential benefits in emotional and cognitive disturbances. AB - As affective and cognitive disturbances frequently co-occur in psychiatric disorders, research into opportunities to simultaneously target both entities is warranted. These disorders are typically treated with monoamine reuptake inhibitors (MRIs), whereas ongoing research suggests that symptoms also improve by nicotinic acetylcholine receptor (nAChR) activation. Preclinical studies have corroborated this and also demonstrated a synergistic antidepressant-like action when nAChR agonists and MRIs are combined. Here, we present the in vitro and in vivo profile of NS9775, a combined full alpha7 nAChR agonist and triple MRI. NS9775 potently inhibited [(3)H]alpha-bungarotoxin binding in vitro (Ki: 1.8 nM), and ex vivo (ED50: 3.6 mg/kg), showing negligible activity at alpha4beta2-(Ki: 1720 nM) or alpha1-containing nAChRs (Ki: 12,200 nM). In alpha7-expressing oocytes, NS9775 displayed an EC50 value of 280 nM, with a maximal response of 77% relative to a saturating acetylcholine concentration. Furthermore, NS9775 inhibited cortical [(3)H]5-HT, [(3)H]NA and [(3)H]DA uptake equipotently (14-43 nM), and inhibited striatal [(3)H]WIN35,428 binding (ED50: 9.1 mg/kg). Behaviourally in mice, NS9775 (0.3-3.0 mg/kg) reversed scopolamine-induced deficits in a modified Y-maze and MK-801-induced learning deficits in 5-trial inhibitory avoidance. Swim distance in the forced swim test was increased by 30 mg/kg NS9775, and 10 and 30 mg/kg NS9775 reduced digging behaviour in the marble burying paradigm and increased the number of punished crossings in the four plate test. This pro-cognitive, antidepressant-like and anxiolytic-like effect of NS9775 suggests that combining alpha7 nAChR agonism and triple monoamine reuptake inhibition could be a step in the evolution of pharmacological treatments of affective and/or cognitive disturbances. PMID- 23748056 TI - Epidemiology, classification and management of undescended testes: does medication have value in its treatment? AB - Genetic, hormonal, and anatomical factors are believed to be involved in the etiology of undescended testes. Due to increased risk of infertility, testicular cancer, torsion and/or accompanying inguinal hernia (>90%) as well as cosmetic concerns, all these patients require treatment. In this review paper, we aimed to evaluate the success rates of treatment modalities used in undescended testes, beginning from 1930 to the present, and to draw attention to the possible risks and benefits and also the efficacy of hormonal therapy in the management of the disorder, which is still a controversial issue. Hormonal therapy may lead to penile growth, painful erection, and behavioral changes while on treatment. In recent years, it has been reported that human chorionic gonadotropin (hCG) treatment was associated with interstitial edema due to increased vascular permeability, inflammation-like changes, and several adverse effects on germ cells by increasing pressure and apoptotic process. It has also been reported that LHRH analogues have positive effects on germ cells by increasing fertility in patients undergoing unilateral or bilateral orchiopexy. In some studies, the success rate of hCG treatment was reported to be higher following buserelin. In some other studies, hCG treatment was recommended before orchiopexy to reduce the risk for surgical ischemia. There are a limited number of randomized controlled studies, so evidence showing the efficacy of hormonal therapy is insufficient. According to the 2007 Consensus Report of Nordic countries, it is recommended that surgery is the first-line treatment modality in undescended testes and that it should be performed by pediatric surgeons and urologists at the age of 6-12 months. PMID- 23748057 TI - Establishment and development of a national newborn screening programme for congenital hypothyroidism in Turkey. AB - OBJECTIVE: To assess the Turkish National Newborn Screening Programme (NNSP) for congenital hypothyroidism (CH). Retrospective study based on the data from NNSP. METHODS: Since December 2006, a nationwide screening programme for CH has been conducted in Turkey by the Turkish Directorate of Public Health (TDPH) in cooperation with several institutions. We evaluated the database between January 2008 and July 2010 of this programme. According to the methodology of the NNSP, between three and five days of age (or at discharge from the hospital, if this occurs earlier) blood specimens were routinely collected from neonates on filter paper, by puncturing the heel. The accepted thyroid-stimulating hormone cut-off level for recall was 20 mU/L initially and 15 mU/L subsequently. The incidence of possible CH by years was reported. RESULTS: During the evaluation period, 3223765 newborns were tested. The mean annual incidence of possible CH showed a gradual increase over the years (1:888 in 2008, 1:592 in 2009, and 1:469 in 2010). Regional differences were noted. Although the mean age of blood sampling did not change by years, the mean age at notification for suspected CH decreased from 19.2 to 15.7 days from 2008 to 2010. CONCLUSIONS: We reported the first assessment of NNSP in Turkey. An improvement in performance measures for the CH screening programme has been noted. Knowledge on incidence of confirmed CH is not yet available in the database. PMID- 23748054 TI - Reward, interrupted: Inhibitory control and its relevance to addictions. AB - There are broad individual differences in the ability to voluntarily and effortfully suppress motivated, reward-seeking behaviors, and this review presents the hypothesis that these individual differences are relevant to addictive disorders. On one hand, cumulative experience with drug abuse appears to alter the molecular, cellular and circuit mechanisms that mediate inhibitory abilities, leading to increasingly uncontrolled patterns of drug-seeking and taking. On the other, native inter-individual differences in inhibitory control are apparently a risk factor for aspects of drug-reinforced responding and substance use disorders. In both cases, the behavioral manifestation of poor inhibitory abilities is linked to relatively low striatal dopamine D2-like receptor availability, and evidence is accumulating for a more direct contribution of striatopallidal neurons to cognitive control processes. Mechanistic research is now identifying genes upstream of dopamine transmission that mediate these relationships, as well as the involvement of other neurotransmitter systems, acting alone and in concert with dopamine. The reviewed research stands poised to identify new mechanisms that can be targeted by pharmacotherapies and/or by behavioral interventions that are designed to prevent or treat addictive behaviors and associated behavioral pathology. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23748058 TI - Can HbA1c and one-hour glucose concentration in standard OGTT be used for evaluation of glucose homeostasis in childhood? AB - OBJECTIVE: To investigate whether glycosylated hemoglobin (HbA1c) and 1-hour glucose level in oral glucose tolerance test (OGTT) are useful parameters for evaluation of glucose homeostasis in childhood. METHODS: The medical records of 106 obese/overweight children aged from 7 to 18 years who underwent OGTT were evaluated retrospectively. The subjects were divided into 2 groups according to their one-hour glucose concentration. Group 1 consisted of subjects whose one hour glucose level was <155 mg/dL, and Group 2 consisted of subjects whose one hour glucose level was >=155 mg/dL. The fasting and 2-hour glucose concentrations of the groups were compared. The sensitivity and specificity levels were determined using the ROC curve to assess the predictive value of HbA1c for impaired glucose tolerance (IGT). RESULTS: The mean 2-hour glucose concentration of the subjects in Group 2 was significantly higher than that of the subjects in Group 1 (137.8+/-35.5 mg/dL versus 113.1+/-21.2 mg/dL, p<0.05). If a 5.5% cut-off value for HbA1c was accepted as predictor of IGT, the sensitivity was 63% and specificity was 70%. 31% of the subjects with HbA1c levels at or above 5.5% had IGT. This rate was significantly lower in subjects who had HbA1c levels below 5.5% (p<0.05). CONCLUSIONS: Obese/overweight children and adolescents whose 1 hour glucose level is >=155 mg/dL in the standard OGTT carry a high risk for IGT. Obese/overweight children and adolescents whose HbA1c level is at or above 5.5% may have IGT even though their fasting glucose level is normal, thus, OGTT is necessary to evaluate the glucose tolerance. PMID- 23748059 TI - Morning cortisol levels affected by sex and pubertal status in children and young adults. AB - OBJECTIVE: Morning cortisol levels are frequently used as screening tests for adrenal insufficiency in both adults and children. Reports differ on the specificity of this measurement. The present study was undertaken to determine whether sex or pubertal status affected morning cortisol values. METHODS: We measured morning cortisol levels and performed low-dose adrenocorticotropic hormone stimulation test in 35 healthy male and female subjects (ages 6-34) ranging in Tanner stage (TS) from TS 1 to TS 5. Testing was initiated at 08:00 after an overnight fast. Morning serum total cortisol, free cortisol, cortisol binding globulin, estradiol (males and females), and testosterone (males) were obtained. RESULTS: Morning total and free cortisol levels were significantly higher in TS 5 participants than in prepubertal children. Using a morning cortisol of 248 nmol/L to define a normal value, 19/21(90%) of healthy TS 5 subjects exhibit normal values. In contrast, 0/8 TS 1 healthy subjects exhibited a value greater than 248 nmol/L (p=0.0005). We also observed sex differences in morning cortisol levels in pubertal but not in prepubertal subjects. We observed sex differences in morning cortisol levels in TS 5 individuals. CONCLUSIONS: Morning cortisol measurements may be more useful as screening tests for adrenal function in adults than in children. TS and sex may be considered in the decision to screen for adrenal insufficiency using morning cortisol or whether to proceed directly to stimulation testing. PMID- 23748060 TI - Maternal and neonatal urinary iodine status and its effect on neonatal TSH levels in a mildly iodine-deficient area. AB - OBJECTIVE: Iodine deficiency and excess are the most important factors that affect screening and recall rates of congenital hypothyroidism. The purpose of this study was to investigate the urinary iodine status in newborns and their mothers and its effects on neonatal thyroid-stimulating hormone (TSH) levels in a mildly iodine-deficient area. METHODS: A total of 116 newborns and their mothers were included in the study. Urinary iodine levels were measured from healthy mothers and their babies on the 5th day following birth. Neonatal TSH levels were screened, and TSH and free thyroxine (fT4) levels were measured on the 15th day in the recall cases. T4 treatment was started in infants with high TSH and low fT4 levels. These measurements were repeated on the 30th day in these newborns. RESULTS: Ninety-nine percent of the mothers included in the study were using iodized salt. The median urinary iodine level in the newborns was 279 ug/L, while it was 84 ug/L in their mothers. The rate of iodine deficiency among the mothers was 56.8%, and the rate of iodine excess was 8.6%. This rate was 10.3% for iodine deficiency and 61.2% for iodine excess in the newborns. The recall rate at the screening was 9.5% (n=11). The urinary iodine levels were above 200 ug/L in three newborns who had transient hyperthyrotropinemia. CONCLUSIONS: Iodine deficiency was more frequently observed in nursing mothers, and iodine excess was more frequently seen in their newborns. The iodine excess noted in the newborns was attributed to the use of antiseptics containing iodine. The iodine excess leads to increases in recall rates, screening costs, and frequency of transient hyperthyrotropinemia. PMID- 23748061 TI - Radioactive iodine for thyrotoxicosis in childhood and adolescence: treatment and outcomes. AB - OBJECTIVE: The aim of the present study was to evaluate the outcome of radioiodine treatment in thyrotoxicosis in childhood and adolescence. METHODS: This was a retrospective study of 27 patients (ages 7.2- 19.8 years) with a diagnosis of thyrotoxicosis who received iodine-131 (I-131) treatment from January 2007 to December 2011 in the Nuclear Medicine Division, Department of Radiology, Faculty of Medicine, Chiang Mai University. Gender, duration of antithyroid drug (ATD) treatment, 24-hour I-131 uptake, thyroid weight, total dose and number of treatments with I-131, and thyroid status at 6 months after treatment were recorded. RESULTS: The outcomes of 27 patients (85.2% female, 14.8% male) treated with radioactive iodine were analyzed to assess the effectiveness of therapy as related to dose and gland size. All children and adolescents received 150 uCi of I-131/g of thyroid tissue (n=27). Six 6 months after treatment, 44.5% of the patients were hyperthyroid, 14.8% were euthyroid, and 40.7% were hypothyroid. Of the 12 cases with hyperthyroidism, 2 cases needed a second dose of I-131 treatment, and they finally reached a hypothyroid state. The patients were classified into 2 groups according to treatment success (euthyroid and hypothyroid) and treatment failure (hyperthyroid). There were no significant differences in age, gender, duration of ATD treatment, 2- and 24-hour I-131 uptake, thyroid weight, and total I-131 dose between these two groups. CONCLUSIONS: Radioiodine treatment is safe and effective for thyrotoxicosis in childhood and adolescence. It is suitable as a good second-line therapy for patients with severe complications, those who show poor compliance, and those who fail to respond to ATD treatment. PMID- 23748062 TI - Incidence of type 1 diabetes mellitus in Turkish children from the southeastern region of the country: a regional report. AB - OBJECTIVE: Variability in the incidence of type 1 diabetes mellitus (T1DM) related to geographical region, ethnic background, gender, and age indicates a need for further epidemiological studies. To date, there are no reported studies on the incidence of T1DM in the pediatric age group from the Southeastern region of Turkey. To define the incidence, demographic and clinical characteristics of T1DM in children 0-14 years of age in Diyarbakir, one of the largest cities in the Southeast region of Turkey. METHODS: Hospital files of patients with the diagnosis of T1DM were reviewed. Data of all patients diagnosed between 1 June 2010 and 31 May 2011 were evaluated. Population data on the 0-14 age group were obtained from the Turkish Statistical Institute (TSI) reports. RESULTS: From a total of 41 T1DM patients, 24 (58.5%) were female (male: 41.5%) with a male/female ratio of 1.4. The overall annual incidence of T1DM was 7.2/10(5), being 8.7/10(5) in females and 5.7/10(5) in males. The peak incidence was found to occur at age 5-9 years in the girls and 10-14 years in the boys. Mean age at diagnosis was 8.1+/-3.8 years. Rate of presentation with diabetic ketoacidosis was 65.9%. Patients applied most frequently in spring and winter months. CONCLUSIONS: In this first T1DM incidence study on the pediatric age group in Diyarbakir, Turkey, T1DM incidence was found to be similar to that in countries with low-middle incidence. PMID- 23748063 TI - Impact of insulin resistance on insulin-like growth factor-1/insulin like growth factor-binding protein-3 axis and on early weight gain in small for gestational age infants. AB - OBJECTIVE: To assess insulin-like growth factor-1 (IGF-1)/IGF-binding protein-3 (IGFBP-3) axis and insulin resistance (IR) and the relationship of these parameters with growth in appropriate for gestational age (AGA) and small for gestational age (SGA) infants at birth and in early infancy. METHODS: Postnatal blood samples for measurement of glucose, insulin, IGF-1, and IGFBP-3 were taken from 60 infants (30 AGA and 30 SGA) at birth and at one, three, and six months of age. Both SGA and AGA infants were divided into two groups: growing well and not growing well. Blood glucose, insulin, IGF-1, and IGFBP-3 values were assessed in all infants. RESULTS: Homeostasis model assessment-IR (HOMA-IR) values in well growing SGA infants in the third and sixth months were found to be higher than in not well-growing SGA infants (3.9+/-0.8 vs. 1.0+/-0.3 at 3 months and 3.3+/-0.9 vs. 2.4+/-0.9 at 6 months, p<0.05). IGF-1 levels in well-growing SGA infants at 3 and 6 months were found to be higher than those in not well-growing SGA infants (83.80+/-44.50 vs. 73.50+/-17.60 ng/mL at 3 months and 95.12+/-50.74 vs. 87.67+/ 22.91 ng/mL at 6 months, p<0.05). The IGF-1 values were significantly lower in well-growing SGA infants than in well-growing AGA infants (83.80+/-44.50 vs. 103.31+/-30.81 ng/mL at 3 months and 95.12+/-50.74 vs. 110.87+/-26.44 ng/mL at 6 months, p<0.05). CONCLUSIONS: This study demonstrates the effects of accelerated early infant growth on IGF-1/IGFBP-3 axis in SGA-born infants. PMID- 23748064 TI - The effect of parental socioeconomic class on children's body mass indices. AB - OBJECTIVE: To assess the effect of education and economic status of parents on obesity in children. METHODS: A cross-sectional survey was conducted in 2006 among school children in Riyadh, Saudi Arabia. A representative sample of 1243 (542 male and 701 female) children aged 6-16 years were contacted using multistage cluster sampling strategy. Social and demographic variables were collected using questionnaires completed by parents. Height and weight of the children were recorded by a trained team. RESULTS: The mean body mass index for all children was 19.8+/-5.4. The prevalence rates of overweight and obesity were 21.1% and 12.7%, respectively. Overweight and obesity were more prevalent in males than in females. By multivariate analysis, children were more likely to be overweight if they were male (OR=0.6, p<0.01), 12 years of age (OR=3.79, p<0.01, compared to age 6 years), and if their families had higher income (OR=3.12, p<0.01, compared to families with low income). Being male (OR=0.545, p<0.01), aged 12 years (OR=3.9, p=0.005, compared to the age of 6), and having a mother who is more educated were determined to be significant risk factors for obesity in children. Mothers educated at university level were found to have a three-fold higher risk of having obese children(OR=3.4, p<0.01, compared to mothers with lower education levels). CONCLUSIONS: Overweight and obesity among Saudi children is associated with educated mothers and higher family income. This finding calls for introducing interventions in health education for both children and parents. PMID- 23748065 TI - Profile of hypothyroidism in Down's syndrome. AB - OBJECTIVE: Although the association between Down's syndrome (DS) and thyroid dysfunction is well recognized, the cause of this condition is not known. METHODS: Hospital records of patients with DS and hypothyroidism referred to our clinic were retrospectively reviewed. Initial thyroid hormone and thyrotropin (TSH) levels, age at admission, initial anthropometric measurements, age at the beginning of therapy, initial L-thyroxine (L-T4) doses, time to normalization of the thyroid function tests, and L-T4 dose at last visit were recorded. Thyroid ultrasound imaging was used to measure the size of the gland. Descriptive data were expressed as mean+/-SD values. Skewed data were shown as median and interquartile ranges (IQR). RESULTS: There were 62 patients with DS (32 male and 30 female). Median TSH level at the first visit was 10.40 (19.4) uIU/mL and median free T4 level was 1.18 (0.43) ng/dL. There was no statistical difference in terms of age, hormone and antibody levels, thyroid volume and L-T4 doses between boys and girls. Thyroid volumes of 54 patients were measured. Only nine of these patients had a normal-sized thyroid gland. Median total thyroid volume was 0.89 (2.07) mL. Thyroid volume was negatively correlated to L-T4 dose at last visit (p=0.006, r=-0.387). CONCLUSIONS: We found a high prevalence of thyroid dysgenesis in patients with DS and hypothyroidism. This association has not been reported before. Further studies investigating the thyroid gland size in these patients need to be performed to confirm the results. PMID- 23748066 TI - Identification of novel mutations in STAR gene in patients with lipoid congenital adrenal hyperplasia: a first report from India. AB - Lipoid congenital adrenal hyperplasia (LCAH), a rare disorder of steroid biosynthesis, is the most severe form of CAH. We report novel molecular findings of three unrelated infants with LCAH diagnosed at our center. A known missense mutation c.653C>T (p.A218V) and two novel mutations [premature termination c.441G>A (or p.W147X) and frameshift deletion c.del815G (or p.R272PfsX35)] were identified after complete sequencing of the STAR gene. Prenatal diagnosis was carried out for the family with mutation c.815delG by molecular testing wherein the fetus was found to be homozygous for the mutation. This is the first report of molecular diagnosis and prenatal testing for LCAH from India. PMID- 23748067 TI - Transient neonatal diabetes mellitus in a Turkish patient with three novel homozygous variants in the ZFP57 gene. AB - Neonatal diabetes mellitus (NDM) is a rare form of diabetes that presents within the first six months of life. Nearly 70% of these cases have loss of methylation at the differentially methylated region on chromosome 6q24. To describe the findings in a Turkish male patient with NDM caused by a loss of methylation at chromosome 6q24 and three novel homozygous mutations in the ZFP57 gene, methylation-specific PCR was carried out at 6q24 and mutation analysis of ZFP57 gene was maintained by direct sequencing. Sequencing of ZFP57 gene revealed the hypomethylation of chromosome 6q24 and three novel mutations (chr6:29.641.413 A>T, 29.641.073 C>T, and 29.640.855 G>C), respectively. The latter mutation seems to display the patient's condition due to a highly conservative amino acid substitution in the protein. We suggest the ZFP57 gene as a causative factor for NDM and it should be considered in genetic testing. Further studies including functional analysis of the detected mutations will provide precise information regarding the effect of the mutations. PMID- 23748068 TI - Aromatase deficiency, a rare syndrome: case report. AB - Aromatase deficiency (AD) is a rare autosomal recessive inheritance syndrome. Its worldwide incidence is unknown, and there are few case reports in the literature. Aromatase dysfunction develops due to CYP19A1 gene mutation and a decrease in estrogen synthesis. Estrogen deficiency can induce delayed epiphyseal closure, eunuchoid body habitus, osteopenia, and osteoporosis in both genders. Our patient was a 27-year-old male who presented with bone pain, recurrent bone fractures associated with minimal trauma starting in puberty, and a progressive increase in height. Laboratory tests revealed that the blood levels of follicle-stimulating hormone and luteinizing hormone were above normal, testosterone level was normal, and estrogen was undetectable. Plain bone radiography of the left wrist and hand demonstrated that the epiphyses were still unfused. Lumbar osteoporosis was detected in bone densitometry. In the genetic analysis, homozygous R375H guanine adenine (G-A) mutation was detected in the CYP19A1 gene, and a diagnosis of AD was reached. Treatment with 25 MUg transdermal estradiol was started. All family members were examined. Homozygous R375H G-A mutation was detected in the patient's younger brother. Heterozygous R375H G-A mutation was found in his mother, father, and older brother. In conclusion, this AD patient requires lifetime estrogen replacement in order to provide sufficient bone mineralization, to reduce the risk of bone fractures, and to lead a healthy life. The best method to prevent the possible complications is to diagnose the AD syndrome at early ages and to provide adequate estrogen replacement starting at puberty. PMID- 23748069 TI - Diabetic ketoacidosis presenting with pseudonormoglycemia in a 15-year-old girl with type 1 diabetes mellitus. AB - Pseudonormoglycemic diabetic ketoacidosis (DKA) is a rare condition and has been reported only in a few adult patients. We present a 15-year-old girl with a 9 year history of type 1 diabetes who presented with euglycemic and extreme hypertriglyceridemia. The acidosis and hypertriglyceridemia resolved with intravenous insulin therapy and rehydration. Hyperlipidemia was the apparent cause of pseudonormoglycemia in this patient. The findings in the present case demonstrate that also in children, DKA can rarely occur without abnormal blood glucose levels. Assessment of the acid-base status, urinary glucose, and ketone readings is therefore important in all diabetic patients who are unwell at admission and have normal glucose levels. In such patients, hyperlipidemia may cause pseudonormoglycemia. An awareness of this rare treatable life-threatening condition is important. PMID- 23748070 TI - Acute vitamin D intoxication possibly due to faulty production of a multivitamin preparation. AB - Vitamin D intoxication usually occurs as a result of inappropriate use of vitamin D preparations and can lead to life-threatening hypercalcemia. It is also known that there are a number of physicians who prescribe vitamin D supplements for various clinical conditions, such as poor appetite and failure to thrive. While inappropriate use of vitamin D supplements may lead to vitamin D intoxication, there are no reports of cases of vitamin D toxicity due to manufacturing errors of vitamin D preparations. Here, we present cases of hypervitaminosis D which developed following the use of a standard dose of a multivitamin preparation. All three cases presented with hypercalcemia symptoms and had characteristic laboratory findings such as hypercalcemia, hypercalciuria, low levels of parathyroid hormone. The very high serum 25(OH) vitamin D levels in these patients indicated vitamin D excess. The vitamin D level of the prescribed multivitamin preparation in the market was studied and was found to contain a very low level of vitamin D (10 IU/5 mL). Although the stated vitamin D content of the preparations ingested by these patients was not high, unproven but possible manufacturing errors were considered to be a possible cause of the hypervitaminosis D diagnosed in these three patients. PMID- 23748071 TI - Metabolic syndrome in school children. PMID- 23748072 TI - Chronic treatment with DCPCX, an adenosine A(1) antagonist, worsens long-term memory. AB - Alzheimer's disease is characterized by progressive cognitive disturbances and neurotransmitter dysfunction. Previous studies targeting the adrenergic A1 pathway suggest that this plays a role in cognitive impairment in Alzheimer's disease. Previous studies have reported that acute treatment with A1 antagonists appears to improve behavioral deficits in rodent models of memory and behavioral impairment. In this study, we addressed whether the chronic administration of 8 cyclopentyl-1,3-dipropylxanthine, a potent and selective adenosine A1 antagonist, could reverse the memory deficits found in aged APPswe/PS1dE9 mice. Chronic treatment did not improve memory in the APPswe/PS1dE9 mouse model and resulted in reduced exploratory behavior, suggestive of reduced anxiety, and a worsening of long-term memory in nontransgenic mice. These results have important implications for understanding the mechanisms of A1 receptor modulation as a target in Alzheimer's disease therapy. PMID- 23748073 TI - Resveratrol induced neuroprotection is mediated via both estrogen receptor subtypes, ER(alpha) and ER(beta). AB - Resveratrol, a dietary polyphenol with antioxidant and anti-inflammatory activity, has been shown to provide neuroprotection in models of ischemia. However, the mechanism of action of resveratrol-induced neuroprotection remains unclear. Previous work in our laboratory has provided evidence that acute, systemic administration of resveratrol is neuroprotective in a permanent model of cerebral ischemia, an effect that was blocked when animals received the non selective estrogen receptor antagonist, ICI, 182,780. The present study was designed to investigate whether the source of neuroprotection afforded by resveratrol action within the cerebral cortex itself is mediated preferentially via selective activation of either alpha or beta estrogen receptor subtype. Intracortical injection of resveratrol (0.1 and 1.0 MUM) 10 min prior to 30 min of ischemia followed by 5.5h of reperfusion significantly reduced infarct volume in the prefrontal cortex. This neuroprotective effect was significantly attenuated when resveratrol injection (1.0 MUM) was preceded by injection of a selective estrogen receptor alpha antagonist, 1,3-bis(4-hydroxyphenyl)-4-methyl-5 [4-(2-piperidinylethoxy)phenol]-1N-pyrozole dihydrochloride (MPP) or a selective estrogen receptor beta (ERbeta) antagonist, 4-[2-phenyo-5,7 bis(trifluoromrthyl)pyrazolo(1,5-a)pyrimidin-3-yl]phenol (PHTPP). These results provide evidence for rapidly induced neuroprotection mediated by resveratrol activation of either estrogen receptor subtype within the ischemic cortex of rats. PMID- 23748074 TI - Mammal retinal distribution of ENKergic amacrine cells and their neurochemical features: evidence from the PPE-GFP transgenic mice. AB - The neuroactive peptide enkephalin (ENK) has been postulated to play important roles in modulating visual information. The retinal presence of ENKergic cells has been revealed with conventional morphological protocols targeting ENK molecule especially in avian, however, the detailed distribution of ENKergic cells and their specific neurochemical features in the mammal retina remain unclear because of the difficulties in visualizing ENKergic cells efficiently and reliably. To address this question, we took advantage of the preproenkephalin green fluorescent protein (PPE-GFP) transgenic mice previously generated and identified in our group, and identified the neurochemical characteristics of retinal ENKergic cells. The majority of ENKergic cells occupied the proximal inner nuclear layer with a few displaced in the ganglion cell layer. Further double labeling revealed that most of these ENKergic amacrine cells used inhibitory glycine or gamma-aminobutyric acid as the primary neurotransmitter. However, some of them also utilized excitatory glutamate as the primary neurotransmitter. The present findings suggest that the retinal ENKergic cells fall into a subpopulation of amacrine cells and show predominantly inhibitory as well as less dominantly excitatory neurochemical features. Our findings offered comprehensive morphological evidence for the function of ENKergic amacrine cells of mammal species. PMID- 23748075 TI - Abnormal cytoplasmic calcium dynamics in central neurons of a dystonia mouse model. AB - Increased activities of cytoplasmic calcium and the excitatory neurotransmitter glutamate have been independently implicated in dystonia pathophysiology. However, cellular-level evidence linking these two features is not available. Here we show that glutamate-dependent changes in neuronal calcium dynamics occur in a knock-in mouse model of DYT1 dystonia, the most common hereditary form of this disorder. Fluorescence-based analysis of the dynamics of cytoplasmic calcium concentration ([Ca(2+)]c) in cultured hippocampal neurons shows that electrical stimulation depolarizes the neurons and increases the dendritic [Ca(2+)]c, which then decays slowly to the pre-stimulus level. Whereas the peak amplitude of [Ca(2+)]c was not affected, the decay period was prolonged in neurons of heterozygous mice whose genotype reflects the human condition. We found that this effect was blocked by the antagonists of ionotropic glutamate receptors, and confirmed that glutamate receptors are present in these neurons. As the [Ca(2+)]c is readout and regulator of neuronal excitability, its abnormality represents an important cellular phenotype of dystonia. PMID- 23748076 TI - Caspr interaction with Amyloid Precursor Protein reduces amyloid-beta generation in vitro. AB - Contactin associated protein (Caspr), an adhesion molecule, plays roles in formation of paranodal junctions in myelinated axons, neurite outgrowth, synaptic plasticity in nervous system. Here we have shown a novel function of Caspr in pathogenesis of Alzheimer's disease (AD). Caspr distributes around amyloid plaques in APP/PS1 mice. Levels of Caspr increase in the cerebral cortex of 7 month-old APP/PS1 mice comparing to wild-type littermates. Caspr decreased protein levels of APP in both HEK-293 cells stably transfected with Indiana mutant APP (V717F; HEK-APP) and CHO cells which express endogenous APP, while it did not alter mRNA levels of APP. Furthermore, Caspr co-localizes and interacts with APP. Amyloid-beta (Abeta) 40 and Abeta42 generation were also reduced in HEK APP cells by Caspr overexpression. PMID- 23748077 TI - Mouse models of gene-environment interactions in schizophrenia. AB - Gene-environment interactions (GEIs) likely play significant roles in the pathogenesis of schizophrenia and underlie differences in pathological, behavioral, and clinical presentations of the disease. Findings from epidemiology and psychiatric genetics have assisted in the generation of animal models of GEI relevant to schizophrenia. These models may provide a foundation for elucidating the molecular, cellular, and circuitry mechanisms that mediate GEI in schizophrenia. Here we critically review current mouse models of GEI related to schizophrenia, describe directions for their improvement, and propose endophenotypes to provide a more tangible basis for molecular studies of pathways of GEI and facilitate the identification of novel therapeutic targets. PMID- 23748078 TI - Modulation of neural stem/progenitor cell proliferation during experimental Herpes Simplex encephalitis is mediated by differential FGF-2 expression in the adult brain. AB - Neural stem cells (NSCs) respond to inflammatory cues induced during brain injury and are thought to be involved in recovery from brain damage. Little is known about NSC response during brain infections. The present study evaluated NSC proliferation during Herpes Simplex Virus-1 brain infection. Total numbers of nestin(+) NSCs increased significantly in infected brains at 6 days post infection (p.i.). However, by 15 days p.i. the nestin(+) population decreased significantly below levels observed in uninfected brains and remained depressed through 30 days p.i. This initial increase in NSC population occurred concurrently with increased brain cell proliferation, which peaked at 3 days p.i. On closer examination, we found that while actively proliferating Sox2(+) NSCs increased in number at 6 days p.i., proliferating DCX(+) neuroblasts contributed to the increased response at 3 days p.i. However, overall proliferation decreased steadily from 15 days p.i. to below control levels. To determine the mechanisms involved in altering NSC proliferation, neurotrophin and growth factor expression profiles were assessed. FGF-2 gene expression increased at 5 days p.i. and was robustly down-regulated at 15 days p.i. (>1000-fold), which was further confirmed by increased FGF-2 immunostaining around the lateral ventricles. Furthermore, supplementing infected animals with recombinant FGF-2, at 15 days p.i., significantly increased the number of proliferating brain cells. These findings demonstrate that the temporal changes in NSC proliferation are mediated through the regulation of FGF-2 and that the NSC niche may benefit from supplementation with FGF-2 during HSV-1 brain infection. PMID- 23748080 TI - Nuclear magnetic resonance imaging of lipid in living plants. AB - This review highlights technological developments in magnetic resonance imaging (MRI), which are creating opportunities for the three dimensional visualization and quantification of lipids in plant materials. A major feature of MRI is that it is a non-invasive platform, and thus can be used for the analysis of living organisms. An overview of the theoretical aspects of MRI is provided, followed by a description of the various analytical modes available, and an explanation of how MRI can be applied to plant samples and what it can achieve. Various lipid maps and three dimensional models of seeds and fruits are included to demonstrate the potential of MRI and to exemplify recent cutting-edge advances in the field. The importance and prospects of the imaging of lipids in living plants, as well as the integration of lipid imaging with other emerging techniques, are outlined to provide impetus for future plant lipid research. PMID- 23748081 TI - FDA officials disagree on safety of angiotensin receptor blockers. PMID- 23748079 TI - Parent behaviors moderate the relationship between neonatal pain and internalizing behaviors at 18 months corrected age in children born very prematurely. AB - Children born very preterm (<= 32 weeks gestation) exhibit greater internalizing (anxious/depressed) behaviors compared to term-born peers as early as 2 years corrected age (CA); however, the role of early stress in the etiology of internalizing problems in preterm children remains unknown. Therefore, we examined the relationship between neonatal pain and internalizing behavior at 18 months CA in children born very preterm and examined whether parent behavior and stress moderated this relationship. Participants were 145 children (96 very preterm, 49 full term) assessed at 18 months CA. Neonatal data were obtained from medical and nursing chart review. Neonatal pain was defined as the number of skin breaking procedures. Cognitive ability was measured with the Bayley Scales of Infant Development II. Parents completed the Parenting Stress Index III, Child Behavior Checklist 1.5-5, and participated in a videotaped play session with their child, which was coded using the Emotional Availability Scale IV. Very preterm children displayed greater Internalizing behaviors compared to full-term control children (P=.02). Parent Sensitivity and Nonhostility moderated the relationship between neonatal pain and Internalizing behavior (all P<.05); higher parent education (P<.03), lower Parenting Stress (P=.001), and fewer children in the home (P<.01) were associated with lower Internalizing behavior in very preterm children, after adjusting for neonatal medical confounders, gender, and child cognitive ability (all P>.05). Parent Emotional Availability and stress were not associated with Internalizing behaviors in full-term control children. Positive parent interaction and lower stress appears to ameliorate negative effects of neonatal pain on stress-sensitive behaviors in this vulnerable population. PMID- 23748082 TI - PFI scheme is blamed for financial collapse of Peterborough and Stamford trust. PMID- 23748083 TI - GPs have been unfairly attacked, says outgoing NHS chief. PMID- 23748084 TI - Biotreatment of textile effluent in static bioreactor by Curvularia lunata URM 6179 and Phanerochaete chrysosporium URM 6181. AB - Investigations on biodegradation of textile effluent by filamentous fungi strains Curvularia lunata URM 6179 and Phanerochaete chrysosporium URM 6181 were performed in static bioreactors under aerated and non-aerated conditions. Spectrophotometric, HPLC/UV and LC-MS/MS analysis were performed as for to confirm, respectively, decolourisation, biodegradation and identity of compounds in the effluent. Enzymatic assays revealed higher production of enzymes laccase (Lac), lignin peroxidase (LiP) and manganese-dependent peroxidase (MnP) by P. chrysosporium URM 6181 in aerated bioreactor (2020; 39 and 392 U/l, respectively). Both strains decolourised completely the effluent after ten days and biodegradation of the most predominant indigo dye was superior in aerated bioreactor (96%). Effluent treated by P. chrysosporium URM 6181 accumulated a mutagenic metabolite derived from indigo. The C. lunata URM 6179 strain, showed to be more successful for assure the environmental quality of treated effluent. These systems were found very effective for efficient fungal treatment of textile effluent. PMID- 23748085 TI - Removal of Ni(II) from aqueous solutions by an Arthrobacter viscosus biofilm supported on zeolite: from laboratory to pilot scale. AB - This study discusses the retention of Ni(II) by Arthrobacter viscosus supported on zeolite 13 X in batch mode and in continuous mode, at laboratory scale and at pilot scale. The maximum adsorption capacities of 28.37, 20.21 and 11.13 mg/g were recorded for lab scale batch, for continuous lab scale minicolumns and for pilot scale bioreactors, respectively. The Sips isotherm and pseudo second order kinetics described well the observations registered in batch assays. The Adams Bohart, Thomas and Yoon-Nelson models were applied to data obtained with the pilot scale bioreactor and a good fit was reached for Adams-Bohart and for Yoon Nelson models. A fed-batch was performed at lab scale and the applicability of the biofilm in continuous mode for the described purpose was confirmed. The sorption mechanism was investigated in detail through FTIR, SEM and EDX analyses. PMID- 23748086 TI - Efficient production of dihydroxyacetone from biodiesel-derived crude glycerol by newly isolated Gluconobacter frateurii. AB - The efficient production of dihydroxyacetone (DHA) on biodiesel-derived glycerol based media was developed. A newly isolated strain, Gluconobacter frateurii CGMCC 5397, could convert crude glycerol to DHA with high yield and productivity. In shake-flask fermentation, the DHA concentration of 73.1 gl(-1) was attained at 48 h using an optimum medium containing biodiesel-derived crude glycerol. When fed batch fermentation was carried out in a 7-l stirred bioreactor with crude glycerol, the DHA concentration, productivity, and yield were 125.8 gl(-1), 2.6 gl(-1)h(-1), and 90.5% at 48 h, respectively. This study suggests that the inexpensive biodiesel-derived crude glycerol could be utilized for efficient production of DHA by G. frateurii. PMID- 23748087 TI - Utilization of pentoses from sugarcane biomass: techno-economics of biogas vs. butanol production. AB - This paper presents the techno-economics of greenfield projects of an integrated first and second-generation sugarcane biorefinery in which pentose sugars obtained from sugarcane biomass are used either for biogas (consumed internally in the power boiler) or n-butanol production via the ABE batch fermentation process. The complete sugarcane biorefinery was simulated using Aspen Plus(r). Although the pentoses stream available in the sugarcane biorefinery gives room for a relatively small biobutanol plant (7.1-12 thousand tonnes per year), the introduction of butanol and acetone to the product portfolio of the biorefinery increased and diversified its revenues. Whereas the IRR of the investment on a biorefinery with biogas production is 11.3%, IRR varied between 13.1% and 15.2% in the butanol production option, depending on technology (regular or engineered microorganism with improved butanol yield and pentoses conversion) and target market (chemicals or automotive fuels). Additional discussions include the effects of energy-efficient technologies for butanol processing on the profitability of the biorefinery. PMID- 23748088 TI - Redox mediator enhanced simultaneous decolorization of azo dye and bioelectricity generation in air-cathode microbial fuel cell. AB - Enhanced simultaneous decolorization of Congo red and bioelectricity generation with anthraquinone-2,6-disulphonic disodium salt (AQDS), riboflavin (RF) and humic acid (HA) as mediators in air-cathode microbial fuel cell (MFC) was demonstrated. Compared with mediator-free MFC, the MFC with added 0.005 mM AQDS, 0.005 mM RF or 1g/L HA showed 36%, 26% and 15% increase in maximum power density along with 394%, 450%, and 258% increases in decolorization rates of Congo red, respectively. Addition of mediators at higher concentration further increased power and Congo red decolorization but the increases were not proportional to the rise in mediator concentration. Based on decreases of anode charge transfer resistance and increases of Congo red decolorization, the mediators kinetically promote the extracellular electron transfer between bacteria, anode and Congo red. Microbial analysis showed that addition of mediators changed the composition of anodic microbial community and stimulated the growth of species belonging to Chlorobi, Endomicrobia and Firmicutes. PMID- 23748089 TI - Improved performance of Yarrowia lipolytica lipase-catalyzed kinetic resolution of (R,S)-2-octanol by an integrated strategy of interfacial activation, bioimprinting and immobilization. AB - Yarrowia lipolytica lipase (YLL) demonstrated an (R)-enantiopreference for efficient resolution of (R,S)-2-octanol. The activity, enantioselectivity, the ratio of substrate to enzyme, acetaldehyde tolerance, and operational stability of YLL were improved by an integrated strategy of interfacial activation, bioimprinting, and immobilization. In comparison with the control, both the enzymatic activity and enantioselectivity increased by a factor of 8.85 and 2.75 by the integrated strategy, respectively. Fifty-one percentage of conversion with 220 of enantioselectivity was obtained using the immobilized YLL prepared by the integrated strategy at a ratio of 104 of substrate to enzyme loaded. The immobilized YLL retained 97% of its initial activity without a decrease in enantioselectivity after 10 successive reuse cycles. Together these results will result in a promising strategy with the YYL for efficient resolution of (R,S)-2 octanol in practice. PMID- 23748090 TI - Biological treatment of gaseous emissions containing dimethyl sulphide generated from pulp and paper industry. AB - A bench scale biofilter packed with compost and wood chips seeded with potential DMS degrading culture (Bacillus sphaericus) could efficiently remove DMS from ambient air with removal efficiency (RE%) of 71 +/- 11 at an effective bed contact time (EBCT) of 360 +/- 20s with loading rate in the range of 4-28 gDMS/m(3)/h. Further, the same biofilter operated for the treatment of vent gas generated from a P&P industry indicated DMS removal of 61 +/- 18% at optimal EBCT of 360 +/- 25s with a loading rate in the range of 3-128 gDMS/m(3)/h. PMID- 23748091 TI - Comparison of pretreatment methods for rye straw in the second generation biorefinery: effect on cellulose, hemicellulose and lignin recovery. AB - The increasing interest in lignocellulose-based biorefineries boosts the further development of the needed pretreatment methods for preprocessing biomass. There are a large number of different processes that are being investigated; however research is made mostly based on different types of biomass with the same pretreatment or several modifications of the same process for a given type of biomass. In this work a comparison of promising chemical pretreatments using the same biomass was performed. Organosolv (OS), Steam (SE) and Liquid-Hot-Water (LHW) processes were used for the pretreatment of rye straw and the treated solids further enzymatically hydrolyzed. Best results for carbohydrate and lignin yield were found for the OS pretreatment followed close by the LHW and SE with similar results. All of the processes showed satisfactory performance for the pretreatment of lignocellulosic biomass for application in the second generation biorefinery. PMID- 23748092 TI - Molecular fingerprinting of bacterial communities in enriched azo dye (Reactive Violet 5R) decolorising native acclimatised bacterial consortia. AB - Reactive Violet 5R (RV5R) decolorising acclimatised bacterial consortia were enriched from industrial effluent contaminated and pristine samples from Gujarat, India on several different media. Twelve acclimatised consortia were selected for the study which were able to decolorise 100mg/L RV5R in 30 h under shaking or static conditions. Eubacterial diversity was studied by 16S rRNA gene based culture-independent methods, using HaeIII and Hinf1 enzymes for ARDRA and V3 region based DGGE analysis, forming total 6 clusters in both analysis. Decolorised end products of all the consortia were analysed by FTIR showing cleavage of the azo bond and group modifications. GC-MS data of dye decolorised end products of Gly consortium obtained from hydrocarbon contaminated soil demonstrated benzene ring cleavage activity. Present study suggests that enrichment of acclimatised consortia under different conditions can result in diverse microbial communities that differentially degrade RV5R and can provide rich source of dye decolorising strains. PMID- 23748093 TI - Bioaugmentation of activated sludge with Acinetobacter sp. TW enhances nicotine degradation in a synthetic tobacco wastewater treatment system. AB - Bioaugmentation (BA) using Acinetobacter sp. TW with high nicotine-degrading efficiency was applied in a bioreactor receiving a load of COD (3,200 +/- 50 mg/L) and nicotine (1.0 +/- 0.1g/L). The results showed that because of the colonization of strain TW, the COD removal was stable at 80-90%, while nicotine removal reached 98% in the BA system. Furthermore, according to PCR-DGGE fingerprinting, compared with the originally activated sludge, more bacteria existed in the BA systems while some bacteria disappeared from the non-BA system. In terms of the quorum sensing, short chain AHLs increased to assist colonization of strain TW, and long chain AHLs were secreted and helped to resist the nicotine toxicity. Compared with the non-BA system, the amounts of ROS, protein carbonyls and 8-OHdG were significant lower in the BA systems, which suggested that strain TW played an important role in eliminating the nicotine toxicity from the bioreactors. PMID- 23748094 TI - On the motivational properties of reward cues: Individual differences. AB - Cues associated with rewards, such as food or drugs of abuse, can themselves acquire motivational properties. Acting as incentive stimuli, such cues can exert powerful control over motivated behavior, and in the case of cues associated with drugs, they can goad continued drug-seeking behavior and relapse. However, recent studies reviewed here suggest that there are large individual differences in the extent to which food and drug cues are attributed with incentive salience. Rats prone to approach reward cues (sign-trackers) attribute greater motivational value to discrete localizable cues and interoceptive cues than do rats less prone to approach reward cues (goal-trackers). In contrast, contextual cues appear to exert greater control over motivated behavior in goal-trackers than sign trackers. It is possible to predict, therefore, before any experience with drugs, in which animals specific classes of drug cues will most likely reinstate drug seeking behavior. The finding that different individuals may be sensitive to different triggers capable of motivating behavior and producing relapse suggests there may be different pathways to addiction, and has implications for thinking about individualized treatment. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23748095 TI - Environmental modulation of drug taking: Nonhuman primate models of cocaine abuse and PET neuroimaging. AB - The current review highlights the importance of environmental variables on cocaine self-administration in nonhuman primate models of drug abuse. In addition to describing the behavioral consequences, potential mechanisms of action are discussed, based on imaging results using the non-invasive and translational technique of positron emission tomography (PET). In this review, the role of three environmental variables - both positive and negative - are described: alternative non-drug reinforcers; social rank (as an independent variable) and punishment of cocaine self-administration. These environmental stimuli can profoundly influence brain function and drug self-administration. We focus on environmental manipulations involving non-drug alternatives (e.g., food reinforcement) using choice paradigms. Manipulations such as response cost and social variables (e.g., social rank, social stress) also influence the behavioral effects of drugs. Importantly, these manipulations are amenable to brain imaging studies. Taken together, these studies emphasize the profound impact environmental variables can have on drug taking, which should provide important information related to individual-subject variability in treatment responsiveness, and the imaging work may highlight pharmacological targets for medications related to treating drug abuse. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23748096 TI - A preclinical evaluation of the discriminative and reinforcing properties of lisdexamfetamine in comparison to D-amfetamine, methylphenidate and modafinil. AB - Lisdexamfetamine dimesylate, which consists of L-lysine covalently bound to D amfetamine, is the first prodrug for treating ADHD. Its metabolic conversion to yield D-amfetamine by rate-limited, enzymatic hydrolysis is unusual because it is performed by peptidases associated with red blood cells. Other stimulants shown to be effective in managing ADHD include D-amfetamine, methylphenidate and modafinil. All have the potential for misuse or recreational abuse. The discriminative and reinforcing effects of these compounds were determined in rats using a 2-choice, D-amfetamine (0.5 mg/kg, i.p.)-cued drug-discrimination test, and by substitution for intravenous cocaine in self-administration. Lisdexamfetamine (0.5-1.5 mg/kg [D-amfetamine base], p.o.) generalised to saline when tested 15 min post-dosing, but dose-dependently generalised to d-amfetamine at 60 min. At 120 min, its D-amfetamine-like effects were substantially diminished. At 15 min, methylphenidate (3.0-10 mg/kg, p.o.) and D-amfetamine (0.1 1.5 mg/kg, p.o.) dose-dependently generalised to the intraperitoneal D-amfetamine cue. Switching to the intraperitoneal route reduced the interval required for lisdexamfetamine to be recognised as D-amfetamine-like, but did not alter its potency. Switching to intraperitoneal injection increased the potency of methylphenidate and D-amfetamine by 3.4* and 2.2*, respectively. Modafinil (50 200 mg/kg, i.p.) generalised partially, but not fully, to d-amfetamine. Methylphenidate (0.1, 0.3, 1.0 mg/kg/injection, i.v.) maintained robust self administration at the 2 highest doses. Neither lisdexamfetamine (0.05, 0.15 or 0.5 mg/kg/injection [D-amfetamine base], i.v.) nor modafinil (0.166, 0.498 or 1.66 mg/kg/injection, i.v.) served as reinforcers. The results reveal important differences between the profiles of these stimulants. Lisdexamfetamine did not serve as a positive reinforcer in cocaine-trained rats, and although it generalised fully to D-amfetamine, its discriminative effects were markedly influenced by its unusual pharmacokinetics. PMID- 23748097 TI - Study of the transcytosis of an anti-transferrin receptor antibody with a Fab' cargo across the blood-brain barrier in mice. AB - One strategy used to transport pharmacologically active substances across the blood-brain barrier (BBB) is to link the substance to a molecule capable of crossing the BBB using a receptor-mediated transcellular transport system in brain capillary endothelial cells. The transferrin receptor (TfR) is related to a transcytosis process in these cells, and the 8D3 antibody, directed against mouse TfR, is able to induce a receptor response. In this work, the potential of 8D3 to carry molecules across the BBB was investigated. This antibody (either unlabeled or FITC-labeled) was intravenously administered to ICR-CD1 mice. Immunocomplexes (ICs) consisting of 8D3 antibody (carrier) and Fab' fragments (simulated cargo), in some cases directly fluorolabeled with FITC, were also administered to ICR-CD1 mice. At different time-points of recirculation, the IC components were studied using immunohistochemical procedures and fluorescence resonance energy transfer (FRET). The results suggested that 8D3 alone or in an IC with Fab' fragments entered the endothelial cells. FRET analysis indicated that the colocalization of their fluorescent signals inside the endothelial cells decreased with time, indicating that ICs can be processed and Fab' fragments probably separated from 8D3. However, neither 8D3 alone nor the IC components crossed the BBB. PMID- 23748098 TI - Tonkean macaques communicate with their right hand. AB - There are two conflicting hypotheses to explain the origins of language. Vocal origin theory states that language results from the gradual evolution of animals' vocal communication, but gestural origin theory considers that language evolved from gestures, with the initial left-hemispheric control of manual gestures gradually encompassing vocalizations. To contribute to this debate, we investigated functional hemispheric specialization related to hand biases when grasping or showing an object through manual gesture in Tonkean macaques. The results of this study, the first quantitative study on Tonkean macaques' handedness, showed a remarkable convergence of the Tonkean macaques' handedness patterns with those of baboons and human infants, with hand preferences for manual communicative gestures significantly favoring the use of the right hand. Our findings support the hypothesis that left hemispheric lateralization for language is derived from a gestural communication system that was present in the common ancestor of macaques, baboons and humans. PMID- 23748099 TI - Gene-environment contributions to energy and macronutrient intakes in 9-year-old children: results from the Quebec Newborn Twin Study. AB - BACKGROUND: Few twin studies have examined nutrition-related phenotypes among children, and none has investigated energy and macronutrient intakes. OBJECTIVE: The objective was to quantify genetic and environmental influences on variations in energy and macronutrient intakes among children aged 9 years. DESIGN: We conducted a nutrition study among children participating in the Quebec Newborn Twin Study, a population-based birth cohort of twins. We derived dietary data from two multiple-pass 24-hour dietary recalls with a parent and his or her child. The analysis employed a classic twin study design and used data from 379 twin pairs. RESULTS: Univariate analyses indicate that heritability for mean daily energy (kcal) and macronutrient (g) intakes was moderate, ranging from 0.34 (95% CI: 0.22, 0.46) to 0.42 (0.31, 0.53). Genetic effects also accounted for 0.28 (0.16, 0.40) of the variance in percent of energy from lipids, while only environmental (shared and unique) effects accounted for the variance in percent of energy from proteins and carbohydrates. The shared environment did not contribute to variations in daily intakes for most of the nutritional variables under study. Multivariate analyses suggest the presence of macronutrient-specific genetic influences for lipids and carbohydrates, estimated at 0.12 (0.04, 0.19) and 0.20 (0.11, 0.29) respectively. CONCLUSIONS: The unique environment (i.e., not shared by family members) has the largest influence on variances in daily energy and macronutrient intakes in 9-year-old children. This finding underscores the need to take obesogenic environments into account when planning dietary interventions for younger populations. PMID- 23748100 TI - Gremlin utilizes canonical and non-canonical TGFbeta signaling to induce lysyl oxidase (LOX) genes in human trabecular meshwork cells. AB - The TGFbeta/BMP signaling pathways are involved in glaucomatous damage to the trabecular meshwork (TM) leading to elevated intraocular pressure (IOP), which is a major risk factor for the development and progression of glaucoma. The BMP antagonist gremlin is elevated in glaucomatous TM cells and tissues and can directly elevate IOP. Gremlin utilizes the TGFbeta2/SMAD pathway to induce TM extracellular matrix (ECM) proteins. The purpose of this study is to determine whether expression of the ECM cross-linking lysyl oxidase (LOX) genes is regulated by gremlin in cultured human TM cells. Human TM cells were treated with recombinant gremlin, and expression of the LOX genes was examined by quantitative RT-PCR and western immunoblotting. TM cells were pretreated with TGFBR inhibitors (LY364947 or SB431542), an inhibitor of the SMAD signaling pathway (SIS3), or with JNK (SP600125) and p38 MAPK (SB203580) inhibitors to identify the signaling pathway(s) involved in gremlin induction of LOX protein expression. All five LOX genes (LOX and LOXL1-4) were induced by gremlin. Gremlin induction of LOX genes and protein expression was blocked by TGFBR inhibitors as well as by inhibitors of the SMAD3, JNK and p38 MAPK signaling pathways. We conclude that gremlin employs both canonical TGFbeta/SMAD and the non-canonical JNK and p38 MAPK signaling pathways to induce LOX genes and proteins in cultured human TM cells. Increased LOX levels may be at least partially responsible for gremlin-mediated IOP elevation and increased aqueous humor outflow resistance leading to glaucoma. PMID- 23748101 TI - Neuroprotective effect of minocycline in a rat model of branch retinal vein occlusion. AB - Branch retinal vein occlusion (BRVO) is the second most frequent retinal vascular disorder. Currently the first-line therapies for BRVO include anti-VEGF and dexamethasone implant treatment, however, with direct or indirect damage on retinal neurons, it has limited effect in improving patients visual acuity. Therefore, novel treatments with neuroprotective effect for BRVO retina were expected. Minocycline is a semisynthetic, broad spectrum tetracycline antibiotic with high penetration through the blood brain barrier. The neuroprotective effects of minocycline have been shown in various central nervous system (CNS) disease. Since both CNS and retina were composed of neurons and glials, it is reasonable to expect a neuroprotective effect by minocycline for BRVO retina. Therefore, the aim of the present study was to study whether minocycline has neuroprotective effect in branch retinal vein occlusion (BRVO) and the possible underlying molecular basis. We created BRVO in rats using laser photocoagulation. The animals were then randomly divided into 4 groups to evaluate the effect of minocycline: group A: minocycline 45 mg/kg intraperitoneal injection (i.p.), group B: minocycline 90 mg/kg i.p., group C: normal saline i.p., group D: sham injection. Fundus photography and fluorescein angiography (FA) were conducted. The changes in thickness of retinal layers were measured with optical coherence tomography (OCT) in vivo. We found that retinal edema occurred predominantly in the inner retinal layers. Intraperitoneal administration of minocycline significantly ameliorated retinal edema in the early stage of BRVO. We performed Full field Electroretinography (ffERG) to evaluate retinal function and found that the reduction of b wave amplitude decreased in the combined maximal response. The expressional levels of apoptosis related genes (Bax, Bcl-2) and inflammation related genes (IL-1 beta, TNF alpha, MCP-1 and CCR2) were measured by real-time PCR, the results showed that minocycline treatment upregulated Bcl-2 expression and inhibits TNF alpha expression since early stage of BRVO. We also performed Hematoxylin-Eosin (HE) and immunostaining for Iba 1 (a microgilal marker), active caspase-3, Bax, Bcl-2, IL-1 beta, TNF alpha and found that minocycline inhibits retinal microglial activation, prevents retinal ganglion cell loss, and inhibits retinal caspase-3 activation. Thus, our study indicates that systemic administration of minocycline ameliorates retinal edema and preserves retinal function in the early stage of BRVO possibly via inhibiting microglia activation and protecting RGC from apoptosis. PMID- 23748102 TI - The influence of nanoscale inorganic content over optical and surface properties of model composites. AB - OBJECTIVES: To investigate the influence of nanoscale inorganic content over optical and surface properties of model composites before and after ageing. METHODS: Three model composites were formulated with silica fillers in nanoscale of 7 nm (G1), 12 nm (G2) and 16 nm (G3), at 45.5% by weight in a matrix of BisGMA/TEGDMA 1:1. Color coordinates (CIE L*a*b* parameters), color difference (DeltaE*), translucency parameter (TP), surface gloss (SG) and surface roughness (SR) were measured before and after ageing procedures of immersion in water and toothbrush abrasion. Surface hardness (SH) were evaluated before and after immersion in absolute ethanol. Results were submitted to two-way ANOVA followed by Tukey's post hoc test performed at a pre-set alpha of 0.05. RESULTS: Regarding CIE L*a*b* parameters, a darkening, a redness and a blueness effect, were respectively detected after water storage for all groups. Smaller filler sizes (G1) had the highest CIE b* values, whereas medium (G2) (p<0.05) had higher values than larger fillers (G3) (p<0.05) either before or after water immersion. Toothbrush abrasion did not produce any significant effect on CIE a* and CIE b* values, however increased CIE L*, decreased TP in addition to produce rougher and matte surfaces in all groups. Filler size did not influence DeltaE* (p>0.05), although a tendency towards lower values in smaller filler materials was observed. Ageing after immersion in absolute ethanol decreased SH for all model composites. CONCLUSIONS: Filler sizes and ageing procedures influenced the optical and surface properties of the nanostructured composites evaluated in this study. CLINICAL SIGNIFICANCE: Filler size influenced optical and surface properties of resin composites. Materials containing smaller filler size offered improved optical stability and surface properties that can lead to longer maintenance of the restoration's appearance in the oral environment. PMID- 23748103 TI - Fate of intracellular H2S/HS- and metallo-proteins. PMID- 23748104 TI - Heterogeneity of bone microstructure in the femoral head in patients with osteoporosis: an ex vivo HR-pQCT study. AB - INTRODUCTION: Trabecular bone in the femoral head has a complicated and heterogeneous structure with few studies having analyzed heterogeneity in this structure quantitatively. We analyze trabecular bone microstructure in the femoral head with osteoporosis (OP) using high resolution peripheral quantitative CT (HR-pQCT) to investigate its regional characteristics. METHODS: Fifteen femoral heads extracted from female OP patients with femoral neck fracture (85 +/ 7, 67-94 years) were scanned by HR-pQCT at 41 MUm voxel size. The femoral head was segmented into 15 regions (3 longitudinal regions: superior, center, and inferior, and 5 axial subregions: center, medial, lateral, anterior, posterior). Of these 15 regions, five were excluded due to overlap with the fracture site, leaving a total of 10 regions of cancellous bone microstructures to be quantitatively assessed using the following parameters: bone volume fraction, trabecular thickness, number, separation, connectivity density, structure model index, and degree and orientation of anisotropy. These parameters were compared among each region. RESULTS: Trabecular bone at the center, superior, and supero posterior regions of the femoral head had higher bone volume, trabecular number, thickness, narrower bone marrow spaces, higher connectivity and anisotropy, and more plate-like structure. This plate-like structure ran supero-inferiorly and antero-posteriorly at the superior and center regions. Bone volume at the anterior, posterior, and medial regions was almost half of the central and superior regions. CONCLUSION: Significant heterogeneity of the trabecular bone microstructure in the OP femoral head was showed quantitatively in this study. These data offer new insight into bone microstructural anatomy and may prove to provide useful information on clinical medicine such as hip surgeries. PMID- 23748105 TI - Targeting long non-coding RNAs in cancers: progress and prospects. AB - Pervasive transcription occurs in the human genome to generate thousands of RNA transcripts, and accumulating evidence suggested that the RNA molecules, without protein coding ability, have important roles in diverse biological functions. Long non-coding RNA (lncRNA), with size larger than 200 nt, is a new class of the non-coding RNA that contributes to cancer development and progression. Roles for several lncRNAs in cancers have been characterized and strategies targeting them have inhibitory effects to malignant cells in vitro and in vivo. These findings point to the potential of lncRNAs as prospective novel therapeutic targets in cancers. Recent advance in biological drugs, led by nucleic acid drugs (i.e. siRNAs, antisense oligonucleotides), suggest directions for the development of cancer therapies targeting lncRNAs. Here, we discuss the characteristics of lncRNAs regarding their synthesis, stability and functional role in cells, and emphasize their unique properties that determine their molecular functions. We then discuss the association of lncRNAs with cancers, and illustrate the anticancer effects induced upon modulating the level and function of lncRNAs. We also revisit established methods for targeting RNA molecules and discuss new agents and strategies to attenuate lncRNAs in cancer. PMID- 23748106 TI - Hepatocellular carcinoma: transcriptome diversity regulated by RNA editing. AB - Hepatocellular carcinoma (HCC) can be envisioned as a prolonged multi-stage process accumulating genetic and epigenetic changes. In the past years, DNA alterations lent us important clues to the comprehension of molecular pathways involved in HCC. However, as an increasing number of RNAs were identified to be subject to A-to-I modifications, it has become apparent that RNA editing might be the causal basis of various human diseases. Recent evidence has strengthened this notion by correlating hyper-edited AZIN1 (antizyme inhibitor 1) protein with HCC onset and the mechanisms that regulate cell transformation. As we continue to demystify it, RNA editing astonishes us with its diverse substrates, esoteric functions, elaborate machinery and complex interaction with HBV/HCV viral infection. In this review, we examine the contribution of A-to-I RNA editing to caner onset/progression and explore its potential implications for cancer treatment advances. PMID- 23748107 TI - CTLA-4 blockade and the renaissance of cancer immunotherapy. AB - Cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) plays a key role in restraining the adaptive immune response of T-cells towards a variety of antigens including tumor associated antigens (TAAs). The blockade of this immune checkpoint elicits an effective anticancer immune response in a range of preclinical models, suggesting that naturally occurring (or therapeutically induced) TAA specific lymphocytes need to be "unleashed" in order to properly fight against malignant cells. Therefore, investigators have tested this therapeutic hypothesis also in humans: the favorable results obtained with this strategy in patients with advanced cutaneous melanoma are revolutionizing the management of this highly aggressive disease and are fueling new enthusiasm on cancer immunotherapy in general. Here we summarize the biology of CTLA-4, overview the experimental data supporting the rational for targeting CTLA-4 to treat cancer and review the main clinical findings on this novel anticancer approach. Moreover, we critically discuss the current challenges and potential developments of this promising field of cancer immunotherapy. PMID- 23748108 TI - Prolapse-related knowledge and attitudes toward the uterus in women with pelvic organ prolapse symptoms. AB - OBJECTIVE: The objective of the study was to describe the basic knowledge about prolapse and attitudes regarding the uterus in women seeking care for prolapse symptoms. STUDY DESIGN: This was a cross-sectional study of English-speaking women presenting with prolapse symptoms. Patients completed a self-administered questionnaire that included 5 prolapse-related knowledge items and 6 benefit-of uterus attitude items; higher scores indicated greater knowledge or more positive perception of the uterus. The data were analyzed using descriptive statistics and multiple linear regression. RESULTS: A total of 213 women were included. The overall mean knowledge score was 2.2 +/- 1.1 (range, 0-5); 44% of the items were answered correctly. Participants correctly responded that surgery (79.8%), pessary (55.4%), and pelvic muscle exercises (34.3%) were prolapse treatment options. Prior evaluation by a female pelvic medicine and reconstructive surgery specialist (beta = 0.57, P = .001) and higher education (beta = 0.3, P = .07) was associated with a higher mean knowledge score. For attitude items, the overall mean score was 15.1 (4.7; range, 6-30). A total of 47.4% disagreed with the statement that the uterus is important for sex. The majority disagreed with the statement that the uterus is important for a sense of self (60.1%); that hysterectomy would make me feel less feminine (63.9%); and that hysterectomy would make me feel less whole (66.7%). Previous consultation with a female pelvic medicine and reconstructive surgery specialist was associated with a higher mean benefit of uterus score (beta = 1.82, P = .01). CONCLUSION: Prolapse-related knowledge is low in women seeking care for prolapse symptoms. The majority do not believe the uterus is important for body image or sexuality and do not believe that hysterectomy will negatively affect their sex lives. PMID- 23748109 TI - Immunofluorescent detection of S-nitrosoproteins in cell culture. AB - The role of S-nitrosylation in cellular signaling has been clearly demonstrated. There a number of mechanisms whereby this post-translational modification can occur and the number of protein targets continue to expand. The need to be able to monitor when this important signaling process occurs within cells is increasingly important. Previously we have identified immunohistochemistry approaches effective for monitoring S-nitrosylation within fixed tissue. Within this paper we show how these techniques can be adapted to use in a cell culture system using immunofluorescence. We have used this protocol to detect S nitrosoprotein formation within LPS stimulated microglial cells using both transformed and primary cultured cells. PMID- 23748110 TI - Detection of BCR-ABL using one step reverse transcriptase- polymerase chain reaction and microchip electrophoresis. AB - One-step reverse transcriptase polymerase chain reaction (RT-PCR) coupled with microchip electrophoresis (MCE) was established to analyze BCR-ABL fusion gene. The use of one-step RT-PCR could simplify the RT-PCR procedure and thus reduced the risk of contamination and sample consumption. This method also enhanced the sensitivity for amplified target DNA and dramatically shorted the analysis time. Moreover, this assay can simultaneously identify b2a2 and b3a2. Orthogonal array design, which can investigated mutual effects of PCR parameters, was used to optimize the reaction system. This approach was highly effective, reproducible and sensitive, and would be suitable for the determination of BCR-ABL in clinic diagnosis. PMID- 23748111 TI - Perspectives for identification of mutations in the zebrafish: making use of next generation sequencing technologies for forward genetic approaches. AB - The ability to identify a phenotype causing mutation is essential for successful use of mutagenesis screens in many model organisms. Mapping mutations was for a long time a bottleneck in zebrafish research, as the standard method for mapping and identification of mutations was time consuming and expensive. The development of new sequencing technologies in the last couple of years has enabled the rapid and cost-effective sequencing of whole genomes. This has led to the establishment of new strategies for mapping and identification of mutations in several model organisms. The application of these techniques to the zebrafish model, with its large genome and the high level of variation in and between strains, was not trivial. Several techniques have been developed recently, taking the specific characteristics of the zebrafish genome into account. Here we give an overview on how to plan a mapping experiment, detail the critical parameters and discuss available tools for mapping and identification of mutations in zebrafish using next-generation sequencing. Using these methods, zebrafish mutants can now be mapped in a couple of weeks for a fraction of the costs. The increased efficiency of identification of mutations in the zebrafish broadens the utility of the model and allows for systematic analysis of gene function in a vertebrate model. PMID- 23748112 TI - Analysis of human invasive cytotrophoblasts using multicolor fluorescence in situ hybridization. AB - Multicolor fluorescence in situ hybridization, or FISH, is a widely used method to assess fixed tissues or isolated cells for numerical and structural chromosome aberrations. Unlike other screening procedures which provide average chromosome numbers for heterogeneous samples, FISH is a sensitive cell-by-cell method to analyze the distribution of abnormal cells in complex tissues. Here, we applied FISH to characterize chromosomal composition of a rare, but very important class of human cells that stabilize the fetal-maternal interface connecting the placenta to the uterine wall during early pregnancy, called invasive cytotrophoblasts (iCTBs). Combining differently-labeled, chromosome-specific DNA probes, we were able to unambiguously determine the number of up to six different autosomes and gonosomes in individual cell nuclei from iCTBs selected on the basis of their invasive behavior. In this manuscript, we describe a method for generation of iCTBs from placental villi, and provide the complete workflow of our FISH experiments including a detailed description of reagents and a trouble shooting guide. We also include an in-depth discussion of the various types and sources of DNA probes which have evolved considerably in the last two decades. Thus, this communication represents both a complete guide as well as a valuable resource, intended to allow an average laboratory to reproduce the experiments and minimize the amount of specialized, and often costly, equipment. PMID- 23748113 TI - Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. AB - Fibromyalgia is a common, disabling syndrome that includes chronic widespread pain plus diverse additional symptoms. No specific objective abnormalities have been identified, which precludes definitive testing, disease-modifying treatments, and identification of causes. In contrast, small-fiber polyneuropathy (SFPN), despite causing similar symptoms, is definitionally a disease caused by the dysfunction and degeneration of peripheral small-fiber neurons. SFPN has established causes, some diagnosable and definitively treatable, eg, diabetes. To evaluate the hypothesis that some patients labeled as having fibromyalgia have unrecognized SFPN that is causing their illness symptoms, we analyzed SFPN associated symptoms, neurological examinations, and pathological and physiological markers in 27 patients with fibromyalgia and in 30 matched normal controls. Patients with fibromyalgia had to satisfy the 2010 American College of Rheumatology criteria plus present evidence of a physician's actual diagnosis of fibromyalgia. The study's instruments comprised the Michigan Neuropathy Screening Instrument (MNSI), the Utah Early Neuropathy Scale (UENS), distal-leg neurodiagnostic skin biopsies, plus autonomic-function testing (AFT). We found that 41% of skin biopsies from subjects with fibromyalgia vs 3% of biopsies from control subjects were diagnostic for SFPN, and MNSI and UENS scores were higher in patients with fibromyalgia than in control subjects (all P <= 0.001). Abnormal AFTs were equally prevalent, suggesting that fibromyalgia-associated SFPN is primarily somatic. Blood tests from subjects with fibromyalgia and SFPN diagnostic skin biopsies provided insights into causes. All glucose tolerance tests were normal, but 8 subjects had dysimmune markers, 2 had hepatitis C serologies, and 1 family had apparent genetic causality. These findings suggest that some patients with chronic pain labeled as fibromyalgia have unrecognized SFPN, a distinct disease that can be tested for objectively and sometimes treated definitively. PMID- 23748114 TI - Efficacy, safety, and tolerability of fulranumab, an anti-nerve growth factor antibody, in the treatment of patients with moderate to severe osteoarthritis pain. AB - Nerve growth factor (NGF) is increased in chronic pain conditions. This study examined analgesic efficacy and safety of fulranumab, a fully human monoclonal anti-NGF antibody, in adults with chronic osteoarthritis pain. Patients (n=466, intent-to-treat) were randomized to receive, in addition to their current pain therapy, subcutaneous injections in 1 of 6 parallel treatment groups: placebo (n=78), fulranumab 1 mg (n=77) or 3 mg (n=79) every 4 weeks (Q4wk), 3 mg (n=76), 6 mg (n=78), or 10 mg (n=78) every 8 weeks (Q8wk). Primary efficacy results showed that fulranumab significantly reduced the average pain intensity score (P < or = 0.030) from baseline to week 12 compared with placebo in the 3mgQ4wk, 6mgQ8wk, and 10mgQ8wk groups. Secondary efficacy outcomes indicated that significant improvement occurred compared with placebo at week 12 on the Western Ontario and McMaster Universities Osteoarthritis Index subscales of pain, stiffness, and physical function (P < 0.040) across all fulranumab groups except 1mgQ4wk, on the Brief Pain Inventory-Short Form subscales of pain intensity (P < or = 0.016) and pain interference (P < or = 0.030) in the 3mgQ4wk and 10mgQ8wk groups, and on the Patient Global Assessment score (P < or = 0.040) in the 3mgQ4wk, 6mgQ8wk, and 10mgQ8wk groups. The most common (> or = 5% of patients) treatment-emergent adverse events in overall fulranumab groups during the first 12weeks included paresthesia (7%), headache (5%), and nasopharyngitis (5%). Most neurologic-related treatment-emergent adverse events were mild or moderate and resolved at the end of week 12. Serious adverse events occurred in 3 patients, but they were not neurologically related and resolved before study completion. Fulranumab treatment resulted in statistically significant efficacy in pain measures and physical function versus placebo and was generally well tolerated. PMID- 23748115 TI - Rethinking the fear avoidance model: toward a multidimensional framework of pain related disability. PMID- 23748116 TI - Gastrointestinal pain: unraveling a novel endogenous pathway through uroguanylin/guanylate cyclase-C/cGMP activation. AB - The natural hormone uroguanylin regulates intestinal fluid homeostasis and bowel function through activation of guanylate cyclase-C (GC-C), resulting in increased intracellular cyclic guanosine-3',5'-monophosphate (cGMP). We report the effects of uroguanylin-mediated activation of the GC-C/cGMP pathway in vitro on extracellular cGMP transport and in vivo in rat models of inflammation- and stress-induced visceral hypersensitivity. In vitro exposure of intestinal Caco-2 cells to uroguanylin stimulated bidirectional, active extracellular transport of cGMP into luminal and basolateral spaces. cGMP transport was significantly and concentration dependently decreased by probenecid, an inhibitor of cGMP efflux pumps. In ex vivo Ussing chamber assays, uroguanylin stimulated cGMP secretion from the basolateral side of rat colonic epithelium into the submucosal space. In a rat model of trinitrobenzene sulfonic acid (TNBS)-induced visceral hypersensitivity, orally administered uroguanylin increased colonic thresholds required to elicit abdominal contractions in response to colorectal distension (CRD). Oral administration of cGMP mimicked the antihyperalgesic effects of uroguanylin, significantly decreasing TNBS- and restraint stress-induced visceromotor response to graded CRD in rats. The antihyperalgesic effects of cGMP were not associated with increased colonic spasmolytic activity, but were linked to significantly decreased firing rates of TNBS-sensitized colonic afferents in rats in response to mechanical stimuli. In conclusion, these data suggest that the continuous activation of the GC-C/cGMP pathway along the intestinal tract by the endogenous hormones guanylin and uroguanylin results in significant reduction of gastrointestinal pain. Extracellular cGMP produced on activation of GC-C is the primary mediator in this process via modulation of sensory afferent activity. PMID- 23748117 TI - Endogenous opioid function mediates the association between laboratory-evoked pain sensitivity and morphine analgesic responses. AB - Predictors of responsiveness to opioid analgesic medications are not well understood. This study tested whether individual differences in endogenous opioid (EO) function are associated with analgesic responsiveness to morphine. In randomized, counterbalanced order over 3 sessions, 45 chronic low back pain participants and 31 healthy controls received an opioid antagonist (8 mg naloxone), morphine (0.08 mg/kg), or placebo. Participants then engaged in 2 laboratory-evoked pain tasks (ischemic and thermal). Outcomes included pain threshold, pain tolerance, and pain ratings. Indexes of EO function and morphine analgesic responsiveness were derived for each measure as the difference in pain responses between the placebo condition and naloxone or morphine condition, respectively. For all 7 pain measures across the 2 laboratory pain tasks, greater EO function was associated with significantly lower morphine analgesic responsiveness (P<0.001-P=0.02). Morphine reduced pain responses of low EO individuals to levels similar to those of high EO individuals receiving placebo. Higher placebo condition-evoked pain sensitivity was associated with significantly greater morphine analgesic responsiveness for 5 of 7 pain measures (P<0.001-P=0.02). These latter associations were significantly mediated by EO function for 4 of these 5 pain outcomes (all P values<0.05). In the laboratory evoked pain context, opioid analgesic medications may supplement inadequate EO analgesia, with little incremental benefit in those with preexisting high EO function. Implications for personalized medicine are discussed. PMID- 23748118 TI - Headache impairs attentional performance. AB - Attentional disruption has been demonstrated using laboratory-induced pain, but has not been reliably established in everyday pain conditions. This study is the first to examine the effect of everyday acute headache on attention. Seventy-five frequent headache sufferers completed a flanker task, n-back task, attentional switching task, and dual task. Participants completed this battery of tasks twice: once when experiencing an episode of tension-type headache, and once when pain free. Headache impaired performance on the n-back task, retarded general responding on the flanker task, and produced more errors on the attentional switching task. Headache did not, however, alter performance on the dual task, or the size of the attentional switching effect or result in a flanker effect. It must therefore be emphasised that headache pain appears to impair general task performance, irrespective of task complexity, rather than specific attentional mechanisms. Headache pain has an effect on the core cognitive components necessary for the successful completion of tasks, and in particular those involving the updating of the cognitive system. PMID- 23748120 TI - Evaluation of the automatic editing tool RECall for HIV-1 pol and V3 loop sequences. AB - Genotypic drug resistance testing is routine practice in HIV-1 clinical care. The visual interpretation of sequencing electropherograms is labour-intensive and subject to intra- and inter-assay variability because decisions are based on operators' judgments. In this study the performance of the automatic editing tool RECall was compared to the current standard of editing manually and editing using the tool ViroSeq. Using RECall a consensus sequence could be generated for 97% of the V3 loop and for 79% of the pol experiments. By comparison, using manual editing a consensus sequence could be reached for 87% of the V3 and 87% of the pol experiments. Using ViroSeq, a consensus sequence was generated for 68% of the pol experiments. On a predefined dataset, manual editing displayed the highest probability to accurately assign mixtures (0.91 vs. 0.88 by ViroSeq vs. 0.76 by RECall) and the lowest probability to inaccurately assign a mixture to a pure base call (0.002 vs. 0.019 by ViroSeq vs. 0.002 by RECall). As differences in base calling have little impact on drug resistance interpretation and hands-on time could be substantially reduced, RECall could be a valuable tool for the standardization and acceleration of the editing process. PMID- 23748121 TI - Comparison of the plaque assay and 50% tissue culture infectious dose assay as methods for measuring filovirus infectivity. AB - Two common methods of quantifying filovirus infectivity, a plaque assay and 50% cell culture infectious dose (TCID50) endpoint dilution assay, were compared. The two assays were performed side by side using the same virus stock sample to determine the correlation between the results of the two assays. The TCID50 assay appeared to be more sensitive but slightly more variable, and there was a tenfold difference in the numerical results of these methods of enumeration. The advantages and disadvantages of both assays are discussed. Both methods are useful and practicable in filovirus research, and this comparison will be hugely beneficial to the filovirus research community as it seeks to become more united. Further work in this area should be performed to ensure consistency in filovirus research. PMID- 23748122 TI - Wound care basics for the pharmacist. AB - Elderly skin is prone to wounds as a result of age-related changes and comorbidities such as diabetes and vascular disease. Wound healing is a complex process that can become compromised, leading to the development of chronic, nonhealing wounds in a frail elderly patient. Pharmacists and other practitioners who care for the elderly should be attuned to the wound-healing process and to the types of medications and wound care products available to aid healing. PMID- 23748119 TI - Interventional management of neuropathic pain: NeuPSIG recommendations. AB - Neuropathic pain (NP) is often refractory to pharmacologic and noninterventional treatment. On behalf of the International Association for the Study of Pain Neuropathic Pain Special Interest Group, the authors evaluated systematic reviews, clinical trials, and existing guidelines for the interventional management of NP. Evidence is summarized and presented for neural blockade, spinal cord stimulation (SCS), intrathecal medication, and neurosurgical interventions in patients with the following peripheral and central NP conditions: herpes zoster and postherpetic neuralgia (PHN); painful diabetic and other peripheral neuropathies; spinal cord injury NP; central poststroke pain; radiculopathy and failed back surgery syndrome (FBSS); complex regional pain syndrome (CRPS); and trigeminal neuralgia and neuropathy. Due to the paucity of high-quality clinical trials, no strong recommendations can be made. Four weak recommendations based on the amount and consistency of evidence, including degree of efficacy and safety, are: 1) epidural injections for herpes zoster; 2) steroid injections for radiculopathy; 3) SCS for FBSS; and 4) SCS for CRPS type 1. Based on the available data, we recommend not to use sympathetic blocks for PHN nor radiofrequency lesions for radiculopathy. No other conclusive recommendations can be made due to the poor quality of available data. Whenever possible, these interventions should either be part of randomized clinical trials or documented in pain registries. Priorities for future research include randomized clinical trials, long-term studies, and head-to-head comparisons among different interventional and noninterventional treatments. PMID- 23748123 TI - Technology tackles dispensing in age of accountable care. AB - Increasingly, long-term care facilities are using technology to improve safety, reduce costs, and save time. The growing role of high-tech tools in this setting is driven partly by regulations calling for facilities to improve outcomes and streamline costs. One tool that long-term pharmacies and their facilities are turning to is the automated dispensing system. These systems vary in term of type, size, cost, and function; and they are approved for use in long-term care facilities in some but not all states. However, where they can be and are used, they often result in reduced medication management costs and improved safety and accuracy. At the same time, automated dispensing systems may make medication administration easier for nurses. While challenges to their implementation and use remain, automated dispensing systems likely will be a key part of health care's future. This article serves as an introduction to the automated dispensing systems, their use in long-term care, and their potential use as a new era of health care begins. PMID- 23748124 TI - Appropriateness of medication prescribing using the STOPP/START criteria in veterans receiving home-based primary care. AB - OBJECTIVE: To evaluate the appropriateness/inappropriateness of medication prescribing using the Screening Tool of Older Person's Prescriptions/Screening Tool to Alert doctors to Right Treatment (STOPP/START) criteria in elderly homebased primary care (HBPC) veterans and to understand the potential impact of the HBPC team on the STOPP/START criteria. DESIGN: Retrospective chart review between September 1, 2007, and September 30, 2009. SETTING: Edward Hines, Jr. VA Hospital, Hines, Illinois, a tertiary care referral center. PARTICIPANTS: Two hundred patients 65 years of age and older who had an initial interdisciplinary evaluation conducted by the HBPC team. Exclusion criteria included admission to the hospital between the initial and follow-up medication review, admission to the HBPC program for palliative or hospice care, or death before completion of a follow-up evaluation. INTERVENTION: Appropriateness/inappropriateness of medication prescribing was assessed by comparing the medication list at the initial pharmacist medication review and follow-up review. Initial and follow-up STOPP and START scores were calculated for each patient. MAIN OUTCOME MEASURES: The primary outcome was to evaluate the appropriateness/inappropriateness of medication prescribing using the STOPP/START criteria. The secondary outcome was to understand the potential impact of the HBPC team on the STOPP/START criteria. RESULTS: There was a statistically significant decrease in the STOPP score between the initial and follow-up medication review (P = 0.0014). There was not a statistically significant increase in the START score between the initial and follow-up medication review (P = 0.5720). CONCLUSIONS: A statistically significant decrease in the STOPP score was found. Although the START score increased, the change was not found to be statistically significant. PMID- 23748125 TI - Demographic and clinical profile of nursing facility residents with gout. AB - OBJECTIVE: To develop a demographic and clinical profile of nursing facility residents with a diagnosis of gout. DESIGN: Descriptive, retrospective database analysis. SETTING: U.S. nursing facilities. PATIENTS, PARTICIPANTS: Nursing facility residents with a diagnosis of gout. INTERVENTIONS: Minimum Data Set and prescription claims records of residents served by Omnicare, Inc., with an International Classification of Diseases Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis of gout, for the time period of October 1, 2009, to September 30, 2010, were linked and de-identified. Acute gouty attacks were defined by a proxy measure of a ? 14-day course of oral nonsteroidal anti inflammatory drugs (NSAIDs), oral or injectable steroids, or oral colchicine. RESULTS: In the 138,724 residents (36.8% male: 76.8% white, 11.6% black) evaluated, the incidence of gout was 1.8% (n = 2,487). Of those with gout, males and females were represented relatively equally. There were 1,420 (57.2%) residents 80 years of age or older. Two-thirds of residents with gout required at least extensive assistance with most activities of daily living. Comorbid conditions-hypertension (82.2%), diabetes mellitus (46.6%), arthritis (43.7%), and renal failure (22.4%)-were common. Pain was reported in 68.7% of residents. Allopurinol (60.2%), colchicine (18.6%), febuxostat (2.3%), probenecid (1.1%), and probenecid/colchicine (< 1%) were prescribed in treated residents. While treatment may or may not have been indicated, 375/2,152 (17.4%) received no treatment. Diuretic therapy was received by 75.8% of residents. Acute gouty attacks were noted in 38% of residents; 53%, 25.2%, and 21.8% received short course treatment with oral or injectable steroids, oral colchicines, or oral NSAIDs, respectively. CONCLUSIONS: Despite the limitations of a retrospective database analysis, this study reveals that nursing facility residents with a diagnosis of gout have significant disease burden. Clinicians should be aware of the potential impact of this disease on physical functioning, pain, and falls in this often-frail population. PMID- 23748126 TI - Effectiveness and safety of dual renin-angiotensin system blockade: a comparison between younger and older cohorts. AB - OBJECTIVE: The purpose of this review was to evaluate blood pressure (BP) reductions and adverse events between patients younger than 65 and older than 65 years of age receiving a combination of an angiotensin converting enzyme inhibitor (ACE-I) and an angiotensin receptor blocker (ARB). DESIGN: A retrospective cohort study comparing the effectiveness of ACE-I and ARB combination in patients < 65 (younger) and >= 65 years of age (elderly). SETTING: This study was conducted at the VA Western New York Healthcare System. PARTICIPANTS: A total of 176 patients: 54 patients in the younger group and 122 in the elderly cohort. INTERVENTIONS: No specific interventions were performed. MAIN OUTCOME MEASURES: The purpose was to evaluate differences in BP reductions and incidence of adverse events in younger and elderly patients receiving a combination of an ACE-I and an ARB. RESULTS: In the elderly group (mean age 76), the mean reduction in standing blood pressure (SBP) was 14.2 +/- 15.6 mmHg (95% confidence interval [CI] 11.2-17.3; P < 0.0001). Similar results were obtained in the younger group (mean age 59), with a mean SBP reduction of 10 +/- 14.9 (95% CI 5.6-14.5; P < 0.0001). The mean SBP reduction was not significantly different between the two age cohorts (P = 0.57). The incidence of adverse events was not different between the two age groups (cough P = 0.67, hyperkalemia P = 1.0, angioedema P = 0.31). CONCLUSION: There was no significant difference in effectiveness or safety between the elderly and younger cohorts. The pharmacist monitoring elderly patients on combination therapy should still closely follow these patients; however it is reassuring that elderly patients do not experience adverse reactions at rates higher than do younger patients. PMID- 23748127 TI - Improving student knowledge in medication management through an advanced pharmacy practice experience. AB - OBJECTIVES: To assess the impact of an advanced pharmacy practice rotation on student therapeutic knowledge, confidence in performing medication therapy management (MTM), and ability to use MTM documentation platforms. DESIGN: Pretest/post-test quasi-experiment. SETTING: This study was conducted at the InterNational Center for Advanced Pharmacy Services (INCAPS), a licensed pharmacy that provides MTM services to geriatric patients in Louisville, Kentucky. PATIENTS, PARTICIPANTS: This research evaluated 37 advanced pharmacy practice students who participated in the five-week learning rotation at INCAPS between October 1, 2011, and June 30, 2012. INTERVENTIONS: Thirty-seven students were tested before (pretest) beginning the rotation. During the rotation, students performed daily MTM consultations and participated in weekly topic discussions pertaining to relevant areas of chronic disease management and geriatric pharmacotherapy. Following the five-week rotation, a post-test was administered to these 37 students to analyze the changes in their knowledge. MAIN OUTCOME MEASURES: The primary outcome measure was the test score for the assessment of chronic disease management and geriatric pharmacotherapy. RESULTS: Compared with baseline, post-test scores showed a statistically significant improvement in the areas that were assessed-osteoporosis, hypertension, diabetes, asthma/chronic obstructive pulmonary disease, and inappropriate medication use in the elderly. A post-rotation survey also reflected positive improvements in student confidence when performing MTM consults for geriatric patients. CONCLUSIONS: The five-week MTM-focused rotation at INCAPS with weekly topic discussions and daily MTM consults showed a positive impact on students' ability to manage medication therapy for chronically ill and geriatric patients. PMID- 23748128 TI - Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed? PMID- 23748129 TI - Actigraphy monitoring of symptoms in patients with Parkinson's disease. AB - Although the Unified Parkinson's Disease Rating Scale (UPDRS) is the "gold standard" tool in assessing the severity of symptoms in patients with Parkinson's disease (PD), not all activity-related disease symptoms can be accurately captured by the well-established clinical rating scale. Using an alternative approach, this study examined the level of physical activity measured by actigraphy over time and whether change in physical activity was associated with disease severity assessed by UPDRS. We used a longitudinal design in which physical activity and disease severity were assessed repeatedly during a 4-month interval, over a 3-year observational period, in a sample of 61 patients with idiopathic PD and a control group of 32 neurologically intact individuals. Physical activity data during awake-time were analyzed using the power-law exponent (PLE) method. Correlational relationships between changes in maxima values of PLE and scores of total UPDRS, UPDRS-part II (Activities of Daily Living), and UPDRS-part III (Motor Examination) in patients with PD were examined. Results show an increase in maxima values of PLE and the UPDRS total score in PD patients and that there is a positive association between changes in maxima values and total UPDRS score (r=0.746, p=0.032), UPDRS-part II score (r=0.687, p=0.027), and UPDRS-part III score (r=0.893, p=0.018). There was no significant change in the level of physical activity over time for the controls. Findings from this study indicate that change in physical activity, as captured by actigraphy, is associated with increased severity in patients' clinical symptoms of PD over time. Thus, these data suggest that, when used in conjunction with the conventional UPDRS measure, an actigraphic measure of physical activity may provide clinicians an adjunct measurement approach to monitor patients' activity-based disease progression or responses to treatment in outpatient clinic settings. PMID- 23748130 TI - DNA binding, DNA cleavage and BSA interaction of a mixed-ligand copper(II) complex with taurine Schiff base and 1,10-phenanthroline. AB - The DNA-binding properties and DNA-cleavage activities of a Cu(II) complex, [Cu(sal-tau(phen)].1.5H2O (sal-tau=a Schiff base derived from salicylaldehyde and taurine, phen=1,10-phenanthroline), have been investigated by using UV-Vis absorption, fluorescence, circular dichroism (CD) spectra and agarose gel electrophoresis. Results indicated that this Cu(II) complex can bind to calf thymus DNA (CT-DNA) via an intercalative mode and shows efficient cleavage activity in the absence and presence of reducer. Its intrinsic binding constant Kb (1.66*10(4)M(-1)) was calculated by absorption spectra and its linear Stern Volmer quenching constant K(sq) (3.05) was obtained from florescence spectroscopy, as well as the cleaving reaction rate constant k1 (2.0*10(-4)s(-1)) was acquired from agarose gel electrophoresis. Meanwhile, the interactions of the complex with BSA have also been studied by spectroscopy. Results showed that the complex could quench the intrinsic fluorescence of bovine serum albumin (BSA) remarkably through a static quenching process, and induce a conformational change with the loss of helical stability of protein. PMID- 23748131 TI - Electrochemical and spectroscopic investigations of carboxylic acid ligand and its triorganotin complexes for their binding with ds.DNA: in vitro biological studies. AB - A carboxylic acid ligand, (Z)-4-(4-acetylphenylamino)-4-oxobut-2-enoic acid (APA 1), and its triphenyl-(APA-2) and tributyl-tin(IV) (APA-3) compounds have been synthesized and investigated for their binding with ds.DNA using UV-visible spectroscopy, fluorescence spectroscopy, cyclic voltammetry, and viscosity measurements under physiological conditions of pH and temperature. The experimental results from all techniques i.e. binding constant (Kb), binding site size (n) and free energy change (DeltaG) were in good agreement and inferred spontaneous compound-DNA complexes formation via intercalation. Among all the compounds APA-3 showed comparatively greater binding at pH 4.7 as evident from its greater Kb values {APA-3: Kb: 5.63*10(4)M(-1) (UV); 7.94*10(4)M(-1) (fluorescence); 9.91*10(4)M(-1) (CV)}. Electrochemical processes of compounds before and after the addition of DNA were found diffusion controlled. Among all compounds, APA-3 exhibited best antitumor activity. PMID- 23748132 TI - Freeze-drying simulation framework coupling product attributes and equipment capability: toward accelerating process by equipment modifications. AB - A physics-based model for the sublimation-transport-condensation processes occurring in pharmaceutical freeze-drying by coupling product attributes and equipment capabilities into a unified simulation framework is presented. The system-level model is used to determine the effect of operating conditions such as shelf temperature, chamber pressure, and the load size on occurrence of choking for a production-scale dryer. Several data sets corresponding to production-scale runs with a load from 120 to 485 L have been compared with simulations. A subset of data is used for calibration, whereas another data set corresponding to a load of 150 L is used for model validation. The model predictions for both the onset and extent of choking as well as for the measured product temperature agree well with the production-scale measurements. Additionally, we study the effect of resistance to vapor transport presented by the duct with a valve and a baffle in the production-scale freeze-dryer. Computation Fluid Dynamics (CFD) techniques augmented with a system-level unsteady heat and mass transfer model allow to predict dynamic process conditions taking into consideration specific dryer design. CFD modeling of flow structure in the duct presented here for a production-scale freeze-dryer quantifies the benefit of reducing the obstruction to the flow through several design modifications. It is found that the use of a combined valve-baffle system can increase vapor flow rate by a factor of 2.2. Moreover, minor design changes such as moving the baffle downstream by about 10 cm can increase the flow rate by 54%. The proposed design changes can increase drying rates, improve efficiency, and reduce cycle times due to fewer obstructions in the vapor flow path. The comprehensive simulation framework combining the system-level model and the detailed CFD computations can provide a process analytical tool for more efficient and robust freeze-drying of bio-pharmaceuticals. PMID- 23748133 TI - Synthesis antimicrobial and antioxidant studies of new oximes of steroidal chalcones. AB - A convenient synthesis of oximes of steroidal chalcones (4a-4j) was performed and structural assignment of the products was confirmed on the basis of IR, (1)HNMR, (13)C NMR, MS and analytical data. The synthesized compounds were screened for in vitro antioxidant activity by using DPPH method and in vitro antimicrobial activity against different bacterial and fungal strains by agar diffusion method. The activity of the tested compounds against each microbe varied due to structural differences between them. Presence and position of different substituents on the benzene ring of the chalconyl pendent had a marked effect on the activity of the compounds. From the results it can be inferred that the compounds 4a-j showed significant antioxidant activity and antimicrobial activity against all microbial strains used for testing. PMID- 23748134 TI - Proteome analysis of the plant-pathogenic bacterium Xanthomonas oryzae pv. oryzae. AB - The plant-pathogenic bacterium Xanthomonas oryzae pv. oryzae (Xoo) is the causal agent of bacterial blight, which is one of the most serious diseases of rice. Xoo has been studied for over one century, and much has been learned about it, but proteomic investigation has been neglected. In this study, proteome reference maps of Xoo were constructed by two-dimensional gel electrophoresis, and 628 spots in the gels representing 469 different protein species were identified with MALDI-TOF/TOF MS. The identified spots were assigned to 15 functional categories according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and the annotations from the National Center for Biotechnology Information (NCBI) database. The data set has been deposited in the World-2DPAGE database (Database ID: 0044). In addition, comparative proteomic analysis revealed that proteins related to the TonB-dependent transportation system and energy metabolism are involved in the phenazine-1-carboxylic acid resistance in Xoo. In conclusion, we have established a proteome database for Xoo and have used this database in a comparative proteomic analysis that identified proteins potentially contributing to phenazine-1-carboxylic acid resistance in Xoo. PMID- 23748135 TI - 4-Aminopyridine ameliorates mobility but not disease course in an animal model of multiple sclerosis. AB - Neuropathological changes following demyelination in multiple sclerosis (MS) lead to a reorganization of axolemmal channels that causes conduction changes including conduction failure. Pharmacological modulation of voltage-sensitive potassium channels (K(V)) has been found to improve conduction in experimentally induced demyelination and produces symptomatic improvement in MS patients. Here we used an animal model of autoimmune inflammatory neurodegeneration, namely experimental autoimmune encephalomyelitis (EAE), to test the influence of the K(V)-inhibitor 4-aminopyridine (4-AP) on various disease and immune parameters as well as mobility in MOG35-55 immunized C57Bl/6 mice. We challenged the hypothesis that 4-AP exerts relevant immunomodulatory or neuroprotective properties. Neither prophylactic nor therapeutic treatment with 4-AP altered disease incidence or disease course of EAE. Histopathological signs of demyelination and neuronal damage as well as MRI imaging of brain volume changes were unaltered. While application of 4-AP significantly reduced the standing outward current of stimulated CD4(+) T cells compared to controls, it failed to impact intracellular calcium concentrations in these cells. Compatibly, KV channel inhibition neither influenced CD4(+) T cell effector functions (proliferation, IL17 or IFNgamma production). Importantly however, despite equal disease severity scores 4-AP treated animals showed improved mobility as assessed by 2 independent methods, 1) foot print and 2) rotarod analysis (0.332 +/- 0.03, n=7 versus 0.399 +/- 0.08, n=14, p<0.001, respectively). Our data suggest that 4-AP while having no apparent immunomodulatory or direct neuroprotective effects, significantly ameliorates conduction abnormalities thereby improving gait and coordination. Improvement of mobility in this experimental model supports trial data and clinical experience with 4-AP in the symptomatic treatment of MS. PMID- 23748136 TI - Effective long-term immunosuppression in rats by subcutaneously implanted sustained-release tacrolimus pellet: effect on spinally grafted human neural precursor survival. AB - Achievement of effective, safe and long-term immunosuppression represents one of the challenges in experimental allogeneic and xenogeneic cell and organ transplantation. The goal of the present study was to develop a reliable, long term immunosuppression protocol in Sprague-Dawley (SD) rats by: 1) comparing the pharmacokinetics of four different subcutaneously delivered/implanted tacrolimus (TAC) formulations, including: i) caster oil/saline solution, ii) unilamellar or multilamellar liposomes, iii) biodegradable microspheres, and iv) biodegradable 3 month lasting pellets; and 2) defining the survival and immune response in animals receiving spinal injections of human neural precursors at 6 weeks to 3 months after cell grafting. In animals implanted with TAC pellets (3.4 mg/kg/day), a stable 3-month lasting plasma concentration of TAC averaging 19.1 +/- 4.9 ng/ml was measured. Analysis of grafted cell survival in SOD+ or spinal trauma-injured SD rats immunosuppressed with 3-month lasting TAC pellets (3.4-5.1 mg/kg/day) showed the consistent presence of implanted human neurons with minimal or no local T-cell infiltration. These data demonstrate that the use of TAC pellets can represent an effective, long-lasting immunosuppressive drug delivery system that is safe, simple to implement and is associated with a long-term human neural precursor survival after grafting into the spinal cord of SOD+ or spinal trauma-injured SD rats. PMID- 23748137 TI - The use of bioreactors as in vitro models in pharmaceutical research. AB - Bringing a new drug to market is costly in terms of capital and time investments, and any development issues encountered during late-stage clinical trials can often be the result of in vitro-in vivo extrapolations (IVIVE) not accurately reflecting clinical outcome. In the discipline of drug metabolism and pharmacokinetics (DMPK), current in vitro cellular methods do not provide the 3D structure and function of organs found in vivo; therefore, new dynamic methods need to be established to aid improvement of IVIVE. In this review, we highlight the importance of model progression into dynamic systems for use within drug development, focusing on devices developed currently in the areas of the liver and blood-brain barrier (BBB), and the potential to develop models for other organ systems, such as the kidney. We discuss the development of dynamic 3D bioreactor-based systems as in vitro models for use in DMPK studies. PMID- 23748138 TI - Influenza vaccination is not associated with detection of noninfluenza respiratory viruses in seasonal studies of influenza vaccine effectiveness. AB - BACKGROUND: The test-negative control study design is the basis for observational studies of influenza vaccine effectiveness (VE). Recent studies have suggested that influenza vaccination increases the risk of noninfluenza respiratory virus infection. Such an effect could create bias in VE studies using influenza-negative controls. We investigated the association between influenza infection, vaccination, and detection of other respiratory viruses among children <5 years old and adults >=50 years old with acute respiratory illness who participated in seasonal studies of influenza vaccine effectiveness. METHODS: Nasal/nasopharyngeal samples collected from 2004-2005 through 2009-2010 were tested for 19 respiratory virus targets using a multiplex reverse-transcription polymerase chain reaction (RT-PCR) platform. Vaccination status was determined using a validated registry. Adjusted odds ratios for influenza and vaccination status were calculated using three different control groups: influenza-negative, other respiratory virus positive, and pan-negative. RESULTS: Influenza was detected in 12% of 2010 children and 20% of 1738 adults. Noninfluenza respiratory viruses were detected in 70% of children and 38% of adults without influenza. The proportion vaccinated did not vary between virus-positive controls and pan negative controls in children (P = .62) or adults (P = .33). Influenza infection was associated with reduced odds of vaccination, but adjusted odds ratios differed by no more than 0.02 when the analysis used influenza-negative or virus positive controls. CONCLUSIONS: Influenza vaccination was not associated with detection of noninfluenza respiratory viruses. Use of influenza-negative controls did not generate a biased estimate of vaccine effectiveness due to an effect of vaccination on other respiratory virus infections. PMID- 23748140 TI - Decreased hematopoietic progenitor cell mobilization in pearl mice. AB - Neutropenia is common to both Hermansky-Pudlak syndrome type 2 and canine cyclic hematopoiesis (CH) which are caused by mutations in the AP3B1 gene. The purpose of this study was to determine if pearl mice were neutropenic. Complete blood counts (CBCs) and bone marrow differential counts, colony forming unit (CFU) assay, bone marrow lineage negative (lin(-)), Sca(+) and c-kit(+) cells (LSK cells), bone marrow elastase, myeloperoxidase, and cathepsin G enzyme activity were compared in C57Bl6 (Bl/6) and pearl mice. Stress granulopoiesis was evaluated following 200 mg/kg cyclophosphamide or 1 mg/kg bortezomib administration and by limiting dilution bone marrow transplantation. The CBCs and CFUs were determined in Bl/6 and pearl mice following AMD3100 or granulocyte colony-stimulating factor (G-CSF) administration. Pearl mice were not neutropenic and did not have cyclic neutropenia. Bone marrow elastase, myeloperoxidase, and cathepsin G enzyme activity were similar in pearl and Bl/6 mice. The numbers of CFU-G, CFU-GEMM, and LSK cells were increased moderately in pearl mice. Stress granulopoiesis was similar in Bl/6 and pearl mice. CFU assays and CBCs performed on Bl/6 and pearl mice administered AMD3100 resulted in similar results. However, normal mice administered G-CSF had higher peripheral blood neutrophil counts and greater CFU numbers compared with pearl mice. Unlike patients with HPS-2 and dogs with CH, pearl mice did not have neutropenia or CH but had decreased hematopoietic progenitor cell and granulocyte mobilization in response to G-CSF. PMID- 23748141 TI - Construction and characterization of a potent, long-lasting recombinant human serum albumin-interferon alpha1 fusion protein expressed in Pichia pastoris. AB - The main obstacles to using Interferon a1 as an antiviral agent are its low stability and fast clearance. Here, we prepared a long-lasting recombinant human serum albumin-interferon alpha1 fusion protein. It was expressed in methylotrophic yeast Pichia pastoris with HSA's natural signal peptide and purified by dye affinity chromatography and ion exchange chromatography. The physicochemical, biological, and pharmaceutical characteristics of HSA-IFN alpha1 were then evaluated in vitro and in vivo. The purity of HSA-IFN alpha1 was about 95% analyzed by SDS-PAGE. Molecular weight determined by MALDI-TOF mass spectrometry was 86,582. Western blot analysis showed that the expressed HSA-IFN alpha1 had the antigenicity of HSA. The N-terminal acid amino sequence was identical to predicted sequence. The antivirus activity in vitro evaluated by cytopathic effect assay was (1.63+/-0.06)*10(5) IU/mg. After administered in rats, the biological activity of HSA-IFN alpha1 were enhanced and maintained for 6days in serum. Overall, these studies demonstrate the feasibility of using albumin-fusion technology to development a long-lasting, antiviral protein HSA IFN alpha1 with high antivirus activity. PMID- 23748142 TI - Purification of phosphinothricin acetyltransferase using Reactive brown 10 affinity in a single chromatography step. AB - The expression of phosphinothricin N-acetyltransferase (PAT) protein in transgenic plants confers tolerance to the herbicide glufosinate. To enable the characterization of PAT protein expressed in plants, it is necessary to obtain high purity PAT protein from the transgenic grain. Because transgenically expressed proteins are typical present at very low levels (i.e. 0.1-50 MUg protein/g grain), a highly specific and efficient purification protocol is required to purify them. Based on the physicochemical properties of PAT, we developed a novel purification method that is simple, time-saving, inexpensive and reproducible. The novel method employs a single chromatography step using a reactive dye resin, Reactive brown 10-agarose. Reactive brown 10 preferentially binds the PAT protein, which can then be specifically released by one of its substrates, acetyl-CoA. Using Reactive brown 10-agarose, PAT protein was purified to homogeneity from cottonseed with high recovery efficiency. As expected, the Reactive brown 10-produced PAT was enzymatically active. Other applications of the method on protein expression and purification, and development of PAT enzymatic inhibitors were also discussed. PMID- 23748139 TI - Sulfenic acid chemistry, detection and cellular lifetime. AB - BACKGROUND: Reactive oxygen species-mediated cysteine sulfenic acid modification has emerged as an important regulatory mechanism in cell signaling. The stability of sulfenic acid in proteins is dictated by the local microenvironment and ability of antioxidants to reduce this modification. Several techniques for detecting this cysteine modification have been developed, including direct and in situ methods. SCOPE OF REVIEW: This review presents a historical discussion of sulfenic acid chemistry and highlights key examples of this modification in proteins. A comprehensive survey of available detection techniques with advantages and limitations is discussed. Finally, issues pertaining to rates of sulfenic acid formation, reduction, and chemical trapping methods are also covered. MAJOR CONCLUSIONS: Early chemical models of sulfenic acid yielded important insights into the unique reactivity of this species. Subsequent pioneering studies led to the characterization of sulfenic acid formation in proteins. In parallel, the discovery of oxidant-mediated cell signaling pathways and pathological oxidative stress has led to significant interest in methods to detect these modifications. Advanced methods allow for direct chemical trapping of protein sulfenic acids directly in cells and tissues. At the same time, many sulfenic acids are short-lived and the reactivity of current probes must be improved to sample these species, while at the same time, preserving their chemical selectivity. Inhibitors with binding scaffolds can be rationally designed to target sulfenic acid modifications in specific proteins. GENERAL SIGNIFICANCE: Ever increasing roles for protein sulfenic acids have been uncovered in physiology and pathology. A more complete understanding of sulfenic acid-mediated regulatory mechanisms will continue to require rigorous and new chemical insights. This article is part of a Special Issue entitled Current methods to study reactive oxygen species - pros and cons and biophysics of membrane proteins. Guest Editor: Christine Winterbourn. PMID- 23748143 TI - On-column refolding of bone morphogenetic protein-2 using cation exchange resin. AB - Refolding is often the bottle-neck step in producing recombinant proteins from inclusion bodies of Escherichia coli, especially for dimer proteins. The refolding process is protein specific, engaging a lot of time and cost to optimize conditions so that the thermodynamics favor protein refolding over competitive aggregation. Bone morphogenetic protein-2 (BMP-2) is a potent osteogenic agent having significant applications in bone regeneration therapy. In this study, we present a novel solid-phase refolding method for rapid and efficient refolding of recombinant BMP-2 dimer from E. coli. We employed a weak cation exchange resin as the adsorbing support, with decreasing gradient of denaturing agent and exposure to oxidizing conditions for adequate disulfide bond formation. Refolded BMP-2 was further purified using size exclusion chromatography and analyzed for its secondary structure and biological activity. The purified BMP-2 dimer showed dose-dependent induction of alkaline phosphatase (ALP) activity in MC3T3 pre-osteoblast cells, thus translating the success of our refolding method. This simple and rapid method can also be applied in refolding and purification of other BMP-2 like dimer proteins. PMID- 23748144 TI - A highly sensitive G-quadruplex-based luminescent switch-on probe for the detection of polymerase 3'-5' proofreading activity. AB - We report herein a luminescent switch-on label-free G-quadruplex-based assay for the rapid and sensitive detection of polymerase proofreading activity using a novel iridium(III) complex as a G-quadruplex-selective probe. The interaction of the iridium(III) complex with the G-quadruplex motif facilitates the highly sensitive switch-on detection of polymerase proofreading activity. Using T4 DNA polymerase (T4 pol) as a model enzyme, the assay achieved high sensitivity and selectivity for T4 pol over other tested enzymes. PMID- 23748145 TI - Discrepancy between fluorescence correlation spectroscopy and fluorescence recovery after photobleaching diffusion measurements of G-protein-coupled receptors. AB - Fluorescence recovery after photobleaching (FRAP) and fluorescence correlation spectroscopy (FCS) are the two most direct methods to measure the diffusion of molecules in intact living cells. Ideally, these methods should produce similar results for an identical system. We have used these methods to monitor the diffusion of two G-protein-coupled receptors and their associated proteins in the plasma membranes of cells that do not or do contain invaginated protein domains called caveolae. FRAP studies show that caveolae domains increase the immobile fraction of receptors without significantly changing their mobility. On the other hand, FCS studies show an unexpected increase the mobility of caveolae-associated proteins. Our data suggest that the geometry of caveolae domains gives rise to a confined diffusion of its attached proteins, resulting in an apparent increase in mobility. PMID- 23748146 TI - Top-down sequencing of Apis dorsata apamin by MALDI-TOF MS and evidence of its inactivity against microorganisms. AB - Apis mellifera venom is one of the best characterized venoms among Hymenoptera, yet relatively little is known about venom belonging to other species in the genus Apis. Melittin, one of the most important bioactive peptides, has been isolated and characterized in A. mellifera, Apis cerana, Apis dorsata and Apis florea, while apamin has been only characterized in A. mellifera and A. cerana. At present, no information is available about the sequence of A. dorsata apamin. Moreover, while the antiseptic properties of melittin and MCD peptides are well documented, the antimicrobial activity of apamin has never been tested. In the present study, we isolated and characterized apamin from the venom of the giant honeybee A. dorsata. We tested the activity of apamin against bacteria and yeasts in a microbiological assay to gain a more complete understanding of the antimicrobial competence of the medium molecular weight venom fraction. We show that A. dorsata apamin toxin has the same primary sequence as apamin in A. mellifera and A. cerana, yet with a different C-terminal amidation. We did not find any antiseptic activity of apamin against any of the tested microorganisms. We discuss the evolutionary processes connected to the ecological context of venom use that drove the generation of Apis venom complexity. PMID- 23748147 TI - The conceptual and practical ethical dilemmas of using health discussion board posts as research data. AB - BACKGROUND: Increasing numbers of people living with a long-term health condition are putting personal health information online, including on discussion boards. Many discussion boards contain material of potential use to researchers; however, it is unclear how this information can and should be used by researchers. To date there has been no evaluation of the views of those individuals sharing health information online regarding the use of their shared information for research purposes. OBJECTIVE: To explore the views of contributors to online diabetes discussion boards with regards to if (and how) they feel their contributions to boards should be used by health researchers. METHODS: A qualitative approach was employed using online semistructured asynchronous (email) interviews. Interpretative description methodology was used to assess the interview transcripts, and quotations were extracted and anonymized to support each theme. RESULTS: 26 interviews were carried out. Participants agreed that forum posts are in the public domain and that aggregated information could be freely used by researchers. This was agreed to be a good way of ensuring that the view of people living with diabetes is being heard in research. There was no consensus on the need for permission to use individual information, such as quotations, with some people happy for this to be freely used and others feeling that permission is necessary. CONCLUSIONS: Participants acknowledged the dichotomy of having placed information into the public domain in an unrestricted way, with some interviewees also wanting to retain control of its use. The Internet is a new research location, and rather than trying to apply traditional ethical norms to this new genre, a new modus operandi is required. The authors propose introducing new norms for presenting research carried out with online discussion boards. PMID- 23748148 TI - Inhibition of herpesvirus and influenza virus replication by blocking polymerase subunit interactions. AB - Protein-protein interactions (PPIs) play a key role in many biological processes, including virus replication in the host cell. Since most of the PPIs are functionally essential, a possible strategy to inhibit virus replication is based on the disruption of viral protein complexes by peptides or small molecules that interfere with subunit interactions. In particular, an attractive target for antiviral drugs is the binding between the subunits of essential viral enzymes. This review describes the development of new antiviral compounds that inhibit herpesvirus and influenza virus replication by blocking interactions between subunit proteins of their polymerase complexes. PMID- 23748149 TI - Effects of menopausal hormonal therapy on occult breast tumors. AB - An estimated 7% of 40-80 year old women dying of unrelated causes harbor occult breast tumors at autopsy. These lesions are too small to be detected by mammography, a method which requires tumors to be approximately 1cm in diameter to be diagnosed. Tumor growth rates, as assessed by "effective doubling times" on serial mammography range from 10 to >700 days with a median of approximately 200 days. We previously reported two models, based on iterative analysis of these parameters, to describe the biologic behavior of undiagnosed, occult breast tumors. One of our models is biologically based and includes parameters of a 200 day effective doubling time, 7% prevalence of occult tumors in the 40-80 aged female population and a detection threshold of 1.16 cm and the other involves computer based projections based on age related breast cancer incidence. Our models facilitate interpretation of the Women's Health Initiative (WHI) and anti estrogen prevention studies. The biologically based model suggests that menopausal hormone therapy with conjugated equine estrogens plus medroxyprogesterone acetate (MPA) in the WHI trial primarily promoted the growth of pre-existing, occult lesions and minimally initiated de novo tumors. The paradoxical reduction of breast cancer incidence in women receiving estrogen alone is consistent with a model that this hormone causes apoptosis in women deprived of estrogen long term as a result of the cessation of estrogen production after the menopause. Understanding of the kinetics of occult tumors suggests that breast cancer "prevention" with anti-estrogens or aromatase inhibitors represents early treatment rather than a reduction in de novo tumor formation. Our in vivo data suggest that the combination of a SERM, bazedoxifene (BZA), with conjugated equine estrogen (CEE) acts to block maturation of the mammary gland in oophorectomized, immature mice. This hormonal combination is defined by the generic term, tissue selective estrogen complex or TSEC. Xenograft studies with the BZA/CEE combination show that it blocks the growth of occult, hormone dependent tumors in nude mice. These pre-clinical data suggest that the BZA/CEE TSEC combination may prevent the growth of occult breast tumors in women. Based on the beneficial effects of this TSEC combination on symptoms and fracture prevention in menopausal women, the combination of BZA/CEE might be used as a means both to treat menopausal symptoms and to prevent breast cancer. This article is part of a Special Issue entitled 'CSR 2013'. PMID- 23748151 TI - Madness, childhood adversity and narrative psychiatry: caring and the moral imagination. AB - The dominance of technological paradigms within psychiatry creates moral and ethical tensions over how to engage with the interpersonal narratives of those experiencing mental distress. This paper argues that such paradigms are poorly suited for fostering principled responses to human suffering, and proposes an alternative approach that considers a view of relationships based in feminist theories about the nature of caring. Four primary characteristics are presented which distinguish caring from technological paradigms: (1) a concern with the particular nature of contexts, (2) embodied practice, (3) the dialogical basis of caring and (4) the existential basis of caring. From this we explore the role of the moral imagination and our ability, through narrative, to acknowledge, engage with and bear witness to the injustices that shape the lives of those who suffer. This, we argue, is at the heart of caring. Clinical implications are discussed, including an exposition of the importance of narrative in recovery from trauma and distress. Narrative Psychiatry, The Sanctuary Model of care, and Soteria, are outlined as examples of this type of practice. PMID- 23748150 TI - AKR1C3 as a target in castrate resistant prostate cancer. AB - Aberrant androgen receptor (AR) activation is the major driver of castrate resistant prostate cancer (CRPC). CRPC is ultimately fatal and more therapeutic agents are needed to treat this disease. Compounds that target the androgen axis by inhibiting androgen biosynthesis and or AR signaling are potential candidates for use in CRPC treatment and are currently being pursued aggressively. Aldo-keto reductase 1C3 (AKR1C3) plays a pivotal role in androgen biosynthesis within the prostate. It catalyzes the 17-ketoreduction of weak androgen precursors to give testosterone and 5alpha-dihydrotestosterone. AKR1C3 expression and activity has been implicated in the development of CRPC, making it a rational target. Selective inhibition of AKR1C3 will be important, however, due to the presence of closely related isoforms, AKR1C1 and AKR1C2 that are also involved in androgen inactivation. We examine the evidence that supports the vital role of AKR1C3 in CRPC and recent developments in the discovery of potent and selective AKR1C3 inhibitors. This article is part of a Special Issue entitled 'CSR 2013'. PMID- 23748152 TI - Synthesis, anticancer activity and photophysical properties of novel substituted 2-oxo-2H-chromenylpyrazolecarboxylates. AB - 2-Oxo-2H-chromenylpyrazolecarboxylates (8a-h and 12a-zb) have been synthesized by [3 + 2] cycloaddition of 2H-chromenophenylhydrazones (7a-h and 11a-w) with diethyl/dimethylbut-2-ynedioates. Phenylchromeno[4,3-c]pyrazol-4(1H)-ones (13i-n) were prepared from corresponding phenylhydrazones (7a-h) with catalytic amount of piperidine in presence of pyridine as a solvent at 100 degrees C. All the synthesized compounds (8a-h, 12a-zb and 13a-n) were screened for anticancer activity against three human cancer cell lines such as prostate (DU-145), lung adenocarcinoma (A549), and cervical (HeLa) by standard MTT assay method. Further, photophysical properties (UV and fluorescence) for these compounds were discussed. PMID- 23748154 TI - How can clinical practice guidelines be adapted to facilitate shared decision making? A qualitative key-informant study. AB - BACKGROUND: To explore how clinical practice guidelines can be adapted to facilitate shared decision making. METHODS: This was a qualitative key-informant study with group discussions and semi-structured interviews. First, 75 experts in guideline development or shared decision making participated in group discussions at two international conferences. Next, health professionals known as experts in depression or breast cancer, experts on clinical practice guidelines and/or shared decision making, and patient representatives were interviewed (N=20). Using illustrative treatment decisions on depression or breast cancer, we asked the interviewees to indicate as specifically as they could how guidelines could be used to facilitate shared decision making. RESULTS: Interviewees suggested some generic strategies, namely to include a separate chapter on the importance of shared decision making, to use language that encourages patient involvement, and to develop patient versions of guidelines. Recommendation-specific strategies, related to specific decision points in the guideline, were also suggested: These include structuring the presentation of healthcare options to increase professionals' option awareness; structuring the deliberation process between professionals and patients; and providing relevant patient support tools embedded at important decision points in the guideline. CONCLUSIONS: This study resulted in an overview of strategies to adapt clinical practice guidelines to facilitate shared decision making. Some strategies seemed more contentious than others. Future research should assess the feasibility and impact of these strategies to make clinical practice guidelines more conducive to facilitate shared decision making. PMID- 23748153 TI - Low toxicity and unprecedented anti-osteoclast activity of a simple sulfur containing gem-bisphosphonate: a comparative study. AB - Bisphosphonates (BPs) are key drugs for the treatment of bone resorption diseases like osteoporosis, Paget's disease and some forms of tumors. Recent findings underlined the importance of lipophilic N-containing BPs to ensure high biological activity. Herein we present some unprecedented results concerning the low toxicity and good anti-osteoclast activity of low molecular weight hydrophilic S-containing BPs. A series of S and N-containing BPs bearing aromatic and aliphatic substitution were prepared through Michael addition reaction between vinylidenebisphosphonate tetraethyl ester and the proper nucleophile under basic catalysis. S-containing BPs showed a generally low toxicity, determined with the neutral-red assay using the L929 cell line, and, in particular for an aliphatic one, a good biological activity assessed on primary cultures of human osteoclasts. PMID- 23748158 TI - Penetrating facial injury. PMID- 23748159 TI - Activity of chitosan-encapsulated Eucalyptus staigeriana essential oil on Haemonchus contortus. AB - Phytotherapy has been described as an alternative method for the control of gastrointestinal nematodes in small ruminants. Goal of the encapsulation of essential oils in biopolymer matrices is to optimize the biological effects of these oils. The aim of the present study was to evaluate the in vitro and in vivo anthelmintic activity of encapsulated Eucalyptus staigeriana essential oil (EncEs) on the eggs and larvae of Haemonchus contortus. Therefore, the egg hatching test (EHT), larval development test (LDT) and worm load evaluation were performed to evaluate Meriones unguiculatus experimentally infected with H. contortus. The chemical constituents of E. staigeriana essential oil (EsEO) and the in vitro oil release profile from the chitosan matrix at a pH of 1.2 and 7.0 were also characterized. EncEs and EsEO inhibited larval hatching by 97.19% and 99.96% at doses of 1.5 and 1.0 mg ml(-1), respectively. In the LDT, EncEs and EsEO induced a larvicidal effect greater than 95% at concentrations of 5.8 and 8 mg ml(-1), respectively. EncEs and EsEO decreased H. contortus load in M. unguiculatus by 40.51% and 46.44%, respectively. The major chemical constituents of EsEO were (+)-Limonene (72.9%), 1,8-Cineole (9.5%) and o-Cimene (4.6%). The release profile of EsEO was 30% in acid and 25% at neutral pH. The similar efficacy of EncEs and EsEO demonstrates that there was no optimization of anthelmintic action following the encapsulation process. Therefore, the use of new encapsulation matrices with controlled release in the pH of the abomasum should be investigated. PMID- 23748155 TI - Epigenetic induction of the Ink4a/Arf locus prevents Schwann cell overproliferation during nerve regeneration and after tumorigenic challenge. AB - The number of Schwann cells is fitted to axonal length in peripheral nerves. This relationship is lost when tumorigenic stimuli induce uncontrolled Schwann cell proliferation, generating tumours such us neurofibromas and schwannomas. Schwann cells also re-enter the cell cycle following nerve injury during the process of Wallerian degeneration. In both cases proliferation is finally arrested. We show that in neurofibroma, the induction of Jmjd3 (jumonji domain containing 3, histone lysine demethylase) removes trimethyl groups on lysine-27 of histone-H3 and epigenetically activates the Ink4a/Arf-locus, forcing Schwann cells towards replicative senescence. Remarkably, blocking this mechanism allows unrestricted proliferation, inducing malignant transformation of neurofibromas. Interestingly, our data suggest that in injured nerves, Schwann cells epigenetically activate the same locus to switch off proliferation and enter the senescence programme. Indeed, when this pathway is genetically blocked, Schwann cells fail to drop out of the cell cycle and continue to proliferate. We postulate that the Ink4a/Arf locus is expressed as part of a physiological response that prevents uncontrolled proliferation of the de-differentiated Schwann cell generated during nerve regeneration, a response that is also activated to avoid overproliferation after tumorigenic stimuli in the peripheral nervous system. PMID- 23748160 TI - Morphological, genotypic, and physiological characterization of Acanthamoeba isolates from keratitis patients and the domestic environment in Vitoria, Espirito Santo, Brazil. AB - Amoebae of the genus Acanthamoeba are free-living protozoa that can cause granulomatous encephalitis and keratitis in humans. In this study, four clinical and three household dust isolates obtained in Vitoria, Espirito Santo, Brazil were characterized by their morphological, genotypic, and physiological properties. All isolates belonged to group II according to Pussard and Pons' cyst morphology. Analysis of their 18S rDNA sequence identified one isolate from household dust as genotype T11 and the others six samples as genotype T4. Five T4 isolates presented a highly variable region (DF3) in 18S rDNA identical to those previously described. Physiological assays carried out with trophozoites in co culture with bacteria or in axenic conditions showed all samples tolerated temperatures up to 37 degrees C, regardless of culture method. One keratitis isolate grew at 42 degrees C in co-culture with bacteria. Most isolates in co culture survived at 1.0M, except a T11 isolate, which tolerated up to 0.5M. The isolates did not grow at 42 degrees C and did not tolerate 0.5M and 1.0M under axenic condition. This is the first report of 18S rRNA gene genotyping applied to Acanthamoeba isolated from keratitis patients in Brazil. The results also indicated that osmo-tolerance is dependent on the culture system. PMID- 23748161 TI - Children's perceptions of the factors helping them to be 'resilient' to sedentary lifestyles. AB - Despite the increased risk of sedentary lifestyles associated with socioeconomic disadvantage, some children living in disadvantaged areas display 'resilience' to unhealthy behaviours whereby they manage to engage in regular physical activity and avoid high levels of screen time. It is important to understand what is helping these children to do well. This qualitative study explored the perceptions of 'resilient' children regarding factors that assist them to engage in high levels of physical activity and low screen time. In-depth face-to-face interviews were conducted with 38 children (7-13 years) living in disadvantaged neighbourhoods in urban and rural areas of Victoria, Australia. Themes that emerged relating to physical activity included: parental support and encouragement of physical activity, having a supportive physical environment and having friends to be active with. Themes relating to screen time included: individual preferences to be active, knowledge of health risks associated with sedentary behaviour, having a home environment supportive of physical activity and parental rules. The results provide valuable insights regarding factors that may help children living in disadvantaged neighbourhoods to be physically active and reduce their screen time and may inform future studies targeting this important population group. PMID- 23748157 TI - Impact from point-of-care devices on emergency department patient processing times compared with central laboratory testing of blood samples: a randomised controlled trial and cost-effectiveness analysis. AB - OBJECTIVE: To determine if time to disposition decisions for emergency department (ED) patients can be reduced when blood tests are processed using point-of-care (POC) devices and to conduct a cost-effectiveness analysis of POC compared with laboratory testing. METHODS: This randomised trial enrolled adults suspected of an acute coronary syndrome or presenting with conditions considered to only require blood tests available by POC. Participants were randomised to have blood tests processed by POC or laboratory. Outcomes measured were time to disposition decision and ED length-of-stay (LOS). The cost-effectiveness analysis calculated the total and mean costs per ED presentation, as well as total and mean benefits in time saved to disposition decision. RESULTS: There were 410 POC participants and 401 controls. The mean times to a disposition decision for POC versus controls were 3.24 and 3.50 h respectively, a difference of 7.6% (95% CI 0.4% to 14.3%, p=0.04), and 4.32 and 4.52 h respectively for ED LOS, a difference of 4.4% (95% CI -2.7% to 11.0%, p=0.21). Improved processing time was greatest for participants enrolled by senior staff with a reduction in time to disposition decision of 19.1% (95% CI 7.3% to 29.4%, p<0.01) and ED LOS of 15.6% (95% CI 4.9% to 25.2%, p=0.01). Mean pathology costs were $12 higher in the POC group (95% CI $7 to $18) and the incremental cost-effectiveness ratio was $113 per hour saved in time to disposition decision for POC compared with standard laboratory testing. CONCLUSIONS: Small improvements in disposition decision time were achieved with POC testing for a moderate increase in cost. Greatest benefit may be achieved when POC is targeted to senior medical staff. PMID- 23748156 TI - The COPE healthy lifestyles TEEN randomized controlled trial with culturally diverse high school adolescents: baseline characteristics and methods. AB - Obesity and mental health disorders remain significant public health problems in adolescents. Substantial health disparities exist with minority youth experiencing higher rates of these problems. Schools are an outstanding venue to provide teens with skills needed to improve their physical and mental health, and academic performance. In this paper, the authors describe the design, intervention, methods and baseline data for a randomized controlled trial with 779 culturally diverse high-school adolescents in the southwest United States. Aims for this prevention study include testing the efficacy of the COPE TEEN program versus an attention control program on the adolescents' healthy lifestyle behaviors, Body Mass Index (BMI) and BMI%, mental health, social skills and academic performance immediately following the intervention programs, and at six and 12 months post interventions. Baseline findings indicate that greater than 40% of the sample is either overweight (n = 148, 19.00%) or obese (n = 182, 23.36%). The predominant ethnicity represented is Hispanic (n = 526, 67.52%). At baseline, 15.79% (n = 123) of the students had above average scores on the Beck Youth Inventory Depression subscale indicating mildly (n = 52, 6.68%), moderately (n = 47, 6.03%), or extremely (n = 24, 3.08%) elevated scores (see Table 1). Anxiety scores were slightly higher with 21.56% (n = 168) reporting responses suggesting mildly (n = 81, 10.40%), moderately (n = 58, 7.45%) or extremely (n = 29, 3.72%) elevated scores. If the efficacy of the COPE TEEN program is supported, it will offer schools a curriculum that can be easily incorporated into high school health courses to improve adolescent healthy lifestyle behaviors, psychosocial outcomes and academic performance. PMID- 23748162 TI - Evaluation of a web-based program promoting healthy eating and physical activity for adolescents: teen choice: food and fitness. AB - This randomized clinical trial tested the impact of a website promoting nutrition and physical activity for adolescents (Teen Choice: Food and Fitness). Participants, (408) 12- to 17-year-old adolescents in the Houston area, completed online surveys measuring diet, physical activity, sedentary behavior and diet/physical activity mediators at baseline. After randomization, they were asked to log onto either the intervention or the control condition website weekly for 8 weeks to review web content and set goals to improve dietary and physical activity behaviors. Post-test occurred after 8 weeks. Logistic regression analyses and one-way analyses of covariance were used in the analyses. At post, more intervention group adolescents reported eating three or more daily vegetable servings in the past week compared with the control group (P < 0.05); both groups reported significant increases in physical activity (P < 0.001) and significant decreases in TV watching (P < 0.01). Average log on rate was 75% over the 8 weeks; there was no difference by condition. The website enabled adolescents to improve vegetable intake and daily physical activity, reduce sedentary behavior and had a high log on rate. Future research should identify effective methods for disseminating this website to wider audiences. PMID- 23748163 TI - Noise models and cryo-EM drift correction with a direct-electron camera. AB - Blurring due to specimen-holder drift is a common occurrence in cryo-EM images. Cameras employing active-pixel sensors are capable of high frame rates such that a single low-dose exposure can be acquired as a series of frames. In this paper we consider the possibility of tracking and compensating for overall drift in typical single-particle specimens through the analysis of frame sequences. A problem that arises in tracking through cross-correlation of frames obtained with the DE-12 camera from Direct Electron LLC is the presence of "hot-pixel noise". This random pattern of bright pixels is highly correlated among frames. We show how a model of this noise can be employed to greatly reduce its effects. A filter function is derived that optimizes the tracking of image shifts by cross correlation, and we demonstrate the tracking of specimen drift in typical cryo-EM specimens. PMID- 23748164 TI - FOXO1 regulates expression of a microRNA cluster on X chromosome. AB - Phosphoinositol-3-kinase (PI3K) pathway is a crucial modulator of many physiological and pathophysiological phenomena, including aging, diabetes and cancer. Protein kinase Akt, a downstream effector of PI3K, controls a plethora of cellular functions, including gene transcription. A key mechanism connecting Akt activity to changes in gene expression is inhibitory phosphorylation of FOXO family of transcription factors. Accordingly, altered expression of FOXO targets may account for many biological consequences of PI3K/Akt signaling. While the previous efforts focused on FOXO-dependent regulation of protein-coding genes, non-coding RNA genes have emerged as equally important targets of many transcription factors. Therefore, we utilized a regulated form of FOXO1 to profile FOXO1-dependent changes in miRNA expression in human cells. Both microarray hybridization and next-generation sequencing revealed changes in the products of a miRNA cluster on X chromosome. Rapid induction of these miRNAs occurred independently of de novo protein synthesis. Furthermore, inhibition of PI3K in cancer cell lines caused derepression of these miRNAs, as would be expected for FOXO-regulated genes. Members of the major oncogenic cascades are significantly overrepresented among the predicted targets of the miRNAs, consistent with tumor-suppressive role of FOXO1. The discovered miRNAs represent new candidate mediators of FOXO1 functions and possible biomarkers of its activity. PMID- 23748165 TI - A novel eukaryotic Na+ methionine selective symporter is essential for mosquito development. AB - AeNAT5 (NCBI, ABZ81822), an orphan member of the insect-specific Nutrient Amino acid Transporter subfamily of SoLute Carrier family 6 (NAT-SLC6) and the first representative of a novel eukaryotic methionine-selective transport system (M), was cloned from cDNA of the vector mosquito, Aedes aegypti. It has orphan orthologs throughout several mosquito genomes, but not in Drosophila or outside Diptera. It shows the highest apparent affinity to L-Met (K(0.5) = 0.021 mM) and its metabolites Homocysteine and Cysteine (K(0.5) = 0.89 and 2.16 mM), but weakly interact with other substrates. It has a Na(+) - coupled mechanism (K(0.5) Na(+) ~ 46 mM) with 1AA:1Na(+) stoichiometry that maintains ~60% activity in Cl(-) - free media. In situ hybridization showed accumof AeNAT5 transcript in the absorptive and secretory epithelia, as well as in specific peripheral neurons and the central ganglia of mosquito larvae. The labeling pattern is distinct from that of the previously characterized AeNAT1. RNAi of AeNAT5 increases larval mortality during ecdysis and dramatically suppresses adult emergence. Our results showed that in addition to previously characterized broad spectra and aromatic amino acid selective transport systems, the mosquito NAT-SLC6 subfamily evolved a unique mechanism for selective absorption of sulfur-containing substrates. We demonstrated specific patterns of alimentary and neuronal transcription of AeNAT5 in mosquito larvae that is collateral with the indispensable function of this transporter in mosquito development. PMID- 23748166 TI - C-reactive protein and future cardiovascular events in statin-treated patients with angina pectoris: the extended TRUTH study. AB - AIM: The TRUTH trial demonstrated that 8-month statin therapy alters the composition of coronary artery plaque using virtual histology (VH)-intravascular ultrasound (IVUS). The extended TRUTH study was conducted to evaluate the relationship between changes in coronary atherosclerosis and mid-term clinical outcomes and identify the factors associated with cardiovascular events. METHODS: Of 164 patients with angina pectoris who participated in the TRUTH trial, 119 subjects with analyzable IVUS data at both enrollment and the 8-month follow-up were enrolled and observed for at least two years. The primary end point was the time to first occurrence of cardiovascular composite events, including cardiovascular death, nonfatal myocardial infarction, nonfatal cerebral infarction, unstable angina and ischemic-driven revascularization, except for target lesion revascularization. RESULTS: The frequency of reaching the primary end point was 13% (16/119), with a mean follow-up period of 41.9+/-9.4 months. Although plaque regression and changes in plaque composition were not associated with future cardiovascular events, the serum high-sensitivity C-reactive protein (hs-CRP) levels at the start of the extended TRUTH study were significantly higher in the event group than in the event-free group (1.43 mg/L vs. 0.58 mg/L, p=0.01). A multivariate logistic regression analysis showed that the hs-CRP level was an independent significant predictor of cardiovascular events (odds ratio: 1.69; 95% confidence interval: 1.14-2.50, p=0.01). CONCLUSIONS: Coronary artery plaque regression and changes in plaque composition during statin therapy do not predict future cardiovascular events in patients with angina pectoris. Instead, the serum hs-CRP level can be used as a predictor of cardiovascular events. PMID- 23748167 TI - Near-term fetal response to maternal spoken voice. AB - Knowledge about prenatal learning has been largely predicated on the observation that newborns appear to recognize the maternal voice. Few studies have examined the process underlying this phenomenon; that is, whether and how the fetus responds to maternal voice in situ. Fetal heart rate and motor activity were recorded at 36 weeks gestation (n = 69) while pregnant women read aloud from a neutral passage. Compared to a baseline period, fetuses responded with a decrease in motor activity in the 10 s following onset of maternal speech and a trend level decelerative heart rate response, consistent with an orienting response. Subsequent analyses revealed that the fetal response was modified by both maternal and fetal factors. Fetuses of women who were previously awake and talking (n = 40) showed an orienting response to onset of maternal reading aloud, while fetuses of mothers who had previously been resting and silent (n = 29) responded with elevated heart rate and increased movement. The magnitude of the fetal response was further dependent on baseline fetal heart rate variability such that largest response was demonstrated by fetuses with low variability of mothers who were previously resting and silent. Results indicate that fetal responsivity is affected by both maternal and fetal state and have implications for understanding fetal learning of the maternal voice under naturalistic conditions. PMID- 23748169 TI - An intelligent surveillance platform for large metropolitan areas with dense sensor deployment. AB - This paper presents an intelligent surveillance platform based on the usage of large numbers of inexpensive sensors designed and developed inside the European Eureka Celtic project HuSIMS. With the aim of maximizing the number of deployable units while keeping monetary and resource/bandwidth costs at a minimum, the surveillance platform is based on the usage of inexpensive visual sensors which apply efficient motion detection and tracking algorithms to transform the video signal in a set of motion parameters. In order to automate the analysis of the myriad of data streams generated by the visual sensors, the platform's control center includes an alarm detection engine which comprises three components applying three different Artificial Intelligence strategies in parallel. These strategies are generic, domain-independent approaches which are able to operate in several domains (traffic surveillance, vandalism prevention, perimeter security, etc.). The architecture is completed with a versatile communication network which facilitates data collection from the visual sensors and alarm and video stream distribution towards the emergency teams. The resulting surveillance system is extremely suitable for its deployment in metropolitan areas, smart cities, and large facilities, mainly because cheap visual sensors and autonomous alarm detection facilitate dense sensor network deployments for wide and detailed coverage. PMID- 23748168 TI - Maternal self-regulation, relationship adjustment, and home chaos: contributions to infant negative emotionality. AB - There has been increasing interest in the direct and indirect effects of parental self-regulation on children's outcomes. In the present investigation, the effects of maternal self-regulation, home chaos, and inter-parental relationship adjustment on broad and specific indicators of infant negative emotionality (NE) were examined. A sample of maternal caregivers and their 4-month-old infants (N = 85) from a rural community participated. Results demonstrated that better maternal self-regulation was associated with lower infant NE broadly, as well as with lower infant sadness and distress to limitations/frustration and better falling reactivity (i.e., emotion regulation), specifically. Maternal self regulation also predicted less chaotic home environments and better maternal inter-parental relationship adjustment. Findings also supported the indirect effects of maternal self-regulation on broad and specific indicators of infant NE through home chaos and maternal relationship adjustment. Some differential effects were also identified. Elevated home chaos appeared to specifically affect infant frustration/distress to limitations whereas maternal relationship adjustment affected broad infant NE, as well as several specific indicators of infant NE: frustration/distress to limitations, sadness, and falling reactivity. In conjunction with other recent investigations that have reported the effects of maternal self-regulation on parenting, the findings in the present investigation suggest that parental self-regulation may influence children's outcomes through several proximal environmental pathways. PMID- 23748170 TI - Theoretical analysis of the optical propagation characteristics in a fiber-optic surface plasmon resonance sensor. AB - Surface plasmon resonance (SPR) sensor is widely used for its high precision and real-time analysis. Fiber-optic SPR sensor is easy for miniaturization, so it is commonly used in the development of portable detection equipment. It can also be used for remote, real-time, and online detection. In this study, a wavelength modulation fiber-optic SPR sensor is designed, and theoretical analysis of optical propagation in the optical fiber is also done. Compared with existing methods, both the transmission of a skew ray and the influence of the chromatic dispersion are discussed. The resonance wavelength is calculated at two different cases, in which the chromatic dispersion in the fiber core is considered. According to the simulation results, a novel multi-channel fiber-optic SPR sensor is likewise designed to avoid defaults aroused by the complicated computation of the skew ray as well as the chromatic dispersion. Avoiding the impact of skew ray can do much to improve the precision of this kind of sensor. PMID- 23748171 TI - A proposal for modeling real hardware, weather and marine conditions for underwater sensor networks. AB - Network simulators are useful for researching protocol performance, appraising new hardware capabilities and evaluating real application scenarios. However, these tasks can only be achieved when using accurate models and real parameters that enable the extraction of trustworthy results and conclusions. This paper presents an underwater wireless sensor network ecosystem for the ns-3 simulator. This ecosystem is composed of a new energy-harvesting model and a low-cost, low power underwater wake-up modem model that, alongside existing models, enables the performance of accurate simulations by providing real weather and marine conditions from the location where the real application is to be deployed. PMID- 23748172 TI - The localized discovery and recovery for query packet losses in wireless sensor networks with distributed detector clusters. AB - An essential application of wireless sensor networks is to successfully respond to user queries. Query packet losses occur in the query dissemination due to wireless communication problems such as interference, multipath fading, packet collisions, etc. The losses of query messages at sensor nodes result in the failure of sensor nodes reporting the requested data. Hence, the reliable and successful dissemination of query messages to sensor nodes is a non-trivial problem. The target of this paper is to enable highly successful query delivery to sensor nodes by localized and energy-efficient discovery, and recovery of query losses. We adopt local and collective cooperation among sensor nodes to increase the success rate of distributed discoveries and recoveries. To enable the scalability in the operations of discoveries and recoveries, we employ a distributed name resolution mechanism at each sensor node to allow sensor nodes to self-detect the correlated queries and query losses, and then efficiently locally respond to the query losses. We prove that the collective discovery of query losses has a high impact on the success of query dissemination and reveal that scalability can be achieved by using the proposed approach. We further study the novel features of the cooperation and competition in the collective recovery at PHY and MAC layers, and show that the appropriate number of detectors can achieve optimal successful recovery rate. We evaluate the proposed approach with both mathematical analyses and computer simulations. The proposed approach enables a high rate of successful delivery of query messages and it results in short route lengths to recover from query losses. The proposed approach is scalable and operates in a fully distributed manner. PMID- 23748173 TI - Direct electrochemistry of hemoglobin at a graphene gold nanoparticle composite film for nitric oxide biosensing. AB - A simple two-step method was employed for preparing nano-sized gold nanoparticles graphene composite to construct a GNPs-GR-SDS modified electrode. Hemoglobin (Hb) was successfully immobilized on the surface of a basal plane graphite (BPG) electrode through a simple dropping technique. Direct electrochemistry and electrocatalysis of the hemoglobin-modified electrode was investigated. The as prepared composites showed an obvious promotion of the direct electro-transfer between hemoglobin and the electrode. A couple of well-defined and quasi reversible Hb CV peaks can be observed in a phosphate buffer solution (pH 7.0). The separation of anodic and cathodic peak potentials is 81 mV, indicating a fast electron transfer reaction. The experimental results also clarified that the immobilized Hb retained its biological activity for the catalysis toward NO. The biosensor showed high sensitivity and fast response upon the addition of NO, under the conditions of pH 7.0, potential -0.82 V. The time to reach the stable state current was less than 3 s, and the linear response range of NO was 0.72 7.92 MUM, with a correlation coefficient of 0.9991. PMID- 23748174 TI - The risk of subsequent malignancies in women with uterine papillary serous or clear cell endometrial cancers. AB - OBJECTIVE: Type II endometrial cancers include uterine papillary serous carcinoma (UPSC) and clear cell endometrial cancer (CC). Given their relative rarity, aggressive nature, and poor prognosis, little is known about the risk of subsequent malignancies at other sites. Our objective was to determine if women with UPSC or CC are at increased risk of subsequent malignancies.Type II endometrial cancers include uterine papillary serous carcinoma (UPSC) and clear cell endometrial cancer (CC). Given their relative rarity, aggressive nature, and poor prognosis, little is known about the risk of subsequent malignancies at other sites. Our objective was to determine if women with UPSC or CC are at increased risk of subsequent malignancies. METHODS: Women diagnosed with UPSC or CC were identified from the SEER (Surveillance Epidemiology and End Results) Program from 1973 to 2005. Cases with a second gynecologic malignancy were excluded. Using SEER*Stat software, standardized incidence ratios (SIRs) of subsequent malignancies were calculated. RESULTS: A total of 8045 and 1740 patients were diagnosed with UPSC and CC, respectively. Four hundred sixty-one (5.7%) of the UPSC cases were diagnosed with at least 1 additional nongynecologic malignancy. Significant associations were found with the following malignancies: the renal pelvis, soft-tissue sarcomas, acute myeloid leukemia, the bladder, and colon. Seventy-eight CC cases (4.5%) were diagnosed with at least 1 additional malignancy. In comparison with the baseline population risk, there was no statistically significant increased risk of any subsequent malignancy with a primary diagnosis of CC. CONCLUSIONS: This is the first large population-based analysis of second primary malignancies after type II endometrial cancers. Uterine papillary serous carcinoma is associated with increased risks of certain subsequent malignancies, and providers should be aware of these when following up patients with this diagnosis, especially those with stage I disease. In contrast, no such associations were found with CC in this cohort. PMID- 23748175 TI - Alterations in expression pattern of splicing factors in epithelial ovarian cancer and its clinical impact. AB - OBJECTIVE: Alternative splicing represents an important nuclear mechanism in the posttranscriptional regulation of gene expression, which is frequently altered during tumorigenesis. Previously, we described marked changes in alternative splicing of the CD44 gene in ovarian and breast cancer as well as specific induction of distinct splicing factors during tumor development. The present study was focused on the expression profiles of different splicing factors, including classical serine-arginine (SR) proteins including ASF/SF2, hTra2beta1, hTra2alpha, and Y-box-binding protein (YB-1) in physiological and malignant epithelial ovarian tissue to evaluate their expression pattern with regard to tumor development and disease progression. MATERIALS AND METHODS: Expression levels of the different splicing factors were analyzed in physiological epithelial ovarian tissue samples, primary tumors, and metastatic samples of patients with a diagnosis of epithelial ovarian cancer using quantified reverse transcription polymerase chain reaction analysis. We examined more closely the splicing factor hTra2beta1 using Western blot analysis and immunohistochemistry. RESULTS: The analysis revealed a marked and specific induction of ASF/SF2, SRp20, hTra2beta1, and YB-1 in primary tumors as well as in their metastatic sites. However, in our patient cohort, no induction was seen for the other investigated splicing factors SRp55, SRp40, and hTra2alpha. CONCLUSIONS: Our results suggest a specific induction of distinct splicing factors in ovarian cancer tumorigenesis. The involvement of hTra2beta1, YB-1, SRp20, and ASF/SF2 in exon recognition and alternative splicing may be important for gene regulation of alternatively spliced genes like CD44 with potential functional consequences in this tumor type leading to progression and metastasis. PMID- 23748176 TI - Timing of referral for genetic counseling and genetic testing in patients with ovarian, fallopian tube, or primary peritoneal carcinoma. AB - OBJECTIVE: The objective of this study was to assess patients' preferences of the timing of referral for genetic counseling and testing in relation to the diagnosis, treatment, and recurrence of ovarian, tubal, or primary peritoneal cancers. METHODS: Ninety-two patients who underwent counseling and testing by 1 certified genetic counselor were identified. An introductory letter, consent form, and questionnaire were mailed to gather information regarding factors influencing the decision to undergo genetic counseling and testing and opinions regarding optimal timing. Medical records were reviewed for demographic and clinical data. RESULTS: Of 47 consenting women, 45 underwent testing. Eight (18%) were found to have a genetic mutation. Women lacked consensus about the optimal time for referral for and to undergo genetic testing, although women with stage I disease preferred testing after completion of chemotherapy. Most women were comfortable receiving the results by phone, but one third preferred an office visit. CONCLUSIONS: Patients' views regarding the best time to be referred for and undergo counseling and testing varied greatly. Because of the high mortality of this disease, clinicians should discuss referral early and personalize the timing to each patient. The subset of patients who prefer results disclosure during an office visit should be identified at the time of their initial counseling. PMID- 23748178 TI - Robot versus laparoscopic nerve-sparing radical hysterectomy for cervical cancer: a comparison of the intraoperative and perioperative results of a single surgeon's initial experience. AB - OBJECTIVE: The aim of the study was to compare the initial surgical outcomes and learning curve of nerve-sparing robotic radical hysterectomy (RRH) with nerve sparing total laparoscopic radical hysterectomy (TLRH) for the treatment of early stage cervical cancer in the first 50 cases. METHODS: Between January 2008 and March 2012, 50 consecutive patients underwent nerve-sparing RRH. These patients were compared with a historic cohort of the first 50 consecutive patients who underwent nerve-sparing TLRH. RESULTS: Both groups were similar with respect to patients and tumor characteristics. The mean operating time in the RRH group was significantly longer than that in the TLRH group (230.1 +/- 35.8 vs 211.2 +/- 46.7 minutes; P = 0.025). The mean blood loss for the robotic group was significantly lower compared with the laparoscopic group (54.9 +/- 31.5 vs 201.9 +/- 148.4 mL; P < 0.001). There was no significant difference in the mean pelvic lymph nodes between the 2 groups (25.0 +/- 9.9 vs 23.1 +/- 10.4; P = 0.361). The mean days to normal residual urine were 9.6 +/- 6.4 in RRH and 11.0 +/- 6.2 in TLRH (P = 0.291). The incidence of intraoperative complication was profoundly lower in RRH compared with that of TLRH (0% vs 8%; P = 0.041). Moreover, no intraoperative transfusion was required in RRH, whereas 4 (8%) were required in TLRH (P = 0.041). In both groups, we found no evidence of a learning effect during the first 50 cases. CONCLUSIONS: During the first 50 cases, surgical outcomes and complication rates of nerve-sparing RRH were found to be comparable to those of nerve-sparing TLRH. Moreover, the mean blood loss and intraoperative complication rate in the robotic group were significantly lower than those in the laparoscopic group. Surgical skills for nerve-sparing TLRH easily and safely translated to nerve-sparing RRH in case of experienced laparoscopic surgeon. PMID- 23748177 TI - Risk factors for ovarian cancers with and without microsatellite instability. AB - OBJECTIVE: The objective of this study was to evaluate the association between microsatellite instability (MSI) status and (1) ovarian cancer risk factors and (2) the distribution of the specific histologic subtypes in a population-based sample of epithelial ovarian cancers. METHODS: Participants were drawn from 3 population-based studies of primary epithelial ovarian cancer. Tumor DNA was analyzed using 5 standardized microsatellite markers to assess MSI status. Patients were divided into 3 groups (MSI-high, MSI-low, and MSI-stable) according to National Cancer Institute criteria. We compared the prevalence of specific known risk and protective factors among the 3 subgroups, including body mass index, smoking history, parity, BRCA1 and BRCA2 mutation status, past oral contraceptive use, and tubal ligation. Similarly, we compared the distribution of the histologic subtypes among the 3 subgroups. RESULTS: A total of 917 ovarian cancer patients were included. One hundred twenty-seven (13.8%) cancers were MSI high. Subgroup analyses according to smoking, body mass index, parity, past oral contraceptive use, and past tubal ligation did not reveal any statistically significant differences among the groups. Among the 29 patients with BRCA1 mutations, 20.7% had MSI-high cancers compared with 5.9% among 17 BRCA2-mutation patients. The proportions of different ovarian cancer histologic findings among the various MSI subgroups were similar. CONCLUSIONS: The prevalence of risk and protective factors among ovarian cancer patients is similar for cancers with and without MSI. The distributions of MSI do not differ significantly among ovarian cancers with different histologic findings. Ovarian cancer patients with BRCA1 mutations had a 21% rate of MSI-high tumors, compared with 6% among patients with BRCA2 mutations, but this difference was not statistically significant. PMID- 23748179 TI - Matching metal pollution with bioavailability, bioaccumulation and biomarkers response in fish (Centropomus parallelus) resident in neotropical estuaries. AB - Two neotropical estuaries affected by different anthropogenic factors were studied. We report levels of metals and metalloids in water and sediment as well as their influence on genetic, biochemical and morphological biomarkers in the native fish Centropomus parallelus. Biomarkers reflected the fish health status. Multivariate statistics indicated both spatial and temporal changes in both water and sediment, which are linked to the elemental composition and health status of inhabitant fish, showing the biggest influence of surface water, followed by sediments and interstitial water. Bioaccumulation in fish muscle was useful to identify elements that were below detection limits in water, pointing out the risk of consuming fish exceeding allowance limits for some elements (As and Hg in this case). Multivariate statistics, including physical, chemical and biological issues, presents a suitable tool, integrating data from different origin allocated in the same estuary, which could be useful for future studies on estuarine systems. PMID- 23748180 TI - The progesterone receptor antagonist, onapristone has differential effects on the timing and control of the luteolytic mechanism depending on timing of administration in sheep. AB - Cyclic ewes were treated with control vehicle or progesterone receptor antagonist (onapristone; 100mg i.m. twice daily) during either early (day 3-5) or late (day 12-14) luteal phase and plasma samples collected for hormone analysis and to determine endogenous and oxytocin induced PGF2alpha release. On day 14 and 17, ewes were euthanised and reproductive tracts collected for ovarian morphology and endometrium for oxytoxin and steroid hormone receptor analysis. Early treatment increased LH, but not progesterone or oestradiol, while late treatment elevated all three hormones. Early treatment delayed the up-regulation of endometrial oxytocin receptors and responsiveness to oxytocin challenge, delaying luteolysis. Late treatment advanced development of oxytocin receptors and responsiveness to oxytocin though not timing of luteolysis. Patterns of hormone receptor mRNA were differentially disrupted by treatments. Results provide mechanistic insight into hormonal control of the oestrous cycle and identify the ability of the luteolytic mechanism to dissociate from functional luteolysis. PMID- 23748181 TI - A phylogenetic model for the detection of epistatic interactions. AB - Paired epistatic interactions, such as those in the stem regions of RNA, play an important role in many biological processes. However, unlike protein-coding regions, paired epistatic interactions have lacked the appropriate statistical tools for the detection of departures from selective neutrality. Here, a model is presented for the analysis of paired epistatic regions that draws upon the population genetics of the compensatory substitution process to detect the relative strength of natural selection acting against deleterious combinations of alleles. The method is based upon the relative rates of double and single substitution, and can differentiate between nonindependent interactions and negatively epistatic ones. The model is implemented in a fully Bayesian framework for parameter estimation and is demonstrated using a 5S rRNA data set. In addition to the detection of selection, modeling the double and single substitution processes in this manner inherently accounts for a substantial proportion of rate variation among stem positions. PMID- 23748182 TI - Collecting maternal health information from HIV-positive pregnant women using mobile phone-assisted face-to-face interviews in Southern Africa. AB - BACKGROUND: Most of the world's women living with human immunodeficiency virus (HIV) reside in sub-Saharan Africa. Although efforts to reduce mother-to-child transmission are underway, obtaining complete and accurate data from rural clinical sites to track progress presents a major challenge. OBJECTIVE: To describe the acceptability and feasibility of mobile phones as a tool for clinic based face-to-face data collection with pregnant women living with HIV in South Africa. METHODS: As part of a larger clinic-based trial, 16 interviewers were trained to conduct mobile phone-assisted personal interviews (MPAPI). These interviewers (participant group 1) completed the same short questionnaire based on items from the Technology Acceptance Model at 3 different time points. Questions were asked before training, after training, and 3 months after deployment to clinic facilities. In addition, before the start of the primary intervention trial in which this substudy was undertaken, 12 mothers living with HIV (MLH) took part in a focus group discussion exploring the acceptability of MPAPI (participant group 2). Finally, a sample of MLH (n=512) enrolled in the primary trial were asked to assess their experience of being interviewed by MPAPI (participant group 3). RESULTS: Acceptability of the method was found to be high among the 16 interviewers in group 1. Perceived usefulness was reported to be slightly higher than perceived ease of use across the 3 time points. After 3 months of field use, interviewer perceptions of both perceived ease of use and perceived usefulness were found to be higher than before training. The feasibility of conducting MPAPI interviews in this setting was found to be high. Network coverage was available in all clinics and hardware, software, cost, and secure transmission to the data center presented no significant challenges over the 21-month period. For the 12 MHL participants in group 2, anxiety about the multimedia capabilities of the phone was evident. Their concern centered on the possibility that their privacy may be invaded by interviewers using the mobile phone camera to photograph them. For participants in group 3, having the interviewer sit beside vs across from the interviewee during the MPAPI interview was received positively by 94.7% of MHL. Privacy (6.3%) and confidentiality (5.3%) concerns were low for group 3 MHL. CONCLUSIONS: Mobile phones were found both to be acceptable and feasible in the collection of maternal and child health data from women living with HIV in South Africa. TRIAL REGISTRATION: Clinicaltrials.gov NCT00972699; http://clinicaltrials.gov/ct2/show/NCT00972699 (Archived by WebCite at http://clinicaltrials.gov/ct2/show/NCT00972699). PMID- 23748183 TI - Biomineralization in living hypercalcified demosponges: toward a shared mechanism? AB - Massive skeletons of living hypercalcified sponges, representative organisms of basal Metazoa, are uncommon models to improve our knowledge on biomineralization mechanisms and their possible evolution through time. Eight living species belonging to various orders of Demospongiae were selected for a comparative mineralogical characterization of their aragonitic or calcitic massive basal skeleton. The latter was prepared for scanning and transmission electron microscopy (SEM and TEM), selected-area electron diffraction (SAED) and X-ray diffraction (XRD) analyses. SEM results indicated distinctive macro- and micro structural organizations of the skeleton for each species, likely resulting from a genetically dictated variation in the control exerted on their formation. However, most skeletons investigated shared submicron to nano-scale morphological and crystallographical patterns: (1) single-crystal fibers and bundles were composed of 20 to 100nm large submicronic grains, the smallest structural units, (2) nano-scale likely organic material occurred both within and between these structural units, (3) {110} micro-twin planes were observed along aragonitic fibers, and (4) individual fibers or small bundles protruded from the external growing surface of skeletons. This comparative mineralogical study of phylogenetically distant species brings further evidence to recent biomineralization models already proposed for sponges, corals, mollusks, brachiopods and echinoderms and to the hypothesis of the universal and ancestral character of such mechanisms in Metazoa. PMID- 23748184 TI - Alternative binding modes of l-histidine guided by metal ions for the activation of the antiterminator protein HutP of Bacillus subtilis. AB - Anti-terminator proteins control gene expression by recognizing control signals within cognate transcripts and then preventing transcription termination. HutP is such a regulatory protein that regulates the expression of the histidine utilization (hut) operon in Bacillus subtilis by binding to cis-acting regulatory sequences in hut mRNAs. During the anti-termination process, l-histidine and a divalent ion are required for hutP to bind to the specific sequence within the hut mRNA. Our previous crystal structure of the HutP-l-histidine-Mg(2+)-RNA ternary complex demonstrated that the l-histidine ligand and Mg(2+) bind together such that the backbone nitrogen and carboxyl oxygen of l-histidine coordinate with Mg(2+). In addition to the Mg(2+), other divalent ions are also known to efficiently support the l-histidine-dependent anti-termination of the hut operon, and the best divalent ion is Zn(2+). In this study, we determined the crystal structure of the HutP-l-histidine-Zn(2+) complex and found that the orientation of l-histidine coordinated to Zn(2+) is reversed relative to that of l-histidine coordinated to Mg(2+), i.e., the imidazole side chain nitrogen of l-histidine coordinates to Zn(2+). This alternative binding mode of the l-histidine ligand to a divalent ion provides further insight into the mechanisms responsible for the activation of RNA binding during the hut anti-termination process. PMID- 23748185 TI - Exercise frequency, health risk factors, and diseases of the elderly. AB - OBJECTIVE: To determine the effect of exercise frequency on various diseases and risk factors of the elderly. DESIGN: Retrospective analysis of a randomized controlled 18-month exercise trial. SETTING: University ambulatory group setting. PARTICIPANTS: Community-dwelling women aged >=65 years (N=162) in the area of Northern Bavaria. INTERVENTION: Mixed, intense aerobic, resistance, and balance protocol for 18 months. Subjects were retrospectively subdivided into 2 groups according to their effective attendance over 18 months (>1-<2 vs >=2-4 sessions/wk). MAIN OUTCOME MEASURES: Bone mineral density (BMD), lean body mass, appendicular skeletal muscle mass by dual-energy x-ray absorptiometry, Framingham study-based 10-year coronary heart disease (CHD) risk, and number of falls by calendar method. RESULTS: Significant differences between the low-frequency exercise group (LF-EG) and the high-frequency exercise group (HF-EG) were observed for lumbar spine BMD (HF-EG, 2.4%+/-2.8% vs LF-EG, 0.3%+/-2.2%; P<.001) and proximal femur BMD (HF-EG, 2.4%+/-2.8% vs LF-EG, -0.5%+/-1.6%; P=.014), lean body mass (1.6%+/-3.4% vs 0.3%+/-2.6%, P=.053), and appendicular skeletal muscle mass (0.9%+/-4.5% vs -1.3%+/-3.2%, P=.011). No differences between both exercise groups were observed for 10-year CHD risk (-1.94%+/-4.14% vs -2.00%+/-3.13%; P=.943) and number of falls (0.95+/-1.36 vs 1.03+/-1.21 falls/person). Comparing the LF-EG with the less active control group (n=47), only nonsignificant effects for fall number (P=.065) and 10-year CHD risk (P=.178) were evaluated. CONCLUSIONS: Although this result might not be generalizable across all exercise types and cohorts, it indicates that an overall exercise frequency of at least 2 sessions/wk may be crucial for impacting bone and muscle mass of elderly subjects. PMID- 23748187 TI - The cigar ambassador: how Snoop Dogg uses Instagram to promote tobacco use. PMID- 23748186 TI - Phagocyte dysfunction, tissue aging and degeneration. AB - Immunologically-silent phagocytosis of apoptotic cells is critical to maintaining tissue homeostasis and innate immune balance. Aged phagocytes reduce their functional activity, leading to accumulation of unphagocytosed debris, chronic sterile inflammation and exacerbation of tissue aging and damage. Macrophage dysfunction plays an important role in immunosenescence. Microglial dysfunction has been linked to age-dependent neurodegenerations. Retinal pigment epithelial (RPE) cell dysfunction has been implicated in the pathogenesis of age-related macular degeneration (AMD). Despite several reports on the characterization of aged phagocytes, the role of phagocyte dysfunction in tissue aging and degeneration is yet to be fully appreciated. Lack of knowledge of molecular mechanisms by which aging reduces phagocyte function has hindered our capability to exploit the therapeutic potentials of phagocytosis for prevention or delay of tissue degeneration. This review summarizes our current knowledge of phagocyte dysfunction in aged tissues and discusses possible links to age-related diseases. We highlight the challenges to decipher the molecular mechanisms, present new research approaches and envisage future strategies to prevent phagocyte dysfunction, tissue aging and degeneration. PMID- 23748188 TI - The cost-effectiveness of call-back counselling for smoking cessation. AB - OBJECTIVE: To assess the cost-effectiveness of the Quitline, a call-back counselling service for smoking cessation, in the states of Queensland, Western Australia and the Northern Territory. METHODS: A cost-effectiveness analysis using a deterministic Markov model, and cost per disability-adjusted life year (DALY) averted over a lifetime as the outcome measure. POPULATION: Current smokers, motivated to quit. RESULTS: Call-back counselling for smoking cessation provided by the Quitline is an intervention that both improves health with additional quitters, and achieves net cost savings due to the cost offsets being greater than the cost of the intervention. If cost offsets are excluded, the cost per quitter is $A773 (95% uncertainty interval $A769$-$A779), and the incremental cost-effectiveness ratio is $A294 per DALY (95% uncertainty interval $A293 $A298). CONCLUSIONS: Call-back counselling is a cost-effective intervention for smoking cessation that can be provided by a centralised service for a large population, and to reach people in isolated communities. PMID- 23748189 TI - Visceral adipose tissue area is associated with coronary stenosis and noncalcified plaques. AB - OBJECTIVE: Few studies have investigated the relationships between visceral adipose tissue (VAT) and coronary stenosis and noncalcified plaques at the subclinical stage. The aim of this study was to investigate relationship between VAT and coronary lesions assessed by coronary computed tomography (CT) in an apparently healthy population. DESIGN: Retrospective cross-sectional study. SUBJECTS: One thousand six hundred and fifty-eight subjects free of cardiovascular disease underwent coronary CT and abdominal fat CT as part of a routine medical examination. MEASUREMENT: VAT area was measured at the level of the umbilicus using CT. Coronary stenoses and plaques were evaluated using coronary CT. RESULTS: The mean age of the study population was 55.9+/-8.0 years, and 1198 (72.3%) subjects were men. There were 201 subjects (12.1%) with coronary stenosis <50% and 144 (8.7%) had significant stenosis. Noncalcified plaques were observed in 108 (6.5%) subjects. Coronary stenosis <50% and noncalcified plaques increased steadily as the VAT area increased (P<0.001). The 4th quartile of VAT area was significantly associated with prevalence of coronary stenosis <50% and the presence of noncalcified plaques when compared with the first through third VAT quartiles in the cardiovascular risk factor-adjusted model (odds ratio (OR): 1.58, 95% confidence interval (CI): 1.09-2.30 and OR: 1.66; 95% CI: 1.02-2.68, respectively). CONCLUSION: Excess VAT area was associated with coronary stenosis <50% and noncalcified plaques, independent of traditional cardiovascular risk factors, in an asymptomatic population without a history of coronary artery disease. PMID- 23748191 TI - Individual performance review in hospital practice: the development of a framework and evaluation of doctors' attitudes to its value and implementation. AB - BACKGROUND: Appraisal, or independent performance review (IPR) is used in human resources management in the commercial and public sectors to evaluate the performance of an employee against agreed local organisational expectations and objectives, and to identify their requirements for development and effective management. IPR for NHS consultants may provide essential information for job planning, contribute towards medical appraisal for revalidation, and facilitate productivity and quality improvement. AIMS: To develop a framework for IPR for consultants, and to determine attitudes on its value, process and content. METHOD: Information from commercial, public and voluntary sector models and published and other literature sources were used to develop an IPR framework. This was assessed through a three-cycle action research methodology involving qualitative interviews with 22 consultants (predominantly with medical management roles). RESULTS: The domains of the IPR framework included: (1) performance against objectives; (2) behaviour and leadership; (3) talent management; (4) agreed future objectives. A number of themes were identified from the consultant interviews including: ineffective current appraisal systems reflecting a lack of valid performance data and allotted time; a lack of empowerment of medical managers to address performance issues; IPR as a more explicit system, offering value in evaluating doctors performance; and the dependence of successful implementation on the engagement of the Trust executive. CONCLUSIONS: IPR may have value for performance evaluation of consultants, contributing toward job planning and complementing medical appraisal. Support by their employing organisation and engagement with medical managers in design and implementation is likely to be essential. PMID- 23748190 TI - Fetal baboon sex-specific outcomes in adipocyte differentiation at 0.9 gestation in response to moderate maternal nutrient reduction. AB - OBJECTIVE: To investigate in vitro adipocyte differentiation in baboon fetuses in response to reduced maternal nutrition. DESIGN: Cross-sectional comparison of adipocyte differentiation in normally grown fetuses and fetuses of pregnant baboons fed 70% of the control global diet from 30 days of pregnancy to term. SUBJECTS: The subjects comprised control (CTR) fetuses (five female and five male) of mothers fed ad libitum and fetuses of mothers fed 70% of the global diet consumed by CTR (maternal nutrient reduction (MNR), five female and five male fetuses). The expression of genes/proteins involved in adipogenesis (PPARgamma, FABP4 and adiponectin) and brown adipose tissue development (UCP1, TBX15 and COXIV) were determined in in vitro-differentiated stromal-vascular cultures from subcutaneous abdominal, subcutaneous femoral and omental adipose tissue depots. Adipocyte number per area (mm(2)) was determined histologically to assist in the evaluation of adipocyte size. RESULTS: Maternal suboptimal nutrition suppressed growth of male but not female fetuses and led to adipocyte hypertrophy accompanied by increased markers of white- and, particularly, brown-type adipogenesis in male but not female fetuses. CONCLUSION: Adipose tissue responses to fetal nonhuman primate undernutrition are sexually dimorphic. While female fetuses adapt adequately, the male ones enhance pathways involved in white and brown adipose tissue development but are unable to compensate for a delayed development of adipose tissue associated with intrauterine growth restriction. These differences need to be considered when assessing developmental programming of adiposity in response to suboptimal maternal nutrition. PMID- 23748192 TI - Hospital workers' perceptions of waste: a qualitative study involving photo elicitation. AB - OBJECTIVES: To elicit sources of waste as viewed by hospital workers. DESIGN: Qualitative study using photo-elicitation, an ethnographic technique for prompting in-depth discussion. SETTING: U.S. academic tertiary care hospital. PARTICIPANTS: Physicians, nurses, pharmacists, administrative support personnel, administrators and respiratory therapists. METHODS: A purposive sample of personnel at an academic tertiary care hospital was invited to take up to 10 photos of waste. Participants discussed their selections using photos as prompts during in-depth interviews. Transcripts were analysed in an iterative process using grounded theory; open and axial coding was performed, followed by selective and thematic coding to develop major themes and subthemes. RESULTS: Twenty-one participants (nine women, average number of years in field=19.3) took 159 photos. Major themes included types of waste and recommendations to reduce waste. Types of waste comprised four major categories: Time, Materials, Energy and Talent. Participants emphasised time wastage (50% of photos) over other types of waste such as excess utilisation (2.5%). Energy and Talent were novel categories of waste. Recommendations to reduce waste included interventions at the micro-level (eg, individual/ward), meso-level (eg, institution) and macro-level (eg, payor/public policy). CONCLUSIONS: The waste hospital workers identified differed from previously described waste both in the types of waste described and the emphasis placed on wasted time. The findings of this study represent a possible need for education of hospital workers about known types of waste, an opportunity to assess the impact of novel types of waste described and an opportunity to intervene to reduce the waste identified. PMID- 23748193 TI - An association between adiposity and serum levels of macrophage inflammatory protein-1alpha and soluble CD14 in HIV-infected adults: results from a cross sectional study. AB - BACKGROUND: Greater adipose tissue is associated with increased circulating high sensitivity C-reactive protein (hsCRP) levels in HIV-infected adults on antiretroviral therapy (ART), but the relationship between adiposity and other inflammation biomarkers is not well-characterized. METHODS: We measured total and regional adipose tissue deposits using dual energy X-ray absorptiometry (DXA) and serum levels of interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) receptor 1 and 2, macrophage inflammatory protein-1alpha (MIP-1alpha), macrophage chemotactic protein-1 (MCP-1), soluble CD14 and hsCRP in a cohort of adults on long-term ART. Regression models were adjusted for age, sex, CD4(+) T-cell count, smoking status, protease-inhibitor-use and daily use of either non-steroidal anti inflammatory drugs or aspirin. RESULTS: The majority (77%) of the 85 study participants were male, median CD4(+) T-cell count was 500 cells/MUl (IQR 315 734) and median BMI was 25.1 kg/m(2) (IQR 22.7-28.1). DXA measurements of total fat mass were positively associated with serum hsCRP (beta=1.82, P<0.01) and MIP 1alpha (beta=1.36, P<0.01), but negatively associated with soluble CD14 (beta=0.90, P<0.01). Results were similar for trunk fat, limb fat and serum leptin level. The positive relationship between DXA measurements and TNF-alpha receptor 1 approached significance (P<=0.07 for all). There was no consistent relationship between adiposity and serum IL-6, TNF-alpha receptor 2 or MCP-1 levels. CONCLUSIONS: Total and regional adiposity was associated with serum hsCRP, but not other inflammatory cytokines shown to predict morbidity and mortality in treated HIV. Greater adiposity is associated with higher MIP-1alpha and lower soluble CD14 levels, possibly reflecting an important role for cells of the monocyte/macrophage lineage. PMID- 23748194 TI - Ultrasensitive photodetectors based on monolayer MoS2. AB - Two-dimensional materials are an emerging class of new materials with a wide range of electrical properties and potential practical applications. Although graphene is the most well-studied two-dimensional material, single layers of other materials, such as insulating BN (ref. 2) and semiconducting MoS2 (refs 3, 4) or WSe2 (refs 5, 6), are gaining increasing attention as promising gate insulators and channel materials for field-effect transistors. Because monolayer MoS2 is a direct-bandgap semiconductor due to quantum-mechanical confinement, it could be suitable for applications in optoelectronic devices where the direct bandgap would allow a high absorption coefficient and efficient electron-hole pair generation under photoexcitation. Here, we demonstrate ultrasensitive monolayer MoS2 phototransistors with improved device mobility and ON current. Our devices show a maximum external photoresponsivity of 880 A W(-1) at a wavelength of 561 nm and a photoresponse in the 400-680 nm range. With recent developments in large-scale production techniques such as liquid-scale exfoliation and chemical vapour deposition-like growth, MoS2 shows important potential for applications in MoS2-based integrated optoelectronic circuits, light sensing, biomedical imaging, video recording and spectroscopy. PMID- 23748195 TI - Ultrasensitive force detection with a nanotube mechanical resonator. AB - Since the advent of atomic force microscopy, mechanical resonators have been used to study a wide variety of phenomena, including the dynamics of individual electron spins, persistent currents in normal metal rings and the Casimir force. Key to these experiments is the ability to measure weak forces. Here, we report on force sensing experiments with a sensitivity of 12 zN Hz(-1/2) at a temperature of 1.2 K using a resonator made of a carbon nanotube. An ultrasensitive method based on cross-correlated electrical noise measurements, in combination with parametric downconversion, is used to detect the low-amplitude vibrations of the nanotube induced by weak forces. The force sensitivity is quantified by applying a known capacitive force. This detection method also allows us to measure the Brownian vibrations of the nanotube down to cryogenic temperatures. Force sensing with nanotube resonators offers new opportunities for detecting and manipulating individual nuclear spins as well as for magnetometry measurements. PMID- 23748196 TI - A plasmonic 'antenna-in-box' platform for enhanced single-molecule analysis at micromolar concentrations. AB - Single-molecule fluorescence techniques are key for a number of applications, including DNA sequencing, molecular and cell biology and early diagnosis. Unfortunately, observation of single molecules by diffraction-limited optics is restricted to detection volumes in the femtolitre range and requires pico- or nanomolar concentrations, far below the micromolar range where most biological reactions occur. This limitation can be overcome using plasmonic nanostructures, which enable the confinement of light down to nanoscale volumes. Although these nanoantennas enhance fluorescence brightness, large background signals and/or unspecific binding to the metallic surface have hampered the detection of individual fluorescent molecules in solution at high concentrations. Here we introduce a novel 'antenna-in-box' platform that is based on a gap-antenna inside a nanoaperture. This design combines fluorescent signal enhancement and background screening, offering high single-molecule sensitivity (fluorescence enhancement up to 1,100-fold and microsecond transit times) at micromolar sample concentrations and zeptolitre-range detection volumes. The antenna-in-box device can be optimized for single-molecule fluorescence studies at physiologically relevant concentrations, as we demonstrate using various biomolecules. PMID- 23748197 TI - Subthalamic nucleus modulates social and anxogenic-like behaviors. AB - In Parkinson's disease, global social maladjustment and anxiety are frequent after subthalamic nucleus (STN) stimulation and are generally considered to be linked with sociofamilial alterations induced by the motor effects of stimulation. We hypothesized that the STN is per se involved in these changes and aimed to explore the role of STN in social and anxogenic-like behaviors using an animal model. Nineteen male Wistar rats with bilateral lesions of the STN were compared with 26 sham-lesioned rats by synchronizing an ethological approach based upon direct observation of social behaviors and a standardized approach, the elevated plus maze (EPM). Comparisons between groups were performed by a Mann Whitney-Wilcoxon test. Lesioned rats showed impairments in their social (P=0.05) and aggressive behaviors with a diminution of attacking (P=0.04) and chasing (P=0.06). In the EPM, concerning the open arms, the percentage of distance, time, inactive time, and entry were significantly decreased in lesioned rats (P=0.02, P=0.01, P=0.04, and P=0.05). The time spent in non-protected head dips was also diminished in the lesioned rats (P=0.01). These results strongly implicate the STN in social behavior and anxogenic-like behavior. In human, as DBS induces changes in the underlying dynamics of the stimulated brain networks, it could create an abnormal brain state in which anxiety and social behavior are altered. These results highlight another level of complexity of the behavioral changes after stimulation. PMID- 23748198 TI - Dislocation rates of perineural catheters: a volunteer study. AB - BACKGROUND: Dislocation rates of continuous peripheral nerve block are poorly described even though this technique is frequently used in clinical practice. The present study was designed to evaluate dislocation rates over time of interscalene and femoral nerve catheters under defined experimental circumstances. Ultrasound (US) monitoring was used to detect the position of the perineural catheters. METHODS: Twenty volunteers received US-guided interscalene and femoral nerve catheters. The volunteers performed standardized physical exercises in regular intervals and the position of both catheters was examined by US confirmation of the spread of fluid. The maximal time of investigation in each volunteer was 6 h. The main outcome parameters were the overall dislocation rates and the cumulative dislocation rates at a given time point. RESULTS: We observed an overall dislocation rate of 15% (5% for interscalene catheters, 25% for femoral nerve catheters) and a significant correlation between time and rate of dislocations (r=0.99, P=0.001). US visualization of the spread of fluid was possible in all cases. CONCLUSIONS: This is the first dedicated evaluation of dislocation rates of peripheral nerve catheters (PNCs) via US investigation. Both movement and time are considerable factors for perineural catheter displacement. US is useful for the performance of PNCs and for the continuous detection of the spread of fluid relative to the nerve and adjacent anatomical structures. Translational research is required to confirm the study results in the clinical practice. PMID- 23748199 TI - Efficacy of dexmedetomidine compared with midazolam for sedation in adult intensive care patients: a systematic review. AB - Patients in Intensive Care Unit (ICU) often require sedatives which commonly include midazolam and the more recently developed alpha2-receptor agonist, dexmedetomidine. It was our aim to compare the sedative and clinical effectiveness of dexmedetomidine vs midazolam in adults admitted to ICU, using an objective appraisal of randomized control trials. Medline, Embase, SCOPUS, Web of Knowledge, Cinhal, the United States National Library of Medicine, and the Cochrane Database of Systematic Reviews were searched using keywords: 'dexmedetomidine', 'midazolam', and 'intensive care'. These were limited to human studies and adults (>18 yr old). Six randomized controlled trials were found and were critically appraised using a standardized appraisal method. Two papers described the time spent by each intervention group within a specified target sedation range and both found no statistically significant difference between midazolam and dexmedetomidine (P=0.18 and P=0.15). A third paper found no statistically significant difference in the length of time that patients were sedated within a target zone (P=0.445). Two additional pilot studies did not report P values as they were insufficiently statistically powered. A final paper found that, of the eight occasions measured, patients on dexmedetomidine were more often within the target sedation range than patients on midazolam. The sedative benefits of dexmedetomidine vs midazolam remain inconclusive. While some secondary outcomes showed clinical effectiveness of dexmedetomidine, more research is needed to validate the findings of these studies. PMID- 23748200 TI - Electroretinographic responses in epileptic children treated with vigabatrin. AB - Vigabatrin is an antiepileptic drug that results in higher gamma-aminobutyrate levels in the brain and retina. Vigabatrin-induced visual field defects are usually asymptomatic and only detectable by perimetry. Further, perimetry requires good cooperation, and children aged under 10 years cannot do it. Electroretinogram response amplitude to full-field 30-Hz flicker shine has been offered to be more specific in predicting visual field defects. This study is scheduled to investigate the vigabatrin-associated visual complications in 67 epileptic children taking vigabatrin using full-field electroretinogram. Electroretinographic surveys showed normal range parameters despite 3 months of vigabatrin treatment, and just 3 (4.47%) children had been visually impaired at the end of 6-month treatment. Among these 3 cases, 1 patient had persistent electroretinogram abnormality despite vigabatrin discontinuation. Our study suggests that vigabatrin is secure for short-term pediatric antiepileptic treatment, with few cases of visual impairments and that are often reversible. PMID- 23748201 TI - Primary Myoclonus-Dystonia: A Diagnosis Often Missed in Children. AB - Primary myoclonus-dystonia is a childhood-onset autosomal-dominant movement disorder with myoclonic jerks and dystonia. The authors report 9 children (4 boys, 5 girls) with myoclonus-dystonia from 8 families seen over a 4-year period at Cleveland Clinic. The mean age of onset of symptoms was 2.8 years, but the diagnosis was made at a mean of 7.3 years. Myoclonus was the presenting symptom in 8 children. A known pathogenic mutation in the epsilon-sarcoglycan gene (SGCE) was identified in 4 of the 9 children, and 2 other children had novel mutations in the same gene. Good response to trihexyphenidyl and clonazepam was seen. Two patients underwent deep brain stimulation surgery of the bilateral globus pallidus pars interna. In 7 children, the diagnosis of myoclonus-dystonia was not considered by the referring child neurologists, which led to extensive investigations and a delay in the final diagnosis. In this report, the authors highlight the need for increased awareness of this entity among child neurologists. PMID- 23748202 TI - Different plasticity patterns of language function in children with perinatal and childhood stroke. AB - Plasticity of language function after brain damage can depend on maturation of the brain. Children with left-hemisphere perinatal (n = 7) or childhood stroke (n = 5) and 12 controls were investigated using functional magnetic resonance imaging. The verb generation and the sentence comprehension tasks were employed to activate the expressive and receptive language areas, respectively. Weighted laterality indices were calculated and correlated with results assessed by neuropsychological test battery. Compared to controls, children with childhood stroke showed significantly lower mean scores for the expressive (P < .05) and receptive (P = .05) language tests. On functional magnetic resonance imaging they showed left-side cortical activation, as did controls. Perinatal stroke patients showed atypical right-side or bilateral language lateralization during both tasks. Negative correlation for stroke patients was found between scores for expressive language tests and laterality index during the verb generation task. (Re)organization of language function differs in children with perinatal and childhood stroke and correlates with neurocognitive performance. PMID- 23748203 TI - Defining encephalopathy in acute disseminated encephalomyelitis. AB - The International Pediatric Multiple Sclerosis Study Group requires the presence of encephalopathy to diagnose acute disseminated encephalomyelitis. Clinical characteristics of encephalopathy are inadequately delineated in the pediatric demyelinating literature. The authors' purpose was to better define encephalopathy in pediatric acute disseminated encephalomyelitis by describing the details of the mental status change. A retrospective chart review was conducted for 25 children diagnosed with acute disseminated encephalomyelitis according to the International Pediatric Multiple Sclerosis Study Group guidelines. Frequency of encephalopathy-defining features was determined. Clinical characteristics, cerebrospinal fluid findings, and electroencephalography (EEG) findings were compared between patients with different stages of encephalopathy. The authors found irritability (36%), sleepiness (52%), confusion (8%), obtundation (20%), and coma (16%) as encephalopathy-defining features in acute disseminated encephalomyelitis. Twenty eight percent had seizures, and 65% demonstrated generalized slowing on EEG. Approximately half of the patients in this study were diagnosed with encephalopathy based on the presence of irritability and/or sleepiness only. Such features in young children are often subtle and transient and thus difficult to objectively determine. PMID- 23748205 TI - Worker education level is a factor in self-compliance with dust-preventive methods among small-scale agate industrial workers. AB - OBJECTIVES: High incidences of silicosis are continuing to be reported among the agate workers of small-scale household agate processing units in the Khambhat region of Gujarat (India). The objective of this study was to investigate reasons behind the high prevalence of silicosis, and factors affecting the noncompliance with preventive methods among agate workers. METHODS: The study was conducted using a questionnaire-based structured interview method among 82 agate workers in Khambhat to assess their awareness level about silicosis and preventive methods, existing morbidity, worker's attitude toward health, and the prevalence of actual use of preventive methods to avoid silica exposure. RESULTS: The majority of the workers (55%) were aware of silicosis and the harmful effects of silica dust exposure (72%) and knew about simple preventive methods to avoid silica dust exposure (80%), but only a minority of the workers (22%) were actually using the simple and available dust-preventive methods. Only 9% of the uneducated workers were using the preventive methods, while usage was higher among educated workers (28%), who had five or more years of schooling, and these workers had fewer health conditions or less morbidity. Gender and job duration had no effect on the usage of dust-preventive methods. CONCLUSIONS: The data suggest that noncompliance with use of dust-preventive methods could be the reason behind the higher prevalence of silicosis and health morbidity in agate workers, and that years of schooling plays a significant role in the increased usage and self compliance with dust-preventive methods among agate workers. PMID- 23748204 TI - The pore-forming haemolysins of bacillus cereus: a review. AB - The Bacillus cereus sensu lato group contains diverse Gram-positive spore-forming bacteria that can cause gastrointestinal diseases and severe eye infections in humans. They have also been incriminated in a multitude of other severe, and frequently fatal, clinical infections, such as osteomyelitis, septicaemia, pneumonia, liver abscess and meningitis, particularly in immuno-compromised patients and preterm neonates. The pathogenic properties of this organism are mediated by the synergistic effects of a number of virulence products that promote intestinal cell destruction and/or resistance to the host immune system. This review focuses on the pore-forming haemolysins produced by B. cereus: haemolysin I (cereolysin O), haemolysin II, haemolysin III and haemolysin IV (CytK). Haemolysin I belongs to the cholesterol-dependent cytolysin (CDC) family whose best known members are listeriolysin O and perfringolysin O, produced by L. monocytogenes and C. perfringens respectively. HlyII and CytK are oligomeric beta barrel pore-forming toxins related to the alpha-toxin of S. aureus or the beta toxin of C. perfringens. The structure of haemolysin III, the least characterized haemolytic toxin from the B. cereus, group has not yet been determined. PMID- 23748206 TI - Work-to-family conflict and family-to-work conflict among Japanese dual-earner couples with preschool children: a spillover-crossover perspective. AB - OBJECTIVES: This study among Japanese dual-earner couples examined the independent and combined associations of work-to-family conflict (WFC) and family to-work conflict (FWC) with psychological health of employees and their partners and the relationship quality between partners. METHODS: The matched responses of 895 couples were analyzed with logistic regression analysis to examine whether there were differences among the four work-family conflict groups (i.e., no conflict, WFC, FWC and both conflicts groups) in terms of own psychological distress, social undermining (i.e., negative behaviors directed toward the target person) reported by partners and partner's psychological distress. The no conflicts group was used as the reference group. RESULTS: The both conflicts group had the highest odds ratios for own psychological distress and social undermining towards the partner for both genders. In addition, for husbands, the both conflicts group had the highest odds ratio for partner's psychological distress, whereas for wives, it did not. CONCLUSIONS: Dual experiences of WFC and FWC have adverse associations with psychological health of employees and relationship quality between partners of both genders. In addition, dual experiences in husbands have an adverse association with psychological health of their partners (i.e., wives), whereas this is not the case for wives. PMID- 23748207 TI - Child work in agriculture in West Bengal, India: assessment of musculoskeletal disorders and occupational health problems. AB - OBJECTIVE: Children are universally considered to be the most important asset for any nation. The main aims of the present study were 1) to investigate the causation of discomfort related to working postures 2) to assess the physiological strain among the child farmers and 3) to assess the thermal stress during work in an agricultural field. METHODS: For this study, 120 child agricultural workers and 120 control subjects aged 10-16 years were selected randomly, and a detailed posture analysis was performed among them by REBA and OWAS methods. The Modified Nordic Questionnaire was applied to assess the discomfort felt among both groups of workers. Physiological assessment of workload was carried out by recording the heart rate and blood pressure of the workers prior to work and just after work in the field. RESULTS: Child agricultural workers suffered from pain especially in the low back (98%), knees (88%), hands (82%), shoulder (77%) and neck (68%). Among the agricultural activities in potato cultivation, the child potato workers, felt discomfort during spading (99%), sprinkling water (90%) and picking crops (87%). The post activity heart rate of the child agricultural workers was 170.1 beats/min, whereas the systolic and diastolic blood pressures were 129.0 and 67.0 mm/Hg respectively. CONCLUSIONS: Most of the agricultural activities in potato cultivation were strenuous ones that affect the children, who suffered from acute pain and discomfort for a long period of time, which mainly hampers and restricts their education. PMID- 23748208 TI - Increased incidence of esophageal thermal lesions using the second-generation 28 mm cryoballoon. AB - BACKGROUND: Pulmonary vein isolation is an established treatment option for atrial fibrillation. To date, the incidence and quality of ablation-induced esophageal thermal lesions (ETLs) using the recently introduced second-generation cryoballoon (CB, ArcticFront Advance, Medtronic) is unknown. METHODS AND RESULTS: In patients with drug-refractory paroxysmal atrial fibrillation or short-standing persistent atrial fibrillation, pulmonary vein (PV) isolation was performed using the second-generation CB. The endoluminal esophageal temperature was monitored via a temperature probe. After PV isolation, esophagogastroduodenoscopy (EGD) was performed to assess the incidence of ETLs. In 50 patients (18 women; age, 61+/-11 years; left atrial diameter, 43+/-5 mm), successful CB-based PV isolation was performed. Lowest median balloon temperature and esophageal temperature for the right superior PV were -51 degrees C and 35.8 degrees C, -47 degrees C and 35 degrees C for the right inferior PV, -51 degrees C and 34.4 degrees C for the left superior PV, -48 degrees C and 34.6 degrees C for the left inferior PV, and 54 degrees C and 34.5 degrees C for the left common PV, respectively. EGD performed 2+/-1 days post ablation demonstrated superficial thermal lesions and thermal ulcerations in 1 of 50 (2%) and 5 of 50 (10%) patients, respectively. In patients with ETLs, during >=1 freeze cycle the endoluminal esophageal temperature measured <3.0 degrees C. All thermal lesions were in the healing process on repeat EGD 4+/-2 days after initial endoscopy. CONCLUSIONS: Using the second-generation 28-mm CB, ETLs were detected in 6 of 50 (12%) patients. All ETLs were in the healing process on repeat EGD. An esophageal temperature safety cutoff may prove valuable in the prevention of ETLs and requires further evaluation. PMID- 23748209 TI - Infant ventricular fibrillation after ST-segment changes and QRS widening: a new cause of sudden infant death? AB - BACKGROUND: Ventricular arrhythmia-related sudden cardiac arrest in infants with structurally normal hearts is rare. There have been no previously published reports of infants <3 months of age with ventricular fibrillation in which a primary diagnosis could not be defined. METHODS AND RESULTS: Retrospective chart review of 3 unrelated infants <2 months of age from 3 different tertiary care centers within the United States and Australia was conducted. All 3 infants survived sudden cardiac arrest secondary to multiple episodes of polymorphic ventricular tachycardia and ventricular fibrillation. Each infant demonstrated unique and transient ECG findings consisting of ST changes and QRS widening before arrhythmia onset, which have not been previously reported. Amiodarone, sedation, sodium channel-blocking agents, and ventricular pacing were effective in suppressing acute events. Despite thorough investigation, including genetic testing, the cause of ventricular arrhythmias in each of these infants remains unclear. CONCLUSIONS: This is the first report of idiopathic ventricular fibrillation in young infants preceded by stereotypical transient ECG changes. These findings may represent a new, potentially treatable cause of sudden infant death. Recognition of these prodromal changes may be important in future management and survival of these infants. PMID- 23748210 TI - Progression of atrial fibrillation after a failed initial ablation procedure in patients with paroxysmal atrial fibrillation: a randomized comparison of drug therapy versus reablation. AB - BACKGROUND: The aim of this prospective randomized study was to assess whether an early reablation was superior to antiarrhythmic drug (AAD) therapy in patients with previous failed pulmonary vein isolation. METHODS AND RESULTS: Patients with paroxysmal atrial fibrillation (AF) eligible for AAD therapy or reablation after a previously failed initial pulmonary vein isolation procedure were eligible for this study and were followed up for 3 years to assess rhythm by means of an implanted cardiac monitor. After the blanking period postablation, 154 patients had symptomatic AF recurrences and were randomized to AAD (n=77) or repulmonary vein isolation (n=77). At the end of follow-up, 61 (79%) patients in the AAD group and 19 (25%) patients in the reablation group demonstrated AF% progression (P<0.01). The AF% at 36 months was significantly greater in the AAD group compared with patients in the reablation group (18.8+/-11.4% versus 5.6+/-9.5%, respectively; P<0.01). In addition, 18 (23%) patients in the AAD group and 3 (4%) patients in the reablation group progressed to persistent AF (P<0.01). Furthermore, 45 (58%) of the 77 reablation group patients were free of AF/atrial tachycardia on no AADs; in contrast, in the AAD group, only 9 (12%) of the 77 patients were free of AF/atrial tachycardia (P<0.01) throughout follow-up. CONCLUSIONS: Redo AF ablation was substantially more effective than AAD in reducing the progression and prevalence of AF after the failure of an initial ablation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01709682. PMID- 23748211 TI - Dietary whey protein stimulates mitochondrial activity and decreases oxidative stress in mouse female brain. AB - In humans and experimental animals, protein-enriched diets are beneficial for weight management, muscle development, managing early stage insulin resistance and overall health. Previous studies have shown that in mice consuming a high fat diet, whey protein isolate (WPI) reduced hepatosteatosis and insulin resistance due in part to an increase in basal metabolic rate. In the current study, we examined the ability of WPI to increase energy metabolism in mouse brain. Female C57BL/6J mice were fed a normal AIN-93M diet for 12 weeks, with (WPI group) or without (Control group) 100g WPI/L drinking water. In WPI mice compared to controls, the oxidative stress biomarkers malondialdehyde and 4-hydroxyalkenals were 40% lower in brain homogenates, and the production of hydrogen peroxide and superoxide were 25-35% less in brain mitochondria. Brain mitochondria from WPI mice remained coupled, and exhibited higher rates of respiration with proportionately greater levels of cytochromes a+a3 and c+c1. These results suggested that WPI treatment increased the number or improved the function of brain mitochondria. qRT-PCR revealed that the gene encoding a master regulator of mitochondrial activity and biogenesis, Pgc-1alpha (peroxisome proliferator activated receptor-gamma coactivator-1alpha) was elevated 2.2-fold, as were the PGC-1alpha downstream genes, Tfam (mitochondrial transcription factor A), Gabpa/Nrf-2a (GA-binding protein alpha/nuclear respiratory factor-2a), and Cox 6a1 (cytochrome oxidase-6a1). Each of these genes had twice the levels of transcript in brain tissue from WPI mice, relative to controls. There was no change in the expression of the housekeeping gene B2mg (beta-2 microglobulin). We conclude that dietary whey protein decreases oxidative stress and increases mitochondrial activity in mouse brain. Dietary supplementation with WPI may be a useful clinical intervention to treat conditions associated with oxidative stress or diminished mitochondrial activity in the brain. PMID- 23748212 TI - Mechanical unfolding of long human telomeric RNA (TERRA). AB - We report the first single molecule investigation of TERRA molecules. By using optical-tweezers and other biophysical techniques, we have found that long RNA constructions of up to 25 GGGUUA repeats form higher order structures comprised of single parallel G-quadruplex blocks, which unfold at lower forces than their DNA counterparts. PMID- 23748214 TI - Organocatalytic functionalization of heteroaromatic N-oxides with C-nucleophiles using in situ generated onium amide bases. AB - Organocatalytic functionalization of heteroaromatic N-oxides was investigated using in situ generated onium amide bases, and C-nucleophiles were efficiently introduced by the sequential addition-elimination reaction under metal-free conditions, affording 2-substituted nitrogen heteroaromatics generally in good to high yields. PMID- 23748215 TI - Diselenolate- and ditellurolate-carborane gold complexes. AB - Gold complexes with selenolate and tellurolate carborane ligands [E2C2B10H10](2-) (E = Se, Te) have been synthesized by reaction of a freshly prepared solution of [1,2-(LiE)2C2B10H10] (E = Se, Te) with [AuClL] (L = PPh3, PPh2Me, PPh2py) in a 1 : 2 molar ratio or [Au2Cl2(P~P)] [P~P = dppf, 1,1' bis(diphenylphosphano)ferrocene; dppe, 1,2-bis(diphenylphosphano)ethane; dppc, 1,2-bis(diphenylphosphano)-o-carborane] in a 1 : 1 molar ratio affording complexes [Au2(MU-1,2-E2C2B10H10)L2] or [Au2(MU-1,2-E2C2B10H10)(P~P)], respectively. The gold(III) species PPN[Au(E2C2B10H10)2] (PPN = bis(triphenylphosphano)iminium) have been afforded by reaction of PPN[AuCl4] with [1,2-(LiE)2C2B10H10]. Complex [Au4(MU-1,2-Se2C2B10H10)2(MU-dppc)2] displays a tetranuclear structure, different from the dinuclear cyclic arrangement proposed for other complexes with diphosphanes of [Au2(MU-1,2-Se2C2B10H10)(P~P)] stoichiometry. PMID- 23748213 TI - Open questions and a proposal: a critical review of the evidence on infant numerical abilities. AB - Considerable research has investigated infants' numerical capacities. Studies in this domain have used procedures of habituation, head turn, violation of expectation, reaching, and crawling to ask what quantities infants discriminate and represent visually, auditorily as well as intermodally. The concensus view from these studies is that infants possess a numerical system that is amodal and applicable to the quantification of any kind of entity and that this system is fundamentally separate from other systems that represent continuous magnitude. Although there is much evidence consistent with this view, there are also inconsistencies in the data. This paper provides a broad review of what we know, including the evidence suggesting systematic early knowledge as well as the peculiarities and gaps in the empirical findings with respect to the concensus view. We argue, from these inconsistencies, that the concensus view cannot be entirely correct. In light of the evidence, we propose a new hypothesis, the Signal Clarity hypothesis, that posits a developmental role for dimensions of continuous quantity within the discrete quantity system and calls for a broader research agenda that considers the covariation of discrete and continuous quantities not simply as a problem for experimental control but as information that developing infants may use to build more precise and robust representations of number. PMID- 23748216 TI - Eubacterial rhodopsins - unique photosensors and diverse ion pumps. AB - Since the discovery of proteorhodopsins, the ubiquitous marine light-driven proton pumps of eubacteria, a large number of other eubacterial rhodopsins with diverse structures and functions have been characterized. Here, we review the body of knowledge accumulated on the four major groups of eubacterial rhodopsins, with the focus on their biophysical characterization. We discuss advances and controversies on the unique eubacterial sensory rhodopsins (as represented by Anabaena sensory rhodopsin), proton-pumping proteorhodopsins and xanthorhodopsins, as well as novel non-proton ion pumps. This article is part of a Special Issue entitled: Retinal Proteins - You can teach an old dog new tricks. PMID- 23748217 TI - Molecular cloning and expression analysis of liver-expressed antimicrobial peptide 1 (LEAP-1) and LEAP-2 genes in the blunt snout bream (Megalobrama amblycephala). AB - Liver-expressed antimicrobial peptide 1 (LEAP-1) and LEAP-2 are widespread in fish and extremely important components of the host innate immune system. In this study, full-length cDNAs of LEAP-1 and LEAP-2 were cloned and sequenced from blunt snout bream, Megalobrama amblycephala. The open reading frames (ORF) of LEAP-1 and LEAP-2 genes encode putative peptides of 94 and 92 amino acids, which possess eight and four conserved cysteine residues, respectively. The homologous identities of deduced amino acid sequences show that the LEAP-1 and LEAP-2 of blunt snout bream share considerable similarity with those of grass carp. The mRNA expressions of LEAP-1 and LEAP-2 were detectable at different early developmental stages of blunt snout bream and varied with embryonic and larval growth. LEAP-1 and LEAP-2 were expressed in a wide range of adult tissues, with the highest expression levels in the liver and midgut, respectively. Bacterial challenge experiments showed that the levels of LEAP-1 and LEAP-2 mRNA expression were up-regulated in the liver, spleen, gill and brain of juvenile blunt snout bream. These results indicate that the LEAP-1 and LEAP-2 may play important roles in early development of embryos and fry, and may contribute to the defense against the pathogenic bacterial invasion. This study will further our understanding of the function of LEAP-1 and LEAP-2 and the molecular mechanism of innate immunity in teleosts. PMID- 23748218 TI - Serum soluble Klotho protein level is associated with residual diuresis in incident peritoneal dialysis patients. AB - AIM: Active vitamin D (1,25-dihydroxyvitamin D3), PTH, fibroblast growth factor 23 (FGF-23) and Klotho protein are key regulators of phosphate metabolism. Hyperphosphatemia and increased FGF-23 level in patients with end-stage renal disease are associated with increased morbidity and mortality. The relationships among key regulators of phosphate metabolism are still being investigated. FGF 23, the humoral factor involved in phosphate metabolism, is strongly associated with serum phosphorus level. Klotho, a transmembrane protein expressed primarily in renal tubules, functions as an obligatory co-receptor for FGF-23. The soluble form of Klotho, produced by the shedding of the transmembrane protein, is detectable in body fluids. The purpose of the study was to assess if serum soluble alpha-Klotho level was related to phosphate metabolism parameters and residual renal function (RRF) in incident peritoneal dialysis (PD) patients. METHODS: Thirty-five clinically stable patients 4 to 6 weeks after the onset of PD were included in the study. For each patient, clinical and laboratory data were reviewed. Serum phosphorus concentration, urinary and peritoneal phosphate clearance, serum FGF-23 and soluble Klotho protein concentrations were determined. RESULTS: Serum soluble alpha-Klotho was strongly negatively correlated with 24-hour diuresis (Rs = -0.55, p = 0.004) and renal phosphate clearance (Rs = -0.40, p = 0.049), but not with RRF. CONCLUSIONS: Serum soluble Klotho protein concentration is inversely related to residual diuresis and renal phosphate clearance in incident PD patients. PMID- 23748219 TI - Single-electron reduction of quinone and nitroaromatic xenobiotics by recombinant rat neuronal nitric oxide synthase. AB - We examined the kinetics of single-electron reduction of a large number of structurally diverse quinones and nitroaromatic compounds, including a number of antitumour and antiparasitic drugs, and nitroaromatic explosives by recombinant rat neuronal nitric oxide synthase (nNOS, EC 1.14.13.39), aiming to characterize the role of nNOS in the oxidative stress-type cytotoxicity of the above compounds. The steady-state second-order rate constants (kcat/Km) of reduction of the quinones and nitroaromatics varied from 102 M-1s-1 to 106 M-1s-1, and increased with an increase in their single-electron reduction potentials (E17). The presence of Ca2+/calmodulin enhanced the reactivity of nNOS. These reactions were consistent with an 'outer sphere' electron-transfer mechanism, considering the FMNH?/FMNH2 couple of nNOS as the most reactive reduced enzyme form. An analysis of the reactions of nNOS within the 'outer sphere' electron-transfer mechanism gave the approximate values of the distance of electron transfer, 0.39 0.47 nm, which are consistent with the crystal structure of the reductase domain of nNOS. On the other hand, at low oxygen concentrations ([O2] = 40-50 MUM), nNOS performs a net two-electron reduction of quinones and nitroaromatics. This implies that NOS may in part be responsible for the bioreductive alkylation by two-electron reduced forms of antitumour aziridinyl-substituted quinones under a modest hypoxia. PMID- 23748220 TI - Vascular mechanics and stroke: study the arteries but do not forget the flow. PMID- 23748221 TI - Response to "vascular mechanics and stroke-a critical appraisal: study the arteries but do not forget the flow". PMID- 23748223 TI - Diacylglycerol lipasealpha (DAGLalpha) and DAGLbeta cooperatively regulate the production of 2-arachidonoyl glycerol in autaptic hippocampal neurons. AB - Cannabinoids are part of an endogenous signaling system consisting of cannabinoid receptors and endogenous cannabinoids as well as the enzymatic machinery for their synthesis and degradation. Depolarization-induced suppression of excitation (DSE) is a form of cannabinoid CB(1) receptor-mediated inhibition of synaptic transmission that involves the production of the endogenous cannabinoid 2 arachidonoyl glycerol (2-AG). Both diacylglycerol lipase alpha (DAGLalpha) and DAGLbeta can produce 2-AG in vitro, but evidence from knockout animals argues strongly for a predominant, even exclusive, role for DAGLalpha in regulation of 2 AG-mediated synaptic plasticity. What role, if any, might be played by DAGLbeta remains largely unknown. Cultured autaptic hippocampal neurons exhibit robust DSE. With the ability to rapidly modulate expression of DAGLalpha and DAGLbeta in these neurons with short hairpin RNA, they are well suited for a comparative study of the roles of each isoform in mediating DSE. We find that RNA interference knockdown of DAGLalpha substantially reduces autaptic DSE, shifting the "depolarization-response curve" from an ED(50) value of 1.7 seconds to 3.0 seconds. Surprisingly, DAGLbeta knockdown diminishes DSE as much or more (ED(50) 6.4 seconds), suggesting that DAGLbeta is also responsible for a portion of 2-AG production in autaptic neurons. Similarly, the two DAGLs both contribute to the production of 2-AG via group I metabotropic glutamate receptors. Our results provide the first explicit evidence for a role of DAGLbeta in modulating neurotransmission. PMID- 23748224 TI - Error correction in latent inhibition and its disruption by opioid receptor blockade with naloxone. AB - Latent inhibition refers to the retardation in the development of conditioned responding when a pre-exposed stimulus is used to signal an unconditioned stimulus. This effect is described by error-correction models as an attentional deficit and is commonly used as an animal model of schizophrenia. A series of experiments studied the role of error-correction mechanism in latent inhibition and its interaction with the endogenous opioid system. Systemic administration of the competitive opioid receptor antagonist naloxone before rats were pre-exposed to a target stimulus prevented latent inhibition of its subsequent fear conditioning; it was without effect on a non-pre-exposed stimulus and did not produce state-dependent learning (Experiments 1a and 1b). Naloxone did not reverse the latent inhibitory effect already accrued to a pre-exposed target. However, it did prevent the enhancement of latent inhibition by a long retention interval interpolated between its initial exposure and re-exposure (Experiment 2) or by a novel stimulus compounded with the pre-exposed target during re-exposure (Experiment 3). These results provide evidence that attentional loss in latent inhibition is instructed by an opioid-mediated error signal which diminishes with repeated stimulus exposures but recovers with the passage of time or reintroduction of novelty. PMID- 23748225 TI - CRF-CRF1 receptor system in the central and basolateral nuclei of the amygdala differentially mediates excessive eating of palatable food. AB - Highly palatable foods and dieting are major contributing factors for the development of compulsive eating in obesity and eating disorders. We previously demonstrated that intermittent access to palatable food results in corticotropin releasing factor-1 (CRF1) receptor antagonist-reversible behaviors, which include excessive palatable food intake, hypophagia of regular chow, and anxiety-like behavior. However, the brain areas mediating these effects are still unknown. Male Wistar rats were either fed chow continuously for 7 days/week (Chow/Chow group), or fed chow intermittently 5 days/week, followed by a sucrose, palatable diet 2 days/week (Chow/Palatable group). Following chronic diet alternation, the effects of microinfusing the CRF1 receptor antagonist R121919 (0, 0.5, 1.5 MUg/side) in the central nucleus of the amygdala (CeA), the basolateral nucleus of the amygdala (BlA), or the bed nucleus of the stria terminalis (BNST) were evaluated on excessive intake of the palatable diet, chow hypophagia, and anxiety like behavior. Furthermore, CRF immunostaining was evaluated in the brain of diet cycled rats. Intra-CeA R121919 blocked both excessive palatable food intake and anxiety-like behavior in Chow/Palatable rats, without affecting chow hypophagia. Conversely, intra-BlA R121919 reduced the chow hypophagia in Chow/Palatable rats, without affecting excessive palatable food intake or anxiety-like behavior. Intra BNST treatment had no effect. The treatments did not modify the behavior of Chow/Chow rats. Immunohistochemistry revealed an increased number of CRF-positive cells in CeA--but not in BlA or BNST--of Chow/Palatable rats, during both withdrawal and renewed access to the palatable diet, compared with controls. These results provide functional evidence that the CRF-CRF1 receptor system in CeA and BlA has a differential role in mediating maladaptive behaviors resulting from palatable diet cycling. PMID- 23748226 TI - Administration of the Y2 receptor agonist PYY3-36 in mice induces multiple behavioral changes relevant to schizophrenia. AB - Functional changes in neuropeptide Y (NPY) signaling at the Y2 receptor subtype have been widely implicated in stress-related neuropsychiatric illnesses such as depression and anxiety disorders. Altered Y2 receptor signaling may also play a role in the precipitation of behavioral and cognitive symptoms associated with schizophrenia. To seek preclinical evidence for this possibility, we explored the functional consequences of treatment with the selective Y2 receptor agonist PYY(3 36) using translational tests for the assessment of schizophrenia-relevant behavioral and cognitive deficits in mice. We found that acute systemic administration of PYY(3-36) at a low dose (1 MUg/100 g body weight) or high dose (20 MUg/100 g body weight) profoundly impaired social interaction without affecting innate anxiety. PYY(3-36) treatment at the high dose further led to a disruption of sensorimotor gating in the form of prepulse inhibition deficiency. This effect was fully antagonized by acute treatment with the preferential dopamine D2 receptor antagonist haloperidol, but not with clozapine. In addition, both doses of PYY(3-36) impaired selective associative learning in the latent inhibition paradigm and spatial working memory in a matching-to-position water maze test. The wide range of abnormalities induced by PYY(3-36) suggests that signaling at the Y2 subtype of NPY receptors is critical for a number of behavioral and cognitive functions, some of which are highly relevant to schizophrenia and related psychotic disorders. At least some of the behavioral deficits induced by augmentation of Y2 receptor signaling may involve increased dopaminergic activity. PMID- 23748228 TI - A novel gadolinium-based trimetasphere metallofullerene for application as a magnetic resonance imaging contrast agent. AB - OBJECTIVE: Macromolecular contrast agents for magnetic resonance imaging (MRI) are useful blood-pool agents because of their long systemic half-life and have found applications in monitoring tumor vasculature and angiogenesis. Macromolecular contrast agents have been able to overcome some of the disadvantages of the conventional small-molecule contrast agent Magnevist (gadolinium-diethylenetriaminepentaacetic acid), such as rapid extravasation and quick renal clearance, which limits the viable MRI time. There is an urgent need for new MRI contrast agents that increase the sensitivity of detection with a higher relaxivity, longer blood half-life, and reduced toxicity from free Gd3+ ions. Here, we report on the characterization of a novel water-soluble, derivatized, gadolinium-enclosed metallofullerene nanoparticle (Hydrochalarone-1) in development as an MRI contrast agent. MATERIALS AND METHODS: The physicochemical properties of Hydrochalarone-1 were characterized by dynamic light scattering (hydrodynamic diameter), atomic force microscopy (particle height), zeta potential analysis (surface charge), and inductively coupled plasma mass spectrometry (gadolinium concentration). The blood compatibility of Hydrochalarone-1 was also assessed in vitro through analysis of hemolysis, platelet aggregation, and complement activation of human blood. In vitro relaxivities, in vivo pharmacokinetics, and a pilot in vivo acute toxicity study were also performed. RESULTS: An extensive in vitro and in vivo characterization of Hydrochalarone-1 is described here. The hydrodynamic size of Hydrochalarone-1 was 5 to 7 nm depending on the dispersing media, and it was negatively charged at physiological pH. Hydrochalarone-1 showed compatibility with blood cells in vitro, and no significant hemolysis, platelet aggregation, or complement activation was observed in vitro. In addition, Hydrochalarone-1 had significantly higher r1 and r2 in vitro relaxivities in human plasma in comparison with Magnevist and was not toxic at the doses administered in an in vivo pilot acute dose toxicity study in mice.In vivo MRI pharmacokinetic analysis after a single intravenous injection of Hydrochalarone-1 (0.2 mmol Gd/kg) showed that the volume of distribution at steady state was approximately 100 mL/kg, suggesting prolonged systemic circulation. Hydrochalarone-1 also had a long blood half-life (88 minutes) and increased relaxivity, suggesting application as a promising blood pool MRI contrast agent. CONCLUSIONS: The evidence suggests that Hydrochalarone 1, with its long systemic half-life, may have significant utility as a blood-pool MRI contrast agent. PMID- 23748229 TI - Computed tomographic perfusion imaging for the prediction of response and survival to transarterial radioembolization of liver metastases. AB - PURPOSE: The purpose of this study was to evaluate prospectively, in patients with liver metastases, the ability of computed tomographic (CT) perfusion to predict the morphologic response and survival after transarterial radioembolization (TARE). METHODS: Thirty-eight patients (22 men; mean [SD] age, 63 [12] years) with otherwise therapy-refractory liver metastases underwent dynamic, contrast-enhanced CT perfusion within 1 hour before treatment planning catheter angiography, for calculation of the arterial perfusion (AP) of liver metastases, 20 days before TARE with Yttrium-90 microspheres. Treatment response was evaluated morphologically on follow-up imaging (mean, 114 days) on the basis of the Response Evaluation Criteria in Solid Tumors criteria (version 1.1). Pretreatment CT perfusion was compared between responders and nonresponders. One year survival was calculated including all 38 patients using the Kaplan-Meier curves; the Cox proportional hazard model was used for calculating predictors of survival. RESULTS: Follow-up imaging was not available in 11 patients because of rapidly deteriorating health or death. From the remaining 27, a total of 9 patients (33%) were classified as responders and 18 patients (67%) were classified as nonresponders. A significant difference in AP was found on pretreatment CT perfusion between the responders and the nonresponders to the TARE (P < 0.001). Change in tumor size on the follow-up imaging correlated significantly and negatively with AP before the TARE (r = -0.60; P = 0.001). Receiver operating characteristics analysis of AP in relation to treatment response revealed an area under the curve of 0.969 (95% confidence interval, 0.911-1.000; P < 0.001). A cutoff AP of 16 mL per 100 mL/min was associated with a sensitivity of 100% (9/9) (95% CI, 70%-100%) and a specificity of 89% (16/18) (95% CI, 62%-96%) for predicting therapy response. A significantly higher 1-year survival after the TARE was found in the patients with a pretreatment AP of 16 mL per 100 mL/min or greater (P = 0.028), being a significant, independent predictor of survival (hazard ratio, 0.101; P = 0.015). CONCLUSIONS: Arterial perfusion of liver metastases, as determined by pretreatment CT perfusion imaging, enables prediction of short-term morphologic response and 1-year survival to TARE. PMID- 23748227 TI - Small-volume analysis of cell-cell signaling molecules in the brain. AB - Modern science is characterized by integration and synergy between research fields. Accordingly, as technological advances allow new and more ambitious quests in scientific inquiry, numerous analytical and engineering techniques have become useful tools in biological research. The focus of this review is on cutting edge technologies that aid direct measurement of bioactive compounds in the nervous system to facilitate fundamental research, diagnostics, and drug discovery. We discuss challenges associated with measurement of cell-to-cell signaling molecules in the nervous system, and advocate for a decrease of sample volumes to the nanoliter volume regimen for improved analysis outcomes. We highlight effective approaches for the collection, separation, and detection of such small-volume samples, present strategies for targeted and discovery-oriented research, and describe the required technology advances that will empower future translational science. PMID- 23748230 TI - Prognostic impact of VEGF and FLT-1 receptor expression in patients with locally advanced squamous cell carcinoma of the head and neck. AB - BACKGROUND AND PURPOSE: This study investigated the prognostic value of tumor cell expression of vascular endothelial growth factor (VEGF) and its receptor fms related tyrosine kinase 1 (FLT-1) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) who had been treated with adjuvant radiotherapy or radiochemotherapy. MATERIAL AND METHODS: The impact of tumor cell VEGF and FLT-1 expression plus 11 additional factors on loco-regional control (LRC), metastases-free survival (MFS) and overall survival (OS) was retrospectively evaluated in 157 patients. The additional factors were age, gender, performance status, pre-radiotherapy (pre-RT) hemoglobin levels, tumor site, histologic grade, T-category, N-category, human papillomavirus (HPV) status, extent of resection and chemotherapy. RESULTS: On multivariate analysis, improved LRC was significantly associated with an absence of VEGF expression (risk ratio, RR: 5.02; p = 0.009), lower T-category (RR: 2.00; p < 0.001), lower N-category (RR: 3.75; p < 0.001) and pre-RT hemoglobin levels >= 12 g/dl (RR: 2.20; p = 0.029). Improved MFS was significantly associated with an absence of VEGF expression (RR: 7.46; p = 0.002), lower T-category (RR: 1.97; p = 0.002), lower N-category (RR: 3.29; p = 0.005) and a favorable tumor location (RR: 1.34; p = 0.033); HPV positivity showed a trend towards improved MFS (RR: 1.43; p = 0.09). Improved OS was significantly associated with an absence of VEFG expression (RR: 3.22; p = 0.041), pre-RT hemoglobin levels >= 12 g/dl (RR: 2.47; p = 0.009), lower T-category (RR: 1.92; p < 0.001) and lower N-category (RR: 3.39; p < 0.001). FLT-1 expression was significantly associated with LRC and OS in the univariate but not in the multivariate analysis. CONCLUSION: VEGF expression proved to be an independent negative predictor for LRC, MFS and OS in patients treated for locally advanced SCCHN with adjuvant radiotherapy or radiochemotherapy. FLT-1 expression was not significant in multivariate analyses. PMID- 23748231 TI - Comparison of two different IMRT planning techniques in the treatment of nasopharyngeal carcinoma. Effect on parotid gland radiation doses. AB - PURPOSE: To compare the effect of two different intensity-modulated radiation therapy (IMRT) planning techniques on parotid gland doses in patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Radiotherapy for 10 NPC patients referred to the University of Istanbul Cerrahpasa Medical School was planned with arc- and static seven-field IMRT. The simultaneous integrated boost (SIB) technique was used to deliver 70 Gy (2.12 Gy per fraction) to the primary tumor and involved nodes; 60 Gy (1.81 Gy per fraction) to the entire nasopharynx and 54 Gy (1.63 Gy per fraction) to elective lymph nodes in 33 fractions. Plans also aimed to keep the mean parotid dose below 26 Gy and limit the maximum doses to the spinal cord and brain stem to 45 and 54 Gy, respectively. Mean parotid gland doses for the two planning techniques were compared using a paired t-test. Target coverage and dose inhomogeneity were evaluated by calculating conformity- (CI) and homogeneity index (HI) values. RESULTS: Target coverage and dose homogeneity were identical and good for both planning techniques: CI = 1.05 +/- 0.08 and 1.05 +/- 0.08; HI = 1.08 +/- 0.02 and 1.07 +/- 0.01 for arc- and static field IMRT, respectively. Mean doses to contralateral parotid glands were 25.73 +/- 4.27 and 27.73 +/- 3.5 Gy(p = 0.008) for arc- and static field IMRT plans, respectively, whereas mean ipsilateral parotid doses were 30.65 +/- 6.25 and 32.55 +/- 5.93 Gy (non-significant p-value), respectively. Mean monitor units (MU) per fraction for the 10 patients were considerably lower for arc- than for static field treatments-540.5 +/- 130.39 versus 1288.4 +/- 197.28 (p < 0.001). CONCLUSION: Normal tissues--particularly the parotid glands--are better spared with the arc technique in patients with NPC. MU and treatment times are considerably reduced in arc IMRT plans. PMID- 23748232 TI - [Prognostic factors for locoregional recurrence after neoadjuvant chemotherapy. Results of a combined analysis from NSABP B-18 and B-27]. PMID- 23748233 TI - [Effect of systematic information about psychosocial support services during outpatient radiotherapy. A controlled trial]. AB - BACKGROUND: Up to 50 % of all cancer patients require psychosocial support during the course of their disease. However, only a proportion of these patients make use of the existing services. This is partly because patients are unaware that psychosocial support services are available to them. We investigated whether systematically providing printed information concerning psychosocial support can increase the knowledge and usage of these services, as well as health-related self-efficacy. MATERIALS AND METHODS: In a controlled trial, 108 breast cancer patients were assigned alternately to either an intervention- or a control group. At two predefined time points before and during radiotherapy, patients in the intervention group received correspondence informing them about psychosocial services (psycho-oncology, clinical social work and the Cancer Information Service).The control group received no systematic information. Using a standardized questionnaire, all patients were subsequently questioned about their knowledge of psychosocial support services, their perceived self-efficacy and their use of psychosocial support services. RESULTS: We found that systematic provision of information had a positive effect on the knowledge of psychosocial support services (p = 0.042; d = 0.45) and self-efficacy (p = 0.047; d = 0.42). However, no increase in the actual usage of these services was observed (p = 0.661; d = 0.10). CONCLUSION: The systematic provision of information in the form of written correspondence can easily be implemented into clinical routine and is an effective way to increase cancer patients' knowledge of psychosocial support services. Furthermore, providing information about the services had a positive impact on patients' perceived self-efficacy. However, simply making this information available did not increase the usage of psychosocial support services. PMID- 23748235 TI - Decreased expression of acetylcholine esterase in cholinergic urticaria with hypohidrosis or anhidrosis. PMID- 23748234 TI - Pharmacological characterization of M1 muscarinic acetylcholine receptor-mediated Gq activation in rat cerebral cortical and hippocampal membranes. AB - This study aimed to pharmacologically characterize the response derived from functional activation of Gq proteins coupled with native muscarinic acetylcholine receptors in rat cerebral cortex and hippocampus. Rat cerebral cortical and hippocampal membranes were prepared, and the effects of a range of mAChR agonists and antagonists, allosteric modulators, and muscarinic toxins were determined by an antibody-capture scintillation proximity assay combined with [(35)S]GTPgammaS binding, using the anti-Galphaq antibody sc-393. Increased specific [(35)S]GTPgammaS binding, elicited by carbachol (CCh), was selectively inhibited by the muscarinic toxin MT7, and was resistant to membrane pretreatment with N ethylmaleimide, indicating that the response derived exclusively from Galphaq, selectively coupled with the M1 mAChR. In addition to CCh, many mAChR agonists, including oxotremorine, arecholine, and methacholine, stimulated binding in a concentration-dependent manner with varied potencies and efficacies. The intrinsic activities of partial M1 mAChR agonists in the present study were generally lower than previously reported in M1-expressing cells. Xanomeline and N desmethylclozapine had negligible or minimal agonist properties. CCh-stimulated [(35)S]GTPgammaS binding to Galphaq was inhibited by mAChR antagonists, including scopolamine, ipratropium, atropine, 4-DAMP, pirenzepine, and AF-DX 116, with a rank order of potency consistent with previous studies of M1-expressing cells. There was a highly significant correlation between the potencies of 13 agonists and 19 antagonists in the cerebral cortex and hippocampus. The effects of several allosteric mAChR modulators were also investigated. These data provide a comprehensive pharmacological profile of the Gq-coupled M1 mAChR subtype natively expressed at physiological levels in rat cerebral cortex and hippocampus. PMID- 23748236 TI - Adhesion of a vesicle on an elastic substrate: 2D analysis. AB - Cell or vesicle adhesion plays an essential role in a plethora of physiological activities. In this study, we established a theoretical model to explore the adhesion behavior of a vesicle adhering on an elastic substrate. Based upon the free energy functional of the system, the governing equation set and the transversality boundary conditions were derived. The morphology of the vesicle substrate system and the phase diagram were presented, and it was found that there exist different wrapping states depending on the work of adhesion and bending stiffness. Finally, the adhesion behavior of a vesicle to a rigid substrate was investigated. These analyses are beneficial to understanding the mechanism of cell motility, and cast a new light on the droplet wrapped by a membrane when input the voltage. PMID- 23748237 TI - Perfusion SPECT in patients with suspected pulmonary embolism: how much sensitivity is needed to keep patients alive? PMID- 23748238 TI - PET/CT and breast cancer subtypes. PMID- 23748239 TI - MicroRNA-132 may play a role in coexistence of depression and cardiovascular disease: a hypothesis. AB - Different individuals have different degrees of neuroplasticity due to their different experiences. Neuroplasticity may play a role in individual differences among neuropsychiatric disease treatment efficacy. Since the nervous system monitors and coordinates internal organ function, neuroplasticity may be associated with other diseases. Cardiovascular disease (CVD) is associated with depression, which is a disorder of disrupted neuroplasticity. MicroRNA-132 (miR 132) has a roles in neuroplasticity and cardiovascular function. Thus, we hypothesize that miR-132 may play a role in coexistence of depression and CVD. PMID- 23748240 TI - Repression of miR-143 mediates Cr (VI)-induced tumor angiogenesis via IGF IR/IRS1/ERK/IL-8 pathway. AB - Hexavalent chromium [Cr (VI)] is a well-known human carcinogen associated with the increased risk of lung cancer. However, the mechanism underlying the Cr (VI) induced carcinogenesis remains unclear due to the lack of suitable experimental models. In this study, we developed an in vitro model by transforming nontumorigenic human lung epithelial BEAS-2B cells through long-term exposure to Cr (VI). By utilizing this model, we found that miR-143 expression levels were dramatically repressed in Cr (VI)-transformed cells. The repression of miR-143 led to Cr (VI)-induced cell malignant transformation and angiogenesis via upregulation of insulin-like growth factor-1 receptor (IGF-IR) and insulin receptor substrate-1 (IRS1) expression. Moreover, we found that interleukin-8 is the major upregulated angiogenesis factor induced by Cr (VI) through activation of IGF-IR/IRS1 axis followed by activation of downstream ERK/hypoxia-induced factor-1alpha/NF-kappaB signaling pathway. These findings establish a causal role and mechanism of miR-143 in regulating Cr (VI)-induced malignant transformation and tumor angiogenesis. PMID- 23748241 TI - Generation and characterization of a Cyp4b1 null mouse and the role of CYP4B1 in the activation and toxicity of Ipomeanol. AB - 4-Ipomeanol (IPO) is a prototypical pulmonary toxin that requires P450-mediated metabolic activation to reactive intermediates in order to elicit its toxic effects. CYP4B1 is a pulmonary enzyme that has been shown, in vitro, to have a high capacity for bioactivating IPO. In order to determine, unambiguously, the role of CYP4B1 in IPO bioactivation in vivo, we generated Cyp4b1 null mice following targeted disruption of the gene downstream of exon 1. Cyp4b1 (-/-) mice are viable and healthy, with no overt phenotype, and no evidence of compensatory upregulation of other P450 isoforms in any of the tissues examined. Pulmonary and renal microsomes prepared from male Cyp4b1 (-/-) mice exhibited no detectable expression of the protein and catalyzed the in vitro bioactivation of IPO at < 10% of the rates observed in tissue microsomes from Cyp4b1 (+/+) animals. Administration of IPO (20mg/kg) to Cyp4b1 (+/+) mice resulted in characteristic lesions in the lung, and to a lesser extent in the kidney, which were completely absent in Cyp4b1 (-/-) mice. We conclude that CYP4B1 is a critical enzyme for the bioactivation of IPO in vivo and that the Cyp4b1 (-/-) mouse is a useful model for studying CYP4B1-dependent metabolism and toxicity. PMID- 23748242 TI - Zooming in on single active genes in living mammalian cells. AB - The kinetic aspects of RNA polymerase II as it transcribes mRNA have been revealed over the past decade by use of live-cell imaging and kinetic analyses. It is now possible to visualize polymerase molecules in action, and most importantly to detect and follow the mRNA product as it is generated in real time on active genes. Questions such as the speed at which mRNAs are transcribed or the number of polymerases running along a particular gene can be addressed at high temporal resolution. These kinetic studies highlight the tight regulation that genes encounter when moving between active and inactive states, and ultimately will shed light on the kinetic aspects of transcription of genes under perturbed states. The scientific pathway along which these findings were unearthed begins with the imaging of the action of hundreds of genes working in concert in fixed cells. The state of the art has reached the capability of analyzing the transcription of single alleles in living mammalian cells. PMID- 23748244 TI - MUyospryn: a multifunctional desmin-associated protein. AB - Desmin, the muscle-specific intermediate filament protein, forms a 3D scaffold that links the contractile apparatus to the costameres of plasma membrane, intercalated disks, the nucleus, and also other membranous organelles. The cellular scaffold formed by desmin and its binding partners might be implicated in signaling and trafficking processes, vital mechanisms for the survival of the mammalian cell. One novel desmin-associated protein is the tripartite motif-like protein myospryn. Myospryn was initially identified as an associated partner to the biogenesis of lysosome-related organelles complex 1 protein dysbindin, implicating its potential involvement in vesicle trafficking and organelle biogenesis and/or positioning. Myospryn is also an A kinase anchoring protein, raising the possibility that together with desmin and other cytoskeletal and signaling proteins, it could participate in the subcellular targeting of protein kinase A activity in striated muscle. As with desmin, different members of this scaffold might play a crucial role in the pathogenesis of muscle disease, since any disturbance in these highly coordinated signaling pathways is expected to compromise efficient maintenance of structure-function integrity of muscle and lead to different cardiac and skeletal myopathies. PMID- 23748243 TI - Plectin-intermediate filament partnership in skin, skeletal muscle, and peripheral nerve. AB - Plectin is a large, 500-kDa, intermediate filament (IF)-associated protein. It acts as a cytoskeletal crosslinker and signaling scaffold, affecting mechanical as well as dynamic properties of the cytoskeleton. As a member of the plakin family of cytolinker proteins, plectin has a multidomain structure that is responsible for its vast binding portfolio. It not only binds to all types of IFs, actin filaments and microtubules, but also to transmembrane receptors, proteins of the subplasma membrane protein skeleton, components of the nuclear envelope, and several kinases with known roles in migration, proliferation, and energy metabolism of cells. Due to alternative splicing, plectin is expressed as various isoforms with differing N-terminal heads that dictate their differential subcellular targeting. Through specific interactions with other proteins at their target sites and their ability to bind to all types of IFs, plectin molecules provide strategically located IF anchorage sites within the cytoplasm of cells. In this review, we will present an overview of the structural features and functional properties of plectin and discuss recent progress in defining the role of its isoforms in stress-prone tissues and the implicated diseases, with focus on skin, skeletal muscle, and Schwann cells of peripheral nerve. PMID- 23748246 TI - Statement from the ILCA Board on PAHO and WHO acceptance of industry funds. PMID- 23748245 TI - Immunocytochemical and biochemical detection of the urokinase-type plasminogen activator receptor (uPAR) in the rat tooth germ and in lipid rafts of PMA stimulated dental epithelial cells. AB - Urokinase-type plasminogen activator receptor (uPAR) regulates pericellular proteolysis by binding the serine proteinase urokinase-type plasminogen activator (uPA) that promotes cell surface activating of plasminogen to plasmin. In addition, uPAR as a glycosylphosphatidylinositol (GPI)-anchored signaling receptor affects cell migration, differentiation, and proliferation. The aim of the present study was to monitor the occurrence and distribution pattern of uPAR in cells of the rat molar tooth germ. By means of immunocytochemistry moderate, uPAR immunoreactivity was detected in epithelial cells of the enamel organ and in ameloblasts and odontoblasts. RT-PCR and Western blotting experiments demonstrated the expression of uPAR in phorbol 12-myristate 13-acetate (PMA) stimulated dental epithelial cells (HAT-7 cells). A substantial part of uPAR was detected in the detergent-insoluble caveolin-1-containing low-density raft membrane fraction of HAT-7 cells suggesting a partial localization within lipid rafts. However, co-immunoprecipitation experiments showed that uPAR and caveolin 1 do not associate with each other directly. Cell stimulation experiments with PMA indicated that protein kinase C (PKC)-mediated signaling pathways contribute to the expression of uPAR in cells of the enamel organ. The localization of uPAR in membrane rafts provides a basis for further investigations on the role of uPAR mediated signaling cascades in ameloblasts. PMID- 23748247 TI - Is the conformational flexibility of piperazine derivatives important to inhibit HIV-1 replication? AB - The conserved binding site of HIV-1 gp120 envelope protein, an essential component in the viral entry process, provides an attractive antiviral target. The structural similarities between two piperazine derivatives: PMS-601, showing a dual activity for anti-PAF and anti-HIV activity, and BMS-378806, known to inhibit HIV-1 gp120, motivated us to merge important structural features of the two compounds. Novel piperazine derivatives were synthesized and evaluated in vitro concerning their ability to inhibit HIV-1 replication in in vitro infected lymphocytes. We described an approach that combines molecular docking, molecular dynamics, MM-PBSA calculations and conformational analysis to rationally predict piperazine derivatives binding mode with HIV-1 gp120. We also inquired about the conformational adaptability of the molecules, upon complex formation, and its importance to their respective inhibitory activity. The analysis suggested that the impact of the flexibility of these molecules revealed to be more important, in the context of drug design, than it has generally been assumed. These new insights at the atomic level might be useful to design inhibitors with improved antiviral activity. PMID- 23748248 TI - Toward breaking the histone code: bayesian graphical models for histone modifications. AB - BACKGROUND: Histones are proteins that wrap DNA around in small spherical structures called nucleosomes. Histone modifications (HMs) refer to the post translational modifications to the histone tails. At a particular genomic locus, each of these HMs can either be present or absent, and the combinatory patterns of the presence or absence of multiple HMs, or the histone codes, are believed to coregulate important biological processes. We aim to use raw data on HM markers at different genomic loci to (1) decode the complex biological network of HMs in a single region, and (2) demonstrate how the HM networks differ in different regulatory regions. We suggest that these differences in network attributes form a significant link between histones and genomic functions. METHODS AND RESULTS: We develop a powerful graphical model under the Bayesian paradigm. Posterior inference is fully probabilistic, allowing us to compute the probabilities of distinct dependence patterns of the HMs using graphs. Furthermore, our model based framework allows for easy but important extensions for inference on differential networks under various conditions, such as the different annotations of the genomic locations (eg, promoters versus insulators). We applied these models to ChIP-Seq data based on CD4+ T lymphocytes. The results confirmed many existing findings and provided a unified tool to generate various promising hypotheses. Differential network analyses revealed new insights on coregulation of HMs of transcriptional activities in different genomic regions. CONCLUSIONS: The use of Bayesian graphical models and borrowing strength across different conditions provide high power to infer histone networks and their differences. PMID- 23748249 TI - Nutritional epidemiology of type 2 diabetes and depressive symptoms. AB - In Japan, the prevalences of type 2 diabetes and depression are increasing, but evidence linking these diseases to diet is limited. The present study reviewed the association of type 2 diabetes with intakes of rice, fish/seafood, and soy product and isoflavone, and the association of depressive symptoms with folate, vitamin D, and dietary pattern, in the Japanese population. The analysis of type 2 diabetes comprised around 55 000 men and women aged 45 to 75 years who completed a questionnaire for the Japan Public Health Center-based Prospective Study and were free of type 2 diabetes at baseline. The odds ratio of self reported physician-diagnosed type 2 diabetes during the subsequent 5 years increased with rice intake among women and among physically inactive men but decreased with total fish/seafood intake among men. In addition, risk tended to decrease with soy product and isoflavone intake among overweight and postmenopausal women. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. The participants were approximately 530 workers aged 21 to 67 years who participated in a health survey at the time of a periodic health check. A cross-sectional and prospective inverse association between serum folate and depressive symptoms was observed. Serum 25 hydroxyvitamin D level was suggestively associated with decreased prevalence of depressive symptoms in late autumn. In addition, a healthy Japanese pattern characterized by high intakes of vegetables, fruit, mushrooms, and soy products was inversely associated with depressive symptoms. The findings suggest that diet has a role in the development of type 2 diabetes and depression in Japanese. PMID- 23748250 TI - Severe constraints for sound communication in a frog from the South American temperate forest. AB - The efficiency of acoustic communication depends on the power generated by the sound source, the quality of the environment across which signals propagate, the environmental noise and the sensitivity of the intended receivers. Eupsophus calcaratus, an anuran from the temperate austral forest, communicates by means of an advertisement call of weak intensity in a sound-attenuating environment. To estimate the range over which these frogs communicate effectively, we conducted measurements of sound level and degradation patterns of propagating advertisement calls in the field, and measurements of auditory thresholds to pure tones and to natural calls in laboratory conditions. The results show that E. calcaratus produces weak advertisement calls of about 72 dB sound pressure level (SPL) at 0.25 m from the caller. The signals are affected by attenuation and degradation patterns as they propagate in their native environment, reaching average values of 61 and 51 dB SPL at 1 and 2 m from the sound source, respectively. Midbrain multi-unit recordings show a relatively low auditory sensitivity, with thresholds of about 58 dB SPL for conspecific calls, which are likely to restrict communication to distances shorter than 2 m, a remarkably short range as compared to other anurans. PMID- 23748251 TI - 2012 Canadian Guidelines for the diagnosis and management of fibromyalgia syndrome: executive summary. AB - BACKGROUND: Recent neurophysiological evidence attests to the validity of fibromyalgia (FM), a chronic pain condition that affects >2% of the population. OBJECTIVES: To present the evidence-based guidelines for the diagnosis, management and patient trajectory of individuals with FM. METHODS: A needs assessment following consultation with diverse health care professionals identified questions pertinent to various aspects of FM. A literature search identified the evidence available to address these questions; evidence was graded according to the standards of the Oxford Centre for Evidence-Based Medicine. Drafted recommendations were appraised by an advisory panel to reflect meaningful clinical practice. RESULTS: The present recommendations incorporate the new clinical concepts of FM as a clinical construct without any defining physical abnormality or biological marker, characterized by fluctuating, diffuse body pain and the frequent symptoms of sleep disturbance, fatigue, mood and cognitive changes. In the absence of a defining cause or cure, treatment objectives should be patient-tailored and symptom-based, aimed at reducing global complaints and enhancing function. Healthy lifestyle practices with active patient participation in health care forms the cornerstone of care. Multimodal management may include nonpharmacological and pharmacological strategies, although it must be acknowledged that pharmacological treatments provide only modest benefit. Maintenance of function and retention in the workforce is encouraged. CONCLUSIONS: The new Canadian guidelines for the treatment of FM should provide health professionals with confidence in the complete care of these patients and improve clinical outcomes. PMID- 23748252 TI - An intensive perioperative regimen of pregabalin and celecoxib reduces pain and improves physical function scores six weeks after total hip arthroplasty: a prospective randomized controlled trial. AB - BACKGROUND: Despite the success of total hip arthroplasty (THA), some patients experience persistent pain and poor function after surgery. Predictors of poor outcomes include the presence of significant pre- and postoperative pain. Patients undergoing THA often experience severe, long-standing pain before surgery that may compromise the outcome of the procedure. OBJECTIVES: To evaluate the effects of administering pregabalin and celecoxib for two weeks before and three weeks after THA in patients with moderate to severe pain before surgery. The aim was to determine whether patients with well-controlled pain both before surgery and in the acute postoperative period experience less pain and better physical function six weeks after THA. METHODS: A randomized, double-blinded, placebo-controlled pilot study was conducted. Group 1 received pregabalin (75 mg twice per day) and celecoxib (100 mg twice per day) for 14 days before THA and for three weeks after discharge. Group 2 received a placebo for the same duration. All patients received pregabalin and celecoxib 2 h before surgery and while in the hospital. RESULTS: On the morning of surgery, patients in group 1 reported less pain at rest (mean [+/- SD] pain intensity measured on a visual analogue scale [VAS] 2.1+/-1.4) compared with group 2 (3.3+/-1.9; P=0.04). Patients in group 1 experienced less pain 3 h to 4 h postoperation (P<0.001). There was no difference in morphine consumption between the two groups. Six weeks after THA, movement-evoked pain was lower in group 1 (VAS 0.8+/-0.6) compared with group 2 (VAS 2.0+/-1.3; P=0.01). Group 1 reported better physical function, measured using the Western Ontario and McMaster University Osteoarthritis Index questionnaire score (P=0.04). There was no significant difference in 6 min walk test performance between the two groups. CONCLUSION: Intensive pain control with pregabalin and celecoxib improves pain and physical function after THA. PMID- 23748253 TI - Life-threatening adverse events following therapeutic opioid administration in adults: is pharmacogenetic analysis useful? AB - BACKGROUND: Systemic approaches are needed to understand how variations in the genes associated with opioid pharmacokinetics and response can be used to predict patient outcome. The application of pharmacogenetic analysis to two cases of life threatening opioid-induced respiratory depression is presented. The usefulness of genotyping in the context of these cases is discussed. METHODS: A panel of 20 functional candidate polymorphisms in genes involved in the opioid biotransformation pathway (CYP2D6, UGT2B7, ABCB1, OPRM1, COMT) were genotyped in these two patients using commercially available genotyping assays. RESULTS: In case 1, the patient experienced adverse outcomes when administered codeine and morphine, but not hydromorphone. Genetic test results suggested that this differential response may be due to an inherent propensity to generate active metabolites from both codeine and morphine. These active metabolites are not generated with hydromorphone. In case 2, the patient experienced severe respiratory depression during postoperative recovery following standard doses of morphine. The patient was found to carry genetic variations that result in decreased morphine efflux transporter activity at the blood-brain barrier and increased sensitivity to opioids. CONCLUSIONS: Knowledge of the relative contribution of pharmacogenetic biomarkers and their influence on opioid response are continually evolving. Pharmacogenetic analysis, together with clinical history, has the potential to provide mechanistic insight into severe respiratory depressive events in patients who receive opioids at therapeutic doses. PMID- 23748254 TI - Effects of hyperbaric oxygen on pain-related behaviors and nitric oxide synthase in a rat model of neuropathic pain. AB - BACKGROUND: Neuropathic pain is complex, and a satisfactory therapeutic method of treatment has yet to be developed; therefore, finding a new and effective therapeutic method is an important issue in the field of neuropathic pain. OBJECTIVE: To determine the effects of hyperbaric oxygen (HBO) on pain-related behaviours and nitric oxide synthase (NOS) expression in a rat model of neuropathic pain. METHODS: Forty male Sprague Dawley rats were randomly divided into five groups (eight rats per group) including control, sham operation, sciatic nerve with chronic constriction injury (CCI), HBO pretreatment (pre-HBO) and HBO post-treatment (post-HBO) groups. Pain-related behaviours and NOS expression in the spinal cord were compared among the five groups. RESULTS: Compared with the CCI group, the mechanical withdrawal threshold was significantly increased and thermal withdrawal latency was significantly extended in the pre-HBO and post-HBO groups (all P<0.05). After CCI, expression of spinal neuronal NOS and inducible NOS were increased. Expression of spinal neuronal NOS and inducible NOS were significantly decreased in the pre-HBO and post-HBO groups compared with the CCI group (all P<0.05). Spinal eNOS expression changed very little. DISCUSSION: HBO has been used as an effective and noninvasive method for the treatment of spinal cord injuries and high-altitude sickness, and in immunosuppression and stem-cell research; however, it has yet to be applied to the treatment of neuropathic pain. The present study indicated that HBO effectively increased mechanical withdrawal threshold and thermal withdrawal latency, demonstrating that HBO has therapeutic effects on neuropathic pain. CONCLUSION: HBO inhibits pain in rats with CCI through the regulation of spinal NOS expression. PMID- 23748255 TI - A qualitative review of the psychometric properties and feasibility of electronic headache diaries for children and adults: where we are and where we need to go. AB - BACKGROUND: While paper headache pain diaries have been used to determine the effectiveness of headache treatments in clinical trials, recent advances in information and communication technologies have resulted in the burgeoning use of electronic diaries (e-diaries) for headache pain. OBJECTIVE: To qualitatively review headache e-diaries, assess their measurement properties, examine measurement components and compare these components with recommended reporting guidelines. METHODS: The databases Medline, the Cumulative Index to Nursing and Allied Health Literature, Embase, PsychInfo, the Education Resources Information Centre and ISI Web of Science were searched for self-report headache e-diaries for children and adults. A total of 21 publications that involved e-diaries were found; five articles reported on the development of an e-diary and 16 used an e diary as an outcome measure in randomized controlled trials or observational studies. The diary measures' components, features and psychometric properties, as well as the quality of evidence of their psychometric properties, were evaluated. RESULTS: Five headache e-diaries met the a priori criteria and were included in the final analysis. None of these e-diaries had well-developed evidence of reliability and validity. Three e-diaries showed evidence of feasibility. E diaries with ad hoc measures developed by the study investigators were most common, with little to no supportive evidence of reliability and/or validity. Compliance with the reporting guidelines was variable, with only one-half of the e-diaries measuring the recommended primary outcome of headache frequency. CONCLUSIONS: Specific recommendations regarding the development (including essential components) and testing of headache e-diaries are discussed. Further research is needed to strengthen the measurement of headache pain in clinical trials using headache e-diaries. PMID- 23748256 TI - A systematic review and meta-analyses of nonsucrose sweet solutions for pain relief in neonates. AB - BACKGROUND: Sucrose has been demonstrated to provide analgesia for minor painful procedures in infants. However, results of trials investigating other sweet solutions for neonatal pain relief have not yet been synthesized. OBJECTIVE: To establish the efficacy of nonsucrose sweet-tasting solutions for pain relief during painful procedures in neonates. METHOD: The present article is a systematic review and meta-analyses of the literature. Standard methods of the Cochrane Neonatal Collaborative Review Group were used. Literature searches were reviewed for randomized controlled trials investigating the use of sweet solutions, except sucrose, for procedural pain management in neonates. Outcomes assessed included validated pain measures and behavioural and physiological indicators. RESULTS: Thirty-eight studies (3785 neonates) were included, 35 of which investigated glucose. Heel lancing was performed in 21/38 studies and venipuncture in 11/38 studies. A 3.6-point reduction in Premature Infant Pain Profile scores during heel lances was observed in studies comparing 20% to 30% glucose with no intervention (two studies, 124 neonates; mean difference -3.6 [95% CI -4.6 to -2.6]; P<0.001; I2=54%). A significant reduction in the incidence of cry after venipuncture for infants receiving 25% to 30% glucose versus water or no intervention was observed (three studies, 130 infants; risk difference 0.18 [95% CI -0.31 to -0.05]; P=0.008, number needed to treat = 6 [95% CI 3 to 20]; I2=63%). CONCLUSIONS: The present systematic review and meta-analyses demonstrate that glucose reduces pain scores and crying during single heel lances and venipunctures. Results indicate that 20% to 30% glucose solutions have analgesic effects and can be recommended as an alternative to sucrose for procedural pain reduction in healthy term and preterm neonates. PMID- 23748260 TI - Organocatalytic asymmetric synthesis of beta(3)-amino acid derivatives. AB - beta(3)-Amino acid derivatives are an essential resource for pharmaceutical production, medicinal chemistry, and biochemistry. In this article, recent developments in versatile organocatalysis, i.e., Bronsted acid catalysis, Bronsted base catalysis, Lewis acid catalysis, Lewis base catalysis, and phase transfer catalysis, for the asymmetric synthesis of beta(3)-amino acid derivatives will be presented. PMID- 23748259 TI - Clinical features of olfactory disorders in patients seeking medical consultation. AB - BACKGROUND: Olfactory disorders are common complaints in ENT clinics. We investigated causes and relevant features of olfactory disorders and the need for gustatory testing in patients with olfactory dysfunction. MATERIAL/METHODS: A total of 140 patients seeking medical consultations were enrolled. All patients were asked about their olfactory disorders in a structured interview of medical history and underwent thorough otolaryngologic examinations and imaging of the head. RESULTS: Causes of olfactory disorders were classified as: upper respiratory tract infection (URTI), sinonasal diseases (NSD), head trauma, idiopathic, endoscopic sinus surgery, congenital anosmia, and other causes. Each of the various causes of olfactory dysfunction had its own distinct clinical features. Nineteen of 54 patients whose gustation was assessed had gustatory disorders. CONCLUSIONS: The leading causes of olfactory dysfunction were URTI, NSD, head trauma, and idiopathic causes. Gustatory disorders were fairly common in patients with olfactory dysfunction. High priority should be given to complaints of olfactory disorders. PMID- 23748261 TI - From the editor. Systemness. PMID- 23748262 TI - Systemness. Introduction. PMID- 23748263 TI - Managing care in Medicaid managed care. AB - This commentary discusses the journey of SoonerCare, Oklahoma's Medicaid program, and its experience going from a statewide fee-for-service system to a partially capitated, commercial managed care system to a statewide medical home program. It describes in detail the current program and how the Oklahoma Health Care Authority, the state's Medicaid agency, addresses utilization control through various patient interventions. While the system and many of its interventions are young, the Oklahoma Health Care Authority continues to look forward in how to build upon and improve its system to ensure quality, appropriate, and efficient service delivery. PMID- 23748264 TI - The value of a safety-net hospital case example: Denver Health. AB - Mergers in the health care are common. The safety nets are being left out, because the operating margins of these hospitals are too thin. The Accountable Care Act (ACA) may increase the financial challenges of safety nets. This is because uncompensated care disbursements such as funding of the disproportionate share hospitals are scheduled to phase down as ACA implementation proceeds. If the safety nets became financially unstable, this would destabilize the local hospital market. Denver Health has gained national recognition for its innovations and excellent quality of care. This article will promote an awareness that safety-net hospitals should be considered for collaborations. PMID- 23748265 TI - The shape of digital engagement: health care and social media. AB - Health care lags behind other industries in engaging with customers via social networking. In part, this reflects concerns regarding health information privacy concerns, organizational fears regarding employee time mismanagement, and the real challenge that health care providers face with multiple and competing demands on time. Despite these fears and concerns, our patients are spending more and more of their time online seeking health care information, more often in social networks. Our greatest capacity for health care change management at present may well center on our strategic capacity to meet our patients where they spend the majority of their time online. PMID- 23748266 TI - Total cost of care: a discipline that leads to better care. AB - The health care system is undergoing dramatic change. Different approaches are underway to achieve the triple aim of improving care and population health, strengthening quality, and lowering costs. Integral to meeting the triple aim is aligning incentives for a population-based system, where the emphasis is on effectively managing and improving the care of patients and populations, thus lowering costs. Focusing on total cost of care, a composite of all cost and utilization for a person or population, enables health care payers and providers to make an impact through a patient-centered system that results in better care and reduced costs. PMID- 23748267 TI - Payment system reform: one state's journey. AB - In June 2011, Texas enacted Senate Bill 7, which mandates a Medicaid quality based outcomes payment program on the basis of a common set of outcomes that apply to all types of provider systems including hospitals, managed care plans, medical homes, managed long-term care plans, and Accountable Care Organizations. The quality-based outcome measures focus on potentially preventable events (services) such as preventable admissions and readmissions that result in unnecessary expense, patient inconvenience, and risk of complications. The payment adjustments relate to a provider system's effectiveness in reducing the rate at which potentially preventable events occur. The program envisioned by Texas Medicaid is one that is administratively simple, establishes the right financial incentives to drive delivery system improvement, and does not intrude on the provider practice or the patient. Rather than imposing a series of processes that must be followed or require rigid adherence to standardized protocols, the payment adjustments are based on risk-adjusted comparisons of the rate of potentially preventable events for an individual provider systems to an empirically derived performance standard such as the state average. This article proposes a payment system design that can meet the ambitious objectives of the Texas legislation. PMID- 23748268 TI - Type of usual source of care and access to care. AB - The goal of the study was to evaluate the association between types of usual source of care (USC) and access to care for people of different race/ethnicity and insurance coverage. Individuals reporting a doctor's office or health maintenance organization as a USC achieved the highest level of access. Individuals reporting a hospital emergency department as a USC were more likely to have access barriers and unmet needs. The independent effects of race/ethnicity were no longer significant after controlling for the type of USC and other factors. Insurance was a significant moderating factor on access to care. PMID- 23748269 TI - Assessing the utility of genetic tests. AB - Genetic testing is a rapidly expanding area with many clinical applications. While the introduction of new genetic tests creates tremendous potential for improving patient care, it is essential to adequately evaluate these tests to ensure their accuracy and utility for clinical practice. This article describes a general approach to the evaluation of genetic tests and discusses common challenges that evaluators face. This article's goal was to provide a starting point for those who are concerned with the safety and utility of genetic tests to develop an overall strategy to perform the assessment. PMID- 23748271 TI - Improvement of patients' health confidence: a comparison of 15 primary care practices and a national sample. AB - Patient health confidence is an easy-to-obtain proxy measure for patient engagement and patient activation. In evidence-based literature syntheses, longitudinal studies, and empiric analyses, this measure is related to desirable consequence of medical care. Adult patients from 15 primary care practices and a national sample report on changes in health confidence over time. Exemplary practices describe how this information is used as a foundation for behaviorally sophisticated actions so necessary for improving health confidence. PMID- 23748272 TI - The right tool for the right job: the value of alternative patient experience measures. AB - Patient-reported experience of care predicts health care outcomes. Fourteen US and Canadian practices intercalated a standard ambulatory care Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey within their usual Internet-based survey to compare results from the Internet survey, Internet CAHPS survey, and a mailed CAHPS survey. They found that practice performance rankings obtained via the multi-item CAHPS survey were equivalent to a single measure captured by the Internet survey. PMID- 23748273 TI - A patient-reported spectrum of adverse health care experiences: harms, unnecessary care, medication illness, and low health confidence. AB - As part of a health "checkup," a large national sample of adults used an Internet technology that also asks about adverse experiences. About half of all respondents do not feel very confident they can manage and control most of their health problems, almost 30% consider that their hospital or emergency department use was unnecessary, 20% believe that their medications may be causing illness, and 1.5% report a medical-related harm. Routine measures across a spectrum of adverse experiences are easy to obtain as part of everyday practice. Attention to these measures by health professionals should make care safer and less wasteful. PMID- 23748274 TI - Internet access and patient portal readiness among patients in a group of inner city safety-net practices. AB - The use of online personal health records (PHRs) threatens to transform the digital divide to a health care divide among the underserved. Little is known about underserved patients' ability to access online PHRs. We examined these factors among patients within safety-net practices. Among respondents (N = 654), only 12% had no experience of using a computer, and most were interested in using it to communicate with their provider. Age, sex, and race were not associated with interest in PHRs. A majority of patients have access to the Internet and are interested in using a PHR to manage their care, but they are not prepared. PMID- 23748275 TI - Early assessment of health care utilization among a workforce population with access to primary care practices with electronic health records. AB - This study assesses the health care costs and utilization among labor union members from 2008 to 2010 and compares whether members accessing primary care providers participating in a public health city program, the Primary Care Information Project (PCIP), had different health care usage or cost patterns. Using claims data, the number of hospital inpatient services utilized decreased by 16 per 100 members among those with chronic conditions accessing PCIP providers, whereas members seeing non-PCIP providers increased by 15 per 100 members. Access to providers participating in a population health initiative was associated with lower utilization of inpatient services and overall costs. PMID- 23748278 TI - Growing of fixed orientation plane of single crystal using the flux growth technique and ferrimagnetic ordering in Ni3TeO6 of stacked 2D honeycomb rings. AB - We report on the growth of a different orientation plane of Ni3TeO6 single crystal by the flux growth method for the first time. X-ray diffraction is used to characterize the single crystal and it crystallizes into the trigonal structure having space group R3 with lattice parameters of a = 5.1087 A and c = 13.767 A. The earlier studies reported that the antiferromagnetic (AFM) ordering below T(N) ~ 52 K confirms to be valid only under high magnetic field. In contrast, the existence of a ferrimagnetic-like ordering due to the antiferromagnetically coupled spins of uncompensated longitudinal staggered moments is revealed from the low field average spin susceptibility data analysis. The spin structure of Ni3TeO6 has been proposed with low magnetic field using single crystal samples. We believe that the Ni ions in the two stacked Ni(I) Ni(II) and Ni(III)-Te 2D honeycomb ring layers have different spin sizes--the former may have an average moment of S = 3/2 and the latter remains to be S = 1, and the interlayer antiferromagnetic interaction of the ferromagnetically coupled layers leads to the incomplete cancellation below ~72 K. The ferrimagnetic ordering and the extra paramagnetic spin moment beyond S = 1, observable at low field, can be suppressed with high magnetic field, suggesting the existence of a field-sensitive spin-orbit coupling in Ni3TeO6, that remains to be explored experimentally and theoretically. PMID- 23748277 TI - Alport syndrome: the effects of spironolactone on proteinuria and urinary TGF beta1. AB - BACKGROUND: Alport syndrome (AS) is a progressive hereditary glomerular disease. Recent data indicate that aldosterone promotes fibrosis mediated by the transforming growth factor-beta1 (TGF-beta1) pathway, which may worsen proteinuria. Spironolactone (SP) antagonizes aldosterone and this study aimed to evaluate the efficacy of SP in reducing proteinuria and urinary TGF-beta1 excretion in proteinuric AS patients. METHODS: The study involved ten children with AS, normal renal function, and persistent proteinuria (>6 months; uPr/uCr ratio >1). SP 25 mg once a day for 6 months was added to existing ACE inhibitor treatment with or without angiotensin-II receptor blockade. Urine and blood samples were examined monthly. Urinary TGF-beta1 levels were measured twice before and three times during SP treatment. Plasma renin activity (PRA) and serum aldosterone levels were also measured. In eight patients, uProt/uCreat was also assessed after 9 months and 12 months of SP treatment. RESULTS: After beginning SP therapy, all patients showed significant decrease in mean uProt/uCreat ratio (1.77 +/- 0.8 to 0.86 +/- 0.6; p < 0.001) and mean urinary TGF-beta1 levels (104 +/- 54 to 41 +/- 20 pg/mgCreatinine; p < 0.01), beginning after 30 days of treatment and remaining stable throughout SP administration. PRA remain unchanged, and mean serum aldosterone increased from 105 +/- 72 pg/ml to 303 +/- 156 pg/ml (p < 0.001). The only side effect was gynecomastia in an obese boy. After 1 year of therapy, mean uProt/uCreat remains low (0.82 +/- 0.48). CONCLUSIONS: Addition of SP to ACE-I treatment with or without angiotensin II receptor blokers (ARB) significantly reduced proteinuria. This was mediated by decreased urinary TGF-beta1 levels and not associated with major side effects. PMID- 23748279 TI - Management of localized and locally advanced renal tumors. A contemporary review of current treatment options. AB - About 70% of patients with renal cell carcinoma present with localized or locally advanced disease at primary diagnosis. Whereas these patients are potentially curable by surgical treatment alone, a further 20% to 30% of patients are diagnosed with primary metastatic disease. Although over the past years medical treatment for metastatic patients has nearly completely changed from immunotherapy to effective treatment with targeted agents, metastatic disease still represents a disease status which is not curable. Also in patients with metastatic disease, surgical treatment of the primary tumor plays an important role, since local tumor related complications can be avoided or minimized by surgery. Furthermore, also improvement of overall survival has been proven for surgery in metastatic patients when combined with cytokine treatment. Hence, surgical combined with systemic treatment as a multi-modal, adjuvant, and neo adjuvant treatment is also required in patients with advanced or metastatic disease. A growing number of elderly and comorbid patients are currently diagnosed with small renal masses, which has led to increased attention paid to alternative ablative treatment modalities as well as active surveillance strategies, which are applied in order to avoid unnecessary overtreatment in these patients. Since surgical treatment also might enhance the risk of chronic kidney disease with consecutive cardiac disorders as well as reduced overall survival, ablative techniques and active surveillance are increasingly applied. In this review article we focus on current surgical and none-surgical treatment options for the management of patients with localized, locally advanced, and metastatic renal cell carcinoma. PMID- 23748280 TI - Lymphadenectomy for renal cell carcinoma and urothelial carcinoma of the upper urinary tract: analysis of evidence in the minimally invasive era. AB - Although lymphnode dissection (LND) provides staging and therapeutic benefit in bladder cancer, the role of lymphadenectomy in renal cell carcinoma (RCC) and urothelial cancer of the upper urinary tract (UCUUT) remains undefined. The aim of this paper was to examine the staging and therapeutic role of LND in RCC and UCUUT with emphasis on applicability to modern minimally invasive approaches. A Pubmed search was conducted to identify literature published between January 1, 2008 and March 11, 2013 addressing the role of lymphadenectomy in renal and upper urinary tract cancer. Key words included "lymphadenectomy", lymphnode dissection", "lymphnode excision", "lymphatic metastasis", "renal cancer", "renal neoplasm", "renal cell carcinoma", "kidney cancer", "kidney neoplasm", "upper urinary tract", "urothelial carcinoma", "kidney pelvis", "ureteral neoplasm", "transitional cell", "ureter, and upper tract urothelial neoplasm". The staging benefit of LND in RCC and UCUUT remains controversial although lymphnode metastasis is an important prognostic factor in both disease processes. It is not well established whether LND improves survival in RCC and UCUUT. There is no consensus regarding the optimal lymphnode yield or template. Much of the current literature is derived from studies of open surgery. Patients with higher grade and stage may derive the most benefit from LND. LND may provide both staging and survival benefit in select patients undergoing surgery for treatment of either RCC or UTUUC. Patients with clinical stage T2 or higher, those with aggressive histologic subtypes and features, and those with clinically enlarged nodes should undergo LND. Simple LND templates based on tumor location should be used and are amenable to both open and minimally invasive approaches. PMID- 23748281 TI - Current management of non-muscle-invasive bladder cancer. AB - AIM: Despite standard treatment with transurethral resection (TURBT) and adjuvant therapy, many bladder cancers (BCs) recur and some progress. Based on a review of the literature, we aimed to establish the optimal current approach for the early diagnosis and management of non-muscle-invasive bladder cancer (NMIBC). METHODS: A Medline(r) search was conducted to identify the published literature relating to early identification and treatment of NMIBC. Particular attention was paid to factors such as quality of TURBT, importance of second TUR, substaging, and carcinoma in situ. In addition, studies on urinary markers, photodynamic diagnosis, predictive clinical and molecular factors for recurrence and progression after BCG, and best management practice were analyzed. RESULTS: Good quality of TUR and the implementation of photodynamic diagnosis in selected cases provide a more accurate diagnosis and reduce the risk of residual tumor in bladder cancer. Although insufficient evidence is available to warrant the use of new urinary molecular markers in isolation, their use in conjunction with cytology and cystoscopy can improve early diagnosis and follow-up. BCG plus maintenance for at least one year remains the standard adjuvant treatment in high risk BC. Moreover, there is enough evidence to consider the implementation of new specific risk tables for patients treated with BCG. CONCLUSION: In high-risk patients with poor prognostic factors after TUR, early cystectomy should be considered. PMID- 23748282 TI - Effects of omega-3 polyunsaturated fatty acid supplementation on serum fetuin-A levels in type 2 diabetic patients. AB - Fetuin-A is an endogenous inhibitor of the insulin-stimulated insulin receptor tyrosine kinase recently shown that high levels of circulating fetuin-A are associated with insulin resistance in humans suggesting that fetuin-A may represent a novel mechanism involved in the pathophysiology of type 2 diabetes (T2DM). Dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) are known to reduce triglyceride levels, but their impact on glycemic control are not well known. The aim of this study to determine the effects of omega-3 PUFA supplementation on fetuin-A and glycemic control in patients with type 2 diabetes mellitus. 40 T2DM patients (17 males/23 females; aged 39-65 years) were included in the study. Serum fetuin-A levels and metabolic and biochemical profiles were measured before (baseline) and two months after n-3 PUFA supplementations (1.2 g/day). Serum fetuin-A levels were measured by enzyme-linked immunosorbent assay. Our results indicated that serum fetuin-A, fasting glucose, HbA1c and triglyceride levels were significantly decreased after supplementation (P<0.02, P<0.001, P<0.02 and P<0.01, respectively). At baseline, serum fetuin-A levels were correlated with HbA1c (r:-0.391, P<0.04). A significant positive correlation between fetuin-A and both triglycerides (r: 0.343, P<0.05) and total cholesterol (r: 0.330, P<0.05) and negative correlation between fetuin-A and fasting glucose (r: -0.405, P<0.01) were found after the supplementations. When performed multiply regression analysis, we found that serum fetuin-a levels were related with triglyceride levels (r: 0.351, P<0.01) at baseline and HbA1c levels (r: 0.344, P<0.04) after the supplementation. Based on the results, it thought that omega-3 PUFA intake decreases serum fetuin-A levels and serum fetuin-A is associated with plasma lipids and glycemic controls in type 2 diabetic patients. Further studies are required to resolve the question. PMID- 23748283 TI - Evidences of dual role of vitamin D through cellular energy homeostasis and inflammation pathway in risk of cancer in obese subjects. AB - AIM: The underlying molecular mechanisms of the role obesity plays in increasing the risk of cancer are not well illuminated. Several mechanisms are proposed for vitamin D as an anti-cancer agent in various malignancies which may be attributed to both its both its anti-inflammatory characteristics as well as its mediatory role in cellular energy homeostasis. This study evaluates the expression of PBMCs' genes which are involved in cellular energy homeostasis such as VDR, PPARgamma, PGC1a and UCP2. Moreover, considering the possible role of vitamin D in the inflammation mechanisms, we also aimed at measurement of some inflammatory mediators such as TNF-alpha, IL-1beta, IL4, IL-6, IL10, IL13 and IL17 in inflammatory state in samples obtained from obese persons with and without positive family history of cancer. Moreover, to expand the study to a clinical context, we assessed the correlation of the resting metabolic rate with the evaluated gene. METHODS: A total of 274 obese women were included in the current cross-sectional study. All of participants were class I obese. By constructing a pedigree that includes 3 generations, twenty-one subjects were at increased risk because of a positive family history of colorectal cancer. Accordingly, current study's analysis was based on positive and negative family history of colorectal cancer. RESULTS: The concentration of Insulin and PTH were significantly high in group with positive history of cancer. 25 (OH) vitamin D, REE/kg and REE/FFM statuses in two groups; the level of mentioned terms were lower in group with positive history of cancer compared to group with negative history of cancer. We found significantly lower REE/kg in deficiency of vitamin D and higher REE/kg in sufficiency status. Our results demonstrated significant higher concentrations of IL1beta, IL17, TNFalpha and IL6 in group with positive history of cancer compared to group with negative history of cancer. The concentrations of IL13, IL10 and IL4 were significantly lower in group with positive history of cancer compared to group with negative history of cancer. The relative expression of VDR, PGC1alphaand PPARgamma gene was significantly lower in group with positive history of cancer. The relative expression of UCP2 was almost significantly lesser in group with positive history of cancer also. CONCLUSION: The observed mutual alteration in the levels of inflammatory markers and relative expression of important gene in energy homeostasis may be caused by vitamin D deficiency among the obese subjects with positive history of colorectal cancer. PMID- 23748284 TI - Plasma ghrelin, leptin, and orexin-A levels and insulin resistance after laparoscopic gastric band applications in morbidly obese patients. AB - AIM: The main cause of obesity is a change in the energy balance in favor of intake. Communication between the hypothalamus and other organs occurs through special peptides, such as ghrelin, leptin, and orexin-A, to provide energy balance. The purpose of this study was to investigate the effects of a laparoscopic gastric band application on insulin resistance and the peptides involved in appetite in morbidly obese patients. METHODS: The study group consisted of 20 patients who were operated on for morbid obesity (body mass index [BMI], 48.3+/-6.7 kg/m2) and the control group contained 20 healthy, normal weight subjects (BMI, 22.6+/-2 kg/m2). We obtained blood samples from the study subjects before surgery and one month after surgery, and once from the control group. We measured plasma levels of ghrelin, leptin, orexin-A, and plasma glucose. RESULTS: Significant weight loss was achieved after surgery (P<0.05). Plasma ghrelin levels were lower in morbidly obese patients (P=0.033), but increased postoperatively (P=0.014), compared with those in the control subjects. Leptin levels were higher in the morbidly obese group (P=0.000), but decreased after the operation (P=0.01). Orexin-A levels were higher in the morbidly obese group (P=0.000), but decreased after the operation (P=0.000). Insulin resistance values also decreased in a manner similar to leptin and orexin-A levels (P=0.000 and P=0.008, respectively). CONCLUSION: Laparoscopic gastric band application results in significant weight loss in morbidly obesity patients, even after one month. We found a decrease in patient BMI, increased ghrelin levels, and decreased leptin and orexin-A levels and insulin resistance. PMID- 23748285 TI - Association between fetal overgrowth and metabolic parameters in cord blood of newborns of women with GDM. AB - AIM: There is evidence that arthrosclerosis may originate at birth, so assessment of serum lipid levels in cord blood might be important. The aim of this study was to investigate the association between fetal overgrowth and metabolic parameters in cord blood of newborns of women with gestational diabetes mellitus (GDM) and to compare these parameters with those in newborns of non-diabetic. METHODS: The study group included 112 women (singleton pregnancy, and GDM diagnosed following WHO criteria), and as controlled subjects, 159 matched healthy pregnant women and their newborn babies were selected. A sample of cord blood was obtained at delivery. The cord blood's insulin, glucose, and lipids (total cholesterol, high density cholesterol, low- density cholesterol, and triglyceride) were determined. The relationships between these metabolic parameters and large for gestational age (LGA) were also assessed. RESULTS: There were no significant differences between total cholesterol (TC), HDL cholesterol (HDL -C), triglyceride (TG) and glucose levels between two groups but the LDL-C level, LDL/HDL ratio and insulin level were significantly higher in newborns of mother with GDM. LGA newborns of diabetic mothers, show the HDL-C level were significantly lower and LDL-C level were significantly higher than AGA (Appropriate for Gestational Age). CONCLUSION: These results show that GDM altered neonatal plasma lipids metabolism and so newborns of diabetic mothers may be predisposed early in life to LDL hypercholesterolemia and thus may be at a greater risk of developing coronary heart disease later in life. PMID- 23748286 TI - Application value of ICU nursing scoring system in nurse allocation. AB - AIM: The aim of this paper was to investigate the application value of the intensive care nursing scoring system (ICNSS) in intensive care unit (ICU) nursing resources allocation. METHODS: The English version of ICNSS scale was translated into Chinese by nursing experts, and was consistently revised and improved based on China's actual conditions. A total of 105 cases were randomly divided into the observation group (N.=55) and the control group (N.=50). In the observation group, the nursing workload was estimated and the nurses were allocated using ICNSS; in the control group, the sickbeds were equally distributed to the nurses and each nurse was equally in charge of managing patients. The ICU duration, medical charge, incidence of complications, nursing quality control scoring and nurses' satisfaction to their resource allocations were compared between the two groups. RESULTS: The ICU duration, medical charge and incidence of complications in the observation group were significantly lower than those in the control group (P=0.032, P=0.024, P=0.006 respectively); while quality control scoring and nurses' satisfaction to their resources allocation in the observation group were significantly higher than those in the control group (P=0.045, P=0.004 respectively). CONCLUSION: The nursing quality and the nurses' satisfaction could be improved using ICNSS to evaluate ICU nursing workload and allocate resources. PMID- 23748287 TI - Recent insights into the pathogenesis of nephrotic syndrome. AB - Nephrotic syndrome is characterized by heavy proteinuria followed by hypoproteinemia, hypercholestrolemia, lipiduria, and edema. The glomerular filtration barrier (GFB) consists of glomerular endothelial cells covered with glycocalyx, the basement membrane, subpodocyte space and podocytes with foot processes and slit membranes between them. The coordinated function of GFB has been considered to be the major barrier against filtration of plasma proteins to urine. However, new hypothesis suggesting more permeable GFB has emerged. According to this, proteinuria might be prevented by tubular protein reabsorbtion. Experiments and human studies have revealed numerous putative permeability factors in idiopathic nephrotic syndrome (minimal change disease/focal segmental glomerulosclerosis). New antigens and antibodies have been suggested in "idiopathic" membranous nephropathy as well. Formation of nephrotic edema, the role of oncotic pressure and of different sodium and water retaining hormones have been subject of intensive study. These findings should pave the way to new therapeutic modalities targeted more precisely to the pathogenic mechanisms. PMID- 23748288 TI - Severe brain damage in premature infants associated with postnatal infection. AB - AIM: This study examined clinical features and neuroimaging characteristics of severe brain damage in premature infants with postnatal infection. METHODS: We retrospectively analyzed clinical data of two preterm infants who developed extensive encephalomalacia secondary to postnatal infection. RESULTS: Two premature boys experienced serious postnatal infection at about 3 weeks after birth; the infection was characterized by lethargy, apnea, increased CRP, severe bilateral pneumonia, positive sputum culture for multidrug-resistant bacteria, and mild changes of cerebrospinal fluid. Both infants required ventilation and antibiotic therapy. While both infants survived, a very extensive encephalomalacia was documented by serial cranial ultrasound, MRI and CT scans 3 to 4 weeks after postnatal infection. Their mothers had no premature ruptures of membranes and no signs of antenatal infection, suggesting potential postnatal infection in the infants. CONCLUSION: More studies are needed to better understand the underlying mechanism of encephalomalacia associated with postnatal infection. To facilitate early diagnosis and effective treatment, cranial ultrasound scans should be done routinely in premature infants with serious postnatal infection. PMID- 23748289 TI - The North American Society of cardiovascular imaging. PMID- 23748293 TI - Controlled surface modification of tissue culture polystyrene for selective cell binding using resilin-inspired polypeptides. AB - Modified tissue culture polystyrene (TCP) surfaces have been fabricated by attachment of recombinant polypeptides based on Drosophila melanogaster resilin and the Anopheles gambiae resilin-like protein. The D. melanogaster polypeptide (Rec-1) was from the first exon of resilin and consisted of 17 very similar repeats of a 15 residue sequence. The A. gambiae polypeptide consisted of 16 repeats of an 11 residue consensus sequence (An16). Polypeptides were attached to the TCP surface through tyrosine-based photo-crosslinking using blue light in combination with (RuII(bpy)3)Cl2 and sodium persulfate. TCP that has been manufactured by mild oxidation has surface phenolic groups that are believed to participate in this crosslinking process. X-ray photoelectron spectroscopy and contact angle analyses were used to demonstrate polypeptide binding. At higher coating concentrations of Rec-1 and An16, the surface was passivated and fibroblasts no longer attached and spread. At coating concentrations of 1 mg ml( 1) for Rec-1 and 0.1 mg ml(-1) for An16, where the surface was fully passivated against fibroblast attachment, addition of a cell attachment peptide, cyclo(Arg Gly-Asp-D-Tyr-Lys) during coating and photo-crosslinking at >0.1 mg ml(-1), led to the restoration of fibroblast binding that was dependent on the integrin alphaV chain. PMID- 23748294 TI - Does anyone really benefit from turf wars? PMID- 23748295 TI - Analysis of dimensional changes in the screw and the surface topography at the interface of a titanium screw and a zirconia abutment under cyclic loading: an in vitro study. AB - PURPOSE: The purpose of this experiment was to analyze the mechanics of the ceramic abutment-implant joint and the dimensional changes in the abutment screws from cyclic loading. MATERIALS AND METHODS: Two groups of experimental assemblies were used, one with zirconia abutments and the other with titanium abutments (n = 10). Each specimen consisted of an implant, an abutment, and a metal crown affixed in an acrylic resin base. The specimens were subjected to cyclic loading of 200 N for 1 million cycles at 10 Hz. After loading, a torque-angle signature analysis was done, the dimensions of the screws were measured, and the implant abutment interfaces were examined with scanning electron microscopy. RESULTS: There was a statistically significant increase in the total length of the screws: 121 MUm in the titanium group versus 88 MUm in the zirconia group (P < .004). Microscopic analysis showed collected debris on the zirconia abutment undersurface and the screws. A statistically similar decrease in torque was observed: 18% for zirconia versus 13.5% for titanium. Radiographic microanalysis revealed that the debris collected in the zirconia assemblies was essentially a collection of titanium, vanadium, and aluminum, with traces of zirconium. CONCLUSIONS: While there was a loss of torque in both types of abutments, the stability of the zirconia abutment-implant joint was not affected by the loading. The study provides a better understanding of zirconia abutments, screw designs, and the mechanism holding together the implant-abutment assembly. PMID- 23748296 TI - Grafting the nasal cavity with 100% anorganic bovine bone: a clinical and histomorphometric pilot report. AB - PURPOSE: The aim of the present study was to evaluate bone formation and survival rates for implants after nasal cavity grafting using exclusively anorganic bovine bone (ABB) by means of clinical, radiographic, and histologic/histomorphometric examinations. MATERIALS AND METHODS: Twelve subjects with edentulous atrophic maxillae were screened for the study; four required bilateral and eight required unilateral nasal cavity grafting. A full-thickness flap was raised to determine the position for the nasal window between the anterior wall of the sinus and the lateral wall of the piriform aperture. A window, 5 to 6 mm wide and 10 to 13 mm high, was created. The window was infractured into the nasal cavity to allow the ABB to be pushed inside and was then covered with a collagen membrane. Cone beam computed tomography (CBCT) was performed before grafting (during screening), after grafting, and 6 months later. Eight months after grafting, from the 16 sites grafted, biopsy cores were taken from three patients using a 2.5-mm trephine and processed to evaluate the percentages of new bone, marrow space, and residual ABB. One screw-form implant was placed in each grafted site and loaded after 3 months. After at least 6 months of loading, the fixed prostheses were removed and all implants placed in grafted areas were tested for mobility. RESULTS: The 6-month CBCTs clearly showed the radiopaque material inside the nasal cavity. The histomorphometric measurements showed 33.34% new bone, 30.30% marrow space, and 36.52% remaining ABB. All implants were osseointegrated and free of pain, infection, and mobility. All implants remained stable at a mean of 13 months after loading (range, 6 to 24 months). CONCLUSIONS: The clinical, radiographic, and histomorphometric results showed that nasal cavity grafting with ABB can be an excellent alternative in patients with extensively atrophic maxillae. PMID- 23748297 TI - Osseointegration of dental implants placed into canine mandibular bone regenerated by bone transport distraction osteogenesis. AB - PURPOSE: The purpose of this study was to compare the osseointegration of dental implants placed in canine mandibular bone and in regenerated bone produced by bone transport distraction osteogenesis. MATERIALS AND METHODS: Ten adult foxhounds were divided into two groups of five animals each. In all animals, a 40 mm defect was created on one side of the mandible. A bone transport reconstruction plate was used to stabilize the mandible and regenerate bone. Six weeks after the distraction period was finished, dental implants were placed in regenerated and native mandibular bone. The animals were sacrificed after another 6 and 12 weeks of healing, respectively. RESULTS: Microcomputed tomographic evaluation showed that bone volume fraction (BV/TV) was greater at the coronal regions of the implants and decreased toward the apical regions. There was an increase in BV/TV around implants placed in regenerated bone from 6 to 12 weeks of healing. The regenerated group showed lower BV/TV at 6 weeks versus implants placed in native bone but had reached the same levels as the native bone at 12 weeks. Histology showed that direct bone-to-implant contact was greater for implants placed in native bone than for those placed in regenerated bone for both time periods. The removal torque of the implants placed in native bone was higher at 6 weeks than that of implants placed in regenerated bone. At 12 weeks, there were no statistically significant differences in removal torque between the groups. CONCLUSIONS: Bone was successfully regenerated in all animals. The implants placed entirely in regenerated bone were osseointegrated. The regenerated bone around the implants became denser over time. This finding suggests that implants placed entirely in regenerated bone will be as well integrated as implants in native mandibular bone by 12 weeks after placement. PMID- 23748298 TI - The precision of fit of cast and milled full-arch implant-supported restorations. AB - PURPOSE: The purpose of this study was to investigate the marginal precision of computer numeric control-milled frameworks fabricated of grade 4 commercially pure titanium or cobalt-chrome alloy through digital technology and to compare them with conventional cast frameworks. MATERIAL AND METHODS: A titanium cast of a mandibular arch with six implant analogs was used as a master. The master cast was measured with a coordinate measuring machine. Fifteen rigid anatomic frameworks were created on the master cast in cast gold alloy and milled in titanium or cobalt-chrome material. The fifteen anatomic frameworks were measured in the same manner as the master cast. While the milled frameworks were measured once, at the end of the milling process, the cast anatomic frameworks were measured twice: immediately after the casting and divesting procedures and again after a technical adaptation procedure. Each anatomic framework was weighed. To compare the measurements obtained from each group of frameworks, descriptive statistics were calculated and one-way analysis of variance was performed, with values considered statistically significant at P < .05. RESULTS: The mean weight of the cast frameworks was 33.41 g, the cobalt-chrome frameworks weighed 18.12 g on average, and the titanium frameworks averaged 8.7 g. The mean values for three dimensional deviation of the center point position for each group of frameworks were 261 MUm (cast frameworks before adaptation), 49 MUm (cast frameworks after adaptation), 26 MUm (milled frameworks in cobalt-chrome), and 26 MUm (milled frameworks in titanium). CONCLUSIONS: Within the limitations of this in vitro study, absolute passive fit cannot be achieved, regardless of material and fabrication technique. Anatomic milled frameworks fabricated in titanium or cobalt-chrome presented reduced center point deviation compared to cast frameworks. Titanium frameworks weighed less than cobalt-chrome and cast gold alloy frameworks. PMID- 23748299 TI - Surface characterization, biomechanical, and histologic evaluation of alumina and bioactive resorbable blasting textured surfaces in titanium implant healing chambers: an experimental study in dogs. AB - PURPOSE: The present study was conducted to determine whether biomechanical and histologic parameters would differ between implant surfaces blasted with bioactive ceramic resorbable media (biologic blasting) and blasted with alumina and acid-etched. MATERIALS AND METHODS: Fourteen beagle dogs were used. Eight animals received two implants of each surface per limb, and each limb provided samples that remained in vivo for 3 and 6 weeks. The other six animals received two implants of each surface in one limb, which remained in vivo for 1 week. After euthanization, half of the implants were subjected to torque-to-interface fracture; the other half of the implants were processed for nondecalcified histology to calculate bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO). Statistical analysis was performed with the Kruskal-Wallis test (95% level of significance). RESULTS: While no significant differences were observed for BIC and BAFO between surfaces at all three times in vivo and for torque levels at 1 and 3 weeks, a significantly higher torque was observed for the biologic blasting group after 6 weeks in vivo. Bone morphology was similar between groups at all times. CONCLUSION: A significant increase in early biomechanical fixation was observed for implants with the biologic blasting surface. However, no significant differences were observed for BIC and BAFO at any observation point. PMID- 23748300 TI - Peri-implantitis progression around thin sputtered hydroxyapatite-coated implants: clinical and radiographic evaluation in dogs. AB - PURPOSE: Soft and hard tissue responses to experimental peri-implantitis around thin sputter hydroxyapatite (HA)-coated implants were evaluated and compared to the responses to implants with other surface treatments. MATERIALS AND METHODS: Forty-eight dental implants with four different surfaces--machined (M), sandblasted/acid-etched (SA), 1-MUm thin sputter HA-coated (S), and plasma sprayed HA-coated (P)--were inserted into the mandibles of six beagle dogs. Three months later, experimental peri-implantitis was induced with ligatures to allow plaque accumulation. After a 4-month period of active breakdown, the ligatures were removed, and plaque accumulation continued for 5 additional months (progression period). Radiographic marginal bone levels, probing depths, clinical attachment levels, and modified Gingival Index were evaluated at baseline, after the active breakdown period, and after the progression period. RESULTS: Significant increases in mean probing depths and clinical attachment levels were seen around all implants after active breakdown, but no significant differences were found during the progression period. Radiographic analysis revealed marginal bone loss of 1 to 1.7 mm during the active breakdown period. Additional bone loss occurred during the progression period (M 0.2 mm, SA 0.3 mm, S 0.2 mm, P 0.4 mm). CONCLUSION: Comparable tissue behavior was demonstrated around dental implants with all four surfaces under peri-implantitis conditions. Thin sputter HA-coated implants possess the favorable osteoconductive properties of calcium phosphate coatings without exacerbating further peri-implant tissue breakdown during the progression of peri-implantitis. PMID- 23748301 TI - Alterations in bone quality after socket preservation with grafting materials: a systematic review. AB - PURPOSE: While the ability of various grafting materials to preserve extraction socket morphology has been adequately reviewed, the quality of the grafted bone in the socket is not as well understood. This systematic review aimed to compare the proportion of vital bone and connective tissue between grafted and naturally healed sockets. MATERIALS AND METHODS: An electronic search of five databases (from 1965 to November 2011) and a hand search of peer-reviewed journals for relevant articles were performed. Human clinical trials that compared histologic components of soft and hard tissues in augmented sockets and naturally healed sites, with at least five samples per group, were included. RESULTS: Eight studies (five randomized controlled trials and three controlled clinical trials) were included. The mean percentages of vital bone and connective tissue in natural healing sockets were 38.5% +/- 13.4% and 58.3% +/- 10.6%, respectively. Limited evidence (one to two articles for each material) implied that vital bone fraction was not different with demineralized allografts and autografts and increased by 6.2% to 23.5% with alloplasts in comparison to nongrafted sites. Four studies investigating the effect of xenografts were available, with equivocal results. The difference in the mean percentage of vital bone ranged from -22.2% (decrease) to 9.8% (increase). Connective tissue content decreased with the use of the aforementioned bone substitutes. Considerable residual hydroxyapatite and xenograft particles (15% to 36%) remained at a mean of 5.6 months after socket augmentation procedures. CONCLUSIONS: Based on a limited number of prospective comparative studies, the use of grafting materials for socket augmentation might change the proportion of vital bone in comparison to sockets allowed to heal without grafting. Whether these changes in bone quality will influence implant success and peri-implant tissue stability remains unknown. PMID- 23748302 TI - Maxillary sinus augmentation with porous titanium granules: a microcomputed tomography and histologic evaluation of human biopsy specimens. AB - PURPOSE: The aim of this study was to assess bone ingrowth into porous titanium granules used for maxillary sinus augmentation. MATERIALS AND METHODS: Eighteen biopsy specimens from 17 patients participating in a clinical trial on sinus augmentation using porous titanium granules (PTG) were received in the laboratory. The specimens (trephine cores of 4.5 mm) were obtained 6 months after PTG placement. After being embedded in methacrylate, the samples were scanned in a microcomputed tomography (micro-CT) scanner. Specimens were then cut along the long axis and central slices were ground to 70 MUm before staining with hematoxylin and eosin. RESULTS: The micro-CT analysis demonstrated an average bone fill of 19% (standard deviation [SD] 5.8%), whereas the graft material occupied 22.7% (SD 4.7%). The volume of newly formed bone decreased with the distance from the residual bone of the sinus floor. Two-dimensional histomorphometric analysis demonstrated a mean area of new bone of 16.1% (SD 9.4%). The PTG alone occupied 25.9% of the total mean area (SD 6.1%). The newly formed bone consisted mainly of woven bone growing in close contact with the granules and bridging the intergranular space. The remaining area was occupied predominantly by nonmineralized connective tissue. There were no signs of inflammation in any of the biopsy specimens. CONCLUSIONS: After 6 months, new bone had formed at a similar rate and quality as has been reported for other well recognized bone graft substitutes. The new bone formed in close contact with the PTG, suggesting that the material is osteoconductive. PMID- 23748303 TI - The effects of simulated bone loss on the implant-abutment assembly and likelihood of fracture: an in vitro study. AB - PURPOSE: The crestal bone level around a dental implant may influence its strength characteristics by offering protection against mechanical failures. Therefore, the present study investigated the effect of simulated bone loss on modes, loads, and cycles to failure in an in vitro model. MATERIALS AND METHODS: Different amounts of bone loss were simulated: 0, 1.5, 3.0, and 4.5 mm from the implant head. Forty narrow-diameter (3.0-mm) implant-abutment assemblies were tested using compressive bending and cyclic fatigue testing. Weibull and accelerated life testing analysis were used to assess reliability and functional life. Statistical analyses were performed using the Fisher-Exact test and the Spearman ranked correlation. RESULTS: Compressive bending tests showed that the level of bone loss influenced the load-bearing capacity of implant-abutment assemblies. Fatigue testing showed that the modes, loads, and cycles to failure had a statistically significant relationship with the level of bone loss. All 16 samples with bone loss of 3.0 mm or more experienced horizontal implant body fractures. In contrast, 14 of 16 samples with 0 and 1.5 mm of bone loss showed abutment and screw fractures. Weibull and accelerated life testing analysis indicated a two-group distribution: the 0- and 1.5-mm bone loss samples had better functional life and reliability than the 3.0- and 4.5-mm samples. CONCLUSION: Progressive bone loss had a significant effect on modes, loads, and cycles to failure. In addition, bone loss influenced the functional life and reliability of the implant-abutment assemblies. Maintaining crestal bone levels is important in ensuring biomechanical sustainability and predictable long-term function of dental implant assemblies. PMID- 23748304 TI - Osseointegration of implants in irradiated bone with and without hyperbaric oxygen treatment: an experimental study in rat Tibiae. AB - PURPOSE: Hyperbaric oxygen (HBO) has been recommended to enhance implant osseointegration in irradiated bone. The aim of this study was to further investigate the effects of HBO on implant integration in irradiated bone tissue. MATERIALS AND METHODS: The present study was an experimental intraindividual study in 16 rats. A single fraction of 20 Gy external irradiation was applied to one rat hind leg, while the other served as a nonirradiated control. Three days after radiation, two implants were inserted in each tibial tuberosity. The rats were divided into two groups: non-HBO treated (group 1) and HBO treated (group 2). Five weeks after radiation, removal torque tests were performed. Implants with surrounding tissue were processed to undecalcified cut and ground sections for histomorphometric evaluations of bone-to-implant contact and bone area. Retrieved bones were also investigated with dual-energy x-ray absorptiometry. RESULTS: The non-HBO treated rats (group 1) demonstrated higher, but not statistically significantly higher, values in the nonirradiated leg for all investigated parameters compared to the HBO-treated rats (group 2). However, the mean value for bone area was significantly higher in the irradiated sides compared to the nonirradiated control sides. CONCLUSIONS: In the present study, HBO treatment did not have a significant impact on osseointegration of implants in irradiated bone. PMID- 23748305 TI - Evaluation of the osteogenic activity of the BMP-2 mimetic peptide, PEP7, in vitro and in vivo. AB - PURPOSE: To evaluate the osteogenic activity of a novel synthetic peptide, PEP7, derived from bone morphogenetic protein 2 (BMP-2) on MG-63, a human osteoblast like cell line, and on new bone formation in vivo. MATERIALS AND METHODS: The novel synthetic peptide was synthesized by a standard Fmoc method and purified to 98% purity. Cell adhesion, proliferation, and differentiation of MG-63 were observed in the presence of different concentrations of PEP7. Eight micropigs were used to evaluate new bone formation in a supra-alveolar peri-implant defect model. The PEP7-coated implants were randomly allocated to mandible defect sites. The animals were sacrificed after 8 weeks for histologic analysis. RESULTS: PEP7 affected an early stage of adhesion and dose-dependently stimulated differentiation of MG-63 cells. The cell adhesion rate in the group coated with 1 MUM PEP7 increased approximately 47% compared to the uncoated group and 32% compared to the group coated with recombinant human bone morphogenetic protein 2 (rhBMP-2) (P < .05). The alkaline phosphatase activities of groups treated with 50 MUM of PEP7 were higher than for the other groups. PEP7 induced production of osteoblast-specific proteins in MG-63 cells. The largest effect was caused by 50 MUM PEP7, followed by the groups treated with 20 MUM synthetic peptide and 10 ng/mL rhBMP-2 (P < .05). CONCLUSIONS: A novel synthetic peptide derived from BMP 2 has osteoinductivity and new bone formation effects, including vertical augmentation of the alveolar ridge. PMID- 23748306 TI - Computed tomographic evaluation of alterations of the buccolingual width of the alveolar ridge after immediate implant placement associated with the use of a synthetic bone substitute. AB - PURPOSE: To evaluate the alterations of the buccolingual width of the alveolar ridge after immediate implant placement using a fully synthetic biphasic calcium phosphate (BCP) consisting of a mixture of 60% hydroxyapatite and 40% ? tricalcium phosphate in esthetic regions. MATERIALS AND METHODS: The buccolingual widths of the alveolar ridge in 20 extraction sites in 20 patients were assessed using computed tomography. Measurements were performed before and 6 months after extractions and immediate implant placement. In group 1 (11 patients), BCP was in the space between the buccal wall of the alveolar ridge and implant. In group 2 (9 patients), the same evaluations and procedures were performed but without using BCP. RESULTS: The buccolingual dimensions of the alveolar ridge in group 1 (BCP) showed no significant preoperative differences (8.49 +/- 1.1 mm) during the 6-month period after surgery (8.82 +/- 0.9 mm) (P = .14). In group 2, the differences in buccolingual dimensions of the alveolar ridge were statistically significant (P = .01) with reduction in dimensions from 8.12 +/- 0.7 mm during the preoperative period to 7.01 +/- 0.4 mm 6-months after surgery. CONCLUSION: The use of BCP was effective in preserving buccolingual dimensions of alveolar ridges in immediate implant surgeries. PMID- 23748307 TI - Bone augmentation in a titanium cap with a porous surface modified by microarc oxidation. AB - PURPOSE: To compare bone augmentation on pure titanium-machined surfaces and surfaces that have been modified by microarc oxidation (MAO) using titanium caps. MATERIALS AND METHODS: Twenty caps were manufactured from rods of commercially pure titanium. The control group (CG) consisted of 10 titanium caps with machined inner walls. The test group (TG) consisted of 10 titanium caps that were modified by MAO in an electrolyte solution containing calcium phosphate ions. The two types of titanium caps were fixed on the calvaria of 10 New Zealand rabbits. Each rabbit received two different caps. Although each cap was unfilled, the marrow and blood from the wound of the rabbit skulls could penetrate into the caps. After 4 weeks, the rabbits were sacrificed, and the skulls were removed for observation. The zenith of new bone was measured directly after the caps were removed from the skulls; subsequently, the bone volume was calculated by microcomputed tomography. RESULTS: Little bone augmentation could be observed in the CG caps, and the new bone height of the CG group was inconspicuous. In contrast, the new bone extended along the inner walls of the TG caps. The mean height of new bone of the TG group was 2.3 +/- 0.28 mm. The mean volume of new bone in the TG group was 18.63 +/- 3.80 mm(3). CONCLUSIONS: New bone formation in a titanium cap surface modified by MAO was greater than that of a nonmodified cap. A titanium cap allowed new bone formation on the MAO surface to be observed and is a promising device for bone augmentation. Additionally, this finding suggests that observation through a titanium cap is a feasible method for biomaterial testing in hard tissue. PMID- 23748308 TI - Comparison of osseointegration between laser-etched and magnesium-incorporated oxidized implants in the rabbit femur. AB - PURPOSE: To compare the osseointegration of a laser-etched (LE) implant with a magnesium-incorporated oxidized (MgO) implant, evaluating their ability to enhance the bond strength between a titanium substrate and rabbit femur. MATERIALS AND METHODS: Two type of dental implants, LE (test, commercially pure [CP] titanium grade 4) and MgO (control, CP titanium grade 4) (length, 8 mm; diameter, 3.3 mm), were evaluated for the surface characteristics using a field emission scanning electron microscope (FE-SEM), an energy dispersive spectrometer (EDS), and an optical three-dimensional profiling system. After that, two types of dental implants were implanted at the right and left distal femoral metaphysis of 10 adult rabbits weighing approximately 3.0 kg. After 6 weeks, histomorphometric analysis, removal torque tests, and surface analysis of the torque-tested implants were performed. RESULTS: After surgery, the LE group showed thick bonelike materials within the pores observed using FE-SEM (magnifications *500 and *900). The mean removal torque was 40.72 +/- 13.3 Ncm for the test (LE) implant and 22.26 +/- 6.4 Ncm for the control (MgO) implant, respectively (P = .041). The mean bone-implant contact in the three best consecutive threads in the cortical region was 63.35% +/- 16.44% in the LE group and 51.63% +/- 5.09% in the MgO. CONCLUSIONS: In the beginning stage of cancellous bone healing, biomechanical properties of the LE implant could influence a more favorable bone response than that of MgO. PMID- 23748309 TI - Flapless single-tooth immediate implant placement. AB - PURPOSE: This 15-year prospective study evaluated the success rate and preservation of the gingival margin of single implants placed in a flapless procedure loaded immediately after extraction or after a healing period. MATERIALS AND METHODS: Immediate flapless implant placement was performed in patients who fulfilled specified inclusion criteria. Implants were either immediately restored with a provisional crown or left unloaded (received healing abutment only). Implant success and gingival margin levels were evaluated after implant placement and after 1 to 15 years. RESULTS: A total of 305 healthy nonsmoking subjects (90 men, 215 women) were treated with 430 immediate implants during a 15-year period (December 1994 to December 2009) and monitored for 1 to 15 years. Two hundred seventy-five implants received an immediate provisional crown, and 155 received a healing abutment. The implant survival rate was 93.03% (+/- 3.74%). The immediate provisional helped to maintain the original gingival margin, although the implant survival rate was higher for implants that were not immediately restored (96.78%) than for the implants that were immediately restored with a provisional (90.9%). CONCLUSIONS: This 15-year prospective study showed a favorable implant success rate related to the flapless immediate implant placement protocol with healing abutment placement or an immediate provisional crown to replace a single missing tooth. PMID- 23748310 TI - Effects of a calcium phosphate-coated and anodized titanium surface on early bone response. AB - PURPOSE: The aim of this study was to evaluate the effectiveness of a calcium phosphate (CaPO4)-coated and anodized titanium surface in vitro and in vivo. MATERIALS AND METHODS: A turned surface was employed as a negative control. A sandblasted/acid-etched surface and an anodized surface were used as positive controls, and a CaPO4-coated and anodized (CPA) surface was investigated as the experimental group. Surface characteristics were analyzed with field emission scanning electron microscopy, energy dispersive spectroscopy, and confocal laser scanning microscopy. In vitro osteoblastic differentiation was evaluated by alkaline phosphatase assay. In vivo bone response was analyzed using bone-to implant contact (BIC) ratios and bone area (BA) of 2- and 4-week specimens obtained from six rabbits. RESULTS: The means and standard deviations for average height deviation (S(a)) and developed surface area ratio (S(dr)) were 0.32 +/- 0.03 MUm and 3.6% +/- 1.5% for the turned group, 1.36 +/- 0.11 MUm and 56.7% +/- 16.1% for the sandblasted/acid-etched group, 0.68 +/- 0.02 MUm and 50.9% +/- 2.9% for the anodized group, and 0.67 +/- 0.11 MUm and 50.0% +/- 16.9% for the CPA group. There were no significant differences in alkaline phosphatase activity among the groups at 7 and 14 days. In the in vivo experiment, the CPA group exhibited a significantly higher BIC ratio than the turned group, and the anodized and CPA groups showed significantly higher BA values than the others after 2 weeks. At 4 weeks, there was no significance in either BIC ratios or BA values among the groups. CONCLUSION: A CaPO(4) coating on an anodized surface may induce rapid osseointegration at the bone-implant interface and more bone formation near the implant surface. PMID- 23748311 TI - Predictors of peri-implant bone loss during long-term maintenance of patients treated with 10-mm implants and single crown restorations. AB - PURPOSE: The aim of this retrospective study was to evaluate the predictors of peri-implant bone loss in a sample of patients treated with 10-mm implants and single crowns who underwent periodontal/peri-implant maintenance (PM) in a Mexican private periodontal practice. MATERIALS AND METHODS: Outcomes of a group of systemically healthy, partially edentulous patients attended up to July 2012 were assessed. Patient data were considered for inclusion if they involved treatment of partially edentulous sites with 10-mm-long implants and single crown restorations, as well as at least 3 years of regular PM following implant placement. Peri-implant bone loss was evaluated from data recorded at the most recent examination. Logistic regression analysis was performed to investigate associations between peri-implant bone loss and sex, duration of PM, location and number of implants placed per patient, region of the mouth, smoking status, type of implant, and retention of restoration. RESULTS: A sample of 104 subjects who had been treated with four different types of dental implants and maintained for at least 3 years was selected. Of the 148 implants placed and followed for an average period of continuing PM of 6 years (range, 3 to 15 years), only one implant (1.8%) was lost. The outcomes of logistic regression analysis showed that the independent variables smoking, retention of restoration (cemented vs screw retained), and type of implant (internal- or external-hex) were found to be correlated with peri-implant bone loss, with odds ratios of 39.64, 4.85, and 0.04, respectively. CONCLUSIONS: Peri-implant bone loss was significantly associated with smoking status, the type of implant (ie, externally hexed), and type of retention (ie, cemented). Overall, all patients maintained low rates of bone loss. PMID- 23748312 TI - Displacement of screw-retained single crowns into implants with conical internal connections. AB - PURPOSE: Internal conical implant-abutment connections without platforms may lead to axial displacement of crowns during screw tightening. This displacement may affect proximal contacts, incisal edge position, or occlusion. This study aimed to measure the displacement of screw-retained single crowns into an implant in three dimensions during screw tightening by hand or via torque driver. MATERIAL AND METHODS: A stereolithic acrylic resin cast was created using computed tomography data from a patient missing the maxillary right central incisor. A 4.0 * 11-mm implant was placed in the edentulous site. Five porcelain-fused-to-metal single crowns were made using "cast-to" abutments. Crowns were tried on the stereolithic model, representing the patient, and hand tightened. The spatial relationship of crowns to the model after hand tightening was determined using three-dimensional digital image correlation (3D DIC), an optical measurement technique. The crowns were then tightened using a torque driver to 20 Ncm and the relative crown positions were again recorded. Testing was repeated three times for each crown, and displacement of the crowns was compared between the hand tightened and torqued states. Commercial image correlation software was used to analyze the data. Mean vertical and horizontal crown displacement values were calculated after torqueing. The interproximal contacts were evaluated before and after torquing using an 8-MUm aluminum foil shim. RESULTS: There were vertical and horizontal differences in crown positions between hand tightening and torqueing. Although these were small in magnitude, detectable displacements occurred in both apical and facial directions. After hand tightening, the 8-MUm shim could be dragged without tearing. However, after torque tightening, the interproximal contacts were too tight and the 8-MUm shim could not be dragged without tearing. CONCLUSION: Differences between hand tightening and torque tightening should be taken into consideration during laboratory and clinical adjustments to prevent esthetic and functional complications. PMID- 23748313 TI - The effect of healing abutment reconnection and disconnection on soft and hard peri-implant tissues: a short-term randomized controlled clinical trial. AB - PURPOSE: It has been reported that multiple abutment disconnections and reconnections following implant placement may compromise the peri-implant mucosal seal and may lead to increased marginal bone loss. Thus, the aim of this study was to evaluate the effect of healing abutment disconnection and reconnection on soft and hard peri-implant tissues. MATERIALS AND METHODS: Sixteen patients were included in this prospective randomized controlled clinical trial. Following one stage implant placement, test group implants (n = 10) received a permanent abutment and control group implants (n = 11) received a healing abutment. After 2 months of healing, control group implants underwent a prosthetic protocol involving implant-level impressions and a two-time abutment disconnection and reconnection process prior to delivery of the definitive prosthesis. Test group implants underwent a prosthetic protocol involving abutment-level impressions without any abutment disconnection. Clinical parameters were recorded at 2 weeks, 2 months, 3 months, and 6 months, and marginal bone levels were assessed radiographically at implant placement, 3 months, and 6 months. RESULTS: The overall survival rate from implant placement to the last follow-up visit was 100% for both groups. The mean marginal bone loss at the 6-month examination was 0.13 mm for test group implants and 0.28 mm for control group implants. There were no significant differences regarding changes in peri-implant mucosal dimensions between the two groups. CONCLUSION: The present study indicates that implants receiving a final abutment at the time of implant placement exhibited minimal marginal bone loss and were similar to implants subjected to abutment disconnection and reconnection two times. Disconnection and reconnection of the abutment two times did not cause negative dimensional changes in the peri-implant mucosa. PMID- 23748314 TI - Clinical evaluation of marginal bone loss and stability in two types of submerged dental implants. AB - PURPOSE: The aim of this prospective clinical trial was to compare the three dimensional marginal bone level, implant stability, and peri-implant health of two types of submerged dental implants that were restored with matching or platform-switched abutments. MATERIALS AND METHODS: Twenty-five subjects were recruited (test group: 43 implants with internal conical connection and back tapered collar carrying a platform-switched abutment; control group: 50 implants carrying a matched-platform abutment). Implant uncovering and conventional loading were performed after 3 months of healing, and the total observation time was 15 months. Marginal bone levels, resonance frequency analysis, insertion torque, and peri-implant health indices were recorded and analyzed statistically. RESULTS: The cumulative implant survival rate was 100%. At the second-stage surgery, bone levels were similar between groups. One year after loading, mean crestal bone loss was 0.35 +/- 0.13 mm for test implants and 0.83 +/- 0.16 mm for control implants, a significant difference. Primary stability was significantly higher in the test group than in the control group, but this difference disappeared after 3 months of healing prior to loading. Between-group differences for peri-implant health indices were negligible. CONCLUSIONS: Both implant systems had the same survival rates. Implants with a built-in platform switch and conical connection with back-tapered collar design achieved higher primary stability at insertion and less bone resorption after 15 months. PMID- 23748315 TI - Early-loaded one-stage implants retaining mandibular overdentures by two different mechanisms: 5-year results. AB - PURPOSE: To compare the biologic and prosthetic outcomes of implants loaded early to retain mandibular overdentures by means of two different attachment systems. MATERIALS AND METHODS: Patients were screened according to specific inclusion/exclusion criteria and randomly allocated to treatment groups involving two-implant-supported early loaded mandibular overdentures retained by ball attachments or Locator attachments. Marginal bone loss, Plaque Index, peri implant infection, Bleeding Index, prosthetic complications, and Kaplan-Meier survival estimates of the groups were assessed at the 5-year recall. RESULTS: Among the 29 patients (58 implants) who completed the study, one implant was lost during healing; all implants survived after prosthesis delivery. Bone loss in the ball attachment group (0.77 +/- 0.05 mm) was significantly greater than that in the Locator group (0.59 +/- 0.03 mm). The Plaque and Bleeding indices of both groups were comparable, and peri-implant inflammation scores in both groups were zero for all implants. The frequencies of activation of the matrix, replacement of the matrix, and denture reline in the ball attachment group were significantly higher than those observed in the Locator group. While assessments for the absence of any complication showed that the 1- and 3-year Kaplan-Meier survival probabilities of both groups were comparable, when activation of the retainer was excluded, survival probabilities of the ball attachment group were higher. CONCLUSIONS: The biologic outcomes of early loaded mandibular overdentures retained by ball attachments or Locators were comparable. Although the frequency of prosthetic complications with ball attachments was higher, this did not decrease the survival probability for the treatment. PMID- 23748316 TI - Clinical outcome and peri-implant findings of four-implant-supported distal cantilevered fixed mandibular prostheses: five-year results. AB - PURPOSE: This retrospective study evaluated implant and prosthodontic survival/success rates of four-implant-supported distal cantilevered mandibular fixed prostheses over more than 5 years of clinical use. MATERIALS AND METHODS: Patients with mandibular edentulism treated with four-implant mandibular prostheses with distal extensions were evaluated. Cumulative implant survival/success rates, peri-implant conditions, and prosthodontic maintenance efforts were assessed. Relationships between the degree of distal implant tilting, length of cantilevers, and implant-generated supporting zone were evaluated. RESULTS: Thirty-eight patients with 152 implants (90.5% of the original sample) were available for follow-up after 5 to 7 years (mean follow-up, 66.5 +/- 3.1 months). The cumulative survival and success rates for included implants were 100% and 98.6%, respectively. Denture cantilever length (mean, 14.7 +/- 2.3 mm; range, 9 to 20 mm) and implant-generated supporting zone (mean, 318.9 +/- 48.1 mm(2); range, 225 to 410 mm(2)) showed significant positive and negative correlations, respectively, with the inclination of tilted distal implants toward the occlusal plane (76 +/- 7.2 degrees; range, 65 to 90 degrees). Peri-implant marginal bone resorption (1.5 +/- 0.4 mm) and pocket depths (1.8 +/- 0.8 mm) were similar for anterior and posterior implants and were not influenced by degree of tilting or cantilever length. Plaque and calculus conditions were poorer for anterior implants than for posterior implants. No dentures fractured; however, fractures of resin tooth veneer material, denture rebasing, and a strong need for cleaning as a result of resin discoloration were seen. CONCLUSION: Fixed four implant rehabilitations with distal cantilevers of a defined length with or without distally tilted implants showed high success rates. Inferior hygiene in the anterior mandible regions may be a result of reduced cleansability and variations in anatomical landmarks. Resin veneering proved advantageous for repair or modification but disadvantageous for discoloration. PMID- 23748317 TI - Long-term results after immediate loading of platform-switched implants in smokers versus nonsmokers with full-arch restorations. AB - PURPOSE: Few studies have compared the effects of immediate loading on implant prognoses in smokers and nonsmokers. The aim of this prospective study was to evaluate the long-term success of immediately loaded platform-switched implants placed in smokers and nonsmokers with edentulous jaws. MATERIALS AND METHODS: Platform-switched implants were placed using the same treatment protocol in the healed edentulous jaws of two groups of patients: group A patients had smoked at least 20 cigarettes a day for more than 10 years, and group B consisted of nonsmokers. All implants were loaded immediately with provisional fixed prostheses, and definitive cement-retained restorations were delivered 4 to 6 weeks later without removing the abutments. In a standardized follow-up protocol, the implants were evaluated clinically and radiographically at the start of loading, 4 to 6 weeks later, and annually thereafter. RESULTS: Sixty-six implants (36 in the maxilla and 30 in the mandible) were placed in eight smokers. Twelve nonsmokers received 97 implants (55 in the maxilla and 42 in the mandible). During an average loading period of 62.53 (+/- 44.13) months for the smokers and 98.20 (+/- 19.53) months for the nonsmokers, three implants failed. Two failed in group A (one because of overloading and one because of peri-implanitis) and one failed in group B (overloading), resulting in implant survival rates of 97% and 99%, respectively. No significant differences were found between groups regarding plaque, bleeding, probing pocket depths, or crestal bone loss, either mesially or distally, resulting in success rates of 92.42% for group A and 98.00% for group B. CONCLUSIONS: Long-term clinical outcomes for immediately loaded platform shifted implants placed in heavy smokers appear to be comparable to those for nonsmokers if the abutments are placed on the day of surgery and never removed. PMID- 23748318 TI - Localized lateral alveolar ridge augmentation with block bone grafts: simultaneous versus delayed implant placement: a clinical and radiographic retrospective study. AB - PURPOSE: To retrospectively evaluate the 1-year outcome of implant therapy involving localized lateral alveolar ridge augmentation with block bone grafts, and to compare outcomes of implants inserted simultaneously with grafting or after a healing period. MATERIALS AND METHODS: Consecutively treated patients undergoing alveolar ridge augmentation with autogenous intraoral block grafts before or simultaneous with implant placement between 2005 and 2010 in the Oral Surgery Unit of the University of Valencia were included. The selection of procedure (simultaneous vs delayed implant placement, donor site) was based upon the criterion of the surgeon and thorough evaluation of each patient. All grafts were obtained with piezosurgery. Complications related to augmentation, implant survival, implant success, and peri-implant marginal bone loss were assessed. RESULTS: Forty-two patients were included; 45 sites were augmented and 71 implants were inserted (33 delayed and 38 simultaneously). Complications (temporary paresthesia, wound dehiscence with bone graft exposure, and exposure of osteosynthesis screw) occurred after bone harvesting in nine patients; four were in the simultaneous group and five were in the delayed group. Six grafts were not successful; four were lost and two provided insufficient bone (after resorption) for ideal implant placement. The implant survival rate was 98.5% (100% for simultaneous and 96.9% for delayed implants) and the implant success rate was 92.9% (89.5% for simultaneous and 96.9% for delayed implants). Average marginal bone loss 1 year after loading was significantly higher for simultaneously placed implants (0.69 +/- 0.67 mm) than for delayed implants (0.20 +/- 0.50 mm). CONCLUSIONS: In lateral bone atrophy, block bone grafts provided sufficient bone for implant therapy, with few complications. Both simultaneous and delayed implant placement yielded high implant survival and success rates. Average marginal bone loss was significantly higher around simultaneously inserted implants. PMID- 23748319 TI - A retrospective analysis of mandibular bone height changes associated with 81 screw-retained implant-supported prostheses with distal cantilevers: a long-term follow-up analysis. AB - PURPOSE: The aims of this study were (1) to evaluate long-term changes in bone height beneath mandibular screw-retained implant-supported prostheses with distal cantilevers and (2) to determine whether the reversal of residual ridge resorption in the posterior mandible is temporary or continues over the long term. MATERIALS AND METHODS: Panoramic radiographs, obtained at surgery and at two follow-up visits, of 81 patients rehabilitated with mandibular screw-retained implant-supported prostheses with distal cantilevers supported by four, five, or six implants were followed for 5 to 19 years (overall mean follow-up, 9.00 years. Changes and trends in bone height adjacent to the most distal implant were evaluated between each follow up visit as well as from time of surgery (baseline) to the final visit using two-way analysis of variance, a two-sample t test, and piecewise linear regression. RESULTS: Average bone height distal to the distal most implant at placement was 10.34 +/- 6.87 mm. From baseline to the first follow-up exam, a mean bone gain of 0.68 mm was noticed, and a mean gain of 0.26 mm was observed from baseline to the second follow-up exam. A statistically significant bone gain (0.92 mm) was noticed in women (n = 49) between the first and second exams, compared to 0.33 mm in men (n = 32). Individuals experienced both bone gain and loss during the study, with an overall gain. Patients with lower initial bone height experienced greater growth, but this was not statistically significant. CONCLUSION: Bone growth is associated with mandibular screw-retained implant-supported prostheses with distal cantilevers, and both bone loss and bone growth may occur in the same patient over time. Within the diverse population of this study, women experienced 2.5 times more gain in bone height than men. No correlation could be established between initial bone height and overall bone height changes. PMID- 23748320 TI - A retrospective study of complications associated with 100 consecutive maxillary sinus augmentations via the lateral window approach. AB - PURPOSE: To report the complications encountered during 100 consecutive maxillary sinus augmentations via the lateral window approach and to propose solutions to manage these complications. MATERIALS AND METHODS: Pretreatment residual bone heights and the presence of septa were recorded. The incidences of any intraoperative or postoperative sinus complications such as excessive bleeding, membrane perforation, infection, wound dehiscence, sinusitis, loss of bone graft, and implant success were reported. results: This study evaluated 42 men and 44 women requiring 100 consecutive sinus elevation procedures between March 2008 and February 2011. Five intraoperative membrane perforations were noted, and one subsequently developed an active infection (2 weeks after surgery). Eight instances of suppuration were noted, while 10 sites presented with wound dehiscence 1 to 2 weeks after surgery. One example of partial loss of the bone graft 6 months after surgery was identified. Of a total of 151 implants placed in 97 sinuses (one patient with bilateral sinuses and one with unilateral sinus did not complete implant placement), 2 implants presented excessive bone loss prior to uncovering. One implant was removed and one was left submerged. conclusions: Sinus floor elevation utilizing the lateral window approach is a predictable approach to manage bone volume deficiency in the posterior maxilla for patients seeking dental implant-based treatment. However, complications may include membrane tear, infection, wound dehiscence, loss of graft, and implant failure. It is vital for the clinician to understand how to recognize and solve these complications. PMID- 23748321 TI - Electrical mallet in implants placed in fresh extraction sockets with simultaneous osteotome sinus floor elevation. AB - PURPOSE: To report the application of an electrical mallet (magnetic mallet) in osteotome-assisted surgery for sinus floor elevation with implants placed in fresh sockets and 2-year follow-up. MATERIALS AND METHODS: A total of 32 patients (70 implants, 36 in the molar and 34 in the premolar regions) requiring extractions of maxillary premolars and molars were included in this prospective study. In all cases, implants were positioned immediately after tooth extraction. The implant site was prepared with osteotomes pushed by a magnetic mallet. Intraoral digital radiographic measurements were reported at 70 days and 1 and 2 years. Initial alveolar bone height and mean gained alveolar bone height were calculated for each implant over time. All implants were followed for 2 years. RESULTS: One of 70 implants failed 1 month after surgery. This implant was successfully replaced 6 months later. The cumulative survival rate at 2 years was 98.57%. After surgery, no membrane perforation was reported, and no patient experienced vertigo, distress, nausea, and vomiting. Radiographic results were reported at 70 days and 1 and 2 years from implant placement. The alveolar bone gain following 70 days of healing resulted in a mean value of 2.63 +/- 1.01 mm and, at 2 years from implant placement, was stable at 4.08 +/- 1.25 mm. Statistically significant differences (P < .05) between values at 70 days and 1 year were reported, whereas there were no statistically significant differences (P > .05) between 1 and 2 years. CONCLUSIONS: The electrical mallet represents a fast and accurate instrument for placing bone expanders in fresh socket implants and simultaneous sinus floor elevation to avoid patient distress. PMID- 23748322 TI - Retrospective study of the survival and associated risk factors of wedge-shaped implants. AB - PURPOSE: To assess the long-term behavior of wedge-shaped implants and evaluate the influence of the associated risk factors on implant survival rates. MATERIALS AND METHODS: A retrospective review of clinical records of patients treated with wedge-shaped implants between 1992 and 2011 was conducted. Data on patient sex, age, smoking habits, and history of periodontitis; details of implant length, diameter, angle, and location; and data on surgical, reconstructive, and prosthetic procedures, and systemic disease were selected for analysis. RESULTS: A total of 1,169 implants placed in 154 patients (mean age 55.17 +/- 11.33 years) were evaluated. Women received 637 implants, and men received 532 implants; 60.4% were placed in patients who were undergoing periodontal maintenance care, 17.9% in smokers, 17.7% in hypertensive patients, 5.7% in diabetic patients, and 4.4% in cardiac patients. The mean overall survival for implants was 194.26 +/- 9.91 months. Seventy-three implants were lost: 3 before implant loading and 70 after loading. The cumulative survival rates at 5 and 10 years were 96.6% (confidence interval [CI]: 95.5% to 97.7%) and 91.8% (CI: 90.1% to 94.1%), respectively. Univariate analysis indicated tobacco smoking (P = .014) and implant location (P < .001) as significant risk factors for implant failure. The multivariate analysis showed tobacco smoking (P = .016), location (P = .001), and male sex (P = .038) as significant, and the latter factor was associated with previous periodontal disease. CONCLUSIONS: Overall survival of the wedge-shaped implant showed good long-term results. Male sex, tobacco smoking, and posterior maxillary location were associated with a greater risk of implant failure. PMID- 23748323 TI - Clinical, microbiologic, and host response characteristics in patients with peri implant mucositis. AB - PURPOSE: To analyze the clinical, microbiologic, and host response characteristics (interleukins 1beta and 6) in the peri-implant sulcus fluid (PISF) of patients with healthy dental implants and with peri-implant mucositis. MATERIALS AND METHODS: Clinical parameters (modified Gingival Index [mGI], modified Plaque Index [mPI], probing pocket depth [PPD], and absence or presence of radiologic bone loss) were recorded, and PISF samples were obtained from peri implant sites showing mucositis as well as healthy sites. The periodontopathogenic bacteria Tannerella forsythia (Tf), Treponema denticola (Td), and Porphyromonas gingivalis (Pg) were evaluated, together with the total bacterial load (TBL) and the interleukin (IL) 1beta and IL-6 values. RESULTS: The study population consisted of 34 individuals, and 77 dental implants were evaluated during the study (23 mucositis and 54 healthy peri-implant sites). The mGI, mPI, and PPD scores of the peri-implant mucositis group were significantly greater than in the healthy group. No differences in detection frequency were found for putative periodontal pathogens and TBL between the healthy peri-implant sites and mucositis sites. The mucositis group showed a significantly greater expression of IL-6 than the healthy group (P < .05). Although IL-1beta was increased in the mucositis group, there was no statistically significant difference versus the healthy implant group. CONCLUSIONS: An analysis was made of the clinical, microbiologic, and host response characteristics in implants with peri-implant mucositis, establishing comparisons with healthy implants. In the patients studied, bacterial plaque induced an inflammatory response that can lead to the development of peri-implant mucositis. Adequate plaque control is therefore able to increase peri-implant health, avoiding the risk of future complications. No specific association to the studied bacterial species was established. PMID- 23748324 TI - Immediate loading of Branemark system TiUnite and machined-surface implants in the posterior mandible, part II: a randomized open-ended 9-year follow-up clinical trial. AB - PURPOSE: To present clinical results with 9 years of follow-up of a protocol of immediately loaded implants with two different surfaces. MATERIALS AND METHODS: A total of 44 patients received 66 Branemark System TiUnite and 55 Branemark machined implants, all immediately loaded. Control examinations were performed on the day of surgery and at 1-, 3-, and 9-year follow-up visits. RESULTS: All implant sites had intact buccal and lingual bone walls. The prefabricated provisional restorations showed an excellent fit. Three TiUnite and 8 machined implants failed within 7 weeks of loading, resulting in a cumulative survival rate of 95.5% and 85.5% respectively after 9 years of load. The survival rate for implants in a partial prosthesis was 98.8% and 92.2% for single restorations in the TiUnite group, and 87.8% and 83.2%, respectively, for partial and single resorations in the control group. The marginal bone resorption in the first year was on average 0.9 mm in the TiUnite group and 1.0 mm in the machined group; at the third year it was 0.4 and 0.5 mm, respectively. On examination at 9 years, there was a general settlement of the bone, with a negligible further loss in height. CONCLUSIONS: The unchanged survival rate and the low bone loss after 9 years confirm the feasibility of an immediate loading protocol in the mandible, which included flapless surgery. TiUnite implants obtained a 10% higher success rate compared with machined fixtures . PMID- 23748325 TI - Dental zirconia implants up to three years in function: a retrospective clinical study and evaluation of prosthetic restorations and failures. AB - PURPOSE: The clinical evaluation of one-piece zirconia dental implants with different diameters to determine survival rate and type of implant failure. MATERIALS AND METHODS: Information concerning implant surgery (number, diameter, length, and position of inserted implants; patient age, sex, risk factors, and bone quality) was extracted from the clinical records. All treated patients were then recalled for a follow-up examination to check the current clinical parameters concerning soft tissue, implants, and prosthetic reconstructions. RESULTS: A total of 79 patients received 170 implants (diameter-reduced 3.25 mm: n = 59; diameter 4.0 mm: n = 82; diameter 5.0 mm: n = 29). The clinical examination showed no signs of gingival inflammation. Prosthetic information was available for 119 implants restored with single crowns (87 implants), fixed partial dentures (25 implants), and removable hybrid dentures (7 implants). Overall, 30 implants were lost due to lack of osseointegration (n = 17) or fracture (n = 13). The diameter-reduced implants showed the lowest survival rate (59.5%) compared to the implants with a diameter of 4.0 mm (90.6%) and 5.0 mm (73.9%). The survival rate for diameters of 3.25 mm was significantly lower than that for diameters of 4.0 mm. The estimated cumulative survival rate up to 3 years demonstrated a survival probability of 82.4% for all types of implant diameters and failure. CONCLUSIONS: Based on these results, diameter-reduced zirconia dental implants cannot be recommended for clinical use. The overall survival rate of 82.4% is not acceptable in comparison to the well-established survival rate of titanium implants. PMID- 23748326 TI - Transnasal endoscopic removal of dental implants from the maxillary sinus. AB - PURPOSE: The penetration of dental implants into the maxillary sinus is becoming more common as a result of the use of new techniques to rehabilitate edentulous jaws. This complication requires the removal of the foreign body, even in asymptomatic patients, to prevent inflammatory disease. This article reports the authors' experience with the surgical removal of dental implants from the maxillary sinus with an endoscopic approach via middle meatotomy. MATERIALS AND METHODS: A 10-year (2001 to 2011) retrospective analysis was performed in the authors' departments to identify all patients who underwent endoscopic removal of a dental implant from the maxillary sinus. RESULTS: Sixteen patients (seven women and nine men, mean age 50.7 years) underwent endoscopic removal of the implant from the maxillary sinus via a middle meatotomy. Seven patients (43.8%) received general anesthesia for the surgery, and nine (56.2%) were treated with local anesthesia. No intraoperative or postoperative complications were observed. The mean follow-up period was 62 months. CONCLUSION: In the authors' experience, endoscopic transnasal removal of dental implants from the maxillary sinus via a middle meatotomy is a successful, rapid, safe, and minimally invasive procedure. PMID- 23748327 TI - Classification of molar extraction sites for immediate dental implant placement: technical note. AB - Dental implants may be successfully placed immediately into fresh extraction sockets when primary implant stability can be attained. This article presents a new classification system for molar extraction sites that describes extraction sockets based upon the bone available within the socket for stabilization of an immediately placed implant. Three categories--types A, B, and C--are employed: the type A socket, which allows for the implant to be placed completely within the septal bone, leaving no gaps between the implant and the socket walls; the type B socket, which has enough septal bone to stabilize but not completely surround the implant, leaving gaps between one or more surfaces of the implant and the socket walls; and the type C socket, which has little to no septal bone, thus requiring that the implant engage the periphery of the socket. Treatment protocols and relevant clinical examples are presented based upon the characterization of the socket according to this classification system. PMID- 23748328 TI - Human dental implants with a sandblasted, acid-etched surface retrieved after 5 and 10 years: a light and scanning electron microscopy evaluation of two cases. AB - The aim of the present study was a light and scanning electron microscopy (SEM) evaluation of the peri-implant tissues around sandblasted, acid-etched implants, retrieved from man, after a loading period of 5 and 10 years, respectively. Two implants (Leone Implant System) had been retrieved for a fracture of the prosthetic superstructure respectively after 5 and 10 years of loading. Both implants were stable before retrieval and had been retrieved using a 5-mm trephine bur. One implant was treated to obtain thin ground sections, while the other underwent evaluation under SEM. Compact, mature lamellar bone was present over most of the implant perimeter in close contact with the implant surface and with many remodeling areas. Under SEM, small concavities, completely filled by mineralized bone, were present on the implant surface. The present histologic results showed that these implants were well integrated over the long term, and the peri-implant bone was undergoing continuous remodeling at the interface. PMID- 23748329 TI - Stress distribution in the abutment and retention screw of a single implant supporting a prosthesis with platform switching. AB - PURPOSE: Three-dimensional finite element analysis was conducted to evaluate and compare the stress distribution in the abutment and retention screw of implant supported single crowns with platform switching and with a conventional platform under vertical and oblique loading. MATERIALS AND METHODS: Two finite element models were created simulating an osseointegrated implant (4 * 10 mm, platform 4.1 mm) embedded in jawbone. One model simulated a 4-mm-diameter abutment connection (conventional model) and the other represented a 3.8-mm-diameter abutment connection (platform-switched model). A crown with a cobalt-chromium framework and feldspathic porcelain veneering was applied to the titanium abutment. Static vertical and oblique loads were applied to the crown, with a maximum load of 150 N. RESULTS: In both models, the highest stress values occurred in the abutment during vertical and oblique loading. Nevertheless, the von Mises stresses in the abutment and the retention screw were lower in the platform-switched model than in the conventional model. During axial loading, the abutment and screw supported slightly less stress in the conventional model than in the platform-switched model. Increases in the angle of force application caused a progressive increase in stresses in the abutment and screw in both models. The maximum stress was distributed at the margin and transgingival area of the abutment and on two-thirds of the flat area and the first threads of the retention screw in both models. CONCLUSIONS: Platform switching reduced the stress values on the abutment and retention screw of a single-unit prosthesis during oblique loading. Regardless of whether platform switching was employed, the stress on the abutment and screw gradually increased as the loading direction changed from vertical to 45 degrees oblique. The locations and distributions of stresses were similar in both models. PMID- 23748330 TI - The effect of platform switching on stress in peri-implant bone in a condition of marginal bone resorption: a three-dimensional finite element analysis. AB - PURPOSE: The aim of the present study was to investigate the stress distribution in the bone around a platform-switched implant with marginal bone loss. MATERIALS AND METHODS: Finite element models of an implant-supported crown on a mandibular first molar were constructed and included an osseointegrated implant, a metal crown, and cancellous and cortical bone. Two kinds of abutments, conventional and platform-switched, were imported into the model. A variety of different levels of conical marginal bone resorption, from 0 to 2.0 mm in height and width, was created around the implant neck. The stresses generated in the peri-implant bone tissue were analyzed under 200 N of vertical or oblique loading. RESULTS: The location of stress concentration extended from the implant neck toward the apex in association with increases in bone resorption depth. In the bone-resorbed models, the platform-switched implant showed lower maximum equivalent stresses in the peri-implant bone than the conventional abutment. The difference between the two implant models decreased as bone resorption increased. CONCLUSION: Within the limitations of this study, the results suggest a biomechanical advantage for platform switching in a condition of marginal bone resorption, but this advantage may be weakened when bone resorption is dramatic. Additional animal or clinical studies are necessary to better clarify the effects of peri-implant bone defects on the biomechanical features of a platform-switched configuration. PMID- 23748331 TI - Implant biomechanical stability variation at early implantation times in vivo: an experimental study in dogs. AB - PURPOSE: To demonstrate the degree of stability decrease and subsequent increase of dental implants at early implantation times in a beagle model. MATERIALS AND METHODS: The mandibular premolars and first molars of eight beagle dogs were extracted and the ridges allowed to heal for 8 weeks. Thirty-two (n = 16 each group) implants were placed bilaterally, and remained in vivo for 1 and 3 weeks. The implants with comparable dimensions were divided as follows: group 1, Straumann Bone Level with SLActive surface; group 2, Nobel Speedy Replace RP with TiUnite surface. During insertion and following sacrifice, the implants were torqued to determine insertion and interface failure values. Histologic sections were prepared for microscopy. Statistical analysis was performed using Kruskal Wallis and multiple paired and non-paired t tests considering unequal variances at a 95% level of significance. RESULTS: High insertion torque values were observed along with a significant decrease at 1 week in vivo (P = .003). At 3 weeks, the biomechanical fixation levels increased and were comparable to the insertion torque value. Histology showed that interfacial bone remodeling and initial woven bone formation was observed around both implant groups at 1 and 3 weeks. CONCLUSIONS: As time elapsed early after implantation, the biomechanical stability of dental implants initially decreased and subsequently increased. PMID- 23748332 TI - Experimental and numeric stress analysis of titanium and zirconia one-piece dental implants. AB - PURPOSE: To compare the stress in bone around zirconia and titanium implants under loading. MATERIALS AND METHODS: A one-piece zirconia implant and a replica of the same implant made of commercially pure titanium were embedded in two self curing acrylic resin blocks. To measure strain, a strain gauge was applied on the surface of the two samples. Loads of 50, 100, and 150 N, with orientations of 30, 45, and 60 degrees with respect to the implant axis were applied on the implant. Strain under all loading conditions on both samples was measured. Three dimensional virtual replicas of both the implants were reproduced using the finite element method and inserted into a virtual acrylic resin block. All the materials were considered isotropic, linear, and elastic. The same geometry and loading conditions of the experimental setup were used to realize two new models, with the implants embedded within a virtual bone block. RESULTS: Very close values of strain in the two implants embedded in acrylic resin were obtained both experimentally and numerically. The stress states generated by the implants embedded in virtual bone were also very similar, even if the two implants moved differently. Moreover, the stress levels were higher on cortical bone than on trabecular bone. CONCLUSIONS: The stress levels in bone, generated by the two implants, appeared to be very similar. From a mechanical point of view, zirconia is a feasible substitute for titanium. PMID- 23748333 TI - The effect of cantilevered bar length on strain around two implants supporting a mandibular overdenture. AB - PURPOSE: The aim of this study was to evaluate the effect of cantilevered bar length on strain produced around two implants supporting a mandibular overdenture. MATERIALS AND METHODS: Two root-form implants were placed bilaterally in the canine region of an edentulous acrylic resin mandibular cast and connected with a resilient bar/clip attachment. Four linear strain gauges were bonded to the acrylic resin at the mesial and distal surfaces of each implant. Each gauge was wired separately into a 1/4 Wheatstone bridge of a multichannel digital bridge amplifier. Strains were measured without cantilevered bar extensions (control group) and with the following lengths of cantilevered bars: 11 mm (group 1), 9 mm (group 2), and 7 mm (group 3). For each cantilevered bar length, strains were measured using clips placed on the cantilevers and attached to the overdenture (bar-clip contact) and without clips (bar-acrylic resin contact). Strain measurements were performed under central and unilateral loading using a loading device. RESULTS: The bar with cantilevers (either with or without clips) demonstrated a significant increase in strain compared to the bar without cantilevers. The 11-mm cantilever length generated the highest peri implant strain values, while the 7-mm length recorded the lowest. For all cantilevered bar lengths, the strains significantly decreased with bar-clip contact compared to bar-acrylic resin contact. Under central loading, distal and mesial peri-implant strains were the highest and the lowest values, respectively, while under unilateral loading, the highest strain was recorded at distal sites of the loading side and the lowest was recorded at distal sites of the nonloading side. A positive correlation was found between the recorded strain and the cantilevered bar length. CONCLUSION: The 7-mm cantilevered bar with clips placed on the cantilevers was recommended when two implants were used to support mandibular overdentures, as it demonstrated the lowest magnitude of strains with no significant differences between peri-implant sites. PMID- 23748334 TI - Finite element analysis of zygomatic implants in intrasinus and extramaxillary approaches for prosthetic rehabilitation in severely atrophic maxillae. AB - PURPOSE: To compare the extramaxillary approach with the widely used intrasinus approach via finite element method. MATERIALS AND METHODS: A unilateral three dimensional model of the craniofacial area surrounding the region of interest was developed using computed tomography image datasets. The zygomatic implants were modeled using three-dimensional computer-aided design software and virtually placed according to the described techniques together with one conventional implant and a prosthesis. The bone was assumed to be linear isotropic with a stiffness of 13.4 GPa, while the implants were of titanium alloy with a stiffness of 110 GPa. Masseter forces were applied at the zygomatic arch, and occlusal loads were applied to the surface of the prosthesis. The stresses and displacements generated on the surrounding bone and within the implant due to the simulated loading configuration were analyzed. RESULTS: The bone-implant interface and zygomatic implant body for the intrasinus approach produced 1.41- and 4.27-fold higher stress, respectively, compared with the extramaxillary approach under vertical loading. However, under lateral loading, the extramaxillary approach generated 2.48-fold higher stress than the intrasinus at the bone-implant interface. The zygomatic implant in the extramaxillary approach had twofold higher micromotion than those with intrasinus approach under lateral loading. CONCLUSIONS: No one technique was found to be superior; however, if lateral loading is used, the intrasinus approach is the most favorable for the rehabilitation of severely atrophic maxillae. PMID- 23748335 TI - Influence of three types of abutments on preload values before and after cyclic loading with structural analysis by scanning electron microscopy. AB - PURPOSE: To evaluate the effectiveness of three types of abutments in the maintenance of screw joint preload before and after cyclic loading as well as to observe possible microdamage in the structure of the components using a scanning electron microscope (SEM). MATERIALS AND METHODS: Forty-five external-hex implants were embedded in epoxy resin, received their respective abutments, and were randomly divided into three experimental groups (n = 15): (1) machined titanium (Ti) abutments; (2) pre-machined gold (Au) abutments; and (3) machined zirconia (ZrO(2)) abutments. The abutment screws were tightened according to the manufacturer's recommended torque. Initially, a static bending test was performed using five specimens of each group to determine the load applied in the cyclic loading test. Thus, 10 specimens of each group were used to measure the reverse torque value (preload) of the abutment screw before and after loading. A cyclic loading (0.5 * 10(6) cycles; 15 Hz) between 11 and 211 N was applied at an angle of 30 degrees to the long axis of the implants. The group means were compared using analysis of variance and the Tukey test (alpha = .05). RESULTS: The reverse torque analysis before cyclic loading showed no significant difference among the groups (P > .05). After cyclic loading, all preload means decreased significantly. The lowest decrease in preload was observed in the Ti group, whereas the highest decrease was observed in the ZrO(2) group, with a significant difference noted between them (P = .010). The Au group presented an intermediate decrease, with no significant difference compared to the other groups (P > .05). SEM images showed structural changes in the mating surfaces of the abutments after cyclic loading. CONCLUSION: The load application reduced the preload means significantly in all groups, and more significantly in the ZrO(2) group. PMID- 23748336 TI - Behavior problems in middle childhood: the predictive role of maternal distress, child attachment, and mother-child interactions. AB - The objective of the study was to examine the longitudinal relation between early school-age measures of maternal psychosocial distress, quality of mother-child interactions, and child attachment behavior, and behavior problem profiles in middle childhood using a multi-informant design. Participants were 243 French speaking mother-child dyads (122 girls) who were part of an ongoing longitudinal project. Maternal psychosocial distress was assessed when children were between 4 and 6 years of age. Mother-child interactive quality and attachment patterns were observed at age 6 during a laboratory visit. At age 8.5, externalizing and internalizing problems were assessed using mother and child reports. Results show that maternal psychosocial distress predicted later social adaptation reported by the child through the mediation of mother-child interactions. Analyses also revealed that higher maternal psychosocial distress and controlling attachment patterns, either of the punitive or caregiving type, significantly predicted membership in both child internalizing and externalizing clinical problem groups. Lower mother-child interactive quality, male gender, and child ambivalent attachment were also predictors of externalizing clinical problems. PMID- 23748337 TI - Associations between maternal mental health and child emotional and behavioral problems: does prenatal mental health matter? AB - This study examined associations between elevated symptoms of prenatal depression or anxiety and offspring emotional and behavioral problems during mid to late childhood taking into account the impact of later maternal mental health symptoms. The sample consisted of 2,891 women and their children (49 % male) from a prospective, community-based study, the Avon Longitudinal Study of Parents and Children. Women completed measures of depressive (Edinburgh Postnatal Depression Scale) and anxious (Crown Crisp Experiential Index) symptoms at regular intervals beginning in pregnancy. Mothers and teachers assessed offspring emotional and behavioral problems using the Strengths and Difficulties Questionnaire when children were 10-11 years old. Multivariable regression models were fit to address study hypotheses. Exposure to elevated symptoms of maternal depression during pregnancy was associated with increased total offspring emotional and behavioral problems, even after controlling for later maternal mental health problems and a range of sociodemographic and psychosocial characteristics, according to mothers' but not teachers' reports. Similarly, children exposed to elevated symptoms of maternal anxiety during pregnancy were reported to have increased total emotional and behavioral problems by mothers but not by teachers. We found support for modest associations between elevated symptoms of maternal depression and anxiety during the prenatal period and certain domains of offspring emotional and behavioral problems in mid to late childhood above and beyond the impact of later maternal mental health problems. These findings highlight the need for additional clinical and research attention to the prenatal period and to both maternal depression and anxiety. PMID- 23748338 TI - Culture-free club. PMID- 23748340 TI - Bacterial transcription: Finding the magic spot on RNAP. PMID- 23748339 TI - The abundance and variety of carbohydrate-active enzymes in the human gut microbiota. AB - Descriptions of the microbial communities that live on and in the human body have progressed at a spectacular rate over the past 5 years, fuelled primarily by highly parallel DNA-sequencing technologies and associated advances in bioinformatics, and by the expectation that understanding how to manipulate the structure and functions of our microbiota will allow us to affect health and prevent or treat diseases. Among the myriad of genes that have been identified in the human gut microbiome, those that encode carbohydrate-active enzymes (CAZymes) are of particular interest, as these enzymes are required to digest most of our complex repertoire of dietary polysaccharides. In this Analysis article, we examine the carbohydrate-digestive capacity of a simplified but representative mini-microbiome in order to highlight the abundance and variety of bacterial CAZymes that are represented in the human gut microbiota. PMID- 23748341 TI - Viral pathogenesis: Enabling HCV's need for fat. PMID- 23748342 TI - The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection. AB - The availability of the first molecular clone of the hepatitis C virus (HCV) genome allowed the identification and biochemical characterization of two viral enzymes that are targets for antiviral therapy: the protease NS3-4A and the RNA dependent RNA polymerase NS5B. With the advent of cell culture systems that can recapitulate either the intracellular steps of the viral replication cycle or the complete cycle, additional drug targets have been identified, most notably the phosphoprotein NS5A, but also host cell factors that promote viral replication, such as cyclophilin A. Here, we review insights into the structures of these proteins and the mechanisms by which they contribute to the HCV replication cycle, and discuss how these insights have facilitated the development of new, directly acting antiviral compounds that have started to enter the clinic. PMID- 23748346 TI - Protein engineering as a tool for the development of novel bioproduction systems. PMID- 23748343 TI - Fortifying the barrier: the impact of lipid A remodelling on bacterial pathogenesis. AB - Gram-negative bacteria decorate their outermost surface structure, lipopolysaccharide, with elaborate chemical moieties, which effectively disguises them from immune surveillance and protects them from the onslaught of host defences. Many of these changes occur on the lipid A moiety of lipopolysaccharide, a component that is crucial for host recognition of Gram negative infection. In this Review, we describe the regulatory mechanisms controlling lipid A modification and discuss the impact of modifications on pathogenesis, bacterial physiology and bacterial interactions with the host immune system. PMID- 23748344 TI - AKT is a therapeutic target in myeloproliferative neoplasms. AB - The majority of patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN) harbor mutations in JAK2 or MPL, which lead to constitutive activation of the JAK/STAT, PI3K and ERK signaling pathways. JAK inhibitors by themselves are inadequate in producing selective clonal suppression in MPN and are associated with hematopoietic toxicities. MK-2206 is a potent allosteric AKT inhibitor that was well tolerated, including no evidence of myelosuppression, in a phase I study of solid tumors. Herein, we show that inhibition of PI3K/AKT signaling by MK-2206 affected the growth of both JAK2V617F- or MPLW515L-expressing cells via reduced phosphorylation of AKT and inhibition of its downstream signaling molecules. Moreover, we demonstrate that MK-2206 synergizes with ruxolitinib in suppressing the growth of JAK2V617F-mutant SET2 cells. Importantly, MK-2206 suppressed colony formation from hematopoietic progenitor cells in patients with primary myelofibrosis and alleviated hepatosplenomegaly and reduced megakaryocyte burden in the bone marrows, livers and spleens of mice with MPLW515L-induced MPN. Together, these findings establish AKT as a rational therapeutic target in the MPNs. PMID- 23748345 TI - Pim kinases phosphorylate Chk1 and regulate its functions in acute myeloid leukemia. AB - Phosphorylation by Akt on Ser 280 was reported to induce cytoplasmic retention and inactivation of CHK1 with consequent genetic instability in PTEN-/- cells. In acute myeloid leukemia cells carrying the FLT3-internal tandem duplication (ITD) mutation, we observed high rates of FLT3-ITD-dependent CHK1 Ser 280 phosphorylation. Pharmacological inhibition and RNA interference identified Pim1/2, not Akt, as effectors of this phosphorylation. Pim1 catalyzed Ser 280 phosphorylation in vitro and ectopic expression of Pim1/2-induced CHK1 phosphorylation. Ser 280 phosphorylation did not modify CHK1 localization, but facilitated its cell cycle and resistance functions in leukemic cells. FLT3, PIM or CHK1 inhibitors synergized with DNA-damaging agents to induce apoptosis, allowing cells to bypass the etoposide-induced G2/M arrest. Consistently, etoposide-induced CHK1-dependent phosphorylations of CDC25C on Ser 216 and histone H3 on Thr11 were decreased upon FLT3 inhibition. Accordingly, ectopic expression of CHK1 improved the resistance of FLT3-ITD cells and maintained histone H3 phosphorylation in response to DNA damage, whereas expression of unphosphorylated Ser 280Ala mutant did not. Finally, FLT3- and Pim-dependent phosphorylation of CHK1 on Ser 280 was confirmed in primary blasts from patients. These results identify a new pathway involved in the resistance of FLT3-ITD leukemic cells to genotoxic agents, and they constitute the first report of CHK1 Ser 280 regulation in myeloid malignancies. PMID- 23748347 TI - Cell-free Biosystems in the Production of Electricity and Bioenergy. AB - : Increasing needs of green energy and concerns of climate change are motivating intensive R&D efforts toward the low-cost production of electricity and bioenergy, such as hydrogen, alcohols, and jet fuel, from renewable sugars. Cell free biosystems for biomanufacturing (CFB2) have been suggested as an emerging platform to replace mainstream microbial fermentation for the cost-effective production of some biocommodities. As compared to whole-cell factories, cell-free biosystems comprised of synthetic enzymatic pathways have numerous advantages, such as high product yield, fast reaction rate, broad reaction condition, easy process control and regulation, tolerance of toxic compound/product, and an unmatched capability of performing unnatural reactions. However, issues pertaining to high costs and low stabilities of enzymes and cofactors as well as compromised optimal conditions for different source enzymes need to be solved before cell-free biosystems are scaled up for biomanufacturing. Here, we review the current status of cell-free technology, update recent advances, and focus on its applications in the production of electricity and bioenergy. PMID- 23748348 TI - Insect-derived chitinases. AB - Insect chitinases belong to family 18 of the glycoside hydrolase superfamily (GH18) and comprise endo-splitting enzymes that retain the anomeric beta-(1,4) configuration of the cleavage products. However, some of them have lost their catalytic activity but retained the chitin binding activity and/or possess imaginal disc growth factor activity. In all sequenced insect genomes, multiple genes encode chitinases, which are differentially expressed during development and in various insect tissues. Some of them have nonredundant functions and are essential for growth and development. A characteristic property is their multidomain architecture, which comprises varying numbers of catalytic and chitin binding domains that are connected by glycosylated serine/threonine linker regions. Based on sequence similarities and domain organization, they have been classified into eight different groups. Insect chitinases have gained increasing interest for use in the biological control of parasites, fungi, and insect pests, and some enzymes have properties that make them highly attractive for biotechnological applications. PMID- 23748349 TI - Tribolium castaneum as a model for high-throughput RNAi screening. AB - Coleopteran insects are a highly diverse and successful order, and many beetle species are significant agricultural pests. New biorational strategies for managing populations of beetles and other insect species are needed as pests develop resistance to chemical insecticides and Bt toxins. There is now an opportunity to use genome sequence data to identify genes that are essential for insect growth, development, or survival as new targets for designing control technology. This goal requires a method for high-throughput in vivo screening of thousands of genes to identify candidate genes that, when their expression is disrupted, have a phenotype that may be useful in insect pest control. Tribolium castaneum, the red flour beetle, is a model organism that offers considerable advantages for such screening, including ease of rearing in large numbers, a sequenced genome, and a strong, systemic RNAi response for specific depletion of gene transcripts. The RNAi effect in T. castaneum can be elicited in any tissue and any stage by the injection of dsRNA into the hemocoel, and injection of dsRNA into adult females can even be used to identify phenotypes in offspring. A pilot RNAi screen (iBeetle) is underway. Several T. castaneum genes with promising RNAi phenotypes for further development as mechanisms for plant protection have been identified. These include heat shock protein 90, chitin synthase, the segmentation gene hairy, and a matrix metalloprotease. Candidate genes identified in T. castaneum screens can then be tested in agricultural pest species (in which screening is not feasible), to evaluate their effectiveness for use in potential plant-based RNAi control strategies. Delivery of dsRNA expressed by genetically modified crops to the midgut of phytophagous insects is under investigation as a new tool for very specific protection of plants from insect pest species. The T. castaneum screening platform offers a system for discovery of candidate genes with high potential benefit. PMID- 23748350 TI - The Red Flour Beetle Tribolium castaneum as a Model to Monitor Food Safety and Functionality. AB - : Food quality is a fundamental issue all over the world. There are two major requirements to provide the highest quality of food: having the lowest reachable concentrations of health-threatening ingredients or contaminants and having the optimal concentrations of health-improving functional ingredients. Often, the boundaries of both requirements are blurred, as might be best exemplified by nutraceuticals (enriched food products invented to prevent or even treat diseases), for which undesirable side effects have been reported sometimes. Accordingly, there is an increasing need for reliable methods to screen for health effects of wanted or unwanted ingredients in a complex food matrix before more complex model organisms or human probands become involved. In this chapter, we present the red flour beetle Tribolium castaneum as a model organism to screen for effects of complex foods on healthspan or lifespan by assessing the survival of the beetles under heat stress at 42 degrees C after feeding different diets. There is a higher genetic homology between T. castaneum and humans when compared to other invertebrate models, such as Drosophila melanogaster or Caenorhabditis elegans. Therefore, the red flour beetle appears as an interesting model to study interactions between genes and food ingredients, with relevance for stress resistance and lifespan. In that context, we provide data showing reduced lifespans of the beetles when the food-relevant contaminant benz(a)pyrene is added to the flour they were fed on, whereas a lifespan extension was observed in beetles fed on flour enriched with an extract of red wine. PMID- 23748351 TI - Product quality considerations for mammalian cell culture process development and manufacturing. AB - The manufacturing of a biologic drug from mammalian cells results in not a single substance, but an array of product isoforms, also known as variants. These isoforms arise due to intracellular or extracellular events as a result of biological or chemical modification. The most common examples related to biomanufacturing include amino acid modifications (glycosylation, isomerization, oxidation, adduct formation, pyroglutamate formation, phosphorylation, sulfation, amidation), amino acid sequence variants (genetic mutations, amino acid misincorporation, N- and C-terminal heterogeneity, clipping), and higher-order structure modifications (misfolding, aggregation, disulfide pairing). Process related impurities (HCP, DNA, media components, viral particles) are also important quality attributes related to product safety. The observed ranges associated with each quality attribute define the product quality profile. A biologic drug must have a correct and consistent quality profile throughout clinical development and scale-up to commercial production to ensure product safety and efficacy. In general, the upstream process (cell culture) defines the quality of product-related substances, whereas the downstream process (purification) defines the residual level of process- and product-related impurities. The purpose of this chapter is to review the impact of the cell culture process on product quality. Emphasis is placed on studies with industrial significance and where the direct mechanism of product quality impact was determined. Where possible, recommendations for maintaining consistent or improved quality are provided. PMID- 23748352 TI - Mammalian cell culture capacity for biopharmaceutical manufacturing. AB - : With worldwide sales of biopharmaceuticals increasing each year and continuing growth on the horizon, the manufacture of mammalian biopharmaceuticals has become a major global enterprise. We describe the current and future industry wide supply of manufacturing capacity with regard to capacity type, distribution, and geographic location. Bioreactor capacity and the use of single-use products for biomanufacturing are also profiled. An analysis of the use of this capacity is performed, including a discussion of current trends that will influence capacity growth, availability, and utilization in the coming years. PMID- 23748353 TI - Challenges in abdominal/pelvic biopsy techniques. AB - There are various methods and techniques that can be utilize for abdominal biopsy. Some of these techniques have been utilized for over four decades. However, there are different variations to these techniques that have been recently developed to increase tissue retrieval and decrease complications. This manuscript will review a number of different modifications of prior CT or ultrasound techniques utilized with either CT or ultrasound that are helpful to be more effective in tissue retrieval. Newer guidance systems including the use of contrast-enhanced sonography and multi-modality image fusion biopsy guidance are reviewed. These different techniques can increase tissues retrieval, increase accuracy of needle placement, decrease the time for the procedure, and minimize complications. PMID- 23748354 TI - Amylolytic activity and carbohydrate levels in relation to coleoptile anoxic elongation in Oryza sativa genotypes. AB - Among starchy seeds, rice has the unique capacity to germinate successfully under complete anaerobiosis. In this conditions, starch degradation is supported by a complete set of starch-degrading enzymes that are absent or inactive in cereals except rice. A characterization of carbohydrate metabolism and starch-degrading enzyme activity across twenty-nine genotypes of Oryza sativa L. is presented here. The zymogram of amylolytic activities present in rice embryos and endosperms under anaerobic conditions seven days after sowing (DAS) revealed marked differences among cultivars. Coleoptile elongation was positively correlated with total amylolytic activities and alpha-amylase activity in embryos, and negatively correlated with alpha-amylase activity in endosperm. Moreover, carbohydrate content in embryos was found to be positively correlated with total amylolytic activities under anaerobic conditions, while a negative relationship was recorded in the endosperm. Carbohydrate status in rice seedlings has a primary importance in sustaining coleoptile elongation towards the surface. The relationship between carbohydrate level in embryo and anoxic germination, as well as with total amylolytic activities present in rice embryo under anaerobic condition 7 DAS, is consistent with the role of sugar metabolism to support rice germination under oxygen-deprived environment. PMID- 23748355 TI - A vagal nerve branch controls swallowing directly in the seawater eel. AB - By developing a new in vivo method to evaluate the esophageal closure, which reflects inhibition of swallowing, we demonstrate that the vagal X1 branch projected from the glossopharyngeal-vagal motor complex (GVC) controls the upper esophageal sphincter (UES) muscle directly. Although eel vagal nerve consisted of five branches, other branches (X2, X3, X4 and X5) did not influence the esophageal pressure. When the X1 nerve branch was stimulated electrically, the balloon pressure in the UES area increased with optimum frequency of 20 Hz. Since similar optimum frequency was observed both in the pithed eel and in the isolated UES preparation, such characteristic of X1 nerve is not due to anesthetic used during experiment. As the isolated UES preparation consists of muscle cells and nerve terminals, and as the optimum frequency of the nerve terminal is identical with that of the X1 branch, it is most likely that the X1 nerve branch is identical with the nerve terminals within the UES preparation. On the other hand, since the GVC neurons fire spontaneously at around 20 Hz, the optimum frequency of 20 Hz means that the eel UES is usually closed vigorously and relaxed only when the GVC neuron is inactivated. The effect of X1 stimulation was inhibited by curare, but not by atropine, indicating that the X1 nerve branch releases acetylcholine, which acts on the nicotinic receptor on the UES striated muscle. Beside vagal nerve X1 branch, spinal nerve SN2, SN3 and SN4 also contributed to the UES closure, but SN1 did not influence the UES movement. However, since the efficacy of these spinal nerve stimulations is about 1/10 of that by vagal X1 branch, the eel UES may be controlled primarily by a vagal nerve X1 branch, and secondarily by spinal nerves (SN2, SN3 and SN4). PMID- 23748356 TI - A stereoselective approach for the southeast segment (C1-C16) of (+)-sorangicin A. AB - The stereoselective protective group-free synthesis of the C1-C16 fragment of (+) sorangicin A consisting of a dihydropyran subunit with a chiral alkyl substituent is achieved. The synthesis of the 4-stereogenic centered subunit involved key reactions such as Noyori asymmetric transfer hydrogenation, Achmatowicz oxidative rearrangement, and highly diastereoselective allylation of the Achmatowicz adduct. PMID- 23748357 TI - Reduced impurity-driven defect states in anodized nanoporous Nb2O5: the possibility of improving performance of photoanodes. AB - Anodized nanoporous Nb2O5 films are synthesized using two different types of electrolyte compositions onto transparent conductive glasses and their impurities induced during the anodization process are assessed. These films are incorporated as photoanodes in dye sensitized solar cells (DSSCs). The one with no traces of impurity-driven defects exhibits higher current density and longer electron lifetimes, and consequently, an improvement in photoconversion efficiencies compared to the one that contains impurities. PMID- 23748359 TI - Inducible knock out of pregnancy-associated plasma protein-a gene expression in the adult mouse: effect on vascular injury response. AB - Pregnancy-associated plasma protein-A (PAPP-A) enhances local IGF signaling through its ability to proteolyze inhibitory IGF binding proteins. In vivo, PAPP A (like IGF) appears to exhibit antagonistic pleiotropy; ie, it has beneficial effects early in life but detrimental effects later in life. Accordingly, PAPP-A knockout (KO) mice are born as proportional dwarfs and have diminished reproductive vigor and reduced peak bone mass acquisition at puberty. On the other hand, PAPP-A KO mice live approximately 30% longer than their wild-type littermates, with decreased incidence and severity of age-related diseases and resistance to adverse responses of vascular injury. To be able to distinguish the impact of PAPP-A deficiency in the adult from that in early life, we developed a mouse model suitable for inducible Cre recombinase-mediated excision of the PAPP A gene. In this study, we characterize the conditional PAPP-A KO mouse model for efficacy of tamoxifen-induced floxed PAPP-A excision in various tissues of adult mice and demonstrate a significant (P = .0001) reduction of neointimal formation in these mice after unilateral carotid artery ligation. PMID- 23748358 TI - FGF23 modifies the relationship between vitamin D and cardiac remodeling. AB - BACKGROUND: There is growing evidence to support an important role for vitamin D and related hormones, parathyroid hormone and fibroblast growth factor 23 (FGF23), on cardiac remodeling in chronic kidney disease. Our objective was to determine the relationships between vitamin D and cardiac remodeling in chronic kidney disease and the effects of parathyroid hormone and FGF23 on these associations. METHODS AND RESULTS: In 1431 participants from the Chronic Renal Insufficiency Cohort study, we measured 25-hydroxyvitamin D (25(OH)D), 1,25 dihydroxyvitamin D (1,25(OH)2D), FGF23, and parathyroid hormone and performed quantitative echocardiography. Using linear regression methods, we determined significant negative interactions between 25(OH)D and FGF23 on left ventricular (LV) mass (P=0.016), end-diastolic volume (P=0.029), and end-systolic volumes (P=0.021). In participants with an FGF23 level greater than the median of 123.5 RU/mL, each doubling of 25(OH)D was associated with a 2.5% (95% confidence interval, -4.8, -0.2) lower LV mass. This association was less pronounced with FGF23 levels less than the median (0.4%; 95% confidence interval, -1.9, 2.7). Conversely, in participants with deficient 25(OH)D levels <20 ng/mL, each doubling of FGF23 was associated with a 3.4% (95% confidence interval, 1.2, 5.6) greater LV mass compared with only a 1.6% (95% confidence interval, -0.2, 3.5) difference in participants with sufficient 25(OH)D. Similar findings were observed with 25(OH)D and volumes (P<0.05), and 1,25(OH)2D and LV mass and volumes (P<0.005). There was no effect modification by parathyroid hormone. CONCLUSIONS: We identified significant interactions among 25(OH)D, 1,25(OH)2D, and FGF23 on cardiac remodeling. Increased LV mass and cavity dilatation were observed with low 25(OH)D and high FGF23. Our findings suggest that consideration of both hormones is crucial to understanding the role of either in cardiac remodeling, and may have important therapeutic implications. PMID- 23748360 TI - Alteration of mitochondrial function and insulin sensitivity in primary mouse skeletal muscle cells isolated from transgenic and knockout mice: role of ogg1. AB - Recent evidence has linked mitochondrial dysfunction and DNA damage, increased oxidative stress in skeletal muscle, and insulin resistance (IR). The purpose of this study was to determine the role of the DNA repair enzyme, human 8-oxoguanine DNA glycosylase/apurinic/apyrimidinic lyase (hOGG1), on palmitate-induced mitochondrial dysfunction and IR in primary cultures of skeletal muscle derived from hind limb of ogg1(-/-) knockout mice and transgenic mice, which overexpress human (hOGG1) in mitochondria (transgenic [Tg]/MTS-hOGG1). Following exposure to palmitate, we evaluated mitochondrial DNA (mtDNA) damage, mitochondrial function, production of mitochondrial reactive oxygen species (mtROS), mitochondrial mass, JNK activation, insulin signaling pathways, and glucose uptake. Palmitate-induced mtDNA damage, mtROS, mitochondrial dysfunction, and activation of JNK were all diminished, whereas ATP levels, mitochondrial mass, insulin-stimulated phosphorylation of Akt (Ser 473), and insulin sensitivity were increased in primary myotubes isolated from Tg/MTS-hOGG1 mice compared to myotubes isolated from either knockout or wild-type mice. In addition, both basal and maximal respiratory rates during mitochondrial oxidation on pyruvate showed a variable response, with some animals displaying an increased respiration in muscle fibers isolated from the transgenic mice. Our results support the model that DNA repair enzyme OGG1 plays a pivotal role in repairing mtDNA damage, and consequently, in mtROS production and regulating downstream events leading to IR in skeletal muscle. PMID- 23748361 TI - Ablation of the androgen receptor gene modulates atrial electrophysiology and arrhythmogenesis with calcium protein dysregulation. AB - Androgen deficiency is important in the pathophysiology of atrial fibrillation. Androgen regulates cardiac electrophysiology and calcium (Ca(2+)) homeostasis. The purpose of this study is to evaluate whether androgen receptor knockout (ARKO) can modulate atrial electrophysiology and arrhythmogenesis with modulation of Ca(2+) homeostasis proteins. We used conventional microelectrodes to study the action potential (AP) in left atrium (LA) tissues prepared from wild-type (WT) and ARKO mice (aged 6-10 months) before and after the administration of isoproterenol, hypocalcemic/hypercalcemic solutions, and ouabain. Echocardiography and Western blots were used to evaluate the cardiac function and expression levels of ionic channel proteins in WT and ARKO LAs. ARKO LAs had larger LA diameter with decreased LA fractional shortening than did WT LAs. In the current study, we found that ARKO LAs had a lower negative resting membrane potential and a greater 90% AP duration (APD) than did WT LAs. Isoproterenol increased the incidence and amplitude of delayed afterdepolarizations (DADs) in ARKO LAs but not in WT LAs. Hypocalcemic solutions prolonged APD in WT and ARKO LAs but increased DAD amplitude only in ARKO LAs. Hypercalcemic solutions shortened APD in ARKO LAs but not in WT LAs. Ouabain increased DAD amplitude in ARKO LAs but not in WT LAs. ARKO LAs expressed higher amounts of Ca(2+)/calmodulin-dependent protein kinase II, Na(+)/Ca(2+) exchanger, and phosphorylated phospholamban (Ser-16/Thr-17 site) and less Cav1.2, Kir2.1, Kir3.1, and Kv7.1 than WT LAs. These observations indicate that ARKO alters atrial electrophysiology with increased atrial arrhythmogenesis. PMID- 23748362 TI - Diet-induced obesity increases tumor growth and promotes anaplastic change in thyroid cancer in a mouse model. AB - Recent epidemiological studies provide strong evidence suggesting obesity is a risk factor in several cancers, including thyroid cancer. However, the molecular mechanisms by which obesity increases the risk of thyroid cancer are poorly understood. In this study, we evaluated the effect of diet-induced obesity on thyroid carcinogenesis in a mouse model that spontaneously develops thyroid cancer (Thrb(PV/PV)Pten(+/-) mice). These mice harbor a mutated thyroid hormone receptor-beta (denoted as PV) and haplodeficiency of the Pten gene. A high-fat diet (HFD) efficiently induced the obese phenotype in Thrb(PV/PV)Pten(+/-) mice after 15 weeks. Thyroid tumor growth was markedly greater and survival was significantly lower in Thrb(PV/PV)Pten(+/-) mice fed an HFD than in controls fed a low-fat diet (LFD). The HFD increased thyroid tumor cell proliferation by increasing the protein levels of cyclin D1 and phosphorylated retinoblastoma protein to propel cell cycle progression. Histopathological analysis showed that the frequency of anaplasia of thyroid cancer was significantly greater (2.6-fold) in the HFD group than the LFD group. The HFD treatment led to an increase in parametrial/epididymal fat pad and elevated serum leptin levels in Thrb(PV/PV)Pten(+/-) mice. Further molecular analyses indicated that the HFD induced more aggressive pathological changes that were mediated by increased activation of the Janus kinase 2-signaling transducer and activator of transcription 3 (STAT3) signaling pathway and induction of STAT3 target gene expression. Our findings demonstrate that diet-induced obesity exacerbates thyroid cancer progression in Thrb(PV/PV)Pten(+/-) mice and suggest that the STAT3 signaling pathway could be tested as a potential target for the treatment of thyroid cancer. PMID- 23748363 TI - The role of urinary TGF-beta1, TNF-alpha, IL-6 and microalbuminuria for monitoring therapy in posterior urethral valves. AB - BACKGROUND: Long-term renal deterioration is common in patients with posterior urethral valves (PUV), and early identification of detrimental factors can help in counselling patients as well as in guiding future therapy. The aim of our study was (1) to evaluate urinary transforming growth factor-beta1 (TGF-beta1), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) levels and microalbuminuria before and after ablation of PUV and (2) to examine the effect of early induction of angiotensin-converting enzyme inhibitors (ACE-I) on renal recovery. METHODS: The study included 30 patients with diagnosed PUV. Urinary cytokines were measured pre-operatively and post-operatively for 1 year. The study group was subdivided into two subgroups at 6 months after surgery. Group 1 included 16 patients whose urinary TGF-beta1 level showed a declining trend. Group 2 included 14 patients whose urinary TGF-beta1 showed a rising trend or plateaued; these patients were started on ACE-I therapy, which they received for at least 6 months. RESULTS: Urinary TGF-beta1, TNF-alpha and microalbumin levels were high in patients with PUV. In Group 1 patients, urinary TGF-beta1, TNF-alpha and microalbumin levels fell significantly following valve ablation and continued to decline for 12 months. In Group 2 patients, after an initial fall following valve ablation, urinary TGF-beta1, TNF-alpha and microalbumin showed a continued rise until 6 months post-surgery. After ACE-I therapy, there was 53.43 % fall in urinary TGF-beta1, 43.15 % fall in microalbuminuria, 28.57 % improvement in split renal function and 35.80 % improvement in GFR. CONCLUSIONS: Based on our results, urinary TGF-beta1, urinary TNF-alpha and microalbuminuria can be used as biomarkers for the early recognition of ongoing renal damage in patients with PUV. ACE-I plays a role in retarding renal damage in these patients. PMID- 23748365 TI - Calcitriol treatment increases serum levels of the soluble receptor of advanced glycation end products in hemodialysis patients with secondary hyperparathyroidism. AB - Cardiovascular disease is common in the patients with end-stage renal disease, who often suffer from secondary hyperparathyroidism (SHP). Vitamin D is considered for the first-line therapy managing SHP in hemodialysis (HD) patients and has a beneficial effect in the chronic inflammation and development of cardiovascular disease. The soluble receptor for advanced glycation end products (sRAGE) may be protective by binding AGE in the pathogenesis of atherosclerotic vascular complications, whereas extracellular RAGE-binding protein (EN-RAGE) represents pro-inflammatory ligands for RAGE. We have hypothesized that vitamin D treatment may alter the levels of sRAGE and EN-RAGE in HD patients. Therefore, this prospective observational study was performed in 51 HD patients with SHP who had low serum 1,25 dihydroxyvitamin D3 (1,25D) levels and elevated intact parathyroid hormone (PTH) levels. We evaluated the changes in the values of sRAGE, EN-RAGE, and other inflammatory marker, interleukin-6 (IL-6), before and at the end of the 8-week calcitriol treatment. After calcitriol treatment, the serum levels of 1,25D were increased, whereas the serum intact PTH levels were decreased. In addition, the sRAGE levels were increased, whereas those of IL-6 were decreased after calcitriol treatment. A positive correlation between 1,25D and sRAGE levels (r = 0.609, P < 0.001) and a negative correlation between sRAGE and EN-RAGE levels (r = -0.368, P = 0.020) were detected after calcitriol treatment. This study suggests that calcitriol treatment could play an anti inflammatory role through the increasing sRAGE in HD patients with SHP. PMID- 23748364 TI - The impact of APOL1, CAV1, and ABCB1 gene variants on outcomes in kidney transplantation: donor and recipient effects. AB - Dramatic improvements have been seen in short-term kidney allograft survival over recent decades with introduction of more potent immunosuppressant medications and regimens. Unfortunately, improvements in long-term graft survival have lagged behind. The genomics revolution is providing new insights regarding the potential impact of kidney donor genotypes on long-term graft survival. Variation in the donor apolipoprotein L1 (APOL1), caveolin 1 (CAV1), and multi-drug resistance 1 encoding P-glycoprotein genes (ABCB1) are all associated with graft survival after kidney transplantation. Although the precise mechanisms whereby these donor gene variants confer risk for graft loss have yet to be determined, these findings provide novel opportunities for modifying interactive environmental factors and optimizing kidney allocation with the ultimate goal of improving long term graft survival rates. PMID- 23748367 TI - Thermodynamics of complexation reactions of borate and phenylboronate with diol, triol and tetritol. AB - In order to fully elucidate the structures and stabilities of borate and phenylboronate complexes with polyols, the complexations with 1,2-ethanediol, 1,3 propanediol, 1,2,3-propanetriol, erythritol and threitol were investigated by NMR spectroscopy and DFT calculations. For the borate, 1 : 1 complexes binding with a ligand in a monodentate manner and 1 : 2 complexes binding with one ligand in an alpha,beta- or alpha,gamma-bidentate manner and the other in a monodentate manner were identified for the first time besides the well-known 1 : 1 and 1 : 2 complexes with five- and/or six-membered chelate rings. In addition, the formations of 1 : 1 alpha,beta,delta-tridentate complexes with tetritol were confirmed. For the phenylboronate, the bidentate and tridentate complexes with 1 : 1 stoichiometries were identified. These complexations were enthalpy-driven processes accompanied by a negative entropic contribution. Linear enthalpy entropy compensation relationships were observed for the stepwise complexations of borate and phenylboronate to form a five- or six-membered chelate ring. The TDeltaS degrees vs. DeltaH degrees plots gave three different straight lines in parallel with one another depending on the number of OH groups outside the chelate ring. For the second intramolecular chelation to form the alpha,beta,delta-tridentate complex from the alpha,beta- or alpha,gamma-bidentate complex with tetritol, the TDeltaS degrees vs. DeltaH degrees plots gave different straight lines for the borate and phenylboronate, being more favorable in enthalpy for the phenylboronate. PMID- 23748366 TI - Contractor-, steward-, and coworker-safety practice: associations with musculoskeletal pain and injury-related absence among construction apprentices. AB - OBJECTIVES: This paper sought to assess organizational safety practices at three different levels of hierarchical workplace structure and to examine their association with injury outcomes among construction apprentices. METHODS: Using a cross-sectional sample of 1,775 construction apprentices, three measures of organizational safety practice were assessed: contractor-, steward-, and coworker safety practice. Each safety practice measure was assessed using three similar questions (i.e., on-the-job safety commitment, following required or recommended safe work practices, and correcting unsafe work practices); the summed average of the responses ranged from 1 to 4, with a higher score indicating poorer safety practice. Outcome variables included the prevalence of four types of musculoskeletal pain (i.e., neck, shoulder, hand, and back pain) and injury related absence. RESULTS: In adjusted analyses, contractor-safety practice was associated with both hand pain (OR: 1.27, 95 % CI: 1.04, 1.54) and back pain (OR: 1.40, 95 % CI: 1.17, 1.68); coworker-safety practice was related to back pain (OR: 1.42, 95 % CI: 1.18, 1.71) and injury-related absence (OR: 1.36, 95 % CI: 1.11, 1.67). In an analysis that included all three safety practice measures simultaneously, the association between coworker-safety practice and injury related absence remained significant (OR: 1.68, 95 % CI: 1.20, 2.37), whereas all other associations became non-significant. CONCLUSIONS: This study suggests that organizational safety practice, particularly coworker-safety practice, is associated with injury outcomes among construction apprentices. PMID- 23748368 TI - Synthesis, characterization and biological evaluation of some novel P heterocyclic androst-4-ene derivatives. AB - The reactions of 21-hydroxyprogesterone with Lawesson's reagent in toluene or [Formula: see text] gave four P-heterocyclic androst-4-ene derivatives (two tautomeric pairs): 4-(3-thioxoandrost-4-en-17[Formula: see text]-yl)-1,3,2 oxathiaphosphole-2- sulfide (2), 4-(3-thioxoandrost-4-en-17[Formula: see text] ylidene)-1,3,2-oxathiaphospholane-2-sulfide (3), 4-(3-oxoandrost-4-en-17[Formula: see text]-yl)-1,3,2-oxathiaphosphole-2-sulfide (4), and 4-(3-oxoandrost-4-en 17[Formula: see text]-ylidene)-1,3,2- oxathiaphospholane-2-sulfide (5). The structures of all novel 17-substituted steroids were elucidated from their analytic and spectral data (HRMS, IR, 1D NMR and 2D NMR-HSQC, HMBC, NOESY, COSY). The detailed NMR analysis for all compounds revealed the presence of two pairs of signals in approx. 8:2 ratio indicating the existence of two diastereoisomers (a and b) with different configurations at the phosphorus atom. A parallel analysis of heteronuclear 2D [Formula: see text]-[Formula: see text] spectra (HSQC and HMBC) and homonuclear 2D spectra (NOESY and COSY) enabled complete [Formula: see text] and [Formula: see text] assignments of each isomer and provided evidence for the preferred configuration on phosphorus atom. Cytotoxic activity in vitro was tested against four tumor cell lines (human cervix carcinoma HeLa cells, chronic myelogenous leukemia K-562 and two human breast carcinoma MDA-MB-361 and MDA-MB-453 cells). Compounds 3a,b and 4a,b showed a poor activity against HeLa and MDA-MB-453 cell lines, while against MDA-MB-361 cell line, all tested compounds exerted very weak cytotoxic effect. All compounds exerted moderate activity against K562 cells. Antimicrobial activity against Gram-positive, Gram negative bacteria and fungal cells, and toxicity to brine shrimp Artemia salina were evaluated. All tested compounds showed strong antifungal activity. PMID- 23748369 TI - Image quality and radiation dose of 128-slice dual-source CT venography using low kilovoltage combined with high-pitch scanning and automatic tube current modulation. AB - To compare vascular enhancement, image quality, and radiation dose of 128-slice dual-source CT venography (CTV) between an imaging setting of 120 kVp with low pitch, and a setting of 100 kVp combined with high pitch and automatic tube current modulation. A total of 100 patients with suspected deep vein thrombosis and varicose veins were divided into two groups: Group 1 [50 patients, 120 kVp, low pitch (0.6), and fixed 120 mA) and Group 2 (50 patients, 100 kVp, high pitch (3.0), and automatic tube current modulation]. Two radiologists, who were blinded to the image protocol, assessed vascular enhancement and image noise in the inferior vena cava (IVC), femoral vein, and popliteal vein. They also assigned an image quality score independently using a 5-point visual scale. Effective dose was estimated using the dose-length product (DLP). Group demographics, radiation dose, vascular enhancement, image noise, and image quality in the two groups were analyzed. Mean vascular enhancement of the IVC, femoral vein, and popliteal vein was significantly higher in group 2 than in group 1, and images in group 2 had significantly higher image noise. However, there were no significant differences in subjective image quality score of the IVC, femoral vein, and popliteal vein. The mean DLP in group 2 (402.10 +/- 94.29 mGy cm) was significantly lower than that in group 1 (973.36 +/- 63.20 mGy cm) (P < 0.001). Lower extremity CTV using 100 kVp, high pitch (3.0), and automatic tube current modulation improved vascular enhancement with acceptable image quality and low radiation dose. PMID- 23748371 TI - Subtypes of bicuspid aortic valves in coarctation of the aorta. AB - Bicuspid aortic valves (BAVs) represent a wide morphologic and functional spectrum. In coarctation of the aorta, BAVs are common, but the proportion of BAV subtypes and their relation to aortic dimensions and development of late valve dysfunction are unknown. Sixty-two cardiovascular magnetic resonance investigations of patients with coarctation of the aorta were reviewed with respect to aortic valve morphology, aortic valve function, and aortic dimensions. BAVs were identified in 45 patients (72.6%), of which 13 (20.9%) were type-0 (two commissures), 28 (45.1%) type-1 (three commissures but fusion of one commissure with a raphe) and 4 (6.5%) valves were bicuspid but not possible to classify further. Patients with BAVs type-0 had larger dimensions in their sinus of Valsalva (35.5 +/- 6.8 vs. 29.7 +/- 2.7 mm, p = 0.002), ascending aorta (33.1 +/- 6.2 vs. 26.0 +/- 4.3 mm, p = 0.005) and sino-tubular junction (29.3 +/- 7.4 vs. 24.2 +/- 3.5 mm, p = 0.040) compared with tricuspid aortic valves (TAVs). Moderate and severe aortic valve disease was more common in BAV type-0 compared with BAV type-1 (p = 0.030) and TAV (p = 0.016). In a multivariate linear regression model BAV type-0 (p = 0.005), BAV type-1 (p = 0.011), age (p < 0.001), patient height (p = 0.009), and aortic valve disease (p = 0.035) were independently associated with increased diameter of the ascending aorta (R (2) of the model 0.54, p < 0.001). BAV type-0 is relatively common in coarctation of the aorta. Both BAV type-0 and type-1 are associated with increased diameter of the ascending aorta but this association is stronger for BAV type-0. Development of aortic valve disease is more common in BAV type-0 than in BAV type-1. Discrimination between BAV subtypes may potentially provide clinical and prognostic information in patients with coarctation of the aorta. PMID- 23748372 TI - Genetic differentiation in Elaeocarpus photiniifolia (Elaeocarpaceae) associated with geographic distribution and habitat variation in the Bonin (Ogasawara) Islands. AB - Gene flow between populations in different environmental conditions can be limited due to divergent natural selection, thus promoting genetic differentiation. Elaeocarpus photiniifolia, an endemic tree species in the Bonin Islands, is distributed in two types of habitats, dry scrubs and mesic forests. We aim to elucidate the genetic differentiation in E. photiniifolia within and between islands and between the habitat types. We investigated genotypes of 639 individuals from 19 populations of E. photiniifolia and its closely-related E. sylvestris at 24 microsatellite loci derived from expressed sequence tags. The data revealed genetic differentiation (1) between E. photiniifolia and E. sylvestris (0.307 <= F ST <= 0.470), (2) between the E. photiniifolia populations of the Chichijima and Hahajima Island Groups in the Bonin Islands (0.033 <= F ST <= 0.121) and (3) between E. photiniifolia populations associated with dry scrubs and mesic forests in the Chichijima Island Group (0.005 <= F ST <= 0.071). Principal coordinate analysis and Bayesian clustering analysis also showed that genetically distinct groups were associated with the habitat types, and isolation by distance was not responsible for the genetic differentiation. These findings suggest that E. photiniifolia is divided into genetically differentiated groups associated with different environmental conditions in the Bonin Islands. PMID- 23748373 TI - Evaluation of the psychometric properties of the Greek version of the Minnesota Living With Heart Failure questionnaire. AB - PURPOSE: One of the major challenges for health care professionals in heart failure (HF) management is to maintain and/or improve HF patient health-related quality of life. The Minnesota Living With Heart Failure Questionnaire (MLHFQ) is one of the most comprehensive and widely used tools for measuring health-related quality of life among patients with HF. The aim of the study was to assess the psychometric properties of the Greek version of the tool. METHODS: The MLHFQ was administered among 128 Greek-Cypriot HF patients to assess the internal consistency, content validity, and contrast validity of its Greek version. Exploratory factor analysis was undertaken to establish its construct validity. RESULTS: The factor analysis in this study provided support for a 3-factor solution explaining 64.15% of the variance (physical, emotional, and social subscales). The internal consistency for the Greek version of the MLHFQ total scale (0.95) and subscales (0.80-0.94) were found to be high. The contrast validity of the Greek version of the MLHFQ was explored through cumulative MLHFQ scores and comparisons that were able to distinguish among all different levels of HF severity, as defined by the New York Heart Association functional class grouping. CONCLUSION: This study provides support for the reliability and validity of the Greek version of the MLHFQ. PMID- 23748375 TI - Metabolic disease and participant age are independent predictors of response to pulmonary rehabilitation. AB - PURPOSE: The study aims were (1) to determine whether baseline measures-including the Body Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity (BODE) index; Age, Dyspnea, and Airflow Obstruction (ADO) index; physical activity; comorbidities (cardiac, metabolic, or musculoskeletal disease); and the number of hospitalizations over the previous 12 months-can predict responders in 6-minute walk distance (6MWD) following pulmonary rehabilitation (PR) and (2) to determine whether different methods in defining improvement in 6MWD affected identifying responders to PR. METHODS: All participants with chronic obstructive pulmonary disease who attended PR at our institution between 2004 and 2009 were evaluated. A participant was classified as a responder with improvement in 6MWD (>=25 m or >=2 SD of this dataset coefficient of repeatability). RESULTS: A total of 203 participants (mean age, 68.2 +/- 8.7 years; mean predicted forced expiratory volume in 1 second, 52.5 +/- 22.4%) were analyzed. One hundred twenty participants (59.1%) had a comorbidity categorized as cardiac, metabolic, or musculoskeletal disease. The binary logistic regression models showed that younger participants (P <= .015) and, when using the coefficient of repeatability method (>=60.9 m), participants with metabolic disease (P = .040) were the only independent predictors of response. No other measure, including participant BODE or ADO index scores, contributed to either model. CONCLUSION: Identifying responders in exercise capacity following PR remains difficult, with only age and participants with metabolic disease identified as independent predictors. PMID- 23748374 TI - Caloric restriction: implications for human cardiometabolic health. AB - PURPOSE: While the impact of caloric restriction on human health is not fully understood, there is strong evidence to support further studies of its influence on cardiovascular health. The purpose of this review was to update the state of the science by examining the relevant literature regarding calorie-restriction effects on aging and cardiovascular health and to discuss the possible role(s) of calorie restriction in preserving cardiovascular function in humans. METHODS: For purpose of this review, we have defined calorie restriction as a reduction in energy intake well below the amount of calories that would be consumed ad libitum (>=10% in humans, >=20% in animals). We examined the relevant literature on calorie-restriction effects on longevity and cardiovascular health, with an emphasis on the state of the science regarding calorie restriction in humans. We have emphasized the importance of the preliminary and expected findings from the Comprehensive Assessment of the Long-term Effect of Reducing Intake of Energy trial. RESULTS: Evidence from animal studies and a limited number of human trials indicates that calorie restriction has the potential to both delay cardiac aging and help prevent atherosclerotic cardiovascular disease via beneficial effects on blood pressure, lipids, inflammatory processes, and potentially other mechanisms. CONCLUSIONS: On the basis of its known benefits to cardiometabolic health, including modest calorie restriction in a combined lifestyle program is likely to improve heart health and prevent subsequent cardiovascular events in overweight and obese individuals. Additional study is needed to further illuminate its long term applicability for older adults and for those with significant comorbidities, such as heart failure. PMID- 23748376 TI - Correlation of early functional capacity with biventricular function and residual pulmonary artery hypertension following mitral valve replacement surgery. AB - PURPOSE: To evaluate the functional capacity following mitral valve replacement in the early postoperative period and to determine the correlation of biventricular function and residual pulmonary artery hypertension (PAH) to the functional capacity. METHODS: On the seventh postoperative day, 53 patients who underwent mitral valve replacement with preoperative diagnosis of PAH underwent a 2-dimensional echocardiographic and Doppler examination for the assessment of right ventricular systolic pressure, along with right ventricular (RV) and left ventricular (LV) myocardial performance indices (MPIs). These assessments were followed by a 6-Minute Walk Test. Five patients were eventually withdrawn from the study. RESULTS: The diminished functional capacity (51.6% +/- 4.1% of predicted 6-Minute Walk Test distance for age, gender, weight, and height) significantly correlated with biventricular dysfunction evident from elevated RVMPI (0.35 +/- 0.09) and LVMPI (0.52 +/- 0.11) (for both Ps <= .001). Furthermore, the residual PAH, with mean right ventricular systolic pressure of 37 +/- 11 mm Hg, showed negative correlation with the functional capacity (P <= .001). In addition, LVMPI had strong association with RVMPI (P <= .001). Linear regression analysis demonstrated that LVMPI and right ventricular systolic pressure were independent predictors of functional capacity. CONCLUSIONS: The RV and LV function, as quantified by MPI, and the degree of residual PAH are associated with functional capacity impairment after mitral valve replacement, with LVMPI and residual PAH as the independent predictorsqbetween RV and LV performance indices indicate that ventricular interactions contribute to the functional capacity impairment in these patients. PMID- 23748377 TI - Evidence for surfactant production by the haloarchaeon Haloferax sp. MSNC14 in hydrocarbon-containing media. AB - The potential for surfactant production by the extreme halophilic archaeon Haloferax sp. MSNC14 in the presence of individual hydrocarbon substrates was studied. This strain was selected for its ability to grow on different types of hydrocarbons at high NaCl concentrations. Linear (n-heptadecane or C17) and isoprenoid (pristane) alkanes, a polyaromatic hydrocarbon (phenanthrene) and ammonium acetate (highly water-soluble control compound) were used as growth substrates. The adherence potential was demonstrated by the ability of the cells to adhere to liquid or solid hydrocarbons. The biosurfactant production was indicated by the reduction of the surface tension (ST) and by the emulsification activity (EA) of cell-free supernatants. Growth on acetate was accompanied by a low EA (lower than 0.1) and a high ST (~70 mN/m), whereas an important EA (up to 0.68 +/- 0.08) and a reduction of ST (down to 32 +/- 2.3 mN/m) were observed during growth on the different hydrocarbons. Both ST and EA varied with the growth phase. The adhesion to hydrocarbons was higher when cells were grown on C17 (by 60-70 %) and pristane (by 30-50 %) than on phenanthrene (~25 %). The results demonstrated that strain MNSC14 was able to increase the bioavailability of insoluble hydrocarbons, thus facilitating their uptake and their biodegradation even at high salt concentration. PMID- 23748378 TI - Molecular dissection of human Argonaute proteins by DNA shuffling. AB - A paramount task in RNA interference research is to decipher the complex biology of cellular effectors, exemplified in humans by four pleiotropic Argonaute proteins (Ago1-Ago4). Here, we exploited DNA family shuffling, a molecular evolution technology, to generate chimeric Ago protein libraries for dissection of intricate phenotypes independently of prior structural knowledge. Through shuffling of human Ago2 and Ago3, we discovered two N-terminal motifs that govern RNA cleavage in concert with the PIWI domain. Structural modeling predicts an impact on protein rigidity and/or RNA-PIWI alignment, suggesting new mechanistic explanations for Ago3's slicing deficiency. Characterization of hybrids including Ago1 and Ago4 solidifies that slicing requires the juxtaposition and combined action of multiple disseminated modules. We also present a Gateway library of codon-optimized chimeras of human Ago1-Ago4 and molecular evolution analysis software as resources for future investigations into RNA interference sequence structure-function relationships. PMID- 23748379 TI - A bacterial-like mechanism for transcription termination by the Sen1p helicase in budding yeast. AB - Transcription termination is essential to generate functional RNAs and to prevent disruptive polymerase collisions resulting from concurrent transcription. The yeast Sen1p helicase is involved in termination of most noncoding RNAs transcribed by RNA polymerase II (RNAPII). However, the mechanism of termination and the role of this protein have remained enigmatic. Here we address the mechanism of Sen1p-dependent termination by using a highly purified in vitro system. We show that Sen1p is the key enzyme of the termination reaction and reveal features of the termination mechanism. Like the bacterial termination factor Rho, Sen1p recognizes the nascent RNA and hydrolyzes ATP to dissociate the elongation complex. Sen1p-dependent termination is highly specific and, notably, does not require the C-terminal domain of RNAPII. We also show that termination is inhibited by RNA-DNA hybrids. Our results elucidate the role of Sen1p in controlling pervasive transcription. PMID- 23748380 TI - Structural mimicry in transcription regulation of human RNA polymerase II by the DNA helicase RECQL5. AB - RECQL5 is a member of the highly conserved RecQ family of DNA helicases involved in DNA repair. RECQL5 interacts with RNA polymerase II (Pol II) and inhibits transcription of protein-encoding genes by an unknown mechanism. We show that RECQL5 contacts the Rpb1 jaw domain of Pol II at a site that overlaps with the binding site for the transcription elongation factor TFIIS. Our cryo-EM structure of elongating Pol II arrested in complex with RECQL5 shows that the RECQL5 helicase domain is positioned to sterically block elongation. The crystal structure of the RECQL5 KIX domain reveals similarities with TFIIS, and binding of RECQL5 to Pol II interferes with the ability of TFIIS to promote transcriptional read-through in vitro. Together, our findings reveal a dual mode of transcriptional repression by RECQL5 that includes structural mimicry of the Pol II-TFIIS interaction. PMID- 23748381 TI - Compensation predicts smoking cessation failure. AB - RATIONALE: Compensation is a potential result of decreasing the available nicotine and tar dose in cigarettes. There is little published data linking compensation with cessation. OBJECTIVES: We sought to examine whether compensation in response to restricted cigarette yield is associated with difficulty quitting smoking. METHODS: Questionnaires and blood samples were collected from 174 smokers interested in quitting smoking as part of a larger smoking cessation study. Participants were instructed to use a filter designed to remove 50 % of tar and nicotine from the cigarette but otherwise smoke normally. Participants returned after 3 days of using the filter for follow-up data collection. RESULTS: Nicotine levels and cigarettes per day decreased after use of the filter. Baseline nicotine and change in nicotine pre/post filter use, but not cigarettes per day or change in cigarettes per day were associated with smoking abstinence at 30 days. CONCLUSIONS: Smokers who demonstrate sensitivity to the biological or behavioral consequences of decreased nicotine content in tobacco smoke have greater difficulty quitting. These findings suggest the need for personalized cessation treatment linked to behavioral compensation. PMID- 23748382 TI - Effects of the adenosine A2A antagonist istradefylline on cognitive performance in rats with a 6-OHDA lesion in prefrontal cortex. AB - RATIONALE: Altered cognitive function is a common feature of both the early and later stages of Parkinson's disease (PD) that involves alterations in cortical dopamine content. Adenosine A2A antagonists, such as istradefylline, improve motor function in PD, but their effect on cognitive impairment has not been determined. OBJECTIVE: The present study investigated whether impairment of working memory due to the loss of dopaminergic input into the prefrontal cortex (PFC) is reversed by administration of istradefylline. We also evaluated whether A2A antagonist administration modulates dopamine levels in the PFC. METHODS: Bilateral lesions of the dopaminergic input to the PFC were produced in rats using 6-hydroxydopamine (6-OHDA). Cognitive performance was evaluated using an object recognition task and delayed alternation task. The effects of istradefylline, donepezil and methamphetamine on cognitive performance were examined. In addition, the effect of istradefylline on extracellular dopamine levels in the PFC was studied. RESULTS: PFC dopamine levels and cognitive performance were significantly reduced by 6-OHDA lesioning. Istradefylline, donepezil and methamphetamine improved cognitive performance of PFC-lesioned rats. Istradefylline increased dopamine levels in the PFC in both normal and PFC lesioned rats. CONCLUSIONS: PFC dopaminergic input plays an important role in working memory performance. Blockade of A2A receptors using istradefylline reverses the changes in cognitive function, and this may be due to an increase in PFC dopamine content. Adenosine A2A receptor antagonists not only improve motor performance in PD but may also lead to improved cognition. PMID- 23748384 TI - Sleep parameters in rhesus monkeys by using actigraphy. PMID- 23748383 TI - Methamphetamine-induced increases in putamen gray matter associate with inhibitory control. AB - RATIONALE: Problematic drug use is associated with difficulty in exerting self control over behaviors, and this difficulty may be a consequence of atypical morphometric characteristics that are exhibited by drug-experienced individuals. The extent to which these structural abnormalities result from drug use or reflect neurobiological risk factors that predate drug use, however, is unknown. OBJECTIVES: The purpose of this study is to determine how methamphetamine affects corticostriatal structure and how drug-induced changes relate to alterations in inhibitory control. METHODS: Structural magnetic resonance images and positron emission tomography (PET) scans, assessing dopamine D2-like receptor and transporter availability, were acquired in monkeys trained to acquire, retain, and reverse three-choice visual discrimination problems before and after exposure to an escalating dose regimen of methamphetamine (or saline, as a control). Voxel based morphometry was used to compare changes in corticostriatal gray matter between methamphetamine- and saline-exposed monkeys. The change in gray matter before and after the dosing regimen was compared to the change in the behavioral performance and in dopaminergic markers measured with PET. RESULTS: Methamphetamine exposure, compared to saline, increased gray matter within the right putamen. These changes were positively correlated with changes in performance of methamphetamine-exposed monkeys in the reversal phase, and were negatively correlated with alterations in D2-like receptor and DAT availability. CONCLUSIONS: The results provide the first evidence that exposure to a methamphetamine dosing regimen that resembles human use alters the structural integrity of the striatum and that gray-matter abnormalities detected in human methamphetamine users are due, at least in part, to the pharmacological effects of drug experience. PMID- 23748385 TI - Early language profiles in infants at high-risk for autism spectrum disorders. AB - Many preschoolers with autism spectrum disorders (ASD) present relative lack of receptive advantage over concurrent expressive language. Such profile emergence was investigated longitudinally in 54 infants at high-risk (HR) for ASD and 50 low-risk controls, with three language measures taken across four visits (around 7, 14, 24, 38 months). HR infants presented three outcome subgroups: ASD, other atypicality, and typical development. Reduced receptive vocabulary advantage was observed in HR infants by 14 months, but was maintained to 24 months only in ASD/other atypicality outcome subgroups while typically-developing HR infants regained a more normative profile. Few group differences appeared on a direct assessment of language and parent-reported functional communication. Processes of early development toward ASD outcome and in intermediate phenotypes are discussed. PMID- 23748387 TI - The path towards perfect practice. PMID- 23748386 TI - The Autism Impact Measure (AIM): initial development of a new tool for treatment outcome measurement. AB - The current study describes the development and psychometric properties of a new measure targeting sensitivity to change of core autism spectrum disorder (ASD) symptoms, the Autism Impact Measure (AIM). The AIM uses a 2-week recall period with items rated on two corresponding 5-point scales (frequency and impact). Psychometric properties were examined using a large sample (n = 440) of children with ASD enrolled in the Autism Treatment Network. The exploratory factor analysis indicated four factors and resulted in a 25-item questionnaire with excellent overall model fit. Test-retest reliability, cross-informant reliability, and convergent validity with other measures of ASD symptoms and overall functioning were strong. The AIM is a reliable and valid measure of frequency and impact of core ASD symptoms. PMID- 23748388 TI - The public health implications of secondary measles vaccine failure. PMID- 23748389 TI - Previous vaccination modifies both the clinical disease and immunological features in children with measles. AB - INTRODUCTION: Measles that develops in previously vaccinated cases has been reported to be associated with modified disease, although severity has usually been assessed by the presence or absence of symptoms. To date no studies have attempted to subjectively grade the severity of the clinical features. AIM: To investigate both the objective and subjective severity of measles in vaccinated and unvaccinated cases in the context of a community outbreak. METHODS: A retrospective observational cohort study conducted in Christchurch in 2009 using notified data compared the presentation of measles in 14 confirmed cases that had received at least one MMR (measles, mumps, rubella) vaccination and 14 age matched unvaccinated confirmed cases. Additional details on the subjective and objective severity of the illness were obtained from parents/guardians using a standardised telephone questionnaire. RESULTS: The vaccinated group had significantly fewer clinical features on presentation (p=0.01, RR=1.3, 95% CI 1.1 1.6) and a less severe illness objectively, as measured by height and duration of fever, the number of days needing medication other than paracetamol and days required in bed. Unvaccinated cases were 2.8 times more likely to have more severe clinical features than vaccinated cases (OR=2.8, 95% CI 1.5-5.0). Unvaccinated cases were 3.0 times more likely to develop IgM antibody (RR=3.0, 95% CI 0.9-9.3). DISCUSSION: Previously vaccinated children who develop measles are likely to have less severe disease and serology results that may be inconclusive, particularly for IgM antibody if tested in the first few days after the rash onset. PMID- 23748390 TI - The impact of patient and practice characteristics on retention in the diabetes annual review programme. AB - INTRODUCTION: Despite more than 10 years of the diabetes annual review (DAR) programme, ensuring the annual return of diabetic patients for review remains a challenge for primary care. Regardless of future arrangements for diabetes review programmes, regular review of patients remains clinically important. AIM: To investigate the effect of patient and practice characteristics on the retention of patients continuously enrolled with the same practice in the DAR programme. METHODS: We undertook a retrospective, observational study of a cohort of enrolled diabetic patients who had a DAR in the July 2006 - June 2007 reporting year and remained enrolled with the same practice for the following three years. Controlling for death and migration, retention rates were calculated for age, gender, ethnicity, rurality, practice funding type and practice nurse (PN) to general practitioner (GP) ratio. RESULTS: The study included data from 78 practices and 6610 patients with Type 2 diabetes. Non-Maori and those aged 60 years and over were more likely to be retained in the programme. For practice factors, those with a higher PN to GP ratio had a significant retention advantage. Rurality and funding type was not shown to have a significant role in retention. DISCUSSION: Results support the view that both patient and practice factors influence a patient's retention within the DAR programme. The PN to GP ratio may be an important factor in the retention of patients in a DAR programme and warrants further research and consideration when planning future primary care models. PMID- 23748391 TI - Mental health promotion for gay, lesbian, bisexual, transgender and intersex New Zealanders. AB - INTRODUCTION: A number of studies have identified that gay, lesbian, bisexual, transgender, and intersex (GLBTI) people have poorer mental health than the general population. This article describes current mental health promotion and service provision for GLBTI people in New Zealand, and the views of stakeholders on current service delivery and concerns facing the sector. METHODS: An email survey of service providers gathered descriptive data about mental health promotion and services provided for GLBTI people. Data obtained from interviews with key informants and online submissions completed by GLBTI individuals were analysed thematically. FINDINGS: Five organisations provide clear, specific and utilised services and programmes to some or all of the GLBTI populations. Twelve GLBTI-focused mental health promotion resources are identified. The analysis of data from key informants and GLBTI respondents identified factors affecting mental health for these populations occurring at three levels-macro-social environment, social acceptance and connection, and services and support. CONCLUSION: While GLBTI individuals have the same basic mental health promotion and service provision needs as members of the general population, they have additional unique issues. To enhance the mental health of GLBTI New Zealanders, a number of actions are recommended, including building sector capacity, allocating sufficient funding, ensuring adequate research and information is available, and reducing stigma, enhancing young people's safety, and supporting practitioners through training and resources. An important role for government, alongside GLBTI input, for improving mental health is noted. PMID- 23748392 TI - Understanding barriers to glycaemic control from the patient's perspective. AB - INTRODUCTION: To better understand barriers to glycaemic control from the patient's perspective. METHODS: An interpretative phenomenological approach was used to study the experiences of 15 adults with Type 2 diabetes. Participants each gave a semi-structured interview of their experiences of living with diabetes. Interviews were transcribed, and themes extracted and organised using a patientcentred framework. FINDINGS: Participants' stories confirmed many of the barriers in the literature, particularly those related to context, such as family, finances, work. Barriers also related to negative emotional reactions to diabetes: fear of new events (diagnosis, starting pills/insulin); guilt about getting diabetes and not controlling it; and shame about having diabetes. Barriers also related to unscientific beliefs and personal beliefs. There were additional barriers related to poor clinician-patient relationships. Overall, participants had a poor understanding of diabetes, and complained that their clinician simply 'told them what to do'. CONCLUSION: Using a patient-centred approach, this study identified many barriers to glycaemic control. We suggest that a key barrier is clinician ignorance of their patients' fears, beliefs, expectations, context; of what constitutes a positive therapeutic relationship; and of the limitations of a biomedical approach to patient non-adherence. Faced with both a worsening diabetes epidemic and increasing health care workforce shortages, clinicians urgently need to understand that it is they, not their patients, who must change their approach if diabetes care is to be improved. PMID- 23748393 TI - Miscommunication between patients and general practitioners: implications for clinical practice. AB - INTRODUCTION: Effective communication is integral to the general practice consultation, yet it is acknowledged that problems commonly occur. Previous research has shown that misunderstandings with potentially significant consequences occur frequently, but does not provide a clear picture of how and why miscommunication occurs, or how such problems can be prevented or resolved. This study explored the occurrence and management of specific examples of miscommunication in two routine general practice consultations. METHODS: A multi method case study approach was used. The primary data collected for each case included a video-recorded consultation and post-consultation interviews with each general practitioner (GP) and patient. Instances of communication mismatch were examined using in-depth interaction analysis techniques. FINDINGS: GPs and patients may not be aware when misunderstandings have occurred. In-depth analysis of the case studies revealed the complexity of miscommunication: it was not a straightforward matter to locate when or why instances of communication mismatch had occurred, and each of the mismatches was quite distinctive: (1) they were identified in different ways; (2) they occurred at different points in the communication process; (3) they arose because of problems occurring at different levels of the communication, and (4) they had different consequences. CONCLUSION: Given the frequency and complexity of miscommunication in general practice consultations, GPs need to consider adopting various strategies, at both the practice/systems level and the level of the consultation interaction to minimise the risk of communication problems. PMID- 23748394 TI - Is it time to talk? Interpreter services use in general practice within Canterbury. AB - INTRODUCTION: Effective communication is fundamental to successful health care service delivery, and has a positive impact on access, quality of care, health outcomes, and patient satisfaction. Although there are a growing number of New Zealanders who do not speak English proficiently, underutilisation of trained interpreter services appears to be common in primary health care settings. AIMS: To describe the pattern of interpreter service need and utilisation by general practice services, and to identify key barriers and enabling factors to the use of trained interpreters. METHODS: A mixed methods study was employed. Census and Partnership Health Canterbury Te Kei o Te Waka (PHC) databases were combined, and quantitative analysis used to derive interpreter service need and utilisation patterns. Transcripts of focus groups and interviews from general practitioners, practice nurses and practice administration staff within the PHC were analysed, using qualitative methods to identify barriers and enablers to interpreter service use. RESULTS: For the years 2008-2010, approximately 10 742 consultations per year involved a non-Englishspeaking patient, yet in only approximately 74.8 (0.7%) consultations per year were interpreter services utilised. Analysis of focus groups and interviews identified four global themes that represented barriers for interpreter service utilisation; namely, practicalities, expectations, knowledge of service, and systems. DISCUSSION: The current use of interpreter services in PHC general practice appears to be significantly less than the need. In order to maximise health outcomes and reduce risk, strategies must be initiated to counter the barriers currently inhibiting interpreter service use, including adopting best practice policies. PMID- 23748395 TI - Transient ischaemic attack and stroke risk: pilot of a primary care electronic decision support tool. AB - INTRODUCTION: Transient ischaemic attacks (TIAs) indicate high risk for stroke and rapid management reduces stroke burden. Rapid specialist access to initiate timely management is often challenging to achieve. AIM: To assess the feasibility of implementing a TIA/Stroke electronic decision support (EDS) tool intended to aid general practitioners (GPs) in the timely management of TIAs. METHODS: An eight-week pilot provided access to the TIA/Stroke EDS to selected GPs in the MidCentral district, with subsequent patient record review and a post-pilot user satisfaction survey. RESULTS: Eleven patients from eight practices were entered into the tool and when EDS-rendered advice was followed, diagnosis was accurate and management was in accordance with New Zealand TIA guidelines. No adverse outcomes resulted and user feedback was positive. DISCUSSION: Results indicate that wider implementation of the TIA/Stroke EDS tool is feasible. PMID- 23748396 TI - Large increase in opportunistic testing for chlamydia during a pilot project in a primary health organisation. AB - INTRODUCTION: The Auckland chlamydia pilot project was one of three funded by the Ministry of Health to trial implementation of the 2008 Chlamydia Management Guidelines. Chlamydia is the most commonly notified sexually transmitted infection in New Zealand. AIM: To increase opportunistic testing in under-25-year olds and to improve documentation of partner notification in primary care. METHODS: A four-month pilot was initiated in Total Healthcare Otara using a nurse led approach. Laboratory testing data was analysed to assess whether the pilot had any impact on chlamydia testing volumes in the target age-group. Data entered in the practice management system was used to assess follow-up and management of chlamydia cases. RESULTS: During the pilot there was a 300% increase in the number of chlamydia tests in the target age group from 812 to 2410 and the number of male tests increased by nearly 500%. Twenty-four percent of people tested were positive for chlamydia, with no significant difference in prevalence by ethnicity. The pilot resulted in better documentation of patient follow-up in the patient management system. DISCUSSION: There was a large increase in chlamydia testing during the pilot with a high prevalence found in the population tested. Chlamydia remains an important health problem in New Zealand. The cost benefit of increased chlamydia screening at a population level has yet to be established. PMID- 23748397 TI - Personal medicines storage in New Zealand. AB - INTRODUCTION: Poor storage of medicines can reduce their efficacy, yet little is known about how people store medicines in their homes and elsewhere, why these locations are chosen, and whether the conditions are suitable for medicines storage. AIM: To investigate where medicines are commonly stored in New Zealand households, why, and the typical conditions-temperature and relative humidity-in those places of storage. METHODS: Data from a large qualitative study on the meanings of medicines were analysed to explore where people store medicines in their households, and why. A data logger was used to log temperature and relative humidity in common medicine storage places, such as homes and cars. RESULTS: Kitchens and bathrooms were the most commonly reported storage places, with people influenced by convenience, desire to remember to take medicines, and child safety when deciding where to store medicines. High temperatures and humidity were found in kitchens and bathrooms, extreme temperatures in a car and a backpack, and extremely low temperatures in checked-in luggage on a plane. DISCUSSION: Temperature- and humidity-sensitive medicines should not be stored long-term in common storage locations, such as kitchens and bathrooms. Conditions in these places may not comply with the recommended storage conditions given by the manufacturer. Furthermore, medicines should not be left in backpacks or cars, especially if the vehicle is in the sun. Medicines that may degrade upon freezing and thawing-such as protein-containing medicines, emulsions, suspensions and some solutions-should not be stored in the cargo hold of a plane. PMID- 23748398 TI - Abortion services in a high-needs district: a community-based model of care. AB - INTRODUCTION: In 2009, a high-deprivation district health board in New Zealand set up a community-based abortion clinic in order to provide a local service and to avoid out-of-region referrals. The service offers medical abortions for women with pregnancies of up to 63 days' gestation, and surgical abortion with local anaesthetic for women with pregnancies of up to 14 weeks' gestation. AIM: To describe the services developed and assess safety and timeliness for the first year of community-based services. METHODS: An audit of clinical records for patients seen in 2010 was performed in order to obtain data on location of services, timeliness, safety and complications. RESULTS: Eighty-two percent of locally provided abortions in 2010 were medical abortions, completed on average less than two days after referral to the service. One percent of patients experienced haemorrhaging post abortion, and 4% had retained products. These rates are within accepted standards for an abortion service. DISCUSSION: This report illustrates that a community-based model of care can be both clinically and culturally safe, while providing a much-needed service to a high-needs population. PMID- 23748399 TI - All people should wear sunscreen or other protection for their skin whenever they are exposed to sunlight: Yes. PMID- 23748400 TI - All people should wear sunscreen or other protection for their skin whenever they are exposed to sunlight: no. PMID- 23748401 TI - Keeping promises, measuring results: the Pacific Maternal and Child Health Indicators Project. PMID- 23748403 TI - Professional accountability of doctors in New Zealand. PMID- 23748404 TI - The New Zealand Centre for Adverse Reactions Monitoring: a source of practice based evidence. PMID- 23748405 TI - Aspirin for primary prevention: no. PMID- 23748407 TI - An alarming symptom. PMID- 23748406 TI - Communication with non-English-speaking patients. PMID- 23748408 TI - Measuring motor coordination in mice. AB - Mice are increasingly being used in behavioral neuroscience, largely replacing rats as the behaviorist's animal of choice. Before aspects of behavior such as emotionality or cognition can be assessed, however, it is vital to determine whether the motor capabilities of e.g. a mutant or lesioned mouse allow such an assessment. Performance on a maze task requiring strength and coordination, such as the Morris water maze, might well be impaired in a mouse by motor, rather than cognitive, impairments, so it is essential to selectively dissect the latter from the former. For example, sensorimotor impairments caused by NMDA antagonists have been shown to impair water maze performance(2). Motor coordination has traditionally been assessed in mice and rats by the rotarod test, in which the animal is placed on a horizontal rod that rotates about its long axis; the animal must walk forwards to remain upright and not fall off. Both set speed and accelerating versions of the rotarod are available. The other three tests described in this article (horizontal bar, static rods and parallel bars) all measure coordination on static apparatus. The horizontal bar also requires strength for adequate performance, particularly of the forelimbs as the mouse initially grips the bar just with the front paws. Adult rats do not perform well on tests such as the static rods and parallel bars (personal observations); they appear less well coordinated than mice. I have only tested male rats, however, and male mice seem generally less well coordinated than females. Mice appear to have a higher strength:weight ratio than rats; the Latin name, Mus musculus, seems entirely appropriate. The rotarod, the variations of the foot fault test(12) or the Catwalk (Noldus)(15) apparatus are generally used to assess motor coordination in rats. PMID- 23748409 TI - A human thyroid cancer cell line, DH-14-3, newly established from poorly differentiated thyroid carcinoma. AB - Poorly differentiated thyroid carcinoma (PDTC) is a newly recognized histological type of malignant thyroid tumor, accounting for about 2 - 13% of all thyroid carcinomas. PDTC is considered as a morphologically and biologically intermediate stage between well-differentiated thyroid carcinoma and anaplastic thyroid carcinoma. PDTC preferentially manifests bone metastases. We here established a cell line from a resected tumor specimen from a 70-year-old male patient with PDTC who presented with multiple bone metastases. This new thyroid tumor cell line was designated as DH-14-3 and was subsequently grown in culture for several years. DH-14-3 cells express thyroglobulin in the cytoplasm and thyroid transcription factor-1 in the nuclei, both proteins of which are specific markers for the thyroid gland. Importantly, triiodothyronine (T3) was detected in the cultured medium of DH-14-3 cells, in which, however, thyroxine (T4) was undetectable. Moreover, DH-14-3 cells secreted interleukin-8, transforming growth factor-beta1, vascular endothelial growth factor, matrix metalloproteinase-1 and parathyroid hormone-related protein, all of which may be responsible for the aggressiveness or bone metastasis of PDTC. Thus, the production of these proteins may reflect the metastatic potential of this cell line. DH-14-3 cells also express CXC chemokine receptor-4 and epidermal growth factor receptor, and carry a missense mutation in the p53 tumor suppressor gene. In fact, transplantation of DH-14-3 cells into the back of nude mice resulted in the formation of tumors, thereby confirming the capability of tumorigenesis. DH-14-3 cells may be useful for investigating the biological features of PDTC and will contribute to the therapeutic study of thyroid cancer. PMID- 23748410 TI - A tri-n-octylphosphine-assisted successive ionic layer adsorption and reaction method to synthesize multilayered core-shell CdSe-ZnS quantum dots with extremely high quantum yield. AB - Multilayered ZnS shells are coated on a CdSe quantum dot (QD) core by a tri-n octylphosphine-assisted successive ionic layer adsorption and reaction (TOP SILAR) method. Notably, the quantum yield (QY) of obtained core-shell CdSe/ZnS QDs can reach up to 95% after coating with a 3-monolayered ZnS shell, and is maintained even after coating with a 6-monolayered ZnS shell, breaking through the bottleneck of low QY at high coverage of the shell. PMID- 23748411 TI - Percutaneous humeral derotational osteotomy in obstetrical brachial plexus palsy: a new technique. AB - Thirty three per cent of children with obstetrical brachial plexus palsy with incomplete neurological recovery develop shoulder internal contracture associated with osseous deformity. Some of the older children are treated by humeral derotational osteotomy. The classical technique of open approach to the humeral diaphysis and plate fixation imposes a longitudinal scar and carries significant risks (nonunion, nerve palsy); a secondary procedure for plate removal is necessary in a significant proportion of patients. The authors report a new technique of percutaneous humeral osteotomy with osteosynthesis by Hoffmann external fixator. In six cases bone healing was obtained at an average of 45 days, without adverse complication. The postoperative results showed improved shoulder function. This new technique is simple and safe; it represents a new option for the treatment of sequelae of obstetrical brachial plexus palsy. PMID- 23748412 TI - Associations between preoperative functional status and functional outcomes of total joint replacement in the Dominican Republic. AB - OBJECTIVE: In developed countries, the functional status scores of patients with poor preoperative scores undergoing total joint replacement (TJR) improve more following TJR than those for patients with better preoperative scores. However, those with better preoperative scores achieve the best postoperative functional outcomes. We determined whether similar associations exist in a developing country. METHODS: Dominican patients undergoing total hip or knee replacement completed WOMAC and SF-36 surveys preoperatively and at 12-month follow-up. Patients were stratified into low-, medium- and high-scoring preoperative groups based on their preoperative WOMAC function scores. We examined the associations between the baseline functional status of these groups and two outcomes improvement in functional status over 12 months and functional status at 12 months-using analysis of variance with multivariable linear regression. RESULTS: Patients who scored the lowest preoperatively made the greatest gains in function and pain relief following their TJRs. However, there were no significant differences in pain or function at 12-month follow-up between patients who scored low and those who scored high on preoperative WOMAC and SF-36 surveys. CONCLUSION: Patients with poor preoperative functional status had greater improvement but similar 12-month functional outcomes compared with patients who had a higher level of function before surgery. These results suggest that a policy of focusing scarce resources on patients with worse functional status in developing countries may optimize improvement following TJR without threatening functional outcome. Additional research is needed to confirm these findings in other developing countries and to understand why these associations vary between patients in the Dominican Republic and patients from developed countries. PMID- 23748413 TI - Abnormal expression of chondroitin sulphate N-acetylgalactosaminyltransferase 1 and Hapln-1 in cartilage with Kashin-Beck disease and primary osteoarthritis. AB - PURPOSE: Kashin-Beck disease (KBD) is an endemic degenerative osteoarthritis associated with extracellular matrix degradation. The aim of this investigation was to evaluate the role of targeting genes in the pathogenesis of KBD and primary osteoarthritis (OA) involved in extracellular matrix degradation. METHODS: Agilent 44 K human whole-genome oligonucleotide microarrays were used to detect the gene expression in KBD and OA cartilage. The mRNA and protein expressions of CSGalNAcT-1 and Hapln-1 in chondrocytes were verified by reverse transcription polymerase chain reaction (RT-PCR) and western blot, and their expression in cartilage were verified with immunocytochemical analysis. Meanwhile, CSGalNAcT-1 and Hapln-1 protein levels in the selenium intervention group of KBD with different concentrations (0.25, 0.1 and 0.05 MUg/ml) were detected by western blot. RESULTS: CSGalNAcT-1 and Hapln-1 were down-regulated in KBD and OA at both mRNA and protein levels, and were increased in Se(Selenium) groups compared to KBD free-Se group. However, Wnt 3a, beta-catenin and Runx-2 were up-regulated in OA and KBD at protein levels. Additionally, immunohistochemical staining showed that CSGalNAcT-1 and Hapln-1 were reduced in all zones of KBD and OA articular cartilage, but not significantly reduced in the up zone of OA articular cartilage. CONCLUSIONS: The CSGalNAcT-1 and Hapln-1 were down-regulated in both KBD and OA cartilage. CSGalNAcT-1 may be involved in the damage of articular cartilage of KBD and OA by regulating Hapln-1 in the Wnt/beta catenin signalling pathway. It was indicated that CSGalNAcT-1 and Hapln-1 may play important roles in the pathogenesis of KBD and OA. PMID- 23748414 TI - Reply to comment on Chen et al: patellar resurfacing versus nonresurfacing in total knee arthroplasty: a meta-analysis of randomised controlled trials. PMID- 23748415 TI - Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease. AB - Mucopolysaccharidosis type IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments. We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LVs) overexpressing SGSH in wild-type (WT) hematopoietic stem cell (HSC) transplants (HSCTs), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LVs in autologous MPSIIIA HSCTs. To improve brain expression via monocyte/microglial specificity, LVs expressing enhanced green fluorescent protein (eGFP) under ubiquitous phosphoglycerate kinase (PGK) or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with either LV-PGK coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice. Eight months after HSCT, LV-PGK-coSGSH vectors produced bone marrow SGSH (576% normal activity) similar to LV-CD11b-coSGSH (473%), but LV-CD11b-coSGSH had significantly higher brain expression (11 versus 7%), demonstrating improved brain specificity. LV-CD11b-coSGSH normalized MPSIIIA behavior, brain HS, GM2 ganglioside, and neuroinflammation to WT levels, whereas LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice. PMID- 23748416 TI - [Inhaled anesthetics]. AB - Inhaled anesthetics are inhaled via the lungs. They subsequently pass through the alveolocapillary membrane and diffuse into the blood to finally target the central nervous system and induce anesthesia. This principle of anesthesia induction was first described for diethylether in 1847. Nevertheless, the use of diethylether for anesthesia is obsolete and even the use of nitrous oxide (introduced for anesthesia in 1847) is declining in Germany. Almost all modern volatile anesthetics are halogenated methylethylethers in which fluorine is used as a halogen. All of these anesthetics depress myocardial contractility and induce hypotension. Depression of CO2 and hypoxia-induced respiration are other serious side effects. Further side effects are liver and kidney related but they are rare and not induced by anesthetics per se but preferentially by toxic metobolites. Another promising inhalative anesthetic is xenon which fulfils many aspects of an ideal inhalative anesthetic. PMID- 23748417 TI - [Effects of overlapping induction on the utilization of complex operating structures: estimation using the practical application of a simulation model]. AB - Reduction of costs or increase in efficiency may lead to optimization of cost effectiveness in operating rooms. Overlapping induction by additional anesthesia teams reduces the changeover time between surgical interventions and, therefore, increases utilization effectiveness of surgical theatres. From an economic point of view overlapping induction should be performed where the highest increase in efficacy and revenues is possible. This article presents a software tool to vary the number of anesthesia teams in different single or clustered operating rooms. Using the example of a university hospital it could be demonstrated that the simulated addition of one anesthesia team to different clusters of operations rooms resulted in an increase of 15-40 % of operations and an increase up to 81 % of utilization effectiveness. Therefore, the presented simulation tool may help to estimate the maximum effect of staff allocation in surgical theatres. PMID- 23748418 TI - [Fentanyl: fast and furious?]. PMID- 23748419 TI - Body composition changes by DXA, BIA and skinfolds during exercise training in women. AB - PURPOSE: Few studies have examined responsiveness of bioimpedance (BIA) to detect changes over time in body composition using a longitudinal design. Accuracy of BIA and skinfold thickness in estimating body composition among 39-64 year-old women was investigated using dual-energy X-ray absorptiometry (DXA) as a criterion method both cross-sectionally and during a training intervention. METHODS: 97 women had percentage of fat assessed using DXA, skinfolds and eight polar BIA using multi-frequency current. Fat mass and lean mass were estimated by DXA and BIA. Measurements were performed before and after the 21-week training intervention. RESULTS: At baseline relative to DXA, BIA under predicted percentage of fat (-6.50 %) and fat mass (-3.42 kg) and overestimated lean mass (3.18 kg) considerably. Also skinfold measurement under predicted percentage of fat compared to DXA, but the difference was smaller (-1.69 % units). Skinfold measurement overestimated percentage of fat at low values and underestimated at high values (r (2) = 0.535). A significant bias was detected between DXA and BIA's estimate of change in percentage of fat, fat mass and lean mass. Compared to DXA, BIA and skinfolds underestimated the training-induced positive changes in body composition. CONCLUSIONS: BIA and skinfold methods compared to DXA are not interchangeable to quantify the percentage of fat, fat mass and lean mass at the cross-sectional design in middle-aged women. Moreover, exercise training-induced small changes in body composition cannot be detected with BIA or skinfold method, even though DXA was able to measure statistically significant within-group changes in body composition after training. PMID- 23748420 TI - WSR-88D doppler radar detection of corn earworm moth migration. AB - Corn earworm (Lepidoptera: Noctuidae) (CEW) populations infesting one crop production area may rapidly migrate and infest distant crop production areas. Although entomological radars have detected corn earworm moth migrations, the spatial extent of the radar coverage has been limited to a small horizontal view above crop production areas. The Weather Service Radar (version 88D) (WSR-88D) continuously monitors the radar-transmitted energy reflected by, and radial speed of, biota as well as by precipitation over areas that may encompass crop production areas. We analyzed data from the WSR-88D radar (S-band) at Brownsville, Texas, and related these data to aerial concentrations of CEW estimated by a scanning entomological radar (X-band) and wind velocity measurements from rawinsonde and pilot balloon ascents. The WSR-88D radar reflectivity was positively correlated (r2=0.21) with the aerial concentration of corn earworm-size insects measured by a scanning X-band radar. WSR-88D radar constant altitude plan position indicator estimates of wind velocity were positively correlated with wind speed (r2=0.56) and wind direction (r2=0.63) measured by pilot balloons and rawinsondes. The results reveal that WSR-88D radar measurements of insect concentration and displacement speed and direction can be used to estimate the migratory flux of corn earworms and other nocturnal insects, information that could benefit areawide pest management programs. In turn, identification of the effects of spatiotemporal patterns of migratory flights of corn earworm-size insects on WSR-88D radar measurements may lead to the development of algorithms that increase the accuracy of WSR-88D radar measurements of reflectivity and wind velocity for operational meteorology. PMID- 23748421 TI - Unwanted spatial bias in predicting establishment of an invasive insect based on simulated demographics. AB - A strategy to estimate the probability of successful establishment of the invasive gypsy moth (given an introduction) is growing in popularity. The strategy calls for an examination of the demographic output of a phenology model of the complete life-cycle to estimate the generational success under the climate of the location under consideration. The probability is maximal where the climate satisfies the life-cycle requirements of all life-stages of 100% of the population every year. The probability decreases where a smaller proportion of the population has its requirements satisfied every year, or where the frequency of unsatisfactory years increases. The strategy can give an unbiased and objective estimate of the probability. However, implementation of the strategy has most often forced unnatural and overly simplistic modifications onto the demographic structure that is simulated by the phenology model, and used an inappropriate and arbitrary calendar date to estimate demographic changes from winter mortality. This produces pronounced spatial bias in the estimates of generational success, and therefore in the estimates of climate-mediated establishment probability. In an examination of the strategy, as implemented in New Zealand, one demographic simplification caused an overestimate of 21% in a southern location; a second simplification caused an overestimate of 17% in a northern location. One hundred percent of the generations were incorrectly considered to have failed in a northern location because of the arbitrary calendar date that was used; and 78% of the generations were incorrectly considered successful in a southern location because of the arbitrary date. PMID- 23748422 TI - From cyanate to cyanurate: cyclotrimerization reactions towards the novel family of metal cyanurates. AB - The novel metal cyanurates LiSr(O3C3N3) and Li3Sr2F(O3C3N3)2 were prepared by exothermic solid state metathesis reactions and characterized by single crystal X ray diffraction. Crystalline powders were prepared by reactions of alkali earth halides (SrCl2 and SrF2) with Li(OCN) in 1:3 molar ratios, at 450 and 575 degrees C. The reaction with chloride yielded LiSr(O3C3N3), and the reaction starting from the fluoride yielded LiSr(O3C3N3).1/2LiF, containing additional LiF in the structure. Both crystal structures revealed the presence of the (O3C3N3)(3 ) ions which were formed by cyclotrimerization reaction of (OCN)(-) ions. The reactions were monitored by differential thermal analysis. Infrared spectra of the compounds are reported. PMID- 23748423 TI - Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling. AB - Cigarette smoking is a major risk factor for atherosclerosis and cardiovascular disease. CD36 mediates oxidized LDL (oxLDL) uptake and contributes to macrophage foam cell formation. We investigated a role for the CD36 pathway in nicotine induced activation of macrophages and foam cell formation in vitro and in vivo. Nicotine in the same plasma concentration range found in smokers increased the CD36(+)/CD14(+) cell population in human peripheral blood mononuclear cells, increased CD36 expression of human THP1 macrophages, and increased macrophage production of reactive oxygen species, PKCdelta phosphorylation, and peroxisome proliferator-activated receptor-gamma (PPARgamma) expression. Nicotine-induced CD36 expression was suppressed by antioxidants and by specific PKCdelta and PPARgamma inhibitors, implicating mechanistic roles for these intermediates. Nicotine synergized with oxLDL to increase macrophage expression of CD36 and cytokines TNF-alpha, monocyte chemoattractant protein-1, IL-6, and CXCL9, all of which were prevented by CD36 small interfering (si)RNA. Incubation with oxLDL (50 MUg/ml) for 72 h resulted in lipid deposition in macrophages and foam cell formation. Preincubation with nicotine further increased oxLDL-induced lipid accumulation and foam cell formation, which was also prevented by CD36 siRNA. Treatment of apoE-/- mice with nicotine markedly exacerbated inflammatory monocyte levels and atherosclerotic plaque accumulation, effects that were not seen in CD36-/- apoE-/- mice. Our results show that physiological levels of nicotine increase CD36 expression in macrophages, a pathway that may account at least in part for the known proinflammatory and proatherogenic properties of nicotine. These results identify such enhanced CD36 expression as a novel nicotine-mediated pathway that may constitute an independent risk factor for atherosclerosis in smokers. The results also suggest that exacerbated atherogenesis by this pathway may be an adverse side effect of extended use of high concentrations of nicotine independent of their mode of administration. PMID- 23748425 TI - Discrete effects of A57G-myosin essential light chain mutation associated with familial hypertrophic cardiomyopathy. AB - The functional consequences of the familial hypertrophic cardiomyopathy A57G (alanine-to-glycine) mutation in the myosin ventricular essential light chain (ELC) were assessed in vitro and in vivo using previously generated transgenic (Tg) mice expressing A57G-ELC mutant vs. wild-type (WT) of human cardiac ELC and in recombinant A57G- or WT-protein-exchanged porcine cardiac muscle strips. Compared with the Tg-WT, there was a significant increase in the Ca2+ sensitivity of force (DeltapCa50 ? 0.1) and an ~1.3-fold decrease in maximal force per cross section of muscle observed in the mutant preparations. In addition, a significant increase in passive tension in response to stretch was monitored in Tg-A57G vs. Tg-WT strips indicating a mutation-induced myocardial stiffness. Consistently, the hearts of Tg-A57G mice demonstrated a high level of fibrosis and hypertrophy manifested by increased heart weight-to-body weight ratios and a decreased number of nuclei indicating an increase in the two-dimensional size of Tg-A57G vs. Tg-WT myocytes. Echocardiography examination showed a phenotype of eccentric hypertrophy in Tg-A57G mice, enhanced left ventricular (LV) cavity dimension without changes in LV posterior/anterior wall thickness. Invasive hemodynamics data revealed significantly increased end-systolic elastance, defined by the slope of the pressure-volume relationship, indicating a mutation-induced increase in cardiac contractility. Our results suggest that the A57G allele causes disease by means of a discrete modulation of myofilament function, increased Ca2+ sensitivity, and decreased maximal tension followed by compensatory hypertrophy and enhanced contractility. These and other contributing factors such as increased myocardial stiffness and fibrosis most likely activate cardiomyopathic signaling pathways leading to pathologic cardiac remodeling. PMID- 23748424 TI - Role of mitochondrial dysfunction and altered autophagy in cardiovascular aging and disease: from mechanisms to therapeutics. AB - Advanced age is associated with a disproportionate prevalence of cardiovascular disease (CVD). Intrinsic alterations in the heart and the vasculature occurring over the life course render the cardiovascular system more vulnerable to various stressors in late life, ultimately favoring the development of CVD. Several lines of evidence indicate mitochondrial dysfunction as a major contributor to cardiovascular senescence. Besides being less bioenergetically efficient, damaged mitochondria also produce increased amounts of reactive oxygen species, with detrimental structural and functional consequences for the cardiovascular system. The age-related accumulation of dysfunctional mitochondrial likely results from the combination of impaired clearance of damaged organelles by autophagy and inadequate replenishment of the cellular mitochondrial pool by mitochondriogenesis. In this review, we summarize the current knowledge about relevant mechanisms and consequences of age-related mitochondrial decay and alterations in mitochondrial quality control in the cardiovascular system. The involvement of mitochondrial dysfunction in the pathogenesis of cardiovascular conditions especially prevalent in late life and the emerging connections with neurodegeneration are also illustrated. Special emphasis is placed on recent discoveries on the role played by alterations in mitochondrial dynamics (fusion and fission), mitophagy, and their interconnections in the context of age-related CVD and endothelial dysfunction. Finally, we discuss pharmacological interventions targeting mitochondrial dysfunction to delay cardiovascular aging and manage CVD. PMID- 23748427 TI - Differentiation of epidermal keratinocytes is dependent on glucosylceramide:ceramide processing. AB - Skin barrier function is primarily assigned to the outer epidermal layer, the stratum corneum (SC), mainly composed of corneocytes and lipid-enriched extracellular matrix. Epidermal ceramides (Cers) are essential barrier lipids, containing ultra-long-chain (ULC) fatty acids (FAs) with a unique omega-hydroxy group, which is necessary for binding to corneocyte proteins. In the SC, Cers are believed to derive from glucosylated intermediates, namely glucosylceramides (GlcCers), as surmised from human Gaucher's disease and related mouse models. Tamoxifen (TAM)-induced deletion of the endogenous GlcCer-synthesizing enzyme UDP glucose:ceramide glucosyltransferase (UGCG) in keratin K14-positive cells resulted in epidermal GlcCer depletion. Although free extractable Cers were elevated in total epidermis and as well in SC, protein-bound Cers decreased significantly in Ugcg(f/fK14CreERT2) mice, indicating glucosylation to be required for regular Cer processing as well as arrangement and extrusion of lipid lamellae. The almost complete loss of protein-bound Cers led to a disruption of the water permeability barrier (WPB). UGCG-deficient mice developed an ichthyosis like skin phenotype marked by impaired keratinocyte differentiation associated with delayed wound healing. Gene expression profiling of Ugcg-mutant skin revealed a subset of differentially expressed genes involved in lipid signaling and epidermal differentiation/proliferation, correlating to human skin diseases such as psoriasis and atopic dermatitis. Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta), a Cer-sensitive transcription factor was identified as potential mediator of the altered gene sets. PMID- 23748426 TI - Blood RNA profiling in a large cohort of multiple sclerosis patients and healthy controls. AB - Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system (CNS). It is characterized by the infiltration of autoreactive immune cells into the CNS, which target the myelin sheath, leading to the loss of neuronal function. Although it is accepted that MS is a multifactorial disorder with both genetic and environmental factors influencing its development and course, the molecular pathogenesis of MS has not yet been fully elucidated. Here, we studied the longitudinal gene expression profiles of whole-blood RNA from a cohort of 195 MS patients and 66 healthy controls. We analyzed these transcriptomes at both the individual transcript and the biological pathway level. We found 62 transcripts to be significantly up-regulated in MS patients; the expression of 11 of these genes was counter-regulated by interferon treatment, suggesting partial restoration of a 'healthy' gene expression profile. Global pathway analyses linked the proteasome and Wnt signaling to MS disease processes. Since genotypes from a subset of individuals were available, we were able to identify expression quantitative trait loci (eQTL), a number of which involved two genes of the MS gene signature. However, all these eQTL were also present in healthy controls. This study highlights the challenge posed by analyzing transcripts from whole blood and how these can be mitigated by using large, well-characterized cohorts of patients with longitudinal follow-up and multi-modality measurements. PMID- 23748428 TI - Type of uromodulin mutation and allelic status influence onset and severity of uromodulin-associated kidney disease in mice. AB - Uromodulin-associated kidney disease (UAKD) is a dominant heritable renal disease in humans which is caused by mutations in the uromodulin (UMOD) gene and characterized by heterogeneous clinical appearance. To get insights into possible causes of this heterogeneity of UAKD, we describe the new mutant mouse line Umod(C93F), leading to disruption of a putative disulfide bond which is also absent in a known human UMOD mutation, and compare the phenotype of this new mouse line with the recently published mouse line Umod(A227T). In both mutant mouse lines, which were both bred on the C3H background, the Umod mutations cause a gain-of-toxic function due to a maturation defect of the mutant uromodulin leading to a dysfunction of thick ascending limb of Henle's loop (TALH) cells of the kidney. Umod mutant mice exhibit increased plasma urea and Cystatin levels, impaired urinary concentration ability, reduced fractional excretion of uric acid and nephropathological alterations including uromodulin retention in TALH cells, interstitial fibrosis and inflammatory cell infiltrations, tubular atrophy and occasional glomerulo- und tubulocystic changes, a phenotype highly similar to UAKD in humans. The maturation defect of mutant uromodulin leads to the accumulation of immature uromodulin in the endoplasmic reticulum (ER) and to ER hyperplasia. Further, this study was able to demonstrate for the first time in vivo that the severity of the uromodulin maturation defect as well as onset and speed of progression of renal dysfunction and morphological alterations are strongly dependent on the particular Umod mutation itself and the zygosity status. PMID- 23748429 TI - Relaxin suppresses atrial fibrillation by reversing fibrosis and myocyte hypertrophy and increasing conduction velocity and sodium current in spontaneously hypertensive rat hearts. AB - RATIONALE: Atrial fibrillation (AF) contributes significantly to morbidity and mortality in elderly and hypertensive patients and has been correlated to enhanced atrial fibrosis. Despite a lack of direct evidence that fibrosis causes AF, reversal of fibrosis is considered a plausible therapy. OBJECTIVE: To evaluate the efficacy of the antifibrotic hormone relaxin (RLX) in suppressing AF in spontaneously hypertensive rats (SHR). METHODS AND RESULTS: Normotensive Wistar-Kyoto (WKY) and SHR were treated for 2 weeks with vehicle (WKY+V and SHR+V) or RLX (0.4 mg/kg per day, SHR+RLX) using implantable mini-pumps. Hearts were perfused, mapped optically to analyze action potential durations, intracellular Ca2+ transients, and restitution kinetics, and tested for AF vulnerability. SHR hearts had slower conduction velocity (CV; P<0.01 versus WKY), steeper CV restitution kinetics, greater collagen deposition, higher levels of transcripts for transforming growth factor-beta, metalloproteinase-2, metalloproteinase-9, collagen I/III, and reduced connexin 43 phosphorylation (P<0.05 versus WKY). Programmed stimulation triggered sustained AF in SHR (n=5/5) and SHR+V (n=4/4), but not in WKY (n=0/5) and SHR+RLX (n=1/8; P<0.01). RLX treatment reversed the transcripts for fibrosis, flattened CV restitution kinetics, reduced action potential duration at 90% recovery to baseline, increased CV (P<0.01), and reversed atrial hypertrophy (P<0.05). Independent of antifibrotic actions, RLX (0.1 umol/L) increased Na+ current density, INa (~2 fold in 48 hours) in human cardiomyocytes derived from inducible pluripotent stem cells (n=18/18; P<0.01). CONCLUSIONS: RLX treatment suppressed AF in SHR hearts by increasing CV from a combination of reversal of fibrosis and hypertrophy and by increasing INa. The study provides compelling evidence that RLX may provide a novel therapy to manage AF in humans by reversing fibrosis and hypertrophy and by modulating cardiac ionic currents. PMID- 23748430 TI - A novel mouse model of atherosclerotic plaque instability for drug testing and mechanistic/therapeutic discoveries using gene and microRNA expression profiling. AB - RATIONALE: The high morbidity/mortality of atherosclerosis is typically precipitated by plaque rupture and consequent thrombosis. However, research on underlying mechanisms and therapeutic approaches is limited by the lack of animal models that reproduce plaque instability observed in humans. OBJECTIVE: Development and use of a mouse model of plaque rupture that reflects the end stage of human atherosclerosis. METHODS AND RESULTS: On the basis of flow measurements and computational fluid dynamics, we applied a tandem stenosis to the carotid artery of apolipoprotein E-deficient mice on high-fat diet. At 7 weeks postoperatively, we observed intraplaque hemorrhage in ~50% of mice, as well as disruption of fibrous caps, intraluminal thrombosis, neovascularization, and further characteristics typically seen in human unstable plaques. Administration of atorvastatin was associated with plaque stabilization and downregulation of monocyte chemoattractant protein-1 and ubiquitin. Microarray profiling of mRNA and microRNA (miR) and, in particular, its combined analysis demonstrated major differences in the hierarchical clustering of genes and miRs among nonatherosclerotic arteries, stable, and unstable plaques and allows the identification of distinct genes/miRs, potentially representing novel therapeutic targets for plaque stabilization. The feasibility of the described animal model as a discovery tool was established in a pilot approach, identifying a disintegrin and metalloprotease with thrombospondin motifs 4 (ADAMTS4) and miR 322 as potential pathogenic factors of plaque instability in mice and validated in human plaques. CONCLUSIONS: The newly described mouse model reflects human atherosclerotic plaque instability and represents a discovery tool toward the development and testing of therapeutic strategies aimed at preventing plaque rupture. Distinctly expressed genes and miRs can be linked to plaque instability. PMID- 23748431 TI - Lipid composition of multilamellar bodies secreted by Dictyostelium discoideum reveals their amoebal origin. AB - When they are fed with bacteria, Dictyostelium discoideum amoebae produce and secrete multilamellar bodies (MLBs), which are composed of membranous material. It has been proposed that MLBs are a waste disposal system that allows D. discoideum to eliminate undigested bacterial remains. However, the real function of MLBs remains unknown. Determination of the biochemical composition of MLBs, especially lipids, represents a way to gain information about the role of these structures. To allow these analyses, a protocol involving various centrifugation procedures has been developed to purify secreted MLBs from amoeba-bacterium cocultures. The purity of the MLB preparation was confirmed by transmission electron microscopy and by immunofluorescence using H36, an antibody that binds to MLBs. The lipid and fatty acid compositions of pure MLBs were then analyzed by high-performance thin-layer chromatography (HPTLC) and gas chromatography (GC), respectively, and compared to those of amoebae as well as bacteria used as a food source. While the bacteria were devoid of phosphatidylcholine (PC) and phosphatidylinositol (PI), these two polar lipid species were major classes of lipids in MLBs and amoebae. Similarly, the fatty acid composition of MLBs and amoebae was characterized by the presence of polyunsaturated fatty acids, while cyclic fatty acids were found only in bacteria. These results strongly suggest that the lipids constituting the MLBs originate from the amoebal metabolism rather than from undigested bacterial membranes. This opens the possibility that MLBs, instead of being a waste disposal system, have unsuspected roles in D. discoideum physiology. PMID- 23748432 TI - Spatial reorganization of Saccharomyces cerevisiae enolase to alter carbon metabolism under hypoxia. AB - Hypoxia has critical effects on the physiology of organisms. In the yeast Saccharomyces cerevisiae, glycolytic enzymes, including enolase (Eno2p), formed cellular foci under hypoxia. Here, we investigated the regulation and biological functions of these foci. Focus formation by Eno2p was inhibited temperature independently by the addition of cycloheximide or rapamycin or by the single substitution of alanine for the Val22 residue. Using mitochondrial inhibitors and an antioxidant, mitochondrial reactive oxygen species (ROS) production was shown to participate in focus formation. Focus formation was also inhibited temperature dependently by an SNF1 knockout mutation. Interestingly, the foci were observed in the cell even after reoxygenation. The metabolic turnover analysis revealed that [U-(13)C]glucose conversion to pyruvate and oxaloacetate was accelerated in focus-forming cells. These results suggest that under hypoxia, S. cerevisiae cells sense mitochondrial ROS and, by the involvement of SNF1/AMPK, spatially reorganize metabolic enzymes in the cytosol via de novo protein synthesis, which subsequently increases carbon metabolism. The mechanism may be important for yeast cells under hypoxia, to quickly provide both energy and substrates for the biosynthesis of lipids and proteins independently of the tricarboxylic acid (TCA) cycle and also to fit changing environments. PMID- 23748433 TI - Diverse effects of prostaglandin E2 on vascular contractility. AB - Prostaglandin E2 (PGE2) is a major prostanoid produced under inflammatory situations. There have been controversial reports showing contractile or relaxant effect of PGE2 on vascular tone in various types of blood vessels. Thus, it is still elusive whether and how PGE2 modulates vascular tone. We here assessed the effects of PGE2 on vascular contractility using different types of vasculatures isolated form rat. In endothelium-denuded aortas and mesenteric arteries, PGE2 (1 nM-10 MUM) concentration-dependently enhanced the contraction elicited by K(+) (35.4 mM) or norepinephrine (10 nM). In pulmonary arteries, PGE2 did not alter the both-induced contraction. Tail arteries were relaxed by a low dose of PGE2 (1 100 nM), but this response shifted to contraction by the higher dose of PGE2 (300 nM-10 MUM). There are four types of PGE2 receptors EP1-4. RT-PCR showed that aortas and mesenteric arteries abundantly expressed EP3, while tail arteries abundantly expressed EP4. We next revealed that selective EP3 agonism enhanced the contraction in mesenteric arteries, whereas EP4 agonism induced relaxation in tail arteries. Taken together, PGE2 causes different contractile responses depending on the type of vascular bed. This phenomenon may be due to the difference in expression pattern and activity of EP receptors. PMID- 23748434 TI - 3-Mercaptopropionic acid-induced repetitive seizures increase GluN2A expression in rat hippocampus: a potential neuroprotective role of cyclopentyladenosine. AB - The N-methyl-D-aspartate receptor (NMDAR) is involved in synaptic plasticity, learning, memory, and neurological diseases like epilepsy and it is the major mediator of excitotoxicity. Functional NMDARs in the mature brain are heteromeric complexes composed of different subunits: GluN1 and GluN2. There are four different GluN2 subunits (A-D) and each of them critically determines the pharmacological and electrophysiological properties of NMDARs. GluN1 is ubiquitously expressed in the central nervous system while the highest GluN2A expression is in the hippocampus. Adenosine, an endogenous anticonvulsant, is a neuromodulator with a critical role in the regulation of neuronal activity, mediating its effect on specific receptors, among which adenosine A1 receptor is highly expressed in the hippocampus. In the present work hippocampal GluN2A expression after the convulsant drug 3-mercaptopropionic acid (MP) induced seizures and the effect of cyclopentyladenosine (CPA) given alone or prior to MP (CPA + MP) in an acute or repetitive experimental model was studied. CPA administered to rats for one or 4 days increases seizure threshold induced by MP. After one administration of MP, no significant difference in GluN2A expression was observed in CPA and CPA + MP by Western blot, although immunohistochemistry revealed an increase in CA2/3 area. However, repetitive MP administration during 4 days showed a significant increase of GluN2A expression, and the repetitive administration of CPA 30 min prior to MP caused a significant decrease of GluN2A expression with respect to MP treatment, returning to control levels. These results show that GluN2A subunit is involved in repetitive MP-induced seizures, while CPA administration displays a protective effect against it. PMID- 23748435 TI - Brain routes for reading in adults with and without autism: EMEG evidence. AB - Reading utilises at least two neural pathways. The temporal lexical route visually maps whole words to their lexical entries, whilst the nonlexical route decodes words phonologically via parietal cortex. Readers typically employ the lexical route for familiar words, but poor comprehension plus precocity at mechanically 'sounding out' words suggests that differences might exist in autism. Combined MEG/EEG recordings of adults with autistic spectrum conditions (ASC) and controls while reading revealed preferential recruitment of temporal areas in controls and additional parietal recruitment in ASC. Furthermore, a lack of differences between semantic word categories was consistent with previous suggestion that people with ASC may lack a 'default' lexical-semantic processing mode. These results are discussed with reference to dual-route models of reading. PMID- 23748436 TI - Factor structure of autistic traits in children with ADHD. AB - Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur. Factor analyses of ASD traits in children with and without ASD indicate the presence of social and restrictive-repetitive behaviour (RRB) factors. This study used exploratory factor analyses to determine the structure of ASD traits (assessed using the Social Communication Questionnaire) in children with ADHD. Distinct factors were observed for 'social' and 'rigidity' traits, corresponding to previous factor analyses in clinical ASD and population samples. This indicates that the split between social-communicative and RRB dimensions is unaffected by ADHD in children. Moreover, the study also finds that there is some overlap across hyperactive-impulsive symptoms and RRB traits in children with ADHD, which merits further investigation. PMID- 23748437 TI - Organocatalytic asymmetric remote aziridination of 2,4-dienals. AB - Highly regio- and stereoselective remote aziridination of 2,4-dienals has been developed, based on a vinylogous iminium-ion-dienamine catalytic cascade reaction. Transformations of the aziridine products into enantioenriched motifs are also demonstrated. Furthermore, the reaction concept is extended to include enantioselective 1,6-addition of thiols. PMID- 23748438 TI - NIH consensus development conference: diagnosing gestational diabetes mellitus. AB - OBJECTIVE: To provide healthcare providers, patients, and the general public with a responsible assessment of currently available data on diagnosing gestational diabetes mellitus (GDM). PARTICIPANTS: A non-U.S. Department of Health and Human Services, nonadvocate 15-member panel representing the fields of obstetrics and gynecology, maternal-fetal medicine, pediatrics, diabetic research, biostatistics, women's health issues, health services research, decision analysis, health management and policy, health economics, epidemiology, and community engagement. In addition, 16 experts from pertinent fields presented data to the panel and conference audience. EVIDENCE: Presentations by experts and a systematic review of the literature prepared by the University of Alberta Evidence-based Practice Centre, through the Agency for Healthcare Research and Quality (AHRQ). Scientific evidence was given precedence over anecdotal experience. CONFERENCE PROCESS: The panel drafted its statement based on scientific evidence presented in open forum and on published scientific literature. The draft statement was posted at http://prevention.nih.gov/ for public comment and the panel released a final statement approximately 10 weeks later. The final statement is an independent report of the panel and is not a policy statement of the NIH or the Federal Government. CONCLUSIONS: At present, GDM is commonly diagnosed in the United States using a 1-hour screening test with a 50-gram glucose load followed by a 3-hour 100-gram glucose tolerance test (a two-step approach) for those found to be abnormal on the screen. This approach identifies approximately 5% to 6% of the population as having GDM. In contrast, newly proposed diagnostic strategies rely on the administration of a 2-hour glucose tolerance test (a one-step approach) with a fasting component and a 75 gram glucose load. These strategies differ on whether a 1-hour sample is included, whether two abnormal values are required, and the diagnostic cutoffs that are used. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) has proposed diagnostic thresholds based on demonstrated associations between glycemic levels and an increased risk of obstetric and perinatal morbidities. The panel considered whether a one-step approach to the diagnosis of GDM should be adopted in place of the two-step approach. The one step approach offers certain operational advantages. The current two-step approach is used only during pregnancy and is largely restricted to the United States. There would be value in a consistent, international diagnostic standard across one's lifespan. This unification would allow better standardization of best practices in patient care and comparability of research outcomes. The one step approach also holds potential advantages for women and their health care providers, as it would allow a diagnosis to be achieved within the context of one visit as opposed to two. However, the one-step approach, as proposed by the IADPSG, is anticipated to increase the frequency of the diagnosis of GDM by twofold to threefold, to a prevalence of approximately 15% to 20%. There are several concerns regarding the diagnosis of GDM in these additional women. It is not well understood whether the additional women identified by this approach will benefit from treatment, and if so, to what extent. Moreover, the care of these women will generate additional direct and indirect health care costs. There is also evidence that the labeling of these women may have unintended consequences, such as an increase in cesarean delivery and more intensive newborn assessments. In addition, increased patient costs, life disruptions, and psychosocial burdens have been identified. Available studies do not provide clear evidence that a one step approach is cost-effective in comparison with the current two-step approach. After much deliberation, the panel believes that there are clear benefits to international standardization with regard to the one-step approach. Nevertheless, at present, the panel believes that there is not sufficient evidence to adopt a one-step approach. The panel is particularly concerned about the adoption of new criteria that would increase the prevalence of GDM, and the corresponding costs and interventions, without clear demonstration of improvements in the most clinically important health and patient-centered outcomes. Thus, the panel recommends that the two-step approach be continued. However, given the potential benefits of a one-step approach, resolution of the uncertainties associated with its use would warrant revision of this conclusion. PMID- 23748439 TI - [Endoscopic video imaging of configuration changes in the larynx and pharynx during selected swallowing techniques]. AB - BACKGROUND: Traditional dysphagia therapy (TDT) aims to improve swallowing by means of compensatory strategies including postural changes or swallowing maneuvers. These techniques are mainly applied in order to modify swallowing by affecting bolus transport to facilitate safe swallowing. Videos demonstrating actual, laryngoscopically verified effects on the pharyngeal and laryngeal structures involved are rare in the current literature. This paper aims to assess various maneuvers used in TDT endoscopically. METHOD: A selective literature search for endoscopic imaging of swallowing maneuvers and postural changes applied in TDT was performed in PubMed. RESULTS: Each of the techniques commonly used in TDT influenced the pharyngeal or laryngeal structures distinctly. DISCUSSION: All of the techniques examined for this paper represent techniques commonly applied in traditional dysphagia therapy. The specific changes observed endoscopically of the anatomic structures involved are distinct, but sometimes seem only marginal in comparison to the initial configurations. It should hence not be surprising that these swallowing techniques occasionally only slightly improve swallowing. The videos included in this article demonstrate the actual impact of the swallowing techniques and may therefore be of use to physicians prescribing and implementing TDT. PMID- 23748440 TI - Electroporation of the hindbrain to trace axonal trajectories and synaptic targets in the chick embryo. AB - Electroporation of the chick embryonic neural tube has many advantages such as being quick and efficient for the expression of foreign genes into neuronal cells. In this manuscript we provide a method that demonstrates uniquely how to electroporate DNA into the avian hindbrain at E2.75 in order to specifically label a subset of neuronal progenitors, and how to follow their axonal projections and synaptic targets at much advanced stages of development, up to E14.5. We have utilized novel genetic tools including specific enhancer elements, Cre/Lox - based plasmids and the PiggyBac-mediated DNA transposition system to drive GFP expression in a subtype of hindbrain cells (the dorsal most subgroup of interneurons, dA1). Axonal trajectories and targets of dA1 axons are followed at early and late embryonic stages at various brainstem regions. This strategy contributes advanced techniques for targeting cells of interest in the embryonic hindbrain and for tracing circuit formation at multiple stages of development. PMID- 23748441 TI - Effect of netupitant, a highly selective NK1 receptor antagonist, on the pharmacokinetics of palonosetron and impact of the fixed dose combination of netupitant and palonosetron when coadministered with ketoconazole, rifampicin, and oral contraceptives. AB - OBJECTIVES: Neurokinin-1 receptor antagonists (NK1 RAs) are commonly coadministered with a 5-HT3 RA such as palonosetron to prevent nausea and vomiting induced by chemotherapy. Netupitant, a new highly selective NK1 RA, is both a substrate for and a moderate inhibitor of CYP3A4. Three studies were designed to evaluate the potential drug-drug interaction of netupitant with palonosetron and of the fixed dose combination of netupitant and palonosetron, NEPA, with an inhibitor (ketoconazole), an inducer (rifampicin) and a substrate (oral contraceptives) of CYP3A4. METHODS: Study 1 was a three-way crossover in 18 healthy subjects receiving netupitant alone, palonosetron alone, and the combination of both antiemetics. Studies 2 and 3 were two-way crossover trials where healthy subjects received NEPA (the fixed dose combination of netupitant and palonosetron). In study 2, 36 subjects received NEPA alone (day 1) and in combination with ketoconazole or rifampicin. In study 3, 24 healthy women received ethinylestradiol/levonorgestrel alone or in combination with NEPA (day 1). RESULTS: There were no significant pharmacokinetic interactions between netupitant and palonosetron. Ketoconazole increased netupitant area under curve (AUC) by 140 % and C max by 25 %. Rifampicin decreased netupitant AUC by 83 % and C max by 62 %. NEPA did not significantly affect exposure to ethinylestradiol, while systemic exposure to levonorgestrel increased by 40 %, but this was not considered clinically relevant. CONCLUSIONS: There were no clinically relevant interactions between netupitant and palonosetron, or between NEPA and oral contraceptives. The coadministration of NEPA with inhibitors or inducers of CYP3A4 may require dose adjustments. Treatments were well tolerated. PMID- 23748442 TI - ZFP36L2 is required for self-renewal of early burst-forming unit erythroid progenitors. AB - Stem cells and progenitors in many lineages undergo self-renewing divisions, but the extracellular and intracellular proteins that regulate this process are largely unknown. Glucocorticoids stimulate red blood cell formation by promoting self-renewal of early burst-forming unit-erythroid (BFU-E) progenitors. Here we show that the RNA-binding protein ZFP36L2 is a transcriptional target of the glucocorticoid receptor (GR) in BFU-Es and is required for BFU-E self-renewal. ZFP36L2 is normally downregulated during erythroid differentiation from the BFU-E stage, but its expression is maintained by all tested GR agonists that stimulate BFU-E self-renewal, and the GR binds to several potential enhancer regions of ZFP36L2. Knockdown of ZFP36L2 in cultured BFU-E cells did not affect the rate of cell division but disrupted glucocorticoid-induced BFU-E self-renewal, and knockdown of ZFP36L2 in transplanted erythroid progenitors prevented expansion of erythroid lineage progenitors normally seen following induction of anaemia by phenylhydrazine treatment. ZFP36L2 preferentially binds to messenger RNAs that are induced or maintained at high expression levels during terminal erythroid differentiation and negatively regulates their expression levels. ZFP36L2 therefore functions as part of a molecular switch promoting BFU-E self-renewal and a subsequent increase in the total numbers of colony-forming unit-erythroid (CFU-E) progenitors and erythroid cells that are generated. PMID- 23748443 TI - Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. AB - The mammalian gut ecosystem has considerable influence on host physiology, but the mechanisms that sustain this complex environment in the face of different stresses remain obscure. Perturbations to the gut ecosystem, such as through antibiotic treatment or diet, are at present interpreted at the level of bacterial phylogeny. Less is known about the contributions of the abundant population of phages to this ecological network. Here we explore the phageome as a potential genetic reservoir for bacterial adaptation by sequencing murine faecal phage populations following antibiotic perturbation. We show that antibiotic treatment leads to the enrichment of phage-encoded genes that confer resistance via disparate mechanisms to the administered drug, as well as genes that confer resistance to antibiotics unrelated to the administered drug, and we demonstrate experimentally that phages from treated mice provide aerobically cultured naive microbiota with increased resistance. Systems-wide analyses uncovered post-treatment phage-encoded processes related to host colonization and growth adaptation, indicating that the phageome becomes broadly enriched for functionally beneficial genes under stress-related conditions. We also show that antibiotic treatment expands the interactions between phage and bacterial species, leading to a more highly connected phage-bacterial network for gene exchange. Our work implicates the phageome in the emergence of multidrug resistance, and indicates that the adaptive capacity of the phageome may represent a community-based mechanism for protecting the gut microflora, preserving its functional robustness during antibiotic stress. PMID- 23748444 TI - EndMT contributes to the onset and progression of cerebral cavernous malformations. AB - Cerebral cavernous malformation (CCM) is a vascular dysplasia, mainly localized within the brain and affecting up to 0.5% of the human population. CCM lesions are formed by enlarged and irregular blood vessels that often result in cerebral haemorrhages. CCM is caused by loss-of-function mutations in one of three genes, namely CCM1 (also known as KRIT1), CCM2 (OSM) and CCM3 (PDCD10), and occurs in both sporadic and familial forms. Recent studies have investigated the cause of vascular dysplasia and fragility in CCM, but the in vivo functions of this ternary complex remain unclear. Postnatal deletion of any of the three Ccm genes in mouse endothelium results in a severe phenotype, characterized by multiple brain vascular malformations that are markedly similar to human CCM lesions. Endothelial-to-mesenchymal transition (EndMT) has been described in different pathologies, and it is defined as the acquisition of mesenchymal- and stem-cell like characteristics by the endothelium. Here we show that endothelial-specific disruption of the Ccm1 gene in mice induces EndMT, which contributes to the development of vascular malformations. EndMT in CCM1-ablated endothelial cells is mediated by the upregulation of endogenous BMP6 that, in turn, activates the transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) signalling pathway. Inhibitors of the TGF-beta and BMP pathway prevent EndMT both in vitro and in vivo and reduce the number and size of vascular lesions in CCM1 deficient mice. Thus, increased TGF-beta and BMP signalling, and the consequent EndMT of CCM1-null endothelial cells, are crucial events in the onset and progression of CCM disease. These studies offer novel therapeutic opportunities for this severe, and so far incurable, pathology. PMID- 23748445 TI - A single pair of interneurons commands the Drosophila feeding motor program. AB - Many feeding behaviours are the result of stereotyped, organized sequences of motor patterns. These patterns have been the subject of neuroethological studies, such as electrophysiological characterization of neurons governing prey capture in toads. However, technical limitations have prevented detailed study of the functional role of these neurons, a common problem for vertebrate organisms. Complexities involved in studies of whole-animal behaviour can be resolved in Drosophila, in which remote activation of brain cells by genetic means enables us to examine the nervous system in freely moving animals to identify neurons that govern a specific behaviour, and then to repeatedly target and manipulate these neurons to characterize their function. Here we show neurons that generate the feeding motor program in Drosophila. We carried out an unbiased screen using remote neuronal activation and identified a critical pair of brain cells that induces the entire feeding sequence when activated. These 'feeding neurons' (here abbreviated to Fdg neurons for brevity) are also essential for normal feeding as their suppression or ablation eliminates sugar-induced feeding behaviour. Activation of a single Fdg neuron induces asymmetric feeding behaviour and ablation of a single Fdg neuron distorts the sugar-induced feeding behaviour to become asymmetric, indicating the direct role of these neurons in shaping motor program execution. Furthermore, recording neuronal activity and calcium imaging simultaneously during feeding behaviour reveals that the Fdg neurons respond to food presentation, but only in starved flies. Our results demonstrate that Fdg neurons operate firmly within the sensorimotor watershed, downstream of sensory and metabolic cues and at the top of the feeding motor hierarchy, to execute the decision to feed. PMID- 23748446 TI - Time-based comparative transcriptomics in engineered xylose-utilizing Saccharomyces cerevisiae identifies temperature-responsive genes during ethanol production. AB - Agricultural residues comprising lignocellulosic materials are excellent sources of pentose sugar, which can be converted to ethanol as fuel. Ethanol production via consolidated bioprocessing requires a suitable microorganism to withstand the harsh fermentation environment of high temperature, high ethanol concentration, and exposure to inhibitors. We genetically enhanced an industrial Saccharomyces cerevisiae strain, sun049, enabling it to uptake xylose as the sole carbon source at high fermentation temperature. This strain was able to produce 13.9 g/l ethanol from 50 g/l xylose at 38 degrees C. To better understand the xylose consumption ability during long-term, high-temperature conditions, we compared by transcriptomics two fermentation conditions: high temperature (38 degrees C) and control temperature (30 degrees C) during the first 12 h of fermentation. This is the first long-term, time-based transcriptomics approach, and it allowed us to discover the role of heat-responsive genes when xylose is the sole carbon source. The results suggest that genes related to amino acid, cell wall, and ribosomal protein synthesis are down-regulated under heat stress. To allow cell stability and continuous xylose uptake in order to produce ethanol, hexose transporter HXT5, heat shock proteins, ubiquitin proteins, and proteolysis were all induced at high temperature. We also speculate that the strong relationship between high temperature and increased xylitol accumulation represents the cell's mechanism to protect itself from heat degradation. PMID- 23748447 TI - Use of fluid filtration method to evaluate the effect of master cone size on the apical seal of severely curved root canals. AB - The apical third of most root canals shows some degree of curvature, which is important in cleaning/shaping and obturation during root canal treatment. The present study evaluated the effect of master cone size on the apical seal of severely curved root canals. Thirty-eight mesial roots of human mandibular first molars were prepared using the crown-down technique. All samples were mature roots with closed apices, had no carious lesions or resorption, and had a canal curvature of > 45o to 60o. Two samples were used as a negative and positive control to evaluate the fluid filtration equipment, and the remaining 36 samples were equally divided into groups A, B, and C based on master cone size, namely, gutta-percha #20, #25, and #30, respectively. The fluid filtration method was used to evaluate microleakage. No significant difference in microleakage was observed among groups (P = 0.31). In conclusion, an increase in master cone size up to #30 does not significantly influence apical microleakage. PMID- 23748448 TI - Effect of alcohol consumption status and alcohol concentration on oral pain induced by alcohol-containing mouthwash. AB - Alcohol exposure alters oral mucosa. Patient compliance with mouthwash use may be reduced by oral pain resulting from rinsing with alcohol-containing mouthwash. However, information regarding the effects of alcohol consumption and mouthwash alcohol concentration on oral pain is limited. In this double-blind, randomized, controlled cross-over study, we investigated the effects of alcohol consumption status and mouthwash alcohol concentration on response to and perception of oral pain induced by alcohol-containing mouthwash. Fifty healthy men aged 33 to 56 years were enrolled and classified as drinkers and nondrinkers according to self reported alcohol consumption. All subjects rinsed with two commercially available mouthwash products (which contained high and low concentrations of alcohol) and a negative control, in randomized order. Time of onset of oral pain, time of cessation of oral pain (after mouthwash expectoration), and pain duration were recorded, and oral pain intensity was recorded on a verbal rating scale. Drinkers had later oral pain onset and lower pain intensity. High-alcohol mouthwash was associated with earlier pain onset and greater pain intensity. In addition, oral pain cessation was later and pain duration was longer in nondrinkers rinsing with high-alcohol mouthwash. In conclusion, alcohol consumption status and mouthwash alcohol concentration were associated with onset and intensity of oral pain. PMID- 23748449 TI - Nasal immunization with the 40-kDa outer membrane protein of Porphyromonas gingivalis plus cholera toxin induces protective immunity in aged mice. AB - Previous studies have demonstrated that nasal administration of the outer membrane protein of Porphyromonas gingivalis (40k-OMP) with cholera toxin (CT) as an adjuvant elicits protective immune responses against P. gingivalis in young mice. In the present study, we investigated whether administration of 40k-OMP plus CT would also induce 40k-OMP-specific antibody (Ab) responses to provide protective immunity against P. gingivalis infection in aged mice. Nasal immunization with 40k-OMP plus CT elicited 40k-OMP-specific IgG and IgA Ab responses in serum and a significant anti-40k-OMP IgA Ab response in nasal washes and saliva in 1- and 2-year-old mice. Furthermore, both Th1- and Th2-type cytokine responses were induced by the immunization, and cytokine-associated IgG1, IgG2a, and IgG2b Ab responses were observed in the spleens of aged mice. Although the aged mice showed lower 40k-OMP-specific Ab responses than young mice, their mucosal IgA Ab titers as well as serum IgG Ab responses indicated a retained ability to mediate protective immunity; the only exception was saliva in 2-year-old mice. These findings suggest that nasal immunization with 40k-OMP plus CT can be a potential vaccination strategy for eliciting levels of Abs sufficient to provide protective immunity against P. gingivalis infection in aged mice. PMID- 23748450 TI - Effect of ammonium hexafluorosilicate application for arresting caries treatment on demineralized primary tooth enamel. AB - Ammonium hexafluorosilicate (AHF) has been applied to arrest caries without discoloration. The purpose of this study was to observe structural and elemental changes of demineralized and AHF applied primary tooth enamel. Enamel from the labial surface of 20 primary canines was divided into an unground side and ground side at the center of the tooth, and demineralized with 35% phosphoric acid for 6 min. The teeth were divided into 4 groups according to a 3-min application of AHF and 1 week of soaking in artificial saliva, as follows: group A (neither AHF nor saliva), group B (only saliva), group C (only AHF), and group D (AHF and saliva), and then subdivided according to whether the enamel was ground or unground. Specimens were analyzed with scanning electron microscopy (SEM) and energy dispersive X-ray spectrometry (EDS). The data were statistically analyzed using ANOVA and Fisher's PLSD test at alpha = 0.05. In groups A and B, prism structures were seen, however, in groups C and D, enamel surfaces were covered with spherical particles. Ca/P ratio was significantly higher in groups C and D than in groups A and B. There was no significant difference between ground and unground enamel in the content of any element. The values for F, Na, Mg and Si persents and Ca/P ratio were significantly higher for the enamel surface than for points 10-30 um beneath the surface. Results of this study suggest the possibility that AHF treatment arrests caries, although further study will be required to confirm this result. PMID- 23748451 TI - Psychometric properties and performance of the Oral Health Impact Profile (OHIP 14s-ar) among Sudanese adults. AB - The aims of this study were to develop a Sudanese-Arabic version of the English language Oral Health Impact Profile-14 (OHIP-14), assess the psychometric properties and performance of this new instrument, and then use it to investigate the impacts of selected oral disorders on oral health-related quality of life (OHRQoL). Sudanese adolescents and adults (age, >= 16 years; 781 males and 1107 females) attending outpatient clinics in Khartoum State were enrolled. The OHIP 14 was adapted, and the validity and reliability of the Sudanese-Arabic version of the questionnaire (OHIP-14s-ar) were assessed. The OHIP-14s-ar was then used to measure OHRQoL. Pearson correlation coefficients and multivariate analysis were used to examine relationships between OHRQoL and characteristics ascertained by interviews and clinical examinations. The OHIP-14s-ar had suitable construct validity, reliability, and internal consistency (i.e., Cronbach alpha). More than half of the participants reported that oral disorders affected quality of life; psychological discomfort and physical pain were the most frequently reported oral health impacts. Our results suggest that being female, tooth decay, systemic illness, and dry mouth worsen OHRQoL. The oral disorder with the greatest impact was dental caries, and tooth condition seemed to be more important than absence of teeth. The OHIP-14s-ar yielded convincing psychometric data, and its performance makes it a suitable measure for future cross-sectional and longitudinal studies in Sudan. PMID- 23748452 TI - Biochemical composition of carious dentin and different layers of sound dentin. AB - The aim of this study was to evaluate the concentrations of calcium (Ca), inorganic phosphate (Pi) and fluoride (F) in carious dentin and in different layers of sound dentin. The samples examined were 52 permanent teeth (26 sound and 26 carious), which were subjected to two experiments to assess the mineral content of: 1) two layers (internal and external) of sound dentin and 2) sound and carious dentin. Ca and Pi were analyzed using a colorimetric method with arsenazo III (C22H18As2N4O14S2) and molybdate reagents, and F was analyzed using a specific electrode. A non-parametric test, the Mann-Whitney test, was used to verify differences between groups. Sound dentin showed a higher concentration of fluoride in the internal layer than in the external layer (P = 0.03), but no inter-layer differences in Ca or Pi concentration were evident. Lower concentrations of Ca, Pi and F were observed in carious dentin than in sound dentin (P < 0.05). The results of this study suggest that the internal layer of sound dentin has a higher fluoride content than the external layer, and that carious dentin has lower concentrations of Ca, Pi and F than sound dentin. PMID- 23748453 TI - Periodontal status, salivary immunoglobulin, and microbial counts after short exposure to an isolated environment. AB - Salivary flow rate, immunoglobulin, and periodontal status were affected during a simulated Skylab mission. The effect is more prominent after long-duration space flights and can persist for several weeks after landing. The objective of this study was to determine the effect of a simulated Mars environment on periodontal status and levels of salivary microorganisms and immunoglobulins in the human oral cavity. Twelve healthy male volunteers were studied before, at 1 and 2 weeks, and after completion of a mission in an isolated, confined simulated Mars environment at the Mars Desert Research Station, USA. We conducted a current stress test, measured salivary immunoglobulin, cortisol, alpha-amylase, salivary flow rate, and levels of plaque and salivary microbes, and assessed clinical periodontal parameters (probing depth, bleeding on probing, and clinical loss of attachment). Salivary IgG levels and Streptococcus mutans activity were significantly higher at 1 week. Values for clinical periodontal parameters (probing depth, bleeding on probing, and clinical loss of attachment) significantly differed at 1 week. Stress might be caused by the difficulty of the mission rather than the isolated environment, as mission duration was quite short. Periodontal condition might worsen due to poor oral hygiene during the mission. The present findings show that all periodontal conditions and levels of oral bacteria and stress after completion of the simulated Mars mission differed from those at baseline. To verify the relationship between stress status and periodontal health in simulated Mars missions, future studies using larger patient samples and longer follow-up will be required. PMID- 23748454 TI - Prevalence of drug-resistant opportunistic microorganisms in oral cavity after treatment for oral cancer. AB - Drug-resistant opportunistic infections may cause health problems in immunocompromised hosts. Representative microorganisms in opportunistic infections of the oral cavity are Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans. We investigated the prevalence of drug-resistant opportunistic microorganisms in elderly adults receiving follow-up examinations after primary treatment of oral cancer. Oral microorganisms were collected from patients satisfactorily treated for oral cancer (defined as good outcomes to date) and a group of healthy adults (controls). After identification of microorganisms, the prevalence of drug-resistant microorganisms was studied. Pulsed-field gel electrophoresis (PFGE) and staphylococcal cassette chromosome mec (SCCmec) typing were also performed for methicillin-resistant S aureus (MRSA). Statistical analysis revealed no significant differences in the prevalences of the three microorganisms between the groups. Surprisingly, 69.2% of S aureus isolates showed oxacillin resistance, suggesting that MRSA colonization is increasing among older Japanese. These MRSA isolates possessed SCCmec types II and IV but no representative toxin genes. Our results indicate that a basic infection control strategy, including standard precautions against MRSA, is important for elderly adults, particularly after treatment for oral cancer. PMID- 23748455 TI - Mycological and histological associations of Candida in oral mucosal lesions. AB - The present study aimed to assess the presence and level of colonization of Candida in patients with oral mucosal lesions, to determine the presence or absence of candidal hyphae in biopsy specimens and to correlate the degree of epithelial dysplasia with the number of colony-forming units of Candida. We performed a prospective study including 50 patients diagnosed as having oral potentially malignant and malignant disorders. These patients had lesions such as leukoplakia, lichen planus, lichenoid reaction, verrucous carcinoma and oral squamous cell carcinoma. An oral swish with 10 mL of normal saline was performed, and this was collected in a sterile plastic container. Candidal colony-forming units were assessed in the specimen. This was followed by a biopsy of the lesion, which was sent for histopathologic examination for dysplasia and severity, and to assess the presence or absence of candidal hyphae. The results of the present study revealed a correlation between higher Candida colonization and increasing severity of dysplasia. An effort was made to correlate Candida by histologic and mycologic means with epithelial dysplasia. If such a correlation is strongly established, then the importance of antimycotic therapy can be emphasized to avoid deterioration. PMID- 23748456 TI - Release and systemic accumulation of heavy metals from preformed crowns used in restoration of primary teeth. AB - Preformed crowns for restoration of primary teeth are used in various treatments and are essential for restoring the crowns of primary molars. However, there are concerns that mechanical, chemical, and thermal stimulation may cause release of components of such crowns. We examined systemic accumulation of heavy metals associated with preformed crowns (3M Stainless Steel Primary Molar Crowns) used in primary tooth restoration. The participants were 37 children who had visited the Pediatric Dental Clinic of Tsurumi University Dental Hospital. They were divided into two groups: 22 participants without a history of being fitted with a preformed crown for primary tooth restoration (controls), and 15 participants with preformed crowns for primary tooth restoration. Analysis of hair samples showed a significant difference in the level of the trace element Cr - an important component of the preformed crowns - between children with and without preformed crowns, but no significant differences in Fe or Ni levels. Levels of the trace elements Ni, Cr, and Fe were within allowable ranges, indicating that these minerals were not likely to be harmful. PMID- 23748457 TI - Are referred inaccessible human primary molar teeth really inaccessible? AB - Despite a body of compelling evidence pertaining to the root canal accessibility of primary teeth, the number of referrals for inaccessibility of primary molars is considerable. The aim of the present study was to evaluate the prevalence of true and false primary molar inaccessibility among subjects who had been referred by general and pediatric dentists. We examined 199 primary molars in 156 patients (87 males, 69 females) aged 3-7 years who were referred by 215 general and 35 pediatric dentists. Problems related to inaccessibility were recorded for each tooth and any individual canal. One hundred seventy-five inaccessible teeth (87.9%) were successfully rehabilitated to accessible status (P < 0.001). The most frequent cause of inaccessibility was an inappropriate access cavity (42.3%), followed by difficult canals (32.6%) and orifice calcification (25.2%). The tooth most frequently reported as inaccessible was the maxillary first molar (40.2%), and that least frequently reported was the mandibular second molar (11.6%). The distobuccal canal of the maxillary first molar and the mesiolingual canal of the mandibular first molar were the most commonly inaccessible canals (P < 0.001). Only 1 out of 8 teeth referred as inaccessible was truly inaccessible. It seems that root canal inaccessibility is mostly attributable to lack of expertise among individual practitioners. PMID- 23748458 TI - Laser therapy and needling in myofascial trigger point deactivation. AB - The aim of this study was to evaluate different approaches to deactivating myofascial trigger points (MTPs). Twenty-one women with bilateral MTPs in the masseter muscle were randomly divided into three groups: laser therapy, needle treatment and control. Treatment effectiveness was evaluated after four sessions with intervals ranging between 48 and 72 h. Quantitative and qualitative methods were used to measure pain perception/sensation. The Wilcoxon test based on results expressed on a visual analog scale (VAS) demonstrated a significant (P < 0.05) decrease in pain only in the laser and needle treatments groups, although a significant increase in the pressure pain threshold was evident only for needling with anesthetic injection (P = 0.0469), and laser therapy at a dose of 4 J/cm2 (P = 0.0156). Based on these results, it was concluded that four sessions of needling with 2% lidocaine injection with intervals between 48 and 72 h without a vasoconstrictor, or laser therapy at a dose of 4 J/cm2, are effective for deactivation of MTPs. PMID- 23748459 TI - Invasive cervical root resorption 15 years after modified Widman flap surgery. AB - Invasive cervical root resorption is a relatively uncommon form of external root resorption. Creeping attachment is defined as postoperative coronal migration of the gingival margin. We describe a case of invasive cervical root resorption following coronal shift of interdental papillae 15 years after modified Widman flap surgery. PMID- 23748460 TI - Acute apical periodontitis and vertical root fracture of the same tooth: a case report. AB - Vertical root fracture is a frequent complication in endodontically treated teeth and usually leads to extraction of the affected tooth. Differential diagnosis may be difficult, especially in patients with periodontal and endodontic disease. This case report describes the diagnosis and clinical and radiographic features of apical periodontitis and vertical root fracture of the same tooth, which were separated by an interval of several years. Vertical root fracture of the mesial root was diagnosed with the help of an exploratory flap and microscopic observation. PMID- 23748461 TI - Association analysis of two candidate polymorphisms in the tumour necrosis factor alpha gene with osteoarthritis in a Chinese population. AB - PURPOSE: The purpose of this study was to investigate the possible association between single nucleotide polymorphisms (SNPs) rs1800629 (TNF-alpha -308) and rs361525 (TNF-alpha -238) of the tumour necrosis factor (TNF)-alpha gene and susceptibility to osteoarthritis (OA) in the Han Chinese population. METHODS: The TNF-alpha -308 and -238 genotypes were determined by TaqMan assay in 200 OA cases and 305 controls. Odds ratios (ORs) for OA and 95% confidence intervals (CIs) from unconditional logistic regression models were used to evaluate relative risks. RESULTS: The frequencies of the allele 'A' of rs1800629 were 16% and 8.85% in OA cases and in controls, respectively, and thus the -308A allele had a 1.9612 fold (95% CI = 1.3323-2.8869, P < 0.001) increased risk for OA as compared to the -308G allele. However, no significant differences were found in the genotype and allele frequencies for rs361525 between OA and HC groups. CONCLUSIONS: In the Han Chinese population, the allele 'A' of TNF-alpha -308 may increase the risk for OA, whereas TNF-alpha -238 polymorphisms do not play a role in OA patients. PMID- 23748462 TI - The use of an eccentric glenosphere compared with a concentric glenosphere in reverse total shoulder arthroplasty: two-year minimum follow-up results. AB - PURPOSE: The current models of reverse shoulder arthroplasty (RSA) expose the procedure to the risk of scapular notching, possibly leading to loosening of the glenoid. We compared the clinical and radiographic results obtained with a concentric or eccentric glenosphere to assess whether the eccentric design might give better clinical results and avoid or decrease the risk of scapular notching METHODS: Of our patients, 31 underwent RSA using a concentric glenosphere (group A), while 29 had an eccentric glenosphere (group B). Postoperatively, patients were followed-up at one to 12 months and annually thereafter, with the mean being 33 months in group A and 27.5 in group B. In both groups the minimum follow up (F U) was 24 months. Preoperatively and at each F-U starting from six months, patients were assessed using the Constant score. On radiographs, prosthesis scapular neck angle (PSNA), distance between scapular neck and glenosphere (DBSNG) and peg-glenoid rim distance (PGRD) were calculated. The severity of notching was classified in four grades. RESULTS: In group A the mean Constant score increased by 30 points compared to the preoperative score and the active ROM increased considerably. At latest F-U, the mean PSNA, DBSNG and PGRD were, respectively, 87 degrees , 3.4 mm and 19.8 mm. Glenoid notching was present in 42% of cases. In group A, the mean Constant score increased by 34 points and the mean ROM was better than in group A. The average PSNA, PGRD and DBSNG were, respectively, 92 degrees , 21.2 mm and 4.3 mm. Radiographs showed no inferior scapular notching. CONCLUSIONS: The eccentric glenosphere yielded better clinical results than the concentric glenosphere and was associated with no scapular notching. PMID- 23748463 TI - One portal simultaneous bilateral endoscopic carpal tunnel release under local anaesthesia. Do the results justify the effort? AB - PURPOSE: The purpose of this study was to evaluate whether simultaneous bilateral endoscopic carpal tunnel release could be effectively and safely performed under local anaesthesia. METHODS: We prospectively evaluated 85 consecutive patients (62 females) who underwent simultaneous one portal endoscopic bilateral carpal tunnel release with subcutaneous injection of 2 mL 2 % lidocaine. In case of pain after discharge, all patients were advised to take paracetamol (i.e., acetaminophen) and to record the dose of drug taken. Patients were reviewed at regular intervals until one year postoperatively. RESULTS: The mean operative time was 31.2 min. Postoperatively, only nine patients (10.6 %) received on average 611 mg of paracetamol. Significant improvement was noticed in the parameters of numbness, pain, positive Phalen and Tinel tests, pinch strength, grip strength, tip pinch strength and Quick DASH Score. Patients returned fully to work after surgery in average 2.2 weeks. Conversion to open release took place in four wrists (2.4 %). Discomfort and pain from tourniquet pressure was reported from two patients (2.4 %). Two wrists (1.2 %) required revision surgery. One patient (1.2 %) reported temporary thenar numbness and another (1.2 %) had slight scar hypersensitivity. CONCLUSIONS: Simultaneous bilateral endoscopic carpal tunnel release under local anaesthesia is well tolerated by patients. The technique may be of benefit in young, active, high-demand patients who require fast recovery, early return to work and less disability time. PMID- 23748464 TI - Irinotecan, vincristine, cisplatin, cyclophosphamide, and etoposide for refractory or relapsed medulloblastoma/PNET in pediatric patients. AB - PURPOSE: The treatment outcome of pediatric refractory or relapsed brain tumor is very dismal, and effective salvage chemotherapy is not established. The combination of irinotecan, vincristine, cisplatin, cyclophosphamide, and etoposide was administered to pediatric patients with refractory or relapsed brain tumors as a salvage treatment at our institution. METHODS: The combination regimen was administered since June 2006 and consisted of irinotecan (300 mg/m(2), d0), vincristine (2 mg/m(2), d0), cisplatin (60 mg/m(2), d0), cyclophosphamide (1,000 mg/m(2), d1), and etoposide (100 mg/m(2)/day, d0-2). Patients could concurrently receive radiotherapy, surgery, and/or high-dose chemotherapy and stem cell rescue. The medical records of all patients were retrospectively analyzed. RESULTS: Thirteen patients with refractory or relapsed brain tumor were included (medulloblastoma, n = 12; central nervous system primitive neuroectodermal tumor, n = 1). Median time from diagnosis to this combination chemotherapy was 30 months (range, 3-111 months), and median cycle administered was four cycles (range 1-22 cycles). Objective tumor response at the end of chemotherapy was 38.5 % including three patients with complete response and two with partial response. One patient showed complete response and achieved long-term survival with this combination chemotherapy, and two patients achieved long-term survival with multimodality treatments. There was no grade III or IV toxicity related to this combination chemotherapy except for thrombocytopenia and neutropenia. CONCLUSIONS: The combination of irinotecan, vincristine, cisplatin, cyclophosphamide, and etoposide may produce objective responses in pediatric patients with refractory or relapsed medulloblastoma or primitive neuroectodermal tumor. PMID- 23748465 TI - Dural sinus and internal jugular vein thrombosis complicating a blunt head injury in a pediatric patient. AB - INTRODUCTION: Cerebral venous sinus thrombosis (CVST) following a blunt head trauma is a rare condition, described in the literature along with the lack of consensus regarding diagnosis and management. We present a case of a pediatric patient with a blunt head injury and epidural hematoma, who developed dural sinus and internal jugular vein thrombosis with fatal outcome. DISCUSSION: Most of reports show good outcome and recovery, but CVST might be related to poor recovery and even lead to death. The diagnosis and management of this condition are discussed based on a literature review. CONCLUSION: It is important to keep a high degree of suspicion of CVST since early diagnosis may prevent potentially treatable catastrophic outcomes. PMID- 23748466 TI - Changes in body composition in triathletes during an Ironman race. AB - PURPOSE: Triathletes lose body mass during an Ironman triathlon. However, the associated body composition changes remain enigmatic. Thus, the purpose of this study was to investigate Ironman-induced changes in segmental body composition, using for the first time dual-energy X-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). METHODS: Before and after an Ironman triathlon, segmental body composition and lower leg tissue mass, areas and densities were assessed using DXA and pQCT, respectively, in eight non professional male triathletes. In addition, blood and urine samples were collected for the determination of hydration status. RESULTS: Body mass decreased by 1.9 +/- 0.8 kg. This loss was due to 0.4 +/- 0.3 and 1.4 +/- 0.8 kg decrease in fat and lean mass, respectively (P < 0.01). Calf muscle density was reduced by 1.93 +/- 1.04 % (P < 0.01). Hemoglobin, hematocrit, and plasma [K(+)] remained unchanged, while plasma [Na(+)] (P < 0.05), urine specific gravity and plasma and urine osmolality increased (P < 0.01). CONCLUSIONS: The loss in lean mass was explained by a decrease in muscle density, as an indicator of glycogen loss, and increases in several indicators for dehydration. The measurement of body composition with DXA and pQCT before and after an Ironman triathlon provided exact values for the loss in fat and lean mass. Consequently, these results yielded more detailed insights into tissue catabolism during ultra-endurance exercise. PMID- 23748467 TI - Anatomical and procedural features associated with aortic root rupture during balloon-expandable transcatheter aortic valve replacement. AB - BACKGROUND: Aortic root rupture is a major concern with balloon-expandable transcatheter aortic valve replacement (TAVR). We sought to identify predictors of aortic root rupture during balloon-expandable TAVR by using multidetector computed tomography. METHODS AND RESULTS: Thirty-one consecutive patients who experienced left ventricular outflow tract (LVOT)/annular/aortic contained/noncontained rupture during TAVR were collected from 16 centers. A caliper-matched sample of 31 consecutive patients without annular rupture, who underwent pre-TAVR multidetector computed tomography served as a control group. Multidetector computed tomography assessment included short- and long-axis diameters and cross-sectional area of the sinotubular junction, annulus, and LVOT, and the presence, location, and extent of calcification of the LVOT, as well. There were no significant differences between the 2 groups in any preoperative clinical and echocardiographic variables. Aortic root rupture was identified in 20 patients and periaortic hematoma in 11. Patients with root rupture had a higher degree of subannular/LVOT calcification quantified by the Agatston score (181.2+/-211.0 versus 22.5+/-37.6, P<0.001), and a higher frequency of >=20% annular area oversizing (79.4% versus 29.0%, P<0.001) and balloon postdilatation (22.6% versus 0.0%, P=0.005). In conditional logistic regression analysis for the matched data, moderate/severe LVOT/subannular calcifications (odds ratio, 10.92; 95% confidence interval, 3.23-36.91; P<0.001) and prosthesis oversizing >=20% (odds ratio, 8.38; 95% confidence interval, 2.67 26.33; P<0.001) were associated with aortic root contained/noncontained rupture. CONCLUSIONS: This study demonstrates that LVOT calcification and aggressive annular area oversizing are associated with an increased risk of aortic root rupture during TAVR with balloon-expandable prostheses. Larger studies are warranted to confirm these findings. PMID- 23748468 TI - Measuring North Carolina pharmacists' support for expanded authority to administer human papillomavirus vaccines. AB - PURPOSE: To assess North Carolina pharmacists' level of support for expanded authority to administer human papillomavirus (HPV) vaccines to identify concerns/benefits about expanded authority and to understand what factors predict support for expanded authority. METHOD: A 16-item electronic survey was e-mailed to all the pharmacists registered with the North Carolina Board of Pharmacy (n = 9502) between January and February 2011 (1600 pharmacists responded). The survey assessed HPV knowledge, level of support for expanded authority, and comfort level of HPV vaccine administration. RESULTS: Many (64%) pharmacists were supportive of a rule change/legislation that would authorize pharmacists to administer HPV vaccines. Younger pharmacists were more supportive of expansion when compared to older pharmacists (r = -.138, P < .001). Pharmacists with higher knowledge scores were more supportive of expansion (r = .223, P < .001). Reporting a higher level of comfort in administering HPV vaccines at their pharmacy was significantly and positively correlated with higher level of support for expansion (r = .624, P < .001). In the multivariate analysis, HPV knowledge, comfort level in administering vaccine, patient age, and type of pharmacy were all predictive of higher level of support for expanded authority where employed. CONCLUSION: A large proportion of pharmacists were supportive of an expanded role in providing HPV vaccines. Exploring alternate delivery mechanisms like this one is advantageous. PMID- 23748469 TI - Osgood-Schlatter disease in an English setter. PMID- 23748470 TI - Cathepsin L inhibition by the small molecule KGP94 suppresses tumor microenvironment enhanced metastasis associated cell functions of prostate and breast cancer cells. AB - Metastasis remains the major cause of therapeutic failure, poor prognosis and high mortality in breast and prostate cancer patients. Aberrant microenvironments including hypoxia and acidic pH are common features of most solid tumors that have been long associated with enhanced metastasis and poor patient outcomes. Novel approaches to reduce metastatic incidences and improve overall survival of cancer patients clearly are needed. The crucial role of Cathepsin L (CTSL) in the dissemination of tumor cells has led to the development of novel cathepsin L inhibition strategies. The present study evaluated the ability of KGP94, a small molecule inhibitor of CTSL, to impair the metastatic phenotype of prostate (PC 3ML) and breast (MDA-MB-231) cancer cells both under normal and aberrant microenvironmental conditions. To assess the role of CTSL in hypoxia and acidosis triggered metastasis associated cell functions, secreted CTSL levels were determined under conditions pertinent to the tumor microenvironment. Acute exposures to hypoxic or acidic conditions significantly elevated secreted CTSL levels either through an increase in intracellular CTSL levels or through activation of lysosomal exocytosis or both, depending on the tumor type. Increases in CTSL secretion closely paralleled enhanced tumor cell migration and invasion suggesting that CTSL could be an essential factor in tumor microenvironment triggered metastasis. Importantly, KGP94 treatment led to marked attenuation of tumor cell invasion and migration under both normal and aberrant microenvironmental conditions suggesting that it may have significant utility as an anti-metastatic agent. PMID- 23748471 TI - Development and characterization of a reliable mouse model of colorectal cancer metastasis to the liver. AB - Colorectal cancer (CRC) is the third most frequent cancer and the third leading cause of cancer deaths in the United States (American Cancer Society, Cancer facts and figures 2012, 20121). The major cause of death is metastasis and frequently, the target organ is the liver. Successful metastasis depends on acquired properties in cancer cells that promote invasion and migration, and on multiple interactions between tumors and host-derived cells in the microenvironment. These processes, however, occur asymptomatically, thus, metastasis remains poorly understood and often diagnosed only at the final stage. To facilitate the elucidation of the mechanisms underlying these processes and to identify the molecular regulators, particularly at the early stages, we developed a mouse model of hepatic metastasis of CRC by cecal implantation of a mouse adenocarcinoma cell line in an immune competent host that reliably recapitulates all steps of tumor growth and metastasis within a defined period. By in vivo selection, we isolated cells of varying metastatic potential. The most highly metastatic CT26-FL3 cells produced liver metastasis as early as 10 days after implantation in 90 % of host mice. These cells expressed elevated levels of genes whose products promote invasion, migration, and mobilization of bone marrow derived cells (BMDCs). Mice bearing tumors from CT26-FL3 had elevated serum levels of OPN, MMP9, S100A8, S100A9, SAA3, and VEGFA that promote invasion and BMDC mobilization, and showed enhanced BMDC recruitment to the liver where they established a pre-metastatic niche. This model provides an important platform to characterize metastatic cells and elucidate tumor-host interactions and mechanisms that drive liver metastasis of CRC. PMID- 23748472 TI - Peroxisome proliferator activated receptor gamma gene variants influence susceptibility and insulin related traits in Indian women with polycystic ovary syndrome. AB - PURPOSE: Peroxisome proliferator activated receptor gamma (PPARgamma), a transcription factor involved in glucose and lipid metabolism is one of the candidate genes associated with polycystic ovary syndrome (PCOS). We investigated individual and combined associations of Pro12Ala and His447His polymorphisms of PPARgamma with PCOS susceptibility and its related traits (hyperinsulinemia, hyperandrogenemia and lipid parameters) in Indian women. METHOD: Genotyping of PPARgamma polymorphisms in this case-control study was performed in PCOS (n = 450) and age-matched controls (n = 300) by direct sequencing. Clinical, anthropometric, hormonal and metabolic parameters were estimated in 275 women with PCOS and 169 controls. Chi-square test was used to compare the categorical data while regression analysis was used to evaluate association of genotypes with PCOS as well as its related phenotypes. RESULTS: The frequencies of CC and CG + GG genotypes of Pro12Ala (chi2 = 15.3, p < 0.0001) and CC and CT + TT genotypes of His447His (chi2 = 12.7, p = 0.0004) polymorphisms were significantly different between PCOS and controls. Logistic regression analysis revealed a significant association of PCOS with Pro12Ala but not the His447His polymorphism. Carriers of variant genotypes at both PPARgamma loci showed significantly reduced 2 h glucose levels while carriers of variant His447His genotype showed lower fasting insulin and HOMA-IR levels in PCOS women. CONCLUSIONS: Pro12Ala polymorphism of PPARgamma showed significant association with decreased PCOS susceptibility. Both polymorphisms influenced insulin related traits (2 h glucose, fasting insulin and HOMA-IR) and improved glucose metabolism in these women. This is the first report to establish that variations in PPARgamma gene influence the insulin resistance pathophysiology in Indian women with PCOS. PMID- 23748473 TI - Legal termination of a pregnancy resulting from transplanted cryopreserved ovarian tissue due to cancer recurrence. AB - PURPOSE: To report on a woman who conceived naturally and had a normal intrauterine pregnancy following transplantation of frozen/thawed ovarian tissue but decided to have an early abortion due to recurrence of breast cancer. METHODS: The patient was diagnosed breast cancer and received antineoplastic treatment that forced her into premature ovarian insufficiency and infertility. Ovarian tissue cryopreserved prior to chemotherapy was transplanted following cancer treatment restoring fertility and regular menstrual cycles. RESULTS: The patient conceived 6 month after transplantation. However, she experienced recurrence of breast cancer and decided on legal termination of the pregnancy in the first trimester. DISCUSSION: The obtained pregnancy only 6 month following transplantation underlines the ability of the procedure. The recurrence occurred near the original site of the tumor and was most unlikely related to the transplantation. The activity of the transplanted tissue is likely to be destroyed by the renewed antineoplastic treatment she will receive. However, she still has the majority of one ovary cryostored and may later want to undergo additional transplantation to regain fertility or to have menstrual cycles back. PMID- 23748474 TI - Phenobarbitone in Rh hemolytic disease of the newborn: a randomized double blinded placebo-controlled trial. AB - OBJECTIVE: To evaluate the efficacy of prophylactic oral phenobarbitone (PB) in neonates with Rh hemolytic disease of the newborn. STUDY DESIGN: In this double blind randomized trial conducted in a tertiary care unit, we randomly allocated neonates with Rh hemolytic disease of the newborn born at or after 32 weeks' gestation to PB (10 mg/kg/day on day 1 followed by 5 mg/kg/day on days 2-5) (n = 23) or oral glucose (n = 21). The primary outcome was the duration of phototherapy. RESULTS: Baseline variables were comparable. There was no difference in the median duration of phototherapy [54 (range: 0-180) vs. 35 h (0 127); p = 0.39] and in the incidences of failure of phototherapy or significant rebounds of serum bilirubin. However, the proportion of infants with cholestasis was significantly lower in the PB group (0 vs. 19%; p = 0.04). CONCLUSIONS: PB does not reduce duration of phototherapy or its episodes. Its potential to reduce cholestasis needs validation in larger studies. PMID- 23748476 TI - [Not Available]. PMID- 23748477 TI - [Not Available]. PMID- 23748475 TI - Malnutrition determinants in young children from Burkina Faso. AB - Childhood malnutrition remains a major challenge to public health in poor countries. Data on malnutrition determinants in African children are scarce. A cross-sectional survey was performed in eight villages of Burkina Faso in June 2009, including 460 children aged 6-31 months. Demographic, socioeconomic, parasitological, clinical and anthropometric characteristics were collected. The main outcome variable was weight-for-length (WFL) z-score (i.e. wasting). A multiple regression model identified village, age group, religion and the presence of younger siblings as significantly associated with wasting. Villages differed in their mean WFL z-score by up to one unit. Compared with younger children, the mean WFL z-score of children aged 24-35 months was 0.63 units higher than the WFL z-score in younger children. This study confirms the still unacceptable high level of malnutrition in young children of rural West Africa and supports the fact that childhood malnutrition is a complex phenomenon highly influenced by contextual variables. PMID- 23748478 TI - [Not Available]. PMID- 23748479 TI - [Not Available]. PMID- 23748480 TI - Synthesis and characterization of coordinatively unsaturated nickel(II) and manganese(II) alkyl complexes supported by the hydrotris(3-phenyl-5 methylpyrazolyl)borate (Tp(Ph,Me)) ligand. AB - The synthesis of several nickel(II) and manganese(II) alkyl complexes supported by hydrotris(3-phenyl-5-methylpyrazolyl)borate (Tp(Ph,Me)) ligand is reported. The metal halide complexes Tp(Ph,Me)MnCl(CH3CN) (1) and Tp(Ph,Me)NiCl (4) were used as precursors for synthesis of Tp(Ph,Me)MnCH2Si(Me)3 (2), Tp(Ph,Me)MnCH2Ph (3), Tp(Ph,Me)NiCH2Si(Me)3 (5) and Tp(Ph,Me)NiCH2Ph (6). The resulting Mn(II) and Ni(II) alkyl complexes, 2-3 and 5-6, were characterized by X-ray crystallography, NMR spectroscopy, and FT-IR spectroscopy. X-ray crystallographic analysis revealed distorted tetrahedral geometries for complexes 2-3 and 5 with a kappa(3) Tp(Ph,Me). Complex 6, on the other hand, was found to have a distorted square planar geometry with kappa(2)-Tp(Ph,Me) and an eta(3)-benzyl ligand. Transformations of 4 and Tp(Ph,Me)CoCl (10) via treatment with NaN3 to yield Tp(Ph,Me)NiN3 (11), Tp(Ph,Me)CoN3 (12), along with the synthesis of (Tp(Ph,Me))2Ni (8) and Tp(Ph,Me)NiCl(3-Ph-5MepzH) (9) are also reported. PMID- 23748481 TI - Theoretical investigation of the selectivity in intramolecular cyclizations of some 2'-aminochalcones to dihydroquinolin-8-ones and indolin-3-ones. AB - The selectivity of the intramolecular cyclizations of a series of 2' aminochalcones was investigated with an approach that combines spin-polarized conceptual density functional theory and energy calculations. To that aim, condensed-to-atoms electrophilic Fukui functions, f NN (+) (r), were utilized as descriptors of the proclivity for nucleophilic attack of the NH2 group on the unsaturated alpha and beta carbons. The results of our model are in excellent agreement with the experimental available evidence permitting us in all cases to predict when the cyclization processes led to the formation of 5-exo and 6-endo products. PMID- 23748482 TI - Cognitive interviewing of bereaved relatives to improve the measurement of health outcomes and care utilisation at the end of life in a mortality followback survey. AB - PURPOSE: The evaluation of end of life care via bereaved relatives is increasingly common. We aimed to improve the measurement of health outcomes and care utilisation at the end of life with this population. METHODS: A cross sectional study of 20 bereaved relatives of cancer patients was conducted. In phase I, nine underwent a cognitive interview for 65-150 min using five measures: Client Service Receipt Inventory, Life Before Death survey care satisfaction items, Palliative care Outcome Scale (POS), EQ-5D and Core Bereavement Items (CBI). In phase II, items/scales were revised and tested with a further 11 participants. Content analysis explored information processing and errors. RESULTS: All 20 participants understood most questions despite finding them demanding and intense. Judging the accuracy of information and formulating final answers posed more difficulties than recalling facts. Uncertainty and missing data on care utilisation were often due to estimating averages; consequently categories were introduced. Participants perceived the care satisfaction rating scale to be positively biased; a very poor category was added. POS was seen to ask relevant but sometimes difficult questions, whilst the EQ-5D produced fewer missing data but lacked intermediate categories. CBI had terms that participants felt were unfamiliar, unrealistic, unclear or too strong; hence, we changed to the Texas Revised Inventory of Grief (with no problems identified). CONCLUSIONS: Cognitive interviewing helped select measures and make changes that improved the measurement of health outcomes and care utilisation at the end of life with bereaved relatives. The use of both generic and specific health measures and cost measurement in bereavement is encouraged. PMID- 23748483 TI - Assessment of long-term rectal function in patients who received pelvic radiotherapy: a pooled North Central Cancer Treatment Group trial analysis, N09C1. AB - PURPOSE: Pelvic radiotherapy (PRT) is known to adversely affect bowel function (BF) and patient well-being. This study characterized long-term BF and evaluated quality of life (QOL) in patients receiving PRT. METHODS: Data from 252 patients were compiled from two North Central Cancer Treatment Group prospective studies, which included assessment of BF and QOL by the BF questionnaire (BFQ) and Uniscale QOL at baseline and 12 and 24 months after completion of radiotherapy. BFQ scores (sum of symptoms), Uniscale results, adverse-event incidence, and baseline demographic data were compared via t test, chi (2), Fisher exact, Wilcoxon, and correlation methodologies. RESULTS: The total BFQ score was higher than baseline at 12 and 24 months (P < 0.001). More patients had five or more symptoms at 12 months (13 %) and 24 months (10 %) than at baseline (2 %). Symptoms occurring in greater than 20 % of patients at 12 and 24 months were clustering, stool-gas confusion, and urgency. Factors associated with worse BF were female sex, rectal or gynecologic primary tumors, prior anterior resection of the rectum, and 5-fluorouracil chemotherapy. Patients experiencing grade 2 or higher acute toxicity had worse 24-month BF (P values, <.001-.02). Uniscale QOL was not significantly different from baseline at 12 or 24 months, despite worse BFQ scores. CONCLUSIONS: PRT was associated with worse long-term BF. Worse BFQ score was not associated with poorer QOL. Further research to characterize the subset of patients at risk of significant decline in BF is warranted. PMID- 23748484 TI - Association of health-related quality of life with gender in patients with B-cell chronic lymphocytic leukemia. AB - PURPOSE: This analysis examined associations between gender and health-related quality of life (HRQOL) in patients with B-cell chronic lymphocytic leukemia (CLL) as they initiate therapy for CLL outside the clinical trial setting. METHODS: Baseline data were collected as part of Connect(r) CLL Registry, a prospective observational study initiated in community, academic, and government centers. Patient demographics and clinical characteristics were provided by clinicians. Patients reported HRQOL using the Brief Fatigue Inventory (BFI), EQ 5D, and Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Mean scores were analyzed, with statistical significance of differences determined by ANOVA. Multivariate analysis also considered age and line of therapy. RESULTS: Baseline HRQOL data were available for 1,140 patients: 710 (62 %) men and 430 (38 %) women from 161 centers. Patients were predominantly white (89 %) with mean age 69 +/- 11 years. Women reported significantly worse global fatigue (P <0.0001), fatigue severity (P <0.0001), and fatigue-related interference (P = 0.0005) versus men (BFI). Pain/discomfort (P = 0.0077), usual activities (P = 0.0015), and anxiety/depression (P = 0.0117) were significantly worse in women than in men (EQ 5D). With women reporting a better social/family score (P = 0.0238) and men reporting a better physical score (P = 0.0002), the mean FACT-G total score did not differ by gender. However, the mean FACT-Leu total score was better among men versus women (P = 0.0223), primarily because the mean leukemia subscale score was significantly better among men (P <0.0001). Multivariate analysis qualitatively confirmed these findings. CONCLUSIONS: Connect(r) CLL Registry results indicate that significant differences exist in certain HRQOL domains, as women reported greater levels of fatigue and worse functioning in physical domains. PMID- 23748485 TI - Pilot study on the efficacy of an ondansetron- versus palonosetron-containing antiemetic regimen prior to highly emetogenic chemotherapy. AB - PURPOSE: Nausea and vomiting are among the most feared complications of chemotherapy reported by patients. The objective of this study was to establish the overall complete response (CR; no emesis or use of rescue medication 0-120 h after chemotherapy) with either ondansetron- or palonosetron-containing antiemetic regimens in patients receiving highly emetogenic chemotherapy (HEC). METHODS: This was a prospective, open-label, randomized, single-center, pilot study that enrolled patients receiving their first cycle of HEC. Patients were randomized to receive either palonosetron 0.25 mg IV (PAD) or ondansetron 24 mg orally (OAD) on day 1 prior to HEC. All patients received oral aprepitant 125 mg on day 1, then 80 mg on days 2 and 3, and oral dexamethasone 12 mg on day 1, then 8 mg on days 2, 3, and 4. Descriptive statistics were used to summarize the data. RESULTS: A total of 40 patients were enrolled, 20 in each arm. All patients were female, and 39 received doxorubicin/cyclophosphamide chemotherapy for breast cancer. For the primary endpoint, 65 % (95 % CI, 40.8-84.6 %) of patients in the PAD arm and 40 % (95 % CI, 19.1-63.9 %) of patients in the OAD arm achieved an overall CR. CONCLUSIONS: While CR rates for aprepitant and dexamethasone plus palonosetron or ondansetron-containing regimens have been published previously, this is the first documentation of CR rates with these regimens in the same patient population. These results may be used to design a larger, adequately powered, prospective study comparing these regimens. PMID- 23748486 TI - Incidence and predictors of febrile neutropenia during chemotherapy in patients with head and neck cancer. AB - PURPOSE: Febrile neutropenia (FN) is an oncologic emergency, and its management is critical during chemotherapy. However, little is known about FN in patients with head and neck cancer. The purpose of this study was to investigate the incidence and predictors of FN in patients with head and neck cancer. METHODS: We performed a retrospective study in a university hospital in Japan between January 2008 and December 2012. Head and neck cancer patients treated with a platinum based regimen were included in the analysis. RESULTS: FN occurred in 47 out of 138 cycles, and the incidence of FN was highest during the first cycle. Severe sepsis or more serious events were observed in 46 % of FN episodes. Patients treated with TPF (docetaxel, cisplatin, and fluorouracil) were more susceptible to FN than those treated with DC (docetaxel, cisplatin). The patient-specific risk factors revealed using univariate analysis were tube feeding, the presence of diabetes mellitus, and gastrointestinal adverse effects. Of these, logistic regression analysis demonstrated tube feeding and diabetes mellitus as independent predictors of FN. CONCLUSIONS: The incidence of FN in head and neck cancer patients in the community setting is higher than previously reported. Patients receiving enteral nutrition and those with diabetes are at high risk for FN. PMID- 23748487 TI - Differences in quality of life and emotional status between infertile women and their partners. AB - STUDY QUESTION: Do the quality of life (QoL) and the risk factors for emotional problems during and after treatment of infertile women differ from their partners? SUMMARY ANSWER: Women have lower levels of fertility-related QoL, and more and differing risk factors for emotional problems during and after treatment than their partners. WHAT IS KNOWN ALREADY?: The psychological impact of infertility in patients negatively affects their QoL and is also related to increased discontinuation of treatment. Moreover, psychological factors might positively affect pregnancy rates. However, it is still unclear if differences in QoL and emotional status exist between infertile women and their partners. So far, research mainly focused on generic instruments to measure patients' QoL in the area of fertility care. STUDY DESIGN, SIZE, DURATION: A cross-sectional study of infertile couples within 32 Dutch fertility clinics. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included infertile women and their partners (both heterosexual and lesbian couples) under any treatment and at any stage of treatment in one of the 32 participating clinics. Per clinic, 25-75 patients were randomly selected depending on clinic size. In total, 1620 women and their partners were invited separately to complete the FertiQoL and SCREENIVF questionnaires to measure their level of QoL and risk factors for emotional problems during and after treatment, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 946 women (response rate 58%) and 670 partners (response rate 41%) completed the questionnaire set. As 250 women and 150 partners were already pregnant, questionnaires from 696 women and 520 partners could be analysed. Women scored significantly lower on the FertiQoL total scores [B = -6.31; 95% confidence interval (CI) = -7.63 to 4.98] and three of the FertiQoL subscales (Emotional, Mind-Body and Social) than their partners, indicating lower QoL. Scores on the SCREENIVF questionnaire were significantly higher for women (B = 0.22; 95% CI = 0.06-0.38), indicating that women are more at risk for developing emotional problems (and these factors differed from those of their partners) during and after fertility treatment than their partners. LIMITATIONS, REASONS FOR CAUTION: Although the number of participants is high (n = 1216), the relatively low response rate, especially for partners (41%), may have influenced the results through selection bias. An analysis of non-responders could not be performed. The FertiQoL and SCREENIVF questionnaires, which have been validated only in women starting a first IVF cycle, should also be validated for studying partners. In addition, the SCREENIVF questionnaire has been validated in Dutch women only and further research in an international setting is also required. WIDER IMPLICATIONS OF THE FINDINGS: Our study results represent the Dutch infertile population as more than one-third of all Dutch clinics participated in the study. As the FertiQoL questionnaire is an internationally validated questionnaire already, these results can be put in a more broader and international perspective. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Merck Sharp & Dohme (MSD), The Netherlands. There are no competing interests. PMID- 23748488 TI - Substrate contributions in micro-ATR of thin samples: implications for analysis of cells, tissue and biological fluids. AB - Low-e microscope slides are a common substrate for biological samples. Typically they are used for transflection infrared microspectroscopy but increasingly they are also being used for micro-ATR experiments since it is assumed that the FTIR ATR absorbance spectra of cells and tissue on low-e substrates will not contain any spectral contributions from the substrate materials. This, in part, is due to the expectation that all the infrared light will be reflected at the highly reflective surface. At low sample thicknesses, however (e.g. less than 2 MUm) the electric field does indeed penetrate through the substrate layers and undergoes absorption, from the glass supporting layer making up the majority of the slide. In this paper we show experimental evidence of the substrate contributions in ATR spectra and also a theoretical model giving insight into the spectral contributions of the substrate as a function of sample thickness. PMID- 23748489 TI - [Rational imaging in internal medicine]. PMID- 23748490 TI - [New treatment strategies for multiple myeloma]. PMID- 23748491 TI - Modern surface plasmon resonance for bioanalytics and biophysics. AB - Physical chemistry, materials science, analytical chemistry and engineering greatly contributed to the increasing popularity of bioanalytical and biophysical applications of surface plasmon resonance (SPR) by providing novel materials, surface chemistry, instrumental concepts, and theory to further understand the plasmonic phenomenon and support innovation in SPR. This perspective article portrays the contemporary state of SPR-based techniques and establishes a list of challenges to be overcome for improving bioanalytical and biophysical applications of plasmonics and surface plasmon resonance. PMID- 23748493 TI - A new colorectal/coloanal anastomotic technique in sphincter-preserving operation for lower rectal carcinoma using transanal pull-through combined with single stapling technique. AB - PURPOSE: This study aims to introduce a new anastomotic technique-transanal pull through combined with single stapling technique (PT-SST), and evaluate the value in the sphincter-preserving operation for lower rectal carcinoma. METHODS: Between January 2004 and September 2011, 131 consecutive patients had sphincter preserving operations using PT-SST and double stapling technique (DST) for low colorectal anastomosis. The data was prospectively collected. RESULTS: There are 45 patients (male 26, median = 55 years) in PT-SST group and 86 (male 46, median = 55 years) in the DST group. Anastomotic leakage took place in three patients in DST group, while no anastomotic leakage happened in PT-SST group. There are recurrences in pelvic cavity for one patient (2.2 %), in anastomotic stoma for no patient, and hepatic metastasis for four patients (8.9 %) in PT-SST group; while there are recurrences in pelvic cavity for three patients (3.5 %), in anastomotic stoma for two patients (2.3 %), and hepatic metastasis for seven patients (8.1 %) in DST group. No significant difference was indicated in the terms of the recurrence and hepatic metastasis between the two groups. Patients were satisfied with functional results. CONCLUSIONS: This new technique can solve some technique problems of DST and has at least comparable outcomes compared with DST. It is a safe and feasible procedure for performing low anastomosis with high rate of sphincter preservation. It can be used especially for patients with small pelvis. PMID- 23748494 TI - Laparoscopic repair of internal hernia following laparoscopic anterior resection. PMID- 23748496 TI - Molecular functions of anoctamin 6 (TMEM16F): a chloride channel, cation channel, or phospholipid scramblase? AB - Anoctamin 6 (Ano6; TMEM16F gene) is a ubiquitous protein; the expression of which is defective in patients with Scott syndrome, an inherited bleeding disorder based on defective scrambling of plasma membrane phospholipids. For Ano6, quite diverse functions have been described: (1) it can form an outwardly rectifying, Ca(2+)-dependent and a volume-regulated Cl(-) channel; (2) it was claimed to be a Ca(2+)-regulated nonselective cation channel permeable for Ca(2+); (3) it was shown to be essential for Ca(2+)-mediated scrambling of membrane phospholipids; and (4) it can regulate cell blebbing and microparticle shedding. Deficiency of Ano6 in blood cells from Scott patients or Ano6 null mice appears to affect all of these cell responses. Furthermore, Ano6 deficiency in mice impairs the mineralization of osteoblasts, resulting in reduced skeletal development. These diverse results have been obtained under different experimental conditions, which may explain some of the contradictions. This review therefore aims to summarize the currently available information on the diverse roles of Ano6 and tries to clear up some of the existing controversies. PMID- 23748497 TI - In vivo chlorine and sodium MRI of rat brain at 21.1 T. AB - OBJECT: MR imaging of low-gamma nuclei at the ultrahigh magnetic field of 21.1 T provides a new opportunity for understanding a variety of biological processes. Among these, chlorine and sodium are attracting attention for their involvement in brain function and cancer development. MATERIALS AND METHODS: MRI of (35)Cl and (23)Na were performed and relaxation times were measured in vivo in normal rat (n = 3) and in rat with glioma (n = 3) at 21.1 T. The concentrations of both nuclei were evaluated using the center-out back-projection method. RESULTS: T 1 relaxation curve of chlorine in normal rat head was fitted by bi-exponential function (T 1a = 4.8 ms (0.7) T 1b = 24.4 +/- 7 ms (0.3) and compared with sodium (T 1 = 41.4 ms). Free induction decays (FID) of chlorine and sodium in vivo were bi-exponential with similar rapidly decaying components of [Formula: see text] ms and [Formula: see text] ms, respectively. Effects of small acquisition matrix and bi-exponential FIDs were assessed for quantification of chlorine (33.2 mM) and sodium (44.4 mM) in rat brain. CONCLUSION: The study modeled a dramatic effect of the bi-exponential decay on MRI results. The revealed increased chlorine concentration in glioma (~1.5 times) relative to a normal brain correlates with the hypothesis asserting the importance of chlorine for tumor progression. PMID- 23748498 TI - Binding of a natural anthocyanin inhibitor to influenza neuraminidase by mass spectrometry. AB - The binding of a natural anthocyanin to influenza neuraminidase has been studied employing mass spectrometry and molecular docking. Derived from a black elderberry extract, cyanidin-3-sambubiocide has been found to be a potent inhibitor of sialidase activity. This study reveals the molecular basis for its activity for the first time. The anthocyanin is shown by parallel experimental and computational approaches to bind in the so-called 430-cavity in the vicinity of neuraminidase residues 356-364 and 395-432. Since this antiviral compound binds remote from Asp 151 and Glu 119, two residues known to regulate neuraminidase resistance, it provides the potential for the development of a new class of antivirals against the influenza virus without this susceptibility. PMID- 23748495 TI - Endothelial control of vasodilation: integration of myoendothelial microdomain signalling and modulation by epoxyeicosatrienoic acids. AB - Endothelium-derived epoxyeicosatrienoic acids (EETs) are fatty acid epoxides that play an important role in the control of vascular tone in selected coronary, renal, carotid, cerebral and skeletal muscle arteries. Vasodilation due to endothelium-dependent smooth muscle hyperpolarization (EDH) has been suggested to involve EETs as a transferable endothelium-derived hyperpolarizing factor. However, this activity may also be due to EETs interacting with the components of other primary EDH-mediated vasodilator mechanisms. Indeed, the transfer of hyperpolarization initiated in the endothelium to the adjacent smooth muscle via gap junction connexins occurs separately or synergistically with the release of K(+) ions at discrete myoendothelial microdomain signalling sites. The net effects of such activity are smooth muscle hyperpolarization, closure of voltage dependent Ca(2+) channels, phospholipase C deactivation and vasodilation. The spatially localized and key components of the microdomain signalling complex are the inositol 1,4,5-trisphosphate receptor-mediated endoplasmic reticulum Ca(2+) store, Ca(2+)-activated K(+) (KCa), transient receptor potential (TRP) and inward rectifying K(+) channels, gap junctions and the smooth muscle Na(+)/K(+)-ATPase. Of these, TRP channels and connexins are key endothelial effector targets modulated by EETs. In an integrated manner, endogenous EETs enhance extracellular Ca(2+) influx (thereby amplifying and prolonging KCa-mediated endothelial hyperpolarization) and also facilitate the conduction of this hyperpolarization to spatially remote vessel regions. The contribution of EETs and the receptor and channel subtypes involved in EDH-related microdomain signalling, as a candidate for a universal EDH-mediated vasodilator mechanism, vary with vascular bed, species, development and disease and thus represent potentially selective targets for modulating specific artery function. PMID- 23748499 TI - Distinct neural activation patterns underlie economic decisions in high and low psychopathy scorers. AB - Psychopathic traits affect social functioning and the ability to make adaptive decisions in social interactions. This study investigated how psychopathy affects the neural mechanisms that are recruited to make decisions in the ultimatum game. Thirty-five adult participants recruited from the community underwent functional magnetic resonance imaging scanning while they performed the ultimatum game under high and low cognitive load. Across load conditions, high psychopathy scorers rejected unfair offers in the same proportion as low scorers, but perceived them as less unfair. Among low scorers, the perceived fairness of offers predicted acceptance rates, whereas in high scorers no association was found. Imaging results revealed that responses in each group were associated with distinct patterns of brain activation, indicating divergent decision mechanisms. Acceptance of unfair offers was associated with dorsolateral prefrontal cortex activity in low scorers and ventromedial prefrontal cortex activity in high scorers. Overall, our findings point to distinct motivations for rejecting unfair offers in individuals who vary in psychopathic traits, with rejections in high psychopathy scorers being probably induced by frustration. Implications of these results for models of ventromedial prefrontal cortex dysfunction in psychopathy are discussed. PMID- 23748500 TI - Neural substrates of classically conditioned fear-generalization in humans: a parametric fMRI study. AB - Recent research on classical fear-conditioning in the anxiety disorders has identified overgeneralization of conditioned fear as an important conditioning correlate of anxiety pathology. Unfortunately, only one human neuroimaging study of classically conditioned fear generalization has been conducted, and the neural substrates of this clinically germane process remain largely unknown. The current generalization study employs a clinically validated generalization gradient paradigm, modified for the fMRI environment, to identify neural substrates of classically conditioned generalization that may function aberrantly in clinical anxiety. Stimuli include five rings of gradually increasing size with extreme sizes serving as cues of conditioned danger (CS+) and safety (CS-). The three intermediately sized rings serve as generalization stimuli (GSs) and create a continuum-of-size from CS+ to CS-. Results demonstrate 'positive' generalization gradients, reflected by declines in responding as the presented stimulus differentiates from CS+, in bilateral anterior insula, dorsomedial prefrontal cortex, and bilateral inferior parietal lobule. Conversely, 'negative' gradients, reflected by inclines in responding as the presented stimulus differentiates from CS+ were instantiated in bilateral ventral hippocampus, ventromedial prefrontal cortex and precuneus cortex. These results as well as those from connectivity analyses are discussed in relation to a working neurobiology of conditioned generalization centered on the hippocampus. PMID- 23748501 TI - COMT Val158Met * SLC6A4 5-HTTLPR interaction impacts on gray matter volume of regions supporting emotion processing. AB - There have been several reports on the association between the Val(158)Met genetic polymorphism of the catechol-O-methyltransferase (COMT) gene, as well as the serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene (SLC6A4), and frontolimbic region volumes, which have been suggested to underlie individual differences in emotion processing or susceptibility to emotional disorders. However, findings have been somewhat inconsistent. This study used diffeomorphic anatomic registration through exponentiated Lie algebra (DARTEL) whole-brain voxel-based morphometry to study the genetic effects of COMT Val(158)Met and SLC6A4 5-HTTLPR, as well as their interaction, on the regional gray matter volumes of a sample of 91 healthy volunteers. An interaction of COMT Val(158)Met * SLC6A4 5-HTTLPR genotypes with gray matter volume was found in bilateral parahippocampal gyrus, amygdala, hippocampus, vermis of cerebellum and right putamen/insula. In particular, the gray matter volume in these regions was smaller in individuals who were both COMT Met and 5-HTTLPR-S carriers, or both COMT-Val and 5-HTTLPR-L homozygotes, as compared with individuals with intermediate combinations of alleles. The interaction of COMT Val(158)Met and SLC6A4 5-HTTLPR adds to the understanding of individual differences in emotion processing. PMID- 23748502 TI - Combinatorial tetramer staining and mass cytometry analysis facilitate T-cell epitope mapping and characterization. AB - It is currently not possible to predict which epitopes will be recognized by T cells in different individuals. This is a barrier to the thorough analysis and understanding of T-cell responses after vaccination or infection. Here, by combining mass cytometry with combinatorial peptide-MHC tetramer staining, we have developed a method allowing the rapid and simultaneous identification and characterization of T cells specific for many epitopes. We use this to screen up to 109 different peptide-MHC tetramers in a single human blood sample, while still retaining at least 23 labels to analyze other markers of T-cell phenotype and function. Among 77 candidate rotavirus epitopes, we identified six T-cell epitopes restricted to human leukocyte antigen (HLA)-A*0201 in the blood of healthy individuals. T cells specific for epitopes in the rotavirus VP3 protein displayed a distinct phenotype and were present at high frequencies in intestinal epithelium. This approach should be useful for the comprehensive analysis of T cell responses to infectious diseases or vaccines. PMID- 23748503 TI - Cardiovascular effects of dipeptidyl peptidase-4 inhibitors: from risk factors to clinical outcomes. AB - Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are oral incretin-based glucose-lowering agents with proven efficacy and safety in the management of type 2 diabetes mellitus (T2DM). In addition, preclinical data and mechanistic studies suggest a possible additional non-glycemic beneficial action on blood vessels and the heart, via both glucagon-like peptide-1-dependent and glucagon-like peptide-1 independent effects. As a matter of fact, DPP-4 inhibitors improve several cardiovascular risk factors: they improve glucose control (mainly by reducing the risk of postprandial hyperglycemia) and are weight neutral; may lower blood pressure somewhat; improve postprandial (and even fasting) lipemia; reduce inflammatory markers; diminish oxidative stress; improve endothelial function; and reduce platelet aggregation in patients with T2DM. In addition, positive effects on the myocardium have been described in patients with ischemic heart disease. Results of post hoc analyses of phase 2/3 controlled trials suggest a possible cardioprotective effect with a trend (sometimes significant) toward lower incidence of major cardiovascular events with sitagliptin, vildagliptin, saxagliptin, linagliptin, or alogliptin compared with placebo or other active glucose-lowering agents. However, the definite relationship between DPP-4 inhibition and better cardiovascular outcomes remains to be proven. Major prospective clinical trials involving various DPP-4 inhibitors with predefined cardiovascular outcomes are under way in patients with T2DM and a high-risk cardiovascular profile: the Sitagliptin Cardiovascular Outcome Study (TECOS) on sitagliptin, the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR-TIMI) 53 trial on saxagliptin, the Cardiovascular Outcomes Study of Alogliptin in Subjects With Type 2 Diabetes and Acute Coronary Syndrome (EXAMINE) trial on alogliptin, and the Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes (CAROLINA) on linagliptin. If these trials confirm that a DPP-4 inhibitor can reduce the cardiovascular burden of T2DM, it would be major progress that would dramatically influence the management of the disease. PMID- 23748504 TI - Sodium-glucose co-transporter 2 inhibitors and the potential for cardiovascular risk reduction in patients with type 2 diabetes mellitus. AB - BACKGROUND: Clinical development programs of investigational antidiabetic agents now include evaluation of cardiovascular (CV) risk as a major research focus. Recently, several compounds in a new class of antihyperglycemic therapy have reached the final stages of development. Treatment with inhibitors of sodium glucose co-transporters 2 (SGLT2) leads to urinary excretion of glucose in patients with type 2 diabetes mellitus (T2DM), and is associated with clinically significant reductions in blood glucose levels. The glucosuria-based mechanism of this class has the potential to induce weight loss through reduced caloric availability, and, in addition, may affect blood pressure (BP) via osmotic diuresis or other as yet incompletely characterized mechanisms. METHODS: Searches of the PubMed database were conducted for published studies evaluating the use of SGLT2 inhibitors that reported data on CV risk factors (eg, weight, BP, lipid levels) or CV events. Searches for presentations at recent major diabetes congresses were performed using the Online Submission and Invitation System. RESULTS: Treatment with SGLT2 inhibitors has consistently been associated with reduction in body weight and BP. Qualitative graphical assessment of 21 studies shows unadjusted reductions in systolic BP and body weight typically ranging between 3 to 5 mm Hg and 2 to 3 kg, respectively. A few reports have suggested the potential for improvement in lipid parameters, such as high-density lipoprotein cholesterol levels; however, not all studies have demonstrated significant changes, and some have noted small increases in low-density lipoprotein cholesterol levels. CONCLUSION: Inhibition of SGLT2 in patients with T2DM may be associated with significant weight loss and BP reduction that are sustainable over the average time span of an investigational clinical study (ie, 3-6 months). When considered in terms of the potential for combination therapy, these features may offer a means of further reducing metabolic and CV risk in patients with T2DM. PMID- 23748505 TI - Genital mycotic infections in patients with diabetes. AB - Patients with diabetes, especially those with poorly controlled glycemia, are prone to developing genital mycotic infections-vulvovaginal candidiasis in women and Candida balanitis in men-the latter almost exclusively in uncircumcised men. Candida albicans is the most common pathogen causing balanitis and is also the dominant cause of vulvovaginal candidiasis in women with diabetes, although Candida glabrata is a prominent pathogen in women with type 2 diabetes mellitus. Candida glabrata is less virulent but also less susceptible to conventional antifungal treatment. High blood glucose levels promote yeast attachment and growth, and also interfere with immune responses in the host. In uncircumcised men, the moist, warm space underneath the foreskin is thought to promote yeast growth, especially when hygiene is poor. Several other risk factors have been identified that predispose to genital mycotic infections, including antibiotic use, corticosteroid use, immunosuppression, atopy, and, in women only, genetics, pregnancy, estrogen/oral contraceptive use, and select sexual behaviors (eg, orogenital sex). In patients with hyperglycemia, risk is increased for not only incident infection but also for recurrence, underscoring the key role of establishing and maintaining euglycemia in the management of genital mycotic infections in patients with diabetes. In addition to blood glucose control, first line treatment involves either an antifungal cream/ointment (or suppository for women only) that is applied intravaginally by women and directly to the affected area(s) by men, or oral treatment, which infrequently causes systemic side effects. Antifungal treatment should also be offered to sexual partners of patients with diabetes with a genital mycotic infection if the partner is similarly infected. Given high efficacy rates, follow-up test-of-cure after the completion of treatment is generally unnecessary. PMID- 23748506 TI - Efficacy, safety, and tolerability of exenatide once weekly in patients with type 2 diabetes mellitus: an integrated analysis of the DURATION trials. AB - BACKGROUND AND AIM: Exenatide is a glucagon-like peptide-1 receptor agonist demonstrated to improve glycemic control with low hypoglycemia risk in patients with type 2 diabetes mellitus. The Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly (DURATION) program comprised 6 randomized, comparator-controlled, 24- to 30-week trials of exenatide once weekly (EQW), an extended-release formulation. This post hoc analysis pooled data from patients taking EQW across 6 trials to assess efficacy and safety in a large, varied patient population. MATERIALS AND METHODS: The intent-to-treat (ITT) population contained 1379 patients (baseline mean +/- standard deviation glycated hemoglobin [HbA1c] levels of 8.4% +/- 1.1%) who were treated with EQW over the course of 24 to 30 weeks. Changes from baseline in efficacy parameters for the ITT population and a completer population (1195 patients with >= 22 weeks of exposure) were evaluated. RESULTS: The ITT population experienced significant reductions from baseline (least-squares mean [95% CI]) in HbA1c levels (-1.4% [-1.5% to -1.4%]), fasting blood glucose levels (-36 mg/dL [-38.4 mg/dL to -33.8 mg/dL]), and body weight ( 2.5 kg [-2.8 kg to -2.3 kg]) after 24 to 30 weeks of EQW treatment. Reductions in HbA1c and fasting blood glucose levels were observed across baseline HbA1c level strata; patients with higher baseline HbA1c levels experienced greater reductions. Treatment with EQW was associated with modest, significant reductions in blood pressure (systolic blood pressure, -2.8 mm Hg [-3.5 mm Hg to -2.1 mm Hg]; diastolic blood pressure, -0.8 mm Hg [-1.2 mm Hg to -0.4 mm Hg]), and fasting lipid levels (total cholesterol, -6.5 mg/dL [-8.2 mg/dL to -4.7 mg/dL]; low-density lipoprotein cholesterol, -3.9 mg/dL [5.3 mg/dL to -2.5 mg/dL]; and triglyceride [geometric least-squares mean percent change (95% CI)], -6% [-8% to 4%] levels). Similar reductions were observed in the completer population. Exenatide once weekly was generally well tolerated. Transient, mild-to-moderate gastrointestinal treatment-emergent adverse events and injection-site treatment emergent adverse events were reported most frequently, but were seldom treatment limiting. No major hypoglycemic events were observed; minor hypoglycemic events occurred infrequently in patients not using a sulfonylurea. CONCLUSION: This post hoc analysis of > 1300 patients demonstrated that EQW was associated with significant reductions in HbA1c levels, body weight, blood pressure, and fasting lipid levels, with minimal hypoglycemia risk. Consistent with established safety profiles, EQW therapy was generally well tolerated. TRIAL REGISTRATION: www.ClinicalTrials.gov identifiers: NCT00308139, NCT00637273, NCT00641056, NCT00676338, NCT00877890, NCT01029886. PMID- 23748507 TI - Efficacy and tolerability of exenatide once weekly versus sitagliptin in patients with type 2 diabetes mellitus: a retrospective analysis of pooled clinical trial data. AB - AIM: Therapies for type 2 diabetes mellitus that leverage the glucagon-like peptide-1 (GLP-1) receptor signaling pathway have been shown to reduce rates of hyperglycemia and have beneficial effects on body weight. This post hoc analysis compared the effects of 2 GLP-1 receptor- based therapies, exenatide once weekly (EQW), a GLP-1 receptor agonist, and sitagliptin (sita), a dipeptidyl peptidase-4 inhibitor, on glucose control across the range of baseline glycated hemoglobin (HbA1c) levels specified in the American Association of Clinical Endocrinologists and American College of Endocrinology treatment algorithm. MATERIALS AND METHODS: Data from patients treated with either EQW or sita for 26 weeks in 2 randomized, double-blind, comparator-controlled clinical trials were pooled and analyzed. Glycemic endpoints and cardiovascular risk factors were evaluated in subgroups and the overall population. RESULTS: Analysis included 737 patients on background therapies of diet and exercise and/or metformin. While both agents reduced HbA1c and fasting blood glucose (FBG) levels from baseline, significantly greater reductions in HbA1c and FBG levels occurred with EQW compared with sita across all baseline HbA1c level strata, and significantly more patients in the EQW group achieved goal HbA1c levels compared with the sita group. Patients treated with EQW also experienced significantly greater reductions in body weight and cholesterol levels compared with patients treated with sita. The incidences of the most common adverse events of nausea and diarrhea were higher in the EQW group compared with the sita group, and incidences of these adverse events decreased over time. Both groups experienced a low incidence of minor hypoglycemic events. CONCLUSION: Significantly greater improvements in HbA1c and FBG levels were observed in EQW- compared with sita-treated patients across all baseline HbA1c level strata. Additionally, greater reductions in body weight and some cardiovascular risk factors were observed with EQW treatment compared with sita treatment. Both EQW and sita were generally well tolerated; sita-treated patients experienced fewer adverse events than EQW-treated patients. TRIAL REGISTRATION: www.ClinicalTrials.gov identifiers: NCT00637273, NCT00676338. PMID- 23748508 TI - Exenatide once weekly: opportunities in the primary care setting. AB - Type 2 diabetes mellitus is a pandemic, with millions of new diagnoses made each year. In the United States, > 90% of patients with type 2 diabetes mellitus are cared for by primary care physicians who bear the primary responsibility of diagnosing and treating this disease. Building an optimal treatment regimen for a patient from the many choices available depends on many factors, including the ability of a given therapy to safely and effectively lower blood glucose levels, and potential benefits on body weight, cardiovascular risk factors, and hypoglycemia risk. With these considerations at the forefront, this article provides an overview of exenatide once weekly (EQW), a recently available antidiabetes therapy in the glucagon-like peptide-1 receptor agonist class designed to provide continuous glycemic control with once-weekly dosing. We discuss the clinical trials that have demonstrated the ability of EQW to effectively lower blood glucose levels and body weight with a minimal risk of hypoglycemia. In addition, we examine other issues likely to be relevant in a primary care setting, including safety and tolerability profiles, pharmacology and dosing, ease of use, recommended place in treatment, and patient perceptions of EQW. PMID- 23748509 TI - Clinical utility of the dipeptidyl peptidase-4 inhibitor linagliptin. AB - INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as new options in the management of type 2 diabetes mellitus, demonstrating meaningful antihyperglycemic effects and good tolerability profiles. Glycemic control is improved by preventing the DPP-4-mediated degradation of incretin hormones, with a resulting increase in insulin secretion and inhibition of glucagon secretion. PURPOSE: This article provides a discussion of the clinical utility of linagliptin. RESULTS AND CONCLUSION: Linagliptin is a xanthine-based, oral DPP-4 inhibitor that has been approved in the United States and Europe. It has been evaluated extensively in clinical trials, and results in improved glycemic control when used as monotherapy, initial combination therapy with metformin or pioglitazone, add-on therapy to metformin and/or a sulfonylurea, or add-on therapy to basal insulin (with or without oral antidiabetic drugs). Consistent with other members of its class, the benefits of linagliptin also include a low risk of hypoglycemia and weight gain. However, linagliptin is the first DPP-4 inhibitor to be approved as a once-daily, 5-mg dose and, due to its primarily non renal route of excretion, no dosage adjustment is required for patients with renal or hepatic impairment. The pharmacokinetics and pharmacodynamics of linagliptin are not affected to a clinically meaningful degree by race or ethnicity and linagliptin has very low potential for drug-drug interactions. PMID- 23748510 TI - Accuracy and clinical utility of a point-of-care HbA1c testing device. AB - BACKGROUND: Point-of-care testing (POCT) is widely used to measure blood glucose levels in people with diabetes, although its use in measuring glycated hemoglobin (HbA1c) levels is less common, perhaps due to perceived performance issues and access to the technology. METHODS: Forty blood samples were analyzed in duplicate using Bayer's A1CNow + (r) Multi-Test A1C system (A1CNow + ) with 3 different reagent lots; HbA1c levels of the samples spanned the clinically relevant range of 4% to 10%. Corresponding samples were sent to a National Glycohemoglobin Standardization Program (NGSP) secondary reference laboratory (University of Missouri Secondary Reference Laboratory #9), which analyzed the samples with a Tosoh Automated Glycohemoglobin Analyzer HLC-723G8 (Tosoh G8; Tosoh Bioscience, Inc). RESULTS: Glycated hemoglobin levels measured with the A1CNow + aligned with measurements obtained using the laboratory method, with correlation coefficients of 0.985, 0.987, and 0.989 for the 3 lots, respectively. The 95% CIs for the differences between the A1CNow + levels and the mean HbA1c levels were within 0.55% to +0.50% for the 3 reagent lots, which is well within the currently acceptable limits of +/-0.75% HbA1c required by the NGSP. Results were further analyzed per the new tighter NGSP performance criteria effective September 1, 2012, requiring that 37 of 40 results be within +/-7% (relative bias) of the NGSP reference laboratory measures. All 3 lots met the tighter NGSP criteria. CONCLUSION: The A1CNow + provides accuracy and precision when performing POCT of HbA1c as an aid in diabetes management. Ongoing improvements in this and other HbA1c POCT devices may lead to a greater global acceptance of the role of POCT of HbA1c in diabetes management. PMID- 23748511 TI - Restless legs syndrome: a review of diagnosis and management in primary care. AB - Restless legs syndrome (RLS) is a common neurological disorder that is characterized by an urge to move the legs (or arms), usually accompanied by uncomfortable and bothersome sensations in the affected limbs. The prevalence of RLS ranges from 7.2% to 11.5% in the general population, and its symptoms are frequent or severe enough to require medical treatment by approximately 3% of the population. However, RLS remains largely undiagnosed, perhaps due to a lack of understanding of RLS as a medically significant disorder. Restless legs syndrome can have serious clinical consequences and a significant impact on patients' quality of life, and therefore correct diagnosis and appropriate management are important. The symptoms of RLS can be managed effectively by treatment. In this review article, we provide a description of RLS and the 4 diagnostic criteria, including a discussion of differentiating symptoms and other medical conditions that mimic RLS. We review the evidence regarding the clinical impact of RLS on sleep disturbance, patients' overall health and quality of life, and the disorder's association with cardiovascular risk. The current focus of RLS therapy is to provide symptom relief; we discuss the available pharmacologic treatment options for RLS, with a focus on the clinical evidence surrounding non-ergot derived dopamine receptor agonists, which are the current agents of choice for moderate-to-severe RLS. Finally, we consider when it may be most appropriate for the primary care physician to refer a patient with RLS to a specialist. PMID- 23748512 TI - Physiologic and weight-focused treatment strategies for managing type 2 diabetes mellitus: the metformin, glucagon-like peptide-1 receptor agonist, and insulin (MGI) approach. AB - The prevalence of type 2 diabetes mellitus (T2DM) is rising in association with an increase in obesity rates. Current treatment options for patients with T2DM include lifestyle modifications and numerous antidiabetic medications. Despite the availability of effective and well-tolerated treatments, many patients do not achieve recommended glycemic targets. Lack of efficacy is complicated by the wide range of available agents and little specificity in treatment guidelines, thus challenging clinicians to understand the relative benefits and risks of individual options for each patient. In this article, lifestyle intervention strategies and current antidiabetic agents are evaluated for their efficacy, safety, and weight-loss potential. Because of the heterogeneous and progressive nature of T2DM, physicians should advocate approaches that emphasize weight management, limit the risk of hypoglycemia and adverse events, and focus on the core pathophysiologic defects in patients with T2DM. A healthy, plant-based diet that is low in saturated fat and refined carbohydrates but high in whole grains, vegetables, legumes, and fruits, coupled with resistance and aerobic exercise regimens, are recommended for patients with T2DM. When necessary, drug intervention, described in this article as the MGI (metformin, glucagon-like peptide-1 receptor agonist, and insulin) approach, should begin with metformin and progress to the early addition of glucagon-like peptide-1 receptor agonists because of their weight loss potential and ability to target multiple pathophysiologic defects in patients with T2DM. For most patients, treatments that induce weight gain and hypoglycemia should be avoided. Long-acting insulin should be initiated if glycemic control is not achieved with metformin and glucagon-like peptide-1 receptor agonist combination therapy, focusing on long acting insulin analogs that induce the least weight gain and have the lowest hypoglycemic risk. Ultimately, a patient-centered treatment approach that addresses the core pathologies of T2DM and obesity will not only increase overall efficacy and the likelihood that a patient adheres to treatment, but may also improve a patient's mental well-being and quality of life. PMID- 23748513 TI - Hypertension in black patients: an update. AB - Black individuals are at high risk for hypertension and increased morbidity from cardiovascular and renal disease, in particular. Increased understanding of racial disparities in hypertension, in terms of risk factors, patient/physician behaviors, and treatment outcomes, is key to improving racially oriented care in black patients. Recent data suggest that black patients progress more rapidly from prehypertension to hypertension, highlighting the need for early and prompt intervention. Unfortunately, adherence to and persistence with antihypertensive therapy are generally poor in black patients and are compounded by the increased need for multidrug therapy in this patient population. Treatment strategies currently under investigation are focusing on methods to improve self-care behaviors and medication adherence. Because this is a constantly and rapidly evolving field of study, this article provides an update of recent findings that should be of relevance and interest to practicing clinicians. PMID- 23748514 TI - Pramlintide improved measures of glycemic control and body weight in patients with type 1 diabetes mellitus undergoing continuous subcutaneous insulin infusion therapy. AB - OBJECTIVE: To assess the safety and efficacy of the addition of pramlintide to continuous subcutaneous insulin infusion (CSII) therapy in patients with type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS: We conducted a post hoc analysis of 2 studies: a 29-week, multicenter, randomized, double-blind, placebo controlled trial (referred to as RCT) (pramlintide, n = 82; placebo, n = 73) and an open-ended, multicenter, open-label, single-arm, observational study (referred to as clinical practice trial) (n = 150), which assessed the addition of pramlintide to CSII therapy in patients with T1DM. Pramlintide was initiated at 15 MUg and titrated to 30 or 60 MUg with major meals. The mealtime insulin dose was reduced by 30% to 50% at initiation, and then adjusted to optimize glycemic control. Endpoints at 29 weeks (RCT) and 6 months (clinical practice trial) included change in glycated hemoglobin (HbA1c) level, insulin dose, body weight, pre- and postprandial blood glucose level, and tolerability and safety. RESULTS: In both studies, mean baseline age was approximately 42 years, duration of diabetes was 20 to 24 years, and HbA1c level was approximately 8%. Pramlintide reduced blood glucose excursions and improved the percentage of recorded postprandial blood glucose levels < 180 mg/dL. Mean (+/- standard deviation) reduction in HbA1c level in the clinical practice trial was -0.3% +/- 0.1% (P < 0.0001), and in the RCT was similar between pramlintide- and placebo-treated patients (-0.4% +/- 0.1% and -0.3% +/- 0.1%, respectively). Glycemic improvements were accomplished, with reductions in mealtime insulin doses (RCT: pramlintide, 23.8% +/- 5.2%; placebo, -3.2% +/- 4.1%; P < 0.0005; clinical practice trial: 27.5% +/- 2.9%; P < 0.0001) and body weight (RCT: pramlintide, -2.2 kg +/- 0.5 kg; placebo, +1.4 kg +/- 0.3 kg; P < 0.0001; clinical practice trial: -3.2 kg +/- 0.4 kg; P < 0.0001). Short-lived nausea, primarily mild to moderate in intensity, was the most common adverse event associated with pramlintide therapy. Severe hypoglycemic events occurred at a rate of 0.56 and 0.34 events per patient-year in pramlintide- and placebo-treated patients, respectively, in the RCT, and at a rate of 0.12 events per patient-year in the clinical practice trial. CONCLUSION: Addition of pramlintide to CSII therapy was safe and effective in patients with T1DM. Pramlintide should be considered for patients who are not able to optimize glycemic control with CSII therapy alone, particularly those with difficulty controlling postprandial blood glucose levels and/or body weight. TRIAL REGISTRATION: www.ClinicalTrials.gov identifiers: NCT00042458, NCT00108004. PMID- 23748515 TI - Saxagliptin efficacy and safety in patients with type 2 diabetes mellitus and cardiovascular disease history or cardiovascular risk factors: results of a pooled analysis of phase 3 clinical trials. AB - OBJECTIVE: This post hoc analysis sought to assess the efficacy, safety, and tolerability of saxagliptin in patients with type 2 diabetes mellitus and cardiovascular (CV) risk factors or disease (CVD). METHODS: Data from 5 randomized controlled trials were pooled to compare saxagliptin 5 mg with placebo: 2 studies of saxagliptin as monotherapy in drug-naive patients and 1 each of saxagliptin as add-on therapy to metformin, glyburide, or a thiazolidinedione. Analysis was performed according to the following baseline/trial entry criteria: 1) history/no history of CVD; 2) >= 2 versus 0 to 1 CV risk factors; 3) statin use versus no statin use; and 4) hypertension versus no hypertension. Change from baseline glycated hemoglobin (HbA1c), fasting plasma glucose, and postprandial glucose levels; and the proportion of patients achieving an HbA1c level < 7% were analyzed (week 24). Safety was assessed by adverse events, hypoglycemia, and body weight. RESULTS: In total, 882 patients received saxagliptin 5 mg and 799 received placebo. Differences in adjusted mean change from baseline HbA1c (95% CI) were greater with saxagliptin compared with placebo in patients with a history of CVD (-0.64% [-0.90 to -0.38]) and no history of CVD (-0.68% [-0.78 to -0.58]); with >= 2 CV risk factors (-0.73% [ 0.85 to -0.60]) and 0 to 1 CV risk factor (-0.62% [-0.75 to -0.48]); with statin use (-0.70% [-0.89 to -0.52]) and no statin use (-0.66% [-0.77 to -0.56]); and with hypertension (-0.69% [-0.82 to -0.57]) and no hypertension (-0.66% [-0.80 to -0.52]). Saxagliptin was well tolerated, with similar adverse event rates and types compared with placebo. There was a < 1% rate of confirmed hypoglycemia in all groups except in patients with CV history who received placebo (2.1%). CONCLUSION: Saxagliptin improved glycemic measures, resulted in low rates of confirmed hypoglycemia, and was well tolerated in patients with or without CVD and CV risk factors. PMID- 23748516 TI - Stroke prevention in patients with atrial fibrillation: focus on new oral anticoagulants. AB - Patients with atrial fibrillation are at an increased risk for stroke. Anticoagulation therapy has been shown to significantly reduce the risk for stroke in these patients. Warfarin therapy is effective at reducing the risk for thromboembolic events, but requires frequent monitoring of its anticoagulation effect using the international normalized ratio and significantly increases the risk for hemorrhagic events, including intracranial hemorrhage. Novel oral anticoagulants provide simpler, effective stroke prophylaxis in patients with atrial fibrillation. These drugs include dabigatran (a direct thrombin inhibitor) as well as rivaroxaban and apixaban (factor Xa inhibitors). The new anticoagulants have rapid onset of effect; their anticoagulatory effect is stable, predictable, and dose related; and they do not require monitoring of anticoagulation effect using the international normalized ratio. The pharmacology, clinical efficacy, and potential adverse effects of these drugs in patients with atrial fibrillation are reviewed herein. PMID- 23748517 TI - Excessive sleepiness and self-reported shift work disorder: an Internet survey of shift workers. AB - OBJECTIVES: To compare excessive sleepiness and quality of life (QoL) scores in shift workers who report having a diagnosis of shift work disorder (SWD) with those who report having no such diagnosis. METHODS: An Internet-based survey was conducted between March and April 2009 that included shift workers with or without a self-reported diagnosis of SWD. Participation required working >= 21 hours/week for 2 weeks prior, a diagnosis of SWD or a score of >= 10 on the Epworth Sleepiness Scale, and a score of >= 5 on any subscale of the Sheehan Disability Scale. RESULTS: Surveys included 260 shift workers (103 with an SWD diagnosis and 157 without an SWD diagnosis). Diagnosed and undiagnosed respondents demonstrated similar Epworth Sleepiness Scale (13.7 vs 13.6, respectively) and Karolinska Sleepiness Scale (6.0 vs 5.5, respectively) scores. Sheehan Disability Scale social life and family life scores were similar between the 2 groups, although diagnosed respondents had a greater mean Sheehan Disability Scale work disability score compared with undiagnosed respondents (6.7 vs 5.5; P < 0.0001). Quality of life was more impaired in diagnosed patients in terms of ability to drive safely, propensity for accidents, work performance, and anxiety (P <= 0.039 vs undiagnosed). Work-related accidents (16% vs 5%; P = 0.0076) and injuries at work (17% vs 7%; P = 0.0233) were also reported by more diagnosed respondents than by undiagnosed respondents. Many respondents used caffeine and 57% of diagnosed respondents received prescription medication to treat symptoms of SWD. CONCLUSION: Individuals with diagnosed SWD demonstrated impairment in QoL and reported more work-related accidents and injuries, although many measures of QoL and prescription drug use were similar between groups. Shift work disorder is underrecognized by clinicians and patients, resulting in undertreatment, despite the availability of several behavioral and therapeutic treatment options. PMID- 23748519 TI - Effects of dapagliflozin on cardiovascular risk factors. AB - People with diabetes are more likely to develop a cardiovascular (CV) disease compared with those without diabetes. Although effective glycemic control has been the focus of the management of type 2 diabetes mellitus (T2DM), it is also important to control other CV risk factors to improve outcomes in these patients. Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, lowers glucose levels in patients with T2DM by increasing urinary glucose excretion. Dapagliflozin therapy has been shown to impact a number of CV risk factors. Dapagliflozin improved glycemia with a low intrinsic propensity to cause hypoglycemia. Caloric loss associated with dapagliflozin-induced glucosuria also led to body weight reduction. Small changes from baseline in mean lipid parameters and reductions in serum uric acid levels were observed in patients taking dapagliflozin. Blood pressure reductions were also noted, consistent with modest drug-induced diuresis and weight loss. Furthermore, a lower rate of cardiac events was seen in patients taking dapagliflozin compared with those taking comparators in a meta-analysis of clinical trials on dapagliflozin. Overall, dapagliflozin has shown beneficial effects on CV risk factors in patients with T2DM. Further studies are underway to evaluate the effect of dapagliflozin on CV outcomes. PMID- 23748520 TI - Value and utility of self-monitoring of blood glucose in non-insulin-treated patients with type 2 diabetes mellitus. AB - Self-monitoring of blood glucose (SMBG) levels provides important information regarding glycemic control for patients with diabetes, and is recommended by European and American diabetes organizations as an essential adjunct to periodic glycated hemoglobin (HbA1c) level monitoring. The benefits of SMBG in improving glycemic control in patients with type 1 diabetes and those with type 2 diabetes (T2DM) who are being treated with insulin are well recognized. In contrast, the potential role of SMBG in patients with T2DM not treated with insulin remains controversial, which may lead to underutilization of SMBG in this population. Structured SMBG, introduced as part of a treatment intervention, has been associated with modest but significant improvements in HbA1c levels in patients with T2DM who are not taking insulin as part of their management plan. Patient obtained readings provide valuable real-time feedback on glucose responses to meals and exercise, and provide the patient with guidance on the day-to-day management of their diabetes. Studies have shown that when patients perform self monitoring as part of their treatment interventions, support through appropriate educational initiatives is critical to ensure that patients understand the rationale for SMBG. Patients should be trained in correct testing technique and data recording for SMBG, as well as target blood glucose and goal HbA1c levels so that they will know when their SMBG readings are out of range. Technology has a potential role in facilitating SMBG-based interventions by improving patient physician communication and optimizing glycemic control through the use of remote data uploading, data analysis tools, and, perhaps, even text messaging. This review outlines the benefits of SMBG in the management of patients with T2DM not treated with insulin, and highlights strategies for improving the effectiveness of SMBG-based treatment interventions in this population. PMID- 23748518 TI - A practice-based research network focused on comparative effectiveness research in type 2 diabetes management. AB - PURPOSE: To establish a real-world research platform focused on comparative effectiveness research and health care decision making in diabetes care in order to obtain a detailed understanding of individualized patient management in primary care. METHODS: Diabetes FORWARD (Foundation of Real-World Assessment and Research in Diabetes) is a North American research platform being organized to conduct longitudinal, noninterventional investigations of an anticipated 10,000 patients with type 2 diabetes mellitus (T2DM). Recruitment will be stratified to reflect typical (primarily primary care) clinical T2DM populations. Streamlined data collection relying on electronic medical records (retrospective) and periodic surveys (prospective) will reduce the burden of study participation and, therefore, enhance enrollment by busy primary care and endocrinology practices. Physician data will include baseline demographic and practice information. Patient data will include demographics, T2DM characteristics and treatment, resource utilization information, and patient-reported outcomes. Responses can be tracked within the observation window in near-real time, allowing immediate, noninterventional reaction at the point of nonresponse. EXPECTED OUTCOMES: Diabetes FORWARD is expected to provide important real-world data describing how actual clinical T2DM management differs across sites, settings, and clinicians, and its impact on glycemic control, treatment adherence and persistence, and clinical outcomes. These data will also help to identify the effect of diabetes management on the onset and progression of retinopathy, neuropathy, nephropathy, and cardiovascular disease at 6-month intervals. CONCLUSION: To our knowledge, Diabetes FORWARD is the first diabetes-focused, practice-based research network in the United States and Canada. The current study will provide robust data that should reflect typical management of T2DM in clinical practice in North America. PMID- 23748521 TI - Clinical and economic outcomes among patients with diabetes mellitus initiating insulin glargine pen versus vial. AB - BACKGROUND: Insulin pens may help patients reach glycated hemoglobin (HbA1c) target levels, but a substantial proportion of patients continue to use insulin vials/syringes. The objective of the current study was to evaluate real-world clinical and economic outcomes of patients with type 2 diabetes mellitus (T2DM) initiating insulin glargine via pen delivery (pen) or vial/syringe (vial) within a large managed-care population in the United States. METHODS: This retrospective administrative claims study used data on adult, insulin-naive patients with T2DM treated with >= 1 oral antidiabetic or glucagon-like peptide-1 receptor agonist at baseline. The index date was the earliest pen or vial prescription date. Propensity score matching (1:1) of patients in the pen and vial cohorts was used when comparing 1-year outcomes, including treatment persistence and adherence, HbA1c levels, hypoglycemia rates, and all-cause and diabetes-related health care costs (computed as paid amounts on claims). RESULTS: Patients in the matched cohorts (n = 733 per cohort) were well balanced with regard to demographics (mean age 52 years; 43% women), clinical measures (mean HbA1c level, 9.4%; mean Quan Modified Charlson Comorbidity Index score, 0.9), and health care utilization at baseline. Following initiation of insulin glargine, pen patients were more persistent (60.6% vs 50.1%; P < 0.001) and adherent (medication possession ratio, 0.73 vs 0.57; P < 0.001), with lower HbA1c levels during follow-up (mean adjusted change, -1.05 vs -0.73; P < 0.001), compared with vial patients. Hypoglycemic events occurred at similar rates across pen and vial cohorts (3.8% vs 5.2%, respectively; P = 0.21). Study drug costs were higher among pen users ($1164 vs $762, respectively; P < 0.001), but this did not translate into higher total all cause or diabetes-related costs. CONCLUSION: For patients with diabetes newly initiating insulin glargine, using an insulin pen device was associated with increased therapy persistence and adherence, and lower HbA1c levels relative to vial/syringe, without increasing total all-cause or diabetes-related costs. PMID- 23748522 TI - Review of insulin-dependent and insulin-independent agents for treating patients with type 2 diabetes mellitus and potential role for sodium-glucose co transporter 2 inhibitors. AB - Diabetes, especially type 2 diabetes mellitus (T2DM), continues to be a global health care problem. Although the beneficial effects of glycemic control are well established, in the United States, > 40% of adults with diabetes fail to achieve target glycated hemoglobin levels. Antidiabetic drug classes vary with respect to their mechanisms of action, glucose-lowering potential, and safety and tolerability profiles. Antidiabetic drug classes include some agents that depend on the presence or action of insulin for their therapeutic effect. As the disease state of T2DM progresses, patient pancreatic beta-cell function declines, and therapies that stimulate insulin secretion or improve insulin sensitivity become less effective for this population. Therefore, the development of additional antidiabetic agents with novel mechanisms of action that can be used alone or in combination with currently approved medications may help patients achieve glycemic control. Agents that have comparable glucose-lowering capabilities but different mechanisms of action may fill treatment gaps or meet the needs of patient subpopulations. For example, inhibitors of sodium-glucose co-transporter 2 (SGLT2) represent an emerging class of glucose-lowering agents. The SGLT2 inhibitors reduce glucose reabsorption by the kidney, leading to increased urinary glucose excretion and caloric loss. In clinical trials, these agents have been shown to improve glycemic control and to reduce body weight in patients with T2DM. Additionally, SGLT2 inhibitors pose a low risk for hypoglycemia and are generally well tolerated; however, their use has been associated with an increase in the frequency of genital infections and, in some studies, urinary tract infections. Sodium-glucose co-transporter 2 inhibitors may provide an alternative or an addition to existing therapies for the treatment of patients with T2DM. PMID- 23748523 TI - Assay sensitivity and the epistemic contexts of clinical trials. AB - This article examines the concept of assay sensitivity in clinical research. Defined as the ability of a clinical trial to distinguish between an effective and ineffective treatment, the need for assay sensitivity has been taken to support the claim that placebos are methodologically superior to active control treatments. The demands of doing good clinical science must trump the physician researcher's ethical duty to provide all trial participants with nothing less than competent medical care. We argue that this supposed implication of assay sensitivity rests on (1) collapsing the distinction between biological efficacy and clinical effectiveness, and (2) conflating the epistemic contexts of a trial as-designed and a trial-as-executed. Once these errors are corrected, it becomes clear that placebos grant no epistemological advantage over active controls, and there is therefore no longer a tension between the epistemic and ethical demands of research. We suggest that the legitimate worries behind assay sensitivity can be better understood as the need for researchers to articulate their experimental heuristics and to demonstrate a robust pattern of evidence across a series of trials. PMID- 23748524 TI - Patient preference clinical trials: why and when they will sometimes be preferred. AB - In a preference clinical trial (PCT), two or more health-care interventions are compared among several groups of patients, at least some of whom have purposefully chosen the intervention to be administered to them. This stands in contrast to the randomized, controlled clinical trial (RCT), where patients are randomly assigned to receive one of the available test interventions. This article argues that when comparing two interventions, A and B, when blinding (or masking) the interventions is difficult or impossible and at least some of the potential participants prefer one or the other of the interventions, then the use of a PCT merits consideration. PCTs can be designed in several different ways, and the selection should be driven by the clinical question posed. PCTs also fall towards the pragmatic endpoint of the explanatory/pragmatic clinical trial continuum, suggesting that they may more favorably influence clinical decision making in real-world contexts. Researchers often want to know not what is the best treatment irrespective of choice and compliance, but whether an intervention can work for the patients who choose it. If we want to answer the latter question, we must let patients choose. PMID- 23748525 TI - Ancestral assumptions and the clinical uncertainty of evolutionary medicine. AB - Evolutionary medicine is an emerging field of medical studies that uses evolutionary theory to explain the ultimate causes of health and disease. Educational tools, online courses, and medical school modules are being developed to help clinicians and students reconceptualize health and illness in light of our evolutionary past. Yet clinical guidelines based on our ancient life histories are epistemically weak, relying on the controversial assumptions of adaptationism and advocating a strictly biophysical account of health. To fulfill the interventionist goals of clinical practice, it seems that proximate explanations are all we need to develop successful diagnostic and therapeutic guidelines. Considering these epistemic concerns, this article argues that the clinical relevance of evolutionary medicine remains uncertain at best. PMID- 23748526 TI - The quagga and science: what does the future hold for this extinct zebra? AB - Quaggas, partially striped zebras from South Africa, have had major impacts on science. In the 19th century, the results of mating between a quagga stallion and a horse mare influenced thinking about mechanisms of inheritance for more than 70 years. In the 20th century, tissue from a quagga yielded the first DNA of an extinct organism to be cloned and sequenced. Selective breeding of plains zebras in South Africa has produced animals whose coat coloration resembles that of some quaggas. This raises the intriguing possibility that quaggas may once again be the focus of scientific investigations. PMID- 23748527 TI - Embracing the certainty of uncertainty: implications for health care and research. AB - "Uncertainty" is the ongoing realization that we cannot predict the future, and "surprise" reminds us lest we forget. Despite the fact that uncertainty is an undeniable fact of everyday experiences, in particular when providing care to patients, it is ignored and under-evaluated scientifically. Understandably and appropriately, medical science seeks knowledge, certainty, and prediction; however, the fundamental truth of intrinsic irreducible uncertainty remains neglected. The principal hypothesis of this article is that greater acceptance and understanding of intrinsic uncertainty offers valuable insights towards improving the delivery and management of health care, as well as the performance of clinical and basic science research. This review highlights the ubiquitous presence and acceptance of irreducible uncertainty in diverse domains of science, defines and classifies uncertainty arising from this awareness, and explores the insights and implications of this understanding with regard to health-care practice, health-care management, physician-patient communication, basic science research, and clinical research. It offers specific recommendations in each area of focus that are proposed to stimulate deliberation and investigation. PMID- 23748528 TI - Darwin's perplexing paradox: intelligent design in nature. AB - Today, many would assume that Charles Darwin absolutely rejected any claim of intelligent design in nature. However, review of his initial writings reveals that Darwin accepted some aspects of this view. His conceptualization of design was founded on both the cosmological and the teleological ideas from classical natural theology. When Darwin discovered the dynamic process of natural selection, he rejected the old teleological argument as formulated by William Paley. However, he was never able to ignore the powerful experience of the beauty and complexity of an intelligently designed universe, as a whole. He corresponded with Asa Gray on religious themes, particularly touching the problem of pain and intelligent design in nature. The term "intelligent design" was probably introduced by William Whewell. Principally for theological and philosophical reasons, Darwin could only accept the concept for the universe as a whole, not with respect to individual elements of the living world. PMID- 23748529 TI - The dawn of medicine: ancient egypt and Athotis, the king-physician. AB - The earliest physician recorded in history is Athotis (Aha), one of the first rulers of ancient Egypt. While it is debatable whether the story of a king physician is a fact or just a legend, it is clear that ancient Egyptian medicine developed around the time of his reign. The fortunate combination of earlier medical observations, the development of script, and favorable social conditions made the dawn of ancient Egypt also the dawn of medicine. PMID- 23748530 TI - Confidentiality, electronic health records, and the clinician. AB - The advent of electronic health records (EHRs) to improve access and enable research in the everyday clinical world has simultaneously made medical information much more vulnerable to illicit, non-beneficent uses. This wealth of identified, aggregated data has and will attract attacks by domestic governments for surveillance and protection, foreign governments for espionage and sabotage, organized crime for illegal profits, and large corporations for "legal" profits. Against these powers with almost unlimited resources no security scheme is likely to prevail, so the design of such systems should include appropriate security measures. Unlike paper records, where the person maintaining and controlling the existence of the records also controls access to them, these two functions can be separated for EHRs. By giving physical control over access to individual records to their individual owners, the aggregate is dismantled, thereby protecting the nation's identified health information from large-scale data mining or tampering. Control over the existence and integrity of all the records--yet without the ability to examine their contents--would be left with larger institutions. This article discusses the implications of all of the above for the role of the clinician in assuring confidentiality (a cornerstone of clinical practice), for research and everyday practice, and for current security designs. PMID- 23748531 TI - Virtue in medicine reconsidered: individual health and global health. AB - One hundred years after the Flexner Report recommended major changes to medical education, an international panel has released a vision of medical education for the 21st century. Two major features of this detailed report that were not adequately articulated or developed were (1) the values that underpin care of individual patients and how these could be sustained and promoted, and (2) the values required to promote global health at a time when health disparities are widening. After reviewing the timeless scientific and humanistic foundations of clinical medicine that are essential for the care of individuals, we consider the role of virtue both in relation to individual patient care and in promoting an ethical framework for population health within a cosmopolitan global health perspective, and suggest that many organs of society should contribute to promoting such progress. PMID- 23748532 TI - Understanding unconscious intelligence and intuition: "blink" and beyond. AB - The importance of unconscious intelligence and intuition is increasingly acknowledged by the scientific community. This essay examines and assesses the varied views on the topic presented in three books that bridge the scientific world and reading public: Blink by Malcolm Gladwell (2005), Gut Feelings by Gerd Gigerenzer (2008), and How Doctors Think by Jerome Groopman (2007). The analysis differentiates among kinds of unconscious intelligence and points towards a more complete understanding of the higher cognitive potential of the unconscious mind. PMID- 23748534 TI - Platelet-derived growth factor-A and sonic hedgehog signaling direct lung fibroblast precursors during alveolar septal formation. AB - Alveolar septal formation is required to support the respiration of growing mammals; in humans effacement of the alveolar surface and impaired gas exchange are critical features of emphysema and pulmonary fibrosis. Platelet-derived growth factor-A (PDGF-A) and its receptor PDGF-receptor-alpha (PDGFRalpha) are required for secondary septal elongation in mice during postnatal days 4 through 12 and they regulate the proliferation and septal location of interstitial fibroblasts. We examined lung fibroblasts (LF) to learn whether PDGFRalpha expression distinguished a population of precursor cells, with enhanced proliferative and migratory capabilities. We identified a subpopulation of LF that expresses sonic hedgehog (Shh) and stem cell antigen-1 (Sca1). PDGF-A and Shh both increased cytokinesis and chemotaxis in vitro, but through different mechanisms. In primary LF cultures, Shh signaled exclusively through a noncanonical pathway involving generation of Rac1-GTP, whereas both the canonical and noncanonical pathways were used by the Mlg neonatal mouse LF cell line. LF preferentially oriented their primary cilia toward their anterior pole during migration. Furthermore, a larger proportion of PDGFRalpha-expressing LF, which are more abundant at the septal tips, bore primary cilia compared with other alveolar cells. In pulmonary emphysema, destroyed alveolar septa do not regenerate, in part because cells fail to assume a configuration that allows efficient gas exchange. Better understanding how LF are positioned during alveolar development could identify signaling pathways, which promote alveolar septal regeneration. PMID- 23748533 TI - Activating the Nrf2-mediated antioxidant response element restores barrier function in the alveolar epithelium of HIV-1 transgenic rats. AB - The master transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) regulates the expression of antioxidant and phase II-metabolizing enzymes by activating the antioxidant response element (ARE) and thereby protects cells and tissues from oxidative stress. Pulmonary complications remain the leading cause of death in human immunodeficiency virus (HIV)-1-infected individuals, who display systemic oxidative stress and glutathione deficiency that can be modeled in transgenic rats where HIV-1-related viral proteins decrease glutathione levels and cause epithelial barrier dysfunction within the alveolar space by as yet unknown mechanisms. We hypothesized that HIV-1-related proteins inhibit Nrf2 mediated antioxidant defenses and thereby disrupt the normally tight alveolar epithelial barrier. Nrf2 RNA silencing dampened Nrf2/ARE activity, decreased the expression of the tight junction proteins zonula occludens-1, occludin, and claudin-18, increased paracellular permeability of alveolar epithelial monolayers derived from wild-type rats, and therefore reproduced the effects of HIV-1 transgene expression on the epithelial barrier that we had previously described. In contrast, upregulating Nrf2 activity, either by plasmid-mediated overexpression or treatment with the Nrf2 activator sulforaphane, increased the expression of ARE-dependent antioxidants, including NAD(P)H dehydrogenase, quinone 1 and glutathione, improved the expression of tight junction proteins, and restored the ability to form tight barriers in alveolar epithelial cells from HIV-1 transgenic rats. Taken together, these new findings argue that HIV-1 related proteins downregulate Nrf2 expression and/or activity within the alveolar epithelium, which in turn impairs antioxidant defenses and barrier function, thereby rendering the lung susceptible to oxidative stress and injury. Furthermore, this study suggests that activating the Nrf2/ARE pathway with the dietary supplement sulforaphane could augment antioxidant defenses and lung health in HIV-1-infected individuals. PMID- 23748536 TI - [The CARRESS study]. PMID- 23748537 TI - [Economy, costs and drug choices in cardiology. A reflection on the 2012 position paper of the Italian Society of Hypertension]. PMID- 23748535 TI - Neonatal hyperoxia alters the host response to influenza A virus infection in adult mice through multiple pathways. AB - Exposing preterm infants or newborn mice to high concentrations of oxygen disrupts lung development and alters the response to respiratory viral infections later in life. Superoxide dismutase (SOD) has been separately shown to mitigate hyperoxia-mediated changes in lung development and attenuate virus-mediated lung inflammation. However, its potential to protect adult mice exposed to hyperoxia as neonates against viral infection is not known. Here, transgenic mice overexpressing extracellular (EC)-SOD in alveolar type II epithelial cells are used to test whether SOD can alleviate the deviant pulmonary response to influenza virus infection in adult mice exposed to hyperoxia as neonates. Fibrotic lung disease, observed following infection in wild-type (WT) mice exposed to hyperoxia as neonates, was prevented by overexpression of EC-SOD. However, leukocyte recruitment remained excessive, and levels of monocyte chemoattractant protein (MCP)-1 remained modestly elevated following infection in EC-SOD Tg mice exposed to hyperoxia as neonates. Because MCP-1 is often associated with pulmonary inflammation and fibrosis, the host response to infection was concurrently evaluated in adult Mcp-1 WT and Mcp-1 knockout mice exposed to neonatal hyperoxia. In contrast to EC-SOD, excessive leukocyte recruitment, but not lung fibrosis, was dependent upon MCP-1. Our findings demonstrate that neonatal hyperoxia alters the inflammatory and fibrotic responses to influenza A virus infection through different pathways. Therefore, these data suggest that multiple therapeutic strategies may be needed to provide complete protection against diseases attributed to prematurity and early life exposure to oxygen. PMID- 23748538 TI - [Monitoring of cardiac damage in cancer patients treated with cardiotoxic drugs]. AB - In recent years, thanks to advances in early diagnosis and especially to substantial improvements in therapy, there has been a significant increase in the survival of cancer patients. Almost all cancers can be cured today, and survival of patients over 5-10 years is a tangible goal in many types of cancer. Cardiovascular complications are a growing problem in clinical practice that may frustrate modern oncological outcome of therapy. For this reason, a careful evaluation of the patient risk profile through a close collaboration among physicians and careful monitoring of patients are necessary for a successful treatment. Among the most common and dangerous complications of many drugs used in cancer chemotherapy, there is the development of myocardial damage and heart failure. The present review focuses on the type of cancer drugs that may induce cardiac dysfunction and provides the clinical cardiologist monitoring schemes applicable in daily clinical practice aimed at early detection of cardiac damage. PMID- 23748539 TI - [Ranolazine in the prevention of anthracycline-related cardiotoxicity]. AB - Anthracyclines rank among the most effective anticancer drugs. They may however cause a dose-dependent and cumulative cardiotoxicity, eventually leading to heart failure. The antitumoral cytotoxicity of anthracyclines and their cardiotoxicity are believed to be due to different mechanisms, and there is therefore an active search for developing drugs able to protect the heart without impairing their chemotherapeutic efficacy. The foremost hypothesis explaining cardiotoxicity is the anthracycline-dependent production of reactive oxygen species (ROS). A ROS induced calcium (Ca 2+)-calmodulin-dependent protein kinase II (CaMKII) hyperactivity can cause diastolic Ca2+ overload secondary to the activation of the late sodium (Na+) current (INaL). Furthermore, INaL hyperactivation can initiate a vicious cycle leading to sustained oxidative stress and energetic stress, with serious ATP depletion, similar to that occurring after the exposure of hearts or isolated cardiomyocytes exposed to anthracyclines. We hypothesize that anthracyclines may cause, through a ROS-dependent CaMKII hyperactivation, increased INaL, leading to a vicious cycle that worsens the redox imbalance with resulting mechanical and electrophysiological dysfunction and heart failure. In this light, we here review the molecular and clinical characteristics of ranolazine, the most powerful and selective clinical inhibitor of INaL, and speculate on the possibility that it may be used as an effective drug protecting against anthracycline-related cardiotoxicity. PMID- 23748540 TI - [Iron overload and cardiotoxicity: from thalassemia to reperfusion damage]. AB - The role of iron toxicity is well known in gastroenterology and hematology: hemochromatosis, thalassemia major and myelodysplastic syndromes represent iron toxicity models with evidence of serious damages to target organs such as the heart, the liver and endocrine tissues. Iron chelation therapy has dramatically changed the survival rate of thalassemia major since the introduction of desferoxamine with quantitative assessment of tissue iron overload by magnetic resonance imaging. Reperfusion hemorrhage is an independent predictor of left ventricular remodeling after acute myocardial infarction. Hemorrhage may be a source of iron toxicity and a mediator of inflammation, directly contributing to left ventricular remodeling. Iron chelation may potentially alleviate these cardiotoxic effects. Cardiac magnetic resonance imaging can provide insights into miocrovascular obstruction, hemorrhage and iron chelation. PMID- 23748541 TI - [Herbs and cardiotoxic effects]. AB - Accidental or deliberate ingestion of poisonous herbs has become an increasingly common phenomenon over the last years. From existing literature data and case reports from emergency room visits or poison control centers, an overview is presented of the potential cardiotoxic manifestations following intoxication by wild herbal plants of the territory. The effects of the consumption of cardiac glycoside-containing plants (e.g., digitalis) are discussed along with tachyarrhythmias induced by Aconitum napellus L., Atropa belladonna L., Mandragora officinarum L. or Ephedra distachya L. herbs, and hypertensive crises associated with licorice abuse. For each plant, a brief historical and botanical background is provided, focusing on pathophysiology of intoxication and cardiotoxic effects on the basis of the most recent literature. Finally, medical management of intoxication, from both a general and cardiological viewpoint, is reviewed. PMID- 23748542 TI - [Usefulness of databases of general practitioners: the study of chronic cardiovascular diseases in a health district of Turin, Italy]. AB - BACKGROUND: The aim of this study was to evaluate the prevalence of chronic cardiovascular diseases in the territory of a health district in Turin (Italy) to achieve better management of healthcare services according to healthcare needs. METHODS: In order to assess healthcare needs, we surveyed the prevalence of five cardiovascular chronic diseases in the general population, using data from the general practitioners of one health district. RESULTS: Eighty-six general practitioners participated in the study, collecting data regarding 87 885 attendees, for the year 2010. Among men, the following prevalence rates were estimated: 2% prior myocardial infarction, 2.4% other forms of chronic ischemic heart disease, 2% cardiac arrhythmias, 0.4% heart failure, 0.9% late effects of cerebrovascular disease. Prevalence rates were lower among women, except for dysrhythmias and heart failure, and were increasing with age. Prevalence rates were higher than those previously reported by the Italian Cardiovascular Epidemiological Observatory for northwestern regions. In addition, differences in disease distribution were observed among patients when comparing male doctors and female doctors. CONCLUSIONS: Our findings show several critical issues in primary care, suggesting the need for improving the healthcare delivery system within the health district according to local care needs. PMID- 23748543 TI - [Life is short, art long, opportunity fleeting, experiment treacherous, judgment difficult]. PMID- 23748544 TI - [Treatment of infective endocarditis. Initial conservative strategy is the best approach]. PMID- 23748545 TI - [Treatment of infective endocarditis. Early surgery is mandatory in most cases]. PMID- 23748546 TI - [Single cardiac metastasis from colorectal cancer: an unusual localization]. AB - Metastasis to the heart from malignancy is a frequent but underestimated event. Tumors that are located in the mediastinum, such as pleural mesothelioma, are more frequently associated with cardiac colonization. Few reports have described metastasis from colon adenocarcinoma, which usually colonizes liver and lungs. Moreover, intracardiac localization is more common for primary cardiac neoplasms than for metastasis. We present an unusual case of a patient operated for colon adenocarcinoma who exhibited a single intracardiac secondary localization. Although the mass was huge, the patient was completely asymptomatic. Strict oncologic follow-up facilitates an early identification of the lesion, which could then be promptly resected. PMID- 23748547 TI - [Arterial hypertension and RU-486: a complex case of secondary hypertension]. AB - Secondary hypertension accounts for 10-15% of all cases of hypertension, and early diagnosis with identification of its etiology can be challenging. In this scenario, therapeutic management of affected patients may be difficult. Hypercortisolism is one of the possible causes of secondary hypertension, but its low prevalence and atypical clinical symptoms can lead to a delayed diagnosis. The complex clinical presentation and potential complications need a close collaboration among different clinicians in order to plan optimal or new treatment protocols. PMID- 23748548 TI - [Primary cardiac Burkitt lymphoma in an African child]. AB - Burkitt lymphoma is a non-Hodgkin lymphoma that is endemic in the Equatorial Belt of Africa, usually affecting children and adolescents with primary head-neck or abdominal involvement. Primary cardiac lymphomas are rare entities (1.3% of all primary cardiac tumors) of difficult clinical identification. Delayed discovery contributes to significant mortality. We report a case of a primitive Burkitt lymphoma in a 14-year-old Cameroonian immunocompetent child, presenting with signs and symptoms of severe right inflow impairment. Echocardiography revealed a right atrial mass involving the right atrial ventricular junction. Surgical excision and chemotherapy regimens, administered according to established protocols, were effective in inducing complete remission at 6 months. PMID- 23748549 TI - [Left anterior descending coronary artery originating from the posterior descending artery and associated with an ectopic origin of the circumflex artery: a complex anomaly of coronary arteries]. PMID- 23748550 TI - [A special podium]. PMID- 23748552 TI - Incidences and predictors of difficult laryngoscopy in adult patients undergoing general anesthesia : a single-center analysis of 102,305 cases. AB - BACKGROUND: Hypoxemia caused by difficulties in airway management presents a major cause for perioperative morbidity and mortality. The ability to predict difficult laryngoscopy more accurately would enable anesthesiologists to take specific precautions to reduce airway risks and prevent patient-threatening events. METHODS: Over a 6-year period of time, all anesthesia records with a documented direct laryngoscopic view were retrieved from the electronic data management system and statistically processed. The Cormack-Lehane four-point scale of grading laryngoscopy was used to assess visibility of the vocal cords. RESULTS: Of 102,306 cases, the overall rate of difficult laryngoscopy was 4.9 %. Male gender (6.5 %), Mallampati score III and IV (17.3 %), obesity with a BMI >=35 kg/m(2) (6.1 %), as well as physical status ASA III or IV (6.2 %), were identified as risk factors for difficult laryngoscopy. Patients undergoing surgery in the departments of oromaxillofacial (8.9 %), ear nose throat surgery (ENT) (7.4 %), and cardiac surgery (7.0 %) showed the highest rates of difficult laryngoscopy. CONCLUSIONS: The results indicate that the risk for difficult airway situations might substantially differ between surgical patient groups. In hospitals with departmental structures and spatially separated operating rooms, the deduction might be increased awareness and particular structural preparation for difficult airway situations in the respective subspecialties. PMID- 23748553 TI - "It's good for me": physical activity in older adults with schizophrenia. AB - Physical activity (PA) interventions to improve the physical function of older adults with schizophrenia are necessary but not available. Older adults with schizophrenia may have unique barriers and facilitators to PA. The purpose of this study was to describe the perceptions of older adults with schizophrenia about barriers and facilitators to engage in physical activities that promote physical function. We conducted qualitative interviews with 16 older adults with schizophrenia. Data were collected and analyzed with grounded theory methodology. Participants expressed interest in becoming more physically active for a variety of perceived benefits including psychiatric symptom management and maintenance of basic function. Key barriers and facilitators to PA emerged in five broad categories: Mental Health, No longer a spring chicken, Pride and Sense of Well being, Comfort and Safety, and Belonging. Interventions in this population should address negative attitudes towards aging and promote routine physical activities that enhance well-being and companionship. PMID- 23748554 TI - Effectiveness of the chronic disease self-management program for persons with a serious mental illness: a translation study. AB - Evaluation of evidence-based interventions in new settings and new populations is the hallmark of successful translation. We evaluated the Chronic Disease Self Management Program in persons with serious mental illness who were receiving care through Michigan Community Mental Health Services (N = 139). At 6-months, participants demonstrated improvements in health indicators (fatigue, quality of life, sleep, depression, health distress, and days health bad) and health behaviors (medical adherence and communication with doctor). The program was successfully administrated in a "real world" setting and continues to be used. In addition, the program appears to be an effective resource for people with serious mental illness. PMID- 23748555 TI - Psychometric investigation of a brief measure of outcomes in children's mental health. AB - The current investigation sought to provide reliability and validity evidence for the Child Outcomes Survey (COS), a brief measure designed with a dual purpose to measure functioning and therapeutic relationship and to serve as a clinician caregiver communication tool. Exploratory (EFA) and confirmatory factor analyses (CFA) were performed using a sample of 774 responses collected from 15 provider sites throughout the state of Pennsylvania. Results of the EFA (n = 387) uncovered a three factor structure (family functioning, child functioning, and therapeutic relationship) which was confirmed in the CFA (n = 387). The internal consistency reliability of the three subscales ranged from alpha = .76 to alpha = .91. There was a significant relationship between the therapeutic relationship subscale and the use of the COS as a communication aid (r s = .50, p < .001). Findings support the COS as an accurate measure of functioning and therapeutic relationship and its utility as a communication aid between clinician and caregiver. PMID- 23748556 TI - Minimal Erythema Dose (MED) testing. AB - Ultraviolet radiation (UV) therapy is sometimes used as a treatment for various common skin conditions, including psoriasis, acne, and eczema. The dosage of UV light is prescribed according to an individual's skin sensitivity. Thus, to establish the proper dosage of UV light to administer to a patient, the patient is sometimes screened to determine a minimal erythema dose (MED), which is the amount of UV radiation that will produce minimal erythema (sunburn or redness caused by engorgement of capillaries) of an individual's skin within a few hours following exposure. This article describes how to conduct minimal erythema dose (MED) testing. There is currently no easy way to determine an appropriate UV dose for clinical or research purposes without conducting formal MED testing, requiring observation hours after testing, or informal trial and error testing with the risks of under- or over-dosing. However, some alternative methods are discussed. PMID- 23748557 TI - Optical chemosensors for Cu(II) ion based on BODIPY derivatives: an experimental and theoretical study. AB - Two BODIPY derivatives for Cu(2+) ion chemosensors containing 4-[2-(diethylamino) 2-oxoethoxy]phenyl (BDP1) and 3,4-bis[2-(diethylamino)-2-oxoethoxy]phenyl (BDP2) were synthesized by coupling appropriate N,N-diethyl-2-(4-formylphenoxy)acetamide and 2,4-dimethylpyrrole moieties in the presence of trifluoroacetic acid and anhydrous dichloromethane at room temperature. The binding abilities between these chemosensors and 50 equivalents of Na(+), K(+), Ag(+), Ca(2+), Fe(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+) and Pb(2+) ions were studied using UV-vis and fluorescence spectrophotometry. The results show that, compared to other ions, both the UV-vis absorption and fluorescence emission intensity of BDP2 decreased dramatically when Cu(2+) ion was added. To explain this behavior, ab initio quantum chemical calculations were performed using correlated second-order Moller-Plesset perturbation theory (MP2/LanL2DZ). The calculated orbital energies indicated that the decrease in UV-vis absorption intensity and the quenching of fluorescene emission were due to the single-electron reduction of Cu(2+) to Cu(+) ion. PMID- 23748558 TI - Predicting the preferred conformations of luteolin-4'-O-beta-D-glucoside in gas phase: a comparison of two computational approaches. AB - A tree-step computational approach has been applied to determine the lowest energy conformers of luteolin-4'-O-beta-D-glucoside (L4'G). Fifty-seven starting structures of the L4'G have been built, and then by performing with density functional theory (DFT) optimizations and second-order Moller-Plesset (MP2) calculations, the preferred conformations of L4'G are predicted. In order to test the accuracy of the computational approach, a hybrid Monte-Carlo multiple minimum (MCMM)/quantum mechanical (QM) approach is applied to determine the favorable conformers of L4'G. The alternative classification is employed to put similar conformations into the same catalogue according to the dihedral angles among the luteolin rings, glycosidic dihedral angles, and the orientations of hydroxyl and hydroxymethyl groups. The low-energy conformations are located after the optimizations at the HF/6-31G(d) and B3LYP/6-311+G(d) levels. Compared with the hybrid MCMM/QM approach, the tree-step computational approach not only remains accurate but also saves a lot of computing resources. PMID- 23748559 TI - Gap junction permeability modulated by dopamine exerts effects on spatial and temporal correlation of retinal ganglion cells' firing activities. AB - Synchronized activities among retinal ganglion cells (RGCs) via gap junctions can be increased by exogenous dopamine (DA). During DA application, single neurons' firing activities become more synchronized with its adjacent neighbors. One intriguing question is how the enhanced spatial synchronization alters the temporal firing structure of single neurons. In the present study, firing activities of bullfrog's dimming detectors in response to binary pseudo-random checker-board flickering were recorded via a multi-channel recording system. DA was applied in the retina to modulate synchronized activities between RGCs, and the effect of DA on firing activities of single neurons was examined. It was found that, during application of DA, synchronized activities between single neuron and its neighboring neurons was enhanced. At the meantime, the temporal structures of single neuron spike train changed significantly, and the temporal correlation in single neuron's response decreased. The pharmacological study results indicated that the activation of D1 receptor might have effects on gap junction permeability between RGCs. Our results suggested that the dopaminergic pathway participated in the modulation of spatial and temporal correlation of RGCs' firing activities, and may exert critical effects on visual information processing in the retina. PMID- 23748560 TI - DNA phosphate crowding correlates with protein cationic side chain density and helical curvature in protein/DNA crystal structures. AB - Sequence-specific binding of proteins to their DNA targets involves a complex spectrum of processes that often induce DNA conformational variation in the bound complex. The forces imposed by protein binding that cause the helical deformations are intimately interrelated and difficult to parse or rank in importance. To investigate the role of electrostatics in helical deformation, we quantified the relationship between protein cationic residue density (Cpc) and DNA phosphate crowding (Cpp). The correlation between Cpc and Cpp was then calculated for a subset of 58 high resolution protein-DNA crystal structures. Those structures containing strong Cpc/Cpp correlation (>+/-0.25) were likely to contain DNA helical curvature. Further, the correlation factor sign predicted the direction of helical curvature with positive (16 structures) and negative (seven structures) correlation containing concave (DNA curved toward protein) and convex (DNA curved away from protein) curvature, respectively. Protein-DNA complexes without significant Cpc/Cpp (36 structures) correlation (-0.25<0<0.25) tended to contain DNA without significant curvature. Interestingly, concave and convex complexes also include more arginine and lysine phosphate contacts, respectively, whereas linear complexes included essentially equivalent numbers of Lys/Arg phosphate contacts. Together, these findings suggest an important role for electrostatic interactions in protein-DNA complexes involving helical curvature. PMID- 23748561 TI - Discovering high-resolution patterns of differential DNA methylation that correlate with gene expression changes. AB - Methylation of the CpG-rich region (CpG island) overlapping a gene's promoter is a generally accepted mechanism for silencing expression. While recent technological advances have enabled measurement of DNA methylation and expression changes genome-wide, only modest correlations between differential methylation at gene promoters and expression have been found. We hypothesize that stronger associations are not observed because existing analysis methods oversimplify their representation of the data and do not capture the diversity of existing methylation patterns. Recently, other patterns such as CpG island shore methylation and long partially hypomethylated domains have also been linked with gene silencing. Here, we detail a new approach for discovering differential methylation patterns associated with expression change using genome-wide high resolution methylation data: we represent differential methylation as an interpolated curve, or signature, and then identify groups of genes with similarly shaped signatures and corresponding expression changes. Our technique uncovers a diverse set of patterns that are conserved across embryonic stem cell and cancer data sets. Overall, we find strong associations between these methylation patterns and expression. We further show that an extension of our method also outperforms other approaches by generating a longer list of genes with higher quality associations between differential methylation and expression. PMID- 23748562 TI - Allelic exclusion of the immunoglobulin heavy chain locus is independent of its nuclear localization in mature B cells. AB - In developing B cells, the immunoglobulin heavy chain (IgH) locus is thought to move from repressive to permissive chromatin compartments to facilitate its scheduled rearrangement. In mature B cells, maintenance of allelic exclusion has been proposed to involve recruitment of the non-productive IgH allele to pericentromeric heterochromatin. Here, we used an allele-specific chromosome conformation capture combined with sequencing (4C-seq) approach to unambigously follow the individual IgH alleles in mature B lymphocytes. Despite their physical and functional difference, productive and non-productive IgH alleles in B cells and unrearranged IgH alleles in T cells share many chromosomal contacts and largely reside in active chromatin. In brain, however, the locus resides in a different repressive environment. We conclude that IgH adopts a lymphoid-specific nuclear location that is, however, unrelated to maintenance of allelic exclusion. We additionally find that in mature B cells-but not in T cells-the distal VH regions of both IgH alleles position themselves away from active chromatin. This, we speculate, may help to restrict enhancer activity to the productively rearranged VH promoter element. PMID- 23748563 TI - PscanChIP: Finding over-represented transcription factor-binding site motifs and their correlations in sequences from ChIP-Seq experiments. AB - Chromatin immunoprecipitation followed by sequencing with next-generation technologies (ChIP-Seq) has become the de facto standard for building genome-wide maps of regions bound by a given transcription factor (TF). The regions identified, however, have to be further analyzed to determine the actual DNA binding sites for the TF, as well as sites for other TFs belonging to the same TF complex or in general co-operating or interacting with it in transcription regulation. PscanChIP is a web server that, starting from a collection of genomic regions derived from a ChIP-Seq experiment, scans them using motif descriptors like JASPAR or TRANSFAC position-specific frequency matrices, or descriptors uploaded by users, and it evaluates both motif enrichment and positional bias within the regions according to different measures and criteria. PscanChIP can successfully identify not only the actual binding sites for the TF investigated by a ChIP-Seq experiment but also secondary motifs corresponding to other TFs that tend to bind the same regions, and, if present, precise positional correlations among their respective sites. The web interface is free for use, and there is no login requirement. It is available at http://www.beaconlab.it/pscan_chip_dev. PMID- 23748564 TI - Investigation of DNA sequence recognition by a streptomycete MarR family transcriptional regulator through surface plasmon resonance and X-ray crystallography. AB - Consistent with their complex lifestyles and rich secondary metabolite profiles, the genomes of streptomycetes encode a plethora of transcription factors, the vast majority of which are uncharacterized. Herein, we use Surface Plasmon Resonance (SPR) to identify and delineate putative operator sites for SCO3205, a MarR family transcriptional regulator from Streptomyces coelicolor that is well represented in sequenced actinomycete genomes. In particular, we use a novel SPR footprinting approach that exploits indirect ligand capture to vastly extend the lifetime of a standard streptavidin SPR chip. We define two operator sites upstream of sco3205 and a pseudopalindromic consensus sequence derived from these enables further potential operator sites to be identified in the S. coelicolor genome. We evaluate each of these through SPR and test the importance of the conserved bases within the consensus sequence. Informed by these results, we determine the crystal structure of a SCO3205-DNA complex at 2.8 A resolution, enabling molecular level rationalization of the SPR data. Taken together, our observations support a DNA recognition mechanism involving both direct and indirect sequence readout. PMID- 23748565 TI - Structural insights into the targeting of mRNA GU-rich elements by the three RRMs of CELF1. AB - The CUG-BP, Elav-like family (CELF) of RNA-binding proteins control gene expression at a number of different levels by regulating pre-mRNA splicing, deadenylation and mRNA stability. We present structural insights into the binding selectivity of CELF member 1 (CELF1) for GU-rich mRNA target sequences of the general form 5'-UGUNxUGUNyUGU and identify a high affinity interaction (Kd ~ 100 nM for x = 2 and y = 4) with simultaneous binding of all three RNA recognition motifs within a single 15-nt binding element. RNA substrates spin-labelled at either the 3' or 5' terminus result in differential nuclear magnetic resonance paramagnetic relaxation enhancement effects, which are consistent with a non sequential 2-1-3 arrangement of the three RNA recognition motifs on UGU sites in a 5' to 3' orientation along the RNA target. We further demonstrate that CELF1 binds to dispersed single-stranded UGU sites at the base of an RNA hairpin providing a structural rationale for recognition of CUG expansion repeats and splice site junctions in the regulation of alternative splicing. PMID- 23748566 TI - Chromosomal deletions and inversions mediated by TALENs and CRISPR/Cas in zebrafish. AB - Customized TALENs and Cas9/gRNAs have been used for targeted mutagenesis in zebrafish to induce indels into protein-coding genes. However, indels are usually not sufficient to disrupt the function of non-coding genes, gene clusters or regulatory sequences, whereas large genomic deletions or inversions are more desirable for this purpose. By injecting two pairs of TALEN mRNAs or two gRNAs together with Cas9 mRNA targeting distal DNA sites of the same chromosome, we obtained predictable genomic deletions or inversions with sizes ranging from several hundred bases to nearly 1 Mb. We have successfully achieved this type of modifications for 11 chromosomal loci by TALENs and 2 by Cas9/gRNAs with different combinations of gRNA pairs, including clusters of miRNA and protein coding genes. Seven of eight TALEN-targeted lines transmitted the deletions and one transmitted the inversion through germ line. Our findings indicate that both TALENs and Cas9/gRNAs can be used as an efficient tool to engineer genomes to achieve large deletions or inversions, including fragments covering multiple genes and non-coding sequences. To facilitate the analyses and application of existing ZFN, TALEN and CRISPR/Cas data, we have updated our EENdb database to provide a chromosomal view of all reported engineered endonucleases targeting human and zebrafish genomes. PMID- 23748567 TI - Uridylation prevents 3' trimming of oligoadenylated mRNAs. AB - Degradation of mRNAs is usually initiated by deadenylation, the shortening of long poly(A) tails to oligo(A) tails of 12-15 As. Deadenylation leads to decapping and to subsequent 5' to 3' degradation by XRN proteins, or alternatively 3' to 5' degradation by the exosome. Decapping can also be induced by uridylation as shown for the non-polyadenylated histone mRNAs in humans and for several mRNAs in Schizosaccharomyces pombe and Aspergillus nidulans. Here we report a novel role for uridylation in preventing 3' trimming of oligoadenylated mRNAs in Arabidopsis. We show that oligo(A)-tailed mRNAs are uridylated by the cytosolic UTP:RNA uridylyltransferase URT1 and that URT1 has no major impact on mRNA degradation rates. However, in absence of uridylation, oligo(A) tails are trimmed, indicating that uridylation protects oligoadenylated mRNAs from 3' ribonucleolytic attacks. This conclusion is further supported by an increase in 3' truncated transcripts detected in urt1 mutants. We propose that preventing 3' trimming of oligo(A)-tailed mRNAs by uridylation participates in establishing the 5' to 3' directionality of mRNA degradation. Importantly, uridylation prevents 3' shortening of mRNAs associated with polysomes, suggesting that a key biological function of uridylation is to confer 5' to 3' polarity in case of co translational mRNA decay. PMID- 23748568 TI - [Distal phalangeal fractures of the finger. Results of conservative and surgical treatment]. AB - BACKGROUND: In this study 56 dorsal phalangeal fractures of the distal segment were classified regarding morphological criteria. MATERIAL AND METHODS: Clinical and radiological results after 4 months were analyzed. Fractures including subluxation of the distal interphalangeal joint occurred rarely (n=3) and were treated by surgery. Fractures without subluxation had either a triangle-shaped fragment (n=40) or a fragment similar to a hunter's hat (n=9). Furthermore, there were two fractures with a tiny bony avulsion and two fractures with more radial or ulnar-oriented fragments. The triangle and hunter's hat type fractures were treated either by splinting (n=20) or by open reduction and stabilization with screws and wires (n=29). RESULTS: Clinical outcome was similar in both groups. In 12 out of the 20 fractures treated by splinting a stepping of the joint surface had to be tolerated. Initially only 8 out of 20 fractures showed a stepping of the joint surface. The fractures treated by surgery showed a better radiological outcome. CONCLUSIONS: Initially 27 fractures showed a stepping in the joint line but after surgical treatment only 9 fractures still presented a stepping. The remaining four fractures were successfully treated by splinting. PMID- 23748569 TI - [The patient rights act - a first overview]. PMID- 23748570 TI - The Two-Week Referral System for colorectal cancer--not fit for purpose. AB - PURPOSE: The UK government target expects all suspected colorectal cancer (CRC) patients to be seen within the Two-Week Referral (TWR) system made by general practitioners. These guidelines originally derived from only level 5 evidence. However, this has significant impact on the workload for colorectal surgeons. The aim of the study is to investigate the effectiveness of this colorectal service and whether the referral criteria are predictive of CRC. METHODS: A retrospective study of all patients referred under the TWR guidance in 2010 was assessed. The first 573 TWRs were piloted for analysis. Clinical information from each patient was collected regarding TWR criteria and additional colorectal symptoms or risk factors. Multiple regression analysis was performed to determine which symptoms independently correlated with CRC. RESULTS: One hundred twenty-six CRCs were diagnosed via all methods of referral in 2010. There were 940 patients referred under the TWR guidelines in that year, when 50 CRC patients were identified. Amongst the 573 patients, 32 CRCs were diagnosed. Multiple regression analysis revealed tenesmus to be independently associated with CRC (p = 0.003, Pearson's r = 0.09185). None of the individual TWR criteria confidently predicted CRC. CONCLUSION: Our preliminary results suggest that the current TWR guidelines cannot effectively predict CRC. There is an urgent need for an evidence-based approach to referral criteria for suspected CRC. PMID- 23748571 TI - Quantitative and qualitative sensing techniques for biogenic volatile organic compounds and their oxidation products. AB - The physiological production mechanisms of some of the organics in plants, commonly known as biogenic volatile organic compounds (BVOCs), have been known for more than a century. Some BVOCs are emitted to the atmosphere and play a significant role in tropospheric photochemistry especially in ozone and secondary organic aerosol (SOA) productions as a result of interplays between BVOCs and atmospheric radicals such as hydroxyl radical (OH), ozone (O3) and NOX (NO + NO2). These findings have been drawn from comprehensive analysis of numerous field and laboratory studies that have characterized the ambient distribution of BVOCs and their oxidation products, and reaction kinetics between BVOCs and atmospheric oxidants. These investigations are limited by the capacity for identifying and quantifying these compounds. This review highlights the major analytical techniques that have been used to observe BVOCs and their oxidation products such as gas chromatography, mass spectrometry with hard and soft ionization methods, and optical techniques from laser induced fluorescence (LIF) to remote sensing. In addition, we discuss how new analytical techniques can advance our understanding of BVOC photochemical processes. The principles, advantages, and drawbacks of the analytical techniques are discussed along with specific examples of how the techniques were applied in field and laboratory measurements. Since a number of thorough review papers for each specific analytical technique are available, readers are referred to these publications rather than providing thorough descriptions of each technique. Therefore, the aim of this review is for readers to grasp the advantages and disadvantages of various sensing techniques for BVOCs and their oxidation products and to provide guidance for choosing the optimal technique for a specific research task. PMID- 23748572 TI - A panel of four cytokines predicts the prognosis of patients with malignant gliomas. AB - A comprehensive evaluation of cytokine levels in patients with gliomas could provide important information for the progression and host responses of gliomas. We studied a panel of 120 cytokines and growth factors and investigated their prognostic values for glioma. A protein antibody array was first performed to study the prognostic significance of 120 cytokines in the plasma samples of 45 glioblastoma patients prior to craniotomy or biopsy procedure. An independent set of plasma samples from 260 patients with astrocytomas (80 grade II, 80 grade III, 100 grade IV) with complete clinicopathologic data and follow-ups were used for validation. Ten cytokines were identified by significance analysis of microarray, in which four were associated with poor prognosis (IL-15, MCP-1, GDNF, IL 1R4/ST2), and six were associated with good prognosis (IGFBP-6, MIP-1delta, ICAM 3, IL-7, MIP-3beta, and sgp130) of the glioblastoma patients. Moreover, a 4 cytokine panel composed of IL-7, IL1R4/ST2, sgp130 and MCP-1 showed significant correlation with overall survival of the glioblastoma patients (HR 2.068; 95 % CI 1.357-3.153; p = 0.001). In the validation set, the cytokine panel was significantly correlated with overall survival in the 260 glioma patients (HR 3.480, 95 % CI 1.890-6.422) in multivariate Cox regression analysis. It also showed strong correlation with survival in patients with malignant gliomas (grade III: HR 2.790, 95 % CI 1.597-3.984, p = 0.002; grade IV: HR 1.753; 95 % CI 1.502 2.255, p < 0.001). This panel of four cytokines: IL-7, IL1R4/ST2, sgp130, and MCP 1 can serve as a prognostic marker for patients with malignant gliomas. PMID- 23748573 TI - CyberKnife radiosurgery for the management of skull base and spinal chondrosarcomas. AB - The use of CyberKnife (CK) stereotactic radiosurgery (SRS) for the management of central nervous system chondrosarcomas has not been previously reported. To evaluate outcomes of primary, recurrent, and metastatic chondrosarcomas of the skull base and spine treated with CK SRS, a retrospective observational study of 16 patients treated between 1996 and 2011 with CK SRS was performed using an IRB approved database at Stanford University Medical Center. Twenty lesions (12 cranial, 8 spinal) across six males and ten females were analyzed. The median age at SRS was 51 years and median follow-up was 33 months. Median tumor volume was 11.0 cm3 and median marginal dosages were 22, 24, 26, 27, and 30 Gy for one to five fractionations, respectively. Overall Kaplan-Meier survival rates were 88, 88, 80, and 66 % at 1, 3, 5, and 10 years after initial presentation. Survival rates at 1, 3, and 5 years after CK were 81, 67, and 55 %, respectively. Actuarial tumor control was 41 +/- 13 % at 60 months. At 36 months follow-up, tumor control was 80 % in primary lesions, 50 % in recurrent lesions, and 0.0 % in metastatic disease (p = 0.07). Tumor control was 58 % in cranial lesions and 38 % in spinal lesions. Radiation injury was reported in one patient. CK SRS appears to be a safe adjuvant therapy and offers moderate control for primary cranial chondrosarcoma lesions. There appears to be a clinically, albeit not statistically, significant trend towards poorer outcomes in similarly treated metastatic, recurrent, and spinal chondrosarcomas (p = 0.07). Lesions not candidates for single fraction SRS may be treated with hypofractionated SRS without increased risk for radiation necrosis. PMID- 23748575 TI - Common core themes in geomorphic, ecological, and social systems. AB - Core themes of geomorphology include: open systems and connectivity; feedbacks and complexity; spatial differentiation of dominant physical processes within a landscape; and legacy effects of historical human use of resources. Core themes of ecology include: open systems and connectivity; hierarchical, heterogeneous, dynamic, and context-dependent characteristics of ecological patterns and processes; nonlinearity, thresholds, hysteresis, and resilience within ecosystems; and human effects. Core themes of environmental governance include: architecture of institutions and decision-making; agency, or ability of actors to prescribe behavior of people in relation to the environment; adaptiveness of social groups to environmental change; accountability and legitimacy of systems of governance; allocation of and access to resources; and thresholds and feedback loops within environmental policy. Core themes common to these disciplines include connectivity, feedbacks, tipping points or thresholds, and resiliency. Emphasizing these points of disciplinary overlap can facilitate interdisciplinary understanding of complex systems, as well as more effective management of landscapes and ecosystems by highlighting drivers of change within systems. We use a previously published conceptual framework to examine how these core themes can be integrated into interdisciplinary research for human-landscape systems via the example of a river. PMID- 23748576 TI - Vibrational signatures of Watson-Crick base pairing in adenine-thymine mimics. AB - The vibrational fingerprints of hydrogen-bonding associated with the adenine thymine (A-T) Watson-Crick (WC) base pair have been identified in an infrared study of the A-T mimics 4-aminopyrimidine-1-methylthymine (4APM-1MT) and 4 aminopyrimidine-6-methyl-4-pyrimidinone (4APM-M4PMN) in the gas-phase. The IR vibrational spectra were measured via a double resonance scheme utilizing femtosecond multiphoton ionization. The changes in the molecular structure, anharmonic vibrational parameters, and the assignment of the observed vibrational spectra in the NH/CH stretch region were investigated by carrying out high-level theoretical calculations of the anharmonic spectra. The experimental observations and theoretical calculations indicate that the hydrogen bonds associated with WC base-pairing are relatively stronger than those associated with reverse WC (rWC) base pairing. This is manifested in a more pronounced red-shift of the H-bonded vibrational modes associated with the WC as compared with the rWC base-pairing. An analysis of the factors contributing to the anharmonicity of the vibrational modes associated with H-bonding reveals that the magnitude of the off-diagonal anharmonic coupling of the H-bonded -NH2 stretch and the -NH2 bend is much smaller in WC base-pairing than in the corresponding rWC base-pairing. The chemical and biological implications of these results, especially in the context of using vibrational spectroscopy as a tool for identifying the signatures of nucleotide base vibrations is addressed. PMID- 23748578 TI - Pseudoaneurysm of the popliteal artery in a child with multiple hereditary exostosis: a rare case report and literature review. AB - Multiple hereditary exostosis (MHE) is a rare condition that tends to be overlooked because of its benign nature. The formation of pseudoaneurysm is a rare complication in association with osteochondromatosis. An 8-year-child with MHE presented with a mass behind her left thigh. Imaging confirmed pseudoaneurysm of the popliteal artery. The patient was operated for closure of rent in the arterial wall with a polytetrafluroethylene graft and excision of osteochondroma. At 2 years of follow-up, circulation was normal and the patient was symptom free, without any growth disturbance. This case report highlights the rare possibility of pseudoaneurysm with osteochondroma and focuses on thorough evaluation and proper management of these patients. PMID- 23748577 TI - Association between ganglion cell complex and axial length. AB - PURPOSE: We evaluated the association between each layer of macular ganglion cell complex (mGCC) and axial length measured with spectral-domain optical coherence tomography (OCT). METHODS: One hundred and one eyes of 101 healthy younger women were assessed in this prospective study. In one eye, mGCC was measured two times with 3D-OCT 2000 (Topcon). The associations between mGCC and axial length were analyzed using single regression analysis. To support the data of this study, repeatability also was assessed by intraclass correlation coefficient (ICC), coefficient of variance (CoV), and test-retest standard deviation (TRTSD). RESULTS: In each layer of the mGCC, ICC ranged from 0.980 to 0.997; CoV ranged from 0.8 to 2.4 %; TRTSD ranged from 0.8 to 3.0 MUm. For every 1 mm of greater axial length, total macular retinal nerve fiber layer (mRNFL) thickness increased by 1.1 MUm (p < 0.01), and total macular ganglion cell layer and inner plexiform layer (mGCL+) and mGCC thickness decreased by 2.5 MUm (p < 0.001) and 1.4 MUm (p = 0.018), respectively. CONCLUSIONS: In healthy younger participants, mGCC measurement using 3D OCT-2000 showed good repeatability. As axial length increased, total mGCC decreased, whereas total mRNFL and mGCL+ showed an inverse correlation. PMID- 23748579 TI - The problem of post-traumatic varization of the distal end of the humerus remaining after the recovery of a supracondylar fracture. AB - We aimed to determine whether the distal end of the humerus had the capacity of spontaneous realignment of the remaining deformity following an inadequate reposition of the supracondylar fracture. The results in 56 children with a supracondylar humerus fracture were analysed. In 45 patients (80%), manual repositioning was performed along with transcutaneous fixation, whereas in 11 patients (20%), only manual repositioning and immobilization in plaster cast was applied. Immobilization was removed and physical therapy was started in all patients on the 21st day following the intervention. Anteroposterior and left lateral radiography was performed and Baumann's angle was determined. Follow-up radiograph of the elbow of the traumatized and healthy extremity was performed at an interval of 5-15 years (median 9.4). There was no statistically significant difference between the relationship of Baumann's angle of the injured arm measured on the 21st day after the reduction of fragments on the one hand and the carrying angle of the injured and healthy arm measured at the long-term follow-up on the other (t=0.48, P=0.63). Similarly, there was no statistically significant difference between the relationship of Baumann's angle of the injured arm measured at the long-term follow-up and the findings of the carrying angle of both the injured and the healthy arm obtained on the same examination (t=0.78, P=0.44). On the basis of our experience, we conclude that there is no biological capacity to rectify a possible remaining postreduction varus deformity by spontaneous remodelling. PMID- 23748580 TI - The treatment of eosinophilic granuloma of the humerus with nonvascularized fibular graft and elastic nail. AB - Eosinophilic granuloma is most common in children. In this paper we describe two children with a history of local swelling and pain in the humeral area who showed pathological fracture of the humerus. Needle biopsies confirmed the diagnosis of eosinophilic granuloma. Surgical procedures were performed in both patients. Both patients showed total remission after wide resection combined with segmental nonvascularized fibular graft and elastic nail. Both patients are currently free of disease after 4-year follow-up. There are several treatment modalities in eosinophilic granulomas such as radiotherapy, chemotherapy, local or systemic steroids, curettage, bone grafting and internal fixation. Although good results have been reported with nonsurgical treatment, surgery is a more effective treatment option in selected cases. In this paper we describe two children with massive solitary eosinophilic granuloma of the humerus who were successfully treated with segment resection and fibular bloc graft. PMID- 23748582 TI - Characterisation of dog sensitisation to grass pollen in western France from 1999 to 2010. AB - Very few studies have investigated the seasonal aspect of grass pollen sensitisation or its evolution in the allergic canine population. The aim of this study was to evaluate both these aspects. A study of canine grass pollen sensitisation was performed throughout the statistical analysis of 261 intradermal skin testings (IDT=25 allergens tested on average) performed from January 1999 to December 2010. IDTs were performed on dogs with pruritic allergic skin disease. chi(2) Tests were used for statistical analysis. Two hundred and thirteen dogs (81.6 per cent) were sensitised to at least one allergen, and 56 (21.5 per cent) to at least one grass pollen. No increase in the rate of positive IDT was recorded over three periods: 1999-2002, 2003-2006 and 2007-2010. No statistical correlation was detected between sex, age or birth month and grass sensitisation. Moreover, no link was found between the season in which the IDT was performed and sensitisation, indicating that there is no seasonality to the sensitisation. However, considering the grasses tested over these three periods (grass mix and rye grass), a clear and significant increase in the percentage of dogs sensitised to grass pollen was observed between 1999-2002 and 2007-2010 (14.4 per cent and 27.7 per cent, respectively). The possible reasons for this sensitisation increase of dogs to grass pollen are discussed. PMID- 23748581 TI - Single-cell juxtacellular transfection and recording technique. AB - Genetic modifications and pharmacological studies enable the analysis of protein function in living cells. While many of these studies investigate the effect of proteins by bulk administration or withdrawal of the protein in complex cellular networks, understanding the more subtle mechanisms of protein function requires fine-tuned changes on a single-cell level without affecting the balance of the system. In order to analyse the consequences of protein modification at the single-cell level, we have developed a single-cell transfection method in the loose patch configuration, which allows juxtacellular recordings of neuronal cells prior to juxtacellular transfection. CA1 pyramidal neurons were selected based on morphological and electrophysiological criteria. Using a patch clamp amplifier which allows sensitive recordings of action currents in the loose seal mode as well as electroporation with high-voltage electrical stimulation the identified neurons were transfected with a combination of specific nucleotides, e.g. siRNA and a plasmid coding for GFP for later cell retrieval. Two days after transfection, whole-cell patch clamp recordings of transfected cells were performed to analyse electrophysiological properties. Action potential firing and synaptic transmission of single electroporated CA1 pyramidal cells were comparable to untransfected cells. Our study presents a method which enables identification of neurons by juxtacellular recording prior to single-cell juxtacellular transfection, allowing subsequent analysis of morphological and electrophysiological parameters several days after the genetic modification. PMID- 23748583 TI - Vaccination of dogs with Duramune DAPPi+LC protects against pathogenic canine parvovirus type 2c challenge. AB - In this study, we determined whether vaccination with Duramune DAPPi+LC containing canine parvovirus (CPV) type 2b protects against challenge with virulent CPV antigenic type 2c. Seven healthy dogs, seronegative for CPV2, were enrolled into two treatment groups; five were vaccinated twice, 21 days apart, with minimum titre vaccine, and two were given saline. Dogs were challenged with CPV 2c three weeks later. Clinical observations, body weight and rectal temperature measurements, blood samples for serology and white blood cell counts and faecal samples for virus excretion were collected. Control dogs remained seronegative until challenge; vaccinated dogs seroconverted and were positive for antibodies to CPV2 from day 21. Four days after challenge, clinical signs associated with parvovirus infection (vomiting, paroxysmal shivering, depression, loose stools) were observed in the control dogs. Both animals were withdrawn from the study for welfare reasons one day later. On day 47, leucopenia was observed in controls, with white blood cell counts less than 50 per cent prechallenge values. No specific clinical sign of parvovirus infection were observed in the vaccinated dogs, nor was (detectable) challenge virus shed in faeces suggesting that antibodies generated contributed sterilising immunity. We conclude that vaccination of dogs with Duramune DAPPi+LC protects against challenge with a virulent field strain of CPV 2c. PMID- 23748584 TI - Investigating the evolution of drug mediated silver nanoparticles. AB - Silver nanoparticles have been prepared by a one-pot synthetic technique using the antibacterial drug, Ciprofloxacin (Cp), under optimized conditions. Several techniques are used to characterize the free and nanoparticle bound states of Cp. The time dependent release of the drug molecules from the nanoparticles proves its importance in drug delivery. PMID- 23748591 TI - 3rd Brazilian Consensus on Helicobacter pylori. AB - Signicant progress has been obtained since the Second Brazilian Consensus Conference on Helicobacter pylori Infection held in 2004, in Sao Paulo, SP, Brazil, and justify a third meeting to establish updated guidelines on the current management of H. pylori infection. The Third Brazilian Consensus Conference on H pylori Infection was organized by the Brazilian Nucleus for the Study of Helicobacter, a Department of the Brazilian Federation of Gastroenterology and took place on April 12-15, 2011, in Bento Goncalves, RS, Brazil. Thirty-one delegates coming from the five Brazilian regions and one international guest, including gastroenterologists, pathologists, epidemiologists, and pediatricians undertook the meeting. The participants were allocated in one of the five main topics of the meeting: H pylori, functional dyspepsia and diagnosis; H pylori and gastric cancer; H pylori and other associated disorders; H pylori treatment and retreatment; and, epidemiology of H pylori infection in Brazil. The results of each subgroup were submitted to a final consensus voting to all participants. Relevant data were presented, and the quality of evidence, strength of recommendation, and level of consensus were graded. Seventy per cent and more votes were considered as acceptance for the final statement. This article presents the main recommendations and conclusions to guide Brazilian doctors involved in the management of H pylori infection. PMID- 23748592 TI - New advances in countercurrent chromatography and centrifugal partition chromatography: focus on coupling strategy. AB - Countercurrent chromatography (CCC) is an attractive separation method because the analytes are partitioned between two immiscible liquid phases avoiding problems related to solid stationary phase. In recent years, this technique has made great progress in separation power and detection potential. This review describes coupling strategies involving high speed CCC (HSCCC) or centrifugal partition chromatography (CPC). It includes on-line extraction-isolation, hyphenation with mass spectrometry (MS) and nuclear magnetic resonance (NMR) detectors, multidimensional CCC (MDCCC), two-dimensional CCC (2D-CCC), on-line coupling with liquid chromatography (LC), and biological tests, and innovative off-line developments. The basic principles of each method are presented and applications are summarized. PMID- 23748593 TI - Selection and identification of ssDNA aptamers recognizing zearalenone. AB - Zearalenone (ZEN) is a nonsteroidal estrogenic mycotoxin produced by Fusarium graminearum on maize and barley. Because most current methods of ZEN detection rely on the use of low-stability antibodies or expensive equipment, we sought to develop a rapid, low-cost determination method using aptamers instead of antibodies as the specific recognition ligands. This work describes the isolation and identification of single-stranded DNA (ssDNA) aptamers recognizing ZEN using the modified systematic evolution of ligands by exponential enrichment methodology based on magnetic beads. After 14 rounds of repeated selection, a highly enriched ssDNA library was sequenced and 12 representative sequences were assayed for their affinity and specificity. The best aptamer, 8Z31, with a dissociation constant (K(d)) of 41 +/- 5 nM, was successfully applied in the specific detection of ZEN in binding buffer and in real samples based on a magnetic separation/preconcentration procedure. This analytical method provided a linear range from 3.14 * 10(-9) to 3.14 * 10(-5) M for ZEN, and the detection limit was 7.85 * 10(-10) M. The selected aptamers are expected to be used in the potential development of affinity columns, biosensors, or other analytical systems for the determination of ZEN in food and agricultural products. PMID- 23748594 TI - Is the level of patient co-payment for medicines associated with refill adherence in Sweden? AB - BACKGROUND: In the Swedish reimbursement scheme, the co-payment is based on the price of the product and decreases in a stepwise manner as the total accumulated co-payment increases. The aim of this study was to analyse how refill adherence in Sweden varies according to patient's co-payment level for medicines, with antiepileptic drug (AED) use as an example. METHODS: Prevalent AED users aged 18 85 years who purchased an AED between 1 January and 30 June 2007 were identified in the Swedish Prescribed Drug Register and followed for a maximum of 2 years. Patient time was categorized based on patient's accumulated co-payment for all drugs per reimbursement period. The continuous measure of medication acquisition (CMA) was used to estimate refill adherence in relation to the patients' co payment level. Associations between patients' co-payment for all medicines and refill adherence were assessed with multilevel mixed-effects linear regression, accounting for clustering within patients. RESULTS: The study population included 2210 patients (mean age: 56 years; 54% men). CMA for AED was 91% for patients where the co-payment corresponded to 100% of the price. Compared with these patients, refill adherence for AED was 2-4% higher (P < 0.001) for patients with reduced co-payment (co-payment of <=50% of the price). Higher age, higher income and fenytoin use were also associated with a higher refill adherence for AED. CONCLUSIONS: Using AED as an example, a higher level of reimbursement was associated with a higher refill adherence compared with full co-payment in Sweden. PMID- 23748595 TI - Parity, age at first birth and risk of death from kidney cancer: a population based cohort study in Taiwan. AB - BACKGROUND: This study was undertaken to examine whether there is an association between parity and age at first birth and risk of kidney cancer. METHODS: The study cohort consisted of 1 292 462 women who had a first and singleton childbirth between 1 January 1978 and 31 December 1987. We tracked each woman from the time of her first childbirth to 31 December 2009, and their vital status was ascertained by linking records with the computerized mortality database. Cox proportional hazard regression models were used to estimate the hazard ratios (HRs) of death from kidney cancer associated with parity and age at first birth. RESULTS: There were 95 kidney cancer deaths during 34,980,246 person-years of follow-up. The mortality rate of kidney cancer was 0.27 cases per 100,000 person years. The adjusted HR was 1.88 [95% confidence interval (CI) 1.10-3.19] for women who gave birth between 24 and 26 years of age and 2.52 (95% CI 1.44-4.40) for women who gave birth after 26 years of age, when compared with women who gave birth when <23 years of age. A trend of increasing risk of kidney cancer was seen with increasing age at first birth. The adjusted HR was 0.88 (95% CI 0.49-1.59) for women who had two children and 0.89 (95% CI 0.47-1.67) for women with three or more births, when compared with women who had given birth to only one child. CONCLUSION: This study is the first to suggest that early age at first birth may confer a protective effect on the risk of kidney cancer. PMID- 23748596 TI - Economic impacts of environmentally attributable childhood health outcomes in the European Union. AB - BACKGROUND: There is increasing evidence of the role that exposure to industrial chemicals plays in the development of childhood disease. The USA and the European Union (EU) have taken divergent policy approaches to managing this issue, and economic estimates of disease costs attributable to environmental exposures in children are available in the USA but not the EU. We undertook the first economic evaluation of the impacts of childhood environmental chemical exposures in the EU. METHODS: We used a cost-of-illness approach to estimate health care system costs, and used environmentally attributable fraction modelling to estimate the proportion of childhood disease due to environmental exposures. We analysed data on exposures, disease prevalence and costs at a country level, and then aggregated costs across EU member states to estimate overall economic impacts within the EU. RESULTS: We found the combined environmentally attributable costs of lead exposure, methylmercury exposure, developmental disabilities, asthma and cancer to be $70.9 billion in 2008 (range: $58.9-$90.6 billion). These costs amounted to ~0.480% of the gross domestic product of the EU in 2008. CONCLUSIONS: Childhood chemical exposures present a significant economic burden to the EU. Our study offers an important baseline of disease costs before the implementation of Registration, Evaluation and Authorization of Chemicals, which is important for studying the impacts of this policy regime. PMID- 23748597 TI - Educational inequalities in leisure-time physical activity in 15 European countries. AB - BACKGROUND: The aim of this study was to assess the patterns of socio-economic inequalities in leisure-time physical activity (LTPA) in the different member states of the European Union. METHODS: Comparable data on subjects aged 16-64 years derived from national health interview surveys from 15 European countries were used for the analysis. We used log-binominal regression to assess prevalence rate ratios (PRRs). The PRR measured the risk of showing a low level of LTPA for a given educational level, relative to the highest educational group. RESULTS: Within Europe, large cross-national differences in the overall prevalence of a low level of LTPA were observed. However, a low level of LTPA was always more common among those of lower educational attainment. The educational inequalities in a low level of LTPA were more pronounced in men. For the lowest compared with the highest educational level, the PRR was 1.53 (95% CI: 1.49-1.57) in males and 1.36 (95% CI: 1.33-1.39) in females. There was no consistent relationship between the absolute level of prevalence rate, as measured by the rate for the highly educated, and the magnitude of these inequalities. CONCLUSIONS: Throughout Europe, physical activity during leisure time is less common among the lower educational groups compared with the higher educational groups. Programs to promote LTPA should consider strategies that target people of lower educational attainment. PMID- 23748598 TI - Community resilience and sense of coherence as protective factors in explaining stress reactions: comparing cities and rural communities during missiles attacks. AB - Based on the salutogenic theory, the aim of this study was to examine sense of coherence and communal resiliency as related to stress reactions during missile attacks. Data were gathered in August 2011 while missiles were being shot from Gaza to the Negev communities in Israel from approximately 150 participants, aged 15-85. Participants lived in cities and different types of small rural villages. Self reported questionnaires were administered via the internet and included demographic data, coping resource of sense of coherence and community resiliency as coping resources, as well as state anxiety, state anger and psychological distress as stress reaction outcomes. Overall, the participants in our study reported strong personal and communal resources and relatively low levels of stress reactions. Personal and communal resources were linked negatively to the different stress reactions. However, some differences emerged when we compared participants from different types of communities. The most resilient group was composed of people who lived in the rural and communal communities. Differences also emerged on patterns of relationships between the community resource and state anxiety. While among the rural citizens, community resilience was strongly linked to anxiety, no relationships were revealed in the urban citizens group. PMID- 23748599 TI - Quantification of the proportion of motor neurons recruited by transcranial electrical stimulation during intraoperative motor evoked potential monitoring. AB - Transcranial motor evoked potentials (TcMEPs) are widely used to monitor motor function during spinal surgery. However, they are much smaller and more variable in amplitude than responses evoked by maximal peripheral nerve stimulation, suggesting that a limited number of spinal motor neurons to the target muscle are excited by transcranial stimulation. The aim of this study was to quantify the proportion of motor neurons recruited during TcMEP monitoring under general anesthesia. In twenty patients who underwent thoracic and/or lumbar spinal surgery with TcMEP monitoring, the triple stimulation technique (TST) was applied to the unilateral upper arm intraoperatively. Total intravenous anesthesia was employed. Trains of four stimuli were delivered with maximal intensity and an inter-pulse interval of 1.5 ms. TST responses were recorded from the abductor digiti minimi muscle, and the negative peak amplitude and area were measured and compared between the TST test (two collisions between transcranial and proximal and distal peripheral stimulation) and control response (two collisions between two proximal and one distal peripheral stimulation). The highest degree of superimposition of the TST test and control responses was chosen from several trials per patient. The average ratios (test:control) were 17.1 % (range 1.8-38 %) for the amplitudes and 21.6 % (range 2.9-40 %) for the areas. The activity of approximately 80 % of the motor units to the target muscle cannot be detected by TcMEP monitoring. Therefore, changes in evoked potentials must be interpreted cautiously when assessing segmental motor function with TcMEP monitoring. PMID- 23748600 TI - The impact of systemic vascular resistance on the accuracy of the FloTrac/VigileoTM system in the perioperative period of cardiac surgery: a prospective observational comparison study. AB - FloTrac/VigileoTM system is based on arterial pressure waveform analysis arterial pressure-based CO (APCO). Therefore, systemic vascular resistance (SVR) can influence the accuracy of APCO. The purpose of this study is to evaluate the relationship between SVR and the accuracy of APCO. We managed 50 consecutive patients in the perioperative period of cardiac surgery with FloTrac/VigileoTM system (v. 3.02) and Swan-Ganz catheter/VigilanceTM system pulmonary artery catheter-based CO (PAC-CO) simultaneously. Continuous hemodynamic measurement using both methods was performed every 20 s from the induction of anesthesia to PAC removal 4 h after extubation. A total of 11,092 (intraoperative), 38,455 (postoperative, pre-extubation), and 44,235 (postoperative, post-extubation) data pairs were finally analyzed. Bland-Altman analysis revealed that in the intraoperative [postoperative pre-extubation, post-extubation] period, the bias was 0.5 [0.1, 0.0] L/min and the limits of agreement ranged from -2.4 to 3.3 [ 2.2 to 2.4, -2.4 to 2.3] L/min. The percentage error was 60.3 [54.5, 48.5] %. Regression analysis of the systemic vascular resistance index (SVRI) and the bias between APCO and PAC-CO showed that the bias was positively correlated to the SVRI. Subanalysis based on SVR with Lin's concordance correlation coefficient revealed that relatively satisfactory concordance was found in the normal-SVR group (concordance correlation coefficient rho c = 0.51-0.56) regardless of vasoactive agent use. The accuracy of the FloTrac/VigileoTM System (v. 3.02) is relatively satisfactory in the condition with normal SVR regardless of vasoactive agent use. Positive correlation between the bias and SVR can be the clue to the more effective use of FloTrac/VigileoTM system. PMID- 23748601 TI - An enriched simulation environment for evaluation of closed-loop anesthesia. AB - To simulate and evaluate the administration of anesthetic agents in the clinical setting, many pharmacology models have been proposed and validated, which play important roles for in silico testing of closed-loop control methods. However, to the authors' best knowledge, there is no anesthesia simulator incorporating closed-loop feedback control of anesthetic agent administration freely available and accessible to the public. Consequently, many necessary but time consuming procedures, such as selecting models from the available literatures and establishing new simulator algorithms, will be repeated by different researchers who intend to explore a novel control algorithm for closed-loop anesthesia. To address this issue, an enriched anesthesia simulator was devised in our laboratory and made freely available to the anesthesia community. This simulator was built by using MATLAB((r)) (The MathWorks, Natick, MA). The GUI technology embedded in MATLAB was chosen as the tool to develop a human-machine interface. This simulator includes four types of anesthetic models, and all have been wildly used in closed-loop anesthesia studies. For each type of model, 24 virtual patients were created with significant diversity. In addition, the platform also provides a model identification module and a control method library. For the model identification module, the least square method and particle swarm optimization were presented. In the control method library, a proportional integral-derivative control and a model predictive control were provided. Both the model identification module and the control method library are extensive and readily accessible for users to add user-defined functions. This simulator could be a benchmark-testing platform for closed-loop control of anesthesia, which is of great value and has significant development potential. For convenience, this simulator is termed as Wang's Simulator, which can be downloaded from http://www.AutomMed.org . PMID- 23748602 TI - Impaired cerebrovascular reactivity after acute traumatic brain injury can be detected by wavelet phase coherence analysis of the intracranial and arterial blood pressure signals. AB - The objective of the study was to evaluate the wavelet spectral energy of oscillations in the intracranial pressure (ICP) signal in patients with acute traumatic brain injury (TBI). The wavelet phase coherence and phase shift in the 0.006-2 Hz interval between the ICP and the arterial blood pressure (ABP) signals were also investigated. Patients were separated into normal or impaired cerebrovascular reactivity, based on the pressure reactivity index (PRx). Spectral energy, phase coherence and phase shift in the low frequency and cardiorespiratory intervals were compared for the two groups. Data were prospectively collected and analyzed retrospectively in 22 patients, within the first week after acute TBI. The ICP and ABP signals were continuously recorded for [Formula: see text]40 min and the wavelet transform was used to calculate the spectral energy and phase of the signals. The average ICP wavelet energy spectrum showed distinct peaks around 1.0 (cardiac), 0.25 (respiratory) and 0.03 Hz. Patients with normal cerebrovascular reactivity (negative PRx) had 38.6 % (+/-SD 16.7 %) of the mean wavelet energy below the lower limit of the respiratory frequency band (0.14 Hz) compared to only 18.1 % (+/-SD 17.8 %) in patients with altered cerebrovascular reactivity (positive PRx) (difference: p = 0.0057). Wavelet phase coherence between the ABP and ICP signals was statistically significant (p < 0.05) in the 0.006-2 Hz interval. The phase shift between the ABP and ICP signals was around zero in the 0.14-1.0 Hz interval. Seven patients with PRx between -0.4943 and -0.1653 had a phase shift in the interval 0.07-0.14 Hz, whereas 15 patients with PRx between -0.1019 and 0.3881 had a phase shift in the interval 0.006-0.07 Hz. We conclude that the wavelet transform of the ICP signal shows spectral peaks at the cardiac, respiratory and 0.03 Hz frequencies. Normal cerebrovascular reactivity seems to be manifested as increased spectral energy in the frequency interval <0.14 Hz. A phase shift between the ICP and ABP signals in the interval 0.07-0.14 Hz indicates normal cerebrovascular reactivity, while a phase shift in the interval 0.006-0.07 Hz indicates altered cerebrovascular reactivity. PMID- 23748603 TI - Ablation of Mina53 in mice reduces allergic response in the airways. AB - The mina53 (myc-induced nuclear antigen with a 53 kDa molecular mass; also known as mina) was identified as a direct transcriptional target of the oncoprotein Myc and encodes a conserved protein in vertebrates. While Mina53 is known to be associated with tumorigenesis, it is not clear what role Mina53 plays in non neoplastic tissues. To directly address the roles of Mina53 in non-neoplastic tissues, we created mina53-deficient mice. Both male and female mina53-deficient mice reached adulthood and were fertile, suggesting that Mina53 is dispensable for the basic developmental processes. Since we found that Mina53 was expressed in cells responsible for immune responses, we investigated whether Mina53 was involved in immune responses. When mice were exposed intranasally to house dust mites as an allergen, the airway tract showed hyperresponsiveness to methacholine in wild-type mice but not in mina53-deficient mice. The mina53-deficient mice also showed a significantly reduced migration of immune cells, including eosinophils, into bronchoalveolar lavage fluid compared with wild-type mice. The levels of Th2 cytokines, IL-4 and IL-5, produced in response to house dust mites were lower in the mina53-deficient mice than in wild-type mice. The level of IFN gamma in bronchoalveolar lavage fluid was significantly decreased by exposure to house dust mites in wild-type mice but not in the mina53-deficient mice. These results suggest that Mina53 plays a role in the allergic response to inhaled allergens, possibly through controlling IL-4 production. PMID- 23748604 TI - RNA secondary structure prediction using high-throughput SHAPE. AB - Understanding the function of RNA involved in biological processes requires a thorough knowledge of RNA structure. Toward this end, the methodology dubbed "high-throughput selective 2' hydroxyl acylation analyzed by primer extension", or SHAPE, allows prediction of RNA secondary structure with single nucleotide resolution. This approach utilizes chemical probing agents that preferentially acylate single stranded or flexible regions of RNA in aqueous solution. Sites of chemical modification are detected by reverse transcription of the modified RNA, and the products of this reaction are fractionated by automated capillary electrophoresis (CE). Since reverse transcriptase pauses at those RNA nucleotides modified by the SHAPE reagents, the resulting cDNA library indirectly maps those ribonucleotides that are single stranded in the context of the folded RNA. Using ShapeFinder software, the electropherograms produced by automated CE are processed and converted into nucleotide reactivity tables that are themselves converted into pseudo-energy constraints used in the RNAStructure (v5.3) prediction algorithm. The two-dimensional RNA structures obtained by combining SHAPE probing with in silico RNA secondary structure prediction have been found to be far more accurate than structures obtained using either method alone. PMID- 23748605 TI - [Can long-term treatment with antipsychotic drugs lead to structural brain damage? Against]. PMID- 23748606 TI - Incidentally discovered pancreatic intraepithelial neoplasia: what is its clinical significance? AB - PURPOSE: Pancreatic intraepithelial neoplasia (PanIN) is a presumed precursor of pancreatic ductal adenocarcinoma (PDAC). We assessed the relationship between incidental PanIN after resection of non-adenocarcinoma lesions and the development of metachronous PDAC in the remnant. METHODS: We retrospectively reviewed the clinicopathologic data of patients who underwent pancreatectomy for non-PDAC from January 2000 to January 2010. Intraductal papillary mucinous lesions were excluded. All available postoperative imaging and clinical follow-up data were reviewed; the risk of developing PDAC was assessed in patients with a minimum follow-up time of 6 months and with imaging studies available for review. RESULTS: A total of 584 patients were analyzed. Median age was 59 years (range 10 85 years), and 338 (58 %) were female. The most common lesions for which resection was performed were serous cystic neoplasms (17 %), pancreatic neuroendocrine tumors (38 %), metastatic tumors (9 %), and mucinous cystic neoplasms (7 %). PanIN was identified in 153 (26 %) patients. The majority of these patients had PanIN-1 or -2 (50 and 41 %, respectively), whereas 13 (8 %) had PanIN-3. Of the 506 (87 %) patients with adequate follow-up (median 3.7 years, range 0.5-12.6 years), 1 patient (0.2 %) with PanIN identified at the time of initial resection developed cancer in the remnant. This occurred 4.4 years after a distal pancreatectomy in the setting of PanIN-1B. No patient with PanIN-3 developed cancer during follow-up. CONCLUSIONS: PanIN was identified in 26 % of patients who underwent resection for histopathology other than PDAC. The presence of PanIN of any grade did not result in an appreciable cancer risk in the pancreatic remnant after short-term follow-up. PMID- 23748607 TI - Predicting postoperative morbidity following cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CS+HIPEC) with preoperative FACT-C (Functional Assessment of Cancer Therapy) and patient-rated performance status. AB - BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CS+HIPEC) is associated with significant perioperative morbidity. One goal of our ongoing patient-reported health-related quality of life (HRQoL) program is to describe the prognostic value of HRQoL measures for predicting postoperative morbidity and mortality following CS+HIPEC. METHODS: A retrospective analysis of a prospectively collected clinical database for all patients treated for peritoneal carcinomatosis and who participated in our patient-reported HRQoL program from 2001 to 2011 was done. Patients completed the Functional Assessment of Cancer Therapy questionnaire plus the colon symptom subscale, in addition to the Eastern Cooperative Oncology Group (ECOG) performance status rating prior to CS+HIPEC. The trial outcome index (TOI), a specific measure of function, symptoms, and physical well being of the patient, was analyzed. The TOI is a combination of the physical and functional well being subscales + the colon specific subscale of the FACT-C. RESULTS: Of 855 patients, 387 (45.2 %) participated in the HRQoL trials. Mean age was 53.3 years, and 213 (55 %) were female versus 174 (45 %) males. There were 240 patients (62 %) who had a complication versus 147 (38 %) who had no complication. A 30-day mortality rate of 7.7 % (30) was documented. Patients who suffered a 30-day postoperative mortality demonstrated a lower mean preoperative score in the FACT-C TOI 52.7 versus 61.7; P < 0.001. Independent predictors of 30-day mortality on multivariate analysis included TOI (0.05), age (0.001), and smoking (0.001). Patients with a higher TOI score were less likely to suffer a mortality (95 % CI 0.9-1.0, P = 0.05). Patients with a higher emotional well being (EWB) score were less likely to suffer a complication 0.9 (95 % CI 0.87-1.0, P = 0.04). Other independent predictors of postoperative morbidity included diabetic status (P = 0.05), ECOG performance status (0.001), and gender (0.02). CONCLUSIONS: Preoperative HRQoL, as measured by FACT-C and ECOG performance status and added to traditional factors, helps predict postoperative morbidity and mortality following CS+HIPEC. PMID- 23748609 TI - A tale of two sisters. PMID- 23748608 TI - A novel approach to collecting satellite cells from adult skeletal muscles on the basis of their stress tolerance. AB - Stem cells are generally collected using flow cytometry, but this method is not applicable when the cell surface marker is not well determined. Satellite cells, which are skeletal muscle stem cells, have the ability to regenerate damaged muscles and are expected to be applicable for treatment of muscle degeneration. Although the transcription factor Pax7 is a known specific marker of satellite cells, it is not located on the cell surface and therefore flow cytometry is not directly applicable. In the present study, we turned our attention to the stress tolerance of adult stem cells, and we propose long-term trypsin incubation (LTT) as a novel approach to collecting satellite cells from mouse and human skeletal muscles. LTT led to a remarkable increase in the ratio of Pax7(+) cells that retain normal myogenic stem cell function. In particular, human Pax7(+) cells made up approximately 30% of primary cultured cells, whereas after LTT, the ratio of Pax7(+) cells increased up to ~80%, and the ratio of Pax7(+) and/or MyoD(+) myogenic cells increased to ~95%. Once transplanted, LTT-treated cells contributed to subsequent muscle regeneration following repetitive muscle damage without additional cell transplantation. The stress tolerance of Pax7(+) cells is related to heat shock protein 27 and alphaB-crystallin, members of the small heat shock protein family. This approach, based on the stress resistance of adult stem cells, is a safe and inexpensive method of efficiently collecting human satellite cells and may also be used for collecting other tissue stem cells whose surface marker is unknown. PMID- 23748611 TI - A screen for morphological complexity identifies regulators of switch-like transitions between discrete cell shapes. AB - The way in which cells adopt different morphologies is not fully understood. Cell shape could be a continuous variable or restricted to a set of discrete forms. We developed quantitative methods to describe cell shape and show that Drosophila haemocytes in culture are a heterogeneous mixture of five discrete morphologies. In an RNAi screen of genes affecting the morphological complexity of heterogeneous cell populations, we found that most genes regulate the transition between discrete shapes rather than generating new morphologies. In particular, we identified a subset of genes, including the tumour suppressor PTEN, that decrease the heterogeneity of the population, leading to populations enriched in rounded or elongated forms. We show that these genes have a highly conserved function as regulators of cell shape in both mouse and human metastatic melanoma cells. PMID- 23748612 TI - Demographic and clinical characteristics of traumatic shoulder dislocations in an urban city of Turkey: a retrospective analysis of 208 cases. AB - OBJECTIVE: The aim of this study was to investigate the demographic and clinical characteristics of traumatic shoulder dislocations in an urban city of Turkey. METHODS: The digital patient database was reviewed to identify all patients with glenohumeral dislocation of the shoulder admitted to the emergency departments of the two hospitals in Diyarbakir between January 2008 and December 2010. Incidence, demographics, clinical characteristics, recurrence, associated injuries, and mechanism of injury were evaluated. RESULTS: Two hundred and eight patients (163 male, 45 female; mean age: 37.2+/-21.3) experienced traumatic shoulder dislocation during the study period. The overall incidence of primary shoulder dislocations was 5.3 per 100,000 person-years. Age distribution peaked between 21 and 30 years (96.5% male) and between 61 and 70 years (66.7% female). Primary shoulder dislocation occurred in 172 patients (82.7%) and recurrent dislocations in 36 (17.3%). Patients with recurrent shoulder dislocations were younger than those with primary dislocations (mean age, 29.7+/-14.5 and 38.8+/ 22.2, respectively; p=0.020). There were 195 (93.4%) anterior dislocations. The mechanism of injury was falls in 155 (74.5%) cases. Reduction was achieved in 165 patients (79.3%) in the emergency department. General anesthesia was used for 43 patients (20.7%). CONCLUSION: The 5.3 per 100,000 person-years incidence of traumatic shoulder dislocations in Turkey was much lower than previous studies. Demographic characteristics also showed various differences closely related to the population pyramid. PMID- 23748610 TI - Proteomic and genomic approaches reveal critical functions of H3K9 methylation and heterochromatin protein-1gamma in reprogramming to pluripotency. AB - Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) involves a marked reorganization of chromatin. To identify post-translational histone modifications that change in global abundance during this process, we have applied a quantitative mass-spectrometry-based approach. We found that iPSCs, compared with both the starting fibroblasts and a late reprogramming intermediate (pre-iPSCs), are enriched for histone modifications associated with active chromatin, and depleted for marks of transcriptional elongation and a subset of repressive modifications including H3K9me2/me3. Dissecting the contribution of H3K9 methylation to reprogramming, we show that the H3K9 methyltransferases Ehmt1, Ehmt2 and Setdb1 regulate global H3K9me2/me3 levels and that their depletion increases iPSC formation from both fibroblasts and pre iPSCs. Similarly, we find that inhibition of heterochromatin protein-1gamma (Cbx3), a protein known to recognize H3K9 methylation, enhances reprogramming. Genome-wide location analysis revealed that Cbx3 predominantly binds active genes in both pre-iPSCs and pluripotent cells but with a strikingly different distribution: in pre-iPSCs, but not in embryonic stem cells, Cbx3 associates with active transcriptional start sites, suggesting a developmentally regulated role for Cbx3 in transcriptional activation. Despite largely non-overlapping functions and the predominant association of Cbx3 with active transcription, the H3K9 methyltransferases and Cbx3 both inhibit reprogramming by repressing the pluripotency factor Nanog. Together, our findings demonstrate that Cbx3 and H3K9 methylation restrict late reprogramming events, and suggest that a marked change in global chromatin character constitutes an epigenetic roadblock for reprogramming. PMID- 23748613 TI - Reliability and reproducibility of classifications for distal radius fractures. AB - OBJECTIVE: The aim of this study was to evaluate the interobserver reliability and intraobserver reproducibility of the Universal, AO, Fernandez and Frykman classifications for distal radius fractures. METHODS: Fifty standard sets of posteroanterior and lateral roentgenograms of displaced distal radius fractures were classified two times by two groups of evaluators at 2-month intervals. The first group consisted of 10 orthopedic surgeons with a minimum of 5 years of experience. The second group consisted of 10 orthopedic residents in their first two years of practice. Interobserver reliability and intraobserver reproducibility were assessed using Cohen's kappa test. RESULTS: None of the classifications achieved good- very good reliability levels. The Fernandez classification had a moderate and the others had a fair interobserver agreement kappa coefficient. All classifications had fair kappa intraobserver agreement although the Frykman and Fernandez classifications had better results. CONCLUSION: None of the classification systems were superior in terms of reliability and reproducibility. The reliability and reproducibility rates of all four classifications were insufficient. PMID- 23748614 TI - Estrogen receptors in hip joint capsule and ligamentum capitis femoris of babies with developmental dysplasia of the hip. AB - OBJECTIVE: The aim of this study was to detect the incidence of estrogen receptors in human hip joint capsule and ligamentum teres. METHODS: The study included biopsies of the ligamentum capitis femoris (LCF) and hip joint capsule from 15 patients undergoing hip surgery for developmental dysplasia of the hip (DDH) and from the control hips of 15 cases of intrauterine fetal death. Mean age was 10.3 (range: 6 to 18) months at the time of surgery. Full-thickness 1x1 cm anterior capsule and LCF portions were taken as biopsy specimens. An immunohistochemical study using monoclonal antibody against estrogen receptors was performed to identify the rate of target estrogen cells in the hip joint capsule and LCF. RESULTS: Estrogen receptor (ER) staining rates were 1.6+/-0.2% for the LCF and 1.3+/-0.2% for the hip joint capsule in the control groups, and 2.5+/-0.3% for the LCF and 2.0+/-0.3% for the hip joint capsule in the DDH groups. Estrogen receptor staining rates in the LCF and hip joint capsule control groups were significantly lower than that in the DDH groups (p<0.001). In both groups, ER rates were significantly lower in the hip joint capsule than in the LCF (p<0.01). CONCLUSION: The high rate of ERs in the LCF and hip joint capsule appears to support the effect of estrogen in the etiology of the DDH. PMID- 23748615 TI - Bilateral low-energy sequential femoral shaft fractures in patients on long-term bisphosphonate therapy. AB - OBJECTIVE: The aim of this study was to evaluate the demographic characteristics of patients with bilateral bisphosphonate-related low-energy femoral shaft fractures. METHODS: The clinical registry was reviewed for patients with bisphosphonate-related low-energy fractures localized at femoral shaft between January 2008 and January 2012. Patients with a diagnosis of postmenopausal osteoporosis, bisphosphonate usage of at least 5 years and prodromal pain prior to fracture were included the study. RESULTS: Five women met the inclusion criteria. All patients had bilateral low-energy sequential femoral shaft fractures. Fracture patterns were similar and atypical (transverse-short oblique fractures with lateral cortical thickening). Mean period of bisphosphonate treatment was 8.6 years. Mean patient age was 76.2 years. Union time of three patients was between 20 and 28 weeks. The remaining two fractures were revised for delayed union or nonunion. CONCLUSION: Long-term (over 5 years) use of bisphosphonates may cause insufficiency fractures due to increased fragility and brittleness which have a close relationship with depressed bone remodeling. While there is still no causal relationship between bisphosphonates and atypical, low energy femoral shaft fractures, we have some concerns about the optimal usage time and long-term safety of bisphosphonate drugs. PMID- 23748616 TI - Biomechanical evaluation of different internal fixation methods for humerus shaft fractures with medial butterfly fragment. AB - OBJECTIVE: The aim of this study was to compare the biomechanical strength of three fixation methods in humerus shaft fractures with medial butterfly fragment. METHODS: An AO 12B2 fracture with butterfly fragment was created in 21 synthetic cortical shell humeri. Humeri were divided into 3 groups which underwent bridge plating, antegrade intramedullary nailing or retrograde intramedullary nailing. Rotational and four-point bending test displacement curves were obtained. RESULTS: Mean displacement values in the torsion tests were 37.38 (range: 25.75 to 55.69) mm in the bridge plating group, 26.55 (range: 21.25 to 41.81) mm in the antegrade nailing group, and 33.23 (range: 27.50 to 46.45) mm in the retrograde nailing group. Mean displacement values in the four-point bending test were 3.27 (range: 2.54 to 3.73) mm in the bridge plating group, 3.17 (range: 2.69 to 3.55) mm in the antegrade nailing group, and 3.15 (range: 2.10 to 4.03) mm in the retrograde nailing group. No significant difference was found among the groups (p>0.05). CONCLUSION: The biomechanical stability of bridge plating, antegrade intramedullary nailing and retrograde intramedullary nailing appears to be similar in the fixation of humerus shaft fractures with medial butterfly fragment. PMID- 23748617 TI - Comparison of repair techniques in small and medium-sized rotator cuff tears in cadaveric sheep shoulders. AB - OBJECTIVE: The aim of this study was to compare new knotless single-row and double-row suture anchor techniques with traditional transosseous suture techniques for different sized rotator cuff tears in an animal model. METHODS: The study included 56 cadaveric sheep shoulders. Supraspinatus cuff tears of 1 cm repaired with new knotless single-row suture anchor technique and supraspinatus and infraspinatus rotator cuff tears of 3 cm repaired with double-row suture anchor technique were compared to traditional transosseous suture techniques and control groups. The repaired tendons were loaded with 5 mm/min static velocity with 2.5 kgN load cell in Instron 8874 machine until the repair failure. RESULTS: The 1 cm transosseous group was statistically superior to 1 cm control group (p=0.021, p<0.05) and the 3 cm SpeedBridge group was statistically superior to the 1 cm SpeedFix group (p=0.012, p<0.05). The differences between the other groups were not statistically significant. CONCLUSION: No significant difference was found between the new knotless suture anchor techniques and traditional transosseous suture techniques. PMID- 23748618 TI - Cisplatin loaded PMMA: mechanical properties, surface analysis and effects on Saos-2 cell culture. AB - OBJECTIVE: Despite wide resection and systemic chemotherapy, bone tumors may present with local recurrences, metastases and pathological fractures. Application of bone cement containing antineoplastic drug to fill the defect after resection of metastatic lesions and to support implants has been suggested to prevent local tumor growth and implant failures. In this study, we aimed to demonstrate the effects of the addition of cisplatin which is a widely used antineoplastic drug for osteosarcoma, on the mechanical properties of bone cement, and to evaluate the cytotoxic effects of eluted cisplatin on Saos-2 cell culture. METHODS: Two cement samples were prepared by mixing 100 mg and 300 mg of cisplatin powder with 40 g cement powder. The bone cement of the control group did not contain cisplatin. Mechanical analyses included 4-point bending, compression and shear testing. For cytotoxicity analysis, samples were incubated in Dulbecco's Modified Eagle's medium for 15 days. Mediums were applied to Saos-2 cell culture and cell viability was measured. Surface analyses were performed by scanning electron microscope (SEM). RESULTS: The addition of cisplatin did not alter the mechanical properties of bone cement. It was observed that the eluted cisplatin had cytotoxic effects on Saos-2 cells. SEM analyses demonstrated cisplatin granules on the surface of cement samples. CONCLUSION: Cisplatin maintains its cytotoxic property when released from bone cement without compromising the mechanical stability. Application of cisplatin loaded bone cement may help local control of tumor growth. We believe that our study will shed light on to these new practices for the treatment of bone cancers and will encourage future studies. PMID- 23748619 TI - The effect of oophorectomy on epidural fibrosis after laminectomy: an experimental study in rats. AB - OBJECTIVE: The aim of this study was to examine the effect of oophorectomy in the formation of epidural fibrosis in a rat laminectomy model. METHODS: Thirty-six 12 month-old adult female Sprague-Dawley rats were used in this study. Rats were evenly divided into two groups; oophorectomized and sham-operated. Bilateral oophorectomy was performed on the 18 rats in the oophorectomized group. Three weeks after oophorectomy, rats in both groups underwent complete bilateral laminectomy at the L2 and L3 vertebral levels. Rats were divided into 3 equal groups and sacrificed in groups of 4 at the 4th, 8t, and 12th weeks postoperatively and the lumbar spine excised en bloc, fixed and decalcified. Sections were stained with hematoxylin and eosin and Masson's trichrome were used to evaluate epidural fibrosis, acute inflammation, chronic inflammation, and vascular proliferation. RESULTS: The mean histological sum grade of the epidural fibrosis was greater in the oophorectomized group (p>0.05). CONCLUSION: Endogenous estrogen could have an effect on epidural fibrosis formation after lumbar laminectomy in rats. PMID- 23748620 TI - Does platelet-rich plasma enhance microfracture treatment for chronic focal chondral defects? An in-vivo study performed in a rat model. AB - OBJECTIVE: The purpose of the present study was to compare the effectiveness of platelet-rich plasma (PRP) + microfracture and microfracture treatments in the healing of chronic focal chondral defects. METHODS: The study included 57 adult male Sprague-Dawley rats. Forty-two rats were divided into three groups of 14 rats with a chondral defect (control, microfracture only, PRP+microfracture). The remaining 15 rats were used to produce the PRP preparation. The rats were then euthanatized at 3 and 6 weeks after treatment and examined. Histological analysis using the modified Pineda scoring system and immunohistochemical staining for Type 2 collagen were performed. RESULTS: At both time intervals, control group histological scores (Week 3: 8.8+/-1.2, Week 6: 8.5+/-0.7) were higher than microfracture (Week 3: 6.8+/-1.0, Week 6: 7.1+/-0.6) and PRP+microfracture (Week 3: 6.4+/-1.3, Week 6: 5.7+/-1.2) scores (p<0.05). The microfracture group score was higher at Week 6 than the PRP+microfracture group (p<0.05). The degree of Type 2 collagen staining was higher at Week 6 in the PRP+microfracture group and was unique in showing staining at the cell membrane. CONCLUSION: The addition of PRP application to microfracture treatment appears to enhance cartilage healing in chronic focal chondral defects. PMID- 23748621 TI - Mucoid hypertrophic mass of the anterior cruciate ligament causing knee extension block. AB - We report on the case of a patient with a knee extension block caused by a mucoid hypertrophic mass on the anterior cruciate ligament (ACL). Magnetic resonance imaging showed diffuse thickening of the ACL with a mass-like lesion anterior to the tibial attachment. Arthroscopy revealed a huge amorphous mass arising from ACL fibers at the tibial attachment that impinged on the femoral intercondylar notch on knee extension. The treatment included excision of the mass and accompanying abnormal ACL fibers and notchplasty, and resulted in complete recovery of knee motion and symptom relief without instability. This case shows that a degenerative mass in the form of a mucoid hypertrophied ACL can cause a knee extension block. PMID- 23748622 TI - The Nocardia farcinica infection developing after total knee arthroplasty surgery. AB - Infection is an important complication in total knee prosthesis implementations and possesses a serious morbidity. We present a case of Nocardia farcinica infection which appeared after application of cemented total knee prosthesis. A 78-year-old male patient had referred to the outpatient clinic with the complaints of restricted movement, pain and swelling of the knee which started after a month following total knee arthroplasty surgery due to left gonarthrosis. As no improvement could be achieved after arthroscopic debridement, synovectomy and antibiotherapy, the components of the total knee prosthesis were removed from him. Although improvement could not be achieved in the knee of the patient at the end of 20-month therapy, the case has still being followed-up. PMID- 23748623 TI - Long-term follow-up of a hip joint osteoblastoma after intralesional curettage and cement packing: a case report. AB - This article reports a case of intraarticularly expanding benign osteoblastoma of the acetabulum caused femoral head destruction by impingement in a 17-year-old male that was diagnosed for two years from the onset of symptoms. As a treatment, by surgical dislocation of the hip joint, polymethyl-methacrylate was packed inside the gap of the acetabular site after intralesional wide curettage. Femoral head remodeling was observed without recurrence after ten years follow-up. PMID- 23748624 TI - Association between angiotensin-converting enzyme I/D polymorphism and sepsis: A meta-analysis. AB - BACKGROUND: Previous studies investigating the association between the angiotensin-converting enzyme I/D polymorphism and sepsis have provided inconsistent results. Thus, a meta-analysis was performed to clarify the effect of the angiotensin-converting enzyme I/D polymorphism on sepsis risk and sepsis related mortality. METHODS: A comprehensive literature search was performed. Six case-control studies and two cohort studies were included in this meta-analysis. Odds ratios and corresponding 95% confidence intervals were estimated using random-effects models. RESULTS: Pooled analysis of six case-control studies showed that there was a significant association between the angiotensin converting enzyme I/D polymorphism and sepsis risk in a recessive genetic model (odds ratio = 0.75, 95% confidence interval 0.62-0.91, p = 0.004). However, no significant association between the angiotensin-converting enzyme I/D polymorphism and mortality was observed (odds ratio = 0.84, 95% confidence interval 0.57-1.24, p = 0.38). CONCLUSIONS: Our meta-analysis confirmed that the angiotensin-converting enzyme I/D polymorphism was associated with sepsis risk. However, the angiotensin-converting enzyme I/D polymorphism was not associated with sepsis mortality. PMID- 23748625 TI - The CYP11B2 -344C/T variant is associated with ischemic stroke risk: An updated meta-analysis. AB - INTRODUCTION: The CYP11B2 gene has been suggested to play an important role in the pathogenesis of ischemic stroke. However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the association of the CYP11B2 -344C/T variant with ischemic stroke. METHODS: Published literature from PubMed and Embase were retrieved. Pooled odds ratio with 95% confidence interval was calculated using a fixed- or random-effects model. A total of seven studies (2765 stroke cases and 3118 controls) for the CYP11B2 -344C/T variant were included in the meta-analysis. RESULTS: The meta-analysis indicated that the CYP11B2 -344C/T variant was significantly associated with ischemic stroke under a homogeneous co-dominant model (TT vs. CC: odds ratio=2.04, 95% confidence interval=1.21-3.45), dominant model (TT+TC vs. CC: odds ratio=1.67, 95% confidence interval=1.09-2.57) and recessive model (TT vs. TC+CC: odds ratio=1.56, 95% confidence interval=1.18-2.05) but not under a heterogeneous co dominant model (TC vs. CC: odds ratio=1.43, 95% confidence interval=0.98-2.07). Further subgroup analysis showed that the CYP11B2 -344C/T variant was significantly associated with ischemic stroke in East Asian and South Asian populations, but not in a Caucasian population. CONCLUSION: The present meta analysis supported the positive association of the CYP11B2 -344C/T variant with ischemic stroke. Further large-scale studies considering gene-gene/gene environment interactions should be conducted to investigate the association. PMID- 23748626 TI - Association between eprosartan-based hypertension therapy and improvement in cognitive function score: long-term follow-up from the OSCAR observational study. AB - OBJECTIVE: The Observational Study on Cognitive function And systolic blood pressure Reduction (OSCAR) was designed to evaluate the impact of eprosartan based therapy on cognitive function in a cohort of 25,745 hypertensive subjects followed for six months. METHODS: In this supplementary analysis, we studied the relationship between eprosartan-based therapy and cognitive function (assessed using the Mini-Mental State Examination (MMSE)) after 12-month follow-up of 3600 patients (the long-term follow-up on-treatment population). RESULTS: Reduction in blood pressure was sustained over 12 months, with mean systolic blood pressure/diastolic blood pressure 130.9/79 mmHg at one year, compared with 164.3/92.8 mmHg at baseline (p<0.001). The overall mean MMSE score at completion of 12-month follow-up was significantly increased from baseline (27.8 +/- 2.7 vs. 26.3 +/- 3.5; p<0.001). The increase in MMSE score was observed when the population was stratified by age (p<0.001) and in a subgroup of patients with cerebrovascular disease at baseline (n=290) (p<0.001, 12 months vs. baseline). CONCLUSIONS: In this cohort of patients, use of eprosartan-based treatment for one year was associated with sustained reduction in blood pressure and stabilization or improvement of MMSE scores. These data are supportive of a role for blood pressure control in the prevention or delay of cognitive decline. PMID- 23748627 TI - Automated identification of drug and food allergies entered using non-standard terminology. AB - OBJECTIVE: An accurate computable representation of food and drug allergy is essential for safe healthcare. Our goal was to develop a high-performance, easily maintained algorithm to identify medication and food allergies and sensitivities from unstructured allergy entries in electronic health record (EHR) systems. MATERIALS AND METHODS: An algorithm was developed in Transact-SQL to identify ingredients to which patients had allergies in a perioperative information management system. The algorithm used RxNorm and natural language processing techniques developed on a training set of 24 599 entries from 9445 records. Accuracy, specificity, precision, recall, and F-measure were determined for the training dataset and repeated for the testing dataset (24 857 entries from 9430 records). RESULTS: Accuracy, precision, recall, and F-measure for medication allergy matches were all above 98% in the training dataset and above 97% in the testing dataset for all allergy entries. Corresponding values for food allergy matches were above 97% and above 93%, respectively. Specificities of the algorithm were 90.3% and 85.0% for drug matches and 100% and 88.9% for food matches in the training and testing datasets, respectively. DISCUSSION: The algorithm had high performance for identification of medication and food allergies. Maintenance is practical, as updates are managed through upload of new RxNorm versions and additions to companion database tables. However, direct entry of codified allergy information by providers (through autocompleters or drop lists) is still preferred to post-hoc encoding of the data. Data tables used in the algorithm are available for download. CONCLUSIONS: A high performing, easily maintained algorithm can successfully identify medication and food allergies from free text entries in EHR systems. PMID- 23748629 TI - Synthesis and electrocatalytic activity of highly porous hollow palladium nanoshells for oxygen reduction in alkaline solution. AB - A series of hollow Pd nanoshells are prepared by employing Co nanoparticles as sacrificial templates with different concentrations of a Pd precursor (1, 6, 12, 20, and 40 mM K2PdCl4), denoted hPd-X (X: concentration of K2PdCl4 in mM unit). The synthesized hPd series are tested as a cathodic electrocatalyst for oxygen reduction reaction (ORR) in alkaline solution. The morphology and surface area of the hPd catalysts are characterized using scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), and cyclic voltammetry (CV). Rotating disk electrode (RDE) voltammetric studies show that the hPd-20 (prepared using 20 mM K2PdCl4) has the highest ORR activity among all the hPd series, while being comparable to commercial Pd and Pt catalysts (E-TEK). The more facilitated ORR at hPd-20 is presumably induced by the enhanced Pd surface area and efficiently high porosity of Pd nanoshells. PMID- 23748628 TI - Perception, signaling and molecular basis of oviposition-mediated plant responses. AB - Eggs deposited on plants by herbivorous insects represent a threat as they develop into feeding larvae. Plants are not a passive substrate and have evolved sophisticated mechanisms to detect eggs and induce direct and indirect defenses. Recent years have seen exciting development in molecular aspects of egg-induced responses. Some egg-associated elicitors have been identified, and signaling pathways and egg-induced expression profiles are being uncovered. Depending on the mode of oviposition, both the jasmonic acid and salicylic acid pathways seem to play a role in the induction of defense responses. An emerging concept is that eggs are recognized like microbial pathogens and innate immune responses are triggered. In addition, some eggs contain elicitors that induce highly specific defenses in plants. Examples of egg-induced suppression of defense or, on the contrary, egg-induced resistance highlight the complexity of plant-egg interactions in an on-going arms race between herbivores and their hosts. A major challenge is to identify plant receptors for egg-associated elicitors, to assess the specificity of these elicitors and to identify molecular components that underlie various responses to oviposition. PMID- 23748630 TI - What is under the hump? Mass spectrometry based analysis of complex mixtures in processed food--lessons from the characterisation of black tea thearubigins, coffee melanoidines and caramel. AB - In this contribution we review our work on the characterisation of processed food. We review novel methods and analysis strategies developed to account for the composition of extraordinarily complex materials such as black tea thearubigins, coffee melanoidines and thermally treated carbohydrates. Our methods are mainly based on modern mass spectrometry and are introduced and critically discussed. A series of novel previously unpublished data interpretation strategies are presented as well. Finally an evaluation of the insight obtained in the composition of selected processed foods is given discussing potential consequences for assessing beneficial and adverse health effects of processed food. PMID- 23748631 TI - Phylogenetic analysis of gene expression. AB - Phylogenetic analyses of gene expression have great potential for addressing a wide range of questions. These analyses will, for example, identify genes that have evolutionary shifts in expression that are correlated with evolutionary changes in morphological, physiological, and developmental characters of interest. This will provide entirely new opportunities to identify genes related to particular phenotypes. There are, however, 3 key challenges that must be addressed for such studies to realize their potential. First, data on gene expression must be measured from multiple species, some of which may be field collected, and parameterized in such a way that they can be compared across species. Second, it will be necessary to develop comparative phylogenetic methods suitable for large multidimensional datasets. In most phylogenetic comparative studies to date, the number n of independent observations (independent contrasts) has been greater than the number p of variables (characters). The behavior of comparative methods for these classic problems is now well understood under a wide variety of conditions. In studies of gene expression, and in studies based on other high-throughput tools, the number n of samples is dwarfed by the number p of variables. The estimated covariance matrices will be singular, complicating their analysis and interpretation, and prone to spurious results. Third, new approaches are needed to investigate the expression of the many genes whose phylogenies are not congruent with species phylogenies due to gene loss, gene duplication, and incomplete lineage sorting. Here we outline general considerations of project design for phylogenetic analyses of gene expression and suggest solutions to these three categories of challenges. These topics are relevant to high-throughput phenotypic data well beyond gene expression. PMID- 23748632 TI - Uncovering a gene duplication of the photoreceptive protein, opsin, in scallops (Bivalvia: Pectinidae). AB - Evolutionary biologists have long been interested in how expansions of the photosensory system might contribute to morphological differentiation of animals. Comparative studies in vertebrate and arthropod lineages have provided considerable insight into how the duplication of opsin, the first gene of the phototransduction pathway, have led to functional differentiation and new ecological opportunities; however, this relationship cannot be examined in many invertebrate groups as we have yet to characterize their opsin content. Scallops (Pectinidae) are a promising molluscan model to study the evolution of opsin and its potential role in speciation. Recently, we discovered a second Gq-coupled, or r-, opsin gene expressed in the eyes of two scallop species. To investigate the evolutionary origin of this opsin, we screened 12 bivalve species from 4 families, representing both mobile and sessile species, with and without eyes. Although only one ortholog was recovered from the genome of the eyeless, immobile oyster, we found both genes to have been retained in 3 families comprising the order Pectinoida. Within this clade, non-mobile species of scallops appear to have lost one gene. Phylogeny-based tests of selection indicate different degrees of purifying selection following duplication. These data, in conjunction with highly divergent gene sequences and ortholog-specific retention, suggest functional differences. Our results are congruent with a Gq-opsin gene duplication in an oyster-Pectinoida ancestor, approximately 470 Mya, and suggest the likelihood of retaining both genes is associated with either the presence of eyes and/or degree of mobility. The identification of two highly divergent Gq opsin genes in scallops is valuable for future functional investigations and provides a foundation for further study of a morphologically and ecologically diverse clade of bivalves that has been understudied with respect to visual ecology and diversification of opsin. PMID- 23748633 TI - Recovery of sponges after extreme mortality events: morphological and taxonomic patterns in regeneration versus recruitment. AB - Sponges on the Belize Barrier Reef were drastically diminished in 2 mortality events during a 6-year period. Patterns in mortality and recovery were revealed by detailed records of assemblage dynamics, in the form of 8 full censuses between June 2006 and July 2012. All sponges on a set of shallow patch reefs were mapped, identified, and measured for volume at yearly or more frequent intervals, allowing population dynamics of 54 sponge species to be quantified with respect to volume of live tissue and number of individuals. The degree to which sponges of different species suffered during each of the mortality events ranged from complete loss to no effect, resulting in immediate significant alterations in composition of the assemblage in addition to extreme losses (49% in 2008 and 71% in 2011) of the volume of living sponge. The repeated census data documented the early stages of recovery, both on the assemblage level and for every individual sponge. Groups of sponge species, defined by higher taxa or by growth form, not only experienced mortality very differently, but also recovered differently, with some showing efficient regeneration after partial mortality, others adding small individuals by recruitment, and still others not recovering at all. During the 2008 mortality event, losses of both volume and numbers of individuals were disproportionately heavy for members of the orders Aplysinida and especially Poecilosclerida, and for sponges of erect branching and semi-cryptic massive growth forms. Post-mortality recruitment was meager, resulting in no rebound in numbers of individuals; regain of volume lost was slowed by the extreme loss of many entire individual poecilosclerids. By contrast, during the 2011 mortality event, loss of volume was disproportionately heavy for members of the orders Hadromerida and Dictyoceratida, while numbers of individuals were lost from all orders in the same proportion. Among the growth forms, volume was disproportionately lost from massive and semi-cryptic massive sponges, while numbers were only disproportionately lost from the semi-cryptic massive species. During the first 7 months of recovery, a quarter of the lost volume and numbers were re-gained, by a combination of regeneration and recruitment. Relatively rapid early recovery stages reflected the high degree to which losses of volume were due to substantial partial mortality of massive sponges. Significant differences between the 2 mortality events in loss and recovery patterns among higher taxa, as well as among species within particular higher taxa, provide strong impetus for accurate identification to species of all sponges encountered in monitoring, and for continuing efforts aimed at understanding all levels of sponge systematics. In turn, patterns of mortality and recovery may be able to contribute additional characters for systematics. PMID- 23748634 TI - [Extravascular lung water: from genes to telemedicine]. AB - Extravascular lung water is a crucial parameter for the management of many different pathological conditions, especially heart failure. Many modalities can be employed for its evaluation, each with different advantages and limitations. In a near future, we hope that extravascular lung water assessment could be performed by non-invasive wearable devices, allowing remote continuous monitoring of pulmonary congestion. Recently, it has been proposed that some specific genetic variations may be responsible for the heterogeneous individual response to the development of extravascular lung water. These data could be relevant to titrate and personalize both treatments and preventive interventions. PMID- 23748635 TI - [Troponin and periprocedural myocardial infarction: the "breadcrumb" or the "mad flight of Icarus"?]. AB - Percutaneous coronary interventions cause frequently an increase in myocardial necrosis markers. Is troponin elevation after percutaneous coronary intervention a predictor of events at follow-up or a consequence of the procedure with no cause-effect relationship with prognosis? The debate is still open. PMID- 23748636 TI - [Hospitalizations performed in patients enrolled in assistance programs for not self-sufficient individuals]. AB - The objective of this study was to verify if the enrollement of patients aged over sixty-five (over 65), in the territorial assistance programs of a mountain area, has reduced and optimized the volume of hospitalizations. During 2009, 422 patients over 65 who were non self-sufficient, with iso-severity level (IL) from 5 to 0 (Regione Toscana, Decreto n. 1354 del 25 Marzo 2010), were enrolled in home care programs. These data were processed despite the following analytical limitations: 1) inability to provide all tax codes (entered manually in database), the corrisponding personal data; 2) necessity to make cross comparisons among numerous archives of data from different sources; and 3) lack to identify the outcome indicators for each patient. The assisted patients are characterized by a very high hospitalization rate. Among the main diseases, the following needed at least one hospitalization: dementia, stroke, cancer, osteoarticular diseases, cerebrovascular disease and Parkinson's disease. Therefore it is necessary to re-evaluate the current procedures adopted for the management of chronic diseases in the elderly in their own homes. PMID- 23748637 TI - [An epidemic strain of Acinetobacter baumannii in two long-term care facilities]. AB - This study describes an epidemic strain of Acinetobacter baumannii (AB) in two long-term care facilities. Assessment was focused on the spreading modalities of AB infection, the risk of acquiring the infection from colonized patients, the multidrug-resistant features, the clinical characteristics of affected patients, and the average length of hospital stay prior to and after AB infection. The effects of AB spreading among the healthcare operators and the environment are also evaluated, along with a description of the clinical course and outcome, and the efficacy of implemented preventive measures. AB is an opportunistic pathogen with increasing relevance in a variety of nosocomial infections. PMID- 23748638 TI - [Chronic cough and worsening dyspnea: a case of idiopathic tracheal stenosis]. AB - We report a case of idiopathic tracheal stenosis in a 75-year-old woman, who presented to our observation with a diagnosis of asthmatic bronchitis characterized by cough and exertional dyspnea, later complicated by the appearance of tirage. Biopsy of the lesion showed focal squamous metaplasia of the epithelium lining, multiple sclerosis and chronic inflammatory infiltration of the corium. The patient was treated with endoscopic destruction via rigid bronchoscopy, through the combined action of YAG laser and mechanical debulking. PMID- 23748639 TI - [Adjuvant chemotherapy for non-small cell lung carcinoma Stage IA p-T1N0M0. A changed "scenario" after the 2009 7th edition of TNM staging system]. AB - More than a decade has elapsed since the earliest reports about the relevant influence of vascular invasion on the outcome of patients with completely resected NSCLC at stage IApT1N0M0,but just after the approved seventh edition of TNM Classification 2009 for non-small cell lung cancer the importance concerning these issues has been put in its true perspective as correlated also to therapeutic features. The main evidences emerged with regard to studies published during the last ten years are reviewed. On the basis of these evidences a new "scenario" has dawned: the adjuvant chemotherapy for non-small cell lung cancer patients Stage IA with poor prognostic factor vessel invasion should be reconsidered as recommended or at least not-contraindicated. PMID- 23748640 TI - [Well-being and physical activity in the frail elderly]. AB - Physical inactivity damage the elderly patients. The Authors stressed the concept about the very important role of daily, moderate, physical activity on self sufficiency and mental health and the importance of the house-care for the efficiency and well-being of elderly patients. PMID- 23748641 TI - [Prevention of post-operative recurrence in Crohn's disease: a critical review of randomized controlled trials and meta-analyses of different therapeutic strategies]. AB - Surgery is an almost inevitable event in Crohn's disease but is not curative; post-operative recurrence follows a sequential and predictable course. Prevention of post-operative recurrence in Crohn's disease is therefore a relevant problem in the management of the disease. Several drugs have been evaluated to decrease the risk of recurrence: these include mesalazine, antibiotics, probiotics, budesonide, thiopurines and biologic agents. This review focuses on the randomised controlled trials and meta-analyses addressing different drugs and strategies for preventing post-operative recurrence in Crohn's disease. PMID- 23748643 TI - Direct high-performance liquid chromatographic enantioseparation of free alpha-, beta- and gamma-aminophosphonic acids employing cinchona-based chiral zwitterionic ion exchangers. AB - We report a chiral high-performance liquid chromatographic enantioseparation method for free alpha-aminophosphonic, beta-aminophosphonic, and gamma aminophosphonic acids, aminohydroxyphosphonic acids, and aromatic aminophosphinic acids with different substitution patterns. Enantioseparation of these synthons was achieved by means of high-performance liquid chromatography on CHIRALPAK ZWIX(+) and ZWIX(-) (cinchona-based chiral zwitterionic ion exchangers) under polar organic chromatographic elution conditions. Mobile phase characteristics such as acid-to-base ratio, type of counterion, and solvent composition were systematically varied in order to investigate their effect on the separation performance and to achieve optimal separation conditions for the set of analytes. Under the optimized conditions, 32 of 37 racemic aminophosphonic acids studied reached baseline separation when we employed a single generic mass-spectrometry compatible mobile phase, with reversal of the elution order when we used (+) and (-) versions of the chiral stationary phase. PMID- 23748642 TI - Osteoprotective effect of soybean and sesame oils in ovariectomized rats via estrogen-like mechanism. AB - The purpose of the present study was to investigate the osteoprotective effects of soybean oil (SbO) and sesame oil (SO) in ovarictomized (OVX) rats. The results indicated that the OVX rats exhibited a significant decrease in Ca and P level in both serum and bone, the activities of the antioxidant enzymes SOD and CAT and the antioxidant biomarker GSH accompanied with a marked increase in the oxidative stress markers MDA and PC, the inflammatory indices (TNF-alpha, CRP levels, WBCs counts and ACP activity) in, both, bone and serum. Supplementating the diet of the OVX rats with SbO (15 % w/w) or SO (10 % w/w) for 2 months to resulted in modulation of the alterations in all tested parameters and succeeded to restore minerals, antioxidant enzymes, antioxidant biomarkers, oxidative stress markers, inflammatory indices, and WBCs counts. It could be concluded that the consumption of diets supplemented with SbO or SO might be useful for preventing bone loss caused by estrogen deficiency in ovariectomy status. PMID- 23748644 TI - Grafting of molecularly imprinted polymer to porous polyethylene filtration membranes by plasma polymerization. AB - An application of plasma-induced grafting of polyethylene membranes with a thin layer of molecularly imprinted polymer (MIP) was presented. High-density polyethylene (HDPE) membranes, "Vyon," were used as a substrate for plasma grafting modification. The herbicide atrazine, one of the most popular targets of the molecular imprinting, was chosen as a template. The parameters of the plasma treatment were optimized in order to achieve a good balance between polymerization and ablation processes. Modified HDPE membranes were characterized, and the presence of the grafted polymeric layer was confirmed based on the observed weight gain, pore size measurements, and infrared spectrometry. Since there was no significant change in the porosity of the modified membranes, it was assumed that only a thin layer of the polymer was introduced on the surface. The experiments on the re-binding of the template atrazine to the membranes modified with MIP and blank polymers were performed. HDPE membranes which were grafted with polymer using continuous plasma polymerization demonstrated the best result which was expressed in an imprinted factor equal to 3, suggesting that molecular imprinting was successfully achieved. PMID- 23748645 TI - Immunoreactivity of Wnt5a, Fzd2, Fzd6, and Ryk in glioblastoma: evaluative methodology for DAB chromogenic immunostaining. AB - The aim of this study was to determine the influence of Wnt5a and its receptors on the survival of glioblastoma patients and to determine reliable evaluation methods for immunohistochemistry. Diagnostic specimens from 41 histopathologically confirmed primary glioblastoma patients whose Gd-enhanced tumors had been totally removed were immunohistochemically stained for Wnt5a, Fzd2, Fzd6, and Ryk. The immunoreactivity was evaluated using the following methods: (A) grayscale optical density after color deconvolution, (B) percentage of stained cells, (C) density of stained cells, (D) staining amount (multiplication product of B and C), and (E) staining rank. The data sets of A to E were statistically evaluated by correlation matrix analysis and regression analysis. The influence of the expression of the markers on survival was analyzed using a proportional hazard model. The results of color deconvolution (A) were well correlated with the results of the staining rank (E). In the semiquantitative results (B, C, and D), the staining amount (D) tended to show a better correlation with results of color deconvolution (A). Among all data sets, color deconvolution (A) demonstrated the most preferable fit in a proportional hazard model, and the expression of Fzd2 and Fzd6 was associated with poor prognosis in glioblastoma patients. PMID- 23748646 TI - Historical roots of the spatial, temporal, and diversity scales of agricultural decision-making in sierra de santa marta, los tuxtlas. AB - Land degradation is a serious problem in tropical mountainous areas. Market prices, technological development, and population growth are often invoked as the prime causes. Using historical agrarian documents, literature sources, and historical population data, we (1) provide quantitative and qualitative evidence that the land degradation present at Sierra de Santa Marta (Los Tuxtlas, Mexico) has involved a historical reduction in the temporal, spatial, and diversity scales, in which individual farmers make management decisions, and has resulted in decreased maize productivity; and (2) analyze how these three scalar changes can be linked to policy, population growth, and agrarian history. We conclude that the historical reduction in the scales of land use decision-making and practices constitutes a present threat to indigenous agricultural heritage. The long-term viability of agriculture requires that initiatives consider incentives for co-responsibility with an initial focus on self-sufficiency. PMID- 23748648 TI - Advances in nano-scaled biosensors for biomedical applications. AB - Recently, a growing amount of attention has been focused on the utility of biosensors for biomedical applications. Combined with nanomaterials and nanostructures, nano-scaled biosensors are installed for biomedical applications, such as pathogenic bacteria monitoring, virus recognition, disease biomarker detection, among others. These nano-biosensors offer a number of advantages and in many respects are ideally suited to biomedical applications, which could be made as extremely flexible devices, allowing biomedical analysis with speediness, excellent selectivity and high sensitivity. This minireview discusses the literature published in the latest years on the advances in biomedical applications of nano-scaled biosensors for disease bio-marking and detection, especially in bio-imaging and the diagnosis of pathological cells and viruses, monitoring pathogenic bacteria, thus providing insight into the future prospects of biosensors in relevant clinical applications. PMID- 23748649 TI - Correlation between computed tomography expression of pulmonary hypertension and severity of lung disease in cystic fibrosis patients. AB - PURPOSE: Pulmonary hypertension (PHTN) is a significant cause of morbidity and mortality in patients with cystic fibrosis (CF), but a routine noninvasive test for evaluating PHTN is lacking. We aimed to determine whether there is a correlation between computed tomography (CT) signs for PHTN and lung disease severity in CF. MATERIALS AND METHODS: We retrospectively evaluated high resolution CT studies of 91 consecutive CF patients. The ratios of the widest diameters of the main pulmonary artery (MPA), right pulmonary artery, and left pulmonary artery to the ascending aorta (Ao) were calculated. MPA/Ao>1 was considered indicative for PHTN. Lung severity was assessed with modified Brody scores for the left lung (LL), right lung (RL), and overall [Total Brody Score (TBS)]. The nonparametric Pearson chi test was performed for determining the correlation between Brody score and objective CT signs for PHTN. RESULTS: This study included 54 male and 37 female patients aged between 3 and 67 years (mean 17.6 y). Mean RL, LL, and TBS were 23.71, 23.31, and 47.15, respectively. Of the 91 patients, 28 (30.8%) had MPA/Ao>1, indicating a high probability for PHTN. Among these patients, the mean TBS was 38.8, as compared to mean of 50.8 in 63 patients with MPA/Ao<=1. No correlation was found for the RL and LL separately. CONCLUSION: There was no correlation between parenchymal lung disease severity assessed by the modified Brody score and CT signs of PHTN in CF patients. PMID- 23748647 TI - Effect of 7,8-dihydroxyflavone as an antioxidant on in vitro maturation of oocytes and development of parthenogenetic embryos in pigs. AB - One of the factors that impairs in vitro produced porcine embryos is the oxidative stress that is mainly caused by the imbalance between reactive oxygen species (ROS) generation and antioxidants activity, especially that of glutathione (GSH). Here, we examined the effect of 7,8-dihydroxyflavone (7,8 DHF), a kind of flavonoid antioxidant, on porcine oocyte maturation and its developmental competence. Porcine oocytes were cultured in media supplemented with 0, 1, 5 and 10 MUM 7,8-DHF during both in vitro maturation (IVM) and in vitro culture (IVC) after parthenogenetic activation. Maturation of oocytes was evaluated based on first polar body (PB) extrusion and intracellular GSH level, and developmental competence was assessed through observing cleavage and blastocyst formation. In each step, the levels of intracellular GSH and ROS were assessed by fluorescence intensity, and the apoptosis-related gene expression was examined using semiquantitative RT-PCR. The group treated with 1 MUM 7,8-DHF during IVM and IVC showed increased cytoplasmic maturation and reached the blastocysts stage (36.1%) at a higher rate than the other groups (24.7, 16.0 and 10.3% for 0, 5 and 10 MUM, P<0.05). In that group, the intracellular GSH level was significantly increased while ROS generation was significantly decreased after IVM and IVC (P<0.05). Moreover, it showed high expression of an anti apoptotic gene (BCL2L1) and low expression of a pro-apoptotic gene (BAK1) (P<0.05). In conclusion, treatment with 1 MUM 7,8-DHF during IVM and IVC showed an anti-apoptotic effect by increasing intracellular GSH synthesis and scavenging ROS and therefore improved the developmental competence of porcine embryos. PMID- 23748650 TI - ACR Appropriateness Criteria(r) pulmonary hypertension. AB - Pulmonary hypertension (PH) may be idiopathic or related to a variety of diseases. The diagnosis, accurate assessment of etiology and severity, prognosis, treatment response, and follow-up of PH can be achieved using a diverse set of diagnostic examinations. In this review, the role of imaging in the evaluation of PH as suggested by the American College of Radiology Appropriateness Criteria Expert Panel on Thoracic Imaging has been discussed. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The development and review of the guidelines include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 23748652 TI - [Universal coverage: the single most powerful concept the public health has to offer]. PMID- 23748651 TI - Quantitative computed tomography in chronic obstructive pulmonary disease. AB - Quantitative computed tomography is being increasingly used to quantify the features of chronic obstructive pulmonary disease, specifically emphysema, air trapping, and airway abnormality. For quantification of emphysema, the density mask technique is most widely used, with threshold on the order of-950 HU, but percentile cutoff may be less sensitive to volume changes. Sources of variation include depth of inspiration, scanner make and model, technical parameters, and cigarette smoking. On expiratory computed tomography (CT), air trapping may be quantified by evaluating the percentage of lung volume less than a given threshold (eg, -856 HU) by comparing lung volumes and attenuation on expiration and inspiration or, as done more recently, by coregistering inspiratory and expiratory CT scans. All of these indices correlate well with the severity of physiological airway obstruction. By constructing a 3-dimensional model of the airway from volumetric CT, it is possible to measure dimensions (external and internal diameters and airway wall thickness) of segmental and subsegmental airways orthogonal to their long axes. Measurement of airway parameters correlates with the severity of airflow obstruction and with the history of chronic obstructive pulmonary disease exacerbation. PMID- 23748653 TI - [Towards universal health coverage: concepts, lessons and public policy challenges]. PMID- 23748654 TI - [Development and validation of BECAD. An instrument derived from the international classification of functioning, disability and health]. AB - BACKGROUND: The International Classification of Functioning, Disability and Health (ICF) provides a useful theoretical framework for the rehabilitation of chronic diseases with complex problems that require interdisciplinary teams. The aim of this study was the development of a set of scales based on ICF for treatment planning and outcome assessment. METHODS: A group of experts conducted several changes of the elements from the Activities and Participation ICF chapter. Tasks and questions were designed and then, submitted to review from another group of experts. An online application was designed. The sample consisted of 116 participants, 34 of them with brain injury, 38 with severe mental disorders and 44 controls. Trained psychologists and other health professionals administered the scales. Exploratory factor analysis of the scales "Learning and applying knowledge and general tasks and demands", "Self-care" and "Mobility" besides reliability coefficients, MANCOVAs and regression analyses were performed. RESULTS: In the scale "Learning and applying knowledge and general tasks and demands" three factors have been extracted, which explain 52,58% of variance. In the scale "Mobility" two factors have been extracted, explaining 76,91 % of variance; and in "Self-care", another two factors were extracted, explaining 77,60 % of variance. MANCOVAs showed significant differences between the three groups in all seven new factors. All factors presented coefficients between 0.91 and 0.99. CONCLUSIONS: These results showed appropriate metric properties of the new scales, whose factors discriminate between groups and have a high reliability. PMID- 23748655 TI - [Cost of Clostridium difficile associated diarrhea in Spain]. AB - BACKGROUND: There are not available adequate studies of the costs of Clostridium difficile-associated diarrhea (CDAD) in Spain. The aim of the study is to estimate the cost of CDAD for the National Health Service (NHS). METHODS: an economic model was carried out to calculate the cost per episode of CDAD (due to antimicrobials, prolonged hospitalization, surgical procedures, measures to control the infection, recurrences of infections treated) and the CDAD annual cost. Resources use in clinical practice was obtained through a Delphi panel of Spanish clinicians with expertise in CDAD and unit costs (? 2012) from Spanish Sources. RESULTS: An estimated 7,601 episodes of CDAD occur annually in Spain (incidence of 17.1 episodes/year/10,000 hospital discharges) with an annual cost to the NHS of ? 32,157,093. Cost per episode of CDAD: ? 3,901 (initial infection), ? 4,875 (first recurrence) and ? 5,916 (second recurrence). Total cost of recurrences: ? 10,426,750 annually. The 95.6% of spending is due to the prolonged hospitalization, 0.5% to antibiotic treatment, 2.8% for surgery and 1.1% for measures of control infection. Study results are sensitive to incidence and case fatality rate of CDAD in Spain and the prolongation of duration of hospital stay due to CDAD. CONCLUSIONS: According to this study, the expense associated with CDAD is primarily due to the prolongation of hospitalization and has a great economic impact on the NHS. PMID- 23748656 TI - [Cardiorespiratory fitness and cardiometabolic risk in young adults]. AB - BACKGROUND: The assessment of VO2max allow classify subjects according to the health risk. However the factors that may affect the classifications have been little studied. The main purpose was to determine whether the type of VO2max prediction equation and the Fitnessgram criterion-referenced standards modified the proportion of young adults classified with a level of aerobic capacity cardiometabolic risk indicative. METHODS: The study design was observational, cross-sectional and relational. Young adults (n= 240) participated voluntarily. The VO2max was estimated by 20-m shuttle run test applying 9 predictive equations. The differences in the classifications were analyzed with the Cochran Q and McNemar tests. RESULTS: The level of aerobic capacity indicative of cardiometabolic risk ranged between 7.1% and 70.4% depending on the criterion referenced standards and predictive equation used (p<0.001). A higher percentage of women were classified with an unhealthy level in all equations (women: 29.4% to 85.3% vs 4.8% to 51% in men), regardless of the criterion-referenced standards (p<0.001). Both sexes and irrespective of the equation applied the old criterion referenced standards classified a lower proportion of subjects (men: 4.8% to 48.1% and women: 39.4% a 68.4%) with unhealthy aerobic capacity (p <= 0.004). CONCLUSIONS: The type of VO2max prediction equation and Fitnessgram criterion referenced standards changed classifications young adults with a level of aerobic capacity of cardiometabolic risk indicative. PMID- 23748657 TI - [Space analysis of breast and cervix cancer morbimortality. Villa Clara. Cuba. 2004-2009]. AB - BACKGROUND: Breast and cervix cancers continues being a problem of health, in spite of the existence of prevention and precocius diagnosis programs, and for not existing in our county similar studies, its decide to realized this investigations to identify space and temporal space conglomerate that allow us the analysis of breast and cervix cancer morbimortality in Villa Clara. METHODS: observational descriptive study to detection space and temporal space of incidence and mortality, using the statistical technique of temporal-space exploration (SatScan programs v .7.01), the sample embraced the entirety of patients diagnosed during the year 2004, to those that were carried out pursuit in the 5 serial years to the diagnosis, until the closing of the year 2009. RESULTS: the breast cancer showed agreement in the results so much space as temporal-space with a risk of suffering the illness of 1.63 and 1.91 respectively, the municipalities that conformed significant conglomerates, were located toward the center and northeast of the county, headed by Santa Clara the municipality provincial head. The cervix cancer evidenced from the temporary point of view the diagnosis of prospective 100 cases of 68.8 during the months of March to July of the 2004. The study temporal-space showed a conglomerate of incidence in the municipalities located to the northeast of the county, the women that live in these areas have 3.46 times more risk of presenting this illness that those of the rest of the county. CONCLUSIONS: the presence of significant conglomerates so much was shown space as temporal-space, of the areas of more risk of to make sick for breast and cervix cancers. Not existing of mortality and late diagnosis conglomerates. PMID- 23748658 TI - [Shared decision making in breast cancer. Womens' attitudes]. AB - BACKGROUND: The patient autonomy and the greater role for women with breast cancer in the decisions about their health are recent issues in healthcare. The objective of this work is to identify and characterize the elements that influence them in treatment decisions. METHODS: A phenomenological type qualitative study. Theoretical Sampling included 70 women diagnosed with breast cancer. 45 semi structured interviews and 3 focus groups were performed between October 2009 and July 2010 in 15 regions of Spain. The analysis was based on the principles of grounded theory with the support of Atlas.ti v6.1. RESULTS: Patients are likely to take an active or passive role regarding decision-making depending on different variables such as their age, the information available, their self-assessment as capable agents to make decisions and the relative importance given to physical appearance. As the disease progresses, it can cause a change in women attitude, from an initially passive attitude to a more active role. The attitude of health professionals concerning shared decision-making and the information they offer determines patient participation while the family plays an essential role as a support or reinforcement of decisions made by patients. CONCLUSIONS: The patients' attitude regarding the decision-making of patients is very variable, becoming increasingly important the emotional status, the level of information available and the influence of the context. PMID- 23748659 TI - [Parental occupational exposures and autism spectrum disorder in children]. AB - BACKGROUND: Studies of siblings and twins suggest a genetic component of autism that does not fully explain its current increase. The aim is to investigate whether environmental factors such as exposure to occupational hazards (night work, handling of solvents and/or electromagnetic fields) increases the likelihood of autism spectrum disorders (ASD) in children. METHODS: Observational case control study by analyzing the records of 206 children (age between 16 and 36 months) evaluated in the Early Intervention Service of Ciudad Real (70 with ASD and 136 unaffected children). To assess the risk of ASD associated with night work, handling of solvents and/or electromagnetic fields, odds ratio (OR) were calculated with 95% confidence intervals (CI). RESULTS: The risk of ASD is multiplied by 2.22 when one parent works in the studied occupations (OR=2.22, 95% CI=1.42-3.48), highlighting work with solvents (OR=2.81, 95% CI=1.28-6.17) and night work (OR=2.18, 95% CI=1.21-3.93). It is multiplied by 3 if the mother's job is one of these occupations (OR=3, 95% CI=1.44-6.26), standing out night work (OR=3.47, 95% CI=1.39-8.63), and handling of solvents (OR=2.88, 95% CI=1.28 6.17); whereas it is multiplied by 1.94 if the father works in these occupations (OR=1.94, 95% CI=1.07-3.53), standing out handling of solvents (OR=2.81, 95% CI=1.01-7.86). A positive association between the educational level of parents and ASD is found. CONCLUSIONS: The results show a significant relationship between the exposure of the parents to occupational hazards and ASD in the children, suggesting the involvement of genetic alterations caused by environmental factors in the origin of the disorder. PMID- 23748660 TI - [Archivos de Prevencion de Riesgos Laborales. Another Spanish journal of public health in Medline/Pubmed]. PMID- 23748661 TI - [Pharmacoeconomics models of simulation, meta-analysis and sponsorship of the industry]. PMID- 23748662 TI - [Author's answer: Pharmacoeconomic models of simulation, meta-analysis and sponsorship of the industry]. PMID- 23748663 TI - Overexpression of hypoxia inducible factor-1 alpha is an independent risk factor for recurrence after curative resection of colorectal liver metastases. AB - BACKGROUND: Hypoxia inducible factor-1alpha (HIF-1alpha) is a major regulator of tumorigenesis in hypoxic conditions and therefore represents a potential therapeutic target in colorectal cancer (CRC). Clinical significance of HIF 1alpha expression in liver metastases has not been elucidated. Therefore, this study aimed to clarify the clinical significance of HIF-1alpha expression in colorectal liver metastasis (CRLM). METHODS: We retrospectively analyzed 64 patients who underwent curative resection of CRLM from 2000 to 2008. We evaluated HIF-1alpha expression by immunohistochemical staining and analyzed its association with several clinicopathological characteristics, including vascular endothelial growth factor (VEGF) expression. We analyzed the mutation status of genes involved in CRC (p53, KRAS, BRAF, and PIK3CA). Finally, we compared HIF 1alpha expression between the primary tumor and the corresponding liver metastases. RESULTS: We found a significant positive correlation between HIF 1alpha expression in liver metastases and PIK3CA mutation status (p = 0.019). A significant correlation was also observed between the expressions of HIF-1alpha and VEGF in liver metastases and primary tumors (p = 0.015, 0.024, respectively). High HIF-1alpha expression in liver metastases was an independent risk factor for recurrence (p = 0.031). CONCLUSIONS: Our results suggest a possible induction of HIF-1alpha expression by mutant PIK3CA. The expressions of HIF-1alpha and VEGF in liver metastases significantly correlated with those in the corresponding primary tumor. Overexpression of HIF-1alpha was an independent risk factor for recurrence after curative resection of CRLM, suggesting that HIF-1alpha represents an important candidate for the treatment of CRLM in a subset of patients with high HIF-1alpha expression. PMID- 23748670 TI - Treatment strategies for infection after reverse shoulder arthroplasty. AB - INTRODUCTION: Infection after reverse shoulder arthroplasty (RSA) is a disastrous complication. No clear guidelines describing specific management strategies for infection after RSA are available. METHODS: We retrospectively analyzed 20 patients treated for deep infection after RSA. Initial irrigation and debridement and exchange of the polyethylene inlay were performed in seven patients, and initial two-stage revision was performed in 12 and initial resection arthroplasty in one patient. Patient charts were reviewed for risk factors, clinical symptoms and investigations of those symptoms, pre- and postoperative X-rays, interval until revision surgery, causative bacteria, complications, final clinical outcome and patient satisfaction. RESULTS: The mean overall postoperative Constant-Murley Score (CMS) was 42.6 points, the mean UCLA score was 20.8, the mean simple shoulder test (SST) was 5.5, and the mean VAS was 1.5. When comparing the CMS, UCLA score and the SST between the revision RSA group and the resection group, significant differences between the groups were found (p<0.05). Irrigation, debridement and exchange of the polyethylene inlay were successful only in two of the four patients with acute infection. The three patients with subacute infections were treated with initial irrigation and debridement and exchange of the polyethylene inlay, which were not successful. CONCLUSION: The relatively high patient satisfaction can be explained by the low pain level once the patient is free from infection. However, functional results are poor in most cases, and this possible outcome must be discussed with the patient in the preoperative setting. PMID- 23748671 TI - New tools to expand regulatory T cells from HIV-1-infected individuals. AB - CD4+ Regulatory T cells (Tregs) are potent immune modulators and serve an important function in human immune homeostasis. Depletion of Tregs has led to measurable increases in antigen-specific T cell responses in vaccine settings for cancer and infectious pathogens. However, their role in HIV-1 immuno-pathogenesis remains controversial, as they could either serve to suppress deleterious HIV-1 associated immune activation and thus slow HIV-1 disease progression or alternatively suppress HIV-1-specific immunity and thereby promote virus spread. Understanding and modulating Treg function in the context of HIV-1 could lead to potential new strategies for immunotherapy or HIV vaccines. However, important open questions remain on their role in the context of HIV-1 infection, which needs to be carefully studied. Representing roughly 5% of human CD4+ T cells in the peripheral blood, studying the Treg population has proven to be difficult, especially in HIV-1 infected individuals where HIV-1-associated CD4 T cell and with that Treg depletion occurs. The characterization of regulatory T cells in individuals with advanced HIV-1 disease or tissue samples, for which only very small biological samples can be obtained, is therefore extremely challenging. We propose a technical solution to overcome these limitations using isolation and expansion of Tregs from HIV-1-positive individuals. Here we describe an easy and robust method to successfully expand Tregs isolated from HIV-1-infected individuals in vitro. Flow-sorted CD3(+)CD4(+)CD25(+)CD127(low) Tregs were stimulated with anti-CD3/anti-CD28 coated beads and cultured in the presence of IL-2. The expanded Tregs expressed high levels of FOXP3, CTLA4 and HELIOS compared to conventional T cells and were shown to be highly suppressive. Easier access to large numbers of Tregs will allow researchers to address important questions concerning their role in HIV-1 immunopathogenesis. We believe answering these questions may provide useful insight for the development of an effective HIV-1 vaccine. PMID- 23748672 TI - Evolution of a designed retro-aldolase leads to complete active site remodeling. AB - Evolutionary advances are often fueled by unanticipated innovation. Directed evolution of a computationally designed enzyme suggests that pronounced molecular changes can also drive the optimization of primitive protein active sites. The specific activity of an artificial retro-aldolase was boosted >4,400-fold by random mutagenesis and screening, affording catalytic efficiencies approaching those of natural enzymes. However, structural and mechanistic studies reveal that the engineered catalytic apparatus, consisting of a reactive lysine and an ordered water molecule, was unexpectedly abandoned in favor of a new lysine residue in a substrate-binding pocket created during the optimization process. Structures of the initial in silico design, a mechanistically promiscuous intermediate and one of the most evolved variants highlight the importance of loop mobility and supporting functional groups in the emergence of the new catalytic center. Such internal competition between alternative reactive sites may have characterized the early evolution of many natural enzymes. PMID- 23748673 TI - Observation of a stable carbene at the active site of a thiamin enzyme. AB - Carbenes are highly reactive chemical compounds that are exploited as ligands in organometallic chemistry and are powerful organic catalysts. They were postulated to occur as transient intermediates in enzymes, yet their existence in a biological system could never be demonstrated directly. We present spectroscopic and structural data of a thiamin enzyme in a noncovalent complex with substrate, which implicate accumulation of a stable carbene as a major resonance contributor to deprotonated thiamin. PMID- 23748674 TI - Design of a nanocarrier with regulated drug release ability utilizing a reversible conformational transition of a peptide, responsive to slight changes in pH. AB - We investigated the drug releasing behavior of a novel nanocarrier system, utilizing a peptide to act as a nanogate to the mesopore, on a mesoporous silica nanoparticle. The surface peptide on mesoporous silica displayed pH-dependant mesopore cap-uncap switching behavior, enabled by the reversible beta-sheet-to random coil conformational transition resulting from slight pH changes between 8.0 and 6.0. The peptide adopted a beta-sheet structure under weakly basic conditions (pH 8.0) and a random coil conformation under weakly acidic conditions (pH 6.0). We demonstrated the pH-dependant regulation of the material's drug release property by the reversible conformational transition of the surface peptide. Under basic pH conditions, the drug release from the nanocarrier was significantly inhibited. However, under acidic pH conditions, the drug in the mesopore was gradually released. PMID- 23748676 TI - Fabrication of integrated porous glass for microfluidic applications. AB - This paper presents a method for the fabrication of integrated porous silica layers in microfluidic channel networks by microfabrication techniques. Porous silica is obtained by anodization of silicon, followed by full conversion of the porous silicon network into porous silica by means of thermal oxidation. A series of experiments were performed with various channel layouts to determine the critical parameters, including the I-V characteristics and the optimal working potential for stable pore formation, during anodic etching. Typical test structures were anodized in 5% HF for 15 min at 1 V, yielding an average pore size of around 5.4 nm and porosity of 49%. Complete conversion of porous silicon into porous glass was accomplished with wet oxidation at 900 degrees C. The average pore size and porosity of porous glass network were around 3.8 nm and 34%, respectively. This decrease in both pore size and porosity is caused by the increase in molar volume when silicon oxidizes to silicon oxide. The transparency and the hydrophilicity of porous glass layers are evidenced by means of monitoring the diffusion of Rhodamine B fluorescent dye through the porous network. This fabrication method can be applied to (3-D) structured microfluidic channels and it is envisioned that the resulting porous silica layers can be employed for a wide range of application areas, such as membrane technology, catalyst supports, chromatography and electrokinetics. PMID- 23748675 TI - Nitrate reductase is required for the transcriptional modulation and bactericidal activity of nitric oxide during the defense response of Arabidopsis thaliana against Pseudomonas syringae. AB - Nitrate reductase (NR) has emerged as a potential NO source in plants. Indeed, the Arabidopsis thaliana NR double-deficient mutant (nia1 nia2) produces low NO and develops abnormal susceptibility to bacterial infection. We have employed quantitative real-time polymerase chain reactions to analyze the effects of NO gas on the expression of defense-related genes in wild-type and nia1 nia2 A. thaliana plants that were inoculated with an avirulent strain of Pseudomonas syringae pv. tomato. The pathogenesis-related gene 1 (PR1) was up-regulated by bacterial infection, and its expression was higher in the wild type than in nia1 nia2. Fumigation with NO attenuated the expression of PR1 and other salicylic acid-related genes in plants that had been inoculated with P. syringae. Nevertheless, NO inhibited the most intense bacterial growth and disease symptoms in nia1 nia2 leaves. The NO fumigation also directly modulated lignin biosynthesis-related gene expression (CAD1) and parts of the auxin (TIR1, ILL1, GH3) and ethylene (ACCS7) pathways, among other defense-related genes, and their modulation was more intense in the NR-deficient mutant. Pathogen inoculation induced delayed but intense H2O2 production in mutant leaves in comparison with the wild type. Hydrogen peroxide potentiated the microbicidal effects of NO against bacterial cultures. These results suggest that NO has a direct microbicidal effect in combination with H2O2 to allow for the attenuation of the SA-mediated defense response, thereby reducing the energy expenditure associated with defense-related gene transcription. Overall, these results highlight the importance of NR-dependent NO production in the establishment of disease resistance. PMID- 23748677 TI - Why is the number of HIV/AIDS-related publications low in the MENA region? PMID- 23748678 TI - Altered precipitation affects plant hybrids differently than their parental species. AB - PREMISE OF THE STUDY: Future changes in environmental conditions may alter evolutionary processes, including hybridization in nature. Frequency of hybrids could be altered via range shifts by the parental species or by changes in prezygotic or postzygotic reproductive isolation. We examined the potential for range shifts and change in postzygotic isolation by determining effects of increasing and decreasing precipitation on leaf physiology and fitness components in the subalpine herbs Ipomopsis aggregata (Polemoniaceae), I. tenuituba and their natural hybrids in a common garden in the habitat of I. aggregata. METHODS: Summer precipitation was experimentally doubled or halved over 3 yr in comparison with ambient conditions. We measured relative growth rate, specific leaf area, intrinsic water-use efficiency, survival to reproduction, biomass, number of flowers produced, and floral morphology. KEY RESULTS: Ipomopsis tenuituba increased relative growth rate with higher precipitation more so than did I. aggregata during the first summer, but this response did not result in changes across treatments in relative survival or final reproductive success of the two species. When precipitation was reduced, the relative success of hybrids was greater than that of the home species, I. aggregata. In dry conditions, hybrids increased water-use efficiency and fitness as indexed by number of flowers more so than the other plant types did. CONCLUSIONS: Increased reproduction in hybrids in the reduced precipitation regime indicates that postzygotic reproductive isolation may breakdown under imposition of dry conditions. These results suggest the potential for frequency of hybrids to increase if severe droughts become more common. PMID- 23748679 TI - Intestinal permeability barrier in Crohn's disease: the difficulty in shifting the paradigm. PMID- 23748682 TI - [Social media and medical apps: how they can change health communication, education and care]. AB - Social media and medical apps for smartphones and tablets are changing health communication, education and care. This change involves physicians and other health care professionals which for their education, training and updating have started to follow public pages and profiles opened by medical journals and professional societies on the online social networking sites (such as Facebook, Twitter and Google+), to access scientific content (videos, images, slides) available on user-generated contents sites (such as SlideShare, Pinterest and YouTube) or on health professional online communities such as Sermo, and to use medical and health apps on their smartphones and tablets. As shown by a number of experiences conducted in US by health institutions such as the Centers for Disease Control and Prevention of Atlanta and hospitals such a the Mayo Clinic, these tools are also transforming the way to make health promotion activities and communication, promote healthy habits and lifestyles, and prevent chronic diseases. Finally this change involves patients which are starting to use medical and health apps on their smartphones and tablets to monitor their diseases, and tools such as Patients Like Me (an online patients' community), Facebook and Twitter to share with others the same disease experience, to learn about the disease and treatments, and to find opinions on physicians, hospitals and medical centers. These new communication tools allow users to move to a kind of collaborative education and updating where news and contents (such as public health recommendations, results of the most recent clinical researches or medical guidelines) may be shared and discussed. PMID- 23748683 TI - [Technological advances and hospital-at-home care]. AB - Advances in the miniaturization and portability of diagnostic technologies, information technologies, remote monitoring, and long-distance care have increased the viability of home-based care, even for patients with serious conditions. Telemedicine and teleradiology projects are active at the Hospital at Home Service of Torino. PMID- 23748684 TI - [Impaired lung function and anemia from large hiatal hernia: a case report]. AB - We present the clinical case of a 54 years old man who accessed for dyspnea and severe anemia. After being transfused, he underwent to gastroscopy, which showed an erosive gastritis with large hiatal hernia. The hernia was surgically reduced with laparoscopic hiatoplastic and Nissen-Rossetti fundoplication. In conclusion, dyspnea is not merely a medical competence but also a surgical one. PMID- 23748685 TI - [The primary mediastinal lymphoma: state of the art and therapeutical perspectives]. AB - Within diffuse large B-cell lymphomas, the Primary Mediastinal Large B-Cell Lymphoma has to be considered as a separate and well-defined clinico-pathological entity. Its tendency to target young adults makes its social impact particularly significant; hence, the General Practitioner carries the responsibility for an early diagnosis. On the contrary, the extreme complexity of the available therapies makes a quick referral to specialized Clinical Centres of outmost importance, since this remains the best way to enrol as many patients as possible in therapeutic protocols. Nowadays, good clinical results and a favourable outcome are achievable, but some questions remain open. The role of radiotherapy still has to be clarified, both as a complete remission consolidation, as well as a treatment of the residual disease. Conversely, a golden standard for the second line treatment has not been clearly established. PMID- 23748686 TI - [Relations between FANS, PPI and atrial fibrillation]. AB - Recent evidence supports the existence of an association between the use of non steroidal anti-inflammatory drugs and the risk of atrial fibrillation. Anti inflammatory drugs are widely used for the treatment of systemic inflammatory disorders, and chronic inflammation is a well-known risk factor for the development of myocardial fibrosis. The latter accounts for atrial inhomogeneities of conduction, thus triggering and perpetuating atrial fibrillation. Atrial inflammatory remodeling may therefore be responsible for the higher incidence of atrial fibrillation among patients assuming steroidal and non steroidal anti-inflammatory drugs because of an underlying inflammatory disorders. Alternative theories contemplate gastroesophageal reflux, which is extremely common during the use of non-steroidal anti-inflammatory drugs and may trigger atrial fibrillation, as mediating the above-mentioned association. PMID- 23748687 TI - [Informed consent and experimental treatments: the case of mesotherapy]. AB - Mesotherapy is a minimally invasive technique based on the introduction of pharmacologically active compounds in the surface layer of the skin. The intradermal route has been known for many years and it has the aim of reducing the dose and slowing the diffusion into the underlying tissues. Mesotherapy requires a clinical diagnosis and informed consent. Patient should be well informed about potential benefits, limitations, and risks (even mild). The process of doctor-patient interaction in mesotherapy is an example of compliance with the basic concept: "first do no harm" and, at the same time, the advantage for the patient to conclude a "therapeutic alliance". We propose a draft form to facilitate the decision-making process. PMID- 23748688 TI - [Physician-patient: shared decisions in pneumo-oncology]. PMID- 23748691 TI - [Proteomics and personalized medicine]. AB - With the disclosure of the human genome a new era for bio-medicine has arisen, characterized by the challenge to investigate pathogenic mechanisms, studying simultaneously metabolites, DNA, RNA, and proteins. As a result, the "omics" revolution boomed, giving birth to a new medicine named "omics-based medicine". Among the other "omics", proteomics has been widely used in medicine, since it can produce a more "holistic" overview of a disease and provide a "constellation" of possible specific markers, a molecular fingerprinting that defines the clinical condition of an individual. Endpoint of this comprehensive and detailed analysis is the "diagnostic-omics", i.e. the achievement of personalized diagnoses with obvious benefits for prevention and therapy and this goal can be reached only with a perfect integration between clinicians and proteomists. To impact on the possible key factors involved in the pathological processes, oligonucleotide-based knock-down strategies can be helpful. They exploit omics derived molecular tools (antisense, siRNA, ribozymes, decoys, and aptamers) that can be used to inhibit, at transcriptional or post-transcriptional levels, the events leading to protein synthesis, thus decreasing its expression. The identification of the pivotal mechanisms involved in diseases using global, "scenic" approaches such as the "omics" ones, and the subsequent validation and detailed description of the processes by specific molecular tools, can result in a more preventive, predictive and personalized medicine. PMID- 23748692 TI - Serotonin2C receptors and drug addiction: focus on cocaine. AB - This review provides an overview of the role of central serotonin2C (5-HT2C) receptors in drug addiction, specifically focusing on their impact on the neurochemical and behavioral effects of cocaine, one of the most worldwide abused drug. First, we described the neurochemical and electrophysiological mechanisms underlying the interaction between 5-HT2C receptors and the mesocorticolimbic dopaminergic network, in keeping with the key role of this system in drug abuse and dependence. Thereafter, we focused on the role of 5-HT2C receptors in the effects of cocaine in various preclinical behavioral models used in drug addiction research, such as locomotor hyperactivity, locomotor sensitization, drug discrimination, and self-administration, to end with an overview of the neurochemical mechanisms underlying the interactions between 5-HT2C receptors, mesocorticolimbic dopamine system, and cocaine. On their whole, the presented data provide compelling preclinical evidence that 5-HT2C receptor agonists may have efficacy in the treatment of cocaine abuse and dependence, thereby underlying the need for additional clinical studies to ascertain whether preclinical data translate to the human. PMID- 23748693 TI - Observation learning of a motor task: who and when? AB - Observation contributes to motor learning. It was recently demonstrated that the observation of both a novice and an expert model (mixed observation) resulted in better learning of a complex spatiotemporal task than the observation of either a novice or an expert model. In experiment 1, we aimed to determine whether mixed observation better promotes learning due to the information that can be gained from two models who exhibit different skill levels or simply because multiple models, regardless of their level of expertise, better promote learning than would a single model. The results revealed that the observation of both an expert and a novice model resulted in better short-term retention than the observation of either two novice or two expert models. In experiment 2, we wanted to determine whether these benefits would last longer if physical practice trials were interspersed with observation. Mixed and (to some extent) expert observations resulted in better long-term retention than observation of a novice model. We suggest that alternating mixed/expert observation with physical practice trials makes one's error more salient than when all observation trials are completed before one first starts performing the experimental task, which increases activation of the action observation network. PMID- 23748694 TI - USP8 is a novel target for overcoming gefitinib resistance in lung cancer. AB - PURPOSE: Common treatment modalities for non-small cell lung cancer (NSCLC) involve the EGF receptor-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib. However, the vast majority of treated patients acquire resistance to EGFR-TKIs, due, in large part, to secondary mutations in EGFR or amplification of the MET gene. Our purpose was to test ubiquitin-specific peptidase 8 (USP8) as a potential therapeutic target for gefitinib-resistant and -sensitive non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Testing the effect of knockdown of USP8 and use of a synthetic USP8 inhibitor to selectively kill gefitinib resistant (or -sensitive) NSCLCs with little effect on normal cells in cell culture and a xenograft mouse model. RESULTS: Knockdown of ubiquitin-specific peptidase 8 (USP8) selectively kills gefitinib-resistant NSCLCs while having little toxicity toward normal cells. Genetic silencing of USP8 led to the downregulation of several receptor tyrosine kinases (RTK) including EGFR, ERBB2, ERBB3, and MET. We also determined that a synthetic USP8 inhibitor markedly decreased the viability of gefitinib-resistant and -sensitive NSCLC cells by decreasing RTK expression while having no effect on normal cells. Moreover, treatment with a USP8 inhibitor led to significant reductions in tumor size in a mouse xenograft model using gefitinib-resistant and -sensitive NSCLC cells. CONCLUSIONS: Our results show for the first time that the inhibition of USP8 activity or reduction in USP8 expression can selectively kill NSCLC cells. We propose USP8 as a potential therapeutic target for gefitinib-resistant and sensitive NSCLC cells. PMID- 23748695 TI - Molecular pathways: PI3K pathway targets in triple-negative breast cancers. AB - The triple-negative breast cancer (TNBC) subtype, defined clinically by the lack of estrogen, progesterone, and Her2 receptor expression, accounts for 10% to 15% of annual breast cancer diagnoses. Currently, limited therapeutic options have shown clinical benefit beyond cytotoxic chemotherapy. Defining this clinical cohort and identifying subtype-specific molecular targets remain critical for new therapeutic development. The current era of high-throughput molecular analysis has revealed new insights into these targets and confirmed the phosphoinositide 3 kinase (PI3K) as a key player in pathogenesis. The improved knowledge of the molecular basis of TNBC in parallel with efforts to develop new PI3K pathway specific inhibitors may finally produce the therapeutic breakthrough that is desperately needed. PMID- 23748696 TI - Humeral head cysts: association with rotator cuff tears and age. AB - The objective of this study was to retrospectively evaluate the prevalence of the cystic changes at rotator cuff footprint on proximal humeral tuberosities and investigate their relationship with rotator cuff tears and patient age. Magnetic resonance (MR) images of 657 patients who underwent shoulder arthroscopy for treatment of rotator cuff disorders were reviewed to localize the cystic changes at anterior (supraspinatus insertion) and posterior (infraspinatus insertion) aspects of greater tuberosity (GT) and lesser tuberosity (subscapularis insertion). Preoperative MR reports as well as cyst size and locations on MR images were correlated with arthroscopic records of rotator cuff pathology (tear type, size, location and tendon involvement) and patient age. The prevalence of cystic changes was 9.1% (60 patients) in the study population. Anterior GT cysts were found in 56% of patients and were strongly associated with full-thickness (p<.001) and articular-sided partial-thickness rotator cuff tears (p=.02). Posterior GT and lesser tuberosity cysts were found in 27 and 17% of patients, respectively, and were not significantly related to rotator cuff tears, although there was an increased trend of posterior cysts in patients with infraspinatus tears (p=.09). A significant relation was found between patient age and the cyst size (p=.01), while none of the cyst localizations were statistically related to age. Anterior GT cysts were more common in this patient group and demonstrated a strong association with rotator cuff disorders regardless of age. Posterior GT and lesser tuberosity cysts were less common and showed no association with rotator cuff pathology or patient age. PMID- 23748697 TI - Live imaging and single-cell analysis reveal differential dynamics of autophagy and apoptosis. AB - Autophagy is induced by many cytotoxic stimuli but it is often unclear whether, under specific conditions, autophagy plays a prosurvival or a prodeath role. To answer this critical question we developed a novel methodology that employs automated live microscopy and image analysis to measure autophagy and apoptosis simultaneously in single cells. We used this approach to perform a systems-level analysis of pathway dynamics for both autophagy and apoptosis. We found that induction of autophagy in response to different stimuli is uniformly unimodal; in contrast, cells induce apoptosis in an all-or-none bimodal fashion. By tracking the fate of single cells we found that autophagy precedes apoptosis, and that within the same population apoptosis is delayed in cells that mount a stronger autophagy response. Inhibition of autophagy by knocking down ATG5 promoted apoptosis, thus confirming that autophagy plays a protective role. We anticipate that our single-cell approach will be a powerful tool for gaining a quantitative understanding of the complex regulation of autophagy, its influence on cell fate decisions and its relationship with other cellular pathways. PMID- 23748698 TI - Rechargeability of Li-air cathodes pre-filled with discharge products using an ether-based electrolyte solution: implications for cycle-life of Li-air cells. AB - The instability of currently used electrolyte solutions and of the carbon support during charge-discharge in non-aqueous lithium-oxygen cells can lead to discharge products other than the desired Li2O2, such as Li2CO3, which is believed to reduce cycle-life. Similarly, discharge in an O2 atmosphere which contains H2O and CO2 impurities would lead to LiOH and Li2CO3 discharge products. In this work we therefore investigate the rechargeability of model cathodes pre-filled with four possible Li-air cell discharge products, namely Li2O2, Li2CO3, LiOH, and Li2O. Using Online Electrochemical Mass Spectrometry (OEMS), we determined the charge voltages and the gases evolved upon charge of pre-filled electrodes, thus determining the reversibility of the formation/electrooxidation reactions. We show that Li2O2 is the only reversible discharge product in ether-based electrolyte solutions, and that the formation of Li2CO3, LiOH, or Li2O is either irreversible and/or reacts with the electrolyte solution or the carbon during its oxidation. PMID- 23748699 TI - Investigation of tryptophan-NADH interactions in live human cells using three photon fluorescence lifetime imaging and Forster resonance energy transfer microscopy. AB - A method to investigate the metabolic activity of intracellular tryptophan (TRP) and coenzyme-NADH using three-photon (3P) fluorescence lifetime imaging (FLIM) and Forster resonance energy transfer (FRET) is presented. Through systematic analysis of FLIM data from tumorigenic and nontumorigenic cells, a statistically significant decrease in the fluorescence lifetime of TRP was observed in response to the increase in protein-bound NADH as cells were treated with glucose. The results demonstrate the potential use of 3P-FLIM-FRET as a tool for label-free screening of the change in metabolic flux occurring in human diseases or other clinical conditions. PMID- 23748700 TI - Analyses of the correlation between dermal and blood carotenoids in female cattle by optical methods. AB - Herd health programs for the maintenance of welfare and productivity in cattle need efficient tools for monitoring the health of individual animals. Recent reports demonstrate that the oxidative status is related to various stress conditions in dairy cows. Biomarkers, among other carotenoids, could serve as indicators of stress originating from the environment (e.g., heat stress or sun radiation) or from the animal itself (e.g., disease). To date, only invasive in vitro tests are available to assess the oxidative status in cattle. The present study compares the results of optical noninvasive in vivo measurements of dermal carotenoids in cattle udder skin using an LED-based miniaturized spectroscopic system (MSS) with those obtained by photometric analysis of beta carotene in whole blood samples using a portable device. Correlations between the concentrations of dermal and blood carotenoids were calculated under consideration of the nutritional status of the animals. Significant correlation (R=0.86) was found for cattle with a moderate to obese body condition. Thus, the blood and skin concentrations of the marker substance beta carotene are comparable under stable stress conditions of the cattle. This demonstrates that the MSS is suitable for noninvasive assessment of dermal carotenoid concentrations in cattle. PMID- 23748701 TI - Visualization of peripheral vasodilative indices in human skin by use of red, green, blue images. AB - We propose a method to visualize the arterial inflow, the vascular resistance, and the venous capacitance in the skin tissue from red, green, blue (RGB) digital color images. The arterial inflow and the venous capacitance in the skin tissue are visualized based on an increase in the rate of change in the total blood concentration and the change of the total blood concentration during upper limb occlusion at a pressure of 50 mmHg. The resultant arterial inflow with the measured mean arterial pressure also provides an image of the vascular resistance in human skin. The arterial inflow, the vascular resistance, and the venous capacitance acquired by the method are well correlated with those obtained from the conventional strain-gauge plethysmograph. The correlation coefficients R between the estimated values by the method and the measurements by the SPG are calculated to be 0.83 (P<0.001) for the arterial inflow, 0.77 (P<0.01) for the vascular resistance, and 0.77 (P<0.01) for the venous capacitance. The arterial inflow and the venous capacitance in the skin tissue are significantly higher in active subjects compared with the sedentary subjects, whereas the vascular resistance was significantly lower in the active subjects compared with the sedentary subjects. The results of the present study indicate the possibility of using the proposed method for evaluating the peripheral vascular functions in human skin. PMID- 23748702 TI - Spectroscopic methods for the photodiagnosis of nonmelanoma skin cancer. AB - The importance of dermatological noninvasive imaging techniques has increased over the last decades, aiming at diagnosing nonmelanoma skin cancer (NMSC). Technological progress has led to the development of various analytical tools, enabling the in vivo/in vitro examination of lesional human skin with the aim to increase diagnostic accuracy and decrease morbidity and mortality. The structure of the skin layers, their chemical composition, and the distribution of their compounds permits the noninvasive photodiagnosis of skin diseases, such as skin cancers, especially for early stages of malignant tumors. An important role in the dermatological diagnosis and disease monitoring has been shown for promising spectroscopic and imaging techniques, such as fluorescence, diffuse reflectance, Raman and near-infrared spectroscopy, optical coherence tomography, and confocal laser-scanning microscopy. We review the use of these spectroscopic techniques as noninvasive tools for the photodiagnosis of NMSC. PMID- 23748703 TI - In vivo wound healing diagnosis with second harmonic and fluorescence lifetime imaging. AB - Skin wounds heal when a series of cell lineages are triggered, followed by collagen deposition, to reconstruct damaged tissues. This study evaluates the regeneration of collagen and change in cellular metabolic rate in vivo during wound healing in rats, with second harmonic generation (SHG) and fluorescence lifetime imaging microscopy respectively. The metabolic rate of cells is reflected through the lifetime of the autofluorescence from the co-enzyme protein, reduced nicotinamide adenine dinucleotide, due to its change in the relative concentration of bound and free forms. A higher than normal cellular metabolic rate is observed during the first week of healing, which decreases gradually after eight days of wound formation. SHG signal intensity change indicates the net degradation of collagen during the inflammatory phase, and net regeneration begins on day five. Eventually, the quantity of collagen increases gradually to form a scar tissue as the final product. Importantly, this work demonstrates the feasibility of an in vivo imaging approach for a normal wound on rat skin, which has the potential to supplement the noninvasive clinical diagnosis of wounds. PMID- 23748707 TI - Embryo-specific expression of soybean oleosin altered oil body morphogenesis and increased lipid content in transgenic rice seeds. AB - Oleosin is the most abundant protein in the oil bodies of plant seeds, playing an important role in regulating oil body formation and lipid accumulation. To investigate whether lipid accumulation in transgenic rice seeds depends on the expression level of oleosin, we introduced two soybean oleosin genes encoding 24 kDa proteins into rice under the control of an embryo-specific rice promoter REG 2. Overexpression of soybean oleosin in transgenic rice leads to an increase of seed lipid content up to 36.93 and 46.06 % higher than that of the non-transgenic control, respectively, while the overall fatty acid profiles of triacylglycerols remained unchanged. The overexpression of soybean oleosin in transgenic rice seeds resulted in more numerous and smaller oil bodies compared with wild type, suggesting that an inverse relationship exists between oil body size and the total oleosin level. The increase in lipid content is accompanied by a reduction in the accumulation of total seed protein. Our results suggest that it is possible to increase rice seed oil content for food use and for use as a low-cost feedstock for biodiesel by overexpressing oleosin in rice seeds. PMID- 23748708 TI - qLTG-9, a stable quantitative trait locus for low-temperature germination in rice (Oryza sativa L.). AB - Low-temperature germination (LTG) is an important agronomic trait for direct seeding of rice in temperate regions of East Asia. To dissect the genetic control of LTG, we constructed a recombinant inbred line (RIL) population derived from a cross of japonica variety USSR5 and indica variety N22. Three putative QTL involved in LTG were detected and named qLTG-7, qLTG-9 and qLTG-12. They explained 9.5, 12.12 and 7.08 % of the phenotypic variation, respectively, and the alleles from USSR5 enhanced LTG. A set of advanced backcross lines selected for the presence of qLTG-9 (with the biggest contribution of the three QTL), by both linked markers and phenotype, was used to validate qLTG-9 in different generations, years and locations. A near-isogenic line in USSR5 background with a qLTG-9 insertion from N22 had retarded germination under low-temperature conditions. Finally, qLTG-9 was fine mapped between markers L9-25D and ID-1, to a 72.3-kb region in chromosome 9, which in the Nipponbare genome contains five predicted genes. This result provides a springboard for map-based cloning of qLTG 9 and is helpful in understanding the mechanism of seed germination under low temperature conditions. PMID- 23748709 TI - Single molecule SERS and detection of biomolecules with a single gold nanoparticle on a mirror junction. AB - Using the bianalyte method we unambiguously demonstrate that a single gold nanosphere on a metal film junction, in the so-called nanoparticle on a mirror configuration, is capable of single molecule detection with surface-enhanced Raman spectroscopy (SERS). Also this configuration serves as a convenient and highly sensitive SERS sensor for detection of biomolecules. Such simple nano junction based systems are ideal for chemical and biomedical analysis. PMID- 23748710 TI - Involvement of WNT/beta-catenin signaling in the treatment of osteoporosis. AB - Osteoblast differentiation is predominantly regulated by the WNT/beta-catenin signaling (canonical WNT pathway), which, together with bone morphogenetic proteins, acts as the master regulator of osteogenesis. The recent characterization of the canonical WNT pathway in the regulation of bone modeling and remodeling provided important insights for our understanding of the pathophysiology of a number of conditions and of the mechanism of action of hormones or drugs with important effect on bone metabolism. This review is mainly focused on the growing therapeutic implications of these new findings. WNT/beta catenin signaling plays a key role in bone tissue by determining the differentiation of stem cells into mature osteoblasts rather than into chondrocytes and adipocytes. Its regulation is predominantly driven by the production of two WNT signaling antagonists: sclerostin (SOST) and Dickkopf related protein 1 (DKK1). The most proximate regulator of SOST expression by osteocytes and its serum levels is bone mechanical load. SOST expression is increased with advancing age, by glucocorticoid treatment and during treatment with antiresorptive agents such as bisphosphonates and denosumab, while it is decreased by parathyroid hormone excess or administration of estrogens. Correlation between DKK1 serum levels and bone formation in various pathological conditions or during osteoporosis treatment has been reported. Inhibitors of the negative regulators of WNT/beta-catenin signaling ("inhibiting the endogenous inhibitors") are potential candidates for the prevention and treatment of bone loss. Inactivating monoclonal antibodies against SOST appears to be the most attractive strategy because SOST is the only component of the WNT pathway expressed almost exclusively by osteocytes. PMID- 23748711 TI - Acute phase response after zoledronic acid is associated with long-term effects on white blood cells. AB - We have recently reported a long-lasting decrease in circulating gammadelta T cells in osteoporotic patients on oral amino-bisphosphonates (N-BPs). Here we verify whether these changes are associated with the occurrence of acute phase response (APR) to intravenous (IV) zoledronic acid (ZOL) or changes of other circulating white blood cells (WBC). WBC count was obtained before and 1 year after a single IV administration of 5 mg ZOL in 36 osteoporotic patients (mean age 72 +/- 9, range 45-86 years) without other relevant diseases; 12 of 36 patients developed the classical APR. After 1 year in the patients who experienced an APR, but not in the others, a significant decrease not only of gammadelta T cells (-30 %), but also of total lymphocytes (-11 %) and eosinophils (-27 %), was observed. The mechanism leading to the observed decrease of circulating lymphocytes and eosinophils remains unclear, but our observation opens a new frontier for the understanding of the immunoeffects of N-BPs. PMID- 23748712 TI - Wireless telemetry and cystic fibrosis: just the pHacts. PMID- 23748713 TI - Murine model of wound healing. AB - Wound healing and repair are the most complex biological processes that occur in human life. After injury, multiple biological pathways become activated. Impaired wound healing, which occurs in diabetic patients for example, can lead to severe unfavorable outcomes such as amputation. There is, therefore, an increasing impetus to develop novel agents that promote wound repair. The testing of these has been limited to large animal models such as swine, which are often impractical. Mice represent the ideal preclinical model, as they are economical and amenable to genetic manipulation, which allows for mechanistic investigation. However, wound healing in a mouse is fundamentally different to that of humans as it primarily occurs via contraction. Our murine model overcomes this by incorporating a splint around the wound. By splinting the wound, the repair process is then dependent on epithelialization, cellular proliferation and angiogenesis, which closely mirror the biological processes of human wound healing. Whilst requiring consistency and care, this murine model does not involve complicated surgical techniques and allows for the robust testing of promising agents that may, for example, promote angiogenesis or inhibit inflammation. Furthermore, each mouse acts as its own control as two wounds are prepared, enabling the application of both the test compound and the vehicle control on the same animal. In conclusion, we demonstrate a practical, easy-to learn, and robust model of wound healing, which is comparable to that of humans. PMID- 23748714 TI - Detection of human herpesviruses (HHVs) in semen of human male infertile patients. AB - Recently we demonstrated an ectopic expression of the human herpesvirus 1 thymidine kinase (HHV1-TK) gene by functioning of an intrinsic endogenous promoter in the transgenic rat (TG-rat), suggesting that HHV1 infection in humans induces expression of the TK gene with the ectopic promoter in the testis and results in accumulation of HHV1-TK protein, triggering male infertility similar to that in the TG-rat. Hence, in this study, we started to investigate a relationship between infection of herpesvirus and human male infertility. Semen was donated by Chinese male infertile patients (153 men, aged 21-49 years) with informed consent, followed by DNA preparation and analysis by PCR and DNA sequencing. Semen volume, sperm number and density, and sperm motility were examined. DNAs of HHV1, HHV4, HHV5 and HHV6 were confirmed by PCR, electrophoresis and DNA sequencing. Finally, virus DNA was identified in 59 patients (39%). The number of carriers was 39 (25%) for HHV1, 6 (4%) for HHV4, 33 (22%) for HHV5 and 3 (2%) for HHV6, respectively. Moreover, double-infection was found in 22 out of 59 specimens (37%), most of which were double-infection of HHV1 and HHV5 (15 out of 22 carriers). Though slight severity was present in some of the carriers, the relationship between virus infection and sperm impairment was not conclusive. Accordingly, it is essential to examine whether the viral HHV1-TK gene is expressed in the testis of the infertile human HHV carrier. PMID- 23748716 TI - [The neuropsychology of prodromal schizophrenia. Brief review and proposal of a tests battery for clinical use]. AB - The study of the neuropsychological profile of schizophrenic patients has provided systematic results in linking specific deficit (working memory, verbal learning, attentive and executive functioning, social cognition) to the functional outcome of subjects. More recently this approach has been applied to younger subjects, from the age of 14, that show prodromal signs of a possible psychotic conversion (ultra-risk subjects). The review is at first intended to describe the clinical and experimental studies that investigated the cognitive and neuropsychological profile of subjects at ultra-risk for psychosis. These studies show the presence of minor cognitive difficulties in several specific areas (working memory, verbal learning, attentive and executive functioning) that can be indicative of both a possible conversion to psychosis and a need for cognitive remediation programs. Secondarily, the article describes several neuropsychological tools, standardized for the Italian population, that can be used to approach the clinical assessment of ultra-risk subjects considering some critical aspects such as their typical age range (adolescents and young adults). PMID- 23748715 TI - Treating cloned embryos, but not donor cells, with 5-aza-2'-deoxycytidine enhances the developmental competence of porcine cloned embryos. AB - The efficiency of cloning by somatic cell nuclear transfer (SCNT) has remained low. In most cloned embryos, epigenetic reprogramming is incomplete, and usually the genome is hypermethylated. The DNA methylation inhibitor 5-aza-2' deoxycytidine (5-aza-dC) could improve the developmental competence of cow, pig, cat and human SCNT embryos in previous studies. However, the parameters of 5-aza dC treatment among species are different, and whether 5-aza-dC could enhance the developmental competence of porcine cloned embryos has still not been well studied. Therefore, in this study, we treated porcine fetal fibroblasts (PFF) that then were used as donor nuclei for nuclear transfer or fibroblast-derived reconstructed embryos with 5-aza-dC, and the concentration- and time-dependent effects of 5-aza-dC on porcine cloned embryos were investigated by assessing pseudo-pronucleus formation, developmental potential and pluripotent gene expression of these reconstructed embryos. Our results showed that 5-aza-dC significantly reduced the DNA methylation level in PFF (0 nM vs. 10 nM vs. 25 nM vs. 50 nM, 58.70% vs. 37.37% vs. 45.43% vs. 39.53%, P<0.05), but did not improve the blastocyst rate of cloned embryos derived from these cells. Treating cloned embryos with 25 nM 5-aza-dC for 24 h significantly enhanced the blastocyst rate compared with that of the untreated group. Furthermore, treating cloned embryos, but not donor cells, significantly promoted pseudo-pronucleus formation at 4 h post activation (51% for cloned embryos treated, 34% for donor cells treated and 36% for control, respectively, P<0.05) and enhanced the expression levels of pluripotent genes (Oct4, Nanog and Sox2) up to those of in vitro fertilized embryos during embryo development. In conclusion, treating cloned embryos, but not donor cells, with 5-aza-dC enhanced the developmental competence of porcine cloned embryos by promotion of pseudo-pronucleus formation and improvement of pluripotent gene expression. PMID- 23748717 TI - [Efficacy of relaxation techniques in different clinical situations]. AB - Relaxation techniques have been investigated by psychological and medical literature for dozen of years. During these years, relaxation techniques have provided an increasingly perception of efficacy toward health professionals, in the promotion of psychological and physical well-being and in the reduction of stress-related pathologies. This review tries to summarize clinical contexts and situations where the efficacy of relaxation has been investigated. Limits and counter-indications of relaxation training are also discussed. PMID- 23748718 TI - [To define internet addiction]. AB - Internet addiction is a new behavioral disorder difficult to define, especially when referring to young teenagers who make great use of web-mediated relationships. It's necessary to separate the cases of overt dependency on those in which the abuse of internet seems to have a different value, offering the only way to achieve the possible relationship. Internet is mediating a new way of communicating and thinking, this may favor the onset of clinical phenomena intended to surprise. PMID- 23748719 TI - [Thinking organization and defense mechanisms in bipolar disorders. Clinical and psychopathological study on bipolar I and bipolar II]. AB - AIM: The aim of this research is to explore the psychical functioning in bipolar I or bipolar II disorder people through the analysis and comparison of their thought styles and defense patterns. METHODS: 29 bipolar I and bipolar II people afferent to Palermo University Policlinical Psychriatic Hospital Department were selected during the whole 2009-2010 year. The following tests were administred: Wechsler Adult Intelligent Scale-R (WAIS-R) in order to measure the general cognitive function; Defense Mechanisms Inventory (DMI) in order to measure defense patterns. Afterwards, the results of the two tests were analysed and compared. OUTCOME: Bipolar disorder people use cognitive mechanisms and defense strategies that are very different from standard population. Bipolar I subjects show both wider and more serious cognitive deterioration and stricter defense mechanisms than bipolar II subjects. Generally bipolar patients show an immature personality based on archaic mechanisms that can be found in all the spheres of their personality: emotions, cognition, Ego-strength, adaptability to reality. DISCUSSION: The peculiar achieved cognitive and defense profile leads to important considerations about how psychological strategies can contribute to use "bespoke" treatments for these patients. PMID- 23748720 TI - Photosensitivity and panic-agoraphobic spectrum: a pilot study. AB - BACKGROUND: The aims of this study were to assess photosensitivity (photophobia and photophilia) in panic disorder (PD) patients compared to healthy controls, and to evaluate the correlation between photosensitivity and panic-agoraphobic spectrum self-report (PAS-SR) scores. METHODS: The PAS-SR and Photosensitivity Assessment Questionnaires were administered to 24 PD subjects and 33 healthy controls. RESULTS: Compared to controls, PD patients showed significantly higher levels of photophobia and lower levels of photophilia items. The PAS-SR total score was positively correlated with the photophobia score. CONCLUSIONS: This study shows a strong correlation between PD and photophobia. However, whether photophobia develops before or after the onset of PD remains unclear. Further research is warranted to assess the potential role of light stimuli exposure in the onset, course and outcome of PD. PMID- 23748721 TI - [Correlation among measures of stress, indicators of biohumoral nature and medico legal considerations]. AB - INTRODUCTION: Man devotes most of the daily time to work, and also a large part of physical and mental resources. Depression and many other morbid conditions can be related etiopathologically to the performance of a dangerous occupation in terms of quality (hazardous work activities, lack of motivation for deficient career opportunities) or merely quantitative (duration of work shifts, frequency shifts work). The medical legal ascertainment is limited because stress cannot be valued by objective nature, but only through precious elements collected directly by workers by questionnaires. This is in response to legal requirements in terms of civil liability, occupational disease and disability. AIM AND METHODS: The objective of this study is to analyze the change of cytokines (IL-6, IL-12, TNF alpha) and stress-related hormones (prolactin and cortisol) in a sample of 314 individuals working at the University Hospital Umberto I in Rome without acute diseases but only with the "feeling stressed" for at least a month and to analyze if there is a correlation between some of these biochemical variables and stress values measured by questionnaire. RESULTS: The results of this study confirm the usefulness to associate laboratory analysis, such as the study of inflammatory cytokines and the hormonal profile, to psychometric tests, precious for the lower cost and in some cases also for the high diagnostic sensitivity, to reach a probative value which satisfies even the most demanding application of accuracy. PMID- 23748722 TI - [Psychological distress and personality characteristics among individuals with primary exercise dependence]. AB - BACKGROUND: The aim of this study was to assess both psychological distress and personality characteristics associat with primary exercise dependence. A cross sectional study was carried out with adult habitual physical exercisers. METHODS: A total of 79 participants voluntarily completed a package of self-report questionnaires including the Exercise Dependence Questionnaire (EDQ), the Eating Disorder Inventory II (EDI-2), the Temperament and Character Inventory (TCI), the Attitude Toward Self scale (ATS), Muscle Dysmorphia Questionnaire (MDQ), and the Symptom Questionnaire (SQ). RESULTS: Significant differences were found in the EDQ exercise for weight control subscale with regard to gender, as well as in the EDI-2 total score and 5 of its subscales, with higher scores for females compared to males. Participants reporting primary exercise dependence (n=32) were more likely to present with disordered eating patterns than controls (n=47). They also showed higher levels of harm avoidance and persistence on the TCI, as well as lower self-directness. Furthermore, primary exercise dependents scored higher on the ATS dysmorphophobia subscale, as well as on the MDQ total score and the anxiety and hostility subscales of the SQ compared to controls. CONCLUSIONS: These findings highlight the importance of performing a clinical assessment of psychological symptoms and personality characteristics that might be associated with primary exercise dependence. PMID- 23748723 TI - [A review of the experience, the effectiveness and the spread of behavioral cognitive group intervention in psychiatric ward]. AB - The use of Cognitive-Behavioral Group Intervention (CBGI) in Psychiatric Ward (SPDC) in Italy began in the year 2000 and it became more and more popular in different geographic areas of our country. In this paper we briefly describe the intervention, the theoretical framework, the effectiveness and efficiency in Italy as well as in the international context. Based on the theoretical model "stress-vulnerability-coping", the ICCG is a manualized treatment, innovative and effective in the acute care, using the group setting to foster a climate of collaboration between users and operators, to raise awareness, the adherence to the treatment plan and the satisfaction. This article provides an overview of studies of effectiveness, in particular those performed in Rome, Campobasso, Foggia, Arezzo which are of different lengths (1, 2, 4 and 5 years of follow-up). The results showed a reduction in voluntary as well as compulsory treatment (p<.01), an increase of ward's atmosphere and of the user satisfaction (p<.01), and also decreased aggressive acts (p.01). Finally, the results obtained through a survey of the various experiences, of the diffusion and how the intervention is applied in the various SPDC Italians are shown. The CBGI is more popular in the North of Italy, according with an increasing demand for training. The practical benefits observed by data collected are also illustrated; they mainly consist in improving the climate of the ward, in a better positive communication among users and between them and the professionals, in the fastest adherence to the treatment and of the active participation and informed care. Are also discussed factors that hinder the use in routine, including the low participation of psychiatrists and the difficulty in changing the organizational style of work in the ward. PMID- 23748724 TI - [Olanzapine in manic/mixed patients with or without substance abuse]. AB - AIM: To evaluate the efficacy of olanzapine in patients in their manic/mixed phase with or without comorbidity with substance abuse/dependence disorder. METHODS: In this observational, controlled, prospective study, 60 patients with a DSM-IV-TR diagnosis of bipolar disorder, manic/mixed episode (30 patients with and 30 patient without comorbidity with a substance abuse/dependence disorder) were treated with olanzapine, evaluated at discharge, and followed-up for 8 weeks. Efficacy of olanzapine was assessed by comparing the proportion of responders (an at least 50% drop in Young Mania Rating Scale [YMRS] score from baseline) and remitters (YMRS <= 12 and Hamilton Depression Rating Scale [HAM-D] <= 8) in both groups. Craving and days of abuse/use were assessed with Visual Analogue Scale (VAS) and Time-line Follow-Back (TLFB), respectively. RESULTS: Differences in response and remission percentages were statistically not significant at discharge and during follow-up. A reduction of days of abuse has been observed in the drug-abuse group, while craving was only slightly decreased. DISCUSSION: These results suggest that olanzapine is effective in both groups and its efficacy in reducing the days of abuse appears to be independent from its action on craving. PMID- 23748725 TI - [Psychopathological spectrum in behavioral variant frontotemporal dementia]. AB - BACKGROUND: The aim of this study was to describe the psychopathological spectrum of behavioral variant frontotemporal dementia. METHODS: The clinical pictures of 8 patients with a diagnosis of behavioral variant frontotemporal dementia are presented, focusing on psychopathological alterations, neurocognitive functioning and neuroimaging. RESULTS: 5 patients have a positive psychiatric history; from the psychopathological point of view, 5 patients mainly present an externalizing/disinhibited symptomatology and 3 patients mainly present an internalizing/apathetic symptomatology; the clinical onset is usually insidious, with a progressive course and a lack of insight related to behavioral and personality changes. From the cognitive point of view, 2 patients present a preserved neuropsychological profile, while 6 patients present several cognitive deficits, mainly episodic memory and executive functions, both dorsolateral and orbital. With regard to neuroimaging, a heterogeneous pattern emerged, with the majority of patients showing cortical atrophy and frontotemporal hypometabolism. CONCLUSIONS: Behavioral variant frontotemporal dementia is clinically characterized by a wide spectrum of psychopathological alterations, including both an externalizing/disinhibited symptomatology and an internalizing/apathetic symptomatology. The neuropsychological assessment may detect early cognitive deficits, especially of prefrontal executive functions; the heterogeneity of neuroimaging findings suggests to add neuroimaging diagnostic criteria to actual behavioral diagnostic PMID- 23748727 TI - [Characteristics of a population of medical students reported to the University Student Counseling Service "Fatti vivo!"]. AB - INTRODUCTION: During the last years, in Italy as well abroad, psychological counseling has been spreading through university environment, offering a range of opportunities, from individual settings to post-counseling group psychotherapies. Medical students, on the basis of data from several works within international literature, would represent a population particularly exposed to stressors. MATERIALS AND METHODS: In our study we have recruited a sample of 44 medical students at Sapienza University of Rome. As evaluation tools we have used: a gathering card of socio-demographic variables, the Structured Clinical Interview for DSM-IV Axis I Disorders Clinical Version (SCID-I CV) and a satisfaction card of the service. RESULTS; Fourteen students showed one or more diagnosis in Axis 1 of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Frequency analysis through chi2 test has underlined statistically significant differences relative to geographic origin variable. The service has been evaluated as alright. DISCUSSION: Although the data presented need deeper and more extensive verifications, our study supports the need of a service of psychological counseling devoted to university population and, even more, to medical students. PMID- 23748726 TI - [Difficulties in emotion regulation and personal distress in young adults with social anxiety]. AB - BACKGROUND: The aim of this study was to assess the association between social anxiety and difficulties in emotion regulation in a sample of Italian young adults. METHODS: Our convenience sample was composed of 298 Italian young adults (184 women and 114 men) aged 18-34 years. Participants were administered the Interaction Anxiousness Scale (IAS), the Audience Anxiousness Scale (AAS), the Difficulties in Emotion Regulation Scale (DERS), and the Interpersonal Reactivity Index (IRI). A Two Step cluster analysis was used to group subjects according to their level of social anxiety. RESULTS: The cluster analysis indicated a two cluster solution. The first cluster included 163 young adults with higher scores on the AAS and the IAS than those included in cluster 2 (n=135). A generalized linear model with groups as dependent variable indicated that people with higher social anxiety (compared to those with lower social anxiety) have higher scores on the dimension personal distress of the IRI (p<0.01), and on the DERS non acceptance of negative emotions (p<0.001) and lack of emotional clarity (p<0.05). CONCLUSIONS: The results are consistent with models of psychopathology, which hypothesize that people who cannot deal effectively with their emotions may develop depressive and anxious disorders. PMID- 23748728 TI - Acute psychiatric presentation of steroid-responsive encephalopathy: the under recognized side of autoimmune thyroiditis. AB - Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT), also known as Hashimoto encephalopathy, represents a rare disorder of presumed autoimmune origins that can be diagnosed when a protean variety of psychiatric symptoms are present in association with elevated titers of anti-thyroid antibodies. Symptoms can have a rapid and complete remission with corticosteroid treatment. A 19-year-old girl, with clinical history of Basedow-Graves disease, has been admitted to our department after presenting acute psychiatric symptomatology. Clinical and serological findings were used to formulate the diagnosis of SREAT, confirmed by subsequent positive response to corticosteroid treatment. SREAT can mimic an acute psychiatric symptomatology, thus it seems extremely relevant for psychiatrists to consider this syndrome in differential diagnosis algorithm, especially in those patients presenting a history of autoimmune thyroid disorder, in order to ensure adequate diagnosis and treatment. PMID- 23748730 TI - TDDFT investigation of the electronic structures and photophysical properties of fluorescent extended styryl push-pull chromophores containing carbazole unit. AB - Push-pull chromophores attached to carbazole based pi-conjugating spacers bearing N-alkylamino donors, cyanovinyl and carbethoxy acceptors have been studied by the means of UV-Visible measurements. The intramolecular charge transfer (ICT) of these pi-conjugated systems has also been tested by investigating the ability of the solute molecules to undergo shifts in their fluorescence emission maxima with increasing solvent polarity. Density Functional Theory [B3LYP/6-31G(d)] and Time Dependent Density Functional Theory [TD-B3LYP/6-31G(d)] computations have been used to have more understanding of the structural, molecular, electronic and photophysical parameters of push-pull dyes. The largest wavelength difference between the experimental and computed electronic absorption maxima was 45 nm. For emission, a largest difference of 61 nm was observed. The ground state and excited state dipole moments in different solvents were determined using experimental solvatochromic data and computed Onsager radii. The dipole moments of the molecules in the excited state were observed to be higher than in the ground state. PMID- 23748731 TI - Mechanical thrombectomy of iliac vein thrombosis in a pig model using the Rotarex and Aspirex catheters. AB - PURPOSE: To investigate the efficacy and safety of mechanical thrombectomy for iliac vein thrombosis using Rotarex and Aspirex catheters in a pig model. MATERIALS AND METHODS: Iliac vein thrombosis was induced in six pigs by means of an occlusion-balloon catheter and thrombin injection. The presence of thrombi was verified by digital subtraction angiography (DSA) and computed tomography (CT). Thrombectomy was performed using 6F and 8F Rotarex and 6F, 8F, and 10F Aspirex catheters (Straub Medical AG, Wangs, Switzerland). After intervention, DSA and CT were repeated to evaluate the efficacy of mechanical thrombectomy and to exclude local complications. In addition, pulmonary CT was performed to rule out pulmonary embolism. Finally, all pigs were killed, and iliac veins were dissected to perform macroscopic and histological examination. RESULTS: Thrombus induction was successfully achieved in all animals as verified by DSA and CT. Subsequent thrombectomy lead to incomplete recanalization of the iliac veins with residual thrombi in all cases. However, the use of the 6F and 8F Rotarex catheters caused vessel perforation and retroperitoneal hemorrhage in all cases. Application of the Aspirex device caused one small transmural perforation in a vessel treated with a 10F Aspirex catheter, and this was only seen microscopically. Pulmonary embolism was detected in one animal treated with the Rotarex catheters, whereas no pulmonary emboli were seen in animals treated with the Aspirex catheters. CONCLUSION: The Aspirex catheter allowed subtotal and safe recanalization of iliac vein thrombosis. In contrast, the use of the Rotarex catheter caused macroscopically obvious vessel perforations in all cases. PMID- 23748732 TI - Transrenal ureteral occlusion using the Amplatzer vascular plug II: a new interventional treatment option for lower urinary tract fistulas. AB - PURPOSE: This study was designed to evaluate the results of a novel technique for transrenal ureteral occlusion using an Amplatzer vascular plug (AVP) II in patients with urinary fistulas. METHODS: We retrospectively evaluated the results of transrenal occlusion of 15 ureters in 9 hospitalized patients [8 females, 1 male, mean age 64 (range 52-79) years] suffering from pelvic malignancy (4 cervix carcinomas, 3 bladder-carcinomas, 1 colorectal carcinoma, and 1 vulva-carcinoma). Seven patients were treated for urinary fistulas (4 ureteroenteral, 3 vesicovaginal); the others showed ileum-conduit-insufficiency and Mainz-pouch incontinence, respectively. From 2008 to 2009, an AVP was used in combination with coils and tissue adhesive (n = 5). Since 2009, ureteral occlusions were performed using a latex-covered AVP (n = 10). All patients had previous nephrostomy with only incomplete clinical improvement. RESULTS: Fourteen of 15 interventions were technically successful. Four of five ureters occluded with a combination of AVP, coils, and tissue adhesive were permanently sealed after a single procedure, whereas one showed slight leakage. After placement of two additional coils 20 days later, permanent occlusion was achieved [mean follow-up 195 (range 30-687) days]. Nine of ten ureters occluded with a latex-covered AVP were completely sealed after a single intervention [mean follow-up 152 (range 10 462) days]. In one case, the latex-cover dislocated during implantation. The AVP alone failed to provide complete dryness. There were no dislocations of the AVP or other major complications. CONCLUSIONS: Transrenal ureteral occlusion using an AVP is a practical, simple, and quick method and can be advantageous in palliative patients suffering from pelvic malignancy. PMID- 23748733 TI - Irreversible electroporation: hype or hope? PMID- 23748734 TI - A lipobead microarray assembled by particle entrapment in a microfluidic obstacle course and used for the display of cell membrane receptors. AB - Platforms which can display cell membrane ligands and receptors as a microarray library of probes for screening against a target are essential tools in drug discovery, biomarker identification, and pathogen detection. Membrane receptors and ligands require their native bilayer environment to retain their selectivity and binding affinity, and this complicates displaying them in a microarray platform. In this study, a design is developed in which the probes are first incorporated in supported lipid bilayers formed around micron-sized particles (lipobeads), and the microbeads themselves are then arrayed on a surface by hydrodynamic capture in a microfluidic obstacle course of traps. The traps are "V" shaped open enclosures, which are arranged in a wide channel of a microfluidic device, and capture the lipobeads (slightly smaller than the channel height) as they are streamed through the course. Screening assays are undertaken directly in the device after assembly, by streaming a fluorescently labeled target through the device and detecting the bead fluorescence. Conditions are first established for which the supported bilayers on the bead surface remain intact during the capture and assay steps, using fluorescent tags in the bilayer to infer bilayer integrity. Numerical calculations of the hydrodynamic drag coefficient on the entrapped beads are presented in conjunction with the stability experiments to develop criteria for the bilayer stability as a function of the screening assay perfusion rate. Simulations of the flow streamlines are also presented to quantify the trapping efficiency of the obstacle course. Screening assays are illustrated, assaying fluorescently labeled NeutrAvidin with biotin, and labeled cholera toxin with its ganglioside binding ligand, GM1. Sequential capturing of sets of lipobeads (one at a time, and with each set bearing a different probe), followed by indexing the bead positions after each set is entrapped, allows for the construction of an indexed array of multiple probes without the need for particle encoding and is illustrated using the NeutrAvidin-biotin pair. Finally, the lipobead platform is used for quantitatively measuring the kinetic rate constants for the binding of a probe (biotin) to a target (NeutrAvidin). PMID- 23748735 TI - Forefoot strikers exhibit lower running-induced knee loading than rearfoot strikers. AB - PURPOSE: Knee pain and Achilles tendinopathies are the most common complaints among runners. The differences in the running mechanics may play an important role in the pathogenesis of lower limb overuse injuries. However, the effect of a runner's foot strike pattern on the ankle and especially on the knee loading is poorly understood. The purpose of this study was to examine whether runners using a forefoot strike pattern exhibit a different lower limb loading profile than runners who use rearfoot strike pattern. METHODS: Nineteen female athletes with a natural forefoot strike (FFS) pattern and pair-matched women with rearfoot strike (RFS) pattern (n = 19) underwent 3-D running analysis at 4 m.s-1. Joint angles and moments, patellofemoral contact force and stresses, and Achilles tendon forces were analyzed and compared between groups. RESULTS: FFS demonstrated lower patellofemoral contact force and stress compared with heel strikers (4.3 +/- 1.2 vs 5.1 +/- 1.1 body weight, P = 0.029, and 11.1 +/- 2.9 vs 13.0 +/- 2.8 MPa, P = 0.04). In addition, knee frontal plane moment was lower in the FFS compared with heel strikers (1.49 +/- 0.51 vs 1.97 +/- 0.66 N.m.kg-1, P =0.015). At the ankle level, FFS showed higher plantarflexor moment (3.12 +/- 0.40 vs 2.54 +/- 0.37 N.m.kg-1; P = 0.001) and Achilles tendon force (6.3 +/- 0.8 vs 5.1 +/- 1.3 body weight; P = 0.002) compared with RFS. CONCLUSIONS: To our knowledge, this is the first study that shows differences in patellofemoral loading and knee frontal plane moment between FFS and RFS. FFS exhibit both lower patellofemoral stress and knee frontal plane moment than RFS, which may reduce the risk of running related knee injuries. On the other hand, parallel increase in ankle plantarflexor and Achilles tendon loading may increase risk for ankle and foot injuries. PMID- 23748736 TI - Periodontopathogens levels and clinical response to periodontal therapy in individuals with the interleukin-4 haplotype associated with susceptibility to chronic periodontitis. AB - Periodontitis is an inflammatory disease that results from an interaction between dental biofilm agents and the host immune-inflammatory response. Periodontopathogenic organisms, such as Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, as well as the host's susceptibility, represented by the host's genetic makeup, are the key factors that influence this complex disease. Recently, we identified haplotypes in the IL4 gene that were associated with chronic periodontitis (CP). This study aimed to evaluate whether subjects with different IL4 haplotypes (TCI/CCI and TTD/CTI) would be differentially colonized by periodontopathogens and whether they would respond differently to non-surgical periodontal therapy. Thirty-nine patients carrying the IL4 haplotype of genetic susceptibility to CP (IL4+) or protection against CP (IL4-) were evaluated. Those groups were further subdivided into individuals with CP (CP IL4+ or CP IL4-) and those that were periodontally healthy (H) (H IL4+ or H IL4-). CP patients were submitted to non-surgical periodontal therapy. Clinical and microbiological analyses were performed considering the data at baseline and 45 and 90 days after periodontal therapy. Periodontopathogens levels were evaluated by absolute quantitative polymerase chain reaction (qPCR). The baseline data revealed that the total levels of periodontopathogens were higher in the CP IL4+ than in the CP IL4- groups. Clinical analyses revealed that the periodontal therapy was equally effective, independent of the subject's IL4 genetic load. The TCI/CCI IL4 haplotype, previously associated with genetic susceptibility to CP, was also associated with increased levels of periodontopathogenic bacteria, but this genetic background did not influence the response to non-surgical periodontal treatment. PMID- 23748737 TI - Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice. AB - Caspases have critical roles in Alzheimer's disease pathogenesis. Here we show that caspase-2 is required for the cognitive decline seen in human amyloid precursor protein transgenic mice (J20). The age-related changes in behaviour and dendritic spine density observed in these mice are absent when they lack caspase 2, in spite of similar levels of amyloid beta (Abeta) deposition and inflammation. A similar degree of protection is observed in cultured hippocampal neurons lacking caspase-2, which are immune to the synaptotoxic effects of Abeta. Our studies suggest that caspase-2 is a critical mediator in the activation of the RhoA/ROCK-II signalling pathway, leading to the collapse of dendritic spines. We propose that this is controlled by an inactive caspase-2/RhoA/ROCK-II complex localized in dendrites, which dissociates in the presence of Abeta, allowing for their activation and entry in the spine. These findings directly implicate caspase-2 as key driver of synaptic dysfunction in Alzheimer's disease and offer novel therapeutic targets. PMID- 23748739 TI - Feasibility of the cut-and-push method for removing large-caliber soft percutaneous endoscopic gastrostomy devices. AB - INTRODUCTION: Percutaneous endoscopic gastrostomy (PEG) is the method of choice for long-term nutrition in patients with longstanding eating difficulties due to pathological entities that impair swallowing. The feeding catheters are designed to be removed by external traction or by endoscopy. AIM: To evaluate the feasibility of the cut-and-push method as a possible safe alternative to the pullout method for removal of soft PEG devices with a large caliber. METHODS: Patients with 20 French (Fr) or larger soft PEG system were enrolled for PEG removal by the cut-and-push technique. The replacement catheters were 2 Fr larger than the original ones. Patients were observed at 24 and 72 hours via home nursing care and then weekly for 1 month for signs of intestinal obstruction, tube leakage, or blockage. RESULTS: Seventy-nine patients (52 men; mean age 67 years) underwent the procedure: 42 due to leakage and 37 due to blockage. Mean time before tube removal was 4.8 months (range, 3-8). PEG devices were 20 Fr and 24 Fr in 57 (72.2%) and 22 (27.8%) cases, respectively. Collection of the inner component from stool was reported within 48 hours in 63 cases (80%). No cases of intestinal obstruction or other severe adverse events due to the inner component being eliminated throughout the intestine were observed in any patient during the study. CONCLUSIONS: The cut-and-push method employed for removal of a soft PEG tube with a large caliber seems to be safe and can be performed when removal by external traction may determine the occurrence of peristomal complications or jeopardize PEG replacement. PMID- 23748738 TI - Involvement of rose aquaporin RhPIP1;1 in ethylene-regulated petal expansion through interaction with RhPIP2;1. AB - Aquaporins (AQPs) are multifunctional membrane channels and facilitate the transport of water across plant cell membranes. Among the plant AQPs, plasma membrane intrinsic proteins (PIPs), which cluster in two phylogenetic groups (PIP1 and PIP2), play a key role in plant growth. Our previous work has indicated that RhPIP2;1, a member of PIP2, is involved in ethylene-regulated cell expansion of rose petals. However, whether PIP1s also play a role in petal expansion is still unclear. Here, we identified RhPIP1;1, a PIP1 subfamily member, from 18 PIPs assemble transcripts in rose microarray database responsive to ethylene. RhPIP1;1 was rapidly and significantly down-regulated by ethylene treatment. RhETRs-silencing also clearly decreased the expression of RhPIP1;1 in rose petals. The activity of the RhPIP1;1 promoter was repressed by ethylene in rosettes and roots of Arabidopsis. RhPIP1;1 is mainly localized on endoplasmic reticulum and plasma membrane. We demonstrated that RhPIP1;1-silencing significantly inhibited the expansion of petals with decreased petal size and cell area, as well as reduced fresh weight when compared to controls. Expression of RhPIP1;1 in Xenopus oocytes indicated that RhPIP1;1 was inactive in terms of water transport, while coexpression of RhPIP1;1 with the functional RhPIP2;1 led to a significant increase in plasma membrane permeability. Yeast growth, beta Galactosidase activity, bimolecular fluorescence complementation, and colocalization assay proved existence of the interaction between RhPIP1;1 and RhPIP2;1. We argue that RhPIP1;1 plays an important role in ethylene-regulated petal cell expansion, at least partially through the interaction with RhPIP2;1. PMID- 23748740 TI - Blind bedside placement of postpyloric feeding tubes by registered dietitians: success rates, outcomes, and cost effectiveness. AB - BACKGROUND: The purpose of this study was to evaluate the success rate, outcomes, and cost-effectiveness of blind bedside placement of postpyloric feeding tubes by registered dietitians. Feeding tubes placed by a physician using fluoroscopy were used to benchmark certain study parameters. MATERIALS AND METHODS: Patients who underwent postpyloric feeding tube insertion between June 1, 2007, and May 31, 2011, were included in the study. Medical charts were reviewed for the time span between physician order and procedure documentation, bedside feeding tube tip location, number of radiographic images to confirm placement of tubes placed at the bedside, physician clearance to use the feeding tube when applicable, and reported complications. Patient charges for each procedure were also compared. RESULTS: Data were collected on 729 patient encounters, with 285 encounters per study group and 159 encounters excluded for incomplete documentation. The average time span to bedside procedure completion was 3.7 hours compared with an average of 4.2 hours for insertion using fluoroscopy. Dietitians achieved postpyloric access 73% of the time, and an additional 16.8% of bedside tubes were deemed appropriate for use for gastric feeding. The majority of bedside insertion encounters required 1 abdominal radiograph to confirm placement, and no reported complications were associated with either technique. A 66% reduction in patient charges was associated with bedside tube insertion. CONCLUSION: Based on this sample, blind bedside postpyloric feeding tube insertion by registered dietitians may be a safe, cost-effective method for achieving short-term feeding tube access in the hospitalized patient. PMID- 23748741 TI - Regulation of ATG8 membrane association by ATG4 in the parasitic protist Toxoplasma gondii. AB - In the process of autophagy, the Atg8 protein is conjugated, through a ubiquitin like system, to the lipid phosphatidylethanolamine (PE) to associate with the membrane of forming autophagosomes. There, it plays a crucial role in the genesis of these organelles and in autophagy in general. In most eukaryotes, the cysteine peptidase Atg4 processes the C terminus of cytosolic Atg8 to regulate its association with autophagosomal membranes and also delipidates Atg8 to release this protein from membranes. The parasitic protist Toxoplasma gondii contains a functional, yet apparently reduced, autophagic machinery. T. gondii Atg8 homolog, in addition to a cytosolic and occasionally autophagosomal localization, also localizes to the apicoplast, a nonphotosynthetic plastid bounded by four membranes. Our attempts to interfere with TgATG8 function showed that it appears to be essential for parasite multiplication inside its host cell. This protein also displays a peculiar C terminus that does not seem to necessitate processing prior to membrane association and yet an unusually large Toxoplasma homolog of ATG4 is predicted in the parasite genome. A TgATG4 conditional expression mutant that we have generated is severely affected in growth, and displays significant alterations at the organellar level, noticeably with a fragmentation of the mitochondrial network and a loss of the apicoplast. TgATG4-depleted parasites appear to be defective in the recycling of membrane-bound TgATG8. Overall, our data highlight a role for the TgATG8 conjugation pathway in maintaining the homeostasis of the parasite's organelles and suggest that Toxoplasma has evolved a specialized autophagic machinery with original regulation. PMID- 23748742 TI - Nearly complete 28S rRNA gene sequences confirm new hypotheses of sponge evolution. AB - The highly collaborative research sponsored by the NSF-funded Assembling the Porifera Tree of Life (PorToL) project is providing insights into some of the most difficult questions in metazoan systematics. Our understanding of phylogenetic relationships within the phylum Porifera has changed considerably with increased taxon sampling and data from additional molecular markers. PorToL researchers have falsified earlier phylogenetic hypotheses, discovered novel phylogenetic alliances, found phylogenetic homes for enigmatic taxa, and provided a more precise understanding of the evolution of skeletal features, secondary metabolites, body organization, and symbioses. Some of these exciting new discoveries are shared in the papers that form this issue of Integrative and Comparative Biology. Our analyses of over 300 nearly complete 28S ribosomal subunit gene sequences provide specific case studies that illustrate how our dataset confirms new hypotheses of sponge evolution. We recovered monophyletic clades for all 4 classes of sponges, as well as the 4 major clades of Demospongiae (Keratosa, Myxospongiae, Haploscleromorpha, and Heteroscleromorpha), but our phylogeny differs in several aspects from traditional classifications. In most major clades of sponges, families within orders appear to be paraphyletic. Although additional sampling of genes and taxa are needed to establish whether this pattern results from a lack of phylogenetic resolution or from a paraphyletic classification system, many of our results are congruent with those obtained from 18S ribosomal subunit gene sequences and complete mitochondrial genomes. These data provide further support for a revision of the traditional classification of sponges. PMID- 23748743 TI - Toll-like receptor 3 regulates cord blood-derived endothelial cell function in vitro and in vivo. AB - Circulating endothelial progenitor cells (cEPC) are capable of homing to neovascularisation sites, in which they proliferate and differentiate into endothelial cells. Transplantation of cEPC-derived cells, in particular those isolated from umbilical cord blood (UCB), has emerged as a promising approach in the treatment of cardio-vascular diseases. After in vivo transplantation, these cells may be exposed to local or systemic inflammation or pathogens, of which they are a common target. Because Toll-like receptors (TLR) are critical in detecting pathogens and in initiating inflammatory responses, we hypothesized that TLR may govern UCB cEPC-derived cells function. While these cells expressed almost all TLR, we found that only TLR3 dramatically impaired cell properties. TLR3 activation inhibited cell proliferation, modified cell cycle entry, impaired the in vitro angiogenic properties and induced pro-inflammatory cytokines production. The anti-angiogenic effect of TLR3 activation was confirmed in vivo in a hind-limb ischemic mice model. Moreover, TLR3 activation consistently leads to an upregulation of miR-29b, -146a and -155 and to a deregulation of cytoskeleton and cell cycle regulator. Hence, TLR3 activation is likely to be a key regulator of cEPC-derived cells properties. PMID- 23748744 TI - Quantitative trait loci analysis of non-enzymatic glucosinolate degradation rates in Brassica oleracea during food processing. AB - Epidemiological and mechanistic studies show health-promoting effects of glucosinolates and their breakdown products. In literature, differences in non enzymatic glucosinolate degradation rates during food processing between different vegetables are described, which provide the basis for studying the genetic effects of this trait and breeding vegetables with high glucosinolate retention during food processing. Non-enzymatic glucosinolate degradation, induced by heat, was studied in a publicly available Brassica oleracea doubled haploid population. Data were modeled to obtain degradation rate constants that were used as phenotypic traits to perform quantitative trait loci (QTL) mapping. Glucosinolate degradation rate constants were determined for five aliphatic and two indolic glucosinolates. Degradation rates were independent of the initial glucosinolate concentration. Two QTL were identified for the degradation rate of the indolic glucobrassicin and one QTL for the degradation of the aliphatic glucoraphanin, which co-localized with one of the QTL for glucobrassicin. Factors within the plant matrix might influence the degradation of different glucosinolates in different genotypes. In addition to genotypic effects, we demonstrated that growing conditions influenced glucosinolate degradation as well. The study identified QTL for glucosinolate degradation, giving the opportunity to breed vegetables with a high retention of glucosinolates during food processing, although the underlying mechanisms remain unknown. PMID- 23748745 TI - Effect of interface on surface morphology and proton conduction of polymer electrolyte thin films. AB - To understand the relationship between surface morphology and proton conduction of polymer electrolyte thin films, perfluorinated ionomer Nafion(r) thin films were prepared on different substrates such as glassy carbon (GC), hydrophilic-GC (H-GC), and platinum (Pt) as models for the ionomer film within a catalyst layer. Atomic force microscopy coupled with an electrochemical (e-AFM) technique revealed that proton conduction decreased with film thickness; an abrupt decrease in proton conductance was observed when the film thickness was less than ca. 10 nm on GC substrates in addition to a significant change in surface morphology. Furthermore, thin films prepared on H-GC substrates with UV-ozone treatment exhibited higher proton conduction than those on untreated GC substrates. However, Pt substrates exhibited proton conduction comparable to that of GCs for films thicker than 20 nm; a decrease in proton conduction was observed at ~5 nm thick film but was still much higher than for carbon substrates. These results indicate that the number of active proton-conductive pathways and/or the connectivity of the proton path network changed with film thickness. The surface morphology of thinner films was significantly affected by the film/substrate interface and was fundamentally different from that of the bulk thick membrane. PMID- 23748746 TI - Electrochemiluminescent polymer films with a suitable redox "turn-off" absorbance window for remote selective sensing of Hg2+. AB - An electrochemiluminescent sensing scheme is presented for remote detection of Hg2+ through an ITO-coated nanostructured optical fibre bundle. It is based on the electropolymerisation of CPDT-linked ruthenium phenanthroline complexes carrying azacrown ethers as the receptor units (CPDT = 4H-cyclopenta[2,1-b:3,4 b']dithiophene). The application of an anodic potential simultaneously induces electrogenerated chemiluminescence (ECL) and turns off the absorbance of the polymer backbone at the ECL emission wavelength. Therefore, the electropolymer film allows ECL light generation and transmission for efficient remote sensing in a synergetic way. As a proof of concept, selective detection of Hg2+ was demonstrated remotely by ECL through an optical fibre bundle. PMID- 23748747 TI - Interaction of ambrisentan with clarithromycin and its modulation by polymorphic SLCO1B1. AB - PURPOSE: We assessed the effect of cytochrome P450 (CYP) 3A4 and the OATP1B1 inhibitor clarithromycin on ambrisentan steady-state kinetics and its relationship to the SLCO1B1 15 haplotype in healthy volunteers. METHODS: In this open-label, monocenter, one-sequence crossover clinical trial ten male healthy participants were stratified according to CYP2C19 and SLCO1B1 (encoding for OATP1B1) genotype into two groups: group 1 (n = 6), with CYP2C19 1/1 (extensive metabolizer, EM) and SLCO1B1 wild-type; group 2 (n = 4), with CYP2C19 EM and homozygous (n = 3) or heterozygous for SLCO1B1 15 (n = 1). The participants were administered a once-daily oral dose of 5 mg ambrisentan on study days 1 and days 3-14 and twice-daily oral doses of 500 mg clarithromycin on study days 11-14. To monitor CYP3A activity 3 mg midazolam was given orally 1 day before the first ambrisentan administration and on days 1, 10, and 14 of ambrisentan treatment. Ambrisentan plasma kinetics was assessed on days 1 (single dose), 10 (steady state), and 14 (CYP3A4/OATP1B1 inhibition by clarithromycin). RESULTS: Consistent with the expectation that ambrisentan does not induce its own metabolism, ambrisentan exposure and peak concentration (Cmax) were similar after the first dose and at steady-state. Clarithromycin increased the area under the plasma concentration-time curve of ambrisentan by 41 % and Cmax by 27 % (n = 10, both p < 0.05). No contribution of SLCO1B1*15 to the extent of this interaction was observed. CONCLUSIONS: Clarithromycin increased ambrisentan exposure to a similar extent to ketoconazole, namely, clinically minor and likely irrelevant. PMID- 23748748 TI - Concentration effect relationship of CYP3A inhibition by ritonavir in humans. AB - PURPOSE: To investigate the dose and concentration dependency of CYP3A inhibition by ritonavir using the established limited sampling strategy with midazolam for CYP3A activity. METHODS: An open, fixed-sequence study was carried out in 12 healthy subjects. Single ascending doses of ritonavir (0.1-300 mg) were evaluated for CYP3A inhibition in two cohorts using midazolam as a marker substance. RESULTS: Ritonavir administered as a single oral dose produced a dose-dependent CYP3A inhibition with an ID50 of 3.4 mg. Using the measured ritonavir concentrations an exposure-inhibition effect curve was established with an IC50 of 600 h pmol/L (AUC2-4). Over the ritonavir dose range studied non-linear exposure of ritonavir was observed. CONCLUSIONS: Ritonavir shows a dose and concentration effect relationship of CYP3A inhibition. In addition, a proposed auto-inhibition of ritonavir metabolism resulted in a non-linear exposure of ritonavir with sub-proportional concentrations at low doses. A time-dependent CYP3A activity may result when inhibitors of CYP3A with short elimination half lives are used. PMID- 23748749 TI - Spontaneous reporting of serious cutaneous reactions with protein kinase inhibitors. AB - PURPOSE: Our aim was to describe all serious cutaneous adverse drug reactions (ADRs) spontaneously reported in France for all oral protein kinase inhibitors, their characteristics and whether they were labeled (reported in the Summary of Product Characteristics) or not. METHODS: We performed a retrospective observational study in the French PharmacoVigilance Database, selecting for analysis serious cutaneous reactions of patients due to treatment with oral protein kinase inhibitors (erlotinib, gefitinib, imatinib, nilotinib, dasatinib, sunitinib, sorafenib, pazopanib, lapatinib, everolimus) between 1 January 2008 and 31 December 31 2010. RESULTS: Ninety-four patients suffered from 115 serious cutaneous reactions due to oral protein kinase inhibitors. Serious cutaneous reactions more frequently reported were maculo-papular rash (mostly with imatinib), followed by hand-foot syndrome (specifically with sorafenib) and papulopustular rash (particularly with erlotinib). Patients were mostly males (63 %) with a mean age of 62.6 +/- 15.4 years. Drug withdrawal was observed in 73.1 % of cases because of these cutaneous reactions. Delay of occurrence of the ADR varied from 11.5 to 58.5 days. Unlabeled serious reactions were found (17.4 %), including skin ulceration, vasculitis or purpura with sorafenib or sunitinib and drug rash with eosinophilia and systemic symptoms with imatinib. CONCLUSION: Some of the serious ADRs spontaneously reported with oral protein kinase inhibitors are labeled and commonly reported in the literature, but others occur only rarely and unlabeled. In our study, most serious ADRs occurred in males within the 2 first months of treatment and were responsible for the withdrawal of therapy with protein kinase inhibitors. PMID- 23748750 TI - A pharmacokinetic interaction study of ticagrelor and digoxin in healthy volunteers. AB - PURPOSE: Ticagrelor is a reversibly binding P2Y12 receptor antagonist for the prevention of atherothrombotic events in patients with acute coronary syndrome. Previous in vitro studies showed that ticagrelor is a substrate and inhibitor of P-glycoprotein (ABCB1). Therefore, we examined the potential interaction between digoxin, a P-glycoprotein substrate, and ticagrelor by evaluating the pharmacokinetics, safety, and tolerability. METHODS: This was a randomized, double-blind, two-period crossover study in healthy volunteers (n = 20). Pharmacokinetic parameters of digoxin and ticagrelor were evaluated following co administration of ticagrelor 400 mg qd or placebo on days 1-16, and digoxin (0.25 mg bid on day 6 and 0.25 mg qd on days 7-14). RESULTS: Co-administration of ticagrelor increased the digoxin maximum plasma concentration by 75 %, from 1.8 ng/ml to 3.0 ng/ml (Gmean ratio [GMR] 1.75 [95 % CI, 1.52-2.01]); minimum plasma concentration by 31 %, from 0.5 ng/ml to 0.7 ng/ml (GMR 1.31, 1.13-1.52); and mean area under the curve by 28 %, from 16.8 ng . h/ml to 21.0 ng . h/ml (GMR 1.28, 1.12-1.46), compared with placebo. Renal clearance of digoxin was unaffected by the presence of ticagrelor. Digoxin had no effect on the pharmacokinetics of ticagrelor or its active metabolite, AR-C124910XX. Co administration of ticagrelor and digoxin was well tolerated. CONCLUSIONS: Collectively, these results indicate that ticagrelor is a weak inhibitor of the P glycoprotein transporter. Based on these findings, it is recommended that serum concentrations of drugs like digoxin (P-glycoprotein transporter substrates with a narrow therapeutic range) are monitored when initiating or changing ticagrelor therapy. PMID- 23748752 TI - Effects of aroma components from oxidized olive oil on preference. AB - The present study explored the possibility that aroma components generated by the oxidation of olive oil may enhance the palatability of olive oil. Using a mouse behavioral model, we found that olive oil oxidized at room temperature for 3 weeks after opening the package, and heated olive oil were both significantly preferred over non-oxidized olive oil. Furthermore, this preference was enhanced with an additive of oxidized refined olive oil flavoring preparation at a certain concentration. These results suggest that the aroma of oxidized fat might be present in most fats, and might act as a signal that makes possible the detection of fats or fatty acid sources. PMID- 23748753 TI - Preparation and characterization of water-in-oil-in-water emulsions containing a high concentration of L-ascorbic acid. AB - This study sought to encapsulate a high concentration of L-ascorbic acid, up to 30% (w/v), in the inner aqueous phase of water-in-oil-water (W/O/W) emulsions with soybean oil as the oil phase. Two-step homogenization was conducted to prepare W/O/W emulsions stabilized by a hydrophobic emulsifier and 30% (v/v) of W/O droplets stabilized by a hydrophilic emulsifier. First-step homogenization prepared W/O emulsions with an average aqueous droplet diameter of 2.0 to 3.0 MUm. Second-step homogenization prepared W/O/W emulsions with an average W/O droplet diameter of 14 to 18 MUm and coefficients of variation (CVs) of 18% to 25%. The results indicated that stable W/O/W emulsions containing a high concentration of L-ascorbic acid were obtained by adding gelatin and magnesium sulfate in the inner aqueous phase and glucose in both aqueous phases. L-Ascorbic acid retention in the W/O/W emulsions was 40% on day 30 and followed first-order kinetics. PMID- 23748751 TI - Statins are associated with reduced risk of gastric cancer: a meta-analysis. AB - BACKGROUND: Statins are widely prescribed to reduce cholesterol levels in the prevention of atherosclerotic cardiovascular disease. However, the debate about the effect of statins on cancer risk remains unsettled. The aim of this study was to investigate the association of utilization of statins with the risk of gastric cancer by carrying out a meta-analysis. METHODS: A literature search was performed on PubMed and EMBASE up to March 2013 to identify the cohort or case control studies or randomized controlled trials (RCTs) that examined the relationship between statins use and the risk of gastric cancer. The bibliographies of the retrieved articles were also reviewed to identify additional studies. A random-effects model was used to calculate the summary relative risks (RRs) with 95 % confidence intervals (CIs). RESULTS: Three post hoc analyses of 26 RCTs involving 290 gastric cancers and eight observational studies totaling 7,321 gastric cancers were included. Statins use was shown to be significantly associated with a 27 % reduction in the risk of gastric cancer (RR = 0.73, 95 % CI = 0.58-0.93), with considerable heterogeneity among studies (I (2) = 88.9 %). Excluding one study in which all subjects are diabetic patients obtained an attenuated, but homogeneous result (RR = 0.85, 95 % CI = 0.80-0.91, I (2) = 0.0 %). These findings were consistent in the subgroup analysis. CONCLUSION: A meta-analysis of existing evidence, primarily from observational studies, indicates that use of statins reduces the risk of gastric cancer. PMID- 23748754 TI - Production of 8-hydroxydaidzein from soybean extract by Aspergillus oryzae KACC 40247. AB - Aspergillus oryzae KACC 40247 was selected from among 60 fungal strains as an effective 7,8,4'-trihydroxyisoflavone (8-hydroxydaidzein)-producing fungus. The optimal culture conditions for production by this strain in a 7-L fermentor were found to be 30 degrees C, pH 6, and 300 rpm. Under these conditions, A. oryzae KACC 40247 produced 62 mg/L of 8-hydroxydaidzein from soybean extract in 30 h, with a productivity of 2.1 mg/L/h. These are the highest production and productivity for 8-hydroxydaidzein ever reported. To increase production, several concentrations of daidzin and of daidzein as precursor were added at several culture times. The optimal addition time and concentration for daidzin were 12 h and 1,248 mg/L, and those for daidzein were 12 h and 254 mg/L respectively. Maximum production and productivity for 8-hydroxydaidzein with the addition of daidzein were 95 mg/L and 3.2 mg/L/h respectively, and those with the addition of daidzin were 160 mg/L and 4.4 mg/L/h respectively. PMID- 23748755 TI - New cardenolide glycosides from the seeds of Digitalis purpurea and their cytotoxic activity. AB - A chemical investigation of Digitalis purpurea seeds led to the isolation of three new cardenolide glycosides (1, 8 and 11), together with 12 known cardenolide glycosides (2-7, 9, 10 and 12-15). The structures of 1, 8 and 11 were determined by 1D and 2D NMR spectroscopic analyses and the results of an acid or enzymatic hydrolysis. The cytotoxic activity of the isolated compounds (1-15) against HL-60 leukemia cells was examined. Compounds 2, 9, 11 and 12 showed potent cytotoxicity against HL-60 cells with respective 50% inhibition concentration (IC50) values of 0.060, 0.069, 0.038, and 0.034 uM. Compounds 2, 9 and 11 also exhibited potent cytotoxic activity against HepG2 human liver cancer cells with respective IC50 values of 0.38, 0.79, and 0.71 uM. An investigation of the structure-activity relationship showed that the cytotoxic activity was reduced by the introduction of a hydroxy group at C-16 of the digitoxigenin aglycone, methylation of the C-3' hydroxy group at the fucopyranosyl moiety, and acetylation of the C-3' hydroxy group at the digitoxopyranoyl moiety. PMID- 23748756 TI - Comparative analysis of gene expression by microarray analysis of male and female flowers of Asparagus officinalis. AB - To identify rapidly a number of genes probably involved in sex determination and differentiation of the dioecious plant Asparagus officinalis, gene expression profiles in early flower development for male and female plants were investigated by microarray assay with 8,665 probes. In total, 638 male-biased and 543 female biased genes were identified. These genes with biased-expression for male and female were involved in a variety of processes associated with molecular functions, cellular components, and biological processes, suggesting that a complex mechanism underlies the sex development of asparagus. Among the differentially expressed genes involved in the reproductive process, a number of genes associated with floral development were identified. Reverse transcription PCR was performed for validation, and the results were largely consistent with those obtained by microarray analysis. The findings of this study might contribute to understanding of the molecular mechanisms of sex determination and differentiation in dioecious asparagus and provide a foundation for further studies of this plant. PMID- 23748757 TI - Styrene altered clock gene expression in serum-shocked cultured human fibroblasts. AB - The circadian clock can regulate the metabolic process of xenobiotics, but little is known as to circadian rhythms can be perturbed by xenobiotics. Styrene is a organic chemical widely used in occupational settings. The effects of styrene on the circadian genes of HuDE cells were evaluated after serum-shocking synchronization. A subtoxic dose of 100 uM of styrene altered the expression of clock genes BMAL1, PER2, PER3, CRY1, CRY2, and REV-ERB-alpha. PMID- 23748758 TI - Maximizing antibody production in suspension-cultured mammalian cells by the customized transient gene expression method. AB - Due to the great diversity in protein expression productivity, a customized transient gene expression (TGE) method was used in the present study to optimize transient expression of three antibodies. Several factors, including host cells, temperature, valproic acid (VPA) treatment, various vectors, and additives were optimized independently and then combined to form a customized TGE protocol for each antibody. In the event, the optimized TGE conditions for three antibodies were different from each other. Compared with the TGE in CHO-S cells by pCDNA3.1 expression vector, the expression productivities of 8C11 cAb, 37 hAb, and 10F7 cAb showed 16-fold, 293-fold, and 19-fold increases respectively by the customized TGE method. For 8C11 cAb, coexpressing L-chain and H-chain on different plasmids led to higher yields. The customized TGE method is an alternative approach that can greatly improve the expression productivity of a variety of recombinant proteins. PMID- 23748759 TI - Mode of IMP and pyrophosphate enhancement of myosin and actin extraction from porcine meat. AB - We examined the mode of IMP and pyrophosphate enhancement of myosin and actin extraction from porcine meat. Extractabilities were determined after homogenates, prepared by adding 9 volumes of 0.3, 0.4, or 0.5 M NaCl solutions containing 0 to 36 mM IMP and 0 to 9 mM tetrapotassium pyrophosphate (KPP) to minced pork, were incubated at 4 degrees C for 0 or 12 h. Irrespective of the NaCl concentrations, IMP-induced extraction of both proteins increased with increasing extraction time. In contrast, that of KPP did not. When 0.3 M NaCl solutions containing both IMP and KPP were used, the solutions with 1.5 mM KPP showed marked enhancement of IMP-induced myosin and actin extraction. Incorporating these results with our previously published data (Nakamura et al., Biosci. Biotechnol. Biochem., 76, 1611-1615 (2012)), we hypothesized that IMP and KPP have the ability to release thick and thin filaments from restraints in myofibrils, in addition to the ability to dissociate actomyosin into myosin and actin, and that the restraint releasing ability of IMP is dependent on reaction time and NaCl concentration while that of KPP is not. PMID- 23748760 TI - Supplementation with 1% energy trans fatty acids had little effect on serum cholesterol levels in healthy young Japanese women. AB - The World Health Organization (WHO) has recommended that trans fatty acid (TFA) intake should be less than 1% of total energy intake, but few data are available as to the influence of energy TFA intake of as low as 1% on blood cholesterol levels. A randomized, double-blind, parallel trial was conducted to assess the effects of 1% TFA dietary supplementation on serum cholesterol levels in healthy young women. Sixty-five volunteers consumed cookies containing 1% (TFA) or 0.04% (control) energy of TFA for 4 weeks and blood was harvested after overnight fasting. There were no significant differences in serum LDL- or HDL-cholesterol levels between the two groups. The hemoglobin A1c level was not influenced by dietary TFA. These results suggest that energy of TFAs at less than 1% has little effect on serum cholesterol or hemoglobin A1c levels in healthy young women. This confirms the correctness of the WHO recommendation. PMID- 23748761 TI - Low and medium but not high doses of green tea polyphenols ameliorated dextran sodium sulfate-induced hepatotoxicity and nephrotoxicity. AB - Our previous study indicated that a diet containing a high dose (1%) of green tea polyphenols (GTPs) disrupted liver and kidney function via a reduction in antioxidant enzyme and heat shock protein (HSP) levels in both colitis and non treated ICR mice. In the present study, we assessed the effects of 0.01%, 0.1%, and 1% dietary GTPs on liver and kidney physiological functioning in dextran sulfate sodium (DSS)-exposed and normal mice. GTPs at 0.01% and 0.1% significantly suppressed DSS-increased serum aspartate 2-oxoglutarate aminotransferase (AST) and alanine aminotransferase (ALT) levels. In contrast, GTPs at 1% increased kidney weight, serum creatinine levels, and thiobarbituric acid-reactive substances (TBARs) in both the kidney and the liver in normal mice, as compared with DSS-exposed mice. GTPs at 0.01% and 0.1% remarkably upregulated the expression of heme oxygenase-1 (HO-1) and heat shock protein 70 (HSP70) mRNA in the liver and kidney of mice exposed to DSS, whereas GTPs at 1% abolished it. Our results indicate that low and medium doses of GTPs have beneficial effects on DSS-induced hepatotoxicity and nephrotoxicity via upregulation of self-protective enzymes, while these effects disappeared at a high dose. PMID- 23748762 TI - Identification of antioxidants produced by Lactobacillus plantarum. AB - We identified two compounds that demonstrated 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity from cultures of Lactobacillus plantarum. Spectroscopic analyses proved these compounds to be L-3-(4-hydroxyphenyl) lactic acid (HPLA) and L-indole-3-lactic acid (ILA). The respective EC50 values for HPLA and ILA were 36.6 +/- 4.3 mM and 13.4 +/- 1.0 mM. PMID- 23748763 TI - Mandelate racemase and mandelate dehydrogenase coexpressed recombinant Escherichia coli in the synthesis of benzoylformate. AB - Benzoylformate is used widely as an organic synthetic intermediate. Mandelate racemase and mandelate dehydrogenase are two enzymes used in producing benzoylformate from racemic mandelate in microbial metabolism. In the present work, the genes encoding mandelate racemase and mandelate dehydrogenase from Pseudomonas aeruginosa strain NUST were cloned and expressed in Escherichia coli to convert racemic mandelate to benzoylformate. The use of whole resting cells of recombinant E. coli allowed the conversion of 65.7 mM solution of racemic mandelate to benzoylformate at a yield of 98.9% in 45 h. The process is a promising alternative for the production of benzoylformate. PMID- 23748764 TI - Orally and topically administered Sparassis crispa (Hanabiratake) improved healing of skin wounds in mice with streptozotocin-induced diabetes. AB - Sparassis crispa (SC) contains significant concentrations of beta-glucan, which can accelerate wound healing, but the dose dependence for oral administration and the effects of topical administration are unknown. In streptozotocin-induced diabetic mice, dietary SC promoted dose-dependent effective wound healing. Similar wound healing activity was observed when purified SC beta-glucan was topically applied to wounds of diabetic mice. PMID- 23748765 TI - Peanut-skin polyphenols, procyanidin A1 and epicatechin-(4 beta -> 6)-epicatechin (2 beta -> O -> 7, 4 beta -> 8)-catechin, exert cholesterol micelle-degrading activity in vitro. AB - We identified epicatechin-(4 beta -> 6)-epicatechin-(2 beta -> O -> 7, 4 beta -> 8)-catechin (EEC) in the skin of the peanut (Arachis hypogaea L.). EEC (a trimer) showed more potent cholesterol micelle-degrading activity than procyanidin A1 (a dimer) did in vitro. The hypercholesterolemia suppressing effect of a peanut skin polyphenol on rats fed high-cholesterol diet in our preceding experiments might thus have been due primarily to a micelle degrading effect in the intestine. PMID- 23748766 TI - Quantification of major royal jelly protein 1 in fresh royal jelly by indirect enzyme-linked immunosorbent assay. AB - Rabbit polyclonal antibody produced by a major royal jelly protein 1 (MRJP1) specific peptide reacted only with a MRJP1. Indirect ELISA with the antibody revealed a MRJP1 level of 4.12-4.67 g/100 g in different company's royal jelly, which almost agreed with that of a hexametric form of MRJP1 (apisin) measured by high performance liquid chromatography. These results suggest that MRJP1 exists mainly as apisin in royal jelly. PMID- 23748767 TI - Lower photostability of capsanthin dispersed in an aqueous solution. AB - Food-additive grades of capsanthin, lutein, lycopene, and beta-carotene dispersed in aqueous solutions were photo-irradiated using a Xenon weather meter, and the levels of carotenoids were measured by HPLC and the absorbance method. Capsanthin photo-degraded more rapidly than the carotenoids tested, with less oxygen consumption. Unlike carotenes, capsanthin was partially converted into analogous colored compounds during degradation. PMID- 23748768 TI - Influence of HbCO structure of the bar-headed goose on photolysis thermodynamics as studied by the nanosecond laser-ultrasonic technique. AB - The bar-headed goose, a specialized high-altitude species, has a capacity for high oxygen uptake from a hypoxic environment. It thus has a higher oxygen affinity than other bird species of lower-altitude environments. Oxygen affinity is determined by molecular structures and genetic mutations of hemoglobin (Hb), which can also influence the coordinating structures and dynamics of oxygen-Hb. To explore the structural differences in Hbs as between high and low altitude species, photolysis dynamic parameters, including quantum yield, enthalpy, and conformational volume changes in carboxy-Hbs (HbCO) for the bar-headed goose and low altitude counterparts (the Chinese goose and chicken) were investigated by the laser pumping-probing technique and photoacoustic calorimetry. Comparing the photolysis results for HbCO of the three species, the enthalpy and conformational volume changes of the bar-headed goose were much smaller than those of the others, although the quantum yields of all three species are similar. To explain the possible mechanisms of these differences, modifications of salt bridges and key residue mutations at the alpha beta subunit interfaces of the proteins are described and discussed briefly. PMID- 23748769 TI - Elicitor(s) in Sogatella furcifera (Horvath) causing the Japanese rice plant (Oryza sativa L.) to induce the ovicidal substance, benzyl benzoate. AB - We elucidate the mechanism for inducing the production of ovicidal benzyl benzoate by Japonica rice varieties to kill eggs of the whitebacked planthopper, Sogatella furcifera (Horvath), lying in the rice plant. Even when subjected to physical damage by a needle or damage with water, the rice plant produced no benzyl benzoate. However, significant benzyl benzoate was produced when the plant was damaged with a methanol extract or homogenate of S. furcifera. The extract of the male did not induce the production of benzyl benzoate, but that of the female did. We concluded from these results that benzyl benzoate was induced by some elicitor(s) in the female of S. furcifera. PMID- 23748770 TI - Identification of phosphorylation sites in the C-terminal region of charged multivesicular body protein 1A (CHMP1A). AB - Human charged multivesicular body protein 1A (CHMP1A) displayed two bands on SDS PAGE and differences in efficiency of complex formation with IST1. By site directed mutagenesis and phosphate-affinity PAGE, we identified Ser(179) and Ser(182) located in the C-terminal region as major phosphorylation sites that cause a mobility shift, but interaction with IST1 was not affected by Ser-to-Ala mutations. PMID- 23748771 TI - MPK6 contributes to non-host resistance to magnaporthe oryzae in Arabidopsis thaliana. AB - The rate of entry of Magnaporthe oryzae into pen2 mpk6 plants was higher than that into pen2 plants. The infection hyphae in the pen2 mpk6 plants were longer than those in the pen2 plants. The proportion of branched hyphae development in the pen2 mpk6 plants was higher than that in the pen2 plants. These results suggest that MPK6 functions in both penetration and post-penetration resistance to M. oryzae in Arabidopsis thaliana. PMID- 23748772 TI - AtRbohF contributes to non-host resistance to Magnaporthe oryzae in Arabidopsis. AB - The infection hyphae in pen2 atrbohF plants were significantly longer than those in pen2 plants. The proportion of branched hyphae development in the pen2 atrbohF plants was significantly higher than in the pen2 plants. These results suggest that AtRbohF is probably involved in post-penetration resistance to Magnaporthe oryzae in Arabidopsis. PMID- 23748773 TI - Inhibition of amyloid beta aggregation by acteoside, a phenylethanoid glycoside. AB - We examined the effects of acteoside (1a), which was isolated from Orobanche minor, and its derivatives on the aggregation of a 42-mer amyloid beta protein (Abeta42) in our search for anti-amyloidogenic compounds for Alzheimer's disease (AD) therapy. Acteoside (1a) strongly inhibited the aggregation of Abeta42 in a dose-dependent manner. The structure-activity relationship for acteoside (1a) and related compounds suggests the catechol moiety of phenylethanoid glycosides to be essential for this inhibitory activity. PMID- 23748774 TI - Effect of licorice flavonoid oil on cholesterol metabolism in high fat diet rats. AB - Dietary licorice fravonoid oil (LFO) significantly decreased hepatic cholesterol and plasma lipoprotein cholesterol levels in high-fat diet rats. It significantly suppressed hydroxymethylglutaryl-CoA synthase activity and increased cholesterol 7alpha-hydroxylase activity. The low density lipoprotein receptor mRNA level was significantly increased by LFO. These results suggest that dietary LFO improves cholesterol metabolism in obese animals. PMID- 23748775 TI - Establishment of a new detection system for the dimerization of IRE1alpha by BiFC assay. AB - We developed a new detection system for the activation of an endoplasmic reticulum (ER) stress sensor, inositol requiring kinase 1 alpha (IRE1alpha), by evaluating dimerization of it by bimolecular fluorescence complementation (BiFC) assay. By detecting the fluorescence derived from the reconstituted cerulean, this assay system enabled us to distinguish the activation behaviors of IRE1alpha as to ER stress-inducing compounds. PMID- 23748776 TI - Biosynthesis of phytoalexins and regulatory mechanisms of it in rice. AB - We performed extensive functional characterization of diterpenoid phytoalexin biosynthetic genes in rice, and found that the genes for the biosynthesis of the major diterpenoid phytoalexins, phytocassanes and momilactones, are clustered on chromosomes 2 and 4, and that their expression is coordinately induced in rice cells after elicitation. Isopentenyl diphosphate, an early precursor of diterpenoid phytoalexins, was found to be synthesized through the plastidic methylerythritol phosphate pathway. We also found that chitin elicitor receptor kinase OsCERK1 and a mitogen-activated protein kinase cascade, the OsMKK4-OsMPK6 cascade, play essential roles in the elicitor-induced production of diterpenoid phytoalexins. In addition, a basic leucine zipper transcription factor, OsTGAP1, was identified as a key regulator of the coordinated expression of the clustered genes and the methylerythritol phosphate pathway genes. Naringenin 7-O methyltransferase (OsNOMT) was also identified as a key enzyme in the biosynthesis of another major rice phytoalexin, sakuranetin. PMID- 23748777 TI - Functional differentiation of chitin synthases in Yarrowia lipolytica. AB - In this study, we identified seven chitin synthase-encoding genes in the genome of the dimorphic yeast Yarrowia lipolytica. Three encoded chitin synthases with myosin motor-like domains at their N-termini, and we designated these CSM1 to CSM3, whereas four were identified as CHS1 to CHS4. To investigate the functions of these seven genes, we constructed and characterized their deletion mutants. The chs2Delta mutant formed chained cells in which daughter cells were connected with mother cells and had abnormally thick septa at the bud neck. The chs4Delta mutant showed remarkably reduced chitin content in its cell wall. The chs2Delta, csm1Delta, and csm2Delta mutants were found to be highly sensitive to chitin binding dyes, calcofluor white (CFW) and Congo red, whereas the chs4Delta mutant was resistant to CFW. These results suggest that Chs2 and Chs4 play major roles in septum formation and cell wall chitin synthesis respectively, whereas Csm1 and Csm2 are involved in the maintenance of cell wall architecture and/or cell wall integrity. The populations of filamentous cells, a type of cell population that are defined by the lengths of the cellular long and short axes, decreased in the chs3Delta mutant, suggesting that Chs3 is involved in cellular morphogenesis. PMID- 23748778 TI - Lutein, a nonprovitamin A, activates the retinoic acid receptor to induce HAS3 dependent hyaluronan synthesis in keratinocytes. AB - Carotenoids have been reported to have potent antioxidant activities and to protect tissues and cells from certain diseases and environmental insults. The molecular mechanism of the action of provitamin A carotenoids such as beta carotene and beta-cryptoxanthin is mediated in part by retinoic acid, an active form of provitamin A, but the molecular basis of the biological activities of non provitamin A carotenoids such as lutein, zeaxanthin, and astaxanthin is not fully understood. In this study, we investigated to determine whether the actions of non-provitamin A carotenoids are mediated via retinoid signaling by monitoring retinoic acid receptor (RAR)-dependent hyaluronan production in cultured human keratinocytes. Not only beta-carotene and beta-cryptoxanthin, but also lutein, zeaxanthin, and astaxanthin, upregulated HAS3 gene expression and were followed by hyaluronan synthesis. We found that LE540, an antagonist of retinoic acid receptors, abolished lutein dependent hyaluronan synthesis and that lutein significantly increased retinoic acid responsive element (RARE)-driven transcript acitivity. In addition, we found that citral, an inhibitor of retinal dehydrogenases, decreased lutein-stimulated hyaluronan synthesis, indicating that lutein metabolites rather than lutein itself act as an RAR ligand in RAR-mediated transcription activity in keratinocytes. A series of non-provitamin A can be substituted for retinoids and should be considered as a potential means of improving skin health. PMID- 23748779 TI - Zinc depletion activates the endoplasmic reticulum-stress sensor Ire1 via pleiotropic mechanisms. AB - Although zinc deficiency evokes the endoplasmic reticulum (ER)-stress response, the activating mechanism remains obscure. Here we show that in yeast cells, the ER-stress sensor Ire1 was activated upon zinc deficiency. ER-stressing stimuli activating Ire1 are known to include ER accumulation of unfolded proteins and membrane-lipid aberrancy. According to the findings presented here, zinc deficiency causes both types of abnormality. PMID- 23748780 TI - Production of hydroxlated flavonoids with cytochrome P450 BM3 variant F87V and their antioxidative activities. AB - A variant of P450 BM3 with an F87V substitution [P450 BM3 (F87V)] is a substrate promiscuous cytochrome P450 monooxygenase. We investigated the bioconversion of various flavonoids (favanones, chalcone, and isoflavone) by using recombinant Escherichia coli cells, which expressed the gene coding for P450 BM3 (F87V), to give their corresponding hydroxylated products. Potent antioxidative activities were observed in some of the products. PMID- 23748781 TI - Metabolism of hydrophobic carbon sources and regulation of it in n-alkane assimilating yeast Yarrowia lipolytica. AB - A potent ability to assimilate hydrophobic compounds, including n-alkanes and fatty acids as carbon sources, is one of important characteristics of the yeast Yarrowia lipolytica, and has been studied for both basic microbiological interest and biotechnological applications. This review summarizes recent progress on the metabolism of n-alkanes and its transcriptional control in response to n-alkanes and to fatty acids in Y. lipolytica. In the metabolism of n-alkanes, cytochromes P450ALK catalyze their initial hydroxylation to fatty alcohols, which are subsequently converted to fatty acids and utilized. The transcription of ALK1, encoding a predominant cytochrome P450ALK, is regulated in response to n-alkanes by two basic helix-loop-helix transcription activators, Yas1p and Yas2p, and Opi1 family transcription repressor Yas3p. Transcription of the genes involved in fatty acid utilization and peroxisome biogenesis is controlled by Ctf1-family Zn2Cys6 type transcription factor Por1p in response to fatty acids in Y. lipolytica. PMID- 23748782 TI - Unique biosynthesis of sesquarterpenes (C35 terpenes). AB - To the best of my knowledge, only 19 cyclic and 8 linear C35 terpenes have been identified to date, and no family name was assigned to this terpene class until recently. In 2011, it was proposed that these C35 terpenes should be called sesquarterpenes. This review highlights the biosynthesis of two kinds of sesquarterpenes (C35 terpenes) that are produced via cyclization of a linear C35 isoprenoid in Bacillus and Mycobacterium species. In Bacillus species, a new type of terpene cyclase that has no sequence homology with any known terpene synthases, as well as a bifunctional terpene cyclase that biosynthesizes two classes of cyclic terpenes with different numbers of carbons as natural products, have been identified. On the other hand, in Mycobacterium species, the first bifunctional Z-prenyltransferase has been found, but a novel terpene cyclase and a unique polyprenyl reductase remain unidentified. The identification of novel enzyme types should lead to the discovery of many homologous enzymes and their products including novel natural compounds. On the other hand, many enzymes responsible for the biosynthesis of natural products have low substrate specificities in vitro. Therefore, to find novel natural products present in organisms, the multifunctionality of enzymes in the biosynthetic pathway of natural products should be analyzed. PMID- 23748783 TI - Evaluation of three RT-qPCR-based miRNA detection methods using seven rice miRNAs. AB - Three frequently-used reverse transcription-quantitative polymerase chain reaction (RT-qPCR)-based miRNA detection methods, stem-loop RT-qPCR, poly(A) tailing RT-qPCR, and miQPCR, were evaluated using seven selected rice miRNAs. The results revealed that miRNA abundance and sequence characteristics can affect capability of detection. The stem-loop amplification technique detected highly and moderately abundant miRNAs. The poly(A)-tailing method detected both highly abundant and sparsely present miRNAs, but failed to detect miRNAs with a hairpin structure. Only a few miRNAs were detectable by the miQPCR method. We suggest that a combination of methods should be used for reliable quantitative investigation of miRNAs. PMID- 23748784 TI - Why food-poisoning bacteria attached to shredded cabbage are not efficiently disinfected by sodium hypochlorite (NaClO). AB - The aim of this study was to determine why food poisoning bacteria attached to cut cabbage are not efficiently disinfected by sodium hypochlorite (NaClO). Pretreatment of shredded cabbage with diethyl ether definitely decreased the survival numbers of Escherichia coli O157:H7 and Salmonella spp. after disinfection with 100 ppm of NaClO. The density of E. coli O157:H7 at the cut edge of a cabbage section was larger than that on the surface. The residual ratio of attached bacteria at the cut edge after NaClO disinfection was significantly higher than that on the surface. Microscopical observation indicated that the cut edge of shredded cabbage pretreated with diethyl ether was almost closed, resulting in a decrease in bacterial infiltration. Pretreatment of shredded cabbage with a higher concentration of NaClO to penetrate it more deeply significantly decreased the numbers of surviving bacteria after NaClO disinfection. Based on these results, we concluded that the bacteria attached to cut cabbage were not efficiently disinfected by NaClO, because not enough NaClO deeply infiltrated into the cut edges, and hence not enough came in contact with the bacteria. PMID- 23748785 TI - Clock-controlled and FLOWERING LOCUS T (FT)-dependent photoperiodic pathway in Lotus japonicus II: characterization of a microRNA implicated in the control of flowering time. AB - Plant circadian clock generates rhythms with a period close to 24 h, and it controls a wide variety of physiological and developmental events, including the transition to reproductive growth (or flowering). During the last decade, significant research progress in Arabidopsis thaliana has been made in defining the molecular mechanism by which the circadian clock regulates flowering time in response to changes in photoperiod. In Lotus japonicus, we have found that LjFTa, which encodes a ortholog of the Arabidopsis FLOWERING LOCUS T (FT), plays an important role in the promotion of flowering, but it is not clear how the expression of LjFTa is regulated in L. japonicus. Based on current knowledge of photoperiodic control of flowering time in A. thaliana, here we examined whether a microRNA is involved in the activation of LjFTa in L. japonicus. Two putative L. japonicus genes that are responsible for the production of miR172 (designated LjmiR172a and LjmiR172b) were cloned. Overexpression of LjmiR172a/b in A. thaliana resulted in markedly accelerated flowering through enhancement of the expression of FT, concomitantly reducing the expression level of TARGET OF EARLY ACTIVATION TAGGED 1 (TOE1) transcripts, the protein product of which functions as a transcriptional repressor of FT. These results suggest that LjmiR172 genes play a positive role in the LjFTa-mediated promotion of flowering in L. japonicus. PMID- 23748786 TI - Identification and quantification of total coumarins from Urtica dentata Hand and its roles in promoting immune tolerance via TLR4-mediated dendritic cell immaturation. AB - Urtica dentata Hand (UDH) is traditionally used in the Alpine region as a herbal medicine. Immunotherapy using total coumarins (TC) of UDH has been proposed, yet the cellular and molecular mechanisms remain incompletely characterized. Additionally, there is no method available for the quantification of the main coumarins in UDH. We describe maturation-resistant, TC-conditioned dendritic cell (DC), which expressed much lower MHC class II (I-Ak) and CD86, showed reduced capacity to stimulate effector T cell responses and upregulated PD-Ll (programmed death ligand-1). TC-DC-stimulated regulatory cells (Treg) were superior alloantigen-specific suppressor of the T effector response as compared to those stimulated by control (CTR)-DC. Furthermore, TC-conditioned DC increased the levels of Foxp3 and CTLA-4 in the CD25 T cell population. TC-DC downregulated toll like receptor 4 (TLR4) protein expression in response to LPS. This indicates that down-regulation of TLR4 in response to TC on DC is a critical signaling pathway that regulates the phenotype and function of DC. We also established a sensitive and specific high-performance liquid chromatography-diodearray detection-mass spectrometry (HPLC-DAD-MS) method for simultaneous identification of its main coumarins, 6,6',7,7'-tetramethoxyl-8,8'-biscoumarin (1), 7,7' dihydroxy-6,6'-dimethoxy-8,8'-biscoumarin (2), 7,7'-dimethoxy-6,6'-biscoumarin (3), and scoparone (4). A demonstration of this mechanism and the method for identification and quantification of TC in UDH endorsed their potential as a tolerance-promoting herbal medicine to prevent or treat transplantation rejection and autoimmune diseases. PMID- 23748787 TI - Stilbene analogs of resveratrol improve insulin resistance through activation of AMPK. AB - Resveratrol (RSV), 3,5,4'-trihydroxy-trans-stilbene, is known to have many beneficial physiological activities. We have synthesized several stilbene analogues and have reported that the hydroxyl group in the 4' position of RSV exhibited strong radical scavenging action. Using stilbene analogs, we investigated the structure of RSV to explain its protective effect against obesity and type 2 diabetes. All six analogs used in this study inhibited the differentiation of 3T3-L1 adipocytes. 3-Hydroxy-trans stilbene (3(OH)ST), and 3,4'-dihydroxy-trans stilbene (3,4'(OH)2ST) increased glucose uptake and induced adenosine monophosphate kinase (AMPK) phosphorylation in C2C12 myotubes independently of insulin. An in vivo study using mice fed high-fat diets indicated that 3(OH)ST was more effective than RSV in improving insulin resistance. In conclusion, RSV and its derivatives, particularly 3(OH)ST, inhibited adipocyte differentiation and enhanced glucose uptake in the myotubes, resulting in a reduction of obesity and an improvement in glucose tolerance in vivo. PMID- 23748788 TI - Degradation of the persistent organic pollutant [14C]heptachlor in Japanese field soils. AB - The fate of [(14)C]heptachlor in Saitama soil and the degradation of [(14)C]heptachlor in four Japanese field soils over 112 d after application were investigated. Heptachlor was degraded mainly to cis-heptachlor epoxide by a biotic process and to 1-hydroxychlordene by an abiotic process in the field soils. Volatilization of heptachlor and cis-heptachlor epoxide from the soil was observed over the experimental period. The amount of 1-hydroxychlordene produced in the soils appeared to be related to the soil water contents. Because heptachlor and heptachlor epoxides are predicted to volatilize to the atmosphere and to persist in soils, these compounds are thought to spread among Japanese environmental compartments even after a ban on their use. PMID- 23748789 TI - Engineered Escherichia coli for short-chain-length medium-chain-length polyhydroxyalkanoate copolymer biosynthesis from glycerol and dodecanoate. AB - Short-chain-length medium-chain-length polyhydroxyalkanoate (SCL-MCL PHA) copolymers are promising as bio-plastics with properties ranging from thermoplastics to elastomers. In this study, the hybrid pathway for the biosynthesis of SCL-MCL PHA copolymers was established in recombinant Escherichia coli by co-expression of beta-ketothiolase (PhaARe) and NADPH-dependent acetoacetyl-CoA reductase (PhaBRe) from Ralstonia eutropha together with PHA synthases from R. eutropha (PhaCRe), Aeromonas hydrophila (PhaCAh), and Pseudomonas putida (PhaC2Pp) and with (R)-specific enoyl-CoA hydratases from P. putida (PhaJ1Pp and PhaJ4Pp), and A. hydrophila (PhaJAh). When glycerol supplemented with dodecanoate was used as primary carbon source, E. coli harboring various combinations of PhaABCJ produced SCL-MCL PHA copolymers of various monomer compositions varying from C4 to C10. In addition, polymer property analysis suggested that the copolymers produced from this recombinant source have thermal properties (lower glass transition and melting temperatures) superior to polyhydroxybutyrate homopolymer. PMID- 23748790 TI - Large-scale preparation of Asn-glycopeptide carrying structurally homologous antigenic N-glycan. AB - In our previous report (M. Okano, et al., Clin. Exp. Allergy, 34, 770-778 (2004)), we found that free plant complex type N-glycans suppressed the production of IL4 from Th2 cells of Japanese cedar pollinosis patients, suggesting that plant complex type N-glycan can be used as a leading compound for developing immuno-pharmaceuticals. Although immunoreactive plant complex type N glycans occur ubiquitously on glycoproteins expressed in plants, an appropriate procedure has not been established to prepare non-labeled immunoreactive glycans or glycopeptides bearing structurally homologous immunoreactive glycans in large amounts. In this study, therefore, we developed a new preparative procedure for the large-scale preparation of Asn-glycopeptide bearing plant complex type N glycan using a combination of gel-filtration and the hydrophilic partitioning method. By this new method, about 103 mg of Asn-glycopeptide bearing the antigenic N-glycans was obtained from 1.9 kg of shelled Ginkgo biloba seeds. PMID- 23748791 TI - Archaeal aldehyde dehydrogenase ST0064 from Sulfolobus tokodaii, a paralog of non phosphorylating glyceraldehyde-3-phosphate dehydrogenase, is a succinate semialdehyde dehydrogenase. AB - Aldehyde dehydrogenase ST0064, the closest paralog of previously characterized allosteric non-phosphorylating glyceraldehyde-3-phosphate (GAP) dehydrogenase (GAPN, ST2477) from a thermoacidophilic archaeon, Sulfolobus tokodaii, was expressed heterologously and characterized in detail. ST0064 showed remarkable activity toward succinate semialdehyde (SSA) (Km of 0.0029 mM and kcat of 30.0 s( 1)) with no allosteric regulation. Activity toward GAP was lower (Km of 4.6 mM and kcat of 4.77 s(-1)), and previously predicted succinyl-CoA reductase activity was not detected, suggesting that the enzyme functions practically as succinate semialdehyde dehydrogenase (SSADH). Phylogenetic analysis indicated that archaeal SSADHs and GAPNs are closely related within the aldehyde dehydrogenase superfamily, suggesting that they are of the same origin. PMID- 23748792 TI - EPIDERMAL PATTERNING FACTOR LIKE5 peptide represses stomatal development by inhibiting meristemoid maintenance in Arabidopsis thaliana. AB - Stomatal development in Arabidopsis epidermis is both positively and negatively regulated by a family of Cys-rich peptides, EPIDERMAL PATTERNING FACTOR LIKEs (EPFLs). We synthesized biologically active synthetic EPFL5 (sEPFL5) peptide, which reduced the number of stoma in leaves and cotyledons. The sEPFL5 possesses three disulfide bonds at positions identical to those of a positive development factor, stomagen. Application of sEPFL5 had little inhibitory effect on protodermal cells entering the stomatal lineage, but did inhibit the maintenance of meristemoid activity, resulting in the differentiation of arrested meristemoids into pavement cells. This phenotype was enhanced in the too many mouths (tmm) mutant background. RNA analysis revealed that sEPFL5 application halved SPEECHLESS expression and abolished MUTE expression in tmm mutants, explaining the phenotype observed. The action of sEPFL5 was mediated by ERECTA family receptors. We propose that EPFL5 functions to establish the differentiation of stomatal lineage cells to pavement cells. PMID- 23748793 TI - Stereoselective synthesis of a promising flower-inducing KODA analog, (9R,12S,13R,15Z)-9-hydroxy-12,13-methylene-10-oxooctadec-15-enoic acid. AB - Stereoselective synthesis of a promising flower-inducing 9,10-ketol octadecadienoic acid (KODA) analog, (9R,12S,13R,15Z)-9-hydroxy-12,13-methylene-10 oxooctadec-15-enoic acid, was designed to obtain the desired stereoisomer via coupling between chiral sulfone and aldehyde segments. A known chiral cyclopropane derivative was converted to the sulfone segment via carbon-chain elongation and sulfonylation. Dec-9-en-1-ol was converted to the aldehyde segment, whose C-9 configuration was introduced by Sharpless asymmetric dihydroxylation. Coupling of the both segments and subsequent assembly gave the desired (9R,12S,13R,15Z)-analog. The (9S,12S,13R,15Z)-analog was also synthesized by using the enatiomeric aldehyde segment. This strategy made it possible to synthesize the remaining stereoisomeric analogs. PMID- 23748794 TI - Application of an in vitro DNA protection assay to visualize stress mediation properties of the Dps protein. AB - Oxidative stress is an unavoidable byproduct of aerobic life. Molecular oxygen is essential for terrestrial metabolism, but it also takes part in many damaging reactions within living organisms. The combination of aerobic metabolism and iron, which is another vital compound for life, is enough to produce radicals through Fenton chemistry and degrade cellular components. DNA degradation is arguably the most damaging process involving intracellular radicals, as DNA repair is far from trivial. The assay presented in this article offers a quantitative technique to measure and visualize the effect of molecules and enzymes on radical-mediated DNA damage. The DNA protection assay is a simple, quick, and robust tool for the in vitro characterization of the protective properties of proteins or chemicals. It involves exposing DNA to a damaging oxidative reaction and adding varying concentrations of the compound of interest. The reduction or increase of DNA damage as a function of compound concentration is then visualized using gel electrophoresis. In this article we demonstrate the technique of the DNA protection assay by measuring the protective properties of the DNA-binding protein from starved cells (Dps). Dps is a mini-ferritin that is utilized by more than 300 bacterial species to powerfully combat environmental stressors. Here we present the Dps purification protocol and the optimized assay conditions for evaluating DNA protection by Dps. PMID- 23748795 TI - Secondary malignancies of the uterine cervix: a potential diagnostic pitfall. AB - The occurrence of a secondary malignancy in the uterine cervix is a very rare event. In the vast majority of cases, this secondary involvement concerns direct spread of a uterine malignancy to the cervix. However, cancer of the ovary, breast, stomach, gallbladder, pancreas and lung has been reported to metastasize to the uterine cervix by hematogenous route. In this context, secondary lesions of the uterine cervix, in particular those of non-epithelial and extra-genital origin, are sufficiently rare to be overlooked, which might result in inappropriate diagnosis with disappointing consequences in terms of treatment planning. We report a single-institution consecutive series of 144 cases of secondary malignancy of the uterine cervix, emphasizing the morphological and immunohistochemical criteria required to arrive at a correct final diagnosis. Secondary malignancies of the uterine cervix have a protean appearance and can present with a wide spectrum of symptoms. Almost invariably metastases to the cervix signal devastating spread to many different organs. Histopathology, as well as immunohistochemical features and close collaboration between clinicians and pathologists, is essential to arrive at a correct final diagnosis. PMID- 23748797 TI - Clinical and biomechanical investigation of an increased articular cavity depth after distal radius fractures: effect on range of motion, osteoarthrosis and loading patterns. AB - INTRODUCTION: After fracture, distal radius malunion with dissociation of the volar and dorsal ulnar fracture fragments can lead to an increased articular cavity. PATIENTS AND METHODS: To investigate its clinical impact we retrospectively analyzed the outcome of 81 patients and simulated this form of malunion in a biomechanical experiment with six cadaver specimens in a dynamic loading set-up. RESULTS: In clinics, a higher arthritis stage was significantly correlated with an increased articular cavity depth and an increased anterioposterior distance. In cadaver specimens, a significantly decreased range of motion and significantly altered intraarticular contact characteristics were recognized for an increased cavity. CONCLUSION: Alterations in contact biomechanics could be one reason for the higher incidence of posttraumatic osteoarthritis when a deeper central impaction of the distal radius is present. From a clinical and experimental point of view, restoration of the normal shape of the distal radius is considered to minimize the risk for posttraumatic radiocarpal osteoarthritis. PMID- 23748796 TI - Alterations of the tunica vasculosa lentis in the rat model of retinopathy of prematurity. AB - PURPOSE: To study the relationship between retinal and tunica vasculosa lentis (TVL) disease in retinopathy of prematurity (ROP). Although the clinical hallmark of ROP is abnormal retinal blood vessels, the vessels of the anterior segment, including the TVL, are also altered. METHODS: ROP was induced in Long-Evans pigmented and Sprague Dawley albino rats; room-air-reared (RAR) rats served as controls. Then, fluorescein angiographic images of the TVL and retinal vessels were serially obtained with a scanning laser ophthalmoscope near the height of retinal vascular disease, ~20 days of age, and again at 30 and 64 days of age. Additionally, electroretinograms (ERGs) were obtained prior to the first imaging session. The TVL images were analyzed for percent coverage of the posterior lens. The tortuosity of the retinal arterioles was determined using Retinal Image multiScale Analysis (Gelman et al. in Invest Ophthalmol Vis Sci 46:4734-4738, 2005). RESULTS: In the youngest ROP rats, the TVL was dense, while in RAR rats, it was relatively sparse. By 30 days, the TVL in RAR rats had almost fully regressed, while in ROP rats, it was still pronounced. By the final test age, the TVL had completely regressed in both ROP and RAR rats. In parallel, the tortuous retinal arterioles in ROP rats resolved with increasing age. ERG components indicating postreceptoral dysfunction, the b-wave, and oscillatory potentials were attenuated in ROP rats. CONCLUSIONS: These findings underscore the retinal vascular abnormalities and, for the first time, show abnormal anterior segment vasculature in the rat model of ROP. There is delayed regression of the TVL in the rat model of ROP. This demonstrates that ROP is a disease of the whole eye. PMID- 23748798 TI - Malposition and revision rates of different imaging modalities for percutaneous iliosacral screw fixation following pelvic fractures: a systematic review and meta-analysis. AB - INTRODUCTION: Percutaneous iliosacral screw placement following pelvic trauma is associated with high rates of revisions, screw malpositioning, the risk of neurological damage and inefficient stability. The correct entry point and the small target corridor may be difficult to visualize using only an image intensifier. Therefore, 2D and 3D image-based navigation and reconstruction techniques could be helpful tools. The aim of this systematic review and meta analysis was to evaluate the best available evidence regarding the rate of malpositioning and revisions using different techniques for screw implantation, i.e., conventional, 2D and 3D image-based navigation and reconstruction techniques, CT navigation. METHODS: A systematic review and meta-analysis were performed using the data available on Ovid Medline. 430 studies published between 1/1948 and 2/2011 were identified by two independent investigators. Inclusion criteria were percutaneous iliosacral screw fixation after traumatic pelvic fractures with included revision rate or positioning of the screw, language of the article English or German. Exclusion criteria were osteoporotic fracture, tumor, reviews, epidemiological studies, biomechanical/cadaveric studies, studies about operative technique. For statistical analysis the random effect model was used. RESULTS: A total of 51 studies fulfilled the inclusion requirements describing 2,353 percutaneous screw implantations following pelvic trauma in 1,731 patients. The estimated rate of malposition was 0.1 % for 262 screws using CT navigation. This rate was significantly lower (p < 0.0001) than for the conventional technique with malposition rate of 2.6 % (total 1,832 screws). Using 2D and 3D image-based navigation and reconstruction techniques, the malposition rate was 1.3 % (total 445 screws). No significance was observed between the conventional and the 2D and 3D image-based navigation and reconstruction techniques. The rates of revision were not statistically significant with 2.7 % (1,832 implantations) in the conventional group, 1.3 % (445 implantations) in the group of 2D and 3D image-based navigation and reconstruction techniques and 0.8 % (262 implantations) using the CT navigation. CONCLUSIONS: CT navigation has the lowest rate of screw malposition, but on the other hand it could not be used for all type of fractures where surgical procedures (reduction maneuvers, additional osteosynthetic procedures) are necessary. The 2D and 3D image-based navigation and reconstruction techniques provide encouraging results with slightly lower rate of complications compared to the conventional technique and are additional tools to enhance the precision and decrease the rate of revision. PMID- 23748799 TI - Is there a relationship between attention deficit/hyperactivity disorder and Osgood-Schlatter disease? AB - PURPOSE: The purpose of this prospective study is to investigate the relationship between Osgood-Schlatter disease (OSD) and attention deficit/hyperactivity disorder (ADHD). METHODS: Seventy-four children with a diagnosis of OSD were referred to child and adolescent psychiatry department for the evaluation of ADHD. Diagnostic and Statistical Manual of Mental Disorders was used for diagnostic criteria. RESULTS: Diagnosis of ADHD was made in 56 (75.6 %) out of 74 children. CONCLUSIONS: Results of this study suggest that ADHD is a significant risk factor for OSD. During the evaluation of a patient with OSD, a thorough history should be obtained about the behavioral symptoms that indicate underlying ADHD. In case of suspicion, these patients should be referred for an additional evaluation by a child psychiatrist. LEVEL OF EVIDENCE: II. PMID- 23748800 TI - Antimicrobial photodynamic therapy against pathogenic bacterial suspensions and biofilms using chloro-aluminum phthalocyanine encapsulated in nanoemulsions. AB - Antimicrobial photodynamic therapy represents an alternative method of killing resistant pathogens. Efforts have been made to develop delivery systems for hydrophobic drugs to improve the photokilling. This study evaluated the photodynamic effect of chloro-aluminum phthalocyanine (ClAlPc) encapsulated in nanoemulsions (NE) on methicillin-susceptible and methicillin-resistant Staphylococcus aureus suspensions and biofilms. Suspensions and biofilms were treated with different delivery systems containing ClAlPc. After the pre incubation period, the drug was washed-out and irradiation was performed with LED source (660 +/- 3 nm). Negative control samples were not exposed to ClAlPc or light. For the suspensions, colonies were counted (colony-forming units per milliliter (CFU/mL)). The metabolic activity of S. aureus suspensions and biofilms were evaluated by the XTT assay. The efficiency was dependent on the delivery system, superficial load and light dose. Cationic NE-ClAlPc and free ClAlPc caused photokilling of the both strains of S. aureus. For biofilms, cationic NE-ClAlPc reduced cell metabolism by 80 and 73% of susceptible and resistant strains, respectively. Although anionic NE-ClAlPc caused a significant CFU/ml reduction for MSSA and MRSA, it was not capable of reducing MRSA biofilm metabolism. This therapy may represent an alternative treatment for eradicating resistant strains. PMID- 23748801 TI - The sensitivity in the IR spectrum of the intact and pathological tissues by laser biophotometry. AB - In this paper, we use the laser biophotometry for in vivo investigations, searching the most sensitive interactions of the near-infrared spectrum with different tissues. The experimental methods are based on the average reflection coefficient (ARC) measurements. For healthy persons, ARC is the average of five values provided by the biophotometer. The probe is applied on dry skin with minimum pilosity, in five regions: left-right shank, left-right forearm, and epigastrium. For the pathological tissues, the emitting terminal is moved over the suspected area, controlling the reflection coefficient level, till a minimum value occurs, as ARC-Pathological. Then, the probe is moved on the symmetrical healthy region of the body to read the complementary coefficient from intact tissue, ARC-Intact, from the same patient. The experimental results show an ARC range between 67 and 59 mW for intact tissues and a lower range, up to 58-42 mW, for pathological tissues. The method is efficient only in those pathological processes accompanied by variable skin depigmentation, water retention, inflammation, thrombosis, or swelling. Frequently, the ARC ranges are overlapping for some diseases. This induces uncertain diagnosis. Therefore, a statistical algorithm is adopted for a differential diagnosis. The laser biophotometry provides a quantitative biometric parameter, ARC, suitable for fast diagnosis in the internal and emergency medicine. These laser biophotometry measurements are representatives for the Romanian clinical trials. PMID- 23748802 TI - Association of breast cancer subtypes and body mass index. AB - AIMS AND BACKGROUND: Breast cancer is a heterogeneous disease with various pathological and molecular subtypes. This study aims to determine the association between BMI and the distribution of breast cancer subtypes defined by estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2/neu) expression in pre- and postmenopausal breast cancers. METHODS AND STUDY DESIGN: A total of 1847 female breast cancer patients were involved. After the exclusion of 457 patients due to missing subtype information (n = 400) or benign histology (n = 57), 1390 were included in the analyses. The histological type of the tumor, ER and PR expression, HER2/neu with immunohistochemistry and HER2/neu gene evaluation with interphase fluorescence in situ hybridization (if necessary), age, body weight, height and menopausal status at diagnosis were investigated retrospectively. The patients were stratified as having a normal body weight if BMI was <=24.9 kg/m2, as being overweight if BMI was between 25.0 and 29.9 kg/m2, and as being obese if BMI was >=30.0 kg/m2. RESULTS: Median BMI was 28.7 kg/m2 (17.6-55.6) in the postmenopausal and 25.6 kg/m2 (16.4-51.1) in the premenopausal group (P <0.001). BMI at diagnosis did not differ significantly between the molecular subtypes (P = 0.12). Distribution of BMI strata was similar between the molecular subtypes both in pre- and postmenopausal breast cancer (P = 0.24 and P = 0.99, respectively). Premenopausal women with a BMI of >=25.0 kg/m2 showed a tendency towards ER- tumors when compared to premenopausal women with a BMI of <25.0 kg/m2 (P = 0.009). CONCLUSIONS: The risk of specific breast cancer subtypes may not be associated with BMI in pre- and postmenopausal breast cancer. However, obesity might be related to an increased risk of premenopausal hormone receptor-negative breast cancer. Further studies are needed for clarification of the probable mechanisms in the pathogenesis of premenopausal hormone receptor-negative breast cancer. PMID- 23748803 TI - Serum pepsinogens and Helicobacter pylori are not associated with esophageal squamous cell carcinoma in a high-risk area in China. AB - AIMS AND BACKGROUND: The role of serum pepsinogen level and Helicobacter pylori infection in esophageal carcinoma remains controversial. It may be a risk or protective factor, or without association with esophageal carcinoma. We prospectively examined associations between serum pepsinogen status, H pylori infection and the risk of esophageal squamous cell carcinoma in the Chinese population. METHODS: In the present study, 1501 subjects from a community-based general population of Northern China were included. The incidence of esophageal carcinoma among the subjects was registered during a 15-year follow-up period by annual home visit, and the risks of low serum pepsinogen level and H pylori infection in the development of ESCC were evaluated using logistic regression. RESULTS: The total accumulated incidence of ESCC in the cohort was 666/100,000 during the 15-year follow-up. Notably, all the cases were verified to be ESCC. Logistic regression analysis showed that age >=60 (OR = 9.67; 95% CI, 2.797 33.423) was the only risk factor for esophageal squamous cell carcinoma in the population. There was no significant association between sex, H pylori infection, pepsinogen level (PG I <=70 ng/ml alone, PG I/II ratio <=3 alone, or PG I <=70 ng/ml and PG I/II ratio <=3) and esophageal squamous cell carcinoma. CONCLUSIONS: In this prospective study, neither H pylori infection nor abnormal pepsinogen status had a predictive role for the development of esophageal squamous cell carcinoma in the rural population of China. PMID- 23748804 TI - Phase II trial of combination chemotherapy with gemcitabine, 5-fluorouracil and cisplatin for advanced cancers of the bile duct, gallbladder, and ampulla of Vater. AB - AIMS AND BACKGROUND: For advanced cancers of the bile duct, gallbladder and ampulla of Vater, there are only a few treatment options. We explored the efficacy of the combination of gemcitabine, 5-fluorouracil and cisplatin for advanced biliary cancers. METHODS: From September 2003 to April 2010, 28 patients with recurrent or metastatic biliary tract cancer were enrolled. A treatment regimen consisting of gemcitabine (800 mg/m2 at a fixed dose rate on days 1 and 8), 5-fluorouracil (1 g/m2/day continuous infusion for 4 days) and cisplatin (60 mg/m2 on day 2) was repeated every 3 weeks. RESULTS: One (3.6%) patient showed complete response, 8 (28.6%) partial response, 14 (50%) stable disease and 5 (17.9%) disease progression. Overall, the objective response rate was 32.1% (95% CI, 17.9-50.6%) and the disease control rate was 82.1% (95% CI, 64.4-92.1%). Median progression-free survival and overall survival were 7.6 months (95% CI, 5.5-9.7) and 11.2 months (95% CI, 6.8-15.5), respectively. G3/4 neutropenia was observed in 44 (24.3%) of 181 cycles and G3/4 thrombocytopenia in 48 (26.5%) of 181 cycles. There was no treatment-related mortality. CONCLUSIONS: The combined regimen of gemcitabine, 5-fluorouracil and cisplatin has comparable activity for patients with advanced cancer of the bile duct, gallbladder and ampulla of Vater. Toxicity was tolerable but substantial. PMID- 23748805 TI - One-day DCF regimen in patients with metastatic gastric cancer. AB - BACKGROUND: Cytotoxic chemotherapy is the basic treatment for metastatic gastric cancer. The "docetaxel, cisplatin, 5-day infusion of 5-FU (DCF5)" regimen is regarded as an effective therapy. However, the poor toxicity profile of this regimen and administration by 5-day infusion are major drawbacks of this method. METHODS: Patients with measurable metastatic gastric carcinoma, Eastern Cooperative Oncology Group (ECOG) performance status <=2, normal hematological and renal function, adequate hepatic function, and not pretreated for advanced disease with chemotherapy, received docetaxel on day 1, cisplatin on day 1, and 5 FU peripheral IV on day 1 (DCF1) every 3 weeks. The patients undergoing the DCF1 regimen could not receive the infusion regimen. This was a retrospective study about the use of DCF in 1 day in not previously treated metastatic gastric cancer. RESULTS: In total, 95 patients were treated with a median of 5 cycles per patient. Those not previously treated for advanced disease received docetaxel 75 mg/m2 on day 1, cisplatin 75 mg/m2 on day 1, and 5-FU peripheral IV 750 mg/m2/day on day 1, plus filgrastim or lenograstim between days 3 and 7. Grade >=3 toxicities were neutropenia (12%), anemia (11%), thrombocytopenia (3%), fatigue (18%), mucositis (10%), diarrhea (3%), nausea/vomiting (6%), neurological (3%), and palmar-plantar (2%). Two nonfatal febrile neutropenia episodes were recorded. There were no treatment-related deaths. In all patients with measurable disease, we observed an overall response rate of 46% (40 partial responses, 4 complete responses). Thirty-one patients (33%) had stable disease. The median overall survival was 9.0 months (95% CI 7.34-10.6). CONCLUSIONS: Use of the DCF1 regimen in metastatic gastric cancer is feasible, with comparable activity to previous results achieved with epirubicin-based chemotherapy and infusion DCF in terms of overall survival. However, randomized and prospective studies need to be carried out with this regimen. PMID- 23748806 TI - Sentinel lymph node biopsy in breast cancer: review on various methodological approaches. AB - AIMS AND BACKGROUND: Sentinel lymph node biopsy has been accepted as a standard procedure for early stage breast cancer. In this retrospective analysis, the results obtained with different methodological approaches using radiocolloid with or without blue dye were examined. METHODS: A total of 158 sentinel lymph node biopsies were performed in 152 patients. Group A (85 patients) underwent lymphatic mapping using a combination of periareolar intradermal radiocolloid and subareolar blue dye injections. Group B (73 patients) underwent only periareolar intradermal radiocolloid injection. One large tin colloid and two small radiocolloids (nanocolloid of serum albumin -NC- and colloidal rhenium sulphide CS-) were used. RESULTS: Successful lymphatic mapping was attained in 157 of 158 procedures (99.4%). Radiocolloids localized sentinel lymph nodes in 99.4% and blue dye in 75.3% of the cases. The number of sentinel lymph nodes removed was greater in nanocolloid and colloidal rhenium sulphide groups (P <=0.05). Among 60 metastatic sentinel lymph nodes, frozen section analysis using hematoxylin and eosin staining failed to detect 1 macro- and 10 micrometastasis. Radiocolloid uptake was higher in sentinel lymph nodes accumulating blue dye (1643 +/- 3216 counts/10 sec vs 526 +/- 1284 counts/10 sec, P <0.001). Higher count rates were obtained by using larger sized colloids (median and interquartile range: tin colloid, 2050 and 4548; nanocolloid, 835 and 1799; colloidal rhenium sulphide, 996 and 2079; P = 0.01). Only 2 extra-axillary sentinel lymph nodes were visualized using periareolar intradermal injection modality. CONCLUSIONS: Radiocolloids were more successful than blue dye in sentinel lymph node detection. More sentinel lymph nodes were harvested with small colloids, but different sized radiocolloids were similarly successful. Sentinel lymph nodes having higher radiocolloid uptake tended to accumulate blue dye more frequently. Sentinel lymph nodes manifested higher count rates when a larger colloid was used. Frozen section was very successful in detecting macrometastatic disease in sentinel lymph nodes, but the technique failed in most of the micrometastates. PMID- 23748807 TI - Total mesorectal excision for rectal cancer: laparoscopic versus open approach. AB - AIMS AND BACKGROUND: To evaluate the oncologic safety of laparoscopic total mesorectal excision for rectal cancer. Methods and study design. Patients who underwent laparoscopic (n = 256) or open (n = 173) total mesorectal excision for rectal cancer between June 2005 and June 2011 were included. Long-term survival operative data and postoperative recovery were retrospectively reviewed from a prospectively collected database. RESULTS: No significant difference was found between the two groups in terms of age, sex, tumor stage and preoperative comorbidities. Twelve patients were converted to open procedures. Differences were found in blood loss (55 +/- 14.1 vs 152 +/- 29.2 ml P <0.05), infection of incision (3.1% vs 12.7%, P <0.05) and postoperative stay (8.1 +/- 3.0 vs 12.4 +/- 6.3 days, P <0.05). Both groups were comparable regarding lymph node clearance specimen length and distal margin. There was no significant difference in overall survival between the two groups by the life-table method. However, operative time in the laparoscopic group was longer than in the open group (168 +/- 27.6 vs 141 +/- 21.9 min, P <0.05). CONCLUSIONS: Laparoscopic total mesorectal excision for rectal cancer offers oncologic results similar to those obtained with the open procedure with a favorable short-term outcome. Continued use of the procedure in these patients is supported. PMID- 23748808 TI - Once-weekly stereotactic radiotherapy for patients with oligometastases: compliance and preliminary efficacy. AB - AIMS AND BACKGROUND: This retrospective analysis reports the outcomes obtained with an original once-weekly stereotactic radiotherapy fractionation given to patients affected by evolving oligometastases from different solid malignancies. METHODS: From 2009 to 2011, patients with symptomatic and/or evolving oligometastases were submitted to a median 5-fraction cycle of stereotactic radiotherapy of one fraction per week in order to exploit a radiobiological rationale designed to increase the therapeutic index. Individual fractionation was mainly planned according to patient performance status, oligometastasis size and site, and record of previous irradiation in the same site. RESULTS: Thirty six patients in stage IV UICC-TNM affected by oligometastases were treated with image-guided intensity-modulated stereotactic tomotherapy with a single weekly radiation. Median age was 70 years (range, 34-89). The median weekly single dose, number of fractions and overall total radiation dose were 7 Gy, 5 fractions and 35 Gy, respectively. Thirty-five (97%) patients completed the treatment schedule. No patient suffered mild or severe radiation-related side effects. Twenty-one (87%) of 24 patients with local pain had complete symptomatic response within 30 days following the end of radiotherapy. Local control assessed at imaging after stereotactic radiotherapy was evidenced in 30 (83%) patients. Median time to response after the end of radiotherapy was 40 days. CONCLUSIONS: The original radiotherapy regimen delivering only a single stereotactic dose per week seems to be highly feasible with an interesting high efficacy rate in patients with oligometastases from different solid tumors. Overall, the once-weekly treatment was very compliant in an advanced cancer stage especially for elderly and frail patients. PMID- 23748809 TI - Predictive factors for Child-Pugh score elevation in hepatocellular carcinoma patients treated with conformal radiation therapy: dose-volume histogram analysis. AB - AIMS AND BACKGROUND: We designed the study to identify the clinical and dose volumetric parameters associated with the risk of Child-Pugh score elevation in hepatocellular carcinoma patients treated with conformal radiation therapy. METHODS AND STUDY DESIGN: All 161 hepatocellular carcinoma patients in the study underwent 4D-computed tomography simulation, and a dose-volume histogram was generated after radiotherapy planning. Patients who had an elevated Child-Pugh (e CP) score of 2 or more without progressive disease within 3 months were defined as e-CP positive. RESULTS: Twenty-six of 142 patients without progressive disease were e-CP positive. Pretreatment Child-Pugh class, further treatment within 30 days of radiotherapy, lymph node metastasis, mean liver dose, V(20 Gy), V(25 Gy), and V(30 Gy) were significantly correlated with e-CP positivity. The e-CP developed in 13 of 106 patients (12.3%) with V(30 Gy) of <=28.1% and in 13 of 36 patients (36.1%) with V(30 Gy) >28.1% (P = 0.001). CONCLUSIONS: Our data demonstrate that mean liver dose, V(10 Gy), V(20 Gy), V(25 Gy), and V(30 Gy) are independent dose-volumetric predictors for e-CP positivity in hepatocellular carcinoma patients treated with conformal radiation therapy. V(30 Gy) should be limited to less than 28.1% to minimize the risk of e-CP. PMID- 23748810 TI - Early-stage esophageal squamous cell carcinoma treated with californium-252 neutron brachytherapy: clinical report on 16 cases. AB - AIMS AND BACKGROUND: Californium-252 (252Cf) neutron brachytherapy is a form of high linear energy transfer radiotherapy, which has proven effective when used in combination with external beam radiotherapy to treat intracavitary cancers of the cervix, colon/rectum and esophagus. No study has been reported for treatment of intracavitary cancers with neutron brachytherapy alone. The aim of the study was to observe and analyze the long-term curative effects and complications for early stage thoracic esophageal cancer patients treated with neutron brachytherapy alone. METHODS: From December 2001 to August 2006, 16 patients of early stage squamous cell carcinoma underwent neutron brachytherapy. The total radiation dose to the reference point was 20-28 Gy-eq in 5 to 7 fractions with 4 Gy-eq/fraction. The 1-, 3-, and 5-year follow-up rates were 100%. RESULTS: The 2-, 3-, 4-, and 5 year survival rates were 100%, 87.5%, 87.5%, and 75%, respectively. The early complication rates for grades 1 and 2 radiation esophagitis were 75% and 25%, respectively. The late complication rates for grades 0 and 1 (according to the RTOG/EORTC standard) were 87.5% and 12.5%, respectively. Barium esophagography after treatments confirmed that the complete response rate was 100%. Fourteen patients were confirmed by endoscopy to have either normal mucosa or inflammation change. CONCLUSIONS: Neutron brachytherapy alone was an effective and safe treatment for early stage esophageal squamous cell cancer. PMID- 23748811 TI - Sorafenib acts synergistically in combination with radiotherapy without causing intestinal damage in colorectal cancer. AB - AIMS AND BACKGROUND: Colorectal cancer is one of the commonest cancers. Chemoradiotherapy gives better results than radiotherapy or chemotherapy in colorectal cancer. To enhance radiosensitivity of tumor cells for chemoradiotherapy, targeted therapy drugs that act as radiosensitizers can be used. In the present study, we provide a scientific rationale for the clinical application of sorafenib as a radiosensitizer in colorectal cancer, without causing significant adverse effects on normal intestinal tissue. METHODS: Three human colorectal adenocarcinoma cell lines (HCT116, HT-29, and SW480) were treated with sorafenib alone, or radiation followed by sorafenib. In vitro tests were performed using colony forming assays, cell cycle analysis, and comet assays. In addition, the effects of sorafenib and radiation therapy on the inhibition HT-29 tumor growth and survival of intestinal jejunum crypts were examined in vivo. RESULTS: Sorafenib increased the radiosensitivity of tumor cells in human colon adenocarcinoma cell lines (HCT116, HT-29, and SW480), as well as in HT-29 xenograft animal models. Sorafenib, in combination with ionizing radiation, induced the accumulation of tumor cells in the G2-M phase and delayed the repair of DNA damage caused by ionizing radiation. The combination of sorafenib and ionizing radiation did not enhance the apoptosis of intestinal crypt cells, compared with the use of radiation alone. CONCLUSIONS: We provide a scientific rationale for the use of sorafenib in combination with radiotherapy in colorectal cancer. PMID- 23748812 TI - Primary radiotherapy with endobronchial high-dose-rate brachytherapy boost for inoperable lung cancer: long-term results. AB - BACKGROUND: To retrospectively evaluate the outcome of patients with inoperable non-small-cell lung cancer treated with primary external beam radiotherapy combined with high-dose-rate endobronchial brachytherapy boost. PATIENTS AND METHODS: Between 1988 and 2005, 35 patients with non-small-cell lung cancer (stage I-III) ineligible for surgical resection and/or chemotherapy, were primarily treated with external beam radiotherapy with a median total dose of 50 Gy (range, 46-60). A median of 3 fractions high-dose-rate endobronchial brachytherapy was applied as a boost after external beam radiotherapy, the median total dose was 15 Gy (range, 8-20). High-dose-rate endobronchial brachytherapy was carried out with iridium-192 sources (370 GBq) and prescribed to 1 cm distance from the source axis. RESULTS: With a median follow-up of 26 months from the first fraction of high-dose-rate endobronchial brachytherapy, the 1-, 2- and 5-year overall (local progression-free) survival rates were 76% (76%), 61% (57%) and 28% (42%), respectively. Complete or partial remission rates 6 to 8 weeks after treatment were 57% and 17%, respectively. Significant prognostic favorable factors were a complete remission 6-8 weeks after treatment and a negative nodal status. In patients without mediastinal node involvement, a long-term local control could be achieved with 56% 5-year local progression-free survival. Common Toxicity Criteria grade 3 toxicities were hemoptysis (n = 2) and necrosis (n = 1). One fatal hemoptysis occurred in combination with a local tumor recurrence. CONCLUSIONS: The combination of external beam radiotherapy with high-dose-rate endobronchial brachytherapy boost is an effective primary treatment with acceptable toxicity in patients with non-small-cell lung cancer ineligible for surgical resection and/or chemotherapy. PMID- 23748813 TI - Is two-dimensional field definition sufficient for pelvic node coverage in rectal cancer compared to technical three-dimensional definition? AB - BACKGROUND AND AIM: To assess the effectiveness of the potential advantages with 3-dimensional-based treatment planning versus 2-dimensional pelvic bone-based treatment planning in patients with rectal cancer, controlled for clinical stage. METHODS AND MATERIALS: Areas at risk from computed tomography in 30 patients were delineated: mesorectum, presacral, internal iliac, obturator and external iliac nodes. Two planning target volumes per patient were created: PTV_T3 (M + PSN + ON + IIN) and PTV_T4 (M + PSN + ON + IIN + EIN). Two- and 3-dimensional treatment plans for each planning target volume were calculated. Three analyses were performed: 1) mean volume receiving doses >95% and >105%; according to the percentage of prescribed dose to cover at least 95% of the planning target volume, the treatment plan was defined as optimal dose >95%, acceptable dose between 95% and 90%, inferior dose <90%; 2) comparison of the percentage of volume covered by the dose for 2- vs 3-dimensional; 3) determination of the doses at which the lack of volume coverage started to decrease significantly. RESULTS: For PTV_T3, the following was seen: 1) 2D vs 3D comparison showed optimal PTV_T3 coverage in 76.7% and 96.7%, respectively; 2) 2D vs 3D TP coverage difference was significant between 29%-95% of the total dose; 3) the lack of volume coverage started at 30% for 2D and 89% for 3D. For PTV_T4, the following was seen: 1) 2D vs 3D comparison showed an optimal PTV_T4 coverage in 33.3% and 86.7%, respectively; 2) 2D vs 3D TP coverage difference was significant between 7%-97% of the total dose; 3) the lack of volume coverage started at 7% for 2D and 87% for 3D. CONCLUSIONS: The 3D treatment planning was superior to 2D treatment planning in covering areas at risk for pelvic recurrence in patients treated for rectal cancer. The areas with suboptimal coverage may lead to an increased risk of recurrence and should be correlated with the patterns of recurrence. PMID- 23748814 TI - The role of mammography after breast-conserving surgery and adjuvant chemotherapy. AB - AIMS AND BACKGROUND: To investigate the impact of postchemotherapy mammography on radiotherapy timing and detection of early locoregional recurrences in breast cancer patients treated with breast-conserving surgery and adjuvant chemotherapy. METHODS: Bilateral mammography was performed before radiotherapy. Mammogram assessments were collected using the Breast Imaging Reporting and Data System (BI RADS) scale. Differences in waiting times for radiotherapy between patients who needed further evaluation after mammograms and who did not were tested by the nonparametric Mann-Whitney U test. RESULTS: A total of 277 patients who underwent locoregional restaging after conservative surgery and adjuvant chemotherapy were evaluated. All patients had surgical margins greater than 2 mm. No locoregional recurrences were detected. Only in 2 patients (0.7%) did preradiotherapy mammograms reveal a contralateral breast cancer, which was histologically confirmed. After chemotherapy, the waiting times for radiotherapy were not different between patients who needed further imaging evaluation and patients who did not (34 days, 95% CI: 29-65 vs 38 days, 95% CI: 32-39; P = NS). CONCLUSION: According to these data, postchemotherapy mammography detected a contralateral breast cancer in very few cases (0.7%); thus, even if performing these exams did not delay the start of radiotherapy, we believe that preradiotherapy mammograms are not necessary for patients undergoing adjuvant chemotherapy after breast conserving surgery. PMID- 23748815 TI - Suspecting malignancy in endometrial polyps: value of hysteroscopy. AB - AIMS AND BACKGROUND: Hysteroscopic polypectomy is the gold standard to treat endometrial polyps and obtain specimens for histological evaluation. There is continuing debate as to when to offer hysteroscopic polypectomy, especially in asymptomatic women with incidental lesions. The aims of this study were to assess the accuracy of hysteroscopy and Vabra sampling in diagnosing atypical hyperplasia and cancer growing on the surface of endometrial polyps and to investigate the association between atypical endometrial polyps and some potential clinical risk factors. METHODS AND STUDY DESIGN: This was a retrospective study. We assessed 1039 hysteroscopies and we identified 345 women with endometrial polyps. All patients with endometrial polyps underwent hysteroscopic polypectomy. Data about age, menopausal status, abnormal uterine bleeding (AUB), hormone replacement therapy and tamoxifen use were collected. Hysteroscopic, histological and clinical data were analyzed. RESULTS: The incidence of endometrial hyperplasia or cancer growing on the surface of endometrial polyps was significantly low (1.7%). Hysteroscopy correctly excluded (negative predictive value: 100%) and accurately predicted (positive predictive value: 85.7%) preneoplastic or neoplastic lesions growing within the epithelial layer of endometrial polyps. Vabra sampling was inadequate for the histological diagnosis in 38.5% of cases. Age over 60 years and postmenopausal AUB were associated with an 8.3-fold ( P = 0.022) and 8.8-fold (P = 0.020) increased risk, respectively, of preneoplastic and neoplastic lesions growing on the surface of endometrial polyps. CONCLUSIONS: Diagnostic hysteroscopy is a good tool to predict malignancy of the epithelial layer of endometrial polyps. Age over 60 years and AUB are associated with an increased risk of malignant polyps. Few suspicious endometrial polyps should undergo surgical resection. PMID- 23748816 TI - Value of diffusion-weighted magnetic resonance imaging in the characterization of complex adnexal masses. AB - AIMS AND BACKGROUND: The aim of the study was to define the role of diffusion weighted imaging in the characterization of adnexal complex masses, with particular regard to the distinction between benign and malignant lesions. Conflicting results on this topic have emerged from studies in the last decade, with a consequent substantial limitation to the use of this relatively novel technique in clinical practice. METHODS AND STUDY DESIGN: Magnetic resonance imaging examinations performed on 91 patients with ovarian masses (56 benign, 35 malignant) were retrospectively evaluated by two observers unaware of the final histopathological diagnosis. Diffusion-weighted sequences with b values of 0, 500 and 1000 were performed in all cases, and apparent diffusion coefficient maps were automatically generated. The signals of both the cystic and solid components of the ovarian masses were evaluated on T2-weighted and diffusion-weighted images acquired with a b value of 1000. Apparent diffusion coefficient values were measured in all cases. RESULTS: With regard to the solid components, hypointensity on both the T2-weighted and diffusion-weighted images has proved to be a reliable indicator of benignancy. In contrast, hyperintensity on both sequences was suggestive of malignancy. Signal intensity of the cystic components and apparent diffusion coefficient values of both components have not proven useful in characterization of the masses. CONCLUSIONS: Only the definition of the signal intensities on diffusion-weighted images obtained with the use of high b values on the solid component of a complex adnexal mass is useful to characterize an ovarian mass as benign or malignant. PMID- 23748817 TI - Home artificial nutrition in advanced cancer patients. AB - AIMS AND BACKGROUND: Malnutrition is over 50% in advanced cancer patients and is related to a decreased survival. Cachexia is the first reason for death in 4-23% of cases. The aim of the study was to estimate the appropriateness of the criteria to select patients for home artificial nutrition and its effectiveness to avoid death from cachexia and to improve quality of life in patients with advanced cancer assisted at home by the National Tumor Association (ANT) Foundation. METHODS AND STUDY DESIGN: The criteria for patient selection are: inadequate caloric intake +/- malnutrition; life expectancy >=6 weeks; suitable psycho-physical conditions; informed consent. The measured parameters were sex, age, tumor site, food intake, nutritional status, Karnofsky performance status, indication for home artificial nutrition, type of home artificial nutrition (enteral or parenteral), and survival after starting home artificial nutrition. RESULTS: The ANT Foundation assisted 29,348 patients in Bologna and its province from July 1990 to July 2012. Home artificial nutrition had been submitted to 618 patients (2.1%): enteral to 285/618 (46.1%) and parenteral to 333/618 (53.9%). Access routes for home artificial nutrition were: 39% nasogastric tube, 26% percutaneous endoscopic gastrostomy, 33% digiunostomy, and 2% gastrostomy. The central venous catheters used for home artificial nutrition were: 61% non tunneled, 13 peripherally inserted, 8% partially tunneled, and 18% totally implanted. By July 2012, all the patients had died. Duration of life >=6 weeks was 78% (484/618). Karnofsky performance status was related to survival ( P <0.0001): one month after starting home artificial nutrition, it decreased in 73 patients (12%), was unchanged in 414 (67%), and increased in 131 (21%). CONCLUSIONS: The low incidence of home artificial nutrition over all the patients assisted by the ANT Foundation and the achievement to avoid death from cachexia in 78% prove the efficacy of the criteria of patient selection in order to prevent its excessive and indiscriminate use. It was effective in maintaining and improving the performance status in 88% of patients. Karnofsky performance status is a reliable prognostic index to start home artificial nutrition. PMID- 23748818 TI - Integrating oncology and palliative home care in Italy: the experience of the "L'Aquila per la Vita" Home Care Unit. AB - AIM: To evaluate the efficacy of a home care program, closely integrated with a medical oncology department. PATIENTS AND METHODS: The charts, prospectively recorded, of all the patients treated at home by the "L'Aquila per la Vita" Home Care Unit from August 2006 to December 2011, were reviewed. The number of patients, home accesses, length of the home care, hospital admission, emergency calls, and the place of death were recorded. Data were analyzed considering the origin of the patients (medical oncology department or other). RESULTS: A total of 461 patients was followed at home for a total of 10,503 home accesses (median accesses/patient, 20; range, 1-159). The median length of home care was 76 days (range, 2-643 days). The median was 101 days for patients coming from the medical oncology department and 53 days for patients coming from other origins (P <0.0005). There were 428 emergency calls (4.1% of all the home accesses). Emergency calls accounted for 253 of 7,364 home accesses (3.4%) among patients coming from the medical oncology department and for 175 of 3,139 home accesses (5.6%) among patients coming from other origins (P = 0.00005). Eighty of 461 patients (17.3%) required one in-hospital admission and 19/461 patients (4.1%) more than one. Fifty-nine of 259 (17.8%) patients coming from the medical oncology department and 40 of 186 (26.9%) coming from other origins required in hospital admissions (P = 0.04). A total of 311 patients died (163 coming from the medical oncology department and 148 from other origins). Twenty-eight of 163 (17.1%) coming from the medical oncology department and 52 of 148 (35.1%) coming from other origins died in the hospital (P = 0.0002). CONCLUSIONS: A multidisciplinary and expert team, closely integrated with the hospital, can guarantee a long length of home care, avoiding hospitalization and closing the gap between the patients' preferences and the services offered regarding the place of death. PMID- 23748819 TI - Comparison of three different treatment modalities in the management of cancer cachexia. AB - AIMS AND BACKGROUND: The optimal treatment of cancer cachexia remains unknown. In this study, we compared the efficacy of three different treatment modalities in the management of cancer cachexia. METHODS: Sixty-two assessable cachectic cancer patients were randomized to one of the following three arms: 1) megesterol acetate (MA) plus meloxicam (n = 23); 2) MA plus meloxicam plus oral eicosapentaenoic acid (EPA)-enriched nutritional supplement (n = 21); or 3) meloxicam plus oral EPA-enriched nutritional supplement (n = 18). Treatment duration was 3 months. RESULTS: The treatment arms were well balanced at baseline. The primary efficacy (body weight and lean body mass) and secondary efficacy (body mass index, quality of life, and serum levels of IL-6 and TNF alpha) parameters improved after treatment in all three arms. There were no statistically significant differences between treatment groups in the mean percentage changes in all efficacy parameters from baseline to end of study. CONCLUSIONS: MA plus meloxicam or EPA supplement plus meloxicam may be effective treatment options in the management of cancer cachexia. The combined use of these agents does not provide further advantages. PMID- 23748820 TI - Pilot research for the correlation between the expression pattern of E-cadherin beta-catenin complex and lymph node metastasis in early gastric cancer. AB - AIMS AND BACKGROUND: Early gastric cancer without lymph node metastasis can be treated with minimally invasive endoscopic surgery. Hence, a better modality for predicting lymph node metastasis should be beneficial to early gastric cancer patients who may only require minimally invasive treatment. In vitro, phosphorylation of beta-catenin induces the loss of membranous beta-catenin and E cadherin, subsequently increasing the potential for metastasis. We investigated the behavior of these molecules comparing lymph node metastasis-positive and lymph node metastasis-negative groups, using the specimens from the patients with early gastric cancer. This was a pilot research evaluating the usefulness of combined analysis of these molecules in predicting lymph node metastasis in early gastric cancer. METHODS: The clinicopathological features and immunohistochemical expression patterns of E-cadherin and beta-catenin in the primary lesion were studied retrospectively in 28 patients (lymph node metastasis-positive versus lymph node metastasis-negative: 14 vs 14) selected from 272 patients. These patients underwent radical surgery for the early gastric cancer treatment from April 2000 to March 2004 at our hospital. All patients gave written informed consent to use their tissues for the clinical study. Statistical analyses were performed by the chi-square test and Mann-Whitney test. RESULTS: More loss of membranous E-cadherin was observed in the lymph node metastasis-positive group than in the lymph node metastasis-negative group. Although the finding was slightly more marked in the intestinal than in the diffuse type early gastric cancer, there was no statistical significance. Loss of membranous beta-catenin showed a similar trend and no statistical significance. When we evaluated the expression patterns of both molecules, dual loss of membranous E-cadherin and beta-catenin significantly correlated with lymph node metastasis [dual loss in lymph node metastasis-positive versus lymph node metastasis-negative patients: 12 (86%) vs 6 (43%), P = 0.046]. Additionally, corresponding proportions in intestinal type early gastric cancer were 5 of 6 (83%) vs 0 of 6 (0%), P = 0.015. CONCLUSIONS: Based on our results, the combined analysis of E-cadherin and beta catenin localizations may be helpful to accurately predict lymph node metastasis in intestinal type early gastric cancer. PMID- 23748821 TI - Antitumor effect of Japanese apricot extract (MK615) on human cancer cells in vitro and in vivo through a reactive oxygen species-dependent mechanism. AB - AIMS AND BACKGROUND: MK615 is produced from Japanese apricot and contains several cyclic triterpenes, such as oleanolic and ursolic acids. MK615 was shown to strongly suppress cutaneous in-transit metastasis in a patient with malignant melanoma. The present investigation was undertaken to clarify the antitumor effects of MK615 in vitro and in vivo. METHODS: Several human cancer cell lines were exposed to MK615 for 7 days to examine its antiproliferative effects. The effect of MK615 on in vivo growth of human pancreatic cancer MIAPaCa-2 cells was also examined. RESULTS: MK615 inhibited the growth of several human cancer cell lines in a concentration-dependent way. Pancreatic cancer MIAPaCa-2 cells were highly sensitive to the growth-inhibiting effects of MK615. Treatment with MK615 preferentially induced cell death in human cancer cells while sparing normal cells such as human umbilical vein endothelial cells (HUVEC) and mouse bone marrow cells. When MIAPaCa-2 cells were incubated with MK615 in the presence of antioxidant, growth-inhibition was significantly reduced, and MK615 induced the accumulation of reactive oxygen species in cancer cells but not in HUVEC. MK615, in both the presence and absence of gemcitabine, significantly inhibited the growth of human pancreatic cancer cells as xenografts without apparent adverse effects. CONCLUSIONS: MK615, a supplement produced from Japanese apricot, may have therapeutic value in treating human cancers through a reactive oxygen species-dependent mechanism. PMID- 23748822 TI - Integrin-linked kinase silencing induces a S/G2/M phases cell cycle slowing and modulates metastasis-related genes in SGC7901 human gastric carcinoma cells. AB - BACKGROUND AND AIM: Integrin-linked kinase has been implicated in metastasis of human tumors. Recent studies have also shown that the down-regulation of integrin linked kinase has anti-tumor potential by inhibiting the metastatic potential of several types of cultured human cancer cells. However, the mechanism by which integrin-linked kinase regulates metastasis in human gastric carcinoma is not fully clear. We investigated the effect of integrin-linked kinase deletion on metastasis-associated markers in human gastric carcinoma SGC-7901 cell lines. METHODS: We generated cell lines depleted for integrin-linked kinase. Cell adhesion and invasion were measured by the MTS assay and transwell assay. The cell cycle was measured by flow cytometry. Expression of metastasis-related genes was assessed by reporter assay, quantitative RT-PCR and western blotting. RESULTS: Our data showed an inhibitory effect on cell adhesion and invasion after silencing of integrin-linked kinase. The cell cycle was slowed in S/G2/M phases. Metastasis-related genes E-cadherin, MMP-2/9 and cystatin B, as well as the signaling molecules p-Akt, NF-kappaB, and AP-1 activation, were also modulated. Our results indicate that integrin-linked kinase plays an important role in metastasis of human gastric carcinoma cells. CONCLUSIONS: Down-regulation of integrin-linked kinase resulted in the impairment of the metastatic potential of gastric tumor cells by regulating metastasis-related gene expression, by inhibiting the Akt pathway as well as the activity of transcription factors. Integrin-linked kinase could be used as a potential therapeutic target. PMID- 23748823 TI - Pretreatment CA 15-3 levels do not predict disease-free survival in patients with advanced epithelial ovarian cancer. AB - AIMS: To evaluate the role of pretreatment CA 15-3 levels as a predictor of disease-free survival in patients with advanced epithelial ovarian cancer. METHODS: A cohort of 65 patients with FIGO stage III or IV epithelial ovarian cancer was evaluated. Patients were treated either with primary cytoreductive surgery followed by adjuvant platinum-based chemotherapy or with neoadjuvant chemotherapy with interval debulking surgery. All patients had pretreatment CA 15 3 and CA 125 tumor marker determinations. The patients were divided into a group with elevated CA 15-3 and a group with normal levels. The two groups were compared with regard to clinical and survival measures. RESULTS: The patients' median age was 65 years (range, 37-90); 34 (52%) were at stage III and 31 (48%) at stage IV. CA 15-3 was elevated (>30 units/mL) in 44 (68%) patients, with a median level of 39 units (range, 4-2282). CA 125 was elevated (>35 units/mL) in 61 (94%) patients, with a median level of 947 units (range, 4-30,642). CA 125 and CA 15-3 levels were not correlated (r = 0.015, P = 0.332). The median follow-up was 22 months (range, 3-120 months). Fifty-three (81%) patients had disease recurrence and 43 (66%) died. Survival analysis showed that patients with elevated and normal CA 15-3 levels had similar recurrence-free survival (P = 0.78) and overall survival (P = 0.55). CONCLUSIONS: Although elevated in the majority of patients with advanced epithelial ovarian cancer, CA 15-3 levels are not predictive of survival. PMID- 23748824 TI - Hepatobiliary cystadenoma and cystadenocarcinoma: a single center experience. AB - AIMS AND BACKGROUND: Hepatobiliary cystadenoma and cystadenocarcinoma are rare cystic lesions of the liver. The aim of the study was to discuss the clinical features, diagnostic methods and surgical treatment of hepatobiliary cystadenoma and cystadenocarcinoma in our hospital. METHODS: Six patients with hepatobiliary cystadenomas and four with hepatobiliary cystadenocarcinomas were evaluated. We collected detailed clinical data, and all patients were followed. RESULTS: Three patients of the 6 with cystadenomas and 2 patients of the 4 with cystadenocarcinomas had marked elevation of CA19-9 (average, 707.0 U/ml and 1078.5 U/ml, respectively). CT scan with contrast revealed typical lesions in all 10 cases, i.e., cyst-occupying lesions with separations in the liver. All patients with hepatobiliary cystadenoma were treated by partial hepatectomy. None of them recurred at a mean follow-up of 40 months. Three patients with hepatobiliary cystadenocarcinoma underwent hepatectomy, without recurrence or metastasis at a mean follow-up of 32 months. CONCLUSIONS: Tumor markers (CA19-9) and imaging findings may be helpful for an early diagnosis. Complete resection is still the best choice. Even for hepatobiliary cystadenocarcinoma, considering the low malignant grade, we suggest that for the best prognosis radical excision should be attempted. PMID- 23748825 TI - Transsternal surgical biopsy of a mediastinal mass under local anesthesia. AB - We describe a minimally invasive transsternal surgical approach to obtain biopsies from retrosternal masses under local anesthesia. This original procedure was carried out in a patient with superior vena cava syndrome because she was unfit to undergo a CT-guided biopsy and at high risk for narcosis. In patients with such features this procedure could be preferable to conventional techniques. The transsternal approach is reliable, produces minimal trauma and no risk of pleural or vessel injury, and is very fast. PMID- 23748826 TI - Proton beam radiotherapy: report of the first patient treated at the Centro Nazionale di Adroterapia Oncologica (CNAO) [National Center of Oncologic Hadron Therapy]. AB - Proton beam radiotherapy, an innovative treatment modality, allows delivery of high radiation doses to the target while sparing surrounding healthy structures. The Centro Nazionale di Adroterapia Oncologica (CNAO), equipped with a synchrotron and capable of using both protons and ions, initiated its clinical activity in September 2011. The first treatment of a skull base tumor with protons is reported here. The case of a 26-year-old man with an intracranial low grade chondrosarcoma of the right petroclival junction is discussed with emphasis on technical and clinical details. Two previous surgical interventions had achieved partial removal of the tumor and the patient was treated with protons for residual disease. The prescribed dose was 70 GyE in 35 fractions of 2 GyE. Treatment was completed with minimal acute toxicity consisting of grade 1 alopecia and nausea. Nine months after treatment the disease is locally controlled. Use of high-energy protons at CNAO is a safe and effective means of treating a tumor located near critical normal structures. PMID- 23748827 TI - Using intensity-modulated radiotherapy to spare the kidney in a patient with seminoma and a solitary kidney: a case report. AB - AIMS AND BACKGROUND: Radiotherapy-related kidney injury is multifactorial and influenced by radiation dose-volume distributions, patient-related factors, and chemotherapy. Traditional radiation parameters for the kidney are based on pre intensity-modulated radiotherapy (IMRT) data and focus on limiting the volume receiving high dose. We report a case of testicular seminoma with paraaortic adenopathy in a patient with a solitary kidney treated with radiotherapy. METHODS: A comparison was performed for IMRT and two 3D-conformal techniques. In our case, IMRT reduced the volume of kidney receiving high dose but increased the volume receiving low dose. RESULTS: Given the lack of data for suggesting that large renal volumes treated to low doses would cause excess toxicity, the consensus opinion was to proceed with IMRT. The patient tolerated treatment well without evidence of radiotherapy-related kidney injury. CONCLUSIONS: As patients are treated with increasingly complex techniques such as IMRT, understanding low dose effects and monitoring low dose parameters may become clinically important. PMID- 23748828 TI - A major response to trabectedin in metastatic malignant fibrous histiocytoma of the vertebra: a case report and review of the literature. AB - Malignant fibrous histiocytoma is an aggressive tumor, the most common soft tissue sarcoma of adult age. It is usually located in the extremities and retroperitoneum, and very rarely there is skeletal involvement. Surgery is the preferred treatment in early disease; in advanced disease, chemotherapy is the main therapeutic strategy. We present a 25-year-old female patient diagnosed with a vertebral mass in T5 with a severely compromised spinal cord. She underwent surgical decompression and the pathological findings were consistent with malignant fibrous histiocytoma. After several surgical treatments she had pulmonary progression and was therefore started on chemotherapy. She had a very poor response to most of the administered regimens until she initiated trabectedin 1 mg/m 2 every three weeks. She showed a significant improvement with a major response of the lung metastases. This report indicates that trabectedin is an active drug in advanced, previously treated metastatic malignant fibrous histiocytoma. PMID- 23748829 TI - Malignant transformation of abdominal wall endometriosis: case report and literature review. AB - In recent years we have seen an increase in the frequency of cesarean sections. We present a case report of an endometrioid adenocarcinoma arising from abdominal wall endometriosis in a patient with a history of cesarean sections and describe its diagnostic and therapeutic management. PMID- 23748830 TI - Adenoid cystic carcinoma of the nasopharynx: a case report and a discussion about prognostic factors and the role of local treatments. AB - Adenoid cystic carcinoma (ACC) is a rare epithelioid malignancy. It occurs most frequently in the salivary glands, while its localization in the nasopharynx is rare and few cases have been reported in the literature. We report the case of a 32-year-old woman presenting with ACC of the nasopharynx who was treated with surgery and adjuvant intensity-modulated radiation therapy (IMRT, total dose: 68 Gy) and concomitant chemotherapy (cisplatin 100 mg/m2 on the first and 21st days of IMRT). During irradiation, the patient developed G1 dermatitis and G2 mucositis (RTOG). Clinical and instrumental reevaluation 17 months after the end of radiotherapy did not show any signs of relapse, and she did not show any sign of local mild-severe toxicity. Adjuvant radiotherapy after standard complete surgical resection seems to be effective and well tolerated and should be strongly considered in the multidisciplinary approach to this infrequent carcinoma. PMID- 23748831 TI - A case report of a patient with advanced acinar cell carcinoma of the pancreas: long-term survival with regional, systemic and targeted therapy. AB - Acinar cell carcinoma of the pancreas is an uncommon malignancy for which there are no prospective, randomized data to guide therapy. We describe the clinical course and management of a patient with advanced pancreatic acinar cell carcinoma who is alive seven years after diagnosis using systemic and regional chemotherapies as well as molecularly targeted agents. PMID- 23748832 TI - Intraabdominal follicular dendritic cell sarcoma: a report of three cases and review of the literature. AB - Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm that originates from follicular dendritic cells in lymphoid follicles. FDCS has been increasingly reported in recent years. However, data on FDCS are mostly based on single case reports or case series and its natural history and standard treatment are not clear. To increase the understanding of this rare disease, we report our experience of three cases of FDCS with an analysis of the morphological and immunophenotypic characteristics, clinical course, treatment options and response to treatment. In addition, we reviewed the literature on FDCS. PMID- 23748833 TI - Uncommon synchronous association between ovarian carcinoma and gastrointestinal stromal tumor: a case study and literature review. AB - BACKGROUND: The association of gastrointestinal stromal tumors (GIST) and other cancers is well known, but its synchronous occurrence with gynecological malignancies is very uncommon. Usually, the diagnosis is accidentally established. We describe a patient with GIST and concurrent ovarian cancer and discuss the clinical implications of this finding. CASE REPORT: A 64-year-old woman with a prior diagnosis of ovarian cancer developed a second recurrence after having undergone two operations and adjuvant chemotherapy. While tumor debulking was performed, a small, nonsuspicious lesion was removed from the greater curvature of the stomach. Histology revealed a GIST. CONCLUSION: The association of GIST and ovarian cancer is a rarity and its synchronicity may alter the oncological prognosis and therapy of the patient. PMID- 23748834 TI - Etoposide and temozolomide in combination for the treatment of progressive small cell lung cancer central nervous system metastases: two cases. AB - INTRODUCTION: Progression of central nervous system (CNS) metastases from small cell lung cancer (SCLC) after radiation therapy is associated with a poor prognosis. CASE REPORTS: We present two cases of patients with progressive CNS metastases from SCLC treated with oral temozolomide and etoposide. Sustained clinical responses and radiographic stability were demonstrated. The palliative chemotherapy regimen was well tolerated. DISCUSSION: A regimen of oral temozolomide and etoposide for progressive CNS metastases from SCLC is well tolerated and may be associated with sustained stability of disease. PMID- 23748835 TI - Bilateral pneumothorax complicating cystic metastases of bronchial squamous cell carcinoma under erlotinib. AB - Cystic lung metastases are a rare presentation in non-small cell lung cancer and occurs mainly in squamous cell carcinoma. We present the case of a 57-year-old woman with a lung squamous cell carcinoma and cystic lung metastases, who developed bilateral metachronous pneumothorax while being administered erlotinib in third-line treatment. The apparition of a pneumothorax under chemotherapy is most often the result of tumor necrosis and formation of bronchopleural fistula. However, very few cases have been reported under targeted therapies, and to our knowledge this is the first case under erlotinib. This complication is potentially life-threatening, especially due to the possibility of pneumothorax bilateralization. PMID- 23748836 TI - Combined chemoradiation for head and neck region myxofibrosarcoma of the maxillary sinus. AB - AIMS AND BACKGROUND: Adult sarcomas of the head and neck region (HNSs) are considered a rare clinicopathological entity. They account for only 2-15% of all adult sarcomas and for less than 1% of all head and neck malignancies. The preferred initial treatment option is wide surgical excision. Whenever surgery is considered infeasible, a frontline combined-modality approach including radiotherapy and chemotherapy might be proposed. We here report on a case of localized sarcoma of the maxillary sinus treated with induction chemotherapy and subsequent intensity-modulated radiation therapy (IMRT), achieving a persistent complete remission status. METHODS: A 66-year-old man was referred to our institution hospital for left-sided facial pain with swollen left cheek and ipsilateral facial palsy. Magnetic resonance imaging showed a mass within the left maxillary sinus extending to the orbital floor and adjacent alveolar bones. Histological examination of the biopsy specimen demonstrated a myxofibrosarcoma. The patient underwent induction chemotherapy with gemcitabine 900 mg/m2 (days 1 8) and taxotere 80 mg/m2 every 3 weeks for 3 cycles and sequential simultaneous integrated boost (SIB) IMRT up to a total dose of 70 Gy/35 fractions to the macroscopic disease with 59.5 Gy/35 fractions to the level IB-II lymph nodes in the left neck. RESULTS: Treatment was well tolerated with mild acute toxicity. Complete remission was achieved at restaging MRI 6 months after the end of the combined modality approach. The patient remains in complete, unmaintained clinical and instrumental complete remission 18 months after treatment, with no late side effects. CONCLUSION: Combination therapy with induction chemotherapy and sequential SIB-IMRT could therefore be a promising modality for head and neck sarcomas, allowing for simultaneous tumor control and normal tissue sparing. PMID- 23748837 TI - Mass spectrometry-based identification and characterisation of lysine and arginine methylation in the human proteome. AB - Protein methylation is a post-translational modification (PTM) by which a variable number of methyl groups are transferred to lysine and arginine residues within proteins. Despite increased interest in this modification due to its reversible nature and its emerging role in a diverse set of biological pathways beyond chromatin, global identification of protein methylation has remained an unachieved goal. To characterise sites of lysine and arginine methylation beyond histones, we employed an approach that combines heavy methyl stable isotope labelling by amino acids in cell culture (hmSILAC) with high-resolution mass spectrometry-based proteomics. Through a broad evaluation of immuno-affinity enrichment and the application of two classical protein separation techniques prior to mass spectrometry, to nucleosolic and cytosolic fractions separately, we identified a total of 501 different methylation types, on 397 distinct lysine and arginine sites, present on 139 unique proteins. Our results considerably extend the number of known in vivo methylation sites and indicate their significant presence on several protein complexes involved at all stages of gene expression, from chromatin remodelling and transcription to splicing and translation. In addition, we describe the potential of the hmSILAC approach for accurate relative quantification of methylation levels between distinct functional states. PMID- 23748838 TI - Synthesis, physical properties and cytotoxicity of stilbene-triazine derivatives containing amino acid groups as fluorescent whitening agents. AB - A series of novel stilbene-triazine derivatives containing amino acid groups were synthesized and screened to evaluate their cytotoxicity. The UV absorptions of the derivatives were in the range of 240-450 nm. The absorption peaks of the cis isomers and trans-isomers were in 281-291 nm and 353-361 nm, respectively. Their fluorescence emission peaks of the derivatives were located in the range of 400 650 nm. The whiteness data indicated that all the stilbene-triazine-amino acid derivatives showed excellent whitening effect on cotton fiber compared to untreated cotton. The preliminary cytotoxicity of these derivatives on a mouse fibroblast cell line (L-929 cells) was also investigated. The results showed that the compounds (7a-h) were nontoxic to L-929 cells as fluorescent whitening agents. PMID- 23748839 TI - Posterior thigh flap revisited: clinical use in oncology patients. AB - PURPOSE: The posterior thigh flap is a reliable flap owing to the dependability of the inferior gluteal artery. Its utility for the reconstruction of sacral, perineal, ischial, pelvic, trochanteric and vulvar defects is well established. We herein describe the use of the flap for a variety of indications, and discuss the results with respect to postoperative complications in oncology patients. METHODS: We reviewed nine oncology patients who were treated with pedicled posterior thigh flaps. We assessed the use of this treatment by recording the site of the defect, the type of flap used, and the presence or absence of previous surgical procedures, radiation therapy and postoperative complications. RESULTS: Defects after resection of soft tissue sarcomas were the most common condition (n = 4), followed by skin cancers (n = 2), gastrointestinal cancers (n = 2) and radiation osteomyelitis (n = 1). Six patients (66 %) developed complications; three (33 %) were major and three (33 %) were minor. There was one case of total necrosis of the flap and two cases of partial necrosis. CONCLUSIONS: In oncology patients, the posterior thigh flap is an excellent choice for the reconstruction of sacral, ischial, pelvic or buttock defects, since it does not cause any donor site morbidity. PMID- 23748841 TI - Bilateral persistent sciatic vein: report of a case with developmental, histological and clinical aspects. AB - OBJECTIVE: Bilateral large variant veins were encountered in the lower extremity. It was aimed to identify the structural characteristics of this rare case and then, regarding the structural features, to overview its formation process and denomination. MATERIAL AND METHOD: During the routine dissection of a 93-year-old male cadaver, bilateral large variant veins were found at the thigh. Valves of the veins were examined and evaluated together with the vascular wall histology. RESULTS: The variant vein was loosely attached to the sciatic nerve by fibrous tissue and had anastomoses with the popliteal vein in the popliteal fossa on each side. The popliteal veins were hypoplastic on both sides. The right variant vein was passing through the fibers of the adductor magnus muscle 56.2 mm above the adductor hiatus, which corresponds to the third perforating branch of deep femoral vein. The left one was turning to the front over the adductor magnus muscle, at the lower border of quadratus femoris muscle. The left variant vein was corresponding to the descending branch of the medial circumflex femoral vein. Both variant veins had one incomplete and three well-developed valves. CONCLUSION: In accordance with the findings, the variant vein was concluded to be an embryonic remnant, rather than an acquired one subsequent to any obstruction of the femoral vein. Regarding their connection with the popliteal vein but not with the internal iliac vein, both variant veins were denominated as "lower type persistent sciatic vein". Such a variation would be important with respect to the risk of complication during popliteal sciatic nerve blockade. PMID- 23748840 TI - Variation in Rubisco content and activity under variable climatic factors. AB - The main objective of the present review is to provide a compilation of published data of the effects of several climatic conditions on Rubisco, particularly its activity, state of activation, and concentration, and its influence on leaf gas exchange and photosynthesis. The environmental conditions analyzed include drought, salinity, heavy metals, growth temperature, and elevated [O3], [CO2], and ultraviolet-B irradiance. The results show conclusive evidence for a major negative effect on activity of Rubisco with increasing intensity of a range of abiotic stress factors. This decrease in the activity of Rubisco is associated with down-regulation of the activation state of the enzyme (e.g., by de carbamylation and/or binding of inhibitory sugar phosphates) in response to drought or high temperature. On the contrary, the negative effects of low temperature, heavy metal stress (cadmium), ozone, and UV-B stress on Rubisco activity are associated with changes in the concentration of Rubisco. Notably, in response to all environmental factors, the regulation of in vivo CO2 assimilation rate was related to Rubisco in vitro parameters, either concentration and/or carboxylation, depending on the particular stress. The importance of the loss of Rubisco activity and its repercussion on plant photosynthesis are discussed in the context of climate change. It is suggested that decreased Rubisco activity will be a major effect induced by climate change, which will need to be considered in any prediction model on plant productivity in the near future. PMID- 23748842 TI - Rasch analysis of Impact of Vision Impairment for Children questionnaire. AB - PURPOSE: To validate the Indian-translated Impact of Vision Impairment for Children (IVI_C), a vision-related quality of life (VRQoL) instrument, and to investigate the effect of sociodemographic and ocular characteristics on VRQoL. METHODS: The 24-item IVI_C was administered face to face to 221 children with vision impairment (VI) (mean age, 12.6 years; male, 68%) referred to the Vision Rehabilitation Centres. Rasch analysis was used to investigate the IVI_C for key indices such as measurement precision as measured by person separation (minimum recommended value, 2.0), unidimensionality (i.e., whether all the items contribute toward measurement of a single underlying construct as assessed by item fit and principal component analysis of residuals), targeting of items to participants' VRQoL (i.e., matching of item difficulty to participant ability; ideal targeting, <1.0 logits). Univariate analysis was performed to determine if the person scores of IVI_C were significantly different across participant subgroups stratified by sociodemographic and ocular characteristics, including the severity of VI. RESULTS: The IVI_C showed misfit to the model and lacked unidimensionality. Principal component analysis confirmed the presence of an additional construct, mobility, but it did not possess adequate person separation when assessed individually. Deleting the mobility-related items restored unidimensionality, but additional items misfit, necessitating item reduction. Finally, a 17-item IVI_C possessed good measurement precision (person separation, 2.04), was unidimensional (albeit not purely), and consisted of items that fit the Rasch model and were well targeted to the participants' VRQoL (targeting 0.76 logits). There was no statistically significant difference in the VRQoL across subgroups stratified by age, sex, type of school, cause of VI, duration of vision loss, and severity of VI (p > 0.05 for all). CONCLUSIONS: The revised 17-item IVI_C is shorter and has better psychometric properties than the original version in school-aged children with VI in India, and the responses are unrelated to sociodemographic and clinical variables. Although it has the potential for use in cross-sectional and outcomes research in children with VI, caution should be exercised while interpreting the 17-item IVI_C scores given the presence of slight multidimensionality. PMID- 23748843 TI - Analyzing patient-reported outcomes to improve cataract care. AB - PURPOSE: The purpose of this study was to analyze three models of how patient reported outcome measures can be connected to clinical outcome measures in cataract surgery to identify opportunities for improvement of quality of care. METHODS: Three models were used to analyze the following questions: Is there a relationship between clinical parameters and patient-reported outcomes? (1) Is there a relationship between clinical parameters and a good or poor patient reported outcome? (2) When and why do clinical and patient-reported outcomes diverge? (3) The study material to exemplify these models consisted of follow-up data on cataract extractions collected by the Swedish National Cataract Register in 2008 to 2011. Patient-reported outcome was measured using the Catquest-9SF questionnaire. A total of 9707 pairs of questionnaires completed before and after a cataract extraction were analyzed together with clinical data. RESULTS: Factors related to any change in patient-reported outcomes after surgery were the preoperative self-assessed visual function, the preoperative visual acuity in both eyes, the postoperative visual acuity, and ocular comorbidity. Factors related to poor patient-reported outcomes after surgery were good preoperative self-assessed visual functions, poor preoperative visual acuity in the better eye, ocular comorbidity, surgical complications, and large refractive deviation. Poor near vision after surgery was the main factor noted in situations where the clinical outcome was good and the patient-reported outcome was poor. Analyses 2 and 3 were the most useful analyses to give ideas for clinical improvement work. CONCLUSIONS: The best models to give ideas for improved quality of care by using a patient questionnaire in our study were analyzing the risk factors for a poor patient-reported outcome and analyzing the factors associated with disagreement between clinical outcomes and patient-reported outcomes. PMID- 23748844 TI - Idiopathic elevated episcleral venous pressure with secondary glaucoma. AB - PURPOSE: Idiopathic elevated episcleral venous pressure (IEEVP) is a rare condition that can lead to glaucoma, which can be difficult to manage. This case report aims to educate clinicians on the importance of considering IEEVP in the differential diagnosis of elevated intraocular pressure (IOP) in the presence of engorged episcleral veins. CASE REPORT: We describe a patient who presented to the office with high IOPs in the presence of engorged episcleral veins. We diagnosed the patient with glaucoma and referred the patient to a glaucoma specialist. The elevated IOP became difficult to manage medically, and the patient underwent a trabeculectomy in the right eye. We eventually diagnosed the patient with IEEVP. CONCLUSIONS: Although rare, IEEVP should be considered when the patient presents with elevated IOP in the presence of engorged episcleral veins. Idiopathic elevated episcleral venous pressure is often difficult to manage both medically and surgically. PMID- 23748845 TI - Central anterior chamber depth changes after prophylactic laser iridotomy. AB - PURPOSE: To evaluate the effect of laser peripheral iridotomy (LPI) on biometric parameters including central anterior chamber depth (CACD) in primary angle closure suspect eyes. METHODS: Eyes classified as primary angle closure suspect were enrolled in this interventional case series. Biometry with Lenstar (Haag Streit AG, Koeniz, Switzerland) was performed before LPI and 6 weeks afterward. Central anterior chamber depth, lens thickness, axial length, and central corneal thickness were measured before and after the intervention. RESULTS: Forty eyes of 40 patients with mean age of 56.5 +/- 5.5 years were studied. Mean central anterior chamber depth was 2.07 +/- 0.21 mm before and 2.08 +/- 0.19 mm after LPI (p = 0.8). There was no significant change in lens thickness, axial length, and central corneal thickness after LPI. CONCLUSIONS: Central anterior chamber depth "measured by Lenstar" does not change after LPI in primary angle closure suspect eyes. PMID- 23748846 TI - Demodex. AB - PURPOSE: Demodex folliculorum and Demodex brevis are ectoparasites with an astounding prevalence of 100% in patients aged 70 years and older. Every person in this age group is estimated to carry a colony of 1000 to 2000 mites. With such a high prevalence, little attention has been paid to the mite among eye care practitioners. We demonstrate a clinical sequence in a set of case reports to identify the mite. The clinical sequence includes a clinical history of blepharitis, dry eyes, and/or ocular allergy; slit lamp examination of cylindrical dandruff; and confirmation using light microscope evaluation of epilated lashes. CASE REPORTS: Patient 1 was a 68-year-old woman who demonstrates associations with dry eyes and diabetes. Patient 2 was a 44-year-old man with uncommonly seen D. brevis present. Patient 3 was a 40-year-old woman with dry eyes and allergy, showing mite tails protruding from base of lashes. Patient 4 was a 60-year-old woman who demonstrates the association with rosacea. Patient 5 was a 53-year-old woman intermittently taking topical steroid and antibiotic combination medications, with an actual mite photographed on the surface. CONCLUSIONS: Following a clinical sequence helps identify Demodex, the underdiagnosed, undertreated, and underappreciated ocular surface disease. PMID- 23748847 TI - Predictive value of corneal topography for ClearKone hybrid contact lenses. AB - PURPOSE: The purpose of this study was to evaluate the predictive value of corneal topography data for fitting ClearKone hybrid contact lenses on eyes with corneal ectasia. METHODS: Ophthalmic records from eyes with established corneal ectasia that had been successfully fitted with SynergEyes ClearKone lenses (n = 73) were retrospectively reviewed. Correlations between corneal parameters (simulated steep and flat keratometry values, average corneal sagittal height, inferior-superior index for keratoconus, corneal eccentricity, cone displacement, and cone diameter) and ClearKone lens parameters (vault and skirt curvature) were analyzed. RESULTS: Two topographical correlates to ClearKone lens parameters were identified. Mean weighted corneal sagittal height at a 7.4-mm chord was strongly predictive of the optimal ClearKone lens vault; a linear relationship was observed between these parameters (R = 0.96). More significant vertical decentration of the corneal apex was found to be associated with the need for a steeper lens skirt curvature (p < 0.05). CONCLUSIONS: This study demonstrates that baseline corneal topography-derived data are valuable for predicting lens parameters for an optimally fit SynergEyes ClearKone hybrid contact lens. PMID- 23748848 TI - The effect of multifocal soft contact lenses on peripheral refraction. AB - PURPOSE: To compare changes in peripheral refraction with single-vision (SV) and multifocal (MF) correction of distance central refraction with commercially available SV and MF soft contact lenses (SCLs) in young myopic adults. METHODS: Thirty-four myopic adult subjects were fitted with Proclear Sphere and Proclear Multifocal SCLs to correct their manifest central refractive error. Central and peripheral refraction were measured with no lens wear and subsequently with the two different types of SCL correction. RESULTS: At baseline, refraction was myopic at all locations along the horizontal meridian. Peripheral refraction was relatively hyperopic compared with center at 30 and 35 degrees in the temporal visual field (VF) in low myopes, and at 30 and 35 degrees in the temporal VF, and 10, 30, and 35 degrees in the nasal VF in moderate myopes. Single-vision and MF distance correction with Proclear Sphere and Proclear Multifocal SCLs, respectively, caused a hyperopic shift in refraction at all locations in the horizontal VF. Compared with SV correction, MF SCL correction caused a significant relative myopic shift at all locations in the nasal VF in both low and moderate myopes and also at 35 degrees in the temporal VF in moderate myopes. CONCLUSIONS: Correction of central refractive error with SV and MF SCLs caused a hyperopic shift in both central and peripheral refraction at all positions in the horizontal meridian. Single-vision SCL correction caused the peripheral retina, which initially experienced absolute myopic defocus at baseline with no correction to experience an absolute hyperopic defocus. Multifocal SCL correction resulted in a relative myopic shift in peripheral refraction compared with SV SCL correction. This myopic shift may explain recent reports of reduced myopia progression rates with MF SCL correction. PMID- 23748849 TI - Work-related mechanical risk factors for long-term sick leave: a prospective study of the general working population in Norway. AB - BACKGROUND: The overall evidence for work-related mechanical exposures as risk factors for long-term sick leave (LTSL) in the general working population is limited. METHODS: The study cohort was randomly drawn from the general population in Norway, aged 18-69 years (n = 12 255, response at baseline = 60.9%). Eligible respondents were interviewed in 2009 and were registered with an active employee relationship of at least 100 actual working days in 2009 and 2010 (n = 6758). The outcome of interest was medically confirmed LTSL >=40 working days during 2010. RESULTS: In total, 9.4% (635 individuals) were classified with LTSL during 2010. The risk of LTSL was higher in women, employees with fewer years of education, regular smokers, employees with chronic health complaints and employees with LTSL during 2009. After adjusting for these factors, we estimated that 24.6% of LTSL cases were attributable to work-related mechanical exposure. Mechanical risk factors were neck flexion, hand/arm repetition, standing, working with upper body bent forward and awkward lifting. The odds ratio for highest exposure levels ranged from 1.32 (95% confidence interval 1.04-1.69) for standing to 2.15 (95% confidence interval 1.24-3.73) for awkward lifting. A test for trend was statistically significant for all contributing factors (P <= 0.05), except standing. No psychosocial factors acted as major confounders related to any of the mechanical risk factors. CONCLUSION: This study underlines the importance of work-related mechanical exposures as risk factors for LTSL in the general working population. An exposure-response relationship was indicated for 5 of the 10 factors evaluated. PMID- 23748850 TI - Risk factors for diagnosed intentional self-injury: a total population-based study. AB - BACKGROUND: Few studies investigate predictors of intentional self-injury over time in non-clinical samples. By using longitudinal data from the whole population of the county of Scania, Sweden, aged 18 years and over (N = 936 449), we aim to identify risk factors for non-fatal diagnosed intentional self-injury. Groups at risk of repeat episodes of self-injury will be identified. METHODS: Information on hospital stays and outpatient specialized care visits registered as intentional self-injury was collected from the Region Skane Healthcare database in 2007. These injuries were studied in relation to sociodemographic factors, previous disease, substance abuse and psychotropic drug treatment at baseline. RESULTS: There were increased odds of diagnosed intentional self-injury during follow-up in association with being single, of young or middle age, having low income and being born in the Nordic countries. Presence of neurological or psychiatric disease, substance abuse and previous assault-related injury were also strongly associated with future intentional self-injury. The use of psychotropic drugs showed a clear dose-response relationship with intentional self-injury during follow-up. Those diagnosed with self-injury in the 3-year period before baseline had more than 10 times increased odds of a new episode of intentional self-injury. The odds of repeated episodes of self-injury among subjects born in Europe, but outside Sweden, were less than half those seen for subjects born in Sweden. CONCLUSIONS: The present study, based on a total general population, expands the knowledge base regarding intentional self-injury in adults, repeat behaviour and its associations with sociodemographic variables, substance use and disease in both men and women. PMID- 23748851 TI - Long-term effect of the influenza A/H1N1 pandemic: attitudes and preventive behaviours one year after the pandemic. AB - This study aimed to describe changes in attitudes and behaviours regarding influenza A infection 1 year after the end of the pandemic. A cross-sectional study was performed based on two population-based telephone surveys including 1027 (February, 2010) and 1000 (February, 2011) participants in Spain. The percentages of the respondents who reported that they had adopted preventive measures to avoid Influenza infection declined 1 year after the pandemic. Influenza-related consultations decreased, whereas confidence in vaccination increased. Despite the decrease observed in adopting preventive measures, some behaviours were still being adopted long time after the pandemic in general population. PMID- 23748852 TI - Persistent infection with Crohn's disease-associated adherent-invasive Escherichia coli leads to chronic inflammation and intestinal fibrosis. AB - Crohn's disease is a chronic inflammatory condition of the gastrointestinal tract in which alterations to the bacterial community contribute to disease. Adherent invasive Escherichia coli are associated with human Crohn's disease; however, their role in intestinal immunopathology is unclear because of the lack of an animal model compatible with chronic timescales. Here we establish chronic adherent-invasive Escherichia coli infection in streptomycin-treated conventional mice (CD1, DBA/2, C3H, 129e and C57BL/6), enabling the study of host response and immunopathology. Adherent-invasive Escherichia coli induces an active T-helper 17 response, heightened levels of proinflammatory cytokines and fibrotic growth factors, with transmural inflammation and fibrosis. Depletion of CD8+ T cells increases caecal bacterial load, pathology and intestinal fibrosis in C57BL/6 mice, suggesting a protective role. Our findings provide evidence that chronic adherent-invasive Escherichia coli infections result in immunopathology similar to that seen in Crohn's disease. With this model, research into the host and bacterial genetics associated with adherent-invasive Escherichia coli-induced disease becomes more widely accessible. PMID- 23748853 TI - Deregulated serum concentrations of circulating cell-free microRNAs miR-17, miR 34a, miR-155, and miR-373 in human breast cancer development and progression. AB - BACKGROUND: MicroRNAs (miRs) are small, noncoding RNAs that target genes involved in tumor development and progression. In the current study, we investigated the use of circulating miR concentrations as biomarkers in the serum of breast cancer patients. METHODS: We analyzed serum samples from 120 patients with primary breast cancer after surgery and before chemotherapy (M0, classified into 3 subgroups of 40 patients with progesterone/estrogen-positive, HER2-positive, and triple-negative cancer), 32 patients with overt metastasis (M1), and 40 healthy women. Using quantitative TaqMan MicroRNA PCR, we measured the relative concentrations of 6 circulating microRNAs (miR-10b, -17, -34a, -93, -155, and 373) known to be relevant for tumor development and progression. The data were correlated with clinicopathologic risk factors, with particular reference to HER2 and hormone receptor status of the primary tumor and the presence of metastases. RESULTS: The relative serum concentrations of circulating miR-34a [P = 0.013, area under the curve (AUC) 0.636], miR-93 (P = 0.001, AUC 0.699), and miR-373 (P = 0.0001, AUC 0.879) were significantly different between M0 breast cancer patients and healthy women, whereas miR-17 (P = 0.002, AUC 0.679) and miR-155 (P = 0.0001, AUC 0.781) were differently expressed between M0 and M1 patients. Increased concentrations of miR-373 were associated with negative HER2 status of the primary tumor (P = 0.0001). Deregulated concentrations of miR-17 (P = 0.019) and miR-34a (P = 0.029) were detected in patients with progesterone/estrogen receptor-positive and -negative status, respectively. CONCLUSIONS: Our findings indicate that serum concentrations of deregulated microRNAs may be linked to a particular biology of breast carcinomas favoring progression and metastatic spread. PMID- 23748854 TI - Transcriptomic approach predicts tempo of disease progression in HIV-1 infections. PMID- 23748855 TI - Evaluation of quality improvement performance in the Community Diabetes Education (CoDE) program for uninsured Mexican Americans: results of a randomized controlled trial. AB - The objective of this article is to quantify quality improvement using data from a randomized controlled trial that tested the effectiveness of a community health worker in the primary role of diabetes educator in a clinic serving uninsured Mexican Americans. The intervention group received 7 hours of diabetes education/case management in excess of usual medical care. Of 16 process and outcome measures evaluated, the intervention group was significantly more likely to have received a dilated retinal examination, and 53% achieved a hemoglobin A1c below 7% compared with 38% of the control group participants. Composite quality measures were similar in magnitude with published practice-based benchmarks at study conclusion. This suggests that the overall diabetes care delivered in this clinic serving uninsured patients was comparable to the levels of excellence achieved in other primary care settings. Quantitative measurements of quality improvement can inform health policy regarding the relative effectiveness of diabetes interventions. PMID- 23748857 TI - A race against time: planning postoperative critical care. PMID- 23748856 TI - 13C NMR metabolomic evaluation of immediate and delayed mild hypothermia in cerebrocortical slices after oxygen-glucose deprivation. AB - BACKGROUND: Mild brain hypothermia (32 degrees -34 degrees C) after human neonatal asphyxia improves neurodevelopmental outcomes. Astrocytes but not neurons have pyruvate carboxylase and an acetate uptake transporter. C nuclear magnetic resonance spectroscopy of rodent brain extracts after administering [1 C]glucose and [1,2-C]acetate can distinguish metabolic differences between glia and neurons, and tricarboxylic acid cycle entry via pyruvate dehydrogenase and pyruvate carboxylase. METHODS: Neonatal rat cerebrocortical slices receiving a C acetate/glucose mixture underwent a 45-min asphyxia simulation via oxygen-glucose deprivation followed by 6 h of recovery. Protocols in three groups of N=3 experiments were identical except for temperature management. The three temperature groups were: normothermia (37 degrees C), hypothermia (32 degrees C for 3.75 h beginning at oxygen--glucose deprivation start), and delayed hypothermia (32 degrees C for 3.75 h, beginning 15 min after oxygen-glucose deprivation start). Multivariate analysis of nuclear magnetic resonance metabolite quantifications included principal component analyses and the L1 penalized regularized regression algorithm known as the least absolute shrinkage and selection operator. RESULTS: The most significant metabolite difference (P<0.0056) was [2-C]glutamine's higher final/control ratio for the hypothermia group (1.75+/-0.12) compared with ratios for the delayed (1.12+/-0.12) and normothermia group (0.94+/-0.06), implying a higher pyruvate carboxylase/pyruvate dehydrogenase ratio for glutamine formation. Least Absolute Shrinkage and Selection Operator found the most important metabolites associated with adenosine triphosphate preservation: [3,4-C]glutamate-produced via pyruvate dehydrogenase entry, [2-C]taurine-an important osmolyte and antioxidant, and phosphocreatine. Final principal component analyses scores plots suggested separate cluster formation for the hypothermia group, but with insufficient data for statistical significance. CONCLUSIONS: Starting mild hypothermia simultaneously with oxygen glucose deprivation, compared with delayed starting or no hypothermia, has higher pyruvate carboxylase throughput, suggesting that better glial integrity is one important neuroprotection mechanism of earlier hypothermia. PMID- 23748859 TI - Casein hydrolysate diet controls intestinal T cell activation, free radical production and microbial colonisation in NOD mice. AB - AIMS/HYPOTHESIS: Dietary and microbial factors and the gut immune system are important in autoimmune diabetes. We evaluated inflammatory activity in the whole gut in prediabetic NOD mice using ex vivo imaging of reactive oxygen and nitrogen species (RONS), and correlated this with the above-mentioned factors. METHODS: NOD mice were fed a normal diet or an anti-diabetogenic casein hydrolysate (CH) diet. RONS activity was detected by chemiluminescence imaging of the whole gut. Proinflammatory and T cell cytokines were studied in the gut and islets, and dietary effects on gut microbiota and short-chain fatty acids were determined. RESULTS: Prediabetic NOD mice displayed high RONS activity in the epithelial cells of the distal small intestine, in conjunction with a proinflammatory cytokine profile. RONS production was effectively reduced by the CH diet, which also controlled (1) the expression of proinflammatory cytokines and colonisation dependent RegIIIgamma (also known as Reg3g) in ileum; (2) intestinal T cell activation; and (3) islet cytokines. The CH diet diminished microbial colonisation, increased the Bacteroidetes:Firmicutes ratio, and reduced lactic acid and butyric acid production in the gut. CONCLUSIONS/INTERPRETATION: Epithelial RONS production and proinflammatory T cell activation appears in the ileum of NOD mice after weaning to normal laboratory chow, but not after weaning to an anti-diabetogenic CH diet. Our data suggest a link between dietary factors, microbial colonisation and mucosal immune activation in NOD mice. PMID- 23748860 TI - Hepatic DNA methylation modifications in early development of rats resulting from perinatal BPA exposure contribute to insulin resistance in adulthood. AB - AIMS/HYPOTHESIS: Perinatal exposure to bisphenol A (BPA), a widely distributed environmental endocrine disruptor, is associated with insulin resistance and diabetes in offspring. The underlying molecular mechanisms could involve epigenetics, as adverse effects induced by environmental exposure in early life are suggested through DNA methylation. In this study we sought to elucidate the relationship between perinatal BPA exposure and alteration of hepatic DNA methylation. METHODS: Pregnant Wistar rats were administered BPA (50 MUg/kg/day) or corn oil by oral gavage throughout gestation and lactation. Variables associated with insulin resistance and hepatic DNA methylation were examined at postnatal week 3 and week 21 in male offspring. RESULTS: In BPA-treated offspring, serum insulin and HOMA-insulin resistance were increased, and the insulin sensitivity index and hepatic glycogen storage were decreased compared with controls at week 21. At week 3, none of these variables were significantly changed. However, hepatic global DNA methylation was decreased, accompanied by overexpression of DNA methyltransferase 3B mRNA at week 3. Meanwhile, perinatal exposure to BPA induced promoter hypermethylation and a reduction in gene expression of hepatic glucokinase. Moreover, increased promoter hypermethylation of Gck became more pronounced in BPA-treated offspring at week 21. CONCLUSIONS/INTERPRETATION: Abnormal DNA methylation in hepatic tissue precedes development of insulin resistance induced by perinatal BPA exposure. These findings support the potential role of epigenetics in fetal reprogramming by BPA induced metabolic disorders. PMID- 23748861 TI - Do current incretin mimetics exploit the full therapeutic potential inherent in GLP-1 receptor stimulation? AB - Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are incretin-derived glucose-lowering agents that have been used for the treatment of type 2 diabetes since 2007. Agents such as exenatide (short-acting and once weekly preparations), liraglutide, taspoglutide, albiglutide and lixisenatide lower fasting glucose and HbA1c upon subcutaneous injection, leading to glycaemic control that is equivalent to, or better than, that observed with other oral glucose-lowering agents or bedtime insulin. However, varying proportions of patients report nausea and vomiting, adverse events that typically narrow the therapeutic dose range. Furthermore, GLP-1 RAs reduce fasting glucose to a clinically meaningful extent, but not into the normal range. In contrast, where GLP-1 is administered as a short-term intravenous infusion, a full normalisation of glucose concentrations (approximately 5 mmol/l) has been observed without any risk of gastrointestinal side effects. Subcutaneous infusions or injections of GLP-1 are much less effective. The present analysis relates the proportion of patients who report nausea following treatment with GLP-1 and GLP-1 RAs to the clinical effectiveness of the treatment (represented by the fasting glucose concentration achieved with treatment). The results suggest that GLP-1 RAs injected into the subcutaneous compartment do not exploit the full potential inherent in GLP-1 receptor activation. Reasons for this may include modifications of the peptide molecules in the subcutaneous environment or high local concentrations triggering side effects through GLP-1 receptors on autonomic nerves in subcutaneous adipose tissue. Elucidation of the mechanisms underlying differential responses to GLP 1/GLP-1 RAs administered intravenously vs subcutaneously may help to develop improved agents or modes of administration that are more effective and have fewer side effects. PMID- 23748862 TI - Is forced migration a barrier to treatment success? Similar HIV treatment outcomes among refugees and a surrounding host community in Kuala Lumpur, Malaysia. AB - In response to an absence of studies among refugees and host communities accessing highly active antiretroviral therapy (HAART) in urban settings, our objective was to compare adherence and virological outcomes among clients attending a public clinic in Kuala Lumpur, Malaysia. A cross-sectional survey was conducted among adult clients (>=18 years). Data sources included a structured questionnaire that measured self-reported adherence, a pharmacy-based measure of HAART prescription refills over the previous 24 months, and HIV viral loads. The primary outcome was unsuppressed viral load (>=40 copies/mL). Among a sample of 153 refugees and 148 host community clients, refugees were younger (median age 35 [interquartile range, IQR 31, 39] vs 40 years [IQR 35, 48], p < 0.001), more likely to be female (36 vs 21 %, p = 0.004), and to have been on HAART for less time (61 [IQR 35, 108] vs 153 weeks [IQR 63, 298]; p < 0.001). Among all clients, similar proportions of refugee and host clients were <95 % adherent to pharmacy refills (26 vs 34 %, p = 0.15). When restricting to clients on treatment for >=25 weeks, similar proportions from each group were not virologically suppressed (19 % of refugees vs 16 % of host clients, p = 0.54). Refugee status was not independently associated with the outcome (adjusted odds ratio, aOR = 1.28, 95 % CI 0.52, 3.14). Overall, the proportions of refugee and host community clients with unsuppressed viral loads and sub-optimal adherence were similar, supporting the idea that refugees in protracted asylum situations are able to sustain good treatment outcomes and should explicitly be included in the HIV strategic plans of host countries with a view to expanding access in accordance with national guidelines for HAART. PMID- 23748863 TI - The utility of a composite biological endpoint in HIV/STI prevention trials. AB - A human immunodeficiency virus (HIV) as a biological endpoint in HIV prevention trials may not be feasible, so investigators have used surrogate biological outcomes. In a multisite trial, the epidemiology of STIs may be different across sites and preclude using one STI as the outcome. This study explored using a composite STI outcome to address that problem. The combined biological endpoint was the incidence of any of six new STIs (chlamydia, gonorrhea, trichomonas (women only), syphilis, herpes simplex virus type 2 infection and HIV) during a 24-month follow up period. We investigated how a composite STI outcome would perform compared to single and dual STI outcomes under various conditions. We simulated outcomes for four populations that represented a wide range of sex and age distributions, and STI prevalences. The simulations demonstrated that a combined biologic outcome was superior to single and dual STI outcomes in assessing intervention effects in 82 % of the cases. A composite biological outcome was effective in detecting intervention effects and might allow more investigations to incorporate multiple biological outcomes in the assessment of behavioral intervention trials for HIV prevention. PMID- 23748858 TI - Molecular characterization of the bacterial community in a potato phytosphere. AB - The bacterial community of a potato phytosphere at the flowering stage was examined using both culture-dependent and -independent methods. Tissues (leaves, stems, roots and tubers) were sampled from field-grown potato plants (cultivar Matilda), and the clone libraries of 16S rRNA genes and the isolate collections using R2A medium were constructed. By analyzing the combined data set of 16S rRNA gene sequences from both clone libraries and isolate collections, 82 genera from 8 phyla were found and 237 OTUs (>=97% identity) at species level were identified across the potato phytosphere. The statistical analyses of clone libraries suggested that stems harbor the lowest diversity among the tissues examined. The phylogenetic analyses revealed that the most dominant phylum was shown to be Proteobacteria for all tissues (62.0%-89.7% and 57.7%-72.9%, respectively), followed by Actinobacteria (5.0%-10.7% and 14.6%-39.4%, respectively). The results of principal coordinates analyses of both clone libraries and isolate collections indicated that distinct differences were observed between above- and below-ground tissues for bacterial community structures. The results also revealed that leaves harbored highly similar community structures to stems, while the tuber community was shown to be distinctly different from the stem and root communities. PMID- 23748864 TI - Measurement of carbon nanotube microstructure relative density by optical attenuation and observation of size-dependent variations. AB - Engineering the density of carbon nanotube (CNT) forest microstructures is vital to applications such as electrical interconnects, micro-contact probes, and thermal interface materials. For CNT forests on centimeter-scale substrates, weight and volume can be used to calculate density. However, this is not suitable for smaller samples, including individual microstructures, and moreover does not enable mapping of spatial density variations within the forest. We demonstrate that the relative mass density of individual CNT microstructures can be measured by optical attenuation, with spatial resolution equaling the size of the focused spot. For this, a custom optical setup was built to measure the transmission of a focused laser beam through CNT microstructures. The transmittance was correlated with the thickness of the CNT microstructures by Beer-Lambert-Bouguer law to calculate the attenuation coefficient. We reveal that the density of CNT microstructures grown by CVD can depend on their size, and that the overall density of arrays of microstructures is affected significantly by run-to-run process variations. Further, we use the technique to quantify the change in CNT microstructure density due to capillary densification. This is a useful and accessible metrology technique for CNTs in future microfabrication processes, and will enable direct correlation of density to important properties such as stiffness and electrical conductivity. PMID- 23748869 TI - Pulmonary resection in the treatment of 43 patients with well-localized, cavitary pulmonary multidrug-resistant tuberculosis in Shanghai. AB - OBJECTIVES: Multidrug-resistant tuberculosis (MDR-TB), defined as tuberculosis resistant to at least isoniazid and rifampicin in vitro, poses a significant challenge to the control of TB worldwide. Despite global efforts to control tuberculosis, it remains the leading cause of death from an infectious agent. Although modern tuberculosis treatment relies on chemotherapy, surgery is accepted as adjuvant treatment for multidrug-resistant tuberculosis. METHODS: In a retrospective cohort study, 43 MDR-TB patients (28 males and 15 females: mean age 45.3 years) who underwent pulmonary resection between January 1993 and December 2011 were reviewed. Every patient with well-localized, cavitary lesions showed sputum-positive preoperatively. Individually tailored treatment regimens were selected at a once-weekly staff conference following review of the patient's case history and drug susceptibility results. The variables that affected treatment outcomes were identified through multivariate regression analysis. RESULTS: There was no surgical mortality. Forty (93.0%) patients demonstrated sputum conversion and/or remained negative after surgery. Each patient had completed treatment, and during a mean of 81 follow-up months (range 18-214 months), 1 patient relapsed. This patient was cured after another course of treatment. Operative procedures included 30 (69.8%) lobectomies, 2 (4.7%) bilobectomies, 8 (18.6%) pneumonectomies and 3 (6.98%) lobectomies plus segmentectomy. There were no operation-related deaths, and there were five major postoperative complications (11.6%). Overall, 40 of 43 (93.0%) MDR-TB patients remained free of TB following surgery. The duration of chemotherapy before surgery had correlation with postoperative outcome (P = 0.001). CONCLUSIONS: The proper selection of the patients and early decision for surgical intervention can achieve a high success rate of pulmonary MDR-TB with well-localized pulmonary cavities. PMID- 23748870 TI - Templates of patient brochures for the preparation, administration and safe handling of oral chemotherapy. AB - PURPOSE: The increased use of oral chemotherapy for the treatment of cancer introduces new challenges for patients and caregivers. Among them are the ability to swallow oral solid dosage forms, the proper administration of the agents and the safe-handling of chemotherapeutic drugs in the home. Since these drugs are hazardous, proper preparation, administration, and disposition introduces a variety of safety issues. The increased toxicity of these drugs coupled with complicated dosing regimens and the occasional need to dilute the drug or measure a liquid dosage form require careful instruction of the patient and/or caregivers. The purpose of this project was to create templates for writing patient instruction brochures. METHODS: A group of clinicians specializing in oncology from several institutions in the United States and Canada met through a series of conference calls. The group included pharmacists with a specialty in pediatric oncology, investigational drug pharmacists, and an oncology nurse practitioner. National guidelines and practices at each institution were used for the creation of templates to be used in developing templates for medication and formulation-specific instruction brochures. RESULTS: The group developed six templates. The templates ranged in scope from instructions on the administration of intact tablets or capsules to directions on opening capsules or crushing tablets and mixing the content with foods or liquids. Thirty-three drug-specific brochures were developed using the templates. CONCLUSION: Templates of patient brochures and drug-specific brochures on the safe handling of chemotherapy in the home can be created using a collaborative, multi-institutional approach. PMID- 23748871 TI - Label-free, high-throughput, electrical detection of cells in droplets. AB - Today, droplet based microfluidics has become a standard platform for high throughput single cell experimentation and analysis. However, until now no label free, integrated single cell detection and discrimination method in droplets is available. We present here a microfluidic chip for fast (>100 Hz) and label-free electrical impedance based detection of cells in droplets. The microfluidic glass PDMS device consists of two main components, the droplet generator and the impedance sensor. The planar electrode pair in the main channel allows the detection of only cells and cell containing droplets passing the electrodes using electrical impedance measurements. At a measurement frequency of 100 kHz non viable cells, in low-conducting (LC) buffer, show an increase in impedance, due to the resistive effect of the membrane. The opposite effect, an impedance decrease, was observed when a viable cell passed the electrode pair, caused by the presence of the conducting cytoplasm. Moreover, we found that the presence of a viable cell in a droplet also decreased the measured electrical impedance. This impedance change was not visible when a droplet containing a non-viable cell or an empty droplet passed the electrode pair. A non-viable cell in a droplet and an empty droplet were equally classified. Hence, droplets containing (viable) cells can be discriminated from empty droplets. In conclusion, these results provide us with a valuable method to label-free detect and select viable cells in droplets. Furthermore, the proposed method provides the first step towards additional information regarding the encapsulated cells (e.g., size, number, morphology). Moreover, this all-electric approach allows for all-integrated Lab on a Chip (LOC) devices for cell applications using droplet-based platforms. PMID- 23748872 TI - Cardiac glycosides in cancer therapy: from preclinical investigations towards clinical trials. AB - Cardiac glycosides have a long history in the treatment of cardiac disease. However, several preclinical studies as well as two phase I studies have shown that cardenolides may also possess anticancer effects. The mechanisms of these anticancer effects may include intracellular decrease of K(+) and increase of Na(+) and Ca(2+); intracellular acidification; inhibition of IL-8 production and of the TNF-alpha/NF-kappaB pathway; inhibition of DNA topoisomerase II and activation of the Src kinase pathway. To date three cardiac glycosides have been developed for treatment of cancer and were tested in a phase 1 clinical trial to determine dose limiting toxicities and maximum tolerated dose. Future studies of this novel class of anticancer drugs are warranted to determine their possible role in cancer treatment. PMID- 23748873 TI - Perceived versus predicted risks of colorectal cancer and self-reported colonoscopies by members of mismatch repair gene mutation-carrying families who have declined genetic testing. AB - People carrying germline mutations in mismatch repair genes are at high risk of colorectal cancer (CRC), yet about half of people from mutation-carrying families decline genetic counselling and/or testing to identify mutation status. We studied the association of quantitative measures of risk perception, risk prediction and self-reported screening colonoscopy in this elusive yet high-risk group. The sample of 26 participants (mean age 43.1 years, 14 women) in the Australasian Colorectal Cancer Family Registry were relatives of mutation carriers; had not been diagnosed with any cancer at the time of recruitment and had declined an invitation to attend genetic counselling and/or testing. A structured elicitation protocol captured perceived CRC risk over the next 10 years. Self-reported colonoscopy screening was elicited during a 45-minute semi structured interview. Predicted 10-year CRC risk based on age, gender, known mutation status and family history was calculated using "MMRpro." Mean perceived 10-year risk of CRC was 31 % [95 % CI 21, 40], compared with mean predicted risk of 4 % [2, 7] (p < 0.001); this was independent of age and sex (p = 0.9). Among those reporting any medical advice and any screening colonoscopy (n = 18), those with higher risk perception had less frequent colonoscopy (Pearson's r = 0.49 [0.02, 0.79]). People who decline genetic testing for CRC susceptibility mutations perceive themselves to be at substantially higher risk than they really are. Those with high perceived risk do not undertake screening colonoscopy more often than those who perceive themselves to be at average risk. PMID- 23748874 TI - Knowledge of and interest in genetic results among Parkinson disease patients and caregivers. AB - The purpose of the study is to investigate Parkinson disease (PD) patients' and caregivers' knowledge of and interest in genetic testing. Gaucher disease (GD) results from recessive mutations in glucocerebrosidase (GBA). Both heterozygote GBA carriers and GD patients are at greater risk for PD. Studies regarding knowledge of and interest in genetic testing have been limited and have not offered genetic results to participants. In this study, 353 PD patients and 180 caregivers were recruited to a PD genetic study. The association between GD, GBA mutations and PD was described to participants who reported their familiarity with genetic terms, answered questions on genetic concepts, and indicated their interest in knowing if they may have GD (two GBA mutations) and other genetic information that could impact their health. Ninety-three-percent of participants were interested in receiving GBA results; however, only 51.6 % of PD participants and 55.6 % of caregivers knew that "scientists have identified genes associated with a higher risk of developing PD." PD patients may benefit from education and genetic counseling on the implications of genetic testing. PMID- 23748875 TI - Diagnostic use of the endomyocardial biopsy: a consensus statement. AB - The Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology created a task force to write a consensus document on when and how endomyocardial biopsy is of help for clinicians in the diagnosis and treatment of patients with heart failure, arrhythmias, and cardiac masses. Endomyocardial biopsy is the gold standard for a definitive diagnosis in disease entities like myocarditis, cardiac allograft rejection, and infiltration/storage myocardial disorders. Use of molecular biology techniques is mandatory to obtain specific information on etiology and pathogenesis and should be carried out as an investigation complementary to histology and immunohistochemistry. Given the complexity of these investigations, endomyocardial biopsy should be performed in or in collaboration with cardiac pathology referral centers, where the whole armamentarium of pathological investigation is available, including molecular techniques. Optimal use of the endomyocardial biopsy requires clinicopathologic correlations. PMID- 23748876 TI - Platelet derived growth factor receptor-beta (PDGFRbeta) expression is limited to activated stromal cells in the bone marrow and shows a strong correlation with the grade of myelofibrosis. AB - Platelet derived growth factor receptor (PDGFR) is a membrane tyrosine-kinase receptor required for fibroblast activation in stromal proliferations. In order to assess the role of PDGFR in myelofibrosis (MF) we determined in 60 bone marrow biopsies the occurrence and distribution of its alpha and beta subunits in normal and fibrotic bone marrow stroma using immunohistochemistry, and compared this with the grade of MF determined by Gomori's silver impregnation. PDGF receptor subunits were found to be differentially expressed in the marrow parenchyma. PDGFRalpha expression identified megakaryocytes, endosteal and endothelial cells while PDGFRbeta was virtually absent from inter-trabecular spaces in normal marrow. Activated fibroblasts characteristic for MF intensely expressed PDGFRbeta but only a moderate increase in PDGFRalpha expression was seen. Semi-quantitative PDGFRbeta immunoreactivity scores correlated well with the grade of MF in the vast majority of the MF cases (Spearman r= 0.83). Altogether, 21/60 (35.0%) cases showed a relative increase of PDGFRbeta expression, compared to the MF grade, suggesting that increased stromal PDGFRbeta expression occurs early and precedes reticulin and collagen fiber production during fibroblast activation. In conclusion, bone marrow PDGFRbeta expression closely correlates with the grade of MF. Increased immunoreactivity for PDGFRbeta occurs already in the prefibrotic stage of the disease and might allow a functional classification of the bone marrow stromal reaction. PMID- 23748877 TI - p53 mutations may be involved in malignant transformation of giant cell tumor of bone through interaction with GPX1. AB - Giant cell tumor of bone (GCTB) is a benign tumor with a tendency for local recurrence. Secondary malignant GCTB is rare, occurring in less than 2 % of GCTB cases. Mechanisms of malignant transformation of GCTB remain unclear. We examined 43 cases of GCTB (38 conventional cases, two lung implantation cases, and three secondary malignant cases) for p53 gene mutations and for loss of heterozygosity (LOH) of p53 when corresponding normal tissue was available. In addition, to elucidate the possible involvement of p53, GPX-1, cyclinD1, and Ki-67 in malignant transformation of GCTB, we assessed the expression of these proteins by immunohistochemistry. Mutations or LOH of p53 were found in all three malignant cases, which also showed p53 overexpression. Non-synonymous p53 mutations were detected in seven of 38 conventional cases (18 %), although none of these showed p53 overexpression, defined as more than 10 % of cells being positive. LOH at the p53 locus was detected in eight of 37 informative cases, although this was not associated with p53 overexpression in conventional GCT. Expression of GPX-1 was higher in the recurrent group, which included metastatic and malignant cases, and patients with high GPX-1 expression were at greater risk for early relapse. We also observed a positive correlation between high p53 expression and high GPX-1 expression in GCTB. Given that GPX-1 is shown to be a target of p53, these results suggest that p53 mutations play a role in tumor recurrence and malignant transformation of GCTB through interactions with GPX-1. PMID- 23748878 TI - Measurement of tension release during laser induced axon lesion to evaluate axonal adhesion to the substrate at piconewton and millisecond resolution. AB - The formation of functional connections in a developing neuronal network is influenced by extrinsic cues. The neurite growth of developing neurons is subject to chemical and mechanical signals, and the mechanisms by which it senses and responds to mechanical signals are poorly understood. Elucidating the role of forces in cell maturation will enable the design of scaffolds that can promote cell adhesion and cytoskeletal coupling to the substrate, and therefore improve the capacity of different neuronal types to regenerate after injury. Here, we describe a method to apply simultaneous force spectroscopy measurements during laser induced cell lesion. We measure tension release in the partially lesioned axon by simultaneous interferometric tracking of an optically trapped probe adhered to the membrane of the axon. Our experimental protocol detects the tension release with piconewton sensitivity, and the dynamic of the tension release at millisecond time resolution. Therefore, it offers a high-resolution method to study how the mechanical coupling between cells and substrates can be modulated by pharmacological treatment and/or by distinct mechanical properties of the substrate. PMID- 23748879 TI - Colon anastomotic leakage: improving the mouse model. AB - PURPOSE: Colon anastomotic leakage remains a serious and common surgical complication. Animal models are valuable to determine the pathophysiological mechanisms and to evaluate possible methods of prevention. The aim of this study was to develop an optimal model of clinical colon anastomotic leakage in a technically insufficient anastomosis in the mouse. METHODS: A total of 110 mice were used in three pilot studies (1-3) and two experiments (A, B). Due to the high complication rates, the analgesic regimen and surgical techniques were changed throughout the pilot studies/experiments. In the final successful experiment (B), eight and four absorbable sutures were used in the control and intervention anastomoses, respectively, and buprenorphine in chocolate spread was used for pain treatment. RESULTS: In the final model (experiment B), significantly more animals in the intervention group had clinical anastomotic leakage compared with controls (40 vs. 0 %, p = 0.003). The weight loss was greater and the wellness score was also lower in these animals (p < 0.001). The breaking strength of the anastomoses was not significantly different between the control group [0.55 N +/- 0.09] and intervention group [0.49 N +/- 0.15] (p = 0.091). CONCLUSIONS: This mouse model closely mimics clinical colon anastomotic leakage in humans. The model is of high clinical relevance, since anastomotic leakage has a similar cause, incidence and manifestations in humans. PMID- 23748880 TI - Imaging studies in extramedullary hematopoiesis of the spleen. PMID- 23748881 TI - Lymphoma-associated paraneoplastic digital ischemia. PMID- 23748882 TI - Follow-up of patients receiving rituximab for diffuse large B cell lymphoma: an overview of systematic reviews. AB - The advent of rituximab has significantly improved the clinical outcomes of patients with diffuse large B cell lymphoma (DLBCL). Although rituximab is considered safe and effective, data on its long-term use are limited, which suggests that patients should undergo systematic, long-term follow-up aiming to identify delayed or yet undescribed adverse reactions and optimize treatment effectiveness. This study presents an overview of systematic reviews of strategies for follow-up of DLBCL patients receiving rituximab and documents the current state of knowledge on efficacy and safety in this population. A highly sensitive strategy was used to identify systematic reviews of randomized clinical trials (RCTs) in the Cochrane Library, Embase, Lilacs, MEDLINE, and Scirus databases. A handsearch of medical and government agency websites was also conducted. Seven studies were included, among them there were RCTs of patients who used CHOP/CHOP-like chemotherapy plus rituximab for three to eight cycles every 14 to 21 days as induction therapy, whereas some studies used maintenance therapy for 3 to 24 months. Only one study described a follow-up model for management of adverse drug reactions. The benefits of rituximab for induction therapy of DLBCL were demonstrated, although there is no evidence of significant improvement in the overall survival of high-risk patients or those with HIV related lymphoma. Rituximab therapy was associated with increased rates of fever, infection, and grade 3/4 hematological toxicity, as well as higher infection related mortality in HIV-positive patients. Although one study addressed the management of adverse reactions to rituximab, our search did not yield any publications on systematic follow-up strategies for these patients. This finding suggests that such instruments should be developed and validated to optimize the effectiveness and long-term safety of novel therapies. PMID- 23748883 TI - Isolation of fucoxanthin and highly unsaturated monogalactosyldiacylglycerol from brown alga Fucus evanescens C Agardh and in vitro investigation of their antitumor activity. AB - Fucoxanthin (FX) and highly unsaturated monogalactosyldiacylglycerol (MGDG) were isolated from the ethanol extract of brown alga Fucus evanescens. Their structures were identified by nuclear magnetic resonance, complemented by electrospray ionization mass spectrometry (ESIMS). MGDG was identified as 1-O (5Z,8Z,11Z,14Z,17Z-eicosapentanoyl)-2-O-(6Z,9Z,12Z,15Z-octadecatetraenoyl)-3-O beta-D-galactopiranosyl-sn-glycerol. Antitumor activity of these compounds was tested on human melanoma (SK-MEL-28) cells. MGDG and FX inhibited the growth of human melanoma cells in a dose-dependent manner. IC50 values for growth inhibition were 104 and 114 MUM, correspondently. PMID- 23748884 TI - Recommendations for international gambling harm-minimisation guidelines: comparison with effective public health policy. AB - Problem gambling represents a significant public health problem, however, research on effective gambling harm-minimisation measures lags behind other fields, including other addictive disorders. In recognition of the need for consistency between international jurisdictions and the importance of basing policy on empirical evidence, international conventions exist for policy on alcohol, tobacco, and illegal substances. This paper examines the evidence of best practice policies to provide recommendations for international guidelines for harm-minimisation policy for gambling, including specific consideration of the specific requirements for policies on Internet gambling. Evidence indicates that many of the public health policies implemented for addictive substances can be adapted to address gambling-related harms. Specifically, a minimum legal age of at least 18 for gambling participation, licensing of gambling venues and activities with responsible gambling and consumer protection strategies mandated, and brief interventions should be available for those at-risk for and experiencing gambling-related problems. However, there is mixed evidence on the effectiveness of limits on opening hours and gambling venue density and increased taxation to minimise harms. Given increases in trade globalisation and particularly the global nature of Internet gambling, it is recommended that jurisdictions take actions to harmonise gambling public health policies. PMID- 23748885 TI - Characterization of mercury-containing protein in human plasma. AB - Characterization of mercury binding protein in the human body is very important for understanding the metabolism and the mechanism of toxication of ingested mercuric compounds. In this study, mercury-containing protein in human plasma was separated by on-line heart-cutting two-dimensional high performance liquid chromatography (2D-HPLC). This 2D separation system used size exclusion liquid chromatography (SEC) followed by weak anion exchange liquid chromatography (WAX) and the two LC parts were coupled by a six-port valve equipped with a storage loop and controled by the computer. The WAX effluent was determined by both UV detection and inductively coupled plasma-mass spectrometry (ICP-MS) to locate the mercury-containing protein. A unique mercury-containing protein fraction was obtained by 2D-HPLC separation and subsequently identified by HPLC coupled with linear ion trap-Fourier transform ion cyclotron resonance mass spectrometry (HPLC LTQ-FT). The database search confirmed that the mercury-containing protein in the human plasma is human serum albumin (HSA). The stoichiometry and thermodyamics interaction of inorganic mercury (Hg(2+)) with HSA was studied by isothermal titration calorimetry (ITC) and two binding types were observed. Mercury containing protein in human plasma was separated and identified in the present study and it is important for understanding the metabolism of mercury in the human body. PMID- 23748886 TI - An investigation of enhanced mercury bioaccumulation in fish from offshore feeding. AB - We investigated the dietary pathways of mercury transfer in the food web of Morency Lake (Canada) to determine the influence of carbon source and habitat use on mercury bioaccumulation in fish. Whole-body concentrations of methylmercury (MeHg) were significantly different in four fish species (white sucker, brown bullhead, pumpkinseed and smallmouth bass) and increased with both trophic position and greater feeding on offshore (versus littoral) carbon. An examination of fish gut contents and the depth distribution of invertebrates in Morency Lake showed that smallmouth bass and brown bullhead were supplementing their littoral diet with the consumption of either opossum shrimp (Mysis diluviana) or profundal amphipods in offshore waters. The zooplanktivore Mysis had significantly higher MeHg concentrations than zooplankton and benthic invertebrates, and it was an elevated source of MeHg to smallmouth bass. In contrast, profundal amphipods consumed by brown bullhead did not have higher MeHg concentrations than littoral amphipods. Instead, partitioning of benthic invertebrate resources likely explains the greater MeHg bioaccumulation in brown bullhead, associated with offshore feeding of amphipods. White sucker and brown bullhead had a similar trophic position but white sucker consumed more chironomids, which had one-third the MeHg concentration of amphipods. Our findings suggest that offshore feeding in a lake can affect fish MeHg bioaccumulation via two different processes: (1) the consumption of MeHg-enriched pelagic prey, or (2) resource partitioning of benthic primary consumers with different MeHg concentrations. These observations on the mechanisms of habitat-specific bioaccumulation highlight the complexity of MeHg transfer through lake food webs. PMID- 23748887 TI - Anxiety and depression in the general population in Colombia: reference values of the Hospital Anxiety and Depression Scale (HADS). AB - PURPOSE: The objective of this study was to generate normative values and to test psychometric properties of the Hospital Anxiety and Depression Scale (HADS) for the general population of Colombia. While there are several normative studies in Europe, Latin American normative values are missing. The identification of people with mental distress requires norms obtained for the specific country. METHODS: A representative face-to-face household study (n = 1,500) was conducted in 2012. The survey questionnaire contained the HADS, several other questionnaires, and sociodemographic variables. RESULTS: HADS mean values (anxiety: M = 4.61 +/- 3.64, depression: M = 4.30 +/- 3.91) were similar to those reported from European studies. Females were more anxious and depressed than males. The depression scale showed a nearly linear age dependency with increasing scores for old people. Mean scores and percentiles (75 and 90%) are presented for each age decade for both genders. Both anxiety and depression correlated significantly with the total score of the multidimensional fatigue inventory and with the mental component summary score of the quality of life questionnaire SF-8. Internal consistency coefficients of both scales were satisfying, but confirmatory factorial analysis results only partially supported the two-dimensional structure of the questionnaire. CONCLUSION: This study supports the reliability of the HADS in one Latin American country. The normative scores can be used to compare a patient's score with those derived from a reference group. However, the generalizability to other Latin American regions requires further research. PMID- 23748888 TI - Mesenchymal stem cells as an alternative for Schwann cells in rat spinal cord injury. AB - BACKGROUND: Spinal cord has a limited capacity to repair; therefore, medical interventions are necessary for treatment of injuries. Transplantation of Schwann cells has shown a great promising result for spinal cord injury (SCI). However, harvesting Schwann cell has been limited due to donor morbidity and limited expansion capacity. Furthermore, accessible sources such as bone marrow stem cells have drawn attentions to themselves. Therefore, this study was designed to evaluate the effect of bone marrow-derived Schwann cell on functional recovery in adult rats after injury. METHODS: Mesenchymal stem cells were cultured from adult rats' bone marrow and induced into Schwann cells in vitro. Differentiation was confirmed by immunocytochemistry and RT-PCR. Next, Schwann cells were seeded into collagen scaffolds and engrafted in 3 mm lateral hemisection defects. For 8 weeks, motor and sensory improvements were assessed by open field locomotor scale, narrow beam, and tail flick tests. Afterwards, lesioned spinal cord was evaluated by conventional histology and immunohistochemistry. RESULTS: In vitro observations showed that differentiated cells had Schwann cell morphology and markers. In this study, we had four groups (n = 10 each): laminectomy, control, scaffold and scaffold + Schwann cells. Locomotor and sensory scores of cell grafted group were significantly better than control and scaffold groups. In histology, axonal regeneration and remyelination were better than control and scaffold groups. CONCLUSION: This study demonstrates that bone marrow-derived Schwann cells can be considered as a cell source for Schwann cells in SCI treatment. PMID- 23748890 TI - Identification and characterization of metallo-beta-lactamases producing Pseudomonas aeruginosa clinical isolates in University Hospital from Zanjan Province, Iran. AB - BACKGROUND: Infectious by Pseudomonas aeruginosa has spread worldwide and metallo beta-lactamases (MBL) are being reported with increasing frequency. The aim of this study was to investigate the antibiotic susceptibility and distribution of blaVIM and blaIMP genes in P. aeruginosa isolates from Zanjan Province of Iran. METHODS: A total of 70 P. aeruginosa isolates were identified from patients admitted at intensive care units. The antimicrobial susceptibility was tested by disk diffusion (Kirby-Bauer) method and for production of MBL using double-disk synergy test (DDST). After DNA extraction, the presence of blaVIM and blaIMP genes and class 1 integron were detected by PCR. RESULTS: Most of the isolates were resistant to meropenem, cefotaxime and imipenem (IPM). Also, 44/70 (62.85%) IPM resistant isolates were confirmed by DDST. Of the 44 clinical isolates, 41 (93%) isolates showed MIC>=4 ug/ml for IPM. Based on the DDST results, 36 (87.8%) were confirmed to be MBL producers. PCR amplification showed that 23/41 (56%) carried blaVIM and 10/41 (24.3%) possessed blaIMP gene. Also, 31/44 (70.5%) isolates contained class 1 integron gene. CONCLUSION: Our results highlight that the genes for Verona integron-encoded metallo-beta-lactamase, IPM beta-lactamases and class 1 integrons were predominantly present among the IPM-resistant P. aeruginosa tested in our province and also the frequency of blaVIM type is higher than blaIMP. This is the first report of P. aeruginosa strains producing blaIMP with high frequency from Zanjan province of Iran. PMID- 23748889 TI - The effect of vitrification and in vitro culture on the adenosine triphosphate content and mitochondrial distribution of mouse pre-implantation embryos. AB - BACKGROUND: The mitochondria are an important source of adenosine triphosphate (ATP) production in pre-implantation embryo. Therefore, the objective of this study was to investigate the effect of vitrification and in vitro culture of mouse embryos on their mitochondrial distribution and ATP content. METHODS: The embryos at 2-PN, 4-cell and blastocyst stages were collected from the oviduct of stimulated pregnant mice and uterine horns. Then, the embryos were vitrified with the cryotop method using ethylene glycol and dimethylsulphoxide. After evaluating the survival rates of vitrified embryos, their development to hatching stages were assessed. The ATP content of collected in vivo and in vitro embryos at different stages was measured by luciferin-luciferase bioluminescence assay. The distribution of mitochondria was studied using Mito-tracker green staining under a fluorescent microscope. RESULTS: The survival rates of vitrified embryos at 2 PN, 4-cell and early blastocyst stages were 84.3, 87.87 and 89.89%, respectively. The hatching rates in previous developmental stages in vitrified group were 57.44, 66.73 and 70.89% and in non-vitrified group were 66.32, 73.25 and 75.89%, respectively (P>0.05). The ATP content of in vivo or in vitro collected embryos was not significantly different in both vitrified and non-vitrified groups (P>0.05). Mitochondrial distribution of vitrified and non-vitrified 2-PN embryos was similar, but some clampings or large aggregation of mitochondria within the vitrified 4-cell embryos was prominent. CONCLUSIONS: Vitrification method did not affect the mouse embryo ATP content. Also, the cellular stress was not induced by this procedure and the safety of vitrification was shown. PMID- 23748891 TI - Chronic Ritalin administration during adulthood increases serotonin pool in rat medial frontal cortex. AB - BACKGROUND: Ritalin has high tendency to be abused. It has been the main indication to control attention deficit hyperactivity disorder. The college students may seek for it to improve their memory, decrease the need for sleep (especially during exams), which at least partially, can be related to serotonergic system. Therefore, it seems worthy to evaluate the effect of Ritalin intake on mature brain. There are many studies on Ritalin effect on developing brain, but only few studies on adults are available. This study was undertaken to find Ritalin effect on serotonin transporter (SERT) density in medial frontal cortex (MFC) of mature rat. METHODS: Thirty male Wistar rats were used in the study. Rats were assigned into five groups (n = 6 per group): one control, two Ritalin and two vehicle groups. Twelve rats received Ritalin (20 mg/kg/twice a day) orally for eleven continuous days. After one week of withdrawal and another two weeks of rest, in order to evaluate short-term effects of Ritalin, six rats were sacrificed. Another six rats were studied to detect the long-term effects of Ritalin; therefore, they were sacrificed 12 weeks after the previous group. The immunohistochemistry was performed to evaluate the results. RESULTS: Immunohistochemistry studies showed a higher density of SERT in both 2 and 12 weeks after withdrawal from Ritalin intake in MFC of rat and there was no significant difference between these two groups. CONCLUSIONS: Our findings demonstrated both short- and long-term effects of Ritalin on frontal serotonergic system after withdrawal period. PMID- 23748892 TI - Transplanting p75-suppressed bone marrow stromal cells promotes functional behavior in a rat model of spinal cord injury. AB - BACKGROUND: Bone marrow stromal cells (BMSC) have been successfully employed for movement deficit recovery in spinal cord injury (SCI) rat models. One of the unsettled problems in cell transplantation is the relative high proportion of cell death, specifically after neural differentiation. According to our previous studies, p75 receptor, known as the death receptor, is only expressed in BMSC in a time window of 6-12 hours following neural induction. Moreover, we have recently reported a decreased level of apoptosis in p75-suppressed BMSC in vitro. Therefore, our objective in this research was to explore the functional effects of transplanting p75:siRNA expressing BMSC in SCI rats. METHODS: Laminectomy was performed at L1 vertebra level to expose spinal cord for contusion using weight drop method. PBS-treated SCI rats (group one) were used as negative controls, in which cavitations were observed 10 weeks after SCI. pRNA-U6.1/Hygro- (group two, as a mock) and pRNA-U6.1/Hygro-p75 shRNA- (group three) transfected BMSC were labeled with a fluorescent dye, CM-DiI, and grafted into the lesion site 7 days after surgery. The Basso-Beattie-Bresnehan locomotor rating scale was performed weekly for 10 weeks. RESULTS: There was a significant difference (P<=0.05) between all groups of treated rats regarding functional recovery. Specifically, the discrepancy among p75 siRNA and mock-transfected BMSC was statistically significant. P75 siRNA BMSC also revealed a higher level of in vivo survival compared to the mock BMSC. CONCLUSION: Our data suggest that genetically modified BMSC that express p75:siRNA could be a more suitable source of cells for treatment of SCI. PMID- 23748893 TI - Colony forming unit endothelial cells do not exhibit telomerase alternative splicing variants and activity. AB - INTRODUCTION: Endothelial progenitor colony forming unit-endothelial cells (CFU EC) were first believed to be the progenitors of endothelial cells, named endothelial progenitor cells. Further studies revealed that they are monocytes regulating vasculogenesis. The main hindrance of these cells for therapeutic purposes is their low frequency and limited replicative potentials. This study was undertaken to determine telomerase activity and alternative splicing variants in CFU-EC as a potential cause of limited replicative capacity in these cells. METHODS: CFU-EC were isolated from peripheral blood using a standard cell culture assay. Colonies were detached mechanically and alternative splicing variant mRNA were evaluated using real-time PCR. Telomerase enzyme activity was assessed using telomerase repeat amplification protocol. The same procedures were done on the cancer cell line Calu6 as the positive control. RESULTS: The cultured peripheral blood mononuclear cells formed colonies with spindle-shaped monocytic cells sprouted from the clusters. These morphological characteristics fulfill the definition of CFU-EC. Telomere length amplification protocol assay revealed no telomerase activity and real-time PCR showed no expression of telomerase enzyme mRNA in CFU-EC. Both parameters were significantly higher in the cancer cell line Calu6 taken as the positive control. CONCLUSION: The absence of telomerase activity in the CFU-EC is a result of pre-transcriptional regulation of gene expression rather than other mechanisms for controlling telomerase activity such as post-transcriptional modifications. This finding can explain the limited proliferative activity of CFU-EC cells. We propose that absence of telomerase activity in CFU-EC can be attributable to their more mature monocytic nature that needs further investigations. PMID- 23748894 TI - Effects of atorvastatin on the hypertension-induced oxidative stress in the rat brain. AB - BACKGROUND: It is well known that the development of brain oxidative stress is one of the most serious complications of arterial hypertension that evokes brain tissue damage. The aim of this study was to examine the effects of atorvastatin treatment (20 mg/kg/day), as an antioxidant, to prevent the brain tissue oxidative stress in the hypertensive (HTN) rats. METHODS: Experiments were performed in four groups of rats (n = 5 each group): sham, sham-treated, HTN and HTN treated. Rats were made HTN by aortic constriction above the renal arteries. After 30 days, rats were slaughtered under deep anesthesia to remove brain hemispheres. After tissue homogenization, enzyme activities of superoxide dismutase (SOD) and catalase (CAT), as well as glutathione (GSH) content and malondialdehyde (MDA) level were determined by biochemical methods. RESULTS: In HTN rats, arterial blood pressure was increased about 40% and brain enzyme activities of SOD and CAT were significantly decreased compared with sham group. Induction of hypertension significantly decreased GSH content and increased MDA level of brain tissue. Treatment with atorvastatin enhanced the activity of SOD and prevented from GSH decrement during hypertension. CONCLUSION: Based on the findings of this study, treatment with atorvastatin might have saved the brain tissue of HTN rats from hypertension-induced oxidative stress. PMID- 23748895 TI - Human granulocyte colony-stimulating factor (hG-CSF) expression in plastids of Lactuca sativa. AB - BACKGROUND: Human granulocyte colony-stimulating factor (hG-CSF) can serve as valuable biopharmaceutical for research and treatment of the human blood cancer. Transplastomic plants have been emerged as a new and high potential candidate for production of recombinant biopharmaceutical proteins in comparison with transgenic plants due to extremely high level expression, biosafety and many other advantages. METHODS: hG-CSF gene was cloned into pCL vector between prrn16S promoter and TpsbA terminator. The recombinant vector was coated on nanogold particles and transformed to lettuce chloroplasts through biolistic method. Callogenesis and regeneration of cotyledonary explants were obtained by Murashige and Skoog media containing 6-benzylaminopurine and 1-naphthaleneacetic acid hormones. The presence of hG-CSF gene in plastome was studied with four specific PCR primers and expression by Western immunoblotting. RESULTS: hG-CSF gene cloning was confirmed by digestion and sequencing. Transplastomic lettuce lines were regenerated and subjected to molecular analysis. The presence of hG-CSF in plastome was confirmed by PCR using specific primers designed from the plastid genome. Western immunoblotting of extracted protein from transplastomic plants showed a 20-kDa band, which verified the expression of recombinant protein in lettuce chloroplasts. CONCLUSIONS: This study is the first report that successfully express hG-CSF gene in lettuce chloroplast. The lettuce plastome can provide a cheap and safe expression platform for producing valuable biopharmaceuticals for research and treatment. PMID- 23748896 TI - Determination of tolerable fatty acids and cholera toxin concentrations using human intestinal epithelial cells and BALB/c mouse macrophages. AB - The positive role of fatty acids in the prevention and alleviation of non-human and human diseases have been and continue to be extensively documented. These roles include influences on infectious and non-infectious diseases including prevention of inflammation as well as mucosal immunity to infectious diseases. Cholera is an acute intestinal illness caused by the bacterium Vibrio cholerae. It occurs in developing nations and if left untreated, can result in death. While vaccines for cholera exist, they are not always effective and other preventative methods are needed. We set out to determine tolerable concentrations of three fatty acids (oleic, linoleic and linolenic acids) and cholera toxin using mouse BALB/C macrophages and human intestinal epithelial cells, respectively. We solubilized the above fatty acids and used cell proliferation assays to determine the concentration ranges and specific concentrations of the fatty acids that are not detrimental to human intestinal epithelial cell viability. We solubilized cholera toxin and used it in an assay to determine the concentration ranges and specific concentrations of cholera toxin that do not statistically decrease cell viability in BALB/C macrophages. We found the optimum fatty acid concentrations to be between 1-5 ng/MUl, and that for cholera toxin to be < 30 ng per treatment. This data may aid future studies that aim to find a protective mucosal role for fatty acids in prevention or alleviation of cholera infections. PMID- 23748897 TI - Aliidiomarina sanyensis sp. nov., a hexabromocyclododecane assimilating bacterium from the pool of Spirulina platensis cultivation, Sanya, China. AB - A novel Gram-negative, rod shaped, motile, non-spore-forming, aerobic, brominated flame retardant hexabromocyclododecane-assimilating bacterium, designated strain GYP-17(T), was isolated from a pool of marine Spirulina platensis cultivation, Sanya, China. Colonies on 1/10 strength of marine Glycerol Enriched Medium plates were circular, dark-brown, 1-2 mm in diameter, and with regular margins. Growth occurred at 10-45 degrees C, 1-10 % (w/v) NaCl and pH of 7-9. The polar lipids were composed of phosphatidylethanolamine, three unidentified phospholipids and one unidentified polar lipid. The major fatty acids were iso-C17:1omega9c/10 methyl-C16:0 (summed feature 9, 20.75 %), iso-C15:0 (17.70 %) and C16:0 (6.40 %). The major respiratory quinone was Q-8. The DNA G + C content of the type strain was 53.6 mol%. Phylogenetic analysis revealed that strain GYP-17(T) was a member of the genus Aliidiomarina and closely related to Aliidiomarina haloalkalitolerans with a 16S rDNA sequence similarity of 96.36 %. Results from the polyphasic taxonomy study support the conclusion that strain GYP-17(T) represents a novel Aliidiomarina species, for which the name Aliidiomarina sanyensis sp. nov. is proposed. The type strain of A. sanyensis is GYP-17(T) (=KCTC 32218(T) =LMG 27471(T)). PMID- 23748898 TI - Scalp necrosis following preoperative embolization for meningeal tumors: two cautionary tales. PMID- 23748899 TI - Inhibitory effects of a new 1H-pyrrolo[3,2-c]pyridine derivative, KIST101029, on activator protein-1 activity and neoplastic cell transformation induced by insulin-like growth factor-1. AB - Diarylureas and diarylamides derivatives are reported to have antitumor activity. Encouraged by the interesting antiproliferative activity of diarylurea and diarylamide derivatives, we synthesized a new series of diarylureas and diarylamides containing pyrrolo[3,2-c]pyridine scaffold. In this study, we demonstrate that a N-(3-(4-benzamido-1H-pyrrolo[3,2-c]pyridin-1-yl)phenyl)-4 morpholino-3-(trifluoromethyl)benzamide, KIST101029, inhibits neoplastic cell transformation induced by insulin-like growth factor 1 (IGF-1) in mouse epidermal JB6 Cl41 cells. The KIST101029 compound inhibited mitogen-activated protein kinase/extracellular signal-regulated kinase kinases (MEK), c-jun N-terminal kinases (JNK), and mechanistic target of rapamycin (mTOR) signaling pathways induced by IGF-1 in JB6 Cl41 cells, resulting in the inhibition of c-fos and c jun transcriptional activity. In addition, the KIST101029 inhibited the associated activator protein-1 (AP-1) transactivation activity and cell transformation induced by IGF-1 in JB6 Cl41 cells. Consistent with these observations, in vivo chorioallantoic membrane assay also showed that the KIST101029 inhibited IGF-1-induced tumorigenicity of JB6 Cl41 cells. Importantly, KIST101029 suppressed the colony formation of A375 cells in soft agar. Taken together, these results indicate that a KIST101029 might exert chemopreventive effects through the inhibition of phosphorylation of MAPK and mTOR signaling pathway. PMID- 23748900 TI - Significant increase in hEGF uptake is correlated with formation of EGFR dimers induced by the EGFR tyrosine kinase inhibitor gefitinib. AB - PURPOSE: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) is approved for cancer treatment. We investigated whether gefitinib treatment can enhance human EGF (hEGF) uptake in vitro, thereby increasing the potential of hEGF as a vehicle for EGFR-targeted therapy. METHODS: Western blotting was used to detect the effect of gefitinib on EGFR signaling. Different EGFR-expressing tumor cells (SCC-1, 22B, A549, and HT-29) were pretreated with gefitinib, and then with (125)I-hEGF or (125)I-Vectibix (an anti EGFR monoclonal antibody). Cell-associated activity was then measured. A cross linking assay detected increased EGFR dimer formation in gefitinib-treated cells. RESULTS: Total EGFR levels were not changed, but EGFR phosphorylation was reduced in cells pretreated with gefitinib. Gefitinib mediated formation of EGFR dimers; binding of (125)I-hEGF to cells pretreated with gefitinib significantly increased. In contrast, binding of (125)I-Vectibix to tumor cells did not increase. Although total EGFR levels did not increase, binding of hEGF to EGFR + tumors was significantly enhanced after gefitinib treatment, because of increased hEGF binding to gefitinib-induced EGFR dimers. CONCLUSION: These results suggest that hEGF could enhance EGFR-targeting when used with gefitinib. PMID- 23748901 TI - alphaTAT1 is the major alpha-tubulin acetyltransferase in mice. AB - Post-translational modification of tubulin serves as a powerful means for rapidly adjusting the functional diversity of microtubules. Acetylation of the epsilon amino group of K40 in alpha-tubulin is one such modification that is highly conserved in ciliated organisms. Recently, alphaTAT1, a Gcn5-related N acetyltransferase, was identified as an alpha-tubulin acetyltransferase in Tetrahymena and C. elegans. Here we generate mice with a targeted deletion of Atat1 to determine its function in mammals. Remarkably, we observe a loss of detectable K40 alpha-tubulin acetylation in these mice across multiple tissues and in cellular structures such as cilia and axons where acetylation is normally enriched. Mice are viable and develop normally, however, the absence of Atat1 impacts upon sperm motility and male mouse fertility, and increases microtubule stability. Thus, alphaTAT1 has a conserved function as the major alpha-tubulin acetyltransferase in ciliated organisms and has an important role in regulating subcellular specialization of subsets of microtubules. PMID- 23748902 TI - Health literacy, acculturation, and the use of preventive oral health care by Somali refugees living in massachusetts. AB - This study investigated the impact of English health literacy and spoken proficiency and acculturation on preventive dental care use among Somali refugees in Massachusetts. 439 adult Somalis in the US <=10 years were interviewed. English functional health literacy, dental word recognition, and spoken proficiency were measured using STOFHLA, REALD, and BEST Plus. Logistic regression tested associations of language measures with preventive dental care use. Without controlling for acculturation, participants with higher health literacy were 2.0 times more likely to have had preventive care (P = 0.02). Subjects with higher word recognition were 1.8 times as likely to have had preventive care (P = 0.04). Controlling for acculturation, these were no longer significant, and spoken proficiency was not associated with increased preventive care use. English health literacy and spoken proficiency were not associated with preventive dental care. Other factors, like acculturation, were more predictive of care use than language skills. PMID- 23748903 TI - Electrochromic and colorimetric properties of nickel(II) oxide thin films prepared by aerosol-assisted chemical vapor deposition. AB - Aerosol-assisted chemical vapor deposition (AACVD) was used for the first time in the preparation of thin-film electrochromic nickel(II) oxide (NiO). The as deposited films were cubic NiO, with an octahedral-like grain structure, and an optical band gap that decreased from 3.61 to 3.48 eV on increase in film thickness (in the range 500-1000 nm). On oxidative voltammetric cycling in aqueous KOH (0.1 mol dm(-3)) electrolyte, the morphology gradually changed to an open porous NiO structure. The electrochromic properties of the films were investigated as a function of film thickness, following 50, 100, and 500 conditioning oxidative voltammetric cycles in aqueous KOH (0.1 mol dm(-3)). Light modulation of the films increased with the number of conditioning cycles. The maximum coloration efficiency (CE) for the NiO (transmissive light green, the "bleached" state) to NiOOH (deep brown, the colored state) electrochromic process was found to be 56.3 cm(2) C(-1) (at 450 nm) for films prepared by AACVD for 15 min followed by 100 "bleached"-to-colored conditioning oxidative voltammetric cycles. Electrochromic response times were <10 s and generally longer for the coloration than the bleaching process. The films showed good stability when tested for up to 10 000 color/bleach cycles. Using the CIE (Commission Internationale de l'Eclairage) system of colorimetry the color stimuli of the electrochromic NiO films and the changes that take place on reversibly oxidatively switching to the NiOOH form were calculated from in situ visible spectra recorded under electrochemical control. Reversible changes in the hue and saturation occur on oxidation of the NiO (transmissive light green) form to the NiOOH (deep brown) form, as shown by the track of the CIE 1931 xy chromaticity coordinates. As the NiO film is oxidized, a sharp decrease in luminance was observed. CIELAB L*a*b* coordinates were also used to quantify the electrochromic color states. A combination of a low L* and positive a* and b* values quantified the perceived deep brown colored state. PMID- 23748904 TI - Elevated blood pressure, heart rate and body temperature in mice lacking the XLalphas protein of the Gnas locus is due to increased sympathetic tone. AB - Imbalances of energy homeostasis are often associated with cardiovascular complications. Previous work has shown that Gnasxl-deficient mice have a lean and hypermetabolic phenotype, with increased sympathetic stimulation of adipose tissue. The Gnasxl transcript from the imprinted Gnas locus encodes the trimeric G-protein subunit XLalphas, which is expressed in brain regions that regulate energy homeostasis and sympathetic nervous system (SNS) activity. To determine whether Gnasxl knock-out (KO) mice display additional SNS-related phenotypes, we have now investigated the cardiovascular system. The Gnasxl KO mice were ~20 mmHg hypertensive in comparison to wild-type (WT) littermates (P <= 0.05) and hypersensitive to the sympatholytic drug reserpine. Using telemetry, we detected an increased waking heart rate in conscious KOs (630 +/- 10 versus 584 +/- 12 beats min(-1), KO versus WT, P <= 0.05). Body temperature was also elevated (38.1 +/- 0.3 versus 36.9 +/- 0.4 degrees C, KO versus WT, P <= 0.05). To investigate autonomic nervous system influences, we used heart rate variability analyses. We empirically defined frequency power bands using atropine and reserpine and verified high-frequency (HF) power and low-frequency (LF) LF/HF power ratio to be indicators of parasympathetic and sympathetic activity, respectively. The LF/HF power ratio was greater in KOs and more sensitive to reserpine than in WTs, consistent with elevated SNS activity. In contrast, atropine and exendin-4, a centrally acting agonist of the glucagon-like peptide-1 receptor, which influences cardiovascular physiology and metabolism, reduced HF power equally in both genotypes. This was associated with a greater increase in heart rate in KOs. Mild stress had a blunted effect on the LF/HF ratio in KOs consistent with elevated basal sympathetic activity. We conclude that XLalphas is required for the inhibition of sympathetic outflow towards cardiovascular and metabolically relevant tissues. PMID- 23748905 TI - Association of patient demographics on quality of life in a sample of adult patients with cardiac arrhythmias. AB - PURPOSE: Identify predictors of quality of life (QOL) in patients with any form of cardiac arrhythmia (CA). METHODS: Data from the Medical Panel Expenditure Survey were analyzed from 2004 to 2009. Patients aged >=18 with any form of CA (identified via ICD-9-CM codes) were included. Primary outcomes included the physical and mental component scores (PCS and MCS) of the Short-Form 12 version 2 (SF-12) and EuroQoL-5D (EQ-5D) utility scores (US version). Patient demographics included insurance status, urban status, geographical region, federal poverty level, education, comorbidities, and disease-related risk factors of CA. RESULTS: Approximately 5,750,440 individuals had CA. Non-Hispanic Whites had the highest SF-12 MCS (mean 50.9; p < 0.001 across racial groups) and utility scores (mean 0.76; p < 0.001 across racial groups). Patients with both private and public insurance had significantly higher PCS (p = 0.001) and MCS (p < 0.001) in comparison with patients only covered by public insurance. Patients on antiarrhythmic agents had higher SF-12 MCS (51.4 vs. 48.4; p < 0.001) compared to individuals not on antiarrhythmic agents. CONCLUSIONS: Significantly lower QOL existed in specific subpopulations (e.g., patients with only public health insurance, racial/ethnic minorities, and those not exposed to antiarrhythmic agents) within the CA population. PMID- 23748906 TI - The valuation of the EQ-5D in Portugal. AB - PURPOSE: The EQ-5D is a preference-based measure widely used in cost-utility analysis (CUA). Several countries have conducted surveys to derive value sets, but this was not the case for Portugal. The purpose of this study was to estimate a value set for the EQ-5D for Portugal using the time trade-off (TTO). METHODS: A representative sample of the Portuguese general population (n = 450) stratified by age and gender valued 24 health states. Face-to-face interviews were conducted by trained interviewers. Each respondent ranked and valued seven health states using the TTO. Several models were estimated at both the individual and aggregated levels to predict health state valuations. Alternative functional forms were considered to account for the skewed distribution of these valuations. RESULTS: The models were analyzed in terms of their coefficients, overall fit and the ability for predicting the TTO values. Random effects models were estimated using generalized least squares and were robust across model specification. The results are generally consistent with other value sets. CONCLUSION: This research provides the Portuguese EQ-5D value set based on the preferences of the Portuguese general population as measured by the TTO. This value set is recommended for use in CUA conducted in Portugal. PMID- 23748907 TI - Long-term results of a total knee prosthesis utilising an all polyethylene tibial component. AB - INTRODUCTION: The aim of this study was to assess the long-term performance of a cemented total knee replacement utilising an All Polyethylene Tibial (APT) component and in addition to perform an engineering analysis of any failures to help refine surgical technique. MATERIALS AND METHODS: A total of 26 patients had a total knee replacement performed using a cemented Depuy Press Fit Condylar (PFC) APT component and a cruciate retaining femoral component. At final review all patients were assessed using The Knee Society Score together with radiographs. An engineering analysis simulated loading conditions of the implants that failed and these were compared with the performance of a modular metal backed Tibial (MBT) component. RESULTS: A total of 20 patients were reviewed at mean time of 116 months following surgery. Knee Society Knee Scores and Function Scores in this cohort were 84/100 and 58/100, respectively. Two patients required revision for tibial component failure. Pre-operatively both had valgus deformities and in each case the tibial tray had been lateralised leaving a gap on the medial side where the APT component had no rigid support. The engineering analysis demonstrated that the volume of highly strained cancellous bone was greater in the APT design compared with the MBT design when a model with a 3 mm medial gap was loaded. The stiffer MBT base plate acted more rigidly and shielded the stress applied to the proximal tibial cancellous bone. CONCLUSION: The APT component demonstrated satisfactory clinical and radiographic performance at long term follow up. Appropriate cortical support of the APT component is important. The implant should be used with a degree of caution in patients with severe deformities and osteoporosis. PMID- 23748909 TI - Population-based study of Kawasaki disease shock syndrome in Taiwan. AB - By using a National Health Insurance database, we investigated the occurrence of Kawasaki disease (KD) shock syndrome in Taiwan. KD shock syndrome occurred most frequently in winter, and the incidence was 1.45 per 100 patients with KD. Compared with KD patients without shock, KD shock syndrome patients were older, more likely to develop coronary lesions (15.9% vs. 7.0%) and had longer hospitalization duration. PMID- 23748908 TI - Immobilization and characterization of a thermostable lipase. AB - Lipases have found a number of commercial applications. However, thermostable lipase immobilized on nanoparticle is not extensively characterized. In this study, a recombinant thermostable lipase (designated as TtL) from Thermus thermophilus WL was expressed in Escherichia coli and immobilized onto 3-APTES modified Fe3O4@SiO2 supermagnetic nanoparticles. Based on analyses with tricine sodium dodecyl sulfate-polyacrylamide gel electrophoresis, X-ray diffraction, transmission electron microscopy, and vibrating sample magnetometer observation, the diameter of immobilized lipase nanoparticle was 18.4 (+/- 2.4) nm, and its saturation magnetization value was 52.3 emu/g. The immobilized lipase could be separated from the reaction medium rapidly and easily in a magnetic field. The biochemical characterizations revealed that, comparing with the free one, the immobilized lipase exhibited better resistance to temperature, pH, metal ions, enzyme inhibitors, and detergents. The K m value for the immobilized TtL (2.56 mg/mL) was found to be lower than that of the free one (3.74 mg/mL), showing that the immobilization improved the affinity of lipase for its substrate. In addition, the immobilized TtL exhibited good reusability. It retained more than 79.5 % of its initial activity after reusing for 10 cycles. Therefore, our study presented that the possibility of the efficient reuse of the thermostable lipase immobilized on supermagnetic nanoparticles made it attractive from the viewpoint of practical application. PMID- 23748910 TI - A novel LTCC electrochemical cell construction and characterization: a detection compartment for portable devices. AB - In this work we described for the first time the construction of a 25 MUL electrochemical cell from low temperature co-fired ceramic (LTCC) material and carbon screen-printed electrode applicable in portable devices. Firstly, a carbon screen-printed electrode was prepared and characterized by cyclic voltammetry and scanning electron microscopy. Afterwards carbon polymeric film and metal pastes were dropped into the LTCC cell cavities in order to determine the device electrodes, and this arrangement was also electrochemically characterized. The great advantage of this promising device is the simple construction method and its widespread applicability in reusable portable devices. PMID- 23748911 TI - A controllable growth-doping approach to synthesize bright white-light-emitting Cd:In2S3 nanocrystals. AB - A new type of doped Cd:In2S3 NC, which exhibits bright white-light emission with a QY of about 18%, synthesized by a one-pot G-doping synthesis approach is presented. The successful realization of temporal separation of nucleation doping and growth doping makes this approach a facile method to synthesize the In2S3/Cd:In2S3 core/shell nanostructure. PMID- 23748912 TI - Reaction selectivity in an ionized water dimer: nonadiabatic ab initio dynamics simulations. AB - We study dynamical processes following water dimer ionization. The nonadiabatic dynamical simulations of the water dimer radical cation are performed using a surface hopping technique and a Complete Active Space-Self Consistent Field (CASSCF) method for the description of electronic structure. The main goal of this study is to find out whether a state-dependent reactivity is observed for the water dimer radical cation. We provide a detailed mapping of the potential energy surfaces (PESs) in the relevant coordinates for different electronic states. Dynamical patterns are discussed on the basis of static PES cuts and available experimental data. As a product of the reaction, we observed either proton transferred structure (H3O(+)...OH) or various dissociated structures (H3O(+) + OH, H2O(+) + H2O, H + OH + H2O(+)). The relative yields are controlled by the populated electronic state of the radical cation. The proton transfer upon the HOMO electron ionization is an ultrafast process, taking less than 100 fs, in cases of higher energy ionization the dynamical processes occur on longer timescales (200-300 fs). We also discuss the implications of our simulations for the efficiency of the recently identified intermolecular coulomb decay (ICD) process in the water dimer. PMID- 23748913 TI - A comparison of particulate and onyx embolization in preoperative devascularization of juvenile nasopharyngeal angiofibromas. AB - INTRODUCTION: Juvenile nasopharyngeal angiofibromas (JNAs) are hypervascular tumors that may benefit from preoperative devascularization to reduce intraoperative blood loss (IBL). The purpose of this study was to compare transarterial particulate embolization (TAPE) with the direct percutaneous embolization (DPE) technique using ethylene vinyl alcohol (Onyx, ev3, Irvine, CA) for the preoperative devascularization of a JNA. METHODS: We retrospectively reviewed 50 consecutive JNA resections since 1995 for which preoperative embolization was either transarterial with particulate material (n = 39) or DPE (n = 11) using only Onyx. The IBL, transfusion requirements, operative time, and length of hospital admission were compared between the two groups. RESULTS: The mean IBL was 1,348.7 +/- 932.2 mL particulate group, 569.1 +/- 700.7 mL Onyx group (one-tailed Student's t test p = 0.003). The mean unit of packed red blood cells was 1.56 +/- 2.01 units particulate group, 0.45 +/- 1.04 units Onyx group (p = 0.009). The relationship between embolization type and IBL remained significant or strongly correlated when accounting for the Fisch stage of the tumor (p = 0.010 and p = 0.056, respectively, by a multivariate least squares fit; alternately p = 0.0003 and p = 0.023, respectively, in the subset of patients with Fisch stage III tumors only). We also found that the proportion of resections for which an endoscopic approach could be used was significantly higher in the Onyx group than the particulate group (81.8 and 18.2 %; Pearson p = 0.0002), and this was also significant both in our multivariate nominal logistic fit (p < 0.001) and in the subset of patients with Fisch stage III tumors (p = 0.018). CONCLUSION: Pre-operative DPE with Onyx of a JNA when compared to TAPE significantly decreased IBL and RBC transfusion requirement during surgical resection. The proportion of surgical resections performed from an endoscopic approach was higher in the DPE Onyx group, which may have affected the results. PMID- 23748914 TI - Detection of USP6 gene rearrangement in nodular fasciitis: an important diagnostic tool. PMID- 23748915 TI - Expression of PAR-4 and PHLDA1 is prognostic for overall and disease-free survival in oral squamous cell carcinomas. AB - PAR-4 is a tumor suppressor protein with a pro-apoptotic function and down regulation of PAR-4 is seen in a variety of tumors. PHLDA1 gene overexpression has been shown to reduce cell proliferation and induce cell death in a variety of cell types. In this study, 229 cases of oral squamous cell carcinoma (OSCC), arranged in a tissue microarray, were analyzed by immunohistochemistry. PAR-4 expression was predominantly moderate to strong and expression of PHLDA1 was predominantly negative or weak. Cytoplasmic expression of PAR-4 was associated with advanced clinical stage. Expression of PHLDA1 was associated with advanced clinical stage of the tumour. Five-year overall and disease-free survival rates differed significantly between cases that did and cases that did not express PHLDA1, and by multivariate analysis, expression of PHLDA1 and PAR-4 were independent prognostic factors in OSCC patients. Expression of PAR-4 and PHLDA1 is altered in OSCC and might be a valuable prognostic indicator for this disease. PMID- 23748916 TI - Ultrasound for localization in primary hyperparathyroidism. AB - OBJECTIVE: To evaluate the capability of ultrasound for preoperative localization in primary hyperparathyroidism. STUDY DESIGN: Prospective study. SETTING: Multi institutional Midwest Head and Neck Cancer Consortium. SUBJECTS AND METHODS: Two hundred twenty patients who underwent preoperative localization and had parathyroid surgery were evaluated. The findings of preoperative localization studies were correlated with surgical findings. RESULTS: Preoperative ultrasonography, sestamibi scintigraphy, or both were obtained in 77%, 93%, and 69% of the patients, respectively. Preoperative ultrasonography and sestamibi scintigraphy localized an abnormality in 71% and 79% of patients, respectively. At the time of surgery, the localization by ultrasound was accurate in 82%. The accuracy of localization was similar for sestamibi scintigraphy (85%). In patients with inaccurate ultrasound localization, the sestamibi scintigraphy correctly identified the site of disease in only 45%. In patients with a nonlocalizing ultrasound, sestamibi scintigraphy was able to localize disease in only 47%, with 2 being in the mediastinum. CONCLUSIONS: Ultrasonography is an acceptable initial localization study for patients with primary hyperparathyroidism. In patients with nonlocalizing ultrasound, sestamibi scintigraphy should be obtained, but can be expected to detect an abnormality in less than 50% of patients. PMID- 23748917 TI - The use of spatial autocorrelation analysis to identify PAHs pollution hotspots at an industrially contaminated site. AB - The identification of contamination "hotspots" are an important indicator of the degree of contamination in localized areas, which can contribute towards the re sampling and remedial strategies used in the seriously contaminated areas. Accordingly, 114 surface samples, collected from an industrially contaminated site in northern China, were assessed for 16 polycyclic aromatic hydrocarbons (PAHs) and were analyzed using multivariate statistical and spatial autocorrelation techniques. The results showed that the PCA leads to a reduction in the initial dimension of the dataset to two components, dominated by Chr, Bbf&Bkf, Inp, Daa, Bgp, and Nap were good representations of the 16 original PAHs; Global Moran's I statistics indicated that the significant autocorrelations were detected and the autocorrelation distances of six indicator PAHs were 750, 850, 1,200, 850, 750, and 1,200 m, respectively; there were visible high-high values (hotspots) clustered in the mid-bottom part of the site through the Local Moran's I index analysis. Hotspot identification and spatial distribution results can play a key role in contaminated site investigation and management. PMID- 23748918 TI - Total petroleum hydrocarbon distribution in soils and groundwater in Songyuan oilfield, Northeast China. AB - In order to investigate the distribution of the total petroleum hydrocarbons (TPH) in groundwater and soil, a total of 71 groundwater samples (26 unconfined groundwater samples, 37 confined groundwater samples, and 8 deeper confined groundwater samples) and 80 soil samples were collected in the Songyuan oilfield, Northeast China, and the vertical variation and spatial variability of TPH in groundwater and soil were assessed. For the groundwater from the unconfined aquifer, petroleum hydrocarbons were not detected in three samples, and for the other 23 samples, concentrations were in the range 0.01-1.74 mg/l. In the groundwater from the confined aquifer, petroleum hydrocarbons were not detected in two samples, and in the other 35 samples, the concentrations were 0.04-0.82 mg/l. The TPH concentration in unconfined aquifer may be influenced by polluted surface water and polluted soil; for confined aquifer, the injection wells leakage and left open hole wells may be mainly responsible for the pollution. For soils, the concentrations of TPH varied with sampling depth and were 0-15 cm (average concentration, 0.63 mg/g), >40-55 cm (average concentration, 0.36 mg/g), >100-115 cm (average concentration, 0.29 mg/g), and >500-515 cm (average concentration, 0.26 mg/g). The results showed that oil spillage and losses were possibly the main sources of TPH in soil. The consequences concluded here suggested that counter measures such as remediation and long-term monitoring should be commenced in the near future, and effective measures should be taken to assure that the oilfields area would not be a threat to human health. PMID- 23748919 TI - Investigating the spatial distribution of phototrophic picoplankton in a tropical estuary. AB - We sampled extensively (29 stations) at the Klang estuarine system over a 3-day scientific expedition. We measured physical and chemical variables (temperature, salinity, dissolved oxygen, total suspended solids, dissolved inorganic nutrients) and related them to the spatial distribution of phototrophic picoplankton (Ppico). Multivariate analysis of variance of the physicochemical variables showed the heterogeneity of the Klang estuarine system where the stations at each transect were significantly different (Rao's F18, 36 = 8.401, p < 0.001). Correlation analyses also showed that variables related to Ppico abundance and growth were mutually exclusive. Distribution of Ppico was best explained by the physical mixing between freshwater and seawater whereas Ppico growth was correlated with temperature. PMID- 23748920 TI - Randomized, double-blind trial to evaluate the safety of apixaban with antiplatelet therapy after acute coronary syndrome in Japanese patients (APPRAISE J). AB - BACKGROUND: Concomitant anticoagulant therapy may further reduce the risk of thrombotic events in patients with acute coronary syndrome (ACS) when given in addition to current standard antiplatelet therapies. This Phase II, randomized, double-blind, placebo-controlled study in Japanese patients with ACS assessed the bleeding risk of apixaban compared with placebo when given in combination with standard antiplatelet therapy, and followed a similar design to APPRAISE-1, the larger global Phase II study. METHODS AND RESULTS: Patients with recently diagnosed ACS were randomized to receive apixaban 2.5mg twice daily (BID; n=49), apixaban 5mg BID (n=50), or placebo (n=52) in addition to standard antiplatelet therapy for 24 weeks. The composite primary endpoint of major or clinically relevant nonmajor bleeding occurred in 2 patients (4.1%) in each apixaban treatment group and 1 patient (2.0%) in the placebo group, and a dose-dependent increase was seen in all bleeding events. No hemorrhagic strokes occurred in either apixaban treatment group. This study was terminated before completion because the APPRAISE-2 global Phase III trial was stopped based on the recommendation of the Data Monitoring Committee, following an increase in bleeding events without a counterbalancing reduction in ischemic events. CONCLUSIONS: The bleeding profile of apixaban in Japanese patients with ACS was similar to that found in the global APPRAISE-1 study, supporting the safety of apixaban in Japanese patients. PMID- 23748921 TI - The pharmacokinetics of letrozole in brain and brain tumor in rats with orthotopically implanted C6 glioma, assessed using intracerebral microdialysis. AB - PURPOSE: Emerging evidence suggests that primary and metastatic brain tumors may be sensitive to hormonal manipulations. However, the pharmacokinetics of compounds against such targets in the brain and, more importantly, in the brain tumor are not well characterized. Here, we investigated the pharmacokinetics of letrozole, a third-generation aromatase inhibitor, in the normal brain and in orthotopically implanted C6 glioma in Sprague-Dawley rats. METHODS: Intracerebral microdialysis was employed to determine the concentrations of unbound letrozole in the brain extracellular fluid (ECF) while simultaneously collecting blood samples (via jugular vein) to assess plasma levels of letrozole. Letrozole was administered intravenously at doses of 4, 6, 8 and 12 mg/kg, and ECF and blood samples were collected over 8 h. For assessing normal versus tumoral brain pharmacokinetics, letrozole (4 or 8 mg/Kg; i.v.) was administered 10 days after implantation of C6 glioma in the brain. Dual-probe intracerebral microdialysis was employed for assessing ECF samples from tumor-free and tumor-bearing regions of the brain. RESULTS: Normal brain ECF and plasma C max and AUC0-8h increased linearly with letrozole doses up to 8 mg/kg dose, but at 12 mg/kg, the pharmacokinetics were nonlinear. The relative brain distribution coefficients, AUCECF/AUCplasma (ub), were 0.3-0.98. The tumoral uptake of letrozole was 1.5- to 2-fold higher relative to tumor-free region. CONCLUSIONS: Thus, letrozole permeability across the blood brain barrier is high, and the exposure to the brain is dose dependent. Furthermore, the brain tumoral letrozole levels are markedly higher than those in the tumor-free regions, which underscore potential selectivity of its activity against tumor cells. PMID- 23748922 TI - A common functional promoter variant links CNR1 gene expression to HDL cholesterol level. AB - Type 1 cannabinoid receptor blockers increase high-density lipoprotein cholesterol levels. Although genetic variation in the type 1 cannabinoid receptor -encoded by the CNR1 gene--is known to influence high-density lipoprotein cholesterol level as well, human studies conducted to date have been limited to genetic markers such as haplotype-tagging single nucleotide polymorphisms. Here we identify rs806371 in the CNR1 promoter as the causal variant. We re-sequence the CNR1 gene and genotype all variants in a DNA biobank linked to comprehensive electronic medical records. By testing each variant for association with high density lipoprotein cholesterol level in a clinical practice-based setting, we localize a putative functional allele to a 100-bp window in the 5'-flanking region. Assessment of variants in this window for functional impact on electrophoretic mobility shift assay identifies rs806371 as a novel regulatory binding element. Reporter gene assays confirm that rs806371 reduces gene expression, thereby linking CNR1 gene variation to high-density lipoprotein cholesterol level in humans. PMID- 23748923 TI - Factors predicting success of emergency extracorporeal shockwave lithotripsy (eESWL) in ureteric calculi--a single centre experience from the United Kingdom (UK). AB - Few studies show that "emergency extracorporeal shockwave lithotripsy (eESWL)" reduces the incidence of ureteroscopy in patients with ureteric calculi. We assess success of eESWL and look to study and identify factors which predict successful outcome. We retrospectively studied patients presenting with their first episode of ureteric colic undergoing eESWL (within 72 h of presentation) over a 5-year period. Patient's age, gender, stone size and location, time between presentation and ESWL, number of shock waves and ESWL sessions, and Hounsfield units (HU) were recorded. 97 patients (mean age 40 years; 76 males, 21 females) were included. 71 patients were stone free after eESWL (73.2 %) (group 1) and 26 patients failed treatment and proceeded to ureteroscopy (group 2). The two groups were well matched for age and gender. Mean stone size in group 1 and 2 was 6.4 mm and 7.7 mm, respectively, (p = 0.00141). Stone location was 34, 21, and 16 in upper, middle and lower ureter in group 1 compared to 11, 5, and 10 in group 2, respectively. Mean HU in group 1 was 480 and 612 in group 2 (p value 0.0036). In group 2, significantly, more patients received treatment after 24 h compared with group 1 (38 vs 22.5 %). The number of shock waves, maximal intensity, and ESWL sessions were not significantly different in the two groups. No complications were noted. eESWL is safe and effective in patients with ureteric colic. Stone size and Hounsfield units are important factors in predicting success. Early treatment (<=24 h) minimizes stone impaction and increases the success rate of ESWL. PMID- 23748924 TI - Evolution of recombination and genome structure in eusocial insects. AB - Eusocial Hymenoptera, such as the European honey bee, Apis mellifera, have the highest recombination rates of multicellular animals.(1) Recently, we showed(2) that a side-effect of recombination in the honey bee, GC biased gene conversion (bGC), helps maintain the unusual bimodal GC-content distribution of the bee genome by increasing GC-content in high recombination areas while low recombination areas are losing GC-content because of biased AT mutations and low rates of bGC. Although the very high recombination rate of A. mellifera makes GC content evolution easier to study, the pattern is consistent with results found in many other species including mammals and yeast.(3) Also consistent across phyla is the association of higher genetic diversity and divergence with high GC and high recombination areas.(4) (,) (5) Finally, we showed that genes overexpressed in the brains of workers cluster in GC-rich genomic areas with the highest rates of recombination and molecular evolution.(2) In this Addendum we present a conceptual model of how eusociality and high recombination rates may co evolve. PMID- 23748925 TI - Enhanced photocatalytic water disinfection properties of Bi2MoO6-RGO nanocomposites under visible light irradiation. AB - Bi2MoO6-RGO composite nanoplates with good uniformity and highly oriented growth of the active lattice were successfully synthesized by a simple hydrothermal process with the assistance of graphene oxide. Reduced graphene oxide was observed to be formed on the surface of the Bi2MoO6 nanoplates after the hydrothermal treatment. A remarkable enhancement in the visible-light-driven (VLD) photocatalytic destruction of bacteria was observed over the Bi2MoO6-RGO composite when compared to pure Bi2MoO6. PMID- 23748926 TI - Lumbar total disc replacement: correlation of clinical outcome and radiological parameters. AB - BACKGROUND: The objective of this study was to correlate various radiological parameters with clinical outcome in patients who had undergone lumbar total disc replacement (TDR). Lumbar TDR is one possible treatment option in patients with low back pain (LBP), offering an alternative to lumbar fusion. Favourable clinical outcome hinges on a number of radiological parameters, such as mobility, sintering, and-most importantly-accurate positioning of the implant. METHODS: A total of 46 patients received a prosthetic disc because of degenerative lumbar disc disorders. Follow-up evaluation included analysis of radiographs and subjective rating of the clinical status by the patient using the North American Spine Society (NASS) patient questionnaire, visual analogue scale (VAS) for pain and state of health, and the EuroQol EQ-5D. Radiological follow-up took place after 2 years. Coronal and sagittal positions of the prosthesis, intervertebral disc height, facet joint pressure, mobility, sintering, and calcification were evaluated. Optimal positioning of the prosthesis was defined as a central coronal position and a most dorsal position in the sagittal plane. Based on the radiologically determined placement of the prosthesis, the patient population was divided into three groups, i.e., prosthesis ideally placed (<2 mm), discretely shifted (2-3 mm), or suboptimally placed (>3 mm). RESULTS: Overall, 81 % of patients stated that they would undergo the operation again. Health status was stable at a VAS score of 7.04 points 2 years after TDR, compared to 3.97 points before TDR. Mean working capacity had increased from 53 % preoperatively to 88 % 2 years after TDR. Overall, 39 % of the prostheses were rated as ideally positioned, while 13 % were discretely shifted and 48 % were suboptimally placed with respect to one of the radiological criteria. In 80.4 % of patients, follow up assessment after >=2 years indicated good mobility at the operated segment, while calcification was noted in 4 % and sintering was detected in 15 % of the implants. CONCLUSIONS: Our data indicate poor correlation between clinical outcome and position of the prosthesis. Although 48 % of the implants were suboptimally placed in either the coronal or sagittal plane, most of the patients reached a very good clinical outcome. However, suboptimally placed devices appeared to cause significantly more neurological symptoms in long-term follow up. PMID- 23748927 TI - A low-lying, solitary, bihemispheric PICA with an associated spontaneous vertebral-PICA dissecting aneurysm. PMID- 23748928 TI - Housing First improves subjective quality of life among homeless adults with mental illness: 12-month findings from a randomized controlled trial in Vancouver, British Columbia. AB - PURPOSE: This study used an experimental design to examine longitudinal changes in subjective quality of life (QoL) among homeless adults with mental illness after assignment to different types of supported housing or to treatment as usual (TAU, no housing or supports through the study). We hypothesized that subjective QoL would improve over time among participants assigned to supported housing as compared to TAU, regardless of the type of supported housing received or participants' level of need. METHODS: Participants (n = 497) were stratified by level of need ("high" or "moderate") and randomly assigned to Housing First (HF) in scattered-site apartments, HF in a congregate setting (high needs only), or TAU. Linear mixed-effects regression was used to model the association between study arm and self-reported QoL at baseline and at 6 and 12 months post-baseline by need level. RESULTS: Based on the adjusted overall score on the QoL measure, participants randomized to HF reported significantly greater overall QoL as compared to TAU, regardless of need level or type of supported housing at both 6 and 12 months post-baseline. Scores on the safety and living situation subscales were significantly greater for both high and moderate need participants assigned to supported housing regardless of type at both 6 and 12 months post-baseline as compared to TAU. CONCLUSIONS: Despite multiple health and social challenges faced by homeless individuals with mental illness, HF in both scattered-site and congregate models results in significantly greater perceived QoL as compared to individuals who do not receive HF even after a relatively short period of time. PMID- 23748929 TI - Tension pneumocephalus: a case report with review of literature. AB - Tension Pneumocephalus (PC) was described 50 years ago. A case of pneumocephalus (PC) following cervical epidural injection in a 50-year-old male worsened by air travel and manifested as tension pneumocephalus, confirmed by advanced neuroimaging, is reported for the first time along with literature review. The patient underwent emergent frontal burr hole evacuation and air gushed under pressure. The patient recovered well and is stable during a follow-up of 12 months. Presenting features and clinical course along with Mount Fuji sign, Peaking sign, and air bubble sign observed in this case are described. Also, the importance of considering neurosurgical and spinal procedures leading to PC have to be considered by practitioners before issuing fitness certificate before air travel, as PC is likely to get transformed to tension PC and can cause an in flight emergency. PMID- 23748930 TI - Distribution of the glucocorticoid receptor in the human amygdala; changes in mood disorder patients. AB - Exposure to stress activates the hypothalamic-pituitary-adrenal (HPA) axis that stimulates glucocorticoid (GC) release from the adrenal. These hormones exert numerous effects in the body and brain and bind to a.o. glucocorticoid receptors (GR) expressed in the limbic system, including the hippocampus and amygdala. Hyperactivity of the HPA axis and disturbed stress feedback are common features in major depression. GR protein is present in the human hypothalamus and hippocampus, but little is known-neither in healthy subjects nor in depressed patients-about GR expression in the amygdala, a brain structure involved in fear and anxiety. Since chronic stress in rodents affects GR expression in the amygdala, altered GR protein level in depressed versus healthy controls can be expected. To test this, we investigated GR-alpha protein expression in the post mortem human amygdala and assessed changes in ten major or bipolar depressed patients and eight non-depressed controls. Abundant GR immunoreactivity was observed in the human amygdala, both in neurons and astrocytes, with a similar pattern in its different anatomical subnuclei. In major depression, GR protein level as well as the percentage of GR-containing astrocytes was significantly higher than in bipolar depressed patients or in control subjects. Taken together, the prominent expression of GR protein in the human amygdala indicates that this region can form an important target for corticosteroids and stress, while the increased GR expression in major, but not bipolar, depression suggests possible involvement in the etiology of major depression. PMID- 23748931 TI - Characterization of the spectrum of insecticidal activity of a double-stranded RNA with targeted activity against Western Corn Rootworm (Diabrotica virgifera virgifera LeConte). AB - The sequence specificity of the endogenous RNA interference pathway allows targeted suppression of genes essential for insect survival and enables the development of durable and efficacious insecticidal products having a low likelihood to adversely impact non-target organisms. The spectrum of insecticidal activity of a 240 nucleotide (nt) dsRNA targeting the Snf7 ortholog in Western Corn Rootworm (WCR; Diabrotica virgifera virgifera) was characterized by selecting and testing insects based upon their phylogenetic relatedness to WCR. Insect species, representing 10 families and 4 Orders, were evaluated in subchronic or chronic diet bioassays that measured potential lethal and sublethal effects. When a specific species could not be tested in diet bioassays, the ortholog to the WCR Snf7 gene (DvSnf7) was cloned and corresponding dsRNAs were tested against WCR and Colorado potato beetle (Leptinotarsa decemlineata); model systems known to be sensitive to ingested dsRNA. Bioassay results demonstrate that the spectrum of activity for DvSnf7 is narrow and activity is only evident in a subset of beetles within the Galerucinae subfamily of Chrysomelidae (>90% identity with WCR Snf7 240 nt). This approach allowed for evaluating the relationship between minimum shared nt sequence length and activity. A shared sequence length of >= 21 nt was required for efficacy against WCR (containing 221 potential 21-nt matches) and all active orthologs contained at least three 21 nt matches. These results also suggest that WCR resistance to DvSnf7 dsRNA due to single nucleotide polymorphisms in the target sequence of 240 nt is highly unlikely. PMID- 23748932 TI - The new pig on the block: modelling cancer in pigs. AB - The molecular mechanisms underlying many human cancers are now reasonably well understood. The challenge now is to bridge the gap between laboratory and clinical oncology, so these accomplishments can be translated into practical benefits for human patients. While genetically modified mice have played a prominent role in basic research, they are less suitable for many preclinical studies. Other animals can provide important complementary resources to aid the development, validation and application of new medicines and procedures. Powerful methods of genetic engineering have now been extended to physiologically more relevant species, particularly the pig, opening the prospect of more representative, genetically defined, cancer models at human scale. We briefly review the field and outline our program to generate gene-targeted pigs carrying mutations in tumour suppressor genes and proto-oncogenes that replicate key lesions responsible for a variety of human cancers. We also highlight some important issues for the future development and usefulness of porcine cancer models. PMID- 23748933 TI - Transgenic accumulation of a defective cucumber mosaic virus (CMV) replicase derived double stranded RNA modulates plant defence against CMV strains O and Y in potato. AB - Cucumber mosaic virus is an important plant pathogen with a broad host range encompassing many plant species. This study demonstrates the production of transgenic potato lines exhibiting complete resistance to cucumber mosaic virus strain O and Y by post transcriptional gene silencing. Two constructs were used, one, pEKH2IN2CMVai, contains inverted repeat of 1,138 bp fragment of a defective CMV replicase gene derived from RNA2 of cucumber mosaic virus strain O (CMV-O), while the other, TRV-based VIGS vector (pTRV2CMVai), contains the same fragment of the replicase gene, but without inverted repeat. These constructs were used to produce transgenic potato lines of cultivar 'Danshaku', a susceptible genotype to CMV. Transgenic lines derived from pEKH2IN2CMVai accumulated small interfering RNA (siRNA) before and after virus challenge, whereas those derived from pTRV2CMVai showed siRNA expression after virus challenge. When transgenic lines were challenged with CMV-O or CMV-Y, four lines exhibited complete (100%) resistance to both strains, whereas the other lines had high levels of resistance. Infectivity of CMV-O was lower than that of CMV-Y in the highly resistant plants. There were no significant differences with regard to resistance between plants derived from pEKH2IN2CMVai and those obtained from pTRV2CMVai. The presence of CMV-specific siRNA in the resistant phenotypes indicates that the resistance was acquired through RNA silencing. PMID- 23748934 TI - Coniochaeta polymorpha, a new species from endotracheal aspirate of a preterm neonate, and transfer of Lecythophora species to Coniochaeta. AB - A new species of Coniochaeta from endotracheal secretion of a preterm neonate, Coniochaeta polymorpha, is described. This anamorphic species is characterized by development of dark brown colonies after 1 week of incubation on culture medium, formation of abundant yeast-like cells and sclerotium-like structures producing discrete, brown, nearly globose phialidic conidiogenous cells and absence of chlamydospores. A combined sequence dataset of the ITS region, partial LSU rDNA, actin and beta-tubulin genes sufficiently resolved the unique phylogenetic status of this species. In response to recent changes in the nomenclature for pleomorphic fungi, we transfer the Lecythophora species to Coniochaeta, and propose the following new combinations: Coniochaeta canina, Coniochaeta cateniformis, Coniochaeta decumbens, Coniochaeta fasciculata, Coniochaeta hoffmannii, Coniochaeta lignicola, Coniochaeta luteorubra, Coniochaeta luteoviridis and Coniochaeta mutabilis. PMID- 23748935 TI - Gas-particle partitioning of atmospheric aerosols: interplay of physical state, non-ideal mixing and morphology. AB - Atmospheric aerosols, comprising organic compounds and inorganic salts, play a key role in air quality and climate. Mounting evidence exists that these particles frequently exhibit phase separation into predominantly organic and aqueous electrolyte-rich phases. As well, the presence of amorphous semi-solid or glassy particle phases has been established. Using the canonical system of ammonium sulfate mixed with organics from the ozone oxidation of alpha-pinene, we illustrate theoretically the interplay of physical state, non-ideality, and particle morphology affecting aerosol mass concentration and the characteristic timescale of gas-particle mass transfer. Phase separation can significantly affect overall particle mass and chemical composition. Semi-solid or glassy phases can kinetically inhibit the partitioning of semivolatile components and hygroscopic growth, in contrast to the traditional assumption that organic compounds exist in quasi-instantaneous gas-particle equilibrium. These effects have significant implications for the interpretation of laboratory data and the development of improved atmospheric air quality and climate models. PMID- 23748936 TI - High performance of cyclic olefin copolymer-based capillary electrophoretic chips. AB - This paper demonstrates a simple, one step, and low cost surface modification technique for producing cyclic olefin copolymer (COC) polymer-based microcapillary electrophoresis chips consisting highly hemocompatible microchannels by UV-photografting with N-vinylpyrrolidone (NVP) monomer. An optimal condition has been identified to achieve the best surface grafting process. It has been found that this surface treatment enables extremely high surface wettability, hemocompatibility, and bond strength to the microchannels. The surface grafting was confirmed by attenuated total reflection Fourier transform-infrared spectroscopic (ATR-FTIR) study. In vitro protein adsorption using fluorescent labeled bovine serum albumin (FITC-BSA) into the COC microchannel results indicates that the modified chips have excellent protein resistance ability because of the increase of surface hydrophilicity. Hence, the modified chips showed fast, reproducible and high efficient separations of proteins (up to 51,000 theoretical plates per meter). Moreover, this surface modification process show no loss in the optical transparency to the modified microchannel surfaces: an important requirement for real capillary electrophoresis since the fluorescent intensity is directly related to the amount of adsorbed protein on the surface. Therefore, we believe that this simple and promising route of surface modification could be very useful for developing high performance COC microfluidic devices for the separation of proteins, amino acids, and other biomolecules. PMID- 23748937 TI - [Alcohol and public health in Latin America: how to prevent a health disaster?]. AB - Alcohol consumption is a public health problem in Latin America, being responsible for thousands of annual deaths and millions of healthy life years lost to acute and chronic conditions caused by alcohol. Consumption is higher and more prevalent among men, but women and adolescent girls are increasing their consumption more rapidly than men and adolescent boys. Beer is the alcoholic beverage most consumed, followed by distilled spirits; however, there are countries differences as some countries drink mostly wine. The industry which produces, distributes and sells alcoholic beverages is powerful, mostly globalized and with great political influence, so the current situation favors commercial interests at the expense of public health. Public policies in Latin America are insufficient to respond to the situation at national level, with little o no regulatory control of the availability of alcoholic beverages, prices and taxation policies or government control of marketing and promotion. There is limited research which can inform policy actions. Gaps in prevention and treatment of alcohol consumption and related problems are discussed as well as some perspectives for the future. PMID- 23748938 TI - [Colombia: out of the eye of the hurricane, but still close]. AB - Colombia is not the same country of the 80s and 90s of last century. The big drug cartels disappeared, but their heirs diversified their activities, created alliances with guerrillas and paramilitaries, and increased the number of minors associated with criminal behaviours. The country has not been systematic in its drug abuse data collection, and there is a remarkable imbalance in the investments made on drug supply and drug demand: 98% and 2%, respectively. However, the official reports assert that there are at least 300,000 people in need of treatment. Regarding drug abuse, Colombia is in the "middle range" in Latin America, together with Peru and Mexico; Chile, Argentina and Uruguay are above them, and Ecuador and Bolivia below. Drug consumption was decriminalized in 1994, and the implication was that those involved in drug abuse problems had to find their way out by themselves; this implication contributed to the poor development of the state treatment system. In spite of a new law imposing the obligation of free treatment to everyone asking for it, the health system is on the border of collapse and won't be able to face those requirements. PMID- 23748939 TI - Sense of coherence and substance use in Spanish adolescents. Does the effect of SOC depend on patterns of substance use in their peer group? AB - The aims of this work were to analyse the relationships between sense of coherence (SOC) and substance use among Spanish adolescents and to examine the potential moderator effect of the patterns of substance use in the peer group. Sample consisted of 5475 Spanish adolescents aged 15 to 18 from the 2010 edition of the Health Behaviour in School-aged Children (HBSC) study. Statistical analysis included cluster analysis to identify groups of adolescents according to their peer group's patterns of substance use and logistic regression with SOC and peers' pattern of consumption as predictors of current tobacco use, current alcohol use, life-time drunkenness and current drunkenness. The results showed that a strong SOC seemed to reduce the adolescents' likelihood of involving in tobacco use and drunkenness, but it was not associated with being a current drinker. In addition, the protective effect of SOC was moderated by peers' patterns of substance use. Specifically, SOC had a significant protective influence in adolescents whose peer group showed either a nonconsumption pattern or a pattern of frequent alcohol use and occasional drunkenness; but the protective effect of SOC disappeared if peers showed a pattern of consumption that included illegal drugs. In conclusion, SOC tends to act as a protective personal variable with respect to substance use during adolescence, but the influence exerted by the peer group seems to moderate the aforementioned protective effect of SOC. PMID- 23748940 TI - [Madrid study on the prevalence and characteristics of outpatients with dual pathology in community mental health and substance misuse services]. AB - The objective was to quantify the prevalence of dual diagnosis and to evaluate the characteristics of these patients from community mental health and substance misuse services in Madrid. The sample consisted of 837 outpatients from Madrid, 208 from mental health services and 629 from substance misuse services. We used the Mini International Neuropsychiatric Interview (MINI) and Personality Disorder Questionnaire (PDQ4+) to evaluate disorders from axis I and II. It was considered that 517 (61.8%) patients had dual pathology (current diagnoses of axis I or II disorders and an addictive disorder): 36,1% in mental health services and 70,3% in substance misuse services. There were fewer males amongst the dual patients and it was also found that they had a worse employment situation, along with higher figures of alcohol and cannabis dependence than addicts without dual diagnoses (n=194). When comparing them with patients with mental disorder diagnoses only, excluding substance use disorder (n=126), there were differences in all socio-demographic characteristics analyzed, and dual patients were associated with diagnoses of bipolar disorder, agoraphobia, generalized anxiety disorder, post-traumatic stress disorder, and had more suicide risk and different personality disorders. Thus, dual pathology is higher in patients who are in treatment and have differential characteristics (higher suicide risk, worse employment situation) that suggest greater severity that could be of help in the planning of care resource policies for these patients. PMID- 23748941 TI - [Relationship between psychopathological comorbidity and outcomes variables in treatment cocaine dependent subject in therapeutic community]. AB - Over the last years, the therapeutic community treatment with people who have cocaine problems and psychopathological comorbidity has been increasing and it is important to know more about the success of these treatments. The aim of this paper is to study the psychopathological profile of cocaine-dependent patients and its association with outcome variables. It is interviewed by the Psychiatric Research Interview for Substance and Mental Disorders (PRISM-IV) and the Conners' Adult ADHD Diagnostic Interview for DSM-IV (CAADID) a total sample of 218 patients who sought treatment at any of the six public therapeutics community of Andalusia (Spain). The results show that the retention rate after three months of 68.3% (149), 43.5% that leaves the resource with a therapeutic discharge and 52.8% with clinically significant changes. Besides, the 57.8% have psychopathological comorbidity. Finally, there is a higher treatment success (measured by days of stay, type of discharge and therapeutic community outcome clinical impression) among people without psychopathological comorbidity. These data show the need to adapt the therapeutic communities to treat people with comorbid psychopathology and, thus, improve therapeutic success. PMID- 23748942 TI - [Utility of dynamic pupillometry in alcohol testing on drivers]. AB - Pupillometry is becoming a relevant tool in Vision Sciences. So far, only a few studies have explored the relationship between pupil reflex measures and drug consumption. The aim of this study was to assess the applicability of dynamic mesopic pupillometry as an objective measurement method for the detection of blood alcohol levels above the legal limit. In a quasiexperimental design, 19 volunteers were asked to participate in two conditions (before and after alcohol intake). In session with alcohol intake, participants were asked to consume 27.5 ml of alcohol in 60 minute intervals for four hours. Pupillometry records were conducted by means of the Power Refractor II, using four types of light stimulation: white (5600 K), blue (450 nm), green (510 nm) and red (600 nm). The basal diameter of the pupil increased significantly for alcohol concentrations equal to or greater than 0.25 mg/l in exhaled breath. Moreover, the value of the amplitude for red light constriction also provided significant differences between the two conditions. These results are promising in the search for new methods to detect illegal alcohol levels among drivers. This study demonstrates that basal pupil diameter increase and amplitude response could be used as an alcohol consumption level indicator. However, further studies are necessary to validate this and other diagnose methods complementary to breathalyzer and other drugs tests. PMID- 23748943 TI - Criminological profile of patients in addiction treatment. AB - This study explores the prevalence of criminal behaviour in patients addicted to drugs who are in treatment. A sample of 252 addicted patients (203 male and 49 female) who sought outpatient treatment at a specialized centre was assessed. Information on criminal behaviours, socio-demographic factors, consumption factors (assessed by the EuropAsi), psychopathological factors (assessed by SCL 90-R) and personality variables (assessed by MCMI-II) was collected. Patients presenting criminal behaviour were compared with those who were not associated with crime for all the variables studied. The rate of drug-addicted patients with criminal behaviour in this sample was 60.3% (n = 150), and it was mainly related to traffic offenses, followed by drug dealing offenses. Significant differences were observed between patients with and without criminal behaviour. Patients with criminal problems were mostly men and single. Moreover, they were more likely to report poly-consumption. Furthermore, significant differences were observed on several variables: EuropAsi, SCL-90-R and MCMI-II. According to these results, patients with associated criminal behaviour presented a more severe addiction problem. The implications of these findings for clinical practice and future research are discussed. PMID- 23748944 TI - Affordability of alcohol and alcohol-related mortality in Belarus. AB - Alcohol abuse has numerous adverse health and social consequences. The consumer response to changes in alcohol affordability is an important issue on alcohol policy debates. Studies from many countries have shown an inverse relationship between alcohol prices and alcohol consumption in the population. There are, however, suggestions that increasing the price of alcohol by rising taxes may have limited effect on alcohol-related problems, associated with long-term heavy drinking. The aim of the present study was to evaluate the relationship between alcohol affordability and alcohol-related mortality rates in post-Soviet Belarus. For this purpose trends in alcohol-related mortality rates (mortality from liver cirrhosis, pancreatitis, alcoholism and alcohol psychoses) and affordability of vodka between 1990 and 2010 were compared. The time series analysis revealed that 1% increase in vodka affordability is associated with an increase in liver cirrhosis mortality of 0,77%, an increase in pancreatitis mortality of 0.53%, an increase in mortality from alcoholism and alcohol psychoses of 0,70%. The major conclusion emerging from this study is that affordability of alcohol is one of the most important predictor of alcohol-related problems in a population. These findings provide additional evidence that decreasing in affordability of alcohol is an effective strategy for reducing alcohol consumption and alcohol-related harm. PMID- 23748945 TI - [Evaluation of visual attentional biases in a sample of university smokers]. AB - The tobacco consumption continues being a worrying problem due to the negative consequences in the health. At presents, strategies of prevention based on the persuasion across clue pictures are used, which need to attract the attention of the smoker in order that they are effective. Nevertheless, the number of experimental studies in Spain on attentional biases in smokers is very limited. For it, in this study the aim was to verify the presence of visual attentional biases using the dot probe task in university smokers, stage where the smoking habit is consolidated. The sample was constituted by 337 students of the University of Huelva, with ages between 17 and 30 years. The participation was voluntary and the participants signed an informed assent. 135 subjects presented consumption history, which were distributed, according to classification of the WHO, in daily smokers, occasional smokers and former smokers. A experimental Ex post facto prospective design was used. The results showed that the smokers group was significantly later time to respond to the clue located in the same place that the tobacco picture than the group of not smokers. This shows that the smokers presented more difficulty to disconnect the attention towards smoking cues than not smokers. PMID- 23748946 TI - Attention deficit hyperactivity disorder and central nervous system depressants dependence. A review. AB - The comorbidity between attention deficit hyperactivity disorder (ADHD) and substance use disorders is very common. A review of literature addressing prevalence, clinical features and treatment of the comorbidity between ADHD and CNS depressants was conducted. The prevalences found have a wide range (4.5% to 58%). ADHD has been associated with greater severity of addiction, early onset of consumption and addiction, more psychiatric comorbidity and more chronicity. In drug-dependent patients the diagnosis is a complex process because the frequent overlap of symptoms. The screening instruments should be used with caution. Drug therapy has shown efficacy in reducing ADHD symptoms, but there is no consensus regarding their influence on substance use. However, results should be interpreted cautiously, because the samples are small. Psychoeducational interventions are relevant, but treatment outcomes have not been described or studied systematically. PMID- 23748947 TI - In-situ tapering of chalcogenide fiber for mid-infrared supercontinuum generation. AB - Supercontinuum generation (SCG) in a tapered chalcogenide fiber is desirable for broadening mid-infrared (or mid-IR, roughly the 2-20 MUm wavelength range) frequency combs(1, 2) for applications such as molecular fingerprinting, (3) trace gas detection, (4) laser-driven particle acceleration, (5) and x-ray production via high harmonic generation. (6) Achieving efficient SCG in a tapered optical fiber requires precise control of the group velocity dispersion (GVD) and the temporal properties of the optical pulses at the beginning of the fiber, (7) which depend strongly on the geometry of the taper. (8) Due to variations in the tapering setup and procedure for successive SCG experiments-such as fiber length, tapering environment temperature, or power coupled into the fiber, in-situ spectral monitoring of the SCG is necessary to optimize the output spectrum for a single experiment. In-situ fiber tapering for SCG consists of coupling the pump source through the fiber to be tapered to a spectral measurement device. The fiber is then tapered while the spectral measurement signal is observed in real time. When the signal reaches its peak, the tapering is stopped. The in-situ tapering procedure allows for generation of a stable, octave-spanning, mid-IR frequency comb from the sub harmonic of a commercially available near-IR frequency comb. (9) This method lowers cost due to the reduction in time and materials required to fabricate an optimal taper with a waist length of only 2 mm. The in-situ tapering technique can be extended to optimizing microstructured optical fiber (MOF) for SCG(10) or tuning of the passband of MOFs, (11) optimizing tapered fiber pairs for fused fiber couplers(12) and wavelength division multiplexers (WDMs), (13) or modifying dispersion compensation for compression or stretching of optical pulses.(14-16.) PMID- 23748949 TI - Barriers to the prescription of systemic therapies for moderate-to-severe psoriasis--a multinational cross-sectional study. AB - Despite the availability of a plethora of approved systemic treatments, high proportions of patients with moderate-to-severe psoriasis do not receive systemic treatment. This study aims at identifying barriers that hinder dermatologists from prescribing systemic treatments for psoriasis. A cross-sectional online survey in six countries (Canada, Germany, Spain, France, Italy, UK) was performed among 300 dermatologists, assessing the relevance of 15 potential barriers towards prescribing acitretin, cyclosporine, methotrexate, adalimumab, etanercept, infliximab and ustekinumab. Multivariate regression analyses were used to explore provider characteristics related to these barriers. Treatment barriers are perceived differently in the countries investigated, with Spanish, Italian and Canadian dermatologists being particularly concerned about the safety of methotrexate and Canadian dermatologists about the safety of cyclosporine. In general, safety concerns were the most important barrier to the use of cyclosporine, (18 % of participants' moderate/9 % strong or very strong barrier). Costs were being perceived as a strong or very strong barrier to the use of the different biologics by 19-24 % of the participants. Overall, country and work place were the most important determinants of treatment barriers. Sex, age, training, position and experience were minor determinants of treatment barriers. Medical reasons such as safety concerns or an inappropriate risk-benefit profile are particularly relevant barriers to the prescription of conventional treatments; whereas for biological treatments, economic reasons such as costs are more prevalent. Country specific analysis showed national differences in the perception of safety. The treatment barriers identified in this exploratory study should be confirmed in further health services research. PMID- 23748948 TI - Silk sericin ameliorates wound healing and its clinical efficacy in burn wounds. AB - The aim of this study was to evaluate the effect of silk sericin, a protein from silkworm cocoon, on scratch wound healing in vitro. For applicable result in clinical use, we also study the efficacy of sericin added to a standard antimicrobial cream, silver zinc sulfadiazine, for open wound care in the treatment of second-degree burn wounds. In vitro scratch assays show that sericin at concentration 100 MUg/mL can promote the migration of fibroblast L929 cells similar to epidermal growth factor (positive control) at 100 MUg/mL. After 1 day of treatment, the length of scratch in wounds treated with sericin was significantly shorter than the length of negative control wounds (culture medium without sericin). For clinical study, a total of 29 patients with 65 burn wounds which covered no less than 15 % of total body surface area were randomly assigned to either control (wounds treated with silver zinc sulfadiazine cream) or treatment (wounds treated with silver zinc sulfadiazine with added sericin cream) group in this randomized, double-blind, standard-controlled study. The results showed that the average time to reach 70 % re-epithelialization of the burned surface and complete healing in the treatment group was significantly shorter, approximately 5-7 days, than in the control group. Regarding time for complete healing, control wounds took approximately 29.28 +/- 9.27 days, while wounds treated with silver zinc sulfadiazine with added sericin cream took approximately 22.42 +/- 6.33 days, (p = 0.001). No infection or severe reaction was found in any wounds. This is the first clinical study to show that silk sericin is safe and beneficial for burn wound treatment when it is added to silver sulfadiazine cream. PMID- 23748950 TI - CABS-fold: Server for the de novo and consensus-based prediction of protein structure. AB - The CABS-fold web server provides tools for protein structure prediction from sequence only (de novo modeling) and also using alternative templates (consensus modeling). The web server is based on the CABS modeling procedures ranked in previous Critical Assessment of techniques for protein Structure Prediction competitions as one of the leading approaches for de novo and template-based modeling. Except for template data, fragmentary distance restraints can also be incorporated into the modeling process. The web server output is a coarse-grained trajectory of generated conformations, its Jmol representation and predicted models in all-atom resolution (together with accompanying analysis). CABS-fold can be freely accessed at http://biocomp.chem.uw.edu.pl/CABSfold. PMID- 23748951 TI - CoPAP: Coevolution of presence-absence patterns. AB - Evolutionary analysis of phyletic patterns (phylogenetic profiles) is widely used in biology, representing presence or absence of characters such as genes, restriction sites, introns, indels and methylation sites. The phyletic pattern observed in extant genomes is the result of ancestral gain and loss events along the phylogenetic tree. Here we present CoPAP (coevolution of presence-absence patterns), a user-friendly web server, which performs accurate inference of coevolving characters as manifested by co-occurring gains and losses. CoPAP uses state-of-the-art probabilistic methodologies to infer coevolution and allows for advanced network analysis and visualization. We developed a platform for comparing different algorithms that detect coevolution, which includes simulated data with pairs of coevolving sites and independent sites. Using these simulated data we demonstrate that CoPAP performance is higher than alternative methods. We exemplify CoPAP utility by analyzing coevolution among thousands of bacterial genes across 681 genomes. Clusters of coevolving genes that were detected using our method largely coincide with known biosynthesis pathways and cellular modules, thus exhibiting the capability of CoPAP to infer biologically meaningful interactions. CoPAP is freely available for use at http://copap.tau.ac.il/. PMID- 23748952 TI - SPARCS: a web server to analyze (un)structured regions in coding RNA sequences. AB - More than a simple carrier of the genetic information, messenger RNA (mRNA) coding regions can also harbor functional elements that evolved to control different post-transcriptional processes, such as mRNA splicing, localization and translation. Functional elements in RNA molecules are often encoded by secondary structure elements. In this aticle, we introduce Structural Profile Assignment of RNA Coding Sequences (SPARCS), an efficient method to analyze the (secondary) structure profile of protein-coding regions in mRNAs. First, we develop a novel algorithm that enables us to sample uniformly the sequence landscape preserving the dinucleotide frequency and the encoded amino acid sequence of the input mRNA. Then, we use this algorithm to generate a set of artificial sequences that is used to estimate the Z-score of classical structural metrics such as the sum of base pairing probabilities and the base pairing entropy. Finally, we use these metrics to predict structured and unstructured regions in the input mRNA sequence. We applied our methods to study the structural profile of the ASH1 genes and recovered key structural elements. A web server implementing this discovery pipeline is available at http://csb.cs.mcgill.ca/sparcs together with the source code of the sampling algorithm. PMID- 23748953 TI - Computational prediction of the localization of microRNAs within their pre-miRNA. AB - MicroRNAs (miRNAs) are short RNA species derived from hairpin-forming miRNA precursors (pre-miRNA) and acting as key posttranscriptional regulators. Most computational tools labeled as miRNA predictors are in fact pre-miRNA predictors and provide no information about the putative miRNA location within the pre miRNA. Sequence and structural features that determine the location of the miRNA, and the extent to which these properties vary from species to species, are poorly understood. We have developed miRdup, a computational predictor for the identification of the most likely miRNA location within a given pre-miRNA or the validation of a candidate miRNA. MiRdup is based on a random forest classifier trained with experimentally validated miRNAs from miRbase, with features that characterize the miRNA-miRNA* duplex. Because we observed that miRNAs have sequence and structural properties that differ between species, mostly in terms of duplex stability, we trained various clade-specific miRdup models and obtained increased accuracy. MiRdup self-trains on the most recent version of miRbase and is easy to use. Combined with existing pre-miRNA predictors, it will be valuable for both de novo mapping of miRNAs and filtering of large sets of candidate miRNAs obtained from transcriptome sequencing projects. MiRdup is open source under the GPLv3 and available at http://www.cs.mcgill.ca/~blanchem/mirdup/. PMID- 23748955 TI - Genome Maps, a new generation genome browser. AB - Genome browsers have gained importance as more genomes and related genomic information become available. However, the increase of information brought about by new generation sequencing technologies is, at the same time, causing a subtle but continuous decrease in the efficiency of conventional genome browsers. Here, we present Genome Maps, a genome browser that implements an innovative model of data transfer and management. The program uses highly efficient technologies from the new HTML5 standard, such as scalable vector graphics, that optimize workloads at both server and client sides and ensure future scalability. Thus, data management and representation are entirely carried out by the browser, without the need of any Java Applet, Flash or other plug-in technology installation. Relevant biological data on genes, transcripts, exons, regulatory features, single-nucleotide polymorphisms, karyotype and so forth, are imported from web services and are available as tracks. In addition, several DAS servers are already included in Genome Maps. As a novelty, this web-based genome browser allows the local upload of huge genomic data files (e.g. VCF or BAM) that can be dynamically visualized in real time at the client side, thus facilitating the management of medical data affected by privacy restrictions. Finally, Genome Maps can easily be integrated in any web application by including only a few lines of code. Genome Maps is an open source collaborative initiative available in the GitHub repository (https://github.com/compbio-bigdata-viz/genome-maps). Genome Maps is available at: http://www.genomemaps.org. PMID- 23748956 TI - ATHLATES: accurate typing of human leukocyte antigen through exome sequencing. AB - Human leukocyte antigen (HLA) typing at the allelic level can in theory be achieved using whole exome sequencing (exome-seq) data with no added cost but has been hindered by its computational challenge. We developed ATHLATES, a program that applies assembly, allele identification and allelic pair inference to short read sequences, and applied it to data from Illumina platforms. In 15 data sets with adequate coverage for HLA-A, -B, -C, -DRB1 and -DQB1 genes, ATHLATES correctly reported 74 out of 75 allelic pairs with an overall concordance rate of 99% compared with conventional typing. This novel approach should be broadly applicable to research and clinical laboratories. PMID- 23748954 TI - Recognition of O6-benzyl-2'-deoxyguanosine by a perimidinone-derived synthetic nucleoside: a DNA interstrand stacking interaction. AB - The 2'-deoxynucleoside containing the synthetic base 1-[(2R,4S,5R)-4-hydroxy-5 (hydroxymethyl)-tetrahydrofuran-2-yl)-1H-perimidin-2(3H)-one] (dPer) recognizes in DNA the O(6)-benzyl-2'-deoxyguanosine nucleoside (O(6)-Bn-dG), formed by exposure to N-benzylmethylnitrosamine. Herein, we show how dPer distinguishes between O(6)-Bn-dG and dG in DNA. The structure of the modified Dickerson-Drew dodecamer (DDD) in which guanine at position G(4) has been replaced by O(6)-Bn-dG and cytosine C(9) has been replaced with dPer to form the modified O(6)-Bn dG:dPer (DDD-XY) duplex [5' d(C(1)G(2)C(3)X(4)A(5)A(6)T(7)T(8)Y(9)G(10)C(11)G(12))-3']2 (X = O(6)-Bn-dG, Y = dPer) reveals that dPer intercalates into the duplex and adopts the syn conformation about the glycosyl bond. This provides a binding pocket that allows the benzyl group of O(6)-Bn-dG to intercalate between Per and thymine of the 3' neighbor A:T base pair. Nuclear magnetic resonance data suggest that a similar intercalative recognition mechanism applies in this sequence in solution. However, in solution, the benzyl ring of O(6)-Bn-dG undergoes rotation on the nuclear magnetic resonance time scale. In contrast, the structure of the modified DDD in which cytosine at position C(9) is replaced with dPer to form the dG:dPer (DDD-GY) [5'-d(C(1)G(2)C(3)G(4)A(5)A(6)T(7)T(8)Y(9)G(10)C(11)G(12))-3']2 duplex (Y = dPer) reveals that dPer adopts the anti conformation about the glycosyl bond and forms a less stable wobble pairing interaction with guanine. PMID- 23748957 TI - The UCSC Interaction Browser: multidimensional data views in pathway context. AB - High-throughput data sets such as genome-wide protein-protein interactions, protein-DNA interactions and gene expression data have been published for several model systems, especially for human cancer samples. The University of California, Santa Cruz (UCSC) Interaction Browser (http://sysbio.soe.ucsc.edu/nets) is an online tool for biologists to view high-throughput data sets simultaneously for the analysis of functional relationships between biological entities. Users can access several public interaction networks and functional genomics data sets through the portal as well as upload their own networks and data sets for analysis. Users can navigate through correlative relationships for focused sets of genes belonging to biological pathways using a standard web browser. Using a new visual modality called the CircleMap, multiple 'omics' data sets can be viewed simultaneously within the context of curated, predicted, directed and undirected regulatory interactions. The Interaction Browser provides an integrative viewing of biological networks based on the consensus of many observations about genes and their products, which may provide new insights about normal and disease processes not obvious from any isolated data set. PMID- 23748958 TI - Scalable web services for the PSIPRED Protein Analysis Workbench. AB - Here, we present the new UCL Bioinformatics Group's PSIPRED Protein Analysis Workbench. The Workbench unites all of our previously available analysis methods into a single web-based framework. The new web portal provides a greatly streamlined user interface with a number of new features to allow users to better explore their results. We offer a number of additional services to enable computationally scalable execution of our prediction methods; these include SOAP and XML-RPC web server access and new HADOOP packages. All software and services are available via the UCL Bioinformatics Group website at http://bioinf.cs.ucl.ac.uk/. PMID- 23748959 TI - HIV N-linked glycosylation site analyzer and its further usage in anchored alignment. AB - N-linked glycosylation is a posttranslational modification that has significantly contributed to the rapid evolution of HIV-1. In particular, enrichment of N linked glycosylation sites can be found within Envelope variable loops, regions that play an essential role in HIV pathogenesis and immunogenicity. The web server described here, the HIV N-linked Glycosylation Site Analyzer, was developed to facilitate study of HIV diversity by tracking gp120 N-linked glycosylation sites. This server provides an automated platform for mapping and comparing variable loop N-linked glycosylation sites across populations of HIV-1 sequences. Furthermore, this server allows for refinement of HIV-1 sequence alignment by using N-linked glycosylation sites in variable loops as alignment anchors. Availability of this web server solves one of the difficult problems in HIV gp120 alignment and analysis imposed by the extraordinary HIV-1 diversity. The HIV N-linked Glycosylation Site Analyzer web server is available at http://hivtools.publichealth.uga.edu/N-Glyco/. PMID- 23748960 TI - Inferring the functional effect of gene expression changes in signaling pathways. AB - Signaling pathways constitute a valuable source of information that allows interpreting the way in which alterations in gene activities affect to particular cell functionalities. There are web tools available that allow viewing and editing pathways, as well as representing experimental data on them. However, few methods aimed to identify the signaling circuits, within a pathway, associated to the biological problem studied exist and none of them provide a convenient graphical web interface. We present PATHiWAYS, a web-based signaling pathway visualization system that infers changes in signaling that affect cell functionality from the measurements of gene expression values in typical expression microarray case-control experiments. A simple probabilistic model of the pathway is used to estimate the probabilities for signal transmission from any receptor to any final effector molecule (taking into account the pathway topology) using for this the individual probabilities of gene product presence/absence inferred from gene expression values. Significant changes in these probabilities allow linking different cell functionalities triggered by the pathway to the biological problem studied. PATHiWAYS is available at: http://pathiways.babelomics.org/. PMID- 23748961 TI - Exploring the origins of the apparent "electrocatalytic" oxidation of kojic acid at graphene modified electrodes. AB - We explore the recent reports that the use of graphene modified electrodes gives rise to the electrocatalytic oxidation of kojic acid. It is demonstrated that large quantifiable voltammetric signatures are observed on bare/unmodified graphitic electrodes, which are shown to be analytically useful and superior to those observed at graphene modified alternatives. This work is of importance as it shows that control experiments are critical and must be undertaken before "electrocatalysis" is conferred when investigating graphene in electrochemistry. In terms of the electroanalytical response of graphene modified electrodes, a bare edge plane pyrolytic graphite electrode is shown to give rise to an improved linear range and limit of detection, questioning the need to modify electrodes with graphene. PMID- 23748962 TI - Does power help or hurt? The moderating role of self-other focus on power and perspective-taking in romantic relationships. AB - Reconciling competing viewpoints suggesting that power helps and hurts perspective-taking in close relationships, in two experiments and two daily experience studies we tested the hypothesis that power's effect on perspective taking depends on the extent to which people are relatively self-versus other focused. In Study 1, recalling a time of high (vs. low) power over a romantic partner reduced inclinations to take the partner's perspective for relatively self-focused but not other-focused individuals. Studies 2 and 3 replicated Study 1 using daily variations in power and perspective-taking. In Study 4, being the "in-charge" partner during a conflict conversation reduced empathic accuracy for more self-focused individuals. Self-other focus was assessed with measures of gratitude, relational self-construal, and social value orientation. The current findings provide evidence that, particularly for the more self-focused, relationship power influences people's inclinations to take their romantic partner's perspective in daily life as well as their empathic accuracy during conflict. PMID- 23748964 TI - Interaction of warm acclimation, low salinity, and trophic fluoride on plasmatic constituents of the Antarctic fish Notothenia rossii Richardson, 1844. AB - The adaptive evolution of the Notothenia rossii occurred under the selective pressure of stable and low temperatures. It is an opportunistic feeder of Antarctic krill and the fluoride in the krill carapace is apparently not toxic. We investigated the interactive effect of fluoride, elevated temperatures, and low salinity on the plasmatic constituents of this Antarctic fish. The experiments were conducted at the Brazilian Antarctic Station Comandante Ferraz (EACF), located on King George Island. The Antarctic fish N. rossii was acclimatized to eight thermo-saline-trophic conditions, combining two temperatures (0 and 4 degrees C), two salinities (35 and 20), and two trophic conditions (with/without fluoride) for an 11-day period. Trophic fluoride was not able to alter the plasmatic levels of glucose, cholesterol, plasmatic protein, Cl , Mg2+, Ca2+, and inorganic phosphate, but induced an acute elevation of triglycerides at 0 degrees C and salinity of 35. At low salinity, hyperglycemia, hypertriglyceridemia, and hypocalcemia were observed. The thermo-saline interaction at 4 degrees C was able to minimize the effects of fluoride and low salinity on the plasmatic constituents levels. PMID- 23748963 TI - Enteroendocrine profile of alpha-transducin immunoreactive cells in the gastrointestinal tract of the European sea bass (Dicentrarchus labrax). AB - In vertebrates, chemosensitivity of nutrients occurs through the activation of taste receptors coupled with G-protein subunits, including alpha-transducin (G(alphatran)) and alpha-gustducin (G(alphagust)). This study was aimed at characterising the cells expressing G(alphatran) immunoreactivity throughout the mucosa of the sea bass gastrointestinal tract. G(alphatran) immunoreactive cells were mainly found in the stomach, and a lower number of immunopositive cells were detected in the intestine. Some G(alphatran) immunoreactive cells in the stomach contained G(alphagust) immunoreactivity. Gastric G(alphatran) immunoreactive cells co-expressed ghrelin, obestatin and 5-hydroxytryptamine immunoreactivity. In contrast, G(alphatran) immunopositive cells did not contain somatostatin, gastrin/cholecystokinin, glucagon-like peptide-1, substance P or calcitonin gene related peptide immunoreactivity in any investigated segments of the sea bass gastrointestinal tract. Specificity of G(alphatran) and G(alphagust) antisera was determined by Western blot analysis, which identified two bands at the theoretical molecular weight of ~45 and ~40 kDa, respectively, in sea bass gut tissue as well as in positive tissue, and by immunoblocking with the respective peptide, which prevented immunostaining. The results of the present study provide a molecular and morphological basis for a role of taste-related molecules in chemosensing in the sea bass gastrointestinal tract. PMID- 23748965 TI - Preliminary studies on the renaturation of denatured catfish (Clarias gariepinus) glutathione transferase. AB - Purified juvenile catfish (Clarias gariepinus) glutathione transferase (cgGST) was denatured in vitro and renatured in the absence and presence of different concentrations of endogenous or xenobiotic model substrates. Protein transitions during unfolding and refolding were monitored by activity measurement as well as changes in protein conformation using UV difference spectra at 230 nm. Gdn-HCl at 0.22 M caused 50 % inactivation of the enzyme and at 1.1 M, the enzyme was completely unfolded. Refolding of cgGST main isozyme was not completely reversible at higher concentrations of Gdn-HCl and is dependent on protein concentration. An enzyme concentration of 30 MUg/ml yielded 40 % percentage residual activity in the presence of glutathione (GSH), regardless of the concentration that was present as opposed to 30 % obtained in its absence. The xenobiotic model substrate, lindane, appears to have no effect on the refolding of the enzyme. In summary, our results show that GSH assists in the refolding of cgGST in a concentration-independent manner and may be involved in the same function in vivo whereas the xenobiotic model substrate does not. PMID- 23748966 TI - Trichoderma reesei histone acetyltransferase Gcn5 regulates fungal growth, conidiation, and cellulase gene expression. AB - Gcn5 is a well-established histone acetyltransferase involved in chromatin modification by catalyzing the acetylation of specific lysine residues within the N-terminal tails of the core histones. To assess the role of chromatin remodeling in the transcriptional response of cellulolytic Trichoderma reesei to the changes of environmental conditions, we identified the T. reesei ortholog of Saccharomyces cerevisiae Gcn5 by sequence alignment and functional analysis. Heterologous expression of TrGcn5 in S. cerevisiae gcn5Delta strain restored the growth defect under nutrient limitation as well as stresses. In contrast, mutant TrGcn5 with site-directed changes of residues critical for Gcn5 histone acetyltransferase activity could not complement the growth defect. The T. reesei gcn5Delta mutant strain displayed a strongly decreased growth rate and dramatic morphological changes including misshapen hyphal cells and abolished conidiation. Moreover, the induced expression of cellulase genes was severely impaired in the gcn5Delta T. reesei with acetylation of K9 and K14 of histone H3 in the cellulase gene promoter dramatically affected in the absence of TrGcn5. The results indicate that TrGcn5 plays a critical role in filamentous growth, morphogenesis, and transcriptional activation of specific genes including cellulase encoding genes. PMID- 23748967 TI - Serological cross-reaction between O-antigens of Shigella dysenteriae type 4 and an environmental Escherichia albertii isolate. AB - An environmental freshwater bacterial isolate, DM104, appearing as Shigella-like colonies on selective agar plates was found to show strong and specific serological cross-reactivity with Shigella dysenteriae type 4. Biochemical identification according to the analytical profile index, molecular serotyping by restriction of the amplified O-antigen gene cluster (rfb-RFLP), together with phylogenetic analysis of the 16S rRNA gene and multi-locus sequence analysis, identified the isolate as Escherichia albertii. rfb-RFLP of DM104, revealed a profile different from that of S. dysenteriae type 4. However, western blot analysis of extracted lipopolysaccharides demonstrated strong cross-reactivity with S. dysenteriae type 4 using specific monovalent antisera and a lipopolysaccharide gel banding profile similar to that of S. dysenteriae type 4. The observed O-antigen cross-reaction between an E. albertii isolate and S. dysenteriae extends our knowledge of the extent of O-antigen cross-reaction within the Escherichia/Shigella group of organisms, and offers the possibility of using DM104 and similar cross-reacting strains as shigellosis vaccine candidates. PMID- 23748968 TI - Not-to-tap cystic lesions: spectrum of hydatid disease. AB - Hydatid disease (HD) may occur almost anywhere in the body. Despite their characteristic radiologic manifestations at times, they may enlarge and produce bizarre imaging features which make diagnosis challenging, particularly for those radiologists working in areas of low incidence. Plain radiography, ultrasonography, computed tomography, and magnetic resonance imaging may demonstrate some of the typical imaging manifestations of HD as well as its exact extension. On the other hand, particular caution is required before any kind of interventions to be done in that biopsy or aspiration of such lesions may cause devastating consequences, in particular anaphylactic shock. Hence, being familiar with various radiologic features of HD is essential in improving diagnostic accuracy and also preventing adverse reactions in these patients. The purpose of this pictorial review is to illustrate the different radiological features of HD in various organs. PMID- 23748969 TI - Therapeutic enema for pediatric ileocolic intussusception: using a balloon catheter improves efficacy. AB - A therapeutic enema for pediatric intussusception may benefit by using a rectal catheter with an inflated balloon. We compared the efficacy of rectal catheters without and with an inflated balloon for air and liquid enemas. We retrospectively reviewed PACS images and hospital records of children who had a therapeutic enema for intussusception at our institution between January 2006 and May 2011. Sixty-two enemas in 60 children were included. Physician assistants with training in pediatric fluoroscopy and pediatric radiologists were more likely to use air enema (37/41 or 90 %), and general radiologists were more likely to use liquid enema (18/21 or 86 %). However, the reduction rate for air enema overall was only slightly higher than for liquid enema using an inflated balloon catheter (36/40 or 90 % versus 14/17 or 82 %) (P=0.653). For air enema, mean procedure time for successful reductions was shorter with an inflated balloon catheter than with a plastic catheter (7.6 versus 28.2 min) (P<0.009), but the reduction rate was not affected. For liquid enema, the reduction rate was higher with an inflated balloon catheter than without inflation (14/17 or 82 % versus 1/5 or 20 %; P=0.021), but the procedure time was not shortened. No procedural complications were directly attributed to using a rectal catheter with an inflated balloon. Using a rectal catheter with an inflated balloon appears to safely shorten the procedure time of a successful air enema and improve the reduction rate of liquid enema. PMID- 23748971 TI - On-surface single molecule synthesis chemistry: a promising bottom-up approach towards functional surfaces. AB - In this review, we introduce recent progress on surface synthesis and focus on supramolecular self-assembled structures driven by several typical chemical reactions at solid surfaces, with the aid of scanning tunneling microscopy (STM). We also emphasize the relationship between the non-covalent self-assembly and surface reactivity, by which we hope to find an effective way for further controllable nano-manufacture. PMID- 23748970 TI - Haemodynamically dependent valvulogenesis of zebrafish heart is mediated by flow dependent expression of miR-21. AB - Heartbeat is required for normal development of the heart, and perturbation of intracardiac flow leads to morphological defects resembling congenital heart diseases. These observations implicate intracardiac haemodynamics in cardiogenesis, but the signalling cascades connecting physical forces, gene expression and morphogenesis are largely unknown. Here we use a zebrafish model to show that the microRNA, miR-21, is crucial for regulation of heart valve formation. Expression of miR-21 is rapidly switched on and off by blood flow. Vasoconstriction and increasing shear stress induce ectopic expression of miR-21 in the head vasculature and heart. Flow-dependent expression of mir-21 governs valvulogenesis by regulating the expression of the same targets as mouse/human miR-21 (sprouty, pdcd4, ptenb) and induces cell proliferation in the valve forming endocardium at constrictions in the heart tube where shear stress is highest. We conclude that miR-21 is a central component of a flow-controlled mechanotransduction system in a physicogenetic regulatory loop. PMID- 23748973 TI - A new pleiotropic effect of statins in elderly: modulation of telomerase activity. AB - Recent evidence suggests a link between statins and telomere biology. Whether statin treatment may modulate telomerase activity and affect telomere erosion rate is unknown. We aimed at investigating the potential impact of statin therapy on peripheral blood mononuclear cells telomerase activity, its implication on LTL variability, and its association with telomere shortening rates along with aging. The cross-sectional study was conducted in 230 subjects (age range: 30-86 y) stratified according to statins treatment. LTL was measured by quantitative polymerase chain reaction and telomerase activity by a PCR-ELISA protocol. Subjects on statin treatment showed higher telomerase activity (P<0.0001) and longer LTL (P=0.028) levels compared to the nonstatin group. Statin therapy was associated with higher telomerase activity independently of multiple covariates, including age, gender, smoking habits, lipid, systemic inflammation, glucose, and blood pressure levels (P=0.019). Indeed, subjects on statin treatment showed significant lower telomere erosion along with aging. Every 1 y increment in age, LTL decreases by 0.058 Kb in no statin and 0.033 Kb in statin groups, respectively, as well as the major difference in telomere attrition between groups was found after the age of 65 yr (P<0.0001). In summary, statins, modulating telomerase activity, affect telomere erosion along with aging. PMID- 23748972 TI - Interplay between the overlapping ends of tropomyosin and the N terminus of cardiac troponin T affects tropomyosin states on actin. AB - The functional significance of the molecular swivel at the head-to-tail overlapping ends of contiguous tropomyosin (Tm) dimers in striated muscle is unknown. Contractile measurements were made in muscle fibers from transgenic (TG) mouse hearts that expressed a mutant alpha-Tm (Tm(H276N)). We also reconstituted mouse cardiac troponin T (McTnT) N-terminal deletion mutants, McTnT(1-44Delta) and McTnT(45-74Delta), into muscle fibers from Tm(H276N). For controls, we used the wild-type (WT) McTnT because altered effects could be correlated with the mutant forms of McTnT. Tm(H276N) slowed crossbridge (XB) detachment rate (g) by 19%. McTnT(1-44Delta) attenuated Ca(2+)-activated maximal tension against Tm(WT) (36%) and Tm(H276N) (38%), but sped g only against Tm(H276N) by 35%. The rate of tension redevelopment decreased (17%) only in McTnT(1-44Delta) + Tm(H276N) fibers. McTnT(45-74Delta) attenuated tension (19%) and myofilament Ca(2+) sensitivity (pCa50=5.93 vs. 6.00 in the control fibers) against Tm(H276N), but not against Tm(WT) background. Thus, altered XB cycling kinetics decreased the fraction of strongly bound XBs in McTnT(1-44Delta) + Tm(H276N) fibers, whereas diminished thin-filament cooperativity attenuated tension in McTnT(45-74Delta) + Tm(H276N) fibers. In summary, our study is the first to show that the interplay between the N terminus of cTnT and the overlapping ends of contiguous Tm effectuates different states of Tm on the actin filament. PMID- 23748974 TI - Molecular analysis of parapoxvirus detected in eight calves in Japan. AB - Molecular analysis of parapoxvirus envelope genes was performed. Parapoxvirus DNA was detected in eight calves from eight farms in Iwate Prefecture, Japan, between April and September 2010. Seven of the detected viruses were identified as bovine papular stomatitis virus (BPSV) by sequencing, because their nucleotide identity was more than 96.8% similar compared with BPSV strain V660. Among them, two formed a subgroup, because their amplicons were digested with Xmn I (a marker for BPSV) and Hinc II and exhibited a T61C nucleotide substitution in the sequenced region. The remaining virus was pseudocowpox virus that had not been reported previously in Japan. Our results demonstrate the presence of a new BPSV variant in Japan with genetic variability in the envelope gene. PMID- 23748975 TI - Characterization of glycoproteins in equine herpesvirus-1. AB - In this study, we attempted to express twelve glycoproteins of equine herpesvirus 1 (EHV-1) in 293T cells and to characterize these using monoclonal antibodies (MAbs) and horse sera against EHV-1. Expression of glycoprotein B (gB), gC, gD, gG, gI and gp2 was recognized by immunoblot analysis using horse sera, but that of gE, gH, gK, gL, gM and gN was not. Four MAbs recognized gB, four recognized gC and one recognized gp2. Two MAbs against gB cross-reacted with EHV-4. Interestingly, coexpression of gE and gI and gM and gN enhanced their antigenicity. Furthermore, immunoblot analysis of gp2 showed that different molecular masses of gp2 were recognized by the MAb against gp2 and horse sera against EHV-1. In this study, it was demonstrated that at least six glycoproteins were immunogenic to horses, and coexpression of gE and gI and gM and gN was important for enhancement of antigenicity. PMID- 23748976 TI - Insulin-ameliorated peripheral motor neuropathy in spontaneously diabetic WBN/Kob rats. AB - Rodent models of diabetes develop a slowing of nerve conduction velocity and mild axonal atrophy, but generally lack overt degenerative neuropathy. Spontaneously diabetic Wistar Bonn Kobori (WBN/Kob) rats develop severe diabetic peripheral motor neuropathy with a slowing of nerve conduction velocity. We examined the effect of glycemic control, using insulin implant, on neuropathic changes in these rats. Animals were divided into 2 groups: WBN group (spontaneously occurring diabetes rats) and WBN + insulin group (spontaneously occurring diabetes rats treated with insulin implants until 90 weeks of age). Conduction velocity was measured in sciatic-tibial motor nerves. These nerves also underwent qualitative and quantitative histomorphologic analysis. Mild to severe hyperglycemia (>200 mg/dl) and glycosuria (>100 mg/dl) were observed in the WBN group. In contrast, the blood glucose level of the WBN + insulin group fluctuated between normoglycemia (<200 mg/dl) and hyperglycemia. Conduction velocity significantly decreased in WBN group compared with WBN + insulin group. Morphologic analysis of the sciatic and tibial nerves of WBN group showed severe changes, including axonal degeneration, myelin distention, endoneurial fibrosis and microangiopathy. Insulin treatment corrected these changes without microangiopathy. These results suggest that insulin could decrease axonal atrophy and myelin distension of peripheral nerve in diabetic WBN/Kob rats. Observation of WBN/Kob rats revealed changes of axon, myelin and capillary caused by diabetes, thus indicating that this animal is a suitable model for investigating diabetic peripheral neuropathy. PMID- 23748977 TI - Headache as a symptom at stroke onset in 4,431 young ischaemic stroke patients. Results from the "Stroke in Young Fabry Patients (SIFAP1) study". AB - Headache as symptom of stroke is linked to gender, history of migraine, younger age, cerebellar stroke, and low blood pressure. These associations have been controversial, large scale studies are missing. We used the stroke in young fabry patients study to examine the association of demographic, clinical and imaging factors with the occurrence of headache in 4,431 young ischaemic stroke patients (18-55 years; mean: 44.7 years) with an ischemic cerebrovascular event (CVE) (ischemic stroke-IS 75.9%, TIA 24.1%). Headache in males occurred more frequently in bilateral localisation (right/left/bilateral: 27.5, 24.6, 39.2%, p < 0.01), but not in females (40.3, 34.7, 39.6%). Headache occurrence was more often associated in both genders with IS or TIA in the posterior cerebral territory (male: 33.2%, p < 0.05; female: 51.0%, p < 0.01) and vertebrobasilar arteries (male: 44.8%, p < 0.001; female: 51.2%, p < 0.001). The larger the size of the most prominent lesion the more likely patients were complaining headache during the IS (<=1 cm vs. >half lobe: 19.5 vs. 28.4% in male, p < 0.001; 28.9 vs. 39.1% in female, p < 0.01). Binary logistic regression analyses revealed lower age (p < 0.001), female sex (p < 0.001), larger size of the largest lesion (p < 0.001), and localization in the vertebrobasilar territory (p < 0.001) as predictors for headache during CVE. Headache at stroke onset is more common during IS in females, younger patients, with greater size of the acute lesion, and affected in posterior cerebral artery or vertebrobasilar system. Headache is a leading symptom in specific combination of stroke factors. These factors should be taken into account when patients report headache during IS or TIA. PMID- 23748978 TI - Is there an association between inflammatory bowel diseases and carotid intima media thickness? Preliminary data. AB - Inflammation is a predictor of cardiovascular disease (CVD). Thus, inflammatory bowel diseases (IBD) may be associated with CVD. We assessed carotid intima-media thickness (cIMT; an indicator of CVD risk) in 42 patients with IBD, free of CVD or diabetes; 26 with Crohn's disease (CD) and 16 with ulcerative colitis (UC). The cIMT was significantly greater in patients with IBD compared to 42 healthy controls (0.62 +/- 0.08 vs 0.52 +/- 0.06 mm; P < .0005). The cIMT did not differ between patients with CD and UC or between the different disease activity and treatment groups. Factors associated with cIMT were age, body mass index, and IBD, with the latter making a greater contribution. The IBD is a predictor of cIMT, even when other CVD risk factors are considered. These findings suggest an association between early arterial wall alterations and IBD. Such an association should be proven in larger studies that should assess the incidence of CVD in patients with IBD. PMID- 23748979 TI - Is the neutrophil-to-lymphocyte ratio a crucial indicator of systemic inflammation, coronary artery ectasia, and atherogenesis? PMID- 23748980 TI - Inflammatory condition in coronary artery ectasia. PMID- 23748982 TI - Smoking cessation can improve arterial stiffness. PMID- 23748981 TI - Prolidase activity in patients with coronary artery aneurysm. AB - Decreased collagen biosynthesis and increased collagenolysis may induce aneurysmal progress in arterial walls. Prolidase plays a role in collagen synthesis. In this study, we sought to evaluate whether there is a correlation between nonatherosclerotic coronary artery aneurysms (CAAs) and prolidase activity. A total of 174 CAAs were diagnosed in 144 (2.1%) patients among 6845 coronary angiographies performed between 2009 and 2012. In all, 23 (15.9%) patients had nonatherosclerotic aneurysms. Prolidase activity was compared to the results of 19 healthy volunteers with normal coronary arteries. Demographic parameters were similar between the groups. Mean prolidase activity was 241.6 +/- 54.4 mU/mL in the coronary aneurysm group and 730.3 +/- 243.1 mU/mL in the control group (P < .001). The incidence of CAAs ranges between 0.3% and 5.3% in the general population. Decreased prolidase activity may reduce collagen biosynthesis that may contribute to aneurysm formation. PMID- 23748983 TI - What brings children home? A prognostic study to predict length of hospitalisation. AB - Adequate discharge planning could improve patient health and reduce readmissions. Increased accessibility and adequate use of hospital capacity are asking for an adequate discharge planning by means of efficient prediction of length of stay (LOS). Predictive factors of LOS for paediatric patients are lacking in the current available evidence. We aimed to identify these predictive factors in order to predict an optimal LOS. We conducted a prognostic study of all patients admitted to five different paediatric wards of Emma Children's Hospital, a tertiary university hospital in the Netherlands. We investigated possible predictive factors based on the literature and an expert panel categorised in patient characteristics and medical and non-medical factors. This preliminary list was scored for all patients at the moment of discharge. All significant or relevant factors were used in a linear regression model to predict the LOS. We included 142 patients and explored the relationship between 28 variables, reflecting a mix of patient characteristics, medical and non-medical factors and LOS. In a univariable analysis, 17 variables were significantly related with LOS. Multivariable analysis found seven independent variables: sex, age category, specialism, risk of malnutrition, complications, home care and the involvement of other disciplines. These seven variables explained 48 % of the LOS (R(2) of 0.476). CONCLUSION: Predictors of LOS consist patient characteristics, medical factors as well as non-medical factors (i.e. the need for home care and other disciplines). The latter factors can be influenced by changes in hospital policies. PMID- 23748984 TI - A rare location of sucking blister in newborn: the lips. AB - A male baby was presented with sucking blisters on the upper and lower lips developed immediately after the birth. Although sucking blister which develops on the lips during the postnatal period is known, its prenatal form has not been described previously. We reported a case of sucking blister on the lips which developed during the intrauterine life. In the present case, these lesions resolved spontaneously after 1 day. PMID- 23748985 TI - Exposure to media predicts use of dietary supplements and anabolic-androgenic steroids among Flemish adolescent boys. AB - This study examined whether different types of media affect the use of dietary proteins and amino acid supplements, and intent to use anabolic-androgenic steroids. A random sample of 618 boys aged 11-18 years from eight schools in the Flemish part of Belgium completed standardized questionnaires as part of the Media and Adolescent Health Study. The survey measured exposure to sports media, appearance-focused media, fitness media, use of dietary supplements, and intent to use anabolic-androgenic steroids. Data were analyzed using logistic regressions and are presented as adjusted odds ratios (OR) and 95 % confidence intervals (CI); 8.6 % indicated to have used dietary proteins, 3.9 % indicated to have used amino acid supplements, and 11.8 % would consider using anabolic androgenic steroids. After adjusting for fitness activity, exposure to fitness media was associated with the use of dietary proteins (OR = 7.24, CI = 2.25 23.28) and amino acid supplements (5.16, 1.21-21.92; 44.30, 8.25-238). Intent to use anabolic-androgenic steroids was associated with exposure to fitness media (2.38, 1.08-5.26; 8.07, 2.55-25.53) and appearance-focused media (6.02, 1.40 25.82; 8.94, 1.78-44.98). Sports media did not correlate with the use of dietary supplements and intent to use anabolic-androgenic steroids. Specific types of media are strong predictors of the use of supplements in adolescent boys. This provides an opportunity for intervention and prevention through the selection of fitness media as a communication channel. Health practitioners should also be aware that the contemporary body culture exerts pressure not only on girls but also on boys. PMID- 23748987 TI - From school paper to published article. PMID- 23748988 TI - Qualitative research in clinical nurse specialist practice. PMID- 23748989 TI - Intravenous acetaminophen--progress in relief of pain?: Implications for clinical nurse specialist practice. PMID- 23748991 TI - Perceived knowledge and self-confidence of pediatric nurses as patient educators. AB - Patient education is an integral component of nursing care. Patient education has been associated with favorable patient outcomes but may be difficult if resources are unavailable, "teachable moments" are unrecognized, or if self-confidence of the nurses providing the education is low. Using the theoretical model developed by the authors and focusing on the delivery of patient/family education, we examined pediatric nurses' perceptions about patient/family education in the hospital setting. A 20-item questionnaire that explored factors affecting teaching behaviors of 54 pediatric nurses in an acute care hospital setting was completed. Results from this study suggest that pediatric nurses' confidence was disorder-specific. Nurses were confident providing education about common disorders (asthma, pneumonia, and bronchiolitis) and less confident providing education about less common disorders (oncology, cardiac). The barrier to providing education identified most often was lack of written materials. Findings from this study can be used to develop teaching resources for nurses and to plan educational programs specific to less common pediatric problems. PMID- 23748990 TI - Caring for parents with neurodegenerative disease: a qualitative description. AB - PURPOSE/OBJECTIVE: The objective of this study was to explore the positive aspects experienced by adult children in providing care to their parent who has either Parkinson's or Alzheimer's disease. DESIGN: A qualitative descriptive approach was used to analyze audiotaped in-depth semistructured interviews that were conducted with 34 adult children who were primary caregivers as part of a larger randomized clinical trial. SETTING: Individual interviews were conducted by trained research assistants in the caregiver's home. SAMPLE: Thirty-four adult children caregivers who were primary caregivers for their respective 34 parents. Seventy-six percent (n = 26) of the caregivers were caring for a parent with Alzheimer's disease. Twenty-four percent (n = 8) were caring for a parent with Parkinson's disease. Eighty-two percent were adult daughters. Mean age of the caregiver was 52 years, and the mean age of the parent was 81 years. Fifty-three percent of caregivers were white, and 47% were black. DATA ANALYSIS: A conventional content analysis was performed to summarize themes. FINDINGS: Results indicated that most caregivers had positive experiences. Three relationship-centered themes were identified: spending and enjoying time together, appreciating each other and becoming closer, and giving back care. A small number of caregivers (n = 6) could not identify positive experiences. CONCLUSION/IMPLICATIONS: Caregivers who had positive experiences in caregiving expressed fewer feelings of being overwhelmed or distressed by their situations. Further study is needed on caregivers who do not experience positive aspects in caring for a parent, and these caregivers potentially may be a group that warrants further intervention by advanced practice nurses. PMID- 23748992 TI - Comparison of 2 techniques used to obtain sterile urine specimens from urethral catheters. AB - OBJECTIVE: The objective of this study was to compare the rates of urine contamination and the frequencies of minor adverse events between the vacuum tube and injector techniques methods for the collection of sterile urine specimens. DESIGN: This study was a cross-sectional study. SAMPLE: The sample population was composed of patients who underwent a urodynamics procedure. SETTING: This study was performed at the urodynamics unit of a rehabilitation and care center in Turkey. METHODS: Sterile urine specimens (n = 576) were collected from 144 patients using the vacuum tube technique and the injector technique; the rates of urine contamination and minor adverse events were evaluated. chi2 Statistics and Fisher exact tests were used to assess the contamination rates and frequencies of minor adverse events during the collection of sterile urine specimens. RESULTS: The contamination rate of urine specimens collected using an injector was 0.9% (P > .05). The rate of minor adverse events during specimen collection was lower when using the vacuum technique than when using an injector and sterile urine container (2 vs 36 events, P < .05). CONCLUSION: The vacuum tube technique of urine specimen collection was not superior to the injector technique in regard to contamination. The use of the vacuum tube technique for the collection of sterile urine specimens can prevent minor adverse events related to spillage/leakage of urine. IMPLICATIONS: More research from multiple settings and work environments is needed to strengthen the evidence base of vacuum tube technique of sterile urine specimen collection. PMID- 23748993 TI - Clinical nurse specialist assessment of nurses' knowledge of heart failure. AB - PURPOSE/OBJECTIVE: Patients' self-management of heart failure (HF) is associated with improved adherence and reduced readmissions. Nurses' knowledge about self management of HF may influence their ability to adequately perform discharge education. Inadequate nurse knowledge may lead to insufficient patient education, and insufficient education may decrease patients' ability to perform self management. Prior to developing interventions to improve patient education, clinical nurse specialists should assess nurses' knowledge of HF. The purpose of this study was to determine nurses' knowledge of HF self-management principles. DESIGN: This was a prospective, exploratory, and descriptive online test. SETTINGS: There were 3 patient care settings: tertiary care teaching hospital, community hospital, and home healthcare division. SAMPLE: The sample was composed of 90 registered nurses who worked directly with patients with HF. METHODS: Nurses completed an online test of knowledge using the Nurses' Knowledge of Heart Failure Education Principles instrument. FINDINGS: Registered nurses (n = 90) completed the knowledge test instrument; their average score was 71% (SD, 10.8%) (range, 20%-90%). The percentage of correct items on each subscale ranged from 63.9% (SD, 30.0) for medications to 83.3% (SD, 25.0) for exercise. Only 8.9% of respondents achieved a passing score of greater than 85%, and a passing score was not associated with any demographic characteristics. CONCLUSIONS: Overall, nursing knowledge of HF self-management principles was low. Scores from our nurses were similar to those found in other studies. IMPLICATIONS: There is a need to develop interventions to improve nursing knowledge of HF self-management principles. Clinical nurse specialists can be instrumental in developing knowledge interventions for nurses. PMID- 23748994 TI - Qualitative analysis of factors affecting adherence to the phenylketonuria diet in adolescents. AB - PURPOSE/OBJECTIVE: Phenylketonuria (PKU) is an inborn error of metabolism that is primarily treated with a severely restricted, low-protein diet to prevent permanent neurological damage. Despite the recognition of the importance of strict dietary adherence in the prevention of intellectual impairment in individuals with PKU, apathy and attrition from diet, especially during adolescence, remain a threat to normal development in this population. This study's aim was to examine adolescents' perception of factors that encourage or inhibit their dietary adherence. DESIGN: This was a qualitative study, with the authors using thematic analysis to interpret the findings. SETTING: The study was conducted as part of a Metabolic Disorders Association conference. SAMPLE: Eight adolescents with PKU were recruited through convenience sampling. METHODS: A focus group was conducted with the adolescents to gather information about factors that encourage and discourage dietary adherence. FINDINGS: Thematic analysis revealed that the adolescents encountered problems explaining the nature and food requirements of their condition to other people. Friends, family, and wanting to maintain "normal" cognitive abilities were identified as factors that encouraged dietary adherence. CONCLUSION: Adolescents with PKU appear to share several barriers and incentives for maintaining the strict dietary regimen. IMPLICATIONS: Considering such perceptions may aid future interventions aiming to reduce diet attrition rates among adolescents. PMID- 23748995 TI - Profile. PMID- 23748996 TI - The creative spirit of Salim Nasser. PMID- 23748997 TI - Increased sarcolipin expression and decreased sarco(endo)plasmic reticulum Ca2+ uptake in skeletal muscles of mouse models of Duchenne muscular dystrophy. AB - Abnormal intracellular Ca(2+) handling is an important factor in the progressive functional decline of dystrophic muscle. In the present study, we investigated the function of sarco(endo)plasmic reticulum (SR) Ca(2+) ATPase (SERCA) in various dystrophic muscles of mouse models of Duchenne muscular dystrophy. Our studies show that the protein expression of sarcolipin, a key regulator of the SERCA pump is abnormally high and correlates with decreased maximum velocity of SR Ca(2+) uptake in the soleus, diaphragm and quadriceps of mild (mdx) and severe (mdx:utr-/-) dystrophic mice. These changes are more pronounced in the muscles of mdx:utr-/- mice. We also found increased expression of SERCA2a and calsequestrin specifically in the dystrophic quadriceps. Immunostaining analysis further showed that SERCA2a expression is associated both with fibers expressing slow-type myosin and regenerating fibers expressing embryonic myosin. Together, our data suggest that sarcolipin upregulation is a common secondary alteration in all dystrophic muscles and contributes to the abnormal elevation of intracellular Ca(2+) concentration via SERCA inhibition. PMID- 23748998 TI - Tanacetum vulgare as a bioindicator of trace-metal contamination: a study of a naturally colonized open-pit lignite mine. AB - We investigated the possibility of use of Tanacetum vulgare (tansy) as an ecological indicator of metal concentration in a naturally colonized open-pit lignite mine in Belchatow (Poland). Tanacetum vulgare is the only species growing abundantly and spontaneously in the lignite mine waste dumps. Metal concentrations in roots, stems, leaves, flowers, and soil were measured in dump sites differing in type and time of reclamation and therefore differing in pollution levels. Tanacetum vulgare appeared to be an accumulator of chromium and iron in roots, whereas highest concentrations of manganese and zinc were found in leaves. A high bioaccumulation factor for cadmium (Cd) was observed in dumps and control sites, indicating that even small amounts of Cd in the environment may result in significant uptake by the plant. The lowest concentrations of metals were found in plants from sites situated on dumps reclaimed with argillaceous limestone. PMID- 23748999 TI - A proteomic approach to study the mechanism of tolerance to Bt toxins in Ostrinia furnacalis larvae selected for resistance to Cry1Ab. AB - A Cry1Ab-resistant population of Asian corn borer (ACB-AbR) exhibiting approximately 100 times greater resistance to activated Cry1Ab than a susceptible population (Ostrinia furnacalis; ACB-BtS), was previously shown to exhibit high levels of cross-resistance to Cry1Ah (131-fold), but no cross-resistance to Cry1Ie. It was suggested that the proposed mechanism of resistance was due to the alteration of specific receptors for Cry toxins in the midgut brush border membrane. In the present study a proteomic-based approach was used to identify proteins from brush border membrane vesicles (isolated from both resistant and susceptible Ostrinia furnacalis larvae) interacting with biotinylated Cry1Ab, Cry1Ah, and Cry1Ie. 2D-Electrophoresis in combination with ligand blots were employed and putative protein identities obtained using MALDI-ToF/ToF mass spectrometry. The V-type proton ATPase catalytic subunit A and heat shock 70 kDa proteins were identified as interacting with the Cry toxins tested in the ACB-AbR and ACB-BtS larvae. The biotinylated Cry toxins showed markedly stronger interactions with proteins in the resistant compared to the susceptible larvae, suggesting an up-regulation of the V-type proton ATPase catalytic subunit A and heat shock 70 kDa proteins in the resistant (ACB-AbR) larvae. Interestingly, Cry1Ie interactions with the V-type proton ATPase catalytic subunit A in the ACB BtS larvae appeared to be absent. PMID- 23749000 TI - Paternal transgenerational glucose intolerance with epigenetic alterations in second generation offspring of GDM. PMID- 23749001 TI - Effects of circumcision on male sexual functions: a systematic review and meta analysis. AB - This meta-analysis was performed to assess sexual functions following adult male circumcision. We searched the Cochrane Central Register of Controlled Trials, PUBMED, EMBASE, the Cochrane Database of Systematic Review and Web of Science from their inception until January 2013 to identify all eligible studies that reported on men's sexual function after circumcision. The Cochrane Collaboration's RevMan 5.2 software was employed for data analysis, and the fixed or the random effect model was selected depending on the proportion of heterogeneity. We identified 10 studies, which described a total of 9317 circumcised and 9423 uncircumcised men who were evaluated for the association of circumcision with male sexual function. There were no significant differences in sexual desire (odds ratio (OR): 0.99; 95% confidence interval (CI): 0.92-1.06), dyspareunia (OR: 1.12; 95% CI: 0.52-2.44), premature ejaculation (OR: 1.13; 95% CI: 0.83-1.54), ejaculation latency time (OR: 1.33; 95% CI: 0.69-1.97), erectile dysfunctions (OR: 0.90; 95% CI: 0.65-1.25) and orgasm difficulties (OR: 0.97; 95% CI: 0.83-1.13). These findings suggest that circumcision is unlikely to adversely affect male sexual functions. However, these results should be evaluated in light of the low quality of the existing evidence and the significant heterogeneity across the various studies. Well-designed and prospective studies are required for a further understanding of this topic. PMID- 23749002 TI - A fusion at the root of prostate cancer. PMID- 23749003 TI - A 32-gene risk index: a new prognostic approach for prostate cancer progression. PMID- 23749005 TI - The e-mjm goes LIVE to PubMed. PMID- 23749006 TI - Associated Factors of Sleep Quality and Behavior among Students of Two Tertiary Institutions in Northern Malaysia. AB - The objective of the study was to investigate the associated factors of sleep quality and behavior among Malaysian tertiary students. The response rate to the questionnaire study was 41.0%. 1,118 students (M = 486, F = 632; mean age = 20.06 +/- 1.53 years) were recruited from Universiti and Kolej Tunku Abdul Rahman (Perak campuses) who completed a sleep quality and behavior questionnaire based on Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Horne Ostberg Morningness-Eveningness Scale (MES) and craving of high-calorie foods. Results showed that students had the following sleeping habits - bed time = 2.41 a.m. +/- 3.35 hr, rise time = 9.00 a.m. +/- 1.76 hr, sleep latency = 16.65 +/- 14.30 min and sleep duration = 7.31 +/- 1.45 hr. 32.9% of the students were defined as poor quality sleepers, 30.6% suffering excessive daytime sleepiness (EDS) and 81.6% were categorized as individuals with 'definitely eveningness', defined as people who are definitely most alert in the late evening hours and prefer to go to bed late. There were no significant gender differences in sleep quality, 'chronotype' and EDS. Although there was no association of sleep quality and EDS with cumulative Grade Point Average (cGPA) and class skipping, EDS was associated with the tendency to fall asleep in class. Body Mass Index (BMI) was not associated with total sleep, PSQI, ESS and MES scores. Meanwhile, high calorie food craving was associated with sleep duration, PSQI and ESS, but not MES. In conclusion, poor sleep behavior among Malaysian tertiary students in this study was not associated with gender, academic performance and BMI, but was associated with craving of high-calorie foods instead. PMID- 23749004 TI - A longitudinal study of PSA and its influential factors in a cohort of Chinese men with initial PSA levels less than 4 ng ml(-1). AB - To evaluate the longitudinal change in prostate-specific antigen (PSA) and the influence of initial PSA on the PSA change. We retrospectively analysed health examination data collected at Beijing Hospital from March 2007 to November 2011. Men with an initial PSA levels less than 4 ng ml(-1) and an annual PSA test for 5 years were enrolled into the study. The men were separated into four groups by the initial PSA level (0-0.99, 1-1.99, 2-2.99 and 3-3.99 ng ml(-1)), and the difference in PSA change among the four groups was analysed. A total of 1330 men were enrolled into the study. The mean age, initial PSA and PSA velocity (PSAV) were 58.17 +/- 14.63 (range 24-91) years, 1.18 +/- 0.79 (range 0-4) ng ml(-1) and 0.04 +/- 0.25 (range -1.34-2.02) ng ml(-1) year(-1). Pearson's correlation analysis showed no correlation between initial PSA and PSAV (r=-0.036, P=0.189). The PSAV of the 0-0.99, 1-1.99, 2-2.99 and 3-3.99 ng ml(-1) initial PSA groups was 0.03 +/- 0.11, 0.07 +/- 0.32, 0.03 +/- 0.34 and -0.01 +/- 0.43 ng ml(-1) year(-1), respectively (P=0.06). As the initial PSA increased, the percentage of having a PSAV over 0.75 ng ml(-1) year(-1) and a negative PSAV both significantly increased. Males with a baseline PSA of 0-0.99, 1-1.99, 2-2.99 and 3-3.99 ng ml( 1) had a 1.88%, 6.16%, 16.30% and 57.81% chance, respectively, that their PSA would increase above 4.0 ng ml(-1) over the following 4 years (P<0.0001). The PSAV has no correlation with the initial PSA level. However, as the initial PSA increases, the chance that males will have an abnormal PSA or PSAV in the future increases. PMID- 23749007 TI - Ultracision versus electrocautery in performing modified radical mastectomy and axillary lymph node dissection for breast cancer: a prospective randomized control trial. AB - BACKGROUND: Treatment for breast cancer has improved dramatically over the decades. Nevertheless, modified radical mastectomy with axillary dissection remains the standard treatment for most patients, especially those with big tumours. The conventional technology is to use diathermy to cut and coagulate blood vessels. The Ultracision dissector has been widely used in laparoscopic surgery and is documented to be safe and fast for cutting and coagulating tissue. The aim of this study is to compare ultracision to electrocautery, looking in terms of amount of post operative drainage, duration of drain days, seroma formation and other complications. METHODOLOGY: This study was a prospective randomized control trial of modified radical mastectomy performed for breast cancer in Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM) between 1st June 2007 to 31st December 2008. Patients were randomized in two groups: group A (n = 20) underwent modified radical mastectomy using ultracision (UC) and group B (n = 20) with the conventional electrocautery (EC) method. Main outcome measures were amount of drainage and duration of drain days. An unpaired 2-tailed Student's t test and the chi2 test to compare the groups. RESULTS: A total of 40 patients were involved in this study. The majority of patients were Malay (55%) followed by Chinese (35%), Indian (5%) and others (5%). The mean volume of drainage from the axilla in the EC group was significantly higher than UC group [489.5 versus 188.1 mls (p < 0.001)]. The mean volume of drainage from the breast and the total drainage from both the breast and axilla was also significantly higher in the EC group compared to UC [169.3 versus 58.8 mls (p = 0.004) and 663.7 versus 247.0 mls (p < 0.002) respectively]. The drainage consequently showed significant reduction in terms of drain days in the axilla [6 days versus 3 days (p < 0.002)] and the breast [3 days versus 2 days (p < 0.002)] in the UC compared to the EC. There was no significant complication in both arms. In conclusion, the use of ultracision able to reduce the amount of drainage and the number of drain days after performing modified radical mastectomy. In doing so, the use of this technology enable us to discharge patients earlier without significant morbidities. PMID- 23749008 TI - Topical insulin for healing of diabetic epithelial defects?: A retrospective review of corneal debridement during vitreoretinal surgery in Malaysian patients. AB - PURPOSE: To investigate whether topical insulin improves healing rate of corneal epithelial erosions induced during vitreoretinal surgery in diabetics. METHODS: We retrospectively reviewed case notes and serial post-operative photographs of 15 eyes of 14 patients who had corneal epithelial debridement performed during various vitreoretinal surgeries to improve one surgeon's view over a 10 month period in 2010. RESULTS: Three groups were identified: DTI, comprising diabetics who received topical insulin 1 unit qds postoperatively (n=5); DCT comprising diabetics treated with conventional post-operative medications only (n=5) and NDCT comprising non diabetic patients on conventional post operative therapy (n=5). Only eyes in which the corneal epithelial defect had been serially photographed at time, t= 0, 12, 24, 36, 48, 60, 72 and 120 hours following commencement of topical medications were included. The size of the defect was calculated using local software. DTI eyes had a significantly smaller defect size at t= 24 (p=0.009), 36 (p=0.009), 48 (p=0.015) and 60 hours (p=0.005) compared to DCT eyes and had no statistical difference from NDCT eyes at all times in the Mann Whitney U analysis (p>0.05). In the diabetic operated bilaterally, the insulin treated eye re-epithelialised by 48 hours whereas fellow eye treated conventionally re-epithelialised in 72 hours. CONCLUSIONS: Topical insulin or insulin eye drops 1 unit qds may be applied to the corneal surface to normalize the rate of healing of epithelial defects in diabetic patients undergoing epithelial debridement to improve the surgeon's view. PMID- 23749009 TI - Outcome of canal wall down mastoidectomy: experience in sixty three cases. AB - A canal wall down mastoidectomy (CWDM) is an effective technique for eradication of advanced chronic otitis media or cholesteatomas. A retrospective study was conducted at a Malaysian Tertiary Medical Center between June 1996 to December 2003 to evaluate the outcome of Modified Radical Mastoidectomy(MRM), a form of CWDM for patients with chronic active otitis media (OM) with cholesteatoma, chronic mastoiditis or chronic active OM with cholesteatoma and mastoiditis. All new cases of MRM which fulfilled the selection criteria were reviewed. The main outcome measures were the hearing outcome and status of dry ear postoperatively. A total of 84 patients had undergone CWDM. However only 63 patients (26 male, 37 female) were included for analysis. The age of the patients ranged between 5 months to 72 years (mean, 31years). The majority of the patients (86%) were adults and 9 (14%) were children. The ossicular chain was eroded in 91% (57 cases). There were 33 patients (53%) who showed no improvement of Air Bone Gap (ABG) closure while 16 patients (25%) had a post-operative improvement. The presence or absence of stapes suprastructure was found to be the major factor in determining the amount of ABG (Chi squared test, P = 0.025 preoperatively and P = 0.031 postoperatively). A dry ear was achieved in 78% of patients with 3% recurrence rate. In conclusion, the study showed that a proper MRM gave high percentage of dry ear and this procedure did not worsen the hearing. PMID- 23749010 TI - The short-term outcome of laser endoureterotomy for ureteric stricture. AB - With the advent of new technology, the treatment for ureteric stricture has moved from open surgery to endoscopic procedures. Our goals were to review and determine the prognostic factors for success of laser endoureterotomy for ureteric stricture. This is a cross sectional study for all cases that underwent laser endoureterotomy in a single centre from 2002 to 2009. Standard treatment in this centre utilizes holmium laser. The fiber used was 365nm, setting as 1J and frequency 8 Hz; power output 8 W. Confirmation of adequacy of incision wss by either visualization of extra-ureteric fat or extravasations of contrast on fluoroscopic imaging. Success or recurrence of the endoureterotomy was confirmed objectively with evidence of improvement from imaging. Of these 77 patients, 42 cases (61.8%) of the strictures were from upper ureter. Eight cases (11.7%) of mid-ureteric while lower ureter had 18 cases (26.5%). Length of stricture has been grouped into two groups; Short (<1cm) and long (>=1cm) and their distributions were 47.1% and 26.5% respectively. Follow-up duration ranged from six months to 88 months with an average of 19.6 months. Success rate was 76.5% (52 patients) while 16 patients (23.5%) developed recurrence. Stone disease, positive presenting symptoms and short length of the stricture were identified as variables with good predictor. This study achieved a 76.5% of success rate for this treatment modality for benign ureteric stricture in wellselected patients. Success is more likely if patient is symptomatic (earlier treatment) and previous stone disease present as a risk factor. PMID- 23749011 TI - Emergency thoracotomy and major lung resection for penetrating chest trauma: Lessons learnt from a review of three cases. AB - Emergency lung resection for chest trauma is a rare event with a reported incidence of 0.08-1.3% but is associated with a high morbidity and mortality especially if a pneumonectomy is required, if due to blunt chest trauma or when concomitant injuries are present. We report three cases of young adult males with penetrating chest injuries that required emergency thoracotomy (ET) and anatomical lung resection to achieve definitive control of life threatening pulmonary haemorrhage. All patients survived to hospital discharge and remained well on follow-up. Indications for an ET and what constitutes the optimal operative management of such patients is discussed. PMID- 23749012 TI - Helicobacter pylori infection in chronic immune thrombocytopenic purpura patients in Malaysia. AB - INTRODUCTION: Helicobacter Pylori has been implicated with a possible link to immune thrombocytopenia purpura (ITP) and studies have shown contradicting results in platelet recovery after eradication of H pylori infection. OBJECTIVES: To determine the prevalence of H pylori infection in adult ITP patients in Malaysia and to examine the effect of eradication of H pylori infection in these patients. METHOD: 50 ITP adult patients from haematology clinics were recruited. A 13C urea breath test for H. pylori infection was performed in all patients. Those with H. pylori infection were treated with standard eradication regimen. Platelet counts were monitored regularly after eradication therapy to assess response. Complete response (CR) was defined as the achievement of platelet counts of >150x10(9)/L within 3 months after eradication therapy and partial response (PR) was defined as platelet count above 50x10(9)/L and/or at least doubling the baseline count. RESULT: The median age of patients recruited was 50 years. The majority of patients were female (76%). Chinese was the largest ethnic groups (56%) followed by Malays (28%) and Indians (16%). 11 of the 50 patients (22%) were found to have H. pylori infection and all but one had eradication therapy. Overall, some response was observed in 3 patients (30%) with a CR seen in 2 patients and PR in one patient. However, all these patients had a drop in their platelet counts at 6th month follow up. CONCLUSION: The prevalence of H. pylori infection is relatively low in our adult ITP patients (22%) and by eradicating the infection did not have any sustained effect in the platelet recovery. PMID- 23749013 TI - Gastro-oesophageal reflux disorders among Nepalese residing in Southeast Asia. AB - INTRODUCTION: Gastro-oesophageal reflux disorders (GORD) are common in Western countries and has been reported to be increasing in the East. This study assessed the prevalence of GORD among the Nepalese residing in the Brunei Darussalam. METHODS: Nepalese residing in two areas were invited to participate in this cross sectional questionnaire study. GORD was considered to be present if there was any heartburn, regurgitation or both experienced at least monthly that were associated with impairment of quality of life measures. Overall, 304 out of 320 (female 68.4%) with completed questionnaire were available for analysis. RESULTS: Overall 45.1% had reported symptoms of gastroesophageal reflux: heartburn and regurgitation (21.4%), heartburn alone (9.2%) and regurgitations alone (14.5%). However, only 7.2% had GORD. GORD was significantly more common among women (p=0.005), being shorter in height (p=0.013), those with co morbid conditions (p=0.023) and previously had endoscopy (p=0.006). There were no difference in age, duration of residence, body mass index (kg/m2), alcohol intake, tobacco and supplements use (all p>0.05). GORD was also significantly associated with the presence of psychosomatic symptoms such as backache, depression, fatigue, headache and insomnia (all p<0.05). Subjects with GORD also experienced significantly more other upper gastrointestinal complaints such as nausea, vomiting, early satiety, post-prandial fullness, and abdominal bloating (all p<0.05). CONCLUSIONS: The prevalence of GORD among Nepalese residing in Brunei Darussalam was 7.2%. Certain subjects' profiles were associated with GORD and patients with GORD were likely to experience more psychosomatic and other gastrointestinal symptoms. PMID- 23749014 TI - Thoracic Endovascular Aortic Repair (TEVAR) in traumatic high-velocity blunt injury to thoracic aorta. PMID- 23749015 TI - The outcome of combining home based and clinic based amblyopia therapy among preschool children. AB - This study determined the outcome of combining home based and clinic based amblyopia therapy among preschool children. A total of 479 preschool children were randomly selected for vision screening. Amblyopic therapy was prescribed to children whose visual acuity (VA) could not be improved to <0.1 LogMAR after a 6 week adaptation period with glasses. Intensive near work activities were conducted daily at home for 12 weeks, monitored by parents while weekly therapy was conducted at the optometry clinic by an optometrist. Six preschool children were diagnosed with refractive amblyopia, spherical equivalent (SE) was -11.25D to +0.75D. Significant improvement was found in the VA of right eye, t(6) = 3.07, left eye t(6) = 3.07 and both eyes t(6) = 3.42) p<0.05, at the end of the 12 week therapy. Combining home based and clinic based amblyopia therapy among preschool children showed a positive improvement in VA after 12 weeks of therapy. PMID- 23749016 TI - Efavirenz does not cause false-positive urine cannabis test in HIV-infected patients on Highly Active Anti-Retroviral Therapy. AB - Efavirenz is a non-nucleoside reverse transcriptase inhibitor used in combination with other drugs for the treatment of patients with HIV infection. Efavirenz has been reported to cause a positive urine cannabis test reaction which may create problems between HIV-infected patients on Efavirenz and law enforcement agencies. Doctors are at loss whether to issue documents certifying the potential false positive urine cannabis test with Efavirenz to patients. We investigated if the urine of HIV-infected patients on Efavirenz caused a positive urine cannabis test using the AxSYM Cannabinoids Assay(r). Urine samples from 51 eligible patients on Efavirenz were tested for cannabis. All tested negative except for one who had used cannabis the day before. Efavirenz does not cause false positive urine cannabis test with the AxSYM Cannabinoids Assay(r). Certification documents from doctors are therefore unnecessary. PMID- 23749017 TI - Review of an 11-year Experience in Retrosigmoid Approach for Treatment of Acoustic Neuromas. AB - This study reviews surgery on acoustic neuromas by the second author using retrosigmoid approach from January 2000 to June 2010 in the state of Sarawak. There was a total of 32 patients in this study. The commonest presenting symptom was hearing loss (81.3%), followed by headache and tinnitus (each 37.5%), ataxia (34.4%) and facial numbness (21.9%). Twenty-seven patients (84.4%) had large tumor (>= 3cm) while 5 patients (15.6%) had medium size tumor (1.5-2.9cm). The mean tumor size was 3.6 cm. Facial nerve outcome was good to moderate in 93.7% (House and Brackmann Grade I-IV). The most common complications were CSF leak with 3 patients(9.4%) and facial numbness with 2 patients(6.3%). All either resolved with treatment or improved. There was no mortality. Excision of acoustic neuromas using retrosigmoid approach could achieve acceptable facial nerve outcome with a low incidence of morbidity without mortality. PMID- 23749018 TI - Congenital absence of pericardium in babies with patent ductus arteriosus. AB - We report a case of two babies with absence of pericardium and patent ductus arteriosus (PDA). The absence of pericardium was found coincidentally during PDA ligation. The PDA was successfully ligated but the pericardium was not reconstructed. Postoperatively, the agenesis of the pericardium did not interfere with cardiac function. PMID- 23749019 TI - Chylous leakage post mastectomy and axillary clearance: clinical aspect, causes and review of literature. AB - Chylous leakage after mastectomy & axillary clearance is a rare complication. The incidence is less than 0.5%. Anatomical variations in the termination of thoracic duct can occur, rendering it susceptible to injury during axillary dissection. Most chyle leaks in the axilla are managed through conservative measures. Surgical intervention is required in high output chylous leaks. We encountered a case of chylous leak post mastectomy with axillary clearance, which was successfully treated conservatively. PMID- 23749020 TI - Pituitary apoplexy: a rare cause of middle cerebral artery infarction. AB - Pituitary apoplexy is a well-known complication of a pituitary adenoma. However, an ischaemic event caused by pituitary apoplexy is rare. We reported a case of pituitary apoplexy with middle cerebral artery infarction in a 44-year old man who presented with a sudden onset of altered sensorium. Vasospasm is the most likely underlying cause of the infarction in this case secondary to transdiaphragmatic rupture of the sella tumour into the subarachnoid space. PMID- 23749021 TI - Ochrobactrum anthropi catheter-related bloodstream infection: the first case report in malaysia. AB - A 60-year old Malay man presented with an intermittent lowgrade fever for 3 days and worsening of right ankle ulcers. He was known to have ischaemic heart disease, diabetes mellitus type 2, hypertension and end stage renal failure and was on regular haemodialysis. The organisms isolated from the peripheral and central blood specimens were identified as Ochrobactrum anthropi, a rarely encountered gramnegative bacillus with a unique antibiotic susceptibility profile. His condition improved after removal of the catheters and administration of antibiotic therapy. This case report highlights the importance of being wary of such rare, opportunistic pathogens and good communication between the microbiologists and the clinicians. PMID- 23749022 TI - Primary lacrimal sac lymphoma with recurrence: a case report. AB - Primary lacrimal sac lymphoma is rare. The common clinical features are epiphora and medial canthal swelling which mimic nasolacrimal duct obstruction. Histological examination is therefore important to avoid delay in diagnosis and treatment. We report a case of primary lacrimal sac lymphoma in a 72-year-old female who developed a metachronous tumour at the hard palate one year after excision of the lacrimal sac tumour. PMID- 23749023 TI - Management of bleeding pseudoaneurysm of gastroduodenal artery secondary to chronic pancreatitis. AB - A bleeding pseudoaneurysm of the peripancreatic artery can present with massive upper gastrointestinal hemorrhage. History of pancreatitis and urgent imaging are crucial in the making of the diagnosis. Here, we report a patient with alcoholic chronic pancreatitis presented with ruptured pseudoaneurysm of gastroduodenal artery (GDA). He was treated with percutaneous angiographic embolisation. PMID- 23749024 TI - Combined laparoscopic cholecystectomy and drainage of pancreatic pseudocyst: a case report and review of current management. AB - Pancreatic pseudocyst is a well recognized complication of acute or chronic pancreatitis. Active treatment (surgical or endoscopic) has been recommended if the pseudocyst persists for more than 6 weeks after the diagnosis. Open trans abdominal drainage was initially the mainstay treatment for it. However, over the past decade, laparoscopic techniques have been developed to provide patient with minimal access alternative. We report a case of a large symptomatic pseudocyst which developed following attack of severe gallstone pancreatitis. Laparoscopic cholecystectomy and cysto-gastrostomy were done at the same sitting. The operative technique is briefly explained. PMID- 23749025 TI - Delay in Diagnosis of Upper Gastrointestinal Cancer: whose fault is it? AB - BACKGROUND: Stomach and esophageal cancers are both deadly and difficult to diagnose early. Stomach cancer is the second most common cancer in Asia. Both these are one of the most common causes of cancer related death in the world. AIM: To determine the mean time delay from appearance of the symptoms to the endoscope procedure [OGDS] and rationalized the reason for this delay in diagnosis. METHOD: This is a cross sectional study of stomach and esophageal cancer data from Jan 2004- July 2008. All patients' records of histologically confirmed stomach or esophageal cancers during the study period were reviewed. RESULT: Total of 112 consecutive patients with stomach and esophageal cancer were analysed. 86 cases of stomach and 26 cases of esophageal cancer were reviewed. The average age for stomach and esophageal cancers are 60.8 years and 58.4 years respectively. The mean duration from the first appearance of cancer symptoms to endoscope procedure was 32.4 weeks for stomach cancer patient and 16.7 weeks for esophageal cancer patients. The reasons for the delays are due to 1) self medication, 2) Empirical treatment for dyspepsia using antacid and H2 antagonist, 3) Delay in endoscope procedure for high risk patients. CONCLUSION: Reducing the delay in endoscope procedure may lead to early detection of cancer and thereby may improve the prognosis of these patients. PMID- 23749026 TI - CNS toxoplasmosis induced hydrocephalus revisited and a brief review of AIDS dementia complex. PMID- 23749027 TI - A Pictorial Review of Diabetic foot Manifestations. AB - The diabetic foot with its many associated complications and presentations can provide a challenge in diagnosis and subsequent treatment. MRI, being increasingly available commonly, is now the main investigative modality. In particular, it is helpful in differentiating between neuroarthropathy and osteomyelitis and in cases where the latter is superimposed on the former. By being well versed in the interpretation of the images, the radiologist can make crucial contribution to the care and management of these patients. PMID- 23749028 TI - Ionothermal synthesis of mesoporous SnO2 nanomaterials and their gas sensitivity depending on the reducing ability of toxic gases. AB - Mesoporous SnO2 with a high surface area of 292.7 m(2) g(-1) has been successfully synthesized via a low-cost NH4Cl-based ionothermal route. When evaluated as a gas sensor, impressive performances towards N2H4 and HCHO are achieved owing to its excellent chemical reactivity towards oxygen. PMID- 23749029 TI - Mitochondria as oxidative signaling organelles in T-cell activation: physiological role and pathological implications. AB - Early scientific reports limited the cell biological role of reactive oxygen species (ROS) to the cause of pathological damage. However, extensive research performed over the last decade led to a wide recognition of intracellular oxidative/redox signaling as a crucial mechanism of homeostatic regulation. Amongst different cellular processes known to be influenced by redox signaling, T cell activation is one of the most established. Numerous studies reported an indispensible role for ROS as modulators of T-cell receptor-induced transcription. Nevertheless, mechanistic details regarding signaling pathways triggered by ROS are far from being delineated. The nature and interplay between enzymatic sources involved in the generation of "oxidative signals" are also a matter of ongoing research. In particular, active participation of the mitochondrial respiratory chain as ROS producer constitutes an intriguing issue with various implications for bioenergetics of activated T cells as well as for T cell-mediated pathologies. The aim of the current review is to address these interesting concepts. PMID- 23749030 TI - On-chip capacitively coupled contactless conductivity detection using "injected" metal electrodes. AB - We demonstrate the use of injected gallium electrodes for capacitively coupled contactless conductivity detection (C(4)D) within a microchip electrophoresis device. Evaluation of the electrodes for quantitative detection of electrophoretically separated lithium, sodium and potassium ions showed the system offers competitive detection limits of 6.1 * 10(-6) M, 6.7 * 10(-6) M and 8.5 * 10(-6) M, respectively. The fabrication process is fast, highly reproducible, and eliminates difficulties with electrode alignment. Using this approach C(4)D can be readily achieved in any microchip by simply adding extra 'electrode' channels to the microchip design. PMID- 23749031 TI - Evaluation of the serum cystatin C values in prediction of indications for hemodialysis in patients with chronic renal failure. AB - BACKGROUND: Indications of dialysis treatment for patients with end-stage renal disease depend on various clinical and laboratory parameters. In this study, we aimed to determine whether standardized serum cystatin C (SCC) equation may be an applicability of marker for dialysis initiation and its relationship to other clearance values among patients with advanced chronic kidney disease. MATERIALS AND METHODS: A total of 84 patients (45 males, 39 females) aged 19-89 were evaluated in this study. Hemodialysis was indicated according to clinical and laboratory findings, and estimated glomerular filtration rate (eGFR) was according to four different formulas [MDRD, EpiCKD, Cockcroft Gault formula (CGF) and SCC equation]. RESULTS: eGFR values of patients in the study were 7.23 +/- 3.26, 7.86 +/- 3.78, 15.09 +/- 10.88 and 11.31 +/- 4.54 according to MDRD, EpiCKD, SCC equation and CGF, respectively. There was a positive correlation between MDRD, EpiCKD and CGF, and between EpiCKD and CGF (p < 0.01). Also, statistically significant correlation was found between SCC equation and CGF (p < 0.05). CONCLUSION: SCC equation was not seemed to be an appropriate marker for starting dialysis in patients with advanced CKD. PMID- 23749032 TI - Distribution of ixodid ticks on dogs in Nuevo Leon, Mexico, and their association with Borrelia burgdorferi sensu lato. AB - This study aimed to document the geographic distribution of Ixodes tick species in dogs and the prevalence of Borrelia burgdorferi s.l. in adult ticks and blood samples by amplification of the ospA region of the B. burgdorferi genome. The study area included nine localities in Nuevo Leon state. DNA amplification was performed on pools of ticks to calculate the maximum likelihood estimation (MLE), and the community composition (prevalence, abundance, and intensity of infestation) was recorded. A total of 2,543 adult ticks, representing four species, Rhipicephalus sanguineus, Dermacentor variabilis, Rhipicephalus (Boophilus) annulatus, and Amblyomma cajennense, were recorded from 338 infested dogs. Statistically significant correlations were observed between female dogs and infestation (P = 0.0003) and between R. sanguineus and locality (P = 0.0001). Dogs sampled in Guadalupe and Estanzuela were positive by PCR (0.9 %) for B. burgdorferi. Rhipicephalus sanguineus had the highest abundance, intensity, and prevalence (10.57, 7.12 and 94.6, respectively). PCR results from 256 pools showed that four pools were positive for D. variabilis (1.6 %), with an MLE of 9.2 %; nevertheless, it is important to consider that in the area under examination probably other reservoir hosts for D. variabilis and B. burgdorferi are present that, very likely, play a much more important role in the ecology of Lyme borreliosis than dogs, which could be considered in future studies. PMID- 23749033 TI - Monitoring the diel activity of Ixodes ricinus ticks in Hungary over three seasons. AB - Ixodes ricinus is the most common tick species in Europe and vector of many diseases of humans. The risk of contracting such a disease is influenced by many factors, but one of the crucial points is questing activity of unfed ticks. In order to supplement the few literature data on patterns of diel activity of this tick species and to examine the correlations between data on diel activity of ticks and their small mammal hosts and some meteorological variables, a survey was performed. Diel activity of questing I. ricinus and small rodents was studied in a known natural tick-borne encephalitis virus focus over 7 months at one sampling day monthly. 1,063 I. ricinus ticks and 25 rodents were sampled. Air temperature and humidity data were also recorded in the 24 study plots at time of sampling. From April to October questing activity of nymphs increased in the 3-h period after sunrise, comparing to activity of the 3 h before sunrise. Proportion of nymphs sampled 3 h after sunset compared to total sampled nymphs 3 h before and 3 h after sunset showed correlation to activity of rodents. In the period of April-July both nymphs and larvae showed stronger activity from sunrise to sunset, this turned to dominant nighttime activity in August-September, whereas activity changed to equal in day and night in October. Our results indicate that natural light and rodent population have positive effect on questing activity of I. ricinus. PMID- 23749034 TI - Survey on helminths in the small intestine of wild foxes in Qinghai, China. AB - The intestinal helminth fauna of Tibetan sand foxes (Vulpes ferrilata) and red foxes (Vulpes vulpes) inhabiting in Qinghai, China, was evaluated by conducting necropsy of hunted foxes and fecal egg examination of field-collected feces. In northeast and south Qinghai, 36 foxes were necropsied, and the species of foxes and the parasites detected were identified by the DNA barcoding. In 27 red foxes and 9 Tibetan sand foxes examined, Mesocestoides litteratus (total prevalence: 64%), Toxascaris leonina (50%), Taenia pisiformis (8%) and Taenia crassiceps (8%) were found in both species of foxes. Echinococcus shiquicus (8%) and Taenia multiceps (6%) were found only in Tibetan sand foxes. Echinococcus multilocularis (3%) and Alaria alata (8%) were found only in red foxes. In the fecal egg examination of the rectal feces, 100% of taeniid cestodes, 73% of Toxascaris and 27% of Mesocestoides worm-positive samples showed egg-positive, indicating that coprological survey for parasite eggs could only provide partial information of intestinal parasite fauna. For field-collected feces, molecular identification of feces origins and fecal egg examination were performed. In 15 Tibetan sand fox and 30 red fox feces, we found E. multilocularis eggs in one feces of Tibetan sand fox. The present study indicated that the upper intestinal helminth fauna of the two fox species in Qinghai does not differ significantly and both species would play an important role in the maintenance of taeniid cestodes. PMID- 23749035 TI - Role of biogenic silica in the removal of iron from the Antarctic seas. AB - Iron has a key role in controlling biological production in the Southern Ocean, yet the mechanisms regulating iron availability in this and other ocean regions are not completely understood. Here, based on analysis of living phytoplankton in the coastal seas of West Antarctica, we present a new pathway for iron removal from marine systems involving structural incorporation of reduced, organic iron into biogenic silica. Export of iron incorporated into biogenic silica may represent a substantial unaccounted loss of iron from marine systems. For example, in the Ross Sea, burial of iron incorporated into biogenic silica is conservatively estimated as 11 MUmol m-2 per year, which is in the same range as the major bioavailable iron inputs to this region. As a major sink of bioavailable iron, incorporation of iron into biogenic silica may shift microbial population structure towards taxa with relatively lower iron requirements, and may reduce ecosystem productivity and associated carbon sequestration. PMID- 23749037 TI - Mesoporous matrix encapsulation for the synthesis of monodisperse Pd5P2 nanoparticle hydrodesulfurization catalysts. AB - The synthesis of monodisperse 5-10 nm Pd5P2 catalytic particles by encapsulation in a mesoporous silica network, along with preliminary data on hydrodesulfurization (HDS) activity, is reported. Precursor Pd-P amorphous nanoparticles are prepared by solution-phase reaction of palladium(II) acetylacetonate with trioctylphosphine at temperatures up to 300 degrees C. Direct crystallization of Pd5P2 in solution by increasing the temperature to 360 degrees C leads to sintering, but particle size can be maintained during the transformation by encapsulation of the amorphous Pd-P particles in a mesoporous silica shell, followed by treatment of the solid at 500 degrees C under a reducing atmosphere, yielding Pd5P2@mSiO2. The resultant materials exhibit high BET surface areas (>1000 m(2)/g) and an average pore size of 3.7 nm. Access to the catalyst surface is demonstrated by dibenzodithiophene (DBT) HDS testing. Pd5P2@mSiO2 shows a consistent increase in HDS activity as a function of temperature, with DBT conversion approaching 60% at 402 degrees C. The ability to control particle size, phase, and sintering is expected to enable the fundamental catalytic attributes that underscore activity in Pd5P2 to be assessed. PMID- 23749036 TI - Cilengitide response in ultra-low passage glioblastoma cell lines: relation to molecular markers. AB - PURPOSE: In glioblastoma multiforme (GBM), a tumor still characterized by dismal prognosis, recent research focuses on novel-targeted compounds, in addition to standard temozolomide (TMZ) chemotherapy. One of these emerging compounds is cilengitide (CGT), which by binding to integrins (i.e., alphavbeta3 and alphavbeta5) may inhibit angiogenesis and also is directly cytotoxic to tumor cells by interfering with intracellular signaling pathways. METHODS: A total of ten patient-derived ultra-low passage GBM cell lines were treated with increasing doses of CGT, TMZ, and a combination of both substances. Inhibitory concentrations of 50% (IC50) were determined for the single agents and as a combination. Cell lines were stratified according to MGMT promoter methylation. The expression of relevant integrins was assessed by flow cytometry. RESULTS: In monotherapy, all GBM cell lines showed higher sensitivity to CGT than to TMZ, as determined by IC50 values in relation to clinically relevant patient plasma levels. MGMT promoter methylation correlated with a significantly higher TMZ response, but tended to be associated with a lower CGT response. Response to CGT was not correlated with cell surface integrin expression as measured by flow cytometry. Finally, addition of CGT to TMZ enhanced growth inhibition, but only in those cell lines with a methylated MGMT promoter. CONCLUSIONS: As suggested by this analysis, patients with MGMT promoter-methylated GBM may benefit from addition of CGT to the standard TMZ treatment, while patients with MGMT promoter unmethylated GBM may better respond to CGT monotherapy. PMID- 23749038 TI - Chlorpyrifos-treated crops in the vicinity of surface water contamination in the San Joaquin Valley, California, USA. AB - Due to frequent contamination of streams in the San Joaquin Valley, California, USA, with the insecticide chlorpyrifos, researchers are working to identify crop specific management practices that will reduce the offsite movement of this compound into surface waters. To guide this effort, crops treated with chlorpyrifos in the vicinity of contaminated streams were identified; walnut, alfalfa, and almond were the primary crops identified. Use was higher on walnut and almond, but due to irrigation practices offsite movement in surface runoff may be more likely from alfalfa. Based on these findings, development of management practices to reduce off-site movement of chlorpyrifos in irrigation runoff from treated alfalfa fields is recommended. PMID- 23749039 TI - Lead accumulation in the straw mushroom, Volvariella volvacea, from lead contaminated rice straw and stubble. AB - Straw mushrooms were grown on lead contaminated rice straw and stubble. Study materials were dried, acid digested, and analyzed for lead using flame atomic absorption spectrophotometry. The results showed the highest lead concentration in substrate was 445.350 mg kg-1 in Treatment 3 (T3) and the lowest was BD (below detection) in Treatment 1 (T1). The maximum lead content in straw mushrooms was 5.072 mg kg-1 dw in pileus of T3 and the minimum lead content in straw mushrooms was BD in egg and mature (stalk and pileus) stage of T1. The lead concentration in straw mushrooms was affected by the age of the mycelium and the morphology of mushrooms. Mushrooms' lead uptake produced the highest accumulation in the cell wall. Some lead concentrations in straw mushrooms exceeded the EU standard (>3 mg kg-1 dw). PMID- 23749040 TI - Polybrominated diphenyl ethers (PBDES) and polychlorinated biphenyls (PCBS) in mussels and two fish species from the estuary of the Guanabara Bay, Southeastern Brazil. AB - The present investigation aimed to analyze PBDE and PCB contamination in mussels (Perna perna) and two commercially important fish species, croaker (Micropogonias furnieri) and mullet (Mugil liza), in the Guanabara Bay, the most important Brazilian estuary, by gas chromatography coupled to mass spectrometry, in order to further knowledge regarding these compounds in the southern hemisphere. This is also the first report of PBDE in this mussel species in the Guanabara Bay. Fish were captured in September (dry season, winter) and March (wet season, summer) 2007 and September 2008. Mussels were collected in August (dry season, winter) 2006, in February (wet season, summer) 2007, and in August 2007 (winter). The results show that all samples showed higher PCB contamination when compared to other ecosystems around the world. On the other hand, PBDEs presented lower concentrations in 41 % of the samples. Croakers presented the highest PCB and PBDE levels, with mullet showing intermediary values and mussels, the lowest. PMID- 23749041 TI - Relation of the Fas and FasL gene polymorphisms with susceptibility to and severity of rheumatoid arthritis. AB - To investigate associations of the Fas and FasL genes polymorphisms with rheumatoid arthritis (RA). One hundred patients with RA and age-, sex- and ethnically matched 101 controls were included. Four polymorphisms of Fas (-670 A>G rs1800682, -1377 G>A rs2234767) and FasL (IVS2nt-124 A>G rs5030772, -844 T>C rs763110) genes were typed from genomic DNA. Genotype distributions and allelic frequencies were compared between patients and control subjects. After the history and clinical examination of patients with RA, in terms of pain, fatigue and general health status were evaluated by visual analogue scale. Thereafter, erythrocyte sedimentation rate, C-reactive protein, blood count and rheumatoid factor levels were measured. The Disease Activity Score-28, Health Assessment Questionnaire and modified Sharp score were used to evaluate the disease activity, functional disability and radiological damage, and their relationships with the Fas and FasL gene polymorphisms were investigated. In patients with RA, CT and TT genotypes of FasL-844, polymorphism were twofold and 4.8-fold higher, and AA genotype of FasL IVS2nt-124 polymorphism was 3.4-fold higher than the control group (respectively, p = 0.05, p = 0.002, p = 0.039). T allele of FasL 844 polymorphism was more frequent in patients than controls (respectively, 52.5 vs. 41.4 %, p = 0.027). Any association was not detected between Fas (-670 A>G, 1377 G>A) and FasL (-844 T>C, IVS2nt-124 A>G) gene polymorphisms with the disease activity scores, functional disability and radiological damage. However, the Fas 670 A>G polymorphism was associated with drug therapy (p = 0.049). The distribution of GG genotype was higher compared to GA or AA genotypes in patients using triple disease-modifying antirheumatic drug therapy (71.4, 14.3 and 14.3 %, respectively). These findings suggest that the -844 T>C and IVS2nt-124 A>G polymorphisms in the FasL gene related with apoptosis may increase genetic susceptibility to RA in a Turkish population. In addition, the Fas-670 A>G gene polymorphism may be associated with disease progression. There is a need for further studies to clarify the genetic role of apoptosis in RA. PMID- 23749042 TI - Li3V2(PO4)3@C core-shell nanocomposite as a superior cathode material for lithium ion batteries. AB - Li3V2(PO4)3@C core-shell nanoparticles with typical sizes of 20-40 nm were synthesized using a hydrothermal-assisted sol-gel method. Ascorbic acid and PEG 400 were adopted as carbon sources and reductants. The uniform Li3V2(PO4)3@C nanocomposite obtained was composed of a Li3V2(PO4)3 core with high-phase purity and a graphitized carbon shell, which was characterized using XRD, SEM, TEM, and Raman analysis. The nanocomposite exhibited a remarkably high rate capability and long cyclability, delivering a discharge capacity of 138 mA h g(-1) at 5 C within a voltage range of 3-4.8 V and the capacity retention was 86% after 1000 cycles. The superior electrochemical performance of Li3V2(PO4)3@C indicates that it has potential for application as a cathode material in advanced rechargeable lithium ion batteries. PMID- 23749044 TI - Cardiac sympathetic innervation and cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) is a disease modifying, device-driven treatment that can reduce morbidity and mortality in patients with heart failure. According to the current guidelines, the indication for CRT is only based on QRS duration and functional class of heart failure. However, a substantial amount of patients do not respond to therapy. In addition, CRT is accompanied by significant cost and potential morbidity. It is therefore vital to improve patient selection for CRT to improve patient outcome and minimize therapy-related complications. In this regard, cardiac sympathetic innervation may be of interest. This review addresses the currently available literature, 9 studies with a total number of 225 patients, on CRT and cardiac innervation scintigraphy with (123)I-metaiodobenzylguanidine. PMID- 23749045 TI - Autocrine insulin-like growth factor 1 and stem cell factor but not interleukin 6 support self-renewal of human myeloma cells. AB - In this study, we have identified the growth factors supporting myeloma self renewal in eight myeloma cell lines. All cell lines able to form self-colonies displayed constitutive P-AKT and P-ERK1,2 but not P-STAT3 and did not express CD45, suggesting the presence of an insulin-like growth factor 1 (IGF1) loop. We showed that a blocking anti-insulin-like growth factor 1 receptor (IGF1R) monoclonal antibody (mAb) inhibited colony formation in correlation with IGF1R expression and decreased P-AKT. Imatinib or a blocking anti-stem cell factor (SCF) mAb also inhibited colony formation of two cell lines expressing C-KIT and SCF, and decreased P-AKT. Moreover, the PI3K/AKT pathway inhibitor wortmannin inhibited colony formation. Blocking interleukin (IL)6R did not inhibit colony formation in good agreement with a lack of constitutive P-STAT3. We showed that primary cells frequently co-expressed IGF1R/IGF1 but not C-KIT/SCF or IL6R/IL6, suggesting that in vivo autonomous growth could be possible via IGF1R. Despite their similar role in clonogenic growth and shared signaling pathway, IGF1R and C KIT had opposite prognostic values, suggesting that they were surrogate markers. Indeed, we showed that both C-KIT and IGF1R prognostic values were not independent of MMSET expression. This study highlights the autocrine role of IGF1 in myeloma cells and reinforces the interest in targeting IGF1R in IGFR1(+) CD45(+/-) patients, such as MMSET(+) patients. PMID- 23749046 TI - A new, previously undescribed monopartite begomovirus infecting Premna serratifolia in Vietnam. AB - The complete genome sequence of a monopartite begomovirus isolate infecting Creek Premna (Premna serratifolia L.) plants that exhibited leaf curl, vein swelling, and enation symptoms in Nha Trang, Vietnam, was cloned and sequenced. It comprises 2,753 nucleotides (JQ793786) and has a typical organization of begomoviruses DNA-A with AV1 and AV2 open reading frames (ORFs) in the viral sense strand and AC1, AC2, AC3, AC4 and AC5 ORFs in the complementary-sense strand. The full-length genome sequence of the isolate (clone VN7) shared the highest level of nucleotide sequence identity (83 %) with the isolate IN:Pusa:Tb:10 of tobacco leaf curl Pusa virus (HQ180391). The phylogenetic relationship of VN7 to other begomoviruses was also investigated. VN7 grouped most closely with a clade containing begomoviruses from China, India and Japan. According to the current taxonomic criteria for the genus Begomovirus, family Geminiviridae, the isolate VN7 represents a new species, herein named "Premna leaf curl virus" (PrLCV). PMID- 23749047 TI - Phylogeographic dispersion and diversification of rabies virus lineages associated with dogs and crab-eating foxes (Cerdocyon thous) in Brazil. AB - Genetic lineages of dog-associated RABV still circulate in some areas of the North and Northeast of Brazil. In parallel, another RABV lineage circulates among wild canids in the Northeast, particularly the crab-eating fox (Cerdocyon thous). Although previous studies and phylogenetic analyses have been carried out, the way in which these lineages are dispersed temporally and spatially remained to be elucidated. In this study, RABV N gene sequences isolated from canids in North and Northeast Brazil were analyzed by the Bayesian Markov Chain Monte Carlo Method, and the results were then used in a phylogeographic study. It was inferred from the findings that the most recent common ancestor became established at the end of the nineteenth century on the border of the Brazilian states of Paraiba and Pernambuco and diversified into the lineages associated with dogs and C. thous. Around 1910, the original C. thous lineage diversified into two main sublineages in the same area, one of which migrated to the south and the other to the north. The dog-associated lineage diversified around 1945 and moved toward the north and south. From the phylogeographic analysis it was possible to infer not only the movement of the virus lineages but also the probable location where dispersion and diversification occurred. The methodology used here enabled the phylogeographic history of RABV in the region to be reconstructed, and the dispersion pattern of the virus can be used to predict its movements, making it easier to stop the advance of a rabies epidemic. PMID- 23749049 TI - Microvascular decompression for hemifacial spasm: focus on late reoperation. AB - The objective of this study is to investigate late repeat microvascular decompression (MVD) with persistent or recurrent hemifacial spasm (HFS) and to compare the clinical characteristics, intraoperative findings, complications, and outcomes with first MVD. We analyzed MVDs performed at the University of Pittsburgh Medical Center between January 1, 2000 and December 31, 2007. Thirty three patients who underwent late redo MVDs were classified as group I and 243 patients who underwent their first MVD as group II. Clinical data were collected to analyze the difference between the two groups. The mean follow-up period was 54.48 months (range, 9-102 months). There is no significant difference in preoperative clinical characteristics (gender, age, side of MVD, botox usage, facial weakness) between the two groups. In present study, we found a vein as the offending vessel in significantly more number of patients who underwent repeat MVD as compared to first MVD (P = 0.02). The lateral spread response disappeared in 66% of patients during repeat MVDs, which is not different from those undergoing their first MVD. No difference in the relief rate was found during the immediate postoperative, discharge, or follow-up stages between repeat and first MVD. Moreover, no difference was found in the incidence of complications between repeat MVD and first MVD. Late repeat MVD for HFS is an effective and safe procedure. No specific preoperative clinical characteristics were identified in patients with repeat MVD. Intraoperative monitoring with lateral spread response (LSR) is an effective tool to evaluate adequate decompression. In patients with persistent LSR at the end of the procedure, facial nerve compression from a vein should be examined. We believe that it is important to undergo a repeat MVD for failed HFS relief irrespective of the timing of the operation. PMID- 23749050 TI - Social determinants and heat shock protein-70 among African American and non Hispanic white women with atherosclerosis: a pilot study. AB - African American (AA) women are nearly twice as likely as non-Hispanic White (NHW) women to develop atherosclerosis associated with cardiovascular disease. Compelling evidence demonstrates that stress-related biomarkers, such as heat shock protein-70 (HSP70), are associated with increased atherosclerosis risk. Yet little is known about how social factors such as perceived discrimination, subjective social status, and socioeconomic status contribute to the levels of these biomarkers in women with atherosclerosis. The aims of this pilot study were to (1) describe perceived everyday discrimination, subjective social status, perceived stress, and HSP70 level in AA and NHW women diagnosed with coronary or carotid artery disease requiring intervention and (2) determine the extent to which perceived discrimination, subjective social status, and perceived stress are associated with HSP70 level, controlling for age, education, and race. The sample for this cross-sectional, descriptive pilot study consisted of 10 AA and 21 NHW women admitted to the hospital for elective percutaneous cardiac intervention or carotid endarterectomy. Participants completed questionnaires measuring psychosocial variables and provided blood samples for analysis of HSP70. Race, age, education, perceived stress, perceived discrimination, and subjective social status significantly (p = .022) explained 34% of the variance in HSP70 levels. However, only subjective social status (p = .031) and AA race (p = .031) were significant independent predictors of HSP70 levels, with lower subjective social status and AA race associated with higher HSP70. Although larger studies are needed to confirm these results, findings imply that race and subjective social status may play an important role in predicting stress biomarker levels. PMID- 23749051 TI - The harm-made mind: observing victimization augments attribution of minds to vegetative patients, robots, and the dead. AB - People often think that something must have a mind to be part of a moral interaction. However, the present research suggests that minds do not create morality but that morality creates minds. In four experiments, we found that observing intentional harm to an unconscious entity--a vegetative patient, a robot, or a corpse--leads to augmented attribution of mind to that entity. A fifth experiment reconciled these results with extant research on dehumanization by showing that observing the victimization of conscious entities leads to reduced attribution of mind to those entities. Taken together, these experiments suggest that the effects of victimization vary according to victims' preexisting mental status and that people often make an intuitive cognitive error when unconscious entities are placed in harm's way. People assume that if apparent moral harm occurs, then there must be someone there to experience that harm-a harm-made mind. These findings have implications for political policies concerning right-to-life issues. PMID- 23749052 TI - The hidden harms of Matching Michigan. PMID- 23749048 TI - The blockade of the neurotransmitter release apparatus by botulinum neurotoxins. AB - The high toxicity of the seven serotypes of botulinum neurotoxins (BoNT/A to G), together with their specificity and reversibility, includes them in the list A of potential bioterrorism weapons and, at the same time, among the therapeutics of choice for a variety of human syndromes. They invade nerve terminals and cleave specifically the three proteins which form the heterotrimeric SNAP REceptors (SNARE) complex that mediates neurotransmitter release. The BoNT-induced cleavage of the SNARE proteins explains by itself the paralysing activity of the BoNTs because the truncated proteins cannot form the SNARE complex. However, in the case of BoNT/A, the most widely used toxin in therapy, additional factors come into play as it only removes a few residues from the synaptosomal associate protein of 25 kDa C-terminus and this results in a long duration of action. To explain these facts and other experimental data, we present here a model for the assembly of the neuroexocytosis apparatus in which Synaptotagmin and Complexin first assist the zippering of the SNARE complex, and then stabilize and clamp an octameric radial assembly of the SNARE complexes. PMID- 23749053 TI - The interplay of hydrogen bonding and dispersion in phenol dimer and trimer: structures from broadband rotational spectroscopy. AB - The structures of the phenol dimer and phenol trimer complexes in the gas phase have been determined using chirped-pulse Fourier transform microwave spectroscopy in the 2-8 GHz band. All fourteen (13)C and (18)O phenol dimer isotopologues were assigned in natural abundance. A full heavy atom experimental substitution structure was determined, and a least-squares fit ground state r0 structure was determined by proper constraint of the M06-2X/6-311++g(d,p) ab initio structure. The structure of phenol dimer features a water dimer-like hydrogen bond, as well as a cooperative contribution from inter-ring dispersion. Comparisons between the experimental structure and previously determined experimental structures, as well as ab initio structures from various levels of theory, are discussed. For phenol trimer, a C3 symmetric barrel-like structure is found, and an experimental substitution structure was determined via measurement of the six unique (13)C isotopologues. The least-squares fit rm((1)) structure reveals a similar interplay between hydrogen bonding and dispersion in the trimer, with water trimer-like hydrogen bonding and C-H...pi interactions. PMID- 23749054 TI - Public place smoke-free regulations, secondhand smoke exposure and related beliefs, awareness, attitudes, and practices among Chinese urban residents. AB - OBJECTIVE: To evaluate the association between smoke-free regulations in public places and secondhand smoke exposure and related beliefs, awareness, attitudes, and behavior among urban residents in China. METHODS: We selected one city (Hangzhou) as the intervention city and another (Jiaxing) as the comparison. A structured self-administered questionnaire was used for data collection, and implemented at two time points across a 20-month interval. Both unadjusted and adjusted logistic methods were considered in analyses. Multiple regression procedures were performed in examining variation between final and baseline measures. RESULTS: Smoke-free regulations in the intervention city were associated with a significant decline in personal secondhand smoke exposure in government buildings, buses or taxis, and restaurants, but there was no change in such exposure in healthcare facilities and schools. In terms of personal smoking beliefs, awareness, attitudes, and practices, the only significant change was in giving quitting advice to proximal family members. CONCLUSIONS: There was a statistically significant association between implementation of smoke-free regulations in a city and inhibition of secondhand tobacco smoking exposure in public places. However, any such impact was limited. Effective tobacco control in China will require comprehensive laws implemented fully and supported by penalties and a combination of strong public health education. PMID- 23749055 TI - Accumulations of heavy metals in roadside soils close to zhaling, eling and nam co lakes in the tibetan plateau. AB - Concentrations of four typical heavy metals (Cu; Zn; Cd and Pb) in roadside soils close to three lakes in the Tibetan Plateau were investigated in this study. The hierarchical tree-based regression method was applied to classify concentrations of the heavy metals and analyze their potential influencing factors. It was found that the Tibetan Plateau meadow soils with higher content of sand lead to higher concentrations of Cu; Zn and Pb. The concentrations of Cd and Pb increase with road traffic volume; and for the road segments with higher traffic volume; the Cd and Pb concentrations significantly decrease with the roadside distance. Additionally; the concentrations of Zn and Pb increase as the altitude of sampling site increases. Furthermore; the Hakanson potential ecological risk index method was used to assess the contamination degree of the heavy metals for the study regions. The results show that accumulations of Cu; Zn and Pb in roadside soils remain an unpolluted level at all sites. However; the Cd indices in the regions with higher traffic volume have reached a strong potential ecological risk level; and some spots with peak concentrations have even been severely polluted due to traffic activities. PMID- 23749056 TI - High dental caries among adults aged 35 to 44 years: case-control study of distal and proximal factors. AB - The aim of this study was to determine whether a high degree of dental caries severity is associated with the distal and proximal determinants of caries in a group of Brazilian adults aged 35 to 44 years. A population-based case-control study was conducted using two groups-a case group with high caries severity (DMFT >= 14) and a control group without high caries severity (DMFT < 14). The sample comprised adults from metropolitan Belo Horizonte, Brazil (180 cases and 180 controls matched for gender and age). The exam was performed by calibrated dentists using the DMFT index. The statistical analysis used the Mann-Whitney test and bivariate and multivariate logistic regression (the conditional backward stepwise method). The mean DMFT was 8.4 +/- 3.9 in the control group and 20.1 +/- 4.5 in the case group. High caries severity was associated with regular visits to the dentist, low income, use of private/supplementary dental service and not petitioning the authorities for community benefits. The results of the study underscore the importance of considering distal and proximal factors in the assessment of the severity of dental caries. Greater caries severity persists among low-income families and among groups with a low degree of social cohesion. PMID- 23749057 TI - Short-term results of Neurelec Digisonic SP cochlear implantation in prelingually deafened children. AB - This paper examines the reports on the selection criteria and the post-operative performance of 25 children implanted with the Neurelec Digisonic SP. This study reported benefits from Neurelec Digisonic SP cochlear implant in auditory and speech perception outcomes. There has been a lack of studies into the additional factors such as level of the mothers' education and bilingualism, which is a factor that may have a significant effect on the success of cochlear implantation. This paper examines the reports on the reasons for the differences in performance and the post-operative performance of 25 children implanted with the Neurelec Digisonic SP. Meaningful Auditory Integration Scale and Meaningful Use of Speech Scale questionnaires were used just before 3, 6, 12, and 18 months following implantation. Electrode array was inserted without difficulty in all cases, with no complications to date. This is a retrospective and cross-sectional study and all the data were collected between March 2010 and December 2012. Auditory performance improved over time for up to 12 months after implantation. Our experience indicates that the Neurelec Digisonic SP cochlear implant system in children under the age of two is relatively safe and reliable. The Neurelec Digisonic SP device surgery can be performed without complications. Auditory performance results support the effectiveness of early implantation. These important findings further support the importance of professionals working very closely with parents or especially mothers and enhancing their involvement in achieving therapy goals to develop auditory skills and speech in young children following cochlear implantation. PMID- 23749058 TI - Prognostic value of interleukin-8 and MMP-9 in nasopharyngeal carcinoma. AB - Nasopharyngeal carcinoma (NPC) is one of the leading causes of cancer related death in China. One of the reasons is the absence of tumor specific prognostic markers. The aim of this study was to examine the prognostic values of interleukin-8 (IL-8) and matrix metalloproteinase-9 (MMP-9) in NPC patients. A total of 99 consecutive NPC patients and 40 healthy controls were recruited for this study. Serum levels of IL-8 and MMP-9 were evaluated in NPC patients who were followed up for 5 years. The serum levels of IL-8 and MMP-9 in NPC patients were significantly higher than those in healthy controls (IL-8 26.3 [2.9-68.0] ng/ml vs. 20.3 [2.3-38.6] ng/ml, P < 0.001; MMP-9 23.5 [3.6-52.1] ng/ml vs. 17.3 [2.6-36.9] ng/ml, P = 0.002), respectively. The serum levels of IL-8 and MMP-9 were positively correlated with the N classification (IL-8, P = 0.041, and MMP-9, P < 0.001, respectively) and clinical stage (IL-8, P = 0.022, and MMP-9, P < 0.001, respectively) in NPC patients. Analysis using the Kaplan-Meier method indicated that patients with high levels of IL-8 or MMP-9 had significantly shorter overall survival (OS) (IL-8, P = 0.012; MMP-9, P < 0.001) and disease free survival (DFS) (IL-8, P = 0.021; MMP-9, P = 0.003) time than those with low levels of MMP-9 or IL-8. Univariate and multivariate analysis revealed elevated MMP-9 level was an independent predictor of shorter OS and DFS. Both MMP-9 and IL 8 are involved in NPC progression. MMP-9 in serum may be the clinically useful indicator for prognostic evaluation in NPC patients. PMID- 23749059 TI - A randomised comparison between an inexpensive, general-purpose headlight and a purpose-built surgical headlight on users' visual acuity and colour vision. AB - To determine if there are any differences in near visual acuity and colour vision between an inexpensive general-purpose light emitting diode (LED) headlight and a purpose-built surgical LED headlight. A prospective study was conducted sequentially comparing near visual acuity and colour vision, the headlights being tested in random order, in a testing room with a constant minimal amount of background light. The participants were NHS employee volunteers, with self declared normal (or corrected) vision, working in occupations requiring full literacy. For visual acuity, outcome was measured by recording the smallest font legible when using each headlight when the subject read a near visual acuity test card. For colour vision, the outcome was passing or failing the Ishihara test. There was no statistically significant difference between the general-purpose and the purpose-built headlights in users' near visual acuity or colour vision. PMID- 23749061 TI - Selection of a representative matrix for the multiresidue analysis of nine beta agonists in animal tissues and urine with LC-MS/MS. AB - In the determination of nine beta-agonists including salbutamol, terbutaline, cimaterol, fenoterol, clorprenaline, ractopamine, tulobuterol, clenbuterol and penbuterol in porcine, bovine, lamb and chicken muscle, liver and urine samples with LC-MS/MS, calibration curves prepared in solvent (SC) were compared with those prepared in each matrix (MC) for all analytes. Significant differences (P < 0.05) between SC and each MC for most analytes indicated the existence of matrix effects and the necessity of using MC for quantitation to compensate MEs. Then MC in each muscle, liver and urine sample was compared with the select potential representative matrix, followed by validating the recoveries of nine analytes calculated through the MC in the potential representative matrix and MC in their corresponding matrices, respectively. The results suggested that porcine muscle could be selected as a representative matrix to calibrate beta-agonist residues in bovine, lamb and chicken muscle samples. PMID- 23749060 TI - Mapping the LINE1 ORF1 protein interactome reveals associated inhibitors of human retrotransposition. AB - LINE1s occupy 17% of the human genome and are its only active autonomous mobile DNA. L1s are also responsible for genomic insertion of processed pseudogenes and >1 million non-autonomous retrotransposons (Alus and SVAs). These elements have significant effects on gene organization and expression. Despite the importance of retrotransposons for genome evolution, much about their biology remains unknown, including cellular factors involved in the complex processes of retrotransposition and forming and transporting L1 ribonucleoprotein particles. By co-immunoprecipitation of tagged L1 constructs and mass spectrometry, we identified proteins associated with the L1 ORF1 protein and its ribonucleoprotein. These include RNA transport proteins, gene expression regulators, post-translational modifiers, helicases and splicing factors. Many cellular proteins co-localize with L1 ORF1 protein in cytoplasmic granules. We also assayed the effects of these proteins on cell culture retrotransposition and found strong inhibiting proteins, including some that control HIV and other retroviruses. These data suggest candidate cofactors that interact with the L1 to modulate its activity and increase our understanding of the means by which the cell coexists with these genomic 'parasites'. PMID- 23749062 TI - Culturing bias in marine heterotrophic flagellates analyzed through seawater enrichment incubations. AB - The diversity of heterotrophic flagellates is generally based on cultivated strains, on which ultrastructural, physiological, and molecular studies have been performed. However, the relevance of these cultured strains as models of the dominant heterotrophic flagellates in the marine planktonic environment is unclear. In fact, molecular surveys typically recover novel eukaryotic lineages that have refused cultivation so far. This study was designed to directly address the culturing bias in planktonic marine heterotrophic flagellates. Several microcosms were established adding increasing amounts and sources of organic matter to a confined natural microbial community pre-filtered by 3 MUm. Growth dynamics were followed by epifluorescence microscopy and showed the expected higher yield of bacteria and heterotrophic flagellates at increased organic matter additions. Moreover, protist diversity analyzed by molecular tools showed a clear substitution in the community, which differed more and more from the initial sample as the organic matter increased. Within this gradient, there was also an increase of sequences related to cultured organisms as well as a decrease in diversity. Culturing bias is partly explained by the use of organic matter in the isolation process, which drives a shift in the community to conditions closer to laboratory cultures. An intensive culturing effort using alternative isolation methods is necessary to allow the access to the missing heterotrophic flagellates that constitute the abundant and active taxa in marine systems. PMID- 23749063 TI - A novel array format for monitoring cellular uptake using a photo-cleavable linker for peptide release. AB - We developed a novel peptide array format incorporating a photo-cleavable linker for monitoring cellular uptake. Model peptides were successfully immobilised via the photo-cleavable linker onto conventional plates and could be released spatiotemporally using UV irradiation. Incorporation of confocal microscopy allowed for detailed real-time monitoring of cellular internalisation of peptides. PMID- 23749064 TI - Cloning and sequence analysis of three variants of the gene encoding alkaline xylanase C from the alkaliphilic Bacillus sp. (NCL 87-6-10). AB - Alkaline xylanase C from the alkaliphilic Bacillus sp. (NCL 87-6-10) has a low molecular weight and alkaline pI and is cellulase-free, properties compatible with its use in the prebleaching of pulp. We report here the cloning and sequence analysis of three variants of the gene encoding xylanase C; xyl C1, xyl C2, and xyl C3. In phylogenetic analysis, the three xylanase C variants clustered into a single group along with other reported alkaline xylanases. Residues contributing to the alkaline pH were present in all three variants. DNA and protein sequence comparison of these variants with other reported alkaline xylanases revealed silent mutations, some of which are due to codon preference in the respective organisms. The recombinant Xyl C1 that was successfully expressed in E. coli BL21 (DE3) had properties similar to the native enzyme. PMID- 23749065 TI - Prevalence of MTHFR C677T single nucleotide polymorphism in genetically isolated populations in Jordan. AB - Methylenetetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphism is a major inherited risk factor of venous thromboembolism. We sought to determine its prevalence in genetically isolated populations of Chechens and Circassians in Jordan. The MTHFR C677T mutation was analyzed from blood samples taken from 120 random unrelated Chechens and 72 Circassians. The prevalence of the MTHFR mutation in the Chechen population was 27.5% (allele frequency 15%); the prevalence among the Circassians was 50% (allele frequency 29.2%). The prevalence in the Chechen population is similar to that in Jordan and other world populations, but it is higher in the Circassian population. This study will contribute to understanding the interaction between genetic and environmental risk factors underlying thrombosis and will be useful in deciding which genetic variants should be tested in a clinical genetic testing service. PMID- 23749066 TI - Gemcitabine and docetaxel, an effective second-line chemotherapy for lung metastasis of urothelial carcinoma. AB - BACKGROUND: The objective of this study was to evaluate the efficacy of a gemcitabine and docetaxel (GD) combination as a second-line treatment for patients with metastatic urothelial carcinoma (UC) after failure of first-line treatment with platinum-based chemotherapy. METHODS: From June 2006 to January 2012, 38 patients with metastatic UC previously treated with platinum-based chemotherapy received GD therapy. This consisted of gemcitabine 800 mg/m(2) and docetaxel 40 mg/m(2) on days 1 and 8 of each 21-day cycle as second-line chemotherapy. All the patients were evaluated for toxicity and assessed every cycle by imaging. We analyzed the efficacy of GD as second-line chemotherapy in the follow-up study. RESULTS: The median number of GD treatment cycles was 4 (range 2-9); the objective response rate was 47.4 %; and the median progression free survival and median overall survival were 4.1 and 10.8 months, respectively. Univariate and multivariate analyses on the GD treated group showed that the existence of lung metastases was the only prognostic factor for tumor response. Grade 3 treatment-related toxicity included neutropenia (31.6 %) and thrombocytopenia (15.8 %), and only one patient with grade 4 toxicity had thrombocytopenia (2.6 %). CONCLUSIONS: The GD regimen as second-line chemotherapy was especially effective for lung metastatic UC and yielded favorable results in patients whose first-line platinum-based chemotherapy had failed. Given the safety and benefit profile seen in this study, a large prospective study is warranted to consider the potential utility of GD chemotherapy as a second-line for UC. PMID- 23749067 TI - [Research on stress measurement biochip for a single drop of saliva]. PMID- 23749068 TI - [Salivary membrane transporters as biomarkers]. PMID- 23749069 TI - [Mental stress and descending neural control to the superior salivatory nucleus]. PMID- 23749070 TI - [D-methionine as a protector for irradiation-induced oral mucositis and xerostomia]. PMID- 23749071 TI - [Paradigm shift in pharmacological treatment of periodontitis]. PMID- 23749072 TI - [Structure and regulation of the muscarinic acetylcholine receptor]. PMID- 23749073 TI - [Open innovation center for drug discovery: a research-supporting network for drug discovery]. PMID- 23749074 TI - [Pharmacological and clinical profile of bixalomer (Kiklin((r)) capsules): a new therapeutic agent for hyperphosphatemia]. PMID- 23749075 TI - [Preclinical and clinical aspects of the dipeptidyl peptidase-4 inhibitor anagliptin]. PMID- 23749076 TI - [Chemical biology of hydrogen sulfide]. PMID- 23749077 TI - [Subcortical vascular dementia]. PMID- 23749078 TI - [Roles of ERK5 in neuronal cells]. PMID- 23749079 TI - The ubiquitin-proteasome system regulates chloroplast biogenesis. AB - In a recently published work, we identified the first chloroplast-localized E3 ligase, and showed that it degrades TOC translocon proteins by the ubiquitin proteasome system (UPS). This regulation was found to be critical for plastid developmental transitions, such as the conversion of etioplasts to chloroplasts. Here we discuss the importance of SP1 for plants under different circumstances, and speculate about SP1 function and its possible application in agriculture. We anticipate that further work in this area may reveal additional roles of the UPS system, through action on other chloroplast OEPs with different roles in plastid biogenesis and function. PMID- 23749080 TI - Deregulation of translation due to post-transcriptional modification of rRNA explains why erm genes are inducible. AB - A key mechanism of bacterial resistance to macrolide antibiotics is the dimethylation of a nucleotide in the large ribosomal subunit by erythromycin resistance methyltransferases. The majority of erm genes are expressed only when the antibiotic is present and the erythromycin resistance methyltransferase activity is critical for the survival of bacteria. Although these genes were among the first discovered inducible resistance genes, the molecular basis for their inducibility has remained unknown. Here we show that erythromycin resistance methyltransferase expression reduces cell fitness. Modification of the nucleotide in the ribosomal tunnel skews the cellular proteome by deregulating the expression of a set of proteins. We further demonstrate that aberrant translation of specific proteins results from abnormal interactions of the nascent peptide with the erythromycin resistance methyltransferase-modified ribosomal tunnel. Our findings provide a plausible explanation why erm genes have evolved to be inducible and underscore the importance of nascent peptide recognition by the ribosome for generating a balanced cellular proteome. PMID- 23749081 TI - Guidance of stem cells to a target destination in vivo by magnetic nanoparticles in a magnetic field. AB - Stem cells contribute to physiological processes such as postischemic neovascularization and vascular re-endothelialization, which help regenerate myocardial defects or repair vascular injury. However, therapeutic efficacy of stem cell transplantation is often limited by inefficient homing of systemically administered cells, which results in a low number of cells accumulating at sites of pathology. In this study, anti-CD34 antibody-coated magnetic nanoparticles (Fe3O4@PEG-CD34) are shown to have high affinity to stem cells. The results of hemolysis rate and activated partial thromboplastin time (APTT) tests indicate that such nanoparticle may be used safely in the blood system. In vitro studies showed that a nanoparticle concentration of 100 MUg/mL gives rise to a significant increase in cell retention using an applicable permanent magnet, exerting minimal negative effect on cell viability and migration. Subsequent in vivo studies indicate that nanopartical can specifically bind stem cells with good magnetic response. Anti-CD34 antibody coated magnetic nanoparticle may be used to help deliver stem cells to a lesion site in the body for better treatment. PMID- 23749082 TI - Nucleation and growth mechanisms of nano magnesium hydride from the hydrogen sorption kinetics. AB - We use a combination of hydrogenography and Johnson-Mehl-Avrami-Kolmogorov (JMAK) analyses to identify (1) the driving force dependence of the nucleation and growth mechanism of MgH2 in thin film multilayers of Mg (10 nm) and (2) the nucleation and growth mechanism of Mg in the earlier formed MgH2, i.e. the hydrogen desorption process. We conclude that JMAK may be successfully applied to obtain the nucleation and growth mechanism of hydrogen absorption. The desorption mechanism, however, is not simply the reverse of the absorption mechanism. We find evidence that the barrier for nucleation of Mg is small. The dehydrogenation probably involves the formation of voids, which is energetically more favorable than elastic and plastic deformation of the multilayer. PMID- 23749083 TI - [Current stuation and new developments in shoulder prosthetics]. PMID- 23749085 TI - The effects of a pour-on formulation of fluazuron 2.5 % and flumethrin 1 % on populations of Rhipicephalus decoloratus and Rhipicephalus microplus both on and off bovine (Bonsmara breed) hosts. AB - The present study demonstrated the efficacy of a pour-on formulation of fluazuron 2.5 % and flumethrin 1 % (Drastic Deadline eXtreme(r)) against Rhipicephalus decoloratus and Rhipicephalus microplus on cattle on pasture previously grazed by experimentally infested animals. Six tick-free cattle were placed on the pasture and treated 7 days later (Day 0) with the pour-on. They were retreated on Days 63, 126 and 189 and monthly tick counts were done. Mean numbers of adult R. decoloratus and/or R. microplus decreased from 53 and 14 on Days 56 and 112 respectively to 2 or less on all other occasions including Day 254. Compared to the numbers of R. decoloratus and/or R. microplus larvae collected from vegetation in the previous year, larval numbers declined by 40.7 % on Day 28, and thereafter reduction remained between 84 % and 100 %. Pairs of tracer calves placed on the pasture for 7 days each month were then held in pens and adult ticks that detached collected. Reduction in the numbers of R. decoloratus collected from tracer animals was 75 % on Day 56 and remained above 93 % except for Day 224 when it temporarily decreased to 78.5 %. Reduction in the numbers of R. microplus was 97.5 % on Day 28 and remained above 98 % until the conclusion of the study on Day 254. Treatment with the pour-on formulation of fluazuron and flumethrin resulted in a marked decrease in the numbers of R. decoloratus and/or R. microplus on treated cattle followed by a reduction in the numbers of larvae questing on the vegetation and ticks picked up by tracer calves. No other potential host species for R. decoloratus and/or R. microplus were present in the camps. PMID- 23749086 TI - Comparison of three different treatment schedules for praziquantel (Cestocur(r), Bayer) in the treatment of tapeworm infections (Moniezia spp.) and their impact on body weight gains in a German sheep flock. AB - In an observational study, three different treatment schedules with praziquantel were assessed in a Merino land sheep flock from southern Germany. The herd had a known history of severe recurrent Moniezia spp. infections. After turnout to pasture, three hundred lambs between 8 and 14 weeks old were weighed and randomly allocated to three different groups. They were treated with praziquantel (Cestocur(r)) at a dose of 3.75 mg/kg body weight using the following schedules: group 1 treated four times at monthly intervals (Days 1, 31, 59, 91); group 2 treated three times at six-week intervals (Days 16, 59, 105), group 3 treated twice at an eight-week interval (Days 31, 91). Based on faecal examinations, all lambs were negative for Moniezia spp. on Day 1. At study end (Day 126), higher body weights were seen in group 1 (49.9 +/- 5.8 kg; 49.9 kg) than in group 2 (48.7 +/- 5.5 kg; 49.0 kg) and in group 3 (47.5 +/- 5.4 kg; 47.5 kg) (mean +/- SD; median). Overall weight gains were significantly higher in group 1 (22.5 +/- 1.8 kg; 22.3 kg) compared to group 2 (20.8 +/- 1.4 kg, 21.0 kg; p < 0.0001) and group 3 (19.3 +/- 2.2 kg, 19.6 kg; p < 0.0001). The results show that praziquantel treatments applied early in the grazing season and in monthly intervals were more beneficial for body weight developments in lambs than applied at six-weekly or eight-weekly intervals. PMID- 23749087 TI - Protective immunity induced by a DNA vaccine-encoding Toxoplasma gondii microneme protein 11 against acute toxoplasmosis in BALB/c mice. AB - Toxoplasma gondii is one of the most prevalent intracellular parasites and is threatening the health of both humans and animals, therefore causing incalculable economic losses worldwide. Vaccination is thought to be an efficient way of controlling toxoplasmosis. T. gondii microneme protein 11 (MIC11) is a soluble microneme protein which is presumably considered facilitating the early stage of cell invasion. To evaluate the protective efficacy of T. gondii MIC11, in the present study, a new DNA vaccine-encoding the alpha-chain of T. gondii MIC11 was constructed using the pcDNA3.1 vector. Expression of MIC11 from this vector was confirmed by indirect immunofluorescence assay following transfection into baby hamster kidney (BHK) cells. Intramuscular immunization of BALB/c mice with pcDNA/MIC11 was carried out to evaluate the immune responses by serum antibodies titers, lymphoproliferation assay, and cytokines assay. The protective efficacy was evaluated by survival rate in mice after challenging with highly virulent strain of T. gondii. The results demonstrated that this vaccination elicited significant humoral responses and T. gondii lysate antigen (TLA)-stimulated lymphoproliferation (p < 0.05). Compared to controls, the pcDNA/MIC11 immunized mice had high production of IFN-gamma, IL-12, and IL-2 (p < 0.05), but not IL-4 (p > 0.05), indicating that a predominant Th1 type response was developed. The vaccination also increased the survival rate of immunized mice when they were challenged with a lethal dose of tachyzoites of T. gondii RH strain. These data suggest that T. gondii MIC11 is a reasonable vaccine candidate deserving further studies, and pcDNA/MIC11 is a potential strategy for the control of toxoplasmosis. PMID- 23749088 TI - Isolation and molecular characterization of potentially pathogenic Acanthamoeba genotypes from diverse water resources including household drinking water from Khyber Pakhtunkhwa, Pakistan. AB - Acanthamoeba, an opportunistic protozoan pathogen, is ubiquitous in nature, and therefore plays a predatory role and helps control microbial communities in the ecosystem. These Acanthamoeba species are recognized as opportunistic human pathogens that may cause blinding keratitis and rare but fatal granulomatous encephalitis. To date, there is not a single report demonstrating Acanthamoeba isolation and identification from environmental sources in Pakistan, and that is the aim of this study. Acanthamoeba were identified by morphological characteristics of their cysts on non-nutrient agar plates seeded with Escherichia coli. Additionally, the polymerase chain reaction (PCR) was performed with genus-specific primers followed by direct sequencing of the PCR product for molecular identification. Furthermore, our PCR and sequencing results confirmed seven different pathogenic and nonpathogenic genotypes, including T2-T10, T4, T5, T7, T15, T16, and T17. To the best of our knowledge, we have identified and isolated Acanthamoeba sp., for the first time, from water resources of Khyber Pakhtunkhwa, Pakistan. There is an urgent need to address (1) the pathogenic potential of the identified genotypes and (2) explore other environmental sources from the country to examine the water quality and the current status of Acanthamoeba species in Pakistan, which may be a potential threat for public health across the country. PMID- 23749084 TI - Wnt and lithium: a common destiny in the therapy of nervous system pathologies? AB - Wnt signaling is required for neurogenesis, the fate of neural progenitors, the formation of neuronal circuits during development, neuron positioning and polarization, axon and dendrite development and finally for synaptogenesis. This signaling pathway is also implicated in the generation and differentiation of glial cells. In this review, we describe the mechanisms of action of Wnt signaling pathways and their implication in the development and correct functioning of the nervous system. We also illustrate how a dysregulated Wnt pathway could lead to psychiatric, neurodegenerative and demyelinating pathologies. Lithium, used for the treatment of bipolar disease, inhibits GSK3beta, a central enzyme of the Wnt/beta-catenin pathway. Thus, lithium could, to some extent, mimic Wnt pathway. We highlight the possible dialogue between lithium therapy and modulation of Wnt pathway in the treatment of the diseases of the nervous system. PMID- 23749089 TI - Endothelial cell invasion by Toxoplasma gondii: differences between cell types and parasite strains. AB - Toxoplasma gondii disseminates and causes congenital infection by invasion of the endothelial cells. The aim of this study was to analyze the ability of two strains to invade two endothelial cell types. Tachyzoites of the RH and ME49 strains were expanded in Balb/c and C57BL6-RAG2-/- mice, respectively. Tachyzoites were harvested from 72 h Vero cell cultures and incubated for 30 min to 4 h at 10:1 parasite/cell ratio in 24-well plates, containing monolayers of either HMEC-1 line or human umbilical cells (HUVECs). The number of infected cells and parasitic vacuoles per infected cell were counted in Wright stained slides. A slow increase in the proportion of infected cells occurred but varied according to cell type-parasite strain combination: ME49 tachyzoites invaded up to 63% HMEC-1 cells, while RH parasites infected up to 19% HUVECs. ME49 and RH tachyzoites invaded 49 and 46% HUVECs and HMEC-1 cells, respectively. Reinvasion and formation of new parasitophorous vacuoles of infected cells was more frequent than invasion of noninfected cells. The results support that the factors influencing invasion, and thus dissemination and vertical transmission, are parasite type, host cell type/subtype, and activation state. Interestingly, T. gondii virulence does not seem to relay on its invasion efficiency, but probably on replication speed. PMID- 23749090 TI - Cytocomposition of the vitellarium in Khawia sinensis Hsu, 1935 (Cestoda, Caryophyllidea, Lytocestidae): another caryophyllidean species with lamellar bodies and lipids. AB - The vitellarium of the invasive caryophyllidean tapeworm Khawia sinensis Hsu, 1935 from carp Cyprinus carpio L. was examined by means of transmission electron microscopy and cytochemical staining for glycogen with periodic acid thiosemicarbazide-silver proteinate (PA-TSC-SP). A vitellarium consists of numerous follicles of irregular size that are interconnected by a net of vitelline ducts. Vitelline follicles are composed of vitelline cells at various stages of development that are interconnected by interstitial tissue. Vitelline follicles are surrounded by a cytoplasmic sheath associated with an intercellular matrix. Extensive development of the granular endoplasmic reticulum and Golgi complexes are both involved in the production of shell globules/shell globule clusters and characterise cytodifferentiation of vitellocytes. Nuclear and nucleolar transformation lead to the formation and storage of intranuclear glycogen, a feature specific for the Caryophyllidea. Newly observed within the mature vitellocytes of Khawia sp. is the presence of lamellar bodies and a few lipid droplets. These cytoplasmic inclusions first occur in the mature cells within the follicles and persist in the vitelline cells within vitelloducts and intrauterine eggs. Two types of lamellar bodies are detected: regular lamellar structured body and irregular lamellar-structured body. None of the lamellar bodies are membrane bound. Results of the present study indicate that the formation of lamellar bodies may be closely related to the endoplasmic reticulum or shell globule clusters. Some of the shell globule clusters are transformed into lamellar body clusters. Ultrastructural features of vitellocytes in K. sinensis are compared with those of other monopleuroid, polypleuroid, and strobilated cestodes. PMID- 23749092 TI - Induced metabolic disturbance and growth depression in rabbits infected with Eimeria coecicola. AB - Eimeria coecicola causes intestinal coccidiosis in rabbits and, thereby, enormous economic losses in rabbit farms. This study aimed to investigate the effect of intestinal coccidial infection, E. coecicola on metabolic status and growth of rabbits. Animals were allocated into two groups with eight rabbits each; one group was orally inoculated with saline and served as control while the other group was orally inoculated with 5 * 10(4) sporulated oocysts. On day 7 postinfection, fecal expulsion of E. coecicola oocysts is maximal (1.2 * 10(6) oocyst/g feces) and rabbits have lost approximately 23% of their weight. Infection induced a severe depletion in plasma growth hormone level. In addition, the energy metabolic status was significantly (P <= 0.05) altered by the infection as, both blood glucose and total lipid levels were significantly elevated with mutual depletion in carbohydrate stores in liver sections. Also, the thyroid-stimulating hormone and cortisol concentrations were raised as a consequence of the infection. Moreover, protein status was affected by the infection as both liver and plasma total proteins were significantly decreased with concurrent disturbance in the blood protein electrophoretic pattern and duplication of blood urea nitrogen concentration. Finally, the infection induced plasma electrolyte imbalance as indicated by a significant decrease in sodium, potassium, calcium, phosphorus, ferrous, and selenium ions. Our data suggested that the intestinal coccidial infection of rabbits with E. coecicola has serious effects on rabbit growth and metabolism and could disrupt endocrine and electrolyte homeostasis. PMID- 23749093 TI - Long-term investigations on Toxoplasma gondii-infected primary chicken macrophages. AB - Toxoplasma (T.) gondii is known to infect various cell types including macrophages. In the present study, we generated monocyte-derived macrophage cultures from chicken blood. By flow cytometrical analysis, 84.5% of the cultivated cells showed typical macrophage properties. Macrophage cultures were cultivated at either 37 degrees C or 40 degrees C, respectively, and were infected 72 to 96 h post isolationem with tachyzoites of the T. gondii type II strain ME49 at a rate of 7.5 tachyzoites per host cell. Light microscopical investigations revealed incorporation of tachyzoites into the macrophages and gradual destruction of the infected macrophage culture. Parasite multiplication was observed by a quantitative real time PCR (qPCR) based on the 529-bp fragment specific for T. gondii. Samples were drawn 1 h post infectionem (p.i.), as well as 12, 24, 36, 48, and 72 h p.i. The parasite replication curve showed a transient decrease of parasite stages 12 h p.i. followed by a tachyzoite multiplication. The comparison of different culture conditions showed a significantly higher replication rate of T. gondii at 37 degrees C (median value 48 h p.i., 289.2% of the initial tachyzoite number) compared to cultures incubated at 40 degrees C (median value 48 h p.i., 73.1% of the initial tachyzoite number) throughout the observation period (P < 0.05). In general, replication rates were significantly lower than in a standard VERO cell cultures at 37 degrees C (P < 0.05). The observed differences were attributed to the physiological chicken macrophage reaction at 40 degrees C probably approximating the situation in vivo. PMID- 23749094 TI - One-step fabrication of micro/nanotunnels in metal interlayers. AB - A micro/nanotunnel is a very useful structure, which has been used as an interconnected pass in various micro/nano systems. Here, a novel micro/nanotunnel fabrication method in a metal interlayer ZnS-SiO2/Sn/ZnS-SiO2 sandwich structure is proposed based on a laser direct writing (LDW) technique. The experimental results show that the arched tunnel is 170 nm in width and 50 nm in height, far beyond the diffraction limit of the LDW system with a 533 nm laser and 0.9 NA objective lens. In only one step, an arbitrary tunnel can be fabricated, exhibiting its simple, designable and practical features, and providing a new route for micro/nanotunnel fabrication. PMID- 23749095 TI - Does breastfeeding offer protection against maternal depressive symptomatology?: A prospective study from pregnancy to 2 years after birth. AB - Mothers who breastfeed typically exhibit lower levels of depressive symptomatology than mothers who do not. However, very few studies have investigated the directionality of this relationship. Of the prospective studies published, all but one focus exclusively on whether maternal depression reduces rates of subsequent breastfeeding. This study again examines this relationship, but also the reverse-that breastfeeding might predict lower levels of later depression. Using multilevel modeling, we investigated the relationship between breastfeeding and self-reported depressive symptomatology in 205 women followed prenatally and at 3, 6, 12, and 24 months after birth. Consistent with previous research, women with prenatal depressive symptomatology weaned their infants 2.3 months earlier, on average, than women without such symptomatology. We also found, however, that women who breastfed more frequently at 3 months postpartum showed greater subsequent declines in depressive symptomatology over time compared to women who breastfed less frequently, resulting in lower absolute levels of depressive symptoms by 24 months postpartum, controlling for important confounds. In sum, these findings are consistent with a bidirectional association between breastfeeding and depression, with prenatal depression predicting less breastfeeding soon after birth and breastfeeding predicting declines in maternal depression up to 2 years after birth. We discuss mechanisms that could potentially explain these associations and avenues for future research. PMID- 23749091 TI - Gut transcriptome of replete adult female cattle ticks, Rhipicephalus (Boophilus) microplus, feeding upon a Babesia bovis-infected bovine host. AB - As it feeds upon cattle, Rhipicephalus (Boophilus) microplus is capable of transmitting a number of pathogenic organisms, including the apicomplexan hemoparasite Babesia bovis, a causative agent of bovine babesiosis. The R. microplus female gut transcriptome was studied for two cohorts: adult females feeding on a bovine host infected with B. bovis and adult females feeding on an uninfected bovine. RNA was purified and used to generate a subtracted cDNA library from B. bovis-infected female gut, and 4,077 expressed sequence tags (ESTs) were sequenced. Gene expression was also measured by a microarray designed from the publicly available R. microplus gene index: BmiGI Version 2. We compared gene expression in the tick gut from females feeding upon an uninfected bovine to gene expression in tick gut from females feeding upon a splenectomized bovine infected with B. bovis. Thirty-three ESTs represented on the microarray were expressed at a higher level in female gut samples from the ticks feeding upon a B. bovis-infected calf compared to expression levels in female gut samples from ticks feeding on an uninfected calf. Forty-three transcripts were expressed at a lower level in the ticks feeding upon B. bovis-infected female guts compared with expression in female gut samples from ticks feeding on the uninfected calf. These array data were used as initial characterization of gene expression associated with the infection of R. microplus by B. bovis. PMID- 23749097 TI - The phytohormone crosstalk paradigm takes center stage in understanding how plants respond to abiotic stresses. AB - The highly coordinated, dynamic nature of growth requires plants to perceive and react to various environmental signals in an interactive manner. Elaborate signaling networks mediate this plasticity in growth and the ability to adapt to changing environmental conditions. The fluctuations of stress-responsive hormones help alter the cellular dynamics and hence play a central role in coordinately regulating the growth responses under stress. Recent experimental data unequivocally demonstrated that interactions among various phytohormones are the rule rather than exception in integrating the diverse input signals and readjusting growth as well as acquiring stress tolerance. The presence of multiple and often redundant signaling intermediates for each phytohormone appears to help in such crosstalk. Furthermore, there are several examples of similar developmental changes occurring in response to distinct abiotic stress signals, which can be explained by the crosstalk in phytohormone signaling. Therefore, in this brief review, we have highlighted the major phytohormone crosstalks with a focus on the response of plants to abiotic stresses. The recent findings have made it increasingly apparent that such crosstalk will also explain the extreme pleiotropic responses elicited by various phytohormones. Indeed, it would not be presumptuous to expect that in the coming years this paradigm will take a central role in explaining developmental regulation. PMID- 23749098 TI - Agrobacterium tumefaciens-mediated in planta seed transformation strategy in sugarcane. AB - KEY MESSAGE: An efficient, reproducible and genotype-independent in planta transformation has been standardized for sugarcane using seed as explant. Transgenic sugarcane production through Agrobacterium infection followed by in vitro regeneration is a time-consuming process and highly genotype dependent. To obtain more number of transformed sugarcane plants in a relatively short duration, sugarcane seeds were infected with Agrobacterium tumefaciens EHA 105 harboring pCAMBIA 1304-bar and transformed plants were successfully established without undergoing in vitro regeneration. Various factors affecting sugarcane seed transformation were optimized, including pre-culture duration, acetosyringone concentration, surfactants, co-cultivation, sonication and vacuum infiltration duration. The transformed sugarcane plants were selected against BASTA((r)) and screened by GUS and GFP visual assay, PCR and Southern hybridization. Among the different combinations and concentrations tested, when 12-h pre-cultured seeds were sonicated for 10 min and 3 min vacuum infiltered in 100 uM acetosyringone and 0.1 % Silwett L-77 containing Agrobacterium suspension and co-cultivated for 72-h showed highest transformation efficiency. The amenability of the standardized protocol was tested on five genotypes. It was found that all the tested genotypes responded favorably, though CoC671 proved to be the best responding cultivar with 45.4 % transformation efficiency. The developed protocol is cost-effective, efficient and genotype independent without involvement of any tissue culture procedure and can generate a relatively large number of transgenic plants in approximately 2 months. PMID- 23749099 TI - Overexpression of AtWRKY28 and AtWRKY75 in Arabidopsis enhances resistance to oxalic acid and Sclerotinia sclerotiorum. AB - KEY MESSAGE: Based on Arabidopsis microarray, we found 8 WRKY genes were up regulated with Oxalic acid (OA) challenge, AtWRKY28 and AtWRKY75 overexpression lines showed enhanced resistance to OA and Sclerotinia sclerotiorum. The WRKY transcription factors are involved in various plant physiological processes and most remarkably in coping with diverse biotic and abiotic stresses. Oxalic acid (OA) is an important pathogenicity-determinant of necrotrophic phytopathogenic fungi, such as Sclerotina sclerotiorum (S. sclerotiorum) and Botrytis cinerea (B. cinerea). The identification of differentially expressed genes under OA stress should facilitate our understanding of the pathogenesis mechanism of OA-producing fungi in host plants, and the mechanism of how plants respond to OA and pathogen infection. Based on Arabidopsis oligo microarray, we found 8 WRKY genes that were up-regulated upon OA challenge. The Arabidopsis plants overexpressing AtWRKY28 and AtWRK75 showed enhanced resistance to OA and S. sclerotiorum simultaneously. Furthermore, our results showed that overexpression of AtWRKY28 and AtWRK75 induced oxidative burst in host plants, which suppressed the hyphal growth of S. sclerotiorum, and consequently inhibited fungal infection. Gene expression profiling indicates that both AtWRKY28 and AtWRKY75 are transcriptional regulators of salicylic acid (SA)- and jasmonic acid/ethylene (JA/ET)-dependent defense signaling pathways, AtWRKY28 and AtWRKY75 mainly active JA/ET pathway to defend Arabidopsis against S. sclerotiorum and oxalic acid stress. PMID- 23749100 TI - IL-10RB rs2834167 (A/G) polymorphism is associated with the susceptibility to systemic lupus erythematosus: evidence from a study in Chinese Han population. AB - Interleukin-10 (IL-10) is a pleiotropic cytokine and plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Unlike IL-10 protein, few studies have focused on the potential association between IL-10 receptor (IL-10R) and SLE. The purpose of this study was to examine the association of a single nucleotide polymorphism, rs2834167 (A/G), in IL-10R2 gene (IL-10RB) with SLE in a Chinese Han population. A total of 667 patients with SLE and 676 healthy controls were enrolled in the present study. IL-10RB rs2834167 (A/G) polymorphism was specified from genomic DNA using TaqMan genotyping assay on a 7300 real-time reverse transcription polymerase chain reaction system. We found that the frequency of A allele for rs2834167 in patients (44.53 %) was significantly higher than in controls (40.16 %) (chi (2) = 5.24, P = 0.022). Allele A was associated with a 1.196-fold (95 % confidence interval (CI), 1.026-1.394) greater risk for the occurrence of SLE compared with the G allele. And both genotypes AG and AA were associated with the susceptibility to SLE as compared with the GG genotype (AG versus GG, odds ratio (OR) = 1.332; 95 %CI, 1.047-1.696; AA versus GG, OR = 1.373; 95 %CI, 1.004-1.878). We also found a statistical significance in the dominant model (AA + AG versus GG, OR = 1.343; 95 %CI, 1.070-1.687). However, no significant evidence for the association of IL-10RB rs2834167 (A/G) polymorphism with any clinical manifestations was detected. Our observations indicate that IL-10RB rs2834167 (A/G) polymorphism may be a potential biomarker for susceptibility to SLE. PMID- 23749101 TI - Mutations of two transmembrane cysteines of hemagglutinin (HA) from influenza A H3N2 virus affect HA thermal stability and fusion activity. AB - Influenza A H3N2 virus caused 1968 Hong Kong influenza pandemic, and has since been one of the most prevalent seasonal influenza viruses in global populations, representing a credible pandemic candidate in future. Previous studies have established that the hemagglutinin (HA) protein is the predominant antigen and executes receptor binding and membrane fusion. Homologous sequence analysis of all HA subtypes of influenza viruses revealed that two cysteine residues (540 and 544) are uniquely present in the transmembrane domain (TM) of HA proteins from all influenza A H3N2 viruses. However, the functions of these two cysteines have not been fully studied. Here, we generated three mutants (C540S, C544L, and 2C/SL) to investigate the effects of the two TM cysteines on the biological functions of H3 HA. We herein presented evidences that the mutations of one or two of the cysteines did not affect the proper expressions of HA proteins in cells, and more importantly all mutant H3 HAs showed decreased thermal stability but increased fusion activity in comparison with wildtype HA. Our results taken together demonstrated that the two TM cysteines are important for the biological functions of H3 HA proteins. PMID- 23749102 TI - Characterization of a key residue for hyperfusogenic phenotype in human parainfluenza virus type 2 (hPIV-2) fusion glycoprotein. AB - Human parainfluenza viruses (hPIV) are pathogens responsible for upper and lower respiratory tract infections. We previously described clinical variant strains of hPIV-2 that display unusual large syncytial cytopathic effects. Their molecular characterization revealed a recurrent conserved specific amino acid substitution: A96T in the F2 subunit of the fusion glycoprotein F. The objective of this study was to investigate the contribution of this A96T substitution to the specific hyperfusogenic properties of the hPIV-2 variant strains. Based on a transient expression strategy, quantification of cell-cell fusion assays, and flow cytometry, we have shown that the A96T mutation strongly alters the fusogenic properties of F hPIV-2, highlighting this key residue in the F2 subunit and its possible role in fusion regulation. This work highlights the benefits of monitoring genetic and phenotypic changes of circulating strains to complete our understanding of Paramyxovirus fusion and related pathogenesis. PMID- 23749103 TI - Reduced-intensity conditioning followed by allogeneic transplantation in pediatric malignancies: a report from the Societe Francaise des Cancers de l'Enfant and the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. AB - We report French prospective experience with reduced-intensity conditioning-allo SCT in 46 patients (median age: 15.5 years, 4.8-20.2) presenting high-risk AL (n=11), Hodgkin's lymphoma (n=15) or solid tumors (n=20). Graft sources were BM (n=21), PBSC (n=20) and cord blood (CB; n=5) from related (n=20) or unrelated (n=26) donors. For CB grafts, only one patient out of five achieved sustained engraftment. For PBSC/BM grafts, engraftment rate was 95%, hematopoietic recovery times were not significantly different between BM, PBSC, sibling or unrelated grafts, day+100. Full donor chimerism was achieved in 94% of patients, and incidences of primary acute GVHD and chronic GVHD were 49% and 14%, respectively. Underlying disease was fatal in 39% of patients. TRM was 6.9%. Three-year OS was 49.15%. OS and EFS were not significantly different between patients transplanted with different grafts and with or without primary GVHD. Patients with solid tumor or measurable disease at transplant had poorer outcomes. Three-year EFS: 33.3% for ALL, 75.0% for AML, 51.8% for Hodgkin's lymphoma, 28.6% for neuroblastoma and 22.2% for sarcoma patients. This multicentre study concluded that Bu/fludarabine/anti-thymocyte globulin conditioning with PB or BM, related or unrelated grafts in patients with various malignancies at high-risk for transplantation toxicity results in high engraftment rates, low TRM and acceptable survival. PMID- 23749104 TI - Efficacy and safety of micafungin for prophylaxis of invasive fungal infections in patients undergoing haplo-identical hematopoietic SCT. AB - Invasive fungal infections (IFIs) such as candidiasis and mold infections have caused significant morbidity and mortality among immunocompromised patients in recent years. Micafungin, a new echinocandin, inhibits fungal cell wall beta glucan synthesis, with potent activity against most species of Candida and Aspergillus. The aim of this observational study was to investigate the efficacy and safety of micafungin in prophylaxis of IFIs in 26 high-risk adult patients with various hematological diseases receiving haplo-identical Allo-SCT. Only two patients had a history of possible aspergillosis before transplant treated by voriconazole. The patients received a median of four lines (2-7) of treatment before Allo-SCT. Thirteen patients (50%) received at least one prior Auto-SCT; and eight patients (31%) received a previous Allo-SCT. Patients received a median of 29 infusions (range, 15-85) of micafungin (50 mg/day i.v. as a 1-h infusion). The treatment was initiated at the beginning of the transplant conditioning regimen until the hospital discharge. None of our patients discontinued the treatment for drug-related adverse events. Micafungin was not associated with any hepatotoxicity. Only one patient (4%) discontinued the treatment because of early disease progression. In all patients no Candida and/or Aspergillus species was documented after 3 and 6 months from transplant. None of our patients presented a positive galactomannan antigenemia >0.5. Nine patients (35%) presented a CMV reactivation. Four patients presented an acute GVHD grade II and two patients presented a chronic GVHD. The median follow-up was 11 months (3-23). At the last follow-up, there were 20 patients (77%) who were alive; four patients (12%) died because of disease progression and two patients because of graft failure. Micafungin has a good safety and tolerability profile, with an efficacy in preventing IFI in this high-risk population. Our data provide support for an efficacy study in a prophylaxis setting, but prospective and comparative clinical trials using micafungin are urgently needed to define the role of this drug in prophylaxis after haplo-identical Allo-SCT. PMID- 23749105 TI - Long-term follow-up of a prospective randomized trial comparing CYA and MTX with CYA and mycophenolate mofetil for GVHD prophylaxis in myeloablative sibling donor hematopoietic cell transplantation. PMID- 23749106 TI - Outcomes of EAM conditioned autologous haematopoietic SCT for lymphoma. A matched pairs retrospective single-centre study analysis. PMID- 23749107 TI - Reduced PTLD-related mortality in patients experiencing EBV infection following allo-SCT after the introduction of a protocol incorporating pre-emptive rituximab. AB - The mortality associated with post-transplant lymphoproliferative disorder (PTLD) induced by EBV infection can be reduced by monitoring EBV by polymerase-chain reaction and rituximab given pre-emptively. We performed a retrospective analysis of the risk factors for the occurrence of EBV infection/disease and EBV-related mortality among 273 consecutive recipients of a T-cell-depleted allo-SCT during two periods: (a) before the implementation of a comprehensive protocol (2006 2008) and (b) afterwards (2009-2011). EBV infection was detected in 61 (22%) cases, and 28 cases were considered to have had EBV disease. Treatment with antithymocyte globulin was the most important risk factor (odds ratio (OR) 2.4; 95% confidence interval (CI) 1.3-4.2, P=0.001). After implementation of the protocol, in patients experiencing EBV infection, pre-emptive therapy was started more often and sooner (median 3 vs 6 days, P=0.002). Moreover, there were fewer cases of monomorphic PTLD (4/33 (12%) vs 11/28 (39%), P=0.01), and the EBV related mortality was lower for patients experiencing EBV infection (2/33 (6%) vs 8/28 (29%), OR 0.2; 95% CI 0.05-0.9, P=0.03). The EBV protocol proved feasible and resulted in faster initiation of pre-emptive therapy, the diagnosis in an earlier stage of EBV disease, and decreased EBV-related mortality. PMID- 23749108 TI - Pre-transplant FDG-PET-based survival model in relapsed and refractory Hodgkin's lymphoma: outcome after high-dose chemotherapy and auto-SCT. AB - Hodgkin's lymphoma (HL) patients with positive (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) post salvage chemotherapy or before high-dose chemotherapy and auto-SCT (HDC ASCT) have inferior outcomes. We reviewed 21 prognostic factors before salvage chemotherapy (at relapse/progression) and integrated post salvage FDG-PET results to develop a prognostic model for post HDC ASCT outcome. We used Fine and Gray method for competing risk analysis and regression model for risks assessment and outcome. One hundred and forty-one patients had post salvage FDG-PET before HDC ASCT (median age 25.5 years); male/female 55%:45%, relapsed/refractory 43%:57%, median follow-up 33 months. Multivariate analysis identified HL International Prognostic Score ?3 (P=0.001; hazard ratio (HR): 3.7 (1.6-8.3)) and post salvage positive FDG-PET (P=0.011; HR: 3.4 (1.3-8.9)) with higher hazard of disease-specific death (model P=0.0001). Cumulative incidence of disease-specific death with 0, 1, 2 risk factors was 7%:29%:52%, respectively (P=0.00003). For disease-specific event (persistent, progressive or relapsed disease), mediastinal involvement (P=0.024; HR: 2.7 (1.14 6.5)), B symptoms (P=0.027; HR: 2.1 (1.09-4.2)) and positive post salvage FDG-PET (P=0.001; HR: 3.3 (1.7-6.7)) were significant (model P=<0.00001). Cumulative incidence of disease-specific event with 0, 1, 2, 3 risk factors was 8%:31%:50%:75%, respectively (P=0.0000006). Patients with higher scores have higher risk of treatment failure. They are potential candidates for newer therapies along with HDC ASCT. PMID- 23749109 TI - Outcomes and costs of autologous stem cell mobilization with chemotherapy plus G CSF vs G-CSF alone. AB - Chemotherapy plus G-CSF (C+G) and G-CSF alone are two of the most common methods used to mobilize CD34(+) cells for autologous hematopoietic SCT (AHSCT). In order to compare and determine the real-world outcomes and costs of these strategies, we performed a retrospective study of 226 consecutive patients at 11 medical centers (64 lymphoma, 162 multiple myeloma), of whom 55% of lymphoma patients and 66% of myeloma patients received C+G. Patients with C+G yielded more CD34(+) cells/day than those with G-CSF alone (lymphoma: average 5.51 * 10(6) cells/kg on day 1 vs 2.92 * 10(6) cells/kg, P=0.0231; myeloma: 4.16 * 10(6) vs 3.69 * 10(6) cells/kg, P<0.00001) and required fewer days of apheresis (lymphoma: average 2.11 vs 2.96 days, P=0.012; myeloma: 2.02 vs 2.83 days, P=0.0015), although nearly all patients ultimately reached the goal of 2 * 10(6) cells/kg. With the exception of higher rates of febrile neutropenia in myeloma patients with C+G (17% vs 2%, P<0.05), toxicities and other outcomes were similar. Mobilization with C+G cost significantly more (lymphoma: median $10,300 vs $7300, P<0.0001; myeloma: $8800 vs $5600, P<0.0001), although re-mobilization adds $6700 for drugs alone. Our results suggest that although both C+G and G-CSF alone are effective mobilization strategies, C+G may be more cost-effective for patients at high risk of insufficient mobilization. PMID- 23749110 TI - Evaluating the association between histological manifestations of cord colitis syndrome with GVHD. AB - Cord colitis syndrome (CCS) is a recently proposed clinical entity characterized by a persistent diarrheal illness after cord blood transplantation (CBT), which is not caused by GVHD or CMV colitis. CCS is histologically characterized by chronic active colitis with granulomatous inflammation and Paneth cell metaplasia suggesting chronicity. However, the specificity of these pathological features to CCS remains to be validated. We conducted a retrospective study of 49 patients who had diarrhea and underwent diagnostic colonoscopy with biopsy following allogeneic hematopoietic SCT. None of the patients met the clinical criteria for CCS. Chronic active colitis with granulomatous inflammation and Paneth cell metaplasia was present in 12/33 (36%) patients with biopsy-proven GVHD, 4/6 (67%) patients with CMV colitis and 2/15 (13%) patients with nonspecific colitis. In patients with GVHD and/or CMV colitis, these pathological features were present in 4/8 (50%) patients after CBT and in 11/26 (42%) patients undergoing BMT or PBSCT. These results demonstrate that chronic active colitis with granuloma and Paneth cell metaplasia is not only a specific feature of CCS but also is present in GVHD and CMV colitis, irrespective of stem cell source. PMID- 23749111 TI - UV radiation and the skin. AB - UV radiation (UV) is classified as a "complete carcinogen" because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter. In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other environmentally influenced skin disorders. However, UV also benefits human health by mediating natural synthesis of vitamin D and endorphins in the skin, therefore UV has complex and mixed effects on human health. Nonetheless, excessive exposure to UV carries profound health risks, including atrophy, pigmentary changes, wrinkling and malignancy. UV is epidemiologically and molecularly linked to the three most common types of skin cancer, basal cell carcinoma, squamous cell carcinoma and malignant melanoma, which together affect more than a million Americans annually. Genetic factors also influence risk of UV-mediated skin disease. Polymorphisms of the melanocortin 1 receptor (MC1R) gene, in particular, correlate with fairness of skin, UV sensitivity, and enhanced cancer risk. We are interested in developing UV-protective approaches based on a detailed understanding of molecular events that occur after UV exposure, focusing particularly on epidermal melanization and the role of the MC1R in genome maintenance. PMID- 23749112 TI - Thrombospondin-1 in urological cancer: pathological role, clinical significance, and therapeutic prospects. AB - Angiogenesis is an important process for tumor growth and progression of various solid tumors including urological cancers. Thrombospondins (TSPs), especially TSP 1, are representative "anti"-angiogenic molecules and many studies have clarified their pathological role and clinical significance in vivo and in vitro. In fact, TSP-1 expression is associated with clinicopathological features and prognosis in many types of cancers. However, TSP-1 is a multi-functional protein and its biological activities vary according to the specific tumor environments. Consequently, there is no general agreement on its cancer-related function in urological cancers, and detailed information regarding regulative mechanisms is essential for a better understanding of its therapeutic effects and prognostic values. Various "suppressor genes" and "oncogenes" are known to be regulators and TSP-1-related factors under physiological and pathological conditions. In addition, various types of fragments derived from TSP-1 exist in a given tissue microenvironment and TSP-1 derived-peptides have specific activities. However, a detailed pathological function in human cancer tissues is not still understood. This review will focus on the pathological roles and clinical significance of TSP 1 in urological cancers, including prostate cancer, renal cell carcinoma, and urothelial cancer. In addition, special attention is paid to TSP-1-derived peptide and TSP-1-based therapy for malignancies. PMID- 23749113 TI - Analysis of transcriptional regulation of the human miR-17-92 cluster; evidence for involvement of Pim-1. AB - The human polycistronic miRNA cluster miR-17-92 is frequently overexpressed in hematopoietic malignancies and cancers. Its transcription is in part controlled by an E2F-regulated host gene promoter. An intronic A/T-rich region directly upstream of the miRNA coding region also contributes to cluster expression. Our deletion analysis of the A/T-rich region revealed a strong dependence on c-Myc binding to the functional E3 site. Yet, constructs lacking the 5'-proximal ~1.3 kb or 3'-distal ~0.1 kb of the 1.5 kb A/T-rich region still retained residual specific promoter activity, suggesting multiple transcription start sites (TSS) in this region. Furthermore, the protooncogenic kinase, Pim-1, its phosphorylation target HP1gamma and c-Myc colocalize to the E3 region, as inferred from chromatin immunoprecipitation. Analysis of pri-miR-17-92 expression levels in K562 and HeLa cells revealed that silencing of E2F3, c-Myc or Pim-1 negatively affects cluster expression, with a synergistic effect caused by c Myc/Pim-1 double knockdown in HeLa cells. Thus, we show, for the first time, that the protooncogene Pim-1 is part of the network that regulates transcription of the human miR-17-92 cluster. PMID- 23749114 TI - Enhanced inhibition of bladder cancer cell growth by simultaneous knockdown of antiapoptotic Bcl-xL and survivin in combination with chemotherapy. AB - The overexpression of antiapoptotic genes, such as Bcl-xL and survivin, contributes to the increased survival of tumor cells and to the development of treatment resistances. In the bladder cancer cell lines EJ28 and J82, the siRNA mediated knockdown of survivin reduces cell proliferation and the inhibition of Bcl-xL sensitizes these cells towards subsequent chemotherapy with mitomycin C and cisplatin. Therefore, the aim of this study was to analyze if the simultaneous knockdown of Bcl-xL and survivin might represent a more powerful treatment option for bladder cancer than the single inhibition of one of these target genes. At 96 h after transfection, reduction in cell viability was stronger after simultaneous inhibition of Bcl-xL and survivin (decrease of 40% 48%) in comparison to the single target treatments (decrease of 29% at best). Furthermore, simultaneous knockdown of Bcl-xL and survivin considerably increased the efficacy of subsequent chemotherapy. For example, cellular viability of EJ28 cells decreased to 6% in consequence of Bcl-xL and survivin inhibition plus cisplatin treatment whereas single target siRNA plus chemotherapy treatments mediated reductions down to 15%-36% only. In conclusion, the combination of simultaneous siRNA-mediated knockdown of antiapoptotic Bcl-xL and survivin-a multitarget molecular-based therapy-and conventional chemotherapy shows great potential for improving bladder cancer treatment. PMID- 23749115 TI - Contribution of the Tyr-1 in Plantaricin149a to disrupt phospholipid model membranes. AB - Plantaricin149a (Pln149a) is a cationic antimicrobial peptide, which was suggested to cause membrane destabilization via the carpet mechanism. The mode of action proposed to this antimicrobial peptide describes the induction of an amphipathic alpha-helix from Ala7 to Lys20, while the N-terminus residues remain in a coil conformation after binding. To better investigate this assumption, the purpose of this study was to determine the contributions of the Tyr1 in Pln149a in the binding to model membranes to promote its destabilization. The Tyr to Ser substitution increased the dissociation constant (KD) of the antimicrobial peptide from the liposomes (approximately three-fold higher), and decreased the enthalpy of binding to anionic vesicles from -17.2 kcal/mol to -10.2 kcal/mol. The peptide adsorption/incorporation into the negatively charged lipid vesicles was less effective with the Tyr1 substitution and peptide Pln149a perturbed the liposome integrity more than the analog, Pln149S. Taken together, the peptide lipid interactions that govern the Pln149a antimicrobial activity are found not only in the amphipathic helix, but also in the N-terminus residues, which take part in enthalpic contributions due to the allocation at a lipid-aqueous interface. PMID- 23749116 TI - An investigation of the effects of self-assembled monolayers on protein crystallisation. AB - Most protein crystallisation begins from heterogeneous nucleation; in practice, crystallisation typically occurs in the presence of a solid surface in the solution. The solid surface provides a nucleation site such that the energy barrier for nucleation is lower on the surface than in the bulk solution. Different types of solid surfaces exhibit different surface energies, and the nucleation barriers depend on the characteristics of the solid surfaces. Therefore, treatment of the solid surface may alter the surface properties to increase the chance to obtain protein crystals. In this paper, we propose a method to modify the glass cover slip using a self-assembled monolayer (SAM) of functional groups (methyl, sulfydryl and amino), and we investigated the effect of each SAM on protein crystallisation. The results indicated that both crystallisation success rate in a reproducibility study, and crystallisation hits in a crystallisation screening study, were increased using the SAMs, among which, the methyl-modified SAM demonstrated the most significant improvement. These results illustrated that directly modifying the crystallisation plates or glass cover slips to create surfaces that favour heterogeneous nucleation can be potentially useful in practical protein crystallisation, and the utilisation of a SAM containing a functional group can be considered a promising technique for the treatment of the surfaces that will directly contact the crystallisation solution. PMID- 23749117 TI - Evolutionary survey of druggable protein targets with respect to their subcellular localizations. AB - The druggable subset of the human genome, termed the "druggable genome," provides the pharmaceutical industry with a unique opportunity for the advancement of new therapeutic interventions for a multitude of diseases and disorders. To date, there is no systematic assessment of the evolutionary history and nature of the defined druggable proteins derived from the contemporary druggable genome (i.e., proteins that bind or are predicted to bind with high affinity to a biologic). An understanding of drug-protein target interactions in specific cellular compartments is crucial for the optimal therapeutic delivery of pharmaceutical agents, as well as for preclinical drug trials in model animals. This study applied the concept of pharmacophylogenomics, the study of genes, evolution, and drug targets, to conduct an evolutionary survey of drug targets with respect to their subcellular localizations. Using multiple models and modes of druggable genome comparison, the results concordantly indicated that orthologous drug targets with a nuclear localization in the human, macaque, mouse, and rat showed a higher trend for evolutionary conservation compared with drug targets in the cell membrane and the extracellular compartment. As such, this study provides important information regarding druggable protein targets and the druggable genome at the pharmacophylogenomics level. PMID- 23749118 TI - Developing Bacillus spp. as a cell factory for production of microbial enzymes and industrially important biochemicals in the context of systems and synthetic biology. AB - Increasing concerns over limited petroleum resources and associated environmental problems are motivating the development of efficient cell factories to produce chemicals, fuels, and materials from renewable resources in an environmentally sustainable economical manner. Bacillus spp., the best characterized Gram positive bacteria, possesses unique advantages as a host for producing microbial enzymes and industrially important biochemicals. With appropriate modifications to heterologous protein expression and metabolic engineering, Bacillus species are favorable industrial candidates for efficiently converting renewable resources to microbial enzymes, fine chemicals, bulk chemicals, and fuels. Here, we summarize the recent advances in developing Bacillus spp. as a cell factory. We review the available genetic tools, engineering strategies, genome sequence, genome-scale structure models, proteome, and secretion pathways, and we list successful examples of enzymes and industrially important biochemicals produced by Bacillus spp. Furthermore, we highlight the limitations and challenges in developing Bacillus spp. as a robust and efficient production host, and we discuss in the context of systems and synthetic biology the emerging opportunities and future research prospects in developing Bacillus spp. as a microbial cell factory. PMID- 23749119 TI - Identification and characterization of genes regulated by AqsR, a LuxR-type regulator in Acinetobacter oleivorans DR1. AB - The complete genome of Acinetobacter oleivorans DR1 contains AqsR and AqsI genes, which are LuxR and LuxI homolog, respectively. In a previous study, we demonstrated that quorum sensing (QS) signals play an important role in biofilm formation and hexadecane biodegradation. However, the regulation of genes controlled by the QS system in DR1 remains unexplored. We constructed an aqsR mutant and performed RNA sequencing analysis to understand the QS system. A total of 353 genes were differentially expressed during the stationary phase of wild type cells compared to that of the aqsR mutant. AqsR appears to be an exceptionally important regulator because knockout of aqsR affected global gene expression. Genes involved in posttranslational modification, chaperones, cell wall structure, secondary metabolites biosynthesis, and stress defense were highly upregulated only in the wild type. Among upregulated genes, both the AOLE_03905 (putative surface adhesion protein) and the AOLE_11355 (L asparaginase) genes have putative LuxR binding sites at their promoter regions. Soluble AqsR proteins were successfully purified in Escherichia coli harboring both aqsR and aqsI. Comparison of QS signals in an AqsI-AqsR co-overexpression strain with N-acyl homoserine lactone standards showed that the cognate N-acyl homoserine lactone binding to AqsR might be 3OH C12HSL. Our electrophoretic mobility shift assays with purified AqsR revealed direct binding of AqsR to those promoter regions. Our data showed that AqsR functions as an important regulator and is associated with several phenotypes, such as hexadecane utilization, biofilm formation, and sensitivity to cumene hydroperoxide. PMID- 23749120 TI - Waste valorization by biotechnological conversion into added value products. AB - Fossil fuel reserves depletion, global warming, unrelenting population growth, and costly and problematic waste recycling call for renewable resources of energy and consumer products. As an alternative to the 100 % oil economy, production processes based on biomass can be developed. Huge amounts of lignocellulosic wastes are yearly produced all around the world. They include agricultural residues, food farming wastes, "green-grocer's wastes," tree pruning residues, and organic and paper fraction of urban solid wastes. The common ways currently adopted for disposal of these wastes present environmental and economic disadvantages. As an alternative, processes for adding value to wastes producing high added products should be developed, that is the upgrading concept: adding value to wastes by production of a product with desired reproducible properties, having economic and ecological advantages. A wide range of high added value products, such as enzymes, biofuels, organic acids, biopolymers, bioelectricity, and molecules for food and pharmaceutical industries, can be obtained by upgrading solid wastes. The most recent advancements of their production by biotechnological processes are overviewed in this manuscript. PMID- 23749121 TI - Comparative genome characterization of Achromobacter members reveals potential genetic determinants facilitating the adaptation to a pathogenic lifestyle. AB - Members of the Achromobacter genus are Gram-negative bacteria including both environmental and clinical isolates, which are increasingly recovered from patients with cystic fibrosis (CF) as emerging pathogens. To better understand the features of the genus and its potential pathogenic mechanisms, six available Achromobacter genomes were compared in this study. The results revealed that: (1) Achromobacter had a pan-genome size of 10,750 genes with 3,398 core genes and a similar global classification of protein functions; (2) the Achromobacter genomes underwent a relatively low recombination that introduced nearly twice nucleotide substitutions less than the point mutation in genome evolution; (3) phylogenomic analysis based on 436 conserved proteins and average nucleotide identity both indicated that the Achromobacter genus had the closest relationship to the human/animal pathogen Bordetella rather than to Alcaligenes. The entire group of Achromobacter clustered with Bordetella in phylogeny, strongly suggesting a common origin, which therefore highlighted the potentially pathogenic nature of Achromobacter from the phylogenetic perspective, and (4) the CF clinical isolate possessed markedly unique genomic features discriminated from the environmental isolate and was equipped with numerous factors that facilitate its adaptation to a pathogenic lifestyle, such as a type III secretion system, a "polysaccharide island" (36.0 kb) of capsular/cellulose synthesis, adhesion-related proteins, alcaligin biogenesis, and several putative toxins. This study provided the first comprehensive genomic comparative analysis for Achromobacter, revealed information to better understand this far less-known genus on the genomic scale, and, importantly, identified potential virulence factors of the Achromobacter pathogen. PMID- 23749124 TI - High sensitive elemental analysis of single yeast cells (Saccharomyces cerevisiae) by time-resolved inductively-coupled plasma mass spectrometry using a high efficiency cell introduction system. AB - Trace elemental analysis of single yeast cells with time-resolved inductively coupled plasma mass spectrometry (ICP-MS) was successfully carried out, where a high efficiency cell introduction system (HECIS) consisting of the high performance concentric nebulizer (HPCN) and a low-volume (15 mL) on-axis spray chamber utilizing a sheath gas flow were used. Cell adsorption to the flow injector and sample tubing was reduced with the addition of a simple 4.3 mmol L( 1) of NaCl solution to the cell suspension and cell flowing liquid, allowing consecutive measurements without fear of significant contamination from previous measurements. Initially using a quadrupole mass analyzer ICP-MS (ICP-QMS) at its lowest integration time (10 ms), current spikes corresponding to separate cell events were detected for several elements (Mg, P, Ca, Mn, Fe, Cu, and Zn) on the introduction of the cell suspension. On comparing the number of peaks in the spectrum for phosphorous with the cell count using a haemocytometer, a reproducible cell transport efficiency of 75.0 +/- 4.7% was achieved. Preliminary experiments into using time of flight ICP-MS (ICP-TOFMS) for single-cell analysis were carried out, allowing quasi-simultaneous multielement detection. The spectra of Mg, P, Ca, Mn, Fe, Cu, and Zn, with a time resolution of 1 ms were simultaneously obtained in one measurement. A relatively strong correlation was observed for the spectra between P and Zn (correlation factor 0.69), P and Mg (0.63), and Mg and Zn (0.63). These results indicate that the time resolved quasi simultaneous multielement measurement may be useful for the correlation analysis of multielements in cells. PMID- 23749125 TI - Simple, colorimetric detection of microRNA based on target amplification and DNAzyme. AB - Considering the crucial role played by microRNAs (miRNAs) in biological processes, we developed a novel strategy for simple and colorimetric detection of miRNA by combining target amplification with DNAzyme. Throughout the work, a 22 nt oligonucleotide sequence was used as a model analyte. A label-free hairpin probe (HP) was used as a simple platform for sensing the target. In the presence of the target, the HP was opened, and then the isothermal circular strand displacement process occurred with the help of a primer, deoxynucleotide solution mixture (dNTPs), Klenow fragment exo(-) polymerase, and Nb.BbvCI nicking enzyme. As a result, the target was recycled and multicopies of target analogues were generated that function in the same manner as the target, accompanied by the accumulation of signal elements. In this work, as low as 0.5 fM nucleic acid target was detected by horseradish peroxidase-mimicking DNAzyme catalyzing the oxidation of ABTS(2-) to colored ABTS(*-). PMID- 23749122 TI - Routine EGFR molecular analysis in non-small-cell lung cancer patients is feasible: exons 18-21 sequencing results of 753 patients and subsequent clinical outcomes. AB - BACKGROUND: Epidermal growth factor receptor (EGFR)-targeting therapies dramatically modified the prognosis of stage 4 non-small-cell lung cancer. Sensitizing EGFR mutations are the best efficacy factor of these treatments. In 2006, the French National Cancer Institute launched a network of 28 centers for EGFR molecular analysis in routine practice. The aim of this retrospective study was to describe the results of routine EGFR analysis in one of these centers (Lyon University Hospital) and to assess outcomes in patients with the mutation. METHODS: EGFR mutations were analyzed for exons 18-21 by direct sequencing. The characteristics of each sample were retrospectively collected from the lab archives. Subsequent outcomes for patients harboring at least one mutation were retrospectively collected from each referring physician. RESULTS: During 1 year, 792 samples were analyzed, corresponding to 753 patients. A total of 133 mutations were diagnosed in 124 samples (15.7 %), corresponding to 121 patients. Most of them (77.4 %) were sensitizing mutations and were located in exons 19 and 21. Others were resistance mutations (8.3 %) or rare mutations (14.3 %) for which effects on tyrosine kinase inhibitor (TKI) sensitivity are unknown. The rate of indeterminate results (i.e., no sequencing of the entire exon 19 or 21) was 6.3 % (n = 50 samples). The only factor statistically associated with a risk of failure was sample from bone tissue: 13.7 % gave incomplete results (i.e., no whole sequencing of exons 18-21). CONCLUSIONS: Eighty-five of the 121 patients with EGFR mutations were treated with TKI. There were no differences in progression free survival (PFS) according to the type of molecule (erlotinib or gefitinib) or to the line of prescription of TKI. By contrast, exon 18 sensitizing mutations showed a worse PFS than exon 19 or 21 mutations. Finally, dose reduction was significantly more frequent in the erlotinib group than in the gefitinib group. PMID- 23749126 TI - Improved direct electrochemistry for proteins adsorbed on a UV/ozone-treated carbon nanofiber electrode. AB - We studied the direct electron transfer (DET) of proteins on a carbon nanofiber (CNF) modified carbon film electrode by employing the one-step UV/ozone treatment of CNF. This treatment changed the CNF surface from hydrophobic to hydrophilic because a sufficient quantity of oxygen functional groups was introduced onto the CNF surface. Furthermore, this simple approach increased both the effective surface area and the number of edge-plane defect sites. As a result, the reversibility of redox species, such as ferrocyanide and dopamine, was greatly improved on the treated electrode surface. We obtained on efficient DET of bilirubin oxidase (BOD) and cytochrome c (cyt c) at the treated CNF electrode, which exhibited 38 (for BOD) and 6 (for cyt c) times higher than that at untreated CNF modified electrode. These results indicate that the combination of nanostructured carbon and this UV/ozone treatment process can efficiently create a functionalized surface for the electron transfer of proteins. PMID- 23749127 TI - Using 2-mercaptobenzothiazole as a nitrogen and sulfur precursor to synthesize highly active Co-N-S/C electrocatalysts for oxygen reduction. AB - Novel Co-N-S/C catalysts supported on carbon were obtained using a two-step procedure. The procedure consisted of the synthesis of a carbon-supported Co-2 mercaptobenzothiazole (denoted as Co-MBT/C) complex using a solvent-milling method and the pyrolysis of the Co-MBT/C complex. 2-Mercaptobenzothiazole (MBT) was used as the nitrogen and sulfur ligand for Co-MBT complex formation. X-ray diffraction (XRD), TEM, EDS and elemental mappings were used to characterize the structure changes in these catalysts before and after the heat-treatment. Several catalysts were synthesized by varying the amount of cobalt salt and pyrolysis temperature. The results showed that the optimal cobalt salt content and pyrolysis temperature were around 25 wt% and 800 degrees C. Under the optimal conditions, an onset potential of 0.20 V and a half-wave potential of 0.05 V were reached in an alkaline electrolyte, and the Co-N-S/C catalyst possessed high catalytic activity and catalytic stability towards an oxygen reduction reaction (ORR). These results indicated that Co-N-S/C is a promising catalyst for the ORR. PMID- 23749128 TI - A simple, but highly sensitive, graphene-based voltammetric sensor for salvianic acid A sodium. AB - A simple, but highly sensitive, electrochemical sensor for the determination of salvianic acid A sodium (SAS) based on reduced graphene oxide (rGO) is reported. The sensor (rGO/GCE(ox)) was prepared by coating an rGO film on the surface of a pre-anodized glassy carbon electrode (GCE(ox)) through a dipping-drying method. The characteristic of the modified electrode was examined by scanning electron microscopy (SEM) and electrochemical impedance spectroscopy (EIS). Compared with bare GCE, GCE(ox) and rGO modified GCE, this sensor exhibited a superior ability for detecting SAS. Under the selected conditions, the reduction current had a good linear relationship with the SAS concentration in the range of 8.0 * 10(-8) 2.0 * 10(-5) mol L(-1), with a low detection limit of 2.0 * 10(-8) mol L(-1). Furthermore, the method was also successfully applied to detect SAS in medicinal tablets. PMID- 23749129 TI - Methacrylate-based diol monolithic stationary phase for the separation of polar and non-polar compounds in capillary liquid chromatography. AB - A monolithic capillary column prepared with glycidyl methacrylate (GMA) and poly(ethylene glycol) dimethacrylate (PEGDMA) was investigated and used in capillary liquid chromatography. The polymer monolith was synthesized in the presence of methanol and decanol as the biporogenic solvents by in situ polymerization of GMA and PEGDMA, and the optimum composition of monomer and porogen was investigated. After polymerization, glycidyl groups were hydrolyzed with sulfuric acid to produce diol groups at the surface of the porous monolith via epoxy-ring-opening. The GMA content in the polymerization mixture affected the hydrophilicity of the monolith. The separation capability was evaluated by separation of phenol compounds, phthalic acids, and polycyclic aromatic hydrocarbons. The poly(GMA-PEGDMA) monolithic capillary column exhibited satisfactory stability. PMID- 23749130 TI - Cellulose 2,3-di(p-chlorophenylcarbamate) bonded to silica gel for resolution of enantiomers. AB - In this study, 6-azido-2,3-di(p-chlorophenylcarbamoylated) cellulose was synthesized and bonded onto aminized silica gel to obtain a new chiral stationary phase. Enantioselectivity of the chiral stationary phase and Chiralcel OF suggested promising chiral separation ability of the new cellulose chiral stationary phase. In addition, the effect of trifluoroacetic acid, diethylamine on enantioselectivity and retention factors on the chiral stationary phase in high performance liquid chromatography was investigated. Experimental results revealed that resolution increased as the trifluoroacetic acid concentration increased to 0.3% while resolution declined as the diethylamine concentration increased. Therefore, the optimal concentrations of trifluoroacetic acid and diethylamine were determined to be 0.3 and 0.1%, respectively. In most cases, trifluoroacetic acid shortened the retention of the first eluted enantiomer while it increased the retention of the other. For acidic compounds, with the existence of diethylamine in the mobile phase, the retention of both enantiomers decreased. But for basic compounds, the retention of both enantiomers increased. PMID- 23749131 TI - Gas chromatographic and mass spectrometric characterization of trimethylsilyl derivatives of some terpene alcohol phenylpropenoids. AB - This paper reports mass spectra and linear temperature programmed retention indices (I(T)) for 31 esters of mono- and sesquiterpene alcohols with hydroxycinnamic acids. In this study, 14 phenylpropenoids were synthesized by esterification of terpenols with p-coumaric, ferulic, caffeic and sinapinic acids. Other phenylpropenoids were semi-quantitatively isolated by column chromatography from exudates covering the buds of two birch species (Betula pubescens and B. litwinowii). Main diagnostic ions in phenylpropenoids mass spectra were determined by GC/MS analysis. The possibility of predicting I(T) values was demonstrated with standard error of prediction between 3 and 11 of retention index units. PMID- 23749132 TI - Fast determination of pyrethroid pesticides in tobacco by GC-MS-SIM coupled with modified QuEChERS sample preparation procedure. AB - An analytical method was developed for the extraction and determination of pyrethroid pesticide residues in tobacco. The modified QuEChERS (Quick, Easy, Cheap, Effective, Rugged and Safe) method was applied for preparing samples. In this study, methyl cyanide (MeCN)-saturated salt aqueous was used as the two phase extraction solvent for the first time, and a vortex shaker was used for the simultaneous shaking and concentration of the analytes. The effects of experimental parameters on extraction and clean-up efficiency were investigated and optimized. The analytes were determined by gas chromatography-mass spectrometry-selected ion monitoring (GC-MS-SIM). The obtained recoveries of the analytes at three different fortification levels were 76.85-114.1% and relative standard deviations (RSDs) were lower than 15.7%. The limits of quantification (LOQs) were from 1.28 to 26.6 MUg kg(-1). This method was also applied to the analysis of actual commercial tobacco products and the analytical results were satisfactory. PMID- 23749133 TI - Green analytical methodology using Indian almond (Terminalia catappa L.) leaf extract for determination of aluminum ion in waste water from ceramic factories. AB - The use of natural reagents from plant extracts for chemical analysis is one of the approaches in the development of low cost and environmentally friendly green analytical chemistry methodology. Here, crude extract from Indian Almond (Terminalia Catappa L.) leaves was used for colorimetric determination of aluminum by monitoring the absorbance of the Al(3+)-extract complex at 435 nm. Dry leaves and freeze-dried fresh leaf extract can be kept for extended use. A simple flow injection analysis (FIA) system was also employed for rapid analysis (approximately 180 injections/h). The linear working range up to 100 mg L(-1) was established with a detection limit (blank + 3SD) of 0.8 mg L(-1), a limit of quantitation (blank + 10SD) of 2.4 mg L(-1), and a relative standard deviation of 3-5%. This simple green analytical chemistry methodology was applied for the determination of Al(3+) in waste water samples from ceramic factories. The results agreed well with the results obtained from the ICP-OES technique. PMID- 23749135 TI - Two-phase extraction of metal ions using a water-acetonitrile-ethyl acetate ternary mixed-solvent separation system. AB - A ternary mixed-solvent solution of water-acetonitrile-ethyl acetate changes from a homogeneous (single-phase) to a heterogeneous (two-phase) system with temperature and/or pressure changes. In this study, we used this system in a batch vessel to extract metal ions. Water-acetonitrile-ethyl acetate at a volume ratio of 3:8:4 containing 8-hydroxyquinoline was used as a ternary mixed-solvent solution, changing from homogeneous at 25 degrees C to heterogeneous after 30 min at 0 degrees C. The two-phase system comprised an upper (organic solvent-rich) phase and a lower (water-rich) phase at a volume ratio of 6:1. Fe(III), Co(II), and Ni(II) were used as model metal ions dissolved in the homogeneous solution at 25 degrees C. The distribution constants and the extraction percentages were determined by measuring the metal ion concentrations in the upper and lower phases with inductively coupled plasma atomic emission spectroscopy. The metal ions were extracted through complexation with 8-hydroxyquinoline in the organic rich phase with distribution constants and extraction percentage values, respectively, of 0.47 and 74 for Fe(III), 0.15 and 47 for Co(II), and 0.08 and 32 for Ni(II). PMID- 23749134 TI - Fourier transform near-infrared spectroscopy used for purity determination of rhein-L-arginine cocrystal (argirein). AB - A method is described using rapid and sensitive Fourier transform near-infrared spectroscopy (FT-NIRS) for the determination of rhein-L-arginine cocrystal (argirein). By mixing different values of argirein into different proportions with rhein and arginine, we obtained 41 batches of samples to deatermine. Partial least squares (PLS) regression was selected as the analysis type and standard normal variate (SNV) and original spectra were adopted for the spectral pretreatment. The correlation coefficient (R) of the calibration model was above 0.99 and the root mean square error of predictions (RMSEP) was under 0.012. The developed model was applied to 10 batches of known samples with satisfactory results. The established method is validated and can be applied to the intrinsic quality control of synthetic products and other cocrystals. PMID- 23749136 TI - Spectrophotometric sequential injection determination of D-penicillamine based on a complexation reaction with nickel ion. AB - A simple and sensitive spectrophotometric method, based on reaction between Ni(II) ion and D-penicillamine (PEN), was developed. The proposed SIA system enhanced the analytical applicability of the reaction of complexation, and allowed the determination of PEN in the concentration range of 3.0 * 10(-6) - 2.0 * 10(-4) mol L(-1) with a sampling rate of 200 h(-1). With the proposed SIA system, PEN could be accurately determinated up to 0.9 nmol quantity. The method was successfully applied to the determination of PEN in laboratory samples and pharmaceuticals. PMID- 23749137 TI - Rapid temperature-programmed separation of carbon monoxide and carbon dioxide on a packed capillary column in gas chromatography: application to the evaluation of photocatalytic activity of TiO2. AB - Carbon monoxide (CO) and carbon dioxide (CO2) were determined in a conventional capillary gas chromatography-flame ionization detector (GC-FID) by introducing a packed-capillary column and a methanizer. Due to good compatibility with rapid temperature-programmed operation of the packed capillary column, several volatile compounds, including CO and CO2, were rapidly eluted along with satisfactory resolution and sample loading capacity. The limit of quantifications of CO and CO2 were 5 and 3 ppm, respectively, with an injection volume of 0.5 mL. The developed system was then successfully applied to evaluating the photocatalytic decomposition of volatile organic compounds on titanium dioxide (TiO2). PMID- 23749138 TI - Solid-phase spectrophotometry for on-site analysis of trace elements in natural water. AB - A new, simple and sensitive solid-phase spectrometry (SPS) that is easily applicable to the on-site analysis of targeted chemical components in water at MUg dm(-3) or sub-MUg dm(-3) levels is proposed in this study. The main features of the SPS are the simplicity of operation, high sensitivity and applicability to real samples without the need for any pretreatment procedures. A portable spectrophotometer, consisting of an LED light source, a grating and a CCD, was used for the solid-phase light measurements. The universal applicability of the proposed system to on-site analysis was evaluated by determining phosphate, chromium(VI) and iron(II) in natural water. PMID- 23749140 TI - Binge eating in obese adolescents: emotional and behavioral characteristics and impact on health-related quality of life. AB - PURPOSE: This study explored binge eating among an adolescent obese population to ascertain the prevalence of bingeing, the relationship between binge eating and body mass index (BMI), and to evaluate significant relationships between binge eating, emotional/behavioral functioning, and health-related quality of life. METHODS: Participants included 102 overweight adolescents aged 12-17 years presenting to a multidisciplinary outpatient obesity clinic. Data obtained included height, weight, and self-report questionnaire data on emotional and behavioral functioning. RESULTS: Binge eating prevalence included 33% moderate to severe binge eating. Binge eating was significantly positively related to BMI and depression, negative mood, feelings of ineffectiveness, negative self-esteem and significantly negatively related to somatic complaints and all aspects of health related quality of life. Important demographic differences emerged with regard to the impact of binge eating on health-related quality of life with Caucasians, females, and older groups experiencing more pervasive impact. CONCLUSIONS: This research suggests that bingeing behaviors have pervasive and important implications for health-related quality of life for obese adolescents. PMID- 23749141 TI - Stimuli-responsive polymer films. AB - Stimuli-responsive polymer films undergo interesting structural and property changes upon external stimuli. Their applications have extended from smart coatings to controlled drug release, smart windows, self-repair and other fields. This tutorial review summarizes non-covalent bonding, reversible reactions and responsive molecules that have played important roles in creating stimuli responsive systems, and presents the recent development of three types of responsive polymer systems: layer-by-layer polymer multilayer films, polymer brushes, and self-repairing polymer films, with a discussion of their response mechanism. Future research efforts include comprehensive understanding of the response mechanism, producing polymer systems with controlled response properties regarding single or multiple external signals, combining polymer film fabrication with nanotechnology, improving the stability of polymer films on substrates, and evaluating the toxicity of the degradation products. PMID- 23749142 TI - Clinical efficacy of sitafloxacin 100 mg twice daily for 7 days for patients with non-gonococcal urethritis. AB - To clarify the clinical efficacy of STFX for patients with non-gonococcal urethritis (NGU), including chlamydial urethritis and Mycoplasma genitalium positive urethritis, this study included male patients with NGU who were 20 years old or older. The pathogens, including Chlamydia trachomatis, M. genitalium and Ureaplasma urealyticum, were detected by nucleic acid amplification tests and the patients were treated with sitafloxacin 100 mg twice daily for 7 days. Microbiological and clinical efficacies were assessed for the patients with NGU posttreatment. Among the 208 patients enrolled in this study, data for a total of 118 patients could be analyzed. The median age was 32 (20-61) years. The median duration from the completion of treatment to the second visit was 21 (14-42) days. There were 68 pathogen-positive NGU cases and 50 with NGU without any microbial detection. Microbiological cure was achieved in 95.6% of the pathogen positive NGU patients. Total clinical cure was achieved in 91.3% (105/115). In this study, STFX was able to eradicate 95.7% of C. trachomatis, 93.8% of M. genitalium and 100% of U. urealyticum. The results of our clinical research indicate that the STFX treatment regimen should become a standard regimen recommended for patients with NGU. In addition, this regimen is recommended for patients with M. genitalium-positive NGU. PMID- 23749143 TI - Intravenous itraconazole against experimental neutropenic Candida parapsilosis infection: efficacy after suppression of bacterial translocation. AB - A variety of studies indicate that itraconazole possesses greater intrinsic activity compared to the other azole derivatives against Candida parapsilosis. Efficacy has never been tested in an experimental setting. To this end, C. parapsilosis was used for challenge of 117 rats rendered neutropenic after a course of cyclophosphamide. Rats were assigned to receive intravenous treatment with saline (group A); itraconazole q12h (group B); fluconazole q12h (group C); single dose of ceftriaxone and saline (group D); single dose of ceftriaxone and itraconazole q12h (group E); and single dose of ceftriaxone and fluconazole q12h (group F). Survival was recorded, and yeast outgrowth of liver, spleen, lung, and kidney was measured after sacrifice at serial time intervals. Growth of the test isolate in tissues was significantly lower in group B than in groups A and C after 72 h. However, outgrowth of enterobacteria was found in tissues of groups A, B, and C, implying a phenomenon of bacterial translocation from the gut. When this phenomenon was suppressed with single doses of ceftriaxone, a striking survival benefit of itraconazole-treated animals was found (p = 0.022, group E vs. group F). The present results suggest than in deep infections by C. parapsilosis intravenously administered intraconazole may eradicate the offending agent and provide survival benefit when chemotherapy-induced bacterial translocation from the gut is suppressed. Further clinical evidence is required to support these findings. PMID- 23749144 TI - TNFalpha reverse signaling promotes sympathetic axon growth and target innervation. AB - Reverse signaling via members of the tumor necrosis factor (TNF) superfamily controls multiple aspects of immune function. Here we document TNFalpha reverse signaling in the nervous system to our knowledge for the first time and show that it has a crucial role in establishing sympathetic innervation. During postnatal development, sympathetic axons express TNFalpha as they grow and branch in their target tissues, which in turn express TNF receptor 1 (TNFR1). In culture, soluble forms of TNFR1 act directly on postnatal sympathetic axons to promote growth and branching by a mechanism that depends on membrane-integrated TNFalpha and on downstream activation of ERK. Sympathetic innervation density is substantially lower in several tissues in postnatal and adult mice lacking either TNFalpha or TNFR1. These findings reveal that target-derived TNFR1 acts as a reverse signaling ligand for membrane-integrated TNFalpha to promote growth and branching of sympathetic axons. PMID- 23749145 TI - The cortical angiome: an interconnected vascular network with noncolumnar patterns of blood flow. AB - What is the nature of the vascular architecture in the cortex that allows the brain to meet the energy demands of neuronal computations? We used high throughput histology to reconstruct the complete angioarchitecture and the positions of all neuronal somata of multiple cubic millimeter regions of vibrissa primary sensory cortex in mouse. Vascular networks were derived from the reconstruction. In contrast with the standard model of cortical columns that are tightly linked with the vascular network, graph-theoretical analyses revealed that the subsurface microvasculature formed interconnected loops with a topology that was invariant to the position and boundary of columns. Furthermore, the calculated patterns of blood flow in the networks were unrelated to location of columns. Rather, blood sourced by penetrating arterioles was effectively drained by the penetrating venules to limit lateral perfusion. This analysis provides the underpinning to understand functional imaging and the effect of penetrating vessels strokes on brain viability. PMID- 23749146 TI - Temporal whitening by power-law adaptation in neocortical neurons. AB - Spike-frequency adaptation (SFA) is widespread in the CNS, but its function remains unclear. In neocortical pyramidal neurons, adaptation manifests itself by an increase in the firing threshold and by adaptation currents triggered after each spike. Combining electrophysiological recordings in mice with modeling, we found that these adaptation processes lasted for more than 20 s and decayed over multiple timescales according to a power law. The power-law decay associated with adaptation mirrored and canceled the temporal correlations of input current received in vivo at the somata of layer 2/3 somatosensory pyramidal neurons. These findings suggest that, in the cortex, SFA causes temporal decorrelation of output spikes (temporal whitening), an energy-efficient coding procedure that, at high signal-to-noise ratio, improves the information transfer. PMID- 23749148 TI - N(4)-tolyl-2-acetylpyridine thiosemicarbazones and their platinum(II,IV) and gold(III) complexes: cytotoxicity against human glioma cells and studies on the mode of action. AB - Complexes [Au(2Ac4oT)Cl][AuCl2] (1), [Au(Hpy2Ac4mT)Cl2]Cl.H2O (2), [Au(Hpy2Ac4pT)Cl2]Cl (3), [Pt(H2Ac4oT)Cl]Cl (4), [Pt(2Ac4mT)Cl].H2O (5), [Pt(2Ac4pT)Cl] (6) and [Pt(L)Cl2OH], L = 2Ac4mT (7), 2Ac4oT (8), 2Ac4pT (9) were prepared with N(4)-ortho- (H2Ac4oT), N(4)-meta- (H2Ac4mT) and N(4)-para- (H2Ac4pT) tolyl-2-acetylpyridine thiosemicarbazone. The cytotoxic activities of all compounds were assayed against U-87 and T-98 human malignant glioma cell lines. Upon coordination cytotoxicity improved in 2, 5 and 8. In general, the gold(III) complexes were more cytotoxic than those with platinum(II,IV). Several of these compounds proved to be more active than cisplatin and auranofin used as controls. The gold(III) complexes probably act by inhibiting the activity of thioredoxin reductase enzyme whereas the mode of action of the platinum(II,IV) complexes involves binding to DNA. Cells treated with the studied compounds presented morphological changes such as cell shrinkage and blebs formation, which indicate cell death by apoptosis induction. PMID- 23749147 TI - Arc in the nucleus regulates PML-dependent GluA1 transcription and homeostatic plasticity. AB - The activity-regulated cytoskeletal protein Arc (also known as Arg3.1) is required for long-term memory formation and synaptic plasticity. Arc expression is robustly induced by activity, and Arc protein localizes to both active synapses and the nucleus. Whereas its synaptic function has been examined, it is not clear why or how Arc is localized to the nucleus. We found that murine Arc nuclear expression is regulated by synaptic activity in vivo and in vitro. We identified distinct regions of Arc that control its localization, including a nuclear localization signal, a nuclear retention domain and a nuclear export signal. Arc localization to the nucleus promotes an activity-induced increase in the expression of promyelocytic leukemia nuclear bodies, which decreases GluA1 (also called Gria1) transcription and synaptic strength. We further show that Arc nuclear localization regulates homeostatic plasticity. Thus, Arc mediates the homeostatic response to increased activity by translocating to the nucleus, increasing promyelocytic leukemia protein expression and decreasing GluA1 transcription, ultimately downscaling synaptic strength. PMID- 23749149 TI - Cobalt binding in the photosynthetic bacterium R. sphaeroides by X-ray absorption spectroscopy. AB - Cobalt is an important oligoelement required for bacteria; if present in high concentration, exhibits toxic effects that, depending on the microorganism under investigation, may even result in growth inhibition. The photosynthetic bacterium Rhodobacter (R.) sphaeroides tolerates high cobalt concentration and bioaccumulates Co(2+) ion, mostly on the cellular surface. Very little is known on the chemical fate of the bioaccumulated cobalt, thus an X-ray absorption spectroscopy investigation was conducted on R. sphaeroides cells to gain structural insights into the Co(2+) binding to cellular components. X-ray absorption near-edge spectroscopy and extended X-ray absorption fine structure measurements were performed on R. sphaeroides samples containing whole cells and cell-free fractions obtained from cultures exposed to 5 mM Co(2+). An octahedral coordination geometry was found for the cobalt ion, with six oxygen-ligand atoms in the first shell. In the soluble portion of the cell, cobalt was found bound to carboxylate groups, while a mixed pattern containing equivalent amount of two sulfur and two carbon atoms was found in the cell envelope fraction, suggesting the presence of carboxylate and sulfonate metal-binding functional groups, the latter arising from sulfolipids of the cell envelope. PMID- 23749150 TI - Glucose-triggered release using enzyme-gated mesoporous silica nanoparticles. AB - A new gated nanodevice design able to control cargo delivery using glucose as a trigger and cyclodextrin-modified glucose oxidase as a capping agent is reported. PMID- 23749151 TI - Evidence for extra-renal production of 1alpha,25(OH)2D 3 in critical illness: a preliminary study. PMID- 23749152 TI - A fresh perfection. PMID- 23749153 TI - Half-molar sodium lactate infusion to prevent intracranial hypertensive episodes in severe traumatic brain injured patients: a randomized controlled trial. AB - PURPOSE: Preventive treatments of traumatic intracranial hypertension are not yet established. We aimed to compare the efficiency of half-molar sodium lactate (SL) versus saline serum solutions in preventing episodes of raised intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI). METHODS: This was a double-blind, randomized controlled trial including 60 patients with severe TBI requiring ICP monitoring. Patients were randomly allocated to receive a 48-h continuous infusion at 0.5 ml/kg/h of either SL (SL group) or isotonic saline solution (control group) within the first 12 h post-trauma. Serial measurements of ICP, as well as fluid, sodium, and chloride balance were performed over the 48-h study period. The primary outcome was the number of raised ICP (>=20 mmHg) requiring a specific treatment. RESULTS: Raised ICP episodes were reduced in the SL group as compared to the control group within the 48-h study period: 23 versus 53 episodes, respectively (p < 0.05). The proportion of patients presenting raised ICP episodes was smaller in the SL group than in the saline group: 11 (36 %) versus 20 patients (66 %) (p < 0.05). Cumulative 48-h fluid and chloride balances were reduced in the SL group compared to the control group (both p < 0.01). CONCLUSION: A 48-h infusion of SL decreased the occurrence of raised ICP episodes in patients with severe TBI, while reducing fluid and chloride balances. These findings suggest that SL solution could be considered as an alternative treatment to prevent raised ICP following severe TBI. PMID- 23749154 TI - Neurologic complications in neonates supported with extracorporeal membrane oxygenation. An analysis of ELSO registry data. AB - BACKGROUND: Neurologic complications in neonates supported with extracorporeal membrane oxygenation (ECMO) are common and diminish their quality of life and survival. An understanding of factors associated with neurologic complications in neonatal ECMO is lacking. The goals of this study were to describe the epidemiology and factors associated with neurologic complications in neonatal ECMO. PATIENTS AND METHODS: Retrospective cohort study of neonates (age <=30 days) supported with ECMO using data reported to the Extracorporeal Life Support Organization during 2005-2010. RESULTS: Of 7,190 neonates supported with ECMO, 1,412 (20 %) had neurologic complications. Birth weight <3 kg [odds ratio (OR): 1.3; 95 % confidence intervals (CI): 1.1-1.5], gestational age (<34 weeks; OR 1.5, 95 % CI 1.1-2.0 and 34-36 weeks: OR 1.4, 95 % CI 1.1-1.7), need for cardiopulmonary resuscitation prior to ECMO (OR 1.7, 95 % CI 1.5-2.0), pre-ECMO blood pH <= 7.11 (OR 1.7, 95 % CI 1.4-2.1), pre-ECMO bicarbonate use (OR 1.3, 95 % CI 1.2-1.5), prior ECMO exposure (OR 2.4, 95 % CI 1.6-2.6), and use of veno arterial ECMO (OR 1.7, 95 % CI 1.4-2.0) increased neurologic complications. Mortality was higher in patients with neurologic complications compared to those without (62 % vs. 36 %; p < 0.001). CONCLUSIONS: Neurologic complications are common in neonatal ECMO and are associated with increased mortality. Patient factors, pre-ECMO severity of illness, and use of veno-arterial ECMO are associated with increased neurologic complications. Patient selection, early ECMO deployment, and refining ECMO management strategies for vulnerable populations could be targeted as areas for improvement in neonatal ECMO. PMID- 23749155 TI - Fluorescent nanoparticle beacon for logic gate operation regulated by strand displacement. AB - A mechanism is developed to construct a logic system by employing DNA/gold nanoparticle (AuNP) conjugates as a basic work unit, utilizing a fluorescent beacon probe to detect output signals. To implement the logic circuit, a self assembly DNA structure is attached onto nanoparticles to form the fluorescent beacon. Moreover, assisted by regulation of multilevel strand displacement, cascaded logic gates are achieved. The computing results are detected by methods using fluorescent signals, gel electrophoresis and transmission electron microscope (TEM). This work is expected to demonstrate the feasibility of the cascaded logic system based on fluorescent nanoparticle beacons, suggesting applications in DNA computation and biotechnology. PMID- 23749156 TI - Enhanced photocatalytic water splitting by BaLa4Ti4O15 loaded with ~1 nm gold nanoclusters using glutathione-protected Au25 clusters. AB - Glutathione-protected Au25 clusters were used to load monodisperse gold nanoclusters (1.2 +/- 0.3 nm) onto BaLa4Ti4O15 to create photocatalysts. The photocatalytic activity of the resulting material for water splitting was determined to be 2.6 times higher than that of catalysts loaded with larger gold nanoparticles (10-30 nm) via conventional photodeposition. PMID- 23749157 TI - Mast cell tryptase induces eosinophil recruitment in the pleural cavity of mice via proteinase-activated receptor 2. AB - Proteinase-activated receptor (PAR) 2 has been implicated in eosinophil migration. Mast cell (MC) tryptase has been similarly implicated in allergic diseases through the activation of PAR-2, but the role of this receptor in MC tryptase-induced inflammation is not well elucidated. This study aims to investigate the ability of MC tryptase or PAR-2 activating peptide (SLIGRL-NH2) to induce eosinophil recruitment to the pleural cavity of mice. Mast cell tryptase-injected mice were pretreated with PAR-2 antagonist ENMD-1068. Mice injected with SLIGRL-NH2 were pretreated with mast cell tryptase inhibitor APC 366, and eosinophil migration into the pleural cavity and PAR-2 expression was analyzed after 24 or 48 h. SLIGRL-NH2-induced eosinophil recruitment was inhibited by APC 366, and MC tryptase-induced eosinophil recruitment was abolished by ENMD-1068. MC tryptase induced PAR-2 expression on pleural eosinophils. Our results demonstrate a key role for PAR-2 in mediating eosinophil recruitment in MC tryptase-induced pleurisy in mice. The ability of MC tryptase to inducing PAR-2 expression on eosinophils corroborates the relevance of MC tryptase and PAR-2 on modulating eosinophil migration. PMID- 23749158 TI - Acetylcholinesterase inhibition and in vitro and in vivo antioxidant activities of Ganoderma lucidum grown on germinated brown rice. AB - In this study, the acetylcholinesterase inhibition and in vitro and in vivo antioxidant activities of Ganoderma lucidum grown on germinated brown rice (GLBR) were evaluated. In antioxidant assays in vitro, GLBR was found to have strong metal chelating activity, DPPH, ABTS, hydroxyl and superoxide radical scavenging activity. Cell-based antioxidant methods were used, including lipid peroxidation on brain homogenate and AAPH-induced erythrocyte haemolysis. In antioxidant assays in vivo, mice were administered with GLBR and this significantly enhanced the activities of antioxidant enzymes in the mice sera, livers and brains. The amount of total phenolic and flavonoid compounds were 43.14 mg GAE/g and 13.36 mg CE/g dry mass, respectively. GLBR also exhibited acetylcholinesterase inhibitory activity. In addition, HPLC analyses of GLBR extract revealed the presence of different phenolic compounds. These findings demonstrate the remarkable potential of GLBR extract as valuable source of antioxidants which exhibit interesting acetylcholinesterase inhibitory activity. PMID- 23749159 TI - Isotope effects in ESR spectroscopy. AB - In order to present the relationship between ESR spectroscopy and isotope effects three levels are considered: (i) ESR spectroscopy is described on a general level up to the models for interpretation of the experimental spectra, which go beyond the usually used time and mass independent spin-Hamilton operator, (ii) the main characteristics of the generalized isotope effects are worked out, and finally (iii) the basic, mainly quantum mechanical effects are used to describe the coupling of electron spins with the degrees of freedom, which are accessible under the selected conditions, of the respective paramagnetic object under investigation. The ESR parameters and the respective models are formalized so far, that they include the time and mass depending influences and reflect the specific isotope effects. Relations will be established between the effects in ESR spectra to spin relaxation, to spin exchange, to the magnetic isotope effect, to the Jahn-Teller effects, as well as to the influence of zero-point vibrations. Examples will be presented which demonstrate the influence of isotopes as well as the kind of accessible information. It will be differentiated with respect to isotope effects in paramagnetic centres itself and in the respective matrices up to the technique of ESR imaging. It is shown that the use of isotope effects is indispensable in ESR spectroscopy. PMID- 23749160 TI - General intermediates for the synthesis of 6-C-alkylated DMDP-related natural products. AB - Protected L-homoDMDP en-8 and its C-6 epimer en-7 were prepared through two different pathways starting from the vinylpyrrolidine en-9. Based on the NMR and X-ray analysis, the stereochemistry of homoDMDP at C-6 was confirmed to be consistent with reported data. Compounds en-7 and en-8 are general intermediates for the synthesis of a series of 6-C-alkylated DMDP-related natural products, such as broussonetine G, homoDMDP-7-O-apioside, homoDMDP-7-O-b-D-xyloside and so on. PMID- 23749161 TI - Eudragit(r) L100/N-trimethylchitosan chloride microspheres for oral insulin delivery. AB - Effective oral delivery of protein and peptide drugs remains an active topic in scientific research. In this study, matrix type microspheres were prepared with Eudragit(r) L100 containing N-trimethylchitosan chloride to improve the permeation of insulin across the intestinal epithelium via the paracellular pathway. Insulin loaded microspheres were initially formulated in accordance with a factorial design (23) and manufactured by means of a single water-in-oil emulsification/evaporation method. Based on external and internal morphology two microsphere formulations were selected from the initial formulations for further investigation in terms of particle size, dissolution behaviour and in vitro insulin transport across excised rat intestinal tissue. The initial eight microsphere formulations exhibited drug loading capacities ranging from 27.9 52.4% with different shapes and internal structures. The two selected microsphere formulations had average particle sizes of 157.3 +/- 31.74 um and 135.7 +/- 41.05 um, respectively, and mean dissolution time values for insulin release of 34.47 and 42.63 min, respectively. In vitro transport of insulin across excised rat intestinal tissue from the two selected microsphere formulations was 10.67-fold and 9.68-fold higher than the control group (insulin alone). The microsphere delivery system prepared from Eudragit(r) L100 containing N-trimethylchitosan chloride is therefore a promising candidate for effective oral insulin delivery. PMID- 23749162 TI - The development of aromas in ruminant meat. AB - This review provides an update on our understanding of the chemical reactions (lipid oxidation, Strecker and Maillard reactions, thiamine degradation) and a discussion of the principal aroma compounds derived from those reaction or other sources in cooked meat, mainly focused on ruminant species. This knowledge is essential in order to understand, control, and improve the quality of food products. More studies are necessary to fully understand the role of each compound in the overall cooked meat flavour and their possible effect in consumer acceptability. PMID- 23749163 TI - A novel combinatorial biocatalytic approach for producing antibacterial compounds effective against Mycobacterium tuberculosis (TB). AB - Two bacterial hosts expressing cloned aromatic oxygenases were used to catalyze the oxidation and polymerization of indole and related substrates, creating mixtures of indigoid compounds comprised of novel dimers and trimers. Crude extracts and purified compounds were tested for their ability to inhibit the growth of Gram-positive organisms, in general, and Mycobacterium tuberculosis (TB), in particular. Of the 74 compounds tested against M. tuberculosis, ~66 % had minimum inhibitory concentrations (MIC) of 5 MUg/ml or less. The most effective antibiotic found was designated SAB-P1, a heterodimer of indole and anthranil, which had a MIC of 0.16 MUg/ml, and did not inhibit kidney cells (IC(50)) at concentrations of >8 MUg/ml. Combinatorial biocatalysis was used to create a series of halogenated derivatives of SAB-P1 with a wider therapeutic window. None of the derivatives had MIC values that were superior to SAB-P1, but some had a wider therapeutic window because of decreased kidney cell toxicity. Generally, the indigoid dimers that were effective against TB appeared to be specific for TB. Some of the trimers generated, however, had a broader spectrum of activity inhibiting not only TB (MIC = 1.1 MUg/ml) but also the growth of Mycobacterium smegmatis MC2 155, Bacillus cereus, Enterococcus faecalis, Staphylococcus epidermidis, Bacillus subtilis 168, and Clostridium acetobutylicum. The structure of two of the novel dimers (SAB-C4 and SAB-P1) and a trimer (SAB-R1) were solved using X-ray crystallography. PMID- 23749165 TI - Proinflammatory conditions promote hepatocellular carcinoma onset and progression via activation of Wnt and EGFR signaling pathways. AB - The aim of the current study was to investigate how proinflammatory conditions affect growth and progression of hepatocellular carcinoma. Human hepatoma cell lines were treated with lipopolysaccharide (LPS) or cyclooxygenase-2 inhibitor, Celecoxib, and in vitro proliferation, apoptosis, and cell cycle progression were assessed. This was followed up with in vivo xenograft assays to monitor tumor growth and metastatic progression under different treatment conditions. While LPS induced cell proliferation, Celecoxib induced apoptosis. Flow cytometry analysis demonstrated that S-phase cell count in LPS group was higher than control group (41.9 +/- 3.2 vs 30.6 +/- 0.1%, respectively), whereas G0/G1-phase cells were significantly higher in the Celecoxib group in comparison with the control group (69.6 +/- 5.0 vs 50.4 +/- 1.6%, respectively) (p < 0.05). Immunoblot analyses showed induction of epidermal growth factor receptor expression and induction and nuclear accumulation of Wnt/beta-catenin and p65 in LPS group. Xenograft assays showed that LPS treatment induced comparatively large, rapidly growing tumors (2,702 +/- 572 mm(3)) that metastasized to lungs, whereas Celecoxib treatment alone (1,008 +/- 296 mm(3)) or in combination with LPS (1,303 +/- 283 mm(3)) suppressed tumor growth in comparison to control groups (2,072 +/- 456 mm(3)) (n = 5; p < 0.05). Inflammation can thus promote hepatoma cell proliferation and growth, and enhance the invasion and metastatic ability of hepatocarcinoma cells through inducing tumor angiogenesis, which in turn may be related to the activation of Wnt/beta-catenin and EGFR signaling pathways. PMID- 23749166 TI - Vascular endothelial growth factor regulates primate choroid-retinal endothelial cell proliferation and tube formation through PI3K/Akt and MEK/ERK dependent signaling. AB - Vascular endothelial growth factor (VEGF) is a hypoxia-induced angiogenic protein that exhibits a broad range of biological and pathological effects in wet age related macular degeneration and proliferative diabetic retinopathy. However, its specific mechanism is still not fully understood. Here, we examined the effects of VEGF on choroid-retinal endothelial cells (RF/6A) proliferation and tube formation, and the underlying signal pathways responsible in this process. RF/6A cells were pretreated with MEK inhibitor or PI3K inhibitor, and then incubated in a hypoxia chamber. Real-time PCR and Western blot analysis were carried out to explore VEGF expression on mRNA and protein levels. Hypoxia inducible factor 1alpha (HIF-1alpha) and VEGFR2 expression levels were also investigated in the presence and absence of hypoxic conditions. CCK-8 analysis and tube formation assay were tested under hypoxia, exogenous recombinant VEGF, and different signal pathway inhibitors, respectively. Mean while, the PI3K/Akt and MEK/ERK pathways in this process were also investigated. Our results showed that VEGF, HIF-1alpha, VEGFR2, p-ERK, and p-Akt were up-regulated in RF/6A cells under hypoxic conditions. MEK inhibitor (PD98059) and PI3K inhibitor (LY294002) decreased ERK and Akt activity, respectively, and reduced VEGF expression. VEGF-induced RF/6A proliferation and tube formation requires MEK/ERK and PI3K/Akt signaling, and both of the two pathways were needed in regulating VEGF expression. These suggest that VEGF plays an important role in RF/6A proliferation and tube formation, and MEK/ERK and PI3K/Akt pathway may be responsible for this process. PMID- 23749164 TI - Genetic insights into the functional elements of language. AB - Language disorders cover a wide range of conditions with heterologous and overlapping phenotypes and complex etiologies harboring both genetic and environmental influences. Genetic approaches including the identification of genes linked to speech and language phenotypes and the characterization of normal and aberrant functions of these genes have, in recent years, unraveled complex details of molecular and cognitive mechanisms and provided valuable insight into the biological foundations of language. Consistent with this approach, we have reviewed the functional aspects of allelic variants of genes which are currently known to be either causally associated with disorders of speech and language or impact upon the spectrum of normal language ability. We have also reviewed candidate genes associated with heritable speech and language disorders. In addition, we have evaluated language phenotypes and associated genetic components in developmental syndromes that, together with a spectrum of altered language abilities, manifest various phenotypes and offer details of multifactorial determinants of language function. Data from this review have revealed a predominance of regulatory networks involved in the control of differentiation and functioning of neurons, neuronal tracks and connections among brain structures associated with both cognitive and language faculties. Our findings, furthermore, have highlighted several multifactorial determinants in overlapping speech and language phenotypes. Collectively this analysis has revealed an interconnected developmental network and a close association of the language faculty with cognitive functions, a finding that has the potential to provide insight into linguistic hypotheses defining in particular, the contribution of genetic elements to and the modular nature of the language faculty. PMID- 23749167 TI - Thymosin beta4 induces angiogenesis through Notch signaling in endothelial cells. AB - Thymosin beta4 (Tbeta4) has multi-functional roles in angiogenesis and arteriogenesis, but little is known about its mechanism. The Notch signaling pathway is important in regulation of angiogenic behavior of endothelial cells, in addition to vascular endothelial growth factor (VEGF). Whether, Tbeta4 regulates angiogenesis through Notch signaling pathway is not clear. In this article, we evaluated the effect of Notch signaling in Tbeta4-induced angiogenesis in human umbilical vein endothelial cell (HUVEC). Our results revealed that Tbeta4 increased Notch1 and Notch4 expression in a dose and time dependent manner. The inhibition of Notch1 or Notch4 with siRNA or the Notch receptor inhibitor DAPT significantly prevented Tbeta4-induced HUVEC tube formation and lymphocyte transendothelial migration. The inhibition of Notch1 or Notch4 also blocked Tbeta4-induced VEGF and HIF-1alpha expression. VE-cadherin is the major endothelial adhesion molecule in the control of angiogenesis. Tbeta4 significantly reduced VE-cadherin expression levels in HUVEC, while the inhibition of Notch signaling prevented Tbeta4-induced VE-cadherin down regulation. The results of this study suggest that Tbeta4 induces HUVEC angiogenesis through Notch signaling pathway. PMID- 23749169 TI - Association of angiotensin I-converting enzyme gene insertion/deletion polymorphism with rheumatic heart disease in Indian population and meta-analysis. AB - Rheumatic heart disease (RHD) is one of the most severe consequences of rheumatic fever. It has been suggested that angiotensin I-converting enzyme (ACE) may be involved in the increased valvular fibrosis and calcification in the pathogenesis of RHD. We conducted a case-control study to look for association of ACE I/D polymorphism with RHD in Indian population. The study incorporated 300 patients (170 males and 130 females) with RHD, and 200 controls (118 males and 82 females). We also subgrouped RHD patients into mitral valve lesion (MVL) and combined valve lesion (CVL). ACE I/D polymorphism was identified using polymerase chain reaction method. We also performed a meta-analysis of three published studies and the present study (636 RHD cases and 533 controls) to evaluate the association between the ACE I/D polymorphisms and RHD risk. A significant difference in ACE ID and DD genotypes distribution between RHD cases (OR = 1.62, 95% CI = 1.11-2.36 and OR = 2.08, 95% CI = 1.02-4.15, respectively) and corresponding controls was observed. On comparing the ACE genotypes of MVL and CVL subgroups with controls, ID and DD genotypes were also significantly associated with CVL (FDR Pcorr = 0.009, OR = 2.19 and FDR Pcorr = 0.014, OR = 3.29, respectively). Meta-analysis also suggested association of the ACE D allele (FDR Pcorr = 0.036, OR-1.22, 95% CI 1.02-1.45) with RHD. In conclusion, ACE ID and DD genotypes are associated with an increased risk of RHD, particularly CVL. This suggests that the ACE I/D gene polymorphism may play an important role in the pathogenesis of RHD. PMID- 23749168 TI - PIP3 but not PIP2 increases GLUT4 surface expression and glucose metabolism mediated by AKT/PKCzeta/lambda phosphorylation in 3T3L1 adipocytes. AB - Phosphatidylinositol-3,4,5-triphosphate (PIP3) and phosphatidylinositol-4,5 biphosphate (PIP2) are two well-known membrane bound polyphosphoinositides. Diabetes is associated with impaired glucose metabolism. Using a 3T3L1 adipocyte cell model, this study investigated the role of PIP3 and PIP2 on insulin stimulated glucose metabolism in high glucose (HG) treated cells. Exogenous PIP3 supplementation (1, 5, or 10 nM) increased the phosphorylation of AKT and PKCzeta/lambda, which in turn upregulated GLUT4 total protein expression as well as its surface expression, glucose uptake, and glucose utilization in cells exposed to HG (25 mM); however, PIP2 had no effect. Comparative signal silencing studies with antisense AKT2 and antisense PKCzeta revealed that phosphorylation of PKCzeta/lambda is more effective in PIP3 mediated GLUT4 activation and glucose utilization than in AKT phosphorylation. Supplementation with PIP3 in combination with insulin enhanced glucose uptake and glucose utilization compared to PIP2 with insulin, or insulin alone, in HG-treated adipocytes. This suggests that a decrease in cellular PIP3 levels may cause impaired insulin sensitivity in diabetes. PIP3 supplementation also prevented HG-induced MCP-1 and resistin secretion and lowered adiponectin levels. This study for the first time demonstrates that PIP3 but not PIP2 plays an important role in GLUT4 upregulation and glucose metabolism mediated by AKT/PKCzeta/lambda phosphorylation. Whether PIP3 levels in blood can be used as a biomarker of insulin resistance in diabetes needs further investigation. PMID- 23749170 TI - Ganglioside GM3 promotes HGF-stimulated motility of murine hepatoma cell through enhanced phosphorylation of cMet at specific tyrosine sites and PI3K/Akt-mediated migration signaling. AB - Ganglioside GM3 plays a well-documented and important role in the regulation of tumor cell proliferation, invasion, and metastasis by modulating tyrosine kinase growth factor receptors. However, the effect of GM3 on the hepatocyte growth factor receptor (HGFR, cMet) has not been fully delineated. In the current study, we investigated how GM3 affects cMet signaling and HGF-stimulated cell motility and migration using three hepatic cancer cell lines of mouse (Hca/A2, Hca/16A3, and Hepa1-6). Decreasing GM3 expression with the use of P4, a specific inhibitor for ganglioside synthesis inhibited the HGF-stimulated phosphorylation of cMet and activity of PI3K/Akt signaling pathway. In contrast, the increased expression of GM3 as a result of adding exogenous GM3 enhanced the HGF-stimulated phosphorylation of cMet and activity of PI3K/Akt signaling pathway. Furthermore, HGF-stimulated cell motility and migration in vitro were inhibited by reduced expression of GM3 and enhanced by increased expression of GM3. All the observations indicate that ganglioside GM3 promotes HGF-stimulated motility of murine hepatoma cell through enhanced phosphorylation of cMet at specific tyrosine sites and PI3K/Akt-mediated migration signaling. PMID- 23749171 TI - Novel and functional variants within the TBX18 gene promoter in ventricular septal defects. AB - Congenital heart disease (CHD) is the most common birth defect in humans. Genetic causes for CHD remain largely unknown. T-box transcription factor 18 (TBX18) gene is expressed in the developing heart, including myocardium of the left ventricle and interventricular septum. Epicardial cells expressing TBX18 gene contribute to the cardiac fibroblast and smooth muscle cells. We speculated that the DNA sequence variants (DSVs) within TBX18 gene promoter may mediate CHD development by affecting TBX18 levels and the cardiac gene regulatory network. In this study, we genetically and functionally analyzed the TBX18 gene promoter in patients with ventricular septal defects (VSD) (n = 326) and ethnic-matched healthy controls (n = 327). Three novel heterozygous DSVs (g.85474435del, g.85474418C>T, and g.85473965C>G) and one single nucleotide polymorphism (g.85474871C>T, rs77693245) were identified in VSD patients, but none in the controls. Functional analysis revealed that the DSVs (g.85474871C>T, g.85474435del, and g.85473965C>G) significantly decreased the transcriptional activities of the TBX18 gene promoter. The effect of DSV (g.85474418C>T) on the TBX18 gene promoter was marginal, but not significant. Therefore, the DSVs within the TBX18 gene promoter identified in VSD patients may be involved in the VSD etiology. PMID- 23749172 TI - Evolution and homologous recombination of the hemagglutinin-esterase gene sequences from porcine torovirus. AB - The objective of the present study was to gain new insights into the evolution, homologous recombination, and selection pressures imposed on the porcine torovirus (PToV), by examining the changes in the hemagglutinin-esterase (HE) gene. The most recent common ancestor of PToV was estimated to have emerged 62 years ago based upon HE gene sequence data obtained from PToV isolates originating from Spain, South Korea, Netherlands, Hungary, and Italy and using the HE gene of Bovine torovirus isolates Niigata1 (AB661456) and Niigata3 (AB661458) as outgroups. The HE gene sequence data segregated all the PToV isolates into two well-supported monophyletic groups; however, various isolates from Spain, Italy, and South Korea did not segregate geographically suggesting very recent translocation of the viruses to these localities. Evidence of recombination was observed between two South Korean isolates that partitioned into two distinct subclades. Data further suggest that most of the nucleotides in the HE gene are under negative selection; however, changes within codon 237 showed an evidence of positive selection. PMID- 23749173 TI - Small proliferative adipocytes: identification of proliferative cells expressing adipocyte markers. AB - It has been thought that adipocytes lack proliferative ability and do not revert to precursor cells. However, numerous findings that challenge this notion have also been reported. The idea that adipocytes dedifferentiate to fibroblast-like cells with increasing cell number was reported in 1975. This possibility has been ignored despite knowledge gained in the 1990s regarding adipocyte differentiation. Several studies on proliferation and dedifferentiation of adipocytes have been published, most of which were conducted from the perspective of regenerative medicine. However, the concept of proliferation of adipocytes remains unclear. In this study, we postulate a new population of adipocytes, which consist of small sized cells (less than 20 MUm in diameter) expressing adipocyte markers, such as adiponectin and peroxisome proliferator-activated receptor gamma (PPARgamma), but not possessing large lipid droplets. These cells show marked ability to incorporate 5-bromo-2'-deoxyuridine (BrdU), for which reason we termed them "small proliferative adipocytes (SPA)". In addition, SPA are observed in the stromal vascular fraction. Since SPA are morphologically different from mature adipocytes, we regarded them as committed progenitor cells. When proliferation of adipocytes in vivo is assessed by measuring BrdU incorporation and expression levels of proliferating cell nuclear antigen (PCNA) in isolated fractions of adipocytes from adipose tissues, subcutaneous SPA proliferate less actively than visceral SPA. Treatment with pioglitazone increases the number of proliferating SPA in subcutaneous, but not visceral, fat, suggesting that SPA may be important in regulating systemic insulin sensitivity and glucose metabolism. PMID- 23749174 TI - Reliability, validity, and responsiveness of the Japanese version of the patient rated elbow evaluation. AB - BACKGROUND: The patient-rated elbow evaluation (PREE) is a joint-specific, self administered questionnaire consisting of a pain scale (PREE-P) and a functional scale (PREE-F), the latter consisting of specific function (PREE-SF) and usual function (PREE-UF). The purpose of this study was to cross-culturally adapt the PREE into Japanese (PREE-J) and to test its reliability, validity, and responsiveness. METHODS: A consecutive series of 74 patients with elbow disorder completed the PREE-J, the Japanese version of the disabilities of the arm, shoulder, and hand (DASH-JSSH) questionnaire, and the official Japanese version of the 36-Item Short-Form Health Survey (SF-36). Of the 74 patients, 53 were reassessed for test-retest reliability 1 or 2 weeks later. Reliability was investigated in terms of reproducibility and internal consistency. The validity of the PREE-J was examined by factor analysis, and correlation coefficients were obtained using the PREE-J, DASH-JSSH, and SF-36. Responsiveness was examined by calculating the standardized response mean (SRM) and effect size after elbow surgery in 53 patients. RESULTS: Cronbach's alpha coefficients for PREE-P, PREE F, and PREE were 0.92, 0.97, and 0.97, respectively, and the corresponding intraclass correlation coefficients were 0.92, 0.93, and 0.94, respectively. Unidimensionality of PREE-P and PREE-F was confirmed by factor analysis. The coefficients of correlation between PREE-P and PREE-F or DASH-JSSH were 0.81 and 0.74, respectively; that between PREE-F and DASH-JSSH was 0.86, and those between DASH-JSSH and PREE-SF or PREE-UF were 0.85 and 0.82, respectively. Moderate correlation was observed in "physical functioning" for SF-36 and PREE-F (r = 0.69) or PREE (r = -0.68). The SRMs/effect sizes of PREE-P (1.31/1.32) or PREE (1.28/1.12) were more responsive than the DASH-JSSH (0.99/0.85), "bodily pain" ( 1.15/-1.43), and "physical functioning" (-0.70/-0.44) in SF-36. CONCLUSION: The PREE-J represents a reliable, valid, and responsive instrument and has evaluation capacities equivalent to those of the original PREE. PMID- 23749175 TI - Genome-wide analysis of the CCCH zinc finger gene family in Medicago truncatula. AB - KEY MESSAGE: In this study, we identified 34 CCCH Znf genes in Medicago truncatula and the results of semi-quantitative RT-PCR revealed that the expression patterns of subfamily VI members were diverse. CCCH-type zinc finger (Znf) proteins are specific transcriptional factors with a typical motif consisting of three cysteine residues and one histidine residue. Increasing evidences have revealed that CCCH Znf proteins participated in the regulation of plant growth, developmental processes and environmental responses. Survey and characterization of CCCH Znf genes in leguminous species would facilitate a better understanding of the evolutionary processes and functions of this gene family. In this study, we performed a comprehensive analysis of CCCH Znf genes in M. truncatula by describing the phylogenetic relationships, chromosomal location and gene structure of each family member. A total of 34 CCCH Znf genes were identified in the latest M. truncatula genome sequence. The 34 predicted members were clustered into nine subfamilies based on their phylogenetic analysis and structure features. In addition, the 34 Medicago CCCH Znf genes were found to be unevenly distributed on eight chromosomes. Furthermore, the expression profiles of subfamily VI were investigated under different stress conditions (PEG-6000, NaCl and ABA) by using semi-quantitative RT-PCR. The data showed that these genes displayed different expression levels in response to various stress conditions. The results presented in this study provide basic information about Medicago CCCH Znf genes and form a fundamental clue for cloning genes with specific functions in further studies and applications. PMID- 23749176 TI - Saving the neck from scission. AB - Secretory granule biogenesis is a pivotal process for regulated release of hormones and neurotransmitters. A prominent example is the pancreatic beta cell that secretes insulin, a major anabolic hormone controlling cellular metabolism upon nutrient availability. We recently described a checkpoint mechanism that halts scission of nascent secretory granules at the trans-Golgi network (TGN) until complete loading of insulin is achieved. We demonstrated that the Bin/Amphiphysin/Rvs (BAR) domain-containing protein Arfaptin-1 prevents granule scission until it is phosphorylated by Protein Kinase D (PKD). Arfaptin-1 phosphorylation releases its binding to ADP-rybosylation factor (ARF) allowing scission to occur. Lack of this control mechanism in beta cells resulted in premature scission, generation of dysfunctional insulin granules and impaired regulated insulin secretion without affecting constitutive release of other transport carriers. Here we discuss two important questions related to this work: How might completion of granule loading be sensed by PKD, and how does Arfaptin-1 specifically regulate insulin granule formation in beta cells? PMID- 23749177 TI - The dark side of TRAIL signaling. PMID- 23749178 TI - Bid-ding for mercy: twisted killer in action. PMID- 23749179 TI - Autophagy protects from liver injury. PMID- 23749180 TI - Interplay between p53 and VEGF: how to prevent the guardian from becoming a villain. PMID- 23749181 TI - Not all p53 gain-of-function mutants are created equal. PMID- 23749182 TI - Recent advances in dynamic covalent chemistry. AB - Dynamic covalent chemistry (DCvC) has been strongly integrated into diverse research fields, and has enabled easy access to a variety of combinatorial libraries, 2-D macrocycles, and 3-D molecular cages that target many important applications, such as drug discovery, biotechnology, molecular separation, light harvesting, etc. DCvC relies on the reversible formation and breaking of rather strong covalent bonding within molecules. Therefore it combines the error correction capability of supramolecular chemistry and the robustness of covalent bonding. Compared to those supramolecular interactions, dynamic covalent reactions usually have slower kinetics and require the assistance of catalysts to achieve rapid equilibrium. Although the scope of dynamic covalent reactions is rapidly expanding, the reversible reactions suitable for DCvC are still very limited. The identification and development of new dynamic reactions and catalysts would be critical for the further advancement of DCvC. This review covers the recent development of dynamic covalent reactions as well as their applications. PMID- 23749183 TI - Pit above the lesser tuberosity in axial view radiography. AB - PURPOSE: This study examined the relationship between the presence of a pit above the lesser tuberosity on axial view radiographs and rotator cuff tears and compared the demographic data between groups according to the presence of a pit above the lesser tuberosity. The hypothesis of this study was that the radiographic finding of a pit above the lesser tuberosity is related to rotator cuff tears. METHODS: For 112 patients with a symptomatic rotator cuff tear, plain radiographs of the symptomatic shoulder (tear side radiographs) and plain radiographs of the asymptomatic contralateral shoulder (no-tear side radiographs) were assessed. Seventeen radiological findings, including a pit above the lesser tuberosity, osteophytes, subchondral cysts, and sclerosis, were recorded by one blinded observer. Demographic data such as age, duration of symptoms, sex, arm dominance, smoking history, trauma history, American Shoulder and Elbow Surgeons score, Constant score, and involved tendon were collected. RESULTS: A pit above the lesser tuberosity was noted on tear side radiographs of 40 patients (35.7 %) and on the no-tear side radiographs of 27 patients (24.1 %), representing a significant difference (P = 0.040). A pit associated with a rotator cuff tear was observed more often in the dominant arm (P = 0.040) and more often in patients with less previous trauma (P = 0.024). CONCLUSIONS: A pit above the lesser tuberosity on axial view radiography was associated with a rotator cuff tear and occurred more often in the dominant arm of patients who had no trauma history. LEVEL OF EVIDENCE: Prognostic study, Level III. PMID- 23749184 TI - Increasing age and female gender are associated with early knee replacement following arthroscopy. AB - PURPOSE: Early knee replacement following arthroscopy may be perceived as a failure of the original treatment and thus a poor use of resources. Factors that may be associated with increased risk of early replacement were explored in this study. METHODS: All adult patients who underwent planned knee arthroscopy in a national cohort over a 6-month period in 2005 were extracted from the administrative hospital admissions database and linked to determine whether and when a knee replacement occurred on the same knee within the subsequent 5 years. A combination of survival analysis and mixed effect modelling was used to investigate risk factors for replacement. RESULTS: There were a total of 20,556 arthroscopies, of which 2,161 (10.6%) subsequently underwent knee replacement. For patients under 60 years, female gender (62.1% higher risk, p < 0.001) and increasing age (12.7% increased risk per increasing year of age, p < 0.001) were significant associations for requiring knee replacement, after risk adjusting. Of those aged >=60, 12.7% (576) had undergone a replacement at 1 year following arthroscopy. Females (33% higher risk), increasing age (7.3% increased risk per increasing year of age, p < 0.001) and hypertension (1,600% higher risk, p < 0.001) were significant predictors. The risk associated with increased age was not proportional for the older age group, with risk declining as time passed from arthroscopy, indicating other factors were influencing progression to knee replacement. CONCLUSIONS: The predictors of early knee replacement following arthroscopy were female sex, age over 60 years and hypertension, irrespective of type of operation. This work may contribute to national recommendations regarding the provision of arthroscopy for patients over 60 years. LEVEL OF EVIDENCE: III. PMID- 23749185 TI - A simple epidural simulator: a blinded study assessing the 'feel' of loss of resistance in four fruits. AB - CONTEXT: Complex epidural simulators are now available, but these are expensive and not widely available. Simple simulators using fruit have been described before. OBJECTIVE: To ascertain which easily available fruit would best simulate the 'feel' of loss of resistance experienced in epidural insertion and be used as a teaching tool. DESIGN: A single blinded study using four different fruits housed in a purpose-built box to conceal the identities of the fruits. The fruits were labelled A, B, C and D. SETTING: Two teaching hospitals in Glasgow, Scotland between 2006 and 2007. PARTICIPANTS: Fifty participants consisting of consultant anaesthetists, specialist registrars and senior house officers all with previous epidural experience. INTERVENTION: Insertion of a Tuohy needle into the four concealed fruits (orange, banana, kiwi and honeydew melon). Each participant then completed a questionnaire that included recording of the realism of the 'feel' of loss of resistance of each fruit. MAIN OUTCOME MEASURES: The 'feel' of loss of resistance for each fruit was scored on a 100-mm Visual Analogue Scale. A '0 mm' represented 'completely unrealistic feel' and '100 mm' represented 'indistinguishable feel from a real patient'. RESULTS: A total of 62.6% of participants recorded the banana as their first choice. This result was statistically significant after taking into account the grades of the participants, their years of experience, the needle gauge used and the participants' chosen technique. CONCLUSION: The banana is a cheap and easily available training tool to introduce novice anaesthetists to the feel of loss of resistance, which is best experienced before the first insertion of an epidural in a patient. PMID- 23749186 TI - Genome-wide inference of natural selection on human transcription factor binding sites. AB - For decades, it has been hypothesized that gene regulation has had a central role in human evolution, yet much remains unknown about the genome-wide impact of regulatory mutations. Here we use whole-genome sequences and genome-wide chromatin immunoprecipitation and sequencing data to demonstrate that natural selection has profoundly influenced human transcription factor binding sites since the divergence of humans from chimpanzees 4-6 million years ago. Our analysis uses a new probabilistic method, called INSIGHT, for measuring the influence of selection on collections of short, interspersed noncoding elements. We find that, on average, transcription factor binding sites have experienced somewhat weaker selection than protein-coding genes. However, the binding sites of several transcription factors show clear evidence of adaptation. Several measures of selection are strongly correlated with predicted binding affinity. Overall, regulatory elements seem to contribute substantially to both adaptive substitutions and deleterious polymorphisms with key implications for human evolution and disease. PMID- 23749188 TI - Genome-wide association study of B cell non-Hodgkin lymphoma identifies 3q27 as a susceptibility locus in the Chinese population. AB - To identify genetic risk factors underlying non-Hodgkin lymphomas (NHLs) from the B cell lineage, we conducted a genome-wide association study (GWAS) of 253 Chinese individuals with B cell NHL (cases) and 1,438 controls and further validation in 1,175 cases and 5,492 controls. We identified a new susceptibility locus, rs6773854, located between BCL6 (encoding B cell lymphoma protein 6) and LPP (encoding lipoma preferred partner) on oncogene-rich chromosome 3q27 that was significantly associated with increased risk of B cell NHL (meta-analysis P = 3.36 * 10-13, per-allele odds ratio (OR) = 1.44) and with diffuse large B cell lymphoma (DLBCL) in particular (meta-analysis P = 1.14 * 10-11, OR = 1.47). We found no evidence of association of rs6773854 with non-B cell NHLs (T cell and natural killer (NK) lineages) (P = 0.17, OR = 1.12) and observed significant heterogeneity between B cell and non-B cell subtypes (Phet = 0.01, I2 = 84%). Our results provide insight that germline variation in the intergenic region between BCL6 and LPP has a role in risk of B cell lymphomagenesis. PMID- 23749187 TI - Identification of multiple risk variants for ankylosing spondylitis through high density genotyping of immune-related loci. AB - Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis-associated haplotypes at 11 loci. Two ankylosing spondylitis-associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression. PMID- 23749189 TI - Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug-resistant tuberculosis. AB - A key question in tuberculosis control is why some strains of M. tuberculosis are preferentially associated with resistance to multiple drugs. We demonstrate that M. tuberculosis strains from lineage 2 (East Asian lineage and Beijing sublineage) acquire drug resistances in vitro more rapidly than M. tuberculosis strains from lineage 4 (Euro-American lineage) and that this higher rate can be attributed to a higher mutation rate. Moreover, the in vitro mutation rate correlates well with the bacterial mutation rate in humans as determined by whole genome sequencing of clinical isolates. Finally, using a stochastic mathematical model, we demonstrate that the observed differences in mutation rate predict a substantially higher probability that patients infected with a drug-susceptible lineage 2 strain will harbor multidrug-resistant bacteria at the time of diagnosis. These data suggest that interventions to prevent the emergence of drug resistant tuberculosis should target bacterial as well as treatment-related risk factors. PMID- 23749192 TI - Aminosilanization nanoadhesive layer for nanoelectric circuits with porous ultralow dielectric film. AB - An ultrathin layer is investigated for its potential application of replacing conventional diffusion barriers and promoting interface adhesion for nanoelectric circuits with porous ultralow dielectrics. The porous ultralow dielectric (k ~ 2.5) substrate is silanized by 3-aminopropyltrimethoxysilane (APTMS) to form the nanoadhesive layer by performing oxygen plasma modification and tailoring the silanization conditions appropriately. The high primary amine content is obtained in favor of strong interaction between amino groups and copper. And the results of leakage current measurements of metal-oxide-semiconductor capacitor structure demonstrate that the aminosilanization nanoadhesive layer can block copper diffusion effectively and guarantee the performance of devices. Furthermore, the results of four-point bending tests indicate that the nanoadhesive layer with monolayer structure can provide the satisfactory interface toughness up to 6.7 +/ 0.5 J/m(2) for Cu/ultralow-k interface. Additionally, an annealing-enhanced interface toughness effect occurs because of the formation of Cu-N bonding and siloxane bridges below 500 degrees C. However, the interface is weakened on account of the oxidization of amines and copper as well as the breaking of Cu-N bonding above 500 degrees C. It is also found that APTMS nanoadhesive layer with multilayer structure provides relatively low interface toughness compared with monolayer structure, which is mainly correlated to the breaking of interlayer hydrogen bonding. PMID- 23749190 TI - The Capsella rubella genome and the genomic consequences of rapid mating system evolution. AB - The shift from outcrossing to selfing is common in flowering plants, but the genomic consequences and the speed at which they emerge remain poorly understood. An excellent model for understanding the evolution of self fertilization is provided by Capsella rubella, which became self compatible <200,000 years ago. We report a C. rubella reference genome sequence and compare RNA expression and polymorphism patterns between C. rubella and its outcrossing progenitor Capsella grandiflora. We found a clear shift in the expression of genes associated with flowering phenotypes, similar to that seen in Arabidopsis, in which self fertilization evolved about 1 million years ago. Comparisons of the two Capsella species showed evidence of rapid genome-wide relaxation of purifying selection in C. rubella without a concomitant change in transposable element abundance. Overall we document that the transition to selfing may be typified by parallel shifts in gene expression, along with a measurable reduction of purifying selection. PMID- 23749191 TI - The duck genome and transcriptome provide insight into an avian influenza virus reservoir species. AB - The duck (Anas platyrhynchos) is one of the principal natural hosts of influenza A viruses. We present the duck genome sequence and perform deep transcriptome analyses to investigate immune-related genes. Our data indicate that the duck possesses a contractive immune gene repertoire, as in chicken and zebra finch, and this repertoire has been shaped through lineage-specific duplications. We identify genes that are responsive to influenza A viruses using the lung transcriptomes of control ducks and ones that were infected with either a highly pathogenic (A/duck/Hubei/49/05) or a weakly pathogenic (A/goose/Hubei/65/05) H5N1 virus. Further, we show how the duck's defense mechanisms against influenza infection have been optimized through the diversification of its beta-defensin and butyrophilin-like repertoires. These analyses, in combination with the genomic and transcriptomic data, provide a resource for characterizing the interaction between host and influenza viruses. PMID- 23749193 TI - Reduced systemic toxicity and preserved vestibular toxicity following co treatment with nitriles and CYP2E1 inhibitors: a mouse model for hair cell loss. AB - Several nitriles, including allylnitrile and cis-crotononitrile, have been shown to be ototoxic and cause hair cell degeneration in the auditory and vestibular sensory epithelia of mice. However, these nitriles can also be lethal due in large part to the microsomal metabolic release of cyanide, which is mostly dependent on the activity of the 2E1 isoform of the cytochrome P450 (CYP2E1). In this study, we co-administered mice with a nitrile and, to reduce their lethal effects, a selective CYP2E1 inhibitor: diallylsulfide (DAS) or trans-1,2 dichloroethylene (TDCE). Both in female 129S1/SvImJ (129S1) mice co-treated with DAS and cis-crotononitrile and in male RjOrl:Swiss/CD-1 (Swiss) mice co-treated with TDCE and allylnitrile, the nitrile caused a dose-dependent loss of vestibular function, as assessed by a specific behavioral test battery, and of hair cells, as assessed by hair bundle counts using scanning electron microscopy. In the experiments, the CYP2E1 inhibitors provided significant protection against the lethal effects of the nitriles and did not diminish the vestibular toxicity as assessed by behavioral effects in comparison to animals receiving no inhibitor. Additional experiments using a single dose of allylnitrile demonstrated that TDCE does not cause hair cell loss on its own and does not modify the vestibular toxicity of the nitrile in either male or female 129S1 mice. In all the experiments, high vestibular dysfunction scores in the behavioral test battery predicted extensive to complete loss of hair cells in the utricles. This provides a means of selecting animals for subsequent studies of vestibular hair cell regeneration or replacement. PMID- 23749195 TI - Syncope as the primary manifestation of hydatid cyst. Report of two cases with different etiologies. AB - Hydatid disease is a parasitic infestation that is caused by the larvae of the tapeworm Echinococcus granulosus. Clinical manifestations are extremely variable and related to the location and the size of the cysts. Syncope as the first clinical presentation of hydatid cyst is a very rare condition. Herein, we report two cases of patients with cardiac and pleural hydatid cysts who had syncope as the initial symptom. PMID- 23749194 TI - Gaze shifts to auditory and visual stimuli in cats. AB - While much is known about the metrics and kinematics of gaze shifts to visual targets in cats, little is known about gaze shifts to auditory targets. Here, cats were trained to localize auditory and visual targets via gaze shifts. Five properties of gaze shifts to sounds were observed. First, gaze shifts were accomplished primarily by large head movements. Unlike primates, the head movement in cats often preceded eye movement though the relative timing of eye in head and head latencies depended upon the target modality and gaze shift magnitude. Second, gaze shift latencies to auditory targets tended to be shorter than equivalent shifts to visual targets for some conditions. Third, the main sequences relating gaze amplitude to maximum gaze velocity for auditory and visual targets were comparable. However, head movements to auditory and visual targets were less consistent than gaze shifts and tended to undershoot the targets by 30 % for both modalities. Fourth, at the end of gaze movement, the proportion of the gaze shift accomplished by the eye-in-head movement was greater to visual than auditory targets. On the other hand, at the end of head movement, the proportion of the gaze shift accomplished by the head was greater to auditory than visual targets. Finally, gaze shifts to long-duration auditory targets were accurate and precise and were similar to accuracy of gaze shifts to long-duration visual targets. Because the metrics of gaze shifts to visual and auditory targets are nearly equivalent, as well as their accuracy, we conclude that both sensorimotor tasks use primarily the same neural substrates for the execution of movement. PMID- 23749196 TI - Thrombotic dysfunction of mechanical mitral valve. PMID- 23749197 TI - Anomalous origin of left coronary artery from right sinus of Valsalva with unusual course. Interarterial left anterior descending coronary artery and retroaortic circumflex coronary artery. PMID- 23749198 TI - The effects of cyclooxygenase and nitric oxide synthase inhibition on oxidative stress in isolated rat heart. AB - Despite the widespread clinical use of cyclooxygenase (COX) inhibitors, dilemmas still exist about potential impact of these drugs on cardiovascular system. The present study was aimed to estimate the effects of different COX inhibitors (meloxicam, acetylsalicylic acid [ASA], and SC-560) on oxidative stress in isolated rat heart, with special focus on L-arginine/NO system. The hearts of male Wistar albino rats (total number n = 96, each group 12 rats, 8 weeks old, body mass 180-200 g) were retrogradely perfused according to the Langendorff technique at gradually increased perfusion pressure (40-120 cmH2O). After control experiments the hearts were perfused with the following drugs: 100 MUmol/l ASA (Aspirin), alone or in combination with 30 MUmol/l L-NAME, 0.3 MUmol/l meloxicam (movalis) with or without 30 MUmol/l L-NAME, 3 MUmol/l meloxicam (alone or in combination with 30 MUmol/l L-NAME), 30 MUmol/l L-NAME, and administration of 0.25 MUmol/l SC-560. In samples of coronary venous effluent the following oxidative stress markers were measured spectrophotometrically: index of lipid peroxidation (measured as thiobarbituric acid reactive substances [TBARS]), superoxide anion radical release (O2(-)), and hydrogen peroxide (H2O2). While ASA was found to have an adverse influence on redox balance in coronary circulation, and coronary perfusion, meloxicam and SC-560 do not negatively affect the intact model of the heart. Furthermore, all effects were modulated by NOS inhibition. It seems that interaction between COX and L-arginine/NO system truly exists in coronary circulation, and can be one of the possible causes for achieved effects. That means: those effects induced by different inhibitors of COX are modulated by subsequent inhibition of NOS. PMID- 23749199 TI - Screening of chemopreventive effect of naringenin-loaded nanoparticles in DMBA induced hamster buccal pouch carcinogenesis by FT-IR spectroscopy. AB - The aim of the present study is to investigate the chemopreventive effects of the prepared naringenin-loaded nanoparticles (NARNPs) relative to efficacy of free naringenin (NAR) in modifying the functional, structural, and compositional changes at the molecular level during 7, 12-dimethylbenz[a]anthracene (DMBA) induced hamster buccal pouch (HBP) carcinogenesis by Fourier transform infrared (FT-IR) spectroscopy. The results revealed that a significant increase in the amount of proteins and nucleic acid contents and a decrease in the amount of lipids and glycogen contents are observed in DMBA-induced tumor tissues. In addition, in tumor tissues a decrease in lipid order and a significant increase in membrane dynamics were noticed. Further, the composition and secondary structure of proteins were found to be altered, which indicates some important structural alterations in the existing proteins and/or the expression of new types of proteins occurring under the tumor transformation. Furthermore, oral administration of free NAR and NARNPs significantly increased lipids and their order as well as increased the glycogen contents and decreased the levels of proteins and nucleic acid contents. On a comparative basis, NARNPs were found to have a more potent antitumor effect than free NAR in completely preventing the formation of squamous cell carcinoma and in improving the biochemical constituents to a normal range in DMBA-induced HBP carcinogenesis. The present study further shows a great potential of FT-IR spectroscopy as a complimentary tool for the screening of various anticancer drugs and follow-up, which may allow faster response to critical problems arising during treatment. PMID- 23749200 TI - Are cultured human myotubes far from home? AB - Satellite cells can be isolated from skeletal muscle biopsies, activated to proliferating myoblasts and differentiated into multinuclear myotubes in culture. These cell cultures represent a model system for intact human skeletal muscle and can be modulated ex vivo. The advantages of this system are that the most relevant genetic background is available for the investigation of human disease (as opposed to rodent cell cultures), the extracellular environment can be precisely controlled and the cells are not immortalized, thereby offering the possibility of studying innate characteristics of the donor. Limitations in differentiation status (fiber type) of the cells and energy metabolism can be improved by proper treatment, such as electrical pulse stimulation to mimic exercise. This review focuses on the way that human myotubes can be employed as a tool for studying metabolism in skeletal muscles, with special attention to changes in muscle energy metabolism in obesity and type 2 diabetes. PMID- 23749201 TI - Assessment of the effects of nickel on benthic macroinvertebrates in the field. AB - A field-based evaluation of the biological effects of potential nickel (Ni) exposures was conducted using monitoring data for benthic macroinvertebrates and water chemistry parameters for streams in England and Wales. Observed benthic community metrics were compared to expected community metrics under reference conditions using RIVPACS III+ software. In order to evaluate relationships between Ni concentrations and benthic community metrics, bioavailable Ni concentrations were also calculated for each site. A limiting effect from Ni on the 90th percentile of the maximum achievable ecological quality was derived at "bioavailable Ni" exposures of 10.3 MUg l(-1). As snails have been identified as particularly sensitive to nickel exposure, snail abundance in the field in response to nickel exposure, relative to reference conditions, was also analysed. A "low effects" threshold for snail abundance based on an average of spring and autumn data was derived as 3.9 MUg l(-1) bioavailable Ni. There was no apparent effect of Ni exposure on the abundance of Ephemeroptera (mayflies), Plecoptera (stoneflies) or Tricoptera (caddisflies) when expressed relative to a reference condition within the range of "bioavailable Ni" exposures observed within the dataset. Nickel exposure concentrations co-vary with the concentrations of other stressors in the dataset, and high concentrations of Ni are also associated with elevated concentrations of other contaminants. PMID- 23749202 TI - Metal accumulation by submerged macrophytes in eutrophic lakes at the watershed scale. AB - Metal concentrations (Al, Ba, Ca, K, Li, Mg, Na, Se, Sr and Ti) in submerged macrophytes and corresponding water and sediments were studied in 24 eutrophic lakes along the middle and lower reaches of the Yangtze River (China). Results showed that these eutrophic lakes have high metal concentrations in both water and sediments because of human activities. Average concentrations of Al and Na in tissues of submerged macrophytes were very high in sampled eutrophic lakes. By comparison, Ceratophyllum demersum and Najas marina accumulated more metals (e.g. Ba, Ca, K, Mg, Na, Sr and Ti). Strong positive correlations were found between metal concentrations in tissues of submerged macrophytes, probably because of co accumulation of metals. The concentrations of Li, Mg, Na and Sr in tissues of submerged macrophytes significantly correlated with their corresponding water values, but not sediment values. PMID- 23749203 TI - Response to comment of Sierra Rayne on "Targeting aquatic microcontaminants for monitoring: exposure categorization and application to the Swiss situation [Gotz et al., Environ Sci Pollut Res (2010) 17:341-354]". PMID- 23749204 TI - Effect of EDTA and citric acid on phytoremediation of Cr- B[a]P-co-contaminated soil. AB - Polycyclic aromatic hydrocarbons and heavy metals in the environment are a concern, and their removal to acceptable level is required. Phytoremediation, the use of plants to treat contaminated soils, could be an interesting alternative to conventional remediation processes. This work evaluates the role of single and combined applications of chelates to single or mixed Cr + benzo[a]pyrene (B[a]P) contaminated soil. Medicago sativa was grown in contaminated soil and was amended with 0.3 g citric acid, 0.146 g ethylenediaminetetraacetic acid (EDTA), or their combination for 60 days. The result shows that in Cr-contaminated soil, the application of EDTA + citric acid significantly (p<0.05) decreased the shoot dry matter of M. sativa by 55 % and, as such, decreased the Cr removal potential from the soil. The soluble Cr concentration in single Cr or Cr + B[a]P-contaminated soil was enhanced with the amendment of all chelates; however, only the application of citric acid in Cr-contaminated soil (44 %) or EDTA and EDTA + citric acid in co-contaminated soil increased the removal of Cr from the soil (34 and 54 %, respectively). The dissipation of B[a]P in single B[a]P-contaminated soil was effective even without planting and amendment with chelates, while in co contaminated soil, it was related to the application of either EDTA or EDTA + citric acid. This suggests that M. sativa with the help of chelates in single or co-contaminated soil can be effective in phytoextraction of Cr and promoting the biodegradation of B[a]P. PMID- 23749205 TI - Effects of vitamin D3 and paricalcitol on immature cardiomyocytes: a novel role for vitamin D analogs in the prevention of cardiovascular diseases. AB - Cardiovascular diseases are more prevalent in patients with chronic kidney disease than in the general population and they are considered the leading cause of death in patients with end-stage renal disease. The discovery that vitamin D3 plays a considerable role in cardiovascular protection has led, in recent years, to an increase in the administration of therapies based on the use of this molecule; nevertheless, several studies warned that an excess of vitamin D3 may increase the risk of hypercalcemia and vascular calcifications. In this study we evaluated the effects of vitamin D3, and of its selective analog paricalcitol, on immature cardiomyocytes. Results show that vitamin D3 induces cAMP-mediated cell proliferation and significant intracellular calcification. Paricalcitol, however, induces cell differentiation, morphological modifications in cell shape and size, and no intracellular calcification. Furthermore, vitamin D3 and paricalcitol differently affect cardiomyoblasts responses to acetylcholine treatment. In conclusion, our results demonstrate that the effects of vitamin D3 and paricalcitol on cardiomyoblasts are different and, if these in vitro observations could be extrapolated in vivo, they suggest that paricalcitol has the potential for cardiovascular protection without the risk of inducing intracellular calcification. PMID- 23749206 TI - The role of viscosity and fermentability of dietary fibers on satiety- and adiposity-related hormones in rats. AB - Dietary fiber may contribute to satiety. This study examined the effect of two dietary fiber characteristics, small intestinal contents viscosity and large intestinal fermentability, on satiety-and adiposity-related hormones in rats. Diets contained fiber sources that were non-viscous, somewhat viscous, or highly viscous, and either highly fermentable or non-fermentable, in a 2 * 3 factorial design. In the fed state (2 h postprandial), rats fed non-fermentable fibers had significantly greater plasma GLP-1 concentration than fermentable fibers. In the fasted state, among non-fermentable fibers, viscosity had no effect on GLP-1 concentration. However, among fermentable fibers, greater viscosity reduced GLP-1 concentration. Plasma peptide tyrosine tyrosine (PYY) concentrations in the fasted state were not influenced by the fermentability of the fiber overall, however animals consuming a fructooligosaccharide greater PYY concentration. In both the fed and fasted states, rats fed non-fermentable fibers had a significantly lower plasma ghrelin concentration than rats fed fermentable fibers. In the fasted state, rats fed non-fermentable fibers had a significantly lower plasma leptin concentration than rats fed fermentable fibers. Thus, fermentability and viscosity of dietary fiber interacted in complex ways to influence satiety- and adiposity-related plasma hormone concentrations. However, the results suggest that highly viscous, non-fermentable fibers may limit weight gain and reduce adiposity and non-fermentable fibers, regardless of viscosity, may promote meal termination. PMID- 23749207 TI - Characterization of a large human transgene following invasin-mediated delivery in a bacterial artificial chromosome. AB - Bacterial artificial chromosomes (BACs) are widely used in transgenesis, particularly for the humanization of animal models. Moreover, due to their extensive capacity, BACs provide attractive tools to study distal regulatory elements associated with large gene loci. However, despite their widespread use, little is known about the integration dynamics of these large transgenes in mammalian cells. Here, we investigate the post-integration structure of a ~260 kb BAC carrying the cystic fibrosis transmembrane conductance regulator (CFTR) locus following delivery by bacterial invasion and compare this to the outcome of a more routine lipid-based delivery method. We find substantial variability in integrated copy number and expression levels of the BAC CFTR transgene after bacterial invasion-mediated delivery. Furthermore, we frequently observed variation in the representation of different regions of the CFTR transgene within individual cell clones, indicative of BAC fragmentation. Finally, using fluorescence in situ hybridization, we observed that the integrated BAC forms extended megabase-scale structures in some clones that are apparently stably maintained at cell division. These data demonstrate that the utility of large BACs to investigate cis-regulatory elements in the genomic context may be limited by recombination events that complicate their use. PMID- 23749208 TI - Plasmonic tuning of silver nanowires by laser shock induced lateral compression. AB - Laser shock induced lateral compression has been demonstrated to controllably flatten cylindrical silver nanowires. Nanowires with circular cross-sections of diameter 70 nm are significantly shaped laterally, which transformed them to metallic ribbons of huge width of 290 nm and of thickness down to 13 nm, amounting the aspect ratio to as high as 22, at a laser intensity of 0.30 GW cm( 2). Above the laser intensity of 0.30 GW cm(-2) though, nanowires are observed to be ruptured. Lateral deformations of nanowires are achieved without altering longitudinal dimensions. Selected area electron diffraction patterns on the laterally deformed nanowires reveal that the flattening gives rise to twinning under high strain rate deformation without actually degrading crystallinity. As the 1D nanowire turns into a 2D metallic nanoribbon, new plasmonic modes and their combinations emerge. The transverse plasmon mode does not shift substantially, whereas longitudinal modes and their combinations are greatly influenced by lateral deformation. Apart from the transverse mode, which is dominant in a 1D nanowire and diminishes heavily when lateral deformation occurs, there is a presence of several longitudinal plasmonic modes and their combinations for metallic nanoribbons, which are revealed by experimental extinction spectra and also supported by finite-difference time-domain (FDTD) simulation. Such plasmonic tuning of silver nanowires across the visible range demonstrates the capability of a laser shock induced lateral compression technique for various emerging plasmonic applications. The laser shock compression technique has the advantages of flexibility, selectivity and tunability while retaining crystallinity of metallic nanowires, all of which enable it to be a potential candidate for plasmonic tuning of nanogeometries. PMID- 23749209 TI - XIAP inhibits autophagy via XIAP-Mdm2-p53 signalling. AB - The primary role of autophagy is adaption to starvation. However, increasing evidence suggests that autophagy inhibition also plays an important role in tumorigenesis. Upregulation of X-linked inhibitor of apoptosis (XIAP) has been associated to a variety of human cancers, yet the underlying mechanisms remain obscure. Here, we report that XIAP suppresses autophagy by exerting a previously unidentified ubiquitin E3 ligase activity towards Mdm2, which is a negative regulator of p53. XIAP controls serum starvation-induced autophagy downstream of the PI3K/Akt pathway. In mouse models, inhibition of autophagy by XIAP promotes tumorigenecity of HCT116 cells. XIAP-mediated autophagy inhibition is also largely validated in clinical tumour samples. These findings reveal a novel XIAP Mdm2-p53 pathway that mediates the inhibition of autophagy, by which XIAP may contribute to tumorigenesis. PMID- 23749210 TI - Think globally, act locally: how bacteria integrate local decisions with their global cellular programme. PMID- 23749211 TI - Break the loop, escape the cycle? PMID- 23749213 TI - A new player in Pol II pausing. AB - Transcriptional control plays a primary role in gene expression and can be exerted at multiple levels of the transcription process, such as RNA polymerase recruitment and promoter-proximal pausing. A recent report published in The EMBO Journal (Li and Gilmour, 2013) provides new insights into the regulation of a large class of paused genes through the identification of a novel transcription factor (TF; Motif 1 binding protein, M1BP) that binds to promoters of paused genes and controls their expression. PMID- 23749212 TI - The kinesin KIF16B mediates apical transcytosis of transferrin receptor in AP-1B deficient epithelia. AB - Polarized epithelial cells take up nutrients from the blood through receptors that are endocytosed and recycle back to the basolateral plasma membrane (PM) utilizing the epithelial-specific clathrin adaptor AP-1B. Some native epithelia lack AP-1B and therefore recycle cognate basolateral receptors to the apical PM, where they carry out important functions for the host organ. Here, we report a novel transcytotic pathway employed by AP-1B-deficient epithelia to relocate AP 1B cargo, such as transferrin receptor (TfR), to the apical PM. Lack of AP-1B inhibited basolateral recycling of TfR from common recycling endosomes (CRE), the site of function of AP-1B, and promoted its transfer to apical recycling endosomes (ARE) mediated by the plus-end kinesin KIF16B and non-centrosomal microtubules, and its delivery to the apical membrane mediated by the small GTPase rab11a. Hence, our experiments suggest that the apical recycling pathway of epithelial cells is functionally equivalent to the rab11a-dependent TfR recycling pathway of non-polarized cells. They define a transcytotic pathway important for the physiology of native AP-1B-deficient epithelia and report the first microtubule motor involved in transcytosis. PMID- 23749214 TI - Evaluating an employee wellness program. AB - What criteria should be used to evaluate the impact of a new employee wellness program when the initial vendor contract expires? Published academic literature focuses on return-on-investment as the gold standard for wellness program evaluation, and a recent meta-analysis concludes that wellness programs can generate net savings after one or two years. In contrast, surveys indicate that fewer than half of these programs report net savings, and actuarial analysts argue that return-on-investment is an unrealistic metric for evaluating new programs. These analysts argue that evaluation of new programs should focus on contract management issues, such as the vendor's ability to: (i) recruit employees to participate and (ii) induce behavior change. We compute difference in-difference propensity score matching estimates of the impact of a wellness program implemented by a mid-sized employer. The analysis includes one year of pre-implementation data and three years of post-implementation data. We find that the program successfully recruited a broad spectrum of employees to participate, and it successfully induced short-term behavior change, as manifested by increased preventive screening. However, the effects on health care expenditures are positive (but insignificant). If it is unrealistic to expect new programs to significantly reduce healthcare costs in a few years, then focusing on return-on investment as the gold standard metric may lead to early termination of potentially useful wellness programs. Focusing short-term analysis of new programs on short-term measures may provide a more realistic evaluation strategy. PMID- 23749215 TI - Single-dose intra-articular bupivacaine after knee arthroscopic surgery: a meta analysis of randomized placebo-controlled studies. AB - PURPOSE: The purpose of this meta-analysis was to examine the efficacy and safety of single-dose intra-articular bupivacaine in the management of pain after knee arthroscopic surgery. METHOD: The comprehensive literature search, using MEDLINE, the Cochrane Central Register of Controlled Trials, and Embase databases, was conducted to identify randomized controlled trials that used single-dose intra articular bupivacaine for postoperative pain. The relative risk (RR), weighted mean difference (WMD), and their corresponding 95 % confidence intervals (CIs) were calculated using RevMan((r)) statistical software. RESULT: Twenty-three studies (n = 1287) were included (647 subjects in bupivacaine group and 640 subjects in the control group). Statistically significant differences were observed in the VAS values (WMD -1.1; 95 % CI -1.7 to -0.5), number of patients requiring supplementary analgesia (RR 0.83; 95 % CI 0.74-0.94), and time to first analgesic request (WMD 129.3; 95 % CI 15.4-243.1) among the bupivacaine group when compared to the control group. However, short-term side effects had no significant difference between these two groups (RR 0.73; 95 % CI 0.44-1.24). CONCLUSIONS: On the basis of the currently available literature, single-dose intra-articular bupivacaine was shown to be significantly better than placebo at relieving pain after knee arthroscopic surgery. More high-quality randomized controlled trials with long follow-up are highly required for examining the safety of single-dose intra-articular bupivacaine. Besides, routine use of single dose intra-articular bupivacaine is still an effective way for pain management after knee arthroscopic surgery. PMID- 23749216 TI - MRI analysis of single-, double-, and triple-bundle anterior cruciate ligament grafts. AB - PURPOSE: The purpose of the study was to evaluate the entire course of ACL grafts on coronal oblique MR images, focusing on differences in graft morphology and graft-to-tunnel healing among single-bundle (SB), double-bundle (DB), and triple bundle (TB) reconstructions. METHODS: Eighty-three patients underwent anatomical ACL reconstruction using the semitendinosus tendon. SB reconstruction was performed on 20 patients, DB on 29 patients, and TB on 34 patients. The anteromedial-bundle (AMB) and posterolateral-bundle (PLB) images were extracted from coronal oblique images of grafts at 6 months to visualize their entire course. Signal intensity of grafts was measured independently in three regions: (1) intra-femoral tunnel region, (2) intra-articular region, and (3) intra-tibial tunnel region, followed by calculation of the signal-to-noise quotient (SNQ). To evaluate graft-to-tunnel healing, T2-weighted images were examined for the presence of a high signal-intensity lesion between the graft and bone tunnel around the tunnel aperture. RESULTS: AMB images showed that SB graft was thick throughout the entire course, while DB graft was thinner than SB graft. TB graft showed a fan shape approaching the tibial tunnels. The SNQ in the femoral tunnel of SB graft was significantly lower than in the DB and TB grafts. High signal intensity lesions were frequently observed around the femoral tunnel aperture in PLB images of DB and TB grafts compared to SB grafts. CONCLUSION: Gross morphology of TB grafts resembled that of the natural ACL. However, the graft-to tunnel healing around the femoral tunnel seemed to be insufficient in PLB images of DB and TB compared to SB grafts. PMID- 23749217 TI - Intra-articular distal radius fractures involving the distal radioulnar joint (DRUJ): three dimensional computed tomography-based classification. AB - PURPOSE: The purpose of this study was to analyze fracture patterns and the magnitude of displacement in the distal radioulnar joint (DRUJ), by three dimensional (3D) computed tomography (CT), for distal radius fractures with intra articular displacement of the radiocarpal joint. METHODS: We reconstructed 3D images for 72 consecutive patients with displaced intra-articular distal radius fracture on the basis of fine-cut axial CT data. The fracture patterns involving the DRUJ were classified on the basis of the location and direction of fracture lines, and the extent of fracture comminution. We measured the maximum spatial distance of the gap and the step between the fragments in each 3D image, and the magnitudes of displacement between the groups were compared by analysis of variance followed by post-hoc analysis by use of Tukey's test. RESULTS: Sixty wrists had a fracture involving the DRUJ. We classified the 60 wrists into 3 types of fracture pattern. Type 1 was a transverse fracture with minimum displacement. Type 2, in which fracture lines extended into the distal margin of the sigmoid notch, was the most common longitudinal fracture. Type 3 was a fracture with multiple fragments. The step and gap in Type 3 was significantly larger than that in the other types. CONCLUSIONS: Eighty-three percent of intra articular distal radius fractures had DRUJ involvement, and 28% of the wrists had multiple fragments. For Type 3 fractures with dorsal or proximal comminution displacement was significantly larger than for simple Type 1 and 2 fractures. Surgical intervention for the DRUJ fragment may be beneficial when there is remarkable intra-articular displacement. PMID- 23749218 TI - More radial shortening after low-energy Colles' fractures is associated with type 2 diabetes mellitus among postmenopausal women, irrespective of bone mineral density. AB - BACKGROUND: Recent meta-analysis data reveal that patients with type 2 diabetes mellitus (DM) have a higher risk of fracture, despite higher bone mineral density (BMD), than patients without type 2 DM. The purpose of this study was to compare BMD and distal radial shortening after low-energy Colles' fractures among Japanese postmenopausal women aged >=50 years with type 2 DM with those in women without it (non-DM). METHODS: One-hundred and ten postmenopausal women aged >=50 years with distal radius fractures resulting from a fall were enrolled in this study. Twelve patients had DM. BMD, type I collagen cross-linked N-telopeptide (NTX), undercarboxylated osteocalcin (ucOC), estimated glomerular filtration rate (eGFR), grip strength of the unfractured hand, unipedal standing time, and the degree of radial shortening were measured. RESULTS: There were no significant differences in age and body height between the two groups. The DM group had significantly greater body weight and body mass index than the non-DM group. BMDs of the lumbar spine and proximal hip were significantly higher in the DM group than in the non-DM group. NTX, ucOC, grip strength, and the percentage of women with unipedal standing time <15 s did not differ between the two groups. Stepwise regression analysis identified DM and shorter unipedal standing time as significant factors associated with more radial shortening, and identified more radial shortening and lower eGFR as significant factors associated with DM. CONCLUSIONS: More radial shortening after low-energy Colles' fractures was significantly associated with type 2 DM among postmenopausal women aged >=50 years, irrespective of BMD. PMID- 23749219 TI - Factors influencing the residual rib hump after posterior spinal fusion for adolescent idiopathic scoliosis with Lenke 1 and 2 curves. AB - BACKGROUND: Despite remarkable improvement in Cobb angle after surgery for scoliosis, many patients have a residual rib hump. We studied the factors responsible for this hump and their influence on patient satisfaction. METHODS: We recruited 2 men and 38 women (mean age 14.9 years) who underwent skip pedicle screw fixation combined with direct vertebral body derotation for adolescent idiopathic scoliosis with Lenke type 1 and 2 curves. Hump size was evaluated by measuring apical trunk rotation (ATR). Patients with postoperative ATR <=10 degrees were categorized as group A and those with postoperative ATR >10 degrees as group B. We analyzed postoperative self-image and satisfaction subscores of the SRS-22 questionnaire. We also compared the rate of postoperative improvement in ATR between patients who underwent additional Ponte osteotomy and those who did not. RESULTS: Preoperative ATR, preoperative apical translation, and preoperative and postoperative apical rotation significantly differed between groups A and B. In contrast, Cobb angles before and after surgery, Cobb angle correction rates, apical translation after correction, and postoperative self image and satisfaction scores did not differ significantly between the groups. However, the rate of improvement in ATR showed a strong correlation with self image (correlation coefficient 0.64) and satisfaction (correlation coefficient 0.52). This improvement rate did not differ significantly between subjects who underwent additional Ponte osteotomy and those who did not. CONCLUSIONS: Preoperative apical rotation and ATR were clearly related to postoperative residual hump. For decreasing the postoperative rib hump, removal of the deformation by apical rotation was considered more important than correction of Cobb angle. Patient satisfaction and self-image scores were not significantly related to postoperative residual hump size, but they were influenced by improvement in ATR. PMID- 23749220 TI - A frequent splicing mutation and novel missense mutations color the updated mutational spectrum of classic galactosemia in Portugal. AB - Classic galactosemia is an autosomal recessive disorder caused by deficient galactose-1-phosphate uridylyltransferase (GALT) activity. Patients develop symptoms in the neonatal period, which can be ameliorated by dietary restriction of galactose. Many patients develop long-term complications, with a broad range of clinical symptoms whose pathophysiology is poorly understood. The high allelic heterogeneity of GALT gene that characterizes this disorder is thought to play a determinant role in biochemical and clinical phenotypes. We aimed to characterize the mutational spectrum of GALT deficiency in Portugal and to assess potential genotype-phenotype correlations. Direct sequencing of the GALT gene and in silico analyses were employed to evaluate the impact of uncharacterized mutations upon GALT functionality. Molecular characterization of 42 galactosemic Portuguese patients revealed a mutational spectrum comprising 14 nucleotide substitutions: ten missense, two nonsense and two putative splicing mutations. Sixteen different genotypic combinations were detected, half of the patients being p.Q188R homozygotes. Notably, the second most frequent variation is a splicing mutation. In silico predictions complemented by a close-up on the mutations in the protein structure suggest that uncharacterized missense mutations have cumulative point effects on protein stability, oligomeric state, or substrate binding. One splicing mutation is predicted to cause an alternative splicing event. This study reinforces the difficulty in establishing a genotype-phenotype correlation in classic galactosemia, a monogenic disease whose complex pathogenesis and clinical features emphasize the need to expand the knowledge on this "cloudy" disorder. PMID- 23749222 TI - A low-temperature solid-phase method to synthesize highly fluorescent carbon nitride dots with tunable emission. AB - Highly fluorescent graphitic carbon nitride quantum dots (g-CNQDs) with a quantum yield of 42% are synthesized by a low-temperature solid-phase method with urea and sodium citrate as the precursors. Notably, the tunable emission of g-CNQDs can be achieved by simply adjusting the molar ratio of the two reactants. PMID- 23749221 TI - Polyphasic characterization of rhizobia isolated from Leucaena leucocephala from Panxi, China. AB - Leucaena leucocephala was introduced into Panxi, Sichuan, China, in the 1980s and 1990s for afforestation and preventing water loss and soil erosion in this area. The co-introduction of rhizobial symbionts of introduced plants has drawn attention since they may influence local soil communities. We studied the phylogenetic position of the L. leucocephala isolates and assessed if the rhizobia were introduced together with the host to Panxi, Sichuan, China. The glnII and atpD genes of fifteen representative isolates were sequenced and analyzed, and applied multilocus sequence analyses in which the housekeeping genes recA, glnII and atpD were included. Furthermore, we estimated the within species diversity directly with 23S rDNA and IGS RFLP and indirectly through phenotypic analysis of forty L. leucocephala isolates. The isolates represented seven species and 38 diversified strains in the genera Ensifer, Mesorhizobium, Bradyrhizobium and Rhizobium. The within species diversity of the Ensifer isolates was large, proposing a potential to occupy novel niches. There was not conclusive evidence to show that any of the strains would have been co-introduced with L. leucocephala. On the contrary, we came to a conclusion that the possible introduction should not be inferred from sequence data alone. PMID- 23749223 TI - Two acentric (6, 3) topological 2-D frameworks with imidazole-containing tripodal ligand and their ferroelectric properties. AB - Hydrothermal reaction of three-connecting ligands 1,3,5-tris(1-imidazolyl) benzene (tib) and MnSO4 or CoSO4.7H2O provides two new metal-organic frameworks, {[Mn(tib)2(H2O)4]SO4}n (1) and {[Co(tib)2(H2O)4]SO4}n (2). Single-crystal X-ray diffraction studies reveal that complexes 1 and 2 belong to the polar point group 3m, and have the same two-dimensional honeycomb networks with (6, 3) topology. The ferroelectric behavior investigation indicates that both compounds are typical ferroelectrics with an electric hysteresis loop showing a remnant polarization (P(r)) of ca. 0.586 MUC cm(-2) and a coercive field (E(c)) of 2000 V cm(-1) for 1 and P(r) of ca. 0.208 MUC cm(-2) and a coercive field (E(c)) of 2600 V cm(-1) for 2. PMID- 23749224 TI - Diffusion-weighted magnetic resonance imaging: new perspectives in the diagnostic pathway of non-complicated acute pyelonephritis. AB - OBJECTIVES: The diagnosis of acute pyelonephritis (APN) requires demonstration of parenchymal involvement. When no predisposing conditions are found, non complicated APN is suspected and CT or MRI should be performed. Diffusion weighted (DW) MRI might be useful, quicker and cheaper than the standard gadolinium-enhanced (GE) MRI. The aim of this study is to compare DW-MRI with GE MRI to test its diagnostic accuracy in APN. METHODS: Of 318 consecutive patients hospitalised for APN, 279 underwent MRI. Four hundred and fourteen MR studies (first test and follow-up examinations) were gathered and data were processed using Diffusion Analysis software. DW-MRI has been compared with GE-MRI for evaluating diagnostic agreement. RESULTS: Two hundred and forty-four patients were diagnosed as having APN; 35 were negative. One hundred and sixty-three APN cases were considered non-complicated and selected for the study. Among the 414 MR examinations, comparing DW-MRI with GE-MRI, positive correlation was found in 258 cases, negative in 133. There were 14 false-negatives and 9 false-positives. DW-MRI achieved sensitivity 95.2 %, specificity 94.9 %, positive predictive value 96.9 %, negative predictive value 92.3 % and accuracy 94.6 %. CONCLUSIONS: DW-MRI is reliable for diagnosing non-complicated APN. The high diagnostic agreement between DW-MRI and GE-MRI offers new perspectives in diagnostic management, enabling diagnosis of non-complicated APN without using ionising radiation or contrast media. KEY POINTS: * The diagnosis of acute pyelonephritis (APN) requires demonstration of renal involvement. * Hitherto magnetic resonance imaging required gadolinium enhancement (GE-MRI) to establish this diagnosis. * But diagnostic agreement between diffusion-weighted and GE-MRI offers new diagnostic opportunities. * Quantification of ADC values can help diagnose and monitor APN. * DW-MRI avoids ionising radiation and paramagnetic contrast medium administration. PMID- 23749225 TI - Evaluation of testicular tumour calcification with digital orchiography. AB - OBJECTIVES: To analyse the calcification of testicular tumours in the orchiectomy specimens detected by digital orchiography obtained in a full-field digital mammography (FFDM) unit. METHODS: Orchiectomy specimens of 37 consecutive patients were imaged by FFDM. Detected foci of calcification were stratified as: type 1, dense microcalcification; type 2, faint microcalcification; type 3, macrocalcification. Histopathology identified the tumour types, the presence of intratubular germ cell neoplasia (IGCN) and associated calcifications. Orchiography results correlated with the histopathology. RESULTS: On orchiography, 32/37of the specimens (86 %) had co-existing foci of calcification. Histopathology results revealed foci of calcification in 23/37 (62 %) of orchiectomy specimens. Of the 20 IGCN cases, 80 % presented with calcifications on orchiography. Fifty-six percent (14/25) of type 1, 70 % (12/17) of type 2, and 30 % (2/6) of type 3 foci of calcification were observed in IGCN-positive cases. CONCLUSION: This study classifies the morphology of testicular tumour calcification in three main groups by digital orchiography. In half of the testicular cancers, histopathologically proven IGCN is also found in addition to the index tumour. Type 2 foci of microcalcification detected by orchiography may be related to IGCN and may prompt further clinical assessment. KEY POINTS: * Orchiography can detect and classify calcification in 86 % of testicular cancers. * Intratubular germ cell neoplasia (IGCN) co-exists in 54 % of testicular cancers. * Type 2 foci of microcalcification detected by orchiography may be related to IGCN. * Orchiography may play a possible future role in the diagnosis of testicular IGCN. PMID- 23749226 TI - Subtracted 3D CT angiography for the evaluation of intracranial aneurysms in 256 slice multidetector CT: usefulness of the 80-kVp plus compact contrast medium bolus protocol. AB - OBJECTIVES: To evaluate the usefulness of an 80-kVp and compact contrast material protocol for arterial phase subtracted cerebral 3D-CTA using 256-slice multidetector CT. METHODS: Thirty-two patients underwent CT with 100 kVp and received a contrast dose of 370 mgI/kg body weight over 15 s (protocol A). Thirty three patients underwent CT with 100 kVp and received a contrast dose of 296 mgI/kg body weight over 10 s (protocol B). Thirty-three other patients underwent CT with 80 kVp and received a contrast medium dose of 296 mgI/kg body weight over 10 s (protocol C). We compared the arterial attenuation and contrast noise ratio (CNR) of each protocol. Two independent readers assessed overall image quality. RESULTS: Arterial attenuation was significantly higher under protocols A (418.6 +/- 71.1 HU) and C (442.7 +/- 79.3 HU) than under protocol B (355.8 +/- 107.2 HU; P < 0.05). The CNR of protocol C (26.1 +/- 6.1) was higher than that of protocol A (20.7 +/- 8.4; P < 0.05). The overall image quality of protocol A was higher than that of protocol C (P < 0.01). CONCLUSION: The 80-kVp plus compact contrast protocol is well suited to arterial phase subtracted cerebral 3D-CTA without confounding venous enhancement. KEY POINTS: * Subtracted 3D CT angiography is useful in the evaluation of intracranial aneurysms. * A compact contrast material protocol increased arterial attenuation without venous contamination. * Low-kVp CT compensated for the decreased amount of contrast medium. * An 80-kVp CT with a compact enhancement bolus provides good intracranial 3D-CT angiography. PMID- 23749227 TI - Microbial consortium and its spatial distribution in a compartmentalized anaerobic reactor. AB - The compartmentalized anaerobic reactor (CAR) is a patent novel high-rate reactor, which consists of three compartments. The reactor has a great potential for application due to its many advantages. In this work, the microbial consortium, spatial distribution, and their relationship with performance of CAR were investigated by means of polymerase chain reaction, denaturing gradient gel electrophoresis, and fluorescence in situ hybridization. The results showed that the predominant archaea were Methanobacterium, Methanosaeta, and Methanospirillum, and the predominant bacteria were Firmicutes, Deltaproteobacteria, Spirochaetes, Actinobacteria, and Gammaproteobacteria in the microbial consortium. The methanogenic archaea (MA), the hydrogen-producing acetogenic bacteria (HAB), and the hydrolytic fermentative bacteria (HFB) were found to be predominant in the upper, middle, and bottom compartments, respectively. The results revealed that the granular sludge took on a stratified microbial structure. The HFB, HAB, and MA were located in the outer shell, middle layer, and core, respectively. The microbial populations from the bottom compartment were relatively homogeneous in the granular sludge, and from the middle and upper compartments, they were relatively heterogeneous in the granular sludge. The microbial consortia and their spatial distribution were in accordance with the organic loading rate and chemical components in the three compartments. PMID- 23749228 TI - Direct L-lysine production from cellobiose by Corynebacterium glutamicum displaying beta-glucosidase on its cell surface. AB - We constructed beta-glucosidase (BGL)-displaying Corynebacterium glutamicum, and direct L-lysine fermentation from cellobiose was demonstrated. After screening active BGLs, Sde1394, which is a BGL from Saccharophagus degradans, was successfully displayed on the C. glutamicum cell surface using porin as an anchor protein, and cellobiose was directly assimilated as a carbon source. The optical density at 600 nm of BGL-displaying C. glutamicum grown on cellobiose as a carbon source reached 23.5 after 48 h of cultivation, which was almost the same as that of glucose after 24 h of cultivation. Finally, Sde1394-displaying C. glutamicum produced 1.08 g/l of L-lysine from 20 g/l of cellobiose after 4 days of cultivation, which was about threefold higher than the amount of produced L lysine using BGL-secretory C. glutamicum strains (0.38 g/l after 5 days of cultivation). This is the first report on amino acid production using cellobiose as a carbon source by BGL-expressing C. glutamicum. PMID- 23749229 TI - From amino alcohol to aminopolyol: one-pot multienzyme oxidation and aldol addition. AB - In this work, the successful coupling of enzymatic oxidation and aldol addition reactions for the synthesis of a Cbz-aminopolyol from a Cbz-amino alcohol was achieved for the first time in a multienzymatic one-pot system. The two-step cascade reaction consisted of the oxidation of Cbz-ethanolamine to Cbz-glycinal catalyzed by chloroperoxidase from the fungus Caldariomyces fumago and aldol addition of dihydroxyacetone phosphate to Cbz-glycinal catalyzed by rhamnulose-1 phosphate aldolase expressed as a recombinant enzyme in Escherichia coli, yielding (3R,4S)-5-{[(benzyloxy)carbonyl]amino}-5-deoxy-1-O-phosphonopent-2 ulose. Tools of enzymatic immobilization, reactor configurations, and modification of the reaction medium were applied to highly increase the production of the target compound. While the use of soluble enzymes yielded only 23.6 % of Cbz-aminopolyol due to rapid enzyme inactivation, the use of immobilized ones permitted an almost complete consumption of Cbz-ethanolamine, reaching Cbz-aminopolyol yields of 69.1 and 71.9 % in the stirred-tank and packed bed reactor, respectively. Furthermore, the reaction production was 18-fold improved when it was catalyzed by immobilized enzymes in the presence of 5 % (v/v) dioxane, reaching a value of 86.6 mM of Cbz-aminopoliol (31 g/L). PMID- 23749230 TI - Inflammasome-derived IL-1beta production induces nitric oxide-mediated resistance to Leishmania. AB - Parasites of the Leishmania genus are the causative agents of leishmaniasis in humans, a disease that affects more than 12 million people worldwide. These parasites replicate intracellularly in macrophages, and the primary mechanisms underlying host resistance involve the production of nitric oxide (NO). In this study we show that the Nlrp3 inflammasome is activated in response to Leishmania infection and is important for the restriction of parasite replication both in macrophages and in vivo as demonstrated through the infection of inflammasome deficient mice with Leishmania amazonensis, Leishmania braziliensis and Leishmania infantum chagasi. Inflammasome-driven interleukin-1beta (IL-1beta) production facilitated host resistance to infection, as signaling through IL-1 receptor (IL-1R) and MyD88 was necessary and sufficient to trigger inducible nitric oxide synthase (NOS2)-mediated production of NO. In this manuscript we identify a major signaling platform for host resistance to Leishmania spp. infection and describe the molecular mechanisms underlying Leishmania-induced NO production. PMID- 23749231 TI - MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion. AB - Hyperlipidemia is a risk factor for various cardiovascular and metabolic disorders. Overproduction of lipoproteins, a process that is dependent on microsomal triglyceride transfer protein (MTP), can contribute to hyperlipidemia. We show that microRNA-30c (miR-30c) interacts with the 3' untranslated region of MTP mRNA and induces its degradation, leading to reductions in MTP activity and in apolipoprotein B (APOB) secretion. miR-30c also reduces lipid synthesis independently of MTP. Hepatic overexpression of miR-30c reduced hyperlipidemia in Western diet-fed mice by decreasing lipid synthesis and the secretion of triglyceride-rich ApoB-containing lipoproteins and decreased atherosclerosis in Apoe(-/-) mice. Furthermore, inhibition of hepatic miR-30c by anti-miR-30c increased hyperlipidemia and atherosclerosis. Therefore, miR-30c coordinately reduces lipid biosynthesis and lipoprotein secretion, thereby regulating hepatic and plasma lipid concentrations. Raising miR-30c levels might be useful in treating hyperlipidemias and associated disorders. PMID- 23749233 TI - Facile fabrication of hierarchically porous CuFe2O4 nanospheres with enhanced capacitance property. AB - In this work, CuFe2O4 nanospheres with hierarchically porous structure have been synthesized via a facile solvothermal procedure. The superstructures consist of the textured aggregations of nanocrystals with high specific surface area, pore volume, and uniform pore size distribution.To figure out the formation mechanism, we discussed in detail the effects of a series of experimental parameters, including the concentrations of the precipitation agent, stabilizer agent, and reaction temperature and time on the size and morphology of the resulting products. Furthermore, the electrochemical properties of CuFe2O4 nanospheres were evaluated by cyclic voltammetry and galvanostatic charge-dischrge studies. The results demonstrate that the as-prepared CuFe2O4 nanospheres are excellent electrode material in supercapacitor with high specific capacitance and good retention. The hierarchically CuFe2O4 nanospheres show the highest capacitance of 334F/g, and 88% of which can still be maintained after 600 charge-discharge cycles. PMID- 23749232 TI - Direct migration of follicular melanocyte stem cells to the epidermis after wounding or UVB irradiation is dependent on Mc1r signaling. AB - During wound healing, stem cells provide functional mature cells to meet acute demands for tissue regeneration. Simultaneously, the tissue must maintain a pool of stem cells to sustain its future regeneration capability. However, how these requirements are balanced in response to injury is unknown. Here we demonstrate that after wounding or ultraviolet type B irradiation, melanocyte stem cells (McSCs) in the hair follicle exit the stem cell niche before their initial cell division, potentially depleting the pool of these cells. We also found that McSCs migrate to the epidermis in a melanocortin 1 receptor (Mc1r)-dependent manner and differentiate into functional epidermal melanocytes, providing a pigmented protective barrier against ultraviolet irradiation over the damaged skin. These findings provide an example in which stem cell differentiation due to injury takes precedence over stem cell maintenance and show the potential for developing therapies for skin pigmentation disorders by manipulating McSCs. PMID- 23749234 TI - DNA triplex folding: moderate versus high salt conditions. AB - Some specific sequences in duplex DNA can give rise to local formation of a triple helical DNA called triplex together with a separate strand. Recent single molecule FRET experiments, performed on DNA strands designed to fold into a triplex, allow us to measure the folding and unfolding time distributions under neutral p H conditions. The average times of both processes are of the order of 1 s. The folding time is moderately sensitive to salt concentration. The average unfolding time is found to be nearly constant. Interestingly, the distributions of the unfolding time revealed heterogeneous kinetics at moderate salt concentration (~ 10 mM), but not at high salt (~ 100 mM). We relate this salt dependence to different folding paths and folded states, which are governed by the (salt-dependent) stiffness of the third single-stranded donor sequence. Finally we comment on the formation of intramolecular triplex named H-DNA in a torsionally constrained duplex under physiological salt conditions, which mimics the in vivo situation of triplex folding. PMID- 23749235 TI - Efficient production of 1,3-propanediol from fermentation of crude glycerol with mixed cultures in a simple medium. AB - The objective of this study was to examine the applicability of mixed cultures for 1,3-propanediol (1,3-PDO) production from crude glycerol. Three different sources of mixed cultures were tested, where the mixed culture from a municipal wastewater treatment plant showed the best results. 1,3-PDO can be produced as the main product in this mixed culture with typical organic acids like acetic and butyric acids as by-products. The yield was in the range of 0.56-0.76 mol 1,3-PDO per mol glycerol consumed depending on the glycerol concentration. A final product concentration as high as 70 g/L was obtained in fed-batch cultivation with a productivity of 2.6 g/L h. 1,3-PDO can be kept in the culture several days after termination of the fermentation without being degraded. Degradation tests showed that 1,3-PDO is degraded much slower than other compounds in the fermentation broth. In comparison to 1,3-PDO production in typical pure cultures, the process developed in this work with a mixed culture achieved the same levels of product titer, yield and productivity, but has the decisive advantage of operation under complete non-sterile conditions. Moreover, a defined fermentation medium without yeast extract can be used and nitrogen gassing can be omitted during cultivation, leading to a strong reduction of investment and production costs. PMID- 23749236 TI - The use of effective fragment potentials in the design and synthesis of molecularly imprinted polymers for the group recognition of PCBs. AB - Effective fragment potential (EFP) molecular modeling approaches have been applied for the first time to the rational design of molecularly imprinted polymers for the group recognition of selected polychlorinated biphenyls (PCBs). EFP calculations were benchmarked using the S22 compound test set and returned energies within 1 kcal mol(-1) of the reported gold standard CCSD(T) approach, but without the computational cost. EFP allowed the rapid identification of trimethylstyrene (TMS) and pentafluorostyrene (PFS) as the functional monomers of choice for the templates (T) 1,2,3,4,5-pentachlorobenzene (4) and for 1,2,3 trichlorobenzne (5) respectively. Ethyleneglycol dimethacrylate was the cross linker (CL) of choice. Using a 1 : 2 : 10 (T : FM : CL) ratio for 4 (TMS as the FM; MIP(4-TMS)) gave imprinting factors (IF) of 2.1; and a 15 : 6 : 29 ratio for 5 gave an IF of 3.66 (PFS as FM; MIP(5-PFS)). MIP(4-TMS) and MIP(5-PFS) showed low levels recognition for non-chlorinated templates with IF values ranging of 1.05, 1.17 and 1.13, 1.54 for toluene (14) and 2,6-dimethylaniline (12) respectively. Higher levels of recognition were observed for the chlorinated analogues 1,3,5-trichlorobenzene (11) and 2,4,6-trichloroaniline (12) with IF values of 1.20, 1.64 and 1.89, 2.66 for MIP(4-TMS) and MIP(5-PFS) respectively suggesting these MIPs were suitable for fragment imprinting of PCBs. Fragment imprinting of 2,2',3,5'-tetrachlorobiphenyl (15), 2,3,3',4,4'-pentachlorobiphenyl (16) and 2,2',3,3',4,5,6'-heptachlorobiphenyl (17) with MIP(4-TMS) gave IF values of 1.38, 1.38 and 1.41 respectively. MIP(5-PFS) performed significantly better with IF values of 6.57, 3.46 and 5.80 for 15-17 respectively. Moreover MIP(5-PFS) displayed a higher binding capacity than MIP(4-TMS) and was less susceptible to non-specific binding influences. PMID- 23749237 TI - Topiramate-induced angle-closure glaucoma: cross-sensitivity with other sulphonamide derivatives causing anterior uveitis. AB - Topiramate is a recognized cause of drug-induced acute angle-closure glaucoma. We describe a case presenting with bilateral acute angle-closure glaucoma caused by topiramate intake. Patient subsequently developed severe anterior uveitis caused by sulphonamide derivatives (acetazolamide and co-trimoxazole) due to cross sensitivity, on two separate occasions. The present case also highlights the role of anterior segment optical tomography in diagnosis and follow-up. In a patient with known drug allergy to topiramate, other sulphonamide derivatives should be avoided to limit the ocular morbidity. PMID- 23749238 TI - Acute visual loss in papilloedema: the diagnostic pitfalls. AB - Papilloedema is the descriptive term for optic disc swelling caused by proven elevated intracranial pressure (ICP). Commonly, there is preservation of vision, particularly central vision, visual acuity and colour vision, early in the disease process. However, some patients with raised ICP may present with a combination of disc swelling and visual loss. We report on two patients who presented with visual loss and optic disc swelling. They were initially referred to the neuro-ophthalmology clinic with a provisional diagnosis of optic neuritis given the clinical picture of disc swelling with reduced visual acuity. However they were subsequently found to have papilloedema. PMID- 23749239 TI - Intra-ureteric placement of a urinary catheter in the previously undiagnosed duplex ureter. AB - We report the inadvertent insertion of a urinary catheter into the upper moiety ureter of a duplex kidney, in a full-term pregnant woman prior to an emergency caesarean section. The patient complained of severe pain during inflation of the catheter balloon. All measures to deflate the balloon and remove the catheter failed. Retrograde ureteric contrast examination showed the placement of the catheter in the proximal part the right upper moiety ureter of a duplex ureter. The catheter was removed with ureteroscopic forceps. We concluded that congenital variation of the urinary tract can complicate a simple catheterisation. PMID- 23749240 TI - Mesh retraction correlates with vaginal pain and overactive bladder symptoms after anterior vaginal mesh repair. AB - INTRODUCTION AND HYPOTHESIS: The aim of the present study was to determine possible correlations between mesh retraction after anterior vaginal mesh repair and de novo stress urinary incontinence (SUI), overactive bladder (OAB), and vaginal pain symptoms. METHODS: One hundred and three women with symptomatic prolapse of the anterior vaginal wall, stages 3 and 4 based on the Pelvic Organ Prolapse Quantification (POP-Q) system, underwent Prolift anteriorTM implantation. At a 6-month follow-up, the patients were interviewed for de novo SUI, OAB, and vaginal pain, and underwent an introital/transvaginal ultrasound examination to measure the mesh length in the midsagittal plane. RESULTS: Mesh retraction was significantly larger in a subgroup of patients (n = 20; 19.4 %) presenting de novo OAB symptoms on the follow-up assessment compared with those without this complication (5.0 cm vs. 4.3 cm; p < 0.05). Mesh retraction was also significantly larger in a subgroup of patients (n = 23; 22.3 %) reporting postoperative vaginal pain compared with the women who did not report any postoperative vaginal pain (5.3 cm vs. 4.2 cm; p < 0.01). A significant correlation was found between mesh retraction and the severity of vaginal pain (R = 0.4, p < 0.01). Mesh retraction did not differ between patients with de novo SUI symptoms and those without this complication. CONCLUSIONS: Mesh retraction assessed on ultrasound examination after anterior vaginal mesh repair may correlate with de novo OAB symptoms and vaginal pain. PMID- 23749241 TI - Too tight to give birth? Assessment of pelvic floor muscle function in 277 nulliparous pregnant women. AB - INTRODUCTION AND HYPOTHESIS: Theoretically, tight or strong pelvic floor muscles may impair the progress of labor and lead to instrumental deliveries. We aimed to investigate whether vaginal resting pressure, pelvic floor muscle strength, or endurance at midpregnancy affect delivery outcome. METHODS: This was a prospective cohort study of women giving birth at a university hospital. Vaginal resting pressure, pelvic floor muscle strength, and endurance in 300 nulliparous pregnant women were assessed at mean gestational week 20.8 (+/-1.4) using a high precision pressure transducer connected to a vaginal balloon. Delivery outcome measures [acute cesarean section, prolonged second stage of labor (> 2 h), instrumental vaginal delivery (vacuum and forceps), episiotomy, and third- and fourth-degree perineal tear) were retrieved from the hospital's electronic birth records. RESULTS: Twenty-three women were lost to follow-up, mostly because they gave birth at another hospital. Women with prolonged second stage had significantly higher resting pressure than women with second stage less than 2 h; the mean difference was 4.4 cmH2O [95 %confidence interval (CI) 1.2-7.6], p < 0.01, adjusted odds ratio 1.049 (95 % CI 1.011-1.089, p = 0.012). Vaginal resting pressure did not affect other delivery outcomes. Pelvic floor muscle strength and endurance similarly were not associated with any delivery outcomes. CONCLUSIONS: While midpregnancy vaginal resting pressure is associated with prolonged second stage of labor, neither vaginal resting pressure nor pelvic floor muscle strength or endurance are associated with operative delivery or perineal tears. Strong pelvic floor muscles are not disadvantageous for vaginal delivery. PMID- 23749242 TI - Fixation of the Ajust minisling based upon cadaveric study. AB - INTRODUCTION AND HYPOTHESIS: The objective was to describe the fixation site of the anchor of the Ajust mid-urethral minisling. METHODS: This cadaveric study was based on a group of 11 formalin-embalmed bodies with legs positioned in 30 degrees flexion and 30 degrees abduction, and a group of five fresh-frozen bodies with legs positioned as normal during the procedure. The groups were later compared. The fixation site was dissected and described. The distance to the obturator bundle was considered as the primary safety parameter. To compare the groups of fresh-frozen bodies and formalin-embalmed bodies, the Student's t test and Mann-Whitney test were used. RESULTS: In the group of formalin-embalmed bodies the mean distance from the anchoring device to the obturator nerve was 4.23 cm. In 19 cases out of 22 the anchor was within the complex of the obturator membrane and obturator muscles. In the group of fresh frozen bodies the mean distance to the obturator nerve was 3.15 cm. In 9 cases out of 10 the anchor was in the complex of the obturator membrane and obturator muscles. CONCLUSION: The distance from the anchor to the obturator nerve was more than 2 cm in all cases. Correct placement in the obturator membrane was achieved in 65.6 % of cases. In 87.5 % of cases the anchor was placed within the complex of obturator membrane and obturator muscles. PMID- 23749243 TI - Hodgkin lymphoma in pregnancy. AB - The peak incidence of Hodgkin lymphoma (HL) coincides with reproductive years, and as many as 3 % of all HL patients present with concurrent pregnancy. The management of a pregnant patient with HL requires a multidisciplinary approach combining expertise in medical oncology, high-risk obstetrics, and neonatology, as well as effective communication with the patient and her family. The goal is to optimize the mother's chance of a cure while allowing for delivery of a healthy child. A pregnant patient with HL should be staged by clinical examination and judicious use of non-radiation imaging such as ultrasound, balancing the need for accurate disease assessment with the need to minimize invasive procedures. The treatment strategy is individualized to the symptoms, lymphoma stage, gestational age and the patients' wishes. Therapeutic options include treatment deferral or single-agent vinblastine with reservation of multi agent chemotherapy until the second or third trimester for the small minority of patients with aggressive clinical presentation. PMID- 23749244 TI - Prevalence of bisphosphonate-associated osteonecrosis of the jaw after intravenous zoledronate infusions in patients with early breast cancer. AB - OBJECTIVES: The definite incidence rate of bisphosphonate-related osteonecrosis of the jaws (BRONJ) is still unknown. The aim of this study was to investigate prevalence of BRONJ in a group of breast cancer patients applying the classification of the Association of Oral and Maxillofacial Surgeons 2009. PATIENTS AND METHODS: Between 2000 and 2008, 63 premenopausal early breast cancer patients who were free of metastases were treated with 4 mg zoledronic acid every 6 months over 3 years as participants of a multicenter, randomized, controlled, adjuvant breast cancer medication trial. Patients were not informed about the risk of jaw necrosis. None reported tooth or jaw complaints during the breast cancer follow-up examinations. In 2010, 48 patients of this cohort were investigated concerning BRONJ by clinical and radiological examinations. RESULTS: No advanced stages (AAOMS 2009)were detected. However, five patients (10.4%) presented purulent (2) and nonpurulent (3) fistulas and radiological signs correlating to BRONJ stage 0. CONCLUSION: Although no case of advanced BRONJ was detected, the study revealed a high prevalence of BRONJ stage 0. This supports the need for tight cooperation between dentists and medical specialists prescribing bisphosphonates including dental pre-therapeutic and follow-up examinations. Adaption of the BRONJ classification taking account to bone exposure via fistulas is recommended. CLINICAL RELEVANCE: BRONJ is said to be a complication linked to high-dosage bisphosphonate therapy. The study demonstrates that even after application of zoledronate in a low-dose protocol, early BRONJ occurred. Radiological signs solely are not sufficient to confirm BRONJ; clinical signs are mandatory. PMID- 23749245 TI - Clinical results after nonsurgical therapy in aggressive and chronic periodontitis. AB - AIM: This study aims to analyze factors influencing treatment results in aggressive (AgP) and chronic (ChP) periodontitis. METHODS: ChP [probing pocket depth (PPD) >= 3.5 mm, attachment loss >= 5 mm at >30 % of sites; age > 35 years] and AgP (clinically healthy; PPD >= 3.5 mm at >30 % of sites, radiographic bone loss >= 50 % at 2 teeth; age <= 35 years) were examined prior and 3 months after nonsurgical therapy according to the full-mouth disinfection concept. Adjunctive systemic antibiotics were used if Aggregatibacter actinomycetemcomitans had been detected at baseline. RESULTS: In 31 ChP (12 female, 10 smokers; 4,808 sites) and 28 AgP (16 female, 9 smokers; 4,769 sites), overall mean PPD reductions were less favorable in AgP (0.9 +/- 0.5 mm) than in ChP (1.3 +/- 0.4 mm; p = 0.033). PPD reductions and relative vertical probing attachment level gain were more favorable at sites with initial PPD >= 6 mm, bleeding on probing, and for adjunctive systemic antibiotics. Furthermore, PPD reductions were more favorable for increased baseline tooth mobility and maxillary teeth, whereas AgP, female sex, and multirooted teeth were associated with less favorable PPD reduction. CONCLUSION: Regarding PPD reduction, AgP responded less favorably to nonsurgical treatment than ChP. PMID- 23749246 TI - Incorporation of omega-3 polyunsaturated fatty acids into soybean lecithin: effect of amines and divalent cations on transesterification by lipases. AB - The transesterification of soybean lecithin with methyl esters of EPA and DHA in an organic solvent (hexane) using various commercially available lipases was studied. Lipases produced by Candida antarctica, Pseudomonas fluorescens, Burkholderia cepacia, Mucor miehei, Thermomyces lanuginosus and Rhizomucor miehei were compared, in the absence or presence of histidine, arginine, urea, Ca2+, Mg2+, or a combination of urea and divalent cations (additives at 5 % of the total lipid mass). Transesterification using the R. miehei enzyme reached 11.32 and 12.30 % in the presence of Ca2+ or Mg2+ respectively, and 8.58 and 9.31 % when urea was also added. These were the greatest degrees of transesterification obtained. The results suggest the potential use of this immobilized lipase as a catalyst for interesterification reactions in organic solvent systems with low water content. PMID- 23749247 TI - Comparative biochemical analysis during the anaerobic digestion of lignocellulosic biomass from six morphological parts of Williams Cavendish banana (Triploid Musa AAA group) plants. AB - We studied banana lignocellulosic biomass (BALICEBIOM) that is abandoned after fruit harvesting, and assessed its biochemical methane potential, because of its potential as an energy source. We monitored biogas production from six morphological parts (MPs) of the "Williams Cavendish" banana cultivar using a modified operating procedure (KOP) using KOH. Volatile fatty acid (VFA) production was measured using high performance liquid chromatography. The bulbs, leaf sheaths, petioles-midribs, leaf blades, rachis stems, and floral stalks gave total biogas production of 256, 205, 198, 126, 253, and 221 ml g-1 dry matter, respectively, and total biomethane production of 150, 141, 127, 98, 162, and 144 ml g-1, respectively. The biogas production rates and yields depended on the biochemical composition of the BALICEBIOM and the ability of anaerobic microbes to access fermentable substrates. There were no significant differences between the biogas analysis results produced using KOP and gas chromatography. Acetate was the major VFA in all the MP sample culture media. The bioconversion yields for each MP were below 50 %, showing that these substrates were not fully biodegraded after 188 days. The estimated electricity that could be produced from biogas combustion after fermenting all of the BALICEBIOM produced annually by the Cameroon Development Corporation-Del Monte plantations for 188 days is approximately 10.5 * 106 kW h (which would be worth 0.80-1.58 million euros in the current market). This bioenergy could serve the requirements of about 42,000 people in the region, although CH4 productivity could be improved. PMID- 23749248 TI - Plant growth promoting bacteria from Crocus sativus rhizosphere. AB - Present study deals with the isolation of rhizobacteria and selection of plant growth promoting bacteria from Crocus sativus (Saffron) rhizosphere during its flowering period (October-November). Bacterial load was compared between rhizosphere and bulk soil by counting CFU/gm of roots and soil respectively, and was found to be ~40 times more in rhizosphere. In total 100 bacterial isolates were selected randomly from rhizosphere and bulk soil (50 each) and screened for in-vitro and in vivo plant growth promoting properties. The randomly isolated bacteria were identified by microscopy, biochemical tests and sequence homology of V1-V3 region of 16S rRNA gene. Polyphasic identification categorized Saffron rhizobacteria and bulk soil bacteria into sixteen different bacterial species with Bacillus aryabhattai (WRF5-rhizosphere; WBF3, WBF4A and WBF4B-bulk soil) common to both rhizosphere as well as bulk soil. Pseudomonas sp. in rhizosphere and Bacillus and Brevibacterium sp. in the bulk soil were the predominant genera respectively. The isolated rhizobacteria were screened for plant growth promotion activity like phosphate solubilization, siderophore and indole acetic acid production. 50 % produced siderophore and 33 % were able to solubilize phosphate whereas all the rhizobacterial isolates produced indole acetic acid. The six potential PGPR showing in vitro activities were used in pot trial to check their efficacy in vivo. These bacteria consortia demonstrated in vivo PGP activity and can be used as PGPR in Saffron as biofertilizers.This is the first report on the isolation of rhizobacteria from the Saffron rhizosphere, screening for plant growth promoting bacteria and their effect on the growth of Saffron plant. PMID- 23749249 TI - Feed or fight: A behavioral shift in blind cavefish. AB - Within the species Astyanax mexicanus, there are several inter-fertile populations of river-dwelling sighted fish and cave-dwelling blind fish which have evolved morphological and behavioral adaptations. We have recently reported a developmental and neurophysiological basis for the loss of aggressive behavior in the blind cavefish morph of Astyanax. Using an appropriate behavioral assay, we have shown that surface Astyanax show intense dominance-related aggressiveness. The expression of this behavior is inversely correlated with the serotonin (5HT) levels in their hindbrain raphe nucleus. Moreover this behavior is not solely visually-evoked and has a genetic component. Conversely in cavefish, there is no raphe-driven dominance aggressiveness. Instead, the embryonic Sonic Hedgehog-dependent modification of the size of a serotonergic neuronal group localized in their hypothalamus causes a shift in their behavioral pattern: instead of fighting, they search for food. Here we further discuss the origin and nature of this behavioral shift. PMID- 23749250 TI - Globalization and health care: global justice and the role of physicians. AB - In today's globalized world, nations cannot be totally isolated from or indifferent to their neighbors, especially in regards to medicine and health. While globalization has brought prosperity to millions, disparities among nations and nationals are growing raising once again the question of justice. Similarly, while medicine has developed dramatically over the past few decades, health disparities at the global level are staggering. Seemingly, what our humanity could achieve in matters of scientific development is not justly distributed to benefit everyone. In this paper, it will be argued that a global theoretical agreement on principles of justice may prove unattainable; however, a grass-roots change is warranted to change the current situation. The UNESCO Declaration on Bioethics and Human Rights will be considered as a starting point to achieve this change through extracting the main values embedded in its principles. These values, namely, respecting human dignity and tending to human vulnerability with a hospitable attitude, should then be revived in medical practice. Medical education will be one possible venue to achieve that, especially through role models. Future physicians will then become the fervent advocates for a global and just distribution of health care. PMID- 23749251 TI - Decreased expression of DUSP4 is associated with liver and lung metastases in colorectal cancer. AB - Dual-specificity protein phosphatase 4 (DUSP4), a negative regulator of extracellular-regulated kinase activity, is a potential mediator of resistance to chemotherapy and a tumor suppressor. The aim of this study is to clarify the association between DUSP4 gene expression and clinical outcome in patients with colorectal cancer. Patients who underwent surgery for colorectal cancer were enrolled in this study (n = 212). We investigated DUSP4 gene expression by real time reverse transcription polymerase chain reaction in colorectal cancer tissue and paired normal mucosa. Immunohistochemical analyses of DUSP4 and ERK1/2 were also conducted. Additionally, we examined the relationship between gene expression and KRAS mutation in 74 of the 212 patients. DUSP4 expression in tumor tissues was significantly higher than that in matched normal mucosa (P < 0.0001). Decreased DUSP4 expression was significantly associated with advanced T classification, lymphatic invasion, vascular invasion, advanced stage, and liver and lung metastases. Logistic regression analysis revealed that decreased DUSP4 expression was an independent risk factor for synchronous distant metastases (P = 0.006). Increased DUSP4 expression was significantly associated with better prognosis (P = 0.0162). Immunohistochemical examination showed DUSP4 expression in the nucleus and cytoplasm of cancer cells, and no correlation was observed between DUSP4 and ERK1/2 expression. There was no significant correlation between DUSP4 expression and KRAS mutation. In conclusion, DUSP4 expression in colorectal cancer was negatively correlated with factors reflecting tumor progression, including distant metastases. Our data suggest that DUSP4 may act as a tumor suppressor in colorectal cancer. PMID- 23749252 TI - Self-reported maternal parenting style and confidence and infant temperament in a multi-ethnic community: results from the Born in Bradford cohort. AB - Ethnic minority children in the United Kingdom often experience health disadvantage. Parenting influences children's current and future health, but little is known about whether parenting behaviours and mother's perception of her infant vary by ethnicity. Using the Born in Bradford (BiB) birth cohort, which is located in an ethnically diverse and economically deprived UK city, we conducted a cross-sectional analysis of mother's self-reported parenting confidence, self efficacy, hostility and warmth, and infant temperament at six months of age. We examined responses from women of Pakistani (N = 554) and White British (N = 439) origin. Pakistani mothers reported feeling more confident about their abilities as a parent. Significantly fewer Pakistani women adopted a hostile approach to parenting, an effect that was attenuated after adjustment for socioeconomic status and mental health. Overall, women with more self-efficacious, warm and less hostile parenting styles reported significantly fewer problems with their infant's temperaments. Of women with higher self-efficacy parenting styles, Pakistani mothers were significantly more likely than White British mothers to report more problematic infant temperaments, although absolute differences were small. It is unlikely that the ethnic variation seen in children's cognitive and behavioural outcomes in childhood is attributable to differences in parenting or infant characteristics reported at six months. PMID- 23749253 TI - The relationship between mothers' coping patterns and children's anxiety about their hospitalization as reflected in drawings. AB - This study explored the relationships between hospitalized children's anxiety level, mothers' use of coping strategies, and mothers' satisfaction with the hospital experience. Twenty-four hospitalized children and their mothers participated in this study. Children were asked to draw a person in the hospital, which was then coded as a projective measure of anxiety; mothers were asked to complete questionnaires on their coping behaviors and their satisfaction with their child's hospital experience. The use of more coping strategies by the mothers was related to less anxiety in the children. In addition, the more coping strategies the mothers used, the higher they reported their satisfaction. The findings suggest the importance of providing resources aimed at increasing maternal coping and satisfaction with the quality of care of a child's hospitalization in order to minimize the negative effects of the hospitalization on the children. PMID- 23749254 TI - Factors influencing the diabetes-specific health-related quality of life in children and adolescents with type 1 diabetes mellitus. AB - This study aimed to investigate the association of the anthropometric, clinical variables and maximal oxygen uptake (Vo2max) with diabetes-specific health related quality of life (HRQoL) in youths with type 1 diabetes mellitus (T1DM) and to find the predictors of HRQoL and blood glucose control. A total of 239 youths with diabetes (124 boys and 115 girls) were recruited from diabetes-based summer camps. HRQoL assessment was carried out with the Pediatric Quality of Life Inventory 3.0 Diabetes Module (Information Resources Centre, Mapi Research Trust, France); Vo2max was evaluated by conducting the 20-m shuttle run test. Higher Vo2max and the insulin pump therapy were significant predictors of the HRQoL in the multiple regression analysis; other clinical and anthropometric variables had no effect. The better blood glucose control was explained only by the higher Vo2max. The good cardiorespiratory fitness (expressed by Vo2max) has clinical and QoL benefits for paediatric patients with T1DM. PMID- 23749256 TI - FVIIIra, CD15, and tryptase performance in the diagnosis of skin stab wound vitality in forensic pathology. AB - The timing of skin wounds is one of the most challenging problems in forensic pathology. In the first minutes or hours after infliction, histological examination fails to determine whether a wound was sustained before or after death. The aim of this study was to evaluate the use of three immunohistochemical markers (FVIIIra, CD15, and tryptase) for the interpretation of the timing of cutaneous stab wounds. We evaluated these markers in intravital wounds from autopsy cases (n = 12) and surgical specimens (n = 58). As controls, we used normal skin samples from autopsies (n = 8) and an original ex vivo surgical human model of recent postmortem wounds (n = 24). We found overexpression of FVIIIra in 100 % of vital wounds, but also in 53 % of the controls. The number of CD15 positive cells was higher in wound margins than in internal controls (p < 0.0001) and was significantly correlated with the time interval between incision and devascularization (p = 0.0005; minimal time for positivity, 9 min). Using the anti-tryptase antibody, we found that the mast cell degranulation rate was higher in wound margins (p < 0.0001) and correlated with the time interval (minimal time, 1 min). The sensitivity and specificity for the diagnosis of vitality were respectively 100 and 47 % for FVIIIra, 47 and 100 % for CD15, and 60 and 100 % for tryptase. The inter-observer agreement coefficients were 0.68 for FVIIIra, 0.90 for CD15, and 0.46 for tryptase. Finally, we demonstrated that these markers were not reliable in putrefied or desiccated specimens. In conclusion, CD15 and tryptase, but not FVIIIra, may be useful markers for differentiating recent antemortem from postmortem injuries. PMID- 23749257 TI - Comparison of an 8-channel and a 32-channel coil for high-resolution FMRI at 7 T. AB - Multi-channel receive array rf-coils have become widely available for fMRI. The improved SNR and possibility of acquisition acceleration through parallel imaging are especially beneficial for high-resolution studies. In this study, an 8 channel and a 32-channel coil were compared in a high-resolution finger tapping fMRI experiment at 7 T. 1.3 mm(3) resolution data acquired with the 32-channel coil provided higher image- and temporal SNR and yielded higher BOLD sensitivity measures, notably higher cluster sizes in MI/SI and increased z-scores, though not an increase in percent signal change. For sub-millimeter resolution fMRI data acquired with the 32-channel coil smaller clusters were found, though percent signal changes were significantly larger, due to reduced partial volume effects. These results demonstrate the utility of the use of an array coil with a large number of receive elements for high-resolution fMRI at ultra-high field. PMID- 23749255 TI - The potential use of bacterial community succession in forensics as described by high throughput metagenomic sequencing. AB - Decomposition studies of vertebrate remains primarily focus on data that can be seen with the naked eye, such as arthropod or vertebrate scavenger activity, with little regard for what might be occurring with the microorganism community. Here, we discuss the necrobiome, or community of organisms associated with the decomposition of remains, specifically, the "epinecrotic" bacterial community succession throughout decomposition of vertebrate carrion. Pyrosequencing was used to (1) detect and identify bacterial community abundance patterns that described discrete time points of the decomposition process and (2) identify bacterial taxa important for estimating physiological time, a time-temperature metric that is often commensurate with minimum post-mortem interval estimates, via thermal summation models. There were significant bacterial community structure differences in taxon richness and relative abundance patterns through the decomposition process at both phylum and family taxonomic classification levels. We found a significant negative linear relationship for overall phylum and family taxon richness as decomposition progressed. Additionally, we developed a statistical model using high throughput sequencing data of epinecrotic bacterial communities on vertebrate remains that explained 94.4 % of the time since placement of remains in the field, which was within 2-3 h of death. These bacteria taxa are potentially useful for estimating the minimum post-mortem interval. Lastly, we provide a new framework and standard operating procedure of how this novel approach of using high throughput metagenomic sequencing has remarkable potential as a new forensic tool. Documenting and identifying differences in bacterial communities is key to advancing knowledge of the carrion necrobiome and its applicability in forensic science. PMID- 23749258 TI - Charge-transfer inclusion complex formation of tropylium cation with pillar[6]arenes. AB - The complexation behavior of pillar[6]arene hosts towards a carbonium ion, tropylium tetrafluoroborate (T.BF4), and the formation of novel charge-transfer (CT) inclusion complexes are described. In contrast, smaller pillar[5]arenes and larger pillar[7]arenes cannot form such complexes due to the unsuitable cavity dimensions. PMID- 23749259 TI - Oxidation of dimethylplatinum(II) complexes with a peroxyacid. AB - The complexes [PtMe2(NN)], NN = 2,2'-bipyridine = bipy, 1a; NN = di-2 pyridylamine = dpa, 1b; NN = di-2-pyridyl ketone = dpk, 1c, NN = 4,4' bis(ethoxycarbonyl)-2,2'-bipyridine, bebipy, react with m-chloroperoxybenzoic acid to give the platinum(IV) complexes [Pt(OH)(O2C-3-C6H4Cl)Me2(NN)], NN = bipy, 2, or [Pt(OH)(OH2...O2C-3-C6H4Cl)Me2(NN)], NN = bipy, 3a; dpa, 3b; bebipy, 3d, or [Pt(OH)2Me2(dpkOH)]3[Pt(OH)(OH2)Me2(dpkOH)][H(O2C-3-C6H4Cl)2].2MeOH, 43.5.2MeOH. The reactions are proposed to occur by a polar oxidative addition mechanism, followed in most cases by the coordination of water. Complex 3a crystallises as a supramolecular polymer, the compound 43.5.2MeOH crystallises as a supramolecular sheet structure, and 3d easily forms a gel, all through strong intermolecular hydrogen bonding. PMID- 23749261 TI - ECG-gated computed tomography to assess pulmonary capillary wedge pressure in pulmonary hypertension. AB - OBJECTIVE: We propose a non-invasive method for diagnosing post-capillary pulmonary hypertension (PH group 2). We evaluated pulmonary capillary wedge pressure (PCWP) by studying the left atrium (LA) on thoracic ECG-gated CT compared with right heart catheterisation (RHC). METHODS: We retrospectively studied 54 patients with suspected PH or followed for PH who underwent thoracic ECG-gated CT and RHC within 15 days. The diagnostic accuracy of CT morphological and functional data of the LA for the detection of PCWP >15 mmHg, evaluated by two independent readers, was assessed using correlation and receiver-operating characteristic (ROC) analysis. RESULTS: Interobserver agreement was high (r = 0.97-0.99). Correlations were found between PCWP and the morphological criteria of the LA such as anteroposterior diameter at 0 % of the R-R interval (r = 0.70, P <= 0.001) as well as at 40 % (r = 0.69, P <= 0.001). ROC curves constructed with a threshold value of PCWP > 15 mmHg showed an area under the curve between 0.88 and 0.91. Significant correlations were found between PCWP and functional criteria of the LA, including distensibility (r = -0.49, P <= 0.001) and ejection fraction (r = -0.58, P <= 0.001). CONCLUSION: Thoracic ECG-gated CT in a PH workup helps distinguish between pre- and post-capillary PH. KEY POINTS: * Computed tomography may help differentiate the various types of pulmonary hypertension (PH). * Post-capillary PH group 2 is due to left heart disease. * Right heart catheterisation is used to separate pre- and post-capillary PH. * Left atrium anteroposterior diameter measured on CT is of value. * ECG-gated CT helps clinicians to assess patients with PH non-invasively. PMID- 23749263 TI - Our health system and the poorest Americans. PMID- 23749262 TI - Epicardial adipose tissue thickness as a predictor of impaired microvascular function in patients with non-obstructive coronary artery disease. AB - OBJECTIVE: To determine if increased epicardial adipose tissue (EAT) measured by cardiac CT could be associated with impaired myocardial flow reserve (MFR) in patients with non-obstructive coronary artery disease (CAD). BACKGROUND: Studies have shown that EAT volume is related to epicardial obstructive CAD, myocardial ischemia and major adverse cardiac events. However, the association between EAT with coronary microvascular dysfunction and impaired MFR has not been well clarified. METHODS: Consecutive patients who underwent Rb-82 positron emission tomography (PET), coronary artery calcium (CAC) scoring and non-invasive coronary computed tomography angiography (CCTA) were screened. PET scans were analysed for standard myocardial perfusion (MPI) and MFR. CCTA results were analysed and only patients with non-obstructive CAD (<50% luminal diameter stenosis) were included. EAT thickness and volumes were measured from CT scans. RESULTS: Of 137 patients without obstructive CAD by CCTA and with normal Rb-82 PET relative MPI, 26 (19.0%) patients had impaired MFR < 2 and 87 (64%) patients had CAC. EAT(thickness), EAT(volume) and CAC values were higher in patients with impaired MFR < 2 than those with normal MFR >= 2 (6.7 +/- 1.6 mm vs 4.4 +/- 1.0 mm, P < .0001; 119.0 +/- 25.3 cm(3) vs 105.8 +/- 30.5 cm(3), P < .04 and 508.9 +/- 554.3 vs 167.8 +/- 253.9, P < .0001, respectively). However, EAT(thickness) had a stronger negative correlation with MFR than EAT(volume) and CAC (r = -0.78 vs r = -0.25 and rho = -0.32, P < .0001). With multivariable logistic regression analysis, only EAT(thickness) was independently associated with impaired MFR (OR 20.7, 95% CI 4.9-87.9, P < .0001). Importantly, the receiver-operator characteristic (ROC) curves demonstrated a superior performance of EAT(thickness) vs EAT(volume) and EAT(thickness) vs CAC in detecting impaired MFR (AUC: 0.945 vs 0.625, difference between AUC: 0.319, P < .0001; AUC: 0.945 vs 0.710, difference between AUC: 0.235, P < .0006, respectively). On ROC curve analysis, an EAT(thickness) cut-off value > 5.6 mm was optimal in detecting impaired MFR with a sensitivity and specificity of 81% and 92%, respectively. CONCLUSIONS: Increased EAT appears to be associated with impaired MFR. This parameter may help improve detection of patients at risk of microvascular dysfunction. PMID- 23749264 TI - A family of binary magnetic icosahedral quasicrystals based on rare earths and cadmium. AB - Examples of stable binary icosahedral quasicrystals are relatively rare, and at present there are no known examples featuring localized magnetic moments. These would represent an ideal model system for attaining a deeper understanding of the nature of magnetic interactions in aperiodic lattices. Here we report the discovery of a family of at least seven rare earth icosahedral binary quasicrystals, i-R-Cd (R = Gd to Tm, Y), six of which bear localized magnetic moments. Our work highlights the importance of carefully motivated searches through phase space and supports the proposal that, like icosahedral Sc12Zn88 (ref. ), binary quasicrystalline phases may well exist nearby known crystalline approximants, perhaps as peritectically forming compounds with very limited liquidus surfaces, offering very limited ranges of composition/temperature for primary solidification. PMID- 23749265 TI - Vapour phase growth and grain boundary structure of molybdenum disulphide atomic layers. AB - Single-layered molybdenum disulphide with a direct bandgap is a promising two dimensional material that goes beyond graphene for the next generation of nanoelectronics. Here, we report the controlled vapour phase synthesis of molybdenum disulphide atomic layers and elucidate a fundamental mechanism for the nucleation, growth, and grain boundary formation in its crystalline monolayers. Furthermore, a nucleation-controlled strategy is established to systematically promote the formation of large-area, single- and few-layered films. Using high resolution electron microscopy imaging, the atomic structure and morphology of the grains and their boundaries in the polycrystalline molybdenum disulphide atomic layers are examined, and the primary mechanisms for grain boundary formation are evaluated. Grain boundaries consisting of 5- and 7- member rings are directly observed with atomic resolution, and their energy landscape is investigated via first-principles calculations. The uniformity in thickness, large grain sizes, and excellent electrical performance signify the high quality and scalable synthesis of the molybdenum disulphide atomic layers. PMID- 23749266 TI - Piezoelectric control of the mobility of a domain wall driven by adiabatic and non-adiabatic torques. AB - The rich internal degrees of freedom of magnetic domain walls make them an attractive complement to electron charge for exploring new concepts of storage, transport and processing of information. Here we use the tunable internal structure of a domain wall in a perpendicularly magnetized GaMnAsP/GaAs ferromagnetic semiconductor and demonstrate devices in which piezoelectrically controlled magnetic anisotropy yields up to 500% mobility variations for an electrical-current-driven domain wall. We observe current-induced domain wall motion over a wide range of current-pulse amplitudes and report a direct observation and the piezoelectric control of the Walker breakdown separating two regimes with different mobilities. Our work demonstrates that in spin-orbit coupled ferromagnets with weak extrinsic domain wall pinning, the piezoelectric control allows one to experimentally assess the upper and lower boundaries of the characteristic ratio of adiabatic and non-adiabatic spin-transfer torques in the current-driven domain wall motion. PMID- 23749267 TI - Carbon monoxide-induced adatom sintering in a Pd-Fe3O4 model catalyst. AB - The coarsening of catalytically active metal clusters is often accelerated by the presence of gases, but the role played by gas molecules is difficult to ascertain and varies from system to system. We use scanning tunnelling microscopy to follow the CO-induced coalescence of Pd adatoms supported on the Fe3O4(001) surface at room temperature, and find Pd-carbonyl species to be responsible for mobility in this system. Once these reach a critical density, clusters nucleate; subsequent coarsening occurs through cluster diffusion and coalescence. Whereas CO induces the mobility in the Pd/Fe3O4 system, surface hydroxyls have the opposite effect. Pd atoms transported to surface OH groups are no longer susceptible to carbonyl formation and remain isolated. Following the evolution from well-dispersed metal adatoms into clusters, atom-by-atom, allows identification of the key processes that underlie gas-induced mass transport. PMID- 23749268 TI - NHC-mediated cross-coupling of sugar-derived cyclic nitrones with enals: general and efficient synthesis of polyhydroxylated pyrrolizidines and indolizidines. AB - A general and efficient method for the synthesis of polyhydroxylated pyrrolizidines and indolizidines has been developed based on the NHC-catalyzed cross-coupling of sugar-derived cyclic nitrones with enals, which afforded the key intermediates, gamma-hydroxyl amino esters, in good to excellent yields. Thus, a variety of polyhydroxylated pyrrolizidines and indolizidines have been synthesized and assayed against various glycosidases, which showed that aryl or alkyl substituents at C-7 of pyrrolizidines or at C-8 of indolizidines reduced the potency of the glycosidase inhibition of these bicyclic iminosugars. PMID- 23749270 TI - Coated meshes for hernia repair provide comparable intraperitoneal adhesion prevention. AB - BACKGROUND: Laparoscopic incisional hernia repair with intraperitoneal mesh is associated with a certain degree of adhesion formation to the mesh. This experimental study examined the efficacy of several coated meshes for adhesion reduction. METHODS: Five commercially available meshes with a layered coating were placed intraperitoneally in rats and followed up for 90 days: polypropylene and polyester meshes, both coated with absorbable collagen (Parietene Composite and Parietex Composite, respectively), and three polypropylene meshes respectively coated with absorbable omega-3 fatty acids (C-Qur Edge), absorbable cellulose (Sepramesh IP), and nonabsorbable expanded polytetrafluoroethylene (Intramesh T1). Uncoated polypropylene and collagen meshs (Parietene and Permacol, respectively) served as the control condition. Adhesions, incorporation, and tissue reaction were evaluated macro- and microscopically. Additionally, the development of the neoperitoneum was examined. RESULTS: All the coated meshes performed equally well in terms of adhesion reduction. The collagen mesh performed comparably, but the uncoated polypropylene mesh performed significantly worse. The different coatings led to very differing degrees of inflammation. Ingrowth was observed only at the place of suture but was comparable for all the meshes except C-Qur Edge, which showed the weakest incorporation. Development of a neoperitoneum on the mesh surface occurred independently of whether an absorbable or nonabsorbable coating or no coating at all was present. CONCLUSIONS: Commercially available meshes with a layered coating deliver comparable adhesion reduction. The physical presence of a layered coating between the intraperitoneal content and the abdominal wall seems to be more important than the chemical properties of the coating in adhesion formation. PMID- 23749271 TI - The diagnostic accuracy of transabdominal ultrasonography needs to be considered when managing gallbladder polyps. AB - BACKGROUND: Transabdominal ultrasonography (TAUS) is the most commonly used modality to diagnose gallbladder (GB) disease. GB polyps are reported in 1-5.6 % of TAUS studies. Histopathologic studies suggest that there is a relationship between GB polyps and GB cancer. Previous literature suggests GB polyps reported on TAUS do not correlate well with histological findings. There have been recent advances in TAUS technology. We hypothesize the recent advances in TAUS technology have improved the accuracy of TAUS for diagnosing GB polyps. METHODS: Radiology and pathology databases at our tertiary care center were retrospectively searched between January 1, 2000, and December 31, 2010. Ultrasound reports that suggested a GB polyp was present on TAUS were correlated to histopathology in cases where a cholecystectomy was performed. The pathology reports where a GB polyp was found were correlated with preoperative TAUS reports. RESULTS: There were 102,740 TAUS reports referring to the GB, of which 6,612 (6.4 %) contained search terms suggesting a GB polyp was present. There were 13,278 cholecystectomy pathology reports, of which 159 (1.2 %) included a diagnosis of GB polyp. TAUS detected only 50 % of the polyps identified on histopathology. The sensitivity and specificity of TAUS for diagnosing GB polyps were 50.0 and 98.3 %, respectively. The positive and negative predictive values were 10.5 and 99.8 %. CONCLUSIONS: Despite improvement in TAUS technology, the accuracy for GB polyps remains poor. This needs to be considered when managing patients with TAUS-detected GB polyps. We recommend that the decision to operate on TAUS-detected GB polyps be largely based on symptoms, and following GB polyps with TAUS should be discouraged. PMID- 23749273 TI - Bacteriophages in gut samples from pediatric Crohn's disease patients: metagenomic analysis using 454 pyrosequencing. AB - BACKGROUND: The role of bacteriophage in Crohn's disease (CD) is unknown. This study investigated the abundance of phages in ileal and colonic samples from pediatric CD patients and controls. METHODS: Ileal and colonic biopsies from 6 CD patients, gut wash samples from 3 CD patients, and ileal biopsies from 6 noninflammatory bowel disease patients (controls) were analyzed for the presence of bacteriophage using 454 high-throughput pyrosequencing. A sequence-independent single-primer amplification method was used to amplify viral sequences. RESULTS: A total of 186,143 high quality reads were obtained from the 4 sample populations. Contigs and sequence clusters (generated from unassembled singletons) were aligned with sequences from the National Center for Biotechnology Information viral reference database and analyzed by MEGAN. The largest number of viral hits was obtained from the CD gut wash samples (n = 691), followed by CD ileal samples (n = 52), control ileum samples (n = 20), and CD colonic samples (n = 1). The most abundant virus sequences identified belonged to the Caudovirales phage. CONCLUSIONS: Our study characterized a diverse phage community in the gut of CD patients. In this study, we have identified differences in phage composition between CD patients and control individuals. The large abundance of phages in CD ileum tissue and CD gut wash sample suggests a role of phage in CD development. The role of phage dysbiosis in CD is currently unknown but opens up a new area of research. PMID- 23749272 TI - Granulocyte-macrophage colony-stimulating factor autoantibodies: a marker of aggressive Crohn's disease. AB - BACKGROUND: Neutralizing autoantibodies (Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF Ab) have been associated with stricturing ileal Crohn's disease (CD) in a largely pediatric patient cohort (total 394, adult CD 57). The aim of this study was to examine this association in 2 independent predominantly adult inflammatory bowel disease patient cohorts. METHODS: Serum samples from 742 subjects from the NIDDK IBD Genetics Consortium and 736 subjects from Australia were analyzed for GM-CSF Ab and genetic markers. We conducted multiple regression analysis with backward elimination to assess the contribution of GM-CSF Ab levels and established CD risk alleles and smoking on ileal disease location in the 477 combined CD subjects from both cohorts. We also determined associations of GM-CSF Ab levels with complications requiring surgical intervention in combined CD subjects in both cohorts. RESULTS: Serum samples from patients with CD expressed significantly higher concentrations of GM-CSF Ab when compared with ulcerative colitis or controls in each cohort. Nonsmokers with ileal CD expressed significantly higher GM-CSF Ab concentrations in the Australian cohort (P = 0.002). Elevated GM-CSF Ab, ileal disease location, and disease duration more than 3 years were independently associated with stricturing/penetrating behavior and intestinal resection for CD. CONCLUSIONS: The expression of high GM-CSF Ab is a risk marker for aggressive CD behavior and complications including surgery. Modifying factors include environmental exposure to smoking and genetic risk markers. PMID- 23749274 TI - Streptococcus rubneri sp. nov., isolated from the human throat. AB - The novel, Gram-stain-positive, ovoid, lactic acid bacterial isolates LMG 27205, LMG 27206, LMG 27207(T) and MRI-F 18 were obtained from throat samples of healthy humans. 16S rRNA gene sequence analyses indicated that these isolates belong to the genus Streptococcus, specifically the Streptococcus mitis group, with Streptococcus australis and Streptococcus mitis as the nearest neighbours (99.45 and 98.56 % 16S rRNA gene sequence similarity to the respective type strains). Genotypic fingerprinting by fluorescent amplified fragment length polymorphism (FAFLP) and pulsed-field gel electrophoresis (PFGE), DNA-DNA hybridizations, comparative sequence analysis of pheS, rpoA and atpA and physiological and biochemical tests revealed that these bacteria formed a taxon well separated from its nearest neighbours and other species of the genus Streptococcus with validly published names and, therefore, represent a novel species, for which the name Streptococcus rubneri sp. nov. is proposed, with LMG 27207(T) ( = DSM 26920(T)) as the type strain. PMID- 23749275 TI - Moorella stamsii sp. nov., a new anaerobic thermophilic hydrogenogenic carboxydotroph isolated from digester sludge. AB - A novel anaerobic, thermophilic, carbon monoxide-utilizing bacterium, strain E3 O(T), was isolated from anaerobic sludge from a municipal solid waste digester. Cells were straight rods, 0.6-1 um in diameter and 2-3 um in length and grew as single cells or in pairs. Cells formed round terminal endospores. The temperature range for growth was 50-70 degrees C, with an optimum at 65 degrees C. The pH range for growth was 5.7-8.0, with an optimum at 7.5. Strain E3-O(T) had the ability to ferment various sugars, such as fructose, galactose, glucose, mannose, raffinose, ribose, sucrose and xylose, producing mainly H2 and acetate. In addition, the isolate was able to grow with CO as the sole carbon and energy source. CO oxidation was coupled to H2 and CO2 formation. The G+C content of the genomic DNA was 54.6 mol%. Based on 16S rRNA gene sequence analysis, this bacterium is most closely related to Moorella glycerini (97 % sequence identity). Based on the physiological features and phylogenetic analysis, it is proposed that strain E3-O(T) should be classified in the genus Moorella as a representative of a novel species, Moorella stamsii. The type strain of Moorella stamsii is E3-O(T) ( = DSM 26271(T) = CGMCC 1.5181(T)). PMID- 23749276 TI - Description of Noviherbaspirillum malthae gen. nov., sp. nov., isolated from an oil-contaminated soil, and proposal to reclassify Herbaspirillum soli, Herbaspirillum aurantiacum, Herbaspirillum canariense and Herbaspirillum psychrotolerans as Noviherbaspirillum soli comb. nov., Noviherbaspirillum aurantiacum comb. nov., Noviherbaspirillum canariense comb. nov. and Noviherbaspirillum psychrotolerans comb. nov. based on polyphasic analysis. AB - An aerobic, Gram-negative, rod-shaped bacterium with polar flagella, strain CC AFH3(T), was isolated from an oil-contaminated site located in Kaohsiung county, Taiwan. Strain CC-AFH3(T) grew at 20-40 degrees C, pH 5.0-10.0 and <2 % (w/v) NaCl. 16S rRNA gene sequence analysis indicated that strain CC-AFH3(T) showed the greatest degree of similarity to Herbaspirillum soli SUEMI10(T) (96.5 %), H. aurantiacum SUEMI08(T) (96.3 %), H. canariense SUEMI03(T) (96.0 %), H. psychrotolerans PB1(T) (95.4 %) and members of other Herbaspirillum species (94.1 95.2 %), and lower similarity to members of other genera (<94 %). Phylogenetic analyses also positioned the novel strain in the genus Herbaspirillum as an independent lineage. The major fatty acids in strain CC-AFH3(T) were C10 : 0 3 OH, C12 : 0, C14 : 0 2-OH, C16 : 0, iso-C15 : 0 3-OH, C17 : 0 cyclo, C16 : 1omega7c/C16 : 1omega6c and C18 : 1omega7c/C18 : 1omega6c. The major polar lipids of strain CC-AFH3(T) were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylcholine. The predominant quinone was ubiquinone 8 (Q-8) and the DNA G+C content was 63.4 mol%. On the basis of 16S rRNA gene sequence analysis in combination with physiological and chemotaxonomic data, strain CC-AFH3(T) represents a novel species in a new genus, for which we propose the name Noviherbaspirillum malthae gen. nov., sp. nov.; the type strain of Noviherbaspirillum malthae is CC-AFH3(T) ( = BCRC 80516(T) = JCM 18414(T)). We also propose the reclassification of Herbaspirillum soli, Herbaspirillum aurantiacum, Herbaspirillum canariense and 'Herbaspirillum psychrotolerans' as Noviherbaspirillum soli comb. nov. (type strain SUEMI10(T) = LMG 26149(T) = CECT 7840(T)), Noviherbaspirillum aurantiacum comb. nov. (type strain SUEMI08(T) = LMG 26150(T) = CECT 7839(T)), Noviherbaspirillum canariense comb. nov. (type strain SUEMI03(T) = LMG 26151(T) = CECT 7838(T)) and Noviherbaspirillum psychrotolerans comb. nov. (type strain PB1(T) = DSM 26001(T) = LMG 27282(T)), respectively. An emended description of Herbaspirillum seropedicae is also presented. PMID- 23749277 TI - Geodermatophilus taihuensis sp. nov., isolated from the interfacial sediment of a eutrophic lake. AB - A novel actinobacterial strain, 3-wff-81(T), was isolated from interfacial sediment of the eutrophic Taihu Lake in Jiangsu Province (China) and subjected to polyphasic taxonomic characterization. The strain formed pale orange-pigmented colonies comprising rod-shaped cells on R2A agar. Phylogenetic analysis based on the 16S rRNA gene sequences showed that strain 3-wff-81(T) belonged to the genus Geodermatophilus, with Geodermatophilus soli PB34(T) (99.1 % similarity) and Geodermatophilus terrae PB261(T) (98.3 % similarity) as closest relatives. The major fatty acids were 16 : 0 iso, 15 : 0 iso, 17 : 1omega8c and 14 : 0 iso. The predominant menaquinones were MK-9(H4) and MK-9. Polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and phosphatidylinositol mannosides. The genomic DNA G+C content was 73.2 mol%. DNA DNA relatedness values with G. soli PB34(T) and G. terrae PB261(T) were 42.8 % and 39.6 %, respectively. Based on the physiological, biochemical and chemotaxonomic data, it is proposed that strain 3-wff-81(T) represents a novel species named Geodermatophilus taihuensis sp. nov. with 3-wff-81(T) ( = CGMCC 1.12303(T) = NBRC 109416(T)) as the type strain. PMID- 23749278 TI - Paraperlucidibaca wandonensis sp. nov., isolated from seawater, and emended description of the genus Paraperlucidibaca Oh et al. 2011. AB - A Gram-stain-negative, aerobic, motile and rod-shaped bacterial strain, designated WT-RY4(T), was isolated from wood falls in the South Sea, South Korea, and its taxonomic position was investigated using a polyphasic approach. Strain WT-RY4(T) grew optimally at 25 degrees C, at pH 7.0-7.5 and in the absence of NaCl. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences showed that strain WT-RY4(T) clustered with the type strain of Paraperlucidibaca baekdonensis with a bootstrap resampling value of 100 %. Strain WT-RY4(T) exhibited 16S rRNA gene sequence similarity values of 98.8 % and 96.3 % to Paraperlucidibaca baekdonensis RL-2(T) and Perlucidibaca piscinae IMCC 1704(T), respectively and less than 91.5 % to the type strains of other species used in the phylogenetic analysis. The DNA G+C content of strain WT-RY4(T) was 52.4 mol% and the mean DNA-DNA relatedness value with Paraperlucidibaca baekdonensis RL 2(T) was 25 %. Strain WT-RY4(T) contained Q-11 as the predominant ubiquinone and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), C16 : 0 and C12 : 0 3-OH as the major fatty acids. Differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, demonstrated that strain WT-RY4(T) was distinguishable from Paraperlucidibaca baekdonensis RL-2(T). On the basis of the data presented, strain WT-RY4(T) is considered to represent a novel species of the genus Paraperlucidibaca, for which the name Paraperlucidibaca wandonensis sp. nov. is proposed. The type strain is WT-RY4(T) ( = KCTC 32216(T) = CCUG 63419(T)). An emended description of the genus Paraperlucidibaca is also provided. PMID- 23749279 TI - Loktanella sediminilitoris sp. nov., isolated from tidal flat sediment. AB - A Gram-stain-negative, non-motile, rod-shaped bacterial strain, designated D1 W3(T), was isolated from tidal flat sediment of the South Sea, South Korea, and subjected to a taxonomic study using a polyphasic approach. Strain D1-W3(T) grew optimally at pH 7.0-8.0, at 25 degrees C and in the presence of 2 % (w/v) NaCl. Neighbour-joining phylogenetic analyses based on 16S rRNA gene sequences revealed that strain D1-W3(T) fell within the clade comprising species of the genus Loktanella, clustering with the type strains of Loktanella tamlensis, Loktanella rosea and Loktanella maricola, with which it exhibited the highest 16S rRNA gene sequence similarity values (98.1-98.2 %). The 16S rRNA gene sequence similarity values between strain D1-W3(T) and the type strains of other species of the genus Loktanella were in the range 93.5-96.5 %. The DNA G+C content of strain D1-W3(T) was 58.1 mol% and the mean DNA-DNA hybridization values with L. tamlensis KCTC 12722(T), L. rosea LMG 22534(T) and L. maricola DSW-18(T) were 13-25 %. Strain D1 W3(T) contained Q-10 as the predominant ubiquinone and C18 : 1omega7c as the predominant fatty acid. The major polar lipids were phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine and one unidentified aminolipid. Differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, showed that strain D1-W3(T) could be differentiated from other species of the genus Loktanella. On the basis of the data presented, strain D1 W3(T) represents a novel species of the genus Loktanella, for which the name Loktanella sediminilitoris sp. nov. is proposed. The type strain is D1-W3(T) ( = KCTC 32383(T) = CECT 8284(T)). PMID- 23749280 TI - Formosa undariae sp. nov., isolated from a reservoir containing the brown algae Undaria pinnatifida. AB - A strain of Gram-staining-negative, aerobic, non-flagellated, non-gliding and rod shaped bacteria, designated WS-MY3(T), was isolated from a brown algae reservoir in South Korea. Strain WS-MY3(T) grew optimally at 25 degrees C, at pH 7.0-8.0 and in the presence of 2.0-3.0 % (w/v) NaCl. Phylogenetic trees based on 16S rRNA gene sequences showed that strain WS-MY3(T) fell within the cluster comprising the type strains of species of the genus Formosa, clustering coherently with the type strains of Formosa agariphila and Formosa algae. It exhibited 16S rRNA gene sequence similarity values of 98.7, 97.9 and 96.8 % to the type strains of F. agariphila, F. algae and Formosa spongicola, respectively. Strain WS-MY3(T) contained MK-6 as the predominant menaquinone and iso-C15 : 0, iso-C16 : 0 3-OH, iso-C15 : 1 G and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) as the major fatty acids. The major polar lipids of strain WS-MY3(T) were phosphatidylethanolamine and two unidentified lipids. The DNA G+C content of strain WS-MY3(T) was 37.3 mol% and its DNA-DNA relatedness values with F. agariphila KCTC 12365(T) and F. algae KCTC 12364(T) were 23 % and 17 %, respectively. The phylogenetic and genetic distinctiveness and differential phenotypic properties revealed that strain WS-MY3(T) is separate from the three recognized species of the genus Formosa. On the basis of the data presented, strain WS-MY3(T) is considered to represent a novel species of the genus Formosa, for which the name Formosa undariae sp. nov. is proposed. The type strain is WS MY3(T) ( = KCTC 32328(T) = CECT 8286(T)). PMID- 23749281 TI - Imperialibacter roseus gen. nov., sp. nov., a novel bacterium of the family Flammeovirgaceae isolated from Permian groundwater. AB - A novel bacterial strain, designated P4(T), was isolated from Permian groundwater and identified on the basis of its phylogenetic, genotypic, chemotaxonomic and phenotypic characteristics. Cells were aerobic, Gram-stain-negative rods. 16S rRNA gene sequence-based phylogenetic analysis revealed that P4(T) is affiliated with the family Flammeovirgaceae in the phylum Bacteroidetes, but forms a distinct cluster within this family. The DNA G+C content of strain P4(T) was 45.2 mol%. The predominant cellular fatty acids were C16 : 1omega6c/C16 : 1omega7c and iso-C15 : 0. MK-7 was the main respiratory quinone. The polar lipids were phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, unidentified phospholipids, an unidentified aminolipid, unidentified glycolipids and unidentified polar lipids. Based on our extensive polyphasic analysis, a novel species in a new genus, Imperialibacter roseus gen. nov., sp. nov., is proposed. The type strain of Imperialibacter roseus is P4(T) ( = CICC 10659(T) = KCTC 32399(T)). PMID- 23749282 TI - Sulfurimonas gotlandica sp. nov., a chemoautotrophic and psychrotolerant epsilonproteobacterium isolated from a pelagic redoxcline, and an emended description of the genus Sulfurimonas. AB - A psychro- and aerotolerant bacterium was isolated from the sulfidic water of a pelagic redox zone of the central Baltic Sea. The slightly curved rod- or spiral shaped cells were motile by one polar flagellum or two bipolar flagella. Growth was chemolithoautotrophic, with nitrate or nitrite as electron acceptor and either a variety of sulfur species of different oxidation states or hydrogen as electron donor. Although the bacterium was able to utilize organic substances such as acetate, pyruvate, peptone and yeast extract for growth, these compounds yielded considerably lower cell numbers than obtained with reduced sulfur or hydrogen; in addition, bicarbonate supplementation was necessary. The cells also had an absolute requirement for NaCl. Optimal growth occurred at 15 degrees C and at pH 6.6-8.0. The predominant fatty acid of this organism was 16 : 1omega7c, with 3-OH 14 : 0, 16 : 0, 16 : 1omega5c+t and 18 : 1omega7c present in smaller amounts. The DNA G+C content was 33.6 mol%. As determined in 16S rRNA gene sequence phylogeny analysis, the isolate belongs to the genus Sulfurimonas, within the class Epsilonproteobacteria, with 93.7 to 94.2 % similarity to the other species of the genus Sulfurimonas, Sulfurimonas autotrophica, Sulfurimonas paralvinellae and Sulfurimonas denitrificans. However, the distinct physiological and genotypic differences from these previously described taxa support the description of a novel species, Sulfurimonas gotlandica sp. nov. The type strain is GD1(T) ( = DSM 19862(T) = JCM 16533(T)). Our results also justify an emended description of the genus Sulfurimonas. PMID- 23749283 TI - Natronobacterium texcoconense sp. nov., a haloalkaliphilic archaeon isolated from soil of a former lake. AB - A novel haloalkaliphilic archaeon, strain B23(T) was isolated from the former lake Texcoco in Mexico. The strain was Gram-stain-negative, the cells coccoid to ovoid rods, red pigmented and aerobic. Strain B23(T) grew in 1.7-4.3 M NaCl, at pH 6.5-9.5 and at 25-45 degrees C with optimal growth at 2.6-3.4 M NaCl, pH 7.5 8.5 and 37 degrees C. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain B23(T) was most closely related to Natronobacterium gregoryi SP2(T) with 97.3 % sequence similarity. The polar lipids of strain B23(T) were phosphatidylglycerol and several unidentified phospholipids. The G+C content of the DNA of the strain was 62.5 mol%. Levels of DNA-DNA relatedness between strain B23(T) and Natronobacterium gregoryi DSM 3393(T) was 32.3 %. The name Natronobacterium texcoconense sp. nov. is proposed. The type strain is B23(T) ( = CECT 8068(T) = JCM 17655(T)). PMID- 23749284 TI - Ogataea kolombanensis sp. nov., Ogataea histrianica sp. nov. and Ogataea deakii sp. nov., three novel yeast species from plant sources. AB - Nine methanol-assimilating yeast strains isolated from olive oil sediments in Slovenia, extra virgin olive oil from Italy and rotten wood collected in Hungary were found to form three genetically separated groups, distinct from the currently recognized yeast species. Sequence analysis from genes of the small subunit (SSU) rRNA, internal transcribed spacer region/5.8S rRNA, large subunit (LSU) rRNA D1/D2 domains and translational elongation factor-1alpha (EF-1alpha) revealed that the three closely related groups represent three different undescribed yeast species. Sequence analysis of the LSU rRNA gene D1/D2 domains placed the novel species in the Ogataea clade. The three novel species are designated as Ogataea kolombanensis sp. nov. (type strain: ZIM 2322(T) = CBS 12778(T) = NRRL Y-63657(T)), Ogataea histrianica sp. nov. (type strain: ZIM 2463(T) = CBS 12779(T) = NRRL Y-63658(T)) and Ogataea deakii sp. nov. (type strain: NCAIM Y.01896(T) = CBS 12735(T) = NRRL Y-63656(T)). PMID- 23749285 TI - Generation of free oligosaccharides from bacterial protein N-linked glycosylation systems. AB - All Campylobacter species are capable of N-glycosylating their proteins and releasing the same oligosaccharides into the periplasm as free oligosaccharides (fOS). Previously, analysis of fOS production in Campylobacter required fOS derivatization or large culture volumes and several chromatography steps prior to fOS analysis. In this study, label-free fOS extraction and purification methods were developed and coupled with quantitative analysis techniques. Our method follows three simple steps: (1) fOS extraction from the periplasmic space, (2) fOS purification using silica gel chromatography followed by porous graphitized carbon purification and (3) fOS analysis and accurate quantitation using a combination of thin-layer chromatography, mass spectrometry, NMR, and high performance anion exchange chromatography with pulsed amperometric detection. We applied our techniques to analyze fOS from C. jejuni, C. lari, C. rectus, and C. fetus fetus that produce different fOS structures. We accurately quantified fOS in Campylobacter species that ranged from 7.80 (+/-0.84) to 49.82 (+/-0.46) nmoles per gram of wet cell pellet and determined that the C. jejuni fOS comprises 2.5% of the dry cell weight. In addition, a novel di-phosphorylated fOS species was identified in C. lari. This method provides a sensitive and quantitative method to investigate the genesis, biology and breakdown of fOS in the bacterial N-glycosylation systems. PMID- 23749286 TI - Global initiatives to tackle organ trafficking and transplant tourism. AB - The increasing gap between organ supply and demand has opened the door for illegal organ sale, trafficking of human organs, tissues and cells, as well as transplant tourism. Currently, underprivileged and vulnerable populations in resource-poor countries are a major source of organs for rich patient-tourists who can afford to purchase organs at home or abroad. This paper presents a summary of international initiatives, such as World Health Organization's Principle Guidelines, The Declaration of Istanbul, Asian Task Force Recommendations, as well as UNESCO's and the United Nation's initiatives against trafficking of human organs, tissues, cells, and transplant tourism. Beyond the summary, it calls for more practical measures to be taken to implement the existing guidelines and recommendations, in order to prevent exploitation of the poor as organ providers. The paper suggests that an international legally binding agreement in criminalizing organ trafficking would be a step forward to bring a change in the global picture of organ trafficking and transplant tourism. PMID- 23749287 TI - Ablation depth and its effects on corneal biomechanical changes in laser in situ keratomileusis and epipolis laser in situ keratomileusis. AB - To assess the corneal biomechanical parameters prior to and following laser in situ keratomileusis (LASIK) and epipolis laser in situ keratomileusis (epi-LASIK) and evaluate the probable correlative factors. Corneal hysteresis (CH), corneal resistance factor (CRF) and other biomechanical metrics were measured and evaluated with an ocular response analyzer preoperatively and 1 month postoperatively. Compared with preoperative values, CH and CRF decreased significantly after surgery in both groups (P = 0.000). The LASIK group exhibited a positive correlation between ablation depth (AD) and ?CH/?CRF with a strong r value (r = 0.543, P = 0.000; r = 0.574, P = 0.000). In the epi-LASIK group, however, the correlation was much weaker (r = -0.090, P = 0.682; r = 0.093, P = 0.673), although there were no significant differences between LASIK and epi LASIK groups in postoperative CH (P = 0.730) and CRF (P = 0.736), and in the changes between CH (P = 0.539) and CRF (P = 0.881). Corneal biomechanical changes correlated with AD in LASIK but not in epi-LASIK, and it appeared that patients with identical demographics and similar attempted corrections are more likely to face a greater danger when undergoing LASIK than epi-LASIK. Therefore, the surface ablation procedure was recommended instead of lamellar ablation especially for correcting high myopia from a biomechanical viewpoint. PMID- 23749288 TI - Oral health considerations in HIV-infected children. AB - Children with the human immunodeficiency virus (HIV) have a higher probability of hard and soft oral tissue diseases because of their compromised immune systems and socioeconomic factors such as poor access to medical and dental care and limited availability of fluoridated water or toothpaste. To improve health outcomes and help monitor the progression of HIV, a preventive, child-specific oral health protocol for children with HIV that is easy to use and appropriate for all different resource settings should be established. Further, both medical and dental health practitioners should incorporate such a protocol into their care routine for HIV-infected children. Using proactive oral health risk assessments complemented by scheduled follow-up visits based on individual risk determination can prevent opportunistic infection, track the HIV disease trajectory, and monitor the effectiveness of highly active antiretroviral therapy (HAART) while improving the quality of life and longevity of children living with HIV. PMID- 23749289 TI - Baicalin improves chronic corticosterone-induced learning and memory deficits via the enhancement of impaired hippocampal brain-derived neurotrophic factor and cAMP response element-binding protein expression in the rat. AB - The purpose of this study was to examine whether baicalin (BAI) improves spatial cognitive impairments induced in rats following the repeated administration of the exogenous stress hormone corticosterone (CORT). The effect of BAI on the hippocampal expression of brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) was also investigated. For 21 days, male rats received daily doses of BAI (20, 50, and 100 mg/kg, i.p.) 1 h prior to a CORT (40 mg/kg) injection. The daily administration of BAI improved memory impairment as measured by the passive avoidance test and reduced the escape latency for finding the platform in the Morris water maze test. Additionally, as assessed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis, the administration of BAI also significantly alleviated memory-associated decreases in the expression levels of BDNF and CREB proteins and mRNAs in the hippocampus. These results demonstrate that the administration of BAI prior to high-dose exogenous CORT results in significant neuroprotective activity against neuronal impairment and memory dysfunction in rats. Thus, these findings suggest that BAI might be useful as a therapeutic agent in various neurodegenerative diseases for the improvement of cognitive function. This likely occurs through the regulation of BDNF and CREB expression. PMID- 23749290 TI - Adenosine A2A receptor (A2AR) is a fine-tune regulator of the collagen1:collagen3 balance. AB - Adenosine is a potent endogenous anti-inflammatory and immunosuppressive metabolite that is a potent modulator of tissue repair. However, the adenosine A2A receptor (A2AR)-mediated promotion of collagen synthesis is detrimental in settings such as scarring and scleroderma. The signaling cascade from A2AR stimulation to increased collagen production is complex and obscure, not least because cAMP and its downstream molecules PKA and Epac1 have been reported to inhibit collagen production. We therefore examined A2AR-stimulated signaling for collagen production by normal human dermal fibroblasts (NHDF). Collagen1 (Col1) and collagen3 (Col3) content after A2AR activation by CGS21680 was studied by western blotting. Contribution of PKA and Epac was analyzed by the PKA inhibitor PKI and by knockdowns of the PKA-Calpha, -Cbeta, -Cgamma, Epac1, and Epac2. CGS21680 stimulates Col1 expression at significantly lower concentrations than those required to stimulate Col3 expression. A2AR stimulates Col1 expression by a PKA-dependent mechanism since PKA inhibition or PKA-Calpha and -Cbeta knockdown prevents A2AR-mediated Col1 increase. In contrast, A2AR represses Col3 via PKA but stimulates both Col1 and Col3 via an Epac2-dependent mechanism. A2AR stimulation with CGS21680 at 0.1 MUM increased Col3 expression only upon PKA blockade. A2AR activation downstream signaling for Col1 and Col3 expression proceeds via two distinct pathways with varying sensitivity to cAMP activation; more highly cAMP-sensitive PKA activation stimulates Col1 expression, and less cAMP-sensitive Epac activation promotes both Col1 and Col3 expression. These observations may explain the dramatic change in Col1:Col3 ratio in hypertrophic and immature scars, where adenosine is present in higher concentrations than in normal skin. PMID- 23749292 TI - Can online benchmarking increase rates of thrombolysis? Data from the Austrian stroke unit registry. AB - Despite its widespread availability and known safety and efficacy, a therapy with intravenous thrombolysis is still undergiven. We aimed to identify whether nationwide quality projects--like the stroke registry in Austria--as well as online benchmarking and predefined target values can increase rates of thrombolysis. Therefore, we assessed 6,394 out of 48,462 patients with ischemic stroke from the Austrian stroke registry (study period from March 2003 to December 2011) who had undergone thrombolysis treatment. We defined lower level and target values as quality parameters and evaluated whether or not these parameters could be achieved in the past years. We were able to show that rates of thrombolysis in Austria increased from 4.9% in 2003 to 18.3% in 2011. In a multivariate regression model, the main impact seen was the increase over the years [the OR ranges from 0.47 (95% CI 0.32-0.68) in 2003 to 2.51 (95% CI 2.20 2.87) in 2011). The predefined lower and target levels of thrombolysis were achieved at the majority of participating centers: in 2011 the lower value of 5% was achieved at all stroke units, and the target value of 15% was observed at 21 of 34 stroke units. We conclude that online benchmarking and the concept of defining target values as a tool for nationwide acute stroke care appeared to result in an increase in the rate of thrombolysis over the last few years while the variability between the stroke units has not yet been reduced. PMID- 23749293 TI - Clinical efficacy of BG-12 (dimethyl fumarate) in patients with relapsing remitting multiple sclerosis: subgroup analyses of the CONFIRM study. AB - In the phase 3, randomized, placebo-controlled and active reference (glatiramer acetate) comparator CONFIRM study in patients with relapsing-remitting multiple sclerosis, oral BG-12 (dimethyl fumarate) reduced the annualized relapse rate (ARR; primary endpoint), as well as the proportion of patients relapsed, magnetic resonance imaging lesion activity, and confirmed disability progression, compared with placebo. We investigated the clinical efficacy of BG-12 240 mg twice daily (BID) and three times daily (TID) in patient subgroups stratified according to baseline demographic and disease characteristics including gender, age, relapse history, McDonald criteria, treatment history, Expanded Disability Status Scale score, T2 lesion volume, and gadolinium-enhancing lesions. BG-12 treatment demonstrated generally consistent benefits on relapse-related outcomes across patient subgroups, reflecting the positive findings in the overall CONFIRM study population. Treatment with BG-12 BID and TID reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in all subgroups analyzed. Reductions in ARR with BG-12 BID versus placebo ranged from 34% [rate ratio 0.664 (95% confidence interval 0.422-1.043)] to 53% [0.466 (0.313-0.694)] and from 13% [0.870 (0.551-1.373)] to 67% [0.334 (0.226-0.493)] with BG-12 TID versus placebo. Treatment with glatiramer acetate reduced the ARR and the proportion of patients relapsed at 2 years compared with placebo in most patient subgroups. The results of these analyses indicate that treatment with BG-12 is effective on relapses across a broad range of patients with relapsing-remitting multiple sclerosis with varied demographic and disease characteristics. PMID- 23749294 TI - Swiss national guideline for reimbursement of enzyme replacement therapy in late onset Pompe disease. AB - Glycogen storage disease type II is a rare multi-systemic disorder characterised by an intracellular accumulation of glycogen due a mutation in the acid alpha glucosidase (GAA) gene. The level of residual enzyme activity, the genotype and other yet unknown factors account for the broad variation of the clinical phenotype. The classical infantile form is characterised by severe muscle hypotonia and cardiomyopathy leading to early death. The late-onset form presents as a limb girdle myopathy with or without pulmonary dysfunction. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) in infants is life saving. In contrast, therapeutic efficacy of rhGAA in the late-onset form is modest. High expenses of rhGAA, on-going infusions and poor pharmacokinetic efficacy raised a discussion of the cost effectiveness of ERT in late-onset Pompe disease in Switzerland. This discussion was triggered by a Swiss federal court ruling which confirmed the reluctance of a health care insurer not to reimburse treatment costs in a 67-year-old female suffering from Pompe disease. As a consequence of this judgement ERT was stopped by all insurance companies in late onset Pompe patients in Switzerland regardless of their clinical condition. Subsequent negotiations lead to the release of a national guideline of the management of late-onset Pompe disease. Initiation and limitation of ERT is outlined in a national Pompe registry. Reimbursement criteria are defined and individual efficacy of ERT with rhGAA is continuously monitored. PMID- 23749295 TI - Changes in regulatory T cells after rituximab in two patients with refractory myasthenia gravis. PMID- 23749296 TI - Asthma and antibodies to pneumococcal virulence proteins. AB - PURPOSE: We previously reported that asthmatics had lower anti-serotype-specific pneumococcal polysaccharide antibody levels than non-asthmatics, and the T-helper 2 (Th2) immune profile was associated with suboptimal pneumococcal polysaccharide antibody. Our objective was to determine the influence of asthma status on anti pneumococcal protein antigen antibody levels. METHODS: We conducted a cross sectional study, which enrolled 16 children and adults with asthma and 14 subjects without asthma. Asthma was ascertained by predetermined criteria. Serum IgG antibody levels to pneumococcal surface protein A (PspA), pneumococcal surface protein C (PspC), pneumococcal choline-binding protein A (PcpA), and pneumolysin (PLY) were measured by enzyme-linked immunosorbent assays (ELISA). These antibody levels were compared between asthmatics and non-asthmatics. The Th2 immune profile was determined by IL-5 secretion from PBMCs cultured with house dust mite (HDM) and staphylococcal enterotoxin B (SEB) at day 7. The correlation between the anti-pneumococcal antibody levels and the Th2-HDM and SEB responsive immune profile was assessed. RESULTS: Of the 30 subjects, 16 (53%) were male and the median age was 26 years. There were no significant differences in anti-PspA, anti-PspC, anti-PcpA, and anti-PLY antibody levels between asthmatics and non-asthmatics. The Th2 immune profile was inversely correlated with the anti-PspC antibody levels (r = -0.53, p = 0.003). This correlation was significantly modified by asthma status (r = -0.74, p = 0.001 for asthmatics vs. r = -0.06, p = 0.83 for non-asthmatics). Other pneumococcal protein antibodies were not correlated with the Th2 immune profile. CONCLUSION: No significant differences in the anti-pneumococcal protein antigen antibody levels between asthmatics and non-asthmatics were found. Asthma status is an important effect modifier determining the negative influence of the Th2 immune profile on anti PspC antibody levels. PMID- 23749297 TI - bFGF and JAGGED1 regulate alkaline phosphatase expression and mineralization in dental tissue-derived mesenchymal stem cells. AB - Basic fibroblast growth factor (bFGF) and Notch signaling play critical roles in various cell behaviors. Here, we investigated the influence of bFGF and Notch signaling in alkaline phosphatase (ALP) expression and mineralization process in human periodontal ligament-derived mesenchymal stem cells (PDLSCs) and stem cells isolated from human exfoliated deciduous teeth (SHEDs). PDLSCs and SHEDs were cultured in osteogenic medium supplemented with bFGF or on the immobilized Notch ligands, JAGGED1. The ALP mRNA and protein expression were measured by quantitative reverse transcriptase polymerase chain reaction and enzymatic activity assay, respectively. Mineral deposition was determined using alizarin red S staining. The results showed that the addition of bFGF resulted in the decrease of ALP mRNA expression and enzymatic activity. In addition, the attenuation of mineralization was noted. These phenomenons were blocked by the addition of a fibroblast growth factor receptor inhibitor (SU5402) or a MEK inhibitor (PD98059). Interestingly, bFGF supplementation also decreased the Notch signaling component mRNA levels. Thus, to evaluate effect of Notch signaling in mineralization process, PDLSCs and SHEDs were exposed to JAGGED1 modified surface. The ALP mRNA and protein expression were significantly upregulated and the mineral deposition was markedly increased. These results could be reversed by the addition of a gamma-secretase inhibitor. In addition, bFGF could attenuate the Notch-signaling-induced mineralization in both PDLSCs and SHEDs. These results suggest that mineralization was enhanced by Notch signaling but attenuated by bFGF signaling. This knowledge can be further utilized to control PDLSCs and SHEDs mineralization for tissue regeneration purpose. PMID- 23749298 TI - Whole-rat conditional gene knockout via genome editing. AB - Animal models with genetic modifications under temporal and/or spatial control are invaluable to functional genomics and medical research. Here we report the generation of tissue-specific knockout rats via microinjection of zinc-finger nucleases (ZFNs) into fertilized eggs. We generated rats with loxP-flanked (floxed) alleles and a tyrosine hydroxylase promoter-driven cre allele and demonstrated Cre-dependent gene disruption in vivo. Pronuclear microinjection of ZFNs, shown by our data to be an efficient and rapid method for creating conditional knockout rats, should also be applicable in other species. PMID- 23749299 TI - Hematopoietic progenitor cell lines with myeloid and lymphoid potential. AB - Investigation of immune-cell differentiation and function is limited by shortcomings of suitable and scalable experimental systems. Here we show that retroviral delivery of an estrogen-regulated form of Hoxb8 into mouse bone marrow cells can be used along with Flt3 ligand to conditionally immortalize early hematopoietic progenitor cells (Hoxb8-FL cells). Hoxb8-FL cells have lost self renewal capacity and potential to differentiate into megakaryocytes and erythrocytes but retain the potential to differentiate into myeloid and lymphoid cells. They differentiate in vitro and in vivo into macrophages, granulocytes, dendritic cells, B lymphocytes and T lymphocytes that are phenotypically and functionally indistinguishable from their primary counterparts. Quantitative in vitro assays indicate that myeloid and B-cell potential of Hoxb8-FL cells is comparable to that of primary lymphoid-primed multipotent progenitors, whereas T cell potential is diminished. The simplicity of this system and the unlimited proliferative capacity of Hoxb8-FL cells will enable studies of immune-cell differentiation and function. PMID- 23749300 TI - OpenSpinMicroscopy: an open-source integrated microscopy platform. PMID- 23749301 TI - Global analysis of phosphorylation and ubiquitylation cross-talk in protein degradation. AB - Cross-talk between different types of post-translational modifications on the same protein molecule adds specificity and combinatorial logic to signal processing, but it has not been characterized on a large-scale basis. We developed two methods to identify protein isoforms that are both phosphorylated and ubiquitylated in the yeast Saccharomyces cerevisiae, identifying 466 proteins with 2,100 phosphorylation sites co-occurring with 2,189 ubiquitylation sites. We applied these methods quantitatively to identify phosphorylation sites that regulate protein degradation via the ubiquitin-proteasome system. Our results demonstrate that distinct phosphorylation sites are often used in conjunction with ubiquitylation and that these sites are more highly conserved than the entire set of phosphorylation sites. Finally, we investigated how the phosphorylation machinery can be regulated by ubiquitylation. We found evidence for novel regulatory mechanisms of kinases and 14-3-3 scaffold proteins via proteasome-independent ubiquitylation. PMID- 23749302 TI - Integrated proteomic analysis of post-translational modifications by serial enrichment. AB - We report a mass spectrometry-based method for the integrated analysis of protein expression, phosphorylation, ubiquitination and acetylation by serial enrichments of different post-translational modifications (SEPTM) from the same biological sample. This technology enabled quantitative analysis of nearly 8,000 proteins and more than 20,000 phosphorylation, 15,000 ubiquitination and 3,000 acetylation sites per experiment, generating a holistic view of cellular signal transduction pathways as exemplified by analysis of bortezomib-treated human leukemia cells. PMID- 23749303 TI - Simultaneous DNA amplification and detection using a pH-sensing semiconductor system. AB - We developed an integrated chip for real-time amplification and detection of nucleic acid using pH-sensing complementary metal-oxide semiconductor (CMOS) technology. Here we show an amplification-coupled detection method for directly measuring released hydrogen ions during nucleotide incorporation rather than relying on indirect measurements such as fluorescent dyes. This is a label-free, non-optical, real-time method for detecting and quantifying target sequences by monitoring pH signatures of native amplification chemistries. The chip has ion sensitive field effect transistor (ISFET) sensors, temperature sensors, resistive heating, signal processing and control circuitry all integrated to create a full system-on-chip platform. We evaluated the platform using two amplification strategies: PCR and isothermal amplification. Using this platform, we genotyped and discriminated unique single-nucleotide polymorphism (SNP) variants of the cytochrome P450 family from crude human saliva. We anticipate this semiconductor technology will enable the creation of devices for cost-effective, portable and scalable real-time nucleic acid analysis. PMID- 23749304 TI - OpenSPIM: an open-access light-sheet microscopy platform. PMID- 23749305 TI - Novel bis(fluorenyl)benzothiadiazole-cored carbazole dendrimers as highly efficient solution-processed non-doped green emitters for organic light-emitting diodes. AB - Bis(fluorenyl)benzothiadiazole-cored carbazole dendrimers show high thermal and electrochemical stability, and great potential as solution processed hole transporting non-doped green emitters for OLEDs. A pure green device with CIE coordinates of (0.27, 0.62) and high luminance efficiencies (up to 10.01 cd A( 1)) is achieved, respectively. PMID- 23749306 TI - Sensory neuroanatomy of stick insects highlights the evolutionary diversity of the orthopteroid subgenual organ complex. AB - The subgenual organ is a scolopidial sense organ located in the tibia of many insects. In this study the neuroanatomy of the subgenual organ complex of stick insects is clarified for two species, Carausius morosus and Siyploidea sipylus. Neuronal tracing shows a subgenual organ complex that consists of a subgenual organ and a distal organ. There are no differences in neuroanatomy between the three thoracic leg pairs, and the sensory structures are highly similar in both species. A comparison of the neuroanatomy with other orthopteroid insects highlights two features unique in Phasmatodea. The subgenual organ contains a set of densely arranged sensory neurons in the anterior-ventral part of the organ, and a distal organ with 16-17 scolopidial sensilla in C. morosus and 20-22 scolopidial sensilla in S. sipylus. The somata of sensory neurons in the distal organ are organized in a linear array extending distally into the tibia, with only a few exceptions of closely associated neurons. The stick insect sense organs show a case of an elaborate scolopidial sense organ that evolved in addition to the subgenual organ. The neuroanatomy of stick insects is compared to that studied in other orthopteroid taxa (cockroaches, locusts, crickets, tettigoniids). The comparison of sensory structures indicates that elaborate scolopidial organs have evolved repeatedly among orthopteroids. The distal organ in stick insects has the highest number of sensory neurons known for distal organs so far. PMID- 23749308 TI - Deep brain stimulation, brain maps and personalized medicine: lessons from the human genome project. AB - Although the appellation of personalized medicine is generally attributed to advanced therapeutics in molecular medicine, deep brain stimulation (DBS) can also be so categorized. Like its medical counterpart, DBS is a highly personalized intervention that needs to be tailored to a patient's individual anatomy. And because of this, DBS like more conventional personalized medicine, can be highly specific where the object of care is an N = 1. But that is where the similarities end. Besides their differing medical and surgical provenances, these two varieties of personalized medicine have had strikingly different impacts. The molecular variant, though of a more recent vintage has thrived and is experiencing explosive growth, while DBS still struggles to find a sustainable therapeutic niche. Despite its promise, and success as a vetted treatment for drug resistant Parkinson's Disease, DBS has lagged in broadening its development, often encountering regulatory hurdles and financial barriers necessary to mount an adequate number of quality trials. In this paper we will consider why DBS-or better yet neuromodulation-has encountered these challenges and contrast this experience with the more successful advance of personalized medicine. We will suggest that personalized medicine and DBS's differential performance can be explained as a matter of timing and complexity. We believe that DBS has struggled because it has been a journey of scientific exploration conducted without a map. In contrast to molecular personalized medicine which followed the mapping of the human genome and the Human Genome Project, DBS preceded plans for the mapping of the human brain. We believe that this sequence has given personalized medicine a distinct advantage and that the fullest potential of DBS will be realized both as a cartographical or electrophysiological probe and as a modality of personalized medicine. PMID- 23749307 TI - Prognostic factors for teenage and adult patients with high-grade osteosarcoma: an analysis of 240 patients. AB - The aim of this retrospective, multicenter study was to evaluate clinicopathological characteristics, prognostic factors and treatment outcomes of teenage and adult patients with high-grade osteosarcoma. A total of 240 osteosarcoma patients who were diagnosed and treated from March 1995 to September 2011 were analyzed. Median age was 20 years (range 13-74 years), and 153 patients (63.8%) were male. Primary tumor localization was extremity in 204 patients (85.4 %), trunk in 21 patients (8.8%) and head and neck region in 14 patients (5.9%). According to American Joint Committee on Cancer staging system, 186 patients (77.5%) were stage II, 3 (1.3%) were stage III and 48 (20.0%) were stage IV. Median overall survival (OS) was 55 months (95 % CI 36.8-73.1 months). OS after 2, 5 and 10 years were 67, 49 and 42%, respectively. Univariable analysis for OS showed that male gender (p = 0.032), high baseline lactate dehydrogenase (LDH) level (p < 0.001), high baseline serum alkaline phosphatase level (p = 0.002), telangiectatic subtype (p = 0.023), presence of metastasis at diagnosis (p < 0.001), presence of tumor positive margins after primary surgery (p = 0.015), poor pathological response to preoperative chemotherapy (p = 0.006) and presence of recurrent disease during follow-up period (p < 0.001) were significantly associated with poor survival. Patients who received postoperative methotrexate plus doxorubicin plus cisplatin (M + A + P) combination regimen (p = 0.019), underwent surgery for recurrent disease (p < 0.001) and received chemotherapy for recurrent disease (p < 0.001) had longer OS. In multivariable analysis for OS, only high LDH level (p = 0.002) and the presence of metastasis at diagnosis (p = 0.011) were associated with poor OS, whereas the patients who received chemotherapy for recurrent disease had a longer OS (p = 0.009). PMID- 23749309 TI - Verbal fluency in adults diagnosed with attention-deficit hyperactivity disorder (ADHD) in childhood. AB - It has been increasingly believed that attention-deficit hyperactivity disorder (ADHD) is a disorder with lifelong course associated with cognitive difficulties including among others, language production, verbal learning, and verbal fluency. However, research is limited to children and adolescents, and very few researchers have examined the impact of ADHD in adulthood on the cognitive domain. The aim of the present study is to examine the performance of adults, diagnosed with ADHD in childhood, on semantic and phonemic verbal fluency tasks. It is hypothesized that adults with ADHD will perform worse on both tasks than matched controls. Sixty university students (30 diagnosed with ADHD in childhood and 30 matched controls) of mean age 20.5 participated in the study. They all completed two verbal fluency tasks. The ADHD group had statistically significant lower scores than the non-ADHD group on the phonemic, but not the semantic task. The study provides some evidence that ADHD in childhood has a negative impact on adults' phonemic verbal fluency. This finding could be probably explained by the fact that phonemic fluency is considered more cognitively demanding and impacting more on the frontal lobe functions, known to be impaired in ADHD, than semantic fluency. PMID- 23749310 TI - [Soft tissue healing in infected arthroplasty]. AB - OBJECTIVE: Soft-tissue defect coverage with well vascularized tissue (musculocutaneous or fasciocutaneous) in the arthroplasty setting. Where arthroplasty has been removed due to infection, as a muscle flap to close infected cavities. INDICATIONS: Soft tissue defects, wound-edge necrosis in arthroplasty, and persistent infection in Girdlestone patients. CONTRAINDICATIONS: Moribund patients. SURGICAL TECHNIQUE: Pedicled flap: as far as possible, lift the flap as an island flap to increase coverage. Then suture the flap into the defect (split skin graft where appropriate). Free flap: lift the flap and prepare a vascular pedicle for anastomosis. Suture the flap into the site and create arterial and vascular micro-anastomoses (split skin graft where appropriate). POSTOPERATIVE MANAGEMENT: Position the extremity according to the flap type used. Use 500 ml HES (hydroxyethyl starch) 6% for 5 days. Avoid compression of the pedicle or anastomosis area. Flaps are generally autonomous after 3 weeks. RESULTS: The survival rate for both flap types, free and pedicled, is >90%. The flap survival rate should not be confused with the healing rate for infected arthroplasty. PMID- 23749311 TI - [Stage-dependent arthroscopic treatment of knee joint infections]. AB - OBJECTIVE: The goal is early diagnostic arthroscopy with irrigation and, if needed, debridement of all 6 recesses of the infected knee joint to quickly gain control of the infection and a satisfactory functional outcome. INDICATIONS: Arthroscopic irrigation without delay is indicated even if a knee joint infection is only suspected. CONTRAINDICATIONS: No existing contraindications. SURGICAL TECHNIQUE: Arthroscopic irrigation of the knee with stage-related debridement. Particularly irrigation and debridement of the two dorsal recesses. In stage IV according to Gachter, open synovectomy and radical debridement is recommended. POSTOPERATIVE MANAGEMENT: In case of persistent infection, early revision. After removement of drainages mobilisation with continous passive motion. Antibiotic therapy is necessary even after the infection has been treated. RESULTS: Arthroscopic irrigation with stage-related debridment of all 6 recesses in combination with antibiotic therapy is the standard procedure for knee joint infections when there is no arthroplasty. Open surgery with debridement of infected bone tissue is indicated in patients with stage IV according to Gachter. Decisive for good results is an early intervention. PMID- 23749312 TI - [Infections in trauma and orthopedic surgery]. PMID- 23749313 TI - Preparative thin-layer chromatographic separation followed by identification of antifungal compound in Cassia laevigata by RP-HPLC and GC-MS. AB - BACKGROUND: Several species of the genus Cassia are known for their antioxidant, antimicrobial and antidiabetic activities, but some of the lesser-known Cassia species, e.g. C. renigera, C. biflora and C. laevigata have not been studied for their biological activities. RESULTS: Methanol extract of C. laevigata was fractionated by preparative thin-layer chromatography. The resulting six different fractions were tested against Fusarium oxysporum and Aspergillus niger for their antifungal activity. Due to higher antifungal activity of fraction 1 of C. laevigata, this was further analyzed by reversed-phase high-performance liquid chromatography (RP-HPLC), resulting in distinct separation of one compound at a retention time of 7.2 min with an absorbance of 252 nm. Further, this compound was analyzed by gas chromatography-mass spectrometry (GC-MS) for its putative structural identification. Mass spectra of this compound resembled the spectra of anthraquinone 1-carboxylic acid by NIST library search. The genomic-level expression of chalcone synthase, a key enzyme involved in the biosynthesis of polyketides, was increased in C. laevigata when compared to other Cassia species. CONCLUSIONS: This study provides an insight into the higher antifungal activity of C. laevigata, including the identification of anthraquinone 1-carboxylic acid, which may be responsible for the antifungal activity. PMID- 23749314 TI - Imagining the future: evidence for a hippocampal contribution to constructive processing. AB - Imagining future events and remembering past events rely on a common core network, but several regions within this network--including the hippocampus--show increased activity for imagining future events compared to remembering past events. It remains unclear whether this hippocampal activity reflects processes related to the demands of constructing details retrieved across disparate episodic memories into coherent imaginary events, encoding these events into memory, novelty detection, or some combination of these processes. We manipulated the degree of constructive processing by comparing activity associated with the initial construction of an imagined scenario with the re-construction of an imagined scenario (imagine vs. re-imagine). After accounting for effects of novelty and subsequent memory, we found that a region in the hippocampus was preferentially activated for newly constructed imagined events compared with re imagined events. Our results suggest that the hippocampus may support several distinct but related processes that are critical for imagining future events, and they also indicate that a particular region within posterior hippocampus may uniquely contribute to the construction of imagined future events. PMID- 23749315 TI - Prospective and randomized comparison of electrical stimulation of the posterior tibial nerve versus oxybutynin versus their combination for treatment of women with overactive bladder syndrome. AB - OBJECTIVE: To verify whether the combination of transcutaneous electrical neural stimulation (TENS) with oxybutynin in the treatment of women with overactive bladder (OAB) would be more effective than isolated treatments. METHODS: We randomized 75 women with OAB, in three groups: GI--30 min TENS, twice a week; GII -daily slow release 10 mg oxybutynin; and GIII--TENS + oxybutynin (multimodal); all for 12 weeks. Patients were evaluated with validated questionnaires International Consultation on Incontinence-Short Form (ICIQ-SF), International Consultation on Incontinence-OAB (ICIQ-OAB), Symptom bother, and 3-day Voiding diary at weeks 0, 12, and 24. RESULTS: The groups were similar before treatment. After treatment, all groups significantly improved in OAB symptoms and quality of life (QoL). At week 12, ICIQ-OAB scores were 5.9, 4.6, and 2.9, in groups I, II, and III, respectively, p = 0.01. At week 24, GI and GIII kept the scores of the end of treatment (week 12), while GII increased ICIQ-OAB from 4.6 to 9.2, p = 0.0001, ICIQ-SF from 9.8 to 13.3, p = 0.0006, and Symptom bother score from 3.4 to 7.0, p = 0.0001. CONCLUSIONS: The multimodal treatment was more effective and TENS alone or in association presented longer lasting results for improvement of clinical symptoms of OAB and QoL. PMID- 23749316 TI - Robotic-assisted hepatic resection: a systematic review. AB - BACKGROUND: Currently, hepatic resections are being performed with robotic assisted systems. There is little evidence regarding the outcomes of this surgical approach. This study aims to systematically review the outcomes related to robotic-assisted hepatic resections. METHODS: A systematic search of electronic databases was completed. All human studies, limited to adults, published between 2000 to August 2011 were included. RESULTS: Eight studies yielded a total of 170 procedures. The overall morbidity rate was 11.6% (range 0 39%). There were no mortalities reported following robotic-assisted hepatic resection. Mean operative time was 264.8 minutes, with a mean hospital length of stay of 7.8 days. Rate of conversion was 6.6%. Cost was greater than either laparoscopy or open hepatic surgery. CONCLUSIONS: Our systematic review suggests robotic-assisted hepatic resection is safe and feasible, with low mortality and morbidity rates. Further research is needed to determine if oncological outcomes are similar. PMID- 23749317 TI - Gender differences in hypertension: myths and reality. AB - Life expectancy is longer in women compared to men, and cardiovascular events occur at a lower rate and at a later age in females than males. The impact of gender on the prevalence, the presentation, and the long-term outcome of cardiovascular disease has long been a topic of active research. Gender differences have been found in several studies but opposite findings also exist. The impact of gender in hypertension and antihypertensive therapy remains poorly clarified. The prevalence, awareness, treatment, and control rates of hypertension exhibit some differences between the two sexes, which are age dependent. The female advantage in the cardiovascular risk of hypertensive patients might be attenuated by comorbidities and target organ damage. Another aspect of major clinical importance is whether gender differences exist on the effects of antihypertensive agents in blood pressure reduction and cardiovascular morbidity and mortality. The aim of this review is to critically evaluate recent data regarding gender differences in hypertension and incorporate new data into the body of existing knowledge. PMID- 23749318 TI - Complete numerical solution of the diffusion equation of random genetic drift. AB - A numerical method is presented to solve the diffusion equation for the random genetic drift that occurs at a single unlinked locus with two alleles. The method was designed to conserve probability, and the resulting numerical solution represents a probability distribution whose total probability is unity. We describe solutions of the diffusion equation whose total probability is unity as complete. Thus the numerical method introduced in this work produces complete solutions, and such solutions have the property that whenever fixation and loss can occur, they are automatically included within the solution. This feature demonstrates that the diffusion approximation can describe not only internal allele frequencies, but also the boundary frequencies zero and one. The numerical approach presented here constitutes a single inclusive framework from which to perform calculations for random genetic drift. It has a straightforward implementation, allowing it to be applied to a wide variety of problems, including those with time-dependent parameters, such as changing population sizes. As tests and illustrations of the numerical method, it is used to determine: (i) the probability density and time-dependent probability of fixation for a neutral locus in a population of constant size; (ii) the probability of fixation in the presence of selection; and (iii) the probability of fixation in the presence of selection and demographic change, the latter in the form of a changing population size. PMID- 23749320 TI - Ion-transfer electrochemistry of rat amylin at the water-organogel microinterface array and its selective detection in a protein mixture. AB - The behavior of proteins and polypeptides at electrified aqueous-organic interfaces is of benefit in label-free detection strategies. In this work, rat amylin (or islet amyloid polypeptide) was studied at the interface formed between aqueous liquid and gelled organic phases. Amylin is a polypeptide that is co secreted with insulin from islet beta-cells and is implicated in fibril formation. In this study, rat amylin was used, which does not undergo aggregation. The polypeptide underwent an interfacial transfer process, from water to the gelled organic phase, under applied potential stimulation. Cyclic voltammetry revealed steady-state forward and peak-shaped reverse voltammograms, which were consistent with diffusion-controlled water-to-organic transfer and thin-film stripping or desorptive back-transfer. The diffusion-controlled forward current was greater when amylin was present in an acidic aqueous phase than when it was present in an aqueous phase at physiological pH; this reflects the greater charge on the polypeptide under acidic conditions. The amylin transfer current was concentration dependent over the range 2-10 MUM, at both acidic and physiological pH. At physiological pH, amylin was selectively detected in the presence of a protein mixture, which illustrated the bioanalytical possibilities for this electrochemical behavior. PMID- 23749319 TI - Probing the boundaries of orthology: the unanticipated rapid evolution of Drosophila centrosomin. AB - The rapid evolution of essential developmental genes and their protein products is both intriguing and problematic. The rapid evolution of gene products with simple protein folds and a lack of well-characterized functional domains typically result in a low discovery rate of orthologous genes. Additionally, in the absence of orthologs it is difficult to study the processes and mechanisms underlying rapid evolution. In this study, we have investigated the rapid evolution of centrosomin (cnn), an essential gene encoding centrosomal protein isoforms required during syncytial development in Drosophila melanogaster. Until recently the rapid divergence of cnn made identification of orthologs difficult and questionable because Cnn violates many of the assumptions underlying models for protein evolution. To overcome these limitations, we have identified a group of insect orthologs and present conserved features likely to be required for the functions attributed to cnn in D. melanogaster. We also show that the rapid divergence of Cnn isoforms is apparently due to frequent coding sequence indels and an accelerated rate of intronic additions and eliminations. These changes appear to be buffered by multi-exon and multi-reading frame maximum potential ORFs, simple protein folds, and the splicing machinery. These buffering features also occur in other genes in Drosophila and may help prevent potentially deleterious mutations due to indels in genes with large coding exons and exon dense regions separated by small introns. This work promises to be useful for future investigations of cnn and potentially other rapidly evolving genes and proteins. PMID- 23749321 TI - T-helper I immunity, specific for the breast cancer antigen insulin-like growth factor-I receptor (IGF-IR), is associated with increased adiposity. AB - Numerous lines of evidence demonstrate that breast cancer is immunogenic; yet, there are few biologically relevant immune targets under investigation restricting the exploration of vaccines to limited breast cancer subtypes. Insulin-like growth factor-I receptor (IGF-IR) is a promising vaccine candidate since it is overexpressed in most breast cancer subtypes, is part of a dominant cancer growth pathway, and has been validated as a therapeutic target. We questioned whether IGF-IR was immunogenic in cancer patients. IGF-IR-specific IgG antibodies were significantly elevated in early-stage breast cancer patients at the time of diagnosis as compared to volunteer donors (p = 0.04). Predicted T helper epitopes, derived from the IGF-IR extracellular and transmembrane domains, elicited a significantly higher incidence of Th2 immunity in breast cancer patients as compared to controls (p = 0.01). Moreover, the magnitude of Th2 immunity was greater in breast cancer patients compared to controls (p = 0.02). In contrast, both breast cancer patients and volunteer donors demonstrated a similar incidence of Th1 immunity to IGF-IR domains with the predominant response directed against epitopes in the intracellular domain of the protein. As the incidence of IGF-IR type I immunity was not associated with a breast cancer diagnosis, we questioned whether other factors were contributing to the presence of IGF-IR-specific T-cells in both populations. While age was not associated with Th1 immunity, we observed a significantly greater magnitude of IGF-IR IFN-gamma secreting T-cells in obese subjects as compared to overweight (p < 0.001) or healthy-weight (p = 0.006) subjects, regardless of breast cancer diagnosis. No significant difference was observed for Th2 incidence or magnitude when stratified by age (p = 0.174, p = 0.966, respectively) or body mass index (p = 0.137, p = 0.174, respectively). Our data demonstrate that IGF-IR is a tumor antigen and IGF-IR-specific Th1 immunity may be associated with obesity rather than malignancy. PMID- 23749322 TI - Endocarditis caused by resistant enterococcus: an overview. AB - Enteroccocal infective endocarditis is a major challenge to clinicians. There are an increasing number of reports of nosocomial acquisition and multidrug-resistant strains complicating management. The therapy of choice for enterococcal endocarditis remains ampicillin and gentamicin; however, high levels of aminoglycoside resistance, vancomycin-resistance, and toxicity of gentamicin with prolonged therapy have necessitated the use of other options in some patients. When the combination of cell wall drug and aminoglycoside cannot be used, the optimal regimen is not well established, due to limited information from clinical trials. There is thus an urgent need to better understand pathogenesis, resistance mechanisms, and optimal management strategies. Clinicians need to explore both antimicrobial and nonantimicrobial strategies for management, including evaluation of those at risk, early diagnosis, appropriate combination, and infection prevention. PMID- 23749323 TI - PI3K-gamma inhibitors in the therapeutic intervention of diseases caused by obligate intracellular pathogens. AB - Our increased understanding of host pathogen interactions shows that pathogens could capitalize on host cell pathways to favor entry and disease establishment. One such pathway used by Leishmania mexicana to enter into neutrophils and macrophages is the PI3Kgamma signaling pathway. We recently showed that the use of the PI3Kgamma inhibitor AS-605240 for the treatment of experimental L. mexicana infection in mice resulted in significantly lower parasite burdens and lesion sizes than WT untreated mice. Further, AS-605240 was found to be as effective as Sodium Stibogluconate, the drug of choice for treatment of L. mexicana infection, in reducing parasite burdens in mice. Here, we provide potential mechanisms of PI3Kgamma blockade in promoting resistance to L. mexicana infection in mice. As a proof of principle, we propose that targeting host cell signaling pathways used in the establishment of infection could be a possible therapeutic option in the management of obligate intracellular pathogens. PMID- 23749324 TI - Myeloid leukemia in a urine specimen: a case report and review of the literature. AB - Urinary tract cytology has a long history of utilization for the diagnosis and follow-up of tumors involving the urothelial tract. As expected, the most common tumor encountered in exfoliative urine cytology is urothelial carcinoma. While the sensitivity of urinary tract cytology for the diagnosis of low-grade urothelial carcinomas is low, its sensitivity and accuracy for high grade urothelial carcinomas is much higher. However, nonurothelial malignancies, such as hematopoietic malignancies, can also be encountered in urine specimens. Leukemic cells in urine can be diagnosed readily by cytological examination in cases where more invasive procedures are difficult to perform. Additionally, cell block sections can be utilized to determine the immunocytochemical profile of the tumor cells to confirm the diagnosis. Herein we report a case of a 75-year-old man with a past medical history of acute myeloid leukemia (AML), who presented with congested heart failure and painless macroscopic hematuria. AML relapse was diagnosed. Cytological examination of the urine using a ThinPrep(r) smear, cytospin preparation, and immunohistochemical stains performed on the cell block sections were examined. Findings were consistent with leukemic cells of myeloid origin in the bladder washing specimen. PMID- 23749325 TI - MCAM expression is associated with poor prognosis in non-small cell lung cancer. AB - BACKGROUND: MCAM has been recently identified as a biomarker for epithelial mesenchymal transition (EMT) and is potentially involved in metastasis of cancer. The current study aimed at investigating the expression of MCAM in non-small-cell lung cancer (NSCLC) and its clinico-pathological significance. METHODS: A follow up analysis was performed on 118 patients with NSCLC resected by lobectomy or pneumectomy with systematic lymph node dissection. All patients were followed for 6-60 months. Immunostaining of tissue sections from primary tumors and their lymph node metastasis was performed and evaluated using monoclonal antibody against MCAM, E-cadherin, and vimentin. Correlations were investigated between MCAM immunostaining in primary tumors and E-cadherin, vimentin immunostaining, lymph node metastasis, and survival. RESULTS: MCAM protein expression was found in 46.61 % of squamous cell carcinomas and 37.47 % of adenocarcinomas; MCAM expression positively correlated with vimentin, but inversely with E-cadherin (both P values <0.05). There were significant correlations between the MCAM immunostaining score in primary tumors and in their lymph node metastasis (P = 0.03). According to the Kaplan-Meier survival estimate, the level of MCAM expression in primary tumors was a statistically significant prognostic factor (P < 0.05). CONCLUSIONS: MCAM expression in surgically treated NSCLC is clearly associated with lymph node metastasis and poor prognosis. PMID- 23749326 TI - Clinical and molecular prognostic predictors of malignant peripheral nerve sheath tumor. AB - OBJECTIVE: Malignant peripheral nerve sheath tumors (MPNST) are relatively rare sarcomas and poorly understood. We sought to find clinicopathological and molecular predictors of survival for Chinese MPNST patients. METHODS: Clinical information from 146 MPNST patients treated in the Tianjin Medical University Cancer Institute and Hospital was collected and 56 cases of formalin-fixed and paraffin-embedded tissues were available for immunohistochemical examination of expression of hepatocyte growth factor receptor (c-MET), E3 ubiquitin-protein ligase Mdm2 (MDM2), and TP53. RESULTS: The 5-year tumor-free survival rate was 24 % and the median tumor-free survival time was 25.64 months. The 5-year overall survival rate was 57 % and the median overall survival time was 132.57 months. The expression patterns of c-MET, TP53, and MDM2 were heterogeneous with total positivity rates of 82.1 % (46/56), 55.4 % (31/56), and 73.2 % (41/56), respectively. The univariate analysis not only showed that tumor size, Neurofibromin 1 (NF1) status, the American Joint Committee on Cancer (AJCC) stage, surgery, MDM2 expression, and TP53 expression had significant correlation with the tumor-free survival, but also demonstrated that radiotherapy, chemotherapy, tumor size, and NF1 status had significant correlation with the overall survival. Even though multivariate analysis found no independent prognostic predictor of MPNST, tumor size and NF1 status had significant correlation with the tumor-free survival and overall survival of MPNST patients. CONCLUSIONS: With this, the largest documented Chinese cohort, our data supply powerful Chinese evidence of the prognostic role of tumor size and NF1 status in MPNST. PMID- 23749327 TI - Guidelines for biomarker testing in gastroenteropancreatic neuroendocrine neoplasms: a national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology. AB - The annual incidence of neuroendocrine tumours in the Caucasian population ranges from 2.5 to 5 new cases per 100,000 inhabitants. Gastroenteropancreatic neuroendocrine tumours is a family of neoplasms widely variable in terms of anatomical location, hormone composition, clinical syndromes they cause and in their biological behaviour. This high complexity and clinical heterogeneity, together with the known difficulty of predicting their behaviour from their pathological features, are reflected in the many classifications that have been developed over the years in this field. This article reviews the main tissue and clinical biomarkers and makes recommendations for their use in medical practice. This document represents a consensus reached jointly by the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP). PMID- 23749328 TI - Group recruitment in a thermophilic desert ant, Ocymyrmex robustior. AB - Thermophilic desert ants-Cataglyphis, Ocymyrmex, and Melophorus species inhabiting the arid zones of the Palaearctic region, southern Africa and central Australia, respectively-are solitary foragers, which have been considered to lack any kind of chemical recruitment. Here we show that besides mainly employing the solitary mode of food retrieval Ocymyrmex robustior regularly exhibits group recruitment to food patches that cannot be exploited individually. Running at high speed to recruitment sites that may be more than 60 m apart from the nest a leading ant, the recruiter, is followed by a loose and often quite dispersed group of usually 2-7 recruits, which often overtake the leader, or may lose contact, fall back and return to the nest. As video recordings show the leader, while continually keeping her gaster in a downward position, intermittently touches the surface of the ground with the tip of the gaster most likely depositing a volatile pheromone signal. These recruitment events occur during the entire diurnal activity period of the Ocymyrmex foragers, that is, even at surface temperatures of more than 60 degrees C. They may provide promising experimental paradigms for studying the interplay of orientation by chemical signals and path integration as well as other visual guidance routines. PMID- 23749329 TI - Insect-machine hybrid system for understanding and evaluating sensory-motor control by sex pheromone in Bombyx mori. AB - To elucidate the dynamic information processing in a brain underlying adaptive behavior, it is necessary to understand the behavior and corresponding neural activities. This requires animals which have clear relationships between behavior and corresponding neural activities. Insects are precisely such animals and one of the adaptive behaviors of insects is high-accuracy odor source orientation. The most direct way to know the relationships between neural activity and behavior is by recording neural activities in a brain from freely behaving insects. There is also a method to give stimuli mimicking the natural environment to tethered insects allowing insects to walk or fly at the same position. In addition to these methods an 'insect-machine hybrid system' is proposed, which is another experimental system meeting the conditions necessary for approaching the dynamic processing in the brain of insects for generating adaptive behavior. This insect-machine hybrid system is an experimental system which has a mobile robot as its body. The robot is controlled by the insect through its behavior or the neural activities recorded from the brain. As we can arbitrarily control the motor output of the robot, we can intervene at the relationship between the insect and the environmental conditions. PMID- 23749331 TI - Low-frequency subthalamic nucleus deep brain stimulation for axial symptoms in advanced Parkinson's disease. AB - Axial symptoms such as freezing of gait and falls are common manifestations of advanced Parkinson's disease (PD) and are partially responsive to medical treatment. High-frequency (>=130 Hz) deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly efficacious in ameliorating appendicular symptoms in PD. However, it is typically less effective in improving axial symptomatology, especially in the long term. We have studied the effects of low frequency stimulation (LFS) (<=80 Hz) for improving speech, gait and balance dysfunction in the largest patient population to date. PD patients with bilateral STN-DBS and resistant axial symptoms were switched from chronic 130 Hz stimulation to LFS and followed up to 4 years. Primary outcome measures were total motor UPDRS scores, and axial and gait subscores before and after LFS. Bivariate analyses and correlation coefficients were calculated for the different conditions. Potential predictors of therapeutic response were also investigated. Forty-five advanced PD patients who had high frequency stimulation (HFS) for 39.5 +/- 27.8 consecutive months were switched to LFS. LFS was kept on for a median period of 111.5 days before the assessment. There was no significant improvement in any of the primary outcomes between HFS and LFS, although a minority of patients preferred to be maintained on LFS for longer periods of time. No predictive factors of response could be identified. There was overall no improvement from LFS in axial symptoms. This could be partly due to some study limitations. Larger prospective trials are warranted to better clarify the impact of stimulation frequency on axial signs. PMID- 23749332 TI - Brainstem encephalitis: etiologies, treatment, and predictors of outcome. AB - Brainstem encephalitis (BE) is an uncommon condition. We sought to characterize clinical presentations, etiologies, response to treatment, and predictors of outcome. We performed a retrospective review of non-HIV infected patients diagnosed with BE at Johns Hopkins Hospital (January 1997-April 2010). We characterized clinical and paraclinical features, and used regression models to assess associations with poor outcome. BE was diagnosed in 81 patients. An etiology was identified in 58 of 81 (71.6%) of cases, most of which were confirmed or probable inflammatory/autoimmune conditions. Of the remaining 23 cases in which a specific diagnosis remained undefined, clinical presentation, CSF, neuroimaging studies, and outcomes were similar to the inflammatory/autoimmune group. Brain biopsy identified a specific diagnosis in 7 of 14 patients (50%). Fifteen patients (18.5%) either died or had a poor outcome. In multivariate logistic regression models, a higher CSF protein (per 5 mg/dl, OR = 1.11, 95% CI: 1.03-1.20), a higher CSF glucose (per 5 mg/dl, OR = 1.36, 95% CI: 1.09-1.70), and higher serum glucose (per 5 mg/dl, OR = 1.27, 95% CI: 1.06-1.52) were independently associated with increased odds of poor outcome. Inflammatory and non-infectious conditions accounted for most cases of BE. Higher CSF protein and glucose were independently associated with poor outcome. In immunocompetent patients with BE of undefined etiology despite extensive investigation, a trial of immunosuppressive treatment may be warranted, though deterioration clinically or on magnetic resonance imaging should prompt a brain biopsy. PMID- 23749333 TI - Short-term effect of verapamil on coronary no-reflow associated with percutaneous coronary intervention in patients with acute coronary syndrome: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: To evaluate the clinical efficacy and safety of intracoronary verapamil injection in the prevention and treatment of coronary no-reflow after percutaneous coronary intervention (PCI). HYPOTHESIS: Intracoronary verapamil injection may be beneficial in preventing no-reflow/slow-flow after PCI. METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials database. Randomized trials comparing the efficacy and safety of intracoronary verapamil infusion vs control in patients with acute coronary syndrome (ACS) were included. Meta-analysis was performed by RevMan 5.0 software (Cochrane Collaboration, Copenhagen, Denmark) . RESULTS: Seven trials involving 539 patients were included in the analysis. Verapamil treatment was significantly more effective in decreasing the incidence of no-reflow (risk ratio [RR]: 0.33; 95% confidence interval [CI]: 0.23 to 0.50) as well as reducing the corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) (weighted mean difference: -11.62; 95% CI: -16.04 to -7.21) and improving the TIMI myocardial perfusion grade (TMPG) (RR: 0.43; 95% CI: 0.29 to 0.64). Verapamil also reduced the 30-day wall motion index (WMI) compared to the control. Moreover, the procedure reduced the incidence of major adverse cardiac events (MACEs) in ACS patients during hospitalization (RR: 0.37; 95% CI: 0.17 to 0.80) and 2 months after PCI (RR: 0.56; 95% CI: 0.33 to 0.95). However, administration of verapamil did not provide an additional improvement of left ventricular ejection fraction regardless of the time that had passed post-PCI. CONCLUSIONS: Intracoronary verapamil injection is beneficial in preventing no-reflow/slow-flow, reducing CTFC, improving TMPG, and lowering WMI. It is also likely to reduce the 2-month MACEs in ACS patients post-PCI. PMID- 23749334 TI - Volumetric analysis of medial temporal lobe subregions in developmental amnesia using high-resolution magnetic resonance imaging. AB - There is great interest in the cognitive consequences of hippocampal volume loss in developmental amnesia (DA). In many DA cases, volume loss occurs before the hippocampus is fully developed, and yet little is known about the locus, extent, and distribution of damage in these cases. We used high-resolution MRI to manually segment the medial temporal lobe (MTL) subregions in H.C., an adult with DA, and a group of sex-, age- and education-matched control participants (n = 10). The hippocampus was defined and divided into anterior (head) and posterior (body and tail) segments. Within the body of the hippocampus, the subregions (CA1 , DG/CA2/3 , and subiculum) were defined. Finally, the entorhinal (ERC), perirhinal (PRC), and parahippocampal (PHC) cortices were segmented. Anterior hippocampus was reduced bilaterally and posterior hippocampus was significantly reduced on the right. In the body of the hippocampus, all three subregions were reduced in the left hemisphere, whereas CA1 and subiculum were reduced in the right hemisphere. No group differences were observed in the PRC and ERC, whereas left PHC volume was marginally increased in H.C. compared to controls. These results can be used to inform patterns of spared and impaired cognitive abilities in DA and perhaps in amnesia more generally. PMID- 23749336 TI - Immunomodulators in inflammatory bowel disease: an emerging role for biologic agents. AB - Crohn's disease and ulcerative colitis, collectively referred to as inflammatory bowel diseases (IBD), are the result of an aberrant immune response to ubiquitous antigens in a genetically susceptible host. In the past, treatment has focused on immunosuppression with the aim of achieving symptom-free remission. Over the last two decades, with a better understanding of the underlying pathomechanisms and an increased knowledge of the natural disease course, mucosal healing (the endoscopic absence of visible inflammation) has become the target of therapy. Anti-tumor necrosis factor (TNF)-alpha therapy was introduced in the late 1990s and, for the first time, targeted and effective medication became available. However, these medications are not without significant side effects, and long term efficacy is only achieved in about one third of patients. Alongside anti-TNF alpha agents, a variety of other drugs targeting different aspects of the immune system will become available over the next few years. This review aims to provide a brief summary of immunologic pathways involved in IBD and shows where current and new drugs fit into these pathways. PMID- 23749335 TI - Cell-based proteome profiling using an affinity-based probe (AfBP) derived from 3 deazaneplanocin A (DzNep). AB - 3-Deazaneplanocin A (DzNep), a global histone methylation inhibitor, has attracted significant interest in epigenetic research in recent years. The molecular mechanism of action and the cellular off-targets of DzNep, however, are still not well-understood. Our aim was to develop novel DzNep-derived small molecule probes suitable to be used in live mammalian cells for identification of potential cellular targets of DzNep under physiologically relevant settings. In the current study, we have successfully designed, synthesized, and tested one such probe, called DZ-1. DZ-1 is a 'clickable' affinity-based probe (AfBP) derived from DzNep with minimal structural modifications. The probe was found to be highly cell-permeable, and possessed similar anti-apoptotic activities as DzNep in MCF-7 mammalian cells. Two additional control probes were made as negative labeling/pull-down probes in order to minimize false identification of background proteins due to unavoidable, intrinsic nonspecific photo-crosslinking reactions. All three probes were subsequently used for in-situ proteome profiling in live mammalian cells, followed by large-scale pull-down/LC-MS/MS analysis for identification of potential cellular protein targets that might interact with DzNep in native cellular environments. Our LC-MS/MS results revealed some highly enriched proteins that had not been reported as potential DzNep targets. These proteins might constitute unknown cellular off-targets of DzNep. Though further validation experiments are needed in order to unequivocally confirm these off targets, our findings shed new light on the future use of DzNep as a validated chemical probe for epigenetic research and as a potential drug candidate for cancer therapy. PMID- 23749338 TI - Impact of antiplatelet therapy on clinical manifestations and outcomes of cardiovascular infections. AB - Despite advances in medical and surgical management, infective endocarditis remains associated with significant morbidity and mortality. Septic embolization to the brain and other organs is one of the most dreaded complications of infective endocarditis. Given the critical role of platelets in bacterial vegetation formation on cardiac valves or cardiac device leads, antiplatelet agents, including aspirin, have recently generated much interest as adjunctive therapies in cardiovascular infections. In this article, we review the published evidence evaluating the role of platelets in the pathogenesis of cardiovascular infections and the rationale for using antiplatelet agents in these infections. PMID- 23749339 TI - Black parents' beliefs, attitudes, and HPV vaccine intentions. AB - This study examined the determinants of Black parents' intention to have their daughters receive the HPV vaccine. Relationships between behavioral beliefs regarding the HPV vaccine, HPV vaccine attitudes, and HPV vaccine intentions among Black parents were explored. A descriptive correlational design and mediation model were used to explain the hypothesized relationships. HPV parental attitudes were significantly related to vaccine intention (r = .865, p < .001). A significant relationship between HPV vaccine behavioral beliefs and HPV vaccine attitudes was found among Black parents (r = .239, p < .001). Parental vaccine attitudes completely mediated the relationship between HPV vaccine behavioral beliefs and parental HPV vaccine intention. Understanding relevant factors associated with parental intent to have their daughters vaccinated are essential to reducing opposition to the HPV vaccine and increase vaccination rates among Black female adolescents. PMID- 23749337 TI - Development of myelination and cholinergic innervation in the central auditory system of a prosimian primate (Otolemur garnetti). AB - Change in the timeline of neurobiological growth is an important source of biological variation, and thus phenotypic evolution. However, no study has to date investigated sensory system development in any of the prosimian primates that are thought to most closely resemble our earliest primate ancestors. Acetylcholine (ACh) is a neurotransmitter critical to normal brain function by regulating synaptic plasticity associated with attention and learning. Myelination is an important structural component of the brain because it facilitates rapid neuronal communication. In this work we investigated the expression of acetylcholinesterase (AChE) and the density of myelinated axons throughout postnatal development in the inferior colliculus (IC), medial geniculate complex (MGC), and auditory cortex (auditory core, belt, and parabelt) in Garnett's greater galago (Otolemur garnetti). We found that the IC and MGC exhibit relatively high myelinated fiber length density (MFLD) values at birth and attain adult-like values by the species-typical age at weaning. In contrast, neocortical auditory fields are relatively unmyelinated at birth and only attain adult-like MFLD values by the species-typical age at puberty. Analysis of AChE expression indicated that, in contrast to evidence from rodent samples, the adult like distribution of AChE in the core area of auditory cortex, dense bands in layers I, IIIb/IV, and Vb/VI, is present at birth. These data indicate the differential developmental trajectory of central auditory system structures and demonstrate the early onset of adult-like AChE expression in primary auditory cortex in O. garnetti, suggesting the auditory system is more developed at birth in primates compared to rodents. PMID- 23749340 TI - Falls prevention and the value of exercise: salient beliefs among South asian and white british older adults. AB - The importance of increasing exercise to prevent falls among older adults remains a key worldwide public health priority. However, older adults do not necessarily take up exercise as a preventative measure for falls. This qualitative study aimed to explore the beliefs of community-dwelling South Asian and White British older adults aged 60 to 70 about falls and exercise for fall prevention through 15 focus groups (n = 87) and 40 in-depth interviews. Data were transcribed verbatim and analyzed using a framework approach. Data analysis identified six salient beliefs that influenced older adults' intention to exercise for fall prevention. In general, older adults aged 60 to 70 did not acknowledge their risk of falling and were not motivated to exercise simply to help prevent falls. Positive beliefs were found to be an unlikely barrier to taking up exercise for fall prevention for those who had experienced a fall. The implications for health promotion and health professionals with this group of older adults are discussed. PMID- 23749341 TI - Defining the terms acute and chronic in orthopaedic sports injuries: a systematic review. AB - BACKGROUND: Although many authors report on acute injuries and chronic injuries in the orthopaedic literature, the actual terms are seldom explicitly defined. HYPOTHESIS: Much of the literature pertaining to sports injuries that are acute or chronic does not define these terms. It is believed that definitions will provide clarity and specificity in future literature. STUDY DESIGN: Systematic review. METHODS: A systematic review of 116 articles was conducted to determine whether and how the terms acute and chronic were defined as they pertain to several commonly treated conditions: Achilles tendon rupture, distal biceps tendon rupture, pectoralis major tendon rupture, anterior cruciate ligament (ACL) tear, anterior shoulder instability, and acromioclavicular (AC) joint dislocation. Articles were isolated from various databases and search engines by use of keywords to identify relevant literature. RESULTS: This study determined that the terms acute and chronic for each injury are defined, respectively, as follows: Achilles tendon rupture: <1 week, >4 weeks; distal biceps tendon rupture: <6 weeks, >12 weeks; pectoralis major tendon rupture: <6 weeks, >6 weeks; ACL tear: <6 weeks, >6 months; anterior shoulder instability: <2 weeks, >6 months; AC joint dislocation, <3 weeks, >6 weeks. CONCLUSION: The current literature varies greatly in defining the terms acute and chronic in common sports injuries. The vast majority of authors imply these terms, based on the method of their studies, rather than define them explicitly. Injuries involving tendons showed greater consistency among authors, thus making a definition based on consensus easier to derive. The literature on ACL and shoulder instability in particular showed great variability in defining these terms, likely representing the more complex nature of these injuries and the fact that timing of surgery in the majority of patients does not particularly affect the complexity of the surgical approach and treatment. CLINICAL RELEVANCE: Defining injuries as acute or chronic is clinically relevant in many cases, particularly concerning tendon injuries, where these terms have implications regarding the anatomic pathologic changes and tissue quality, which may necessitate augmentation and alter the initial surgical plan. In cases where these terms are less pertinent to operative treatment considerations, they bring clarity to the discussion of the acuity of the injury (as it pertains to time from insult). PMID- 23749342 TI - Biomechanical characteristics of osteochondral defects of the humeral capitellum. AB - BACKGROUND: The repetitive, excessive compression forces in the radiocapitellar joint caused by elbow valgus stresses during throwing motions can result in osteochondritis dissecans (OCD) of the humeral capitellum in adolescent athletes. PURPOSE: To assess the effect of elbow valgus torque on contact pressure in the radiocapitellar joint and that of central and lateral capitellar osteochondral defects on radiocapitellar joint contact pressure, elbow valgus laxity, and ulnar collateral ligament (UCL) strain. STUDY DESIGN: Controlled laboratory study. METHODS: In 8 matched pairs of fresh-frozen cadaveric upper limbs, lateral osteochondral defects of the humeral capitellum (5-, 10-, 15-, and 20-mm diameters) were evaluated in one side, and central defects were evaluated in the contralateral side. Radiocapitellar joint contact pressure, elbow valgus laxity, and UCL strain were all measured with and without 2 N.m of valgus torque at 30 degrees , 60 degrees , and 90 degrees of elbow flexion in neutral forearm rotation. RESULTS: Applying valgus torque increased contact pressure in radiocapitellar joints with intact or damaged capitula. Contact pressure in joints with 15-mm (90 degrees of elbow flexion) and 20-mm (60 degrees and 90 degrees of elbow flexion) lateral capitellar defects was greater than that in joints with intact capitula. Radiocapitellar contact pressure was greater with a 20-mm lateral capitellar defect than in the same-sized central defect at 60 degrees and 90 degrees of elbow flexion. In both central and lateral defect groups, elbow valgus laxity increased as the size of the capitellar defect increased, and UCL strain remained unchanged regardless of the size of the capitellar defect. CONCLUSION: Elbow valgus torque increases contact pressure in the radiocapitellar joint. Capitellar osteochondral defects increase elbow valgus laxity and contact pressure without increasing UCL strain. When valgus torque is applied, contact pressure in the radiocapitellar joint is greater with a lateral defect than with a central defect. CLINICAL RELEVANCE: Adolescent baseball players with capitellar OCD should stop throwing, even if the UCL is intact, to prevent exacerbating the osteochondral defect. Lateral capitellar OCD is more severe than central capitellar OCD. PMID- 23749343 TI - Incidence of postoperative anterior cruciate ligament reconstruction infections: graft choice makes a difference. AB - BACKGROUND: Infections after anterior cruciate ligament reconstruction (ACLR) can be devastating. Hamstring tendon autografts may be more susceptible to infections than other graft types. PURPOSE: To determine the incidence of surgical site infections (SSIs) in a large sample of patients who underwent ACLR and to evaluate the risk of superficial and deep SSIs associated with grafts used for ACLR. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: All primary ACLRs performed between February 2005 and September 2010 registered in the Kaiser Permanente ACLR registry were included in the study. The graft types evaluated included the bone-patellar tendon-bone (BPTB) autograft, hamstring tendon autograft, and allograft (all types). The main end point of the study, SSIs (deep and superficial), was prospectively ascertained using an electronic screening algorithm and adjudicated by the principal investigator. Descriptive statistics were used to describe the cohort, and logistic regression models were used to evaluate the likelihood of an infection. RESULTS: There were 10,626 cases that fit the study criteria. The overall cohort was 64% male, mean age was 29 +/- 11 years, and mean body mass index (BMI) was 27 +/- 5 kg/m2. The overall incidence of SSIs was 0.48% (n = 51), with 17 (0.16%) superficial infections and 34 (0.32%) deep infections. Hamstring tendon autografts (n = 20; 0.61%) had the highest incidence of deep SSIs of the graft types (BPTB autograft, n = 2 [0.07%]; allograft, n = 12 [0.27%]; P < .001). After adjusting for age, sex, and BMI, the likelihood of a patient with a hamstring autograft having a deep SSI was 8.24 times higher (95% CI, 1.91-35.55; P = .005) than someone receiving a BPTB autograft. The risk of infections in allografts was not statistically significantly higher than BPTB autografts. CONCLUSION: The overall SSI rate after ACLR was 0.48%. Deep SSIs were identified in 0.32% of the ACLR cases and superficial SSIs in 0.16%. An 8.2-times higher risk of SSIs was observed in hamstring tendon autografts compared with BPTB autografts. No difference in SSI incidence was identified between allografts and BPTB autografts. Surgeons should bear in mind that although the overall infection rates after ACLR are low, there is an increased risk of deep infections with hamstring tendon autografts. PMID- 23749345 TI - Don't hinder pilot badger culls, appeals BVA. PMID- 23749344 TI - Adherence to screening mammography among American Indian women of the Northern Plains. AB - Breast cancer is a burden for American Indian (AI) women who have younger age at diagnosis and higher stage of disease. Rural areas also have had less access to screening mammography. An Indian Health Service Mobile Women's Health Unit (MWHU) was implemented to improve mammogram screening of AI women in the Northern Plains. Our purpose was to determine the past adherence to screening mammography at a woman's first presentation to the MWHU for mammogram screening. Date of the most recent prior non-MWHU mammogram was obtained from mammography records. Adherence to screening guidelines was defined as the prior mammogram occurring 1 2 years before the first MWHU visit among women >41 years, and was the main outcome, whereas, age and clinic site were predictors. Adherence was compared with national data of the Breast Cancer Surveillance Consortium (BCSC). Among 1,771 women >41 years, adherence to screening mammography guidelines was 48.01 % among >65 years, 42.05 % among 50-64 years, 33.43 % among 41-49 years, and varied with clinic site (25.23-65.93 %). Age (p < 0.0001) and clinic site (p < 0.0001) were associated with adherence. Overall, adherence to screening mammography guidelines was found in 39.86 % (706/1771) of MWHU women versus 74.34 % (747,095/1,004,943) of BCSC women. The majority (60.14 %) of women at first presentation to the MWHU had not had mammograms in the previous 2 years, lower screening adherence than nationally (25.66 %). Adherence was lowest among women ages 41-49, and varied with clinic site. Findings suggest disparities in mammography screening among these women. PMID- 23749347 TI - Rabies mission ready to roll. PMID- 23749349 TI - Community clinic benefits students and pets. PMID- 23749351 TI - Vet to be struck off for lack of courtesy and failures in care. PMID- 23749352 TI - Free tips for final-year students. PMID- 23749353 TI - Feline fellowship still going strong. PMID- 23749354 TI - Tailored treatment and monitoring key to tackling ketosis in dairy cows. PMID- 23749355 TI - Before and after: research in action. PMID- 23749356 TI - Outcomes assessed at AWF discussion forum. PMID- 23749358 TI - The business of being a vet. PMID- 23749360 TI - Badger culling pilots. PMID- 23749359 TI - Sequence variation of the feline immunodeficiency virus genome and its clinical relevance. AB - The ongoing evolution of feline immunodeficiency virus (FIV) has resulted in the existence of a diverse continuum of viruses. FIV isolates differ with regards to their mutation and replication rates, plasma viral loads, cell tropism and the ability to induce apoptosis. Clinical disease in FIV-infected cats is also inconsistent. Genomic sequence variation of FIV is likely to be responsible for some of the variation in viral behaviour. The specific genetic sequences that influence these key viral properties remain to be determined. With knowledge of the specific key determinants of pathogenicity, there is the potential for veterinarians in the future to apply this information for prognostic purposes. Genomic sequence variation of FIV also presents an obstacle to effective vaccine development. Most challenge studies demonstrate acceptable efficacy of a dual subtype FIV vaccine (Fel-O-Vax FIV) against FIV infection under experimental settings; however, vaccine efficacy in the field still remains to be proven. It is important that we discover the key determinants of immunity induced by this vaccine; such data would compliment vaccine field efficacy studies and provide the basis to make informed recommendations on its use. PMID- 23749361 TI - Multidrug resistant Salmonella Java found in British broiler flocks. PMID- 23749362 TI - A baseline process for the production, recovery, and purification of bacterial influenza vaccine candidates. AB - The current commercial system for influenza vaccine production depends on the culture of virus in embryonated eggs--a strategy that is both costly and poorly scalable. Consequently, a sudden pandemic event with a demand for millions of vaccine doses in a short time could readily overwhelm the available world production capacity. In this communication, we present a process that uses Escherichia coli for scalable production of recombinant vaccine candidates against influenza. A monomeric and a dimeric fragment of hemagglutinin of the influenza A H1N1/2009 virus were successfully expressed in a BL21 (DE3) pLysS variety of C41 E. coli. We present results from batch processes where induction is made with isopropyl thiogalactoside and from fed-batch experiments where expression is induced using lactose/glucose pulses. Concentrations in the range of 1.188-0.605 g/L of recombinant protein were observed in 2-L stirred tank bioreactors. The genetic construct included an N-terminal histidine tag sequence that facilitated recovery, purification, and proper refolding of the vaccine candidate by affinity chromatography in columns loaded with Ni(+2) . The proteins produced by this strategy selectively and specifically recognizes antibodies from patients diagnosed as positive to influenza A H1N1/2009. Overall protein recovery yields between 30.0 and 34.7% were typically observed. Based on these yields, a production of 4.6 * 10(3) doses L(-3) day(-1) is feasible. PMID- 23749363 TI - Immobilization of aluminum with mucilage secreted by root cap and root border cells is related to aluminum resistance in Glycine max L. AB - The root cap and root border cells (RBCs) of most plant species produced pectinaceous mucilage, which can bind metal cations. In order to evaluate the potential role of root mucilage on aluminum (Al) resistance, two soybean cultivars differing in Al resistance were aeroponic cultured, the effects of Al on root mucilage secretion, root growth, contents of mucilage-bound Al and root tip Al, and the capability of mucilage to bind Al were investigated. Increasing Al concentration and exposure time significantly enhanced mucilage excretion from both root caps and RBCs, decreased RBCs viability and relative root elongation except roots exposed to 400 MUM Al for 48 h in Al-resistant cultivar. Removal of root mucilage from root tips resulted in a more severe inhibition of root elongation. Of the total Al accumulated in root, mucilage accounted 48-72 and 12 27 %, while root tip accounted 22-52 and 73-88 % in Al-resistant and Al-sensitive cultivars, respectively. A (27)Al nuclear magnetic resonance spectrum of the Al adsorbed mucilage showed Al tightly bound to mucilage. Higher capacity to exclude Al in Al-resistant soybean cultivar is related to the immobilization and detoxification of Al by the mucilage secreted from root cap and RBCs. PMID- 23749364 TI - Photodegradation of sulfonamides and their N (4)-acetylated metabolites in water by simulated sunlight irradiation: kinetics and identification of photoproducts. AB - Once released into the aquatic environment, pharmaceuticals may undergo different degradation processes. Photodegradation, for example, might be an important elimination process for light-sensitive pharmaceuticals, such as antibiotics. In this study, the fate of sulfonamides (sulfamethazine, sulfadiazine, and sulfamethoxazole) and their N (4)-acetylated metabolites (N (4) acetylsulfadiazine, N (4)-acetylsulfamethazine, and N (4)-acetylsulfamethoxazole) under simulated sunlight irradiation was investigated. The irradiation resulted in total or almost total degradation (88 to 98 %) of the pharmaceuticals tested, except for sulfamethazine (52 %), during 24 h of irradiation. The photoproducts of all investigated pharmaceuticals have been analyzed using high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry. Structure elucidation performed from photodegradation products of both, sulfonamides and their N (4)-acetylated metabolites, clearly showed two major formation pathways. These were cleavage of the sulfonamide bond as well as SO2 extrusion. In total, nine photoproducts were elucidated. Among these photoproducts, the tautomers of sulfamethoxazole and desulfonated products of sulfadiazine and sulfamethazine were also present. Tautomers of sulfadiazine and sulfamethazine have been characterized here for the first time as well as some photoproducts of sulfadiazine, sulfametoxazole, and their metabolites N (4) acetylsulfadiazine and N (4)-acetylsulfametoxazole. The obtained results are an important piece in the complex puzzle for assessing the environmental fate of sulfonamides and their metabolites in the environment. PMID- 23749365 TI - Metal-tolerant PAH-degrading bacteria: development of suitable test medium and effect of cadmium and its availability on PAH biodegradation. AB - The use of metal-tolerant polyaromatic hydrocarbon (PAH)-degrading bacteria is viable for mitigating metal inhibition of organic compound biodegradation in the remediation of mixed contaminated sites. Many microbial growth media used for toxicity testing contain high concentrations of metal-binding components such as phosphates that can reduce solution-phase metal concentrations thereby underestimate the real toxicity. In this study, we isolated two PAHs-degrading bacterial consortia from long-term mixed contaminated soils. We have developed a new mineral medium by optimising the concentrations of medium components to allow the bacterial growth and at the same time maintain high bioavailable metal (Cd(2+) as a model metal) in the medium. This medium has more than 60 % Cd as Cd(2+) at pH 6.5 as measured by an ion selective electrode and visual MINTEQ model. The Cd-tolerant patterns of the consortia were tested and minimum inhibitory concentration (MIC) derived. The consortium-5 had the highest MIC of 5 mg l(-1) Cd followed by consortium-9. Both cultures were able to completely metabolise 200 mg l(-1) phenanthrene in less than 4 days in the presence of 5 mg l(-1) Cd. The isolated metal-tolerant PAH-degrading bacterial cultures have great potential for bioremediation of mixed contaminated soils. PMID- 23749366 TI - Effects of pH, Fe, and Cd on the uptake of Fe(2+) and Cd (2+) by rice. AB - The rhizosphere plays an important role in altering cadmium (Cd) solubility in paddy soils and Cd accumulation in rice. However, more studies are needed to elucidate the mechanism controlling rice Cd solubility and bioavailability under different rhizosphere conditions to explain the discrepancy of previous studies. A rice culture with nutrient solution and vermiculite was conducted to assess the effects of pH, Eh, and iron (Fe) concentration on Cd, Fe fractions on the vermiculite/root surface and their uptake by rice. The solution pH was set from 4.5 to 7.5, with additions of Fe (30 and 50 mg L(-1)) and Cd (0.5 and 0.9 mg L( 1)). At pH 5.5, the Eh in the rice rhizosphere was higher whereas transpiration, Cd(2+), and Fe(2+) adsorption on the vermiculite/root surface and accumulation in rice were lower than the other pH treatments. Cadmium addition had no impact on pH and Eh in rice rhizosphere while Fe addition decreased pH and increased Eh significantly. Compared with control, Fe addition resulted in the decrease of rhizosphere Cd, Fe solubility and bioavailability. Higher redox potential in the rice rhizosphere resulted in the decline of transpiration, Cd, and Fe accumulation in the rice tissues, suggesting that the transfer of two elements from soil to rice was depressed when the rhizosphere was more oxidized. PMID- 23749367 TI - Historical trend of nitrogen and phosphorus loads from the upper Yangtze River basin and their responses to the Three Gorges Dam. AB - Excessive inputs of nitrogen and phosphorus (N and P) degrade surface water quality worldwide. Impoundment of reservoirs alters the N and P balance of a basin. In this study, riverine nutrient loads from the upper Yangtze River basin (YRB) at the Yichang station were estimated using Load Estimator (LOADEST). Long term load trends and monthly variabilities during three sub-periods based on the construction phases of the Three Gorges Dam (TGD) were analyzed statistically. The dissolved inorganic nitrogen (DIN) loads from the upper YRB for the period from 1990 to 2009 ranged from 30.47 * 10(4) to 78.14 * 10(4) t, while the total phosphorus (TP) loads ranged from 2.54 * 10(4) to 7.85 * 10(4) t. DIN increased rapidly from 1995 to 2002 mainly as a result of increased fertilizer use. Statistics of fertilizer use in the upper YRB agreed on this point. However, the trend of the TP loads reflected the combined effect of removal by sedimentation in reservoirs and increased anthropogenic inputs. After the TGD impoundment in 2003, decreasing trends in both DIN and TP loads were found. The reduction in DIN was mainly caused by ammonium consumption and transference. From an analysis of monthly loads, it was found that DIN had a high correlation to discharges. For TP loads, an average decrease of 4.91 % in October was found when the TGD impoundment occurred, but an increase of 4.23 % also occurred in July, corresponding to the washout from sediment deposited in the reservoir before July. Results of this study revealed the TGD had affected nutrient loads in the basin, and it had played a role in nutrient reduction after its operation. PMID- 23749368 TI - Chiral profiling of azole antifungals in municipal wastewater and recipient rivers of the Pearl River Delta, China. AB - Enantiomeric compositions and fractions (EFs) of three chiral imidazole (econazole, ketoconazole, and miconazole) and one chiral triazole (tebuconazole) antifungals were investigated in wastewater, river water, and bed sediment of the Pearl River Delta, South China. The imidazole pharmaceuticals in the untreated wastewater were racemic to weakly nonracemic (EFs of 0.450-0.530) and showed weak enantioselectivity during treatment in the sewage treatment plant. The EFs of the dissolved azole antifungals were usually different from those of the sorbed azoles in the suspended particulate matter, suggesting different behaviors for the enantiomers of the chiral azole antifungals in the dissolved and particulate phases of the wastewater. The azole antifungals were widely present in the rivers. The bed sediment was a sink for the imidazole antifungals. The imidazoles were prevalently racemic, whereas tebuconazole was widely nonracemic in the rivers. Seasonal effects were observed on distribution and chirality of the azole antifungals. Concentrations of the azole antifungals in the river water were relatively higher in winter than in spring and summer while the EF of miconazole in the river water was higher in summer. The mechanism of enantiomeric behavior of the chiral azole antifungals in the environment warrants further research. PMID- 23749369 TI - Characterization of shallow groundwater quality in the Lower St. Johns River Basin: a case study. AB - Characterization of groundwater quality allows the evaluation of groundwater pollution and provides information for better management of groundwater resources. This study characterized the shallow groundwater quality and its spatial and seasonal variations in the Lower St. Johns River Basin, Florida, USA, under agricultural, forest, wastewater, and residential land uses using field measurements and two-dimensional kriging analysis. Comparison of the concentrations of groundwater quality constituents against the US EPA's water quality criteria showed that the maximum nitrate/nitrite (NO x ) and arsenic (As) concentrations exceeded the EPA's drinking water standard limits, while the maximum Cl, SO 4 (2-) , and Mn concentrations exceeded the EPA's national secondary drinking water regulations. In general, high kriging estimated groundwater NH 4 (+) concentrations were found around the agricultural areas, while high kriging estimated groundwater NO x concentrations were observed in the residential areas with a high density of septic tank distribution. Our study further revealed that more areas were found with high estimated NO x concentrations in summer than in spring. This occurred partially because of more NO x leaching into the shallow groundwater due to the wetter summer and partially because of faster nitrification rate due to the higher temperature in summer. Large extent and high kriging estimated total phosphorus concentrations were found in the residential areas. Overall, the groundwater Na and Mg concentration distributions were relatively more even in summer than in spring. Higher kriging estimated groundwater As concentrations were found around the agricultural areas, which exceeded the EPA's drinking water standard limit. Very small variations in groundwater dissolved organic carbon concentrations were observed between spring and summer. This study demonstrated that the concentrations of groundwater quality constituents varied from location to location, and impacts of land uses on groundwater quality variation were profound. PMID- 23749370 TI - Effects of light, microbial activity, and sediment resuspension on the phosphorus immobilization capability of drinking water treatment residuals in lake sediment. AB - Drinking water treatment residuals (WTRs), nonhazardous by-products generated in a drinking water treatment plant, can be reused to immobilize phosphorus (P) to control the internal P loading from lake sediments for eutrophication control. Reasonably, before practical application, it is essential to determine the P immobilization capability of WTRs in lake sediments under various conditions. In this work, laboratory scale experiments were conducted to investigate the effects of light, microbial activity, and sediment resuspension on the P immobilization capability of WTRs. The results suggested that absence of light, low microbial activity, and sediment resuspension can increase the internal P loading from lake sediments. WTRs can, however, reduce the internal P loading significantly. Further analysis demonstrated that WTRs can stabilize P, decreasing the P bioavailability in the sediments under varied conditions. WTRs also presented little undesirable effects on the dissolved oxygen levels and pH of overlying water. Therefore, light, microbial activity, and sediment resuspension have little effect on the P immobilization capability of WTRs in lake sediments. PMID- 23749371 TI - Comment on "Targeting aquatic microcontaminants for monitoring: exposure categorization and application to the Swiss situation [Gotz et al., Environ Sci Pollut Res (2010) 17:341-354]". PMID- 23749372 TI - Monthly water quality forecasting and uncertainty assessment via bootstrapped wavelet neural networks under missing data for Harbin, China. AB - In this paper, bootstrapped wavelet neural network (BWNN) was developed for predicting monthly ammonia nitrogen (NH(4+)-N) and dissolved oxygen (DO) in Harbin region, northeast of China. The Morlet wavelet basis function (WBF) was employed as a nonlinear activation function of traditional three-layer artificial neural network (ANN) structure. Prediction intervals (PI) were constructed according to the calculated uncertainties from the model structure and data noise. Performance of BWNN model was also compared with four different models: traditional ANN, WNN, bootstrapped ANN, and autoregressive integrated moving average model. The results showed that BWNN could handle the severely fluctuating and non-seasonal time series data of water quality, and it produced better performance than the other four models. The uncertainty from data noise was smaller than that from the model structure for NH(4+)-N; conversely, the uncertainty from data noise was larger for DO series. Besides, total uncertainties in the low-flow period were the biggest due to complicated processes during the freeze-up period of the Songhua River. Further, a data missing-refilling scheme was designed, and better performances of BWNNs for structural data missing (SD) were observed than incidental data missing (ID). For both ID and SD, temporal method was satisfactory for filling NH(4+)-N series, whereas spatial imputation was fit for DO series. This filling BWNN forecasting method was applied to other areas suffering "real" data missing, and the results demonstrated its efficiency. Thus, the methods introduced here will help managers to obtain informed decisions. PMID- 23749373 TI - Effect of modified montmorillonites on the biodegradation and adsorption of biomarkers such as hopanes, steranes and diasteranes. AB - The effect of modified montmorillonites on the biodegradation and adsorption of selected steranes, diasteranes and hopanes was investigated in aqueous clay/oil microcosm experiments with a hydrocarbon degrading microorganism community. The unmodified montmorillonite was treated with didecyldimethylammonium bromide, hydrochloric acid and the relevant metallic chloride to produce organomontmorillonite, acid activated montmorillonite and homoionic montmorillonite respectively which were used in this study. The study indicated that organomontmorillonite, acid activated montmorillonite and potassium montmorillonite did not support the biodegradation of the selected steranes, diasteranes and hopanes as alteration of the biomarkers via biodegradation varied from a paltry 2-6 %. The adsorption of the selected biomarkers on acid activated montmorillonite and organomontmorillonite was also poor. However, adsorption of the biomarkers on potassium montmorillonite was relatively high. Sodium montmorillonite and unmodified montmorillonite appear to stimulate the biodegradation of the selected biomarkers moderately (30-35 %) with adsorption occurring at low level. Calcium montmorillonite and ferric montmorillonite effected significant biodegradation (51-60 %) of the selected biomarkers. PMID- 23749374 TI - Non-neutralizing antibodies protect from chronic LCMV infection independently of activating FcgammaR or complement. AB - Chronic viral infections lead to CD8(+) T cell exhaustion, characterized by impaired cytokine secretion. The presence of the immune-regulatory cytokine IL-10 promotes chronic lymphocytic choriomeningitis virus (LCMV) Clone 13 infection in mice, whereas the absence of IL-10/IL-10R signaling early during infection results in viral clearance and higher percentages and numbers of antiviral, cytokine-producing T cells. However, it is currently unclear which cell populations and effector molecules are crucial to protect against chronic infection. In this study, we demonstrate that antiviral, LCMV-binding, non neutralizing antibodies are needed, in addition to CD4(+) and CD8(+) T cells, to clear a high-dose LCMV infection in mice, in the absence of IL-10. The interaction between CD4(+) T cells and B cells in B-cell follicles via CD40/CD40L, in addition to class switch and/or somatic hypermutation, is crucial for viral control in the absence of IL-10. Interestingly, transfer of LCMV binding non-neutralizing antibodies protected recipients from chronic infection. In addition, viral clearance in the absence of IL-10R signaling was independent of activating Fcgamma receptors and complement. These data highlight that non neutralizing antibodies effectively contribute to the control of LCMV infection when present prior to infection, suggesting that the induction of neutralizing antibodies is not implicitly necessary for the generation of successful vaccines. PMID- 23749375 TI - Dosage schedule for antipyretic combination formulations: experts' reply II. PMID- 23749376 TI - Bilateral submandibular duct transposition with sublingual gland excision for cerebral palsy children with drooling. PMID- 23749377 TI - Dosage schedule for antipyretic combination formulations: correspondence. PMID- 23749378 TI - Association rules for rat spatial learning: the importance of the hippocampus for binding item identity with item location. AB - Three cohorts of rats with extensive hippocampal lesions received multiple tests to examine the relationships between particular forms of associative learning and an influential account of hippocampal function (the cognitive map hypothesis). Hippocampal lesions spared both the ability to discriminate two different digging media and to discriminate two different room locations in a go/no-go task when each location was approached from a single direction. Hippocampal lesions had, however, differential effects on a more complex task (biconditional discrimination) where the correct response was signaled by the presence or absence of specific cues. For all biconditional tasks, digging in one medium (A) was rewarded in the presence of cue C, while digging in medium B was rewarded in the presences of cue D. Such biconditional tasks are "configural" as no individual cue or element predicts the solution (AC+, AD-, BD+, and BC-). When proximal context cues signaled the correct digging choice, biconditional learning was seemingly unaffected by hippocampal lesions. Severe deficits occurred, however, when the correct digging choice was signaled by distal room cues. Also, impaired was the ability to discriminate two locations when each location was approached from two directions. A task demand that predicted those tasks impaired by hippocampal damage was the need to combine specific cues with their relative spatial positions ("structural learning"). This ability makes it possible to distinguish the same cues set in different spatial arrays. Thus, the hippocampus appears necessary for configural discriminations involving structure, discriminations that potentially underlie the creation of cognitive maps. PMID- 23749379 TI - Antioxidative effects of extracts from Trifolium species on blood platelets exposed to oxidative stress. AB - Clovers (Trifolium) may possess a significant therapeutic potential, but the effects of compounds from these plants on blood platelets and haemostasis have been poorly recognized. The present study was designed to evaluate the antioxidative action of extracts from three species of clovers: Trifolium pratense, Trifolium pallidum and Trifolium scabrum in the protection of human blood platelets in vitro. Platelet suspensions were pre-incubated with crude extract and phenolic fraction of T. pratense or phenolic fractions of T. scabrum and T. pallidum, at the final concentrations of 0.5-50 MUg/ml. Then, for the induction of oxidative stress, 100 MUM peroxynitrite was added. The antioxidative activity of plant extracts was assessed by measurements of the level of 3 nitrotyrosine, thiol groups and lipid peroxidation products (hydroperoxides and thiobarbituric acid-reactive substances). Despite the significant differences in the composition of the investigated extracts, we observed antioxidative effects of all used mixtures. The presence of Trifolium extracts considerably reduced the peroxynitrite-mediated modifications of proteins and diminished peroxidation of lipids in platelets. Our results indicate on a strong antioxidative activity of the tested extracts-statistically significant effects were found even for the lowest concentrations (0.5 MUg/ml) of all extracts. This action may be useful in the protection of blood components, very susceptible to oxidative modifications. The obtained results suggest that the examined clovers are a promising source of compounds, valuable for the protection against oxidative stress-induced damage to blood platelets. PMID- 23749380 TI - Morphogenesis of T-tubules in heart cells: the role of junctophilin-2. AB - The T-tubule (TT) system forms the structural basis for excitation-contraction coupling in heart and muscle cells. The morphogenesis of the TT system is a key step in the maturation of heart cells because it does not exist in neonatal cardiomyocytes. In the present study, we quantified the morphological changes in TTs during heart cell maturation and investigated the role of junctophilin-2 (JP2), a protein known to anchor the sarcoplasmic reticulum (SR) to TT, in changes to TT morphological parameters. Analysis of confocal images showed that the transverse elements of TTs increased, while longitudinal elements decreased during the maturation of TTs. Fourier transform analysis showed that the power of ~2 MUm spatial components increased with cardiomyocytes maturation. These changes were preceded by increased expression of JP2, and were reversed by JP2 knockdown. These findings indicate that JP2 is required for the morphogenesis of TTs during heart development. PMID- 23749381 TI - Secretory/releasing proteome-based identification of plasma biomarkers in HBV associated hepatocellular carcinoma. AB - For successful therapy, hepatocellular carcinoma (HCC) must be detected at an early stage. Herein, we used a proteomic approach to analyze the secretory/releasing proteome of HCC tissues to identify plasma biomarkers. Serum free conditioned media (CM) were collected from primary cultures of cancerous tissues and surrounding noncancerous tissues. Proteomic analysis of the CM proteins permitted the identification of 1365 proteins. The enriched molecular functions and biological processes of the CM proteins, such as hydrolase activity and catabolic processes, were consistent with the liver being the most important metabolic organ. Moreover, 19% of the proteins were characterized as extracellular or membrane-bound. For validation, secretory proteins involved in transforming growth factor-beta signaling pathways were validated in plasma samples. Alphafetoprotein (AFP), metalloproteinase (MMP)1, osteopontin (OPN), and pregnancy-specific beta-1-glycoprotein (PSG)9 were significantly increased in HCC patients. The overall performance of MMP1 and OPN in the diagnosis of HCC remained greater than that of AFP. In addition, this study represents the first report of MMP1 as a biomarker with a higher sensitivity and specificity than AFP. Thus, this study provides a valuable resource of the HCC secretome with the potential to investigate serological biomarkers. MMP1 and OPN could be used as novel biomarkers for the early detection of HCC and to improve the sensitivity of biomarkers compared with AFP. PMID- 23749382 TI - Magnetic resonance ultrashort echo time spin-echo imaging of the deepest layers of articular cartilage. PMID- 23749383 TI - Serum dehydroepiandrosterone sulphate, total antioxidant capacity, and total oxidant status in central serous chorioretinopathy. AB - BACKGROUND: The objective of this work is to evaluate plasma total antioxidant capacity (TAC), total oxidant status (TOS), and dehydroepiandrosterone sulphate (DHEA-S) levels in patients diagnosed with acute central serous chorioretinopathy (CSCR) and control samples. METHODS: The TAC, TOS, and DHEA-S levels were assessed in the plasma of 46 CSCR patients and compared with 40 control samples. RESULTS: The TAC level was 1.16 +/- 0.08 and 1.20 +/- 0.09 mmol Trolox eq./l; TOS level was 28.77 +/- 33.33 and 19.95 +/- 10.42 MUmol H202/l; DHEA-S level was 203.79 +/- 84.75 MUg/dl and 249.36 +/- 122.93 MUg/dl in the CSCR group and in the control group, respectively. The plasma TAC and DHEA-S values were significantly lower in the CSCR group than in the control group (p = 0.027 and p = 0.046, respectively). There was no significant difference between the CSCR and the control groups in terms of age, gender, and TOS levels (p > 0.05). CONCLUSIONS: We demonstrated that the levels of plasma DHEA-S and antioxidative parameters were reduced in CSCR. Our results suggest that the antioxidant defense system may be inadequate or corrupted in CSCR. Reduced DHEA-S level is one of the factors that trigger this insufficiency. PMID- 23749384 TI - Synthesis of Phenanthridinones from N-methoxybenzamides and aryltriethoxysilanes through Rh(III)-catalyzed C-H and N-H bond activation. AB - An efficient method for the one-pot synthesis of substituted phenanthridinone derivatives from N-methoxybenzamides and aryltriethoxysilanes through rhodium catalyzed dual C-H bond activation and annulation reactions is described. A double-cycle mechanism is proposed to account for this catalytic reaction. In addition, isotope-labeling studies were performed to understand the intimate mechanism of the reaction. PMID- 23749385 TI - Therapeutic red cell exchange for severe carbon monoxide poisoning. AB - BACKGROUND AND OBJECTIVE: Carbon monoxide (CO) is the most common cause of fatal poisoning worldwide. Therapeutic red cell exchange (TREX) has been used in the treatment of many different diseases. Therefore, we aimed to evaluate the efficacy of TREX on the clinical status, outcome, and discharge of patients with severe CO poisoning. METHODS: Demographic data, clinical status, and outcomes of 12 patients that were treated with TREX for severe CO poisoning after referral to the Emergency and Hematology Departments of Gaziantep University between November 2011 and April 2012 were evaluated. RESULTS: Mean carboxyhemoglobin level decreased from (59.7 +/- 12.7)% (38-79%) to (17 +/- 9.4)% (8-43%), and mean Glasgow Coma Scale score increased from 4 +/- 1.6 (3-8) to 9.4 +/- 3.5 (3-14) after TREX therapy. Five patients were admitted to the intensive care unit. Rhabdomyolysis developed in one case. Of the 12 patients, 11 were discharged alive, and one patient died. CONCLUSION: TREX may be an alternative treatment method for reducing mortality and morbidity in cases of severe CO poisoning. PMID- 23749386 TI - Parallelization of a multiconfigurational perturbation theory. AB - In this work, we present a parallel approach to complete and restricted active space second-order perturbation theory, (CASPT2/RASPT2). We also make an assessment of the performance characteristics of its particular implementation in the Molcas quantum chemistry programming package. Parallel scaling is limited by memory and I/O bandwidth instead of available cores. Significant time savings for calculations on large and complex systems can be achieved by increasing the number of processes on a single machine, as long as memory bandwidth allows, or by using multiple nodes with a fast, low-latency interconnect. We found that parallel efficiency drops below 50% when using 8-16 cores on the shared-memory architecture, or 16-32 nodes on the distributed-memory architecture, depending on the calculation. This limits the scalability of the implementation to a moderate amount of processes. Nonetheless, calculations that took more than 3 days on a serial machine could be performed in less than 5 h on an InfiniBand cluster, where the individual nodes were not even capable of running the calculation because of memory and I/O requirements. This ensures the continuing study of larger molecular systems by means of CASPT2/RASPT2 through the use of the aggregated computational resources offered by distributed computing systems. PMID- 23749388 TI - "Shall I compare thee to a dose of donepezil?": cultural arts interventions in dementia care research. AB - The cultural arts have gained attention for their potential to generate social and behavioral changes in people with dementia. Although individual cultural arts intervention studies have reported positive outcomes, most are excluded from systematic reviews because of methodological weakness. We reviewed findings from 27 systematic and integrative reviews of pharmacologic, psychosocial, and cultural arts interventions to identify promising outcomes as well as limitations in current approaches. Although results point to the potential success of interventions tailored to individual interests, most focused on limited measurements of individual change. In moving forward, cultural arts intervention research must not be limited to the tools of the clinical trial model. Instead, researchers should carefully rethink what constitutes rigorous and effective research for interventions aimed at creating a meaningful personal experience for the participant rather than measurable change. PMID- 23749387 TI - Update on the evaluation of repeated stone formers. AB - Office management of stone disease is an important component of a urologist's practice. Evaluation should include analysis of stone composition, 24-hour urine studies, identification of modifiable risk factors, and targeted dietary, lifestyle, and/or medical therapy. A sizeable portion of investigated etiologies and risk factors for stone disease have centered on the complex interplay between obesity, diabetes, and other disease states that comprise the metabolic syndrome. Alternatives to traditional preventive therapy, such as probiotics and various fruit juices, are still being studied but may prove useful adjuncts to traditional preventive therapy, where the mainstays remain increased fluid intake, dietary modification, and pharmacologic therapy. Future studies on preventive therapy of urolithiasis are likely to focus on strategies to increase compliance, cost-effectiveness, and systems-based implementation. PMID- 23749389 TI - The relevance of Marjory Warren's writings today. AB - Marjory Warren was one of the initial geriatricians in the United Kingdom. She established specialized geriatric units, held important administrative positions, and wrote influential papers where she argued for the need of the specialty of geriatric medicine and outlined principles for inpatient care of older adults with chronic illness. We compare and contrast Warren's early papers describing these principles with contemporary models for improving inpatient care of older adults and the need for the specialty of geriatrics. Warren's writings on the inpatient care of older adults presage the principles of both Hospital Elder Life Programs and Acute Care of the Elderly units. The importance of multidisciplinary teams, the physical environment, attention to diverse issues (medical, social, functional), early ambulation, and the active involvement of the older person in their daily routine are present in Warren's writings and in contemporary approaches. Warren's arguments for both the specialty of geriatric medicine and increased training of nonspecialist physicians and other health professionals are remarkably similar to those made in a recent Institute of Medicine report. Across time and place, there has been consistency in the general principles perceived as required for the effective cares of older persons, but challenges persist in implementing and sustaining them. PMID- 23749391 TI - Predictors of older adults' personal and community mobility: using a comprehensive theoretical mobility framework. AB - PURPOSE OF THE STUDY: Forty-six percent of older adults report limitations in their mobility, and maintaining mobility is considered an important factor in keeping adults independent and active in later life. This study tests a comprehensive theoretical framework of mobility (Webber, S. C., Porter, M. M., & Menec, V. H. [2010]. Mobility in older adults: A comprehensive framework. The Gerontologist, 50[4], 443-450. doi:10.1093/geront/gnq013) identifying multiple determinants that additively influence mobility (financial, psychosocial, environmental, physical, and cognitive), as well as cross-cutting influences of gender, culture, and biography. DESIGN AND METHODS: Structural equation modeling was used to examine several models of mobility using data from 6,112 respondents in the Health and Retirement Study (mean age: 74.74, 85% white, 41% male, 57% married). RESULTS: The original measurement model fit the data well. When both personal and community mobility were simultaneously predicted, only the physical, cognitive, psychosocial, and environmental determinants were retained in the independent models. Age and marital status also predicted personal and community mobility. Although most of these relationships were in the expected direction, interestingly when both forms of mobility were included in the model, poorer cognitive ability was associated with greater personal mobility in the final model. IMPLICATIONS: Results indicate the importance of accounting for and examining comprehensive models of mobility. The factors affecting older adults' mobility are complex, and these relationships need to be explored in more depth to ensure the maintenance of individuals' independence and quality of life. PMID- 23749390 TI - Confidant network types and well-being among older europeans. AB - PURPOSE OF THE STUDY: To derive a typology of confidant networks among older adults in Europe and to examine them in relation to country differences and well being (CASP-12). DESIGN AND METHODS: The study population was composed of persons aged 65 and older in 16 countries from the 4th wave of the Survey of Health, Ageing and Retirement in Europe (N = 28,697). K-means cluster analysis was applied to data from a newly implemented name-generating network inventory. CASP 12 scores were regressed on network type controlling for country and potential sociodemographic and health confounders. RESULTS: Six prototypical confidant network types were discerned, including proximal and distal family-based networks of varying configurations, as well as friend-based and other-based network types. Regional country differences in network type constellations were observed. Better well-being was found to be associated with network types with greater social capital. Respondents with no named confidants had the lowest CASP-12 scores, and those embedded in "other" network types also exhibited a negative association with well-being. IMPLICATIONS: The study demonstrates the utility of name generating network inventories in understanding the social capital of older persons. It also shows that accessible family ties are strong correlates of well being in this population. Finally, it documents the importance of improving the means to detect the small but significant subgroup of isolated older people-those who have no confidants on whom they may rely. PMID- 23749395 TI - Influence of pubertal stage on local sweating patterns of girls exercising in the heat. AB - The influence of puberty on sweating patterns of girls exercising in the heat is not known. Nine- to 17-year-old girls, representing 4 stages of breast development: T1 (n = 21); T2 (n = 22); T3 (n = 25); and T4 (n = 22), cycled for 20 min at 60% in 35 degrees C. The population density of heat activated sweat glands was higher in T1 vs T3 and T4 and in T2 vs T4. Sweat drop area was lower in T1 vs T3 and in T1 vs T4, T2 vs T4 and T3 vs T4. The proportion of skin covered by sweat was lower in T1 vs T4. Sweating patterns of girls exercising in the heat are influenced by pubertal stage. PMID- 23749404 TI - Comparative analysis of Tsc1 and Tsc2 single and double radial glial cell mutants. AB - Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder with variable expressivity. Heterozygous mutations in either of two genes, TSC1 (hamartin) or TSC2 (tuberin), are responsible for most cases. Hamartin and tuberin form a heterodimer that functions as a major cellular inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) kinase. Genotype-phenotype studies suggest that TSC2 mutations are associated with a more severe neurologic phenotype, although the biologic basis for the difference between TSC1- and TSC2-based disease is unclear. Here we performed a study to compare and contrast the brain phenotypes of Tsc1 and Tsc2 single and double mutants. Using Tsc1 and Tsc2 floxed alleles and a radial glial transgenic Cre driver (FVB-Tg(GFAP-cre)25Mes/J), we deleted Tsc1 and/or Tsc2 in radial glial progenitor cells. Single and double mutants had remarkably similar phenotypes: early postnatal mortality, brain overgrowth, laminar disruption, astrogliosis, a paucity of oligodendroglia, and myelination defects. Double Tsc1/Tsc2 mutants died earlier than single mutants, and single mutants showed differences in the location of heterotopias and the organization of the hippocampal stratum pyramidale. The differences were not due to differential mTORC1 activation or feedback inhibition on Akt. These data provide further genetic evidence for individual hamartin and tuberin functions that may explain some of the genotype-phenotype differences seen in the human disease. PMID- 23749405 TI - A comparison of the steady-state pharmacokinetic and pharmacodynamic profiles of 100 and 200 U/mL formulations of ultra-long-acting insulin degludec. AB - BACKGROUND AND OBJECTIVE: Insulin degludec (IDeg) is a new-generation basal insulin that forms soluble multi-hexamers upon subcutaneous injection, resulting in a depot from which IDeg monomers are slowly and continuously absorbed to provide an ultra-long action profile. This double-blind, crossover, randomized study compared the pharmacokinetic and pharmacodynamic properties between IDeg 100 U/mL (U100) and IDeg 200 U/mL (U200) under steady-state (SS) conditions in subjects with type 1 diabetes mellitus. METHODS: Participants (n = 33 adults) underwent 8-day treatment periods with 0.4 U/kg IDeg U100 and IDeg U200 given once daily with insulin aspart at mealtimes. On day 8, a 26-h euglycaemic glucose clamp (5.5 mmol/L) was performed. RESULTS: The concentration-time profiles of IDeg U100 and IDeg U200 were similar, and a post-hoc analysis showed bioequivalence between these formulations, as the 90 % confidence intervals (CIs) of the U200/U100 ratios for area under the steady-state serum IDeg concentration time curve during a dosing interval (tau; 0-24 h) (AUCtau,SS,IDeg) (0.99 [0.91 1.07]) and maximum steady-state IDeg concentration during a dosing interval (tau) (C max,SS,IDeg) (0.93 [0.84-1.02]) were within the interval 0.80-1.25. Comparable glucose infusion rates (GIR) were observed for IDeg U100 and IDeg U200 (AUCtau,SS,GIR [mg/kg]: 2,255 vs. 2,123) and the mean ratio (95 % CI) of IDeg U200/U100 for the primary endpoint (AUCtau,SS,GIR) was 0.94 [0.86-1.03]. For both formulations, the glucose-lowering effect of IDeg was evenly distributed between the first and second 12 h post-dosing (U100: AUC12,SS,GIR/AUC24,SS,GIR = 48 %; U200: AUC12,SS,GIR/AUC24,SS,GIR = 46 %). Both formulations were well tolerated, and no safety events of significance were identified. CONCLUSION: IDeg U100 and U200 formulations are bioequivalent and have similar pharmacodynamic profiles at SS, implying that they can be used interchangeably in clinical practice. PMID- 23749406 TI - Representations of recent and remote autobiographical memories in hippocampal subfields. AB - The hippocampus has long been implicated in supporting autobiographical memories, but little is known about how they are instantiated in hippocampal subfields. Using high-resolution functional magnetic resonance imaging (fMRI) combined with multivoxel pattern analysis we found that it was possible to detect representations of specific autobiographical memories in individual hippocampal subfields. Moreover, while subfields in the anterior hippocampus contained information about both recent (2 weeks old) and remote (10 years old) autobiographical memories, posterior CA3 and DG only contained information about the remote memories. Thus, the hippocampal subfields are differentially involved in the representation of recent and remote autobiographical memories during vivid recall. PMID- 23749408 TI - [Lymphogranuloma venereum: new serovariant L2b and old "groove sign"]. AB - An ongoing lymphogranuloma venereum (LGV) outbreak has been reported in several European countries since 2003, related to a new variant L2b. This serovar appears to affect men who have sex with men (MSM), most of them being co-infected with the Human Immunodeficiency Virus (HIV). The secondary stage of LGV may involve lymph nodes and the inguinal form has sometimes been described on each side of the inguinal ligament thus named the "groove sign". We report the case of LGV serovariant L2b acquired by an heterosexual intercourse in an HIV seronegative patient who presented with an inguinal lymph node and a "groove sign". This is an uncommon but suggestive sign of LGV and we suggest that the clinical presentation of L2b LGV might not be so different than other variants and than the 20th century authors' description. Such a new Chlamydia trachomatis variant may circulate in other populations than MSM in Europe and clinical awareness must prevail. PMID- 23749407 TI - Review on intermediate filaments of the nervous system and their pathological alterations. AB - Intermediate filaments (IFs) of the nervous system, including neurofilaments, alpha-internexin, glial fibrillary acidic protein, synemin, nestin, peripherin and vimentin, are finely expressed following elaborated cell, tissue and developmental specific patterns. A common characteristic of several neurodegenerative diseases is the abnormal accumulation of neuronal IFs in cell bodies or along the axon, often associated with impairment of the axonal transport and degeneration of neurons. In this review, we also present several perturbations of IF metabolism and organization associated with neurodegenerative disorders. Such modifications could represent strong markers of neuronal damages. Moreover, recent data suggest that IFs represent potential biomarkers to determine the disease progression or the differential stages of a neuronal disorder. Finally, recent investigations on IF expression and function in cancer provide evidence that they may be useful as markers, or targets of brain tumours, especially high-grade glioma. A better knowledge of the molecular mechanisms of IF alterations, combined to neuroimaging, is essential to improve diagnosis and therapeutic strategies of such neurodegenerative diseases and glioma. PMID- 23749409 TI - Nucleoprotein-specific nonneutralizing antibodies speed up LCMV elimination independently of complement and FcgammaR. AB - CD8(+) T cells have an essential role in controlling lymphocytic choriomeningitis virus (LCMV) infection in mice. Here, we examined the contribution of humoral immunity, including nonneutralizing antibodies (Abs), in this infection induced by low virus inoculation doses. Mice with impaired humoral immunity readily terminated infection with the slowly replicating LCMV strain Armstrong but showed delayed virus elimination after inoculation with the faster replicating LCMV strain WE and failed to clear the rapidly replicating LCMV strain Docile, which is in contrast to the results obtained with wild-type mice. Thus, the requirement for adaptive humoral immunity to control the infection was dependent on the replication speed of the LCMV strains used. Ab transfers further showed that LCMV specific IgG Abs isolated from LCMV immune serum accelerated virus elimination. These Abs were mainly directed against the viral nucleoprotein (NP) and completely lacked virus neutralizing activity. Moreover, mAbs specific for the LCMV NP were also able to decrease viral titers after transfer into infected hosts. Intriguingly, neither C3 nor Fcgamma receptors were required for the antiviral activity of the transferred Abs. In conclusion, our study suggests that rapidly generated nonneutralizing Abs specific for the viral NP speed up virus elimination and thereby may counteract T-cell exhaustion. PMID- 23749410 TI - Application of a nonradioactive method of measuring protein synthesis in industrially relevant Chinese hamster ovary cells. AB - Due to the high medical and commercial value of recombinant proteins for clinical and diagnostic purposes, the protein synthesis machinery of mammalian host cells is the subject of extensive research by the biopharmaceutical industry. RNA translation and protein synthesis are steps that may determine the extent of growth and productivity of host cells. To address the problems of utilization of current radioisotope methods with proprietary media, we have focused on the application of an alternative method of measuring protein synthesis in recombinant Chinese hamster ovary (CHO) cells. This method employs puromycin as a nonradioactive label which incorporates into nascent polypeptide chains and is detectable by western blotting. This method, which is referred to as SUnSET, successfully demonstrated the expected changes in protein synthesis in conditions that inhibit and restore translation activity and was reproducibly quantifiable. The study of the effects of feed and sodium butyrate addition on protein synthesis by SUnSET revealed an increase following 1 h feed supplementation while a high concentration of sodium butyrate was able to decrease translation during the same treatment period. Finally, SUnSET was used to compare protein synthesis activity during batch culture of the CHO cell line in relation to growth. The results indicate that as the cells approached the end of batch culture, the global rate of protein synthesis declined in parallel with the decreasing growth rate. In conclusion, this method can be used as a "snapshot" to directly monitor the effects of different culture conditions and treatments on translation in recombinant host cells. PMID- 23749411 TI - Activation of C-H bond in methane by Pd atom from the bonding evolution theory perspective. AB - We report detailed study focused on the electron density redistribution during the simple oxidative addition reaction being the crucial stage of various catalytic processes. The bonding evolution theory based on the electron localization function and Thom's catastrophe theory shows that activation of methane's C-H bond by Pd atom consist of six elementary steps. The important feature revealed is the pronounced reorganization of Pd's outer core maxima corresponding to N-shell electrons of metal. Electronic rearrangements identified in this model reaction are likely to be the case in the more complex reactions of the same type involving transition metal compounds and, in principle, can be observed by modern ultrafast spectroscopy and diffraction techniques. PMID- 23749412 TI - Stimulus discrimination by the polymodal sensory neuron. AB - Polymodal sensory neurons inform organisms about the nature of the physical world around them. The activity of these cells guide behaviors including the withdrawal from nocifensive stimuli such as intense heat or harsh force to feeling the comforting weight of a warm blanket. Molecular and genetic analysis of the channel proteins required for these divers behavioral responses have revealed an elaborate and disparate collection of channel proteins within the polymodal sensory neuron. Recent data supports that the biophysical traits of the channel proteins combined with the collection of channels activated during stimulation is sufficient to describe the nature of the stimulus. It is currently unclear what the functional arrangement of channel proteins are during perception. Specifically, are channel proteins arranged in parallel and function independently during perception, or are these channel proteins arranged in functional sensory networks. We propose a hierarchal functional arrangement of channels within polymodal sensory neurons that incorporates aspects of both parallel and serial arrangements of channel proteins. PMID- 23749413 TI - Silyl effects on 1,3-diphosphacyclobutane-2,4-diyl: ring-opening of tetrahydrofuran and promotion of reductive P-C cleavage. AB - Mind your "P"s: Silylated P-heterocyclic biradicals activated tetrahydrofuran to give the corresponding 4-siloxybutyl-substituted 1,3-diphosphacyclobutane-2,4 diyls via ring-opening of the solvent molecule. Reductive P-C bond cleavage was found as an alternative approach to 1,3-diphosphacyclobuten-4-yl anion. Redox properties of the new P-heterocyclic biradicals were discussed in terms of hitherto unknown substituent effects. PMID- 23749414 TI - Validity of rapid antigen detection testing in group A beta-hemolytic streptococcal tonsillopharyngitis. AB - OBJECTIVE: To evaluate the utility of rapid antigen detection testing (RADT) for the diagnosis of group A beta-hemolytic streptococcal tonsillopharyngitis in children, and to detect the sensitivity and specificity of rapid antigen detection of group A beta-hemolytic streptococci from throat specimen compared with throat culture. METHODS: Rapid antigen detection and throat culture results for group A beta-hemolytic streptococci from outpatients attending university hospital between 1st January 2011 and 31st of December 2011 were evaluated retrospectively. The antigen test negative-throat culture positive patients were investigated for streptococcal carriage. For this purpose, the throat culture results taken from these patients were reviewed after treatment. RESULTS: Eight hundred and ninetytwo children were included in the studywith a mean age of 5.34 y. There were 639 and 253 children in two groups with age of 0-6 and 7-17 y, RADT sensitivity and specificity were found to be 59.5 % and 97.2 %, respectively. The positive predictive value was 87.1 %, whereas negative predictive value was 88.4 %. After treatment of 74 patients with throat culture positive and antigen test negative. Group A beta-hemolytic streptococci were isolated in 12 of them (16.2 %) and accepted as a carrier. CONCLUSIONS: The low sensitivity of the RADT may be related to streptococcal carriage in some patients. The throat culture should be repeated after treatment to detect streptococcal carriage. PMID- 23749415 TI - Evaluation of renal function in term babies with perinatal asphyxia. AB - OBJECTIVE: To study the renal function in term newborns with perinatal asphyxia including urinary excretion of beta2 microglobulin (beta2M). METHODS: This case control study included 50 term newborn babies with perinatal asphyxia and 50 normal babies as matched controls. In all cases, asphyxia grading (using Apgar score) and Hypoxic ischemic encephalopathy (HIE) staging (Sarnat and Sarnat) were done. Blood and urinary parameters (including beta2M) for renal function were done in all and Fractional excretion of sodium (FENa) and Renal failure index (RFI) were calculated. The renal parameters were compared within subgroups as well as controls using analysis of variance test and the independent samples t test. RESULTS: Acute kidney Injury (AKI) was noted in 56 % of cases (24 % prerenal and 32 % intrinsic type). All 9 babies who died had AKI. Serum parameters like urea, creatinine, sodium and potassium had better correlation with the renal function as compared to urine parameters. All individual urine parameters except beta2M showed wide variations. FENa, RFI and urinary beta2M increased with increasing severity of asphyxia and HIE staging. CONCLUSION: AKI is common in term babies with perinatal asphyxia. FENa and RFI are useful parameters for assessing the renal function and urinary beta2M is a good biomarker for diagnosis and prognosis of acute tubular injury in term babies with perinatal asphyxia. PMID- 23749416 TI - Knowledge and awareness about benefits of Kangaroo Mother Care. AB - OBJECTIVE: To determine mothers' prior knowledge of Kangaroo Mother Care (KMC) and awareness about benefits of KMC for preterm babies. METHODS: Mothers of a consecutive sample of 46 preterm babies, eligible for KMC admitted to a teaching hospital, from June through August 2009, were studied to determine the attitude and knowledge about KMC. A structured questionnaire was prepared. Mothers were asked questions to determine their baseline knowledge about KMC. Then each mother was explained about KMC and instructed to do KMC. After one hour of KMC, mothers were asked questions again to know their feelings and difficulties regarding KMC and feasibility of breast feeding during KMC. RESULTS: Most of the mothers could understand what was explained to them (97.8 %; 95 % CI 88.5-99.9 %) in a single session. Positive feelings like closeness to baby (93.5 %) and sense of goodness (97.8 %) were noted amongst mothers. Though statistically not significant, the proportion of mothers who felt it impracticable to give breast feeding while doing KMC was considerable (39.1 %; 95 % CI 25.1-54.6 %) compared to those who felt no difficulty in breast feeding (60.9 %; 95 % CI 45.4-74.9 %). Practicable duration of KMC is 1, 2 and 12 h as felt by 52 %, 19.6 % and 6.5 % of mothers respectively. All the mothers expressed their willingness to continue KMC at home. CONCLUSIONS: Mothers can understand and implement KMC with simple and clear oral instructions in local language. Positive feelings arise in mothers even with 1 h of KMC. KMC of 24 h is not practicable to almost all of the mothers. There is a need for special emphasis on breast feeding the child while doing the KMC. PMID- 23749417 TI - Impact of behavior change communication among pregnant women regarding neonatal care. AB - OBJECTIVES: To assess the behavior of pregnant women regarding neonatal care. Also to implement and assess impact of Behaviour Change Communication (BCC) package among pregnant women regarding neonatal care. METHODS: This community based intervention study was conducted in field practice area of Urban Health Training Centre (UHTC), Department of Community Medicine, Jawaharlal Nehru Medical College and Hospital (JNMCH), Aligarh Muslim University (A.M.U), Aligarh (UP), India. Two hundred pregnant women were included. Epi Info version 3.5.1. Percentages, and Chi square test were used for statistical analysis. RESULTS: Due to implementation of BCC package, institutional deliveries improved (RR = 2.47, P < 0.05), delivery practices significantly increased (RR = 2.47, P < 0.05). There was significant difference regarding breastfeeding practices on 7th and 28th d of delivery. More (80 %) deliveries were conducted in warm room (RR = 1.87, p < 0.05), bathing to the baby was delayed (RR = 0.81, p < 0.05) and decreased, vigorous removal of vernix caseosa was observed (RR = 0.45, p < 0.05). Correct knowledge about danger signs and physiological conditions in newborns were increased (RR = 2.5.0, p < 0.05 for cold to touch, RR = 1.22, p < 0.05 for peeling of skin). CONCLUSIONS: There was a significant impact of BCC package on the behavior of pregnant women regarding neonatal care. PMID- 23749419 TI - Role of telemedicine in providing tertiary neurological care. AB - OPINION STATEMENT: Remote consultation via telemedicine for neurologic indications is in the mainstream. This holds most true for cerebrovascular concerns such as acute stroke, but its use has extended into most of the breadth of neurologic subspecialty practice. This is ostensibly a major advance for enhancing access to neurologic specialty care and a path toward better outcomes overall. Currently, there is a lack of randomized controlled trials and health economic analyses to support this conclusion. The continued use and expansion of teleneurologic practice is encouraged, so long as it is accompanied by clinical data tracking and leads to more randomized controlled trials. A solid evidence base should be established for its use such that future trials and monetary investments can be made with a better understanding of what teleneurology has to offer patients and society. PMID- 23749418 TI - Functional brain abnormalities during finger-tapping in HIV-infected older adults: a magnetoencephalography study. AB - Despite the availability of combination antiretroviral therapy, at least mild cognitive dysfunction is commonly observed in HIV-infected patients, with an estimated prevalence of 35-70 %. Neuropsychological studies of these HIV associated neurocognitive disorders (HAND) have documented aberrations across a broad range of functional domains, although the basic pathophysiology remains unresolved. Some of the most common findings have been deficits in fine motor control and reduced psychomotor speed, but to date no neuroimaging studies have evaluated basic motor control in HAND. In this study, we used magnetoencephalography (MEG) to evaluate the neurophysiological processes that underlie motor planning in older HIV-infected adults and a matched, uninfected control group. MEG is a noninvasive and direct measure of neural activity with good spatiotemporal precision. During the MEG recording, participants fixated on a central crosshair and performed a finger-tapping task with the dominant hand. All MEG data was corrected for head movements, preprocessed, and imaged in the time-frequency domain using beamforming methodology. All analyses focused on the pre-movement beta desynchronization, which is known to be an index of movement planning. Our results demonstrated that HIV-1-infected patients have deficient beta desynchronization relative to controls within the left/right precentral gyri, and the supplementary motor area. In contrast, HIV-infected persons showed abnormally strong beta responses compared to controls in the right dorsolateral prefrontal cortex and medial prefrontal areas. In addition, the amplitude of beta activity in the primary and supplementary motor areas correlated with scores on the Grooved Pegboard test in HIV-infected adults. These results demonstrate that primary motor and sensory regions may be particularly vulnerable to HIV associated damage, and that prefrontal cortices may serve a compensatory role in maintaining motor performance levels in infected patients. PMID- 23749420 TI - Simultaneous measurement of tissue oxygen level-dependent (TOLD) and blood oxygenation level-dependent (BOLD) effects in abdominal tissue oxygenation level studies. AB - PURPOSE: To assess oxygenation in abdominal organs with magnetic resonance imaging (MRI), a novel approach is presented to simultaneously measure both T1 - and T2*-maps serially during a single dynamic MRI scan in response to an oxygen challenge. MATERIALS AND METHODS: The proposed acquisition scheme consists of a multishot multiecho gradient echo planar imaging sequence (ms-GEPI) interleaved with a multishot inversion recovery echo planar imaging (ms-IR-EPI) sequence. Respiratory motion compensation was accomplished with standard belt triggering and by acquiring all image data at the same phase of expiration. This respiratory triggered, free-breathing, interleaved tissue oxygenation level-dependent (TOLD) and blood oxygenation level-dependent (BOLD) acquisition technique was validated on phantoms and seven healthy volunteers in response to an oxygen challenge. RESULTS: Measurements of relaxation times both in vitro and in vivo were in good agreement with those obtained using conventional pulse sequences and reported in the literature. The interleaved sequence was able to measure oxygen-induced relaxation time changes in human abdominal organs. CONCLUSION: The free-breathing respiratory-triggered interleaved T1 and T2* sequence successfully provided relaxation time maps of abdominal organs in a dynamic scan without the need for image registration. The simultaneous monitoring of tissue and blood oxygenation improves time efficiency and should enhance studies comparing dynamic T1 and T2* data within the abdomen. PMID- 23749422 TI - Novel variant of neuronal intranuclear rodlet immunoreactive for 40 kDa huntingtin associated protein and ubiquitin in the mouse brain. AB - Intranuclear rodlets (INRs), also known as rodlets of Roncoroni, are poorly understood intranuclear bodies originally identified within neuronal nuclei on the basis of their unique morphology. The mechanisms of their formation, their biochemical composition and their physiological significance remain unknown. Using double immunofluorescence staining of mouse brain sections, we identified a novel variant of INR that is immunoreactive for the 40 kDa huntingtin associated protein (Hap40) and ubiquitin, and provide evidence for the existence of additional INR subtypes sharing ubiquitin immunoreactivity as a common feature. We describe a selective association of these INRs with melanin concentrating hormone (MCH) and tyrosine hydroxylase immunoreactive neurons of the hypothalamus and the locus coeruleus, respectively. We also demonstrate for the first time that biochemically distinct INR subtypes can coexist within a single nucleus where they engage in nonrandom spatial interactions. Our findings highlight the biochemical diversity and cell type-specific expression of these enigmatic intranuclear structures. PMID- 23749423 TI - Perceptions of risk factors for colorectal cancer and colorectal cancer risk related behaviors among current, ex-, and nonsmokers. AB - Smoking significantly increases risk for colorectal cancer (CRC). We examined smokers' and nonsmokers' perceptions of behavioral factors for the increased risk of CRC and evaluated how these related to CRC screening. Self-reported questionnaire data were obtained from a random, average CRC risk sample of women and men (aged 50-75 years) during 2004. Smokers less frequently reported recent CRC screening than nonsmokers (p = 0.03). Smokers not adherent to screening less frequently agreed that smoking and alcohol consumption (both strongly linked to CRC) increased the risk for CRC (p values < 0.05) than nonsmokers. Notably, the number of concurrent CRC risk behaviors reported by smokers not adherent to CRC screening increased with the number of cigarettes smoked per day, identifying heavy smokers who do not screen as a subgroup most in need of intervention. Findings extend current understanding on processes underlying smokers' perceptions of risk for CRC and how these relate to screening utilization, which can guide provider efforts to improve CRC screening among smokers and reduce their CRC risk-related behaviors. PMID- 23749421 TI - Pharmacological management of bipolar depression: acute treatment, maintenance, and prophylaxis. AB - Although the most distinctive clinical feature of bipolar disorder is the pathologically elevated mood, it does not usually constitute the prevalent mood state of bipolar illness. The majority of patients with bipolar disorder spend much more time in depressive episodes, including subsyndromal depressive symptoms, and bipolar depression accounts for the largest part of the morbidity and mortality of the illness. The pharmacological treatment of bipolar depression mostly consists of combinations of at least two drugs, including mood stabilizers (lithium and anticonvulsants), atypical antipsychotics, and antidepressants. Antidepressants are the most frequently prescribed drugs, but recommendations from evidence-based guidelines are not conclusive and do not overtly support their use. Among antidepressants, best evidence exists for fluoxetine, but in combination with olanzapine. Although some guidelines recommend the use of selective serotonin reuptake inhibitors or bupropion in combination with antimanic agents as first-choice treatment, others do not, based on the available evidence. Among anticonvulsants, the use of lamotrigine is overall recommended as a first-line choice, but acute monotherapy studies have failed. Valproate is generally mentioned as a second-line treatment. Lithium monotherapy is also suggested by most guidelines as a first-line treatment, but its efficacy in acute use is not totally clear. Amongst atypical antipsychotics, quetiapine, in monotherapy or as adjunctive treatment, is recommended by most guidelines as a first-line choice. Olanzapine monotherapy is also suggested by some guidelines and is approved in Japan. Armodafinil, pramipexole, ketamine, and lurasidone are recent proposals. Long-term treatment in bipolar disorder is strongly recommended, but guidelines do not recommend the use of antidepressants as a maintenance treatment. Lithium, lamotrigine, valproate, olanzapine, quetiapine, and aripiprazole are the recommended first-line maintenance options. PMID- 23749424 TI - The effectiveness of a community-based breast cancer education intervention in the New York State Capital Region. AB - We determined the effectiveness of a community-based breast cancer education intervention among understudied populations in the New York State (NYS) Capital Region by assessing and comparing baseline and post-education breast cancer knowledge. Participants included 417 students recruited from five colleges/universities and 67 women from four community group organizations. Baseline and post-education knowledge was assessed via self-administered mostly multiple-choice questionnaires. An open-ended question soliciting opinions about public health prevention strategies against breast cancer was included on college/university students' questionnaires. Effectiveness of education intervention was estimated through a paired t test. Stratified analysis was done using demographic and descriptive variables. Answers to the open-ended questions were analyzed qualitatively. The mean percentage of correct answers increased from 39.9% at baseline to 80.8% post-education (P < 0.0001) among college/university students and from 43.5% to 77.8% (P < 0.0001) among community group members. Effectiveness remained statistically significant in all stratified analyses with similarly high percentage of correct answers achieved post education irrespective of knowledge level at baseline. Stratified analysis also revealed similar patterns of improvement in overall knowledge and narrowing of the gap in post-education knowledge. Primary prevention emerged as the dominant theme post-education in students' responses to the open-ended question, signifying the effectiveness of our education in raising awareness about modifiable risk factors and inspiring proactive thinking about public health prevention strategies. This community-based education intervention was effective in increasing breast cancer knowledge among demographically diverse groups with low levels of baseline knowledge in the NYS Capital Region. Our findings provide leads for future public health prevention strategies. PMID- 23749425 TI - SO2 -catalyzed steam explosion: the effects of different severity on digestibility, accessibility, and crystallinity of lignocellulosic biomass. AB - Lignocellulosic biomass is the most promising feedstock for biofuels production. To enhance the efficiency of enzymatic hydrolysis, lignocellulosics needs to be pretreated to lower their recalcitrance. SO(2) -catalyzed steam explosion is an efficient and relatively cost-efficient pretreatment method for softwood. This work investigates the effects of steam explosion severity on the digestibility, accessibility, and crystallinity of Loblolly pine. Higher severity was found to increase the accessibility of the feedstock while also promoting nonselective degradation of carbohydrates. The adsorption behavior of Celluclast(r) enzymes on steam-exploded Loblolly pine (SELP) can be described by a Langmuir isotherm. Cellulose crystallinity was found to first increase and then decrease with increasing pretreatment severity. A linear relationship between initial hydrolysis rates and crystallinity index (CrI) of pretreated Loblolly pine was found; moreover, a strong correlation between X-ray diffraction intensities and initial rates was confirmed. The findings demonstrate the significance of CrI in enzymatic hydrolysis of pretreated lignocellulosic biomass. PMID- 23749426 TI - Low-level laser therapy for fat layer reduction: a comprehensive review. AB - BACKGROUND AND OBJECTIVE: Low-level laser (light) therapy (LLLT) is a noninvasive, nonthermal approach to disorders requiring reduction of pain and inflammation and stimulation of healing and tissue regeneration. Within the last decade, LLLT started being investigated as an adjuvant to liposuction, for noninvasive body contouring, reduction of cellulite, and improvement of blood lipid profile. LLLT may also aid autologous fat transfer procedures by enhancing the viability of adipocytes. However the underlying mechanism of actions for such effects still seems to be unclear. It is important, therefore, to understand the potential efficacy and proposed mechanism of actions of this new procedure for fat reduction. MATERIALS AND METHODS: A review of the literature associated with applications of LLLT related to fat layer reduction was performed to evaluate the findings from pre-clinical and clinical studies with respect to the mechanism of action, efficacy, and safety. RESULTS: The studies as of today suggest that LLLT has a potential to be used in fat and cellulite reduction as well as in improvement of blood lipid profile without any significant side effects. One of the main proposed mechanism of actions is based upon production of transient pores in adipocytes, allowing lipids to leak out. Another is through activation of the complement cascade which could cause induction of adipocyte apoptosis and subsequent release of lipids. CONCLUSION: Although the present studies have demonstrated safety and efficacy of LLLT in fat layer reduction, studies demonstrating the efficacy of LLLT as a stand-alone procedure are still inadequate. Moreover, further studies are necessary to identify the mechanism of action. PMID- 23749427 TI - CD73 expression on extracellular vesicles derived from CD4+ CD25+ Foxp3+ T cells contributes to their regulatory function. AB - CD4(+)CD25(+)Foxp3(+) Treg cells maintain immunological tolerance. In this study, the possibility that Treg cells control immune responses via the production of secreted membrane vesicles, such as exosomes, was investigated. Exosomes are released by many cell types, including T cells, and have regulatory functions. Indeed, TCR activation of both freshly isolated Treg cells and an antigen specific Treg-cell line resulted in the production of exosomes as defined morphologically by EM and by the presence of tetraspanin molecules LAMP-1/CD63 and CD81. Expression of the ecto-5-nucleotide enzyme CD73 by Treg cells has been shown to contribute to their suppressive function by converting extracellular adenosine-5-monophosphate to adenosine, which, following interaction with adenosine receptors expressed on target cells, leads to immune modulation. CD73 was evident on Treg cell derived exosomes, accordingly when these exosomes were incubated in the presence of adenosine-5-monophosphate production of adenosine was observed. Most importantly, CD73 present on Treg cell derived exosomes was essential for their suppressive function hitherto exosomes derived from a CD73 negative CD4(+) T-cell line did not have such capabilities. Overall our findings demonstrate that CD73-expressing exosomes produced by Treg cells following activation contribute to their suppressive activity through the production of adenosine. PMID- 23749428 TI - Camptothecin-induced expression of programmed cell death gene 11 in Spodoptera litura. AB - BACKGROUND: Camptothecin, one of the main active components of extract from the bark of the Chinese camptotheca tree, has been reported as a potent insecticide against various insect species. However, the mechanism of action of camptothecin as a botanical pesticide is not completely understood. RESULTS: In this study, the full-length cDNA (GeneBank number JF681972) of Spodoptera litura programmed cell death protein 11 (pcdp 11) isoform 1 was cloned, sequenced and characterised. Quantitative real-time PCR (qRT-PCR) data showed that pcdp 11 was differentially expressed during the developmental stages, with significantly high expression during the transition from egg to larva and larva to pupa. Furthermore, pcdp 11 was upregulated in a time-dependent manner in SL-1 cells after treatment with 1.2 ug mL(-1) of camptothecin. The induced expression profile of pcdp 11 in the larval midgut after feeding camptothecin was visualised by fluorescence in situ hybridisation (FISH) and further quantified by qRT-PCR. Apoptosis in camptothecin-treated larval midguts was confirmed using terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining. CONCLUSION: The results reveal a clear functional link between pcdp 11 expression and camptothecin-induced apoptosis, and prove that camptothecin exhibits strong toxicity towards S. litura by inducing midgut epithelial cell apoptosis. PMID- 23749429 TI - Diagnostic vertigo: the journey to diagnosis in systemic lupus erythematosus. AB - Systemic lupus erythematosus (lupus) is a complex condition characterised by wide ranging symptoms that are sometimes transient in nature. This makes recognising and diagnosing lupus particularly challenging for both patients and practitioners. The diagnostic process in this condition is a complex interplay between the boundaries of knowledge and power, control, integrity and legitimacy, which are (re)constructed and (re)negotiated between contemporary medicine, the patient and practitioner. Utilising data generated through a qualitative research design, this article illustrates some of the challenges lupus presents in the clinical encounter. We argue that the diagnosis of lupus is not a clinical event or a 'diagnostic moment'. Rather, it constitutes a journey in and of itself, one which, for many of the respondents in this study, has no diagnostically satisfying conclusion. We conclude that uncertain diagnoses, such as lupus, illustrate the extent of both embodied and clinical doubt in, what might be termed, contemporary conditions and, concomitantly, throw into sharp relief the nature of the diagnostic process. This process, in the context of lupus, and other uncertain conditions, generates, we would argue, a sense of diagnostic vertigo. PMID- 23749430 TI - Factors associated with adherence to physical activity guidelines in patients with prostate cancer. AB - OBJECTIVE: This study aimed to estimate the proportion of patients with prostate cancer (PCa) meeting the National Physical Activity Guidelines of Australia (NPAGA) and determine sociodemographic and medical factors associated with meeting these guidelines. Secondary aims included examining physical activity (PA) levels by treatment type and domain (leisure, work, transport and domestic) and establishing a predictive model of the likelihood that men with PCa would meet NPAGA. METHODS: A questionnaire was mailed to 638 men with PCa attending for treatment at the Alfred, Cabrini or Latrobe Regional Hospitals during 2010 and 2011, with a response rate of 59%. Measures included International Physical Activity Questionnaire, Hospital Anxiety and Depression Scale, Functional Assessment of Cancer Therapy - Prostate and sociodemographic items. Inclusion criteria were English speaking men aged 40 to 80 years, who had undergone radiotherapy (RT) between 9 and 30 months prior to the survey. RESULTS: Of 356 men with PCa, less than half were meeting NPAGA (41.9%). Lower education and quality of life (QoL), a higher number of comorbid conditions and symptoms of depression and anxiety were associated with decreased leisure-time PA. Patients treated with androgen deprivation therapy were significantly less active than patients treated with RT only. Logistic regression analyses indicated that the likelihood of meeting NPAGA was significantly lower with higher levels of depressive symptoms and lower levels of education. CONCLUSIONS: Meeting NPAGA is associated with higher QoL and psychosocial well-being in men with PCa. These findings contribute important information for targeting PA interventions to PCa survivors. PMID- 23749431 TI - Backbone and side-chain 1H, 13C and 15N resonance assignments of the OB domain of the single stranded DNA binding protein from Sulfolobus solfataricus and chemical shift mapping of the DNA-binding interface. AB - Single stranded DNA binding proteins (SSBs) are present in all known cellular organisms and are critical for DNA replication, recombination and repair. The SSB from the hyperthermophilic crenarchaeote Sulfolobus solfataricus (SsoSSB) has an unusual domain structure with a single DNA-binding oligonucleotide binding (OB) fold coupled to a flexible C-terminal tail. This 'simple' domain organisation differs significantly from other known SSBs, such as human replication protein A (RPA). However, it is conserved in another important human SSB, hSSB1, which we have recently discovered and shown to be essential in the DNA damage response. In this study we report the solution-state backbone and side-chain chemical shift assignments of the OB domain of SsoSSB. In addition, using the recently determined crystal structure, we have utilized NMR to reveal the DNA-binding interface of SsoSSB. These data will allow us to elucidate the structural basis of DNA-binding and shed light onto the molecular mechanism by which these 'simple' SSBs interact with single-stranded DNA. PMID- 23749432 TI - Editor's Spotlight/Take 5: Nano-ceramic composite scaffolds for bioreactor-based bone engineering. PMID- 23749434 TI - Li-S battery analyzed by UV/Vis in operando mode. AB - Battery watch: UV/Vis spectrophotometry is demonstrated as a powerful analytical method for the in situ study of polysulfides. Through the interactions that occur between different chain-length polysulfide molecules and the UV/Vis radiation, quantitative and qualitative determination of the polysulfides formed during Li-S battery operation can be achieved. PMID- 23749433 TI - Validation of PROMIS (r) Physical Function computerized adaptive tests for orthopaedic foot and ankle outcome research. AB - BACKGROUND: In 2012, the American Orthopaedic Foot & Ankle Society((r)) established a national network for collecting and sharing data on treatment outcomes and improving patient care. One of the network's initiatives is to explore the use of computerized adaptive tests (CATs) for patient-level outcome reporting. QUESTIONS/PURPOSES: We determined whether the CAT from the NIH Patient Reported Outcome Measurement Information System((r)) (PROMIS((r))) Physical Function (PF) item bank provides efficient, reliable, valid, precise, and adequately covered point estimates of patients' physical function. METHODS: After informed consent, 288 patients with a mean age of 51 years (range, 18-81 years) undergoing surgery for common foot and ankle problems completed a web-based questionnaire. Efficiency was determined by time for test administration. Reliability was assessed with person and item reliability estimates. Validity evaluation included content validity from expert review and construct validity measured against the PROMIS((r)) Pain CAT and patient responses based on tradeoff perceptions. Precision was assessed by standard error of measurement (SEM) across patients' physical function levels. Instrument coverage was based on a person item map. RESULTS: Average time of test administration was 47 seconds. Reliability was 0.96 for person and 0.99 for item. Construct validity against the Pain CAT had an r value of -0.657 (p < 0.001). Precision had an SEM of less than 3.3 (equivalent to a Cronbach's alpha of >= 0.90) across a broad range of function. Concerning coverage, the ceiling effect was 0.32% and there was no floor effect. CONCLUSIONS: The PROMIS((r)) PF CAT appears to be an excellent method for measuring outcomes for patients with foot and ankle surgery. Further validation of the PROMIS((r)) item banks may ultimately provide a valid and reliable tool for measuring patient-reported outcomes after injuries and treatment. PMID- 23749435 TI - Complement C4 maintains peripheral B-cell tolerance in a myeloid cell dependent manner. AB - The factors that allow self-reactive B cells to escape negative selection and become activated remain poorly defined. Using a BCR knock-in mouse strain, we identify a pathway by which B-cell selection to nucleolar self-antigens is complement dependent. Deficiency in complement component C4 led to a breakdown in the elimination of autoreactive B-cell clones at the transitional stage, characterized by a relative increase in their response to a range of stimuli, entrance into follicles, and a greater propensity to form self-reactive GCs. Using mixed BM chimeras, we found that the myeloid compartment was sufficient to restore negative selection in the autoreactive mice. A model is proposed in which in the absence of complement C4, inappropriate clearance of apoptotic debris promotes chronic activation of myeloid cells, allowing the maturation and activation of self-reactive B-cell clones leading to increased spontaneous formation of GCs. PMID- 23749436 TI - Intraspinal stretch receptor neurons mediate different motor responses along the body in lamprey. AB - In lampreys, stretch receptor neurons (SRNs) are located at the margins of the spinal cord and activated by longitudinal stretch in that area caused by body bending. The aim of this study was a comprehensive analysis of motor responses to bending of the lamprey body in different planes and at different rostrocaudal levels. For this purpose, in vitro preparation of the spinal cord isolated together with notochord was used, and responses to bending were recorded from SRNs, as well as from motoneurons innervating the dorsal (dMNs) and ventral (vMNs) parts of a myotome. It was found that SRNs were activated on the convex (stretched) side of the preparation during bending both in the yaw and in the pitch plane. By contrast, responses of motoneurons depended on the site and plane of bending. In the yaw plane, concave responses to bending of rostral segments and convex responses to bending of mid-body segments prevailed. In the pitch plane, convex responses in dMNs and concave responses in vMNs to bending in mid body segments prevailed. These spinal reflexes could contribute to feedback regulation of locomotor body undulations and to the control of body configuration during locomotion. After a longitudinal split of the spinal cord, only convex responses in motoneurons were present, suggesting an important role of contralateral networks in determining the type of motor response. Stimulation of the brainstem changed the type of motor response to bending, suggesting that these spinal reflexes can be modified by supraspinal signals in accordance with different motor behaviors. PMID- 23749437 TI - Applying the knowledge to action framework to plan a strategy for implementing breast cancer screening guidelines: an interprofessional perspective. AB - Integrated knowledge translation (IKT) interventions may be one solution to improving the uptake of clinical guidelines. IKT research initiatives are particularly relevant for breast cancer research and initiatives targeting the implementation of clinical guidelines and guideline implementation initiatives, where collaboration with an interdisciplinary team of practitioners, patients, caregivers, and policy makers is needed for producing optimum patient outcomes. The objective of this paper was to describe the process of developing an IKT strategy that could be used by guideline developers to improve the uptake of their new clinical practice guidelines on breast cancer screening. An interprofessional group of students as well as two faculty members met six times over three days at the KT Canada Summer Institute in 2011. The team used all of the phases of the action cycle in the Knowledge to Action Framework as an organizing framework. While the entire framework was used, the step involving assessing barriers to knowledge use was judged to be particularly relevant in anticipating implementation problems and being able to inform the specific KT interventions that would be appropriate to mitigate these challenges and to accomplish goals and outcomes. This activity also underscored the importance of group process and teamwork in IKT. We propose that an a priori assessment of barriers to knowledge use (i.e., level and corresponding barriers), along with the other phases of the Knowledge to Action Framework, is a strategic approach for KT strategy development, implementation, and evaluation planning and could be used in the future planning of KT strategies. PMID- 23749438 TI - Model-based identifiable parameter determination applied to a simultaneous saccharification and fermentation process model for bio-ethanol production. AB - In this work, a methodology for the model-based identifiable parameter determination (MBIPD) is presented. This systematic approach is proposed to be used for structure and parameter identification of nonlinear models of biological reaction networks. Usually, this kind of problems are over-parameterized with large correlations between parameters. Hence, the related inverse problems for parameter determination and analysis are mathematically ill-posed and numerically difficult to solve. The proposed MBIPD methodology comprises several tasks: (i) model selection, (ii) tracking of an adequate initial guess, and (iii) an iterative parameter estimation step which includes an identifiable parameter subset selection (SsS) algorithm and accuracy analysis of the estimated parameters. The SsS algorithm is based on the analysis of the sensitivity matrix by rank revealing factorization methods. Using this, a reduction of the parameter search space to a reasonable subset, which can be reliably and efficiently estimated from available measurements, is achieved. The simultaneous saccharification and fermentation (SSF) process for bio-ethanol production from cellulosic material is used as case study for testing the methodology. The successful application of MBIPD to the SSF process demonstrates a relatively large reduction in the identified parameter space. It is shown by a cross validation that using the identified parameters (even though the reduction of the search space), the model is still able to predict the experimental data properly. Moreover, it is shown that the model is easily and efficiently adapted to new process conditions by solving reduced and well conditioned problems. PMID- 23749439 TI - Development of a female attractant for the click beetle pest Agriotes brevis. AB - BACKGROUND: Traps suitable for catching female Agriotes click beetles may provide better reconnaissance than pheromone-baited traps which catch only males, thereby contributing to more efficient crop protection. The basis for this study came from (i) observations of female Agriotes brevis (Candeze) aggregating beneath foliage of Medicago sativa (L.) and Lolium italicum (A. Br.) placed on plastic sheets on bare soil, and (ii) field tests demonstrating attraction of females to traps baited with foliage from these plants. The aim was to identify and field test volatile compounds from M. sativa and L. italicum leaves. RESULTS: A number of electrophysiologically active chemicals were identified from headspace extracts of M. sativa and L. italicum. Three different synthetic blends of the identified compounds, comprising four, seven and nine components, were field tested. The four- and nine-component blends caught more female A. brevis than unbaited traps, with the proportion of females not differing between blends. CONCLUSION: The plant-derived blends were shown to catch female A. brevis under field conditions when applied in traps. Of these, the four-component blend, given its relatively simple composition [(Z)-3-hexenyl acetate:methyl benzoate:(Z)-3 hexen-1-ol:methyl salicylate 300:5:30:30 mg bait(-1)], may be a suitable 'standard' blend for bait optimisation. PMID- 23749440 TI - Recent advances in the structure elucidation of small organic molecules by the LSD software. AB - The LSD software proposes the structures of small organic molecules that fit with structural constraints from 1D and 2D NMR spectroscopy. Its initial design introduced limits that needed to be eliminated to extend its scope and help its users choose the most likely structure among those proposed. The LSD software code has been improved, so that it recognizes a wider set of atom types to build molecules. More flexibility has been given in the interpretation of 2D NMR data, including the automatic detection of very long-range correlations. A program named pyLSD was written to deal with problems in which atom types are ambiguously defined. It also provides a (13)C NMR chemical shift-based solution ranking algorithm. PyLSD was able to propose the correct structure of hexacyclinol, a natural product whose structure determination has been highly controversal. The solution was ranked first within a list of ten structures that were produced by pyLSD from the literature NMR data. The structure of an aporphin natural product was determined by pyLSD, taking advantage of the possibility of handling electrically charged atoms. The structure generation of the insect antifeedant azadirachtin by LSD was reinvestigated by pyLSD, considering that three (13)C resonances did not lead to univocal hybridization states. PMID- 23749441 TI - Young breast cancer patients' involvement in treatment decisions: the major role played by decision-making about surgery. AB - OBJECTIVE: The objective of this study is to investigate young breast cancer patients' preferred and actual involvement in decision-making about surgery, chemotherapy, and adjuvant endocrine therapy (AET). METHODS: A total of 442 women aged 18-40 years at the time of the diagnosis participated in the region-wide ELIPPSE40 cohort study (southeastern France). Logistic regression analyses were performed on various factors possibly affecting patients' preferred and perceived involvement in the decisions about their cancer treatment. RESULTS: The women's mean age was 36.8 years at enrollment. Preference for a fully passive role in decision-making was stated by 20.7% of them. It was favored by regular breast surveillance (p = 0.04) and positive experience of being informed about cancer diagnosis (p = 0.02). Patients' preferences were independently associated with their reported involvement in decision-making about surgery (p = 0.01). A fully passive role in decision-making about chemotherapy and AET was more likely to be reported by patients who perceived their involvement in decision-making about surgery as having been fully passive (adjusted odds ratio = 4.8, CI95% [2.7-8.7], and adjusted odds ratio = 9.8, CI95% [3.3-29.2], respectively). This study shows a significant relationship between the use of antidepressants and involvement in decision-making about surgery, and confirms the relationship between impaired quality of life (in the psychological domain) and a fully passive role in decisions about cancer treatment. CONCLUSIONS: Patients' involvement in decision making about chemotherapy and AET was strongly influenced by their experience of decision-making about surgery, regardless of their tumor stage and history of breast or ovarian cancer. When decisions are being made about surgery, special attention should be paid to facilitating breast cancer patients' involvement in the decision-making. PMID- 23749442 TI - Decision support using anesthesia information management system records and accreditation council for graduate medical education case logs for resident operating room assignments. AB - Our goal in this study was to develop decision support systems for resident operating room (OR) assignments using anesthesia information management system (AIMS) records and Accreditation Council for Graduate Medical Education (ACGME) case logs and evaluate the implementations. We developed 2 Web-based systems: an ACGME case-log visualization tool, and Residents Helping in Navigating OR Scheduling (Rhinos), an interactive system that solicits OR assignment requests from residents and creates resident profiles. Resident profiles are snapshots of the cases and procedures each resident has done and were derived from AIMS records and ACGME case logs. A Rhinos pilot was performed for 6 weeks on 2 clinical services. One hundred sixty-five requests were entered and used in OR assignment decisions by a single attending anesthesiologist. Each request consisted of a rank ordered list of up to 3 ORs. Residents had access to detailed information about these cases including surgeon and patient name, age, procedure type, and admission status. Success rates at matching resident requests were determined by comparing requests with AIMS records. Of the 165 requests, 87 first choice matches (52.7%), 27 second-choice matches (16.4%), and 8 third-choice matches (4.8%) were made. Forty-three requests were unmatched (26.1%). Thirty nine first-choice requests overlapped (23.6%). Full implementation followed on 8 clinical services for 8 weeks. Seven hundred fifty-four requests were reviewed by 15 attending anesthesiologists, with 339 first-choice matches (45.0%), 122 second choice matches (16.2%), 55 third-choice matches (7.3%), and 238 unmatched (31.5%). There were 279 overlapping first-choice requests (37.0%). The overall combined match success rate was 69.4%. Separately, we developed an ACGME case-log visualization tool that allows individual resident experiences to be compared against case minimums as well as resident peer groups. We conclude that it is feasible to use ACGME case-log data in decision support systems for informing resident OR assignments. Additional analysis will be necessary to assess the educational impact of these systems. PMID- 23749443 TI - The cytotoxicity of bupivacaine, ropivacaine, and mepivacaine on human chondrocytes and cartilage. AB - BACKGROUND: Intraarticular injections of local anesthetics are frequently used as part of multimodal pain regimens. However, recent data suggest that local anesthetics affect chondrocyte viability. In this study, we assessed the chondrotoxic effects of mepivacaine, ropivacaine, and bupivacaine. We hypothesized that specific cytotoxic potencies directly correlate with analgesic potencies, and that cytotoxic effects in intact cartilage are different than in osteoarthritic tissue. METHODS: Human articular chondrocytes were exposed to equal and equipotent concentrations of bupivacaine, ropivacaine, and mepivacaine for 1 hour. Cell viability, apoptosis, and necrosis were determined at predefined time points using flow cytometry, live-dead staining, and caspase detection. Intact and osteoarthritic human cartilage explants were treated with equipotent concentrations of named drugs to determine cell viability applying fluorescence microscopy. RESULTS: Chondrotoxic effects increased from ropivacaine to mepivacaine to bupivacaine in a time-dependent and concentration-dependent manner. Compared with control, bupivacaine 0.5% decreased chondrocyte viability to 78% +/- 9% (P = 0.0183) 1 hour and 16% +/- 10% (P < 0.0001) 24 hours later, as determined by live-dead staining in monolayer cultures. Viability rates were reduced to 80% +/- 7% (P = 0.0475) 1 hour and 80% +/- 10% (P = 0.0095) 24 hours after treatment with ropivacaine 0.75%. After exposure to mepivacaine 2%, viable cells were scored 36% +/- 6% (P < 0.0001) after 1 hour and 30% +/- 11% (P < 0.0001) after 24 hours. Ropivacaine treatment was less chondrotoxic than bupivacaine (P = 0.0006) and mepivacaine exposure (P = 0.0059). Exposure to concentrations up to 0.25% of bupivacaine, 0.5% of ropivacaine, and 0.5% of mepivacaine did not reveal significant chondrotoxicity in flow cytometry. However, chondrotoxicity did not correlate with potency of local anesthetics. Immediate cell death was mainly due to necrosis followed by apoptosis. Cellular death rates were clearly higher in osteoarthritic compared with intact cartilage after bupivacaine, mepivacaine, and ropivacaine treatment in a decreasing order. CONCLUSION: Bupivacaine, ropivacaine, and mepivacaine are chondrotoxic in a time dependent, concentration-dependent, and drug-dependent manner. Chondrotoxic and analgesic potencies do not directly correlate. Cellular death rates were higher in osteoarthritic compared with intact cartilage after local anesthetic treatment. PMID- 23749444 TI - Acute hypotension associated with intraoperative cell salvage using a leukocyte depletion filter during management of obstetric hemorrhage due to amniotic fluid embolism. AB - Amniotic fluid embolism (AFE) is a rare but catastrophic obstetric complication that can lead to profound coagulopathy and hemorrhage. The role of cell salvage and recombinant human Factor VIIa (rFVIIa) administration in such cases remains unclear. We present a case of AFE and describe our experience with the use of cell salvage and rFVIIa administration during the resuscitation. Cell salvage and transfusion through a leukocyte depletion filter was attempted after the diagnosis of AFE was made, but the attempted transfusion was immediately followed by hypotension and a worsening of hemodynamics. rFVIIa, on the contrary, was used with clinical improvement in coagulopathy and without apparent adverse thrombotic effect. PMID- 23749445 TI - The frequency of cardiac arrests in patients with congenital heart disease undergoing cardiac catheterization. AB - BACKGROUND: Cardiac catheterization for patients with congenital heart disease has shifted from diagnostic to predominantly interventional procedures because of advances in catheter-based technologies. Children undergoing therapeutic catheterization may be at higher risk of adverse events, and the purpose of our study was to determine the incidence of cardiac arrest (CA) in patients with congenital heart disease undergoing cardiac catheterization at a large pediatric tertiary referral center. METHODS: All CAs from January 2004 through December 2009 occurring in the cardiac catheterization laboratory were reviewed. A CA was defined as an event in which cessation of circulation required chest compressions. Procedure, patient, practitioner, and system-related factors were examined. RESULTS: Over the study period, during 7289 catheterization procedures, 70 procedures were associated with a CA (0.96 [99% confidence interval, 0.7-1.3] per 100 procedures); 48 events (69%) were successfully resuscitated to a perfusing rhythm, 18 events (26%) resulted in need for extracorporeal membrane oxygenation, and 4 events (6%) resulted in unsuccessful resuscitation. Sudden onset of cardiac arrhythmia led to CA during 38 events (54%). The duration of resuscitation after CA was <=11 minutes in 71%. Occurrence of CA was associated with interventional procedures (P < 0.001) and younger age (P < 0.001). A change in systems for scheduling and communication of cases was associated with a significant reduction in the incidence of CA (1.5% vs 0.7%; P = 0.002). CONCLUSIONS: The incidence of CA in children undergoing cardiac catheterization is high compared with pediatric noncardiac surgery. Procedural and system factors were associated with occurrence of CA in this cohort. These issues highlight the need for close communication, anticipation, and preparation. PMID- 23749446 TI - Leaving more than your fingerprint on the intravenous line: a prospective study on propofol anesthesia and implications of stopcock contamination. AB - BACKGROUND: Acute care handling of IV stopcocks during anesthesia and surgery may result in contaminated IV tubing sets. In the context of widespread propofol use, a nutrient-rich hypnotic drug, we hypothesized that propofol anesthesia increases bacterial contamination of IV stopcocks and may compromise safety of IV tubing sets when continued to be used after propofol anesthesia. METHODS: We conducted an in vitro trial by collecting IV tubing sets at the time of patient discharge from same-day ambulatory procedures performed with and without propofol anesthesia. These extension sets were then held at room temperature for 6, 24, or 48 hours. We cultured 50 samples at each interval for both cohorts. Quantitative cultures were done by aspirating the IV stopcock dead space and plating the aspirate on blood agar for colony count and speciation. RESULTS: Positive bacterial counts were recovered from 17.3% of propofol anesthesia stopcocks (26/150) and 18.6% of nonpropofol stopcocks (28/150). At 6 hours, the average bacterial counts from stopcocks with visible residual propofol was 44 colony forming units (CFU)/mL, compared with 41 CFU/mL with no visible residual propofol and 37 CFU/mL in nonpropofol anesthesia stopcocks. There was a 100-fold increase in bacterial number in contaminated stopcock dead spaces at 48 hours after propofol anesthesia. This difference remained significant when comparing positive counts from stopcocks with no visible residual propofol and nonpropofol anesthesia (P = 0.034). CONCLUSIONS: There is a covert incidence and degree of IV stopcock bacterial contamination during anesthesia which is aggravated by propofol anesthetic. Propofol anesthesia may increase risk for postoperative infection because of bacterial growth in IV stopcock dead spaces. PMID- 23749447 TI - Geography and ESRD care: what contributes most to hemodialysis patient-provider visit variation? PMID- 23749448 TI - Genomes of Ashbya fungi isolated from insects reveal four mating-type loci, numerous translocations, lack of transposons, and distinct gene duplications. AB - The filamentous fungus Ashbya gossypii is a cotton pathogen transmitted by insects. It is readily grown and manipulated in the laboratory and is commercially exploited as a natural overproducer of vitamin B2. Our previous genome analysis of A. gossypii isolate ATCC10895, collected in Trinidad nearly 100 years ago, revealed extensive synteny with the Saccharomyces cerevisiae genome, leading us to use it as a model organism to understand the evolution of filamentous growth. To further develop Ashbya as a model system, we have investigated the ecological niche of A. gossypii and isolated additional strains and a sibling species, both useful in comparative analysis. We isolated fungi morphologically similar to A. gossypii from different plant-feeding insects of the suborder Heteroptera, generated a phylogenetic tree based on rDNA-ITS sequences, and performed high coverage short read sequencing with one A. gossypii isolate from Florida, a new species, Ashbya aceri, isolated in North Carolina, and a genetically marked derivative of ATCC10895 intensively used for functional studies. In contrast to S. cerevisiae, all strains carry four not three mating type loci, adding a new puzzle in the evolution of Ashbya species. Another surprise was the genome identity of 99.9% between the Florida strain and ATCC10895, isolated in Trinidad. The A. aceri and A. gossypii genomes show conserved gene orders rearranged by eight translocations, 90% overall sequence identity, and fewer tandem duplications in the A. aceri genome. Both species lack transposable elements. Finally, our work identifies plant-feeding insects of the suborder Heteroptera as the most likely natural reservoir of Ashbya, and that infection of cotton and other plants may be incidental to the growth of the fungus in its insect host. PMID- 23749449 TI - Phylogenetic portrait of the Saccharomyces cerevisiae functional genome. AB - The genome of budding yeast (Saccharomyces cerevisiae) contains approximately 5800 protein-encoding genes, the majority of which are associated with some known biological function. Yet the extent of amino acid sequence conservation of these genes over all phyla has only been partially examined. Here we provide a more comprehensive overview and visualization of the conservation of yeast genes and a means for browsing and exploring the data in detail, down to the individual yeast gene, at http://yeast-phylogroups.princeton.edu. We used data from the OrthoMCL database, which has defined orthologs from approximately 150 completely sequenced genomes, including diverse representatives of the archeal, bacterial, and eukaryotic domains. By clustering genes based on similar patterns of conservation, we organized and visualized all the protein-encoding genes in yeast as a single heat map. Most genes fall into one of eight major clusters, called "phylogroups." Gene ontology analysis of the phylogroups revealed that they were associated with specific, distinct trends in gene function, generalizations likely to be of interest to a wide range of biologists. PMID- 23749450 TI - Targeted sequence capture provides insight into genome structure and genetics of male sterility in a gynodioecious diploid strawberry, Fragaria vesca ssp. bracteata (Rosaceae). AB - Gynodioecy is a sexual system wherein females coexist with hermaphrodites. It is of interest not only because male-sterile plants are advantageous in plant breeding but also because it can be a crucial step in the evolutionary transition to entirely separate sexes (dioecy) from a hermaphroditic ancestor. The gynodioecious diploid wild strawberry, Fragaria vesca ssp. bracteata (Rosaceae), is a member of a clade with both dioecious and cultivated species, making it an ideal model in which to study the genetics of male sterility. To create a genetic map of F. v. ssp. bracteata, we identified informative polymorphisms from genomic sequencing (3-5x coverage) of two outbred plants from the same population. Using targeted enrichment, we sequenced 200 bp surrounding each of 6575 polymorphisms in 48 F1 offspring, yielding genotypes at 98% of targeted sites with mean coverage >100x, plus more than 600-kb high-coverage nontargeted sequence. With the resulting linkage map of 7802 stringently filtered markers (5417 targeted), we assessed recombination rates and genomic incongruities. Consistent with past work in strawberries, male sterility is dominant, segregates 1:1, and maps to a single location in the female. Further mapping an additional 55 offspring places male sterility in a gene-dense, 338-kb region of chromosome 4. The region is not syntenic with the sex-determining regions in the closely related octoploids, F. chiloensis and F. virginiana, suggesting either independent origins or translocation. The 57 genes in this region do not include protein families known to control male sterility and thus suggest alternate mechanisms for the suppression of male function. PMID- 23749453 TI - 1H, 15N, and 13C chemical shift assignments of cyanobacteriochrome NpF2164g3 in the photoproduct state. AB - Cyanobacteriochrome (CBCR) photosensory proteins are phytochrome relatives using bilin chromophores for light sensing across the visible spectrum. Structural information is not available for two of the four known CBCR subfamilies. NpF2164g3 is a member of one such subfamily, exhibiting a violet/orange photocycle. We report backbone NMR chemical shift assignments for the light activated orange-absorbing state of NpF2164g3 (BMRB no. 19150). PMID- 23749451 TI - Microarray comparison of anterior and posterior Drosophila wing imaginal disc cells identifies novel wing genes. AB - Signaling between cells in the anterior (A) and posterior (P) compartments directs Drosophila wing disc development and is dependent on expression of the homeodomain transcription factor Engrailed (En) in P cells. Downstream of en, posteriorly expressed Hedgehog (Hh) protein signals across the A/P border to establish a developmental organizer that directs pattern formation and growth throughout the wing primordium. Here we extend investigations of the processes downstream of en by using expression array analysis to compare A and P cells. A total of 102 candidate genes were identified that express differentially in the A and P compartments; four were characterized: Stubble (Sb) expression is restricted to A cells due to repression by en. CG15905, CG16884; CG10200/hase und igel (hui) are expressed in A cells downstream of Hh signaling; and RNA interference for hui, Stubble, and CG16884 revealed that each is essential to wing development. PMID- 23749454 TI - 1H, 13C and 15N resonance assignments of the apo and holo states of flavodoxin YqcA from Escherichia coli. AB - Flavodoxins are a family of FMN binding proteins widely distributed in prokaryotes. They involve in various electron transfer reactions using the non covalently bound FMN cofactor as the redox center. The Escherichia coli yqcA gene was identified to encode a short-chain favodoxin based on sequence information. However, the structure of YqcA protein is unknown and its exact biological function in cell is yet to be investigated. Herein, we report the resonance assignments of (1)H, (13)C and (15)N atoms of E. coli YqcA in both the apo and holo states. PMID- 23749455 TI - Comments on recent discussions providing differing causation methodologies. PMID- 23749456 TI - (S)-Goniothalamin induces DNA damage, apoptosis, and decrease in BIRC5 messenger RNA levels in NCI-H460 cells. AB - (R)-Goniothalamin (R-GNT) is a secondary metabolite isolated from the plants of the genus Goniothalamus. This molecule has attracted the attention of researchers because of its selective cytotoxicity against tumor cells and its ability to induce apoptosis. (S)-Goniothalamin (S-GNT) is a synthetic enantiomer of R-GNT, and its mechanism of action is largely unknown. In this study, we investigated the activity of S-GNT in a human non-small cell lung cancer NCI-H460 cells. We observed that the cells exposed to this compound exhibited cytotoxicity in a concentration-dependent manner. Based on the data obtained through the assessment of apoptosis induction in situ and the comet assay, we suggest that this cytotoxicity occurs due to the potential ability of this molecule to induce DNA damage with the consequent induction of cell death via apoptosis. A significant reduction in the messenger RNA levels of baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) gene that encodes the survivin protein was found. This novel finding may explain the inhibition of cell proliferation and induction of apoptosis in tumor cells caused by this compound. PMID- 23749457 TI - Podocyte loss involves MDM2-driven mitotic catastrophe. AB - Podocyte apoptosis as a pathway of podocyte loss is often suspected but rarely detected. To study podocyte apoptosis versus inflammatory forms of podocyte death in vivo, we targeted murine double minute (MDM)-2 for three reasons. First, MDM2 inhibits p53-dependent apoptosis; second, MDM2 facilitates NF-kappaB signalling; and third, podocytes show strong MDM2 expression. We hypothesized that blocking MDM2 during glomerular injury may trigger p53-mediated podocyte apoptosis, proteinuria, and glomerulosclerosis. Unexpectedly, MDM2 blockade in early adriamycin nephropathy of Balb/c mice had the opposite effect and reduced intra renal cytokine and chemokine expression, glomerular macrophage and T-cell counts, and plasma creatinine and blood urea nitrogen levels. In cultured podocytes exposed to adriamycin, MDM2 blockade did not trigger podocyte death but induced G2/M arrest to prevent aberrant nuclear divisions and detachment of dying aneuploid podocytes, a feature of mitotic catastrophe in vitro and in vivo. Consistent with these observations, 12 of 164 consecutive human renal biopsies revealed features of podocyte mitotic catastrophe but only in glomerular disorders with proteinuria. Furthermore, delayed MDM2 blockade reduced plasma creatinine levels, blood urea nitrogen, tubular atrophy, interstitial leukocyte numbers, and cytokine expression as well as interstitial fibrosis. Together, MDM2 mediated mitotic catastrophe is a previously unrecognized variant of podocyte loss where MDM2 forces podocytes to complete the cell cycle, which in the absence of cytokinesis leads to podocyte aneuploidy, mitotic catastrophe, and loss by detachment. MDM2 blockade with nutlin-3a could be a novel therapeutic strategy to prevent renal inflammation, podocyte loss, glomerulosclerosis, proteinuria, and progressive kidney disease. PMID- 23749458 TI - The relationship between discrimination and high-risk social ties by race/ethnicity: examining social pathways of HIV risk. AB - High-risk social ties portend differences in opportunity for HIV exposures and may contribute to racial/ethnic disparities in HIV transmission. Discrimination may affect the formation of high-risk social ties and has not been explored as a possible explanation for these persistent disparities. Using data from injection and non-injection drug users, we examined the association between the number of high-risk sex and drug ties with discrimination due to race, drug use, and incarceration stratified by race/ethnicity. Negative binomial regression models were used. While blacks had significantly fewer injecting ties than Latinos and whites, blacks who reported racial discrimination compared to blacks who did not, had more sex and injecting ties. Latinos who reported drug use discrimination compared to Latinos who did not also had more sex ties. Latinos and whites who reported drug use discrimination had more injecting ties than Latinos and whites who did not. Discrimination is associated with high-risk social ties among all racial/ethnic groups. But, these data highlight different forms of discrimination within racial/ethnic group are associated with risky social ties. More research is needed to confirm these findings and further explore the association between various forms of discrimination and social ties that may help explain racial/ethnic disparities in HIV. PMID- 23749459 TI - Estimation of isotropic nuclear magnetic shieldings in the CCSD(T) and MP2 complete basis set limit using affordable correlation calculations. AB - A linear correlation between isotropic nuclear magnetic shielding constants for seven model molecules (CH2 O, H2 O, HF, F2 , HCN, SiH4 and H2 S) calculated with 37 methods (34 density functionals, RHF, MP2 and CCSD(T)), with affordable pcS-2 basis set and corresponding complete basis set results, estimated from calculations with the family of polarization-consistent pcS-n basis sets is reported. This dependence was also supported by inspection of profiles of deviation between CBS estimated nuclear shieldings and shieldings obtained with the significantly smaller basis sets pcS-2 and aug-cc-pVTZ-J for the selected set of 37 calculation methods. It was possible to formulate a practical approach of estimating the values of isotropic nuclear magnetic shielding constants at the CCSD(T)/CBS and MP2/CBS levels from affordable CCSD(T)/pcS-2, MP2/pcS-2 and DFT/CBS calculations with pcS-n basis sets. The proposed method leads to a fairly accurate estimation of nuclear magnetic shieldings and considerable saving of computational efforts. PMID- 23749460 TI - Spiritual well-being in long-term colorectal cancer survivors with ostomies. AB - OBJECTIVE: Spiritual well-being (SpWB) is integral to health-related quality of life. The challenges of colorectal cancer (CRC) and subsequent bodily changes can affect SpWB. We analyzed the SpWB of CRC survivors with ostomies. METHODS: Two hundred-eighty-three long-term (>= 5 years) CRC survivors with permanent ostomies completed the modified City of Hope Quality of Life-Ostomy (mCOH-QOL-O) questionnaire. An open-ended question elicited respondents' greatest challenge in living with an ostomy. We used content analysis to identify SpWB responses and develop themes. We analyzed responses on the three-item SpWB sub-scale. RESULTS: Open-ended responses from 52% of participants contained SpWB content. Fifteen unique SpWB themes were identified. Sixty percent of individuals expressed positive themes such as "positive attitude", "I am fortunate", "appreciate life more", and "strength through religious faith". Negative themes, expressed by only 29% of respondents, included "struggling to cope", "not feeling 'normal' ", and "loss". Fifty-five percent of respondents expressed ambivalent themes including "learning acceptance", "an ostomy is the price for survival", "reason to be around despite suffering", and "continuing to cope despite challenges". The majority (64%) had a high SpWB sub-scale score. CONCLUSIONS: Although CRC survivors with ostomies infrequently mentioned negative SpWB themes as a major challenge, ambivalent themes were common. SpWB themes were often mentioned as a source of resilience or part of the struggle to adapt to an altered body after cancer surgery. Interventions to improve the quality of life of cancer survivors should contain program elements designed to address SpWB that support personal meaning, inner peace, inter connectedness, and belonging. PMID- 23749461 TI - Serum interferon gamma level predicts recurrence in hepatocellular carcinoma patients after curative treatments. AB - Host immunity may have important role in the prognosis of hepatocellular carcinoma (HCC). The aim of this study was to evaluate the correlation between circulating immune regulators and clinical outcome in patients with HCC. Sixty three HCC patients were prospectively enrolled. Serum levels of interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), interferon-gamma (IFN-gamma) and interferon gamma-inducible protein 10 (IP-10) were measured, as well as the prevalence of regulatory T cells (Treg), NK(+) T cells, invariant natural killer T cells (iNKT), programmed cell death-1 (PD-1)(+) CD8(+) T cells, T helper 17 cells (Th17), CD69(+) and CD45RO(+) T cells in peripheral blood mononuclear cells (PBMC). Correlation between these immune regulators and clinical outcome were analyzed. A low serum IFN-gamma level (<50 pg/mL) was significantly associated tumor stage (BCLC stage B: 61.25% vs. stage A: 25%, p = 0.010) and tumor size (>5 cm: 53.8% vs. <5 cm: 25%, p = 0.047). Recurrence-free survival was evaluated in 48 patients receiving curative treatment of HCC. By multivariate analysis, BCLC stage [hazard ratio (HR) = 32.180, p < 0.001], tumor size (HR = 15.373, p = 0.005), AST (HR = 3.796, p = 0.011) and IFN-gamma (HR = 0.354, p = 0.018) levels were independent factors associated with recurrence-free survival. In conclusion, serum IFN-gamma level correlates with tumor stage and tumor size in HCC patients. Patients with lower baseline IFN-gamma levels have a higher risk of tumor recurrence after curative treatment. IFN-gamma may reflect host anti-tumor immunity and may be a potential marker of HCC recurrence after curative treatment. PMID- 23749462 TI - A cross-cultural study of noblesse oblige in economic decision-making. AB - A cornerstone of economic theory is that rational agents are self-interested, yet a decade of research in experimental economics has shown that economic decisions are frequently driven by concerns for fairness, equity, and reciprocity. One aspect of other-regarding behavior that has garnered attention is noblesse oblige, a social norm that obligates those of higher status to be generous in their dealings with those of lower status. The results of a cross-cultural study are reported in which marked noblesse oblige was observed on a reciprocal contract decision-making task. Participants from seven countries that vary along hierarchical and individualist/collectivist social dimensions were more tolerant of non-reciprocation when they adopted a high-ranking perspective compared with a low-ranking perspective. PMID- 23749463 TI - Evaluation of candidate systems for mass trapping against Ceratitis spp. on La Reunion island. AB - BACKGROUND: Two Ceratitis spp. coexist on the island of La Reunion, Ceratitis rosa (Karsch) and C. capitata (Wiedemann). The effectiveness of candidate systems based on attractants and traps to control both species was evaluated through comparative studies of trap types, attractants, insecticides and commercial complete systems. RESULTS: The Ceratitis spp. most captured in all trials was C. rosa. Captures of C. rosa and C. capitata were not significantly different when Maxitrap(r) or Tephri-trap(r) were used. Captures with the Easy-trap(r) were lower for both species. The BioLure(r) Med Fly lure showed higher catches of C. rosa than Ferag(r) CC D TM. The proportion of dead C. rosa did not differ significantly when deltamethrin or dichlorvos was used. There were no significant differences in the capture of C. rosa and C. capitata between commercial systems composed of the lure Ferag(r) CC D TM, the Maxitrap(r) and dichlorvos and the BioLure(r) Unipak, the Tephri-trap(r) and dichlorvos. The Cera Trap(r) system performed less effectively. CONCLUSION: The most effective traps for the capture of C. rosa and C. capitata were Maxitrap(r) and Tephri-trap(r); the most effective attractants were BioLure(r) Med Fly for C. rosa and BioLure(r) Med Fly, BioLure(r) Unipak and Ferag(r) CC D TM for C. capitata. However, for both species the most effective commercial combinations of trap and attractant were Maxitrap(r) with Ferag(r) CC D TM and Tephri-trap(r) with BioLure(r) Unipak, both using dichlorvos. The insecticide deltamethrin showed good efficacy when used inside traps. PMID- 23749464 TI - Fast and robust extraction of surrogate respiratory signal from intra-operative liver ultrasound images. AB - PURPOSE: In model-based respiratory motion estimation for the liver or other abdominal organs, the surrogate respiratory signal is usually obtained by using special tracking devices from skin or diaphragm, and subsequently applied to parameterize a 4D motion model for prediction or compensation. However, due to the intrinsic limits and economical costs of these tracking devices, the identification of the respiratory signal directly from intra-operative ultrasound images is a more attractive alternative. METHODS: We propose a fast and robust method to extract the respiratory motion of the liver from an intra-operative 2D ultrasound image sequence. Our method employs a preprocess to remove speckle-like noises in the ultrasound images and utilizes the normalized cross-correlation to measure the image similarity fast. More importantly, we present a novel adaptive search strategy, which makes full use of the inter-frame dependency of the image sequence. This search strategy narrows the search range of the optimal matching, thus greatly reduces the search time, and makes the matching process more robust and accurate. RESULTS: The experimental results on four volunteers demonstrate that our method is able to extract the respiratory signal from an image sequence of 256 image frames in 5 s. The quantitative evaluation using the correlation coefficient reveals that the respiratory motion, extracted near the liver boundaries and vessels, is highly consistent with the reference motion tracked by an EM device. CONCLUSIONS: Our method can use 2D ultrasound to track natural landmarks from the liver as surrogate respiratory signal and hence provide a feasible solution to replace special tracking devices. PMID- 23749465 TI - Construction of protein phosphorylation networks by data mining, text mining and ontology integration: analysis of the spindle checkpoint. AB - Knowledge representation of the role of phosphorylation is essential for the meaningful understanding of many biological processes. However, such a representation is challenging because proteins can exist in numerous phosphorylated forms with each one having its own characteristic protein-protein interactions (PPIs), functions and subcellular localization. In this article, we evaluate the current state of phosphorylation event curation and then present a bioinformatics framework for the annotation and representation of phosphorylated proteins and construction of phosphorylation networks that addresses some of the gaps in current curation efforts. The integrated approach involves (i) text mining guided by RLIMS-P, a tool that identifies phosphorylation-related information in scientific literature; (ii) data mining from curated PPI databases; (iii) protein form and complex representation using the Protein Ontology (PRO); (iv) functional annotation using the Gene Ontology (GO); and (v) network visualization and analysis with Cytoscape. We use this framework to study the spindle checkpoint, the process that monitors the assembly of the mitotic spindle and blocks cell cycle progression at metaphase until all chromosomes have made bipolar spindle attachments. The phosphorylation networks we construct, centered on the human checkpoint kinase BUB1B (BubR1) and its yeast counterpart MAD3, offer a unique view of the spindle checkpoint that emphasizes biologically relevant phosphorylated forms, phosphorylation-state-specific PPIs and kinase substrate relationships. Our approach for constructing protein phosphorylation networks can be applied to any biological process that is affected by phosphorylation. Database URL: http://www.yeastgenome.org/ PMID- 23749466 TI - Regulation of muscle hydration upon hypo- or hyper-osmotic shocks: differences related to invasion of the freshwater habitat by decapod crustaceans. AB - Decapod crustaceans have independently invaded freshwater habitats from the sea/estuaries. Tissue hydration mechanisms are necessary for the initial stages of habitat transitions but can be expected to diminish, as the capacity for extracellular homeostasis increases in hololimnetic species. Six decapod species have been compared concerning the maintenance of muscle hydration in vitro: Hepatus pudibundus (marine); Palaemon pandaliformis (estuarine resident), Macrobrachium acanthurus (freshwater diadromous), and the three hololimnetic Macrobrachium potiuna, Dilocarcinus pagei, and Aegla parana. The effects of inhibitors of potassium channels (barium chloride) and NKCC (furosemide) were evaluated under isosmotic, and respectively hypo- (50% below iso) or hyper- (50% above iso) conditions. There was high muscle hydration control in H. pudibundus with a possible role of NKCC in isosmotic conditions. Shrimps consistently showed small deviations in muscle hydration under anisosmotic conditions; P. pandaliformis has shown evidence of the presence of NKCC; M. potiuna was the species less affected by both inhibitors, under iso- or anisosmotic conditions. In the two hololimnetic crab species, both independent long-time inhabitants of freshwater, while the capacity to deal with hyper-osmotic shock is decreased, the capacity to deal with hyposmotic shock is retained, possibly because of hemolymph dilution during molting in fresh water. D. pagei apparently depends on potassium channels for volume recovery after swelling, whereas A. parana shows some dependence on NKCC to minimize volume loss in hyper-osmotic conditions. Although no molecular screening techniques have been tried here, data point to distinct cell/tissue transport mechanisms acting upon hydration/volume challenges in decapods of different habitats and lineages. PMID- 23749468 TI - CHOP-mediated hepcidin suppression modulates hepatic iron load. AB - The liver is the central regulator of iron metabolism and accordingly, chronic liver diseases often lead to systemic iron overload due to diminished expression of the iron-regulatory hormone hepcidin. To study the largely unknown regulation of iron metabolism in the context of hepatic disease, we used two established models of chronic liver injury, ie repeated carbon tetrachloride (CCl(4)) or thioacetamide (TAA) injections. To determine the impact of CCAAT/enhancer-binding protein (C/EBP)-homologous protein (CHOP) on hepcidin production, the effect of a single TAA injection was determined in wild-type and CHOP knockout mice. Furthermore, CHOP and hepcidin expression was assessed in control subjects and patients with alcoholic liver disease. Both chronic injury models developed a distinct iron overload in macrophages. TAA-, but not CCl(4) - injected mice displayed additional iron accumulation in hepatocytes, resulting in a significant hepatic and systemic iron overload which was due to suppressed hepcidin levels. C/EBPalpha signalling, a known hepcidin inducer, was markedly inhibited in TAA mice, due to lower C/EBPalpha levels and overexpression of CHOP, a C/EBPalpha inhibitor. A single TAA injection resulted in a long-lasting (> 6 days) suppression of hepcidin levels and CHOP knockouts (compared to wild-types) displayed significantly attenuated hepcidin down-regulation in response to acute TAA administration. CHOP mRNA levels increased 5-fold in alcoholic liver disease patients versus controls (p < 0.005) and negatively correlated with hepcidin expression. Our results establish CHOP as an important regulator of hepatic hepcidin expression in chronic liver disease. The differences in iron metabolism between the two widely used fibrosis models likely reflect the differential regulation of hepcidin expression in human liver disease. PMID- 23749469 TI - Reflections on TEAP: training for the future of medical physics. PMID- 23749470 TI - Lipase production by Botryosphaeria ribis EC-01 on soybean and castorbean meals: optimization, immobilization, and application for biodiesel production. AB - The effects of soybean and castorbean meals were evaluated separately, and in combinations at different ratios, as substrates for lipase production by Botryosphaeria ribis EC-01 in submerged fermentation using only distilled water. The addition of glycerol analytical grade (AG) and glycerol crude (CG) to soybean and castorbean meals separately and in combination, were also examined for lipase production. Glycerol-AG increased enzyme production, whereas glycerol-CG decreased it. A 2(4) factorial design was developed to determine the best concentrations of soybean meal, castorbean meal, glycerol-AG, and KH2PO4 to optimize lipase production by B. ribis EC-01. Soybean meal and glycerol-AG had a significant effect on lipase production, whereas castorbean meal did not. A second treatment (2(2) factorial design central composite) was developed, and optimal lipase production (4,820 U/g of dry solids content (ds)) was obtained when B. ribis EC-01 was grown on 0.5 % (w/v) soybean meal and 5.2 % (v/v) glycerol in distilled water, which was in agreement with the predicted value (4,892 U/g ds) calculated by the model. The unitary cost of lipase production determined under the optimized conditions developed ranged from US$0.42 to 0.44 based on nutrient costs. The fungal lipase was immobilized onto Celite and showed high thermal stability and was used for transesterification of soybean oil in methanol (1:3) resulting in 36 % of fatty acyl alkyl ester content. The apparent K m and V max were determined and were 1.86 mM and 14.29 MUmol min(-1) mg(-1), respectively. PMID- 23749471 TI - mRNA fluorescence in situ hybridization to determine overlapping gene expression in whole-mount mouse embryos. AB - BACKGROUND: Whole-mount in situ hybridization (ISH) is a prevalent tool to examine the spatial distribution of gene transcripts in intact embryos. Chromogenic-based methods of signal development are commonly used in mouse embryos because of their high sensitivity. Fluorescence techniques, however, offer several advantages over chromogenic methods including the ability to visualize multiple signals in a specimen at once. RESULTS: We describe a procedure for fluorescence in situ hybridization (FISH) for whole mouse embryos up to embryonic day 13.5. We show that this approach successfully produces a bright expression signal for several genes, validating the procedure in multiple tissues. Further, we show that double FISH can be used to visualize the expression of two genes in a single embryo by determining that Hoxd13 and Shh are co-expressed in both the limb bud and the hindgut. Finally, we demonstrate that FISH can be paired with confocal microscopy to take optical sections of interior regions of the embryo. CONCLUSIONS: FISH is a valid alternative to chromogenic based ISH for visualizing gene expression in whole mouse embryos. This work provides a framework to add additional fluorescence signals in the mouse such as visualizing both mRNA and protein by pairing the procedure with immunofluorescence. PMID- 23749472 TI - Research on the practical parameters of sex pheromone traps for the oriental fruit moth. AB - BACKGROUND: The oriental fruit moth (OFM) is a worldwide fruit-boring insect pest. In China, OFM monitoring traps use a sex pheromone lure, but their overall design is varied. As such, there is a critical need to develop a standardised OFM trap design. In this field study, ten different trap shapes in varying combinations of colours and sizes (such as trap length and surface area) were examined. RESULTS: The results showed that there was no significant difference in the trapping efficiency between eight colours. The ship-shaped trap could kill more OFM in a short period, whereas the automatic watering basin trap could be more effective in the long run. The optimal trapping diameter of the basin trap was 25 cm. The trapping efficiency of triangle traps with diameters of less than 10 cm was better than that of triangle traps with diameters of over 30 cm. The trapping number of pasteboard traps obviously declined when the surface area increased, and the pasteboard trap with a single board possessed excellent trapping efficiency. CONCLUSION: The results provide useful information for the design of standardised sex pheromone traps for monitoring as well as trapping of OFM in the field. PMID- 23749473 TI - Response of millet and sorghum to a varying water supply around the primary and nodal roots. AB - BACKGROUND AND AIMS: Cereals have two root systems. The primary system originates from the embryo when the seed germinates and can support the plant until it produces grain. The nodal system can emerge from stem nodes throughout the plant's life; its value for yield is unclear and depends on the environment. The aim of this study was to test the role of nodal roots of sorghum and millet in plant growth in response to variation in soil moisture. Sorghum and millet were chosen as both are adapted to dry conditions. METHODS: Sorghum and millet were grown in a split-pot system that allowed the primary and nodal roots to be watered separately. KEY RESULTS: When primary and nodal roots were watered (12 % soil water content; SWC), millet nodal roots were seven times longer than those of sorghum and six times longer than millet plants in dry treatments, mainly from an 8-fold increase in branch root length. When soil was allowed to dry in both compartments, millet nodal roots responded and grew 20 % longer branch roots than in the well-watered control. Sorghum nodal roots were unchanged. When only primary roots received water, nodal roots of both species emerged and elongated into extremely dry soil (0.6-1.5 % SWC), possibly with phloem-delivered water from the primary roots in the moist inner pot. Nodal roots were thick, short, branchless and vertical, indicating a tropism that was more pronounced in millet. Total nodal root length increased in both species when the dry soil was covered with plastic, suggesting that stubble retention or leaf mulching could facilitate nodal roots reaching deeper moist layers in dry climates. Greater nodal root length in millet than in sorghum was associated with increased shoot biomass, water uptake and water use efficiency (shoot mass per water). Millet had a more plastic response than sorghum to moisture around the nodal roots due to (1) faster growth and progression through ontogeny for earlier nodal root branch length and (2) partitioning to nodal root length from primary roots, independent of shoot size. CONCLUSIONS: Nodal and primary roots have distinct responses to soil moisture that depend on species. They can be selected independently in a breeding programme to shape root architecture. A rapid rate of plant development and enhanced responsiveness to local moisture may be traits that favour nodal roots and water use efficiency at no cost to shoot growth. PMID- 23749474 TI - beta-Glucan signaling connects phagocytosis to autophagy. AB - A growing list of innate immune receptors is being defined that recognize polysaccharides of microbial cell walls. Fungal beta-glucan recognition by the receptor Dectin-1 triggers inflammatory immune responses in macrophages and dendritic cells that are appropriate for defense against fungal pathogens. Among these responses is the specific recruitment of the autophagy-related protein light chain 3 (LC3) to phagosomes containing fungi. Studies documenting LC3's recruitment to phagosomes containing beta-glucan and other nonsugar particles suggest that LC3 plays a role in regulating phagocytosis and its related immunological responses. PMID- 23749475 TI - Rationalizing prescribing for older patients with multimorbidity: considering time to benefit. AB - Given the growing number of older adults with multimorbidity who are prescribed multiple medications, clinicians need to prioritize which medications are most likely to benefit and least likely to harm an individual patient. The concept of time to benefit (TTB) is increasingly discussed in addition to other measures of drug effectiveness in order to understand and contextualize the benefits and harms of a therapy to an individual patient. However, how to glean this information from available evidence is not well established. The lack of such information for clinicians highlights a critical need in the design and reporting of clinical trials to provide information most relevant to decision making for older adults with multimorbidity. We define TTB as the time until a statistically significant benefit is observed in trials of people taking a therapy compared to a control group not taking the therapy. Similarly, time to harm (TTH) is the time until a statistically significant adverse effect is seen in a trial for the treatment group compared to the control group. To determine both TTB and TTH, it is critical that we also clearly define the benefit or harm under consideration. Well-defined benefits or harms are clinically meaningful, measurable outcomes that are desired (or shunned) by patients. In this conceptual review, we illustrate concepts of TTB in randomized controlled trials (RCTs) of statins for the primary prevention of cardiovascular disease. Using published results, we estimate probable TTB for statins with the future goal of using such information to improve prescribing decisions for individual patients. Knowing the relative TTBs and TTHs associated with a patient's medications could be immensely useful to a clinician in decision making for their older patients with multimorbidity. We describe the challenges in defining and determining TTB and TTH, and discuss possible ways of analyzing and reporting trial results that would add more information about this aspect of drug effectiveness to the clinician's evidence base. PMID- 23749476 TI - Phenotypic variability of prenatally presenting Gaucher's disease. PMID- 23749477 TI - Effects of cadmium and high temperature on some parameters of calcium metabolism in the killifish (Aphanius fasciatus). AB - This study aims to investigate the influence of high temperature on cadmium (Cd) toxicity in Aphanius fasciatus (Pisces: Cyprinodontidae). For this reason, Cd, mineral, and organic content in the vertebral column as well as the histological structure of gills and bone were compared in fishes exposed for 30 days to Cd (2 mg/L CdCl2) and/or high temperature (26 degrees C). Cd exposure caused a negative correlation between Cd and Ca concentrations (r = 0.98, p < 0.05), as well as a significant decrease in inorganic components (p < 0.05) and ash weight/dry weight ratio (p < 0.05) in the vertebral column. These changes were accompanied by an increased frequency of histological alterations in gills and bone. Concomitant treatment with Cd and high temperature increases Cd accumulation and Ca depletion in the skeletal tissue and increases the frequency and the severity of histological alterations. These results confirm that temperature increases Cd toxicity and needs to be taken into account for the accurate prediction and assessment of Cd-induced spinal deformities in fish. PMID- 23749478 TI - Comparative study of serum zinc, copper, manganese, and iron in preeclamptic pregnant women. AB - Preeclampsia complicates 2-8 % of all pregnancies and it is one of the leading causes of maternal mortality and pre-term delivery in the world. Unfortunately, there is scarcity of document discussing the circulating level of several essential trace elements in preeclampsia patients in Bangladesh. The present study was designed to evaluate the serum concentration of four trace elements, namely zinc, copper, manganese, and iron, in preeclamptic pregnant women. The study was conducted as a case-control study with 50 preeclamptic pregnant women as cases and 58 normotensive pregnant women as controls. Obstetric, anthropometric, and clinical data were collected at routine obstetric visits. Serum trace elements were determined by flame atomic absorption spectroscopy. Independent sample t test and Pearson's correlation test were done for the statistical analysis using the statistical software package SPSS, version 16.0 (SPSS Inc., Chicago, IL). We observed significant differences for gestational age, body mass index, and systolic and diastolic blood pressure between patient and control groups (p < 0.05). Analysis of serum trace elements explored significantly lower level of all the four elements in preeclampsia patients in comparison to the control group (p < 0.05). Pearson's correlation analysis explored that the correlation between serum level of different trace elements was statistically insignificant (p > 0.05) except the correlation between zinc and iron in preeclampsia patients (p < 0.05). Establishment of inter-element relationship strongly supports that there was a disturbance in the element homeostasis in patient with preeclampsia. In conclusion, our study suggests that preeclampsia patients have considerably lower level of serum zinc, copper, manganese, and iron compared to the healthy pregnant women. PMID- 23749479 TI - The effects of prenatal stress on alpha4 beta2 and alpha7 hippocampal nicotinic acetylcholine receptor levels in adult offspring. AB - Prenatal stress in humans is associated with psychiatric problems in offspring such as anxiety, depression, and schizophrenia. These same illnesses are also associated with neuronal nicotinic acetylcholine receptor (nAChR) dysfunction. Despite the known associations between prenatal stress exposure and offspring mental illness, and between mental illness and nAChR dysfunction, it is not known whether prenatal stress exposure impacts neuronal nAChRs. Thus, we tested the hypothesis that maternal stress alters the development of hippocampal alpha4 beta2 (alpha4beta2*) and alpha7 (alpha7*) nicotinic receptor levels in adult offspring. Female Sprague-Dawley rats experienced unpredictable variable stressors two to three times daily during the last week of gestation. At weaning (21 days) the offspring of prenatally stressed (PS) and nonstressed (NS) dams were assigned to same-sex PS or NS groups. In young adulthood (56 days), the brains of offspring were collected and adjacent sections processed for quantitative autoradiography using [125I]-epibatidine (alpha4beta2* nicotinic receptor-selective) and [125I]-alpha-bungarotoxin (alpha-BTX; alpha7* nicotinic receptor-selective) ligands. We found that PS significantly increased hippocampal alpha4beta2* nAChRs of males and females in all subfields analyzed. In contrast, only females showed a trend toward PS-induced increases in alpha7* nAChRs in the dentate gyrus. Interestingly, NS females displayed a significant left-biased lateralization of alpha7* nAChRs in the laconosum moleculare of area CA1, whereas PS females did not, suggesting that PS interfered with normal lateralization patterns of alpha7* nAChRs during development. Taken together, our results suggest that PS impacts the development of hippocampal nAChRs, which may be an important link between PS exposure and risk for neuropsychiatric illness. PMID- 23749480 TI - Is it necessary to repeat CT imaging and replanning during the course of intensity-modulated radiation therapy for locoregionally advanced nasopharyngeal carcinoma? AB - PURPOSE: Our aim was to evaluate the volumetric and dosimetric changes of target volumes and organs at risk (OARs) during intensity-modulated radiation therapy (IMRT) for locoregionally advanced nasopharyngeal carcinoma (NPC) and the necessity of replanning. MATERIALS AND METHODS: Twenty locoregionally advanced NPC patients treated by concurrent chemotherapy and IMRT were included. CT and MR images were acquired before treatment and at weeks 2, 3, 4, 5 and 6 during treatment. The target volumes and OARs were contoured based on the fused CT-MRI images and hybrid plans were generated. The changes of volume and dosimetry were measured by comparing original plan and hybrid plans. RESULTS: Significant volumetric changes of target volumes and parotid gland were observed. The primary nasopharyngeal tumor (GTVnx), CTV1, involved lymph nodes (GTVnd) and left and right parotid glands, shrank at a mean rate of 14.7, 11.56, 11.40, 6.54 and 6.78 % per treatment week, respectively. There were no significant dosimetric changes in GTVnx, GTVnd, CTV1, spinal cord and brain stem while the differences of dose to left and right parotid glands were significant (F = 6.73, P = 0.007; F = 7.43, P = 0.007). CONCLUSIONS: Remarkable volumetric changes were observed. However, the dosimetric changes were inconspicuous except for the parotid. Replanning might contribute to protect the parotid gland. PMID- 23749481 TI - Effects of qigong exercise on upper limb lymphedema and blood flow in survivors of breast cancer: a pilot study. AB - HYPOTHESIS: Qigong exercise is a popular method for relieving the side effects of conventional cancer treatments in survivors of breast cancer, yet its effects are not empirically assessed. This study aimed to investigate the effects of qigong exercise on upper limb lymphedema, arterial resistance, and blood flow velocity in survivors with breast cancer and mastectomy. STUDY DESIGN: This study was conducted as a prospective clinical trial. METHODS: Eleven survivors of breast cancer with qigong experience (mean age = 58.3 +/- 10.1 years) were assigned to the experimental group and 12 survivors of breast cancer without qigong experience (mean age = 53.8 +/- 4.2 years) were assigned to the control group. They all had breast cancer-related lymphedema. All procedures were completed within one session. After baseline measurements were taken, the experimental group performed 18 Forms Tai Chi Internal Qigong for approximately 6 minutes while the control group rested for similar duration in a sitting position. Both groups were then reassessed. All participants were measured on their affected upper limb circumference (by using tape measures), peripheral arterial resistance, and blood flow velocities (using a Doppler ultrasound machine). RESULTS: The between-group differences were not significant for all outcome measures at baseline (P > .05). The circumferences of the affected upper arm, elbow, forearm and wrist decreased after qigong exercise (P < .05). However, no significant difference was found in the circumference measures between the 2 groups posttest (P > .0125). In terms of vascular outcomes, the resistance index decreased and the maximum systolic arterial blood flow velocity (SV) and minimum diastolic arterial blood flow velocity (DV) increased significantly after qigong exercise (P < .05). The between-group difference was close to significant for SV (P = .018) and was significant for DV (P < .001) posttest. CONCLUSION: Qigong exercise could reduce conventional cancer therapy side effects such as upper limb lymphedema and poor circulatory status in survivors of breast cancer. However, such effects may be temporary, and further studies must be conducted to explore longer term effects. PMID- 23749482 TI - Habenular commissure formation in zebrafish is regulated by the pineal gland specific gene unc119c. AB - BACKGROUND: The zebrafish pineal gland (epiphysis) is a site of melatonin production, contains photoreceptor cells, and functions as a circadian clock pacemaker. Since it is located on the surface of the forebrain, it is accessible for manipulation and, therefore, is a useful model system to analyze pineal gland function and development. We previously analyzed the pineal transcriptome during development and showed that many genes exhibit a highly dynamic expression pattern in the pineal gland. RESULTS: Among genes preferentially expressed in the zebrafish pineal gland, we identified a tissue-specific form of the unc119 gene family, unc119c, which is highly preferentially expressed in the pineal gland during day and night at all stages examined from embryo to adult. When expression of unc119c was inhibited, the formation of the habenular commissure (HC) was specifically compromised. The Unc119c interacting factors Arl3l1 and Arl3l2 as well as Wnt4a also proved indispensible for HC formation. CONCLUSIONS: We suggest that Unc119c, together with Arl3l1/2, plays an important role in modulating Wnt4a production and secretion during HC formation in the forebrain of the zebrafish embryo. PMID- 23749483 TI - Hilar interneuron vulnerability distinguishes aged rats with memory impairment. AB - Hippocampal interneuron populations are reportedly vulnerable to normal aging. The relationship between interneuron network integrity and age-related memory impairment, however, has not been tested directly. That question was addressed in the present study using a well-characterized model in which outbred, aged, male Long-Evans rats exhibit a spectrum of individual differences in hippocampal dependent memory. Selected interneuron populations in the hippocampus were visualized for stereological quantification with a panel of immunocytochemical markers, including glutamic acid decarboxylase-67 (GAD67), somatostatin, and neuropeptide Y. The overall pattern of results was that, although the numbers of GAD67- and somatostatin-positive interneurons declined with age across multiple fields of the hippocampus, alterations specifically related to the cognitive outcome of aging were observed exclusively in the hilus of the dentate gyrus. Because the total number of NeuN-immunoreactive hilar neurons was unaffected, the decline observed with other markers likely reflects a loss of target protein rather than neuron death. In support of that interpretation, treatment with the atypical antiepileptic levetiracetam at a low dose shown previously to improve behavioral performance fully restored hilar SOM expression in aged, memory impaired rats. Age-related decreases in GAD67- and somatostatin-immunoreactive neuron number beyond the hilus were regionally selective and spared the CA1 field of the hippocampus entirely. Together these findings confirm the vulnerability of hippocampal interneurons to normal aging and highlight that the integrity of a specific subpopulation in the hilus is coupled with age-related memory impairment. PMID- 23749484 TI - Deafblind people, communication, independence, and isolation. AB - This paper discusses issues related to communication, independence, and isolation for an understudied group of deaf people who also have visual impairments. The discussion is based on the experiences of 28 deafblind people in 6 different countries, obtained from interviews that were carried out as part of a larger research project on travel issues. However, the similarities in experiences between countries were stronger than the differences. In particular, barriers to communication and inadequate support, with resulting problems of isolation and depression, were found in all the countries. Equally, deafblind people in all the countries were interested in being involved in and contributing to society and supporting other people, particularly through organizations of blind and deafblind people. This runs counter to the tendency to present deafblind and other disabled people purely as recipients of support rather than also as active participants in society. However, there were some differences in the support available in the different countries. PMID- 23749485 TI - Association between NQO1 C609T polymorphism and bladder cancer susceptibility: a systemic review and meta-analysis. AB - There is growing evidence for the important roles of genetic factors in the host's susceptibility to bladder cancer. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a cytosolic enzyme that catalyzes the two-electron reduction of quinoid compounds into hydroquinones. Since the NQO1 C609T polymorphism is linked to enzymatic activity of NQO1, it has also been hypothesized that NQO1 C609T polymorphism may affect the host's susceptibility to bladder cancer by modifying the exposure to carcinogens. There were many studies carried out to assess the association between NQO1 C609T polymorphism and bladder cancer risk, but they reported contradictory results. We conducted a meta-analysis to examine the hypotheses that the NQO1 C609T polymorphism modifies the risk of bladder cancer. Eleven case-control studies with 2,937 bladder cancer cases and 3,008 controls were included in the meta-analysis. Overall, there was no obvious association between NQO1 C609T polymorphism and bladder cancer susceptibility (for T versus C: odds ratio (OR) = 1.12, 95 % confidence interval (95 %CI) 0.99-1.26, P OR = 0.069; for TT versus CC: OR = 1.31, 95 %CI 0.95-1.81, P OR = 0.100; for TT/CT versus CC: OR = 1.06, 95 %CI 0.95-1.18, P OR = 0.304; for TT versus CT/CC: OR = 1.29, 95 %CI 0.94-1.77, P OR = 0.112). After adjusting for heterogeneity, meta analysis of those left 10 studies showed that there was an obvious association between NQO1 C609T polymorphism and bladder cancer susceptibility (for T versus C: OR = 1.18, 95 %CI 1.06-1.31, P OR = 0.003; for TT versus CC: OR = 1.47, 95 %CI 1.14-1.90, P OR = 0.003; for TT/CT versus CC: OR = 1.16, 95 %CI 1.01-1.34, P OR = 0.036; for TT versus CT/CC: OR = 1.39, 95 %CI 1.10-1.75, P OR = 0.006). There was low risk of publication bias. Therefore, our meta-analysis suggests that NQO1 C609T polymorphism is associated with bladder cancer susceptibility. PMID- 23749486 TI - Association between the XRCC3 C241T polymorphism and lung cancer risk in the Asian population. AB - X-ray repair cross-complementing group 3 (XRCC3) plays a vital role in maintaining the stability of genome by homologous recombination repair for DNA double-strand breaks. The genetic polymorphism of XRCC3 C241T has been implicated in lung cancer risk, but the findings across published studies in Asians are inconsistent and inconclusive. To estimate the precise association of XRCC3 C241T polymorphism with lung cancer risk, a meta-analysis of all currently available studies in Asians was performed. A comprehensive search of the PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases was conducted for eligible studies based on the inclusion criteria. The pooled odds ratios (ORs) with corresponding 95 % confidence intervals (CIs) were calculated to assess the association. Besides, subgroup analysis and sensitivity analysis were also performed for further estimation. Seven available studies with a total of 7,398 subjects were finally included into this meta-analysis. The overall ORs indicated that the XRCC3 C241T polymorphism was not associated with a lung cancer risk among Asians in all genetic contrast modes (ORT allele vs. C allele = 1.08, 95 % CI 0.95-1.24, P OR = 0.252; ORTT vs. CC = 1.30, 95 % CI 0.69-2.45, P OR = 0.426; ORCT vs. CC = 1.07, 95 % CI 0.93-1.24, P OR = 0.363; ORTT + CT vs. CC = 1.08, 95 % CI 0.94-1.24, P OR = 0.300; ORTT vs. CC + CT = 1.29, 95 % CI 0.68 2.43, P OR = 0.439). We failed to identify significant association between the XRCC3 C241T polymorphism and risk of lung cancer in Chinese and population-based studies. Interestingly, the pooled ORs in hospital-based studies indicated that the XRCC3 C241T variant carriers were more susceptible to lung cancer (ORT allele vs. C allele = 1.27, 95 % CI 1.04-1.56, P OR = 0.019; ORCT vs. CC = 1.26, 95 % CI 1.01-1.57, P OR = 0.045; ORTT + CT vs. CC = 1.28, 95 % CI 1.03-1.59, P OR = 0.027). Sensitivity analysis confirmed the stability and liability of all results. This meta-analysis suggests that the XRCC3 C241T polymorphism may not exert a risk effect on the lung cancer risk in Asians, although a statistically significant association was observed among the hospital-based studies. Thus, the precise relationship between the XRCC3 C241T variant and lung cancer risk needs further confirmation in future studies with large available data. PMID- 23749487 TI - Chromosomal imbalances exclusively detected in invasive front area are associated with poor outcome in laryngeal carcinomas from different anatomical sites. AB - Laryngeal squamous cell carcinoma (LSCC) is a malignant neoplasm exhibiting aggressive phenotype, high recurrence rate, and risk of developing second primary tumors. Current evidence suggests that cells in the invasive front of carcinomas have different molecular profiles compared to those in superficial areas. This study aimed to identify candidate genes in the invasive front and superficial cells from laryngeal carcinomas that would be useful as molecular markers. Invasive front and tumor surface cells of 32 LSCC were evaluated by high resolution comparative genomic hybridization. Both CCND1 copy number gains and cyclin D1 protein expression were evaluated to confirm gains of 11q13.3. Losses of 3q26.2-q29 and 18q23 were confirmed by loss of heterozygosity analysis. The most frequent chromosomal alterations observed only in invasive front cells involved gains of 1p, 4q, and 9p and losses of 3p, 11p, 12p, 13q, 17q, 18p, 19q, 20q, 21q, and Xp. Gains of 11q13 were detected in both components from glottis and supraglottis but only in invasive front cells from transglottic tumors. Fluorescence in situ hybridization confirmed gains of CCND1/CPE11 in a subset of cases. In supraglottic tumors, cyclin D1 positivity was associated with distant metastasis (P = 0.0018) and with decreased disease-free survival (P = 0.042). Loss of heterozygosity at 3q26.2 and 18q23 were associated with lymph node involvement (P = 0.055) and worsened prognosis, respectively. In conclusion, this study revealed regions that could be targeted in the search for molecular markers in LSCC. Cyclin D1 may be useful as a prognostic marker in supraglottic tumors. PMID- 23749488 TI - GSTM1 and GSTT1 polymorphism and susceptibility to esophageal cancer in high- and low-risk regions of India. AB - Glutathione transferases, a super family of dimeric phase II metabolic enzymes play a vital role in biotransformation of many substances. This study evaluates the influence of genetic polymorphism of GSTM1 and GSTT1 gene loci on esophageal cancer risk in Assam and Delhi from India. DNA from blood samples of esophageal cancer cases (203,112) and controls (286,150) from Assam and Delhi, respectively, were extracted. GSTM1 and GSTT1 polymorphisms were analyzed by multiplex PCR procedure. Differences in proportions were tested using Pearson's chi-square test with odds ratio (OR) and 95 % confidence interval (CI). Risk of esophageal cancer was approximately twice in individuals having homozygous GSTM1 (OR-2.1, 95 % CI, 1.44-3.13) and GSTT1 null genotypes (OR-1.7,95 % CI, 0.99-2.77) in Assam, and around three times in GSTT1 null genotype (OR-2.9, 95 % CI, 1.56-5.27) in Delhi population. GSTM1 null genotype seems to play a protective role (OR-0.7, 95 % CI, 0.39-1.27) in Delhi. A significant association of GSTM1 null genotype with esophageal cancer was observed in a younger age group in Assam (OR-2.7, 95 % CI, 1.48-5.01), and in Delhi population association was observed in smokers with GSTT1 null genotype (OR-2.5, 95 % CI, 1.04-6.07), and alcoholics having GSTM1 null genotype (OR-2.6, 95 % CI, 0.99-6.77). Significant association of GSTM1 null genotype in Assam was observed between cancer cases and controls in fermented betel nut chewers only (OR-2.8, 95 % CI, 1.19-6.72), whereas, smoking and alcohol failed to show any correlation with GSTM1/GSTT1 genotypes. Cancer development is not only due to exogenous or endogenous carcinogens but depends on their interaction with genes that are involved in the detoxification of these carcinogens. PMID- 23749489 TI - DNA polymerase beta promoter mutations and transcriptional activity in esophageal squamous cell carcinoma. AB - The present study analyzed the correlation of DNA polymerase beta (DNA polbeta) promoter mutations and activity in esophageal squamous cell carcinoma (ESCC). The DNA polbeta promoter was amplified from 108 ESCC samples and adjacent paracancerous samples by PCR and cloned into the pGL3-enhancer luciferase vector. The recombined vectors were transfected into esophageal carcinoma cells (EC9706, Eca109, and KYSE30), and luciferase activity was detected using dual luciferase reporter gene technology. Eleven polbeta promoter mutations were identified and submitted to GenBank. The mutation rate of the DNA polbeta promoter was higher in ESCC tissues (36/108, 33.3 %) than in the paired paracancerous tissues (21/108, 19.4 %) (P = 0.021). The C -> A mutation at locus -37 was the hotspot mutation in cancerous tissues, and its frequency was higher in ESCC tissues (26/108) than in paracancerous tissues (7/108) (P = 0.00). The highest relative luciferase activity (RLA) was observed in the DNA polbeta promoter, with a C -> A mutation at -37. Significant differences in RLA were observed between mutant DNA polbeta promoters (except for C detected at -19, T -> C at -194, C -> A at -37, and T -> C at 30) and the wild-type DNA polbeta promoter (P = 0.000), and RLA was significantly higher in ESCC tissues than in paracancerous tissues (P = 0.003). Our findings suggest that the upregulation of transcriptional activity induced by mutations in the DNA polbeta promoter in ESCC tissues may be one of the molecular mechanisms mediating abnormal overexpression of DNA polbeta in ESCC. PMID- 23749490 TI - Clinical significance of RECK promoter methylation in pancreatic ductal adenocarcinoma. AB - The aim of this study was to analyze the clinical significance of reversion inducing-cysteine-rich protein with Kazal motifs (RECK) promoter methylation in pancreatic ductal adenocarcinoma (PDA). Methylation-specific polymerase chain reaction was used to examine the promoter methylation status of RECK in 60 pairs of PDA tissue samples and adjacent non-cancerous tissue samples. Statistical analyses were applied to test the associations between RECK promoter methylation status, clinicopathologic factors, and prognosis. The rate of RECK promoter methylation was significantly higher in PDA tissues than in adjacent non cancerous tissues (P < 0.001). RECK methylation status was significantly associated with clinical stage (P = 0.017), histological differentiation (P = 0.046), and lymph node metastasis (P = 0.003), but was not associated with gender, age, and tumor location (all P > 0.05). Additionally, RECK promoter methylation is associated with malignant behavior and poor prognosis. In conclusion, determination of RECK promoter methylation status in tumor tissues may assist in the identification of patients who require aggressive postoperative intervention in order to improve prognosis. PMID- 23749491 TI - Seasonal impact in the frequency of isolated spina bifida. AB - OBJECTIVES: To evaluate whether a relationship exists between season at conception and occurrence of isolated spina bifida (ISB). STUDY DESIGN: All fetuses with prenatal diagnosis of ISB were analyzed according to date of conception. We compared the seasonal rates of conception between ISB fetuses and a control group consisting of a cohort of fetuses delivered during the same period from 1992 to 2009. RESULTS: In the control group, conceptions were equally distributed among the four seasons. Chi-square analysis showed a significantly higher rate of ISB conceptions in the fall compared with the control group (16/36, 44% vs. 12467/50533, 25%, Odds Ratio (OR) 2.44, 95% confidence interval 1.21-4.92). Not a single woman with a fetus affected by ISB took preconceptional supplement of folic acid. CONCLUSIONS: Seasonality affects the frequency of ISB. We hypothesize that the seasonal differences may reflect dietary and climate changes with reduced intake of folic acid in the fall. PMID- 23749492 TI - Epoxiconazole-induced degeneration in rat placenta and the effects of estradiol supplementation. AB - Epoxiconazole (CAS-No. 133855-98-8) was recently shown to cause both a marked depletion of maternal estradiol blood levels and a significantly increased incidence of late fetal mortality when administered to pregnant rats throughout gestation (GD 7-18 or 21); estradiol supplementation prevented this epoxiconazole effect in rats (Stinchcombe et al., 2013), indicating that epoxiconazole-mediated estradiol depletion is a critical key event for induction of late fetal resorptions in rats. For further elucidation of the mode of action, the placentas from these modified prenatal developmental toxicity experiments with 23 and 50 mg/kg bw/d epoxiconazole were subjected to a detailed histopathological examination. This revealed dose-dependent placental degeneration characterized by cystic dilation of maternal sinuses in the labyrinth, leading to rupture of the interhemal membrane. Concomitant degeneration occurred in the trophospongium. Both placentas supporting live fetuses and late fetal resorptions were affected; the highest degree of severity was observed in placentas with late resorptions. Placental degeneration correlated with a severe decline in maternal serum estradiol concentration. Supplementation with 0.5 and 1.0 MUg of the synthetic estrogen estradiol cyclopentylpropionate per day reduced the severity of the degeneration in placentas with live fetuses. The present study demonstrates that both the placental degeneration and the increased incidence of late fetal resorptions are due to decreased levels of estrogen, since estrogen supplementation ameliorates the former and abolishes the latter. PMID- 23749493 TI - Relationship between polyphenol oxidase activity and nutrition, maturity and quality parameters in flat peach. AB - BACKGROUND: Polyphenol oxidase (PPO) is one of the main factors that determine postharvest stability and therefore commercial possibilities of peach orchards. Since the activity of this enzyme depends on several variables of different nature, stating the relationships among them is essential to manage crop inputs so as to achieve the desired quality. RESULTS: Multivariate projection techniques were used to identify these relationships throughout on-tree maturation in flat peach samples that had received different fertilisation doses, but harvested in equal conditions of soluble solids, fruit weight, diameter, firmness and skin and flesh colour. A relatively low fertilisation dose that was enough to avoid any lack of nutrients provided the lowest crop yield, but also with the lowest PPO activity. Fruit N/Ca ratio turned out to be a better indicator of PPO activity than isolated nitrogen or calcium content. Nutrient analyses on leaves did not have strong correlations with any significant parameter. The most useful variables to predict PPO activity before harvest were fruit firmness and skin colour, both of them read at the onset of on-tree maturation. CONCLUSION: High fertilisation doses resulted in greater yields, but also with higher PPO activity, which is detrimental for the commercial chances of the fruit. PMID- 23749494 TI - Safety and effectiveness of nitroprusside in preventing no-reflow during percutaneous coronary intervention: a systematic review. AB - The objective of this study was to evaluate the clinical efficacy and safety of nitroprusside injection for preventing the slow-flow/no-reflow phenomenon after percutaneous coronary intervention (PCI). We searched the Cochrane Central Register of Controlled Trials (Issue 2, 2011), PubMed, EMbase, and Google Scholar for data. Two reviewers independently evaluated the quality of the included studies and extracted the data. A meta-analysis was performed using RevMan 5.0 software. Four randomized controlled trials (RCTs) involving 319 patients were included. The results of the meta-analyses showed that intracoronary nitroprusside is beneficial in preventing no-reflow/slow-flow, in reducing corrected TIMI frame count, and in improving left ventricular ejection fraction. It also likely reduces adverse reactions in patients after PCI and rehospitalization due to cardiovascular events. However, we must caution that in this review, there is a moderate possibility of bias with regard to patient selection, performance, and publication because of the small number of included studies. A larger sample size and high-quality RCTs are needed for a more reassuring analysis. PMID- 23749495 TI - The effect of uridine diphosphate glucuronosyltransferase (UGT)1A6 genetic polymorphism on valproic acid pharmacokinetics in Indian patients with epilepsy: a pharmacogenetic approach. AB - BACKGROUND AND OBJECTIVE: Sodium valproate is a widely prescribed broad-spectrum antiepileptic drug. It shows high inter-individual variability in pharmacokinetics and pharmacodynamics and has a narrow therapeutic range. We evaluated the effects of polymorphic uridine diphosphate glucuronosyltransferase (UGT)1A6 (541A>G, 552A>C) metabolizing enzyme on the pharmacokinetics of sodium valproate in the patients with epilepsy who showed toxicity to therapy. METHODS: Genotype analysis of the patients was made with polymerase chain-restriction fragment length polymorphism (RFLP) with sequencing. Plasma drug concentrations were measured with reversed phase high-performance liquid chromatography (HPLC) and concentration-time data were analyzed by using a non-compartmental approach. RESULTS: The results of this study suggested a significant genotypic as well as allelic association with valproic acid toxicity for UGT1A6 (541A>G) or UGT1A6 (552A>C) polymorphic enzymes. The elimination half-life (t 1/2 = 40.2 h) of valproic acid was longer and the clearance rate (CL = 917 ml/h) was lower in the poor metabolizers group of UGT1A6 (552A>C) polymorphism who showed toxicity than in the intermediate metabolizers group (t 1/2 = 35.5 h, CL = 1,022 ml/h) or the extensive metabolizers group (t 1/2 = 25.4 h, CL = 1,404 ml/h). CONCLUSION: Our findings suggest that the UGT1A6 (552A>C) genetic polymorphism plays a significant role in the steady state concentration of valproic acid, and it thereby has an impact on the toxicity of the valproic acid used in the patients with epilepsy. PMID- 23749496 TI - Unicompartmental arthritis in the aging athlete: osteotomy and beyond. AB - The vitality of the aging athlete is largely dependent on continued mobility and pain-free motion. The early onset of osteoarthritis often has devastating consequences for these athletes and if left untreated, mobility declines and eventually prevents sporting activities all together. Recent advances in operative treatment for unicompartmental arthritis of the knee aim to delay the need for total joint arthroplasty by preserving or restoring the form and function of the knee to allow for continued sport participation. This review focuses on the recent literature of several surgical treatment options for unicompartmental disease including cartilage procedures, osteotomy, and unicompartmental arthroplasty. PMID- 23749498 TI - Adjuvant radiation therapy and lymphadenectomy in esophageal cancer: a SEER database analysis. AB - OBJECTIVES: This study seeks to determine the effects of postoperative radiation therapy and lymphadenectomy on survival in esophageal cancer. METHODS: An analysis of patients with surgically resected esophageal cancer from the SEER database between 2004 and 2008 was performed to determine association of adjuvant radiation and lymph node dissection on survival. Survival curves were calculated according to the Kaplan-Meier method and log-rank analysis. Multivariate analysis (MVA) was performed by the Cox proportional hazard model. RESULTS: We identified 2109 patients who met inclusion criteria. Radiation was associated with increased survival in stage III patients (p = 0.005), no benefit in stage II (p = 0.075) and IV (p = 0.913) patients, and decreased survival in stage I patients (p < 0.0001). Univariate analysis revealed that radiation therapy was associated with a survival benefit node positive (N1) patients while it was associated with a detriment in survival for node negative (N0) patients. Removing >12 and >15 lymph nodes was associated with increased survival in N0 patients, while removing >8, >10, >12, >15, and >20 lymph nodes was associated with a survival benefit in N1 patients. MVA revealed that age, gender, tumor and nodal stage, tumor location, and number of lymph nodes removed were prognostic for survival in N0 patients. In N1 patients, MVA showed the age, tumor stage, number of lymph nodes removed, and radiation were prognostic for survival. CONCLUSION: The number of lymph nodes removed in esophageal cancer is associated with increased survival. The benefit of adjuvant radiation therapy on survival in esophageal cancer is limited to N1 patients. PMID- 23749499 TI - Gold nanorods as probes in two-photon fluorescence correlation spectroscopy: emerging applications and potential artifacts. AB - Owing to the highly efficient two-photon fluorescence of gold nanorods and very short fluorescence lifetime compared with the rotational correlation time, the rotation and diffusion of a single gold nanorod can be easily observed by two photon fluorescence correlation spectroscopy (TP-FCS). This property, along with the previous successful use as a contrast agent in two-photon fluorescence imaging, suggests a potential application in TP-FCS as well. Although the FCS measurement becomes highly efficient with gold nanorods as probes, the amplitude and temporal decay of the measured correlation functions depend critically on excitation power. Here, we investigate various photophysical processes of gold nanorods to determine the cause of such a sensitive power dependency. This understanding provides a basis for choosing appropriate FCS models to recover reasonable physical parameters. Although the correlation function amplitude G(0) is 32 times lower when the excitation power increases from 20 uW to 1.12 mW, the application of a saturation-modified FCS model yields very good fit to each data set and the fitted concentration of 0.64 nM is comparable to the 0.7 nM given by the inductively coupled plasma mass spectrometry measurement. The FCS assay appears to be an efficient method for the quantification of gold nanorods when correctly interpreted. However, even with the saturation considered in the fitting model, the fitted rotational and translational diffusion rates are getting faster as the power increases. This indicates that other effects such as photothermal effects may raise the local temperature, and thus increasing the rotational and translational diffusion rate. PMID- 23749501 TI - Fungi, beta-glucan, and bacteria in nasal lavage of greenhouse workers and their relation to occupational exposure. AB - The nose and mouth are the first regions of the respiratory tract in contact with airborne microorganisms. Occupational exposures to airborne microorganisms are associated with inflammation and different symptoms of the airways. The purpose of this study is to investigate the relation between occupational exposure to fungi, beta-glucan, and bacteria and contents of fungi, beta-glucan, and bacteria in nasal lavage (NAL) of greenhouse workers. We also studied whether contents of microorganisms in NAL were related to gender, time of the work week, and runny nose. NAL samples (n = 135) were taken Monday morning and Thursday at noon and personal exposure to inhalable bioaerosols was measured during a working day. The content of fungi and beta-glucan in NAL of men was affected by their exposure to fungi and beta-glucan. The content of fungi, beta-glucan, and bacteria in NAL was higher Thursday at noon than Monday morning. The ratios of fungi in NAL between Thursday at noon and Monday morning were 14 (median value) for men and 3.5 for women. Gender had no effect on the exposure level but had a significant effect on the content of fungi, beta-glucan, and bacteria in NAL, with the highest contents in NAL of men. On Thursdays, the median content of fungi in NAL samples of men without runny noses was 9408 cfu per NAL sample, whereas the same content for women was 595 cfu per NAL sample. Workers with runny noses had fewer fungi in NAL than workers without runny noses. A higher content of beta-glucan per fungal spore was found in NAL than in the air. This indicates that mainly the larger fungal spores or pollen grains deposit in the nose. The difference between genders and the fact that the content of fungi in NAL was significantly affected by the exposure indicate that the two genders are affected by the same exposure level differently. PMID- 23749502 TI - Comparison of established systems for measuring the dustiness of powders with the UNC Dustiness Tester developed especially for pharmaceutical substances. AB - Four methods for evaluating the dustiness of powders have been compared. The relatively new UNC Dustiness Tester first described by Boundy et al. (2006) in the Annals of Occupational Hygiene, which was developed specifically for the measurement of hazardous and/or highly potent substances, a single-drop device, a rotating-drum method, and a continuous drop-down apparatus. The four methods show four different ratings of dustiness for nine reference materials. This article describes the differences, explores reasons for the deviations, identifies a need for distinct dustiness test methods, and highlights the significance for occupational health and safety. PMID- 23749500 TI - Anterior insular cortex and emotional awareness. AB - This paper reviews the foundation for a role of the human anterior insular cortex (AIC) in emotional awareness, defined as the conscious experience of emotions. We first introduce the neuroanatomical features of AIC and existing findings on emotional awareness. Using empathy, the awareness and understanding of other people's emotional states, as a test case, we then present evidence to demonstrate: 1) AIC and anterior cingulate cortex (ACC) are commonly coactivated as revealed by a meta-analysis, 2) AIC is functionally dissociable from ACC, 3) AIC integrates stimulus-driven and top-down information, and 4) AIC is necessary for emotional awareness. We propose a model in which AIC serves two major functions: integrating bottom-up interoceptive signals with top-down predictions to generate a current awareness state and providing descending predictions to visceral systems that provide a point of reference for autonomic reflexes. We argue that AIC is critical and necessary for emotional awareness. PMID- 23749503 TI - The associations between the polymorphisms of the ER-alpha gene and the risk of uterine leiomyoma (ULM). AB - The ER-alpha gene polymorphisms have been reported to be associated with uterine leiomyoma (ULM) risk. The purpose of the present study was to perform a meta analysis to explore the polymorphisms in the ER-alpha gene and the risk of ULM. A comprehensive search for relevant articles was conducted in MEDLINE (Ovid), PubMed, Embase, Springer, EBSCO, Web of Science, CNKI, Wanfang, Weipu, and Google Scholar. A total of nine articles were identified. Among the nine articles, 11 cohorts reported the PvuII polymorphism and six reported the XbaI polymorphism. The strength of the relationships between the polymorphisms in ER-alpha (PvuII and XbaI) and the risk of ULM was assessed by odds ratios (ORs). The studies provided overall OR estimates for PvuII and XbaI, leading to a pooled OR of 1.41 (PP+Pp vs. pp: OR = 1.41, 95 % confidence interval (95 %CI) = 1.02-1.96, P = 0.04), 1.13 (XX+Xx vs. xx: OR = 1.13, 95 %CI = 0.91-1.41, P = 0.25), respectively. The PvuII polymorphism in the ER-alpha gene may be a risk factor for ULM. Future studies are needed to validate our conclusions. PMID- 23749504 TI - TCTP overexpression is associated with the development and progression of glioma. AB - Upregulation of translationally controlled tumor protein (TCTP) has been reported in a variety of malignant tumors. However, the impact of TCTP in glioma remains unclear. The objective of this study was to investigate the expression and prognostic value of TCTP in glioma patients. Western blot analysis was used to characterize the expression patterns of TCTP in 45 glioma and 22 normal brain tissues. Immunohistochemistry on a tissue microarray containing 127 cases of glioma was performed to analyze the association between TCTP expression and clinicopathological features. Compared with normal brain tissues, TCTP expression was significantly higher in glioma tissues (p <0.001). In addition, high TCTP expression in glioma was significantly associated with advanced pathological grade (p = 0.018). Kaplan-Meier analysis showed that patients with glioma and higher TCTP expression tend to have shorter overall survival time (p <0.001). In multivariate analysis, TCTP expression was proved to be an independent prognostic factor for patients with glioma (p <0.001). In conclusion, this study confirmed the overexpression of TCTP and its association with tumor progression in glioma. It also provided the first evidence that TCTP expression in glioma was an independent prognostic factor of patients, which might be a potential diagnostic and therapeutic target of glioma. PMID- 23749505 TI - Studies of asymmetric styrene cyclopropanation with a rhodium(II) metallopeptide catalyst developed with a high-throughput screen. AB - Dirhodium metallopeptides have been developed as selective catalysts for asymmetric cyclopropanation reactions. A selective ligand sequence has been identified by screening on-bead metallopeptide libraries in a 96-well plate format. Efficient ligand synthesis and screening allows a 200-member library to be created and assayed in less than three weeks. These metallopeptides catalyze efficient cyclopropanation of aryldiazoacetates, providing asymmetric access to cyclopropane products in high diastereoselectivity. PMID- 23749513 TI - Q&A: Ashok Venkitaraman on "undruggable" targets. Interview by Eric Bender. PMID- 23749514 TI - Second chances for shelved compounds. AB - Pharmaceutical companies are increasingly looking to see if compounds they shelved might have other uses. However, rescuing these agents, and finding new uses for approved drugs, presents some challenges, such as dwindling patent life, that can make their development financially risky. PMID- 23749525 TI - The new kid on the block: RET in lung cancer. AB - RET has recently been identified as a potential new oncogenic driver in a subset of patients with non-small cell lung cancer (NSCLC). In this issue of Cancer Discovery, Drilon and colleagues report preliminary trial data with a RET inhibitor in RET fusion-positive NSCLC, validating RET as a therapeutic target in lung cancer. PMID- 23749526 TI - FGFR fusions in the driver's seat. AB - Through a clinical deep sequencing protocol, Wu and colleagues have identified multiple FGFR fusion proteins in diverse cancers. Pharmacologic inhibition of FGFR suppressed the growth of FGFR fusion-positive tumor models, suggesting that these FGFR fusions are oncogenic drivers and highlighting the use of streamlined clinical sequencing efforts to identify novel, actionable driver oncoproteins in human tumors. PMID- 23749527 TI - Extending the convergence of canonical WNT signaling and classic cancer pathways for treatment of malignant peripheral nerve sheath tumors. AB - Malignant peripheral nerve sheath tumors (MPNST) are incurable tumors of the Schwann cell lineage that progress unpredictably from benign plexiform neurofibromas. In this issue of Cancer Discovery, Watson and colleagues use an insertional mutagenesis screen combined with network analysis to identify the canonical WNT signaling pathway as an important potential biomarker of tumor progression and target for combination therapy in MPNSTs. PMID- 23749528 TI - A new alpha in line between KRAS and NF-kappaB activation? AB - Bang and colleagues report a novel role for GSK-3alpha, rather than the well studied GSK-3beta, as the link between oncogenic KRAS and the canonical and noncanonical activation pathways of NF-kappaB in pancreatic cancer. Although the mechanism through which it promotes noncanonical activation remains unclear, the authors show that GSK-3alpha binds and stabilizes TAK1-TAB complexes to constitutively activate canonical NF-kappaB signaling. Consequently, the inhibition of GSK-3alpha retards pancreatic cancer growth in vitro and in vivo, thereby revealing this relatively less-studied kinase as a potential therapeutic target for treatment of KRAS-positive pancreatic cancer. PMID- 23749546 TI - Trials show delayed recurrence in ovarian cancer. AB - Phase I trials of 2 treatments for recurrent ovarian cancer-a 2-step immunotherapy treatment and an antibody-drug conjugate-demonstrated promising early results in delaying recurrence, in work presented at the American Association for Cancer Research Annual Meeting 2013. PMID- 23749548 TI - Acute exacerbation of Toxoplasma gondii infection after hematopoietic stem cell transplantation: five case reports among 279 recipients. AB - Toxoplasmosis is a rare and possibly underestimated complication following hematopoietic stem cell transplantation (HSCT) associated with a high mortality rate, although the incidence of toxoplasmosis after HSCT in Japan has not been established. We retrospectively studied patients with toxoplasmosis after HSCT, and identified five patients who had been diagnosed with an acute exacerbation of toxoplasmosis among 279 HSCT recipients at our institution between 1998 and 2011, representing an incidence of 1.8 %. Among 87 autologous HSCT recipients, one definite case was diagnosed. The serological test for Toxoplasma gondii before HSCT was positive in 18 of 192 allogeneic HSCT recipients. Of the 18 seropositive patients, three had definite infections, and one had possible infection. All four definite cases were diagnosed at autopsy. In the definite cases, three allogeneic HSCT recipients had disseminated or pulmonary toxoplasmosis and one autologous HSCT recipient had toxoplasmic encephalitis, although toxoplasmosis was not suspected at the premortem examination due to non-specific clinical and radiological manifestations. Thus, acute exacerbation of toxoplasmosis should be suspected in recipients after HSCT. Early diagnosis and treatment for toxoplasmosis would certainly contribute to a decrease in mortality after HSCT. PMID- 23749549 TI - Postnatal mandibular cheek tooth development in the miniature pig based on two dimensional and three-dimensional X-ray analyses. AB - The miniature pig is a useful large laboratory animal model. Various tissues and organs of miniature pigs are similar to those of humans in terms of developmental, anatomical, immunological, and physiological characteristics. The oral and maxillofacial region of miniature pigs is often used in preclinical studies of regenerative dentistry. However, there is limited information on the dentition and tooth structure of miniature pigs. The purpose of this study was to examine the time-course changes of dentition and tooth structure (especially the root) of the miniature pig mandibular cheek teeth through X-ray analyses using soft X-ray for two-dimensional observations and micro-CT for three-dimensional observations. The mandibles of male Clawn strain miniature pigs (2 weeks and 3, 5, 7, 9, 11, 14, 17, and 29 months of age) were used. X-ray analysis of the dentition of miniature pig cheek teeth showed that the eruption pattern of the miniature pig is diphyodont and that the replacement pattern is vertical. Previous definitions of deciduous and permanent teeth often varied and there has been no consensus on the number of teeth (dentition); however, we found that three molars are present in the deciduous dentition and that four premolars and three molars are present in the permanent dentition. Furthermore, we confirmed the number of tooth roots and root canals. We believe that these findings will be highly useful in future studies using miniature pig teeth. PMID- 23749551 TI - Effect of P-glycoprotein and breast cancer resistance protein inhibition on the pharmacokinetics of sunitinib in rats. AB - The aim of this study was to elucidate the roles of P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) in the plasma concentration, biliary excretion, and distribution to the liver, kidney, and brain of sunitinib. The pharmacokinetics of sunitinib was examined in rats treated with PSC833 (valspodar) and pantoprazole, potent inhibitors of P-gp and BCRP, respectively. The sunitinib concentrations in plasma, bile, liver, kidney, and brain were determined by liquid chromatography-tandem mass spectrometry. It was found that the area under the concentration-time curve for 4 hours (AUC0-4) and maximum concentration (Cmax) of sunitinib administered intraintestinally were significantly increased by pretreatment with PSC833 or pantoprazole. Each inhibitor markedly reduced the biliary excretion of sunitinib for 60 minutes after an intravenous administration and significantly increased the distribution of sunitinib to the liver as well as kidney. In addition, the brain distribution of sunitinib was significantly increased by PSC833 but not pantoprazole, and coadministration of both inhibitors further enhanced the accumulation of sunitinib in the brain. These results demonstrate that plasma concentrations of sunitinib and the biliary excretion and distribution to the kidney, liver, and brain of sunitinib are influenced by pharmacologic inhibition of P-gp and/or BCRP. PMID- 23749550 TI - Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. AB - OBJECTIVE: Enterochromaffin cell-derived serotonin (5-HT) promotes intestinal inflammation. We tested hypotheses that peripheral tryptophan hydroxylase (TPH) inhibitors, administered orally, block 5-HT biosynthesis and deplete 5-HT from enterochromaffin cells sufficiently to ameliorate intestinal inflammation; moreover, peripheral TPH inhibitors fail to enter the murine enteric nervous system (ENS) or central nervous systems and thus do not affect constitutive gastrointestinal motility. DESIGN: Two peripheral TPH inhibitors, LP-920540 and telotristat etiprate (LX1032; LX1606) were given orally to mice. Effects were measured on 5-HT levels in the gut, blood and brain, 5-HT immunoreactivity in the ENS, gastrointestinal motility and severity of trinitrobenzene sulfonic acid (TNBS)-induced colitis. Quantitation of clinical scores, histological damage and intestinal expression of inflammation-associated cytokines and chemokines with focused microarrays and real-time reverse transcriptase PCR were employed to evaluate the severity of intestinal inflammation. RESULTS: LP-920540 and LX1032 reduced 5-HT significantly in the gut and blood but not in the brain. Neither LP 920540 nor LX1032 decreased 5-HT immunoreactive neurons or fibres in the myenteric plexus and neither altered total gastrointestinal transit time, colonic motility or gastric emptying in mice. In contrast, oral LP-920540 and LX1032 reduced the severity of TNBS-induced colitis; the expression of 24% of 84 genes encoding inflammation-related cytokines and chemokines was lowered at least fourfold and the reduced expression of 17% was statistically significant. CONCLUSIONS: Observations suggest that that peripheral TPH inhibitors uncouple the positive linkage of enterochromaffin cell-derived 5-HT to intestinal inflammation. Because peripheral TPH inhibitors evidently do not enter the murine ENS, they lack deleterious effects on constitutive intestinal motility in mice. PMID- 23749552 TI - A Langevin canonical approach to the dynamics of chiral systems: populations and coherences. AB - A canonical framework for chiral two-level systems coupled to a bath of harmonic oscillators is developed to extract, from a stochastic dynamics, the thermodynamic equilibrium values of both the population difference and coherences. The incoherent and coherent tunneling regimes are analyzed for an Ohmic environment in terms of a critical temperature defined by the maximum of the heat capacity. The corresponding numerical results issued from solving a non linear coupled system of equations are fitted to approximate path-integral analytical expressions beyond the so-called non-interacting blip approximation in order to determine the different time scales governing both regimes. PMID- 23749553 TI - Large-scale variations in the vegetation growing season and annual cycle of atmospheric CO2 at high northern latitudes from 1950 to 2011. AB - We combine satellite and ground observations during 1950-2011 to study the long term links between multiple climate (air temperature and cryospheric dynamics) and vegetation (greenness and atmospheric CO(2) concentrations) indicators of the growing season of northern ecosystems (>45 degrees N) and their connection with the carbon cycle. During the last three decades, the thermal potential growing season has lengthened by about 10.5 days (P < 0.01, 1982-2011), which is unprecedented in the context of the past 60 years. The overall lengthening has been stronger and more significant in Eurasia (12.6 days, P < 0.01) than North America (6.2 days, P > 0.05). The photosynthetic growing season has closely tracked the pace of warming and extension of the potential growing season in spring, but not in autumn when factors such as light and moisture limitation may constrain photosynthesis. The autumnal extension of the photosynthetic growing season since 1982 appears to be about half that of the thermal potential growing season, yielding a smaller lengthening of the photosynthetic growing season (6.7 days at the circumpolar scale, P < 0.01). Nevertheless, when integrated over the growing season, photosynthetic activity has closely followed the interannual variations and warming trend in cumulative growing season temperatures. This lengthening and intensification of the photosynthetic growing season, manifested principally over Eurasia rather than North America, is associated with a long term increase (22.2% since 1972, P < 0.01) in the amplitude of the CO(2) annual cycle at northern latitudes. The springtime extension of the photosynthetic and potential growing seasons has apparently stimulated earlier and stronger net CO(2) uptake by northern ecosystems, while the autumnal extension is associated with an earlier net release of CO(2) to the atmosphere. These contrasting responses may be critical in determining the impact of continued warming on northern terrestrial ecosystems and the carbon cycle. PMID- 23749555 TI - When parallel worlds converge. PMID- 23749554 TI - Central projections of lagenar primary neurons in the chick. AB - Perception of linear acceleration and head position is the function of the utricle and saccule in mammals. Nonmammalian vertebrates possess a third otolith endorgan, the macula lagena. Different functions have been ascribed to the lagena in arboreal birds, including hearing, equilibrium, homing behavior, and magnetoreception. However, no conclusive evidence on the function of the lagena in birds is currently available. The present study is aimed at providing a neuroanatomical substrate for the function of the lagena in the chicken as an example of terrestrial birds. The afferents from the lagena of chick embryos (E19) to the brainstem and cerebellum were investigated by the sensitive lipophilic tracer Neuro Vue Red in postfixed ears. The results revealed that all the main vestibular nuclei, including the tangential nucleus, received lagenar projections. No lagenar terminals were found in auditory centers, including the cochlear nuclei. In the cerebellum, the labeled terminals were found variably in all of the cerebellar nuclei. In the cerebellar cortex, the labeled fibers were found mostly in the uvula, with fewer afferents in the flocculus and paraflocculus. None was seen in the nodulus. The absence of lagenar afferent projections in auditory nuclei and the presence of a projection pattern in the vestibular nuclei and cerebellum similar to that of the utricle and saccule suggest that the primary role of the lagena in the chick lies in the processing of vestibular information related to linear acceleration and static head position. PMID- 23749556 TI - Oil contamination in Ogoniland, Niger Delta. AB - The study shows extensive oil contamination of rivers, creeks, and ground waters in Ogoniland, Nigeria. The levels found in the more contaminated sites are high enough to cause severe impacts on the ecosystem and human health: extractable petroleum hydrocarbons (EPHs) (>10-C40) in surface waters up to 7420 MUg L(-1), drinking water wells show up to 42 200 MUg L(-1), and benzene up to 9000 MUg L( 1), more than 900 times the WHO guidelines. EPH concentrations in sediments were up to 17 900 mg kg(-1). Polycyclic aromatic hydrocarbons concentrations reached 8.0 mg kg(-1), in the most contaminated sites. The contamination has killed large areas of mangroves. Although the natural conditions for degradation of petroleum hydrocarbons are favorable with high temperatures and relatively high rainfall, the recovery of contaminated areas is prevented due to the chronic character of the contamination. Oil spills of varying magnitude originates from facilities and pipelines; leaks from aging, dilapidated, and abandoned infrastructure; and from spills during transport and artisanal refining of stolen oil under very primitive conditions. PMID- 23749557 TI - In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin modulates dysregulation of the lipid metabolism in mouse offspring fed a high calorie diet. AB - Exposure to environmental chemicals, including dioxins, is a risk factor for type 2 diabetes mellitus in humans. This study explored the hypothesis that in utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener among dioxins, aggravates this disease state later in adulthood. Pregnant C57Bl/6 J mice were administered either a single oral dose of TCDD (3.0 ug kg(-1) body weight) or corn oil on gestational day 12.5. The male pups born to these two groups of dams were given either a regular diet or a high-calorie diet, after postnatal day (PND) 28. The four groups of investigated offspring were thus termed T-R (TCDD regular diet), T-H (TCDD high-calorie diet), V-R (vehicle regular diet), and V-H (vehicle high-calorie diet). The mice were regularly monitored for body weight, blood pressure and glucose, until they reached 26 weeks of age. Mice in the V-H group were significantly obese at weeks 15 and 26, but they exhibited no diabetes-associated signs of insulin resistance or hypertension. However, metabolic syndrome-related alterations with marginal signs of liver damage were found at week 26. Pronounced signs of dysregulated lipid metabolism with altered gene expression and liver inflammation were already present at week 15, whereas such alterations were suppressed in the T-H group. Although the mechanism is unclear, this study showed that in utero and lactational exposure to low-dose TCDD does not aggravate obesity-induced disease states, such as adult-onset diabetes, but instead attenuates the dysregulation of lipid metabolism brought on by a high-calorie diet. PMID- 23749558 TI - Novel precursors of fluorescent dyes. 1. Interaction of the dyes with model phospholipid in monolayers. AB - Photoactivated ("caged") fluorescent dyes are modern tools for structure and function studies of cell membranes and subcellular organelles. Recently synthesized precursors of rhodamine fluorescent dyes (abbreviations PFD813 and PFD814) important for microscopic probing of biological objects have been studied in solution. In order to characterize the behavior at interfaces, monolayers of PFD813 and PFD814 on water have been formed and investigated. The interactions of these precursors with the biomembrane component dimyristoylphosphatidylethanolamine in monolayers at the air-water interface and after transfer to glass plates have been studied by measuring monolayer parameters and spectroscopic properties before and after photo-chemical formation of the fluorescent rhodamine dyes Rho813 and Rho814, respectively. PMID- 23749559 TI - The resistance analysis of Ureaplasma urealyticum and Mycoplasma hominis in female reproductive tract specimens. AB - The aim of this study was to analyze the drug resistance of Ureaplasma urealyticum (Uu) and Mycoplasma hominis (Mh) in female reproductive track from 2007 to 2011 in Hangzhou. Antibiotics sensitivity test in Mycoplasma, which was isolated in clinics from 2007 to 2011 were analyzed retrospectively. The detection of Mycoplasma during 2007-2011 was 20,146 (54.37 %), of which the single infection rate of Uu was 42.08 %, of Mh 1.26 %, and of Uu+Mh was 11.02 %. The drug resistance rate of Uu was increased significantly in ofloxacin in 2007 (41.80 %), 2008 (45.94 %), 2009 (46.07 %), 2010 (50.36 %), and 2011 (53.22 %) (P < 0.05). The resistance rate to ciprofloxacin was significantly increased in 2007 (67.15 %), 2008 (67.44 %), 2009 (73.00 %), 2010 (75.28 %), and 2011 (75.28 %) (P < 0.05). Exceptionally, the resistance rates of the other antibiotics were low. The drug resistance rate of Uu was significantly increased with quinolones at increasing tendency. It is necessary to monitor the local drug resistance rate of Uu regularly to provide reasonable guidelines in clinics. PMID- 23749560 TI - Hyperostosis in three fish species collected from the Sea of Oman. AB - Hyperostotic conditions are described in three teleost fishes. Pomadasys stridens, (Haemulidae; 326 mm TL, 314 mm SL), Drepane longimana (Drepanidae; 450 mm, TL, 440 mm SL), and Platax teira (Ephippidae) captured off the coast of Muscat City. There are regions of hyperostosis in four bones in P. stridens, three in D. longimana and seven in P. teira. Size, shape, position, and species specific characteristics showed wide variation in these three species. PMID- 23749561 TI - Observer-independent nodule-detectability index for low-dose lung cancer screening CT: a pilot study. AB - For the wide dissemination of lung cancer screening by low-dose computed tomography (CT), it is important to determine the optimal conditions for scan and image reconstruction based on objective standards of evaluation. Our aim in this study was to propose a quantitative index of nodule detectability without an observer test. It was essential to determine the apparent size and density of nodules visible on CT images for developing the nodule-detectability index based on a statistical observer-independent method. Therefore, we introduced a computer simulation technique for CT images based on the spatial resolution of the system to evaluate the size and density accurately. By use of scan/reconstruction parameter settings as employed for low-dose CT screening, a detectability index was obtained for target nodules (ideal spheres) of various sizes and with varying contrast (DeltaCT) between nodule density and background density. The index was compared with the qualitative results of observer tests of nodule detectability. As the target nodule diameter or DeltaCT was increased, the index value increased, implying improved nodule visibility. According to the index, the detection limits for nodules with DeltaCTs of 70, 100, or 150 Hounsfield units were approximately 6, 5, and 4 mm in diameter, respectively. Index values were well correlated with nodule detectability as assessed by four observers. The proposed index was effective for quantifying nodule detectability, and its validity was confirmed by an observer test. This index has potential use in the determination of optimal scan/reconstruction parameters for lung cancer screening by low-dose CT without observer test. PMID- 23749562 TI - Identification of Arabidopsis VTC3 as a putative and unique dual function protein kinase::protein phosphatase involved in the regulation of the ascorbic acid pool in plants. AB - Ascorbic acid (AsA) is present at high levels in plants and is a potent antioxidant and cellular reductant. The major plant AsA biosynthetic pathway is through the intermediates D-mannose and L-galactose. Although there is ample evidence that plants respond to fluctuating environmental conditions with changes in the pool size of AsA, it is unclear how this regulation occurs. The AsA deficient Arabidopsis thaliana mutants vtc3-1 and vtc3-2 define a locus that has been identified by positional cloning as At2g40860. Confirmation of this identification was through the study of AsA-deficient At2g40860 insertion mutants and by transgenic complementation of the AsA deficiency in vtc3-1 and vtc3-2 with wild-type At2g40860 cDNA. The very unusual VTC3 gene is predicted to encode a novel polypeptide with an N-terminal protein kinase domain tethered covalently to a C-terminal protein phosphatase type 2C domain. Homologues of this gene exist only within the Viridiplantae/Chloroplastida and the gene may therefore have arisen along with the D-mannose/L-galactose AsA biosynthetic pathway. The vtc3 mutant plants are defective in the ability to elevate the AsA pool in response to light and heat, suggestive of an important role for VTC3 in the regulation of the AsA pool size. PMID- 23749565 TI - High-aspect-ratio gold nanorods: their synthesis and application to image cell induced strain fields in collagen films. AB - Gold nanoparticles are receiving considerable attention due to their novel properties and the potential variety of their uses. Long gold nanorods with dimensions of approximately 20 * 400 nm exhibit strong light scattering and can be easily observed under dark-field microscopy. Here we describe the use of this light-scattering property to track micrometer scale strains in collagen gels and thick films, which result from cell traction forces applied by neonatal heart fibroblasts. The use of such collagen constructs to model cell behavior in the extracellular matrix is common, and describing local mechanical environments on such a small scale is necessary to understand the complex factors associated with the remodeling of the collagen network. Unlike other particles used for tracking purposes, gold nanorods do not photobleach, allowing their optical signal to be tracked for longer periods of time, and they can be easily synthesized and coated with various charged or neutral shells, potentially reducing the effect of their presence on the cell system or allowing selective placement. Techniques described here are ultimately applicable for investigations with a wide variety of cells and cell environments. PMID- 23749566 TI - Imaging intracellular quantum dots: fluorescence microscopy and transmission electron microscopy. AB - Quantum dots (QDs) and other nanoparticles require delivery and targeting for most intracellular applications. Despite many advances, intracellular delivery and targeting remains inefficient with many QDs remaining bound to the plasma membrane rather than internalized into the cell. The fluorescence resulting from these extracellular QDs results in a background signal that competes with intracellular QDs of interest. We present two methods for the reduction and discrimination of signal resulting from plasma membrane-bound QDs. The first method, a photophysical approach, uses an extracellular quencher to greatly reduce the fluorescence signal from extracellular QDs. This method is compatible with fast, widefield, fluorescence imaging in live cells. Results are presented for two extracellular quenchers, QSY-21 and trypan blue, used in combination with 655 nm emitting QDs. The use of an extracellular quencher can be extended to a wide variety of fluorophores. The second method uses transmission electron microscopy (TEM) to image thin (60-70 nm) slices of resin-embedded cells. The use of sectioned cells and high-resolution TEM makes it possible to discriminate between plasma membrane-bound and intracellular QDs. To overcome the difficulties associated with using TEM to image individual QDs in cells, we have utilized a silver enhancement method that significantly improves the contrast of QDs in TEM images. PMID- 23749567 TI - Imaging of cell populations in atherosclerosis using quantum dot nanocrystals. AB - Atherosclerosis, a leading cause of morbidity and mortality worldwide, is characterized by the accumulation of lipid deposits inside arterial walls, leading to narrowing of the arterial lumen. A significant challenge in the development of diagnostic and therapeutic strategies is to elucidate the contribution of the various cellular participants, including macrophages, endothelial cells, and smooth muscle cells, in the initiation and progression of the atheroma. This protocol details a strategy using quantum dot nanocrystals to monitor homing and distribution of cell populations within atherosclerotic lesions with high signal to noise ratios over prolonged periods of analysis. This fluorescence-based approach enables the loading of quantum dots into cells such as macrophages without perturbing native cell functions in vivo, and has been used for the multiplexed imaging of quantum dot-labeled cells with biomarkers of atherosclerotic disease using conventional immunofluorescence techniques. PMID- 23749568 TI - Imaging of endothelial progenitor cell subpopulations in angiogenesis using quantum dot nanocrystals. AB - Over the last decade, research has identified a class of bone marrow-derived circulating stem cells, termed endothelial progenitor cells (EPCs), that are capable of homing to vascular lesions in the eye and contributing to pathological ocular neovascularization (NV). In preclinical and biological studies, EPCs are frequently identified and tracked using a intracellularly loaded fluorescent tracer, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbo cyanine perchlorate labeled acetylated LDL (DiI-acLDL). However, this method is limited by photobleaching and insufficient quantum efficiency for long-term imaging applications. We have developed a method for conjugation of high quantum efficiency, photostable, and multispectral quantum dot nanocrystals (QD) to acLDL for long-term tracking of EPCs with improved signal-to-noise ratios. Specifically, we conjugated QD to acLDL (QD-acLDL) and used this conjugated fluorophore to label a specific CD34(+) subpopulation of EPCs isolated from rat bone marrow. We then utilized this method to track CD34(+) EPCs in a rat model of laser-induced choroidal neovascularization (LCNV) to evaluate its potential for tracking EPCs in ocular angiogenesis, a critical pathologic feature of several blinding conditions. PMID- 23749569 TI - Imaging single synaptic vesicles in mammalian central synapses with quantum dots. AB - This protocol describes a sensitive and rigorous method to monitor the movement and turnover of single synaptic vesicles in live presynaptic terminals of mammalian central nerve system. This technique makes use of fluorescent semiconductor nanocrystals, quantum dots (Qdots), by their nanometer size, superior photoproperties, and pH-sensitivity. In comparison with other fluorescent probes like styryl dyes and pH-sensitive fluorescent proteins, Qdots offer strict loading ratio, multi-modality detection, single vesicle precision, and most importantly distinctive signals for different modes of vesicle recycling. This application is spectrally compatible with existing optical labels for synapses and thus allows multichannel and simultaneous imaging. With easy modification, this technique can be applied to other types of cells. PMID- 23749570 TI - Quantum dot-based single-molecule microscopy for the study of protein dynamics. AB - Real-time microscopic visualization of single molecules in living cells provides a molecular perspective of cellular dynamics, which is difficult to be observed by conventional ensemble techniques. Among various classes of fluorescent tags used in single-molecule tracking, quantum dots are particularly useful due to their unique photophysical properties. This chapter provides an overview of single quantum dot tracking for protein dynamic studies. First, we review the fundamental diffraction limit of conventional optical systems and recent developments in single-molecule detection beyond the diffraction barrier. Second, we describe methods to prepare water-soluble quantum dots for biological labeling and single-molecule microscopy experimental design. Third, we provide detailed methods to perform quantum dot-based single-molecule microscopy. This technical section covers three protocols including (1) imaging system calibration using spin-coated single quantum dots, (2) single quantum dot labeling in living cells, and (3) tracking algorithms for single-molecule analysis. PMID- 23749571 TI - Three-dimensional molecular imaging with photothermal optical coherence tomography. AB - Optical coherence tomography (OCT) is a three-dimensional optical imaging technique that has been successfully implemented in ophthalmology for imaging the human retina, and in studying animal models of disease. OCT can nondestructively visualize structural features in tissue at cellular-level resolution, and can exploit contrast agents to achieve molecular contrast. Photothermal OCT relies on the heat-producing capabilities of antibody-conjugated gold nanoparticles to achieve molecular contrast. A pump laser at the nanoparticle resonance wavelength is used to heat the nanoparticles in the sample, and the resulting changes in the index of refraction around the nanoparticles are detected by phase-sensitive OCT. Lock-in detection of the pump beam amplitude-modulated frequency and the detector frequency allow for high-sensitivity images of molecular targets. This approach is attractive for nondestructive three-dimensional molecular imaging deep (approximately 2 mm) within biological samples. The protocols described here achieve a sensitivity of 14 parts per million (weight/weight) nanoparticles in the sample, which is sufficient to differentiate EGFR (epidermal growth factor receptor)-overexpressing cells from minimally expressing cells in three dimensional cell constructs. PMID- 23749573 TI - Gold nanoparticle-oligonucleotide conjugates for the profiling of malignant melanoma phenotypes. AB - This chapter discusses the preparation and subsequent profiling capabilities of gold nanoparticle-oligonucleotide conjugates for multiple melanoma mRNA targets. We will outline the attachment of DNA hairpins modified with a thiol for facile attachment to gold nanoparticle surfaces through gold-sulfur bond formation. Furthermore, the ability of these conjugates to detect and distinguish phenotypic variations utilizing -several melanoma cell lines and the nonmalignant cell line, HEp-2, will be investigated using flow cytometry and RT-PCR analytical techniques. The behavior of the housekeeping probe beta-actin will also be investigated as a control. PMID- 23749572 TI - Detecting respiratory syncytial virus using nanoparticle-amplified immuno-PCR. AB - Early-stage detection is essential for effective treatment of pediatric virus infections. In traditional -immuno-PCR, a single antibody recognition event is associated with one to three DNA tags, which are subsequently amplified by PCR. In this protocol, we describe a nanoparticle-amplified immuno-PCR assay that combines antibody recognition of traditional ELISA with a 50-fold nanoparticle valence amplification step followed by amplification by traditional PCR. The assay detects a respiratory syncytial virus (RSV) surface fusion protein using a Synagis antibody bound to a 15 nm gold nanoparticle co-functionalized with thiolated DNA complementary to a hybridized 76-base Tag DNA. The Tag DNA to Synagis ratio is 50 to 1. The presence of virus particles triggers the formation of a "sandwich" complex comprised of the gold nanoparticle construct, virus, and a 1 MUm antibody-functionalized magnetic particle used for extraction. Virus containing complexes are isolated using a magnet, DNA tags released by heating to 95 degrees C, and detected via real-time PCR. The limit of detection of the nanoparticle-amplified immuno-PCR assay was compared to traditional ELISA and traditional RT-PCR using RSV-infected HEp-2 cell extracts. Nanoparticle-amplified immuno-PCR showed a ~4,000-fold improvement in the limit of detection compared to ELISA and a fourfold improvement in the limit of detection compared to traditional RT-PCR. Nanoparticle-amplified immuno-PCR offers a viable platform for the development of an early-stage diagnostics requiring an exceptionally low limit of detection. PMID- 23749574 TI - Methods for isolating RNA sequences capable of binding to or mediating the formation of inorganic materials. AB - The ability of oligonucleotides to mediate the formation of inorganic materials is now well established. RNA and DNA are proving to be capable of mediating the formation of inorganic nanoparticles with sequence-specific control over nanoparticle size, shape, and even atomic-level crystallinity. Here we describe methods for isolating specific RNA sequences from large random sequence libraries that either bind to precut inorganic crystal wafers with high affinity or influence inorganic crystal growth. PMID- 23749575 TI - Single-walled carbon nanotube-mediated small interfering RNA delivery for gastrin releasing peptide receptor silencing in human neuroblastoma. AB - Small interfering RNA (siRNA) has the potential to influence gene expression with a high degree of target gene specificity. However, the clinical application of siRNA therapeutics has proven to be less promising as evidenced by its poor intracellular uptake, instability in vivo, and nonspecific immune stimulations. Recently, we have demonstrated that single-walled carbon nanotube (SWNT)-mediated siRNA delivery can enhance the efficiency of siRNA-mediated gastrin-releasing peptide receptor (GRP-R) gene silencing by stabilizing siRNA while selectively targeting tumor tissues. Based on our recent findings, we introduce a novel technique to silence specific gene(s) in human neuroblastoma through SWNT mediated siRNA delivery in vitro and in vivo. PMID- 23749576 TI - Amino acid mediated linear assembly of Au nanomaterials. AB - Nanoparticles possess unique properties that are enhanced due to their small size and varied shapes. These properties can be directly manipulated by controlling the aggregation state, which can further be exploited for applications in bio/chemical sensing, plasmonics, and as supports for catalysts. While the advantages of controlled aggregates of nanomaterials are great, synthetic strategies to achieve such structures with precision over the final arrangement of the materials in three-dimensional space remain limited. We have shown that ligand exchange reactions on Au nanomaterials of various shapes using simple amino acids can induce the formation of linear aggregates of the materials. The assembly process is mediated by partial ligand exchange on the particle surface, followed by the surface segregation of the two ligands that produces an electric dipole across the nanomaterial from which alignment occurs in solution via dipole dipole interactions. This linear-based assembly can be used to tune the optical properties of the materials and could represent new pathways to study the interactions between biological molecules and inorganic nanomaterials. PMID- 23749577 TI - Enzyme-gold nanoparticle bioconjugates: quantification of particle stoichiometry and enzyme specific activity. AB - Enzyme-gold nanoparticle bioconjugates have a wide variety of uses ranging from nanoreactors to sensors and model systems. While easy to make, these bioconjugates are often not well characterized. This protocol outlines preparation of enzyme-nanoparticle bioconjugates and two complementary methods for quantifying enzyme:nanoparticle stoichiometry from which the specific activity of the adsorbed enzymes can be determined. Characterizations such as these can aid researchers in improving the design and application of future bioconjugate systems. PMID- 23749578 TI - In vivo testing for gold nanoparticle toxicity. AB - A technique for measuring the toxicity of nanomaterials using a murine model is described. Blood samples are collected via submandibular bleeding while urine samples are collected on cellophane sheets. Both biosamples are then analyzed by inductively coupled plasma optical emission spectroscopy (ICP-OES) for nanotoxicity. Blood samples are further tested for immunological response using a standard Coulter counter. The major organs of interest for filtration are also digested and analyzed via ICP-OES, producing useful information regarding target specificity of the nanomaterial of interest. Collection of the biosamples and analysis afterward is detailed, and the operation of the technique is described and illustrated by analysis of the nanotoxicity of an injection of a modified tiopronin monolayer-protected cluster. PMID- 23749579 TI - Methods for studying toxicity of silica-based nanomaterials to living cells. AB - A number of silica-based nanomaterials have been developed in recent years. An important application of these nanomaterials is in the field of biological and biomedical applications. However, a major concern about the safety of the nanomaterials in vitro has been proposed. To address this problem, several approaches have been developed for a systematic investigation of the cytotoxicity and genotoxicity of silica-based nanoparticles. These methods are mainly based on the traditional toxicity study approaches but with some modifications. In this chapter, four important methods for studying of toxicity of silica-based nanomaterials are summarized. These methods can detect cell proliferation, cell viability, DNA damage, and the generation of reactive oxygen species (ROS). The protocols of each method are introduced in detail. PMID- 23749580 TI - Aphid-willow interactions in a high Arctic ecosystem: responses to raised temperature and goose disturbance. AB - Recently, there have been several studies using open top chambers (OTCs) or cloches to examine the response of Arctic plant communities to artificially elevated temperatures. Few, however, have investigated multitrophic systems, or the effects of both temperature and vertebrate grazing treatments on invertebrates. This study investigated trophic interactions between an herbivorous insect (Sitobion calvulum, Aphididae), a woody perennial host plant (Salix polaris) and a selective vertebrate grazer (barnacle geese, Branta leucopsis). In a factorial experiment, the responses of the insect and its host to elevated temperatures using open top chambers (OTCs) and to three levels of goose grazing pressure were assessed over two summer growing seasons (2004 and 2005). OTCs significantly enhanced the leaf phenology of Salix in both years and there was a significant OTC by goose presence interaction in 2004. Salix leaf number was unaffected by treatments in both years, but OTCs increased leaf size and mass in 2005. Salix reproduction and the phenology of flowers were unaffected by both treatments. Aphid densities were increased by OTCs but unaffected by goose presence in both years. While goose presence had little effect on aphid density or host plant phenology in this system, the OTC effects provide interesting insights into the possibility of phenological synchrony disruption. The advanced phenology of Salix effectively lengthens the growing season for the plant, but despite a close association with leaf maturity, the population dynamics of the aphid appeared to lack a similar phenological response, except for the increased population observed. PMID- 23749581 TI - Early remission is associated with improved survival in patients with inflammatory polyarthritis: results from the Norfolk Arthritis Register. AB - OBJECTIVES: This study aimed to evaluate whether the early achievement of clinical remission influences overall survival in an inception cohort of patients with inflammatory polyarthritis (IP). METHODS: Consecutive early IP patients, recruited to a primary care based inception cohort from 1990 to 1994 and from 2000 to 2004 were eligible for this study. Remission was defined as absence of clinically detectable joint inflammation on a 51-joint count. In sensitivity analyses, less stringent definitions of remission were used, based on 28-joint counts. Remission was assessed at 1, 2 and 3 years after baseline. All patients were flagged with the national death register. Censoring was set at 1 May 2011. The effect of remission on mortality was analysed using the Cox proportional hazard regression model, and presented as HRs and 95% CIs. RESULTS: A total of 1251 patients were included in the analyses. Having been in remission at least once within the first 3 years of follow-up was associated with a significantly lower risk of death: HR 0.72 (95% CI 0.55 to 0.94). Patients who were in remission 1 year after the baseline assessments and had persistent remission over time had the greatest reduction in mortality risk compared with patients who never achieved remission within the first 3 years of follow-up: HR 0.58 (95% CI 0.37 to 0.91). Remission according to less stringent definitions was associated with progressively lower protective effect. CONCLUSIONS: Early and sustained remission is associated with decreased all-cause mortality in patients with IP. This result supports clinical remission as the target in the management of IP. PMID- 23749582 TI - Functional allocation of synaptic contacts in microcircuits from rods via rod bipolar to AII amacrine cells in the mouse retina. AB - Retinal microcircuits for night vision at the absolute threshold are required to relay a single-photon rod signal reliably to ganglion cells via rod bipolar (RB) cells and AII amacrine cells. To assess the noise reduction of intercellular signal transmission in this rod-specific pathway, we quantified its synaptic connectivity by 3D reconstruction of a series of electron micrographs. In most cases (94%), each rod made ribbon synaptic contacts onto two adjacent RB cells. Conversely, each RB cell was contacted by 25 rods. Each RB axon terminal contacted four or five AII amacrine cells via 53 ribbon synapses. Thus, the signal from one rod may be represented as 106 replicates at two RB axons. Moreover, the two adjacent RB cells contacted two to four AII amacrine cells in common, where the signals relayed by two RB cells were reunited. In more detail, over 50% of each RB output was directed predominantly to a single, preferred AII amacrine cell, although each RB cell also separately contacted another one to three AII amacrine cells. Most of the replicate signals at two RB axons were collected on a few AII amacrine cells via reunions, dominant connections, and electrical coupling by AII-AII gap junctions. Thus the original signal may be reliably represented by signal amplification with focal accumulation without gathering unnecessary noise from a wide surrounding area. This allocation of RB AII synaptic contacts may serve as the structural basis for the physiological properties of the AII single-photon response that include high amplification, local adaptation, and regenerative acceleration. PMID- 23749583 TI - Serum 25-hydroxyvitamin D status in individuals with psoriasis in the general population. AB - There is a dearth of data assessing serum 25-hydroxyvitamin D (25[OH]D) status in psoriasis. This population-based study in the United States evaluated 25(OH)D status in psoriasis and examined the associations between 25(OH)D and psoriasis severity. The 2003-2006 National Health and Nutrition Examination Survey was analyzed. Participants aged 20-59 years self-reported psoriasis, psoriasis body surface area (BSA), and psoriasis life impairment (PLI). Serum 25(OH)D was assessed with the DiaSorin radioimmunoassay. General linear models were used to examine the associations between psoriasis and 25(OH)D while accounting for age, gender, race/ethnicity, season, and body mass index (BMI). Among the 5,841 participants with complete data, 148 reported a psoriasis diagnosis. Mean 25(OH)D levels and deficiency prevalences (<20 and <30 ng/mL) were not different between those with and without psoriasis. Among those with psoriasis, a multivariate model showed participants with BSA >10 hand palms trended towards lower 25(OH)D compared to those with minimal BSA (-4.98 ng/mL, P = 0.07). PLI was not associated with 25(OH)D, but BMI showed an inverse association with 25(OH)D (coefficient = -0.40, P < 0.001). In summary, dermatologists may consider measures of adiposity as better screening tools for vitamin D deficiency than BSA involvement among psoriatics with mild-to-moderate disease. PMID- 23749584 TI - Fatal acute encephalopathy in a young man with Graves' disease. PMID- 23749585 TI - Concomitant myasthenia gravis and macroprolactinoma: the immunomodulatory role of prolactin and its potential therapeutic use. AB - Considerable evidence attests to the role of the hypothalamic-pituitary endocrine axis (HPA) in the maintenance of normal immunocompetence. The immune and neuroendocrine systems are integrally linked and coordinated with bidirectional communication maintaining immune balance. Any disturbance of the normal function of the HPA may significantly alter native immunocompetence and therefore be associated with the development of disorders which have a clearly established autoimmune basis. Molecular and functional evidence shows prolactin, produced by the anterior pituitary, to be a cytokine, exerting its effect via both paracrine and endocrine mechanisms [1]. Its involvement in the activation of multiple immune responses may adversely upregulate certain autoimmune diseases. Myasthenia gravis (MG) has long been recognized as an autoimmune disorder. In this mini review, we present the coterminous presentation of MG and prolactin-secreting macroadenoma. We review published cases in the world literature, discuss pathological mechanism, and consider future targeted therapies. PMID- 23749586 TI - Pharmacokinetic interaction of enrofloxacin/trimethoprim combination following single-dose intraperitoneal and oral administration in rats. AB - The pharmacokinetic interaction of enrofloxacin and trimethoprim was evaluated after single-dose intraperitoneal or oral co-administration in rats. Plasma concentrations of the two drugs were determined by high-performance liquid chromatography. Following intraperitoneal combination, a significant (P < 0.05) increase in mean values of plasma half-life (t 1/2) and maximum plasma concentration (C max) was observed for enrofloxacin and trimethoprim, respectively. There was a significant (P < 0.05) increase in mean values of area under the plasma drug concentration versus time from time zero to infinity (AUC0 infinity) and C max between combined oral doses (10, 30 and 100 mg/kg) of both antibacterial drugs. Also, after oral conjugation a significant difference in mean values of MRT0-infinity was observed between lower (10 mg/kg) and higher (100 mg/kg) doses of both drugs. A significant increase in pharmacokinetic parameters of both drugs in combined intraperitoneal and oral doses indicated pharmacokinetic interaction of enrofloxacin and trimethoprim. Further study is recommended in other species of animals. PMID- 23749587 TI - An in vitro metabolic system of gut flora and the metabolism of ginsenoside Rg3 and cholic acid. AB - For orally administered drugs, the metabolism of a drug by the gut flora plays an important role in the bioavailability, activation and disposition of the drug in vivo. However, no in vitro system is currently available to evaluate the metabolism of a drug by the gut flora before the drug is absorbed into the body. This paper presents an in vitro metabolic system in an anaerobic environment that could be used to evaluate the metabolism of an endogenous compound, cholic acid, and a xenobiotic compound, ginsenoside Rg3. We showed that the proliferation of the anaerobic bacteria of the gut content of hamsters produced a similar composition of gut flora in a culture medium for yeast to that in vivo. Incubation of ginsenoside Rg3 and cholic acid in the anaerobic in vitro system efficiently produced the metabolites Rh2 and deoxycholic acid, respectively, similar to those seen in the gut content in vivo. In comparison with in vivo analysis, this anaerobic in vitro metabolic system is convenient, reproducible, economic and animal saving, and can easily be applied to assess the transformation and disposition of a drug before it enters into the circulatory system. PMID- 23749588 TI - Reply: To PMID 21725989. PMID- 23749589 TI - Quantification of aconitine in post-mortem specimens by validated liquid chromatography-tandem mass spectrometry method: three case reports on fatal 'monkshood' poisoning. AB - The diester-diterpene alkaloid aconitine was quantified by liquid chromatography tandem mass spectrometry in post-mortem specimens of three cases where suicidal ingestion of Aconitum napellus L. ('monkshood') was supposed. In an attempt at rationalization, sample preparation and chromatographic conditions of plasma/serum drug analysis routine were utilized. Linearity was established from 0.5 to 20 ug L-1 using newborn calf serum (NCS) as a surrogate calibration matrix for all sample types and mesaconitine as an internal standard. Validation (selectivity, sensitivity, precision, accuracy, recovery of the extraction procedure, matrix effect, processed sample stability) confirmed the applicability of the analytical method to various post-mortem matrices. Internal standard selection was based on multi-matrix process efficiency data. In human post-mortem peripheral blood a lower limit of quantification of 0.51 ug L-1 and a limit of detection of 0.13 ug L-1 were accomplished (0.1 ml sample aliquots). Aconitine was degraded to a large extent in different sample types when being stored at +20 degrees C for 30 days, while at -20 degrees C and for some matrices also at +4 degrees C no appreciable degradation occurred. Aconitine concentrations in real samples were 10.3-17.9 ug L-1 (peripheral blood, n = 3), 14.9-87.9 ug L-1 (heart blood, n = 3), 317-481 ug L-1 (urine, n = 2), 609-4040 ug L-1 (stomach content, n = 3), 139-240 ug L-1 (bile, n = 2), 8.4 ug L-1 (vitreous humor, n = 1), 54.7 ug L 1 (pericardial fluid, n = 1), 492 ug kg-1 (liver, n = 1), 15.2-19.7 mg L-1 (unknown liquids secured onsite, n = 3). Together with concomitant circumstances the analytical data provided compelling evidence for acute Aconitum poisoning as being the cause of death. PMID- 23749590 TI - In vitro characteristics of a gelling PEGDA-QT polymer system with model drug release for cerebral aneurysm embolization. AB - A liquid-to-solid gelling polymer system, such as the poly(ethylene glycol) diacrylate-pentaerythritol tetrakis (3-mercaptopropionate) (PEGDA-QT) system, can fill cerebral aneurysms more completely than current embolization materials, reducing the likelihood of aneurysm recurrence. PEGDA-QT gels were formulated using PEGDA of different molecular weights (PEGDA575 and PEGDA700 ), and their characteristics were examined in vitro. Experiments examined gel time, mass change, crosslink integrity, cytotoxicity, and protein release capabilities. In general, PEGDA575 -QT gels were more hydrophobic, requiring an initiating solution with a higher pH (pH 9.5) to achieve a gel time comparable to PEGDA700 QT gels, which used an initiating solution at pH 9.19. The mass change and crosslink integrity of gels were analyzed over time after gels were submerged in 150 mM phosphate buffered saline. After 380 days, PEGDA575 -QT gels achieved a maximum mass increase of 72% due to water uptake, while PEGDA700 -QT gels doubled their initial mass (100% increase) by 165 days. Compression tests showed that PEGDA700 -QT gels hydrolyzed more quickly than PEGDA575 -QT gels. Cytotoxicity assays showed that in general, PEGDA575 -QT negatively affected cell growth, while PEGDA700 -QT gels promoted cell viability. Sustained, controlled release of lysozyme, a 14.3 kDa protein, was achieved over an 8-week period when loaded into PEGDA700 -QT gels, but PEGDA575 -QT gels did not show sustained release. These studies show that although they are similar in composition, these PEGDA-QT gel formulations behave considerably differently. Although PEGDA700 -QT gels swell more and degrade faster than PEGDA575 -QT gels, their cytocompatibility and protein release characteristics may prove to be more beneficial for in vivo aneurysm treatment. (c) 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2013. PMID- 23749591 TI - Attitudes towards cross-border reproductive care among infertile Japanese patients. AB - OBJECTIVES: The attitudes towards cross-border reproductive care (CBRC) held by infertile Japanese patients have not been explored. The objective of the present study was to examine interest levels, preferred destinations, motivations, and sources of information related to CBRC. Our findings provide a general outline of CBRC and the future of reproduction and assisted reproductive technology (ART) in Japan. METHODS: The study used a cross-sectional design. Data were collected from 2,007 infertile Japanese patients from 65 accredited ART clinics in Japan (response rate, 27.4 %) via anonymous questionnaires. RESULTS: Most of the infertile Japanese patients who responded denied using CBRC. However, by group, 171 (8.5 %) patients in non-donor in vitro fertilization, 150 (7.5 %) in egg donation, 145 (7.2 %) in pre-implantation genetic diagnosis, and 129 (6.4 %) in surrogacy said that, depending on the situation, they might travel abroad in the future. Older respondents were more likely to express an intention to travel overseas for egg donation in the future. The most popular destination for CBRC was the United States. Popular reasons for interest in CBRC among those considering or planning using this approach to third-party reproduction were that egg donation or surrogacy was unavailable or that obtaining ethical approval takes too long in Japan, whereas these processes are legal and affordable overseas. However, high cost was the most common reason for hesitancy regarding CBRC. Among the participants who were considering or planning to travel abroad for this purpose, TV, medical agencies, print media, and message boards on websites were popular sources of information, whereas doctors, friends, and patient self-help groups were not. CONCLUSIONS: Although CBRC among infertile Japanese patients is not at present common, the demand for and use of this approach may increase in the future in the context of the increasingly aging population. Lack of regulation and unavailability of third-party reproduction is a major cause of CBRC among Japanese patients. Health care provider faces an urgent need for giving useful information for patients regarding CBRC. PMID- 23749592 TI - [Pleura solitary fibrous tumor associated with Doege-Potter Syndrome]. AB - The Doege-Potter Syndrome is known as a combination of intrathoracic tumor associated to symptomatic hypoglycemia. Solitary Fibrous Tumor is a mesenchymal neoplasm. Initially, it was described in the pleura, however, it starts out in any organ or tissue at the expense of a stromal CD34+ cell. Most of the patients are asymptomatic at the time of diagnosis. Symptoms such as cough, dyspnea, chest pain, and hypoglycemia due to production of IGF-2 have been reported (Doegge- Potter Syndrome). Others described paraneoplastic profiles are hypertrophic osteoarthropathy and in some cases galactorrhea. We report on a case of a 77 year old patient with solitary fibrous tumor in the pleura as well as symptomatic hypoglycemia. The primary treatment is surgical resection, and a longtime monitoring is necessary because recurrences can occur even after a long period of remission. PMID- 23749593 TI - [Foundation for the German Sanatorium in Davos and Agra]. PMID- 23749594 TI - [The new GOLD recommendation cannot be implemented in everyday life]. PMID- 23749595 TI - [Omalizumab therapy in adolescents with severe allergic asthma - observational study ]. PMID- 23749596 TI - [Reply]. PMID- 23749597 TI - [S2K guideline on diagnosis and treatment of idiopathic pulmonary fibrosis]. PMID- 23749599 TI - Choline acetyltransferase-like immunoreactivity in a physiologically distinct subtype of olfactory nonspiking local interneurons in the cockroach (periplaneta americana). AB - Behavioral and physiological studies have shown that local interneurons are pivotal for processing odor information in the insect antennal lobe. They mediate inhibitory and excitatory interactions between the glomerular pathways and ultimately shape the tuning profile of projection neurons. To identify putative cholinergic local interneurons in the antennal lobe of Periplaneta americana, an antibody raised against the biosynthetic enzyme choline acetyltransferase (ChAT) was applied to individual morphologically and electrophysiologically characterized local interneurons. In nonspiking type IIa1 local interneurons, which were classified in this study, we found ChAT-like immunoreactivity suggesting that they are most likely excitatory. This is a well-defined population of neurons that generates Ca(2+) -driven spikelets upon depolarization and stimulation with odorants, but not Na(+) -driven action potentials, because they lack voltage-activated transient Na(+) currents. The nonspiking type IIa2 and type IIb local interneurons, in which Ca(2+) -driven spikelets were absent, had no ChAT-like immunoreactivity. The GABA-like immunoreactive, spiking type I local interneurons had no ChAT-like immunoreactivity. In addition, we showed that uniglomerular projection neurons with cell bodies located in the ventral portion of the ventrolateral somata group and projections along the inner antennocerebral tract exhibited ChAT-like immunoreactivity. Assigning potential transmitters and neuromodulators to distinct morphological and electrophysiological types of antennal lobe neurons is an important prerequisite for a detailed understanding of odor information processing in insects. PMID- 23749600 TI - Diatoms can be an important exception to temperature-size rules at species and community levels of organization. AB - Climate warming has been linked to an apparent general decrease in body sizes of ectotherms, both across and within taxa, especially in aquatic systems. Smaller body size in warmer geographical regions has also been widely observed. Since body size is a fundamental determinant of many biological attributes, climate warming-related changes in size could ripple across multiple levels of ecological organization. Some recent studies have questioned the ubiquity of temperature size rules, however, and certain widespread and abundant taxa, such as diatoms, may be important exceptions. We tested the hypothesis that diatoms are smaller at warmer temperatures using a system of geothermally heated streams. There was no consistent relationship between size and temperature at either the population or community level. These field data provide important counterexamples to both James' and Bergmann's temperature-size rules, respectively, undermining the widely held assumption that warming favours the small. This study provides compelling new evidence that diatoms are an important exception to temperature size rules for three reasons: (i) we use many more species than prior work; (ii) we examine both community and species levels of organization simultaneously; (iii) we work in a natural system with a wide temperature gradient but minimal variation in other factors, to achieve robust tests of hypotheses without relying on laboratory setups, which have limited realism. In addition, we show that interspecific effects were a bigger contributor to whole-community size differences, and are probably more ecologically important than more commonly studied intraspecific effects. These findings highlight the need for multispecies approaches in future studies of climate warming and body size. PMID- 23749601 TI - Medical management strategies to prevent recurrent nephrolithiasis are stagnant and stronger evidence is needed to reduce morbidity. PMID- 23749602 TI - Randomised controlled trial: extended-duration dabigatran is non-inferior to warfarin and more effective than placebo for symptomatic VTE. PMID- 23749603 TI - Impact of honey as a topical treatment for wounds remains unclear. PMID- 23749604 TI - Observations suggesting bioactive Fgf15 is not present in mouse blood. PMID- 23749605 TI - The future of colorectal cancer: implications of screening. PMID- 23749607 TI - Colorectal cancer: dichotomous or continuum model? Perhaps, a combination of both. PMID- 23749606 TI - Recent advances in autoimmune pancreatitis: type 1 and type 2. AB - Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterised clinically by frequent presentation with obstructive jaundice, histologically by a lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to steroids. When so defined, AIP can be sub-classified into two subtypes, 1 and 2. Recent international consensus diagnostic criteria for AIP have been developed for diagnosis of both forms of AIP. Type 1 AIP is the pancreatic manifestation of a multiorgan disease, recently named IgG4-related disease. Little is known about the pathogenesis of either form of AIP. Despite frequent association of type 1 AIP with elevated serum IgG4 levels and infiltration with IgG4-positive plasma cells, it is unlikely that IgG4 plays a pathogenic role in AIP. Type 1 AIP responds to steroids, but there needs to be consensus on treatment regimens for induction and therapeutic end points. Relapses are common, but can be reduced by long-term use of low-dose steroids. Recent reports suggest that immunomodulators (azathioprine, 6-mercaptopurine and mycophenolate mofetil), as well biological agents (the antibody to CD20, rituximab) may have a role in maintaining remission in relapsing type 1 AIP. Future studies should clarify the best management options for treatment of relapses and maintenance of remission. Type 2 AIP is a pancreas-specific disorder not associated with IgG4. It presents in younger individuals equally with obstructive jaundice and pancreatitis. The inflammatory process responds to steroid therapy; relapses are uncommon. The clinical spectrum and long-term outcomes of medically treated type 2 AIP are still being evaluated. PMID- 23749608 TI - Primary GIST of the liver masquerading as primary intra-abdominal tumour: a rare extra-gastrointestinal stromal tumour (EGIST) of the liver. PMID- 23749609 TI - Obesity surgery smartphone apps: a review. AB - BACKGROUND: The purpose of this study are to review available smartphone applications ('apps') relating to weight loss surgery, and assess the level of medical professional involvement in their design METHODS: Smartphone apps relating to weight loss surgery were identified by searching the three app stores: Apple's App Store, Google Play (Android) and Blackberry AppWorld. A data search was undertaken using keywords and phrases relating to weight loss surgery. Apps designed for the non-surgical treatment of obesity were excluded. RESULTS: A total of 38 apps were identified (Google Play = 17, Apple App Store = 21, Blackberry World = 0). Ten of 38 apps were duplicated therefore 28 apps were reviewed. Mean app rating was 3.6/5 and mean app cost was L1.89. Twenty-six of 28 (92.9%) apps were designed for use by patients. Apps were categorised into the following categories: patient information (ten), patient support forums (six), patient record tools (six), weight loss clinic advertisements (four), a journal app (one) and a conference tool (one). Health professional involvement was evident in 12 of 28 (42.9%) apps. CONCLUSIONS: This study has identified that the majority of available apps relating to weight loss surgery do not have health professional input. The establishment of a 'quality stamp' provided by an established bariatric surgical body could improve the confidence with which patients and clinicians use these new information sources. Weight loss surgery apps offer a unique opportunity to provide accurate and reliable patient information and their use as part of the informed consent process should be explored. PMID- 23749610 TI - Non-steroidal anti-inflammatory drugs and risk of cardiovascular disease in patients with rheumatoid arthritis: a nationwide cohort study. AB - OBJECTIVE: To examine the risk of major cardiovascular disease associated with non-steroidal anti-inflammatory drugs (NSAIDs) in a large 'real-world' contemporary rheumatoid arthritis (RA) cohort. METHODS: A longitudinal cohort study was conducted with use of Danish nationwide individual-level registry data on inpatient and outpatient health care provision, pharmacotherapy and income during 1997-2009. 17 320 RA patients were identified and matched with 69 280 controls (4 : 1) by age and sex. NSAID-associated risk of major cardiovascular disease defined as the combined endpoint of myocardial infarction, stroke or cardiovascular mortality was assessed in multivariable survival models. RESULTS: During follow-up (median 4.9 years) 6283 events occurred. The cardiovascular risk associated with overall NSAID use was significantly lower in RA patients than in controls (HR 1.22 (95% CI 1.09 to 1.37) vs 1.51 (1.36 to 1.66), p<0.01). The pattern of lower NSAID-associated risk in RA patients was generally found with the individual NSAIDs investigated. While use of rofecoxib (HR 1.57 (1.16 to 2.12)) and diclofenac (HR 1.35 (1.11 to 1.64)) was associated with increased cardiovascular risk in RA patients, there was no significant risk increase associated with use of other NSAIDs in these patients. CONCLUSIONS: The cardiovascular risk associated with NSAID use in RA patients was modest and significantly lower than in non-RA individuals. Moreover, only a few of the individual NSAIDs were associated with increased cardiovascular risk. NSAID use should be assessed in the individual patient based on the indication for pain relief and risk factors for adverse effects, and not automatically be avoided due to concerns of severe cardiovascular outcomes alone. PMID- 23749612 TI - Unusual oral mucosa damage during telaprevir treatment of chronic hepatitis C. PMID- 23749611 TI - Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force. AB - BACKGROUND: Therapeutic targets have been defined for diseases like diabetes, hypertension or rheumatoid arthritis and adhering to them has improved outcomes. Such targets are just emerging for spondyloarthritis (SpA). OBJECTIVE: To define the treatment target for SpA including ankylosing spondylitis and psoriatic arthritis (PsA) and develop recommendations for achieving the target, including a treat-to-target management strategy. METHODS: Based on results of a systematic literature review and expert opinion, a task force of expert physicians and patients developed recommendations which were broadly discussed and voted upon in a Delphi-like process. Level of evidence, grade and strength of the recommendations were derived by respective means. The commonalities between axial SpA, peripheral SpA and PsA were discussed in detail. RESULTS: Although the literature review did not reveal trials comparing a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated the development of recommendations. The group agreed on 5 overarching principles and 11 recommendations; 9 of these recommendations related commonly to the whole spectrum of SpA and PsA, and only 2 were designed separately for axial SpA, peripheral SpA and PsA. The main treatment target, which should be based on a shared decision with the patient, was defined as remission, with the alternative target of low disease activity. Follow-up examinations at regular intervals that depend on the patient's status should safeguard the evolution of disease activity towards the targeted goal. Additional recommendations relate to extra-articular and extramusculoskeletal aspects and other important factors, such as comorbidity. While the level of evidence was generally quite low, the mean strength of recommendation was 9-10 (10: maximum agreement) for all recommendations. A research agenda was formulated. CONCLUSIONS: The task force defined the treatment target as remission or, alternatively, low disease activity, being aware that the evidence base is not strong and needs to be expanded by future research. These recommendations can inform the various stakeholders about expert opinion that aims for reaching optimal outcomes of SpA. PMID- 23749613 TI - Characterization of a 5HS-7DS.7DL wheat-barley translocation line and physical mapping of the 7D chromosome using SSR markers. AB - A spontaneous wheat-barley translocation line was previously detected in the progenies of the Mv9kr1 * 'Igri' wheat-barley hybrid and the translocation was identified as 5HS-7DS.7DL. Multicolor genomic in situ hybridization (mcGISH) with D and H genomic DNA probes and three-color fluorescence in situ hybridization (FISH) with repetitive DNA probes (Afa-family, pSc119.2, and pTa71) were performed to characterize the rearranged chromosome. The effect of 5HS and the deleted 7DS fragment on the morphological traits (plant height, fertility, yield, and spike characteristics) of wheat was assessed. Despite the non-compensating nature of the translocation, the plants showed good viability. The aim of the study was to physically localize SSR markers to the telomeric and subtelomeric regions of the 7DS chromosome arm. Of the 45 microsatellite markers analyzed, ten (Xbarc0184, Xwmc0506, Xgdm0130, Xgwm0735, Xgwm1258, Xgwm1123, Xgwm1250, Xgwm1055, Xgwm1220, and Xgwm0635) failed to amplify any 7DS-specific fragments, signaling the elimination of a short chromosome segment in the telomeric region. The breakpoint of the 5HS-7DS.7DL translocation appeared to be more distal than that of reported deletion lines, which provides a new physical landmark for future deletion mapping studies. PMID- 23749615 TI - [Evaluation of a Vocationally Oriented Concept within Inpatient Oncological Rehabilitation]. AB - AIM OF THE STUDY: We evaluated an occupation-related rehabilitation program, which has been designed to enhance the return to work of cancer patients. As return to work plays an important role to get back to normalcy after suffering from cancer, there is a substantial need for support and evaluated programs. METHODS: The study had a quasi-experimental design with an intervention group (IG) and a comparison group (CG). We defined performance-related outcomes (e. g. return to work, self-assessed working capacity), asked patients if they needed further vocational advice and how helpful they estimated the rehabilitation treatment. 1 year after the end of rehabilitation 309 employed patients had completed the study (65%). We addressed our research questions using non parametric tests, t-tests, analyses of variance and logistic regressions. RESULTS: Of the 309 patients 58% started rehabilitation not later than 14 days after the end of acute treatment while the other 42% had finished their treatments at least some weeks or even months ago. Patients of the IG evaluated the work-related rehabilitation offers significantly better and needed less additional vocational advice after the end of rehabilitation (n. s.). Regarding the patients, who started rehabilitation not later than 14 days after the end of acute treatment (beginning of rehabilitation n=269, 12 months after rehabilitation n=174), the IG achieved a slightly higher return-to-work-rate 12 months after the end of rehabilitation (81% IG, 76% CG, n. s.). Above that the IG estimated their subjective working capacity significantly more often as fully re established (IG 46%; CG 29%, p=0,030). CONCLUSIONS: A high percentage of the patients return to work (78%). These results show the success of oncological rehabilitation in helping patients to return to work. In addition, the occupation related rehabilitation program enhances subjective variables as the satisfaction of the patients regarding the information and the improvement of the patients' working-capacity. PMID- 23749614 TI - Subcellular organization of camkii in rat hippocampal pyramidal neurons. AB - Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a key role in N methyl-D-aspartate (NMDA) receptor-dependent long-term synaptic plasticity; its location is critical for signal transduction, and may provide clues that further elucidate its function. We therefore examined the subcellular localization of CaMKII in CA1 stratum radiatum of adult rat hippocampus, by using immuno-electron microscopy after chemical fixation. When tissue was fixed quickly, the concentration of CaMKIIalpha (assessed by pre-embedding immunogold) was significantly higher in dendritic shafts than in spine heads. However, when tissue was fixed 5 minutes after perfusion with normal saline, the density of labeling decreased in dendritic shaft while increasing in spine heads, implying rapid translocation into the spine during brief perimortem stress. Likewise, in quickly fixed tissue, CaMKII within spine heads was found at comparable concentrations in the "proximal" half (adjacent to the spine neck) and the "distal" half (containing the postsynaptic density [PSD]), whereas after delayed fixation, label density increased in the distal side of the spine head, suggesting that CaMKII within the spine head moves toward the PSD during this interval. To estimate its distribution at the synapse in vivo, we performed postembedding immunogold staining for CaMKII in quick-fixed tissue, and found that the enzyme did not concentrate primarily within the central matrix of the PSD. Instead, labeling density peaked ~40 nm inside the postsynaptic membrane, at the cytoplasmic fringe of the PSD. Labeling within 25 nm of the postsynaptic membrane concentrated at the lateral edge of the synapse. This lateral "PSD core" pool of CaMKII may play a special role in synaptic plasticity. PMID- 23749616 TI - [Examination of calibrated item banks for the assessment of work capacity in an outpatient sample of cardiological patients]. AB - BACKGROUND: Work capacity is a major outcome variable in cardiological rehabilitation. However, there is a lacks of capacious and economic assessment instruments for work capacity. By developing item response theory based item banks a first step to close this gap is done. The present study aims to validate the work capacity item banks for cardiovascular rehabilitation inpatients (WCIB Cardio) in a sample of cardiovascular rehabilitation outpatients. Additionally, we examined differences between in- and outpatients with regard to their work capacity. METHODS: Data of 283 cardiovascular rehabilitation inpatients and 77 cardiovascular rehabilitation outpatients were collected in 15 rehabilitation centres. The WCIB-Cardio contains the 2 domains of "cognitive work capacity"(20 items) and "physical work capacity"(18 items). Validation of the item bank for cardiological outpatients was conducted with separate Rasch analysis for each domain. RESULTS: For the domain of cognitive work capacity 10 items showed satisfying quality criteria (Rasch reliability=0.71; overall model fit=0.07). For the domain of physical work capacity good values for Rasch-reliability (0.83) and overall -model fit (0.65) could be proven after exclusion of 3 items. Unidimensionality and a broad ability spectrum could be covered for both domains. With regard to content, outpatients evaluate themselves less burdened than inpatients for the domain of cognitive work capacity (?X outpatient =-2.06 vs. ?X inpatient =-2.49; p<0.07) similarly for the domain of physical work capacity (?X outpatient =-3.68 vs. ?X inpatient =-2.88; p<0.01). DISCUSSION: With the WCIB Cardio II there is a precondition to develop self-report instruments of work capacity in cardiological in- and outpatients. PMID- 23749617 TI - [Consideration of Rehabilitation within High Class Quality Guidelines, Registered by the German Association of the Scientific Medical Professional Societies (AWMF)]. AB - Clinical practice guidelines are systematically developed documents aiming at guiding decisions in specific areas of health care. Therefore, incorporating rehabilitation in guidelines adressing chronic diseases is of major importance. As information regarding consideration of rehabilitation in guidelines is lacking, the intention of our study was to analyse to what degree rehabilitation experts participated in guideline development and whether guidelines for chronic diseases include relevant information and recommendations concerning rehabilitation.In order to answer these questions we investigated 97 guidelines of high class quality, registered by the German Association of the Scientific Medical Professional Societies (AWMF). 36 out of these guidelines addressed chronic health conditions in which rehabilitation may be of relevance. Guidelines identified were analysed using a set of defined criteria.In 11 out of the 36 guidelines one or more medical rehabilitation societies participated in the development process, 17 include a chapter on rehabilitation issues, and 20 information concerning indication for rehabilitation processes. 24 guidelines consider rehabilitation in their recommendations.There is substantial variance concerning inclusion of rehabilitation in German guidelines on chronic diseases. Rehabilitation societies are encouraged to strive for stronger integration of rehabilitation into guidelines of other societies. PMID- 23749618 TI - [The improvement of the transfer into daily life of progressive relaxation after an inpatient psychosomatic rehabilitation]. AB - AIM OF THE STUDY: The aim of the current study was the identification of predictors for a successful transfer of progressive relaxation (PR) into clinical and daily life. Furthermore the development of tension-related symptoms dependening of the frequency of continuous practise was detected. METHODS: 411 patients of a psychosomatic rehabilitation clinic attended a 6-h-course of progressive relaxation and were interviewed at 3 different times by a modified version of the "diagnostisches und evaluatives Instrumentarium fur Entspannungstraining und Entspannungstherapie (ET-EVA)": at the beginning of therapy (T1), at discharge (T2) and 3 months after discharge by postal service (T3). After 3 months 274 patients (78.3%) sent the completed questionnaires back. The frequency of exercising by at least once a week was defined as successful. To detect the extent of symptom improvement, difference values between the different measuring times and effect sizes were calculated. To identify predictors of the frequency of daily practise, bivariate correlations and linear regression were used. RESULTS: 69.4% of the patients continued the exercises successfully beyond the course. The improved experience of relaxation directly after the program (r= 0.184; p<0.01) had a positive influence on the frequency of practising during hospital stay. 3 months after discharge 50.4% of the participants were practising at least once a week. The frequency of practise during hospital stay (r=0.558; p<0.01) and the experience of relaxation at T3 (r=-0.356; p<0.01) could be identified as predictors of a successful transfer into daily life of progressive relaxation. In the context of the linear regression the effect of the frequency of practise during hospital stay (Beta=0.506; p<0.01) and the experience of relaxation after 3 months (Beta=-0.275; p<0.01) remained significant predictors and explaines 40.9% of the variance. The items of all 6 symptom scales decreased significantly from T1 to T2 (p<0.01) and the feeling of discomfort after 3 months was significantly below the base level of T1 (p<0.01). The patients who practised at least once a week - compared to the not-practising patients - declared significantly less tension-related symptoms at T3 (p<0.01) and could achieve a significantly stronger change of wellbeing and relaxation experience at T2 and T3 (p<0.01). CONCLUSION: 50.4% of the patient implemented the relaxation training in their daily routine. The experienced alteration in terms of self-efficacy plays a meaningful role concerning the frequency of practise in hospital stay and daily routine. In future courses attention should be paid to the initial experience of relaxation. The frequency of practise once a week turned out to be the most effective. PMID- 23749619 TI - [Recommendations for overcoming interface problems in medical rehabilitation of federal pension funds and statutory health insurance]. AB - OBJECTIVE: Interface problems in medical rehabilitation are a consequence of problems with communication and cooperation, lack of information and transparency. Different stakeholders are trying to solve these problems since many years or decades respectively. Following a series of deficit-oriented studies we tried to develop recommendations for possible solutions of important interface problems together with affected people based on a qualitative analysis of main problem areas. METHOD: 10 separate group discussions with rehabilitation patients, general practitioners and specialists in private practices, representatives of the federal pension fund and statutory health insurance as well as clinicians from rehabilitation clinics and 3 mixed group discussions (all before mentioned groups excluding rehabilitation patients) were conducted. These group discussions served to prepare a semidiurnal final conference. All meetings were recorded and content analyzed or summarized in protocols respectively. RESULTS: Results are recommendations on strategies to reduce interface problems in medical rehabilitation. Those are: development of a rehabilitation-information website for insurees and general practitioners and specialists in private practices; changes in forms, applications, notifications; advanced training for general practitioners and specialists in private practices und support in detecting rehabilitation need. CONCLUSION: Due to divided structures of care provision and increasing specialization, overcoming interface problems is one of the main challenges in the provision of medical rehabilitation. It can be met if different stakeholder approach each other without prejudices, share instead of demarcate competencies and are willing to strike new paths. Our recommendations represent the first step to reaching this goal. PMID- 23749620 TI - [Medical rehabilitation group-programmes concerning health promotion, patient education and psychoeducation - a 2010 national survey]. AB - OBJECTIVE: High quality demands are being placed on concepts of educational group programmes in medical rehabilitation as well as the related trainer qualifications. A nationwide survey of German medical rehabilitation clinics in 2005 had revealed a need for improving educational practice according to these quality criteria. An updated investigation was performed in 2010 aiming at describing group programmes used in medical rehabilitation. METHOD: 1 473 inpatient and outpatient medical rehabilitation clinics were invited to participate. 908 clinics reported on their training programmes. Data from clinics caring for patients with somatic disorders could be compared to the 2005 survey. Data from clinics for both psychosomatic and substance abuse disorders was collected for the first time in 2010. RESULTS: Overall, psychologists and physicians were reported to be the most frequent conductors of educative programmes. In somatic clinics, psychologists, dieticians and occupational therapists or physiotherapists were the most common conductors. Two-thirds of the institutions reported no training prerequisites for staff members to perform patient education. 80% of the education programmes were categorized post hoc into 3 classes: "generic health education", "disorder-specific patient education", and "psychoeducational group programmes". Almost two-thirds of all programmes were carried out with 8-15 participants, and many used several interactive didactic methods. Programmes conducted in small groups (<8 participants) used significantly more interactive methods than those conducted in larger groups did (>15 participants). Only half of the programmes were manualized. Significantly more interactive methods were used in completely manualized programmes. Only about half of the programmes were evaluated, and only very few evaluation studies were published. The institutions wished additional support by workshops especially concerning qualification of their staff and concerning educational concepts. CONCLUSIONS: A need for further improvement and support exists relative to the training of educators and the development of manuals as well as evaluation and publication of the programmes. PMID- 23749621 TI - [Validation of the Patient Classification System Rehabilitee-Management Categories (RMK) in Patients with Chronic Back Pain in Regular Medical Treatment]. AB - BACKGROUND AND OBJECTIVE: The Rehabilitee-Management-Categories (RMK) have been developed by the Charite - University Medicine Berlin for 10 years. A content- and time-stable classification approach should support health care providers to offer therapy standards that are better adjusted to the needs of patients. At the same time, stability means for healthcare payers that the admission management to clinics with specialised services could be optimized. METHODS: The stability of the RMK classification was tested with the help of latent class analysis (LCA) in independent samples. The data sets are taken from 3 different studies carried out from 2006 to 2011. Only patients with chronic back pain (M40-M54) who were in regular medical treatment provided by the German Pension Fund were included. RESULTS: A statistically stable 4-class solution was found in all samples. Kappa coefficients from 0.605 to 0.72 showed a good consistence of the RMK-algorithm from the first LCA with the respective latent class analyses. CONCLUSION: The RMK approach offers possible uses for both healthcare providers and healthcare payers by assessing the need of treatments according to the ICF approach. Among other things, this approach can be used to fulfil the quality guideline in a differing way. PMID- 23749622 TI - [Development and short-term effects of a standardized patient education program for in-patient cardiologic rehabilitation]. AB - BACKGROUND: Patient education is an essential part in the treatment of coronary heart disease in medical rehabilitation. In the German-speaking area, no standardized and evaluated patient education program for coronary heart disease is available so far. In this paper, we demonstrate the development of a quality assured patient education program based on a health-education program of the German statutory pension insurance scheme. METHODS: In a multi-level approach, an existing program was modified concerning treatment evidence, practical guidelines, theories of health and illness behavior and quality criteria for patient education as well as clinical experience and thereafter manualized. In a formative evaluation, feasibility and patient acceptance of this modified program were assessed using evaluation questionnaires of patients and trainers. Afterwards, effects of the patient education program as compared to a traditional education program were assessed on a short-term (at discharge), medium-term (6 month follow-up) and long-term (12-month follow-up) basis in a multicenter quasi experimental control group study of patients with coronary heart disease (n=434). RESULTS: Results of the formative evaluation demonstrate an overall good acceptance and a good feasibility of the manualized program. Short-term results show a significant small treatment effect in the primary outcome variable patients' knowledge (p=0.001, eta2 =0.028). Furthermore, small effects were also observed among some secondary outcomes, such as attitude towards medication, planning of physical activity, psychological quality of life and satisfaction with the education program. CONCLUSION: A standardized education program for patients with coronary heart disease has been developed in a systematic process based on established quality standards. Depending on the outstanding medium and long-term effects, the program may be recommended for general use in medical rehabilitation. The manual provides the prerequisites allowing for a successful transfer into clinical practice. PMID- 23749623 TI - [Female patients with fibromyalgia syndrome in somatic and psychosomatic rehabilitation center - an exploratory study on access routes and differences in patient characteristics]. AB - STUDY OBJECTIVE: Fibromyalgia syndrome (FMS) is characterized by e. g. chronic, multilocular pain, and mental health problems. In Germany, patients with FMS are treated in somatic and psychosomatic rehabilitation centers - specialized for rheumatic diseases (somatic) or psychosomatic diseases. The aim of this study is to identify the status quo of FMS patients' access routes to the rehabilitation system, and to identify their predictors for being assigned to one or the other indication group. METHOD: Our cohort consists of 197 FMS patients from 3 psychosomatic (M=49.9 years) and 223 FMS patients (M=50.2 years) from 3 somatic rehabilitation centers. At the beginning of rehabilitation, patients filled out a questionnaire packet to identify their access routes to the rehabilitation centers and to record patients' disease-related, psychosocial and socio demographic characteristics. To analyze the results we used descriptive calculations, calculated bivariate correlations, and conducted binary logistic regression analysis for the prediction of group membership. RESULTS: The access routes of FMS patients to a somatic or a psychosomatic rehabilitation center were often similar. Some items revealed significant group differences, i. e., a higher primary -rejection rate, longer waiting period between application for rehabilitation and its approval, and between the application itself and initiation of psychosomatic rehabilitation in comparison to somatic FMS patients. Prior experience of out-patient psychotherapy, and expectations ("psychological support") for the rehabilitation were predictive patient characteristics for the assignment into a psychosomatic rehabilitation center. Marriage, motivation, and expectations ("physical improvement" and "interaction with other patients") for the rehabilitation were predictive patient characteristics for the assignment in a somatic rehabilitation center. The predictors clarified 32% of the variance of group membership. CONCLUSION: Our results provide initial evidence of how FMS patients access the German rehabilitation system and which of their characteristics are responsible for being assigned to a particular rehabilitation setting. PMID- 23749624 TI - [Evaluation of a collaborative goal setting intervention in patients with chronic back pain]. AB - BACKGROUND AND OBJECTIVE: Although setting rehabilitation goals is considered to be a core rehabilitation process, in actual rehabilitation practice there is a considerable need for improvement with respect to consistent goal orientation. The objective of the PARZIVAR project was therefore to develop an intervention for participative goal setting in medical rehabilitation. This article reports the results of the evaluation of the PARZIVAR intervention in patients with chronic back pain. METHODS: The PARZIVAR intervention was evaluated in a sequential control group design with 3 measurement points (before the start of rehabilitation, at the end of rehabilitation, and at 6-month follow-up). The proximal endpoints were defined as patient perception of participative goal setting, subjective awareness of goals, and satisfaction with goal setting. The distal endpoints were intensity of pain and generic and illness-specific functioning. RESULTS: Overall, the degree of achieving aspects of participative goal setting was higher in the intervention group. There were no differences regarding satisfaction with goal setting, however, and distal outcomes also remained unchanged after the intervention was implemented. DISCUSSION: Participation in the PARZIVAR intervention was partially reflected in the perception of the rehabilitation patients, but the effects regarding distal outcomes in the intervention group did not exceed those of usual care. There is a need for more research into how concepts of goal setting can be improved in the future to better address the diverse functions of goal setting. PMID- 23749625 TI - Steady-state nuclear actin levels are determined by export competent actin pool. AB - A number of studies in the last decade have irrevocably promoted actin into a fully fledged member of the nuclear compartment, where it, among other crucial tasks, facilitates transcription and chromatin remodeling. Changes in nuclear actin levels have been linked to different cellular processes: decreased nuclear actin to quiescence and increased nuclear actin to differentiation. Importin 9 and exportin 6 transport factors are responsible for the continuous nucleocytoplasmic shuttling of actin, but the mechanisms, which result in modulated actin levels, have not been characterized. We find that in cells growing under normal growth conditions, the levels of nuclear actin vary considerably from cell to cell. To understand the basis for this, we have extensively quantified several cellular parameters while at the same time recording the import and export rates of green fluorescent protein (GFP)-tagged actin. Surprisingly, our dataset shows that the ratio of nuclear to cytoplasmic fluorescence intensity, but not nuclear shape, size, cytoplasm size, or their ratio, correlates negatively with both import and export rate of actin. This suggests that high-nuclear actin content is maintained by both diminished import and export. The high nuclear actin containing cells still show high mobility of actin, but it is not export competent, suggesting increased binding of actin to nuclear complexes. Creation of such export incompetent actin pool would ensure enough actin is retained in the nucleus and make it available for the various nuclear functions described for actin. PMID- 23749627 TI - DFT study of a 5-endo-trig-type cyclization of 3-alkenoic acids by using Pd-spiro bis(isoxazoline) as catalyst: importance of the rigid spiro framework for both selectivity and reactivity. AB - The reaction pathway of an enantioselective 5-endo-trig-type cyclization of 3 alkenoic acids catalyzed by a chiral palladium-spiro-bis(isoxazoline) complex, Pd SPRIX, has been studied by density functional theory calculations. The most plausible pathway involves intramolecular nucleophilic attack of the carboxylate moiety on the C=C double bond activated by Pd-SPRIX and beta-H elimination from the resulting organopalladium intermediate. The enantioselectivity was determined in the cyclization step through the formation of a pi-olefin complex, in which one of the two enantiofaces of the olefin moiety was selected. The beta-H elimination occurs via a seven-membered cyclic structure in which the acetate ligand plays a key role in lowering the activation barrier of the transition state. In the elimination step, the SPRIX ligand was found to behave as a monodentate ligand due to the hemilability of one of the isoxazoline units thereby facilitating the elimination. Natural population analysis of this pathway showed that the more weakly electron-donating SPRIX ligand, compared with the bis(oxazoline) ligand, BOX, facilitated the formation of the pi-olefin complex intermediate, leading to a smaller overall activation energy and a higher reactivity of the Pd-SPRIX catalyst. PMID- 23749626 TI - Local neuronal circuits that may shape the discharge patterns of inferior collicular neurons. AB - The discharge patterns of neurons in auditory centers encode information about sounds. However, few studies have focused on the synaptic mechanisms underlying the shaping of discharge patterns using intracellular recording techniques. Here, we investigated the discharge patterns of inferior collicular (IC) neurons using intracellular recordings to further elucidate the mechanisms underlying the shaping of discharge patterns. Under in vivo intracellular recording conditions, recordings were obtained from 66 IC neurons in 18 healthy adult mice (Mus musculus, Km) under free field-stimulation. Fifty-eight of these neurons fi red bursts of action potentials (APs) to auditory stimuli and the remaining eight just generated local responses such as excitatory (n = 4) or inhibitory (n = 4) postsynaptic potentials. Based on the APs and subthreshold responses, the discharge patterns were classified into seven types: phasic (24/58, 41.4%), phasic burst (8/58,13.8%), pauser (4/58, 6.9%), phasic-pauser (1/58, 1.7%), chopper (2/58, 3.4%), primary-like tonic (14/58, 24.1%) and sound-induced inhibitory (5/58,8.6%). We concluded that (1) IC neurons exhibit at least seven distinct discharge patterns; (2) inhibition participates in shaping the discharge pattern of most IC neurons and plays a role in sculpting the pattern, except for the primary-like tonic pattern which was not shaped by inhibition; and (3) local neural circuits are the likely structural basis that shapes the discharge patterns of IC neurons and can be formed either in the IC or in lower-level auditory structures. PMID- 23749628 TI - Soil moisture's underestimated role in climate change impact modelling in low energy systems. AB - Shifts in precipitation regimes are an inherent component of climate change, but in low-energy systems are often assumed to be less important than changes in temperature. Because soil moisture is the hydrological variable most proximally linked to plant performance during the growing season in arctic-alpine habitats, it may offer the most useful perspective on the influence of changes in precipitation on vegetation. Here we quantify the influence of soil moisture for multiple vegetation properties at fine spatial scales, to determine the potential importance of soil moisture under changing climatic conditions. A fine-scale data set, comprising vascular species cover and field-quantified ecologically relevant environmental parameters, was analysed to determine the influence of soil moisture relative to other key abiotic predictors. Soil moisture was strongly related to community composition, species richness and the occurrence patterns of individual species, having a similar or greater influence than soil temperature, pH and solar radiation. Soil moisture varied considerably over short distances, and this fine-scale heterogeneity may contribute to offsetting the ecological impacts of changes in precipitation for species not limited to extreme soil moisture conditions. In conclusion, soil moisture is a key driver of vegetation properties, both at the species and community level, even in this low-energy system. Soil moisture conditions represent an important mechanism through which changing climatic conditions impact vegetation, and advancing our predictive capability will therefore require a better understanding of how soil moisture mediates the effects of climate change on biota. PMID- 23749629 TI - Bipolar disorder and disruptive mood dysregulation in children and adolescents: assessment, diagnosis and treatment. PMID- 23749630 TI - Retroperitoneal schwannomas: dilemmas in diagnostic approach and therapeutic management. AB - INTRODUCTION: Schwannomas are rare tumors arising from Schwan cells of the peripheral nerve sheath. The majority of the cases are sporadic and familial clustering is often observed in association with von Rechlinghausen's disease. Cases of intrasacral (osseous) and spinal tumors have also been described. Histologically, schwannomas are distinguished by the presence of areas of high and low cellularity called Antoni A and B tissue, respectively. CLINICAL PRESENTATION: Clinical features are highly non-specific and depend on the location and size of the lesion, with abdominal pain and neurological deficit being the most common abnormalities. Radiological studies are fundamental in the diagnostic evaluation of RSs. THERAPEUTIC MANAGEMENT: Despite recent research on the therapeutic strategies against RS, surgical resection appears the only potentially curative approach. Unfortunately, a mere minority of patients is eligible to undergo surgical intervention. In addition, surgical removal of RS does not necessarily guarantee patient's long-term survival. Laparoscopic approach and enucleation of the tumor have been suggested as well. Alternative therapies, such as radio- and chemotherapy often proved insufficient. The aim of this review was to evaluate the results of surgical treatment for RS with special reference to the extent of its histological spread and to analyze the recent literature in order to provide an update on the current concepts of therapeutic management of this entity. PMID- 23749632 TI - HLA peptide length preferences control CD8+ T cell responses. AB - Class I HLAs generally present peptides of 8-10 aa in length, although it is unclear whether peptide length preferences are affected by HLA polymorphism. In this study, we investigated the CD8(+) T cell response to the BZLF1 Ag of EBV, which includes overlapping sequences of different size that nevertheless conform to the binding motif of the large and abundant HLA-B*44 supertype. Whereas HLA B*18:01(+) individuals responded strongly and exclusively to the octamer peptide (173)SELEIKRY(180), HLA-B*44:03(+) individuals responded to the atypically large dodecamer peptide (169)EECDSELEIKRY(180), which encompasses the octamer peptide. Moreover, the octamer peptide bound more stably to HLA-B*18:01 than did the dodecamer peptide, whereas, conversely, HLA-B*44:03 bound only the longer peptide. Furthermore, crystal structures of these viral peptide-HLA complexes showed that the Ag-binding cleft of HLA-B*18:01 was more ideally suited to bind shorter peptides, whereas HLA-B*44:03 exhibited characteristics that favored the presentation of longer peptides. Mass spectrometric identification of > 1000 naturally presented ligands revealed that HLA-B*18:01 was more biased toward presenting shorter peptides than was HLA-B*44:03. Collectively, these data highlight a mechanism through which polymorphism within an HLA class I supertype can diversify determinant selection and immune responses by varying peptide length preferences. PMID- 23749633 TI - T cell activation threshold regulated by E3 ubiquitin ligase Cbl-b determines fate of inducible regulatory T cells. AB - E3 ubiquitin ligase Casitas-B-lineage lymphoma protein-b (Cbl-b) is critical for establishing the threshold for T cell activation and is essential for induction of T cell anergy. Recent studies suggest that Cbl-b is involved in the development of CD4(+)CD25(+) inducible regulatory T cells (iTregs). In this study, we report that the optimal induction of Foxp3 by naive CD4(+)CD25(-) T cells requires suboptimal TCR triggering. In the absence of Cbl-b, the TCR strength for optimal Foxp3 induction is downregulated in vitro. Using TCR transgenic Rag(-/-) mice in combination with Cbl-b deficiency, we show that in vivo iTreg development is also controlled by Cbl-b via tuning the TCR strength. Furthermore, we show that Akt-2 but not Akt-1 regulates Foxp3 expression downstream of Cbl-b. Therefore, we demonstrate that Cbl-b regulates the fate of iTregs via controlling the threshold for T cell activation. PMID- 23749636 TI - James Douglas Morrison AO (1924-2013). PMID- 23749634 TI - Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms. AB - Macrophages in granulomas are both antimycobacterial effector and host cell for Mycobacterium tuberculosis, yet basic aspects of macrophage diversity and function within the complex structures of granulomas remain poorly understood. To address this, we examined myeloid cell phenotypes and expression of enzymes correlated with host defense in macaque and human granulomas. Macaque granulomas had upregulated inducible and endothelial NO synthase (iNOS and eNOS) and arginase (Arg1 and Arg2) expression and enzyme activity compared with nongranulomatous tissue. Immunohistochemical analysis indicated macrophages adjacent to uninvolved normal tissue were more likely to express CD163, whereas epithelioid macrophages in regions where bacteria reside strongly expressed CD11c, CD68, and HAM56. Calprotectin-positive neutrophils were abundant in regions adjacent to caseum. iNOS, eNOS, Arg1, and Arg2 proteins were identified in macrophages and localized similarly in granulomas across species, with greater eNOS expression and ratio of iNOS/Arg1 expression in epithelioid macrophages as compared with cells in the lymphocyte cuff. iNOS, Arg1, and Arg2 expression in neutrophils was also identified. The combination of phenotypic and functional markers support that macrophages with anti-inflammatory phenotypes localized to outer regions of granulomas, whereas the inner regions were more likely to contain macrophages with proinflammatory, presumably bactericidal, phenotypes. Together, these data support the concept that granulomas have organized microenvironments that balance antimicrobial anti-inflammatory responses to limit pathology in the lungs. PMID- 23749635 TI - SARM is required for neuronal injury and cytokine production in response to central nervous system viral infection. AB - Four of the five members of the Toll/IL-1R domain-containing adaptor family are required for signaling downstream of TLRs, promoting innate immune responses against different pathogens. However, the role of the fifth member of this family, sterile alpha and Toll/IL-1R domain-containing 1 (SARM), is unclear. SARM is expressed primarily in the CNS where it is required for axonal death. Studies in Caenorhabditis elegans have also shown a role for SARM in innate immunity. To clarify the role of mammalian SARM in innate immunity, we infected SARM(-/-) mice with a number of bacterial and viral pathogens. SARM(-/-) mice show normal responses to Listeria monocytogenes, Mycobacterium tuberculosis, and influenza virus, but show dramatic protection from death after CNS infection with vesicular stomatitis virus. Protection correlates with reduced CNS injury and cytokine production by nonhematopoietic cells, suggesting that SARM is a positive regulator of cytokine production. Neurons and microglia are the predominant source of cytokines in vivo, supporting a role for SARM as a link between neuronal injury and innate immunity. PMID- 23749637 TI - Switchable transport strategy to deposit active Fe/Fe3C cores into hollow microporous carbons for efficient chromium removal. AB - Magnetic hollow structures with microporous shell and highly dispersed active cores (Fe/Fe3 C nanoparticles) are rationally designed and fabricated by solution phase switchable transport of active iron species combined with a solid-state thermolysis technique, thus allowing selective encapsulation of functional Fe/Fe3 C nanoparticles in the interior cavity. These engineered functional materials show high loading (~54 wt%) of Fe, excellent chromium removal capability (100 mg g(-1)), fast adsorption rate (8766 mL mg(-1) h(-1)), and easy magnetic separation property (63.25 emu g(-1)). During the adsorption process, the internal highly dispersed Fe/Fe3 C nanoparticles supply a driving force for facilitating Cr(VI) diffusion inward, thus improving the adsorption rate and the adsorption capacity. At the same time, the external microporous carbon shell can also efficiently trap guest Cr(VI) ions and protect Fe/Fe3 C nanoparticles from corrosion and subsequent leaching problems. PMID- 23749639 TI - eIF4B phosphorylation by pim kinases plays a critical role in cellular transformation by Abl oncogenes. AB - Alterations in translation occur in cancer cells, but the precise pathogenic processes and mechanistic underpinnings are not well understood. In this study, we report that interactions between Pim family kinases and the translation initiation factor eIF4B are critical for Abl oncogenicity. Pim kinases, Pim-1 and Pim-2, both directly phosphorylated eIF4B on Ser406 and Ser422. Phosphorylation of eIF4B on Ser422 was highly sensitive to pharmacologic or RNA interference mediated inhibition of Pim kinases. Expression and phosphorylation of eIF4B relied upon Abl kinase activity in both v-Abl- and Bcr-Abl-expressing leukemic cells based on their blockade by the Abl kinase inhibitor imatinib. Ectopic expression of phosphomimetic mutants of eIF4B conferred resistance to apoptosis by the Pim kinase inhibitor SMI-4a in Abl-transformed cells. In contrast, silencing eIF4B sensitized Abl-transformed cells to imatinib-induced apoptosis and also inhibited their growth as engrafted tumors in nude mice. Extending these observations, we found that primary bone marrow cells derived from eIF4B knockdown transgenic mice were less susceptible to Abl transformation, relative to cells from wild-type mice. Taken together, our results identify eIF4B as a critical substrate of Pim kinases in mediating the activity of Abl oncogenes, and they highlight eIF4B as a candidate therapeutic target for treatment of Abl induced cancers. PMID- 23749638 TI - Percutaneous approaches for efficient cardiac gene delivery. AB - Gene therapy for heart failure treatment is currently being optimized and validated. The results to date are encouraging but challenges remain before it becomes a therapeutic approach in clinical cardiology. Much effort is dedicated to improve gene transduction efficiency by improving the vectors and the delivery methods. Successful translation from the benchtop to the bedside requires teams including biologists focusing on vector modification and cardiologists refining delivery methods. Two key components for translation to the clinic include safety and efficacy. Transduction efficiency is closely linked to invasiveness in most delivery methods. However, current candidates for cardiac gene therapy are patients without effective treatment option and are in advanced heart failure, thus a less invasive approach is preferred. This review focuses on injection methods of gene delivery with emphasis on percutaneous and endovascular approaches to summarize currently available percutaneous gene delivery methods and their features. PMID- 23749641 TI - Intravital FLIM-FRET imaging reveals dasatinib-induced spatial control of src in pancreatic cancer. AB - Cancer invasion and metastasis occur in a complex three-dimensional (3D) environment, with reciprocal feedback from the surrounding host tissue and vasculature-governing behavior. In this study, we used a novel intravital method that revealed spatiotemporal regulation of Src activity in response to the anti invasive Src inhibitor dasatinib. A fluorescence lifetime imaging microscopy fluorescence resonance energy transfer (FLIM-FRET) Src biosensor was used to monitor drug-targeting efficacy in a transgenic p53-mutant mouse model of pancreatic cancer. In contrast to conventional techniques, FLIM-FRET analysis allowed for accurate, time-dependent, live monitoring of drug efficacy and clearance in live tumors. In 3D organotypic cultures, we showed that a spatially distinct gradient of Src activity exists within invading tumor cells, governed by the depth of penetration into complex matrices. In parallel, this gradient was also found to exist within live tumors, where Src activity is enhanced at the invasive border relative to the tumor cortex. Upon treatment with dasatinib, we observed a switch in activity at the invasive borders, correlating with impaired metastatic capacity in vivo. Src regulation was governed by the proximity of cells to the host vasculature, as cells distal to the vasculature were regulated differentially in response to drug treatment compared with cells proximal to the vasculature. Overall, our results in live tumors revealed that a threshold of drug penetrance exists in vivo and that this can be used to map areas of poor drug-targeting efficiency within specific tumor microenvironments. We propose that using FLIM-FRET in this capacity could provide a useful preclinical tool in animal models before clinical translation. PMID- 23749640 TI - Enhanced radiation sensitivity in HPV-positive head and neck cancer. AB - Patients with human papillomavirus (HPV+)-associated head and neck cancer (HNC) show significantly improved survival outcome compared with those with HPV negative (HPV-) tumors. Published data examining this difference offers conflicting results to date. We systematically investigated the radiation sensitivity of all available validated HPV+ HNC cell lines and a series of HPV- HNC cell lines using in vitro and in vivo techniques. HPV+ HNCs exhibited greater intrinsic radiation sensitivity (average SF2 HPV-: 0.59 vs. HPV+: 0.22; P < 0.0001), corresponding with a prolonged G2-M cell-cycle arrest and increased apoptosis following radiation exposure (percent change 0% vs. 85%; P = 0.002). A genome-wide microarray was used to compare gene expression 24 hours following radiation between HPV+ and HPV- cell lines. Multiple genes in TP53 pathway were upregulated in HPV+ cells (Z score 4.90), including a 4.6-fold increase in TP53 (P < 0.0001). Using immortalized human tonsillar epithelial (HTE) cells, increased radiation sensitivity was seen in cell expressing HPV-16 E6 despite the effect of E6 to degrade p53. This suggested that low levels of normally functioning p53 in HPV+ HNC cells could be activated by radiation, leading to cell death. Consistent with this, more complete knockdown of TP53 by siRNA resulted in radiation resistance. These results provide clear evidence, and a supporting mechanism, for increased radiation sensitivity in HPV+ HNC relative to HPV- HNC. This issue is under active investigation in a series of clinical trials attempting to de-escalate radiation (and chemotherapy) in selected patients with HPV+ HNC in light of their favorable overall survival outcome. PMID- 23749642 TI - Peroxiredoxin-2 represses melanoma metastasis by increasing E-Cadherin/beta Catenin complexes in adherens junctions. AB - In melanoma, transition to the vertical growth phase is the critical step in conversion to a deadly malignant disease. Here, we offer the first evidence that an antioxidant enzyme has a key role in this transition. We found that the antioxidant enzyme peroxiredoxin-2 (Prx2) inversely correlated with the metastatic capacity of human melanoma cells. Silencing Prx2 expression stimulated proliferation and migration, whereas ectopic expression of Prx2 produced the opposite effect. Mechanistic investigations indicated that Prx2 negatively regulated Src/ERK activation status, which in turn fortified adherens junctions function by increasing E-cadherin expression and phospho-Y654-dependent retention of beta-catenin in the plasma membrane. In murine melanoma cells, Prx2 silencing enhanced lung metastasis in vivo. Interestingly, the natural compound gliotoxin, which is known to exert a Prx-like activity, inhibited proliferation and migration as well as lung metastasis of Prx2-deficient melanoma cells. Overall, our findings reveal that Prx2 is a key regulator of invasion and metastasis in melanoma, and also suggest a pharmacologic strategy to effectively decrease deadly malignant forms of this disease. PMID- 23749643 TI - PanIN-specific regulation of Wnt signaling by HIF2alpha during early pancreatic tumorigenesis. AB - Hypoxia promotes angiogenesis, proliferation, invasion, and metastasis of pancreatic cancer. Essentially, all studies of the hypoxia pathway in pancreatic cancer research to date have focused on fully malignant tumors or cancer cell lines, but the potential role of hypoxia inducible factors (HIF) in the progression of premalignant lesions has not been critically examined. Here, we show that HIF2alpha is expressed early in pancreatic lesions both in human and in a mouse model of pancreatic cancer. HIF2alpha is a potent oncogenic stimulus, but its role in Kras-induced pancreatic neoplasia has not been discerned. We used the Ptf1aCre transgene to activate Kras(G12D) and delete Hif2alpha solely within the pancreas. Surprisingly, loss of Hif2alpha in this model led to markedly higher, rather than reduced, number of low-grade pancreatic intraepithelial neoplasia (mPanIN) lesions. These lesions, however, failed to progress to high-grade mPanINs, and displayed exclusive loss of beta-catenin and SMAD4. The relationship among HIF2alpha, beta-catenin, and Smad4 was further confirmed in vitro, where silencing of Hif2alpha resulted in reduced beta-catenin and Smad4 transcript levels. Thus, with oncogenic Ras expressed in the pancreas, HIF2alpha modulates Wnt-signaling during mPanIN progression by maintaining appropriate levels of both Smad4 and beta-catenin. PMID- 23749644 TI - Vaccine-instructed intratumoral IFN-gamma enables regression of autochthonous mouse prostate cancer in allogeneic T-cell transplantation. AB - Vaccination can synergize with transplantation of allogeneic hematopoietic stem cells to cure hematologic malignancies, but the basis for this synergy is not understood to the degree where such approaches could be effective for treating solid tumors. We investigated this issue in a transgenic mouse model of prostate cancer treated by transplantation of a nonmyeloablative MHC-matched, single Y chromosome-encoded, or multiple minor histocompatibility antigen-mismatched hematopoietic cell preparation. Here, we report that tumor-directed vaccination after allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion is essential for acute graft versus tumor responses, tumor regression, and prolonged survival. Vaccination proved essential for generation of CD8(+) IFN gamma(+) tumor-directed effector cells in secondary lymphoid organs and also for IFN-gamma(+) upregulation at the tumor site, which in turn instructed local expression of proinflammatory chemokines and intratumoral recruitment of donor derived T cells for disease regression. Omitting vaccination, transplanting IFN gamma-deficient donor T cells, or depleting alloreactive T cells all compromised intratumoral IFN-gamma-driven inflammation and lymphocyte infiltration, abolishing antitumor responses and therapeutic efficacy of the combined approach. Our findings argue that posttransplant tumor-directed vaccination is critical to effectively direct donor T cells to the tumor site in cooperation with allogeneic hematopoietic cell transplantation. PMID- 23749645 TI - Proteomic and lipidomic signatures of lipid metabolism in NASH-associated hepatocellular carcinoma. AB - Nonalcoholic steatohepatitis (NASH) is a common preneoplastic condition of hepatocellular carcinoma (HCC). Mice with hepatocytic deletion of Pten develop NASH and HCC later in life. This model is highly valuable for studies aimed at identifying the molecular mechanism by which metabolic disorders contribute to tumor development. We applied proteomic and lipidomic profiling approaches to Pten-null NASH liver and tumors. Circulating fatty acid composition was also characterized in these mice. The relevance to human NASH and HCC was further validated. This integrative proteomic and lipidomic study from mouse to human and from liver to blood identified the following disease signatures: (i) an HCC signature: upregulated hepatic scd1/scd2, fads2, and acsl5:acsl1 ratio, elevated vaccenic and erucic acids, and reduced margaric and linoleic acids in both liver and plasma; (ii) a NASH signature that correlates with tumor burden: upregulated hepatic elovl6, elevated oleic, adrenic, and osbond acids, and reduced cervonic acid in liver and plasma; and (iii) a NASH signature: reduced hepatic and circulating lignoceric and eicosapentaenoic acids. Altogether, these results show the role of lipid-modifying enzymes converting saturated fatty acids (SFA) to monounsaturated fatty acids (MUFA) in HCC and the importance of an increased ratio of long chain n6-polyunsaturated fatty acids over n3-polyunsaturated fatty acids in NASH and HCC risk. They also highlight the relevance of the Pten-null model for studies related to NASH and HCC and show that circulating lipid metabolome provides a direct read of lipid changes in the liver. Most importantly, novel candidate targets for HCC diagnosis, therapy, risk assessment, and prevention were identified. PMID- 23749647 TI - Proton-conducting supramolecular metallogels from the lowest molecular weight assembler ligand: a quote for simplicity. AB - Oxalic acid has been proven to be the lowest molecular weight organic ligand able to form robust supramolecular metallogel networks in the presence of metal salts. In particular, two novel multifunctional metallogels were readily prepared at room temperature by simple mixing of stock solutions of Cu(II) acetate monohydrate or Cu(II) perchlorate hexahydrate and oxalic acid dihydrate. Formation of different polymorphs and unprecedented proton conduction under anhydrous conditions were also demonstrated with some of these materials. PMID- 23749646 TI - Nuclear factor one B regulates neural stem cell differentiation and axonal projection of corticofugal neurons. AB - During development of the cerebral cortex, neural stem cells divide to expand the progenitor pool and generate basal progenitors, outer radial glia, and cortical neurons. As these newly born neurons differentiate, they must properly migrate toward their final destination in the cortical plate, project axons to appropriate targets, and develop dendrites. However, a complete understanding of the precise genetic mechanisms regulating these steps is lacking. Here we show that a member of the nuclear factor one (NFI) family of transcription factors, NFIB, is essential for many of these processes in mice. We performed a detailed analysis of NFIB expression during cortical development, and investigated defects in cortical neurogenesis, neuronal migration, and differentiation in NfiB(-/-) brains. We found that NFIB is strongly expressed in radial glia and corticofugal neurons throughout cortical development. However, in NfiB(-/-) cortices, radial glia failed to generate outer radial glia, subsequently resulting in a loss of late basal progenitors. In addition, corticofugal neurons showed a severe loss of axonal projections, whereas late-born cortical neurons displayed defects in migration and ectopically expressed the early-born neuronal marker CTIP2. Furthermore, gene expression analysis, by RNA sequencing, revealed a misexpression of genes that regulate the cell cycle, neuronal differentiation and migration in NfiB(-/-) brains. Together these results demonstrate the critical functions of NFIB in regulating cortical development. PMID- 23749648 TI - Gelsolin: the tail of a molecular gymnast. AB - Gelsolin superfamily members are Ca(2+) -dependent, multidomain regulators of the actin cytoskeleton. Calcium binding activates gelsolin by inducing molecular gymnastics (large-scale conformational changes) that expose actin interaction surfaces by releasing a series of latches. A specialized tail latch has distinguished gelsolin within the superfamily. Active gelsolin exhibits actin filament severing and capping, and actin monomer sequestering activities. Here, we analyze a combination of sequence, structural, biophysical and biochemical data to assess whether the molecular plasticity, regulation and actin-related properties of gelsolin are also present in other superfamily members. We conclude that all members of the superfamily will be able to transition between a compact conformation and a more open form, and that most of these open forms will interact with actin. Supervillin, which lacks the severing domain 1 and the F actin binding-site on domain 2, is the clear exception. Eight calcium-binding sites are absolutely conserved in gelsolin, adseverin, advillin and villin, and compromised to increasing degrees in CapG, villin-like protein, supervillin and flightless I. Advillin, villin and supervillin each contain a potential tail latch, which is absent from CapG, adseverin and flightless I, and ambiguous in villin-like protein. Thus, calcium regulation will vary across the superfamily. Potential novel isoforms of the superfamily suggest complex regulation at the gene, transcript and protein levels. We review animal, clinical and cellular data that illuminate how the regulation of molecular flexibility in gelsolin-like proteins permits cells to exploit the force generated from actin polymerization to drive processes such as cell movement in health and disease. PMID- 23749649 TI - Impact of a 4th generation iterative reconstruction technique on image quality in low-dose computed tomography of the chest in immunocompromised patients. AB - PURPOSE: To determine the image quality of an iterative reconstruction (IR) technique in low-dose MDCT (LDCT) of the chest of immunocompromised patients in an intraindividual comparison to filtered back projection (FBP) and to evaluate the dose reduction capability. MATERIALS AND METHODS: 30 chest LDCT scans were performed in immunocompromised patients (Brilliance iCT; 20-40 mAs; mean CTDIvol: 1.7 mGy). The raw data were reconstructed using FBP and the IR technique (iDose4TM, Philips, Best, The Netherlands) set to seven iteration levels. 30 routine-dose MDCT (RDCT) reconstructed with FBP served as controls (mean exposure: 116 mAs; mean CDTIvol: 7.6 mGy). Three blinded radiologists scored subjective image quality and lesion conspicuity. Quantitative parameters including CT attenuation and objective image noise (OIN) were determined. RESULTS: In LDCT high iDose4TM levels lead to a significant decrease in OIN (FBP vs. iDose7: subscapular muscle 139.4 vs. 40.6 HU). The high iDose4TM levels provided significant improvements in image quality and artifact and noise reduction compared to LDCT FBP images. The conspicuity of subtle lesions was limited in LDCT FBP images. It significantly improved with high iDose4TM levels (> iDose4). LDCT with iDose4TM level 6 was determined to be of equivalent image quality as RDCT with FBP. CONCLUSION: iDose4TM substantially improves image quality and lesion conspicuity and reduces noise in low-dose chest CT. Compared to RDCT, high iDose4TM levels provide equivalent image quality in LDCT, hence suggesting a potential dose reduction of almost 80%. PMID- 23749650 TI - Validation of EBUS-TBNA-integrated nodal staging in potentially node-positive non small cell lung cancer. AB - OBJECTIVE: Nodal staging of lung cancer is important for selecting surgical candidates. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was evaluated as a modality for nodal staging of patients with potentially node-positive non-small cell lung cancer (NSCLC). METHODS: Endobronchial ultrasound-guided transbronchial needle aspiration was used for nodal staging of NSCLC patients with radiological N2/3 disease (short axis >10 mm on computed tomography and/or standardized positron emission uptake value >2.5 on 2-deoxy-2[F-18] fluoro-D-glucose positron emission tomography), T-stage >= T2, or positive serum carcinoembryonic antigen. Data on eligible patients were extracted from the database of our institution and analyzed for differences in nodal stages between radiological staging (RS) and EBUS-TBNA-integrated staging (ES), with validation by pathological staging of patients who had undergone surgery. RESULTS: Of 480 eligible patients, there were 135 N0/1 and 345 N2/3 patients according to RS. Out of the 345 patients staged as N2/3 by RS, 113 (33 %) were downgraded to N0/1 by ES. Out of the 135 patients staged as N0/1 by RS, 12 (9 %) were upgraded to N2/3 by ES. Patients were restaged as N0/1 in 236 cases and N2/3 in 244 cases by ES, and the distributions of nodal stage between RS and ES were significantly different (p < 0.001). Finally, 215 out of the 236 ES-N0/1 patients underwent lung resection, and 195 (90.7 %) and 20 patients were staged by pathology as N0/1 and N2, respectively. CONCLUSIONS: Endobronchial ultrasound guided transbronchial needle aspiration is more accurate for lymph node staging compared to radiological staging. EBUS-TBNA can identify patients who are true candidates for surgery. PMID- 23749651 TI - Health system strengthening in Myanmar during political reforms: perspectives from international agencies. AB - Myanmar has undergone a remarkable political transformation in the last 2 years, with its leadership voluntarily transitioning from an isolated military regime to a quasi-civilian government intent on re-engaging with the international community. Decades of underinvestment have left the country underdeveloped with a fragile health system and poor health outcomes. International aid agencies have found engagement with the Myanmar government difficult but this is changing rapidly and it is opportune to consider how Myanmar can engage with the global health system strengthening (HSS) agenda. Nineteen semi-structured, face-to-face interviews were conducted with representatives from international agencies working in Myanmar to capture their perspectives on HSS following political reform. They explored their perceptions of HSS and the opportunities for implementation. Participants reported challenges in engaging with government, reflecting the disharmony between actors, economic sanctions and barriers to service delivery due to health system weaknesses and bureaucracy. Weaknesses included human resources, data and medical products/infrastructure and logistical challenges. Agencies had mixed views of health system finance and governance, identifying problems and also some positive aspects. There is little consensus on how HSS should be approached in Myanmar, but much interest in collaborating to achieve it. Despite myriad challenges and concerns, participants were generally positive about the recent political changes, and remain optimistic as they engage in HSS activities with the government. PMID- 23749652 TI - Hospitalized for fever? Understanding hospitalization for common illnesses among insured women in a low-income setting. AB - BACKGROUND: Health microinsurance is a financial tool that increases utilization of health care services among low-income persons. There is limited understanding of the illnesses for which insured persons are hospitalized. Analysis of health claims at VimoSEWA, an Indian microinsurance scheme, shows that a significant proportion of hospitalization among insured adult women is for common illnesses fever, diarrhoea and malaria-that are amenable to outpatient treatment. This study aims to understand the factors that result in hospitalization for common illnesses. METHODS: The article uses a mixed methods approach. Quantitative data were collected from a household survey of 816 urban low-income households in Gujarat, India. The qualitative data are based on 10 in-depth case studies of insured women hospitalized for common illnesses and interviews with five providers. Quantitative and qualitative data were supplemented with data from the insurance scheme's administrative records. RESULTS: Socioeconomic characteristics and morbidity patterns among insured and uninsured women were similar with fever the most commonly reported illness. While fever was the leading cause for hospitalization among insured women, no uninsured women were hospitalized for fever. Qualitative investigation indicates that 9 of 10 hospitalized women first sought outpatient treatment. Precipitating factors for hospitalization were either the persistence or worsening of symptoms. Factors that facilitated hospitalization included having insurance and the perceptions of doctors regarding the need for hospitalization. CONCLUSION: In the absence of quality primary care, health insurance can lead to hospitalization for non-serious illnesses. Deterrents to hospitalization point away from member moral hazard; provider moral hazard cannot be ruled out. This study underscores the need for quality primary health care and its better integration with health microinsurance schemes. PMID- 23749653 TI - Drought-induced saltwater incursion leads to increased wetland nitrogen export. AB - Coastal wetlands have the capacity to retain and denitrify large quantities of reactive nitrogen (N), making them important in attenuating increased anthropogenic N flux to coastal ecosystems. The ability of coastal wetlands to retain and transform N is being reduced by wetland losses resulting from land development. Nitrogen retention in coastal wetlands is further threatened by the increasing frequency and spatial extent of saltwater inundation in historically freshwater ecosystems, due to the combined effects of dredging, declining river discharge to coastal areas due to human water use, increased drought frequency, and accelerating sea-level rise. Because saltwater incursion may affect N cycling through multiple mechanisms, the impacts of salinization on coastal freshwater wetland N retention and transformation are not well understood. Here, we show that repeated annual saltwater incursion during late summer droughts in the coastal plain of North Carolina changed N export from organic to inorganic forms and led to a doubling of annual NH(4)(+) export from a 440 hectare former agricultural field undergoing wetland restoration. Soil solution NH(4)(+) concentrations in two mature wetlands also increased with salinization, but the magnitude of increase was smaller than that in the former agricultural field. Long-term saltwater exposure experiments with intact soil columns demonstrated that much of the increase in reactive N released could be explained by exchange of salt cations with sediment NH(4)(+). Using these findings together with the predicted flooding of 1661 km(2) of wetlands along the NC coast by 2100, we estimate that saltwater incursion into these coastal areas could release up to 18 077 Mg N, or approximately half the annual NH(4)(+) flux of the Mississippi River. Our results suggest that saltwater incursion into coastal freshwater wetlands globally could lead to increased N loading to sensitive coastal waters. PMID- 23749654 TI - Gastrointestinal stromal tumor with synchronous gallbladder adenocarcinoma. PMID- 23749655 TI - Road rage: an exploratory study on aggressive driving experience on Indian roads. AB - BACKGROUND: Driving on Indian roads is a stressful experience. A lacuna of research on aggressive driving experiences in the Indian set-up highlights the need to address this growing concern for individuals, society and mental health professionals. AIM: To explore and compare driving-related anger triggers and anger expression among high- and low-angry Indian drivers. METHOD: Two hundred randomly chosen drivers from the city of Delhi were administered a semi structured questionnaire intended to understand driving-related aggression. RESULTS: Honking, overtaking from the wrong side, loud music in other cars and hot and humid climate significantly increased the risk of experiencing anger among high-angry drivers. High-angry drivers were significantly more likely to engage in direct and aggressive expression of anger, including overtaking, verbal abuse, yelling and arguing, not giving space to other drivers, fighting, and hitting and bumping other cars in protest. Passive anger expressions such as holding grudges against other drivers and eating or drinking something to cool down were significantly more likely to be used by low-angry drivers. CONCLUSIONS: Drivers who are high on anger have a significantly higher risk of experiencing anger triggered by a variety of individual and environmental factors on Indian roads and are more susceptible to engage in aggressive driving behaviour. PMID- 23749658 TI - Nutrition 411: understanding iron deficiency and anemia. PMID- 23749659 TI - Nurses beware: don't "write off" sleep-disturbing voiding. PMID- 23749657 TI - Withdrawal and restoration of central vagal afferents within the dorsal vagal complex following subdiaphragmatic vagotomy. AB - Vagotomy, a severing of the peripheral axons of the vagus nerve, has been extensively utilized to determine the role of vagal afferents in viscerosensory signaling. Vagotomy is also an unavoidable component of some bariatric surgeries. Although it is known that peripheral axons of the vagus nerve degenerate and then regenerate to a limited extent following vagotomy, very little is known about the response of central vagal afferents in the dorsal vagal complex to this type of damage. We tested the hypothesis that vagotomy results in the transient withdrawal of central vagal afferent terminals from their primary central target, the nucleus of the solitary tract (NTS). Sprague-Dawley rats underwent bilateral subdiaphragmatic vagotomy and were sacrificed 10, 30, or 60 days later. Plastic changes in vagal afferent fibers and synapses were investigated at the morphological and functional levels by using a combination of an anterograde tracer, synapse-specific markers, and patch-clamp electrophysiology in horizontal brain sections. Morphological data revealed that numbers of vagal afferent fibers and synapses in the NTS were significantly reduced 10 days following vagotomy and were restored to control levels by 30 days and 60 days, respectively. Electrophysiology revealed transient decreases in spontaneous glutamate release, glutamate release probability, and the number of primary afferent inputs. Our results demonstrate that subdiaphragmatic vagotomy triggers transient withdrawal and remodeling of central vagal afferent terminals in the NTS. The observed vagotomy-induced plasticity within this key feeding center of the brain may be partially responsible for the response of bariatric patients following gastric bypass surgery. PMID- 23749660 TI - Skin and wound issues in patients with Parkinson's disease: an overview of common disorders . AB - Parkinson's Disease is a chronic neurodegenerative disorder that is expected to increase in coming decades as the American population continues to age. Although the motor dysfunction (bradykinesia, tremor, rigidity) of Parkinson's Disease is well described in the literature, the nonmotor dysfunction related to autonomic system changes is not as commonly addressed. Ironically, nonmotor changes, such as seborrhea, sialorrhea, hyperhidrosis, and sensory denervation occur earlier in the disease process and exert a profound effect on patients' quality of life. The depletion of dopamine, a critically important neurotransmitter, is the critical pathology of Parkinson's disease. Therapies targeting this abnormality and the effect of insufficient dopamine itself can affect the integumentary system and potentially wound healing. The purpose of this review is to describe changes in the autonomic nervous system due to Parkinson's Disease with a focused overview of common skin and wound care issues that may affect wound care clinician practice. Implications for nurses and other clinicians caring for Parkinson's Disease patients include surveillance for melanoma and other skin cancers, skin protection against excessive moisture or the effects of insufficient moisture, monitoring of wound healing progress, and interventions to prevent or ameliorate complications of immobility. PMID- 23749661 TI - The effect of multiple layers of linens on surface interface pressure: results of a laboratory study. AB - Underpads and layers of linens are frequently placed under patients who are incontinent, have other moisture-related issues, and/or are immobile and cannot reposition independently. Many of these patients are also at risk for pressure ulcers and placed on pressure-redistribution surfaces. The purpose of this study was to measure the effects of linens and incontinence pads on interface pressure. Interface sacral pressures were measured (mm Hg) using a mannequinlike pelvic indenter that has pressure transducers integrated into the unit and is covered with a soft flesh-like elastomer. The indenter was loaded to simulate a median weight male (80 kg/176 lb), and the testing was performed at head-of bed (HOB) angles of 0 degrees , 30 degrees , and 45 degrees . Two different surfaces, a high performance low-air-loss support (LAL) surface and a standard foam support surface, were used and covered with a fitted sheet (FS) only or a combination of the FS and various incontinence pads and transfer sheets. Linen combinations typically used for relatively immobile patients (n = 4), moisture management (n = 4), and moisture management and immobility (n = 1) were tested, as was the heavy use of linens/pads (nine layers, n = 1). All combinations were tested 10 times at HOB angles of 0 degrees , 30 degrees , and 45 degrees . The highest pressure observed was recorded (peak pressure). Ninety five percent (95%) confidence interval (CI) surrounding the mean of the 10 trials for each combination was calculated using the t-distribution; differences between means for all surface combinations were determined using one-way ANOVA with follow-up Fisher Hayter test. Results indicated that each incontinence pad, transfer sheet, or combination of linens significantly increased the mean peak sacral pressure when compared to a single FS on both the low-air-loss surface and the foam surface, regardless of the head-of-bed angle. The magnitude of peak sacral interface pressure increase for the LAL surface at 30 degrees head-of-bed angle was 20% to 64% depending on the linen combination. At 30 degrees , the foam surface showed increases 6% to 29% (P <0.0001) compared with a FS baseline. If linens were wet, peak interface sacral pressures were equivalent to or less than pressures measured on the same pads when measured dry. The presence of linens on both surface types adversely affected the pressure redistribution capabilities of the surfaces; added layers increased pressure proportionally. The effect on interface pressure from the linen layers was more pronounced on the LAL than the foam surface. The study results illustrate that significant increases in peak interface pressure occur in a laboratory setting when linen layers are added to pressure redistribution surfaces. Results also indicated wetting incontinence pads on a support surface did not significantly increase interface pressure. Although additional preclinical and clinical studies are needed to guide practice, excessive linen usage for patients on therapeutic support surfaces should be discouraged. PMID- 23749662 TI - Development of two enteroatmospheric fistulae after split-thickness skin grafting: a case report. AB - An enteroatmospheric fistula is a devastating complication in the open abdomen. Usually the fistula forms before the completion of split-thickness skin graft surgery. A 35-year-old woman admitted with pancreatic and liver injuries, and postoperative sepsis underwent open abdomen treatment and developed two enteroatmospheric fistulae 14 days after split-thickness skin grafting. The complication was believed to have occurred as a result of multiple surgical manipulations for intra-abdominal hemorrhage and skin graft dressing changes. One fistula, measuring 0.5 cm in diameter, was managed using a tailored 20-mL syringe, secured to the surrounding tissues with ostomy paste, and a suction catheter. The other fistula, measuring 1.8 cm in diameter, required insertion of a catheter to collect the effluent. Once the effluent was controlled effectively, a second split-thickness skin graft procedure was performed to facilitate fistula management. The patient remained stable until successful fistula repair 8 months later, and she is now awaiting elective abdominal wall reconstruction. This case study is an important reminder that patients with an open abdomen, even after split-thickness skin grafting, are at risk for enteroatmospheric fistula formation. Once this severe complication occurs, effective control of fistula effluent and subsequent split-thickness skin grafting procedures are needed. PMID- 23749664 TI - Current perspectives on chronic hepatitis B. PMID- 23749663 TI - Health-related quality of life, lifestyle behaviors, and intervention preferences of survivors of childhood cancer. AB - PURPOSE: Childhood cancer survivors (CCSs) are at increased risk for poor health related quality of life (HRQOL) and chronic health conditions-both of which can be exacerbated by unhealthy lifestyle behaviors. Developing a clearer understanding of the associations between HRQOL, lifestyle behaviors, and medical and demographic variables (e.g., age/developmental stage at time of diagnosis) is an important step toward developing more targeted behavioral interventions for this population. METHOD: Cross-sectional questionnaires were completed by 170 CCSs who were diagnosed with leukemia, lymphoma, sarcoma, or a cancer of the central nervous system (CNS) and treated at a comprehensive cancer center between 1992 and 2007. Questionnaires addressed weight status, lifestyle behaviors, aspects of HRQOL, and intervention preferences. RESULTS: Adolescent and young adult survivors (AYAs) and survivors of CNS tumors or lymphoma reported significantly (p < .05) poorer HRQOL across multiple domains compared to those diagnosed at an earlier age, survivors of leukemia or sarcoma, and healthy populations. A significant proportion also failed to meet national recommendations for dietary intakes (39-94 %) and physical activity (65 %). Female survivors reported poorer physical functioning and consumed less dietary fiber and fruits and vegetables than did male survivors. They also expressed the strongest interest in participating in diet and exercise interventions. CONCLUSION: Findings support the premise that females, AYAs, and survivors of cancers of the CNS or lymphoma are "at risk" subgroups within the CCS population for poor dietary practices, sedentary behaviors, and poor HRQOL. Future research should focus on developing diet and PA interventions to improve HRQOL that target these groups. IMPLICATIONS FOR CANCER SURVIVORS: Greater consideration of the role of gender, developmental stage, and the HRQOL challenges facing CCSs may help researchers to develop targeted behavioral interventions for those who stand to benefit the most. PMID- 23749665 TI - Global perspective on the natural history of chronic hepatitis B: role of hepatitis B virus genotypes A to J. AB - Clinical outcomes of chronic hepatitis B virus (HBV) infection vary widely. In addition to host factors, several viral factors including HBV genotype, viral load, specific viral mutations and quantitative HBsAg levels, have been associated with disease outcomes. Among viral factors, HBV genotype correlates with not only the clinical outcomes, but also with the response to interferon treatment. Currently, 10 HBV genotypes have been identified. Compared with genotype A and B cases, patients with genotypes C and D have lower rates and usually delayed onset of spontaneous HBeAg seroconversion. HBV-genotype C has a higher frequency of basal core promoter (BCP) A1762T/G1764A mutation and preS deletion, and a higher viral load than genotype B. Similarly, genotype D has a higher prevalence of BCP A1762T/G1764A mutation than genotype A. These observations suggest pathogenic differences between HBV genotypes. Genotyping of HBV can help practicing physicians identify chronic hepatitis B patients at risk of disease progression. PMID- 23749666 TI - The molecular virology of hepatitis B virus. AB - Hepatitis B virus (HBV) is one of the smallest enveloped DNA viruses and the prototype member of the family of Hepadnaviridae that causes acute and chronic infections of mammals (including human) and birds. HBV has evolved an extreme adaptation and dependency to differentiated hepatocytes of its host. Despite its very limited coding capacity with only four open-reading frames, HBV is able to evade the immune system of the host and persist lifelong within infected hepatocytes. During active replication, HBV produces enormous viral loads in the blood and a massive surplus of subviral surface antigen particles in the serum of infected patients without killing their hepatocytes. Together with the use of a reverse transcriptase during replication, it provides an enormous genetic flexibility for selection of viral mutants upon selective pressure, for example, by the immune system or antiviral therapy. In addition, viral wild-type and mutated genomes are stably archived in the nucleus of the infected hepatocyte in an episomal DNA form that provides independence from cellular replication or integration within the host genome. We are just beginning to understand the delicate molecular and cellular interactions during the HBV replicative cycle within infected hepatocytes, so further studies are urgently needed to provide a better basis for further diagnostic and therapeutic options. PMID- 23749667 TI - Advances in the molecular diagnosis of hepatitis B infection: providing insight into the next generation of disease. AB - Hepatitis B virus (HBV) infection continues to represent a significant health threat, affecting over 400 million people worldwide. Historically, the diagnosis and treatment of chronic hepatitis B (CHB) relied in detection of the hepatitis B surface antigen (HBsAg) and more recently realtime polymerase chain reaction (PCR) analysis. The advent of novel technologies and equipment for the identification and staging of the different stages of HBV infection has resulted in dramatic changes to patient monitoring and management. Through the use of rapid, quantitative HBsAg immunoassays, it is now possible to predict the likelihood of patient response to treatment as well as the clinical course of disease. Ultradeep sequencing technologies (also known as next-generation sequencing) overcome many of the traditional limitations associated with population-based sequencing approaches, and have provided significant insight into the viral response to therapeutic intervention and the molecular pathogenesis of CHB. The authors discuss recent developments in the molecular diagnosis of HBV infection, as well as potential advantages and caveats resultant of this rapid progression of technology. PMID- 23749668 TI - Chronic hepatitis B: a treatment update. AB - In the past two decades, there have been major developments in the treatment of chronic hepatitis B. Peginterferon can be given conveniently with weekly dosing, and its effect on hepatitis B e antigen seroconversion is highly durable. However, it carries numerous side effects and the treatment is successful in only 30 to 40% of patients. On-treatment hepatitis B surface antigen level is an indirect marker of the level and transcriptional activity of covalently closed circular DNA in the liver and may identify nonresponders to peginterferon. New oral nucleos(t)ide analogs such as entecavir and tenofovir can effectively suppress hepatitis B virus with minimal risk of drug resistance. Many patients, however, develop virologic relapse after cessation of oral antiviral therapy despite prolonged viral suppression and would require long-term treatment. During oral antiviral drug treatment, hepatitis B virus DNA monitoring is essential to assess treatment effect and drug adherence and detect drug resistance. In treatment-naive patients, none of the drug combinations have been shown to be superior to monotherapy. Studies combining peginterferon and potent oral agents (entecavir and tenofovir) are underway. Tenofovir is effective in patients with lamivudine resistance and previous exposure to multiple agents. Its long-term efficacy as monotherapy in this setting warrants more studies. PMID- 23749669 TI - New therapeutic targets and drugs for the treatment of chronic hepatitis B. AB - Chronic hepatitis B virus (CHB) is managed effectively with either nucleoside/nucleotide-based or interferon-based therapies. However, most patients receiving these therapies do not establish long-term, durable control of infection after treatment withdrawal. In particular, rates of hepatitis B surface antigen loss and seroconversion to antisurface-antigen antibody are very low. Thus, novel therapies and treatment modalities are necessary to achieve either elimination of the virus from the liver or durable immune control of hepatitis B virus (HBV) infection in the absence of chronic therapy ("functional cure"). Here the authors review new targets and approaches for treating CHB. These approaches can be divided into two broad categories-those targeting the virus or host factors required by the virus and those targeting the innate or adaptive immune systems. Unfortunately, although a variety of promising strategies have been identified and several new approaches have achieved preclinical validation, relatively few novel drug candidates are in active clinical studies to treat CHB. Thus, functional cure of CHB infection remains an important therapeutic challenge. PMID- 23749670 TI - Antiviral therapy for chronic hepatitis B in pregnancy. AB - The management of chronic hepatitis B (CHB) during pregnancy remains a challenge and involves various aspects of maternal-fetal care. Despite the standard immunoprophylaxis, a significant portion of infants born to highly viremic mothers remain infected with hepatitis B virus (HBV). Emerging data suggest that antiviral therapy in the third trimester can prevent immunoprophylaxis failure. To minimize fetal exposure to antiviral agents, antiviral therapy during pregnancy should be reserved for mothers with advanced disease or who are at risk for hepatic decompensation. Current safety data suggest that lamivudine, telbivudine, or tenofovir may be used during pregnancy. However, the timing in initiating antiviral therapy requires careful assessment of risks and benefit. The authors provide a systematic review of the features of HBV during pregnancy, risk factors for vertical transmission, and evidence-based data on antiviral use during pregnancy. They propose an algorithm to assess the need of antiviral treatment and monitor mothers with CHB. PMID- 23749671 TI - Molecular mechanisms of HBV-associated hepatocarcinogenesis. AB - Hepatitis B virus (HBV) contributes to hepatocellular carcinoma (HCC) development through direct and indirect mechanisms. HBV-DNA integration into the host genome occurs at early steps of clonal tumor expansion and induces both genomic instability and direct insertional mutagenesis of diverse cancer-related genes. Prolonged expression of the viral regulatory protein HBx and the large envelope protein deregulate the cellular transcription program and proliferation control and sensitize liver cells to carcinogenic factors. Epigenetic changes targeting the expression of tumor suppressor genes occur early in the development of HCC. A major role is played by HBx that is recruited on cellular chromatin and modulates chromatin dynamics at specific gene loci. Compared with tumors associated with other risk factors, HBV-related tumors have a higher rate of chromosomal alterations and p53 inactivation by mutations, overexpress fetal liver/hepatic progenitor cells genes, and show a specific activation of the AKT pathway. The wnt/beta-catenin pathway is also often activated, but HBV-related tumors display a low rate of activating beta-catenin mutations. All available evidence strongly supports the notion that chronic HBV infection triggers both common and etiology specific oncogenic pathways, thus playing a direct role beyond stimulation of host immune responses and chronic necroinflammatory liver disease. PMID- 23749672 TI - Does antiviral therapy for chronic hepatitis B reduce the risk of hepatocellular carcinoma? AB - Chronic hepatitis B infection (CHB) is common and can lead to serious consequences including liver cirrhosis, failure, and hepatocellular carcinoma (HCC). The hepatitis B virus (HBV) has a simple genome, but a complex lifecycle that includes the production of covalently closed circular DNA (cccDNA). Currently approved antiviral treatments for CHB include interferon (IFN) and nucleos(t)ide analogues. These drugs work either by stimulating the immune system to eliminate virus-infected cells or to inhibit viral replication, respectively. The drugs do not affect the cccDNA pool in the nucleus; therefore, this molecule represents a persistent source of recurrent infection that is difficult to eradicate. With longer-term follow-up of patients treated with antiviral therapy, investigators have looked at whether treatment can prevent the development of HCC. Unfortunately, the data are fairly heterogeneous in terms of both quality and conclusions. IFN appears to reduce the risk of HCC, but the benefit seems to be restricted to cirrhotic patients who have a lasting response to therapy. Oral agents successfully suppress HBV DNA replication and slow or even reverse hepatic fibrosis. Studies suggest that long-term therapy reduces the risk of HCC in patients with active disease and again primarily in those with advanced fibrosis or cirrhosis. The mechanism by which any of the therapies reduce the risk of HCC is not clear. The authors review the lifecycle of HBV and mechanisms by which the virus may be carcinogenic followed by a review of the literature on the efficacy of therapy in reducing the risk of HCC. PMID- 23749673 TI - Immunosuppression and HBV reactivation. AB - Hepatitis B virus (HBV) reactivation following immunosuppression is defined by an abrupt rise in HBV replication followed by laboratory signs of hepatocellular injury in a "silent" hepatitis B surface antigen (HBsAg) carrier. Reactivation can also occur, albeit at a lower rate, in patients with occult HBV infection. The clinical presentation of reactivation is variable ranging from an asymptomatic course to severe hepatitis, liver failure, and death. It is most frequently observed in patients with lymphoma treated with rituximab and corticosteroids as well as in patients undergoing stem cell and bone marrow transplantation. Other risk groups include patients with solid tumors, subjects infected with human immunodeficiency virus, organ transplant recipients, and those with autoimmune diseases (i.e., inflammatory bowel disease, rheumatoid arthritis). In cancer patients, HBV reactivation can lead to interruption of chemotherapy with serious impact on prognosis. In HBsAg-positive patients who are candidates for chemotherapy or treatment with biologic agents, preemptive treatment with an antiviral agent such as lamivudine, and lately with the more potent tenofovir or entecavir, has become a standard of care, effectively preventing HBV reactivation. Patients with occult HBV should be monitored for alanine aminotransferase and HBV DNA during the course of immunosuppression. Prompt administration of a potent antiviral agent upon diagnosis of reactivation may be lifesaving in such patients. PMID- 23749674 TI - Telangiectatic hyperplastic nodule associated with vascular malformation in a patient with chronic hepatitis B: radiologic and pathologic features. AB - Recognizing hepatocellular nodules that cannot be classified as typical for hepatocellular carcinoma, hepatocellular adenoma, or focal nodular hyperplasia is important, especially in a patient with high risk for hepatocellular carcinoma. The authors report a case of a 53-year-old man with chronic hepatitis B, who was referred to the hospital with a liver mass found on routine imaging follow-up. Abdominal ultrasound revealed a 2.4-cm hypoechoic lesion. Contrast computed tomography showed homogeneous arterial enhancement and mild hyperdensity on portal venous phase images. Due to the high risk for hepatocellular carcinoma, the patient underwent laparoscopic left lateral segmentectomy that revealed a 2.2 cm poorly defined red-brown lesion. The nodule was diagnosed as a hypervascular/telangiectatic hyperplastic hepatocellular nodule based on histopathologic findings and immunostaining profile with negative glutamine synthetase, diffuse positive CD34 highlighting hyperplastic endothelial cells along the telangiectatic sinusoids and dilated vascular channels, and CK7 and CK19 reactive normal bile ducts within the lesion. PMID- 23749676 TI - Electro-acupuncture treatment improves neurological function associated with downregulation of PDGF and inhibition of astrogliosis in rats with spinal cord transection. AB - The aim of the current study was to determine the effects of electro-acupuncture (EA) on the improvement of locomotor function in injured spinal cord and underlying mechanism. Forty-five female Sprague-Dawley rats (180~200 g) were randomly divided into three groups, sham operation control group (sham), spinal cord transection group (SCT) and EA group. The Basso, Beattie, and Bresnahan (BBB) Locomotor Rating Scale was used to evaluate functional recovery of rats in hindlimbs at 1, 3, 5 weeks after injury and EA therapy. The gene and protein expression of glial fibrillary acidic protein (GFAP) and platelet derived growth factor (PDGF) were measured by reverse transcription-polymerase chain reaction and Western blot analysis, respectively, and the number of GFAP-positive cells was counted, also. Compared with SCT group, the locomotor function in hindlimbs of rats was improved after 1, 3, 5 weeks following EA therapy. EA treatment not only decreased effectively the number of GFAP immunostaining and GFAP expression, but also downregulated the PDGF expression both gene and protein, in addition decreased the number of PDGF immunostaining in injured spinal cord of rats with transection. It therefore concluded that EA therapy can significantly promote the recovery of locomotor function, and this may be linked to the inhibition of astrogliosis, together with the downregulation of PDGF. PMID- 23749677 TI - Catalytic enantioselective ring-opening reaction of meso-aziridines with alpha isothiocyanato imides. PMID- 23749678 TI - Comparison of leafy kale populations from Italy, Portugal, and Turkey for their bioactive compound content: phenolics, glucosinolates, carotenoids, and chlorophylls. AB - BACKGROUND: Kales are primitive leafy Brassica oleracea L. forms, widespread in local farming systems of several European countries and employed in the preparation of traditional recipes. Kales are also potential sources of healthy bioactive phytochemical components. The present study compared the bioactive compound content of kale populations from Italy, Portugal, and Turkey, either from local sources or grown in an experimental field. RESULTS: Total phenolics, glucosinolates (GLS), carotenoids, and chlorophylls were in the ranges 8310-38 110, 755-8580, 135-2354, and 1740-16,924 mg kg(-1) dry matter, respectively. On average, locally harvested samples showed a total GLS content about twice as high as populations from the experiment. Conversely, pigments were significantly more abundant in experimental than in local kales, owing to the higher soil fertility. Portuguese samples showed higher phenolic and GLS amounts than Italian and Turkish kales, whereas some of the Italian samples were the richest in carotenoids. CONCLUSION: This paper represented the first cross-country comparison of local kale accessions with respect to bioactive compound amounts. Both geographic origin and growing environment appeared to be remarkable and discriminating factors in determining bioactive levels in leafy kales, with possible effects on their health-promoting and sensorial attributes. PMID- 23749679 TI - Automatic identification of familiar faces. AB - Much research has suggested that facial identification has some characteristics of automaticity, in that it is rapid, nonconscious, and mandatory. However, little research has tested whether it can occur even if attention is already devoted to the demanding central processes of another task. In the present study, we addressed this type of automaticity using the psychological refractory period paradigm. In Experiments 1 and 2, participants successfully identified familiar faces, even while they were engaged with another task, indicating the automaticity of familiar-face identification. In Experiments 3 and 4, however, participants could not identify unfamiliar faces as automatically as they could identify the familiar faces. We concluded that automatic face identification is possible, but dependent on prior familiarity. PMID- 23749680 TI - Isolation of terpenoids from Pimpinella anisum essential oil by high-performance counter-current chromatography. AB - High-performance counter-current chromatography was successfully used for the isolation and purification of terpenoid compounds from the essential oil of Pimpinella anisum L. A two-phase solvent system composed of n heptane/methanol/ethyl acetate/water (5:2:5:2, v/v/v/v) was suitable for the purification of linalool, terpinen-4-ol, alpha-terpineol, p-anisaldehyde, while n heptane/methanol (1:1, v/v) was used for the isolation of anethole and foeniculin. A scale-up process from analytical to preparative was developed. Additionally, a stepwise gradient elution was applied and instead of two different runs, 40 min each, one 80 min separation was performed; although the time of separation remains the same, it was possible to repeat the efficiency even if the water-containing mobile phase was changed to a nonaqueous system. The obtained essential oil, as well as purified compounds, was analyzed by GC. A total of 0.64 mg of linalool, 0.52 mg of terpinen-4-ol, 0.10 mg of alpha terpineol, 0.62 mg of p-anisaldehyde, 15 mg of anethole, and 2.12 mg of foeniculin were obtained from 210 mg of the essential oil of P. anisum L. in a short time with purities of 99, 98, 94, 93.54, 93, and 93.6%, respectively. PMID- 23749681 TI - The influence of taurine pretreatment on aluminum chloride induced nephrotoxicity in Swiss albino mice. AB - The present study was carried out to investigate (1) the alterations in biochemical parameters, free radicals and enzyme activities induced by aluminum chloride (AlCl₃) in kidney of male Swiss albino mice, and (2) the role of taurine in alleviating the nephrotoxic effects of AlCl₃. Taurine plays an important role as an antioxidant and is consequently expected to protect tissues from damage caused by reactive oxygen metabolites.The animals were randomized into four groups (n=6/group). Group I was the control group. Group II received a single dose of AlCl₃ (25 mg Al³⁺/kg b.w, ip). Group III received taurine (100 mg/kg b.w., ip) for 5 consecutive days before administration of AlCl₃ (25 mg Al³⁺/kg b.w, ip). Group IV received taurine (100 mg/kg b.w., ip) for 5 consecutive days. 24 h following the administration of compounds, all the mice were assessed using serum and tissue homogenate biomarkers as well as the pathological evaluation. Exposure to AlCl₃ led to an increased level of renal lipid peroxidation as measured by malondialdehyde (MDA), while reduced glutathione (GSH), glutathione peroxidase (GPx) and catalase (CAT) decreased. Marked elevation of blood urea and serum creatinine concentrations were also observed in AlCl₃ treated mice, thereby indicating renal damage. All these factors were significantly improved by taurine pretreatment. The histological and ultrastructural observations on the kidney tissues also confirmed the renoprotective nature of taurine. Thus these results may indicate that taurine treatment protects against functional, biochemical and morphological damage in AlCl₃-induced acute renal failure in mice. PMID- 23749682 TI - Satellite microwave detection of boreal forest recovery from the extreme 2004 wildfires in Alaska and Canada. AB - The rate of vegetation recovery from boreal wildfire influences terrestrial carbon cycle processes and climate feedbacks by affecting the surface energy budget and land-atmosphere carbon exchange. Previous forest recovery assessments using satellite optical-infrared normalized difference vegetation index (NDVI) and tower CO(2) eddy covariance techniques indicate rapid vegetation recovery within 5-10 years, but these techniques are not directly sensitive to changes in vegetation biomass. Alternatively, the vegetation optical depth (VOD) parameter from satellite passive microwave remote sensing can detect changes in canopy biomass structure and may provide a useful metric of post-fire vegetation response to inform regional recovery assessments. We analyzed a multi-year (2003 2010) satellite VOD record from the NASA AMSR-E (Advanced Microwave Scanning Radiometer for EOS) sensor to estimate forest recovery trajectories for 14 large boreal fires from 2004 in Alaska and Canada. The VOD record indicated initial post-fire canopy biomass recovery within 3-7 years, lagging NDVI recovery by 1-5 years. The VOD lag was attributed to slower non-photosynthetic (woody) and photosynthetic (foliar) canopy biomass recovery, relative to the faster canopy greenness response indicated from the NDVI. The duration of VOD recovery to pre burn conditions was also directly proportional (P < 0.01) to satellite (moderate resolution imaging spectroradiometer) estimated tree cover loss used as a metric of fire severity. Our results indicate that vegetation biomass recovery from boreal fire disturbance is generally slower than reported from previous assessments based solely on satellite optical-infrared remote sensing, while the VOD parameter enables more comprehensive assessments of boreal forest recovery. PMID- 23749683 TI - Outcome of older patients with acute myeloid leukemia in first relapse. AB - To provide data for future drug evaluation, we analyzed the outcome of 393 patients aged 50 years or older (median, 64 years) with AML in first relapse after treatment in recent ALFA trials. Salvage options were retrospectively classified as follows: best supportive care (BSC), low-dose cytarabine (LDAC), gemtuzumab ozogamicin (GO), intensive chemotherapy (ICT), or ICT combined with GO. Second complete remission (CR2) rate was 31% and median post-relapse survival was 6.8 months (0, 17, 42.5, 53, and 80% and 3.2, 5.6, 8.9, 9, and 19.8 months in BSC, LDAC, GO, ICT, and ICT + GO subsets, respectively). Age, performance status, WBC, CR1 duration, and favorable AML karyotype, but not other cytogenetic or molecular features, influenced post-relapse outcome. Multivariate adjustment and propensity score matching showed that intensive salvage (ICT/ICT+GO/GO versus LDAC/BSC) was associated with longer post-relapse survival, at least in patients with CR1 duration >=12 months (P = 0.001 and 0.0005, respectively). Of interest, GO appeared to be as effective as standard ICT, and ICT + GO combination more effective than standard ICT. In conclusion, older patients with CR1 duration >=12 months appeared to benefit from intensive salvage and results observed with GO containing salvage suggest that GO combination studies should be actively pursued in this setting. PMID- 23749684 TI - Class III delocalization and exciton coupling in a bimetallic bis-ligand radical complex. AB - The geometric and electronic structure of an oxidized bimetallic Ni complex incorporating two redox-active Schiff-base ligands connected via a 1,2-phenylene linker has been investigated and compared to a monomeric analogue. Information from UV/Vis/NIR spectroscopy, electron paramagnetic resonance (EPR) spectroscopy, electrochemistry, and density functional theory (DFT) calculations provides important information on the locus of oxidation for the bimetallic complex. The neutral bimetallic complex is conformationally dynamic at room temperature, which complicates characterization of the oxidized forms. Comparison to an oxidized monomer analogue 1 provides critical insight into the electronic structure of the oxidized bimetallic complex 2. Oxidation of 1 provides [1](+), which is characterized as a fully delocalized ligand radical complex; the spectroscopic signature of this derivative includes an intense NIR band at 4500 cm(-1). Oxidation of 2 to the bis-oxidized form affords a bis-ligand radical species [2](2+). Variable temperature EPR spectroscopy of [2](2+) shows no evidence of coupling, and the triplet and broken symmetry solutions afforded by theoretical calculations are essentially isoenergetic. [2](2+) is thus best described as incorporating two non-interacting ligand radicals. Interestingly, the intense NIR intervalence charge transfer band observed for the delocalized ligand-radical [1](+) exhibits exciton splitting in [2](2+), due to coupling of the monomer transition dipoles in the enforced oblique dimer geometry. Evaluating the splitting of the intense intervalence charge transfer band can thus provide significant geometric and electronic information in less rigid bis-ligand radical systems. Addition of excess pyridine to [2](2+) results in a shift in the oxidation locus from a bis-ligand radical species to the Ni(III) /Ni(III) derivative [2(py)4](2+), demonstrating that the ligand system can incorporate significant bulk in the axial positions. PMID- 23749686 TI - Clinical significance of atypical squamous cells cannot exclude high grade squamous intraepithelial lesion with histologic correlation-: a 9-year experience. AB - Atypical squamous cells, cannot exclude high grade squamous intraepithelial lesion (ASC-H) is a recognized category in the 2001 Bethesda Nomenclature System for cervical cytology. Although current ASCCP guidelines recommend colposcopic follow-up, more recent studies are suggesting prior triage for HPV-DNA analysis. We report on our experience at the University of Wisconsin Hospital and Clinics. From January 1, 2003 through December 31, 2011 (9-y), the cytopathology laboratory processed 109,424 Pap Tests, of which 281 (0.26%) were diagnosed as ASC-H. Tissue follow-up was available in 181 (64%) of these cases, of which 45 (25%) were negative/cervicitis, 41 (23%) were CIN 1, 36 (20%) were CIN 2 and 59 (32%) were CIN 3. Stratification by age groups showed a higher percentage of high grade (CIN 2+) lesions (65%) in the premenopausal age group as compared with high grade lesion (35%) in the postmenopausal age group, whereas negative/CIN1 biopsies were more common in postmenopausal (65%) as compared to premenopausal (44%) women. Our data support the use of colposcopy in the management of women with ASC-H on Pap Tests. However, in the older age group, prior HPV-DNA testing may be of benefit to better identify those women at risk for high grade lesions. PMID- 23749687 TI - Risk of subsequent malignancies in survivors of childhood leukemia. AB - PURPOSE: The diagnosis of childhood leukemia now carries a much improved overall survival. With this knowledge comes concern for late effects of therapy, especially the risk of secondary malignancy. METHODS: Patients diagnosed with AML or ALL between the ages of 0 and 18 years who survived at least 5 years after diagnosis were included in analysis. Cumulative incidence of subsequent malignancy at 30 years was calculated. To compare incidence of subsequent malignancies with rates of the US population, standardized incidence ratios (SIRs) were calculated. RESULTS: Four thousand eight hundred six patients were included in the analysis. Median follow-up was 14.5 years (range 5.0-35.9 years). A total of 82 patients developed a second malignancy. The most common second tumor was brain (24 %) followed by thyroid (22 %). Cumulative incidences of secondary malignancy at 30 years for ALL patients and AML patients were 3.9 and 4.3 %, respectively (p = 0.10). Patients were at an increased risk of malignancy compared to the US population (SIR = 3.9, 95 % CI = 3.2-4.8). The SIR for all malignancies for patients diagnosed between 1973 and 1979, 1980 and 1989, and 1990 and 1999 were 2.1 (95 % CI = 1.3-3.4), 4.3 (95 % CI = 3.1-5.9), and 4.4 (95 % CI = 2.7-6.6), respectively. CONCLUSIONS: Although incidence of secondary malignancy at 30 years in survivors of childhood leukemia is low, the rate exceeds the expected rate of malignancy for a cohort of this age by nearly 4:1. The development of a subsequent malignancy has significant impact on overall survival and continued research is needed to assess the long-term risk of subsequent malignancy with modern therapy. IMPLICATIONS FOR CANCER SURVIVORS: Although survivors of childhood leukemia experience an increased rate of malignancy compared to their peers, the development of a subsequent malignancy is still a rare event. However, continued long-term follow-up is warranted. PMID- 23749685 TI - Odd-skipped labels a group of distinct neurons associated with the mushroom body and optic lobe in the adult Drosophila brain. AB - Olfactory processing has been intensively studied in Drosophila melanogaster. However, we still know little about the descending neural pathways from the higher order processing centers and how these connect with other neural circuits. Here we describe, in detail, the adult projections patterns that arise from a cluster of 78 neurons, defined by the expression of the Odd-skipped transcription factor. We term these neurons Odd neurons. By using expression of genetically encoded axonal and dendritic markers, we show that a subset of the Odd neurons projects dendrites into the calyx of the mushroom body (MB) and axons into the inferior protocerebrum. We exclude the possibility that the Odd neurons are part of the well-known Kenyon cells whose projections form the MB and conclude that the Odd neurons belong to a previously not described class of extrinsic MB neurons. In addition, three of the Odd neurons project into the lobula plate of the optic lobe, and two of these cells extend axons ipsi- and contralaterally in the brain. Anatomically, these cells do not resemble any previously described lobula plate tangential cells (LPTCs) in Drosophila. We show that the Odd neurons are predominantly cholinergic but also include a small number of gamma aminobutyric acid (GABA)ergic neurons. Finally, we provide evidence that the Odd neurons are a hemilineage, suggesting they are born from a defined set of neuroblasts. Our anatomical analysis hints at the possibility that subgroups of Odd neurons could be involved in olfactory and visual processing. PMID- 23749688 TI - Feasibility and efficacy of a supervised exercise intervention in de-conditioned cancer survivors during the early survivorship phase: the PEACH trial. AB - PURPOSE: This study aims to evaluate the feasibility and efficacy of an 8-week supervised exercise program in de-conditioned cancer survivors within 2-6 months of chemotherapy completion. METHODS: Participants were randomly assigned to an 8 week, twice-weekly, supervised aerobic exercise training regime (n = 23) or a usual care group (n = 20). Feasibility was assessed by recruitment rate, program adherence and participant feedback. The primary outcome was aerobic fitness assessed by the Modified Bruce fitness test at baseline (0 weeks), post intervention (8 weeks) and at 3-month follow-up. Secondary outcomes included physical activity, waist circumference, fatigue and quality of life. RESULTS: The recruitment rate was 81 % and adherence to the supervised exercise was 78.3 %. Meaningful differences in aerobic fitness between the exercise and usual care groups at both the 8-week [mean 3.0 mL kg(-1) min(-1) (95 % CI -1.1-7.0)] and 3 month follow-up [2.1 mL kg(-1) min(-1) (-2.3-6.6)] were found, although these differences did not achieve statistical significance (p values >0.14). Self reported physical activity increased in the exercise group (EG) compared to the usual care group at both 8-week (p = 0.01) and 3-month follow-up (p = 0.03) and significant differences in favour of the EG were found for physical well-being at both the 8-week (p = 0.03) and 3-month follow-up (p = 0.04). Improvements in fatigue (p = 0.01), total quality of life plus fatigue (p = 0.04), and a composite physical functioning score (p = 0.01) at the 3-month follow-up were also found. CONCLUSION: The PEACH trial suggests that 8 weeks of supervised aerobic exercise training was feasible and may improve aerobic fitness, fatigue and quality of life in de-conditioned cancer survivors during the early survivorship phase. IMPLICATIONS FOR CANCER SURVIVORS: Exercise interventions commenced in the early survivorship phase appear safe, feasible and may lead to improvements in QOL and fatigue. PMID- 23749689 TI - Prognostic value of phosphorylated HER2 in HER2-positive breast cancer patients treated with adjuvant trastuzumab. AB - BACKGROUND: Adjuvant trastuzumab has been routinely used in HER2-positive operable breast cancer patients. Prognostic factors remain to be well characterized in these patients and might correlate with primary and/or acquired resistance to trastuzumab. PATIENTS AND METHODS: The study subjects were 78 HER2 positive operable breast cancer patients treated with adjuvant chemotherapy followed by 1-year trastuzumab between 2005 and 2010 in our institute. All breast tumors showed a HercepTest score of 3+ or that of 2+ and positive fluorescence in situ hybridization. Expression levels of HER1, phosphorylated HER2 (pY1248), HER3, HER4, and p53 were assessed by immunohistochemistry. Prognostic factors were investigated with univariate and multivariate analyses using the Kaplan Meier/log-rank test and Cox proportional hazards model, respectively. RESULTS: The median age and follow-up period of the patients were 54 years and 39 months, respectively. The mean tumor size was 2.1 cm and the node-positive rate was 42 %. Eight patients had recurrent diseases but no patient died of cancer. Univariate analysis revealed that pHER2 positivity was only a significantly worse prognostic factor for relapse-free survival (RFS) (P = 0.049). A HercepTest score of 2+ and high expression level of p53 showed a trend. Multivariate analysis revealed three biological markers: pHER2 positivity [hazard ratio (HR) = 11.6, 95 % confidence interval (CI) 1.3-111.1, P = 0.031], p53 positivity (HR = 6.4, 95 % CI 1.0-40.0, P = 0.047) and a HercepTest score of 2+ (HR = 8.6, 95 % CI 1.6-45.2, P = 0.011) to be worse prognostic factors for RFS. Notably, three out of five patients with breast tumors expressing HER2 at a score of 2+ and pHER2 had recurrent diseases. Interestingly, the expression level of pHER2 significantly correlated with the expression levels of HER2 and HER3 in HER2-positive breast tumors. CONCLUSIONS: This retrospective cohort study suggests that a lower expression level of HER2 and high expression levels of pHER2 and p53 may indicate a worse prognosis in HER2-positive breast cancer patients treated with trastuzumab and chemotherapy. Further studies are needed to evaluate pHER2 expression in HER2-positive breast cancer as a prognostic and/or predictive marker. PMID- 23749690 TI - Early life programming of obesity. AB - As the prevalence of obesity increases across the globe, vast efforts are being directed towards understanding the origins of obesity and mechanisms underlying this rapid increase. It is well known that the current environment of an individual can affect body weight, however, growing evidence suggests that the environment in very early life may be particularly important in determining long term obesity risk. This was prompted by a series of epidemiological studies demonstrating a relationship between suboptimal early growth and later risk of obesity. Evidence from human studies as well as animal models have shown that alterations in nutrition and growth in utero and during early postnatal life can have permanent effects on systems mediating regulation of energy balance. Rapid postnatal growth in particular has been associated with increased risk of developing obesity while slower postnatal growth lowers this risk. Alterations in pathways mediating energy homeostasis have been associated with both patterns of early growth. These include changes in structure and function of neuronal pathways in the brain which lead to deregulation of pathways mediating energy balance. In addition to the alterations at the central level, early nutrition can have detrimental long-lasting effects on peripheral physiological systems, for example the storage of fat and utilization of nutrients that make an individual more prone to development of obesity. The fundamental mechanisms underlying these programmed changes are still to be fully defined, although epigenetic mechanisms may play an important role. PMID- 23749691 TI - Transepithelial nasal potential difference (NPD) measurements in cystic fibrosis (CF). AB - The main underlying physiologic abnormality in cystic fibrosis (CF) is dysfunction of the CF transmembrane conductance regulator (CFTR), which results in abnormal transport of sodium and chloride across epithelial surfaces. CFTR function could be tested in vivo using measurements of nasal transepithelial potential difference (PD). Nasal measurements show characteristic features of CF epithelia, including hyperpolarized baseline readings (basal PD), excessive depolarization in response to sodium channel inhibitors, such as amiloride (DeltaAmiloride), and little or no chloride (Cl-) secretion in response to isoproterenol in a chloride-free solution (DeltaCl- free-isoproterenol). PD test is applied for CF diagnosis and monitoring of new therapeutic modulations and corrections. PMID- 23749692 TI - [An updated overview on the anatomy and function of the female pelvic floor, with emphasis on the effect of vaginal delivery]. AB - Phylogenetically, the pelvic floor is a relatively old group of skeletal muscles which, along the acquisition of the erect posture by the human, gained a number of new important roles or were subjected to adaptation of some other roles performed earlier. The functional tasks of the pelvic floor in women (mostly of its prominent representatives - the levator ani muscles) include: supporting the contents of the abdominal cavity at the upright position, participation in the volitional and reflex compression of the urethra, narrowing the transverse dimension of the vagina and urogenital hiatus, involvement in sexual functions, and securing the terminal portion of the alimentary tract. The aim of this overview was to briefly review the information on the latest understanding of the anatomy of the pelvic floor, delineate its nomenclature recommended by the Federative Committee on Anatomical Terminology, and emphasize an array of physiological findings related to the contractility of these important muscles. The functional specialization of striated muscle fiber types and the anatomical basis of the relationship between vaginal delivery at term and postpartum urinary incontinence have been underlined. Nowadays, some intrapartum injuries to the pelvic floor can be successfully detected with ultrasound in the immediate postpartum period. This updated information should be part of a basic professional knowledge for obstetrician-gynecologist. PMID- 23749693 TI - Study of angiogenic gene ointments designed for skin neovascularization. AB - AIM: In this study attention was focused on gene preparations that stimulate angiogenesis in the skin. Angiogenesis was stimulated by gene preparations encoding angiogenic factors introduced into the skin by injection, and applied as ointments. MATERIAL AND METHODS: The appropriate angiogenic formulations containing angiogenic nonviral vectors (pVEGF, pFGF, pSDF, pVIF), or viral vectors (rAAV/VEGF, rAAV/SDF) were prepared for the test. Cholesterol ointment was used as the vehicle for viral and non-viral vectors. The new vessels in the mouse skin were counted according to the criteria suggested by Sidky and Auerbach. RESULTS: Studies indicate that all non-viral (pVEGF, pFGF, pSDF, pVIF) and viral (rAAV/VEGF, rAAV/SDF) vectors strongly stimulate new vessel formation when administered into mouse skin as injections. The impact of angiogenic gene ointments for skin angiogenesis was about 3-4 times weaker than that observed for injection preparations. CONCLUSIONS: Angiogenic injection gene preparations strongly stimulate skin neovascularization. The clinical usefulness of gene ointments should stimulate further laboratory studies in the field of experimental skin gene therapy. PMID- 23749694 TI - [Influence of selected factors on the treatment and prognosis in newborns with gastroschisis on the basis of own experience]. AB - AIM: The purpose of the study was to evaluate the influence of selected prognostic factors for postoperative course and prognosis in newborns with gastroschisis. MATERIAL AND METHODS: A study of all newborns with gastroschisis treated between 2000-2010 in the Clinic of Surgery of Children and Adolescents, Institute of Mother and Child was performed. Data collected from medical documentation included the following: presence or lack of prenatal diagnosis, mode of delivery, gestational age (below or above 37 weeks), birth weight, necessity on transportation from provincial hospitals or transfer within Institute, condition of the bowel (good - little fibrinous inflammation or bad - massive inflammatory peel, necrosis, perforation, atresia), interval between delivery and operation, kind of surgery (primary repair, silo closure), complication requiring secondary operation, period of ventilatory support (PVS), time needed to achieve full enteral feeding (FEF), total length of hospital stay (TH), number and cause of death. Selected information obtained from the data of the patients were separated into two periods of time: 2000-2005 and 2006-2010 for better evaluation of the influence of individual factors on the efficiency of treatment and prognosis. Multivariate logistic regression was used to investigate the association between selected risk factors and end points (PVS,FEF,TH). Statistical analyses were performed using Stata v.10 (College Station, TX, Stata Corporation LP 2007). RESULTS: During the study period 32 newborns with gastroschisis were treated. Prenatal diagnosis was made in 22 patients (69%) and the mean age of diagnosis was 30.7 weeks. Cesarean section was performed in 25 cases and vaginal delivery occurred in 7 cases. The mean gestational age during delivery was 35.7 weeks, mean weight was 2430 g. Twenty one newborns were delivered before 37 week of gestation, eleven after 37 week. Fifteen patients were transported from provincial obstetrics hospitals, seventeen were transferred within the Institute (from the Obstetrics Clinic to Clinic of Pediatric Surgery). A good condition of the externalized bowel was found in 18, a bad condition in 14 patients (therein necrosis with perforation in 2, atresia in 2). Mean delivery - operation interval was 6.3 hours. The operation was performed till 3rd hour after birth in 12, over 3rd hour in 20 newborns. During the first surgical intervention primary closure was possible in 29 cases, silo was used in 3 patients. Five patients required more than one surgical intervention (2 patients after silo closure and 3 patients after primary repair). For patients who survived mean PVS was 4.6, mean time FEF was 24.7 days, TH was 34.5 days. Five patients died. The reasons for death were heart tamponade in 2 and complications in the course of sepsis in 3 patients. In the period 2006-2010 versus 2000-2005 number of prenatal diagnosis significantly increased (46% and 84% respectively), mean age at delivery decreased (38.6 and 35.3 respectively), period between delivery and operation shortened from 8.8 to 3.8 hours, more patients were operated on during first three hours after birth (7.6% and 58% respectively). The condition of the bowel was assessed similarly in both periods (bad condition 38% and 47% respectively). All deaths occurred in newborns treated in the years 2000-2005. Multivariate logistic regression showed there was one independent risk factor that influenced the two end points: the period of respiratory support and the length of hospital stay, i. e. the delivery - operation interval. Patients with delivery - operation interval over 3 hours after birth had a significantly higher risk of long-standing ventilatory support or death (OR=12.4, 95%CI {1.7, 89.3}, p=0.013) and a significantly higher risk of longer total hospital stay or death (OR=12.7, 95%CI {1.7, 97.0}, p=0.014). None of the factors analyzed had statistical significance with respect to the length of time needed to achieve full enteral feeding. CONCLUSION: The main independent risk factor having influence on the course of treatment and prognosis was the delivery - operation interval. Early repair of gastroschisis makes primary closure easier and shortens the post-operative course. Newborns with gastroschisis despite progress in prenatal diagnostics, neonatal intensive care and surgical methods remains a serious therapeutic problem requiring multidisciplinary care and long-standing hospital stay. PMID- 23749695 TI - Is there any association between secretory IgA and lactoferrin concentration in mature human milk and food allergy in breastfed children. AB - BACKGROUND: Breastfeeding is recommended as a protective method against the development of allergy. However, some studies have reported an increased risk of allergies development in breastfed infants of atopic mothers, which implies that atopic mothers may have an altered composition of breast milk. AIM: The aim of the study was to determine the concentration of secretory immunoglobulin A (S IgA) and lactoferrin in human mature milk and to evaluate the association between the levels of these proteins in breast milk with food allergy in children, depending on the allergy status of the breastfeeding mother. MATERIAL AND METHODS: Medical data was collected from birth to 24 months of age from 84 mother child pairs participating in an EU-funded project "EuroPrevall - The prevalence, cost and basis of food allergy across Europe". The diagnosis of food allergy in children was based on the positive result of a double-blind placebo-controlled food challenge (DBPCFC). S-IgA and lactoferrin levels were measured in the whey of mature breast milk with commercial enzyme-linked immunosorbent assay (ELISA) kits. Statistical analysis (the U Mann-Whitney and Kruskal-Wallis tests as well as the Spearman's rank correlation coefficient) was performed using STATISTICA 8.0 PL (Statsoft, Tulsa, USA). RESULTS: Ten out of eighty four participating children had positive skin prick tests (SPT) and/or sIgE to food antigens and in 7 (8.4%) DBPCFC confirmed food allergy. the median concentration of S-IgA was 476,83 MUg/ml (range 6.51-1359.61 MUg/ml). the median concentration of Lf was 15.68 MUg/ml (range 11.68-36.43 MUg/ml). The concentrations of S-IgA and Lf showed a moderate, negative, correlation R=-0.28; p=0.05. CONCLUSIONS: Mature breast milk of mothers of children with food allergy and of healthy children showed similar concentrations of both proteins. The level of S-IgA in the mature milk of mothers with atopic allergy was significantly lower, compared to non atopic mothers. More studies are needed to reveal the mystery of the lack of protective effect of breastfeeding on allergy development in children. PMID- 23749696 TI - [The concentration of lipid parameters in newborns and in older children]. AB - AIM: The study aimed to compare the concentrations of triglycerides, total cholesterol and its fractions and apolipoproteins in cord blood serum in newborns and in blood serum in older children. The influence of gender, intrauterine development, nutritional status and diet on lipid parameters was also assessed. MATERIAL AND METHODS: The longitudinal study was performed in three stages. During stage I the tests were carried out in 137 newborns after birth. Stage II of the study included 41 children aged 18-30 months, and stage III covered 47 children aged 5-6 years. Due to the long-term and multi-stage study, in the evaluation of the results, only 41 children were included; they were only the ones who participated in all three stages, and the test results of whom were complete. In newborns, the gestational age and the birth weight were evaluated. In the older children, the nutritional status was rated by measuring the Body Mass Index and the skin folds thickness as well as the nutrition from birth was assessed. In all of the studied children the concentration of triglycerides, total cholesterol and its fractions: HDL, LDL and VLDL cholesterol and apolipoproteins (AI and B) were measured. RESULTS: The concentrations of lipids, lipoproteins and apolipoproteins in serum increase during the first years of children's life as compared with the values of cord blood serum (p<0.001). Differences in the concentration of lipids and lipoproteins in cord blood serum in the newborns were noticed with relation to gender and birth weight. No fundamental statistical differences were shown between the studied parameters in older children with relation to the gender, nutritional status and the method of feeding after the birth. CONCLUSION: Based on the long-term studies in this group of children, one may conclude that the gender and birth weight have the largest effect on the lipid parameters in the cord blood. However, the gender, the nutritional status and the method of feeding after birth were not related with lipid metabolism. It seems advisable to continue further studies in the same group of children in order to assess the impact of environmental factors on selected parameters of lipid metabolism. PMID- 23749697 TI - [Etiology and clinical course of urticaria in hospitalized children]. AB - INTRODUCTION: Data concerning the epidemiology, etiology and clinical course of childhood urticaria are still under discussion. AIM: To investigate the clinical presentation of urticaria in hospitalized children and to define its possible etiologies. MATERIAL AND METHODS: Ninety eight children (male/female 42/57) aged 0.2-17.6 years, (mean age 8.22+/-0.55) hospitalized due to urticaria were included in the study. The nature and localization of skin lesions, accompanying diseases and diagnostic test results were analyzed. RESULTS: Sixty nine children (70.4%) were diagnosed as having acute, 22 (22.5%) acute recurrent and 7 (7.1%) chronic urticaria. Allergic diseases, family history of atopy and adenoid hypertrophy and/or chronic tonsillitis were present respectively in 10 (10.2%), 28 (28.6%), 21 (21.4%) children. In 32 children (46.3%) with acute urticaria, in 8 (36.3%) with recurrent and in 2 (28.5%) with chronic urticaria skin lesions covered the whole body. Serum C-reactive protein and leukocyte levels in children with acute urticaria were significantly higher compared to children with chronic urticaria (p<0.05). The serum IgE levels, the percentage and absolute count of eosinophils were similar in different forms of urticaria. Probable etiology in 62/69 children with acute urticaria (respiratory tract infections - 43, drugs - 8, lambliosis - 6, food allergy - 2, antiallergy shots - 2, urinary tract infection - 1 child), in 9/22 children with recurrent urticaria (respiratory tract infection - 7, lambliosis - 2 children) and in 3/7 children with chronic urticaria (physical urticaria - 2, urinary tract infection - 1 child) was determined. CONCLUSIONS: Among children with urticaria, the most frequent cause for hospitalization is acute urticaria. The outbreak of hives wheels is usually triggered by upper respiratory tract infection. IgE-related allergy is a rare reason of childhood urticaria. In more than 50% of cases of recurrent and chronic urticaria the etiology was not determined. PMID- 23749698 TI - [Dentigerous cyst associated with maxillary canine as a reason of occlusion defect - case report of 7-year old boy]. AB - Dentigerous cysts are characterized by slow and non-symptomatic growth. Usually they are recognized accidentally during the radiological examination of patients with an occlusion defect or dental age different than growing age. In the case described, the patient presented for dental treatment with the complaint of an occlusion defect and the appearance of a right deciduous maxillary lateral incisor (52). Radiological examination showed the presence of a horizontally positioned maxilla right lateral incisor (12) and dentigerous cyst of tooth 13 (right canine) in the maxilla sinus. After surgical consultation the cyst enucleation and extraction of the unerupted maxillary right canine were performed. Four months later the orthodontic treatment began. PMID- 23749699 TI - [Influence of inflammatory bowel disease on pregnancy and fertility - optimal treatment and management]. AB - Inflammatory bowel diseases (IBD) affect mainly the young population and therefore fertility and pregnancy-related issues are important clinical considerations. Generally, men and women with IBD do not have decreased fertility compared to the general population. Drugs used for IBD do not affect significantly fertility in humans, except sulfasalazine, which causes a temporary reduction in spermatogenesis, but does not reduce fertility itself. The disease course during pregnancy and the risk of pregnancy-related complications depend mainly on the disease activity at the time of conception, therefore, pregnancy should be planned during a phase of remission. Except for methotrexate, mycophenolate mofetil and thalidomide, which are strongly contraindicated, drugs used for IBD appear safe in pregnancy, if they are administered carefully. The highest degree of safety was proved for 5-ASA- -containing agents, thiopurines and corticosteroids. The use of TNFalpha agents remains disputable, especially in the third trimester of pregnancy, due to their high concentration in the infant's blood and the lack of data concerning its long-term safety. Surgery, if necessary, should be delayed if possible, although pregnancy is not a contraindication for surgical procedures. The management of IBD in reproductive age and pregnant women remains still controversial, because literature data comes mostly from retrospective studies. The aim of this paper was to summarize and to present proper management of patients with IBD prior to conception, as well as pregnant women and breast-feeding mothers with IBD, based on current European Crohn's and Colitis Organisation (ECCO) guidelines and available literature. PMID- 23749700 TI - [Etiopathogenesis of dysmenorrhea]. AB - Dysmenorrhea is a common and frequently disabling condition among women of childbearing age. Based on results of large epidemiological studies, it is estimated that over a half of the population of young women suffers from dysmenorrhea. In spite of such a high frequency of this condition, its literature. Pain and lower abdominal cramps are among the most common causes for gynecological referral. Dysmenorrhea is sometimes associated with nausea, vomiting, diarrhea, fatigue, fever, headache, back pain, and dizziness. The exact cause of the disorder is not completely understood. However, there are many known factors that play significant roles in the pathogenesis of dysmenorrhea. The most important are: excessive uterine contractility, disturbances in uterine blood supply, synthesis of prostaglandins and anatomical abnormalities of the female reproductive tract. Primary dysmenorrhea refers to painful menstrual bleedings in the absence of any detectable underlying pathology. Secondary dysmenorrhea represents the clinical situation where menstrual pain can be related to an underlying disease, disorder, or structural abnormality either within or outside the uterus. Unexplained mechanisms and multiple factors involved in the pathogenesis of primary dysmenorrhea indicate a vivid need for further studies on this subject. PMID- 23749701 TI - [Nutritional guidelines for healthy children aged 1-3 years - Polish Expert Group statement. Part I- energy and nutritional components demand]. AB - Updating of the nutritional guidelines for the Polish population requires updates of the nutritional norms for children. We present the Polish Expert Group statement (2012) on intake of selected nutrients (protein, lipids, carbohydrates, vitamin D and E) essential in nutrition of children aged 1-3 years. For this purpose the Expert Group reviewed available scientific data: the recent guidelines, nutritional norms and recommendations, systematic reviews and expert opinions as well as original publications, in relation to the specific requirements of the Polish population. PMID- 23749702 TI - An allotetraploid Brassica napus early-flowering mutant has BnaFLC2-regulated flowering. AB - BACKGROUND: Flowering time is an important agronomic trait, and wide variation in flowering time exists among Brassica napus accessions. GX50 early-flowering mutant, induced from Brassica napus by Ethyl Methane Sulfonate (EMS), exhibits a remarkable early transition from vegetative to reproductive growth. RESULTS: GX50 plants flowered about 60 days earlier than the control wild-type plant B. napus XY15 under greenhouse conditions. Cytological examination revealed that the GX50 plants form inflorescences as early as from 5 weeks old, flower primordium from 6 weeks old, and siliques from 10 weeks old, whereas 10-week-old XY15 plants are still at vegetative growth stage. To unravel the molecular mechanisms underlying the GX50 flowering phenotype, we analyzed the expression of several key regulatory genes. Expressions of all five BnaFLCs (BnaFLC1 to BnaFLC5), BnaFT and BnaSOC1 were detected. Interestingly, BnaFLCs expression levels were lower in GX50 than those in XY15. Among the five BnaFLCs, only the expression pattern of BnaFLC2 corresponded to the timing of floral organ differentiation in GX50. In agreement with previous knowledge that BnaFLCs repress expression of BnaFT and BnaSOC1, increased levels of BnaFT and BnaSOC1 were observed in GX50 compared with XY15. CONCLUSION: BnaFLC2, but not the other BnaFLC genes, plays an important role in B. napus GX50 floral transition. PMID- 23749704 TI - Distal semimembranosus muscle-tendon-unit review: morphology, accurate terminology, and clinical relevance. AB - BACKGROUND: Our knowledge of the stability of the posteromedial knee is evolving. The distal semimembranosus is an important posteromedial stabilizer of the knee. Current anatomical texts and atlases do not accurately detail the distal insertion. Journal literature commonly mentions multiple distal insertions, one of which contributes to the oblique popliteal ligament. The purpose of this study was to review the literature, current morphology, terminology and clinical relevance of the distal semimembranosus muscle-tendon-unit (SMTU), and suggest alternative nomenclature. : METHODS: Literature search was conducted on anatomical and clinical texts, atlases, journals and websites to analyze the distal morphology of the semimembranosus muscle. Deep dissections were performed on 31 embalmed cadavers, 56 knees in total (27Rt and 29L), identifying the distal semimembranosus tendon morphology. : : RESULTS: Literature search revealed significantly inconsistent morphology of the distal semimembranosus muscle-tendon unit. Cadaver dissection revealed a consistent trifurcation with three dominant expansions. Cadaver dissection also revealed an oblique popliteal tendon/expansion, indigenous to SMTU, not a ligament. : CONCLUSION: This study provides evidence of a consistent morphology and suggests a more precise nomenclature of the distal SMTU, which includes renaming the oblique popliteal ligament as the oblique popliteal tendon/expansion. PMID- 23749703 TI - Influence of environmental enrichment and depleted uranium on behaviour, cholesterol and acetylcholine in apolipoprotein E-deficient mice. AB - Alzheimer's disease is associated with genetic risk factors, of which the apolipoprotein E (ApoE) is the most prevalent, and is affected by environmental factors that include education early in life and exposure to metals. The industrial and military use of depleted uranium (DU) resulted in an increase of its deposition in some areas and led to a possible environmental factor. The present study aims to ascertain the effects on the behaviour and the metabolism of cholesterol and acetylcholine of ApoE-/- mice exposed to enriched environment (EE) and exposed to DU (20 mg/L) for 14 weeks. Here we show that ApoE-/- mice were unaffected by the EE and their learning and memory were similar to those of the non-enriched ApoE-/- mice. ApoE-/- mice showed a significant decrease in total (-16 %) and free (-16 %) cholesterol in the entorhinal cortex in comparison to control wild-type mice. Whatever the housing conditions, the exposure to DU of ApoE-/- mice impaired working memory, but had no effect on anxiety-like behaviour, in comparison to control ApoE-/- mice. The exposure of ApoE-/- mice to DU also induced a trend toward higher total cholesterol content in the cerebral cortex (+15 %) compared to control ApoE-/- mice. In conclusion, these results demonstrate that enriched environment does not ameliorate neurobehaviour in ApoE /- mice and that ApoE mutation induced specific effects on the brain cholesterol. These findings also suggested that DU exposure could modify the pathology in this ApoE model, with no influence of housing conditions. PMID- 23749705 TI - Morphology and digitally aided morphometry of the human paracentral lobule. AB - The human paracentral lobule, the junction of the precentral and postcentral gyri at the medial hemispheric surface, contains several important functional regions, and its variable morphology requires exact morphological and quantitativedata. In order to obtain precise data we investigated the morphology of the paracentral lobule and quantified its visible (extrasulcal) surface. This surface corresponds to commonly used magnetic resonance imaging scout images. We studied 84 hemispheres of adult persons (42 brains; 26 males and 16 females; 20-65 years) fixed in neutral formalin for at least 4 weeks. The medial hemispheric surface was photographed at standard distance and each digital photo was calibrated. Using the intercommissural line system (commissura anterior-commissura posterior or CA-CP line), we performed standardised measurements of the paracentral lobule. Exact determination of its boundaries and morphological types was followed by digital morphometry of its extrasulcal surface using AutoCAD software. We found two distinct morphological types of the human paracentral lobule: continuous type, which was predominant (95.2%), and rare segmented type (4.8%). In hemispheres with segmented cingulate sulcus we also found the short transitional lobulo-limbic gyrus (13.1%). The mean extrasulcal surface of the left paracentral lobule was significantly larger, both in males (left 6.79 cm2 vs. right 5.76 cm2) and in females (left 6.05 cm2 vs. right 5.16 cm2). However, even larger average surfaces in males were not significantly different than the same in females. Reported morphological and quantitative data will be useful during diagnostics and treatment of pathologies affecting the human paracentral lobule, and in further studies of its cytoarchitectonic and functional parcellations. PMID- 23749706 TI - A preliminary study of three-dimensional reconstruction of the human osseous labyrinth from micro-computed tomography scans. AB - The adult human temporal bone was investigated using micro-CT scans. Various aspects of the osseous labyrinth were presented in figures which are effect of the volume rendering. The 3D reconstructions were performed to visualize the cochlea and the semicircular canals embedded in the petrous bone. The final product of this study was a digital three-dimensional model of the entire osseous labyrinth which can be viewed at different angles on the computer screen. PMID- 23749707 TI - Investigation of temporal bone asymmetry in cases with unilateral tinnitus: morphometric and multicentric clinical study. AB - The aim of this multicentric study was to compare the anatomical structures of temporal bone in patients with unilateral tinnitus with their healthy ears. We also aimed at evaluating whether age and gender-related asymmetrical changes occur in temporal bones or not. Fifty two ears of 26 patients who had unilateral tinnitus were included into the retrospective study. The patients who had subjective nonpulsatile tinnitus and who previously had temporal computed tomography according to their file records were accepted to study. Temporal CT scans and audiometric results of patients were examined retrospectively. Middle ear volume, diameter of internal acoustic meats and diameter of jugular bulb were evaluated by both anatomist and radiologist, interobserverly. Internal acoustic meats and jugular bulb were found larger in the ears that had tinnitus than healthy ears; however, there was no statistically significance. The stereological morphometrical study of temporal bone asymmetry in humans correlate with sex is of importance for both otolarygologs and anatomists. These results will contribute to data on middle ear volume, internal acustic meats and jugular bulb sizes. PMID- 23749708 TI - A 3D cone beam computed tomography study of the styloid process of the temporal bone. AB - BACKGROUND: To investigate the length and three-dimensional orientation and to detail the morphological variations of the styloid process. MATERIALS AND METHODS: Forty-four patients undergoing temporal bone evaluation for different reasons were randomly selected and included in the present study. The length, angulation in the coronal and sagittal planes, as well as morphological variations of the styloid processes were assessed using conebeam computer tomography. Pearson's correlation coefficient was used to test possible associations between the length of styloid process and angulations, as well as between angulations. Student's t-test was used to compare the differences between the sample mean length and angulations in normal and elongated styloid process groups. RESULTS: The sagittal angle showed weak positive correlations with the styloid process length and the transverse angle (r = 0.24, p = 0.02, n = 88). A medium positive correlation was found between the sagittal and transverse angulations in the elongated styloid process group (r = 0.49, p = 0.0015, n = 38). There was a statistical significant difference between the mean sagittal angulation in elongated styloid and normal styloid process groups (p = 0.015). The styloid process morphology also varied in terms of shape, number, and degree of ossification. CONCLUSIONS: The morphometric and morphologic variations of the styloid process may be important factors to be taken into account not only from the viewpoint of styloid syndromes, but also in preoperatory planning and during surgery. PMID- 23749709 TI - Immunopresence and functional activity of prostaglandin-endoperoxide synthases and nitric oxide synthases in bovine corpora lutea during diestrus. AB - The aim of this study was to evaluate the occurrence and the activity of prostaglandin-endoperoxide synthase 1 (PTGS1), PTGS2, and endothelial, neuronal, and inducible nitric oxide synthase (e-, n-, and iNOS) in early, mid, late, and regressive corpora lutea (CL) of bovines during diestrus. PTGS1 immunoreactivity was localised mainly in the cytoplasm of small luteal cells, whereas PTGS2 was detected in the cytoplasm of large luteal cells during early, mid, and late stages. The immunoexpression of all NOS isoforms was observed in the nuclei of luteal cells in the CL stages examined. PTGS1 enzyme activity was higher in late CL and lower in regressive ones; PTGS2 increased from early to late CL and lowered in regressive ones. Constitutive NOS enzymatic activity (eNOS plus nNOS) was higher in late CL and lower in regressive ones; iNOS was lower in regressive CL. These results support the idea that PTGSs and NOSs regulate the bovine CL life span mainly during the transition from the luteotrophic to the luteolytic phase. PMID- 23749710 TI - An artery accompanying the sciatic nerve (arteria comitans nervi ischiadici) and the position of the hip joint: a comparative histological study using chick, mouse, and human foetal specimens. AB - Birds and reptiles always carry a long and thick artery accompanying the sciatic nerve (i.e., the sciatic artery), whereas mammals do not. We attempted to demonstrate a difference in courses of the nerve and artery in fetuses in relation with the hip joint posture. Eight mid-term human fetuses (15-18 weeks), five mouse fetuses (E18) and five chick embryos (11 days after incubation) were examined histologically. Thin feeding arteries in the sciatic nerve were consistently observed in human fetuses in spite of the long, inferiorly curved course of the nerve around the ischium. The tissue around the human sciatic nerve was not so tight because of the medial and inferior shift of the nerve away from the hip joint. The fetal hip joint position differed among the species, being highly flexed in humans and almost at right angle flexion in mice and chicks. Because of deep adduction of the hip joint in the mouse, the knee was located near the midline of the body. The mouse sciatic nerve ran through the tight tissue along the head of the femur, whereas the chick nerve ran through the loose space even in the gluteal region. In birds, evolution of the pelvis including the hip joint without adduction seemed to make the arterial development possible. In mammals, highly flexed or adducted hip joint seemed to be one of the disturbing factors against development of the long and thick artery. A slight change in posture may cause significant arterial variation. PMID- 23749711 TI - Variations in popliteal fossa venous anatomy: implications for diagnosis of deep vein thrombosis. AB - BACKGROUND: To retrospectively review the bilateral venous system within the popliteal fossa to evaluate the types of variations and their frequency seen in venous anatomy. MATERIALS AND METHODS: During routine dissection of formalin fixed cadavers, a retrospective review of 32 bilateral (64 limbs) lower limbs obtained from adult donors was performed. Deep veins present in the popliteal fossa were evaluated according to predetermined criteria for the presence of duplication of vessels and interindividual variations in venous anatomy. RESULTS: More than one deep venous vessel was seen in the popliteal fossa in 20 (31.3%) of 64 limbs. In 12 (18.7%) cases there was a high (just below the level of the adductor hiatus) origin of the popliteal vein: from 2 tributaries in 10 (15.6%) and 3 tributaries in 2 (3.1%). In 5 (7.8%) cases true duplicated popliteal veins were observed. There were also 3 (4.7%) cases, including one bilateral, of persistent sciatic vein. CONCLUSIONS: Variations in popliteal fossa venous anatomy are common and have important implications for the diagnosis of deep vein thrombosis. PMID- 23749712 TI - Conventional and variant termination of the portal vein in a black Kenyan population. AB - BACKGROUND: Knowledge of the variant terminations of the portal vein is important in surgical and interventional radiological procedures of the liver. Their pattern and frequency are important in planning surgery to minimize complications. They differ between populations, but data from Africa is unavailable. AIM: To investigate the variant termination of the main portal vein. MATERIALS AND METHODS: One hundred livers from adult black Kenyans (age range 35 79 years) were studied at the Department of Human Anatomy, University of Nairobi, Kenya, by gross dissection. The livers were cleared of blood, fixed with 10% formaldehyde solution and the venous system infused with Acrylate monomers to keep the veins firm. The level of termination relative to the capsule and the branching pattern of the portal vein were examined. Various patterns were photographed using a digital camera. Data was analyzed using SPSS version 16.0 for windows and presented in tables and macrographs. RESULTS: Main portal vein termination was extracapsular in 14%, capsular in 40% and intrahepatic in 46%. Variant termination occurred in 49% of cases while conventional bifurcation occurred in 51% cases. Types, 2, 3 and 4 pattern of termination of main portal vein occurred in 15%, 22% and 12% cases respectively. The level of termination of the MPV had a positive correlation with its pattern (p=0.05). CONCLUSIONS: The high prevalence of variant termination of MPV in the current study suggests that the population is more vulnerable to inadvertent injury during surgery and radiological intervention. Besides, an extra hepatic termination of the MPV is more likely to have a conventional branching pattern compared to an intra-hepatic termination. PMID- 23749713 TI - Splenomesenteric vein: formally recognising a clinically relevant section of the portal venous drainage system. AB - BACKGROUND AND AIMS: The objective of this study was to identify and examine a common vein in the portal system that is not consistently named, and when named, to assess whether fundamental concepts were applied in the process of naming. Essentially, the portal venous system drains 3 regions of the gastrointestinal system into 3 major veins (superior mesenteric - SMV, splenic - SV, and inferior mesenteric - IMV) ultimately forming the portal vein (PV). The SMV is formed from midgut veins generally representing the right side of the abdomen. The IMV is formed from hindgut veins generally representing the left side of the lower abdomen and pelvis, classically draining into the SV. The SV is formed from the foregut veins and generally accepts the IMV. The SV then joins the superior mesenteric vein to become the PV. MATERIALS AND METHODS: Sixty cadavers were dissected to observe the frequency of this morphology. Current anatomy and atlas texts were reviewed to identify the morphology and nomenclature. RESULTS: Observations from this study identified a vein being formed from the convergence of the SV and IMV the author named "splenomesenteric vein", which joins the superior mesenteric to form the PV. CONCLUSIONS: These findings suggest re evaluating the morphology and nomenclature of this structure because of the pathology and clinical relevance of this area. PMID- 23749714 TI - Anatomical factors causing oedema of the lower limb during pregnancy. AB - BACKGROUND: The objective of this study was to investigate the morphology of the common iliac artery and vein (CIA&V) comparing right and left sides in females versus males. Pregnant women favour lying on one side at rest and during sleep. The reason for this may be due to the morphology and orientation between the CIA&V. Virtually all women during their pregnancy suffer from lower limb swelling. This study provides an anatomical explanation for the propensity to lie consistently on one side, for lower limb swelling, and offers prevention measures. MATERIALS AND METHODS: A literature search was conducted on anatomical texts, atlases, journals, and websites regarding the morphology and orientation of the right and left CIA&V, lower limb oedema, and sleeping positions during pregnancy. Measurements from 15 dissected cadavers were conducted on the right and left CIA&V. RESULTS: The literature search revealed very limited studies on the morphology and orientation of the right and left CIA&V with no studies relating this orientation to lower limb oedema or sleeping positions during pregnancy. Cadaver dissection revealed a relatively direct anterior to posterior orientation left CIA&V and an oblique lateral to medial right CIA&V. CONCLUSIONS: This study suggests an explanation of why women lie on their left side when resting and sleeping during the third trimester due to the clinically relevant anatomy between the CIA&V. PMID- 23749715 TI - Morphological study of linea aspera variations - proposal of classification and sexual dimorphism. AB - The linea aspera is a roughened, longitudinally-oriented irregular crest composed of two lips located on the posterior surface of the femoral shaft. The purpose of this research was to investigate the morphological variations of the linea aspera in humans. The study was carried out on 90 femurs. Osteometric measurements of the bones were taken using two complementary methods: classical osteometry and a new one based on the analysis of digital photographic documentation of the femur using MultiScanBase v.18.03 software. The analysis allowed four types of the linea aspera to be determined: parallel (type I - 27.2%), concave (type II - 25.7%), convex (type III - 5.7%) and variform (type IV - 41.4%). The frequency of the each type in female and male was also described. Better knowledge of the anatomical variations of the linea aspera may be helpful in Orthopaedy and Radiology to distinguish pathological from normal anatomical variations. PMID- 23749716 TI - A rare cadaveric finding of ectopic origin of a bronchial artery: surgical and imaging consequences. AB - Bronchial arteries arise normally directly from the descending thoracic aorta, at the level between the fourth and sixth thoracic vertebra. However the anatomical variations are very frequent regarding the origin or the number of branches. We present a rare cadaveric finding of an ectopic right bronchial artery originating from the right subclavian artery through common stem with the right internal thoracic artery and we discuss the clinical significance of this finding. A 72 year-old formalin-embalmed male cadaver was dissected during a routine anatomical course. The right bronchial artery originated from the right subclavian artery with a common stem with the right internal thoracic artery. Although ectopic origin of the right bronchial artery from the right internal thoracic artery is rare, recognition of this anatomical variation is important in bronchial embolization due to hemoptysis, in coronary bypass grafting and in lung transplantation. PMID- 23749717 TI - An interconnected duplicated femoral vein and its clinical significance. AB - Anatomical variations in the femoral vein are of great clinical importance especially in cases of deep vein thrombosis (DVT). Knowledge of the variable anatomy of the femoral vein is important to minimise false-negative findings on ultrasound examination in patients with DVT and help to explain the 'silent' DVT. Furthermore, the presence of a duplicated femoral vein itself is associated with higher incidence of DVT. These venous anomalies are usually due to the truncular venous malformation. In the present study, while dissecting the right lower limb, we found a case of variation of the femoral vein. In this case, besides a duplicated femoral vein, we also noticed a 3rd interconnecting channel near the apex of the femoral triangle joining the two veins. This variation has not been reported previously by other authors. Considering its uniqueness and clinical importance, we decided to report this case. PMID- 23749718 TI - Why cachexia kills: examining the causality of poor outcomes in wasting conditions. AB - Weight loss is the hallmark of any progressive acute or chronic disease state. In its extreme form of significant lean body mass (including skeletal muscle) and fat loss, it is referred to as cachexia. It has been known for millennia that muscle and fat wasting leads to poor outcomes including death. On one hand, conditions and risk factors that lead to cachexia and inadequate nutrition may independently lead to increased mortality. Additionaly, cachexia per se, withdrawal of nutritional support in progressive cachexia, and advanced age may lead to death via cachexia-specific pathways. Despite the strong and consistent association of cachexia with mortality, no unifying mechanism has yet been suggested as to why wasting conditions are associated with an exceptionally high mortality risk. Hence, the causality of the cachexia-death association, even though it is biologically plausible, is widely unknown. This century-long uncertainty may have played a role as to why the field of cachexia treatment development has not shown major advances over the past decades. We suggest that cachexia-associated relative thrombocytosis and platelet activation may play a causal role in cachexia-related death, while other mechanisms may also contribute including arrhythmia-associated sudden deaths, endocrine disorders such as hypothyroidism, and immune system compromise leading to infectious events and deaths. Multidimensional research including examining biologically plausible models is urgently needed to investigate the causality of the cachexia-death association. PMID- 23749719 TI - An improved biofunction of titanium for keratoprosthesis by hydroxyapatite coating. AB - Titanium framework keratoprosthesis has been commonly used in the severe corneal blindness, but the tissue melting occurred frequently around titanium. Since hydroxyapatite has been approved to possess a good tissue integration characteristic, nanostructured hydroxyapatite was coated on the surface of titanium through the aerosol deposition method. In this study, nanostructured hydroxyapatite coating was characterized by X-ray diffraction, scanning electron microscopy, atomic force microscopy, and auger electronic spectrometer. Biological evaluations were performed with rabbit cornea fibroblast in vitro and an animal model in vivo. The outcomes showed the coating had a grain-like surface topography and a good atomic mixed area with substrate. The rabbit cornea fibroblasts appeared a good adhesion on the surface of nanostructured hydroxyapatite in vitro. In the animal model, nanostructured hydroxyapatite titanium implants were stably retained in the rabbit cornea, and by contrast, the corneal stroma became thinner anterior to the implants in the control. Therefore, our findings proved that nanostructured hydroxyapatite-titanium could not only provide an improved bond for substrate but also enhance the tissue integration with implants in host. As a promising material, nanostructured hydroxyapatite titanium-based keratoprosthesis prepared by the aerosol deposition method could be utilized for the corneal blindness treatment. PMID- 23749721 TI - A strategy for separating and recycling solid catalysts based on the pH-triggered Pickering-emulsion inversion. AB - Turn you inside out: A novel method for performing in situ separation and recycling of submicrometer-sized solid catalysts is developed based on the pH triggered inversion of Pickering emulsions (see scheme; o = oil, w = water). Solid catalysts can be recycled 36 times without significant loss of activity. The method differs from conventional methods in terms of speed, energy consumption, catalyst separation, and recycling effectiveness. PMID- 23749720 TI - Just-in-time rescue plerixafor in combination with chemotherapy and granulocyte colony stimulating factor for peripheral blood progenitor cell mobilization. AB - Plerixafor, a recently approved peripheral blood progenitor cell mobilizing agent, is often added to granulocyte-colony stimulating factor (G-CSF) to mobilize peripheral blood progenitor cells in patients with lymphoma or myeloma who cannot mobilize enough CD34+ cells with G-CSF alone to undergo autologous stem cell transplantation. However, data are lacking regarding the feasibility and efficacy of just-in-time plerixafor in combination with chemotherapy and G CSF. We reviewed the peripheral blood stem cell collection data of 38 consecutive patients with lymphoma (Hodgkin's and non-Hodgkin's) and multiple myeloma who underwent chemomobilization and high-dose G-CSF and just-in-time plerixafor to evaluate the efficacy of this treatment combination. All patients with multiple myeloma and all but one patient with lymphoma collected the minimum required number of CD34+ cells to proceed with autologous stem cell transplantation (>2 * 10(6) /kg of body weight). The median CD34+ cell dose collected in patients with non-Hodgkin lymphoma was 4.93 * 10(6) /kg of body weight. The median CD34+ cell dose collected for patients with multiple myeloma was 8.81 * 10(6) /kg of body weight. Plerixafor was well tolerated; no grade 2 or higher non-hematologic toxic effects were observed. PMID- 23749722 TI - Preparation of a novel carboxyl stationary phase by "thiol-ene" click chemistry for hydrophilic interaction chromatography. AB - A novel carboxyl-bonded silica stationary phase was prepared by "thiol-ene" click chemistry. The resultant Thiol-Click-COOH phase was evaluated under hydrophilic interaction liquid chromatography (HILIC) mobile phase conditions. A comparison of the chromatographic performance of Thiol-Click-COOH and pure silica columns was performed according to the retention behaviors of analytes and the charged state of the stationary phases. The results indicated that the newly developed Thiol-Click-COOH column has a higher surface charge and stronger hydrophilicity than the pure silica column. Furthermore, the chromatographic behaviors of five nucleosides on the Thiol-Click-COOH phase were investigated in detail. Finally, a good separation of 13 nucleosides and bases, and four water-soluble vitamins was achieved. PMID- 23749723 TI - Non-covalent activation of a titanium(IV) oxygen-transfer catalyst. PMID- 23749725 TI - Effect of water-soluble fraction of cherry tomatoes on the adhesion of probiotics and Salmonella to intestinal epithelial cells. AB - BACKGROUND: Tomato is one of the most consumed vegetables in the world and contains many valuable nutritional components. Here we investigate the prebiotic effects of cherry tomatoes for improving gut health. RESULTS: Water-soluble dietary fiber was prepared from fresh and processed (heat treatment at 80 degrees C for 15 min) cherry tomato samples, each with and without Viscozyme L treatment. In the adhesion assays, all water-soluble dietary fiber samples improved adhesion of probiotics (Lactobacillus rhamnosus and Bifidobacterium bifidum) to intestinal epithelial cells (Caco-2 cells). Heat treatment in the preparation of juice from cherry tomatoes showed no significant effect on the adhesion of probiotics to Caco-2 cells. The oligofructose content of samples affected the intestinal adhesion of probiotic bacteria, with higher oligosaccharide concentrations associated with greater adhesion of probiotics and more inhibition of the adhesion of pathogens to Caco-2 cells. CONCLUSION: The present results suggest that cherry tomato can act as a prebiotic, with oligofructose potentially being one of its major prebiotic components. PMID- 23749726 TI - Pulmonary alveolar proteinosis: report of two cases in the West of Ireland with review of current literature. AB - BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare lung condition characterised by the accumulation of lipoproteinaceous surfactant material within alveolar airspaces resulting in clinical manifestations ranging from asymptomatic to severe respiratory failure. Three disease subtypes are recognised: autoimmune, secondary and congenital. METHODS: We describe two presentations of PAP in the West of Ireland with a review of the current literature. RESULTS: Autoimmune PAP, associated with the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, accounts for >90 % of cases. Treatment with whole lung lavage is the current standard of care. Novel therapies targeting alveolar macrophages (recombinant GM-CSF therapy) and anti-GM-CSF antibodies (rituximab, plasmapharesis) are under investigation. CONCLUSIONS: This is a summary of available literature outlining current clinical practice in the diagnosis, management, and treatment of PAP. PAP should be considered in the differential diagnosis of any patient with a restrictive pulmonary defect. Without high clinical suspicion, this diagnosis can easily be missed. PMID- 23749724 TI - Neuronal and nonneuronal cholinergic structures in the mouse gastrointestinal tract and spleen. AB - Accumulating evidence demonstrates that acetylcholine can directly modulate immune function in peripheral tissues including the spleen and gastrointestinal tract. However, the anatomical relationships between the peripheral cholinergic system and immune cells located in these lymphoid tissues remain unclear due to inherent technical difficulties with currently available neuroanatomical methods. In this study, mice with specific expression of the tdTomato fluorescent protein in choline acetyltransferase (ChAT)-expressing cells were used to label preganglionic and postganglionic cholinergic neurons and their projections to lymphoid tissues. Notably, our anatomical observations revealed an abundant innervation in the intestinal lamina propria of the entire gastrointestinal tract principally originating from cholinergic enteric neurons. The aforementioned innervation frequently approached macrophages, plasma cells, and lymphocytes located in the lamina propria and, to a lesser extent, lymphocytes in the interfollicular areas of Peyer's patches. In addition to the above innervation, we observed labeled epithelial cells in the gallbladder and lower intestines, as well as Microfold cells and T-cells within Peyer's patches. In contrast, we found only a sparse innervation in the spleen consisting of neuronal fibers of spinal origin present around arterioles and in lymphocyte-containing areas of the white pulp. Lastly, a small population of ChAT-expressing lymphocytes was identified in the spleen including both T- and B-cells. In summary, this study describes the variety of cholinergic neuronal and nonneuronal cells in a position to modulate gastrointestinal and splenic immunity in the mouse. PMID- 23749727 TI - Nodular fasciitis in the parotid gland: a case report and review of the literature. AB - Nodular fasciitis (NF) is a benign, reactive lesion with a self-limiting process. Because NF is rare in the parotid gland and has many cytological similarities to other benign or malignant tumors, cytological misinterpretation is common. The patient, a 30-year-old woman, had a painless mass in her right parotid gland. Fine needle aspiration cytology (FNAC) was performed. Spindle cells with basophilic and well-demarcated cytoplasm were observed in a mucoid-like background. The mucoid-like substance was metachromatic and appeared to be the matrix of PA. Histopathologically, spindle-shaped cells with intervening birefringent mature collagen were arranged in short irregular bundles. Prominent mucoid-like matrixes as well as few infiltrating neutrophils and lymphocytes were found in the background. Lesional cells were positive for CD10 and beta-catenin in the cytoplasm, but negative for cytokeratin, the S-100 protein, CD34, and neurofilament. Ultimately, this patient was diagnosed with NF. In FNAC of the parotid gland region, distinguishing NF from other real tumors is important for deciding treatment strategies. PMID- 23749728 TI - Early ambulatory palliative care visits focus on psychosocial elements such as building rapport and coping, as well as managing symptoms and enhancing illness understanding. PMID- 23749729 TI - Daily calcium intake in excess of 1400 mg is associated with increased all-cause and cardiovascular disease mortality in women. PMID- 23749730 TI - Older adults reporting social isolation or loneliness show poorer cognitive function 4 years later. PMID- 23749731 TI - Can the osteosynthesis with locking plates be a better treatment for unstable fractures of the proximal humerus? AB - PURPOSE: The purpose of this study is to review our experience with proximal humeral locking plates, including complications, functional outcomes, strength recovery and predictors of successful treatment. METHODS: Seventy unstable proximal humeral fractures were treated with open reduction internal fixation (ORIF) with the use of locking proximal humerus plate. At an average follow-up of 31 months, the clinical and subjective outcomes were evaluated, and complication was analysed. RESULTS: The average Constant score was 72. The mean disabilities of the arm, shoulder and hand score was 23. The average range of motion was as follows: mean range of anterior elevation and abduction 120 degrees -150 degrees ; external rotation in abduction 64 degrees and in adduction 44 degrees ; and internal rotation T12. CONCLUSION: On the basis of the overall functional and clinical outcome obtained, it is possible to suggest that the ORIF of the proximal humerus fractures using locking plate represents a helpful option that can lead to a good clinical and functional outcome even in the most complex fractures. PMID- 23749732 TI - Effects of extracellular calcium on viability and osteogenic differentiation of bone marrow stromal cells in vitro. AB - Bone marrow stromal cells (BMSCs) have been extensively used for tissue engineering. However, the effect of Ca(2+) on the viability and osteogenic differentiation of BMSCs has yet to be evaluated. To determine the dose-dependent effect of Ca(2+) on viability and osteogenesis of BMSCs in vitro, BMSCs were cultured in calcium-free DMEM medium supplemented with various concentrations of Ca(2+) (0, 1, 2, 3, 4, and 5 mM) from calcium citrate. Cell viability was analyzed by MTT assay and osteogenic differentiation was evaluated by alkaline phosphatase (ALP) assay, Von Kossa staining, and real-time PCR. Ca(2+) stimulated BMSCs viability in a dose-dependent manner. At slightly higher concentrations (4 and 5 mM) in the culture, Ca(2+) significantly inhibited the activity of ALP on days 7 and 14 (P < 0.01 or P < 0.05), significantly suppressed collagen synthesis (P < 0.01 or P < 0.05), and significantly elevated calcium deposition (P < 0.01) and mRNA levels of osteocalcin (P < 0.01 or P < 0.05) and osteopontin (P < 0.01 or P < 0.05). Therefore, elevated concentrations of extracellular calcium may promote cell viability and late-stage osteogenic differentiation, but may suppress early-stage osteogenic differentiation in BMSCs. PMID- 23749733 TI - Pharmacological interventions for pruritus in adult palliative care patients. AB - BACKGROUND: Pruritus is not the most prevalent but one of the most puzzling symptoms in palliative care patients. It can cause considerable discomfort and has a major impact on patients' quality of life. In the field of palliative care, pruritus is a symptom occurring in patients with disparate underlying diseases and based on different pathologic mechanisms but ending in the same phenomenon. The pathogenesis of pruritus is complex and not fully elucidated. Thus, it is still very difficult to treat pruritus effectively. Evidence-based treatment approaches are needed. OBJECTIVES: The objective was to evaluate the efficacy of different pharmacological treatments for preventing or treating pruritus in adult palliative care patients. SEARCH METHODS: A systematic literature search up to January 2012 was performed and it was updated in August 2012. The following databases were searched: The Cochrane Library (CENTRAL, DARE, CDSR) (2012, issue 8 of 12); MEDLINE (1950 to August 2012); EMBASE (1980 to August 2012) and three other databases. In addition, we searched trials registries and checked the reference lists of all relevant studies, key textbooks, reviews, and websites, and contacted investigators and specialists in pruritus and palliative care regarding unpublished data. SELECTION CRITERIA: We included randomised controlled trials assessing the effects of different pharmacological treatments on preventing or treating pruritus in palliative care patients. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed identified titles and abstracts. Three independent review authors performed assessment of all potentially relevant studies, data extraction, assessment of risk of bias and methodological quality. Results were summarised descriptively according to the different pharmacological interventions and the type of underlying pruritus. Where possible, results were presented in meta-analyses. MAIN RESULTS: In total, 38 reports comprising 40 studies and 1286 participants were included in the review. Altogether, 30 different treatments for pruritus in four different patient groups were included.The findings of this review indicated that the treatment of pruritus for palliative care patients is challenging and requires an individualistic approach. Results showed that effective therapeutic choices have to be guided by the pathophysiology of the pruritus. Various forms of pruritus occur, especially in the field of palliative care, and sometimes the origin of the pruritus is difficult to determine. Therefore, identifying the underlying cause of pruritus is of prime importance in order to develop tailored treatment plans, even if in palliative care the treatment is focused towards the symptom and not necessarily the underlying disease.Results show that in palliative care patients with pruritus of different natures, treatment with the drug paroxetine, a selective serotonin reuptake inhibitor, may be beneficial. For patients suffering from pruritus associated with HIV infection, indomethacin was described as the most effective drug, although the evidence was weak. For patients suffering from chronic kidney disease-associated pruritus, gabapentin may be an option. An alternative treatment for this patient group seems to be the kappa opioid receptor agonist nalfurafine, which has shown significant amelioration of pruritus and acceptable adverse effects. As they have exhibited a low incidence of adverse effects, rifampicin and flumecinol may be recommended for patients with cholestatic pruritus. The opioid antagonist naltrexone has been shown to offer a therapeutic alternative for patients suffering from uraemic or cholestatic pruritus. However, these drugs are often inappropriate in the palliative population because of the risk of reducing analgesia when giving high doses of naltrexone. AUTHORS' CONCLUSIONS: The findings of this review indicate that the number of systemic and topical drugs used for the different subforms of pruritus is increasing. Different interventions have been shown to be effective in the treatment of pruritus of different origins. Nevertheless, an optimal therapy for pruritus is constrained due to the limited understanding of crucial itch mediators and receptors in the various subforms of itch. Ideal antipruritic therapies are still lacking, especially for palliative care patients.This systematic review also indicates that there is insufficient evidence to give any concrete recommendations regarding treatment of pruritus in palliative care patients. Due to the very small sample sizes and poor methodological quality of the majority of studies that were included, the results of this review need to be interpreted with caution. Furthermore, the generalizability is questionable. Additional studies, and particularly carefully designed treatment trials, are needed to provide valid evidence for adequate treatment of pruritus in palliative care patients. PMID- 23749734 TI - When do vertical programmes strengthen health systems? A comparative assessment of disease-specific interventions in India. AB - OBJECTIVE: Disease-specific programmes have had a long history in India and their presence has increased over time. This study has two objectives: first, it reports on the interaction between local health systems and key disease-specific programmes in India-National AIDS Control Program (NACP) (HIV/AIDS), Revised National Tuberculosis Control Program (RNTCP) (TB) and National Vector Borne Disease Control Program (NVBDCP) (Malaria), and second, it examines which factors create an enabling environment for disease-specific programmes to strengthen health systems. METHODS: A total of 103 in-depth interviews were conducted in six states in 2009 and 2010. Key informants included managers of disease control programmes and health systems, central and state health ministry and staff from peripheral health facilities. Analytical themes were derived from the World Health Organization (WHO) building block and the Systems Rapid Assessment framework. FINDINGS: Disease-specific programmes contribute to strengthening some components of the health system by sharing human and material resources, increasing demand for health services by improving public perceptions of service quality, encouraging civil society involvement in service delivery and sharing diseasespecific information with local health system managers. These synergies were observed more frequently in the RNTCP and NVBDCP compared with the NACP. CONCLUSIONS: Disease-specific programmes in India are widely regarded as having made a substantial contribution in disease control. They can have both positive and negative effects on health systems. Certain conditions are necessary for them to have a positive influence on health systems-the programme needs to have an explicit policy to strengthen local health systems, and should also be embedded within the health system administration. PMID- 23749735 TI - Abortion law in Muslim-majority countries: an overview of the Islamic discourse with policy implications. AB - Religion plays a significant role in a patient's bioethical decision to have an abortion as well as in a country's abortion policy. Nevertheless, a holistic understanding of the Islamic position remains under-researched. This study first conducted a detailed and systematic analysis of Islam's position towards abortion through examining the most authoritative biblical texts (i.e. the Quran and Sunnah) as well as other informative factors (i.e. contemporary fatwas, Islamic mysticism and broader Islamic principles, interest groups, and transnational Islamic organizations). Although Islamic jurisprudence does not encourage abortion, there is no direct biblical prohibition. Positions on abortion are notably variable, and many religious scholars permit abortion in particular circumstances during specific stages of gestational development. It is generally agreed that the least blameworthy abortion is when the life of the pregnant woman is threatened and when 120 days have not lapsed; however, there is remarkable heterogeneity in regards to other circumstances (e.g. preserving physical or mental health, foetal impairment, rape, or social or economic reasons), and later gestational development of the foetus. This study secondly conducted a cross country examination of abortion rights in Muslim-majority countries. A predominantly conservative approach was found whereby 18 of 47 countries do not allow abortion under any circumstances besides saving the life of the pregnant woman. Nevertheless, there was substantial diversity between countries, and 10 countries allowed abortion 'on request'. Discursive elements that may enable policy development in Muslim-majority countries as well as future research that may enhance the study of abortion rights are discussed. Particularly, more lenient abortion laws may be achieved through disabusing individuals that the most authoritative texts unambiguously oppose abortion, highlighting more lenient interpretations that exist in certain Islamic legal schools, emphasizing significant actors that support abortion, and being mindful of policy frames that will not be well-received in Muslim-majority countries. PMID- 23749736 TI - Highly conductive aluminum textile and paper for flexible and wearable electronics. AB - Light to wear: Aluminum coated fibrous materials with excellent electrical conductivity and mechanical endurance are fabricated at room temperature by a chemical solution process. The resulting aluminum-coated conductive papers and threads can be used in electric circuits for flexible and wearable electronics. PMID- 23749737 TI - Paranuclear and extracellular globules in intraoperative cytology preparations of anaplastic large cell lymphoma. PMID- 23749738 TI - Surgery for varicose veins: use of tourniquet. AB - BACKGROUND: Varicose vein surgery is a common surgical procedure but there is no consensus regarding the best surgical technique. The use of tourniquets during varicose vein surgery has been advocated as a means of reducing the potential for blood loss during the operation. OBJECTIVES: To identify whether the use of a tourniquet should be recommended when undertaking surgery for the management of primary varicose veins. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2013) and the CENTRAL (2013, Issue 3). SELECTION CRITERIA: All studies described as randomised controlled trials that examined the use of tourniquets during surgery for patients with primary varicose veins were included. DATA COLLECTION AND ANALYSIS: Data from eligible studies were extracted and summarised independently by two authors. All studies were cross-checked independently by the authors. MAIN RESULTS: No additional studies were included or excluded in the updated review. Twenty papers detailing 18 trials were considered. Only three trials were randomised controlled trials and were included in the review. The remaining fifteen studies were excluded for various reasons. All three included trials had a small sample size and reported the trial design, outcome measures and analysis poorly. There were also variations in the outcome measures used between the trials. In addition, there was no consistency on the reporting of mean and medians for blood loss during the operation. It was therefore not possible to pool the data to perform meta-analysis. However, the reported blood loss when using a tourniquet was between 0 and 16 ml compared to between 107 to 133 ml when not using a tourniquet (P < 0.01). AUTHORS' CONCLUSIONS: Although there were significant quality issues with the available evidence, the use of a tourniquet would appear to reduce blood loss during surgery. There were no reported differences between the use or non-use of a tourniquet in terms of complications and morbidity. However, the available trials were not of sufficient size to detect rarer complications such as nerve damage. PMID- 23749739 TI - Immunosuppressive mechanisms of regulatory dendritic cells in cancer. AB - Three major functional subsets of dendritic cells (DCs) have been described in the tumor microenvironment in patients with cancer and tumor-bearing animals: (i) conventional DCs with intact antigen-presenting capabilities, (ii) functionally defective DCs with decreased motility and low ability to uptake, process and present antigens or produce cytokines and (iii) regulatory DCs with high capacity to suppress T cell proliferation, induce differentiation of regulatory T cells or support immune tolerance. Phenotypic characteristics of regulatory DCs (regDCs), as well as the mechanisms of T cell inhibition, vary in different experimental conditions and environments, suggesting high level of their plasticity and probably different origin. Although new data demonstrate that regDCs may play an important role at early stages of tumor development, functional differences and clinical significance of emergence of different myeloid regulatory cells (MDSCs, regDCs, M2 macrophages, N2 neutrophils, mast cells) in cancer remain to be determined. PMID- 23749741 TI - Pathways to age-related cognitive decline. PMID- 23749740 TI - Cortical connections to single digit representations in area 3b of somatosensory cortex in squirrel monkeys and prosimian galagos. AB - The ventral posterior nucleus of thalamus sends highly segregated inputs into each digit representation in area 3b of primary somatosensory cortex. However, the spatial organization of the connections that link digit representations of areas 3b with other somatosensory areas is less understood. Here we examined the cortical inputs to individual digit representations of area 3b in four squirrel monkeys and one prosimian galago. Retrograde tracers were injected into neurophysiologically defined representations of individual digits of area 3b. Cortical tissues were cut parallel to the surface in some cases and showed that feedback projections to individual digits overlapped extensively in the hand representations of areas 3b, 1, and parietal ventral (PV) and second somatosensory (S2) areas. Other regions with overlapping populations of labeled cells included area 3a and primary motor cortex (M1). The results were confirmed in other cases in which the cortical tissues were cut in the coronal plane. The same cases also showed that cells were primarily labeled in the infragranular and supragranular layers. Thus, feedback projections to individual digit representations in area 3b mainly originate from multiple digits and other portions of hand representations of areas 3b, 1, PV, and S2. This organization is in stark contrast to the segregated thalamocortical inputs, which originate in single digit representations and terminate in the matching digit representation in the cortex. The organization of feedback connections could provide a substrate for the integration of information across the representations of adjacent digits in area 3b. PMID- 23749743 TI - The neurologic revolving door: time to pay attention to readmissions. PMID- 23749744 TI - Massachusetts General Hospital honors Anne Young for two decades as chief of neurology service: world-renowned researcher enters the next phase of her career by focusing on mentoring of the next generation. PMID- 23749745 TI - Encode: life, the universe, and everything. PMID- 23749746 TI - Role of epigenetic modulation for the treatment of sarcoma. AB - OPINION STATEMENT: Sarcoma is a disease that includes many different subtypes that can present with a wide range of differing clinical findings, prognosis, and treatment options. For certain subsets (e.g., Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, gastrointestinal stromal tumor [GIST]), extensive clinical trials have delineated effective treatment regimens often involving combination therapy, including surgery, radiation, systemic chemotherapy, and small molecular inhibitors of tyrosine kinases (as in the case of GIST). For nearly all patients with sarcoma who have relapsed or developed metastasis, the therapeutic benefit of chemotherapy has reached a plateau and as such new treatment approaches are needed to move this field forward. We recommend that all patients have the opportunity to participate in clinical trials where available. Recently, in our clinic we have started to increase our use of molecular testing and DNA sequencing studies to help identify potential treatment options for patients. One area of evolving basic and clinical research in sarcomas is the field of epigenetic therapeutics. The enclosed article reviews the basics of epigenetics and highlights some completed and ongoing clinical trials of epigenetic treatments in sarcoma. We anticipate in the future that diagnostic platforms will be developed to help clinicians determine if an epigenetic therapy could be effective for an individual patient with sarcoma. PMID- 23749748 TI - Physicochemical properties and antimicrobial activity of Roselle (Hibiscus sabdariffa L.). AB - BACKGROUND: The therapeutic action of a plant depends on its chemical constituents. In this study, experiments were carried out in order to evaluate the effect of extraction conditions on the antioxidative and antimicrobial activities of Roselle (Hibiscus sabdariffa L.). RESULTS: Roselle was found to be rich in malic acid, anthocyanins, ascorbic acid and minerals, especially Ca and Fe, but low in glucose. More than 18 volatile compounds were identified by gas chromatography and gas chromatography-mass spectrometry. This herb, which is rich in phenolic compounds and displays DPPH radical scavenging activity, could be a good source of natural antioxidants. The antimicrobial activity of the Roselle water and ethanol extracts was tested with Bacillus subtilis (ATCC6633), Staphylococcus aureus (ATCC6538) and Escherichia coli (ATCC 8739). The inhibition of the Roselle ethanol extract against B. subtilis and S. aureus was slightly higher than that of water extract but this difference was not significant. However, E. coli was strongly inhibited by the Roselle water extract at concentrations of 25 and 50 mg mL(-1) as determined by a paper disc method. CONCLUSION: The obtained results indicated that antioxidant and antimicrobial activity was related to different methods of extraction and Roselle extracts could be a source of therapeutically useful products. PMID- 23749747 TI - The Human Eye Proteome Project: perspectives on an emerging proteome. AB - There are an estimated 285 million people with visual impairment worldwide, of whom 39 million are blind. The pathogenesis of many eye diseases remains poorly understood. The human eye is currently an emerging proteome that may provide key insight into the biological pathways of disease. We review proteomic investigations of the human eye and present a catalogue of 4842 nonredundant proteins identified in human eye tissues and biofluids to date. We highlight the need to identify new biomarkers for eye diseases using proteomics. Recent advances in proteomics do now allow the identification of hundreds to thousands of proteins in tissues and fluids, characterization of various PTMs and simultaneous quantification of multiple proteins. To facilitate proteomic studies of the eye, the Human Eye Proteome Project (HEPP) was organized in September 2012. The HEPP is one of the most recent components of the Biology/Disease-driven Human Proteome Project (B/D-HPP) whose overarching goal is to support the broad application of state-of-the-art measurements of proteins and proteomes by life scientists studying the molecular mechanisms of biological processes and human disease. The large repertoire of investigative proteomic tools has great potential to transform vision science and enhance understanding of physiology and disease processes that affect sight. PMID- 23749749 TI - Boron-substituted 1,3-dihydro-1,3-azaborines: synthesis, structure, and evaluation of aromaticity. AB - Getting the family together: A general synthetic strategy based on nucleophilic substitution provided B-substituted 1,3-dihydro-1,3-azaborines (see scheme), BN isosteres of arenes with potential for application in biomedicine and materials science. Experimental structural analysis and calculations suggest that the aromaticity of the 1,3-dihydro-1,3-azaborine heterocycle is intermediate between that of benzene and that of 1,2-dihydro-1,2-azaborine. PMID- 23749750 TI - Long-term effects of beraprost sodium on arteriosclerosis obliterans: a single center retrospective study of Japanese patients. AB - INTRODUCTION: Arteriosclerosis obliterans (ASO) causes ischemic symptoms of the lower limbs, reducing quality of life (QOL), and has a poor prognosis. Early diagnosis and treatment are necessary. In this study, the effects of long-term administration of beraprost sodium (beraprost) to treat ASO were investigated. METHODS: One hundred and eighty eight patients treated with beraprost for >=1 year were retrospectively identified. Outcomes were lower limb ischemic symptoms, carotid intima/media thickness (IMT), and cardiovascular events. Patients reported visual analog scale scores for major symptoms at baseline and after 3, 6, and 12 months of treatment. RESULTS: Overall, 188 patients (mean age 70.8 +/- 10.15 years, Fontaine classification: grade I 14.4%, grade II 85.6%) treated with beraprost for 2.4-10.7 years (mean 6.5 years) were included in this study. Administration of beraprost significantly reduced patient-reported severity of lower limb ischemic symptoms in all patients at 12 months, including those with diabetes, hypertension, or dyslipidemia. IMT decreased from 1.09 +/- 0.09 mm at baseline to 1.04 +/- 0.11 mm at 12 months (P < 0.001). Decreases in IMT were similar in patients with diabetes, hypertension, or dyslipidemia. Overall, 26 (13.8%) events occurred during a mean follow-up of 6.5 years, including 23 cardiovascular events (unstable angina in three patients, myocardial infarction in six patients, cerebral infarction in eight patients, and transient cerebral ischemic attack in six patients) and non-cardiovascular death in three patients. Beraprost at 120 MUg/day significantly reduced the risk of ischemic symptoms compared with <120 MUg/day (adjusted hazard ratio: 0.17; 95% confidence interval: 0.06, 0.45; P < 0.001). No severe adverse events or adverse events requiring dose reductions/discontinuation occurred during long-term administration of beraprost. CONCLUSION: Beraprost reduced lower limb ischemic symptoms, IMT, and the incidence of cardiovascular events in patients with ASO. PMID- 23749752 TI - Using the iPlant collaborative discovery environment. AB - The iPlant Collaborative is an academic consortium whose mission is to develop an informatics and social infrastructure to address the "grand challenges" in plant biology. Its cyberinfrastructure supports the computational needs of the research community and facilitates solving major challenges in plant science. The Discovery Environment provides a powerful and rich graphical interface to the iPlant Collaborative cyberinfrastructure by creating an accessible virtual workbench that enables all levels of expertise, ranging from students to traditional biology researchers and computational experts, to explore, analyze, and share their data. By providing access to iPlant's robust data-management system and high-performance computing resources, the Discovery Environment also creates a unified space in which researchers can access scalable tools. Researchers can use available Applications (Apps) to execute analyses on their data, as well as customize or integrate their own tools to better meet the specific needs of their research. These Apps can also be used in workflows that automate more complicated analyses. This module describes how to use the main features of the Discovery Environment, using bioinformatics workflows for high throughput sequence data as examples. PMID- 23749753 TI - An introduction to sequence similarity ("homology") searching. AB - Sequence similarity searching, typically with BLAST, is the most widely used and most reliable strategy for characterizing newly determined sequences. Sequence similarity searches can identify "homologous" proteins or genes by detecting excess similarity- statistically significant similarity that reflects common ancestry. This unit provides an overview of the inference of homology from significant similarity, and introduces other units in this chapter that provide more details on effective strategies for identifying homologs. PMID- 23749754 TI - Phylogenetic analysis with the iPlant discovery environment. AB - The iPlant Collaborative's Discovery Environment is a unified Web portal to many bioinformatics applications and analytical workflows, including various methods of phylogenetic analysis. This unit describes example protocols for phylogenetic analyses, starting at sequence retrieval from the GenBank sequence database, through to multiple sequence alignment inference and visualization of phylogenetic trees. Methods for extracting smaller sub-trees from very large phylogenies, and the comparative method of continuous ancestral character state reconstruction based on observed morphology of extant species related to their phylogenetic relationships, are also presented. PMID- 23749755 TI - Creating databases for biological information: an introduction. AB - The essence of bioinformatics is dealing with large quantities of information. Whether it be sequencing data, microarray data files, mass spectrometric data (e.g., fingerprints), the catalog of strains arising from an insertional mutagenesis project, or even large numbers of PDF files, there inevitably comes a time when the information can simply no longer be managed with files and directories. This is where databases come into play. This unit briefly reviews the characteristics of several database management systems, including flat file, indexed file, relational databases, and NoSQL databases. It compares their strengths and weaknesses and offers some general guidelines for selecting an appropriate database management system. PMID- 23749751 TI - Towards incorporating epigenetic mechanisms into carcinogen identification and evaluation. AB - Remarkable progress in the field of epigenetics has turned academic, medical and public attention to the potential applications of these new advances in medicine and various fields of biomedical research. The result is a broader appreciation of epigenetic phenomena in the a etiology of common human diseases, most notably cancer. These advances also represent an exciting opportunity to incorporate epigenetics and epigenomics into carcinogen identification and safety assessment. Current epigenetic studies, including major international sequencing projects, are expected to generate information for establishing the 'normal' epigenome of tissues and cell types as well as the physiological variability of the epigenome against which carcinogen exposure can be assessed. Recently, epigenetic events have emerged as key mechanisms in cancer development, and while our search of the Monograph Volume 100 revealed that epigenetics have played a modest role in evaluating human carcinogens by the International Agency for Research on Cancer (IARC) Monographs so far, epigenetic data might play a pivotal role in the future. Here, we review (i) the current status of incorporation of epigenetics in carcinogen evaluation in the IARC Monographs Programme, (ii) potential modes of action for epigenetic carcinogens, (iii) current in vivo and in vitro technologies to detect epigenetic carcinogens, (iv) genomic regions and epigenetic modifications and their biological consequences and (v) critical technological and biological issues in assessment of epigenetic carcinogens. We also discuss the issues related to opportunities and challenges in the application of epigenetic testing in carcinogen identification and evaluation. Although the application of epigenetic assays in carcinogen evaluation is still in its infancy, important data are being generated and valuable scientific resources are being established that should catalyse future applications of epigenetic testing. PMID- 23749756 TI - Identification of lactic acid bacteria in salted Chinese cabbage by SDS-PAGE and PCR-DGGE. AB - BACKGROUND: Lactic acid bacteria (LAB) in salted Chinese cabbage, the main ingredient of kimchi, were analyzed by culture-dependent sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), followed by sequencing of the 16S rRNA gene and by culture-independent polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE), followed by sequencing of the V3 region of the 16S rRNA gene. The results were compared to those of LAB that had previously been found in kimchi. RESULTS: The two identification methods produced distinct overall LAB profiles. The PCR-DGGE method detected a more diverse microflora, including non-LAB strains. The culture-dependent method uniquely detected Weissella sp. and was able to provide the quantitative distribution of LAB in samples. However, Leuconostoc mesenteroides, Lactobacillus curvatus and Leuconostoc carnosum, which had also been reported as the dominant LAB in kimchi in previous studies, were identified by both methods. CONCLUSION: The two identification methods gave different bacterial profiles, while both methods were sufficient to identify the most prevalent LAB in salted Chinese cabbage samples. The quantitative feature of the culture-dependent identification method would make it preferable for studying and monitoring LAB viability in kimchi at each fermentation stage. The availability of the culture-independent identification method to identify a broader bacterial profile, including non-LAB, would make it a more effective tool for controlling contamination of undesirable bacteria during kimchi fermentation. PMID- 23749757 TI - Construction of a novel oligonucleotide array-based transcription factor interaction assay platform and its uses for profiling STAT1 cofactors in mouse fibroblast cells. AB - Here, we describe a novel oligonucleotide array-based transcription factor (TF) interaction assay platform that can directly identify cointeracting TF complexes following binding to their regulatory DNA elements. This platform that combines immuno-coprecipitation technology with our previously reported oligonucleotide array-based TF assay (OATFA), is named targeted immuno-coprecipitation OATFA (TIC OATFA). We illustrate use of the system to identify interaction partners of STAT1 (signal transducer and activator of transcription proteins 1) in mouse fibroblasts. Several previously known partners of STAT1, as well as new partners, were identified by TIC-OATFA, including the upstream stimulatory factors 1 and 2 (USF1, USF2), nuclear factor of activated T cells, TATA box-binding protein, nuclear factor erythroid-derived 2, nuclear factor-kappa B, and nuclear factor 1. Both USF1 and nuclear factor-kappa B are well known to interact with STAT1, but the other five TFs are previously unreported STAT1 interaction partners. We examined interactions between one new TF, USF2, and STAT1 in detail. USF2 belongs to the group of bHLH-zip transcription factors, which in a number of diseases including cancers, has enhanced activity. In summary, a novel oligonucleotide array-based assay platform was developed and used to study interactions between STAT1 and functional TF binding partners, revealing that USF2 and potentially four other new TFs are partners of STAT1 in an IFN-gamma stimulated mouse fibroblast cell line. PMID- 23749758 TI - Forming of polymer nanofibers by a pressurised gyration process. AB - A new route consisting of simultaneous centrifugal spinning and solution blowing to form polymer nanofibers is reported. The fiber diameter (60-1000 nm) is shown to be a function of polymer concentration, rotational speed, and working pressure of the processing system. The fiber length is dependent on the rotational speed. The process can deliver 6 kg of fiber per hour and therefore offers mass production capabilities compared with other established polymer nanofiber generation methods such as electrospinning, centrifugal spinning, and blowing. PMID- 23749759 TI - Knockdown of PU.1 AS lncRNA inhibits adipogenesis through enhancing PU.1 mRNA translation. AB - PU.1 is an Ets family transcription factor involved in the myelo-lymphoid differentiation. We have previously demonstrated that PU.1 is also expressed in the adipocyte lineage. However, the expression levels of PU.1 mRNA and protein in preadipocytes do not match the levels in mature adipocytes. PU.1 mRNA level is higher in preadipocytes, whereas its protein is expressed in the adipocytes but not in the preadipocytes. The underlying mechanism remains elusive. Here, we find that miR-155 knockdown or overexpression has no effect on the levels of PU.1 mRNA and protein in preadipocytes or adipocytes. MiR-155 regulates adipogenesis not through PU.1, but via C/EBPbeta which is another target of miR-155. We also checked the expression levels of PU.1 mRNA and antisense long non-coding RNA (AS lncRNA). Interestingly, compared with the level of PU.1 mRNA, the level of PU.1 AS lncRNA is much higher in preadipocytes, whereas it is opposite in the adipocytes. We further discover that PU.1 AS lncRNA binds to its mRNA forming an mRNA/AS lncRNA compound. The knockdown of PU.1 AS by siRNA inhibits adipogenesis and promotes PU.1 protein expression in both preadipocytes and adipocytes. Furthermore, the repression of PU.1 AS decreases the expression and secretion of adiponectin. We also find that the effect of retroviral-mediated PU.1 AS knockdown on adipogenesis is consistent with that of PU.1 AS knockdown by siRNA. Taken together, our results suggest that PU.1 AS lncRNA promotes adipogenesis through preventing PU.1 mRNA translation via binding to PU.1 mRNA to form mRNA/AS lncRNA duplex in preadipocytes. PMID- 23749760 TI - A comparison of thiolated and disulfide-crosslinked polyethylenimine for nonviral gene delivery. AB - Branched polyethylenimine (25 kDa) is thiolated and compared with redox-sensitive crosslinked derivatives. Both polymers thiol contents are assessed; the thiolated polymers have 390-2300 mmol SH groups/mol, whereas the crosslinked polymers have lower thiol contents. Cytotoxicity assays show that both modified polymers give lower hemolysis than unmodified PEI. Increased thiol content increases gene transfer efficiency but also elevates cytotoxicity. Crosslinking improves plasmid DNA condensation and enhances transfection efficiency, but extensive crosslinking overstabilizes the polyplexes and decreases transfection, emphasizing the need to balance polyplex stabilization and unpacking. Thus, at low levels of crosslinking, 25 kDa PEI can be an efficient redox-sensitive carrier system. PMID- 23749761 TI - Effects of pravastatin on angiogenic and placental hypoxic imbalance in a mouse model of preeclampsia. AB - In order to determine the effects of pravastatin (Pra) on angiogenic and placental hypoxic imbalance in a model of preeclampsia induced by overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), we randomly allocated pregnant CD1 mice to injection with adenovirus-carrying sFlt-1 or mFc (control). The sFlt 1 group received either Pra (sFlt-1 + Pra) or water (sFlt-1). Mice were sacrificed at day 18, and serum levels of sFlt-1 and soluble endoglin (sEng) were measured. Placental expression of placental (PLGF) and vascular endothelial (VEGF) growth factors and other markers of angiogenesis and hypoxia were assayed. We observed that Pra treatment in sFlt-1 mice reduced sFlt-1 and sEng concentrations at day 18 to levels similar to control group. Placental PLGF and VEGF expression were upregulated, and markers of hypoxia downregulated to levels similar to control group. Hence, Pra prevents the rise in circulating antiangiogenic factors in a mouse model of preeclampsia. Statins may represent a novel approach to prevention of preeclampsia. PMID- 23749762 TI - Impact of lycopene on epididymal androgen and estrogen receptors' expression in polychlorinated biphenyls-exposed rat. AB - The aim of the study was to evaluate the androgen (AR) and estrogen receptors' (ER) expression in epididymis of polychlorinated biphenyls (PCBs)-exposed rats. The rats were assigned to groups. Group I controls were treated with corn oil 80 uL/d intraperitoneally (ip), group II were treated with 2 mg/kg/d of A1254 ip; and group III were treated with 2 mg/kg/d of A1254 ip along with simultaneous oral supplementation of 4 mg/kg/d lycopene . The treatment was given daily for 30 days. After 24 hours of treatment, the rats were killed, and the epididymal regions (caput, corpus, and cauda) were dissected out, weighed, and prepared to estimate the levels of sialic acid, glyceryl phosphoryl choline (GPC), hydrogen peroxide (H2O2), and lipid peroxidation (LPO). The messenger RNA (mRNA) expressions of AR, ERalpha, and ERbeta were analyzed by reverse transcriptase polymerase chain reaction, and ERalpha and ERbeta protein expressions were analyzed by immunoblotting. The toxicity of PCBs was also confirmed by histology. There was a marked decrease in epididymal weight, sialic acid, and GPC levels, while oxidative stress markers H2O2 and LPO were increased in PCBs-treated rats. The mRNA and protein expression of AR, ERalpha, and ERbeta were decreased in PCBs treated groups, and the histology confirms the cytoplasmic damage in the regions of caput, corpus, and cauda in PCBs-treated rats. Simultaneous supplementation of lycopene to PCBs-exposed rats resulted in significant decrease in the oxidative stress markers as that of control, while the AR, ERalpha, and ERbeta gene expressions were near to control. The results suggest that lycopene has ameliorative effect against PCBs-induced toxicity in epididymis. PMID- 23749763 TI - The interplay of the interleukin 1 system in pregnancy and labor. AB - This work assessed the temporal coexpression of interleukin 1 (IL-1) and its inhibitor, IL-1 receptor antagonist (IL-1ra), in the cervicovaginal fluid (CVF) beyond 24 weeks gestation including women in spontaneous term labor. Two cohorts of women were recruited at 24 to 35 weeks' gestation (n = 65) and in late pregnancy (>36 weeks' gestation; n = 88). The CVF was serially collected either every 4 weeks between 24 and 35 weeks' gestation (n = 123 samples) or weekly during late pregnancy (n = 240 samples). The IL-1 and IL-1ra were quantitated by enzyme-linked immunosorbent assay, and the effect of vaginal microflora and unprotected sexual intercourse were also investigated. The IL-1beta and IL-1ra remain unaltered between 24 and 35 weeks' gestation. At late pregnancy, IL-1alpha and beta concentrations peak at 4 to 14 days prior to labor onset, while IL-1ra decreases with approaching spontaneous term labor (P < .05, 2-way analysis of variance). The IL-1 and IL-1ra were significantly correlated (P < .001, Pearson r). A combined biomarker model of IL-1alpha, IL-1beta, and IL-1ra can predict term labor with 86% sensitivity and 92% specificity. This study indicates a shifting inflammatory balance in the gestational tissues prior to labor onset. PMID- 23749764 TI - Influence of ovarian endometrioma on expression of steroid receptor RNA activator, estrogen receptors, vascular endothelial growth factor, and thrombospondin 1 in the surrounding ovarian tissues. AB - This study investigates the influence of ovarian endometrioma on expression of steroid receptor RNA activator (SRA), estrogen receptors (ERs), vascular endothelial growth factor (VEGF), and thrombospondin 1 (TSP-1) in the surrounding ovarian tissues. Taken from the women with ovarian endometrioma and mature teratoma during laparoscopy, the biopsies were analyzed by real-time polymerase chain reaction and Western blot. Our results indicated that ovarian tissues surrounding endometrioma had lower SRA and ER-alpha levels but higher SRA protein (SRAP) and ER-beta levels than ovarian endometrioma. With lower VEGF levels and higher TSP-1 levels, the surrounding ovarian tissues showed higher expression levels of SRA, SRAP, ER-alpha, and ER-beta in the ovarian endometrioma group when compared to the controls. These data showed that ovarian endometrioma increases SRA, ERs, and TSP-1 but decreases VEGF levels in the surrounding ovarian tissues, suggesting that abnormal expression of these molecules may affect biological behaviors of ovarian endometrioma. PMID- 23749765 TI - High-throughput evaluation method for drug association with pregnane X receptor (PXR) using differential scanning fluorometry. AB - The pregnane xenobiotic receptor (PXR) is a key transcriptional regulator of cytochrome P450 (CYP) 3A, a crucial enzyme in the metabolism and detoxification of xenobiotics and endobiotics. PXR is activated by a wide variety of chemicals and serves as a master regulator of detoxification in mammals. Here, we report a fast evaluation method for PXR-drug interactions using differential scanning fluorometry (DSF). DSF analysis revealed that PXR associates with a fluorescence dye in the native state as well as in the unfolded state, which prevented precise evaluation of any shift in the transition midpoint (DeltaT (m)) due to association with a drug. Hence, we defined a new parameter, (dF/dT)(50), where F is fluorescence intensity and T is temperature, to describe the ligand concentration. (dF/dT)(50) exhibited better correlation with EC(50) (r(2) = 0.84) than with DeltaT m (r(2) = 0.71). The correlation of DeltaT m measured using differential scanning calorimetry (DSC) with EC(50) (r(2) = 0.86) was similar to the above (dF/dT)(50) correlation. Therefore, the use of (dF/dT)(50) enables DSF to be used for the rapid evaluation of PXR-drug interactions and could provide prescreening to narrow down the collection of candidate ligands that most likely result in transcriptional activation of CYP3A4. PMID- 23749766 TI - Designer xanthone: an inhibitor scaffold for MDR-involved human glutathione transferase isoenzyme A1-1. AB - Glutathione transferases (GSTs) are cell detoxifiers involved in multiple drug resistance (MDR), hampering the effectiveness of certain anticancer drugs. To our knowledge, this is the first report on well-defined synthetic xanthones as GST inhibitors. Screening 18 xanthones revealed three derivatives bearing a bromomethyl and a methyl group (7) or two bromomethyl groups (8) or an aldehyde group (17), with high inhibition potency (>85%), manifested by low IC(50) values (7: 1.59 +/- 0.25 uM, 8: 5.30 +/- 0.30 uM, and 17: 8.56 +/- 0.14 uM) and a competitive modality of inhibition versus CDNB (Ki(7) = 0.76 +/- 0.18 and Ki(17) = 1.69 +/- 0.08 uM). Of them, derivative 17 readily inhibited hGSTA1-1 in colon cancer cell lysate (IC(50) = 10.54 +/- 2.41 uM). Furthermore, all three derivatives were cytotoxic to Caco-2 intact cells, with 17 being the least cytotoxic (LC(50) = 151.3 +/- 16.3 uM). The xanthone scaffold may be regarded as a pharmacophore for hGSTA1-1 and the three derivatives, especially 17, as potent precursors for the synthesis of new inhibitors and conjugate prodrugs for human GSTs. PMID- 23749767 TI - Cytologic features of lipid-rich variant of pancreatic endocrine tumor-report of two cases with literature review. AB - Pancreatic endocrine tumor (PET) is an uncommon neoplasm of the pancreas with distinct cytomorphologic features. Lipid-rich PET, a rare variant, histologically deviates from that of a conventional PET. There is only one case report of the cytologic features of this rare entity in the literature. We report two cases of lipid-rich PETs diagnosed by endoscopic ultrasound-guided FNA biopsy. Case 1 showed large aggregates, small clusters, and single cells with plasmacytoid appearance, small uniform nuclei, coarse chromatin, and prominent nucleoli. Abundant distinct small cytoplasmic vacuoles were present in almost all tumor cells and the background was clean. Case 2 showed flat cohesive sheets of medium sized uniform cells with indistinct plasmacytoid appearance, uniform nuclei, fine and evenly distributed chromatin, and inconspicuous nucleoli. Distinct small cytoplasmic vacuoles were seen only focally. Immunohistochemical stains in cell blocks of both cases confirmed the diagnosis of PET. Lipid-rich PET may be misinterpreted on cytology specimens if the pathologist is not aware of this rare entity since it mimics clear cell carcinoma of the kidney, adrenal cortical neoplasm, or adenocarcinoma of the pancreas. PMID- 23749768 TI - Development of a rapid chemiluminescent ciELISA for simultaneous determination of florfenicol and its metabolite florfenicol amine in animal meat products. AB - BACKGROUND: A rapid one-step chemiluminescent competitive indirect enzyme-linked immunosorbent assay (CL-ciELISA) for florfenicol (FF) and its major metabolite florfenicol amine (FFA) residues in animal meat products has been developed. RESULTS: The 50% binding inhibition (IC50) values of the method were 0.195 ug kg 1 for FFA and 0.24 ug kg-1 for FF under optimum conditions. The cross-reactive rates for FF and FFA were 100.0% and 81.2%, respectively. FF and FFA were easily extracted from animal meat product with an FF/FFA extraction buffer, obtaining recoveries of 81.8-92.0% (FF) and 77.2-100% (FFA). The whole one-step CL-ciELISA test can be accomplished within 40 min in theory. The detection limits (LODs) of the assay were 0.98 ug kg-1 for FF and 0.80 ug kg-1 for FFA in animal meat samples. Finally, field animal meat samples were analyzed with the CL-ciELISA method, and the results correlated well with those obtained using traditional ELISA and a previously reported liquid chromatographic-tandem mass spectrometric method. CONCLUSION: The combined results confirmed the utility of this faster one step CL-ciELISA for simultaneous trace analysis of FF and FFA. To date, this is the most rapid developed ELISA and CL-ELISA method for detection of FF and FFA. PMID- 23749769 TI - Adding sentence types to a model of syntactic category acquisition. AB - The acquisition of syntactic categories is a crucial step in the process of acquiring syntax. At this stage, before a full grammar is available, only surface cues are available to the learner. Previous computational models have demonstrated that local contexts are informative for syntactic categorization. However, local contexts are affected by sentence-level structure. In this paper, we add sentence type as an observed feature to a model of syntactic category acquisition, based on experimental evidence showing that pre-syntactic children are able to distinguish sentence type using prosody and other cues. The model, a Bayesian Hidden Markov Model, allows for adding sentence type in a few different ways; we find that sentence type can aid syntactic category acquisition if it is used to characterize the differences in word order between sentence types. In these models, knowledge of sentence type permits similar gains to those found by extending the local context. PMID- 23749770 TI - The expanding role of cytopathology in the diagnosis of HPV-related squamous cell carcinoma of the head and neck. AB - Confirmation of human papillomavirus (HPV) as a causative agent for a subset of biologically and clinically distinct squamous cell carcinomas of the head and neck (HNSCC) has resulted in a growing need and expectation for HPV testing of head and neck cancers. At the same time, opportunities to obtain tissue samples for HPV testing are diminishing: The sensitivity of HPV-related HNSCC to chemotherapy and ionizing radiation has limited the role of surgical resection, and diagnostic tissue biopsies/resections may not be available in a substantial portion of patients with small or occult primaries. Into this quandary steps the cytopathologist. Fine needle aspirates of metastatic HNSCCs and brushes of oropharyngeal cancers provide a valuable substrate for HPV analysis. These cytologic specimens are suitable for standard tissue-based methods of HPV detection such as immunoperoxidase and in situ hybridization, but the expanding demands for biomarker analysis of these limited samples is driving the development of alternative assays that eliminate the requirement for high cellularity and complex specimen processing. Various liquid phase assays already in widespread use for HPV analysis of cervical cancer risk may be directly transferrable to the head and neck context. Implementation of these assays may abrogate the current need for tissue acquisition of HNSCCs via a more aggressive surgical procedure. PMID- 23749771 TI - Nuclear karyopherin-alpha2 expression in primary lesions and metastatic lymph nodes was associated with poor prognosis and progression in gastric cancer. AB - Karyopherin-alpha2 (KPNA2) functions as an adaptor that transports several proteins to the nucleus. We investigated the clinical and functional significance of KPNA2 in gastric cancer (GC). Immunohistochemistry was performed to examine KPNA2 expression in primary GC and metastatic lymph nodes. Next, KPNA2 was suppressed by small interfering RNA (siRNA) to examine KPNA2 function in proliferation and cisplatin-induced apoptosis of GC cell lines. Nuclear expression of KPNA2 in marginal regions of primary GC was stronger than in central regions of GC and normal tissues. The high expression of marginal KPNA2 was significantly associated with beta-catenin accumulation in the nucleus and poor prognosis in two independent GC cohorts (discovery cohort, n = 90, P = 0.018; validation cohort, n = 89, P = 0.0125). We detected correlations between nuclear KPNA2 expression in marginal region and progression of macroscopic type (P = 0.036), tumor depth (P = 0.013), lymph node metastasis (P = 0.0064), venous invasion (P = 0.034) and clinical stage (P = 0.0006). Nuclear KPNA2 expression in marginal regions of metastatic lymph nodes was significantly higher than in the central region. It was associated with poor survival of GC patients with lymph node metastasis (n = 96; center, P = 0.4384; marginal, P < 0.0001). KPNA2 suppression enhanced cisplatin-induced apoptosis and reduced proliferation in the KPNA2 siRNA group compared with the control siRNA group. The expression of the DNA repair gene NBS1 (NBN) in the nucleus was suppressed in KPNA2-suppressed cells. KPNA2 might be a useful prognostic marker and an effective therapeutic target for GC. PMID- 23749772 TI - A functional BRCA1 coding sequence genetic variant contributes to risk of esophageal squamous cell carcinoma. AB - As a tumor suppressor, breast cancer susceptibility gene 1 (BRCA1) plays a pivotal role in maintaining genomic stability. A functional rs799917 T>C polymorphism located in the BRCA1 coding sequence could influence miR-638 mediated regulation of BRCA1 expression. Therefore, we examined the association between this polymorphism and esophageal squamous cell carcinoma (ESCC) risk as well as its biological function. Genotypes were determined in two independent case-control studies consisted of 1128 ESCC patients and 1150 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. The allele-specific regulation on BRCA1 expression by the polymorphism was investigated in vitro and in vivo. We found that the BRCA1 rs799917 CC genotype was significantly associated with increased ESCC risk compared with the TT genotype in both studies (Jinan population: OR = 1.28, 95% CI = 1.04-1.58, P = 0.020; Huaian population: OR = 1.46, 95% CI = 1.17-1.83, P = 0.001). Stratified analyses with pooled data indicated that a multiplicative interaction between rs799917 and smoking or drinking in intensifying ESCC risk was evident (gene-smoking: P interactio n = 5.8 * 10(-5); gene-drinking: P interaction = 7.1 * 10(-7)). In vitro experiments indicate that miR-638 could negatively regulate BRCA1 expression and enhance proliferation of ESCC cells. In vivo BRCA1 messenger RNA expression analyses showed that the rs799917 C allele carriers had significantly decreased BRCA1 expression in both normal and cancerous esophagus tissues compared with T allele carriers, suggesting that lower BRCA1 expression may lead to higher risk for malignant transformation of esophagus cells. These results suggest that BRCA1 functional rs799917 polymorphism is involved in susceptibility to developing ESCC, alone and in a gene-environment interaction manner. PMID- 23749773 TI - Using the Common Sense Model of Self-regulation to review the effects of self monitoring of blood glucose on glycemic control for non-insulin-treated adults with type 2 diabetes. AB - PURPOSE: This systematic review examined the relationship between self-monitoring of blood glucose (SMBG) and glycemic control in patients with type 2 diabetes. The Common Sense Model of Self-Regulation (CSM) served as a theoretical framework for examining how, when (mediators), and for whom (moderators) SMBG improved glycemic control. DATA SOURCES: Five databases were searched: Medline, PsychInfo, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing & Allied Health Literature. STUDY SELECTION: Included studies had cross-sectional, longitudinal, or randomized controlled trial designs; were published between 2007 and 2011; and included patients with type 2 diabetes at least some of whom were not taking insulin; 1318 studies were screened, 119 were reviewed in detail, and 26 were included. DATA EXTRACTION: Data were collected on the relationship between SMBG and glycemic control, study design, mediators, moderators, participant characteristics, the CSM, and limitations. DATA SYNTHESIS: Twenty-six studies met criteria for inclusion: 11 cross-sectional, 4 longitudinal, and 11 randomized controlled trials. The results of the cross-sectional studies were inconclusive. Results from the longitudinal studies and randomized control trials suggested that SMBG may improve glycemic control. The few studies investigating mediators or moderators reported mixed results. Few studies effectively measured the CSM. CONCLUSION: Data suggested that SMBG may help improve glycemic control. Future trials must be designed to test hypotheses and improve our understanding of when, how, and for whom SMBG can enhance glycemic control. Rigorously controlled repetitions of current 2-arm trials will yield little new knowledge of theoretical or practical value. PMID- 23749775 TI - Did Christianity lead to schizophrenia? Psychosis, psychology and self reference. AB - Both geographically and historically, schizophrenia may have emerged from a psychosis that was more florid, affective, labile, shorter lived and with a better prognosis. It is conjectured that this has occurred with a reflexive self consciousness in Western and globalising societies, a development whose roots lie in Christianity. Every theology also presents a psychology. Six novel aspects of Christianity may be significant for the emergence of schizophrenia-an omniscient deity, a decontexualised self, ambiguous agency, a downplaying of immediate sensory data, and a scrutiny of the self and its reconstitution in conversion. PMID- 23749774 TI - Evaluation of a community health worker pilot intervention to improve diabetes management in Bangladeshi immigrants with type 2 diabetes in New York City. AB - PURPOSE: The purpose of this study is to explore the impact and feasibility of a pilot Community Health Worker (CHW) intervention to improve diabetes management among Bangladeshi-American individuals with type 2 diabetes living in New York City. METHODS: Participants were recruited at clinic- and community-based venues. The intervention consisted of 6 monthly, CHW-facilitated group sessions on topics related to management of diabetes. Surveys were collected at baseline and follow up time points. Study outcomes included clinical, behavioral, and satisfaction measures for participants, as well as qualitative measures from CHWs. RESULTS: Improvements were seen in diabetes knowledge, exercise and diet to control diabetes, frequency of checking feet, medication compliance, and self-efficacy of health and physical activity from baseline to 12 months. Additionally, there were decreases in A1C, weight, and body mass index. Program evaluation revealed a high acceptability of the intervention, and qualitative findings indicated that CHWs helped overcome barriers and facilitated program outcomes through communal concordance, trust, and leadership. CONCLUSIONS: The intervention demonstrated high acceptability and suggested efficacy in improving diabetes management outcomes among Bangladeshi immigrants in an urban setting. The US Bangladeshi population will continue to increase, and given the high rates of diabetes, as well as linguistic and economic barriers faced by this community, effective and culturally tailored health interventions are needed to overcome barriers and provide support for diabetes management. PMID- 23749776 TI - Interaction of NADPH oxidase 1 with Toll-like receptor 2 induces migration of smooth muscle cells. AB - AIMS: NADPH oxidase (Nox) isozymes that generate intracellular reactive oxygen species (ROS) and Toll-like receptor 2 (TLR2), an inflammatory mediator, are both involved in the development of atherosclerotic lesions. To identify the molecular connection between TLR2 and Nox isozymes in vascular remodelling, we analysed generation of ROS and pro-inflammatory cytokines in aortic smooth muscle cells from Nox1-deficient mice in response to the synthetic triacylated lipoprotein Pam3CSK, a TLR2 agonist. METHODS AND RESULTS: We showed that TLR2 signalling stimulates progression of the pro-inflammatory phenotype in mouse aortic smooth muscle cells (MASMCs) through activation of Nox1. We demonstrated the interaction of TLR2 with Nox1 using yeast two-hybrid and co-immunoprecipitation assays. MASMCs from Nox1-deficient mice failed to generate of ROS in response to Pam3CSK4, indicating that Nox1 is essential for TLR2-dependent production of ROS. We also found that Pam3CSK4 stimulated migration of MASMCs from wild-type mice in a Transwell system, but MASMCs from Nox1-deficient mice failed to show this response. Wild-type MASMCs produced matrix metalloprotease 2 in response to Pam3CSK4, whereas Nox1-deficient MASMCs failed to generate this protease. Moreover, stimulation of MASMCs with Pam3CSK4 resulted in increased expression of the pro-inflammatory cytokine macrophage inflammatory protein 2 in a Nox1 dependent manner, leading to enhanced monocyte-endothelial cell adhesion and trans-endothelial migration of U937 cells. CONCLUSION: These data suggest that Nox1 plays an important role in TLR2-mediated intracellular H2O2 generation, activation of matrix metalloprotease 2, and secretion of pro-inflammatory cytokines, which in turn stimulate MASMC migration and vascular remodelling. PMID- 23749778 TI - Long-term efficacy of percutaneous mitral commissurotomy for recurrent mitral stenosis. PMID- 23749777 TI - NQO1 activation regulates angiotensin-converting enzyme shedding in spontaneously hypertensive rats. AB - AIMS: Angiotensin-converting enzyme (ACE) plays a key role in blood pressure (BP) homeostasis via regulation of angiotensin II. Active ACE ectodomain is enzymatically cleaved and released into body fluids, including plasma, and elevated plasma ACE levels are associated with increased BP. beta-lapachone (betaL) has been shown to increase cellular NAD(+)/NADH ratio via activation of NAD(P)H:quinone oxidoreductase 1 (NQO1). In this study, we evaluated whether NQO1 activation by betaL modulates BP through regulation of ACE shedding in an animal model of hypertension. METHODS AND RESULTS: Spontaneously hypertensive rats (SHR) and a human ACE-overexpressing rat lung microvascular endothelial cell line (RLMVEC-hACE) were used to investigate the mechanism by which betaL exerts a hypotensive effect. In vitro studies revealed that betaL significantly increased intracellular Ca(2+) ([Ca(2+)]i) levels and CaMKII Thr(286) phosphorylation, followed by diminished ACE cleavage secretion into culture media. Inhibition of betaL-induced [Ca(2+)]i level changes through intracellular Ca(2+) chelation, Nqo1-specific siRNA or ryanodine receptor blockade abolished not only betaL induced increase in [Ca(2+)]i levels and CaMKII phosphorylation, but also betaL mediated decrease in ACE shedding. The effect of betaL on ACE shedding was also blocked by inhibition of CaMKII. In SHR, betaL reduced BP following increase of CaMKII Thr(286) phosphorylation in the lung and decrease of ACE activity and angiotensin II levels in plasma. CONCLUSION: This is the first study demonstrating that ACE shedding is regulated by NQO1 activation, which is possibly correlated with relieving hypertension in SHR. These findings provide strong evidence suggesting that NQO1 might be a new target for ACE modulation and BP control. PMID- 23749779 TI - Assessment of valve haemodynamics, reverse ventricular remodelling and myocardial fibrosis following transcatheter aortic valve implantation compared to surgical aortic valve replacement: a cardiovascular magnetic resonance study. AB - OBJECTIVE: To compare the effects of transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) on aortic valve haemodynamics, ventricular reverse remodelling and myocardial fibrosis (MF) by cardiovascular magnetic resonance (CMR) imaging. DESIGN: A 1.5 T CMR scan was performed preoperatively and 6 months postoperatively. SETTING: University hospitals of Leeds and Leicester, UK. PATIENTS: 50 (25 TAVI, 25 SAVR; age 77+/-8 years) high-risk severe symptomatic aortic stenosis (AS) patients. MAIN OUTCOME MEASURES: Valve haemodynamics, ventricular volumes, ejection fraction (EF), mass and MF. RESULTS: Patients were matched for gender and AS severity but not for age (80+/-6 vs 73+/-7 years, p=0.001) or EuroSCORE (22+/-14 vs. 7+/-3, p<0.001). Aortic valve mean pressure gradient decreased to a greater degree post-TAVI compared to SAVR (21+/-8 mm Hg vs. 35+/-13 mm Hg, p=0.017). Aortic regurgitation reduced by 8% in both groups, only reaching statistical significance for TAVI (p=0.003). TAVI and SAVR improved (p<0.05) left ventricular (LV) end-systolic volumes (46+/-18 ml/m2 vs. 41+/-17 ml/m2; 44+/-22 ml/m2 vs. 32+/-6 ml/m2 and mass (83+/-20 g/m2 vs. 65+/-15 g/m2; 74+/-11 g/m2 vs. 59+/-8 g/m2). SAVR reduced end diastolic volumes (92+/-19 ml/m2 vs. 74+/-12 ml/m2, p<0.001) and TAVI increased EF (52+/-12% vs. 56+/-10%, p=0.01). MF reduced post-TAVI (10.9+/-6% vs. 8.5+/-5%, p=0.03) but not post-SAVR (4.2+/-2% vs. 4.1+/-2%, p=0.98). Myocardial scar (p<=0.01) and baseline ventricular volumes (p<0.001) were the major predictors of reverse remodelling. CONCLUSIONS: TAVI was comparable to SAVR at LV reverse remodelling and superior at reducing the valvular pressure gradient and MF. Future work should assess the prognostic importance of reverse remodelling and fibrosis post-TAVI to aid patient selection. PMID- 23749780 TI - Exercise training improves activity in adolescents with congenital heart disease. AB - OBJECTIVES: To ascertain if motivational techniques and a structured exercise programme can increase activity in adolescents afflicted with congenital heart disease (CHD). DESIGN: Prospective randomised controlled trial. SETTING: One hundred and forty-three patients aged 12-20 years attending the tertiary centre for paediatric cardiology in Northern Ireland. MAIN OUTCOME MEASURES: Increase in exercise capacity as assessed by duration of exercise stress test, and number of minutes spent in moderate to vigorous physical activity (MVPA) per day. RESULTS: Eighty-six patients were men (60%), mean age was 15.60 +/- 2.27 years. Seventy three percent were considered to have major CHD. Seventy-two participants were randomised to the intervention group. Following intervention, duration of exercise test increased by 1 min 5 s for the intervention group (p value 0.02) along with increase in predicted VO2Max (p value 0.02). There was a significant increase in minutes of MVPA per day for the intervention group from baseline to reassessment (p value <0.001) while MVPA remained much the same for the control group. Fourteen patients met the current recommendation for more than 60 min MVPA per day at baseline. This doubled to 29 participants at reassessment. There were no adverse effects or mortalities reported. CONCLUSIONS: Exercise training is safe, feasible and beneficial in adolescents with CHD. Psychological techniques can be employed to maximise the impact of interventions. TRIAL REGISTRATION NUMBER: ISRCTN27986270. PMID- 23749781 TI - Right coronary artery 'diverticulosis' 4 years after sirolimus-eluting stent implantation associated with very late stent thrombosis. PMID- 23749782 TI - Unprotected single coronary artery main-stem angioplasty. PMID- 23749783 TI - Scientific letter: could tranexamic acid use in surgery reduce perioperative myocardial infarction? PMID- 23749784 TI - Percutaneous valve-in-valve implantations: importance of knowing the effective internal diameter of bioprosthetic valves. PMID- 23749785 TI - Gefitinib selectively inhibits tumor cell migration in EGFR-amplified human glioblastoma. AB - BACKGROUND: Tissue invasion is a hallmark of most human cancers and remains a major source of treatment failure in patients with glioblastoma (GBM). Although EGFR amplification has been previously associated with more invasive tumor behavior, existing experimental models have not supported quantitative evaluation of interpatient differences in tumor cell migration or testing of patient specific responses to therapies targeting invasion. To explore these questions, we optimized an ex vivo organotypic slice culture system allowing for labeling and tracking of tumor cells in human GBM slice cultures. METHODS: With use of time-lapse confocal microscopy of retrovirally labeled tumor cells in slices, baseline differences in migration speed and efficiency were determined and correlated with EGFR amplification in a cohort of patients with GBM. Slices were treated with gefitinib to evaluate anti-invasive effects associated with targeting EGFR. RESULTS: Migration analysis identified significant patient-to patient variation at baseline. EGFR amplification was correlated with increased migration speed and efficiency compared with nonamplified tumors. Critically, gefitinib resulted in a selective and significant reduction of tumor cell migration in EGFR-amplified tumors. CONCLUSIONS: These data provide the first identification of patient-to-patient variation in tumor cell migration in living human tumor tissue. We found that EGFR-amplified GBM are inherently more efficient in their migration and can be effectively targeted by gefitinib treatment. These data suggest that stratified clinical trails are needed to evaluate gefitinib as an anti-invasive adjuvant for patients with EGFR-amplified GBM. In addition, these results provide proof of principle that primary slice cultures may be useful for patient-specific screening of agents designed to inhibit tumor invasion. PMID- 23749786 TI - Reply to "[18F]-fluoro-ethyl-L-tyrosine PET: a valuable diagnostic tool in neuro oncology, but not all that glitters is glioma" by Hutterer et al. PMID- 23749789 TI - Temporary Solitaire stent neck remodeling in the coiling of ruptured aneurysms. AB - BACKGROUND: Stent-assisted coiling is a commonly adopted technique employed in the coiling of broader-based aneurysms. It avoids flow arrest and the risk of vessel rupture associated with balloon-assisted coiling. However, there is a risk of stent thrombosis with the corollary risk of stroke during and after the procedure. Antiplatelet agents are used to mitigate this risk but raise a secondary concern of hemorrhagic complications, particularly with ruptured aneurysm where further interventions such as ventriculostomy occur not infrequently. Stent removal after coil embolization would eliminate the risk of post-procedure stent thromboembolic complications and alleviate the need for continuing antiplatelet therapy. METHODS: A prospectively maintained endovascular database was searched to identify patients who underwent stent-assisted coil embolization followed by stent retrieval and removal. The clinical and technical aspects of the cases were obtained in addition to the procedural outcomes. RESULTS: Three cases were identified where the use of the fully resheathable Solitaire AB Neurovascular Remodeling Device permitted the coiling of broad-based aneurysms with subsequent retrieval and removal of the stent. All patients presented with subarachnoid hemorrhage and received aspirin prior to the procedure. Two patients did not require antiplatelet therapy after the procedure. No coil herniation or thromboembolic events were encountered. CONCLUSIONS: Stent retrieval and removal can be done safely in selected cases at the end of stent assisted coil embolization using the Solitaire AB device. This technique avoids the need for continuing antiplatelet therapy, which can be particularly important in the setting of acute subarachnoid hemorrhage. PMID- 23749790 TI - Resting heart rate and physical activity as risk factors for lone atrial fibrillation: a prospective study of 309,540 men and women. AB - OBJECTIVE: To study the impact of resting heart rate and leisure time physical activity at middle age on long term risk of drug treated lone atrial fibrillation (AF). DESIGN: Longitudinal cohort study of 309 540 Norwegian men and women aged 40-45 years examined during 1985-1999 followed from 2005 through 2009. SETTING: Data from a national health screening programme were linked to the Norwegian Prescription Database (NorPD). PATIENTS: The cohort comprised 162 078 women and 147 462 men; 575 (0.4%) men and 288 women (0.2%) received flecainide and 568 men and 256 women sotalol and were defined as patients with AF. INTERVENTIONS: No interventions. MAIN OUTCOME MEASURES: The outcome was lone fibrillation defined by having at least one prescription of flecainide or sotalol registered in NorPD between 2005 and 2009. Cox proportional hazard regression models were used to assess time to first prescription. RESULTS: The risk for being prescribed these drugs increased with decreasing baseline resting heart. Adjusted hazard ratio (HR) per 10 beats/min decrease in resting heart rate for flecainide prescription was 1.26 in men (95% CI 1.17 to 1.35) and 1.15 (95% CI 1.05 to 1.27) in women. Similar effects were seen for sotalol in men, but not in women. Men who reported intensive physical activity were more often prescribed flecainide than those in the sedentary group (adjusted HR=3.14, 95% CI 2.17 to 4.54). CONCLUSIONS: This population based study supports the hypothesis that the risk of drug treated lone AF increases with declining resting heart rate in both sexes, and with increasing levels of self-reported physical activity in men. PMID- 23749791 TI - An association between gestational diabetes mellitus and long-term maternal cardiovascular morbidity. AB - OBJECTIVE: To investigate whether a diagnosis of gestational diabetes mellitus (GDM) is a risk factor for subsequent long-term cardiovascular morbidity. DESIGN: A population-based study. SETTING: Soroka University Medical Center, a tertiary centre in the southern region of Israel. PATIENTS: A cohort of women with and without a diagnosis of GDM who delivered during the years 1988-1999 with a follow up period until 2010. INTERVENTIONS: A comparison of the incidence of cardiovascular morbidity. RESULTS: Of 47 909 deliveries that met the inclusion criteria, 4928 (10.3%) occurred in patients who were diagnosed with GDM. During a follow-up period of more than 10 years, compared with women who gave birth at the same time period, after adjustment for age and ethnicity, patients with GDM had higher rates of cardiovascular morbidity including non-invasive cardiac diagnostic procedures (OR=1.8; 95% CI 1.4 to 2.2), simple cardiovascular events (OR=2.7; 95% CI 2.4 to 3.1) and total cardiovascular hospitalisations (OR=2.3; 95% CI 2.0 to 2.5). In a Cox proportional hazards model, adjusted for comorbidities such as pre-eclampsia and obesity, GDM was independently associated with cardiovascular hospitalisations (adjusted HR 2.6, 95% CI 2.3 to 3). CONCLUSIONS: GDM is an independent risk factor for long-term cardiovascular morbidity in a follow-up period of more than a decade. PMID- 23749792 TI - The impact of smoking on clinical efficacy and pharmacodynamic effects of clopidogrel: a systematic review and meta-analysis. AB - CONTEXT: Previous findings regarding the relationship between smoking and clopidogrel effects were considerably discrepant. OBJECTIVE: To assess the impact of smoking on clinical and pharmacodynamic response to clopidogrel. DATA SOURCES: Medline, EMBASE and the Cochrane Library through January 2013 were searched. Reference lists of pertinent literatures and abstracts of major cardiovascular conferences were screened. STUDY SELECTION: Clinical and laboratory studies, which reported major adverse cardiovascular events and on-clopidogrel platelet reactivity categorised by smoking status respectively, were selected. DATA EXTRACTION: Descriptive and quantitative data were extracted. The main analyses were performed under a random-effects model. For clinical studies, HR estimates were synthesised according to smoking status; for laboratory studies, standardised mean difference (SMD) of on-clopidogrel platelet reactivity and OR for high on-clopidogrel platelet reactivity were pooled. Heterogeneity was quantified by computing I(2) statistic. RESULTS: Of the 1869 citations retrieved, seven clinical studies and 12 laboratory studies involving 111 132 patients with established cardiovascular disease and 6658 patients with acute coronary syndrome and/or stent deployment, respectively, were included for meta-analysis. Pooled clinical results showed that an intensified antiplatelet regimen involving clopidogrel was associated with 10% reduced risk for major adverse cardiovascular events among non-current smokers (HR 0.90; 95% CI 0.85 to 0.96), while this clinical benefit was enhanced by 2.9-fold among current smokers (HR 0.71; 95% CI 0.62 to 0.80). Pooled analysis of laboratory studies revealed that current smokers had significantly lower on-clopidogrel platelet reactivity (SMD -0.30; 95% CI -0.46 to -0.15) but, notably, there was considerable inter-study heterogeneity (I(2) 76.2%; p=0.000). The analysis based on four studies (n=1423) suggested a significantly lower odds of high on-clopidogrel platelet reactivity among current smokers than those among never smokers (OR 0.33; 95% CI 0.22 to 0.43). CONCLUSIONS: Smoking appears to positively modify the relative clinical efficacy and pharmacodynamic effects of clopidogrel. PMID- 23749793 TI - Swinging heart and vector alternans: signs of impending doom. PMID- 23749787 TI - Addressing gene tree discordance and non-stationarity to resolve a multi-locus phylogeny of the flatfishes (Teleostei: Pleuronectiformes). AB - Non-homogeneous processes and, in particular, base compositional non-stationarity have long been recognized as a critical source of systematic error. But only a small fraction of current molecular systematic studies methodically examine and effectively account for the potentially confounding effect of non-stationarity. The problem is especially overlooked in multi-locus or phylogenomic scale analyses, in part because no efficient tools exist to accommodate base composition heterogeneity in large data sets. We present a detailed analysis of a data set with 20 genes and 214 taxa to study the phylogeny of flatfishes (Pleuronectiformes) and their position among percomorphs. Most genes vary significantly in base composition among taxa and fail to resolve flatfish monophyly and other emblematic groups, suggesting that non-stationarity may be causing systematic error. We show a strong association between base compositional bias and topological discordance among individual gene partitions and their inferred trees. Phylogenetic methods applying non-homogeneous models to accommodate non-stationarity have relatively minor effect to reduce gene tree discordance, suggesting that available computer programs applying these methods do not scale up efficiently to the data set of modest size analysed in this study. By comparing phylogenetic trees obtained with species tree (STAR) and concatenation approaches, we show that gene tree discordance in our data set is most likely due to base compositional biases than to incomplete lineage sorting. Multi-locus analyses suggest that the combined phylogenetic signal from all loci in a concatenated data set overcomes systematic biases induced by non stationarity at each partition. Finally, relationships among flatfishes and their relatives are discussed in the light of these results. We find support for the monophyly of flatfishes and confirm findings from previous molecular phylogenetic studies suggesting their close affinity with several carangimorph groups (i.e., jack and allies, barracuda, archerfish, billfish and swordfish, threadfin, moonfish, beach salmon, and snook and barramundi). PMID- 23749794 TI - Cerebral aneurysm treatment is beginning to shift to low volume centers. AB - BACKGROUND AND PURPOSE: A recent expansion of the neurointerventional workforce in the USA could lead to a trend toward cerebral aneurysms being increasingly treated at low volume centers. Such a trend could have a negative impact on patient care as higher volume centers are known to have better outcomes. METHODS: Using the Nationwide Inpatient Sample, we evaluated trends in aneurysm treatment in the USA from 2001 to 2010. Annual volumes of both ruptured and unruptured aneurysms were counted, as well as annual percentages of cases treated at high volume centers (>=50 aneurysms/year clipped or coiled). RESULTS: The number of ruptured aneurysms treated per year has fluctuated between 9000 and 12 000 from 2003 to 2010. In 2001-2002, 27.4% of intracranial aneurysm patients were treated with clipping or coiling at high volume centers, with a peak of 70.1% in 2007 2008. This proportion dropped to 61.8% in 2009-2010. The proportion of patients clipped at high volume centers was 23.3% in 2001-2002 and peaked at 65.0% in 2007 2008. In 2009-2010, the proportion dropped to 58.6%. For coiling patients, 46.4% were treated at high volume centers in 2001-2002, with a peak of 70.1% in 2007 2008, and a drop to 61.8% in 2009-2010. CONCLUSION: A trend toward less cerebral aneurysms being treated in high volume centers in 2009 and 2010 is worrisome because high volume centers are known to tend to have better outcomes. This trend is likely due to recent expansion of the neurointerventional workforce. PMID- 23749795 TI - Double-lumen arterial balloon catheter technique for Onyx embolization of dural arteriovenous fistulas: initial experience. AB - BACKGROUND: Dural arteriovenous fistulas are vascular malformations with variable clinical symptoms that range in severity from completely asymptomatic to seizures, dementia, loss of vision and intracranial hemorrhage. Historically, surgical obliteration was the treatment of choice but, more recently, endovascular embolization has become the first-line treatment. The liquid embolic agent Onyx (ethyl vinyl copolymer) has become the agent of choice, but problems with reflux around the delivery microcatheter and inadvertent venous penetration have arisen. METHODS AND RESULTS: We present six cases in which the double-lumen balloon microcatheter was used to transarterially embolize dural arteriovenous fistulas via injection of Onyx through the wire lumen. Depending on the individual pathology a venous balloon was also used in some cases. The advantages and disadvantages of the use of these devices are discussed. CONCLUSIONS: We consider that the use of the double-lumen balloon technique for fistula embolization has the potential for reducing overall procedural times, procedural failures and catheter retention in certain situations. In such cases we would advocate this as a first-line technique. When lower profile, more navigable balloon catheters become available, this may become the standard of care. PMID- 23749796 TI - Etiology of hippocampal sclerosis: evidence for a predisposing familial morphologic anomaly. AB - OBJECTIVE: We sought evidence of a hereditary component for hippocampal sclerosis (HS) by determining whether close relatives of probands with temporal lobe epilepsy (TLE) with HS also had asymptomatic HS or subtle variation in hippocampal morphology. METHODS: First-degree relatives from 15 families in which probands had TLE with HS and 32 age- and sex-matched controls were included in the study. Left and right hippocampal volumes and T2 relaxometry were measured using 3-tesla MRI. RESULTS: Thirty-two asymptomatic first-degree relatives and 3 relatives with a history of seizures or epilepsy were studied. None of the first degree relatives had HS on visual analysis and T2 relaxation times were normal, excluding the presence of HS. Mean hippocampal volume was smaller (6.4%) in asymptomatic relatives (2.94 +/- 0.27 cm(3), 95% confidence interval = 2.87-3.01) than in controls (3.14 +/- 0.22 cm(3), 95% confidence interval = 3.09-3.19, p < 0.005); the effect was greater in relatives of probands with a positive family history of epilepsy. The relatives also had more asymmetric hippocampi (asymmetric index 0.92 +/- 0.05) than controls (0.96 +/- 0.03, p = 0.001). CONCLUSIONS: Small asymmetric hippocampi in healthy relatives are likely to represent a familial developmental variant that may predispose to the formation of TLE with HS. The underlying histopathology of these small hippocampi is unknown. This observation may provide an imaging marker for future studies seeking susceptibility genes for HS. PMID- 23749797 TI - SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3. AB - OBJECTIVE: To identify the genetic cause of an autosomal recessive demyelinating Charcot-Marie-Tooth disease type 4B (CMT4B) family. METHODS: We enrolled 14 members of a Korean family in which 3 individuals had demyelinating CMT4B phenotype and obtained distal sural nerve biopsies from all affected participants. We conducted exome sequencing on 6 samples (3 affected and 3 unaffected individuals). RESULTS: One pair of heterozygous missense mutations in the SET binding factor 1 (SBF1) gene (22q13.33), also called MTMR5, was identified as the underlying cause of the CMT4B family illness. Clinical phenotypes of affected study participants with CMT4B were similar, to some extent, to patients with CMT4B1 and CMT4B2. We found a similar loss of large myelinated fibers and focally folded myelin sheaths in our patients, but the actual number of myelinated fibers was different from CMT4B1 and CMT4B2. CONCLUSIONS: We suggest that the compound heterozygous mutations in SBF1 are the underlying causes of a novel CMT4B subtype, designated as CMT4B3. We believe that this study will lead to mechanistic studies to discover the function of SBF1 and to the development of molecular diagnostics for CMT disease. PMID- 23749799 TI - Predictors of placebo response in restless legs syndrome studies. PMID- 23749800 TI - Patient and public involvement in research: future challenges. PMID- 23749798 TI - Restless legs syndrome and daytime sleepiness are prominent in myotonic dystrophy type 2. AB - OBJECTIVES: Although sleep disturbances are common in myotonic dystrophy type 1 (DM1), sleep disturbances in myotonic dystrophy type 2 (DM2) have not been well characterized. We aimed to determine the frequency of sleep disturbances in DM2. METHODS: We conducted a case-control study of 54 genetically confirmed DM2 subjects and 104 medical controls without DM1 or DM2, and surveyed common sleep disturbances, including symptoms of probable restless legs syndrome (RLS), excessive daytime sleepiness (EDS), sleep quality, fatigue, obstructive sleep apnea (OSA), probable REM sleep behavior disorder (pRBD), and pain. Thirty patients with DM2 and 43 controls responded to the survey. Group comparisons with parametric statistical tests and multiple linear and logistic regression analyses were conducted for the dependent variables of EDS and poor sleep quality. RESULTS: The mean ages of patients with DM2 and controls were 63.8 and 64.5 years, respectively. Significant sleep disturbances in patients with DM2 compared to controls included probable RLS (60.0% vs 14.0%, p < 0.0001), EDS (p < 0.001), sleep quality (p = 0.02), and fatigue (p < 0.0001). EDS and fatigue symptoms were independently associated with DM2 diagnosis (p < 0.01) after controlling for age, sex, RLS, and pain scores. There were no group differences in OSA (p = 0.87) or pRBD (p = 0.12) scores. CONCLUSIONS: RLS, EDS, and fatigue are frequent sleep disturbances in patients with DM2, while OSA and pRBD symptoms are not. EDS was independently associated with DM2 diagnosis, suggesting possible primary CNS hypersomnia mechanisms. Further studies utilizing objective sleep measures are needed to better characterize sleep comorbidities in DM2. PMID- 23749801 TI - Occupational contact dermatitis to acrylates in a manicurist. AB - We report the case of a manicurist who developed an allergic skin reaction to acrylates, manifested by bullous lesions on fingertips and eczema of the hands and ears. Patch tests showed positive reactions to 2-hydroxyethyl methacrylate, 2 hydroxypropyl methacrylate, ethyleneglycol dimethacrylate, triethyleneglycol dimethacrylate, 1,6-hexandiol diacrylate, 2-hydroxyethyl acrylate and triethyleneglycol diacrylate. Because of her skin disorder, she had to give up her job. She was not correctly advised on retraining and started to work as a dental nurse. Soon after re-exposure to acrylates in dental materials, she experienced recurrence of the skin symptoms. PMID- 23749802 TI - Self-harm in the UK military. AB - BACKGROUND: Self-harm in the UK military has variously been estimated at 1-5.6% compared with 4.9% in the general UK population. AIMS: To establish the overall prevalence of self-harm within the UK military, to establish the association between deployment and self-harm and to identify sociodemographic and social factors associated with self-harm within the UK military. METHODS: A cross sectional postal survey of UK military personnel. RESULTS: There were 9803 respondents. The overall prevalence of self-harm was 2.3% in the UK military. Self-harm was not associated with deployment but was significantly associated with being discharged, separated, of lower rank, female and younger age, reporting no close friends or family, reporting fewer social activities, having spent time in local authority care as a child, and having adversity in family relationships as a child. CONCLUSIONS: Contrary to predictions, self-harm in the UK military is not associated with deployment. It is linked to available social support in childhood and adulthood. PMID- 23749803 TI - Occupational egg allergy in an embryological research facility. AB - BACKGROUND: Hen and quail eggs are commonly used in embryological research. While immunoglobin E (IgE)-associated allergy to hens' egg proteins is recognized in employees in the food industry, there are no previous reports from workers in embryological research. Two newly identified cases prompted us to examine the extent of this problem in a university laboratory. AIMS: To determine the prevalence and determinants of sensitization to egg among a group of workers in an embryological research laboratory. METHODS: Following the identification of egg sensitization in two research workers, we surveyed 116 employees from a single embryology research laboratory in 2005. Sensitization to egg was assessed by skin prick tests and/or specific IgE measurement and examined in relation to a number of potential determinants, including the extent of appropriate control measures. RESULTS: Four employees were sensitized to egg, each with digestive symptoms of egg allergy. All had worked directly with eggs, giving a prevalence of specific sensitization in that group of 6.1% (95% confidence interval (CI) [1.7%, 14.8%]). There was a statistically significant trend for those sensitized to report a shorter duration of exposure to eggs and less frequent use of hygiene control measures to reduce exposure. CONCLUSIONS: Sensitization to eggs among those occupationally exposed to egg protein in research work occurs more commonly than in the general population. The presence of digestive symptoms after eating eggs may be indicative of sensitization to egg and should be incorporated into health evaluation of exposed workers. PMID- 23749804 TI - Lung function in fragrance industry employees. AB - BACKGROUND: Production employees in the UK fragrance industry are exposed to large numbers of chemical substances and mixtures. There is a lack of published literature describing the effects of occupational respiratory exposure in this industry. AIMS: To investigate whether occupational respiratory exposure to chemicals in the UK fragrance industry is linked to a statistically significant change in lung function as measured using spirometry. METHODS: A multi-site cross sectional study in which five UK companies took part, comprising an exposed group (fragrance production and associated functions) and a control group (non-exposed industry employees, e.g. office staff). Spirometric measurements (forced expiratory volume in 1 second, forced vital capacity and peak expiratory flow) were taken pre- and post-shift. Participants provided information on potential confounding factors (smoking, history of respiratory problems and body mass index). Post-shift measurements were compared between groups, using analysis of covariance to adjust for the baseline pre-shift measurements. RESULTS: A total of 112 subjects participated: 60 in the exposed group and 52 in control group (response rate 33 and 24%, respectively). Adjusted mean differences in post-shift spirometric measurements between exposed and control groups were not statistically significant. CONCLUSIONS: No significant effects were observed on the spirometric performance of the study population. This work is the first step in a novel area of research, and the industry would benefit from further such research. PMID- 23749805 TI - Respiratory and dermal symptoms in Thai nurses using latex products. AB - BACKGROUND: Despite known health risks related to the use of powdered latex gloves (PLGs), they are still widely used in hospitals in developing countries due to the high cost of alternatives. AIMS: To determine the prevalence of dermal and respiratory symptoms associated with latex glove use in nurses in Thailand and evaluate the influence of previously reported occupational risk factors in this population. METHODS: A cross-sectional study in female nurses working in three Thai hospitals. Participants completed a questionnaire on demographics, occupational and personal history, use of latex products at work and dermal and respiratory symptoms attributed to occupational use of latex gloves. RESULTS: Of 899 nurses, 18% reported health effects attributed to the use of latex products. After adjustment for confounding, occupational risk factors associated with increased reporting of dermal symptoms included wearing more than 15 pairs of PLG per day (odds ratio (OR): 2.10, 95% confidence interval (CI): [1.32-3.34]), using chlorhexidine (OR: 2.07, 95% CI: [1.22-3.52]) and being an operating theatre nurse (OR: 2.46, 95% CI: [1.47-4.12]). Being a labour ward nurse (OR: 3.52, 95% CI: [1.26-9.85]) was the only factor associated with increased reporting of respiratory symptoms. CONCLUSIONS: Continuing use of PLGs in Thai nurses is associated with increased prevalence of dermal symptoms compared with data from developed countries. Measures to reduce such health effects are well established and should be considered. Additionally, replacement of chlorhexidine with an alternative detergent seems advisable. PMID- 23749811 TI - Involvement of microRNA in copper deficiency-induced repression of chloroplastic CuZn-superoxide dismutase genes in the moss Physcomitrella patens. AB - Superoxide dismutases (SODs) are metallo-enzymes that catalyze the dismutation of superoxide radicals. In Arabidopsis thaliana, the expression of CuZn-SOD in both the chloroplast and cytosol was reported to be down-regulated by microRNA398 (miR398) during growth on low copper. The moss Physcomitrella patens contains chloroplastic and cytosolic CuZn-SOD genes, but lacks miR398. From analysis of P. patens microRNA, miR1073 was predicted to target CuZn-SOD mRNAs. We noticed that two chloroplastic CuZn-SOD genes contain the miR1073 target sequence in the 3' untranslated region; however, the cytosolic isozyme genes lack this sequence. In this study, we investigated the involvement of miR1073 in the expression of CuZn SOD genes in P. patens. When protonemata of P. patens were cultured on a copper depleted medium, SOD activity and mRNA levels of chloroplastic CuZn-SODs were decreased markedly. In contrast, cytosolic CuZn-SODs showed little or no change in mRNA levels or SOD activity. The precursor transcript and the mature form of miR1073 were induced by copper deficiency. The chloroplastic CuZn-SOD (PpCSD1) mRNA was cleaved at the miR1073 target site under copper deficiency. These results suggest that miR1073 is involved in the down-regulation of PpCSD1 expression. In addition to PpCSD1 mRNA, antisense RNAs of PpCSD1 were also detected under normal conditions; however, under copper deficiency, they were cleaved within the open reading frame (ORF) region. The cleavage of sense PpCSD1 mRNA was also detected within the ORF region. Although only miR1073 exists in the database, it is presumed that RNA cleavage, other than that mediated by miR1073, is involved in the regulation of PpCSD1 expression. PMID- 23749810 TI - Photosynthesis of root chloroplasts developed in Arabidopsis lines overexpressing GOLDEN2-LIKE transcription factors. AB - In plants, genes involved in photosynthesis are encoded separately in nuclei and plastids, and tight cooperation between these two genomes is therefore required for the development of functional chloroplasts. Golden2-like (GLK) transcription factors are involved in chloroplast development, directly targeting photosynthesis-associated nuclear genes for up-regulation. Although overexpression of GLKs leads to chloroplast development in non-photosynthetic organs, the mechanisms of coordination between the nuclear gene expression influenced by GLKs and the photosynthetic processes inside chloroplasts are largely unknown. To elucidate the impact of GLK-induced expression of photosynthesis-associated nuclear genes on the construction of photosynthetic systems, chloroplast morphology and photosynthetic characteristics in greenish roots of Arabidopsis thaliana lines overexpressing GLKs were compared with those in wild-type roots and leaves. Overexpression of GLKs caused up-regulation of not only their direct targets but also non-target nuclear and plastid genes, leading to global induction of chloroplast biogenesis in the root. Large antennae relative to reaction centers were observed in wild-type roots and were further enhanced by GLK overexpression due to the increased expression of target genes associated with peripheral light-harvesting antennae. Photochemical efficiency was lower in the root chloroplasts than in leaf chloroplasts, suggesting that the imbalance in the photosynthetic machinery decreases the efficiency of light utilization in root chloroplasts. Despite the low photochemical efficiency, root photosynthesis contributed to carbon assimilation in Arabidopsis. Moreover, GLK overexpression increased CO2 fixation and promoted phototrophic performance of the root, showing the potential of root photosynthesis to improve effective carbon utilization in plants. PMID- 23749812 TI - In vitro tuberization of Chlorophytum Borivilianum Sant & Fern (Safed musli) as influenced by sucrose, CCC and culture systems. AB - This study focuses on the establishment of in vitro tuberization of Chlorophytum borivilianum using solid and liquid culture systems. A high in vitro tuberization rate on solid and stationary liquid Murashige and Skoog media was observed in the presence of 60 g l-1 sucrose with 950, 1,265 and 1,580 uM 2-chloroethyl trimethylammonium chloride (CCC). Application of a higher sucrose concentration of 90 g l-1 showed a negative interaction with CCC on in vitro tuber number and days to in vitro tuber induction. For economic feasibility, 950 uM CCC with 60 g l-1 sucrose was chosen as the best combination for in vitro tuberization in both solid and stationary liquid media. For optimization of in vitro tuber production,a comparison between solid, stationary liquid and shake liquid culture was carried out. Liquid culture with shaking at 80 r.p.m. resulted in a >2.5-fold increase in in vitro tuber production compared with solid culture. PMID- 23749813 TI - The AP2/EREBP gene PUCHI Co-Acts with LBD16/ASL18 and LBD18/ASL20 downstream of ARF7 and ARF19 to regulate lateral root development in Arabidopsis. AB - The developmental process of lateral root formation consists of priming, initiation, primordium development and the emergence of lateral roots from the primary root. Molecular genetic studies with Arabidopsis have revealed several key transcriptional regulators involved in lateral root development. However, their functional interaction has not been fully characterized yet. Here we utilized a genetic approach to understand some of these interactions, revealing that PUCHI functioning in morphogenesis of early lateral root primordium is regulated downstream of ARF7/ARF19 and acts with LBD16(ASL18)/LBD18(ASL20) to regulate lateral root development. We showed that auxin-responsive expression of PUCHI was significantly reduced in arf7 or arf19 single mutants and completely abolished in arf7 arf19 double mutants. Consistent with this, beta-glucuronidase (GUS) expression under the PUCHI promoter in arf7 arf19 was greatly reduced in the lateral root primordium compared with that in the wild type and did not respond to exogenous auxin. Results of GUS expression analyses under the PUCHI, LBD16 or LBD18 promoter in lbd16, lbd18 single and double mutants or puchi demonstrated that PUCHI and LBD16 or LBD18 do not regulate each other's expression. Lateral root phenotypes of double and triple mutants of lbd16, lbd18 and puchi showed that the puchi mutation in lbd16 and lbd18 mutants synergistically decreased the number of emerged lateral roots. These analyses also showed that puchi affected lateral root primordium development of lbd16 or lbd18 additively but differentially. Taken together, these results suggest that PUCHI co-acts with LBD16 and LBD18 to control lateral root primordium development and lateral root emergence. PMID- 23749814 TI - Imbalance between subpopulations of regulatory T cells in COPD. AB - BACKGROUND: Recent evidence indicates that human regulatory T cells (Tregs) are composed of three distinct subpopulations: CD25(++) CD45RA(+) resting Tregs (rTregs), CD25(+++) CD45RA(-) activated Tregs (aTregs), which are suppressive, and CD25(++) CD45RA(-) cytokine-secreting (Fr III) cells with pro-inflammatory capacity. OBJECTIVES: To evaluate the dynamic changes in circulating and pulmonary Treg subpopulations in smokers and patients with chronic obstructive pulmonary disease (COPD), and to explore their potential roles in COPD pathogenesis. METHODS: Blood samples were obtained from 57 never-smokers, 32 smokers with normal lung function and 66 patients with COPD. Bronchoalveolar lavage (BAL) samples were taken from 12 never-smokers, 12 smokers and 18 patients with COPD. The proportions of Treg subpopulations and activated CD8 T cells were evaluated using flow cytometry. RESULTS: In peripheral blood, increased proportions of rTregs, aTregs and Fr III cells were found in smokers compared with never-smokers, whereas patients with COPD showed decreased rTregs and aTregs, and significantly increased Fr III cells compared with smokers. The changes in Treg subpopulations, with an overall decrease in the (aTreg+rTreg):(Fr III) ratio, indicated that immune homeostasis favoured inflammation and correlated with enhanced CD8 T-cell activation (r=-0.399, p<0.001) and forced expiratory volume in 1 s (FEV1) % predicted value (r=0.435, p<0.001).The BAL (aTreg+rTreg):(Fr III) ratios displayed more robust correlations with FEV1% predicted value (r=0.741, p<0.01) and activation of effector T cells (r=-0.763, p<0.001). CONCLUSIONS: The imbalance between the anti-inflammatory subsets (aTreg+rTreg) and the pro-inflammatory subset (Fr III) of Tregs may play an important role in COPD progression. PMID- 23749815 TI - Lung function after preterm birth: development from mid-childhood to adulthood. AB - BACKGROUND: As a result of advances in perinatal care, more small preterm infants survive. There are concerns that preterm birth and its treatments may harm pulmonary development and thereby lead to chronic airway obstruction in adulthood. OBJECTIVE: To assess the development of spirometric lung function variables from mid-childhood to adulthood after extreme preterm birth. METHODS: Two population-based cohorts born at gestational age <=28 weeks or with birth weight <=1000 g performed lung function tests at 10 and 18 and at 18 and 25 years of age, respectively, together with matched term-born controls. The results are presented as z scores, normalised for age, sex and height. Longitudinal development was compared for groups born at term and preterm, split by a history of absence (n=20), mild (n=38) or moderate/severe (n=25) neonatal bronchopulmonary dysplasia (BPD). RESULTS: The preterm-born cohorts, particularly those with neonatal BPD, had significantly lower forced expiratory volume in 1 s and mid-expiratory flow than those born at term at all assessments (z scores in the range -0.40 to -1.84). Within each of the subgroups the mean z scores obtained over the study period were largely similar, coefficients of determination ranging from 0.64 to 0.82. The pattern of development for the BPD subgroups did not differ from each other or from the groups born at term (tests of interaction). CONCLUSIONS: Airway obstruction was present from mid-childhood to adulthood after extreme preterm birth, most evident after neonatal BPD. Lung function indices were tracking similarly in the preterm and term-born groups. PMID- 23749816 TI - Tuberculosis vaccines: time to reset the paradigm? PMID- 23749817 TI - Peri-implant galactocele following vacuum-assisted core biopsy of the breast: a cautionary tale. AB - A lactating woman in her early 40s with a strong family history of breast cancer presented with a markedly swollen breast days after having a vacuum-assisted core biopsy performed to sample indeterminate microcalcifications in her left breast. Ultrasound showed a large peri-implant fluid collection which yielded milky fluid on aspiration consistent with galactocele formation. Histology of the core specimens revealed a fragment of fibrous capsule suggesting that the core biopsy had created a fistula between the breast tissue and the peri-implant space. Bromocriptine was given and the galactocele slowly resolved. PMID- 23749818 TI - An unusual presentation of MEN2A. AB - A 35-year-old woman presented with non-specific symptoms of fatigue and weight loss. Radiological investigations diagnosed a metastatic process and large bilateral adrenal masses. Histology from a liver biopsy and skin biopsy confirmed a diagnosis of metastatic medullary thyroid cancer. Further biochemical investigations revealed a positive 24-h urinary metanephrine collection and evidence of primary hyperparathyroidism. Genetic testing confirmed a mutant RET oncogene, confirming our clinical suspicion of multiple endocrine neoplasia type 2 (MEN2A) syndrome. The patient had no family history of endocrine disease and presented with widespread metastatic disease, making this an unusual presentation of MEN2A syndrome. Furthermore cutaneous metastases are rarely encountered in conjunction with metastatic medullary thyroid cancer. This case draws attention to the importance of genetic counselling in first-degree relatives of patients with confirmed MEN2A. This allows for timely diagnosis and reduced morbidity and mortality. PMID- 23749819 TI - Disturbance of motor development: a manifestation of stroke in early childhood. AB - Stroke has been recognised more frequently in children and represents a major cause of morbidity and mortality. It usually has an acute presentation, characterised by focal neurological signs, headache, altered state of consciousness or seizures. We report the case of an 18-month-male child with motor development disturbance, gait difficulty and preferential use of the left arm with right hemiparesis at clinical exam. Brain MRI showed an extensive damage involving corona radiata, thalamus, posterior arm of the internal capsule and left lenticular nucleus with atrophic retraction of the adjacent cerebrospinal fluid pathways, suggesting old ischaemic injury of the middle cerebral artery territory. Causal research pointed out at methyltetrahydrofolate reductase (MTHFR) C677T heterozygosity. He was referenced to physiotherapy and paediatric neurology consultation with favourable evolution and no recurrence of ischaemic events. Stroke is a relatively rare phenomenon in children; however, we have to consider it as a diagnosis in the presence of focal neurological deficits. MTHFR C677T mutation is considered a prothrombotic factor; however, in the absence of hyperhomocysteinaemia, no direct therapeutic approach is necessary. PMID- 23749820 TI - Self-inflicted long complex urethro-vesical foreign body: is open surgery always needed? AB - In this case report, we describe our experience of a self-inflicted long complex urethrovesical foreign body managed suprapubically through the minimally invasive technique. A 21-year-old man with antipsychotic treatment for the past 10 years presented with a long electric cable wire in his bladder with the distal end in the penile urethra. He presented with symptoms of voiding difficulty and gross haematuria. An attempt of gentle retrieval of wire through the cystoscopic forceps was not successful due to a very complex knot of cable in the bladder. To avoid open surgery such as suprapubic cystotomy, the percutaneous minimally invasive approach was planned. Access to the bladder was achieved by the suprapubic puncture of the bladder, placement of a guide-wire and serial dilation of supra-pubic tract. With the help of nephroscope, through suprapubic tract, the cable wire was retrieved antegradely without causing undue trauma to the bladder or urethra. PMID- 23749821 TI - The prolonged clotting time in two female patients with thromboangiitis obliterans. AB - Thromboangiitis obliterans (TAO), also known as Buerger's disease, is segmental non-atherosclerotic inflammatory disease, which affects the small and medium sized peripheral arteries, veins and nerves of young adult smokers. The paper reports two TAO female patients, 26-year-old and 42-year-old, with prolonged clotting time. We compared 13 male patients and 2 female patients with TAO. The prothrombin time (PT), activated partial thromboplastin time (APTT) and thrombin time (TT) were normal in the male patients, whereas the clotting times were prolonged in the female patients. Coagulation tests including PT, APTT and TT evaluation could be the potential markers to female patients with TAO. PMID- 23749822 TI - Acute abdominal pain and diarrhoea in healthy adult. PMID- 23749823 TI - Central nervous system relapse in a patient with acute promyelocytic leukaemia: does the risk stratification matter? AB - Extramedullary relapse is an uncommon complication of acute promyelocytic leukaemia (APL). The most common site of extramedullary relapse is the central nervous system (CNS), and the majority of CNS relapses occur in patients with high-risk disease in which white blood cell count at presentation is greater than 10*10(3)/MUL. The best management of such patients is still controversial. We describe a 47-year-old man with APL who developed two CNS relapses which were diagnosed through the presence of t(15;17)(q22;q21) on PCR of the cerebrospinal fluid (CSF), despite presenting initially with intermediate-risk disease. We conclude that the intermediate risk group is very heterogeneous and these patients sometimes may behave like high-risk patients. Also, clinicians should take into account symptoms that can be related to CNS relapse in patients with APL and consider lumbar puncture even if radiological imaging does not reveal anything. PMID- 23749824 TI - L-2 hydroxyglutaric aciduria presenting with anxiety symptoms. AB - l-2 Hydroxyglutaric aciduria is a rare autosomal recessively inherited metabolic disorder of organic acid metabolism. Cerebellar and pyramidal signs with progressive neurological syndromes, mental deterioration, tremors, seizures, epilepsy and rarely macrocephaly are clinical findings of the disease. The diagnosis depends on increased levels of l-2 hydroxyglutaric acid in urine, plasma and cerebrospinal fluid. Brain MRI shows peripheral white matter abnormalities in cerebral hemispheres, bilateral symmetrically abnormal signal intensity in basal ganglia and dentate nuclei. In this case report, we present a 13-year-old patient who presented with tremors and anxiety symptoms and was diagnosed as l-2 hydroxyglutaric aciduria after consultation with the child neurology department. We present a patient suffering from psychiatric symptoms with a metabolic disorder. PMID- 23749825 TI - 'Crohn'z meanz Heinz': foreign body inflammatory mass mimicking Crohn's disease. AB - The authors present a patient with a presumed diagnosis of Crohn's disease for 6 years turning out to be an unusual inflammatory mass caused by ileal perforation due to a foreign body. When surgical intervention became necessary for admissions with recurrent obstruction, laparoscopy revealed an inflammatory mass in the terminal ileum, exposing two pieces of plastic bearing the word 'Heinz'. Resection of the inflammatory mass led to the complete resolution of symptoms. Histology from the operative specimen showed no features of Crohn's disease. There were no granulomas and no fissuring ulcers. This case highlights that an inflammatory mass in the small intestine caused by the perforation of ingested foreign body can mimic Crohn's disease. To our knowledge, this is the first report of a synthetic plastic packaging causing ileo-caecal junctional perforation mimicking Crohn's disease. PMID- 23749826 TI - A regenerative approach towards mucosal fenestration closure. AB - Mucosal fenestration is an opening or an interstice through the oral mucosa. A lesion which occurs with greater frequency than generally realised, its occurrence is attributed to a myriad of causes. Mucogingival procedures including connective tissue grafts, free gingival grafts and lateral pedicle grafts are generally considered to be the treatment of choice in the closure of a mucosal fenestration. More often, these procedures are performed in conjunction with other procedures such as periradicular surgery and with bone grafts. However, the concomitant use of gingival grafts and bone grafts in mucosal fenestrations secondary to infections in sites exhibiting severe bone loss is highly debatable. In this article, we report two cases of mucosal fenestrations secondary to trauma and their management by regenerative periodontal surgery with the placement of guided tissue regeneration membrane and bone graft. The final outcome was a complete closure of the fenestration in both the cases. PMID- 23749827 TI - Primary intraosseous squamous cell carcinoma: a devil in disguise. AB - Primary intraosseous squamous cell carcinoma (PIOSCC) is a rare central jaw carcinoma derived from odontogenic epithelial remnants. When the tumour arises in an existing cyst, it may be difficult to recognise early PIOSCC and carry out necessary treatment. We report a case diagnosed in a 50-year-old man where timely intervention was delayed and prognosis was affected and the case diagnosed eventually by comprehensive clinical, radiological and histopathological examination. PMID- 23749828 TI - Caecal volvulus: a consequence of acute cholecystitis. AB - Caecal volvulus is an uncommon cause of closed loop intestinal obstruction which can lead to caecal gangrene and high mortality. Delay in diagnosis is one of the causes of this high mortality. Caecal volvulus is reported to be associated with previous abdominal surgery in most cases. We present the first reported case of caecal volvulus following/associated with acute cholecystitis. PMID- 23749829 TI - Immunoglobulin G4-related disease with scant tissue IgG4. AB - A 56-year-old man was admitted to our hospital for renal dysfunction and symmetrical swelling of submandibular glands. Laboratory and imaging findings were consistent with immunoglobulin G4-related disease (IgG4RD). Histological findings of the submandibular gland and the kidney were also consistent with IgG4RD. However, the patient did not have elevated serum or tissue IgG4 levels. Oral prednisolone therapy, initially 50 mg/day and gradually tapered over 12 months, improved his laboratory abnormalities and the swelling of his affected organs. These findings prompted our final diagnosis of IgG4RD. IgG4RD is a newly recognised disease with an unknown aetiology. This case suggests that IgG4 antibodies do not play a primary role in the aetiology of IgG4RD. Furthermore, clinicians should not exclude the diagnosis of IgG4RD in patients lacking elevated IgG4 levels in their affected tissues, particularly if they have other features of IgG4RD. Steroid therapy should be considered for such patients. PMID- 23749830 TI - Splinting with diastema closure as an adjunct to periodontal therapy. AB - A variety of treatment modalities, from removable partial dentures, fixed prosthesis to implant placement can be used for replacement of missing teeth. Anterior diastema closure is one of the most challenging tasks; it is appreciable that restorative approach is the fastest, simplest and most predictable. This case report presents a successfully accomplished closure of diastema in mandibular anterior teeth, and splinting of the adjacent teeth which were grade II mobile. This present treatment modality offers a conservative, aesthetic and non-invasive treatment which can be considered as a long-lasting treatment. PMID- 23749831 TI - Rapid resolution of pulmonary Langerhans cell histiocytosis. AB - A 38-year-old woman with a long-term history of smoking presented to the lung cancer clinic with weight loss and recurrent lower respiratory tract infections. A diagnosis of Langerhans cell histiocytosis was made by specimen samples taken from video-assisted thoracoscopic surgery. She was advised to stop smoking, which she adhered to. She was followed up in the respiratory clinic with pulmonary function tests every 6 months, which were all normal. Follow-up chest x-ray showed complete resolution of the multifocal interstitial infiltrates, and with smoking cessation, the patient has sustained an excellent quality of life. PMID- 23749832 TI - Diagnosis and management of a ruptured rudimentary horn pregnancy in a low resource setting. AB - A 22-year-old woman presented with amenorrhoea, lower abdominal pain and brown vaginal discharge. She was noted to be in hypovolaemic shock with a distended and peritonitic abdomen. On bimanual examination, the uterus was not palpated, the posterior fornix was full and cervical excitation was present. A clinical diagnosis of a ruptured ectopic pregnancy was made. She was resuscitated and an emergency laparotomy was performed. Intraoperatively, a ruptured rudimentary horn with an ex utero pregnancy was discovered. The right horn and tube were removed, as was the non-viable fetus. There were no postoperative complications and the patient was discharged after 5 days of observation. PMID- 23749833 TI - Stress urinary incontinence as a rare presentation of large prostatic stones in neurogenic bladder: implications and management. AB - We report a case of a 38-year-old man with a background of a neglected neurogenic bladder, who presented with a recent onset history of stress urinary incontinence. He was diagnosed as having large prostatic stones along with a low compliance, small capacity bladder and bilateral hydronephrosis with deranged renal functions. As self-catheterisation was not possible due to obstructing prostatic stones, holmium-YAG laser lithotripsy of prostatic stones was performed as initial procedure that resulted in complete resolution of stress incontinence as well. Successful gastrocystoplasty was performed as a second step to deal with the underlying condition of neurogenic poorly compliant bladder. The present case describes the successful endoscopic management of prostatic calculi using holmium laser lithotripsy and draws attention to other important issues that need to be addressed in certain special situations like neurogenic bladder. PMID- 23749834 TI - Solid variant of papillary thyroid carcinoma in a 14-year-old girl. AB - Solid variant of papillary thyroid carcinoma (PTC) is a rare, poorly characterised variant and predominantly reported in children with a history of radiation exposure. This variant has a high propensity for extra-thyroidal extension and cervical lymph node metastases. A 14-year-old Malay girl who had no history of radiation exposure, presented with multiple cervical lymphadenopathy and it was clinically suspicious for tuberculosis or lymphoma. An incisional biopsy revealed a metastatic PTC. The patient underwent total thyroidectomy with bilateral lateral neck dissection and histopathology report was solid variant of PTC. Whole-body I(131) scan was performed which revealed an intense tracer uptake in the neck. She was planned for radioactive iodine ablation and now on regular follow-up for monitoring of possible tumour metastasis. PMID- 23749835 TI - Isolated multiple invasive cardiac hydatid cyst. PMID- 23749836 TI - An unexpected difficult intubation in a patient with myasthenia gravis undergoing video-assisted transcervical thymectomy. AB - Although there are different methods to evaluate predictive parameters of difficult intubation in apparently normal patients, sometimes this event is unpredictable.We herein report a clinical case of difficult intubation during anaesthesia for video-assisted thymectomy in non-thymomatous myasthenia gravis. PMID- 23749837 TI - Syncope caused by coronary artery spasm without chest pain leading to ventricular fibrillation. AB - We present a case of syncope caused by coronary artery spasm without chest pain leading to ventricular fibrillation despite of vasodilator therapy with a calcium channel blocker (CCB). A 68-year-old man presented with two episodes of syncope without chest pain. Ergonovine provocation test induced a diffuse spasm in the right coronary artery (RCA) and subsequently, ventricular fibrillation. Under the therapy with multiple vasodilators including two CCBs, a second ergonovine provocation induced a spasm of the proximal RCA resulting in complete obstruction. Owing to drug-resistant coronary spasm complicated by ventricular fibrillation, an implantable cardioverter defibrillator (ICD) was implanted. This case report highlights the occurrence of syncope caused by coronary artery spasm without chest pain that was refractory to single CCB therapy and needed ICD implantation. Therapy with multiple vasodilators, including two or more CCBs, along with ICD implantation may be required to treat such refractory coronary artery spasms leading to lethal arrhythmia. PMID- 23749838 TI - Restoration of fractured anterior permanent teeth using reference guide technique. AB - The most common consequence of traumatic dental injury is uncomplicated crown fracture. The main techniques for reconstructing fractured teeth include the use of direct adhesive restorative materials. However, this type of treatment is time consuming and requires a skilled operator. An alternative to the direct restorative technique is the use of a reference guide. The advantage is that the restorative procedure can be carried out in two short clinical sessions with a drastic reduction in chair time. The size, shape and inclination of the teeth are determined in advance, which reduces the need for eventual adjustments. In addition, the use of a reference guide makes it possible for two or more teeth to be restored simultaneously; in contrast, with the conventional technique. This paper offers a step-by-step description, of a reference guide technique for restoration of permanent maxillary incisors fractured through trauma. PMID- 23749839 TI - Congenital thoracic malformation. PMID- 23749841 TI - Use of inhaled corticosteroids and the risk of tuberculosis. AB - BACKGROUND: Inhaled corticosteroid (ICS) use could decrease local immunity of the lung. Concerns have been raised regarding the risk of tuberculosis (TB) development among ICS users. The aim of this study was to elucidate the association between ICS use and development of TB among patients with various respiratory diseases in South Korea, an intermediate-TB-burden country. METHODS: A nested case-control study based on the Korean national claims database was performed. The eligible cohort consisted of 853 439 new adult users of inhaled respiratory medications between 1 January 2007 and 31 December 2010. Patients diagnosed as having TB after initiation of inhaled medication were included as cases. For each case individual, up to five control individuals matched for age, sex, diagnosis of asthma or chronic obstructive pulmonary disease (COPD) and initiation date of inhaler use were selected. RESULTS: From the cohort population, we matched 4139 individuals diagnosed as having TB with 20 583 controls. ICS use was associated with increased rate of TB diagnosis (adjusted OR (aOR), 1.20; 95% CI 1.08 to 1.34). The association was dose dependent (p for trend <0.001). A subgroup analysis revealed that ICS use increased the risk of TB development among non-users of oral corticosteroid (OCS) but not among OCS users. CONCLUSIONS: ICS use increases the risk of TB in an intermediate-TB-burden country. Clinicians should be aware of the possibility of TB development among patients who are long-term high-dose ICS users. PMID- 23749840 TI - Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection. AB - RATIONALE: Arikace is a liposomal amikacin preparation for aerosol delivery with potent Pseudomonas aeruginosa killing and prolonged lung deposition. OBJECTIVES: To examine the safety and efficacy of 28 days of once-daily Arikace in cystic fibrosis (CF) patients chronically infected with P aeruginosa. METHODS: 105 subjects were evaluated in double-blind, placebo-controlled studies. Subjects were randomised to once-daily Arikace (70, 140, 280 and 560 mg; n=7, 5, 21 and 36 subjects) or placebo (n=36) for 28 days. Primary outcomes included safety and tolerability. Secondary outcomes included lung function (forced expiratory volume at one second (FEV1)), P aeruginosa density in sputum, and the Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R). RESULTS: The adverse event profile was similar among Arikace and placebo subjects. The relative change in FEV1 was higher in the 560 mg dose group at day 28 (p=0.033) and at day 56 (28 days post treatment, 0.093L+/-0.203 vs -0.032L+/-0.119; p=0.003) versus placebo. Sputum P aeruginosa density decreased >1 log in the 560 mg group versus placebo (days 14, 28 and 35; p=0.021). The Respiratory Domain of the CFQ-R increased by the Minimal Clinically Important Difference (MCID) in 67% of Arikace subjects (560 mg) versus 36% of placebo (p=0.006), and correlated with FEV1 improvements at days 14, 28 and 42 (p<0.05). An open-label extension (560 mg Arikace) for 28 days followed by 56 days off over six cycles confirmed durable improvements in lung function and sputum P aeruginosa density (n=49). CONCLUSIONS: Once-daily Arikace demonstrated acute tolerability, safety, biologic activity and efficacy in patients with CF with P aeruginosa infection. PMID- 23749842 TI - Morbidity and mortality in children with obstructive sleep apnoea: a controlled national study. AB - BACKGROUND: Little is known about the diagnostic patterns of obstructive sleep apnoea (OSA) in children. A study was undertaken to evaluate morbidity and mortality in childhood OSA. METHODS: 2998 patients aged 0-19 years with a diagnosis of OSA were identified from the Danish National Patient Registry. For each patient we randomly selected four citizens matched for age, sex and socioeconomic status, thus providing 11 974 controls. RESULTS: Patients with OSA had greater morbidity at least 3 years before their diagnosis. The most common contacts with the health system arose from infections (OR 1.19, 95% CI 1.01 to 1.40); endocrine, nutritional and metabolic diseases (OR 1.30, 95% CI 0.94 to 1.80); nervous conditions (OR 2.12, 95% CI 1.65 to 2.73); eye conditions (OR 1.43, 95% CI 1.07 to 1.90); ear, nose and throat (ENT) diseases (OR 1.61, 95% CI 1.33 to 1.94); respiratory system diseases (OR 1.78, 95% CI 1.60 to 1.98); gastrointestinal diseases (OR 1.34, 95% CI 1.09 to 1.66); skin conditions (OR 1.32, 95% CI 1.02 to 1.71); congenital malformations (OR 1.56, 95% CI 1.31 to 1.85); abnormal clinical or laboratory findings (OR 1.21, 95% CI 1.06 to 1.39); and other factors influencing health status (OR 1.29, 95% CI 1.16 to 1.43). After diagnosis, OSA was associated with incidences of endocrine, nutritional and metabolic diseases (OR 1.78, 95% CI 1.29 to 2.45), nervous conditions (OR 3.16, 95% CI 2.58 to 3.89), ENT diseases (OR 1.45, 95% CI 1.14 to 1.84), respiratory system diseases (OR 1.94, 95% CI 1.70 to 2.22), skin conditions (OR 1.42, 95% CI 1.06 to 1.89), musculoskeletal diseases (OR 1.29, 95% CI 1.01 to 1.64), congenital malformations (OR 1.83, 95% CI 1.51 to 2.22), abnormal clinical or laboratory findings (OR 1.16, 95% CI 1.06 to 1.27) and other factors influencing health status (OR 1.35, 95% CI 1.20 to 1.51). The 5-year death rate was 70 per 10 000 for patients and 11 per 10 000 for controls. The HR for cases compared with controls was 6.58 (95% CI 3.39 to 12.79; p<0.001). CONCLUSIONS: Children with OSA have significant morbidities several years before and after their diagnosis. PMID- 23749843 TI - Reply to Balta et al. PMID- 23749845 TI - Data integration through proximity-based networks provides biological principles of organization across scales. AB - Plant behaviors across levels of cellular organization, from biochemical components to tissues and organs, relate and reflect growth habitats. Quantification of the relationship between behaviors captured in various phenotypic characteristics and growth habitats can help reveal molecular mechanisms of plant adaptation. The aim of this article is to introduce the power of using statistics originally developed in the field of geographic variability analysis together with prominent network models in elucidating principles of biological organization. We provide a critical systematic review of the existing statistical and network-based approaches that can be employed to determine patterns of covariation from both uni- and multivariate phenotypic characteristics in plants. We demonstrate that parameter-independent network based approaches result in robust insights about phenotypic covariation. These insights can be quantified and tested by applying well-established statistics combining the network structure with the phenotypic characteristics. We show that the reviewed network-based approaches are applicable from the level of genes to the study of individuals in a population of Arabidopsis thaliana. Finally, we demonstrate that the patterns of covariation can be generalized to quantifiable biological principles of organization. Therefore, these network-based approaches facilitate not only interpretation of large-scale data sets, but also prediction of biochemical and biological behaviors based on measurable characteristics. PMID- 23749844 TI - Salicylic acid regulates Plasmodesmata closure during innate immune responses in Arabidopsis. AB - In plants, mounting an effective innate immune strategy against microbial pathogens involves triggering local cell death within infected cells as well as boosting the immunity of the uninfected neighboring and systemically located cells. Although not much is known about this, it is evident that well-coordinated cell-cell signaling is critical in this process to confine infection to local tissue while allowing for the spread of systemic immune signals throughout the whole plant. In support of this notion, direct cell-to-cell communication was recently found to play a crucial role in plant defense. Here, we provide experimental evidence that salicylic acid (SA) is a critical hormonal signal that regulates cell-to-cell permeability during innate immune responses elicited by virulent bacterial infection in Arabidopsis thaliana. We show that direct exogenous application of SA or bacterial infection suppresses cell-cell coupling and that SA pathway mutants are impaired in this response. The SA- or infection induced suppression of cell-cell coupling requires an enhanced desease resistance1- and nonexpressor of pathogenesis-related genes1-dependent SA pathway in conjunction with the regulator of plasmodesmal gating Plasmodesmata-located protein5. We discuss a model wherein the SA signaling pathway and plasmodesmata mediated cell-to-cell communication converge under an intricate regulatory loop. PMID- 23749846 TI - AUGMIN subunit8 participates in microtubule reorientation in Arabidopsis hypocotyls. PMID- 23749848 TI - Surviving the onslaught: salicylic acid regulates Plasmodesmata closure during pathogen attack in Arabidopsis. PMID- 23749847 TI - Hierarchical nuclear and cytoplasmic genetic architectures for plant growth and defense within Arabidopsis. AB - To understand how genetic architecture translates between phenotypic levels, we mapped the genetic architecture of growth and defense within the Arabidopsis thaliana Kas * Tsu recombinant inbred line population. We measured plant growth using traditional size measurements and size-corrected growth rates. This population contains genetic variation in both the nuclear and cytoplasmic genomes, allowing us to separate their contributions. The cytoplasmic genome regulated a significant variance in growth but not defense, which was due to cytonuclear epistasis. Furthermore, growth adhered to an infinitesimal model of genetic architecture, while defense metabolism was more of a moderate-effect model. We found a lack of concordance between quantitative trait loci (QTL) regulating defense and those regulating growth. Given the published evidence proving the link between glucosinolates and growth, this is likely a false negative result caused by the limited population size. This size limitation creates an inability to test the entire potential genetic landscape possible between these two parents. We uncovered a significant effect of glucosinolates on growth once we accounted for allelic differences in growth QTLs. Therefore, other growth QTLs can mask the effects of defense upon growth. Investigating direct links across phenotypic hierarchies is fraught with difficulty; we identify issues complicating this analysis. PMID- 23749849 TI - Ki-67 is a predictor of acromegaly control with octreotide LAR independent of SSTR2 status and relates to cytokeratin pattern. AB - INTRODUCTION: Only one study has evaluated Ki-67 as a predictor of the response to somatostatin analog therapy in acromegaly; however, other predictors like somatostatin receptor type 2 (SSTR2) and cytokeratin pattern expressions were not considered. OBJECTIVE: To evaluate whether Ki-67 is a predictor of octreotide LAR (OCT-LAR) response in somatotropinomas independent of SSTR2 and cytokeratin expression patterns. METHODS: Protein expression was analyzed by immunohistochemistry. The percentage of cell nuclei that were immunolabeled for Ki-67 and the percentage of cells with positive SSTR2 staining were calculated. SSTR2 expression was considered high when >=25%, and a cutoff of 2.3% was designated for Ki-67. Tumors were classified as densely or sparsely granulated according to the cytokeratin pattern. RESULTS: Thirty-one somatotropinomas were studied. Fourteen patients (45.2%) were controlled with OCT-LAR therapy. The median Ki-67 labeling index (LI) was higher in patients not controlled with OCT LAR than in those controlled (1.63 and 0.15 respectively, P=0.002). Higher SSTR2 expression and densely granulated tumors were correlated with control as well (P=0.04 and 0.038 respectively). There was no difference in Ki-67 levels between patients with high and low SSTR2 expression (P=0.651). After multivariate analysis, both Ki-67 and SSTR2 remained statistically significant as predictors of OCT-LAR response (P=0.017 and 0.012 respectively). The Ki-67 LI was higher in sparsely than in densely granulated tumors (P=0.047). CONCLUSIONS: Ki-67 is a predictor of response to OCT-LAR in acromegaly, independent of SSTR2 expression and relates to cytokeratin patterns. PMID- 23749850 TI - Characterization of AtSTOP1 orthologous genes in tobacco and other plant species. AB - Aluminum (Al) and proton (H+) tolerances are essential traits for plants to adapt to acid soil environments. In Arabidopsis (Arabidopsis thaliana), these tolerances are mediated by a zinc-finger transcription factor, SENSITIVE TO PROTON RHIZOTOXICITY1 (AtSTOP1), which regulates the transcription of multiple genes critical for tolerance to both stressors. Here, the functions of orthologous proteins (STOP1-like proteins) in other plant species were characterized by reverse genetics analyses and in planta complementation assays. RNA interference of a gene for NtSTOP1 repressed Al and H+ tolerances of tobacco (Nicotiana tabacum) roots. Tobacco roots released citrate in response to Al, concomitant with the up-regulated transcription of an ortholog of an Al tolerance gene encoding a citrate-transporting multidrug and toxic compound extrusion protein. The RNA interference repression of NtSTOP1 blocked this process and also repressed the transcription of another orthologous gene for Al tolerance, ALUMINUM SENSITIVE3, which encodes a prokaryote-type transporter. These results demonstrated that NtSTOP1 regulates Al tolerance in tobacco through the transcriptional regulation of these genes. The in planta complementation assays revealed that other plant species, including woody plants, a legume, and a moss (Physcomitrella patens), possess functional STOP1-like proteins that can activate several H+ and Al-tolerance genes in Arabidopsis. Knocking out the gene encoding the STOP1-like protein decreased the Al tolerance of P. patens. Together, our results strongly suggest that transcriptional regulation by STOP1-like proteins is evolutionarily conserved among land plants and that it confers the ability to survive in acid soils through the transcriptional regulation of Al- and H+ tolerance genes. PMID- 23749851 TI - Ocean acidification alters the photosynthetic responses of a coccolithophorid to fluctuating ultraviolet and visible radiation. AB - Mixing of seawater subjects phytoplankton to fluctuations in photosynthetically active radiation (400-700 nm) and ultraviolet radiation (UVR; 280-400 nm). These irradiance fluctuations are now superimposed upon ocean acidification and thinning of the upper mixing layer through stratification, which alters mixing regimes. Therefore, we examined the photosynthetic carbon fixation and photochemical performance of a coccolithophore, Gephyrocapsa oceanica, grown under high, future (1,000 MUatm) and low, current (390 MUatm) CO2 levels, under regimes of fluctuating irradiances with or without UVR. Under both CO2 levels, fluctuating irradiances, as compared with constant irradiance, led to lower nonphotochemical quenching and less UVR-induced inhibition of carbon fixation and photosystem II electron transport. The cells grown under high CO2 showed a lower photosynthetic carbon fixation rate but lower nonphotochemical quenching and less ultraviolet B (280-315 nm)-induced inhibition. Ultraviolet A (315-400 nm) led to less enhancement of the photosynthetic carbon fixation in the high-CO2-grown cells under fluctuating irradiance. Our data suggest that ocean acidification and fast mixing or fluctuation of solar radiation will act synergistically to lower carbon fixation by G. oceanica, although ocean acidification may decrease ultraviolet B-related photochemical inhibition. PMID- 23749852 TI - Nuclear calcium signaling in plants. PMID- 23749854 TI - Spontaneous free floating carotid artery thrombosis. AB - A 64-year-old man, with no history of trauma, presented with transient visual loss. He was diagnosed with amaurosis fugax and started on dipyridamole and simvastatin. An inconclusive ultrasound (US) Doppler was followed by CT angiogram (CTA) and MRI, which demonstrated free floating intraluminal thrombus in the distal right common carotid artery. ECG showed sinus rhythm and an echocardiogram showed no cardiac thrombus. Following discussion at the vascular multidisciplinary team the decision was made to treat with intravenous heparin followed by warfarin. He has been regularly followed up with CTA/USS, the most recent (Oct 2012) showing no evidence of thrombus. He has had no further symptoms. Despite no initial aetiology being found we suggest that his undiagnosed oesophageal carcinoma (diagnosed 5 months after initial presentation) could have been responsible for a hypercoagulability state giving an increased risk of thrombosis and leading to the thrombus in the common carotid artery. PMID- 23749855 TI - Organising pneumonia in common variable immunodeficiency. AB - Common variable immunodeficiency (CVID) is the most common of the primary immunodeficiency disorders. Pulmonary manifestations are characterised by recurrent rhinosinusitis, respiratory tract infections and bronchiectasis. Less commonly the lung may be affected by lymphoid disorders and sarcoid-like granulomas. Organising pneumonia (OP) is a rare pulmonary manifestation. We report the case of a 32-year-old woman with CVID who presented with fever, dyspnoea and persistent lung infiltrates despite antibiotic therapy. CT of the chest showed bilateral patchy alveolar infiltrates. Pulmonary function tests revealed moderate restriction and reduction in diffusion capacity. Initial bronchoscopy with transbronchial biopsies did not yield a diagnosis but surgical lung biopsies identified OP. Significant clinical, radiographic and physiological improvement was achieved after institution of corticosteroid therapy. PMID- 23749853 TI - There's more to the picture than meets the eye: nitric oxide cross talk with Ca2+ signaling. AB - Calcium and nitric oxide (NO) are two important biological messengers. Increasing evidence indicates that Ca(2+) and NO work together in mediating responses to pathogenic microorganisms and microbe-associated molecular patterns. Ca(2+) fluxes were recognized to account for NO production, whereas evidence gathered from a number of studies highlights that NO is one of the key messengers mediating Ca(2+) signaling. Here, we present a concise description of the current understanding of the molecular mechanisms underlying the cross talk between Ca(2+) and NO in plant cells exposed to biotic stress. Particular attention will be given to the involvement of cyclic nucleotide-gated ion channels and Ca(2+) sensors. Notably, we provide new evidence that calmodulin might be regulated at the posttranslational level by NO through S-nitrosylation. Furthermore, we report original transcriptomic data showing that NO produced in response to oligogalacturonide regulates the expression of genes related to Ca(2+) signaling. Deeper insight into the molecules involved in the interplay between Ca(2+) and NO not only permits a better characterization of the Ca(2+) signaling system but also allows us to further understand how plants respond to pathogen attack. PMID- 23749856 TI - Lithobezoar, a rare cause of acute oesophageal obstruction: surgery after failure of endoscopic removal. AB - Oesophageal lithobezoar is a very rare clinical entity, especially presenting as a case of acute dysphagia. A 54-year-old man, with long-standing psychiatric illness, presented with a recent episode of vomiting and chest pain followed by dysphagia. Chest x-ray revealed a radio opaque shadow in the posterior mediastinum. Endoscopy showed a calcified foreign body in the lower oesophagus. Endoscopic attempts to remove or fragment the foreign body were unsuccessful. Foreign body was removed successfully through oesophagotomy using left posterolateral thoracotomy. Pathology revealed oesophageal lithobezoar. PMID- 23749857 TI - Unusual breast neoplasm: primary breast lymphoma. AB - Primary breast lymphoma (PBL) is a rare clinical entity. The clinical and imaging findings in breast lymphoma can mimic those of breast carcinoma. As a result, the diagnosis of PBL relies on histological evaluation and confirmed by immunohistochemical staining. The treatment of choice of this rare disease is controversial. This case report highlights the diagnosis and management of a 48 year-old woman residing in Iran with PBL. PMID- 23749858 TI - Hepatic myelopathy: an unusual neurological complication of chronic liver disease presenting as quadriparesis. AB - Hepatic myelopathy is a rare neurological complication of chronic liver disease, which is usually seen in adults, presenting as pure motor spastic paraparesis. It is almost always associated with portosystemic shunts and hepatic decompensation. We report a rare case of a young adult man presenting as rapidly progressive spastic quadriparesis because of hepatic myelopathy and associated spontaneous splenorenal shunt and early hepatic decompensation. PMID- 23749859 TI - Personhood within the context of sedation at the end of life in Singapore. AB - The concept of personhood is critical to the provision of holistic, patient centred, palliative care yet no common definition of this term exists. Some characterise personhood by the presence of consciousness-related features such as self-awareness while others deem personhood present by virtue of Divine endowment or as a result of one's social relations. Efforts to appropriately delineate this concept come under scrutiny following suggestions that patients rendered deeply and irreversibly unconscious lack personhood and ought to be considered 'dead'. This case report studies the views of a family caring for a deeply sedated terminally ill patient, to appropriately site local views of personhood within the context of sedation at the end of life. The resultant Ring Theory of Personhood dispenses with concerns that personhood is solely dependent upon consciousness and distances sedative treatments of last resort such as continuous deep sedation from euthanasia. PMID- 23749860 TI - Modified Nance palatal arch appliance for anterior tooth replacement. AB - The following case report presents a new and an innovative technique for the postextraction replacement of maxillary central incisors using the natural teeth as pontics. The novel appliance fabricated fully satisfied the demands of the adolescent patient for a fixed prosthetic, while fulfilling the aesthetic and functional requirements presented by the case. PMID- 23749861 TI - Poor outcome associated with probable bilateral extracranial ICA vasospasm. AB - We describe a woman with bilateral extracranial internal carotid artery (ICA) vasospasm. Initial MRI of the brain showed multiple areas of high-signal intensity in the white matter of both the frontoparietal lobes. She was alert, and the muscle strength of the four extremities was moderately decreased. Cranial CT on day 3 showed increased numbers of low-density areas in both the anterior cerebral arteries (ACA) and middle cerebral arteries (MCA), accompanied by neurological deterioration. Cranial and cervical CT angiography on day 9 showed that all areas of both the ACA and MCA had become low density. Both ICAs were markedly narrowed along their entire length and tapered. On day 16, the patient died. Three patients with bilateral extracranial ICA spasms have been described previously. To our knowledge, this is the first time to document bilateral ICA spasm causing elongated narrowing of the carotid arteries, leading to an unfortunate outcome. PMID- 23749862 TI - Successful thrombolytic treatment of prosthetic mitral valve thrombosis. AB - Prosthetic heart valve thrombosis is a rare but serious complication. Surgery is the first-line therapy in symptomatic obstructive mechanical valve thrombosis, thrombolytic therapy has been used as an alternative to surgical treatment. In this case report we described a 47-year-old woman who had undergone coronary artery bypass graft and mitral valve replacement operation 9 months ago. A thrombus was detected on the prosthetic mitral valve with high transmitral gradient by transoesophageal echocardiography. Tissue plasminogen activator treatment was administered successfully. The gradient was improved on prosthetic mitral valve and embolic complications or bleeding were not occurred. PMID- 23749863 TI - Pneumomediastinum secondary to mephedrone inhalation. AB - A 23-year-old man presented to the emergency department with severe, central, pleuritic chest pain. The pain was present on waking and exacerbated by movement. On examination, supraclavicular and anterior chest wall surgical emphysema was noted, otherwise examination and initial observations were normal. A chest x-ray and subsequent chest CT demonstrated a pneumomediastium with significant subcutaneous emphysema. There was no history of vomiting or chest trauma, but the patient had inhaled mephedrone, a synthetic stimulant drug, 36 h prior. Pneumomediastinum is an uncommon complication of inhalational drug use. PMID- 23749864 TI - Tension pneumocephalus after administration of two 0.25 mg cabergoline tablets in MEN1-related macroprolactinoma. PMID- 23749865 TI - L-2 hydroxyglutaric aciduria presenting with status epilepticus. AB - L-2 Hydroxyglutaric aciduria is a rare, progressive, autosomal recessively inherited metabolic disorder of organic acid metabolism. It is characterised by macrocephaly, progressive neurological syndrome with cerebellar features, mental deterioration, typical brain MRI findings and the presence of L-2 hydroxyglutaric acid in urine samples. We report on an 11-year-old patient who presented to the emergency department with a generalised status epilepticus, which was subsequently diagnosed as L-2 hydroxyglutaric aciduria owing to rare and different clinical presentation. Brain MRI showed peripheral white matter abnormalities in cerebral hemispheres, basal ganglia and dentate nuclei, In conclusion, L-2 hydroxyglutaric aciduria should be considered in cases of epileptic seizures such as status epilepticus, cerebellar signs and progressive neurological course. PMID- 23749867 TI - International Committee on Systematics of Prokaryotes. Subcommittee on the taxonomy of Mollicutes: Minutes of the meetings, July 15th and 19th 2012, Toulouse, France. PMID- 23749868 TI - Plasma sphingolipids and lung cancer: a population-based, nested case-control study. AB - BACKGROUND: Sphingosine-1-phosphate (S1P) and ceramides are bioactive signaling sphingolipids that regulate pathways that are central to cancer pathogenesis. METHODS: A nested case-control study was implemented to test whether prediagnostic circulating concentrations of S1P and ceramides were associated with future lung cancer risk. In the community-based CLUE II cohort study in Washington County, Maryland, the study consisted of 100 incident lung cancer cases, each matched to two cancer-free controls on age, sex, race, and cigarette smoking status. Plasma stored at -70 degrees C at the beginning of follow-up in 1989 was assayed for sphingolipids using liquid chromatography/tandem mass spectrometry methodology (LC/MS-MS). RESULTS: Compared with controls, geometric mean plasma concentrations of S1P and total ceramides were 2.9% (P = 0.10) and 5.1% (P = 0.02), respectively, greater in lung cancer cases. For S1P, the ORs and 95% confidence intervals (CI) for lung cancer risk were 2.7 (1.2-5.9), 2.7 (1.1 6.4), and 1.9 (0.8-4.5) for the second, third, and highest fourth, respectively, compared with the lowest fourth (overall P = 0.006). Compared with those with total ceramide concentrations in the lowest fourth, the ORs (and 95% CI) for lung cancer risk were 1.6 (0.7-3.3), 1.5 (0.7-3.4), and 2.1 (0.9-4.7) for the second, third, and highest fourth, respectively (P(trend) = 0.01). CONCLUSIONS: Higher concentrations of S1P and total ceramide in plasma were associated with increased future risk of lung cancer. IMPACT: These novel findings suggest that perturbation of sphingolipid metabolism and S1P generation may either contribute to the etiology of lung cancer or be a marker of latent lung cancer. PMID- 23749869 TI - Landscape of protein-protein interactions in Drosophila immune deficiency signaling during bacterial challenge. AB - The Drosophila defense against pathogens largely relies on the activation of two signaling pathways: immune deficiency (IMD) and Toll. The IMD pathway is triggered mainly by Gram-negative bacteria, whereas the Toll pathway responds predominantly to Gram-positive bacteria and fungi. The activation of these pathways leads to the rapid induction of numerous NF-kappaB-induced immune response genes, including antimicrobial peptide genes. The IMD pathway shows significant similarities with the TNF receptor pathway. Recent evidence indicates that the IMD pathway is also activated in response to various noninfectious stimuli (i.e., inflammatory-like reactions). To gain a better understanding of the molecular machinery underlying the pleiotropic functions of this pathway, we first performed a comprehensive proteomics analysis to identify the proteins interacting with the 11 canonical members of the pathway initially identified by genetic studies. We identified 369 interacting proteins (corresponding to 291 genes) in heat-killed Escherichia coli-stimulated Drosophila S2 cells, 92% of which have human orthologs. A comparative analysis of gene ontology from fly or human gene annotation databases points to four significant common categories: (i) the NuA4, nucleosome acetyltransferase of H4, histone acetyltransferase complex, (ii) the switching defective/sucrose nonfermenting-type chromatin remodeling complex, (iii) transcription coactivator activity, and (iv) translation factor activity. Here we demonstrate that sumoylation of the IkappaB kinase homolog immune response-deficient 5 plays an important role in the induction of antimicrobial peptide genes through a highly conserved sumoylation consensus site during bacterial challenge. Taken together, the proteomics data presented here provide a unique avenue for a comparative functional analysis of proteins involved in innate immune reactions in flies and mammals. PMID- 23749870 TI - cis-regulatory change associated with snake body plan evolution. PMID- 23749871 TI - Sticky bacteriophage protect animal cells. PMID- 23749872 TI - Therapeutic potential of deglycosylated antibodies. PMID- 23749873 TI - Exogenous Reelin modifies the migratory behavior of neurons depending on cortical location. AB - Malformations of cortical development can arise when projection neurons generated in the germinal zones fail to migrate properly into the cortical plate. This process is critically dependent on the Reelin glycoprotein, which when absent leads to an inversion of cortical layers and blurring of borders. Reelin has other functions including supporting neuron migration and maintaining their trajectories; however, the precise role on glial fiber-dependent or -independent migration of neurons remains controversial. In this study, we wish to test the hypothesis that migrating cortical neurons at different levels of the cortical wall have differential responses to Reelin. We exposed neurons migrating across the cortical wall to exogenous Reelin and monitored their migratory behavior using time-lapse imaging. Our results show that, in the germinal zones, exogenous Reelin retarded neuron migration and altered their trajectories. This behavior is in contrast to the response of neurons located in the intermediate zone (IZ), possibly because Reelin receptors are not expressed in this zone. In the reeler cortex, Reelin receptors are expressed in the IZ and exposure to exogenous Reelin was able to rescue the migratory defect. These studies demonstrate that migrating neurons have nonequivalent responses to Reelin depending on their location within the cortical wall. PMID- 23749875 TI - Brain signal variability is parametrically modifiable. AB - Moment-to-moment brain signal variability is a ubiquitous neural characteristic, yet remains poorly understood. Evidence indicates that heightened signal variability can index and aid efficient neural function, but it is not known whether signal variability responds to precise levels of environmental demand, or instead whether variability is relatively static. Using multivariate modeling of functional magnetic resonance imaging-based parametric face processing data, we show here that within-person signal variability level responds to incremental adjustments in task difficulty, in a manner entirely distinct from results produced by examining mean brain signals. Using mixed modeling, we also linked parametric modulations in signal variability with modulations in task performance. We found that difficulty-related reductions in signal variability predicted reduced accuracy and longer reaction times within-person; mean signal changes were not predictive. We further probed the various differences between signal variance and signal means by examining all voxels, subjects, and conditions; this analysis of over 2 million data points failed to reveal any notable relations between voxel variances and means. Our results suggest that brain signal variability provides a systematic task-driven signal of interest from which we can understand the dynamic function of the human brain, and in a way that mean signals cannot capture. PMID- 23749876 TI - Intradural spinal tumours and their mimics: a review of radiographic features. AB - Intradural spinal tumours, although relatively uncommon, can be diagnostically challenging, and often result in significant morbidity. They can be subdivided according to their cell of origin and whether they are within the cord (intramedullary) or intradural but extramedullary in location. The differential diagnosis for masses of the cauda equina region is often considered separately. Additionally, some inflammatory processes, cysts, benign tumour-like masses and vascular malformations may mimic intradural tumours. Although in many instances, a precise preoperative diagnosis is not possible as many of the imaging findings overlap, some features may strongly suggest one diagnosis over others. This article reviews the range of intradural spinal tumours in the adult and paediatric populations, with an emphasis on pertinent imaging characteristics. An approach is provided for distinguishing tumours from lesions that mimic tumours and for narrowing the differential diagnosis according to imaging findings. PMID- 23749877 TI - Detection of previously unknown fumonisin P analogue mycotoxins in a Fusarium verticillioides culture by high-performance liquid chromatography-electrospray ionization time-of-flight and ion trap mass spectrometry. AB - Five previously unknown fumonisin mycotoxins (iso-FP1, iso-FP(2,3a), iso FP(2,3b), FP4 and iso-FP4) and three previously described FP analogues (FP(1-3)) were detected in a solid rice culture inoculated with Fusarium verticillioides. The fumonisins were characterized by high-performance liquid chromatography electrospray ionization time-of-flight mass spectrometry (HPLC-ESI-TOFMS) and ion trap mass spectrometry (ITMS). The FP isomers were separated by using a flat gradient on a special, high-coverage C18, narrow-bore HPLC column (YMC-Pack J'sphere ODS H80), which was suggested for the separation of structural isomers. The verified structures of the FP(1-3) mycotoxins, the relative retention times (by HPLC-ESI-TOFMS and ITMS), the exact masses of the molecular ions (by TOFMS) and the masses of the product ions, including the hydrocarbon backbones (by ITMS) of the new compounds, strongly suggested their structures. PMID- 23749874 TI - Anxious/depressed symptoms are linked to right ventromedial prefrontal cortical thickness maturation in healthy children and young adults. AB - The relationship between anxious/depressed traits and neuromaturation remains largely unstudied. Characterizing this relationship during healthy neurodevelopment is critical to understanding processes associated with the emergence of child/adolescent onset mood/anxiety disorders. In this study, mixed effects models were used to determine longitudinal cortical thickness correlates of Child Behavior Checklist (CBCL) and Young Adult Self Report Anxious/Depressed scores in healthy children. Analyses included 341 subjects from 4.9 to 22.3 year old with repeated MRI at up to 3 time points, at 2-year intervals (586 MRI scans). There was a significant "CBCL Anxious/Depressed by Age" interaction on cortical thickness in the right ventromedial prefrontal cortex (vmPFC), including the medial orbito-frontal, gyrus rectus, and subgenual anterior cingulate areas. Anxious/Depressed scores were negatively associated with thickness at younger ages (<9 years), but positively associated with thickness at older ages (15-22 years), with the shift in polarity occurring around age 12. This was secondary to a slower rate of vmPFC cortical thinning in subjects with higher scores. In young adults (18-22 years), Anxious/Depressed scores were also positively associated with precuneus/posterior cingulate cortical thickness. Potential neurobiological mechanisms underlying this maturation pattern are proposed. These results demonstrate the dynamic impact of age on relations between vmPFC and negative affect in the developing brain. PMID- 23749878 TI - Stability-indicating HPLC-DAD determination of ribavirin in capsules and plasma. AB - A simple, selective and stability-indicating high-pressure liquid chromatographic method was developed for the analysis of ribavirin. Chromatographic separation was achieved by using a CPS Hypersil cyano column (4.6 * 250 mm, 5 um particle size) with isocratic elution of the mobile phase, which was composed of 50 mM phosphate buffer, adjusted at pH 4 with phosphoric acid. The mobile phase was pumped at a flow rate of 0.8 mL/min. The detector was set at 240 nm and quantification of the analyte was based on peak area measurement. The method was validated with respect to linearity, range, precision, accuracy, selectivity, robustness, limit of detection and limit of quantitation. The calibration curve was linear in the range of 5-200 ug/mL with correlation coefficient > 0.999. Ribavirin was subjected to forced degradation studies under two conditions: mild and extensive stress testing. These studies included the effects of hydrolysis (neutral, acidic and alkaline) and oxidation, photolysis and dry heat). The proposed method was proved to be stability-indicating by the resolution of the drug from its forced degradation products, making use of the diode array detector as a tool for confirmation of peak identity and purity. Moreover, the kinetics of alkaline degradation of ribavirin were investigated, an Arrhenius plot was constructed and the activation energy was calculated. The developed method was also extended to analyze ribavirin in capsules and in human plasma with good recovery values. PMID- 23749879 TI - A pain in the neck. PMID- 23749880 TI - Mesothelioma and anti-Ma paraneoplastic syndrome; heterogeneity in immunogenic tumours increases. AB - We present a patient with opsoclonus and diffuse cerebellar signs who had an anti Ma2 antibody-associated paraneoplastic syndrome secondary to a sarcomatoid mesothelioma. This case highlights the importance of early tumour detection, instigation of therapeutic measures, and the heterogeneity of underlying malignancies in neurological paraneoplastic syndromes. PMID- 23749881 TI - A dialogue: how to run an educational meeting for GPs. PMID- 23749882 TI - Junctional adhesion molecules in cerebral endothelial tight junction and brain metastasis. AB - Brain metastasis is one of the most deadly types of metastasis, frequently seen as a result of cancer spread from lung cancer, breast cancer and malignant melanoma. A key cellular structure in controlling brain metastasis is the blood brain barrier (BBB). The BBB is known to protect metastatic tumour cells from chemotherapy and antitumor immunity. On the other hand, the BBB is also a key cellular structure which cancer cells must breach before settling in brain tissues. Tight junctions (TJs), central to the BBB, have received much attention in recent decades. There has been progress in investigating cerebral TJs and brain microvascular endothelial cells. Junctional adhesion molecules (JAMs) are transmembrane proteins within TJs and have been shown to be key to the integrity of the BBB and to play a role in controlling brain metastasis. The current article summarizes the recent progress in the regulation of JAMs in BBB TJs and the signaling pathways involved during brain metastasis. PMID- 23749883 TI - Inguinal canal tumors of adulthood. AB - AIM: To review benign and malignant paratesticular lesions. MATERIALS AND METHODS: A non-systematic review of the English literature in the National Library of Medicine Database (MEDLINE) was performed using the key words "spermatic cord", "inguinal canal", "neoplasms" (focusing on soft tissue sarcomas). The 74 most significant contributions were selected. RESULTS: Although generally benign (lipoma is the most frequent), paratesticular tumors have a high incidence of malignancy (30%). Ultrasonography, computed tomography and magnetic resonance imaging represent the main tools in the evaluation of a solid paratesticular mass. Most malignant tumors are sarcomas and commonly spread via local invasion to adjacent structures. The definitive diagnosis is made postoperatively. Surgical excision in the form of radical orchiectomy and wide local resection of tumor margins is mandatory and represents the mainstay of treatment options. CONCLUSION: Surgical treatment of paratesticular tumors is fundamental in order to determine the histology so as to define the correct follow-up for each patient. PMID- 23749884 TI - Endoscopic and endobronchial ultrasound-guided needle aspiration in the mediastinal staging of non-small cell lung cancer. AB - Invasive staging of mediastinal lymph nodes is recommended for the majority of patients with potentially resectable non-small cell lung cancer. In the past, 'blind' transbronchial needle aspiration during bronchoscopy and mediastinoscopy, a surgical procedure conducted under general anesthesia, were the only diagnostic methods. The latter is still considered the 'gold standard'; however, two novel, minimally-invasive techniques have emerged for the evaluation of the mediastinum: endoscopic (transesophageal) and endobronchial ultrasound--both performed using a dedicated echoendoscope, facilitating the ultrasound-guided, real-time aspiration of mediastinal lymph nodes. These methods are well-tolerated under local anesthesia and moderate sedation, with very low complication rates. Current guidelines on the invasive mediastinal staging of lung cancer still state that a negative needle aspiration result from these methods should be confirmed by mediastinoscopy. As more experience is gathered and echoendoscopes evolve, a thorough endosonographic evaluation of the mediastinum by both techniques, will obviate the need for surgical staging in the vast majority of patients and reduce the number of futile thoracotomies. PMID- 23749885 TI - Is there a benefit from addiction to anti-VEGF therapy in patients with colorectal cancer? AB - Studies carried out through the past two decades have evidenced that addition of bevacizumab to chemotherapy improves the efficacy both in first-line and second line treatment in patients with metastatic colorectal cancer. Benefit of adding bevacizumab to second-line regimen after failing a bevacizumab-containing regimen, or aflibercept plus FOLFIRI) (irinotecan, 5-FU and leucovorin) after failing first-line oxaliplatin regimen with or without bevacizumab or regorafenib as a salvage therapy, do indicate the addiction to anti-vascular endothelial growth factor (VEGF) agents in these patients. This concept also lends some support from the NSABP C-08 adjuvant trial of colon cancer which showed very substantial improvement in time-to-recurrence for the one year of bevacizumab administration, but this benefit was quickly lost once the drug was stopped. The author reviews the data on anti-VEGF therapy in metastatic colorectal cancer. PMID- 23749886 TI - Expression of VEGF and its receptors VEGFR1/VEGFR2 is associated with invasiveness of bladder cancer. AB - AIM: Vascular endothelial growth factor (VEGF) signaling is frequently altered in invasive tumor cells and is associated with patient outcome. In the present study, we examined VEGF, VEGFR1, and VEGFR2 expression in non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC), and evaluated the association between VEGF and its receptors with disease characteristics and bladder cancer recurrence. MATERIALS AND METHODS: Tissue microarrays containing bladder cancer specimens (n=212) and adjacent normal bladder mucosa (n=131) were immunostained using antibodies against VEGF, VEGFR1, and VEGFR2. The association between the expression of these proteins and clinical parameters including stage, lymph node metastasis, and recurrence-free survival were statistically evaluated. VEGF mRNA expression data were extracted from the public Oncomine database. RESULTS: VEGF and VEGFR1 mRNA levels were significantly higher in bladder cancer specimens than that of normal mucosa (for VEGF, p<0.001; for VEGFR1, p=0.02). Analysis of their expression at protein levels showed that levels of VEGF and VEGFR1 were significantly higher in NMIBC than in MIBC (p<0.001), while that of VEGFR2 was significantly higher in all cancer specimens compared to benign urothelial mucosa (p=0.001). Further-more, the expression of VEGFR2 was significantly higher in MIBC, as compared to NMIBC (p<0.001). Patients with higher levels of VEGF, VEGFR1, and VEGFR2 tended to have poorer recurrence-free survival than those with lower levels, but this was not statistically significant. CONCLUSION: Our results suggest that alterations in the expression of VEGF and VEGF receptors are associated with disease stage and recurrence. PMID- 23749888 TI - Sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor requires E-cadherin in esophageal cancer and malignant pleural mesothelioma. AB - BACKGROUND/AIM: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) has limited anticancer efficacy in EGFR-positive esophageal cancer (EsC) and malignant mesothelioma (MPM). The underlying molecular mechanism of resistance to EGFR-TKI in these types of cancer remains unclear. MATERIALS AND METHODS: We tested sensitivity to EGFR-TKI, expression/activity of common signal transduction pathways and epithelial to mesenchymal transition (EMT) gene signatures in 14 EsC and MPM cultured cell lines in vitro. RESULTS: More than 50% EGFR-positive EsC and MPM cells were resistant to EGFR-TKI, and susceptibility to EGFR-TKI growth inhibitory effect correlated positively with expression of E-cadherin (epithelial gene marker) and negatively with mesenchymal gene markers. Acquired resistance to EGFR-TKI in intrinsically sensitive cancer cells coincided with spontaneous loss of E-cadherin, while ectopic expression of E-cadherin sensitized resistant cells to EGFR-TKI. CONCLUSION: E-Cadherin expression appears to be not only a strong biomarker but also a functional requirement and potential therapeutic target for sensitivity to EGFR-TKI. PMID- 23749887 TI - Acetaminophen enhances cisplatin- and paclitaxel-mediated cytotoxicity to SKOV3 human ovarian carcinoma. AB - BACKGROUND: Ovarian cancer is commonly treated with cisplatin/paclitaxel but many tumors become resistant. Acetaminophen reduced glutathione and enhanced chemotherapy efficacy in hepatic cancer treatment. The objective of this study was to examine if acetaminophen enhances the cytotoxicity of cisplatin/paclitaxel in ovarian cancer. MATERIALS AND METHODS: SKOV3 human ovarian carcinoma cells in vitro and a subcutaneous tumor nude rat model were used and treated with cisplatin/paclitaxel with or without acetaminophen. RESULTS: In vitro, acetaminophen enhanced apoptosis induced by cisplatin and paclitaxel with similar effects on glutathione, reactive oxygen species and mitochondrial membrane potential, but different effects on nuclear factor erythroid 2-related factor 2 (NRF2) translocation. In vivo, acetaminophen was uniformly distributed in tissues and significantly reduced hepatic glutathione. Acetaminophen enhanced the cisplatin chemotherapeutic effect by reducing tumor recurrence. CONCLUSION: Our results suggest that acetaminophen as a chemoenhancing adjuvant could improve the efficacy of cisplatin and paclitaxel in treating patients with ovarian carcinoma and other tumor types. PMID- 23749889 TI - Central role of beta-catenin in anticancer effects of cardiac hormones. AB - BACKGROUND: beta-Catenin causes malignant growth of colonic, pancreatic and renal cancer. Four cardiac hormones, namely atrial natriuretic peptide (ANP), vessel dilator, long-acting natriuretic peptide (LANP) and kaliuretic peptide eliminate up to 80% of human pancreatic carcinomas growing in mice. MATERIALS AND METHODS: Four cardiac hormones were evaluated for their ability to reduce the expression of human beta-catenin, measured by enzyme-linked immunosorbent assay (ELISA) in human colorectal, pancreatic and renal cancer cells. RESULTS: Vessel dilator, LANP, kaliuretic peptide, and ANP, over a concentration range of 100 pM to 10 MUM, maximally reduced expression of beta-catenin in human colorectal cancer cells by 78%, 71%, 69%, and 83%, respectively. Vessel dilator, LANP, kaliuretic peptide, and ANP reduced beta-catenin expression in human pancreatic cancer cells by 76%, 66%, 72%, and 88%, and by 64%, 54%, 58% and 73%, in human renal cancer cells, respectively. CONCLUSION: Part of the anticancer action of these four cardiac hormones is a potent inhibition of beta-catenin. PMID- 23749890 TI - Hedgehog targeting by cyclopamine suppresses head and neck squamous cell carcinoma and enhances chemotherapeutic effects. AB - BACKGROUND: The hedgehog signaling pathway (HH) is involved in tumorigenesis in a variety of human malignancies. In head and neck squamous cell carcinomas (HNSCC), Hh overexpression was associated with poor prognosis. Therefore, we analyzed the effect of Hh signaling blockade with cyclopamine on colony formation of cells from HNSCC samples. PATIENTS AND METHODS: HNSCC biopsies were cultured alone for reference or with serial dilutions of cyclopamine (5-5,000 nM), docetaxel (137.5 550 nM), or cisplatin (1,667-6,667 nM) and their binary combinations. Cytokeratin positive colonies were counted after fluorescent staining. RESULTS: Cyclopamine concentration-dependently inhibited HNSCC ex vivo [(IC50) at about 500 nM]. In binary combinations, cyclopamine additively enhanced the suppressive effects of cisplatin and docetaxel on HNSCC colony formation. CONCLUSION: Our findings define SMO--a Hh component- as a potential target in HNSCC and suggest the utility of Hh targeting in future multimodal treatment regimens for HNSCC. PMID- 23749891 TI - Hyaluronic acid-decorated PLGA-PEG nanoparticles for targeted delivery of SN-38 to ovarian cancer. AB - BACKGROUND: Extreme hydrophobicity and poor stability of SN-38, a highly potent topoisomerase I inhibitor, has prevented its clinical use. Its encapsulation into nanoparticles may be a way to overcome these problems. Here we report the use of SN-38-loaded hyaluronic acid (HA)-decorated poly(lactic-co-glycolic acid) polyethylene glycol (PLGA-PEG) nanoparticles (NPs) for targeted ovarian cancer therapy. MATERIALS AND METHODS: PLGA-PEG nanoparticles loaded with SN-38 were prepared by single- emulsion (O/W) solvent evaporation method. HA was decorated onto the nanoparticles by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) coupling and the extent of HA conjugation was quantified by hexadecyltrimmethylammonium bromide (CTAB) assay. Cancer cell specificity of the NPs was determined by flow cytometry and cytotoxicity of the NPs was tested by 3 [4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium (MTT) bromide assay. RESULTS: Mean size, zeta potential and encapsulation efficiency of PLGA-PEG-HA NPs were 265.6 +/- 3.8 nm, -30.4 +/- 0.1 mV and 75.8 +/- 4.1%, respectively. Cellular uptake of PLGA-PEG-HA NPs was 8- and 16-fold higher in CD44-positive cell lines, SKOV-3 and OVCAR-8, as compared to CD44-negative cells (CHO). Cytotoxicity of the targeted NPs was significantly higher as compared to non-targeted NPs for the above cell lines. These results suggest that PLGA-PEG-HA NPs could be an efficient delivery system for SN-38 for targeted therapy of ovarian cancer. PMID- 23749892 TI - Targeting renal cancer with a combination of WNT inhibitors and a bi-functional peptide. AB - AIM: Advanced renal cancer has still a very poor prognosis. We combined wingless related integration site (WNT) inhibitors with a bi-functional peptide, as previous research has proven their individual efficacy in cancer therapy. Each targets cancer cells differently. We wanted to determine whether they have an additive effect. MATERIALS AND METHODS: Our bi-functional peptide consists of a target domain (LTVSPWY) and a lytic domain (KLAKLAK)2. We used three WNT inhibitors: Ethacrinic acid, ciclopirox olamine, piroctone olamine and combined each with the bi-functional peptide. They were tested on three different renal cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: We demonstrated a synergistic effect of WNT inhibitors with the bi-functional peptide. The vitality of cancer cells was reduced significantly (p<0.05), while healthy cells were mostly unaffected. CONCLUSION: The combination of WNT inhibitor and the bi-functional peptide may lead to new treatment options as toxic side-effects can be reduced due to the lower doses of agent required. PMID- 23749893 TI - IGF-IEc expression is associated with advanced clinical and pathological stage of prostate cancer. AB - BACKGROUND: Recent evidence suggests a role for the insulin-like growth factor 1Ec (IGF-IEc) transcript variant in cancer biology. The aim of the present study was to investigate whether IGF-IEc expression is associated with prostate cancer stage. MATERIALS AND METHODS: Formalin-fixed and paraffin-embedded prostate cancer surgical specimens from 83 patients were assessed by immunohistochemistry for IGF-IEc expression. RESULTS: Normal prostate epithelium was negative or demonstrated mild IGF-IEc cytoplasmic expression whereas prostate cancer exhibited mild to strong cytoplasmic immunoexpression. The mean IGF-1Ec expression, was significantly lower (p=0.004) in localized (stage <= IIb) prostate cancer, compared to locally advanced tumors (stage >= III). Only one out of 83 (1.2%) prostate cancer samples was completely negative for IGF-IEc. A weak positive correlation was also observed between IGF-IEc expression levels and Gleason score (r=0.247; p=0.024). CONCLUSION: The present data demonstrate that the expression of IGF-IEc is positively-associated with more advanced stage and higher Gleason score of prostate carcinomas. PMID- 23749894 TI - Changes in thymidine phosphorylase gene expression related to treatment of rectal cancer. AB - BACKGROUND: The enzyme thymidine phosphorylase (TYMP) has tumor-promoting functions and its expression is often elevated in tumors. PATIENTS AND METHODS: TYMP gene expression in tumorous and mucosal tissues was assessed using real-time polymerase chain reaction, in a study of patients with rectal cancer where chemotherapy and radiotherapy were given sequentially. RESULTS: TYMP levels decreased after chemotherapy. For patients given radiotherapy, there was a significant increase in TYMP expression comparing biopsies before and after radiotherapy. The increase was also observed in the mucosa, although it was less pronounced. CONCLUSION: Cancer treatment alters gene expression in tumor and adjacent mucosa of patients with rectal cancer. Chemotherapy may cause a decrease in TYMP gene expression, whereas radiotherapy, given as adjuvant treatment, causes a significant increase in expression. These results are of importance when interpreting TYMP expression data in rectal cancer and may be of clinical interest as TYMP participates in the activation of capecitabine. PMID- 23749895 TI - Assessment of planning target volume margin for a small number of vertebral metastatic lesions using image-guided intensity-modulated radiation therapy by helical tomotherapy. AB - AIM: To evaluate an appropriate planning target volume (PTV) margin in for one to three vertebral metastases using megavolt computed tomography (MVCT) images during the course of image-guided and stereotactic intensity-modulated radiotherapy (IGRT-IMRT) by use of helical tomotherapy. PATIENTS AND METHODS: A total of 25 lesions in 24 patients with vertebral metastases who received IGRT IMRT were analyzed. MVCT images were acquired before and after radiation therapy. Intra-fractional movement and PTV margin were calculated by comparing treatment planning images and these 310 MVCT images for right-left (RL), superior-inferior (SI), and anteroposterior (AP) dimensions. Five patients were treated by 35 Gy/5 fractions, 17 by 30 Gy/5 fractions, one by 25 Gy/5 fractions, and one by 60 Gy/30 fractions. A margin to compensate for these variations was calculated with the formula of vanHerk's equation. RESULTS: The intra-fractional motion was 0.02 ( 1.3 to 1.4) +/- 0.34 mm in the RL direction, -0.09 (-1.8 to 0.28) +/- 0.44 mm in the SI direction, and 0.20 (-1.8 to 1.8) +/- 0.36 mm in the AP direction. The required PTV margin was 0.98 mm in the RL direction, 0.69 mm in the SI direction, and 1.26 mm in the AP direction. No patient showed a deviation greater than 2 mm. CONCLUSION: The PTV margin in hypofractionated IGRT-IMRT, using helical tomotherapy for a few vertebral metastases, was 2 mm or less and our tentative PTV margin of 5 mm was sufficient and reducible. PMID- 23749896 TI - Unexpected alteration of beta-catenin and c-KIT expression by 5-FU and docetaxel in p16-positive squamous cell carcinoma compared to HPV-negative HNSCC cells in vitro. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide. In several tumour entities, the tyrosine kinase receptor c-KIT is associated with tumour transformation in the epithelial tissue in cases of aberrant expression. Furthermore, tumour development and dissemination are a result of dysregulated cellular pathways such as the WNT/beta catenin pathway. beta-Catenin is a multifunctional protein within the canonical WNT signalling pathway and a pivotal factor for the stabilization of cell-cell interactions. In malignant tissues, beta-catenin triggers tumour proliferation and progression. The aim of this study is to investigate the expression patterns of c-KIT and beta-catenin in human papillomavirus-negative and p16-positive SCC and to evaluate the chemosensitivity of the tumour cells to the chemotherapeutical agents docetaxel and 5-fluorouracil (5-FU). MATERIALS AND METHODS: We incubated the tumour cell lines with docetaxel (5 MUmol/ml) and 5-FU (1 MUmol/ml) and detected beta-catenin and c-KIT by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) after 48, 72, 120, 192 and 240 h. RESULTS: We found a reliable trend towards decreased beta-catenin expression levels in p16-positive and p16-negative tumour cell lines when incubated with docetaxel, in addition to induced apoptotic effect. At best, 5-FU had a slight influence on the alteration of the expression of beta-catenin. Dose escalation of docetaxel and 5-FU had no statistically significant effect on the expression of beta-catenin or c-KIT. In HPV-negative HNSCC, a reduced expression level of beta catenin and c-KIT was detected in an incubation period-dependent manner. p16 transformed SCC (CERV196) cells were characterized by a reduced susceptibility to docetaxel induced alteration of beta-catenin expression. CONCLUSION: We were unable to confirm the clinically-substantiated increased chemosensitivity of p16 positive tumour cells in vitro. Extended studies and clinical trials are needed to investigate these findings further in HPV-associated HNSCC. PMID- 23749897 TI - Lipid profiles for HER2-positive breast cancer. AB - BACKGROUND: Accumulating data indicate that human epidermal growth factor receptor-2 (HER2)-positive breast cancer is a heterogeneous disease. We undertook a study to correlate lipid profiles with heterogeneous clinicopathological features of HER2-positive breast cancer. MATERIALS AND METHODS: Histology directed matrix-assisted laser desorption/ionization (MALDI)-mass spectrometry (MS) analyses were performed on 22 retrospective frozen tissue samples collected from patients with HER2-positive metastatic breast cancer, in order to correlate lipid profiles with clinicopathological characteristics. Additionally, a pair of tumor and adjacent normal tissue was profiled to identify cancer-associated changes in lipid profiles. RESULTS: Sphingomyelin 34:1, phosphatidylcholine (PC) 32:0, and PC 34:1, and PC 36:2 were overexpressed in HER2-positive breast cancer compared to adjacent normal tissue (HER2 signature). Lipid MALDI-MS profiles were different between Ki-67-high and Ki-67-low tumors. The proliferation signature (Ki-67-high vs. Ki-67-low) and the HER2 signature (cancer vs. normal) did not significantly overlap with each other. CONCLUSION: For the first time to our knowledge, this study describes lipid profiles correlated with various clinicopathological characteristics of HER2-positive breast cancer. Lipid profiling might be helpful for the molecular characterization of this disease. PMID- 23749898 TI - Antiestrogens suppress effects of transforming growth factor-beta in breast cancer cells via the signaling axis estrogen receptor-alpha and Y-box Binding Protein-1. AB - BACKGROUND: Multifunctional Y-box Binding Protein-1 (YB1) is correlated with a poor outcome in breast cancer. We found YB1 expression to be regulated by antiestrogens commonly used in the hormonal therapy of breast cancer and known as activators of Transforming Growth Factor-beta (TGFbeta). Thus, a putative influence of YB1 on TGFbeta signaling should be investigated. MATERIALS AND METHODS: The effect of YB1 on TGFbeta signaling was monitored by expression analysis and reporter gene assays in breast cancer cells overexpressing YB1 and treated with antiestrogens. RESULTS: Antiestrogen-mediated inhibition of estrogen receptor-alpha led to a suppression of YB1 protein synthesis. On the other hand, YB1 was found to be an enhancer of TGFbeta signaling. CONCLUSION: High levels of YB1 expression lead to a stimulation of TGFbeta pathways, thereby counteracting antihormonal breast cancer therapy and representing a putative resistance mechanism. PMID- 23749899 TI - Cytokine changes in response to radio-/chemotherapeutic treatment in head and neck cancer. AB - BACKGROUND: Radiation and systemic chemotherapy are standard treatment strategies for advanced or metastatic head and neck cancer. However, little is known about the implications and changes in the tumor microenvironment, including the T helper (TH)1/TH2 balance in response to these treatment regimens. The aim of the current study was to unravel the effects of chemotherapeutic drugs and radiation on cytokine changes. MATERIALS AND METHODS: In this study, the effect of radiation and chemotherapeutic treatment (5-fluorouracil and cisplatin) on eight cell lines was determined. Before and after exposure, cytokine levels in culture supernatants of cell lines were evaluated using the Bio-Plex Assay (Bio-Rad) and the Human TH1/TH2 Cytometric Bead Array (Becton Dickinson). Results were correlated with parallel measurements for cellular proliferation assessed by cytotoxicity assay. RESULTS: Seven out of eight cell lines of primary tumors or metastases demonstrated an enhanced level of the cytokines interleukin (IL) 1beta, IL-6, IL-8, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha), after sub-lethal radiation doses. Under treatment with low concentrations of 5-fluorouracil and cisplatin, all examined cell lines showed an increasing secretion of the cytokines IL-6 and G-CSF. In contrast, sub-lethal doses of both cytostatic drugs revealed a dose-dependent decrease in secretion IL 1beta. Regarding GM-CSF and TNF-alpha, we demonstrated an increase in secretion by the primary tumors under low doses of 5-fluorouracil and cisplatin, whereas the metastases showed a sharp drop of GM-CSF and TNF-alpha secretion. Chemotherapeutic treatment led to no changes of the IL-8 cytokine profile. CONCLUSION: The results suggest complex cytokine changes of the tumor microenvironment and more aberrant expression profiles under treatment with radiation and the chemotherapeutic drugs 5-fluorouracil and cisplatin. PMID- 23749900 TI - The AutoDiSC: development and validation of a novel chemotherapy sensitivity and resistance assay. AB - BACKGROUND: Measurement of cell survival as performed by the differential staining cytotoxicity (DiSC) assay allows for a comprehensive prediction of individual chemotherapy response. This assay has not reached routine clinical application because of its several limitations. In order to improve the DiSC assay, we developed a new type of chemotherapy sensitivity and resistance assay (CSRA) by combining a novel evaluation methodology with automated measurement of cell survival based on flow cytometry, termed AutoDiSC. MATERIALS AND METHODS: Tumour cell lines were treated with cytostatic drugs and cultured in 96-well plates for four days at 37 degrees C. Subsequently, propidium iodide was added and 96-well plates were analyzed using flow cytometry in order to determine the number of living cells in each well. Each component was evaluated for reproducibility and impact on assay read-out. RESULTS: The evaluation process allowed for specification of all relevant parameters that determine assay performance. CONCLUSION: AutoDiSC is a new fully-automated CSRA which meets all criteria required for routine clinical use. PMID- 23749901 TI - Combination of CYP inhibitor with MEK/ERK inhibitor enhances the inhibitory effect on ERK in BRAF mutant colon cancer cells. AB - BACKGROUND/AIM: To investigate mechanisms of discrepancy in response to a MEK/ERK inhibitor, U0126, in KRAS- and BRAF-mutant colorectal cancer cells. MATERIALS AND METHODS: Multiparametric flow cytometry was performed on two colon cancer cell lines, HCT116 and HT29. Cells were treated with U0126, and phospho-specific antibodies were used to monitor ERK signaling. RESULTS: HCT116 and HT29 cells were treated with increasing amounts of U0126. The western blot analysis revealed that by increasing the amount of U0126 resulted in inhibition of phospho-ERK, in HCT116 and to a lesser degree in HT29 cells. Microarray profiling identified CYP1A1 and 1A2 overexpression in HT29 cells and that inhibition of CYP1A1 with alpha-naphthoflavone and furanfylline restored sensitivity to U0126 in HT29 cells. CONCLUSION: Combination of a CYP inhibitor with MEK/ERK inhibitor enhances the inhibitory effect on ERK in BRAF-mutant colon cancer cells. PMID- 23749902 TI - Correlation of phosphorylated HER2 with clinicopathological characteristics and efficacy of trastuzumab treatment for breast cancer. AB - AIM: To determine the correlation of phosphorylated human epidermal growth factor receptor-2 (pHER2) with clinicopathological characteristics of breast cancer (BC) and patients' response to trastuzumab-based therapy. PATIENTS AND METHODS: pHER2 was determinated immuno-histochemically in 88 cases of HER2-positive and 50 cases of HER2-negative BC. All patients with HER2-positive BC received trastuzumab based therapy and 16 of them (18.2%) had disease progression during therapy treatment (i.e. trastuzumab-resistant). RESULTS: pHER2 was predominantly expressed in HER2-positive BC, with 55 cases (62.5%) of tumours expressing pHER2. Six cases of HER2-negative cancer (12.5%) displayed positive expression of pHER2. Expression of pHER2 correlated with younger age of patients and negative oestrogen receptor status. Acquisition of resistance to trastuzumab correlated with negativity for pHER2 (p=0.028). CONCLUSION: Positive expression of pHER2 may yield additional information regarding the poor prognosis of BC and could be used for pre-selection of patients with HER2-overexpressing BC displaying resistance to trastuzumab treatment. PMID- 23749903 TI - Design, synthesis and in vitro anticancer evaluation of a stearic acid-based ester conjugate. AB - AIM: Chemical synthesis and characterization of a lipophilic ester conjugate, propofol stearate and evaluation of its anticancer efficacy on human breast cancer cell lines MDA-MB-361, MCF-7 and MDA-MB-231. MATERIALS AND METHODS: The chemical structure of the synthesized conjugate was characterized by spectroscopic studies. Its anticancer potential was evaluated on the basis of growth inhibition, cancer cell adhesion and migration and apoptosis induction. RESULTS: Propofol stearate exhibited significant (p<0.05) growth inhibition of breast cancer cells in a concentration-dependent manner. MDA-MB-231 cells showed highest susceptibility towards the inhibitory effect of the conjugate. Moreover, treatment of MDA-MB-231 cancer cells with 25 MUM propofol stearate potentially suppressed their adhesion (~34%) and migration (~41%), and induced apoptosis (~25%). CONCLUSION: Exogenously-applied stearic acid as an ester derivative, inhibits the growth of human breast cancer cells and shows a beneficial role in the treatment of breast cancer, in vitro. PMID- 23749904 TI - Immunological characterization of glioblastoma cells for immunotherapy. AB - The aim of this study was the immunological characterization of glioblastoma cells. Glioblastoma cell lines were cultured in serum and serum-free neurobasal (NBE) medium conditions. These cell lines were characterized by flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR), western blot and natural killer (NK) cell-cytotoxicity assays. A previously described NK cell expansion method that uses K562 cells expressing interleukin (IL)-15 and 4-1 BB Ligand (BBL) (K562-mb15-41BBL) was used. RT-PCR and western blots for the expression of tumor-associated antigens (TAAs), were carried out in 32 glioblastoma and seven normal brain tissues. U87 and U343 tumor cell lines showed increased expression for major histocompatibility complex (MHC)-I and -II molecules. No significant differences in the levels of CD133, MHC class I/II, MHC class I-related chain A (MICA), MICB, UL16 binding protein 1-3 (ULBP 1-3) expression in these cell lines and in NK cell cytotoxicity were observed between serum and NBE conditions. Regardless of culture conditions, U87 and U343 cell lines were sensitive to expanded NK cells, with median cytotoxicities at 4:1 effector/target ratio of 43.2% and 46.5%, respectively. In RT-PCR, U343 and U87 showed the expression of most TAAs at a high ratio compared with U251. Western blots demonstrated positive expression for BIRC5, CD99 and ERBB2 in U251, U87 and U343 cell lines and tissues. These highly-expressed TAAs such as BIRC5, CD99 and ERBB2 in glioblastoma tissue could be the targets for immunotherapy. U87 and U343 cell lines could be useful for studying the efficacy of immunotherapy related to various TAAs and NK cell immunotherapy. PMID- 23749905 TI - Oral chemoprevention of skin cancer in mice by benzophenone sunscreens dioxybenzone and octabenzone in drinking water. AB - BACKGROUND: Sunscreen compounds with added benefit of skin cancer prevention have both public and commercial interests. Our earlier study using the Epstein-Barr virus early antigen in vitro assay reported on skin cancer chemoprevention potential of benzophenone sunscreens. We now report the in vivo antitumor activity of two of the benzophenone sunscreens which tested positively in the in vitro assay, octabenzone (UV-1) and dioxybenzone (UV-2), in the two-stage mouse skin carcinogenesis model using (+/-)-(E)-4-methyl-2-[-(E)-hydroxyamino]-5-nitro 6-methoxy-3-hexanamide (NOR-1) as inducer and 12-O-tetradecanoyl-phorbol-13 acetate (TPA) as promoter. MATERIALS AND METHODS: Pathogen-free, female hairless mice of HOS:HR-1 strain, 15 animals per control and test groups, were used. Skin tumors were induced by a single dose of NOR-1 (390 nmol in 100 MUl of acetone). One week later, TPA (1.7 nmol in 100 MUl of acetone) was applied to skin twice weekly for 20 weeks as tumor a promoter. The test compounds UV-I or UV-2 were administered at 0.0025% to mice through drinking water ad libitum, starting one week prior to and stopping one week after tumor initiation. All animals were examined weekly for the development of skin papillomas. RESULTS: In both UV-1- and UV-2-treated mice, a two-week delay in tumor appearance, and significant inhibition (p<0.001) of tumor incidence (50% and 60%, respectively) and tumor burden (papilloma inhibition/mouse, 50% and 70%, respectively) were observed when compared to the positive control group. UV-2 (dihydroxy derivative) was a more potent inhibitor of skin tumor than UV-1 (monohydroxy derivative), which followed their antioxidant activity ranking. CONCLUSION: The results affirm the skin cancer chemoprevention potential of orally-ingested benzophenone sunscreens in mice and warrant studies in humans to validate synergistic protection achievable by complementation of oral and topical sunscreen usage. PMID- 23749906 TI - Cannabinoid receptor agonist as an alternative drug in 5-fluorouracil-resistant gastric cancer cells. AB - Fluorouracil is the main chemotherapeutic drug used for gastrointestinal cancers, which suffers the important problem of treatment resistance. There is little information whether cannabinoid agonists can be used as an alternative drug for fluorouracil-resistant gastric cancer cells. In this study, we investigated the effects of a cannabinoid agonist, WIN-55,212-2, on 5-fluorouracil (5-FU) resistant human gastric cancer cells, to examine whether the cannabinoid agonist may be an alternative therapy. Survival of the 5-FU-resistant gastric cancer cell line, SNU-620-5FU/1000, was not significantly reduced even by a high dose of 5-FU treatment. However, WIN-55,212-2 inhibited the proliferation of SNU-620-5FU/1000 and enhanced their apoptosis, as indicated by an increase of apoptotic cell proportion, activated caspase-3 and Poly (ADP-ribose) polymerase cleavage. Furthermore, WIN-55,212-2 reduced phospho-extracellular-signal-regulated kinases (ERK) 1/2, phospho-Akt (protein kinase B), B-cell lymphoma-2 (BCL2) and BCL2 associated X (BAX) protein expression in 5-FU-resistant gastric cancer cells. These results indicate that a cannabinoid agonist may, indeed, be an alternative chemotherapeutic agent for 5-FU-resistant gastric cancer. PMID- 23749907 TI - Lack of relevance of HIF-1alpha polymorphisms in breast cancer in a Portuguese population. AB - We aimed to study the prevalence of Hypoxia inducible factor-1alpha (HIF-1alpha) P582S and A588T polymorphisms in a Portuguese breast cancer population and its effect on the transcriptional activity of HIF-1alpha in MCF7 breast adenocarcinoma cells. We performed a polymerase chain Reaction--restriction fragment length polymorphism (PCR-RFLP)-based genotyping of a Portuguese breast cancer population for two HIF-1alpha polymorphisms. Furthermore, by site-directed mutagenesis, we generated a variant form of HIF-1alpha and compared its transcriptional activity with the wild-type HIF-1alpha in MCF7 cells. There were no significant differences in genotypic frequencies for P582S and A588T between breast cancer patients and controls, nor between the transcriptional activity of the 582S mutant and the wild-type HIF-1alpha. In conclusion, there is no association between HIF-1alpha polymorphisms and incidence of breast cancer in the Portuguese examined population. Furthermore, the P582S mutation does not affect transcriptional activity of HIF-1alpha in breast cancer cells, contrary to previous findings in other cell lines, suggesting that the impact of this mutation is cell-type specific. PMID- 23749908 TI - Up-regulation of DDX39 in human malignant pleural mesothelioma cell lines compared to normal pleural mesothelial cells. AB - Malignant pleural mesothelioma (MPM) is a malignant tumor originating from mesothelial cells existing in pleura. Since its incidence, it is closely related to the amount and time of exposure to asbestos, and the latency period after exposure to asbestos is very long, the incidence may increase over the next two decades. Since early detection is very difficult and there is no standard curative therapy, it is important to understand the biology of MPM, and to find biomarkers and molecular targets for its therapy. DDX39 is one of the Asp-Glu-Ala Asp (DEAD)-box RNA helicases, which are required for the export of mRNA out of the nucleus, and transcription, splicing and transport of mRNA. Some reports have shown differential expression of DDX39 in tumor cells or tissues such as lung squamous cell cancer, gastrointestinal stromal tumor and urinary bladder cancer. In the present study, the protein levels of DDX39 in the human MPM cell lines NCI H28, NCI-H2052 and NCI-H2452, and the human pleural mesothelial cell line MeT-5A were investigated by western blotting. The protein levels of DDX39 were found to be higher in NCI-H28, NCI-H2052 and NCI-H2452 compared to MeT-5A. The intensity of the bands of DDX39 in NCI-H28, NCI-H2052 and NCI-H2452 cells were increased by 1.351-, 1.887- and 2.024-fold, respectively, compared to MPM cells. These results suggest that DDX39 is a possible candidate biomarker for molecular-targeting of MPM. PMID- 23749909 TI - Unique microRNA expression profiles in cervical cancer. AB - Cervical cancer is the second leading cause of death among female patients with cancer in the world. Our aim was to analyze cervical cancer cases, in the Southwestern Transdanubian Region of Hungary, with regard to human papillomavirus (HPV) genotype and histological and clinical grading. After HPV testing and genotyping, the expressions of eight different pre-microRNAs (miR-21, miR-27a, miR-34a, miR-146a, miR-155, miR-196a, miR-203, miR-221) in formalin-fixed paraffin-embedded (FFPE) primary human cervical cancer samples were evaluated with the help of the LightCycler 480 PCR System (Roche). Statistically significant overexpression of miR-21 (p=0.004), miR-27a (p=0.018), miR-34a (p<0.001), miR-155 (p=0.021), miR-196a (p=0.032), miR-203 (p=0.037) and miR-221 (p=0.017) were observed in squamous cell carcinoma, regardless of HPV status and clinical grading. Significant overexpression of miR-21 (p=0.004), miR-27a (p=0.02), miR-34a (p<0.001), miR-196a (p=0.027) and miR-221 (p=0.031) was characteristic of HPV-positive squamous cell carcinomas in contrast to adenocarcinomas of the same HPV status. PMID- 23749910 TI - Alcohol and HER2 polymorphisms as risk factor for cardiotoxicity in breast cancer treated with trastuzumab. AB - BACKGROUND: Trastuzumab has no major side-effects except the potential for cardiac toxicity. The main objective of this study was to evaluate the association between trastuzumab-associated cardiac toxicity and two potential risk factors: alcohol intake and HER2 polymorphisms. PATIENTS AND METHODS: In a retrospective cohort study of 237 women with non-metastatic HER2-positive breast cancer treated with trastuzumab, traditional risk factors were assessed by review of medical records, alcohol use by an administered questionnaire to women (n=132), and HER2 polymorphisms (Ile655Val and Ala1170Pro) using TaqMan assays (n=73). RESULTS: Association was observed between alcohol intake (10 drinks and more per week) during the trastuzumab treatment and cardiac toxicity (p=0.04). For polymorphisms, compared to Ile/Ile carriers, HER2 Ile/Val was associated with a higher risk of cardiac toxicity (p=0.02). CONCLUSION: Heavy alcohol use during the course of trastuzumab treatment and the HER2 Ile/Val genotype may constitute risk factors for cardiac toxicity. PMID- 23749911 TI - Novel technique for dissection of subcarinal and main bronchial lymph nodes using a laparoscopic transhiatal approach for esophageal cancer. AB - BACKGROUND: Although metastasis to subcarinal or main bronchial lymph nodes (LNs) is common in patients with esophageal cancer, the procedure for their dissection using a laparoscopic transhiatal approach (LTHA) has not been established because of the difficulties associated with this surgery. We developed a novel and simple technique for their dissection using LTHA. PATIENTS AND METHODS: An abdominal wall sealing device was placed in the upper abdomen, and four ports were inserted. After division of the gastrosplenic ligament by hand-assisted laparoscopic surgery, the esophageal hiatus was opened and carbon dioxide was introduced into the mediastinum. The pericardial adipose tissue was divided, and the pericardium was exposed. The posterior plane of the pericardium was separated and extended, and the anterior side of the subcarinal LNs and bilateral main bronchial LNs were separated. The posterior side of these LNs was then separated. Finally, while lifting these LNs like a membrane, they were resected from the bilateral main bronchi and tracheal bifurcation. The treatment outcomes of 18 patients with esophageal cancer who underwent subcarinal and main bronchial LN dissection by LTHA were compared with those of 19 patients who underwent the procedure by video-assisted thoracic surgery. RESULTS: The number of resected subcarinal and main bronchial LNs in the two groups was not significantly different. The total operative time and total operative bleeding in the two groups was also not significantly different. Postoperative factors, such as the extubation time after surgery, frequency of postoperative complications, and the length of the postoperative hospital stay in the two groups was not significantly different. CONCLUSION: Our surgical procedure resulted in a good surgical view of the mediastinum, and en-bloc dissection of the subcarinal and main bronchial LNs was performed safely. PMID- 23749912 TI - The role of trastuzumab in the management of salivary ductal carcinomas. AB - BACKGROUND: Salivary ductal carcinoma (SDC) is a high-grade malignancy, and molecular studies show frequent overexpression of human epidermal growth factor receptor 2 (HER2). We reviewed our experience with molecular-targeted therapy using trastuzumab for patients with HER2-positive SDC. PATIENTS AND METHODS: The records of all patients treated with trastuzumab for HER2-tested SDC at The University of Texas MD Anderson Cancer Center between 1997 and 2011 were reviewed. RESULTS: Thirteen patients with SDC overexpressing HER2 were treated with trastuzumab as a single agent or in combination with chemotherapy. Ten of these had 3+ immunohistochemistry or HER2 gene amplification by fluorescence in situ hybridization. Patients underwent therapy in the surgical adjuvant setting (n=2), as a component of combined therapy for advanced disease (n=8), or as single therapy near end of life (n=3). Treatment efficacy via radiographic review for response could not be assessed. CONCLUSION: Trastuzumab should undergo prospective therapeutic clinical trials, in SDC which will likely require international cooperation. PMID- 23749913 TI - Carboxy-terminal telopeptide (CTX) and amino-terminal propeptide (PINP) of type I collagen as markers of bone metastases in patients with non-small cell lung cancer. AB - The early diagnosis of non-small cell lung carcinoma (NSCLC) is difficult, and 30 40% of patients with NSCLC develop bone metastases (BMs) during the course of their disease. Because the delayed demonstration of skeletal involvement may seriously affect survival, there is a need for early diagnosis of BMs. Unfortunately, the sensitivity of common serum tumor markers is low and they are used mainly for monitoring the efficacy of therapy and detection of recurrence. The aim of this study was to evaluate the utility of a panel of serum biomarkers in patients with NSCLC and BMs. Sixteen patients (11 males, 5 females; median age=64 years, range 54-68 years) with NSCLC and BMs (cases), and 18 age- and stage-matched patients without BMs (controls) underwent measurement of serum carboxy-terminal telopeptide of type I collagen (CTX), tartrate-resistant acid phosphatase isoform type 5b (TRAP5b) and amino-terminal propeptide of type I collagen (PINP), carcinoembryonic antigen (CEA) and fragments of cytokeratin 19 (CYFRA 21-1. CTX (443.7 +/- 945.1 vs. 402.7 +/- 28.4 pg/ml, p=0.003) and PINP (75.9 +/- 11.4 vs. 64.1 +/- 7.5 MUg/l, p=0.001) were significantly higher in patients with BMs, while the mean value of the other markers did not differ (p=NS) between cases and controls. The sensitivity, specificity and accuracy were 73.3%, 86.7% and 79.4% for CTX; 55.5%, 62.5% and 58.8% for CEA; 65.0%, 78.6% and 70.6% for CYFRA; 30.4%, 76.2% and 67.6% for TRAP5b; and 72.2%, 81.2% and 76.5% for PINP, respectively. The area under the receiver operating characteristic curve (AUC) for CTX was 0.68. In conclusion, CTX and PINP measurement can be useful in monitoring patients with NSCLC during follow-up, with the aim of detecting BMs early. PMID- 23749914 TI - Incidence and survival in sarcoma in the United States: a focus on musculoskeletal lesions. AB - BACKGROUND/AIM: The purpose of this study was to analyze the incidence and survival in all sarcomas based on year of diagnosis, anatomical site, grade, stage, and age of patient. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried for the years 1975 to 2009 and included 18 registries across the United States representing 28% of the national population. Incidence rates for 2005-2009 and five-year survival rates for 2000 2004 were calculated for all categories of sarcomas for multiple key variables. RESULTS: Sarcomas are rare, with most occurring in fewer than 5 per 1,000,000. The most common were leiomyosarcoma, Kaposi sarcoma, malignant fibrous histiocytoma, liposarcoma and fibrosarcoma. Survival was poorer for those with more advanced grade, stage, and age at-diagnosis. Most sarcomas affected the lower extremities, followed by the upper extremities and torso. Pelvic tumors were less common, but generally led lower survival than lesions of the extremities. CONCLUSION: The epidemiology of sarcomas varies widely by type and other variables. Incidence and survival data provide valuable information for patient counseling and may have implications in understanding the natural history of sarcoma. This study represents the most recently updated comprehensive report on all types of sarcomas in the United States. PMID- 23749915 TI - Prognostic value of complete response in patients with muscle-invasive bladder cancer undergoing concurrent chemoradiotherapy. AB - AIM: To evaluate the feasibility of concurrent chemoradiotherapy (CCRT) in very advanced bladder cancer (stage IV) and further analyze the prognostic factors in these patients. PATIENTS AND METHODS: We retrospectively reviewed the clinicopathological features and outcomes of patients with muscle-invasive bladder cancer after CCRT. Sixty-one patients with muscle-invasive bladder cancer who underwent CCRT between January 1996 and March 2011 were eligible for evaluation. Chemotherapy consisted of cisplatin (50 mg/m(2)) at day one, and 5 fluorouracil (500 mg/m(2)/day) and leucovorin (50 mg/m(2)/day) at days 1, 2, and 3, every three weeks, for a maximum of six cycles. The radiation dose was 44-45 Gy to the entire pelvis and 60-66 Gy to the entire bladder, with a daily fraction of 1.8-2 Gy. RESULTS: By August 2012, the estimated median progression-free survival (PFS), cancer-specific survival, and overall survival (OS) were 25.7, 64.3 and 35.8 months, respectively; the complete response (CR) rate was 68.8%. Both clinical stage and CR following CCRT, were independent prognostic factors for PFS, cancer-specific survival, and OS. Patients with stage IV disease who achieved CR had significantly better PFS (log-rank p=0.01), cancer-specific survival (log-rank p=0.01), and OS (log-rank p=0.01) than those with stage II/III disease but no CR. The absence of hydronephrosis was the only factor predictive of CR after CCRT (odd ratio, 4.21; p=0.04). CONCLUSION: CR was the most important prognostic factor in muscle-invasive bladder cancer. Selected patients with stage IV bladder cancer could benefit from CCRT if a CR is achieved. PMID- 23749916 TI - Wide-field pulsed reduced dose rate radiotherapy (PRDR) for recurrent ependymoma in pediatric and young adult patients. AB - AIM: This retrospective analysis evaluates feasibility of wide-field re irradiation using pulsed reduced dose rate (PRDR) technique in patients with recurrent ependymoma. PRDR employs a dose rate of 6 cGy/min, as opposed to 400 600 cGy/min for conventional radiation, allowing for enhanced normal tissue repair. PATIENTS AND METHODS: Five patients with recurrent ependymoma having eight lesions (two brain, six spinal cord) were treated with PRDR. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan Meier method. RESULTS: The median interval between two radiation courses was 58 months (range: 32-212 months). The median PRDR dose was 40 Gy (range: 30.6-54 Gy) with a median cumulative lifetime dose of 105.2 Gy (range: 90-162.4 Gy). At a median post-PRDR follow-up of 64 months, estimated 4-year OS and PFS from PRDR was 60% and 35.7%, respectively. None of the patients developed necrosis on serial magnetic resonance imaging scans, and only one patient had progressive mild radiculopathy. CONCLUSION: In patients with large-volume recurrent ependymoma, re irradiation with wide-field PRDR is a feasible option. PMID- 23749917 TI - A pilot study of salvage irinotecan monotherapy for advanced biliary tract cancer. AB - AIM: To evaluate the treatment outcomes of irinotecan monotherapy for patients with advanced biliary tract cancer refractory to gemcitabine, cisplatin, and oral fluoropyrimidine. PATIENTS AND METHODS: Irinotecan (100 mg/m(2)) was administered intravenously on days 1, 8, and 15, repeated every four weeks. RESULTS: Thirteen patients were enrolled. The dose intensity was only 55.0%. The response rate and disease control rate were 1/13 (7.7%) and 3/13 (23.1%), respectively. The median overall survival and time-to-progression were 6.7 months (95% confidence interval=3.0-10.4 months) and 1.8 months (95% confidence interval=1.6-3.9 months), respectively. Grade 3/4 adverse events included leukopenia (7/13), neutropenia (8/13), anemia (6/13), nausea (1/13), vomiting (1/13), anorexia (2/13), diarrhea (1/13), and constipation (1/13). CONCLUSION: Irinotecan monotherapy had a modest antitumor effect even for patients who were refractory to gemcitabine, cisplatin, and oral fluoropyrimidine. However, this regimen was not fully tolerated as third-line or fourth-line therapy. Therefore, further evaluation of a modified irinotecan regimen is necessary. PMID- 23749918 TI - Weekly paclitaxel--an effective treatment for advanced breast cancer. AB - AIM: Weekly paclitaxel is widely used in the treatment of metastatic breast cancer (MBC). Our aim was to test its efficacy and tolerability as a second-line therapy for MBC in daily oncology practice. PATIENTS AND METHODS: Paclitaxel (90 mg/m(2)) was given intravenously three times weekly in a 4-week cycle to 91 patients with disease progression after hormonal (42%) or cytostatic therapy (57%). The median age was 54 years; metastatic sites were the lung (39%), liver (52%) and bone (47%). 64% of patients had more than one site of metastasis. RESULTS: Median time-to-progression was 7.5 months (range=6.5-8.5 months) and median overall survival time was 20.1 months (range=13.7-26.5 months). We observed 10 complete (12%) and 37 partial (43%) responses (an overall response rate of 55%). Severe side-effects were rare (grade 3-4 neutropenia 13% and septic episodes in three cases). CONCLUSION: Weekly paclitaxel was shown to be an effective and well-tolerated treatment for advanced breast cancer. PMID- 23749919 TI - Combination phase II study of weekly paclitaxel and 5'-DFUR for unresectable or recurrent gastric cancer. AB - BACKGROUND: Paclitaxel and 5'-deoxy-5-fluorouridine (5'-DFUR) have single-agent activity in gastric cancer and have distinct mechanisms of action and no overlap of key toxicities. To evaluate the efficacy and safety of their combination, we conducted a combination phase II study of paclitaxel and 5'-DFUR in patients with unresectable or recurrent gastric cancer who had received up to one prior chemotherapy. PATIENTS AND METHODS: Treatment included paclitaxel at 70 mg/m(2) i.v. on days 1, 8 and 15 every four weeks, and 5'-DFUR at 600 mg p.o. every day. The primary end-point was the response rate (RR) and secondary end-points were overall survival (OS), progression-free survival (PFS), time-to-treatment failure (TTF) and rate of adverse events. RESULTS: In 42 eligible patients, the RR was 40.5%. OS, PFS and TTF were 371 days, 170 days, and 147 days, respectively. Adverse events were relatively mild. Commonly observed grade 3/4 adverse events were neutropenia (26.2%), anorexia (4.8%), neuropathy (4.8%) and fatigue (4.8%). CONCLUSION: The combination of weekly paclitaxel and 5'-DFUR chemotherapy is active and well-tolerated. PMID- 23749920 TI - Primary neuroendocrine carcinoma of the appendix: a case report and review of the literature. AB - AIM: We report on a rare case of appendiceal primary neuroendocrine carcinoma (NEC) and discuss three cases previously described. CASE REPORT: A 58-year-old woman presented with acute abdominal pain and a low-grade fever. She was diagnosed with acute appendicitis and underwent laparoscopic appendectomy. Pathological examination of the resected specimen revealed NEC. Immunohistochemical analyses were positive for synaptophysin, chromogranin, and CD-56. The tumour was high grade and the Ki-67 index was >20%. Primary NEC of the appendix is extremely rare. To our knowledge, this is the first case report of an appendiceal NEC that meets the 2010 diagnostic criteria of the World Health Organization. CONCLUSION: Due to its non-specific clinical presentation, NEC is often misdiagnosed as appendicitis; however, it can advance rapidly and carries a very poor prognosis, despite chemotherapy. In the future, a treatment protocol for immunohistochemical analyses should be established to improve the survival rate. PMID- 23749921 TI - An isolated penile mass in a young adult turned out to be a primary marginal zone lymphoma of the penis. A case report and a review of literature. AB - AIM: to discuss the rationale of the management of penile MALT lymphoma. CASE REPORT: A 24-year-old patient presented with a painless and mobile nodule localized in the ventral part of the penis. The lesion was firstly evaluated through Doppler ultrasonography, which showed a hypoechoic and vascularized solid mass, a subsequent magnetic resonance confirmed size and position of the lesion. Subsequently the patient underwent a surgical excision of the mass, the pathological diagnosis was consistent with penile lymphoma, MALT-type. The patient underwent a consolidative immunotherapy with rituximab. Disease re staging was performed through a MR without any detection of local or systemic recurrences. CONCLUSION: To our knowledge, no cases of MALT lymphoma involving the penis have been reported in the literature so far. Surgical excision with organ sparing and immunotherapy with rituximab, successfully induced a complete response. Based upon this experience, we may recommend a conservative surgery associated with a systemic approach. PMID- 23749922 TI - Immunohistochemical expression of telomerase in patients with non-small cell lung cancer: prediction of metastasis and prognostic significance. AB - AIM: To detect telomerase reverse transcriptase (TERT) expression in tissue and metastatic and non-metastatic lymph node samples from patients with non-small cell lung cancer; to evaluate whether TERT expression is correlated with pathological and clinical features, and/or patient survival times; to determine differences between TERT expression in metastatic and non-metastatic lymph nodes. PATIENTS AND METHODS: Tumor tissue samples from 17 patients with squamous cell lung cancer and 11 patients with adenocarcinoma diagnosed between 2003 and 2004 were included in this study. All patients were diagnosed at our hospital and had samples stored in the pathology archive. Additionally, dissected lymph node samples, with and without metastases, were studied. Telomerase Gene Tex, Inc, Irvine, CA USA (TERT (2C4) antibody), Universal Kit (Lab Vision, Newmarket, UK) were used for immunohistochemical staining. Statistical analyses were performed using SPSS 17.0 statistical software. RESULTS: TERT was positive in 18/28 of the samples, regardless of the histological tumor type. There was no significant correlation between TERT expression in lymph nodes with metastasis and clinical stage, histological type, tumor differentiation, or survival time. CONCLUSION: TERT expression may be used as a target for therapy. It may also be helpful in predicting metastasis but not in predicting survival time. PMID- 23749923 TI - The impact of breast cancer screening among younger women in the Barretos Region, Brazil. AB - AIM: To verify the impact of breast cancer screening in women aged 40-49 years in one region of Brazil. PATIENTS AND METHODS: This is a cross-sectional study, targeted to asymptomatic women aged 40-69 years who had breast cancer screening mammography performed between January 2003 and December 2007. Logistic regression was used to estimate the risk of breast cancer by age groups (40-49, 50-59, 60-69 years). RESULTS: Of the 27,133 screened women, 51.9% (14,082) were aged between 40-49 years. The odds ratio (OR) of breast cancer among the 45-49 year age cohort was not significantly different from that of 60 to 69-year-old women (OR=0.64; 95% Confidence Interval 0.39 to 1.03). CONCLUSION: The risk of breast cancer among women aged 45 to 49 years is equivalent to that of women aged 60 to 69 years, indicating that breast cancer screening in this region of Brazil should start at the age of 45 years or immediately thereafter. PMID- 23749924 TI - Phase II study of a triple combination of oral vinorelbine, capecitabine and trastuzumab as first-line treatment in HER2-positive metastatic breast cancer. AB - Chemotherapy plus trastuzumab is the standard first-line treatment for Human Epidermal Receptor 2-positive (HER2-positive) metastatic breast cancer. The aim of this international phase II trial was to determine the efficacy and safety profile of an oral chemotherapy doublet, oral vinorelbine plus capecitabine, and trastuzumab in this setting. PATIENTS AND METHODS: In this single-arm, multicenter, open-label phase II study, in the first-line metastatic setting, patients received 3-weekly cycles of oral vinorelbine at 80 mg/m(2) (first cycle dose 60 mg/m(2)) day 1 and day 8, plus capecitabine at 1000 (750 if >= 65 years) mg/m(2) twice daily on days 1-14, plus trastuzumab at 4 mg/kg intravenously (i.v.) on day 1 (loading dose) then 2 mg/kg i.v. weekly thereafter. Treatment was continued until progression or unacceptable toxicity. RESULTS: Fifty patients with a median age of 53.5 years were enrolled. Most (82%) had visceral involvement and 34% had more than two metastatic sites. The objective response rate (RECIST 1.0) in 44 evaluable patients was 77% [95% Confidence Interval (CI)=62-89%], including complete response in 21%. The clinical benefit rate (response or stable disease for >= 6 months) was 93% [95% CI=81-99%]. Median duration of response was 13.3 [95% CI=9.8-15.7] months, median progression-free survival was 12.8 [95% CI=10.8-16.9] months and median overall survival was 47.0 [95% CI=30.5-64.3] months. Median number of cycles was 10 (range 1-81). The majority of patients (72%) received more than 18 weeks and 32% more than 48 weeks of treatment. The most frequent treatment-related grade 3/4 adverse events were neutropenia (71%), hand-foot syndrome (20%) and diarrhea (16%). A low-rate of grade 2 alopecia was observed (14%). CONCLUSION: The triple combination of oral vinorelbine, capecitabine and trastuzumab is highly active in terms of response rate, progression-free survival and overall survival, with a manageable toxicity profile. PMID- 23749925 TI - 18F-FDG-PET/CT in potentially advanced renal cell carcinoma: a role in treatment decisions and prognosis estimation. AB - AIM: to assess the influence of positron emission tomography/computed tomography with (18)F-fluorodeoxyglucose ((18)F-FDG-PET/CT) on the treatment decision in renal cell carcinoma and to assess the prognostic value of the (18)F-FDG accumulation assessments. PATIENTS AND METHODS: Data from 60 patients were included. The cohort consisted of 43 males, 17 females, mean age 66.2 years (range=49-86 years). All patients underwent (18)F-FDG-PET/CT including two-phase CT-angiography of the kidneys. Locally advanced or generalized renal cell carcinoma was suspected in all patients. The level of the (18)F-FDG accumulation within the tumor was compared with the histological grading and the development of the disease was assessed 12 months after (18)F-FDG-PET/CT. RESULTS: Overall mortality reached 46.7%, the highest (18)F-FDG accumulation showed tumor of grade 4 (mean SUV(max)=10.7, range=5-23), the highest mortality was found for tumors exceeding SUV(max) value of 10 (mortality 62.5%). New information was brought by (18)F-FDG-PET/CT in 85% of cases. CONCLUSION: (18)F-FDG-PET/CT has the potential to estimate the patient's survival according to the (18)F-FDG accumulation measured in SUV(max). Depiction of occult metastatic disease has an emerging role in decision making regarding surgery. PMID- 23749926 TI - Adenomatoid odontogenic tumor: a case report with immunohistological profile. AB - The adenomatoid odontogenic tumor (AOT) is an uncommon tumor of odontogenic origin, composed of odontogenic epithelium and characterized by slow but progressive growth. We report a rare case of AOT in an 18-year-old, who presented with a palpable bony-hard swelling in the anterior maxillary region. The tumor was radiographically well-defined, and exhibited unilocular radiolucency. Histologically, the appearance was of solid nodules of cuboid or columnar cells of odontogenic epithelium, forming typical nests or duct-like structures. Immunohistochemistry was positive for cytokeratins (CK) CK5/6, CK17, CK19 and negative for KI-67. The results were consistent with a diagnosis of AOT. CONCLUSION: A case of AOT is presented, emphasizing on the importance of recognizing neoplasms arising in odontogenic tissues. Recurrences seldom occur, and surgical cure is recommended. PMID- 23749927 TI - Prognostic role of bone sialoprotein in clear cell renal carcinoma. AB - BACKGROUND: Renal cell carcinoma (RCC) follows a variable clinical course related to disease stage and metastatic spread (including to bone). Molecular and genetic factors bear prognostic significance in RCC, including proteins involved in extracellular matrix invasion. Among these, bone sialoprotein (BSP) and osteopontin (OPN) are physiologically implicated in bone metabolism, and have a prognostic role in several tumors. BSP expression was also predictive of bone spread propensity in lung and prostate carcinoma. In RCC, no data are available for BSP, while OPN has been correlated with tumor stage, grade and survival. We aimed to define the predictive (of bone spread) and prognostic role of BSP and OPN immunohistochemical expression in clear cell RCC. MATERIALS AND METHODS: from a series of 305 renal tumors resected between 1993 and 2002, 75 surgically resected clear cell RCCs with tissue material, clinical data and follow-up information available, were selected for the preliminary series; a second group of 126 chemo-naive, radically-resected, consecutive RCCs was collected as a validation series. Immunohistochemical expression of BSP and OPN on paraffinized samples was evaluated by H-score [=Sigma (intensity * percentage of positively stained cells)]. RESULTS: In the preliminary series, BSP and OPN reactivity was found in 85% and 77% of cases, respectively. No predictive role of bone spread propensity of RCC was identified. Conversely, both BSP and OPN were significantly associated with shorter survival considering median (p=0.002) and upper quartile (p=0.03) expression values, respectively. In the validation group, a prognostic role was confirmed for BSP only (p=0.008), while OPN showed a trend of association with poorer survival (borderline p-value of 0.058). CONCLUSION: BSP was shown for the first time to be an independent parameter associated with poor prognosis in RCC. Its coexpression with OPN identifies a subgroup of RCC having the worst outcome. PMID- 23749928 TI - NX-PVKA levels before and after hepatectomy of hepatocellular carcinoma as predictors of patient survival: a preliminary evaluation of an improved assay for PIVKA-II. AB - Although the protein-induced vitamin K absence or antagonist-II (PIVKA-II) is used as a prognostic marker in hepatocellular carcinoma (HCC), a newly-improved assay, NX-PVKA (PIVKA-II measured using P-11 and P-16 antibodies) and NX-PVKA-R (ratio of PIVKA-II and NX-PVKA), are more accurate markers of PIVKA-II. We conducted a prospectively preliminary analysis of the relationship between NX PVKA-R and clinicopathological parameters and prognosis in 22 patients with HCC who underwent hepatectomy and measured changes of this marker's levels after treatment. Median value of PIVKA-II (80 mAU/ml), NX-PVKA (60 mAU/ml), NX-PVKA-R (1.5) and NX-PVKA-D (difference of markers, 15 mAU/ml) were determined. Tumor relapse was observed in six patients, and the one year relapse-free survival rate was 88%. Correlation between PIVKA-II or alpha-fetoprotein levels and NX-PVKA, NX PVKA-R or -D levels was significant (p<0.001). NX-PVKA-R was significantly correlated with tumor size (p<0.05). In patients who underwent pre-treatment before hepatectomy, PIVKA-II, NX-PVKA and NX-PVKA-R tended to be higher than in patients without pre-treatment, but this difference was not significant (p>0.10). For macroscopic findings, NX-PVKA-R for the confluent-nodular type was significantly higher than that for the simple-nodular type (p<0.05). The tumor free survival rate in the group with a high NX-PVKA-R was significantly lower than that in the group with a low NX-PVKA-R group (p<0.05). In patients with tumor recurrence, postoperative NX-PVKA-R increased again. We conclude that a high value of NX-PVKA-R after hepatectomy for HCC reflects malignant potential and predicts early recurrence in patients with HCC. PMID- 23749929 TI - Prognostic impact of tumor IL-6 expression after preoperative chemoradiotherapy in patients with advanced esophageal squamous cell carcinoma. AB - Elevated serum interleukin-6 (IL-6) levels have been associated with tumor progression and poor prognosis in patients with esophageal carcinoma. The purpose of the present study was to clarify such a relationship in patients with esophageal squamous cell carcinoma with a focus on the possible influence of chemoradiotherapy (CRT) on tumor IL-6 expression. Data regarding 41 patients with clinical T3-T4 tumors who underwent induction chemoradiotherapy followed by surgery (CRT group) and 60 patients with clinical T1-T4 tumors who underwent surgery alone (Surgery group) between 2001 and 2010, were retrospectively analyzed. Tumor IL-6 expression in resected specimens was evaluated by immunohistochemistry. Tumor IL-6 expression was detected in patients with advanced tumors in the Surgery group (21.1% in p(stage) III-IV vs. 0.2% in p(stage) I-II; 27.8% in pT3-4 vs. 0% in pT1-2), and also correlated with primary tumor progression and surgical curability in the Surgery group. In addition, patients with IL-6-positive tumors had significantly shorter overall survival than those with IL-6-negative tumors in the CRT group, and tumor IL-6 expression had an independent prognostic value in multivariate analysis, whereas no significant difference in overall survival was observed between patients with IL 6-positive and those with IL-6-negative tumors in the Surgery group. These results indicate that pre-treatment tumor IL-6 expression correlates with primary tumor progression, and CRT-induced tumor IL-6 expression predicts poor prognosis. PMID- 23749930 TI - Mesothelin is more useful in pleural effusion than in serum in the diagnosis of pleural mesothelioma. AB - BACKGROUND/AIM: Soluble mesothelin-related peptide (SMRP) is regarded as a biomarker of malignant pleural mesothelioma (MPM). Herein, we compared the diagnostic performances of SMRP in matched pleural effusion (PE-SMRP) and serum (S-SMRP). MATERIALS AND METHODS: Diagnosis on pleural biopsies was performed for all patients including 43 with MPM, 23 with non-MPM pleural metastases (MTS) and 36 with benign (BNG) pleural diseases. SMRP was measured by a MesoMark ELISA (Cis Bio International Gif/Yvette; France). RESULTS: Using the receiver operating characteristic (ROC) analysis, 12.70 and 1.08 nM were detected as cut-off values to optimal discrimination for PE-SMRP and S-SMRP, respectively. PE-SMRP showed a better diagnostic accuracy than S-SMRP in MPM vs. MTS+BNG (area under the ROC curve=81.6 vs. 70.5; sensitivity=69.8% vs. 46.5%; specificity=88.1% vs. 84.7%; diagnostic odds ratio (DOR)=17.1 vs. 4.8). In S-SMRP-negative patients, PE-SMRP maintained an acceptable performance (Sensitivity=47.8%; DOR=8.3; p=0.001), whereas in PE-SMRP-negative patients, S-SMRP performed very poorly (Sensitivity=15.4%; DOR=1.2; p=0.858). CONCLUSION: PE-SMRP detection has a superior diagnostic accuracy than S-SMRP detection in the diagnosis of MPM. PMID- 23749931 TI - Glasgow prognostic score predicts therapeutic outcome after pancreaticoduodenectomy for carcinoma of the ampulla of vater. AB - BACKGROUND: Systemic inflammation, as evidenced by the Glasgow prognostic score (GPS), predicts cancer-specific survival in various types of cancer. The aim of this study was to evaluate the significance of GPS on the therapeutic outcome after pancreaticoduodenectomy for carcinoma of the ampulla of Vater. PATIENTS AND METHODS: The subjects of this study were 30 patients who underwent elective pancreaticoduodenectomy for carcinoma of the ampulla of Vater. For the assessment of systemic inflammatory response using the GPS, patients were classified into three groups: patients with normal albumin (>= 3.5 g/dl) and normal C-reactive protein (CRP) (<= 1.0 mg/dl) as GPS 0 (n=23), those with low albumin (<3.5 g/dl) or elevated CRP (>1.0 mg/dl) as GPS 1 (n=5), and those with low albumin (<3.5 g/dl) and elevated CRP (>1.0 mg/dl) as GPS 2 (n=2). We retrospectively investigated the relationship between patients' characteristics, including GPS, and disease-free survival, as well as overall survival. RESULTS: For disease-free survival, advanced tumor stage (p=0.0401), advanced lymph node metastasis (p<0.0001), and preoperative biliary drainage (p=0.0157) in univariate analysis, and advanced lymph node metastasis (p=0.0271) in multivariate analysis were significant and independent predictors of cancer recurrence. For overall survival, in both univariate and multivariate analyses, advanced lymph node metastasis (p=0.0006 and p=0.0411, respectively) and GPS 1 or 2 (p=0.0034 and p=0.0484, respectively) were significant and independent predictors of poor patient outcome. CONCLUSION: The GPS in patients with carcinoma of the ampulla of Vater is an independent prognostic predictor after elective pancreaticoduodenectomy. PMID- 23749932 TI - Negative impact of fresh-frozen plasma transfusion on prognosis after hepatic resection for liver metastases from colorectal cancer. AB - BACKGROUND: In perioperative management of hepatic resection for colorectal cancer liver metastasis (CRLM), excessive blood loss and blood transfusion greatly influence postoperative complications and prognosis of the patients. We evaluated the influence of the use of blood products on prognosis of patients with CRLM. PATIENTS AND METHODS: The subjects of this study were 65 patients who underwent elective hepatic resection between January 2001 and April 2011 for CRLM without distant metastasis or other malignancy. We retrospectively investigated the influence of the use of blood products, including red cell concentrate (RC) and fresh frozen plasma (FFP), and clinical variables on overall survival. RESULTS: In univariate analysis, bilobar distribution (p=0.0332), more than four lymph node metastases of the primary cancer (p=0.0155), perioperative RC use (p=0.0205), and perioperative FFP use (p=0.0065) were positively associated with poor overall survival rate. In multivariate analysis, bilobar distribution (p=0.0012), more than four lymph node metastases of the primary cancer (p=0.0171), and perioperative FFP use (p=0.0091), were independent risk factors for poor overall survival rate. CONCLUSION: The use of FFP is associated with worse overall survival after elective hepatic resection for patients with CRLM. PMID- 23749933 TI - Different impact of IL10 haplotype on prognosis in lung squamous cell carcinoma and adenocarcinoma. AB - BACKGROUND: Polymorphisms (1082A>G, - 819C>T, and -592G>A) in the interleukin-10 (IL10) promoter are associated with its transcriptional activity. IL10 induction by cigarette smoking plays a role in smoking-related lung tumor progression. We therefore expected to find a difference in impact of IL10 haplotypes on overall survival (OS) and relapse-free survival (RFS) between squamous cell carcinomas (SCC) and adenocarcinomas (ADC) of lung. MATERIALS AND METHODS: Normal lung tissues adjacent to resected tumors from 439 lung cancer patients were collected to determine IL10 haplotypes (ATA and non-ATA) by direct sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Kaplan-Meier and multivariate Cox regression models were used to assess the impact of IL10 haplotype on OS and RFS. Resluts: The non-ATA haplotype was more prevalent in patients with nodal metastatic tumors (N1 and N2) than in those with non-nodal metastatic tumors (N0). This observation was only made for patients with SCC and not ADC. Patients with SCC with the non-ATA haplotype had poorer OS and RFS when compared to those with the ATA haplotype, whereas IL10 haplotype was not associated with the clinical outcome of patients with ADC. CONCLUSION: The IL10 haplotype may independently predict survival and relapse in patients with surgically resected SCC, but not ADC. PMID- 23749934 TI - Prognostic factors in early-stage triple-negative breast cancer: lessons and limits from clinical practice. AB - AIM: Triple-negative breast cancer has a poor prognosis due to its aggressive behaviour and lack of effective targeted therapies. We aimed to verify whether clinical and/or pathological features may help us identify triple-negative breast cancer with a different outcome. PATIENTS AND METHODS: Patients diagnosed with stage I-III triple-negative breast cancer at our Institution were included in the analysis. The impact of various factors (age, menopausal status, tumor characteristics, adjuvant treatment, etc.) on survival was evaluated. Univariate and multivariate analyses were performed. RESULTS: A total of 149 patients were included in this retrospective analysis. At univariate analysis, a better disease free survival was related to smaller tumour size and absence of lymphovascular involvement or necrosis. At multivariate analysis, tumour size and lympho vascular invasion were independent prognostic factors. CONCLUSION: Triple negative breast cancer represents a heterogeneous disease with different biology and clinical behaviour. These results re-inforce the wide use of adjuvant chemotherapy for all types of triple-negative breast cancer, regardless of tumour size or lymphovascular invasion. New biomarkers are mandatory for a better stratification of this heterogeneous population. PMID- 23749935 TI - Mitomycin-C and capecitabine (MIXE) as salvage treatment in patients with refractory metastatic colorectal cancer: a retrospective study. AB - AIM: To report on the efficacy and safety of mitomycin-C-capecitabine (MIXE) regimen as salvage chemotherapy regimen for patients with refractory metastatic colorectal cancer. PATIENTS AND METHODS: We retrospectively reviewed patients who were treated with mitomycin-C (7 mg/m(2)) every three weeks in combination with capecitabine (1,000 mg) twice daily (2,000 mg per day) days 1 to 14 every three weeks. All patients had previously received at least three chemotherapy regimens including biological agents, such as a monoclonal antibody either against vascular endothelial growth factor receptor or epidermal growth factor receptor (only if wild-type KRAS). Laboratory tests including complete blood count were checked weekly, while chemistries, liver function tests and carcinoembryogenic antigen levels were determined every three weeks. Radiological assessment of their disease with computed tomography scans was performed every nine weeks. RESULTS: Fifteen patients were included: Male:female ratio, 9:6; age ranged from 52-70 years; Eastern Cooperative Oncologic Group performance status 1 in 5 patients and 2 in the remaining 10 patients. Seven patients demonstrated a clinical benefit (one partial response, two minor responses, five stable disease), disease in six patients progressed and one patient participated in a phase I clinical study and hence was not evaluable. No grade 3 or 4 hematological toxicities were noticed; the most common toxicities included grade 2 hand-foot syndrome (HFS), grade 1 fatigue and grade 2 diarrhea. CONCLUSION: The MIXE regimen showed a modest efficacy in heavily pre-treated patients with mCRC. The MIXE regimen may be considered for patients with mCRC who are refractory to primary treatment and are without other options or who are not eligible for clinical studies. PMID- 23749936 TI - Unresectable perihilar cholangiocarcinoma: multimodal palliative treatment. AB - AIM: To evaluate the survival of patients with unresectable perihilar cholangiocarcinoma (PHC) treated with multimodal palliative approaches. PATIENTS AND METHODS: thirty-two patients were enrolled in a multimodal protocol including: bilateral biliary drainage; Yridium-192 intraluminal brachytherapy (BT); metal biliary stenting; external-beam radiotherapy (EBRT); systemic chemotherapy (ChT). All patients underwent BT and biliary stenting: this was the only treatment for 14 patients, it was combined with EBRT in 11, and with EBRT and ChT in seven. Mean and median survival, complication rates and duration of hospital stay were calculated for each group. RESULTS: BT with EBRT and ChT obtained the best median (15 months) and one year (71.42%) survival followed by BT with EBRT (14 months and 63.63%, respectively). BT with EBRT in a total dose of 54-60 Gy, with or without ChT, led to a significantly higher median survival rate (14 months) than that for BT alone (seven months). CONCLUSION: BT with EBRT, with or without ChT, improves survival and should be considered as a suitable alternative to palliative surgery for patients with unresectable perihilar cholangiocarcinoma. PMID- 23749937 TI - Early-onset neutropenia during perioperative chemotherapy is predictive of increased survival in patients with completely resected non-small cell lung cancer: a retrospective analysis. AB - BACKGROUND: Chemotherapy-induced neutropenia (CIN) has been found to be predictive of better therapeutic outcomes in studies of patients with various tumors. This study investigated whether CIN occurring during perioperative chemotherapy cycles 1 or 2 is a prognostic indicator in patients with completely resected non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The records of patients with completely resected NSCLC receiving at least two cycles of perioperative platinum-based doublet chemotherapy were reviewed retrospectively. Early-onset CIN was defined as a neutrophil count <2.0 * 10(9)/l during chemotherapy cycles 1 or 2. Subjects were stratified into two groups: presence or absence of early-onset CIN. RESULTS: A total of 93 patients were included in this analysis. Early-onset CIN developed in 54.8% (51/93) cases. The median overall survival (OS) of patients developing early-onset CIN was significantly longer than the survival of patients without early-onset CIN (92.4 vs. 35.8 months, p=0.022), and the median disease-free survival (DFS) of patients with early-onset CIN was also longer, although the difference was not significant (48.3 vs. 18.6 months, p=0.138). Multivariate analysis demonstrated that early-onset CIN was an independent prognostic indicator for OS [hazard ratio (HR) for death=0.422, 95% confidence interval (CI)=0.201-0.884; p=0.022] and DFS (HR for recurrence=0.482, 95% CI=0.247-0.943; p=0.033). CONCLUSION: Early-onset CIN during perioperative chemotherapy is predictive of better OS and DFS in patients with completely resected NSCLC. PMID- 23749938 TI - Identification of FKBP11 as a biomarker for hepatocellular carcinoma. AB - BACKGROUND: Glycine N-methyltransferase (GNMT) is a tumor suppressor of hepatocellular carcinoma (HCC). High proportions of GNMT knockout mice developed HCC. We previously identified a potential novel marker from Gnmt knockout mice, FK506 binding protein 11 (FKBP11). Here, we determined the clinical usefulness of FKBP11. PATIENTS AND METHODS: FKBP11 expression levels were analyzed in 123 paired tumor and tumor-adjacent non-tumorous (TA) tissue samples from patients with HCC and in 29 benign liver samples from patients with hemangioma using quantitative real-time polymerase-chain-reaction. RESULTS: FKBP11 was expressed at a higher level in tumor tissues compared to TA tissues (p<0.01). Moreover, we observed a significantly higher level of FKBP11 in TA tissues than in benign liver samples (p<0.01). Interestingly, expression of FKBP11 was higher in hepatitis viral-infected TA and benign tissues than in samples without viral etiology (p<0.05). CONCLUSION: These results suggest a progressively elevated expression of FKBP11 during the development of HCC and FKBP11 has the potential to be an early marker for HCC. PMID- 23749939 TI - Laparoscopic supracervical hysterectomy with concomitant bilateral salpingectomy- why not? AB - AIM: The aim of this investigation was to analyze the feasibility and postoperative outcome of laparoscopic supracervical hysterectomy (LASH) with and without bilateral salpingectomy. PATIENTS AND METHODS: Between February and October 2012, a total of 25 patients were prospectively enrolled to undergo LASH with bilateral salpingectomy. A retrospective cohort of 25 matched patients who underwent LASH without bilateral salpingectomy at our Institution, performed by the same surgeon, served as the control collective. RESULTS: Comparing both collectives, there were no statistically significant differences concerning overall hospital stay, duration of surgery and blood loss. CONCLUSION: LASH with bilateral salpingectomy is a fast and safe procedure. PMID- 23749940 TI - The contribution of DNA apurinic/apyrimidinic endonuclease genotype and smoking habit to Taiwan lung cancer risk. AB - To evaluate the association and interaction of genotypic polymorphism the gene for DNA-apurinic/apyrimidinic endonuclease (APEX1) with personal smoking habit and lung cancer risk in Taiwan, the polymorphic variants of APEX1, Asp(148)Glu (rs1130409), were analyzed in association with lung cancer risk, and their joint effect with personal smoking habits on lung cancer susceptibility was discussed. In this hospital-based case-control study, 358 patients with lung cancer and 716 cancer-free controls, frequency-matched by age and sex, were recruited and genotyped by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). The results showed that the percentages of TT, TG and GG APEX1 Asp(148)Glu genotypes were not significantly different at 43.0%, 41.1% and 15.9% in the lung cancer patient group and 39.9%, 46.1% and 14.0% in non-cancer control group, respectively. We further analyzed the genetic-lifestyle effects on lung cancer risk and found the contribution of APEX1 Asp(148)Glu genotypes to lung cancer susceptibility was neither enhanced in the cigarette smokers nor in the non-smokers (p=0.3550 and 0.8019, respectively). Our results provide evidence that the non-synonymous polymorphism of APEX1 Asp(148)Glu may not be directly associated with lung cancer risk, nor enhance the effects of smoking habit on lung cancer development. PMID- 23749941 TI - IgG4-related inflammation of the orbit simulating malignant lymphoma. AB - Immunoglobulin (IgG) 4-related disease is characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. We report a case of IgG4 related inflammation of the orbit simulating extranodal marginal zone B-cell lymphoma (EMZL). A 72-year-old female complained of bilateral eyelid swelling for three years. A MRI scan demonstrated two kinds of lesions, tumor 1, presenting with a predominantly low density, and tumor 2, of relatively high density. Laboratory tests showed high serum IgG4 concentrations, measuring 991 mg/dl. Partial resection of each tumor was conducted in September 2011. Based on the clinicopathological findings, tumors 1 and 2 were diagnosed as IgG4-related inflammation and EMZL, respectively. The patient initially received oral prednisolone at 30 mg/per day, followed by irradiation with a total dosage of 30 Gy to both eyes. The bilateral tumors consequently diminished, and she is currently well with no recurrence or systemic involvement. In conclusion, EMZL can arise from massive IgG4-related orbital inflammation. Since IgG4-related inflammation can represent multiple nodular lesions, biopsies from multiple sites within the lesion are required to make a correct diagnosis in selected cases. Oral prednisolone combined with radiotherapy is an effective treatment for patients with IgG4-related ophthalmic disease simulating EMZL. PMID- 23749942 TI - Hypofractionated intensity-modulated radiotherapy with simultaneous integrated boost after radical prostatectomy: preliminary results of a phase II trial. AB - AIM: To report the acute toxicity of a hypofractionated regimen of intensity modulated radiotherapy with simultaneous integrated boost (SIB-IMRT) to the pelvic nodes and the prostatic bed after radical prostatectomy. PATIENTS AND METHODS: Patients with prostate adenocarcinoma at high risk of relapse after radical prostatectomy or with biochemical relapse were deemed eligible for study. SIB-IMRT was prescribed to the whole pelvis (45-Gy delivered in 1.8-Gy fractions) and the prostatic bed [62.5 Gy, 2.5-Gy fractions, Equivalent Dose in 2-Gy fraction (EQD2)=68.75 Gy, alpha/beta=3]. Acute toxicity was recorded and graded according to Radiation Therapy Oncology Group (RTOG) criteria. RESULTS: Forty nine patients were enrolled. No cases of grade >= 3 acute toxicity were recorded. Grade 2 acute genitourinary and gastrointestinal toxicity was observed in 9.6% and 29.7% of patients, respectively. CONCLUSION: After radical prostatectomy, hypofractionated high-dose SIB-IMRT enables for reduction of the overall treatment time, with an acute toxicity profile which compares favourably with that of conventionally fractionated high-dose three-dimensional conformal radiotherapy (3D-CRT). PMID- 23749943 TI - A role of multifactorial evaluation of prostatic 3T MRI in patients with elevated prostatic-specific antigen levels: prospective comparison with ultrasound-guided transrectal biopsy. AB - AIM: To assess the role of multiparametric 3T magnetic resonance (3TMRI) of the prostate in detection of the prostatic carcinoma in a male population with elevated prostatic-specific antigen (PSA) and to compare the results with those of transrectal biopsies. MATERIALS AND METHODS: A prospectively collected cohort of 191 men underwent 3T MRI before transrectal biopsy. The evaluation consisted of the assessment of T2-weighted images, diffusion-weighted images, MR spectroscopy and the pharmacokinetic evaluation of the data obtained during the dynamic post-contrast T1 imaging. The assessment included the calculation of the blood volume and transfer constant evaluations. The diagnosis of prostate carcinoma was based on a minimum of three positive signs obtained from MR studies -hypointensive T2 lesion, diffusion restriction, elevated choline/creatine peak in spectrum and malignant type of saturation by contrast agents. All biopsies were evaluated by a specialist in uropathology. RESULTS: 164 patients underwent biopsy, in 27 the biopsy was omitted due to a lack or low probability of carcinoma: Overall, 84 carcinomas were found. Based on the comparison of biopsy results, 3T MRI reached a sensitivity of 97.6%, specificity of 85.0%, positive predictive value of 74.6% and negative predictive value of 96,3% respectively. There were only three false negative findings. In three patients with very suspicious MRI findings and PSA levels over 30 ng/ml, the biopsy did not confirm carcinoma, even though it was highly suspected. CONCLUSION: The implementation of 3T MRI in routine assessment of patients with elevated PSA should reduce the number of biopsies performed and improve the number of tumors detected due to better targeted biopsies. PMID- 23749944 TI - Phase I adjuvant trial of sorafenib in patients with hepatocellular carcinoma after orthotopic liver transplantation. AB - BACKGROUND: Post-transplant hepatocellular carcinoma recurrence has been reported to be between 15-18% and is higher among patients with high-risk features (bilobar tumor, macrovascular invasion, or multifocality). There are no known treatments which reduce risk of recurrence post-transplant. Sorafenib is currently approved for the treatment of advanced hepatocellular carcinoma. The objective of this phase I trial was to establish the safety and toxicity profile of sorafenib in high-risk patients with hepatocellular carcinoma who have undergone orthotopic liver transplantation. PATIENTS AND METHODS: Patients with hepatocellular carcinoma on explant with above high risk features were eligible to start the study drug between 28 and 60 days after liver transplantation. Sorafenib was administered and escalated twice daily on three cohort dose levels: i) 400 mg/day, ii) 600 mg/day and iii) 800 mg/day. RESULTS: Four patients newly transplanted were enrolled and received standard post-transplant medications. Dose-limiting toxicity was reached at the first cohort dose, with three out of four patients experiencing grade 3 toxicities. One patient experienced emerging grade 3 hand foot skin reaction leading to discontinuation of the study drug. Duration of sorafenib in the four patients was 0.7 months, 1.6 months, 3.5 months and 1.6 months, respectively. CONCLUSION: Although a small number of patients were studied, toxicity seen at 400 mg/day is consistent with toxicity reported by a small parallel study by Siegel AB. PMID- 23749946 TI - Can I (still) resuscitate a baby? PMID- 23749947 TI - Setting the research agenda for women and children: the role of Health Technology Assessment. PMID- 23749949 TI - Doxycycline suppresses Chlamydia pneumoniae-mediated increases in ongoing immunoglobulin E and interleukin-4 responses by peripheral blood mononuclear cells of patients with allergic asthma. AB - OBJECTIVES: Chlamydia pneumoniae, an obligate intracellular bacterium, has been associated with asthma and the induction of immunoglobulin E (IgE) responses. Whereas tetracyclines have anti-chlamydial activity, their effect on human IgE responses to C. pneumoniae has not been studied. METHODS: Peripheral blood mononuclear cells (PBMCs) from serum IgE+ allergic asthmatic subjects (n = 11) and healthy controls (n = 12) were infected with C. pneumoniae and cultured for 12 days with or without doxycycline (0.01-1.0 mg/L). IgE, interferon (IFN)-gamma and interleukin (IL)-4 levels in supernatants were determined on days 1-12 post infection, and C. pneumoniae DNA copy numbers in PBMC culture were measured on day 2 (quantitative PCR). RESULTS: C. pneumoniae-infected PBMCs from allergic asthmatic individuals had increased levels of IgE in supernatants compared with uninfected PBMCs (520% on day 10 post-infection, P = 0.008). IgE levels in PBMC cultures from controls were undetectable (<0.3 ng/mL). Increases in C. pneumoniae induced IgE in asthmatics correlated with those of C. pneumoniae-induced IL-4 (r = 0.98; P < 0.001), but not with IFN-gamma. The addition of doxycycline (1.0 mg/L) to the culture strongly suppressed the production of IgE (>70%, P = 0.04) and IL-4 (75%, P = 0.018), but not IFN-gamma. The suppressive effect on IL-4 production remained significant even at concentrations of doxycycline that were subinhibitory (0.01 mg/L) for C. pneumoniae. In both asthmatic participants and controls, no significant effect of doxycycline on DNA copy numbers of C. pneumoniae was observed. CONCLUSIONS: Doxycycline suppressed the C. pneumoniae induced production of IgE and IL-4, but not IFN-gamma, in PBMCs from IgE+ allergic asthmatic subjects. These findings resulted from the immunomodulatory anti-allergic properties of tetracyclines. PMID- 23749950 TI - European mitochondrial haplogroups are associated with CD4+ T cell recovery in HIV-infected patients on combination antiretroviral therapy. AB - BACKGROUND: There is substantial interindividual variability in the rate and extent of CD4+ T cell recovery after starting combination antiretroviral therapy (cART). The aim of our study was to determine whether mitochondrial DNA (mtDNA) haplogroups are associated with recovery of CD4+ in HIV-infected patients on cART. METHODS: We carried out a retrospective study on 275 cART-naive patients with CD4+ counts <350 cells/mm(3), who were followed-up during at least 24 months after initiating cART. mtDNA genotyping was performed by Sequenom's MassARRAY platform. RESULTS: Patients within cluster JT and haplogroup J had a lower chance of achieving a CD4+ count >=500 cells/mm(3) than patients within cluster HV and haplogroup H [hazard ratio (HR) = 0.68 (P = 0.058) and HR = 0.48 (P = 0.010), respectively]. The time of follow-up during which the CD4+ count was >=500 cells/mm(3) was longer in haplogroups HV and H than in haplogroups JT and J [20 months versus 6.2 months (P = 0.029) and 20 months versus 0 months (P = 0.024), respectively]. Additionally, haplogroups HV and H had greater chances of achieving a CD4+ count >=500 cells/mm(3) during at least 12, 36, 48 and 60 months post-cART initiation compared with patients within haplogroups JT and J. Patients within haplogroup T only had a lesser chance of achieving a CD4+ count >=500 cells/mm(3) during at least 48 months and 60 months post-cART initiation. CONCLUSION: European mitochondrial haplogroups might influence CD4+ recovery in HIV-infected patients following initiation with cART. Haplogroups J and T appear to be associated with a worse profile of CD4+ recovery, whereas haplogroup H was associated with a better CD4+ reconstitution. PMID- 23749951 TI - A Phase 2 study of the novel fluoroquinolone JNJ-Q2 in community-acquired bacterial pneumonia. PMID- 23749952 TI - Evolution of the K65R, K103N and M184V/I reverse transcriptase mutations in HIV-1 infected patients experiencing virological failure between 2005 and 2010. AB - OBJECTIVES: To assess the prevalence of the K65R, K103N and M184V/I resistance mutations in the reverse transcriptase (RT) region in HIV-1-infected patients failing antiretroviral-based regimens between the years 2005 and 2010. PATIENTS AND METHODS: HIV-1-infected patients experiencing virological failure between 2005 and 2010 with RT genotypic resistance tests available at the time of virological failure were analysed. K65R, K103N and M184V/I mutation frequencies were determined each year. Statistical analyses were performed using Fisher's exact test. RESULTS: Among 9586 patients failing their antiretroviral-based regimens from 2005 to 2010, the prevalence of K65R tended to decrease (P = 0.054), while K103N and M184V/I mutation frequencies decreased significantly over time (P < 0.001). The increased use of a tenofovir/emtricitabine/efavirenz single tablet regimen was associated with decreased selection of these mutations. CONCLUSIONS: The global prevalence of resistance-associated mutations to tenofovir, lamivudine/emtricitabine and efavirenz decreased over time between 2005 and 2010. Despite a stable rate of efavirenz and protease inhibitor use, this phenomenon can be explained by an increased use of single-tablet regimens, which simplify drug intake and maximize adherence. PMID- 23749953 TI - Pharmacokinetics of four different brands of colistimethate and formed colistin in rats. AB - OBJECTIVES: Very different labelling conventions are employed by different products of colistimethate (CMS), an inactive prodrug of colistin that is used as a last-line defence against Gram-negative 'superbugs'. This study examined the chemical composition and pharmacokinetics in rats of four commercial parenteral products of CMS. METHODS: Contents per vial of four brands of CMS from three different continents were weighed (n = 3). Elemental analysis and HPLC examination were conducted. The pharmacokinetics of CMS and formed colistin were investigated for each product after intravenous administration in rats (28.1 mg/kg CMS; n = 4). Blood was collected over 180 min, and concentrations of CMS and colistin were measured followed by pharmacokinetic analysis. RESULTS: X-GEN, Paddock and Atlantic products, labelled with 150 mg 'colistin base activity', contained 366.8 +/- 0.80, 340.6 +/- 0.08 and 380.0 +/- 5.97 mg CMS (sodium) per vial, respectively; while the Forest product (labelled with 2 000 000 IU) contained 159.3 +/- 1.75 mg CMS (sodium). The elemental compositions of the four products were similar; however, the HPLC profile of the Atlantic CMS was different from those of the other three products. The pharmacokinetics of CMS were generally comparable across brands; however, the molar ratios (%) of the AUC0-180min of colistin to CMS (1.68% +/- 0.35% to 3.29% +/- 0.43%) were significantly different (P = 0.0157). CONCLUSION: This is the first study to demonstrate that although different brands of CMS from various parts of the world have similar elemental compositions, they lead to different exposures to the microbiologically active formed colistin. The study has significant implications for the interpretation of pharmacological studies of CMS conducted in different parts of the world. PMID- 23749954 TI - The preferential selection of K65R in HIV-1 subtype C is attenuated by nucleotide polymorphisms at thymidine analogue mutation sites. AB - OBJECTIVES: We recently reported the preferential selection of the K65R resistance mutation in subtype C HIV-1 compared with subtype B and showed the underlying mechanism to be dependent on subtype C-specific silent nucleotide polymorphisms, i.e. genomic mutations that change the genotype but not the phenotype. The number of clinical reports demonstrating elevated numbers of K65R nevertheless suggests the existence of factors limiting the increased incidence of K65R mutations. Thus, we investigated the contributions of subtype C-specific silent nucleotide polymorphisms at thymidine analogue mutation (TAM) sites 70, 210 and/or 219 that might reduce the previously described preferential selection of K65R in subtype C HIV-1 associated with subtype C-specific nucleotide polymorphisms at sites 64/65. METHODS: Cell culture drug selections were performed with various drugs in MT2 cells. RESULTS: The use of nucleoside/nucleotide reverse transcriptase inhibitors [N(t)RTIs] as single drugs or in combination confirmed the more frequent selection of K65R by multiple N(t)RTIs in a subtype B virus that contained the 64/65 nucleotide polymorphisms of subtype C than in a wild-type subtype B virus. This effect was attenuated in the presence of several silent TAM nucleotide polymorphisms, except when stavudine was employed in the selection protocol. CONCLUSIONS: These results further demonstrate that stavudine can preferentially select for K65R in subtype C virus and also provide a basis for understanding the importance of silent nucleotide polymorphisms in regard to altered HIV drug resistance profiles. PMID- 23749955 TI - Identification of a rare mutation at reverse transcriptase Lys65 (K65E) in HIV-1 infected patients failing on nucleos(t)ide reverse transcriptase inhibitors. AB - OBJECTIVES: The HIV reverse transcriptase (RT) mutation K65R confers resistance to nucleos(t)ide reverse transcriptase inhibitors (NRTIs). Here, analysing a large database, we report the selection of another rare K65E mutation in patients failing on NRTI-containing regimens. METHODS: Clinical and virological characteristics of patients harbouring the K65E mutation were analysed using a large RT sequence database from treatment-experienced individuals. Structural analysis of the K65E RT mutant complex was performed by means of docking simulations. The replication capacity was assessed using viruses harbouring the K65E mutation introduced by site-directed mutagenesis (SDM) in pNL 4-3. RESULTS: Overall, in 23 530 sequences from patients failing on antiretroviral therapy, the prevalence of substitutions at position K65 in RT was 2.4%. In addition to K65R (n = 395) and K65N (n = 9), another mutation, K65E, was found in 15 patients. In 11 out of 15 cases, tenofovir, abacavir, didanosine or stavudine were present at the time of K65E selection. The molecular recognition of RT containing K65E supports evidence for the role of this mutation in resistance to tenofovir. The SDM pNL4-3 K65E variant harboured a very low replicative capacity (5% versus wild type). CONCLUSIONS: We investigated the role of a novel rare NRTI mutation located at position Lys65 of RT (K65E), found in drug-experienced patients failing on NRTIs. The low frequency of this mutation is probably related to the high impairment of replicative capacity induced by this mutation. This study should have significant clinical implications, as these findings warn clinicians that other minor substitutions at Lys65 (such as K65E) play a role in NRTI resistance. PMID- 23749956 TI - Inferring disease association using clinical factors in a combinatorial manner and their use in drug repositioning. AB - MOTIVATION: Complex physiological relationships exist among human diseases. Thus, the identification of disease associations could provide new methods of disease care and diagnosis. To this end, numerous studies have investigated disease associations. However, combinatorial effect of physiological factors, which is the main characteristic of biological systems, has not been considered in most previous studies. RESULTS: In this study, we inferred disease associations with a novel approach that considered disease-related clinical factors in combinatorial ways by using the National Health and Nutrition Examination Survey data, and the results have been shown as disease networks. Here, the FP-growth algorithm, an association rule mining algorithm, was used to generate a clinical attribute combination profile of each disease. In addition, we characterized the 22 clinical risk attribute combinations frequently discovered from the 26 diseases in this study. Furthermore, we validated that the results of this study have great potential for drug repositioning and outperform other existing disease networks in this regard. Finally, we suggest a few disease pairs as new candidates for drug repositioning and provide the evidence of their associations from the literature. PMID- 23749958 TI - PurBayes: estimating tumor cellularity and subclonality in next-generation sequencing data. AB - SUMMARY: We have developed a novel Bayesian method, PurBayes, to estimate tumor purity and detect intratumor heterogeneity based on next-generation sequencing data of paired tumor-normal tissue samples, which uses finite mixture modeling methods. We demonstrate our approach using simulated data and discuss its performance under varying conditions. AVAILABILITY: PurBayes is implemented as an R package, and source code is available for download through CRAN at http://cran.r-project.org/package=PurBayes. CONTACT: larson.nicholas@mayo.edu SUPPLEMENTARY INFORMATION: Supplementary data are available online at Bioinformatics online. PMID- 23749959 TI - SVGenes: a library for rendering genomic features in scalable vector graphic format. AB - MOTIVATION: Drawing genomic features in attractive and informative ways is a key task in visualization of genomics data. Scalable Vector Graphics (SVG) format is a modern and flexible open standard that provides advanced features including modular graphic design, advanced web interactivity and animation within a suitable client. SVGs do not suffer from loss of image quality on re-scaling and provide the ability to edit individual elements of a graphic on the whole object level independent of the whole image. These features make SVG a potentially useful format for the preparation of publication quality figures including genomic objects such as genes or sequencing coverage and for web applications that require rich user-interaction with the graphical elements. RESULTS: SVGenes is a Ruby-language library that uses SVG primitives to render typical genomic glyphs through a simple and flexible Ruby interface. The library implements a simple Page object that spaces and contains horizontal Track objects that in turn style, colour and positions features within them. Tracks are the level at which visual information is supplied providing the full styling capability of the SVG standard. Genomic entities like genes, transcripts and histograms are modelled in Glyph objects that are attached to a track and take advantage of SVG primitives to render the genomic features in a track as any of a selection of defined glyphs. The feature model within SVGenes is simple but flexible and not dependent on particular existing gene feature formats meaning graphics for any existing datasets can easily be created without need for conversion. AVAILABILITY: The library is provided as a Ruby Gem from https://rubygems.org/gems/bio-svgenes under the MIT license, and open source code is available at https://github.com/danmaclean/bioruby-svgenes also under the MIT License. CONTACT: dan.maclean@tsl.ac.uk. PMID- 23749957 TI - Differential network analysis for the identification of condition-specific pathway activity and regulation. AB - MOTIVATION: Identification of differential expressed genes has led to countless new discoveries. However, differentially expressed genes are only a proxy for finding dysregulated pathways. The problem is to identify how the network of regulatory and physical interactions rewires in different conditions or in disease. RESULTS: We developed a procedure named DINA (DIfferential Network Analysis), which is able to identify set of genes, whose co-regulation is condition-specific, starting from a collection of condition-specific gene expression profiles. DINA is also able to predict which transcription factors (TFs) may be responsible for the pathway condition-specific co-regulation. We derived 30 tissue-specific gene networks in human and identified several metabolic pathways as the most differentially regulated across the tissues. We correctly identified TFs such as Nuclear Receptors as their main regulators and demonstrated that a gene with unknown function (YEATS2) acts as a negative regulator of hepatocyte metabolism. Finally, we showed that DINA can be used to make hypotheses on dysregulated pathways during disease progression. By analyzing gene expression profiles across primary and transformed hepatocytes, DINA identified hepatocarcinoma-specific metabolic and transcriptional pathway dysregulation. AVAILABILITY: We implemented an on-line web-tool http://dina.tigem.it enabling the user to apply DINA to identify tissue-specific pathways or gene signatures. CONTACT: dibernardo@tigem.it SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23749960 TI - Network2Canvas: network visualization on a canvas with enrichment analysis. AB - MOTIVATION: Networks are vital to computational systems biology research, but visualizing them is a challenge. For networks larger than ~100 nodes and ~200 links, ball-and-stick diagrams fail to convey much information. To address this, we developed Network2Canvas (N2C), a web application that provides an alternative way to view networks. N2C visualizes networks by placing nodes on a square toroidal canvas. The network nodes are clustered on the canvas using simulated annealing to maximize local connections where a node's brightness is made proportional to its local fitness. The interactive canvas is implemented in HyperText Markup Language (HTML)5 with the JavaScript library Data-Driven Documents (D3). We applied N2C to visualize 30 canvases made from human and mouse gene-set libraries and 6 canvases made from the Food and Drug Administration (FDA)-approved drug-set libraries. Given lists of genes or drugs, enriched terms are highlighted on the canvases, and their degree of clustering is computed. Because N2C produces visual patterns of enriched terms on canvases, a trained eye can detect signatures instantly. In summary, N2C provides a new flexible method to visualize large networks and can be used to perform and visualize gene-set and drug-set enrichment analyses. AVAILABILITY: N2C is freely available at http://www.maayanlab.net/N2C and is open source. CONTACT: avi.maayan@mssm.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 23749961 TI - NOA: a cytoscape plugin for network ontology analysis. AB - SUMMARY: The Network Ontology Analysis (NOA) plugin for Cytoscape implements the NOA algorithm for network-based enrichment analysis, which extends Gene Ontology annotations to network links, or edges. The plugin facilitates the annotation and analysis of one or more networks in Cytoscape according to user-defined parameters. In addition to tables, the NOA plugin also presents results in the form of heatmaps and overview networks in Cytoscape, which can be exported for publication figures. AVAILABILITY: The NOA plugin is an open source, Java program for Cytoscape version 2.8 available via the Cytoscape App Store (http://apps.cytoscape.org/apps/noa) and plugin manager. A detailed user manual is available at http://nrnb.org/tools/noa. .ucsf.edu PMID- 23749962 TI - TASUKE: a web-based visualization program for large-scale resequencing data. AB - SUMMARY: Because an enormous amount of sequence data is being collected, a method to effectively display sequence variation information is urgently needed. tasuke is a web application that visualizes large-scale resequencing data generated by next-generation sequencing technologies and is suitable for rapid data release to the public on the web. The variation and read depths of multiple genomes, as well as annotations, can be shown simultaneously at various scales. We demonstrate the use of TASUKE by applying it to 50 rice and 100 human genome resequencing datasets. AVAILABILITY AND IMPLEMENTATION: The tasuke program package and user manual are available from http://tasuke.dna.affrc.go.jp/. CONTACT: taitoh@affrc.go.jp. PMID- 23749963 TI - Comment on "TLR9 provokes inflammation in response to fetal DNA: mechanism for fetal loss in preterm birth and preeclampsia". PMID- 23749964 TI - Comment on "Induced IL-17-producing invariant NKT cells require activation in presence of TGF-beta and IL-1beta". PMID- 23749965 TI - Response to comment on "Induced IL-17-producing invariant NKT cells require activation in presence of TGF-beta and IL-1beta". PMID- 23749966 TI - What is and what should always have been: long-lived plasma cells induced by T cell-independent antigens. AB - It is well accepted that Ag-induced B cell differentiation often results in the generation of exceptionally long-lived plasma cells. Much of the work supporting this viewpoint stems from studies focused on germinal center-derived plasma cells secreting high-affinity isotype-switched Abs in mice immunized with T cell dependent Ags. In contrast, less attention has been devoted to understanding Ab responses to T cell-independent Ags and pathogens. In this study, we review recent work showing that T cell-independent Ags consisting of either polysaccharides or LPSs also induce the formation of long-lived plasma cells, despite their general inability to sustain germinal center responses. This new information provides a framework for more fully understanding the forces underlying immunity to pathogens that resist T cell recognition and the extracellular cues governing plasma cell longevity. PMID- 23749967 TI - Heterozygosity for the F508del mutation in the cystic fibrosis transmembrane conductance regulator anion channel attenuates influenza severity. AB - BACKGROUND: Seasonal and pandemic influenza are significant public health concerns. Influenza stimulates respiratory epithelial Cl(-) secretion via the cystic fibrosis transmembrane conductance regulator (CFTR). The purpose of this study was to determine the contribution of this effect to influenza pathogenesis in mice with reduced CFTR activity. METHODS: C57BL/6-congenic mice heterozygous for the F508del CFTR mutation (HET) and wild-type (WT) controls were infected intranasally with 10 000 focus-forming units of influenza A/WSN/33 (H1N1) per mouse. Body weight, arterial O2 saturation, and heart rate were monitored daily. Pulmonary edema and lung function parameters were derived from ratios of wet weight to dry weight and the forced-oscillation technique, respectively. Levels of cytokines and chemokines in bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay. RESULTS: Relative to WT mice, influenza virus infected HET mice showed significantly delayed mortality, which was accompanied by attenuated hypoxemia, cardiopulmonary dysfunction, and pulmonary edema. However, viral replication and weight loss did not differ. The protective HET phenotype was correlated with exaggerated alveolar macrophage and interleukin 6 responses to infection and was abrogated by alveolar macrophage depletion, using clodronate liposomes. CONCLUSIONS: Reduced CFTR expression modulates the innate immune response to influenza and alters disease pathogenesis. CFTR-mediated Cl(-) secretion is therefore an important host determinant of disease, and CFTR inhibition may be of therapeutic benefit in influenza. PMID- 23749968 TI - Impaired CD4+ T-cell restoration in the small versus large intestine of HIV-1 positive South Africans receiving combination antiretroviral therapy. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) infection is associated with a massive depletion of intestinal CD4(+) T cells that is only partially reversed by combination antiretroviral therapy (cART). Here, we assessed the ability of nucleoside reverse-transcriptase inhibitor/nonnucleoside reverse transcriptase inhibitor treatment to restore the CD4(+) T-cell populations in the intestine of South African patients with AIDS. METHODS: Thirty-eight patients with advanced HIV-1 infection who had chronic diarrhea (duration, >4 weeks) and/or unintentional weight loss (>10% decrease from baseline) of uncertain etiology were enrolled. Blood specimens were collected monthly, and gastrointestinal tract biopsy specimens were collected before cART initiation (from the duodenum, jejunum, ileum, and colon), 3 months after cART initiation (from the duodenum), and 6 months after cART initiation (from the duodenum and colon). CD4(+), CD8(+), and CD38(+)CD8(+) T cells were quantified by flow cytometry and immunohistochemistry analyses, and the HIV-1 RNA load was determined by the Nuclisens assay. RESULTS: CD4(+) T-cell and HIV-1 RNA levels were significantly lower, whereas CD8(+) T-cell levels, including activated CD38(+)CD8(+) T cell levels, were higher in the duodenum and jejunum, compared with the colon. After 6 months of cART, a significant but incomplete recovery of CD4(+) T cells was detected in the colon and peripheral blood but not in the duodenum. Failed restoration of the CD4(+) T-cell count in the duodenum was associated with nonspecific enteritis and CD8(+) T-cell activation. CONCLUSIONS: Strategies that target inflammation and immune activation in the small intestine may be required to expedite CD4(+) T-cell recovery and improve therapeutic outcomes. PMID- 23749969 TI - Has the bacterial biphenyl catabolic pathway evolved primarily to degrade biphenyl? The diphenylmethane case. AB - In this work, we have compared the ability of Pandoraea pnomenusa B356 and of Burkholderia xenovorans LB400 to metabolize diphenylmethane and benzophenone, two biphenyl analogs in which the phenyl rings are bonded to a single carbon. Both chemicals are of environmental concern. P. pnomenusa B356 grew well on diphenylmethane. On the basis of growth kinetics analyses, diphenylmethane and biphenyl were shown to induce the same catabolic pathway. The profile of metabolites produced during growth of strain B356 on diphenylmethane was the same as the one produced by isolated enzymes of the biphenyl catabolic pathway acting individually or in coupled reactions. The biphenyl dioxygenase oxidizes diphenylmethane to 3-benzylcyclohexa-3,5-diene-1,2-diol very efficiently, and ultimately this metabolite is transformed to phenylacetic acid, which is further metabolized by a lower pathway. Strain B356 was also able to cometabolize benzophenone through its biphenyl pathway, although in this case, this substrate was unable to induce the biphenyl catabolic pathway and the degradation was incomplete, with accumulation of 2-hydroxy-6,7-dioxo-7-phenylheptanoic acid. Unlike strain B356, B. xenovorans LB400 did not grow on diphenylmethane. Its biphenyl pathway enzymes metabolized diphenylmethane, but they poorly metabolize benzophenone. The fact that the biphenyl catabolic pathway of strain B356 metabolized diphenylmethane and benzophenone more efficiently than that of strain LB400 brings us to postulate that in strain B356, this pathway evolved divergently to serve other functions not related to biphenyl degradation. PMID- 23749970 TI - Numbers of individual nutrient germinant receptors and other germination proteins in spores of Bacillus subtilis. AB - Germination of dormant Bacillus subtilis spores with specific nutrient germinants is dependent on a number of inner membrane (IM) proteins, including (i) the GerA, GerB, and GerK germinant receptors (GRs) that respond to nutrient germinants; (ii) the GerD protein, essential for optimal GR function; and (iii) SpoVA proteins, essential for the release of the spore-specific molecule dipicolinic acid (DPA) during spore germination. Levels of GR A and C subunit proteins, GerD, and SpoVAD in wild-type spores were determined by Western blot analysis of spore fractions or total disrupted spores by comparison with known amounts of purified proteins. Surprisingly, after disruption of decoated B. subtilis spores with lysozyme and fractionation, ~90% of IM fatty acids and GR subunits remained with the spores' insoluble integument fraction, indicating that yields of purified IM are low. The total lysate from disrupted wild-type spores contained ~2,500 total GRs/spore: GerAA and GerAC subunits each at ~1,100 molecules/spore and GerBC and GerKA subunits each at ~700 molecules/spore. Levels of the GerBA subunit determined previously were also predicted to be ~700 molecules/spore. These results indicate that the A/C subunit stoichiometry in GRs is most likely 1:1, with GerA being the most abundant GR. GerD and SpoVAD levels were ~3,500 and ~6,500 molecules/spore, respectively. These values will be helpful in formulating mathematic models of spore germination kinetics as well as setting lower limits on the size of the GR-GerD complex in the spores' IM, termed the germinosome. PMID- 23749971 TI - Regulation of the ald gene encoding alanine dehydrogenase by AldR in Mycobacterium smegmatis. AB - The regulatory gene aldR was identified 95 bp upstream of the ald gene encoding L alanine dehydrogenase in Mycobacterium smegmatis. The AldR protein shows sequence similarity to the regulatory proteins of the Lrp/AsnC family. Using an aldR deletion mutant, we demonstrated that AldR serves as both activator and repressor for the regulation of ald gene expression, depending on the presence or absence of L-alanine. The purified AldR protein exists as a homodimer in the absence of L alanine, while it adopts the quaternary structure of a homohexamer in the presence of L-alanine. The binding affinity of AldR for the ald control region was shown to be increased significantly by L-alanine. Two AldR binding sites (O1 and O2) with the consensus sequence GA-N2-ATC-N2-TC and one putative AldR binding site with the sequence GA-N2-GTT-N2-TC were identified upstream of the ald gene. Alanine and cysteine were demonstrated to be the effector molecules directly involved in the induction of ald expression. The cellular level of L-alanine was shown to be increased in M. smegmatis cells grown under hypoxic conditions, and the hypoxic induction of ald expression appears to be mediated by AldR, which senses the intracellular level of alanine. PMID- 23749972 TI - In the absence of RidA, endogenous 2-aminoacrylate inactivates alanine racemases by modifying the pyridoxal 5'-phosphate cofactor. AB - Members of the RidA (YjgF/YER057c/UK114) protein family are broadly conserved across the domains of life. In vitro, these proteins deaminate 3- or 4-carbon enamines that are generated as mechanistic intermediates of pyridoxal 5' phosphate (PLP)-dependent serine/threonine dehydratases. The three-carbon enamine 2-aminoacrylate can inactivate some enzymes by forming a covalent adduct via a mechanism that has been well characterized in vitro. The biochemical activity of RidA suggested that the phenotypes of ridA mutant strains were caused by the accumulation of reactive enamine metabolites. The data herein show that in ridA mutant strains of Salmonella enterica, a stable 2-aminoacrylate (2-AA)/PLP adduct forms on the biosynthetic alanine racemase, Alr, indicating the presence of 2 aminoacrylate in vivo. This study confirms the deleterious effect of 2 aminoacrylate generated by metabolic enzymes and emphasizes the need for RidA to quench this reactive metabolite. PMID- 23749973 TI - Phage-encoded inhibitor of Staphylococcus aureus transcription exerts context dependent effects on promoter function in a modified Escherichia coli-based transcription system. AB - Promoter recognition in bacteria is mediated primarily by the sigma subunit of RNA polymerase (RNAP), which makes sequence-specific contacts with the promoter 10 and -35 elements in the context of the RNAP holoenzyme. However, the RNAP alpha subunit can also contribute to promoter recognition by making sequence specific contacts with upstream (UP) elements that are associated with a subset of promoters, including the rRNA promoters. In Escherichia coli, these interactions between the RNAP alpha subunit (its C-terminal domain [CTD], in particular) and UP element DNA result in significant stimulation of rRNA transcription. Among the many cellular and bacteriophage-encoded regulators of transcription initiation that have been functionally dissected, most exert their effects via a direct interaction with either the sigma or the alpha subunit. An unusual example is provided by a phage-encoded inhibitor of RNA synthesis in Staphylococcus aureus. This protein, phage G1 gp67, which binds tightly to sigma in the context of the S. aureus RNAP holoenzyme, has recently been shown to exert selective effects on transcription by inhibiting the function of the alpha subunit CTD (alphaCTD). Here we report the development of a gp67-responsive E. coli-based transcription system. We examine transcription in vitro from promoters that do or do not carry the UP element associated with a well-characterized E. coli rRNA promoter. Our findings indicate that the alphaCTD can increase promoter activity significantly even in the absence of an UP element. We also find that gp67 can exert alphaCTD-dependent or alphaCTD-independent effects on transcription depending on the particular promoter, indicating that the mechanism of gp67 action is context dependent. PMID- 23749974 TI - Length control of the flagellar hook in a temperature-sensitive flgE mutant of Salmonella enterica serovar Typhimurium. AB - The flagellar hook is a short, curved, extracellular structure located between the basal body and the filament. The hook is composed of the FlgE protein. In this study, we analyzed flagellum assembly in a temperature-sensitive flgE mutant of Salmonella enterica serovar Typhimurium. When the mutant cells were grown at 30 degrees C, they produced flagella of a normal length (71% of the population) and short hooks without filaments (26%). At 37 degrees C, 70% of the basal bodies lacked hooks, and intact flagella made up only 6% of the population. Mutant cells secreted monomeric FlgE in abundance at 37 degrees C, suggesting that the mutant FlgE protein might be defective in polymerization at higher temperatures. The average length of the hooks in intact filaments was 55 nm, whereas after acid treatment, it was 45 nm. SDS-PAGE analysis of the hook-basal body showed that HAP1 was missing in the mutant but not in the wild type. We concluded that hook length in the mutant is controlled in the same way as in the wild type, but the hook appeared short after acid treatment due to the lack of HAP1. We also learned that the true length of the hook is possibly 45 nm, not 55 nm, as has been believed. PMID- 23749975 TI - Chemoreceptor gene loss and acquisition via horizontal gene transfer in Escherichia coli. AB - Chemotaxis allows bacteria to more efficiently colonize optimal microhabitats within their larger environment. Chemotaxis in Escherichia coli is the best studied model system, and a large number of E. coli strains have been sequenced. The Escherichia/Shigella genus encompasses a great variety of commensal and pathogenic strains, but the role of chemotaxis in their association with the host remains poorly understood. Here we show that the core chemotaxis genes are lost in many, but not all, nonmotile strains but are well preserved in all motile strains. The genes encoding the Tar, Tsr, and Aer chemoreceptors, which mediate chemotaxis to a broad spectrum of chemical and physical cues, are also nearly uniformly conserved in motile strains. In contrast, the clade of extraintestinal pathogenic E. coli strains apparently underwent an ancestral loss of Trg and Tap chemoreceptors, which sense sugars, dipeptides, and pyrimidines. The broad range of time estimated for the loss of these genes (1 to 3 million years ago) corresponds to the appearance of the genus Homo. PMID- 23749976 TI - Quorum sensing regulatory cascades control Vibrio fluvialis pathogenesis. AB - Quorum sensing (QS) is a process by which individual bacteria are able to communicate with one another, thereby enabling the population as a whole to coordinate gene regulation and subsequent phenotypic outcomes. Communication is accomplished through production and detection of small molecules in the extracellular milieu. In many bacteria, particularly Vibrio species, multiple QS systems result in multiple signals, as well as cross talk between systems. In this study, we identify two QS systems in the halophilic enteric pathogen Vibrio fluvialis: one acyl-homoserine lactone (AHL) based and one CAI-1/AI-2 based. We show that a LuxI homolog, VfqI, primarily produces 3-oxo-C10-HSL, which is sensed by a LuxR homolog, VfqR. VfqR-AHL is required to activate vfqI expression and autorepress vfqR expression. In addition, we have shown that similar to that in V. cholerae and V. harveyi, V. fluvialis produces CAI-1 and AI-2 signal molecules to activate the expression of a V. cholerae HapR homolog through LuxO. Although VfqR-AHL does not regulate hapR expression, HapR can repress vfqR transcription. Furthermore, we found that QS in V. fluvialis positively regulates production of two potential virulence factors, an extracellular protease and hemolysin. QS also affects cytotoxic activity against epithelial tissue cultures. These data suggest that V. fluvialis integrates QS regulatory pathways to play important physiological roles in pathogenesis. PMID- 23749977 TI - Large linear plasmids of Borrelia species that cause relapsing fever. AB - Borrelia species of relapsing fever (RF) and Lyme disease (LD) lineages have linear chromosomes and both linear and circular plasmids. Unique to RF species, and little characterized to date, are large linear plasmids of ~160 kb, or ~10% of the genome. By a combination of Sanger and next-generation methods, we determined the sequences of large linear plasmids of two New World species: Borrelia hermsii, to completion of its 174-kb length, and B. turicatae, partially to 114 kb of its 150 kb. These sequences were then compared to corresponding sequences of the Old World species B. duttonii and B. recurrentis and to plasmid sequences of LD Borrelia species. The large plasmids were largely colinear, except for their left ends, about 27 kb of which was inverted in New World species. Approximately 60% of the B. hermsii lp174 plasmid sequence was repetitive for 6 types of sequence, and half of its open reading frames encoded hypothetical proteins not discernibly similar to proteins in the database. The central ~25 kb of all 4 linear plasmids was syntenic for orthologous genes for plasmid maintenance or partitioning in Borrelia species. Of all the sequenced linear and circular plasmids in Borrelia species, the large plasmid's putative partition/replication genes were most similar to those of the 54-kb linear plasmids of LD species. Further evidence for shared ancestry was the observation that two of the hypothetical proteins were predicted to be structurally similar to the LD species' CspA proteins, which are encoded on the 54-kb plasmids. PMID- 23749978 TI - The Streptococcus mutans aminotransferase encoded by ilvE is regulated by CodY and CcpA. AB - The aminotransferase IlvE was implicated in the acid tolerance response of Streptococcus mutans when a mutation in its gene resulted in an acid-sensitive phenotype (B. Santiago, M. MacGilvray, R. C. Faustoferri, and R. G. Quivey, Jr., J. Bacteriol. 194:2010-2019, 2012). The phenotype suggested that amino acid metabolism is important for acid adaptation, as turnover of branched-chain amino acids (bcAAs) could provide important signals to modulate expression of genes involved in the adaptive process. Previous studies have demonstrated that ilvE is regulated in response to the external pH, though the mechanism is not yet established. CodY and CcpA have been shown to regulate expression of branched chain amino acid biosynthetic genes, suggesting that the ability to sense carbon flow and the nutritional state of the cell also plays a role in the regulation of ilvE. Electrophoretic mobility shift assays using the ilvE promoter and a purified recombinant CodY protein provided evidence of the physical interaction between CodY and ilvE. In order to elucidate the signals that contribute to ilvE regulation, cat reporter fusions were utilized. Transcriptional assays demonstrated that bcAAs are signaling molecules involved in the repression of ilvE through regulation of CodY. In a codY deletion background, ilvE transcription was elevated, indicating that CodY acts a repressor of ilvE transcription. Conversely, in a ccpA deletion background, ilvE transcription was reduced, showing that CcpA activated ilvE transcription. The effects of both regulators were directly relevant for transcription of ilvE under conditions of acid stress, demonstrating that both regulators play a role in acid adaptation. PMID- 23749979 TI - Functional consequences of substitution mutations in MepR, a repressor of the Staphylococcus aureus MepA multidrug efflux pump gene. AB - The expression of mepA, encoding the Staphylococcus aureus MepA multidrug efflux protein, is repressed by the MarR homologue MepR. MepR dimers bind differently to operators upstream of mepR and mepA, with affinity being greatest at the mepA operator. MepR substitution mutations may result in mepA overexpression, with A103V most common in clinical strains. Evaluation of the functional consequences of this and other MepR substitutions using a lacZ reporter gene assay revealed markedly reduced repressor activity in the presence of Q18P, F27L, G97E, and A103V substitutions. Reporter data were generally supported by susceptibility and efflux assays, and electrophoretic mobility shift assays (EMSAs) confirmed compromised affinities of MepR F27L and A103V for the mepR and mepA operators. One mutant protein contained two substitutions (T94P and T132M); T132M compensated for the functional defect incurred by T94P and also rescued that of A103V but not F27L, establishing it as a limited-range suppressor. The function of another derivative with 10 substitutions was minimally affected, and this may be an extreme example of suppression involving interactions among several residues. Structural correlations for the observed functional effects were ascertained by modeling mutations onto apo-MepR. It is likely that F27L and A103V affect the protein-DNA interaction by repositioning of DNA recognition helices. Negative functional consequences of MepR substitution mutations may result from interference with structural plasticity, alteration of helical arrangements, reduced protein-cognate DNA affinity, or possibly association of MepR protomers. Structural determinations will provide further insight into the consequences of these and other mutations that affect MepR function, especially the T132M suppressor. PMID- 23749980 TI - The Escherichia coli CydX protein is a member of the CydAB cytochrome bd oxidase complex and is required for cytochrome bd oxidase activity. AB - Cytochrome bd oxidase operons from more than 50 species of bacteria contain a short gene encoding a small protein that ranges from ~30 to 50 amino acids and is predicted to localize to the cell membrane. Although cytochrome bd oxidases have been studied for more than 70 years, little is known about the role of this small protein, denoted CydX, in oxidase activity. Here we report that Escherichia coli mutants lacking CydX exhibit phenotypes associated with reduced oxidase activity. In addition, cell membrane extracts from DeltacydX mutant strains have reduced oxidase activity in vitro. Consistent with data showing that CydX is required for cytochrome bd oxidase activity, copurification experiments indicate that CydX interacts with the CydAB cytochrome bd oxidase complex. Together, these data support the hypothesis that CydX is a subunit of the CydAB cytochrome bd oxidase complex that is required for complex activity. The results of mutation analysis of CydX suggest that few individual amino acids in the small protein are essential for function, at least in the context of protein overexpression. In addition, the results of analysis of the paralogous small transmembrane protein AppX show that the two proteins could have some overlapping functionality in the cell and that both have the potential to interact with the CydAB complex. PMID- 23749981 TI - The Sinorhizobium meliloti essential porin RopA1 is a target for numerous bacteriophages. AB - The symbiotic nitrogen-fixing bacterium Sinorhizobium meliloti harbors a gene, SMc02396, which encodes a predicted outer membrane porin that is conserved in many symbiotic and pathogenic bacteria in the order Rhizobiales. Here, this gene (renamed ropA1) is shown to be required for infection by two commonly utilized transducing bacteriophages (PhiM12 and N3). Mapping of S. meliloti mutations conferring resistance to PhiM12, N3, or both phages simultaneously revealed diverse mutations mapping within the ropA1 open reading frame. Subsequent tests determined that RopA1, lipopolysaccharide, or both are required for infection by all of a larger collection of Sinorhizobium-specific phages. Failed attempts to disrupt or delete ropA1 suggest that this gene is essential for viability. Phylogenetic analysis reveals that ropA1 homologs in many Rhizobiales species are often found as two genetically linked copies and that the intraspecies duplicates are always more closely related to each other than to homologs in other species, suggesting multiple independent duplication events. PMID- 23749982 TI - A clinical study of transoral pharyngectomies to treat superficial hypopharyngeal cancers. AB - BACKGROUND: For years, it has been a major interest for surgeons and oncologists to develop a novel technique to detect hypopharyngeal cancers at an early stage and to treat the lesions in a less invasive manner. The advent of the narrow band imaging system combined endoscopy and various endoscopic approaches shed light on the new era of the minimum invasive management of superficial cancers in hypopharyngeal regions. METHODS: Three endoscopic approaches, endoscopic mucosal resection, endoscopic submucosal dissection and endoscopic laryngopharyngeal surgery, were chronologically introduced at our institute. In this study, we focused on the clinical outcomes, advantages and limitations of each procedure. RESULTS: A total of 30 patients (42 procedures) received transoral pharyngectomies between June 2006 and May 2012. Tracheotomy was performed in 9 of 42 (21%) patients. Three patients developed local recurrence and were subsequently controlled by additional transoral pharyngectomies. The 2- and 5 year local control rates were 92.8 and 83.5%. The 2- and 5-year overall survival rates were 82.1%. CONCLUSIONS: Endoscopic mucosal resection, endoscopic submucosal dissection and endoscopic laryngopharyngeal surgery-transoral pharyngectomies are useful procedures for treating superficial hypopharyngeal cancers. Endoscopic mucosal resection manifested the least invasiveness and may be beneficial for resecting small superficial lesions, endoscopic submucosal dissection may be advantageous for patients with difficult laryngopharyngeal exposure and endoscopic laryngopharyngeal surgery has shown the optimal effectiveness and minimal complications and can be applied to most of the hypopharyngeal sub-sites. All three procedures require a high level of technical skill and close collaboration between otolaryngologists and gastroenterologists. PMID- 23749983 TI - Cancer care in Pakistan. AB - Pakistan is a lesser-developed country in South-West Asia, with a large and young population. We review here the current burden of cancer in Pakistan, followed by an assessment of the current facilities for diagnosis and treatment of cancer in the country. An effort is made to define the key problems in the delivery of optimal cancer care, and some possible solutions are offered. PMID- 23749984 TI - Prevention of TGFbeta induction attenuates angII-stimulated vascular biglycan and atherosclerosis in Ldlr-/- mice. AB - Angiotensin II (angII) accelerates atherosclerosis, but the mechanisms are not fully understood. The aim of this study was to determine whether TGFbeta is required for angII-induced atherosclerosis. Ldlr-null mice fed a normal chow diet were infused with angII or saline for 28 days. A single injection of TGFbeta neutralizing antibody 1D11 (2 mg/kg) prevented angII-induction of TGFbeta1 levels, and strikingly attenuated angII-induced accumulation of aortic biglycan content. To study atherosclerosis, mice were infused with angII or saline for 4 weeks, and then fed Western diet for a further 6 weeks. 1D11 had no effect on systolic blood pressure or plasma cholesterol; however, angII-infused mice that received 1D11 had reduced atherosclerotic lesion area by 30% (P < 0.05). Immunohistochemical analyses demonstrated that angII induced both lipid retention and accumulation of biglycan and perlecan which colocalized with apoB. 1D11 strikingly reduced the effect of angII on biglycan but not perlecan. 1D11 decreased total collagen content (P < 0.05) in the lesion area without changing plaque inflammation markers (CD68 and CD45). Thus, this study demonstrates that neutralization of TGFbeta attenuated angII stimulation of biglycan accumulation and atherogenesis in mice, suggesting that TGFbeta-mediated biglycan induction is one of the mechanisms underlying angII-promoted atherosclerosis. PMID- 23749985 TI - Phosphatidylglycerol provides short-term prophylaxis against respiratory syncytial virus infection. AB - Respiratory syncytial virus (RSV) causes respiratory tract infections in young children, and significant morbidity and mortality in the elderly, immunosuppressed, and immunocompromised patients and in patients with chronic lung diseases. Recently, we reported that the pulmonary surfactant phospholipid palmitoyl-oleoyl-phosphatidylglycerol (POPG) inhibited RSV infection in vitro and in vivo by blocking viral attachment to epithelial cells. Simultaneous application of POPG along with an RSV challenge to mice markedly attenuated infection and associated inflammatory responses. Based on these findings, we expanded our studies to determine whether POPG is effective for prophylaxis and postinfection treatment for RSV infection. In vitro application of POPG at concentrations of 0.2-1.0 mg/ml at 24 h after RSV infection of HEp-2 cells suppressed interleukin-8 production up to 80% and reduced viral plaque formation by 2-6 log units. In vivo, the turnover of POPG in mice is relatively rapid, making postinfection application impractical. Intranasal administration of POPG (0.8-3.0 mg), 45 min before RSV inoculation in mice reduced viral infection by 1 log unit, suppressed inflammatory cell appearance in the lung, and suppressed virus-elicited interferon-gamma production. These findings demonstrate that POPG is effective for short-term protection of mice against subsequent RSV infection and that it has potential for application in humans. PMID- 23749986 TI - Joint network and node selection for pathway-based genomic data analysis. AB - MOTIVATION: By capturing various biochemical interactions, biological pathways provide insight into underlying biological processes. Given high-dimensional microarray or RNA-sequencing data, a critical challenge is how to integrate them with rich information from pathway databases to jointly select relevant pathways and genes for phenotype prediction or disease prognosis. Addressing this challenge can help us deepen biological understanding of phenotypes and diseases from a systems perspective. RESULTS: In this article, we propose a novel sparse Bayesian model for joint network and node selection. This model integrates information from networks (e.g. pathways) and nodes (e.g. genes) by a hybrid of conditional and generative components. For the conditional component, we propose a sparse prior based on graph Laplacian matrices, each of which encodes detailed correlation structures between network nodes. For the generative component, we use a spike and slab prior over network nodes. The integration of these two components, coupled with efficient variational inference, enables the selection of networks as well as correlated network nodes in the selected networks. Simulation results demonstrate improved predictive performance and selection accuracy of our method over alternative methods. Based on three expression datasets for cancer study and the KEGG pathway database, we selected relevant genes and pathways, many of which are supported by biological literature. In addition to pathway analysis, our method is expected to have a wide range of applications in selecting relevant groups of correlated high-dimensional biomarkers. AVAILABILITY: The code can be downloaded at www.cs.purdue.edu/homes/szhe/software.html. CONTACT: alanqi@purdue.edu. PMID- 23749987 TI - DMEAS: DNA methylation entropy analysis software. AB - SUMMARY: DMEAS is the first user-friendly tool dedicated to analyze the distribution of DNA methylation patterns for the quantification of epigenetic heterogeneity. It supports the analysis of both locus-specific and genome-wide bisulfite sequencing data. DMEAS progressively scans the mapping results of bisulfite sequencing reads to extract DNA methylation patterns for contiguous CpG dinucleotides. It determines the DNA methylation level and calculates methylation entropy for genomic segments to enable the quantitative assessment of DNA methylation variations observed in cell populations. AVAILABILITY AND IMPLEMENTATION: DMEAS program, user guide and all the testing data are freely available from http://sourceforge.net/projects/dmeas/files/ PMID- 23749988 TI - Recessive truncating NALCN mutation in infantile neuroaxonal dystrophy with facial dysmorphism. AB - BACKGROUND: Infantile neuroaxonal dystrophy (INAD) is a recessive disease that results in total neurological degeneration and death in childhood. PLA2G6 mutation is the underlying genetic defect, but rare genetic heterogeneity has been demonstrated. One of the five families we studied did not link to PLA2G6 locus, and in the family one of the two affected siblings additionally had atypical features including facial dysmorphism, pectus carinatum, scoliosis, pes varus, zygodactyly and bilateral cryptorchidism as well as cerebellar atrophy, as previously reported. METHODS: Sural biopsy was investigated by electron microscopy. PLA2G6 was screened for mutations by Sanger sequencing. In the mutation-free family, candidate disease loci were found via linkage analysis using data from single nucleotide polymorphism genome scans. Exome sequencing was applied to find the variants at the loci. RESULTS: PLA2G6 mutations were identified in four families including the one with an unusually severe phenotype that led to death within the first 2 years of life. In the remaining family, seven candidate loci totalling 15.2 Mb were found and a homozygous truncating mutation p.Q642X was identified in NALCN at 13q32.3. The patients are around 20 years-old. CONCLUSIONS: NALCN is the gene responsible for INAD with facial dysmorphism. The patients have lived to adulthood despite severe growth and neuromotor retardation. NALCN forms a voltage-independent ion channel with a role in the regulation of neuronal excitability. Our findings broaden the spectrum of genes associated with neuroaxonal dystrophy. Testing infants with idiopathic severe growth retardation and neurodegeneration for NALCN mutations could benefit families. PMID- 23749989 TI - A de novo X;8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia. AB - BACKGROUND AND AIM: We identified a balanced de novo translocation involving chromosomes Xq25 and 8q24 in an eight year-old girl with a non-progressive form of congenital ataxia, cognitive impairment and cerebellar hypoplasia. METHODS AND RESULTS: Breakpoint definition showed that the promoter of the Protein Tyrosine Kinase 2 (PTK2, also known as Focal Adhesion Kinase, FAK) gene on chromosome 8q24.3 is translocated 2 kb upstream of the THO complex subunit 2 (THOC2) gene on chromosome Xq25. PTK2 is a well-known non-receptor tyrosine kinase whereas THOC2 encodes a component of the evolutionarily conserved multiprotein THO complex, involved in mRNA export from nucleus. The translocation generated a sterile fusion transcript under the control of the PTK2 promoter, affecting expression of both PTK2 and THOC2 genes. PTK2 is involved in cell adhesion and, in neurons, plays a role in axonal guidance, and neurite growth and attraction. However, PTK2 haploinsufficiency alone is unlikely to be associated with human disease. Therefore, we studied the role of THOC2 in the CNS using three models: 1) THOC2 ortholog knockout in C.elegans which produced functional defects in specific sensory neurons; 2) Thoc2 knockdown in primary rat hippocampal neurons which increased neurite extension; 3) Thoc2 knockdown in neuronal stem cells (LC1) which increased their in vitro growth rate without modifying apoptosis levels. CONCLUSION: We suggest that THOC2 can play specific roles in neuronal cells and, possibly in combination with PTK2 reduction, may affect normal neural network formation, leading to cognitive impairment and cerebellar congenital hypoplasia. PMID- 23749990 TI - Mechanisms of nitrosylation and denitrosylation of cytoplasmic glyceraldehyde-3 phosphate dehydrogenase from Arabidopsis thaliana. AB - Nitrosylation is a reversible post-translational modification of protein cysteines playing a major role in cellular regulation and signaling in many organisms, including plants where it has been implicated in the regulation of immunity and cell death. The extent of nitrosylation of a given cysteine residue is governed by the equilibrium between nitrosylation and denitrosylation reactions. The mechanisms of these reactions remain poorly studied in plants. In this study, we have employed glycolytic GAPDH from Arabidopsis thaliana as a tool to investigate the molecular mechanisms of nitrosylation and denitrosylation using a combination of approaches, including activity assays, the biotin switch technique, site-directed mutagenesis, and mass spectrometry. Arabidopsis GAPDH activity was reversibly inhibited by nitrosylation of catalytic Cys-149 mediated either chemically with a strong NO donor or by trans-nitrosylation with GSNO. GSNO was found to trigger both GAPDH nitrosylation and glutathionylation, although nitrosylation was widely prominent. Arabidopsis GAPDH was found to be denitrosylated by GSH but not by plant cytoplasmic thioredoxins. GSH fully converted nitrosylated GAPDH to the reduced, active enzyme, without forming any glutathionylated GAPDH. Thus, we found that nitrosylation of GAPDH is not a step toward formation of the more stable glutathionylated enzyme. GSH-dependent denitrosylation of GAPC1 was found to be linked to the [GSH]/[GSNO] ratio and to be independent of the [GSH]/[GSSG] ratio. The possible importance of these biochemical properties for the regulation of Arabidopsis GAPDH functions in vivo is discussed. PMID- 23749991 TI - Nerve growth factor receptor TrkA, a new receptor in insulin signaling pathway in PC12 cells. AB - TrkA is a cell surface transmembrane receptor tyrosine kinase for nerve growth factor (NGF). TrkA has an NPXY motif and kinase regulatory loop similar to insulin receptor (INSR) suggesting that NGF->TrkA signaling might overlap with insulin->INSR signaling. During insulin or NGF stimulation TrkA, insulin receptor substrate-1 (IRS-1), INSR (and presumably other proteins) forms a complex in PC12 cells. In PC12 cells, tyrosine phosphorylation of INSR and IRS-1 is dependent upon the functional TrkA kinase domain. Moreover, expression of TrkA kinase inactive mutant blocked the activation of Akt and Erk5 in response to insulin or NGF. Based on these data, we propose that TrkA participates in insulin signaling pathway in PC12 cells. PMID- 23749992 TI - A proximal promoter element required for positive transcriptional control by guanosine tetraphosphate and DksA protein during the stringent response. AB - The alarmone guanosine tetraphosphate (ppGpp) acts as both a positive and a negative regulator of gene expression in the presence of DksA, but the underlying mechanisms of this differential control are unclear. Here, using uspA hybrid promoters, we show that an AT-rich discriminator region is crucial for positive control by ppGpp/DksA. The AT-rich discriminator makes the RNA polymerase promoter complex extremely stable and therefore easily saturated with RNA polymerase. A more efficient transcription is achieved when the RNA polymerase promoter complex is destabilized with ppGpp/DksA. We found that exchanging the AT rich discriminator of uspA with the GC-rich rrnB-P1 discriminator made the uspA promoter negatively regulated by ppGpp/DksA both in vivo and in vitro. In addition, the GC-rich discriminator destabilized the RNA polymerase-promoter complex, and the effect of ppGpp/DksA on the kinetic properties of the promoter was reversed. We propose that the transcription initiation rate from promoters with GC-rich discriminators, in contrast to the uspA-promoter, is not limited by the stability of the open complex. The findings are discussed in view of models for both direct and indirect effects of ppGpp/DksA on transcriptional trade-offs. PMID- 23749993 TI - Crystal structures of copper-depleted and copper-bound fungal pro-tyrosinase: insights into endogenous cysteine-dependent copper incorporation. AB - Tyrosinase, a dinuclear copper monooxygenase/oxidase, plays a crucial role in the melanin pigment biosynthesis. The structure and functions of tyrosinase have so far been studied extensively, but the post-translational maturation process from the pro-form to the active form has been less explored. In this study, we provide the crystal structures of Aspergillus oryzae full-length pro-tyrosinase in the holo- and the apo-forms at 1.39 and 2.05 A resolution, respectively, revealing that Phe(513) on the C-terminal domain is accommodated in the substrate-binding site as a substrate analog to protect the dicopper active site from substrate access (proteolytic cleavage of the C-terminal domain or deformation of the C terminal domain by acid treatment transforms the pro-tyrosinase to the active enzyme (Fujieda, N., Murata, M., Yabuta, S., Ikeda, T., Shimokawa, C., Nakamura, Y., Hata, Y., and Itoh, S. (2012) ChemBioChem. 13, 193-201 and Fujieda, N., Murata, M., Yabuta, S., Ikeda, T., Shimokawa, C., Nakamura, Y., Hata, Yl, and Itoh, S. (2013) J. Biol. Inorg. Chem. 18, 19-26). Detailed crystallographic analysis and structure-based mutational studies have shown that the copper incorporation into the active site is governed by three cysteines as follows: Cys(92), which is covalently bound to His(94) via an unusual thioether linkage in the holo-form, and Cys(522) and Cys(525) of the CXXC motif located on the C terminal domain. Molecular mechanisms of the maturation processes of fungal tyrosinase involving the accommodation of the dinuclear copper unit, the post translational His-Cys thioether cross-linkage formation, and the proteolytic C terminal cleavage to produce the active tyrosinase have been discussed on the basis of the detailed structural information. PMID- 23749994 TI - Antimalarial activity of cupredoxins: the interaction of Plasmodium merozoite surface protein 119 (MSP119) and rusticyanin. AB - The discovery of effective new antimalarial agents is urgently needed. One of the most frequently studied molecules anchored to the parasite surface is the merozoite surface protein-1 (MSP1). At red blood cell invasion MSP1 is proteolytically processed, and the 19-kDa C-terminal fragment (MSP119) remains on the surface and is taken into the red blood cell, where it is transferred to the food vacuole and persists until the end of the intracellular cycle. Because a number of specific antibodies inhibit erythrocyte invasion and parasite growth, MSP119 is therefore a promising target against malaria. Given the structural homology of cupredoxins with the Fab domain of monoclonal antibodies, an approach combining NMR and isothermal titration calorimetry (ITC) measurements with docking calculations based on BiGGER is employed on MSP119-cupredoxin complexes. Among the cupredoxins tested, rusticyanin forms a well defined complex with MSP119 at a site that overlaps with the surface recognized by the inhibitory antibodies. The addition of holo-rusticyanin to infected cells results in parasitemia inhibition, but negligible effects on parasite growth can be observed for apo-rusticyanin and other proteins of the cupredoxin family. These findings point to rusticyanin as an excellent therapeutic tool for malaria treatment and provide valuable information for drug design. PMID- 23749995 TI - Nucleotide excision repair in human cells: fate of the excised oligonucleotide carrying DNA damage in vivo. AB - Nucleotide excision repair is the sole mechanism for removing the major UV photoproducts from genomic DNA in human cells. In vitro with human cell-free extract or purified excision repair factors, the damage is removed from naked DNA or nucleosomes in the form of 24- to 32-nucleotide-long oligomers (nominal 30 mer) by dual incisions. Whether the DNA damage is removed from chromatin in vivo in a similar manner and what the fate of the excised oligomer was has not been known previously. Here, we demonstrate that dual incisions occur in vivo identical to the in vitro reaction. Further, we show that transcription-coupled repair, which operates in the absence of the XPC protein, also generates the nominal 30-mer in UV-irradiated XP-C mutant cells. Finally, we report that the excised 30-mer is released from the chromatin in complex with the repair factors TFIIH and XPG. Taken together, our results show the congruence of in vivo and in vitro data on nucleotide excision repair in humans. PMID- 23749996 TI - 99mTc-macroaggregated albumin poorly predicts the intrahepatic distribution of 90Y resin microspheres in hepatic radioembolization. AB - In hepatic (90)Y radioembolization, pretreatment (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) nuclear imaging is used for lung shunt analysis, evaluation of extrahepatic deposition, and sometimes for treatment planning, using a partition model. A high level of agreement between pretreatment (99m)Tc-MAA distribution and final (90)Y-microsphere distribution is assumed. The aim of this study was to investigate the value of pretreatment (99m)Tc-MAA SPECT to predict intrahepatic posttreatment (90)Y-microsphere distribution. METHODS: Volumes of interest (VOIs) were delineated on pretreatment contrast-enhanced CT or MR images according to Couinaud liver segmentation. All VOIs were registered to the (99m)Tc-MAA SPECT and (90)Y SPECT images. The (99m)Tc-MAA SPECT and (90)Y SPECT activity counts were normalized to the total administered activity of (90)Y. For each VOI, this practice resulted in a predictive amount of (90)Y (MBq/cm(3)) based on (99m)Tc MAA SPECT in comparison with an actual amount of (90)Y based on (90)Y SPECT. Bland-Altman analysis was used to investigate the agreement of the activity distribution between (99m)Tc-MAA SPECT and (90)Y SPECT. RESULTS: A total of 39 procedures (225 VOIs) in 31 patients were included for analysis. The overall mean difference between pretreatment and posttreatment distribution of activity concentration for all segments was -0.022 MBq/cm(3) with 95% limits of agreement of -0.581 to 0.537 MBq/cm(3) (-28.9 to 26.7 Gy absorbed dose). A difference of >10%, >20%, and >30% of the mean activity per milliliter was found in, respectively, 153 (68%), 97 (43%), and 72 (32%) of the 225 segments. In every (99m)Tc-MAA procedure, at least 1 segment showed an under- or overestimation of >10%. The position of the catheter tip during administrations, as well as the tumor load of the liver segments, significantly influenced the disagreement. CONCLUSION: In current clinical practice, (99m)Tc-MAA distribution does not accurately predict final (90)Y activity distribution. Awareness of the importance of catheter positioning and adherence to specific recommendations may lead to optimization of individualized treatment planning based on pretreatment imaging. PMID- 23749997 TI - Efficacy considerations for U.S. Food and Drug Administration approval of diagnostic radiopharmaceuticals. AB - The safety and efficacy expectations for U.S. Food and Drug Administration (FDA) approval of diagnostic radiopharmaceuticals (DRs) are described in laws that broadly apply to all prescription drugs and biologic products. These laws also outline efficacy expectations that are unique for DRs. The FDA regulations and guidance documents elaborate on DR efficacy expectations for clinical uses of the drugs, such as the delineation of anatomy, the characterization of a physiologic process, or the diagnosis of disease. As described in the FDA regulations, the approval of a DR necessitates that the imaging drug has the ability to provide clinically useful information. Here we cite approved DRs to illustrate how the imaging performance of the drugs was characterized in clinical studies and the clinical usefulness of the imaging information described in drug labels. PMID- 23749998 TI - Mediator complex recruits epigenetic regulators via its two cyclin-dependent kinase subunits to repress transcription of immune response genes. AB - The Mediator complex (Mediator) plays pivotal roles in activating transcription by RNA polymerase II, but relatively little is known about its roles in repression. Here, we identified the histone arginine methyltransferase PRMT5 and WD repeat protein 77/methylosome protein 50 (WDR77/MEP50) as Mediator cyclin dependent kinase (CDK)-interacting proteins and studied the roles of PRMT5 in the transcriptional regulation of CCAAT enhancer-binding protein (C/EBP) beta target genes. First, we purified CDK8- and CDK19-containing complexes from HeLa nuclear extracts and subjected these purified complexes to mass spectrometric analyses. These experiments revealed that two Mediator CDKs, CDK8 and CDK19, individually interact with PRMT5 and WDR77, and their interactions with PRMT5 cause transcriptional repression of C/EBPbeta target genes by regulating symmetric dimethylation of histone H4 arginine 3 (H4R3me2s) in the promoter regions of those genes. Furthermore, the recruitment of the DNA methyltransferase DNMT3A correlated with H4R3 dimethylation potentially leading to DNA methylation at the promoter proximal region and tight inhibition of preinitiation complex formation. In vertebrates, C/EBPbeta regulates many genes involved in immune responses and cell differentiation. These findings shed light on the molecular mechanisms of the repressive roles of Mediator CDKs in transcription of C/EBPbeta target genes and might provide clues that enable future studies of the functional associations between Mediators and epigenetic regulation. PMID- 23749999 TI - Cleavage of the JunB transcription factor by caspases generates a carboxyl terminal fragment that inhibits activator protein-1 transcriptional activity. AB - The activator protein-1 (AP-1) family transcription factor, JunB, is an important regulator of proliferation, apoptosis, differentiation, and the immune response. In this report, we show that JunB is cleaved in a caspase-dependent manner in apoptotic anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma cell lines and that ectopically expressed JunB is cleaved in murine RAW 264.7 macrophage cells treated with the NALP1b inflammasome activator, anthrax lethal toxin. In both cases, we identify aspartic acid 137 as the caspase cleavage site and demonstrate that JunB can be directly cleaved in vitro by multiple caspases at this site. Cleavage of JunB at aspartic acid 137 separates the N-terminal transactivation domain from the C-terminal DNA binding and dimerization domains, and we show that the C-terminal cleavage fragment retains both DNA binding activity and the ability to interact with AP-1 family transcription factors. Furthermore, this fragment interferes with the binding of full-length JunB to AP 1 sites and inhibits AP-1-dependent transcription. In summary, we have identified and characterized a novel mechanism of JunB post-translational modification and demonstrate that the C-terminal JunB caspase cleavage product functions as a potent inhibitor of AP-1-dependent transcription. PMID- 23750000 TI - A structural basis for the regulation of the LIM-homeodomain protein islet 1 (Isl1) by intra- and intermolecular interactions. AB - Islet 1 (Isl1) is a transcription factor of the LIM-homeodomain (LIM-HD) protein family and is essential for many developmental processes. LIM-HD proteins all contain two protein-interacting LIM domains, a DNA-binding homeodomain (HD), and a C-terminal region. In Isl1, the C-terminal region also contains the LIM homeobox 3 (Lhx3)-binding domain (LBD), which interacts with the LIM domains of Lhx3. The LIM domains of Isl1 have been implicated in inhibition of DNA binding potentially through an intramolecular interaction with or close to the HD. Here we investigate the LBD as a candidate intramolecular interaction domain. Competitive yeast-two hybrid experiments indicate that the LIM domains and LBD from Isl1 can interact with apparently low affinity, consistent with no detection of an intermolecular interaction in the same system. Nuclear magnetic resonance studies show that the interaction is specific, whereas substitution of the LBD with peptides of the same amino acid composition but different sequence is not specific. We solved the crystal structure of a similar but higher affinity complex between the LIM domains of Isl1 and the LIM interaction domain from the LIM-HD cofactor protein LIM domain-binding protein 1 (Ldb1) and used these coordinates to generate a homology model of the intramolecular interaction that indicates poorer complementarity for the weak intramolecular interaction. The intramolecular interaction in Isl1 may provide protection against aggregation, minimize unproductive DNA binding, and facilitate cofactor exchange within the cell. PMID- 23750001 TI - Sirtuin-7 inhibits the activity of hypoxia-inducible factors. AB - Hypoxia-inducible factor (HIF) 1 and HIF-2 are heterodimeric proteins composed of an oxygen-regulated HIF-1alpha or HIF-2alpha subunit, respectively, and a constitutively expressed HIF-1beta subunit, which mediate adaptive transcriptional responses to hypoxia. Here, we report that Sirt7 (sirtuin-7) negatively regulates HIF-1alpha and HIF-2alpha protein levels by a mechanism that is independent of prolyl hydroxylation and that does not involve proteasomal or lysosomal degradation. The effect of Sirt7 was maintained in the presence of the sirtuin inhibitor nicotinamide and upon deletion or mutation of its deacetylase domain, indicating a non-catalytic function. Knockdown of Sirt7 led to an increase in HIF-1alpha and HIF-2alpha protein levels and an increase in HIF-1 and HIF-2 transcriptional activity. Thus, we identify a novel molecular function of Sirt7 as a negative regulator of HIF signaling. PMID- 23750002 TI - Nonhomologous end-joining promotes resistance to DNA damage in the absence of an ADP-ribosyltransferase that signals DNA single strand breaks. AB - ADP-ribosylation of proteins at DNA lesions by ADP-ribosyltransferases (ARTs) is an early response to DNA damage. The best defined role of ADP-ribosylation in the DNA damage response is in repair of single strand breaks (SSBs). Recently, we initiated a study of how ADP-ribosylation regulates DNA repair in Dictyostelium and found that two ARTs (Adprt1b and Adprt2) are required for tolerance of cells to SSBs, and a third ART (Adprt1a) promotes nonhomologous end-joining (NHEJ). Here we report that disruption of adprt2 results in accumulation of DNA damage throughout the cell cycle following exposure to agents that induce base damage and DNA SSBs. Although ADP-ribosylation is evident in adprt2(-) cells exposed to methylmethanesulfonate (MMS), disruption of adprt1a and adprt2 in combination abolishes this response and further sensitises cells to this agent, indicating that in the absence of Adprt2, Adprt1a signals MMS-induced DNA lesions to promote resistance of cells to DNA damage. As a consequence of defective signalling of SSBs by Adprt2, Adprt1a is required to assemble NHEJ factors in chromatin, and disruption of the NHEJ pathway in combination with adprt2 increases sensitivity of cells to MMS. Taken together, these data indicate overlapping functions of different ARTs in signalling DNA damage, and illustrate a critical requirement for NHEJ in maintaining cell viability in the absence of an effective SSB response. PMID- 23750003 TI - P2 receptor networks regulate signaling duration over a wide dynamic range of ATP concentrations. AB - The primordial intercellular signaling molecule ATP acts through two families of cell-surface P2 receptors - the P2Y family of G-protein-coupled receptors and the P2X family of ligand-gated cation channels. Multiple P2 receptors are expressed in a variety of cell types. However, the significance of these networks of receptors in any biological system remains unknown. Using osteoblasts as a model system, we found that a low concentration of ATP (10 uM, ATPlow) induced transient elevation of cytosolic Ca(2+), whereas a high concentration of ATP (1 mM, ATPhigh) elicited more sustained elevation. Moreover, graded increases in the Ca(2+) signal were achieved over a remarkable million-fold range of ATP concentrations (1 nM to 1 mM). Next, we demonstrated that ATPlow caused transient nuclear localization of the Ca(2+)-regulated transcription factor NFATc1; whereas, ATPhigh elicited more sustained localization. When stimulated with ATPhigh, osteoblasts from P2X7 loss-of-function mice showed only transient Ca(2+) NFATc1 signaling; in contrast, sustained signaling was observed in wild-type cells. Additional experiments revealed a role for P2Y receptors in mediating transient signaling induced by low ATP concentrations. Thus, distinct P2 receptors with varying affinities for ATP account for this wide range of sensitivity to extracellular nucleotides. Finally, ATPhigh, but not ATPlow, was shown to elicit robust expression of the NFAT target gene Ptgs2 (encoding COX-2), consistent with a crucial role for the duration of Ca(2+)-NFAT signaling in regulating target gene expression. Taken together, ensembles of P2 receptors provide a mechanism by which cells sense ATP over a wide concentration range and transduce this input into distinct cellular signals. PMID- 23750004 TI - Septin rings act as a template for myosin higher-order structures and inhibit redundant polarity establishment. AB - The mechanisms of the coordinated assembly and disassembly of the septin/myosin ring is central for the understanding of polar growth and cytokinesis in yeast and other organisms. The septin- and myosin-binding protein Bni5p provides a dual function during the formation and disassembly of septin/myosin rings. Early in the cell cycle, Bni5p captures Myo1p at the incipient bud site and actively transforms it into higher-order structures. Additionally, Bni5p stabilizes the septin/myosin ring and is released from the septins shortly before the onset of cytokinesis. If this Bni5p dissociation from the septins is artificially prevented, ring disassembly is impaired and the untimely appearance of septin/myosin ring is induced. The prematurely formed septin/myosin rings delay the establishment of a new polarity axis and the progression into a new cell cycle. This observation suggests a negative feedback between septin/myosin ring formation and polarity establishment that might help to guarantee the singular assembly of this structure and the synchronization of its formation with the cell cycle. PMID- 23750006 TI - Oligomerization is required for normal endocytosis/transcytosis of a GPI-anchored protein in polarized hepatic cells. AB - Targeting of glycosyl-phosphatidylinositol (GPI)-anchored proteins (GPI-APs) in polarized epithelial cells depends on their association with detergent-resistant membrane microdomains called rafts. In MDCK cells, GPI-APs associate with rafts in the trans-Golgi network and are directly delivered to the apical membrane. It has been shown that oligomerization is required for their stabilization in rafts and their apical targeting. In hepatocytes, GPI-APs are first delivered to the basolateral membrane and secondarily reach the apical membrane by transcytosis. We investigated whether oligomerization is required for raft association and apical sorting of GPI-APs in polarized HepG2 cells, and at which step of the pathway oligomerization occurs. Model proteins were wild-type GFP-GPI and a double cysteine GFP-GPI mutant, in which GFP dimerization was impaired. Unlike wild-type GFP-GPI, which was efficiently endocytosed and transcytosed to the apical surface, the double cysteine mutant was basolaterally internalized, but massively accumulated in early endosomes, and reached the bile canaliculi with delayed kinetics. The double cysteine mutant was less resistant to Triton X-100 extraction, and formed fewer high molecular weight complexes. We conclude from these results that, in hepatocytes, oligomerization plays a key role in targeting GPI-APs to the apical membrane, by increasing their affinity for rafts and allowing their transcytosis. PMID- 23750005 TI - The reprogrammed pancreatic progenitor-like intermediate state of hepatic cells is more susceptible to pancreatic beta cell differentiation. AB - Induced pluripotent stem cells (iPSCs) hold great promise for cell therapy. However, their low efficiency of lineage-specific differentiation and tumorigenesis severely hinder clinical translation. We hypothesized that reprogramming of somatic cells into lineage-specific progenitor cells might allow for large-scale expansion, avoiding the tumorigenesis inherent with iPSCs and simultaneously facilitating lineage-specific differentiation. Here we aimed at reprogramming rat hepatic WB cells, using four Yamanaka factors, into pancreatic progenitor cells (PPCs) or intermediate (IM) cells that have characteristics of PPCs. IM clones were selected based on their specific morphology and alkaline phosphatase activity and stably passaged under defined culture conditions. IM cells did not have iPSC properties, could be stably expanded in large quantity, and expressed all 14 genes that are used to define the PPC developmental stage. Directed differentiation of IM and WB cells by Pdx1-Ngn3-MafA (PNM) into pancreatic beta-like cells revealed that the IM cells are more susceptible to directed beta cell differentiation because of their open chromatin configuration, as demonstrated by expression of key pancreatic beta cell genes, secretion of insulin in response to glucose stimulation, and easy access to exogenous PNM proteins at the rat insulin 1 and Pdx1 promoters. This notion that IM cells are superior to their parental cells is further supported by the epigenetic demonstration of accessibility of Pdx1 and insulin 1 promoters. In conclusion, we have developed a strategy to derive and expand PPC cells from hepatic WB cells using conventional cell reprogramming. This proof-of-principal study may offer a novel, safe and effective way to generate autologous pancreatic beta cells for cell therapy of diabetes. PMID- 23750007 TI - Reciprocal cross-regulation between RNF41 and USP8 controls cytokine receptor sorting and processing. AB - The mechanisms controlling the steady-state cell surface levels of cytokine receptors, and consequently the cellular response to cytokines, remain poorly understood. The number of surface-exposed receptors is a dynamic balance of de novo synthesis, transport to the plasma membrane, internalization, recycling, degradation and ectodomain shedding. We previously reported that the E3 ubiquitin ligase RING finger protein 41 (RNF41) inhibits basal lysosomal degradation and enhances ectodomain shedding of JAK2-associated cytokine receptors. Ubiquitin specific protease 8 (USP8), an RNF41-interacting deubiquitylating enzyme (DUB) stabilizes RNF41 and is involved in trafficking of various transmembrane proteins. The present study identifies USP8 as a substrate of RNF41 and reveals that loss of USP8 explains the aforementioned RNF41 effects. RNF41 redistributes and ubiquitylates USP8, and reduces USP8 levels. In addition, USP8 knockdown functionally matches the effects of RNF41 ectopic expression on the model leptin and leukemia inhibitory factor (LIF) receptors. Moreover, RNF41 indirectly destabilizes the ESCRT-0 complex through suppression of USP8. Collectively, our findings demonstrate that RNF41 controls JAK2-associated cytokine receptor trafficking by acting as a key regulator of USP8 and ESCRT-0 stability. Balanced reciprocal cross-regulation of RNF41 and USP8 thus determines whether receptors are sorted for lysosomal degradation or recycling, this way regulating basal cytokine receptor levels. PMID- 23750008 TI - The role of PLK1-phosphorylated SVIL in myosin II activation and cytokinetic furrowing. AB - Polo-like kinase 1 (PLK1) is a widely conserved serine/threonine kinase that regulates progression of multiple stages of mitosis. Although extensive studies about PLK1 functions during cell division have been performed, it is still not known how PLK1 regulates myosin II activation at the equatorial cortex and ingression of the cleavage furrow. In this report, we show that an actin/myosin II-binding protein, supervillin (SVIL), is a substrate of PLK1. PLK1 phosphorylates Ser238 of SVIL, which can promote the localization of SVIL to the central spindle and association with PRC1. Expression of a PLK1 phosphorylation site mutant, S238A-SVIL, inhibited myosin II activation at the equatorial cortex and induced aberrant furrowing. SVIL has both actin- and myosin-II-binding regions in the N-terminus. Expression of DeltaMyo-SVIL (deleted of the myosin-II binding region), but not of DeltaAct-SVIL (deleted of actin-binding region), reduced myosin II activation and caused defects in furrowing. Our study indicates a possible role of phosphorylated SVIL as a molecular link between the central spindle and the contractile ring to coordinate the activation of myosin II for the ingression of the cleavage furrow. PMID- 23750009 TI - Differential and competitive regulation of human melanocortin 1 receptor signaling by beta-arrestin isoforms. AB - The melanocortin 1 receptor (MC1R) is a G-protein-coupled receptor (GPCR) crucial for the regulation of melanocyte proliferation and differentiation. MC1R activation by melanocortin hormones triggers the cAMP pathway and stimulates the extracellular-signal-regulated protein kinases ERK1 and ERK2 to promote synthesis of photoprotective eumelanin pigments, among other effects. Signaling from most GPCRs is regulated by the beta-arrestin (ARRB) family of cytosolic multifunctional adaptor proteins, which mediate signal termination and endocytosis of GPCR-agonist complexes. The ubiquitously expressed non-visual beta arrestin1 (ARRB1) and beta-arrestin2 (ARRB2) are highly similar but not functionally equivalent. Their role in the regulation of MC1R is unknown. Using a combination of co-immunoprecipitation, gel filtration chromatography, confocal microscopy, siRNA-mediated knockdown and functional assays, we demonstrated agonist-independent competitive interactions of ARRB1 and ARRB2 with MC1R, which might also be independent of phosphorylation of Ser/Thr residues in the C terminus of the MC1R. The effects of ARRBs were isoform specific; ARRB2 inhibited MC1R agonist-dependent cAMP production but not ERK activation, stimulated internalization and showed prolonged co-localization with the receptor in endocytic vesicles. By contrast, ARRB1 had no effect on internalization or functional coupling, but competed with ARRB2 for binding MC1R, which might increase signaling by displacement of inhibitory ARRB2. These data suggest a new mechanism of MC1R functional regulation based on the relative expression of ARRB isoforms, with possible activatory ARRB1-dependent effects arising from partial relief of inhibitory ARRB2-MC1R interactions. Thus, competitive displacement of inhibitory ARRBs by functionally neutral ARRB isoforms might exert a paradigm shifting signal-promoting effect to fine-tune signaling downstream of certain GPCRs. PMID- 23750010 TI - Drebrin preserves endothelial integrity by stabilizing nectin at adherens junctions. AB - Regulation of cell-cell contacts is essential for integrity of the vascular endothelium. Here, a critical role of the F-actin-binding protein drebrin in maintaining endothelial integrity is revealed under conditions mimicking vascular flow. Drebrin knockdown leads to weakening of cell-cell contacts, characterized by loss of nectin from adherens junctions and its subsequent lysosomal degradation. Immunoprecipitation, FRAP and mitochondrial re-targeting experiments show that nectin stabilization occurs through a chain of interactions: drebrin binding to F-actin, interaction of drebrin and afadin through their polyproline and PR1-2 regions, and recruitment of nectin through the PDZ region of afadin. Key elements are modules in drebrin that confer binding to afadin and F-actin. Evidence for this was obtained using constructs containing the PDZ region of afadin coupled to the F-actin-binding region of drebrin or to lifeact, which restore junctional nectin under knockdown of drebrin or of both drebrin and afadin. Drebrin, containing binding sites for both afadin and F-actin, is thus uniquely equipped to stabilize nectin at endothelial junctions and to preserve endothelial integrity under vascular flow. PMID- 23750011 TI - Plectin-containing, centrally localized focal adhesions exert traction forces in primary lung epithelial cells. AB - Receptor clustering upon cell attachment to the substrate induces assembly of cytoplasmic protein complexes termed focal adhesions (FAs), which connect, albeit indirectly, the extracellular matrix to the cytoskeleton. A subset of cultured primary alveolar epithelial cells (AEC) display a unique pattern of vinculin/paxillin/talin-rich FAs in two concentric circles when cultured on glass and micropatterned substrates: one ring of FAs located at the cell periphery (pFAs), and another FA ring located centrally in the cell (cFAs). Unusually, cFAs associate with an aster-like actin array as well as keratin bundles. Moreover, cFAs show rapid paxillin turnover rates following fluorescence recovery after photobleaching and exert traction forces similar to those generated by FAs at the cell periphery. The plakin protein plectin localizes to cFAs and is normally absent from pFAs, whereas tensin, a marker of mature/fibrillar adhesions, is found in both cFAs and pFAs. In primary AEC in which plectin expression is depleted, cFAs are largely absent, with an attendant reorganization of both the keratin and actin cytoskeletons. We suggest that the mechanical environment in the lung gives rise to the assembly of unconventional FAs in AEC. These FAs not only show a distinctive arrangement, but also possess unique compositional and functional properties. PMID- 23750012 TI - Enhancement of c-Myc degradation by BLM helicase leads to delayed tumor initiation. AB - The spectrum of tumors that arise owing to the overexpression of c-Myc and loss of BLM is very similar. Hence, it was hypothesized that the presence of BLM negatively regulates c-Myc functions. By using multiple isogenic cell lines, we observed that the decrease of endogenous c-Myc levels that occurs in the presence of BLM is reversed when the cells are treated with proteasome inhibitors, indicating that BLM enhances c-Myc turnover. Whereas the N-terminal region of BLM interacts with c-Myc, the rest of the helicase interacts with the c-Myc E3 ligase Fbw7. The two BLM domains act as 'clamp and/or adaptor', enhancing the binding of c-Myc to Fbw7. BLM promotes Fbw7-dependent K48-linked c-Myc ubiquitylation and its subsequent degradation in a helicase-independent manner. A subset of BLM regulated genes that are also targets of c-Myc were determined and validated at both RNA and protein levels. To obtain an in vivo validation of the effect of BLM on c-Myc-mediated tumor initiation, isogenic cells from colon cancer cells that either do or do not express BLM had been manipulated to block c-Myc expression in a controlled manner. By using these cell lines, the metastatic potential and rate of initiation of tumors in nude mice were determined. The presence of BLM decreases c-Myc-mediated invasiveness and delays tumor initiation in a mouse xenograft model. Consequently, in tumors that express BLM but not c-Myc, we observed a decreased ratio of proliferation to apoptosis together with a suppressed expression of the angiogenesis marker CD31. Hence, partly owing to its regulation of c-Myc stability, BLM acts as a 'caretaker tumor suppressor'. PMID- 23750013 TI - The Tudor protein survival motor neuron (SMN) is a chromatin-binding protein that interacts with methylated lysine 79 of histone H3. AB - Spinal muscular atrophy (SMA) is a muscular disease characterized by the death of motoneurons, and is a major genetic cause of infant mortality. Mutations in the SMN1 gene, which encodes the protein survival motor neuron (SMN), are responsible for the disease. SMN belongs to the Tudor domain protein family, whose members are known to interact with methylated arginine (R) or lysine (K) residues. SMN has well-defined roles in the metabolism of small non-coding ribonucleoproteins (snRNPs) and spliceosome activity. We previously showed that SMN relocated to damaged interphase centromeres, together with the Cajal-body-associated proteins coilin and fibrillarin, during the so-called interphase centromere damage response (iCDR). Here we reveal that SMN is a chromatin-binding protein that specifically interacts with methylated histone H3K79, a gene expression- and splicing-associated histone modification. SMN relocation to damaged centromeres requires its functional Tudor domain and activity of the H3K79 methyltransferase DOT1L. In vitro pulldown assays showed that SMN interacts with H3K79me1,2 at its functional Tudor domain. Chromatin immunoprecipitation confirmed that SMN binds to H3K79me1,2-containing chromatin in iCDR-induced cells. These data reveal a novel SMN property in the detection of specific chromatin modifications, and shed new light on the involvement of a putative epigenetic dimension to the occurrence of SMA. PMID- 23750014 TI - FXR activation normalizes insulin sensitivity in visceral preadipocytes of a rabbit model of MetS. AB - Insulin resistance is the putative key underlying mechanism linking adipose tissue (AT) dysfunction with liver inflammation and steatosis in metabolic syndrome (MetS). We have recently demonstrated that the selective farnesoid X receptor (FXR) agonist obeticholic acid (OCA) ameliorates insulin resistance and the metabolic profile with a marked reduction in the amount of visceral AT (VAT) in a high-fat diet (HFD)-induced rabbit model of MetS. These effects were mediated by the activation of FXR, since treatment with the selective TGR5 agonist INT-777 was not able to ameliorate the metabolic parameters evaluated. Herein, we report the effects of in vivo OCA dosing on the liver, the VAT, and the adipogenic capacity of VAT preadipocytes (rPADs) isolated from rabbits on a HFD compared with those on a control diet. VAT and liver were studied by immunohistochemistry, Western blot analysis, and RT-PCR. rPADs were exposed to a differentiating mixture to evaluate adipogenesis. Adipocyte size, hypoxia, and the expression of perilipin and cytosolic insulin-regulated glucose transporter GLUT4 (SLC2A4) were significantly increased in VAT isolated from the HFD rabbits, and normalized by OCA. The expression of steatosis and inflammation markers was increased in the liver of the HFD rabbits and normalized by OCA. rPADs isolated from the HFD rabbits were less sensitive to insulin, as demonstrated by the decreased insulin-induced glucose uptake, triglyceride synthesis, and adipogenic capacity, as well as by the impaired fusion of lipid droplets. OCA treatment preserved all the aforementioned metabolic functions. In conclusion, OCA dosing in a MetS rabbit model ameliorates liver and VAT functions. This could reflect the ability of OCA to restore insulin sensitivity in AT unable to finalize its storage function, counteracting MetS-induced metabolic alterations and pathological AT deposition. PMID- 23750015 TI - The contents of the search template for category-level search in natural scenes. AB - Visual search involves the matching of visual input to a "search template," an internal representation of task-relevant information. The present study investigated the contents of the search template during visual search for object categories in natural scenes, for which low-level features do not reliably distinguish targets from nontargets. Subjects were cued to detect people or cars in diverse photographs of real-world scenes. On a subset of trials, the cue was followed by task-irrelevant stimuli instead of scenes, directly followed by a dot that subjects were instructed to detect. We hypothesized that stimuli that matched the active search template would capture attention, resulting in faster detection of the dot when presented at the location of a template-matching stimulus. Results revealed that silhouettes of cars and people captured attention irrespective of their orientation (0 degrees , 90 degrees , or 180 degrees ). Interestingly, strong capture was observed for silhouettes of category-diagnostic object parts, such as the wheel of a car. Finally, attentional capture was also observed for silhouettes presented at locations that were irrelevant to the search task. Together, these results indicate that search for familiar object categories in real-world scenes is mediated by spatially global search templates that consist of view-invariant shape representations of category-diagnostic object parts. PMID- 23750016 TI - The psi-marginal adaptive method: How to give nuisance parameters the attention they deserve (no more, no less). AB - Adaptive testing methods serve to maximize the information gained regarding the values of the parameters of a psychometric function (PF). Such methods typically target only one or two ("threshold" and "slope") of the PF's four parameters while assuming fixed values for the "nuisance" parameters ("guess rate" and "lapse rate"). Here I propose the "psi-marginal" adaptive method, which can target nuisance parameters but only when this is the most optimal manner in which to reduce uncertainty in the value of the parameters of primary interest. The method is based on Kontsevich and Tyler's (1999) psi-method. However, in the proposed method a posterior distribution defined across all parameters of unknown value is maintained. Each of the parameters is specified either as a parameter of primary interest whose estimation should be optimized or as a nuisance parameter whose estimation should be subservient to the estimation of the parameters of primary interest. Critically, selection of stimulus intensities is based on the expected information gain in the marginal posterior distribution defined across the parameters of interest only. The appeal of this method is that it will target nuisance parameters adaptively and only when doing so maximizes the expected information gain regarding the values of the parameters of interest. Simulations indicate that treating the lapse rate as a nuisance parameter in the psi-marginal method results in smaller bias and higher precision in threshold and slope estimates compared to the original psi method. The method is highly flexible and various other uses are discussed. PMID- 23750017 TI - Best lighting for naturalness and preference. AB - Spectral optimization for naturalness and preference was carried out empirically in a set of psychophysical experiments in which observers adjusted the spectral composition of the illumination to render commercial food counters containing a variety of fruits and vegetables as well as meat and fish. The scenes were simulated with high chromatic precision on a calibrated computer monitor from data obtained by hyperspectral imaging. The illuminants were daylight-like and their metamers, representing a set of nearly arbitrary spectra. For daylights, the most natural colors were produced with illuminants with an average correlated color temperature (CCT) of 6040 K and the most preferred colors with an average CCT of 4410 K. For metamers, the CCT for the two conditions were a little higher than for daylights, and the corresponding spectra were considerably different from daylight with characteristic peaks at both ends of the visible band and at about 490 nm and 560 nm. When compared directly with daylights, these metamers were preferred for most of the scenes. It was hypothesized that observers' choices may be determined by the chromatic volume and the symmetry of the color distributions: The best illuminants for preference produced larger gamuts, and the best illuminants for naturalness produced gamuts with aspect ratios closer to unity, i.e., more symmetrically distributed. PMID- 23750018 TI - Transfer in motion perceptual learning depends on the difficulty of the training task. AB - One hypothesis in visual perceptual learning is that the amount of transfer depends on the difficulty of the training and transfer tasks (Ahissar & Hochstein, 1997; Liu, 1995, 1999). Jeter, Dosher, Petrov, and Lu (2009), using an orientation discrimination task, challenged this hypothesis by arguing that the amount of transfer depends only on the transfer task but not on the training task. Here we show in a motion direction discrimination task that the amount of transfer indeed depends on the difficulty of the training task. Specifically, participants were first trained with either 4 degrees or 8 degrees direction discrimination along one average direction. Their transfer performance was then tested along an average direction 90 degrees away from the trained direction. A variety of transfer measures consistently demonstrated that transfer performance depended on whether the participants were trained on 4 degrees or 8 degrees directional difference. The results contradicted the prediction that transfer was independent of the training task difficulty. PMID- 23750019 TI - Treatment of adolescent obesity comparing self-guided and group lifestyle modification programs: a potential model for primary care. AB - Lifestyle modification programs (LMP) for weight loss in adolescents with obesity are effective but not available. Primary care may be a setting for reaching more adolescents. Two models of LMP for use in primary care were examined. Adolescents and caregivers enrolled in a 1-year randomized trial comparing Group LMP with Self-Guided LMP. All participants (N = 169) received the same treatment recommendations and met with a health coach six times in clinic. Group LMP participants had an additional 17 group sessions; those in Self-Guided LMP followed the remainder of the program at home with parental support. The primary outcome was percentage change in initial body mass index. The mean (SE) 1.31% (0.95%) reduction in Group LMP did not differ significantly from the 1.17% (0.99%) decrease in the Self-Guided LMP (p = 0.92). Both treatments were significantly effective in reducing body mass index. Given its brevity, the Self Guided LMP offers an innovative approach for primary care. PMID- 23750020 TI - HAMI 3379, a CysLT2 receptor antagonist, attenuates ischemia-like neuronal injury by inhibiting microglial activation. AB - The cysteinyl leukotrienes (CysLTs) are inflammatory mediators closely associated with neuronal injury after brain ischemia through the activation of their receptors, CysLT1R and CysLT2R. Here we investigated the involvement of both receptors in oxygen-glucose deprivation/recovery (OGD/R)-induced ischemic neuronal injury and the effect of the novel CysLT2R antagonist HAMI 3379 [3 ({[(1S,3S)-3- carboxycyclohexyl]amino}carbonyl)-4-(3-{4-[4-(cyclo hexyloxy)butoxy]phenyl}propoxy)benzoic acid] in comparison with the CysLT1R antagonist montelukast. In primary neurons, neither the nonselective agonist leukotriene D4 (LTD4) nor the CysLT2R agonist N-methyl-leukotriene C4 (NMLTC4) induced neuronal injury, and HAMI 3379 did not affect OGD/R-induced neuronal injury. However, in addition to OGD/R, LTD4 and NMLTC4 induced cell injury and neuronal loss in mixed cultures of cortical cells, and neuronal loss and necrosis in neuron-microglial cocultures. Moreover, they induced phagocytosis and cytokine release (interleukin-1beta and tumor necrosis factor-alpha) from primary microglia, and conditioned medium from the treated microglia induced neuronal necrosis. HAMI 3379 inhibited all of these responses, and its effects were the same as those of CysLT2R interference by CysLT2R short hairpin RNA, indicating CysLT2R dependence. In comparison, montelukast moderately inhibited OGD/R-induced primary neuronal injury and most OGD/R- and LTD4-induced (but not NMLTC4-induced) responses in mixed cultures, cocultures, and microglia. The effects of montelukast were both dependent and independent of CysLT1Rs because interference by CysLT1R small interfering RNA had limited effects on neuronal injury in neuron microglial cocultures and on cytokine release from microglia. Our findings indicated that HAMI 3379 effectively blocked CysLT2R-mediated microglial activation, thereby indirectly attenuating ischemic neuronal injury. Therefore, CysLT2R antagonists may represent a new type of therapeutic agent in the treatment of ischemic stroke. PMID- 23750022 TI - Results of radical radiotherapy for squamous cell carcinoma of the eyelid. AB - PURPOSE: To analyze the results of radical radiotherapy by electron beams for squamous cell carcinoma (SCC) of the eyelid and to find the possible prognostic factors. MATERIALS AND METHODS: Records of 38 patients with histologically confirmed SCC of the eyelid who underwent electron beam radiation therapy between 1964 and 2010 in our institution were retrospectively reviewed. Median tumor size was 15 mm (range, 3-40 mm). T stage was T1 in three, T2a in six, T2b in 14, and T3a in 15 patients. Four patients had nodal metastasis. Of the 38 patients, 14 had relapsed disease after prior treatment. Median radiation dose was 60.0 Gy (range, 45.0-70.4 Gy). Median follow-up was 72.5 months (range, 2.0-369 months). RESULTS: 5-year local relapse-free, nodal relapse-free, distant metastasis-free and relapse-free rates for all patients were 71.8%, 77.5%, 90.6% and 58.0%, respectively. In seven patients, lymph node metastases occurred in 11 faciocervical regions. The 5-year overall survival was 79.5%. T stage and radiation dose expressed in EQD2 Gy tended to have impacts on local control. Relapsed patients showed unfavorable local relapse-free rate, however this was without statistical significance. Of the 14 patients who died, 12 succumbed to concurrent diseases. Grade 3 or greater severe late morbidities (CTCAE ver4.0) were observed in nine patients. Due to the morbidities, two patients lost their vision. CONCLUSION: Radical radiotherapy for SCC of the eyelid yielded good results and could be a treatment option. Whether radiation-dose escalation could improve local control in advanced T stages and relapsed patients needs further study. PMID- 23750021 TI - Monitoring tumor response to linifanib therapy with SPECT/CT using the integrin alphavbeta3-targeted radiotracer 99mTc-3P-RGD2. AB - The objective of this study was to determine the utility of (99m)Tc-3P-Arg-Gly Asp (RGD2) single photon emission computed tomography (SPECT)/computed tomography (CT) for noninvasive monitoring of integrin alphavbeta3-expression response to antiangiogenic treatment with linifanib. Linifanib or vehicle therapy was carried out in female athymic nu/nu mice bearing U87MG glioma (high alphavbeta3 expression) or PC-3 prostate (low alphavbeta3 expression) tumors at 12.5 mg/kg twice daily. The average tumor volume was 180 +/- 90 mm(3) the day prior to baseline SPECT/CT. Longitudinal (99m)Tc-3P-RGD2 SPECT/CT imaging was performed at baseline (-1 day) and days 1, 4, 11, and 18. Tumors were harvested at all imaging time points for histopathological analysis with H&E and immunohistochemistry. A significant difference in tumor volumes between vehicle- and linifanib-treated groups was observed after 4 days of linifanib therapy in the U87MG model. The percent injected dose (%ID) tumor uptake of (99m)Tc-3P-RGD2 peaked in the vehicle treated group at day 11, while the %ID/cm(3) tumor uptake decreased slowly over the whole study period. During the first 2 days of linifanib treatment, a rapid decrease in both %ID/cm(3) tumor uptake and tumor/muscle ratios of (99m)Tc-3P RGD2 was observed, followed by a slow decrease until day 18. No decrease in tumor uptake of (99m)Tc-3P-RGD2 or tumor volume was observed for either treatment group in the PC-3 model. Changes in tumor vasculature were confirmed by histopathological H&E analysis and immunohistochemistry. Longitudinal imaging using (99m)Tc-3P-RGD2 SPECT/CT may be a useful tool for monitoring the downstream biologic effects of linifanib therapy. PMID- 23750025 TI - Dynamic protein pathway activation mapping of adipose-derived stem cell differentiation implicates novel regulators of adipocyte differentiation. AB - Next to embryonic stem cell research, adult stem cell research is providing a promising alternative for enhanced tissue regeneration and transplantation. The key biochemical networks controlling the differentiation processes regulating stem cell biology remain largely disputed and or undefined, contributing to a lack of knowledge of the principle phosphoregulatory events propagating signal transduction. To effectively monitor these events relative to adipocyte differentiation, this study utilized a high throughput reverse phase protein microarray platform and characterized adult adipose-derived stem cell (ASC) differentiation through the monitoring of ~100 phosphospecific endpoints with 33 distinct time points examined across 14 days. This kinetic-based analysis showed time ordered signal transduction ultimately implicating pathways correlated with adipogenic differentiation. To further validate the causal significance of these network activations, pharmacological targeting was implemented to include the chemical inhibitors MAPK inhibitor PD169316, rapamycin, and HNMPA-(AM)3 yielding partial or complete disruption of adipocytic differentiation, as noted by a decrease or lack of lipid formation within the mature adipocytes. Based on this analysis, v-crk sarcoma virus CT10 oncogene homolog (CRKII) and c-abl oncogene 1, non-receptor tyrosine kinase (c-ABL) were implicated as novel key regulators of adipocyte differentiation, with v-akt murine thymoma viral oncogene (AKT), mammalian target of rapamycin (mTOR), and SMAD family member (SMAD) pathways being implicated as secondary regulators. This dynamic molecular profiling provides a novel insight into the signaling architecture of mesenchymal stem cell differentiation and may be useful in the development of therapeutic modulators for clinical applications; in addition to advancing the collective understanding of key cellular processes, ultimately contributing to more confident stem cell manipulation. PMID- 23750026 TI - Targeted identification of SUMOylation sites in human proteins using affinity enrichment and paralog-specific reporter ions. AB - Protein modification by small ubiquitin-like modifier (SUMO) modulates the activities of numerous proteins involved in different cellular functions such as gene transcription, cell cycle, and DNA repair. Comprehensive identification of SUMOylated sites is a prerequisite to determine how SUMOylation regulates protein function. However, mapping SUMOylated Lys residues by mass spectrometry (MS) is challenging because of the dynamic nature of this modification, the existence of three functionally distinct human SUMO paralogs, and the large SUMO chain remnant that remains attached to tryptic peptides. To overcome these problems, we created HEK293 cell lines that stably express functional SUMO paralogs with an N-terminal His6-tag and an Arg residue near the C terminus that leave a short five amino acid SUMO remnant upon tryptic digestion. We determined the fragmentation patterns of our short SUMO remnant peptides by collisional activation and electron transfer dissociation using synthetic peptide libraries. Activation using higher energy collisional dissociation on the LTQ-Orbitrap Elite identified SUMO paralog-specific fragment ions and neutral losses of the SUMO remnant with high mass accuracy (< 5 ppm). We exploited these features to detect SUMO modified tryptic peptides in complex cell extracts by correlating mass measurements of precursor and fragment ions using a data independent acquisition method. We also generated bioinformatics tools to retrieve MS/MS spectra containing characteristic fragment ions to the identification of SUMOylated peptide by conventional Mascot database searches. In HEK293 cell extracts, this MS approach uncovered low abundance SUMOylated peptides and 37 SUMO3-modified Lys residues in target proteins, most of which were previously unknown. Interestingly, we identified mixed SUMO-ubiquitin chains with ubiquitylated SUMO proteins (K20 and K32) and SUMOylated ubiquitin (K63), suggesting a complex crosstalk between these two modifications. PMID- 23750027 TI - The moral case for the clinical placebo. AB - Placebos are arguably the most commonly prescribed drug, across cultures and throughout history. Nevertheless, today many would consider their use in the clinic unethical, since placebo treatment involves deception and the violation of patients' autonomy. We examine the placebo's definition and its clinical efficacy from a biopsychosocial perspective, and argue that the intentional use of the placebo and placebo effect, in certain circumstances and under several conditions, may be morally acceptable. We highlight the role of a virtue-based ethical orientation and its implications for the beneficent use of the placebo. In addition, the definitions of lying and deception are discussed, clarified and applied to the clinical placebo dilemma. Lastly, we suggest that concerns about patient autonomy, when invoked as a further argument against administering placebos, are extended beyond their reasonable and coherent application. PMID- 23750028 TI - Immunology and bone. AB - It is now well acknowledged that the immune and skeletal systems interact and affect one another during developmental physiology and pathology. With the aid of modern conditional gene targeting and transgenic technologies, this field of interdisciplinary research, known as osteoimmunology, is rapidly advancing. Numerous bone phenotypes have been described in immune-compromised gene-deficient mice and, albeit to a lesser extent, immune deficiencies exist in osteo compromised gene-deficient mice, suggesting that bone cells themselves actually regulate the development of immune cells directly. In this review, I discuss the essential role of key cytokines, signalling transduction pathways and transcription factors during immune and bone development, and how pathology driven dysregulation of these shared mechanisms can lead to clinical manifestations. Diseases that are within the remit of osteoimmunology continue to cause significant morbidity, for example, rheumatoid arthritis, osteoporosis, multiple myeloma and breast/prostate cancer. The complexity and overlapping cellular and molecular interactions between the immune and bone tissues, mean that despite fervent research of these diseases, it remains a major challenge to discover therapeutics that can specifically target one system without detrimentally affecting the other. PMID- 23750029 TI - Initiation of meiotic recombination in chromatin structure. AB - Meiotic homologous recombination is markedly activated during meiotic prophase to play central roles in faithful chromosome segregation and conferring genetic diversity to gametes. It is initiated by programmed DNA double-strand breaks (DSBs) by the conserved protein Spo11, and preferentially occurs at discrete sites called hotspots. Since the functions of Spo11 are influenced by both of local chromatin at hotspots and higher-order chromosome structures, formation of meiotic DSBs is under regulation of chromatin structure. Therefore, investigating features and roles of meiotic chromatin is crucial to elucidate the in vivo mechanism of meiotic recombination initiation. Recent progress in genome-wide chromatin analyses tremendously improved our understanding on this point, but many critical questions are left unaddressed. In this review, we summarize current knowledge in the field, and also discuss the future problems that must be solved to understand the role of chromatin structure in meiotic recombination. PMID- 23750030 TI - Mutation in the a-subunit of F(1)F(O)-ATPase causes an increased motility phenotype through the sodium-driven flagella of Vibrio. AB - Bacterial flagellar motors exploit the electrochemical potential gradient of a coupling ion as energy source and are composed of stator and rotor proteins. Vibrio alginolyticus has a Na(+)-driven motor and its stator is composed of PomA and PomB. Recently, we isolated increased motility strains (sp1-sp4) from the PomA-N194D/PomB-D24N mutant whose motility was quite weak. To detect the responsible mutation, we have used a next-generation sequencer and determined the entire genome sequences of the sp1 and sp2 strains. Candidate mutations were identified in the gene encoding the a-subunit of F1Fo-ATPase (uncB). To confirm this, we constructed a deletion strain, which gave the increased motility phenotype. The amount of membrane-bound ATPase was reduced in the sp2 and DeltauncB mutants. From these results, we conclude that a mutation in the uncB gene causes the increased motility phenotype in V. alginolyticus. They confer faster motility in low concentrations of sodium than in the parental strain and this phenotype is suppressed in the presence of KCN. Those results may suggest that the proton gradient generated by the respiratory chain is increased by the uncB mutation, consequently the sodium motive force is increased and causes the increased motility phenotype. PMID- 23750031 TI - Role of Insulin-like growth factors in initiation of follicle growth in normal and polycystic human ovaries. AB - CONTEXT: Polycystic ovary syndrome (PCOS), the commonest cause of anovulatory infertility, is characterized by disordered follicle development including increased activation and accelerated growth of preantral follicles. Data from experimental animals and preliminary results from studies of human ovarian tissue suggest that IGFs affect preantral follicle development. OBJECTIVE: Our objectives were to investigate the expression of the type-1 IGF receptor (IGFR-1) in the human ovary and to determine whether IGFs are involved in stimulating the transition of follicles from primordial to primary stage in normal and polycystic ovaries. DESIGN: We used archived ovarian tissue for protein expression studies and small cortical biopsies for follicle isolation and for tissue culture. SETTING: This was a laboratory-based study, using clinical tissue samples. PATIENTS: A total of 54 women, 33 with normal ovaries and 21 with polycystic ovaries, were classified by reference to menstrual cycle history and ultrasonography. MAIN OUTCOME MEASURES: We evaluated expression of IGFR-1 mRNA in isolated preantral follicles and of IGFR-1 protein in archived ovarian tissue samples from normal and polycystic ovaries and effects of exogenous IGF-1 on preantral follicle development and survival in cultured fragments of normal and polycystic ovaries. RESULTS: IGFR-1 mRNA and protein was expressed in preantral follicles at all stages of development and enhanced expression was noted in PCOS follicles during early preantral development. IGF-1 stimulated initiation of follicle growth in normal tissue but had little effect on preantral follicle growth in polycystic ovaries in which, characteristically, there was a higher proportion of follicles that had entered the growing phase even before culture. CONCLUSIONS: IGFs are plausible candidates in regulation of initiation of human follicle growth, and accelerated preantral follicle growth in PCOS may be due to increased activity of endogenous IGFs. PMID- 23750032 TI - Severe hyperemesis gravidarum is associated with reduced insulin sensitivity in the offspring in childhood. AB - BACKGROUND: Hyperemesis gravidarum alters maternal (and possibly fetal) nutrition throughout pregnancy, but there are no data on long-term effects on offspring metabolism. Thus, we aimed to assess whether severe hyperemesis gravidarum (SHG) affects glucose homeostasis and body composition in the offspring in childhood. METHODS: Healthy prepubertal children (aged 4-11 years) born at term were studied: offspring of mothers who were admitted to hospital with SHG (n = 36) and offspring of mothers from control pregnancies (n = 42). Primary outcome was insulin sensitivity measured using iv glucose tolerance tests and Bergman's minimal model. Other assessments included lipid and hormonal profiles and body composition using whole-body dual-energy x-ray absorptiometry. RESULTS: Insulin sensitivity in SHG children was 20% lower than in controls (8.49 vs 10.60 * 10( 4).min(-1).(mU/L); P = .014). SHG children also had higher fasting insulin (6.88 vs 5.04 mIU/L; P = .024) and lower IGF binding protein 1 (11.8 vs 19.0 ng/mL; P = .004) concentrations than controls. Baseline cortisol concentrations were 22% higher in SHG offspring (256 vs 210 nmol/L; P = .021). Children in both groups were anthropometrically similar. CONCLUSION: Children born to mothers who experienced SHG have lower insulin sensitivity, which may increase their long term risk of developing diabetes mellitus. Follow-up of SHG offspring is essential to determine later risk of metabolic disease. PMID- 23750034 TI - Germline SDHA mutation detected by next-generation sequencing in a young index patient with large paraganglioma. PMID- 23750033 TI - One day of mixed meal overfeeding reduces hepatic insulin sensitivity and increases VLDL particle but not VLDL-triglyceride secretion in overweight and obese men. AB - CONTEXT: The exact mechanisms responsible for increased plasma triglyceride (TG) concentration in obese people are unclear, and it is not known whether excess energy intake per se is involved in the pathophysiology of this abnormality. OBJECTIVE: The purpose of our study was to examine how excess energy intake from a balanced diet for 1 day affects very-low-density lipoprotein (VLDL)-TG kinetics and its putative regulators hepatic insulin sensitivity and plasma free fatty acid availability. SUBJECTS AND DESIGN: We used stable isotope-labeled tracer methods to evaluate glucose and lipid kinetics in 8 overweight and obese men (age, 38 +/- 3 years; body mass index, 33.7 +/- 1.7 kg/m(2); means +/- SEM) on 2 occasions (randomized crossover design): once, the day after they consumed a balanced diet that provided an amount of energy that matched their energy expenditure, and another time, the day after they consumed a balanced diet that provided 30% excess calories. Eight healthy, lean men (34 +/- 1 years; 22.5 +/- 0.6 kg/m(2)) were studied under isocaloric conditions only to provide a reference for normal lipid kinetics. RESULTS: VLDL-TG and VLDL-apolipoprotein B-100 (apoB 100) concentrations and secretion rates were significantly greater (P < .01) in overweight/obese compared with lean men. Hypercaloric, compared with isocaloric, feeding in overweight/obese men increased glucose rate of appearance in plasma (904 +/- 21 vs 873 +/- 26 MUmol/min), the hepatic insulin resistance index (10.9 +/- 2.2 vs 8.3 +/- 1.8), and VLDL-apoB-100 concentration and secretion rate (1.91 +/- 0.24 vs. 1.53 +/- 0.13 nmol/min), whereas VLDL-apoB-100 plasma clearance rate, VLDL-TG secretion and plasma clearance rates, and free fatty acid rate of appearance in plasma were not affected by overfeeding. CONCLUSION: One day of moderate overfeeding (30% excess energy intake) stimulates hepatic glucose and VLDL-apo B-100 secretion rates but has no effect on hepatic and adipose tissue fatty acid metabolism in overweight/obese men. PMID- 23750035 TI - Concurrence of primary hyperparathyroidism and metastatic breast carcinoma affected a parathyroid gland. AB - OBJECTIVE: Involvement of the parathyroid glands by metastatic tumor is rare. Breast is 1 of the primary sites in metastatic cancers. We introduce a rare case of metastatic breast carcinoma affecting a parathyroid gland, which was clinically combined with parathyroid gland hyperplasia. CASE REPORT: A 65-year old woman was referred due to hypercalcemia and constipation. The patient had a history of left breast carcinoma. She was admitted to the hospital because of the recent discovery of hypercalcemia and elevation of PTH. A Tc99m-sestamibi scan showed retained uptake in the right thyroid and in the lower pole of the left thyroid gland. Aspiration biopsy results revealed that the nodule in the posterior portion of the right thyroid was metastatic breast cancer and the nodule in the left thyroid gland was the hyperplastic parathyroid gland. CONCLUSION: This case illustrates that hyperparathyroidism caused by parathyroid hyperplasia was concurrent with metastatic breast cancer to a parathyroid gland without disseminated systemic metastasis. Although this case is very uncommon and it is not clear whether there is a relationship between breast cancer and primary hyperparathyroidism, that possibility should always be considered as the cause of hypercalcemia in patients with breast cancer. PMID- 23750036 TI - Preservation of nucleic acids and tissue morphology in paraffin-embedded clinical samples: comparison of five molecular fixatives. AB - Formalin fixation preserves tissue morphology at the expense of macromolecule integrity. Freshly frozen samples are the golden standard for DNA and RNA analyses but require laborious deep-freezing and frozen sectioning for morphological studies. Alternative tissue stabilisation methods are therefore needed. We analysed the preservation of nucleic acids, immunohistochemical staining properties and tissue morphology in paraffin-embedded clinical tissue samples fixed with Z7, RCL2, PAXgene, Allprotect and RNAlater. Formalin-fixed and deep-frozen samples were used as controls. Immunohistochemical analyses showed good preservation of antigenicity in all except Allprotect and RNAlater-fixed samples. RNA quality, based on RNA integrity number value by Bioanalyzer, was comparable with freshly frozen samples only in PAXgene-fixed samples. According to quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses, RNA from PAXgene samples yielded results similar to freshly frozen samples. No difference between fixatives was seen in DNA analyses (PCR and real time PCR). In conclusion, PAXgene seems to be superior to other molecular fixatives and formaldehyde. PMID- 23750037 TI - The role of NDRG1 in the pathology and potential treatment of human cancers. AB - N-myc downstream regulated gene 1 (NDRG1) has been well characterised to act as a metastatic suppressor in a number of human cancers. It has also been implicated to have a significant function in a number of physiological processes such as cellular differentiation and cell cycle. In this review, we discuss the role of NDRG1 in cancer pathology. NDRG1 was observed to be downregulated in the majority of cancers. Moreover, the expression of NDRG1 was found to be significantly lower in neoplastic tissues as compared with normal tissues. The most important function of NDRG1 in inhibiting tumour progression is associated with its ability to suppress metastasis. However, it has also been shown to have important effects on other stages of cancer progression (primary tumour growth and angiogenesis). Recently, novel iron chelators with selective antitumour activity (ie, Dp44mT, DpC) were shown to upregulate NDRG1 in cancer cells. Moreover, Dp44mT showed its antimetastatic potential only in cells expressing NDRG1, making this protein an important therapeutic target for cancer chemotherapy. This observation has led to increased interest in the examination of these novel anticancer agents. PMID- 23750038 TI - Clinico-pathological characteristics and clinical outcome of different histological types of pancreatic cancer in a large Middle European series. AB - AIMS: Pancreatic cancer (PC) is a heterogeneous disease in terms of histological and molecular subtypes. The aim of this study was to evaluate the prognostic impact of different histological subtypes on cancer-specific survival (CSS) in a large single-centre Middle European cohort. METHODS: We retrospectively studied the records of 400 consecutive PC patients who were treated from 2004 to 2010 at a single tertiary academic centre. The association of histological subtypes and parameters such as tumour stage, tumour grade, levels of tumour markers carcinoembryonic antigen and CA19-9 at diagnosis, was studied. CSS was calculated using the Kaplan-Meier method, and the influence of each parameter on CSS was assessed with univariate and multivariable Cox proportional models. RESULTS: The survival time was significantly shorter in the ductal adenocarcinoma and acinar histological subtypes compared to neuroendocrine differentiation (p<0.001). No survival difference was observed between ductal adenocarcinomas and patients with a histological variant of ductal adenocarcinoma, namely, mucinous non-cystic adenocarcinoma (p=0.7). In multivariable analysis, ductal adenocarcinoma (HR=3.1, CI 1.6 to 6.1, p=0.001) and acinar carcinoma (HR=3.2, CI 1.3 to 8.5, p=0.016) were identified as independent predictors for CSS. CONCLUSIONS: Our findings suggest that the main histological subtype is an independent predictor of CSS in patients with PC. Thus, our data underline the importance of routine assessment of histological type in PC for individual risk assessment. However, no clinical rationale for the subdivision of ductal adenocarcinoma and mucinous non-cystic adenocarcinoma can be supported by our study. PMID- 23750039 TI - What counts for 'counting'? Chimpanzees, Pan troglodytes, respond appropriately to relevant and irrelevant information in a quantity judgment task. AB - Nonhuman animals quantify all manner of things, and the way in which this is done is fairly well understood. However, little research has been conducted to determine how they know what is or is not relevant in the instances in which they quantify stimuli. We assessed how four chimpanzees chose between two sets of food items when the items were distributed across separate spatial arrays. Each item was covered by a container, and then was revealed in sequence so that neither whole set was visible at one time. After all containers were revealed, some were revealed again. The chimpanzees should have ignored items that were seen a second time and instead enumerated each item only once. In another test, some of the items were transposed in location and then uncovered again. Here, the chimpanzees needed to recognize that the newly shown food items were ones they already had seen. Overall, the chimpanzees were successful in selecting the truly larger array of items despite these potential distracting re-presentations of items. Discrimination performance also reflected analogue magnitude estimation because comparisons of sets that differed by larger amounts were easier than comparisons that differed by smaller amounts. Thus, chimpanzee quantity judgments for nonvisible sets of items are inexact, but they include an aspect of control for determining when items are uniquely presented versus re-presented. PMID- 23750040 TI - Integration of multiple cues allows threat-sensitive anti-intraguild predator responses in predatory mites. AB - Intraguild (IG) prey is commonly confronted with multiple IG predator species. However, the IG predation (IGP) risk for prey is not only dependent on the predator species, but also on inherent (intraspecific) characteristics of a given IG predator such as its life-stage, sex or gravidity and the associated prey needs. Thus, IG prey should have evolved the ability to integrate multiple IG predator cues, which should allow both inter- and intraspecific threat-sensitive anti-predator responses. Using a guild of plant-inhabiting predatory mites sharing spider mites as prey, we evaluated the effects of single and combined cues (eggs and/or chemical traces left by a predator female on the substrate) of the low risk IG predator Neoseiulus californicus and the high risk IG predator Amblyseius andersoni on time, distance and path shape parameters of the larval IG prey Phytoseiulus persimilis. IG prey discriminated between traces of the low and high risk IG predator, with and without additional presence of their eggs, indicating interspecific threat-sensitivity. The behavioural changes were manifest in distance moved, activity and path shape of IG prey. The cue combination of traces and eggs of the IG predators conveyed other information than each cue alone, allowing intraspecific threat-sensitive responses by IG prey apparent in changed velocities and distances moved. We argue that graded responses to single and combined IG predator cues are adaptive due to minimization of acceptance errors in IG prey decision making. PMID- 23750041 TI - Enantioselective synthesis of (R)-tolterodine using lithiation/borylation protodeboronation methodology. AB - The synthesis of the pharmaceutical (R)-tolterodine is reported using lithiation/borylation-protodeboronation of a homoallyl carbamate as the key step. This step was tested with two permutations: an electron-neutral aryl Li-carbamate reacting with an electron-rich boronic ester and an electron-rich aryl Li carbamate reacting with an electron-neutral boronic ester. It was found that the latter arrangement was considerably better than the former. Further improvements were achieved using magnesium bromide in methanol leading to a process that gave high yield and high enantioselectivity in the lithiation/borylation reaction. The key step was used in an efficient synthesis of (R)-tolterodine in a total of eight steps in a 30% overall yield and 90% ee. PMID- 23750042 TI - Quantifying accumulation or exclusion of H+, HO-, and Hofmeister salt ions near interfaces. AB - Recently, surface spectroscopies and simulations have begun to characterize the non-uniform distributions of salt ions near macroscopic and molecular surfaces. The thermodynamic consequences of these non-uniform distributions determine the often-large ion-specific effects of Hofmeister salts on a very wide range of processes in water. For uncharged surfaces, where these nonuniform ion distributions are confined to the first few layers of water at the surface, a two state approximation to the distributions of water and ions, called the salt ion partitioning model (SPM) has both molecular and thermodynamic signiicance. Here, we summarize SPM results quantifying the local accumulation of H+, exclusion of HO-, and range of partitioning behavior of Hofmeister anions and cations near macroscopic and molecular interfaces. These results provide a database to interpret or predict Hofmeister salt effects on aqueous processes in terms of structural information regarding amount and composition of the surface exposed or buried in these processes. PMID- 23750043 TI - Ion selectivity from local configurations of ligands in solutions and ion channels. AB - Probabilities of numbers of ligands proximal to an ion lead to simple, general formulae for the free energy of ion selectivity between different media. That free energy does not depend on the definition of an inner shell for ligand counting, but other quantities of mechanistic interest do. If analysis is restricted to a specific coordination number, then two distinct probabilities are required to obtain the free energy in addition. The normalizations of those distributions produce partition function formulae for the free energy. Quasi chemical theory introduces concepts of chemical equilibrium, then seeks the probability that is simplest to estimate, that of the most probable coordination number. Quasi-chemical theory establishes the utility of distributions of ligand number, and sharpens our understanding of quasi-chemical calculations based on electronic structure methods. This development identifies contributions with clear physical interpretations, and shows that evaluation of those contributions can establish a mechanistic understanding of the selectivity in ion channels. PMID- 23750045 TI - CAPITAL FLOWS, CONSUMPTION BOOMS AND ASSET BUBBLES: A BEHAVIOURAL ALTERNATIVE TO THE SAVINGS GLUT HYPOTHESIS. AB - Bernanke (2005) hypothesized that a "global savings glut" was causing large trade imbalances. However, we show that the global savings rates did not show a robust upward trend during the relevant period. Moreover, if there had been a global savings glut there should have been a large investment boom in the countries that imported capital. Instead, those countries experienced consumption booms. National asset bubbles explain the international imbalances. The bubbles raised consumption, resulting in large trade deficits. In a sample of 18 OECD countries plus China, movements in home prices alone explain half of the variation in trade deficits. PMID- 23750044 TI - Lack of discrimination against non-proteinogenic amino acid norvaline by elongation factor Tu from Escherichia coli. AB - The GTP-bound form of elongation factor Tu (EF-Tu) brings aminoacylated tRNAs (aa tRNA) to the A-site of the ribosome. EF-Tu binds all cognate elongator aa-tRNAs with highly similar affinities, and its weaker or tighter binding of misacylated tRNAs may discourage their participation in translation. Norvaline (Nva) is a non proteinogenic amino acid that is activated and transferred to tRNALeu by leucyl tRNA synthetase (LeuRS). No notable accumulation of Nva-tRNALeu has been observed in vitro, because of the efficient post-transfer hydrolytic editing activity of LeuRS. However, incorporation of norvaline into proteins in place of leucine does occur under certain conditions in vivo. Here we show that EF-Tu binds Nva-tRNALeu and Leu-tRNALeu with similar affinities, and that Nva-tRNALeu and Leu-tRNALeu dissociate from EF-Tu at comparable rates. The inability of EF-Tu to discriminate against norvaline may have driven evolution of highly efficient LeuRS editing as the main quality control mechanism against misincorporation of norvaline into proteins. PMID- 23750046 TI - "Once Upon a Time There Was a Saint...": Re-evaluating Folklore in Anglo-Latin Hagiography. AB - This article examines methods for identifying folklore in hagiography. Using hagiographical materials from eleventh and twelfth century England, it critiques the current trend of equating folklore motifs with oral transmission and argues in favour of a "performer-centred" understanding of folklore and hagiographical composition. PMID- 23750047 TI - Magnetic Heating of Iron Oxide Nanoparticles and Magnetic Micelles for Cancer Therapy. AB - The inclusion of magnetic nanoparticles into block copolymer micelles was studied towards the development of a targeted, magnetically triggered drug delivery system for cancer therapy. Herein, we report the synthesis of magnetic nanoparticles and poly(ethylene glycol-b-caprolactone) block copolymers, and experimental verification of magnetic heating of the nanoparticles, self-assembly of the block copolymers to form magnetic micelles, and thermally-enhanced drug release. The semicrystalline core of the micelles melted at temperatures just above physiological conditions, indicating that they could be used to release a chemotherapy agent from a thermo-responsive polymer system. The magnetic nanoparticles were shown to heat effectively in high frequency magnetic fields ranging from 30-70 kA/m. Magnetic micelles also showed heating properties, that when combined with a chemotherapeutic agent and a targeting ligand could be developed for localized, triggered drug delivery. During the magnetic heating experiments, a time lag was observed in the temperature profile for magnetic micelles, likely due to the heat of fusion of melting of polycaprolactone micelle cores before bulk solution temperatures increased. Doxorubicin, incorporated into the micelles, released faster when the micelles were heated above the core melting point. PMID- 23750048 TI - The synthesis and structural characterization of the technetium nitrosyl complexes [TcCl(NO)(SC5H4N)(PPh3)2] and [Tc(NO)(SC5H4N)2(PPh3)]. AB - The reaction of the Tc(I) complex [Tc(NO)Cl2(HOMe)(PPh3)2] with stoichiometric amounts of 2-mercatopyridine and a proton scavenger yields [Tc(NO)Cl(Spy)(PPh3)2] or [Tc(NO)(Spy)2(PPh3)], depending upon quantities of ligands employed. These two complexes have been structurally characterized. The small bite angles of the bidentate mercaptopyridine ligands cause significant deviation from octahedral coordination geometry. PMID- 23750049 TI - Retirement and health benefits for Mexican migrant workers returning from the United States. AB - In the absence of a bilateral agreement for the portability and totalization of social security contributions between the United States and Mexico, this article examines the access to pension and health insurance benefits and employment status of older Mexican return migrants. We find that return migrants who have spent less than a year in the United States have a similar level of access to social security benefits as non-migrants. Return migrants who have spent at least a year in the United States are less likely to have public health insurance or social security benefits, and could be more vulnerable to poverty in old age. These results inform the debate on a bilateral social security agreement between the United States and Mexico to improve return migrants' social security. PMID- 23750050 TI - Systems Factorial Technology provides new insights on global-local information processing in autism spectrum disorders. AB - Previous studies of global-local processing in autism spectrum disorders (ASDs) have indicated mixed findings, with some evidence of a local processing bias, or preference for detail-level information, and other results suggesting typical global advantage, or preference for the whole or gestalt. Findings resulting from this paradigm have been used to argue for or against a detail focused processing bias in ASDs, and thus have important theoretical implications. We applied Systems Factorial Technology, and the associated Double Factorial Paradigm (both defined in the text), to examine information processing characteristics during a divided attention global-local task in high-functioning individuals with an ASD and typically developing controls. Group data revealed global advantage for both groups, contrary to some current theories of ASDs. Information processing models applied to each participant revealed that task performance, although showing no differences at the group level, was supported by different cognitive mechanisms in ASD participants compared to controls. All control participants demonstrated inhibitory parallel processing and the majority demonstrated a minimum-time stopping rule. In contrast, ASD participants showed exhaustive parallel processing with mild facilitatory interactions between global and local information. Thus our results indicate fundamental differences in the stopping rules and channel dependencies in individuals with an ASD. PMID- 23750052 TI - University Software Ownership and Litigation: A First Examination. AB - Software patents and university-owned patents represent two of the most controversial intellectual property developments of the last twenty-five years. Despite this reality, and concerns that universities act as "patent trolls" when they assert software patents in litigation against successful commercializers, no scholar has systematically examined the ownership and litigation of university software patents. In this Article, we present the first such examination. Our empirical research reveals that software patents represent a significant and growing proportion of university patent holdings. Additionally, the most important determinant of the number of software patents a university owns is not its research and development ("R&D") expenditures (whether computer science related or otherwise) but, rather, its tendency to seek patents in other areas. In other words, universities appear to take a "one size fits all" approach to patenting their inventions. This one size fits all approach is problematic given the empirical evidence that software is likely to follow a different commercialization path than other types of invention. Thus, it is perhaps not surprising that we see a number of lawsuits in which university software patents have been used not for purposes of fostering commercialization, but instead, to extract rents in apparent holdup litigation. The Article concludes by examining whether this trend is likely to continue in the future, particularly given a 2006 Supreme Court decision that appears to diminish the holdup threat by recognizing the possibility of liability rules in patent suits, as well as recent case law that may call into question certain types of software patents. PMID- 23750051 TI - A critical evaluation of random copolymer mimesis of homogeneous antimicrobial peptides. AB - Polymeric synthetic mimics of antimicrobial peptides (SMAMPs) have recently demonstrated similar antimicrobial activity as natural antimicrobial peptides (AMPs) from innate immunity. This is surprising, since polymeric SMAMPs are heterogeneous in terms of chemical structure (random sequence) and conformation (random coil), in contrast to defined amino acid sequence and intrinsic secondary structure. To understand this better, we compare AMPs with a 'minimal' mimic, a well characterized family of polydisperse cationic methacrylate-based random copolymer SMAMPs. Specifically, we focus on a comparison between the quantifiable membrane curvature generating capacity, charge density, and hydrophobicity of the polymeric SMAMPs and AMPs. Synchrotron small angle x-ray scattering (SAXS) results indicate that typical AMPs and these methacrylate SMAMPs generate similar amounts of membrane negative Gaussian curvature (NGC), which is topologically necessary for a variety of membrane-destabilizing processes. Moreover, the curvature generating ability of SMAMPs is more tolerant of changes in the lipid composition than that of natural AMPs with similar chemical groups, consistent with the lower specificity of SMAMPs. We find that, although the amount of NGC generated by these SMAMPs and AMPs are similar, the SMAMPs require significantly higher levels of hydrophobicity and cationic charge to achieve the same level of membrane deformation. We propose an explanation for these differences, which has implications for new synthetic strategies aimed at improved mimesis of AMPs. PMID- 23750053 TI - Dearomatization applications of I(III) reagents and some unusual reactivity amongst resorcinol derived cyclohexadienones. AB - The oxidative dearomatization of resorcinol derivatives, which are outfitted with a lactic acid derived chiral tether, and mitigated by hypervalent iodine derivatives of PhIO, affords stable chiral cyclohexadienones as useful building blocks for the construction of many highly functionalized chiral six and seven membered ring systems. Herein, we report a multitude of remarkable and unexpected diastereoselective transformations stemming from these cyclohexadienone adducts. PMID- 23750055 TI - A partitioned model order reduction approach to rationalise computational expenses in nonlinear fracture mechanics. AB - We propose in this paper a reduced order modelling technique based on domain partitioning for parametric problems of fracture. We show that coupling domain decomposition and projection-based model order reduction permits to focus the numerical effort where it is most needed: around the zones where damage propagates. No a priori knowledge of the damage pattern is required, the extraction of the corresponding spatial regions being based solely on algebra. The efficiency of the proposed approach is demonstrated numerically with an example relevant to engineering fracture. PMID- 23750054 TI - Constructing the Architecturally Distinctive ABD-Tricycle of Phomactin A through an Intramolecular Oxa-[3 + 3] Annulation Strategy. AB - Our efforts in constructing the ABD-ring of phomactin A through an intramolecular oxa-[3 + 3] annulation strategy is described. This struggle entailed finding a practical and efficient preparation of annulation precursor, and a realization of the unexpected competing regioisomeric pathway. The success entailed accessing the A-ring through Diels-Alder cycloaddition of Rawal's diene. Furthermore, the discovery that the regioisomers from the annulation existed as atropisomers with respect to the D-ring olefin and that they could be equilibrated to the desired ABD-tricycle, allowing large quantities of tricycle to be accessed. PMID- 23750056 TI - THE IMPACT OF KINSHIP NETWORKS ON OLD-AGE VULNERABILITY IN INDONESIA. AB - This article examines the problem of care provision for elderly people in Java, a contemporary developing society characterised by lack of formal welfare services, nuclear family organisation and high levels of childlessness. A similar socio demographic, cultural and economic regime existed in historical Northwest Europe, where it has been seen as having contributed to the early emergence of community based old-age care and low involvement of wider kin networks. Here the role of kin in providing old-age care in a nuclear family system is re-examined by drawing on longitudinal data of elderly people's life histories and support networks in a village in East Java. The central argument is that the identification of elders most vulnerable to a lack of care and support in old age requires understanding the nature and functioning of kin networks over time. The paper discusses three key aspects of networks-network membership, exchanges within networks and network dynamics-and arrives at a characterisation of different kin networks on the basis of size, composition, location and social status. By focusing on the effects of a specific crisis, namely the loss of a wife, on care outcomes in old age, it is possible to determine what kinds of kin networks are best able to adjust to a sudden change in older people's circumstances and protect them from declines in welfare. This reveals the importance, especially for childless elderly people, of extended, heterogeneous and well-connected kin networks. PMID- 23750057 TI - License to Sin: The Liberating Role of Reporting Expectations. AB - This research examines the impact of asking intention questions about "vice behaviors," or behaviors about which respondents simultaneously hold both negative explicit and positive implicit attitudes. Asking questions about the likelihood of engaging in behaviors for which respondents maintain conflicting attitude structures appears to give respondents a "license to sin," resulting in increased rates of behavior versus those of a control group not asked intention questions. However, when provided with defensive tools that highlight the negative explicit component of their attitudes toward the behaviors, respondents are able to dampen the increase in behavior caused by the act of prediction. PMID- 23750058 TI - Actual and de facto Childlessness in Old Age: Evidence and Implications from East Java, Indonesia. PMID- 23750059 TI - Early production of the passive in two Eastern Bantu languages. AB - The passive construction is acquired relatively late by children learning to speak many languages, with verbal passives not fully acquired until age 6 in English. In other languages it appears earlier, around age 3 or before. Use of passive construction in young children was examined in two Eastern Bantu languages spoken in Kenya (Kiswahili and Kigiriama), both with frequent use of passive. The passive was used productively very early (2;1) in these languages, regardless of the method used to measure productivity. In addition, non-actional passives, particularly rare in English and some other European languages, were seen at these early ages. The proportion of verbs that were passive varied between individuals, both in children's speech and in the input to children. Pragmatic and grammatical features of the passive in some languages have previously been suggested to drive early passive acquisition, but these features are not found consistently in the two languages studied here. Findings suggest that the relatively high frequency of input found in these languages is the most plausible reason for early productive use of the passive. PMID- 23750060 TI - Inter-generational family support provided by older people in Indonesia. AB - Most social research on ageing in Asia has focused on the support provided by adult children to their parents, and thereby suggests that as a matter of course older people are in need of support. This paper offers a different perspective. Drawing on ethnographic and quantitative data from a village in East Java, it examines the extent of older people's dependence on others and highlights the material and practical contributions that they make to their families. It is shown that only a minority of older people are reliant on children or grandchildren for their daily survival. In the majority of cases, the net flow of inter-generational support is either downwards - from old to young - or balanced. Far from merely assisting with childcare and domestic tasks, older people are often the economic pillars of multi-generational families. Pension and agricultural incomes serve to secure the livelihoods of whole family networks, and the accumulated wealth of older parents is crucial for launching children into economic independence and underwriting their risks. Parental generosity does not generally elicit commensurate reciprocal support when it is needed, leaving many people vulnerable towards the end of their lives. PMID- 23750061 TI - Guest Editorial: Understanding vulnerabilities in old age. PMID- 23750062 TI - A framework for understanding old-age vulnerabilities. AB - Identifying vulnerable older people and understanding the causes and consequences of their vulnerability is of human concern and an essential task of social policy. To date, vulnerability in old age has mainly been approached by identifying high risk groups, like the poor, childless, frail or isolated. Yet vulnerability is the outcome of complex interactions of discrete risks, namely of being exposed to a threat, of a threat materialising, and of lacking the defences or resources to deal with a threat. In this article, we review approaches to vulnerability in various disciplines in order to develop a systematic framework for approaching vulnerability. This framework distinguishes and examines the interactions among the domains of exposure, threats, coping capacities and outcomes. Drawing on European and Asian gerontological literature, we discuss what might be meant by these domains and their place in the understanding of vulnerability in old age. Two case studies are presented - one on homelessness in Britain, the other on familial care provision in Indonesia - to illustrate the ways in which specific vulnerabilities are created and distributed over the lifecourse. PMID- 23750063 TI - Migration, social structure and old-age support networks: a comparison of three Indonesian communities. AB - Contemporary trends in population ageing and urbanisation in the developing world imply that the extensive out-migration of young people from rural areas coincides with, and is likely to exacerbate, a rise in the older share of the rural population. This paper examines the impact of migration on vulnerability at older ages by drawing on the results of anthropological and demographic field studies in three Indonesian communities. The methodology for identifying vulnerable older people has a progressively sharper focus, beginning first with important differences between the communities, then examining variations by socio-economic strata, and finally the variability of older people's family networks. Comparative analysis indicates considerable heterogeneity in past and present migration patterns, both within and between villages. The migrants' contributions are a normal and important component of older people's support, often in combination with those of local family members. Higher status families are commonly able to reinforce their position by making better use of migration opportunities than the less advantaged. Although family networks in the poorer strata may effect some redistribution of the children's incomes, their social networks are smaller and insufficient to overcome their marked disadvantages. Vulnerability thus arises where several factors, including migration histories, result in unusually small networks, and when the migrations are within rural areas. PMID- 23750064 TI - Conceptual structure: Towards an integrated neuro-cognitive account. AB - How are the meanings of concepts represented and processed? We present a cognitive model of conceptual representations and processing - the Conceptual Structure Account (CSA; Tyler & Moss, 2001) - as an example of a distributed, feature-based approach. In a first section, we describe the CSA and evaluate relevant neuropsychological and experimental behavioral data. We discuss studies using linguistic and non-linguistic stimuli, which are both presumed to access the same conceptual system. We then take the CSA as a framework for hypothesising how conceptual knowledge is represented and processed in the brain. This neuro cognitive approach attempts to integrate the distributed feature-based characteristics of the CSA with a distributed and feature-based model of sensory object processing. Based on a review of relevant functional imaging and neuropsychological data, we argue that distributed accounts of feature-based representations have considerable explanatory power, and that a cognitive model of conceptual representations is needed to understand their neural bases. PMID- 23750065 TI - Can We Trust Parental Reports of Child Care Subsidy Receipt? AB - In recent years, research examining determinants and consequences of the means tested child care subsidy program (the Child Care and Development Fund [CCDF]) has grown dramatically. To measure subsidy utilization, existing studies typically rely on parent-reported measures of subsidy receipt drawn from large surveys. As the research literature on child care subsidies has grown, however, so have concerns about the trustworthiness of parent-reported subsidy use. One way to assess the quality of parent-reported subsidy use is to examine its overlap with another subsidy receipt measure, drawn from a different source. The current paper uses the Fragile Families and Child Well-Being Study (FFCWS), the only existing survey data source that contains an alternate measure of subsidy receipt - based on child care provider report - which permits a comparison to parent-reported measures. We find evidence that increases our confidence in the trustworthiness of parents as accurate reporters of subsidy receipt. In recognition that neither data source reflects "true" subsidy receipt, however, we conclude with a discussion of limitations and steps for future research. PMID- 23750066 TI - Percutaneous intracardiac beating-heart surgery using metal MEMS tissue approximation tools. AB - Achieving superior outcomes through the use of robots in medical applications requires an integrated approach to the design of the robot, tooling and the procedure itself. In this paper, this approach is applied to develop a robotic technique for closing abnormal communication between the atria of the heart. The goal is to achieve the efficacy of surgical closure as performed on a stopped, open heart with the reduced risk and trauma of a beating-heart catheter-based procedure. In the proposed approach, a concentric tube robot is used to percutaneously access the right atrium and deploy a tissue approximation device. The device is constructed using a metal microelectromechanical system (MEMS) fabrication process and is designed to both fit the manipulation capabilities of the robot as well as to reproduce the beneficial features of surgical closure by suture. The effectiveness of the approach is demonstrated through ex vivo and in vivo experiments. PMID- 23750067 TI - Linking Places to Problems: Geospatial Theories of Neighborhoods, Alcohol and Crime. AB - This paper provides a critical review of two broad categories of social ecological theories of crime, social integration and place-based theories, and their relationships to spatial assessments of crime patterns. Social integration theories emphasize the role of neighborhood disorganization on crime, while place theories stress the social interactions within and between places as a source of crime. We provide an analysis of the extent to which these two types of theorizing describe processes and mechanisms that are truly ecologic (identify specific interactions between individuals and their environments) and truly spatial (identify specific movement and interaction patterns of individuals and groups) as they endeavor to explain crime outcomes. We suggest that social integration theories do not provide spatial signatures of sufficient specificity to justify the application of spatial statistical techniques as quantitative arbiters of the theory. On the other hand, place based theories go some way toward addressing these issues because the emphasis is placed on understanding the exact physical and social characteristics of place and the activities that occur around locations as sources of crime. Routine activities and crime potential theories attempt to explain clustering or "hot spots" of crime in ways that give clear spatial dimension by looking at micro-spatial interactions between offenders and targets of crime. These theories have strong ecological implications as well, since they contain specific statements about how people use the space around them and how these patterns of use are related to patterns of criminal activity. We conclude by identifying a set of requirements for successful empirical tests of geospatial theories, including the development of valid measures of key theoretical constructs and the formulation of critical empirical assessments of geospatial hypotheses derived from motivating theory. PMID- 23750068 TI - Geospatial Analyses of Alcohol and Drug Problems: Empirical Needs and Theoretical Foundations. AB - Over the past four decades geospatial analyses of alcohol and drug problems have moved to the forefront of ecological studies of the correlates and determinants of drug addictions in community health. These advances have been predicated upon the expanding computational capabilities of geographic information systems, advancement of statistical tools for the analysis of spatial data, and the formulation of suitable social ecological theory. This paper provides an introduction to the study of drug markets in the US as a model social problem for geospatial research and analysis. Market and epidemic models of the growth of the methamphetamine abuse and dependence in California are used as examples of two fruitful approaches to understanding the social processes that underlie use of this dangerous substance. Data on the growth of the epidemic are described and used to motivate theoretical and empirical concerns regarding further analyses of the development of drug markets over space and time. These concerns, in turn, begin to be addressed by the remaining four papers in this series, each providing some examples and insights into avenues of geospatial research which can be profitably explored in the future. PMID- 23750069 TI - Exploring the Spread of Methamphetamine Problems within California, 1980 to 2006. AB - BACKGROUND: The introduction and spread of high potency methamphetamine has led to dramatic increases in drug-related problems in California. Prior research suggests that drug abuse rates are related to local demographic and economic characteristics, law enforcement activities, and sentencing practices. Methamphetamine abuse in particular has been shown to be reduced by laws regulating the raw materials needed for its production. This research models the regional effects of such laws on the spatio-temporal patterns of growth of methamphetamine-related problems across California from 1980 to 2006. METHODS: Amphetamine-related arrests and hospital discharges related to amphetamine abuse / dependence were assembled for California counties over the years 1980 through 2006. Varying-parameter Bayesian space-time models were used to relate the implementation of major laws controlling the distribution of methamphetamine precursors to observed patterns of arrests and discharges and to allow such associations to vary by location. The models used conditionally autoregressive (CAR) Bayesian spatial priors to allow spatial correlation in estimation of county-specific growth in these measures over three distinct time periods: before the 1989 law, between the 1989 and 1997 laws, and after the 1997 law. Growth of arrests and discharges were related to demographic and economic indicators to determine geographic areas more or less susceptible to the spread of methamphetamine problems. RESULTS: Although both problem measures increased during all three periods, each of the precursor laws was associated with short term reductions in the growth of arrests and discharges. Growth was greatest in central California counties prior to 1989 and increased in coastal counties in later years. From 1980 to 1989 growth was highest for counties with low incomes and high proportions of white residents, while 1989-1997 growth was highest in counties with fewer whites and more Hispanics. Growth after 1997 was not significantly associated with county characteristics. CONCLUSION: This research demonstrates that the precursor laws did suppress the growth of methamphetamine related arrests and hospital discharges. It also demonstrates specific geographic patterns in the growth of methamphetamine arrests and abuse across California during this time. Early patterns of growth were related to economic and demographic characteristics, while later patterns were not. This suggests that some counties were uniquely susceptible to the early spread of the methamphetamine epidemic, although problems eventually grew dramatically in all California counties. PMID- 23750070 TI - Random effects coefficient of determination for mixed and meta-analysis models. AB - The key feature of a mixed model is the presence of random effects. We have developed a coefficient, called the random effects coefficient of determination, [Formula: see text], that estimates the proportion of the conditional variance of the dependent variable explained by random effects. This coefficient takes values from 0 to 1 and indicates how strong the random effects are. The difference from the earlier suggested fixed effects coefficient of determination is emphasized. If [Formula: see text] is close to 0, there is weak support for random effects in the model because the reduction of the variance of the dependent variable due to random effects is small; consequently, random effects may be ignored and the model simplifies to standard linear regression. The value of [Formula: see text] apart from 0 indicates the evidence of the variance reduction in support of the mixed model. If random effects coefficient of determination is close to 1 the variance of random effects is very large and random effects turn into free fixed effects-the model can be estimated using the dummy variable approach. We derive explicit formulas for [Formula: see text] in three special cases: the random intercept model, the growth curve model, and meta-analysis model. Theoretical results are illustrated with three mixed model examples: (1) travel time to the nearest cancer center for women with breast cancer in the U.S., (2) cumulative time watching alcohol related scenes in movies among young U.S. teens, as a risk factor for early drinking onset, and (3) the classic example of the meta-analysis model for combination of 13 studies on tuberculosis vaccine. PMID- 23750071 TI - Significant Other Enhanced Cognitive-Behavioral Therapy for PTSD and Alcohol Misuse in OEF/OIF Veterans. AB - This manuscript describes early work to develop a cognitive-behavioral therapy protocol for returning OEF/OIF Veterans with co-occurring posttraumatic stress disorder (PTSD) and alcohol use disorders (AUD). Based on the unique characteristics of this population, and on the literature supporting cognitive behavioral coping skills and significant other involvement for both PTSD and for AUD, the new therapy involves both of those components. The paper includes brief descriptions of two patients who were successfully treated with this approach. Although preliminary, these case studies suggest that cognitive-behavioral therapy enhanced by significant other involvement may be a promising approach for OEF/OIF Veterans with PTSD-AUD. PMID- 23750072 TI - PMN-PT-PZT composite films for high frequency ultrasonic transducer applications. AB - We have successfully fabricated x(0.65PMN-0.35PT)-(1 - x)PZT (xPMN-PT-(1 - x)PZT), where x is 0.1, 0.3, 0.5, 0.7 and 0.9, thick films with a thickness of approximately 9 um on platinized silicon substrate by employing a composite sol gel technique. X-ray diffraction analysis and scanning electron microscopy revealed that these films are dense and creak-free with well-crystallized perovskite phase in the whole composition range. The dielectric constant can be controllably adjusted by using different compositions. Higher PZT content of xPMN PT-(1 - x)PZT films show better ferroelectric properties. A representative 0.9PMN PT-0.1PZT thick film transducer is built. It has 200 MHz center frequency with a 6 dB bandwidth of 38% (76 MHz). The measured two-way insertion loss is 65 dB. PMID- 23750073 TI - Hydrogel based sensor arrays (2 * 2) with perforated piezoresistive diaphragms for metabolic monitoring (in vitro). AB - This report details the first experimental results from novel hydrogel sensor array (2 * 2) which incorporates analyte diffusion pores into a piezoresistive diaphragm for the detection of hydrogel swelling pressures and hence chemical concentrations. The sensor assembly was comprised of three components, the active four sensors, HPMA/DMA/TEGDMA (hydroxypropyl methacrylate (HPMA), N,N dimethylaminoethyl methacrylate (DMA) and crosslinker tetra-ethyleneglycol dimethacrylate (TEGDMA)) hydrogel, and backing plate. Each of the individual sensors of the array can be used with various hydrogels used to measure the presence of a number of stimuli including pH, ionic strength, and glucose concentrations. Ideally, in the future, these sensors will be used for continuous metabolic monitoring applications and implanted subcutaneously. In this paper and to properly characterize the sensor assembly, hydrogels sensitive to changes ionic strength were synthesized using hydroxypropyl methacrylate (HPMA), N,N dimethylaminoethyl methacrylate (DMA) and crosslinker tetra-ethyleneglycol dimethacrylate (TEGDMA) and inserted into the sensor assembly. This hydrogel quickly and reversibly swells when placed environments of physiological buffer solutions (PBS) with ionic strengths ranging from 0.025 to 0.15 M, making it ideal for proof-of-concept testing and initial characterization. The assembly was wire bonded to a printed circuit board and coated with 3 +/- 0.5 MUm of Parylene C using chemical vapor deposition (CVD) to protect the sensor and electrical connections during ionic strength wet testing. Two versions of sensors were fabricated for comparison, the first incorporated diffusion pores into the diaphragm, and the second used a solid diaphragm with perforated backing plate. This new design (perforated diaphragm) was shown to have slightly higher sensitivity than solid diaphragm sensors with separate diffuse backing plates when coupled with the hydrogel. The sensitivities for the 1 mm * 1 mm, 1.25 mm * 1.25 mm, 1.5 mm * 1.5 mm perforated diaphragm sensors were 53.3 +/- 6.5, 171.7 +/ 8.8, and 271.47 +/- 27.53 mV/V-M, respectively. These results show that perforations in the diaphragm can be used not only to allow the diffusion of analyte into the cavity but to increase mechanical stress in the piezoresistive diaphragm, thereby increasing sensor output signal. The time constants for swelling (tauswelling) and contracting (taucontracting) were calculated by fitting the sensor output half cycles to an exponential growth function. We found that the sensors' response was initially retarded during the preliminary hydrogel conditioning period then improved after 3-5 cycles with values of approximately 9 and 7 min for tauswelling and taucontracting. For all sensors tested tauswelling > taucontracting. This may be due to the increased loading on the hydrogel from the diaphragm during the swelling process. During contraction the diaphragm aids the hydrogel by reversibly applying mechanical pressure and therefore reducing taucontracting. Long term stability testing showed the sensors remained functional for upwards of 2 weeks in the test phosphate buffer solution (PBS). PMID- 23750074 TI - Input Distribution Influences Degree of Auxiliary Use by Children with Specific Language Impairment. AB - Children with specific language impairment (SLI) show a protracted period of inconsistent use of tense/agreement morphemes. The purpose of this investigation was to determine whether this inconsistent use could be attributed to the children's misinterpretations of particular syntactic structures in the input. In Study 1, preschool-aged children with SLI and typically developing peers heard sentences containing novel verbs preceded by auxiliary was or sentences in which the novel verb formed part of a nonfinite subject-verb sequence within a larger syntactic structure (e.g., We saw the dog relling). The children were then tested on their use of the novel verbs in contexts that obligated use of auxiliary is. The children with SLI were less accurate than their peers and more likely to produce the novel verb without is if the verb had been heard in a nonfinite subject-verb sequence. In Study 2, children with SLI and typically developing peers were tested on their comprehension of sentences such as The cow sees the horse eating. The children with SLI were less accurate than their peers and were disproportionately influenced by the nonfinite subject-verb clause at the end of the sentence. We interpret these findings within the framework of construction learning. PMID- 23750075 TI - Chemo-informatic design of antibiotic geldenamycin analogs to target stress proteins HSP90 of pathogenic protozoan parasites. AB - Stress proteins HSP90 (Heat shock proteins) are essential molecular chaperones involved in signal transduction, cell cycle control, stress management, folding and degradation of proteins. HSP90 have been found in a variety of organisms including pathogens suggesting that they are ancient and conserved proteins. Here, using molecular modeling and docking protocols, antibiotic Geldenamycin and its analog are targeted to the HSP90 homolog proteins of pathogenic protozoans Plasmodium falciparum, Leishmania donovani, Trypanosoma brucei and Entamoeba Histolytica. The designed analogs of geldenamycin have shown drug like property with improved binding affinity to their targets. A decrease in insilico affinity of the analogs for the Human HSP90 target indicates that they can be used as potential drug candidates. PMID- 23750076 TI - Docking studies of piperine - iron conjugate with human CYP450 3A4. AB - Piperine, a major constituent of Piper nigrum (Black pepper), is one of the well known components in many Ayurvedic formulations. Piperine is most studied bioenhancer because it inhibits drug metabolizing enzymes in rodents and increases plasma concentrations of several drugs, including P-glycoprotein substrates. However, there areno evidences on piperine-iron conjugate to inhibit human CYP450 3A4. We therefore investigated the influence of piperine-Fe conjugate to study the metabolism of iron with CYP450 3A4. Our in silico results showed that Piperine when conjugated with iron, inhibited activity of CYP450 3A4. This improved the binding of piperine-Fe conjugate with CYP450 3A4 and increased bioavailability. PMID- 23750077 TI - In silico characterization of putative drug targets in Staphylococcus saprophyticus, causing bovine mastitis. AB - The bovine mastitis caused by coagulase negative staphylococci (CNS) has increased in many herds of urban and rural areas of India. Emergence of multi drug resistant bacteria has further made its management more complex and serious. Therefore, innovation of novel specific drug for the treatment of disease caused by particular organism remained to be a challenge. Hence, in the present study a bacterium was isolated from milk of the cow with bovine mastitis and was identified as S. saprophyticus, 44 pathways of S. saprophyticus retrieved (KEGG) from web server were found to be non homologous to the host Bos taurus, out of which 39 pathways were found to be in cytoplasm, 2 in cell wall and 3 in the cell membrane. The knowledge of the present study could make the drug discovery easier which have high affinity to the target site of the causative organism. PMID- 23750078 TI - Artificial signal peptide prediction by a hidden markov model to improve protein secretion via Lactococcus lactis bacteria. AB - A hidden Markov model (HMM) has been utilized to predict and generate artificial secretory signal peptide sequences. The strength of signal peptides of proteins from different subcellular locations via Lactococcus lactis bacteria correlated with their HMM bit scores in the model. The results show that the HMM bit score +12 are determined as the threshold for discriminating secreteory signal sequences from the others. The model is used to generate artificial signal peptides with different bit scores for secretory proteins. The signal peptide with the maximum bit score strongly directs proteins secretion. PMID- 23750079 TI - Statistical analysis of pentose phosphate pathway genes from eubacteria and eukarya reveals translational selection as a major force in shaping codon usage pattern. AB - Comparative analysis of metabolic pathways among widely diverse species provides an excellent opportunity to extract information about the functional relation of organisms and pentose phosphate pathway exemplifies one such pathway. A comparative codon usage analysis of the pentose phosphate pathway genes of a diverse group of organisms representing different niches and the related factors affecting codon usage with special reference to the major forces influencing codon usage patterns was carried out. It was observed that organism specific codon usage bias percolates into vital metabolic pathway genes irrespective of their near universality. A clear distinction in the codon usage pattern of gram positive and gram negative bacteria, which is a major classification criterion for bacteria, in terms of pentose phosphate pathway was an important observation of this study. The codon utilization scheme in all the organisms indicates the presence of translation selection as a major force in shaping codon usage. Another key observation was the segregation of the H. sapiens genes as a separate cluster by correspondence analysis, which is primarily attributed to the different codon usage pattern in this genus along with its longer gene lengths. We have also analyzed the amino acid distribution comparison of transketolase protein primary structures among all the organisms and found that there is a certain degree of predictability in the composition profile except in A. fumigatus and H. sapiens, where few exceptions are prominent. In A. fumigatus, a human pathogen responsible for invasive aspergillosis, a significantly different codon usage pattern, which finally translated into its amino acid composition model portraying a unique profile in a key pentose phosphate pathway enzyme transketolase was observed. PMID- 23750080 TI - Heparin-benzyl alcohol enhancement of biofilms formation and antifungal susceptibility of vaginal Candida species isolated from pregnant and nonpregnant Saudi women. AB - Biofilm formation by Candida species is a major contribute to their pathogenic potential.The aim of this study was to determine in vitro effects of EDTA, cycloheximide, and heparin-benzyl alcohol preservative on C. albicans (126) and non-albicans (31)vaginal yeast isolates biofilm formations and their susceptibility against three antifungal Etest strips. Results of the crystal violet-assay, indicated that biofilms formation were most commonly observed [100%] for C. kefyr, C. utilis, C. famata, and Rhodotorula mucilaginosa, followed by C. glabrata [70%], C. tropicalis [50%], C. albicans [29%], Saccharomyces cerevisiae [0.0%]. EDTA (0.3mg/ml) significantly inhibited biofilm formation in both C. albicans and non-albicans isolates (P=0.0001) presumably due to chelation of necessary metal cations for the process-completion. In contrast, heparin ( benzyl alcohol preservative) stimulated biofilm formation in all tested isolates, but not at significant level (P=0.567). Conversely, cycloheximide significantly (P=0.0001) inhibited biofilm formation in all C. albicans strains(126) and its effect was even 3 fold more pronounced than EDTA inhibition, probably due to its attenuation of proteins (enzymes) and/or complex molecules necessary for biofilm formation. Results also showed that all nonalbicans yeasts isolates were susceptible to 5-flucytosine (MIC50, 0.016 ug/ml; MIC90, 0.064 ug/ml), but 14% of C. albicans isolates were resistant (MIC50, 0.064 ug/ml; MIC90 >32 ug/ml). The MIC50 value of amphotricin B for all C. albicans and non-albicans isolates was at a narrow range of 0.023 ug /ml, and the MIC90 values were 0.047 ug/ml and 0.064 ug/ml respectively, thereby confirming its efficacy as a first line empiric- treatment of Candida spp infections. PMID- 23750081 TI - Constructing phylogenetic trees using interacting pathways. AB - Phylogenetic trees are used to represent evolutionary relationships among biological species or organisms. The construction of phylogenetic trees is based on the similarities or differences of their physical or genetic features. Traditional approaches of constructing phylogenetic trees mainly focus on physical features. The recent advancement of high-throughput technologies has led to accumulation of huge amounts of biological data, which in turn changed the way of biological studies in various aspects. In this paper, we report our approach of building phylogenetic trees using the information of interacting pathways. We have applied hierarchical clustering on two domains of organisms-eukaryotes and prokaryotes. Our preliminary results have shown the effectiveness of using the interacting pathways in revealing evolutionary relationships. PMID- 23750083 TI - Phyto diab care: Phytoremedial database for antidiabetics. AB - Diabetes, a chronic disease debilitating to normal healthy lifestyle, onsets due to insufficient amount of insulin production or ineffective utilization of the amount produced. Although, pharmaceutical research has brought up remedial drugs and numerous candidates in various phases of clinical trials, off-target effects and unwanted physiological actions are a constant source of concern and contra indicatory in case of diabetic patients. Here we present a phytoremedial database, Phyto Diab Care, broadly applicable to any known anti-diabetic medicinal plant and phytochemicals sourced from them. Utilization of the traditional medicine knowledge for combating diabetes without creating unwanted physiological actions is our major emphasis. Data collected from peer-reviewed publications and phytochemicals were added to the customizable database by means of an extended relational design. The strength of this resource is in providing rapid retrieval of data from large volumes of text at a high degree of accuracy. Enhanced web interface allows multi-criteria based information filtering. Furthermore, the availability of 2D and 3D structures from molecular docking studies with any efficacy on the insulin signaling pathway makes the resource searchable and comparable in an intuitive manner. Phyto Diab Care compendium is publicly available and can be found in online. AVAILABILITY: http://www.gbpuat cbsh.ac.in/departments/bi/database/phytodiabcare/HOME%20PAGE/Home%20page.html. PMID- 23750082 TI - An improved hypergeometric probability method for identification of functionally linked proteins using phylogenetic profiles. AB - Predicting functions of proteins and alternatively spliced isoforms encoded in a genome is one of the important applications of bioinformatics in the post-genome era. Due to the practical limitation of experimental characterization of all proteins encoded in a genome using biochemical studies, bioinformatics methods provide powerful tools for function annotation and prediction. These methods also help minimize the growing sequence-to-function gap. Phylogenetic profiling is a bioinformatics approach to identify the influence of a trait across species and can be employed to infer the evolutionary history of proteins encoded in genomes. Here we propose an improved phylogenetic profile-based method which considers the co-evolution of the reference genome to derive the basic similarity measure, the background phylogeny of target genomes for profile generation and assigning weights to target genomes. The ordering of genomes and the runs of consecutive matches between the proteins were used to define phylogenetic relationships in the approach. We used Escherichia coli K12 genome as the reference genome and its 4195 proteins were used in the current analysis. We compared our approach with two existing methods and our initial results show that the predictions have outperformed two of the existing approaches. In addition, we have validated our method using a targeted protein-protein interaction network derived from protein protein interaction database STRING. Our preliminary results indicates that improvement in function prediction can be attained by using coevolution-based similarity measures and the runs on to the same scale instead of computing them in different scales. Our method can be applied at the whole-genome level for annotating hypothetical proteins from prokaryotic genomes. PMID- 23750084 TI - InDiaMed: A Comprehensive Database of Indian Medicinal plants for Diabetes. AB - According to International Diabetes Federation (IDF), India has 62.4 million people with diabetes and by 2030 it is predicted that the number will rise to 100 million. Studies claim that there are around 410 experimentally proven Indian medicinal plants which have anti-diabetic activity, of which the mechanism of action of 109 plants has been elucidated or reported. So, the need of the hour is to explore the claims of Indian medicinal flora and open up the facets of many Indian plants which are being examined for their beneficial role in diabetes. So, we created a database (InDiaMed) of Indian medicinal plants that captures their role in anti-diabetic activity. InDiaMed's features include chemical, pharmacological, biochemical and geographical information of the medicinal plant, scientifically relevant information of the plant, and the coherent research done on it in the field of diabetes. The database also includes the list of poly herbal formulations which are used for treatment of diabetes in India. AVAILABILITY: http://www.indiamed.info. PMID- 23750085 TI - Molecule of the month: miRNA and Parkinson's disease protein PARK2. PMID- 23750086 TI - Interaction of active compounds from Aegle marmelos CORREA with histamine-1 receptor. AB - The aim of this study is to determine the affinity of six active compounds of Aegle Marmelos Correa, they are (E, R)-Marmin, skimmianine, (S)-aegeline, aurapten, zeorin, and dustanin as antihistamines in histamine H1 receptor in comparison to cetirizin, diphenhydramine and chlorpheniramine as ligands comparison. Previously, in the in vitro study marmin obviously antagonized the histamine H1 receptor in a competitive manner. METHODS: molecular docking to determine the interaction of ligand binding to its receptor. Lower docking score indicates more stable binding to that protein. RESULTS: Marmin, skimmianine, aegeline, aurapten, zeorin, and dustanin were potential to develop as antihistamine agents, especially as histamine H1 receptor antagonists by interacting with amino acid residues, Asp107, Lys179, Lys191, Asn198, and Trp428 of histamine H1 receptor. CONCLUSIONS: Based on molecular docking, Amino acid residues involved in ligand protein interactions were Asp107, Lys179, Lys191, Asn198, and Trp428. PMID- 23750087 TI - Preimplantation genetic diagnosis in Saudi Arabia. AB - Preimplantation genetic diagnosis (PGD) testing is the practice of obtaining a cellular biopsy sample from a developing human oocyte or embryo, acquired via a cycle of in vitro fertilization (IVF); evaluating the genetic composition of this sample; and using this information to determine which embryos will be optimal for subsequent uterine transfer. PGD has become an increasingly useful adjunct to IVF procedures. The ability to provide couples who are known carriers of genetic abnormalities the opportunity to deliver healthy babies has opened a new frontier in reproductive medicine. The purpose of the PGD is enables us to choose which embryos will be implanted into the mother. In the present study 137 families who had undergone IVF at Habib Medical Centre, were enrolled for the PGD analysis. The couple visited the clinic for the sex selection, recurrent fetal loss and with the recurrent IVF failure. 802 embryos were tested by the biopsy method and 512 are found to be normal and 290 were abnormal embryos. In this study only 24% of the embryos were transferred and the remaining was not transferred because of the abnormalities or undesired sex of the embryos. The structural and numerical abnormalities were found to be 16.8%. PMID- 23750088 TI - PathAct: a novel method for pathway analysis using gene expression profiles. AB - We developed PathAct, a novel method for pathway analysis to investigate the biological and clinical implications of the gene expression profiles. The advantage of PathAct in comparison with the conventional pathway analysis methods is that it can estimate pathway activity levels for individual patient quantitatively in the form of a pathway-by-sample matrix. This matrix can be used for further analysis such as hierarchical clustering and other analysis methods. To evaluate the feasibility of PathAct, comparison with frequently used gene enrichment analysis methods was conducted using two public microarray datasets. The dataset #1 was that of breast cancer patients, and we investigated pathways associated with triple-negative breast cancer by PathAct, compared with those obtained by gene set enrichment analysis (GSEA). The dataset #2 was another breast cancer dataset with disease-free survival (DFS) of each patient. Contribution by each pathway to prognosis was investigated by our method as well as the Database for Annotation, Visualization and Integrated Discovery (DAVID) analysis. In the dataset #1, four out of the six pathways that satisfied p < 0.05 and FDR < 0.30 by GSEA were also included in those obtained by the PathAct method. For the dataset #2, two pathways ("Cell Cycle" and "DNA replication") out of four pathways by PathAct were commonly identified by DAVID analysis. Thus, we confirmed a good degree of agreement among PathAct and conventional methods. Moreover, several applications of further statistical analyses such as hierarchical cluster analysis by pathway activity, correlation analysis and survival analysis between pathways were conducted. PMID- 23750089 TI - Molecular signaling cascade of miRNAs in causing Diabetes Nephropathy. AB - Diabetic nephropathy (DN) is one of the major microvascular diseases and most common in diabetic patient, finally results in kidney failure. The main features of DN are basement membrane thickening, microalbuminuria, proteinuria, glomerular, mesangial hypertrophy and ECM protein accumulation. Recent discoveries have been shown that numerous pathways are activated during the development of DN in Diabetes mellitus. The small non-coding miRNA plays an important role in regulating the pathway which is involved in DN. In our study we consolidate different pathways which regulated by miRNAs in molecular signaling which results in causing DN. We embedded entire pathway in the form of regulatory network and we could able to understand that some of the miRNAs like miR-29 family, miR-377 and miR-25 would be able to control DN. PMID- 23750090 TI - Binding interactions of porphyrin derivatives with Ca(2+) ATPase of sarcoplasmic reticulum (SERCA1a). AB - The use of Porphyrin derivatives as photosensitizers in Photodynamic Therapy (PDT) was investigated by means of a molecular docking study. These molecules can bind to intracellular targets such as P-type CaCa(2+) ATPase of sarcoplasmic reticulum (SERCA1a). CAChe software was successfully employed for conducting the docking of Tetraphenylporphinesulfonate(TPPS), 5,10,15,20- Tetrakis (4 sulfonatophenyl) porphyrinato Iron(III) Chloride (FeTPPS) and 5,10,15,20-Tetrakis (4-sulfonatophenyl) porphyrinato Iron(III) nitrosyl Chloride (FeNOTPPS) with CaCa(2+) ATPase from sarcoplasmic reticulum of rabbit. The results show that FeNOTPPS forms the most stable complex with CaCa(2+) ATPase. PMID- 23750091 TI - Design of a set of probes with high potential for influenza virus epidemiological surveillance. AB - An Influenza Probe Set (IPS) consisting in 1,249 9-mer probes for genomic fingerprinting of closely and distantly related Influenza Virus strains was designed and tested in silico. The IPS was derived from alignments of Influenza genomes. The RNA segments of 5,133 influenza strains having diverse degree of relatedness were concatenated and aligned. After alignment, 9-mer sites having high Shannon entropy were searched. Additional criteria such as: G+C content between 35 to 65%, absence of dimer or trimer consecutive repeats, a minimum of 2 differences between 9mers and selecting only sequences with Tm values between 34.5 and 36.5oC were applied for selecting probes with high sequential entropy. Virtual Hybridization was used to predict Genomic Fingerprints to assess the capability of the IPS to discriminate between influenza and related strains. Distance scores between pairs of Influenza Genomic Fingerprints were calculated, and used for estimating Taxonomic Trees. Visual examination of both Genomic Fingerprints and Taxonomic Trees suggest that the IPS is able to discriminate between distant and closely related Influenza strains. It is proposed that the IPS can be used to investigate, by virtual or experimental hybridization, any new, and potentially virulent, strain. PMID- 23750092 TI - Isolation and characterization of ethanol tolerant yeast strains. AB - Yeast strains are commonly associated with sugar rich environments. Various fruit samples were selected as source for isolating yeast cells. The isolated cultures were identified at Genus level by colony morphology, biochemical characteristics and cell morphological characters. An attempt has been made to check the viability of yeast cells under different concentrations of ethanol. Ethanol tolerance of each strain was studied by allowing the yeast to grow in liquid YEPD (Yeast Extract Peptone Dextrose) medium having different concentrations of ethanol. A total of fifteen yeast strains isolated from different samples were used for the study. Seven strains of Saccharomyces cerevisiae obtained from different fruit sources were screened for ethanol tolerance. The results obtained in this study show a range of tolerance levels between 7%-12% in all the stains. Further, the cluster analysis based on 22 RAPD (Random Amplified polymorphic DNA) bands revealed polymorphisms in these seven Saccharomyces strains. PMID- 23750093 TI - Binding mode prediction of biologically active compounds from plant Salvia Miltiorrhiza as integrase inhibitor. AB - Integrase (IN), an essential enzyme for HIV-1 replication, has been targeted in antiretroviral drug therapy. The emergence of HIV-1 variants clinically resistant to antiretroviral agents has lead to the development of alternative IN inhibitors. In the present work, binding modes of a high potent IN inhibitor, M522 and M532, within the catalytic binding site of wild type (WT) IN were determined using molecular docking calculation. Both M522 and M532 displayed similar modes of binding within the IN putative binding pocket and exhibited favorable interactions with the catalytic Mg(2+) ions, the nearby amino acids and viral DNA through metal-ligand chelation, hydrogen bonding and pi-pi stacking interactions. Furthermore, the modes of action of these two compounds against the mutated Y212R, N224H and S217H PFV IN were also predicted. Although the replacement of amino acid could somehow disturb inhibitor binding mode, almost key interactions which detected in the WT complexes were fairly conserved. Detailed information could highlight the application of M522 and M532 as candidate IN inhibitors for drug development against drug resistant strains. PMID- 23750094 TI - Aromatic-aromatic interactions: analysis of pi-pi interactions in interleukins and TNF proteins. AB - Aromatic-aromatic hydrogen bonds are important in many areas of chemistry, biology and materials science. In this study we have analyzed the roles played by the pi-pi interactions in interleukins (ILs) and tumor necrosis factor (TNF) proteins. Majority of pi-pi interacting residues are conserved in ILs and TNF proteins. The accessible surface area calculations in these proteins reveal that these interactions might be important in stabilizing the inner core regions of these proteins. In addition to pi-pi interactions, the aromatic residues also form pi-networks in ILs and TNF proteins. The results obtained in the present study indicate that pi-pi interactions and pi-pi networks play important roles in the structural stability of ILs and TNF proteins. PMID- 23750095 TI - Are Deaf Students Visual Learners? AB - It is frequently assumed that by virtue of their hearing losses, deaf students are visual learners. Deaf individuals have some visual-spatial advantages relative to hearing individuals, but most have been are linked to use of sign language rather than auditory deprivation. How such cognitive differences might affect academic performance has been investigated only rarely. This study examined relations among deaf college students' language and visual-spatial abilities, mathematics problem solving, and hearing thresholds. Results extended some previous findings and clarified others. Contrary to what might be expected, hearing students exhibited visual-spatial skills equal to or better than deaf students. Scores on a Spatial Relations task were associated with better mathematics problem solving. Relations among the several variables, however, suggested that deaf students are no more likely to be visual learners than hearing students and that their visual-spatial skill may be related more to their hearing than to sign language skills. PMID- 23750096 TI - Adolescent substance abuse treatment: Organizational change and quality of care. AB - Substance abuse treatment agencies serving youth face unique barriers to providing quality care. Interviews with 17 adolescent programs found that family engagement, community involvement, and gender and diversity issues impacted treatment delivery. Programs report organizational change efforts with implications for future process improvement initiatives. PMID- 23750097 TI - A Lethal Case of Pseudomonas putida Bacteremia Due to Soft Tissue Infection. AB - Pseudomonas putida is an uncommon cause of skin and soft tissue infections. It is often associated with trauma or immunocompromised state. We present the first lethal case of bacteremia due to skin and soft tissue infections, which had malnutrition, immobility, and peripheral vascular disease as risk factors. PMID- 23750098 TI - Should we ask our Children about Sex, Drugs and Rock & Roll?: Potentially Harmful Effects of Asking Questions About Risky Behaviors. AB - Research shows that asking questions can fundamentally change behavior. We review literature on this question-behavior effect, which demonstrates that asking questions changes both normal and risky behaviors. We discuss potential explanations for the effect and review recent findings that reveal interesting moderators of the influence of questions on behavior. We then highlight the potential impact of the question-behavior effect in an important public health context: screening adolescents for risky behavior. While medical guidelines emphasize the importance of asking adolescents questions about substance (drug, alcohol) use and sexual behaviors, research on the question-behavior effect suggests that asking adolescents about risky behaviors has the potential to increase the frequency with which they engage in these behaviors. We argue that the act of screening or measuring risky behavior is potentially counterproductive. We emphasize the importance of interventions beyond screening, and suggest ways in which screening can be carried out to minimize its impact. In short, asking questions about behaviors can change behavior, and asking questions about risky behaviors may itself be a risky undertaking. PMID- 23750099 TI - Crystal structure of a benzimidazole hepatitis C virus inhibitor free and in complex with the viral RNA target. AB - The crystal structure of 8-((dimethylamino)methyl)-1-(3-(dimethylamino)propyl) 1,7,8,9-tetrahydrochromeno[5,6-d]imidazol-2-amine (1), an inhibitor of the hepatitis C virus internal ribosome entry site, is described and compared to the structure of the compound in complex with the viral RNA target. Compound 1 crystallized by pentane vapor diffusion into dichloroethane solution. It crystallized in the monoclinic system, P21/c space group with unit cell parameters a = 15.7950(5) A, b = 14.0128(4) A, c = 8.8147(3) A, beta = 94.357(2) degrees and a cell volume of 1945.34(11) A-3. Packing interactions in the small molecule crystal lattice correspond to key interactions of the compound with the viral RNA target. PMID- 23750100 TI - Is Exercise a Viable Treatment for Depression? AB - Depression is a common disorder that is associated with compromised quality of life, increased health care costs, and greater risk for a variety of medical conditions, particularly coronary heart disease. This review examines methods for assessing depression and discusses current treatment approaches. Traditional treatments include psychotherapy and antidepressant medications, but such treatments are not effective for all patients and alternative approaches have recently received increased attention, especially the use of aerobic exercise. This review examines evidence that exercise is effective in improving depressive symptoms among patients with major depression and offers practical suggestions for helping patients initiate and maintain exercise in their daily lives. PMID- 23750103 TI - Severe hypophosphatemia induced after first cycle of the ESHAP protocol for Hodgkin's lymphoma: a case report. AB - The effect of the ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) salvage protocol on serum electrolytes has been previously reported by individual observational studies. The most commonly described electrolyte affected by the ESHAP protocol is magnesium. In addition, hypophosphatemia has been studied and reported as a complication of cisplatin therapy, although it is usually asymptomatic. This is a case report of a 51-year-old woman with relapsed Hodgkin's lymphoma who developed severe hypophosphatemia following administration of the first cycle of the ESHAP protocol. The patient started to develop gradually decreasing phosphate levels 2 weeks after receiving chemotherapy, which needed to be corrected by phosphate supplementation. This case report raises concern regarding hypophosphatemia as a possible side effect of the ESHAP protocol and points to a need for close monitoring, taking into consideration vitamin D levels, urinary phosphate excretion, parathyroid hormone levels, and arterial blood gas analysis to rule out other contributing factors. Health care providers should be made aware of this possible toxicity. Critical monitoring of phosphate levels and considering supplementation is warranted with the ESHAP protocol, especially when it is used in combination with granulocyte colony stimulating factor and diuretics, to prevent such possible hypophosphatemia. Further investigations may be required to confirm and evaluate the significance of this type of toxicity. PMID- 23750101 TI - Considerations for ceramic inlays in posterior teeth: a review. AB - This review of ceramic inlays in posterior teeth includes a review of the history of ceramic restorations, followed by common indications and contraindications for their use. A discussion on the potential for tooth wear is followed by a review of recommended preparation design considerations, fabrication methods, and material choices. Despite the improved materials available for fabrication of porcelain inlays, fracture remains a primary mode of inlay failure. Therefore, a brief discussion on strengthening methods for ceramics is included. The review concludes with a section on luting considerations, and offers the clinician specific recommendations for luting procedures. In conclusion, inlay success rates and longevity, as reported in the literature, are summarized. PMID- 23750104 TI - Repeated renal infarction in native and transplanted kidneys due to left ventricular thrombus formation caused by antiphospholipid antibody syndrome. AB - Antiphospholipid syndrome can be a feature of several underlying conditions, such as lupus, but it can also occur idiopathically. Diagnosis usually comes after investigation of recurrent venous or arterial thromboses, emboli, or hypertension/proteinuria where the kidney is involved and is usually confirmed by laboratory testing. We describe a case of a man with a myocardial infarction who developed mural thrombus in an akinetic left ventricular segment but then who recurrently embolized first to one of his native kidneys and then later to a transplanted kidney. Although the clinical behavior was typical of antiphospholipid syndrome, it took numerous laboratory assays over many years until finally the problem was confirmed and life-long warfarin therapy instituted. PMID- 23750102 TI - Posterior composite restoration update: focus on factors influencing form and function. AB - Restoring posterior teeth with resin-based composite materials continues to gain popularity among clinicians, and the demand for such aesthetic restorations is increasing. Indeed, the most common aesthetic alternative to dental amalgam is resin composite. Moderate to large posterior composite restorations, however, have higher failure rates, more recurrent caries, and increased frequency of replacement. Investigators across the globe are researching new materials and techniques that will improve the clinical performance, handling characteristics, and mechanical and physical properties of composite resin restorative materials. Despite such attention, large to moderate posterior composite restorations continue to have a clinical lifetime that is approximately one-half that of the dental amalgam. While there are numerous recommendations regarding preparation design, restoration placement, and polymerization technique, current research indicates that restoration longevity depends on several variables that may be difficult for the dentist to control. These variables include the patient's caries risk, tooth position, patient habits, number of restored surfaces, the quality of the tooth-restoration bond, and the ability of the restorative material to produce a sealed tooth-restoration interface. Although clinicians tend to focus on tooth form when evaluating the success and failure of posterior composite restorations, the emphasis must remain on advancing our understanding of the clinical variables that impact the formation of a durable seal at the restoration-tooth interface. This paper presents an update of existing technology and underscores the mechanisms that negatively impact the durability of posterior composite restorations in permanent teeth. PMID- 23750105 TI - Stargadt's disease in two Nigerian siblings. AB - Stargardt's disease is an inherited macular dystrophy that is transmitted in an autosomal recessive or dominant pattern. The disorder is typically characterized by impairment of central vision, with onset around the first 10-20 years of life. Stargardt's disease is rare in sub-Saharan Africa. This is probably the first reported case in the subregion. We present two siblings with the disease. Presentation, pathophysiology, and management modalities are discussed. PMID- 23750106 TI - Spontaneous regression of splenic artery pseudoaneurysm: a rare complication of acute pancreatitis. AB - Spontaneous pseudoaneurysm regression is a rare event. In particular, the spontaneous regression of a splenic artery pseudoaneurysm has, to our knowledge, been previously documented in only two case reports. Furthermore, the pathophysiological mechanism of this event remains unclear. However, it is fully known that this vascular complication is potentially life-threatening and presents a high mortality rate if untreated. We report the case of a 49-year-old man affected by acute pancreatitis. Computed tomography was performed, and showed a pseudoaneurysm of the splenic artery. This patient underwent endoscopic retrograde cholangiopancreatography to treat the pancreatitis, while the vascular complication was managed with a careful and conservative treatment. On day 6 of hospitalization, a second computed tomography scan was performed and revealed complete regression of the pseudoaneurysm. This case describes the diagnosis and management of splenic artery pseudoaneurysm following acute pancreatitis and its spontaneous regression. PMID- 23750107 TI - Hypertension and obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is increasingly being recognized as a major health burden with strong focus on the associated cardiovascular risk. Studies from the last two decades have provided strong evidence for a causal role of OSA in the development of systemic hypertension. The acute physiological changes that occur during apnea promote nocturnal hypertension and may lead to the development of sustained daytime hypertension via the pathways of sympathetic activation, inflammation, oxidative stress, and endothelial dysfunction. This review will focus on the acute hemodynamic disturbances and associated intermittent hypoxia that characterize OSA and the potential pathophysiological mechanisms responsible for the development of hypertension in OSA. In addition the epidemiology of OSA and hypertension, as well as the role of treatment of OSA, in improving blood pressure control will be examined. PMID- 23750108 TI - Oral pressure therapy for treatment of obstructive sleep apnea: clinical feasibility. AB - PURPOSE: This feasibility study examined the initial-use safety and effectiveness of a new noninvasive oral pressure therapy (OPT) system developed to treat obstructive sleep apnea (OSA). METHODS: The OPT system consists of a console that connects with flexible tubing to a premanufactured polymer mouthpiece. Through the mouthpiece, a pump in the console creates oral vacuum intended to move the soft palate anteriorly to decrease obstruction of the airway during sleep. The mouthpiece was produced in ten different sizes to accommodate a range of oral dimensions. Subjects with OSA in this single-center, single-night study underwent a polysomnography (PSG) study at baseline, followed by PSG during use of OPT. RESULTS: Fifty-six men and 20 women, aged 50.8 +/- 12.0 years (mean +/- standard deviation [SD]), had OSA with apnea-hypopnea indices (AHI) greater than five events per hour at baseline. Body weight averaged 98.0 +/- 18.2 kg (mean +/- SD), body mass index ranged from 22.6 kg/m(2) to 57.9 kg/m(2) and averaged 32.5 +/- 5.8 kg/m(2) (mean +/- SD). OPT was generally well tolerated without any serious adverse events. Baseline AHI was 38.7 +/- 27.5 events/hour (mean +/- SD) and was reduced with treatment to 24.6 +/- 25.7 events/hour (P < 0.001, Cohen's d 0.53). Treatment produced AHI less than or equal to ten events/hour in 38% of the subjects. Oxygen desaturation index was 30.1 +/- 23.7 events/hour at baseline versus 15.8 +/- 19.1 events/hour with treatment (P < 0.001, Cohen's d 0.66). The minimum oxygen saturation increased with treatment from 77.9 +/- 8.3 to 82.2 +/- 7.9 (P < 0.001, Cohen's d 0.53). Stage-N1 sleep shifts, total sleep-stage shifts, and awakenings were significantly reduced with treatment. CONCLUSION: This single center, single-night feasibility study demonstrates that OPT can improve OSA in certain subjects identifiable by PSG during systematic usage. In appropriately responsive patients, OPT shows potential as a clinically useful new alternative for treatment of OSA without the need for custom manufacture of an oral device component. PMID- 23750109 TI - New classification of acute papilledema in children with severe malaria. AB - Raised intracranial pressure is a feature of cerebral malaria in children living in Africa. We investigated specific clinical optic disc features of papilledema to establish their prognostic significance in this encephalopathy. We developed a classification of acute papilledema and tested it against disease outcome. Kenyan children admitted with severe falciparum malaria (cerebral or impaired consciousness) underwent dilated fundal examination using direct and indirect ophthalmoscopy. Clinical features of the optic disc were systematically recorded and compared to the child's outcome. Poor outcome defined as death or neurological impairment on discharge was used to construct and test a clinical classification of papilledema. Forty-five children were examined (26 cerebral malaria, 17 severe malaria with an impaired conscious level or prostration) of whom seven had a poor outcome (three died, four had residual neurological impairment). Loss of the optic disc cup and marked optic disc elevation were significantly correlated with a poor outcome (P < 0.05). Increasing severity in the proposed classification of acute papilledema was positively correlated with a poor outcome (P < 0.05, chi-square test for trend). Loss of the optic disc cup and marked elevation of the optic disc head appear to be correlated with poor outcome in children with severe malaria whereas the presence of dilated veins suggests a good outcome. The proposed classification of acute papilledema is useful as a prognostic indicator and may be applicable to other encephalopathies with raised intracranial pressure. PMID- 23750110 TI - A case of bicuspid aortic valve with two raphes. PMID- 23750111 TI - A generalization of Nash's theorem with higher-order functionals. AB - The recent theory of sequential games and selection functions by Escardo & Oliva is extended to games in which players move simultaneously. The Nash existence theorem for mixed-strategy equilibria of finite games is generalized to games defined by selection functions. A normal form construction is given, which generalizes the game-theoretic normal form, and its soundness is proved. Minimax strategies also generalize to the new class of games, and are computed by the Berardi-Bezem-Coquand functional, studied in proof theory as an interpretation of the axiom of countable choice. PMID- 23750112 TI - Regiochemical Reversals in Nitrosobenzene Reactions with Carbonyl Compounds: alpha-Aminooxyketone versus alpha-Hydroxyaminoketone Products. AB - The Lewis acid-catalyzed reaction of nitrosobenzene with a ketone can produce an alpha-aminooxyketones or an alpha-hydroxyaminoketone, with reaction regiochemistry switching from the latter to the former, dependent upon the addition of Lewis acid or sterically-hindered solvent. While the latter (C-N bond formation) is easily explained by attack of the enolate alpha-carbon at N, the former (C-O bond formation) has been an enigma, with few proposed explanations, and none which explain simultaneously formation of both products and all the regiochemical reversals. Herein, the regiochemistry reversal is proposed to occur via (1) nucleophile formation governed by Hard and Soft Acids and Bases (HSAB) theory, (2) a nucleophilic attack by the enolate O at N, followed by (3) a [2,3] sigmatropic rearrangement. This mechanistic pathway and HSAB considerations account for formation of both products and explain the three reported regiochemistry reversals, which are observed upon the introduction of (A) Lewis acid catalyst, (B) AcOH, or (C) solvent bulkiness. PMID- 23750113 TI - Indonesia against the trend? Ageing and inter-generational wealth flows in two Indonesian communities. AB - Indonesian family systems do not conform to the prevailing image of Asian families, the predominant arrangements being nuclear and bilateral, with an important matrilineal minority. This paper considers the strength of family ties in two communities, focussing particularly on inter-generational flows of support to and from older members. Data are drawn from a longitudinal anthropological demography that combines ethnographic and panel survey methods. Several sources of variation in family ties are detailed, particularly the heterogeneity of support flows - balanced, upward, and downward - that co-exist in both communities. Different norms in each locale give sharply contrasting valuations of these flows. The ability of families to observe norms is influenced by the effectiveness of networks and by socio-economic status. PMID- 23750114 TI - Parental Reasoning, Denying Privileges, Yelling, and Spanking: Ethnic Differences and Associations with Child Externalizing Behavior. AB - OBJECTIVE: This study was designed to examine whether African American and European American mothers differ in their discipline use when reasoning, denying privileges, yelling, and spanking are considered simultaneously and whether there are ethnic group differences in how these four forms of discipline are associated with child externalizing behavior. DESIGN: Structural equation models were used to examine relations between children's externalizing behavior in kindergarten (age 5), mothers' discipline in grades 1-3 (ages 6-8), and children's externalizing behavior in grade 4 (age 9) in a sample of 585 mothers and children. RESULTS: African American and European American mothers showed the same rank order frequency of reported use of each of the four forms of discipline, most frequently using reasoning, followed by yelling, denying privileges, and least frequently spanking. However, European American mothers more frequently reported using three of the four forms of discipline than did African American mothers, with no ethnic differences in the frequency with which mothers reported spanked. For European American children, higher levels of teacher-reported child externalizing in kindergarten predicted mothers' more frequent report of denying privileges, yelling, and spanking in grades 1-3; only spanking was associated with more child externalizing behaviors in grade 4. For African American children, teacher-reported child externalizing in kindergarten was unrelated to mothers' report of discipline in grades 1-3; considering predictions from discipline to grade 4 child externalizing, only denying privileges was predictive. CONCLUSIONS: European American and African American families differ in links between children's teacher-reported externalizing behaviors and subsequent mother-reported discipline as well as links between mother-reported discipline and children's subsequent teacher-reported externalizing. PMID- 23750115 TI - Alcoholic Hepatitis: Steroids vs. Pentoxifylline. AB - Alcoholic hepatitis (AH) remains a major cause of liver-related morbidity and mortality in the United States and is actually increasing in certain areas of Europe. Thus, there is a pressing need for new therapies/approaches. Major barriers for reducing morbidity, mortality, and costs of care include: lack of translational animal and human studies of new therapies for AH; limited trials of combination therapies in AH targeted at specific disease mechanisms (e.g., gut permeability, cytokines, oxidative stress); limited studies on non-invasive, non mortality end points; few studies on mechanisms of steroid non-responsiveness; and inadequate prognostic indicators, to name only a few. In spite of these gaps, we have made major advances in understanding mechanisms for AH and appropriate therapies for AH. This article reviews mechanisms and rationale for use of steroids and pentoxifylline in AH and future directions in therapy. PMID- 23750116 TI - Bimodal control of dendritic and axonal growth by the dual leucine zipper kinase pathway. AB - Knowledge of the molecular and genetic mechanisms underlying the separation of dendritic and axonal compartments is not only crucial for understanding the assembly of neural circuits, but also for developing strategies to correct defective dendrites or axons in diseases with subcellular precision. Previous studies have uncovered regulators dedicated to either dendritic or axonal growth. Here we investigate a novel regulatory mechanism that differentially directs dendritic and axonal growth within the same neuron in vivo. We find that the dual leucine zipper kinase (DLK) signaling pathway in Drosophila, which consists of Highwire and Wallenda and controls axonal growth, regeneration, and degeneration, is also involved in dendritic growth in vivo. Highwire, an evolutionarily conserved E3 ubiquitin ligase, restrains axonal growth but acts as a positive regulator for dendritic growth in class IV dendritic arborization neurons in the larva. While both the axonal and dendritic functions of highwire require the DLK kinase Wallenda, these two functions diverge through two downstream transcription factors, Fos and Knot, which mediate the axonal and dendritic regulation, respectively. This study not only reveals a previously unknown function of the conserved DLK pathway in controlling dendrite development, but also provides a novel paradigm for understanding how neuronal compartmentalization and the diversity of neuronal morphology are achieved. PMID- 23750117 TI - Promote one, inhibit the other: a single pathway controls axon and dendrite growth, oppositely. PMID- 23750118 TI - Self-renewal of single mouse hematopoietic stem cells is reduced by JAK2V617F without compromising progenitor cell expansion. AB - Recent descriptions of significant heterogeneity in normal stem cells and cancers have altered our understanding of tumorigenesis, emphasizing the need to understand how single stem cells are subverted to cause tumors. Human myeloproliferative neoplasms (MPNs) are thought to reflect transformation of a hematopoietic stem cell (HSC) and the majority harbor an acquired V617F mutation in the JAK2 tyrosine kinase, making them a paradigm for studying the early stages of tumor establishment and progression. The consequences of activating tyrosine kinase mutations for stem and progenitor cell behavior are unclear. In this article, we identify a distinct cellular mechanism operative in stem cells. By using conditional knock-in mice, we show that the HSC defect resulting from expression of heterozygous human JAK2V617F is both quantitative (reduced HSC numbers) and qualitative (lineage biases and reduced self-renewal per HSC). The defect is intrinsic to individual HSCs and their progeny are skewed toward proliferation and differentiation as evidenced by single cell and transplantation assays. Aged JAK2V617F show a more pronounced defect as assessed by transplantation, but mice that transform reacquire competitive self-renewal ability. Quantitative analysis of HSC-derived clones was used to model the fate choices of normal and JAK2-mutant HSCs and indicates that JAK2V617F reduces self renewal of individual HSCs but leaves progenitor expansion intact. This conclusion is supported by paired daughter cell analyses, which indicate that JAK2-mutant HSCs more often give rise to two differentiated daughter cells. Together these data suggest that acquisition of JAK2V617F alone is insufficient for clonal expansion and disease progression and causes eventual HSC exhaustion. Moreover, our results show that clonal expansion of progenitor cells provides a window in which collaborating mutations can accumulate to drive disease progression. Characterizing the mechanism(s) of JAK2V617F subclinical clonal expansions and the transition to overt MPNs will illuminate the earliest stages of tumor establishment and subclone competition, fundamentally shifting the way we treat and manage cancers. PMID- 23750119 TI - Household air pollution in low- and middle-income countries: health risks and research priorities. PMID- 23750120 TI - Patented drug extension strategies on healthcare spending: a cost-evaluation analysis. AB - BACKGROUND: Drug manufacturers have developed "evergreening" strategies to compete with generic medication after patent termination. These include marketing of slightly modified follow-on drugs. We aimed to estimate the financial impact of these drugs on overall healthcare costs and also to examine the impact of listing these drugs in hospital restrictive drug formularies (RDFs) on the healthcare system as a whole ("spillover effect"). METHODS AND FINDINGS: We used hospital and community pharmacy invoice office data in the Swiss canton of Geneva to calculate utilisation of eight follow-on drugs in defined daily doses between 2000 and 2008. "Extra costs" were calculated for three different scenarios assuming replacement with the corresponding generic equivalent for prescriptions of (1) all brand (i.e., initially patented) drugs, (2) all follow-on drugs, or (3) brand and follow-on drugs. To examine the financial spillover effect we calculated a monthly follow-on drug market share in defined daily doses for medications prescribed by hospital physicians but dispensed in community pharmacies, in comparison to drugs prescribed by non-hospital physicians in the community. Estimated "extra costs" over the study period were ?15.9 (95% CI 15.5; 16.2) million for scenario 1, ?14.4 (95% CI 14.1; 14.7) million for scenario 2, and ?30.3 (95% CI 29.8; 30.8) million for scenario 3. The impact of strictly switching all patients using proton-pump inhibitors to esomeprazole at admission resulted in a spillover "extra cost" of ?330,300 (95% CI 276,100; 383,800), whereas strictly switching to generic cetirizine resulted in savings of ?7,700 (95% CI 4,100; 11,100). Overall we estimated that the RDF resulted in "extra costs" of ?503,600 (95% CI 444,500; 563,100). CONCLUSIONS: Evergreening strategies have been successful in maintaining market share in Geneva, offsetting competition by generics and cost containment policies. Hospitals may be contributing to increased overall healthcare costs by listing follow-on drugs in their RDF. Therefore, healthcare providers and policy makers should be aware of the impact of evergreening strategies. PMID- 23750122 TI - Improvements in Markov State Model Construction Reveal Many Non-Native Interactions in the Folding of NTL9. AB - Markov State Models (MSMs) provide an automated framework to investigate the dynamical properties of high-dimensional molecular simulations. These models can provide a human-comprehensible picture of the underlying process, and have been successfully used to study protein folding, protein aggregation, protein ligand binding, and other biophysical systems. The MSM requires the construction of a discrete state-space such that two points are in the same state if they can interconvert rapidly. In the following, we suggest an improved method, which utilizes second order Independent Components Analysis (also known as time structure based Independent Components Analysis, or tICA), to construct the state space. We apply this method to simulations of NTL9 (provided by Lindorff-Larsen et al. Science2011), and show that the MSM is an improvement over previously built models using conventional distance metrics. Additionally, the resulting model provides insight into the role of non-native contacts by revealing many slow timescales associated with compact, non-native states. PMID- 23750123 TI - An Open Trial of Relapse Prevention Therapy for Smokers With Schizophrenia. AB - OBJECTIVE: Following successful smoking cessation, smokers with schizophrenia are vulnerable to relapse shortly after treatment discontinuation. Our objective was to assess the feasibility and effectiveness of a 12-month relapse prevention intervention in recently abstinent smokers with schizophrenia. METHOD: Adult outpatient smokers with schizophrenia received weekly cognitive behavioral therapy groups, bupropion slow release, transdermal nicotine patch, and nicotine gum or lozenge for three months. Subjects with seven-day point prevalence abstinence at month 3 received an additional 12 months (months 4-15) of therapy with bupropion, transdermal nicotine patch, and nicotine gum/lozenge in conjunction with relapse prevention-based cognitive behavioral therapy groups that were held weekly in month 4, biweekly in months 5-6, and monthly in months 7 15. RESULTS: Seventeen of 41 participants (41.5%) attained biochemically verified self-report of seven-day point prevalence abstinence at the end of three months of treatment and entered relapse prevention treatment. There was an 81% attendance rate at relapse prevention groups. At the end of the 12-month relapse prevention phase (month 15 overall), 11 of 17 (64.7%) demonstrated biochemically verified seven-day point prevalence abstinence, and 10 of 17 (58.8%) reported four-week continuous abstinence. Almost one quarter of the sample (23.5%) demonstrated long-term prolonged abstinence through the end of the trial. There were no clinically detected cases of psychiatric symptom exacerbation. One participant, who was managed as an outpatient, self-reported psychiatric symptom exacerbation in the interim period between study visits. CONCLUSIONS: Extended duration smoking cessation treatment is well-tolerated and may improve smoking outcomes for recently abstinent smokers with schizophrenia. Controlled trials are warranted. PMID- 23750124 TI - Drosophila functional elements are embedded in structurally constrained sequences. AB - Modern functional genomics uncovered numerous functional elements in metazoan genomes. Nevertheless, only a small fraction of the typical non-exonic genome contains elements that code for function directly. On the other hand, a much larger fraction of the genome is associated with significant evolutionary constraints, suggesting that much of the non-exonic genome is weakly functional. Here we show that in flies, local (30-70 bp) conserved sequence elements that are associated with multiple regulatory functions serve as focal points to a pattern of punctuated regional increase in G/C nucleotide frequencies. We show that this pattern, which covers a region tenfold larger than the conserved elements themselves, is an evolutionary consequence of a shift in the balance between gain and loss of G/C nucleotides and that it is correlated with nucleosome occupancy across multiple classes of epigenetic state. Evidence for compensatory evolution and analysis of SNP allele frequencies show that the evolutionary regime underlying this balance shift is likely to be non-neutral. These data suggest that current gaps in our understanding of genome function and evolutionary dynamics are explicable by a model of sparse sequence elements directly encoding for function, embedded into structural sequences that help to define the local and global epigenomic context of such functional elements. PMID- 23750125 TI - Time, self, and intertemporal choice. AB - Neuroscientific studies of intertemporal choice (IC) have focused mainly on the neural representation of self-control mechanisms and valuation. This reflects what has been considered as the core of the IC phenomenon. The claim of this paper is that deviations from exponential reward discounting as a function of time might be fully accounted for by the deviation of subjective time from calendar time. This claim is based on evidence that specificities of time perception can modulate discounting. Consequently, time perception is fundamental to IC and it is crucial to understand the mechanisms underlying time processing in different situations; to investigate when human time perception differs from time as represented by the calendar metric system; and to study how time perception predicts choices. This paper surveys the recent literature on time perception in order to discuss the measuring of IC through time-perception specificities. The notion of self is also discussed within this temporal perspective. If time perception modulates discounting, and time perception is related to self, the relationship between self and time perception becomes a new path to be explored in the IC studies. PMID- 23750121 TI - Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study. AB - BACKGROUND: Although levels of iron are known to be increased in the brains of patients with Parkinson disease (PD), epidemiological evidence on a possible effect of iron blood levels on PD risk is inconclusive, with effects reported in opposite directions. Epidemiological studies suffer from problems of confounding and reverse causation, and mendelian randomization (MR) represents an alternative approach to provide unconfounded estimates of the effects of biomarkers on disease. We performed a MR study where genes known to modify iron levels were used as instruments to estimate the effect of iron on PD risk, based on estimates of the genetic effects on both iron and PD obtained from the largest sample meta analyzed to date. METHODS AND FINDINGS: We used as instrumental variables three genetic variants influencing iron levels, HFE rs1800562, HFE rs1799945, and TMPRSS6 rs855791. Estimates of their effect on serum iron were based on a recent genome-wide meta-analysis of 21,567 individuals, while estimates of their effect on PD risk were obtained through meta-analysis of genome-wide and candidate gene studies with 20,809 PD cases and 88,892 controls. Separate MR estimates of the effect of iron on PD were obtained for each variant and pooled by meta-analysis. We investigated heterogeneity across the three estimates as an indication of possible pleiotropy and found no evidence of it. The combined MR estimate showed a statistically significant protective effect of iron, with a relative risk reduction for PD of 3% (95% CI 1%-6%; p = 0.001) per 10 ug/dl increase in serum iron. CONCLUSIONS: Our study suggests that increased iron levels are causally associated with a decreased risk of developing PD. Further studies are needed to understand the pathophysiological mechanism of action of serum iron on PD risk before recommendations can be made. PMID- 23750126 TI - A process analysis of the CA3 subregion of the hippocampus. AB - From a behavioral perspective, the CA3a,b subregion of the hippocampus plays an important role in the encoding of new spatial information within short-term memory with a duration of seconds and minutes. This can easily be observed in tasks that require rapid encoding, novelty detection, one-trial short-term or working memory, and one-trial cued recall primarily for spatial information. These are tasks that have been assumed to reflect the operations of episodic memory and require interactions between CA3a,b and the dentate gyrus (DG) via mossy fiber inputs into the CA3a,b. The CA3a,b is also important for encoding of spatial information requiring the acquisition of arbitrary and relational associations. All these tasks are assumed to operate within an autoassociative network function of the CA3 region. The CA3a,b also supports retrieval of short term memory information based on a spatial pattern completion process. Based on afferent inputs into CA3a,b from the DG via mossy fibers and afferents from the entorhinal cortex into CA3a,b as well as reciprocal connections with the septum, CA3a,b can bias the process of encoding utilizing the operation of spatial pattern separation and the process of retrieval utilizing the operation of pattern completion. The CA3a,b also supports sequential processing of information in cooperation with CA1 based on the Schaffer collateral output from CA3a,b to CA1. The CA3c function is in part based on modulation of the DG in supporting pattern separation processes. PMID- 23750127 TI - The medial habenula as a regulator of anxiety in adult zebrafish. PMID- 23750128 TI - Age-related similarities and differences in brain activity underlying reversal learning. AB - The ability to update associative memory is an important aspect of episodic memory and a critical skill for social adaptation. Previous research with younger adults suggests that emotional arousal alters brain mechanisms underlying memory updating; however, it is unclear whether this applies to older adults. Given that the ability to update associative information declines with age, it is important to understand how emotion modulates the brain processes underlying memory updating in older adults. The current study investigated this question using reversal learning tasks, where younger and older participants (age ranges 19-35 and 61-78, respectively) learn a stimulus-outcome association and then update their response when contingencies change. We found that younger and older adults showed similar patterns of activation in the frontopolar OFC and the amygdala during emotional reversal learning. In contrast, when reversal learning did not involve emotion, older adults showed greater parietal cortex activity than did younger adults. Thus, younger and older adults show more similarities in brain activity during memory updating involving emotional stimuli than during memory updating not involving emotional stimuli. PMID- 23750130 TI - Visual cues for manual control of headway. AB - The ability to maintain appropriate gaps to objects in one's environment is important when navigating through a three-dimensional world. Previous research has shown that the visual angle subtended by a lead/approaching object and its rate of change are important variables for timing interceptions, collision avoidance, continuous regulation of braking, and manual control of headway. However, investigations of headway maintenance have required participants to maintain a fixed distance headway and have not investigated how information about own-speed is taken into account. In the following experiment, we asked participants to use a joystick to follow computer-simulated lead objects. The results showed that ground texture, following speed, and the size of the lead object had significant effects on both mean following distances and following distance variance. Furthermore, models of the participants' joystick responses provided better fits when it was assumed that the desired visual extent of the lead object would vary over time. Taken together, the results indicate that while information about own-speed is used by controllers to set the desired headway to a lead object, the continuous regulation of headway is influenced primarily by the visual angle of the lead object and its rate of change. The reliance on visual angle, its rate of change, and/or own-speed information also varied depending on the control dynamics of the system. Such findings are consistent with an optimal control criterion that reflects a differential weighting on different sources of information depending on the plant dynamics. As in other judgements of motion in depth, the information used for controlling headway to other objects in the environment varies depending on the constraints of the task and different strategies of control. PMID- 23750129 TI - A review of the neural and behavioral consequences for unitizing emotional and neutral information. AB - A special type of association, called a "unitization," is formed when pieces of information are encoded as a single representation in memory (e.g., "shirt" and "blue" are encoded as a "blue shirt"; Graf and Schacter, 1989) and typically are later reactivated in memory as a single unit, allowing access to the features of multiple related stimuli at once (Bader et al., 2010; Diana et al., 2011). This review examines the neural processes supporting memory for unitizations and how the emotional content of the material may influence unitization. Although associative binding is typically reliant on hippocampal processes and supported by recollection, the first part of this review will present evidence to suggest that when two items are unitized into a single representation, memory for those bound items may be accomplished on the basis of familiarity and without reliance on the hippocampus. The second part of this review discusses how emotion may affect the processes that give rise to unitizations. Emotional information typically receives a mnemonic benefit over neutral information, but the literature is mixed on whether the presence of emotional information impedes or enhances the associative binding of neutral information (reviewed by Mather, 2007). It has been suggested that the way the emotional and neutral details are related together may be critical to whether the neutral details are enhanced or impeded (Mather, 2007; Mather and Sutherland, 2011). We focus on whether emotional arousal aids or inhibits the creation of a unitized representation, presenting preliminary data, and future directions to test empirically the effects of forming and retrieving emotional and neutral unitizations. PMID- 23750132 TI - The value of the dual systems model of adolescent risk-taking. PMID- 23750131 TI - Prognostic and symptomatic aspects of rapid eye movement sleep in a mouse model of posttraumatic stress disorder. AB - Not every individual develops Posttraumatic Stress Disorder (PTSD) after the exposure to a potentially traumatic event. Therefore, the identification of pre existing risk factors and early diagnostic biomarkers is of high medical relevance. However, no objective biomarker has yet progressed into clinical practice. Sleep disturbances represent commonly reported complaints in PTSD patients. In particular, changes in rapid eye movement sleep (REMS) properties are frequently observed in PTSD patients. Here, we examined in a mouse model of PTSD whether (1) mice developed REMS alterations after trauma and (2) whether REMS architecture before and/or shortly after trauma predicted the development of PTSD-like symptoms. We monitored sleep-wake behavior via combined electroencephalogram/electromyogram recordings immediately before (24 h pre), immediately after (0-48 h post) and 2 months after exposure to an electric foot shock in male C57BL/6N mice (n = 15). PTSD-like symptoms, including hyperarousal, contextual, and generalized fear, were assessed 1 month post-trauma. Shocked mice showed early onset and sustained elevation of REMS compared to non-shocked controls. In addition, REMS architecture before trauma was correlated with the intensity of acoustic startle responses, but not contextual fear, 1 month after trauma. Our data suggest REMS as prognostic (pre-trauma) and symptomatic (post trauma) marker of PTSD-like symptoms in mice. Translated to the situation in humans, REMS may constitute a viable, objective, and non-invasive biomarker in PTSD and other trauma-related psychiatric disorders, which could guide pharmacological interventions in humans at high risk. PMID- 23750133 TI - Prefrontal inhibition of threat processing reduces working memory interference. AB - Bottom-up processes can interrupt ongoing cognitive processing in order to adaptively respond to emotional stimuli of high potential significance, such as those that threaten wellbeing. However it is vital that this interference can be modulated in certain contexts to focus on current tasks. Deficits in the ability to maintain the appropriate balance between cognitive and emotional demands can severely impact on day-to-day activities. This fMRI study examined this interaction between threat processing and cognition; 18 adult participants performed a visuospatial working memory (WM) task with two load conditions, in the presence and absence of anxiety induction by threat of electric shock. Threat of shock interfered with performance in the low cognitive load condition; however interference was eradicated under high load, consistent with engagement of emotion regulation mechanisms. Under low load the amygdala showed significant activation to threat of shock that was modulated by high cognitive load. A directed top-down control contrast identified two regions associated with top down control; ventrolateral PFC and dorsal ACC. Dynamic causal modeling provided further evidence that under high cognitive load, top-down inhibition is exerted on the amygdala and its outputs to prefrontal regions. Additionally, we hypothesized that individual differences in a separate, non-emotional top-down control task would predict the recruitment of dorsal ACC and ventrolateral PFC during top-down control of threat. Consistent with this, performance on a separate dichotic listening task predicted dorsal ACC and ventrolateral PFC activation during high WM load under threat of shock, though activation in these regions did not directly correlate with WM performance. Together, the findings suggest that under high cognitive load and threat, top-down control is exerted by dACC and vlPFC to inhibit threat processing, thus enabling WM performance without threat-related interference. PMID- 23750135 TI - Segmenting sign language into motor primitives with Bayesian binning. AB - The endpoint trajectories of human movements fulfill characteristic power laws linking velocity and curvature. The parameters of these power laws typically vary between different segments of longer action sequences. These parameters might thus be exploited for the unsupervised segmentation of actions into movement primitives. For the example of sign language we investigate whether such segments can be identified by Bayesian binning (BB), using a Gaussian observation model whose mean has a polynomial time dependence. We show that this method yields good segmentation and correctly models ground truth kinematics composed of consecutive segments derived from wrist trajectories recorded from users of Israeli Sign Language (ISL). Importantly, polynomial orders between 3 and 5 yield an optimal trade-off between complexity and accuracy of the trajectory approximation, in accordance with the minimum acceleration and minimum jerk models. Comparing the orders of the polynomials best approximating natural kinematics against those needed to fit the power law ground truth data suggests that kinematic properties not compatible with power laws are also not adequately represented by low order polynomials and require higher order polynomials for a good approximation. PMID- 23750134 TI - Desynchronization boost by non-uniform coordinated reset stimulation in ensembles of pulse-coupled neurons. AB - Several brain diseases are characterized by abnormal neuronal synchronization. Desynchronization of abnormal neural synchrony is theoretically compelling because of the complex dynamical mechanisms involved. We here present a novel type of coordinated reset (CR) stimulation. CR means to deliver phase resetting stimuli at different neuronal sub-populations sequentially, i.e., at times equidistantly distributed in a stimulation cycle. This uniform timing pattern seems to be intuitive and actually applies to the neural network models used for the study of CR so far. CR resets the population to an unstable cluster state from where it passes through a desynchronized transient, eventually resynchronizing if left unperturbed. In contrast, we show that the optimal stimulation times are non-uniform. Using the model of weakly pulse-coupled neurons with phase response curves, we provide an approach that enables to determine optimal stimulation timing patterns that substantially maximize the desynchronized transient time following the application of CR stimulation. This approach includes an optimization search for clusters in a low-dimensional pulse coupled map. As a consequence, model-specific non-uniformly spaced cluster states cause considerably longer desynchronization transients. Intriguingly, such a desynchronization boost with non-uniform CR stimulation can already be achieved by only slight modifications of the uniform CR timing pattern. Our results suggest that the non-uniformness of the stimulation times can be a medically valuable parameter in the calibration procedure for CR stimulation, where the latter has successfully been used in clinical and pre-clinical studies for the treatment of Parkinson's disease and tinnitus. PMID- 23750136 TI - Schizophrenia: one coat of many colors. PMID- 23750137 TI - The Plasticity of Extinction: Contribution of the Prefrontal Cortex in Treating Addiction through Inhibitory Learning. AB - Theories of drug addiction that incorporate various concepts from the fields of learning and memory have led to the idea that classical and operant conditioning principles underlie the compulsiveness of addictive behaviors. Relapse often results from exposure to drug-associated cues, and the ability to extinguish these conditioned behaviors through inhibitory learning could serve as a potential therapeutic approach for those who suffer from addiction. This review will examine the evidence that extinction learning alters neuronal plasticity in specific brain regions and pathways. In particular, subregions of the prefrontal cortex (PFC) and their projections to other brain regions have been shown to differentially modulate drug-seeking and extinction behavior. Additionally, there is a growing body of research demonstrating that manipulation of neuronal plasticity can alter extinction learning. Therefore, the ability to alter plasticity within areas of the PFC through pharmacological manipulation could facilitate the acquisition of extinction and provide a novel intervention to aid in the extinction of drug-related memories. PMID- 23750139 TI - Neurofunctional underpinnings of audiovisual emotion processing in teens with autism spectrum disorders. AB - Despite successful performance on some audiovisual emotion tasks, hypoactivity has been observed in frontal and temporal integration cortices in individuals with autism spectrum disorders (ASD). Little is understood about the neurofunctional network underlying this ability in individuals with ASD. Research suggests that there may be processing biases in individuals with ASD, based on their ability to obtain meaningful information from the face and/or the voice. This functional magnetic resonance imaging study examined brain activity in teens with ASD (n = 18) and typically developing controls (n = 16) during audiovisual and unimodal emotion processing. Teens with ASD had a significantly lower accuracy when matching an emotional face to an emotion label. However, no differences in accuracy were observed between groups when matching an emotional voice or face-voice pair to an emotion label. In both groups brain activity during audiovisual emotion matching differed significantly from activity during unimodal emotion matching. Between-group analyses of audiovisual processing revealed significantly greater activation in teens with ASD in a parietofrontal network believed to be implicated in attention, goal-directed behaviors, and semantic processing. In contrast, controls showed greater activity in frontal and temporal association cortices during this task. These results suggest that in the absence of engaging integrative emotional networks during audiovisual emotion matching, teens with ASD may have recruited the parietofrontal network as an alternate compensatory system. PMID- 23750140 TI - A cross-species study of gesture and its role in symbolic development: implications for the gestural theory of language evolution. AB - Using a naturalistic video database, we examined whether gestures scaffold the symbolic development of a language-enculturated chimpanzee, a language enculturated bonobo, and a human child during the second year of life. These three species constitute a complete clade: species possessing a common immediate ancestor. A basic finding was the functional and formal similarity of many gestures between chimpanzee, bonobo, and human child. The child's symbols were spoken words; the apes' symbols were lexigrams - non-iconic visual signifiers. A developmental pattern in which gestural representation of a referent preceded symbolic representation of the same referent appeared in all three species (but was statistically significant only for the child). Nonetheless, across species, the ratio of symbol to gesture increased significantly with age. But even though their symbol production increased, the apes continued to communicate more frequently by gesture than by symbol. In contrast, by 15-18 months of age, the child used symbols more frequently than gestures. This ontogenetic sequence from gesture to symbol, present across the clade but more pronounced in child than ape, provides support for the role of gesture in language evolution. In all three species, the overwhelming majority of gestures were communicative (i.e., paired with eye contact, vocalization, and/or persistence). However, vocalization was rare for the apes, but accompanied the majority of the child's communicative gestures. This species difference suggests the co-evolution of speech and gesture after the evolutionary divergence of the hominid line. Multimodal expressions of communicative intent (e.g., vocalization plus persistence) were normative for the child, but less common for the apes. This species difference suggests that multimodal expression of communicative intent was also strengthened after hominids diverged from apes. PMID- 23750138 TI - The computational anatomy of psychosis. AB - This paper considers psychotic symptoms in terms of false inferences or beliefs. It is based on the notion that the brain is an inference machine that actively constructs hypotheses to explain or predict its sensations. This perspective provides a normative (Bayes-optimal) account of action and perception that emphasizes probabilistic representations; in particular, the confidence or precision of beliefs about the world. We will consider hallucinosis, abnormal eye movements, sensory attenuation deficits, catatonia, and delusions as various expressions of the same core pathology: namely, an aberrant encoding of precision. From a cognitive perspective, this represents a pernicious failure of metacognition (beliefs about beliefs) that can confound perceptual inference. In the embodied setting of active (Bayesian) inference, it can lead to behaviors that are paradoxically more accurate than Bayes-optimal behavior. Crucially, this normative account is accompanied by a neuronally plausible process theory based upon hierarchical predictive coding. In predictive coding, precision is thought to be encoded by the post-synaptic gain of neurons reporting prediction error. This suggests that both pervasive trait abnormalities and florid failures of inference in the psychotic state can be linked to factors controlling post synaptic gain - such as NMDA receptor function and (dopaminergic) neuromodulation. We illustrate these points using biologically plausible simulations of perceptual synthesis, smooth pursuit eye movements and attribution of agency - that all use the same predictive coding scheme and pathology: namely, a reduction in the precision of prior beliefs, relative to sensory evidence. PMID- 23750141 TI - When Language Switching has No Apparent Cost: Lexical Access in Sentence Context. AB - We report two experiments that investigate the effects of sentence context on bilingual lexical access in Spanish and English. Highly proficient Spanish English bilinguals read sentences in Spanish and English that included a marked word to be named. The word was either a cognate with similar orthography and/or phonology in the two languages, or a matched non-cognate control. Sentences appeared in one language alone (i.e., Spanish or English) and target words were not predictable on the basis of the preceding semantic context. In Experiment 1, we mixed the language of the sentence within a block such that sentences appeared in an alternating run in Spanish or in English. These conditions partly resemble normally occurring inter-sentential code-switching. In these mixed-language sequences, cognates were named faster than non-cognates in both languages. There were no effects of switching the language of the sentence. In Experiment 2, with Spanish-English bilinguals matched closely to those who participated in the first experiment, we blocked the language of the sentences to encourage language specific processes. The results were virtually identical to those of the mixed language experiment. In both cases, target cognates were named faster than non cognates, and the magnitude of the effect did not change according to the broader context. Taken together, the results support the predictions of the Bilingual Interactive Activation + Model (Dijkstra and van Heuven, 2002) in demonstrating that bilingual lexical access is language non-selective even under conditions in which language-specific cues should enable selective processing. They also demonstrate that, in contrast to lexical switching from one language to the other, inter-sentential code-switching of the sort in which bilinguals frequently engage, imposes no significant costs to lexical processing. PMID- 23750142 TI - Detection is unaffected by the deployment of focal attention. AB - There has been much debate regarding how much information humans can extract from their environment without the use of limited attentional resources. In a recent study, Theeuwes et al. (2008) argued that even detection of simple feature targets is not possible without selection by focal attention. Supporting this claim, they found response time (RT) benefits in a simple feature (color) detection task when a target letter's identity was repeated on consecutive trials, suggesting that the letter was selected by focal attention and identified prior to detection. This intertrial repetition benefit remained even when observers were required to simultaneously identify a central digit. However, we found that intertrial repetition benefits disappeared when a simple color target was presented among a heterogeneously (rather than homogeneously) colored set of distractors, thus reducing its bottom-up salience. Still, detection performance remained high. Thus, detection performance was unaffected by whether a letter was focally attended and identified prior to detection or not. Intertrial identity repetition benefits also disappeared when observers were required to perform a simultaneous, attention-demanding central task (Experiment 2), or when unfamiliar Chinese characters were used (Experiment 3). Together, these results suggest that while shifts of focal attention can be affected by target salience, by the availability of excess cognitive resources, and by target familiarity, detection performance itself is unaffected by these manipulations and is thus unaffected by the deployment of focal attention. PMID- 23750143 TI - A dynamical systems account of sensorimotor contingencies. AB - According to the sensorimotor approach, perception is a form of embodied know how, constituted by lawful regularities in the sensorimotor flow or in sensorimotor contingencies (SMCs) in an active and situated agent. Despite the attention that this approach has attracted, there have been few attempts to define its core concepts formally. In this paper, we examine the idea of SMCs and argue that its use involves notions that need to be distinguished. We introduce four distinct kinds of SMCs, which we define operationally. These are the notions of sensorimotor environment (open-loop motor-induced sensory variations), sensorimotor habitat (closed-loop sensorimotor trajectories), sensorimotor coordination (reliable sensorimotor patterns playing a functional role), and sensorimotor strategy (normative organization of sensorimotor coordinations). We make use of a minimal dynamical model of visually guided categorization to test the explanatory value of the different kinds of SMCs. Finally, we discuss the impact of our definitions on the conceptual development and empirical as well as model-based testing of the claims of the sensorimotor approach. PMID- 23750144 TI - On the Acoustics of Emotion in Audio: What Speech, Music, and Sound have in Common. AB - WITHOUT DOUBT, THERE IS EMOTIONAL INFORMATION IN ALMOST ANY KIND OF SOUND RECEIVED BY HUMANS EVERY DAY: be it the affective state of a person transmitted by means of speech; the emotion intended by a composer while writing a musical piece, or conveyed by a musician while performing it; or the affective state connected to an acoustic event occurring in the environment, in the soundtrack of a movie, or in a radio play. In the field of affective computing, there is currently some loosely connected research concerning either of these phenomena, but a holistic computational model of affect in sound is still lacking. In turn, for tomorrow's pervasive technical systems, including affective companions and robots, it is expected to be highly beneficial to understand the affective dimensions of "the sound that something makes," in order to evaluate the system's auditory environment and its own audio output. This article aims at a first step toward a holistic computational model: starting from standard acoustic feature extraction schemes in the domains of speech, music, and sound analysis, we interpret the worth of individual features across these three domains, considering four audio databases with observer annotations in the arousal and valence dimensions. In the results, we find that by selection of appropriate descriptors, cross-domain arousal, and valence regression is feasible achieving significant correlations with the observer annotations of up to 0.78 for arousal (training on sound and testing on enacted speech) and 0.60 for valence (training on enacted speech and testing on music). The high degree of cross-domain consistency in encoding the two main dimensions of affect may be attributable to the co-evolution of speech and music from multimodal affect bursts, including the integration of nature sounds for expressive effects. PMID- 23750145 TI - The functional role of the periphery in emotional language comprehension. AB - Language can impact emotion, even when it makes no reference to emotion states. For example, reading sentences with positive meanings ("The water park is refreshing on the hot summer day") induces patterns of facial feedback congruent with the sentence emotionality (smiling), whereas sentences with negative meanings induce a frown. Moreover, blocking facial afference with botox selectively slows comprehension of emotional sentences. Therefore, theories of cognition should account for emotion-language interactions above the level of explicit emotion words, and the role of peripheral feedback in comprehension. For this special issue exploring frontiers in the role of the body and environment in cognition, we propose a theory in which facial feedback provides a context sensitive constraint on the simulation of actions described in language. Paralleling the role of emotions in real-world behavior, our account proposes that (1) facial expressions accompany sudden shifts in wellbeing as described in language; (2) facial expressions modulate emotional action systems during reading; and (3) emotional action systems prepare the reader for an effective simulation of the ensuing language content. To inform the theory and guide future research, we outline a framework based on internal models for motor control. To support the theory, we assemble evidence from diverse areas of research. Taking a functional view of emotion, we tie the theory to behavioral and neural evidence for a role of facial feedback in cognition. Our theoretical framework provides a detailed account that can guide future research on the role of emotional feedback in language processing, and on interactions of language and emotion. It also highlights the bodily periphery as relevant to theories of embodied cognition. PMID- 23750146 TI - U-shaped development: an old but unsolved problem. AB - Even today the investigation of U-shaped functions in human development is of considerable importance for different domains of Developmental Psychology. More and more scientific researchers focus their efforts on the challenge to describe and explain the phenomenon by identifying those skills and abilities being affected. The impact of U-shaped functions on diagnostic decision-making and on therapeutic treatment programs highlights the importance of understanding the nature of non-monotonic development. The present article therefore addresses the relevant questions of how U-shaped functions are defined in theory, in which developmental domains such non-monotonic growth curves are suggested to occur, and which implications there are for future methodology and diagnostic practice. Finally, it is recommended to clearly identify those interactions between proximal and distal subcomponents which are expected to contribute to a U-shaped development. PMID- 23750147 TI - On defining quantifying and measuring the SNARC effect. PMID- 23750148 TI - The role of self-blaming moral emotions in major depression and their impact on social-economical decision making. AB - People with major depressive disorder (MDD) are more prone to experiencing moral emotions related to self-blame, such as guilt and shame. DSM-IV-TR recognizes excessive or inappropriate guilt as one of the core symptoms of current MDD, whereas excessive shame is not part of the criteria for MDD. However, previous studies specifically assessing shame suggested its involvement in MDD. In the first part of this review, we will consider literature discussing the role of self-blaming moral emotions in MDD. These self-blaming moral emotions have been purported to influence people when they make social and financial decisions in cognitive studies, particularly those using neuroeconomical paradigms. Such paradigms aim to predict social behavior in activities of daily living, by using important resource tangibles (especially money) in laboratory conditions. Previous literature suggests that guilt promotes altruistic behavior via acting out reparative tendencies, whereas shame reduces altruism by means of increasing social and interpersonal distance. In the second part of this review, we will discuss the potential influence of self-blaming moral emotions on overt behavior in MDD, reviewing clinical and experimental studies in social and financial decision-making, in which guilt, and shame were manipulated. This is not a well established area in the depression literature, however in this opinion paper we will argue that studies of moral emotions and their impact on behavioral decision making are of potential importance in the clinical field, by linking specific symptoms of a disorder to a behavioral outcome which may lead to stratification of clinical diagnoses in the future. PMID- 23750149 TI - Magnetic resonance imaging to visualize stroke and characterize stroke recovery: a review. AB - The global burden of stroke continues to grow. Although stroke prevention strategies (e.g., medications, diet, and exercise) can contribute to risk reduction, options for acute interventions (e.g., thrombolytic therapy for ischemic stroke) are limited to the minority of patients. The remaining patients are often left with profound neurological disabilities that substantially impact quality of life, economic productivity, and increase caregiver burden. In the last decade, however, the future outlook for such patients has been tempered by movement toward the view that the brain is capable of reorganizing after injury. Many now view brain recovery after stroke as an area of scientific research with large potential for therapeutic advances, far into the future (Broderick and William, 2004). As a probe of brain anatomy, function and physiology, magnetic resonance imaging (MRI) is a non-invasive and highly versatile modality that promises to play a particularly important role in such research. Here we provide a basic review of MRI physical principles and applications for assessing stroke, looking toward the future role MRI may play in improving stroke rehabilitation methods and stroke recovery. PMID- 23750151 TI - Alzheimer's disease diagnosis by detecting exogenous fluorescent signal of ligand bound to Beta amyloid in the lens of human eye: an exploratory study. AB - We report results of a clinical exploratory human trial involving 10 participants using a combination of a fluorescent ligand and a laser scanning device, SAPPHIRE System, as an aid in the diagnosis of Probable Alzheimer's disease (AD). To the best of our knowledge, this is the first time that such a technique has been used in vivo of a human lens. The primary goal of the clinical trial, in addition to safety assessment, was to evaluate efficacy of the system. By detecting specific fluorescent signature of ligand bound beta amyloid in the supranucleus (SN) region of the human lens, a twofold differentiation factor between AD patients and Control groups is achieved. Data from our studies indicates that deeper regions of the SN provide the highest measures of ligand bound fluorescence signal from both controls and patients with AD. In addition, we present preclinical studies that were performed to investigate the binding affinity of the ligand to beta amyloid and evaluate the pharmacokinetics of the ligand in rabbit eyes. Further studies are underway involving a larger population for statistical evaluation of the method. PMID- 23750150 TI - Integration of proteomics, bioinformatics, and systems biology in traumatic brain injury biomarker discovery. AB - Traumatic brain injury (TBI) is a major medical crisis without any FDA-approved pharmacological therapies that have been demonstrated to improve functional outcomes. It has been argued that discovery of disease-relevant biomarkers might help to guide successful clinical trials for TBI. Major advances in mass spectrometry (MS) have revolutionized the field of proteomic biomarker discovery and facilitated the identification of several candidate markers that are being further evaluated for their efficacy as TBI biomarkers. However, several hurdles have to be overcome even during the discovery phase which is only the first step in the long process of biomarker development. The high-throughput nature of MS based proteomic experiments generates a massive amount of mass spectral data presenting great challenges in downstream interpretation. Currently, different bioinformatics platforms are available for functional analysis and data mining of MS-generated proteomic data. These tools provide a way to convert data sets to biologically interpretable results and functional outcomes. A strategy that has promise in advancing biomarker development involves the triad of proteomics, bioinformatics, and systems biology. In this review, a brief overview of how bioinformatics and systems biology tools analyze, transform, and interpret complex MS datasets into biologically relevant results is discussed. In addition, challenges and limitations of proteomics, bioinformatics, and systems biology in TBI biomarker discovery are presented. A brief survey of researches that utilized these three overlapping disciplines in TBI biomarker discovery is also presented. Finally, examples of TBI biomarkers and their applications are discussed. PMID- 23750152 TI - Spike dynamic and epigenetic malfunctions in epilepsy: a tale of two codes. PMID- 23750153 TI - The Glutamate-Glutamine (GABA) Cycle: Importance of Late Postnatal Development and Potential Reciprocal Interactions between Biosynthesis and Degradation. AB - The gold standard for studies of glutamate-glutamine (GABA) cycling and its connections to brain biosynthesis from glucose of glutamate and GABA and their subsequent metabolism are the elegant in vivo studies by (13)C magnetic resonance spectroscopy (NMR), showing the large fluxes in the cycle. However, simpler experiments in intact brain tissue (e.g., immunohistochemistry), brain slices, cultured brain cells, and mitochondria have also made important contributions to the understanding of details, mechanisms, and functional consequences of glutamate/GABA biosynthesis and degradation. The purpose of this review is to attempt to integrate evidence from different sources regarding (i) the enzyme(s) responsible for the initial conversion of alpha-ketoglutarate to glutamate; (ii) the possibility that especially glutamate oxidation is essentially confined to astrocytes; and (iii) the ontogenetically very late onset and maturation of glutamine-glutamate (GABA) cycle function. Pathway models based on the functional importance of aspartate for glutamate synthesis suggest the possibility of interacting pathways for biosynthesis and degradation of glutamate and GABA and the use of transamination as the default mechanism for initiation of glutamate oxidation. The late development and maturation are related to the late cortical gliogenesis and convert brain cortical function from being purely neuronal to becoming neuronal-astrocytic. This conversion is associated with huge increases in energy demand and production, and the character of potentially incurred gains of function are discussed. These may include alterations in learning mechanisms, in mice indicated by lack of pairing of odor learning with aversive stimuli in newborn animals but the development of such an association 10-12 days later. The possibility is suggested that analogous maturational changes may contribute to differences in the way learning is accomplished in the newborn human brain and during later development. PMID- 23750154 TI - Epigenetic control of gonadotropin releasing hormone neurons. AB - Epigenetic modifications to the genome, including DNA methylation and histone modifications, occur in response to external stimuli. Reproductive function is highly sensitive to environmental conditions including season, diet, hormonal changes, and exposure to chemical contaminants. GnRH neurons, which play a key role in reproduction, are particularly sensitive to various environmental stimuli. We recently reported that the rhesus monkey GnRH gene exhibits distinct epigenetic changes during embryonic development. More recently, we further found that a similar epigenetic phenomenon occurs across puberty. In this article we highlight recent findings, including those of afferent inputs, to describe the epigenetic control of GnRH circuit development as a link between the environment and reproductive function. PMID- 23750155 TI - Contrasting activity patterns determined by BrdU incorporation in bacterial ribotypes from the Arctic Ocean in winter. AB - The winter Arctic Ocean is one of the most unexplored marine environments from a microbiological perspective. Heterotrophic bacteria maintain their activity at a baseline level during the extremely low-energy conditions of the winter, but little is known about the specific phylotypes that have the potential to survive and grow in such harsh environment. In this study, we aimed at identifying actively growing ribotypes in winter Arctic Ocean seawater cultures by experimental incubations with the thymidine analog bromodeoxyuridine (BrdU), followed by immunocapturing, terminal restriction fragment length polymorphism fingerprinting, cloning, and sequencing the 16S rRNA gene. We incubated water collected at different months over the Arctic winter and showed that the actively growing bacterial fraction, taking up BrdU, represented only a subset of the total community. Among the BrdU-labeled bacterial taxa we identified the Flavobacteria Polaribacter, the Alphaproteobacteria SAR11, the Gammaproteobacteria Arctic 96B-16 cluster and, predominately, members of Colwellia spp. Interestingly, Colwellia sequences formed three clusters (93 and 97% pairwise 16S rRNA identity) that contributed in contrasting ways to the active communities in the incubations. Polaribacter, Arctic 96B-16 and one cluster of Colwellia were more abundant in the active community represented by the BrdU-labeled DNA. In contrast, SAR11 and two other Colwellia clusters were underrepresented in the BrdU-labeled community compared to total communities. Despite the limitation of the long incubations needed to label slow growing arctic communities, the BrdU approach revealed the potential for active growth in low-energy conditions in some relevant groups of polar bacteria, including Polaribacter and Arctic 96B-16. Moreover, under similar incubation conditions, the growth of different Colwellia ribotypes varied, suggesting that related clusters of Colwellia may have distinct metabolic features. PMID- 23750156 TI - Contrasting genomic properties of free-living and particle-attached microbial assemblages within a coastal ecosystem. AB - The Columbia River (CR) is a powerful economic and environmental driver in the US Pacific Northwest. Microbial communities in the water column were analyzed from four diverse habitats: (1) an estuarine turbidity maximum (ETM), (2) a chlorophyll maximum of the river plume, (3) an upwelling-associated hypoxic zone, and (4) the deep ocean bottom. Three size fractions, 0.1-0.8, 0.8-3, and 3-200 MUm were collected for each habitat in August 2007, and used for DNA isolation and 454 sequencing, resulting in 12 metagenomes of >5 million reads (>1.6 Gbp). To characterize the dominant microorganisms and metabolisms contributing to coastal biogeochemistry, we used predicted peptide and rRNA data. The 3- and 0.8 MUm metagenomes, representing particulate fractions, were taxonomically diverse across habitats. The 3-MUm size fractions contained a high abundance of eukaryota with diatoms dominating the hypoxic water and plume, while cryptophytes were more abundant in the ETM. The 0.1-MUm metagenomes represented mainly free-living bacteria and archaea. The most abundant archaeal hits were observed in the deep ocean and hypoxic water (19% of prokaryotic peptides in the 0.1-MUm metagenomes), and were homologous to Nitrosopumilus maritimus (ammonia-oxidizing Thaumarchaeota). Bacteria dominated metagenomes of all samples. In the euphotic zone (estuary, plume and hypoxic ocean), the most abundant bacterial taxa (>=40% of prokaryotic peptides) represented aerobic photoheterotrophs. In contrast, the low-oxygen, deep water metagenome was enriched with sequences for strict and facultative anaerobes. Interestingly, many of the same anaerobic bacterial families were enriched in the 3-MUm size fraction of the ETM (2-10X more abundant relative to the 0.1-MUm metagenome), indicating possible formation of anoxic microniches within particles. Results from this study provide a metagenome perspective on ecosystem-scale metabolism in an upwelling-influenced river dominated coastal margin. PMID- 23750157 TI - Effect of subtherapeutic vs. therapeutic administration of macrolides on antimicrobial resistance in Mannheimia haemolytica and enterococci isolated from beef cattle. AB - Macrolides are the first-line treatment against bovine respiratory disease (BRD), and are also used to treat infections in humans. The macrolide, tylosin phosphate, is often included in the diet of cattle as a preventative for liver abscesses in many regions of the world outside of Europe. This study investigated the effects of administering macrolides to beef cattle either systemically through a single subcutaneous injection (therapeutic) or continuously in-feed (subtherapeutic), on the prevalence and antimicrobial resistance of Mannheimia haemolytica and Enterococcus spp. isolated from the nasopharynx and faeces, respectively. Nasopharyngeal and faecal samples were collected weekly over 28 days from untreated beef steers and from steers injected once with tilmicosin or tulathromycin or continuously fed tylosin phosphate at dosages recommended by manufacturers. Tilmicosin and tulathromycin were effective in lowering (P < 0.05) the prevalence of M. haemolytica, whereas subtherapeutic tylosin had no effect. M. haemolytica isolated from control- and macrolide-treated animals were susceptible to macrolides as well as to other antibiotics. Major bacteria co isolated with M. haemolytica from the nasopharynx included Pasteurella multocida, Staphylococcus spp., Acinetobacter spp., Escherichia coli and Bacillus spp. With the exception of M. haemolytica and P. multocida, erythromycin resistance was frequently found in other isolated species. Both methods of macrolide administration increased (P < 0.05) the proportion of erythromycin resistant enterococci within the population, which was comprised almost exclusively of Enterococcus hirae. Injectable macrolides impacted both respiratory and enteric microbes, whereas orally administered macrolides only influenced enteric bacteria. PMID- 23750158 TI - Biophysical description of multiple events contributing blood leukocyte arrest on endothelium. AB - Blood leukocytes have a remarkable capacity to bind to and stop on specific blood vessel areas. Many studies have disclosed a key role of integrin structural changes following the interaction of rolling leukocytes with surface-bound chemoattractants. However, the functional significance of structural data and mechanisms of cell arrest are incompletely understood. Recent experiments revealed the unexpected complexity of several key steps of cell-surface interaction: (i) ligand-receptor binding requires a minimum amount of time to proceed and this is influenced by forces. (ii) Also, molecular interactions at interfaces are not fully accounted for by the interaction properties of soluble molecules. (iii) Cell arrest depends on nanoscale topography and mechanical properties of the cell membrane, and these properties are highly dynamic. Here, we summarize these results and we discuss their relevance to recent functional studies of integrin-receptor association in cells from a patient with type III leukocyte adhesion deficiency. It is concluded that an accurate understanding of all physical events listed in this review is needed to unravel the precise role of the multiple molecules and biochemical pathway involved in arrest triggering. PMID- 23750160 TI - Of creatures great and small: the advantages of farm animal models in immunology research. PMID- 23750159 TI - Immunogenetics: Genome-Wide Association of Non-Progressive HIV and Viral Load Control: HLA Genes and Beyond. AB - Very early after the identification of the human immunodeficiency virus (HIV), host genetics factors were anticipated to play a role in viral control and disease progression. As early as the mid-1990s, candidate gene studies demonstrated a central role for the chemokine co-receptor/ligand (e.g., CCR5) and human leukocyte antigen (HLA) systems. In the last decade, the advent of genome wide arrays opened a new era for unbiased genetic exploration of the genome and brought big expectations for the identification of new unexpected genes and pathways involved in HIV/AIDS. More than 15 genome-wide association studies targeting various HIV-linked phenotypes have been published since 2007. Surprisingly, only the two HIV-chemokine co-receptors and HLA loci have exhibited consistent and reproducible statistically significant genetic associations. In this chapter, we will review the findings from the genome-wide studies focusing especially on non-progressive and HIV control phenotypes, and discuss the current perspectives. PMID- 23750161 TI - Disruption of a rice gene for alpha-glucan water dikinase, OsGWD1, leads to hyperaccumulation of starch in leaves but exhibits limited effects on growth. AB - To identify potential regulators of photoassimilate partitioning, we screened for rice mutant plants that accumulate high levels of starch in the leaf blades, and a mutant line leaf starch excess 1 (LSE1) was obtained and characterized. The starch content in the leaf blades of LSE1 was more than 10-fold higher than that in wild-type plants throughout the day, while the sucrose content was unaffected. The gene responsible for the LSE1 phenotype was identified by gene mapping to be a gene encoding alpha-glucan water dikinase, OsGWD1 (Os06g0498400), and a 3.4-kb deletion of the gene was found in the mutant plant. Despite the hyperaccumulation of starch in their leaf blades, LSE1 plants exhibited no significant change in vegetative growth, presenting a clear contrast to the reported mutants of Arabidopsis thaliana and Lotus japonicus in which disruption of the genes for alpha-glucan water dikinase leads to marked inhibition of vegetative growth. In reproductive growth, however, LSE1 exhibited fewer panicles per plant, lower percentage of ripened grains and smaller grains; consequently, the grain yield was lower in LSE1 plants than in wild-type plants by 20~40%. Collectively, although alpha-glucan water dikinase was suggested to have universal importance in leaf starch degradation in higher plants, the physiological priority of leaf starch in photoassimilate allocation may vary among plant species. PMID- 23750162 TI - Iron biofortification of myanmar rice. AB - Iron (Fe) deficiency elevates human mortality rates, especially in developing countries. In Myanmar, the prevalence of Fe-deficient anemia in children and pregnant women are 75 and 71%, respectively. Myanmar people have one of the highest per capita rice consumption rates globally. Consequently, production of Fe-biofortified rice would likely contribute to solving the Fe-deficiency problem in this human population. To produce Fe-biofortified Myanmar rice by transgenic methods, we first analyzed callus induction and regeneration efficiencies in 15 varieties that are presently popular because of their high-yields or high qualities. Callus formation and regeneration efficiency in each variety was strongly influenced by types of culture media containing a range of 2,4 dichlorophenoxyacetic acid concentrations. The Paw San Yin variety, which has a high-Fe content in polished seeds, performed well in callus induction and regeneration trials. Thus, we transformed this variety using a gene expression cassette that enhanced Fe transport within rice plants through overexpression of the nicotianamine synthase gene HvNAS1, Fe flow to the endosperm through the Fe(II)-nicotianamine transporter gene OsYSL2, and Fe accumulation in endosperm by the Fe storage protein gene SoyferH2. A line with a transgene insertion was successfully obtained. Enhanced expressions of the introduced genes OsYSL2, HvNAS1, and SoyferH2 occurred in immature T2 seeds. The transformants accumulated 3.4-fold higher Fe concentrations, and also 1.3-fold higher zinc concentrations in T2 polished seeds compared to levels in non-transgenic rice. This Fe biofortified rice has the potential to reduce Fe-deficiency anemia in millions of Myanmar people without changing food habits and without introducing additional costs. PMID- 23750163 TI - Complexities and protein complexes in the antimycin A-sensitive pathway of cyclic electron flow in plants. PMID- 23750164 TI - Efficient selection and evaluation of transgenic lines of Crambe abyssinica. AB - Crambe abyssinica is a dedicated oilseed crop suitable for production of industrial feedstocks. Genetic modification of crambe has progressed substantially in the last few years, but the transformation efficiency needs to be further improved. Meanwhile, developing a reliable molecular system including Southern blot and qRT-PCR analyses is desired for effectively evaluating transgenic lines and gene expression levels of both endogenous and transgenes. In this study, we have developed an efficient transformation protocol with hygromycin as the selective agent for crambe transformation. In the regeneration test, addition of hygromycin at concentration of 5 mg L(-1) resulted in 18% of shoot regeneration using crambe hypocotyls as explants, while no regeneration occurred when the hygromycin concentration reached 10 mg L(-1). Based on this result, the hygromycin concentration up to 10 mg L(-1) was used in the subsequent transformations. The results showed that the transformation efficiency under constant low selection pressure (H3-H3) was similar to that under higher selection pressure first, followed by transfer to lower selection pressure (H10 H3). The PCR, Southern blot and fatty acid composition analyses confirmed the integration of transgenes in the crambe genome. We have also optimized the Southern and qRT-PCR methods for future studies on crambe or related species. For Southern blot analysis on crambe, more than 50 MUg DNA is required for a clear band. The choice of enzymes for DNA digestion was not rigid for confirmation of the T-DNA integration, while for determining the copy number of transgenes, suitable enzymes should be chosen. Increasing the enzyme concentration could improve the digestion and 20 MUl enzyme was recomended for a complete digestion of up to 80 MUg crambe DNA. For qRT-PCR analysis, around 20 days after flowering was observed to be the suitable sampling time for expresseion analysis of genes invovled in the seed oil biosynthesis. PMID- 23750165 TI - Effect of lead on root growth. AB - Lead (Pb) is one of the most widespread heavy metal contaminant in soils. It is highly toxic to living organisms. Pb has no biological function but can cause morphological, physiological, and biochemical dysfunctions in plants. Plants have developed a wide range of tolerance mechanisms that are activated in response to Pb exposure. Pb affects plants primarily through their root systems. Plant roots rapidly respond either (i) by the synthesis and deposition of callose, creating a barrier that stops Pb entering (ii) through the uptake of large amounts of Pb and its sequestration in the vacuole accompanied by changes in root growth and branching pattern or (iii) by its translocation to the aboveground parts of plant in the case of hyperaccumulators plants. Here we review the interactions of roots with the presence of Pb in the rhizosphere and the effect of Pb on the physiological and biochemical mechanisms of root development. PMID- 23750166 TI - Gomphrena claussenii, the first South-American metallophyte species with indicator-like Zn and Cd accumulation and extreme metal tolerance. AB - Plant species with the capacity to tolerate heavy metals are potentially useful for phytoremediation since they have adapted to survive and reproduce under toxic conditions and to accumulate high metal concentrations. Gomphrena claussenii Moq., a South-American species belonging to the Amaranthaceae, is found at a zinc (Zn) mining area in the state of Minas Gerais, Brazil. Through soil and hydroponic experiments, the metal tolerance and accumulation capacities of G. claussenii were assessed and the effects on physiological characteristics were compared with a closely related non-tolerant species, G. elegans Mart. G. claussenii plants grown in soil sampled at the Zn smelting area accumulated up to 5318MUgg(-) (1) of Zn and 287 MUg g(-) (1) of cadmium (Cd) in shoot dry biomass after 30 days of exposure. Plants were grown in hydroponics containing up to 3000 MUM of Zn and 100 MUM of Cd for G. claussenii and 100 MUM of Zn and 5 MUM of Cd for G. elegans. G. claussenii proved to be an extremely tolerant species to both Zn and Cd, showing only slight metal toxicity symptoms at the highest treatment levels, without significant decrease in biomass and no effects on root growth, whereas the non-tolerant species G. elegans showed significant toxicity effects at the highest exposure levels. Both species accumulated more Zn and Cd in roots than in shoots. In G. elegans, over 90% of the Cd remained in the roots, but G. claussenii showed a root:shoot concentration ratio of around 2, with shoots reaching 0.93% Zn and 0.13% Cd on dry matter base. In G. claussenii shoots, the concentrations of other minerals, such as iron (Fe) and manganese (Mn), were only affected by the highest Zn treatment while in G. elegans the Fe and Mn concentrations in shoots decreased drastically at both Zn and Cd treatments. Taking together, these results indicate that G. claussenii is a novel metallophyte, extremely tolerant of high Zn and Cd exposure and an interesting species for further phytoremediation studies. PMID- 23750168 TI - Usefulness of plasma procalcitonin to predict severity in elderly patients with community-acquired pneumonia. AB - BACKGROUND: Community-acquired pneumonia (CAP) is one of the leading causes of death among the elderly. Several studies have reported the clinical usefulness of serum procalcitonin, a biomarker of bacterial infection. However, the association between the levels of procalcitonin and the severity in the elderly with CAP has not yet been reported. The aim of this study was to evaluate usefulness of procalcitonin as a predictor of severity and mortality in the elderly with CAP. METHODS: This study covers 155 CAP cases admitted to Pusan National University Hospital between January 2010 and December 2010. Patients were divided into two groups (>=65 years, n=99; <65 years, n=56) and were measured for procalcitonin, C reactive protein (CRP), white blood cell, confusion, uremia, respiratory rate, blood pressure, 65 years or older (CURB-65) and pneumonia severity of index (PSI). RESULTS: The levels of procalcitonin were significantly correlated with the CURB-65, PSI in totals. Especially stronger correlation was observed between the levels of procalcitonin and CURB-65 in the elderly (procalcitonin and CURB 65, rho=0.408 with p<0.001; procalcitonin and PSI, rho=0.293 with p=0.003; procalcitonin and mortality, rho=0.229 with p=0.023). The correlation between the levels of CRP or WBC and CAP severity was low. The existing cut-off value of procalcitonin was correlated with mortality rate, however, it was not correlated with mortality within the elderly. CONCLUSION: The levels of procalcitonin are more useful than the levels of CRP or WBC to predict the severity of CAP. However, there was no association between the levels of procalcitonin and mortality in the elderly. PMID- 23750169 TI - Identification and distribution of nontuberculous mycobacteria from 2005 to 2011 in cheonan, Korea. AB - BACKGROUND: Nontuberculous mycobacteria (NTM) are considered opportunistic pathogens, and several species of NTM are associated with human diseases that typically involve the pulmonary, skin/soft tissue, or lymphatic systems; such infection may also cause disseminated diseases. Recent studies have reported increasing rates of NTM-induced disease worldwide. METHODS: Respiratory samples are being analyzed for acid-fast bacilli (AFB) culture and NTM identification at Dankook University Hospital in Cheonan, Korea, from September 2005 to September 2011. Identification is performed by using polymerase chain reaction-restriction fragment length polymorphism analysis targeting a novel region of the rpoB gene. RESULTS: A total of 25,133 specimens were received for AFB culture, of which 1,014 (4.0%) were NTM-positive. A total of 267 samples from 186 patients were tested for NTM identifications, and 232 samples from 157 patients were positive for NTM species. Among the patients who tested positive for NTM, 65.6% were men and the average age was 63.3 years. Mycobacterium avium complex, the most commonly detected NTM pathogen, was found in 65.9% of the 232 samples. The annual average percentage of NTM isolates from AFB culture-positive specimens was 31.3%: the highest rate was seen in 2011 (44.3%), followed by 2009 (37.4%) and 2010 (37.2%). An upward trend in NTM incidence was found during the study period. CONCLUSION: The prevalence of pulmonary NTM isolates continues to increase in Cheonan, suggesting that pulmonary NTM disease is becoming increasingly common. PMID- 23750167 TI - The Growing Importance of CNVs: New Insights for Detection and Clinical Interpretation. AB - Differences between genomes can be due to single nucleotide variants, translocations, inversions, and copy number variants (CNVs, gain or loss of DNA). The latter can range from sub-microscopic events to complete chromosomal aneuploidies. Small CNVs are often benign but those larger than 500 kb are strongly associated with morbid consequences such as developmental disorders and cancer. Detecting CNVs within and between populations is essential to better understand the plasticity of our genome and to elucidate its possible contribution to disease. Hence there is a need for better-tailored and more robust tools for the detection and genome-wide analyses of CNVs. While a link between a given CNV and a disease may have often been established, the relative CNV contribution to disease progression and impact on drug response is not necessarily understood. In this review we discuss the progress, challenges, and limitations that occur at different stages of CNV analysis from the detection (using DNA microarrays and next-generation sequencing) and identification of recurrent CNVs to the association with phenotypes. We emphasize the importance of germline CNVs and propose strategies to aid clinicians to better interpret structural variations and assess their clinical implications. PMID- 23750170 TI - Primary malignant fibrous histiocytoma of the pleura. AB - Malignant fibrous histiocytoma, a type of sarcoma, is a malignant neoplasm with uncertain origin that arises in both the soft tissues and the bone. The occurrence of primary malignant fibrous histiocytoma of the pleura is extremely rare. We report a case of a 65-year-old Korean man who is being diagnosed with primary malignant fibrous histiocytoma of the pleura. PMID- 23750171 TI - A case of locally advanced well-differentiated fetal adenocarcinoma of the lung treated with concurrent chemoradiation therapy. AB - Fetal adenocarcinoma is a rare adenocarcinoma subtype of pulmonary blastoma. A 48 year-old male patient is being referred to our hospital due to progressive dyspnea. A chest X-ray showed a lung mass of unknown origin that was obstructing the right main bronchus. After relieving the airway obstruction with stent insertion via bronchoscopy, a diagnosis of fetal adenocarcinoma is being confirmed through thoracoscopic biopsy. Due to the locally advanced state of the lung cancer, it seemed to be inoperable, and concurrent chemo-radiation therapy was being administered with docetaxel. The stent was removed after improvements in the airway obstruction followed by a lung mass shrinkage. Comparing to other contexts which describe fetal adenocarcinoma as lower grade malignancy with low associated mortality, herein, we describe a case of locally-advanced fetal adenocarcinoma (T4N3M0). This is the first documented case being treated with concurrent chemoradiation therapy. The followed-up image studies represent a partial response and the patient is currently under further observations. PMID- 23750172 TI - A Case of Endobronchial Aspergilloma Associated with Foreign Body in Immunocompetent Patient without Underlying Lung Disease. AB - Aspergillus causes a variety of clinical syndromes in the lung including tracheobronchial aspergillosis, invasive aspergillosis, chronic necrotizing pulmonary aspergillosis, allergic bronchopulmonary aspergillosis, and aspergilloma. Aspergilloma usually results from ingrowths of colonized Aspergillus in damaged bronchial tree, pulmonary cyst or cavities of patients with underlying lung diseases. There are a few reports on endobronchial aspergilloma without underlying pulmonary lesion. We have experienced a case of endobronchial aspergilloma associated with foreign body developed in an immunocompetent patient without underlying lung diseases. A 59-year-old man is being hospitalized with recurring hemoptysis for 5 months. X-ray and computed tomography scans of chest showed a nodular opacity in superior segment of left lower lobe. Fiberoptic bronchoscopy revealed an irregular, mass-like, brownish material which totally obstructed the sub-segmental bronchus and a foreign body in superior segmental bronchus of the lower left lobe. Histopathologic examinations of biopsy specimen revealed fungal hyphae, characteristic of Aspergillus species. PMID- 23750173 TI - Fatal Interstitial Pneumonitis Rapidly Developed after the First Cycle of CHOP with Etoposide Combination Chemotherapy in a Patient with Lymphoma. AB - Several chemotherapeutic agents are known to develop pulmonary toxicities in cancer patients, although the frequency of incidence varies. Cyclophosphamide is a commonly encountered agent that is toxic to the lung. Additionally, granulocyte colony-stimulating factor (G-CSF) being used for the recovery from neutropenia can exacerbate lung injury. However, most of the patients reported previously that the drug-induced interstitial pneumonitis were developed after three to four cycles of chemotherapy. Hereby, we report a case of peripheral T cell lymphoma which rapidly developed a fatal interstitial pneumonitis after the first cycle of combined chemotherapy with cyclophosphamide, adriamycin, vincristine, prednisolone, and etoposide and the patient had also treated with G-CSF during neutropenic period. PMID- 23750174 TI - Biomarkers, the molecular gaze and the transformation of cancer survivorship. AB - Over the past two decades, molecular technologies have transformed the landscape of cancer diagnosis, treatment and disease surveillance. However, although the effects of these technologies in the areas of primary and secondary cancer prevention have been the focus of growing study, their role in tertiary prevention remains largely unexamined. Treating this topic as a problematic to be conceptually explored rather than empirically demonstrated, this article focuses on the molecularisation of tertiary prevention, especially the growing use of molecular biomarkers to monitor disease recurrence. Taking a semiotic approach, I speculate on the potential meanings of molecular biomarkers for people living with and beyond cancer and suggest the meanings of these technologies may differ in important ways for those on both sides of the risk divide: that is, those 'at risk' for cancer and those living with realised risk. Although molecular biomarkers may intensify a sense of 'measured vulnerability', by indexing cancer's presence they may also prove reassuring. Moreover, as an invisible but ostensibly 'transparent' sign, in some contexts they appear to enable cancer survivors to challenge biomedical decision making. In the light of recent oncological debates about the value of these biomarkers in tertiary prevention, I conclude by suggesting that signs can never be reduced to their 'objective' biomedical denotation in spite of professional attempts to expunge meaning and value from care. PMID- 23750175 TI - Health economists, tobacco control and international development: On the economisation of global health beyond neoliberal structural adjustment policies. AB - This article addresses the increasing influence of economic rationalities in global health over the past 30 years by examining the genealogy of one economic strategy - taxation - that has become central to international anti-smoking initiatives in the global South. It argues that this genealogy sits uncomfortably with the usual story about economics and global health, which reduces the economisation of international health to neoliberal structural adjustment policies aimed at stabilisation, liberalisation and privatisation and laments their detrimental effect on health. While not disputing these policies' importance and damaging impact, the genealogy of tobacco taxes outlined in this article shows that the economisation of global health is not only about neoliberal structural adjustment policies but also about sin taxes, market failures and health economics. By stressing how changes in health like the global South's epidemiological transition can impact on economics and how beneficial taxation can be for health, it also shows that the relation between economics and health is not always unidirectional and detrimental to the latter. In doing so, the article contributes to the critique of the often mechanical use of neo liberalism to explicate change and calls for other stories about the economisation of global health to be told. PMID- 23750176 TI - Pixelated CdTe detectors to overcome intrinsic limitations of crystal based positron emission mammographs. AB - A positron emission mammograph (PEM) is an organ dedicated positron emission tomography (PET) scanner for breast cancer detection. State-of-the-art PEMs employing scintillating crystals as detection medium can provide metabolic images of the breast with significantly higher sensitivity and specificity with respect to standard whole body PET scanners. Over the past few years, crystal PEMs have dramatically increased their importance in the diagnosis and treatment of early stage breast cancer. Nevertheless, designs based on scintillators are characterized by an intrinsic deficiency of the depth of interaction (DOI) information from relatively thick crystals constraining the size of the smallest detectable tumor. This work shows how to overcome such intrinsic limitation by substituting scintillating crystals with pixelated CdTe detectors. The proposed novel design is developed within the Voxel Imaging PET (VIP) Pathfinder project and evaluated via Monte Carlo simulation. The volumetric spatial resolution of the VIP-PEM is expected to be up to 6 times better than standard commercial devices with a point spread function of 1 mm full width at half maximum (FWHM) in all directions. Pixelated CdTe detectors can also provide an energy resolution as low as 1.5% FWHM at 511 keV for a virtually pure signal with negligible contribution from scattered events. PMID- 23750177 TI - Energy and coincidence time resolution measurements of CdTe detectors for PET. AB - We report on the characterization of 2 mm thick CdTe diode detector with Schottky contacts to be employed in a novel conceptual design of PET scanner. Results at 8 degrees C with an applied bias voltage of -1000 V/mm show a 1.2% FWHM energy resolution at 511 keV. Coincidence time resolution has been measured by triggering on the preamplifier output signal to improve the timing resolution of the detector. Results at the same bias and temperature conditions show a FWHM of 6 ns with a minimum acceptance energy of 500 keV. These results show that pixelated CdTe Schottky diode is an excellent candidate for the development of next generation nuclear medical imaging devices such as PET, Compton gamma cameras, and especially PET-MRI hybrid systems when used in a magnetic field immune configuration. PMID- 23750178 TI - From Racial Discrimination to Substance Use: The Buffering Effects of Racial Socialization. AB - The experience of race-based discrimination may place African American youth at risk for substance use initiation and substance use disorders. This article examines the potential of parental racial socialization-a process by which parents convey messages to their children about race-to protect against the impact of racial discrimination on substance use outcomes. Focusing on stress as a major precipitating factor in substance use, the article postulates several possible mechanisms by which racial socialization might reduce stress and the subsequent risk for substance use. It discusses future research directions with the goal of realizing the promise of racial socialization as a resilience factor in African American and ethnic minority youth mental health. PMID- 23750180 TI - Use of RE-AIM to Address Health Inequities: Application in a low-income community health center based weight loss and hypertension self-management program. AB - BACKGROUND: While health inequities are well documented, and there are helpful frameworks to understand health disparities, implementation frameworks are also needed to focus the design, evaluation and reporting on interventions targeting populations at increased risk. PURPOSE: Describe how the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, and Maintenance) can be used for these purposes and illustrate its application in the context of a randomized, pragmatic weight-loss and hypertension self-management intervention. METHODS: RE-AIM was used to both plan and evaluate the Be Fit Be Well program for urban community health center patients. RESULTS: The RE-AIM framework helped to focus attention on and produce high rates of adoption and reach. Implementation rates varied across components. Weight losses were statistically significant, but not clinically significant. They were robust across a variety of patient characteristics, and the program was relatively low cost. Individual weight losses and blood pressure reductions were maintained throughout the 24-month period, but the program was not sustained at any of the three settings. CONCLUSION: Implementation frameworks such as RE-AIM can help design pragmatic interventions that focus on both the context for disparities reduction and the ultimate goal of public health impact. PMID- 23750179 TI - Comparison of endocrine and cellular mechanisms regulating the corpus luteum of primates and ruminants. AB - The corpus luteum (CL) is a transient endocrine organ that is essential for maintenance of pregnancy in both ruminants and primates. The cellular and endocrine mechanisms that regulate the CL in these species have commonalities and some distinct and intriguing differences. Both species have similar cellular content with large luteal cells derived from the granulosa cells of the follicle, small luteal cells from follicular thecal cells, and large numbers of capillary endothelial cells that form the vasculature that has an essential role in optimal CL function. Intriguingly, the large luteal cells in ruminants grow larger than in primates and acquire a capacity for high constitutive progesterone (P4) production that is independent of stimulation from LH. In contrast, the primate CL and the granulosa lutein cells from primates continue to require stimulation by LH/CG throughout the luteal phase. Although the preovulatory follicle of women and cows had similar size and steroidogenic output (10 to 20 mg/h), the bovine CL had about ten-fold greater P4 output compared to the human CL (17.4 vs. 1.4 mg/h), possibly due to the development of high constitutive P4 output by the bovine large luteal cells. The continued dependence of the primate CL on LH/CG/cAMP also seems to underlie luteolysis, as there seems to be a requirement for greater luteotropic support in the older primate CL than is provided by the endogenous LH pulses. Conversely, regression of the ruminant CL is initiated by PGF from the nonpregnant uterus. Consequently, the short luteal phase in ruminants is primarily due to premature secretion of PGF by the nonpregnant uterus and early CL regression, whereas CL insufficiency in primates is related to inadequate luteotropic support and premature CL regression. Thus, the key functions of the CL, pregnancy maintenance and CL regression in the absence of pregnancy, are produced by common cellular and enzymatic pathways regulated by very distinct luteotropic and luteolytic mechanisms in the CL of primates and ruminants. PMID- 23750181 TI - Floral visual signal increases reproductive success in a sexually deceptive orchid. AB - Sexually deceptive orchids mimic signals emitted by female insects in order to attract mate-searching males. Specific attraction of the targeted pollinator is achieved by sex pheromone mimicry, which constitutes the major attraction channel. In close vicinity of the flower, visual signals may enhance attraction, as was shown recently in the sexually deceptive orchid Ophrys heldreichii. Here, we conducted an in situ manipulation experiment in two populations of O. heldreichii on Crete to investigate whether the presence/absence of the conspicuous pink perianth affects reproductive success in two natural orchid populations. We estimated reproductive success of three treatment groups (with intact, removed and artificial perianth) throughout the flowering period as pollinaria removal (male reproductive success) and massulae deposition (female reproductive success). Reproductive success was significantly increased by the presence of a strong visual signal-the conspicuous perianth-in one study population, however, not in the second, most likely due to the low pollinator abundance in the latter population. This study provides further evidence that the coloured perianth in O. heldreichii is adaptive and thus adds to the olfactory signal to maximise pollinator attraction and reproductive success. PMID- 23750182 TI - Prenatal and Postnatal Cell Phone Exposures and Headaches in Children. AB - OBJECTIVE: Children today are exposed to cell phones early in life, and may be at the greatest risk if exposure is harmful to health. We investigated associations between cell phone exposures and headaches in children. STUDY DESIGN: The Danish National Birth Cohort enrolled pregnant women between 1996 and 2002. When their children reached age seven years, mothers completed a questionnaire regarding the child's health, behaviors, and exposures. We used multivariable adjusted models to relate prenatal only, postnatal only, or both prenatal and postnatal cell phone exposure to whether the child had migraines and headache-related symptoms. RESULTS: Our analyses included data from 52,680 children. Children with cell phone exposure had higher odds of migraines and headache-related symptoms than children with no exposure. The odds ratio for migraines was 1.30 (95% confidence interval: 1.01-1.68) and for headache-related symptoms was 1.32 (95% confidence interval: 1.23-1.40) for children with both prenatal and postnatal exposure. CONCLUSIONS: In this study, cell phone exposures were associated with headaches in children, but the associations may not be causal given the potential for uncontrolled confounding and misclassification in observational studies such as this. However, given the widespread use of cell phones, if a causal effect exists it would have great public health impact. PMID- 23750184 TI - Transient cystoid macular oedema in multiple choroidal naevi. AB - Choroidal Naevi are generally thought to be trivial. However, sometimes they cause visual loss, visual filed defect and rarely transform into malignant melanoma. We report the first case of unilateral numerous choroidal naevi in a healthy female associated with transient cystoid macular oedema and postulate about its pathogenesis. PMID- 23750183 TI - Human Endogenous Retroviruses (HERVs) and Autoimmune Rheumatic Disease: Is There a Link? AB - Autoimmune rheumatic diseases, such as RA and SLE, are caused by genetic, hormonal and environmental factors. Human Endogenous Retroviruses (HERVs) may be triggers of autoimmune rheumatic disease. HERVs are fossil viruses that began to be integrated into the human genome some 30-40 million years ago and now make up 8% of the genome. Evidence suggests HERVs may cause RA and SLE, among other rheumatic diseases. The key mechanisms by which HERVS are postulated to cause disease include molecular mimicry and immune dysregulation. Identification of HERVs in RA and SLE could lead to novel treatments for these chronic conditions. This review summarises the evidence for HERVs as contributors to autoimmune rheumatic disease and the clinical implications and mechanisms of pathogenesis are discussed. PMID- 23750185 TI - Nurse-driven training courses: impact on implementation of ambulatory blood pressure monitoring. AB - BACKGROUND: Ambulatory blood pressure monitoring (ABPM) predicts cardiovascular risk and identifies white-coat and masked hypertension, efficacy of treatment and the circadian cycle of hypertensive patients. OBJECTIVE: To analyze the effectiveness of ABPM implementation thoughtout a nurse-driven training program. MATERIALS AND METHODOLOGY: Twenty eight professionals were involved in the study carried out in the primary care center of the metropolitan area of Barcelona that serves 34,289 inhabitants. The ABPM implementation program was driven by two nurses that held four education sessions. After a 2-year follow-up period, we assessed the outcome of attendance at the educational sessions. First, we evaluated whether the program increased the number of orders of ABPM. Second, we used a survey to evaluate to what extent the input of our educational sessions was understood by attendants. Third, we analyzed the effect ABPM results had on the treatment of patients with a bad control of their hypertension. RESULTS: After the training sessions we found a 6-fold increase in the number of patients undergoing ABPM. We analyzed 204 hypertensive individuals: 41% dippers, 34% were non-dippers, 20% were risers and 5% were extremely dippers. According to our survey, 100% of attendants had a good practice regarding ABPM management. However only 27% of riser patients were studied with a second ABPM. CONCLUSIONS: Specific training processes are needed for implementation of ABPM and an even more concentrated effort should be focused on training in the correct interpretation of ABPM results. PMID- 23750186 TI - Evaluation of Staff's Job Satisfaction in the Spinal Cord Unit in Italy. AB - In July 2007 a Spinal Cord Unit was set up in Turin (Italy) within the newly integrated structure of the Orthopaedic Traumatologic Centre, warranting a multidisciplinary and professional approach according to International Guidelines. This approach will be possible through experimentation of a personalized care model. To analyze job satisfaction of health care professionals operating within the Spinal Cord Unit, preliminary to organizational change. Data collection was carried out by using questionnaires, interviews, shadowing. Results from quantitative analysis on the self-filled questionnaires were integrated with results from qualitative analysis. All the health care professionals operating in the field were involved. Positive aspects were the perception of carrying out a useful job, the feeling of personal fulfilment and the wish to engage new energies and resources. Problematic aspects included role conflict among staff categories and communication with managers. The positive aspects can be exploited to create professional practices facilitating role and expertise integration, information spreading and staff identification within the organization rather than team work. Data of job satisfaction and self efficacy of health care workers can be considered basic requirement before implementing an organizational change. The main challenges is multiprofessional collaboration. PMID- 23750187 TI - Dysfunctional cortical connectivity during the auditory oddball task in patients with schizophrenia. AB - BACKGROUND: We studied the imaginary coherence (IC) of gamma frequency oscillations between brain regions of male schizophrenia patients during an auditory oddball task using magnetoencephalography (MEG) and electroencephalography (EEG). METHODS: Subjects were 10 right-handed male schizophrenia patients, evaluated by the positive and negative symptom scale (PANSS), and 10 healthy controls. Functional connectivity during the auditory oddball task was reconstructed in low (30-50 Hz) and high (50-100 Hz) gamma bands, and represented by imaginary coherence (IC) based on significant oscillatory power changes. We calculated correlations between PANSS scores and IC. RESULTS: In the high gamma band, IC between left occipital and right prefrontal lobe areas during the time window 750-1000 ms from stimulus onset showed negative correlations with total negative scores, total positive scores, the sum of positive and negative scores in PANSS, conceptual disorganization, and social avoidance scores. In the low gamma band, IC between the same areas from 250-500 ms also showed a negative correlation with the conceptual disorganization score. In the same time window, IC between left occipital and right frontoparietal lobe areas in the low gamma band showed a positive correlation with hallucinatory behavior; IC between right temporal pole and left prefrontal lobe areas showed a positive correlation with delusion scores, although these ICs were decreased relative to controls. CONCLUSIONS: Functional disconnection of high and low gamma bands in auditory oddball task may play an important role in the auditory processing in schizophrenia patients. PMID- 23750188 TI - Aerodynamic assessment of phonatory onset in Parkinson's disease: evidence of decreased scaling of laryngeal and respiratory control. AB - BACKGROUND: Phonatory onset is important for speech and voice and may be substantially impaired in people with Parkinson's Disease (PD). However, the physiologic contributions of laryngeal and respiratory control to phonatory onset in PD are not well understood. Acoustic measurement of phonatory onset in neurological disease has been limited due to the confounding effects of dysarthria and the limited yield of physiologic detail. OBJECTIVE: The purpose of this study was to test whether air flow measures would be useful to characterize respiratory and laryngeal contributions to phonatory onset, whether acoustic and air flow measures of phonatory onset were aberrant in PD, and whether deficits were significantly associated with voice severity. METHODS: Twenty-one PD participants were tested and compared with 25 healthy controls. Testing included acoustic and air flow measures of phonatory onset during syllable production ([pa]) and measures of voice severity. RESULTS: Air flow assessment was possible for all participants; acoustic assessment was only possible for 86% of PD participants. Air flow and acoustic measures revealed shorter phonatory onset times for PD participants than controls. Air flow measures also revealed that PD participants expelled less lung air volume per syllable. Aberrant timing of phonatory onset and reduced lung air volume were associated with increased voice severity. CONCLUSIONS: These findings suggest that air flow measures may be useful to assess the laryngeal and respiratory contributions to phonatory onset. These results also suggest that both respiratory and laryngeal control deficits may contribute to phonatory errors in PD, and that phonatory onset deficits are associated with voice severity. PMID- 23750189 TI - Spatio-temporal analysis of tamoxifen-induced bystander effects in breast cancer cells using microfluidics. AB - The bystander effect in cancer therapy is the inhibition or killing of tumor cells that are adjacent to those directly affected by the agent used for treatment. In the case of chemotherapy, little is known as to how much and by which mechanisms bystander effects contribute to the elimination of tumor cells. This is mainly due to the difficulty to distinguish between targeted and bystander cells since both are exposed to the pharmaceutical compound. We here studied the interaction of tamoxifen-treated human breast cancer MCF-7 cells with their neighboring counterparts by exploiting laminar flow patterning in a microfluidic chip to ensure selective drug delivery. The spatio-temporal evolution of the bystander response in non-targeted cells was analyzed by measuring the mitochondrial membrane potential under conditions of free diffusion. Our data show that the bystander response is detectable as early as 1 hour after drug treatment and reached effective distances of at least 2.8 mm. Furthermore, the bystander effect was merely dependent on diffusible factors rather than cell contact-dependent signaling. Taken together, our study illustrates that this microfluidic approach is a promising tool for screening and optimization of putative chemotherapeutic drugs to maximize the bystander response in cancer therapy. PMID- 23750191 TI - Anthropogenic resource subsidies determine space use by Australian arid zone dingoes: an improved resource selection modelling approach. AB - Dingoes (Canis lupus dingo) were introduced to Australia and became feral at least 4,000 years ago. We hypothesized that dingoes, being of domestic origin, would be adaptable to anthropogenic resource subsidies and that their space use would be affected by the dispersion of those resources. We tested this by analyzing Resource Selection Functions (RSFs) developed from GPS fixes (locations) of dingoes in arid central Australia. Using Generalized Linear Mixed effect Models (GLMMs), we investigated resource relationships for dingoes that had access to abundant food near mine facilities, and for those that did not. From these models, we predicted the probability of dingo occurrence in relation to anthropogenic resource subsidies and other habitat characteristics over ~ 18,000 km(2). Very small standard errors and subsequent pervasively high P-values of results will become more important as the size of data sets, such as our GPS tracking logs, increases. Therefore, we also investigated methods to minimize the effects of serial and spatio-temporal correlation among samples and unbalanced study designs. Using GLMMs, we accounted for some of the correlation structure of GPS animal tracking data; however, parameter standard errors remained very small and all predictors were highly significant. Consequently, we developed an alternative approach that allowed us to review effect sizes at different spatial scales and determine which predictors were sufficiently ecologically meaningful to include in final RSF models. We determined that the most important predictor for dingo occurrence around mine sites was distance to the refuse facility. Away from mine sites, close proximity to human-provided watering points was predictive of dingo dispersion as were other landscape factors including palaeochannels, rocky rises and elevated drainage depressions. Our models demonstrate that anthropogenically supplemented food and water can alter dingo-resource relationships. The spatial distribution of such resources is therefore critical for the conservation and management of dingoes and other top predators. PMID- 23750192 TI - Monitoring influenza epidemics in china with search query from baidu. AB - Several approaches have been proposed for near real-time detection and prediction of the spread of influenza. These include search query data for influenza-related terms, which has been explored as a tool for augmenting traditional surveillance methods. In this paper, we present a method that uses Internet search query data from Baidu to model and monitor influenza activity in China. The objectives of the study are to present a comprehensive technique for: (i) keyword selection, (ii) keyword filtering, (iii) index composition and (iv) modeling and detection of influenza activity in China. Sequential time-series for the selected composite keyword index is significantly correlated with Chinese influenza case data. In addition, one-month ahead prediction of influenza cases for the first eight months of 2012 has a mean absolute percent error less than 11%. To our knowledge, this is the first study on the use of search query data from Baidu in conjunction with this approach for estimation of influenza activity in China. PMID- 23750199 TI - Molecular phylogeny and biogeography of percocypris (Cyprinidae, Teleostei). AB - Fierce predatory freshwater fishes, the species of Percocypris (Cyprinidae, Teleostei) inhabit large rivers or lakes, and have a specific distribution pattern. Only a single species or subspecies occurs in each large-scale drainage basin of the Southeastern Tibetan Plateau. In this study, the molecular phylogenetic relationships for all but one of the described subspecies/species of Percocypris were investigated based on three mitochondrial genes (16S; COI; Cyt b) and one nuclear marker (Rag2). The results of Maximum Likelihood and Bayesian Inference analyses show that Percocypris is a strongly supported monophyletic group and that it is the sister group of Schizothorax. Combined with analyses of morphological characters, our results suggest that Percocypris needs to be reclassified, and we propose that six species be recognized, with corresponding distributions in five main drainages (including one lake). In addition, based on the results of the estimation of divergence times and ancestral drainages, we hypothesize that Percocypris likely originated in the early Miocene from a paleo connected drainage system containing the contemporary main drainages of the Southeastern Tibetan Plateau. This study suggests that vicariance (due to the uplift of the Tibetan Plateau modifying the large-scale morphologies of drainage basins in the Southeastern Tibetan Plateau) has played an important role in the speciation of the genus. Furthermore, external morphological characters (such as the length of the fins) and an internal trait (the position of pterygiophore) appear to be correlated with different habitats in rivers and the lake. PMID- 23750200 TI - Reinterpreting behavioral receptive fields: lightness induction alters visually completed shape. AB - BACKGROUND: A classification image (CI) technique has shown that static luminance noise near visually completed contours affects the discrimination of fat and thin Kanizsa shapes. These influential noise regions were proposed to reveal "behavioral receptive fields" of completed contours-the same regions to which early cortical cells respond in neurophysiological studies of contour completion. Here, we hypothesized that 1) influential noise regions correspond to the surfaces that distinguish fat and thin shapes (hereafter, key regions); and 2) key region noise biases a "fat" response to the extent that its contrast polarity (lighter or darker than background) matches the shape's filled-in surface color. RESULTS: To test our hypothesis, we had observers discriminate fat and thin noise embedded rectangles that were defined by either illusory or luminance-defined contours (Experiment 1). Surrounding elements ("inducers") caused the shapes to appear either lighter or darker than the background-a process sometimes referred to as lightness induction. For both illusory and luminance-defined rectangles, key region noise biased a fat response to the extent that its contrast polarity (light or dark) matched the induced surface color. When lightness induction was minimized, luminance noise had no consistent influence on shape discrimination. This pattern arose when pixels immediately adjacent to the discriminated boundaries were excluded from the analysis (Experiment 2) and also when the noise was restricted to the key regions so that the noise never overlapped with the physically visible edges (Experiment 3). The lightness effects did not occur in the absence of enclosing boundaries (Experiment 4). CONCLUSIONS: Under noisy conditions, lightness induction alters visually completed shape. Moreover, behavioral receptive fields derived in CI studies do not correspond to contours per se but to filled-in surface regions contained by those contours. The relevance of lightness to two-dimensional shape completion supplies a new constraint for models of object perception. PMID- 23750201 TI - Integrative phylogeography of Calotriton newts (Amphibia, Salamandridae), with special remarks on the conservation of the endangered Montseny brook newt (Calotriton arnoldi). AB - The genus Calotriton includes two species of newts highly adapted to live in cold and fast-flowing mountain springs. The Pyrenean brook newt (Calotriton asper), restricted to the Pyrenean region, and the Montseny brook newt (Calotriton arnoldi), endemic to the Montseny massif and one of the most endangered amphibian species in Europe. In the present manuscript, we use an integrative approach including species distribution modeling (SDM), molecular analyses of mitochondrial and nuclear DNA sequence data and morphology to unravel the historical processes that have contributed to shaping the biogeography and genetic structure of the genus Calotriton, with special emphasis on the conservation of C. arnoldi. The results of the molecular analyses confirm that, despite having originated recently, being ecologically similar and geographically very close, there is no signal of hybridization between C. asper and C. arnoldi. SDM results suggest that tough environmental conditions on mountains tops during glacial periods, together with subsequent warmer periods could have prevented the contact between the two species. Within the critically endangered C. arnoldi, a high genetic structure is revealed despite its extremely small distribution range compared to C. asper. Haplotype networks, AMOVA and SAMOVA analyses suggest that two distinct groups of populations can be clearly differentiated with absence of gene flow. This is in concordance with morphological differentiation and correlates with its geographical distribution, as the two groups are situated on the eastern and western sides of a river valley that acts as a barrier. The genetic and morphological results are highly important for the ongoing conservation program of C. arnoldi and strongly justify the management of this species into at least two independent evolutionary significant units (eastern and western sectors) to guarantee the long-term population viability. PMID- 23750202 TI - Evaluation of specific absorption rate as a dosimetric quantity for electromagnetic fields bioeffects. AB - PURPOSE: To evaluate SAR as a dosimetric quantity for EMF bioeffects, and identify ways for increasing the precision in EMF dosimetry and bioactivity assessment. METHODS: We discuss the interaction of man-made electromagnetic waves with biological matter and calculate the energy transferred to a single free ion within a cell. We analyze the physics and biology of SAR and evaluate the methods of its estimation. We discuss the experimentally observed non-linearity between electromagnetic exposure and biological effect. RESULTS: WE FIND THAT: a) The energy absorbed by living matter during exposure to environmentally accounted EMFs is normally well below the thermal level. b) All existing methods for SAR estimation, especially those based upon tissue conductivity and internal electric field, have serious deficiencies. c) The only method to estimate SAR without large error is by measuring temperature increases within biological tissue, which normally are negligible for environmental EMF intensities, and thus cannot be measured. CONCLUSIONS: SAR actually refers to thermal effects, while the vast majority of the recorded biological effects from man-made non-ionizing environmental radiation are non-thermal. Even if SAR could be accurately estimated for a whole tissue, organ, or body, the biological/health effect is determined by tiny amounts of energy/power absorbed by specific biomolecules, which cannot be calculated. Moreover, it depends upon field parameters not taken into account in SAR calculation. Thus, SAR should not be used as the primary dosimetric quantity, but used only as a complementary measure, always reporting the estimating method and the corresponding error. Radiation/field intensity along with additional physical parameters (such as frequency, modulation etc) which can be directly and in any case more accurately measured on the surface of biological tissues, should constitute the primary measure for EMF exposures, in spite of similar uncertainty to predict the biological effect due to non linearity. PMID- 23750203 TI - Protective effects of andrographolide analogue AL-1 on ROS-induced RIN-mbeta cell death by inducing ROS generation. AB - Oxidative stress is considered to be a major factor contributing to pathogenesis and progression of many diseases. A novel andrographolide-lipoic acid conjugate (AL-1) could protect pancreatic beta-cells from reactive oxygen species (ROS) induced oxidative injury. However, its protective mechanism is still unclear. In this work, we used proteomics to identify AL-1-regulated proteins in beta-cells and found that 13 of the 71 proteins regulated by AL-1 were closely associated with antioxidation. These differential proteins were mainly involved in the ERK1/2 and AKT1 signaling pathways. Functional investigation demonstrated that AL 1 exerted its protective effects on H2O2-induced cell death of beta-cells by generating NADPH oxidase-dependent ROS to activate ERK1/2 and AKT1 signaling pathways. As a consequence, the expressions of antioxidant proteins including Trx1, Prx1 and Prx5, and anti-apoptotic proteins including PDCD6IP, prohibitin, galectin-1 and HSP were upregulated. AL-1 probably worked as a "vaccinum" to activate the cellular antioxidant system by inducing the generation of low concentration ROS which then reciprocally protected beta-cells from oxidative damage caused by high-level ROS from H2O2. To the best of our knowledge, this is the first comprehensive proteomic analysis illustrating a novel molecular mechanism for the protective effects of antioxidants on beta-cells from H2O2 induced cell death. PMID- 23750204 TI - The increased risk of joint venture promotes social cooperation. AB - The joint venture of many members is common both in animal world and human society. In these public enterprizes, highly cooperative groups are more likely to while low cooperative groups are still possible but not probable to succeed. Existent literature mostly focuses on the traditional public goods game, in which cooperators create public wealth unconditionally and benefit all group members unbiasedly. We here institute a model addressing this public goods dilemma with incorporating the public resource foraging failure risk. Risk-averse individuals tend to lead a autarkic life, while risk-preferential ones tend to participate in the risky public goods game. For participants, group's success relies on its cooperativeness, with increasing contribution leading to increasing success likelihood. We introduce a function with one tunable parameter to describe the risk removal pattern and study in detail three representative classes. Analytical results show that the widely replicated population dynamics of cyclical dominance of loner, cooperator and defector disappear, while most of the time loners act as savors while eventually they also disappear. Depending on the way that group's success relies on its cooperativeness, either cooperators pervade the entire population or they coexist with defectors. Even in the later case, cooperators still hold salient superiority in number as some defectors also survive by parasitizing. The harder the joint venture succeeds, the higher level of cooperation once cooperators can win the evolutionary race. Our work may enrich the literature concerning the risky public goods games. PMID- 23750205 TI - Efficient control of epidemics spreading on networks: balance between treatment and recovery. AB - We analyse two models describing disease transmission and control on regular and small-world networks. We use simulations to find a control strategy that minimizes the total cost of an outbreak, thus balancing the costs of disease against that of the preventive treatment. The models are similar in their epidemiological part, but differ in how the removed/recovered individuals are treated. The differences in models affect choice of the strategy only for very cheap treatment and slow spreading disease. However for the combinations of parameters that are important from the epidemiological perspective (high infectiousness and expensive treatment) the models give similar results. Moreover, even where the choice of the strategy is different, the total cost spent on controlling the epidemic is very similar for both models. PMID- 23750206 TI - LRRTM3 interacts with APP and BACE1 and has variants associating with late-onset Alzheimer's disease (LOAD). AB - Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within alpha-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer's disease (LOAD) risk and plasma amyloid beta (Abeta) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted Abeta, although the mechanism of this is unclear. In SH-SY5Y cells overexpressing APP and transiently transfected with LRRTM3 alone or with BACE1, we showed that LRRTM3 co-localizes with both APP and BACE1 in early endosomes, where BACE1 processing of APP occurs. Additionally, LRRTM3 co localizes with APP in primary neuronal cultures from Tg2576 mice transduced with LRRTM3-expressing adeno-associated virus. Moreover, LRRTM3 co-immunoprecipitates with both endogenous APP and overexpressed BACE1, in HEK293T cells transfected with LRRTM3. SH-SY5Y cells with knock-down of LRRTM3 had lower BACE1 and higher CTNNA3 mRNA levels, but no change in APP. Brain mRNA levels of LRRTM3 showed significant correlations with BACE1, CTNNA3 and APP in ~400 humans, but not in LRRTM3 knock-out mice. Finally, we assessed 69 single nucleotide polymorphisms (SNPs) within and flanking LRRTM3 in 1,567 LOADs and 2,082 controls and identified 8 SNPs within a linkage disequilibrium block encompassing 5'UTR-Intron 1 of LRRTM3 that formed multilocus genotypes (MLG) with suggestive global association with LOAD risk (p = 0.06), and significant individual MLGs. These 8 SNPs were genotyped in an independent series (1,258 LOADs and 718 controls) and had significant global and individual MLG associations in the combined dataset (p = 0.02-0.05). Collectively, these results suggest that protein interactions between LRRTM3, APP and BACE1, as well as complex associations between mRNA levels of LRRTM3, CTNNA3, APP and BACE1 in humans might influence APP metabolism and ultimately risk of AD. PMID- 23750207 TI - Suppressed retinal degeneration in aged wild type and APPswe/PS1DeltaE9 mice by bone marrow transplantation. AB - Alzheimer's disease (AD) is an age-related condition characterized by accumulation of neurotoxic amyloid beta peptides (Abeta) in brain and retina. Because bone marrow transplantation (BMT) results in decreased cerebral Abeta in experimental AD, we hypothesized that BMT would mitigate retinal neurotoxicity through decreased retinal Abeta. To test this, we performed BMT in APPswe/PS1DeltaE9 double transgenic mice using green fluorescent protein expressing wild type (wt) mice as marrow donors. We first examined retinas from control, non-transplanted, aged AD mice and found a two-fold increase in microglia compared with wt mice, prominent inner retinal Abeta and paired helical filament-tau, and decreased retinal ganglion cell layer neurons. BMT resulted in near complete replacement of host retinal microglia with BMT-derived cells and normalized total AD retinal microglia to non-transplanted wt levels. Abeta and paired helical filament-tau were reduced (61.0% and 44.1% respectively) in BMT recipient AD mice, which had 20.8% more retinal ganglion cell layer neurons than non-transplanted AD controls. Interestingly, aged wt BMT recipients also had significantly more neurons (25.4%) compared with non-transplanted aged wt controls. Quantitation of retinal ganglion cell layer neurons in young mice confirmed age-related retinal degeneration was mitigated by BMT. We found increased MHC class II expression in BMT-derived microglia and decreased oxidative damage in retinal ganglion cell layer neurons. Thus, BMT is neuroprotective in age-related as well as AD-related retinal degeneration, and may be a result of alterations in innate immune function and oxidative stress in BMT recipient mice. PMID- 23750208 TI - Identification and enhancement of HLA-A2.1-restricted CTL epitopes in a new human cancer antigen-POTE. AB - Identification of CD8(+) T cell epitopes that can induce T cells to kill tumor cells is a fundamental step for development of a peptide cancer vaccine. POTE protein is a newly identified cancer antigen that was found to be expressed in a wide variety of human cancers, including prostate, colon, lung, breast, ovary and pancreas. Here, we determined HLA-A2.1-restricted cytotoxic T lymphocyte (CTL) epitopes in the POTE protein, and also designed enhanced epitopes by amino acid (AA) substitutions. Five 9-mer peptides were first selected and their binding affinity to HLA-A2 molecules was measured by the T2 binding assay. POTE 272-280 and POTE 323-331 showed the strongest HLA-A2 binding affinity. AA substituted peptides POTE 252-9V (with valine at position 9), POTE 553-1Y (with tyrosine at position 1) and POTE 323-3F (with phenylalanine at position 3) conferred higher affinity for HLA-A2, and induced CTL responses cross-reactive with wild type antigens. While POTE 252-9V was the strongest in this respect, POTE 323-3F had the greatest increase in immunogenicity compared to wild type. Importantly, two modified epitopes (POTE-553-1Y and POTE-323-3F) induced CTLs that killed NCI H522, a POTE-expressing HLA-A2(+) human non-small cell lung cancer cell line, indicating natural endogenous processing of these epitopes. In conclusion, the immunogenicity of POTE epitopes can be enhanced by peptide modification to induce T cells that kill human cancer cells. A combination of POTE 553-1Y and POTE 323 3F epitopes might be an attractive vaccine strategy for HLA-A2 cancer patients to overcome tolerance induced by tumors and prevent escape. PMID- 23750209 TI - In vitro analysis of breast cancer cell line tumourspheres and primary human breast epithelia mammospheres demonstrates inter- and intrasphere heterogeneity. AB - Mammosphere and breast tumoursphere culture have gained popularity as in vitro assays for propagating and analysing normal and cancer stem cells. Whether the spheres derived from different sources or parent cultures themselves are indeed single entities enriched in stem/progenitor cells compared to other culture formats has not been fully determined. We surveyed sphere-forming capacity across 26 breast cell lines, immunophenotyped spheres from six luminal- and basal-like lines by immunohistochemistry and flow cytometry and compared clonogenicity between sphere, adherent and matrigel culture formats using in vitro functional assays. Analyses revealed morphological and molecular intra- and inter-sphere heterogeneity, consistent with adherent parental cell line phenotypes. Flow cytometry showed sphere culture does not universally enrich for markers previously associated with stem cell phenotypes, although we found some cell-line specific changes between sphere and adherent formats. Sphere-forming efficiency was significantly lower than adherent or matrigel clonogenicity and constant over serial passage. Surprisingly, self-renewal capacity of sphere-derived cells was similar/lower than other culture formats. We observed significant correlation between long-term-proliferating-cell symmetric division rates in sphere and adherent cultures, suggesting functional overlap between the compartments sustaining them. Experiments with normal primary human mammary epithelia, including sorted luminal (MUC1(+)) and basal/myoepithelial (CD10(+)) cells revealed distinct luminal-like, basal-like and mesenchymal entities amongst primary mammospheres. Morphological and colony-forming-cell assay data suggested mammosphere culture may enrich for a luminal progenitor phenotype, or induce reversion/relaxation of the basal/mesenchymal in vitro selection occurring with adherent culture. Overall, cell line tumourspheres and primary mammospheres are not homogenous entities enriched for stem cells, suggesting a more cautious approach to interpreting data from these assays and careful consideration of its limitations. Sphere culture may represent an alternative 3-dimensional culture system which rather than universally 'enriching' for stem cells, has utility as one of a suite of functional assays that provide a read-out of progenitor activity. PMID- 23750210 TI - Application of hyperbranched rolling circle amplification for direct detection of mycobacterium tuberculosis in clinical sputum specimens. AB - BACKGROUND: Global tuberculosis (TB) control is encumbered by the lack of a rapid and simple detection method for diagnosis, especially in low-resource areas. An isothermal amplification method, hyperbranched rolling circle amplification (HRCA), was optimized to detect Mycobacterium tuberculosis (Mtb) in clinical sputum specimens. METHODS: A clinical validation study was performed to assess the diagnostic accuracy of HRCA. In order to analyze the detection limit of HRCA under optimal conditions, the method was initially used to detect purified H37Rv strain DNA and culture suspensions. Next, three strains of Mycobacterium tuberculosis complex (MTC) and eight strains of non-tuberculosis mycobacterium (NTM) were analyzed in order to evaluate specificity. Sputum specimens from 136 patients with diagnosed pulmonary TB, 38 lung cancer patients, and 34 healthy donors were tested by HRCA to validate the clinical application of HRCA for the rapid detection of Mtb. RESULTS: The detection limit of HRCA for purified H37Rv DNA and culture suspensions was 740 aM and 200cfu/ml, respectively. The results of all MTC strains were positive in contrast to the NTM specimens which were all negative. The detection sensitivity for the 136 sputum specimens from TB patients was 77.2% (105/136), which was slightly lower than that of quantitative real-time PCR(79.4%, 108/136) and culture (80.9%,110/136). The sensitivity of all three methods was statistically higher than smear microscopy (44.9%, 61/136). The overall specificity of HRCA was 98.6% (71/72) which was similar to that of quantitative real-time PCR (qRT-PCR) and smear/culture methods (100%, 72/72). CONCLUSIONS: Use of the HRCA assay for detection of Mtb within clinical sputum specimens was demonstrated to be highly sensitive and specific. Moreover, the performance of HRCA is simple and cost-effective compared with qRT-PCR and is less time consuming than culture. Therefore, HRCA is a promising TB diagnostic tool that can be used routinely in low-resource clinical settings. PMID- 23750211 TI - Signal transducer and activator of transcription-3 induces microRNA-155 expression in chronic lymphocytic leukemia. AB - MicroRNA (miR) abnormalities play a key role in the pathogenesis of chronic lymphocytic leukemia (CLL). High levels of miR-155 have been detected in human neoplasms, and overexpression of miR-155 has been found to induce lymphoma in mice. High levels of miR-155 were detected in CLL cells and STAT3, which is known to induce miR-21 and miR-181b-1 expression, is constitutively activated in CLL. Given these findings, we hypothesized that STAT3 induces miR-155. Sequence analysis revealed that the miR-155 promoter harbors two putative STAT3 binding sites. Therefore, truncated miR-155 promoter constructs and STAT3 small interfering RNA (siRNA) were co-transfected into MM1 cells. Of the two putative binding sites, STAT3-siRNA reduced the luciferase activity of the construct containing the 700-709 bp STAT3 binding site, suggesting that this site is involved in STAT3-induced transcription. Electrophoretic mobility shift assay confirmed that STAT3 bound to the miR-155 promoter in CLL cells, and chromatin immunoprecipitation and luciferase assay confirmed that STAT3 bound to the 700 709 bp but not the 615-624 bp putative STAT3 binding site in CLL cells. Finally, STAT3-small hairpin RNA downregulated miR-155 gene expression, suggesting that constitutively activated STAT3 binds to the miR-155 gene promoter. Together, these results suggest that STAT3 activates miR-155 in CLL cells. PMID- 23750212 TI - Reestablishing neuronal networks in the aged brain by stem cell factor and granulocyte-colony stimulating factor in a mouse model of chronic stroke. AB - Stroke has a high incidence in the elderly. Stroke enters the chronic phase 3 months after initial stroke onset. Currently, there is no pharmaceutical treatment available for chronic stroke. We have demonstrated the therapeutic effects of the combination of stem cell factor (SCF) and granulocyte-colony stimulating factor (G-CSF) (SCF+G-CSF) on chronic stroke. However, it remains unclear how SCF+G-CSF repairs the brain in chronic stroke. In this study, we determined the effects of SCF+G-CSF on neuronal network remodeling in the aged brain of chronic stroke. Cortical brain ischemia was produced in 16-18 month-old transgenic mice expressing yellow fluorescent protein in layer V pyramidal neurons. SCF+G-CSF was subcutaneously injected for 7 days beginning at 3.5 months post-ischemia. Using both live brain imaging and immunohistochemistry, we observed that SCF+G-CSF increased the mushroom-type spines on the apical dendrites of layer V pyramidal neurons adjacent to the infarct cavities 2 and 6 weeks after treatment. SCF+G-CSF also augmented dendritic branches and post synaptic density protein 95 puncta in the peri-infarct cortex 6 weeks after treatment. These data suggest that SCF+G-CSF treatment in chronic stroke remodels neural circuits in the aged brain. This study provides evidence to support the development of a new therapeutic strategy for chronic stroke. PMID- 23750213 TI - Does size matter? Scaling of CO2 emissions and US urban areas. AB - Urban areas consume more than 66% of the world's energy and generate more than 70% of global greenhouse gas emissions. With the world's population expected to reach 10 billion by 2100, nearly 90% of whom will live in urban areas, a critical question for planetary sustainability is how the size of cities affects energy use and carbon dioxide (CO2) emissions. Are larger cities more energy and emissions efficient than smaller ones? Do larger cities exhibit gains from economies of scale with regard to emissions? Here we examine the relationship between city size and CO2 emissions for U.S. metropolitan areas using a production accounting allocation of emissions. We find that for the time period of 1999-2008, CO2 emissions scale proportionally with urban population size. Contrary to theoretical expectations, larger cities are not more emissions efficient than smaller ones. PMID- 23750214 TI - Targeting Aurora B to the equatorial cortex by MKlp2 is required for cytokinesis. AB - Although Aurora B is important in cleavage furrow ingression and completion during cytokinesis, the mechanism by which kinase activity is targeted to the cleavage furrow and the molecule(s) responsible for this process have remained elusive. Here, we demonstrate that an essential mitotic kinesin MKlp2 requires myosin-II for its localization to the equatorial cortex, and this event is required to recruit Aurora B to the equatorial cortex in mammalian cells. This recruitment event is also required to promote the highly focused accumulation of active RhoA at the equatorial cortex and stable ingression of the cleavage furrow in bipolar cytokinesis. Specifically, in drug-induced monopolar cytokinesis, targeting Aurora B to the cell cortex by MKlp2 is essential for cell polarization and furrow formation. Once the furrow has formed, MKlp2 further recruits Aurora B to the growing furrow. This process together with continuous Aurora B kinase activity at the growing furrow is essential for stable furrow propagation and completion. In contrast, a MKlp2 mutant defective in binding myosin-II does not recruit Aurora B to the cell cortex and does not promote furrow formation during monopolar cytokinesis. This mutant is also defective in maintaining the ingressing furrow during bipolar cytokinesis. Together, these findings reveal that targeting Aurora B to the cell cortex (or the equatorial cortex) by MKlp2 is essential for the maintenance of the ingressing furrow for successful cytokinesis. PMID- 23750215 TI - Correlation spectroscopy and molecular dynamics simulations to study the structural features of proteins. AB - In this work, we used a combination of fluorescence correlation spectroscopy (FCS) and molecular dynamics (MD) simulation methodologies to acquire structural information on pH-induced unfolding of the maltotriose-binding protein from Thermus thermophilus (MalE2). FCS has emerged as a powerful technique for characterizing the dynamics of molecules and it is, in fact, used to study molecular diffusion on timescale of microsecond and longer. Our results showed that keeping temperature constant, the protein diffusion coefficient decreased from 84+/-4 um(2)/s to 44+/-3 um(2)/s when pH was changed from 7.0 to 4.0. An even more marked decrease of the MalE2 diffusion coefficient (31+/-3 um(2)/s) was registered when pH was raised from 7.0 to 10.0. According to the size of MalE2 (a monomeric protein with a molecular weight of 43 kDa) as well as of its globular native shape, the values of 44 um(2)/s and 31 um(2)/s could be ascribed to deformations of the protein structure, which enhances its propensity to form aggregates at extreme pH values. The obtained fluorescence correlation data, corroborated by circular dichroism, fluorescence emission and light-scattering experiments, are discussed together with the MD simulations results. PMID- 23750216 TI - Host response and bacterial virulence factor expression in Pseudomonas aeruginosa and Streptococcus pneumoniae corneal ulcers. AB - P. aeruginosa and S. pneumoniae are major bacterial causes of corneal ulcers in industrialized and in developing countries. The current study examined host innate immune responses at the site of infection, and also expression of bacterial virulence factors in clinical isolates from patients in south India. Corneal ulcer material was obtained from 49 patients with confirmed P. aeruginosa and 27 patients with S. pneumoniae, and gene expression of Toll Like Receptors (TLR), cytokines and inflammasome proteins was measured by quantitative PCR. Expression of P. aeruginosa type III secretion exotoxins and S. pneumoniae pneumolysin was detected by western blot analysis. We found that neutrophils comprised >90% cells in corneal ulcers, and that there was elevated expression of TLR2, TLR4, TLR5 and TLR9, the NLRP3 and NLRC4 inflammasomes and the ASC adaptor molecule. IL-1alpha IL-1beta and IFN-gamma expression was also elevated; however, there was no significant difference in expression of any of these genes between corneal ulcers from P. aeruginosa and S. pneumoniae infected patients. We also show that 41/49 (84%) of P. aeruginosa clinical isolates expressed ExoS and ExoT, whereas 5/49 (10%) of isolates expressed ExoS, ExoT and ExoU with only 2/49 isolates expressing ExoT and ExoU. In contrast, all 27 S. pneumoniae clinical isolates produced pneumolysin. Taken together, these findings demonstrate that ExoS/T expressing P. aeruginosa and pneumolysin expressing S. pneumoniae predominate in bacterial keratitis. While P. aeruginosa strains expressing both ExoU and ExoS are usually rare, these strains actually outnumbered strains expressing only ExoU in the current study. Further, as neutrophils are the predominant cell type in these corneal ulcers, they are the likely source of cytokines and of the increased TLR and inflammasome expression. PMID- 23750217 TI - SOMA: a single oligonucleotide mutagenesis and cloning approach. AB - Modern biology research requires simple techniques for efficient and restriction site-independent modification of genetic material. Classical cloning and mutagenesis strategies are limited by their dependency on restriction sites and the use of complementary primer pairs. Here, we describe the Single Oligonucleotide Mutagenesis and Cloning Approach (SOMA) that is independent of restriction sites and only requires a single mutagenic oligonucleotide to modify a plasmid. We demonstrate the broad application spectrum of SOMA with three examples. First, we present a novel plasmid that in a standardized and rapid fashion can be used as a template for SOMA to generate GFP-reporters. We successfully use such a reporter to assess the in vivo knock-down quality of morpholinos in Xenopus laevis embryos. In a second example, we show how to use a SOMA-based protocol for restriction-site independent cloning to generate chimeric proteins by domain swapping between the two human hRMD5a and hRMD5b isoforms. Last, we show that SOMA simplifies the generation of randomized single-site mutagenized gene libraries. As an example we random-mutagenize a single codon affecting the catalytic activity of the yeast Ssy5 endoprotease and identify a spectrum of tolerated and non-tolerated substitutions. Thus, SOMA represents a highly efficient alternative to classical cloning and mutagenesis strategies. PMID- 23750218 TI - The role of recombination in the origin and evolution of Alu subfamilies. AB - Alus are the most abundant and successful short interspersed nuclear elements found in primate genomes. In humans, they represent about 10% of the genome, although few are retrotransposition-competent and are clustered into subfamilies according to the source gene from which they evolved. Recombination between them can lead to genomic rearrangements of clinical and evolutionary significance. In this study, we have addressed the role of recombination in the origin of chimeric Alu source genes by the analysis of all known consensus sequences of human Alus. From the allelic diversity of Alu consensus sequences, validated in extant elements resulting from whole genome searches, distinct events of recombination were detected in the origin of particular subfamilies of AluS and AluY source genes. These results demonstrate that at least two subfamilies are likely to have emerged from ectopic Alu-Alu recombination, which stimulates further research regarding the potential of chimeric active Alus to punctuate the genome. PMID- 23750219 TI - Harnessing natural recovery processes to improve restoration outcomes: an experimental assessment of sponge-mediated coral reef restoration. AB - BACKGROUND: Restoration is increasingly implemented to reestablish habitat structure and function following physical anthropogenic disturbance, but scientific knowledge of effectiveness of methods lags behind demand for guidelines. On coral reefs, recovery is largely dependent on coral reestablishment, and substratum stability is critical to the survival of coral fragments and recruits. Concrete is often used to immobilize rubble, but its ecological performance has not been rigorously evaluated, and restoration has generally fallen short of returning degraded habitat to pre-disturbance conditions. Fragments of erect branching sponges mediate reef recovery by facilitating rubble consolidation, yet such natural processes have been largely overlooked in restoring reefs. METHODS: On two reefs in Curacao, four treatments coral rubble alone, rubble seeded with sponge fragments, rubble bound by concrete, and concrete "rubble" bound by concrete - were monitored over four years to investigate rubble consolidation with and without sponges and the ecological performance of treatments in terms of the number and diversity of coral recruits. Species specific rates of sponge fragment attachment to rubble, donor sponge growth and tissue replacement, and fragment survival inside rubble piles were also investigated to evaluate sponge species performance and determine rates for sustainably harvesting tissue. FINDINGS/SIGNIFICANCE: Rubble piles seeded with sponges retained height and shape to a significantly greater degree, lost fewer replicates to water motion, and were significantly more likely to be consolidated over time than rubble alone. Significantly more corals recruited to sponge-seeded rubble than to all other treatments. Coral diversity was also greatest for rubble with sponges and it was the only treatment to which framework building corals recruited. Differences in overall sponge species performance suggest species selection is important to consider. Employing organisms that jump start successional pathways and facilitate recovery can significantly improve restoration outcomes; however, best practices require techniques be tailored to each system. PMID- 23750220 TI - Possible associations of NTRK2 polymorphisms with antidepressant treatment outcome: findings from an extended tag SNP approach. AB - BACKGROUND: Data from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment. METHODS: We performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples. RESULTS: In the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (Pcorr = .018, Pcorr = .015 and Pcorr = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients. CONCLUSIONS/LIMITATIONS: Although not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies. PMID- 23750221 TI - Oxidoreductases that act as conditional virulence suppressors in Salmonella enterica serovar Typhimurium. AB - In Salmonella enterica serovar Typhimurium, oxidoreductases of the thioredoxin superfamily contribute to bacterial invasiveness, intracellular replication and to the virulence in BALB/c mice as well as in the soil nematode Caenorhabditis elegans. The scsABCD gene cluster, present in many but not all enteric bacteria, codes for four putative oxidoreductases of the thioredoxin superfamily. Here we have analyzed the potential role of the scs genes in oxidative stress tolerance and virulence in S. Typhimurium. An scsABCD deletion mutant showed moderate sensitization to the redox-active transition metal ion copper and increased protein carbonylation upon exposure to hydrogen peroxide. Still, the scsABCD mutant was not significantly affected for invasiveness or intracellular replication in respectively cultured epithelial or macrophage-like cells. However, we noted a significant copper chloride sensitivity of SPI1 T3SS mediated invasiveness that strongly depended on the presence of the scs genes. The scsABCD deletion mutant was not attenuated in animal infection models. In contrast, the mutant showed a moderate increase in its competitive index upon intraperitoneal challenge and enhanced invasiveness in small intestinal ileal loops of BALB/c mice. Moreover, deletion of the scsABCD genes restored the invasiveness of a trxA mutant in epithelial cells and its virulence in C. elegans. Our findings thus demonstrate that the scs gene cluster conditionally affects virulence and underscore the complex interactions between oxidoreductases of the thioredoxin superfamily in maintaining host adaptation of S. Typhimurium. PMID- 23750222 TI - Characterization of the oligomerization and aggregation of human Serum Amyloid A. AB - The fibrillation of Serum Amyloid A (SAA) - a major acute phase protein - is believed to play a role in the disease Amyloid A (AA) Amyloidosis. To better understand the amyloid formation pathway of SAA, we characterized the oligomerization, misfolding, and aggregation of a disease-associated isoform of human SAA - human SAA1.1 (hSAA1.1) - using techniques ranging from circular dichroism spectroscopy to atomic force microscopy, fluorescence spectroscopy, immunoblot studies, solubility measurements, and seeding experiments. We found that hSAA1.1 formed alpha helix-rich, marginally stable oligomers in vitro on refolding and cross-beta-rich aggregates following incubation at 37 degrees C. Strikingly, while hSAA1.1 was not highly amyloidogenic in vitro, the addition of a single N-terminal methionine residue significantly enhanced the fibrillation propensity of hSAA1.1 and modulated its fibrillation pathway. A deeper understanding of the oligomerization and fibrillation pathway of hSAA1.1 may help elucidate its pathological role. PMID- 23750223 TI - Quantitative trait loci (QTL) associated with resistance to a monogenean parasite (Benedenia seriolae) in yellowtail (Seriola quinqueradiata) through genome wide analysis. AB - Benedenia infections caused by the monogenean fluke ectoparasite Benedenia seriolae seriously impact marine finfish aquaculture. Genetic variation has been inferred to play a significant role in determining the susceptibility to this parasitic disease. To evaluate the genetic basis of Benedenia disease resistance in yellowtail (Seriola quinqueradiata), a genome-wide and chromosome-wide linkage analyses were initiated using F1 yellowtail families (n = 90 per family) based on a high-density linkage map with 860 microsatellite and 142 single nucleotide polymorphism (SNP) markers. Two major quantitative trait loci (QTL) regions on linkage groups Squ2 (BDR-1) and Squ20 (BDR-2) were identified. These QTL regions explained 32.9-35.5% of the phenotypic variance. On the other hand, we investigated the relationship between QTL for susceptibility to B. seriolae and QTL for fish body size. The QTL related to growth was found on another linkage group (Squ7). As a result, this is the first genetic evidence that contributes to detailing phenotypic resistance to Benedenia disease, and the results will help resolve the mechanism of resistance to this important parasitic infection of yellowtail. PMID- 23750224 TI - Altered functionality of anti-bacterial antibodies in patients with chronic hepatitis C virus infection. AB - BACKGROUND: Using comparative glycoproteomics, we have previously identified a glycoprotein that is altered in both amount and glycosylation as a function of liver cirrhosis. The altered glycoprotein is an agalactosylated (G0) immunoglobulin G molecule (IgG) that recognizes the heterophilic alpha-gal epitope. Since the alpha gal epitope is found on gut enterobacteria, it has been hypothesized that anti-gal antibodies are generated as a result of increased bacterial exposure in patients with liver disease. METHODS: The N-linked glycosylation of anti-gal IgG molecules from patients with fibrosis and cirrhosis was determined and the effector function of anti-bacterial antibodies from over 100 patients examined. In addition, markers of microbial exposure were determined. RESULTS: Surprisingly, the subset of agalactosylated anti-gal antibodies described here, was impaired in their ability to mediate complement mediated lysis and inhibited the complement-mediated destruction of common gut bacteria. In an analysis of serum from more than 100 patients with liver disease, we have shown that those with increased levels of this modified anti-gal antibody had increased levels of markers of bacterial exposure. CONCLUSIONS: Anti-gal antibodies in patients with liver cirrhosis were reduced in their ability to mediate complement mediated lysis of target cells. As bacterial infection is a major complication in patients with cirrhosis and bacterial products such as LPS are thought to play a major role in the development and progression of liver fibrosis, this finding has many clinical implications in the etiology, prognosis and treatment of liver disease. PMID- 23750225 TI - Adverse reactions due to directly observed treatment strategy therapy in Chinese tuberculosis patients: a prospective study. AB - BACKGROUND: More than 1 million tuberculosis (TB) patients are receiving directly observed treatment strategy (DOTS) therapy in China every year. As to the profile of adverse drug reactions (ADRs) due to DOTS therapy, no consensus has been reached. There is no report regarding ADRs due to DOTS therapy with a large Chinese TB population. This study aimed to determine the incidence and prognosis of ADRs due to DOTS therapy, and to evaluate their impact on anti-TB treatment in China. METHODS: A prospective population-based cohort study was performed during 2007-2008. Sputum smear positive pulmonary TB patients who received DOTS therapy were included and followed up for six to nine months in 52 counties of four regions in China. The suspected ADRs were recorded and reviewed by Chinese State Food and Drug Administration. RESULTS: A total of 4304 TB patients were included in this study. 649 patients (15.08%) showed at least one ADR and 766 cases in total were detected. The incidence (count) of ADR based on affected organ was: liver dysfunction 6.34% (273), gastrointestinal disorders 3.74% (161), arthralgia 2.51% (108), allergic reactions 2.35% (101), neurological system disorders 2.04% (88), renal impairment 0.07% (3) and others 0.05% (2). Most cases of ADRs (95%) had a good clinical outcome, while two with hepatotoxicity and one with renal impairment died. Compared with patients without ADRs, patients with ADRs were more likely to have positive smear test results at the end of the intensive phase (adjusted OR, 2.00; 95%CI, 1.44-2.78) and unsuccessful anti-TB outcomes (adjusted OR, 2.58; 95%CI, 1.43-4.68). CONCLUSIONS: The incidence of ADRs due to DOTS therapy was 15.08%. Those ADRs had a substantial impact on TB control in China. This highlighted the importance of developing strategies to ameliorate ADRs both to improve the quality of patient care and to control TB safely. PMID- 23750226 TI - Replication and transcription activities of ribonucleoprotein complexes reconstituted from avian H5N1, H1N1pdm09 and H3N2 influenza A viruses. AB - Avian influenza viruses pose a serious pandemic threat to humans. Better knowledge on cross-species adaptation is important. This study examined the replication and transcription efficiency of ribonucleoprotein complexes reconstituted by plasmid co-transfection between H5N1, H1N1pdm09 and H3N2 influenza A viruses, and to identify mutations in the RNA polymerase subunit that affect human adaptation. Viral RNA polymerase subunits PB1, PB2, PA and NP derived from influenza viruses were co-expressed with pPolI-vNP-Luc in human cells, and with its function evaluated by luciferase reporter assay. A quantitative RT-PCR was used to measure vRNA, cRNA, and mRNA levels for assessing the replication and transcription efficiency. Mutations in polymerase subunit were created to identify signature of increased human adaptability. H5N1 ribonucleoprotein complexes incorporated with PB2 derived from H1N1pdm09 and H3N2 viruses increased the polymerase activity in human cells. Furthermore, single amino acid substitutions at PB2 of H5N1 could affect polymerase activity in a temperature-dependent manner. By using a highly sensitive quantitative reverse transcription-polymerase chain reaction, an obvious enhancement in replication and transcription activities of ribonucleoproteins was observed by the introduction of lysine at residue 627 in the H5N1 PB2 subunit. Although less strongly in polymerase activity, E158G mutation appeared to alter the accumulation of H5N1 RNA levels in a temperature-dependent manner, suggesting a temperature-dependent mechanism in regulating transcription and replication exists. H5N1 viruses can adapt to humans either by acquisition of PB2 from circulating human-adapted viruses through reassortment, or by mutations at critical sites in PB2. This information may help to predict the pandemic potential of newly emerged influenza strains, and provide a scientific basis for stepping up surveillance measures and vaccine production. PMID- 23750227 TI - Spatial prediction of N2O emissions in pasture: a Bayesian model averaging analysis. AB - Nitrous oxide (N2O) is one of the greenhouse gases that can contribute to global warming. Spatial variability of N2O can lead to large uncertainties in prediction. However, previous studies have often ignored the spatial dependency to quantify the N2O - environmental factors relationships. Few researches have examined the impacts of various spatial correlation structures (e.g. independence, distance-based and neighbourhood based) on spatial prediction of N2O emissions. This study aimed to assess the impact of three spatial correlation structures on spatial predictions and calibrate the spatial prediction using Bayesian model averaging (BMA) based on replicated, irregular point-referenced data. The data were measured in 17 chambers randomly placed across a 271 m(2) field between October 2007 and September 2008 in the southeast of Australia. We used a Bayesian geostatistical model and a Bayesian spatial conditional autoregressive (CAR) model to investigate and accommodate spatial dependency, and to estimate the effects of environmental variables on N2O emissions across the study site. We compared these with a Bayesian regression model with independent errors. The three approaches resulted in different derived maps of spatial prediction of N2O emissions. We found that incorporating spatial dependency in the model not only substantially improved predictions of N2O emission from soil, but also better quantified uncertainties of soil parameters in the study. The hybrid model structure obtained by BMA improved the accuracy of spatial prediction of N2O emissions across this study region. PMID- 23750229 TI - Utility and limitation of cumulative stone diameter in predicting urinary stone burden at flexible ureteroscopy with holmium laser lithotripsy: a single-center experience. AB - PURPOSE: To retrospectively assess the clinical utility in ureteroscopy (URS) planning of cumulative stone diameter (CSD), which does not account for stone width or depth, as a predictor of URS outcome and compare it with stone volume. MATERIALS AND METHODS: Patients with renal stones treated at a single institute by flexible URS were retrospectively evaluated. To assess the clinical utility of CSD, relationships between stone-free (SF) status and stone burden (CSD and volume) were analyzed using the area under the receiver operating characteristics (AUROC) curve. To identify stone number impact on CSD, the AUROC of CSD divided by stone number was evaluated. Correlation coefficients of CSD and stone volume were also calculated for groups by stone number. RESULTS: In cases with CSD <20.0 mm, CSD and stone volume revealed equal ability to predict SF status. In cases with CSD >=20.0 mm, stone volume showed higher predictive ability. The ROC curves for cases with >=4 stones showed that CSD was less predictive of SF status than stone volume. The correlation coefficients of CSD and stone volume by stone number were 0.922 for 1 stone, 0.900 for 2-3 stones, and 0.661 for >=4 stones. CONCLUSIONS: In cases with CSD >=20.0 mm or >=4 stones, we should evaluate stone volume for a more predictive stone burden, and pretreatment non-contrast CT seems sufficient. In cases with CSD <20.0 mm or 1-3 stones, CSD was as valid a predictor of preoperative stone burden as stone volume, so preoperative kidney ureter-bladder (KUB) films may be sufficient. PMID- 23750228 TI - Interaction of Medicago truncatula lysin motif receptor-like kinases, NFP and LYK3, produced in Nicotiana benthamiana induces defence-like responses. AB - Receptor(-like) kinases with Lysin Motif (LysM) domains in their extracellular region play crucial roles during plant interactions with microorganisms; e.g. Arabidopsis thaliana CERK1 activates innate immunity upon perception of fungal chitin/chitooligosaccharides, whereas Medicago truncatula NFP and LYK3 mediate signalling upon perception of bacterial lipo-chitooligosaccharides, termed Nod factors, during the establishment of mutualism with nitrogen-fixing rhizobia. However, little is still known about the exact activation and signalling mechanisms of MtNFP and MtLYK3. We aimed at investigating putative molecular interactions of MtNFP and MtLYK3 produced in Nicotiana benthamiana. Surprisingly, heterologous co-production of these proteins resulted in an induction of defence like responses, which included defence-related gene expression, accumulation of phenolic compounds, and cell death. Similar defence-like responses were observed upon production of AtCERK1 in N. benthamiana leaves. Production of either MtNFP or MtLYK3 alone or their co-production with other unrelated receptor(-like) kinases did not induce cell death in N. benthamiana, indicating that a functional interaction between these LysM receptor-like kinases is required for triggering this response. Importantly, structure-function studies revealed that the MtNFP intracellular region, specific features of the MtLYK3 intracellular region (including several putative phosphorylation sites), and MtLYK3 and AtCERK1 kinase activity were indispensable for cell death induction, thereby mimicking the structural requirements of nodulation or chitin-induced signalling. The observed similarity of N. benthamiana response to MtNFP and MtLYK3 co-production and AtCERK1 production suggests the existence of parallels between Nod factor-induced and chitin-induced signalling mediated by the respective LysM receptor(-like) kinases. Notably, the conserved structural requirements for MtNFP and MtLYK3 biological activity in M. truncatula (nodulation) and in N. benthamiana (cell death induction) indicates the relevance of the latter system for studies on these, and potentially other symbiotic LysM receptor-like kinases. PMID- 23750230 TI - A genome-wide survey of genetic variation in gorillas using reduced representation sequencing. AB - All non-human great apes are endangered in the wild, and it is therefore important to gain an understanding of their demography and genetic diversity. Whole genome assembly projects have provided an invaluable foundation for understanding genetics in all four genera, but to date genetic studies of multiple individuals within great ape species have largely been confined to mitochondrial DNA and a small number of other loci. Here, we present a genome wide survey of genetic variation in gorillas using a reduced representation sequencing approach, focusing on the two lowland subspecies. We identify 3,006,670 polymorphic sites in 14 individuals: 12 western lowland gorillas (Gorilla gorilla gorilla) and 2 eastern lowland gorillas (Gorilla beringei graueri). We find that the two species are genetically distinct, based on levels of heterozygosity and patterns of allele sharing. Focusing on the western lowland population, we observe evidence for population substructure, and a deficit of rare genetic variants suggesting a recent episode of population contraction. In western lowland gorillas, there is an elevation of variation towards telomeres and centromeres on the chromosomal scale. On a finer scale, we find substantial variation in genetic diversity, including a marked reduction close to the major histocompatibility locus, perhaps indicative of recent strong selection there. These findings suggest that despite their maintaining an overall level of genetic diversity equal to or greater than that of humans, population decline, perhaps associated with disease, has been a significant factor in recent and long-term pressures on wild gorilla populations. PMID- 23750232 TI - On-call duty effects on sleep-state physiological stability in male medical interns. AB - BACKGROUND: On-call duty among medical interns is characterized by sleep deprivation and stressful working conditions, both of which alter cardiac autonomic modulation. We hypothesized that sleep stability decreased in medical interns during on-call duty. We used cardiopulmonary-coupling (CPC) analysis to test our hypothesis. METHODS: We used electrocardiogram (ECG)-based CPC analysis to quantify physiological parameters of sleep stability in 13 medical interns during on-call and on-call duty-free periods. There were ten 33.5-h on-call duty shifts per month for interns, each followed by 2 on-call duty-free days, over 3 months. Measurements during sleep were collected before, during, and after an on call shift. Measurements were repeated 3 months later during an on-call duty-free period. RESULTS: The medical interns had significantly reduced stable sleep, and displayed increased latency to the first epoch of stable sleep during the on-call night shift, compared to the pre-call and on-call duty-free nights. Interns also had significantly increased rapid-eye-movement (REM) sleep during the on-call night shift, compared to the pre-call and on-call duty-free nights. CONCLUSION: Medical interns suffer disrupted sleep stability and continuity during on-call night shifts. The ECG-based CPC analysis provides a straightforward means to quantify sleep quality and stability in medical staff performing shift work under stressful conditions. PMID- 23750233 TI - The morphology and adhesion mechanism of Octopus vulgaris suckers. AB - The octopus sucker represents a fascinating natural system performing adhesion on different terrains and substrates. Octopuses use suckers to anchor the body to the substrate or to grasp, investigate and manipulate objects, just to mention a few of their functions. Our study focuses on the morphology and adhesion mechanism of suckers in Octopus vulgaris. We use three different techniques (MRI, ultrasonography, and histology) and a 3D reconstruction approach to contribute knowledge on both morphology and functionality of the sucker structure in O. vulgaris. The results of our investigation are two-fold. First, we observe some morphological differences with respect to the octopus species previously studied (i.e., Octopus joubini, Octopus maya, Octopus bimaculoides/bimaculatus and Eledone cirrosa). In particular, in O. vulgaris the acetabular chamber, that is a hollow spherical cavity in other octopuses, shows an ellipsoidal cavity which roof has an important protuberance with surface roughness. Second, based on our findings, we propose a hypothesis on the sucker adhesion mechanism in O. vulgaris. We hypothesize that the process of continuous adhesion is achieved by sealing the orifice between acetabulum and infundibulum portions via the acetabular protuberance. We suggest this to take place while the infundibular part achieves a completely flat shape; and, by sustaining adhesion through preservation of sucker configuration. In vivo ultrasonographic recordings support our proposed adhesion model by showing the sucker in action. Such an underlying physical mechanism offers innovative potential cues for developing bioinspired artificial adhesion systems. Furthermore, we think that it could possibly represent a useful approach in order to investigate any potential difference in the ecology and in the performance of adhesion by different species. PMID- 23750231 TI - MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons. AB - Clinical, epidemiological, and genetic evidence suggest overlapping pathogenic mechanisms between autism spectrum disorder (ASD) and schizophrenia. We tested this hypothesis by asking if mutations in the ASD gene MECP2 which cause Rett syndrome affect the expression of genes encoding the schizophrenia risk factor dysbindin, a subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1), and associated interacting proteins. We measured mRNA and protein levels of key components of a dysbindin interaction network by, quantitative real time PCR and quantitative immunohistochemistry in hippocampal samples of wild type and Mecp2 mutant mice. In addition, we confirmed results by performing immunohistochemistry of normal human hippocampus and quantitative qRT-PCR of human inducible pluripotent stem cells (iPSCs)-derived human neurons from Rett syndrome patients. We defined the distribution of the BLOC-1 subunit pallidin in human and mouse hippocampus and contrasted this distribution with that of symptomatic Mecp2 mutant mice. Neurons from mutant mice and Rett syndrome patients displayed selectively reduced levels of pallidin transcript. Pallidin immunoreactivity decreased in the hippocampus of symptomatic Mecp2 mutant mice, a feature most prominent at asymmetric synapses as determined by immunoelectron microcopy. Pallidin immunoreactivity decreased concomitantly with reduced BDNF content in the hippocampus of Mecp2 mice. Similarly, BDNF content was reduced in the hippocampus of BLOC-1 deficient mice suggesting that genetic defects in BLOC 1 are upstream of the BDNF phenotype in Mecp2 deficient mice. Our results demonstrate that the ASD-related gene Mecp2 regulates the expression of components belonging to the dysbindin interactome and these molecular differences may contribute to synaptic phenotypes that characterize Mecp2 deficiencies and ASD. PMID- 23750234 TI - Association between provider volume and healthcare expenditures of patients with oral cancer in Taiwan: a population-based study. AB - BACKGROUND: Oral cancer requires considerable utilization of healthcare services. Wide resection of the tumor and reconstruction with free flap are widely used. Due to high recurrence rate, close follow-up is mandatory. This study was conducted to explore the relationship between the healthcare expenditure of oncological surgery and one-year follow up and provider volume. METHODS: From the National Health Insurance Research Database published by the Taiwanese National Health Research Institute, the authors selected a total of 1300 oral cancer patients who underwent tumor resection and free flap reconstruction in 2008. Hierarchical linear regression analysis was subsequently performed to explore the relationship between provider volume and expenditures of oncological surgery and one-year follow-up period. Emergency department (ED) visits and 30-day readmission rates were also analyzed. RESULTS: The mean expenditure for oncological surgery was $11080+/-4645 (all costs are given in U.S. dollars) and $10129+/-9248 for one-year follow up. For oncological surgery expenditure, oral cancer patients treated by low-volume surgeons had an additional $845 than those in high-volume surgeons in mixed model. For one-year follow-up expenditure, patients in low-volume hospitals had an additional $3439 than those in high volume hospitals; patient in low-volume surgeons and medium-volume surgeons incurred an additional expenditure of $2065 and $1811 than those in high-volume surgeons. Oral cancer patients treated in low-volume hospitals incurred higher risk of 30-day readmission rate (odds ratio, 6.6; 95% confidence interval, 1.6 27). CONCLUSIONS: After adjusting for physician, hospital, and patient characteristics, low-volume provider performing wide excision with reconstructive surgery in oral cancer patients incurred significantly higher expenditure for oncological surgery and one-year healthcare per patient than did others with higher volumes. Treatment strategies adapted by high-volume providers should be further analyzed. PMID- 23750235 TI - Adaptability and persistence of the emerging pathogen Bordetella petrii. AB - The first described, environmentally isolated, Bordetella petrii was shown to undergo massive genomic rearrangements in vitro. More recently, B. petrii was isolated from clinical samples associated with jaw, ear bone, cystic fibrosis and chronic pulmonary disease. However, the in vivo consequences of B. petrii genome plasticity and its pathogenicity remain obscure. B. petrii was identified from four sequential respiratory samples and a post-mortem spleen sample of a woman presenting with bronchiectasis and cavitary lung disease associated with nontuberculous mycobacterial infection. Strains were compared genetically, phenotypically and by antibody recognition from the patient and from inoculated mice. The successive B. petrii strains exhibited differences in growth, antibiotic susceptibility and recognition by the patient's antibodies. Antibodies from mice inoculated with these strains recapitulated the specificity and strain dependent response that was seen with the patient's serum. Finally, we characterize one strain that was poorly recognized by the patient's antibodies, due to a defect in the lipopolysaccharide O-antigen, and identify a mutation associated with this phenotype. We propose that B. petrii is remarkably adaptable in vivo, providing a possible connection between immune response and bacterial evasion and supporting infection persistence. PMID- 23750236 TI - Different effects of three polymorphisms in MicroRNAs on cancer risk in Asian population: evidence from published literatures. AB - MicroRNAs (miRNAs) are a class of small non-protein-coding RNAs, which have emerged as integrated and important post-transcriptional regulators of gene expression. It has been demonstrated that single nucleotide polymorphisms (SNPs) exist in protein-coding genes. Accumulated studies have evaluated the association of miRNA SNPs with cancer risk, especially in Asian population, which included a series of related studies. However, the results remain controversial for the different genetic backgrounds, living habits and environment exposed. To evaluate the relationship between SNPs in miRNAs and cancer risk, 21 studies focused on Asian population were enrolled for the pooled analysis for three polymorphisms rs2910164, rs11614913, rs3746444 in three miRNAs miR-146aG>C, miR-196a2C>T, miR 499A>G using odds ratios (ORs) with 95% confidence intervals (CIs). For rs2910164 polymorphism, C allele was observed association with decreased overall cancer risk. In addition, subgroup analysis revealed of rs2910164 C allele decreased hepatocellular carcinoma (HCC), cervical cancer and prostate cancer risk among Chinese population. For rs11614913 polymorphism, TT genotype was observed to be associated with decreased cancer risk, especially for cancer type of colorectal cancer (CRC), lung cancer and country of Korea, North India. Whereas, rs3746444 G allele was an increased cancer risk factor in Chinese population, especially for breast cancer. In conclusion, this meta-analysis indicated that rs2910164 C allele was associated with decreased cancer risk in Chinese population. However, the association varied from different cancer types. Furthermore, TT genotype of rs11614913 was associated with decreased cancer risk. While different cancer types and countries contributed to different effects. Whereas, rs3746444 G allele was a risk factor in Chinese population, and the association varied from different cancer types. PMID- 23750238 TI - Epithelial cell differentiation regulated by MicroRNA-200a in mammary glands. AB - Mammary gland epithelial cells undergo periodic cycles of proliferation, differentiation, and involution. Many studies have reported that miRNAs, which are small, non-coding RNAs, influence a variety of biological processes during posttranscriptional regulation. Here, we found that one miRNA, miR-200a, was relatively highly expressed in epithelial cell-rich organs such as mammary glands, lung, and kidney in mice. In mammary glands, miR-200a expression increased during mid-pregnancy through lactation; its expression was stimulated by lactogenic hormone treatment of mammary epithelial cells. Lactogenic hormone also induced the expression of milk protein beta-casein mRNA (a marker of cell differentiation) and E-cadherin mRNA (a marker of epithelial cells). However, knockdown of miR-200a prevented increases in beta-casein and E-cadherin mRNA expression. Protein analysis revealed that E-cadherin signal was decreased and ZEB1 (a marker of EMT) was increased following miR-200a knockdown. Finally, in a three-dimensional culture system modeling lumen-containing mammary ducts, miR 200a knockdown decreased the cavity formation rate and suppressed claudin-3 and par-6b expression, indicating reduced epithelial cell polarity. These observations suggest that miR-200a is important for maintaining the epithelial cell phenotype, which contributes to lactogenic hormone induction of cellular differentiation in mammary glands. PMID- 23750237 TI - Glycogen and glucose metabolism are essential for early embryonic development of the red flour beetle Tribolium castaneum. AB - Control of energy metabolism is an essential process for life. In insects, egg formation (oogenesis) and embryogenesis is dependent on stored molecules deposited by the mother or transcribed later by the zygote. In oviparous insects the egg becomes an isolated system after egg laying with all energy conversion taking place during embryogenesis. Previous studies in a few vector species showed a strong correlation of key morphogenetic events and changes in glucose metabolism. Here, we investigate glycogen and glucose metabolism in the red flour beetle Tribolium castaneum, an insect amenable to functional genomic studies. To examine the role of the key enzymes on glycogen and glucose regulation we cloned and analyzed the function of glycogen synthase kinase 3 (GSK-3) and hexokinase (HexA) genes during T. castaneum embryogenesis. Expression analysis via in situ hybridization shows that both genes are expressed only in the embryonic tissue, suggesting that embryonic and extra-embryonic cells display different metabolic activities. dsRNA adult female injection (parental RNAi) of both genes lead a reduction in egg laying and to embryonic lethality. Morphological analysis via DAPI stainings indicates that early development is impaired in Tc-GSK-3 and Tc HexA1 RNAi embryos. Importantly, glycogen levels are upregulated after Tc-GSK-3 RNAi and glucose levels are upregulated after Tc-HexA1 RNAi, indicating that both genes control metabolism during embryogenesis and oogenesis, respectively. Altogether our results show that T. castaneum embryogenesis depends on the proper control of glucose and glycogen. PMID- 23750239 TI - MiR-26a inhibits proliferation and migration of breast cancer through repression of MCL-1. AB - Breast cancer is the most commonly malignancies in women. MicroRNAs are a family of small non-coding RNAs 18-25 nucleotides in length that post-transcriptionally modulate gene expression. MiR-26a has been reported as a tumor suppressor microRNA in breast cancer, which is attributed mainly to targeting of MTDH and EZH2, however, the expression profile and therapeutic potential of miR-26a is still unclear. Here we demonstrate that miR-26a is down-regulated in breast cancer cells and clinical specimens and its modulation in breast cancer cells regulates cell proliferation, colony formation, migration and apoptosis. MCL-1, an anti-apoptotic member of the Bcl-2 family, as novel targets of miR-26a was found to be in reverse correlation with ectopic expression of miR-26a and knockdown of MCL-1 phenocopied the effect of miR-26a in breast cancer cell lines. It was further explored that miR-26a increased sensitivity of breast cancer cells to paclitaxel in which MCL-1 was involved. Thus, miR-26a impacts on cell proliferation and migration of breast cancer by regulating several carcinogenesis related processes, including a novel mechanism involving the targeting of MCL-1. PMID- 23750240 TI - Effect of ethiopia's health extension program on maternal and newborn health care practices in 101 rural districts: a dose-response study. AB - BACKGROUND: Improving newborn survival is essential if Ethiopia is to achieve Millennium Development Goal 4. The national Health Extension Program (HEP) includes community-based newborn survival interventions. We report the effect of these interventions on changes in maternal and newborn health care practices between 2008 and 2010 in 101 districts, comprising 11.6 million people, or 16% of Ethiopia's population. METHODS AND FINDINGS: Using data from cross-sectional surveys in December 2008 and December 2010 from a representative sample of 117 communities (kebeles), we estimated the prevalence of maternal and newborn care practices, and a program intensity score in each community. Women with children aged 0 to 11 months reported care practices for their most recent pregnancy and childbirth. The program intensity score ranged between zero and ten and was derived from four outreach activities of the HEP front-line health workers. Dose response relationships between changes in program intensity and the changes in maternal and newborn health were investigated using regression methods, controlling for secular trend, respondents' background characteristics, and community-level factors. Between 2008 and 2010, median program intensity score increased 2.4-fold. For every unit increase in the score, the odds of receiving antenatal care increased by 1.13 times (95% CI 1.03-1.23); the odds of birth preparedness increased by 1.31 times (1.19-1.44); the odds of receiving postnatal care increased by 1.60 times (1.34-1.91); and the odds of initiating breastfeeding immediately after birth increased by 1.10 times (1.02-1.20). Program intensity score was not associated with skilled deliveries, nor with some of the other newborn health care indicators. CONCLUSIONS: The results of our analysis suggest that Ethiopia's HEP platform has improved maternal and newborn health care practices at scale. However, implementation research will be required to address the maternal and newborn care practices that were not influenced by the HEP outreach activities. PMID- 23750241 TI - External validation of a nomogram that predicts the pathological diagnosis of thyroid nodules in a Chinese population. AB - INTRODUCTION: Nomograms are statistical predictive models that can provide the probability of a clinical event. Nomograms have better performance for the estimation of individual risks because of their increased accuracy and objectivity relative to physicians' personal experiences. Recently, a nomogram for predicting the likelihood that a thyroid nodule is malignant was introduced by Nixon. The aim of this study was to determine whether Nixon's nomogram can be validated in a Chinese population. MATERIALS AND METHODS: All consecutive patients with thyroid nodules who underwent surgery between January and June 2012 in our hospital were enrolled to validate Nixon's nomogram. Univariate and multivariate analyses were used to identify the risk factors for thyroid carcinoma. Discrimination and calibration were employed to evaluate the performance of Nixon's model in our population. RESULTS: A total of 348 consecutive patients with 409 thyroid nodules were enrolled. Thyroid ultrasonographic characteristics, including shape, echo texture, calcification, margins, vascularity and number (solitary vs. multiple nodules), were associated with malignance in the multivariate analysis. The discrimination of all nodules group, the group with a low risk of malignancy (predictive proportion <50%) and the group with a high risk of malignancy (predictive proportion >=50%) using Nixon's nomogram was satisfactory, and the area under the receiver operating characteristic curve of the three groups were 0.87, 0.75 and 0.72, respectively. However, the calibration was significant (p = 0.55) only in the high-risk group. CONCLUSION: Nixon's nomogram is a valuable predictive model for the Chinese population and has been externally validated. It has good performance for patients with a high risk of malignancy and may be more suitable for use with these patients in China. PMID- 23750242 TI - Predators and resources influence phosphorus transfer along an invertebrate food web through changes in prey behaviour. AB - Predators play a fundamental role in prey trophic behaviour, with indirect consequences for species coexistence and ecosystem functioning. Resource quality and availability also influence prey trophic behaviour, with potential effects on predator-prey dynamics. Although many studies have addressed these topics, little attention has been paid to the combined effects of predators and resources on prey species coexistence and nutrient transfer along food chains, especially in detritus-based systems. To determine the influence of predators and resource quality on the movement and P uptake of detritivores, we carried out a field experiment on the River Kelvin (Scotland) using (32)P to test the hypothesis of reduced prey vagility among resource patches as a strategy to avoid predation. Thirty leaf sacks containing alder leaves and two detritivore prey populations (Asellus aquaticus and Lymnaea peregra) were placed in cages, half of them with two predator species (Dendrocoelum lacteum and Erpobdella octoculata) and the other half without predators. Five alder leaf bags, each individually inoculated with a different fungus strain to simulate a patchy habitat, were placed inside each leaf sack. One bag in each sack was labelled with (32)P, in order to assess the proportion of detritivores using it as food and thus their movement among the five resource patches. Three replicates for each labelled fungus and each predation treatment (i.e. with and without predators) were left on the riverbed for 7 days. The presence of predators had negligible effects on the number of detritivores in the leaf bags, but it did reduce the proportion of (32)P-labelled detritivores and their P uptake. The most strongly affected species was A. aquaticus, whose vagility, trophic overlap with L. peregra and P uptake were all reduced. The results confirm the importance of bottom-up and top-down forces acting simultaneously to regulate nutrient transfer along food chains in patchy habitats. PMID- 23750243 TI - Physical activity in German adolescents measured by accelerometry and activity diary: introducing a comprehensive approach for data management and preliminary results. AB - INTRODUCTION: Surveillance of physical activity (PA) is increasingly based on accelerometry. However, data management guidelines are lacking. We propose an approach for combining accelerometry and diary based PA information for assessment of PA in adolescents and provide an example of this approach using data from German adolescents. METHODS: The 15-year-old participants comprised a subsample the GINIplus birth cohort (n = 328, 42.4% male). Data on PA was obtained from hip-worn accelerometers (ActiGraph GT3X) for seven consecutive days, combined with a prospective activity diary. Major aspects of data management were validity of wear time, handling of non-wear time and diary comments. After data cleaning, PA and percentage of adolescents meeting the recommendations for moderate-to-vigorous activity (MVPA) per day were determined. RESULTS: From the 2224 recorded days 493 days (25%) were invalid, mainly due to uncertainties relating to non-wear time (322 days). Ultimately, 269 of 328 subjects (82%) with valid data for at least three weekdays and one weekend day were included in the analysis. Mean MVPA per day was 39.1 minutes (SD +/-25.0), with boys being more active than girls (41.8+/-21.5 minutes vs. 37.1+/-27.8 minutes, p<0.001). Accordingly, 24.7% of boys and 17.2% of girls (p<0.01) met the WHO recommendations for PA. School sport accounted for only 6% of weekly MVPA. In fact, most MVPA was performed during leisure time, with the majority of adolescents engaging in ball sports (25.4%) and endurance sports (19.7%). Girls also frequently reported dancing and gymnastics (23%). CONCLUSION: For assessment of PA in adolescents, collecting both accelerometry and diary-based information is recommended. The diary is vital for the identification of invalid data and non compliant participants. Preliminary results suggest that four out of five German adolescents do not meet WHO recommendations for PA and that school sport contributes only little to MVPA. PMID- 23750244 TI - Cell-autonomous defects in thymic epithelial cells disrupt endothelial perivascular cell interactions in the mouse thymus. AB - The thymus is composed of multiple stromal elements comprising specialized stromal microenvironments responsible for the development of self-tolerant and self-restricted T cells. Here, we investigated the ontogeny and maturation of the thymic vasculature. We show that endothelial cells initially enter the thymus at E13.5, with PDGFR-beta(+) mesenchymal cells following at E14.5. Using an allelic series of the thymic epithelial cell (TEC) specific transcription factor Foxn1, we showed that these events are delayed by 1-2 days in Foxn1 (Delta/Delta) mice, and this phenotype was exacerbated with reduced Foxn1 dosage. At subsequent stages there were fewer capillaries, leaky blood vessels, disrupted endothelium - perivascular cell interactions, endothelial cell vacuolization, and an overall failure of vascular organization. The expression of both VEGF-A and PDGF-B, which are both primarily expressed in vasculature-associated mesenchyme or endothelium in the thymus, were reduced at E13.5 and E15.5 in Foxn1 (Delta/Delta) mice compared with controls. These data suggest that Foxn1 is required in TECs both to recruit endothelial cells and for endothelial cells to communicate with thymic mesenchyme, and for the differentiation of vascular-associated mesenchymal cells. These data show that Foxn1 function in TECs is required for normal thymus size and to generate the cellular and molecular environment needed for normal thymic vascularization. These data further demonstrate a novel TEC-mesenchyme endothelial interaction required for proper fetal thymus organogenesis. PMID- 23750245 TI - Transcriptome sequencing and de novo analysis of a cytoplasmic male sterile line and its near-isogenic restorer line in chili pepper (Capsicum annuum L.). AB - BACKGROUND: The use of cytoplasmic male sterility (CMS) in F1 hybrid seed production of chili pepper is increasingly popular. However, the molecular mechanisms of cytoplasmic male sterility and fertility restoration remain poorly understood due to limited transcriptomic and genomic data. Therefore, we analyzed the difference between a CMS line 121A and its near-isogenic restorer line 121C in transcriptome level using next generation sequencing technology (NGS), aiming to find out critical genes and pathways associated with the male sterility. RESULTS: We generated approximately 53 million sequencing reads and assembled de novo, yielding 85,144 high quality unigenes with an average length of 643 bp. Among these unigenes, 27,191 were identified as putative homologs of annotated sequences in the public protein databases, 4,326 and 7,061 unigenes were found to be highly abundant in lines 121A and 121C, respectively. Many of the differentially expressed unigenes represent a set of potential candidate genes associated with the formation or abortion of pollen. CONCLUSIONS: Our study profiled anther transcriptomes of a chili pepper CMS line and its restorer line. The results shed the lights on the occurrence and recovery of the disturbances in nuclear-mitochondrial interaction and provide clues for further investigations. PMID- 23750246 TI - 2-aminopurine enhances the oncolytic activity of an E1b-deleted adenovirus in hepatocellular carcinoma cells. AB - Adenoviruses with deletions of viral genes have been extensively studied as potential cancer therapeutics. Although a high degree of cancer selectivity has been demonstrated with these conditionally replicating adenoviruses, low levels of virus replication can be detected in normal cells. Furthermore, these mutations were also found to reduce the activity of the replicating viruses in certain cancer cells. Recent studies have shown that co-administration of chemotherapeutic drugs may increase the activity of these viruses without affecting their specificity. We constructed an adenovirus with deletions of both the E1b and the VA-RNA genes and found that replication of this virus was selective for human hepatocellular carcinoma (HCC) cell lines when compared to normal cell lines. Furthermore, we show that 2-aminopurine (2'AP) treatment selectively enhanced virus replication and virus-mediated death of HCC cells. 2'AP did not compensate for the loss of VA-RNA activities, but rather the loss of an E1b-55K activity, such as the DNA damage response, suggesting that co administration of 2'AP derivatives that block host DNA damage response, may increase the oncolytic activity of AdDeltaE1bDeltaVA without reducing its selectivity for HCC cells. PMID- 23750247 TI - TWEAK-independent Fn14 self-association and NF-kappaB activation is mediated by the C-terminal region of the Fn14 cytoplasmic domain. AB - The tumor necrosis factor (TNF) superfamily member TNF-like weak inducer of apoptosis (TWEAK) is a pro-inflammatory and pro-angiogenic cytokine implicated in physiological tissue regeneration and wound repair. TWEAK binds to a 102-amino acid type I transmembrane cell surface receptor named fibroblast growth factor inducible 14 (Fn14). TWEAK:Fn14 engagement activates several intracellular signaling cascades, including the NF-kappaB pathway, and sustained Fn14 signaling has been implicated in the pathogenesis of chronic inflammatory diseases and cancer. Although several groups are developing TWEAK- or Fn14-targeted agents for therapeutic use, much more basic science research is required before we fully understand the TWEAK/Fn14 signaling axis. For example, we and others have proposed that TWEAK-independent Fn14 signaling may occur in cells when Fn14 levels are highly elevated, but this idea has never been tested directly. In this report, we first demonstrate TWEAK-independent Fn14 signaling by showing that an Fn14 deletion mutant that is unable to bind TWEAK can activate the NF-kappaB pathway in transfected cells. We then show that ectopically-expressed, cell surface-localized Fn14 can self-associate into Fn14 dimers, and we show that Fn14 self-association is mediated by an 18-aa region within the Fn14 cytoplasmic domain. Endogenously-expressed Fn14 as well as ectopically-overexpressed Fn14 could also be detected in dimeric form when cell lysates were subjected to SDS PAGE under non-reducing conditions. Additional experiments revealed that Fn14 dimerization occurs during cell lysis via formation of an intermolecular disulfide bond at cysteine residue 122. These findings provide insight into the Fn14 signaling mechanism and may aid current studies to develop therapeutic agents targeting this small cell surface receptor. PMID- 23750248 TI - Global loss of bmal1 expression alters adipose tissue hormones, gene expression and glucose metabolism. AB - The close relationship between circadian rhythm disruption and poor metabolic status is becoming increasingly evident, but role of adipokines is poorly understood. Here we investigated adipocyte function and the metabolic status of mice with a global loss of the core clock gene Bmal1 fed either a normal or a high fat diet (22% by weight). Bmal1 null mice aged 2 months were killed across 24 hours and plasma adiponectin and leptin, and adipose tissue expression of Adipoq, Lep, Retn and Nampt mRNA measured. Glucose, insulin and pyruvate tolerance tests were conducted and the expression of liver glycolytic and gluconeogenic enzyme mRNA determined. Bmal1 null mice displayed a pattern of increased plasma adiponectin and plasma leptin concentrations on both control and high fat diets. Bmal1 null male and female mice displayed increased adiposity (1.8 fold and 2.3 fold respectively) on the normal diet, but the high fat diet did not exaggerate these differences. Despite normal glucose and insulin tolerance, Bmal1 null mice had increased production of glucose from pyruvate, implying increased liver gluconeogenesis. The Bmal1 null mice had arrhythmic clock gene expression in epigonadal fat and liver, and loss of rhythmic transcription of a range of metabolic genes. Furthermore, the expression of epigonadal fat Adipoq, Retn, Nampt, AdipoR1 and AdipoR2 and liver Pfkfb3 mRNA were down-regulated. These results show for the first time that global loss of Bmal1, and the consequent arrhythmicity, results in compensatory changes in adipokines involved in the cellular control of glucose metabolism. PMID- 23750250 TI - Emissions of CH4 and N2O under different tillage systems from double-cropped paddy fields in Southern China. AB - Understanding greenhouse gases (GHG) emissions is becoming increasingly important with the climate change. Most previous studies have focused on the assessment of soil organic carbon (SOC) sequestration potential and GHG emissions from agriculture. However, specific experiments assessing tillage impacts on GHG emission from double-cropped paddy fields in Southern China are relatively scarce. Therefore, the objective of this study was to assess the effects of tillage systems on methane (CH4) and nitrous oxide (N2O) emission in a double rice (Oryza sativa L.) cropping system. The experiment was established in 2005 in Hunan Province, China. Three tillage treatments were laid out in a randomized complete block design: conventional tillage (CT), rotary tillage (RT) and no-till (NT). Fluxes of CH4 from different tillage treatments followed a similar trend during the two years, with a single peak emission for the early rice season and a double peak emission for the late rice season. Compared with other treatments, NT significantly reduced CH4 emission among the rice growing seasons (P<0.05). However, much higher variations in N2O emission were observed across the rice growing seasons due to the vulnerability of N2O to external influences. The amount of CH4 emission in paddy fields was much higher relative to N2O emission. Conversion of CT to NT significantly reduced the cumulative CH4 emission for both rice seasons compared with other treatments (P<0.05). The mean value of global warming potentials (GWPs) of CH4 and N2O emissions over 100 years was in the order of NT>2 h) than deprotonation of functional groups (<2 h) and was described by a Langmuir model. The maximum uptake increased with pH of cation addition and decreased with increasing cation valency. Sorption coefficients were similar for all cations and at both pH. This contradicts the general expectations for electrostatic interactions, suggesting that not only the interaction chemistry but also spatial distribution of functional groups in OM determines binding of cations in this peat. The reaction of contact angle, matrix rigidity due to water molecule bridges (WaMB) and molecular mobility of water (NMR analysis) suggested that cross-linking via CaB has low relevance in this peat. This unexpected finding is probably due to the low cation exchange capacity, resulting in low abundance of charged functionalities. Molecular modeling demonstrates that large average distances between functionalities (~3 nm in this peat) cannot be bridged by CaB-WaMB associations. However, aging strongly increased matrix rigidity, suggesting successive increase of WaMB size to connect functionalities and thus increasing degree of cross-linking by CaB-WaMB associations. Results thus demonstrated that the physicochemical structure of OM is decisive for CaB and aging-induced structural reorganisation can enhance cross link formation. PMID- 23750257 TI - Type 1 interferons inhibit myotube formation independently of upregulation of interferon-stimulated gene 15. AB - INTRODUCTION: Type 1 interferon (IFN)-inducible genes and their inducible products are upregulated in dermatomyositis muscle. Of these, IFN-stimulated gene 15 (ISG15) is one of the most upregulated, suggesting its possible involvement in the pathogenesis of this disease. To test this postulate, we developed a model of type 1 IFN mediated myotube toxicity and assessed whether or not downregulation of ISG15 expression prevents this toxicity. METHODS: Mouse myoblasts (C2C12 cell line) were cultured in the presence of type 1 or type 2 IFNs and ISG15 expression assessed by microarray analysis. The morphology of newly formed myotubes was assessed by measuring their length, diameter, and area on micrographs using imaging software. ISG15 expression was silenced through transfection with small interference RNA. RESULTS: Type 1 IFNs, especially IFN-beta, increased ISG15 expression in C2C12 cells and impaired myotube formation. Silencing of ISG15 resulted in knockdown of ISG15 protein, but without phenotypic rescue of myotube formation. DISCUSSION: IFN-beta affects myoblast differentiation ability and myotube morphology in vitro.These studies provide evidence that ISG15, which is highly upregulated in dermatomyositis muscle, does not appear to play a key role in IFN-beta-mediated C2C12 myoblast cell fusion. PMID- 23750258 TI - Induction of autophagy by a novel small molecule improves abeta pathology and ameliorates cognitive deficits. AB - Growing evidence has demonstrated a neuroprotective role of autophagy in Alzheimer's disease (AD). Thus, autophagy has been regarded as a potential therapeutic target, attracting increasing interest in pharmaceutical autophagy modulation by small molecules. We designed a two-cycle screening strategy on the basis of imaging high-throughout screening (HTS) and cellular toxicity assay, and have identified a novel autophagy inducer known as GTM-1. We further showed that GTM-1 exhibits dual activities, such as autophagy induction and antagonism against Abeta-oligomer toxicity. GTM-1 modulates autophagy in an Akt-independent and mTOR-independent manner. In addition, we demonstrated that GTM-1 enhances autophagy clearance and reverses the downregulation of autophagy flux by thapsigargin and asparagine. Furthermore, administration of GTM-1 attenuated Abeta pathology and ameliorated cognitive deficits in AD mice. PMID- 23750259 TI - Winter temperature affects the prevalence of ticks in an Arctic seabird. AB - The Arctic is rapidly warming and host-parasite relationships may be modified by such environmental changes. Here, I showed that the average winter temperature in Svalbard, Arctic Norway, explained almost 90% of the average prevalence of ticks in an Arctic seabird, the Brunnich's guillemot Uria lomvia. An increase of 1 degrees C in the average winter temperature at the nesting colony site was associated with a 5% increase in the number of birds infected by these ectoparasites in the subsequent breeding season. Guillemots were generally infested by only a few ticks (<=5) and I found no direct effect of tick presence on their body condition and breeding success. However, the strong effect of average winter temperature described here clearly indicates that tick-seabird relationships in the Arctic may be strongly affected by ongoing climate warming. PMID- 23750260 TI - Role of murine intestinal interleukin-1 receptor 1-expressing lymphoid tissue inducer-like cells in Salmonella infection. AB - Interleukin (IL)-1 signaling plays a critical role in intestinal immunology. Here, we report that the major population of intestinal lamina propria lymphocytes expressing IL-1 receptor 1 (IL-1R1) is the lymphoid tissue inducer (LTi)-like cell, a type of innate lymphoid cell. These cells are significant producers of IL-22, and this IL-22 production depends on IL-1R1 signaling. LTi like cells are required for defense against Salmonella enterica serovar Typhimurium. Moreover, colonic LTi-like cell numbers depend on the presence of the intestinal microbiota. LTi-like cells require IL-1R1 for production of protective cytokines and confer protection in infectious colitis, and their cell numbers in the colon depend upon having a microbiome. PMID- 23750261 TI - Attentional bias for emotional information in older adults: the role of emotion and future time perspective. AB - OBJECTIVES: Research suggests that older adults display a positivity bias at the level of information processing. However, because studies investigating attentional bias for emotional information in older adults have produced mixed findings, research identifying inter-individual differences that may explain these inconsistent results is necessary. Therefore, we investigated whether mood, symptoms of depression, symptoms of anxiety and future time perspective are related to attentional bias in older adults. METHOD: Thirty-seven healthy older adults and 25 healthy middle-aged adults completed questionnaires to assess mood, symptoms of depression, symptoms of anxiety and future time perspective. Attentional bias towards happy, sad and neutral information was measured using a modified exogenous cueing paradigm with long cue presentations, to measure maintained attention versus avoidance of emotional stimuli. RESULTS: Older adults showed attentional avoidance for all emotional faces, whereas no attentional biases were found in the middle-aged group. Moreover, in the older adult group, avoidance for negative information was related to anxiety. Future time perspective was unrelated to attentional bias. DISCUSSION: These findings suggest that anxiety may lead to inter-individual differences in attentional bias in older adults, and that avoidance from negative information may be an emotion regulation strategy. PMID- 23750262 TI - Effects of feed supplementation on mineral composition, mechanical properties and structure in femurs of Iberian red deer hinds (Cervus elaphus hispanicus). AB - Few studies in wild animals have assessed changes in mineral profile in long bones and their implications for mechanical properties. We examined the effect of two diets differing in mineral content on the composition and mechanical properties of femora from two groups each with 13 free-ranging red deer hinds. Contents of Ca, P, Mg, K, Na, S, Cu, Fe, Mn, Se, Zn, B and Sr, Young's modulus of elasticity (E), bending strength and work of fracture were assessed in the proximal part of the diaphysis (PD) and the mid-diaphysis (MD). Whole body measures were also recorded on the hinds. Compared to animals on control diets, those on supplemented diets increased live weight by 6.5 kg and their kidney fat index (KFI), but not carcass weight, body or organ size, femur size or cortical thickness. Supplemental feeding increased Mn content of bone by 23%, Cu by 9% and Zn by 6%. These differences showed a mean fourfold greater content of these minerals in supplemental diet, whereas femora did not reflect a 5.4 times greater content of major minerals (Na and P) in the diet. Lower content of B and Sr in supplemented diet also reduced femur B by 14% and Sr by 5%. There was a subtle effect of diet only on E and none on other mechanical properties. Thus, greater availability of microminerals but not major minerals in the diet is reflected in bone composition even before marked body effects, bone macro-structure or its mechanical properties are affected. PMID- 23750264 TI - Aptamer selection based on G4-forming promoter region. AB - We developed a method for aptamer identification without in vitro selection. We have previously obtained several aptamers, which may fold into the G-quadruplex (G4) structure, against target proteins; therefore, we hypothesized that the G4 structure would be an excellent scaffold for aptamers to recognize the target protein. Moreover, the G4-forming sequence contained in the promoter region of insulin can reportedly bind to insulin. We thus expected that G4 DNAs, which are contained in promoter regions, could act as DNA aptamers against their gene products. We designated this aptamer identification method as "G4 promoter derived aptamer selection (G4PAS)." Using G4PAS, we identified vascular endothelial growth factor (VEGF)165, platelet-derived growth factor-AA (PDGF)-AA, and RB1 DNA aptamers. Surface plasmon resonance (SPR) analysis revealed that the dissociation constant (K d) values of VEGF165, PDGF-AA, and RB1 DNA aptamers were 1.7 * 10(-7) M, 6.3 * 10(-9) M, and 4.4 * 10(-7) M, respectively. G4PAS is a simple and rapid method of aptamer identification because it involves only binding analysis of G4 DNAs to the target protein. In the human genome, over 40% of promoters contain one or more potential G4 DNAs. G4PAS could therefore be applied to identify aptamers against target proteins that contain G4 DNAs on their promoters. PMID- 23750263 TI - Performance of different scan protocols of fetal echocardiography in the diagnosis of fetal congenital heart disease: a systematic review and meta analysis. AB - OBJECTIVE: The rapid progress in fetal echocardiography has lead to early detection of congenital heart diseases. Increasing evidences have shown that prenatal diagnosis could be life saving in certain cases. However, there is no agreement on which protocol is most adaptive diagnostic one. Thus, we use meta analysis to conduct a pooled performance test on 5 diagnostic protocols. METHODS: We searched PUBMED, EMBASE, the Cochrane Central Register of Controlled Trials and WHO clinical trails registry center to identify relevant studies up to August, 2012. We performed meta-analysis in a fixed/random-effect model using Meta-disc 1.4. We used STATA 11.0 to estimate the publication bias and SPSS 17.0 to evaluate variance. RESULTS: We use results from 81 studies in 63 articles to analyze the pooled accuracy. The overall performance of pooled sensitivities of spatiotemporal image correlation (STIC), extend cardiac echography examination (ECEE) and 4 chambers view + outflow tract view + 3 vessels and trachea view (4 CV+OTV+3 VTV) were around 0.90, which was significant higher than that of 4 chambers view + outflow tract view or 3 vessels and trachea view (4 CV+OTV/3 VTV) and 4 chambers view (4 CV). Unfortunately the pooled specificity of STIC was 0.92, which was significant lower than that of other 4 protocols which reached at 1.00. The area under the summary receiver operating characteristic curves value of STIC, ECEE, 4 CV+OTV+3 VTV, 4 CV+OTV/3 VTV and 4 CV were 0.9700, 0.9971, 0.9983, 0.9929 and 0.9928 respectively. CONCLUSION: These results suggest a great diagnostic potential for fetal echocardiography detection as a reliable method of fetal congenital heart disease. But at least 3 sections view (4 CV, OTV and 3 VTV) should be included in scan protocol, while the STIC can be used to provide more information for local details of defects, and can not be used to make a definite diagnosis alone with its low specificity. PMID- 23750265 TI - Comparison of anterior segment optical tomography parameters measured using a semi-automatic software to standard clinical instruments. AB - OBJECTIVE: To compare anterior segment parameters measured using a semi-automatic software (Zhongshan Angle Assessment Program, ZAP) applied to anterior segment optical coherence tomography (AS-OCT) images, with commonly used instruments. METHODS: Cross-sectional study of a total of 1069 subjects (1069 eyes) from three population-based studies of adults aged 40-80 years. All subjects underwent AS OCT imaging and ZAP software was applied to determine anterior chamber depth (ACD), central corneal thickness (CCT), anterior and keratometry (K) - readings. These were compared to auto-refraction, keratometry and ocular biometry measured using an IOLMaster, ultrasound pachymeter and auto-refractor respectively. Agreements between AS-OCT (ZAP) and clinical instrument modalities were described using Bland-Altman, 95% limits of agreement (LOA). RESULTS: The mean age of our subjects was 56.9+/-9.5 years and 50.9% were male. The mean AS-OCT (ZAP) parameters of our study cohort were: ACD 3.29+/-0.35 mm, CCT 560.75+/-35.07 um; K reading 46.79+/-2.72 D. There was good agreement between the measurements from ZAP analysis and each instrument and no violations in the assumptions of the LOA; albeit with a systematic bias for each comparison: AS-OCT consistently measured a deeper ACD compared to IOLMaster (95% LOA -0.24, 0.55); and a thicker CCT for the AS-OCT compared to ultrasound pachymetry (16.8+/-0.53 um 95% LOA -17.3, 50.8). AS OCT had good agreement with auto-refractor with at least 95% of the measurements within the prediction interval (P value <0.001). CONCLUSION: This study demonstrates that there is good agreement between the measurements from the AS OCT (ZAP) and conventional tools. However, small systematic biases remain that suggest that these measurement tools may not be interchanged. PMID- 23750266 TI - Surgery or consultation: a population-based cohort study of use of orthopaedic surgeon services. AB - BACKGROUND: This population-based cohort study has the objective to understand the sociodemographic characteristics and health conditions of patients who do not receive surgery within 18 months following an ambulatory visit to an orthopaedic surgeon. METHODS: Administrative healthcare databases in Ontario, Canada were linked to identify all patients making an initial ambulatory visit to orthopaedic surgeons between October 1(st), 2004 and September 30(th), 2005. Logistic regression was used to examine predictors of not receiving surgery within 18 months. RESULTS: Of the 477,945 patients in the cohort 49% visited orthopaedic surgeons for injury, and 24% for arthritis. Overall, 79.3% did not receive surgery within 18 months of the initial visit, which varied somewhat by diagnosis at first visit (84.5% for injury and 73.0% for arthritis) with highest proportions in the 0-24 and 25-44 age groups. The distribution by income quintile of patients visiting was skewed towards higher incomes. Regression analysis for each diagnostic group showed that younger patients were significantly more likely to be non-surgical than those aged 65+ years (age 0-24: OR 3.45 95%CI 3.33-3.57; age 25-44: OR 1.30 95%CI 1.27-1.33). The odds of not getting surgery were significantly higher for women than men for injury and other conditions; the opposite was true for arthritis and bone conditions. CONCLUSION: A substantial proportion of referrals were for expert diagnosis or advice on management and treatment. The findings also suggest socioeconomic inequalities in access to orthopaedic care. Further research is needed to investigate whether the high caseload of non-surgical cases affects waiting times to see a surgeon. This paper contributes to the development of evidence-based strategies to streamline access to surgery, and to develop models of care for non-surgical patients to optimize the use of scarce orthopaedic surgeon resources and to enhance the management of musculoskeletal disorders across the care continuum. PMID- 23750267 TI - Lipopolysaccharide preconditioning protects hepatocytes from ischemia/reperfusion injury (IRI) through inhibiting ATF4-CHOP pathway in mice. AB - BACKGROUND: Low-dose lipopolysaccharide (LPS) preconditioning-induced liver protection has been demonstrated during ischemia-reperfusion injury (IRI) in several organs but has not been sufficiently elucidated underlying causal mechanism. This study investigated the role of low-dose LPS preconditioning on ATF4-CHOP pathway as well as the effects of the pathway on tissue injury and inflammation in a mouse model of liver partial-warm IRI. METHODS: LPS (100 ug/kg/d) was injected intraperitoneally two days before ischemia. Hepatic injury was evaluated based on serum alanine aminotransferase levels, histopathology, and caspase-3 activity. The ATF4-CHOP pathway and its related apoptotic molecules were investigated after reperfusion. The role of LPS preconditioning on apoptosis and ATF4-CHOP pathway was examined in vitro. Moreover, the effects of the ATF4 CHOP pathway on apoptosis, Caspase-12, and Caspase-3 were determined with ATF4 small interfering RNA (siRNA). Inflammatory cytokine expression was also checked after reperfusion. Inflammatory cytokines and related signaling pathways were analyzed in vitro in macrophages treated by LPS preconditioning or ATF4 siRNA. RESULTS: LPS preconditioning significantly attenuated liver injury after IRI. As demonstrated by in vitro experiments, LPS preconditioning significantly reduced the upregulation of the ATF4-CHOP pathway and inhibited Caspase-12 and Caspase-3 activation after IRI. Later experiments showed that ATF4 knockdown significantly suppressed CHOP, cleaved caspase-12 and caspase-3 expression, as well as inhibited hepatocellular apoptosis. In addition, in mice pretreated with LPS, TNF alpha and IL-6 were inhibited after reperfusion, whereas IL-10 was upregulated. Similarly, low-dose LPS significantly inhibited TNF-alpha, IL-6, ATF4-CHOP pathway, NF-kappaB pathway, and ERK1/2 in high-dose LPS-stimulated macrophages, whereas IL-10 and cytokine signaling (SOCS)-3 suppressor were induced. Importantly, ATF4 siRNA is consistent with results of LPS preconditioning in macrophages. CONCLUSIONS: This work is the first time to provide evidence for LPS preconditioning protects hepatocytes from IRI through inhibiting ATF4-CHOP pathway, which may be critical to reducing related apoptosis molecules and modulating innate inflammation. PMID- 23750268 TI - Skin autofluorescence based decision tree in detection of impaired glucose tolerance and diabetes. AB - AIM: Diabetes (DM) and impaired glucose tolerance (IGT) detection are conventionally based on glycemic criteria. Skin autofluorescence (SAF) is a noninvasive proxy of tissue accumulation of advanced glycation endproducts (AGE) which are considered to be a carrier of glycometabolic memory. We compared SAF and a SAF-based decision tree (SAF-DM) with fasting plasma glucose (FPG) and HbA1c, and additionally with the Finnish Diabetes Risk Score (FINDRISC) questionnaire+/-FPG for detection of oral glucose tolerance test (OGTT)- or HbA1c defined IGT and diabetes in intermediate risk persons. METHODS: Participants had >=1 metabolic syndrome criteria. They underwent an OGTT, HbA1c, SAF and FINDRISC, in adition to SAF-DM which includes SAF, age, BMI, and conditional questions on DM family history, antihypertensives, renal or cardiovascular disease events (CVE). RESULTS: 218 persons, age 56 yr, 128M/90F, 97 with previous CVE, participated. With OGTT 28 had DM, 46 IGT, 41 impaired fasting glucose, 103 normal glucose tolerance. SAF alone revealed 23 false positives (FP), 34 false negatives (FN) (sensitivity (S) 68%; specificity (SP) 86%). With SAF-DM, FP were reduced to 18, FN to 16 (5 with DM) (S 82%; SP 89%). HbA1c scored 48 FP, 18 FN (S 80%; SP 75%). Using HbA1c-defined DM-IGT/suspicion >=6%/42 mmol/mol, SAF-DM scored 33 FP, 24 FN (4 DM) (S76%; SP72%), FPG 29 FP, 41 FN (S71%; SP80%). FINDRISC>=10 points as detection of HbA1c-based diabetes/suspicion scored 79 FP, 23 FN (S 69%; SP 45%). CONCLUSION: SAF-DM is superior to FPG and non-inferior to HbA1c to detect diabetes/IGT in intermediate-risk persons. SAF-DM's value for diabetes/IGT screening is further supported by its established performance in predicting diabetic complications. PMID- 23750269 TI - Lack of variation at phosphoglucose isomerase (pgi) in bumblebees: implications for conservation genetics studies. AB - Assessing genetic variation underlying ecologically important traits is increasingly of interest and importance in population and conservation genetics. For some groups generally useful markers exist for examining the relative role of selection and drift in shaping genetic diversity e.g. the major histocompatibility complex in vertebrates and self-incompatibility loci in plants. For invertebrates there is no such generally useful locus. However, phosphoglucose isomerase (Pgi) has been proposed as a useful functional marker in the conservation genetics of invertebrates. Where thermal microclimate varies, balanced polymorphisms may be maintained due to trade-offs between thermally stable and kinetically advantageous allelic forms. We here report very low levels of Pgi variation in bumblebees rendering this locus to be of little use as an adaptive marker in a conservation genetics context in this group. Potential explanations for this lack of variation are considered. PMID- 23750270 TI - A novel selenocystine-accumulating plant in selenium-mine drainage area in Enshi, China. AB - Plant samples of Cardamine hupingshanesis (Brassicaceae), Ligulariafischeri (Ledeb.) turcz (Steraceae) and their underlying top sediments were collected from selenium (Se) mine drainage areas in Enshi, China. Concentrations of total Se were measured using Hydride Generation-Atomic Fluorescence Spectrometry (HG-AFS) and Se speciation were determined using liquid chromatography/UV irradiation hydride generation-atomic fluorescence spectrometry (LC-UV-HG-AFS). The results showed that C. hupingshanesis could accumulate Se to 239+/-201 mg/kg DW in roots, 316+/-184 mg/kg DW in stems, and 380+/-323 mg/kg DW in leaves, which identifies it as Se secondary accumulator. Particularly, it could accumulate Se up to 1965+/ 271 mg/kg DW in leaves, 1787+/-167 mg/kg DW in stem and 4414+/-3446 mg/kg DW in roots, living near Se mine tailing. Moreover, over 70% of the total Se accumulated in C. hupingshanesis were in the form of selenocystine (SeCys2), increasing with increased total Se concentration in plant, in contrast to selenomethionine (SeMet) in non-accumulators (eg. Arabidopsis) and secondary accumulators (eg. Brassica juncea), and selenomethylcysteine (SeMeCys) in hyperaccumulators (eg. Stanleya pinnata). There is no convincing explanation on SeCys2 accumulation in C. hupingshanesis based on current Se metabolism theory in higher plants, and further study will be needed. PMID- 23750271 TI - Effect of intravitreal methotrexate and rituximab on interleukin-10 levels in aqueous humor of treated eyes with vitreoretinal lymphoma. AB - Intraocular cytokines are promising diagnostic biomarkers of vitreoretinal lymphoma. Here, we evaluate the utility of IL-10, IL-6 and IL-10/IL-6 for discriminating lymphoma from uveitis and report the effects of intraocular methotrexate and rituximab on aqueous cytokine levels in eyes with lymphoma. This is a retrospective case series including 10 patients with lymphoma and 7 patients with uveitis. Non-parametric Mann-Whitney analysis was performed to determine statistical significance of difference in interleukin levels between lymphoma and uveitis. Compared to eyes with uveitis, eyes with lymphoma had higher levels of IL-10 (U = 7.0; two-tailed p = 0.004) and IL-10/IL-6 (U = 6.0; two-tailed p = 0.003), whereas IL-6 levels were more elevated, although insignificant, in those patients with uveitis than in lymphoma (U = 15.0; two-tailed p = ns). Using a receiver operating characteristic analysis to identify threshold values diagnostic for lymphoma, optimal sensitivity and specificity improved to 80.0% and 100%, respectively, for IL-10>7.025 pg/ml and 90.0% and 100.0%, respectively, for IL-10/IL-6>0.02718. In patients in whom serial interleukin levels were available, regular intravitreal treatment with methotrexate and rituximab was associated with reduction in IL-10 levels over time. In conclusion, optimal IL-10 and IL-10/IL-6 threshold values are associated with a diagnostic sensitivity >=80% and specificity of 100%. Therefore, these cytokines may serve as a useful adjunct in the diagnosis of lymphoma. While negative IL-10 and IL-10/IL-6 values do not exclude a diagnosis of lymphoma, elevated levels do appear to be consistent with lymphoma clinically. Moreover, elevated levels of IL-10 in the setting of a clinically quiet eye may point to impending disease recurrence. Lastly, once lymphoma is diagnosed, IL-10 levels can be monitored over time to assess disease activity and therapeutic response. PMID- 23750272 TI - Anti-migratory effect of vinflunine in endothelial and glioblastoma cells is associated with changes in EB1 C-terminal detyrosinated/tyrosinated status. AB - We previously showed that vinflunine, a microtubule-targeting drug of the Vinca alkaloid family exerted its anti-angiogenic/anti-migratory activities through an increase in microtubule dynamics and an inhibition of microtubule targeting to adhesion sites. Such effect was associated with a reduction of EB1 comet length at microtubule (+) ends. In this work we first showed that the pro-angiogenic vascular endothelial growth factor VEGF suppressed microtubule dynamics in living Human Umbilical Vein Endothelial Cells (HUVECs), increased EB1 comet length by 40%, and induced EB1 to bind all along the microtubules, without modifying its expression level. Such microtubule (+) end stabilization occurred close to the plasma membrane in the vicinity of focal adhesion as shown by TIRF microscopy experiments. Vinflunine completely abolished the effect of VEGF on EB1 comets. Interestingly, we found a correlation between the reduction of EB1 comet length by vinflunine and the inhibition of cell migration. By using 2D gel electrophoresis we demonstrated for the first time that EB1 underwent several post-translational modifications in endothelial and tumor cells. Particularly, the C-terminal EEY sequence was poorly detectable in control and VEGF-treated HUVECs suggesting the existence of a non-tyrosinated form of EB1. By using specific antibodies that specifically recognized and discriminated the native tyrosinated form of EB1 and a putative C-terminal detyrosinated form, we showed that a detyrosinated form of EB1 exists in HUVECs and tumor cells. Interestingly, vinflunine decreased the level of the detyrosinated form and increased the native tyrosinated form of EB1. Using 3-L-Nitrotyrosine incorporation experiments, we concluded that the EB1 C-terminal modifications result from a detyrosination/retyrosination cycle as described for tubulin. Altogether, our results show that vinflunine inhibits endothelial cell migration through an alteration of EB1 comet length and EB1 detyrosination/retyrosination cycle. PMID- 23750274 TI - Behavioural disturbances in a temperate fish exposed to sustained high-CO2 levels. AB - As atmospheric CO2 levels rise, the CO2 concentration in ocean surface waters increases through a process commonly referred to as ocean acidification. Recently, surprising behavioural modifications has been detected in the early life stages of tropical coral reef fish exposed to ocean acidification-relevant CO2 concentrations, but it has been unclear if this effect could occur in temperate waters. Here we show several severe behavioural disturbances, including effects on boldness, exploratory behaviour, lateralisation, and learning in a temperate fish, the three-spined stickleback (Gasterosteus aculeatus). The behavioural effects were consistent throughout the exposure period and increased in effect size with exposure time. We observed the effects on adult sticklebacks, a species known to be tolerant to other environmental stressors. Our findings suggest that behavioural abnormalities that stem from CO2 exposure are not restricted to sensitive tropical species or early life stages and may therefore affect fish on a global scale. The severity of disturbances and the possibility of a serious behavioural problem for fish across the globe is cause for concern. PMID- 23750273 TI - Elevated protein carbonylation, and misfolding in sciatic nerve from db/db and Sod1(-/-) mice: plausible link between oxidative stress and demyelination. AB - Diabetic peripheral polyneuropathy is associated with decrements in motor/sensory neuron myelination, nerve conduction and muscle function; however, the mechanisms of reduced myelination in diabetes are poorly understood. Chronic elevation of oxidative stress may be one of the potential determinants for demyelination as lipids and proteins are important structural constituents of myelin and highly susceptible to oxidation. The goal of the current study was to determine whether there is a link between protein oxidation/misfolding and demyelination. We chose two distinct models to test our hypothesis: 1) the leptin receptor deficient mouse (dbdb) model of diabetic polyneuropathy and 2) superoxide dismutase 1 knockout (Sod1(-/-) ) mouse model of in vivo oxidative stress. Both experimental models displayed a significant decrement in nerve conduction, increase in tail distal motor latency as well as reduced myelin thickness and fiber/axon diameter. Further biochemical studies demonstrated that oxidative stress is likely to be a potential key player in the demyelination process as both models exhibited significant elevation in protein carbonylation and alterations in protein conformation. Since peripheral myelin protein 22 (PMP22) is a key component of myelin sheath and has been found mutated and aggregated in several peripheral neuropathies, we predicted that an increase in carbonylation and aggregation of PMP22 may be associated with demyelination in dbdb mice. Indeed, PMP22 was found to be carbonylated and aggregated in sciatic nerves of dbdb mice. Sequence-driven hydropathy plot analysis and in vitro oxidation-induced aggregation of purified PMP22 protein supported the premise for oxidation-dependent aggregation of PMP22 in dbdb mice. Collectively, these data strongly suggest for the first time that oxidation-mediated protein misfolding and aggregation of key myelin proteins may be linked to demyelination and reduced nerve conduction in peripheral neuropathies. PMID- 23750275 TI - Resting state brain function analysis using concurrent BOLD in ASL perfusion fMRI. AB - The past decade has seen astounding discoveries about resting-state brain activity patterns in normal brain as well as their alterations in brain diseases. While the vast majority of resting-state studies are based on the blood-oxygen level-dependent (BOLD) functional MRI (fMRI), arterial spin labeling (ASL) perfusion fMRI can simultaneously capture BOLD and cerebral blood flow (CBF) signals, providing a unique opportunity for assessing resting brain functions with concurrent BOLD (ccBOLD) and CBF signals. Before taking that benefit, it is necessary to validate the utility of ccBOLD signal for resting-state analysis using conventional BOLD (cvBOLD) signal acquired without ASL modulations. To address this technical issue, resting cvBOLD and ASL perfusion MRI were acquired from a large cohort (n = 89) of healthy subjects. Four widely used resting-state brain function analyses were conducted and compared between the two types of BOLD signal, including the posterior cingulate cortex (PCC) seed-based functional connectivity (FC) analysis, independent component analysis (ICA), analysis of amplitude of low frequency fluctuation (ALFF), and analysis of regional homogeneity (ReHo). Consistent default mode network (DMN) as well as other resting-state networks (RSNs) were observed from cvBOLD and ccBOLD using PCC-FC analysis and ICA. ALFF from both modalities were the same for most of brain regions but were different in peripheral regions suffering from the susceptibility gradients induced signal drop. ReHo showed difference in many brain regions, likely reflecting the SNR and resolution differences between the two BOLD modalities. The DMN and auditory networks showed highest CBF values among all RSNs. These results demonstrated the feasibility of ASL perfusion MRI for assessing resting brain functions using its concurrent BOLD in addition to CBF signal, which provides a potentially useful way to maximize the utility of ASL perfusion MRI. PMID- 23750276 TI - The Marker State Space (MSS) method for classifying clinical samples. AB - The development of accurate clinical biomarkers has been challenging in part due to the diversity between patients and diseases. One approach to account for the diversity is to use multiple markers to classify patients, based on the concept that each individual marker contributes information from its respective subclass of patients. Here we present a new strategy for developing biomarker panels that accounts for completely distinct patient subclasses. Marker State Space (MSS) defines "marker states" based on all possible patterns of high and low values among a panel of markers. Each marker state is defined as either a case state or a control state, and a sample is classified as case or control based on the state it occupies. MSS was used to define multi-marker panels that were robust in cross validation and training-set/test-set analyses and that yielded similar classification accuracy to several other classification algorithms. A three marker panel for discriminating pancreatic cancer patients from control subjects revealed subclasses of patients based on distinct marker states. MSS provides a straightforward approach for modeling highly divergent subclasses of patients, which may be adaptable for diverse applications. PMID- 23750277 TI - A simple method for purification of vestibular hair cells and non-sensory cells, and application for proteomic analysis. AB - Mechanosensitive hair cells and supporting cells comprise the sensory epithelia of the inner ear. The paucity of both cell types has hampered molecular and cell biological studies, which often require large quantities of purified cells. Here, we report a strategy allowing the enrichment of relatively pure populations of vestibular hair cells and non-sensory cells including supporting cells. We utilized specific uptake of fluorescent styryl dyes for labeling of hair cells. Enzymatic isolation and flow cytometry was used to generate pure populations of sensory hair cells and non-sensory cells. We applied mass spectrometry to perform a qualitative high-resolution analysis of the proteomic makeup of both the hair cell and non-sensory cell populations. Our conservative analysis identified more than 600 proteins with a false discovery rate of <3% at the protein level and <1% at the peptide level. Analysis of proteins exclusively detected in either population revealed 64 proteins that were specific to hair cells and 103 proteins that were only detectable in non-sensory cells. Statistical analyses extended these groups by 53 proteins that are strongly upregulated in hair cells versus non-sensory cells and vice versa by 68 proteins. Our results demonstrate that enzymatic dissociation of styryl dye-labeled sensory hair cells and non-sensory cells is a valid method to generate pure enough cell populations for flow cytometry and subsequent molecular analyses. PMID- 23750278 TI - Resident CD8(+) and migratory CD103(+) dendritic cells control CD8 T cell immunity during acute influenza infection. AB - The identification of the specific DC subsets providing a critical role in presenting influenza antigens to naive T cell precursors remains contentious and under considerable debate. Here we show that CD8(+) T lymphocyte (TCD8+) responses are severely hampered in C57BL/6 mice deficient in the transcription factor Batf3 after intranasal challenge with influenza A virus (IAV). This transcription factor is required for the development of lymph node resident CD8(+) and migratory CD103(+)CD11b(-) DCs and we found both of these subtypes could efficiently stimulate anti-IAV TCD8+. Using a similar ex vivo approach, many publications on this subject matter excluded a role for resident, non migratory CD8(+) DC. We postulate the differences reported can partially be explained by how DC are phenotyped, namely the use of MHC class II to segregate subtypes. Our results show that resident CD8(+) DC upregulate this marker during IAV infection and we advise against its use when isolating DC subtypes. PMID- 23750279 TI - A cotton annexin protein AnxGb6 regulates fiber elongation through its interaction with actin 1. AB - Annexins are assumed to be involved in regulating cotton fiber elongation, but direct evidence remains to be presented. Here we cloned six Annexin genes (AnxGb) abundantly expressed in fiber from sea-island cotton (G. barbadense). qRT-PCR results indicated that all six G. barbadense annexin genes were expressed in elongating cotton fibers, while only the expression of AnxGb6 was cotton fiber specific. Yeast two hybridization and BiFC analysis revealed that AnxGb6 homodimer interacted with a cotton fiber specific actin GbAct1. Ectopic-expressed AnxGb6 in Arabidopsis enhanced its root elongation without increasing the root cell number. Ectopic AnxGb6 expression resulted in more F-actin accumulation in the basal part of the root cell elongation zone. Analysis of AnxGb6 expression in three cotton genotypes with different fiber length confirmed that AnxGb6 expression was correlated to cotton fiber length, especially fiber elongation rate. Our results demonstrated that AnxGb6 was important for fiber elongation by potentially providing a domain for F-actin organization. PMID- 23750280 TI - Characterization of Bacillus anthracis persistence in vivo. AB - Pulmonary exposure to Bacillus anthracis spores initiates inhalational anthrax, a life-threatening infection. It is known that dormant spores can be recovered from the lungs of infected animals months after the initial spore exposure. Consequently, a 60-day course antibiotic treatment is recommended for exposed individuals. However, there has been little information regarding details or mechanisms of spore persistence in vivo. In this study, we investigated spore persistence in a mouse model. The results indicated that weeks after intranasal inoculation with B. anthracis spores, substantial amounts of spores could be recovered from the mouse lung. Moreover, spores of B. anthracis were significantly better at persisting in the lung than spores of a non-pathogenic Bacillus subtilis strain. The majority of B. anthracis spores in the lung were tightly associated with the lung tissue, as they could not be readily removed by lavage. Immunofluorescence staining of lung sections showed that spores associated with the alveolar and airway epithelium. Confocal analysis indicated that some of the spores were inside epithelial cells. This was further confirmed by differential immunofluorescence staining of lung cells harvested from the infected lungs, suggesting that association with lung epithelial cells may provide an advantage to spore persistence in the lung. There was no or very mild inflammation in the infected lungs. Furthermore, spores were present in the lung tissue as single spores rather than in clusters. We also showed that the anthrax toxins did not play a role in persistence. Together, the results suggest that B. anthracis spores have special properties that promote their persistence in the lung, and that there may be multiple mechanisms contributing to spore persistence. PMID- 23750281 TI - A binding-site barrier affects imaging efficiency of high affinity amyloid reactive peptide radiotracers in vivo. AB - Amyloid is a complex pathology associated with a growing number of diseases including Alzheimer's disease, type 2 diabetes, rheumatoid arthritis, and myeloma. The distribution and extent of amyloid deposition in body organs establishes the prognosis and can define treatment options; therefore, determining the amyloid load by using non-invasive molecular imaging is clinically important. We have identified a heparin-binding peptide designated p5 that, when radioiodinated, was capable of selectively imaging systemic visceral AA amyloidosis in a murine model of the disease. The p5 peptide was posited to bind effectively to amyloid deposits, relative to similarly charged polybasic heparin-reactive peptides, because it adopted a polar alpha helix secondary structure. We have now synthesized a variant, p5R, in which the 8 lysine amino acids of p5 have been replaced with arginine residues predisposing the peptide toward the alpha helical conformation in an effort to enhance the reactivity of the peptide with the amyloid substrate. The p5R peptide had higher affinity for amyloid and visualized AA amyloid in mice by using SPECT/CT imaging; however, the microdistribution, as evidenced in micro-autoradiographs, was dramatically altered relative to the p5 peptide due to its increased affinity and a resultant "binding site barrier" effect. These data suggest that radioiodinated peptide p5R may be optimal for the in vivo detection of discreet, perivascular amyloid, as found in the brain and pancreatic vasculature, by using molecular imaging techniques; however, peptide p5, due to its increased penetration, may yield more quantitative imaging of expansive tissue amyloid deposits. PMID- 23750282 TI - Feedback from horizontal cells to cones mediates color induction and may facilitate color constancy in rainbow trout. AB - Color vision is most beneficial when the visual system is color constant and can correct the excitations of photoreceptors for differences in environmental irradiance. A phenomenon related to color constancy is color induction, where the color of an object shifts away from the color of its surroundings. These two phenomena depend on chromatic spatial integration, which was suggested to originate at the feedback synapse from horizontal cells (HC) to cones. However, the exact retinal site was never determined. Using the electroretinogram and compound action potential recordings, we estimated the spectral sensitivity of the photoresponse of cones, the output of cones, and the optic nerve in rainbow trout. Recordings were performed before and following pharmacological inhibition of HC-cone feedback, and were repeated under two colored backgrounds to estimate the efficiency of color induction. No color induction could be detected in the photoresponse of cones. However, the efficiency of color induction in the cone output and optic nerve was substantial, with the efficiency in the optic nerve being significantly higher than in the cone output. We found that the efficiency of color induction in the cone output and optic nerve decreased significantly with the inhibition of HC-cone feedback. Therefore, our findings suggest not only that color induction originates as a result of HC-cone feedback, but also that this effect of HC-cone feedback is further amplified at downstream retinal elements, possibly through feedback mechanisms at the inner plexiform layer. This study provides evidence for an important role of HC-cone feedback in mediating color induction, and therefore, likely also in mediating color constancy. PMID- 23750283 TI - Role of activated Rac1/Cdc42 in mediating endothelial cell proliferation and tumor angiogenesis in breast cancer. AB - Angiogenesis is a well-established target in anti-cancer therapy. Although vascular endothelial growth factor (VEGF)-mediated angiogenesis apparently requires the Rho GTPases Rac1 and Cdc42, the relevant mechanisms are unclear. Here, we determined that activated Rac1/Cdc42 in MCF-7 breast cancer cells could decrease p53 protein levels and increase VEGF secretion to promote proliferation and tube formation of human umbilical vein endothelial cells (HUVECs). However, these effects are reversed after ubiquitin-proteasome breakage. In exploring potential mechanisms for this relationship, we confirmed that activated Rac1/Cdc42 could enhance p53 protein ubiquitination and weaken p53 protein stability to increase VEGF expression. Furthermore, in a xenograft model using nude mice that stably express active Rac1/Cdc42 protein, active Rac1/Cdc42 decreased p53 levels and increased VEGF expression. Additionally, tumor angiogenesis was inhibited, and p53 protein levels were augmented, by intratumoral injection of the ubiquitin-proteasome inhibitor MG132. Finally in 339 human breast cancer tissues, our analyses indicated that Rac1/Cdc42 expression was related to advanced TNM staging, high proliferation index, ER status, and positive invasive features. In particular, our data suggests that high Rac1/Cdc42 expression is correlated with low wt-p53 and high VEGF expression. We conclude that activated Rac1/Cdc42 is a vascular regulator of tumor angiogenesis and that it may reduce stability of the p53 protein to promote VEGF expression by enhancing p53 protein ubiquitin. PMID- 23750284 TI - Lysyl oxidase is downregulated by the EWS/FLI1 oncoprotein and its propeptide domain displays tumor supressor activities in Ewing sarcoma cells. AB - Ewing sarcoma is the second most common bone malignancy in children and young adults. It is driven by oncogenic fusion proteins (i.e. EWS/FLI1) acting as aberrant transcription factors that upregulate and downregulate target genes, leading to cellular transformation. Thus, identificating these target genes and understanding their contribution to Ewing sarcoma tumorigenesis are key for the development of new therapeutic strategies. In this study we show that lysyl oxidase (LOX), an enzyme involved in maintaining structural integrity of the extracellular matrix, is downregulated by the EWS/FLI1 oncoprotein and in consequence it is not expressed in Ewing sarcoma cells and primary tumors. Using a doxycycline inducible system to restore LOX expression in an Ewing sarcoma derived cell line, we showed that LOX displays tumor suppressor activities. Interestingly, we showed that the tumor suppressor activity resides in the propeptide domain of LOX (LOX-PP), an N-terminal domain produced by proteolytic cleavage during the physiological processing of LOX. Expression of LOX-PP reduced cell proliferation, cell migration, anchorage-independent growth in soft agar and formation of tumors in immunodeficient mice. By contrast, the C-terminal domain of LOX, which contains the enzymatic activity, had the opposite effects, corroborating that the tumor suppressor activity of LOX is mediated exclusively by its propeptide domain. Finally, we showed that LOX-PP inhibits ERK/MAPK signalling pathway, and that many pathways involved in cell cycle progression were significantly deregulated by LOX-PP, providing a mechanistic explanation to the cell proliferation inhibition observed upon LOX-PP expression. In summary, our observations indicate that deregulation of the LOX gene participates in Ewing sarcoma development and identify LOX-PP as a new therapeutic target for one of the most aggressive paediatric malignancies. These findings suggest that therapeutic strategies based on the administration of LOX propeptide or functional analogues could be useful for the treatment of this devastating paediatric cancer. PMID- 23750285 TI - Reciprocal interactions between breast tumor and its adipose microenvironment based on a 3D adipose equivalent model. AB - Breast cancer has become the most common cancer among women in industrialized countries. Obesity is well established as a risk factor, in particular owing to the attendant secretion of the entities called adipokines; there is growing evidence for a role of cells and factors present in the mammary tumor microenvironment such as fibroblasts, preadipocytes, adipocytes and their secretions. To study how the microenvironment influences breast cancer growth, we developed a novel tridimensional adipose model epithelialized with normal human keratinocytes or with breast cancer cell lines. These mimicked a breast tumor in contact with an adipose microenvironment and allowed monitoring of the interactions between the cells. Leptin and adiponectin, two major adipokines, and their respective receptors, ObRt and AdipoR1, were expressed in the model, but not the second adiponectin receptor, AdipoR2. The differentiation of preadipocytes into adipocytes was greater when they were in contact with the breast cancer cell lines. The contact of breast cancer cell lines with the microenvironment completely modified their transcriptional programs by increasing the expression of genes involved in cell proliferation (cyclinD1, MAPK), angiogenesis (MMP9, VEGF) and hormonal pathways (ESR1, IL6). This tridimensional adipose model provides new insights into the interactions between breast cancer cells and their adipose microenvironment, and provides a tool to develop new drugs for the treatment of both cancer and obesity. PMID- 23750286 TI - Conductance-Based Determination of Solid-State Nanopore Size and Shape: An Exploration of Performance Limits. AB - Knowledge of nanopore size and shape is critical for many implementations of these single-molecule sensing elements. Geometry determination by fitting the electrolyte-concentration-dependence of the conductance of surface-charged, solid state nanopores has been proposed to replace demanding electron microscope-based methods. The functional form of the conductance poses challenges for this method by restricting the number of free parameters used to characterize the nanopore. We calculated the electrolyte-dependent conductance of nanopores with an exponential-cylindrical radial profile using three free geometric parameters; this profile, itself, could not be uniquely geometry-optimized by the conductance. Several different structurally simplified models, however, generated quantitative agreement with the conductance, but with errors exceeding 40% for estimates of key geometrical parameters. A tractable conical-cylindrical model afforded a good characterization of the nanopore size and shape, with errors of less than 1% for the limiting radius. Understanding these performance limits provides a basis for using and extending analytical nanopore conductance models. PMID- 23750287 TI - Is sickle cell anemia a neglected tropical disease? PMID- 23750288 TI - Correlated Noise: How it Breaks NMF, and What to Do About It. AB - Non-negative matrix factorization (NMF) is a problem of decomposing multivariate data into a set of features and their corresponding activations. When applied to experimental data, NMF has to cope with noise, which is often highly correlated. We show that correlated noise can break the Donoho and Stodden separability conditions of a dataset and a regular NMF algorithm will fail to decompose it, even when given freedom to be able to represent the noise as a separate feature. To cope with this issue, we present an algorithm for NMF with a generalized least squares objective function (glsNMF) and derive multiplicative updates for the method together with proving their convergence. The new algorithm successfully recovers the true representation from the noisy data. Robust performance can make glsNMF a valuable tool for analyzing empirical data. PMID- 23750289 TI - Order Selection of the Linear Mixing Model for Complex-valued FMRI Data. AB - Functional magnetic resonance imaging (fMRI) data are originally acquired as complex-valued images, which motivates the use of complex-valued data analysis methods. Due to the high dimension and high noise level of fMRI data, order selection and dimension reduction are important procedures for multivariate analysis methods such as independent component analysis (ICA). In this work, we develop a complex-valued order selection method to estimate the dimension of signal subspace using information-theoretic criteria. To correct the effect of sample dependence to information-theoretic criteria, we develop a general entropy rate measure for complex Gaussian random process to calibrate the independent and identically distributed (i.i.d.) sampling scheme in the complex domain. We show the effectiveness of the approach for order selection on both simulated and actual fMRI data. A comparison between the results of order selection and ICA on real-valued and complex-valued fMRI data demonstrates that a fully complex analysis extracts more information about brain activation. PMID- 23750290 TI - Group Study of Simulated Driving fMRI Data by Multiset Canonical Correlation Analysis. AB - In this work, we apply a novel statistical method, multiset canonical correlation analysis (M-CCA), to study a group of functional magnetic resonance imaging (fMRI) datasets acquired during simulated driving task. The M-CCA method jointly decomposes fMRI datasets from different subjects/sessions into brain activation maps and their associated time courses, such that the correlation in each group of estimated activation maps across datasets is maximized. Therefore, the functional activations across all datasets are extracted in the order of consistency across different dataset. On the other hand, M-CCA preserves the uniqueness of the functional maps estimated from each dataset by avoiding concatenation of different datasets in the analysis. Hence, the cross-dataset variation of the functional activations can be used to test the hypothesis of functional-behavioral association. In this work, we study 120 simulated driving fMRI datasets and identify parietal-occipital regions and frontal lobe as the most consistently engaged areas across all the subjects and sessions during simulated driving. The functional-behavioral association study indicates that all the estimated brain activations are significantly correlated with the steering operation during the driving task. M-CCA thus provides a new approach to investigate the complex relationship between the brain functions and multiple behavioral variables, especially in naturalistic tasks as demonstrated by the simulated driving study. PMID- 23750291 TI - An Analysis of Applicants Presenting to a Medical Marijuana Specialty Practice in California. AB - For more than a decade, medical marijuana has been at the forefront of the marijuana policy debate in the United States. Fourteen states allow physicians to recommend marijuana or provide a legal defense for patients and physicians if prosecuted in state courts; however, little is known about those individuals using marijuana for medicinal purposes and the symptoms they use it for. This study provides descriptive information from 1,655 patients seeking a physician's recommendation for medical marijuana, the conditions for which they seek treatment, and the diagnoses made by the physicians. It conducts a systematic analysis of physician records and patient questionnaires obtained from consecutive patients being seen during a three month period at nine medical marijuana evaluation clinics belonging to a select medical group operating throughout the State of California. While this study is not representative of all medical marijuana users in California, it provides novel insights about an important population being affected by this policy. PMID- 23750292 TI - Too much noise on the dance floor: Intra- and inter-dance angular error in honey bee waggle dances. AB - Successful honey bee foragers communicate where they have found a good resource with the waggle dance, a symbolic language that encodes a distance and direction. Both of these components are repeated several times (1 to > 100) within the same dance. Additionally, both these components vary within a dance. Here we discuss some causes and consequences of intra-dance and inter-dance angular variation and advocate revisiting von Frisch and Lindauer's earlier work to gain a better understanding of honey bee foraging ecology. PMID- 23750293 TI - Unravelling the mechanisms of trapline foraging in bees. AB - Trapline foraging (repeated sequential visits to a series of feeding locations) is a taxonomically widespread but poorly understood behavior. Investigating these routing strategies in the field is particularly difficult, as it requires extensive tracking of animal movements to retrace their complete foraging history. In a recent study, we used harmonic radar and motion-triggered video cameras to track bumblebees foraging between artificial flowers in a large open field. We describe how all bees gradually developed a near optimal trapline to link all flowers and have identified a simple learning heuristic capable of replicating this optimisation behavior. Our results provide new perspectives to clarify the sequence of decisions made by pollinating insects during trapline foraging, and explore how spatial memory is organized in their small brains. "I have always regretted that I did not mark the bees by attaching bits of cotton wool or eiderdown to them with rubber, because this would have made it much easier to follow their paths." Charles Darwin(1.) PMID- 23750294 TI - Nuclear localization signals in phage terminal proteins provide a novel gene delivery tool in mammalian cells. AB - Terminal proteins (TPs) of bacteriophages prime DNA replication and become covalently linked to the genome ends. Unexpectedly, we have found functional eukaryotic nuclear localization signals (NLSs) within the TP sequences of bacteriophages from diverse families and hosts. Given the role of bacteriophages as vehicles for horizontal gene transfer (HGT), we postulated that viral genomes that have covalently linked NLS-containing terminal proteins might behave as vectors for HGT between bacteria and the eukaryotic nucleus. To validate this hypothesis, we profited from the in vitro Phi29 amplification system that allows the amplification of heterologous DNAs producing linear molecules of DNA with TP covalently attached to both 5' ends. Interestingly, these in vitro-generated TP DNA molecules showed enhanced gene delivery in mammalian cells, supporting a possible role in HGT by transferring genes between prokaryotes and eukaryotes. Moreover, these TP-DNA molecules are a useful tool to amplify and subsequently deliver genes efficiently into the eukaryotic nucleus. Here, we suggest various possible applications and further developments of the technique with biotechnological and therapeutic purposes. PMID- 23750295 TI - Allostery and instability in the functional plasticity of synaptotagmin I. AB - Synaptotagmin I (Syt I) is the calcium ion sensor for regulated release of neurotransmitter. How Syt I mediates this cellular event has been a question of extensive study for decades and yet, a clear understanding of the protein's diverse functionality has remained elusive. Using tools of thermodynamics, we have identified two intrinsic properties that may account for Syt I's functional plasticity: marginal stability and negative coupling. These two intrinsic properties have the potential to provide great conformational flexibility and suggest that Syt I's functional plasticity stems in part from subtle rearrangements in the protein's conformational ensemble. This model for Syt I function is discussed within the context of the nervous system's overall plasticity. PMID- 23750296 TI - Inter-organellar communication with mitochondria regulates both the intrinsic and extrinsic pathways of apoptosis. AB - One of our major research interests is to define BCL-2 family function in the cellular decision to induce mitochondrial outer membrane permeabilization and apoptosis. Curiosity in BCL-2 family - mitochondrial interactions led to the identification that the sphingolipid pathway plays a crucial role in BCL-2 family function. For approximately 20 years, sphingolipid biology and apoptotic mechanisms have criss-crossed, but remained distinct, as neither literature could explain the observable interplay between these pathways. We recently identified that two products within the sphingolipid pathway, sphingosine-1-PO4 and hexadecenal, directly regulate BAK and BAX activation, respectively. Furthermore, our work suggests that mitochondrial communication with heterotypic membrane and/or organelles may be an important regulatory mechanism for apoptotic sensitivity. PMID- 23750297 TI - c-Cbl reduces stability of rescued ?F508-CFTR in human airway epithelial cells: Implications for cystic fibrosis treatment. AB - CFTR is a PKA activated Cl(-) channel expressed in the apical membrane of fluid transporting epithelia. We previously demonstrated that c-Cbl decreases CFTR stability in the plasma membrane by facilitating its endocytosis and lysosomal degradation in human airway epithelium. The most common mutation associated with cystic fibrosis, deletion of Phe508 (?F508), leads to a temperature sensitive biosynthetic processing defect in the CFTR protein. Mature ?F508-CFTR that has been rescued by low temperature or chemical chaperones is partially functional as a Cl(-) channel but has decreased plasma membrane stability due to altered post maturational trafficking. Our present data demonstrate that c-Cbl controls the post-maturational trafficking of rescued ?F508-CFTR. Partial depletion of c-Cbl increased stability of the plasma membrane associated mature ?F508-CFTR and the ?F508-CFTR mediated Cl(-) secretion. These data indicate that correcting the post maturational trafficking of ?F508-CFTR may represent a therapeutic approach complementary to the biosynthetic rescue. Because c-Cbl functions as an adaptor and scaffolding protein during CFTR endocytosis, we propose that interfering with the c-Cbl mediated endocytic recruitment of ?F508-CFTR may increase stability of ?508-CFTR in the plasma membrane after its biosynthetic rescue. PMID- 23750298 TI - In silico analysis of Plasmodium species specific UvrD helicase. AB - Malaria is still a devastating disease caused by the mosquito-transmitted parasite Plasmodium, particularly Plasmodium falciparum. During the last few years the situation has worsened in many ways, mainly due to malarial parasites becoming increasingly resistant to several anti-malarial drugs. Thus there is an urgent need to find alternate ways to control malaria and therefore it is necessary to identify new drug targets and new classes of anti-malarial drugs. A malaria vaccine would be the ultimate weapon to fight this deadly disease but unfortunately despite encouraging advances a vaccine is not likely soon. DNA helicases from the PcrA/UvrD/Rep (PUR) subfamily are important for the survival of the various organisms, mainly pathogenic bacteria. Members from this subfamily can be targeted and inhibited by a variety of synthetic compounds. Using bioinformatics analysis we have shown that UvrD from this subfamily is the only member present in the P. falciparum genome, while PcrA and Rep are absent in the genome. UvrD from the parasite shows no homology to any protein or enzyme from human and thus can be considered as a strong potential drug target. In the present study we report an in silico analysis of this important enzyme from a variety of Plasmodium species. The results suggest that among all the species of Plasmodium, P. falciparum contains the largest UvrD and this enzyme is variable at the sequence and structural level. PMID- 23750299 TI - At the origin of spliceosomal introns: Is multiplication of introner-like elements the main mechanism of intron gain in fungi? AB - The recent discovery of introner-like elements (ILEs) in six fungal species shed new light on the origin of regular spliceosomal introns (RSIs) and the mechanism of intron gains. These novel spliceosomal introns are found in hundreds of copies, are longer than RSIs and harbor stable predicted secondary structures. Yet, they are prone to degeneration in sequence and length to become undistinguishable from RSIs, suggesting that ILEs are predecessors of most RSIs. In most fungi, other near-identical introns were found duplicated in lower numbers in the same gene or in unrelated genes, indicating that intron duplication is a widespread phenomenon. However, ILEs are associated with the majority of intron gains, suggesting that the other types of duplication are of minor importance to the overall gains of introns. Our data support the hypothesis that ILEs' multiplication corresponds to the main mechanism of intron gain in fungi. PMID- 23750300 TI - Geometrical constraints and physical crowding direct collective migration of fibroblasts. AB - Migrating cells constantly interact with their immediate microenvironment and neighbors. Although studies on single cell migration offer us insights into the molecular and biochemical signaling pathways, they cannot predict the influence of cell crowding and geometrical cues. Using microfabrication techniques, we examine the influence of cell density and geometrical constraints on migrating fibroblasts. Fibroblasts were allowed to migrate on fibronectin strips of different widths. Under such conditions, cells experience various physical guidance cues including boundary effect, confinement and contact inhibition from neighboring cells. Fibroblasts migrating along the edge of the fibronectin pattern exhibit spindle-like morphology, reminiscent of migrating cells within confined space and high cell density are associated with increased alignment and higher speed in migrating fibroblasts. PMID- 23750301 TI - A multifunctional, multi-pathway intracellular localization signal in Huntingtin. AB - Nuclear accumulation of the polyglutamine-expanded mutant huntingtin protein remains one of the most predictive cell biological phenotypes of Huntington's disease (HD) progression in patient brain samples and mouse models of the disease. Yet, the relationship between huntingtin nuclear import, neuronal dysfunction and toxicity is not fully understood and it remains unclear whether nuclear accumulation is required for disease onset. Here, we discuss several studies that have guided current understanding of this subject, and highlight our recent data detailing the discovery of a karyopherin beta1/beta2-type nuclear localization signal near the N-terminus of huntingtin. This signal can function through multiple pathways of nuclear import, and may also be responsible for huntingtin import into the primary cilium. This work represents a significant step forward in our knowledge of the regulatory pathways that govern huntingtin nuclear accumulation and will allow direct examination of both normal and mutant huntingtin nuclear function. This work also suggests a re-examination of the cell biology of any protein that contains a multi-pathway nuclear localization signal. The possibility of targeting huntingtin nuclear import therapeutically and the potential impacts of such a strategy for the treatment of HD are also discussed. PMID- 23750302 TI - Relative amount of symbionts in Bemisia tabaci (Gennadius) Q changes with host plant and establishing the method of analyzing free amino acid in B. tabaci. AB - The impact of symbionts on their insect hosts depends on their infection density. In the current study, we investigated the effects of host plants (cucumber, cabbage, and cotton) on the relative amount of symbionts Portiera and Hamiltonella in the whitefly Bemisia tabaci (Gennadius) Q. The relative amounts of symbionts in 3 host plant B. tabaci Q populations with the same genetic background were evaluated by quantitative PCR. The whiteflies of cabbage population harbored more Portiera than those of cucumber and cotton populations, and the relative amount of Portiera did not differ statistically between cotton and cucumber populations. The whiteflies of cucumber and cabbage populations harbored more Hamiltonella than that of cotton population, and the relative amount of Hamiltonella did not differ statistically between cabbage and cucumber populations, indicated that the relative amount of symbionts was significantly affected by host plant. In addition, the method of analyzing the composition of free amino acid in B. tabaci was established. Twenty-eight amino acids were detected in the B. tabaci Q population, the non-essential amino acids, such as glutamate, glutamine, alanine, proline and the essential amino acid arginine were the dominant amino acids in B. tabaci Q. PMID- 23750303 TI - Run-length encoding graphic rules, biochemically editable designs and steganographical numeric data embedment for DNA-based cryptographical coding system. AB - There have been a wide variety of approaches for handling the pieces of DNA as the "unplugged" tools for digital information storage and processing, including a series of studies applied to the security-related area, such as DNA-based digital barcodes, water marks and cryptography. In the present article, novel designs of artificial genes as the media for storing the digitally compressed data for images are proposed for bio-computing purpose while natural genes principally encode for proteins. Furthermore, the proposed system allows cryptographical application of DNA through biochemically editable designs with capacity for steganographical numeric data embedment. As a model case of image-coding DNA technique application, numerically and biochemically combined protocols are employed for ciphering the given "passwords" and/or secret numbers using DNA sequences. The "passwords" of interest were decomposed into single letters and translated into the font image coded on the separate DNA chains with both the coding regions in which the images are encoded based on the novel run-length encoding rule, and the non-coding regions designed for biochemical editing and the remodeling processes revealing the hidden orientation of letters composing the original "passwords." The latter processes require the molecular biological tools for digestion and ligation of the fragmented DNA molecules targeting at the polymerase chain reaction-engineered termini of the chains. Lastly, additional protocols for steganographical overwriting of the numeric data of interests over the image-coding DNA are also discussed. PMID- 23750304 TI - Drosophila larvae as a model to study physiological alcohol dependence. AB - Alcohol addiction is a disease that includes a diverse set of phenotypes. Functional alcohol tolerance is an adaptation to the effects of alcohol that restores neuronal homeostatic balance while the drug is present. When the drug is suddenly withheld, these adaptations unbalance the nervous system and are thought to be the origin of some withdrawal symptoms. Withdrawal symptoms, which can be a motivating factor for alcoholics to relapse, are taken as evidence of physiological ethanol dependence. Both tolerance and withdrawal symptoms are diagnostic criteria for alcoholism. Recent studies have demonstrated that the larvae of Drosophila show conserved alcohol tolerance and withdrawal phenotypes indicating that Drosophila genetics can now be used in studying this endophenotype of alcohol addiction. PMID- 23750305 TI - Using hormetic strategies to improve ischemic preconditioning and postconditioning against stroke. AB - Both ischemic preconditioning (IPreC) and ischemic postconditioning (IPostC) trigger endogenous neuroprotective mechanisms in cerebral ischemia. IPreC is defined as a brief ischemia that protects against a subsequent severe ischemia, while IPostC refers to a series of brief cerebral blood vessel occlusions performed at reperfusion following an ischemic event. Hormesis describes a biphasic dose-response relationship in toxicology, where a low dose of toxicant stimulates and a high dose inhibits biological responses. In general, any minor stress will stimulate a biological system to generate an adaptive response; in most cases, if not all, such an adaptive response to a minor stress is beneficial to the biological system. Proponents of hormesis suggest that this effect is independent of any models, either in vivo or in vitro, from animal, plant, fungi, yeast, to bacteria, by any measurement of end points, survival ratio or time, growth, tissue repair, life span, cognition, learning and memory. In this review, we examine whether IPreC and IPostC are actually sub-forms of hormesis and whether quantitative hormetic strategies can be used to study IPreC and IPostC. By integrating the concepts of IPreC and IPostC with hormesis, we aim to broaden the avenues leading to clinical translation of IPreC and IPostC in stroke treatment. PMID- 23750307 TI - An autocrine gamma-aminobutyric acid signaling system exists in pancreatic beta cell progenitors of fetal and postnatal mice. AB - Gamma-aminobutyric acid (GABA) is produced and secreted by adult pancreatic beta cells, which also express GABA receptors mediating autocrine signaling and regulating beta-cell proliferation. However, whether the autocrine GABA signaling involves in beta-cell progenitor development or maturation remains uncertain. By means of immunohistochemistry we analyzed the expression profiles of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) and the alpha1-subunit of type-A GABA receptor (GABAARalpha1) in the pancreas of mice at embryonic day 15.5 (E15.5), E18.5, postnatal day 1 (P1) and P7. Our data showed that at E15.5 the pancreatic and duodenum homeobox-1 (Pdx1) was expressed in the majority of cells in the developing pancreata. Notably, insulin immunoreactivity was identified in a subpopulation of pancreatic cells with a high level of Pdx1 expression. About 80% of the high-level Pdx-1 expressing cells in the pancreas expressed GAD and GABAARalpha1 at all pancreatic developmental stages. In contrast, only about 30% of the high-level Pdx-1 expressing cells in the E15.5 pancreas expressed insulin; i.e., a large number of GAD/GABAARalpha1-expressing cells did not express insulin at this early developmental stage. The expression level of GAD and GABAARalpha1 increased steadily, and progressively more GAD/GABAARalpha1-expressing cells expressed insulin in the course of pancreatic development. These results suggest that 1) GABA signaling proteins appear in beta-cell progenitors prior to insulin expression; and 2) the increased expression of GABA signaling proteins may be involved in beta-cell progenitor maturation. PMID- 23750306 TI - Microglia and ischemic stroke: a double-edged sword. AB - Inflammatory processes have a fundamental role in the pathophysiology of stroke. A key initial event is the rapid activation of resident immune cells, primarily microglia. This cell population is an important target for new therapeutic approaches to limit stroke damage. Activation of microglia is normally held in check by strictly controlled mechanisms involving neuronal-glial communication. Ischemic stroke is a powerful stimulus that disables the endogenous inhibitory signaling and triggers microglial activation. Once activated, microglia exhibit a spectrum of phenotypes, release both pro- and anti-inflammatory mediators, and function to either exacerbate ischemic injury or help repair depending on different molecular signals the microglial receptors receive. Various ligands and receptors have been identified for microglial activation. Experimental tools to detect these inflammatory signals are being increasingly developed in an effort to define the functional roles of microglia. Fine-tuning immunomodulatory interventions based on the heterogeneous profiles of microglia are urgently needed for ischemic stroke. PMID- 23750308 TI - Antioxidant activity of simvastatin prevents L-arginine-induced acute toxicity of pancreas. AB - L-arginine is a semi-essential amino acid that found naturally in food. It has been shown that administration of large doses of L-arginine can induce acute pancreatitis. In the present study, we evaluated if simvastatin, a 3-hydroxy methylglutaryl coenzyme A reductase (HMG-CoA reductase) inhibitor, might prevent acute pancreatitis induced by L-arginine. Thirty male Wistar rats were randomly allocated to five groups. Groups were: DMSO, saline, simvastatin, L-arginine, and simvastatin with L-arginine. Twenty four hours after the last dose, rats were sacrificed and their blood was collected from heart for biochemical analysis. Pancreatic tissues were obtained for analysis of glutathione peroxidase (GPx), glutathione s-transferase (GST), lipid peroxide levels (MDA) and histology analysis was examined for pancreas. Results indicated that treatment with simvastatin significantly enhanced levels of GPx and GST and decreased lipid peroxide levels induced by L-arginine compared to the vehicle. Moreover, histopathological analysis further confirmed that administration of simvastatin relatively prevented pancreatic acinar cell damage compared to those animals received L-arginine alone. These findings pointed out the protective role of simvastatin against acute pancreatitis induced by high doses of L-arginine. PMID- 23750309 TI - Effect of angiotensin II type 1 receptor blocker on renal function, arterial blood pressure and parathyroid hormone related protein over expression in cadmium induced nephrotoxicity in adult male rats. AB - OBJECTIVE: To study the possible effect of angiotensin II type 1 Receptor blocker (AT1 blocker) on renal function, arterial blood pressure and parathyroid hormone related protein over expression in cadmium induced nephrotoxicity in adult male rats. Forty five rats were divided randomly into a control (group I), group II, received cadmium chloride at a dose of 5 mg/kg/day, orally, for nine weeks, group III received telmisartan (TEL) treatment (1 mg/kg/day, orally) one week before cadmium administration and continued for ten weeks. RESULTS: Telmisartan significantly reduced blood urea nitrogen (BUN) and serum creatinine levels which were increased significantly by cadmium. Telmisartan significantly suppressed lipid peroxidation, compensated deficits in the antioxidant defenses (super oxide dismutase (SOD) level and catalase activity), decreased the elevations of nitric oxide (NO) and cadmium ion concentrations in renal tissue observed in Cd-treated rats. Group III had a significant decrease of urinary levels of total protein, N acetyl-beta-d-glucosaminidase (NAG), alkaline phosphatase (ALP) and gamma glutamyl-transpeptidase (GGT) and urinary 8-isoprostanes than those of group II. Telmisartan decreased the systolic blood pressure significantly than those of group II. Histopathological examination revealed that cadmium-induced renal tissue damage was ameliorated by telmisartan treatment. Immunohistochemical analysis revealed that telmisartan significantly decreased the cadmium-induced overexpression of parathyroid hormone receptor 1 (PTHR1) in renal tissue. RT-PCR analysis showed that Cd increased renal expression of PTHrP; however telmisartan could decrease the expression of PTHrP in group III. CONCLUSION: Blocking AT1 receptors significantly decreases PTHrP over expression and ameliorates renal dysfunction in Cd induced nephrotoxicity. These data suggest that Ang II might contribute to pathophysiology and deleterious effects in cadmium nephrotoxicity. PMID- 23750310 TI - Inpatient antibiotics pharmacology and physiological use in Hayatabad medical complex, Pakistan. AB - Antibiotics are used commonly and as powerful medicines, it well known that they affect the variety and composition of the microflora which has important physiological roles, therefore and for other health complications, the aim of the current study was to evaluate and estimate the appropriateness of antimicrobial drugs use in Hayatabad Medical Complex (HMC), Peshawar, Pakistan. The present work is based on the hospitalized patient's case studies. Individual patients were interviewed using the prepared questionnaire for the study. All hospitalized patients who received antibiotics were evaluated by a cross-sectional study. The total number of patients interviewed was 270 in medical department. According to our study in medical department, for prophylaxis 64.3% of antibiotic was used, whereas, an empirical use was 35.7%. Prodigious double regimen of antibiotics was observed throughout the study. The most prescribed antimicrobial group is penicillin and followed by tetracycline, macrolides, quinolones, and cephalosporin. Furthermore, 14.56% antibiotics were prescribed on generic name and 85.43% were prescribed on the basis of brand names. Taken together, the antibiotic use in medical department was unsatisfactory and irrational. In summary, in order to protect the physiological functions of flora microorganisms, a combination of both limitation, continuous education of physicians and elaboration of local guidelines appear to be necessary to improve rational antibiotic use. PMID- 23750311 TI - Behavioral and neuronal biochemical possible effects in experimental induced chronic mild stress in male albino rats under the effect of oral barley administration in comparison to venlafaxine. AB - Venlafaxine is an antidepressant of choice, whose effectiveness could be modified by a commonly used medicinal plant and nutrient. The current study had evaluated the barley extract (1 g/kg) when compared to or combined to venlafaxine (32 mg/kg) in a rat stress model. The present study was conducted on 40 male Wister albino rats; divided to five groups. Four groups were subjected to social chronic mild stress. Drugs or saline were orally daily administered one week before stress induction and extended up to ten weeks. Behavioral, brain biochemical tests and serum magnesium were assessed at the end. The study revealed significant change in the combined group on behavioral tests; forced swim test, elevated plus maze and saccharin preference test when compared to barley extract group. Furthermore, there was significant reduction in brain malondialdehyde level, no significant change in brain nitric oxide level, while significant increase in serum magnesium level was noticed. Whereas, the barley extract group recorded a lowest significant improvement in behavioral, brain and serum biochemical tests. It could be concluded that barley and venlafaxine together had muffled the oxidant stress and increased brain serotonin, serum magnesium level that might had a crucial role in experimental induced chronic mild stress in rats. PMID- 23750312 TI - Chemically Programmed Antibodies AS HIV-1 Attachment Inhibitors. AB - Herein we describe the design and application of two small-molecule anti-HIV compounds for the creation of chemically programmed antibodies. N-acyl-beta lactam derivatives of two previously described molecules BMS-378806 and BMS 488043 that inhibit the interaction between HIV-1 gp120 and T-cells were synthesized and used to program the binding activity of aldolase antibody 38C2. Discovery of a successful linkage site to BMS-488043 allowed for the synthesis of chemically programmed antibodies with affinity for HIV-1 gp120 and potent HIV-1 neutralization activity. Derivation of a successful conjugation strategy for this family of HIV-1 entry inhibitors enables its application in chemically programmed antibodies and vaccines and may facilitate the development of novel bispecific antibodies and topical microbicides. PMID- 23750313 TI - United States medical students' knowledge of Alzheimer disease. AB - PURPOSE: A knowledge gap exists between general physicians and specialists in diagnosing and managing Alzheimer disease (AD). This gap is concerning due to the estimated rise in prevalence of AD and cost to the health care system. Medical school is a viable avenue to decrease the gap, educating future physicians before they specialize. The purpose of this study was to assess the knowledge level of students in their first and final years of medical school. METHODS: Fourteen participating United States medical schools used e-mail student rosters to distribute an online survey of a quantitative cross-sectional assessment of knowledge about AD; 343 students participated. Knowledge was measured using the 12-item University of Alabama at Birmingham AD Knowledge Test for Health Professionals. General linear models were used to examine the effect of demographic variables and previous experience with AD on knowledge scores. RESULTS: Only 2.5% of first year and 68.0% of final year students correctly scored ten or more items on the knowledge scale. Personal experience with AD predicted higher knowledge scores in final year students (P= 0.027). CONCLUSION: Knowledge deficiencies were common in final year medical students. Future studies to identify and evaluate the efficacy of AD education programs in medical schools are warranted. Identifying and disseminating effective programs may help close the knowledge gap. PMID- 23750314 TI - Adaptive Distributed Video Coding with Correlation Estimation using Expectation Propagation. AB - Distributed video coding (DVC) is rapidly increasing in popularity by the way of shifting the complexity from encoder to decoder, whereas no compression performance degrades, at least in theory. In contrast with conventional video codecs, the inter-frame correlation in DVC is explored at decoder based on the received syndromes of Wyner-Ziv (WZ) frame and side information (SI) frame generated from other frames available only at decoder. However, the ultimate decoding performances of DVC are based on the assumption that the perfect knowledge of correlation statistic between WZ and SI frames should be available at decoder. Therefore, the ability of obtaining a good statistical correlation estimate is becoming increasingly important in practical DVC implementations. Generally, the existing correlation estimation methods in DVC can be classified into two main types: pre-estimation where estimation starts before decoding and on-the-fly (OTF) estimation where estimation can be refined iteratively during decoding. As potential changes between frames might be unpredictable or dynamical, OTF estimation methods usually outperforms pre-estimation techniques with the cost of increased decoding complexity (e.g., sampling methods). In this paper, we propose a low complexity adaptive DVC scheme using expectation propagation (EP), where correlation estimation is performed OTF as it is carried out jointly with decoding of the factor graph-based DVC code. Among different approximate inference methods, EP generally offers better tradeoff between accuracy and complexity. Experimental results show that our proposed scheme outperforms the benchmark state-of-the-art DISCOVER codec and other cases without correlation tracking, and achieves comparable decoding performance but with significantly low complexity comparing with sampling method. PMID- 23750315 TI - Maternal predictors of neonatal bone size and geometry: the Southampton Women's Survey. AB - Early growth is associated with later risk of osteoporosis and fractures. In this study, we aimed to evaluate the relationships between maternal lifestyle and body composition and neonatal bone size, geometry and density in the offspring. Participants were recruited from the Southampton Women's Survey, a unique prospective cohort of 12,500 initially non-pregnant women aged 20-34 years, resident in Southampton, UK. These women were studied in detail before and during pregnancy, and the offspring underwent anthropometric and bone mineral assessment (using dual energy-X-ray absorptiometry) at birth. A total of 841 mother-baby pairs were studied (443 boys and 398 girls). The independent predictors of greater neonatal whole body bone area (BA) and bone mineral content included greater maternal birthweight, height, parity, triceps skinfold thickness and lower walking speed in late pregnancy. Maternal smoking was independently associated with lower neonatal bone mass. Neonatal BA adjusted for birth length (a measure of bone width) was predicted positively by maternal parity and late pregnancy triceps skinfold thickness and negatively by late pregnancy walking speed. These findings were similar in both genders. We have confirmed, in a large cohort, previous findings that maternal lifestyle and body build predict neonatal bone mineral; additionally, maternal parity and fat stores and walking speed in late pregnancy were associated with neonatal bone geometry. These findings may suggest novel public health strategies to reduce the burden of osteoporotic fracture in future generations. PMID- 23750316 TI - The relationship of birthweight, muscle size at birth and post-natal growth to grip strength in 9-year-old Indian children: findings from the Mysore Parthenon study. AB - Foetal development may permanently affect muscle function. Indian newborns have a low mean birthweight, predominantly due to low lean tissue and muscle mass. We aimed to examine the relationship of birthweight, and arm muscle area (AMA) at birth and post-natal growth to handgrip strength in Indian children. Grip strength was measured in 574 children aged 9 years, who had detailed anthropometry at birth and every 6-12 months post-natally. Mean (standard deviation (s.d.)) birthweight was 2863 (446) g. At 9 years, the children were short (mean height s.d. -0.6) and light (mean weight s.d. -1.1) compared with the World Health Organization growth reference. Mean (s.d.) grip strength was 12.7 (2.2) kg (boys) and 11.0 (2.0) kg (girls). Weight, length and AMA at birth, but not skinfold measurements at birth, were positively related to 9-year grip strength (beta = 0.40 kg/s.d. increase in birthweight, P < 0.001; and beta = 0.41 kg/s.d. increase in AMA, P < 0.001). Grip strength was positively related to 9 year height, body mass index and AMA and to gains in these measurements from birth to 2 years, 2-5 years and 5-9 years (P < 0.001 for all). The associations between birth size and grip strength were attenuated but remained statistically significant for AMA after adjusting for 9-year size. We conclude that larger overall size and muscle mass at birth are associated with greater muscle strength in childhood, and that this is mediated mainly through greater post-natal size. Poorer muscle development in utero is associated with reduced childhood muscle strength. PMID- 23750317 TI - New fluorescent probes for sulfane sulfurs and the application in bioimaging. AB - A sulfane sulfur mediated benzodithiolone formation was developed. Based on this reaction, two fluorescent probes (SSP1 and SSP2) for the detection of sulfane sulfur species (persulfide, polysulfide, and elemental sulfur) were prepared and evaluated. The probes showed high selectivity and sensitivity to sulfane sulfurs. Moreover, SSP2 was successfully applied for bioimaging sulfane sulfurs in living cells. PMID- 23750319 TI - Comparative study of guanidine-based and lysine-based brush copolymers for plasmid delivery. AB - Polyethylenimine (PEI), one of the most frequently used polycations for non-viral nucleic acid delivery, exhibits good transfection efficiency to cultured cells but generally has to be used in restricted concentration ranges due to high cytotoxicity. We recently reported a family of HPMA-co-oligolysine brush copolymers that show nucleic acid delivery efficiencies approaching that of PEI. Guanidine-containing polymers have been reported in some systems to be more effective at cellular delivery of cargo than their primary-amine analogs. The goal of this work is to investigate the effect of guanidinylation on gene transfer ability of HPMA-co-oligolysine copolymers. Several parameters were evaluated: arginine versus homoarginine monomers, oligopeptide length, and charge density within the peptide. Using reversible addition-fragmentation chain transfer (RAFT) polymerization, a series of six copolymers were synthesized containing the cationic peptides K10, R10, K5, and (GK)5. Lysine-containing copolymers were functionalized with guanidine by reaction with O-methylisourea to generate an additional five homoarginine-based copolymers. All eleven copolymers readily condensed DNA into small, < 150 nm polyplexes and remained stable in physiological salt conditions. The best performing copolymers provided more efficient gene transfection with less associated cytotoxicity than PEI. Reducing the number of charge centers (from 10 to 5) further reduced toxicity while retaining comparable transfection efficiency to PEI. PMID- 23750318 TI - Mechanisms of evasive resistance to anti-VEGF therapy in glioblastoma. AB - Angiogenesis inhibitors targeting the VEGF signaling pathway have been US FDA approved for various cancers including glioblastoma (GBM), one of the most lethal and angiogenic tumors. This has led to the routine use of the anti-VEGF antibody bevacizumab in recurrent GBM, conveying substantial improvements in radiographic response, progression-free survival and quality of life. Despite these encouraging beneficial effects, patients inevitably develop resistance and frequently fail to demonstrate significantly better overall survival. Unlike chemotherapies, to which tumors exhibit resistance due to genetic mutation of drug targets, emerging evidence suggests that tumors bypass antiangiogenic therapy while VEGF signaling remains inhibited through a variety of mechanisms that are just beginning to be recognized. Because of the indirect nature of resistance to VEGF inhibitors there is promise that strategies combining angiogenesis inhibitors with drugs targeting such evasive resistance pathways will lead to more durable antiangiogenic efficacy and improved patient outcomes. Further identifying and understanding of evasive resistance mechanisms and their clinical importance in GBM relapse is therefore a timely and critical issue. PMID- 23750320 TI - COMPETING PROPERTIES OF MUCOADHESIVE FILMS DESIGNED FOR LOCALIZED DELIVERY OF IMIQUIMOD. AB - Oral mucosal delivery has gained prominence in the last two decades because the rich vasculature of the tissue enables rapid delivery and avoidance of first pass metabolism. Although commercial mucoadhesives are used for systemic delivery, systems are not currently available for treatment of local conditions. In the present work, mucoadhesive films are being developed for locally controlled release of an immune response modifier for preventing precancerous lesions from progressing to oral squamous cell carcinoma. Previous research showed that films composed of polyvinylpyrrolidone (PVP) and carboxymethylcellulose (CMC) released imiquimod in a sustained manner for 3 hr. In continuing development of the system, additional key properties were investigated with changes in composition. While adhesive properties in pull-off (0.42+/-0.03 to 1.1+/-0.1 N/cm2) and shear adhesion (1.7+/-0.25 to 5.6+/-1.4 N/cm2) increased with increasing PVP content of films, tensile properties, such as modulus (6.9+/-1.5 to 1.8+/-0.2 MPa) and ultimate strength (4.2+/-0.7 to 2.1+/-0.02 MPa), decreased as PVP content increased. Release profiles of the films showed that an increased PVP content resulted in burst release and faster erosion compared to sustained release and slower erosion with more CMC. Studies of transport kinetics showed that the films doubled the amount of imiquimod localized within epithelium compared to drug in solution, increasing their potential for local treatment of oral dysplasia. The mucoadhesive drug delivery system based on CMC and PVP offers a wide range of these properties without addition of new constituents. PMID- 23750321 TI - Mental Stress Elicits Sustained and Reproducible Increases in Skin Sympathetic Nerve Activity. AB - Mental stress (MS) is a known trigger of myocardial infarction and sudden death. By activating the sympathetic nervous system, MS may have deleterious effect on the cardiovascular system but this process is not completely understood. The primary aim of this study was to quantify the effect of MS on skin sympathetic nerve activity (SSNA). The secondary aim was to determine the reproducibility of SSNA to MS within a given day and ~1 week later. Ten subjects (26+/-1 yr.) performed two bouts of mental arithmetic lasting 3 min. The bouts were separated by 45 min. One week later the subjects returned to repeat MS. All experiments were conducted in the supine posture during the morning hours. To maintain neutral skin temperature, each subject wore a custom suit (34-35 degrees C). Skin blood flow and sweat rate were measured on the dorsal foot. MS elicited a marked increase in SSNA within the first 10 s (184+/-42%; P<0.01) in all subjects, which was less during the remaining period of MS but remained elevated (87+/-20; P<0.01). The pattern of responses to MS was unchanged during the second bout (10 s, 247+/-55%; 3 min avg., 133+/-29%) and during the retest 1 week later (10 s, 196+/-55%; 3 min avg., 117+/-36%). MS did not significantly affect cutaneous vascular conductance or sweat rate during any trial. In summary, MS elicits robust and reproducible increases in SSNA in humans which may be followed over time to observe alterations in the regulation of the autonomic nervous system. PMID- 23750322 TI - Next-generation sequencing: application in liver cancer-past, present and future? AB - Hepatocellular Carcinoma (HCC) is the third most deadly malignancy worldwide characterized by phenotypic and molecular heterogeneity. In the past two decades, advances in genomic analyses have formed a comprehensive understanding of different underlying pathobiological layers resulting in hepatocarcinogenesis. More recently, improvements of sophisticated next-generation sequencing (NGS) technologies have enabled complete and cost-efficient analyses of cancer genomes at a single nucleotide resolution and advanced into valuable tools in translational medicine. Although the use of NGS in human liver cancer is still in its infancy, great promise rests in the systematic integration of different molecular analyses obtained by these methodologies, i.e., genomics, transcriptomics and epigenomics. This strategy is likely to be helpful in identifying relevant and recurrent pathophysiological hallmarks thereby elucidating our limited understanding of liver cancer. Beside tumor heterogeneity, progress in translational oncology is challenged by the amount of biological information and considerable "noise" in the data obtained from different NGS platforms. Nevertheless, the following review aims to provide an overview of the current status of next-generation approaches in liver cancer, and outline the prospects of these technologies in diagnosis, patient classification, and prediction of outcome. Further, the potential of NGS to identify novel applications for concept clinical trials and to accelerate the development of new cancer therapies will be summarized. PMID- 23750324 TI - IgA transglutaminase levels in children with Juvenile Idiopathic Arthritis. AB - OBJECTIVES: Several studies have indicated that adult patients with spondyloarthritis (SpA) have elevated levels of antibodies associated with celiac disease (CD). This has not been studied in children, and none of the studies corrected for total IgA levels. METHODS: We measured total IgA and IgA against tissue transglutaminase (TTG) levels in 42 children with Juvenile Idiopathic Arthritis (JIA), of whom 11 had SpA, along with 10 non-inflammatory control subjects. RESULTS: Median (IQR) TTG IgA levels were elevated among children with ERA (8.8, 4.6 - 21) compared to 'JIA controls' (JIA subgroups other than ERA) (2.8, 1.5 - 5.9) and a healthy non-inflammatory control group (1.5, 0.82 - 12), p = 0.017, Kruskal-Wallis. There was no correlation between TTG IgA levels and measures of disease activity or with medicine use. None of the children were diagnosed endoscopically with celiac disease. Patients with ERA likewise had elevated total IgA level compared to the other groups (p = 0.001), and total IgA levels correlated highly with TTG IgA (r = 0.599, p<0.001). CONCLUSION: These findings suggest that elevations in TTG IgA may reflect increased polyclonal IgA production, rather than a specific intestinal inflammatory process. PMID- 23750325 TI - The Molecular Chaperone GRP78/BiP as a Therapeutic Target for Neurodegenerative Disorders: A Mini Review. AB - The glucose regulated protein 78 (GRP78), also known as BiP, is the endoplasmatic reticulum (ER) homologue of HSP70, which plays a dual role in the ER by controlling protein folding, in order to prevent aggregation, and by regulating the signaling of the unfolded protein response (UPR). Most neurodegenerative disorders including Parkinson's, Alzheimer's diseases and progressive retinal degeneration are characterized by activation of the UPR and modified expression of GRP78. The expression levels and activity of GRP78 are altered with age raising the question of whether the lack of GRP78 could be a predisposing factor for many neurodegenerative disorders associated with age including PD, Alzheimer and Age-related macular degeneration. Attempts to induce or upregulate GRP78 in animal models of neurodegeneration have recently been made with the help of pharmacological BiP protein Inducer X (BIX) and GRP78 cDNA delivery via adeno associated virus (AAV) vectors. The results of these studies validate GRP78 as a new therapeutic target for treatments of forebrain ischemia, Parkinson disease and retinal degeneration. These data, together with the results from age-related studies, highlight the importance for developing drugs to induce elevation of endogenous GRP78 in order to increase cellular survival and extend functional longevity. PMID- 23750323 TI - PATHOLOGIES OF AXONAL TRANSPORT IN NEURODEGENERATIVE DISEASES. AB - Gene products such as organelles, proteins and RNAs are actively transported to synaptic terminals for the remodeling of pre-existing neuronal connections and formation of new ones. Proteins described as molecular motors mediate this transport and utilize specialized cytoskeletal proteins that function as molecular tracks for the motor based transport of cargos. Molecular motors such as kinesins and dynein's move along microtubule tracks formed by tubulins whereas myosin motors utilize tracks formed by actin. Deficits in active transport of gene products have been implicated in a number of neurological disorders. We describe such disorders collectively as "transportopathies". Here we review current knowledge of critical components of active transport and their relevance to neurodegenerative diseases. PMID- 23750327 TI - Empirically-derived dietary patterns, diet quality scores, and markers of inflammation and endothelial dysfunction. AB - Atherosclerosis is one of the most important contributors to the global burden of cardiovascular diseases. With the recognition of atherosclerosis as an inflammatory disease, nutrition research interest has expanded towards the role of dietary patterns in the prevention of atherosclerosis primarily focused on associations with early inflammatory markers. This review summarizes the latest evidence from January 2010 until January 2013 of eight observational studies on the associations between empirically-derived dietary patterns and diet quality scores with markers of inflammation and endothelial function. Overall, results of recently published cohort studies support those of previously published cross sectional studies suggesting that consuming a healthy type of diet characteristically abundant in fruits and vegetables is associated with lower concentrations of C-reactive protein and other inflammatory markers. Unfavourable associations were found between eating a Western dietary pattern high in meat and inflammatory markers. Different statistical approaches of deriving dietary patterns were applied in these studies and most of them lacked in reporting absolute intakes of foods and/or food groups. Future prospective cohort studies are needed to evaluate long-term associations between dietary patterns and changes in inflammatory markers by comparing various approaches of dietary pattern derivation within a population. Reporting absolute intakes of foods and/or food groups may also facilitate the identification of a typical dietary pattern that may beneficially influence inflammation. PMID- 23750326 TI - Autophagy - An Emerging Anti-Aging Mechanism. AB - Autophagy is a cytoplasmic catabolic process that protects the cell against stressful conditions. Damaged cellular components are funneled by autophagy into the lysosomes, where they are degraded and can be re-used as alternative building blocks for protein synthesis and cellular repair. In contrast, aging is the gradual failure over time of cellular repair mechanisms that leads to the accumulation of molecular and cellular damage and loss of function. The cell's capacity for autophagic degradation also declines with age, and this in itself may contribute to the aging process. Studies in model organisms ranging from yeast to mice have shown that single-gene mutations can extend lifespan in an evolutionarily conserved fashion, and provide evidence that the aging process can be modulated. Interestingly, autophagy is induced in a seemingly beneficial manner by many of the same perturbations that extend lifespan, including mutations in key signaling pathways such as the insulin/IGF-1 and TOR pathways. Here, we review recent progress, primarily derived from genetic studies with model organisms, in understanding the role of autophagy in aging and age-related diseases. PMID- 23750328 TI - Low intensity laser therapy accelerates muscle regeneration in aged rats. AB - BACKGROUND: Elderly people suffer from skeletal muscle disorders that undermine their daily activity and quality of life; some of these problems can be listed as but not limited to: sarcopenia, changes in central and peripheral nervous system, blood hypoperfusion, regenerative changes contributing to atrophy, and muscle weakness. Determination, proliferation and differentiation of satellite cells in the regenerative process are regulated by specific transcription factors, known as myogenic regulatory factors (MRFs). In the elderly, the activation of MRFs is inefficient which hampers the regenerative process. Recent studies found that low intensity laser therapy (LILT) has a stimulatory effect in the muscle regeneration process. However, the effects of this therapy when associated with aging are still unknown. OBJECTIVE: This study aimed to evaluate the effects of LILT (lambda=830 nm) on the tibialis anterior (TA) muscle of aged rats. SUBJECTS AND METHODS: The total of 56 male Wistar rats formed two population sets: old and young, with 28 animals in each set. Each of these sets were randomly divided into four groups of young rats (3 months of age) with n=7 per group and four groups of aged rats (10 months of age) with n=7 per group. These groups were submitted to cryoinjury + laser irradiation, cryoinjury only, laser irradiation only and the control group (no cryoinjury/no laser irradiation). The laser treatment was performed for 5 consecutive days. The first laser application was done 24 h after the injury (on day 2) and on the seventh day, the TA muscle was dissected and removed under anesthesia. After this the animals were euthanized. Histological analyses with toluidine blue as well as hematoxylin-eosin staining (for counting the blood capillaries) were performed for the lesion areas. In addition, MyoD and VEGF mRNA was assessed by quantitative polymerase chain reaction. RESULTS: The results showed significant elevation (p<0.05) in MyoD and VEGF genes expression levels. Moreover, capillary blood count was more prominent in elderly rats in laser irradiated groups when compared to young animals. CONCLUSION: In conclusion, LILT increased the maturation of satellite cells into myoblasts and myotubes, enhancing the regenerative process of aged rats irradiated with laser. PMID- 23750329 TI - Entropy of never born protein sequences. AB - BACKGROUND: A Never Born protein is a theoretical protein which does not occur in nature. The reason why some proteins were selected and some were not during evolution is not known. We applied information theory to find similarities and differences in information content in Never Born and natural proteins. FINDINGS: Both block and relative entropies are similar what means that both protein kinds contain strongly random sequences. An artificially generated Never Born protein sequence is closely as random as a natural one. CONCLUSIONS: Information theory approach suggests that protein selection during evolution was rather random/non deterministic. Natural proteins have no noticeable unique features in information theory sense. PMID- 23750330 TI - Innate immune response after adenoviral gene delivery into skin is mediated by AIM2, NALP3, DAI and mda5. AB - Methods for human skin gene therapy requires efficient and stable introduction of genes into skin cells. Transient cutaneous gene therapy is an attractive approach in the treatment of skin diseases. The 'Achilles heel' of adenoviral gene therapy is its immunogenicity and many aspects of adenovirus induced cutaneous immune reaction still remain unanswered, particularly the role of keratinocytes. Therefore, human keratinocytes were transfected with adenoviral DNA and cytokine expression was analyzed. Moreover, adenoviral transduction of full-skin was performed ex vivo and in vivo. We observed cytokine induction after cytoplasmatic internalization of adenoviral DNA into epidermal cells. Inhibition of AIM2, NALP3, DAI or mda5 downregulated the cytokine response. Transduction of immunocompetent mice led to a detectable transgene expression for 12 days. Re application of the vector led to a decrease in intensity and duration of transgene expression limited to 4 days and an increased cytokine expression. In contrast, immunodeficient mice showed a reduced expression of cytokines after DNA internalization. AIM2, NALP3, DAI and mda5 are essential in the induction of an innate immune response towards adenoviral DNA. This immune reaction leads to a decrease in transduction efficiency of the vector after re-application and modulation of these receptor systems stabilizes transgene expression. PMID- 23750331 TI - A Phase I, open-label, randomized, crossover study in three parallel groups to evaluate the effect of Rifampicin, Ketoconazole, and Omeprazole on the pharmacokinetics of THC/CBD oromucosal spray in healthy volunteers. AB - ABSTRACT: This Phase I study aimed to assess the potential drug-drug interactions (pharmacokinetic [PK] and safety profile) of Delta9-tetrahydrocannabinol (THC)/cannabidiol (CBD) oromucosal spray (Sativex ((r)), nabiximols) in combination with cytochrome P450 (CYP450) inducer (rifampicin) or inhibitors (ketoconazole or omeprazole). Thirty-six healthy male subjects were divided into three groups of 12, and then randomized to one of two treatment sequences per group. Subjects received four sprays of THC/CBD (10.8/10 mg) alongside single doses of the CYP3A and 2C19 inducer rifampicin (600 mg), CYP3A inhibitor ketoconazole (400 mg) or CYP2C19 inhibitor omeprazole (40 mg). Plasma samples were analyzed for CBD, THC and its metabolite 11-hydroxy-THC (11-OH-THC). A single dose of four sprays of THC/CBD spray (10.8/10 mg) following repeated doses of rifampicin (600 mg) reduced the Cmax and AUC of all analytes. Cmax reduced from 2.94 to 1.88 ng/mL (-36%), 1.03 to 0.50 ng/mL (-52%) and 3.38 to 0.45 ng/mL (-87%) for THC, CBD and 11-OH-THC, respectively compared to single dose administration of THC/CBD spray alone. Ketoconazole co-administration with THC/CBD spray had the opposite effect, increasing the Cmax of the respective analytes from 2.65 to 3.36 ng/mL (+27%), 0.66 to 1.25 ng/mL (+89%) and 3.59 to 10.92 ng/mL (+204%). No significant deviations in Cmax or AUC for any analyte were observed when THC/CBD spray was co-administered with omeprazole. THC/CBD spray was well tolerated by the study subjects both alone and in combination with rifampicin, ketoconazole and omeprazole. Evaluation of the PKs of THC/CBD spray alone and in combination with CYP450 inhibitors/inducers suggests that all analytes are substrates for the isoenzyme CYP3A4, but not CYP2C19. On the basis of our findings, there is likely to be little impact on other drugs metabolized by CYP enzymes on the PK parameters of THC/CBD spray, but potential effects should be taken into consideration when co-administering THC/CBD spray with compounds which share the CYP3A4 pathway such as rifampicin or ketoconazole. TRIALS REGISTRATION: NCT01323465. PMID- 23750332 TI - A novel Arabidopsis marker line that strongly labels uninucleate microspores and the subsequent male gametophyte development stages. AB - Here is reported a novel histological marker line that strongly and specifically labels the male gametophyte in Arabidopsis flowers, from the uninucleate microspore to the pollination stage. In this marker line, the expression of the UidA and GFP marker genes is driven by the promoter of the At5g17340 Arabidopsis gene, a gene highly expressed in the male gametophyte. Strong GUS histochemical staining is detected in the uninucleate microspores. Strong GUS, and GFP, histological labelling is also detected in the subsequent stages of male gametophyte development. The potential applications of this marker line are discussed. PMID- 23750333 TI - Black tea, green tea and risk of breast cancer: an update. AB - Previous meta-analysis indicated conflicting results in case-control versus cohort studies on the association of green tea with breast cancer risk, and conflicting results were also found in case-control versus cohort studies in another meta-analysis on the association of black tea with breast cancer risk. Many studies were published after the previous meta-analysis. Besides, the dose response relationship of tea consumption with breast cancer risk is unclear. Thus the association of tea consumption with breast cancer risk was assessed incorporating new publications. Summary relative risk (RR) for highest versus lowest level of tea consumption was calculated based on fixed or random effect models. Dose-response relationship was assessed by restricted cubic spline model and multivariate random-effect meta-regression. The combined results from 9 studies suggested no significant association between green tea consumption and breast cancer risk (RR = 0.82, 95% CI = 0.64-1.04). No significant association was found among cohort studies and case-control studies after sensitivity analysis, respectively. A linear but not significant dose-response association was found between green tea consumption and breast cancer risk. The combined results from 25 studies demonstrated no significant association between black tea consumption and breast cancer risk (RR = 0.98, 95% CI = 0.93-1.03), and no significant association was found in subgroup analysis. A linear but not significant dose-response association was found between black tea consumption and breast cancer risk. Based on the current evidence, black tea and green tea might not contribute significantly to breast cancer risk, respectively. PMID- 23750334 TI - Conditional QTL mapping for waterlogging tolerance in two RILs populations of wheat. AB - Waterlogging is a widespread limiting factor for wheat production throughout the world, specially irrigated and high rainfall environments. Only few studies reported QTLs for waterlogging tolerance. To identify quantitative trait loci (QTLs) for waterlogging tolerance, root dry weight index (RDWI), shoot dry weight index (SDWI), total dry weight index (TDWI) were measured at seedling stage in two unrelated recombinant inbred lines (RILs) populations. These populations were International Triticeae Mapping Initiative (ITMI) population 'W7984 / Opata85', and 'SHW-L1 * Chuanmai 32' (SC) population. Conditional QTL mapping and unconditional QTL mapping were studied to dissect the genetic relationship between TDWI and its components of SDWI and TDWI. Total of 36 QTLs for waterlogging tolerance in ITMI population and 10 QTLs in SC population were identified in present study. Of them, 17 alleles from synthetic hexaploid wheat 'W7984' and 3 alleles from synthetic hexaploid wheat 'SHW-L1' contribute positively to waterlogging tolerance. Combinations of conditional and unconditional mapping methods indicate that SDWI showed tighter genetic correlation with TDWI than RDWI. This QTL identification study and dissection provide theoretical basis and application foundation to Marker-assisted selection (MAS) of waterlogging tolerance improvement in wheat. PMID- 23750335 TI - Cardiovascular Disease Risk Assessment: Insights from Framingham. AB - Cardiovascular disease (CVD) is among the leading causes of death and disability worldwide. Since its beginning, the Framingham study has been a leader in identifying CVD risk factors. Clinical trials have demonstrated that when the modifiable risk factors are treated and corrected, the chances of CVD occurring can be reduced. The Framingham study also recognized that CVD risk factors are multifactorial and interact over time to produce CVD. In response, Framingham investigators developed the Framingham Risk Functions (also called Framingham Risk Scores) to evaluate the chance or likelihood of developing CVD in individuals. These functions are multivariate functions (algorithms) that combine the information in CVD risk factors such as sex, age, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking behavior, and diabetes status to produce an estimate (or risk) of developing CVD or a component of CVD (such as coronary heart disease, stroke, peripheral vascular disease, or heart failure) over a fixed time, for example, the next 10 years. These estimates of CVD risk are often major inputs in recommending drug treatments such as cholesterol-lowering drugs. PMID- 23750336 TI - In vivo Modeling and Molecular Characterization: A Path Toward Targeted Therapy of Melanoma Brain Metastasis. AB - Brain metastasis (B-Met) from melanoma remains mostly incurable and the main cause of death from the disease. Early stage clinical trials and case studies show some promise for targeted therapies in the treatment of melanoma B-Met. However, the progression-free survival for currently available therapies, although significantly improved, is still very short. The development of new potent agents to eradicate melanoma B-Met relies on the elucidation of the molecular mechanisms that allow melanoma cells to reach and colonize the brain. The discovery of such mechanisms depends heavily on pre-clinical models that enable the testing of candidate factors and therapeutic agents in vivo. In this review we summarize the effects of available targeted therapies on melanoma B-Met in the clinic. We provide an overview of existing pre-clinical models to study the disease and discuss specific molecules and mechanisms reported to modulate different aspects of melanoma B-Met and finally, by integrating both clinical and basic data, we summarize both opportunities and challenges currently presented to researchers in the field. PMID- 23750337 TI - The role of the iodothyronine deiodinases in the physiology and pathophysiology of thyroid hormone action. AB - Thyroxine (T4) is a prohormone and must be activated to 3,5,3' triodothyronine (T3) by either the type 1 (D1) or 2 (D2) selenodeiodinase. A third deiodinase (D3) inactivates T3 or T4 by removal of an inner ring iodine. These reactions require both a deiodinase enzyme and a cofactor, probably a thiol, to reduce the oxidized selenolyl group in the active center of each deiodinase. Thus, deiodination rates depend on both the enzyme and cofactor. The source of most of the circulating T3 is D1-mediated, while D2 provides nuclear receptor-bound hormone. Using sensitive and specific assays, it has become apparent that both D2 and D3 are widespread throughout vertebrate tissues. The complex interactions between the activating D2 and the inactivating D3 in tissues expressing these two enzymes determine the intracellular T3 concentration. This provides enormous flexibility for both developmental and tissue regeneration processes, allowing exquisite control of intracellular T3 concentrations. The endogenous factors regulating the activity of these enzymes, such as the hedgehog proteins, FoxO3, or the wnt/beta catenin pathway together with the actions of thyroid hormone transporters, direct adjustments of nuclear receptor bound T3 which in turn can control the balance between cellular proliferation and differentiation. Their actions provide dynamic flexibility to what appears on the surface to be a very static hormonal system. PMID- 23750338 TI - Biofilm-derived Legionella pneumophila evades the innate immune response in macrophages. AB - Legionella pneumophila, the causative agent of Legionnaire's disease, replicates in human alveolar macrophages to establish infection. There is no human-to-human transmission and the main source of infection is L. pneumophila biofilms established in air conditioners, water fountains, and hospital equipments. The biofilm structure provides protection to the organism from disinfectants and antibacterial agents. L. pneumophila infection in humans is characterized by a subtle initial immune response, giving time for the organism to establish infection before the patient succumbs to pneumonia. Planktonic L. pneumophila elicits a strong immune response in murine, but not in human macrophages enabling control of the infection. Interactions between planktonic L. pneumophila and murine or human macrophages have been studied for years, yet the interface between biofilm-derived L. pneumophila and macrophages has not been explored. Here, we demonstrate that biofilm-derived L. pneumophila replicates significantly more in murine macrophages than planktonic bacteria. In contrast to planktonic L. pneumophila, biofilm-derived L. pneumophila lacks flagellin expression, do not activate caspase-1 or -7 and trigger less cell death. In addition, while planktonic L. pneumophila is promptly delivered to lysosomes for degradation, most biofilm-derived bacteria were enclosed in a vacuole that did not fuse with lysosomes in murine macrophages. This study advances our understanding of the innate immune response to biofilm-derived L. pneumophila and closely reproduces the natural mode of infection in human. PMID- 23750340 TI - A large national Thai Cohort Study of the Health-Risk Transition based on Sukhothai Thammathirat Open University students. AB - Thailand 's dynamic economic development has been accompanied by great changes in cultural, social, environmental and other forces that shape population health in ways that are poorly understood. To study Thailand's health-risk transition we began to follow a large cohort of students enrolled at Sukhothai Thammathirat Open University (STOU) - an accessible transitional group. STOU students are not affluent but are aspiring to modernize. Our Thai Cohort Study (TCS) started at baseline with 87,134 cohort members in 2005, with over 60,000 successfully being followed up in 2009; the next round of follow-up is scheduled for 2013. Here we show that the Thai population, the STOU student body and the TCS cohort are comparable for social geography and socio-economic status. Productive results make us sure the project can have substantial long-term impacts on regional population health by enabling Thailand and similar middle-income countries to understand and mitigate emerging disease trends. Our study shows that Open University students are able and willing to represent their source populations for a variety of useful social and health research. PMID- 23750341 TI - Has the manual gone mental? PMID- 23750339 TI - Polyunsaturated fatty acids and calcaneal ultrasound parameters among Inuit women from Nuuk (Greenland): a longitudinal study. AB - BACKGROUND: The traditional diet of Inuit people comprises large amounts of fish and marine mammals that are rich in omega-3 polyunsaturated fatty acids (PUFAs). Results from in vitro studies, laboratory animal experiments and population studies suggest that omega-3 PUFA intake and a high omega-3/omega-6 ratio exert a positive effect on bone health. OBJECTIVE: This longitudinal study was conducted to examine the relationship between omega-3 and omega-6 PUFA status and quantitative ultrasound (QUS) parameters in Greenlandic Inuit women. METHODS: The study included 118 Inuit women from Nuuk (Greenland), aged 49-64 years, whose QUS parameters measured at baseline (year 2000), along with PUFA status and covariates, and follow-up QUS measurements 2 years later (year 2002). QUS parameters [speed of sound (SOS); broadband ultrasound attenuation (BUA)] were measured at the right calcaneus with a water-bath Lunar Achilles instrument. Omega-3 and omega-6 PUFA contents of erythrocyte membrane phospholipids were measured after transmethylation by gas chromatography coupled with a flame ionization detector. Relationships between QUS parameters and different PUFAs were studied in multiple linear regression models. RESULTS: Increasing values of EPA, DHA and the omega-3/omega-6 PUFA ratio were associated with increased BUA values measured at follow-up (year 2002). These associations were still present in models adjusted for several confounders and covariates. We found little evidence of associations between PUFAs and SOS values. CONCLUSION: The omega-3 PUFA intake from marine food consumption seems to have a positive effect on bone intrinsic quality and strength, as revealed by higher BUA values in this group of Greenlandic Inuit women. PMID- 23750342 TI - Rosemary and Peter Grant. PMID- 23750343 TI - The efficacy of preoperative halo-gravity traction in pediatric spinal deformity the effect of traction duration. AB - STUDY DESIGN: Retrospective case review OBJECTIVE: To assess the appropriate length of halo-gravity traction that provides the most preoperative correction and minimizes halo associated complications. SUMMARY OF BACKGROUND: Rapid correction of severe scoliosis increases the risk of neurological compromise. To minimize complications, some patients undergo preoperative halo traction providing gradual correction before definitive management. The appropriate length of traction to provide the most preoperative correction is unknown. METHODS: Twenty pediatric patients (age: range, 220 y, average 11.2 y) with severe operative scoliosis, kyphoscoliosis, or kyphosis were retrospectively studied. The major structural coronal curves before traction (n = 11 patients, 19 curves, range 44128 degrees, average 84.7 degrees) or immediately after anterior release (n = 7 patients, 10 curves, range 3598 degrees, average 67.7 degrees) were measured as well as weekly during traction and postoperatively at 1 year. Sagittal kyphosis (n = 12 patients, range 60143 degrees, average 97.6 degrees) was measured at the same time intervals. Patients in traction(maximum traction weight range 15.5% to 46.5% of bodyweight, average 32.9%) for a duration of at least 3 weeks (range 310.5 wk, average 4.6 wk) were included. Patients with prior surgical fusion were excluded; however, patients who under went a stage anterior posterior were included. Halo-traction related complications were noted in each case. RESULTS: The major coronal and sagittal curve corrected 66.3% and 62.7% (change in curve per week/total change in curve), respectively at 2 weeks (n = 29, 12 curves), 21.7% and 24.3% at 3 weeks (n = 29, 12), and 7.5% and 15.9% at 4 weeks (n = 14,6). Traction-related complications during the traction duration included 2 cases of ileus, 1 respiratory complication, 2 pin loosening, and 1 superficial pin infection. CONCLUSION: The treatment of severe scoliosis can be very challenging. The use of long-term halo traction preoperatively can assist in the surgical correction. The majority of correction occurs during the first 2 weeks of traction. No permanent neurological complications occurred during traction. PMID- 23750345 TI - Cytoplasmic globules in erythroid blasts and CLL. PMID- 23750346 TI - Comparative evaluation of warfarin utilisation in two primary healthcare clinics in the Cape Town area. AB - BACKGROUND: Although warfarin remains the anticoagulant drug of choice in a wide range of patients, its narrow therapeutic window makes patients susceptible to a high risk of bleeding complications or failure to prevent clotting. This has necessitated therapeutic monitoring in warfarinised patients. Factors that could be responsible for the fluctuating responses to warfarin vary from pharmacogenetic to concomitant morbidity, diet and medication. In order to assess the quality of management of warfarin treatment in a local primary-care setting, the current study evaluated warfarin utilisation and monitoring records in two hospitals with different patient groups. METHODS: A retrospective study was undertaken in the specialised warfarin clinics at Wesfleur and Gugulethu hospitals (Western Cape, South Africa) covering all warfarin-related therapy records over a 12-month period. Data extracted from the patients' folders included age, gender, race, weight, address, concurrent chronic illnesses, treatment and medication, indication for warfarin and INR history. RESULTS: A total of 119 patients' folders were analysed. Attendance at the clinics reflects the demographics and racial distribution of the host location of the hospitals. While all the patients were maintained above the minimum international normalised ratio (INR) value of 2, about 50% had at least one record of INR above the cut off value of 3.5. However, over a third of the patients (32.2%) had at least one record of INR greater than 3.5 in Gugulethu Hospital, compared to over half (58.3%) in Wesfleur Hospital. In total, atrial fibrillation was the most common indication for warfarinisation while hypertension was the most common concurrent chronic condition in warfarinised patients. All patients who received quinolone antibiotics had INR values above the cut-off point of 3.5 within the same month of the initiation of antibiotic therapy, suggesting drug-induced warfarin potentiation. Other co-medications, including beta-lactam antibiotics, non steroidal anti-inflammatory drugs (NSAIDs) and anti-ulcer drugs appeared to alter warfarin responses as measured by recorded INR values. CONCLUSION: The study found inter-individual variability in the response to warfarin therapy, which cut across racial classifications. It also confirms the possible influence of concomitant morbidity on patient response to anticoagulant therapy. PMID- 23750347 TI - Is clopidogrel adequate in 2013? PMID- 23750348 TI - Incretins: cardiovascular safety and rationale for use. PMID- 23750349 TI - Professor Andries Jacob Brink: 29 August 1923--17 October 2012. PMID- 23750350 TI - Tribute to the late Professor Oluwole Ademola Adebo. PMID- 23750351 TI - Intradural extramedullary lesion of the conus medullaris. Solitary fibrous tumor. PMID- 23750352 TI - An African immigrant with seizures and multiple brain lesions. Neurocysticercosis. PMID- 23750353 TI - The Peyronie's plaque "scratch": an adjunct to modeling. PMID- 23750354 TI - Bordetella hinzii in rodents, Southeast Asia. PMID- 23750355 TI - Melioidosis and hairy cell leukemia in 2 travelers returning from Thailand. PMID- 23750356 TI - Plague epidemics and lice, Democratic Republic of the Congo. PMID- 23750357 TI - Armillifer armillatus pentastomiasis in African immigrant, Germany. PMID- 23750358 TI - Mycobacterium kyorinense infection. PMID- 23750359 TI - Recurring influenza B virus infections in seals. PMID- 23750360 TI - Reemerging Schmallenberg virus infections, Germany, 2012. PMID- 23750361 TI - Peritoneal tuberculosis in a pregnant woman from Haiti, United States. PMID- 23750362 TI - Microsporidial keratoconjunctivitis outbreak among athletes from Hong Kong who visited Singapore, 2012. PMID- 23750363 TI - Mycobacterium fortuitum endocarditis associated with cardiac surgery, Serbia. PMID- 23750364 TI - Cryptococcus gattii, Florida, USA, 2011. PMID- 23750365 TI - Characterization of Mycobacterium orygis. PMID- 23750366 TI - Mycobacterium tuberculosis Beijing type mutation frequency. PMID- 23750367 TI - Mycobacterium tuberculosis Beijing type mutation frequency--author's response. PMID- 23750368 TI - Author's replay. PMID- 23750369 TI - Consensus statements. Advancing knowledge and practice in adolescents coping with cancer. PMID- 23750370 TI - Stroke prevention. PMID- 23750371 TI - Hoarsing around: is it time to grow up? PMID- 23750373 TI - A different type of fight bite- an unusual cause for rupture of the pectoralis major tendon. PMID- 23750374 TI - Pyoderma Gangrenosum: The role of surgical treatment. PMID- 23750375 TI - 'Too much, too soon,' or ' a step too far ?' exercise induced Rhabdomyolysis. PMID- 23750376 TI - Toward an evolutionary history of female sociosexual variation. AB - Considerable progress has been made in behavioral genetics toward providing theoretical accounts of individual differences. One theoretical ask, however, has been largely neglected-that of constructing evolutionary accounts of behaviorally relevant genetic variance. We attempt to address this ask with respect to the genetic variance underlying sociosexuality, that is, the differences in the implicit prerequisites (in terms of time, attachment, commitment, etc.) to entering a sexual relationship. Specifically, we argue that genetic variance on this trait for females could have been maintained through frequency-dependent selection. In our evolutionary past, restricted females-those who require relatively more time, attachment, and commitment-could have benefited through paternal investment in their offspring. Unrestricted females-those who require relatively less time, attachment, and commitment-could have benefited through the quality of their mate's genes passed onto their sons. Moreover, the value of these alternate "strategies" could have been frequency-dependent. One prediction that follows from this evolutionary history is tested and supported in three studies. Those females genetically predisposed to be unrestricted are found to produce relatively more sons than females predisposed to be restricted. Additional predictions are offered and alternative accounts are discussed. PMID- 23750377 TI - Evolution, traits, and the stages of human courtship: qualifying the parental investment model. AB - Individual differences are explicitly connected to social interaction in Darwin's notion of sexual selection. Traits that increase the probability of successful reproduction will tend to increase in frequency. This process operates partly through differential choice, by one sex, of certain traits in the other. According to the parental investment model, females frequently have more stringent criteria for the traits they will accept in a mate because they have a relatively larger investment in each offspring. Because human mating arrangements often involve a substantial commitment of resources by the male, it is necessary to invoke a distinction between the selectivity involved during casual mating opportunities and the selectivity exercised when choosing a long-term partner. Ninety-three undergraduate men and women rated their minimum criteria on 24 partner characteristics at four levels of commitment. In line with an unqualified parental investment model, females were more selective overall, particularly on status-linked variables. In line with a qualified parental investment model, males' trait preferences depended upon the anticipated investment in the relationship. Males had lower requirements for a sexual partner than did females, but were nearly as selective as females when considering requirements for a long term partner. PMID- 23750378 TI - Sir Francis Galton, epigenetic rules, genetic similarity theory, and human life history analysis. AB - In this article, an evolutionary perspective is applied to individual differences. Among the issues discussed are (a) the seminal contributions of Francis Galton and the subsequent ideological reaction, (b) the distal proximal continuum for understanding levels of explanation in social behavior, (c) consistent patterns of group differences in behavior (age, sex, social class,and race), (d) the heritability of personality and the role epigenetic rules play in guiding development in one direction over alternatives, (e) the genetic similarity theory perspective on friendship and mate choice, and (f) the view that personality is part of an r-K reproductive strategy involving a compensatory exchange between the production of gametes and parental care. It is suggested in conclusion that personality traits be considered aspects of a coordinated life cycle deeply embedded m evolutionary history. PMID- 23750379 TI - Genetic and environmental contributions to individual differences: the three major dimensions of personality. AB - This article deals with the contribution of genetic and environmental factors to individual differences in the three major dimensions of personality (Psychoticism, Extraversion, and Neuroticism). Twin studies indicate, and family studies confirm within limits, the strong genetic determination of these and many other personality factors, additive genetic variance accounting for roughly half the total phenotypic variance. On the environmental side, shared family environment plays little or no part, all environmental effects being within family. Assortative mating, important in the formation of social attitudes, has little impact on personality. Dominance may be important for Extraversion. Epistasis (emergenesis) may account for the comparative low values of dizygotic (DZ) twins' correlations. Evidence for differential heritability of traits is present, but not very strong. It is concluded that behavioral genetics forms a vital part of the psychological understanding of the causes of individual differences in personality. PMID- 23750380 TI - Genetic and rearing environmental influences on adult personality: an analysis of adopted twins reared apart. AB - We report a genetic and environmental analysis of California Psychological Inventory (CPI) scale scores gathered on a sample of 45 sets of monozygotic twins reared apart (MZA) and 26 sets of dizygotic twins reared apart (DZA). Analysis of twin intraclass correlations and the results of models fit to the twin data demonstrate that the heritability of most scales and five factors of the CPI is about 50. When compared to results from studies of adult MZ and DZ twins reared together few of the scales demonstrate any common family environmental influence. Placement coefficients on the Family Environmental Scale (FES) can explain only a minor portion of the correlations for twins reared apart. The influence of specific rearing environmental factors on adult personality was evaluated by analyzing the relationship between the FES and the CPI in this adoptee sample. One FES factor (Cohesion vs. Conflict) does correlate substantially with the CPI factor of Consensuality and may account for up to 24% of the variance in that factor, but the retrospectively gathered rearing environment measures generally explain very little variance in adult personality. PMID- 23750381 TI - Author's reply: To PMID 22569457. PMID- 23750382 TI - Author's reply: To PMID 23354192. PMID- 23750383 TI - Hospital sharing in organ donation program. PMID- 23750384 TI - [Stevens-Johnson syndrome and toxic epidermal necrolysis in children]. PMID- 23750385 TI - [Stevens-Johnson syndrome and toxic epidermal necrolysis in children. Author reply]. PMID- 23750386 TI - ["Skill mix", nothing new under the sun...]. PMID- 23750387 TI - [Prevention of infection in immunocompromised travelers]. AB - Every year there are more immunocompromised patients with a better quality of life and, therefore, that travel more frequently. While traveling, patients may be exposed to several infections, such as traveler's diarrhea or malaria, which can be associated with a high rate of complications in this population. An appropriate strategy for the prevention of travel-related infections is essential, including education about hygiene measures, vaccinations and prescription of a tailored antimicrobial prophylaxis/stand-by treatment, according to the type of immunosuppression. Potential drug interactions, particularly between antimalaric and immunosuppressive drugs, must also be considered for decision taking. Collaboration between the general practitioner and the travel medicine and infectious diseases specialists is highly recommended to improve the management of these patients. PMID- 23750388 TI - [Key aspects regarding HIV and travel]. AB - The risk of contracting a sexually transmitted infection while traveling abroad is increased in certain populations. Pre-travel consultation should include the education of travelers on the prevalence of HIV in the countries visited and on appropriate prevention measures. In patients infected with HIV (PHIV), combined antiretroviral therapy (cART) improves immunity, enabling them to travel with less risk for their health. Pre-travel consultation of PVIH has the following objectives: to determine immune status, to update immunization and to decide on anti-malaria drug prophylaxis, taking into account potential drug interactions with antiretroviral therapy. Vaccine response and duration of protection is shorter-lived in PVIH, especially if the CD4 count is below 200 cells/mm3 and the HIV viral load is detectable. Therefore cART is a cornerstone for disease prevention among patients infected with HIV who travel. PMID- 23750389 TI - [Immunization for the immunosuppressed traveler]. AB - With the increased number of international travelers and that of immunosuppressive therapies, it is usual to see immunosuppressed patients asking for advice before a trip exposing them to a certain risk of infectious diseases. The difficulty with vaccinating the immunosuppressed is twofold as risk as well as effectiveness has to be taken into account. Immune responses to vaccines are more effective if they are based on immunological memory. In other cases, antibody level determination may be useful to assess the potential for protection. Clinical cases are presented to illustrate difficulties faced by the general practitioner. PMID- 23750390 TI - [Imported malaria: safer and more efficacious drugs?]. AB - In response to the spread of parasite resistance to old antimalarial drugs, the large-scale implementation of artemisinine-based combinations has allowed to improving patient survival and reducing parasite transmission. Even though decreased susceptibility of parasites to artemisinine has been observed in South East Asia, this phenomenon has no practical implications for travelers with uncomplicated malaria. The combination of artemether-lumefantrine is still very effective and safe, be it for P. falciparum or vivax. Intravenous administration of artesunate has allowed to significantly reducing case fatality rate of severe malaria patients when compared to quinine treatment in endemic areas. Artesunate is also recommended in travelers, but with close monitoring, especially for hematological parameters, in order to confirm its superiority. PMID- 23750391 TI - [Vaccination of asylum seekers in the canton Vaud, Switzerland]. AB - Even if only a small proportion of asylum seekers obtains a permanent resident permit, a significant number of them stay for a prolonged or indefinite period in Switzerland in a legal or illegal way. The asylum seekers can be either vectors or victims of infectious diseases. Some of these diseases can be prevented by vaccination. This article summarizes the recent decisions which have been taken in the canton Vaud concerning the vaccination of asylum seekers. These new recommendations privilege a large coverage of a maximum number of asylum seekers. Vaccinations against varicella and human papillomavirus will be proposed in addition to the already previously recommended vaccines. Finally the medical visits for the vaccinations will also be an opportunity to screen for chronic hepatitis B which has been neglected until now. PMID- 23750392 TI - [Old World cutaneous leishmaniasis]. AB - Cutaneous leishmaniasis is a parasitic disease that causes various clinical features depending on the infecting Leishmania species and the host immune response. Transmission occurs through the bite of an infected sand fly (subfamily of Phlebotominae). Leishmaniasis must be part of the differential diagnosis of persistent cutaneous lesions in travellers returning from an endemic area. The disease is most frequently characterized by one or more ulcerative lesions, which are predominant on the exposed parts of the body. The diagnosis is confirmed by microscopical observation of the parasite on a scraping or biopsy of the lesion, or by PCR, the latter allowing an identification of the Leishmania species. Treatment is dependent on the clinical presentation, the species of Leishmania and the comorbidities of the patient. PMID- 23750393 TI - [Thoracic pain]. PMID- 23750394 TI - [What are patients' attitudes towards generic drugs? The example of metformin]. AB - The success of cost containment with generic drugs is based on consumer's willingness to accept substitution. This investigation reveals 3 major themes that can explain attitudes of patients towards generics: 1) personal beliefs and knowledge (coming from the media issues, family, friends) are fragmented and sometimes erroneous, with a background of suspicion on the quality of the generics; 2) relation with the prescriber (indirectly pharmacist) is central to build up patient's trust; suspicious professionals generate an anxious patient; 3) previous experience from the consumer with generics. Starting from patients' experiences and beliefs allows to anticipate their resistance to the generic and to adapt drug prescription choices. PMID- 23750395 TI - [As one ages... aging will come anyway]. PMID- 23750396 TI - [A(H7N9): should we or should we not be scared?]. PMID- 23750397 TI - [Welcome to democratic eugenics? (1)]. PMID- 23750398 TI - [The physician fish is not welcome in France]. PMID- 23750399 TI - [Strange double temporality]. PMID- 23750400 TI - [Chlorophyll fluorescence transient kinetics of ginkgo leaves during expansion]. AB - OBJECTIVE: To provide the theoretical basis for cultivating ginkgo (Ginkgo biloba). METHODS: Changes of chlorophyll fluorescence transient kinetics in chloroplasts of 10-year-old seeded ginkgo leaves during expansion were studied in the field under natural environmental conditions. RESULTS: W(k) peaked between 12: 00 - 15: 00, phiE(o) and psi(o) declined gradually between 8: 00 - 12: 00. ABS/ RC,TR(o)/RC and DI(o)/RC increased, while RC/CS decreased at noon. PI(abs) and F(v)/F(m) declined and reached its lowest value at 13:00, then increased, and the levels at 19:00 could restore to the levels at 7: 00. CONCLUSION: The donor and acceptor sides of PS II are temporarily inhibited. The reaction centers of PS II are damaged, leading to the light energy transfer efficiency of PS II decrease and excess excitation energy increase at noon. The damage of reaction centers of PS II and inhibition of photosynthetic primary reaction are reversible inactivation not irreversible damaged. PMID- 23750401 TI - [Classification and RAPD analysis of cultivate varieties of Lonicera japonica cultivated in Xinmi]. AB - OBJECTIVE: To study the classification and genetic relationship among difference cultivated varieties of Lonicera japonica cultivated in Xinmi. METHODS: Observed the biological characteristics of Lonicera japonica cultivated in Xinmi and visited farmers; Genetic diversity was analyzed by RAPD molecular biology techniques. RESULTS: Classified the cultivated varieties and set up an index key. RAPD fingerprint was established, 10 primers were chosen. A total of 60 DNA fragments, among which 50 bands was polymorphic, accounting for 83.33% which indicated the genetic diversity of the samples was good. CONCLUSION: Genetic relationship among different cultivated varieties are determined which provide scientific basis for resources protection, development of Lonicera japonica cultivated in Xinmi and its quality evaluation. PMID- 23750402 TI - Preliminary characterization of proteoglycan from Hyriopsis cumingii. AB - OBJECTIVE: To study the preliminary characterizations of Hyriopsis cumingii proteoglycan (HCPG). METHODS: The content of carbohydrate and protein were measured by spectrophotometry. FTIR spectrum was used to analyze the functional groups. Relative molecular mass and amino acid composition were detected by HPLC. GC was utilized to determine the monosaccharide composition. The glycopeptide linkage-bond was detected by using the method of beta-elimination reaction. RESULTS: In HCPG,the content of carbohydrate and protein was 80.06% and 9.42%, respectively. FTIR spectrum showed the characteristic absorptions of polysaccharides and protein. Relative molecular mass of HCPG, determined by size exclusive HPLC, was 503.1 kDa. GC spectra demonstrated that polysaccharide of HCPG was composed of rhamnose, fucose, mannose, glucose and galactose with a molar ratio of 13.80: 4.51: 7.70: 64.92 : 9.07. Fourteen amino acids (13 known and one unknown) have been detected by pre-column derivation HPLC. From beta elimination reaction, peptide chain was attached to the carbohydrate chain by O glycosidic bond. CONCLUSION: Basic characterizations of HCPG have been determined preliminarily. PMID- 23750403 TI - [Analysis of inorganic elements of several species from Moghania genus and M. philippinensis from different habitats]. AB - OBJECTIVE: To compare the contents of inorganic elements in root, stem and leaf of several species from Moghania genus and root of M. philippinensis from different habitats. METHODS: Inductively Coupled Plasma Optical Emission Spectrum (ICP-OES) was used to determine twenty five inorganic elements simultaneously. The correlation analysis, principal component analysis and cluster analysis were applied for the study of inorganic elements. RESULTS: The content of inorganic elements from different species was difference. As for M. philippinensis from different habitats, the content sequence was Guangxi > Jiangxi > Guangdong > Sichuan. There was significant correlation between different inorganic elements. The principal component analysis results showed that V, Co, K, Fe, Cr, P, Mo, Si, Na, Ca and Mg might be the characteristic elements of these species from Moghania genus. The results of cluster analysis showed that M. philippinensis and M. strobilifera could be separated and M. philippinensis from Guangxi, Jiangxi, Guangdong and Sichuan could be separated. CONCLUSION: This experiment provided theoretical basis for distinguish and quality assessment of species from Moghania genus and M. philippinensis from different habitats. PMID- 23750404 TI - [Determination of the active constituents in aurantii fructus from Jiangxi province at different harvest time by HPLC]. AB - OBJECTIVE: To determine the contents of the main active constituents in Aurantii Fructus from Jiangxi at different harvest time and make sure the best harvest time. METHODS: RP-HPLC was used to assay the active constituents (including naringin, neohesperidin, synephrine, nobiletin, tangeretin, meranzin hydrate, meranzin, marmin and auraptene) contents in the Aurantii Fructus at different harvest periods from Xingan and Zhangshu countries. RESULTS: The trend of the contents of those active constituents was basically decreased as the day trailing. CONCLUSION: The best harvest time of Aurantii Fructus from Jiangxi is about the Great Heat. PMID- 23750405 TI - [Study on optimal processing technology of three kinds of processed coptidis rhizoma]. AB - OBJECTIVE: To optimize the processing technology of Coptidis Rhizoma and study the effects of different adjuvants on alkaloids during processing. METHODS: The moistening time of adjuvants (A), processing temperature (B) and processing time (C) were investigated by using the single factor test method and L9 (3(4)) orthogonal experiment design with the contents of four alkaloids as indexes. RESULTS: The sequence of importance of the factors that affect the wine processed Coptidis Rhizoma (WC) was C > B > A, turmeric processed Coptidis Rhizoma (TC) and dogwood processed Coptidis Rhizoma (DC) was B > A > C. CONCLUSION: The optimal processing technology of WC, TC and DC are drying for 4 h at 130 degrees C after moistening for 90 min, drying for 3 h at 100 degrees C after moistening for 60 min and drying for 2 h at 160 degrees C after moistening for 90 min, respectively. PMID- 23750406 TI - [Chemical change of chuanxiong raw materials during storage]. AB - OBJECTIVE: To evaluate the chemical changes in Chuanxiong raw material (CX), the rhizome of Ligusticum chuanxiong Hort., during CX storage and further assess its quality variety. METHODS: Four CX samples were sealed and stored at ambient temperature in room for two years. These samples were quantified on the amounts of characteristic chemical compounds by HPLC-DAD-(APCI) MS techniques. RESULTS: Eight characteristic peaks in HPLC fingerprint were found to be good separation and assigned as vanillin (1), ferulic acid (2), senkyunolide I (3), senkyunolide H (4), coniferyl ferulate (5), senkyunolide A (6), Z-ligustilide (7) and levistolide A(8), respectively based on their on-line APCI-MS data and UV spectra. After CX being stored, compounds 1 - 4, and 8 were decreased by 44.4%, 52.1%, 37.6%, 52.8% and 47.5% (n = 4), respectively, whilst compounds 5 - 7 were increased by 59.1%, 40.1% and 47.5% (n = 4), respectively. CONCLUSION: Multiple chemical compounds are found to be changed during CX storage, which results in the variety of quality and therapeutic effect because most of the tested compounds have been demonstrated to be bioactive by pharmacological study and clinical trials. It is suggested that CX should be stored under dark, cool and dry condition. PMID- 23750407 TI - [Study on the chromatographic fingerprints of Reineckia carnea from different habitats by HPLC-ELSD]. AB - OBJECTIVE: To investigate the HPLC-ELSD fingerprints of Reineckia carnea from different habitats and provide a theoretical evidence to evaluate its quality. METHODS: The chromatographic conditions were Diamonsil (R) C18 column (4.6 mm x 250 mm, 5 microm) by linear gradient elution using water and acetonitrile as mobile phase at a flow rate of 0.8 mL/min, column temperature at 25 degrees C and sample injection 30 microL. An Agilent 1260 infintiy ELSD operated at 85 degrees C, gain 6 and 3.5 bar nitrogen. RESULTS: The HPLC-ELSD fingerprints were established with 6 common peaks and methodology reached the required standard. CONCLUSION: The method is simple, rapid, accurate, and can be used for quality evaluation of Reineckia carnea from different habituts. PMID- 23750408 TI - [Study on MEKC-DAD fingerprint of Scutellariae radix]. AB - OBJECTIVE: To establish the analytical method for the fingerprint of Scutellariae Radix by MEKC-DAD and compare the fingerprints of Scutellariae Radix, Scutellariae Radix Stir-baked and Scutellariae Radix Green. METHODS: Based on the mode of micellar electrokinetic chromatography, 40 mmol/L sodium hydrogen phosphate, 15 mmol/L sodium borate, 40 mmol/L SDS, 15% acetonitrile, 7.5% propyl alcohol were selected for the running buffer (pH 8.4). The separation voltage was 20 kV and the detection wavelength was set at 280 nm. Baicalin was used as reference standard, the chromatographic fingerprint was established. RESULTS: MEKC-DAD fingerprint with 9 main peaks was established preliminarily. Regarding to the fingerprints of Scutellariae Radix and its processed products, the samples before and after storage moisture, there were obvious differences in the relative areas of common peaks. CONCLUSION: The method is reliable, accurate and can be used for quality control of Scutellariae Radix. PMID- 23750409 TI - [Study on chemical constituents of Hyssopus cuspidatus]. AB - OBJECTIVE: To study the chemical constituents of Hyssopus cuspidatus. METHODS: Compounds were isolated and purified by extraction and different kinds of column chromatography. Their structures were determined on the basis of the physicochemical properties and spectral analysis. RESULTS: Six compounds were identified as caffeic acid methyl ester (1), luteolin 7-O-alpha-L-rhamnopyranosyl (1 --> 6)-beta-D-glucopyranoside (2), luteolin 7-O-beta-D-glucuronide (3), diosmin (4), acacetin 7-O-alpha-L-rhamnopyranosyl(1 --> 6)-beta-D-glucopyranoside (5) and rosmarinic acid (6). CONCLUSION: Compounds 1, 4 and 6 are isolated from this plant for the first time, and compounds 2, 3 and 5 are firstly obtained from Hyssopus genus. PMID- 23750410 TI - [Chemical constituents from aerial part of Rumex patientia]. AB - OBJECTIVE: To study the chemical constituents from aerial part of Rumex patientia. METHODS: The compounds were isolated and purified by silica gels and polyamide column chromatography. Their structures were elucidated by physicochemical and spectroscopic evidences. RESULTS: Twelve compounds were identified as: chrysophanol (1), chrysophanol-8-O-beta-D-glucopyranoside (2), physcion (3), emodin(4), emodin-8-O-beta-D-glucopyranoside (5), maackiain (6), maackiain-3-O-beta-D-glucopyranoside (7), quercetin-3-O-beta-D-glucopyranoside (8), quercetin-3-O-beta-D-glucuronide(9), 2-O-methylinositol (10), torachrysone-8 O-beta-D-glucopyranoside (11) and nepodin-8-O-beta-D-glucopyranoside (12). CONCLUSION: Compounds 6, 7, 10 are isolated from this genus for the first time, and compound 9 is isolated from this plant for the first time. PMID- 23750411 TI - [GC-MS analysis of low polar components from Ainsliaea yunnanensis]. AB - OBJECTIVE: To analyze the chemical constituents of low polar components from ethanol extract of Ainsliaea yunnanensis. METHODS: The air-dried stems and leaves of Ainsliaea yunnanensis were extracted with ethanol using ultrasonic extration. After removal of solvent under reduced pressure, the residue was suspended in H2O, and then partitioned sequentially with petroleum ether, EtOAc and n-BuOH, respectively. Then the petroleum ether fraction was chromatographed on normal phase silica gels eluting with a gradient increasing Me2 CO in petroleum ether. Then the components of low polarity were separated from the petroleum ether Me2CO(50:1 - 20: 1) fraction and identified by GC-MS, and the relative contents of the components were determined with area percentage method. RESULTS: 50 constituents were identified from the low polar components of Ainsliaea yunnanensis. CONCLUSION: The research provides a theoretical basis for the study of chemical constituents and pharmaceutical activities of Ainsliaea yunnanensis. PMID- 23750412 TI - [Phenolic constituents of Ampelopsis grossedentata from zhangjiajie]. AB - OBJECTIVE: To study the phenolic constituents from Ampelopsis grossedentata. METHODS: Compounds were isolated using column chromatographic techniques (silica gel, polyamide gel, Sephadex LH-20) and semi-preparative HPLC. Structures were elucidated on the basis of spectral data (NMR and HR-MS). RESULTS: Eight compounds were isolated and identified as ampelopsin (I), 5, 7, 3',4',5' pentahydroxyflavanone (II), galloyl-beta-D-glucopyranoside (III), gallic acid (IV), ethyl gallate (V), myricitrin (VI), (2R, 3S)-5,7,3',4',5' pentahydroxyflavanonol (VII) and myricetin (VIII). CONCLUSION: Compounds II and VII are obtained from this genus for the first time. PMID- 23750413 TI - [Study on the chemical constituents of Clerodendron philippinum var. simplex]. AB - OBJECTIVE: To study the chemical constituents of Clerodendron philippinum var. simplex. METHODS: The ethanol extract of Clerodendron philippinum var. simplex was isolated and purified by extraction, chromatography on silica gel and recrystallization. The structures of compounds isolated were identified by physicochemical properties and spectral analysis. RESULTS: Four compounds were isolated and identified as friedelin (1), 25 (27)-dehydroporiferasterol (2), 22 dehydroclerosteryl acetate (3), uncinatone (4). CONCLUSION: Compound 2, 3 are isolated form this genus for the first time, Compounds 4 is isolated from this plant for the first time. PMID- 23750414 TI - [Effects of soothing liver and invigorating spleen recipes on the mRNA and protein expression of TLR4 in hepatic tissues of rats with NASH]. AB - OBJECTIVE: To research the effects of soothing liver and invigorating spleen recipes on expression of TLR4 mRNA and protein expression in hepatic tissue of rats with non-alcoholic steatohepatitis and its mechanism. METHODS: 72 male SD rats were randomly divided into 8 groups: normal group, model group, high-dose soothing liver group (receiving gavage of Chaihu Shugan Powder 9. 6 g/kg), low dose soothing liver group (receiving gavage of Chaihu Shugan Powder 3.2 g/kg), high-dose invigorating spleen group (receiving gavage of Shen Ling Baizhu Powder 30 g/kg), low-dose invigorating spleen group (receiving gavage of Shen Ling Baizhu Powder 10 g/kg), high-dose integrated Group (receiving gavage of Chaihu Shugan Powder and Shen Ling Baizhu Powder combination recipes 39.6 g/kg), low dose integrated Group (receiving gavage of Chaihu Shugan Powder and Shen Ling Baizhu Powder combination recipes 13.2 g/kg), 9 rats were in each group. Used high fat diet (10 mL/kg) to establish experiment model of NASH rat. At the end of the sixteenth weeks, the levels of serum lipids, liver lipids and serum aminotransferase were measured by automatic biochemical analyzer; Liver pathology was analyzed by HE and Oil red O staining; TLR4 mRNA was assayed by real-time fluorescent quantitative polymerase chain reaction (RT Q-PCR); TLR4 protein was detected by Western blot. RESULTS: Compared with normal group, the levels of TC, LDL-C in the serum, TC,TG as well as the expression of TLR4 mRNA and protein in the hepatic tissue were dramatically increased in model group (P < 0.01). Compared with the model group, the levels of serum lipids, liver lipids, the expression of TLR4 mRNA and protein in the hepatic tissue were decreased in each treatment group (P < 0.05 or P < 0.01). CONCLUSION: Soothing liver and invigorating spleen recipes can inhibit hepatic TLR4 expression, that may be one of their therapeutic mechanisms. There is much difference between high-does and low-does treatment groups in various testing items, which shows that there is does-effect relationship in intervention NASH. PMID- 23750415 TI - [Hepatoprotective effects of extracts from processed corni fructus against D galactose-induced liver injury in mice]. AB - OBJECTIVE: To study the hepatoprotective effects of extracts from processed Corni Fructus against D-galactose-induced liver injury in mice. METHODS: Acute liver injury model was established by D-galactose. The activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD) and level of liver malondialdehyde (MDA) of serum was measured. Hematoxylin and Eosin (HE) staining of pathological section and transmission electron microscopic observation were used to measure the apoptosis of liver cells. RESULTS: Compared with the normal control group, SOD activity was decreased, MDA level and ALT, AST activity was increased in the model group, and the differences were significant (P < 0.05); While three kinds of cornel active sites showed significant improvement with increasing SOD activity and decreasing ALT, AST activity and MDA levels (P < 0.05). Furthermore, model group appeared obvious necrosis inflammation, and apoptosis characteristics; While liver structural damage were improved significantly in cornel active site groups. CONCLUSION: Cornel polysaccharide extract, n-butanol extraction site and petroleum ether extraction sites all have hepatoprotective effects, suggesting that they are the active material of cornel product, and the mechanism may be related to the inhibition of oxidative stress and inflammatory response. PMID- 23750416 TI - [Research on the effect of biyan qingdu granula drug-containing serum on inhibition of nasopharyngeal carcinoma cells growth in vitro]. AB - OBJECTIVE: To investigate the effect of Biyan Qingdu Granula drug-containing serum (BQG-DS) on cell growth and apoptosis in nasopharyngeal carcinoma cell lines CNE1, CNE2, TWO3, C666-1, and explore the antineoplastic mechanism of Biyan Qingdu Granula. METHODS: SD rats were randomly divided into three groups: experimental (Biyan Qingdu Granula) group, positive control (cytoxan) group and negative control group. After administration of drug, the serum was collected from the treated animals. MTT assay was used to examine the effect of BQG-DS on the proliferation of CNE1, CNE2, TWO3, C666-1 cell, and flow cytometry was used to observe the cell cycle distribution. Apoptosis of CNE1, CNE2, TWO3, C666-1 cell was further investigated by inverted microscope. RESULTS: BQG-DS inhibited the proliferation of CNE1, CNE2, TWO3, C666-1 cell and the effects were in a time and concentration-dependent manner. BQG-DS could also induce apoptosis while the G1 phase was arrested. CONCLUSION: BQG-DS inhibits proliferation of nasopharyngeal carcinoma cells via induction of apoptosis and arrest of cell cycle. PMID- 23750417 TI - [Research of inhibition of compound gan shu kang on hepatitis B virus]. AB - OBJECTIVE: To study the anti-HBV effect in vitro of each extract from compound Gan Shu Kang. METHODS: The toxicity was investigated with cytopathic effect (CPE) by enzyme linked immuno-adsorbed assay (ELISA), the inhibitory effect of each extract on HBsAg and HBeAg secreted by 2215 cell line infected by HBV DNA was evaluated. RESULTS: The half of the toxic concentration (TC50) of petroleum ether, ethyl acetate and n-butanol was 125, 375 and 62.5 microg/mL, respectively. The maximum nontoxic concentration (TC0) was 62.5, 125 and 31.3 microg/mL, respectively. The medium effective concentration (IC50) of petroleum ether and ethyl acetate on 2215 cellular HBsAg express the inhibitory effect was 48.6 and 14.0 microg/mL, HBeAg was 52.4 and 19.7 microg/mL, while the IC50 of n-butanol for HBsAg and HBeAg was more than 125 microg/mL. The therapeutic index (TI) of petroleum ether was 2.57 and 2.43, ethyl acetate was 26.7 and 19.04, n-butanol was both less than 2. CONCLUSION: The anti-HBV effect of ethyl acetate extract of compound Gan Shu Kang is better than that of petroleum ether, while the n-butanol extract shows no effect. PMID- 23750418 TI - [Study on the rule of influence of two purification methods on the chemical compositions in aqueous solution of paeoniae radix alba]. AB - OBJECTIVE: To explore the rule of influence of chitosan flocculation clarification and alcohol precipitation on the chemical compositions in aqueous extract of Paeoniae Radix Alba. METHODS: The fingerprints of aqueous extracts of Radix Paeoniae Alba were established by HPLC method, and the influences of the two purification methods on the chemical compositions in aqueous extract of Paeoniae Radix Alba were compared with the apparent content and relative apparent content of the composition as evaluation indexes. RESULTS: The chitosan flocculation clarification was superior to alcohol precipitation for keeping the polar compositions in aqueous extract, close to alcohol precipitation for keeping the medium polar compositions, and inferior to alcohol precipitation for keeping the lower polar compositions. CONCLUSION: The experiment result provides evidence for reasonably selecting above two purification methods to purify aqueous extract of Chinese medicinal herbs. PMID- 23750419 TI - [Optimization of extraction of Clerodendranthus spicatus using response surface methodology]. AB - OBJECTIVE: To obtain the optimal conditions of extraction of Clerodendranthus spicatus and provide the theoretical foundation for its further processing and utilization. METHODS: On the basis of the single factor test, response surface methodology was applied to optimize the extraction conditions. RESULTS: The results showed that extraction time, water-feed ratio, ethanol concentration and extraction temperature all had significant effects on the extraction rate of polysaccharides. The optimal extraction time was 3h, solid-liquid ratio was 50:1, ethanol concentration was 30% and extraction temperature was 80 degrees C. Under these optimized conditions, the extraction rate was 27.71%. CONCLUSION: The extraction technology is simple, reliable and highly predictive. PMID- 23750420 TI - [Study on preparation of total flavones in Glechoma longituba sustained-release tablets and its in vitro release]. AB - OBJECTIVE: To study the preparation of total flavones in Glechoma longituba sustained-release tablets and evaluate its releasing features in vitro. METHODS: Orthogonal experiment (L(9)3(4)) was used to optimize the process of preparation of total flavones in Glechoma longituba sustained-release tablets. Investigated the release effect in vitro of optimization test result. RESULTS: The optimized prescription was HPMC-K4M and carbopol 934p account for 30% of the total tablet weight, their dosage ratio was 2: 1; Lactose as additives, 20% dosage; 5% PVP ethanol as adhesives, and compressed the wet granule of the materials into the total flavones in Glechoma longituba sustained-release tablets. The released profiles of the sustained-release tablets followed zero-order equation. CONCLUSION: The sustained-release effect of total flavones in Glechoma longituba sustained-release tablets is good, the preparation craft is easy and feasible and worth widely promoting. PMID- 23750421 TI - [Simultaneous determination of five flavonoids and specific chromatograms analysis of huangkui capsule]. AB - OBJECTIVE: To Set up a method for determining the contents of the five flavonoids simultaneously in the HuangKui capsule and analyze their specific chromatograms. METHODS: HPLC method was used. The analytical column was Thermo scientific Hypersil GOLD (250 mm x 4.6 mm, 5 microm). The mobile phase was composed of acetonitrile (A) and 0.2% orthophosphoric acid (B) with gradient elution. The flow rate was 0.8 mL/min and detection wavelength was 360 nm. The column temperature was maintained at 30 degrees C. RESULTS: Contents of the five flavonoids (Rutin, Hyperoside, Isoquercitrin, Myricetin, Quercitrin) had good resolution with the correlation coefficients exceed 0.9999 and the average percent recovery lied in 98.46% to 100.33%. The chromatograms of the HuangKui capsule shared 15 common peaks in which 5 of them were recognized by the reference standard. Chromatograms of 10 lots of HuangKui capsule were analyzed with the similarities over 0.95. CONCLUSION: The proposed method of contents determination and chromatogram analysis has strong characteristic and specificity. This method is fast, easy and reliable, and can be applied for quality control of the preparation. PMID- 23750422 TI - [Clinical efficacy of special effect san xiao decoction on type 2 diabetes mellitus]. AB - OBJECTIVE: To investigate the clinical efficacies of the special effect San Xiao decoction on type 2 diabetes mellitus and its impact on inflammatory factors. METHODS: 116 patients with type 2 diabetes mellitus were randomly divided into control group and observation group from Aug. 2010 to Aug. 2012, and each group had 58 cases. Both of the two groups were given the conventional basic treatment and 0.5 g/time, oral, 2 times/d of metformin. The observation group was received 1 dose/d of special effect San Xiao decoction on the basis of the basic treatment, and the treatment course was 12 weeks. The fasting blood glucose (FBG), 2h postprandial blood glucose (PBG), glycosylated hemoglobin (HbA1c), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 ( IL-6) and c-reactive protein (CRP) were observed after the treatment. RESULTS: The FBG, PBG, HbA1c and insulin sensitive index (ISI) of the observation group were better than those of the control group (P < 0.05 or P < 0.01); BMI and body weight of the observation group were lower than those of the control group (P < 0.05); The blood sugar control effect of the observation group was better than that of the control group (P < 0.05); The hypoglycemia incidence of the observation group was lower than that of the control group (P < 0.01); TNF-alpha, IL-6 and CRP of the observation group were lower than those of the control group (P < 0.01). CONCLUSION: The clinical efficacy of the special effect San Xiao decoction on type 2 diabetes mellitus is significant, it has the role of alleviating inflammatory response for diabetes and it also has less adverse reactions, which is worth to be applied in clinical. PMID- 23750423 TI - [Antiepileptic drugs in treatment of epilepsy and follow up of their efficacy]. AB - Epilepsy is one of the most common neurological diseases usually demanding long term treatment. The prime goal of therapy is to achieve seizure freedom with avoidance of side effects. Precise diagnosis is fundamental selecting the proper antiepileptic drug(s). In addition of wide-spectrum antiepileptics, selective syndrome-specific antiepileptic drugs are available. Pharmacological features of the new antiepileptics allow more personalized clinical use. Aim of this paper is to provide a comprehensive pragmatic review of therapeutic possibilities and recommendations currently accessible in Hungary. PMID- 23750424 TI - [Inclusion body myositis--a rarely recognized disorder]. AB - Inclusion body myositis is the most common disabling inflammatory myopathy in the elderly. It is more frequent in men and after the age of 50 years. Inflammatory and degenerative features coexist. There is a T-cell mediated autoimmunity driven by in situ clonally expanded cytotoxic CD8-positive T-cells invading non-necrotic muscle fibres expressing MHC-I antigen. The hallmarks of degeneration are the deposition of protein aggregates and the formation of vesicles. The course of the disease is slow and the diagnosis is usually set after several years. The muscle weakness and wasting is assymetric, affecting predominantly distal muscles of the upper extremity and proximal muscles of the legs. The signs and clinical course can be characteristic, but the diagnosis is established by muscle biopsy. There is currently no evidence based effective treatment for sIBM. Prednisone, azathioprine, methotrexate, cyclosporine and IFN-beta failed. Oxandrolon did not improve symptoms. Treatment with intravenous immunglobuline (IVIG) induced in some patients a transient improvement of swallowing and of muscle strenght, but the overall study results were negative. A T-cell depleting monoclonal antibody (alemtuzumab), in a small uncontrolled study slowed down disease progression for a six-month period. Repeated muscle biopsies showed the reduction of T-cells in the muscle and the suppression of some degeneration associated molecules. An effective therapeutic mean should act on both aspects of the pathomechanism, on the inflammatory and the degenerative processes as well. PMID- 23750425 TI - Effects of spinal cord stimulation on heart rate variability in patients with chronic pain. AB - BACKGROUND: Spinal cord stimulation has become an established clinical option for treatment of refractory chronic pain and angina pectoris, but its precise mechanism of action is unclear. We investigated the effect of spinal cord stimulation (SCS) on heart rate variability (HRV) and evaluating its influence on the sympathetic/parasympathetic balance in chronic pain. MATERIALS AND PURPOSE: Seven patients (three men, four women) with SCS due to chronic pain were included. The SCS was programmed in three different ways: (i) to stimulate at an amplitude known to generate paresthesias (ON-state), (ii) at a subliminal level (SUB state), or (iii) switched off (OFF-state). HRV analysis was based on 5-min segments of the consecutive normal RR intervals and was performed with custom software (Kubios HRV Analysis). RESULTS: The mean heart rate was higher in ON state compared to SUB state (p = 0.018) and the high-frequency component of the HRV was lower in ON compared to OFF period (p = 0.043). Other HRV parameters values did not significantly differ during the three tested periods. CONCLUSION: Spinal cord stimulation in chronic pain seems to be accompanied by reduced parasympathetic tone, unlike SCS in angina pectoris where previous studies found a reduced cardiac sympathetic tone. Our study might lead to understand the mechanism of action of SCS We investigated a relatively small number of patients, which is the main limitation of our study. Thus, further studies with larger number of patients are required for validation of our results. PMID- 23750426 TI - [10 years, 600 monitoring sessions--our experience with the video EEG monitoring of children]. AB - INTRODUCTION: The only Hungarian video EEG laboratory where children of ages 0-18 can be continuously monitored for several days was opened 1 June 2001 at Department of Neurology of Bethesda Children's Hospital. OBJECTIVES: Summarizing our 10 years of experience with the video EEG monitoring (VEM) of children and defining the place of VEM in the treatment of childhood epilepsy in Hungary. PATIENTS AND METHODS: We have processed data from 597 monitoring sessions on 541 patients between June 1, 2001 and 31 May, 2011 based on our database and the detailed summaries of the procedures. RESULTS: 509 patients were under the age of 18. The average length of the sessions was 3.1 days. We have observed habitual episodes or episodes in question in 477 (80%) sessions. 241 (40%) sessions were requested with an epilepsy surgery indication, and 74 patients had 84 operations. 356 (60%) were requested with a differential diagnosis indication, and 191 (53%) cases of epilepsy were diagnosed. We most commonly diagnosed symptomatic generalized epilepsy (57 cases). In 165 sessions the episode in question was not diagnosed as epilepsy. Among the paroxysmal episodes we have identified events of psychogenic origin, movement disorders, sleep disorders and behavioral disorders. Only 3% of the differential diagnosis procedures brought no additional clinical information. DISCUSSION: The diagnostic efficiency in our VEM laboratory is in accordance with the data found in the literature. Besides epilepsy surgery VEM is recommended if suspected epileptic episodes occur and interictal epileptiform signs are not present or are not in accordance with the symptoms, if there is no explanation for therapy resistance and if paroxysmal episodes of non-epileptic origin are suspected but they cannot be identified based on the anamnesis. VEM is also helpful in diagnosing subtle seizures. The procedure has numerous additional benefits in patient care and in training the parents and hospital staff. PMID- 23750427 TI - [Efficacy of deep brain stimulation in our patients with Parkinson's disease]. AB - BACKGROUND AND PURPOSES: In advanced Parkinson's disease, medically refractory motor fluctuation or medically resistant tremor considerably affects quality of life. However, these symptoms can be mostly successfully treated by deep brain stimulation. We analyzed the efficacy of bilateral subthalamic stimulation in our patients with Parkinson's disease. METHODS: We assessed the clinical data of ten patients who have been treated in the Department of Neurology, Semmelweis University and have been operated in the National Institute of Neurosciences between 2008 and 2011. The Hoehn-Yahr scale score, the Unified Parkinson's Disease Rating Scale score and the Parkinson's Disease Questionnaire 39, as well as the dose of antiparkinson medication were documented prior to and one year after surgery. RESULTS: Patient condition improved according to the Hoehn-Yahr scale, approximately by two stages. The dose of antiparkinson medication could be reduced by 63.4% (p = 0.005) post operation. Unified Parkinson's Disease Rating Scale scores decreased by 70.9% (p = 0.005). 12 hours after medication withdrawal, execution of daily activity improved by 57.1% (p < 0.01) and motor functions developed by 79.1% (p < 0.01). Duration of dyskinesias decreased by 62.5% (p = 0.018), duration of akinesia diminished by 87.5% (p = 0.005). Quality of life rose by 41.6% (p < 0.01). Neuropsychological tests detected improvement in verbal memory. CONCLUSION: With deep brain stimulation, the dosage of antiparkinson medication could be significantly reduced, with considerable improvements in motor function and quality of life. Although the number of patients is still low, good results have been established by careful patient selection, precise neurosurgical procedure and by appropriate programming and patient care. PMID- 23750428 TI - [The use of minimally invasive instrumental spinal surgical technique in lumbar diseases of degenerative or traumatic origin]. AB - Paradigm change has recently taken place in spine surgery with the application of minimally invasive techniques. Minimally invasive techniques have several advantages over the open traditional techniques: less blood loss, preservation of spine muscle integrity, shorter hospitalization, early mobilization, reduced pain levels, lower risk of infection. The presented cases cover following lumbar pathologies: segmental spinal instability, LV-SI grade II. spondylolisthesis, degenerative spondylolisthesis, spine trauma. Unilateral or bilateral mini-open technique was employed in the degenerative cases, depending on symptoms and signes. If unilateral symptoms--pathology was identified, screws and rod were implanted percutaneously on the side contralateral to the pathology. The segmental fusion between vertebral bodies was always assured by a cage and autologous bone. The presented trauma case involved combined AO type A2 and B fractures. The anterior column was strengthened with vertebral body stents filled with bone cement, the posterior column was fixed with a percutaneously implanted screw rod system. Insertion of stents in the collapsed vertebra significantly increased the vertebral body height and also improved the stability of the spine. Minimally invasive spine surgery techniques appear more advantageous over the traditional open spine surgery that necessitates for large midline approaches. PMID- 23750429 TI - [Not Available]. PMID- 23750430 TI - [Better life expectations of SM patients: 21 years follow up of patients treated with interferon beta-1b]. PMID- 23750431 TI - [The relationship between advancement of secondary hyperparathyroidism and selected calcification parameters in peritoneal dialysis patients]. AB - The aim of the study was to assess the relationship between the advancement of secondary hyperparathyroidism and the concentrations of selected calcification markers, i.e. osteopontin (OPN), osteoprotegerin (OPG), osteocalcin (OC), fetuin A as well as fibroblast growth factor-23 (FGF-23) in peritoneal dialysis patients (PD). MATERIAL AND METHODS: The study included 67 patients (36 male and 31 females) aged 52.9 years (19-75 years) with chronic kidney disease (CKD) on peritoneal dialysis therapy 30.4 +/- 24.2 months. BMI was calculated using Quetelet formula. Serum Pi, Ca, albumin, fibrinogen, iPTH were performed using standard laboratory methods, while the selected bone metabolism parameters: fetuin-A, OC, OPG, OPN and FGF-23 were measured based on commercially available ELISA kits. RESULTS: Patients with high iPTH levels (> 300 pg/ml) had higher OC levels (median 68.5 ng/mL) comparing to patients with target iPTH, i.e. 100-300 pg/ mi (57.3 ng/mL; p = 0.003) and patients with low iPTH < 100 pg/ml (17.3 ng/mL; p < 0.0001). Also, OPN and FGF-23 concentrations were significantly higher in patients with high iPTH comparing to patients with target iPTH (1535 vs. 1001 ng/mL; p = 0.04 and 4952 vs. 702 RU/ mL; p = 0.02, respectively). Patients with increased Ca x P values (> 45 mg2/dl2) as compared with patients having lower Ca x P had higher FGF-23 (4308 vs. 678 RUlmL; p < 0.0001), higher OC (67.0 vs. 60.2 ng/mL; p = 0.049) and lower OPG concentrations (8.97 vs. 11.97 pmol/L; p = 0.02). OC strongly correlated with iPTH concentration (R = 0.78; p < 0.0001) and FGF-23 strongly correlated with Ca x P value (R = 0.74; p < 0.0001). CONCLUSIONS: In peritoneal dialysis patients along with increment of IPTH concentrations and enchancement of calcium-phosphate imbalance, significantly rise concentrations of calcification markers such as: osteocalcin (OC), osteopontin (OPN), as well as fibroblast growth factor-23 (FGF-23). PMID- 23750432 TI - [Posture types in children aged 7-12 from rural environment]. AB - The aim of this research was to evaluate posture types in children aged 7-12 from rural environment. MATERIALS AND METHODS: This study was conducted among 562 children from Podkarpackie and Swietokrzyskie region. Evaluation of posture was studied by photogrammetry method with the use of projection moire phenomenon. RESULTS: The most common type of posture was lordosis (44.84%), then kyfosis (37.19%) and balanced type (17.97%): CONCLUSION: Early diagnosis of posture defects allows their correction and undertaking early prophylactic actions. PMID- 23750433 TI - [The benefits of using basophil activation test as a diagnostic tool prior to specific immunotherapy with inhalant allergens]. AB - BACKGROUND: Routine qualification for specific immunotherapy (SIT) is based on clinical history and skin prick tests (SPT) or specific IgE (sIgE). In cases of discordance between these two, basophil activation test (BAT) may be decisive. The aim of the present study was to determine the specificity and sensitivity of BAT, sIgE, and SPT, and to analyse cases, in which clinical data and SPT alone would result in wrongful qualification for SIT. PATIENTS AND METHODS: BAT results and sIgE levels to Dermatophagoides pteronyssinus (Dp) and Dermatophagoides farinae (Df) were determined in 52 pediatric patients qualified for SIT based on clinical history and positive SPT. The group included 21 children qualified for SIT with birch or timothy grass, used as reference for specificity and sensitivity calculations for BAT, sIgE and SPT. RESULT: The sensitivity and specificity of BAT, using SPT as "gold standard" was 96.9% and 88.9% for Dp, and 89.3% and 100% for Df, respectively and the sensitivity and specificity of sIgE were 89.7%, 88.9% for Dp, and 92.9% and 94.4% for Df. When using BAT as "gold standard", the sensitivity and specificity of SPT was 90% and 90.5% for Dp, 92% and 84,6% for Df, and these indices for sIgE were 87.1% and 90.5% for Dp, 100% and 87.5% for Df. BAT did not confirm the initial qualification for SIT in 2 patients, revealing an unspecific basophil activation. Negative nasal provocation test ultimately confirmed the false-positive SPT, which could be explained by the co-existence of urticaria in those children. In further 2 children qualified for SIT with timothy and birch, BAT revealed lack of reactivity to respective allergens. Altogether BAT helped in avoiding unnecessary SIT in 4 out of 52 children (7.7%). CONCLUSIONS: In most cases, SPT, sIgE and BAT provide comparable information, however, SPT results care is advised in patients with co-existing urticaria. BAT is useful in verifying the actual relevance of allergens selected for SIT and helps in avoiding long-lasting, arduous, costly, and ineffective immunotherapy of wrongly qualified cases. PMID- 23750434 TI - Survey of biological particles in the atmosphere of the Cracow center (southern Poland) in 2011. Preliminary study. AB - The seasonal concentrations of pollen and spores of selected fungi taxa in the area of the Main Square Market in Cracow, in 2011 were analysed using the volumetric method of sampling in order to compare these concentrations with results obtained in the continuous monitoring. The highest percentages of pollen in total pollen were noted for Urtica, Pinus and Poaceae. The fungal spore concentrations, with dominant contribution of Cladosporium spores, were relatively higher in comparison with pollen grains. The U Mann-Whitney test indicated that the differences between total pollen in both sites were not statistically significant for most of the taxa, on the contrary to fungal spores. The highest total pollen was reached in the second decade of May and the third decade of August in both study sites. The pollen and fungal spore season characteristics indicate similar pollen season duration for most taxa in both study sites, except at Rumex. Herb pollen seasons are clearly longer than tree pollen seasons and show periods of different concentrations. The statistically significant differences in pollen season dynamics were found for Plantago, Rumex and Urtica in both study sites. The period of high Alternaria spore concentrations coincided with high concentrations of Artemisia, however the time of high Cladosporium spore concentrations was related to relatively high concentrations of Poaceae and Urtica pollen. PMID- 23750435 TI - [Influence of venom immunotherapy on anxiety level of being re-stung]. AB - Hymenoptera venom allergy is related to higher risk of potential life threatening anaphylactic reactions, which leads to anxiety and decreased quality of life. AIM: The aim of this paper was: 1) estimation of fear level of being re stung among venom allergy adults treated with venom specific immunotherapy (VIT)- before and during treatment; 2) estimation of expectation of outcome of VIT as compared to level of anxiety of being re-strug, in the Visual Analogue Scale--VAS score; 3) identification of factors influencing changes in the fear level among patients during VIT. MATERIAL AND METHODS: The study group comprised 42 patients (18 women, 24 men) in the mean age 42.6 years, with bee or vespid allergy, who had been qualified to the VIT treatment with Alutard SQ. Visual Analogue Scale- VAS and the Expectation of Outcome Questionnaire were used. The demographic data were collected. RESULTS: The VAS score before VIT for insect venom allergic patients was 8.8 (SD = 0.9). It decreased after achieving maintenance dose to 3.1 (SD = 1.6) and was significantly lower in men (p < 0.05). Score achieved in the Expectation of Outcome Questionnaire was for each question 2.2 (SD = 1.5) and there was correlation with VAS score during VIT. CONCLUSIONS: The patients with insect venom allergy, who undergo a serious allergic reaction (SR) as a result of being stung and who are qualified to VIT, have a high level of anxiety of being re-stung. Achieving the maintenance dose of VIT, results in a significant decrease of anxiety level in women and men, significantly so in men. There is a significant correlation between VAS score and the Expectation of Outcome Questionnaire results during VIT. Both VAS for anxiety level and the Expectation of Outcome Questionnaire can be simple, easily available and useful instruments helping to estimate quality of life. VIT significantly decreases the patients level of anxiety of being restung and improves their quality of life. PMID- 23750436 TI - [An attempt to objectify the assessment of extension or recurrence of Dupuytren's disease on the basis of ultrasound]. AB - Dupuytren's contracture is a disease of unknown etiology, leading with time to decreased hand function caused by increasing contracture of fingers. Excision of contracted longitudinal palmar fascia constitutes the most important way of treatment. Due to fact that disease has progressive course in many patients recurrence (i.e. overgrowth of longitudinal palmar aponeurosis apart from the operated site) or extension (i.e. similar process affecting formerly operated site) occurs. An attempt to objectify the assessment of recurrence or extension of Dupuytren's disease on the basis of sonographic examination of palmar surface of the hand during distant (at least 24 months from surgery) followup constituted the aim of the study. 41 patients operated on from January 2000 to February 2009 in 2nd Department of General Surgery in Krakow due to Dupuytren's contracture constituted the study material. Mean age of the patients reached 62,78 years (SD +/- 9,32), and mean follow up time 5,74 years (SD +/- 2,90). Sonographic assessment was performed in 26 operated on left hands and 24 right hands. 9 patients had both hands operated on. In most of the patients during surgery the contralateral hand was also affected by the disease. Extension of Dupuytren's disease was found in 11 hands, recurrence--in 18 hands, while concurrent extension and recurrence was found in 17 hands. Extension usually was found on the radial side and affected mainly I interphalangeal space followed by disease affecting I and III ray of the hand. In one patient 2 independent foci of the disease were found within I interphalangeal space. Recurrences affected mainly ulnar side of the hand: V and IV rays of the hand. Concurrently found extension and recurrence affected 2 or 3 rays. In the cases of 3 rays affected extension dominated (2 rays vs. 1 ray of recurrence). On sonographic assessment mean diameters of lesions during distant follow- up were 12,69 x 4,62 x 3,95 [mm] with recurrent lesions being larger than mean values found in extensions. With partial fasciectomy being the most commonly performed operation in cases of Dupuytren's disease ultrasound can constitute very important technique of assessment of exacerbation of the lesions of palmar aponeurosis allowing for the choice of appropriate surgical technique for particular case, detection of postoperative extension and/or recurrence and for the cases clinically doubtful. PMID- 23750437 TI - [The value of three-dimensional multiplanar (MPV) and volume contrast imaging (VCI) in the ultrasound evaluation of endometrial pathology]. AB - The aging of the women population as well as widespread use of the ultrasound leads to an increased detection of abnormal endometrial characteristics. The aim of this study was to assess the value of three-dimensional ultrasound viewing options: multi-planar view (MPV) and volume contrast imaging (VCI) in the endometrial evaluation. 147 women, referred for endometrial sampling, because of bleeding or an abnormal endometrial two-dimensional ultrasound image were enrolled in the study. Before dilation and curettage, all patients underwent three-dimension ultrasound scans for endometrial thickness measurements and endometrial-myometrial junction assessment. Ultrasound results and the presence of abnormal vaginal bleeding were compared with pathological diagnosis. Sensitivity, specificity, negative predictive value, and positive predictive value for abnormal vaginal bleeding, irregular endometrial-myometrial junction and endometrial thickness were established. Logistic regression model was used to assessed the relationship between the characteristics and the incidence of endometrial pathology. For each of the independent variables odds ratios were calculated. Sensitivity, specificity of the endometrial thickness cut-off 11 mm were 73.8%, 74.4%, for 10.5 mm 76.2%, 69.8% respectively. The irregular endometrial-myometrial junction reached 70.5% sensitivity and 93% specificity. Odds ratios for 10,5 mm cu-off value of the endometrial thickening and irregular E-M junction were calculated: 4.10 [95% CI: 1.14-14.74] and 36.07 [95% CI: 7.10 183.27]. The negative predictive value of any of these parameters did not exceed 70%. The combination of 3D ultrasound parameters and the occurrence of abnormal vaginal bleeding has reached only 53% sensitivity. In the case of connection of two of these three indices, increased sensitivity of 76.9% and specificity of 82.4%. In an unselected group of women in terms of menopausal status and symptoms endometrial thickness measured and the evaluation of endometrial-myometrial junction using 3D ultrasound is less value in predicting the occurrence of endometrial cancer than in 2D and the endometrial volume calculation. PMID- 23750438 TI - [Nonalcoholic fatty liver disease as a risk factor of macroangiopahty in patients with type 2 diabetes]. AB - Nonalcoholic fatty liver disease (NAFLD) is recognized in 20-30% of general population but among the people with impaired glucose metabolism is about 70-90%. There is increasing number publications that show strong association between NAFLD, metabolic syndrome and insulin resistance as risk factors of cardiovascular complication. Gens PNPLAL3 NCAN, LYPAL1 and GCKR that have been linked to lipid metabolism disorders or impaired glucose metabolism can also contribute to development of NAFLD. The reduction of body mass and of known risk factors of atherosclerosis and restriction of simple carbohydrates in diet contribute to regression of NAFLD. PMID- 23750439 TI - Two hundred years after discovery of iodine--less known functions of the element in human organism. AB - The main role of iodine in human organism is related to biosynthesis of thyroid hormones. The less known metabolic pathway of the element is formation of iodolipids (mainly iodoaldehydes and iodolactones). One of the compounds, 6-iodo 5-hydroxy-eicosatrienoic acid delta-lactone (6-IL), is believed to inhibit goiter growth, to modulate the cell response on some growth factors, and to trigger apoptosis in some types of cells. Another one, 2-iodohexadecanal (2-IHDA), probably also inhibits goiter growth and mediates the Wolff-Chaikoff-effect. Epidemiological and experimental data suggest a relation of iodine to some tumor diseases. Preventing of iodine deficiency diminishes prevalence of goiter as well as some non-goiter diseases. PMID- 23750440 TI - [Current guidelines for prevention and management of chemotherapy extravasation]. AB - Cytostatic drugs extravasation is the serious side effect of chemotherapy. It may lead to health-threatening complications as well as to impairment of cancer patients quality of life. Prevention, early diagnosis and appropriate treatment significantly reduce the consequences of extravasation. Training of medical staff and patients education have enormous importance on this point. PMID- 23750441 TI - [Methodological aspects of use of scales as measurement instruments in epidemiological studies]. AB - Quality of life and health status measurement in epidemiological studies requires high level approach. It concerns not only the matter of choice or development of measurement tools; it requires also consciousness of the consequences, which may follow mistakes made during their development. Development of new measurement tool by means of adaptation of tool used in another country also may be touched by the risk of committing some mistakes, which may be followed by serious consequences including problems with interpretation of obtained data. This paper presents examples of mistakes made during development of questionnaires and some guidelines, which let to avoid the most serious mistakes. PMID- 23750442 TI - [Contemporary views on etiology and pathogenesis of halitosis]. AB - Halitosis is an unpleasant condition that causes social restraint. Studies worldwide indicate a high prevalence of moderate halitosis, whereas severe cases are restricted to around 5% of the populations. There is the presence of odoriferous substances in exhaled air, especially the volatile sulphur compounds (VSC) produced by bacteria. Halitosis is caused mainly by tongue coating and periodontal disease. Bacterial metabolism of amino acids leads to metabolites including many compounds, such as indole, skatole and volatile sulphur compounds (VSC), hydrogen sulphide, methyl mercaptan and dimethyl sulphide. They are claimed to be the main etiological agents for halitosis. The paper reviews the prevalence and distribution of halitosis, oral malodour, its aetiology, concepts of general and oral health and diseases. Eating, smoking and drinking habits and understanding of halitosis as a social norm has been highlighted. It is a public social health problem. The dental professionals should be aware of the cultural perceptions of halitosis among racially and culturally diverse populations. In general, physicians and dentists are poorly informed about the causes and treatments for halitosis. PMID- 23750443 TI - [Oxidative stress and its significance in prostate diseases]. AB - The disturbed balance between production of reactive oxygen and nitrogen species (RONS) and efficiency of antioxydative systems leads to oxidative stress. This may be the cause of permanent biomolecules' damage. The results of many researches show dependence between disturbance in oxidative balance. And oxidative damage in prostate cells. However no clear evidence have been found that oxidative stress may lead to development of prostate cancer. PMID- 23750444 TI - [Paget-Schroetter syndrome as an unexpected and uncommon aspect of pacemaker implantation: a case report]. AB - We present the rare case of Paget-Schroetter syndrome as an idiopathic and asymptomatic left subclavian vein thrombosis, which was diagnosed during the procedure of pacemaker implantation. Intracardiac lead was successfully implanted through the opposite vessel. PMID- 23750445 TI - [Lumbar hernia]. AB - Lumbar region constitutes one of the least common localizations for hernia formation. There are only slightly more than 300 cases found in English literature till the end of the 20th century, while there are only 8 cases presented in Polish literature. Exceptionally rare incidence together with diagnostic dilemma related to it made us to present cases of 2 patients operated on in the 2nd Chair of Surgery of Jagiellonian University Medical College due to lumbar hernia. PMID- 23750446 TI - [Sudden cardiac arrest in ventricular fibrillation mechanism as a first manifestation of primary mitral valve prolapse]. AB - We present the case of a 58 year-old patient with a primary mitral valve prolapse (MVP) at whose first manifestation of the disease was a sudden cardiac death (SCD) in ventricular fibrillation mechanism. In ECG paroxysmal atrial fibrillation was detected. The arrhythmia became persistent atrial fibrillation but in ECG sinus rhythm recording, QT dispersion occurred. In the echocardiography we found a classic MVP syndrome with large mitral regurgitation, preserved left ventricular systolic function and recent infective endocarditis features on posterior cusp of mitral valve. In the computed tomography of the head we found acute and recent history of stroke. The patient was qualified for implantable cardioverter-defibrillators (ICD) implantation as a secondary SCD preventive treatment. An artificial mitral valve was implanted. In the long-term observation (36 month) two adequate ICD interventions caused by ventricular tachycardia were recorded. General condition of the patient remains stable. PMID- 23750447 TI - [The types of social support for the elderly]. AB - The elderly are a growing segment of our society. However, this is not reflected by greater expenditure on pensions which should guarantee the adequate means for dignified ageing. More and more frequently the elderly cannot cope with the complexity of daily life and they become clients of social support systems. The current paper presents the need for broad support of the elderly, stemming both from health-related issues and inadequate pensions. PMID- 23750448 TI - [Mieczyslaw Justyna--member of the Founding Committee of the Polish Urological Association]. PMID- 23750449 TI - [Zenon Lenko medical doctor. Member of the Founding Committee of the Polish Urological Association]. PMID- 23750450 TI - Isolation and first total synthesis of PM050489 and PM060184, two new marine anticancer compounds. AB - Microtubules continue to be one of the most successful anticancer drug targets and a favorite hit for many naturally occurring molecules. While two of the most successful representative agents in clinical use, the taxanes and the vinca alkaloids, come from terrestrial sources, the sea has also proven to be a rich source of new tubulin-binding molecules. We describe herein the first isolation, structural elucidation and total synthesis of two totally new polyketides isolated from the Madagascan sponge Lithoplocamia lithistoides . Both PM050489 and PM060184 show antimitotic properties in human tumor cells lines at subnanomolar concentrations and display a distinct inhibition mechanism on microtubules. The development of an efficient synthetic procedure has solved the supply problem and, following pharmaceutical development, has allowed PM060184 to start clinical studies as a promising new drug for cancer treatment. PMID- 23750451 TI - Characterization of polydopamine thin films deposited at short times by autoxidation of dopamine. AB - Current interest in melanin films derived from the autoxidation of dopamine stems from their use as a universal adhesion layer. Here we report chemical and physical characterization of polydopamine films deposited on gold surfaces from stirred basic solutions at times ranging from 2 to 60 min, with a focus on times <=10 min. Data from Fourier transform infrared (FTIR), X-ray photoelectron spectroscopy (XPS), and electrochemical methods suggest the presence of starting (dopamine) and intermediate (C=N-containing tautomers of quinone and indole) species in the polydopamine films at all deposition times. A uniform overlayer analysis of the XPS data indicates that film thickness increased linearly at short deposition times of <=10 min. At deposition times >=10 min, the films appeared largely continuous with surface roughness ~ <= 2 nm, as determined by atomic force microscopy (AFM). Pinhole-free films, as determined by anionic redox probe measurements, required deposition times of 60 min or greater. PMID- 23750452 TI - An altered maturation and adhesion phenotype of dendritic cells in diseased individuals compared to asymptomatic carriers of human T cell leukemia virus type 1. AB - The immunopathogenic mechanisms underlying human T cell leukemia virus type 1 (HTLV-1)-mediated diseases such as adult T cell leukemia (ATL) and HTLV associated myelopathy/tropical spastic paraparesis (HAM/TSP) are not clearly understood. As critical effectors of antiviral immune response, dendritic cells (DCs) are implicated to play an important role in determining the outcome of HTLV 1 infection. However, a complete understanding of their role in any disease pathogenesis requires extensive assessment of the phenotypic and functional state of DCs. To enable this, we developed a polychromatic antibody cocktail comprising key phenotypic and functional markers of DCs and applied it in a patient cohort from the HTLV-1 endemic region, Jamaica, consisted of seronegative controls, asymptomatic carriers (ACs), ATL, and HAM/TSP patients. This ex vivo analyses included two major subsets of blood DCs, myeloid and plasmacytoid (mDCs and pDCs, respectively). The comparative analyses of results demonstrated a decreased pDC frequency in both ATL and HAM/TSP patients as compared to ACs and seronegative controls. Similarly, CD86 expression on both mDCs and pDCs was significantly higher in HAM/TSP (but not ATL) patients compared to ACs. Interestingly, HLA-DR expression was significantly lower on pDCs of patients as compared to carriers; however, for mDCs, only the HAM/TSP group had significantly lower expression of HLA-DR. Unlike HAM/TSP individuals, ATL individuals had higher HLA-ABC expression on mDCs compared to ACs. Finally, both mDCs and pDCs of HAM/TSP patients had significantly higher expression of the programmed death ligand 1 (PD-L1) compared to ACs. Overall, this study suggests that DCs exhibit a differential phenotypic and functional profile between patients (ATL and HAM/TSP) and carriers of HTLV-1 and could provide an important tool for understanding HTLV-1 immunopathogenesis during infection and disease. PMID- 23750453 TI - Development of a new thiol site-specific prosthetic group and its conjugation with [Cys(40)]-exendin-4 for in vivo targeting of insulinomas. AB - A new tracer, N-5-[(18)F]fluoropentylmaleimide ([(18)F]FPenM), for site-specific labeling of free thiol group in proteins and peptides was developed. The tracer was synthesized in three steps ((18)F displacement of the aliphatic tosylate, di Boc removal by TFA to expose free amine, and incorporation of the free amine into a maleimide). The radiosynthesis was completed in 110 min with 11-17% radiochemical yield (uncorrected), and specific activity of 20-49 GBq/MUmol. [(18)F]FPenM showed comparable labeling efficiency with N-[2-(4 [(18)F]fluorobenzamido)ethyl]maleimide ([(18)F]FBEM). Its application was demonstrated by conjugation with glucagon-like peptide type 1 (GLP-1) analogue [cys(40)]-exendin-4. The cell uptake, binding affinity, imaging properties, biodistribution, and metabolic stability of the radiolabeled [(18)F]FPenM [cys(40)]-exendin-4 were studied using INS-1 tumor cells and INS-1 xenograft model. Positron emission tomography (PET) results showed that the new thiol specific tracer, [(18)F]FPenM-[cys(40)]-exendin-4, had high tumor uptake (20.32 +/- 4.36%ID/g at 60 min postinjection) and rapid liver and kidney clearance, which was comparable to the imaging results with [(18)F]FBEM-[cys(40)]-exendin-4 reported by our group. PMID- 23750454 TI - Adjusting the chemical and physical properties of hydrogels leads to improved stem cell survival and tissue ingrowth in spinal cord injury reconstruction: a comparative study of four methacrylate hydrogels. AB - Currently, there is no effective strategy for the treatment of spinal cord injury (SCI). A suitable combination of modern hydrogel materials, modified to effectively bridge the lesion cavity, combined with appropriate stem cell therapy seems to be a promising approach to repair spinal cord damage. We demonstrate the synergic effect of porosity and surface modification of hydrogels on mesenchymal stem cell (MSC) adhesiveness in vitro and their in vivo survival in an experimental model of SCI. MSCs were seeded on four different hydrogels: hydroxypropylmethacrylate-RGD prepared by heterophase separation (HPMA-HS-RGD) and three other hydrogels polymerized in the presence of a solid porogen: HPMA SP, HPMA-SP-RGD, and hydroxy ethyl methacrylate [2-(methacryloyloxy)ethyl] trimethylammonium chloride (HEMA-MOETACl). Their adhesion capability and cell survival were evaluated at 1, 7, and 14 days after the seeding of MSCs on the hydrogel scaffolds. The cell-polymer scaffolds were then implanted into hemisected rat spinal cord, and MSC survival in vivo and the ingrowth of endogenous tissue elements were evaluated 1 month after implantation. In vitro data demonstrated that HEMA-MOETACl and HPMA-SP-RGD hydrogels were superior in the number of cells attached. In vivo, the highest cell survival was found in the HEMA-MOETACl hydrogels; however, only a small ingrowth of blood vessels and axons was observed. Both HPMA-SP and HPMA-SP-RGD hydrogels showed better survival of MSCs compared with the HPMA-HS-RGD hydrogel. The RGD sequence attached to both types of HPMA hydrogels significantly influenced the number of blood vessels inside the implanted hydrogels. Further, the porous structure of HPMA-SP hydrogels promoted a statistically significant greater ingrowth of axons and less connective tissue elements into the implant. Our results demonstrate that the physical and chemical properties of the HPMA-SP-RGD hydrogel show the best combination for bridging a spinal cord lesion, while the HEMA-MOETACl hydrogel serves as the best carrier of MSCs. PMID- 23750456 TI - Time-resolved spectroscopic characterization of a novel photodecarboxylation reaction mediated by homolysis of a carbon alpha-bond in flurbiprofen. AB - Flurbiprofen (Fp), a nonsteroidal anti-inflammatory drug (NSAID) currently in use for arthritis pain relief and in clinical trials for metastatic prostate cancer, can induce photosensitization and phototoxicity upon exposure to sunlight. The mechanisms responsible for Fp phototoxicity are poorly understood and deserve investigation. In this study, the photodecarboxylation reaction of Fp, which has been assumed to underpin its photoinduced side effects, was explored by femtosecond transient absorption (fs-TA), nanosecond transient absorption (ns TA), and nanosecond time-resolved resonance Raman (ns-TR(3)) spectroscopic techniques in pure acetonitrile (MeCN) solvent. Density functional theory (DFT) calculations were also performed to facilitate the assignments of transient species. The resonance Raman and DFT calculation results reveal that the neutral form of Fp was the predominant species present in MeCN. Analysis of the ultraviolet/visible absorption spectrum and results from TD-DFT calculations indicate that the second excited singlet (S2) can be excited by 266 nm light. Due to its intrinsic instability, S2 rapidly underwent internal conversion (IC) to decay to the lowest lying excited singlet (S1), which was observed in the fs-TA spectra at very early delay times. Intriguingly, three distinct pathways for S1 decay seem to coexist. Specifically, other than fluorescence emission back to the ground state and transformation to the lowest triplet state T1 through intersystem crossing (ISC), the homolysis of the carbon alpha-bond decarboxylation reaction proceeded simultaneously to give rise to two radical species, one being carboxyl and another being the residual, denoted as FpR. The coexistence of the triplet Fp (T1) and FpR species was verified by means of TR(3) spectra along with ns-TA spectra. As a consequence of its apparent high reactivity, the FpR intermediate was observed to undergo oxidation under oxygen saturated conditions to yield another radical species, denoted as FOR, which subsequently underwent intramolecular hydrogen transfer (IHT) and dehydroxylation (DHO) to form a final product, which could react with the carboxyl from the decarboxylation reaction to generate a minor final product. TD-DFT and transient state (TS) calculations for predicting the absorption bands and activation energies of the transient species produced in the photodecarboxylation reaction have provided valuable mechanistic insights for the assignment of the intermediate species observed in the time-resolved spectroscopy experiments reported here. The results of the time-resolved spectroscopy experiments and DFT calculations were used to elucidate the reaction mechanisms and intermediates involved in the photochemistry of Fp. PMID- 23750455 TI - Design, synthesis, and biological evaluation of (E)-N-aryl-2 arylethenesulfonamide analogues as potent and orally bioavailable microtubule targeted anticancer agents. AB - A series of novel (E)-N-aryl-2-arylethenesulfonamides (6) were synthesized and evaluated for their anticancer activity. Some of the compounds in this series showed potent cytotoxicity against a wide spectrum of cancer cell-lines (IC50 values ranging from 5 to 10 nM) including all drug resistant cell-lines. Nude mice xenograft assays with compound (E)-N-(3-amino-4-methoxyphenyl)-2-(2',4',6' trimethoxyphenyl)ethenesulfonamide (6t) showed dramatic reduction in tumor size, indicating their in vivo potential as anticancer agents. A preliminary drug development study with compound 6t is predicted to have increased blood-brain barrier permeability relative to many clinically used antimitotic agents. Mechanistic studies indicate that 6t and some other analogues disrupted microtubule formation, formation of mitotic spindles, and arrest of cells in mitotic phase. Compound 6t inhibited purified tubulin polymerization in vitro and in vivo and circumvented drug resistance mediated by P-glycoprotein. Compound 6t specifically competed with colchicine binding to tubulin and with similar avidity as podophylltoxin, indicating its binding site on tubulin. PMID- 23750457 TI - The type III TGFbeta receptor regulates filopodia formation via a Cdc42-mediated IRSp53-N-WASP interaction in epithelial cells. AB - Cell adhesion and migration are tightly controlled by regulated changes in the actin cytoskeleton. Previously we reported that the TGFbeta (transforming growth factor beta) superfamily co-receptor, TbetaRIII (type III TGFbeta receptor; also known as betaglycan), regulates cell adhesion, migration and invasion, and suppresses cancer progression, in part, through activation of the small GTPase Cdc42 (cell division cycle 42), and Cdc42-dependent alterations to the actin cytoskeleton. In the present study we demonstrate that TbetaRIII specifically promotes filopodial formation and extension in MCF10A and HMEC (human mammary epithelial cell) mammary epithelial cells. Mechanistically, cell-surface TbetaRIII and Cdc42 co-localize to filopodial structures and co-complex in a beta arrestin2-dependent, and a TbetaRI/TbetaRII-independent manner. The beta arrestin2-mediated interaction between TbetaRIII and Cdc42 increases complex formation between the Cdc42 effectors IRSp53 with N-WASP (neuronal Wiskott Aldrich syndrome protein) to increase filopodial formation. We demonstrate a function link between filopodial structures and epithelial cell adhesion as regulated by the TbetaRIII-Cdc42 interaction. The present studies identify TbetaRIII as a novel regulator of IRSp53/N-WASP via Cdc42 to regulate filopodial formation and cell adhesion. PMID- 23750458 TI - Quantification of nanoscale silver particles removal and release from municipal wastewater treatment plants in Germany. AB - The majority of pure silver nanoparticles in consumer products are likely released into sewer systems and usually end up in wastewater treatment plants (WWTPs). Research investigating the reduction in nanoscale silver particles (n-Ag Ps) has focused on the biological treatment process, generally in controlled laboratory experiments. This study, analyzing the field-collected samples from nine municipal WWTPs in Germany, is the first to evaluate the reduction in n-Ag Ps by mechanical and biological treatments in sequence in WWTPs. Additionally, the concentration of n-Ag-Ps in effluent was determined through two different methods that are presented here: novel ionic exchange resin (IER) and cloud point extraction (CPE) methods. The n-Ag-Ps concentrations in influent were all low (<1.5 MUg/L) and decreased (average removal efficiency of ~35%) significantly after mechanical treatment, indicating that the mechanical treatment contributes to the n-Ag-Ps removal. Afterward, more than 72% of the remaining n-Ag-Ps in the semi-treated wastewater (i.e., wastewater after mechanical treatment) were reduced by biological treatment. Together, these processes reduced 95% of the n Ag-Ps that entered WWTPs, which resulted in low concentration of n-Ag-Ps in the effluents (<12 ng/L). For a WWTP with 520,000 t/d treatment capacity, we estimated that the daily n-Ag-Ps load in effluent discharge equated to about 4.4 g/d. Obviously, WWTPs are not potential point sources for n-Ag-Ps in the aquatic environment. PMID- 23750459 TI - Combining imagination and reason in the treatment of depression: a randomized controlled trial of internet-based cognitive-bias modification and internet-CBT for depression. AB - OBJECTIVE: Computerized cognitive-bias modification (CBM) protocols are rapidly evolving in experimental medicine yet might best be combined with Internet-based cognitive behavioral therapy (iCBT). No research to date has evaluated the combined approach in depression. The current randomized controlled trial aimed to evaluate both the independent effects of a CBM protocol targeting imagery and interpretation bias (CBM-I) and the combined effects of CBM-I followed by iCBT. METHOD: Patients diagnosed with a major depressive episode were randomized to an 11-week intervention (1 week/CBM-I + 10 weeks/iCBT; n = 38) that was delivered via the Internet with no face-to-face patient contact or to a wait-list control (WLC; n = 31). RESULTS: Intent-to-treat marginal models using restricted maximum likelihood estimation demonstrated significant reductions in primary measures of depressive symptoms and distress corresponding to medium-large effect sizes (Cohen's d = 0.62-2.40) following CBM-I and the combined (CBM-I + iCBT) intervention. Analyses demonstrated that the change in interpretation bias at least partially mediated the reduction in depression symptoms following CBM-I. Treatment superiority over the WLC was also evident on all outcome measures at both time points (Hedges gs = .59-.98). Significant reductions were also observed following the combined intervention on secondary measures associated with depression: disability, anxiety, and repetitive negative thinking (Cohen's d = 1.51-2.23). Twenty-seven percent of patients evidenced clinically significant change following CBM-I, and this proportion increased to 65% following the combined intervention. CONCLUSIONS: The current study provides encouraging results of the integration of Internet-based technologies into an efficacious and acceptable form of treatment delivery. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23750460 TI - Mechanisms of change in an exposure-based treatment for irritable bowel syndrome. AB - OBJECTIVE: The aim of this study was to identify mediators of change in a previously published randomized controlled trial that compared Internet-delivered cognitive behavioral treatment based on exposure exercises (ICBT) with Internet delivered stress management (ISM) for irritable bowel syndrome (IBS). ICBT and ISM targeted distinct proposed mechanisms of illness maintenance and symptom exacerbation, gastrointestinal symptom-specific anxiety (GSA), and stress reactivity, respectively. The original study found that ICBT was more effective than ISM in improving IBS symptoms. METHOD: Weekly measurements of GSA and stress reactivity (putative mediators) and treatment outcome were obtained from 195 participants with IBS, who had been randomized to ICBT or ISM. RESULTS: Parallel process growth mediational analyses revealed that the larger reduction of IBS symptoms from ICBT compared to ISM was mediated by changes in GSA, alphabeta = 0.42, 95% CI asymmetric [-0.71, -0.16]. In contrast, changes in stress reactivity did not mediate the difference in outcomes between treatments, alphabeta = 0.04, 95% CI asymmetric [-0.09, 0.20]. Analyses of the temporal sequence of week-to week changes in process and outcome measures showed that only GSA displayed a pattern consistent with a causal model in which change in process preceded and contributed to symptom change. Furthermore, engagement in treatment specific activities was related to change in GSA but not to stress reactivity in the ICBT arm, whereas treatment specific activities were not related to change in any of the putative processes in the ISM arm. CONCLUSIONS: We conclude that ICBT works through directly targeting GSA, rather than by means of reducing stress reactivity. PMID- 23750461 TI - Emotional congruence with children and sexual offending against children: a meta analytic review. AB - OBJECTIVE: Emotional congruence with children is an exaggerated affective and cognitive affiliation with children that is posited to be involved in the initiation and maintenance of sexual offending against children. The current meta analysis examined the relationship between emotional congruence with children and sexual offending against children, sexual recidivism, and change following sexual offender treatment. METHOD: A systematic literature review of online academic databases, conference proceedings, governmental agency websites, and article, book chapter, and book reference lists was performed. Thirty studies on emotional congruence with children in sexual offenders against children (SOC) were included in a random-effects meta-analysis. RESULTS: Extrafamilial SOC-especially those with male victims--evidenced higher emotional congruence with children than most non--SOC comparison groups and intrafamilial SOC. In contrast, intrafamilial SOC evidenced less emotional congruence with children than many of the non-SOC comparison groups. Higher levels of emotional congruence with children were associated with moderately higher rates of sexual recidivism. The association between emotional congruence with children and sexual recidivism was significantly stronger in extrafamilial SOC samples (d = 0.58, 95% CI [0.31, 0.85]) compared with intrafamilial SOC samples (d = -0.15, 95% CI [-0.58, 0.27]). Similarly, emotional congruence with children showed a significant reduction from pre- to posttreatment for extrafamilial SOC (d = 0.41, 95% CI [0.33, 0.85]), but not for intrafamilial SOC (d = 0.06, 95% CI [-0.10, 0.22]). CONCLUSIONS: Emotional congruence with children is a characteristic of extrafamilial SOC, is moderately predictive of sexual recidivism, and is potentially amenable through treatment efforts. PMID- 23750462 TI - Detecting critical decision points in psychotherapy and psychotherapy + medication for chronic depression. AB - OBJECTIVE: We sought to quantify clinical decision points for identifying depression treatment nonremitters prior to end-of-treatment. METHOD: Data came from the psychotherapy arms of a randomized clinical trial for chronic depression. Participants (n = 352; 65.6% female; 92.3% White; mean age = 44.3 years) received 12 weeks of cognitive behavioral analysis system of psychotherapy (CBASP) or CBASP plus an antidepressant medication. In half of the sample, receiver operating curve analyses were used to identify efficient percentage of symptom reduction cut points on the Inventory of Depressive Symptoms-Self-Report (IDS-SR) for predicting end-of-treatment nonremission based on the Hamilton Rating Scale for Depression (HRSD). Sensitivity, specificity, predictive values, and Cohen's kappa for identified cut points were calculated using the remaining half of the sample. RESULTS: Percentage of IDS-SR symptom reduction at Weeks 6 and 8 predicted end-of-treatment HRSD remission status in both the combined treatment (Week 6 cut point = 50.0%, Cohen's kappa = .42; Week 8 cut point = 54.3%, Cohen's kappa = .45) and psychotherapy only (Week 6 cut point = 60.7%, Cohen's kappa = .41; Week 8 cut point = 48.7%, Cohen's kappa = .49). Status at Week 8 was more reliable for identifying nonremitters in psychotherapy-only treatment. CONCLUSIONS: Those with chronic depression who will not remit in structured, time-limited psychotherapy for depression, either with therapy alone or in combination with antidepressant medication, are identifiable prior to end of treatment. Findings provide an operationalized strategy for designing adaptive psychotherapy interventions. PMID- 23750463 TI - Relationship of childhood trauma to depression and smoking outcomes in pregnant smokers. AB - OBJECTIVE: We evaluated whether childhood trauma moderated the treatment effect on depression and smoking outcomes in pregnant smokers. METHOD: The sample included pregnant smokers participating in a randomized trial evaluating the efficacy of a 10-session interpersonally focused therapy-cognitive behavioral analysis system of psychotherapy (CBASP)-versus a time-matched health and wellness control (HW) for smoking cessation and depression reduction. Women (N = 248) who completed the Childhood Trauma Questionnaire (CTQ) were included. On average, women were 25 years old (SD = 5.91) and smoked 10 (SD = 6.9) cigarettes per day. Depressive symptoms were assessed with the Center for Epidemiological Studies Depression Scale (CES-D), and women had an average score of 21 (SD = 11.03). Seventy-six percent of women had experienced some form of moderate to severe childhood trauma as assessed by the CTQ. RESULTS: In women with a history of moderate to severe childhood trauma, there was a dose-response association of treatment on depression outcome through 6 months postpartum; those with increasing amounts of childhood trauma benefitted more from CBASP, whereas those in the HW condition did not. Childhood trauma did not moderate the treatment effect on abstinence, although increasing amounts of trauma were associated with reduced likelihood of abstinence at 6 months posttreatment. CONCLUSIONS: An interpersonally focused therapy may be beneficial for the treatment of depression during the prenatal period in pregnant smokers with childhood trauma histories, and such treatment becomes increasingly more important with cumulative trauma experience. Childhood trauma increases risk for cessation failure in pregnant smokers. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23750464 TI - Indicated prevention for college student marijuana use: a randomized controlled trial. AB - OBJECTIVE: Marijuana is the most frequently reported illicit substance used on college campuses. Despite the prevalence, few published intervention studies have focused specifically on addressing high-risk marijuana use on college campuses. The present study evaluated the efficacy of an in-person brief motivational enhancement intervention for reducing marijuana use and related consequences among frequently using college students. METHOD: Participants included 212 college students from 2 campuses who reported frequent marijuana use (i.e., using marijuana at least 5 times in the past month). Participants completed Web-based screening and baseline assessments and upon completion of the baseline survey were randomized to either an in-person brief intervention or an assessment control group. Follow-up assessments were completed approximately 3 and 6 months post-baseline. Marijuana use was measured by number of days used in the past 30 days, typical number of joints used in a typical week in the last 60 days, and marijuana-related consequences. RESULTS: Results indicated significant intervention effects on number of joints smoked in a typical week and a trend toward fewer marijuana-related consequences compared with the control group at 3 month follow-up. CONCLUSION: This study provides preliminary data on short-term effects of a focused marijuana intervention for college students at reducing marijuana use during the academic quarter. PMID- 23750465 TI - Who gets the most out of cognitive behavioral therapy for anxiety disorders? The role of treatment dose and patient engagement. AB - OBJECTIVE: The present study explored treatment dose and patient engagement as predictors of treatment outcome in cognitive behavioral therapy (CBT) for anxiety disorders. METHOD: Measures of high versus low treatment dose and high versus low patient engagement in CBT were compared as predictors of 12- and 18-month outcomes for patients being treated for anxiety disorders with CBT (with or without concurrent pharmacotherapy) in primary care settings as part of a randomized controlled effectiveness trial of the Coordinated Anxiety Learning and Management (CALM) intervention. Measures of dose (attendance, exposure completion) and engagement in CBT (homework adherence, commitment) were collected throughout treatment, and blinded follow-up phone assessments of outcome measures (12-item Brief Symptom Inventory, Patient Health Questionnaire 8, Sheehan Disability Scale) were completed at 12 and 18 months. Propensity score weighting controlled for baseline differences in demographics and symptom severity between patients with high and low dose and engagement. These analyses included the 439 patients who selected CBT as treatment modality. RESULTS: Completing exposures, having high attendance, and being more adherent to completing homework predicted better outcomes across all measures at 12 and 18 months, and high CBT commitment predicted better outcomes on all measures at 18 months. CONCLUSIONS: This study found that higher treatment dose and patient engagement in CBT for anxiety disorders were stable and robust predictors of greater reductions in anxiety symptoms, depression symptoms, and functional disability. PMID- 23750466 TI - Fifteen-year follow-up of a randomized trial of a preventive intervention for divorced families: effects on mental health and substance use outcomes in young adulthood. AB - OBJECTIVE: This 15-year follow-up assessed the effects of a preventive intervention for divorced families, the New Beginnings Program (NBP), versus a literature control condition (LC). METHOD: Mothers and their 9- to 12-year-olds (N = 240 families) participated in the trial. Young adults (YAs) reported on their mental health and substance-related disorders, mental health and substance use problems, and substance use. Mothers reported on YA's mental health and substance use problems. Disorders were assessed over the past 9 years (since previous follow-up) and 15 years (since program entry). Alcohol and marijuana use, other substance use and polydrug use, and mental health problems and substance use problems were assessed over the past month, past year, and past 6 months, respectively. RESULTS: YAs in NBP had a lower incidence of internalizing disorders in the past 9 years (7.55% vs. 24.4%; odds ratio [OR] = .26) and 15 years (15.52% vs. 34.62%; OR = .34) and had a slower rate of onset of internalizing symptoms associated with disorder in the past 9 years (hazard ratio [HR] = .28) and 15 years (HR = .46). NBP males had a lower number of substance related disorders in the past 9 years (d = 0.40), less polydrug (d = 0.55) and other drug use (d = 0.61) in the past year, and fewer substance use problems (d = 0.50) in the past 6 months than LC males. NBP females used more alcohol in the past month (d = 0.44) than LC females. CONCLUSIONS: NBP reduced the incidence of internalizing disorders for females and males and substance-related disorders and substance use for males. PMID- 23750467 TI - Posttraumatic stress and posttraumatic growth among low-income mothers who survived Hurricane Katrina. AB - OBJECTIVE: The purpose of the study was to explore the relationship between posttraumatic stress (PTS) and posttraumatic growth (PTG) after Hurricane Katrina, and the role of demographics, predisaster psychological distress, hurricane-related stressors, and psychological resources (optimism and purpose) in predicting each. METHOD: Participants were 334 low-income mothers (82.0% non Hispanic Black) living in the New Orleans area prior to Hurricane Katrina, who completed surveys in the year prior to the hurricane (T1 [Time 1]) and 1 and 3 years thereafter (T2 and T3). RESULTS: Higher T2 and T3 PTS full-scale and symptom cluster subscales (Intrusion, Avoidance, and Hyperarousal) were significantly associated with higher T3 PTG, and participants who surpassed the clinical cutoff for probable posttraumatic stress disorder at both T2 and T3 had significantly higher PTG than those who never surpassed the clinical cutoff. Older and non-Hispanic Black participants, as well as those who experienced a greater number of hurricane-related stressors and bereavement, reported significantly greater T3 PTS and PTG. Participants with lower T2 optimism reported significantly greater T3 intrusive symptoms, whereas those with higher T1 and T2 purpose reported significantly greater T3 PTG. CONCLUSIONS: Based on the results, we suggest practices and policies with which to identify disaster survivors at greater risk for PTS, as well as longitudinal investigations of reciprocal and mediational relationships between psychological resources, PTS, and PTG. PMID- 23750469 TI - MR neurography in diagnosing nondiabetic lumbosacral radiculoplexus neuropathy. AB - Here we describe the imaging findings in a 73-year-old woman who had pain in the right inguinal region, followed by progressive weakness of muscles innervated by the right femoral and obturator nerves, diagnosed as nondiabetic lumbosacral radiculoplexus neuropathy. Magnetic resonance neurography showed thickening and increase in signal intensity of the right femoral and obturator nerves. PMID- 23750468 TI - The therapeutic relationship in cognitive-behavioral therapy and pharmacotherapy for anxious youth. AB - OBJECTIVE: We examined the therapeutic relationship with cognitive-behavioral therapists and with pharmacotherapists for youth from the Child/Adolescent Anxiety Multimodal Study (Walkup et al., 2008). The therapeutic relationship was examined in relation to treatment outcomes. METHOD: Participants were 488 youth (ages 7-17 years; 50% male) randomized to cognitive-behavioral therapy (CBT; Coping Cat), pharmacotherapy (sertraline), their combination, or placebo pill. Participants met criteria for generalized anxiety disorder, social phobia, and/or separation anxiety disorder according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994). The therapeutic relationship was assessed by youth report at Weeks 6 and 12 of treatment using the Child's Perception of Therapeutic Relationship scale (Kendall et al., 1997). Outcome measures (Pediatric Anxiety Rating Scale; Research Units on Pediatric Psychopharmacology Anxiety Study Group, 2002; and Clinical Global Impressions Scales; Guy, 1976) were completed by independent evaluators blind to condition. RESULTS: For youth who received CBT only, a stronger therapeutic relationship predicted positive treatment outcome. In contrast, the therapeutic relationship did not predict outcome for youth receiving sertraline, combined treatment, or placebo. CONCLUSION: A therapeutic relationship may be important for anxious youth who receive CBT alone. PMID- 23750470 TI - Theoretical and experimental insights into the origin of the catalytic activity of subnanometric gold clusters: attempts to predict reactivity with clusters and nanoparticles of gold. AB - Particle size is one of the key parameters determining the unexpected catalytic activity of gold, with reactivity improving as the particle gets smaller. While this is valid in the 1-5 nm range, chemists are now investigating the influence of particle size in the subnanometer regime. This is due to recent advances in both characterization techniques and synthetic routes capable of stabilizing these size-controlled gold clusters. Researchers reported in early studies that small clusters or aggregates of a few atoms can be extremely active in some reactions, while 1-2 nm nanoparticles are catalytically more efficient for other reactions. Furthermore, the possibility that small gold clusters generated in situ from gold salts or complexes could be the real active species in homogeneous gold-catalyzed organic reactions should be considered. In this Account, we address two questions. First, what is the origin of the enhanced reactivity of gold clusters on the subnanometer scale? And second, how can we predict the reactions where small clusters should work better than larger nanoparticles? Both geometric factors and electronic or quantum size effects become important in the subnanometer regime. Geometric reasons play a key role in hydrogenation reactions, where only accessible low coordinated neutral Au atoms are needed to dissociate H2. The quantum size effects of gold clusters are important as well, as clusters formed by only a few atoms have discrete molecule-like electronic states and their chemical reactivity is related to interactions between the cluster's frontier molecular orbitals and those of the reactant molecules. From first principles calculations, we predict an enhanced reactivity of small planar clusters for reactions involving activation of CC multiple bonds in alkenes and alkynes through Lewis acid-base interactions, and a better catalytic performance of 3D gold nanoparticles in redox reactions involving bond dissociation by oxidative addition and new bond formation by reductive elimination. In oxidation reactions with molecular O2, initial dissociation of O2 into basic oxygen atoms would be more effectively catalyzed by gold nanoparticles of ~1 nm diameter. In contrast, small planar clusters should be more active for reactions following a radical pathway involving peroxo or hydroperoxo intermediates. We have experimentally confirmed these predictions for a series of Lewis acid and oxidation reactions catalyzed by gold clusters and nanoparticles either in solution or supported on solid carriers. PMID- 23750472 TI - Novel anti-c-Mpl monoclonal antibodies identified multiple differentially glycosylated human c-Mpl proteins in megakaryocytic cells but not in human solid tumors. AB - Thrombopoietin and its cognate receptor, c-Mpl, are the primary molecular regulators of megakaryocytopoiesis and platelet production. To date the pattern of c-Mpl expression in human solid tumors and the distribution and biochemical properties of c-Mpl proteins in hematopoietic tissues are largely unknown. We have recently developed highly specific mouse monoclonal antibodies (MAb) against human c-Mpl. In this study we used these antibodies to demonstrate the presence of full-length and truncated human c-Mpl proteins in various megakaryocytic cell types, and their absence in over 100 solid tumor cell lines and in the 12 most common primary human tumor types. Quantitative assays showed a cell context dependent distribution of full-length and truncated c-Mpl proteins. All forms of human c-Mpl protein were found to be modified with extensive N-linked glycosylation but different degrees of sialylation and O-linked glycosylation. Of note, different variants of full-length c-Mpl protein exhibiting differential glycosylation were expressed in erythromegakaryocytic leukemic cell lines and in platelets from healthy human donors. This work provides a comprehensive analysis of human c-Mpl mRNA and protein expression on normal and malignant hematopoietic and non-hematopoietic cells and demonstrates the multiple applications of several novel anti-c-Mpl antibodies. PMID- 23750473 TI - Surrogate antibodies that specifically bind and neutralize CCL17 but not CCL22. AB - The chemokines CCL17 (TARC) and CCL22 (MDC) function through the same receptor, CCR4, but have been proposed to differentially affect the immune response. To better understand the role of the individual ligands, a panel of rat anti-mouse CCL17 surrogate antibodies was generated that can be used to differentiate CCL17 and CCL22 function in vitro and in vivo. We have successfully identified a panel of neutralizing antibodies by screening hybridomas for the ability to inhibit CCL17-mediated calcium mobilization. Chemotaxis in response to CCL17 is also inhibited, providing further evidence that the antibodies in this panel are antagonistic. Using a recombinant cell line expressing human CCR4, we show that the antibodies block beta-arrestin recruitment as evidence that the antibodies are specifically blocking CCL17 signaling through CCR4. The antibodies within this panel inhibit calcium mobilization with varying potency in the calcium flux assay, having apparent IC50 ranging from approximately 1 to >400 ng/mL. Although both CCL17 and CCL22 function through CCR4, only a single antibody was identified as having detectable binding to CCL22. This panel of CCL17-specific antibodies provides tools that can be used to differentiate CCL17 and CCL22 function through CCR4 interaction in vitro and in vivo. PMID- 23750474 TI - Production and characterization of recombinant scFv against digoxin by phage display technology. AB - The cardiac glycoside digoxin is widely used for the treatment of congestive heart failure and cardiac arrhythmias. Digoxin is a highly toxic drug and consequently is routinely measured in sera of treated patients. In such cases, antibodies are required against digoxin for detection as well as detoxification purposes. To obtain recombinant single chain antibody against digoxin, RNA was extracted from spleen of BALB/c mice immunized with digoxin-BSA and converted to cDNA. The gene fragment corresponding to the variable regions of the repertoire of antibody genes were amplified by PCR. ScFv construct was generated by randomly joining individual heavy- and light-chain variable domains through gene splicing by overlapping extension PCR. Recombinant phage library expressing scFv polypeptides were produced. Phages with higher affinity toward digoxin were selected in the biopanning process. Sensitivity of produced recombinant MAb (AR85) was determined to be about 100 pg/well, while intact MAb (BBA) produced by hybridoma technology (data not shown) was reported to be around 100 pg/well too. The saturation value for recombinant scFv MAb was found to be 1000 ng/well while that for hybridoma MAb was reported to be 10 ng/well. The affinity constant of recombinant MAb (AR85) towards digoxin was also found to be around ka=3.8*10(7) M(-1) while that for hybridoma MAb (BBA) was reported to be ka=2.6*10(8) M(-1). PMID- 23750471 TI - Sex-based differences in cardiac ischaemic injury and protection: therapeutic implications. AB - Ischaemic heart disease (IHD) is the most frequent cause of mortality among men and women. Many epidemiological studies have demonstrated that premenopausal women have a reduced risk for IHD compared with their male counterparts. The incidence of IHD in women increases after menopause, suggesting that IHD is related to declining oestrogen levels. Experimental observations have confirmed the results of epidemiological studies investigating sex-specific differences in cardiac tolerance to ischaemia. Female sex appears also to favourably influence cardiac remodelling after ischaemia/reperfusion injury. Furthermore, sex-related differences in ischaemic tolerance of the adult myocardium can be influenced by interventions during the early phases of ontogenetic development. Detailed mechanisms of these sex-related differences remain unknown; however, they involve the genomic and non-genomic effects of sex steroid hormones, particularly the oestrogens, which have been the most extensively studied. Although the protective effects of oestrogen have many potential therapeutic implications, clinical trials have shown that oestrogen replacement in postmenopausal women may actually increase the incidence of IHD. The results of these trials have illustrated the complexity underlying the mechanisms involved in sex-related differences in cardiac tolerance to ischaemia. Sex-related differences in cardiac sensitivity to ischaemia/reperfusion injury may also influence therapeutic strategies in women with acute coronary syndrome. Women undergo coronary intervention less frequently and a lower proportion of women receive evidence-based therapy compared with men. Although our understanding of this important topic has increased in recent years, there is an urgent need for intensive experimental and clinical research to develop female-specific therapeutic strategies. Only then we will be able to offer patients better evidence-based treatment, a better quality of life and lower mortality. PMID- 23750475 TI - Characterization of monoclonal antibodies against a human chondrocyte surface antigen. AB - Chondrocytes express a number of cell-surface molecules that mediate cell-cell or cell-matrix interactions. Identification and full characterization of new chondrocyte surface molecules will lead to a better understanding of the function of the chondrocyte. Researchers used primary human chondrocytes as an immunogen, and various monoclonal antibodies (MAbs) were generated using standard hybridoma technology. A monoclonal antibody named 5D2 was selected for further characterization. The antigen recognized by 5D2 MAb is expressed by primary human chondrocytes, primary synovial fibroblasts, synovial fibroblast cell lines (SW982), primary skin fibroblasts, and osteoblasts, but not expressed in blood cells. Biochemical analysis revealed that the 5D2 antigen is a protein with a molecular weight of approximately 25-35 kDa. Protein identification by mass spectrometry and molecular cloning revealed that 5D2 antigen is identical to the Thy-1 molecule. Furthermore we confirmed this specificity of the antibody by the isolated and cloned Thy-1 gene to the COS-7 and probed it with the 5D2 antibody using Western blot analysis. We examined the role of the Thy-1 molecule in arthritis models and tissue; one was papain-induced rat arthritis, the other was immunohistological staining of osteoarthritic (OA) human articular cartilage. OA cartilage showed a higher expression of Thy-1 as compared with normal tissue in all experimental approaches. The in vitro studies showed that the inflammatory cytokine interleukin-1beta up-regulated Thy-1 molecule expression in the cartilage tissue. It can be concluded that the Thy-1 might be a potential biomarker for cartilage pathogenesis, degradation, and metabolic turnover. PMID- 23750476 TI - Phage display generation of a novel humanized single-chain antibody against brain natriuretic peptide with potent neutralizing activity. AB - Cerebral salt wasting syndrome (CSW) is defined as a renal loss of sodium and water during intracranial disease leading to hyponatremia, which is the most frequent electrolyte disorder in critically neurological patients. Abnormal brain natriuretic peptide (BNP) secretion is implicated as the main offender. Development of antagonist against BNP is therefore of potential clinical relevance. In this study, synthetic human BNP peptide (hBNP) was used as bait and a humanized single chain fragment variable (scFv) phage antibody library as the source of antagonists. After three rounds of biopanning, hBNP-specific phage clones were greatly enriched. The scFv gene from the best phage clone was inserted into pET-22b and expressed in Escherichia coli BL21 (DE3) PlysS cells. After purification by nickel-affinity and refolding, this scFv antibody (Ab) was proven to recognize hBNP specifically and sensitively in ELISA and dot-blotting assay. Its binding constant to hBNP was 1.98*10(-8) M, measured by surface plasmon resonance. Thus, the humanized scFv Ab prepared with this approach has potential therapeutic value for neutralizing abnormally high level of BNP correlated well with CSW. PMID- 23750477 TI - Polyclonal and monoclonal antibodies specific for ubiquitin-specific protease 20. AB - Ubiquitination and deubiquitination are important processes for numerous intracellular mechanisms, and the imbalance of these two processes can cause severe diseases including cancer. Accordingly, deubiquitinating enzymes (DUBs) responsible for deubiquitination from their protein substrates become attractive targets for many studies. USP20, also known as VDU2, belongs to ubiquitin specific protease (USP) subfamily of DUBs and has several important roles in cells as shown with other DUBs. USP20 stabilizes HIF-1alpha by abolishing von Hippel-Lindau protein (pVHL)-E3 ligase complex-mediated HIF-1alpha degradation. USP20 is also associated with beta2 adrenergic receptor recycling. In addition, a previous study demonstrated that USP20 regulates Tax-induced NF-kappaB activation through its deubiquitinating activity. These studies provide a line of evidence that USP20 has critical roles in cellular functions. In this study, we generated and characterized a polyclonal and two monoclonal antibodies against USP20. It is feasible that USP20 antibodies can be useful to investigate USP20-related cellular mechanisms and to find novel substrates of USP20. PMID- 23750478 TI - Monoclonal antibodies against tyrosyl-tRNA synthetase and its isolated cytokine like domain. AB - Tyrosyl-tRNA synthetase (TyrRS) is one of the key enzymes of protein biosynthesis. In addition to its basic role, this enzyme reveals some important non-canonical functions. Under apoptotic conditions, the full-length enzyme splits into two fragments having distinct cytokine activities, thereby linking protein synthesis to cytokine signaling pathways. The NH2-terminal catalytic fragment, known as miniTyrRS, binds strongly to the CXC-chemokine receptor CXCR1 and, like interleukin 8, functions as a chemoattractant for polymorphonuclear leukocytes. On the other hand, an extra COOH-terminal domain of human TyrRS has cytokine activities like those of a mature human endothelial monocyte-activating polypeptide II (EMAP II). Moreover, the etiology of specific diseases (cancer, neuronal pathologies, autoimmune disorders, and disrupted metabolic conditions) is connected to specific aminoacyl-tRNA synthetases. Here we report the generation and characterization of monoclonal antibodies specific to N- and C terminal domains of TyrRS. Recombinant TyrRS and its N- and C-terminal domains were expressed as His-tag fusion proteins in bacteria. Affinity purified proteins have been used as antigens for immunization and hybridoma cell screening. Monoclonal antibodies specific to catalytic N-terminal module and C-terminal EMAP II-like domain of TyrRS may be useful as tools in various aspects of TyrRS function and cellular localization. PMID- 23750479 TI - Monoclonal antibodies directed against chicken beta2-microglobulin developed with a synthesized peptide. AB - We developed a panel of monoclonal antibodies (MAb) against chicken beta2 microglobulin (chbeta2M) by fusions between SP2/0 myeloma cells and spleen cells from mice immunized with a synthesized peptide corresponding to positions 91-119 of the COOH domain of chbeta2M. Two of them, 6E7 and 3D1, identified as IgG1/kappa, could react with chbeta2M protein from avian macrophage HD11 cells and human 293T cells transfected with pcDNA3.1-chbeta2M in immunofluorescence assays. Only a 12 kDa protein band of chbeta2M could be detected in the HD11 and 293T/chbeta2M cell lysates by Western blot analysis. Chicken beta2M in serum and plasma could be found in Western blot by MAb 3D1. Moreover, MAb 3D1 also recognized the chbeta2M antigen on the cell membranes in flow cytometry. Immunohistochemical staining with these MAbs revealed that chbeta2M was present in chicken thymus, spleen, and bursa. These MAbs will be good tools for analyzing the mechanism of the chicken immune system. PMID- 23750480 TI - Polyclonal antibody against conserved peptide in transmembrane protein of avian leukosis virus subgroup J. AB - The ALV-J gp37 pocket region located in transmembrane (TM) protein is an ideal viral target because it is extracellular, highly conserved, and essential for viral entry. Although it has been a target of drug and vaccine design, there are not any polyclonal antibody tools to specifically probe the antigenicity and immunogenicity of the pocket region. Our goal was to elicit a neutralizing polyclonal antibody that targets this pocket region. A conserved peptide designated R73 that is derived from the pocket region of TM of ALV-J was synthesized. New Zealand rabbits were immunized with R73 conjugated with keyhole limpet hemocyanin (KLH), and the antiserum was gained 10 days after the third immunity boost. The antibody titers were tested by endpoint ELISA, and the specificity and affinity were tested by Western blot analysis. The results showed that R73 has good antigenicity (antibody titers~1:64,000~1:128,000), immunogenicity, and affinity. The results of the indirect fluorescent assay (IFA) and real-time RT-PCR test showed that R73 polyclonal antibody can recognize ALV-J antigen and completely inhibit viral replication in DF-1 cells. The results of the neutralization assay showed that neutralization titer of the antiserum was 1:16. Therefore, a polyclonal antibody against the neutralizing epitope on an existing pocket region may be a useful tool in ALV-J diagnosis or for preventing infection. PMID- 23750481 TI - Generation and characterization of two novel monoclonal antibodies produced against human TLT-2 molecule. AB - Trem-like transcript 2 (TLT-2), one of the TREM family members, which is expressed on B cells, T cells, and macrophages, plays a critical role in immune response mechanism. In this study, two novel mouse anti-human TLT-2 monoclonal antibodies (MAbs) were prepared using hybridoma technology and their immunological characteristics were determined. The results showed that the two MAbs (clones 10F5 and 8C10) were both IgG1 (kappa) and bound specifically to human TLT-2. Furthermore, 10F5 and 8C10 seemed to recognize a different site (epitope) of TLT-2 by competition assay. MAb 10F5 was proven in Western blot analysis to specifically bind to denatured TLT-2 protein while both MAbs were proven in dot blot analyses and immunofluorescence to specifically bind to natural TLT-2 protein. In addition, crosslinking of TLT-2 with MAb 8C10 markedly blocked TLT-2 positive signal and T cell proliferation. Taken together, these two monoclonal antibodies might be of great value as tools for further exploration of the expression and function of TLT-2. PMID- 23750482 TI - Novel monoclonal antibodies GMab-r1 and LMab-1 specifically recognize IDH1-R132G and IDH1-R132L mutations. AB - Isocitrate dehydrogenase 1 (IDH1) catalyzes the oxidative carboxylation of isocitrate to alpha-ketoglutarate in cytosol. IDH1 mutations, which are specific to a single codon in the conserved and functionally important Arginine 132 (R132), result in the ability of the enzyme to catalyze the reduced NADP dependent reduction of alpha-ketoglutarate to onco-metabolite R(-)-2 hydroxyglutarate (2-HG). IDH1 mutations, which are early and frequent genetic alterations that occur in gliomas, cartilaginous tumors, and leukemias. We previously established two monoclonal antibodies (MAbs) that are specific for IDH1 mutations: clone HMab-1 against IDH1-R132H and clone SMab-1 against IDH1 R132S. However, specific MAbs against IDH1-R132G or IDH1-R132L have not been reported. To establish IDH1-R132G-specific or IDH1-R132L-specific MAbs, we immunized rats with each mutation-containing IDH1 peptides, and IDH1-R132G specific or IDH1-R132L-specific MAbs were screened in ELISA. Established MAb GMab r1 reacted with the IDH1-R132G peptide, but not with IDH1-wild type (WT) in ELISA. In contrast, LMab-1 reacted with the IDH1-R132L peptide, but not with IDH1 WT. Western blot analysis also showed that GMab-r1 and LMab-1 reacted with the IDH1-R132G and IDH1-R132L recombinant proteins, respectively, but not with IDH1 WT or other IDH1 mutants, indicating that GMab-r1 and LMab-1 are IDH1-mutation specific. Furthermore, GMab-r1 and LMab-1 specifically stained the IDH1-R132G- and IDH1-R132L-expressing cells in immunocytochemistry, respectively. This is the first report to establish anti-IDH1-R132G-specific or IDH1-R132L-specific MAbs, which could be useful in the diagnosis of mutation-bearing tumors. PMID- 23750483 TI - Production of a monoclonal antibody specific for Pou5f1/Oct4. AB - Pou5f1/Oct4, a member of the POU transcription factor family, is exclusively expressed in embryonic stem cells, which are involved in self-renewal and maintaining pluripotency. In the present study, we report on the establishment of a monoclonal antibody that is specific for Oct4 using the rat medial iliac lymph node method. In an immunoblotting analysis, our antibody detected endogenous Oct4. In addition, immunocytochemical staining using the antibody revealed the nuclear localization of Oct4. This monoclonal antibody has the potential for use in the further analysis of Oct4 function in stem cells. PMID- 23750489 TI - Risk of oral antifungal agent-induced liver injury in Taiwanese. AB - AIM: Oral antifungal agent-induced liver injury is a common safety concern that may lead to patients' hesitation in treating fungal infections such as onychomycosis. This study evaluated risk of drug-induced liver injury (DILI) caused by oral antifungal agents in Taiwanese populations. METHODS: A population based study was conducted by analyzing who used oral antifungal agents from 2002 to 2008 from the Taiwan National Health Insurance Database. A comparison control group was randomly extracted from the remainder of the original cohort. RESULTS: Of the 90,847 oral antifungal agents users, 52 patients had DILI. Twenty-eight DILI cases used ketoconazole, 12 fluconazole, eight griseofulvin, three itraconazole and two terbinafine. The incidence rates (IR) of DILI per 10,000 persons were 31.6, 4.9, 4.3, 3.6 and 1.6 for fluconazole, ketoconazole, griseofulvin, itraconazole and terbinafine, respectively. Longer exposure duration increased the risk of DILI, with IR for exposure duration >= 60 defined daily dose (DDD) of 170.9, 62.5, and 36.1 per 10,000 persons for ketoconazole, itraconazole and terbinafine, respectively. Patients taking antifungal agents had higher incidences of developing DILI compared with those in the control group after adjusting for age, gender and co-morbidities (relative risk 2.38, P < 0.001). All of the six patients with fatal DILI used fluconazole. Old age and fluconazole increased the risk of oral antifungal-induced fatal DILI. CONCLUSIONS: Oral antifungal agents are associated with low incidence of acute liver injury, but which may be fatal, especially for the elderly. Longer treatment duration may increase the risk of antifungal agent-induced liver injury, especially ketoconazole. PMID- 23750490 TI - A systematic review of two-stage hepatectomy in patients with initially unresectable colorectal liver metastases. AB - OBJECTIVES: Selected patients with unresectable colorectal liver metastases (CLM) may be rendered resectable using the two-stage hepatectomy (TSH) approach. This review was conducted with the aim of collating and evaluating published evidence for TSH in patients with initially unresectable CLM. METHODS: Searches of the MEDLINE and EMBASE databases were undertaken to identify studies of TSH in patients with initially unresectable CLM. Studies were required to focus on the perioperative treatment regimen, operative strategy, morbidity, technical success and survival outcomes. RESULTS: Ten observational studies were reviewed. A total of 459 patients with initially unresectable CLM were selected for the first stage of TSH. Preoperative chemotherapy was used in 88% of patients and achieved partial and stable response rates of 59% and 39%, respectively. Postoperative morbidity and mortality after the first stage of TSH were 17% and 0.5%, respectively. Portal vein embolization (PVE) was used in 76% of patients. Ultimately, 352 of the initial 459 (77%) patients underwent the second stage of TSH. Major liver resection was undertaken in 84% of patients; the negative margin (R0) resection rate was 75%. Postoperative morbidity and mortality after the second stage of TSH were 40% and 3%, respectively. Median overall survival was 37 months (range: 24-44 months) in patients who completed both stages of TSH. In patients who did not complete both stages of TSH, median survival was 16 months (range: 10-29 months). The 3-year disease-free survival rate was 20% (range: 6 27%). CONCLUSIONS: Two-stage hepatectomy is safe and effective in selected patients with initially unresectable CLM. Further studies are required to better define patient selection criteria for TSH and the exact roles of PVE and preoperative and interval chemotherapy. PMID- 23750491 TI - Systematic review and meta-analysis of the role of vascular resection in the treatment of hilar cholangiocarcinoma. AB - BACKGROUND: The management of hilar cholangiocarcinoma has evolved over time and extended liver resection, including the caudate lobe, and major vascular resection and extended lymphadenectomy have become established practice. The benefit of vascular resection has not been investigated. METHODS: A systematic search of the MEDLINE and EMBASE databases was used to identify studies. A systematic review and a meta-analysis of the available studies were conducted according to PRISMA guidelines. Odds ratios were calculated using the Mantel Haenszel method. Primary outcome variables assessed included morbidity, mortality, vascular complications and the effect of vascular resection on longterm survival. RESULTS: Of 411 search results, only 24 studies reported the results of vascular resection in hilar cholangiocarcinoma. Meta-analysis showed increased morbidity and mortality with hepatic artery resection. Portal vein resection was achievable with no impact on postoperative mortality. Vascular resection did not improve negative margin rates and had no impact on longterm survival. CONCLUSIONS: Portal vein resection does not preclude curative resection; however, it is not routinely recommended unless there is suspicion of tumour invasion. There was no proven survival advantage with portal vein resection. Arterial resection results in higher morbidity and mortality with no proven benefit. PMID- 23750492 TI - Obesity portends increased morbidity and earlier recurrence following liver transplantation for hepatocellular carcinoma. AB - BACKGROUND: Obesity has been associated with poor oncologic outcomes following pancreatoduodenectomy for pancreatic cancer. However, there is a paucity of evidence on the impact of obesity on postoperative complications, oncologic outcome and survival in patients with hepatocellular carcinoma (HCC) undergoing orthotopic liver transplantation (OLT). METHODS: From a database of over 1000 patients who underwent OLT during 1996-2008, 159 patients with a diagnosis of HCC were identified. Demographic data, body mass index (BMI), perioperative parameters, recurrence and survival were obtained. Complications were grouped according to Clavien-Dindo grading (Grades I-V). RESULTS: There were increased incidences of life-threatening complications in overweight (58%) and obese (70%) patients compared with the non-obese patient group (41%) (P < 0.05). Furthermore, the incidence of recurrence of HCC was doubled in the presence of overweight (15%) and obesity (15%) compared with non-obesity (7%) (P < 0.05). Time to recurrence also decreased significantly. Differences in mean +/- standard deviation survival in the overweight (45 +/- 3 months) and obese (41 +/- 4 months) groups compared with the non-obese group (58 +/- 6 months) did not reach statistical significance. CONCLUSIONS: These findings indicate that BMI is an important surrogate marker for obesity and portends an increased risk for complications and a poorer oncologic outcome following OLT for HCC. PMID- 23750493 TI - Clinical outcomes of a percutaneous cholecystostomy for acute cholecystitis: a multicentre analysis. AB - BACKGROUND: The aim of this study was to review a series of consecutive percutaneous cholecystostomies (PC) to analyse the clinical outcomes. METHODS: All patients who underwent a PC between 2000 and 2010 were reviewed retrospectively for indications, complications, and short- and long-term outcomes. RESULTS: Fifty-three patients underwent a PC with a median age was 74 years (range 14-93). 92.4% (n = 49) of patients were American Society of Anesthesiologists (ASA) III and IV. 82% (43/53) had ultrasound-guided drainage whereas 18% (10/53) had computed tomography (CT)-guided drainage. 71.6% (n = 38) of PC's employed a transhepatic route and 28.4% (n = 15) transabdominal route. 13% (7/53) of patients developed complications including bile leaks (n = 5), haemorrhage (n = 1) and a duodenal fistula (n = 1). All bile leaks were noted with transabdominal access (5 versus 0, P = 0.001). 18/53 of patients underwent a cholecystectomy of 4/18 was done on the index admission. 6/18 cholecystectomies (33%) underwent a laparoscopic cholecystectomy and the remaining required conversion to an open cholecystectomy (67%). 13/53 (22%) patients were readmitted with recurrent cholecystitis during follow-up of which 7 (54%) had a repeated PC. 12/53 patients died on the index admission. The overall 1-year mortality was 37.7% (20/53). CONCLUSIONS: Only a small fraction of patients undergoing a PC proceed to a cholecystectomy with a high risk of conversion to an open procedure. A quarter of patients presented with recurrent cholecystitis during follow-up. The mortality rate is high during the index admission from sepsis and within the 1 year of follow-up from other causes. PMID- 23750494 TI - Does the placement of a cystic duct tube after a hepatic resection help reduce the incidence of post-operative bile leak? AB - BACKGROUND: In this retrospective study, the effects of cystic duct (C) tube use on the incidence of post-hepatectomy bile leak were assessed. METHODS: The subjects were 550 patients who underwent a hepatectomy during 1990-2011, with (n = 83) and without (n = 467) C tube drainage. The use of a C tube was based on the surgeon's choice. RESULTS: Bile leakage was observed in 44 (8%) patients, and its incidence post-operatively correlated with intrahepatic cholangiocarcinoma, parenchymal transection with forceps fracture and tie, a major hepatectomy, prolonged surgery and excessive blood loss (P < 0.050) but not with the use of a C tube. The incidence of an intra-abdominal infection was higher and the hospital stay was longer in the leak (49 days) than non-leak group (21 days, P < 0.001). ISGLS grade B and C bile leak post-hemi-hepatectomy and extended-hepatectomy were more frequent in the non-C than C tube group (P = 0.016). The duration of hospitalization was not different between the two groups; however, 7 patients in the non-C tube group had prolonged hospitalization (> 60 days) compared with none in the C tube group (P = 0.454). CONCLUSION: The usefulness of the C tube in preventing post-hepatectomy bile leak could not be confirmed; however, both bile leak requiring clinical management and long hospitalization after a major hepatectomy could be reduced with C tube use. PMID- 23750495 TI - Dynamic nature of organ failure in severe acute pancreatitis: the impact of persistent and deteriorating organ failure. AB - BACKGROUND AND AIMS: In acute pancreatitis (AP), patients with persistent organ failure [POF, duration of organ failure (OF) >=48 h] and transient organ failure (TOF, duration of OF <48 h) have different outcomes. We have compared the clinical course and outcome of patients with severe AP (SAP) with TOF and POF in the first week of hospitalization as well as the impact of change in the OF score in the first week on patient outcome. METHODS: Consecutive patients with SAP were evaluated for OF and its dynamics during the first week of hospitalization. The modified multiple organ failure score (MOFS) was used to identify OF, grade its severity and monitor its progression. The clinical course and outcome of patients were studied. RESULTS: Of 114 patients, mean age 39.2 +/- 13.7 years, 37 (32.5%) patients had no OF, 34 (29.8%) had TOF and 43(37.7%) had POF. Patients with POF had the higher infected necrosis, increased requirement for percutaneous drain placement, surgery and higher mortality as compared with those with TOF. The odds ratio for mortality with persistent and deteriorating OF was 26.2 [confidence interval (CI) 5.1-134.9] compared with only persistent OF. CONCLUSION: The dynamics of OF in the first week of SAP predicts the clinical course and outcome. Persistent and deteriorating OF indicates a poor outcome. PMID- 23750496 TI - Outcomes of central bisectionectomy for hepatocellular carcinoma. AB - BACKGROUND: Central bisectionectomy (resection of Couinaud segments IV, V and VIII) for malignant or benign disease poses a technical challenge to the surgeon but if feasible, has significant benefits in terms of conserving liver volume and options for future intervention. This study reviews a cohort of patients who underwent this procedure; outlines the indications, optimal operative technique as well as both short- and long-term outcomes. METHODS: A retrospective review of a prospectively maintained database was performed. Pre-operative clinicopathological data, operative details and post-operative outcomes including overall and disease-free survival were analysed. RESULTS: Between 1989 and 2009, 21 patients underwent a central bisectionectomy. All procedures were performed for hepatocellular carcinoma (HCC). All patients underwent a R0 resection with a median resection margin of 5 mm (1-15 mm). The 1-, 3- and 5-year disease-free survivals were 65%, 34.8% and 34.8%, and the corresponding overall survival rates were 90.5%, 66.8% and 66.8%, respectively. CONCLUSION: These data support the use of a central bisectionectomy in selected cases in the management of HCC. With the use of a meticulous operative technique and adherence to surgical oncological principles, satisfactory long-term outcomes were achievable. PMID- 23750497 TI - Portal biliopathy: is splenectomy with devascularization really effective? PMID- 23750498 TI - Pre-abortion counselling from women's point of view. AB - OBJECTIVE: The value of mandatory pre-abortion counselling for women seeking abortions has been repeatedly questioned. The aim of this study was to explore the perspectives and feelings of almost 1000 women regarding pre-abortion counselling in Flanders. METHODS: Participating women (N = 971) - all requesting an abortion at one of the five Flemish abortion centres - were offered a questionnaire prior to the counselling session and immediately afterwards. Both questionnaires measured their emotional and cognitive state as well as aspects of the content and the perceived value of the counselling session. RESULTS: Prior to the counselling, women are hesitant regarding the value of the sessions, feel distressed, yet decisive about their abortion. After the counselling session, women assign an increased value to the counselling, are very satisfied, and experience less distress and greater decisiveness. During counselling the abortion procedure (89%), the use of contraceptives (83%) and the individual decision-making process (81%) are nearly always addressed. The sessions are tailored to each woman and to the needs they expressed with regard to the content of the counselling. CONCLUSIONS: Pre-abortion counselling in Flanders is standardised as well as personalised. The women in this study positively valued it. PMID- 23750499 TI - Rabies update for Latin America and the Caribbean. PMID- 23750500 TI - Reduced-energy cranberry juice increases folic acid and adiponectin and reduces homocysteine and oxidative stress in patients with the metabolic syndrome. AB - The metabolic syndrome (MetS) comprises pathological conditions that include insulin resistance, arterial hypertension, visceral adiposity and dyslipidaemia, which favour the development of CVD. Some reports have shown that cranberry ingestion reduces cardiovascular risk factors. However, few studies have evaluated the effect of this fruit in subjects with the MetS. The objective of the present study was to assess the effect of reduced-energy cranberry juice consumption on metabolic and inflammatory biomarkers in patients with the MetS, and to verify the effects of cranberry juice concomitantly on homocysteine and adiponectin levels in patients with the MetS. For this purpose, fifty-six individuals with the MetS were selected and divided into two groups: control group (n 36) and cranberry-treated group (n 20). After consuming reduced-energy cranberry juice (0.7 litres/d) containing 0.4mg folic acid for 60 d, the cranberry-treated group showed an increase in adiponectin (P=0.010) and folic acid (P=0.033) and a decrease in homocysteine (P<0.001) in relation to baseline values and also in comparison with the controls (P<0.05). There was no significant change in the pro-inflammatory cytokines TNF-a, IL-1 and IL-6. In relation to oxidative stress measurements, decreased (P<0.05) lipoperoxidation and protein oxidation levels assessed by advanced oxidation protein products were found in the cranberry-treated group when compared with the control group. In conclusion, the consumption of cranberry juice for 60 d was able to improve some cardiovascular risk factors. The present data reinforce the importance of the inverse association between homocysteine and adiponectin and the need for more specifically designed studies on MetS patients. PMID- 23750501 TI - Genome-wide analysis of recurrent copy-number alterations and copy-neutral loss of heterozygosity in head and neck squamous cell carcinoma. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the eighth most commonly diagnosed malignancy worldwide, and it is generally characterized by a poor prognosis. The aim of our study has been to identify possible recurring genomic abnormalities in this malignancy, likely to have a key role in pathogenesis. METHODS: The single-nucleotide polymorphism (SNP)-array data relative to 19 HNSCC samples (submitted by Poage et al., PloS ONE 2010; 5: e9651), accessible at NCBI GEO database (GSE20939), were analyzed using criteria that take into account both genotyping and intensity data. By this method, we determined the number and localization of recurrent copy-neutral loss of heterozygosity (CN-LOH) regions and compared them with recurrent somatic copy number alterations (CNAs). RESULTS: Single-nucleotide polymorphism-array data analysis allowed us to detect, for the first time in HNSCC, chromosomal segment of CN-LOHs in addition to CNAs. Chromosomal alterations have been detected in 14 (73.7%) of 19 samples, and the 12.1% of all alterations observed (LOHs, gains, and CN-LOHs) were CN-LOHs. The most recurrent gain events, occurring in 78.5% of cases (11 samples), were harbored within 8q21.11-q21.13 and 8q23.1-q24.22 loci, while the most recurrent loss and CN-LOH events were present at 3p21.31-p21.1 (57.1%; 8 samples) and 17p13.3-p13.1 (28.6%; 4 samples) loci, respectively. CONCLUSION: The investigated chromosomal regions, in particular those with CN LOH, harbored some interesting genes, such as HIC1, DOCK8, KANK1, and NOTCH1 whose role, mutations and epigenetic modifications in HNSCC deserve to be investigated, in order to understand the significance of CN-LOH events in HNSCC pathogenesis. PMID- 23750502 TI - Neuropathic pain and pharmacological treatment. AB - Neuropathic pain is a serious chronic condition strongly affecting quality of life, which can be relieved but cannot be cured. Apart from symptomatic management, treatment should focus on the underlying disorder. The estimated prevalence is at least 1% to 5% of the general population. Neuropathic pain is characterized both by spontaneous and evoked pain. A diagnosis of neuropathic pain can usually be established based solely on history and neurological examination. Ancillary investigations may include EMG and computerized tomography/magnetic resonance imaging scans, depending on the localization of the suspected lesion. A limited number of agents, primarily directed at symptom control, are currently approved for use in neuropathic pain. A mechanism-based approach to pharmacological intervention supports the use of polypharmacy in neuropathic pain. PMID- 23750503 TI - Translational models of ocular disease. AB - Animals provide indispensable models to translate basic mechanistic discoveries and realize their therapeutic potential in humans. Conversely, advances in human medicine often inform management of similar conditions in clinical veterinary medicine. In this paper, key experimental model species are introduced, with emphasis on genetic contributions of the mouse. Its role and those of larger animal models are described in common ocular research areas including intraocular neoplasia, corneal epithelial and stromal disease, cataract, uveitis, glaucoma, and retinal dystrophies. Emphasis is placed on those conditions shared by humans and domestic animals, with the intent of exploring how the study of comparable conditions in humans, domestic animals, and laboratory animals informs one another. PMID- 23750504 TI - The physical interaction of Mcm10 with Cdc45 modulates their DNA-binding properties. AB - The eukaryotic DNA replication protein Mcm10 (mini-chromosome maintenance 10) associates with chromatin in early S-phase and is required for assembly and function of the replication fork protein machinery. Another essential component of the eukaryotic replication fork is Cdc45 (cell division cycle 45), which is required for both initiation and elongation of DNA replication. In the present study we characterize, for the first time, the physical and functional interactions of human Mcm10 and Cdc45. First we demonstrated that Mcm10 and Cdc45 interact in cell-free extracts. We then analysed the role of each of the Mcm10 domains: N-terminal, internal and C-terminal (NTD, ID and CTD respectively). We have detected a direct physical interaction between CTD and Cdc45 by both in vitro co-immunoprecipitation and surface plasmon resonance experiments. On the other hand, we have found that the interaction of the Mcm10 ID with Cdc45 takes place only in the presence of DNA. Furthermore, we found that the isolated ID and CTD domains are fully functional, retaining DNA-binding capability with a clear preference for bubble and fork structures, and that they both enhance Cdc45 DNA binding affinity. The results of the present study demonstrate that human Mcm10 and Cdc45 directly interact and establish a mutual co-operation in DNA binding. PMID- 23750505 TI - Infant language development is related to the acquisition of walking. AB - The present investigation explored the question of whether walking onset is related to infant language development. Study 1 used a longitudinal design (N = 44) to assess infant locomotor and language development every 2 weeks from 10 to 13.5 months of age. The acquisition of walking was associated with a significant increase in both receptive and productive language, independent of age. Study 2 used an age-held-constant study with 12.5-month-old infants (38 crawling infants; 37 walking infants) to further explore these findings. Results from Study 2 replicated the differences in infant language development between locomotor groups. Additionally, a naturalistic observation of parent-infant interactions (20 crawling dyads; 24 walking dyads) revealed that language development was predicted by multiple factors in the social environment, but only for walking infants. Possible explanations of the findings (e.g., social, cognitive, neurological) are discussed, and topics for future research are highlighted. PMID- 23750506 TI - Novel Hantavirus in Wildlife, United Kingdom PMID- 23750507 TI - Serosurvey of dogs for human, livestock, and wildlife pathogens, Uganda. PMID- 23750508 TI - Single residues dictate the co-evolution of dual esterases: MCP hydrolases from the alpha/beta hydrolase family. AB - Several members of the C-C MCP (meta-cleavage product) hydrolase family demonstrate an unusual ability to hydrolyse esters as well as the MCPs (including those from mono- and bi-cyclic aromatics). Although the molecular mechanisms responsible for such substrate promiscuity are starting to emerge, the full understanding of these complex enzymes is far from complete. In the present paper, we describe six distinct alpha/beta hydrolases identified through genomic approaches, four of which demonstrate the unprecedented characteristic of activity towards a broad spectrum of substrates, including p-nitrophenyl, halogenated, fatty acyl, aryl, glycerol, cinnamoyl and carbohydrate esters, lactones, 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoate and 2-hydroxy-6-oxohepta-2,4 dienoate. Using structural analysis and site-directed mutagenesis we have identified the three residues (Ser32, Val130 and Trp144) that determine the unusual substrate specificity of one of these proteins, CCSP0084. The results may open up new research avenues into comparative catalytic models, structural and mechanistic studies, and biotechnological applications of MCP hydrolases. PMID- 23750509 TI - Effect of dynamic DNA methylation and histone acetylation on cPouV expression in differentiation of chick embryonic germ cells. AB - As a crucial pluripotency-related factor, the epigenetic regulation of Oct4 has been studied intensively in mammalians. However, its dynamic changes of DNA methylation and histone modification in avians remain poorly understood. In the present study, we first described the alterations of DNA methylation and histone acetylation in the promoter of chicken PouV (cPouV; the homologue of Oct4 in avian) during chick embryonic germ (EG) cell differentiation. The epigenetic modification analysis showed that DNA methylation in the cPouV promoter increased obviously, while histone acetylation decreased dramatically detected by chromatin immunoprecipitation assay in the process of differentiation. Gene expression analysis detection indicated that the levels of DNA methyltransferase 3a (Dnmt 3a), Dnmt 3b, and histone deacetylase 3 (HDAC 3) transcripts were significantly high, whereas the relative abundance of Dnmt 1, histone acetyltransferase (HAT), and cPouV mRNA was significantly decreased during the conversion of EG to embryoid body-like structures (EBs), which was correlated with the increased level of methylation and reduced level of H3 acetylation. Moreover, in vitro methylation assay indicated that the reporter gene was remarkably inhibited by the methylated promoter of cPouV. To further understand the effect of epigenetic modifiers on cPouV expression, we performed an analysis of EB cells treated with trichostatin A (TSA), Aza-2'-deoxycytidine (Aza), or TSA plus Aza (TSA/Aza). We observed that the effect of TSA/Aza is more sensitive to the reactivation of cPouV compared with TSA or Aza, indicating that these epigenetic inhibitors can function synergistically to facilitate the reprogramming process. The present study provided evidences that a critical role for cPouV activation/repression by DNA methylation and/or histone modifications is involved in the pluripotency maintenance and differentiation process of chick EG. PMID- 23750511 TI - Iatrogenic Creutzfeldt-Jakob disease from commercial cadaveric human growth hormone. PMID- 23750510 TI - Early-life air pollution and asthma risk in minority children. The GALA II and SAGE II studies. AB - RATIONALE: Air pollution is a known asthma trigger and has been associated with short-term asthma symptoms, airway inflammation, decreased lung function, and reduced response to asthma rescue medications. OBJECTIVES: To assess a causal relationship between air pollution and childhood asthma using data that address temporality by estimating air pollution exposures before the development of asthma and to establish the generalizability of the association by studying diverse racial/ethnic populations in different geographic regions. METHODS: This study included Latino (n = 3,343) and African American (n = 977) participants with and without asthma from five urban regions in the mainland United States and Puerto Rico. Residential history and data from local ambient air monitoring stations were used to estimate average annual exposure to five air pollutants: ozone, nitrogen dioxide (NO2), sulfur dioxide, particulate matter not greater than 10 MUm in diameter, and particulate matter not greater than 2.5 MUm in diameter. Within each region, we performed logistic regression to determine the relationship between early-life exposure to air pollutants and subsequent asthma diagnosis. A random-effects model was used to combine the region-specific effects and generate summary odds ratios for each pollutant. MEASUREMENTS AND MAIN RESULTS: After adjustment for confounders, a 5-ppb increase in average NO2 during the first year of life was associated with an odds ratio of 1.17 for physician diagnosed asthma (95% confidence interval, 1.04-1.31). CONCLUSIONS: Early-life NO2 exposure is associated with childhood asthma in Latinos and African Americans. These results add to a growing body of evidence that traffic-related pollutants may be causally related to childhood asthma. PMID- 23750512 TI - Issues in the development of a research and education framework for one health. PMID- 23750513 TI - Pharmacokinetic considerations for antithrombotic therapies in stroke. AB - INTRODUCTION: Strategies to prevent stroke recurrences and stroke-related morbidity and mortality are a major concern for healthcare systems worldwide. Antithrombotic therapy is the cornerstone for the secondary prevention of ischemic stroke. AREAS COVERED: This article is an overview of currently used antithrombotic therapies in the management of ischaemic stroke with special focus on their pharmacokinetic properties and how these properties may influence their clinical utility. This review covers both antiplatelet drugs and antitcoagulants used in the primary and secondary prevention of ischaemic stroke. EXPERT OPINION: The role of aspirin in the early management of stroke is well established. Furthermore, antiplatelet drugs (aspirin, aspirin/dypiridamol and clopidogrel) are the cornerstone of secondary prevention of ischaemic stroke, while their role in the primary prevention is less well established. There are limited data on the use of novel antiplatelet agents for the management of stroke patients. Anticoagulation has not been associated with clinical benefits when used early in the management of acute ischaemic stroke. Long-term therapy with vitamin K antagonists provides prognostic benefit in patients with atrial fibrillation and additional stroke risk factors. New oral anticoagulants have demonstrated at least similar efficacy with vitamin K anatagonists in preventing stroke in patients with atrial fibrillation. PMID- 23750514 TI - Transient receptor potential channels and mechanosensation. AB - Transient receptor potential (TRP) channels act as sensors for a range of stimuli as diverse as light, sound, touch, pheromones, and tissue damage. Their role in mechanosensation in the animal kingdom, identified by gene ablation studies, has raised questions about whether they are directly mechanically gated, whether they act alone or in concert with other channels to transduce mechanical stimuli, and their relative importance in various functions and disease states in humans. The ability of these channels to form heteromultimers and interact with other ion channels underlies a range of cell-specific functions in different cell types. Here we overview recent advances in this rapidly expanding field, focusing on somatosensation, hearing, the cardiovascular system, and interactions between TRP channels and other proteins involved in mechanoelectrical signaling. PMID- 23750516 TI - Preliminary examination of a mutual intimate partner violence intervention among treatment-mandated couples. AB - Intimate partner violence (IPV) is a widespread global health problem. Despite growing evidence indicating that men and women commit IPV, most traditional interventions focus on male-to-female violence and do not address mutual violence. This circumscribed focus represents one potential reason traditional treatments have had only a modest effect on recidivism. The current study investigated a pilot intervention for mutually violent couples with ethnically diverse, treatment-mandated men and women. Using a longitudinal design, 121 couples were assessed (semistructured clinical interview, Conflict Tactics Scale Revised [CTS-2]) and mandated to either the pilot intervention or another community agency. Of the 92 couples referred for the 12-week, pilot group intervention (plus 1-2 preparatory, individual sessions), 89% of couples had one or both partners complete. Posttreatment assessments were conducted (CTS-2, satisfaction ratings), anticipating reductions in perpetrated and received IPV among treatment completers. Using 1-year conviction data to assess recidivism (IPV and general violence convictions), it was hypothesized that the lowest recidivism rates would be found when both partners completed, intermediate rates when one partner completed, and the highest rates when neither completed. Consistent with hypotheses, men who completed treatment reported reduced perpetration of physical assault and received less injury, and women who completed reported receiving less physical assault and injury. At 1-year follow up, couples who completed had lower recidivism rates, with couples in which both partners completed evidencing the best outcomes. Results provide preliminary support for the proposed mutual violence intervention. Clinical implications, including the effect of a thorough assessment and tailored treatment recommendations, are discussed. PMID- 23750517 TI - Duration and mutual entrainment of changes in parenting practices engendered by behavioral parent training targeting recently separated mothers. AB - Parent management training (PMT) has beneficial effects on child and parent adjustment that last for 5 to 10 years. Short-term changes in parenting practices have been shown to mediate these effects, but the manner in which changes in specific components of parenting are sequenced and become reciprocally reinforcing (or mutually entrained) to engender and sustain the cascade of long term beneficial effects resulting from PMT has received modest empirical attention. Long-term changes in parenting resulting from the Oregon model of PMT (PMTO) over a 2-year period were examined using data from the Oregon Divorce Study-II in which 238 recently separated mothers and their 6- to 10-year-old sons were randomly assigned to PMTO or a no treatment control (NTC) group. Multiple indicators of observed parenting practices were used to define constructs for positive parenting, monitoring and discipline at baseline, and at 6-, 12-, 18- and 30-months postbaseline. PMTO relative to NTC resulted in increased positive parenting and prevented deterioration in discipline and monitoring over the 30 month period. There were reliable sequential, transactional relationships among parenting practices; positive parenting supported better subsequent monitoring, and positive parenting and better monitoring supported subsequent effective discipline. Small improvements in parenting resulting from PMTO and small deteriorations in parenting in the NTC group may be sustained and amplified by mutually entrained relationships among parenting practices. These data about the change processes engendered by PMTO may provide information needed to enhance the power, effectiveness, and efficiency of behavioral parent training interventions. PMID- 23750515 TI - Translating birdsong: songbirds as a model for basic and applied medical research. AB - Songbirds, long of interest to basic neuroscience, have great potential as a model system for translational neuroscience. Songbirds learn their complex vocal behavior in a manner that exemplifies general processes of perceptual and motor skill learning and, more specifically, resembles human speech learning. Song is subserved by circuitry that is specialized for vocal learning and production but that has strong similarities to mammalian brain pathways. The combination of highly quantifiable behavior and discrete neural substrates facilitates understanding links between brain and behavior, both in normal states and in disease. Here we highlight (a) behavioral and mechanistic parallels between birdsong and aspects of speech and social communication, including insights into mirror neurons, the function of auditory feedback, and genes underlying social communication disorders, and (b) contributions of songbirds to understanding cortical-basal ganglia circuit function and dysfunction, including the possibility of harnessing adult neurogenesis for brain repair. PMID- 23750518 TI - Coparenting moderates the association between firstborn children's temperament and problem behavior across the transition to siblinghood. AB - The contribution of individual (i.e., negative reactivity) and environmental (i.e., coparenting) characteristics in predicting firstborns' adjustment after a sibling's birth were examined. Mothers, fathers, and firstborn children from 241 families participated in a family freeplay to assess coparenting interactions before the birth of the second child and parents completed questionnaires on children's temperamental characteristics and behavior problems. Children's externalizing problems significantly increased from pre- to postbirth. Children, on average, did not display more internalizing problems after the infant sibling's birth; however, children high in negative reactivity were more sensitive to undermining coparenting behavior and displayed greater internalizing behaviors across the transition to siblinghood. Negatively reactive children also displayed increases in externalizing behavior across the transition to siblinghood when parents showed high levels of undermining coparenting and low levels of supportive coparenting. Supportive coparenting appeared to be a protective factor in the face of this transition for negatively reactive children in families where parents engaged in high levels of undermining coparenting. Findings suggest that both individual and environmental factors play an important role in firstborns' adjustment to an infant sibling's birth. Parents of temperamentally sensitive children may benefit from participating in workshops geared toward improving coparenting partnerships prior to the birth of the second child. PMID- 23750519 TI - Cultural values, U.S. neighborhood danger, and Mexican American parents' parenting. AB - To begin accounting for cultural and contextual factors related to child rearing among Mexican American parents we examined whether parents' Mexican American cultural values and perceptions of neighborhood danger influenced patterns of parenting behavior in two-parent Mexican-origin families living in the U.S. To avoid forcing Mexican American parents into a predefined model of parenting styles, we used latent profile analysis to identify unique patterns of responsiveness and demandingness among mothers and fathers. Analyses were conducted using parent self-reports on parenting and replicated with youth reports on mothers' and fathers' parenting. Across reporters, most mothers and fathers exhibited a pattern of responsiveness and demandingness consistent with authoritative parenting. A small portion of parents exhibited a pattern of less involved parenting. None of the patterns were indicative of authoritarianism. There was a modicum of evidence for no nonsense parenting among fathers. Both neighborhood danger and parents' cultural values were associated with the likelihood of employing one style of parenting over another. The value of using person-centered analytical techniques to examine parenting among Mexican Americans is discussed. PMID- 23750520 TI - Mothers' trajectories of depressive symptoms across Mexican-origin adolescent daughters' transition to parenthood. AB - This study draws from a life-course perspective in examining trajectories of mothers' depressive symptoms across their adolescent daughters' adjustment to parenthood in 204 Mexican-origin families using latent class growth analysis. Four distinct trajectories were identified based on mothers' depressive symptoms before the birth and 10 and 24 months postpartum. Two trajectories were characterized by stable levels of depressive symptoms but were differentiated in their levels of symptoms (i.e., High/Stable and Low/Stable). The remaining two trajectories were characterized by changes from pre- to post-birth, with one group exhibiting increases in depressive symptoms (i.e., Low/Post-Birth Increase) and the other group characterized by decreases in depressive symptoms (i.e., Low/Post-Birth Decrease). Consistent with a risk and resilience perspective, mothers with more disadvantaged socioeconomic circumstances and fewer intrapersonal resources (i.e., self-esteem, ethnic identity affirmation) were more likely to be members of the High/Stable group. In addition, daughters of mothers in the High/Stable group were more likely to have lower self-esteem as compared with daughters in the other three groups. Collectively, these findings suggested that the High/Stable group was at risk for adjustment difficulties from the third trimester to two years postpartum. In contrast, membership in the Low/Post-Birth Decrease trajectory group was associated with lower depressive symptoms and higher self-esteem for mothers and daughters. Findings point to the need to identify mothers who are at risk for depressive symptoms during their adolescent daughters' pregnancy and offer prevention and intervention programs that reduce risks and enhance protective factors. PMID- 23750521 TI - Family and cultural processes linking family instability to Mexican American adolescent adjustment. AB - Despite the rapidly growing Mexican American population, no studies to date have attempted to explain the underlying relations between family instability and Mexican American children's development. Using a diverse sample of 740 Mexican American adolescents (49% female; 5th grade, M age = 10.4 years; 7th grade, M age = 12.8 years) and their mothers, we prospectively examined the relations between family instability and adolescent academic outcomes and mental health in the 7th grade. The model fit the data well and results indicated that family instability between 5th and 7th grade was related to increased 7th-grade mother-adolescent conflict, and, in turn, mother-adolescent conflict was related to decreased school attachment and to increased externalizing and internalizing symptoms in the 7th grade. Results also indicated that 7th-grade mother-adolescent conflict mediated the relations between family instability and 7th-grade academic outcomes and mental health. Further, we explored adolescent familism values as a moderator and found that adolescent familism values served as a protective factor in the relation between mother-adolescent conflict and grades. Implications for future research and intervention strategies are discussed. PMID- 23750522 TI - Family caregivers' narratives of mental health treatment usage processes by their Latino adult relatives with serious and persistent mental illness. AB - Family caregivers' views and experiences related to treatment usage processes by their adult relatives with serious and persistent mental illness (SPMI) were empirically examined in a sample of Latino caregivers (n = 17) who were users of services at the National Alliance on Mental Illness (NAMI) in a predominantly Latino- (80%) and Mexican-descent large city in the Southwest United States. We conducted a stability check of qualitative findings with a second sample of Latino caregivers with no exposure to NAMI (n = 15). Overall, the combined sample (N = 32) compared similarly with larger samples of Latino adults and caregivers in quantitative measures of acculturation, familism, caregiver stigma, and depression symptoms. Together, caregivers' stigma and cultural beliefs, such as verguenza (shame), use of folk healers, and lack of insurance, were major reported barriers to service usage. Family support (and lack of) for treatment also weighed heavily as a facilitator (and a barrier) of service usage, thus highlighting the complexity of family relationship contexts. Substantial portions of caregivers reported that treatment initiation was prompted by psychiatric hospitalization (50%), and that positive experiences with service providers were influential in treatment retention (72%). Given the high levels of family involvement reported among Latino caregivers, the findings underscore the potential role of family caregivers in treatment engagement and retention. Future research is needed that examines family caregivers' role in treatment with models that consider the interplay between cultural background, family level relationships, and service system contexts. PMID- 23750523 TI - Preadoption adversities and postadoption mediators of mental health and school outcomes among international, foster, and private adoptees in the United States. AB - Adopted children are a heterogeneous group, varying along numerous factors, including type of adoption (international, foster, private), length of exposure to preadoption adversities as indexed by age of adoption, history of preadoption maltreatment, and prenatal substance exposure. Yet, we know little about how these adversity factors are mediated by quality of postadoption parent-child relationships and/or the presence of special health care needs to produce specific child outcomes across different groups of U.S. adopted children. This study uses structural equation modeling to analyze cross-sectional data from the National Survey of Adoptive Parents to investigate differences in outcomes among three groups of U.S. adopted children: international, foster, and private. SEM results indicate that compared with privately adopted children, (a) children adopted from the foster care system were more likely to be identified with special health care needs, and (b) internationally adopted children showed on average poorer school performance as indexed by math and reading. Analyses yielded both direct and indirect paths between preadoption adversities and child outcomes, with the majority of associations mediated or partially mediated by quality of parent-child relationships and/or special health care needs status. The results of these analyses highlight the heterogeneity among different groups of adopted children within the United States and also underline the important mediating roles that the quality of parent-child relationship and children's special health care needs status have on adopted children's selected mental health and academic outcomes. PMID- 23750524 TI - Parent-adolescent relationships, religiosity, and the social adjustment of Indonesian Muslim adolescents. AB - Parent-adolescent relationships invariably occur within a complex cultural context that in some populations include strong religious influences. Using data from multiple sources that were analyzed using structural equation modeling, we found that parental warmth and parental religiosity predicted adolescent religiosity in a sample of 296 Indonesian 15-year-old adolescents. The significant interaction of parental warmth and parent religiosity indicated that parental warmth moderated the relation between parent religiosity and adolescent religiosity. We expanded this model to predict externalizing and prosocial behavior where direct paths from adolescent religiosity to outcomes were significant for prosocial but not antisocial behavior; parental warmth, parent religiosity, and their interaction did not predict either outcome. Adolescent religiosity was found to be a mediator of these relations between predictor and outcomes for prosocial but not antisocial behavior. These results suggest that, in Indonesia and perhaps other highly religious cultures, parent-adolescent relationships and social competence may be interconnected with religion. PMID- 23750525 TI - Predictors of psychological adjustment in early placed adopted children with lesbian, gay, and heterosexual parents. AB - Little research has focused on predictors of psychological adjustment among early placed adopted children. Additionally, the research on adopted children in lesbian or gay parent-families is sparse. The current study examined 40 female same-sex, 35 male same-sex, and 45 different-sex parent families with adopted children, all of whom were placed in their adoptive homes under the age of 18 months. We explored aspects of children's preadoptive and postadoptive contexts (measured at 3 months postplacement) in relation to children's externalizing and internalizing symptoms (measured at 2 years postplacement; M age = 2.33 years). Findings revealed that lack of parental preparation for the adoption, and parental depressive symptoms, were associated with higher parent-reported levels of both externalizing and internalizing symptoms. Additionally, parents' relationship conflict was associated with higher levels of parent- and partner reported internalizing symptoms. Children's adjustment outcomes did not differ by family type. Our findings point to the importance of considering the adoptive family context (including parent and couple subsystems) in predicting later adjustment in early placed adopted children, in diverse family contexts. PMID- 23750526 TI - Family adversity and inhibitory control for economically disadvantaged children: preschool relations and associations with school readiness. AB - This study examined longitudinal relations linking aspects of family adversity to inhibitory control and school readiness for 120 economically disadvantaged children attending a Head Start preschool. The aspects of family adversity included income-to-needs ratios and an adversity index representing family instability and family chaos. The results showed that the adversity index but not the income ratios contributed to explaining diversity in the development of inhibitory control over the course of the preschool year. Additionally, the adversity index predicted school readiness at the end of the year, and the results suggested that inhibitory control mediated this effect. The implications concern understanding family sources of diversity in inhibitory control for economically disadvantaged preschool children. PMID- 23750527 TI - Psychological control in daily parent-child interactions increases children's negative emotions. AB - The aim of the present study was to investigate the temporal dynamics between parental behaviors in daily interactions with their offspring, that is, affection and psychological control, and children's negative emotions. The participants were 152 Finnish families with a 6- to 7-year-old child. Children's negative emotions and parental affection and psychological control in interactions with their child were measured daily using diary questionnaires filled in by the mothers and fathers over 7 successive days. The results of multilevel modeling showed that psychological control applied by mothers and fathers in daily interactions with their child leads to an increase in negative emotions in the child. Parental affection in daily interactions with their child was not associated with the child's negative emotions. PMID- 23750528 TI - Preschoolers' emotion knowledge and the differential effects of harsh punishment. AB - This study examined the influence of caregiver-reported harsh physical and verbal punishment on children's behavioral and self-system adjustment. Children's emotion knowledge was evaluated as a heretofore unrecognized moderator of these relations. We assessed 250 preschool-aged children (50% female; Mage = 49.06 months) from diverse backgrounds (50% Hispanic, 18% African American, 10.4% Caucasian, 21.6% multiracial/other) using various instruments through teacher, caregiver, self, and observer report in the domains of harsh punishment, conduct problems, self-concept, and emotion knowledge. Emotion knowledge moderated the relation between harsh punishment and child adjustment. Harsh physical punishment was associated with conduct problems for children with higher emotion knowledge, especially for boys. Harsh verbal punishment was associated with self-concept deficits among children with higher emotion knowledge, especially for girls. These relations were also specifically applicable to non-Hispanic children. These results highlight the importance of investigating hypothesis-driven interactive effects and the specificity of experience to understand the psychosocial sequelae of parenting practices broadly, and to clarify the mixed evidence in the punishment literature specifically. Clinical implications point to the salience of emotion processes in parent-child disciplinary interventions for understanding the prevalence and pattern of child behavioral adjustment and self-concept, as well as more broadly to the role of individual differences in children's responses to adversity and subsequent therapeutic needs. PMID- 23750529 TI - "Don't stand so close to me": an attachment perspective of disengagement and avoidance in marriage. AB - Theory and research support a link between disengaging or avoidant communication and global marital distress; however, questions remain regarding individual differences and situational influences associated with partners' tendency to disengage. Guided by an attachment framework, this study addressed two aims. The first aim was to replicate and extend previous research that has found mixed support for a link between higher attachment avoidance and more disengaging or avoidant behaviors during conflict interactions. To accomplish this aim, the authors examined two moderators of this link. The second aim was to clarify the relation between avoidant attachment and disengaging behaviors across two relationship contexts central to both the attachment and marital literatures couples' conflictual and supportive interactions. In addressing these aims the authors proposed two hypotheses: first, spouses with higher attachment avoidance would be more disengaged during interactions in which their partners evidenced greater negative affect; second, spouses with higher attachment avoidance would be more disengaged during conflict interactions that they perceived as more destructive. Couples were assessed annually over 5 years. Aims were addressed both cross-sectionally and longitudinally and via questionnaire and behavioral observation data. During both conflictual and supportive interactions, wives' negative affect predicted husbands' disengagement when husbands were higher on avoidant attachment. Longitudinally, the link between husbands' perceptions of their couple conflict as destructive and husbands' conflict avoidance was stronger for husbands who were higher on attachment avoidance. Theoretical and clinical implications are discussed. PMID- 23750530 TI - Separation anxiety in families with emerging adults. AB - In several developmental theories, separation anxiety has been identified as an important feature of close interpersonal relationships. Most often, separation anxiety has been examined in the context of mother-child dyads in infancy. Increasingly, however, it is recognized that separation anxiety is also relevant in other relationships (e.g., the father-child relationship) and in later developmental periods (e.g., adolescence and emerging adulthood). The present study aimed to investigate separation anxiety at the family level in families with emerging adults. By using the Social Relations Model, we aimed to determine the extent to which the actor, the partner, their specific relationships, and the family contribute to separation anxiety in dyadic family relationships. A total of 119 Belgian two-parent families with an emerging adult participated in a round robin design, in which family members reported on their feelings of separation anxiety toward each other. Findings showed that separation anxiety can be represented as a personal characteristic (i.e., an actor effect) and as a specific feature of the mother-child dyad. Further, findings indicate that separation anxiety is also characteristic of the father-mother marital relationship and of the family climate as a whole. Implications for the meaning of separation anxiety and clinical practice are discussed. PMID- 23750531 TI - Cooperative coparenting moderates the association between parenting practices and children's prosocial behavior. AB - This study examined how aspects of the parenting and coparenting relationships relate to children's prosocial behavior in early childhood. Fifty-eight 2-parent families from a larger ongoing longitudinal study participated in this study. Mothers completed questionnaires that measured their use of inductive reasoning, as well as their children's prosocial behavior. Furthermore, parents and their children participated in 3 triadic interaction tasks that were coded to assess cooperative coparenting behavior. Results revealed that cooperative coparenting was positively associated with children's prosocial behavior. A significant interaction also emerged between maternal inductive reasoning and cooperative coparenting behavior. These findings underscore the important role of a cooperative coparenting subsystem in influencing children's emerging prosocial behavior, as well as highlight the association between positive parenting practices and children's prosocial development within the context of cooperative coparenting behaviors. This study demonstrates the utility of understanding family-level processes that contribute to children's prosocial development during early childhood. PMID- 23750532 TI - Toddler inhibited temperament, maternal cortisol reactivity and embarrassment, and intrusive parenting. AB - The relevance of parenting behavior to toddlers' development necessitates a better understanding of the influences on parents during parent-child interactions. Toddlers' inhibited temperament may relate to parenting behaviors, such as intrusiveness, that predict outcomes later in childhood. The conditions under which inhibited temperament relates to intrusiveness, however, remain understudied. A multimethod approach would acknowledge that several levels of processes determine mothers' experiences during situations in which they witness their toddlers interacting with novelty. As such, the current study examined maternal cortisol reactivity and embarrassment about shyness as moderators of the relation between toddlers' inhibited temperament and maternal intrusive behavior. Participants included 92 24-month-old toddlers and their mothers. Toddlers' inhibited temperament and maternal intrusiveness were measured observationally in the laboratory. Mothers supplied saliva samples at the beginning of the laboratory visit and 20 minutes after observation. Maternal cortisol reactivity interacted with inhibited temperament in relation to intrusive behavior, such that mothers with higher levels of cortisol reactivity were observed to be more intrusive with more highly inhibited toddlers. Embarrassment related to intrusive behavior as a main effect. These results highlight the importance of considering child characteristics and psychobiological processes in relation to parenting behavior. PMID- 23750533 TI - Appraisals of daily romantic relationship experiences in individuals with borderline personality disorder features. AB - The current study examined the relationship between borderline personality disorder (BPD) features and appraisals of daily romantic relationship experiences. The sample included 114 ethnically diverse, young adult dating couples (total N = 228). Participants completed a 14-day daily diary study and reported negative impact and emotional loss to their romantic partner in response to daily positive and negative self-initiated and partner-initiated romantic experiences. Results indicated that BPD features, even when controlling for relationship satisfaction, total number of relationship experiences, and depressive symptoms, were associated with reporting greater negative impact and greater emotional loss to both partner-initiated negative and positive experiences. BPD features were generally not associated with reporting greater negative impact and emotional loss in response to self-initiated negative and positive experiences. The results suggest that individuals with BPD features have a negative interpretation bias to both negative and positive experiences and the effect is generally specific to partner-initiated experiences. Negative appraisals may be one mechanism underlying interpersonal dysfunction in those with BPD features and interventions that directly assess and target these cognitive biases may help improve individual well-being and overall couple functioning. PMID- 23750534 TI - Gender differences in the impact of posttraumatic stress disorder symptoms on community couples' intimacy behaviors. AB - Problems in intimate relationships frequently occur among individuals with posttraumatic stress disorder (PTSD). This study includes examination of whether deficits in the intimacy process occur among couples affected by PTSD, and whether gender differences exist in the association between PTSD symptom severity and intimate behaviors. Heterosexual community couples in which at least 1 partner was experiencing elevated symptoms of PTSD were video-recorded while discussing positive and negative aspects of their relationship. Each partner's intimacy behaviors (i.e., self-disclosure and support provision) were coded. Results of an actor-partner interdependence model indicate that husbands, but not wives, with greater PTSD symptom severity provided less support (i.e., expressions of understanding, validation, and caring) to their partners during discussions of negative aspects of their relationship. This finding supports prior literature while increasing generalizability beyond samples of male combat veterans and addressing a possible confound of prior research that has exclusively relied on self-reported intimacy. In addition, wives' PTSD symptom severity was associated with husbands engaging in more self-disclosure when discussing negative aspects of their relationship, which may have represented husbands' expression of more negative thoughts and feelings in this context. Overall, women appeared to be resilient against the potential negative impact of PTSD symptoms on their ability to continue providing intimacy behaviors to their partners. PMID- 23750535 TI - Isolation of pluripotent neural crest-derived stem cells from adult human tissues by connexin-43 enrichment. AB - Identification and isolation of pluripotent stem cells in adult tissues represent an important advancement in the fields of stem cell biology and regenerative medicine. For several years, research has been performed on the identification of biomarkers that can isolate stem cells residing in neural crest (NC)-derived adult tissues. The NC is considered a good model in stem cell biology as cells from it migrate extensively and contribute to the formation of diverse tissues in the body during organogenesis. Migration of these cells is modulated, in part, by gap junction communication among the cell sheets. Here we present a study in which, selection of connexin 43 (Cx43) expressing cells from human adult periodontal ligament yields a novel pluripotent stem cell population. Cx43+ periodontal ligament stem cells express pluripotency-associated transcription factors OCT4, Nanog, and Sox2, as well as NC-specific markers Sox10, p75, and Nestin. When injected in vivo into an immunodeficient mouse model, these cells were capable of generating teratomas with tissues from the three embryological germ layers: endoderm, mesoderm, and ectoderm. Furthermore, the cells formed mature structures of tissues normally arising from the NC during embryogenesis such as eccrine sweat glands of the human skin, muscle, neuronal tissues, cartilage, and bone. Immunohistochemical analysis confirmed the human origin of the neoplastic cells as well as the ectodermal and endodermal nature of some of the structures found in the tumors. These results suggest that Cx43 may be used as a biomarker to select and isolate the remnant NC pluripotent stem cells from adult human tissues arising from this embryological structure. The isolation of these cells through routine medical procedures such as wisdom teeth extraction further enhances their applicability to the regenerative medicine field. PMID- 23750536 TI - Glutamate supplementation is associated with improved glucose metabolism following carbohydrate ingestion in healthy males. AB - Glutamate is linked to the glycolytic process, particularly when co-ingested with carbohydrate, but its effects on glucose metabolism are poorly characterised. The present study aimed to (1) specifically examine the effects of carbohydrate administration on circulating glutamate concentrations and (2) investigate the effect of increased glutamate availability, independent of carbohydrate ingestion, on glucose metabolism. A total of nine participants underwent four trials: (1) glutamate supplement+carbohydrate drink (GLU+CHO); (2) glutamate supplement+placebo drink (GLU); (3) placebo supplement+carbohydrate drink (CHO); (4) placebo supplement+placebo drink (CON). Following a fasting blood sample, participants ingested monosodium L-glutamate (MSG; 150 mg/kg body weight) or placebo capsules at each trial followed by a 75 g carbohydrate or a non-energy placebo drink 30 min later. Blood samples were taken at 0, 10, 20, 30, 40, 50, 60, 75, 90, 105 and 120 min. Plasma glutamate concentrations were significantly elevated relative to baseline during the GLU (approximately 10-fold) and GLU+CHO trials (approximately 6-fold). The glucose response to a carbohydrate load was blunted when glutamate was increased in the circulation (peak serum glucose: 5.50 (SE 0.54) mmol/l during the GLU+CHO trial v. 7.69 (SE 0.53) mmol/l during the CHO trial, P< 0.05). On average, c-peptide results revealed that insulin secretion did not differ between the GLU+CHO and CHO trials; however, four participants demonstrated increased insulin secretion during the GLU+CHO trial and five participants demonstrated decreased insulin secretion under the same conditions. In conclusion, when administration is staggered, MSG and carbohydrate supplementation can be used to manipulate plasma glutamate; however, future studies should control for this dichotomous insulin response. PMID- 23750537 TI - Synthesis and mechanism of hypoglycemic activity of benzothiazole derivatives. AB - Adenosine 5'-monophosphate activated protein kinase (AMPK) has emerged as a major potential target for novel antidiabetic drugs. We studied the structure of 2 chloro-5-((Z)-((E)-5-((5-(4,5-dimethyl-2-nitrophenyl)furan-2-yl)methylene)-4 oxothiazolidin-2-ylidene)amino)benzoic acid (PT-1), which attenuates the autoinhibition of the enzyme AMPK, for the design and synthesis of different benzothiazoles with potential antidiabetic activity. We synthesized several structurally related benzothiazole derivatives that increased the rate of glucose uptake in L6 myotubes in an AMPK-dependent manner. One compound, 2 (benzo[d]thiazol-2-ylmethylthio)-6-ethoxybenzo[d]thiazole (34), augmented the rate of glucose uptake up to 2.5-fold compared with vehicle-treated cells and up to 1.1-fold compared to PT-1. Concomitantly, it elevated the abundance of GLUT4 in the plasma membrane of the myotubes and activated AMPK. Subcutaneous administration of 34 to hyperglycemic Kuo Kondo rats carrying the Ay-yellow obese gene (KKAy) mice lowered blood glucose levels toward the normoglycemic range. In accord with its activity, compound 34 showed a high fit value to a pharmacophore model derived from the PT-1. PMID- 23750538 TI - LaparoEndoscopic Single Site orchidopexy for intra-abdominal testes in the pediatric population with a multichannel single port and flexible tip laparoscope. AB - PURPOSE: To assess the outcomes of pediatric LaparoEndoscopic Single Site (LESS) orchidopexy using a commercially available multi-channel single port (MCSP) and flexible tip laparoscope (FTL). PATIENTS AND METHODS: A retrospective cohort study was performed of children who underwent LESS orchidopexy by a single surgeon at a pediatric institution. A commercially available MCSP was utilized at the umbilicus. A 5 mm FTL and 3 mm and 5 mm instruments were used for the dissection. Follow-up visits were performed 2-4 weeks and 6-12 months after surgery to assess position and size of the testes. RESULTS: A total of 17 patients were identified. Median age was 11 months (range 3-43). Sixteen patients underwent primary orchidopexy, including two bilateral procedures and five primary Fowler-Stephens (FS) procedures. One patient underwent a staged FS orchidopexy, with the LESS technique utilized during the second stage. Median laparoscopic dissection time for each testis was 35 minutes (range 22-40). There was no blood loss or intraoperative complications. All testes were noted to be in the scrotum without testicular atrophy. CONCLUSIONS: Our initial experience with this technique was favorable with excellent outcomes. LESS orchidopexy is facilitated with a MCSP and FTL. PMID- 23750539 TI - Catalytic and photocatalytic transformations on metal nanoparticles with targeted geometric and plasmonic properties. AB - Heterogeneous catalysis by metals was among the first enabling technologies that extensively relied on nanoscience. The early intersections of catalysis and nanoscience focused on the synthesis of catalytic materials with high surface to volume ratio. These synthesis strategies mainly involved the impregnation of metal salts on high surface area supports. This would usually yield quasi spherical nanoparticles capped by low-energy surface facets, typically with closely packed metal atoms. These high density areas often function as the catalytically active surface sites. Unfortunately, strategies to control the functioning surface facet (i.e., the geometry of active sites that performs catalytic turnover) are rare and represent a significant challenge in our ability to fine-tune and optimize the reactive surfaces. Through recent developments in colloidal chemistry, chemists have been able to synthesize metallic nanoparticles of both targeted size and desired shape. This has opened new possibilities for the design of heterogeneous catalytic materials, since metal nanoparticles of different shapes are terminated with different surface facets. By controlling the surface facet exposed to reactants, we can start affecting the chemical transformations taking place on the metal particles and changing the outcome of catalytic processes. Controlling the size and shape of metal nanoparticles also allows us to control the optical properties of these materials. For example, noble metals nanoparticles (Au, Ag, Cu) interact with UV-vis light through an excitation of localized surface plasmon resonance (LSPR), which is highly sensitive to the size and shape of the nanostructures. This excitation is accompanied by the creation of short-lived energetic electrons on the surface of the nanostructure. We showed recently that these energetic electrons could drive photocatalytic transformations on these nanostructures. The photocatalytic, electron-driven processes on metal nanoparticles represent a new family of chemical transformations exhibiting fundamentally different behavior compared with phonon-driven thermal processes, potentially allowing selective bond activation. In this Account, we discuss both the impact of the shape of metal nanoparticles on the outcome of heterogeneous catalytic reactions and the direct, electron-driven photocatalysis on plasmonic metal nanostructures of noble metals. These two phenomena are important examples of taking advantage of physical properties of metal materials that are controlled at nanoscales to affect chemical transformations. PMID- 23750540 TI - Crizotinib-induced acute interstitial lung disease in a patient with EML4-ALK positive non-small cell lung cancer and chronic interstitial pneumonia. PMID- 23750541 TI - Visiting "noncodarnia". PMID- 23750542 TI - Digital PCR to determine the number of transcripts from single neurons after patch-clamp recording. AB - Whole-cell patch-clamp recording enables detection of electrophysiological signals from single neurons as well as harvesting of perisomatic RNA through the patch pipette for subsequent gene expression analysis. Amplification and profiling of RNA with traditional quantitative real-time PCR (qRT-PCR) do not provide exact quantitation due to experimental variation caused by the limited amount of nucleic acid in a single cell. Here we describe a protocol for quantifying mRNA or miRNA expression in individual neurons after patch-clamp recording using high-density nanocapillary digital PCR (dPCR). Expression of a known cell-type dependent marker gene (gabrd), as well as oxidative-stress related induction of hspb1 and hmox1 expression, was quantified in individual neurogliaform and pyramidal cells, respectively. The miRNA mir-132, which plays a role in neurodevelopment, was found to be equally expressed in three different types of neurons. The accuracy and sensitivity of this method were further validated using synthetic spike-in templates and by detecting genes with very low levels of expression. PMID- 23750543 TI - Production of single-stranded DNAs by self-cleavage of rolling-circle amplification products. AB - DNA molecules that encode a small, high-speed self-hydrolyzing deoxyribozyme are used as templates for rolling circle amplification (RCA) to produce single stranded DNAs (ssDNAs) of single- and multiple-unit lengths. Including self cleaving deoxyribozymes in RCA products can generate large amounts of ssDNAs with defined sequence and length as well as precise termini. We also demonstrate the use of this method to efficiently generate ssDNA size markers by using deoxyribozyme reaction conditions that permit partial processing. PMID- 23750544 TI - Development of a high density hemagglutinin protein microarray to determine the breadth of influenza antibody responses. AB - We have developed an influenza hemagglutinin protein microarray to assess humoral recognition of diverse influenza strains induced by vaccination and infection. Each array consists of controls and 127 hemagglutinin antigens from 60 viruses, spotted in replicates to generate a single array of 1296 spots. Six arrays are configured on a single slide, which in the following analysis was probed simultaneously with 2 isotype-specific fluorescent secondary antibodies yielding over 15,000 data points per slide. Here we report the use of this system to evaluate mouse, ferret, and human sera. The array allows simultaneous examination of the magnitude of antibody responses, the isotype of such antibodies, and the breadth of influenza strain recognition. We are advancing this technology as a platform for rapid, simple, high-throughput assessment of homologous and heterologous antibody responses to influenza disease and vaccination. PMID- 23750545 TI - In vivo mercury methylation and demethylation in freshwater tilapia quantified by mercury stable isotopes. AB - In vivo methylation and demethylation processes were simultaneously investigated in freshwater tilapia after dietary exposure to mercury ((198)Hg(II) and methyl(200)Hg). During one month dietary exposure followed by two month depuration, both MeHg and THg increased continuously in muscle tissues but decreased in liver during depuration, indicating the inter-organ transportation of MeHg from liver toward muscle. Direct evidence of in vivo net methylation process in freshwater tilapia was observed. Specifically, 0.67-1.60% of the ingested Hg(198)(II) was converted into Me(198)Hg and deposited in fish muscle at the end of depuration. The methylation potential in terms of methylated fraction was elevated at higher temperature and decreased at higher dosage. However, no direct evidence of MeHg demethylation was observed. In contrast to some previous reports of dose-dependent demethylation, the percentage of MeHg in the liver decreased significantly with increasing THg concentrations, likely due to the faster inter-organ MeHg transportation from liver toward muscle. Our study demonstrates the important role of organ- and species-specific biodynamics in understanding mercury transformation and speciation in fish. The observed in vivo methylation process in tilapia was slow, suggesting that the high %MeHg in fish should be mainly derived from MeHg ingestion instead of in vivo transformation. PMID- 23750546 TI - Synthesis, biological evaluation, and in vivo imaging of the first camptothecin fluorescein conjugate. AB - The first synthesis and photophysical properties of a fluorecently labeled camptothecin derivative, namely, camptothecin-FI (CPT-FI), an antitumoral agent that targets topoisomerase I, are reported. The preparation of this fluorescent conjugate is based on a highly convergent and flexible approach which enables the rapid chemical modification of the AB ring system of this fragile pentacyclic alkaloid, aimed at introducing an anchoring point to graft the fluorophore. The selection of a fluorescein analogue as the reporter group has enabled us to get the first green-emitting CPT conjugate exhibiting valuable spectral properties and retaining biological properties of native CPT. Indeed, in biological models, i.e., glioma cell lines U87 and/or T98, the kinetics of cell endocytosis, as well as the efficacy of CPT-FI were compared to those of CPT. CPT-FI fluorescence was measured in the cytosolic compartment of T98 glioma cells from 5 min treatment and remained detectable until 48 h. As CPT, CPT-FI drastically inhibited glioma growth and cell cycle but exhibited a reduced affinity as compared to the native CPT. In vivo and ex vivo imaging studies of CPT-FI intratumoraly injected into a model of NIH-3T3 murine tumor xenografts in nude mice, showed accumulation around the injected site area, which is very promising to target tumors and follow biodistribution in vivo. PMID- 23750547 TI - Gravity and surface tension effects on the shape change of soft materials. AB - Surface tension and gravity, whose influence on the deformation of conventional engineering materials is negligible, become important for soft materials that are typically used in the microfabrication of devices such as microfluidic channels. Although for soft materials the shape change due to these forces can be large, it is often neglected in the design processes. To capture conditions under which the influence of these forces is important, we propose a deformation map in which the shape change is captured by two dimensionless material parameters. Our idea is demonstrated by simulating the large deformation of a short circular cylinder made of a neo-Hookean material in frictionless contact with a rigid substrate. These simulations are carried out using a finite element model that accounts for surface tension and gravity. Our model integrates the two different approaches typically used to determine the shape change of solids and liquid drops in contact with a substrate. PMID- 23750550 TI - Impression management ("lie") scales are associated with interpersonally oriented self-control, not other-deception. AB - This article explores the status of impression management (IM) scales ("lie scales," notably, BIDR-IM) as measures of response bias, offers theory-driven substantive meaning to them, and compares them with self-deception enhancement (SDE). Study 1 (N = 99) compared self-descriptions of actual self and ideal self given in a non-anonymous setting. High similarity indicates self-enhancement. Study 2 (70 dyads) analyzed self-other agreement about IM and SDE. Agreement indicates substantive basis to the scales' scores. Study 3 (N = 182) explored the centrality of self-control in the self-perception of individuals varying in IM and SDE. Study 4 (95 dyads) corroborated self-reports about self-control using informants' reports. In Study 1, IM was associated with relative humility, whereas SDE was associated with self-enhancement. In Study 2, strong self-other agreement was found only for IM, indicating that high IM (but not SDE) is grounded in real-life behavior. In Study 3, self-control was central in the self perception of high IM and high SDE individuals. In Study 4, strong relations with self-control were corroborated by informants only for IM. IM scales measure substantive content associated with self-control aimed at social adaptation, whereas the SDE scale depicts individuals with a grandiose self-perception, who fail to impress knowledgeable others. PMID- 23750549 TI - Facilitation of short-term memory by histaminergic neurons in the nucleus accumbens is independent of cholinergic and glutamatergic transmission. AB - BACKGROUND AND PURPOSE: Here, we have investigated whether learning and/or short term memory was associated with release of ACh and glutamate in the rat nucleus accumbens (NAc). Additionally, neurotransmitter release in the NAc was assessed during facilitation of cognitive processes by antagonists of inhibitory histamine autoreceptors. EXPERIMENTAL APPROACH: The olfactory, social memory test was used in combination with push-pull superfusion of the NAc. A male, juvenile rat was exposed twice to an adult male rat at intervals of 60 or 90 min, and release of ACh and glutamate was determined in the NAc of the conscious adult rat. Histamine receptor antagonists were applied i.c.v. KEY RESULTS: First exposure of a juvenile rat to an adult rat increased ACh and glutamate release in the NAc of the adult rat. Repetition of exposure after 60 min did not change release of ACh and glutamate, while contact time to recognition (CTR) was shortened. Repetition of exposure after an interval of 90 min prolonged CTR and enhanced accumbal ACh and glutamate release rates. Injection (i.c.v.) of thioperamide (histamine H3 receptor antagonist) together with famotidine (H2 receptor antagonist), 80 min prior to second exposure, diminished CTR and abolished ACh and glutamate release when second exposure was carried out 90 min after the first one. CONCLUSIONS AND IMPLICATIONS: Histaminergic neurons per se facilitated short-term memory, without activation of cholinergic and/or glutamatergic neurons in the NAc of rats. Cholinergic and glutamatergic neurons within the NAc contributed to learning but not to recall of memory. PMID- 23750551 TI - An unusual scaly rash. PMID- 23750552 TI - Crystal engineering: from molecule to crystal. AB - How do molecules aggregate in solution, and how do these aggregates consolidate themselves in crystals? What is the relationship between the structure of a molecule and the structure of the crystal it forms? Why do some molecules adopt more than one crystal structure? Why do some crystal structures contain solvent? How does one design a crystal structure with a specified topology of molecules, or a specified coordination of molecules and/or ions, or with a specified property? What are the relationships between crystal structures and properties for molecular crystals? These are some of the questions that are being addressed today by the crystal engineering community, a group that draws from the larger communities of organic, inorganic, and physical chemists, crystallographers, and solid state scientists. This Perspective provides a brief historical introduction to crystal engineering itself and an assessment of the importance and utility of the supramolecular synthon, which is one of the most important concepts in the practical use and implementation of crystal design. It also provides a look to the future from the viewpoint of the author, and indicates some directions in which this field might be moving. PMID- 23750553 TI - Sub-millisecond chain collapse of the Escherichia coli globin ApoHmpH. AB - Myoglobins are ubiquitous proteins that play a seminal role in oxygen storage, transport, and NO metabolism. The folding mechanism of apomyoglobins from different species has been studied to a fair extent over the last two decades. However, integrated investigations of the entire process, including both the early (sub-ms) and late (ms-s) folding stages, have been missing. Here, we study the folding kinetics of the single-Trp Escherichia coli globin apoHmpH via a combination of continuous-flow microfluidic and stopped-flow approaches. A rich series of molecular events emerges, spanning a very wide temporal range covering more than 7 orders of magnitude, from sub-microseconds to tens of seconds. Variations in fluorescence intensity and spectral shifts reveal that the protein region around Trp120 undergoes a fast collapse within the 8 MUs mixing time and gradually reaches a native-like conformation with a half-life of 144 MUs from refolding initiation. There are no further fluorescence changes beyond ca. 800 MUs, and folding proceeds much more slowly, up to 20 s, with acquisition of the missing helicity (ca. 30%), long after consolidation of core compaction. The picture that emerges is a gradual acquisition of native structure on a free energy landscape with few large barriers. Interestingly, the single tryptophan, which lies within the main folding core of globins, senses some local structural consolidation events after establishment of native-like core polarity (i.e., likely after core dedydration). In all, this work highlights how the main core of the globin fold is capable of becoming fully native efficiently, on the sub millisecond time scale. PMID- 23750554 TI - Impact of diabetes mellitus on clinical parameters and treatment outcomes of newly diagnosed pulmonary tuberculosis patients in Thailand. AB - BACKGROUND: To assess the clinical and laboratory parameters, response to therapy and development of antituberculosis (TB) drug resistance in pulmonary TB (PTB) patients with diabetes mellitus (DM) and without DM. METHODS: Using a prospective design, 227 of 310 new cases of culture-positive PTB diagnosed at the Queen Savang Vadhana Memorial Hospital and the Chonburi Hospital between April 2010 and July 2012 that met the study criteria were selected. Data regarding clinical and laboratory parameters, drug susceptibility and treatment outcomes were compared between PTB patients with DM and those without DM. To control for age, the patients were stratified into two age groups (< 50 and >= 50 years) and their data were analysed. RESULTS: Of the 227 patients, 37 (16.3%) had DM, of which 26 (70.3%) had been diagnosed with DM prior to PTB diagnosis and 11 (29.7%) had developed DM at PTB diagnosis. After controlling for age, no significant differences were found between the two groups regarding mycobacterium burden, sputum-culture conversion rate, evidence of multidrug-resistant tuberculosis, frequency of adverse drug events from anti-TB medications, treatment outcomes and relapse rate. The presenting symptoms of anorexia (p = 0.050) and haemoptysis (p = 0.036) were observed significantly more frequently in PTB patients with DM, while the presenting symptom of cough was observed significantly more frequently in PTB patients without DM (p = 0.047). CONCLUSIONS: Plasma glucose levels should be monitored in all newly diagnosed PTB patients and a similar treatment regimen should be prescribed to PTB patients with DM and those without DM in high TB burden countries. PMID- 23750555 TI - A comparative study of corneal sensitivity in birds of prey. AB - OBJECTIVE: To determine and compare the corneal sensitivity in healthy wild diurnal and nocturnal birds of prey (BP) indigenous to Catalonia (Spain), and to establish if age is a determining factor in corneal sensitivity in those species. METHODS: Ophthalmic examination was performed in 105 BP. Only birds with no ocular abnormalities were included in the study (n = 81): 21 diurnal BP (Falco tinnunculus: 16 fledglings, 5 adults) and 60 nocturnal BP (20 Athene noctua [9 fledglings, 11 adults], 20 Strix aluco [15 fledglings, 5 adults], and 20 Otus scops [6 fledglings and 14 adults]). Corneal touch threshold (CTT) was determined for each eye in five different corneal regions. Five attempts to cause a blink reflex were made in each region, and when three or more reflexes were positive, the pressure was deemed the CTT. Statistical analysis was performed using a Student's t-test for independent data or an anova model. The results between species and age groups were compared using the Generalized Estimated Equations model. RESULTS: There were no significant differences between any of the corneal regions (P = 0.25), or between the right (CTT = 4.9 +/- 1.7 cm) and left (CTT = 4.8 +/- 1.7 cm) eye in any of the species (P = 0.692). No difference was found between diurnal and nocturnal species (P = 0.913). Considering all the species, a significant difference was found between the mean CTT of fledglings (5.4 +/- 1.2 cm) and adults (4.1 +/- 2 cm), P < 0.001. A significant difference was found between fledglings and adults of A. noctua (P < 0.001) and S. aluco (P = 0.002). CONCLUSIONS: There is no significant difference in CTT between the different corneal regions in all the species studied. Corneal sensitivity is similar between diurnal and nocturnal birds of prey. Age is a determining factor in the CTT of A. noctua and S. aluco, with fledglings having a significantly higher CTT. PMID- 23750556 TI - Up-regulation of endothelial nitric oxide synthase (eNOS), silent mating type information regulation 2 homologue 1 (SIRT1) and autophagy-related genes by repeated treatments with resveratrol in human umbilical vein endothelial cells. AB - Resveratrol, a polyphenolic phytoalexin found in red wine and various plants, has been reported to up-regulate the expression of endothelial NO synthase (eNOS) in human umbilical vein endothelial cells (HUVEC). However, this effect was neither long term in nature nor physiologically relevant at the concentration of resveratrol studied. In the present study, we investigated the effects of repeated treatments with a lower concentration of resveratrol on the expression of genes in HUVEC. The expression levels of eNOS and silent mating type information regulation 2 homologue 1 (SIRT1) were up-regulated in HUVEC by repeated treatments with 1 MUM-resveratrol for 6 d, but not with fenofibrate. Moreover, resveratrol treatment increased the expression of autophagy-regulated genes such as gamma-aminobutyric acid A receptor-associated protein (GABARAP), microtubule-associated protein 1 light chain 3B (LC3B) and autophagy-related protein 3 (ATG3), the radical scavenger activity-related metallothionein-1X (MT1X) gene and the anti-inflammatory activity-related annexin A2 (ANXA) gene. In addition, resveratrol treatment down-regulated the expression of the cell-cycle checkpoint control RAD9 homologue B (RAD9B) gene. These results indicate the beneficial effects of resveratrol on the cardiovascular system. PMID- 23750557 TI - Iliopsoas impingement: a report of 2 cases. AB - Iliopsoas impingement is an under recognized cause of failed total hip arthroplasty. We report 2 cases of iliopsoas impingement resolution diagnosed with the aid of imaging techniques and fluoroscopically guided injection. PMID- 23750558 TI - In vitro characterization and engraftment of adipocytes derived from human induced pluripotent stem cells and embryonic stem cells. AB - Human induced pluripotent stem (iPS) and embryonic stem (ES) cells can differentiate into a variety of cell types. We reported on adipogenic potential of human iPS and ES cells in vitro. In the present study, we investigate the survival and maintenance of adipocytes differentiated in vitro from human iPS and ES cells after transplantation. Following adipogenic induction in vitro, the differentiated cells exhibited functional properties of adipocytes such as lipid storage, lipolysis, and insulin responsiveness. Subsequently, Matrigel containing the differentiated human iPS and ES cells was transplanted into the subcutaneous tissue of nude mice. After 1-4 weeks, the cells with adipocyte-like features were observed in transplanted Matrigel by histological analysis. The human origin of the cells, their lipid accumulation, and gene expression of adipocyte markers in transplanted cells were then confirmed, suggesting the presence of adipocytes in transplanted Matrigel. When the relative areas of these cells were calculated by dividing the adipocyte areas by the total Matrigel areas, we found that they peaked at 2 weeks after transplantation, and that the adipocytes persisted at 4 weeks. The present study demonstrates that human iPS and ES cells can differentiate into adipocytes with functional properties and that adipocytes derived from human iPS and ES cells can survive and maintain the differentiated properties of adipocytes for at least 4 weeks after transplantation. Adipocytes derived from human iPS and ES cells thus have the potential to open new avenues for stem cell-based research into metabolic diseases and future therapeutic applications. PMID- 23750559 TI - Arsenic methylation in soils and its relationship with microbial arsM abundance and diversity, and as speciation in rice. AB - Methylation of arsenic in soil influences its environmental behavior and accumulation by plants, but little is known about the factors affecting As methylation. As speciation was determined in the pore waters of six soils from diverse geographical locations over 54 days of incubation under flooded conditions. The concentration of methylated As (monomethylarsonic acid, MMA, and dimethylarsinic acid, DMA) varied from 0 to 85 MUg L(-1) (0 - 69% of the total As in pore water). Two Bangladeshi paddy soils contaminated by irrigation of As laden groundwater produced large concentrations of inorganic As but relatively little methylated As. Two contaminated paddy soils from China produced a transient peak of DMA during the early phase of incubation. Methylated As represented considerable proportions of the total soluble As in the two uncontaminated soils from the UK and U.S. The copy number of the microbial arsenite methyltransferase gene (arsM) correlated positively with soil pH. However, pore-water methylated As correlated negatively with pH or arsM copy number, and positively with dissolved organic C. GeoChip assay revealed considerable arsM diversity among the six soils, with 27-35 out of 66 sequences in the microarray being detected. As speciation in rice plants grown in the soils generally mirrored that in the pore water. The results suggest that methylated As species in plants originated from the soil and As methylation in soil was influenced strongly by the soil conditions. PMID- 23750560 TI - Stress distribution around osseointegrated implants with different internal-cone connections: photoelastic and finite element analysis. AB - The goal of this study was to evaluate the distribution of stresses generated around implants with different internal-cone abutments by photoelastic (PA) and finite element analysis (FEA). For FEA, implant and abutments with different internal-cone connections (H- hexagonal and S- solid) were scanned, 3D meshes were modeled and objects were loaded with computer software. Trabecular and cortical bones and photoelastic resin blocks were simulated. The PA was performed with photoelastic resin blocks where implants were included and different abutments were bolted. Specimens were observed in the circular polariscope with the application device attached, where loads were applied on same conditions as FEA. FEA images showed very similar stress distribution between two models with different abutments. Differences were observed between stress distribution in bone and resin blocks; PA images resembled those obtained on resin block FEA. PA images were also quantitatively analyzed by comparing the values assigned to fringes. It was observed that S abutment distributes loads more evenly to bone adjacent to an implant when compared to H abutment, for both analysis methods used. It was observed that the PA has generated very similar results to those obtained in FEA with the resin block. PMID- 23750561 TI - Renal transposition during minimally invasive partial nephrectomy: a safe technique for excision of upper pole tumors. AB - Minimally invasive partial nephrectomy (MIPN) for upper pole masses, particularly for those located posteriorly, is challenging because of difficult visualization during tumor resection and renorrhaphy. Complete renal transposition facilitates access to and excision of upper pole renal masses during MIPN. Sixteen patients with upper pole renal masses underwent laparoscopic or robot-assisted partial nephrectomy with renal transposition from October 2009 to March 2012 with a mean follow-up of 22 months. Mean operative time was 242.6 minutes, and mean warm ischemic time was 14.7 minutes. No patient needed an intraoperative or postoperative blood transfusion. Five (31%) patients had a postoperative complication (four Clavien grade I, one Clavien grade II). There were no delayed complications, positive surgical margins, or tumor recurrences. Mean postoperative eGFR change within 3 months was -9.4%. These results show that complete renal transposition can be safely used to facilitate excision of upper pole tumors. PMID- 23750562 TI - Powassan virus encephalitis, Minnesota, USA. PMID- 23750563 TI - Chronic pain and the development of a symptom checklist: a pilot study. AB - BACKGROUND: There is currently no instrument to systematically assess the range of symptoms/problems and their bothersomeness in patients with chronic non-cancer pain (CNPN). Systematic assessment and prioritizing may target treatments and improve outcomes. METHODS: The authors developed a checklist of symptoms and problems, the Copenhagen Symptom Checklist (CSC), presented clinically by patients. Fifty-three items representing biological, psychological and social areas were selected. Symptom/problem severity was rated on a 5-point scale anchored at 0 = 'not at all' and 4 = 'severe'. Patients ranked the five most bothersome symptoms/problems and could add five open-ended items. Patients completed the CSC after the first visit at the multidisciplinary pain centre. RESULTS: One hundred and twelve consecutive patients completed the CSC. Eighty nine percent scored pain as rather severe or very severe (score = 3 plus score = 4), followed by reduction in physical activity (67%), fatigue (66%) and sleep disturbance (53%). Pain and fatigue, but not reduction in physical activity, were given highest priority. Cognitive problems were important to a third of the patients. Depressive symptoms, cognitive problems and worry explained 17.5% of the total variance. Patients filled in the CSC without important loss of information, but a minority prioritized more than three areas or used the free text alternative. CONCLUSIONS: Patients prioritized pain and fatigue as the most burdensome symptoms, but reduction in physical activity and sleep problems were also highly ranked. Patients were positive to the idea of symptom reporting; however, the 53-item number in this version of CSC is larger than may be necessary. PMID- 23750564 TI - Guilty, but not ashamed: "true" self-conceptions influence affective responses to personal shortcomings. AB - The current research examined how true self-conceptions (who a person believes he or she truly is) influence negative self-relevant emotions in response to shortcomings. In Study 1 (N = 83), an Internet sample of adults completed a measure of authenticity, reflected on a shortcoming or positive life event, and completed state shame and guilt measures. In Study 2 (N = 49), undergraduates focused on true versus other determined self-attributes, received negative performance feedback, and completed state shame and guilt measures. In Study 3 (N = 138), undergraduates focused on self-determined versus other determined self aspects, reflected on a shortcoming or neutral event, and completed state shame, guilt, and self-esteem measures. In Study 4 (N = 75), undergraduates thought about true self-attributes, an achievement, or an ordinary event; received positive or negative performance feedback; and completed state shame and guilt measures. In Study 1, differences in true self-expression positively predicted shame-free guilt (but not guilt-free shame) following reminders of a shortcoming. Studies 2-4 found that experimental activation of true self-conceptions increased shame-free guilt and generally decreased guilt-free shame in response to negative evaluative experiences. The findings offer novel insights into true self conceptions by revealing their impact on negative self-conscious emotions. PMID- 23750566 TI - Is there any benefit in surgery for potentially malignant disorders of the oral cavity? AB - Oral epithelial dysplasia grading is currently recognised as the most useful prognostic indicator for predicting conversion of potentially malignant disorders of the oral cavity to squamous cell carcinoma. It is also used as a basis for deciding management options. However, the diagnosis of oral epithelial dysplasia is subjective and thus unreliable. Surgery is currently recommended for removal of high-risk lesions; however, the evidence for its success is lacking, and in some cases, there have been reports of increased recurrence of malignancy following surgical excision. Molecular and genetic markers have been identified and show promising results in identifying which potential malignant disorders are at risk of malignant transformation. The current evidence available for prognosis of potential malignant disorders and its treatment is based on observational and retrospective data. No randomised control trials have been conducted to date to assess the efficacy of surgery in oral epithelial dysplasia. Until good quality evidence is available from well-designed randomised control trials, experts still recommend the surgical removal of potential malignant disorders which are regarded as high risk. PMID- 23750565 TI - Diversity and distributional patterns of ciliates in Guaymas Basin hydrothermal vent sediments. AB - Little is known about protists at deep-sea hydrothermal vents. The vent sites at Guaymas Basin in the Gulf of California are characterized by dense mats of filamentous pigmented or nonpigmented Beggiatoa that serve as markers of subsurface thermochemical gradients. We constructed 18S rRNA libraries to investigate ciliate assemblages in Beggiatoa mats and from bare sediments at the Guaymas vent site. Results indicated a high diversity of ciliates, with 156 operational taxonomic units identified in 548 sequences. Comparison between mat environments demonstrated that ciliate and bacterial assemblages from pigmented mats, nonpigmented mats, and bare sediments were significantly different and highly correlated with bacterial assemblages. Neither bacterial nor ciliate assemblages were correlated with environmental factors. The most abundant ciliates at Guaymas were more likely to be represented in clone libraries from other hydrothermal, deep-sea, and/or anoxic or microaerophilic environments, supporting the hypothesis that these ciliate species are broadly distributed. The orange mat environment included a higher proportion of ciliate sequences that were more similar to those from other environmental studies than to cultured ciliate species, whereas clone libraries from bare sediments included sequences that were the most highly divergent from all other sequences and may represent species that are endemic to Guaymas. PMID- 23750567 TI - A simple geometric validation approach to assess the basic behaviour of space- and time- distributed models of epidemic spread - an example using the Ontario rabies model. AB - Dynamic mathematical modelling and stochastic simulation of disease-host systems for the purpose of epidemiological analysis offer great opportunities for testing hypotheses, especially when field experiments are impractical or when there is a need to evaluate multiple experimental scenarios. This, combined with the ever increasing computer power available to researchers, has contributed to the development of many mathematical models for epidemic simulations, such as the individual-based model (IBM). Nevertheless, few of these models undergo extensive validation and proper assessment of intrinsic variability. The Ontario rabies model (ORM) will be used here to exemplify some advantages of appropriate model behaviour validation and to illustrate the use of a simple geometric procedure for testing directional bias in distributed stochastic dynamic model of spread of diseases. Results were obtained through the comparison of 10 000 epizootics resulting from 100 epidemic simulations started using 100 distinct base populations. The analysis results demonstrated a significant directional bias in epidemic dispersion, which prompted further verification of the model code and the identification of a coding error, which was then corrected. Subsequent testing of the corrected code showed that the directional bias could no longer be detected. These results illustrate the importance of proper validation and the importance of sufficient knowledge of the model behaviour to ensure the results will not confound the objectives of the end-users. PMID- 23750568 TI - Self-templated free-radical polymerization to form tactic chains in confined environment. AB - It is known that the free-radical propagation chain possesses no stereospecificity as the single electron in the p-orbital of radical is equally accessible to the reactants from the bilateral sides, leading to the formation of atactic polymer chains. This sterically uncontrolled radical chain propagation could be rectified through repressing the degrees of freedom of the reactive vinyl monomer molecules by compression as predicted by our molecular simulation. The simulation unveils that molecules undergo ordered alignment upon being compressed to a certain extent to counteract the increase in chemical potential. We validated this concept by polymerizing N-isopropylacrylamide, a solid monomer, in a highly confined environment, from which a block copolymers consisting of 68% isotactic blocks was achieved. The additional account was attained from polymerizing liquid styrene under compression, which led to 43.1% isotactic polystyrene blocks. It is thus conceived that an ordered array of vinyl monomers would regulate their steric orientation until they join the propagating polymer chains. In conclusion, specifically, molecular confinement results in self templated effect and hence offers a unique pathway for stereoselective chain growth. PMID- 23750569 TI - Could parental rules play a role in the association between short sleep and obesity in young children? AB - Short sleep duration is associated with obesity in young children. This study develops the hypothesis that parental rules play a role in this association. Participants were 3-year-old children and their parents, recruited at nursery schools in socioeconomically deprived and non-deprived areas of a North-East England town. Parents were interviewed to assess their use of sleep, television viewing and dietary rules, and given diaries to document their child's sleep for 4 days/5 nights. Children were measured for height, weight, waist circumference and triceps and subscapular skinfold thicknesses. One-hundred and eight families participated (84 with complete sleep data and 96 with complete body composition data). Parental rules were significantly associated together, were associated with longer night-time sleep and were more prevalent in the non-deprived-area compared with the deprived-area group. Television-viewing and dietary rules were associated with leaner body composition. Parental rules may in part confound the association between night-time sleep duration and obesity in young children, as rules cluster together across behavioural domains and are associated with both sleep duration and body composition. This hypothesis should be tested rigorously in large representative samples. PMID- 23750570 TI - Alcohol: is the evidence base guiding public policy? PMID- 23750571 TI - Adjunct ultrasonography for breast cancer screening in women at average risk: a systematic review. AB - BACKGROUND: Screening with mammography has the ability to detect breast cancer at an early stage but misses some cancers. Supporters of adjunct ultrasonography to the screening regimen argue that it might be a safe and inexpensive approach to reduce the false-negative rates of screening. Critics are concerned that adjunct ultrasonography will also increase the rate of false-positive findings and can lead to unnecessary biopsies and treatments in women at average risk. AIMS: The purpose of this review was to systematically assess the comparative benefits and harms of mammography with adjunct breast ultrasonography and mammography only in breast cancer screening. METHODS: We searched multiple electronic databases and the Cochrane Breast Cancer Group's Specialised Register (from 1995 to February 2012). To detect ongoing or unpublished studies, we searched trial registries and multiple sources of grey literature. Two researchers independently reviewed all abstracts and full-text articles against pre-defined eligibility criteria. We dually rated the risk of bias of studies and the strength of evidence based on established guidance. RESULTS: We did not detect any controlled studies that provide evidence for (or against) the use of adjunct ultrasonography for screening in women at average risk for breast cancer. Extrapolations of results from women at elevated risk for breast cancer indicate that the false-positive rates in women at average risk who were recalled because of positive ultrasonographies will exceed 98%. In women with dense or very dense breast tissue, the evidence regarding the use of adjunct ultrasonography is not conclusive. CONCLUSIONS: No methodologically sound evidence is available justifying the routine use of ultrasonography as an adjunct screening tool in women at average risk for breast cancer. IMPLICATIONS FOR PRACTICE: Clinicians should not use ultrasonography as a screening tool for breast cancer screening on a routine basis. The use should be limited to women with dense breasts for whom the accuracy of mammography is low, or for diagnostic purposes. PMID- 23750572 TI - Towards a conceptual consensus of continuity in mental healthcare: focused literature search and theory analysis. AB - AIM: While continuity of care is an important component in the provision of mental health services, a universally accepted definition is missing. There is a need to identify areas of consensus and discrepancy in continuity theory and provide a foundation for advancing measurement capabilities. The purpose of this study was to systematically identify and examine scholarship on continuity in mental healthcare. METHODS: Using a focused literature review modelled on the Joanna Briggs Methodology for systematic reviews, MEDLINE, CINAHL, Embase, PsycINFO and Health STAR were searched from 1950 to 2011 for articles on the theoretical nature of continuity in mental healthcare. Included conceptualisations were subject to a theory analysis to critically examine similarities and differences. Next, a content analysis on the extracted data was used to identify a global understanding and set of theoretically defined concepts for the whole. Finally, the identified global concepts were compared with the original documents and to items identified on existing quantitative measurement tools to assess areas of consensus and discrepancy. RESULTS: Seven documents describing the conceptualisation of continuity in mental healthcare were identified. From these, a deductive theoretical summary is proposed and theoretical consensus exists to support nine global concepts of continuity in mental healthcare. These global concepts include Longitudinality, Input & Individuality, Comprehensiveness, Flexible Consistency, Stability & Relationship, Accessibility, Information & Sharing, Realities, and Responsibility/Accountability. The original theories proposed by Dr Bachrach and colleagues and Dr Joyce and colleagues, as well as the ACSS-MH measurement tool, provide the best coverage of the proposed concepts. CONCLUSIONS: Consensus exists across conceptualisations of continuity in mental healthcare, yet it is obscured by inconsistent use of language. Existing tools capture many of the associated concepts and elements, but none do so entirely. Further tool development and psychometric testing is needed. This study provides the foundational work required to advance research priorities in this area. PMID- 23750573 TI - Advance care planning in the oncology settings. AB - BACKGROUND: Self-determination and patient choice of end-of-life care are emphasised in palliative care. Advance care planning (ACP) is an approach to enabling patients' choices. The use of ACP has not been extensively studied in our current context. Little is known about oncology care nurses' views and the barriers they face in the implementation of ACP. OBJECTIVE: The aims of this study were to assess the uptake of ACP by health professionals and explore nurses' perceived barriers for implementing ACP. METHODS: This study employed a pre- and post-implementation audit design using the Joanna Briggs Institute (JBI) Practical Application of Clinical Evidence System (PACES) and Getting Research into Practice (GRIP) programs. An education programme on ACP was provided between pre-and post-implementation audits. Nurses and medical professionals (pre-audit, n = 32; post-audit, n = 30) working in oncology departments were invited to complete a questionnaire based on the audit criteria. A convenience sample of 25 nurses participated in the focus group interview. Interview data were analysed by content analysis. RESULTS: The post-audit results were lower than the pre-audit results with a range of decreased compliance from 1% for criterion 5 to 14% for criterion 6. Lack of time to implement ACP was the most frequently raised barrier by oncology nurses. CONCLUSIONS: The study findings were disappointing, but this first audit is significant to provide insights for future dissemination and implementation of ACP interventions. An ongoing mandatory professional development programme in ACP for healthcare staff is promising to promote the uptake of ACP in healthcare settings. PMID- 23750574 TI - Assessment of cardiovascular risk and target organ damage among adult patients with primary hypertension in Thika Level 5 Hospital, Kenya: a criteria-based clinical audit. AB - BACKGROUND: Appropriate management of hypertension reduces the risk of death from stroke and cardiac disease and includes routine assessment for target organ damage and estimation of cardiovascular risk. However, implementation of evidence based hypertension management guidelines is unsatisfactory. We explore the use of audit and feedback as a quality improvement (QI) strategy for reducing the knowledge practice gap in hypertension care in a resource poor setting. AIMS: The aim of this study is to determine the level of compliance to evidence-based guidelines on assessment of cardiovascular risk and target organ damage among patients with hypertension in Thika Level 5 Hospital in central Kenya and to implement best practice with regard to evidence utilisation among clinicians in the hospital. METHOD: A retrospective clinical audit done in three phases spread over 5 months. Phase one involved identifying five audit criteria on assessment of cardiovascular risk and target organ damage in patients with hypertension and conducting a baseline audit in which compliance to audit criteria, blood pressure control and drug prescription practices were assessed. Phase two involved identifying barriers to compliance to audit criteria and strategies to overcoming these barriers. The third phase was a follow-up audit. RESULTS: There was no use of a cardiovascular risk assessment tool in both audits (0% vs. 0%; P = 1.00). Testing urine for haematuria and proteinuria reduced from 13% to 8% (P = 0.230) while taking a blood sample for measuring blood glucose, electrolytes and creatinine levels improved from 11% to 17% (P = 0.401). Performance of fundoscopy and electrocardiography remained unchanged at 2% and 8%, respectively (P = 0.886 and P = 0.898). High patient load was identified as the biggest barrier to implementation of best practice. Blood pressure control improved from 33% to 70% (P <= 0.001), whereas the proportion of patients on two or more recommended antihypertensive drugs rose from 59% to 72% (P = 0.158). CONCLUSION: In Thika Level 5 Hospital, audit and feedback has a poor impact on assessment of cardiovascular risk and target organ damage but positive impact on blood pressure control and prescription practices. Time and sample size may have affected observed results. Additional audits and alternative QI strategies are warranted. PMID- 23750575 TI - Experience of adapting and implementing an evidence-based nursing guideline for prevention of diaper dermatitis in a paediatric oncology setting. AB - BACKGROUND: Diaper dermatitis is one of the most common skin problems in children often caused by irritants that promote skin breakdown, such as moisture and faecal enzymes. It has been estimated that the incidence of diaper dermatitis is as high as 50% in children receiving chemotherapy. The scientific literature suggests a variety of preventative measures, but only a minority are systematically tested and supported by clinical evidence. AIM: The purpose of this paper is to adapt and implement a skincare guideline to better prevent diaper dermatitis in the paediatric oncology population. METHODS: The Knowledge to Action process was used to guide the adaptation and implementation of the new guideline. As part of this process, different tools were used to identify and review selected knowledge (Appraisal of Guidelines Research Evaluation instrument), to tailor and adapt knowledge to the local context (ADAPTE process), to implement interventions (Registered Nurses' Association of Ontario toolkit) and to evaluate outcomes (qualitative analysis). The main outcomes measured included implementation of the guideline and nursing practice change. RESULTS: The guideline was successfully implemented as reported by nurses in focus group sessions and as measured by changes in nursing documentation. CONCLUSION: The implementation of the guideline was successful on the account of the interplay of three core elements: The level and nature of the evidence; the context in which the research was placed; the method in which the process was facilitated. PMID- 23750576 TI - Implementation of the best practice in nasogastric tube feeding of critically ill patients in a neurosurgical intensive care unit. AB - OBJECTIVES: This project was designed to implement the best practice in nasogastric tube feeding of critically ill patients in a neurosurgical intensive care unit. METHODS: Clinical audit software programmes of the Joanna Briggs Institute (Practical Application of Clinical Evidence System and Getting Research Into Practice) were used in this project. A baseline audit, feedback, follow-up audit cycle was followed. The audit team analysed the results of the baseline audit, conducted a situational analysis and formulated and implemented a strategic plan to improve the nasogastric tube care. RESULTS: Initially, the compliance with the criteria varied from 0% to 87%. The Getting Research Into Practice phase of the project identified several barriers of each criterion. After implementation of best practice, the following audit showed an improvement in all criteria, ranging from 33% to 95%. Marked improvement was achieved in the criteria that were not strictly required by local standards, such as rechecking the tube position, assessing the gastric residual volume and maintaining the airway cuff pressure. CONCLUSION: The project had some success in improving the practice of nasogastric tube feeding. Collaboration, education, monitoring and a reward system were the key elements used to drive the project. Further actions and changes are expected to produce 100% compliance. PMID- 23750577 TI - Role of international registries in enhancing the care of familial hypercholesterolaemia. AB - Familial hypercholesterolaemia (FH) is a relatively common genetic disorder associated with high risk of coronary heart disease that is preventable by early diagnosis and treatment. In a previous article, we reviewed the evidence for clinical management, models of care and health economic evaluations. The present commentary emphasises that collective action is needed to strengthen our approaches to evidence-based care, including better diagnosis and access to effective therapies. We detail how contemporary innovations in inter-operable, web-based, open-source and secure registries can provide the supporting infrastructure to: (i) address a current gap in the flow of data for measuring the quality of healthcare; (ii) support basic research through provision of high quality, de-identified aggregate data; (iii) enable equitable access to clinical trials; and (iv) support efforts to disseminate evidence for best practice and information for care services. We describe how these aspects of enabling infrastructure will be incorporated into the development of a National FH Registry for Australasia, and proffer that a coordinated response to FH would be enhanced through a global network of inter-operable registries. PMID- 23750582 TI - Risk factors for oral mucositis in children receiving hematopoietic cell transplantation for primary immunodeficiencies: a retrospective study. AB - OM is a frequent complication for patients undergoing HSCT. The aim of this study was to evaluate the possible risk factors for OM in children undergoing HSCT for PI. A retrospective study was carried out on 55 consecutive medical records of patients with PI (including osteopetrosis) who underwent HSCT. Age at the time of HSCT, gender, diagnosis, type of donor, conditioning regimen, engraftment, graft versus-host disease, and severity and duration of OM were collected at the beginning of the conditioning until day 100 post-HSCT or death. OM was measured using the WHO scale. Patients' age range at the time of HSCT was quite wide; 59.2% of the patients who were under nine months (n = 13) developed OM vs. 87.8% of the patients older than nine months (n = 29) (p = 0.01). T-cell positive patients had a statistically significant higher risk of developing OM (p = 0.04), as did those receiving a more intensive conditioning regimen (p < 0.01). PI patients undergoing HSCT are at higher risk of developing OM if the PI is a T lymphocyte-positive disease and/or if the HSCT recipient is over nine months of age. PMID- 23750583 TI - Photoswitching azo compounds in vivo with red light. AB - The photoisomerization of azobenzenes provides a general means for the photocontrol of molecular structure and function. For applications in vivo, however, the wavelength of irradiation required for trans-to-cis isomerization of azobenzenes is critical since UV and most visible wavelengths are strongly scattered by cells and tissues. We report here that azobenzene compounds in which all four positions ortho to the azo group are substituted with bulky electron rich substituents can be effectively isomerized with red light (630-660 nm), a wavelength range that is orders of magnitude more penetrating through tissue than other parts of the visible spectrum. When the ortho substituent is chloro, the compounds also exhibit stability to reduction by glutathione, enabling their use in intracellular environments in vivo. PMID- 23750585 TI - A dose titration study into the effects of diazepam or midazolam on the propofol dose requirements for induction of general anaesthesia in client owned dogs, premedicated with methadone and acepromazine. AB - OBJECTIVE: To assess the effect of a benzodiazepine co-induction on propofol dose requirement for induction of anaesthesia in healthy dogs, to describe any differences between midazolam and diazepam and to determine an optimal benzodiazepine dose for co-induction. STUDY DESIGN: Prospective, randomised, blinded placebo controlled clinical trial. ANIMALS: Ninety client owned dogs (ASA I-III, median body mass 21.5kg (IQR 10-33)) presented for anaesthesia for a variety of procedures. METHODS: Dogs were randomised to receive saline 0.1 mL kg( 1) , midazolam or diazepam at 0.2, 0.3, 0.4 or 0.5 mg kg(-1) . All dogs received 0.01 mg kg(-1) acepromazine and 0.2 mg kg(-1) methadone intravenously (IV). Fifteen minutes later, sedation was assessed and scored prior to anaesthetic induction. Propofol, 1 mg kg(-1) , was administered IV, followed by the treatment drug. Further propofol was administered until endotracheal intubation was possible. Recorded data included patient signalment, sedation score, propofol dosage and any adverse reactions. RESULTS: Midazolam (all groups combined) significantly reduced propofol dose requirement compared to saline (p < 0.001) and diazepam (p = 0.008). Midazolam (0.4 mg kg(-1) ) significantly reduced propofol dose requirement (p = 0.014) compared to saline, however other doses failed to reach statistical significance. Diazepam did not significantly reduce propofol dose requirement compared to saline (p = 0.089). Dogs weighing <5 kg, regardless of treatment group, required a greater propofol dose than those weighing 5-40 kg (p = 0.002) and those >40 kg (p = 0.008). Dogs which were profoundly sedated required less propofol than those which were mildly sedated (p < 0.001) and adequately sedated (p = 0.003). CONCLUSIONS AND CLINICAL RELEVANCE: Midazolam (0.4 mg kg(-1) ) given IV after 1 mg kg(-1) of propofol significantly reduced the further propofol dose required for intubation compared to saline. At the investigated doses, diazepam did not have significant propofol dose sparing effects. PMID- 23750584 TI - Arabidopsis CHROMOSOME TRANSMISSION FIDELITY 7 (AtCTF7/ECO1) is required for DNA repair, mitosis and meiosis. AB - The proper transmission of DNA in dividing cells is crucial for the survival of eukaryotic organisms. During cell division, faithful segregation of replicated chromosomes requires their tight attachment, known as sister chromatid cohesion, until anaphase. Sister chromatid cohesion is established during S-phase in a process requiring an acetyltransferase that in yeast is known as Establishment of cohesion 1 (Eco1). Inactivation of Eco1 typically disrupts chromosome segregation and homologous recombination-dependent DNA repair in dividing cells, ultimately resulting in lethality. We report here the isolation and detailed characterization of two homozygous T-DNA insertion mutants for the Arabidopsis thaliana Eco1 homolog, CHROMOSOME TRANSMISSION FIDELITY 7/ESTABLISHMENT OF COHESION 1 (CTF7/ECO1), called ctf7-1 and ctf7-2. Mutants exhibited dwarfism, poor anther development and sterility. Analysis of somatic tissues by flow cytometry, scanning electron microscopy and quantitative real-time PCR identified defects in DNA repair and cell division, including an increase in the area of leaf epidermal cells, an increase in DNA content and the upregulation of genes involved in DNA repair including BRCA1 and PARP2. No significant change was observed in the expression of genes that influence entry into the endocycle. Analysis of meiocytes identified changes in chromosome morphology and defective segregation; the abundance of chromosomal-bound cohesion subunits was also reduced. Transcript levels for several meiotic genes, including the recombinase genes DMC1 and RAD51C and the S-phase licensing factor CDC45 were elevated in mutant anthers. Taken together our results demonstrate that Arabidopsis CTF7/ECO1 plays important roles in the preservation of genome integrity and meiosis. PMID- 23750588 TI - On the role of electronic friction for dissociative adsorption and scattering of hydrogen molecules at a Ru(0001) surface. AB - The role of electronic friction and, more generally, of nonadiabatic effects during dynamical processes at the gas/metal surface interface is still a matter of discussion. In particular, it is not clear if electronic nonadiabaticity has an effect under "mild" conditions, when molecules in low rovibrational states interact with a metal surface. In this paper, we investigate the role of electronic friction on the dissociative sticking and (inelastic) scattering of vibrationally and rotationally cold H2 molecules at a Ru(0001) surface theoretically. For this purpose, classical molecular dynamics with electronic friction (MDEF) calculations are performed and compared to MD simulations without friction. The two H atoms move on a six-dimensional potential energy surface generated from gradient-corrected density functional theory (DFT), that is, all molecular degrees of freedom are accounted for. Electronic friction is included via atomic friction coefficients obtained from an embedded atom, free electron gas (FEG) model, with embedding densities taken from gradient-corrected DFT. We find that within this model, dissociative sticking probabilities as a function of impact kinetic energies and impact angles are hardly affected by nonadiabatic effects. If one accounts for a possibly enhanced electronic friction near the dissociation barrier, on the other hand, reduced sticking probabilities are observed, in particular, at high impact energies. Further, there is always an influence on inelastic scattering, in particular, as far as the translational and internal energy distribution of the reflected molecules is concerned. Additionally, our results shed light on the role played by the velocity distribution of the incident molecular beam for adsorption probabilities, where, in particular, at higher impact energies, large effects are found. PMID- 23750587 TI - Pouch Roll Technique for Implant Soft-Tissue Augmentation of Small Defects: Two Case Reports With 5-Year Follow-Up. PMID- 23750586 TI - Chronic activation of the low affinity site of beta1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling. AB - BACKGROUND AND PURPOSE: The beta1-adrenoceptor has at least two binding sites, high and low affinity sites (beta1H and beta1L, respectively), which mediate cardiostimulation. While beta1H-adrenoceptor can be blocked by all clinically used beta-blockers, beta1L-adrenoceptor is relatively resistant to blockade. Thus, chronic beta1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of beta1H-adrenoceptors. Hence, it is important to determine the potential significance of beta1L adrenoceptors in vivo, particularly in pathological situations. EXPERIMENTAL APPROACH: C57Bl/6 male mice were used. Chronic (4 or 8 weeks) beta1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)-CGP12177 (10 mg.kg(-1).day(-1)). Cardiac function was assessed by echocardiography and micromanometry. KEY RESULTS: (-)-CGP12177 treatment of healthy mice increased heart rate and left ventricular (LV) contractility. (-)-CGP12177 treatment of mice subjected to transverse aorta constriction (TAC), during weeks 4-8 or 4-12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)-CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC. CONCLUSIONS AND IMPLICATIONS: beta1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained beta1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure. PMID- 23750590 TI - Air quality impact and physicochemical aging of biomass burning aerosols during the 2007 San Diego wildfires. AB - Intense wildfires burning >360000 acres in San Diego during October, 2007 provided a unique opportunity to study the impact of wildfires on local air quality and biomass burning aerosol (BBA) aging. The size-resolved mixing state of individual particles was measured in real-time with an aerosol time-of-flight mass spectrometer (ATOFMS) for 10 days after the fires commenced. Particle concentrations were high county-wide due to the wildfires; 84% of 120-400 nm particles by number were identified as BBA, with particles <400 nm contributing to mass concentrations dangerous to public health, up to 148 MUg/m(3). Evidence of potassium salts heterogeneously reacting with inorganic acids was observed with continuous high temporal resolution for the first time. Ten distinct chemical types shown as BBA factors were identified through positive matrix factorization coupled to single particle analysis, including particles comprised of potassium chloride and organic nitrogen during the beginning of the wildfires, ammonium nitrate and amines after an increase of relative humidity, and sulfate dominated when the air mass back trajectories passed through the Los Angeles port region. Understanding BBA aging processes and quantifying the size-resolved mass and number concentrations are important in determining the overall impact of wildfires on air quality, health, and climate. PMID- 23750591 TI - Allogeneic lethally irradiated cord blood mononuclear cells in no-option critical limb ischemia: a "box of rain". AB - Critical limb ischemia (CLI) is burdened by a 40% major amputation rate, and a 5 year life expectancy <50%. We report the first in-human injection of lethally gamma-irradiated non-human leukocyte antigen (HLA)-matched cord blood (CB) derived mononuclear cells in a no-option CLI patient, to induce therapeutic neo angiogenesis, with evidence of successful outcome supported by clinical findings (ulcer healing and pain relief), instrumental assessment (transcutaneous O2 pressure, ankle/brachial index, and contrast-enhanced ultrasonography), and histological demonstration of muscular tissue repair and capillary network expansion. If our approach will be confirmed, the huge number of CB units currently discarded might be redirected toward regenerative medicine purposes, leading to cutting-edge solutions for important unmet clinical needs, such as ischemic diseases, which remain the main cause of disability and mortality in western countries. PMID- 23750592 TI - Human enterovirus genotype C104, China. PMID- 23750593 TI - Dutasteride for the treatment of benign prostatic hyperplasia. AB - INTRODUCTION: Benign prostatic hyperplasia (BPH) is an age-related phenomenon associated with prostatic enlargement and bladder outlet obstruction that can cause significant lower urinary tract symptoms that greatly affect quality of life. Dutasteride is a selective inhibitor of type 1 and type 2 isoforms of 5 alpha-reductase, an enzyme responsible for the conversion of testosterone to 5 alpha-dihydrotestosterone, approved as a treatment for symptomatic BPH. AREAS COVERED: This article will cover the efficacy and safety of dutasteride in the treatment of BPH, with focus on landmark trials conducted on this drug. Medical literature on the use of dutasteride in men with BPH were identified by searching databases since 1996 (including MEDLINE and EMBASE) as well as bibliographies from published literature, clinical trial registries and manufacturer and federal drug regulatory websites. EXPERT OPINION: Dutasteride is an effective, safe and well-tolerated treatment either as monotherapy or in combination with an alpha blocker, for the management of symptomatic BPH to improve symptoms, reduce the risk of acute urinary retention and risk for BPH-related surgery. A new prostate specific antigen baseline should be established after 6 months of therapy for clinical decision making. The relationship between dutasteride and high-grade prostate cancer is not clear, and dutasteride is not approved for prostate cancer chemoprevention. PMID- 23750595 TI - Long-term significance (15 years) of pathological complete response after dose dense neoadjuvant chemotherapy in breast cancer. PMID- 23750596 TI - Levels and sources of sound in the intensive care unit - an observational study of three room types. AB - BACKGROUND: Many intensive care unit (ICU) patients describe noise as stressful and precluding sleep. No previous study in the adult setting has investigated whether room size impacts sound levels or the frequency of disruptive sounds. METHODS: A-frequency S-time weighted equivalent continuous sound (LAS eq), A frequency S-time weighted maximum sound level (LAS max) and decibel C peak sound pressure (LC peak) were measured during five 24-h periods in each of the following settings: three-bed room with nursing station (NS) alcove, single-bed room with NS alcove (1-BR with NSA) and single-bed room with bedside NS. Cumulative restorative time (CRT) (> 5 min with LAS max < 55 dB and LC peak < 75 dB) was calculated to describe calm periods. Two 8-h bedside observations were performed in each setting in order to note the frequency and sources of disruptive sounds. RESULTS: Mean sound pressure levels (LAS eq) ranged between 52 and 58 dBA, being lowest during night shifts. There were no statistically significant differences between the room types in mean sound levels or in CRT. However, disruptive sounds were 40% less frequent in the 1-BR with NSA than in the other settings. Sixty-four percent of disruptive sounds were caused by monitor alarms and conversations not related to patient care. CONCLUSIONS: Single bed rooms do not guarantee lower sound levels per se but may imply less frequent disruptive sounds. Sixty-four percent of disruptive sounds were avoidable. Our findings warrant sound reducing strategies for ICU patients. PMID- 23750598 TI - Detecting insider threats through language change. AB - The act of conducting an insider attack carries with it cognitive and social challenges that may affect an offender's day-to-day work behavior. We test this hypothesis by examining the language used in e-mails that were sent as part of a 6-hr workplace simulation. The simulation involved participants (N = 54) examining databases and exchanging information as part of a four-stage organized crime investigation. After the first stage, 25% of the participants were covertly incentivized to act as an "insider" by providing information to a provocateur. Analysis of the language used in participants' e-mails found that insiders became more self-focused, showed greater negative affect, and showed more cognitive processing compared to their coworkers. At the interpersonal level, insiders showed significantly more deterioration in the degree to which their language mimicked other team members over time. Our findings demonstrate how language may provide an indirect way of identifying employees who are undertaking an insider attack. PMID- 23750597 TI - Does IQ moderate the relation between psychopathy and juvenile offending? AB - Although evidence indicates that both psychopathy and intelligence independently predict juvenile offending, relations among IQ, psychopathy, and offending are inconsistent. We investigated whether intelligence moderates the relation between psychopathy and both income and aggressive offending concurrently and over time among 1,354 juvenile offenders enrolled in Pathways to Desistance, a prospective study of serious juvenile offenders in Philadelphia, Pennsylvania, and Phoenix, Arizona. Participants were assessed on intelligence, psychopathy, and self reported offending at their initial interview (age range: 14-18 years old), and at 36 and 84 months later. Results indicate that intelligence moderates the concurrent relation between both income and aggressive offending and total psychopathy, as well as scores on Factor 1 (interpersonal/affective) and Factor 2 (social deviance); the 36-month prospective relation between all aspects of psychopathy and income offending; and the 84-month prospective relation between Factor 2 psychopathy and aggressive offending. As expected, higher levels of psychopathy are associated with higher levels of offending, but the highest levels of offending are evinced among youth with relatively higher levels of psychopathy and relatively higher IQ. PMID- 23750599 TI - The influence of multiple interviews on the verbal markers of children's deception. AB - This study investigated different verbal expressive markers of children recounting both true and false events. Seventy-eight children (M age = 7.58 years) interacted with a research assistant on 3 consecutive days. All children played a game that included a touching component in which the research assistant placed stickers on the child's body. Parents were then asked to coach their children to lie during subsequent interviews occurring 1 week later. Children were interviewed over 3 consecutive days. Results indicated that verbal expressive markers (e.g., cognitive operations, spontaneous corrections, admissions of lack of knowledge, temporal markers) of true and intentionally false reports were different in the first interview. However, these differences disappeared over subsequent interviews. Results of the current study highlight the importance of recording the first interview in which children disclose, particularly when using verbal markers as indicators of deception. PMID- 23750600 TI - The expression and interpretation of uncertain forensic science evidence: verbal equivalence, evidence strength, and the weak evidence effect. AB - Standards published by the Association of Forensic Science Providers (2009, Standards for the formulation of evaluative forensic science expert opinion, Science & Justice, Vol. 49, pp. 161-164) encourage forensic scientists to express their conclusions in the form of a likelihood ratio (LR), in which the value of the evidence is conveyed verbally or numerically. In this article, we report two experiments (using undergraduates and Mechanical Turk recruits) designed to investigate how much decision makers change their beliefs when presented with evidence in the form of verbal or numeric LRs. In Experiment 1 (N = 494), participants read a summary of a larceny trial containing inculpatory expert testimony in which evidence strength (low, moderate, high) and presentation method (verbal, numerical) varied. In Experiment 2 (N = 411), participants read the same larceny trial, this time including either exculpatory or inculpatory expert evidence that varied in strength (low, high) and presentation method (verbal, numerical). Both studies found a reasonable degree of correspondence in observed belief change resulting from verbal and numeric formats. However, belief change was considerably smaller than Bayesian calculations would predict. In addition, participants presented with evidence weakly supporting guilt tended to "invert" the evidence, thereby counterintuitively reducing their belief in the guilt of the accused. This "weak evidence effect" was most apparent in the verbal presentation conditions of both experiments, but only when the evidence was inculpatory. These findings raise questions about the interpretability of LRs by jurors and appear to support an expectancy-based account of the weak evidence effect. PMID- 23750601 TI - "Go ahead and sign": an experimental examination of Miranda waivers and comprehension. AB - This research examined whether the protections afforded by Miranda are compromised by two situational factors that may be present during the Miranda administration process. The factors examined were the police tactic of trivializing the importance of a waiver and the stress that accompanies an accusation of serious misconduct. All participants (N = 89) were accused of misconduct on an experimental task and were led to believe that they would have to discuss the incident with the professor in charge of the experiment. In addition, all participants were asked to sign a waiver of their right to have a student advocate present during that meeting, after which their comprehension of the waiver was assessed. To manipulate the police tactic of trivializing a waiver, participants were told that the waiver had important or trivial implications for their future outcomes. To manipulate stress, participants were told that their misconduct was either a serious or minor violation of the experiment. Results indicated that participants were more likely to sign the waiver and had worse comprehension of its content when it was described as trivial versus important. Participants' comprehension of the waiver was also worse when their misconduct was described as a serious versus a minor violation of the experiment. These findings have implications for policy regarding the standardization of Miranda administration protocols as well as for future research aimed at understanding the influence of situational factors on Miranda waivers and comprehension. PMID- 23750602 TI - FasL expression in articular discs of human temporomandibular joint and association with osteoarthrosis. AB - BACKGROUND: Apoptosis is a programme of cell death which does not induce an inflammatory response. Recent previous research has suggested a correlation between temporomandibular internal derangement and apoptosis. Fas ligand (FasL) is an apoptosis-inducing factor, known to trigger apoptosis through distinct signal pathways. This study aims to examine, by immunohistochemistry, the expression of FasL in temporomandibular joint (TMJ) articular discs of patients with anterior disc displacement with reduction (ADDwR) and without reduction (ADDwoR) in patients with and without osteoarthrosis (OA). METHODS: Forty-two (n = 42) TMJ articular discs were divided into two cut-offs: (i) 8 control, 17 ADDwR, 17 ADDwoR, and (ii) without OA (n = 25) and with OA (n = 17). The area of immunostaining was compared statistically between groups (P < 0.05). RESULTS: Statistically significant differences were found in the expression of FasL in TMJ discs between the three groups (P = 0.001). ADDwR presented significant higher FasL expression when compared with ADDwoR (P < 0.001). Significant higher FasL expression was observed in the group without OA (P = 0.001). All patients without OA presented ADDwR, while all the patients with OA presented ADDwoR. CONCLUSION: A higher area of in situ immunostaining of FasL was found in temporomandibular discs with reduction, which is the less severe condition. Moreover, a reduced expression of FasL in the discs of patients with osteoarthrosis was found, suggesting that some aspects of apoptosis might underlie the progression of TMJ disorders. PMID- 23750603 TI - When the going gets tough: the "why" of goal striving matters. AB - No prior research has examined how motivation for goal striving influences persistence in the face of increasing goal difficulty. This research examined the role of self-reported (Study 1) and primed (Study 2) autonomous and controlled motives in predicting objectively assessed persistence during the pursuit of an increasingly difficult goal. In Study 1, 100 British athletes (64 males; M(age) = 19.89 years, SD(age) = 2.43) pursued a goal of increasing difficulty on a cycle ergometer. In Study 2, 90 British athletes (43 males; M(age) = 19.63 years, SD(age) = 1.14) engaged in the same task, but their motivation was primed by asking them to observe a video of an actor describing her or his involvement in an unrelated study. In Study 1, self-reported autonomous goal motives predicted goal persistence via challenge appraisals and task-based coping. In contrast, controlled goal motives predicted threat appraisals and disengagement coping, which, in turn, was a negative predictor of persistence. In Study 2, primed autonomous (compared to controlled) goal motives predicted greater persistence, positive affect, and future interest for task engagement. The findings underscore the importance of autonomous motivation for behavioral investment in the face of increased goal difficulty. PMID- 23750604 TI - Activation-induced CD137 is a fast assay for identification and multi-parameter flow cytometric analysis of alloreactive T cells. AB - Detection and isolation of viable alloreactive T cells at the single-cell level requires a cell surface marker induced specifically upon T cell receptor activation. In this study, a member of the tumour necrosis factor receptor (TNFR) family, CD137 (4-1BB) was investigated for its potential to identify the total pool of circulating alloreactive T cells. Optimal conditions for sensitive and specific detection of allogeneic-induced CD137 expression on circulating T cells were established. Thereafter, CD137(+) alloreactive T cells were phenotypically and functionally characterized by multi-parameter flow cytometry. Alloantigen induced CD137 expression identified both alloreactive CD8(+) T cells (mean +/- standard error of the mean: 0.21 +/- 0.07%) and alloreactive CD4(+) T cells (0.21 +/- 0.05%). CD137(+) alloreactive T cells were detected in different T cell subsets, including naive T cells, but were found preferentially in CD28(+) T cells and not in the terminally differentiated T cell subset. Upon allogeneic (re )stimulation, the cytokine-producing as well as proliferative capacity of T cells resided mainly within the CD137-expressing fraction. About 10% of the CD137(+) alloreactive T cells produced any combination of interferon (IFN)-gamma, interleukin (IL)-2 and TNF-alpha. Polyfunctional alloreactive T cells, defined by multiple cytokine expression, were observed infrequently. In conclusion, activation-induced CD137 expression is a fast assay allowing for detection and functional analysis of the total alloreactive T cell compartment at the single cell level by multi-parameter flow cytometry. PMID- 23750605 TI - Relationship between clinical fieldwork educator performance and health professional students' perceptions of their practice education learning environments. AB - The Dundee Ready Education Environment Measure, Clinical Teaching Effectiveness Instrument, and Clinical Learning Environment Inventory were completed by 548 undergraduate students (54.5% response rate) enrolled in eight health professional bachelor degree courses. Regression analysis was used to investigate the significant predictors of the Clinical Teaching Effectiveness Instrument with the Dundee Ready Education Environment Measure and Clinical Learning Environment Inventory subscales as independent variables. The results indicated that the Dundee Ready Education Environment Measure and Clinical Learning Environment Inventory Actual version subscale scores explained 44% of the total variance in the Clinical Teaching Effectiveness Instrument score. The Dundee Ready Education Environment Measure subscale Academic Self-Perception explained 1.1% of the variance in the Clinical Teaching Effectiveness Instrument score. The Clinical Learning Environment Inventory Actual subscales accounted for the following variance percentages in the Clinical Teaching Effectiveness Instrument score: personalization, 1.1%; satisfaction, 1.7%; task orientation, 5.1%; and innovation, 6.2%. Aspects of the clinical learning environment appear to be predictive of the effectiveness of the clinical teaching that students experience. Fieldwork educator performance might be a significant contributing factor toward student skill development and practitioner success. PMID- 23750606 TI - Long-term survival rates of implants supporting overdentures. AB - The study aims were to evaluate survival rates of dental implants in patients wearing maxillary and mandibular overdentures in relation to age, sex, smoking, implant splinting or non-splinting, the maxilla rehabilitated, and number of implants per dental arch. This was a prospective study of patients who were completely edentulous in either mandible or maxilla or both, rehabilitated with implant-retained overdentures, with a follow-up of at least 3 years. 95 patients with 107 overdentures were supported by 360 implants were included in the study. Rehabilitations were monitored over an average of 95 +/- 20.3 months (range 36 159). Implant survival in the maxilla was 91.9% and in the mandible 98.6%, representing a statistically significant difference (P < .05). Age, sex and implant splinting did not influence survival rates significantly. Smokers presented a lower survival rate. Implant numbers in the maxilla had a significant influence on survival, 100% for 6 but 85.7% for 4. Three mandibular implants achieved higher survival rates (100%) but with 2 (96.6%) or 4 (99%) survival was lower, although without significant difference. Long-term results suggest that 3 implant mandibular overdentures have an equivalent survival rate to 4-implant overdentures. In the maxilla, results showed that 6 implants may be the best treatment strategy. For smokers with fewer implants retaining the overdentures, there were higher numbers of implant failures. PMID- 23750607 TI - Divergence between organometallic and single-electron-transfer mechanisms in copper(II)-mediated aerobic C-H oxidation. AB - Copper(II)-mediated C-H oxidation is the subject of extensive interest in synthetic chemistry, but the mechanisms of many of these reactions are poorly understood. Here, we observe different products from Cu(II)-mediated oxidation of N-(8-quinolinyl)benzamide, depending on the reaction conditions. Under basic conditions, the benzamide group undergoes directed C-H methoxylation or chlorination. Under acidic conditions, the quinoline group undergoes nondirected chlorination. Experimental and computational mechanistic studies implicate an organometallic C-H activation/functionalization mechanism under the former conditions and a single-electron-transfer mechanism under the latter conditions. This rare observation of divergent, condition-dependent mechanisms for oxidation of a single substrate provides a valuable foundation for understanding Cu(II) mediated C-H oxidation reactions. PMID- 23750608 TI - Structure of 1-alkyl-1-methylpyrrolidinium bis(trifluoromethylsulfonyl)amide ionic liquids with linear, branched, and cyclic alkyl groups. AB - X-ray scattering and molecular dynamics simulations have been carried out to investigate structural differences and similarities in the condensed phase between pyrrolidinium-based ionic liquids paired with the bis(trifluoromethylsulfonyl)amide (NTf2(-)) anion where the cationic tail is linear, branched, or cyclic. This is important in light of the charge and polarity type alternations that have recently been shown to be present in the case of liquids with cations of moderately long linear tails. For this study, we have chosen to use the 1-alkyl-1-methylpyrrolidinium, Pyrr(1,n(+)) with n = 5 or 7, as systems with linear tails, 1-(2-ethylhexyl)-1-methylpyrrolidinium, Pyrr(1,EtHx(+)), as a system with a branched tail, and 1-(cyclohexylmethyl)-1 methylpyrrolidinium, Pyrr(1,ChxMe(+)), as a system with a cyclic tail. We put these results into context by comparing these data with recently published results for the Pyrr(1,n(+))/NTf2(-) ionic liquids with n = 4, 6, 8, and 10.1,2 General methods for interpreting the structure function S(q) in terms of q dependent natural partitionings are described. This allows for an in-depth analysis of the scattering data based on molecular dynamics (MD) trajectories that highlight the effect of modifying the cationic tail. PMID- 23750609 TI - Simulation of titanium metal/titanium dioxide etching with chlorine and hydrogen chloride gases using the ReaxFF reactive force field. AB - In this study, a new ReaxFF reactive force field has been developed to describe reactions in Ti/O/Cl/H materials. This force field was applied to etching simulations for titanium metal and titanium dioxide with chlorine and hydrogen chloride gases. The ReaxFF force field parameters are fitted against a quantum mechanical (QM) training set containing structures and energies related to bond dissociations, angle and dihedral distortions, and reactions between titanium and chlorine gases as well as heats of formation of TiClx crystals. These newly developed Ti-Cl force field parameters were combined with a recently developed Ti O-H force field. ReaxFF accurately reproduces the QM training set for structures and energetics of small clusters and TiClx crystals. In the etching simulations, titanium and titanium dioxide slab models with chlorine and hydrogen chloride gases were used in molecular dynamics simulations. The etching ratio between HCl and Cl2 are compared to experimental results, and satisfactory results are obtained, indicating that this ReaxFF extension provides a useful tool for studying the atomistic-scale details of the etching process. PMID- 23750610 TI - What's new in atopic eczema? An analysis of systematic reviews published in 2010 11. AB - This review provides a summary of key findings from 24 systematic reviews of atopic eczema (AE) published or indexed between 1 August 2010 and 31 December 2011, updating published summaries from previous years. Epidemiological evidence points to the protective effects of early daycare, endotoxin exposure, consumption of unpasteurized milk, and early exposure to dogs, but antibiotic use in early life may increase the risk for AE. With regard to prevention of AE, there is currently no strong evidence of benefit for exclusive breastfeeding, hydrolysed protein formulas, soy formulas, maternal antigen avoidance, omega-3 or omega-6 fatty-acid supplementation, or use of prebiotics or probiotics. With respect to AE treatments, the most compelling new systematic review evidence was for proactive treatment with topical anti-inflammatory agents (topical corticosteroids and topical calcineurin inhibitors) for the prevention of AE flares in patients with moderate to severe AE. A meta-analysis of 4 trials confirmed the superiority of tacrolimus 0.1% over pimecrolimus for the treatment of AE, and a review of 17 trials found that tacrolimus (0.1% or 0.03%) was broadly similar in efficacy to mild/moderate topical corticosteroids. Evidence for the role of education in the management of AE was less conclusive, with evidence from randomized controlled trials showing mixed results. Further work is needed in this area to conduct high-quality trials of educational interventions that are clearly described and reproducible. There is no clear evidence for the efficacy of homeopathy, botanical extracts or Chinese herbal medicine in the treatment of AE, as large well-designed trials are lacking in these areas. PMID- 23750611 TI - Monkey bites among U.S. military members, Afghanistan, 2011. PMID- 23750612 TI - A framework for rehabilitation for cancer survivors. AB - This paper introduces a theoretical framework that recognises the rehabilitation needs of people who have cancer and offers a multi-tiered model to meet these needs. Various models for providing survivorship care have been previously proposed, giving rise to multiple possible delivery systems. Existing cancer rehabilitation frameworks recognise different phases of illness, goals of care and the need for services at all stages of illness. The 'Stained Glass Cancer Rehabilitation Framework' incorporates survivor needs and rehabilitation modalities, arranged in a practical hierarchy and builds on earlier models. A broad view of rehabilitation services considers complexity, temporal and geographic factors. Recognition that needs emerge over time demands a routine long-term approach to screening for physical, functional and psychosocial rehabilitation needs by medical and other health professionals. New methods of care delivery and coordination from specialist to primary care settings are needed, long after treatment is completed. Service delivery infrastructure supported by funding reform and training of rehabilitation professionals in delivering appropriate interventions for cancer survivors is essential, together with more research into cancer rehabilitation interventions, functional outcomes and their delivery. PMID- 23750613 TI - The use of soy protein polymers as a release device for nematophagous fungi in the control of parasitic nematodes in ruminants. AB - This trial was conducted to evaluate the predatory activity of Duddingtonia flagrans incorporated into soy protein-based polymers as a controlled-release device (CRD). The rate of fungal release from the polymers and time of residence of the CRD in the rumen of a cannulated sheep was also determined. After administration to the sheep, the CRD was extracted at weekly intervals over a month for observation of its physical structure and faeces were collected to observe the subsequent predatory activity of the fungus in Petri dishes with water-agar 2% and Panagrellus spp. as bait. The CRD slowly degraded in the rumen over 4 weeks and liberated D. flagrans into the faeces. The formulation of the soy protein-based polymers did not affect the predatory activity of the fungus. The study demonstrates that biodegradable soy protein polymers could potentially improve the use of nematophagous fungi for controlling nematode parasites of ruminants. PMID- 23750614 TI - Ectopic expression of cytosolic superoxide dismutase and ascorbate peroxidase leads to salt stress tolerance in transgenic plums. AB - To fortify the antioxidant capacity of plum plants, genes encoding cytosolic antioxidants ascorbate peroxidase (cytapx) and Cu/Zn-superoxide dismutase (cytsod) were genetically engineered in these plants. Transgenic plum plants expressing the cytsod and/or cytapx genes in cytosol have been generated under the control of the CaMV35S promoter. High levels of cytsod and cytapx gene transcripts suggested that the transgenes were constitutively and functionally expressed. We examined the potential functions of cytSOD and cytAPX in in vitro plum plants against salt stress (100 mm NaCl). Several transgenic plantlets expressing cytsod and/or cytapx showed an enhanced tolerance to salt stress, mainly lines C5-5 and J8-1 (expressing several copies of sod and apx, respectively). Transformation as well as NaCl treatments influenced the antioxidative metabolism of plum plantlets, including enzymatic and nonenzymatic antioxidants. Transgenic plantlets exhibited higher contents of nonenzymatic antioxidants glutathione and ascorbate than nontransformed control, which correlated with lower accumulation of hydrogen peroxide. Overall, our results suggest that transformation of plum plants with genes encoding antioxidant enzymes enhances the tolerance to salinity. PMID- 23750615 TI - Palladium-catalyzed direct C-H arylation of cyclic enaminones with aryl iodides. AB - A ligand-free method for the Pd-catalyzed direct arylation of cyclic enaminones using aryl iodides was developed. This method can be applied to a wide range of cyclic enaminones and aryl iodides with excellent C5-regioselectivity. Using widely available aryl iodides, the generality of this transformation provides easy access to a variety of 3-arylpiperidine structural motifs. PMID- 23750616 TI - Do college drinkers learn from their mistakes? Effects of recent alcohol-related consequences on planned protective drinking strategies among college freshmen. AB - This study examined whether recent alcohol-related consequences affect intentions to use protective drinking strategies. Responses were collected from incoming college freshmen (N = 84,367) at 279 U.S. colleges and universities. Plans to limit future drinking were significantly lower among students who were male, younger, White, or were in or intending to join a fraternity or sorority. For heavy drinkers, having recently experienced a higher level of external harms predicted increased plans to limit drinking. For all drinkers, a lower level of recent impaired driving predicted increased plans to limit drinking. Limitations and implications are discussed. PMID- 23750617 TI - Goal directed fluid therapy: careful with conclusions. PMID- 23750620 TI - Invisible and at risk: STDs among young adult sexual minority women in the United States. AB - CONTEXT: Sexual minority women are not adequately assessed by national STD surveillance systems, and research regarding STD burden in nationally representative samples of such women is rare. Moreover, few studies have assessed STD risk exclusively among young adult women. METHODS: Wave 4 (2007-2008) data from the National Longitudinal Study of Adolescent Health on 7,296 females aged 24-32 were used to examine the relationship between sexual orientation and receipt of an STD diagnosis in the past year. Multivariate logistic regression analyses used two measures of sexual orientation: sexual identity and gender of sex partners. RESULTS: Eighty percent of women considered themselves straight; 16% mostly straight; and 4% bisexual, mostly gay or gay. Eighty-five percent had had only male partners, while 7% had had one female partner, and 8% two or more female partners. In unadjusted models, women who identified themselves as mostly straight were more likely than straight women to have had an STD (odds ratio, 1.4); mostly gay or gay women were at lower risk (0.4). Women who had had two or more female partners had a higher STD risk than did women who had had only male partners (1.7). Adjusting for social and demographic characteristics did not substantially alter these results; however, the associations between sexual identity, gender of sex partners and STD diagnosis were eliminated after adjustment for sexual behaviors (e.g., having had anal sex). CONCLUSIONS: Sexual identity, gender of sex partners and sexual behaviors should be taken into account in assessments of women's STD risk. PMID- 23750621 TI - Prevalence of and characteristics associated with use of withdrawal among women in Victoria, Australia. AB - CONTEXT: Popularly regarded as "ineffective," withdrawal is a form of contraception largely ignored by health -professionals. Thus, little is known of the prevalence and correlates of its use. METHODS: A survey of 1,006 sexually active women aged 16-50 and not intending to conceive was conducted in three Family Planning Victoria clinics in 2011. The questionnaire asked about contraceptive behavior and characteristics associated with contraceptive use. Univariate and multivariate analyses were conducted to assess prevalence of withdrawal use and characteristics associated with reliance solely on this method. RESULTS: Ninety-six percent of women reported having used some form of contraception in the last three months, most commonly male condoms (67%), the pill (49%) and withdrawal (32%); use of withdrawal was especially common among the youngest women. Of women reporting withdrawal use, 40% relied solely on this method. Eighty percent of sole users of withdrawal were also inconsistent users. Women who used only withdrawal had elevated odds of saying that they were dissatisfied with their current method (odds ratio, 1.6), had had more than one partner in the last three months (1.7), had no access to contraceptives when needed (2.4) and found it too inconvenient to use contraceptives (2.1). CONCLUSION: Withdrawal use is common, but there is a need for better education on proper use. Health professionals should discuss the risks and benefits of withdrawal, along with those of other methods, when discussing con-traception with their patients. Further research is needed into why women choose withdrawal. PMID- 23750622 TI - The stigma of having an abortion: development of a scale and characteristics of women experiencing abortion stigma. AB - CONTEXT: Although abortion is common in the United States, women who have abortions report significant social stigma. Currently, there is no standard measure for individual-level abortion stigma, and little is known about the social and demographic characteristics associated with it. METHODS: To create a measure of abortion stigma, an initial item pool was generated using abortion story content analysis and refined using cognitive interviews. In 2011, the final item pool was used to assess individual-level abortion stigma among 627 women at 13 U.S. Planned Parenthood health centers who reported a previous abortion. Factor analysis was conducted on the survey responses to reduce the number of items and to establish scale validity and reliability. Differences in level of reported abortion stigma were examined with multivariable linear regression. RESULTS: Factor analysis revealed a four-factor model for individual-level abortion stigma: worries about judgment, isolation, self-judgment and community condemnation (Cronbach's alphas, 0.8-0.9). Catholic and Protestant women experienced higher levels of stigma than nonreligious women (coefficients, 0.23 and 0.18, respectively). On the subscales, women with the strongest religious beliefs had higher levels of self-judgment and greater perception of community condemnation than only somewhat religious women. Additional differences were found by race, age, education, religiosity and motherhood status on the subscales. CONCLUSION: This valid and reliable scale can be used in research examining abortion stigma and related outcomes (e.g., women's health, relationships and behavior). The scale can also be used to evaluate programs and interventions that aim to reduce the stigma experienced by women who have abortions. PMID- 23750623 TI - Racial and ethnic differences in the transition to a teenage birth in the United States. AB - CONTEXT: Rates of teenage childbearing are high in the United States, and they differ substantially by race and ethnicity and nativity status. METHODS: Data from the National Longitudinal Survey of Youth 1997 cohort were used to link characteristics of white, black, U.S.-born Hispanic and foreign-born Hispanic adolescents to teenage childbearing. Following a sample of 3,294 females aged 12 16 through age 19, discrete-time logistic regression analyses were used to examine which domains of teenagers' lives were associated with the transition to a teenage birth for each racial and ethnic group, and whether these associations help explain racial and ethnic and nativity differences in this transition. RESULTS: In a baseline multivariate analysis controlling for age, compared with whites, foreign-born Hispanics had more than three times the odds of a teenage birth (odds ratio, 3.5), while blacks and native-born Hispanics had about twice the odds (2.1 and 1.9, respectively). Additional controls (for family environments; individual, peer and dating characteristics; characteristics of first sexual relationships; and subsequent sexual experience) reduced the difference between blacks and whites, and between foreign-born Hispanics and whites, and eliminated the difference between U.S.-born Hispanics and whites. Further, if racial or ethnic minority adolescents had the same distribution as did white teenagers across all characteristics, the predicted probability of a teenage birth would be reduced by 40% for blacks and 35% for U.S.-born Hispanics. CONCLUSIONS: Differences in the context of adolescence may account for a substantial portion of racial, ethnic and nativity differences in teenage childbearing. PMID- 23750632 TI - Teenagers' perceptions of teenage childbearing. PMID- 23750633 TI - Drops of energy: conserving urban water to reduce greenhouse gas emissions. AB - Water and energy are two essential resources of modern civilization and are inherently linked. Indeed, the optimization of the water supply system would reduce energy demands and greenhouse gas emissions in the municipal water sector. This research measured the climatic cobenefit of water conservation based on a water flow analysis. The results showed that the estimated energy consumption of the total water system in Changzhou, China, reached approximately 10% of the city's total energy consumption, whereas the industrial sector was found to be more energy intensive than other sectors within the entire water system, accounting for nearly 70% of the total energy use of the water system. In addition, four sustainable water management scenarios would bring the cobenefit of reducing the total energy use of the water system by 13.9%, and 77% of the energy savings through water conservation was indirect. To promote sustainable water management and reduce greenhouse gas emissions, China would require its water price system, both for freshwater and recycled water, to be reformed. PMID- 23750624 TI - Life experiences of instability and sexual risk behaviors among high-risk adolescent females. AB - CONTEXT: Understanding the interplay of multiple contexts of adolescents' sexual risk behaviors is essential to helping them avoid pregnancy and STDs. Although a body of research has identified multiple individual- and family-level variables associated with adolescents' sexual risk behaviors, relatively few studies have examined relationships between these behaviors and latent indicators of unstable, chaotic environments. METHODS: In 2007-2008, a sample of 241 sexually active adolescent females who were at high risk for pregnancy and STDs were recruited through two school-based clinics and two community clinics in Minneapolis and St. Paul. Confirmatory factor analysis was used with baseline data to specify latent constructs of individual risk and family disengagement. Structural equation models examined longitudinal relationships between baseline measures of these constructs and sexual risk behaviors assessed six months later. RESULTS: The latent construct of individual risk encompassed substance use, violence perpetration, violence victimization and having witnessed violence; that of family disengagement included family disconnection, poor family communication and perceived lack of safety at home. Baseline level of individual risk was positively associated with number of male sex partners six months later (path coefficient, 0.2); it was not associated with consistent condom use at follow-up. Level of family disengagement was negatively associated with condom use consistency six months later (-0.3), but was not associated with number of male sex partners. CONCLUSIONS: To meet the health needs of vulnerable adolescents, health systems should incorporate coordinated and interdisciplinary services that acknowledge adolescents' relevant familial and social contexts. PMID- 23750634 TI - Myocardial velocities, dynamics of the septum primum, and placental dysfunction in fetuses with growth restriction. AB - INTRODUCTION: Diastolic dysfunction may occur in fetuses with intrauterine growth restriction (IUGR) and may be assessed by myocardial tissue Doppler (MTD). We previously have shown that excursion index of the septum primum (EISP) is reduced in IUGR fetuses over 30 weeks because of a higher left atrial pressure. PATIENTS, SETTING, AND DESIGN: The sample was made up of 14 fetuses with IUGR. MTD examination was carried out with the sample volume placed at the basal lateral wall of the left ventricle (LV), interventricular septum (IVS), and free wall of the right ventricle (RV) to determine E'/A' ratios. EISP was calculated as the ratio between the maximal excursion of the septum primum into the left atrium during diastole and the maximal diastolic diameter of the left atrium. Mitral and tricuspid flows were assessed by the conventional Doppler method. OUTCOME MEASURES: Pearson's correlation test was used to analyze the correlations between the parameters. RESULTS: A positive correlation was observed between UARI and E'/A' ratios for RV (r = 0.63, P = .02), IVS (r = 0.59, P = .03), and LV (r = 0.41, P = .15). There was a negative correlation between EISP and IVS E'/A' ratios (r = -0.58, P = .03), and a positive correlation for LV (r = 0.49, P = .08). At the RV position, a weak negative correlation was observed (r = -0.32, P = .26). CONCLUSIONS: A higher left atrial pressure in fetuses with IUGR, indicated by the lower mobility of the septum primum, is accompanied by higher ratios between early and late diastolic myocardial velocities. Placental dysfunction was correlated to septal E'/A' ratios. Fetal MTD can be a useful method to assess severity of placental dysfunction and fetal distress. PMID- 23750635 TI - Parallel synthesis of 1,6-disubstituted-1,2,4-triazin-3-ones on solid-phase. AB - A parallel solid-phase synthesis of 1,6-disubstituted-1,2,4-triazin-3-ones from MBHA resin is described. The reduction of resin-bound nitrosamino acids provides hydrazines efficiently without affecting the amide bond. The trityl protected hydrazine is then reduced with borane, and cyclized with 1,1-carbonyldiimidazole. The desired products are cleaved from their solid support and obtained in good yield and purity. This methodology is of value for the rapid parallel preparation of these potentially bioactive molecules. PMID- 23750636 TI - Attachment-related individual differences in the consistency of relationship behavior interpretation. AB - The consistency with which people interpret relationship-based information has important implications for attachment theory and research. Our objective is to determine whether there are attachment-related individual differences in the manner and the consistency with which individuals interpret hypothetical relationship behaviors. In two studies (N = 629, 79% female, 63% American, M(age) = 29; N = 820, 78% female, 65% American, M(age) = 29), we assessed participants' ability and consistency in relationship behavior interpretation across two blocks and estimated how they would have performed had they interpreted information perfectly consistently. Secure participants were generally more consistent in their interpretations relative to insecure participants. Estimates of perfectly consistent interpretation revealed that improvements to both systematic factors related to behavior interpretation (e.g., working models) and consistency would have led to a more secure interpretation style for participants of all attachment styles. Results imply that both secure and insecure individuals process relationship-based information according to secure scripts, but insecure individuals do so inconsistently. Our results imply that, due to the inconsistent behavioral responses that may occur as a result of inconsistent information processing, the consistency with which people process relationship-related information will be related to relationship satisfaction. Further directions for future research are discussed. PMID- 23750638 TI - Age-related macular degeneration and DNA methylation. PMID- 23750637 TI - Influence of fluorescence on screening decisions for oral mucosal lesions in community dental practices. AB - BACKGROUND: Quality of oral screening examinations is dependent upon the experience of the clinician and can vary widely. Deciding when a patient needs to be referred is a critical and difficult decision for general practice clinicians. A device to aid in this decision would be beneficial. The objective of this study was to to examine the utility of direct fluorescence visualization (FV) by dental practitioners as an aid in decision-making during screening for cancer and other oral lesions. METHODS: Dentists were trained to use a stepwise protocol for evaluation of the oral mucosa: medical history, head, neck and oral exam, and fluorescent visualization exam. They were asked to use clinical features to categorize lesions as low (LR), intermediate (IR), or high (HR) risk and then to determine FV status of these lesions. Clinicians made the decision of which lesions to reassess in 3 weeks and based on this reassessment, to refer forward. RESULTS: Of 2404 patients screened over 11 months, 357 initially had lesions with 325 (15%) identified as LR, 16 (4.5%) IR, and 16 (4.5%) HR. Lesions assessed initially as IR and HR had a 2.7-fold increased risk of FV loss persisting to the reassessment appointment versus the LR lesions. The most predictive model for lesion persistence included both FV status and lesion risk assessment. CONCLUSION: A protocol for screening (assess risk, reassess, and refer) is recommended for the screening of abnormal intraoral lesions. Integrating FV into a process of assessing and reassessing lesions significantly improved this model. PMID- 23750639 TI - New opportunities for organ transplantation research: epigenetics is likely to be an important determinant of the host immune response. PMID- 23750642 TI - Characterization of the DNA methylome and its interindividual variation in human peripheral blood monocytes. AB - AIM: Peripheral blood monocytes (PBMs) play multiple and critical roles in the immune response, and abnormalities in PBMs have been linked to a variety of human disorders. However, the DNA methylation landscape in PBMs is largely unknown. In this study, we characterized epigenome-wide DNA methylation profiles in purified PBMs. MATERIALS & METHODS: PBMs were isolated from freshly collected peripheral blood from 18 unrelated healthy postmenopausal Caucasian females. Epigenome-wide DNA methylation profiles (the methylome) were characterized by using methylated DNA immunoprecipitation combined with high-throughput sequencing. RESULTS: Distinct patterns were revealed at different genomic features. For instance, promoters were commonly (~58%) found to be unmethylated; whereas protein coding regions were largely (~84%) methylated. Although CpG-rich and -poor promoters showed distinct methylation patterns, interestingly, a negative correlation between promoter methylation levels and gene transcription levels was consistently observed across promoters with high to low CpG densities. Importantly, we observed substantial interindividual variation in DNA methylation across the individual PBM methylomes and the pattern of this interindividual variation varied between different genomic features, with highly variable regions enriched for repetitive DNA elements. Furthermore, we observed a modest but significant excess (p < 2.2 * 10(-16)) of genes showing a negative correlation between interindividual promoter methylation and transcription levels. These significant genes were enriched in biological processes that are closely related to PBM functions, suggesting that alteration in DNA methylation is likely to be an important mechanism contributing to the interindividual variation in PBM function, and PBM-related phenotypic and disease-susceptibility variation in humans. CONCLUSION: This study represents a comprehensive analysis of the human PBM methylome and its interindividual variation. Our data provide a valuable resource for future epigenomic and multiomic studies, exploring biological and disease-related regulatory mechanisms in PBMs. PMID- 23750644 TI - Age-related methylation patterning of housekeeping genes and tissue-specific genes is distinct between the stomach antrum and body. AB - AIM: The methylation-variable sites around CpG islands are frequently overmethylated in Helicobacter pylori-infected stomachs. Age-related patterns of the overmethylation changes were compared between the fast-growing antrum cells and the slow-growing body cells. MATERIALS & METHODS: A total of 316 H. pylori positive tissues and 380 H. pylori-negative tissues were obtained by endoscopic biopsy. The methylation-variable sites of ten housekeeping genes and nine tissue specific genes were semiquantitatively analyzed, based on the ten-level classification of methylation-specific PCR intensity. The overmethylated genes were scored when their methylation levels were higher than an intermediate level of each gene common in the H. pylori-negative mucosa. RESULTS: The age-dependent methylation level of the inactive APC gene observed similarly in the antrum and the body was used as an age standard of methylation variation in a biopsy tissue. The overmethylation of housekeeping genes and stomach-specific genes rapidly increased to a high plateau frequency in the young-aged APC methylation cases (mean age: 43 years) in the H. pylori-positive antrum. In the H. pylori-positive body, most of the overmethylated housekeeping genes slowly increased to a peak frequency in the middle-aged APC methylation cases (mean age: 53 years). The housekeeping gene pairs showed high correlations (Spearman's correlation coefficient > 0.4) in both the antrum and the body. CONCLUSION: The overmethylation of housekeeping genes rapidly and slowly increased to a high frequency in concordance with a rapid and slow growth of epithelial cells in the H. pylori-infected stomach. PMID- 23750643 TI - Association between birth weight and DNA methylation of IGF2, glucocorticoid receptor and repetitive elements LINE-1 and Alu. AB - AIM: We examined the association between birth weight and methylation in the imprinted IGF/H19 loci, the nonimprinted gene NR3C1 and repetitive element DNA (LINE-1 and Alu). MATERIALS & METHODS: We collected umbilical cord venous blood from 219 infants born in Mexico City (Mexico) as part of a prospective birth cohort study and analyzed DNA methylation using pyrosequencing. RESULTS: Birth weight was not associated with DNA methylation of the regions studied. One of the CpG dinucleotides in the IGF2 imprinting control region (ICR)1 includes a potential C-T SNP. Among individuals with an absence of methylation at this site, probably due to a paternally inherited T allele, birth weight was associated with mean methylation status of both IGF2 ICR1 and ICR2. However, this association would not have survived adjustment for multiple testing. CONCLUSION: While we did not detect an association between DNA methylation and birth weight, our study suggests a potential gene-epigene interaction between a T allele in the IGF2 ICR1 and methylation of ICRs of IGF2, and fetal growth. PMID- 23750646 TI - The multidimensional nature of metabolic syndrome in schizophrenia: lessons from studies of one-carbon metabolism and DNA methylation. AB - Large data sets indicate that the prevalence of metabolic syndrome (MetS) is significantly higher in patients with schizophrenia in comparison with the general population. Given that interactions between genes and the environment may underlie the etiology of MetS in subjects with schizophrenia, it is feasible that epigenetic phenomena can serve as the etiological consensus between genetic and environmental factors. However, there is still a striking scarcity of studies aimed at investigating the role of aberrant DNA methylation in the development of MetS in this group of patients. This article provides an update on the epigenetics of schizophrenia and reviews studies on the role of one-carbon metabolism and aberrant DNA methylation in the development of MetS. PMID- 23750645 TI - DNA methylation data analysis and its application to cancer research. AB - With the rapid development of genome-wide high-throughput technologies, including expression arrays, SNP arrays and next-generation sequencing platforms, enormous amounts of molecular data have been generated and deposited in the public domain. The application of computational approaches is required to yield biological insights from this enormous, ever-growing resource. A particularly interesting subset of these resources is related to epigenetic regulation, with DNA methylation being the most abundant data type. In this paper, we will focus on the analysis of DNA methylation data and its application to cancer studies. We first briefly review the molecular techniques that generate such data, much of which has been obtained with the use of the most recent version of Infinium HumanMethylation450 BeadChip((r)) technology (Illumina, CA, USA). We describe the coverage of the methylome by this technique. Several examples of data mining are provided. However, it should be understood that reliance on a single aspect of epigenetics has its limitations. In the not too distant future, these defects may be rectified, providing scientists with previously unavailable opportunities to explore in detail the role of epigenetics in cancer and other disease states. PMID- 23750647 TI - Genes, assisted reproductive technology and trans-illumination. AB - Genomic imprinting is a parent-of-origin allele-specific epigenetic process that is critical for normal development and health. The establishment and maintenance of normal imprinting is dependent on both cis-acting imprinting control centers, which are marked by differentially (parental allele specific) methylated marks, and trans mechanisms, which regulate the establishment and/or maintenance of the correct methylation epigenotype at the imprinting control centers. Studies of rare human imprinting disorders such as familial hydatidiform mole, Beckwith Wiedemann syndrome and familial transient neonatal diabetes mellitus have enabled the identification of genetic (e.g., mutations in KHDC3L [C6ORF221], NLRP2 [NALP2], NLRP7 [NALP7] and ZFP57) and environmental (assisted reproductive technologies) factors that can disturb the normal trans mechanisms for imprinting establishment and/or maintenance. Here we review the clinical and molecular aspects of these imprinting disorders in order to demonstrate how the study of rare inherited disorders can illuminate the molecular characteristics of fundamental epigenetic processes, such as genomic imprinting. PMID- 23750650 TI - A pentacoordinate boron-containing pi-electron system with Cl-B-Cl three-center four-electron bonds. AB - Tricoordinate boron-containing pi-electron systems are an attractive class of compounds with intense fluorescence and strong electron-accepting properties. However, the impact of pentacoordination of the boron atoms on their properties has not been determined. We now disclose a B,B'-bis(1,8-dichloro-9-anthryl) substituted 9,10-dihydro-9,10-diboraanthracene as a new pentacoordinate organoboron compound. In this skeleton, with the aid of the orthogonal arrangement of the anthryl substituent, the B and Cl atoms can form a three center four-electron (3c-4e) Cl-B-Cl bond. The pentacoordination of the boron atom significantly perturbs the electronic structure and thereby the photophysical and electrochemical properties. PMID- 23750648 TI - Storage conditions and stability of global DNA methylation in placental tissue. AB - AIM: The placenta is an informative and easily available tissue for many epidemiological studies. We analyzed the extent to which storage delay affects DNA methylation. MATERIAL & METHODS: Biopsies from two placentas were sequentially stored at -80 degrees C after standing at room temperature for 30 min, 1 h, 2 h, 6 h and 24 h. Global DNA methylation was measured by bisulfite pyrosequencing of repetitive elements and the luminometric methylation assay. RESULTS: Small changes in global DNA methylation in relation to time-to-storage were observed by pyrosequencing, with a coefficient of variation (COV) of 2.49% (placenta 1) and 2.86% (placenta 2), similar to the mean technical variation observed for pyrosequencing (COV: 1.91 and 1.51%, respectively). A luminometric methylation assay yielded more variable results in the two placentas analyzed, both among time points (COV: 9.13 and 10.35%, respectively) and technical replicates (COV: 11.60 and 9.80%, respectively). CONCLUSION: Global DNA methylation is stable at room temperature. However, some techniques to measure methylation might be confounded by DNA degradation caused by a delay in storage. PMID- 23750651 TI - The association of sore throat and psoriasis might be explained by histologically distinctive tonsils and increased expression of skin-homing molecules by tonsil T cells. AB - Recent studies have highlighted the involvement of the palatine tonsils in the pathogenesis of psoriasis, particularly among patients with recurrent throat infections. However, the underlying immunological mechanism is not well understood. In this study we confirm that psoriasis tonsils are infected more frequently by beta-haemolytic Streptococci, in particular Group C Streptococcus, compared with recurrently infected tonsils from patients without skin disease. Moreover, we show that tonsils from psoriasis patients contained smaller lymphoid follicles that occupied a smaller tissue area, had a lower germinal centre to marginal zone area ratio and contained fewer tingible body macrophages per unit area compared with recurrently infected tonsils from individuals without skin disease. Psoriasis patients' tonsils had a higher frequency of skin-homing [cutaneous lymphocyte-associated antigen (CLA(+) )] CD4(+) and CD8(+) T cells, and this correlated significantly with their frequency of blood CLA(+) T cells. The psoriasis patients also had a higher frequency of tonsil T cells expressing the interleukin (IL)-23 receptor that was expressed preferentially by the CLA(+) T cell population. In contrast, recurrently infected tonsils of individuals without skin disease had a higher frequency of tonsil T cells expressing the activation marker CD69 and a number of chemokine receptors with unknown relevance to psoriasis. These findings suggest that immune responses in the palatine tonsils of psoriasis patients are dysregulated. The elevated expression of CLA and IL-23 receptor by tonsil T cells may promote the egression of effector T cells from tonsils to the epidermis, suggesting that there may be functional changes within the tonsils, which promote triggering or exacerbation of psoriasis. PMID- 23750652 TI - Impact of surgery-radiation interval on locoregional outcome in patients receiving neo-adjuvant therapy and mastectomy. AB - Delays in the initiation of radiation are increasingly common for medically underserved patients. We evaluated the impact of delay in initiation of postmastectomy radiation (PMRT) in breast cancer patients treated with neo adjuvant therapy (NAT) in a cohort of medically underserved patients with multiple barriers to timely care. We retrospectively reviewed medical records of 248 consecutively treated patients. Clinical stage was 34.4% II, 65.6% III. The median interval from surgery to PMRT was 11.9 weeks; 22.2% started PMRT within 8 weeks of surgery, 52% within 12 weeks, and 67.3% within 16 weeks. The cumulative 5-year incidence of locoregional recurrence (LRR) was 5.8% (95% CI: 3.2-9.7). There was no significant difference in locoregional outcome among patients starting PMRT within 8 weeks versus >8 weeks (p = 0.634), <= 12 versus >12 weeks (p = 0.332), or <= 16 versus >16 weeks (p = 0.549) after surgery. Although timely initiation of PMRT remains a priority, the locoregional control benefit of PMRT appears to be maintained up to at least 16 weeks, and in those without early locoregional recurrence, PMRT should be offered despite such a delay. PMID- 23750653 TI - Electrophysiologic mechanism of deteriorating cardiac function in a patient with inappropriate CRT indication and frequent ventricular ectopy. PMID- 23750654 TI - Nitrate superhalogens as building blocks of hypersalts. AB - Using density functional theory (DFT) with a generalized gradient approximation for the exchange and correlation potential, we have studied the geometrical structure and electronic properties of NOx (x = 1-3), Li(NO3)x (x = 1,2), Mg(NO3)x (x = 1-3), and Al(NO3)x (x = 1-4) clusters. To validate the accuracy of the DFT-based method, calculations were also performed on small clusters using coupled cluster method with singles and doubles and noniterative inclusion of triples (CCSD(T)). With an electron affinity of 4.03 eV, NO3 behaves as a superhalogen molecule and forms the building block of hyperhalogens when interacting with metal atoms such as Li, Mg, and Al. This is confirmed by calculating the adiabatic detachment energies (ADEs) of Li(NO3)2, Mg(NO3)3, and Al(NO3)4, which are 5.69, 6.64, and 6.42 eV, respectively. We also demonstrate that these hyperhalogens can form salts when counter balanced by a cation such as K. PMID- 23750655 TI - Blueberry treatment attenuates D-galactose-induced oxidative stress and tissue damage in rat liver. AB - AIM: d-galactose (GAL) causes aging-related changes and oxidative stress in the organism. We investigated the effect of whole fresh blueberry (BB; Vaccinium corymbosum L.) treatment on oxidative stress in age-related liver injury model. METHODS: Rats received GAL (300 mg/kg, s.c.; 5 days per week) alone or together with 5% (BB1) and 10% (BB2) BB-containing chow for 2 months. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and hepatic malondialdehyde (MDA), protein carbonyl (PC) and glutathione (GSH) levels, and CuZn-superoxide dismutase (SOD1), glutathione peroxidase (GPx1) and glutathione transferase (GST) activities together with mRNA expressions of SOD1, GPx1, MnSOD (SOD2) and phospholipid hydroperoxide glutathione peroxidase (GPx4) were determined in GAL-treated rats. RESULTS: MDA and PC levels increased, but GSH levels, SOD1 and GPx1 activities decreased together with histopathological structural damage in the liver in GAL-treated rats. There was no change in hepatic mRNA expressions of SOD2 and GPx1, but SOD1 and GPx4 expressions decreased. BB1 and BB2 caused significant decreases in serum ALT and AST activities together with the amelioration in histopathological findings in GAL treated rats. Both BB1 and BB2 reduced MDA and PC levels, and elevated GSH levels, and SOD1 and GPx1 activities. However, hepatic mRNA expressions of SOD1, SOD2, GPx1 and GPx4 remained unchanged in GAL-treated rats. CONCLUSIONS: These results show that BB restored liver pro-oxidant status together with histopathological amelioration by acting as an anti-oxidant (radical scavenger) itself without affecting mRNA expressions of anti-oxidant enzymes in GAL-treated rats. PMID- 23750656 TI - Expression of DPP6 in Meckel's cartilage and tooth germs during mouse facial development. AB - Dipeptidyl peptidase-like protein 6 (DPP6), a member of the dipeptidyl aminopeptidase family, plays distinct roles in brain development, but its expression in embryonic Meckel's cartilage and tooth germs development is unknown. We analyzed the expression pattern of DPP6 in Meckel's cartilage and tooth germs development using in situ hybridization. DPP6 was detected in different patterns in Meckel's cartilage and tooth germs during mouse facial development from 11.5 to 13.5 days post-coitus (dpc) embryos. The expression pattern of DPP6 suggests that it may be involved in mandible and tooth development. PMID- 23750657 TI - Simulation training for breast and pelvic physical examination: a systematic review and meta-analysis. AB - BACKGROUND: Breast and pelvic examinations are challenging intimate examinations. Technology-based simulation may help to overcome these challenges. OBJECTIVE: To synthesise the evidence regarding the effectiveness of technology-based simulation training for breast and pelvic examination. SEARCH STRATEGY: Our systematic search included MEDLINE, EMBASE, CINAHL, PsychINFO, Scopus, and key journals and review articles; the date of the last search was January 2012. SELECTION CRITERIA: Original research studies evaluating technology-enhanced simulation of breast and pelvic examination to teach learners, compared with no intervention or with other educational activities. DATA COLLECTION AND ANALYSIS: The reviewers evaluated study eligibility and abstracted data on methodological quality, learners, instructional design, and outcomes, and used random-effects models to pool weighted effect sizes. MAIN RESULTS: In total, 11 272 articles were identified for screening, and 22 studies were eligible, enrolling 2036 trainees. In eight studies comparing simulation for breast examination training with no intervention, simulation was associated with a significant improvement in skill, with a pooled effect size of 0.86 (95% CI 0.52-1.19; P < 0.001). Four studies comparing simulation training for pelvic examination with no intervention had a large and significant benefit, with a pooled effect size of 1.18 (95% CI 0.40-1.96; P = 0.003). Among breast examination simulation studies, dynamic models providing feedback were associated with improved outcomes. In pelvic examination simulation studies, the addition of a standardised patient to the simulation model and the use of an electronic model with enhanced feedback improved outcomes. AUTHOR'S CONCLUSIONS: In comparison with no intervention, breast and pelvic examination simulation training is associated with moderate to large effects for skills outcomes. Enhanced feedback appears to improve learning. PMID- 23750658 TI - Monitoring population levels of alcohol consumption in pregnant women: a case for using biomarkers. AB - A challenge to biochemically monitoring alcohol consumption in pregnancy is the prohibitive costs of collecting thousands of blood samples. This pilot study looks at the feasibility of using residual samples to monitor chronic and acute alcohol consumption in pregnancy. Residual anomalies screening samples (n = 150, 2006/7) were tested for carbohydrate-deficient transferrin (CDT, chronic marker) and ethyl glucuronide (EtG, acute marker). Valid readings were obtained for CDT but not EtG. These results pave the way for a larger representative study, to provide, for the first time, a national biochemical baseline estimate of chronic alcohol consumption in the pregnant population. PMID- 23750659 TI - Slovenian adaptation of the original AUDIT-C questionnaire. AB - BACKGROUND: Alcohol Use Disorders Identification Test Consumption (AUDIT-C) questionnaire as a screening instrument for identification of hazardous and harmful drinkers give some false-positive and negative results. Changes of answers decrease the number of false results. METHODS: Changes in second and third questions with theoretical simulation of possible answers' combinations was made; cutoff scores have to be changed. Study with original and adapted AUDIT-C was conducted among 298 students to analyze the differences. RESULTS: Adapted Slovenian version of AUDIT-C gives less false-positive and less false-negative results. CONCLUSIONS: Changes of AUDIT-C questionnaire that give less false results means less potential disharmony in doctor-patient relationship, less unnecessary questioning, less time spent inadequately, and also less missed hazardous drinkers. PMID- 23750660 TI - The feasibility of pharmacy-based naloxone distribution interventions: a qualitative study with injection drug users and pharmacy staff in Rhode Island. AB - This study analyzed qualitative data from a Rapid Policy Assessment and Response project to assess the feasibility of a potential pharmacy-based naloxone intervention to reduce opioid overdose mortality among injection drug users (IDUs). We conducted in-depth, semistructured interviews with 21 IDUs and 21 pharmacy staff (pharmacists and technicians). Although most participants supported the idea of a pharmacy-based naloxone intervention, several barriers were identified, including misinformation about naloxone, interpersonal relationships between IDUs and pharmacy staff, and costs of such an intervention. Implications for future pharmacy-based overdose prevention interventions for IDUs, including pharmacy-based naloxone distribution, are considered. The study's limitations are noted. PMID- 23750661 TI - Bidirectional associations between future time perspective and substance use among continuation high-school students. AB - We examined whether a bidirectional, longitudinal relationship exists between future time perspective (FTP), measured with the Zimbardo Time Perspective Inventory, and any past 30-day use of alcohol, tobacco, marijuana, or hard drugs among continuation high school students (N = 1,310, mean age 16.8 years) in a large urban area. We found increased FTP to be protective against drug use for all substances except alcohol. While any baseline use of substances did not predict changes in FTP 1 year later. The discussion explores why alcohol findings may differ from other substances. Future consideration of FTP as a mediator of program effects is explored. PMID- 23750662 TI - Etymologia: syncytium. PMID- 23750663 TI - Impaired surface expression and conductance of the KCNQ4 channel lead to sensorineural hearing loss. AB - KCNQ4, a voltage-gated potassium channel, plays an important role in maintaining cochlear ion homoeostasis and regulating hair cell membrane potential, both essential for normal auditory function. Mutations in the KCNQ4 gene lead to DFNA2, a subtype of autosomal dominant non-syndromic deafness that is characterized by progressive sensorineural hearing loss across all frequencies. Despite recent advances in the identification of pathogenic KCNQ4 mutations, the molecular aetiology of DFNA2 remains unknown. We report here that decreased cell surface expression and impaired conductance of the KCNQ4 channel are two mechanisms underlying hearing loss in DFNA2. In HEK293T cells, a dramatic decrease in cell surface expression was detected by immunofluorescent microscopy and confirmed by Western blot for the pathogenic KCNQ4 mutants L274H, W276S, L281S, G285C, G285S, G296S and G321S, while their overall cellular levels remained normal. In addition, none of these mutations affected tetrameric assembly of KCNQ4 channels. Consistent with these results, all mutants showed strong dominant-negative effects on the wild-type (WT) channel function. Most importantly, overexpression of HSP90beta, a key component of the molecular chaperone network that controls the KCNQ4 biogenesis, significantly increased cell surface expression of the KCNQ4 mutants L281S, G296S and G321S. KCNQ4 surface expression was restored or considerably improved in HEK293T cells mimicking the heterozygous condition of these mutations in DFNA2 patients. Finally, our electrophysiological studies demonstrated that these mutations directly compromise the conductance of the KCNQ4 channel, since no significant change in KCNQ4 current was observed after KCNQ4 surface expression was restored or improved. PMID- 23750664 TI - Employment status 1 year after out-of-hospital cardiac arrest in comatose patients treated with therapeutic hypothermia. AB - BACKGROUND: Therapeutic hypothermia for comatose survivors of out-of-hospital cardiac arrest (OHCA) has improved survival and neurologic outcome. This study focused on return to work 1 year after therapeutic hypothermia. METHODS: From June 2004 to June 2009, patients between 18 and 65 years of age with OHCA, who were treated with hypothermia from two regions, representing one third of the national population, were identified from the Danish National Patient Registry, and from hospital and ambulance records. The patients' employment status was obtained from the Danish Ministry of Employment. RESULTS: One hundred thirty three comatose patients after OHCA treated with hypothermia were identified. One hundred and four (78%) patients were employed, or able to work, at the time of cardiac arrest. This particular group of patients showed significant lower in hospital mortality compared to the group of patients who were not able to work before cardiac arrest; 13% vs. 48%, respectively (P < 0.001). The workable group had a lower Charlson comorbidity score (P = 0.004), a higher incidence of witnessed cardiac arrest (P = 0.004) and a higher incidence of shockable heart rhythm (P < 0.001). Eighty-seven patients (84%), who were able to work prior to cardiac arrest, survived, and 55 (65%) of these patients were employed or able to work at 1 year follow-up. CONCLUSION: The majority of patients employed, or able to work prior to OHCA, had returned to work at one year follow-up. Predictors of return to work in comatose patients treated with hypothermia have to be identified in a larger-scale study. PMID- 23750665 TI - Effect of relative humidity on the aerosolization and total inflammatory potential of fungal particles from dust-inoculated gypsum boards. AB - The aim of this study was to investigate the effect of relative humidity (RH) on the aerosolization and total inflammatory potential (TIP) of microbial particles released from gypsum boards inoculated with dust samples from homes. After microbial colonization, the gypsum boards were incubated at either high or low RH. The aerosolized particles (0.54-19.8 MUm), culturable fungi, beta-glucan and the TIP of the aerosolized particles were quantified. Despite the colonization of several fungal groups, Penicillium dominated the aerosolized fraction. Higher emission rates of particles and culturable fungi were found from low RH compared with high RH in both the inhalable and particulate matter <1 MUm (PM1 ) fractions, and the TIP was accordingly higher. However, for the aerosolized fractions, the TIP or concentration beta-glucan relative to the number of fungi or particles present was higher from high RH compared with low RH. Despite the low number of culturable fungi in PM1 , this fraction showed a high TIP, and the concentration of beta-glucan correlated strongly with the TIP of this fraction. The individual particles of the aerosolized PM1 fraction were more inflammatory than the larger particles of the inhalable fraction, and beta-glucan may be an important contributor to the inflammatory potential of the aerosolized particles. PMID- 23750666 TI - Integration of pharmacists into general practice clinics in Australia: the views of general practitioners and pharmacists. AB - BACKGROUND: Pharmacists working collaboratively with general practitioners (GPs) in primary-care settings can improve patient outcomes; however, there are challenges to the implementation of collaborative services. A possible solution is the co-location of pharmacists within general practice clinics. OBJECTIVE: To elicit the views of GPs and pharmacists on the integration of pharmacists into general practice in Australia. METHODS: Semi-structured, individual interviews with a sample of 11 GPs and 16 pharmacists. KEY FINDINGS: Four major themes emerged: the current GP-pharmacist relationship; the role of the general practice pharmacist; the pros and cons of integration; and the barriers to and facilitators for integration. Most participants had experienced positive inter professional relationships, though there were limitations in the collaborative services currently provided. Various methods of integration were discussed, including the co-location of pharmacists within practices. The potential roles for practice pharmacists were deemed to be multifaceted and in some cases allowed for role expansion. Although these roles were thought to offer potential benefits to practice staff, patients and pharmacists, they were also perceived to be potentially disadvantageous. The integration of pharmacists into general practice was believed to be hindered by limited funding and infrastructure and by practitioner perceptions. Various facilitating factors were proposed that could help ensure viability of the role. CONCLUSIONS: Various roles and methods of integration were identified for pharmacists in general practice; however, a number of barriers and facilitators to integration would need to be considered to ensure viability of services. Future research should explore different methods of collaboration and trial their implementation. PMID- 23750667 TI - Pentalogy of Cantrell with ectopia cordis totalis, total anomalous pulmonary venous connection, and tetralogy of Fallot: a case report and review of the literature. AB - Pentalogy of Cantrell is a rare condition with a varied expression and a high mortality. We present a patient with the classic pentad (type 1), but with a previously undescribed constellation of cardiac manifestations including ectopia cordis totalis, total anomalous pulmonary venous return, and tetralogy of Fallot. This case reminds us of the challenges associated with the management of various forms of this condition. We discuss the prenatal diagnosis, genetic basis, postnatal evaluation, and management of this entity. PMID- 23750668 TI - Giant cell reparative granuloma of the temporal bone successfully resected with preservation of hearing. AB - OBJECTIVE: To describe a case of giant cell reparative granuloma of the temporal bone which extended into the middle-ear cavity, and which was successfully treated surgically via a transmastoid approach, with hearing preservation. CASE: A 37-year-old man presented with a one-year history of right-sided hearing loss, complicated by a three-month history of otalgia and a sensation of aural fullness. Computed tomography and magnetic resonance imaging demonstrated an osteolytic tumour lesion in the right temporal bone. The diagnosis was confirmed by biopsy from the mastoid lesion. INVESTIGATION AND INTERVENTION: Pure-tone audiometry, computed tomography and magnetic resonance imaging were conducted, followed by total resection. RESULT: The giant cell reparative granuloma of the temporal bone was completely resected, with preservation of hearing. CONCLUSION: Although this patient's giant cell reparative granuloma of the temporal bone extended into the middle-ear cavity, total resection was achieved, with preservation of hearing. To the best of our knowledge, hearing preservation following resection of giant cell reparative granuloma of the temporal bone has not previously been reported. PMID- 23750669 TI - New records of Amblyomma multipunctum and Amblyomma naponense from Ecuador, with description of A. multipunctum nymph. AB - We provide new data for the ticks Amblyomma multipunctum and Amblyomma naponense from Ecuador. In addition, we describe the nymph of A. multipunctum for the first time. During December 2012, ticks were collected by dragging in forest trails of 1 locality at Puyo, Pastaza Province (elevation 979 m), and another locality at Papallacta, Napo Province (3,474 m). A total of 10 adults of A. naponense were collected at Puyo, whereas 27 adults and 3 nymphs of A. multipunctum were collected at Papallacta. Compared to sequences of a fragment of the mitochondrial 16S rDNA gene of adult and nymphal ticks, the sequence of an Amblyomma nymph was identical to the sequences generated from the A. multipunctum adults. The 3 collected nymphs (including the 1 used for molecular analysis) had the same morphotype, and were used for the first morphological description of the nymphal stage of A. multipunctum. Sequences generated from the A. naponense specimens were closest (97% identity by BLAST) to a corresponding sequence of A. naponense from Brazil, whereas the A. multipunctum sequences were closer to (90-91% identity) several Neotropical Amblyomma species. Herein, we provide just the second record of A. naponense in Ecuador, more than 100 yr after this tick was reported in this country. Adults and nymphs of A. multipunctum were found in highland, humid montane forest areas, in agreement with the only 2 previous reports of A. multipunctum in Ecuador and Colombia. No genetic differences were found among A. multipunctum ticks that presented significant morphological differences, suggesting intraspecific polymorphism in the adult stages of this species. PMID- 23750670 TI - A highly active phosphine-borane organocatalyst for the reduction of CO2 to methanol using hydroboranes. AB - In this work, we report that organocatalyst 1-Bcat-2-PPh2-C6H4 ((1); cat = catechol) acts as an ambiphilic metal-free system for the reduction of carbon dioxide in presence of hydroboranes (HBR2 = HBcat (catecholborane), HBpin (pinacolborane), 9-BBN (9-borabicyclo[3.3.1]nonane), BH3.SMe2 and BH3.THF) to generate CH3OBR2 or (CH3OBO)3, products that can be readily hydrolyzed to methanol. The yields can be as high as 99% with exclusive formation of CH3OBR2 or (CH3OBO)3 with TON (turnover numbers) and TOF (turnover frequencies) reaching >2950 and 853 h(-1), respectively. Furthermore, the catalyst exhibits "living" behavior: once the first loading is consumed, it resumes its activity on adding another loading of reagents. PMID- 23750671 TI - Strategies to improve control of blood pressure in hypertension: moving towards a 70% objective. PMID- 23750672 TI - Influence of blood pressure on atrial fibrillation. PMID- 23750673 TI - Recent progress in the use of induced pluripotent stem cells in vascular regeneration. PMID- 23750675 TI - The next 10 years in antihypertensive treatment. Interview by Tanya Stezhka. AB - Interview by Tanya Stezhka Dr Cooper-DeHoff is an Associate Professor in the Department of Pharmacotherapy and Translational Research, and the Department of Pharmaceutics in the College of Pharmacy, and in the Division of Cardiovascular Medicine, at the University of Florida (FL, USA). Her principle research focuses on hypertension, diabetes and the metabolic syndrome. She was a principle investigator of the INVEST study, which evaluated hypertension treatments in older coronary artery disease patients, and is currently a coinvestigator on two NIH grants evaluating pharmacogenetic hypertension associations. She is a member of the American Heart Association, American Society of Hypertension, American College of Cardiology and Florida Society of Hospital Pharmacists. PMID- 23750676 TI - An update on telmisartan/hydrochlorothiazide combinations for the management of hypertensive patients with additional cardiovascular risk factors. AB - International hypertension guidelines endorse the use of combination therapy to achieve blood pressure control in the majority of patients. Angiotensin AT1 receptor blockers, in combination with diuretics, are among the preferred combinations, with telmisartan plus hydrochlorothiazide (HCTZ) being an effective and well-tolerated combination. This article provides an up-to-date review of the existing data on telmisartan/HCTZ combination for the management of hypertension in patients with additional cardiovascular risk factors, including reports emerging from a number of recent clinical trials and secondary analyses of older trials. The accumulated evidence from clinical trials demonstrates that telmisartan/HCTZ combinations are effective and well tolerated in patients with mild-to-severe hypertension, including subgroups of patients with cardiovascular risk factors such as advanced age, obesity, chronic kidney disease, diabetes mellitus and treatment-resistant hypertension. PMID- 23750677 TI - Clinical end points in baroreflex activation therapy: what do we need to know? AB - Many studies have shown that the sympathetic nervous system plays an important part in blood pressure regulation. One of its components is the baroreceptor reflex, which buffers sudden and also potentially chronic changes in blood pressure. The carotid baroreceptors have become a new target in the treatment of hypertensive patients in whom optimal antihypertensive medication fails to normalize the pressure. By electrically stimulating the baroreceptor area, it is now possible to substantially reduce blood pressure in such patients and the effect is well maintained over a prolonged period of time. The hypotensive response is associated with a fall in muscle sympathetic nerve activity, which lends support to the view that baropacing suppresses overall sympathetic outflow from the brain. The procedure appears to be safe and well tolerated. Nevertheless, the authors still need definite proof from prognostic trials that baropacing is superior to intensified medical treatment. PMID- 23750678 TI - Can the effectiveness of hypertension management be improved? AB - Hypertension is a modifiable risk factor for cardiovascular disease. Lowering blood pressure (BP) reduces cardiovascular risk; yet despite the availability of numerous antihypertensives, the proportion of patients achieving BP control remains low. Treatment guidelines are based on evidence from clinical trials, however this evidence may not be representative of real-world treatment effectiveness. Many studies evaluating antihypertensives continue to rely on office BP measurements that provide a less realistic evaluation of hypertension status than ambulatory measures. New studies are needed with greater consideration on evaluating efficacy for translation into clinical effectiveness. In addition, novel therapies for reducing BP and with a greater capacity to improve BP control are still required. This article discusses some of the challenges of hypertension management and reviews strategies and treatment advances that may pave the way to more effective BP control. PMID- 23750679 TI - Catheter ablation of atrial fibrillation in the elderly: does the benefit outweigh the risk? AB - Atrial fibrillation (AF) is the most common arrhythmia and its prevalence increases with age. Elderly patients with AF require careful management to assure optimal outcomes and prevention of untoward consequences such as stroke. Although radiofrequency catheter ablation has evolved as a highly effective treatment modality to eliminate AF in younger patients, the data on the role of catheter ablation in elderly patients with AF have been rather limited. However, several studies suggest that outcomes of catheter ablation for AF in the elderly can be just as successful as in younger patients. On the other hand, the elderly may be at higher risk for periprocedural complications, specifically thromboembolic events. In this review, the role of catheter ablation for AF in the elderly is discussed in detail. PMID- 23750680 TI - The impact of ACE inhibition on all-cause and cardiovascular mortality in contemporary hypertension trials: a review. AB - The renin-angiotensin-aldosterone system is a key therapeutic target in hypertension. The latest meta-analysis of mortality reduction with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in hypertension features 158,998 patients from 20 contemporary hypertension trials. ACE inhibitors and ARBs significantly reduced relative risk for all-cause mortality by 5% (p = 0.032) and cardiovascular mortality by 7% (p = 0.018) in populations with a high prevalence of hypertension (>=66%). ACE inhibitors produced a 10% reduction in relative risk for all-cause mortality (p = 0.004) and a trend toward a 12% reduction in cardiovascular mortality (p = 0.051), whereas ARBs had no effect. On balance, mortality evidence suggests that in hypertension, ACE inhibitors should be considered ahead of ARBs, and ARBs restricted to patients intolerant of ACE inhibitors. PMID- 23750681 TI - Assessment and management of left ventricular hypertrophy in Type 2 diabetes patients with high blood pressure. AB - Diabetes is associated with left ventricular hypertrophy (LVH). This article reviews the assessment and management of LVH in Type 2 diabetic patients and the available evidence on blood-pressure management in these patients in order to reduce LVH. The best treatment of LVH starts with early identification and rapid implementation of adequate treatment, especially in populations at higher risk. Angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors should be the first-line therapy, because they are proven to be the most effective in reducing LVH in Type 2 diabetic patients. In patients where angiotensin II receptor antagonists and angiotensin-converting enzyme inhibitors are contraindicated or not tolerated, calcium-channel blockers should be the second option. PMID- 23750682 TI - Evaluating exercise capacity in patients with pulmonary arterial hypertension. AB - Cardiopulmonary exercise testing (CPET), performed in a clinical laboratory setting, has long been used to evaluate persons with suspected or confirmed cardiopulmonary disease. This form of testing is now recognized as the gold standard for evaluating a person's aerobic exercise performance. In addition, simplified submaximal approaches to assessing functional capacity are readily available; perhaps the most recognized being the 6-min walk test. With the growing interest in CPET for evaluating patients with pulmonary artery hypertension (PAH), gaining a better understanding of the significance of the various outcomes used and how they are relevant to evaluating patients with PAH is a an important endeavor. This review highlights the utility of CPET; the various outcomes that can be derived from this assessment and the various functional tests commonly used as well as related tests that may have a role in clinical assessment of patients with PAH. PMID- 23750683 TI - Renal denervation in treatment-resistant hypertension: the need for restraint and more and better evidence. AB - The Symplicity studies suggest that intravascular renal sympathetic nervous denervation improves blood pressure in patients with resistant hypertension, thus potentially opening a market for devices to be used when conventional drug therapy fails to restore blood pressure control. However, the size and durability of the antihypertensive, renal and sympatholytic effects of renal denervation, the long-term safety, improvement of quality of life, the possibility to relax antihypertensive drug treatment, the cost-effectiveness, and long-term hard cardiovascular-renal outcomes still remain to be firmly established. Most ongoing studies are small, industry-driven and purely observational with objectives to test new catheters and source of energy for renal nerve ablation or to search for ancillary benefits and new indications of the technique. The most urgent need, that is adequately powered randomized clinical trials testing renal denervation versus usual medical therapy delivered according to the state-of-the-art are under-represented and seldom funded by industry. The authors make a plea for a coordinated research effort in Europe. With this objective, they established collaboration with leading European experts and started the European Network for Coordinating Research on Renal Denervation. In the meantime, renal denervation should remain the ultima ratio in adherent and truly resistant patients with severe hypertension, confirmed by ambulatory monitoring, in whom secondary hypertension has been excluded and in whom all other efforts to reduce blood pressure have failed. PMID- 23750684 TI - Adapting the D-dimer cutoff for thrombosis detection in elderly outpatients. AB - D-dimer measurement is an important step in diagnostic strategies for venous thromboembolism. It allows the safe ruling out of the diagnosis with no need for imaging tests in approximately 30% of outpatients. However, the usefulness of d dimer is limited in elderly patients; the likelihood of a negative d-dimer strongly decreases with age, making physicians reluctant to order the test. Several attempts to improve the performance of D-dimer in elderly patients have been pursued. Recently, an age-adjusted cutoff was derived; the optimal cutoff value (in ug/l) appears to be equal to the patient's age (in years) multiplied by ten in patients over 50 years of age with a low pretest clinical risk of venous thromboembolism. This age-adjusted cutoff value has been extensively and externally validated in retrospective studies that included mostly outpatients with suspected deep vein thrombosis or pulmonary embolism and used various quantitative D-dimer assays. All available studies confirmed the increased usefulness and similar safety of the age-adjusted cutoff compared with the conventional cutoff, the most important benefit being obtained in elderly patients. However, before any recommendation for clinical practice can be made, a prospective diagnostic management outcome study is lacking, in which all low clinical risk patients with D-dimer levels below their age-adjusted cutoff would be left untreated with no further diagnostic testing. PMID- 23750685 TI - Decision-making in transcatheter aortic valve replacement: the impact of frailty in older adults with aortic stenosis. AB - Patients with severe aortic stenosis are commonly elderly and with significant comorbidity. Surgical intervention can improve symptoms and survival in severe aortic stenosis. However, a large proportion of patients do not undergo surgical intervention because they are deemed to be inoperable or too high risk. Over the last decade, transcatheter aortic valve replacement (TAVR) has been developed, providing an effective, less-invasive alternative to open cardiac surgery for inoperable or high-risk patients. The purpose of this review is to provide an overview of risk assessment in TAVR. Specifically, this article reviews the epidemiology of aortic stenosis, describes the risks and benefits of TAVR across multiple outcome measures, explores frailty and other elderly risk factors as metrics for improved risk assessment and discusses the application of improved risk assessment in TAVR decisions. PMID- 23750686 TI - Biomarkers in congenital heart disease: do natriuretic peptides hold the key? AB - Congenital heart disease is the most common congenital abnormality. The long-term prognosis of these patients has changed significantly over the last half century, thanks to improvements in cardiovascular diagnosis, surgery and postoperative care. However, residual lesions are not uncommon and many of the interventions performed remain palliative rather than reparative, leading to the development of ventricular dysfunction and heart failure. Natriuretic peptides are well established markers of disease severity and prognosis in patients with heart failure due to noncongenital (acquired) heart disease. However, the role of biomarkers in congenital heart disease is unclear. This review highlights the impact of neurohormonal activation in patients with congenital heart disease, as well as the usefulness of assessing natriuretic peptide levels in specific clinical situations. PMID- 23750687 TI - Update on psychological functioning in adults with congenital heart disease: a systematic review. AB - The population of adults with congenital heart disease is increasing due to advancements in cardiology and cardiac surgery. Many patients face medical complications and psychosocial difficulties; however, it is not yet clear whether there is a direct relationship between medical status and the psychological functioning of these patients. This systematic review of the relevant literature is an attempt to: provide a comparison between the population of adults with congenital heart disease, the healthy reference population and similar cardiac populations when it comes to psychological functioning; explore the relationship between medical status/cardiac condition and psychological functioning; and identify the predictors of psychological distress in this population. PMID- 23750689 TI - beta1-Adrenoceptor blocker aggravated ventricular arrhythmia. AB - OBJECTIVES: To assess the impact of beta1 -adrenoceptor blockers (beta1 -blocker) and isoprenaline on the incidence of idiopathic repetitive ventricular arrhythmia that apparently decreases with preprocedural anxiety. METHODS: From January 2010 to July 2012, six patients were identified who had idiopathic ventricular arrhythmias that apparently decreased (by greater than 90%) with preprocedural anxiety. The number of ectopic ventricular beats per hour (VPH) was calculated from Holter or telemetry monitoring to assess the ectopic burden. The mean VPH of 24 hours from Holter before admission (VPH-m) was used as baseline (100%) for normalization. beta1 -Blockers, isoprenaline, and/or aminophylline were administrated successively on the ward and catheter lab to evaluate their effects on the ventricular arrhythmias. RESULTS: Among 97 consecutive patients with idiopathic ventricular arrhythmias, six had reduction in normalized VPHs in the hour before the scheduled procedure time from (104.6 +/- 4.6%) to (2.8 +/- 1.6%) possibly due to preprocedural anxiety (P < 0.05), then increased to (97.9 +/- 9.7%) during beta1 -blocker administration (P < 0.05), then quickly reduced to (1.6 +/- 1.0%) during subsequent isoprenaline infusion. Repeated beta1 -blocker quickly counteracted the inhibitory effect of isoprenaline, and VPHs increased to (120.9 +/- 2.4%) from (1.6 +/- 1.0%; P < 0.05). Isoprenaline and beta1 -blocker showed similar effects on the arrhythmias in catheter lab. CONCLUSIONS: In some patients with structurally normal heart and ventricular arrhythmias there is a marked reduction of arrhythmias associated with preprocedural anxiety. These patients exhibit a reproducible sequence of beta1 -blocker aggravation and catecholamine inhibition of ventricular arrhythmias, including both repetitive ventricular premature beats and monomorphic ventricular tachycardia. PMID- 23750690 TI - Impact of aerobic exercise intensity on craving and reactivity to smoking cues. AB - Aerobic exercise can acutely reduce cigarette cravings during periods of nicotine deprivation. The primary aim of this study was to assess the differential effects of light and vigorous intensity aerobic exercise on cigarette cravings, subjective and physiological reactivity to smoking cues, and affect after overnight nicotine deprivation. A secondary aim was to examine cortisol change as a mediator of the effects of exercise on smoking motivation. 162 (55 female, 107 male) overnight nicotine-deprived smokers were randomized to one of three exercise conditions: light intensity, vigorous intensity, or a passive control condition. After each condition, participants engaged in a standardized cue reactivity assessment. Self-reported urges to smoke, affect, and salivary cortisol were assessed at baseline (i.e., before each condition), immediately after each condition, and after the cue reactivity assessment. Light and vigorous exercise significantly decreased urges to smoke and increased positive affect, relative to the control condition. In addition, those in the vigorous exercise condition demonstrated suppressed appetitive reactivity to smoking cues, as indexed by the startle eyeblink reflex. Although exercise intensity was associated with expected changes in cortisol concentration, these effects were not related to changes in craving or cue reactivity. Both light and vigorous exercise can reduce general cravings to smoke, whereas vigorous exercise appears especially well-suited for reducing appetitive reactions to cues that may precede smoking. Results did not support exercise-induced cortisol release as a mechanism for these effects. PMID- 23750691 TI - Acceptability of an Internet-based contingency management intervention for smoking cessation: views of smokers, nonsmokers, and healthcare professionals. AB - The acceptability of an Internet-based contingency management (CM) intervention for cigarette smoking was evaluated in two experiments. In Experiment 1, 67 participants (46% female) completed an Internet-based CM intervention and then answered questions about the intervention. Experiment 2 assessed the acceptability of the intervention among potential treatment users who had never used the intervention, (smokers, n = 164, 52% female), nonsmokers (n = 166, 73% female), and health-care providers (n = 139, 63% female). Participants in Experiment 2 were randomly assigned to either watch a video describing the standard CM intervention (no-deposit group) or to watch a video about the standard intervention plus a deposit incentive (deposit group). Overall, results of both experiments indicated high acceptability across all dimensions of the intervention. In Experiment 1, 74% (n = 26 of participants in the treatment group) of participants said they would use it if they needed to quit, as well as 92% (n = 150 among smokers) of those in Experiment 2. Of the health-care providers, 81% (n = 113) reported that they would be very likely to recommend the intervention to patients. Participants in both experiments reported that monitoring their progress and earning vouchers were strengths of the intervention. The no-deposit group rated voucher earnings, cash earnings, and cost-effectiveness of the intervention higher than the deposit group. Health-care professionals did not differ in their ratings across video conditions. Overall, the results suggest that Internet-based CM is acceptable as a method to help people quit smoking. PMID- 23750692 TI - Biphasic effects of alcohol on delay and probability discounting. AB - Delay discounting and probability discounting are behavioral economic indices of impulsive and risky decision making that have been associated with addictive behavior, but the acute biphasic effects of alcohol on these decision-making processes are not well understood. This study sought to investigate the biphasic effects of alcohol on delay and probability discounting across the ascending and descending limbs of the breath alcohol concentration (BAC) curve, which are respectively characterized by the stimulant and sedative effects of alcohol. Delay and probability discounting were measured at four time points (Baseline, Ascending, Descending, and End point) across the BAC curve at two target alcohol doses (40 mg/dl and 80 mg/dl) in healthy adults (n = 23 and 27, for both doses, respectively). There was no significant effect of alcohol on delay discounting at either dose. Alcohol significantly affected probability discounting, such that reduced discounting for uncertain rewards was evident during the descending limb of the BAC curve at the lower dose (p < .05) and during both the ascending and descending limb of the BAC curve at the higher dose (p < .05). Thus, alcohol resulted in increased risky decision making, particularly during the descending limb, which is primarily characterized by the sedative effects of alcohol. These findings suggest that the biphasic effects of alcohol across the ascending and descending limbs of the BAC have differential effects on behavior related to decision-making for probabilistic, but not delayed, rewards. Parallels to and distinctions from previous findings are discussed. PMID- 23750694 TI - Prescription drug misuse, illicit drug use, and their potential risk and protective correlates in a Hispanic college student sample. AB - Illicit substance use has increased in Hispanics. Recent trends also warrant focus on prescription drug misuse, given its increased prevalence among college students. The aims of this study were to assess prescription drug misuse and illicit drug use in Hispanic students, as well as potential theoretically and empirically based risk and protective factors. Hispanic students (n = 435; 59% female) from a U.S. university located on the border with Mexico completed a sociodemographic survey, licit, illicit, and prescription drug use frequency questionnaires, an attitudes and beliefs about prescription drugs survey, the Short Acculturation Scale for Hispanics, the Depression, Anxiety, and Stress Scales, the Collectivist Coping Styles Measure, and the Multidimensional Scale of Perceived Social Support. A hierarchical logistic regression assessed prescription drug misuse predictors including demographics, licit/illicit substance use, attitudes toward prescription drug use, acculturation, distress symptoms, coping style, perceived social support, and the interaction between distress symptoms and acculturation. A negative binomial regression assessed predictors of past 30-day illegal drug use (the same predictors as the previous model except illicit drug use). Results indicated that positive attitudes toward prescription drugs, higher anxiety, and lower depressive symptomatology increased the odds of prescription drug misuse. Past 30-day alcohol use, positive attitudes toward prescription drugs, and higher acculturation predicted past 30-day illicit drug use. Prescription drug misuse was differentially associated with distress symptoms, whereas the convergence model of acculturation was supported regarding illegal drug use. Inconsistent with hypotheses, protective factors were not significantly associated with substance use. PMID- 23750693 TI - The combined effects of alcohol, caffeine, and expectancies on subjective experience, impulsivity, and risk-taking. AB - Caffeinated alcoholic beverage (CAB) consumption is a rapidly growing phenomenon among young adults and is associated with a variety of health-risk behaviors. The current study examined whether either caffeinated alcohol or the expectation of receiving caffeinated alcohol altered affective, cognitive, and behavioral outcomes hypothesized to contribute to risk behavior. Young adult social drinkers (N = 146) participated in a single session where they received alcohol (peak Breath Alcohol Content = .088 g/dL, SD = .019; equivalent to about four standard drinks) and were randomly assigned to one of four further conditions: 1) no caffeine, no caffeine expectancy, 2) caffeine and caffeine expectancy, 3) no caffeine but caffeine expectancy, 4) caffeine but no caffeine expectancy. Participants' habitual CAB consumption was positively correlated with measures of impulsivity and risky behavior, independently of study drugs. Administration of caffeine (mean dose = 220 mg, SD = 38; equivalent to about 2.75 Red Bulls) in the study reduced subjective ratings of intoxication and reversed the decrease in desire to continue drinking, regardless of expectancy. Caffeine also reduced the effect of alcohol on inhibitory reaction time (RT) (faster incorrect responses). Participants not expecting caffeine were less attentive after alcohol, whereas participants expecting caffeine were not, regardless of caffeine administration. Alcohol decreased response accuracy in all participants except those who both expected and received caffeine. Findings suggest that CABs may elevate risk for continued drinking by reducing perceived intoxication, and by maintaining the desire to continue drinking. Simply expecting to consume caffeine may reduce the effects of alcohol on inattention, and either expecting or consuming caffeine may protect against other alcohol-related performance decrements. Caffeine, when combined with alcohol, has both beneficial and detrimental effects on mechanisms known to contribute to risky behavior. PMID- 23750695 TI - Adult rats treated with risperidone during development are hyperactive. AB - Risperidone is an antipsychotic drug approved for use in children, but little is known about the long-term effects of early-life risperidone treatment. In animals, prolonged risperidone administration during development increases forebrain dopamine receptor expression immediately upon the cessation of treatment. A series of experiments was performed to ascertain whether early-life risperidone administration altered locomotor activity, a behavior sensitive to dopamine receptor function, in adult rats. One additional behavior modulated by forebrain dopamine function, spatial reversal learning, was also measured during adulthood. In each study, Long-Evans rats received daily subcutaneous injections of vehicle or 1 of 2 doses of risperidone (1.0 and 3.0 mg/kg per day) from postnatal Days 14 to 42. Weight gain during development was slightly yet significantly reduced in risperidone-treated rats. In the first 2 experiments, early-life risperidone administration was associated with increased locomotor activity at 1 week postadministration through approximately 9 months of age, independent of changes in weight gain. In a separate experiment, it was found that the enhancing effect of early-life risperidone on locomotor activity occurred in males and female rats. A final experiment indicated that spatial reversal learning was unaffected in adult rats administered risperidone early in life. These results indicate that locomotor activity during adulthood is permanently modified by early-life risperidone treatment. The findings suggest that chronic antipsychotic drug use in pediatric populations (e.g., treatment for the symptoms of autism) could modify brain development and alter neural set points for specific behaviors during adulthood. PMID- 23750696 TI - Pressure-dependent release of guest molecules and structural transitions in hydroquinone clathrate. AB - Structural phase transitions of N2-loaded and guest-free hydroquinone (HQ) clathrates have been investigated as a function of pressure using synchrotron X ray diffraction and Raman spectroscopy. The N2-loaded beta-form HQ clathrate reveals a structural transition to a new high pressure phase near 4 GPa and exhibits gradual N2 release from the hydrogen-bonded organic framework (HOF) cage with a further increase in pressure. Upon reducing the pressure to ambient conditions, the crystal structure reverts to the original beta-form HQ clathrate, indicating that the pressure-induced structural transition is fully reversible. In contrast, around 0.4 GPa, the guest-free beta-form HQ clathrate undergoes an irreversible phase transition to the nonporous alpha-form HQ, which is retained at ambient conditions. These results suggest that HOF encaged guest molecules play an important role in the structural transitions under high pressure. PMID- 23750697 TI - Glomerular mannose-binding lectin deposition is a useful prognostic predictor in immunoglobulin A nephropathy. AB - There is accumulating evidence to support a hypothesis of the activation of the lectin complement pathway in immunoglobulin A nephropathy (IgAN). The glomerular deposition of mannose-binding lectin (MBL), an initiator of the lectin pathway, has been identified, but its clinical significance has not been defined consistently. The aim of the present study was to investigate the value of glomerular MBL deposition as a useful histological biomarker in evaluating the severity and predicting the prognosis of IgAN. We included all consecutive patients with biopsy-proven primary IgAN from December 2008 to July 2010. Renal deposition of MBL was detected by immunofluorescence. The biopsy material from 131 patients (72 men) was thus used for MBL staining. The deposition of MBL was observed in a predominantly mesangial pattern in 45 patients (34.35%), which presented as global or segmental deposition. Compared with the patients without glomerular MBL deposition, those with glomerular MBL deposition had more severe proteinuria, decreased renal function, lower levels of serum albumin and a greater possibility of hypertension at the time of renal biopsy; they had more severe histological changes according to the Oxford classification (i.e. mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity and tubular atrophy/interstitial fibrosis), and their ratio presented an increase as the histopathological phenotypes segregated according to Lee's classification; furthermore, the follow-up data demonstrated that they had a lower renal remission rate. In conclusion, glomerular MBL deposition may predict a poor prognosis, and thus can be a new prognostic factor in IgA nephropathy. PMID- 23750698 TI - Inspired gas humidity and temperature during mechanical ventilation with the Stephanie ventilator. AB - AIMS: To measure inspired gas humidity and temperature delivered by a Stephanie neonatal ventilator with variations in (i) circuit length; (ii) circuit insulation; (iii) proximal airway temperature probe (pATP) position; (iv) inspiratory temperature (offset); and (v) incubator temperatures. METHODS: Using the Stephanie neonatal ventilator, inspired gas humidity and temperature were measured during mechanical ventilation at the distal inspiratory limb and 3 cm down the endotracheal tube. Measurements were made with a long or short circuit; with or without insulation of the inspiratory limb; proximal ATP (pATP) either within or external to the incubator; at two different inspiratory temperature (offset) of 37(-0.5) and 39(-2.0) degrees C; and at three different incubator temperatures of 32, 34.5, and 37 degrees C. RESULTS: Long circuits produced significantly higher inspired humidity than short circuits at all incubator settings, while only at 32 degrees C was the inspired temperature higher. In the long circuits, insulation further improved the inspired humidity especially at 39(-2.0) degrees C, while only at incubator temperatures of 32 and 37 degrees C did insulation significantly improve inspired temperature. Positioning the pATP outside the incubator did not result in higher inspired humidity but did significantly improve inspired temperature. An inspiratory temperature (offset) of 39(-2.0) degrees C delivered significantly higher inspired humidity and temperature than the 37(-0.5) degrees C especially when insulated. CONCLUSIONS: Long insulated Stephanie circuits should be used for neonatal ventilation when the infant is nursed in an incubator. The recommended inspiratory temperature (offset) of 37(-0.5) degrees C produced inspired humidity and temperature below international standards, and we suggest an increase to 39(-2.0) degrees C. PMID- 23750699 TI - Source personality and persuasiveness: big five predispositions to being persuasive and the role of message involvement. AB - In the present studies we incorporate a Person * Situation perspective into the study of the persuasion source. Specifically, we aimed to identify the personality characteristics of the persuasive individual and test the moderating role of target and source involvement. In three studies we found support for hypothesized relationships between source persuasiveness and Extraversion, Neuroticism, and Openness to Experience, and evidence for a moderating effect of involvement. In a preliminary study (N = 66, M(age) = 22.7, 64% female), we demonstrated expected differences in the personality ratings assigned to a hypothetical persuasive versus nonpersuasive individual. In Study 1 (N = 95, M(age) = 24.1, 62% female), through sets of two-person debates, we showed that source Extraversion and Openness to Experience were positively, and Neuroticism negatively, associated with source persuasiveness. In Study 2 (N = 148, M(age) = 24.3, 61% female), we manipulated the level of involvement and mostly replicated the results from Study 1, but, corresponding with our predictions, only when involvement was low. Our findings demonstrate the relevance of an interactionist approach to the study of persuasion, highlighting the role of personality in the study of the persuasion source. PMID- 23750700 TI - Facile formation of stable tris(imido)phosphate trianions as their tri- and hexanuclear Pd(II) complexes in protic solvents. AB - Employing Pd(OAc)2, a facile deprotonation route to access the highly basic tris(alkylimido)phosphate trianions, [(RN)3PO](3-) (R = (t)Bu, (c)Hex, or (i)Pr), analogous to the orthophosphate (PO4(3-)) ion in polar and in protic solvents has been achieved. Trinuclear and prismatic Pd(II) clusters of these imido trianions having the formula {Pd3[(NR)3PO](OAc)3}n (n = 1 or 2) or as mixed-bridged clusters of the type {Pd3[(N(i)Pr)3PO](OAc)2(OR')}2 (R' = Me or H) were isolated exclusively in all these reactions in which the trianionic species acts as a tripodal chelating ligand to the trinuclear Pd3 unit. Reactivity studies aiming at the Pd(II) atoms in these clusters with nucleophilic reagents, such as primary amines (R"NH2), have led to a new trimeric cluster with the formula {Pd3[(NR)3PO](OAc)3(R"NH2)3} in which the tripodal coordination of the Pd-Nimido moieties remained unaffected, exemplifying the robustness of the Pd3 unit in all these clusters. We have also shown the catalytic activity of these Pd(II) complexes in Mizoroki-Heck type coupling reactions in the presence of Cu(OAc)2. PMID- 23750701 TI - How much water is needed to ionize formic acid? AB - Structure, molecular properties, energy parameters, and vibrational IR spectra of hydrated clusters of formic acid (FOH), FOH.nH2O (n = 1-8), are presented following first principle based electronic structure theory. Several geometrical arrangements are considered as initial guess structures to look for the minimum energy equilibrium structures applying omegaB97X-D density functional and aug-cc pVDZ set of atomic basis functions. Results on FOH-water clusters suggest that the most stable structure of formic acid exists as a charge-separated ion pair, FO(-delta)---H(+delta)---O(-delta)H2, in hydrated clusters, FOH.nH2O, for cluster size n >= 7. The calculated interaction energy between FOH and the solvent water cluster increases significantly by adding the seventh solvent water molecule to the FOH.6H2O cluster whereas the solvent stabilization energy of FOH increases continuously on successive addition of solvent water molecules (n = 1-8). Energy partitioning of the solvent stabilization energy of FOH.nH2O clusters suggests an electrostatic component of energy to play the major role in solvent stability and does depict sudden variation for n = 7. Formation of a charge-separated ion pair for cluster size n >= 7 is manifested in simulated IR spectra of FOH.nH2O clusters. Static polarizabilities of hydrated formic acid clusters are calculated and observed to vary linearly with the size of the clusters, suggesting reliability in prediction of polarizability for larger size hydrated clusters of formic acid. PMID- 23750702 TI - Genetic analysis of attachment glycoprotein (G) gene in new genotype ON1 of human respiratory syncytial virus detected in Japan. AB - We studied the evolution of the G gene in the new genotype ON1 of RSV detected from patients with acute respiratory infection in Japan. Phylogenetic analyses and the evolutionary timescale were obtained by the Bayesian MCMC method. We also analyzed p-distance and positive selection sites. A new genotype ON1 emerged around 2001. The evolution rate was rapid (3.57 * 10(-3) substitutions/site per year). The p-distance was short and no positive selection site was found in the present strains. These results suggested that a new genotype ON1 of RSV-A emerged approximately10 years ago and spread to some countries with a high evolution rate. PMID- 23750703 TI - Dissipation of excess excitation energy by drought-induced nonphotochemical quenching in two species of drought-tolerant moss: desiccation-induced acceleration of photosystem II fluorescence decay. AB - Drought-tolerant mosses survive with their green color intact even after long periods of dehydration that would kill ordinary plants. The mechanism of dissipation of excitation energy under drought stress was studied in two species of drought-tolerant moss, Rhytidium rugosum and Ceratodon purpureus. They showed severe quenching of photosystem II chlorophyll fluorescence (PSII) after being dehydrated in the dark. Quenching was induced by the acceleration of the fluorescence decay rate. This drought-induced nonphotochemical quenching (designated d-NPQ) was fully reversed by rehydration. Global analysis of fluorescence decay at 77 K indicated rapid 46 ps transfer of excitation energy from the 680-690 nm PSII bands to a 710 nm band, and to 740-760 nm bands. The latter bands decayed to the ground state with the same time constant showing the rapid dissipation of excitation energy into heat. The quenching by d-NPQ in dry moss was stronger than that by PSII charge separation or nonphotochemical quenching (NPQ), which operates under hydrating conditions. Drought-tolerant mosses, thus, dissipate excess excitation energy into heat. The d-NPQ mechanism in moss resembles that reported in lichens, suggesting their common origin. PMID- 23750704 TI - High normotension is associated with higher metabolic syndrome risk in postmenopausal women. AB - AIM: Cardiovascular disease and diabetes are important causes for mortality in older people. Both hypertension and prehypertension are correlated with them. Recently, health promotion and disease prevention in postmenopausal women have become an essential issue of public health policy. The present study aimed to evaluate whether the harmful effects of blood pressure (BP) could still be found in normotensive postmenopausal women (below 120/80 mmHg). METHODS: A total of 4539 normotensive postmenopausal women aged 51 years or older, undergoing routine health examinations, were enrolled in the cross-sectional analyses. To mitigate the effect of age on BP, participants within the same age were divided into tertiles according to their systolic BP (SBP). Then, participants in the low-SBP tertile of each age stratum were pooled together to form a larger group (low normal SBP group [LNSBP]). Similarly, the middle- and high-normal SBP were grouped accordingly (MNSBP and HNSBP). Metabolic syndrome (MetS) was considered to be a surrogate for future cardiovascular disease and diabetes. RESULTS: The study showed that HNSBP bore a higher likelihood of having abnormal MetS components, elevated low-density lipoprotein cholesterol levels and a higher odds ratio (1.46; 95% confidence interval 1.17-1.81) for having MetS than LNSBP. In contrast, age, body mass index, fasting plasma glucose and low-density lipoprotein cholesterol were significantly related to SBP in multiple regression analysis. CONCLUSIONS: The risk of having MetS was significantly associated with higher SBP even within normotension. Primary prevention, such as lifestyle modification, and more strict control of BP should be stressed in postmenopausal women. PMID- 23750706 TI - Mobility impairment is associated with urge but not stress urinary incontinence in community-dwelling older women: results from the Ossebo study. AB - OBJECTIVE: To assess the association between functional limitations related to mobility and urinary incontinence (UI) in elderly women. DESIGN: An observational cross-sectional study. SETTING: Nine 'balance' workshops in France. POPULATION: A total of 1942 community-dwelling women aged 75-85 years, who were invited, based on voter registration lists, to a 'balance assessment'. METHODS: Mobility and balance test results for incontinent women were compared with those for continent women according to the severity and type of incontinence. MAIN OUTCOME MEASURES: Data on UI were collected using a self-administered questionnaire (International Consultation on Incontinence Questionnaire-Short Form). Motor-related physical abilities were assessed using standardised balance and functional gait tests. RESULTS: Forty-two per cent of women had involuntary urine leakage, with daily leaks in 57% of them; 24% had stress UI, 31% had urge UI, and 37% had mixed UI. Results for each functional test were poorer for women with UI and the limitation was more pronounced when the incontinence was severe. Multivariate logistic regression analyses showed that balance and gait impairments were significantly and independently associated with urge UI (walking speed, lower versus higher quartile, odds ratio (OR) 2.2; 95% confidence interval (95% CI) 1.4-3.5; walking balance, unable versus able to do four tandem steps (OR 1.6; 95% CI 1.2-2.2) but not with stress UI. CONCLUSIONS: In this large population of older women living at home, there was a strong association between limitation of motor and balance skills and UI, which was proportional to the severity of incontinence and related specifically to urge incontinence. These results offer new perspectives on the prevention and treatment of urge incontinence in elderly women. PMID- 23750707 TI - Ion pairing with bile salts modulates intestinal permeability and contributes to food-drug interaction of BCS class III compound trospium chloride. AB - In the current study the involvement of ion pair formation between bile salts and trospium chloride (TC), a positively charged Biopharmaceutical Classification System (BCS) class III substance, showing a decrease in bioavailability upon coadministration with food (negative food effect) was investigated. Isothermal titration calorimetry provided evidence of a reaction between TC and bile acids. An effect of ion pair formation on the apparent partition coefficient (APC) was examined using (3)H-trospium. The addition of bovine bile and bile extract porcine led to a significant increase of the APC. In vitro permeability studies of trospium were performed across Caco-2-monolayers and excised segments of rat jejunum in a modified Ussing chamber. The addition of bile acids led to an increase of trospium permeation across Caco-2-monolayers and rat excised segments by approximately a factor of 1.5. The addition of glycochenodeoxycholate (GCDC) was less effective than taurodeoxycholate (TDOC). In the presence of an olive oil emulsion, a complete extinction of the permeation increasing effects of bile salts was observed. Thus, although there are more bile acids in the intestine in the fed state compared to the fasted state, these are not able to form ion pairs with trospium in fed state, because they are involved in the emulsification of dietary fats. In conclusion, the formation of ion pairs between trospium and bile acids can partially explain its negative food effect. Our results are presumably transferable to other organic cations showing a negative food effect. PMID- 23750708 TI - Electrical impedance tomography for verification of correct endotracheal tube placement in paediatric patients: a feasibility study. AB - BACKGROUND: Endotracheal tubes (ETTs) are frequently used in paediatric anaesthesia. Correct placement is crucial. The aim of this study was to evaluate electrical impedance tomography (EIT) for guiding and confirmation of paediatric ETT placement. In a retrospective analysis of stored EIT data, distribution of ventilation between left and right lung was used to verify correct paediatric ETT placement. METHODS: Left and right lung ventilation was studied by EIT in 18 paediatric patients (median age: 53 months) requiring anaesthesia and endotracheal intubation. EIT was recorded before induction of anaesthesia, during mask ventilation, during ETT placement (including deliberate mainstem intubation), and after ETT repositioning according to the formula: ETT intubation depth (cm) = 3* ETT internal diameter (mm) or the mainstem intubation method (withdrawing the ETT 2 cm). Final ETT position was confirmed by fluoroscopy. RESULTS: Following deliberate mainstem intubation, distribution of ventilation to the right lung was unequivocally demonstrated by EIT. Homogeneous distribution of ventilation between left and right lung monitored with EIT correlated in each patient with correct endotracheal ETT placement. The distribution of left and right lung ventilation differed significantly (P < 0.05) between the initial two lung ventilation and subsequent right one-lung ventilation, and between right one lung and subsequent two-lung ventilation according to auscultation and the final ETT position, respectively. In one patient, ETT was misplaced within the oesophagus which was also obvious from the EIT record. CONCLUSION: This study demonstrates that EIT enables non-invasive recognition of correct ETT placement. Homogeneous right-left-lung ventilation is an indicator for correct ETT placement. PMID- 23750709 TI - Single sublattice endotaxial phase separation driven by charge frustration in a complex oxide. AB - Complex transition-metal oxides are important functional materials in areas such as energy and information storage. The cubic ABO3 perovskite is an archetypal example of this class, formed by the occupation of small octahedral B-sites within an AO3 network defined by larger A cations. We show that introduction of chemically mismatched octahedral cations into a cubic perovskite oxide parent phase modifies structure and composition beyond the unit cell length scale on the B sublattice alone. This affords an endotaxial nanocomposite of two cubic perovskite phases with distinct properties. These locally B-site cation-ordered and -disordered phases share a single AO3 network and have enhanced stability against the formation of a competing hexagonal structure over the single-phase parent. Synergic integration of the distinct properties of these phases by the coherent interfaces of the composite produces solid oxide fuel cell cathode performance superior to that expected from the component phases in isolation. PMID- 23750711 TI - Hepatitis C among injecting drug users is two times higher in Stockholm, Sweden than in Rotterdam, the Netherlands. AB - This study assessed risk behavior and preventive measures for hepatitis C among injecting drug users in Rotterdam, the Netherlands (452 participants, 2002-2003) and Stockholm, Sweden (310 participants, 2004-2006), two cities with contrasting drug policies. Uni- and multivariate logistic regression models were used. We found that the prevalence of hepatitis C was almost two times higher in participants from Stockholm than in participants from Rotterdam, even after adjustment for sex sharing paraphernalia (adjusted relative risk: 1.92, 95% confidence interval: 1.60-2.29). Follow-up comparative studies are needed to determine if policies with structured health programs can decrease transmission of hepatitis C. PMID- 23750710 TI - Essential role of Pin1 via STAT3 signalling and mitochondria-dependent pathways in restenosis in type 2 diabetes. AB - Type 2 diabetes (T2D) is associated with accelerated restenosis rates after angioplasty. We have previously proved that Pin1 played an important role in vascular smooth muscle cell (VSMC) cycle and apoptosis. But neither the role of Pin1 in restenosis by T2D, nor the molecular mechanism of Pin1 in these processes has been elucidated. A mouse model of T2D was generated by the combination of high-fat diet (HFD) and streptozotocin (STZ) injections. Both Immunohistochemistry and Western blot revealed that Pin1 expression was up regulated in the arterial wall in T2D mice and in VSMCs in culture conditions mimicking T2D. Next, increased activity of Pin1 was observed in neointimal hyperplasia after arterial injury in T2D mice. Further analysis confirmed that 10% serum of T2D mice and Pin1-forced expression stimulated proliferation, inhibited apoptosis, enhanced cell cycle progression and migration of VSMCs, whereas Pin1 knockdown resulted in the converse effects. We demonstrated that STAT3 signalling and mitochondria-dependent pathways played critical roles in the involvement of Pin1 in cell cycle regulation and apoptosis of VSMCs in T2D. In addition, VEGF expression was stimulated by Pin1, which unveiled part of the mechanism of Pin1 in regulating VSMC migration in T2D. Finally, the administration of juglone via pluronic gel onto injured common femoral artery resulted in a significant inhibition of the neointima/media ratio. Our findings demonstrated the vital effect of Pin1 on the VSMC proliferation, cell cycle progression, apoptosis and migration that underlie neointima formation in T2D and implicated Pin1 as a potential therapeutic target to prevent restenosis in T2D. PMID- 23750712 TI - Cardiac findings in Noonan syndrome on long-term follow-up. AB - OBJECTIVE: Noonan syndrome (NS) is the second most common genetic syndrome associated with cardiac abnormalities, including, most notably, pulmonary stenosis (PS) and hypertrophic cardiomyopathy (HCM). Little is known about the natural history of heart disease in this unique subset of patients. We sought to contribute information on the natural history of NS by looking at how the cardiac disease progresses with time. DESIGN: This is a retrospective review of the medical records of patients with NS seen at our institution between 1963 and 2011. RESULTS: Records were available for 113 patients. Average length of follow up was 14.16 years (2 months to 44 years, median 12.5 years). Sixty-six percent (75/113) of our patients had PS; within this subset, 57% (43) were classified as mild, 9% (7) moderate, and 33% (25) severe. None of the cases of mild PS worsened with time. All of the severe cases had an intervention, as did some moderate cases. Fourteen percent (16/113) of our patients had HCM; 56% (9/16) were mild, diagnosed at an average age of 3.8 years. Seven of these were stable with time, while one did progress. Forty-four percent (7/16) of cases were classified as severe, diagnosed at an average age of 4.2 months, and all were managed medically, surgically, or both. Our cohort had seven deaths (ages 6 months and 6, 10, 20, 40, 49, and 50 years). CONCLUSION: Mild PS in patients with NS is nonprogressive. Severe, and in some cases moderate, PS will invariably require a therapeutic intervention. It is uncommon for HCM to progress or have new onset beyond early childhood. Prognosis of heart disease in NS is influenced most by the findings on presentation. PMID- 23750714 TI - Physical characteristics of commercial and home-made nasal lavage solutions. AB - INTRODUCTION: Nasal saline lavage forms a cornerstone of chronic rhinosinusitis management. A number of saline lavage recipes and products are currently available but little is known of their relative physical characteristics. AIMS: To determine the osmolarity and pH of nasal lavage solutions, both commercial preparations and home-made recipes, and to determine the reproducibility of saline solution preparation. METHODS: Five home-made recipes and two commercial products were prepared in triplicate and analysed. Eight consecutive clinic patients prepared a commercial product and 11 prepared a home-made recipe, and the osmolarity and pH were measured. RESULTS: The osmolarity of the solutions varied widely, from 140 to 788 mmol/l and the pH varied from 7.88 to 8.50. The commercial and home-made solutions had similar reproducibility when prepared by patients. CONCLUSION: Some recipes were markedly hypo-osmolar and some were hyper osmolar. All were slightly alkaline. The home-made recipes had similar physical characteristics and reproducibility to commercial preparations. PMID- 23750713 TI - Systematic improvement of a classical molecular model of water. AB - We report the iAMOEBA ("inexpensive AMOEBA") classical polarizable water model. The iAMOEBA model uses a direct approximation to describe electronic polarizability, in which the induced dipoles are determined directly from the permanent multipole electric fields and do not interact with one another. The direct approximation reduces the computational cost relative to a fully self consistent polarizable model such as AMOEBA. The model is parameterized using ForceBalance, a systematic optimization method that simultaneously utilizes training data from experimental measurements and high-level ab initio calculations. We show that iAMOEBA is a highly accurate model for water in the solid, liquid, and gas phases, with the ability to fully capture the effects of electronic polarization and predict a comprehensive set of water properties beyond the training data set including the phase diagram. The increased accuracy of iAMOEBA over the fully polarizable AMOEBA model demonstrates ForceBalance as a method that allows the researcher to systematically improve empirical models by efficiently utilizing the available data. PMID- 23750715 TI - COMMITTEE FOR THE STUDY OF ETHICAL ASPECTS OF HUMAN REPRODUCTION: GUIDELINES REGARDING INFORMED CONSENT. PMID- 23750716 TI - COMMITTEE FOR THE STUDY OF ETHICAL ASPECTS OF HUMAN REPRODUCTION: VIOLENCE AGAINST WOMEN. PMID- 23750717 TI - COMMITTEE FOR THE STUDY OF ETHICAL ASPECTS OF HUMAN REPRODUCTION: ETHICAL ASPECTS IN THE MANAGEMENT OF THE DECLARATION OF INUYAMA. PMID- 23750718 TI - THE DECLARATION OF INUYAMA: Human Genome Mapping, Genetic Screening and Gene Therapy* PMID- 23750719 TI - STATEMENT ON HUMAN GENE THERAPY: International Symposium on Human Gene Therapy. PMID- 23750720 TI - Whole blood stimulation with Toll-like receptor (TLR)-7/8 and TLR-9 agonists induces interleukin-12p40 expression in plasmacytoid dendritic cells in rhesus macaques but not in humans. AB - Macaques provide important animal models in biomedical research into infectious and chronic inflammatory disease. Therefore, a proper understanding of the similarities and differences in immune function between macaques and humans is needed for adequate interpretation of the data and translation to the human situation. Dendritic cells are important as key regulators of innate and adaptive immune responses. Using a new whole blood assay we investigated functional characteristics of blood plasmacytoid dendritic cells (pDC), myeloid dendritic cells (mDC) and monocytes in rhesus macaques by studying induction of activation markers and cytokine expression upon Toll-like receptor (TLR) stimulation. In a head-to-head comparison we observed that rhesus macaque venous blood contained relatively lower numbers of pDC than human venous blood, while mDC and monocytes were present at similar percentages. In contrast to humans, pDC in rhesus macaques expressed the interleukin (IL)-12p40 subunit in response to TLR-7/8 as well as TLR-9 stimulation. Expression of IL-12p40 was confirmed by using different monoclonal antibodies and by reverse transcription-polymerase chain reaction (RT-PCR). Both in humans and rhesus macaques, TLR-4 stimulation induced IL-12p40 expression in mDC and monocytes, but not in pDC. The data show that, in contrast to humans, pDC in macaques are able to express IL-12p40, which could have consequences for evaluation of human vaccine candidates and viral infection. PMID- 23750721 TI - Possible association of Neu2 with plasma membrane fraction from mouse thymus exhibited sialidase activity with fetuin at pH 7.0 but not at pH 4.5. AB - Compared to other organs, the mouse thymus exhibits a high level of sialidase activity in both the soluble and crude membrane fractions, as measured at neutral pH using 4MU-Neu5Ac as a substrate. The main purpose of the present study was to identify the sialidase with a high level of the activity at neutral pH in the crude membrane. Several parameters were analyzed using the soluble (S) fraction, N and D fractions that were obtained by NP-40 or DOC/NP-40 solubilization from the thymus crude membrane. The main sialidase activity in the N fraction exhibited almost the same pI as that of soluble Neu2 and 60% of the activity was removed from the membrane by three washes with 10 mM Tris-buffer, at pH 7.0. The N fraction preferentially hydrolyzed the sialic acid bond of glycoprotein and exhibited sialidase activity with fetuin at pH 7.0 but not at pH 4.5. The same activity was observed in a plasma membrane-rich fraction. To date, the removal of sialic acid from fetuin at pH 7.0 was reported only with soluble Neu2 and the membrane fraction from Neu2-transfected COS cells. We analyzed the gene that controls the sialidase activity in the crude membrane fraction at pH 7.0 using SMXA recombinant mice and found that compared with other three genes, Neu2 presented the best correlation with the activity level. We suggest that Neu2 is most likely responsible for the main activity in the N fraction, due to its association with the membrane by an unknown mechanism. PMID- 23750722 TI - Blood pressure and pulse wave velocity as metrics for evaluating pathologic ageing of the cardiovascular system. AB - The influence of chronological ageing on the components of the cardiovascular system is of fundamental importance for understanding how hemodynamics change and the cardiovascular risk increases with age, the most important risk marker. An increase in peripheral vascular resistance associated with increased stiffness of central elastic arteries represents hallmarks of this ageing effect on the vasculature, referred to as early vascular ageing (EVA). In clinical practice, it translates into increased brachial and central systolic blood pressure and corresponding pulse pressure in subjects above 50 years of age, as well as increased carotid-femoral pulse wave velocity (c-f PWV)--a marker of arterial stiffness. A c-f PWV value >= 10 m/s is threshold for increased risk according. Improved lifestyle and control of risk factors via appropriate drug therapy are of importance in providing vascular protection related to EVA. One target group might be members of risk families including subjects with early onset cardiovascular disease. PMID- 23750723 TI - Addressing the current challenges to finding new anthelminthic drugs. PMID- 23750724 TI - Increasing prevalence of carbapenem-resistant Enterobacteriaceae and strategies to avert a looming crisis. PMID- 23750725 TI - Enterovirus 71 receptors: promising drug targets? PMID- 23750727 TI - H1N1 pandemic: clinical and epidemiologic characteristics of the Canadian pediatric outbreak. AB - Canada was one of the first countries affected by the 2009 influenza H1N1 pandemic with two waves - one from May to June and one from October to December. The 2009 influenza H1N1 pandemic had many unique features when compared with seasonal influenza, including the following: more than half of the affected people were children; asthma was the most significant risk factor for hospital admission; and Aboriginal and pregnant women had a higher risk of hospital admission and complications. Antiviral therapy was widely used but data did not show any effect on the pediatric population. Outbreak spread was possibly promoted from child-child and child-adult contact, and therefore the vaccination campaign targeted the pediatric population and achieved good coverage among young children (57%). Vaccination efficacy was difficult to test because of the vaccination delay. Improvement in models of prevention and treatment are urgently needed to prepare for the possible future pandemics. PMID- 23750728 TI - Pneumocystis jirovecii pneumonia in Latin America. A public health problem? AB - Pneumocystis jirovecii pneumonia (PcP) is a well-recognized major opportunistic infection in HIV-infected patients. During the 1980s, the HIV pandemic turned PcP into a major worldwide medical and public health problem. With the introduction of Pneumocystis chemoprophylaxis and the development of highly active antiretroviral therapy (ART) for the treatment of HIV infection, there has been a decrease in PcP incidence in developed countries. However, the prevalence of AIDS related PcP in developing countries remains high because a lot of people do not have access to ART or ignore their HIV infection status. This article discusses the information available about PcP among Latin American countries where there is a great regional heterogeneity in the prevalence of HIV infection and in ART coverage, as well as in the observed frequencies of PcP that range from 5.9 to 55% in this area. PMID- 23750729 TI - Screening and deciphering antibiotic resistance in Acinetobacter baumannii: a state of the art. AB - Acinetobacter baumannii, recognized as a serious threat in healthcare facilities, has the ability to develop resistance to antibiotics quite easily. This resistance is related to either gene acquisition (horizontal gene transfer) or mutations in the genome, leading to gene disruption, over- or down-expression of genes. The clinically relevant antibiotic resistances in A. baumannii include resistance to aminoglycosides, broad-spectrum cephalosporins, carbapenems, tigecycline and colistin, which are the last resort antibiotics. The intrinsic and acquired resistance mechanisms of A. baumannii are presented here, with special focus on beta-lactam resistance. The most up-to-date techniques for identification, including phenotypical and molecular tests, and screening of those emerging resistance traits are also highlighted. The implementation of early detection and identification of multidrug-resistant A. baumannii is crucial to control their spread. PMID- 23750730 TI - Extended or continuous versus short-term intravenous infusion of cephalosporins: a meta-analysis. AB - The authors sought to study whether extended or continuous infusion of cephalosporins is associated with better clinical outcomes than short-term infusion. PubMed and Scopus databases were systematically searched. Studies reporting the clinical outcomes of patients receiving extended or continuous infusion (>=3 or 24 h, respectively) versus short-term infusion (<=1 h) of cephalosporins were considered eligible. Eleven studies (1250 clinically evaluable patients) were included. Clinical cure and mortality were not statistically different between the compared groups (risk ratio: 1.14; 95% CI: 0.94-1.37 and risk ratio: 0.96; 95% CI: 0.80-1.15, respectively). This meta analysis did not show a difference in clinical cure or mortality regarding extended or continuous versus short-term intravenous infusion of cephalosporins. However, in most of the included studies, patients in the extended/continuous infusion group received a substantially lower total dosage of antibiotic than those in the short-term group for the total duration of treatment. PMID- 23750731 TI - The burden and impact of severe and long-term sequelae of meningococcal disease. AB - This review describes current knowledge on the severity and long-term sequelae of meningococcal disease (MD) specifically. The literature databases Medline and Embase were used by combining search terms for MD and Neisseria meningitidis with terms for severity, mortality and sequelae. Case fatality for sufferers of MD remains high, typically 5-10%, despite the best medical care. Long-term sequelae in survivors may include physical, neurological, cognitive, behavioral and psychological consequences, such as hearing loss, amputations, skin scarring and neurodevelopmental deficits. A significantly lower quality of life is seen in survivors of MD compared with unaffected controls, with detrimental effects of childhood MD continuing into adulthood. MD carries a substantial risk of long term sequelae and mortality. This should be recognized by physicians treating patients with this disease and lends support for the implementation of preventative measures such as vaccination. PMID- 23750732 TI - Drug-resistant tuberculous meningitis. AB - Drug-resistant tuberculosis, including drug-resistant tuberculous meningitis, is an emerging health problem in many countries. An association with Beijing strains and drug resistance-related mutations, such as mutations in katG and rpoB genes, has been found. The pathology, clinical features and neuroimaging characteristics of drug-resistant tuberculous meningitis are similar to drug-responsive tuberculous meningitis. Detection of mycobacteria in cerebrospinal fluid (CSF) by conventional methods (smear examination or culture) is often difficult. Nucleic acid amplification assays are better methods owing to their rapidity and high sensitivity. The Xpert MTB/RIF assay (Cepheid, CA, USA) is a fully-automated test that has also been found to be effective for CSF samples. Treatment of multidrug resistant tuberculous meningitis depends on the drug susceptibility pattern of the isolate and/or the previous treatment history of the patient. Second-line drugs with good penetration of the CSF should be preferred. Isoniazid monoresistant disease requires addition of another drug with better CSF penetration. Drug-resistant tuberculous meningitis is associated with a high mortality. HIV infected patients with drug-resistant tuberculous meningitis have severe clinical manifestations with exceptionally high mortality. Prevention of tuberculosis is the key to reduce drug-resistant tuberculous meningitis. PMID- 23750733 TI - The silent threat: asymptomatic parasitemia and malaria transmission. AB - Scale-up of malaria control interventions has resulted in a substantial decline in global malaria morbidity and mortality. Despite this achievement, there is evidence that current interventions alone will not lead to malaria elimination in most malaria-endemic areas and additional strategies need to be considered. Use of antimalarial drugs to target the reservoir of malaria infection is an option to reduce the transmission of malaria between humans and mosquito vectors. However, a large proportion of human malaria infections are asymptomatic, requiring treatment that is not triggered by care-seeking for clinical illness. This article reviews the evidence that asymptomatic malaria infection plays an important role in malaria transmission and that interventions to target this parasite reservoir may be needed to achieve malaria elimination in both low- and high-transmission areas. PMID- 23750735 TI - Correlation between subjective and objective evaluation of peri-implant soft tissue color. AB - PURPOSE: While extensive references are present in the literature dealing with the correlation between subjective and objective evaluation of tooth shade, there is a lack of information on this correlation regarding the soft tissue color. The purpose of this experimental study was to verify whether a correlation between the objective and subjective evaluation exists in analyzing soft tissue color. MATERIAL AND METHODS: A total of 39 patients with at least one implant-supported restoration in the anterior maxilla were included in the study. The shade of the peri-implant mucosa was compared with the shade of the gingiva at the adjacent tooth in a subjective and in an objective manner. The subjective evaluation was performed by five dental professionals (prosthodontist, periodontist, general dentist, dental hygienist, and dental assistant) in a subjective scale (ranging from 1 to 4). The objective evaluation was obtained by means of a spectrophotometer in a CIELAB* Color Scale, and the differences were evaluated through formula DeltaE=[(DeltaL)2+(Deltaa)2+(Deltab)2]1/2. To correlate the subjective and the objective evaluation, for each arithmetical median value of the subjective evaluation, a mean value of objective evaluation has been calculated, and the Spearman's rank correlation coefficient has been used. The differences have been also analyzed for thin and thick tissue biotypes. RESULTS: The mean ?E value for the subjective evaluation between peri-implant soft tissue and adjacent tooth gingival tissue was ?E = 9.74. Also, mean ?E values of 10.35 and 7.54 have been reported for thin and thick biotypes, respectively. Mean values of ?E = 6.63, 8.54, and 15.54 were presented by median values of 1 (perfect matching), 2 (good matching), and 3 (clinically distinguishable), respectively. The threshold for the distinction of differences of mucosal color by the human eyes between perfect or good matching and distinguishable values has been calculated in ?E = 8.74. CONCLUSIONS: Within the limitation of this study, a correlation between the subjective and the objective evaluation of the peri implant soft tissue exists and the threshold for the distinction of mucosal color differences between perfect or good matching and distinguishable subjective values has been calculated in ?E = 8.74 in the objective evaluation. PMID- 23750737 TI - Real-time observation of the formation of excited radical ions in bimolecular photoinduced charge separation: absence of the Marcus inverted region explained. AB - Unambiguous evidence for the formation of excited ions upon ultrafast bimolecular photoinduced charge separation is found using a combination of femtosecond time resolved fluorescence up-conversion, infrared and visible transient absorption spectroscopy. The reaction pathways are tracked by monitoring the vibrational energy redistribution in the product after charge separation and subsequent charge recombination. For moderately exergonic reactions, both donor and acceptor are found to be vibrationally hot, pointing to an even redistribution of the energy dissipated upon charge separation and recombination in both reaction partners. For highly exergonic reactions, the donor is very hot, whereas the acceptor is mostly cold. The asymmetric energy redistribution is due to the formation of the donor cation in an electronic excited state upon charge separation, confirming one of the hypotheses for the absence of the Marcus inverted region in photoinduced bimolecular charge separation processes. PMID- 23750738 TI - Cyclometalated platinum complexes with luminescent quantum yields approaching 100%. AB - A new class of cyclometalated tetradentate platinum complexes of the type Pt[N(/?)C-O-LL'] was synthesized and characterized. N(/?)C is a cyclometalating ligand such as phenyl-pyrazole (ppz), phenyl-methylimidazole (pmi), or phenyl pyridine (ppy), and LL' is an ancillary ligand such as phenoxyl-pyridine (popy). The complexes in this series are highly luminescent, emitting blue to green light in solution with quantum efficiencies ranging from 0.39 to 0.64 and luminescent lifetimes from 2 to 9 MUs. When doped in a poly(methyl methacrylate) (PMMA) thin film, measured quantum efficiencies increase to 0.81-0.97 with lifetimes ranging from 4.5-10.4 MUs. One notable example, the metal complex PtOO3, emits green light with a luminescent quantum efficiency approaching 100% and achieves approximately 100% electron-to-photon conversion efficiency in device settings. PMID- 23750736 TI - Role of the highly conserved threonine in cytochrome P450 2E1: prevention of H2O2 induced inactivation during electron transfer. AB - A highly conserved threonine in the I-helix of cytochrome P450s has been suggested to play an important role in dioxygen activation, a critical step for catalytic turnover. However, subsequent studies with some P450s in which this highly conserved threonine was replaced by another residue such as alanine showed that significant catalytic activities were still retained when the variants were compared with the wild type enzymes. These results make the role of this residue unclear. We provide data here that suggest a novel role for this highly conserved threonine (Thr303) in the function of P450 2E1. We found that the P450 2E1 T303A mutant undergoes rapid autoinactivation in the reconstituted system during catalytic turnover when the electrons are provided by NADPH. This inactivation was much faster than that of the wild type P450 2E1 and was prevented by catalase. Both the P450 2E1 wild type and T303A mutants produce hydrogen peroxide during the incubations. The inactivation was accompanied by heme destruction with part of the heme becoming covalently attached to protein. The heme destruction was prevented by catalase or by the presence of substrate. Interestingly, this inactivation occurred much more rapidly in the presence of both an electron transfer system and hydrogen peroxide externally added to the enzyme. This accelerated inactivation during catalytic turnover was also found with a 2B4 T302A mutant, which corresponds to 2E1 T303A. Our results suggest that the conserved threonine in these P450s prevents rapid autoinactivation during the catalytic cycle and that this residue may be highly conserved in P450s since it allows them to remain catalytically active for longer periods of time. PMID- 23750739 TI - An unusual reason for loss of biventricular pacing. PMID- 23750740 TI - Cardiopulmonary resuscitation: outcome and its predictors among hospitalized elderly patients in Egypt. AB - AIM: Our aim was to study the outcome and the predictors of in-hospital cardiopulmonary resuscitation (CPR) among elderly patients admitted to Ain Shams University Hospitals, Egypt. METHODS: We carried out a cross-sectional study for all elderly patients (age >=60 years) who underwent CPR after cardiac arrest at Ain Shams University Hospitals, Egypt, during a 1.5-year study period. We excluded patients who were declared dead on arrival. RESULTS: We found 380 cases of elderly in-hospital cardiac arrest that underwent CPR. Asystole was the most common arrhythmia detected at the time of arrest (85.1%), followed by ventricular tachycardia (8.7%) and ventricular fibrillation (6.2%). Return of spontaneous circulation was achieved in 32.6% of patients and 8.4% survived to discharge from hospital. Multivariate logistic regression analysis identified three independent predictors of better outcome (survival >24 h): response time <=5 min (OR 5.1, 95% CI 1.9-13.4), location of CPR in emergency department (OR 3.2, 95% CI 1.6-6.4) and pre-arrest morbidity (PAM) score <=7 (OR 3.1, 95% CI 1.6-6.1). CONCLUSION: Outcome of CPR after in-hospital cardiac arrest in our setting was poor. The response time <=5 min, CPR in the emergency department and PAM score <=7 were independent predictors of good outcome. PMID- 23750741 TI - Yes, but are they happy? Effects of trait self-control on affective well-being and life satisfaction. AB - Does trait self-control (TSC) predict affective well-being and life satisfaction- positively, negatively, or not? We conducted three studies (Study 1: N = 414, 64% female, Mage = 35.0 years; Study 2: N = 208, 66% female, Mage = 25.24 years; Study 3: N = 234, 61% female, Mage = 34.53 years). The key predictor was TSC, with affective well-being and life satisfaction ratings as key outcomes. Potential explanatory constructs including goal conflict, goal balancing, and emotional distress also were investigated. TSC is positively related to affective well-being and life satisfaction, and managing goal conflict is a key as to why. All studies, moreover, showed that the effect of TSC on life satisfaction is at least partially mediated by affect. Study 1's correlational study established the effect. Study 2's experience sampling approach demonstrated that compared to those low in TSC, those high in TSC experience higher levels of momentary affect even as they experience desire, an effect partially mediated through experiencing lower conflict and emotional distress. Study 3 found evidence for the proposed mechanism--that TSC may boost well-being by helping people avoid frequent conflict and balance vice-virtue conflicts by favoring virtues. Self-control positively contributes to happiness through avoiding and dealing with motivational conflict. PMID- 23750742 TI - Training and fidelity monitoring of alcohol treatment interventions integrated into routine tuberculosis care in Tomsk, Russia: the IMPACT Effectiveness Trial. AB - IMPACT (Integrated Management of Physician-Delivered Alcohol Care for Tuberculosis patients) is a randomized, controlled effectiveness trial based in Tomsk, Russia, that assesses the effect of oral naltrexone and brief behavioral counseling on tuberculosis outcomes and alcohol use in 200 patients. Tuberculosis physicians without addiction experience delivered interventions as part of routine care over a 6-month period, focusing on alcohol intake reduction to support successful tuberculosis treatment. We describe design, training, and fidelity monitoring using a Russian and American team of physicians, bilingual coders, and supervisors. Culturally appropriate adaptations, limitations, and implications for future trials are discussed. The clinical trial identification number is NCT00675961. Funding came from the National Institutes of Health and National Institute on Drug Abuse. PMID- 23750743 TI - Fractures in children with cerebral palsy: a total population study. AB - AIM: To analyse factors associated with fractures in children with cerebral palsy (CP) in different levels of Gross Motor Function Classification System (GMFCS). METHOD: This was an epidemiological retrospective study of a total population of 536 children (214 females, 322 males) with CP born between 1990 and 2005. CP type was unilateral spastic (n=159), bilateral spastic (n=225), ataxic (n=60), dyskinetic (n=80), and mixed type (n=12); 384 children were in Gross Motor Function Classification Scale (GMFCS) levels I-III and 152 children were in GMFCS levels IV-V. Data were collected for a 9-year period on sex, CP-type, GMFCS level, gastrostomy, height, weight, the use of a standing device, antiepileptic drug (AED) therapy, and fractures. RESULTS: The risk of fracture in the total population of children with CP was similar to that for typically developing children. The risk for fractures of those in GMFCS levels I-III was not significantly associated with any of the studied risk factors. The risk of fractures for those in GMFCS levels IV-V on AED therapy was a twofold increase (p=0.004). The risk for fractures without trauma in children with stunted growth (height for age <-3 SD) and those who did not use standing devices was significantly increased: adjusted incidence rate ratio (AIRR) 4.16 (p=0.011) and 3.66 (p=0.010) respectively. Results regarding gastrostomy feeding for those in GMFCS levels IV-V were conflicting: a gastrostomy was associated with a reduced risk of fractures with trauma, but with increased risk of fractures without trauma (AIRR 0.10, p=0.003 and 4.36, p=0.012) respectively. INTERPRETATION: Children in GMFCS levels I-III had a similar incidence and pattern for fractures as normally developing children. Those in GMFCS levels IV-V had stunted growth, often a sign of longstanding undernourishment, and were associated with an increased risk of fractures. Children using standing devices had a fourfold reduction of fractures without trauma. Regular loading exercises and early adequate nutritional intake could prevent fractures in severe CP. PMID- 23750744 TI - Magnetic-responsive hybrids of Fe3O4 nanoparticles with beta-lactoglobulin amyloid fibrils and nanoclusters. AB - We report on the synthesis and magnetic-responsive behavior of hybrids formed by dispersing negatively charged iron oxide (Fe3O4) magnetic nanoparticles in positively charged beta-lactoglobulin protein solutions at acidic pH, followed by heating at high temperatures. Depending on the pH used, different hybrid aggregates can be obtained, such as nanoparticle-modified amyloid fibrils (pH 3) and spherical nanoclusters (pH 4.5). We investigate the effect of magnetic fields of varying strengths (0-5 T) on the alignment of these Fe3O4-modified amyloid fibrils and spherical nanoclusters using a combination of scattering, birefringence and microscopic techniques and we find a strong alignment of the hybrids upon increasing the intensity of the magnetic field, which we quantify via 2D and 3D order parameters. We also demonstrate the possibility of controlling magnetically the sol-gel behavior of these hybrids: addition of salt (NaCl, 150 mM) to a solution containing nanoparticles modified with beta lactoglobulin amyloid fibrils (2 wt % fibrils modified with 0.6 wt % Fe3O4 nanoparticles) induces first the formation of a reversible gel, which can then be converted back to solution upon application of a moderate magnetic field of 1.1 T. These hybrids offer a new appealing functional colloidal system in which the aggregation, orientational order and rheological behavior can be efficiently controlled in a purely noninvasive way by external magnetic fields of weak intensity. PMID- 23750745 TI - Mineral pitch stimulates humoral, cellular and innate immune responses in mice. AB - CONTEXT: Mineral pitch (MP), a traditional medicine, is proposed to boost immunity in conditions that suppress Th1 cytokines such as AIDS/HIV, tuberculosis, leishmaniasis and cancer. OBJECTIVE: This study investigates the immunoregulatory mechanisms of MP in innate, humoral and cell-mediated immunity. MATERIALS AND METHODS: Mice given MP (100, 200, 300 or 400 mg/kg, orally) for 10 consecutive days were immunized intravenously with goat RBC or ovalbumin, and investigated for plaque-forming cells (PFC), hemagglutination titer, hypersensitivity response, lymphocyte proliferation and macrophage function. RESULTS: MP increased PFC (330.2 versus 182.2/106 splenocytes) in mice immunized with goat RBC and elicited ovalbumin-specific IgG titer at 400 mg/kg. Increase in Th1 immunity was correlated with the increased level of IFN-gamma (724 versus 470 pg/ml) and decreased IL-4 (96 versus 178 pg/ml). CD4+/CD3+ ratio and delayed-type hypersensitivity response also increased to, respectively, 20.62 +/- 0.59 (versus 16.47 +/- 0.72) and 1.59 +/- 0.12 (versus 0.87 +/- 0.10 mm) in MP-treated mice. MP increased lymphocyte proliferation (11.14 +/- 0.60 versus 5.81 +/- 0.40 SI) and macrophage phagocyte response (0.24 +/- 0.02 versus 0.15 +/- 0.009), expressed as absorbance at 570 nm, but decreased nitrite production (17.4 +/- 1.10 versus 24.3 +/- 1.30 uM/106 cells). We also observed an increased bone marrow cellularity (24.5 +/- 1.10 versus 17.10 +/- 0.70 cells/femur) and WBC count (12 667 +/- 377 versus 9178 +/- 213 cells/mm3) following MP treatment. There was no sign of toxicity at 400 mg/kg, 1/12th of reported LD50. CONCLUSION: MP elicits a dose-dependent Th1 immune response. PMID- 23750747 TI - Pulmonary administration of PEGylated polylysine dendrimers: absorption from the lung versus retention within the lung is highly size-dependent. AB - The systemic delivery of drugs via the inhaled route is an attractive, needle free means of improving the systemic exposure of molecules such as peptides and proteins that are poorly absorbed after oral administration. Directed delivery into the lungs also provides a means of increasing drug concentrations at the site of action for lung-specific disease states such as pulmonary infections and lung cancer. The current study has examined the potential utility of PEGylated polylysine dendrimers as pulmonary delivery agents and in particular sought to explore the relationship between dendrimer size and absorption of the intact construct (as a potential systemic delivery mechanism) versus retention within the lungs (as a potential pulmonary depot for controlled local release). Dendrimer absorption from the lungs was inversely correlated with molecular weight, with approximately 20-30% of the dose of relatively small (<22 kDa) dendrimers systemically absorbed compared to only 2% absorption for a larger (78 kDa) PEGylated dendrimer. Increasing the molecular weight of the dendrimers led to slower absorption and more prolonged retention in the lung tissue and bronchoalveolar lavage fluid. Oral administration of the two smaller dendrimers confirmed that oral bioavailability of the PEGylated dendrimers was essentially zero and did not contribute to exposure after pulmonary administration. The smaller PEGylated dendrimers were also degraded in the lungs to low molecular weight products that were subsequently absorbed and excreted via the urine, while the larger constructs showed good stability in the lungs. The data suggest first, that small PEGylated dendrimer-based drug delivery systems may be delivered to the blood via inhalation, providing a more attractive alternative to injections, and second that larger PEGylated dendrimers may be retained in the lungs providing the potential for controlled delivery of medications to the blood or lung tissue. PMID- 23750746 TI - Biliary epithelial senescence and plasticity in acute cellular rejection. AB - Biliary epithelial cells (BEC) are important targets in some liver diseases, including acute allograft rejection. Although some injured BEC die, many can survive in function compromised states of senescence or phenotypic de differentiation. This study was performed to examine changes in the phenotype of BEC during acute liver allograft rejection and the mechanism driving these changes. Liver allograft sections showed a positive correlation (p < 0.0013) between increasing T cell mediated acute rejection and the number of BEC expressing the senescence marker p21(WAF1/Cip) or the mesenchymal marker S100A4. This was modeled in vitro by examination of primary or immortalized BEC after acute oxidative stress. During the first 48 h, the expression of p21(WAF1/Cip) was increased transiently before returning to baseline. After this time BEC showed increased expression of mesenchymal proteins with a decrease in epithelial markers. Analysis of TGF-beta expression at mRNA and protein levels also showed a rapid increase in TGF-beta2 (p < 0.006) following oxidative stress. The epithelial de-differentiation observed in vitro was abrogated by pharmacological blockade of the ALK-5 component of the TGF-beta receptor. These data suggest that stress induced production of TGF-beta2 by BEC can modify liver allograft function by enhancing the de-differentiation of local epithelial cells. PMID- 23750748 TI - Is Al2Cl6 aromatic? Cautions in superficial NICS interpretation. AB - In this article, we employed the induced magnetic field method to show that the Al2X6 (X = F, Cl, Br, I) clusters cannot be classified as aromatic systems. Interestingly, even nucleus independent chemical shift (NICS) reveals the same conclusion when analyzed in greater detail, showing that a superficial analysis of this index can easily lead to incorrect interpretations. In view of the fact that the NICS index is extensively used by computational and theoretically oriented experimental chemists, this is an important warning against superficial analyses, as it can lead to erroneous chemical interpretation. PMID- 23750749 TI - Modified Lothrop procedure in cystic fibrosis patients: does it have a role? AB - BACKGROUND: The management of frontal sinus disease in cystic fibrosis patients represents a challenge for many surgeons. Procedures can vary from the minimally invasive to those involving extensive open surgery. OBJECTIVE: This study describes the outcomes of the endoscopic modified Lothrop procedure, in terms of safety and morbidity, for cystic fibrosis patients with frontal sinus disease who did not improve following traditional functional endoscopic sinus surgery. METHOD AND RESULTS: The study setting was a tertiary referral unit in a London teaching hospital, the largest national base for adult cystic fibrosis patients. Two patients diagnosed in childhood with cystic fibrosis presented with histories of recurrent, severe frontal sinusitis; both had previously undergone multiple endoscopic sinus surgical procedures. The modified Lothrop procedure was performed on both patients. The outcome measures were symptom resolution and post operative complications. CONCLUSION: The endoscopic modified Lothrop procedure was beneficial in the cystic fibrosis patients with frontal sinus disease who failed to respond to standard functional endoscopic sinus surgery procedures. PMID- 23750750 TI - Intramural atrial hematoma: a rare complication of a common procedure. PMID- 23750751 TI - Rapid HIV testing experience at Veterans Affairs North Texas Health Care System's Homeless Stand Downs. AB - In the USA, 21% of the estimated 1.1 million people living with human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) are unaware they are HIV-infected. In 2011, Veterans Health Administration (VHA)'s Office of Public Health in conjunction with VHA's Health Care for Homeless Veterans Program funded grants to support rapid HIV testing at homeless outreach events because homeless populations are more likely to obtain emergent rather than preventive care and have a higher HIV seroprevalence as compared to the general population. Because of a Veterans Affairs North Texas Health Care System (VANTHCS)'s laboratory testing requirement, VANTHCS partnered with community agencies to offer rapid HIV testing for the first time at VANTHCS' 2011 Homeless Stand Downs in Dallas, Fort Worth, and Texoma, Texas. Homeless Stand Downs are outreach events that connect Veterans with services. Veterans who declined testing were asked their reasons for declining. Comparisons by Homeless Stand Down site used Pearson chi2, substituting Fisher's Exact tests for expected cell sizes <5. Of the 910 Veterans attending the Homeless Stand Downs, 261 Veterans reported reasons for declining HIV testing, and 133 Veterans were tested, where 92% of the tested Veterans obtained their test results at the events - all tested negative. Veterans' reported reasons for declining HIV testing included previous negative result (n=168), no time to test (n=49), no risk factors (n=36), testing is not a priority (n=11), uninterested in knowing serostatus (n=6), and HIV-infected (n=3). Only "no time to test" differed significantly by Homeless Stand Down site. Nonresponse rate was 54%. Offering rapid HIV testing at Homeless Stand Downs is a promising testing venue since 15% of Veterans attending VANTHCS' Homeless Stand Downs were tested for HIV, and majority obtained their HIV test results at point of-care while further research is needed to determine how to improve these rates. PMID- 23750752 TI - Evidence that transport of iron from the lysosome to the cytosol in African trypanosomes is mediated by a mucolipin orthologue. AB - Bloodstream-form Trypanosoma brucei acquire iron by receptor-mediated endocytosis of host transferrin. However, the mechanism(s) by which iron is then transferred from the lysosome to the cytosol are unresolved. Here, we provide evidence for the involvement of a protein (TbMLP) orthologous to the mammalian endolysosomal cation channel Mucolipin 1. In T. brucei, we show that this protein is localized to the single parasite lysosome. TbMLP null mutants could only be generated in the presence of an expressed ectopic copy, suggesting that the protein is essential. RNAi-mediated ablation resulted in a growth defect in vitro and led to a sevenfold increase in susceptibility to the iron-chelators deferoxamine and salicylhydroxamic acid. Conditional null mutants remained viable when the ectopic copy was repressed, but were hypersensitive to deferoxamine and displayed a growth defect similar to that observed following RNAi. The conditional nulls also retained virulence in vivo in the absence of the doxycycline inducer. These data provide strong evidence that TbMLP has a role in import of iron into the cytosol of African trypanosomes. They also indicate that even when expression is greatly reduced, there is sufficient protein, or an alternative mechanism, to provide the parasite with an adequate supply of cytosolic iron. PMID- 23750753 TI - Novel serotype of bluetongue virus, western North America. PMID- 23750754 TI - Cryptocaryols A and B: total syntheses, stereochemical revision, structure elucidation, and structure-activity relationship. AB - The first total syntheses and structural elucidation of cryptocaryol A and cryptocaryol B were achieved in 23 and 25 linear steps, respectively. The synthesis relied on the use of a key pseudo-Cs symmetric pentaol intermediate, which in a stereochemically divergent manner was converted into either enantiomer as well as diastereomers. This synthetic effort enabled the first structure activity relationships of this class of PDCD4 stabilizing natural products. PMID- 23750755 TI - Epilepsy misdiagnosed as long QT syndrome: it can go both ways. AB - Cardiogenic seizures are common and could be the sentinel event heralding the presence of congenital long QT syndrome (LQTS). Distinguishing a cardiogenic seizure from a neurogenic one is of the utmost importance. Herein, we present the case of a 12-year-old boy with recurrent episodes of syncope and seizures. Despite absence of QT prolongation on electrocardiogram, absence of documented arrhythmias, a negative LQTS genetic test, and recurrent episodes while on nadolol beta-blocker therapy, he was diagnosed with LQTS and implanted with an implantable cardioverter defibrillator (ICD). When syncope and seizure occurred with normal sinus rhythm documented on the ICD, he was referred to neurology, and an electroencephalogram was positive for numerous bursts of bilaterally synchronous generalized discharges. He was started on antiepileptic treatment after which his seizures resolved. His LQTS diagnosis was removed, beta-blocker therapy discontinued, and his ICD was explanted. He has been seizure-free for over 2 years. PMID- 23750756 TI - Epilepsy in Prader-Willi syndrome: experience of a national referral centre. AB - AIM: The aim of the study was to characterize epilepsy, febrile seizures, electrographic features, and brain abnormalities in a large, national cohort of individuals with Prader-Willi syndrome (PWS). METHOD: This was an observational cohort study. Clinic charts of 126 individuals (63 males, 63 females) with genetically confirmed PWS (due to a deletion in 72 cases, to uniparental disomy [UPD] in 51 cases, and to an imprinting centre defect in two cases), aged from 1 month to 48 years (mean age 13y), were reviewed and 119 interviews conducted. Information regarding seizures, medication, imaging studies, and family history of seizures was collected. Ninety-five individuals (aged 1mo-48y) underwent electroencephalography (EEG). RESULTS: Five individuals had epilepsy (4.0%), three of whom had major cerebral findings on imaging, and eight others had febrile seizures (6.4%). Of the three genetic abnormalities, deletion was associated with seizures. Focal epileptiform abnormalities were found in 12 out of 94 individuals, and five out of these 12 had a frank electrographic seizure pattern. Epileptogenic EEG abnormalities were associated with young age. INTERPRETATION: The risk of epilepsy and febrile seizures in PWS is significantly lower than in Angelman syndrome and is associated with brain abnormalities. Electrographic seizures and focal epileptiform activity were present in 5% of individuals and were associated with young age. The underpinnings of epileptiform abnormalities in PWS and how they differ from those of the Angelman syndrome should be studied further. PMID- 23750757 TI - From tragedy to healing. AB - Trauma can affect anyone's life. However, some people are more likely than others to have experienced trauma in their lives and are more sensitive to its effects. In particular, people with a serious mental illness tend to have been exposed to high levels of trauma, both before and after the onset of their mental illness, and not surprisingly they have higher rates of PTSD than in the general population. Just as there is a need to educate the general public about PTSD and its treatment, mental health professionals and service users would benefit from learning similar information and understanding that there is realistic hope for developing a worthwhile and rewarding life after recovery from trauma and PTSD. PMID- 23750758 TI - Stigma associated with PTSD: perceptions of treatment seeking combat veterans. AB - OBJECTIVE: Although stigma associated with serious mental illness, substance abuse disorders, and depression has been studied very little is known about stigma associated with Posttraumatic Stress Disorder (PTSD). This study explored stigma related to PTSD among treatment-seeking Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) combat veterans. METHOD: Sixteen treatment seeking OEF/OIF veterans with combat-related PTSD participated in focus groups. We used qualitative methods to explore PTSD-related stigma. RESULTS: Common perceived stereotypes of treatment-seeking veterans with PTSD included labels such as "dangerous/violent," or "crazy," and a belief that combat veterans are responsible for having PTSD. Most participants reported avoiding treatment early on to circumvent a label of mental illness. Participants initially reported experiencing some degree of self-stigma; however, following engagement in treatment they predominantly resisted these stereotypes. Although most participants considered combat-related PTSD as less stigmatizing than other mental illnesses, they reported difficulties with reintegration. Such challenges likely stem from both PTSD symptoms and veterans' perceptions of how the public views them. Most reported that fellow combat veterans best understood them. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Awareness of public stereotypes impacts help seeking at least early in the course of illness. Peer-based outreach and therapy groups may help veterans engage in treatment early and resist stigma. PMID- 23750759 TI - Older adults' perceptions of recovery from mental illness: Impact of psychiatric hospitalization prior to 1990. AB - OBJECTIVE: We tested the hypothesis that older adults are more likely than younger adults to consider their current mental health status when estimating their own recovery from psychiatric illness because many older people were first hospitalized for psychiatric illness prior to the emergence of the recovery movement in the 1990s, before recovery was redefined to include life improvements other than symptom alleviation. METHOD: Seventy-one members of a rehabilitation program (age 23 to 69; M = 49) were asked to rate satisfaction with their own recovery and with their current mental and physical health. The study hypothesis was tested in two hierarchical regression analyses that examined variation in the correlation between mental health and recovery self-ratings first by age and then by year of first hospitalization. RESULTS: The correspondence between mental health and recovery self-ratings was twice as strong for adults age 50 and older compared with those younger than age 50 and this same age difference in self ratings was also evident for participants first hospitalized for a psychiatric illness earlier versus later than 1990. The correlation between physical health and recovery self-ratings did not vary by age or year of first hospitalization. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Recovery-oriented interventions will be most effective for older individuals when service providers take into account their personal histories and the propensity of many older adults to associate recovery with symptom improvement even while embracing other life improvements. PMID- 23750760 TI - A demonstration project involving peers as providers of evidence-based, supported employment services. AB - OBJECTIVE: The present demonstration project involved development of a training program designed to teach recovering consumers employed as peer advocates how to provide evidence-based supported employment services to consumers with severe mental illness. METHODS: A training curriculum was developed to teach the core competencies of the Individual Placement and Support (IPS) model of supported employment. Three peers participated in training and provided work outcome data from their caseloads. Assessments were conducted of peers' competence in implementing IPS and effectiveness in promoting job placements. Peer competency was assessed by the following: (a) a formal IPS fidelity review performed by two external reviewers to evaluate service implementation, and (b) the Kansas Employment Specialist Job Performance Evaluation, an objective measure of employment specialist attitudes and skills. Program efficacy was assessed by examining the number of job placements and corresponding tenure. RESULTS: The fidelity review revealed that peers met IPS standards of implementation on 7 of 14 items assessing service delivery. The Kansas scale results revealed attitudes to be a relative strength and job performance competency ratings fell in the average to above average range across skill areas assessed (e.g., vocational assessment, job development). Thirty-three percent of consumers from the peers' caseloads got competitive jobs; mean tenure was 26.1 weeks. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: This demonstration project provides a starting point for future efforts aimed at expanding the role of peers as providers of evidence based mental health services and provides a measured degree of optimism that this is a realistic, attainable goal. PMID- 23750761 TI - The reconstruction of narrative identity during mental health recovery: a complex adaptive systems perspective. AB - OBJECTIVES: 1) to understand the reconstruction of narrative identity during mental health recovery using a complex adaptive systems perspective, 2) to address the need for alternative approaches that embrace the complexities of health care. METHOD: A narrative review of published literature was conducted. RESULTS: A complex adaptive systems perspective offers a framework and language that can assist individuals to make sense of their experiences and reconstruct their narratives during an often erratic and uncertain life transition. It is a novel research direction focused on a critical area of recovery and addresses the need for alternative approaches that embrace the complexities of health care. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: A complexity research approach to narrative identity reconstruction is valuable. It is an accessible model for addressing the complexities of recovery and may underpin the development of simple, practical recovery coaching tools. PMID- 23750762 TI - Participant perspectives on housing first and recovery: early findings from the At Home/Chez Soi project. AB - OBJECTIVE: This study presents early qualitative findings from participant narratives collected for At Home/Chez Soi, a pan-Canadian demonstration project evaluating the Housing First approach. The aim of the study was to better understand how receiving housing prior to treatment impacts engagement and envisioned recovery for previously homeless individuals with mental illness. METHOD: Semistructured interviews were conducted with recently housed participants within the five research sites (N = 27). An analysis of early findings was performed, and themes were identified using the constant comparative method. RESULTS: Most participants reported that housing represents an early step in rebuilding identity, which enabled them to envision a different future. A subgroup experienced demoralization related to personal challenges, and expressed concerns about adjustment issues and social isolation. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: By providing choice regarding housing, Housing First facilitates a sense of personhood, which is essential to recovery. However, some recently housed individuals with complex needs may require additional supports to address early adjustment issues. ( PMID- 23750763 TI - Mental health consumers and providers dialogue in an institutional setting: a participatory approach to promoting recovery-oriented care. AB - OBJECTIVE: This brief report presents the preliminary findings of a participatory project, to answer a question raised by stakeholders in mental health services: How can providers and patients create a process for knowledge exchange to support recovery-oriented care? METHOD: Participatory action research (PAR) and narrative phenomenological methodology guided the selection of methods, which consisted of an iterative process between telling stories and dialoguing about personal values related to recovery. The sample consisted of three occupational therapists, a psychiatrist, an academic-clinician, and five consumers of mental health services who were involved in each stage of the research, including design, interpretation, dissemination, and implementation. RESULTS: Significant interpersonal and intrapersonal tensions were named, and conditions for a more sustainable process of knowledge exchange were explored. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The project revealed both the challenges with situating research within an institution (hierarchy of knowledge, power, and vulnerability) and face-to-face dialogue, as well as positive changes in professional attitudes and consumer empowerment, as providers and patients came to understand what was at stake for each other. The project underscored the need for provider-consumer dialogue as a process to explore tensions and values in promoting recovery-oriented care. PMID- 23750764 TI - Recovery and money management. AB - OBJECTIVE: Social recovery and external money management are important approaches in contemporary mental health care, but little research has been done on the relationship between the two or on application of recovery principles to money management for people at risk of being assigned a representative payee or conservator. METHOD: Out of 49 total qualitative interviews, 25 transcripts with persons receiving Social Security insurance or Social Security disability insurance who were at risk of being assigned a money manager were analyzed to assess the presence of recognized recovery themes. RESULTS: The recovery principles of self-direction and responsibility were strong themes in participant comments related to money management. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Money management interventions should incorporate peoples' recovery-related motivations to acquire financial management skills as a means to direct and assume responsibility for one's finances. Staff involved in money management should receive training to support client's recovery-related goals. PMID- 23750765 TI - The implementation of psychiatric advance directives: experiences from a Dutch crisis card initiative. AB - OBJECTIVE: The crisis card is a specific form of psychiatric advance directive, documenting mental clients' treatment preferences in advance of a potential psychiatric crisis. In this paper, we aim to provide insight into implementation issues surrounding the crisis card. METHOD: A Dutch crisis-card project formed the scope of this study. Data were collected through interviews with 15 participants from six stakeholder groups. RESULTS: Identified implementation issues are: (a) The role of the crisis-card counselor, (b) lack of distribution and familiarity, (c) care professionals' routines, and (d) client readiness. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The crisis-card counselor appears to play a key role in fostering benefits of the crisis card by supporting clients' perspectives. More structural integration of the crisis card in care processes may enhance its impact, but should be carefully explored. PMID- 23750766 TI - Job development guidelines in supported employment. AB - TOPIC: This article describes methods for building relationships with employers that benefit both employers and job seekers. PURPOSE: Many employment specialists receive little training on how to work with employers and, therefore, resort to online job searches. This article describes a simple framework for developing long-term relationships with employers. SOURCES USED: Personal observations and published literature. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Employment specialists benefit from a structured format to develop relationships with employers, as well as good supervision in the field. PMID- 23750767 TI - Hope, meaning, and purpose: making recovery possible. AB - Hope, meaning, and purpose are three key ingredients that compose a recovery oriented approach to living, but it all starts with hope. It is helpful for people in distress to dream of something better, with hope supplying the motivation to explore valued life goals and learn new skills to navigate new roads. If needed, professional support can also help to change our narrative. PMID- 23750768 TI - Psychiatric rehabilitation education for physicians. AB - As part of a rapidly spreading reform toward recovery-oriented services, mental health care systems are adopting Psychiatric/Psychosocial Rehabilitation (PSR). Accordingly, PSR education and training programs are now available and accessible. Although psychiatrists and sometimes other physicians (such as family physicians) provide important services to people with serious mental illnesses and may, therefore, need knowledge and skill in PSR, it seems that the medical profession has been slow to participate in PSR education. Based on our experience working in Canada as academic psychiatrists who are also Certified Psychiatric Rehabilitation Practitioners (CPRPs), we offer descriptions of several Canadian initiatives that involve physicians in PSR education. Multiple frameworks guide PSR education for physicians. First, guidance is provided by published PSR principles, such as the importance of self-determination (www.psrrpscanada.ca). Second, guidance is provided by adult education (andragogy) principles, emphasizing the importance of addressing attitudes in addition to knowledge and skills (Knowles, Holton, & Swanson, 2011). Third, guidance in Canada is provided by Canadian Medical Education Directives for Specialists (CanMEDS) principles, which delineate the multiple roles of physicians beyond that of medical expert (Frank, 2005) and have recently been adopted in Australia (Boyce, Spratt, Davies, & McEvoy, 2011). PMID- 23750769 TI - Plasticity in the proteome of Emiliania huxleyi CCMP 1516 to extremes of light is highly targeted. AB - Optimality principles are often applied in theoretical studies of microalgal ecophysiology to predict changes in allocation of resources to different metabolic pathways, and optimal acclimation is likely to involve changes in the proteome, which typically accounts for > 50% of cellular nitrogen (N). We tested the hypothesis that acclimation of the microalga Emiliania huxleyi CCMP 1516 to suboptimal vs supraoptimal light involves large changes in the proteome as cells rebalance the capacities to absorb light, fix CO2 , perform biosynthesis and resist photooxidative stress. Emiliania huxleyi was grown in nutrient-replete continuous culture at 30 (LL) and 1000 MUmol photons m(-2) s(-1) (HL), and changes in the proteome were assessed by LC-MS/MS shotgun proteomics. Changes were most evident in proteins involved in the light reactions of photosynthesis; the relative abundance of photosystem I (PSI) and PSII proteins was 70% greater in LL, light-harvesting fucoxanthin-chlorophyll proteins (Lhcfs) were up to 500% greater in LL and photoprotective LI818 proteins were 300% greater in HL. The marked changes in the abundances of Lhcfs and LI818s, together with the limited plasticity in the bulk of the E. huxleyi proteome, probably reflect evolutionary pressures to provide energy to maintain metabolic capabilities in stochastic light environments encountered by this species in nature. PMID- 23750770 TI - The role of gender in the association between child maltreatment and substance use behavior: a systematic review of longitudinal research from 1995 to 2011. AB - This systematic review analyzes the role of gender in the association between childhood maltreatment and substance use outcomes, among longitudinal papers published between 1995 and 2011. Ten papers examined gender as a moderating variable. Results on gender differences were mixed. When studies that found no gender effects were compared with studies that did identify gender effects, differences in measurement, sample composition, and developmental timing of outcomes were identified. This review also examines how gender effects are assessed. Implications and limitations of these findings are discussed. Areas for future research are identified. PMID- 23750771 TI - Participatory research with an online drug forum: a survey of user characteristics, information sharing, and harm reduction views. AB - Visitors to a popular online drug forum completed an online survey between November 2011 and January 2012, which covered (1) demographic characteristics, (2) substance use (including nonmedical prescription opioid use), (3) forum activity, and (4) harm reduction beliefs. The study sample (N = 897) primarily included Caucasian males in their twenties from the United States, the United Kingdom, Australia, and Canada. The practice of harm reduction was overwhelmingly endorsed by participants. Current nonmedical prescription opioid users reported more activity in forums and past substance abuse treatment. The study's implications and limitations are noted and future research is suggested. PMID- 23750773 TI - Situational and affective risk situations of relapse and the quality of implementation intentions in an e-health smoking relapse prevention programme. AB - The quality of coping plans made to deal with personal smoking related risk situations and the relation between plan quality (PQ) and continued smoking abstinence (CA) were assessed. The respondents (N = 563) were smokers who had made a coping planning assignment in the experimental conditions of a larger randomized controlled trial. Descriptive and logistic regression analyses were conducted. The specificity of the plans made was related to short and long-term CA and was significantly lower for plans made to deal with situational situations. More research on how to foster specificity and target the difficulties that quitters have with specifying plans for affective situations is required. PMID- 23750772 TI - Members, isolates, and liaisons: meta-analysis of adolescents' network positions and their smoking behavior. AB - Existing research finds that peer networks play an important role in adolescents' smoking behaviors. To evaluate this research, meta-analysis was utilized to investigate the relationship between social positions (e.g., group members vs. isolates vs. liaisons) in friendship networks and smoking behaviors. The results (N = 5,067, k = 8) showed that adolescents from multiple countries who are isolated in friendship networks are more likely to report smoking behaviors than those with friends (members or liaisons). The results also show that these differential odds of smoking based on network position has decreased over the past 15 years. PMID- 23750774 TI - Engagement, retention, and abstinence for three types of opioid users in Florida. AB - Prescription opioid use has grown rapidly, but few studies examined whether users have similar treatment responses as heroin users. Participants were 1,648 opioid users in Florida Access to Recovery (2004-2007). Participants engaged in methadone or buprenorphine maintenance had better retention than those in nonmaintenance treatment. Heroin only users (HO) had better engagement in nonmaintenance treatments and had worse retention than prescription opioid only users (PO). In methadone maintenance, PO were more likely to report opioid abstinence during treatment than heroin and prescription opioid users (H&P). Future research should focus on understanding and improving the treatment experience of opioid use subgroups. PMID- 23750775 TI - Facilitating factors in implementing four evidence-based practices: reports from addiction treatment staff. AB - In this Robert Wood Johnson Foundation-funded study (2009-2011), treatment staff (n = 178) from 330 federally funded U.S. addiction treatment programs provided data through semistructured telephone interviews about factors that facilitated their implementation of four evidence-based practices (EBPs). Such studies can assist the addiction field in improving EBP implementation and ultimately, client care. RESEARCH QUESTIONS: What factors were identified as facilitating implementation of the four EBPs? And, Do facilitating factors vary by EBP? Coders classified facilitating factors (n = 518) using a six-category schema. Results showed that although facilitating factors varied by EBP, organization-related factors dominated. Study implications and limitations are described. PMID- 23750776 TI - Changes in the characteristics and levels of comorbidity among new patients into methadone maintenance treatment program in British Columbia during its expansion period from 1998-2006. AB - We described the changing characteristics and comorbidity levels of new patients into Methadone maintenance treatment (MMT) program in British Columbia, Canada, during its expansion period of 1998-2006. Analyses used administrative data. Generalized regression models were applied using Charlson Comorbidity Index (CCI) and Chronic Disease Score (CDS) as outcomes. 12,615 individuals initiated MMT during 1998-2006, while their odds of having moderate CCI (1 <= CCI <= 4) and mean CDS increased by 60% and 11%, respectively, after adjusting for confounders. MMT entrants were presented with progressively higher levels of comorbidity, independent of other characteristics. Future MMT policies should address higher levels of comorbidity among new patients. PMID- 23750777 TI - Current status of the genetics and molecular taxonomy of Echinococcus species. AB - The taxonomy of Echinococcus has long been controversial. Based mainly on differences in morphology and host-parasite specificity characteristics, 16 species and 13 subspecies were originally described. Subsequently, most of these taxa were regarded as synonyms for Echinococcus granulosus and only 4 valid species were recognised: E. granulosus; E. multilocularis; E. oligarthrus and E. vogeli. But, over the past 50 years, laboratory and field observations have revealed considerable phenotypic variability between isolates of Echinococcus, particularly those of E. granulosus, which include differences in: morphology in both larval and adult stages, development in vitro and in vivo, host infectivity and specificity, chemical composition, metabolism, proteins and enzymes, pathogenicity and antigenicity. The application of molecular tools has revealed differences in nucleic acid sequences that reflect this phenotypic variation and the genetic and phenotypic characteristics complement the previous observations made by the descriptive parasitologists many years ago. The fact that some of these variants or strains are poorly or not infective to humans has resulted in a reappraisal of the public health significance of Echinococcus in areas where such variants occur. A revised taxonomy for species in the Echinococcus genus has been proposed that is generally accepted, and is based on the new molecular data and the biological and epidemiological characteristics of host-adapted species and strains. PMID- 23750778 TI - Mitral isthmus ablation is feasible, efficacious, and safe using a remote robotic catheter system. AB - BACKGROUND: There are limited data on the use of a remote robotic catheter system (RCS) for mitral isthmus (MI) ablation. METHODS: This single-center, prospective, matched control study included 45 patients who underwent atrial fibrillation ablation using a remote RCS compared to 45 patients who underwent conventional ablation. All patients had circumferential pulmonary vein isolation (PVI), roof, and MI ablation. RESULTS: There were no significant differences in baseline clinical characteristics. There were no significant differences in MI block (RCS: 44/45 [98%] vs CONTROL: 43/45 [96%], P = 1.0), roof block (RCS: 45/45 [100%] vs CONTROL: 44/45 [98%], P = 1.0), and PVI (RCS: 45/45 [100%] vs CONTROL: 45/45 [100%], P = 1.0). Ablation and procedural times were similar in both arms. Using RCS, mean total MI ablation and procedure times were 13 +/- 6 minutes and 23 +/- 15 minutes, respectively. Coronary sinus (CS) ablation was significantly less in the RCS arm (48% vs 72%, P = 0.03). It was possible to "drive" the ablation catheter into the distal CS using the RCS in 19/22 (86%) patients. There was a significant trend of reduction in mean MI ablation (P = 0.008) and procedural times (P = 0.004) over the course of the study period. There was a significant reduction in fluoroscopy time in the RNS arm (33 +/- 17 minutes vs 49 +/- 20 minutes, P = 0.0004). CONCLUSION: It is feasible and safe to use a remote RCS for MI ablation, including "driving into the CS." MI block was achieved in 98% with a significant reduction in the need for CS ablation (48%). There is a short learning curve. PMID- 23750779 TI - Provision of long-term care in relation to needs in urban and rural municipalities in Japan and Sweden. AB - AIM: The aim of the study was to establish whether there are differences in long term care (LTC) provision with regard to needs between rural and urban municipalities in Japan and Sweden, and we propose possible causes for these differences. METHODS: Using comparable datasets from Japan (n = 20 699) and Sweden (n = 17 576), the care systems have been compared on an individual level. The datasets each contain information from nine large urban, midsize urban and rural municipalities regarding disability levels and the LTC services provided. RESULTS: LTC users in the large urban municipalities in both countries are, on average, less disabled than users in the midsize urban and rural municipalities. In both countries, per capita costs for LTC were lower in the large urban municipalities than in the rural municipalities (10% and 14%, respectively). However, when standardized for the level of disability, the per capita costs were higher in the large urban municipalities (4% in both cases). Multivariate analysis showed that there were significant per capita cost differences between the large urban and the rural municipalities in Japan. In Sweden, there were no significant per capita cost differences between the different types of municipality when age, sex and disability differences were accounted for. CONCLUSION: The findings seem to reflect the effect of differences in household structure, which in the large urban municipalities result in less access to informal LTC, thereby influencing the propensity to apply for formal, public LTC especially for those with lesser needs. In Japan, where the number of extended family households is decreasing, this gives an idea of the future challenges facing LTC provision. PMID- 23750780 TI - Anti-angiogenic activity of salvicine. AB - CONTEXT: Salvicine is a pharmacologically active derivative from Chinese medicinal plant Salvia prionitis Hance (Labiatae). It has been reported that salvicine inactivates beta1 integrin and inhibits integrin-mediated cell adhesion to fibronectin. Given the emerging correlation between integrins and angiogenesis, we propose that salvicine abolishes cell adhesion and subsequent metastasis by inhibiting angiogenisis. OBJECTIVE: The anti-angiogenesis activities of salvicine were investigated for the first time. MATERIALS AND METHODS: The cytotoxicity of salvicine on human microvascular endothelial cells (HMECs) and non-small cell lung adenocarcinoma A549 cells were measured at doses between 0.625 and 200 uM. Changes of cell migration were detected with doses of salvicine at 1.25-5 uM, and basement membrane matrigel matrix was used for the assessment of tube formation at concentrations ranging from 0.078 to 1.25 uM. In addition, mRNA expression of basic fibroblast growth factor (bFGF) in A549 cells was studied with the RT-PCR assay. RESULTS: In vitro studies revealed that the IC50 of salvicine on A549 cells (18.66 uM) was two-fold higher than that of HMECs (7.91 uM). Salvicine (1.25, 2.5 and 5.0 MUM) inhibited significantly the endothelial cell migration up to 56, 73 and 82%, respectively. Salvicine decreased capillary-like tube formation of HMECs with high potency. Furthermore, it (30 uM) markedly reduced the mRNA expression of bFGF in A549 cells, while vascular endothelial growth factor (VEGF) mRNA expression remained unchanged. DISCUSSION AND CONCLUSION: Our results suggest that salvicine has potent anti angiogenic activity through the inhibition on the sequential angiogenic cascades: proliferation, migration and tube formation and is associated with influence on the expression of bFGF of tumor cell. PMID- 23750781 TI - Consequences of being Rhesus D immunized during pregnancy and how to optimize new prevention strategies. AB - OBJECTIVE: To analyze the timing of Rhesus D (RhD) immunization in pregnancy and the consequences for the index pregnancy and for subsequent pregnancies to be able to optimize the design of antenatal screening and prevention programs. DESIGN: Retrospective cohort study. SETTING: Stockholm county, Sweden. POPULATION: All RhD immunized pregnant women 1990-2008 before the introduction of routine antenatal anti-D prophylaxis. METHODS: Data were collected from transfusion medicine registers and databases, medical records, the Swedish Medical Birth Register and the National Perinatal Quality Register and entered into a standardized database before analysis. MAIN OUTCOME MEASURES: The order of pregnancy and trimester when immunization occurred and treatment of hemolytic disease of the fetus and newborn. RESULTS: A total of 290 RhD immunized women were included in the study. In 147/290 (51%) of the women, sensitization occurred with their first-born child and in 96/290 (33%) it occurred with their second born child. Anti-D antibodies developed during the second or third trimester in 212/290 (73%) and in 61/290 (21%) at term or after delivery. In subsequent pregnancies 56% (144/259) of the neonates required treatment for hemolytic disease of the fetus and newborn. CONCLUSIONS: Based on our study, at least half of the cases could potentially have been avoided by routine antenatal anti-D prophylaxis in the beginning of the third trimester. To optimize the beneficial effects of new prevention programs, we propose providing anti-D prophylaxis in gestational week 28-30 selectively to all RhD-negative women with RhD-positive fetuses. PMID- 23750782 TI - Tracing the physical conditions in active galactic nuclei with time-dependent chemistry. AB - We present an extension of the code ProDiMo that allows for a modeling of processes pertinent to active galactic nuclei and to an ambient chemistry that is time dependent. We present a proof-of-concept and focus on a few astrophysically relevant species, e.g., H+, H2(+), and H3(+); C+ and N+; C and O; CO and H2O; OH+, H2O+, and H3O+; and HCN and HCO+. We find that the freeze-out of water is strongly suppressed and that this affects the bulk of the oxygen and carbon chemistry occurring in the active galactic nucleus (AGN). The commonly used AGN tracer HCN/HCO+ is strongly time-dependent, with ratios that vary over orders of magnitude for times longer than 10(4) years. Through Atacama large millimeter array observations this ratio can be used to probe how the narrow-line region evolves under large fluctuations in the supermassive black hole accretion rate. Strong evolutionary trends, on time scales of 10(4)-10(8) years are also found in species such as H3O+, CO, and H2O. These reflect, respectively, time-dependent effects in the ionization balance, the transient nature of the production of molecular gas, and the freeze-out/sublimation of water. PMID- 23750783 TI - Complexes with hybrid phosphorus-NHC ligands: pincer-type Ir hydrides, dinuclear Ag and Ir and tetranuclear Cu and Ag complexes. AB - Three types of hybrid phosphorus-imidazolium salts, 1-methyl-3-(3 ((diphenylphosphino)methyl)benzyl)-1H-imidazol-3-ium hexafluorophosphate (2.PF6), 1-methyl-3-(3-(di-tert-butylphosphinooxy)phenyl)imidazolium iodide (8a), and 3-(3 ((diphenylphosphoryl)methyl)phenyl)-1-methyl-1H-imidazol-3-ium iodide (11) have been prepared and used as precursors to phosphine-NHC, phosphinite-NHC, and phosphoryl-NHC metal complexes, respectively. The structure of 11 has been determined by X-ray diffraction. The Ag(I) and Ir(I) complexes of the phosphine NHC ligand, [Ag(MU-P-NHC,kappaC,kappaP)]2(PF6)2 (3) and [Ir(cod)(MU-P NHC,kappaC,kappaP)]2(PF6)2 (4), were obtained and characterized by NMR, ESI-MS, elemental analysis, and X-ray diffraction. Both complexes are dinuclear and dicationic, with two P-NHC ligands bridging the two metal centers. The presence of the P donor led for 3 to an unprecedented structure compared to that of related Ag(I) complexes with trans spanning bis-NHC ligands. Complex 4 is the first example of a dinuclear iridium complex with a hybrid P-NHC ligand. The new hydrido, Ir(III) pincer-type complex [IrH(CNHCCCNHC)(MeCN)]PF6 (7) is suggested to have a square-pyramidal structure. The tetranuclear Ag(I) complex with the phosphinite-NHC ligand, [Ag2(MU3-I)(MU-PO-NHC,kappaP,kappaCNHC)]2 (9a) has a cubane-type structure, with alternating silver and iodine apexes and two PO-NHC ligands bridging opposite edges of the Ag4 tetrahedron. The Ir(III) pincer complexes [IrH(I)(PO-NHC,kappaP,kappaC,kappaCNHC)(Me)] (10a) and [IrH(I)(PO NHC,kappaP,kappaC,kappaCNHC)(n-Bu)] (10b), with Me or n-Bu substituents on the nitrogen atom, respectively, have been prepared and characterized. Ag(I) and Cu(I) complexes with the phosphoryl-NHC ligand are reported and the centrosymmetric structure of the latter, [Cu(OP-NHC,kappaCNHC)2(MU-I){Cu(MU-I)}]2 (13), was established by X-ray diffraction and consists of a central Cu2(MU-I)2 rhombus connected by single iodide bridges to two Cu(OP-NHC,kappaCNHC)2 moieties. The Ir(III) hydride pincer complexes 10a,b were tested as catalyst precursors for the C-H bond activation of alkanes. Although their efficiency was significantly lower for transfer dehydrogenation from cyclooctane (coa) to t-butylethylene (tbe) than that of known PCP-Ir systems, these results represent the first attempts to study the catalytic properties of hybrid P-NHC iridium pincer complexes. PMID- 23750784 TI - A call to order at the spirochaetal host-pathogen interface. AB - As the Lyme disease spirochaete Borrelia burgdorferi shuttles back and forth between arthropod vector and vertebrate host, it encounters vastly different and hostile environments. Major mechanisms contributing to the success of this pathogen throughout this complex transmission cycle are phase and antigenic variation of abundant and serotype-defining surface lipoproteins. These peripherally membrane-anchored virulence factors mediate niche-specific interactions with vector/host factors and protect the spirochaete from the perils of the mammalian immune response. In this issue of Molecular Microbiology, Tilly, Bestor and Rosa redefine the roles of two lipoproteins, OspC and VlsE, during mammalian infection. Using a variety of promoter fusions in combination with a sensitive in vivo 'use it or lose it' gene complementation assay, the authors demonstrate that proper sequential expression of OspC followed by VlsE indeed matters. A previously suggested general functional redundancy between these and other lipoproteins is shown to be limited and dependent on an immunodeficient experimental setting that is arguably of diminished ecological relevance. These data reinforce the notion that OspC plays a unique role during initial infection while the antigenically variant VlsE proteins allow for persistence in the mammalian host. PMID- 23750786 TI - Factor structure of the Beck Depression Inventory-II among South Africans receiving antiretroviral therapy. AB - Considerable evidence suggests that mood disturbance is common among patients living with HIV and may be an important barrier to anti-retroviral therapy (ART) adherence. Thus the assessment of depressed mood is an important and necessary aspect of the experience of persons living with HIV as it may impact the health status of individuals directly and indirectly. We sought to determine the factor structure of the Beck Depression Inventory (BDI) among a sample of 185 South Africans living with HIV and receiving ART. The mean BDI score was 16.5 (SD 12.15) with a range from 0-50 (out of a possible 63), indicating on average moderate levels of depression. Cronbach's alpha for the total scale was 0.90. Although the four factors had eigenvalues that were technically above 1.0, only three factors could logically be extracted, the combination of which accounted for 47.29% of the variance. These three factors were Cognitive, Affective and Somatic. The results indicate that the BDI-II is a reliable measure of symptoms of depression among persons living with HIV. The factor structure among South Africans receiving ART is similar to that of other samples, although surprisingly, the item assessing appetite disturbance did not load on any factor. The results of the study suggest that the BDI-II is a useful measure among South Africans living with HIV. In the context of the need to rapidly identify depressed mood among persons receiving ART in public health clinics, the BDI may be a useful instrument. We end the paper with certain cautions associated with routine screening. PMID- 23750785 TI - Characterization of molecules binding to the 70K N-terminal region of fibronectin by IFAST purification coupled with mass spectrometry. AB - Fibronectin (Fn) is a large glycoprotein present in plasma and extracellular matrix and is important for many processes. Within Fn the 70 kDa N-terminal region (70k-Fn) is involved in cell-mediated Fn assembly, a process that contributes to embryogenesis, development, and platelet thrombus formation. In addition, major human pathogens including Staphlycoccus aureus and Streptococcus pyogenes bind the 70k-Fn region by a novel form of protein-protein interaction called beta-zipper formation, facilitating bacterial spread and colonization. Knowledge of blood plasma and platelet proteins that interact with 70k-Fn by beta zipper formation is incomplete. In the current study, we aimed to characterize these proteins through affinity purification. For this affinity purification, we used a novel purification technique termed immiscible filtration assisted by surface tension (IFAST). The foundation of this technology is immiscible phase filtration, using a magnet to draw paramagnetic particle (PMP)-bound analyte through an immiscible barrier (oil or organic solvent) that separates an aqueous sample from an aqueous eluting buffer. The immiscible barrier functions to remove unbound proteins via exclusion rather than dilutive washing used in traditional isolation methods. We identified 31 interactors from plasma, of which only seven were previously known to interact with Fn. Furthermore, five proteins were identified to interact with 70k-Fn from platelet lysate, of which one was previously known. These results demonstrate that IFAST offers advantages for proteomic studies of interacting molecules in that the technique requires small sample volumes, can be done with high enough throughput to sample multiple interaction conditions, and is amenable to exploratory mass spectrometric and confirmatory immuno-blotting read-outs. PMID- 23750787 TI - Integrating a 'danger' signal into molecular chaperoning to improve vaccination against cancer. PMID- 23750788 TI - Rotavirus vaccination: short-term indirect herd protection, long-term uncertainty. PMID- 23750790 TI - Perspectives on vaccination in adults. AB - In the Second Conference on Controversies in Vaccination in Adults, leading vaccine experts among manufacturers, physicians, microbiologists, virologists, immunologists and public health specialists came together to discuss recent approaches, developments and strategies in vaccination against worldwide pressing epidemic and endemic infectious diseases (pneumococcal, staphylococcal, influenza, papillomavirus-associated tumors, varicella-zoster, AIDS and tuberculosis), and noninfectious epidemics (atherosclerosis and smoking) outlining arguments surrounding the progress of vaccines. PMID- 23750792 TI - Cancer vaccines targeting carcinoembryonic antigen: state-of-the-art and future promise. AB - Concurrent with the US FDA's approval of the first therapeutic cancer vaccine, and supported by mounting clinical evidence indicating that targeting carcinoembryonic antigen (CEA) can safely overcome pre-existing tolerance, a multitude of novel CEA cancer vaccines are now in various stages of development. Since cancer-driven immune suppression often limits the efficacy of vaccines, numerous strategies are being examined in both preclinical and clinical settings to overcome immunosuppressive elements, including the combined use of vaccines with certain chemotherapies, immune checkpoint inhibitors, small-molecule targeted therapies and radiation. This review discusses the current state and future direction of therapeutic cancer vaccines targeting CEA, based on advances achieved over the last 5 years. PMID- 23750793 TI - CD40-activated B cells as antigen-presenting cells: the final sprint toward clinical application. AB - Efficient antigen presentation is a prerequisite for the development of a T-cell mediated immune response in vitro and in vivo. CD40-activated B cells (CD40B cells) are a promising alternative to dendritic cells as professional APCs for immunotherapy. CD40 activation dramatically improves antigen presentation by normal and malignant B cells, efficiently inducing naive and memory CD4(+) and CD8(+) T-cell responses. Moreover, CD40B cells do not only attract T cells by release of chemokines, but also home to secondary lymphoid organs. Furthermore, CD40B cells can be expanded exponentially over several weeks at high purity without a loss of antigen-presenting function, providing an almost unlimited source of cellular adjuvant. Vaccination with CD40B cells was shown in mice and dogs to induce a specific immune response. This article summarizes the achievements of intense research on CD40B cells over the last decade, as well as novel developments critical for a rapid translation into clinical application. PMID- 23750794 TI - Allergen-specific immunotherapy in asthmatic children: from the basis to clinical applications. AB - Atopic asthma in childhood with the tendency to persist into adult life is an important issue in pediatrics. Allergen-specific immunotherapy (SIT) is the only curative treatment option for these children, being directed to the causes of the disease. The Th2 phenotype is a predominant immunological pattern in atopic asthma and SIT leads to apoptosis/anergy of T cells and induces immune-regulatory responses and immune deviation towards Th1. Many factors can affect the safety and efficacy of SIT, such as pattern of sensitization, allergy vaccine (allergen extracts, adjuvants and conjugated molecules), route of administration (subcutaneous or sublingual) and different treatment schedules. Overall, asthma symptoms and medication scores usually decrease following a SIT course and the most common observed side effects are restricted to local swelling, erythema and pruritus. Compared with conventional pharmacotherapy, SIT may be more cost effective, providing a benefit after discontinuation and a steroid-sparing effect. In addition, it can prevent new sensitizations in monosensitized asthmatic children. Microbial supplements such as probiotics, immunomodulatory substances like anti-IgE/leukotrienes, antibodies and newer allergen preparations such as recombinant forms have been tested to improve the efficacy and safety of SIT with inconclusive results. In conclusion, SIT provides an appropriate solution for childhood asthma that should be employed more often in clinical practice. Further studies are awaited to improve current knowledge regarding the mechanisms behind SIT and determine the most appropriate materials and schedule of immunotherapy for children with asthma. PMID- 23750795 TI - Recent advances in designing an effective vaccine to prevent cytomegalovirus associated clinical diseases. AB - It is now well over a decade since the US Institute of Medicine of the National Academy of Sciences assigned the highest priority for a vaccine to prevent congenital human CMV infection, which was subsequently endorsed by the US National Vaccine Program Office. In spite of extensive efforts over many years, successful licensure of a CMV vaccine formulation remains elusive. While the understanding of immune regulation of CMV infection in healthy virus carriers and diseased patients has dramatically improved, traditional vaccine development programs have failed to exploit this knowledge. Until recently, most efforts have concentrated on designing vaccine formulations that block CMV infection through neutralizing antibodies. However, studies carried out in various disease settings, especially in transplant patients, have clearly emphasized the importance of cellular immunity and it is indeed encouraging to see that recent CMV vaccine development programs have started to incorporate this arm of the immune system. A number of new vaccine candidates have been found to be effective in preclinical studies, and are able to induce CMV-specific immune responses in clinical studies, although firm evidence for long-term efficacy is not yet available. For successful implementation of these vaccines in clinical settings, it will be important to demonstrate that the vaccine can induce effective levels of immunity for prevention of transmission of viral infection from mother to unborn baby and thus reduce CMV-related pathogenesis. For transplant recipients, vaccine strategies should be aimed at the induction of immunity that restricts viral reactivation and limits development of disease. PMID- 23750791 TI - An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma. AB - Outcome for glioblastoma (GBM), the most common primary CNS malignancy, remains poor. The overall survival benefit recently achieved with immunotherapeutics for melanoma and prostate cancer support evaluation of immunotherapies for other challenging cancers, including GBM. Much historical dogma depicting the CNS as immunoprivileged has been replaced by data demonstrating CNS immunocompetence and active interaction with the peripheral immune system. Several glioma antigens have been identified for potential immunotherapeutic exploitation. Active immunotherapy studies for GBM, supported by preclinical data, have focused on tumor lysate and synthetic antigen vaccination strategies. Results to date confirm consistent safety, including a lack of autoimmune reactivity; however, modest efficacy and variable immunogenicity have been observed. These findings underscore the need to optimize vaccination variables and to address challenges posed by systemic and local immunosuppression inherent to GBM tumors. Additional immunotherapy strategies are also in development for GBM. Future studies may consider combinatorial immunotherapy strategies with complimentary actions. PMID- 23750796 TI - Live-attenuated Yersinia pestis vaccines. AB - Plague caused by Yersinia pestis is one of the most dangerous infectious diseases. There is no ideal plague vaccine available for human use, but a number of licensed killed whole-cell and live-attenuated vaccines have been available in the past. Currently, there are a number of vaccines under development, including live-attenuated, DNA and subunit vaccines, among others. This review deals with the development of live-attenuated plague vaccines. Traditionally, live attenuated plague vaccines have been developed by multiple passages of fully virulent Y. pestis, but they have not gained general acceptance due to safety concerns. Recent attempts to construct attenuated Y. pestis strains with specifically defined mutations have opened the door for developing new candidates for live-attenuated plague vaccines, with a proper balance between safety and protective efficacy. PMID- 23750797 TI - Intradermal powder immunization with protein-containing vaccines. AB - The central importance for global public health policy of delivering life-saving vaccines for all children makes the development of efficacious and safe needle free alternatives to hypodermic needles, preferably in a thermostable form, a matter of pressing urgency. This paper comprehensively reviews past in vivo studies on intradermal powder immunization with vaccine formulations that do not require refrigeration. Particular emphasis is given to the immune response in relation to antigen adjuvantation. While needle-free intradermal delivery of vaccines induces a predominantly Th2-type immune response, adjuvants powerfully enhance and modulate the magnitude and nature of the elicited immune response at various effector sites. PMID- 23750799 TI - Rapid loss of efficacy to the antiseizure drugs lamotrigine and carbamazepine: a novel experimental model of pharmacoresistant epilepsy. AB - PURPOSE: Kindling is a well-established model of secondarily generalized partial seizures that is widely employed in the search for novel antiseizure drugs. During the kindling and postkindling acquisition phase, an active process of neuronal remodeling occurs. We tested the hypothesis that exposure to the voltage gated sodium channel blockers lamotrigine (LTG) and carbamazepine (CBZ) during the period of active remodeling will lead to a diminished therapeutic effect. METHODS: Two days after the last kindling stimulation, fully kindled rats were randomized to receive either 0.5% methyl cellulose (MC), LTG (30 mg/kg), or CBZ (40 mg/kg). The effect of LTG and CBZ on behavioral seizure severity and electrographic afterdischarge duration (ADD) was recorded. One week after this treatment, rats in both groups were rechallenged with LTG 30 or CBZ 40 mg/kg and their seizure score and ADD recorded. In vitro efficacy of LTG on neuronal action potentials was also evaluated using whole cell current clamp recording in hippocampal brain slices obtained from kindled control rats, LTG-sensitive kindled rats, and LTG-resistant kindled rats. KEY FINDINGS: When acutely administered 48 h after the last kindling stimulation, LTG and CBZ blocked the expression of behavioral seizures and reduced the ADD. In contrast, a second challenge dose of LTG or CBZ administered after a 7-day "no drug, no stimulation" period did not result in reduction of either the seizure score or the ADD. Interestingly, the potassium channel opener, ezogabine, also known as retigabine (EZG; 40 mg/kg), blocked the expression of behavioral seizures at both time points evaluated (i.e., 2 days and 9 days after last stimulation). In vivo resistance to LTG was associated with a similar reduction in the ability of LTG to limit action potential firing in CA1 neurons. LTG (50 MUm) significantly decreased the number of action potentials generated by a depolarizing current pulse in neurons recorded from slices obtained from kindled control and LTG sensitive rats, but not in slices obtained from LTG-resistant rats. SIGNIFICANCE: Collectively, results obtained from both in vivo and in vitro studies demonstrate that even a single exposure to the sodium channel blockers LTG, or CBZ, during the postkindling remodeling phase leads to an altered pharmacologic response to these two ASDs, but not to EZG. The LTG- and CBZ-resistant amygdala kindled rats may serve as a useful model of therapy-resistant epilepsy. PMID- 23750800 TI - Delayed anti-CD3 therapy results in depletion of alloreactive T cells and the dominance of Foxp3+ CD4+ graft infiltrating cells. AB - The engineered Fc-nonbinding (crystallizable fragment-nonbinding) CD3 antibody has lower mitogenicity and a precise therapeutic window for disease remission in patients with type 1 diabetes. Before anti-CD3 can be considered for use in transplantation, the most effective timing of treatment relative to transplantation needs to be elucidated. In this study anti-CD3F(ab')2 fragments or saline were administered intravenously for 5 consecutive days (early: d1-3 or delayed: d3-7) to mice transplanted with a cardiac allograft (H2(b)-to-H2(k); d0). Survival of allografts was prolonged in mice treated with the early protocol (MST = 48 days), but most were rejected by d100. In contrast, in mice treated with the delayed protocol allografts continued to survive long term. The delayed protocol significantly inhibited donor alloreactivity at d30 as compared to the early protocol. A marked increase in Foxp3(+) T cells (50.3 +/- 1.6%) infiltrating the allografts in mice treated with the delayed protocol was observed (p < 0.0001 vs. early (24.9 +/- 2.1%)) at d10; a finding that was maintained in the accepted cardiac allografts at d100. We conclude that the timing of treatment with anti-CD3 therapy is critical for inducing long-term graft survival. Delaying administration effectively inhibits the alloreactivity and promotes the dominance of intragraft Foxp3(+) T cells allowing long-term graft acceptance. PMID- 23750801 TI - Synthesis and in vitro efficacy of MMP9-activated NanoDendrons. AB - Chemotherapeutics such as doxorubicin (DOX) and paclitaxel (PXL) have dose limiting systemic toxicities, including cardiotoxicity and peripheral neuropathy. Delivery strategies to minimize these undesirable effects are needed and could improve efficacy, while reducing patient morbidity. Here, DOX and PXL were conjugated to a nanodendron (ND) through an MMP9-cleavable peptide linker, producing two new therapies, ND2(DOX) and ND2(PXL), designed to improve delivery specificity to the tumor microenvironment and reduce systemic toxicity. Comparative cytotoxicity assays were performed between intact ND-drug conjugates and the MMP9 released drug in cell lines with and without MMP9 expression. While ND2(DOX) was found to lose cytotoxicity due to the modification of DOX for conjugation to the ND; ND2(PXL) was determined to have the desired properties for a prodrug delivery system. ND2(PXL) was found to be cytotoxic in MMP9-expressing mouse mammary carcinoma (R221A-luc) (53%) and human breast carcinoma (MDA-MB-231) (66%) at a concentration of 50 nM (in PXL) after 48 h. Treating ND2(PXL) with MMP9 prior to the cytotoxicity assay resulted in a faster response; however, both cleaved and intact versions of the drug reached the same efficacy as the unmodified drug by 96 h in the R221A-luc and MDA-MB-231 cell lines. Further studies in modified Lewis lung carcinoma cells that either do (LLC(MMP9)) or do not (LLC(RSV)) express MMP9 demonstrate the selectivity of ND2(PXL) for MMP9. LLC(MMP9) cells were only 20% viable after 48 h of treatment, while LLC(RSV) were not affected. Inclusion of an MMP inhibitor, GM6001, when treating the LLC(MMP9) cells with ND2(PXL) eliminated the response of the MMP9 expressing cells (LLC(MMP9)). The data presented here suggests that these NDs, specifically ND2(PXL), are nontoxic until activated by MMP9, a protease common in the microenvironment of tumors, indicating that incorporation of chemotherapeutic or cytostatic agents onto the ND platform have potential for tumor-targeted efficacy with reduced in vivo systemic toxicities. PMID- 23750802 TI - Utility of preprocedure checklists in the congenital cardiac catheterization laboratory. AB - OBJECTIVE: Preprocedure meetings have become more commonplace in medicine but are not performed routinely in the cardiac catheterization laboratory. We sought to create, implement, and evaluate a preprocedural meeting in the form of a checklist for the cardiac catheterization laboratory. Staff attitudes and perceptions toward safety and sense of teamwork were also analyzed. DESIGN: All procedures performed in the cardiac catheterization laboratory on patients with structural heart disease from January 2010 to February 2012 were retrospectively reviewed for demographics, procedural details, and reported complications. A checklist was introduced to the preprocedure protocol at the halfway point, and patients were divided into pre- and postchecklist cohorts. Anesthesia and cardiac catheterization laboratory staff were surveyed at the beginning and end of the study period regarding attitude toward safety, team climate, and the impact of errors. RESULTS: Total number of procedures (prechecklist, n = 371; postchecklist, n = 370) and demographics were similar among groups. Complication rates were equivalent pre- and postchecklist, but there was a greater proportion of interventional cases and higher median complication level in the postchecklist group. Cardiac catheterization laboratory staff reported improved awareness of being briefed with the checklist. Anesthesia differed from cardiac catheterization staff in perception of communication as well as team and safety climate. CONCLUSIONS: A preprocedure checklist for congenital cardiac catheterization cases is easy to perform and serves to update cardiac catheterization laboratory staff. Anesthesia and cardiac catheterization staff had different perceptions of safety and teamwork climate. Further studies are needed to determine if this briefing could lead to better communication among services and ultimately reduce complications. PMID- 23750803 TI - Personal beliefs, learned resourcefulness, and adaptive functioning in depressed adults. AB - Learned resourcefulness and personal beliefs are significant predictors of adaptive functioning. The mediating effect of personal beliefs on the relationship between learned resourcefulness and adaptive functioning was validated in adults with depression. The findings from this study may provide the basis for developing a useful nursing intervention constituting resourcefulness skills with positive personal beliefs to help patients with depression improve their ability to function well in their daily activities. ABSTRACT: Research has shown that patients with depression have difficulty with performing daily tasks and meeting their own personal care needs. According to Beck's cognitive theory of depression, such deficits in adaptive functioning are affected by disturbances in specific personal beliefs that reflect the process of regulating cognitions. Rosenbaum's learned resourcefulness theory proposed that adaptive functioning is influenced by learned resourcefulness, while learned resourcefulness is associated with the process regulating cognitions. This study aims to test the mediating effect of personal beliefs on the relationship between resourcefulness and adaptive functioning. The study involved a cross-sectional design. Participants consisted of 187 adults with depression in southern Taiwan. The data were collected through four instruments: Cognitive Triad Inventory, Self-Control Schedule, modified Community Living Skills Scale, and a demographic questionnaire. Both resourcefulness and personal beliefs were significant predictors of adaptive functioning, and personal beliefs mediated the effect of learned resourcefulness on the adaptive functioning of the adults with depression. The results validate the role played by personal beliefs in effecting learned resourcefulness and adaptive functioning among adults with depression and provide direction for designing nursing interventions that consider personal beliefs when teaching resourcefulness skills to adults with depression. PMID- 23750804 TI - Platinum monolayer electrocatalyst on gold nanostructures on silicon for photoelectrochemical hydrogen evolution. AB - Pt monolayer decorated gold nanostructured film on planar p-type silicon is utilized for photoelectrochemical H2 generation in this work. First, gold nanostructured film on silicon was spontaneously produced by galvanic displacement of the reduction of gold ion and the oxidation of silicon in the presence of fluoride anion. Second, underpotential deposition (UPD) of copper under illumination produced Cu monolayer on gold nanostructured film followed by galvanic exchange of less-noble Cu monolayer with more-noble PtCl6(2-). Pt(shell)/Au(core) on p-type silicon showed the similar activity with platinum nanoparticle on silicon for photoelectrochemical hydrogen evolution reaction in spite of low platinum loading. From Tafel analysis, Pt(shell)/Au(core) electrocatalyst shows the higher area-specific activity than platinum nanoparticle on silicon demonstrating the significant role of underlying gold for charge transfer reaction from silicon to H(+) through platinum catalyst. PMID- 23750805 TI - Placental abruption and placental weight - implications for fetal growth. AB - OBJECTIVE: Placental abruption is associated with increased risks of preterm delivery and fetal growth restriction. As abruption is apparently a disease of the placenta, the extent to which abruption impacts the growth and development of the placenta remains poorly understood. We reasoned that a study of fetal growth and placental growth in relation to abruption might provide some clues to understanding the process through which placental abruption impacts fetal growth. DESIGN: Multicenter, prospective cohort study. SETTING: USA, 1959-1966. POPULATION: A total of 38 684 pregnancies resulting in singleton live births (22 44 weeks). MAIN OUTCOME MEASURES: Risk ratio of placental ratio <10th centile for gestational age in relation to abruption. Placental ratio was defined as the difference between placental weight and birthweight divided by birthweight (and expressed per 100 births). RESULTS: Mean birthweight and placental weight were, on average, lower among abruption than nonabruption births, but this difference was observed only among births at <37 weeks. Births with placental ratio <10th centile were lower among abruption than nonabruption births at 22-36 weeks (risk ratio 0.4, 95% CI 0.2-0.8), but not at term (risk ratio 0.9, 95% CI 0.6-1.2). CONCLUSIONS: In normal pregnancies, fetal weight and placental weight may operate under independent mechanisms, but in the presence of abruption, the associations appear largely through an interaction of both the maternal and fetal environments. This study underscores the importance of examining both the maternal and fetal compartments - and their interactions - to fully understand the consequences of abruption on fetal growth impairment. PMID- 23750806 TI - Underweight/overweight and the risk of long-term care: follow-up study using data of the Japanese long-term care insurance system. AB - AIM: Both being underweight and overweight can lead to reduced activity of daily living, which subsequently can require long-term care. The aim of the present study was to clarify the association between underweight/overweight and the subsequent risk of long-term care introduction. METHODS: We tracked the data of long-term care insurance for 1580 men and women aged >=65 years who had participated in the official population-based health check-up program in 2001 in Tsunan town and Sekikawa village, Japan. The health check-up data and medical expenditure data for the fiscal year 2001 were used as baseline data. Participants were classified into underweight (body mass index (BMI) <18.5 kg/m(2) ), normal range (BMI = 18.5 to <25.0 kg/m(2) ) and overweight (BMI >=25.0 kg/m(2) ); the normal range was used as a reference category in Cox proportional hazards models. RESULTS: During the average 5.8 years of follow up, 156 participants were identified to start using long-term care services. Among the young-old elderly (65-74 years-of-age), underweight was significantly associated with the risk of long-term care introduction (multivariable-adjusted HR 4.26, 95% CI 1.69-10.72), whereas overweight was not (multivariable-adjusted HR 1.45, 95% CI 0.69-3.06). Neither underweight nor overweight were significantly associated with long-term care introduction among the old-old elderly (>=75 years-of-age). CONCLUSIONS: Underweight could be a good predictor of long-term care introduction in the young-old elderly. We should pay attention to underweight in the elderly, as it might be a manifestation of some physical or mental problems related to future long-term care introduction. PMID- 23750807 TI - Tobacco consumption induces alveolar crest height loss independently of mandibular bone mass and bone density. AB - AIM: To investigate the relationship of tobacco consumption with alveolar crest height (ACH) loss and mandibular bone mass estimated by digital panoramic radiography and cone-beam computed tomography (CBCT). MATERIAL AND METHODS: We studied 315 patients (43.2% [n = 136] men and 56.8% [n = 179] women) with mean age of 36.6 +/- 5.3 (range 21-30 years (16.2%), range 31-46 years (83.8%); 9% (n = 71) were smokers (>10 cig./day). A mean of 13.0 +/- 2.0 mandibular teeth were present: 37.5% of patients had 6-12 teeth and 62.5% 13-16 teeth. We analyzed 315 digital panoramic radiographs (2D) and calculated the ACH, mandibular cortical width, and basal and alveolar bone gray level values. ACH and bone density were also measured on CBCT (3D) in the 110 patients scheduled for implantation. RESULTS: In the univariate analysis, ACH loss was greater in older patients (P = 0.012) and in those with fewer mandibular teeth (P < 0.001) and showed a relationship with tobacco consumption that was close to significant (P = 0.079). In the multivariate analysis, the number of mandibular teeth (P < 0.001) and tobacco consumption (P = 0.048) were significantly associated with ACH. Alveolar and basal bone densities were associated, respectively, with number of mandibular teeth (P = 0.012) and cortical width (P = 0.030). CONCLUSION: In a Caucasian population aged 21-46 years, tobacco consumption was significantly associated with ACH loss. However, ACH loss showed no significant relationship with mandibular bone mass estimated either as mandibular cortical width index or bone density on digital panoramic radiographs or as bone density on CBCT. ACH loss was a local event independent of mandibular bone mass status. PMID- 23750808 TI - Intracuticular wax fixes and restricts strain in leaf and fruit cuticles. AB - This paper investigates the effects of cuticular wax on the release of strain and on the tensile properties of enzymatically isolated cuticular membranes (CMs) taken from leaves of agave (Agave americana), bush lily (Clivia miniata), holly (Ilex aquifolium), and ivy (Hedera helix) and from fruit of apple (Malus * domestica), pear (Pyrus communis), and tomato (Lycopersicon esculentum). Biaxial strain release was quantified as the decrease in CM disc area following wax extraction. Stiffness, maximum strain and maximum force were determined in uniaxial tensile tests using strips of CM and dewaxed CMs (DCMs). Biaxial strain release, stiffness, and maximum strain, but not maximum force, were linearly related to the amount of wax extracted. Apple CM has the most wax and here the effect of wax extraction was substantially accounted for by the embedded cuticular wax. Heating apple CM to 80 degrees C melted some wax constituents and produced an effect similar to, but smaller than, that resulting from wax extraction. Our results indicate that wax 'fixes' strain, effectively converting reversible elastic into irreversible plastic strain. A consequence of 'fixation' is increased cuticular stiffness. PMID- 23750809 TI - Energy balance and obesity: a UK perspective on the gluttony v. sloth debate. AB - Obesity in the UK was assumed to have developed against a population decline in physical activity, with health messages focused on diet and exercise prevention strategies. Doubly-labelled water (DLW) studies of energy expenditure have indicated the alternative scenario that the increased obesity prevalence reflects excessive food energy intake with physical activity levels unchanged. This analysis is questionable, deriving in part from a weakness of the DLW methodology in identifying changing physical activity levels within populations of increasing body weight. This has resulted in an underestimation of the reduction in physical activity in the overweight and obese, as revealed by direct studies of such behaviour. Furthermore, a close examination of food energy supply, household food purchases and individual food energy consumption since 1955, in relation to likely estimates of current intakes indicated by simple modelling of predicted energy expenditure, identifies: (a) food energy supply as markedly overestimating energy intakes; (b) individual food energy consumption as markedly underestimating energy intakes; and (c) household food purchase data as the closest match to predicted current food energy intakes. Energy intakes indicated by this latter method have fallen by between 20 to 30%, suggesting comparable falls in physical activity. Although unequivocal evidence for a matching UK trend in falling physical activity is limited, as is evidence that obesity follows reductions in physical activity, such a link has been recently suggested in a large prospective study in adolescents. Thus, for the UK, obesity has developed within a 'move less-eat somewhat less but still too much' scenario. A focus on both diet and exercise should remain the appropriate public health policy. PMID- 23750810 TI - Perceived emotional intelligence in nursing: psychometric properties of the Trait Meta-Mood Scale. AB - AIMS AND OBJECTIVES: To examine the psychometric properties of the Trait Meta Mood Scale in the nursing context and to determine the relationships between emotional intelligence, self-esteem, alexithymia and death anxiety. BACKGROUND: The Trait Meta-Mood Scale is one of the most widely used self-report measures for assessing perceived emotional intelligence. However, in the nursing context, no extensive analysis has been conducted to examine its psychometric properties. DESIGN: Cross-sectional and observational study. METHODS: A total of 1417 subjects participated in the study (1208 nursing students and 209 hospital nurses). The Trait Meta-Mood Scale, the Toronto Alexithymia Scale, the Rosenberg Self-Esteem Scale and the Death Anxiety Inventory were all applied to half of the sample (n = 707). A confirmatory factor analysis was carried out, and statistical analyses examined the internal consistency and test-retest reliability of the Trait Meta-Mood Scale, as well as its relationship with relevant variables. RESULTS: Confirmatory factor analysis confirmed the three dimensions of the original scale (Attention, Clarity and Repair). The instrument showed adequate internal consistency and temporal stability. Correlational results indicated that nurses with high scores on emotional Attention experience more death anxiety, report greater difficulties identifying feelings and have less self-esteem. By contrast, nurses with high levels of emotional Clarity and Repair showed less death anxiety and higher levels of self-esteem. CONCLUSIONS: The Trait Meta-Mood Scale is an effective, valid and reliable tool for measuring perceived emotional intelligence in the nursing context. Training programmes should seek to promote emotional abilities among nurses. RELEVANCE TO CLINICAL PRACTICE: Use of the Trait Meta-Mood Scale in the nursing context would provide information about nurses' perceived abilities to interpret and manage emotions when interacting with patients. PMID- 23750811 TI - Shape modulation of octanuclear Cu(I) or Ag(I) dichalcogeno template clusters with respect to the nature of their encapsulated anions: a combined theoretical and experimental investigation. AB - M8L6 clusters (M = Cu(I), Ag(I); L = dichalcogeno ligand) are known for their ability to encapsulate various kinds of saturated atomic anions. Calculations on the models [M8(E2PH2)6](2+) (M = Cu(I), Ag(I); E = S, Se) and the ionic or neutral [M8(X)(E2PH2)6](q) (X = H, F, Cl, Br, O, S, Se, N, P, C) indicate that the cubic M8L6 cage adapts its shape for maximizing the host-guest bonding interaction. The interplay between size, covalent and ionic bonding favors either a cubic, tetracapped tetrahedral, or bicapped octahedral structure of the metal framework. Whereas the large third- and fourth-row main group anions maintain the cubic shape, a distortion toward a tetracapped tetrahedral arrangement of the metals occurs in the case of hydride, fluoride, and oxide. The distortion is strong in the case of hydride, weak in the case of fluoride, and intermediate in the case of oxide. Density functional theory (DFT) calculations predict a bicapped octahedral architecture in the case of nitride and carbide. These computational results are supported by X-ray structures, including those of new fluorine- and oxygen-containing compounds. It is suggested that other oxygen containing as well as so far unknown nitride-containing clusters should be feasible. For the first time, the dynamical behavior of the encapsulated hydride has been investigated by metadynamics simulations. Our results clearly demonstrate that the interconversion mechanism between two identical tetracapped tetrahedral configurations occurs through a succession of M-H bonds breaking and forming which present very low activation energies and which involve a rather large number of intermediate structures. This mechanism is full in accordance with (109)Ag and (1)H state NMR measurements. PMID- 23750812 TI - Solid-state NMR characterization of the molecular conformation in disordered methyl alpha-L-rhamnofuranoside. AB - A combination of solid-state (13)C NMR tensor data and DFT computational methods is utilized to predict the conformation in disordered methyl alpha-L rhamnofuranoside. This previously uncharacterized solid is found to be crystalline and consists of at least six distinct conformations that exchange on the kHz time scale. A total of 66 model structures were evaluated, and six were identified as being consistent with experimental (13)C NMR data. All feasible structures have very similar carbon and oxygen positions and differ most significantly in OH hydrogen orientations. A concerted rearrangement of OH hydrogens is proposed to account for the observed dynamic disorder. This rearrangement is accompanied by smaller changes in ring conformation and is slow enough to be observed on the NMR time scale due to severe steric crowding among ring substituents. The relatively minor differences in non-hydrogen atom positions in the final structures suggest that characterization of a complete crystal structure by X-ray powder diffraction may be feasible. PMID- 23750813 TI - Gender dichotomization at the level of ingroup identity: what it is, and why men use it more than women. AB - In 5 studies (N = 756), we show that men's relative to women's gender ingroup identities are characterized by greater levels of gender dichotomization, a tendency to distance masculine from feminine traits. We demonstrate further that men's gender dichotomization is motivated, in part, by a need to eschew femininity from their ingroup identity to bolster a precarious gender status. Studies 1-3 establish and replicate the basic effect, and rule out alternative explanations (positivity, projection, status striving) for men's tendency to dichotomize more than women. Studies 4 and 5 demonstrate the motivated nature of gender dichotomization by establishing that men, but not women, dichotomize more strenuously when reminded of the precariousness of their gender status, and report stronger motivation to restore their gender status upon learning that their ingroup is becoming less dichotomized. Across 3 studies, strength of identification with their gender group moderates men's dichotomization tendencies. Discussion considers the implications of these findings for understanding the precarious nature of manhood and identifies practical applications of gender dichotomization in the interpersonal realm. PMID- 23750814 TI - Feeling in with the outgroup: outgroup acceptance and the internalization of the motivation to respond without prejudice. AB - Over 10 years of research has illustrated the benefits of internal motivation to respond without prejudice (IMS) for prejudice regulation and high-quality intergroup contact (see Plant & Devine, 1998). Yet, it is unclear how this motivation develops. The current work tested one route through which feelings of acceptance from outgroup members facilitate the development of IMS. Longitudinally, feeling accepted by outgroup members predicted increases in IMS across a 15-week period (Study 1). Experimental manipulations of outgroup acceptance also increased IMS toward racial outgroups (Studies 2 and 3). Furthermore, IMS mediated the relationship between outgroup acceptance and participants' increased willingness to pay money to increase opportunities for interracial contact (Study 2). Tests of mediation also demonstrated that feelings of acceptance mediated the effect of outgroup acceptance on internal motivation (Study 3). In addition, this pattern of responses held for members of both high- and low-status racial groups. This research demonstrates one pathway through which the fulfillment of fundamental needs influences motivated intergroup processes. PMID- 23750815 TI - Boehmeria nivea attenuates LPS-induced inflammatory markers by inhibiting p38 and JNK phosphorylations in RAW264.7 macrophages. AB - CONTEXT: Boehmeria nivea (Linn.) Gaudich (Urticaceae), a natural herb, has a long history of treating several diseases including wound healing. However, the anti inflammatory effect of B. nivea has not been investigated. OBJECTIVE: We investigated whether the 70% ethanol extract of B. nivea (Ebn) can exert anti inflammatory activity. Several phenolic compounds of extracts were determined to provide further information on the correlation between anti-inflammatory effects and phenolic compounds. MATERIALS AND METHODS: We prepared a 70% ethanol extract of B. nivea leaves and evaluated its anti-inflammatory activity (200, 400, 800, 1200 ug/mL) by measuring the secretions of nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), which were stimulated by lipopolysaccharide (LPS) in RAW264.7 macrophages. The total phenolic compounds were determined by the Folin-Ciocalteu method and major compounds were determined by HPLC. RESULTS: Ebn was able to abolish the LPS-induced secretions of NO, TNF alpha and IL-6. It also decreased the protein levels (IC50 = 186 ug/mL) of LPS induced inducible nitric oxide synthase (iNOS). The LPS stimulated p38, JNK and ERK phosphorylations significantly more than the controls. Surprisingly, although Ebn reduced p38 and JNK phosphorylations, it did not influence ERK phosphorylation. We found that Ebn revealed several major compounds such as chlorogenic acid (1.96 mg/100 g), rutin (46.48 mg/100 g), luteolin-7-glucoside (11.29 mg/100 g), naringin (1.13 mg/100 g), hesperidin (23.69 mg/100 g) and tangeretin (1.59 mg/100 g). DISCUSSION AND CONCLUSION: Boehmeria nivea exerts an anti-inflammatory effect on macrophages by inhibiting p38 and JNK, suggesting that it may be used as a functional ingredient against inflammation. PMID- 23750816 TI - Enablers and barriers affecting medication-taking behaviour in aging men with benign prostatic hyperplasia. AB - OBJECTIVES: To identify the enablers and barriers affecting medication-taking behaviour in aging men with benign prostatic hyperplasia. METHODS: A total of 40 patients attending the urology outpatient clinic in Melbourne in 2012 were screened. Patients who successfully met the inclusion criteria were interviewed using a structured interview schedule. Information regarding the patient's medication, demographic data and presence of co-morbidities was collected. Content analysis was compared with patient demographic and medical data, contributing to the analysis. RESULTS: Problems with medication-taking were reported in 58% of patients. All patients without co-morbidities reported issues regarding their medications, whereas only 27% of patients with co-morbidities reported concerns regarding their medications. Statistical analysis revealed that patients without co-morbidities were significantly more likely (p = 0.002) to have complaints with their medications compared to those with co-morbidities. Furthermore, patients with co-morbidities who required help of caregivers to assist with their medication-taking were significantly less likely (p = 0.05) to have complaints with their medications compared to patients who self-managed. CONCLUSIONS: Older patients with caregivers who assisted managing their medication-taking had better adherence. Those receiving aid from their caregivers were significantly less likely to have complaints regarding their medications as opposed to those not requiring a caregiver. This highlights the importance of having support for medication-taking in patients with co-morbidities to assist with better adherence. PMID- 23750817 TI - Dispersible and thermal stable nanofibrils derived from glycated whey protein. AB - Formation of nanofibrils by heating proteins at pH 2.0 has been studied extensively because of the potential as novel biomaterials. However, nanofibrils of whey proteins have poor dispersibility and heat stability, limiting their application in fluidic and transparent products. We report, for the first time, the formation of nanofibrils from whey protein isolate (WPI) glycated with lactose (WPI-g-L) that were highly dispersible and remained transparent after heating at pH 3.0-7.0 and 0-150 mM NaCl. The WPI-g-L followed similar nanofibril formation mechanism as WPI based on reducing protein electrophoresis, analytical ultracentrifugation, and circular dichroism spectroscopy. The rate of nanofibril formation from WPI-g-L was similar to that of WPI, but the yield was lower based on thioflavin-T fluorescence spectroscopy. The presence of the glycated lactose on nanofibril surface provided steric hindrance enabling the dispersibility and thermal stability and supplying functions such as viscosity in various fluidic, transparent consumer products. PMID- 23750818 TI - The pathogenicity island encoded PvrSR/RcsCB regulatory network controls biofilm formation and dispersal in Pseudomonas aeruginosa PA14. AB - Pseudomonas aeruginosa biofilm formation is linked to persistent infections in humans. Biofilm formation is facilitated by extracellular appendages, some of which are assembled by the Chaperone Usher Pathway (Cup). The cupD gene cluster is located on the PAPI-1 pathogenicity island of strain PA14 and has probably been acquired together with four genes encoding two-component signal transduction proteins. We have previously showed that the RcsB response regulator activates expression of the cupD genes, which leads to the production of CupD fimbriae and increased attachment. Here we show that RcsB activity is tightly modulated by two sensors, RcsC and PvrS. While PvrS acts as a kinase that enhances RcsB activity, RcsC has a dual function, first as a phosphorelay, and second as a phosphatase. We found that, under certain growth conditions, overexpression of RcsB readily induces biofilm dispersal. Microarray analysis shows that RcsB positively controls expression of pvrR that encodes the phosphodiesterase required for this dispersal process. Finally, in addition to the PAPI-1 encoded cupD genes, RcsB controls several genes on the core genome, some of which encode orphan response regulators. We thus discovered that RcsB is central to a large regulatory network that fine-tunes the switch between biofilm formation and dispersal. PMID- 23750819 TI - Maternal body mass index and the association between folic acid supplements and neural tube defects. AB - AIM: To study the influence of maternal body mass index (BMI) on the association between folic acid supplementation and neural tube defects (NTDs) risk in offspring. METHODS: A hospital-based, case-control study was conducted between 2006 and 2008 on 459 mothers with NTDs-affected births and 459 mothers without NTDs-affected births. Logistic regression models examined the associations between folic acid supplementation and the NTDs risk in offspring for all mothers, underweight/normal weight mothers (BMI<24.0) and overweight/obese mothers (BMI >=24.0). The effects were evaluated by adjusted odds ratio (AOR) and 95% confidence intervals (CIs) with SAS 9.1.3 software. RESULTS: The overall AOR for periconceptional folic acid supplementation was 0.315 (95% CI = 0.172-0.577) when compared with no supplements. Stratified by maternal BMI, the AOR for periconceptional folic acid supplementation in overweight/obese mothers was greater than in underweight/normal weight mothers (0.646 vs. 0.208). The AOR for folic acid supplementation within 3 months before conception was 0.711 (95% CI = 0.323-1.563) in all mothers. Stratified by maternal BMI, the AOR for folic acid supplementation within 3 months before conception in overweight/obese mothers was greater than in underweight/normal weight mothers (0.658 vs. 0.527). CONCLUSION: The association between folic acid supplementation and the reduced NTDs risk was weaker in overweight/obese mothers (BMI >=24.0) than in underweight/normal weight mothers (BMI <24.0). PMID- 23750820 TI - Rates and predictors of prenatal depression in women living with and without HIV. AB - Depression is a significant mental health and public health concern, and women living with HIV are at increased risk for depression. This risk may be especially elevated during pregnancy; however, few studies have attempted to identify rates and predictors of depression in pregnant, HIV-infected women. The purpose of the present study was to investigate rates and predictors of prenatal depression, such as history of depression, childhood sexual abuse (CSA), and social support among HIV-infected and HIV-uninfected women in Philadelphia, Pennsylvania. It was hypothesized that pregnant women with HIV will have higher rates of depressive symptoms and will exhibit a greater number of mood disorder diagnoses as compared to HIV-uninfected pregnant women. It was also hypothesized that HIV status, history of depression, CSA, and inadequate social support will emerge as predictors of depressive symptoms. A sample of 163 women, 31% (n=50) of whom were HIV-infected and 69% (n=113) of whom were HIV-uninfected, were recruited from an obstetrics/gynecology clinic affiliated with an urban university hospital. The Center for Epidemiological Studies-Depression Scale (CES-D) was used to identify depressive symptoms, and Modules A and D of the Structured Clinical Interview for DSM-IV (SCID) confirmed the presence of a mood disorder. Findings demonstrated that rates of depressive symptoms and mood disorder diagnoses during pregnancy did not differ according to HIV serostatus. History depression, CSA, and inadequate social support predicted depressive symptoms during pregnancy in this sample. Due to their association with depressive symptoms, history of depression, CSA, and inadequate social support may be important to identify during pregnancy. PMID- 23750821 TI - Changes in medical student and doctor attitudes toward older adults after an intervention: a systematic review. AB - Research investigating the effects of attitude-focused interventions on doctors' and medical students' attitudes toward older adults has produced mixed results. The objective of this systematic review was to determine whether factors pertaining to study design and quality might provide some explanation of this inconclusive picture. Articles were judged of interest if they reported doctors' or medicals students' attitude scores before and after a geriatric-focused intervention. Articles that did not report the measure used, mean scores, or inferential statistics were excluded. Twenty-seven databases, including Medline, PsychInfo, and Embase, were searched through April 2011 using a systematic search strategy. After assessment and extraction, 27 studies met the eligibility criteria for this review. These studies demonstrated inconsistent results; 14 appeared successful in effecting positive attitude change toward older adults after an intervention, and 13 appeared unsuccessful. Attitude change results differed in line with the content of the intervention. Of the 27 studies, 11 interventions contained solely knowledge-building content. Three of these studies demonstrated positive changes in doctors' or medical students' attitudes toward older adults after the intervention. The remaining 16 interventions incorporated an empathy-building component, such as an aging simulation exercise or contact with a healthy older adult. Of these, 11 successfully demonstrated positive attitude change after the intervention. The inclusion of an empathy-building task in an intervention appears to be associated with positive attitude change in medical students' and doctors' attitudes toward older adults. PMID- 23750822 TI - Influenza A infection of primary human airway epithelial cells up-regulates proteins related to purine metabolism and ubiquitin-related signaling. AB - Virus-host interactions are important determinants of virus replication and immune responses, but they are not well-defined. In this study we analyzed quantitative host protein alterations in nuclei-enriched fractions from multiple primary human bronchial airway epithelial (HBAE) cells infected by an H1N1 influenza A virus (A/PR/8/34). We first developed an effective detergent-free nuclear lysis method that was coupled with in-solution digestion and LC-MS/MS. Using SILAC, we identified 837 HBAE nuclear proteins in three different donors and compared their responses to infection at 24 h. Some proteins were altered in all three donors, of which 94 were up-regulated and 13 were down-regulated by at least 1.5-fold. Many of these up-regulated proteins clustered into purine biosynthesis, carbohydrate metabolism, and protein modification. Down-regulated proteins were not associated with any specific pathways or processes. These findings further our understanding of cellular processes that are altered in response to influenza in primary epithelial cells and may be beneficial in the search for host proteins that may be targeted for antiviral therapy. PMID- 23750823 TI - Evaluation of an intra-institutional diabetes disease management program for the glycemic control of elderly long-term care diabetic patients. AB - AIM: Increasing numbers of nursing home elderly patients suffer from diabetes requiring individually optimized glycemic control. This is a complicated challenge because of their high comorbidity level, and heterogeneous and changing eating status varying from independent to dysphagia and enteral feeding. In order to cope with these complex needs, we developed and implemented a diabetes disease management program. The purpose of the present study was to evaluate this program. METHODS: We used the point prevalence approach by checking for fasting blood glucose, glycated hemoglobin and other routine biochemical tests. Eating status was evaluated by the Functional Outcome Swallowing Scale. Details about the diabetes disease management program are given in the text. RESULTS: A total of 86 (36%) of the 234 patients on the study day were diabetics. Of these, 80 were eligible for the study. Their mean fasting blood glucose was 143.1 +/- 60.6 mg/dL. The mean glycated hemoglobin level was 7.23 +/- 1.39%. CONCLUSION: No case of hypoglycemia was detected on the examination day, or during the preceding 3 weeks. No significant difference was found among the different Functional Outcome Swallowing Scale categories. These results are within satisfactory range for this category of patients suggesting that our diabetes disease management program contributes to a better glycemic control. PMID- 23750824 TI - How young is too young to be a living donor? AB - Assessing people in adolescence and early adulthood who wish to become living organ donors (LDs) provides unique challenges. In several Canadian provinces, 16 year-old can legally consent to living organ donation. While the World Health Organization states that adolescence corresponds roughly to the ages of 10-19 years, parts of the brain associated with judgment continue to develop into the mid-20s. Therefore, it is legally possible for some young people to donate organs before their capacity to judge the benefits and risks of surgery has fully matured. Potential young living donors (YLDs) may be financially and/or psychologically dependent on their recipients (e.g. parents), which can make it difficult to determine if the YLD's donation is voluntary. This paper suggests ways to manage three ethical challenges in the use of young people as LDs: (1) determining the YLD's ability to appreciate the consequences of living organ donation, (2) determining whether the YLD's donation is voluntary and (3) evaluating the unique risks and benefits to the YLD. We conclude that there are compelling ethical reasons to offer the opportunity of living donation to selected young people. A thorough and fair evaluation process can address social, emotional and developmental issues associated with YLDs. PMID- 23750825 TI - Incidence of convulsive epilepsy in a rural area in Kenya. AB - PURPOSE: There are only a few studies of incidence of epilepsy in low and middle income countries (LMICs). These are often small and conducted in specific age groups or areas where the prevalence of risk factors is high; therefore, these studies are not representative of the wider populations. We determined the incidence of convulsive epilepsy (CE) in a large rural population in Kenya. METHODS: We conducted two cross-sectional surveys 5 years apart within a health and demographic surveillance system. Initially we identified residents without epilepsy who were then reexamined in the follow-up survey to determine incidence. We estimated the overall incidence of CE and incidence by age-group, sex, and by administrative location. Estimates were adjusted for attrition during case identification and for the sensitivity of the screening method. KEY FINDINGS: In a cohort of 151,408 people, 194 developed CE over the 5 years. The minimum crude incidence rate was 37.6/100,000 persons per year (95% confidence interval (CI) 32.7-43.3) and adjusted for loss to follow-up, and the sensitivity of the survey methodology was 77.0/100,000 persons per year (95% CI 67.7-87.4). Incidence was highest in children 6-12 years (96.1/100,000 persons per year; 95% CI 78.4 117.9), and was lowest in the 29-49 year age group (37.4/100,000 persons per year; 95% CI 25.7-54.7). SIGNIFICANCE: We estimated a high incidence of convulsive epilepsy in this population. Incidence was highest early and late in life, suggesting that preventive interventions should target exposures that occur in these age groups. Incidence of focal epilepsy was more than twice that of generalized epilepsy, suggesting that etiologies that are amenable to intervention were most important in this population. It is likely that incidence is underestimated because of the early mortality of incident cases. PMID- 23750826 TI - Bioinspired nonheme iron complexes derived from an extended series of N,N,O ligated BAIP ligands. AB - A series of mononuclear Fe(II) triflate complexes based on the 3,3-bis(1 alkylimidazole-2-yl)propionate ester (BAIP) ligand scaffold are reported. In these complexes, the tripodal N,N,O-BAIP ester ligand is varied by (i) changing the ester moiety (i.e., n-Pr, tert-Bu esters, n-Pr amide), (ii) changing the methylimidazole moieties to methylbenzimidazole moieties, and (iii) changing the methylimidazole moieties to 1-ethyl-4-isopropylimidazole moieties. The general structure of the resulting complexes comprises two facially capping BAIP ligands around a coordinatively saturated octahedral Fe(II) center, with either a transoid or cisoid orientation of the N,N,O-donor manifold that depends on the combined steric and electronic demand of the ligands. In the case of the sterically most encumbered ligand, a four-coordinate all N-coordinate complex is formed as well, which cocrystallizes with the six-coordinate complex. In combination with the catalytic properties of the new complexes in the epoxidation/cis-dihydroxylation of cyclooctene with H2O2, in terms of turnover number and cis-diol formation, these studies provide a number of insights for further ligand design and catalyst development aimed at Fe-mediated cis dihydroxylation. PMID- 23750827 TI - Novel respiratory syncytial virus subtype ON1 among children, Cape Town, South Africa, 2012. PMID- 23750828 TI - SWIRL, a clinically validated, objective, and quantitative method for facial wrinkle assessment. AB - BACKGROUND: Facial wrinkles are an undesirable feature caused by extrinsic photodamage and intrinsic aging process. Many cosmetic products and esthetic procedures strive to ameliorate the appearance of wrinkles. Currently the effects of those products and procedures on wrinkles are mainly evaluated by clinical grading, subjective self-assessment questionnaires, and optical profilometry of replica impressions. An objective and quantitative method is in demand. METHODS: Raking light optical profilometry was applied directly to facial photography to cast wrinkles as dark shadows. The resulting high-resolution digital images were analyzed using Image Pro software. A high-throughput method, Stephens Wrinkle Imaging using Raking Light (SWIRL), was developed to analyze the severity of wrinkles using photographs taken under the raking light condition. This method was applied to photographs taken from many panelists with a wide range of wrinkle severity scores. The result was compared with clinical grading scores to determine its validity. In addition, this method was applied to photographs taken from panelists before and after product usage to determine its sensitivity. RESULTS: Using the SWIRL method, multiple wrinkle parameters were quantitatively assessed, including wrinkle count, length, width, area, and relative depth. Those parameters correlated well with clinical grading scores, showing correlation coefficient (r value) of about 0.8 for all parameters. This result indicates that the SWIRL method is a valid method for analyzing wrinkle severity. When applied to a clinical study, the SWIRL method was sensitive enough to detect improvement after 8 weeks of product application. CONCLUSIONS: The SWIRL method has been fully validated through clinical studies. It is accurate, objective, and quantitative. As multiple wrinkle parameters are analyzed simultaneously, it can provide more detailed information on how wrinkles change over time and therefore has the potential to shed light on the action and mechanism of antiwrinkle products. PMID- 23750829 TI - Socio-economic determinants of micronutrient intake and status in Europe: a systematic review. AB - OBJECTIVE: To provide the evidence base for targeted nutrition policies to reduce the risk of micronutrient/diet-related diseases among disadvantaged populations in Europe, by focusing on: folate, vitamin B12, Fe, Zn and iodine for intake and status; and vitamin C, vitamin D, Ca, Se and Cu for intake. DESIGN: MEDLINE and Embase databases were searched to collect original studies that: (i) were published from 1990 to 2011; (ii) involved >100 subjects; (iii) had assessed dietary intake at the individual level; and/or (iv) included best practice biomarkers reflecting micronutrient status. We estimated relative differences in mean micronutrient intake and/or status between the lowest and highest socio economic groups to: (i) evaluate variation in intake and status between socio economic groups; and (ii) report on data availability. SETTING: Europe. SUBJECTS: Children, adults and elderly. RESULTS: Data from eighteen publications originating primarily from Western Europe showed that there is a positive association between indicators of socio-economic status and micronutrient intake and/or status. The largest differences were observed for intake of vitamin C in eleven out of twelve studies (5-47 %) and for vitamin D in total of four studies (4-31 %). CONCLUSIONS: The positive association observed between micronutrient intake and socio-economic status should complement existing evidence on socio economic inequalities in diet-related diseases among disadvantaged populations in Europe. These findings could provide clues for further research and have implications for public health policy aimed at improving the intake of micronutrients and diet-related diseases. PMID- 23750830 TI - Evaluating the in vitro inhibition of UGT1A1, OATP1B1, OATP1B3, MRP2, and BSEP in predicting drug-induced hyperbilirubinemia. AB - Hyperbilirubinemia may arise due to inadequate clearance of bilirubin from the body. Bilirubin elimination is a multifaceted process consisting of uptake of bilirubin into the hepatocytes facilitated by OATP1B1 and OATP1B3. Once in the hepatocytes, it is extensively glucuronidated by UGT1A1. Eventually, the glucuronide metabolite is excreted into the bile via MRP2. UGT1A1 inhibition has been previously shown to be linked with hyperbilirubinemia. However, because drug transporters also contribute to bilirubin elimination, the purpose of this work was to investigate the in vitro inhibition of OATP1B1, OATP1B3, MRP2, and BSEP of select test drugs known to elicit hyperbilirubinemia. Test drugs investigated in this study were atazanavir and indinavir, which are associated with hyperbilirubinemia and elevations in serum transaminase; ritonavir and nelfinavir, which are not associated with hyperbilirubinemia; and bromfenac, troglitazone, and trovafloxacin, which are associated with severe idiosyncratic hepatotoxicity exhibiting elevations in serum bilirubin and transaminase. Due to limited solubility and poor ionization of bilirubin and its glucuronide, the formation of estradiol 3-glucuronide was used as a surrogate to assess UGT1A1 activity, while the transport of pitavastatin, CDCF, and taurocholate were used as surrogate probe substrates to monitor the function of OATP1B1/OATP1B3, MRP2, and BSEP, respectively. It was assumed that any inhibition of the surrogate probe substrates by test drugs is indicative of the potential impact of test drugs to modulate the function of proteins involved in bilirubin disposition. In vitro inhibition was determined by calculating IC50. Moreover, Cmax and Cmax,free were integrated with IC50 values to calculate R and Rfree, respectively, which represents the ratio of probe drug glucuronidation/transport in the absence and presence of test drugs. Analysis of the data showed that Rfree demonstrated the best correlation to hyperbilirubinemia. Specifically, Rfree was above the 1.1 target threshold against UGT1A1, OATP1B1, and BSEP for atazanavir and indinavir. In contrast, Rfree was below this threshold for ritonavir and nelfinavir as well as for bromfenac, troglitazone, and trovafloxacin. For all test drugs examined, only minor inhibition against OATP1B3 and MRP2 were observed. These data suggest that the proposed surrogate probe substrates to evaluate the in vitro inhibition of UGT1A1, OATP1B1, and BSEP may be suitable to assess bilirubin disposition. For protease inhibitors, inclusion of OATP1B1 and BSEP inhibition may improve the predictability of hyperbilirubinemia. PMID- 23750831 TI - The nature and transfer of cognitive skills. AB - This article presents the primitive elements theory of cognitive skills. The central idea is that skills are broken down into primitive information processing elements that move and compare single pieces of information regardless of the specific content of this information. Several of these primitive elements are necessary for even a single step in a task. A learning process therefore combines the elements in increasingly larger, but still context-independent, units. If there is overlap between tasks, this means the larger units learned for 1 task can be reused for the other task, producing transfer. The theory makes it possible to construct detailed process models of 2 classic transfer studies in the literature: a study of transfer in text editors and 1 in arithmetic. I show that the approach produces better fits of the amount of transfer than Singley and Anderson's (1985) identical productions model. The theory also offers explanations for far transfer, in which the 2 tasks have no surface characteristics in common, which I demonstrate with 2 models in the domain of cognitive control, where training on either task-switching or working memory control led to an improvement of performance on other control tasks. The theory can therefore help evaluate the effectiveness of cognitive training that has the goal to improve general cognitive abilities. PMID- 23750832 TI - A theory and a computational model of spatial reasoning with preferred mental models. AB - Inferences about spatial arrangements and relations like "The Porsche is parked to the left of the Dodge and the Ferrari is parked to the right of the Dodge, thus, the Porsche is parked to the left of the Ferrari," are ubiquitous. However, spatial descriptions are often interpretable in many different ways and compatible with several alternative mental models. This article suggests that individuals tackle such indeterminate multiple-model problems by constructing a single, simple, and typical mental model but neglect other possible models. The model that first comes to reasoners' minds is the preferred mental model. It helps save cognitive resources but also leads to reasoning errors and illusory inferences. The article presents a preferred model theory and an instantiation of this theory in the form of a computational model, preferred inferences in reasoning with spatial mental models (PRISM). PRISM can be used to simulate and explain how preferred models are constructed, inspected, and varied in a spatial array that functions as if it were a spatial working memory. A spatial focus inserts tokens into the array, inspects the array to find new spatial relations, and relocates tokens in the array to generate alternative models of the problem description, if necessary. The article also introduces a general measure of difficulty based on the number of necessary focus operations (rather than the number of models). A comparison with results from psychological experiments shows that the theory can explain preferences, errors, and the difficulty of spatial reasoning problems. PMID- 23750833 TI - Henipaviruses and fruit bats, Papua New Guinea. PMID- 23750834 TI - A Rasch-based dimension of delivery experience: spontaneous vs. medically assisted conception. AB - AIMS AND OBJECTIVES: To devise a set of indices representative of a latent dimension of delivery perception, aimed at the assessment of birth experience after both spontaneous and medically assisted conception. BACKGROUND: Birth experience is of great importance for its prognostic value for the woman and newborn's psychophysical well-being, especially after the experience of assisted reproduction technology. Up to date, a delivery perception assessment measure targeted to both spontaneously and medically assisted conceiving women does not exist yet. DESIGN: Measure development and psychometric analysis; quantitative and qualitative analysis of women's delivery experience measures. METHODS: Thirty one indices characterising seven relevant aspects of birth perception were devised from the literature and evaluated on a 4-point Likert-type scale by 98 childbearing women (54 spontaneously and 44 medically assisted conceiving) in the 24-48 hours postpartum time frame. Women's obstetric history information was also collected. The dimension psychometric definition was pursued within a latent trait perspective, by applying the many-facet Rasch measurement model. RESULTS: A latent delivery perception dimension composed of 18 valid and reliable indices, qualifying six labour and delivery perception clinical aspects, was identified. Medically assisted conceiving women evidenced a more positive birth perception, but when analysing each index, they showed peculiar intense worries about themselves and their baby's health, even if they felt more satisfied, safer and stronger in almost every labour and birth aspect. CONCLUSIONS: The delivery perception dimension integrates all relevant birth experience aspects in 18 easy to-administer indices and provides a valid, reliable and feasible assessment tool for both the clinical practice and research purposes. RELEVANCE TO CLINICAL PRACTICE: The delivery perception dimension clearly discriminates between women's types of conception and identifies relevant differences in their birth experience, which are interesting for their clinical implications within a prognostic and intervention perspective of support provision in the early postpartum period. PMID- 23750835 TI - Immunoglobulin G4 thyroiditis in a Graves' disease patient with a large goiter developing hypothyroidism. PMID- 23750836 TI - Improved phase-modulated homonuclear dipolar decoupling for solid-state NMR spectroscopy from symmetry considerations. AB - We explore the effects of symmetry on the performance of phase-modulated homonuclear dipolar decoupling in (1)H solid-state NMR. We demonstrate that the symmetry of the DUMBO family of decoupling sequences is the result of two well defined symmetry expansions. The first is an antipalindromic expansion that arises from the symmetrization step that was built into the original architecture of the DUMBO sequence. The second is a mirror-pair expansion that inverts the sign of the phase modulation in the second half of the pulse sequence relative to the first. The combination of these two symmetry expansions generates a sequence of four Lee-Goldburg-type rotations in the rotating frame. The axes of rotation, oriented at the magic angle, are separated in the transverse plane by 2alpha, where alpha is chosen to minimize the sensitivity of the sequence to instrument imperfections such as rf inhomogeneity. The efficiency of the DUMBO symmetry for decoupling is demonstrated experimentally, and the effect of the alpha-phase shift parameter is investigated. A new decoupling sequence (LG4) that combines the DUMBO symmetry with alpha = 55 degrees is introduced and is shown to produce very efficient decoupling as well as a nearly 2-fold increase in coherence lifetimes when compared to standard PMLG/FSLG decoupling. PMID- 23750837 TI - Poppers toxic maculopathy misdiagnosed as atypical optic neuritis. PMID- 23750838 TI - Major eosinophilia induced by subcutaneous apomorphine infusion: four cases. PMID- 23750839 TI - A novel compound heterozygous mutation of C20orf54 gene associated with Brown Vialetto-Van Laere syndrome in an Italian family. PMID- 23750840 TI - Dramatic improvement after rituximab in a patient with paraneoplastic treatment refractory Morvan syndrome associated with anti-CASPR2 antibodies. PMID- 23750841 TI - Cotard delusion after stroke. PMID- 23750843 TI - Good radiological and functional results after intramedullary nailing of distal radius fractures. AB - To evaluate the results after fixation of distal radius fractures using Micronail internal fixation, a prospective cohort study was performed, including displaced fractures of the distal radius (AO type A 2.2, A3.1, and A3.2). In total, 60 patients were included and 44 patients were available for 1-year follow-up (radiological and clinical examination) and 39 for 5-year follow-up (telephone interview). It was found that all fractures healed, with an average radial volar tilt of 2 degrees , radial length of 11 mm, and a radial inclination of 22 degrees . The functional result was excellent-to-good in 93% of the patients. Thirteen patients (30%) reported paraesthesia of the superficial branch of the radial nerve at the 1-year follow-up. In four patients the paraesthesia of the radial nerve was persistent. No other complications or reoperations were reported by the patients at the 5-year follow-up and only one implant had been removed. The study confirms that the Micronail is a minimal invasive method that can provide a stable fixation of selected distal radius fractures and provide a good functional outcome with a very low need of implant removal after fracture healing with few complications related to the operation, the main complication being permanent damage to the radial nerve. PMID- 23750844 TI - Functional reconstruction of bilateral injuries to the dorsum of hand using radial forearm tendocutaneous flaps. AB - We treated a patient with skin and tendon defects of both hands as a result of injury by a heat press. There have been no reports of bilateral hand injuries being treated using simultaneous bilateral tendocutaneous flaps. In this case, we reconstructed the injured tissue using simultaneous bilateral radial forearm tendocutaneous flaps, with satisfactory results. PMID- 23750845 TI - Extra-adrenal paraganglioma of the median nerve. AB - An extra-adrenal paraganglioma is an uncommon tumour that arises from the paraganglia associated with the autonomous nervous system. A paraganglioma arising in the sensory-somatic nervous system is extremely rare and clinically is easily confused with other neurogenic tumours. We describe a paraganglioma that arose in the median nerve of a 22-year-old woman. PMID- 23750846 TI - Can ultrasound be used to estimate bone mineral density in children with growth problems? AB - AIM: To assess predictability of bone mineral density (BMD) of the lumbar spine (LS) determined by dual-energy x-ray absorptiometry (DXA) using by ultrasound speed of sound of the right and left radii (SOS-R and SOS-L) in patients with growth problems. METHODS: Ultrasound and DXA were compared in patients with advanced, normal and delayed bone ages assessed by Greulich and Pyle (GP) and Tanner and Whitehouse (TW3) methods. RESULTS: There was a strong correlation (r), of raw scores, between SOS-R and SOS-L, r = 0.81, p = 0.000 and their respective Z-scores, r = 0.78, p = 0.000. Z-score correlations were poor between SOS-R or SOS-L and LS-BMD. Sensitivity, specificity, positive and negative predictive values of SOS-R and Z-scores for predicting normal (>-1 to <1) and low (<-1) LS BMD were poor. For high (>1) LS-BMD, Z-scores were 22%, 93%, 29% and 90%, respectively, for SOS-R and for SOS-L, 25%, 89%, 20% and 91%. For very low (<-2) LS-BMD, SOS-R and SOS-L were the same, respectively, 29%, 91%, 40% and 86%. CONCLUSION: Ultrasound of the radius is a poor predictor of radiologically assessed BMD at the LS, especially with delayed bone age. PMID- 23750847 TI - Korean red ginseng extract prevents APAP-induced hepatotoxicity through metabolic enzyme regulation: the role of ginsenoside Rg3, a protopanaxadiol. AB - BACKGROUND: Inappropriate use of acetaminophen (APAP) can lead to morbidity and mortality secondary to hepatic necrosis. AIMS: We evaluated the beneficial effect and molecular mechanism of Korean red ginseng (KRG) on the APAP-mediated hepatotoxicity and identified a major component of KRG for hepatoprotection. METHODS: Survival test, liver function test, histopathological study, APAP metabolic profiling and gene expression were examined in mice. We determined the enzyme expression and upstream signalling in H4IIE cells analysed by RT-PCR, immunoblotting, siRNA gene knockdown and promoter-luciferase assay. RESULTS: High doses of KRG reduced mortality at the LD50 of APAP. APAP increased AST and ALT activities, which were abrogated by low doses of KRG. These protective effects were consistent with the results from histopathological examinations. KRG altered APAP metabolic profiles through inhibition of cytochrome P450 2E1 and induction of glutathione S-transferase A2 (GSTA2). Knockdown of GSTA2 catalyses the conjugation of glutathione reversed KRG-mediated protection against N-acetyl-p benzoquinone imine in H4IIE cells. The nuclear Nrf2 and C/EBPbeta, which are essential transcriptional factors for GSTA2 were increased by KRG. These effects were downstream of multiple signalling, including PI3K, JNK or PKA. Ginsenoside Rg3 but not Rb1, Rc and Rg1 significantly increased GSTA2 protein expression. Rg3 resulted in the transcriptional activation of GSTA2 downstream of the multiple cellular signalling. CONCLUSIONS: These results demonstrate that KRG is efficacious in protection against APAP-induced hepatotoxicity and mortality through metabolic regulation and that Rg3 is a major component of KRG for the GST induction, implying that Rg3 should be considered to be a potential hepatoprotective agent. PMID- 23750848 TI - In vitro resistance mechanisms of Neisseria meningitidis against neutrophil extracellular traps. AB - Neisseria meningitidis (Nm) is a leading cause of septicemia in childhood. Nm septicemia is unique with respect to very quick disease progression, high in vivo bacterial replication rate and its considerable mortality. Nm circumvents major mechanisms of innate immunity such as complement system and phagocytosis. Neutrophil extracellular traps (NETs) are formed from neutrophils during systemic infection and are suggested to contain invading microorganisms. Here, we investigated the interaction of Nm with NETs. Both, meningococci and spontaneously released outer membrane vesicles (SOMVs) were potent NET inducers. NETs were unable to kill NET bound meningococci, but slowed down their proliferation rate. Using Nm as model organism we identified three novel mechanisms how bacteria can evade NET-mediated killing: (i) modification of lipid A of meningococcal LPS with phosphoethanolamine protected Nm from NET-bound cathepsin G; (ii) expression of the high-affinity zinc uptake receptor ZnuD allowed Nm to escape NET-mediated nutritional immunity; (iii) binding of SOMVs to NETs saved Nm from NET binding and the consequent bacteriostatic effect. Escape from NETs may contribute to the most rapid progression of meningococcal disease. The induction of NET formation by Nm in vivo might aggravate thrombosis in vessels ultimately directing to disseminated intravascular coagulation (DIC). PMID- 23750849 TI - Inner strength in relation to age, gender and culture among old people--a cross sectional population study in two Nordic countries. AB - OBJECTIVES: The theoretical framework for the study was the Model of Inner Strength, and the Inner Strength Scale (ISS)developed based on the Model was used. The aim was to examine inner strength in relation to age, gender and culture among old people in Sweden and Finland. METHOD: This study forms part of the GErontological Regional DAtabase (GERDA)-Botnia project that investigates healthy ageing with focus on the dignity, social participation and health of old people. The participants (N = 6119) were 65-, 70-, 75- and 80-year old and living in two counties in Sweden or Finland. The ISS consists of 20 items relating to four interrelated dimensions of inner strength, according to the Model of Inner Strength. The range of possible ISS scores is 20-120, a higher score denoting higher inner strength. RESULT: The result showed that the 65-year-old participants had the highest mean ISS score, with a decrease in score for every subsequent age. The lowest score was achieved by the 80-year-old participants. Women had slightly but significantly higher mean ISS scores than men. Only small differences were found between the counties. CONCLUSION: The study population came from Sweden and Finland; still, despite the different backgrounds, patterns in the distribution of inner strength were largely similar. The present study provides basic and essential information about inner strength in a population of old people. PMID- 23750850 TI - Counteracting effect of supine leg resistance exercise on systolic orthostatic hypotension in older adults. AB - OBJECTIVES: To assess the efficacy of a leg exercise performed in supine position to prevent orthostatic hypotension (OH) in older adults. DESIGN: Case-control study. SETTING: Division of Physical Medicine and Rehabilitation, Salvatore Maugeri Foundation, Scientific Institute of Veruno, Veruno, Italy. PARTICIPANTS: Individuals aged 65 and older admitted with degenerative joint disease screened (n = 90) and found positive for OH (n = 42). MEASUREMENTS: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were recorded using an automatic oscillometric device in the supine position after 10 minutes of bed rest; immediately upon standing up; and after 1, 3 and 5 minutes standing. In 42 participants, a fall in SBP of 20 mmHg or more within 3 minutes of standing was found. Participants with OH were alternately assigned to the control or exercise group. The following day, both groups were reassessed as above. In the exercise group, before standing up, participants were required to perform 10 full extensions of the lower limbs, starting from 60 degrees flexion of hip and 90 degrees flexion of knee and ankle joints, against the resistance of an elastic band. RESULTS: In both participant groups, SBP, DBP, and HR were similar in the supine position. When standing, the same decrease in SBP and DBP and increase in HR occurred over a similar time-course in both participant groups. The next day, the reduction in SBP was significantly smaller at each time interval after standing up in the exercise than in the control group, but no difference between the exercise and control groups was observed in DBP or HR. CONCLUSION: Supine leg exercise is effective in reducing an initial fall in SBP when passing from a supine to an upright position in older adults. The duration of the effect requires further investigation. PMID- 23750852 TI - Degradation rate of mitochondrial proteins in Arabidopsis thaliana cells. AB - The turnover of the proteomes of organelles in plant cells are known to be governed by both whole cell and organelle-specific processes. However, the rate and specificity of this protein turnover has not been explored in depth to understand how it affects different organellar processes. Here we have used progressive 15N labeling of Arabidopsis cells, and focused on the turnover rate of proteins in mitochondria. We provide estimates of degradation rate (K(d)) for 224 mitochondrial proteins, showing a range of over 50-fold in K(d). Protein complexes, most notably the respiratory chain complexes, had K(d) values that were generally coordinated and we have interpreted these measurements to outline how protein K(d) differs within protein complexes and between functional categories. The fastest turnover rates were reported for DNA/RNA metabolism enzymes, chaperones, and proteases. PMID- 23750851 TI - Cryptic B cell response to renal transplantation. AB - Transplantation reliably evokes allo-specific B cell and T cell responses in mice. Yet, human recipients of kidney transplants with normal function usually exhibit little or no antibody specific for the transplant donor during the early weeks and months after transplantation. Indeed, the absence of antidonor antibodies is taken to reflect effective immunosuppressive therapy and to predict a favorable outcome. Whether the absence of donor-specific antibodies reflects absence of a B cell response to the donor, tolerance to the donor or immunity masked by binding of donor-specific antibodies to the graft is not known. To distinguish between these possibilities, we devised a novel ELISPOT, using cultured donor, recipient and third-party fibroblasts as targets. We enumerated donor-specific antibody-secreting cells in the blood of nine renal allograft recipients with normal kidney function before and after transplantation. Although none of the nine subjects had detectable donor-specific antibodies before or after transplantation, all exhibited increases in the frequency of donor-specific antibody-secreting cells eight weeks after transplantation. The responses were directed against the donor HLA-class I antigens. The increase in frequency of donor-specific antibody-secreting cells after renal transplantation indicates that B cells respond specifically to the transplant donor more often than previously thought. PMID- 23750853 TI - Systemic perspective of violence and aggression in mental health care: towards a more comprehensive understanding and conceptualization: part 2. AB - This is the second of a two part paper which seeks to explore a wide range of phenomena that have been found to have an association with aggression and violence (A/V) in inpatient mental health care, synthesize these propositions according to fit or congruence into a systemic model of A/V, explore the empirical evidence pertaining to these propositions, and begin to consider application of this model to better inform our individual and/or organizational responses to A/V in mental health care. The systemic model is comprised of four thematic categories with part two of the paper focusing on the final two categories: mental health-care system-related phenomena and clinician-related phenomena. The paper then discusses a number of implications arising out of embracing a more systemic model of A/V in mental health care. In broadening our understanding to include all the phenomena that contribute increased risk of A/V incidents, we are able to move away from inaccurate views that disproportionately assign 'responsibility' to clients for causing A/V when the evidence indicates that the client-related phenomena may only account for a small portion of these incidents. PMID- 23750855 TI - Synergism of lacosamide with established antiepileptic drugs in the 6-Hz seizure model in mice. AB - PURPOSE: Lacosamide (LCM, Vimpat) is an anticonvulsant with a unique mode of action. This provides lacosamide with the potential to act additively or even synergistically with other antiepileptic drugs (AEDs). The objective of this study was to determine the presence of such interactions by isobolographic analysis. METHODS: The anticonvulsant effect of LCM in combination with other AEDs including carbamazepine (CBZ), phenytoin (PHT), valproate (VPA), lamotrigine (LTG), topiramate (TPM), gabapentin (GBP), and levetiracetam (LEV) at fixed dose ratios of 1:3, 1:1, and 3:1, was evaluated in the 6-Hz-induced seizure model in mice. In addition, the impact of the combinations of LCM with the other AEDs on motor coordination was assessed in the rotarod test. Finally, AED concentrations were measured in blood and brain to evaluate potential pharmacokinetic drug interactions. KEY FINDINGS: All studied AEDs produced dose-dependent anticonvulsant effects against 6-Hz-induced seizures. Combinations of LCM with CBZ, LTG, TPM, GBP, or LEV were synergistic. All other LCM/AED combinations displayed additive effects with a tendency toward synergism. Furthermore, no enhanced adverse effects were observed in the rotarod test by combining LCM with other AEDs. No pharmacokinetic interactions were seen on brain AED concentrations. Coadministration of LCM and TPM led to an increase in plasma levels of LCM, whereas the plasma concentration of PHT was increased by coadministration of LCM. SIGNIFICANCE: The synergistic anticonvulsant interaction of LCM with various AEDs, without exacerbation of adverse motor effects, highlights promising properties of LCM as add-on therapy for drug refractory epilepsy. PMID- 23750856 TI - Imaging of hemoglobin oxygen saturation ratio in the face by spectral camera and its application to evaluate dark circles. AB - BACKGROUND: Contact-type spectrophotometers have been widely used to measure skin color to determine the color values and melanin and hemoglobin contents. Recently, a spectral camera was introduced to evaluate two-dimensional color distribution. However, its application to skin color measurement has been limited. METHODS: The original spectral imaging system developed for facial skin consisted of a spectral camera and an original lighting unit for uniform irradiation of the face. The distribution of skin chromophores in the face, including melanin and oxy- and deoxyhemoglobin, was calculated from the reflectance data for each pixel of the spectral images. In addition, to create a mean spectral image of the group, a face morphing technology for spectral data was proposed. Using the system, we determined the characteristics of the dark circles around the eyes and also evaluated the effects of an anti-dark circle cosmetic. RESULTS: This system enabled the sensitive detection of skin chromophores in the face. Melanin content increased and hemoglobin oxygen saturation ratio decreased locally in the infraorbital areas of women with dark circles compared with those of women without dark circles. In addition, we were able to detect improvement in the dark circles after 6 weeks' use of anti-dark circle cosmetic products by visualizing the distribution of the relative concentrations of melanin and hemoglobin oxygen saturation ratio. CONCLUSION: Using a spectral camera, we developed a non-contact image-processing system that was capable of capturing a wide area of the face to visualize the distribution of the relative concentrations of skin chromophores in the face. PMID- 23750857 TI - The experiences, coping mechanisms, and impact of death and dying on palliative medicine specialists. AB - OBJECTIVES: Research on the experiences, coping mechanisms, and impact of death and dying on the lives of palliative medicine specialists is limited. Most research focuses on the multidisciplinary team or on nurses who work with the dying. Fewer studies consider medical professionals trained in palliative medicine. This study aimed to explore the experiences, coping mechanisms, and impact of death and dying on palliative medicine specialists when dealing with their patients at the end of life. METHODS: A qualitative research approach guided the study, one-on-one interview data were analyzed thematically. A purposeful sampling technique was employed for participant recruitment. Seven palliative medicine specialists practicing in one city participated in open ended, in-depth interviews. RESULTS: The analysis of participants' accounts identified three distinct themes. These were Being with the dying, Being affected by death, and dying and Adjusting to the impact of death and dying. SIGNIFICANCE OF RESULTS: This study further contributes to the understanding of the impact of death and dying on professionals who care for dying patients and their families. Despite the stressors and the potential for burnout and compassion fatigue, these participants employed strategies that enhanced meaning-making and emphasized the rewards of their work. However, the consequences of work stressors cannot be underestimated in the practice of palliative care. PMID- 23750859 TI - Health related quality of life across the perinatal period among Australian women. AB - AIMS AND OBJECTIVES: To investigate the significant features in health-related quality of life and to examine the changes over time during the perinatal period. BACKGROUND: Health-related quality of life during the perinatal period is significant for women. Screening or surveillance during the perinatal period is inconsistent and often not part of continued assessment. DESIGN: Prospective. METHODS: Setting involved antenatal clinics at three public hospitals in metropolitan Brisbane, Australia. A total of 363 participants out of a cohort of 605 women completed all items of the Short Form-12 Health Survey in late pregnancy and again at 6 and 12 weeks postpartum. RESULTS: There was a significant difference across the three perinatal time periods in all the health related quality-of-life subscales. Significant improvements were noted from late pregnancy to 6 weeks following childbirth and again at 12 weeks particularly in physical health, role physical, bodily pain, vitality, role emotional and mental health. Even when confounding variables such as maternal ages, partner status, parity, delivery type and ethnicity were introduced, significant improvements were noted. Maternal distress significantly related to almost all quality-of-life factors over time even when all possible confounding factors were controlled. CONCLUSION: Significant changes occur in health-related quality of life across the perinatal period. All dimensions of health-related quality of life except for social functioning and maternal distress showed marked improvement following childbirth. During this period, maternal distress was negatively related to health-related quality of life. RELEVANCE TO CLINICAL PRACTICE: Nurses need to be mindful of the broader view of health as encompassed in health-related quality-of life measures and the potential these have for alerting health professionals when providing care. More rigorous health assessment for mothers at risk is useful so that appropriate support and follow-up can be given. PMID- 23750858 TI - Evaluation of the contribution of the ATP binding cassette transporter, P glycoprotein, to in vivo cholesterol homeostasis. AB - P-glycoprotein (Pgp, encoded by ABCB1, commonly known as MDR1), an ATP-dependent transporter with a broad range of hydrophobic drug substrates, has been associated with the in vitro intracellular transport of cholesterol; however, these findings have not been confirmed in vivo. In this manuscript we tested the contributions of Pgp to in vivo cholesterol homeostasis by comparing the cholesterol phenotype of wild type mice with mice lacking both murine isoforms of Pgp (Abcb1a(-/-)/1b(-/-)) by measuring cholesterol absorption, circulating cholesterol, and lipoprotein cholesterol profiles. The mice were fed diets containing normal or high levels of dietary fat (25% vs 45% kcal from fat) and cholesterol (0.02% vs 0.20% w/w) for 8 weeks to challenge their capacity to maintain homeostasis. There were no significant differences in cholesterol absorption, circulating cholesterol levels, and lipoprotein profiles between Pgp knockout and wild type mice fed matching diets. Compensatory shifts were observed in the activation of two key transcription factors involved in maintaining cholesterol balance, the Liver X Receptor and SREBP-2, which may have maintained the wild type phenotype in the knockout mice. Deletion of Pgp affected the molar composition of gallbladder bile, when the mice were fed diets containing high levels of dietary fat, cholesterol, or both. The mole fraction of bile salts was reduced in the gallbladder bile of Pgp knockout mice, while the mole fraction of cholesterol was increased. In this paper, we provide evidence that Pgp knockout mice maintain cholesterol homeostasis, even when challenged with high cholesterol diets. We suggest that the specific shifts in cholesterol regulatory networks identified in the jejunum and liver of the knockout mice may have compensated for the lack of Pgp. Our finding that Pgp knockout mice were unable to maintain gallbladder bile composition when challenged with high dietary fat and/or cholesterol compliments recent reports that Pgp may be a secondary bile salt export pump. PMID- 23750860 TI - Effectiveness of modular CBT for child anxiety in elementary schools. AB - Most randomized controlled trials of cognitive-behavioral therapy (CBT) for children with anxiety disorders have evaluated treatment efficacy using recruited samples treated in research settings. Clinical trials in school settings are needed to determine if CBT can be effective when delivered in real world settings. This study evaluated a modular CBT program for childhood anxiety disorders in two elementary schools. Forty children (5-12 years old) with anxiety disorders, referred by teachers and school staff, were randomly assigned to modular CBT or a 3-month waitlist. Clinicians worked with individual families as well as teachers and school staff. Evaluators blind to treatment condition conducted structured diagnostic interviews and caregivers and children completed symptom checklists at pre- and posttreatment. The primary study outcome, the Clinical Global Impressions-Improvement scale, yielded a positive treatment response at posttreatment for 95.0% of CBT participants, as compared with only 16.7% of the waitlist participants. CBT also outperformed the waitlist on diagnostic outcomes and caregiver-report measures of anxiety. Treatment effects did not extend beyond anxiety diagnoses and symptoms. Results suggest that modular CBT delivered within the elementary school setting may be effective for the treatment of child anxiety disorders. A replication of the study results with a larger sample is indicated. PMID- 23750861 TI - Networks of professional supervision. AB - An ecological analysis of the supervisory activity of 31 New Zealand school psychologists examined simultaneously the theories of school psychology, supervision practices, and the contextual qualities that mediated participants' supervisory actions. The findings indicated that the school psychologists worked to achieve the supervision goals of support, knowledge, and accountability through reciprocal interaction in multiple relationships within and outside of their professional community. With the notion of supervision broadened to include all activity undertaken to meet the supervisory goals, greater levels of participation and satisfaction with supervisory provision were shown than in many previous studies. The school psychologists utilized various opportunities for supervision support in their day-to-day practice rather than relying solely on traditional dyadic or fixed-group forms. Supervision practices of the school psychologists were situated within the activity of a networked community of supervision practice. Implications for conceptualizing supervision as a broad, situated activity are discussed. PMID- 23750862 TI - Prognostic factors affecting disease-specific survival in patients with recurrent and/or metastatic differentiated thyroid carcinoma detected by positron emission tomography/computed tomography. AB - AIM: We aimed to analyze the prognostic factors affecting disease-specific survival in patients with recurrent and/or metastatic differentiated thyroid carcinoma. METHODS: Seventy-seven patients with recurrent/metastatic differentiated thyroid carcinoma who were previously treated with total thyroidectomy followed by radioactive iodine therapy were enrolled. Recurrent/metastatic disease was detected by positron emission tomography/computed tomography. At the time of last follow-up (mean 4.8+/-1.3 years), patients were grouped as having (i) clinical remission (n=17), (ii) stable disease (n=22), or (iii) progressive disease (n=38). We retrospectively examined the prognostic impact of clinical factors (age, sex, TNM stage), histopathological factors of the primary tumor (tumor size, histology, the presence of vascular invasion, extrathyroidal spread, and lymph node metastasis), serum thyroglobulin levels, and metabolic parameters of recurrent/metastatic disease such as radioactive iodine avidity, F18-fluorodeoxyglucose uptake (SUVmax) in metastatic deposits, number and location of F18-fluorodeoxyglucose avid lesions (locoregional vs. distant), and the impact of surgery on disease specific survival. RESULTS: Lack of vascular invasion (p=0.04), presence of surgically amenable recurrence/metastasis (p=0.0001), and suppressible on-therapy serum thyroglobulin levels at the time of recurrent/metastatic disease (p=0.01) were strong predictors of clinical remission and good prognosis on multivariate analysis. Lesional SUVmax, number or location of F18-fluorodeoxyglucose-avid lesions, and TNM stage did not correlate with clinical outcome. Clinical remission could only be achieved by curative surgery. Patients without curative surgery for recurrence/metastasis had a 43 times higher risk to develop progressive disease than patients with disease amenable to surgery. CONCLUSIONS: Curative surgery is an essential therapeutic modality to achieve clinical remission in metastatic/recurrent differentiated thyroid carcinoma. Positron emission tomography/computed tomography is a powerful method to detect surgically resectable disease for the selection of patients who may benefit from curative surgery. PMID- 23750863 TI - High incidence of Japanese encephalitis, southern China. PMID- 23750864 TI - Empowering patients to determine their own health goals. PMID- 23750866 TI - EURIPA-EURACT: Medical education in rural practice improves quality of care and can attract more physicians to enter rural practice. PMID- 23750868 TI - IPCRG: INTERNATIONAL PRIMARY CARE RESPIRATORY GROUP: Respiratory News from the IPCRG. PMID- 23750871 TI - Preparation of microfibrillated cellulose/chitosan-benzalkonium chloride biocomposite for enhancing antibacterium and strength of sodium alginate films. AB - The nonantibacterial and low strength properties of sodium alginate films negatively impact their application for food packaging. In order to improve these properties, a novel chitosan-benzalkonium chloride (C-BC) complex was prepared by ionic gelation using tripolyphosphate (TPP) as a coagulant, and a biocomposite obtained through the adsorption of C-BC complex on microfibrillated cellulose, MFC/C-BC, was then incorporated into a sodium alginate film. The TEM image showed that the C-BC nanoparticles were spherical in shape with a diameter of about 30 nm, and the adsorption equilibrium time of these nanoparticles on the surface of MFC was estimated to be 6 min under the driving forces of hydrogen bonds and electrostatic interactions. According to the disc diffusion method, the MFC/C-BC biocomposite-incorporated sodium alginate film exhibited remarkable antibacterial activity against Staphylococcus aureus and certain antibacterial activity against Escherichia coli . The strength tests indicated that the tensile strength of the composite sodium alginate film increased about 225% when the loading of MFC/C-BC biocomposite was 10 wt %. These results suggested that the MFC/C-BC biocomposite incorporated sodium alginate film with excellent antibacterial and strength properties would be a promising material for food packaging, and the MFC/C-BC may also be a potential multifunctional biocomposite for other biodegradable materials. PMID- 23750872 TI - Hepatotoxicity from anabolic androgenic steroids marketed as dietary supplements: contribution from ATP8B1/ABCB11 mutations? AB - BACKGROUND: Though possession of androgenic anabolic steroids (AAS) is illegal, non-prescription use of AAS persists. METHODS: We describe two Caucasian males (aged 25 and 45 years) with cholestatic hepatitis following ingestion of the dietary supplement Mass-Drol ('Celtic Dragon') containing the AAS 2alpha-17alpha dimethyl-etiocholan-3-one,17beta-ol. RESULTS: Despite substantial hyperbilirubinaemia peak gamma-glutamyl transferase (GGT) remained normal. Besides 'bland' intralobular cholestasis, liver biopsy in both found deficiency of canalicular expression of ectoenzymes as seen in ATP8B1 disease. In the older patient, bile salt export pump marking (encoded by ABCB11) was focally diminished. We hypothesized that AAS had either induced inhibition of normal ATP8B1/ABCB11 expression or triggered initial episodes of benign recurrent intrahepatic cholestasis (BRIC) type 1/or 2. On sequencing, ATP8B1 was normal in both patients although the younger was heterozygous for the c.2093G>A mutation in ABCB11, a polymorphism previously encountered in drug-induced liver injury. CONCLUSION: AAS marketed as dietary supplements continue to cause hepatotoxicity in the UK; underlying mechanisms may include unmasking of genetic cholestatic syndromes. PMID- 23750873 TI - Management strategies and medication use for treating paediatric patients with concussions. AB - AIM: To assess management strategies for paediatric patients suffering from concussions. METHODS: A 17-item questionnaire was distributed to 1305 section members of the American Academy of Pediatrics Sections on Adolescent Health, Sports Medicine and Fitness, Community Pediatrics and School Health. The use of medications, neuropsychological testing, neuroimaging and published guidelines in concussion management was queried. RESULTS: Two hundred and twenty respondents (17%) completed the questionnaire, of which 64% had been an attending for greater than 10 years. A majority of respondents (92%) managed patients with concussions, with 26% treating more than 24 patients per year. Most paediatricians (84%) reported using a published guideline. The majority of respondents (89%) manage the symptoms of concussed patients with medications, most commonly acetaminophen (62%) or nonsteroidal anti-inflammatory medications (54%). The use of prescriptions medications such as tricyclic antidepressants (23%), amantadine (10%) and methylphenidate (8%) was also commonly reported. Paediatricians treating >16 patients per year with concussion were more likely to prescribe tricyclic antidepressants, stimulants and agents used for sleep disturbance. CONCLUSION: Paediatricians nationwide routinely use medications when managing patients with concussions. The pharmacological agents used differ according to number of patients treated per year. In addition, most paediatricians use published guidelines in concussion management. PMID- 23750874 TI - Housing type and depressive symptoms among older adults: a test of sense of belonging as a mediating and moderating variable. AB - OBJECTIVES: Higher levels of depression have been documented among older adults who reside in an assisted living facility, compared with those who remain in their own homes. The aims of the current study were to test whether the relationship between housing type and depressive symptoms was mediated by a sense of belonging and whether housing type and sense of belonging interact to influence the depressive symptoms among older adults (moderation model). METHOD: A sample of 257 older adults who lived in their own homes and 166 older adults who lived in an assisted living facility completed the psychological subscale of the Sense of Belonging Instrument and the Center for Epidemiologic Studies Depression Scale. RESULTS: Results showed that a sense of belonging partially mediated the relationship between housing type and depressive symptoms, such that living in a nursing home was associated with lower levels of belonging, and lower levels of belonging were, in turn, associated with higher levels of depressive symptoms. Residing in an assisted living facility was associated with depressive symptoms at low and average levels of belonging. CONCLUSION: Results highlight the need for more research on the role of sense of belonging as an influencing factor on depressive symptoms among institutionalised older adults for both theoretical and treatment goals. PMID- 23750875 TI - Consequences of switching from prophylactic treatment to on-demand treatment in late teens and early adults with severe haemophilia A: the TEEN/TWEN study. AB - Although many people with haemophilia discontinue prophylaxis in their late teens or early adulthood, the consequences of this decision are largely not known. This 18-month, observational, case-controlled, multicentre study evaluated long-term prophylaxis and the consequences of switching from prophylaxis to on-demand treatment in late teens and young adults with severe haemophilia A. Participants with haemophilia (aged 14-29 years) on prophylaxis >= 60% of the time for the 5 years before study entry were enrolled into 1 of 2 prospective or 1 retrospective group. Group 1 was prophylaxis, group 2 had voluntarily discontinued prophylaxis <= 12 months before study entry and group 3 had voluntarily discontinued prophylaxis >= 13 months before study entry. Assessments included bleeding frequency (primary endpoint), Haemo-QoL-A health-related quality of life (HRQoL) scores, Gilbert score, development of target joints, Haemophilia Activities List, Godin Leisure-Time, treatment satisfaction and State-Trait Anxiety Inventory (secondary and exploratory endpoints). Descriptive statistics were provided for all variables. Thirty-eight participants (group 1, n = 22; group 2, n = 5; group 3, n = 11; median age, 19.5 years) were enrolled. The median annualized number of bleeding events was 0, 4.8 and 24 in groups 1, 2 and 3 respectively. HRQoL was lower in participants who discontinued prophylaxis vs. those who remained on prophylaxis. Changes in the remaining secondary and exploratory variables were small, but were generally worse in participants who discontinued prophylaxis. Following a switch from prophylaxis to on-demand therapy, the number of bleeding events increased and HRQoL worsened in late teens and young adults with severe haemophilia A. PMID- 23750876 TI - Haemorrhagic purpura in an elderly man. BHD. AB - You are asked to review an 85 year old man with bullous lesions on the torso and limbs (as shown), which developed after treatment with low-molecular weight heparin (LMWH), unfractionated heparin (UFH), and furosemide. Based on the given history and the clinical and histological images, what is your diagnosis? PMID- 23750877 TI - A deletion in the wapB promoter in many serotypes of Pseudomonas aeruginosa accounts for the lack of a terminal glucose residue in the core oligosaccharide and resistance to killing by R3-pyocin. AB - Pseudomonas aeruginosa is an opportunistic human pathogen producing a variety of virulence factors. One of them is lipopolysaccharide, consisting of endotoxic lipid A and long-chain O-antigen polysaccharide, which are connected together through a short linker region, called core oligosaccharide. Chemical structures of the core oligosaccharide are well conserved, with one exception, in that certain strains of P. aeruginosa add a terminal glucose residue (Glc(IV) ) to core by a transferase reaction, due to the activity of a glucosyltransferase, WapB. Here, we investigated the regulation of wapB expression. Our results showed that while the majority of analysed genomes of P. aeruginosa contain wapB, many of these have a conserved identical 5-nucleotide deletion in the upstream region that inactivated the promoter. This deletion is within the -10 hexamer that is recognized by a principle sigma factor (RpoD, or sigma70) as proven by data from an electromobility shift assay. These results provide the molecular basis of why LPS core of many P. aeruginosa strains is lacking Glc(IV) . In addition, we show that absence of Glc(IV) due to an inactive wapB promoter confers resistance to killing by R3-pyocin, a phage tail-like bacteriocin of P. aeruginosa. PMID- 23750879 TI - Substituted (E)-2-oxo-3-butenoates: reagents for every enantioselectively catalyzed reaction. PMID- 23750878 TI - Association between steroid dosage and death with a functioning graft after kidney transplantation. AB - Death with a functioning graft remains a major challenge following kidney transplantation. Steroid dosing may be a modifiable risk factor. Collaborative Transplant Study (CTS) data were analyzed to assess the relationship between long term steroid dose and death with function during years 2-5 posttransplant in 41 953 adult recipients of a deceased-donor kidney transplant during 1995-2010. Steroid dose at year 1 correlated significantly with death with function overall, and with death due to cardiovascular disease or infection (all p < 0.001). In patients with optimal graft function (serum creatinine <130 umol/L) and no anti rejection treatment during (a) year 1 (b) years 1 and 2, these significant associations remained (all p < 0.001). The center-specific incidence of steroid withdrawal during year 2 showed a significant inverse association with death due to cardiovascular disease (p < 0.001) or infection (p < 0.001) overall, and within the subpopulation with good graft function and no rejection during year 1 (p = 0.002 and p < 0.001, respectively). Maintenance steroid dose shows a highly significant association with death with a functioning graft caused by cardiovascular disease or infection during years 2-5 after kidney transplantation, even in patients with good graft outcomes in whom steroid treatment would appear to be unnecessary. PMID- 23750880 TI - Characterization of Chinese body skin through in vivo instrument assessments, visual evaluations, and questionnaire: influences of body area, inter-generation, season, sex, and skin care habits. AB - BACKGROUND/PURPOSE: The varying influence of multiple factors (e.g., aging, sex, season, skin care habits) on skin structure and function necessitates study within ethnic groups to fully characterize their skin. METHODS: Men and women aged 40-50 years (n = 43) and their consanguineous same-sex children, aged 18-25 years (n = 43), living in Chengdu, China were enrolled in this single center, non interventional study. Volunteers attended two study visits (summer, 2010 and winter, 2011) at which dermatologists measured transepidermal water loss (TEWL), skin hydration, sebum secretion, fine lines/roughness, melanin/erythema, temperature, and color, and clinically graded participants' skin. Participants answered a questionnaire, indicating their perceived skin type/condition. Data were analyzed using t-test/anova or Friedman/Wilcoxon test. RESULTS: Objective measurements demonstrated statistically significant inter-generational differences in skin condition, with aged skin more wrinkled at most sites, having reduced oil/colder facial and decolletage skin, darker/more erythematous skin in exposed areas, and less hydrated/rougher heel skin; similarities were detected in skin melanin, erythema, and TEWL. There were also statistically significant differences between seasons and sexes. The intersection between instrument measurements and subjective perceptions of skin revealed notable differences. CONCLUSION: Objective measurements and their intersection with subjective perceptions demonstrate the influences of inter-generation, season, sex, and living habits on Chinese body skin. PMID- 23750881 TI - Systemic perspective of violence and aggression in mental health care: towards a more comprehensive understanding and conceptualization: part 1. AB - Aggression and violence (A/V) in mental health care are all too frequent occurrences; they produce a wide range of deleterious impacts on the individual client, staff, organizations, and the broader community. A/V is a multifaceted and highly-complex problem, and is associated empirically with a wide range of phenomena. However, most attempts to reduce A/V in mental health care have invariably focused on one or two aspects of the problem at the expense of a more comprehensive, systemic approach; these have produced inconclusive results. As a result, this two-part paper seeks to: (i) recognize the wide range of phenomena that have been found to have an association with A/V in mental health care; (ii) synthesize these propositions according to fit or congruence into a systemic model of A/V; (iii) explore empirical evidence pertaining to these propositions; and (iv) begin to consider the application of this model to better inform our individual and/or organizational responses to A/V in mental health care. The paper advances a systemic model of these phenomena comprised of four thematic categories, with Part 1 of this paper focusing on the first two categories: environmental and intrapersonal (client-related) phenomena. PMID- 23750882 TI - Sodium-centered dodecanuclear Co(II) and Ni(II) complexes with 2 (phosphonomethylamino)succinic acid: studies of spectroscopic, structural, and magnetic properties. AB - Two new isostructural cobalt(II) and nickel(II) polynuclear complexes with 2 (phosphonomethyl)aminosuccinic acid, H4PMAS, namely, Na[Co12(PMAS)6(H2O)17(OH)].x2H2O, 1.x2H2O, and Na[Ni12(PMAS)6(H2O)17(OH)].xH2O, 2.xH2O, have been synthesized for the first time from aqueous solutions and studied by single crystal X-ray diffraction, infrared, and UV-visible diffuse reflectance spectroscopy; TG/DTA analysis; and magnetochemistry. Both 1 and 2 crystallize in the rhombohedral crystal system with the R3[overline] space group with 1/6 of the Co12(PMAS)6 or Ni12(PMAS)6 moieties in the asymmetric unit. The X ray refinements reveal the presence of 18 water sites, but unit cell charge balance requires that one water molecule must be an OH(-) anion, an anion which is disordered over the 18 sites. The PMAS(4-) ligand forms two five-membered and one six-membered chelation ring. Both 1 and 2 contain 24-membered metallacycles as a result of the bridging nature of the PMAS(4-) ligands. The resulting three dimensional structures have one-dimensional channels with a sodium cation at the center of symmetry. The temperature dependence of the magnetic susceptibility reveals the presence of weak antiferromagnetic exchange coupling interactions in both 1 and 2. Two exchange coupling constants, J1 = -15.3(7) cm(-1) and J2 = 1.06(2) cm(-1) with S1 = S2 = 3/2 for the Co(1)...Co(1) and Co(1)...Co(2) exchange pathways, respectively, are required for 1, and J1 = -1.17(6) cm(-1) and J2 = -4.00(8) cm(-1) with S1 = S2 = 1 for the Ni(1)...Ni(1) and Ni(1)...Ni(2) exchange pathways, respectively, are required for 2, in order to fit the temperature dependence of the observed magnetic susceptibilities. PMID- 23750883 TI - Mixed monolayer of DPPC and lysine-based cationic surfactants: an investigation into the antimicrobial activity. AB - In this paper, we report studies which aim to elucidate the mechanisms involved in the antimicrobial activity of three cationic lysine-based surfactants: LLM, LALM, and C6 (LL)2. To this end, a simple membrane model (i.e., 1,2-dipalmitoyl sn-phosphatidylcholine, DPPC) was used to explore the monolayer properties at the air/liquid interface. Compression pi-A isotherms of mixtures of DPPC/lysine surfactants at different pH showed an expansion of the DPPC monolayer, suggesting cationic lysine surfactant/DPPC interactions, which strongly depend on surfactant structure and hydrophobic interactions. Antimicrobial activity of the three surfactants has also been assessed with transmission electron microscopy, observing the effects on Staphylococcus aureus and Escherichia coli . The three surfactants caused various kinds of damage to the bacteria tested, such as structural alterations, leakage of internal material, and cell destruction. PMID- 23750884 TI - Prevalence and characteristics of children with mild intellectual disability in a French county. AB - BACKGROUND: Studies conducted on mild intellectual disability (MID) in children are infrequent and the prevalence rates vary widely. This study aimed to estimate the prevalence of MID in children in a French county (Isere), to describe the clinical signs and associated comorbidities, and to specify the aetiologies of this disability. METHODS: The target population was comprised of the 15 100 children born in 1997 residing in Isere County, France, in 2008. Our goal was to find the children in this group with MID diagnosed between 9 and 13 years of age. MID was defined as an overall IQ score of between 50 and 69 [International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10)]; this definition was adjusted for the study by integrating confidence intervals so that the risk of IQ measurement relativity and possible discrepancy of scores could be taken into account. Children were identified through an administrative data source designed to assist disabled persons that contains health information, and an educational data source. Parents who agreed to let their children participate responded to an in-depth questionnaire on their child's medical and academic history. A genetic investigation was proposed for those children whose MID had an unknown aetiology. RESULTS: The preliminary selection included 267 children, resulting in a prevalence rate of 18 per 1000 (CI [15.6; 19.9]), within the expected mean. Of these 267 cases, 181 families agreed to participate in the study (68%). MID more often affected boys [male gender ratio = 1.4 (CI [1.2; 1.6])], low socioeconomic groups, and families with a history of intellectual disability. The clinical signs and comorbidities associated with MID were very frequent, with 54% spoken language disorders and 10% pervasive developmental disorder. Only 9% of the children had undergone a genetic investigation before the study. The known aetiology rate for MID was 19% among all the children who had had genetic tests performed. CONCLUSION: MID is an important public health issue based on its prevalence. The associated clinical signs and comorbidities may be warning signs of MID in case of learning difficulties. This study may help decision-makers to develop and organise screening and care for MID. PMID- 23750885 TI - Has the prevalence of cholesterol gallstones increased in Korea? A preliminary single-center experience. AB - OBJECTIVES: We aimed to determine the prevalence of cholesterol gallstones, the compositional changes of gallstones and its predisposing factors in Korea with this single-center study. METHODS: Data of 365 patients who underwent cholecystectomy for cholecystolithiasis from July 2008 to September 2011 were reviewed. Based on the compositional analysis of the gallstones, patients were assigned to either cholesterol gallstone group or pigment gallstone group. The characteristics of the patients and the gallstones were summarized and compared. RESULTS: After eight patients with mixed gallstones were excluded, 357 patients were enrolled in the study, including cholesterol gallstones in 175 (49.0%) and pigment gallstones in 182 (51.0%). The number of patients with cholecystolithiasis increased but the prevalence of cholesterol gallstone decreased with age. Compared with the pigment gallstone group, the cholesterol gallstone group was associated with young age (<50 years), female gender, obesity (body mass index >= 25 kg/m2) and the absence of chronic liver diseases. CONCLUSION: The relative prevalence of cholesterol gallstones in Korea has been stationary so far, but may change in the future since cholesterol gallstones are increasingly prevalent in the young generation. PMID- 23750886 TI - Dynamic guiding of motor-driven microtubules on electrically heated, smart polymer tracks. AB - Biomolecular motor systems are attractive for future nanotechnological devices because they can replace nanofluidics by directed transport. However, the lack of methods to externally control motor-driven transport along complex paths limits their range of applications. Based on a thermo-responsive polymer, we developed a novel technique to guide microtubules propelled by kinesin-1 motors on a planar surface. Using electrically heated gold microstructures, the polymers were locally collapsed, creating dynamically switchable tracks that successfully guided microtubule movement. PMID- 23750887 TI - Thyroid dysfunction as an unintended side effect of anticancer drugs. AB - BACKGROUND: Several of the currently used anticancer drugs may variably affect thyroid function, with impairment ranging from modified total but not free concentration of thyroid hormones to overt thyroid disease. SUMMARY: Cytotoxic agents seem to alter thyroid function in a relatively small proportion of adult patients. Anticancer hormone drugs may mainly alter serum levels of thyroid hormone-binding proteins without clinically relevant thyroid dysfunction. Old immunomodulating drugs, such as interferon-alpha and interleukin-2, are known to induce variably high incidence of autoimmune thyroid dysfunction. Newer immune checkpoint inhibitors, such as anti-CTLA4 monoclonal antibodies, are responsible for a relatively low incidence of thyroiditis and may induce secondary hypothyroidism resulting from hypophysitis. Central hypothyroidism is a well recognized side effect of bexarotene. Despite their inherent selectivity, tyrosine kinase inhibitors may cause high rates of thyroid dysfunction. Notably, thyroid toxicity seems to be restricted to tyrosine kinase inhibitors targeting key kinase-receptors in angiogenic pathways, but not other kinase-receptors (e.g., epidermal growth factor receptors family or c-KIT). In addition, a number of these agents may also increase the levothyroxine requirement in thyroidectomized patients. CONCLUSIONS: The pathophysiology of thyroid toxicity induced by many anticancer agents is not fully clarified and for others it remains speculative. Thyroid dysfunction induced by anticancer agents is generally manageable and dose reduction or discontinuation of these agents is not required. The prognostic relevance of thyroid autoimmunity, overt and subclinical hypothyroidism induced by anticancer drugs, the value of thyroid hormone replacement in individuals with abnormal thyrotropin following anticancer systemic therapy, and the correct timing of replacement therapy in cancer patients need to be defined more accurately in well-powered prospective clinical trials. PMID- 23750888 TI - Communication between filamentous pathogens and plants at the biotrophic interface. AB - Fungi and oomycetes that colonize living plant tissue form extensive interfaces with plant cells in which the cytoplasm of the microorganism is closely aligned with the host cytoplasm for an extended distance. In all cases, specialized biotrophic hyphae function to hijack host cellular processes across an interfacial zone consisting of a hyphal plasma membrane, a specialized interfacial matrix, and a plant-derived membrane. The interface is the site of active secretion by both players. This cross talk at the interface determines the winner in adversarial relationships and establishes the partnership in mutualistic relationships. Fungi and oomycetes secrete many specialized effector proteins for controlling the host, and they can stimulate remarkable cellular reorganization even in distant plant cells. Breakthroughs in live-cell imaging of fungal and oomycete encounter sites, including live-cell imaging of pathogens secreting fluorescently labeled effector proteins, have led to recent progress in understanding communication across the interface. PMID- 23750889 TI - Associations between insulin-like growth factor I, vascular endothelial growth factor and its soluble receptor 1 in umbilical serum and endothelial cells obtained from normotensive and preeclamptic pregnancies. AB - The aim of this study was to investigate the associations between insulin-like growth factor I (IGF-I) with vascular endothelial growth factor (VEGF) and its soluble receptor 1 (sFlt-1) in umbilical serum and to study the effects of IGF-I upon sFlt-1 synthesis in human umbilical vein endothelial cells (HUVEC) in normotensive (NT) and preeclamptic (PE) pregnancies. As compared with the NT group, umbilical serum IGF-I and VEGF levels were lower in the PE group, while sFlt-1 concentrations were higher. Levels of sFlt-1 correlated with IGF-I in the NT group and with VEGF in the PE group. Basal concentration of sFlt-1 in HUVEC culture media was higher in the PE group. IGF-I stimulated sFlt-1 synthesis only in the NT group. In summary, umbilical serum sFlt-1 is associated with IGF-I in normotensive pregnancy and with VEGF in preeclampsia. IGF-I stimulates sFlt-1 synthesis in endothelial cells in normotensive but not in PE pregnancies. PMID- 23750891 TI - Expression, purification, and lipolytic activity of recombinant human serum albumin fusion proteins with one domain of human growth hormone in Pichia pastoris. AB - Human growth hormone (hGH) can mobilize lipid and inhibit the synthesis of triglycerides. However, it is not a potentially useful drug for treating obesity because it has many other actions resulting in several side effects. Here, we report a novel approach to develop the lipolytic function of hGH. The amino terminus of hGH was replaced by an inactive protein so that the actions unrelated to lipolytic function would be avoided. The fusion genes encoding human serum albumin (HSA) and lipolytic domain of hGH were constructed and expressed in Pichia pastoris. The recombinant proteins were purified and characterized by SDS PAGE and Western blot. The preliminary stability tests demonstrated that HSA hGH166-191 and HSA-hGH177-191 were stable at different pH levels after four days at 37 degrees C. Lipolytic activity assay revealed that fusion proteins could increase the amounts of glycerol released from the isolated adipocytes. The HSA fusion proteins constructed in this work can be further developed as antiobesity agents. PMID- 23750892 TI - Incidence and outcome of pancreatitis in children and young adults with acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003. PMID- 23750890 TI - Polymicrogyria-associated epilepsy: a multicenter phenotypic study from the Epilepsy Phenome/Genome Project. AB - PURPOSE: Polymicrogyria (PMG) is an epileptogenic malformation of cortical development. We describe the clinical epilepsy and imaging features of a large cohort with PMG-related epilepsy. METHODS: Participants were recruited through the Epilepsy Phenome/Genome Project, a multicenter collaborative effort to collect detailed phenotypic data on individuals with epilepsy. We reviewed phenotypic data from participants with epilepsy and PMG. KEY FINDINGS: We identified 87 participants, 43 female and 44 male, with PMG and epilepsy. Median age of seizure onset was 3 years (range <1 month to 37 years). Most presented with focal epilepsy (87.4%), some in combination with seizures generalized from onset (23.0%). Focal seizures with dyscognitive features were most common (54.3%). Of those presenting with generalized seizure types, infantile spasms were most prevalent (45.2%). The most common topographic pattern was perisylvian PMG (77.0%), of which the majority was bilateral (56.7%). Generalized PMG presented with an earlier age of seizure onset (median age of 8 months) and an increased prevalence of developmental delay prior to seizure onset (57.1%). Of the unilateral, and asymmetric bilateral groups where PMG was more involved in one hemisphere, the majority (71.4%) of participants had seizures that lateralized to the same hemisphere as the PMG or the hemisphere with greater involvement. SIGNIFICANCE: Participants with PMG had both focal and generalized onset of seizures. Our data confirm the involvement of known topographic patterns of PMG and suggest that more extensive distributions of PMG present with an earlier age of seizure onset and increased prevalence of developmental delay prior to seizure onset. PMID- 23750893 TI - Decomposition pathways and rates of human urine in soils. AB - This study proposes a comprehensive reaction network of the soil microbial breakdown of the main compounds in human urine to the end products NH3 and NH4+. A reactive model was developed and parameters were determined against experimental data. The model was used to assess the amount and release rate of NH3 and NH4+ in a soil control volume flushed with (i) pulses of urine at various dilutions and (ii) a continuous flow of urine at various dilutions and flow rates. In scenario i, 90% of incoming organic nitrogen was converted to NH3 and NH4+ between 5 and 20 days from application at rates strongly dependent on the initial microbial soil content. Urea and hippuric acid were largely correlated to NH3 and NH4+ release, whereas microbial functional groups in the same scenarios were poorly correlated with NH3 and NH4+ release. In scenario ii, 90% conversion was generally reached for low flow rates and was highly nonlinear with the dilution. Finally, a stochastic analysis showed that urine decomposition was more sensitive to uncertainty in microbial growth rate parameters than half-saturation concentrations. PMID- 23750894 TI - Effects of circadian phase and melatonin injection on anxiety-like behavior in nocturnal and diurnal rodents. AB - Animals show daily rhythms in most bodily functions, resulting from the integration of information from an endogenous circadian clock and external stimuli. These rhythms are adaptive and are expected to be related to activity patterns, i.e., to be opposite in diurnal and nocturnal species. Melatonin is secreted during the night in all mammalian species, regardless of their activity patterns. Consequently, in diurnal species the nocturnal secretion of melatonin is concurrent with the resting phase, whereas in nocturnal species it is related to an increase in activity. In this research, we examined in three diurnal and three nocturnal rodent species whether a daily rhythm in anxiety-like behavior exists; whether it differs between nocturnal and diurnal species; and how melatonin affects anxiety-like behavior in species with different activity patterns. Anxiety-like behavior levels were analyzed using the elevated plus maze. We found a daily rhythm in anxiety-like behavior and a significant response to daytime melatonin administration in all three nocturnal species, which showed significantly lower levels of anxiety during the dark phase, and after melatonin administration. The diurnal species showed either an inverse pattern to that of the nocturnal species in anxiety-like behavior rhythm and in response to daytime melatonin injection, or no rhythm and, accordingly, no response to melatonin. PMID- 23750895 TI - Sleep timing is more important than sleep length or quality for medical school performance. AB - Overwhelming evidence supports the importance of sleep for memory consolidation. Medical students are often deprived of sufficient sleep due to large amounts of clinical duties and university load, we therefore investigated how study and sleep habits influence university performance. We performed a questionnaire-based study with 31 medical students of the University of Munich (second and third clinical semesters; surgery and internal medicine). The students kept a diary (in 30-min bins) on their daily schedules (times when they studied by themselves, attended classes, slept, worked on their thesis, or worked to earn money). The project design involved three 2-wk periods (A: during the semester; B: directly before the exam period--pre-exam; C: during the subsequent semester break). Besides the diaries, students completed once questionnaires about their sleep quality (Pittsburgh Sleep Quality Index [PSQI]), their chronotype (Munich Chronotype Questionnaire [MCTQ]), and their academic history (previous grades, including the previously achieved preclinical board exam [PBE]). Analysis revealed significant correlations between the actual sleep behavior during the semester (MS(diary); mid-sleep point averaged from the sleep diaries) during the pre-exam period and the achieved grade (p = 0.002) as well as between the grades of the currently taken exam and the PBE (p = 0.002). A regression analysis with MS(diary) pre-exam and PBE as predictors in a model explained 42.7% of the variance of the exam grade (effect size 0.745). Interestingly, MS(diary)- especially during the pre-exam period-was the strongest predictor for the currently achieved grade, along with the preclinical board exam as a covariate, whereas the chronotype did not significantly influence the exam grade. PMID- 23750897 TI - Evidence for a relationship between chronotype and reproductive function in women. AB - There is evidence for the reciprocal interaction between circadian oscillation and reproduction, and disruption of circadian rhythms has been associated with impaired menstrual functions and reduced fertility in women. However, only little information is available on the relationship between reproduction and chronotype. The aim of the present study is to better assess this relationship. The participants (aged 25 to 74 yrs) were selected randomly from the Finnish Population Information System. The data from 2672 female participants of the National FINRISK Survey 2007 were analyzed to test the associations between chronotype (morning, intermediate, or evening) and reproductive features. Of the participants, 139 (5.6%) were evening, 1217 (48.7%) intermediate, and 1145 (45.8%) morning chronotypes. Among the participants aged 25 to 54 yrs, the duration of menstrual cycle was longer among evening chronotypes (28.8 +/- 4.4 d) than among morning (27.7 +/- 2.6 d; p < 0.01) and intermediate (27.8 +/- 3.3 d; p = 0.05) chronotypes. Significant correlations were found between the higher morningness-eveningness scores (the more of morning chronotype) and the shorter durations of menstrual bleeding, both in the whole sample (p < 0.001) and after limiting the analyses to women younger than 55 yrs (p < 0.05). In multivariable analyses on the whole sample, as compared with morning chronotypes, intermediate chronotypes had a significantly longer duration of menstrual bleeding (B = 0.160, 95% confidence interval [CI] = 0.044 to 0.276; p < 0.01) as well as a higher odds for difficulties in getting pregnant (odds ratio [OR] = 1.464, 95% CI = 1.118 to 1.917; p < 0.01). Our findings suggest that chronotype is related to the reproductive function in women. PMID- 23750898 TI - Two haemophilia patients with inhibitors who became ambulatory after physiotherapy under haemostatic cover with bypassing agents. PMID- 23750899 TI - Incidence of surgery related to problems with peri-implantitis: a retrospective study on patients followed up between 2003 and 2010 at one specialist clinic. AB - BACKGROUND: Little knowledge is available on incidence of patients treated for peri-implantitis problems in routine follow-up protocols. PURPOSE: The aim was to report the incidence, and clinical and radiographic characteristics related to routine follow-up patients who are surgically treated for peri-implantitis problems during 8 years of inclusion. MATERIALS AND METHODS: Patients with a history of peri-implantitis surgery were identified from patients examined on routine basis at one clinic (Branemark clinic) between January 2003 and December 2010. Data on included patients were retrospectively retrieved and reported from dental records and radiographs. RESULTS: On an average, 1,294 patients per year (SD 96) were followed up during inclusion period. Altogether, 134 patients had surgery related to peri-implantitis problems, corresponding to an average of 1.2% of followed-up patients per year. No prosthesis was completely lost, but altogether, 37 implants (6% of included implants) were removed in 34 patients (25%) during these surgical interventions. Peri-implantitis surgery was observed more often in the edentulous upper jaw (p < .05), and there was a tendency that surgery increased by time of follow-up. No significant differences were found between patients provided with machined or medium-rough implant surfaces. CONCLUSIONS: Incidence of peri-implantitis surgery was on an average 1.2% of followed-up patients per year during an 8 years period of inclusion. As no data were available on patient compliance, it could be assumed that the result may underscore the clinical need. Significantly, more edentulous upper jaws were included compared with other treated jaw situations. Data also indicated that the need for surgery may increase by time of follow-up, but no significant differences were observed between patients provided with machined and medium rough implant surfaces. PMID- 23750901 TI - The nurse's role in addressing unmet treatment and management needs of patients with rheumatoid arthritis: Delphi-based recommendations. AB - PURPOSE: Evaluate nurse's role in management of patients with rheumatoid arthritis (RA). METHODS: Modified Delphi with two rounds of questionnaires, followed by in-person meeting. International group of 12 nurses experienced with RA patients receiving biologic therapy. FINDINGS: Nurses often spend more time with patients than doctors do. Nurse is in unique position to explore patient needs; educate about treatment, administration, product storage, and self injection technique; determine readiness for and understanding of treatment; monitor safety and progress; and coordinate care within multidisciplinary setting. CONCLUSIONS: Nurse's role is complex and vitally important to optimal RA patient care. Additional nurse involvement may address unmet needs. IMPLICATIONS FOR NURSING PRACTICE: Rheumatology nurses can address unmet patient needs by expanding current roles and by adopting additional functions. PMID- 23750902 TI - Thermodynamic properties of solid binary antimonides. PMID- 23750904 TI - Analysis of the skin surface and inner structure around pores on the face. AB - BACKGROUND/PURPOSE: Facial pores do not appear to close again in old skin. Therefore, the tissue structure around the pore has been speculated to keep the pore open. To elucidate the reason for pore enlargement, we examined the relationship between the skin surface and inner skin structural characteristics in the same regions especially around the pore. METHODS: Samples of the skin surface were obtained from the cheek and examined using a laser image processor to obtain three-dimensional (3D) data. The inner structure of the skin was analyzed using in vivo confocal laser scanning microscopy (CLSM). RESULTS: The conspicuous pore not only had a concave structure but also a discontinuous convex structure on the skin surface surrounding the pore. Furthermore, CLSM image indicated that the skin inner structure developed a discontinuous dermal papilla structure and isotropic dermal fiber structure. CONCLUSION: There were structural changes in the skin surface around conspicuous pores, including not only a concave structure but also a convex structure with skin inner structure changing. PMID- 23750903 TI - Genetic and structural validation of Aspergillus fumigatus UDP-N acetylglucosamine pyrophosphorylase as an antifungal target. AB - The sugar nucleotide UDP-N-acetylglucosamine (UDP-GlcNAc) is an essential metabolite in both prokaryotes and eukaryotes. In fungi, it is the precursor for the synthesis of chitin, an essential component of the fungal cell wall. UDP-N acetylglucosamine pyrophosphorylase (UAP) is the final enzyme in eukaryotic UDP GlcNAc biosynthesis, converting UTP and N-acetylglucosamine-1-phosphate (GlcNAc 1P) to UDP-GlcNAc. As such, this enzyme may provide an attractive target against pathogenic fungi. Here, we demonstrate that the fungal pathogen Aspergillus fumigatus possesses an active UAP (AfUAP1) that shows selectivity for GlcNAc-1P as the phosphosugar substrate. A conditional mutant, constructed by replacing the native promoter of the A. fumigatus uap1 gene with the Aspergillus nidulans alcA promoter, revealed that uap1 is essential for cell survival and important for cell wall synthesis and morphogenesis. The crystal structure of AfUAP1 was determined and revealed exploitable differences in the active site compared with the human enzyme. Thus AfUAP1 could represent a novel antifungal target and this work will assist the future discovery of small molecule inhibitors against this enzyme. PMID- 23750905 TI - Linking anti-predator behaviour to prey demography reveals limited risk effects of an actively hunting large carnivore. AB - Ecological theory predicts that the diffuse risk cues generated by wide-ranging, active predators should induce prey behavioural responses but not major, population- or community-level consequences. We evaluated the non-consumptive effects (NCEs) of an active predator, the grey wolf (Canis lupus), by simultaneously tracking wolves and the behaviour, body fat, and pregnancy of elk (Cervus elaphus), their primary prey in the Greater Yellowstone Ecosystem. When wolves approached within 1 km, elk increased their rates of movement, displacement and vigilance. Even in high-risk areas, however, these encounters occurred only once every 9 days. Ultimately, despite 20-fold variation in the frequency of encounters between wolves and individual elk, the risk of predation was not associated with elk body fat or pregnancy. Our findings suggest that the ecological consequences of actively hunting large carnivores, such as the wolf, are more likely transmitted by consumptive effects on prey survival than NCEs on prey behaviour. PMID- 23750907 TI - Structures, magnetochemistry, spectroscopy, theoretical study, and catechol oxidase activity of dinuclear and dimer-of-dinuclear mixed-valence Mn(III)Mn(II) complexes derived from a macrocyclic ligand. AB - The work in this paper presents syntheses, characterization, magnetic properties (experimental and density functional theoretical), catecholase activity, and electrospray ionization mass spectroscopic (ESI-MS positive) studies of two mixed valence dinuclear Mn(III)Mn(II) complexes, [Mn(III)Mn(II)L(MU O2CMe)(H2O)2](ClO4)2.H2O.MeCN (1) and [Mn(III)Mn(II)L(MU O2CPh)(MeOH)(ClO4)](ClO4) (2), and a Mn(III)Mn(II)Mn(II)Mn(III) complex, [{Mn(III)Mn(II)L(MU-O2CEt)(EtOH)}2(MU-O2CEt)](ClO4)3 (3), derived from the Robson type macrocycle H2L, which is the [2 + 2] condensation product of 2,6-diformyl-4 methylphenol and 2,2-dimethyl-1,3-diaminopropane. In 1 and 2 and in two Mn(III)Mn(II) units in 3, the two metal centers are bridged by a bis(MU-phenoxo) MU-carboxylate moiety. The two Mn(II) centers of the two Mn(III)Mn(II) units in 3 are bridged by a propionate moiety, and therefore this compound is a dimer of two dinuclear units. The coordination geometry of the Mn(III) and Mn(II) centers are Jahn-Teller distorted octahedral and distorted trigonal prism, respectively. Magnetic studies reveal weak ferro- or antiferromagnetic interactions between the Mn(III) and Mn(II) centers in 1 (J = +0.08 cm(-1)), 2 (J = -0.095 cm(-1)), and 3 (J1 = +0.015 cm(-1)). A weak antiferromagnetic interaction (J2 = -0.20 cm(-1)) also exists between the Mn(II) centers in 3. DFT methods properly reproduce the nature of the exchange interactions present in such systems. A magneto-structural correlation based on Mn-O bridging distances has been proposed to explain the different sign of the exchange coupling constants. Utilizing 3,5-di-tert-butyl catechol (3,5-DTBCH2) as the substrate, catecholase activity of all the three complexes has been checked in MeCN and MeOH, revealing that all three are active catalysts with Kcat values lying in the range 7.5-64.7 h(-1). Electrospray ionization mass (ESI-MS positive) spectra of the complexes 1-3 have been recorded in MeCN solutions, and the positive ions have been well characterized. ESI-MS positive spectrum of complex 1 in presence of 3,5-DTBCH2 has also been recorded, and a positive ion, [Mn(III)Mn(II)L(MU-3,5-DTBC(2-))](+), having most probably a bridging catecholate moiety has been identified. PMID- 23750908 TI - Factors that promote and hinder joint and integrated working between health and social care services: a review of research literature. AB - This article reports the results of a review of the research evidence related to joint working in the field of adult health and social care services in the UK. It explores whether recent reforms to joint working have met the objectives set by policy-makers. The review followed an established methodology: electronic databases were searched using predetermined terms, abstracts were screened against inclusion criteria, studies that met the criteria were read in full and assessed for inclusion and data were extracted systematically. The findings of the review suggest that there is some indication that recent developments, in particular the drive to greater integration of services, may have positive benefits for organisations as well as for users and carers of services. However, the evidence consistently reports a lack of understanding about the aims and objectives of integration, suggesting that more work needs to be done if the full potential of the renewed policy agenda on integration is to be realised. Additionally, while the review acknowledges that greater emphasis has been placed on evaluating the outcome of joint working, studies largely report small-scale evaluations of local initiatives and few are comparative in design and therefore differences between 'usual care' and integrated care are not assessed. This makes it difficult to draw firm conclusions about the effectiveness of UK-based integrated health and social care services. PMID- 23750910 TI - Extraordinary sunlight absorption and one nanometer thick photovoltaics using two dimensional monolayer materials. AB - Graphene and monolayer transition metal dichalcogenides (TMDs) are promising materials for next-generation ultrathin optoelectronic devices. Although visually transparent, graphene is an excellent sunlight absorber, achieving 2.3% visible light absorbance in just 3.3 A thickness. TMD monolayers also hold potential as sunlight absorbers, and may enable ultrathin photovoltaic (PV) devices due to their semiconducting character. In this work, we show that the three TMD monolayers MoS2, MoSe2, and WS2 can absorb up to 5-10% incident sunlight in a thickness of less than 1 nm, thus achieving 1 order of magnitude higher sunlight absorption than GaAs and Si. We further study PV devices based on just two stacked monolayers: (1) a Schottky barrier solar cell between MoS2 and graphene and (2) an excitonic solar cell based on a MoS2/WS2 bilayer. We demonstrate that such 1 nm thick active layers can attain power conversion efficiencies of up to ~1%, corresponding to approximately 1-3 orders of magnitude higher power densities than the best existing ultrathin solar cells. Our work shows that two dimensional monolayer materials hold yet untapped potential for solar energy absorption and conversion at the nanoscale. PMID- 23750909 TI - Meta-analysis using individual patient data: efficacy and durability of topical alicaforsen for the treatment of active ulcerative colitis. AB - BACKGROUND: The antisense ICAM-1 inhibitor alicaforsen has been studied in four phase 2 studies in ulcerative colitis (UC). Recruited patients varied as to the extent of their colitis and in the severity of disease at entry. AIM: To investigate the efficacy of alicaforsen enema in specific UC populations. Efficacy was analysed for short-term (week 6-10) and long-term (week 30) outcomes compared with either placebo or a high-dose mesalazine (mesalamine) enema in patients with disease extent up to 40 cm from the anal verge in patients with moderate or severe disease, and in patients with both of these features. METHODS: Individual patient data meta-analyses of 200 patients from four phase 2 studies evaluating nightly alicaforsen 240 mg enema and comparators. Patient data were pooled and analysed in a single data set. Continuous outcomes were evaluated using anova; dichotomous outcomes were evaluated using Pearson chi-square or Fisher's exact tests. RESULTS: Alicaforsen showed superior efficacy vs. placebo in: patients with disease extent up to 40 cm, patients with moderate and severe disease and especially when both those conditions were satisfied. In these patient groups, mesalazine also showed short-term efficacy. At week 30, however, the efficacy of mesalazine waned and alicaforsen became significantly more efficacious. CONCLUSIONS: This post hoc meta-analysis showed that alicaforsen is effective in patients with active UC, especially in patients with distal disease, which is of moderate/severe activity. The efficacy of alicaforsen was durable in these sub-groups, suggesting a disease-modifying effect. This analysis suggests that alicaforsen enema may offer an effective, potentially durable response in moderate/severe distal active UC. PMID- 23750911 TI - Implications of Bt traits on mycotoxin contamination in maize: Overview and recent experimental results in southern United States. AB - Mycotoxin contamination levels in maize kernels are controlled by a complex set of factors including insect pressure, fungal inoculum potential, and environmental conditions that are difficult to predict. Methods are becoming available to control mycotoxin-producing fungi in preharvest crops, including Bt expression, biocontrol, and host plant resistance. Initial reports in the United States and other countries have associated Bt expression with reduced fumonisin, deoxynivalenol, and zearalenone contamination and, to a lesser extent, reduced aflatoxin contamination in harvested maize kernels. However, subsequent field results have been inconsistent, confirming that fumonisin contamination can be reduced by Bt expression, but the effect on aflatoxin is, at present, inconclusive. New maize hybrids have been introduced with increased spectra of insect control and higher levels of Bt expression that may provide important tools for mycotoxin reduction and increased yield due to reduced insect feeding, particularly if used together with biocontrol and host plant resistance. PMID- 23750912 TI - Individual differences in learning and transfer: stable tendencies for learning exemplars versus abstracting rules. AB - We hypothesize that during training some learners may focus on acquiring the particular exemplars and responses associated with the exemplars (termed exemplar learners), whereas other learners attempt to abstract underlying regularities reflected in the particular exemplars linked to an appropriate response (termed rule learners). Supporting this distinction, after training (on a function learning task), participants displayed an extrapolation profile reflecting either acquisition of the trained cue-criterion associations (exemplar learners) or abstraction of the function rule (rule learners; Studies 1a and 1b). Further, working memory capacity (measured by operation span [Ospan]) was associated with the tendency to rely on rule versus exemplar processes. Studies 1c and 2 examined the persistence of these learning tendencies on several categorization tasks. Study 1c showed that rule learners were more likely than exemplar learners (indexed a priori by extrapolation profiles) to resist using idiosyncratic features (exemplar similarity) in generalization (transfer) of the trained category. Study 2 showed that the rule learners but not the exemplar learners performed well on a novel categorization task (transfer) after training on an abstract coherent category. These patterns suggest that in complex conceptual tasks, (a) individuals tend to either focus on exemplars during learning or on extracting some abstraction of the concept, (b) this tendency might be a relatively stable characteristic of the individual, and (c) transfer patterns are determined by that tendency. PMID- 23750913 TI - Balancing the "inner" and the "outer" self: interoceptive sensitivity modulates self-other boundaries. AB - Distinguishing self from other is necessary for self-awareness and social interactions. This distinction is thought to depend on multisensory integration dominated by visual feedback. However, self-awareness also relies on the processing of interoceptive signals. We contrasted the exteroceptive and interoceptive models of the self to investigate the hitherto unexplored interaction between the perception of the self from the outside and from within. Multisensory stimulation between self and other was used to induce controlled changes in the representation of one's identity. Interoceptive sensitivity predicted the malleability of self-representations in response to multisensory integration across behavioral, physiological, and introspective responses, suggesting that interoception plays a key modulating role in the self-recognition system. In particular, only participants with low interoceptive sensitivity experienced changes in self-other boundaries in response to multisensory stimulation. These results support the view that interoceptive predictive coding models are used to monitor and assign the sources of sensory input either to the self or to others, as well as support the hypothesis of the insular cortex as a convergence zone in the processing and global representation of the material self given its involvement in both interoceptive feelings, multisensory integration, and self-processing. PMID- 23750914 TI - Complexity vs. simplicity: groundwater model ranking using information criteria. AB - A groundwater model characterized by a lack of field data about hydraulic model parameters and boundary conditions combined with many observation data sets for calibration purpose was investigated concerning model uncertainty. Seven different conceptual models with a stepwise increase from 0 to 30 adjustable parameters were calibrated using PEST. Residuals, sensitivities, the Akaike information criterion (AIC and AICc), Bayesian information criterion (BIC), and Kashyap's information criterion (KIC) were calculated for a set of seven inverse calibrated models with increasing complexity. Finally, the likelihood of each model was computed. Comparing only residuals of the different conceptual models leads to an overparameterization and certainty loss in the conceptual model approach. The model employing only uncalibrated hydraulic parameters, estimated from sedimentological information, obtained the worst AIC, BIC, and KIC values. Using only sedimentological data to derive hydraulic parameters introduces a systematic error into the simulation results and cannot be recommended for generating a valuable model. For numerical investigations with high numbers of calibration data the BIC and KIC select as optimal a simpler model than the AIC. The model with 15 adjusted parameters was evaluated by AIC as the best option and obtained a likelihood of 98%. The AIC disregards the potential model structure error and the selection of the KIC is, therefore, more appropriate. Sensitivities to piezometric heads were highest for the model with only five adjustable parameters and sensitivity coefficients were directly influenced by the changes in extracted groundwater volumes. PMID- 23750915 TI - 'Hypopyon' in the anterior chamber: unilateral ocular relapse of acute myeloid leukaemia in a 2-year-old girl. PMID- 23750916 TI - Clinical and professional ethics guidelines for the practice of thyroidology. PMID- 23750917 TI - Masticatory muscle tendon-aponeurosis hyperplasia exhibits heterotopic calcification in tendons. AB - OBJECTIVE: Masticatory muscle tendon-aponeurosis hyperplasia is a new disease entity associated with limited mouth opening. In this study, we analyzed the microstructural characteristics of muscles and tendons in masticatory muscle tendon-aponeurosis hyperplasia by electron microscopy and energy-dispersive X-ray analysis to determine the elemental composition. METHODS: Histological analysis was performed to detect the calcification. Transmission electron microscopy and scanning electron microscopy were conducted to clarify the microstructural characteristics of muscles and tendons. Energy-dispersive X-ray microanalysis was performed to identify the distribution of elements. RESULTS: Mineralized nodules were observed in tendon tissues of masticatory muscle tendon-aponeurosis hyperplasia as compared with facial deformity. Electron microscopy revealed that the muscle and tendon tissues in masticatory muscle tendon-aponeurosis hyperplasia showed degenerative changes and distinctive histological findings as compared with tissues in facial deformity. We found that Ca, P, and Si were detected only in masticatory muscle tendon-aponeurosis hyperplasia. CONCLUSION: We demonstrated that masticatory muscle tendon-aponeurosis hyperplasia exhibits heterotopic calcification in tendon tissues. PMID- 23750918 TI - A thermally responsive phospholipid pseudogel: tunable DNA sieving with capillary electrophoresis. AB - In an aqueous solution the phospholipids dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC) self-assemble to form thermo-responsive non-Newtonian fluids (i.e., pseudogels) in which small temperature changes of 5-6 degrees C decrease viscosity dramatically. This characteristic is useful for sieving-based electrophoretic separations (e.g., of DNA), as the high viscosity of linear sieving additives, such as linear polyacrylamide or polyethylene oxide, hinders the introduction and replacement of the sieving agent in microscale channels. Advantages of utilizing phospholipid pseudogels for sieving are the ease with which they are introduced into the separation channel and the potential to implement gradient separations. Capillary electrophoresis separations of DNA are achieved with separation efficiencies ranging from 400,000 to 7,000,000 theoretical plates in a 25 MUm i.d. fused silica capillary. Assessment of the phospholipid pseudogel with a Ferguson plot yields an apparent pore size of ~31 nm. Under isothermal conditions, Ogston sieving is achieved for DNA fragments smaller than 500 base pairs, whereas reptation-based transport occurs for DNA fragments larger than 500 base pairs. Nearly single base resolution of short tandem repeats relevant to human identification is accomplished with 30 min separations using traditional capillary electrophoresis instrumentation. Applications that do not require single base resolution are completed with faster separation times. This is demonstrated for a multiplex assay of biallelic single nucleotide polymorphisms relevant to warfarin sensitivity. The thermo-responsive pseudogel preparation described here provides a new innovation to sieving-based capillary separations. PMID- 23750919 TI - Molecular tweezers with varying anions: a comparative study. AB - Selective binding of the phosphate-substituted molecular tweezer 1a to protein lysine residues was suggested to explain the inhibition of certain enzymes and the aberrant aggregation of amyloid petide Abeta42 or alpha-synuclein, which are assumed to be responsible for Alzheimer's and Parkinson's disease, respectively. In this work we systematically investigated the binding of four water-soluble tweezers 1a-d (substituted by phosphate, methanephosphonate, sulfate, or O methylenecarboxylate groups) to amino acids and peptides containing lysine or arginine residues by using fluorescence spectroscopy, NMR spectroscopy, and isothermal titration calorimetry (ITC). The comparison of the experimental results with theoretical data obtained by a combination of QM/MM and ab initio(1)H NMR shift calculations provides clear evidence that the tweezers 1a-c bind the amino acid or peptide guest molecules by threading the lysine or arginine side chain through the tweezers' cavity, whereas in the case of 1d the guest molecule is preferentially positioned outside the tweezer's cavity. Attractive ionic, CH-pi, and hydrophobic interactions are here the major binding forces. The combination of experiment and theory provides deep insight into the host-guest binding modes, a prerequisite to understanding the exciting influence of these tweezers on the aggregation of proteins and the activity of enzymes. PMID- 23750920 TI - Depigmented skin and phantom color measurements for realistic prostheses. AB - PURPOSE: The purpose of this study was to test the hypothesis that regardless of human skin phototype, areas of depigmented skin, as seen in vitiligo, are optically indistinguishable among skin phototypes. The average of the depigmented skin measurements can be used to develop the base color of realistic prostheses. METHODS AND MATERIALS: Data was analyzed from 20 of 32 recruited vitiligo study participants. Diffuse reflectance spectroscopy measurements were made from depigmented skin and adjacent pigmented skin, then compared with 66 pigmented polydimethylsiloxane phantoms to determine pigment concentrations in turbid media for making realistic facial prostheses. RESULTS: The Area Under spectral intensity Curve (AUC) was calculated for average spectroscopy measurements of pigmented sites in relation to skin phototype (P = 0.0505) and depigmented skin in relation to skin phototype (P = 0.59). No significant relationship exists between skin phototypes and depigmented skin spectroscopy measurements. The average of the depigmented skin measurements (AUC 19,129) was the closest match to phantom 6.4 (AUC 19,162). CONCLUSION: Areas of depigmented skin are visibly indistinguishable per skin phototype, yet spectrometry shows that depigmented skin measurements varied and were unrelated to skin phototype. Possible sources of optical variation of depigmented skin include age, body site, blood flow, quantity/quality of collagen, and other chromophores. The average of all depigmented skin measurements can be used to derive the pigment composition and concentration for realistic facial prostheses. PMID- 23750922 TI - [Share with women. Should I have a C-section?]. PMID- 23750923 TI - Golgi organization and the apical extension of fungal hyphae: an essential relationship. AB - The Golgi apparatus performs crucial functions in the sorting and processing of proteins destined for secretion from eukaryotic cells. In filamentous fungi, organization of the Golgi apparatus reflects the unique challenges brought about by the highly polarized nature of hyphal growth. Recent results show that Golgi compartments are spatially segregated within hyphal tip cells in a manner that depends upon the integrity of the cytoskeleton. Moreover, loss of normal Golgi organization stops polarized hyphal extension and triggers de-polarization of the hyphal tip. These results emphasize the point that a spatially organized and dynamic Golgi apparatus represents an adaptation that is as important for hyphal extension as is the presence of a Spitzenkorper. In addition, they also identify regulatory mechanisms that could enable controlled de-polarization of hyphae during development or infection-related morphogenesis. PMID- 23750925 TI - Kinesin-2: a family of heterotrimeric and homodimeric motors with diverse intracellular transport functions. AB - Kinesin-2 was first purified as a heterotrimeric, anterograde, microtubule-based motor consisting of two distinct kinesin-related subunits and a novel associated protein (KAP) that is currently best known for its role in intraflagellar transport and ciliogenesis. Subsequent work, however, has revealed diversity in the oligomeric state of different kinesin-2 motors owing to the combinatorial heterodimerization of its subunits and the coexistence of both heterotrimeric and homodimeric kinesin-2 motors in some cells. Although the functional significance of the homo- versus heteromeric organization of kinesin-2 motor subunits and the role of KAP remain uncertain, functional studies suggest that cooperation between different types of kinesin-2 motors or between kinesin-2 and a member of a different motor family can generate diverse patterns of anterograde intracellular transport. Moreover, despite being restricted to ciliated eukaryotes, kinesin-2 motors are now known to drive diverse transport events outside cilia. Here, I review the organization, assembly, phylogeny, biological functions, and motility mechanism of this diverse family of intracellular transport motors. PMID- 23750926 TI - Intraoperative device closure of subaortic ventricular septal defects. AB - OBJECTIVES: To evaluate the safety and the indication for percardiac device closure of subaortic ventricular septal defects (VSDs) under guidance of transesophageal echocardiography. METHODS: A total of 62 patients with VSDs immediately below the aortic valve underwent percardiac device closure without cardiopulmonary bypass. RESULTS: There were no deaths. Of 62 patients, 52 (83.9%) underwent successful closure and 10 (16.1%) were converted to open-heart surgery due to tricuspid regurgitation, aortic regurgitation, and a residual shunt. Multiple logistic regression analysis showed the type and diameter of VSD were associated with the failure of device closure. There were no severe adverse events. Follow-up ranged from 13 to 31 months (mean, 22.3 +/- 5.2 months). Early and late complications occurred in 10 patients (19.2%) and two patients (3.8%), respectively. CONCLUSIONS: Excellent short-term results can be achieved in selected patients with percardiac device closure of subaortic ventricular septal defects. PMID- 23750927 TI - Psychologists' perspectives on the diagnostic classification of mental disorders: results from the WHO-IUPsyS Global Survey. AB - This study examined psychologists' views and practices regarding diagnostic classification systems for mental and behavioral disorders so as to inform the development of the ICD-11 by the World Health Organization (WHO). WHO and the International Union of Psychological Science (IUPsyS) conducted a multilingual survey of 2155 psychologists from 23 countries, recruited through their national psychological associations. Sixty percent of global psychologists routinely used a formal classification system, with ICD-10 used most frequently by 51% and DSM IV by 44%. Psychologists viewed informing treatment decisions and facilitating communication as the most important purposes of classification, and preferred flexible diagnostic guidelines to strict criteria. Clinicians favorably evaluated most diagnostic categories, but identified a number of problematic diagnoses. Substantial percentages reported problems with crosscultural applicability and cultural bias, especially among psychologists outside the USA and Europe. Findings underscore the priority of clinical utility and professional and cultural differences in international psychology. Implications for ICD-11 development and dissemination are discussed. PMID- 23750928 TI - Is the 30-minute rule still applicable in the 21st century? PMID- 23750929 TI - Transfusion medicine data as product. PMID- 23750924 TI - The Montastraea faveolata microbiome: ecological and temporal influences on a Caribbean reef-building coral in decline. AB - Coral-associated microbial communities, including protists, bacteria, archaea and viruses, are important components of the coral holobiont that influence the health of corals and coral reef ecosystems. Evidence suggests that the composition of these microbial communities is affected by numerous parameters; however, little is known about the confluence of these ecological and temporal effects. In this study, we used ribosomal RNA gene sequencing to identify the zooxanthellae, bacteria and archaea associated with healthy and yellow band diseased (YBD) colonies in the Media Luna reef of La Parguera, Puerto Rico, in order to examine the influence of YBD on the Montastraea faveolata microbiome. In addition, we evaluated the influence of season on the differences between healthy and YBD M. faveolata microbiomes by sampling from the same tagged colonies in both March and September of 2007. To the best of our knowledge, this is the first coral microbiome study to examine sequences from the zooxanthellar, bacterial and archaeal communities simultaneously from individual coral samples. Our results confirm differences in the M. faveolata zooxanthellar, bacterial and archaeal communities between healthy and YBD colonies in March; however, the September communities do not exhibit the same differences. Moreover, we provide evidence that the differences in the M. faveolata microbiomes between March and September are more significant than those observed between healthy and YBD. This data suggest that the entire coral microbiome, not just the bacterial community, is a dynamic environment where both disease and season play important roles. PMID- 23750930 TI - Transfusion medicine illustrated. Tissue hypoxia results in lactic acidosis. PMID- 23750931 TI - Could cost-effectiveness of postoperative shed blood salvage after elective knee arthroplasty be improved? PMID- 23750932 TI - Brachial artery pseudoaneurysm after phlebotomy for iron overload: first case report. PMID- 23750933 TI - A new mutation in the platelet GPIbalpha gene interfering with HPA-2 genotyping approaches: a case report. PMID- 23750934 TI - Vascular access site injury after transfemoral transcatheter aortic valve insertion. AB - BACKGROUND: Vascular complications associated with transfemoral transcatheter aortic valve insertion (TAVI) are a frequent untoward consequence of arterial sheath insertion. We report the prevalence of anatomic arterial injury with open artery access TAVI. METHODS: This review consisted of 53 consecutive patients who received transfemoral Sapien 23 or 26 mm TAVI via the 22- or 24-French sheath through open artery access from November 2008. The median age of the patients was 83 years (range, 59 to 94), and there were 31 males (58%). All arteries were examined to determine the optimal point of access and then explored after removal of the sheath to document injury. RESULTS: The accessed artery had a minimal lumen diameter of 8.9 mm (7.2 to 14.7) and a sheath-to-artery ratio of 1.0 (0.6 to 1.2). The point of access was the common femoral artery in 33 patients (62%) and the external iliac artery in 20 (38%). Exploration of the artery demonstrated localized arterial injury in 22 patients (42%). Female gender was predictive of injury (p = 0.03), but arterial access site location, presence of arterial access calcification, sheath-to-artery ratio, and sheath size were not. Techniques of artery repair included primary closure in 34 patients (64%), pericardial patch angioplasty in 15 (28%), and graft interposition in 4 (8%). There was one minor groin wound complication. CONCLUSIONS: Open artery access allows for direct examination and optimal access site choice of the vessel during transfemoral TAVI. Localized arterial injury was commonly encountered after 22- and 24-French sheath insertion, but the associated artery repair complication rate was low. PMID- 23750935 TI - Tangeretin sensitizes SGS1-deficient cells by inducing DNA damage. AB - Tangeretin, a polymethoxyflavone found in citrus peel, has been shown to have antiatherogenic, anti-inflammatory, and anticarcinogenic properties. However, the underlying target pathways are not fully characterized. We investigated the tangeretin sensitivity of yeast (Saccharomyces cerevisiae) mutants for DNA damage response or repair pathways. We found that tangeretin treatment significantly reduced (p < 0.05) survival rate, induced preferential G1 phase accumulation, and elevated the DNA double-strand break (DSB) signal gammaH2A in DNA repair defective sgs1Delta cells, but had no obvious effects on wild-type cells or mutants of the DNA damage checkpoint (including tel1Delta, sml1Delta mec1Delta, sml1Delta mec1Delta tel1Delta, and rad9Delta mutants). Additionally, microarray data indicated that tangeretin treatment up-regulates genes involved in nutritional processing and down-regulates genes related to RNA processing in sgs1Delta mutants. These results suggest tangeretin may sensitize SGS1-deficient cells by increasing a marker of DNA damage and by inducing G1 arrest and possibly metabolic stress. Thus, tangeretin may be suitable for chemosensitization of cancer cells lacking DSB-repair ability. PMID- 23750936 TI - Spinal muscular atrophy: new findings for an old pathology. AB - Understanding the events that are responsible for a disease is mandatory for setting up a therapeutic strategy. Although spinal muscular atrophy (SMA) is considered a rare neurodegenerative pathology, its impact in our society is really devastating as it strikes young people from birth onward, and it affects their families either emotionally or financially. Moreover, it requires intensive care for the children, and this diverts both parents and relatives from their occupations. Each neuron is very different from one another; therefore, in a neurodegenerative disease, the population of axons, synapses and cell bodies degenerate asynchronously, and subpopulations of neurons have different vulnerabilities. The knowledge of the sequence of events along the lengths of individual neurons is crucial to understand if each synapse degenerates before the corresponding axon, or if each axon degenerates before the corresponding cell body. Early degeneration of one neuronal compartment in disease often reflects molecular defects somewhere else. Up until now, SMA is considered mostly a lower motor neuron disease caused by the loss-of-function mutations in the SMN1 gene; here, we inspect other features that can be altered by this defect, such as the cross talk between muscle and motor neuron and the role of physical inactivity. PMID- 23750938 TI - I Working with dissociative dynamics and the longing for excess in binge eating disorders. AB - In this paper the author describes her work with a woman who, in her mid 20s, sought analysis for her non-vomiting binge eating disorder. The paper explores how two aspects of Jung's view of the psyche as healthily dissociable were used to think about the potential for change contained within the explosive, aggressive energies in this patient's bingeing. The resultant approach takes the patient's splitting defences, dissociations and self-destructive behaviour as a point of access to her unconscious. Seen in this way, these behaviours contain the seeds of recovery and are the starting point for analysis rather than defences against it. The paper also brings a number of Jungian and post-Jungian ideas into conversation with aspects of contemporary thinking about subjectivity, identity and the longing for excess developed by Leo Bersani and Judith Butler. PMID- 23750937 TI - Microbes, the gut and ankylosing spondylitis. AB - It is increasingly clear that the interaction between host and microbiome profoundly affects health. There are 10 times more bacteria in and on our bodies than the total of our own cells, and the human intestine contains approximately 100 trillion bacteria. Interrogation of microbial communities by using classic microbiology techniques offers a very restricted view of these communities, allowing us to see only what we can grow in isolation. However, recent advances in sequencing technologies have greatly facilitated systematic and comprehensive studies of the role of the microbiome in human health and disease. Comprehensive understanding of our microbiome will enhance understanding of disease pathogenesis, which in turn may lead to rationally targeted therapy for a number of conditions, including autoimmunity. PMID- 23750939 TI - II Spatial metaphors and somatic communication: the embodiment of multigenerational experiences of helplessness and futility in an obese patient. AB - This paper explores the analysis of an obese woman who came to experience her flesh as a bodying forth of personal and multigenerational family and cultural experiences of helplessness. The paper discusses the ideas and images that formed the basis of how I engaged with these themes as they presented countertransferentially. My thesis is that clinical approaches which draw on spatial metaphors for the psyche offer valuable tools for working with people whose inner world expresses itself somatically because such metaphors can be used to engage simultaneously with the personal, cultural, and ancestral dimensions of these unconscious communications. The paper builds on Jung's view of the psyche as comprised of pockets of inner otherness (complexes), on Redfearn's image of psyche as landscape-like and on Samuels' thinking on embodied countertransference and on the political psyche. It also draws on Butler's work on the body as a social phenomenon and on the theme of being a helpless non-person or nobody as explored in Tom Stoppard's play Rosencrantz and Guildenstern are Dead which retells Shakespeare's Hamlet from the perspective of two of the play's 'bit' characters. PMID- 23750940 TI - The 'Holy Mother' and the shadow: revisiting Jung's work on the quaternity. AB - Through a series of clinical vignettes, this paper considers the impact of religious belief, specifically Roman Catholicism, on the psyche and development of mind; in particular, there will be a focus on the influences of the conflation of maternal beliefs with a Catholic belief system when the loss or absence of the father is a primary factor. Further, it will be shown in case examples that split off aspects of the personal shadow such as conflicted and aggressive emotions related to mother and father can conflate with the collective numinous and religious aspects of the 'dark side' of the God-representation and result in 'religious' persecutory symptoms. This has a debilitating effect on the emerging personality, leaving it prone to fears, anxieties and psychotic pockets of experience when there is a numinous persecutory shadow in the background that affects and limits the individual's development. The implications and findings drawn from the clinical vignettes are used to consider the impact of an interrelationship and conflation between aspects of the psyche and religious beliefs. Jung's work on the Trinity and the 'problem of the fourth' (Jung 1942/1948/1991) is also reconsidered in relation to the role of the feminine, the maternal and the 'reality of matter'. A diagram of the multiple levels of the quaternity is used to elaborate and expand on Jung's concept. PMID- 23750941 TI - Secular and religious: the intrinsic doubleness of analytical psychology and the hegemony of naturalism in the social sciences. AB - In recent years a number of prominent social theorists, including Jurgen Habermas and Charles Taylor, have voiced concern about the hegemony of naturalistic, secular assumptions in the social sciences, and in their different ways have sought to address this by establishing greater parity between secular and religious perspectives. This paper suggests that C.G. Jung's analytical psychology, which hitherto has been largely ignored by social theory, may have something to contribute on this issue as it can be understood coherently both empirically, without reference to transcendent reality, and metaphysically, with reference to transcendent reality. It is argued that, despite his denials of any metaphysical intent, Jung does in fact engage in metaphysics and that together the empirical and metaphysical vectors of his thought result in a rich and distinctive double perspective. This dual secular and religious perspective can be seen as part of Jung's own critique of the hegemony of naturalism and secularism, which for Jung has profound social as well as clinical relevance. The concern and approach that Habermas and Taylor share with Jung on this issue may provide some grounds for increased dialogue between analytical psychology and the social sciences. PMID- 23750942 TI - Recurrent motifs as resonant attractor states in the narrative field: a testable model of archetype. AB - At the most basic level, archetypes represented Jung's attempt to explain the phenomenon of recurrent myths and folktale motifs (Jung 1956, 1959, para. 99). But the archetype remains controversial as an explanation of recurrent motifs, as the existence of recurrent motifs does not prove that archetypes exist. Thus, the challenge for contemporary archetype theory is not merely to demonstrate that recurrent motifs exist, since that is not disputed, but to demonstrate that archetypes exist and cause recurrent motifs. The present paper proposes a new model which is unlike others in that it postulates how the archetype creates resonant motifs. This model necessarily clarifies and adapts some of Jung's seminal ideas on archetype in order to provide a working framework grounded in contemporary practice and methodologies. For the first time, a model of archetype is proposed that can be validated on empirical, rather than theoretical grounds. This is achieved by linking the archetype to the hard data of recurrent motifs rather than academic trends in other fields. PMID- 23750943 TI - fMRI responses to Jung's Word Association Test: implications for theory, treatment and research. AB - Jung's Word Association Test was performed under fMRI conditions by 12 normal subjects. Pooled complexed responses were contrasted against pooled neutral ones. The fMRI activation pattern of this generic 'complexed response' was very strong (corrected Z scores ranging from 4.90 to 5.69). The activation pattern in each hemisphere includes mirror neurone areas that track 'otherness' (perspectival empathy), anterior insula (both self-awareness and emotional empathy), and cingulated gyrus (self-awareness and conflict-monitoring). These are the sites described by Siegel and colleagues as the 'resonance circuitry' in the brain which is central to mindfulness (awareness of self) and empathy (sense of the other), negotiations between self awareness and the 'internal other'. But there is also an interhemispheric dialogue. Within 3 seconds, the left hemisphere over rides the right (at least in our normal subjects). Mindfulness and empathy are central to good psychotherapy, and complexes can be windows of opportunity if left-brain hegemony is resisted. This study sets foundations for further research: (i) QEEG studies (with their finer temporal resolution) of complexed responses in normal subjects (ii) QEEG and fMRI studies of complexed responses in other conditions, like schizophrenia, PTSD, disorders of self organization. PMID- 23750947 TI - Facile synthesis of free-standing silicon membranes with three-dimensional nanoarchitecture for anodes of lithium ion batteries. AB - We propose a facile method for synthesizing a novel Si membrane structure with good mechanical strength and three-dimensional (3D) configuration that is capable of accommodating the large volume changes associated with lithiation in lithium ion battery applications. The membrane electrodes demonstrated a reversible charge capacity as high as 2414 mAh/g after 100 cycles at current density of 0.1 C, maintaining 82.3% of the initial charge capacity. Moreover, the membrane electrodes showed superiority in function at high current density, indicating a charge capacity >1220 mAh/g even at 8 C. The high performance of the Si membrane anode is assigned to their characteristic 3D features, which is further supported by mechanical simulation that revealed the evolution of strain distribution in the membrane during lithiation reaction. This study could provide a model system for rational and precise design of the structure and dimensions of Si membrane structures for use in high-performance lithium ion batteries. PMID- 23750948 TI - Endothelin-1 concentrations in bronchoalveolar lavage fluid of cats with experimentally induced asthma. AB - BACKGROUND: There is a need for biomarkers for diagnosis, therapeutic monitoring, and prognosis for asthma in cats. Endothelin-1 (ET-1) is implicated in the pathogenesis of inflammatory airway diseases in other species but not the cat. OBJECTIVE: To conduct a prospective experimental study to show that experimentally asthmatic cats, but not control cats without airway inflammation, would have increased concentrations of ET in BALF. ANIMALS: Eleven healthy, adult research cats. METHODS: Prospective experimental study. Six healthy cats without airway inflammation were used as controls. Asthma was induced using Bermuda grass allergen (BGA) in 5 cats. Collection of BALF for total nucleated cell and differential counts was performed. The concentration of ET-1 in cell-free BALF samples was determined. Data were analyzed using a Mann-Whitney U-test with P < .05 considered significant. RESULTS: The median [range] BALF total cell numbers, eosinophil numbers, and eosinophil percentages were significantly higher in the cats following experimental induction of asthma (1,870 cells/MUL [1,450-3,440], 711 cells/MUL [356-1,686] and 38% [20-49]) compared to baseline control parameters (462 cells/MUL [239-780], 18 cells/MUL [18-62] and 3.5% [0-8]) (P < .01). The median [range] BALF ET concentration was also significantly higher after induction of asthma (1.393 fmol/mL[0.977-2.247]) compared to healthy control cats (0.83250 fmol/mL [0.625-1.038]) (P = .012). CONCLUSIONS AND CLINICAL IMPORTANCE: This study suggests that BAL ET-1 concentration can be used to differentiate normal cats from those with experimentally induced asthma. If the same holds true for cats with naturally developing asthma, BAL ET-1 may prove a useful diagnostic biomarker for asthma. PMID- 23750949 TI - Regulatory evolution at the host-pathogen interface. AB - Horizontal gene transfer plays a major role in microbial evolution by innovating the bacterial genome with new genetic blueprints to adapt to previously unexploited niches. However, to benefit from these genetic acquisitions, the bacterium must integrate the expression of these new genes into existing regulatory nodes and deploy them at the right time. There is much to gain from uncovering the genetic diversity in noncoding DNA that is selective during host infection because of the beneficial effect it has on bacterial gene expression. By identifying genes that have undergone regulatory evolution, a deeper understanding of the arms race between host and pathogen is gained. PMID- 23750950 TI - Decrease in fungal biodiversity along an available phosphorous gradient in arable Andosol soils in Japan. AB - Andosols comprise one of the most important soil groups for agricultural activities in Japan because they cover about 46.5% of arable upland fields. In this soil group, available phosphorus (P) is accumulated by application of excessive fertilizer, but little is known about the influence of increasing P availability on microbial community diversity at large scales. We collected soil samples from 9 agro-geographical sites with Andosol soils across an available P gradient (2048.1-59.1 mg P2O5.kg(-1)) to examine the influence of P availability on the fungal community diversity. We used polymerase chain reaction - denaturing gradient gel electrophoresis to analyze the fungal communities based on 18S rRNA genes. Statistical analyses revealed a high negative correlation between available P and fungal diversity (H'). Fungal diversity across all sites exhibited a significant hump-shaped relationship with available P (R(2) = 0.38, P < 0.001). In addition, the composition of the fungal community was strongly correlated with the available P gradient. The ribotype F6, which was positively correlated with available P, was closely related to Mortierella. The results show that both the diversity and the composition of the fungal community were influenced by available P concentrations in Andosols, at a large scale. This represents an important step toward understanding the processes responsible for the maintenance of fungal diversity in Andosolic soils. PMID- 23750951 TI - Site-directed mutagenesis studies on the uridine monophosphate binding sites of feedback inhibition in carbamoyl phosphate synthetase and effects on cytidine production by Bacillus amyloliquefaciens. AB - A major problem when pyrimidine de novo biosynthesis is used for cytidine production is the existence of many negative regulatory factors. Cytidine biosynthesis in Bacillus amyloliquefaciens proceeds via a pathway that is controlled by uridine monophosphate (UMP) through feedback inhibition of carbamoyl phosphate synthetase (CPS), the enzyme that converts CO2, NH3, and glutamine to carbamoyl phosphate. In this study, the gene carB encoding the large subunit of CPS from B. amyloliquefaciens CYT1 was site directed, and the UMP binding sites of feedback inhibition in Bam-CPS are described. The residues Thr 941, Thr-970, and Lys-986 in CPS from B. amyloliquefaciens were subjected to site directed mutagenesis to alter UMP's feedback inhibition of CPS. To find feedback resistant B. amyloliquefaciens, the influence of the T941F, T970A, K986I, T941F/K986I, and T941F/T970A/K986I mutations on CPS enzymatic properties was studied. The recombinant B. amyloliquefaciens with mutated T941F/K986I and T941F/T970A/K986I CPS showed a 3.7- and 5.7-fold increase, respectively, in cytidine production in comparison with the control expressing wild-type CPS, which was more suitable for further application of the cytidine synthesis. To a certain extent, the 5 mutations were found to release the enzyme from UMP inhibition and to improve B. amyloliquefaciens cytidine-producing strains. PMID- 23750952 TI - Bacterial communities associated with lesions of two forms of shell disease in the American lobster (Homarus americanus, Milne Edwards) from Atlantic Canada. AB - Shell disease is a major threat to the American lobster (Homarus americanus, Milne Edwards) fishery. Here we describe the composition of microbial communities associated with lesions of 2 forms of shell disease in Atlantic Canada, (i) a trauma shell disease (TSD) characterized by massive lesions and (ii) an enzootic shell disease (EnSD) characterized by irregularly shaped lesions with a distinct orange to yellow color. The microbiology of the lesions was described by polymerase chain reaction and denaturing gradient gel electrophoresis of 16S rDNA amplified from scrapings of the shell lesions and was compared with communities of unaffected carapaces and previously described forms of shell diseases. Both TSD and EnSD lesions were dominated by members of Alphaproteobacteria, Gammaproteobacteria, and Flavobacteria, all commonly detected in other forms of shell disease; however, unique members of Epsilonproteobacteria were also present. Two Vibrio spp. and 2 Pseudoalteromonas spp. were dominant in lesions of TSD and a Tenacibaculum sp. and Tenacibaculum ovolyticum were dominant in lesions of EnSD. The TSD and EnSD in this study contained similar taxa as other shell disease forms; however, their microbiology is mostly different and neither resembles that of epizootic shell disease. PMID- 23750953 TI - The Streptococcus thermophilus protein Wzh functions as a phosphotyrosine phosphatase. AB - Amino acid residues that are important for metal binding and catalysis in Gram positive phosphotyrosine phosphatases were identified in the Wzh protein of Streptococcus thermophilus MR-1C by using sequence comparisons. A His-tagged fusion Wzh protein was purified from Escherichia coli cultures and tested for phosphatase activity against synthetic phosphotyrosine and phosphoserine threonine peptides. Purified Wzh released 2316.5 +/- 138.7 pmol PO4.min(-1).MUg( 1) from phosphotyrosine peptide-1 and 2345.7 +/- 135.2 pmol PO4.min(-1).MUg(-1) from phosphotyrosine peptide-2. The presence of the phosphotyrosine phosphatase inhibitor sodium vanadate decreased purified Wzh activity by 45%-50% at 1 mmol.L( 1), 74%-84% at 5 mmol.L(-1), and by at least 88% at 10 mmol.L(-1). Purified Wzh had no detectable activity against the phosphoserine-threonine peptide. These results clearly establish that S. thermophilus MR-1C Wzh functions as a phosphotyrosine phosphatase that could function to remove phosphate groups from proteins involved in exopolysaccharide biosynthesis, including the protein tyrosine kinase Wze and priming glycosyltransferase. PMID- 23750954 TI - Characterization and genus identification of rhizobial symbionts from Caragana arborescens in western Canada. AB - Naturally occurring nitrogen-fixing symbionts from root nodules of caragana (Caragana arborescens) growing in central Saskatchewan were isolated following surface sterilization of caragana root nodules and squashing and spreading of the contents on yeast extract - mannitol medium. The symbiotic nature of the strains was confirmed following inoculation onto surface-sterilized C. arborescens seed in a gnotobiotic Leonard jar system. The Rhizobium isolates from C. arborescens root nodules were intermediate in generation time (g) (mean g of 5 isolates was 6.41 h) compared with the fast growers, Rhizobium leguminosarum NRG457 (g: 4.44 h), Rhizobium tropici 899 (g: 3.19 h), and Sinorhizobium meliloti BALSAC (g: 3.45 h), but they were faster than the slow-growing Bradyrhizobium japonicum USDA 110 (g: 13.86 h) and similar to Mesorhizobium amorphae (g: 7.76 h). Nitrogen derived from fixation by measuring changes in delta(15)N natural abundance in plant tissue confirmed the effectiveness of the strains; approximately 80% N2 from fixation. Strain identification was carried out by determining the sequences of 3 genes: 16S rRNA-encoding genes, cpn60, and recA. This analysis determined that the symbiotic partner of Canadian C. arborescens belongs to the genus Mesorhizobium and seems more related to M. loti than to previously described caragana symbionts like M. caraganae. This is the first report of Mesorhizobium sp. nodulating C. arborescens in western Canada. PMID- 23750955 TI - Manual faucets induce more biofilms than electronic faucets. AB - Electronic faucets (types E1 and E2) and manual (M) faucets were studied for microbial quality, i.e., biomass and pathogenic microbes of biofilms in the faucet aerator, the water, and the outer surface of faucet in a hospital in Finland. Heterotrophic plate count content reflecting culturable microbial biomass and adenosine triphosphate content representing viable microbial biomass were smaller in the biofilms of E1-type electronic faucets than E2-type electronic faucets or M faucets. The likely explanation is the mixing point of cold and hot water (E1 and M: in the faucet; E2: in a separate box 50 cm before the actual faucet part). The highest amounts of Legionella (serogroups 2-15 of Legionella pneumophila) in a water sample (5000 cfu/L) and in biofilm samples (May-June 2008 sampling: 240 cfu/mL; November 2008: 1100 cfu/mL) were found in one E1-type faucet, which was lacking a back pressure valve due to faulty installation. This study reveals that certain types of electronic faucets seem to promote hospital hygiene, as they were associated with less microbial growth in biofilms in the faucet aerator, than some other types of electronic faucets or manual faucets, likely owing to the mixing point of cold and hot water. However, the faucet type had no direct effect on the presence of Legionella spp. Also correct installation is crucial. PMID- 23750956 TI - The "firing cannons" of Dipodascopsis uninucleata var. uninucleata. AB - According to literature, the elongated ascospores of Dipodascopsis uninucleata var. uninucleata exhibit smart movement when forcefully ejected from bottle shaped asci. This type of movement is defined as the unique patterns of non random movement of ascospores with specialized morphology thereby facilitating release from asci. Smart movement is required to actively release ascospores individually through the narrow ascus neck, without causing an obstruction and blocking ascospore release. However, little is known about the propulsion mechanism of this cannon-type release system. We show that asci of this yeast contain a central channel (barrel) filled with ascospores. These are surrounded by a sheath-like structure that lines the inner surface of the ascus wall. We found that this sheath is responsible for forcing the naked ascospores out of the ascus by exerting turgor pressure from the bottom towards the tip of the ascus. This cannon firing system is in contrast to that found in Dipodascus geniculatus, where no sheaths lining the ascus interior were observed. Instead, sheaths were found enveloping each ascospore. PMID- 23750957 TI - Regulation of three genes encoding cell-wall-degrading enzymes of Trichoderma aggressivum during interaction with Agaricus bisporus. AB - Members of the genus Trichoderma are very effective competitors of a variety of fungi. Cell-wall-degrading enzymes, including proteinases, glucanases, and chitinases, are commonly secreted as part of the competitive process. Trichoderma aggressivum is the causative agent of green mould disease of the button mushroom, Agaricus bisporus. The structures of 3 T. aggressivum genes, prb1 encoding a proteinase, ech42 encoding an endochitinase, and a beta-glucanase gene, were determined. Promoter elements in the prb1 and ech42 genes suggested that transcription is regulated by carbon and nitrogen levels and by stress. Both genes had mycoparasitism-related elements indicating potential roles for the protein products in competition. The promoter of the beta-glucanase gene contained CreA and AreA binding sites indicative of catabolite regulation but contained no mycoparasitism elements. Transcription of the 3 genes was measured in mixed cultures of T. aggressivum and A. bisporus. Two A. bisporus strains, U1, which is sensitive to green mould disease, and SB65, which shows some resistance, were used in co-cultivation tests to assess possible roles of the genes in disease production and severity. prb1 and ech42 were coordinately upregulated after 5 days, whereas beta-glucanase transcription was upregulated from day 0 with both Agaricus strains. Upregulation was much less pronounced in mixed cultures of T. aggressivum with the resistant strain, SB65, than with the sensitive strain, U1. These observations suggested that the proteins encoded by these genes have roles in both nutrition and in severity of green mould disease. PMID- 23750958 TI - A simple method for the detection of Leptolegnia chapmanii from infected Aedes aegypti larvae. AB - Significant progress in developing Leptolegnia chapmanii as a biological control agent against mosquitoes will be accelerated by improved and simpler methods to detect and to isolate this virulent and rapidly lethal watermold from field collected mosquito larvae. To date, however, this oomycete has remained understudied and little used. This study presents a simplified method to detect Leptolegnia in infected Aedes aegypti larvae. The development of L. chapmanii inside mosquitoes is easily monitored when pathogen-treated larvae are quasi immobilized for an initial 48 h in the water film on plates of water agar amended with antibiotic (chloramphenicol, 0.5-1 g/L) and fungicide (thiabendazole, 4-8 g/L) and then transferred to a larger volume of water for an additional 48 h. Surprisingly, chloramphenicol stimulated oosporogenesis by L. chapmanii. The method permits processing of large numbers of A. aegypti and other culicid larvae and is useful for both obtaining new strains and also monitoring the efficacy of L. chapmanii during field tests. PMID- 23750959 TI - Cranberry impairs selected behaviors essential for virulence in Proteus mirabilis HI4320. AB - Proteus mirabilis is an etiological agent of complicated urinary tract infections. North American cranberries (Vaccinium macrocarpon) have long been considered to have protective properties against urinary tract infections. This work reports the effects of cranberry powder (CP) on the motility of P. mirabilis HI4320 and its expression of flaA, flhD, and ureD. Our results show that swimming and swarming motilities and swarmer-cell differentiation were inhibited by CP. Additionally, transcription of the flagellin gene flaA and of flhD, the first gene of the flagellar master operon flhDC, decreased during exposure of P. mirabilis to various concentrations of CP. Moreover, using ureD-gfp, a fusion of the urease accessory gene ureD with gfp, we show that CP inhibits urease expression. Because we demonstrate that CP does not inhibit the growth of P. mirabilis, the observed effects are not attributable to toxicity. Taken together, our results demonstrate that CP hinders motility of P. mirabilis and reduces the expression of important virulence factors. PMID- 23750960 TI - The occurrence of subtilase-cytotoxin-encoding genes in environmental Escherichia coli isolated from a Northern California estuary. AB - The presence of subtilase-cytotoxin-encoding genes was determined in 397 environmental Escherichia coli strains isolated from water, suspended solids, and sediments sampled from different hydrological and environmental conditions in a California estuary. A total of 7 strains (1.76%) were found to harbor subtilase cytotoxin-encoding genes. Using primers targeting subA only, we generated PCR amplicons from 2 strains; while using primers targeting the 3' end of SubA downstream to the 5' end of SubB, amplicons of 232 bp were generated from 5 additional strains. The 556 bp subA sequences were almost identical to that in the subtilase-cytotoxin-positive strain ED 591 (98%), while subAB sequences of 2 non-Shiga-toxigenic strains revealed 100% similarity with the Shiga-toxigenic E. coli O113:H21 strain 98NK2 that was isolated from an outbreak of hemolytic uremic syndrome. Additionally, the serogroup O113:H21 was present in this collection of environmental E. coli, and it was found to harbor stx2d, hra1 that encodes the heat resistant agglutinin 1, and a subAB sequence similar to that in the non Shiga-toxigenic E. coli subtilase cytotoxin strain ED 591. To further understand potential health risks posed by strains encoding SubAB, future epidemiological studies should consider screening isolates for subAB regardless of the presence of Shiga-toxin-encoding genes. PMID- 23750961 TI - The Berlin Heart EXCOR Pediatric ventricular assist device: history, North American experience, and future directions. AB - Options for long-term mechanical circulatory support to sustain pediatric heart failure patients requiring cardiac transplantation while they wait for donor hearts have been unsatisfactory. The conventional approach has been to use extracorporeal membrane oxygenation (ECMO), but its lack of feasibility for long term use and the major complications associated with the technology have limited its use, especially in light of lengthy waiting lists for donor hearts. With the advent of the Berlin Heart EXCOR(r) Pediatric ventricular assist device (VAD), pediatric heart failure specialists have gained an important tool for helping this patient population survive until a donor heart can be identified. The EXCOR Pediatric VAD is designed to support pediatric patients of all age groups, from newborns to teenagers, and can be used successfully for many months. This paper describes the early experience with the EXCOR Pediatric VAD and the challenging journey undertaken to gain U.S. FDA approval, including successful completion of the first worldwide prospective clinical study of VADs in a pediatric population. PMID- 23750962 TI - Pointing the way to new constraints on the dynamical claims of computational models. AB - The reach-to-touch paradigm has become an increasingly popular tool in the study of human cognition. It is widely held that reaching responses are able to reveal the moment-by-moment unfolding of decision processes by virtue of an assumed continuity between reaching trajectories and the underlying "cognitive trajectory." Yet the standard analysis of reaching trajectories aggregates the trajectories across stimulus viewing times, which yields ambiguous results. Here we introduce a new version of the reach-to-touch paradigm that incorporates the response-signal procedure to elicit reaching movements across a wide range of stimulus viewing times. We then analyze the direction of the initial movement by stimulus viewing time, which produces a sigmoidal growth pattern. Of note, we show how this sigmoidal relationship between stimulus viewing time and initial direction can be used to test and constrain the dynamical claims of computational models of basic cognitive processes. We introduce our new version of the reach-to touch paradigm and analyses in the context of a lexical decision task and we compare our results with the dynamical claims of the dual-route cascaded model of reading. PMID- 23750963 TI - Effect of haptic feedback from self-touch on limb movement coordination. AB - Touching one's own body provides haptic feedback about the spatial configuration and movement of body parts. However, the influence of self-touch on movement performance has not been investigated so far. The authors evaluated the contribution of self-touch by asking participants to perform cyclic movement sequences with their feet while touching them with their hands, or vice versa. Hands and feet were either crossed or uncrossed (parallel), manipulating anatomical congruency of haptic feedback. The effects of self-touch (vs. object touch), active limb (feet vs. hands) and sequence complexity were assessed in three separate experiments. Task performance was strongly and specifically disrupted in one of the anatomically incongruent conditions (hands-parallel/feet crossed). This disruption occurred only with self-touch (Experiment 1), with the feet active (Experiment 2), and was more pronounced for the more complex movement sequence (Experiment 3). Thus, incongruent self-touch can strongly interfere with motor performance, showing that haptic information is automatically integrated in the online control of movement. The observed asymmetry between hands and feet indicates limb-specific differences regarding the use of spatial frames of reference and/or regarding the weighting of sensory information. The results emphasize the intimate connection between programming of action sequences and the anticipation of somatic feedback from self-touch. PMID- 23750964 TI - Visual control of foot placement when walking over complex terrain. AB - The aim of this study was to investigate the role of visual information in the control of walking over complex terrain with irregularly spaced obstacles. We developed an experimental paradigm to measure how far along the future path people need to see in order to maintain forward progress and avoid stepping on obstacles. Participants walked over an array of randomly distributed virtual obstacles that were projected onto the floor by an LCD projector while their movements were tracked by a full-body motion capture system. Walking behavior in a full-vision control condition was compared with behavior in a number of other visibility conditions in which obstacles did not appear until they fell within a window of visibility centered on the moving observer. Collisions with obstacles were more frequent and, for some participants, walking speed was slower when the visibility window constrained vision to less than two step lengths ahead. When window sizes were greater than two step lengths, the frequency of collisions and walking speed were weakly affected or unaffected. We conclude that visual information from at least two step lengths ahead is needed to guide foot placement when walking over complex terrain. When placed in the context of recent research on the biomechanics of walking, the findings suggest that two step lengths of visual information may be needed because it allows walkers to exploit the passive mechanical forces inherent to bipedal locomotion, thereby avoiding obstacles while maximizing energetic efficiency. PMID- 23750965 TI - The visual system's intrinsic bias influences space perception in the impoverished environment. AB - A dimly lit target in the intermediate distance in the dark is judged at the intersection between the target's projection line from the eye to its physical location and an implicit slanted surface, which is the visual system's intrinsic bias. We hypothesize that the intrinsic bias also contributes to perceptual space in the impoverished environment. We first showed that a target viewed against sparse texture elements delineating the horizontal ground surface in the dark is localized along an implicit slanted surface that is less slanted than that of the intrinsic bias, reflecting the weighted integration of the weak texture information and intrinsic bias. We also showed that while the judged egocentric locations are similar between 0.15- to 5-s exposure durations, the judged precision improves with duration. Furthermore, the precision for the judged target angular declination does not vary with the physical angular declination and is better than the precision of the eye-to-target distance. Second, we used both action and perceptual tasks to directly reveal the perceived surface slant. Confirming our hypothesis, we found that an L-shaped target on the horizontal ground with sparse texture information is perceived with a slant that is less than that of the intrinsic bias. PMID- 23750967 TI - Affine operations plus symmetry yield perception of metric shape with large perspective changes (>=45 degrees ): data and model. AB - G. P. Bingham and M. Lind (2008, Large continuous perspective transformations are necessary and sufficient for accurate perception of metric shape, Perception & Psychophysics, Vol. 70, pp. 524-540) showed that observers could perceive metric shape, given perspective changes >= 45 degrees relative to a principal axis of elliptical cylinders. In this article, we tested (a) arbitrary perspective changes of 45 degrees , (b) whether perception gradually improves with more perspective change, (c) speed of rotation, (d) whether this works with other shapes (asymmetric polyhedrons), (e) different slants, and (f) perspective changes >45 degrees . Experiment 1 compared 45 degrees perspective change away from, versus centered on, a principal axis. Observers adjusted an ellipse to match the cross-section of an elliptical cylinder viewed in a stereo-motion display. Experiment 2 tested whether performance would improve gradually with increases in perspective change, or suddenly with a 45 degrees change. We also tested speed of rotation. Experiment 3 tested (a) asymmetric polyhedrons, (b) perspective change beyond 45 degrees , and (c) the effect of slant. The results showed (a) a particular perspective was not required, (b) judgments only improved with >= 45 degrees change, (c) speed was not relevant, (d) it worked with asymmetric polyhedrons, (e) slant was not relevant, and (f) judgments remained accurate beyond 45 degrees of change. A model shows how affine operations, together with a symmetry yielded by 45 degrees perspective change, bootstrap perception of metric shape. PMID- 23750966 TI - Top-down influences of written text on perceived clarity of degraded speech. AB - An unresolved question is how the reported clarity of degraded speech is enhanced when listeners have prior knowledge of speech content. One account of this phenomenon proposes top-down modulation of early acoustic processing by higher level linguistic knowledge. Alternative, strictly bottom-up accounts argue that acoustic information and higher-level knowledge are combined at a late decision stage without modulating early acoustic processing. Here we tested top-down and bottom-up accounts using written text to manipulate listeners' knowledge of speech content. The effect of written text on the reported clarity of noise vocoded speech was most pronounced when text was presented before (rather than after) speech (Experiment 1). Fine-grained manipulation of the onset asynchrony between text and speech revealed that this effect declined when text was presented more than 120 ms after speech onset (Experiment 2). Finally, the influence of written text was found to arise from phonological (rather than lexical) correspondence between text and speech (Experiment 3). These results suggest that prior knowledge effects are time-limited by the duration of auditory echoic memory for degraded speech, consistent with top-down modulation of early acoustic processing by linguistic knowledge. PMID- 23750968 TI - Magnitude comparison with different types of rational numbers. AB - An important issue in understanding mathematical cognition involves the similarities and differences between the magnitude representations associated with various types of rational numbers. For single-digit integers, evidence indicates that magnitudes are represented as analog values on a mental number line, such that magnitude comparisons are made more quickly and accurately as the numerical distance between numbers increases (the distance effect). Evidence concerning a distance effect for compositional numbers (e.g., multidigit whole numbers, fractions and decimals) is mixed. We compared the patterns of response times and errors for college students in magnitude comparison tasks across closely matched sets of rational numbers (e.g., 22/37, 0.595, 595). In Experiment 1, a distance effect was found for both fractions and decimals, but response times were dramatically slower for fractions than for decimals. Experiments 2 and 3 compared performance across fractions, decimals, and 3-digit integers. Response patterns for decimals and integers were extremely similar but, as in Experiment 1, magnitude comparisons based on fractions were dramatically slower, even when the decimals varied in precision (i.e., number of place digits) and could not be compared in the same way as multidigit integers (Experiment 3). Our findings indicate that comparisons of all three types of numbers exhibit a distance effect, but that processing often involves strategic focus on components of numbers. Fractions impose an especially high processing burden due to their bipartite (a/b) structure. In contrast to the other number types, the magnitude values associated with fractions appear to be less precise, and more dependent on explicit calculation. PMID- 23750969 TI - Physio-behavioral coupling in a cooperative team task: contributors and relations. AB - Research indicates that coactors performing cooperative tasks often exhibit spontaneous and unintended similarities in their physiological and behavioral responses--a phenomenon referred to here as physio-behavioral coupling (PBC). The purpose of this research was to identify contributors to PBC; examine relationships between PBC, team performance, and perceived team attributes (e.g., cohesion, trust); and compare a set of time-series measures(cross-correlation [CC], cross-recurrence quantification analysis [CRQA], and cross-fuzzy entropy [CFEn]) in their characterization of PBC across comparisons. To accomplish this, PBC was examined in human postural sway (PS) and cardiac interbeat intervals (IBIs) from dyadic teams performing a fast-paced puzzle task (Quadra--a variant of the video game Tetris). Results indicated that observed levels of PBC were not a chance occurrence, but instead driven by features of the team-task environment, and that PBC was likely influenced by similar individual task demands and interpersonal coordination dynamics that were not "unique" to a particular team. Correlation analysis revealed that PBC exhibited negative relationships with team performance and team attributes, which were interpreted to reflect complementary coordination (as opposed to mimicry) during task performance, potentially due to differentiated team roles. Finally, qualitative comparison of time-series measures used to characterize PBC indicated that CRQA percent recurrence and CFEn (both nonlinear measures) settled on mostly analogous characterizations, whereas linear CC did not. The disparity observed between the linear and nonlinear measures highlights underlying computational and interpretational differences between the two families of statistics and supports the use of multiple metrics for characterizing PBC. PMID- 23750970 TI - Form features provide a cue to the angular velocity of rotating objects. AB - As an object rotates, each location on the object moves with an instantaneous linear velocity, dependent upon its distance from the center of rotation, whereas the object as a whole rotates with a fixed angular velocity. Does the perceived rotational speed of an object correspond to its angular velocity, linear velocities, or some combination of the two? We had observers perform relative speed judgments of different-sized objects, as changing the size of an object changes the linear velocity of each location on the object's surface, while maintaining the object's angular velocity. We found that the larger a given object is, the faster it is perceived to rotate. However, the observed relationships between size and perceived speed cannot be accounted for simply by size-related changes in linear velocity. Further, the degree to which size influences perceived rotational speed depends on the shape of the object. Specifically, perceived rotational speeds of objects with corners or regions of high-contour curvature were less affected by size. The results suggest distinct contour features, such as corners or regions of high or discontinuous contour curvature, provide cues to the angular velocity of a rotating object. PMID- 23750971 TI - Isolating the perceptual from the social: tapping in shared space results in improved synchrony. AB - Current theory suggests that interpersonal synchrony is an important social behavior in that it not only serves as a form of "social glue," but it also arises automatically in a social context. Theorists suggest potential mechanisms for interpersonal synchrony, ranging from a "low-level" social-perceptual system account to a "high-level" social-motivational explanation. Past studies that suggest synchrony can be influenced by social factors do not discriminate between these accounts. The current investigation seeks to isolate the effect of the high level social system on interpersonal synchrony by investigating the effects of spatial proximity on unintentional coordinated tapping between two naive participants. Dyads performed a synchronization-continuation task either in the same room, in different rooms, or in different rooms but with the ability to hear each other tap. Participant taps were represented by a box that flashed on the monitor to control visual information across all three conditions. Same-room dyads had increased coordination over different-room dyads, whereas dyads that shared audio but were in different rooms showed an intermediate level of coordination. The present study demonstrates that shared space, independent of perceptual differences in stimuli, can increase unintentional coordinated tapping. PMID- 23750972 TI - A meta-analysis of web-delivered tailored health behavior change interventions. AB - Web-based tailored intervention programs show considerable promise in effecting health-promoting behaviors and improving health outcomes across a variety of medical conditions and patient populations. This meta-analysis compares the effects of tailored versus nontailored web-based interventions on health behaviors and explores the influence of key moderators on treatment outcomes. Forty experimental and quasi-experimental studies (N =20,180) met criteria for inclusion and were analyzed using meta-analytic procedures. The findings indicated that web-based tailored interventions effected significantly greater improvement in health outcomes as compared with control conditions both at posttesting, d =.139 (95% CI = .111, .166, p <.001, k =40) and at follow-up, d =.158 (95% CI = .124, .192, p <.001, k =21). The authors found no evidence of publication bias. These results provided further support for the differential benefits of tailored web-based interventions over nontailored approaches. Analysis of participant/descriptive, intervention, and methodological moderators shed some light on factors that may be important to the success of tailored interventions. Implications of these findings and directions for future research are discussed. PMID- 23750973 TI - Seasonality and disturbance: annual pattern and response of the bacterial and microbial eukaryotic assemblages in a freshwater ecosystem. AB - High-throughput pyrosequencing of SSU rDNA genes was used to obtain monthly snapshots of eukaryotic and bacterial diversity and community structure at two locations in Lake Texoma, a low salinity lake in the south central United States, over 1 year. The lake experienced two disturbance events (i) a localized bloom of Prymnesium parvum restricted to one of the locations that lasted from January to April, and (ii) a large (17 cm), global rain event in the beginning of May, overlaid onto seasonal environmental change. Eukaryotic species richness as well as both eukaryotic and bacterial community similarity exhibited seasonal patterns, including distinct responses to the rain event. The P. parvum bloom created a natural experiment in which to directly explore the effects of an Ecosystem Disruptive Algal Bloom (EDAB) on the microbial community separated from seasonal changes. Microbial species richness was unaffected by the bloom, however, the eukaryotic community structure (evenness) and the patterns of both eukaryotic and bacterial community similarity at bloom and non-bloom sites were statistically distinct during the 4 months of the bloom. These results indicate that physical and biological disturbances as well as seasonal environmental forces contribute to the structure of both the eukaryotic and bacterial communities. PMID- 23750974 TI - Study of fluid and transport properties of porous anodic aluminum membranes by dynamic atomic force microscopy. AB - Recent work on carbon nanotubes (CNT) has focused on their potential application in water treatment as a result of their predicted and observed enhanced flow rates. Recent work on the lesser-known porous anodic alumina membranes (PAAMs) has also shown flow enhancement, albeit at only a fraction of what has been observed in CNTs. Despite their potential applications, little research has been conducted on PAAMs' hydrodynamic properties, and in this Article we present experimental results and theoretical models that explore the fluid flow behavior around and through these membranes. The experiments were conducted using an atomic force microscope (AFM) that pushed a solid silica particle against PAAMs that were characterized with different pore diameters. Furthermore, the PAAMs were classified as either closed or open, with the latter allowing fluid to pass through. The theoretical model developed to describe the experimental data incorporates Derjaguin-Landau-Verwey-Overbeek (DLVO) effects, cantilever drag, and hydrodynamic forces. By using the slip boundary condition for the hydrodynamic forces, we were able to fit the model to experimental findings and also demonstrate that the difference between closed and open PAAMs was negligible. The slip lengths did not correspond to any physical feature of the PAAMs, but our model does provide a simple yet effective means of describing the hydrodynamics for not only PAAMs but for membranes in general. PMID- 23750975 TI - A single amino acid substitution in the MurF UDP-MurNAc-pentapeptide synthetase renders Streptococcus pneumoniae dependent on CO2 and temperature. AB - The respiratory tract pathogen Streptococcus pneumoniae encounters different levels of environmental CO2 during transmission, host colonization and disease. About 8% of all pneumococcal isolates are capnophiles that require CO2 -enriched growth conditions. The underlying molecular mechanism for caphnophilic behaviour, as well as its biological function is unknown. Here, we found that capnophilic S. pneumoniae isolates from clonal complex (CC) 156 (i.e. Spain(9V) -3 ancestry) and CC344 (i.e. Norway(NT) -42 ancestry) have a valine at position 179 in the MurF UDP-MurNAc-pentapeptide synthetase. At <= 30 degrees C, the growth characteristics of capnophilic and non-capnophilic CC156 strains were equal, but at > 30 degrees C growth and survival of MurF(V) (179) strains was dependent on > 0.1% CO2 -enriched conditions. Expression of MurF(V) (179) in S. pneumoniae R6 and G54 rendered these, otherwise non-capnophilic strains, capnophilic. Time lapse microscopy revealed that a capnophilic CC156 strain undergoes rapid autolysis upon exposure to CO2 -poor conditions at 37 degrees C, and staining with fluorescently labelled vancomycin showed a defect in de novo cell wall synthesis. In summary, in capnophilic S. pneumoniae strains from CC156 and CC344 cell wall synthesis is placed under control of environmental CO2 levels and temperature. This mechanism might represent a novel strategy of the pneumococcus to rapidly adapt and colonize its host under changing environmental conditions. PMID- 23750976 TI - The role of dietitians in providing guidance on the use of natural health products. AB - PURPOSE: Dietitians are experts on nutrition, and yet much uncertainty remains about their readiness and capacity to address a rapidly evolving marketplace of novel foods, nutrients, and nutrient-like substances (i.e., natural health products [NHPs]), which are available to consumers. In 2011, we conducted a qualitative examination of current thinking on the scope of practice, as well as barriers to and facilitators of dietitians' role as experts in providing guidance on NHP use. METHODS: We sought rich descriptions of existing and future dietetic competencies with NHPs. We therefore conducted six focus groups. Participants were 18 dietitians practising in rural settings and 21 practising in urban settings of Atlantic Canada. RESULTS: Themes identified included people, products, and information; future education and training underlay these themes. The "food first" philosophy of dietetics practice was a primary convergent theme, the consensus being that NHPs can be used for select populations, lifestyles, and health conditions. The less food-related the NHP, the more divergent opinions were on specific competencies and scope of practice; focus group participants often referred to the importance of "doing no harm" and evidence-based practice. CONCLUSIONS: Dietitians' achievement of competency in providing guidance on NHPs will require core, consistent, and cross-disciplinary information and competencies, as well as enhanced integrative practice models. PMID- 23750977 TI - Adequacy of niacin, folate, and vitamin B12 intakes from foods among Newfoundland and Labrador adults. AB - PURPOSE: Adequacy of intake for niacin, folate, and vitamin B12 from food was estimated in an adult population in Newfoundland and Labrador (NL). Also considered was whether study findings support current Canadian food fortification policies. METHODS: Four hundred randomly selected adult NL residents were surveyed by telephone. Secondary analysis was performed on two 24-hour food recalls for each participant. Mean daily intakes of niacin, folate, and vitamin B12 were estimated from foods only and compared by sex/age subgroup. Adequacy of intakes was estimated. Contributions of folate by ready-to-eat cereal and bread products were also estimated. RESULTS: Intakes of all three nutrients were higher in men. In comparison with recommendations, daily niacin intakes were as follows: excessive for 21.9% of all participants (and for 56.8% of men aged 28 to 54), within the recommended range for 73.6%, and less than adequate for 4.5%. In comparison with recommendations, daily folate intakes were as follows: within the recommended range for 18.1% of participants and less than adequate for 81.9%. In comparison with recommendations, daily vitamin B12 intakes were less than adequate for 36.3% of participants. CONCLUSIONS: More than 20% of those surveyed were consuming, from food alone, niacin at levels above the maximum recommended. Food fortification policies pertaining to niacin should be revisited. In addition, despite fortification, NL adults may be consuming inadequate amounts of folate from foods. PMID- 23750978 TI - Sarcopenia and physical function in overweight patients with advanced cancer. AB - Advanced cancer is associated with numerous metabolic abnormalities that may lead to significant body composition changes, particularly muscle loss or sarcopenia. Sarcopenia in cancer has been associated with poor clinical outcomes, including poor physical function. Accurate tools to assess body composition are expensive and not readily available in clinical settings. Unfortunately, little is known about the efficacy of affordable and portable techniques to assess functional status in patients with cancer. We investigated the prevalence of sarcopenia and its association with different portable and low-cost functional status measurement tools (i.e., handgrip strength testing, a two-minute walking test, and a self-report questionnaire) in overweight/obese patients (body mass index >= 25 kg/m2) with advanced cancer. Twenty-eight patients (68% men) aged 64.5 +/- 9.5 years with advanced lung or colorectal cancer were included. Sarcopenia was assessed by measuring appendicular skeletal muscle (ASM) adjusted by height (ASM index), using dual energy X-ray absorptiometry. Approximately 36% of patients had sarcopenia. Average handgrip strength was greater in men without sarcopenia than in men with it (p=0.035). In men, ASM index was positively correlated with average (r=0.535, p=0.018) and peak handgrip strength (r=0.457, p=0.049). No differences were observed among female patients. Handgrip strength was associated with sarcopenia in male patients with advanced cancer, and therefore it may be used as a portable and simple nutritional screening tool. PMID- 23750979 TI - Role of the nutrition professional in high-risk obstetrics inpatient teams. AB - Beyond the management of gestational diabetes and weight control, limited literature exists on nutritional management in high-risk pregnancies. This study is a starting point for understanding the role of the registered dietitian (RD) in high-risk obstetrics (HRO) inpatient teams. Demographic information was gathered on Ontario HRO inpatient units and patient characteristics, and the RD's role in this setting was explored. Representatives from all six HRO units in Ontario completed a questionnaire. Five of the HRO units had an RD on the team. The RDs stated that their primary role in the unit involved providing nutrition education and support, screening patients for nutritional risk, and writing vitamin and mineral orders. This was the first study in which RDs' role in HRO inpatient units was examined. Existing literature supports the role of good nutrition in preventing and treating the conditions seen in HRO units; however, RDs' specific role remains unclear. Future studies are needed to analyze the effect of nutrition on these HRO conditions, and to support the development of best practice guidelines. PMID- 23750980 TI - The role of registered dietitians in health promotion. AB - We used our experience assisting in the development of and evaluating the Alberta Nutrition Guidelines for Children and Youth (ANGCY) as a basis for exploring roles that registered dietitians (RDs) can play within health promotion, and how others perceive the RD role. Data were generated via 12 key informant interviews and observations during a multiple case study of recreation facilities that had and had not adopted the ANGCY. We also drew on dialogue and personal observations during development of the ANGCY. Dietitians working in government, academia, community settings, private practice, and industry played an important role throughout the development and implementation of the ANGCY. Some sectors proactively sought RD expertise, while others with less ability to pay accessed RDs' services less. Informants generally regarded RDs in a positive light. Findings indicate the profession should incrementally adjust training models to reflect emerging areas of practice, and highlight the need for RDs to proactively seek new avenues in which to apply their skills. These actions will help RDs remain the trusted source of food and nutrition information, not only in health care, but also within health promotion settings. PMID- 23750982 TI - Dietetic students' experiences providing meal assistance in long-term care facilities. AB - PURPOSE: This qualitative study involved describing the experiences of dietetic students who provided meal help to older adults. Of interest were benefits and challenges, and how training could be enhanced. METHODS: Individual, face-to face, semi-structured interviews were conducted with nine undergraduate dietetic students. In the preceding year, these students had volunteered as meal helpers in a long-term care home. Interviews were digitally recorded and transcribed verbatim. Qualitative thematic analysis was used to analyze the transcripts. RESULTS: All participating students were female and from one undergraduate program. Three main themes emerged: growing into the role, learning outside the classroom, and providing quality assistance. CONCLUSIONS: This study provides an understanding of how meal helping can be a valuable experience for emerging dietitians. It also gives insights into training and the development of the meal helper role. PMID- 23750981 TI - Challenges in planning long-term care menus that meet dietary recommendations. AB - PURPOSE: Long-term care (LTC) homes plan menus based on Eating Well with Canada's Food Guide (CFG) recommendations for older adults. To determine whether recommended CFG servings and nutrients were being provided, we analyzed the menu of a large LTC facility in a metropolitan area and compared our analysis with a similar one conducted in 2000. METHODS: A full week's menu from a large Saskatoon LTC facility was analyzed and compared with CFG and recent Dietary Recommended Intake nutrient recommendations. The menu was analyzed using The Food Processor SQL. The 2011 menu was compared with the similar 2000 menu analysis to permit an evaluation of changes over a decade. RESULTS: The 2011 menu demonstrated a significant improvement in servings of vegetables and fruit (4.6 to 7.2 servings). Servings of grain products had declined from 4.9 to 3.6 and servings of milk and alternatives had declined from 2.4 to 1.2 since 2000. Servings of meat and alternatives, total carbohydrate, and protein were not significantly different. Foods on the 2011 menu were lower in fat and higher in dietary fibre and offered more vitamins and minerals. CONCLUSIONS: Greater attention to the planning of LTC menus may explain improvements in the 2011 LTC menu. The current menu, however, needs to overcome the challenges that prevent it from meeting CFG recommendations for older adults. PMID- 23750983 TI - Knowledge, perceptions, and consumption of whole grains among university students. AB - PURPOSE: Differences in knowledge, perceptions, and consumption of whole grains were compared between students who had taken an introductory university nutrition course and those who had not. METHODS: The sample consisted of two groups: 109 students who had completed a nutrition course and 61 who had not. The two samples were drawn from second-year nursing students and students in second-year psychology courses, respectively. All students completed a 25-item questionnaire. Chi-square tests were used to identify associations between completion of a nutrition course and responses. RESULTS: Nutrition education students had more knowledge of whole grain recommendations, of whole grains available in stores, and of whole grains as a factor in disease risk reduction (p<0.05). In contrast, non-nutrition education students had more knowledge of whole grain health claims, reported a greater preference for the taste of whole grains, and had a greater than mean intake of whole grain cereals (p<0.05). CONCLUSIONS: This prelimary study indicates that completion of an introductory nutrition course has a greater influence on positive perceptions of whole grains than on students' consumption frequency or knowledge of whole grains. Further study may provide more information on nutrition education and whole grains. PMID- 23750984 TI - Dietetic students' understanding of what becoming a dietitian means. AB - PURPOSE: We explored dietetic students' beliefs about what becoming a dietitian means. METHODS: A phenomenological approach to inquiry was used. Thirteen undergraduate students enrolled in a dietetics program were interviewed, and data were analyzed thematically. RESULTS: The overarching theme was students' expectations of what being a dietitian means and how those expectations change throughout their education. Exposure to a variety of dietitians in practice helped shape participants' understanding of being a dietitian. CONCLUSIONS: For dietetic students to develop a strong identity as dietitians and to strengthen the profession, they must be exposed to practising professionals early and often. PMID- 23750985 TI - Direct detection of a sulfonate ester genotoxic impurity by atmospheric-pressure thermal desorption-extractive electrospray-mass spectrometry. AB - A direct, ambient ionization method has been developed using atmospheric pressure thermal desorption-extractive electrospray-mass spectrometry (AP/TD-EESI-MS) for the detection of the genotoxic impurity (GTI) methyl p-toluenesulfonate (MTS) in a surrogate pharmaceutical matrix. A custom-made thermal desorption probe was used to the desorb and vaporize MTS from the solid state, by rapid heating to 200 degrees C then cooling to ambient temperature, with a cycle time of 6 min. The detection of MTS using EESI with a sodium acetate doped solvent to generate the [MTS+Na](+) adduct ion provided a significant sensitivity enhancement relative to the [M+H](+) ion generated using a 0.1% formic acid solvent modifier. The MTS detection limit is over an order of magnitude below the long-term daily threshold of toxicological concern (TTC) of 1.5 MUg/g and the potential for quantitative analysis has been determined using starch as a surrogate active pharmaceutical ingredient (API). PMID- 23750986 TI - Prevalence and correlates of eating disorders among young adults in Finland. AB - BACKGROUND: This study investigated the epidemiology of eating disorders in a population-based sample of young adults. METHOD: A mental health questionnaire was sent to a nationally representative two-stage cluster sample of 1863 Finns aged 20-35 years. All screen-positives and a random sample of screen-negatives were invited to participate in a Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) interview. Case records from all lifetime mental health treatments were also obtained and were used to complement the diagnostic assessment. RESULTS: The lifetime prevalence of anorexia nervosa, bulimia nervosa, eating disorder not otherwise specified and any eating disorder among women were 2.1%, 2.3%, 2.0% and 6.0%, respectively, while there was only one man with an eating disorder. Unlike other mental disorders, they are associated with high education. Of women diagnosed with lifetime eating disorder, 67.9% had at least one comorbid Axis I psychiatric disorder, most commonly depressive disorder. While 79.3% of women with lifetime eating disorder had had a treatment contact, only one third of persons with current eating disorder had a current treatment contact. Women whose eating disorder had remitted still experienced more psychological distress and had lower psychosocial functioning that women without lifetime Axis I disorders. CONCLUSION: Eating disorders are the fourth largest group of mental disorders among young women. They tend to be comorbid, often remain untreated and are associated with residual symptoms after the remission of eating disorder symptoms. PMID- 23750987 TI - The impact of the Danish Medico-Legal Council on the choice between treatment and punishment for non-psychotic offenders. AB - BACKGROUND: The Danish Medico-Legal Council provides the court with statements based on available psychiatric assessment reports to assist the law in the use of the Penal Code sections on mentally disordered offenders. AIMS: To analyse the impact of the Council on the courts' choice between punishment and treatment in cases of offenders falling under S69 of the Penal Code, i.e. mentally disordered, although not psychotic offenders. METHODS: In 298 cases of defendants who according to the Medico-Legal Council might fall under S69 the recommendations of the assessment reports, the recommendations of the Council and the final verdicts are compared; and assessment reports from forensic psychiatric centres are compared with those from other psychiatrists. RESULTS: The recommendations of the Medico-Legal Council were often, but not blindly followed by the courts. The probability for the Council to recommend some measure of treatment was about 50% for adult males, and higher for adolescents and for females. In court, however, the two genders as well as adolescents and adults alike all had the same probability, approximately 50%, of being sentenced with treatment instead of punishment. When measured by the final verdict, the Medico-Legal Council is of higher quality than the assessment reports, especially those from outside forensic psychiatry. CONCLUSION: The Council serves as a quality assurance of Danish forensic psychiatric assessments, and the Council's statements are by the court considered to represent the state of the art of these assessments. PMID- 23750988 TI - Applying flow chemistry: methods, materials, and multistep synthesis. AB - The synthesis of complex molecules requires control over both chemical reactivity and reaction conditions. While reactivity drives the majority of chemical discovery, advances in reaction condition control have accelerated method development/discovery. Recent tools include automated synthesizers and flow reactors. In this Synopsis, we describe how flow reactors have enabled chemical advances in our groups in the areas of single-stage reactions, materials synthesis, and multistep reactions. In each section, we detail the lessons learned and propose future directions. PMID- 23750990 TI - Hairy cell lymphoma: a unique presentation of hairy cell leukaemia. PMID- 23750992 TI - Improving medication adherence through technology: analyzing the managing meds video challenge. AB - BACKGROUND: Poor adherence to medication is an enormous problem. While many measures to improve adherence have been proposed, patients may be a good source of novel approaches. The Managing Meds Video Challenge was designed, by the U.S. Department of Health and Human Services (HHS), in collaboration with the National Consumers League Script Your Future campaign, for patients to create short videos containing ideas on how to better take medications as directed. PURPOSE: Determine what forms of technology patients use to help adhere to their medication regimens. METHODS: The 17 available videos from the Managing Meds Video Challenge were analyzed to determine what forms of technology patients use to help adhere to their medication regimens. RESULTS: Approaches to improve adherence included calendar and reminder applications, and third-party applications such as MedCoach Medication Reminder, Walgreens Pharmacy, and CVS/Pharmacy. Patients also improved adherence by using the Internet to access websites such as www.rememberitnow.com to manage medications, access electronic health records, and to order medications from online pharmacies. LIMITATIONS: This study only analyzes the 17 available videos from the Managing Meds Video Challenge. CONCLUSIONS: Patients are using a variety of technology to manage their medications. They appear to rely primarily on reminder systems. PMID- 23750991 TI - Surveillance for hepatocellular cancer with ultrasonography vs. computed tomography -- a randomised study. AB - BACKGROUND: Guidelines recommend screening for hepatocellular cancer (HCC) with ultrasonography. The performance of ultrasonography varies widely. Computed tomography (CT) is less operator dependent. AIM: To compare the performance and cost of twice-a-year ultrasonography to once-a-year triple-phase-contrast CT for HCC screening in veterans. We hypothesised that CT detects smaller HCCs at lower overall cost. METHOD: One hundred and sixty-three subjects with compensated cirrhosis were randomised to biannual ultrasonography or yearly CT. Twice-a-year alpha-feto protein testing was performed in all patients. Contingency table analysis using chi-squared tests was used to determine differences in sensitivity and specificity of screening arms, survival analysis with Kaplan-Meier method to determine cumulative cancer rates. Multivariate logistic regression models were used to examine predictive factors. RESULTS: Hepatocellular cancer incidence rate was 6.6% per year. Nine HCCs were detected by ultrasonography and eight by CT. Sensitivity and specificity were 71.4% and 97.5%, respectively, for ultrasonography vs. 66.7% and 94.4%, respectively, for CT. Although 58.8% of screen-detected HCC were early stage (Barcelona Clinic Liver Cancer stage A), only 23.5% received potentially curative treatment despite all treatment options being available. HCC-related and overall mortality were 70.5% and 82.3%, respectively, in patients with screen-detected tumour. Overall costs were less for biannual ultrasonography than annual CT. CONCLUSIONS: Biannual ultrasonography was marginally more sensitive and less costly for detection of early HCC compared with annual CT. Despite early detection, HCC-related mortality was high. These data support the use of biannual ultrasonography for HCC surveillance in a US patient population (NCT01350167). PMID- 23750993 TI - Glycogen synthase kinase-3beta in the ventral tegmental area mediates diurnal variations in cocaine-induced conditioned place preference in rats. AB - Cocaine sensitization and reward are reported to be under the influence of diurnal rhythm. However, no previous studies have reported brain areas that play a role as modulators and underlie the mechanism of diurnal variations in cocaine reward. We examined (1) the diurnal rhythm of glycogen synthase kinase-3beta (GSK 3beta) activity in the suprachiasmatic nucleus (SCN) and reward-related brain areas in naive rats; (2) the effect of day and night on the acquisition of cocaine-induced conditioned place preference (CPP); (3) the influence of cocaine induced CPP on GSK-3beta activity in the SCN and reward-related brain areas; and (4) the effect of the GSK-3beta inhibitor SB216763 microinjected bilaterally into the ventral tegmental area (VTA) on cocaine-induced CPP. A significant diurnal rhythm of GSK-3beta activity was found in the SCN and reward-related brain areas, with diurnal variations in cocaine-induced CPP. GSK-3beta activity in the SCN and reward-related brain areas exhibited marked diurnal variations in rats treated with saline. GSK-3beta activity in rats treated with cocaine exhibited distinct diurnal variations only in the prefrontal cortex and VTA. Cocaine decreased the expression of phosphorylated GSK-3beta (i.e. increased GSK-3beta activity) only in the VTA in rats trained and tested at ZT4 and ZT16. SB216763 microinjected into the VTA bilaterally eliminated the diurnal variations in cocaine-induced CPP, but did not affect the acquisition of cocaine-induced CPP. These findings suggest that the VTA may be a critical area involved in the diurnal variations in cocaine-induced CPP, and GSK-3beta may be a regulator of diurnal variations in cocaine-induced CPP. PMID- 23750994 TI - Effect of water deficit and domestic storage on the procyanidin profile, size, and aggregation process in pear-jujube (Z. jujuba) fruits. AB - No information exists on the proanthocyanidin content of pear-jujube (Ziziphus jujuba Mill) fruit, their polymeric types and sizes, and their self-aggregation, or on the effect of different water deficit levels during the fruit maturation period on these compounds. Two trimers, two tetramers, and six B type procyanidin pentamers were identified and quantified for the first time. Water deficit increased the content of procyanidins of low molecular mass, improving their potential bioavailability and possible physiological effects on human health. The tendency of procyanidins to self-aggregate was similar in the edible portion and pit, and was not affected by water deficit. The procyanidin content of fruit from well watered trees increased during domestic cold storage, whereas the fruits from trees suffering severe water stress lost some of their procyanidin content. PMID- 23750995 TI - Use of intravenous immunoglobulin in an Asian paediatric population over a 10 year period. AB - AIMS: There is a paucity of data on the pattern of intravenous immunoglobulin (IVIG) usage in the paediatric population. This study aimed to assess the prevalence, trends, indications and burden of cost of IVIG usage in the Singaporean paediatric population. METHODS: Pharmacy data of all IVIG prescriptions between 2000 and 2009 in the two major paediatric public hospitals in Singapore were retrospectively reviewed. Each prescription was cross referenced with the patient's hospital records to confirm the administration of IVIG and indication of use. RESULTS: Over the 10-year period, a total 78,155 g of IVIG valued at an estimated $5.2 million was prescribed. There was an increasing trend of 445.6 g/year (P = 0.02) over this period. Analysis of patients showed that the most common indication for IVIG use was Kawasaki disease, both in terms of the proportion of patients (60%) and amount of IVIG used (34%). Kawasaki disease was also the only indication where there were significant increasing trends in both patient numbers (7.4 patients/year) and amount of IVIG used (247.5 g/year). The indications with the highest amount of IVIG used per patient were for conditions related to primary immunodeficiency diseases and stem cell transplantation, where repeat transfusions were required. More than 75% of indications were Food and Drug Administration approved. CONCLUSION: Albeit substantial and increasing, the use of IVIG in Singaporean children is mostly evidence based. PMID- 23750996 TI - Climate change and species interactions: beyond local communities. AB - It is increasingly recognized that the wide-scale modification of habitats caused by climate change requires scientists to consider how species and species interactions change both locally and at larger, regional scales. Metacommunity approaches explicitly link local and regional dynamics for communities of species, providing a conceptual and mathematical framework for global change biologists. These approaches can scale between community-level impacts and the regional distributions and movements of species, and likewise determine how changes to regional processes, such as dispersal and habitat configuration, influence local abundances and occurrences. This review discusses several lessons that have recently emerged from climate change studies and metacommunity theory to identify some of the key processes that link local-scale studies to regional scale properties of communities, and vice versa. We then use simple models to highlight how these linkages function and to identify where research could gain most by studying specific local and regional processes. Finally, we propose methods for the field to move forward by clarifying how to incorporate metacommunity approaches into empirical research, and by identifying important gaps in metacommunity research. PMID- 23750997 TI - Stability of proteins inside a hydrophobic cavity. AB - We study the effects of confinement and hydrophobicity of a spherical cavity on the structural and thermal stability of proteins in the framework of a hydrophobic-polar (HP) lattice model. We observe that a neutral confinement stabilizes the folded state of the protein by eliminating many of the open-chain conformations of the unfolded state. Hydrophobic confinement always destabilizes the protein because of protein-surface interactions. However, for moderate surface hydrophobicities, the protein remains stabilized relative to its state in free solution because of the dominance of entropic effects. These results are consistent with our experimental findings of (a) enhanced activity of alcohol dehydrogenase (ADH) when immobilized inside the essentially cylindrical pores of hydrophilic mesoporous silica (SBA-15) and (b) unaffected activity when immobilized inside weakly hydrophobic pores of methacrylate resin compared to its activity in free solution. In the same vein, our predictions are also consistent with the behavior of lysozyme and myoglobin in hydrophilic and hydrophobic SBA 15, which show qualitatively the same trends. Apparently, our results have validity across these very different enzymes, and we therefore suggest that confinement can be used to selectively improve enzyme performance. PMID- 23750998 TI - Size and composition dependent multiple exciton generation efficiency in PbS, PbSe, and PbS(x)Se(1-x) alloyed quantum dots. AB - Using ultrafast transient absorption and time-resolved photoluminescence spectroscopies, we studied multiple exciton generation (MEG) in quantum dots (QDs) consisting of either PbSe, PbS, or a PbSxSe1-x alloy for various QD diameters with corresponding bandgaps (Eg) ranging from 0.6 to 1 eV. For each QD sample, we determine the MEG efficiency, etaMEG, defined in terms of the electron hole pair creation energy (epsiloneh) such that etaMEG = Eg/epsiloneh. In previous reports, we found that etaMEG is about two times greater in PbSe QDs compared to bulk PbSe, however, little could be said about the QD-size dependence of MEG. In this study, we find for both PbS and PbSxSe1-x alloyed QDs that etaMEG decreases lineally with increasing QD diameter within the strong confinement regime. When the QD radius is normalized by a material-dependent characteristic radius, defined as the radius at which the electron-hole Coulomb and confinement energies are equivalent, PbSe, PbS, and PbSxSe1-x exhibit similar MEG behaviors. Our results suggest that MEG increases with quantum confinement, and we discuss the interplay between a size-dependent MEG rate versus hot exciton cooling. PMID- 23750999 TI - Subacute effects of the thiodicarb pesticide on target organs of male Wistar rats: biochemical, histological, and flow cytometry studies. AB - Thiodicarb, a carbamate pesticide widely used on crops, may pose several environmental and health concerns. This study aimed to explore its toxicological profile on male rats using hematological, biochemical, histopathological, and flow cytometry markers. Exposed animals were dosed daily at 10, 20, or 40 mg/kg/body weight (group A, B, and C, respectively) during 30 d. No significant changes were observed in hematological parameters among all groups. After 10 d, a decrease of total cholesterol levels was noted in rats exposed to 40 mg/kg. Aspartate aminotransferase (AST) activity increased (group A at 20 d; groups A and B at 30 d) and alkaline phosphatase (ALP) (group B at 30 d) activity significantly reduced. At 30 d a decrease of some of the other evaluated parameters was observed with total cholesterol and urea levels in group A as well as total protein and creatinine levels in groups A and B. Histological results demonstrated multi-organ dose-related damage in thiodicarb-exposed animals, evidenced as hemorrhagic and diffuse vacuolation in hepatic tissue; renal histology showed disorganized glomeruli and tubular cell degeneration; spleen was ruptured with white pulp and clusters of iron deposits within red pulp; significant cellular loss was noted at the cortex of thymus; and degenerative changes were observed within testis. The histopathologic alterations were most prominent in the high-dose group. Concerning flow cytometry studies, an increase of lymphocyte number, especially T lymphocytes, was seen in blood samples from animals exposed to the highest dose. Taken together, these results indicate marked systemic organ toxicity in rats after subacute exposure to thiodicarb. PMID- 23751000 TI - Revised methods for estimating potential reentry exposure associated with indoor crack and crevice and perimeter application. AB - Surface deposition of insecticides applied as indoor residential foggers, baseboard or perimeter sprays, spot sprays, and crack-and-crevice (C&C) sprays represent pathways of unintentional, postapplication exposure for children and adults. Estimation of the magnitude of this exposure following an application event is associated with uncertainty due to many factors, including (1) surface residue deposition and distribution, (2) access to and the nature of contact with treated surfaces based on time-activity patterns of residents, and (3) the role of residue removal mechanisms such as cleaning treated surfaces, pesticide degradation or redistribution, and hand washing and bathing following contact. A comparative spatial deposition study was conducted involving broadcast, perimeter, and C&C application methods. Residues measured using a spatial grid of deposition dosimeters on floor surfaces demonstrated significantly lower residue concentrations in readily accessible areas following C&C and perimeter applications, versus broadcast treatment. Analyses of other monitoring studies support this finding. The implications of these findings are discussed for both screening-level and higher tier probabilistic postapplication, residential exposure assessment. The U.S. Environmental Protection Agency (EPA) current guidance on interpretation of deposition following C&C application is supported by data in this study and others that indicate a ratio of 10:1 for deposition for broadcast versus C&C application. However, the perimeter deposition data are quite similar to C&C deposition and do not support a 70/30 default relative to broadcast recommended by the U.S. EPA (2012). PMID- 23751001 TI - Evaluation of predictive algorithms used for estimating potential postapplication, nondietary ingestion exposures to pesticides associated with children's hand-to-mouth behavior. AB - Postapplication exposure assessment related to indoor residential application of pesticide products requires consideration of product use information, application methods, chemical-specific deposition, time-dependent availability and transferability of surface residues, reentry time, and temporal location and macro- and microactivity/behavior patterns ( Baker et al., 2000 ). Children's mouthing behavior results in potential postapplication exposure to available pesticides in treated microenvironments through the nondietary ingestion route, in addition to the dermal or inhalation routes. Children's activities and associated behaviors may result in multiple or repeat contact of dermal areas (clothed and unclothed body areas and hands) with treated surfaces, or surfaces that may have indirect sources of residues. Further, some surfaces contacted may have transferable pesticide residues and others may not. Transfer of residues from the indoor residential environment to the dermal surface (e.g., hands) of an individual has been assumed to be linear as a function of time and number of contacts. However, studies suggest that this transfer process to the hands and other body areas may be rapidly saturable. In the most recent U.S. Environmental Protection Agency (EPA), Office of Pesticide Programs (OPP) "Residential Exposure Assessment Standard Operating Procedures" (U.S. EPA, 2012), the input variable for the number of dermal contacts (with treated surfaces) is an exponent, making the relationship nonlinear. Further, removal processes such as hand washing and transfer to untreated surfaces are important to consider. Predictive algorithms for estimating children's hand-to-mouth-related incidental ingestion exposures post pesticide application have been developed by the EPA/OPP and incorporated into probabilistic models. A review of literature addressing variables used to estimate potential incidental ingestion exposure is presented. Data relevant to input variables for predictive algorithms are discussed, including the results of a multiyear, pesticide transferable residue measurement program conducted by the Non-Dietary Exposure Task Force (NDETF) and the associated distributional characterization for this key variable. Sources of conservative bias in current hand-to-mouth, incidental ingestion exposure estimation and the role of biomonitoring to evaluate predicted exposures are discussed. PMID- 23751002 TI - Incidence, nature, and etiology of metabolic alkalosis in dogs and cats. AB - BACKGROUND: The incidence and causes of metabolic alkalosis in dogs and cats have not been fully investigated. OBJECTIVES: To describe the incidence, nature, and etiology of metabolic alkalosis in dogs and cats undergoing blood gas analysis at a veterinary teaching hospital. ANIMALS: Dogs and cats at a veterinary medical teaching hospital. METHODS: Acid-base and electrolyte results for dogs and cats measured during a 13-month period were retrospectively collected from a computer database. Only the first measured (venous or arterial) blood gas analyzed in a single hospitalization period was included. Animals with a base excess above the reference range for the species were included. RESULTS: A total of 1,805 dogs and cats were included. Of these, 349 (19%) were identified as having an increased standardized base excess, 319 dogs and 30 cats. The mixed acid-base disorder of metabolic alkalosis with respiratory acidosis was the most common abnormality identified in both dogs and cats. Hypokalemia and hypochloremia were more common in animals with metabolic alkalosis compared to animals without metabolic alkalosis. The 4 most commonly identified underlying diseases were respiratory disease, gastrointestinal tract obstruction, furosemide administration, and renal disease. CONCLUSIONS AND CLINICAL IMPORTANCE: Metabolic alkalosis was less common than metabolic acidosis in the same population of animals. Evidence of contraction alkalosis was present in many patients in this study. Hypokalemia and hypochloremia were more frequent in patients with metabolic alkalosis and suggest the importance of evaluation of acid-base status in conjunction with serum electrolyte concentrations. PMID- 23751003 TI - The extracellular matrix protects Pseudomonas aeruginosa biofilms by limiting the penetration of tobramycin. AB - Biofilm cells are less susceptible to antimicrobials than their planktonic counterparts. While this phenomenon is multifactorial, the ability of the matrix to reduce antibiotic penetration into the biofilm is thought to be of limited importance studies suggest that antibiotics move fairly rapidly through biofilms. In this study, we monitored the transport of two clinically relevant antibiotics, tobramycin and ciprofloxacin, into non-mucoid Pseudomonas aeruginosa biofilms. To our surprise, we found that the positively charged antibiotic tobramycin is sequestered to the biofilm periphery, while the neutral antibiotic ciprofloxacin readily penetrated. We provide evidence that tobramycin in the biofilm periphery both stimulated a localized stress response and killed bacteria in these regions but not in the underlying biofilm. Although it is unclear which matrix component binds tobramycin, its penetration was increased by the addition of cations in a dose-dependent manner, which led to increased biofilm death. These data suggest that ionic interactions of tobramycin with the biofilm matrix limit its penetration. We propose that tobramycin sequestration at the biofilm periphery is an important mechanism in protecting metabolically active cells that lie just below the zone of sequestration. PMID- 23751005 TI - Who is this man? Francis Peyton Rous. PMID- 23751004 TI - Functional-group-tolerant, nickel-catalyzed cross-coupling reaction for enantioselective construction of tertiary methyl-bearing stereocenters. AB - The first Negishi nickel-catalyzed stereospecific cross-coupling reaction of secondary benzylic esters is reported. A series of traceless directing groups is evaluated for ability to promote cross-coupling with dimethylzinc. Esters with a chelating thioether derived from commercially available 2-(methylthio)acetic acid are most effective. The products are formed in high yield and with excellent stereospecificity. A variety of functional groups are tolerated in the reaction including alkenes, alkynes, esters, amines, imides, and O-, S-, and N heterocycles. The utility of this transformation is highlighted in the enantioselective synthesis of a retinoic acid receptor agonist and a fatty acid amide hydrolase inhibitor. PMID- 23751006 TI - The production effect: costs and benefits in free recall. AB - The production effect, the memorial benefit for information read aloud versus silently, has been touted as a simple memory improvement tool. The current experiments were designed to evaluate the relative costs and benefits of production using a free recall paradigm. Results extend beyond prior work showing a production effect only when production is manipulated within subject, not between, using a free recall paradigm. Furthermore, the results also indicate that the production effect is primarily driven by decreased memory for items read silently, not increased memory for items read aloud. PMID- 23751008 TI - Toward a definition of intrinsic axes: the effect of orthogonality and symmetry on the preferred direction of spatial memory. AB - Mou, Zhao, and McNamara (2007) proposed the "intrinsic model of human spatial memory," which posits that a viewer's memory of an array of objects will exhibit a preferred direction that is aligned with an intrinsic axis of the array. They defined intrinsic axes as salient axes created in part by the physical (geometric) properties of the array. To date, these geometric characteristics have received little research attention. We begin such an endeavor by evaluating the role of symmetry and orthogonality (i.e., number of right angles in an array of objects) in spatial memory. Participants viewed a layout of objects from a single (Experiment 1) viewpoint or 2 (Experiment 2) viewpoints and then judged relative directions within the layout from memory. Orthogonality and symmetry were associated with decreased reliance on egocentric reference systems but were qualified by a generally greater reliance on egocentric reference frames than is common in the literature. Indeed, for only 1 array-a highly orthogonal and symmetric one-did participants consistently respond nonegocentrically. We suggest that overuse of this array in the literature has led to an overestimation of the importance of allocentricity in spatial memory. PMID- 23751007 TI - The visual system's intrinsic bias and knowledge of size mediate perceived size and location in the dark. AB - Dimly lit targets in the dark are perceived as located about an implicit slanted surface that delineates the visual system's intrinsic bias (Ooi, Wu, & He, 2001). If the intrinsic bias reflects the internal model of visual space-as proposed here-its influence should extend beyond target localization. Our first 2 experiments demonstrated that the intrinsic bias also influences perceived target size. We employed a size-matching task and an action task to measure the perceived size of a dimly lit target at various locations in the dark. Then using the size distance invariance hypothesis along with the accurately perceived target angular declination, we converted the perceived sizes to locations. We found that the derived locations from the size judgment tasks can be fitted by slanted curves that resemble the intrinsic bias profile from judged target locations. Our third experiment revealed that armed with the explicit knowledge of target size, an observer perceives target locations in the dark following an intrinsic bias-like profile that is shifted slightly farther from the observer than the profile obtained without knowledge of target size (i.e., slightly more veridical). Altogether, we showed that the intrinsic bias serves as an internal model, or memory, of ground surface layouts when the visual system cannot rely on external depth information. This memory/model can also be weakly influenced by top-down knowledge. PMID- 23751009 TI - Revisiting age-of-acquisition effects in Spanish visual word recognition: the role of item imageability. AB - Word age-of-acquisition (AoA) affects reading. The mapping hypothesis predicts AoA effects when input-output mappings are arbitrary. In Spanish, the orthography to-phonology mappings required for word naming are consistent; therefore, no AoA effects are expected. Nevertheless, AoA effects have been found, motivating the present investigation of how AoA can affect reading in Spanish. Four experiments were run to examine reading with a factorial design manipulating AoA and frequency. In Experiments 1 and 2 (immediate and speeded naming), only word frequency affected word naming. In Experiment 3 (lexical decision), both AoA and frequency affected word recognition. In Experiment 4 (immediate naming with highly imageable items), both frequency and AoA affected naming. The results suggest that highly imageable items induce a larger reliance on semantics in reading aloud. Such reliance causes faster naming of earlier acquired words because the corresponding concepts have richer visual and sensory features acquired mainly through direct sensory experience. PMID- 23751010 TI - Learning what to learn: the effects of task experience on strategy shifts in the allocation of study time. AB - Learners typically allocate more resources to learning items that are higher in value than they do to items lower in value. For instance, when items vary in point value for learning, participants allocate more study time to the higher point items than they do to the lower point items. The current experiments extend this research to a context where the value of items is not explicitly labeled by evaluating whether learners' study decisions are sensitive to statistical regularities in the testing environment that signal which items are valuable to learn. In 4 experiments, participants studied English-English and Swahili-English paired associates across 4 study-test trials. On each trial, they were tested on only 1 type of item (e.g., only Swahili-English pairs), and, hence, only 1 type of item was valuable for performance. Some participants were cued to which information was valuable, and other participants had to learn from task experience. Experiment 2 examined the effect of performance incentives on study decisions, and Experiment 3 examined how the organization of the task environment influences learners' decisions. Finally, Experiment 4 examined the role of working memory span, fluid intelligence, and need for cognition on decisions. Findings indicated that some people can learn from task experience which items are important to study. However, many learners fail to do so (in particular, learners with low working memory spans); as a consequence, they dysregulate their study by allocating time to items that are not valuable to performance. PMID- 23751011 TI - Opposite effects of working memory on subjective visibility and priming. AB - Cognitive theories on consciousness propose a strong link between consciousness and working memory (WM). This link is also present at the neural level: Both consciousness and WM have been implicated in a prefrontal parietal network. However, the link remains empirically unexplored. The present study investigates the relation between consciousness and WM by studying the impact of WM load on one aspect of consciousness, the threshold for subjective visibility. At the same time, we investigated how WM affects cognitive control, a function that has been implicated to consciousness. Results showed an increase in the threshold of subjective visibility when WM load increased. Furthermore, the impact of a prime stimulus on the response to the target was also modulated by WM load. We propose that the observed interference is caused by the functional and neural overlap of these functions. PMID- 23751012 TI - [Share with women. Good self-care during pregnancy]. PMID- 23751013 TI - Organocatalyzed Michael-Michael cascade reaction: asymmetric synthesis of polysubstituted chromans. AB - An enantioselective cascade Michael-Michael reaction between chalcones enolates and nitromethane catalyzed by a bifunctional thiourea is developed. This reaction provides a mild but efficient approach to chiral benzopyrans bearing three consecutive stereocenters in high yields with excellent stereoselectivities, and the benzopyrans can be easily transformed to the corresponding tricyclic product. PMID- 23751014 TI - Hand, foot, and mouth disease outbreak and coxsackievirus A6, northern Spain, 2011. PMID- 23751015 TI - FT-IR product study of the reactions of NO3 radicals with ortho-, meta-, and para cresol. AB - Product analyses of the NO3 radical-initiated oxidation of ortho-, meta-, and para-cresol have been performed in large-volume chamber systems at the University of Wuppertal (1080 L quartz glass reactor: QUAREC) and the European Photoreactor (EUPHORE), Valencia, Spain. The reaction of O3 with NO2 was used for the in situ generation of NO3 radicals in both QUAREC and EUPHORE. In the QUAREC experiments the gas-phase reaction of ortho-cresol isomer with NO3 yielded (11.5 +/- 0.8) % 6 methyl-2-nitrophenol (6M2NP), (4.4 +/- 0.3) % methyl-1,4-benzoquinone (MQUIN) and (77.2 +/- 6.3) % HNO3. The reaction of NO3 radicals with meta-cresol yielded (21.2 +/- 1.4) % 3-methyl-2-nitrophenol (3M2NP), (22.8 +/- 1.8) % 3-methyl-4 nitrophenol (3M4NP), (23.5 +/- 1.8) % 5-methyl-2-nitrophenol (5M2NP), (4.2 +/- 0.7) % MQUIN and (72.3 +/- 6.4) % HNO3. In the reaction of NO3 radicals with para cresol, 4-methyl-2-nitrophenol (4M2NP) and HNO3 were identified as products with yields of (41.3 +/- 3.7) % and (85.0 +/- 10.2) %, respectively. In the EUPHORE chamber not all products were formed at levels above the detection limit, however, in cases where detection was possible similar product yields were observed. The product formation yields determined in both chambers are compared with available literature data and a gas-phase mechanism is proposed to explain the formation of the products observed from the reaction of NO3 and with cresol isomers. PMID- 23751016 TI - Laser electrospray mass spectrometry minimizes ion suppression facilitating quantitative mass spectral response for multicomponent mixtures of proteins. AB - A comparison of the mass spectral response for myoglobin, cytochrome c, and lysozyme is presented for laser electrospray mass spectrometry (LEMS) and electrospray ionization-mass spectrometry (ESI-MS). Analysis of multicomponent protein solutions using nonresonant femtosecond (fs) laser vaporization with electrospray postionization mass spectrometry exhibited significantly reduced ion suppression effects in comparison with conventional ESI analysis, enabling quantitative measurements over 4 orders of magnitude in concentration. No significant charge reduction was observed in the LEMS experiment while the ESI measurement revealed charge reduction for myoglobin and cytochrome c as a function of increasing protein concentration. Conventional ESI-MS of each analyte from a multicomponent solution reveals that the ion signal detected for myoglobin and cytochrome c reaches a plateau and then begins to decrease with increasing protein concentration preventing quantitative analysis. The ESI mass spectral response for lysozyme from the mixture initially decreased, before increasing, with increasing multicomponent solution concentration. PMID- 23751017 TI - Evaluating clinical significance: incorporating robust statistics with normative comparison tests. AB - The purpose of this study was to evaluate a modified test of equivalence for conducting normative comparisons when distribution shapes are non-normal and variances are unequal. A Monte Carlo study was used to compare the empirical Type I error rates and power of the proposed Schuirmann-Yuen test of equivalence, which utilizes trimmed means, with that of the previously recommended Schuirmann and Schuirmann-Welch tests of equivalence when the assumptions of normality and variance homogeneity are satisfied, as well as when they are not satisfied. The empirical Type I error rates of the Schuirmann-Yuen were much closer to the nominal alpha level than those of the Schuirmann or Schuirmann-Welch tests, and the power of the Schuirmann-Yuen was substantially greater than that of the Schuirmann or Schuirmann-Welch tests when distributions were skewed or outliers were present. The Schuirmann-Yuen test is recommended for assessing clinical significance with normative comparisons. PMID- 23751019 TI - Commercial clinical genetic sequencing panels for evaluating patients with familial disease--are they ready for prime time? PMID- 23751018 TI - Clinical review: Statins and trauma--a systematic review. AB - Statins, in addition to their lipid-lowering properties, have anti-inflammatory actions. The aim of this review is to evaluate the effect of pre-injury statin use, and statin treatment following injury. MEDLINE, EMBASE, and CENTRAL databases were searched to January 2012 for randomised and observational studies of statins in trauma patients in general, and in patients who have suffered traumatic brain injury, burns, and fractures. Of 985 identified citations, 7 (4 observational studies and 3 randomised controlled trials (RCTs)) met the inclusion criteria. Two studies (both observational) were concerned with trauma patients in general, two with patients who had suffered traumatic brain injury (one observational, one RCT), two with burns patients (one observational, one RCT), and one with fracture healing (RCT). Two of the RCTs relied on surrogate outcome measures. The observational studies were deemed to be at high risk of confounding, and the RCTs at high risk of bias. Three of the observational studies suggested improvements in a number of clinical outcomes in patients taking statins prior to injury (mortality, infection, and septic shock in burns patients; mortality in trauma patients in general; mortality in brain injured patients) whereas one, also of trauma patients in general, showed no difference in mortality or infection, and an increased risk of multi-organ failure. Two of three RCTs on statin treatment in burns patients and brain injured patients showed improvements in E-selectin levels and cognitive function. The third, of patients with radial fractures, showed no acceleration in fracture union. In conclusion, there is some evidence that pre-injury statin use and post-injury statin treatment may have a beneficial effect in patients who have suffered general trauma, traumatic brain injury, and burns. However, these studies are at high risk of confounding and bias, and should be regarded as 'hypothesisgenerating'. A well-designed RCT is required to determine the therapeutic efficacy in improving outcomes in this patient population. PMID- 23751020 TI - Ohio CTSAs implement a reliant IRB model for investigator-initiated multicenter clinical trials. PMID- 23751021 TI - Family history of dilated cardiomyopathy among patients with heart failure from the HF-ACTION genetic ancillary study. AB - BACKGROUND: The value of family history (FH) is well established, but its sensitivity to detect familial dilated cardiomyopathy (FDC) has been infrequently examined. METHODS: A genetic ancillary study was created as a component of the HF ACTION trial, a multicenter, prospective, randomized clinical trial of exercise in patients with heart failure and an ejection fraction <35%. A FH-based study using a structured questionnaire mailed to all consenting individuals was incorporated into the genetic ancillary. FH responses were analyzed for dilated cardiomyopathy (DCM) in family members. RESULTS: Of the 741 individuals with data available, 358 (48.3%) had nonischemic and 383 (51.6%) had ischemic etiology, and of these 164 (45.8%) and 201 (52.4%), respectively, returned evaluable questionnaires. Of those with nonischemic etiology, 14/164 (8.5%) reported at least one first-degree family member with DCM or an enlarged heart; another 21/164 (12.8%) reported a FH of "cardiomyopathy," a less specific term to indicate DCM. CONCLUSION: At least 8.5% of patients with nonischemic etiology in the HF-ACTION genetic ancillary study provided FH indicating familial DCM, information important to inform further genetic analyses of this cohort and to plan other studies. PMID- 23751023 TI - Nurse engagement and contributions to the clinical and translational science awards initiative. AB - CTSAs are mandated to follow a multidisciplinary model. Requests for applications direct responsive applications to "integrate clinical and translational science across multiple departments, schools," listing disciplines in addition to medicine such as engineering, nursing, and public health. This inventory of nurse engagement in CTSAs describes the extent of nursing's CTSA engagement from the perspective of participating nurse scientists within individual CTSAs, including institutional/national contributions and best practices that foster a multidisciplinary model. Of the 50 CTSAs affiliated with a nursing school, 44 responded (88% response rate). Of the ten CTSAs not affiliated with a nursing school, four responded (40% response rate). Overall funding success rates of nurse applicants are: TL1 fellowships 81%, KL2 fellowships 54%, and nurse-led pilots 58%. At most CTSAs nursing is contributing to the accomplishment of the CTSA mandate. The strongest categories of contribution are community engagement, implementation science, and training. Best practices to enhance multidisciplinary collaboration are: (1) inclusion of multiple disciplines on key committees who meet regularly to guide individual core and overall CTSA strategic planning and implementation; (2) required multidisciplinary co-mentors (ideally from different schools within the CTSA) on training grants and as co-investigators on pilot projects; and (3) documentation of multidisciplinary activity in annual reports. PMID- 23751022 TI - Clinical significance of vimentin expression and Her-2 status in patients with gastric carcinoma. AB - OBJECTIVES: To determine whether vimentin could be used as a marker of gastric carcinomas with more aggressive behavior. To detect the extent of Her-2 status in gastric carcinoma and explore the correlation between vimentin expression and Her 2 status. METHODS: Vimentin expression was detected in surgically resected gastric carcinoma tissue specimens from 143 patients by immunohistochemistry. The human epidermal growth factor receptor 2 (Her2) status was evaluated by fluorescence in situ hybridization (FISH). Correlations between vimentin expression, Her-2 status and clinicopathological factors were evaluated using Kaplan-Meier method and Cox multivariate survival models. RESULTS: Vimentin expression was significantly correlated with age, advanced stage, poorly differentiated type, venous invasion, hepatic metastasis, and recurrence (p < 0.05). Her-2 gene was amplified in 16 (11.2%) out of the 143 gastric carcinoma tissue specimens. Her-2 status was correlated with advanced cancer, poor differentiation, venous invasion, hepatic metastasis, and recurrence (p < 0.05). The result of multivariate analysis showed that vimentin expression and lymph node metastasis were independent prognostic factors. CONCLUSIONS: Vimentin expression in epithelial cells of the surgically resected gastric adenocarcinoma tissue is an independent predictor of short survival, and Her-2 status shows a valuable correlation with clinical parameters. PMID- 23751024 TI - Assessing the impact of the NIH CTSA program on institutionally sponsored clinical trials. AB - OBJECTIVE: To assess the impact of the NIH CTSA program on patient enrollment in clinical trials sponsored/collaborated by CTSA consortium institutions. MATERIAL AND METHODS: Using publicly available clinical trial data at ClinicalTrials.gov, we identify positive trend changes in the number of patients enrolled in clinical trials performed at CTSA consortium institutions over the years before and after their respective CTSA award dates. CTSA consortium institutions were matched with similar non-CTSA institutions. RESULTS: As compared to matched non-CTSA institutions CTSA consortium sites noted an increase in patient enrollment after the CTSA awards. In particular, we detected a change-point, where a new enrollment trend emerged, 338 days after the CTSA award. No such trend was noted over the same period in the non-CTSA institutions. CONCLUSION: Our analysis provides evidence that the NIH CTSA funding program made a positive impact on patient enrollment. PMID- 23751025 TI - Teaching research ethics better: focus on excellent science, not bad scientists. AB - A recent report of the United States' Presidential Commission for the Study of Bioethical Issues highlights how important it is for the research community to enjoy the "earned confidence" of the public and how creating a "culture of responsibility" can contribute to that confidence. It identifies a major role for "creative, flexible, and innovative" ethics education in creating such a culture. Other recent governmental reports from various nations similarly call for a renewed emphasis on ethics education in the sciences. We discuss why some common approaches to ethics education in the graduate sciences fail to meet the goals envisioned in the reports and we describe an approach, animated by primary attention on excellent science as opposed to bad scientists, that we have employed in our ethics teaching that we think is better suited for inspiring and sustaining responsible, trustworthy science. PMID- 23751026 TI - Promotion and tenure for community-engaged research: an examination of promotion and tenure support for community-engaged research at three universities collaborating through a Clinical and Translational Science Award. AB - INTRODUCTION: Community-engaged health research, an approach to research which includes the participation of communities, promotes the translation of research to address and improve social determinants of health. As a way to encourage community-engaged research, the National Institutes of Health required applicants to the Clinical and Translational Science Award (CTSA) to include a community engagement component. Although grant-funding may support an increase in community engaged research, faculties also respond to the rewards and demands of university promotion and tenure standards. This paper measures faculty perception of how three institutions funded by a CTSA support community-engaged research in the promotion and tenure process. METHODS: At three institutions funded by a CTSA, tenure track and nontenure track faculty responded to a survey regarding perceptions of how promotion and tenure committees value community-engaged research. RESULTS: Faculty view support for community-engaged research with some reserve. Only 36% agree that community-engaged research is valued in the promotion and tenure process. DISCUSSION: Encouraging community-engaged scholarship requires changing the culture and values behind promotion and tenure decisions. Institutions will increase community-engaged research and more faculty will adopt its principles, when it is rewarded by promotion and tenure committees. PMID- 23751027 TI - Assessing the need for a research ethics remediation program. AB - With supplement funding to the Washington University CTSA, the Restoring Professionalism and Integrity in Research (RePAIR) program was developed at Saint Louis University to meet the remediation needs of institutions nationwide regarding investigators who violate research regulations. With the aim of determining the frequency and kinds of wrongdoing at leading research institutions in the United States, as well as institutional responses and levels of interest in a formal remediation program, an online questionnaire was distributed by email to a research integrity officer (RIO) and institutional review board (IRB) chair at all medical schools and comprehensive doctoral institutions in the United States (N = 194). One hundred sixty-one individuals responded (44%) representing 66% of institutions. For those institutions that had both RIOs and IRB chairs responding, 96% had investigated at least one case over the past 2 years; the modal individual response was 3-5 cases, with a range from 0 to more than 16 cases. The most common forms of wrongdoing were violations of procedure, informed consent, research integrity (fabrication, falsification, plagiarism), privacy, and conflict of interest policies. Most RIOs and IRB chairs expressed interest in the RePAIR program, despite concerns about costs and faculty resistance. PMID- 23751028 TI - A novel program trains community-academic teams to build research and partnership capacity. AB - The Community-Engaged Research Team Support (CERTS) program was developed and tested to build research and partnership capacity for community-engaged research (CEnR) teams. Led by the Northwestern University Clinical and Translational Sciences Institute (NUCATS), the goals of CERTS were: (1) to help community academic teams build capacity for conducting rigorous CEnR and (2) to support teams as they prepare federal grant proposal drafts. The program was guided by an advisory committee of community and clinical partners, and representatives from Chicago's Clinical and Translational Science Institutes. Monthly workshops guided teams to write elements of NIH-style research proposals. Draft reviewing fostered a collaborative learning environment and helped teams develop equal partnerships. The program culminated in a mock-proposal review. All teams clarified their research and acquired new knowledge about the preparation of NIH-style proposals. Trust, partnership collaboration, and a structured writing strategy were assets of the CERTS approach. CERTS also uncovered gaps in resources and preparedness for teams to be competitive for federally funded grants. Areas of need include experience as principal investigators, publications on study results, mentoring, institutional infrastructure, and dedicated time for research. PMID- 23751029 TI - The secure medical research workspace: an IT infrastructure to enable secure research on clinical data. AB - Clinical data have tremendous value for translational research, but only if security and privacy concerns can be addressed satisfactorily. A collaboration of clinical and informatics teams, including RENCI, NC TraCS, UNC's School of Information and Library Science, Information Technology Service's Research Computing and other partners at the University of North Carolina at Chapel Hill have developed a system called the Secure Medical Research Workspace (SMRW) that enables researchers to use clinical data securely for research. SMRW significantly minimizes the risk presented when using identified clinical data, thereby protecting patients, researchers, and institutions associated with the data. The SMRW is built on a novel combination of virtualization and data leakage protection and can be combined with other protection methodologies and scaled to production levels. PMID- 23751030 TI - How to build an integrated biobank: the Washington University Translational Cardiovascular Biobank & Repository experience. AB - Translational studies that assess and extend observations made in animal models of human pathology to elucidate relevant and important determinants of human diseases require the availability of viable human tissue samples. However, there are a number of technical and practical obstacles that must be overcome in order to perform cellular and electrophysiological studies of the human heart. In addition, changing paradigms of how diseases are diagnosed, studied and treated require increasingly complex integration of rigorous disease phenotyping, tissue characterization and detailed delineation of a multitude of "_omics". Realizing the need for quality-controlled human cardiovascular tissue acquisition, annotation, biobanking and distribution, we established the Translational Cardiovascular Biobank & Repository at Washington University School of Medicine. Several critical details are essential for the success of cardiovascular biobanking including coordinated, trained and dedicated staff members; adequate, nonrestrictive informed consent protocols; and fully integrated clinical data management applications for annotating, tracking and sharing of tissue and data resources. Labor and capital investments into growing biobanking resources will facilitate collaborative efforts aimed at limiting morbidity and mortality due to heart disease and improving overall cardiovascular health. PMID- 23751031 TI - Enhancing Quality Interventions Promoting Healthy Sexuality (EQUIPS): a novel application of translational research methods. AB - Translational research is expanding, in part, because Evidence-Based Programs or Practices (EBPs) are not adopted in many medical domains. However, little translational research exists on EBPs that are prevention programs delivered in nonclinical, community-based settings. These organizations often have low capacity, which undermines implementation quality and outcomes. Rigorous translational research is needed in these settings so within a single study, capacity, implementation quality, and outcomes are measured and links between them tested. This paper overviews the study Enhancing Quality Interventions Promoting Healthy Sexuality (EQUIPS), which tests how well a community-based setting (Boys & Girls Clubs) conducts an EBP called Making Proud Choices that aims to prevent teen pregnancy and sexually transmitted infections, with and without an implementation support intervention called Getting To Outcomes. The study design is novel as it assesses: Getting To Outcomes' impact on capacity, implementation quality, and outcomes simultaneously and in both study conditions; will assess sustainability by measuring capacity and fidelity a year after the Getting To Outcomes support ends; and will operate on a large scale similar to many national initiatives. Many studies have not incorporated all these elements and thus EQUIPS could serve as a model for translational research in many domains. PMID- 23751032 TI - Self-regulation of sleep, emotion, and weight during adolescence: implications for translational research and practice. AB - Self-regulation-the ability to manage motivations, emotions, physiological sensations, and behavior to meet internal and external demands of the environment is critical to health and development. Adolescence represents a dynamic period of change in both the demand and capacity for self-regulation. As teens mature and become more autonomous, they are confronted with decisions in determining where they spend their time, what they eat, when they go to bed, and how they prioritize and pursue various social, academic, and recreational goals. We highlight opportunities to improve self-regulatory capacities and related health outcomes during this important developmental window. In particular, we focus on emotion regulation, sleep regulation, and weight regulation as three separate but synergistic self-regulatory systems that may provide unique opportunities for intervention to optimize health outcomes. To this end, we begin by describing developmental changes that occur in emotion, sleep and weight regulatory systems during the transitional period of adolescence, as well as how these changes can lead to profound and enduring health consequences. Next, we describe emerging evidence that indicates complex and synergistic interactions among these regulatory systems during adolescence. Last, we end with possible prevention and intervention efforts that capitalize on the interactions among these three regulatory domains. PMID- 23751033 TI - An evaluation tool for collaborative clinical research centers. AB - There is a need for metrics that describe the full range of services provided by a clinical research unit; given that services have expanded to include such things as investigator training, regulatory compliance monitoring, and budget negotiations. We developed a tool and methodology that allows tracking of these expanded services. This not only allowed us to more accurately describe the work of the research unit staff, but to monitor the status of a study across the entire study lifespan from the idea to the publication. In addition to measuring work, it allows us to anticipate future needs in clinical staff and expertise because we are involved very early in study planning. We also expect that by analyzing these data from many studies over time, we will identify process barriers that will direct future program improvement. PMID- 23751035 TI - Deviance and dissent in groups. AB - Traditionally, group research has focused more on the motivations that make people conform than on the motivations and conditions underpinning deviance and dissent. This has led to a literature that focuses on the value that groups place on uniformity and paints a relatively dark picture of dissent and deviance: as reflections of a lack of group loyalty, as signs of disengagement, or as delinquent behavior. An alternative point of view, which has gained momentum in recent years, focuses on deviance and dissent as normal and healthy aspects of group life. In this review, we focus on the motivations that group members have to deviate and dissent, and the functional as well as the dysfunctional effects of deviance and dissent. In doing so we aim for a balanced and complete account of deviance and dissent, highlighting when such behaviors will be encouraged as well as when they will be punished. PMID- 23751036 TI - Psychological research on retirement. AB - Retirement as a research topic has become increasingly prominent in the psychology literature. This article provides a review of both theoretical development and empirical findings in this literature in the past two decades. We first discuss psychological conceptualizations of retirement and empirical operationalizations of retirement status. We then review three psychological models for understanding the retirement process and associated antecedents and outcomes, including the temporal process model of retirement, the multilevel model of retirement, and the resource-based dynamic model for retirement adjustment. We next survey the empirical findings regarding how various individual attributes, job and organizational factors, family factors, and socioeconomic context are related to the retirement process. We also discuss outcomes associated with retirement in terms of retirees' financial well-being, physical well-being, and psychological well-being. PMID- 23751037 TI - Mapping the functional neuroanatomy of spatial neglect and human parietal lobe functions: progress and challenges. AB - Spatial neglect is generally defined by various deficits in processing information from one (e.g., left) side of space contralateral to focal (e.g., right) hemisphere damage. Although classically associated with parietal lobe functions, there is now compelling evidence that neglect can follow lesions in many different cortical and subcortical sites, suggesting a dysfunction in distributed brain networks. In addition, neglect is likely to result from a combination of distinct deficits that co-occur due to concomitant damage affecting juxtaposed brain areas and their connections, but the exact nature of core deficits and their neural substrates still remains unclear. The present review describes recent progress in identifying functional components of the neglect syndrome and relating them to distinct subregions of parietal cortex. A comprehensive understanding of spatial neglect will require a more precise definition of cognitive processes implicated in different behavioral manifestations, as well as meticulous mapping of these processes onto specific brain circuits, while taking into account functional changes in activity that may arise in structurally intact areas subsequent to damage in distant portions of the relevant networks. PMID- 23751038 TI - Mechanism of cell fate choice between neural and mesodermal development during early embryogenesis. AB - During early embryogenesis, Sox2 expression distinguishes the neural plate from other embryonic domains, suggesting that the mechanism underlying the activation of the Sox2 gene is highly relevant to the development of this tissue. At the earliest stages of neural plate development, the Sox2 enhancer N1 regulates Sox2 expression in the extending posterior end of the neural plate. The N1 enhancer is initially activated in the axial stem cells, bipotential precursors of both neural and mesodermal lineages, therefore the activation does not immediately lead to Sox2 expression. A population of axial stem cells that remains in the superficial layer starts expressing Sox2, whereas another population that migrates through the primitive streak loses the N1 activity and becomes mesoderm. Multiple signaling cascades and transcription factors, including Wnt, fibroblast growth factor (FGF), bone morphogenetic protein (BMP) and Tbx6, are responsible for the regulation of Sox2 expression in axial stem cells to guide the development of the posterior neural plate and paraxial mesoderm. PMID- 23751039 TI - Craniofacial and dental malformations in Costello syndrome: A detailed evaluation using multi-detector row computed tomography. AB - Costello syndrome is a rare multiple congenital anomaly syndrome caused by heterozygous germline HRAS mutations, which is characterized by intellectual disability, growth retardation, distinctive facies, loose skin, cardiomyopathy and a preposition to malignancies. Although teeth abnormalities have been encountered in nearly two-thirds of the patients in literature, the evaluation tended to be limited to the extent which can be obtained from physical examination. We investigated detailed craniofacial, oral and dental findings in four patients with Costello syndrome. In this study, images reconstructed by multi-detector row computed tomography (MDCT) were used as substitutes for dental cast study and panoramic and lateral cephalometric radiograph studies to evaluate dental arches, tooth size, relationships between craniofacial and dental structures, and hypodontia. All four patients showed true/relative macrocephaly with facial bone hypoplasia and gingival hypertrophy. Occlusal attrition, malocclusion, small dental arches, microdontia, and convex face were noted in three patients. In addition, one patient showed dental caries, conic tooth and gingivitis, and another patient showed hypodontia. Our study suggests that craniofacial and dental abnormalities are common in Costello syndrome patients and comprehensive dental care should be provided from early infancy. To our knowledge, this is the first study of thorough craniofacial and dental evaluation by using MDCT in Costello syndrome. MDCT is a useful tool for precise evaluation of craniofacial and oral manifestations in patients with congenital anomaly/intellectual disability syndromes. PMID- 23751040 TI - Bifid choroid plexus: always a normal fetal brain structure variant? AB - Choroid plexus, a fetal organ developing approximately from the sixth week of gestation, plays a fundamental role in developing fetal brain organization. As relatively little is known about the relationship between anomalies of choroid plexuses structure and their role in brain function, we examined cases of bifid choroid plexus (BCP) and discussed their potential association with lateral ventriculomegaly, other abnormal ultrasound findings, and their potential role as markers of fetal chromosomal abnormalities. In the present study, we described 23 cases of fetal BCP found in 2145 routine second trimester ultrasounds. For each patient 2D and 3D ultrasound volumes were acquired. BCP was defined as a choroid plexus whose body was divided into two portions (arms) differently located and oriented on the three spatial axes in correspondence to the lateral ventricle, in one or both sides. The entity of the separation and reciprocal orientation of the two arms was examined. The presence of BCP in a low-risk population of pregnant women undergoing routine second trimester ultrasound was showed. Lateral ventricles significantly increased in the presence of BCP. Malformations were found in four of 23 fetuses with BCP. Pregnancy outcome was favorable only in one of these four cases. We suggest that in the presence of mono or bilateral BCP without associated abnormal ultrasound findings, a closer look at fetal brain or extra-cranial structures is recommended. If no related abnormalities are found, serial prenatal and postnatal sonographic follow-up should be considered. In the presence of concomitant abnormal findings, genetic counseling, fetal karyotyping and magnetic resonance imaging, if possible by gestational age, are strongly advised. PMID- 23751041 TI - Radiographic features of Kirner's deformity. AB - We conducted a study of Kirner's deformity to investigate its radiologic features and consider its possible causes. Sixty-seven patients with Kirner's deformity, 41 in our series and 26 retrieved in a survey of the literature were investigated. We divided Kirner's deformity into three types according to the site of curvature: the epiphyseal line, diaphysis, and distal tip. Among our series, 12 hands were affected in males and 26 in females. The gender of the patients for the other three hands was unknown. Twelve cases occurred on the right side, five on the left side, and 24 on both sides. Radiographic data for 34 hands were available. The palmar surface of the distal phalanx was at a mean angle of 27.4 degrees to the long axis of the middle phalanx. Epiphyseal line curvature was seen in four hands (mean patient age, 11 years), diaphysis curvature in 10 (mean age, 12.4 years), and distal tip curvature in 20 (mean age, 26.5 years). Dorsal subluxation of the distal phalanx was noticed in six hands (18%). Radiographic data for 26 hands reported previously were analyzable. The differences between epiphyseal line or diaphysis curvature and distal tip curvature in terms of age were significant in both the present study and the literature. PMID- 23751042 TI - FGF18 accelerates osteoblast differentiation by upregulating Bmp2 expression. AB - Fibroblast growth factor (FGF) signaling is involved in skeletal development. Among total 22 FGFs, it is suggested that FGF18 functions in promotion of osteoblast differentiation. In order to elucidate the mechanism of FGF18 dependent acceleration of osteogenesis, we implanted rhFGF18 soaked beads over mouse fetal coronal sutures using ex-utero surgery. The coronal suture area comprises the peripheries of the developing frontal and parietal bones, separated by the sutural mesenchyme. rhFGF18 accelerated osteogenesis by promoting connection of the frontal and parietal bone domains, resulting in elimination of the sutural mesenchyme. Expression of Fgf receptors, Fgfr1, -2 and -3 involved in skeletal development, was maintained or upregulated in the developing bone domains, consistent with enhanced osteogenesis. Bone morphogenetic protein (Bmp) 2 was specifically upregulated in the skeletogenic layer and the application of Bmp antagonist, rmNoggin, inhibited rhFGF18-dependent upregulation of osteoblast markers. These results suggest that FGF18 accelerates osteogenesis by upregulation of Bmp2 as well as maintenance or upregulation of Fgfr1, -2 and -3 expression in osteoblasts. PMID- 23751043 TI - Prenatal cytogenetic diagnosis from fetal urine in lower urinary tract obstruction. AB - The aim of this study was to test if prenatal cytogenetic diagnosis can be performed on fetal urine in fetal lower urinary tract obstruction. In this retrospective cohort study of fetuses with lower urinary tract obstruction (LUTO) over a 4-year period at one institution, cytogenetic evaluation was attempted on fetal urine samples as well as amniotic fluid specimens. A total of 11 cases, ranging in gestational age from 15 to 25 weeks, underwent amniocentesis and vesicocentesis. Traditional cytogenetic evaluation was successfully completed in amniotic fluid and fetal urine samples in all 11 cases (100%). The karyotype was normal in seven (64%), trisomy 21 in two (18%), Trisomy 13 in one (9%), and partial chromosome 4 deletion in one (9%). Traditional cytogenetic evaluation can be successfully performed on fetal urine samples in cases of lower urinary tract obstruction. PMID- 23751044 TI - Two cases of prenatally diagnosed sacrococcygeal teratoma type I with different clinical features. AB - Sacrococcygeal teratoma (SCT) is a rare congenital disease and prognostic factors have not been entirely established. We report two cases of fetal SCT with different clinical courses. Case 1 was a cystic, slow growing tumor with mild vascularity. The tumor was removed one week after delivery at 35 weeks, and there was no recurrence at 1.5-year follow-up. Case 2 was a solid, rapid growing tumor with rich vascularity. Cesarean section was performed due to severe fetal hydrops and mirror syndrome in the mother at 27 weeks. The tumor had ruptured and was removed soon after delivery to control bleeding, but the baby died the next day. Our cases suggest that solid component and rich vascularity might correlate with poor prognosis. PMID- 23751045 TI - Monochorionic twin fetus with VACTERL association after intracytoplasmic sperm injection. AB - We report a rare case of a monochorionic twin gestation after intracytoplasmic sperm injection (ICSI) in which one of the fetuses had VACTERL association. A 27 year-old woman became pregnant by ICSI and was found to have monochorionic twin fetuses. One fetus was noted to have the following anomalies: a multicystic, dysplastic left kidney with a hydroureter, and a dilated colon. A normal-sized stomach and normal amount of amniotic fluid were observed during the prenatal period with no other anomalies. The postnatal examination revealed hypospadias, and anal, esophageal, and duodenal atresia; thus, a diagnosis of VACTERL association was established. Although the prenatal diagnosis of this disorder is a challenge, even in a singleton, some of the characteristic features observed during antepartum ultrasonography may be a clue to the diagnosis, especially in a twin pregnancy after ICSI. PMID- 23751046 TI - Tabriz Registry of Congenital Anomalies: a report of 10 years of monitoring birth defects in Iran. PMID- 23751047 TI - Fabricating nanoscale chemical gradients with ThermoChemical NanoLithography. AB - Production of chemical concentration gradients on the submicrometer scale remains a formidable challenge, despite the broad range of potential applications and their ubiquity throughout nature. We present a strategy to quantitatively prescribe spatial variations in functional group concentration using ThermoChemical NanoLithography (TCNL). The approach uses a heated cantilever to drive a localized nanoscale chemical reaction at an interface, where a reactant is transformed into a product. We show using friction force microscopy that localized gradients in the product concentration have a spatial resolution of ~20 nm where the entire concentration profile is confined to sub-180 nm. To gain quantitative control over the concentration, we introduce a chemical kinetics model of the thermally driven nanoreaction that shows excellent agreement with experiments. The comparison provides a calibration of the nonlinear dependence of product concentration versus temperature, which we use to design two-dimensional temperature maps encoding the prescription for linear and nonlinear gradients. The resultant chemical nanopatterns show high fidelity to the user-defined patterns, including the ability to realize complex chemical patterns with arbitrary variations in peak concentration with a spatial resolution of 180 nm or better. While this work focuses on producing chemical gradients of amine groups, other functionalities are a straightforward modification. We envision that using the basic scheme introduced here, quantitative TCNL will be capable of patterning gradients of other exploitable physical or chemical properties such as fluorescence in conjugated polymers and conductivity in graphene. The access to submicrometer chemical concentration and gradient patterning provides a new dimension of control for nanolithography. PMID- 23751048 TI - Immunization in end-stage renal disease: opportunity to improve outcomes. AB - Infection is the second most common cause of death in patients with end-stage renal disease (ESRD), following cardiovascular causes. Immunization is a fairly simple, but underutilized, strategy for prevention of infectious morbidity and mortality in patients with kidney failure. It is imperative for nephrologists and primary care providers to have an understanding of immunization as an essential component of preventive healthcare measures in this high-risk population. Patients with ESRD represent a unique population due to their immunosuppressed state, dialysis-related exposures and suboptimal response to routine vaccines. While the Advisory Committee on Immunization Practices (ACIP) provides guidelines for vaccination of patients with renal disease against Hepatitis B, influenza and pneumococcal disease, the data on immunization against other commonly preventable infectious diseases are lacking. This article reviews the recent evidence on immunization in the ESRD population and synthesizes the related implications for maximizing prevention of infectious diseases in this high-risk population. PMID- 23751049 TI - A fullerene-based organic exciton blocking layer with high electron conductivity. AB - We demonstrate the concentration dependence of C60 absorption in solid solutions of C60 and bathocuprione (BCP), revealing a nonlinear decrease of the C60 charge transfer (CT) state absorption. These blends are utilized to study the photocurrent contribution of the CT in bilayer organic photovoltaics (OPVs); 1:1 blends produce 40% less photocurrent. As exciton blocking electron transporting layers, the blends achieve power conversion efficiencies of 5.3%, an increase of 10% compared to conventional buffers. PMID- 23751050 TI - The required beta cell research for improving treatment of type 2 diabetes. AB - In healthy individuals, insulin resistance is associated with physiological conditions such as pregnancy or body weight gain and triggers an increase in beta cell number and insulin secretion capacity to preserve normoglycaemia. Failure of this beta cell compensation capacity is a fundamental cause of diabetic hyperglycaemia. Incomplete understanding of the molecular mechanisms controlling the plasticity of adult beta cells mechanisms and how these cells fail during the pathogenesis of diabetes strongly limits the ability to develop new beta cell specific therapies. Here, current knowledge of the signalling pathways controlling beta cell plasticity is reviewed, and possible directions for future research are discussed. PMID- 23751051 TI - The principal PINK1 and Parkin cellular events triggered in response to dissipation of mitochondrial membrane potential occur in primary neurons. AB - PINK1 and PARKIN are causal genes for hereditary Parkinsonism. Recent studies have shown that PINK1 and Parkin play a pivotal role in the quality control of mitochondria, and dysfunction of either protein likely results in the accumulation of low-quality mitochondria that triggers early-onset familial Parkinsonism. As neurons are destined to degenerate in PINK1/Parkin-associated Parkinsonism, it is imperative to investigate the function of PINK1 and Parkin in neurons. However, most studies investigating PINK1/Parkin have used non-neuronal cell lines. Here we show that the principal PINK1 and Parkin cellular events that have been documented in non-neuronal lines in response to mitochondrial damage also occur in primary neurons. We found that dissipation of the mitochondrial membrane potential triggers phosphorylation of both PINK1 and Parkin and that, in response, Parkin translocates to depolarized mitochondria. Furthermore, Parkin's E3 activity is re-established concomitant with ubiquitin-ester formation at Cys431 of Parkin. As a result, mitochondrial substrates in neurons become ubiquitylated. These results underscore the relevance of the PINK1/Parkin mediated mitochondrial quality control pathway in primary neurons and shed further light on the underlying mechanisms of the PINK1 and Parkin pathogenic mutations that predispose Parkinsonism in vivo. PMID- 23751052 TI - Fitness limitations in non-disabled extremely low birthweight adolescents. AB - AIM: This study aims to compare non-disabled otherwise healthy extremely low birthweight (ELBW) (<1000 g) children and term-born peers in an investigation of relationship between cardiorespiratory endurance and parent report of competence. METHODS: Forty-eight of 105 eligible ELBW 11- to 13-year-old children (27 male) and 55 term-born school peers (28 male) completed a 20-m shuttle run, anthropometric measures, respiratory function tests and the Motor Assessment Battery for Children. Parents completed the Child Behavior Checklist (CBCL). RESULTS: The ELBW group had poorer cardiorespiratory endurance (P = 0.002), growth (P = 0.002), respiratory function (P = 0.003) and motor ability (P < 0.001) than term-born peers. Parents reported the ELBW children to be less competent than term-born peers: CBCL total T score mean difference -9, 95% confidence interval -14, -5 (P < 0.001). Cardiorespiratory endurance predicted competence (regression coefficient 0.865; 95% confidence interval 0.352, 1.378; P = 0.001) independent of prematurity, growth, respiratory function, motor score, gender and socio-economic status. Cardiorespiratory endurance had association with social competence for all participating children, but was related to CBCL Activities Competence only for the ELBW children who were the significantly less fit group. CONCLUSIONS: The poor cardiorespiratory endurance prevalent in non disabled otherwise healthy ELBW children is associated with general competence independent of prematurity and of the impact of other mild physical deficits, gender or socio-economic status. The relationship demonstrated between cardiorespiratory endurance and competence to engage in general activities of daily living, seen only in the less fit ELBW children, identifies the fitness levels in non-disabled ELBW children as a barrier to participation. PMID- 23751053 TI - Aerotaxis governs floating biofilm formation in Shewanella oneidensis. AB - Floating biofilm, or pellicle, is a biofilm found at the air-liquid interface. Here, we show that pellicle development of the aquatic bacterium Shewanella oneidensis is under the control of the chemotaxis system (Che3), a regulatory system known to pilot planktonic cell motion according to environmental cues. Deletion of the histidine kinase cheA3 or the response regulator cheY3 gene led to a heterogeneous pellicle or to the absence of pellicle respectively. In addition, a non-phosphorylatable CheY3-D56A mutant was unable to promote pellicle formation. Kinetic analysis revealed that pellicle formation occurs in three steps: rapid formation of a thin pellicle evolving into a heterogeneous biofilm and finally into a thick homogeneous biofilm. Depletion of oxygen not only abolished initiation of pellicle formation but also blocked pellicle maturation. This study thus demonstrates an essential role of aerotaxis (chemotaxis towards oxygen) in floating biofilm development in S. oneidensis, and it also reveals that pellicle formation is a step-by-step process. PMID- 23751054 TI - Fertility outcome of breast cancer and Hodgkin's lymphoma female survivors: a growing clinical challenge for gynecologists and oncologists. AB - The issue of taking into consideration future fertility in young women with breast cancer and Hodgkin's lymphoma [HL] will become more and more common and represent a growing clinical challenge for gynecologists and oncologists. The present paper will review literature data on the attempts of preventing chemotherapy-induced ovarian damage in these women and on their fertility outcome. Gonadotropin-releasing hormone [Gn-RH] agonists have been widely investigated as agents able to prevent ovarian failure in animal models and in humans. The majority of the studies on women with breast cancer and HL have shown a protective effect of Gn-RH agonists. A recent meta-analysis of five randomized trials, including 528 premenopausal breast cancer patients, revealed that relative risk [RR] of developing premature ovarian failure within one year was 0.40 (95% confidence interval [CI] = 0.21-0.75) for the women who received Gn-RH agonists with chemotherapy compared to those who received chemotherapy alone. However, the concurrent administration of Gn-RH agonists during chemotherapy appeared to have no effect on spontaneous pregnancy rates. Limited information are available about pregnancies in breast cancer and HL survivors, but the current literature appears to show no apparent increase in pregnancy complications, spontaneous abortions, or congenital abnormalities compared to general obstetric population. PMID- 23751055 TI - Myth dispelled. PMID- 23751056 TI - Participatory research and capacity building for community health and development. Introduction. AB - It is my pleasure to introduce this themed issue on "Participatory Research and Capacity Building for Community Health and Development." While most of the literature is still dominated by targeted interventions, run by researchers, that have a limited reach (usually affecting change among much less than 100 persons), these community interventions affect the broader social ecology. Even further, there is a growing literature on community-engaged scholarship that calls for this kind of active partnership but often falls far short of its goals (Calleson, Jordan, & Seifer, 2005 ). The articles in this themed issue represent the possibility of collaborations between university researchers, state-level policy makers, and community-based groups to affect widespread changes in the social and physical environment. PMID- 23751057 TI - Participatory research and capacity building for community health and development. AB - This report describes engagement of the Work Group for Community Health and Development at the University of Kansas in pursuing its mission of collaborative research, teaching, and public service. In research, this team uses capabilities for community measurement to help discover factors and conditions that affect community change and improvement. In teaching and training, it prepares new generations of leadership for collaborative research and community practice. As part of its public service mission, the team serves as home base for the Community Tool Box, the largest Web resource of its kind for community building. This work reflects the two-fold aim of engaged scholarship: to contribute to understanding about what affects community health and development and to apply that knowledge to assure conditions that promote well-being for all those living in our communities. PMID- 23751058 TI - Community-based participatory research within the Latino health for all coalition. AB - Despite widespread recognition that Latinos and other minorities are at higher risk for diabetes and cardiovascular diseases, much less is known about how to create conditions for health and health equity. This report presents information about implementation of the Health for All Model in accordance with principles of community-based participatory research (CBPR). Using an empirical case study design, we reported on community changes (i.e., new or modified programs, policies, or practices) facilitated by the coalition and their distribution among primary goal areas (i.e., healthy nutrition, physical activity, and access to health services) and in different community sectors and ecological levels. Qualitative information suggested that the community and scientific partners shared decision making and control, as well as adherence to other principles of community-based participatory research. Such systematic efforts contribute to our understanding of how collaborative action can achieve the changes in conditions necessary to assure health for all. PMID- 23751059 TI - Supporting a community-based participatory evaluation approach to violence prevention in Kansas City. AB - Disparities in rates of firearm-related homicide exist for some segments of the population and by geographic area. There are interrelated factors across multiple social-ecological levels that increase the risk of violence for some individuals and groups, which may suggest the importance of comprehensive community intervention approaches for addressing violence. Participatory approaches can aid in the implementation of community interventions by engaging community and researcher partners in collaboratively addressing community-identified concerns. The purpose of the present study is to demonstrate the application of a participatory evaluation framework used to support the Aim4Peace Violence Prevention Project in Kansas City, Missouri. The study presents data from the second year of program implementation to examine the contributions of the program in addressing violence. PMID- 23751060 TI - The role of advocacy in occasioning community and organizational change in a medical-legal partnership. AB - Health disparities among low-income individuals remain a significant problem. A number of social determinants are associated with adverse health outcomes. Medical-legal partnerships address legal concerns of low-income individuals to improve health and wellness in adults and children. The Medical-Legal Partnership at Legal Aid of Western Missouri provides free direct legal services for patients with legal concerns affecting health. There is limited evidence regarding the association between advocacy-related efforts and changes within both the medical legal partnership structure and in health-care facilities. Three health-care organizations in Kansas City, MO participated in implementing the medical-legal partnership model between 2007 and 2010. Advocacy efforts conducted by key medical-legal partnership personnel were strongly associated with changes in health-care organizations and within the medical-legal partnership structure. This study extends the current evidence base by examining the types of advocacy efforts required to bring about community and organizational changes. PMID- 23751061 TI - Enhancing the capacity of substance abuse prevention coalitions through training and technical assistance. AB - Community capacity may be enhanced through intermediary supports that provide training and technical assistance (TA). This study used a randomized pre/posttest design to assess the impact of training and TA on coalition capacity. Seven community coalitions from the Midwest participated in the 2-year study, which included 36 hours of training, followed by monthly TA calls to support action planning implementation for prioritized processes. Collaborative processes most commonly identified as high-need areas for TA were Developing Organizational Structure, Documenting Progress, Making Outcomes Matter, and Sustaining the Work. Based on a coalition survey, the average change for processes prioritized through TA across all seven coalitions was .27 (SD = .29), while the average change for non-prioritized processes was .09 (SD = .20) (t(6) = 4.86, p = .003, d = 1.84). The findings from this study suggest that TA can increase coalition capacity for implementing collaborative processes using a participatory approach. PMID- 23751062 TI - Participatory monitoring and evaluation within a statewide support system to prevent adolescent substance abuse. AB - To prevent youth substance abuse, a state prevention system aims to support implementation of best practices statewide. A critical component is the prevention support system; that is, the network of people and organizations that build capacity within communities to implement prevention activities. This study describes the Kansas Prevention Network (KPN), the prevention support system within Kansas. It examines how KPN uses monitoring and evaluation to guide support for implementation of prevention activities. From 2009 to 2011, support organizations implemented nearly 4,000 activities to build capacity of local coalitions to better implement interventions. Activities focused primarily on building capacity for community-based processes, such as assessment and planning, and for dissemination of information. This report describes innovative approaches to documenting and monitoring the statewide effort as well as structured approaches for using the data to guide decision making and technical assistance. PMID- 23751063 TI - Disseminating online tools for building capacity among community practitioners. AB - To prepare the workforce for building healthier communities, we need to assure capabilities of a diverse and geographically distributed community of practitioners. Although the Internet is used extensively to disseminate practice information, less is known about the relative impact of various strategies for promoting its use. This empirical case study examines implementation of dissemination strategies and their association with increased user sessions in the online Community Tool Box (CTB), a widely used resource for community building. Dissemination activities included social media efforts, eNewsletters, search engine optimization efforts, partnering with other Web sites, and implementing a global Out of the Box Prize. Results suggest that increased user sessions were associated with search optimization and "mashups" delivering CTB content through partners' Web sites. The report concludes with a discussion of challenges and opportunities in promoting widespread use of capacity-building tools among those working to improve their communities. PMID- 23751064 TI - [Share with women. Motherhood: the first days]. PMID- 23751065 TI - Adenosine triphosphate hydrolysis mechanism in kinesin studied by combined quantum-mechanical/molecular-mechanical metadynamics simulations. AB - Kinesin is a molecular motor that hydrolyzes adenosine triphosphate (ATP) and moves along microtubules against load. While motility and atomic structures have been well-characterized for various members of the kinesin family, not much is known about ATP hydrolysis inside the active site. Here, we study ATP hydrolysis mechanisms in the kinesin-5 protein Eg5 by using combined quantum mechanics/molecular mechanics metadynamics simulations. Approximately 200 atoms at the catalytic site are treated by a dispersion-corrected density functional and, in total, 13 metadynamics simulations are performed with their cumulative time reaching ~0.7 ns. Using the converged runs, we compute free energy surfaces and obtain a few hydrolysis pathways. The pathway with the lowest free energy barrier involves a two-water chain and is initiated by the Pgamma-Obeta dissociation concerted with approach of the lytic water to PgammaO3-. This immediately induces a proton transfer from the lytic water to another water, which then gives a proton to the conserved Glu270. Later, the proton is transferred back from Glu270 to HPO(4)2- via another hydrogen-bonded chain. We find that the reaction is favorable when the salt bridge between Glu270 in switch II and Arg234 in switch I is transiently broken, which facilitates the ability of Glu270 to accept a proton. When ATP is placed in the ADP-bound conformation of Eg5, the ATP-Mg moiety is surrounded by many water molecules and Thr107 blocks the water chain, which together make the hydrolysis reaction less favorable. The observed two-water chain mechanisms are rather similar to those suggested in two other motors, myosin and F1-ATPase, raising the possibility of a common mechanism. PMID- 23751066 TI - James Cook University MBBS graduate intentions and intern destinations: a comparative study with other Queensland and Australian medical schools. AB - INTRODUCTION: Since 1999 the number of medical school places in Australia has increased substantially in response to workforce shortages, with some of the increased capacity in regional and rural communities. The James Cook University (JCU) School of Medicine, the first of a number of new medical schools, was established with a mission to address the health needs of rural, remote and tropical Australia through aligning student selection, curriculum and assessment practices to encourage generalist postgraduate careers needed in rural and regional areas. This article reports early evidence on the career outcomes of graduates in the first six cohorts from 2005 to 2010, and compares this with available data from other Queensland and Australian medical schools. METHODS: Data were gathered from two sources to allow comparisons of career intentions and intern allocations of graduates from JCU with those from other Australian medical schools. An exit survey of JCU graduates provided JCU student data while the Medical Students Outcomes Database provided comparable data for eight other, largely metropolitan, schools. RESULTS: At graduation, 88% of JCU medical students intended to practise outside Australian capital cities compared with 31% of graduates from other medical schools (odds ratio [OR]: 16.5). More JCU medical graduates than others planned to work in rural towns or regional centres with a population of less than 100 000 (46% compared with 16% for the rest of Australia; OR: 4.6). Sixty-seven percent of JCU graduates undertook their internship outside a metropolitan centre compared with 17% of others (OR: 10.0), and 47% in outer regional centres compared with 5% (OR: 16.6), respectively. Medical graduates from JCU were more likely to prefer general practice as a career (OR: 1.5), particularly rural medicine (OR 2.5), but otherwise had similar preferences to others. Interest in 'working in a rural area' increased over the course duration from 68% at entry to 76% at graduation. CONCLUSION: While further follow up is needed to track career progression over a longer time, the data so far suggest that the career outcomes of JCU medical graduates are aligned with the workforce needs of the region, and different from those graduating from Australia's predominantly metropolitan medical schools, as predicted by the program's design. PMID- 23751067 TI - Arsenate and phosphate adsorption in relation to oxides composition in soils: LCD modeling. AB - The pH dependent solid-solution distribution of arsenate and phosphate in five Dutch agricultural soil samples was measured in the pH range 4-8, and the results were interpreted using the LCD (ligand and charge distribution) adsorption modeling. The pH dependency is similar for both oxyanions, with a minimum soluble concentration observed around pH 6-8. This pH dependency can be successfully described with the LCD model and it is attributed mainly to the synergistic effects from Ca adsorption. The solubility of phosphate is much lower than that of arsenate. This big difference cannot be sufficiently explained by the reduction of small amount of As(V) into As(III), neither by slow desorption/adsorption. The difference between phosphate and arsenate in their solid-solution distribution becomes larger with the increase of aluminum (hydr)oxides (Al-oxides) contribution to the total amount of metal (Al and Fe) (hydr)oxides. The influence of Al-oxides is much larger than its relative amount extracted from the soils. When Al-oxides account for >40% of the soil oxides, the whole adsorbents behave apparently similarly to that of pure Al-oxides. These results indicated that surface coating and substitution may have modified significantly oxyanion adsorption to Fe-oxides in soils, and how to account for this complexity is a challenge for geochemical modeling. PMID- 23751068 TI - Resveratrol prevents development of eosinophilic rhinosinusitis with nasal polyps in a mouse model. AB - BACKGROUND: Since the recent establishment of a murine model of eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP), both the development of new drugs for treatment or prevention of eosinophilic CRSwNP and elucidation of their pathogenesis have been feasible. We investigated the therapeutic effects of resveratrol on CRSwNP and its mechanism of action using a murine model. METHODS: After induction of eosinophilic CRSwNP, the therapeutic effects of resveratrol were tested and compared with those of triamcinolone acetonide. Histopathologic changes were evaluated using hematoxylin and eosin for overall inflammation, Sirius red for eosinophils, and Masson's trichrome stain for collagen. The expression levels of the interleukin (IL)-4, IL-5, prostaglandin D synthase, and leukotriene C4 synthase genes were assessed by quantitative real-time PCR. Cyclooxygense-2 and 5-lipoxygense levels were evaluated by immunohistochemical staining and Western blot analysis. RESULTS: The degree of eosinophilic infiltration and subepithelial fibrosis was significantly decreased by administration of high-dose resveratrol, the potency of which was similar to that of triamcinolone acetonide. The expression levels of the IL-4, IL-5, prostaglandin D synthase, and leukotriene C4 synthase genes were significantly decreased by administration of low- or high-dose resveratrol. The production of 5 lipoxygenase was strongly inhibited by high-dose resveratrol. CONCLUSIONS: Resveratrol may be useful for the prevention of eosinophilic CRSwNP. A key mechanism of its action is believed to be its anti-inflammatory effect, particularly on eosinophils, by inhibiting the lipoxygenase pathway. PMID- 23751070 TI - Searching for recursively defined generic chemical patterns in nonenumerated fragment spaces. AB - Retrieving molecules with specific structural features is a fundamental requirement of today's molecular database technologies. Estimates claim the chemical space relevant for drug discovery to be around 1060 molecules. This figure is many orders of magnitude larger than the amount of molecules conventional databases retain today and will store in the future. An elegant description of such a large chemical space is provided by the concept of fragment spaces. A fragment space comprises fragments that are molecules with open valences and describes rules how to connect these fragments to products. Due to the combinatorial nature of fragment spaces, a complete enumeration of its products is intractable. We present an algorithm to search fragment spaces for generic chemical patterns as present in the SMARTS chemical pattern language. Our method allows specification of the chemical surrounding of an atom in a query and, therefore, enables a chemically intuitive search. During the search, the costly enumeration of products is avoided. The result is a fragment space that exactly describes all possible molecules that contain the user-defined pattern. We evaluated the algorithm in three different drug development use-cases and performed a large scale statistical analysis with 738 SMARTS patterns on three public available fragment spaces. Our results show the ability of the algorithm to explore the chemical space around known active molecules, to analyze fragment spaces for the presence of likely toxic molecules, and to identify complex macromolecular structures under additional structural constraints. By searching the fragment space in its nonenumerated form, spaces covering up to 1019 molecules can be examined in times ranging between 47 s and 19 min depending on the complexity of the query pattern. PMID- 23751069 TI - Long-range 1H-15N J couplings providing a method for direct studies of the structure and azide-tetrazole equilibrium in a series of azido-1,2,4-triazines and azidopyrimidines. AB - The selectively (15)N labeled azido-1,2,4-triazine 2*A and azidopyrimidine 4*A were synthesized by treating hydrazinoazines with (15)N-labeled nitrous acid. The synthesized compounds were studied by (1)H, (13)C, and (15)N NMR spectroscopy in DMSO, TFA, and DMSO/TFA solutions, where the azide-tetrazole equilibrium could lead to the formation of two tetrazoles (T, T') and one azide (A) isomer for each compound. The incorporation of the (15)N label led to the appearance of long range (1)H-(15)N coupling constants (J(HN)), which can be measured easily by using amplitude-modulated 1D (1)H spin-echo experiments with selective inversion of the (15)N nuclei. The observed J(HN) patterns enable the unambiguous determination of the mode of fusion between the azole and azine rings in the two groups of tetrazole isomers (2*T', 4*T' and 2*T, 4*T), even for minor isoforms with a low concentration in solution. However, the azide isomers (2*A and 4*A) are characterized by the absence of detectable J(HN) coupling. The analysis of the J(HN) couplings in (15)N-labeled compounds provides a simple and efficient method for direct NMR studies of the azide-tetrazole equilibrium in solution. PMID- 23751071 TI - Editorial: Issues in Comprehensive Pediatric Nursing spreads its wings. PMID- 23751072 TI - Are young people welcome in the English National Health Service? AB - An audit of baseline compliance with contemporary health care policies pertinent to the care of young people in hospital was undertaken in 1 large English District General Hospital. Children's and adult services within the hospital were benchmarked against the government audit tool standards. The aim of the study was to identify good and less optimum compliance to best practice policy driven benchmarks of care, using a 1-4 scale. Each clinical area within the hospital was contacted to make arrangements with members of the inter-professional team to complete the baseline benchmarking exercise. The audit was conducted over 3 days and the majority of the evidence sourced comprised of documented evidence and verbal affirmation of the individual perceptions of key informants of how the various clinical areas scored against the best practice benchmarks. Scores of policy compliance in some clinical areas of the hospital ranged from 1 not yet started (non-compliant) through to 4 you're welcome (fully compliant). The results demonstrate that many of the clinical areas within the hospital are making good efforts to ensure full compliance to policy guidelines and mandates. There are some aspects of policy standards that hospital has yet to fully embrace. This initial benchmarking exercise on behalf of 1 English hospital has revealed some areas of outstanding and good practice which have the potential to be shared. PMID- 23751073 TI - Paediatric Nursing: Teaching Excellence and Patient Safety. PMID- 23751074 TI - Identification of anaplastic lymphoma kinase break points and oncogenic mutation profiles in acral/mucosal melanomas. AB - Acral and mucosal melanomas, the two most common subtypes of melanoma in China, exhibit different genetic alterations and biologic behavior compared with other subtypes of melanomas. The purpose of this study was to identify the genetic alterations in patients with acral or mucosal melanomas in southern China. Fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) analysis, polymerase chain reaction (PCR), and quantitative real-time reverse transcriptase PCR (qRT-PCR) were used to assess the anaplastic lymphoma kinase (ALK) break points. Furthermore, a mass spectrometry-based genotyping platform was used to analyze 30 acral melanomas and 28 mucosal melanomas to profile 238 known somatic mutations in 19 oncogenes. ALK break points were identified in four acral cases (6.9%). Eight (13.8%) cases harbored BRAF mutations, six (10.3%) had NRAS mutations, four (6.9%) had KIT mutations, two (3.5%) had EGFR mutations, two (3.5%) had KRAS mutations, two (3.5%) had MET mutations, one (1.7%) had an HRAS mutation, and one (1.7%) had a PIK3CA mutation. Two cases exhibited co-occurring mutations, and one case with a BRAF mutation had a translocation in ALK. This study represents a comprehensive and concurrent analysis of the major recurrent oncogenic mutations involved in melanoma cases from southern China. These data have implications for both clinical trial designs and therapeutic strategies. PMID- 23751075 TI - Distinguishing folate-receptor-positive cells from folate-receptor-negative cells using a fluorescence off-on nanoprobe. AB - Based on the high affinity of folic acid (FA) for folate receptor (FR) that is overexpressed on the surface of many human cancer cells, we have developed a simple fluorescence nanoprobe (1) with multiple capability (fluorescence off-on response and cell-targeting ability) for imaging of FR-positive cells by covalently linking both FA and Rhodamine B (RB) to graphene oxide (GO) through disulfide bonds. The nanoprobe shows a weak fluorescence due to the electron transfer from GO to RB. However, the specific binding of FA to FR-positive cells leads to the internalization of the nanoprobe into the cells. As a result, the disulfide bonds of 1 are cleaved by intracellular glutathione, causing the release of the RB moiety from GO and thereby the generation of fluorescence. Compared to most of the reported fluorescence always-on nanoprobes for imaging FR positive cells, the present fluorescence off-on nanoprobe can not only produce a high signal/background ratio but also avoid the false positive results often caused by nonspecific adsorption of the always-on nanoprobes on the surface of nontarget cells. Notably, the proposed off-on nanoprobe has been demonstrated to distinguish the cells with different expression levels of FR by culturing and analyzing different cell mixtures (Hela/NIH-3T3 and Hela/MCF-7 cells). Moreover, the nanoprobe is capable of discriminating FR-positive from FR-negative cells even with similar morphology. This method is simple and selective for fluorescence imaging of FR-positive cells. PMID- 23751076 TI - Genome variation and personalized cancer medicine. AB - Genomic variation, through effects on gene structure and expression, plays an important role in understanding disease predisposition, biology and clinical response to therapy. Transforming this knowledge into clinically relevant information that tailors interventions to an individual's specific genetic, physical, social and environmental profile is challenging. To illustrate how research initiatives at preclinical phases of development are attempting to address clinically important issues in oncology, six clinical problems related to cancers of the colon, prostate, breast, pancreas and brain (medulloblastoma) as well as metastatic disease of different origins are described. A unifying theme across applications is that healthy individuals previously indistinguishable in regards to cancer risk and patients with cancer previously categorized as similar with regard to prognosis or drug response are being stratified into more refined subgroups with different clinical profiles. Effective matching of a broad range of tests with more tailored strategies for prevention and/or treatment will require well-designed clinical studies to evaluate benefits and costs. PMID- 23751077 TI - Gadd45g regulates dental epithelial cell proliferation through p38 MAPK-mediated p21 expression. AB - Ectodermal organs, such as teeth, hair follicles, and mammary glands, arise from their respective germs through epithelial-mesenchymal interactions during organogenesis. Growth arrest and DNA damage-inducible gene gamma (Gadd45g) have been shown to play important roles in various biological processes, such as stress responses, cell differentiation, and tumor suppression, through the regulation of cell proliferation and gene expression. We found that Gadd45g was expressed in enamel knots, which orchestrate tooth germ development as epithelial signaling centers. Gadd45g induced the expression of p21 and inhibited the proliferation of dental epithelial cells. The up-regulation of p21 expression was regulated by Gadd45g-mediated activation of the p38 MAPK pathway. Thus, our results suggest that Gadd45g is involved in the regulation of p21-mediated epithelial cell proliferation through the p38 MAPK pathway during tooth organ development. PMID- 23751079 TI - Virtual histology intravascular ultrasound analysis of attenuated plaque and ulcerated plaque detected by gray scale intravascular ultrasound and the relation between the plaque composition and slow flow/no reflow phenomenon during percutaneous coronary intervention. AB - OBJECTIVE: This study aimed to assess the plaque characteristics of attenuated and ulcerated plaques in virtual-histology intravascular ultrasound (VH-IVUS) and the incidence of slow flow/no reflow during percutaneous coronary intervention (PCI). BACKGROUND: The attenuated and ulcerated plaques are thought as embolic prone plaque; however, the plaque characteristics are unclear. METHODS: Subjects were 119 patient's 121 lesions undergoing VH-IVUS before coronary stenting. These lesions were divided into the 15 lesions showing attenuated plaque, 24 lesions showing ulcerated plaque, and 82 lesions revealing neither attenuated nor ulcerated plaque (the control group). RESULTS: Fibro-fatty tissue in the attenuation group was significantly larger than the control group (27.5 +/- 9.5% vs 13.9 +/- 8.2%, P < 0.01, 3.5 +/- 1.9 mm(2) vs 1.6 +/- 1.2 mm(2), P < 0.01). Necrotic core in ulceration group was significantly larger than the control group (20.7 +/- 9.0% vs 15.9 +/- 9.0%, P < 0.05, 2.5 +/- 1.3 mm(2) vs 1.7 +/- 1.0 mm(2), P < 0.01). Dense calcium in ulceration group was significantly larger than the control group (12.3 +/- 6.4% vs 8.3 +/- 7.1%, P < 0.05, 1.4 +/- 0.7 mm(2) vs 0.9 +/- 0.8 mm(2), P < 0.01). In the ulceration group, the necrotic core area of acute coronary syndrome was significantly larger than the stable angina pectoris (3.0 +/- 1.4 mm(2) vs 1.8 +/- 1.0 mm(2), P < 0.05). The incidence of slow flow/no reflow was significantly higher in the attenuation and ulceration group than the control group (20.0% [3/15], 20.8% [4/24] vs 4.9% [4/82], P < 0.05, 0.05). CONCLUSION: The attenuated plaque had significantly larger fibro-fatty tissue. The ulcerated plaque had significantly larger necrotic core and dense calcium. The lesions with the attenuated and the ulcerated plaque had more frequent slow flow/no reflow during PCI. PMID- 23751080 TI - Aortic annulus measurement and relevance to successful transcatheter aortic valve replacement: a new technique using 3D TEE. AB - BACKGROUND: There are limitations of using 2D imaging to accurately size the aortic annulus. This article highlights the limitations of 2D technology and proposes a new 3D TEE method for sizing of the aortic annulus. METHODS: Three dimensional echocardiography with the method described can identify the "true" aortic annulus with precision. A 3D dataset of the aortic annulus is collected. The 3D quantification program is then activated. The three multiplanar reconstruction planes (the aortic short-axis, long-axis, and coronal planes) are aligned during systole, to obtain the 3 nadirs of the sinuses of Valsalva simultaneously in the short-axis MPR. Rotating the sagittal and coronal planes to identify the hinge points is necessary to measure the diameter of the "true" annulus. The "true" aortic annulus is defined by the blood-tissue interface in the aortic short-axis MPR. RESULTS: This method has been prospectively validated with surgical AVR sizing in a small study of 10 patients. During surgical AVR, the annulus was directly measured using a sizer. This served as a gold standard for comparison. The annulus was measured using the method described in a blinded fashion by the cardiac anesthesiologist and then confirmed offline by a blinded echocardiographer. In this small study, the Pearson correlation coefficient was 0.9833 with 23.4 and 23.22 mm being the mean measurements with the 2 methods. DISCUSSION: The method described in this article is complementary to multidetector computed tomography and provides a real-time measurement of the annulus during the TAVR procedure without need for radiographic contrast. PMID- 23751082 TI - Open membranes are the precursors for assembly of large DNA viruses. AB - Nucleo cytoplasmic large DNA viruses (NCLDVs) are a group of double-stranded DNA viruses that replicate their DNA partly or entirely in the cytoplasm in association with viral factories (VFs). They share about 50 genes suggesting that they are derived from a common ancestor. Using transmission electron microscopy (TEM) and electron tomography (ET) we showed that the NCLDV vaccinia virus (VACV) acquires its membrane from open membrane intermediates, derived from the ER. These open membranes contribute to the formation of a single open membrane of the immature virion, shaped into a sphere by the assembly of the viral scaffold protein on its convex side. We now compare VACV with the NCLDV Mimivirus by TEM and ET and show that the latter also acquires its membrane from open membrane intermediates that accumulate at the periphery of the cytoplasmic VF. In analogy to VACV this membrane is shaped by the assembly of a layer on the convexside of its membrane, likely representing the Mimivirus capsid protein. By quantitative ET we show for both viruses that the open membrane intermediates of assembly adopt an 'open-eight' conformation with a characteristic diameter of 90 nm for Mimi- and 50 nm for VACV. We discuss these results with respect to the common ancestry of NCLDVs and propose a hypothesis on the possible origin of this unusual membrane biogenesis. PMID- 23751083 TI - Ultrathin endoscope-assisted self-expandable metallic stent placement following initial unsuccessful attempt in malignant upper gastrointestinal obstruction. AB - BACKGROUND: Conventional endoscopy for self-expandable metallic stent (SEMS) placement may be technically limited in long and tortuous strictures. Therefore, we analyzed the feasibility, safety and usefulness of ultrathin endoscopy (UTE) guided SEMS placement. PATIENTS AND METHODS: This study involved 24 patients with upper gastrointestinal obstruction and unsuccessful initial attempts to place SEMS using conventional endoscopy. After completely passing a UTE across the stricture, the UTE was withdrawn, leaving a guidewire placed via the working channel. Through-the-scope SEMS placement was done using a conventional endoscope inserted along the guidewire. The primary endpoints were assessed by technical/clinical success and stent patency duration. RESULTS: Stents were successfully placed at target locations in all but one case with a long tortuous stricture, with 95.8% (23/24) technical success. One week after stent placement, mean gastricoutlet obstruction score improved significantly from baseline (1.74 +/- 0.62 and 0.33 +/- 0.48, respectively; P < 0.001). Stent migration, restenosis, and fracture occurred in four (17.4%), six (26.1%), and one (4.3%) of 23 stents, respectively. Median stent patency duration was 79 days. Mean stent patency was significantly longer in patients who received palliative chemotherapy than in those who did not (122.9 +/- 11.0 and 38.3 +/- 4.6, respectively; P < 0.001). CONCLUSIONS: UTE guidance SEMS delivery can be a feasible and safe rescue treatment method for malignant upper gastrointestinal obstruction in cases of failed attempts to place SEMS using conventional endoscopy. Our result warrants a further study to define the efficacy of this method in difficult SEMS placement cases. PMID- 23751084 TI - Occurrence of steam pops during irrigated RF ablation: novel insights from microwave radiometry. AB - BACKGROUND: The disparity between catheter and tissue temperatures during irrigated RF ablation frustrates one's ability to predict steam pops. Microwave radiometry allows for "volumetric" temperature assessment-i.e., within a circumscribed volume around the catheter tip-permitting, direct assessment of temperature during ablation. The aim of this study was to examine (i) the ability of microwave radiometry to predict steam pops, and (ii) compare this to traditional parameters such as power, catheter temperature, and impedance. METHODS AND RESULTS: Irrigated RF ablation was performed in 8 sheep using the Tempasure ablation catheter in all chambers. Power, impedance, catheter tip, and volumetric temperature were continually monitored. Ablation was terminated after a pop or at 60 seconds. A pop was defined as an audible or visualized pop (intracardiac echocardiography). Predictors of pops were determined by univariate and multivariate GEE logistic regression modeling. A total of 48 pops occurred during 143 lesions applied at 20-50 W. There was no association between the chamber of the heart and the occurrence of pops. The rate of rise of volumetric temperature (greater than 1.5 degrees C/s) was the single best predictor of pops (OR: 88.8 [95% CI: 12-604], P < 0.0007). Pops only occurred above a maximum volumetric temperature threshold of 89 degrees C. CONCLUSIONS: During irrigated RF ablation, steam pop occurrence can be predicted by both, the rate of rise and the maximum volumetric temperature measured by microwave radiometry. PMID- 23751085 TI - Differentiated control of deranged nitric oxide metabolism: a therapeutic option in sepsis? AB - Derangement of nitric oxide (NO) metabolism represents one of the key mechanisms contributing to macro- and microcirculatory failure in sepsis. Sepsis-related therapy combining fluid resuscitation with administration of vasopressor and inotropic agents, however, does not guarantee correction of maldistributed nutritive perfusion between and within organs. Therefore, the differentiated and selective pharmacologic modulation of NO-mediated vascular function could play a useful role in hemodynamic management of patients with sepsis. This viewpoint carefully evaluates the potential role of intentionally using partially opposing effects of NO donors and NO synthase inhibitors to complement current therapy of hemodynamic stabilization in patients with sepsis. PMID- 23751086 TI - One-pot synthesis of 3-triazolyl-2-iminochromenes via a catalytic three component cascade reaction. AB - A variety of 3-triazolyl-2-iminochromenes were synthesized in a one-pot, catalytic, three component condensation. In this event, a Cu(I)-catalyzed cycloaddition between 2-azidoacetonitrile and an acetylene formed a triazole and activated the neighboring methylene group, inducing an aldol-cyclization dehydration sequence in the presence of a salicylaldehyde. Further elaboration led to more complex polyheterocycles. PMID- 23751088 TI - Variable range hopping in single-wall carbon nanotube thin films: a processing structure-property relationship study. AB - By varying the ultrasonication and ultracentrifugation conditions, single-walled carbon nanotube (SWCNT) dispersions with a broad range of SWCNT length and diameter (L = 342-3330 nm; d = 0.5-12 nm) were prepared and characterized by a preparative ultracentrifuge method (PUM) and dynamic light scattering (DLS) technique. The well-characterized dispersions were then fabricated into SWCNT thin films by spray coating. Combined optical, spectroscopic, and temperature dependent electrical measurements were performed to study the effect of SWCNT structures on the charge transport behavior of SWCNT thin films. Regardless of SWCNT size in the dispersion and the thin film thickness, the three-dimensional variable range hopping (3D VRH) conduction model was found to be appropriate in explaining the temperature-dependent sheet resistance results for all SWCNT thin films prepared in this study. More importantly, with the SWCNT structural information determined by the PUM method, we were able to identify a strong correlation between the length of SWCNTs and the 3D VRH parameter T0, the Mott characteristic temperature. When the SWCNT length is less than ~700 nm, the T0 of SWCNT thin films shows a drastic increase, but when the length is greater than ~700 nm, T0 is only weakly dependent on the SWCNT length. Under the framework of traditional VRH, we further conclude that the electron localization length of SWCNT thin films shows a similar dependence on the SWCNT length. PMID- 23751087 TI - Tofogliflozin, a novel sodium-glucose co-transporter 2 inhibitor, improves renal and pancreatic function in db/db mice. AB - BACKGROUND AND PURPOSE: Although inhibition of renal sodium-glucose co transporter 2 (SGLT2) has a stable glucose-lowering effect in patients with type 2 diabetes, the effect of SGLT2 inhibition on renal dysfunction in type 2 diabetes remains to be determined. To evaluate the renoprotective effect of SGLT2 inhibition more precisely, we compared the effects of tofogliflozin (a specific SGLT2 inhibitor) with those of losartan (an angiotensin II receptor antagonist) on renal function and beta-cell function in db/db mice. EXPERIMENTAL APPROACH: The effects of 8-week tofogliflozin or losartan treatment on renal and beta-cell function were investigated in db/db mice by quantitative image analysis of glomerular size, mesangial matrix expansion and islet beta-cell mass. Blood glucose, glycated Hb and insulin levels, along with urinary albumin and creatinine were measured KEY RESULTS: Tofogliflozin suppressed plasma glucose and glycated Hb and preserved pancreatic beta-cell mass and plasma insulin levels. No improvement of glycaemic conditions or insulin level was observed with losartan treatment. Although the urinary albumin/creatinine ratio of untreated db/db mice gradually increased from baseline, tofogliflozin or losartan treatment prevented this increase (by 50-70%). Tofogliflozin, but not losartan, attenuated glomerular hypertrophy. Neither tofogliflozin nor losartan altered matrix expansion. CONCLUSIONS AND IMPLICATIONS: Long-term inhibition of renal SGLT2 by tofogliflozin not only preserved pancreatic beta-cell function, but also prevented kidney dysfunction in a mouse model of type 2 diabetes. These findings suggest that long-term use of tofogliflozin in patients with type 2 diabetes may prevent progression of diabetic nephropathy. PMID- 23751090 TI - Conceptualizing women's attitudes toward condom use with the tripartite model. AB - BACKGROUND: The Centers for Disease Control and Prevention (2011) estimated that women represent 24% of HIV diagnoses in the United States, with most infections resulting from heterosexual contact. However, consistent condom use is highly effective in preventing the spread of HIV. The current study examined women's attitudes toward condom use and potential inconsistencies related to the conceptualization and measurement of attitudes. METHOD: Data were collected from October 2009 through March 2010. Researchers included 556 female undergraduate students from the Southeast region of the United States. Exploratory and confirmatory factor analyses were used to determine whether women's condom use attitudes were composed of an affective and a cognitive component. RESULTS: Evidence for a two-factor model of condom use attitudes consisting of an affective and cognitive component was found, with participants reporting slightly negative feelings toward condom use but favorable beliefs about using condoms. Affect accounted for more variance (42%) than cognition (8%) in condom use attitudes. Notably, affect and cognition were differentially associated with past behavior and intentions to use condoms. CONCLUSION: Understanding the structure of women's attitudes toward using condoms can aid in the creation of appropriate HIV prevention and condom use messaging targeted toward promoting positive attitudes and normative change. Changing women's attitudes in this manner could enhance the effectiveness of condom use interventions. PMID- 23751089 TI - Women are at a higher risk of metabolic syndrome in rural Malaysia. AB - Metabolic syndrome has been associated with an increased risk of cardiovascular disease and diabetes mellitus. The objective of this study was to determine gender differences in the prevalence and factors associated with metabolic syndrome in a rural Malay population. This cross-sectional study, conducted in Bachok, Kelantan, involved 306 respondents aged 18 to 70 years. The survey used a structured questionnaire to collect information on demographics, lifestyle, and medical history. Anthropometric measurements, such as weight, height, body mass index, waist and hip circumference, and blood pressure were measured. Venous blood samples were taken by a doctor or nurses and analyzed for lipid profile and fasting glucose. The overall prevalence of metabolic syndrome was 37.5% and was higher among females (42.9%). Being unemployed or a housewife and being of older age were independently associated with metabolic syndrome in a multivariate analysis. Weight management and preventive community-based programs involving housewives, the unemployed, and adults of poor education must be reinforced to prevent and manage metabolic syndrome effectively in adults. PMID- 23751091 TI - HIV testing among pregnant wives of migrant men in a rural district of India: urgent call for scale up. AB - In India, despite the fact that more pregnant women are being tested for HIV under the purview of the Prevention of Parent-to-Child HIV Transmission program, official figures indicate low rates of HIV testing, evidencing missed opportunities for HIV prevention. The present study examined the prevalence of HIV testing and the barriers to testing among pregnant women, whose vulnerability to HIV is enhanced by their spouses' risky behaviors. A cross-sectional study was conducted from November 2010 to January 2011 among 357 women who had given birth in the last two years in a district in Orissa. Only one-third of women had been tested for HIV during pregnancy. Women with more than six years of education (OR: 2.39, 95% CI: 1.06-5.39), having knowledge of sexually transmitted infections (OR: 12.37, 95% CI: 5.55-27.58), having discussions with spouses about HIV (OR: 3.56, 95% CI: 1.61-7.86), and seeking antenatal care in government district hospitals and private clinics as opposed to peripheral community health centers, were more likely to receive HIV testing during pregnancy. The findings point to the need to widen HIV testing to community-based services, increase coverage of HIV/sexually transmitted infection awareness and prevention programs, and encourage spousal communication through quality counseling. PMID- 23751092 TI - History of sexual abuse and development of sexual risk behavior in low-income, urban African American girls seeking mental health treatment. AB - OBJECTIVE: This study examined relationships between sexual abuse and patterns of sexual risk-taking among low-income, urban African American adolescent girls seeking mental health treatment. METHOD: Participants (N = 158) were 12- to 16 year-old African American girls recruited from outpatient mental health clinics serving urban, mostly low-socioeconomic status communities in Chicago, Illinois and followed for two years between 2003 and 2010. This study included self reports of sexual abuse and four waves (T2-T5) of self-reported data on sexual experience and sexual risk-taking (number of partners, inconsistent condom use, and sex with a risky partner). Latent curve modeling was used to examine patterns of sexual behavior over the four time points with sexual abuse and mental health symptoms as covariates. RESULTS: Sexual abuse was significantly associated with T2 sexual experience, T2-T4 number of partners, T3 inconsistent condom use, and T2-T3 having a risky partner. These relationships decreased when mental health symptoms were controlled. CONCLUSIONS: This longitudinal study revealed a complex relationship between sexual abuse and sexual risk that would be missed if sexual risk were assessed at a single time point. Findings supported early intervention to delay onset of sexual risk behavior among low-income African American girls with mental health concerns and histories of sexual abuse. PMID- 23751093 TI - Sedentary behavior and food cravings in diverse overweight women: a pilot study. AB - Obesity rates have risen sharply in the United States, with minority women among those most affected. Although a majority of Americans are considered inactive, little attention has been devoted to studying the correlation of sedentary behavior with dietary cravings in adults. OBJECTIVE: The current study used objective and self-report methods to measure sedentary behavior and its relationship to food cravings in a sample of overweight African American and Caucasian women. DESIGN: Thirty-nine adult women (54% African American) with an average body mass index of 33.7 wore accelerometers for one week and completed self-report measures of sedentary behavior, physical activity, and food cravings. RESULTS: Self-reported television viewing time was slightly longer (3.0 versus 2.5 hours), although total sedentary time was shorter (6.7 versus 8.0 hours) on weekends versus weekdays. Weekend but not weekday sedentary time and television viewing were associated with stable aspects of food cravings rather than craving for specific foods. CONCLUSION: In this small sample, only a third of all sedentary time was attributed to viewing television. Assessing whether sedentary behavior occurs by necessity versus choice may be a factor to consider in examining its relationship to food cravings. PMID- 23751094 TI - Discursive constructions of breastfeeding in U.S. state laws. AB - Previous research has identified several ways that breastfeeding is constructed in public discourses, each with consequences for breastfeeding attitudes, policies, and practices. Researchers analyzed discursive constructions of breastfeeding in U.S. state laws regarding breastfeeding in public to see if common representations were replicated in law and to identify patterns among states that used similar language. Results indicated that laws varied in the level of protection they offered, with the least protective laws decriminalizing breastfeeding in public and the most protective laws criminalizing interference with breastfeeding. The least protective states were located in the Western and North-Central regions, Republican-leaning, and less urban, whereas the most protective states were located in the New England and North-Central regions, Democrat-leaning, and more urban. Most states that fell on either end of this continuum had breastfeeding rates above the national average. Laws also varied in the level of regulation implied in their language, with the most regulative laws specifying that "a mother" can breastfeed "her baby" only in certain places and under certain conditions (discreetly). The most regulative states were located in the Southern and North-Central regions and had low breastfeeding rates, whereas the least regulative states were Western and had high breastfeeding rates. PMID- 23751095 TI - Characteristics of quantitative nursing research from 1990 to 2010. AB - PURPOSE: To assess author credentials of quantitative research in nursing, the composition of the research teams, and the disciplinary focus of the theories tested. DESIGN: Nursing Research, Western Journal of Nursing Research, and Journal of Advanced Nursing were selected for this descriptive study; 1990, 1995, 2000, 2005, and 2010 were included. The final sample consisted of 484 quantitative research articles. FINDINGS: From 1990 to 2010, there was an increase in first authors holding doctoral degrees, research from other countries, and funding. Solo authorship decreased; multi-authorship and multidisciplinary teams increased. Theories tested were mostly from psychology; the testing of nursing theory was modest. Multidisciplinary research far outdistanced interdisciplinary research. CONCLUSIONS: Quantitative nursing research can be characterized as multidisciplinary (distinct theories from different disciplines) rather than discipline-specific to nursing. Interdisciplinary (theories synthesized from different disciplines) research has been conducted minimally. CLINICAL RELEVANCE: This study provides information about the growth of the scientific knowledge base of nursing, which has implications for practice. PMID- 23751097 TI - Depassivation of aged Fe0 by inorganic salts: implications to contaminant degradation in seawater. AB - In this study, aged (iron oxide coated) Fe(0) was applied to the degradation of trichloroethylene (TCE) in seawater. It was found that while the aged Fe(0) was inactive with regard to TCE degradation in Milli-Q water, more than 95% of the TCE present was degraded in real and synthetic seawater solutions after exposure to aged Fe(0) for 21 days. Results with individual salts from the synthetic seawater revealed that no significant TCE degradation was observed in the presence of Na2SO4, CaCl2, and NaHCO3. Partial TCE degradation (28.4%) was observed in 500 mM NaCl after 21 days, while a similar extent of degradation to that found in the seawater solutions was observed in 50 mM solutions of magnesium salts (MgCl2 and MgSO4). Results of open circuit potential analysis suggested that the Fe(0) corrosion potential was not a key determinant of extent of TCE reduction since the corrosion potential decreased to levels similar to that of Fe(0)/Fe(2+) in the presence of all salts examined. Lower final pH values and higher dissolved Fe(II) concentrations were observed in the presence of magnesium salts compared to other salts. Formation of the surface complex >FeOMg(+) was identified as being critical to protonation of surface sites, reductive dissolution of the passivating Fe(III) oxyhydroxide layer coating the underlying Fe(0) and enhancement in extent of TCE reduction. These findings provide insight into the molecular-scale mechanism of depassivation of aged Fe(0) by inorganic salts with particular implications for the Fe(0)-mediated degradation of contaminants in saline natural waters such as seawater and saline groundwaters. PMID- 23751096 TI - Methamphetamine inhibits Toll-like receptor 9-mediated anti-HIV activity in macrophages. AB - Toll-like receptor 9 (TLR9) is one of the key sensors that recognize viral infection/replication in the host cells. Studies have demonstrated that methamphetamine (METH) dysregulated host cell innate immunity and facilitated HIV infection of macrophages. In this study, we present new evidence that METH suppressed TLR9-mediated anti-HIV activity in macrophages. Activation of TLR9 by its agonist CpG-ODN 2216 inhibits HIV replication, which was demonstrated by increased expression of TLR9, interferon (IFN)-alpha, IFN regulatory factor-7 (IRF-7), myeloid differentiation factor 88 (MyD88), and myxovirus resistance gene A (MxA) in macrophages. However, METH treatment of macrophages greatly compromised the TLR9 signaling-mediated anti-HIV effect and inhibited the expression of TLR9 downstream signaling factors. Dopamine D1 receptor (D1R) antagonists (SCH23390) could block METH-mediated inhibition of anti-HIV activity of TLR9 signaling. Investigation of the underlying mechanisms of the METH action showed that METH treatment selectively down-regulated the expression of TLR9 on macrophages, whereas it had little effect on the expression of other TLRs. Collectively, our results provide further evidence that METH suppresses host cell innate immunity against HIV infection by down-regulating TLR9 expression and its signaling-mediated antiviral effect in macrophages. PMID- 23751098 TI - Highly efficient biocompatible neuroprotectants with dual activity as antioxidants and P2Y receptor agonists. AB - Currently, there is a need for novel, biocompatible, and effective neuroprotectants for the treatment of neurodegenerative diseases and brain injury associated with oxidative damage. Here, we developed nucleotide-based neuroprotectants acting dually as antioxidants and P2Y-R agonists. To improve the potency, selectivity, and metabolic stability of ATP/ADP, we substituted adenine C2-position by Cl and Palpha/Pbeta position by borano group, 6-9. Nucleotides 6-9 inhibited oxidation in cell-free systems (Fe(II)-H2O2), as detected by ESR (IC50 up to 175 MUM), and ABTS assay (IC50 up to 40 MUM). They also inhibited FeSO4 induced oxidative stress in PC12 cells (IC50 of 80-200 nM). 2-Cl-ADP(alpha-BH3), 7a, was found to be the most potent P2Y1-R agonist currently known (EC50 7 nM) and protected primary cortical neurons from FeSO4 insult (EC50 170 nM). In addition, it proved to be metabolically stable in human blood serum (t(1/2) 7 vs 1.5 h for ADP). Hence, we propose 7a as a highly promising neuroprotectant. PMID- 23751099 TI - Hepatitis E virus genotype 3 strains in domestic pigs, Cameroon. PMID- 23751100 TI - Low vitamin D serum level is inversely associated with eczema in children and adolescents in Germany. AB - BACKGROUND: Recent studies have yielded heterogeneous results regarding the relationship between vitamin D and atopic conditions. The aim of this study was to investigate the association between serum vitamin D level and the prevalence of eczema in German children and adolescents. METHODS: Data were drawn for children aged 1-17 from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS), a nationwide cross-sectional representative survey. 25-hydroxyvitamin D (25(OH)D) serum concentration was measured in 9838 individuals with eczema and categorized into quartiles. We investigated the association of vitamin D level and eczema by means of logistic regression models. RESULTS: Weighted prevalence of eczema was 13.5% (95% confidence interval (CI) 12.6-14.4%). Mean vitamin D level was significantly higher in those with eczema compared with those without (P < 0.0001). Logistic regression revealed an inverse association between low levels of vitamin D and eczema (multivariate OR for quartile 1 vs quartile 2: 0.76 (95% CI 0.61-0.94)). CONCLUSIONS: This study suggests that low serum vitamin D level is inversely associated with eczema in German children and adolescents. Prospective studies are required to confirm this result, to discuss a potential opportunity for prevention of eczema. PMID- 23751101 TI - Anisotropic dielectric relaxation of the water confined in nanotubes for terahertz spectroscopy studied by molecular dynamics simulations. AB - The dynamics and structure of the hydrogen-bond network in confined water are of importance in understanding biological and chemical processes. Recently, terahertz (THz) time domain spectroscopy was widely applied for studying the kinetics of molecules and the hydrogen-bond network in water. However, the characteristics of the THz spectroscopy varying with respect to the confinement and the mechanism underlying the variation are still unclear. Here, on the basis of molecular dynamics simulations, the relationship between the anisotropic dielectric relaxation and the structure of the water confined in a carbon nanotube (CNT) was investigated. The results show that there are two preferred hydrogen-bond orientations of the confined water in the nanotube: (1) parallel to the CNT axis and (2) perpendicular to the CNT axis, which are clearly different. Moreover, the response of the orientations to the increment of the CNT diameters is opposite, leading to the opposite variations of the dielectric relaxation times along the two directions. The anisotropy in the relaxation time can be presented by the anisotropic dielectric permittivity which is able to be observed through THz spectroscopy. The anormal behaviors above are attributed to the special structure of the water close to the nanotube wall due to the confinement and hydrophobicity of CNT. These studies contribute an important step in understanding the THz experiments of water in nanoscales, and designing a chamber for specific chemical and biological reactions by controlling the diameters and materials of the nanotube. PMID- 23751102 TI - Ensuring the best care for our increasing aging population: health engagement and positive technology can help patients achieve a more active role in future healthcare. PMID- 23751105 TI - Smelling in chemically complex environments: an optofluidic Bragg fiber array for differentiation of methanol adulterated beverages. AB - A novel optoelectronic nose for analysis of alcohols (ethanol and methanol) in chemically complex environments is reported. The cross-responsive sensing unit of the optoelectronic nose is an array of three distinct hollow-core infrared transmitting photonic band gap fibers, which transmit a specific band of IR light depending on their Bragg mirror structures. The presence of alcohol molecules in the optofluidic core quenches the fiber transmissions if there is an absorption band of the analyte overlapping with the transmission band of the fiber; otherwise they remain unchanged. The cumulative response data of the fiber array enables rapid, reversible, and accurate discrimination of alcohols in chemically complex backgrounds such as beer and fruit juice. In addition, we observed that humidity of the environment has no effect on the response matrix of the optoelectronic nose, which is rarely achieved in gas-sensing applications. Consequently, it can be reliably used in virtually any environment without precalibration for humidity or drying the analytes. Besides the discussed application in counterfeit alcoholic beverages, with its superior sensor parameters, this novel concept proves to be a promising contender for many other applications including food quality control, environmental monitoring, and breath analysis for disease diagnostics. PMID- 23751106 TI - Match-related fatigue reduces physical and technical performance during elite rugby league match-play: a case study. AB - This study examined the influence of match-related fatigue on physical and technical skill performance in ball playing positions at two different levels of rugby league competition. Time-motion analyses were performed using global positioning systems from 6 elite National Rugby League (NRL) and 11 junior elite National Youth Competition (NYC) players from 45 matches. A standardised 5-point technical coding criteria was used to qualitatively assess skill involvements during match-play. The distance travelled in the 0-5 and 40-45 min period were significantly higher compared to the 30-35, 35-40, 70-75 and 75-80 min periods (P < 0.001). Skill rating and involvements were higher in the 0-5 and 40-45 min compared to 70-75 and 75-80 min periods (P < 0.001 and P < 0.001, respectively).There was no significant difference in the number of physical collisions between the 5-min periods (P = 0.051). Following the peak 5-min bout of exercise intensity there were reductions in distance (P < 0.001), quality of skill involvements (P < 0.001), number of involvements (P < 0.001) and collisions (P < 0.001). Elite NRL and NYC "ball players" exhibit reductions in physical performance towards the end of matches and following brief periods of intense exercise. There also appears to be a reduction in technical performance for NRL and NYC ball players, which may be attributable to match-related fatigue. PMID- 23751107 TI - Evaluation of PAX3 genetic variants and nevus number. AB - The presence of a high nevus number is the strongest phenotypic predictor of melanoma risk. Here, we describe the results of a three-stage study directed at identifying risk variants for the high nevus phenotype. At the first stage, 263 melanoma cases from Barcelona were genotyped for 223 single-nucleotide polymorphisms (SNPs) in 39 candidate genes. Seven SNPs in the PAX3 gene were found to be significantly associated with nevus number under the additive model. Next, the associations for seven PAX3 variants were evaluated in 1217 melanoma cases and 475 controls from Leeds; and in 3054 healthy twins from TwinsUK. Associations with high nevus number were detected for rs6754024 (P values < 0.01) in the Barcelona and Leeds datasets and for rs2855268 (P values < 0.01) in the Barcelona and the TwinsUK sets. Associations (P values < 0.001) in the opposite direction were detected for rs7600206 and rs12995399 in the Barcelona and TwinsUK sets. This study suggests that SNPs in PAX3 are associated with nevus number, providing support for PAX3 as a candidate nevus gene. Further studies are needed to examine the role of PAX3 in melanoma susceptibility. PMID- 23751108 TI - Evidence of purinergic neurotransmission in isolated, intact horse sweat glands. AB - BACKGROUND: Fluid secretion by sweat glands in response to heat and exercise is underpinned by increases in intracellular calcium. In horses, this is primarily via beta2-adrenoceptors, but studies in equine sweat gland cell lines have indicated a possible role for purinergic agonists. Knowledge of equine sweating stimulus-secretion mechanisms in intact glands from healthy animals would allow future comparison to determine whether these mechanisms are affected in equine anhidrosis. HYPOTHESIS/OBJECTIVES: To determine whether purinergic agonists can induce changes in intracellular calcium in intact, freshly isolated equine sweat glands. ANIMALS: Eleven healthy thoroughbred horses from the Hong Kong Jockey Club were used in this study. METHODS: Freshly isolated equine sweat glands were loaded with the calcium-sensitive fluorescent dye fura-2 AM, and changes in intracellular calcium were recorded before, during and after stimulation by purinergic agonists. RESULTS: Purinergic agonists ATP and UTP generated significant increases in intracellular calcium. CONCLUSIONS AND CLINICAL IMPORTANCE: The results show that it is possible to investigate stimulus secretion coupling mechanisms by fluorescence imaging in equine sweat glands that have been isolated from fresh skin samples. Such isolated glands retain functional beta2-adrenoceptors and P2Y purinergic receptors that couple to a calcium-signalling pathway. Using isolated, intact sweat glands therefore offers a very useful model for the further study of secretory processes in equine sweat glands, and using this experimental approach could facilitate a better understanding of how these mechanisms are affected in equine anhidrosis. PMID- 23751110 TI - Dial M(RF) for myogenesis. AB - The transcriptional regulatory network that controls the determination and differentiation of skeletal muscle cells in the embryo has at its core the four myogenic regulatory factors (MRFs) Myf5, MyoD, Mrf4 and MyoG. These basic helix loop-helix transcription factors act by binding, as obligate heterodimers with the ubiquitously expressed E proteins, to the E-box sequence CANNTG. While all skeletal muscle cells have the same underlying function their progenitors arise at many sites in the embryo and it has become apparent that the upstream activators of the cascade differ in these various populations so that it can be switched on by a variety of inductive signals, some of which act by initiating transcription, some by maintaining it. The application of genome-wide approaches has provided important new information as to how the MRFs function to activate the terminal differentiation programme and some of these data provide significant mechanistic insights into questions which have exercised the field for many years. We also consider the emerging roles played by micro-RNAs in the regulation of both upstream activators and terminal differentiation genes. PMID- 23751109 TI - Dieting and the self-control of eating in everyday environments: an experience sampling study. AB - OBJECTIVE: The literature on dieting has sparked several debates over how restrained eaters differ from unrestrained eaters in their self-regulation of healthy and unhealthy food desires and what distinguishes successful from unsuccessful dieters. We addressed these debates using a four-component model of self-control that was tested using ecological momentary assessment, long-term weight change, and a laboratory measure of inhibitory control. DESIGN: A large sample of adults varying in dietary restraint and inhibitory control (as measured by a Stroop task) were equipped with smartphones for a week. They were beeped on random occasions and provided information on their experience and control of healthy and unhealthy food desires in everyday environments. MAIN OUTCOME MEASURES: The main outcome measures were desire strength, experienced conflict, resistance, enactment of desire, and weight change after a 4-month follow-up. RESULTS AND CONCLUSIONS: Dietary restraint was unrelated to desire frequency and strength, but associated with higher conflict experiences and motivation to use self-control with regard to food desires. Most importantly, relationships between dietary restraint and resistance, enactment of desire, and long-term weight change were moderated by inhibitory control: Compared with dieters low in response inhibition, dieters high in response inhibition were more likely to attempt to resist food desires, not consume desired food (especially unhealthy food), and objectively lost more weight over the ensuing 4 months. These results highlight the combinatory effects of aspects of the self-control process in dieters and highlight the value in linking theoretical process frameworks, experience sampling, and laboratory-based assessment in health science. STATEMENT OF CONTRIBUTION: What is already known on this subject? Dieting is a multifaceted process that can be viewed from the lens of self-control. Dietary restraint measures can be used to capture dieting status, but it is relatively unclear what differentiates successful from unsuccessful dieters (e.g., differences in desire frequency, desire strength, motivation, executive functions). What does this study add? A novel four-step conceptual model of self-control is applied to eating behaviour in everyday life. This model allows a fine-grained look at the self-control process in restrained eaters (dieters) as compared to non-dieters. Dieters and non-dieters do not differ in desire frequency and strength (they are not simply more tempted). Dieters high (as compared to low) in inhibitory control are more likely to engage in self-control. Dieters high (as compared to low) in inhibitory control are more likely to resist unhealthy food desires. Dieters high (as compared to low) in inhibitory control are more likely to loose weight over a 4-month period. Together, the study shows clear differences among successful and unsuccessful dieters that can be linked to differences in executive functioning (inhibitory control). The present article is one of the first studies combining a conceptual model with smartphone experience sampling to study weight control and thus paradigmatic from a methodological perspective. PMID- 23751111 TI - Testing for hypersensitivity to seminal fluid-free spermatozoa. AB - Hypersensitivity to human semen (HHS) is an increasingly reported condition with symptoms manifested locally and systemically, which in some cases may result in anaphylaxis. This report describes four cases of HHS all with positive allergy skin prick tests to partner's whole semen. None of the patients elicited a response to seminal fluid-free washed spermatozoa. In cases of high risk of anaphylaxis, we recommend avoiding exposure to semen. By carrying out an allergy skin prick test on seminal fluid-free washed spermatozoa, the risk of immunogenic reaction to the spermatozoa could be eliminated. PMID- 23751112 TI - 'Double guidewire in one catheter' method for a difficult endoscopic retrograde cholangiopancreatography cannulation (with video). PMID- 23751113 TI - Percutaneous endocardial occlusion of incompletely surgically ligated left atrial appendage. AB - INTRODUCTION: Surgical ligation of the left atrial appendage is considered standard of care in patients who undergo mitral valve surgery or as an adjunct to a surgical Maze procedure for treatment of atrial fibrillation (AF). However, several studies have demonstrated that this can result in incompletely surgically ligated left atrial appendage (ISLL) in a significant number of patients. It is believed that ISLL may in turn promote thrombus formation and lead to clinically relevant thromboembolic events. A novel approach for percutaneous endocardial occlusion of ISLL is described. METHODS AND RESULTS: Seven patients with AF and ISLL following prior open-chest, surgical suture ligation in the absence of rheumatic heart disease, underwent percutaneous endocardial ISLL occlusion using an Amplatzer Septal Occluder device guided by fluoroscopy and transesophageal echocardiography through a novel approach. Three patients were diagnosed in the setting of acute embolic stroke, 2 at the time of cardiac arrhythmia ablation and 2 by elective precardioversion transesophageal echocardiography. All patients were treated with oral anticoagulation therapy. Acute and long-term ISLL occlusion was successfully achieved in 6 patients, in whom oral anticoagulation was eventually discontinued without any embolic events during 10 +/- 2 months of follow-up. CONCLUSION: Percutaneous endocardial occlusion of ISLL is feasible using an Amplatzer Septal Occluder device. Additional studies are required to evaluate the long-term safety and efficacy of this therapeutic treatment strategy in patients with ISLL. PMID- 23751114 TI - Hepatitis E virus and porcine-derived heparin. PMID- 23751115 TI - Nonresectional management of colorectal cancer: multidisciplinary factors that influence treatment strategy. AB - AIM: Surgical resection of a primary colorectal tumour remains the treatment of choice and offers the best chance of cure. However, in some patients, resection is not achieved. There are few published data on this group of patients. The aim of this study was to evaluate this group to determine the frequency and reasons for nonresection, and to analyse the subsequent management. METHOD: A retrospective review was performed using a Trust colorectal cancer database and individual electronic patient records. Patients who presented to our unit with a diagnosis of primary colorectal cancer managed by nonresectional intervention over a 2-year period were identified. Data analysed included: patient demographics, radiological staging, histological data, nonsurgical therapy, tumour-specific complications and requirement for palliative surgical procedures. RESULTS: A total of 671 patients were identified with primary colorectal cancer. One hundred and fifty-six (23%) were managed without resection, following discussion at a multidisciplinary team meeting. Of 156 patients, histological confirmation was obtained in 131 (84%), with the remainder of the diagnoses being based on unequivocal radiological imaging and/or operative findings. Complete radiological staging was achieved in 150 (96%) patients. The predominant reasons for nonresectional management were: advanced metastatic disease (66%), significant medical comorbidity (19%) and patient refusal (6%). Fifty-nine of 156 patients (38%) subsequently received palliative chemotherapy, 9 (6%) radiotherapy and or 9 (6%) combination chemo-radiotherapy. Seventy-nine (51%) of 156 patients received no therapy other than best supportive palliative care, for reasons including significant medical comorbidity (62%) and patient refusal (19%). Following the initial decision not to resect, 68 (44%) patients did at some point undergo some form of palliative intervention (stenting, stoma or bypass) for obstruction - 44 (28%) electively and 24 (15%) as an emergency. CONCLUSION: Nonresectional management of patients with primary colorectal cancer is not an uncommon outcome following discussion at a multidisciplinary meeting. In these patients, nonsurgical palliation should be employed when necessary, though is frequently limited by comorbidity. However, subsequent surgical palliation is still required in a substantial proportion of cases. PMID- 23751116 TI - Asymmetric synthesis of vabicaserin via oxidative multicomponent annulation and asymmetric hydrogenation of a 3,4-substituted quinolinium salt. AB - An efficient, asymmetric synthesis of the 5-HT2C agonist vabicaserin in four chemical steps and 54% overall yield from commercially available benzodiazepine was achieved. The synthesis was highlighted by a novel oxidative, multicomponent reaction to affect the quinolinium ring assembly in one step followed by an unprecedented asymmetric hydrogenation of a 3,4-substituted quinolinium salt. PMID- 23751117 TI - Grafting of functionalized [Fe(III)(salten)] complexes to Au(111) surfaces via thiolate groups: surface spectroscopic characterization and comparison of different linker designs. AB - Functionalization of surfaces with spin crossover complexes is an intensively studied topic. Starting from dinuclear iron(III)-salten complexes [Fe(salten)(pyS)]2(BPh4)2 and [Fe(thiotolylsalten)(NCS)]2 with disulfide containing bridging ligands, corresponding mononuclear complexes [Fe(salten)(pyS)](+) and [Fe(thiotolylsalten)(NCS)] are covalently attached to Au(111) surfaces (pySH, pyridinethiol; salten, bis(3-salicylidene aminopropyl)amine). The adsorbed monolayers are investigated by infrared reflection absorption spectroscopy (IRRAS) in combination with X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine structure (NEXAFS). Comparison of the surface vibrational spectra with bulk data allows us to draw conclusions with respect to the geometry of the adsorbed complexes. An anomaly is observed in the spectra of the surface-adsorbed monolayer of [Fe(salten)(pyS)](+), which suggests that the salten ligand is partially decoordinated from the Fe(III) center and one of its phenolate arms binds to the Au(111) surface. For complex [Fe(thiotolylsalten)(NCS)] that is bound to the Au(111) surface via a thiolate-functionalized salten ligand, this anomaly is not observed, which indicates that the coordination sphere of the complex in the bulk is retained on the surface. The implications of these results with respect to the preparation of surface-adsorbed monolayers of functional transition-metal complexes are discussed. PMID- 23751118 TI - Postoperative respiratory management in living donor lobar lung transplantation. AB - BACKGROUND: We evaluated postoperative respiratory management of living donor lobar lung transplantation (LDLLT). METHODS: Perioperative variables were reviewed in 21 patients who underwent LDLLT at our institution. Recipients were kept intubated for at least two d after LDLLT to maintain optimal expansion of the implanted lobes. Subsequently, if weaning from artificial ventilation could be tolerated, extubation was considered with the assistance of non-invasive ventilation (NIV). If this could not be tolerated, early tracheostomy was considered. RESULTS: All 21 recipients were weaned from artificial ventilation. Twelve patients underwent tracheotomy 4.4 +/- 1.8 d after LDLLT and were weaned from artificial ventilation 24.3 +/- 17.0 d after LDLLT. Eleven patients were extubated 3.6 +/- 1.7 d after LDLLT with NIV, but two of them were reintubated, and finally weaned from artificial ventilation via tracheostomy. Excluding these two patients, NIV was required for 3.8 +/- 3.9 d after extubation. The early postoperative course was significantly eventful in patients with tracheostomies, and artificial ventilation, ventilatory support, and intensive care unit stays were longer. Twenty patients (95%) showed survival at 24.4 +/- 13.4 months of follow-up. CONCLUSIONS: Postoperative respiratory management with NIV and early tracheostomy were useful after LDLLT. PMID- 23751119 TI - Increases in dissolved organic carbon accelerate loss of toxic Al in Adirondack lakes recovering from acidification. AB - Increasing pH and decreasing Al in surface waters recovering from acidification have been accompanied by increasing concentrations of dissolved organic carbon (DOC) and associated organic acids that partially offset pH increases and complicate assessments of recovery from acidification. To better understand the processes of recovery, monthly chemistry from 42 lakes in the Adirondack region, NY, collected from 1994 to 2011, were used to (1) evaluate long-term changes in DOC and associated strongly acidic organic acids and (2) use the base-cation surplus (BCS) as a chemical index to assess the effects of increasing DOC concentrations on the Al chemistry of these lakes. Over the study period, the BCS increased (p < 0.01) and concentrations of toxic inorganic monomeric Al (IMAl) decreased (p < 0.01). The decreases in IMAl were greater than expected from the increases in the BCS. Higher DOC concentrations that increased organic complexation of Al resulted in a decrease in the IMAl fraction of total monomeric Al from 57% in 1994 to 23% in 2011. Increasing DOC concentrations have accelerated recovery in terms of decreasing toxic Al beyond that directly accomplished by reducing atmospheric deposition of strong mineral acids. PMID- 23751120 TI - Copper chaperone Atox1 interacts with the metal-binding domain of Wilson's disease protein in cisplatin detoxification. AB - Human copper transporters ATP7B (Wilson's disease protein) and ATP7A (Menkes' disease protein) have been implicated in tumour resistance to cisplatin, a widely used anticancer drug. Cisplatin binds to the copper-binding sites in the N terminal domain of ATP7B, and this binding may be an essential step of cisplatin detoxification involving copper ATPases. In the present study, we demonstrate that cisplatin and a related platinum drug carboplatin produce the same adduct following reaction with MBD2 [metal-binding domain (repeat) 2], where platinum is bound to the side chains of the cysteine residues in the CxxC copper-binding motif. This suggests the same mechanism for detoxification of both drugs by ATP7B. Platinum can also be transferred to MBD2 from copper chaperone Atox1, which was shown previously to bind cisplatin. Binding of the free cisplatin and reaction with the cisplatin-loaded Atox1 produce the same protein-bound platinum intermediate. Transfer of platinum along the copper-transport pathways in the cell may serve as a mechanism of drug delivery to its target in the cell nucleus, and explain tumour-cell resistance to cisplatin associated with the overexpression of copper transporters ATP7B and ATP7A. PMID- 23751121 TI - Optic nerve sheath diameter on initial brain CT, raised intracranial pressure and mortality after severe TBI: an interesting link needing confirmation. AB - Optic nerve sheath diameter (ONSD) enlargement on initial computed tomography (CT) scan has been found to be associated with increased mortality after severe traumatic brain injury. This could offer the possibility to detect patients with raised intracranial pressure requiring urgent therapeutic interventions and/or invasive intracranial monitoring to guide the treatment. The method to measure ONSD using CT scan, however, needs further confirmation. Moreover, the link between ONSD enlargement on initial CT scan and raised intracranial pressure also needs to be confirmed by further studies. PMID- 23751122 TI - Identification and frequency of circulating CD4(+) T lymphocytes specific to Benzylpenicillin in healthy donors. AB - BACKGROUND: Drug hypersensitivity is known to rely on a drug-specific T-cell response. Amplitude of antigen-specific T-cell response is partly controlled by the size of the antigen-specific naive CD4(+) T-cell repertoire, but estimate of this repertoire has never been investigated for allergenic drugs. The purpose of this study was to evaluate the frequency of benzylpenicillin-specific CD4(+) T lymphocytes in healthy donors. METHODS: Co-cultures were established with CD4(+) T lymphocytes from healthy donors and mature autologous dendritic cells loaded with benzylpenicillin coupled to human serum albumin. CD4(+) T lymphocytes were stimulated once a week for 4 weeks with benzylpenicillin coupled to human serum albumin. The CD4(+) T-cell response was measured using an interferon-gamma ELISPOT assay. Frequency of benzylpenicillin-specific naive CD4(+) T lymphocytes was then calculated using the Poisson distribution law. RESULTS: Results showed the presence of benzylpenicillin-specific CD4(+) T lymphocytes in 9 of 10 tested healthy donors irrespective of their HLA typing, with a mean frequency of 0.29 cells per million of CD4(+) T cells. Experiments performed on naive (CD45RA(+) ) and on memory (CD45RO(+) ) CD4(+) T lymphocytes showed that these benzylpenicillin-specific CD4(+) T lymphocytes belonged to the naive T-cell subpopulation. CONCLUSION: This study showed for the first time the existence of naive CD4(+) T lymphocytes specific to benzylpenicillin in healthy donors. PMID- 23751123 TI - Extraction tools for identification of chemical contaminants in estuarine and coastal waters to determine toxic pressure on primary producers. AB - The extent to which chemical stressors affect primary producers in estuarine and coastal waters is largely unknown. However, given the large number of legacy pollutants and chemicals of emerging concern present in the environment, this is an important and relevant issue that requires further study. The purpose of our study was to extract and identify compounds which are inhibitors of photosystem II activity in microalgae from estuarine and coastal waters. Field sampling was conducted in the Western Scheldt estuary (Hansweert, The Netherlands). We compared four different commonly used extraction methods: passive sampling with silicone rubber sheets, polar organic integrative samplers (POCIS) and spot water sampling using two different solid phase extraction (SPE) cartridges. Toxic effects of extracts prepared from spot water samples and passive samplers were determined in the Pulse Amplitude Modulation (PAM) fluorometry bioassay. With target chemical analysis using LC-MS and GC-MS, a set of PAHs, PCBs and pesticides was determined in field samples. These compound classes are listed as priority substances for the marine environment by the OSPAR convention. In addition, recovery experiments with both SPE cartridges were performed to evaluate the extraction suitability of these methods. Passive sampling using silicone rubber sheets and POCIS can be applied to determine compounds with different structures and polarities for further identification and determination of toxic pressure on primary producers. The added value of SPE lies in its suitability for quantitative analysis; calibration of passive samplers still needs further investigation for quantification of field concentrations of contaminants. PMID- 23751124 TI - Bivalve mollusks in metal pollution studies: from bioaccumulation to biomonitoring. AB - Contemporary environmental challenges have emphasized the need to critically assess the use of bivalve mollusks in chemical monitoring (identification and quantification of pollutants) and biomonitoring (estimation of environmental quality). Many authors, however, have considered these approaches within a single context, i.e., as a means of chemical (e.g. metal) monitoring. Bivalves are able to accumulate substantial amounts of metals from ambient water, but evidence for the drastic effects of accumulated metals (e.g. as a TBT-induced shell deformation and imposex) on the health of bivalves has not been documented. Metal bioaccumulation is a key tool in biomonitoring; bioavailability, bioaccumulation, and toxicity of various metals in relation to bivalves are described in some detail including the development of biodynamic metal bioaccumulation model. Measuring metal in the whole-body or the tissue of bivalves themselves does not accurately represent true contamination levels in the environment; these data are critical for our understanding of contaminant trends at sampling sites. Only rarely has metal bioaccumulation been considered in combination with data on metal concentrations in parts of the ecosystem, observation of biomarkers and environmental parameters. Sclerochemistry is in its infancy and cannot be reliably used to provide insights into the pollution history recorded in shells. Alteration processes and mineral crystallization on the inner shell surface are presented here as a perspective tool for environmental studies. PMID- 23751125 TI - Efficiency assessment and pH effect in removing nitrogen and phosphorus by algae bacteria combined system of Chlorella vulgaris and Bacillus licheniformis. AB - To achieve better removal of NH4(+) and TP in wastewater, a new algae-bacteria combined system of Chlorella vulgaris and Bacillus licheniformis was investigated in a 6-d experiment. The results showed that 78% of NH4(+) could be removed in the combined system, while 29% in single algae system and only 1% in single bacteria system. Approximately 92% of TP was removed in the combined system, compared with 55% and 78% in single algae and bacteria system, respectively. B. licheniformis was proven to be a growth-promoting bacterium for C. vulgaris by comparing Chl a concentrations in the single and combined systems. In the removal process, pH of the combined system was observed to reduce significantly from 7.0 to 3.5. Whereas with pH regulated to 7.0, higher removal efficiencies of NH4(+) (86%) and TP (93%) were achieved along with the recovery of algal cells and the increase of Chl a. These results suggest that nutrients in wastewater can be removed efficiently by the algae-bacteria combined system and pH control is crucial in the process. PMID- 23751127 TI - Organogels from dimeric bile acid esters: in situ formation of gold nanoparticles. AB - A new class of steroid dimers (bile acid derivatives) linked through ester functionalities were synthesized, which gelled various aromatic solvents. The organogels formed by the three dimeric ester molecules showed birefringent textures and fibrous nature by polarizing optical microscopy and scanning electron microscopy, respectively. A detailed rheological study was performed to estimate the mechanical strengths of two sets of organogels. In these systems, the storage modulus varied in the range of 0.8-3.5 * 10(4) at 1% w/v of the organogelators. The exponents of scaling of the storage modulus and yield stress of the two systems agreed well with those expected for viscoelastic soft colloidal gels with fibrillar flocs. The nanofibers in the organogel were utilized to engineer gold nanoparticles of different sizes and shapes and generate new gel-nanoparticle hybrid materials. PMID- 23751128 TI - In situ electrochemical digital holographic microscopy; a study of metal electrodeposition in deep eutectic solvents. AB - This study has shown for the first time that digital holographic microscopy (DHM) can be used as a new analytical tool in analysis of kinetic mechanism and growth during electrolytic deposition processes. Unlike many alternative established electrochemical microscopy methods such as probe microscopy, DHM is both the noninvasive and noncontact, the unique holographic imaging allows the observations and measurement to be made remotely. DHM also provides interferometric resolution (nanometer vertical scale) with a very short acquisition time. It is a surface metrology technique that enables the retrieval of information about a 3D structure from the phase contrast of a single hologram acquired using a conventional digital camera. Here DHM has been applied to investigate directly the electro-crystallization of a metal on a substrate in real time (in situ) from two deep eutectic solvent (DES) systems based on mixture of choline chloride and either urea or ethylene glycol. We show, using electrochemical DHM that the nucleation and growth of silver deposits in these systems are quite distinct and influenced strongly by the hydrogen bond donor of the DES. PMID- 23751126 TI - Targeted delivery of antibody-based therapeutic and imaging agents to CNS tumors: crossing the blood-brain barrier divide. AB - INTRODUCTION: Brain tumors are inherently difficult to treat in large part due to the cellular blood-brain barriers (BBBs) that limit the delivery of therapeutics to the tumor tissue from the systemic circulation. Virtually no large molecules, including antibody-based proteins, can penetrate the BBB. With antibodies fast becoming attractive ligands for highly specific molecular targeting to tumor antigens, a variety of methods are being investigated to enhance the access of these agents to intracranial tumors for imaging or therapeutic applications. AREAS COVERED: This review describes the characteristics of the BBB and the vasculature in brain tumors, described as the blood-brain tumor barrier (BBTB). Antibodies targeted to molecular markers of central nervous system (CNS) tumors will be highlighted, and current strategies for enhancing the delivery of antibodies across these cellular barriers into the brain parenchyma to the tumor will be discussed. Noninvasive imaging approaches to assess BBB/BBTB permeability and/or antibody targeting will be presented as a means of guiding the optimal delivery of targeted agents to brain tumors. EXPERT OPINION: Preclinical and clinical studies highlight the potential of several approaches in increasing brain tumor delivery across the BBB divide. However, each carries its own risks and challenges. There is tremendous potential in using neuroimaging strategies to assist in understanding and defining the challenges to translating and optimizing molecularly targeted antibody delivery to CNS tumors to improve clinical outcomes. PMID- 23751129 TI - Description of the finger mechanical load of climbers of different levels during different hand grips in sport climbing. AB - Currently, direct empirical evidence exists about the amount of mechanical load that climbers apply to each finger during several hand grips specific to sport climbing, but not yet in a specific hanging position. The objectives of this study are a) to draw and build a solid and rigid support that simulates the real action of a hand grip in a hanging position in sport climbing, to enable the measurement of the mechanical load endured by the fingers in a hanging position and in addition, b) to describe the distribution of mechanical load among fingers as a function of the level of climbing during different hand grips in a hanging position. Thirty young male participants took part in the initial phase of reliability of the measurements, while another 64 male climbers participated in the subsequent study phase to check the relations between independent and dependent variables. The level of on sight climbing and the total practice experience were used to define the groups. The research task consisted of performing hanging positions on the created support in order to measure the mechanical load endured by the fingers in the three most characteristic hand grips in climbing (crimp, half crimp and slope). It has been concluded that the performance level of the climbers had no influence on the production of a pattern of differentiated finger mechanical load during the research task. PMID- 23751130 TI - Phosphoproteomics-based network medicine. AB - One of the major tasks of phosphoproteomics is providing potential biomarkers for either diagnosis or drug targets in medical applications. Because most complex diseases are due to the actions of multiple genes/proteins, the identification of complex phospho-signatures containing multiple phosphorylation events within phosphoproteomics-based networks generates more efficient and robust biomarkers than a single, differentially phosphorylated substrate or site. Here, we briefly summarize the current efforts and progress in this newly emerging field of phosphoproteomics-based network medicine by reviewing the computational (re)construction of phosphorylation-mediated signaling networks from unannotated phosphoproteomic data, the discovery of robust network phospho-signatures and the application of these signatures for classifying cancers and predicting drug responses. The challenges as well as the potential advantages are evaluated and discussed. Although the current techniques are at present far from mature, we believe that such a systematic approach as we describe can generate more useful and robust biomarkers for biomedical usage, even at the current stage of development. PMID- 23751133 TI - Canine ocular neoplasia: a review. AB - Ocular neoplasia is relatively rare in dogs but can have significant impact on vision, comfort, and longevity. Prognosis for life and for the globe varies with tumor type. In this review, the clinicopathologic features of the most common canine ocular neoplasms are detailed, with emphasis on histologic and immunohistochemical characteristics. PMID- 23751132 TI - Change over time in brain serotonin transporter binding in major depression: effects of therapy measured with [(123) I]-ADAM SPECT. AB - Several studies have reported low brain serotonin transporter (SERT) binding in individuals with major depression. We hypothesized that the SERT standardized uptake ratio (SUR) values using [(123) I]-ADAM single photon emission computed tomography would increase in depressed subjects who responded to cognitive behavior therapy (CBT) compared to CBT nonresponders. [(123) I]-ADAM scans were acquired before and after 12 weeks of CBT from 20 depressed subjects and on two occasions 12 weeks apart from 10 nondepressed, healthy volunteers. The primary outcome measure was change over time in SUR values in the midbrain, medial temporal lobe, and basal ganglia regions. Depressed subjects demonstrated low pretreatment mean SUR values that significantly increased over time in the midbrain (P = .011), right medial temporal lobe (P = .008), and left medial temporal lobe (P = .000) regions. Treatment responders showed a significant increase over time in SUR values in left medial temporal lobe (P = .029) and right medial temporal lobe (P = .007) regions. Partial and nonresponder subjects also showed a significant increase over time in SUR values in the left medial temporal region (P = .040) (vs. healthy volunteers), but to a lesser degree. The findings suggest that low pretreatment SERT binding may increase over time in some depressed individuals who experience symptom improvement. PMID- 23751134 TI - Tuning PDMS brush chemistry by UV-O3 exposure for PS-b-PDMS microphase separation and directed self-assembly. AB - The directed self-assembly (DSA) of block copolymer (BCP) thin films could enable a scalable, bottom-up alternative to photolithography for the generation of substrate features. The PS-b-PDMS (polystyrene-b-polydimethylsiloxane) system is attractive as it can be extended toward very small feature sizes as well as having two blocks that can be readily differentiated during pattern transfer. However, PS-b-PDMS offers a considerable challenge because of the chemical differences in the blocks which lead to poor surface-wetting, poor pattern orientation control, and structural instabilities. These challenges can be mitigated by careful definition of the interface chemistry between the substrate and the BCP. Here, we report controlled pattern formation in cylinder forming PS b-PDMS system by use of a carefully controlled PDMS brush. Control of the brush was achieved using exposure to UV-O3 for varying time. It is demonstrated that this treatment enhances surface wetting and coverage of the BCP. The modified brushes also enable DSA of the BCP on topographically patterned substrates. UV-O3 exposure was also used to reveal the BCP structure and provide an in situ "hard mask" for pattern transfer to the substrate. PMID- 23751135 TI - Assessment of prostate cancer aggressiveness using dynamic contrast-enhanced magnetic resonance imaging at 3 T. AB - BACKGROUND: A challenge in the diagnosis of prostate cancer (PCa) is the accurate assessment of aggressiveness. OBJECTIVE: To validate the performance of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) of the prostate at 3 tesla (T) for the assessment of PCa aggressiveness, with prostatectomy specimens as the reference standard. DESIGN, SETTINGS, AND PARTICIPANTS: A total of 45 patients with PCa scheduled for prostatectomy were included. This study was approved by the institutional review board; the need for informed consent was waived. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Subjects underwent a clinical MRI protocol including DCE-MRI. Blinded to DCE-images, PCa was indicated on T2-weighted images based on histopathology results from prostatectomy specimens with the use of anatomical landmarks for the precise localization of the tumor. PCa was classified as low-, intermediate-, or high-grade, according to Gleason score. DCE-images were used as an overlay on T2-weighted images; mean and quartile values from semi-quantitative and pharmacokinetic model parameters were extracted per tumor region. Statistical analysis included Spearman's rho, the Kruskal-Wallis test, and a receiver operating characteristics (ROC) analysis. RESULTS AND LIMITATIONS: Significant differences were seen for the mean and 75th percentile (p75) values of wash-in (p = 0.024 and p = 0.017, respectively), mean wash-out (p = 0.044), and p75 of transfer constant (K(trans)) (p = 0.035), all between low-grade and high-grade PCa in the peripheral zone. ROC analysis revealed the best discriminating performance between low-grade versus intermediate-grade plus high-grade PCa in the peripheral zone for p75 of wash-in, K(trans), and rate constant (Kep) (area under the curve: 0.72). Due to a limited number of tumors in the transition zone, a definitive conclusion for this region of the prostate could not be drawn. CONCLUSIONS: Quantitative parameters (K(trans) and Kep) and semi-quantitative parameters (wash-in and wash-out) derived from DCE-MRI at 3 T have the potential to assess the aggressiveness of PCa in the peripheral zone. P75 of wash-in, K(trans), and Kep offer the best possibility to discriminate low-grade from intermediate-grade plus high-grade PCa. PMID- 23751136 TI - The Swedish six-community alcohol and drug prevention trial: effects on youth drinking. AB - INTRODUCTION AND AIMS: Local communities are increasingly targeted for alcohol and drug prevention campaigns. This study describes some of the key findings from the Swedish six-community alcohol and drug prevention trial (2003-2007) and lessons learned following an evaluation of the trial's effectiveness. The paper focuses mainly on changes in youth drinking and related harms. DESIGN AND METHODS: This was a pre- to post-intervention effect study comparing six trial communities that received added training and technical support with six control communities where regular prevention efforts were supported by national alcohol and drug action plans. A repeated, cross-sectional survey of 8092 youths aged 15 19 years assessed changes in alcohol consumption, binge drinking, perceived alcohol availability, access to alcohol via parents and adult attitudes towards the supply of alcohol to youths. National registry data were used to assess changes in hospital admissions due to alcohol intoxication. RESULTS: Overall, there were few significant improvements in the six trial communities compared with the control communities. DISCUSSION AND CONCLUSIONS: The absence of program effects was largely attributable to the selection of strategies (in particular, school and parental programs) lacking evidence of effectiveness in reducing alcohol consumption at the aggregate level. Prevention programs based on efficacy studies need to be tested in community-based effectiveness trials before being disseminated. PMID- 23751138 TI - Interprofessional non-technical skills for surgeons in disaster response: a literature review. AB - Natural disasters impose a significant burden on society. Current disaster training programmes do not place an emphasis on equipping surgeons with non technical skills for disaster response. This literature review sought to identify non-technical skills required of surgeons in disaster response through an examination of four categories of literature: "disaster"; "surgical"; "organisational management"; and "interprofessional". Literature search criteria included electronic database searches, internet searches, hand searching, ancestry searching and networking strategies. Various potential non-technical skills for surgeons in disaster response were identified including: interpersonal skills such as communication, teamwork and leadership; cognitive strategies such flexibility, adaptability, innovation, improvisation and creativity; physical and psychological self-care; conflict management, collaboration, professionalism, health advocacy and teaching. Such skills and the role of interprofessionalism should be considered for inclusion in surgical disaster response training course curricula. PMID- 23751139 TI - Toward directionally controlled molecular motions and kinetic intra- and intermolecular self-sorting: threading processes of nonsymmetric wheel and axle components. AB - We have investigated the self-assembly of pseudorotaxanes composed of viologen type axle and calix[6]arene wheel components. The distinctive feature of this system is that both components are structurally nonsymmetric; hence, their self assembly can follow four distinct pathways and eventually give rise to two different orientational pseudorotaxane isomers. We found that the alkyl side chains of the viologen recognition site on the molecular axle act as strict kinetic control elements in the self-assembly, thereby dictating which side of the axle pierces the calixarene cavity. Specifically, nonsymmetric axles with alkyl side chains of different length thread the wheel with the shorter chain. Such a selectivity, in combination with the face-selective threading of viologen type axles afforded by tris(N-phenylureido)calix[6]arenes, enables a strict directional control of the self-assembly process for both the face of the wheel and the side of the axle. This kinetic selectivity allows both intramolecular self-sorting between two different side chains in a nonsymmetric axle and intermolecolar self-sorting among symmetric axles with alkyl substituents of different length. PMID- 23751140 TI - Autonomy support and control in weight management: what important others do and say matters. AB - OBJECTIVES: Drawing from self-determination theory (Ryan & Deci, 2002, Overview of self-determination theory: An organismic-dialectical perspective. In E. L. Deci & R. M. Ryan (Eds.), Handbook of self-determination research (pp. 3-33). Rochester, NY: The University of Rochester Press.), we examined how individuals' psychological needs, motivation, and behaviours (i.e., physical activity and eating) associated with weight management could be predicted by perceptions of their important others' supportive and controlling behaviours. METHODS: Using a cross-sectional survey design, 235 participants (mean age = 27.39 years, SD = 8.96 years) completed an online questionnaire. RESULTS: Statistical analyses showed that when important others were perceived to be more supportive, participants reported higher levels of more optimal forms of motivation for weight management, which in turn predicted more physical activity and healthy eating behaviours. In contrast, when important others were perceived to be controlling, participants reported higher levels of less optimal forms of motivation, which in turn predicted less physical activity and healthy eating behaviours, as well as more unhealthy eating behaviours. Significant indirect effects were also found from perceived support and control from important others to physical activity and eating behaviours, all in the expected directions. CONCLUSIONS: The findings support the importance of important others providing support and refraining from controlling behaviours in order to facilitate motivation and behaviours conducive to successful weight management. STATEMENT OF CONTRIBUTION: What is already known on this subject? Autonomy support is related to basic need satisfaction and autonomous motivation in the context of weight management. In turn, these variables are related to adaptive outcomes for weight management. What does this study add? Measurement of perceived controlling behaviours by important others. Measurement of perceived need thwarting. Structural model on how important others affect weight management behaviours of the individual. PMID- 23751141 TI - The effect of palm oil addition to the diet of dairy sheep on the immune response. AB - The aim of this study was to evaluate whether a diet based on palm oil has any influence on the immune response and on the number of eggs per gram of faeces (EPG) of gastrointestinal nematodes (GIN) in dairy sheep. To address this issue, 30 ewes in early lactation were confined and divided into three groups (n = 10) receiving a daily isoproteic and isoenergetic diet. Palm oil was added to the feed at different concentrations: 0% (control; group A), 4% (group B) and 6% (group C). The animals were treated with levamisole 10 days before the beginning of the experiment. Faecal samples were collected and analysed for EPG on day zero of the experiment. On days 60 and 120, individual faecal and blood samples were collected, and the FAMACHA((c)) score for assessing clinical anaemia was carried out. The groups receiving palm oil showed a significant reduction in EPG in relation to the control group (A) on day 120. Serum immunoglobulin levels (IgG, IgM and IgE) and proinflammatory cytokine levels (TNF-alpha, IL-1 and IL-6) were significantly increased on days 60 and 120 (p < 0.05) in groups B and C. Therefore, these results suggest that palm oil stimulates the immune response in sheep, thus reducing EPG of GIN. The hypothesis that palm oil has direct anthelmintic activity should be tested in future studies. PMID- 23751142 TI - Validation of the cephalosporin intradermal skin test for predicting immediate hypersensitivity: a prospective study with drug challenge. AB - BACKGROUND: Cephalosporin is a major offending agent in terms of drug hypersensitivity along with penicillin. Cephalosporin intradermal skin tests (IDTs) have been widely used; however, their validity for predicting immediate hypersensitivity has not been studied. This study aimed to determine the predictive value of cephalosporin intradermal skin testing before administration of the drug. METHODS: We prospectively conducted IDTs with four cephalosporins, one each of selected first-, second-, third-, or fourth-generation cephalosporins: ceftezol; cefotetan or cefamandole; ceftriaxone or cefotaxime; and flomoxef, respectively, as well as with penicillin G. After the skin test, whatever the result, one of the tested cephalosporins was administered intravenously and the patient was carefully observed. RESULTS: We recruited 1421 patients who required preoperative cephalosporins. Seventy-four patients (74/1421, 5.2%) were positive to at least one cephalosporin. However, none of responders had immediate hypersensitivity reactions after a challenge dose of the same or different cephalosporin, which were positive in the skin test. Four patients who suffered generalized urticaria and itching after challenge gave negative skin tests for the corresponding drug. The IDT for cephalosporin had a sensitivity of 0%, a specificity of 97.5%, a negative predictive value of 99.7%, and a positive predictive value (PPV) of 0%, when challenged with the same drugs that were positive in the skin test. CONCLUSION: Routine skin testing with a cephalosporin before its administration is not useful for predicting immediate hypersensitivity because of the extremely low sensitivity and PPV of the skin test (CRIS registration no. KCT0000455). PMID- 23751143 TI - Advanced IgA nephropathy with impaired renal function benefits from losartan treatment in rats. AB - BACKGROUND: Treatment with angiotensin receptor blockers (ARBs) is successful in mitigating IgA nephropathy (IgAN), independent of blood pressure changes, but the therapeutic role of ARB in advanced IgAN with impaired renal function is to be ascertained. The present study was performed to investigate the effect of losartan on advanced IgAN induced by staphylococcal enterotoxin B (SEB) combined with 5/6 nephrectomy in rats. METHODS: Fifty-four male SD rats were randomly divided into three group: Rats in the model group were treated with SEB plus 5/6 nephrectomy, and those in the losartan group were gavaged with losartan (33.3 mg kg(-1 )d(-1)) besides the treatment with SEB plus 5/6 nephrectomy. The urine and blood biochemical changes of rats were tested. IgA, IgG, IgM and C3 depositions were studied dynamically with immunofluorescence. The renal tissue structures were observed under light microscopy. The expressions of TGF-beta1, FN, alpha-SMA and FGF-1 in rat renal tissues were determined with immunohistochemical methods and real-time PCR. RESULTS: At 12 weeks, rats with SEB treatment plus 5/6 nephrectomy showed gradually increased urinary red blood cell (URBC) with a gradual elevation of the 24 h urinary protein, serum BUN and Scr, but losartan treatment lowered the levels of 24 h urinary protein, serum BUN and Scr. A large number of IgA depositions in the mesangial area, glomerulosclerosis and tubulointerstitial fibrosis were found in the model group, and the losartan group showed relieved injury. The expressions of TGF-beta1, FN, alpha-SMA and FGF-1 were significantly elevated in the model. Losartan lessened their expressions. CONCLUSION: Losartan treatment can delay the progression of advanced IgA nephropathy with impaired renal function. PMID- 23751144 TI - Effect of hemoglobin variability on mortality and some cardiovascular parameters in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Most hemodialysis patients show hemoglobin fluctuations between low-normal and high levels. This hemoglobin variability may cause left ventricle hypertrophy and may increase mortality as well. Recently, many studies were designed to evaluate the effect of hemoglobin variability on mortality but results were conflicting. We aimed to investigate the effect of hemoglobin variability on mortality and some cardiovascular parameters in hemodialysis population. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Hundred and seventy-five prevalent hemodialysis patients classified into three hemoglobin variability groups according to their hemoglobin levels throughout 24 month observation period: Low-Normal, Low-High, Normal-High. Groups were compared in terms of laboratory, demographical data and mortality rates, initial and the end of 24 month echocardiographic data. Initial and last echocardiographic data were compared within groups in terms of left ventricle mass index increase. RESULTS: Mortality rates and cardiovascular risk factors such as coronary heart disease, diabetes mellitus and hypertension that may affect mortality were same between three groups. There was no significant difference between three groups in terms of echocardiographic and laboratory parameters. Only Low-High group showed significant increase on left ventricle mass index when initial and last echocardiographic parameters were compared. CONCLUSIONS: Consistent with previous studies, we found that most of the patients exhibited hemoglobin variability and our study is consistent with some of the studies that did not find any relationship between hemoglobin variability and mortality. Firstly, in this study based on objective data, it was shown that hemoglobin variability has adverse effect on left ventricle geometry independent from anemia. PMID- 23751145 TI - Correlation of kidney size with kidney function and anthropometric parameters in healthy subjects and patients with chronic kidney diseases. AB - BACKGROUND/AIM: Echosonography is a simple, noninvasive method of kidney visualization. The objective of this study was to compare the kidney echosonograpic characteristics with the kidney function and anthropometric characteristics in healthy subjects and patients with the chronic kidney disease (CKD). METHODS: The study involved 49 patients (21 men; 46.02 +/- 14.27 years) with CKD and the control group of 46 healthy persons (20 males; 45.45 +/- 18.48 years). Physical examination, kidney echosonography and laboratory analyses including creatinine clearance (Ccr; 24 h and calculated by Cockroft--Gault (C- G) formula) were done in all persons. RESULTS: There was no significant difference in age and sex between two groups but serum creatinine concentration was significantly higher (218.8 vs. 84.5 MUmol/L) and Ccr significantly lower (66.44 vs. 94.20 mL/min, C--G) in patient group. The left kidney was larger in both groups, but the only significant difference was in kidney depth (p < 0.01). There was significant correlation between all measured kidney dimensions, volume, parenchymal thickness and serum creatinine concentration and Ccr (C--G) in patient group. In the controls, there was no significant correlation between the kidney size and function, but there was a significant correlation between the kidney width, depth, volume and patients' age and anthropometric parameters. On the contrary, all analyzed parameters of kidney size, except volume, did not correlate significantly with the anthropometric parameters of patients. CONCLUSION: Kidney size of patients with CKD correlated significantly with kidney function, while correlation with anthropometric parameters, which is otherwise present in healthy subjects, was lost in patients with CKD. PMID- 23751146 TI - Mycophenolate mofetil for primary focal segmental glomerulosclerosis: systematic review. AB - BACKGROUND: Current treatments for primary focal segmental glomerulosclerosis (FSGS), including corticosteroids and cyclosporine, are not satisfactory for all patients and may induce significant side effects. Antidotal benefits of mycophenolate mofetil (MMF) as an add-on to these immunosuppressive therapies have been reported. This review aims to systematically summarize the efficacy and safety of MMF as a treatment for primary FSGS. METHOD: Controlled and uncontrolled clinical trials evaluating the use of MMF in primary FSGS patients were identified from nine electronic databases and four clinical trial registries. Kidney failure was selected as the primary outcome. RESULTS: Three randomized controlled trials (RCT) and 18 uncontrolled pre-post studies were included. Results from RCTs revealed that MMF is no more effective than cyclosporine or cyclophosphamide for promoting kidney function preservation when corticosteroid is used as baseline treatment. One underpowered RCT reported that MMF provides no extra benefit on top of prednisolone, but the result is unlikely to be reliable. Amongst the small, uncontrolled pre-post studies, three of them used MMF as monotherapy, two of which reported successful prevention of kidney failure in all patients. The remaining 15 uncontrolled studies used MMF as add-on therapy and 11 reported kidney failure as an outcome. Amongst them, eight reported no patients developed kidney failure. MMF was generally well tolerated with mild adverse effects, including abdominal discomfort, diarrhea and infections. CONCLUSIONS: MMF tended to show beneficial effects in uncontrolled studies which recruited patients with resistance to routine treatments, but such favorable results have only been reported in small, uncontrolled trials. No RCT results suggested that MMF was a good alternative to cyclosporine or cyclophosphamide. The role of MMF as an add-on to current therapies, or as monotherapy, should further be evaluated. PMID- 23751147 TI - High frequency of IKZF1 genetic alterations in adult patients with B-cell acute lymphoblastic leukemia. AB - Alterations in the IKZF1 gene are associated with poor prognosis in pediatric B cell acute lymphoblastic leukemia (B-ALL). We examined the relationship between IKZF1 alterations and clinical findings in 78 adult patients with B-ALL. Aberrant isoforms of IKZF1 were detected using RT-PCR. The copy numbers of IKZF1 exons and fusion genes caused by exon deletions were determined using RQ-PCR and genomic PCR, respectively. We detected aberrant IKZF1 isoforms in 20 of the 78 patients (13 Ik6 and seven Ik10) and deletions of the entire or parts of the IKZF1 gene in 40 of 70 patients. No IKZF1 point mutations were detected by direct sequencing. Nineteen Ik6 and Ik10 isoforms had been generated through genomic exon deletions, but one through aberrant splicing. In total, 41 of the 78 (52.6%) patients harbored IKZF1 alterations, which were identified in 20 of 24 (83.3%) patients with Philadelphia chromosome (Ph)-positive B-ALL compared with 21 of 54 (38.9%) Ph-negative B-ALL (P = 0.0004). IKZF1 alterations are highly involved even in adults with B-ALL. To fully detect IKZF1 alterations, several methods with alternative approaches are required. To elucidate the clinical significance of IKZF1 alterations in adult B-ALL, our study warrants prospective clinical studies with a full analysis of IKZF1 alterations. PMID- 23751148 TI - Minimally invasive mitral valve repair in a patient with porcelain aorta. AB - A woman aged 79 years with a history of stroke was admitted to undergo surgical treatment of a severe mitral regurgitation caused by active endocarditis. A preoperative computed tomography scan showed the presence of a porcelain aorta. The mitral valve was successfully repaired with an endovascular cardiopulmonary bypass system. The patient was discharged on postoperative day 10 with no complication. Endoaortic clamping is thought to be a useful technique in patients with a severely calcified aorta. PMID- 23751149 TI - Atrial fibrillation and congestive heart failure: a cost analysis of rhythm control vs. rate-control strategies. AB - BACKGROUND: Atrial fibrillation (AF) is common in patients with heart failure. Rhythm- and rate-control strategies are associated with similar efficacy outcomes. We compared the economic impact of the 2 treatment strategies in patients with AF and heart failure from the province of Quebec, Canada. METHODS: In a substudy of the Atrial Fibrillation and Congestive Heart Failure trial, health care expenditures of patients from Quebec randomized to rhythm and rate control treatment strategies were compared from a single-payer perspective using a cost-minimization approach. In-trial resource utilization and unit costs were estimated from Quebec Health Insurance Board databases supplemented by disease specific costs from the Ontario Case Costing Initiative. RESULTS: In all, 304 patients were included, aged 68 +/- 9 years; 86% male; ejection fraction, 26% +/- 6%. Baseline characteristics were similar in rhythm-control (n = 149) and rate control (n = 155) groups. Arrhythmia-related costs accounted for 45% of total expenditures. Rate-control patients had fewer cardiac procedures (146 vs. 238, P < 0.001), driven by fewer cardioversions, and lower costs related to antiarrhythmic drugs (CAD $48 per patient [95% confidence interval {CI}, $21-$96] vs. $1319 per patient [95% CI, $1124-$1522]). However, these differences were offset by higher expenditures due to hospitalizations for noncardiovascular diagnoses, implantable cardiac arrhythmia devices, and noncardiovascular drugs in the rate-control group. The total cost per patient was not significantly different between rhythm-control ($72,764 [95% CI, $61,575-$85,145]) and rate control ($78,767 [95% CI, $67,101-$92,139]) strategies. CONCLUSION: In the study population, the therapeutic strategy used to manage AF in patients with severe heart failure appears to have little influence on the overall financial burden, which remains substantial. PMID- 23751150 TI - Influence of chelation on Cu distribution and barriers to translocation in lolium perenne. AB - Strong chelating agents are reported to enhance Cu translocation in plants; however, the mechanisms responsible have not yet been fully established. In this study, both ethylenediaminetetraacetic acid (EDTA) and diethylenetriamine pentaacetic acid (DTPA) were found to increase Cu translocation to shoot tissue, while citric acid did not. Although all three amendments decreased Cu sorption to roots, which should cause greater Cu mobility within plants, this did not correspond with translocation. Energy-dispersive X-ray analysis of root cell walls showed that the endodermis presented a barrier (albeit partial) to the movement of free Cu ions, but this effect was negated by amendment addition. With EDTA, Cu levels in the stele were higher than those in the cortex after 1 week of exposure. Using Si deposition as an indicator, the presence of free Cu increased endodermal development, while amendments prevented this effect. Confocal microscopy and lipid peroxidation observations show that Cu and citric acid increased membrane damage, while EDTA and DTPA had transient effects. Strong chelating agents are less damaging alone than when present in conjunction with elevated Cu levels. Chelating amendments are proposed to enhance Cu phytoextraction by facilitating transport across the endodermis, ostensibly by influencing both membrane integrity and endodermal development. PMID- 23751151 TI - Stable and uniform SERS signals from self-assembled two-dimensional interfacial arrays of optically coupled Ag nanoparticles. AB - Densely packed interfacial nanoparticle films form spontaneously when aqueous Ag colloid is shaken with CH2Cl2 in the presence of a "promoter" such as 10(-4) mol dm(-3) tetrabutylammonium nitrate (TBA(+)NO3(-)), which induces rapid self assembly of the nanoparticles at the liquid/liquid interface without adsorbing onto their surfaces. The particles within these reflective, metal-like liquid films (MeLLFs) are optically coupled and give strong SERS enhancement, similar to that obtained for the same colloid aggregated with optimized concentration of metal salt. However, unlike aggregated colloids their structure means they do not sediment out of solution so they give SERS spectra that are stable for >20 h) and have good uniformity (relative standard deviation in absolute intensity over 1 mm(2) array of 25 points was 1.1%). Since the films lie at the aqueous/organic interface they are open to adsorption of analytes from either of the phases and can be probed in situ to detect both water- and nonwater-soluble analytes. The detection limit for mercaptobenzoic acid (MBA) added to the organic layer was found to be <2 ppb. These materials therefore combine many of the best features of both patterned surfaces and metal colloids for quantitative SERS analysis. PMID- 23751152 TI - Sublingual misoprostol prior to insertion of a T380A intrauterine device in women with no previous vaginal delivery. AB - OBJECTIVE: To investigate whether sublingual misoprostol administered one hour before intrauterine device (IUD) insertion reduces failed insertions, insertion related complications and pain in parous women delivered only by elective caesarean section (CS). METHODS: Single-blind randomised controlled trial conducted in Ismailia, Egypt, between July 2010 and December 2011. Women who had never delivered otherwise than by elective CS and desirous of using an IUD were randomly allocated to receive sublingually 400 MUg misoprostol and 100 mg diclofenac (misoprostol group) or 100 mg diclofenac alone (control group) one hour before IUD insertion. Outcome measures were failed insertion, ease of insertion judged by the investigators, insertion-related complications, and patients' satisfaction. RESULTS: In all, 255 women (130 and 125 in the study and control groups, respectively) had an IUD inserted. Seven insertions failed: five in the control group, and two in the study group. Ease of insertion and patients' satisfaction were comparable in both groups. Abdominal pain and nausea were the commonest side effects reported in the misoprostol group. CONCLUSION: Sublingual administration of misoprostol one hour before IUD insertion in parous women with no previous vaginal delivery does not facilitate the procedure and may cause undesirable side effects. This approach is not recommended as a standard treatment. PMID- 23751153 TI - Memory-related hippocampal activity can be measured robustly using FMRI at 7 tesla. AB - High field strength functional magnetic resonance imaging (fMRI) has developed rapidly. However, it suffers from increased artifacts in brain regions such as the medial temporal lobe (MTL), challenging functional imaging of the hippocampus with the objective of high-spatial resolution, which is particularly useful for this region both from a clinical and cognitive neuroscience perspective. We set out to compare a BOLD sequence at 7 T versus 3 T to visualize the MTL activity during an associative memory-encoding task. Twenty-eight healthy volunteers underwent a blocked-design fMRI at either 3 T or 7 T while performing a face profession associative memory encoding task. Qualitative analyses of overall image quality revealed that functional images at 7 T were of high quality, showing a good white/gray matter contrast, with reasonably acceptable signal dropouts and artifacts at the lower portion of the temporal lobe. Analyses of task-related fMRI data revealed robust activations in the bilateral MTL during associative memory encoding at both field strengths. Notably, we observed significantly stronger memory-related hippocampal activation at 7 T than at 3 T, suggesting higher BOLD sensitivity at 7 T. These results are discussed in the light of the feasibility of 7 T scanning protocols for the MTL. PMID- 23751154 TI - Neurophysiological evidence of differential mechanisms involved in producing opposing and following responses to altered auditory feedback. AB - OBJECTIVE: When hearing perturbations in voice auditory feedback, people produce responses that mostly oppose the perturbation direction, whereas a few responses follow the direction of feedback perturbation. The causes of opposing and following responses, however, remain poorly understood. The present event-related potential (ERP) study sought to examine the neurophysiological processing of opposing and following responses to pitch feedback perturbations during self monitoring of vocal production. METHOD: Twelve Mandarin-native speakers participated in the experiment. Vocal and neurophysiological responses to pitch perturbations (+/- 50 and +/- 200 cents) in voice auditory feedback were measured. Individual-trial responses were categorized according to the response direction and then separately averaged in groups of opposing and following responses. ERPs indexed by the P1-N1-P2 complex corresponding to two types of vocal responses were also obtained. RESULTS: Opposing and following vocal responses did not differ in the magnitude, but there were greater proportions of opposing to following responses to 50 cents stimuli. The amplitude and latency of the P1 and N1 components showed none of significance across conditions, whereas there was a direction * magnitude effect on the P2 response. Following responses elicited greater P2 amplitudes than opposing responses only when pitch feedback was perturbed for downward 200 cents, and upward pitch perturbation elicited greater P2 amplitudes than those with downward direction only in the production of opposing responses. CONCLUSION: These findings demonstrate that cortical processing of opposing responses is different from that of following responses, which can be modulated by the physical properties of feedback perturbation. SIGNIFICANCE: Different neural mechanisms are involved in the production of opposing and following responses to feedback perturbations during self-monitoring of vocal production. PMID- 23751155 TI - Quantitative local photosynthetic flux measurements at isolated chloroplasts and thylakoid membranes using scanning electrochemical microscopy (SECM). AB - Scanning electrochemical microscopy (SECM) offers a fast and quantitative method to measure local fluxes within photosynthesis. In particular, we have measured the flux of oxygen and ferrocyanide (Fe(CN)6(4-)), from the artificial electron acceptor ferricyanide (Fe(CN)6(3-)), using a stationary ultramicroelectrode at chloroplasts and thylakoid membranes (sourced from chloroplasts). Oxygen generation at films of chloroplasts and thylakoid membranes was detected directly during photosynthesis, but in the case of thylakoid membranes, this switched to sustained oxygen consumption at longer illumination times. An initial oxygen concentration spike was detected over both chloroplast and thylakoid membrane films, and the kinetics of the oxygen generation were extracted by fitting the experimental data to a finite element method (FEM) simulation. In contrast to previous work, the oxygen generation spike was attributed to the limited size of the plastoquinone pool, a key component in the linear electron transport pathway and a contributing factor in photoinhibition. Finally, the mobile nature of the SECM probe, and its high spatial resolution, also allowed us to detect ferrocyanide produced from a single thylakoid membrane. These results further demonstrate the power of SECM for localized flux measurements in biological processes, in this case photosynthesis, and that the high time resolution, combined with FEM simulations, allows the elucidation of quantitative kinetic information. PMID- 23751156 TI - Pregnancy and puerperium-related strokes in Asian women. AB - BACKGROUND: Despite an increased risk of stroke in pregnancy and puerperium, the overall incidence of the condition in this population is low. Therefore, there is limited data pertaining to these patients particularly from Asian countries. Our objective was to describe the risk factors and outcomes of 110 pregnancy-related ischemic strokes from 5 Asian countries. METHODS: Data were collected by retrospective chart review in most cases and prospectively in the rest. Inclusion criteria for this subanalysis were women, pregnant or within 1-month postpartum, presenting to the study center with acute ischemic stroke (arterial or venous) confirmed by neuroimaging. Intracranial hemorrhages other than the ones associated with cerebral venous thrombosis or hemorrhagic infarct were excluded. Risk factors were diagnosed based on already published criteria. Outcomes were measured using modified Rankin score. Statistical analysis was done using Statistical Package for Social Sciences version 19.0. RESULTS: In all, 110 women with mean age of 27.94 years presented with pregnancy-related ischemic strokes; 58.2% of the strokes occurred postpartum and 49.1% were secondary to cerebral venous thrombosis. Venous strokes were significantly more likely to occur postpartum compared with arterial strokes (P=.01), to have abnormal "hypercoagulable panel result on admission" (P<.001), less likely to have traditional stroke risk factors (P<.001), to have hemorrhagic conversion of stroke (P<.001), and to have lesser stroke severity and better functional outcome at 3 months (P<.001 for each). CONCLUSION: Cerebral venous thrombosis is a significant contributor to pregnancy-related strokes in Asian women. Both traditional and pregnancy-specific risk factors should be addressed to control ischemic stroke risk in these women. PMID- 23751157 TI - Nitric oxide-releasing polymeric microspheres improve diabetes-related erectile dysfunction. AB - INTRODUCTION: We have used a long-acting nitric oxide (NO)-releasing polymer to develop injectable biodegradable microspheres capable of localized NO release over prolonged periods of time. AIM: The aim of this study was to evaluate the therapeutic potential of these microspheres for diabetes-related erectile dysfunction (ED) in the rat model. METHODS: NO-releasing microspheres were incubated in physiologic buffer, and in vitro NO release was measured using a Griess assay. To ensure no migration, microspheres were fluorescently tagged and injected into the corpus cavernosum of adult rats, and fluorescent imaging was performed weekly for 4 weeks, at which point rats were sacrificed. To assess physiologic efficacy, diabetes was induced in 40 rats using streptozotocin (STZ), whereas 10 rats were kept as age-matched controls. Diabetic rats were divided into four groups: no treatment, sildenafil, NO-releasing microspheres, and combination therapy. For each rat, the cavernosal nerve (CN) was stimulated at various voltages, and intracavernosal pressure (ICP) and mean arterial pressure (MAP) were measured via corpus cavernosum and carotid artery catheterization, respectively. Long-term efficacy was determined by injecting diabetic rats with microspheres and measuring erectile response at predetermined intervals for up to 5 weeks. MAIN OUTCOME MEASURES: Erectile response was determined via calculation of mean peak ICP/MAP and area under curve (AUC) for each experimental group. RESULTS: Under physiologic conditions in vitro, microspheres continued NO release for up to 4 weeks. Fluorescent imaging revealed no detectable signal in tissues besides cavernosal tissue at 4 weeks postinjection. Upon CN stimulation, peak ICP/MAP ratio and AUC of diabetic rats improved significantly (P < 0.05) in microsphere and combination therapy groups compared with no treatment and sildenafil groups. In long-term efficacy studies, microspheres augmented the effect of sildenafil for 3 weeks following injection (P < 0.05). CONCLUSIONS: NO releasing microspheres significantly improved erectile response in diabetic rats for 3 weeks and hence offer a promising approach to ED therapy, either as monotherapy or combination therapy. PMID- 23751158 TI - A method for controlling the aggregation of gold nanoparticles: tuning of optical and spectroscopic properties. AB - Gold nanoparticles (AuNPs) have many interesting optical properties, which are derived from their surface plasmon resonance (SPR). However, the SPR of single AuNPs occurs around 520 nm, which is a limitation for biomedical imaging applications, because the maximum falls outside the tissue transparency window (~650-1000 nm). Here the aggregation of AuNPs is mediated by balancing aggregation and steric stabilization processes. This is achieved by varying the relative amounts of hydrophobic small molecules, which act as aggregating agents, and end functional hydrophilic polymers that serve as steric stabilizing agents. This approach allows the position of the SPR shifted into the tissue transparency window, while maintaining colloidal stability. Importantly, increased depolarized scattering and surface enhanced Raman scattering (SERS) cross sections in this region are achieved compared to the single nanoparticles. By varying the structure of the aggregating agent slightly, the SERS spectra exhibit significant changes, thus demonstrating the potential to encode different aggregates. The aggregates have potential applications in biomedical imaging, as an encoding strategy for combinatorial chemistry, and for use in flow cytometry applications. PMID- 23751159 TI - Total synthesis of (-)-nakadomarin A. AB - The convergent synthesis of the polycyclic alkaloid (-)-nakadomarin A (1) is reported. The synthesis plan identified macrocyclic lactam 4 as one of the important synthons (eight steps). The other synthon (five steps) was bicyclo[6.3.0] lactam 5 containing a single stereocenter that controlled all of the subsequent stereochemistry during the assembly process. A silyl triflate promoted cascade of 4 and 5 was used to assemble the bulk of the alkaloid skeleton with the exception of the C5-C6 bond. The nakadomarin synthesis was then completed in one additional step. PMID- 23751160 TI - Cardiovascular risk factors in children and adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. AB - OBJECTIVE: The prevalence of cardiovascular risk factors in congenital adrenal hyperplasia (CAH) varies widely. In the light of recent changes in treatment regimens, we have reassessed the prevalence of these risk factors in our current cohort of patients with CAH due to P450c21 deficiency. METHODS: A retrospective cross-sectional study of 107 children (39 m) with CAH aged 9.2 years (range 0.4 20.5 years). Anthropometric, systolic (SBP) and diastolic (DBP) blood pressure data were collected and expressed as standard deviation scores (SDS) using UK growth reference data and the Fourth Task Force data set, respectively. Fasting blood glucose with plasma insulin and lipids was measured, and insulin resistance (HOMA IR) calculated using the homoeostasis assessment model. RESULTS: 23.6% (33% men; 18% women) of the cohort were obese (BMI SDS>2). BMI SDS was significantly higher (P < 0.001) when compared with the UK population. Nineteen (20.9%) of 91 patients (20% men; 21% women) had systolic hypertension and 8 [8.8% (8.6% men; 8.9% women)] had diastolic hypertension. Mean SBP [108 (SD 13.5)] mm Hg was significantly higher than the normal population (P < 0.001), but mean DBP was not (P = 0.07). Both SBP SDS and DBP SDS were not related to BMI SDS. 9.5% of the subjects had hyperlipidaemia, but HOMA IR was more favourable compared with the normal population. CONCLUSION: Despite a reduction in steroid doses over the last decade, a number of children with CAH are still obese and hypertensive. Whether this reflects general population trends or indicates a need to further optimize treatment regimens remains to be determined. PMID- 23751161 TI - A false nasal septum deviation. PMID- 23751162 TI - Disparities in motor vehicle-related deaths among females-United States, 2005 2009. AB - BACKGROUND: In 2010, almost 11,000 females were killed in motor vehicle crashes, and racial/ethnic minorities were affected disproportionally. METHODS: To assess disparities in motor vehicle-related death rates by race/ethnicity among females in the United States, the Centers for Disease Control and Prevention analyzed 2005-2009 data from the National Vital Statistics System. Death rates and corresponding 95% confidence intervals were calculated, and differences between 2005 and 2009 death rates were examined. RESULTS: The motor vehicle-related death rate for females was 6.8 deaths per 100,000 population in 2009. American Indian/Alaska Native females had the highest motor vehicle-related death rates, followed by whites, blacks, Hispanics, and Asian/Pacific Islanders. The greatest decrease in death rates between 2005 and 2009 occurred among whites from a rate of 9.4 per 100,000 population (95% CI: 9.2-9.6) to 7.1 per 100,000 population (95% CI: 6.9-7.2; absolute rate change: -2.3; p<0.001). CONCLUSION: Despite the recent declines in motor vehicle-related death rates noted in this article, the need remains for increased use of evidence-based strategies to reduce the burden of motor vehicle-related deaths among females overall and especially among American Indian/Alaska Natives. PMID- 23751163 TI - Lifestyle and cancer prevention in women: knowledge, perceptions, and compliance with recommended guidelines. AB - BACKGROUND: Most women in the United States do not meet minimum recommendations for physical activity or fruit/vegetable consumption. Thus, many are overweight/obese and are at increased risk for cancer morbidity and mortality. This study investigated women's perceptions about the importance of physical activity and a healthy diet in preventing cancer, perceptions of engaging in these behaviors, and whether or not the behaviors met cancer prevention recommendations. METHOD: A cross-sectional, national, random-digit-dialed telephone survey was conducted with 800 women, ages 18 and older. The response rate was 24.5%. Measures assessed demographics, perceived health status, beliefs about the role of physical activity and diet in cancer prevention, perceived engagement in these behaviors, and actual behaviors. RESULTS: Only 9.9% of women who reported eating a healthy diet met minimum fruit and vegetable recommendations; 39.7% of women who reported regular physical activity met the minimum recommendation. Analyses adjusted for demographics indicated that low education was associated with reporting regular physical activity to prevent cancer, yet failing to meet the minimum recommendation (odds ratio [OR]=0.90, 95% confidence interval [CI]: 0.82-0.98, p=0.01). Racial/ethnic minority status was marginally significantly associated with reporting eating a healthy diet to prevent cancer, yet failing to consume sufficient fruits and vegetables (OR=2.94, 95% CI: 0.99-8.71, p=0.05). CONCLUSIONS: Most women who reported eating a healthy diet and being physically active to prevent cancer failed to meet the minimum cancer prevention recommendations. Furthermore, low socioeconomic status and racial/ethnic minority women may be particularly vulnerable to discrepancies between beliefs and behavior. PMID- 23751165 TI - From antenatal to postnatal depression: associated factors and mitigating influences. AB - INTRODUCTION: Postnatal depression has a serious impact on new mothers and their children and families. Risk factors identified include a history of depression, multiparity, and young age. The study aimed to investigate factors associated with experiencing antenatal depression and developing subsequent postnatal depression. METHODS: The study utilized survey data from 5332 women about their experience and well-being during pregnancy, in labor, and postnatally up to 3 months. Prespecified sociodemographic and clinical variables were tabulated against the incidence of antenatal depression and postnatal depression. Binary logistic regression was used to estimate the effects of the principal underlying variables. RESULTS: Risk factors for antenatal depression were multiparity, black and minority ethnic (BME) status, physical or mental health problems, living in a deprived area, and unplanned pregnancy. Different factors for postnatal depression were evident among women who had experienced antenatal depression: multiparity and BME status were protective, whereas being left alone in labor and experiencing poor postnatal health increased the risk of postnatal depression. CONCLUSION: This study confirms previous research on risk factors for antenatal depression and stresses the importance of continuous support in labor and vigilance in the postnatal period regarding the potential ill effects of continuing postnatal health problems. PMID- 23751164 TI - Exploring potential health disparities in excessive gestational weight gain. AB - INTRODUCTION: Although previous public health efforts have focused on redressing health disparities associated with insufficient gestational weight gain, examination of the impact of excessive gestational weight gain is warranted currently given the 2009 revision of the Institute of Medicine (IOM) gestational weight gain guidelines for obese women coupled with rising rates of obesity, particularly among African American women. MATERIALS AND METHODS: In the years 2004-2008, 4619 African American and Caucasian women gave birth to a single, live, and full-term infant, completed Arkansas Pregnancy Risk Assessment Monitoring System questions about gestational weight gain and prepregnancy weight status, and gained within or in excess of the guidelines. Logistic regression was used to identify sociodemographic and health variables associated with the odds of exceeding the 2009 IOM guidelines overall and by race. RESULTS: Regardless of race, overweight (odds ratio [OR]=3.21; 95% confidence interval [CI]: 2.64-3.91) and obese (OR=4.37; 95% CI: 3.50-5.46) women had significantly higher odds of gaining excessively, as compared with normal weight women. In the multivariate model, women who were overweight or obese prepregnancy and who were married had higher odds of exceeding the IOM guidelines, while lower odds of exceeding the guidelines were seen among African American women, those who had Medicaid at any point in their pregnancy, who were multiparous, and those of Hispanic ethnicity. DISCUSSION: These findings can inform efforts to promote appropriate gestational weight gain among those at highest risk (i.e., overweight/obese women) and facilitate targeting to produce greatest improvement in the health of mothers and children. PMID- 23751166 TI - Gender and other disparities in referral to specialized heart failure clinics following emergency department visits. AB - BACKGROUND: Persons with heart failure (HF) at high risk for adverse events should be followed by specialized HF clinics, since follow-up by specialized HF clinics improves outcomes for HF patients. The objective was to determine whether there were disparities for gender and other factors associated with referral of patients to specialized HF clinics. METHODS: In this prospective cohort study, patients with a confirmed primary diagnosis of HF were recruited by nurses at 8 hospital emergency departments (ED) in Quebec, Canada. They were interviewed by telephone at 6 weeks post ED discharge and subsequently at 3 months and 6 months. Pertinent clinical variables were extracted from medical charts by trained nurses. Bivariate analysis and multiple logistic regression were used to identify whether gender and other potential factors were associated with referral to the HF clinic. RESULTS: We enrolled 549 patients (mean age 75.5+/-11.0 years; 51% males). By 6 months after their ED visit for HF, 37.6% of the cohort were referred to specialized HF clinics. Men were more likely to be referred (odds ratio [OR] 2.04; 95% confidence interval [CI] 1.12, 3.74). Other factors associated with referral were younger age (OR 0.95; 95% CI 0.92, 0.98), and systolic dysfunction HF (left ventricle ejection fraction <40%) (OR 3.08; 95% CI 1.77, 5.46). CONCLUSION: There are disparities in referral with respect to gender, age, and type of HF. These disparities in referral need to be addressed. PMID- 23751168 TI - Starting well: induction immunosuppression after organ transplantation. PMID- 23751169 TI - Testing the limits: Investigating the effect of tDCS dose on working memory enhancement in healthy controls. AB - Transcranial Direct Current Stimulation (tDCS) is a non-invasive form of brain stimulation which has been shown to induce changes in brain activity and subsequent functioning. In particular, there is a rapidly growing evidence base showing that anodal tDCS applied to the left prefrontal cortex (PFC) is able to enhance aspects of cognitive functioning, in particular working memory (WM). This has led to both excitement and concerns regarding the possibility of 'electrodoping' in order to greatly improve one's cognitive performance. We investigated the behavioural and neurophysiological effects of increasing the current (or 'dose') of tDCS on the degree of WM improvement in healthy controls. Single sessions of 1 mA, 2 mA and sham anodal tDCS to the left PFC were undertaken over a period of three weeks. Participants underwent a WM task at three time points post-stimulation (0, 20 and 40 min) with concurrent electrophysiological (EEG) recordings. Our results showed that while active tDCS can enhance behavioural performance, with neurophysiological findings indicating improve efficiency of cognitive processing; we showed that 1 mA produced the most significant effects. These findings are somewhat unexpected as tDCS dose effects in cognitive enhancement have been shown previously in patient populations. Our results provide valuable information regarding the potential limits of tDCS induced cognitive enhancement in healthy controls, as well as providing additional insights into the possible mechanisms of action of tDCS. PMID- 23751170 TI - Our actions in my mind: motor imagery of joint action. AB - How do people imagine performing actions together? The present study investigated motor imagery of joint actions that requires integrating one's own and another's part of an action. In two experiments, individual participants imagined jumping alone or jointly next to an imagined partner. The joint condition required coordinating one's own imagined actions with an imagined partner's actions to synchronize landing times. We investigated whether the timing of participants' own imagined jumps would reflect the difference in jump distance to their imagined partner's jumps. The results showed that participants' jump imagery was indeed modulated to achieve coordination with an imagined task partner, confirming prior findings from a performance task. Moreover, when manipulating both target distance and target size, the same violation of Fitts' law reported for individual jumping was present in imagery of joint jumping. These findings link research on motor imagery and joint action, demonstrating that individuals are able to integrate simulations of different parts of a joint action. PMID- 23751171 TI - Neural processing stages during object-substitution masking and their relationship to perceptual awareness. AB - The extent of visual perceptual processing that occurs in the absence of awareness is as yet unclear. Here we examined event-related-potential (ERP) indices of visual and cognitive processes as awareness was manipulated through object-substitution masking (OSM), an awareness-disrupting effect that has been hypothesized to result from the disruption of reentrant signaling to low-level visual cortical areas. In OSM, a visual stimulus array is briefly presented that includes a parafoveal visual target denoted by a cue, typically consisting of several surrounding dots. When the offset of the target-surrounding cue dots is delayed relative to the rest of the array, a striking reduction in the perception of the target image surrounded by the dots is observed. Using faces and houses as the target stimuli, we found that successful OSM reduced or eliminated all the measured electrophysiological indices of visual processing stages after 130ms post-stimulus. More specifically, when targets were missed within the masked condition (i.e., on trials with effective OSM that disrupted awareness), we observed fully intact early feed-forward processing up through the visual extrastriate P1 ERP component peaking at 100ms, followed by reduced low-level activity over the occipital pole 130-170ms post-stimulus, reduced ERP indices of lateralized shifts of attention toward the parafoveal target, reduced object generic visual processing, abolished object-category-specific (face-specific) processing, and reduced late visual short-term-memory processing activity. The results provide a comprehensive electrophysiological account of the neurocognitive underpinnings of effective OSM of visual-object images, including evidence for central roles of early reentrant signal disruption and insufficient visual attentional deployment. PMID- 23751172 TI - Prototype learning and dissociable categorization systems in Alzheimer's disease. AB - Recent neuroimaging studies suggest that prototype learning may be mediated by at least two dissociable memory systems depending on the mode of acquisition, with A/Not-A prototype learning dependent upon a perceptual representation system located within posterior visual cortex and A/B prototype learning dependent upon a declarative memory system associated with medial temporal and frontal regions. The degree to which patients with Alzheimer's disease (AD) can acquire new categorical information may therefore critically depend upon the mode of acquisition. The present study examined A/Not-A and A/B prototype learning in AD patients using procedures that allowed direct comparison of learning across tasks. Despite impaired explicit recall of category features in all tasks, patients showed differential patterns of category acquisition across tasks. First, AD patients demonstrated impaired prototype induction along with intact exemplar classification under incidental A/Not-A conditions, suggesting that the loss of functional connectivity within visual cortical areas disrupted the integration processes supporting prototype induction within the perceptual representation system. Second, AD patients demonstrated intact prototype induction but impaired exemplar classification during A/B learning under observational conditions, suggesting that this form of prototype learning is dependent on a declarative memory system that is disrupted in AD. Third, the surprisingly intact classification of both prototypes and exemplars during A/B learning under trial-and-error feedback conditions suggests that AD patients shifted control from their deficient declarative memory system to a feedback dependent procedural memory system when training conditions allowed. Taken together, these findings serve to not only increase our understanding of category learning in AD, but to also provide new insights into the ways in which different memory systems interact to support the acquisition of categorical knowledge. PMID- 23751173 TI - The involvement of several enzymes in methanol detoxification in Drosophila melanogaster adults. AB - Methanol is among the most common short-chain alcohols in fermenting fruits, the natural food and oviposition sites of the fruit fly Drosophila melanogaster. Our previous results showed that cytochrome P450 monooxygenases (CYPs) were associated with methanol detoxification in the larvae. Catalases, alcohol dehydrogenases (ADHs), esterases (ESTs) and glutathione S-transferases (GSTs) were specifically inhibited by 3-amino-1,2,4-triazole (3-AT), 4-methylpyrazole (4 MP), triphenyl phosphate (TPP) and diethylmeleate (DEM), respectively. CYPs were inhibited by piperonyl butoxide (PBO) and 1-aminobenzotriazole (1-ABT). In the present paper, the involvements of these enzymes in methanol metabolism were investigated in female and male adults by determining the combination indices of methanol and their corresponding inhibitors. When PBO, 1-ABT, 3-AT, 4-MP and TPP were individually mixed with methanol, they exhibited significant synergism to the mortality of the adults after 72h of dietary exposure. In contrast, the DEM and methanol mixture showed additive effects. Moreover, methanol exposure dramatically increased CYP activity and up-regulated mRNA expression levels of several Cyp genes. Bioassays using different strains revealed that the variation in ADH activity and RNAi-mediated knockdown of alpha-Est7 significantly changed LC50 values for methanol. These results suggest that CYPs, catalases, ADHs and ESTs are partially responsible for methanol elimination in adults. It seems that there are some differences in methanol metabolism between larvae and adults, but not between female and male adults. PMID- 23751174 TI - Different stages of white matter changes in the original HDLS family revealed by advanced MRI techniques. AB - BACKGROUND: The temporal evolution of white matter (WM) changes on MR examinations in hereditary diffuse leukoencephalopathy with spheroids (HDLS) is largely unknown. Our purpose was to investigate the evolution of these WM changes with diffusion weighted/tensor imaging (DWI/DTI) and MR Spectroscopy (MRS). METHODS: A newly diagnosed patient with HDLS from the original Swedish family was followed prospectively with 5 MRI as well as DWI/DTI and MRS examinations during 16 months. RESULTS: The DTI eigenvalues demonstrated changes that suggested early myelin and axonal disturbances in the normal appearing WM (NAWM). DWI/DTI showed a rim of decreased diffusion progressively expanding through the WM from the initial frontal periventricular zones, and indicated complete destruction of axons and myelin in the area behind the front. MRS findings were suggestive of axonal destruction in the NAWM. CONCLUSION: We describe HDLS changes in three temporal stages of development corresponding to lesions outside, in the vicinity of, and behind a characteristic rim centrifugally progressing from the ventricular horns. The axonal disturbances indicated by MRS changes in the NAWM support a primary axonal degeneration, as proposed in the original HDLS report, rather than axonal degeneration secondary to demyelination. These findings could help in differential diagnosis of HDLS. PMID- 23751175 TI - Indigenous Maori perspectives on urban transport patterns linked to health and wellbeing. AB - There is a growing body of research linking urban transport systems to inequities in health. However, there is a lack of research providing evidence of the effect of transport systems on indigenous family wellbeing. We examined the connections between urban transport and the health and wellbeing of Maori, the indigenous people of New Zealand. We provide an indigenous exploration of current urban transport systems, with a particular focus on the impacts of car dependence and the need for culturally relevant travel. We interviewed nineteen Maori participants utilising qualitative research techniques underpinned by an indigenous research methodology (Kaupapa Maori). The data highlighted the importance of accessing cultural activities and sites relevant to 'being Maori', and issues with affordability and safety of public transport. Understanding the relationship between indigenous wellbeing and transport systems that goes further than limited discourses of inequity is essential to improving transport for indigenous wellbeing. Providing an indigenous voice in transport decision-making will make it more likely that indigenous health and wellbeing is prioritised in transport planning. PMID- 23751176 TI - A cross-sectional analysis of over-the-counter codeine use among an Australian sample of people who regularly inject drugs. AB - INTRODUCTION AND AIMS: The study aims to examine the medical and non-medical use of over-the-counter (OTC) codeine combination drugs in a sample of people who inject drugs; and to examine risk factors associated with exceeding the recommended dose of OTC codeine, including the experience of pain. DESIGN AND METHODS: This study analysed annual survey data from a convenience sample of people who inject drugs in Australia who are interviewed for the Illicit Drug Reporting System. People who have injected drugs (n = 902) on at least a monthly basis in the preceding six months across Australia were interviewed. Participants were asked about their use of OTC codeine and their experience of pain. RESULTS: One third (35%) of participants had used OTC codeine in the preceding six months and 52% (95% confidence interval 48.7-55.3) of this group had exceeded the recommended dose on their last occasion of use. This clearly places them at increased risk of harms associated with toxicity from the accompanying analgesic found in combination codeine products. Multivariate analyses demonstrated that those exceeding the recommended codeine dose of OTC codeine were more likely to be experiencing moderate to very severe pain. DISCUSSION AND CONCLUSION: There is a need to evaluate the approach to pain management in this population. Greater pharmacist involvement, real-time monitoring of sales, the development of screening tools to identify those at risk of harm and further education of primary care practitioners could be beneficial in reducing the risk of harm associated with these medications for all users of OTC codeine, including people who inject drugs. PMID- 23751178 TI - Introduction to the special issue on stress and the adolescent brain. PMID- 23751177 TI - Distribution of transmembrane AMPA receptor regulatory protein (TARP) isoforms in the rat spinal cord. AB - The transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor regulatory proteins (TARPs) are a family of auxiliary AMPA receptor subunits that differentially modulate trafficking and many functional properties of the receptor. To investigate which TARP isoforms may be involved in AMPA receptor-mediated spinal synaptic transmission, we have mapped the localization of five of the known TARP isoforms, namely gamma-2 (also known as stargazin), gamma-3, gamma-4, gamma-7 and gamma-8, in the rat spinal cord. Immunoblotting showed expression of all isoforms in the spinal cord to varying degrees. At the light microscopic level, immunoperoxidase labeling of gamma-4, gamma-7 and gamma-8 was found throughout spinal gray matter. In white matter, gamma-4 and gamma-7 immunolabeling was observed in astrocytic processes and in mature oligodendrocytes. In pepsin-treated spinal cord, gamma-7 often colocalized with GluA2 immunopositive puncta in the deep dorsal horn as well as in the ventral horn, but not in the superficial dorsal horn. Postembedding immunogold labeling was further used to assess the synaptic localization of gamma-2, gamma-7 and gamma-8 in the dorsal horn. Synaptic immunogold labeling of gamma-2 was sparse throughout the dorsal horn, with some primary afferent synapses weakly labeled, whereas relatively strong gamma-7 immunogold labeling was found at deep dorsal horn synapses, including at synapses formed by low-threshold mechanosensitive primary afferent terminals. Prominent immunogold labeling of gamma-8 was frequently detected at synapses established by primary afferent fibers. The spinal localization patterns of TARP isoforms reported here suggest that AMPA receptors at spinal synaptic populations and in glial cells may exhibit different functional characteristics owing to differences in auxiliary subunit composition. PMID- 23751179 TI - Suggested guidelines for systematic reviews of periodontal genetic association studies. PMID- 23751180 TI - Nutritional status of patients with alcoholic cirrhosis undergoing liver transplantation: time trends and impact on survival. AB - Alcoholic cirrhotics evaluated for liver transplantation are frequently malnourished or obese. We analyzed alcoholic cirrhotics undergoing transplantation to examine time trends of nutrition/weight, transplant outcome, and effects of concomitant hepatitis C virus (HCV) and/or hepatocellular carcinoma (HCC). Nutrition and transplant outcomes were reviewed for alcoholic cirrhosis with/without HCV/HCC. Malnutrition was defined by subjective global assessment. Body mass index (BMI) classified obesity. A total of 261 patients receiving transplants were separated (1988-2000, 2001-2006, and 2007-2011) to generate similar size cohorts. Mean BMI for the whole cohort was 28 +/- 6 with 68% classified as overweight/obese. Mean BMI did not vary among cohorts and was not affected by HCV/HCC. While prevalence of malnutrition did not vary among cohorts, it was lower in patients with HCV/HCC (P < 0.01). One-year graft/patient survival was 90% and not impacted by time period, HCV/HCC, or malnutrition after adjusting for demographics and model end-stage liver disease (MELD). Alcoholic cirrhotics undergoing transplantation are malnourished yet frequently overweight/obese. Among patients selected for transplantation, 1-year post transplant graft/patient survival is excellent, have not changed over time, and do not vary by nutrition/BMI. Our findings support feasibility of liver transplantation for alcoholic cirrhotics with obesity and malnutrition. PMID- 23751181 TI - Using Genome Query Language to uncover genetic variation. AB - MOTIVATION: With high-throughput DNA sequencing costs dropping <$1000 for human genomes, data storage, retrieval and analysis are the major bottlenecks in biological studies. To address the large-data challenges, we advocate a clean separation between the evidence collection and the inference in variant calling. We define and implement a Genome Query Language (GQL) that allows for the rapid collection of evidence needed for calling variants. RESULTS: We provide a number of cases to showcase the use of GQL for complex evidence collection, such as the evidence for large structural variations. Specifically, typical GQL queries can be written in 5-10 lines of high-level code and search large datasets (100 GB) in minutes. We also demonstrate its complementarity with other variant calling tools. Popular variant calling tools can achieve one order of magnitude speed-up by using GQL to retrieve evidence. Finally, we show how GQL can be used to query and compare multiple datasets. By separating the evidence and inference for variant calling, it frees all variant detection tools from the data intensive evidence collection and focuses on statistical inference. AVAILABILITY: GQL can be downloaded from http://cseweb.ucsd.edu/~ckozanit/gql. PMID- 23751182 TI - Anti-thrombosis effect of LRRFIP1 shRNA lentivirus in a mouse model of deep vein thrombosis. AB - INTRODUCTION: Deep vein thrombosis (DVT) is one of the common complications of orthopedic surgery. Low molecular weight heparin (LMWH) is a usually used agent for DVT, but it would increase the risk of bleeding. LRRFIP1 has been shown to play an important role in the formation of thrombosis. Therefore, we investigated the effect of LRRFIP1 shRNA lentivirus on DVT in mice. MATERIALS AND METHODS: Lentiviral Vectors carrying LRRFIP1 shRNA were constructed and transfected into cultured mouse bone marrow cells (BMCs). Male ICR mice were irradiated with a single dose of 9.5 Gy and then were injected with different agents through the tail vein. Stasis venous thrombosis was induced by inferior vena cava (IVC) ligation. Mice were sacrificed on the 1st, 3rd and 7th day post operation and the thrombi were removed, blotted the excess blood on it with filter paper and immediately weighed. P-selectin and d-Dimer were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: LRRFIP1 shRNA significantly suppressed the expression of LRRFIP1 in the thrombi. In contrast, low molecular weight heparin (LMWH) and negative shRNA exhibited little effect on the expression of LRRFIP1. LRRFIP1 shRNA, LMWH and negative shRNA inhibited the thrombus formation in vivo significantly. The plasma P-selectin and d-Dimer levels were significantly increased after IVC ligation. LRRFIP1 shRNA significantly decreased the plasma P selectin and d-Dimer levels. However, LMWH and negative shRNA showed little effects on the levels of plasma P-selectin and d-Dimer. CONCLUSION: LRRFIP1 shRNA might represent a promising prevention strategy for DVT. PMID- 23751183 TI - The omnifarious shades of sleep. PMID- 23751184 TI - N-linked protein glycosylation in the endoplasmic reticulum. AB - The attachment of glycans to asparagine residues of proteins is an abundant and highly conserved essential modification in eukaryotes. The N-glycosylation process includes two principal phases: the assembly of a lipid-linked oligosaccharide (LLO) and the transfer of the oligosaccharide to selected asparagine residues of polypeptide chains. Biosynthesis of the LLO takes place at both sides of the endoplasmic reticulum (ER) membrane and it involves a series of specific glycosyltransferases that catalyze the assembly of the branched oligosaccharide in a highly defined way. Oligosaccharyltransferase (OST) selects the Asn-X-Ser/Thr consensus sequence on polypeptide chains and generates the N glycosidic linkage between the side-chain amide of asparagine and the oligosaccharide. This ER-localized pathway results in a systemic modification of the proteome, the basis for the Golgi-catalyzed modification of the N-linked glycans, generating the large diversity of N-glycoproteome in eukaryotic cells. This article focuses on the processes in the ER. Based on the highly conserved nature of this pathway we concentrate on the mechanisms in the eukaryotic model organism Saccharomyces cerevisiae. PMID- 23751186 TI - Combination therapy for hypertension 2013: an update. AB - We provide a review of recent additions to the antihypertensive armamentarium in the form of combination therapy. These include two-drug and three-drug combinations in a single pill. There is evidence that such combinations are more efficacious than the individual components and that patient adherence to therapy is improved. PMID- 23751187 TI - Vegetarian low-protein diets supplemented with keto analogues: a niche for the few or an option for many? AB - BACKGROUND: Low-protein diets are often mentioned but seldom used to slow chronic kidney disease (CKD) progression. The aim of the study was to investigate the potential for implementation of a simplified low-protein diet supplemented with alpha-keto analogues (LPD-KA) as part of the routine work-up in CKD patients. METHODS: In an implementation study (December 2007-November 2011), all patients with CKD Stages IV-V not on dialysis, rapidly progressive Stage III and/or refractory proteinuria, were offered either a simplified LPD-KA, or commercially available low-protein food. LPD-KA consisted of proteins 0.6 g/kg/day, supplementation with Ketosteril 1 pill/10 Kg, 1-3 free-choice meals/week and a simplified schema based on 'allowed' and 'forbidden' foods. 'Success' was defined as at least 6 months on LPD-KA. Progression was defined as reduction in glomerular filtration rate (GFR)[(Chronic Kidney Disease Epidemiology Collaboration) formula CKD-EPI] in patients with at least 6 months of follow-up. RESULTS: Of about 2500 patients referred (8% CKD Stages IV-V), 139 started LPD KA; median age (70 years) and prevalence of comorbidity (79%) were in line with the dialysis population. Start of dialysis was the main reason for discontinuation (40 cases, unplanned in 7); clinical reasons were recorded in 7, personal preference in 14 and improvement and death in 8 each. The low gross mortality (4% per year) and the progression rate (from -8 to 0 mL/min/year at 6 months) are reassuring concerning safety. None of the baseline conditions, including age, educational level, comorbidity or kidney function, discriminated the patients who followed the diet for at least 6 months. CONCLUSIONS: Our data suggest a wider offer of LPD-KA to patients with severe and progressive CKD. The promising results in terms of mortality and progression need confirmation with different study designs. PMID- 23751185 TI - Chromatin and DNA replication. AB - The size of a eukaryotic genome presents a unique challenge to the cell: package and organize the DNA to fit within the confines of the nucleus while at the same time ensuring sufficient dynamics to allow access to specific sequences and features such as genes and regulatory elements. This is achieved via the dynamic nucleoprotein organization of eukaryotic DNA into chromatin. The basic unit of chromatin, the nucleosome, comprises a core particle with 147 bp of DNA wrapped 1.7 times around an octamer of histones. The nucleosome is a highly versatile and modular structure, both in its composition, with the existence of various histone variants, and through the addition of a series of posttranslational modifications on the histones. This versatility allows for both short-term regulatory responses to external signaling, as well as the long-term and multigenerational definition of large functional chromosomal domains within the nucleus, such as the centromere. Chromatin organization and its dynamics participate in essentially all DNA-templated processes, including transcription, replication, recombination, and repair. Here we will focus mainly on nucleosomal organization and describe the pathways and mechanisms that contribute to assembly of this organization and the role of chromatin in regulating the DNA replication program. PMID- 23751189 TI - [Standards of ophthalmologic health care in the Czech Republic]. PMID- 23751188 TI - Early growth response 2 (Egr2) plays opposing roles in committing C3H10T1/2 stem cells to adipocytes and smooth muscle-like cells. AB - Early growth response 2 (Egr2) is a zinc-finger transcription factor that acts as an important modulator of a variety of physiological processes, such as cell differentiation, proliferation and apoptosis. Here we showed that Egr2 was downregulated by bone morphogenetic protein (BMP) signaling pathways during the commitment of C3H10T1/2 stem cells to adipocyte lineage. Overexpression of Egr2 completely prevented BMP4-induced adipocyte lineage commitment of C3H10T1/2 stem cells, while simultaneously stimulating early smooth muscle-like differentiation. We also demonstrated that Egr2-induced early smooth muscle-like differentiation is transforming growth factor beta1-independent. Egr2 can activate the transcription of early smooth muscle cell specific genes smooth muscle protein 22alpha and calponin 1. Together, the results indicated a novel role for Egr2 in repressing adipocyte lineage commitment and promoting early smooth muscle-like cell differentiation. PMID- 23751190 TI - [Standards in diagnosis and therapy: cataracts in adults]. PMID- 23751191 TI - [Recommendations for diagnosis and therapy of diabetic retinopathy]. PMID- 23751192 TI - [Recommendations for diagnosis and therapy of patients with retinal vein occlusion]. PMID- 23751193 TI - [Standards of care of acute vitreoretinal conditions]. PMID- 23751194 TI - Adult-onset cerebral X-linked adrenoleukodystrophy with major contrast enhancement mimicking acquired disease. PMID- 23751195 TI - Multiple supratentorial brain abscesses due to Listeria monocytogenes in a patient with myasthenia gravis. PMID- 23751196 TI - Enhanced Cry1Da production in Bacillus thuringiensis by driving expression from the sigma(E) -dependent BtI promoter. AB - AIMS: To increase the Cry1Da production in Bacillus thuringiensis by enhancing BtI promoter activity and fusion with upstream sequence from cry1Ab. METHODS AND RESULTS: The effects of joining the upstream sequence of cry1Ab that contains E2 subunit pyruvate dehydrogenase (PDH) recognition site to the cry1Da promoter as well as the effects of substitution mutation of conserved sequences of its BtI promoter on cry1Da expression was monitored by constructing cry1Da promoter-lacZ fusions. Changing the -35 region of the cry1Da BtI promoter to that of cry1Ab enhanced beta-galactosidase activity about three fold as comparing to that of the wild-type promoter with its own upstream sequence. In contrast, the same cry1Da mutated promoter linked to the above upstream sequence of cry1Ab enhanced enzyme activity up to seven fold, but was five fold lower than that of the full-length cry1Ab promoter. The cry1Ab-cry1Da hybrid promoter with the -35 BtI mutation efficiently increased Cry1Da synthesis by 133% and resulted in a 2.3-fold increase in insect larval toxicity when comparing to the wild type. CONCLUSIONS: The cry1Ab promoter as well as mutation of -35 region of BtI promoter together with fusion with E2 subunit PDH recognition site efficiently enhanced Cry1Da production in B. thuringiensis. SIGNIFICANCE AND IMPACT OF THE STUDY: The results provide useful information to construct an efficient cry1Da gene expression in B. thuringiensis. PMID- 23751197 TI - Brainstem raphe alterations depicted by transcranial sonography do not result in serotonergic functional impairment. AB - In transcranial sonography (TCS), hypoechogenic signal of mesencephalic raphe structures has been described as a frequent finding in unipolar depression. It remains unclear if raphe hypoechogenicity represents a correlate for an altered serotonergic system. The loudness dependence of auditory evoked potentials (LDAEP) has been proposed as an indirect indicator of central serotonergic activity. Aim of this study was to evaluate TCS and LDAEP as independent variables of the human cerebral serotonergic system. Sonographic and electrophysiological investigations as well as psychometric assessment were performed blindly in 44 healthy subjects (28.7 +/- 7.0 years; 24 females). Hypoechogenic raphe was detected in 6 subjects (13.6%). Three probands (6.8%) exhibit hyperechogenicity of Substantia nigra. LDAEP values ranged between -2.80 and 8.40 mVeff/10dB (2.31 +/- 2.44). No correlations between LDAEP and sonographic findings were found. There were no significant correlations with the psychometric assessments. At least in healthy subjects, our findings do not support the hypothesis that abnormal structural finding of hypoechogenic BR in TCS is accompanied by a functional impairment of serotonergic system as assessed by LDAEP. Further multimodal studies on patients with depressive disorders are needed to elucidate the impact of the hypoechogenic raphe signal in the pathophysiology of depression. PMID- 23751198 TI - Repeated electroacupuncture attenuating of apelin expression and function in the rostral ventrolateral medulla in stress-induced hypertensive rats. AB - Studies have revealed that apelin is a novel multifunctional peptide implicated both in blood pressure (BP) regulation and cardiac function control. Evidence shows that apelin and its receptor (APJ) in the rostral ventrolateral medulla (RVLM) may play an important role in central BP regulation; however, its role is controversial and very few reports have shown the relationship between acupuncture and apelin. Our study aims to both investigate the apelinergic system role in stress-induced hypertension (SIH) and determine whether acupuncture therapy effects on hypertension involve the apelinergic system in the RVLM. We established the stress-induced hypertensive rat (SIHR) model using electric foot shock stressors with noise interventions. The expression of both apelin and the APJ receptor in the RVLM neurons was examined by immunohistochemical staining and Western blots. The results showed apelin expression increased remarkably in SIHR while APJ receptor expression showed no significant difference between control and SIHR groups. Microinjection of apelin-13 into the RVLM of control rats or SIHR produced pressor and tachycardic effects. Furthermore, effects induced by apelin-13 in SIHR were significantly greater than those of control rats. In addition, repetitive electroacupuncture (EA) stimulation at the Zusanli (ST-36) acupoint attenuated hypertension and apelin expression in the RVLM in SIHR; it also attenuated the pressor effect elicited by exogenous apelin-13 microinjection in SIHR. The results suggest that augmented apelin in the RVLM was part of the manifestations of SIH; the antihypertensive effects of EA might be associated with the attenuation of apelin expression and function in the RVLM, which might be a novel role for EA in SIH setting. PMID- 23751199 TI - Convergent synthesis and cytotoxic activities of 26-thio- and selenodioscin. AB - Convergent block syntheses of 26-thio- and selenodioscin have been achieved by developing the highly stereoselective 1,2-trans glycosylations of chacotriosyl imidate without recourse to neighboring group assistance. Both thiodioscin and selenodioscin possess cytotoxic activities similar to dioscin, a natural spirostanol glycoside. PMID- 23751200 TI - LC/ESI-MS/MS analysis of urinary 3beta-sulfooxy-7beta-N-acetylglucosaminyl-5 cholen-24-oic acid and its amides: new biomarkers for the detection of Niemann Pick type C disease. AB - We developed a sensitive, reliable, and accurate LC/ESI-MS/MS method for measurement of 3beta-sulfooxy-7beta-N-acetylglucosaminyl-5-cholen-24-oic acid and its glycine and taurine amides in urine. This atypical C24 bile acid has been reported previously to be present in the urine of patients with Niemann-Pick Type C (NPC) disease. In the method, targeted analytes are concentrated at the front edge of a trapping column, Shim-pack MAYI-C8, which permits elimination of contaminating molecules in the urinary matrix. The trapped analytes are then eluted, separated on a YMC-Pack Pro C18, and quantified with MS/MS using selected reaction monitoring. The method could detect (as amount injected) 2pg of nonamidated 3beta-sulfooxy-7beta-N-acetylglucosaminyl-5-cholen-24-oic acid, 2pg of its glycine-amide, and 0.6pg of its taurine-amide, and is linear up to 300pg. The method was then used to measure the three analytes in the urine of NPC patients (N=2), 3beta-hydroxysteroid dehydrogenase deficiency patients (N=2), and healthy volunteers (N=8). Measurable concentrations of all three analytes were present in all subjects. The urinary concentration of the sum of all three analytes was four hundred times greater in the 3month NPC patient and 40times greater in the adult patient than that of healthy volunteers. The markedly elevated urinary concentration of 3beta-sulfooxy-7beta-N-acetylglucosaminyl-5 cholen-24-oic acid and its amides in NPC patients suggests that these compounds may be valuable biomarkers for detection of NPC disease. PMID- 23751201 TI - Patterns of family identification and self-congruence in childhood separation anxiety disorder. AB - BACKGROUND: Patterns of identification among family members may differ in families with children with separation anxiety disorder (SAD) as compared with healthy children. However, this has not been explored to date. METHOD: The present study examines identification processes in 199 families: 100 families of children with SAD, 43 families of children with other anxiety disorders, and 56 families of nondisordered children, using the Family Identification Test. RESULTS: Children with SAD and their parents generally identify significantly less with each other and report less desire to be similar to each other than nondisordered children and their parents. Further, children with SAD are less self-congruent than healthy children. There were no significant differences between children with SAD and with other anxiety disorders. CONCLUSIONS: Identification and self-congruence distinguish families of children with SAD from families of healthy children. Future studies should aim to determine the direction of effects over time, as well as to determine the contribution of identification and coherence in explaining SAD after accounting for other factors such as attachment and self-esteem. PMID- 23751202 TI - Ultraviolet B irradiation induces the expression of hornerin in xenotransplanted human skin. AB - Ultraviolet (UV) irradiation exerts numerous effects on the skin. Exposure of human skin to UVB at doses that induce mild sunburn reactions causes epidermal hyperproliferation and alterations in the expression of several epidermal differentiation markers. This study investigated the effects of UVB irradiation on the expression of hornerin, a member of the S100 fused-type protein family, using the xenotransplantation of normal human skin onto nude mice. Hornerin mRNA was detected in the UVB-irradiated skin on day 2 using RT-PCR. In accordance with the results of the RT-PCR, the expression of hornerin was induced in the granular layers of the UVB-exposed skin beginning two days after UVB irradiation and occurred in parallel with the expressions of cytokeratin 6 and Ki67. This finding suggests that hornerin induction in UVB-irradiated skin might be associated with epidermal hyperproliferation. This study demonstrated that hornerin is a protein whose expression is changed by UVB irradiation and suggests that the expression of hornerin might be a useful marker of acute UV damage in skin. PMID- 23751203 TI - Cell therapy with autologous mesenchymal stem cells-how the disease process impacts clinical considerations. AB - The prospective clinical use of multipotent mesenchymal stromal cells (MSCs) holds enormous promise for the treatment of a large number of degenerative and age-related diseases. In particular, autologous MSCs isolated from bone marrow (BM) are considered safe and have been extensively evaluated in clinical trials. Nevertheless, different efficacies have been reported, depending on the health status and age of the donor. In addition, the biological functions of BM-MSCs from patients with various diseases may be impaired. Furthermore, medical treatments such as long-term chemotherapy and immunomodulatory therapy may damage the BM microenvironment and affect the therapeutic potential of MSCs. Therefore, a number of practical problems must be addressed before autologous BM-MSCs can be widely applied with higher efficiency in patients. As such, this review focuses on various factors that directly influence the biological properties of BM-MSCs, and we discuss the possible mechanisms of these alterations. PMID- 23751204 TI - Prenatal cocaine exposure and gray matter volume in adolescent boys and girls: relationship to substance use initiation. AB - BACKGROUND: Studies of prenatal cocaine exposure have primarily examined childhood populations. Studying adolescents is especially important because adolescence is a time of changing motivations and initiation of substance use. METHODS: Using magnetic resonance imaging and whole-brain voxel-based morphometry, we assessed gray matter volume (GMV) differences in 42 prenatally cocaine exposed (PCE) and 21 noncocaine-exposed (NCE) adolescents, aged 14 to 17 years. Associations between GMV differences in significant clusters and the probability of substance use initiation were examined. RESULTS: PCE relative to NCE adolescents demonstrated three clusters of lower GMV involving a limbic and paralimbic (p < .001, family-wise error [FWE] corrected), superior frontal gyrus (p = .001, FWE corrected), and precuneus (p = .019, FWE corrected) cluster. GMVs in the superior frontal and precuneus clusters were associated with initiation of substance use. Each 1-mL decrease in GMV increased the probability of initiating substance use by 69.6% (p = .01) in the superior frontal cluster and 83.6% (p = .02) in the precuneus cluster. CONCLUSIONS: PCE is associated with structural differences in cortical and limbic regions. Lower GMVs in frontal cortical and posterior regions are associated with substance use initiation and may represent biological risk markers for substance use. PMID- 23751205 TI - Scopolamine rapidly increases mammalian target of rapamycin complex 1 signaling, synaptogenesis, and antidepressant behavioral responses. AB - BACKGROUND: Clinical studies report that scopolamine, an acetylcholine muscarinic receptor antagonist, produces rapid antidepressant effects in depressed patients, but the mechanisms underlying the therapeutic response have not been determined. The present study examines the role of the mammalian target of rapamycin complex 1 (mTORC1) and synaptogenesis, which have been implicated in the rapid actions of N-methyl-D-aspartate receptor antagonists. METHODS: The influence of scopolamine on mTORC1 signaling was determined by analysis of the phosphorylated and activated forms of mTORC1 signaling proteins in the prefrontal cortex (PFC). The numbers and function of spine synapses were analyzed by whole cell patch clamp recording and two-photon image analysis of PFC neurons. The actions of scopolamine were examined in the forced swim test in the absence or presence of selective mTORC1 and glutamate receptor inhibitors. RESULTS: The results demonstrate that a single, low dose of scopolamine rapidly increases mTORC1 signaling and the number and function of spine synapses in layer V pyramidal neurons in the PFC. Scopolamine administration also produces an antidepressant response in the forced swim test that is blocked by pretreatment with the mTORC1 inhibitor or by a glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonist. CONCLUSIONS: Taken together, the results demonstrate that the antidepressant actions of scopolamine require mTORC1 signaling and are associated with increased glutamate transmission, and synaptogenesis, similar to N-methyl-D-aspartate receptor antagonists. These findings provide novel targets for safer and more efficacious rapid-acting antidepressant agents. PMID- 23751207 TI - Estimations of bulk geometrically necessary dislocation density using high resolution EBSD. AB - Characterizing the content of geometrically necessary dislocations (GNDs) in crystalline materials is crucial to understanding plasticity. Electron backscatter diffraction (EBSD) effectively recovers local crystal orientation, which is used to estimate the lattice distortion, components of the Nye dislocation density tensor (alpha), and subsequently the local bulk GND density of a material. This paper presents a complementary estimate of bulk GND density using measurements of local lattice curvature and strain gradients from more recent high resolution EBSD (HR-EBSD) methods. A continuum adaptation of classical equations for the distortion around a dislocation are developed and used to simulate random GND fields to validate the various available approximations of GND content. PMID- 23751208 TI - Boundary identification in EBSD data with a generalization of fast multiscale clustering. AB - Electron backscatter diffraction (EBSD) studies of cellular or subgrain microstructures present problems beyond those in the study of coarse-grained polycrystalline aggregates. In particular, identification of boundaries delineating some subgrain structures, such as microbands, cannot be accomplished simply with pixel-to-pixel misorientation thresholding because many of the boundaries are gradual transitions in crystallographic orientation. Fast multiscale clustering (FMC) is an established data segmentation technique that is combined here with quaternion representation of orientation to segment EBSD data with gradual transitions. This implementation of FMC addresses a common problem with segmentation algorithms, handling data sets with both high and low magnitude boundaries, by using a novel distance function that is a modification of Mahalanobis distance. It accommodates data representations, such as quaternions, whose features are not necessarily linearly correlated but have known distance functions. To maintain the linear run time of FMC with such data, the method requires a novel variance update rule. Although FMC was originally an algorithm for two-dimensional data segmentation, it can be generalized to analyze three dimensional data sets. As examples, several segmentations of quaternion EBSD data sets are presented. PMID- 23751206 TI - Kappa opioid receptor-mediated dysregulation of gamma-aminobutyric acidergic transmission in the central amygdala in cocaine addiction. AB - BACKGROUND: Studies have demonstrated an enhanced dynorphin/kappa-opioid receptor (KOR) system following repeated cocaine exposure, but few reports have focused on neuroadaptations within the central amygdala (CeA). METHODS: We identified KOR related physiological changes in the CeA following escalation of cocaine self administration in rats. We used in vitro slice electrophysiological (intracellular and whole-cell recordings) methods to assess whether differential cocaine access in either 1-hour (short access [ShA]) or 6-hour (long access [LgA]) sessions induced plasticity at CeA gamma-aminobutyric acid (GABA)ergic synapses or altered the sensitivity of these synapses to KOR agonism (U50488) or antagonism (norbinaltorphimine [norBNI]). We then determined the functional effects of CeA KOR blockade in cocaine-related behaviors. RESULTS: Baseline evoked GABAergic transmission was enhanced in the CeA from ShA and LgA rats compared with cocaine-naive rats. Acute cocaine (1 umol/L) application significantly decreased GABA release in all groups (naive, ShA, and LgA rats). Application of U50488 (1 umol/L) significantly decreased GABAergic transmission in the CeA from naive rats but increased it in LgA rats. Conversely, norBNI (200 nmol/L) significantly increased GABAergic transmission in the CeA from naive rats but decreased it in LgA rats. Norbinaltorphimine did not alter the acute cocaine induced inhibition of GABAergic responses. Finally, CeA microinfusion of norBNI blocked cocaine-induced locomotor sensitization and attenuated the heightened anxiety-like behavior observed during withdrawal from chronic cocaine exposure in the defensive burying paradigm. CONCLUSIONS: Together these data demonstrate that CeA dynorphin/KOR systems are dysregulated following excessive cocaine exposure and suggest KOR antagonism as a viable therapeutic strategy for cocaine addiction. PMID- 23751209 TI - Recording low and high spatial frequencies in exit wave reconstructions. AB - Aberration corrected Transmission Electron Microscope (TEM) images can currently resolve information at significantly better than 0.1 nm. Aberration corrected imaging conditions seek to optimize the transfer of high-resolution information but in doing so they prevent the transfer of low spatial frequency information. To recover low spatial frequency information, aberration corrected images must be acquired at a large defocus which compromises high spatial frequency information transfer. In this paper we present two a posteriori solutions to this problem in which the information bandwidth in an exit wave reconstruction is increased. In the first we reconstruct the electron exit wavefunction from two focal series datasets, with different, uniform focal steps, experimentally demonstrating that the width of the transfer interval can be extended from 0.2 nm-1 (~5 nm) to better than 10 nm-1 (0.1 nm). In the second we outline the use of a focal series recorded with a non-uniform focal step to recover a wider range of spatial frequencies without the need for a large number of images. Using simulated data we show that using this non-uniform focal step the spatial frequency interval for a five image data set may be increased to between 0.25 nm-1 (4 nm) and 8.3 nm-1 (0.12 nm) compared to between 0.74 nm-1 (1.4 nm) and 8.3 nm-1 (0.12 nm) for the standard focal series geometry. PMID- 23751211 TI - Development of 10 novel polymorphic microsatellite markers for the Indo-Pacific horned starfish, Protoreaster nodosus. AB - Ten novel polymorphic nuclear microsatellite simple sequence repeat (SSR) markers were isolated from an Indo-Pacific horned starfish, Protoreaster nodosus. The isolated SSR markers provided polymorphisms of 2-9 alleles per locus in three populations obtained from Indonesia and the Philippines. The expected and observed heterozygosities ranged from 0.049 to 0.691 and from 0.050 to 0.800, respectively. Pairwise FST values among three populations ranged from 0.018 to 0.050 (global FST=0.031). All P. nodosus individuals collected from three populations exhibited different genotypes for the ten identified SSR markers, indicating that P. nodosus reproduces sexually. Then the developed SSR markers will be useful for studying the population and conservation genetics of P. nodosus. PMID- 23751212 TI - Chronic radioisotope effects on residents of the Techa River (Russia) region: cytogenetic analysis more than 50 years after onset of exposure. AB - This paper presents the results of a cytogenetic study conducted among residents of the Techa Riverside communities (Southern Urals, Russia) exposed in the early 1950s as a result of releases of liquid radioactive wastes from the Mayak plutonium-production facility. The study was performed 50-60 years after the beginning of the exposure for those individuals who were predominantly exposed to strontium radioisotopes ((89,90)Sr) through drinking contaminated river water and consumption of local foodstuff. Standard cytogenetic methods were used for evaluation of the frequency of unstable chromosome aberrations in exposed persons as well as in persons from the control group who were of similar age and sex, living in similar socio-economic conditions in non-contaminated territories of the Southern Urals. The exposure doses were reconstructed for the studied donors using the Techa River Dosimetry System developed in 2009. The doses of internal exposure from ingested radionuclides were evaluated using individual or family in vivo measurements of (90)Sr-body burden. Individual cumulative absorbed doses in red bone marrow (RBM) in the studied persons varied in the range of 0.01-4.4Gy. A significantly higher level of unstable chromosome aberrations (UCA) in T-cells was observed in the group of exposed individuals as compared to control group. The highest UCA level was detected in the individuals who were suspected of having chronic radiation syndrome. PMID- 23751213 TI - Apoptotic signaling pathways in uteri of rats with endometrial hyperplasia induced by ovariectomy combined with estrogen. AB - AIMS: To explore a new reliable method inducing an animal model similar to the morphology and apoptotic signaling pathways in endometrial hyperplasia patients. METHODS: After the rats were ovariectomized, estradiol benzoate (60 ug/100 g) was intramuscularly injected on alternate days for 4 weeks. The morphology in the uterus was observed under a light microscope and by electron microscopy. The expression levels of survivin/caspase-3 and Fas/FasL were checked by immunohistochemistry, Western blotting and real-time polymerase chain reaction. RESULTS: After the models were induced, the edema and hypertrophy in uteri were observed 4 weeks later. The glands in the endometrium had increased, indented hyperplasia of glandular cells appeared, and a pseudo-stratified phenomenon occurred. Under a transmission electron microscope, free ribosomes had markedly increased and the nucleus was enlarged in the cytoplasm. Compared with the control group, the expression of survivin increased (p < 0.05) while that of caspase-3 and Fas/FasL declined (p < 0.05). CONCLUSIONS: In the rat model of endometrial hyperplasia induced by ovariectomy with pharmacological estrogen add back treatment, survivin, caspase-3 and Fas/FasL signaling pathways play an important role in regulating the apoptosis of glandular cells in uteri. PMID- 23751215 TI - Phillyrin attenuates LPS-induced pulmonary inflammation via suppression of MAPK and NF-kappaB activation in acute lung injury mice. AB - Phillyrin (Phil) is one of the main chemical constituents of Forsythia suspensa (Thunb.), which has shown to be an important traditional Chinese medicine. We tested the hypothesis that Phil modulates pulmonary inflammation in an ALI model induced by LPS. Male BALB/c mice were pretreated with or without Phil before respiratory administration with LPS, and pretreated with dexamethasone as a control. Cytokine release (TNF-alpha, IL-1beta, and IL-6) and amounts of inflammatory cell in bronchoalveolar lavage fluid (BALF) were detected by ELISA and cell counting separately. Pathologic changes, including neutrophil infiltration, interstitial edema, hemorrhage, hyaline membrane formation, necrosis, and congestion during acute lung injury in mice were evaluated via pathological section with HE staining. To further investigate the mechanism of Phil anti-inflammatory effects, activation of MAPK and NF-kappaB pathways was tested by western blot assay. Phil pretreatment significantly attenuated LPS induced pulmonary histopathologic changes, alveolar hemorrhage, and neutrophil infiltration. The lung wet-to-dry weight ratios, as the index of pulmonary edema, were markedly decreased by Phil pretreatment. In addition, Phil decreased the production of the proinflammatory cytokines including (TNF-alpha, IL-1beta, and IL-6) and the concentration of myeloperoxidase (MPO) in lung tissues. Phil pretreatment also significantly suppressed LPS-induced activation of MAPK and NF kappaB pathways in lung tissues. Taken together, the results suggest that Phil may have a protective effect on LPS-induced ALI, and it potentially contributes to the suppression of the activation of MAPK and NF-kappaB pathways. Phil may be a new preventive agent of ALI in the clinical setting. PMID- 23751214 TI - Structure and function of the mucus clearance system of the lung. AB - In cystic fibrosis (CF), a defect in ion transport results in thick and dehydrated airway mucus, which is difficult to clear, making such patients prone to chronic inflammation and bacterial infections. Physiotherapy using a variety of airway clearance techniques (ACTs) represents a key treatment regime by helping clear the airways of thickened, adhered, mucus and, thus, reducing the impact of lung infections and improving lung function. This article aims to bridge the gap between our understanding of the physiological effects of mechanical stresses elicited by ACTs on airway epithelia and the reported effectiveness of ACTs in CF patients. In the first part of this review, the effects of mechanical stress on airway epithelia are discussed in relation to changes in ion transport and stimulation in airway surface layer hydration. The second half is devoted to detailing the most commonly used ACTs to stimulate the removal of mucus from the airways of patients with CF. PMID- 23751216 TI - Nutritional and functional potential of Beta vulgaris cicla and rubra. AB - Swiss chard (Beta vulgaris cicla, BVc) and beetroot (Beta vulgaris rubra, BVr) are vegetables of the Chenopodiaceae family, widely consumed in traditional western cooking. These vegetables represent a highly renewable and cheap source of nutrients. They can be cultivated in soils with scarce organic material and little light and water. BVc and BVr have a long history of use in folk medicine. Modern pharmacology shows that BVc extracts possess antihypertensive and hypoglycaemic activity as well as excellent antioxidant activity. BVc contains apigenin flavonoids, namely vitexin, vitexin-2-O-rhamnoside and vitexin-2-O xyloside, which show antiproliferative activity on cancer cell lines. BVr contains secondary metabolites, called betalains, which are used as natural dyes in food industry and show anticancer activity. In this light, BVc and BVr can be considered functional foods. Moreover, the promising results of their phytochemicals in health protection suggest the opportunity to take advantage of the large availability of this crop for purification of chemopreventive molecules to be used in functional foods and nutraceutical products. PMID- 23751217 TI - Addition of vardenafil into storage solution protects the endothelium in a hypoxia-reoxygenation model. AB - OBJECTIVE: Based upon the well known protective effect of intracellular cyclic guanosine monophosphate (cGMP) accumulation, we tested the hypothesis that storage solution enriched with optimal concentration of the phosphodiestherase-5 inhibitor vardenafil could provide better protection of vascular grafts against reperfusion injury after long-term cold ischaemic storage. METHODS: Isolated thoracic aorta obtained from rats underwent 24-h cold ischaemic preservation in physiological saline or vardenafil (10(-11) M)-supplemented saline solution. Reperfusion injury was simulated by hypochlorite (200 MUM) exposure for 30 minutes. Endothelium-dependent vasorelaxation was assessed, and histopathological and molecular-biological examination of the aortic tissue were performed. RESULTS: Compared with the control group, the saline group showed significantly attenuated endothelium-dependent maximal relaxation (Rmax) to acetylcholine after hypoxia-reoxygenation, which was significantly improved by vardenafil supplementation (Rmax control: 98 +/- 1%; saline: 48 +/- 6%; vardenafil: 75 +/- 4%; p < .05). Vardenafil treatment significantly reduced DNA strand breaks (control: 10.6 +/- 6.2%; saline: 72.5 +/- 4.0%; vardenafil: 14.2 +/- 5.2%; p < .05) and increased cGMP score in the aortic wall (control: 8.2 +/- 0.6; saline: 4.5 +/- 0.3; vardenafil: 6.7 +/- 0.6; p < .05). CONCLUSIONS: Our results support the view that impairment of intracellular cGMP signalling plays a role in the pathogenesis of the endothelial dysfunction induced by cold storage warm reperfusion, which can be effectively reversed by pharmacological phosphodiesterase-5 inhibition. PMID- 23751218 TI - When moral identity symbolization motivates prosocial behavior: the role of recognition and moral identity internalization. AB - This article examines the role of moral identity symbolization in motivating prosocial behaviors. We propose a 3-way interaction of moral identity symbolization, internalization, and recognition to predict prosocial behavior. When moral identity internalization is low, we hypothesize that high moral identity symbolization motivates recognized prosocial behavior due to the opportunity to present one's moral characteristics to others. In contrast, when moral identity internalization is high, prosocial behavior is motivated irrespective of the level of symbolization and recognition. Two studies provide support for this pattern examining volunteering of time. Our results provide a framework for predicting prosocial behavior by combining the 2 dimensions of moral identity with the situational factor of recognition. PMID- 23751219 TI - The evolutionary potential of paramutation: a population-epigenetic model. AB - Paramutation involves an interaction between homologous alleles resulting in a heritable change in gene expression without altering the DNA sequence. Initially believed to be restricted to plants, paramutation has recently been observed in animal models, and a paramutation-like event has been noted in humans. Despite the accumulating evidence suggesting that trans-acting epigenetic effects can be inherited transgenerationally and therefore generate non-genomic phenotypic variation, these effects have been largely ignored in the context of evolutionary theory. The model presented here incorporates paramutation into the standard model of viability selection at one locus and demonstrates that paramutation can create long-term biological diversity in the absence of genetic change, and even in the absence of the original paramutagenic allele. Therefore, if paramutation is present, attributing evolution to only a traditional genetic model may fail to encompass the broad scope of phenotypic differences observed in nature. Moreover, we show also that an unusual mathematical behaviour, analogous to "Ewens' gap" of the two-locus two-allele symmetric-selection model, occurs: when the rate of one parameter-for example, the rate of paramutation-is increased, a pair of equilibria may disappear only to reappear as this parameter increases further. In summary, by incorporating even the simplest epigenetic parameters into the standard population-genetic model of selection, we show how this type of inheritance system can profoundly alter the course of evolution. PMID- 23751220 TI - The impact on vision of aspheric to spherical monofocal intraocular lenses in cataract surgery: a systematic review with meta-analysis. AB - PURPOSE: To provide a summary of the impact on vision of an aspheric intraocular lens (IOL) compared with a spherical IOL in cataract surgery. DESIGN: Systematic review with meta-analysis. PARTICIPANTS: Patients from published randomized controlled trials (RCTs) of cataract surgery with aspheric compared with spherical monofocal IOL implantation. METHODS: We systematically searched the peer-reviewed literature in MEDLINE, EMBASE, Web of Science, BIOSIS, and the Cochrane Library according to the Cochrane Collaboration method to identify relevant RCTs. The inclusion criteria were RCTs on cataract surgery comparing the use of aspheric versus spherical IOL implantation that assessed visual acuity, contrast sensitivity, or quality of vision. The effects were calculated as mean differences or standardized mean differences (Hedges' g) and pooled using random effect models. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA), contrast sensitivity, and subjective perception of the quality of vision. RESULTS: Forty-three studies provided data and were included, comprising 2076 eyes implanted with aspheric IOLs and 2034 eyes implanted with spherical IOLs. The BCVA showed a significant difference for aspheric IOLs (-0.01 logarithm of the minimum angle of resolution; 95% confidence interval [CI], -0.02 to -0.00). For contrast sensitivity, a significant advantage for aspheric IOLs was found under photopic and mesopic light conditions (photopic: Hedges' g 0.42, 95% CI 0.24-0.61 (3 cycles per degree [cpd]) to 0.53, 95% CI 0.33-0.73 (12 cpd); mesopic: Hedges' g 0.49, 95% CI 0.23-0.75 (1.5 cpd) to 0.76, 95% CI 0.52-1.00 (18 cpd)). Questionnaires targeting the subjective perception of quality of vision yielded less conclusive results. CONCLUSIONS: Overall, a patient may achieve better contrast sensitivity with an aspheric IOL than with a spherical IOL, especially under dim light. There was no clinically relevant difference in BCVA between aspheric and spherical IOL implantation. The findings on the subjective perception of visual quality were heterogeneous with no clear result favoring either option. PMID- 23751221 TI - FT-IR, micro-Raman and UV-vis spectroscopic and quantum chemical investigations of free 2,2'-dithiodipyridine and its metal (Co, Cu and Zn) halide complexes. AB - In this study the elemental analysis results, molecular geometries, vibrational and electronic absorption spectra of free 2,2'-dithiodipyridine(C10H8N2S2), (or DTDP) (with synonym, 2,2'-dipyridyl disulfide) and M(C10H8N2S2)Cl2 (M=Co, Cu and Zn) complexes have been reported. Vibrational wavenumbers of free DTDP and its metal halide complexes have been calculated by using DFT/B3LYP calculation method with 6-31++G(d,p) and Lanl2DZ basis sets, respectively, in the ground state, for the first time. The calculated fundamental vibrational frequencies are in a good agreement with experimental data. The HOMO, LUMO and MEP analyses of all compounds are performed by DFT method. PMID- 23751222 TI - High performance B doped BiVO4 photocatalyst with visible light response by citric acid complex method. AB - A B-doped BiVO4 photocatalyst was synthesized by citric acid complex method and using H3BO3 as the dopant source, and the photocatalyst was characterized with XPS, XRD, SEM, BET and UV-Vis DRS. The photocatalytic activity was evaluated by the photocatalytic degradation of a methyl orange (MO) solution under visible light. This assay revealed that both the pure BiVO4 and all of the B doped samples were the monoclinic phase. Doping the BiVO4 with B increased the number of V(4+) and oxygen vacancies, which led to the red shift of the absorbing boundary of the B-doped BiVO4 but had little influence on the morphology and crystal size. The B doping improved the photocatalytic activity, and the highest photocatalytic degradation rate of 98% occurred with a B dopant concentration of 0.04. PMID- 23751223 TI - Comparative studies by IR, Raman, and surface-enhanced Raman spectroscopy of azodicarbonamide, biurea and semicarbazide hydrochloride. AB - Azodicarbonamide is widely applied in the food industry as a new flour gluten fortifier in China, Canada, the United States, and some other countries, whose metabolites of biurea and semicarbazide hydrochloride are reaction products during baking. In this study, IR, Raman and surface-enhanced Raman scattering (SERS) spectra of azodicarbonamide, biurea, and semicarbazide hydrochloride have been studied, and vibrational bands have been assigned on the basis of density functional theory (DFT) calculations. The calculated Raman spectra were in good agreement with experimental Raman spectra. The SERS method coupled with active gold substrates has also been applied for detection of the three chemicals with pure water as solvent, with the limit of detection of this method being as low as 10 MUg/mL (less than 45 MUg/mL). These results showed that azodicarbonamide and its metabolites could be detected by the vibrational spectra technique, which might be applied as a powerful tool for the rapid detection on these species derived from agents added to flour. PMID- 23751224 TI - Vibrational spectroscopic (FT-IR and FT-Raman) studies, natural bond orbital analysis and molecular electrostatic potential surface of Isoxanthopterin. AB - The FTIR and FT-Raman spectra of Isoxanthopterin have been recorded in the region 4000-450 and 4000-100 cm(-1), respectively. The optimized geometry, frequency and intensity of the vibrational bands of Isoxanthopterin were obtained by the density functional theory (DFT) using 6-311++G(d,p) basis set. The harmonic vibrational frequencies were scaled and compared with experimental values. The observed and the calculated frequencies are found to be in good agreement. The (1)H and (13)C nuclear magnetic resonance chemical shifts of the molecule were also calculated using the gauge independent atomic orbital (GIAO) method. The UV visible spectrum was also recorded and compared with the theoretical values. The calculated HOMO and LUMO energies show that charge transfer occurs within molecule. The first order hyperpolarizability (beta0), related properties (beta, alpha0 and Deltaalpha) and the Mulliken charges of the molecule were also computed using DFT calculations. Stability of the molecule arising from hyperconjugative interactions, charge delocalization have been analyzed using natural bond orbital (NBO) analysis. The results show that charge in electron density (ED) in the sigma* and pi* antibonding orbitals and second order delocalization energies (E2) confirms the occurrence of intramolecular charge transfer (ICT) within the molecule. Information about the charge density distribution of the molecule and its chemical reactivity has been obtained by mapping molecular electrostatic potential surface. In addition, the non-linear optical properties were discussed from the dipole moment values and excitation wavelength in the UV-visible region. PMID- 23751225 TI - Use of potentially harmful skin-lightening products among immigrant women in Rome, Italy: a pilot study. AB - BACKGROUND: Skin-lightening products are increasingly common in European cities. These products may contain substances that are banned under EU regulations as they can induce adverse effects, including cutaneous and systemic reactions (e.g., mercury, hydroquinone and topical corticosteroids). OBJECTIVES: To assess the knowledge, attitudes and practices of women regarding skin-lightening products and to quantify the potentially harmful substances in the products used. METHODS: We performed a cross-sectional study among 82 non-Italian women visiting an outpatient facility in Rome, Italy. The women completed a questionnaire on product use, side effects and risk awareness. We performed patch tests among a subgroup of 48 women who presented with contact dermatitis. We also quantified the allergenic and toxic substances in the 14 products reported, using dynamic reaction cell inductively coupled plasma mass spectrometry for metals and high performance liquid chromatography for hydroquinone and topical corticosteroids. RESULTS: Out of the 82 women, 33 used skin-lightening products; about one fourth of these women were aware of potential risks. Three cosmetic creams and two soaps contained high concentrations of metals (Cr, Ni and Pb); hydroquinone was found in three creams and one oil. The only topical corticosteroid detected was dexamethasone, in one product. More than half of the women in the clinical evaluation had irritant contact dermatitis (i.e., negative response to patch test). CONCLUSIONS: Among immigrant women in Rome, the use of skin-lightening products seems to be fairly common, and some of these products contain potentially hazardous substances. Consumers must be informed of the potential risks, and EU regulations must be more strictly enforced. PMID- 23751226 TI - Gastrointestinal imaging: tips and traps in the diagnosis of small HCC. AB - Improvement in survival of patients with HCC depends on detecting small lesions. This is possible by screening all patients with cirrhosis for HCC. However, these small lesions are difficult to characterise as only 50 to 80% of lesions less than 3cm have a typical HCC appearance, depending on the imaging technique used. MRI, with its various possibilities (dynamic sequences, diffusion-weighting, liver-specific contrast agents), is currently the most effective imaging technique for characterising these small HCCs, but at present we do not know the best combination of imaging examinations for diagnosing the condition. PMID- 23751227 TI - Coping with the problems of diagnosis of acute colitis. AB - Acute colitis is an acute condition of the colon. For the radiologist, it is mainly diagnosed during differential diagnosis of acute abdominal conditions. There are many causes of colitis and the degree of its severity varies. A CT scan is the best imaging examination for diagnosing it and also for analysing and characterising colitis. The topography, type of lesion and associated factors can often suggest a precise diagnosis but it is nevertheless essential to integrate these findings into the clinical context and take laboratory values into account. The use of endoscopy is still the rule where a doubt remains, or to obtain necessary histological evidence. PMID- 23751228 TI - MRI of cholangitis: traps and tips. AB - There are many limitations to the examination of the bile ducts by magnetic resonance imaging, which may be four orders: (1) technical, requiring analysis of Maximum Intensity Projection (MIP) three-dimensional (3D) volume reconstructions as well as native images, the use of T1-weighted sequences obtained in 3D to avoid entry slice phenomena, and knowledge of the inherent limits of the method, the spatial resolution of which is still less than optimal; (2) anatomical: you need to know the appearance of flow artefacts within the bile ducts and the traps that the presence of air or bleeding into the bile ducts can create; you also need to know the characteristic appearance of the indentation caused by the hepatic artery on the bile ducts and the variants and modifications seen in cases of portal biliopathy; (3) semiological: the terms used to describe bile duct abnormalities seen in MRI are often derived from imprecise descriptions used in retrograde cholangiography: irregularities of the bile ducts, a beaded 'string of pearls' appearance, a 'dead tree' appearance; (4) related to a complex disease, cholangitis which is a complex pathological condition, with possible overlaps between different conditions, such as primary sclerosing cholangitis (PSC), secondary sclerosing cholangitis, autoimmune cholangitis. In any case, the diagnosis of cholangiocarcinoma associated with PSC is always difficult. These limitations can be circumvented by using a precise exploration technique comprised of 3D magnetic resonance cholangiography sequences, which allow volume analysis, examination of native slices and of thick or thin MIP reconstructions, and heavily T2-weighted and T1-weighted 3D sequences with and without gadolinium injection, which is not always essential. The examination must be interpreted according to a stereotyped plan that includes (1) examination of the bile ducts, searching for and describing any stenosis, the presence or absence of dilatation, (2) a systematic search for any intrahepatic calculus, (3) examination of the heterogeneity of the liver parenchyma, investigation to find any liver dysmorphia and signs of portal hypertension, (4) analysis of the enhancement of the liver parenchyma and any enhancement of the wall of the bile ducts. PMID- 23751229 TI - Hepatic steatosis: a major trap in liver imaging. AB - Hepatic steatosis is a common condition, the prevalence of which is increasing along with non-alcoholic hepatic steatosis. In imaging, it can present in a typical homogeneous or heterogeneous way. Some forms create traps in imaging, whether localised steatosis is concerned or areas which have been spared by steatosis, and the purpose of this paper is to explain and illustrate them. The role of different imaging methods is described while emphasizing the importance of MRI. PMID- 23751230 TI - A solid pancreatic mass: tumour or inflammation? AB - The prognosis for pancreatic cancer is poor, and early diagnosis is essential for surgical management. By comparison with its classic form, the presence of acute or chronic inflammatory signs will hinder its detection and delay its diagnosis. The atypical forms of acute pancreatitis need to be known in order to detect patients who require additional morphological investigations to search for an underlying tumour. In contrast, pseudotumoral forms of inflammation (chronic pancreatitis, cystic dystrophy in heterotopic pancreas, autoimmune pancreatitis) may simulate a cancer, and make up 5-10% of the surgical procedures for suspected cancer. Faced with these pseudotumoral masses, interpretation relies on various differentiating signs and advances in imaging. PMID- 23751232 TI - A commentary on 'effects of screening for psychological distress on patient outcomes in cancer: a systematic review'. PMID- 23751233 TI - Moving forward by moving back: re-assessing guidelines for cancer distress screening. PMID- 23751231 TI - Effects of screening for psychological distress on patient outcomes in cancer: a systematic review. AB - OBJECTIVE: Several practice guidelines recommend routine screening for psychological distress in cancer care. The objective was to evaluate the effect of screening cancer patients for psychological distress by assessing the (1) effectiveness of interventions to reduce distress among patients identified as distressed; and (2) effects of screening for distress on distress outcomes. METHODS: CINAHL, Cochrane, EMBASE, ISI, MEDLINE, PsycINFO, and SCOPUS databases were searched through April 6, 2011 with manual searches of 45 relevant journals, reference list review, citation tracking of included articles, and trial registry reviews through June 30, 2012. Articles in any language on cancer patients were included if they (1) compared treatment for patients with psychological distress to placebo or usual care in a randomized controlled trial (RCT); or (2) assessed the effect of screening on psychological distress in a RCT. RESULTS: There were 14 eligible RCTs for treatment of distress, and 1 RCT on the effects of screening on patient distress. Pharmacological, psychotherapy and collaborative care interventions generally reduced distress with small to moderate effects. One study investigated effects of screening for distress on psychological outcomes, and it found no improvement. CONCLUSION: Treatment studies reported modest improvement in distress symptoms, but only a single eligible study was found on the effects of screening cancer patients for distress, and distress did not improve in screened patients versus those receiving usual care. Because of the lack of evidence of beneficial effects of screening cancer patients for distress, it is premature to recommend or mandate implementation of routine screening. PMID- 23751234 TI - The impact of personal attributes on the association between cumulative exposure to work stressors and cardiovascular disease. AB - OBJECTIVE: To examine the impact of personal attributes (coping and negative affectivity) on the association between cumulative exposure to work stressors and cardiovascular disease (CVD). METHODS: 6154 employees from the Maastricht Cohort Study (MCS) were selected who had complete data on the MCS Work Stressor Score (MCS-WSS) at three consecutive time points during 1998-2000 and free of CVD during the exposure assessment period. CVD was assessed from 2000 until 2008 with questionnaires. Cumulative exposure to work stressors was calculated as the frequency of exposure in the upper quartile of the MCS-WSS and consisted of the categories: none, once, twice or thrice exposed. Cox regression analyses were used to examine the direct effect of personal attributes on CVD incidence and the intermediating, confounding and moderating effect on the association between cumulative exposure to work stressors and CVD. Logistic regression was used to examine the influence of personal attributes on the odds of high cumulative exposure (thrice exposed). RESULTS: High NA was significantly associated with high cumulative exposure to work stressors. There was no significant evidence supporting an intermediating, confounding or moderating effect of NA or coping on the association between cumulative exposure to work stressors and CVD. CONCLUSION: The association between cumulative exposure to work stressors and CVD is not confounded or intermediated by NA or coping. High NA showed a direct effect on high cumulative exposure to work stressors. However, it should be examined whether high NA individuals experience more work stressors or are actually exposed to more work stressors. PMID- 23751235 TI - Autonomic effects of suggestive placebo interventions to increase or decrease blood pressure: a randomized controlled trial in healthy subjects. AB - OBJECTIVE: Placebo effects on pain and other subjective parameters are well established, but the evidence for placebo effects on autonomic functions is scarce. Our randomized-controlled trial aimed to investigate autonomic responses after a suggestive placebo intervention intended to increase or decrease blood pressure (BP). METHODS: 92 healthy subjects inhaled a placebo spray with the prior suggestion that it contained an effective drug to either increase or decrease BP, or the information that a placebo was administered (controls). BP, heart rate, stroke volume, peripheral resistance, heart rate variability and skin conductance level were monitored 30min before and after placebo administration. The expected and the subjectively perceived drug effect were measured by means of visual analog scales. RESULTS: We found no statistically significant differences between the groups with respect to BP, heart rate, stroke volume, total peripheral resistance and heart rate variability responses to the verbal suggestions. Skin conductance response was more pronounced in the BP decrease group compared with controls (p=0.04), but this finding might be due to chance, given the multiple tests. Within the total study sample, BP, total peripheral resistance, low frequency power of heart rate variability and skin conductance were significantly higher after the placebo spray independent of the associated suggestions. Subjects in the BP increase and BP decrease condition had higher ratings of the expected and the subjectively perceived drug effect compared with controls (all p<0.05). CONCLUSION: We found no evidence that specific verbal suggestions during placebo interventions affect BP in healthy subjects. PMID- 23751237 TI - A prospective study of physical fitness, obesity, and the subsequent risk of mental disorders among healthy young adults in army training. AB - OBJECTIVE: Mental health disorders contribute substantially to medical and occupational morbidity. The role of fitness and physical activity in the prevention of mental health disorders is not well established, but epidemiologic data suggest that physical activity can protect against anxiety and depression. METHOD: The analyses presented in this report, from a prospective cohort study, evaluate the association between fitness (as measured by a 5-minute step test), and being overweight (defined as exceeding weight and body fat allowances) at military entrance, with subsequent onset of mental disorder diagnosis in the first year of service. The association between risk factors and mental disorder diagnosis was analyzed using multivariate Poisson regression with the adjusted incidence rate ratio (aIRR) as the measure of association. RESULTS: Among weight qualified participants, factors associated with increased incidence of mental disorder included failing the physical fitness test (aIRR: 1.36, p<0.0001), female sex (aIRR: 2.17, p<0.0001), and smoking (aIRR: 1.49, p<0.0001). Among fit participants, being overweight was not significantly associated with mental disorder (aIRR: 1.11, p=0.1540). CONCLUSIONS: This test has potential military utility as an adjunct part of the medical examination process. Additional research is needed among civilians to determine if similar associations exist. If so, intervention studies should be conducted to determine if improving physical fitness reduces subsequent psychiatric disorder risk, particularly among young adults entering into stressful situations. PMID- 23751238 TI - The relative importance of body change strategies, weight perception, perceived social support, and self-esteem on adolescent depressive symptoms: longitudinal findings from a national sample. AB - OBJECTIVE: This study aimed to evaluate the relative importance of body change strategies and weight perception in adolescent depression after accounting for established risk factors for depression, namely low social support across key adolescent contexts. The moderating effect of self-esteem was also examined. METHODS: Participants (N=4587, 49% female) were selected from the National Longitudinal Study of Adolescent Health. Regression analyses were conducted on the association between well-known depression risk factors (lack of perceived support from parents, peers, and schools), body change strategies, weight perception, and adolescent depressive symptoms one year later. RESULTS: Each well known risk factor significantly predicted depressive symptoms. Body change strategies related to losing weight and overweight perceptions predicted depressive symptoms above and beyond established risk factors. Self-esteem moderated the relationship between trying to lose weight and depressive symptoms. CONCLUSION: Maladaptive weight loss strategies and overweight perceptions should be addressed in early identification depression programs. PMID- 23751236 TI - A double-blind, randomized pilot trial of chromium picolinate for binge eating disorder: results of the Binge Eating and Chromium (BEACh) study. AB - OBJECTIVE: Chromium treatment has been shown to improve mood, appetite, and glucose regulation in various psychiatric and medical patient populations. The authors propose that chromium may be useful in the treatment of binge eating disorder (BED). METHOD: Twenty-four overweight adults with BED were enrolled in a 6-month double-blind placebo-controlled trial and randomly assigned to receive either 1000mcg chromium/day ("high dose"; n=8) or 600mcg chromium/day ("moderate dose"; n=9) as chromium picolinate or placebo (n=7). Mixed linear regression models were used to estimate mean change in binge frequency and related psychopathology, weight, symptoms of depression, and fasting glucose. RESULTS: Fasting glucose was significantly reduced in both chromium groups compared to the placebo group; similarly, numerically, but not significantly, greater reductions in binge frequency, weight, and symptoms of depression were observed in those treated with chromium versus placebo, although statistical power was limited in this pilot trial. For fasting glucose, the findings suggest a dose response with larger effects in the high dose compared to moderate dose group. CONCLUSION: These initial findings support further larger trials to determine chromium's efficacy in maintaining normal glucose regulation, reducing binge eating and related psychopathology, promoting modest weight loss, and reducing symptoms of depression in individuals with BED. Studies designed to link the clinical effects of chromium with changes in underlying insulin, serotonin, and dopamine pathways may be especially informative. If efficacious, chromium supplementation may provide a useful, low-cost alternative to or augmentation strategy for selective serotonin reuptake inhibitors, which have partial efficacy in BED. ClinicalTrials.gov NCT00904306. PMID- 23751239 TI - Cutaneous body image dissatisfaction and suicidal ideation: mediation by interpersonal sensitivity. AB - OBJECTIVE: Cutaneous body image (CBI) dissatisfaction, feelings of social exclusion and stigmatization have been associated with increased suicidality in dermatology patients. We examined the relation between CBI dissatisfaction and suicidal ideation in a non-clinical sample, and examined the possible mediating effect of interpersonal sensitivity (IS), a symptom dimension related to self consciousness, feelings of inferiority and social exclusion. METHODS: As part of a larger study, 312 community-based participants from London, Ontario, Canada (241 women, 71 men; mean+/-SD age: 38.4+/-14.9years) rated their CBI satisfaction, measured with the Cutaneous Body Image Scale (Gupta MA et al., 2004). The Brief Symptom Inventory (BSI) (Derogatis L et al.,1982) was used to measure the constructs of suicidal ideation (4 suicide-related items from the BSI) and IS (Interpersonal Sensitivity subscale of BSI). RESULTS: Assessing mediation using the Baron & Kenny (1986) model, CBI satisfaction had a significant negative effect on suicidal ideation [c=-0.316, t(296)=-5.73, p<0.001] and IS [a=-0.365, t(297)=-6.76, p<0.001]; when CBI satisfaction and IS were considered together, IS had a significant positive effect on suicidal ideation (b=.690, t(295)=15.80, p<.001) while the effect of CBI satisfaction on suicidal ideation was no longer significant [c*=-.063, t(295)=-1.44, ns]. CONCLUSION: Our findings suggest an inverse relationship between CBI satisfaction and suicidal ideation, which is mediated by IS. This relationship likely falls in a continuum between non-clinical and clinical situations, with suicide risk being greater when individuals experience greater CBI dissatisfaction and social alienation. PMID- 23751240 TI - The factor structure of the PHQ-9 in palliative care. AB - OBJECTIVES: The Primary Care Evaluation of Mental Disorders Patient Health Questionnaire (PRIME-MD PHQ-9) is a common screening tool designed to facilitate detection of depression according to DSM-IV criteria. However, the factor structure of the PHQ-9 within the palliative care population has not been evaluated. METHODS: 300 participants completed the PHQ-9 within one week of referral to a palliative care service. Participants completed the PHQ-9 again four weeks later (n=213). Confirmatory factor analysis (CFA) and multiple-group CFA were undertaken to test the factor structure of the PHQ-9 and evaluate model invariance over time. RESULTS: A two-factor model comprising somatic and cognitive-affective latent factors provided the best fit to the data. Multiple group CFA suggested model invariance over time. Structural equation modelling revealed that follow-up (time 2) cognitive-affective and somatic symptoms were predicted by their baseline (time 1) factors. CONCLUSIONS: The PHQ-9 measures two stable depression factors (cognitive-affective and somatic) within the palliative care population. Studies are now required to examine the trajectories of these symptoms over time in relation to clinical intervention and events. PMID- 23751241 TI - Prevalence, risk factors and recognition rates of depressive disorders among inpatients of tertiary general hospitals in Shanghai, China. AB - OBJECTIVE: To investigate the prevalence, risk factors and recognition rates of depressive disorders among inpatients of tertiary general hospitals in Shanghai, China. METHODS: A total of 784 inpatients were randomly selected from three tertiary general hospitals and evaluated with a Chinese version of the Mini International Neuropsychiatric Interview 5.0 by ten trained psychiatrists. A questionnaire, containing socio-demographic and clinical data, and a social support scale were also administered to subjects during the course of the clinical interview. Logistic regression was used to identify factors that were associated with depression. RESULTS: The current prevalence rates (95% confidence intervals) of any depressive disorder and major depressive disorder (MDD) were found to be 13.1% (10.7%-15.5%) and 6.9% (5.1%-8.7%), respectively. The risk factors for depression included poor marital status, living alone or with others, lack of medical insurance, poor or very poor self-rated physical health, hospitalization in the internal medicine department, and a subjective support score <=23. Only 18.5% of the patients with current MDD were detected. CONCLUSION: Depression, especially MDD, has been a major mental health problem for Chinese tertiary general hospitals. There is an urgent need for the development of efficacious hospital-based consultation-liaison psychiatry programs aimed at improving Chinese physicians' recognition and ability to manage inpatient depression. PMID- 23751242 TI - Mental health in adults with sudden sensorineural hearing loss: an assessment of depressive symptoms and its correlates. AB - OBJECTIVE: Sudden sensorineural hearing loss (SSNHL) is defined as >30dB of hearing loss in at least three contiguous test frequencies occurring within 3days or less and may be accompanied by tinnitus and vertigo. Despite the well documented association between hearing loss and depressive symptoms, research on the emotional distress after SSNHL receives only scant attention. DESIGN: The current study sought to (1) investigate the degree of self-reported mental distress in patients with SSNHL after a median follow-up period of 1year, (2) investigate the association between mental distress, hearing recovery, and tinnitus. STUDY SAMPLE: 147 patients admitted for sudden hearing loss and diagnosed with SSNHL. RESULTS: Patients who recovered from SSNHL reported significantly less depressive symptoms. Patients with tinnitus, compared to those without tinnitus, reported more depressive thoughts and feelings, more disruptive activities and personal relationships, and more physical symptoms. CONCLUSIONS: This study showed that SSNHL patients who developed continuous tinnitus had a higher rate of greater emotional distress than those without tinnitus. Further research on the consequences of different risk factors specific to SSNHL, their impact on psychological well-being, and the development of better treatment strategies is needed to lessen the burdens associated with SSNHL. PMID- 23751243 TI - Anxiety and depression in Chinese patients with glaucoma: sociodemographic, clinical, and self-reported correlates. AB - OBJECTIVES: To assess the prevalence of anxiety and depression in Chinese glaucoma patients, and explore their predictive factors. METHODS: This cross sectional study included 506 Chinese glaucoma patients. Hospital Anxiety and Depression Scales (HADS) and the Chinese-version Glaucoma Quality of Life-15 questionnaire (CHI-GQL-15) were administered to all participants to evaluate their psychological distresses and quality of life (QoL). Visual functions (habitual-corrected visual acuity (HCVA), intraocular pressure (IOP), and mean defect (MD) of visual field) were assessed through clinical examinations by professionals. Sociodemographic information and other treatment histories were collected via interviews and chart review. Multiple linear regression analyses were performed to identify predictors of anxiety and depression. To evaluate the impact of anxiety or depression on patients QoL, the CHI-GQL-15 summary and subscores of patients with and without psychological disturbances were compared using covariate-adjusted regression analyses. RESULTS: The prevalence of anxiety and depression in Chinese glaucoma patients was 22.92% and 16.40%, respectively. A younger age (beta=-0.058, p<0.001), female gender (beta=1.219, p=0.001), moderate and heavy economic burden (beta=1.186, p=0.009; beta=2.705, p<0.001, respectively) and the CHI-GQL-15 summary score (beta=0.101, p<0.001) were independent predictors of anxiety. Significant independent predictors of depression included the duration of glaucoma (beta=-0.065, p=0.019) and the CHI GQL-15 summary score (beta=0.147, p<0.001). Difference in the CHI-GQL-15 summary and its subscores of patients with and without psychological disturbance were statistically significant (p<0.001). CONCLUSIONS: Prevalence of anxiety and depression among Chinese glaucoma patients is relatively high. Self-reported measures were informative in evaluating patients' psychological disturbances, whereas objective measures of visual function were not. PMID- 23751244 TI - Visual contrast sensitivity in major depressive disorder. AB - OBJECTIVE: Through the eyes of those depressed, the world may appear dull and gray. Visual contrast sensitivity has recently been reported to be lower in depressed patients compared to healthy controls. We aimed to examine the consistency of this finding and to explore the underlying retinal electrophysiology. METHODS: Twenty subjects with major depressive disorder and 20 matched healthy controls were studied. Pattern electroretinogram (PERG) and subjective visual contrast test were used to assess visual contrast sensitivity. Full-field electroretinography (ffERG) was additionally used to assess retinal neurophysiology. Depression was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and depression severity was measured using standard psychometric scales. RESULTS: Visual contrast sensitivity was significantly lower in depressed patients compared to controls based on the Landolt C visual contrast test, but no difference was found between groups using PERG and ffERG. Greater severity of depressive symptoms correlated (r=0.49, p=0.001) with poorer visual contrast sensitivity. CONCLUSIONS: Depressed subjects had reduced visual contrast discrimination performance, but this finding could not be consistently determined using PERG. The neurobiological link between major depressive disorder and visual contrast sensitivity warrants further investigation. PMID- 23751245 TI - The effects of maternal major depression, generalized anxiety disorder, and panic disorder on birth weight and gestational age: a comparative study. AB - OBJECTIVE: The present study comparatively examined the impact of maternal major depression, generalized anxiety disorder and panic disorder on gestational age and birth weight. METHODS: A total of 90 women (24 subjects with major depression, 19 subjects with panic disorder, 22 subjects with generalized anxiety disorder, and 25 healthy subjects) in the perinatal period who were admitted to three hospitals were included in the study. Psychiatric diagnoses were determined by means of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The birth weight and gestational age of the subjects in each groups were compared with one-way analysis of variance (ANOVA). RESULTS: There were significant differences among the study groups for birth weight and gestational age (P<0.001 for both variables). These parameters were significantly lower in the subjects with major depression (P=0.021 and P=0.015, respectively) and panic disorder (P<0.001 for both variables) compared to healthy controls. Compared with major depression, panic disorder was associated more negatively with birth weight (P=0.036). CONCLUSION: Major depression, and especially panic disorder, may negatively affect the gestational length and birth weight. PMID- 23751247 TI - Cross-sectional validation of the Rasch-based Depression Screening (DESC) in a mixed sample of patients with mental and somatic diseases. AB - BACKGROUND: The study aimed to cross-validate the psychometric properties of the two parallel versions of the "Rasch-based Depression Screening (DESC)" in a mixed clinical sample of patients with mental disorders and somatic diseases. Additionally, it was intended to confirm the initially proposed cut-off scores. METHODS: One hundred eleven inpatients from the Departments of Psychiatry (n=50), Cardiology (n=39) and Otorhinolaryngology (n=22) were examined. Accordance to Rasch model assumptions was determined by analyzing item infit and outfit as well as unidimensionality and local independence via residual principal components factor analysis (PCFA). Furthermore, separation, reliability and the targeting were considered. Differential item functioning (DIF) was investigated with regard to gender, age and clinical group. Finally, receiver operating characteristics (ROC) curves analyses were conducted and parallel test reliability was calculated. RESULTS: Item and person separation and reliability were good with separation values being above 2.90 and reliability exceeding being .90. Rasch model fit was good for all items except for the two items "sad" and "hopeless" displaying slight misfit. Targeting was appropriate with a person mean of -1.6 (DESC-I) and -1.5 (DESC-II) reflecting as expected that the two DESC versions were in average to easy for a mixed sample of patients with mental disorders and somatic. PCFA showed unidimensionality and local independence: The Rasch dimension "depression" explained 84.8% (DESC-I) and 82.2% (DESC-II) of the observed variance. No DIF was found. ROC curves confirmed the proposed cut-off score of 12 points. The area under the curve amounted to .91 for both DESC forms. The Youden index was 75.5 for DESC-I and 75.7 for DESC-II. A high parallel test reliability of .94 showed virtual equivalence of both DESC forms. CONCLUSIONS: Results of the present study support the good psychometric properties of both DESC forms in patients with mental disorders and somatic diseases. This study confirmed the cut-off scores that had already been determined in former patient samples. Thus, both DESC forms can be used validly as screening instruments for depression in clinical practice. PMID- 23751246 TI - Examining the relationship between food thought suppression and binge eating disorder. AB - Food thought suppression, or purposely attempting to avoid thoughts of food, is related to a number of unwanted eating- and weight-related consequences, particularly in dieting and obese individuals. Little is known about the possible significance of food thought suppression in clinical samples, particularly obese patients who binge eat. This study examined food thought suppression in 150 obese patients seeking treatment for binge eating disorder (BED). Food thought suppression was not associated with binge eating frequency or body mass index but was significantly associated with higher current levels of eating disorder psychopathology and variables pertaining to obesity, dieting, and binge eating. PMID- 23751248 TI - Scalable synthesis of urchin- and flowerlike hierarchical NiO microspheres and their electrochemical property for lithium storage. AB - A nickel salt-urea-H2O ternary system has been developed for the large-scale synthesis of hierarchical alpha-Ni(OH)2 microspheres, the solid precursor for the subsequent topotactic transition to NiO upon calcination. In this facile synthetic system, hierarchical structure is self-assembled under the cooperative direction of urea and anions in nickel salts. Thus, simply tuning the Ni salts leads to the selective construction of urchin and flowerlike hierarchical alpha Ni(OH)2 and NiO microspheres consisting of radial 1D nanowires and 2D nanoplates, respectively. The obtained NiO microspheres possessing accessible nanopores, excellent structural stability and large surface area up to 130 m(2)/g show promising electrochemical performance in anodic lithium storage for lithium-ion battery. PMID- 23751249 TI - An observational study of the association between adenovirus 36 antibody status and weight loss among youth. AB - OBJECTIVE: Although the human adenovirus 36 (Ad-36) is associated with obesity and relative hypolipidemia, its role in pediatric weight loss treatment response is uncertain. Therefore, the primary study objective was to determine whether Ad 36 antibody (AB) status was associated with response to a pediatric weight loss program. The secondary objective was to assess the association between Ad-36 AB status and baseline lipid values. METHODS: Participants included 73 youth aged 10 17 years in a residential camp-based weight loss program. The study examined differences in baseline lipid values between Ad-36 AB+ and AB- youth as well as differences in response to treatment, including indices of body size and fitness. RESULTS: At baseline, results showed that Ad-36 AB+ youth evidenced significantly lower levels of total cholesterol and triglycerides than Ad-36 AB- youth (all p < 0.05). After 4 weeks of treatment, the Ad-36 AB+ youth showed a smaller reduction in BMI percentile than the Ad-36 AB- youth (p < 0.05), a difference of about 0.48 kg. CONCLUSION: Ad-36 AB status showed a weak association with treatment response, but was associated with a better lipid profile. Ad-36 AB status should be assessed in studies of pediatric obesity treatment and prevention. PMID- 23751250 TI - Laparoscopic ovarian cystectomy versus fenestration/coagulation or laser vaporization for the treatment of endometriomas: a meta-analysis of randomized controlled trials. AB - AIM: To compare outcomes after laparoscopic ovarian cystectomy versus fenestration/coagulation or laser ablation for the treatment of endometriomas. METHODS: Studies were identified by searching the PubMed, EMBASE, SCOPUS, and Cochrane Central Register of Controlled Trials databases using the terms ovarian, endometrioma or endometriosis, cystectomy, fenestration, coagulation, laser, and ablation or vaporization. The outcomes of interest were recurrence of signs/symptoms and endometrioma, reoperation, pregnancy, and ovarian reserve. RESULTS: Seven studies were included. The risk of recurrence of signs/symptoms after surgery was significantly lower for laparoscopic cystectomy compared with fenestration/coagulation [risk ratio (RR): 0.29; 95% CI: 0.15-0.55; I2 = 0%; p < 0.001], as was the risk of recurrence compared with fenestration/coagulation (RR: 0.50; 95% CI: 0.26-0.97; I2 = 0%; p = 0.04) and laser vaporization (RR: 0.33; 95% CI: 0.12-0.88; I2 = 0%; p = 0.03). The risk of pregnancy was significantly higher for cystectomy compared with fenestration/coagulation (RR: 2.64; 95% CI: 1.49 4.69; I2 = 0%; p < 0.001), but not laser vaporization (RR: 0.92; 95% CI: 0.30 2.80; p = 0.89). There were inadequate data for the meta-analysis of ovarian reserve. CONCLUSIONS: Our findings suggest that cystectomy provides better outcomes than fenestration/coagulation or laser ablation regarding recurrence of symptoms and endometrioma as well as pregnancy rate (fenestration/coagulation only). Further studies are needed to clarify the effect of these surgical approaches on ovarian reserve. PMID- 23751251 TI - An intervention to discourage Australian mothers from unnecessarily exposing their babies to the sun for therapeutic reasons. AB - Parents play a key role in children's sun-protective behaviour, with good sun protective habits established early tending to be sustained. We designed a maternity hospital-based educational intervention to reduce myths that could result in mothers intentionally sunning their babies. Interviews were conducted with two cross-sections of healthy post-partum inpatients in the maternity ward of a large regional public hospital. The first group (n = 106) was recruited before the commencement of educational in-services for maternity nursing staff; the second group (n = 203) was interviewed after the last staff in-service session. More pre-intervention than post-intervention women reported they would expose their baby to sunlight to: treat suspected jaundice (28.8% vs. 13.3%; p < 0.001) or help their baby's skin adapt to sunlight (10.5% vs. 2.5%; p = 0.003). Fewer post-intervention women indicated they would sun themselves to treat breastfeeding-associated sore/cracked nipples (7.6% vs. 2%; p = 0.026). This educational intervention should be used to educate parents, health professionals and students. PMID- 23751252 TI - Effectiveness of indigenous ready-to-use therapeutic food in community-based management of uncomplicated severe acute malnutrition: a randomized controlled trial from India. AB - A randomized controlled trial was conducted in Chandigarh, India (2011), to determine the effectiveness of indigenous ready-to-use therapeutic food (RUTF) in community-based management of uncomplicated severe acute malnutrition (SAM). Intervention was through outpatient therapeutic program site (OTP). Study and control group children (6 months-5 years) were followed up weekly for 12 weeks, in OTP and at home. All children received supplementary nutrition through anganwadis under integrated child development scheme. Study children, in addition, received therapeutic dose of RUTF in OTP. Primary outcome, 115% of baseline weight, was attained in 6 of 13 (46.2%) and 1 of 13 (7.7%) children among study and control group, respectively [odds ratio: 10.28, 95% confidence interval (CI): 1.02-103.95]. Compared with control group, addition of RUTF in study group resulted in average additional increase in weight by 13 g/kg of baseline weight/week/child (95% CI: 2-23). Indigenous RUTF was effective in community-based management of uncomplicated SAM. PMID- 23751253 TI - Preventing HIV-1 transmission in breastfed infants in low resource settings: early HIV infection and late postnatal transmission in a routine prevention of mother-to-child transmission program in Yaounde, Cameroon. AB - OBJECTIVE: To report on overall HIV-transmission rates [early and late postnatal transmission (LPNT)] in breastfed infants born to HIV-positive women. METHODS: Mother-baby pairs in a routine prevention of mother-to-child transmission program. Promotion of exclusive breastfeeding (EBF) coupled with access to antiretroviral treatment (ART) or prevention using antiretroviral (pARV). Early infant diagnosis using HIV-RNA/PCR or HIV-DNA/PCR >6 weeks. LPNT assessed 6 weeks after weaning in infant earlier tested negative. MAIN MEASUREMENT: early HIV infection and LPNT. RESULTS: We included 285 infants for analysis; 89.5 % of mothers were receiving ART or pARV; 86% babies took daily pARV (median duration, 6 weeks). Exclusive breastfeeding (EBF) rate: 96% (median duration, 4 months). The cumulative transmission of HIV-1 was 2.8% at 8 weeks (95% confidence interval: 1.9-3.7). After weaning (abrupt 44%), 3 of 212 infants were HIV infected (1.4%). Nine-month cumulative HIV-transmission rate was 4.2% (1.5-6.9). Incidence of late postnatal HIV infection stood at 1.5/100 child-years of breastfeeding (BF). Cumulative risk of HIV transmission (8 weeks-9 months) was 1%. CONCLUSION: Both promotion of EBF and access to antiretroviral therapy contribute to lower HIV transmission in breastfed infants in low resource settings. PMID- 23751254 TI - Effect of households' social networks on lice infestation among vulnerable Mexican children: a qualitative comparative analysis. AB - The prevalence of pediculosis is high among elementary and secondary school children, which favors the belief that infestation occurs more often in schools than in homes. This study explored the role of households' social networks in the transmission of head lice. Seventeen school children and their social networks (n = 22) from Acatlipa (Morelos, Mexico) participated in a prospective observational study during school vacation. The hair of all the school children was washed with shampoo containing permethrin at the beginning of the study and the incidence of pediculosis (O) was evaluated at the beginning of the school term (follow-up at 1.5 months). The sets included in the qualitative comparative analysis were sex (S), length of hair (H), baseline diagnostic of pediculosis (I) and degree (D) and infestation index (N) obtained through the analysis of social networks. The prevalence of pediculosis was the same at the beginning and the end of follow-up (17.6%). The degree of the school children's networks ranged between 2 and 14. There were 8 configurations, the most frequent being F*i*d*n*h. The most parsimonious configuration associated with the incidence of pediculosis was F*I*d*H (female, previous infestation, low degree and long hair), with a coverage of 0.344 and a consistency of 0.941. Indicators of social networks made it possible to identify the role of households' social networks in the transmission of lice. Individual actions such as the use of shampoo containing insecticides are temporary and, therefore, structural actions should be favored. PMID- 23751255 TI - Chronic active Epstein-Barr virus infection-associated hydroa vacciniforme-like eruption and Behcet's-like orogenital ulcers. AB - The cutaneous manifestations of chronic active Epstein-Barr virus (EBV) infection can be diverse. Among them, hydroa vacciniforme-like eruption is one of the best known features. Although rare, mucosal ulcers have been reported to be associated with EBV as a result of primary infection or immune suppression. We describe a 65 year-old female with recurrent necrotic papulovesicles on the face and both arms for 2 years. She also complained of recurrent oral and genital mucosal ulcers developing simultaneously with skin eruptions. They appeared periodically during the spring and summer and were triggered or aggravated by sun exposure. Skin biopsies from the face and genitalia showed identical findings with dense lymphocytic infiltrations. In addition, in situ hybridization revealed EBV positive lymphoid cells in both specimens. To our knowledge, this is the first case of serologically and pathologically proven chronic active EBV infection presenting hydroa vacciniforme-like eruption and orogenital ulcers at the same time in one patient. PMID- 23751256 TI - Timeout from a high-force requirement as a reinforcer: an effective procedure for human operant research. AB - A procedure to study human operant conditioning is described using a timeout from a high-force requirement as reinforcer when a high force response was required. Experiment 1 reported evidence that a timeout from a high-force requirement acted as a reinforcer and a second experiment demonstrated sensitivity to delay to escape from the force requirement as a parameter of choice in a self-control paradigm. The results of the two experiments indicate a functional similarity between unconditioned reinforcers (e.g., food) used in nonhuman subjects and the present reinforcer, demonstrating that the present procedure is well-suited to study operant conditioning in humans. PMID- 23751257 TI - Timing: an attribute of associative learning. AB - The evidence reviewed in this paper suggests that when two events occur in spatiotemporal proximity to one another, an association between the two events is formed which encodes the timing of the events in relation to one another (including duration, order, and interval). The primary evidence supporting the view that temporal relationships are encoded is that subsequent presentation of one event ordinarily elicits behavior indicative of an expectation of the other event at a specific time. Thus, temporal relationships appear to be one of several attributes encoded at acquisition. PMID- 23751258 TI - Accelerated biological ageing in HIV-infected individuals in South Africa: a case control study. AB - OBJECTIVES: Little is known about the impact of HIV infection on biological ageing in sub-Saharan Africa. The study aimed to assess biological ageing in South African HIV-infected adults and HIV-seronegative individuals using two validated biomarkers, telomere length and CDKN2A expression (a mediator of cellular senescence). DESIGN: A case-control study. METHODS: Two hundred and thirty-six HIV-infected adults aged at least 30 years and 250 age and sex frequency matched HIV-seronegative individuals were recruited from clinics in township communities in Cape Town. Biological ageing was evaluated by measurement of telomere length and CDKN2A expression in peripheral blood leukocytes. RESULTS: The median ages of the HIV-infected and HIV-seronegative participants were 39 and 40 years, respectively. Among HIV-infected participants, 87.1% were receiving antiretroviral therapy (ART), their median CD4+ cell count was 468 cells/MUl and 84.3% had undetectable viral load. Both biomarkers were validated against chronological age in HIV-seronegative individuals. Telomere length was significantly shorter in HIV-infected individuals than in HIV-seronegative individuals (mean relative T/S ratio +/-SE:0.91 +/- 0.007 vs. 1.07 +/- 0.008, P < 0.0001). CD2NKA expression was higher in HIV-infected participants than in HIV seronegative individuals (mean expression: 0.45 +/- 0.02 vs. 0.36 +/- 0.03, P = 0.003). Socioeconomic factors were not associated with biological ageing in HIV infected participants. However, in participants on ART with undetectable viral load, biomarker levels indicated greater biological ageing in those with lower current CD4+ cell counts. CONCLUSION: Telomere length and CDKN2A expression were both consistent with increased biological ageing in HIV-infected individuals. Prospective studies of the impact of HIV on biological ageing in sub-Saharan Africa are warranted. PMID- 23751260 TI - Realtime adherence monitoring of antiretroviral therapy among HIV-infected adults and children in rural Uganda. AB - A real-time wireless electronic adherence monitor (EAM) and weekly self-report of missed doses via interactive voice response (IVR) and short message service (SMS) queries were used to measure antiretroviral therapy adherence in 49 adults and 46 children in rural Uganda. Median adherence was 89.5% among adults and 92.8% among children by EAM, and 99-100% for both adults and children by IVR/SMS self-report. Loss of viral suppression was significantly associated with adherence by EAM (odds ratio 0.58 for each 10% increase), but not IVR/SMS. Wireless EAM creates an exciting opportunity to monitor and potentially intervene with adherence challenges as they are happening. PMID- 23751259 TI - A novel bivalent HIV-1 entry inhibitor reveals fundamental differences in CCR5-MU opioid receptor interactions between human astroglia and microglia. AB - OBJECTIVE: We explored whether the opiate, morphine, affects the actions of maraviroc, as well as a recently synthesized bivalent derivative of maraviroc linked to an opioid antagonist, naltrexone, on HIV-1 entry in primary human glia. METHODS: HIV-1 entry was monitored in glia transiently transfected with an LTR construct containing a luciferase reporter gene under control of a promoter for the HIV-1 transactivator protein Tat. The effect of maraviroc and the bivalent ligand with or without morphine on CCR5 surface expression and cytokine release was also explored. RESULTS: Maraviroc inhibits HIV-1 entry into glial cells, whereas morphine negates the effects of maraviroc leading to a significant increase in viral entry. We also demonstrate that the maraviroc-containing bivalent ligand better inhibits R5-tropic viral entry in astrocytes than microglia compared to maraviroc when coadministered with morphine. Importantly, the inhibitory effects of the bivalent compound in astrocytes were not compromised by morphine. Exposure to maraviroc decreased the release of pro inflammatory cytokines and restricted HIV-1-dependent increases in CCR5 expression in both astrocytes and microglia, whereas exposure to the bivalent had a similar effect in astrocytes but not in microglia. The CCR5-MU-opioid receptor (MOR) stoichiometric ratio varied among the two cell types with CCR5 expressed at much higher levels than MOR in microglia, which could explain the effectiveness of the bivalent ligand in astrocytes compared to microglia. CONCLUSION: A novel bivalent compound reveals fundamental differences in CCR5-MOR interactions and HIV-1 infectivity among glia, and has unique therapeutic potential in opiate abuse-HIV interactive comorbidity. PMID- 23751261 TI - Evaluation of brief screening tools for neurocognitive impairment in HIV/AIDS: a systematic review of the literature. AB - OBJECTIVE(S): To systematically review literature on brief screening tools used to detect and differentiate between normal cognition and neurocognitive impairment and HIV-associated neurocognitive disorders (HANDs) in adult populations of persons with HIV. DESIGN: A formal systematic review. METHODS: We searched six electronic databases in 2011 and contacted experts to identify relevant studies published through May 2012. We selected empirical studies that focused on evaluating brief screening tools (<20 min) for neurocognitive impairment in persons with HIV. Two reviewers independently reviewed retrieved literature for potential relevance and methodological quality. Meta-analyses were completed on screening tools that had sufficient data. RESULTS: Fifty-one studies met inclusion criteria; we focused on 31 studies that compared brief screening tools with reference tests. Within these 31 studies, 39 tools were evaluated and 67% used a comprehensive neuropsychological battery as a reference. The majority of these studies evaluated HIV-associated dementia (HAD). Meta-analyses demonstrated that the HIV Dementia Scale (HDS) has poor pooled sensitivity (0.48) and the International HIV Dementia Scale (IHDS) has moderate pooled sensitivity (0.62) in detecting a range of cognitive impairment. Five newer screening tools had relatively good sensitivities (>0.70); however, none of the tools differentiated HAND conditions well enough to suggest broader use. There were significant methodological shortcomings noted in most studies. CONCLUSION: HDS and IHDS perform well to screen for HAD but poorly for milder HAND conditions. Further investigation, with improved methodology, is required to understand the utility of newer screening tools for HAND; further tools may need to be developed for milder HAND conditions. PMID- 23751263 TI - A federated semantic metadata registry framework for enabling interoperability across clinical research and care domains. AB - In order to enable secondary use of Electronic Health Records (EHRs) by bridging the interoperability gap between clinical care and research domains, in this paper, a unified methodology and the supporting framework is introduced which brings together the power of metadata registries (MDR) and semantic web technologies. We introduce a federated semantic metadata registry framework by extending the ISO/IEC 11179 standard, and enable integration of data element registries through Linked Open Data (LOD) principles where each Common Data Element (CDE) can be uniquely referenced, queried and processed to enable the syntactic and semantic interoperability. Each CDE and their components are maintained as LOD resources enabling semantic links with other CDEs, terminology systems and with implementation dependent content models; hence facilitating semantic search, much effective reuse and semantic interoperability across different application domains. There are several important efforts addressing the semantic interoperability in healthcare domain such as IHE DEX profile proposal, CDISC SHARE and CDISC2RDF. Our architecture complements these by providing a framework to interlink existing data element registries and repositories for multiplying their potential for semantic interoperability to a greater extent. Open source implementation of the federated semantic MDR framework presented in this paper is the core of the semantic interoperability layer of the SALUS project which enables the execution of the post marketing safety analysis studies on top of existing EHR systems. PMID- 23751262 TI - Obesity, immunomodulation and chronic kidney disease. AB - Obesity-induced inflammation is associated with numerous pathologies and is an independent risk factor of chronic kidney disease (CKD). The prevalence of CKD is escalating and current therapeutic strategies are seriously lacking in efficacy, and immunomodulation has been suggested as a potential new therapeutic approach. Indeed, specialized pro-resolving mediators (SPMs), such as lipoxins (LXs), resolvins and protectins, have demonstrated protection in adipose inflammation, restoring insulin sensitivity and adiponectin production, while modulating leukocyte infiltration and promoting resolution in visceral adipose tissue. Furthermore, SPMs display direct renoprotective effect. Thus we review current evidence of immunomodulation as a potential strategy to subvert obesity-related CKD. PMID- 23751264 TI - The anatomical classification of AICA/PICA branching and configurations in the cerebellopontine angle area on 3D-drive thin slice T2WI MRI. AB - BACKGROUND: With the technical advance of magnetic resonance imaging (MRI), we have been able to observe not only the small cranial nerves arising from the brain stem but also the branches of vertebrobasilar artery in the cerebellopontine angle (CPA) cistern. PURPOSE: The purpose was to demonstrate the courses and configurations of the anterior inferior cerebellar artery (AICA) or posterior inferior cerebellar artery (PICA) branch including the internal auditory artery in the CPA cistern and evaluate the relationship between the facial-vestibulocochlear (VIIth-VIIIth) nerves and AICA/PICA on high-resolution, thin-slice, three-dimensional T2-weighted MRI using driven equilibrium pulse. MATERIAL AND METHODS: Thirty-three men and 27 women aged 8-85 years old with sensory hearing loss or vertigo, and/or tinnitus were evaluated by thin-slice (0.75 mm) T2-weighted MRI. Five subjects (3 men, 2 women) without any auditory symptoms were also examined. RESULTS: Thin-slice T2WI drive MRI revealed several variations of the AICA/PICA coursing, such as a loop formation (n=30, 48 sides) or the IAC extension (n=19, 30 sides). Contact with the vestibulocochlear nerve was seen in 31.7% subjects (n=19, 27 sides). The AICA/PICA branching and shape patterns relative to the CPA and IAC were classified into four major types: type 1A, nonloop AICA/PICA in the CPA cistern; type 1 B, nonloop AICA/PICA (internal auditory artery) entering the IAC; type 2A, loop-type AICA/PICA in the CPA cistern; and type 2B, loop-type AICA/PICA entering the IAC. CONCLUSION: There was statistically significant association between types 1A and 2A (P<.01) regarding the existence of any auditory 3 symptoms. The results of our study suggest that this classification is simple and very useful for the elucidation of the mechanism of auditory symptoms and deciding the therapeutic strategies. PMID- 23751265 TI - Isolated IgG4-related cholecystitis mimicking gallbladder cancer: a case report. AB - A 58-year-old man with right upper quadrant pain was referred to the radiology department. The patient underwent computed tomography and magnetic resonance imaging, which suggested the diagnosis of gallbladder cancer invading the liver. After surgical removal of the gallbladder, and the adjacent liver parenchyma was performed, the histologic diagnosis of IgG4-related cholecystitis was made. PMID- 23751266 TI - Mass-like and extensive secondary tumoral calcinosis in the neck and body of a patient on peritoneal dialysis. AB - We present a case of extensive tumoral calcinosis in a 42-year-old female with end-stage renal disease and secondary hyperparathyroidism on peritoneal dialysis. Periarticular calcified masses demonstrating fluid-calcium levels on computed tomography and containing chalky amorphous calcified material in the absence of neoplastic cells are the salient features of tumoral calcinosis. Although renal failure is the most common cause of secondary tumoral calcinosis, there are few reported cases of this condition occurring in patients on peritoneal dialysis. This case is also unusual due to the widespread and bulky nature of the disease with involvement of the neck and its quick onset and progression. PMID- 23751268 TI - An unusual green macular lesion of the gingiva: a foreign-body granulomatous reaction. AB - The current clinical case highlights the diagnostic process in characterizing an unusual green macular lesion of the maxillary gingiva. A review of the history revealed that the patient had suffered trauma to the oral tissues during a soccer match 2 years prior. An incisional biopsy was performed and microscopic analysis demonstrated the presence of a granulomatous reaction to a needle-shaped, birefringent foreign material. Comparative analysis of a specimen collected from the soccer field confirmed that the foreign material was artificial grass. Foreign material was also found inside the gingival epithelial cells. PMID- 23751269 TI - Electrical contact at the interface between silicon and transfer-printed gold films by eutectic joining. AB - This paper presents the electrical and morphological properties at the interface between a metal (Au) and a semiconductor (Si) formed by a novel transfer-printing technology. This work shows that a transfer-printed thin (hundreds of nanometers) Au film forms excellent electrical contact on a Si substrate when appropriate thermal treatment is applied. The successful electrical contact is attributed to eutectic joining, which allows for the right amount of atomic level mass transport between Au and Si. The outcomes suggest that transfer-printing-based micromanufacturing can realize not only strong mechanical bonding but also high quality electrical contact via eutectic joining. PMID- 23751270 TI - Production of mesenchymal stromal/stem cells according to good manufacturing practices: a review. AB - Because of their multi/pluripotency and immunosuppressive properties, mesenchymal stem/stromal cells (MSCs) are important tools for treating immune disorders and for tissue repair. The increasing use of MSCs, their definition as advanced therapy medicinal products in European regulations, and the US Food and Drug Administration requirements for their production and use imply the use of production processes that should be in accordance with Good Manufacturing Practices (GMPs). Complying with GMPs requires precisely defining the production process (es) as well as the multiple criteria required for a quality final product. Such variables include the environment, staff training and qualification, and controls. Developing processes based on well-defined or completely defined media and operating in closed systems or bioreactors is important and will increase safety and reproducibility. One of the most challenging issues remains implementation of relevant and reproducible controls for safety and efficacy. A linking of researchers, research and development teams, producers, and clinicians is mandatory to achieve GMP-compliant processes with relevant controls for producing well-defined, safe, and efficient MSCs. PMID- 23751271 TI - Natural pathways to polyploidy in plants and consequences for genome reorganization. AB - The last decade highlighted polyploidy as a rampant evolutionary process that triggers drastic genome reorganization, but much remains to be understood about their causes and consequences in both autopolyploids and allopolyploids. Here, we provide an overview of the current knowledge on the pathways leading to different types of polyploids and patterns of polyploidy-induced genome restructuring and functional changes in plants. Available evidence leads to a tentative 'diverge, merge and diverge' model supporting polyploid speciation and stressing patterns of divergence between diploid progenitors as a suitable predictor of polyploid genome reorganization. The merging of genomes at the origin of a polyploid lineage may indeed reveal different kinds of incompatibilities (chromosomal, genic and transposable elements) that have accumulated in diverging progenitors and reduce the fitness of nascent polyploids. Accordingly, successful polyploids have to overcome these incompatibilities through non-Mendelian mechanisms, fostering polyploid genome reorganization in association with the establishment of new lineages. See also sister article focusing on animals by Collares-Pereira et al., in this themed issue. PMID- 23751272 TI - Physiological and medical findings in insomnia: implications for diagnosis and care. AB - This review will examine objective physiological abnormalities and medical comorbidities associated with insomnia and assess the need to measure parameters associated with these abnormalities for diagnosis and to monitor treatment outcomes. Findings are used to develop a decision tree for the work-up of insomnia patients. Currently available measures and those with possible future predictive value will be discussed. Costs, advantages, and the development of screening laboratory tests will be presented. It is concluded that there is a need to differentially evaluate insomnia patients based upon their comorbidities and the presence of objectively decreased total sleep time to direct optimal treatment. The development of objective diagnostic criteria and treatment outcome goals beyond subjective symptomatic relief will establish insomnia as a true medical problem and improve patient care. PMID- 23751273 TI - Serum lipid levels are associated with the severity of acute pancreatitis. AB - BACKGROUND/AIMS: Serum lipid concentrations react during acute disease. We sought to measure changes in the serum lipid profile during acute pancreatitis and ascertain whether these changes were associated with the severity of the disease. METHODS: A total of 233 patients (71% male, median age 48 years) hospitalized for acute pancreatitis were included in the study. The most common etiology for acute pancreatitis was alcohol (n = 131, 56%), followed by biliary (n = 48, 21%) and idiopathic pancreatitis (n = 36, 16%). Serum lipid levels were measured enzymatically. We analyzed samples obtained during the first days of hospitalization and later follow-up samples to measure changes during the course of the disease. RESULTS: We report profound changes in the serum lipid concentrations during acute pancreatitis. Serum total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol concentrations measured within 2 days of admission (n = 203) were significantly lower in patients who developed severe pancreatitis (3.20 vs. 3.80 mmol/l, p = 0.001; 0.72 vs. 1.05 mmol/l, p < 0.000, and 1.60 vs. 2.14 mmol/l, p < 0.000, respectively). Low serum total cholesterol, HDL cholesterol and LDL cholesterol concentrations were moreover associated with in-hospital mortalities and longer hospitalization (p < 0.05). In the subgroup analysis, the findings remained statistically significant in patients with alcohol-induced acute pancreatitis. CONCLUSION: Levels of serum total cholesterol, HDL cholesterol and LDL cholesterol are significantly lower in patients with severe acute pancreatitis and are associated with longer hospitalization. PMID- 23751274 TI - The roles of autophagy and apoptosis in burn wound progression in rats. AB - Understanding the role of cell death in burn wound progression is crucial for giving appropriate diagnoses and designing therapy regimens for burn patients. A well-described and reliable "comb burns model" was employed to evaluate the roles of autophagy and apoptosis in burn wound progression at 2 h, 6 h, 12 h, 24 h, and 48 h post-burn in a rat model. Immunohistochemistry (IHC) results showed that autophagy was detectable in hair follicle epithelium at 2 h post-burn, peaked at 12 h post-burn, then declined. Conversely, apoptosis was mainly located in the stratum epidermis and took place at low levels until 6 h post-burn, at which point it slowly increased. Bcl-2 and Bax, which are regulators of both processes, showed protein expression level patterns that were consistent with the IHC results. This study of autophagy in burn wound tissue progression represents a conceptual expansion of cell death in burn wounds. Based on these results, we suggest that different treatments should be performed on a specific post-burn time course depending on the most prevalent type of cell death occurring at that time. PMID- 23751275 TI - Comments on 'Fixation of proseal laryngeal mask airway in a child with facial burns.'. PMID- 23751276 TI - Response to letter to the editor: Comments on 'Fixation of proseal laryngeal mask airway in a child with facial burns.'. PMID- 23751277 TI - Atorvastatin treatment induces uptake and efflux transporters in human liver. AB - The metabolism and disposition of statins are highly dependent on different cytochrome P450 enzymes, such as CYP3A4 and CYP2C9, as well as membrane transporters SLCO1B1, SLCO2B1, ABCB1, and ABCG2. Interindividual gene expression differences among these enzymes may explain part of the variability in tolerance and effect for statin treatment. The aim of the present study was to investigate the effect of statin treatment on these genes in human liver tissue. Levels of CYP3A4, CYP2C9, SLCO1B1, SLCO2B1, ABCB1, and ABCG2 mRNA in liver tissue from a previously performed clinical trial in 29 patients randomized to treatment with placebo, 80 mg/day of atorvastatin, or 20 mg/day of fluvastatin for 4 weeks were measured using quantitative polymerase chain reaction. Treatment with atorvastatin (n = 10), but not with fluvastatin (n = 10), resulted in 3-fold higher expression of SLCO2B1 compared with placebo-treated patients (n = 9) (P < 0.05). Atorvastatin increased the expression of both ABCB1 and ABCG2 by more than 2-fold (P < 0.05). No difference was found in CYP2C9, CYP3A4, or SLCO1B1 mRNA expression in patients administered statins or those administered placebo. Premenopausal women (n = 8) had higher expression of CYP3A4 (P < 0.05) and lower expression of CYP2C9 (P < 0.05) compared with postmenopausal women (n = 10) and men (n = 11), respectively. Here we show for the first time that atorvastatin treatment leads to increased expression of the membrane transporters SLCO2B1, ABCB1, and ABCG2 in human liver tissue, which potentially may counteract the efficacy of the treatment, and our findings may cast light on the mechanisms of clinical problems with adverse reactions and drug interactions in statin treatment. PMID- 23751278 TI - A novel ICK peptide from the Loxosceles intermedia (brown spider) venom gland: cloning, heterologous expression and immunological cross-reactivity approaches. AB - The venom of a Loxosceles spider is composed of a complex mixture of biologically active components, consisting predominantly of low molecular mass molecules (3-45 kDa). Transcriptome analysis of the Loxosceles intermedia venom gland revealed ESTs with similarity to the previously described LiTx peptides. Sequences similar to the LiTx3 isoform were the most abundant, representing approximately 13.9% of all ESTs and 32% of the toxin-encoding messengers. These peptides are grouped in the ICK (Inhibitor Cystine Knot) family, which contains single chain molecules with low molecular mass (3-10 kDa). Due to their high number of cysteine residues, ICK peptides form intramolecular disulfide bridges. The aims of this study were to clone and express a novel ICK peptide isoform, as well as produce specific hyperimmune serum for immunoassays. The corresponding cDNA was amplified by PCR using specific primers containing restriction sites for the XhoI and BamHI enzymes; this PCR product was then ligated in the pET-14b vector and transformed into E. coli AD494 (DE3) cells. The peptide was expressed by IPTG induction for 4 h at 30 degrees C and purified by affinity chromatography with Ni-NTA resin. Hyperimmune serum to the recombinant peptide was produced in rabbits and was able to specifically recognize both the purified recombinant peptide and the native form present in the venom. Furthermore, the recombinant peptide was recognized by antisera raised against L. intermedia, L. gaucho and L. laeta whole venoms. The recombinant peptide obtained will enable future studies to characterize its biological activity, as well as investigations regarding possible biotechnological applications. PMID- 23751279 TI - Estimating structure quality trends in the Protein Data Bank by equivalent resolution. AB - The quality of protein structures obtained by different experimental and ab initio calculation methods varies considerably. The methods have been evolving over time by improving both experimental designs and computational techniques, and since the primary aim of these developments is the procurement of reliable and high-quality data, better techniques resulted on average in an evolution toward higher quality structures in the Protein Data Bank (PDB). Each method leaves a specific quantitative and qualitative "trace" in the PDB entry. Certain information relevant to one method (e.g. dynamics for NMR) may be lacking for another method. Furthermore, some standard measures of quality for one method cannot be calculated for other experimental methods, e.g. crystal resolution or NMR bundle RMSD. Consequently, structures are classified in the PDB by the method used. Here we introduce a method to estimate a measure of equivalent X-ray resolution (e-resolution), expressed in units of A, to assess the quality of any type of monomeric, single-chain protein structure, irrespective of the experimental structure determination method. We showed and compared the trends in the quality of structures in the Protein Data Bank over the last two decades for five different experimental techniques, excluding theoretical structure predictions. We observed that as new methods are introduced, they undergo a rapid method development evolution: within several years the e-resolution score becomes similar for structures obtained from the five methods and they improve from initially poor performance to acceptable quality, comparable with previously established methods, the performance of which is essentially stable. PMID- 23751280 TI - Association between the self-insertion of nasal and aural foreign bodies and attention-deficit/hyperactivity disorder in children. AB - OBJECTIVE: To investigate whether the prevalence of attention deficit/hyperactivity disorder (ADHD) is higher in children presenting with nasal and aural foreign bodies than in the control group. METHODS: The present study was conducted between April 2012 and December 2012 and included 60 pediatric patients presenting with self-inserted nasal and aural foreign bodies and 50 healthy controls aged between 3 and 9 years. The Conner Parent Rating Scale (CPRS) and Turgay's DSM-IV based ADHD and disruptive behavior disorders screening scale (T-DSM-IV-Scale) were used to investigate ADHD. RESULTS: The difference between the patient group and the control group was significant with respect to the abnormal scores obtained from all the subscales (p < 0.05). In children between 5 and 9 years of age, the abnormal scores were significantly higher in the patients than the controls for all the subscales (p < 0.05). However, in children between 3 and 4 years of age, there were no significant differences between the patients and the controls for the scores obtained from all the subscales (p > 0.05). No statistically significant difference was found between the patients with a previous history of self-inserted foreign bodies and those without any history of foreign body insertion (p > 0.05). CONCLUSIONS: The findings of our study demonstrated a possible association between the self insertion of nasal and aural foreign bodies and ADHD. Clinicians should be aware of the possible presence of ADHD in children, especially in those patients between 5 and 9 years of age who present with self-inserted nasal and aural foreign bodies. PMID- 23751281 TI - Hair phenotype in non-syndromic deafness. AB - The GJB2 gene is located on chromosome 13q12 and it encodes the connexin 26, a transmembrane protein involved in cell-cell attachment of almost all tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss. Moreover, it has been demonstrated that connexins are involved in regulation of growth and differentiation of epidermal tissues. Hence, mutations in GJB2 gene, which is responsible for non-syndromic deafness, may be associated with an abnormal skin and hair phenotype. We analyzed hair samples from 96 subjects: a study group of 42 patients with hearing impairments of genetic origin (38 with a non-syndromic form, 4 with a syndromic form), and a control group including 54 people, i.e. 43 patients with other, non genetic hearing impairments and 11 healthy volunteers aged up to 10 years old. The surface structure of 49 hair samples was normal, whereas in 45 cases it was altered, with a damaged appearance. Two hair samples were considered unclassifiable: one from the patient heterozygotic for the pendrin mutation (Fig. 2C), the other from a patient from Ghana with a R134W mutation (Fig. 2D). Among the 43 altered hair samples, 31 belonged to patients with connexin mutations and the other 12 came from patients without connexin mutations. PMID- 23751283 TI - Toxicity of concurrent radiochemotherapy for locally advanced non--small-cell lung cancer: a systematic review of the literature. AB - Concurrent radiochemotherapy (RCT) is the treatment of choice for patients with locally advanced non-small-cell lung cancer (NSCLC). Two meta-analyses were inconclusive in an attempt to define the optimal concurrent RCT scheme. Besides efficacy, treatment toxicity will influence the appointed treatment of choice. A systematic review of the literature was performed to record the early and late toxicities, as well as overall survival, of concurrent RCT regimens in patients with NSCLC. The databases of PubMed, Ovid, Medline, and the Cochrane Library were searched for articles on concurrent RCT published between January 1992 and December 2009. Publications of phase II and phase III trials with >= 50 patients per treatment arm were selected. Patient characteristics, chemotherapy regimen (mono- or polychemotherapy, high or low dose) and radiotherapy scheme, acute and late toxicity, and overall survival data were compared. Seventeen articles were selected: 12 studies with cisplatin-containing regimens and 5 studies using carboplatin. A total of 13 series with mono- or polychemotherapy schedules--as single dose or double or triple high-dose or daily cisplatin-containing (<= 30 mg/m(2)/wk) chemotherapy were found. Acute esophagitis >= grade 3 was observed in up to 18% of the patients. High-dose cisplatin regimens resulted in more frequent and severe hematologic toxicity, nausea, and vomiting than did other schemes. The toxicity profile was more favorable in low-dose chemotherapy schedules. From phase II and III trials published between 1992 and 2010, it can be concluded that concurrent RCT with monochemotherapy consisting of daily cisplatin results in favorable acute and late toxicity compared with concurrent RCT with single high dose chemotherapy, doublets, or triplets. PMID- 23751282 TI - Rational Helicobacter pylori therapy: evidence-based medicine rather than medicine-based evidence. AB - Data are available such that choice of Helicobacter pylori therapy for an individual patient can be reliably predicted. Here, treatment success is defined as a cure rate of 90% or greater. Treatment outcome in a population or a patient can be calculated based on the effectiveness of a regimen for infections with susceptible and with resistant strains coupled with the knowledge of the prevalence of resistance (ie, based on formal measurement, clinical experience, or both). We provide the formula for predicting outcome and we illustrate the calculations. Because clarithromycin-containing triple therapy and 10-day sequential therapy are now only effective in special populations, they are considered obsolete; neither should continue to be used as empiric therapies (ie, 7- and 14-day triple therapies fail when clarithromycin resistance exceeds 5% and 15%, respectively, and 10-day sequential therapy fails when metronidazole resistance exceeds 20%). Therapy should be individualized based on prior history and whether the patient is in a high-risk group for resistance. The preferred choices for Western countries are 14-day concomitant therapy, 14-day bismuth quadruple therapy, and 14-day hybrid sequential-concomitant therapy. We also provide details regarding the successful use of fluoroquinolone-, rifabutin-, and furazolidone-containing therapies. Finally, we provide recommendations for the efficient development (ie, identification and optimization) of new regimens, as well as how to prevent or minimize failures. The trial-and-error approach for identifying and testing regimens frequently resulted in poor treatment success. The described approach allows outcome to be predicted and should simplify treatment and drug development. PMID- 23751284 TI - Role of tramadol in premature ejaculation: a systematic review and meta-analysis. AB - OBJECTIVE: This systematic review was performed to evaluate the efficacy and safety of tramadol in patients with premature ejaculation (PE). METHODS: A systematic search of PubMed(r), Embase(r) and the Cochrane Library was performed to identify all randomized controlled trials (RCTs) that compared the effects of tramadol with placebo or no drug for patients with PE. The outcomes included post therapeutic intravaginal ejaculation latency time (IELT), increases in IELT, satisfaction with sexual intercourse, control over ejaculation and side effects (SEs). The Cochrane Collaboration Review Manager software (RevMan 5.1.4) was used for statistical analysis. RESULTS: A total of 5 trials, involving 715 patients, met the inclusion criteria. The synthesized data from these RCTs indicated that compared with the control, tramadol significantly increased IELT values post therapeutically (SMD 3.51, 95% CI 2.14-4.88, p < 0.00001) and changes in IELT values were more pronounced in the tramadol group (SMD 2.87, 95% CI 2.63-3.10, p < 0.00001). Satisfaction with sexual intercourse and the ability to control ejaculation were both improved in patients in the tramadol group (p < 0.05). The incidence of SEs in the tramadol group were significantly higher than in the control group (RR 3.55, 95% CI 1.34-9.40, p = 0.01), however most SEs were mild or moderate and transient. CONCLUSIONS: Tramadol may be effective in PE treatment, especially when patients have failed therapies, like selective serotonin reuptake inhibitors. However, the possibility of drug addiction and SEs should still be considered before initial use or after chronic use of this agent. More high-quality (clear randomization sequences, allocation concealment and blinding introduction), long-term, RCTs with a large number of PE patients are expected. PMID- 23751285 TI - Effect of selected dietary compounds on extracellular superoxide dismutase in the vitreous of chinchillas. AB - PURPOSE: The purpose of this study was to evaluate the effect of diet on the extracellular superoxide dismutase (EC-SOD) activity in the vitreous of chinchillas. METHODS: Seventy-eight male chinchillas were randomly divided into 7 subgroups: controls, receiving a standard basal diet, and 6 experimental groups additionally receiving 10% nonoxidized and 10% oxidized olive oil, a garlic extract and lipoic acid in their diet. The activities of EC-SOD were measured. RESULTS: The highest EC-SOD activity was similar in the controls [2.17 +/- 0.27 nitric units (NU)/mg protein] and in rabbits fed oxidized olive oil (2.29 +/- 0.31 NU/mg protein; p = 0.519). Nonoxidized olive oil appeared to be the strongest antioxidant component of diet (1.58 +/- 0.20 NU/mg protein) as compared with the subgroups above (p = 0.008 and p = 0.012, respectively). Administration of garlic and lipoic acid decreased the SOD activity only in the groups fed oxidized olive oil (p = 0.014). CONCLUSIONS: The SOD activity in laboratory animals is possibly modulated by diet. Work will be continued to extrapolate these results to humans. PMID- 23751287 TI - High-sensitivity troponin T as a diagnostic tool for acute coronary syndrome in the real world: an observational study. AB - BACKGROUND: The 2011 European Society of Cardiology guidelines state that acute coronary syndrome (ACS) may be excluded with a rapid 3 h high-sensitivity troponin T (HsTnT) sampling protocol. We aimed to evaluate the diagnostic and prognostic performance of HsTnT in patients with chest pain admitted with possible ACS in routine care. METHODS: A total of 773 consecutive patients admitted for in-hospital care for chest pain suspicious of ACS were included retrospectively. HsTnT values at admission and at 3-4 and 6-7 h were analysed for diagnostic performance. In addition, prognostic performance towards a combined 60 day endpoint of ACS, nonelective revascularization or death of all causes was studied. RESULTS: Twenty-three per cent of the patients had ACS during the hospital stay and 1.6% had an endpoint after discharge but within 60 days. The sensitivity of HsTnT for ACS at admission, 3-4 and 6-7 h was only 68, 79 and 81%, respectively. Sensitivity and negative predictive value for acute myocardial infarction alone were 80 and 93% on admission and 97 and 99% at 3-4 h. Among patients aged 75 years and older, 63% had a positive HsTnT on admission, but only 39% of these had an ACS during hospital stay. CONCLUSION: Our data confirm that prolonged testing with HsTnT after 3-4 h does not improve diagnostic performance for ACS. However, although sensitivity for acute myocardial infarction was very good, sensitivity for ACS was insufficient to rule out ACS even at 6-7 h. Less than half of all recorded positive HsTnT were true positives. On the basis of these results, we find it unlikely that HsTnT has improved the diagnosis of ACS in the emergency care setting. PMID- 23751288 TI - Old age and chronic disease: is the emergency medical system the appropriate provider for the elderly? AB - OBJECTIVE: The use of emergency medical services increases with the age of patients. Some care providers hold on to the prejudice that these alarms are unnecessary or of a lower importance. We assessed the relation of age and age dependent emergency characteristics, taking into consideration the ratings of emergency physicians on whether or not emergency cases were considered truly in need of emergency physician attendance. METHODS: Emergency physicians dispatched by the Berlin Fire Department evaluated for each case the necessity of emergency physician attendance. Case characteristics such as the day of the week and location of the emergency as well as patient characteristics such as age, sex, prior status, and care dependency were recorded. In addition, whether or not the physician accompanied the patient to the hospital was recorded as a parameter for emergency severity. Analysis was performed using multiple logistic regression modeling. RESULTS: During the 6-month prospective study period, 2702 cases were evaluated. Emergency medical services are used more frequently by older individuals, especially octogenarians. Emergency cases in older individuals were significantly more often rated as in need of emergency physician attendance; however, the rate of patients accompanied by the emergency physician to the hospital did not differ between the age groups. The age of patients, the primary diagnosis, the day and location of the emergency, and the presence of pre existing dementia showed a significant impact on the necessity of physician attended emergency missions. CONCLUSION: Despite common prejudices, emergency cases in elder patients are rated more often as in need of emergency physician attendance compared with those involving younger patients. PMID- 23751289 TI - Simple technique for spatially separated nanofibers/nanobeads by multinozzle electrospinning toward white-light emission. AB - Electrospun, emission color-tunable nanofibrous sheets were fabricated by multinozzle electrospinning equipped with a secondary electrode for the preparation of white-emissive sheets under a single excitation source, manipulating energy transfer between dyes. By control of the concentration of commercially available red, green, and blue dyes in the matrix polymer [poly(methyl methacrylate)], emission color tuning can be easily accomplished because each dye is located in spatially separated fibers to maintain enough distance to prevent or suppress energy transfer, allowing white-light emission. The application of dye separation for the white-light emission upon excitation with a blue light-emitting-diode lamp is demonstrated, indicative of its potential application for the easy and facile tuning of fluorescence color toward flexible illumination. PMID- 23751290 TI - Upper-extremity and mobility subdomains from the Patient-Reported Outcomes Measurement Information System (PROMIS) adult physical functioning item bank. AB - OBJECTIVE: To create upper-extremity and mobility subdomain scores from the Patient-Reported Outcomes Measurement Information System (PROMIS) physical functioning adult item bank. DESIGN: Expert reviews were used to identify upper extremity and mobility items from the PROMIS item bank. Psychometric analyses were conducted to assess empirical support for scoring upper-extremity and mobility subdomains. SETTING: Data were collected from the U.S. general population and multiple disease groups via self-administered surveys. PARTICIPANTS: The sample (N=21,773) included 21,133 English-speaking adults who participated in the PROMIS wave 1 data collection and 640 Spanish-speaking Latino adults recruited separately. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We used English- and Spanish-language data and existing PROMIS item parameters for the physical functioning item bank to estimate upper-extremity and mobility scores. In addition, we fit graded response models to calibrate the upper-extremity items and mobility items separately, compare separate to combined calibrations, and produce subdomain scores. RESULTS: After eliminating items because of local dependency, 16 items remained to assess upper extremity and 17 items to assess mobility. The estimated correlation between upper extremity and mobility was .59 using existing PROMIS physical functioning item parameters (r=.60 using parameters calibrated separately for upper-extremity and mobility items). CONCLUSIONS: Upper-extremity and mobility subdomains shared about 35% of the variance in common, and produced comparable scores whether calibrated separately or together. The identification of the subset of items tapping these 2 aspects of physical functioning and scored using the existing PROMIS parameters provides the option of scoring these subdomains in addition to the overall physical functioning score. PMID- 23751291 TI - Ketogenic diet in 3 cases of childhood refractory status epilepticus. AB - INTRODUCTION: Refractory status epilepticus (RSE) in children is associated with a significant risk of death or neurological morbidity. Recently attention has been drawn to the ketogenic diet (KD) as an acute treatment, as it has shown promise in controlling seizures in otherwise refractory status epilepticus in several cases. We have listed these and reviewed all cases of KD used in RSE at our centre. KD was given as 4:1 fat:carbohydrate-protein solution. RESULTS: A 3 year-old girl with RSE due to Hemiconvulsion-Hemiplegia Epilepsy syndrome. KD was instigated on day 6. Seizures stopped with ketosis on day 7. A 10-year-old boy rapidly developing RSE. After months a mitochondrial disorder was discovered. KD was tried twice with severe side-effects but no seizure control. 11-year-old healthy boy with RSE as FIRES. On KD seizures stopped for 24 h one day after reaching ketosis. He improved over 3-4 weeks. DISCUSSION: KD was efficient in two of three cases of RSE. The non-responder had severe side-effects and proved to have a mitochondrial disorder which is arguably a contraindication for KD. More studies are needed to prove efficacy of KD in RSE, to define optimal timing of KD and possible contraindications for KD in RSE. PMID- 23751292 TI - Genetic and epigenetic aspects of polyploid evolution in plants. AB - Polyploidy, the condition of possessing more than 2 complete chromosome sets in the same nucleus, is frequent in nature and has implications for a species' prospects for evolution. Newly formed polyploids, so-called neopolyploids, undergo a wide spectrum of genomic changes upon genome merger and duplication. Here, we review recent literature describing genomic and transcriptomic changes along the pathway from neoallopolyploid formation to the stabilization of species and diversification at the allopolyploid level. We begin by reviewing pathways of polyploid formation and discuss the effects of genome doubling and hybridization on chromosome pairing. We then review our knowledge of epigenetic changes in allopolyploids, followed by a consideration of the effects of these structural genomic and epigenetic changes on the transcriptional activity of genes in allopolyploids. We discuss the effects of changes in gene expression in polyploids with respect to current evolutionary theory. Finally, we draw attention to the general question of the relationships between genomic and transcriptomic alteration and incipient diversification among sibling polyploid lines and populations. PMID- 23751293 TI - The relationship between autism spectrum disorders and attention deficit/hyperactivity disorder: an overview. AB - The autism spectrum has become a highly studied topic, perhaps the most researched of all developmental disorders. A host of related topics are being studied, with one of the most common being comorbidity of autism with other conditions such as epilepsy, sleep, and anxiety disorders. One of the most prevalent of these comorbid conditions is attention-deficit/hyperactivity disorder (AD/HD). A considerable amount of research has appeared on this topic with respect to symptom expression, prevalence of overlap, type of symptom overlap, and the effect of these two conditions co-occurrence on other symptoms and disorders. Given the substantial data base that has accrued, review and synthesis of these data are in order. This is the purpose of the present manuscript. PMID- 23751294 TI - Healthcare utilization and expenditure analysis between individuals with intellectual disabilities and the general population in Taiwan: a population based nationwide child and adolescent study. AB - This study examines differences in outpatient-visit frequency and medical expenditures between (1) children and adolescents in Taiwan with intellectual disabilities and (2) children and adolescents in Taiwan's general population. A cross-sectional study was conducted to analyze data from 2007 provided by Taiwan's National Health Insurance program. A total of 236,045 beneficiaries younger than 19 years made use of outpatient services; among them, 35,802 had a principal diagnosis of mental retardation (intellectual disability). The average number of ambulatory visits was 14.9 +/- 12.4, which is much higher than in the United States and other developed countries. The mean number of annual visits of the individuals with intellectual disabilities was significantly higher than that of the general population in Taiwan (20.1 +/- 20.0 vs. 14.0 +/- 12.2); age, gender, urbanization level of residential area, and copayment status affected outpatient visit frequency. The mean annual outpatient costs were NTD6371.3 +/- NTD11989.1 for the general population and NTD19724.9 +/- NTD40469.9 for those with intellectual disabilities (US $1 equals approximately NTD30). Age, gender, urbanization level of residential area, and copayment status were the determinants that accounted for this difference in cost. Children and adolescents with intellectual disabilities had higher use rates of rehabilitative and psychiatric services than the general population. We conclude that individuals with intellectual disabilities had higher demands than the general population for healthcare services, especially for rehabilitative and psychiatric services. PMID- 23751295 TI - Association between executive/attentional functions and caries in children with cerebral palsy. AB - The aim of the present study was to evaluate the existence of an association between attention/executive functions and the development of dental caries in individuals with cerebral palsy (CP). Seventy-six children with CP were selected from a physical rehabilitation center and a school serving children with disabilities. The control group was made up of 89 children without neurological impairment. Socioeconomic status, presence of teeth with cavities due to caries, degree of motor impairment and intellectual, executive and attentional functions were assessed. Mean age of participants was 8.9 years (SD=3.56). The CP group had a significantly lower performance (p<0.05, Mann-Whitney test) on the intelligence, attentional function and executive function tests in comparison to the control group. Controlling for the clinical diagnosis (CP or control group), motor impairment and intellectual function, the significant explanatory variables for the presence of teeth with cavities were performance on the Complex Rey figure test (OR=0.941) and the Digit Span subtest of the Wechsler Intelligence Scale for Children in backward order (OR=0.581). After controlling for intellectual function, clinical diagnosis and motor impairment, deficits in executive and attentional functions increased the odds of developing dental caries in children with cerebral palsy. PMID- 23751296 TI - Practicing a matching movement with a mirror in individuals with spastic hemiplegia. AB - This experimental study aimed to determine the effect of practicing a position matching task with (mirror) visual feedback of the less-impaired arm on the matching accuracy of the impaired arm in children and adolescents with spastic hemiparetic cerebral palsy. Practice consisted of 40 trials of bimanual target matching, where one group received regular visual feedback and a second group received mirror visual feedback of the less-impaired arm. On three occasions (pre, post, and after a 1-week-retention) position sense (matching accuracy measured as the endpoint error in cm) of the impaired arm was tested with a unimanual and bimanual matching task, performed without any visual information of either hand. Matching accuracy of the impaired arm was better in the post-test than in the pre-test, but this improvement was similar for both practice groups. In the retention-test, accuracy had returned to pre-test-level, which might be ascribed to the short duration of the practice period. These outcomes suggest that practicing a matching task with visual feedback of the less-impaired arm might help to improve the matching accuracy of the impaired arm in individuals with spastic hemiparetic cerebral palsy. PMID- 23751297 TI - Evidence-based practice: a quality indicator analysis of peer-tutoring in adapted physical education. AB - The purpose of the research was to conduct a quality indicator analysis of studies investigating peer-tutoring for students with a disability in adapted physical education. An electronic search was conducted among English journals published from 1960 to November 2012. Databases included ERIC, PsycINFO, and SPORTDiscus. Fifteen research studies employing group-experimental (Gersten et al., 2005) or single-subject designs (Horner et al., 2005) met inclusion criteria. Each study was assessed for the presence and clarity of quality indicators. Group designs met an average of 62.5% essential and 69% desirable indicators. An average of 80% of indicators was present for single-subject designs. Results suggest claims of peer-tutoring being an evidence-based practice are premature. Recommendations for clarifying and applying the quality indicators are offered. PMID- 23751298 TI - Developmental changes in lateralized inhibition of symmetric movements in children with and without Developmental Coordination Disorder. AB - The present study investigates developmental changes in selective inhibition of symmetric movements with a lateralized switching task from bimanual to unimanual tapping in typically developing (TD) children and with Developmental Coordination Disorder (DCD) from 7 to 10 years old. Twelve right-handed TD children and twelve gender-matched children with DCD and probable DCD produce a motor switching task in which they have (1) to synchronize with the beat of an auditory metronome to produce bimanual symmetrical tapping and (2) to selectively inhibit their left finger's tapping while continuing their right finger's tapping and conversely. We assess (1) the development of the capacity to inhibit the stopping finger (number of supplementary taps after the stopping instruction) and (2) the development of the capacity to maintain the continuing finger (changes in the mean tempo and its variability for the continuing finger's tapping) and (3) the evolution of performance through trials. Results indicate that (1) TD children present an age related increase in the capacity to inhibit and to maintain the left finger's tapping, (2) DCD exhibits persistent difficulties to inhibit the left finger's tapping, and (3) both groups improve their capacity to inhibit the left finger's movements through trials. In conclusion, the lateralized switching task provides a simple and fine tool to reveal differences in selective inhibition of symmetric movements in TD children and children with DCD. More theoretically, the specific improvement in selective inhibition of the left finger suggests a progressive development of inter-hemispheric communication during typical development that is absent or delayed in children with DCD. PMID- 23751299 TI - Prevalence of ADHD in a sample of Italian students: a population-based study. AB - Attention-deficit/hyperactivity disorder (ADHD) is one of the most common diagnosis for children and adolescents, although the reported estimates for prevalence are extremely variable worldwide. In the present work we investigate the prevalence of ADHD in a sample of Italian students in a study divided in two phases. In Phase I, a total of 6183 schoolchildren (3178 males and 3005 females, aged range 5-15 years) were screened using the SDAI rating scale for teachers. In Phase II, the parents of children and adolescents who met high screen criteria according to SDAI (cut-off>14; n=471, 7.3%) were invited to complete a specific clinical-diagnostic assessment for ADHD with the help of an experienced clinician. Within the entire sample, 107 children dropped out and 12 had mental retardation, whereas 332 subjects (278 males and 54 females, age range 5-14 years) completed the Phase II of the study. One hundred ninety subjects (163 males and 27 females, male: female ratio 6:1, mean age 8 years) were diagnosed with ADHD, indicating a prevalence of 3%. ADHD subtypes included the following: combined (n=108; 56.8%), inattentive (n=48; 25.2%) and hyperactive/impulsive (n=33; 17.3%). Our findings are in line with other reports of ADHD prevalence in the European Countries, and may contribute to underline the impact of this phenomenon in the population, and the need of achieving an improvement in the quality of the public health mental service for the prevention and treatment of ADHD. PMID- 23751301 TI - Relationship between sleep habits, anthropometric characteristics and lifestyle habits in adolescents with intellectual disabilities. AB - The aim was to explore the relationship between sleep habits and overweight/obesity, physical activity and sedentary behaviours in French adolescents with intellectual disabilities. This observational study was conducted on 535 French adolescents with intellectual deficiency. Sleep habits were analyzed and related to anthropometric measures, physical activity and sedentary behaviours. The study was conducted using a self-administered questionnaire. Adolescents completed the questionnaire during an interview with the principle investigator. Sleep timing behaviour was classified into 4 sleep patterns: Early-bed/Early-rise, Early-bed/Late-rise, Late-bed/Late-rise, and Late bed/Early-rise. Of 573 eligible participants, 125 were excluded because of missing data on age, weight or height. The number of participants identified in each of the four sleep patterns was as follows: Early-bed/Early-rise, N=59 (15.4%), Early-bed/Late-rise, N=164 (43%), Late-bed/Early-rise, N=56 (15%), Late bed/Late-rise N=102 (27%). Adolescents who woke up early were more active than those from the late rise group (p<0.001). The number of adolescents who are sedentary was higher in late rise vs. early rise subjects (p<0.001). Subjects in the late-bed group were more likely overweight and obese (p<0.05). Results suggest that sleep behaviour was associated with overweight/obesity, physical activity and sedentary behaviour in adolescents with intellectual deficiency. Sleep behaviours should be considered in planning health promotion strategies. PMID- 23751300 TI - Feasibility and preliminary efficacy data from a computerized cognitive intervention in children with chromosome 22q11.2 deletion syndrome. AB - Children with chromosome 22q11.2 deletion syndrome (22q11DS) are significantly impaired in their academic performance and functionality due to cognitive deficits, especially in attention, memory, and other facets of executive function. Compounding these cognitive deficits is the remarkably high risk of major psychoses, occurring in 25% of adolescents and adults with the disorder. There are currently no evidence-based interventions designed to improve the cognitive deficits in these individuals. We implemented a neuroplasticity-based computerized cognitive remediation program for 12 weeks in 13 adolescents with 22q11DS, assessed feasibility, and measured changes in cognition before and after the intervention compared to a control group of 10 age- and gender-matched children with 22q11DS. Our results indicated that despite their cognitive impairments, this intervention is feasible in children with 22q11DS, with high rates of adherence and satisfaction. Our preliminary analyses indicate that gains in cognition occur with the intervention. Further study in a larger randomized controlled trial would enable assessment of efficacy of this novel intervention. PMID- 23751302 TI - Determinants of participation in leisure activities among adolescents with cerebral palsy. AB - Studies have identified restrictions in engagement in leisure activities for adolescents with disabilities. Participation is a complex construct and likely influenced by a variety of factors. These potential determinants have not yet been sufficiently explored in the population of adolescents with cerebral palsy (CP). The objective of this study is to estimate the potential influence of adolescent characteristics and environmental factors as determinants of participation in leisure activities for adolescents with CP. A cross-sectional design was used. Participants were adolescents (12-19 years old) with cerebral palsy. Participants were assessed with the Vineland Adaptive Behavior Scale - II, Gross Motor Function Measure, Gross Motor Function Classification System, Manual Ability Classification System and completed the Self-Perception Profile for Adolescents, Dimensions of Mastery Questionnaire, Strengths and Difficulties Questionnaire, Family Environment Scale, the European Child Environment Questionnaire and the Preferences for Activities of Children. The main outcome measure was the Children's Assessment of Participation and Enjoyment. 187 adolescents (age M=15.4; SD=2.2) completed the study. Multivariate models of participation in leisure revealed associations with factors related to the adolescents' functional characteristics and attitudes, the family environment, socioeconomic status, and contextual factors such as school type, and collectively explained from 28% (diversity of skill-based activities) up to 48% (intensity and diversity of self-improvement activities) of the variance in intensity and diversity in five leisure participation domains (diversity: r(2)=.33 recreational; r(2)=.39 active-physical; r(2)=.33 social activities). Adolescent's mastery motivation, self-perception and behavior were individually associated with participation in different activity domains, but did not strongly predict participation within multivariate models, while preferences for activities were strong predictors of participation in all domains, except for skill-based activities. Engagement in different types of leisure activities is important for adolescents' development and well-being. Health care professionals should consider adolescents' and families' characteristics to promote participation in leisure activities. PMID- 23751303 TI - A comparative study of performance in simple and choice reaction time tasks between obese and healthy-weight children. AB - This study investigated weight status related differences in executive functions and movement execution to determine whether or not childhood obesity is associated with impaired perceptual-motor function. Nineteen obese (OB) children (10 ? and 9 ?, aged 6-12 years) and nineteen gender and age matched healthy weight (HW) peers performed two computer-based reaction time tasks. For both the simple and four choice reaction time (SRT/CRT) task condition, absolute mean reaction time (RT) and movement time (MT) were determined and expressed as a percentage of total response time (RsT). During the SRT task, OB children were intrinsically slower than their HW peers as reflected by a significantly higher absolute RT, MT and RsT. In the CRT task, however, between-group differences were only present for RT and RsT, whereas absolute MT was comparable among OB and HW participants. As a result, the relative temporal structure of RsT significantly differed between BMI groups, with a greater RT percentage among the OB children. During the CRT condition, OB children probably await final decision-making with regard to the execution of their response movement, which then no longer needs to be adjusted. Our results therefore indicate the use of a more conservative strategy within the OB group, suggesting that childhood obesity is associated with impaired perceptual-motor function. Besides the widely accepted mechanical explanation, a better understanding of the mechanisms underlying OB children's motor incompetence is needed to set up appropriate interventions to tackle this deficit and indirectly address associated health-related problems. PMID- 23751304 TI - How could Theory of Mind contribute to the differentiation of social adjustment profiles of children with externalizing behavior disorders and children with intellectual disabilities? AB - This study compared Theory of Mind (ToM) emotion and belief abilities in 43 children with externalized behavior (EB) disorders presenting low intelligence, 40 children with intellectual disabilities (ID) and 33 typically developing (TD) preschoolers (as a control group), matched for developmental age. The links between their ToM abilities, their level in seven self-regulation strategies as displayed in social problem-solving tasks and their social adjustment profiles (assessed by the Social Competence and Behavior Evaluation, completed by their teachers) were examined. Children with EB presented lower comprehension of causes of emotions and lower self-regulation of joint attention and of attention than children with ID and TD children. In comparison with TD children, lower social adjustment was observed in nearly all dimensions of profiles in both atypical groups. Specifically, children with EB were significantly angrier than children with ID. Although variable patterns of positive correlations were obtained in atypical groups between self-regulation strategies and ToM abilities, the most numerous positive links were obtained in the group with EB. Regression analyses showed that developmental age predicted ToM abilities and certain dimensions of social adjustment profiles in atypical groups. In the ID group, ToM emotions predicted general adaptation, affective adaptation, interactions with peers and with adults and low internalizing problems. In the EB group, general adaptation was predicted by ToM emotions and self-regulation, interactions with peers by ToM beliefs, and a low level of externalizing problems by ToM emotions. Some implications for intervention and perspectives for research are suggested. PMID- 23751305 TI - Identification and expression analysis of a new glycoside hydrolase family 55 exo beta-1,3-glucanase-encoding gene in Volvariella volvacea suggests a role in fruiting body development. AB - The edible straw mushroom Volvariella volvacea is an important crop in South East Asia and is predominantly harvested in the egg stage. Rapid stipe elongation and cap expansion result in a swift transition from the egg to elongation and maturation stage, which are subjected to fast senescence and deterioration. In other mushrooms, beta-1,3-glucanases have been associated with degradation (softening) of the cell wall during stipe elongation and senescence. We present a new glycoside hydrolase family 55 (GH55) exo-beta-1,3-glucanase gene, exg2, and highly conserved deduced EXG2 protein. The 3D model and presumed catalytic residues of V. volvacea EXG2 are identical to Lentinula edodes EXG2 and Phanerochaete chrysosporium Lam55A, supporting similar enzymatic functions. In addition to previous association to stipe elongation and senescence, our data clearly indicates a role for cap (pileus) expansion. Digital gene expression, quantitative PCR and isobaric tags for relative and absolute quantification analysis showed low exg2 and EXG2 levels in primordia, button, egg and elongation stages and significantly increased levels in the maturation stage. Subsequent relative quantitative PCR analysis designated expression of exg2 to the stipe in the elongation stage and to the pileus and stipe in the maturation stage. EXG2 cell wall softening activity, close correlation of exg2 expression with the principal expanding mushroom tissues and a strong conservation of expression patterns and protein sequences in other mushrooms, make V. volvacea exg2 an important candidate for future studies on mechanisms of fruiting body expansion and senescence causing commodity value loss. PMID- 23751306 TI - Association between Leptin gene polymorphisms and plasma leptin level in three consanguineous families with obesity. AB - INTRODUCTION: Leptin (LEP) gene is one of the most promising candidate genes for obesity. Previous studies have tested the association of polymorphisms in LEP gene with obesity and obesity-related metabolic biomarkers (anthropometric variables, glucose, insulin level, leptin level and lipid profile). However, the results of these studies were still controversial. To determine whether LEP gene is associated with obesity in Tunisian population, we performed a family-based association study between LEP polymorphisms and obesity and obesity-related metabolic biomarkers. METHODS: Seven single nucleotide polymorphisms (SNPs) in 5' region of LEP gene were genotyped in three consanguineous families including 33 individuals. The previously reported LEP SNPs (H1328084, H1328082, rs10487506, H1328081, H1328080, G-2548A and A19G) were evaluated by PCR-RFLP and direct sequencing methods. Single SNP association and haplotype association analyses were performed using the family-based association test (FBAT). To determine allele frequencies of these SNPs in general population, 52 unrelated individuals from the general Tunisian population were also analyzed. RESULTS: Two SNPs showed significant associations with plasma leptin level (H1328084: A>G, Z=2.058, p=0.039; A19G: G>A, Z=2.058, p=0.039). When haplotypes were constructed with these two-markers, the risk AA haplotype (frequency 57.1%) was positively associated with plasma leptin level (Z=2.058, p=0.039). Moreover, SNPs H1328084 and A19G are predicted to modify transcription-factor binding sites. CONCLUSIONS: Our study provided that two functional variants in 5' regulatory region of LEP gene are associated with plasma leptin level as a quantitative trait. It suggested that H1328084 and A19G have an important role in regulating plasma leptin level. PMID- 23751307 TI - Density peaks of paralog pairs in human and mouse genomes. AB - Paralog gene trees, which reflect the increase of genomic complexity in the evolution, can be complicated and ambiguous. A simpler complementary approach is analysis of density distribution of paralog pairs. It can reveal general features of genome evolution, which may be hidden in the forest of gene trees. It is known that distribution of human paralog pairs along the axis of protein divergence between pair members forms two main peaks. Here I show that there are three main peaks in the mouse genome. Thus, the multimodality of paralog pair distribution seems to be a fundamental feature of mammalian genomes. Despite the great diversity of domains presented in small amounts or in multidomain architectures with a few predominant domains, both in human and mouse the first peak consists mostly of gene pairs with zinc finger domains or olfactory receptor domain. In the mouse the olfactory receptor predominates, which stipulates the three-peak distribution (since in the olfactory receptors the second peak is closer to the first peak than in other genes). The mammalian-wide zinc finger orthologs are biased towards the second peak. Thus, the marsupial orthologs are nearly absent in the first peak of human and mouse. The gene pairs in the first peak show a lower ratio of nonsynonymous to synonymous substitutions, which suggests that their evolution is more constrained. The plausible explanation is that they are in subfunctionalization state (partition of initial function of ancestral gene), whereas the second peak contains gene pairs that are already in neofunctionalization state (acquiring of novel functions). These data suggest that the adaptive radiation of mammals was accompanied by a burst of duplication of zinc finger genes, which are located in the first (most recent) peak of paralog pairs. PMID- 23751308 TI - Major vault protein (MVP) gene polymorphisms and drug resistance in mesial temporal lobe epilepsy with hippocampal sclerosis. AB - The human major vault protein (MVP) has been implicated in the development of drug resistance in cancer cells. Over expression of MVP has also been reported in brain tissue samples from antiepileptic drug (AED)-resistant human focal epilepsies. To investigate the relationship between single nucleotide polymorphisms (SNPs) involving the MVP gene and AED-resistance, we compared the distribution of three SNPs in the MVP gene, rs4788187, rs3815824 and rs3815823, among 220 patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (prototype of AED-resistant epilepsy syndrome), 201 patients with juvenile myoclonic epilepsy (JME) (prototype of AED-responsive epilepsy syndrome) and 213 ethnically matched non-epilepsy controls. All the patients and controls were residents of the South Indian state of Kerala for more than three generations. We did not find any significant difference in allele and genotypic frequencies of the studied SNPs between AED-resistant and AED-responsive cohorts, and between AED-resistant and AED-responsive cohorts independently and pooled together when compared with the controls. We conclude that rs4788187, rs3815824, rs3815823 variants of the MVP gene are associated neither with predisposition for epilepsy nor with AED-resistance in the population that we have studied. Our results suggest the need for further research into the link between MVP and AED resistance. PMID- 23751309 TI - Loss of light in the eyes: a window to melancholia. AB - Melancholia has long evaded attempts at clarifying underlying biological signals. Techniques that have attempted differentiation of melancholia from the non melancholic conditions have largely weighted a greater contribution of biological factors to melancholia. More recently, several avenues of research have highlighted the potential utility of visual electrophysiological technologies in clarifying disease processes, driven by reports of those with melancholia that life loses its 'colour', and by clinical observations that such patients often 'lose the light in their eyes' during an episode. This led to the development of our hypothesis that melancholia may be able to be measured through the eyes reflected by disrupted dopaminergic signaling in the retina, thus allowing clarification of any hypodopaminergic contribution to the disorder. We report on research from visual neuroscience and research localizing key brain structures as well as consider likely genetic contributions to propose a unique paradigm for pursuing the biological basis of melancholic depression. PMID- 23751310 TI - Adverse effect of metformin therapy on serum vitamin B12 and folate: short-term treatment causes disadvantages? AB - Diabetes is a global public health challenge that imposes heavy burdens on communities and individuals. Metformin, the first-line medication for diabetes, has the superiority of reducing risk of macrovascular diseases, all-cause mortality and even possibly cancers. Recent observational studies, however, have demonstrated that long-term metformin therapy increases the probability of vitamin B12 and folate deficiency, and might contribute to the progression of diabetic peripheral neuropathy. Despite metformin is widely used and extensively studied, randomized controlled trials performed to explore the effects of metformin on vitamin B12 and folate are limited. Besides, whether short-term treatment causes vitamin deficiency is a pending issue. We postulate that even a few-month treatment with metformin results in the decrease of vitamin B12 and folate. However, supplementation of vitamin B12 rather than the combination of vitamin B12 and folate might be profitable based on the mechanism of metformin on vitamins in patients with type 2 diabetes. This viewpoint differs from those of majority that a combined supplementation of vitamin B12 and folate is inclined to be advised. PMID- 23751311 TI - Psychotherapy as entropy management. AB - We present the hypothesis that the laws of thermodynamics can be usefully applied to psychotherapy. In this model psychotherapy is presented as a means of entropy management, whereby the patient trades entropy (in this case the expressed symptoms of mental disorder) with the therapist. The therapist serves to increase the capacity of the patient, both through developing a shared understanding of the challenges the patient faces and through generating shared solutions. This process can be understood in terms of entropy trade where energy is successfully redirected into adaptive behaviour. The hypothesis and proposed model of psychotherapy are evaluated in the context of current thinking about the components of successful psychotherapeutic outcomes; including evidence based practice, therapist competence and adherence and the therapeutic alliance. PMID- 23751312 TI - Aripiprazole: a dopamine modulator that mimics methylphenidate in producing faster antidepressant effects. AB - Up to 60% of depressed patients do not respond to two months of pharmacotherapy, and late treatment responses are often correlated with poor outcomes and may be characterized as treatment-resistant depression (TRD). Previous studies have noted that the addition of a psychostimulant such as methylphenidate to the therapeutic regimen of patients with TRD or those depressed patients with comorbid fatigue, advanced age, or a major medical illness showed significant improvement within two weeks. One explanation for the benefit of methylphenidate in treating TRD is that it enhances the level of dopamine in the brain. Adjunctive low dose aripiprazole in patients with TRD has also become a common intervention. Several studies have focused on aripiprazole's pharmacodynamic and pharmacokinetic profiles, but no definitive comments on its antidepressant effects. We hypothesize that a low dose of aripiprazole might play a role as a dopamine agonist similar to that of methylphenidate due to its partial dopamine D2 agonist and 30% intrinsic dopaminergic activity. In addition to its use in patients with TRD, adjunctive aripiprazole might work like methylphenidate in those depressed patients with fatigue, advanced age, or major illnesses. A new drug invention which combined an antidepressant with an adequate dose of aripiprazole should be considered. The neurobiological basis for this combination in treating TRD awaits further study. PMID- 23751313 TI - Should we seek cold agglutinins in celiac disease? PMID- 23751314 TI - Early manifestations of pancreatic cancer: the effect of cancer-nerve interaction. AB - Clinical manifestation is important for the diagnosis of pancreatic cancer (PanCa). No typical symptoms have been identified that clearly indicate the early stage of PanCa, although most patients with PanCa have symptoms before the cancer is diagnosed. These symptoms are often regarded as common gastrointestinal symptoms and are ignored. The pancreas is richly supplied with nerves, and neuro cancer interactions begin prior to PanCa cell migration. We hypothesise that the cancer-nerve interaction does generate typical symptoms such as pseudomorphous satiety and mild pain in early PanCa. Constant satiety leads to weight loss. This biological behaviour allows the cancer to progress without attention from the cancer-bearing host. Cancer cells also target the endocrine pancreas, generating a hyperglycaemic state that results in increased energy for cancer cells. The combination of the so-called common gastrointestinal symptoms and diabetes may represent early typical symptoms of PanCa that can be used to improve early diagnosis. PMID- 23751315 TI - Inhibiting the motility and invasion of cancer cells by biomineralization. AB - Many kinds of cancer are difficult to treat because of their highly metastatic abilities. Thus, seeking new anticancer drugs or therapy strategies, which could reduce the motility of cancer cells or inhibit the migration and invasion of the cells, is an urgent affair. Several recent reports suggest various techniques (such as layer-by-layer assembly and biomimetic mineralization) aimed to functionalize human cells and microbial with polyelectrolytes, nanoparticles, or mineral coatings. Inspired by these studies, an artificial mineral shell could be formed to enclose cancer cells under the regulation of SIBLINGs-like proteins. Consequently, the connection between the cancer cell and substrate would be interfered or inhibited. Therefore, the motility of cancer cells would be weakened or inhibited due to the restriction of the artificial mineral shell. This hypothetical strategy might be as a new concept for cancer therapy. PMID- 23751316 TI - Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants. AB - BACKGROUND/AIMS: Idiopathic pancreatitis is considered to be a multigenic and multifactorial disease. Genetically determined pancreatitis is associated with mutations in the PRSS1,SPINK1 and CFTR genes. This study aimed at examining the clinical and morphological characteristics of patients diagnosed with genetically determined sporadic pancreatitis. METHODS: Inclusion criteria were the presence of PRSS1,CFTR or SPINK1 gene mutations in patients with idiopathic recurrent or chronic pancreatitis. Patients with hereditary pancreatitis were excluded. Age- and sex-matched patients with idiopathic pancreatitis and negative genetic testing served as controls (n = 68). RESULTS: Genetic testing was performed in 351 probands referred to our centre since 1999. Sixty-one patients (17.4%) carried at least 1 detected mutation in 1 of the 3 tested genes (34 CFTR, 10 PRSS1 and 13 SPINK1 mutations), and 4 patients showed a combination of mutations. Follow-up has been currently extended to a median of 5 years (range 1-40). Similar clinical features were noted in the case and matched groups except for an earlier age of onset of pancreatic symptoms and a higher incidence of pancreatic cancer in the case group and in patients with CFTR mutations compared to the control group (p < 0.05). The standardized incidence ratio, the ratio of observed to expected pancreatic cancers, averaged 26.5 (95% confidence interval 8.6-61.9). All pancreatic cancer patients were smokers. CONCLUSION: Clinical parameters of patients with sporadic idiopathic pancreatitis and gene mutations are similar to those of age- and sex-matched patients without gene mutations, except for the age of pancreatic disease onset. A significantly higher occurrence of pancreas cancer was observed in the case group, particularly in those patients carrying CFTR mutations. We therefore suggest to include patients with CFTR variants presenting with risk factors in a screening and surveillance programme and to strongly advise them to stop smoking. PMID- 23751317 TI - In vivo anti-radiation activities of the Ulva pertusa polysaccharides and polysaccharide-iron(III) complex. AB - Polysaccharides with different molecular weights were extracted from Ulva pertusa and fractionated by ultrafiltration. Iron(III) complex of the low molecular weight U. pertusa polysaccharides were synthesized. Atomic absorption spectrum showed that the iron content of iron(III)-polysaccharide complex was 27.4%. The comparison between U. pertusa polysaccharides and their iron(III) complex showed that iron chelating altered the structural characteristics of the polysaccharides. The bioactivity analysis showed that polysaccharide with low molecular weight was more effective than polysaccharide with high molecular weight in protecting mice from radiation induced damages on bone marrow cells and immune system. Results also proved that the anti-radiation and anti-oxidative activity of iron(III) complex of low molecular-weight polysaccharides were not less than that of low molecular-weight polysaccharides. PMID- 23751318 TI - Nanocrystalline cellulose from aspen kraft pulp and its application in deinked pulp. AB - Nanocrystalline cellulose (NCC) isolated from bleached aspen kraft pulp was characterized, and its application as pulp strengthening additive and retention aid was investigated. Results showed that NCC with high crystallinity of more than 80% can be obtained using 64 wt% sulfuric acid. The structure of nanocrystalline cellulose is parallelepiped rod-like, and their cross-sectional dimension is in the nanometer range with a high aspect ratio. The formation of microparticle retention systems during the application of NCC together with cationic polyacrylamide and cationic starch in deinked pulp was able to further improve pulp retention and strength properties without negative influence on the drainage. PMID- 23751319 TI - Sulfated Astragalus polysaccharide can regulate the inflammatory reaction induced by LPS in Caco2 cells. AB - This study evaluates the effect of sulfated Astragalus polysaccharide (SAPS) on inflammatory reaction induced by LPS in Caco2 cells. Sulfated modification was conducted using the chlorosulfonic acid-pyridine method. Caco2 cells were cultured with 25, 50 and 100 MUg/mL SAPS or 100 MUg/mL Astragalus polysaccharide (APS) for 24 h. Then, 1 MUg/mL LPS was added for the next 24 h to trigger an inflammatory response. DMEM culture medium was used as a blank control. In present study, LPS stimulation significantly increased the mRNA expression of TNF alpha, IL-1beta, IL-8 and TLR4, and reduced the expression of ZO-1 and occludin. Compared with the LPS control group, APS (100 MUg/mL) or SAPS (100 MUg/mL) administration decreased the expression of TNF-alpha, IL-1beta and IL-8. Moreover, 25 MUg/mL and 50 MUg/mL SAPS down-regulated TNF-alpha and IL-1beta expression. APS administration (100 MUg/mL) up-regulated occludin expression, but did not affect ZO-1 expression. However, the expression of ZO-1 and occludin was up-regulated by lower dose SAPS administration (25 MUg/mL and 50 MUg/mL). Compared with the other groups, the expression of TLR4 was lower in the SAPS group at all concentrations of SAPS. These results suggest that SAPS was to be a more effective anti-inflammatory agent than APS in vitro. PMID- 23751320 TI - Uterine and ovary carcinosarcomas: outcome, prognosis factors, and adjuvant therapy. AB - OBJECTIVES: The aim of this study was to assess the outcome and the prognosis factors of uterine and ovarian carcinosarcomas. METHODS: From January 1993 to January 2010, data from 68 consecutively treated patients with uterine (n=59) and ovarian (n=9) carcinosarcomas were retrospectively analyzed in a single French comprehensive cancer center. RESULTS: The median follow-up was 24.2 months (interquartile range [IQR]: 13.5 to 54.6). The median age was 69 years (IQR: 63 to 77). Patients were classified as FIGO stage I (n=28; 41%) and FIGO stage II to IV (n=40; 59%), respectively. There were 33 (49%) and 29 (43%) homologous and heterologous type, respectively. The median disease-free survival and overall survival were 21.9 months (IQR: 7.9 to 22.3) and 27.1 months (IQR: 14.5 to 72), respectively. No statistical differences of survival were reported concerning the initial location of the carcinosarcoma (uterine vs. ovarian). Radiation therapy (hazards ratio [HR]=0.3; 95% confidence interval [CI], 0.16-0.67) and FIGO stage I (HR=0.4; 95% CI, 0.17-0.9) were associated with an increased disease-free survival. Homologous type (HR=3; 95% CI, 1.4-6.3) and FIGO stage II to IV (HR=2.64; 95% CI, 1.3-5.4) were associated with a decreased overall survival. There was no survival improvement for the 12% of patients receiving a multimodal adjuvant therapy. CONCLUSIONS: Uterine and ovary carcinosarcomas present a worse prognosis. On the basis of the present study data, although it should be prospectively confirmed, a sequential or multimodal adjuvant therapy should be proposed to patients with early-stage uterine and ovary carcinosarcomas. PMID- 23751322 TI - Primary erector spinae pyomyositis with an epidural abscess. PMID- 23751323 TI - Revision of failed distal interphalangeal arthrodesis complicated by retained headless screw. AB - Arthrodesis of the distal interphalangeal joint is a well-accepted treatment for painful arthritis. Although headless screw fixation across the distal interphalangeal joint is an overall effective method for achieving bony union, failures and nonunions still occur. We present a salvage technique to address both the retained headless screw within the medullary canal as well as the persistent nonunion. PMID- 23751324 TI - Single-stage surgery combining nerve and tendon transfers for bilateral upper limb reconstruction in a tetraplegic patient: case report. AB - A 39-year-old tetraplegic patient had paralysis of elbow, thumb, and finger extension and thumb and finger flexion. We transferred axillary nerve branches to the triceps long and upper medial head motor branches, supinator motor branches to the posterior interosseous nerve, and brachioradialis tendon to the flexor pollicis longus and flexor superficialis of the index finger. Surgery was performed bilaterally 18 months after spinal cord injury. At 12 months after surgery, we performed bilateral distal radioulnar arthrodesis percutaneously. By 22 months postoperatively, we observed triceps strength scoring M3 bilaterally and full metacarpophalangeal joint extension scoring M4 bilaterally. The thumb span was 53 and 66 mm from the proximal index phalanx on the right and left sides, respectively. Pinch strength measured 1.5 kg on the left side and 2.0 kg on the right. Before surgery, the patient was incapable of grasping; after surgery, a useful grasp had been restored bilaterally. PMID- 23751325 TI - Controversies in the treatment of nail bed injuries. PMID- 23751326 TI - Dorsal locked plate fixation of distal radius fractures. AB - Distal radius fractures are common, and internal fixation for operative management of these injuries is widely accepted. Although use of the volar approach for plate fixation has become more popular, benefits of the dorsal surgical approach include the potential for direct reduction and assessment of articular alignment, evaluation and management of concomitant intrinsic intercarpal ligament injury, and initiation of early range of motion. For certain fracture patterns, dorsal plate fixation is the preferred surgical technique. Improvements in implant design, in particular the use of low-profile dorsal plates, has decreased the rate of complications seen previously with this technique. Here, we provide an overview of the evaluation of patients with distal radius fractures, as well as the surgical indications and contraindications, techniques, and complications after dorsal locked plate fixation of intra articular distal radius fractures. PMID- 23751328 TI - Non-Q-wave myocardial infarction: comprehensive analysis of electrocardiogram, pathophysiology, and therapeutics. AB - Since the invention of electrocardiogram (ECG or EKG), its significance in the diagnosis of acute ischemic disease, chronic ischemic disease, and its contribution to cardiology has been no less than remarkable. The pathophysiology of acute coronary syndromes in most cases correlates with the clinical outcomes, biochemical findings (cardiac biomarkers), and electrocardiographic patterns. Electric activity in the myocardium is registered in the ECG describing positive deflections when the depolarization potential orientates positive charges to the recording electrode (approaches to it) and negative deflections when the depolarization potential orientates negative charges to the recording electrode and gets away from it. The abnormal Q-wave is the cornerstone of the myocardial infarction diagnosis after several days of the ischemic event. Findings in the ECG suggestive of ischemia and necrosis are ST elevation/depression and deep Q waves, respectively, and the presence of a deep abnormal Q-wave in the ECG is evidence of necrotic areas and an inert myocardium, which is not capable to depolarize. Non-Q-wave myocardial infarction has been defined as acute myocardial infarction without a new-onset deep Q-wave on the ECG after day(s) of evolution, and because of the anatomopathological concept of infarction is usually related to necrosis, it results paradoxical to consider this widely known clinical and biochemical entity as a myocardial infarction when there is no evidence of necrosis in the ECG. PMID- 23751327 TI - Renal transplantation in 4 patients with methylmalonic aciduria: a cell therapy for metabolic disease. AB - INTRODUCTION: Patients with methylmalonic acidemia (MMA) may develop many complications despite medical treatment, in particular, severe central nervous system damage and chronic kidney disease (CKD). A kidney transplant may partially correct the metabolic dysfunctions. Liver, kidney and combined liver-kidney transplantations have been advocated but no guidelines are available to identify the most suitable organ to transplant. PATIENTS AND METHODS: Four patients with MMA (mut degrees phenotype) received a kidney graft because of repeated metabolic decompensations, with progression to CKD in 3 patients (end-stage kidney disease in two patients and CKD stage III in one patient with an estimated glomerular filtration rate [eGFR] of 40ml/min/1.73m(2)) but normal renal function in one (eGFR of 93ml/min/1.73m(2)) before transplantation. RESULTS: The medium age at transplantation was 7.9y (5-10.2) and the median follow-up was 2.8years (1.8-4.6). Renal transplantation improved the relevant metabolic parameters in 4/4 patients and renal function in the patients with CKD. Plasma and urinary MMA levels immediately decreased and remained normal or subnormal (mean values of plasma MMA before transplantation 1530MUmol/L versus 240MUmol/L after transplantation, and mean values of urine MMA before transplantation 4700mmol/mol creatinine versus 2300mmol/mol creatinine after transplantation). No further acute metabolic decompensation was observed and protein-intake was increased from 0.60 to 0.83g/Kg/day. One patient transplanted at age 9.7years developed a hepatoblastoma at age 11years with subsequent neurological complications and eventually died. The three other patients are alive. Two of them remained neurologically stable. The 3rd patient who displayed choreoathetosis transiently improved his neurological condition immediately after transplantation and then remained stable. CONCLUSION: Kidney transplantation represents an interesting alternative therapeutic option in methylmalonic aciduria, for renal complications but also as a "cellular therapy" that may significantly reduce metabolic decompensations and hospitalizations. However, further neurological impairment remains possible. PMID- 23751329 TI - Shuffling Adaptive Clinical Trials. AB - Clinical trials are interventional studies on human beings, designed to test the hypothesis for diagnostic techniques, treatments, and disease preventions. Any novel medical technology should be evaluated for its efficacy and safety by clinical trials. The costs associated with developing drugs have increased dramatically over the past decade, and fewer drugs are obtaining regulatory approval. Because of this, the pharmaceutical industry is continually exploring new ways of improving drug developments, and one area of focus is adaptive clinical trial designs. Adaptive designs, which allow for some types of prospectively planned mid-study changes, can improve the efficiency of a trial and maximize the chance of success without undermining validity and integrity of the trial. However it is felt that in adaptive trials; perhaps by using accrued data the actual patient population after the adaptations could deviate from the originally target patient population and so to overcome this drawback; special methods like Bayesian Statistics, predicted probability are used to deduce data analysis. Here, in this study, mathematical model of a new adaptive design (shuffling adaptive trial) is suggested which uses real-time data, and because there is no gap between expected and observed data, statistical modifications are not needed. Results are obviously clinically relevant. PMID- 23751330 TI - Chicken interferons, their receptors and interferon-stimulated genes. AB - The prevalence of pathogenic viruses is a serious issue as they pose a constant threat to both the poultry industry and to human health. To prevent these viral infections an understanding of the host-virus response is critical, especially for the development of novel therapeutics. One approach in the control of viral infections would be to boost the immune response through administration of cytokines, such as interferons. However, the innate immune response in chickens is poorly characterised, particularly concerning the interferon pathway. This review will provide an overview of our current understanding of the interferon system of chickens, including their cognate receptors and known interferon stimulated gene products. PMID- 23751331 TI - Application of bacterial lipopolysaccharide to improve survival of the black tiger shrimp after Vibrio harveyi exposure. AB - This study investigates an effect of bacterial lipopolysaccharide (LPS) as feed supplement to improve immunity of the black tiger shrimp (Penaeus monodon). LPS was coated to commercial feed pellets and given to the shrimp once or twice a day for 10 days before an exposure with shrimp pathogenic bacterium Vibrio harveyi. The growth rates, percent weight gains, total hemocyte and granulocyte counts and survival rates of shrimp between the LPS-coated pellet fed groups and a control group where shrimp fed with commercial feed pellets were compared. After 10 days of the feeding trials, growth rates were not significantly different in all groups, suggesting no toxicity from LPS supplement. To determine beneficial effect of LPS diets, each group was subsequently exposed to V. harveyi by immersion method and the survival rates were recorded for seven days after the immersion. Regardless of the dosages of LPS, the shrimp groups fed with LPS coated pellets showed higher survival rates than the control group. There was no significant difference in survival rates between the two LPS dosages groups. In addition to survival under pathogen challenge, we also determine effect of LPS on immune-related genes after 10-day feeding trial. Gene expression analysis in the P. monodon intestines revealed that antilipopolysaccharide factor isoform 3 (ALF3), C-type lectin, and mucine-like peritrophin (mucin-like PM) were expressed significantly higher in a group fed with LPS supplemental diet once or twice a day than in a control group. The transcript levels of C-type lectin and mucin like PM had increased significantly when LPS was given once a day, while significant induction of ALF3 transcripts was observed when shrimp were fed with LPS twice a day. The up-regulation of the immune gene levels in intestines and higher resistance to V. harveyi of the shrimp fed with LPS provide the evidence for potential application of LPS as an immunostimulant in P. monodon farming. PMID- 23751332 TI - Treatment of micropollutants in municipal wastewater: ozone or powdered activated carbon? AB - Many organic micropollutants present in wastewater, such as pharmaceuticals and pesticides, are poorly removed in conventional wastewater treatment plants (WWTPs). To reduce the release of these substances into the aquatic environment, advanced wastewater treatments are necessary. In this context, two large-scale pilot advanced treatments were tested in parallel over more than one year at the municipal WWTP of Lausanne, Switzerland. The treatments were: i) oxidation by ozone followed by sand filtration (SF) and ii) powdered activated carbon (PAC) adsorption followed by either ultrafiltration (UF) or sand filtration. More than 70 potentially problematic substances (pharmaceuticals, pesticides, endocrine disruptors, drug metabolites and other common chemicals) were regularly measured at different stages of treatment. Additionally, several ecotoxicological tests such as the Yeast Estrogen Screen, a combined algae bioassay and a fish early life stage test were performed to evaluate effluent toxicity. Both treatments significantly improved the effluent quality. Micropollutants were removed on average over 80% compared with raw wastewater, with an average ozone dose of 5.7 mg O3 l(-1) or a PAC dose between 10 and 20 mg l(-1). Depending on the chemical properties of the substances (presence of electron-rich moieties, charge and hydrophobicity), either ozone or PAC performed better. Both advanced treatments led to a clear reduction in toxicity of the effluents, with PAC-UF performing slightly better overall. As both treatments had, on average, relatively similar efficiency, further criteria relevant to their implementation were considered, including local constraints (e.g., safety, sludge disposal, disinfection), operational feasibility and cost. For sensitive receiving waters (drinking water resources or recreational waters), the PAC-UF treatment, despite its current higher cost, was considered to be the most suitable option, enabling good removal of most micropollutants and macropollutants without forming problematic by products, the strongest decrease in toxicity and a total disinfection of the effluent. PMID- 23751333 TI - Spatial and temporal trends in estimates of nutrient and suspended sediment loads in the Ishikari River, Japan, 1985 to 2010. AB - Nutrients and suspended sediment in surface water play important roles in aquatic ecosystems and contribute strongly to water quality with implication for drinking water resources, human and environmental health. Estimating loads of nutrients (nitrogen and phosphorus) and suspended sediment (SS) is complicated because of infrequent monitoring data, retransformation bias, data censoring, and non normality. To obtain reliable unbiased estimates, the Maintenance of Variance Extension type 3 (MOVE. 3) and the regression model Load Estimator (LOADEST) were applied to develop regression equations and to estimate total nitrogen (TN), total phosphorus (TP) and SS loads at five sites on the Ishikari River, Japan, from 1985 to 2010. Coefficients of determination (R(2)) for the best-fit regression models for loads of TN, TP, and SS for the five sites ranged from 71.86% to 90.94%, suggesting the model for all three constituents successfully simulated the variability in constituent loads at all studied sites. Estimated monthly average loads at Yishikarikakou-bashi were larger than at the other sites, with TN, TP, and SS loads ranging from 8.52*10(3) to 2.00*10(5) kg/day (Apr. 1999), 3.96*10(2) to 5.23*10(4) kg/ day (Apr. 1999), and 9.21*10(4) to 9.25*10(7) kg/day (Sep. 2001), respectively. Because of variation in river discharge, the estimated seasonal loads fluctuated widely over the period 1985 to 2010, with the greatest loads occurring in spring and the smallest loads occurring in winter. Estimated loads of TN, TP, and especially SS showed decreasing trends during the study period. Accurate load estimation is a necessary goal of water quality monitoring efforts and the methods described here provide essential information for effectively managing water resources. PMID- 23751334 TI - Modelling nitrogen leaching from sewage sludge application to arable land in the Lombardy region (northern Italy). AB - Sewage sludge can be used as fertiliser, offering the possibility of safely recycling this waste product as a resource in agricultural applications. As the environmental concerns related to waste recycling in agricultural applications are well-known, restrictions on the use of sewage sludge have been implemented by the EU and local authorities. This work aimed to evaluate the nitrogen leaching associated with the application of sludge and the effectiveness of the temporal restrictions on its application implemented to safeguard the environment in the Lombardy region of northern Italy (120 days in Nitrate Vulnerable Zones and 90 days elsewhere) using the CropSyst model which was first validated. The effects of fertilisation using four different sludge types on N leaching were simulated at five sites under cultivation with maize and rice crops; six different timing schemes for sludge application were tested, three of which involved dates that were in agreement (AT) with the regulation, while the other three were not in agreement (NAT). We detected a significant effect of the sludge type and application timing, whereas the effect of their interaction was never significant. The mean annual leaching was 22 to 154 kg N ha(-1). The higher the ammonium N content in the sludge was, the greater the potential for N leaching was found to be. For the maize crop, the distribution of sludge in the late fall period resulted in significantly greater N leaching (61 kg N ha(-1)) and led to lower yields (9 t DM ha(-1)) compared to late winter fertilisation (49 kg N ha( 1); 10 t DM ha(-1)), whereas no differences in N leaching or yield were detected between AT and NAT, which was also observed for the rice crop. Therefore, the applied temporal constraints did not always appear to be advantageous for protecting the environment from leaching. PMID- 23751335 TI - Widespread occurrence of neuro-active pharmaceuticals and metabolites in 24 Minnesota rivers and wastewaters. AB - Concentrations of 17 neuro-active pharmaceuticals and their major metabolites (bupropion, hydroxy-bupropion, erythro-hydrobupropion, threo-hydrobupropion, carbamazepine, 10,11,-dihydro-10,11,-dihydroxycarbamazepine, 10-hydroxy carbamazepine, citalopram, N-desmethyl-citalopram, fluoxetine, norfluoxetine, gabapentin, lamotrigine, 2-N-glucuronide-lamotrigine, oxcarbazepine, venlafaxine and O-desmethyl-venlafaxine), were measured in treated wastewater and receiving surface waters from 24 locations across Minnesota, USA. The analysis of upstream and downstream sampling sites indicated that the wastewater treatment plants were the major source of the neuro-active pharmaceuticals and associated metabolites in surface waters of Minnesota. Concentrations of parent compound and the associated metabolite varied substantially between treatment plants (concentrations+/-standard deviation of the parent compound relative to its major metabolite) as illustrated by the following examples; bupropion and hydrobupropion 700+/-1000 ng L(-1), 2100+/-1700 ng L(-1), carbamazepine and 10 hydroxy-carbamazepine 480+/-380 ng L(-1), 360+/-400 ng L(-1), venlafaxine and O desmethyl-venlafaxine 1400+/-1300 ng L(-1), 1800+/-2300 ng L(-1). Metabolites of the neuro-active compounds were commonly found at higher or comparable concentrations to the parent compounds in wastewater effluent and the receiving surface water. Neuro-active pharmaceuticals and associated metabolites were detected only sporadically in samples upstream from the effluent outfall. Metabolite to parent ratios were used to evaluate transformation, and we determined that ratios in wastewater were much lower than those reported in urine, indicating that the metabolites are relatively more labile than the parent compounds in the treatment plants and in receiving waters. The widespread occurrence of neuro-active pharmaceuticals and metabolites in Minnesota effluents and surface waters indicate that this is likely a global environmental issue, and further understanding of the environmental fate and impacts of these compounds is warranted. PMID- 23751336 TI - CFD modelling of the aerodynamic effect of trees on urban air pollution dispersion. AB - The current work evaluates the impact of urban trees over the dispersion of carbon monoxide (CO) emitted by road traffic, due to the induced modification of the wind flow characteristics. With this purpose, the standard flow equations with a kepsilon closure for turbulence were extended with the capability to account for the aerodynamic effect of trees over the wind field. Two CFD models were used for testing this numerical approach. Air quality simulations were conducted for two periods of 31h in selected areas of Lisbon and Aveiro, in Portugal, for distinct relative wind directions: approximately 45 degrees and nearly parallel to the main avenue, respectively. The statistical evaluation of modelling performance and uncertainty revealed a significant improvement of results with trees, as shown by the reduction of the NMSE from 0.14 to 0.10 in Lisbon, and from 0.14 to 0.04 in Aveiro, which is independent from the CFD model applied. The consideration of the plant canopy allowed to fulfil the data quality objectives for ambient air quality modelling established by the Directive 2008/50/EC, with an important decrease of the maximum deviation between site measurements and CFD results. In the non-aligned wind situation an average 12% increase of the CO concentrations in the domain was observed as a response to the aerodynamic action of trees over the vertical exchange rates of polluted air with the above roof-level atmosphere; while for the aligned configuration an average 16% decrease was registered due to the enhanced ventilation of the street canyon. These results show that urban air quality can be optimised based on knowledge based planning of green spaces. PMID- 23751337 TI - Phenotypic evaluation of severely damaged ocular surface after reconstruction by cultured limbal epithelial cell transplantation. AB - OBJECTIVE: To report the clinical outcome of autologous cultured limbal epithelial cell transplantation (CLECT) followed by deep anterior lamellar keratoplasty (DALK) in paediatric eyes and to correlate the clinical outcome with the phenotype of rejuvenated corneal epithelium. METHODS: Four patients with total limbal stem cell deficiency (LSCD) underwent autologous CLECT. Cultivated cell sheets were transplanted onto the damaged ocular surface followed by DALK surgery. Excised corneal buttons were subjected to histopathological analysis. Data recorded included age, sex, laterality, nature of injury, follow-up period, severity of stem cell deficiency, visual acuity, Schirmer's test and impression cytology. RESULTS: At a mean follow-up period of 19.5 +/- 7.4 (range 9-26) months after CLECT, all 4 eyes showed epithelialized and clinically stabilized ocular surface. Manual DALK was performed in all 4 eyes, with a mean follow-up of 9.75 +/- 4.5 (range 5-15) months. All eyes exhibited smooth and clear corneal epithelium with improved visual acuity. Excised corneal buttons demonstrated organized corneal epithelial morphology and showed expression of cornea-specific CK3/12 marker. CONCLUSION: Restoration of severely damaged ocular surface following chemical injury by using 2-stage meticulous approaches offers a new modality for the treatment of severe LSCD. Transplantation of cultivated autologous limbal epithelial cell sheet followed by DALK surgery can efficiently restore the corneal phenotype with improved vision. PMID- 23751338 TI - Four generations of rare familial lymphedema (Milroy disease). AB - OBJECTIVE: To report a rare case of familial lymphedema (Milroy disease) affecting 4 generations of individuals. CLINICAL PRESENTATION AND INTERVENTION: A 28-year-old woman presented with bilateral pedal edema which she had since birth. A detailed evaluation including blood counts, metabolic panel and imaging studies ruled out secondary causes of lymphedema. The family history revealed many affected individuals up to 4 generations. She was reassured about the potential benign yet familial nature of this condition. She was advised to wear compression stockings and to avoid scratches or skin breakdowns in the lower extremities to prevent cellulitis. CONCLUSION: This case showed the occurrence of asymptomatic progressive lymphedema in 4 generations of individuals. PMID- 23751339 TI - It can be done: an effective and organized cardiac MRI workflow. PMID- 23751340 TI - An open and shut case? PMID- 23751341 TI - Amorphous solid dispersions and nano-crystal technologies for poorly water soluble drug delivery. AB - Poor water-solubility is a common characteristic of drug candidates in pharmaceutical development pipelines today. Various processes have been developed to increase the solubility, dissolution rate and bioavailability of these active ingredients belonging to BCS II and IV classifications. Over the last decade, nano-crystal delivery forms and amorphous solid dispersions have become well established in commercially available products and industry literature. This article is a comparative analysis of these two methodologies primarily for orally delivered medicaments. The thermodynamic and kinetic theories relative to these technologies are presented along with marketed product evaluations and a survey of commercial relevant scientific literature. PMID- 23751342 TI - Evaluating the inter and intra batch variability of protein aggregation behaviour using Taylor dispersion analysis and dynamic light scattering. AB - Biosimilar pharmaceuticals are complex biological molecules that have similar physicochemical properties to the originator therapeutic protein. They are produced by complex multi-stage processes and are not truly equivalent. Therefore, for a biosimilar to be approved for market it is important to demonstrate that the biological product is highly similar to a reference product. This includes its primary and higher order structures and its aggregation behaviour. Representative lots of both the proposed biosimilar and the reference product are analysed to understand the lot-to-lot variability of both drug substances in the manufacturing processes. Whilst it is not easy to characterise every variation of a protein structure at present additional analytical technologies need to be utilised to ensure the safety and efficacy of any potential biosimilar product. We have explored the use of Taylor dispersion analysis (TDA) to analyse such batch to batch variations in the model protein, bovine serum albumin (BSA) and compared the results to that obtained by conventional dynamic light scattering analysis (DLS). Inter and intra batch differences were evident in all grades of BSA analysed. However, the reproducibility of the TDA measurements, enabled the stability and reversibility of BSA aggregates to be more readily monitored. This demonstrates that Taylor dispersion analysis is a very sensitive technique to study higher order protein states and aggregation. The results, here, also indicate a correlation between protein purity and the physical behaviour of the samples after heat shocking. Here, the protein with the highest quoted purity resulted in a reduced increase in the measured hydrodynamic radius after heat stressing, indicating that less unfolding/aggregation had occurred. Whilst DLS was also able to observe the presence of aggregates, its bias towards larger aggregates indicated a much larger increase in hydrodynamic radii and is less sensitive to small changes in hydrodynamic radii. TDA was also able to identify low levels of larger aggregates that were not observed by DLS. Therefore, given the potential for immunogenicity effects that may result from such aggregates it is suggested that TDA may be suitable in the evaluating detailed batch to batch variability and process induced physical changes of biopharmaceuticals and biosimilars. PMID- 23751343 TI - Heart rate: the hummingbird effect. PMID- 23751344 TI - Mammalian galectins bind galactosebeta1-4fucose disaccharide, a unique structural component of protostomial N-type glycoproteins. AB - Galactosebeta1-4Fucose (Galbeta1-4Fuc) is a unique disaccharide exclusively found in N-glycans of protostomia, and is recognized by some galectins of Caenorhabditis elegans and Coprinopsis cinerea. In the present study, we investigated whether mammalian galectins also bind such a disaccharide. We examined sugar-binding ability of human galectin-1 (hGal-1) and found that hGal-1 preferentially binds Galbeta1-4Fuc compared to Galbeta1-4GlcNAc, which is its endogenous recognition unit. We also tested other human and mouse galectins, i.e., hGal-3, and -9 and mGal-1, 2, 3, 4, 8, and 9. All of them also showed substantial affinity to Galbeta1-4Fuc disaccharide. Further, we assessed the inhibitory effect of Galbeta1-4Fuc, Galbeta1-4Glc, and Gal on the interaction between hGal-1 and its model ligand glycan, and found that Galbeta1-4Fuc is the most effective. Although the biological significance of galectin-Galbeta1-4Fuc interaction is obscure, it might be possible that Galbeta1-4Fuc disaccharide is recognized as a non-self-glycan antigen. Furthermore, Galbeta1-4Fuc could be a promising seed compound for the synthesis of novel galectin inhibitors. PMID- 23751345 TI - Mutation of cysteine residues alters the heme-binding pocket of indoleamine 2,3 dioxygenase-1. AB - The hemoprotein indoleamine 2,3-dioxygenase-1 (IDO1) is the first and rate limiting enzyme in mammalian tryptophan metabolism. Interest in IDO1 continues to grow, due to the ever expanding influence IDO1 plays in the immune response. This study examined the contribution of all individual cysteine residues towards the overall catalytic properties and stability of recombinant human IDO1 via mutagenesis studies using a range of biochemical and spectroscopic techniques, including in vitro kinetic assessment, secondary structure identification via circular dichroism spectroscopy and thermal stability assessment. Upon mutation of cysteine residues we observed changes in secondary structure (principally, shifting from alpha-helix/beta-sheet features to random coil structures) that produced out of plane heme torsion and puckering, changes to thermal stability (including gains in stability for one mutant protein) and differences in enzymatic activity (such as, increased ability to convert non-natural substrates, e.g.d-tryptophan) from wild type IDO1 enzyme. PMID- 23751347 TI - Determination of dissociation constant of the NFkappaB p50/p65 heterodimer using fluorescence cross-correlation spectroscopy in the living cell. AB - Two-laser-beam fluorescence cross-correlation spectroscopy (FCCS) is promising technique that provides quantitative information about the interactions of biomolecules. The p50/p65 heterodimer is the most abundant and well understood of the NFkappaB dimers in most cells. However, the quantitative value of affinity, namely the K(d), for the heterodimer in living cells is not known yet. To quantify the heterodimerization of the IPT domain of p50/p65 in the living cell, we used two-laser-beam FCCS. The K(d) values of mCherry2- and EGFP-fused p50 and p65 were determined to be 0.46 MUM in the cytoplasm and 1.06 MUM in the nucleus of the living cell. These results suggest the different binding affinities of the p50/p65 heterodimer in the cytoplasm and nucleus of the living cell and different complex formation in each region. PMID- 23751346 TI - Ambient ultrafine particles reduce endothelial nitric oxide production via S glutathionylation of eNOS. AB - Exposure to airborne particulate pollutants is intimately linked to vascular oxidative stress and inflammatory responses with clinical relevance to atherosclerosis. Particulate matter (PM) has been reported to induce endothelial dysfunction and atherosclerosis. Here, we tested whether ambient ultrafine particles (UFP, diameter <200 nm) modulate eNOS activity in terms of nitric oxide (NO) production via protein S-glutathionylation. Treatment of human aortic endothelial cells (HAEC) with UFP significantly reduced NO production. UFP mediated reduction in NO production was restored in the presence of JNK inhibitor (SP600125), NADPH oxidase inhibitor (Apocynin), anti-oxidant (N-acetyl cysteine), and superoxide dismutase mimetics (Tempol and MnTMPyP). UFP exposure increased the GSSG/GSH ratio and eNOS S-glutathionylation, whereas over-expression of Glutaredoxin-1 (to inhibit S-glutathionylation) restored UFP-mediated reduction in NO production by nearly 80%. Thus, our findings suggest that eNOS S glutathionylation is a potential mechanism underlying ambient UFP-induced reduction of NO production. PMID- 23751348 TI - Autocrine TNF-alpha-mediated NF-kappaB activation is a determinant for evasion of CD40-induced cytotoxicity in cancer cells. AB - Activation of CD40 by CD40L results in diverse effects on different malignant cells, causing either promotion of survival, growth and resistance to chemotherapy, or induction of cytostasis and apoptosis. The molecular mechanisms underlying CD40-mediated growth regulation and apoptosis induction in cancer cell are not fully understood. In this study, we investigated the role of NF-kappaB activation in CD40-mediated cytotoxicity in cancer cells. The results show that activation of CD40 by recombinant soluble CD40 ligand (rsCD40L) readily induced NF-kappaB activation and blocking NF-kappaB significantly enhanced rsCD40L induced apoptosis in cancer cells. Importantly, autocrine of TNF-alpha induced by rsCD40L was indispensable for both NF-kappaB activation and cytotoxicity induction, establishing a dual role of autocrine TNF-alpha that constitutes both pro-apoptotic and anti-apoptotic arms of CD40 signaling. Our results indicate that autocrine TNF-alpha-mediated NF-kappaB activation is a determinant for cancer cells' evasion of CD40L-induced cytotoxicity and blocking NF-kappaB may have potential for improve the value of CD40 as an anticancer agent. PMID- 23751349 TI - Protocadherin-7 induces bone metastasis of breast cancer. AB - Breast cancer had a propensity to metastasize to bone, resulting in serious skeletal complications associated with poor outcome. Previous study showed that Protocadherin-7 (PCDH7) play an important role in brain metastatic breast cancer, however, the role of PCDH7 in bone metastatic breast cancer has never been explored. In the present study, we found that PCDH7 expression was up-regulation in bone metastatic breast cancer tissues by real-time PCR and immunohistochemistry assays. Furthermore, suppression of PCDH7 inhibits breast cancer cell proliferation, migration, and invasion in vitro by MTT, scratch, and transwell assays. Most importantly, overexpression of PCDH7 promotes breast cancer cell proliferation and invasion in vitro, and formation of bone metastasis in vivo. These data provide an important insight into the role of PCDH7 in bone metastasis of breast cancer. PMID- 23751350 TI - The xanthine oxidase inhibitor oxypurinol reduces cancer cachexia-induced cardiomyopathy. AB - BACKGROUND: Cachexia is a common complication of cancer and may be responsible for 22% of all cancer-related deaths. The exact cause of death in cancer cachexia patients is unknown. Recently, atrophy of the heart has been described in cancer cachexia animal models, which resulted in impaired cardiac function and is likely to contribute to mortality. In cancer patients hyperuricaemia independent of tumour lysis syndrome is often associated with a worse prognosis. Xanthine oxidase (XO) metabolizes purines to uric acid and its inhibition has been shown to improve clinical outcome in patients with chronic heart failure. METHODS: The rat Yoshida AH-130 hepatoma cancer cachexia model was used in this study. Rats were treated with 4 or 40 mg/kg/d oxypurinol or placebo starting one day after tumour-inoculation for maximal 15 days. Cardiac function was analyzed by echocardiography on day 11. RESULTS: Here we show that inhibition of XO by oxypurinol significantly reduces wasting of the heart and preserves cardiac function. LVEF was higher in tumour-bearing rats treated with 4 mg/kg/d (61+/-4%) or 40 mg/kg/d (64+/-5%) oxypurinol vs placebo (51+/-3%, both p<0.05). Fractional shortening was improved by 4 mg/kg/d (43+/-3%) oxypurinol vs placebo (30+/-2, p<0.05), while 40 mg/kg/d oxypurinol (41+/-5%) did not reach statistical significance. Cardiac output was increased in the 4 mg/kg/d dose only (71+/-11 mL/min vs placebo 38+/-4 mL/min, p<0.01). CONCLUSION: Inhibition of XO with oxypurinol has beneficial effects on cardiac mass and function in a rat model of severe cancer cachexia, suggesting that XO might be a viable drug target in cancer cachexia. PMID- 23751351 TI - Noncompliance with guidelines for the treatment of hepatitis C is frequent in daily practice. AB - PURPOSE: In trials of pegylated interferons (PEG-IFNs), the lack of an early virological response (EVR) was associated with sustained virological response (SVR) rates of only 0-3%. The rates were similarly low when hepatitis C virus (HCV)-RNA was positive at week 24. Treatment guidelines therefore recommend 'stop rules' on the basis of HCV-RNA levels at weeks 12 and 24 of treatment. We analyzed the use of these rules under 'real-life' conditions. PATIENTS AND METHODS: This was a prospective, community-based cohort study involving 467 physicians from institutions throughout Germany, including 4727 treatment-naive genotype-1 patients who received a full course of treatment with PEG-IFN alpha-2a plus ribavirin between 2003 and 2009. RESULTS: The overall SVR rate was 43.1%. Failure to determine EVR decreased from 20% in 2003-2004 to 10% in 2006-2007. Unexpectedly, treatment was continued in 86.1% of patients without an EVR and in those who had an EVR but were HCV-RNA positive at week 24 (67.5%), resulting in SVR rates of 15.7 and 40.9%, respectively. Between 77.5 and 95.3% of physicians did not follow prescribed recommendations to reduce PEG-IFN or ribavirin in cases of hematological abnormalities. CONCLUSION: Although recommendations to assess EVR and HCV-RNA at week 24 were increasingly observed in daily practice, the corresponding 'stop rules' in nonresponders were neglected. The subsequent SVR was 5-10 times higher than that reported in controlled trials. This may partly be because of the fact that reductions in PEG-IFN or ribavirin dose were not performed despite recommendations. The issue of stop rules will gain even more interest since the first HCV protease inhibitors have been approved. Prolongation of treatment beyond the new stop rules is associated with risks of resistant HCV variants. Thus, the new stop rules are to be observed more strictly when compared with previous therapy with interferons and ribavirin. PMID- 23751352 TI - Downregulation of microRNA-206 is a potent prognostic marker for patients with gastric cancer. AB - BACKGROUND: MicroRNA-206 (miR-206), as a homolog of miR-1, plays important roles in tumorigenesis and tumor progression of various human malignancies, including breast cancer, endometrial endometrioid carcinoma, rhabdomyosarcoma, glioma, lung cancer, and laryngeal cancer. However, its involvement in gastric cancer has remained unclear. AIM: To examine the expression patterns and clinical implications of miR-206 in gastric cancer. MATERIALS AND METHODS: Quantitative RT PCR was performed to evaluate the expression levels of miR-206 in 98 pairs of gastric cancer and normal adjacent mucosa. In addition, the clinicopathologic significance and the prognostic value of miR-206 expression were further determined. RESULTS: At first, miR-206 expression was significantly downregulated in gastric cancer tissues when compared with normal adjacent mucosa (P<0.001). Next, tumors with low miR-206 expression had a greater extent of lymph node metastasis (P=0.01), presence of venous invasion (P=0.008), and hematogenous recurrence (P=0.01), and were at a worse stage (P=0.03) than the tumors with a high miR-206 expression. Then, the gastric cancer patients with a low miR-206 expression had shorter overall survival than those with a high miR-206 expression (P=0.02). Furthermore, multivariate analysis showed that miR-206 expression was an independent prognostic factor for patients with gastric cancer. CONCLUSION: Our results strongly suggest that the downregulation of miR-206 was significantly correlated with tumor progression and may be a potent prognostic marker of gastric cancer. miR-206 might serve as a promising therapeutic target for the treatment of this cancer. PMID- 23751353 TI - Double-balloon enteroscopy in the elderly with obscure gastrointestinal bleeding: safety and feasibility. AB - BACKGROUND: Double-balloon enteroscopy (DBE) is a novel endoscopic procedure to access the small bowel. There is paucity of data on its use in the elderly. OBJECTIVE: The aim of this study was to assess the utility of DBE in patients with obscure gastrointestinal bleeding (OGB) in terms of safety and feasibility. MATERIALS AND METHODS: A prospective review of consecutive patients who underwent DBE for OGB was conducted. Data were collected on demographics, dose of sedation/analgesia, diagnostic yield, and management and complications. Patients were divided into group 1, age of at least 70 years, and group 2, age less than 70 years. RESULTS: A total of 148 DBE procedures were carried out for OGB. Group 1 (age>=70 years) comprised 27% (n=40) of the cohort with a mean age of 77 years (range 70-83 years). The mean age in group 2 (n=108) was 54 years, 44% women. The diagnostic yield in group 1 was 53 versus 35% in group 2 (P=0.06). Subsequent management was altered more frequently in group 1 (50 vs. 28%, P=0.01, odds ratio 2.6, 95% confidence interval 1.2-5.5). Sedation requirement was less in the elderly (median dose of midazolam, group 1: 4.5 mg versus group 2: 6 mg, P<0.001; fentanyl, group 1: 50 mcg vs. group 2: 75 mcg, P<0.001). There was no significant difference in complications between the two groups (0/40 vs. 1/108, P=0.54). On logistic regression, increasing age (P=0.008) was associated with a higher yield with DBE in all patients. CONCLUSION: DBE is safe, has a high diagnostic yield and has a positive impact on patient management in the elderly. PMID- 23751354 TI - Early prenatal diagnosis of orofacial clefts: evaluation of the retronasal triangle using a new three-dimensional reslicing technique. AB - BACKGROUND: The role of three-dimensional ultrasound in the prenatal diagnosis of orofacial clefts is increasing in recent time. MATERIALS AND METHODS: We obtained three-dimensional data sets of the fetal face from 100 low-risk and 50 high-risk first-trimester fetuses to evaluate the offline reformatting accuracy of the retronasal triangle (RNT) using a novel reslicing technique. RESULTS: Adequate volume data sets for offline analysis were captured in 98% of cases. The RNT view was reformatted in 96% of cases by offline analysis. The secondary palate could be assessed in 93% by offline analysis and an abnormal RNT in the coronal plane was detected in 2 cases of lethal aneuploidy. The false-positive rate was 1.33% in the two studied groups. CONCLUSION: Abnormal RNT seems to be a valuable ultrasound marker for the early diagnosis of facial clefting. This novel reslicing technique has proven to be easy, fast and accurate, which suggest that this technology could be included in daily practice and integrated with other applications such as multiplanar mode and volume NT. Prospective studies are needed to confirm these promising results and to demonstrate if these diagnostic armamentarium tools will lead to a diagnostic enhancement of cleft lip and palate in early pregnancy. PMID- 23751355 TI - Mechanisms of fluoroquinolone resistance in Vibrio parahaemolyticus. PMID- 23751356 TI - Inadequate nutrient intake in patients with celiac disease: results from a German dietary survey. AB - BACKGROUND: Currently, the only treatment for celiac disease (CD) is a lifelong gluten-free diet (GFD). Research has been carried out in various countries into the nutritional adequacy of the GFD in terms of macro- and micronutrients, mostly presenting conflicting results. However, no data for Germany are available to date. AIM: To elucidate the nutritional composition of a GFD and to compare it with non-GFD in a representative German non-CD population. METHODS AND PATIENTS: A total of 1,000 patients who were members of the German Celiac Society (DZG) were invited to fill out a prospective 7-day food diary and a questionnaire. Data from 88 patients aged 14-80 years were analyzed and compared to the DACH reference values and to data from the German National Diet and Nutrition Survey (NVS II). RESULTS: No significant difference was observed for the intake of energy and macronutrients in male celiac patients compared to the NVS II. Only the fiber intake of male patients was significantly lower than that of the general population. Female patients, however, showed a significantly higher fat intake, but lower carbohydrate consumption. The average daily micronutrient intake of male and female patients, specifically of vitamin B1, B2, B6, folic acid, magnesium and iron, was significantly lower in celiac patients compared to the NVS II. CONCLUSION: This study reveals inadequate nutrient intake by male and female celiac patients in Germany. Based on our findings, regular (laboratory) monitoring of celiac patients should be recommended. PMID- 23751358 TI - Sleep modulation of epileptic activity in mesial and neocortical temporal lobe epilepsy: a study with depth and subdural electrodes. AB - This study characterizes the spatial-temporal distribution of epileptic activity in mesial and neocortical temporal lobe epilepsy (TLE) assessed by subdural and depth electrodes during sleep. We determined in 13 patients the frequency, lateralization, and localization of interictal epileptic discharges (IEDs). As compared to the waking state, IEDs increased in light sleep (196%, p < 0.05) and in deep sleep (601%, p < 0.05) but did not change significantly in REM sleep ( 8.33%, p = 0.94). From 11 patients with unilateral TLE, in all cases, IEDs lateralized to the seizure onset side during REM sleep and the waking state. In mesial TLE, IEDs tended to shift in an anterior-posterior axis and remained always localized in the amygdalo-hippocampal complex. By contrast, in neocortical TLE, the maximal activity moved in a mesial-lateral axis between neocortical and mesial structures. Twenty-six seizures were registered in 7 patients, 22 of which occurred in light sleep and 4 in wakefulness, but none occurred in deep or REM sleep. PMID- 23751359 TI - Synthesis of bacteria promoted reduced graphene oxide-nickel sulfide networks for advanced supercapacitors. AB - Supercapacitors with potential high power are useful and have attracted much attention recently. Graphene-based composites have been demonstrated to be promising electrode materials for supercapacitors with enhanced properties. To improve the performance of graphene-based composites further and realize their synthesis with large scale, we report a green approach to synthesize bacteria reduced graphene oxide-nickel sulfide (BGNS) networks. By using Bacillus subtilis as spacers, we deposited reduced graphene oxide/Ni3S2 nanoparticle composites with submillimeter pores directly onto substrate by a binder-free electrostatic spray approach to form BGNS networks. Their electrochemical capacitor performance was evaluated. Compared with stacked reduced graphene oxide-nickel sulfide (GNS) prepared without the aid of bacteria, BGNS with unique nm-MUm structure exhibited a higher specific capacitance of about 1424 F g(-1) at a current density of 0.75 A g(-1). About 67.5% of the capacitance was retained as the current density increased from 0.75 to 15 A g(-1). At a current density of 75 A g(-1), a specific capacitance of 406 F g(-1) could still remain. The results indicate that the reduced graphene oxide-nickel sulfide network promoted by bacteria is a promising electrode material for supercapacitors. PMID- 23751357 TI - Genome editing of human pluripotent stem cells to generate human cellular disease models. AB - Disease modeling with human pluripotent stem cells has come into the public spotlight with the awarding of the Nobel Prize in Physiology or Medicine for 2012 to Drs John Gurdon and Shinya Yamanaka for the discovery that mature cells can be reprogrammed to become pluripotent. This discovery has opened the door for the generation of pluripotent stem cells from individuals with disease and the differentiation of these cells into somatic cell types for the study of disease pathophysiology. The emergence of genome-editing technology over the past few years has made it feasible to generate and investigate human cellular disease models with even greater speed and efficiency. Here, recent technological advances in genome editing, and its utility in human biology and disease studies, are reviewed. PMID- 23751360 TI - Histopathological investigation of neuroprotective effects of Nigella sativa on motor neurons anterior horn spinal cord after sciatic nerve crush in rats. AB - The aim of this study was designed to evaluate the possible protective effects of Nigella sativa (NS) on the neuronal injury in the sciatic nerve of rats. The rats were randomly allotted into one of the three experimental groups: A (control), B (only trauma) and C (trauma and treated with NS); each group contain 10 animals. Sciatic nerve injury was performed by placing an aneurysm clip on the left leg. Rats were neurologically tested over 24h after trauma. The rats in NS-treated group was given NS (in a dose of 400mg/kg body weight) once a day orally for 30 days starting just after trauma. Control and untreated (only trauma) rats were injected with the same volume of isotonic NaCl as the treated animals that received NS. Tissue samples were obtained for histopathological investigation. To date, no histopathological changes of neurodegeneration in the sciatic nerve after trauma in rats by NS treatment have been reported. Results showed in the group B (only trauma), the neurons of sciatic nerve tissue became extensively dark and degenerated with picnotic nuclei. Treatment of NS markedly reduced degenerating neurons after trauma and the distorted nerve cells were mainly absent in the NS-treated rats. The morphology of neurons in groups treated with NS was well protected, but not as neurons of the control group. The number of neurons in sciatic nerve tissue of group B (only trauma) was significantly less than both control and treated with NS groups. The morphology of neurons revealed that the number of neurons were significantly less in group B compared to control (P<0.001) and group C (P<0.01) rats' motor neurons anterior horn spinal cord tissue. We conclude that NS therapy causes morphologic improvement on neurodegeneration in sciatic nerve after trauma in rats. PMID- 23751361 TI - Reynosin protects against neuronal toxicity in dopamine-induced SH-SY5Y cells and 6-hydroxydopamine-lesioned rats as models of Parkinson's disease: Reciprocal up regulation of E6-AP and down-regulation of alpha-synuclein. AB - Aggregation of alpha-synuclein (ASYN) is considered a major determinant of neuronal loss in Parkinson's disease (PD). E6-associated protein (E6-AP), an E3 ubiquitin protein ligase, has been known to promote the degradation of alpha synuclein. The aim of this study was to assess the effects of the sesquiterpene lactone reynosin on dopamine (DA)-induced neuronal toxicity and regulation of E6 associated protein and alpha-synuclein proteins in both in vitro and in vivo models of Parkinson's disease. Usi"ng flow cytometry and western blot analysis, we determined that reynosin significantly protected both against cell death from dopamine-induced toxicity in human neuroblastoma SH-SY5Y cells and against the loss of tyrosine hydroxylase (TH)-positive cells in 6-hydroxydopamine (6-OHDA) lesioned rats (a rodent Parkinson's disease model system). In addition, reynosin made up-regulation of E6-associated protein expression and down-regulation of the over-expression of alpha-synuclein protein in both dopamine-treated SH-SY5Y cells and 6-hydroxydopamine-lesioned rats. These results suggest that the protective effect of reynosin against dopamine-induced neuronal cell death may be due to the reciprocal up-regulation of E6-associated protein and down-regulation of alpha synuclein protein expression. PMID- 23751363 TI - Endothelin-1 downregulates angiotensin-converting enzyme-2 expression in human bronchial epithelial cells. AB - BACKGROUND/AIMS: Both endothelin-1 (ET-1) and the renin-angiotensin system (RAS) are implicated in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). In the present study, we explored the interaction between ET-1 and the RAS by examining the effect of ET-1 on angiotensin converting enzyme-2 (ACE2) expression and activity in human bronchial epithelial cells (HBEpCs). METHODS: HBEpCs were treated with ET-1 (1, 10, 20, 40 or 50 nmol/l) for 6, 12, 18, 24 or 30 h with or without the transcription inhibitor actinomycin D, endothelin A (ETA) receptor blocker BQ123, endothelin B receptor blocker BQ788, or different kinase inhibitors. RESULTS: ET-1 decreased the ACE2 mRNA level in a dose- and time-dependent manner within 24 h, which led to dose dependent downregulation of the ACE2 promoter activity, protein level and the cell membrane ACE2 activity. Actinomycin D (1 mg/ml), BQ123 (1 MUmol/l), and the p38 mitogen-activated protein kinase (MAPK) siRNA and inhibitor PD169316 (25 MUmol/l) completely abolished the effect of ET-1 on ACE2 expression in HBEpCs. CONCLUSION: ET-1 downregulates ACE2 expression and activity at the transcription level in HBEpCs via the ETA receptor by a p38 MAPK-dependent mechanism. This is the first evidence of crosstalk between the ET-1/ETA axis and the RAS in regard to the pathogenesis and progression of COPD. PMID- 23751362 TI - Differential subcellular localization of the glucocorticoid receptor in distinct neural stem and progenitor populations of the mouse telencephalon in vivo. AB - Glucocorticoids are given to pregnant women at risk for premature delivery to promote lung maturation. Despite reports of detrimental effects of glucocorticoids on telencephalic neural stem/progenitor cells (NSPCs), the regional and cellular expressions of the glucocorticoid receptor (GR) in various NSPC populations in the intact brain have not been thoroughly assessed. Therefore in this study we performed a detailed analysis of GR protein expression in the developing mouse ventral and dorsal telencephalon in vivo. At embryonic day 11.5 (E11.5), the majority of Pax6-positive radial glial cells (RGCs) and Tbr2 positive intermediate progenitor cells (IPCs) expressed nuclear GR, while a small number of RGCs on the apical ventricular zone (aVZ), expressed cytoplasmic GR. However, on E13.5, the latter population of RGCs increased in size, whereas abventricular NSPCs and especially neurons of the cortical plate, expressed nuclear GR. In IPCs, GR was always nuclear. A similar expression profile was observed throughout the ventral telencephalon, hippocampus and olfactory bulb, with NSPCs of the aVZ primarily expressing cytoplasmic GR, while abventricular NSPCs and mature cells primarily expressed nuclear GR. Close to birth, nuclear GR accumulated within specific cortical areas such as layer V, the subplate and CA1 area of the hippocampus. In summary, our data show that GR protein is present in early NSPCs of the dorsal and ventral telencephalon at E11.5 and primarily occupies the nucleus. Moreover, our study suggests that the subcellular localization of the receptor may be subjected to region and neurodevelopmental stage-specific regulation. PMID- 23751364 TI - In-line capillary electrophoretic evaluation of the enantioselective metabolism of verapamil by cytochrome P3A4. AB - In this paper a methodology for the in-line evaluation of enantioselective metabolism by capillary electrophoresis has been developed and applied to the study of verapamil metabolism by cytochrome P3A4. The developed methodology comprises an in-capillary reaction step carried out by electrophoretically mediated microanalysis and a separation step in which highly sulfated beta cyclodextrin with partial filling technique has been employed as chiral selector for verapamil and norverapamil enantiomers resolution, joining the advantages of both methodologies in a unique assay. Kinetic parameters of the enzymatic reaction (Km and Vmax) have been evaluated for both verapamil enantiomers by non linear fitting of experimental data obtained under intermediate precision conditions to Michaelis-Menten equation. Km and Vmax estimated values were 51+/-9 MUM and 22+/-2 pmol min(-1) (pmol CYP)(-1) for S-VER and 47+/-9 MUM and 21+/-2 pmol min(-1) (pmol CYP)(-1) for R-VER. Consequently, slight enantioselectivity was found for the CYP3A4 metabolism of verapamil. However, since confidence intervals of estimates overlap, we cannot assure a significant enantioselectivity. Intrinsic clearance values were also estimated from Km and Vmax for both enantiomers. PMID- 23751365 TI - Application of a strong anion exchange material in electrostatic repulsion hydrophilic interaction chromatography for selective enrichment of glycopeptides. AB - Glycoproteins are involved in various cellular activities, including inter- and extracellular signaling. However, glycopeptide signals are significantly suppressed by coeluting non-glycosylated peptides in mass spectrometry-based analysis. For detailed elucidation of the biological functions of glycoproteins, selective enrichment of glycopeptides from non-glycosylated peptides is crucial. In the present study, a SAX material, XCharge SAX, was used in a column in the ERLIC mode with the aim of specifically enriching glycopeptides. Enrichment conditions were initially optimized, and selectivity, glycosylation heterogeneity coverage and detection sensitivity of XCharge SAX were subsequently assessed. In the selectivity assessment, glycopeptides were effectively isolated from a peptide mixture (human serum immunoglobulin G (IgG) and human serum albumin digests) and a tryptic digest of human serum using XCharge SAX. In the evaluation of glycosylation heterogeneity coverage, five glycosites and eleven glycopeptides from horseradish peroxidase were identified after enrichment with XCharge SAX. In detection sensitivity assessment, glycopeptides within four orders of magnitude were identified after enrichment with XCharge SAX. In addition, volatile solvents were used in the loading and eluting buffers so that desalting was not necessary for ERLIC fractions. Our results collectively support the utility of XCharge SAX as a suitable chromatographic material for global glycosylation site analysis. PMID- 23751366 TI - Genuine cross-correlations: which surrogate based measure reproduces analytical results best? AB - The analysis of short segments of noise-contaminated, multivariate real world data constitutes a challenge. In this paper we compare several techniques of analysis, which are supposed to correctly extract the amount of genuine cross correlations from a multivariate data set. In order to test for the quality of their performance we derive time series from a linear test model, which allows the analytical derivation of genuine correlations. We compare the numerical estimates of the four measures with the analytical results for different correlation pattern. In the bivariate case all but one measure performs similarly well. However, in the multivariate case measures based on the eigenvalues of the equal-time cross-correlation matrix do not extract exclusively information about the amount of genuine correlations, but they rather reflect the spatial organization of the correlation pattern. This may lead to failures when interpreting the numerical results as illustrated by an application to three electroencephalographic recordings of three patients suffering from pharmacoresistent epilepsy. PMID- 23751367 TI - A novel Ebola virus expressing luciferase allows for rapid and quantitative testing of antivirals. AB - Ebola virus (EBOV) causes a severe hemorrhagic fever with case fatality rates of up to 90%, for which no antiviral therapies are available. Antiviral screening is hampered by the fact that development of cytopathic effect, the easiest means to detect infection with wild-type EBOV, is relatively slow. To overcome this problem we generated a recombinant EBOV carrying a luciferase reporter. Using this virus we show that EBOV entry is rapid, with viral protein expression detectable within 2 h after infection. Further, luminescence-based assays were developed to allow highly sensitive titer determination within 48 h. As a proof of-concept for its utility in antiviral screening we used this virus to assess neutralizing antibodies and siRNAs, with significantly faster screening times than currently available wild-type or recombinant viruses. The availability of this recombinant virus will allow for more rapid and quantitative evaluation of antivirals against EBOV, as well as the study of details of the EBOV life cycle. PMID- 23751368 TI - A case of globular glial tauopathy presenting clinically as alzheimer disease. PMID- 23751369 TI - The red cell distribution width and anemia in association with prevalent dementia. AB - The red cell distribution width (RDW), a measure of anisocytosis, independently predicts cardiovascular disease outcomes and chronic disease mortality. Little is known about the RDW, or the interplay between RDW and anemia, in relation to dementia risk. We evaluated the association between the RDW and prevalent dementia, overall and by anemia status, among 2556 community-dwelling older adults participating in the Chicago Health and Aging Project. RDW measurements came from complete blood counts, and participants underwent diagnosis for dementia according to standard clinical criteria. Five hundred twenty-five participants were diagnosed with dementia. Elevated RDW was associated with increased odds of having dementia: after adjusting for age, sex, race, and education, the odds of prevalent dementia increased progressively over increasing quartile of RDW (Ptrend=0.02), and persons in the highest RDW quartile (>=14.8%) had 42% greater odds of having dementia than those in the lowest quartile [odds ratio (OR), 1.42; 95% confidence interval (CI), 1.05-1.92)]. Per unit (%) increment in RDW, the odds of dementia were higher by 6% (OR, 1.06; 95% CI, 1.00 1.13). Findings were similar upon further adjustment for health behaviors and diabetes. In analyses adjusted for hemoglobin concentration, the RDW-dementia association was attenuated, whereas the inverse association between hemoglobin and dementia remained significant. However, RDW was associated with dementia more strongly among participants without anemia (OR, 1.09; 95% CI, 1.00-1.43) than among those with anemia (OR, 0.99; 95% CI, 0.86-1.18), although this difference was not statistically significant. The RDW, a readily available and inexpensive hematologic measure, may offer novel information about dementia risk, particularly among persons without anemia. Future studies should establish the RDW's ability to predict risk prospectively. PMID- 23751370 TI - Need for and challenges facing functional communication as outcome parameter in AD clinical trials. AB - This paper (1) highlights the relevance of functional communication as an outcome parameter in Alzheimer disease (AD) clinical trials; (2) identifies studies that have reported functional communication outcome measures in AD clinical trials; (3) critically reviews the scales of functional communication used in recent AD clinical trials by summarizing the sources of information, characteristics, and available psychometric data for these scales; and (4) evaluates whether these measures actually or partially assess functional communication. To provide direction for future research and generate suggestions to assist in the development of a valid and reliable functional communication scale for the needs of AD clinical trials, we have included not only functional communication scales, but also related concepts that give thought-provoking impulses for the development of a functional communication scale. As outcome measures for AD clinical trials, the 6 identified papers use 6 different scales, for functional communication and for related concepts. All of the scales appear to have questionable psychometric properties, but still provide a promising basis for the creation of a functional communication scale. We conclude with concrete suggestions on how to combine the advantages of the existing scales for future research aimed at developing a valid and reliable functional communication scale for the needs of AD clinical trials. PMID- 23751371 TI - Cortical and subcortical atrophy in Alzheimer disease: parallel atrophy of thalamus and hippocampus. AB - Brain atrophy is a key imaging hallmark of Alzheimer disease (AD). In this study, we carried out an integrative evaluation of AD-related atrophy. Twelve patients with AD and 13 healthy controls were enrolled. We conducted a cross-sectional analysis of total brain tissue volumes with SIENAX. Localized gray matter atrophy was identified with optimized voxel-wise morphometry (FSL-VBM), and subcortical atrophy was evaluated by active shape model implemented in FMRIB's Integrated Registration Segmentation Toolkit. SIENAX analysis demonstrated total brain atrophy in AD patients; voxel-based morphometry analysis showed atrophy in the bilateral mediotemporal regions and in the posterior brain regions. In addition, regarding the diminished volumes of thalami and hippocampi in AD patients, subsequent vertex analysis of the segmented structures indicated shrinkage of the bilateral anterior thalami and the left medial hippocampus. Interestingly, the volume of the thalami and hippocampi were highly correlated with the volume of the thalami and amygdalae on both sides in AD patients, but not in healthy controls. This complex structural information proved useful in the detailed interpretation of AD-related neurodegenerative process, as the multilevel approach showed both global and local atrophy on cortical and subcortical levels. Most importantly, our results raise the possibility that subcortical structure atrophy is not independent in AD patients. PMID- 23751372 TI - Oncological outcome of primary versus secondary muscle-invasive bladder cancer is comparable after radical cystectomy. AB - BACKGROUND: High-risk non-muscle-invasive bladder cancer (NMIBC) progressing to muscle-invasive bladder cancer (MIBC) is associated with adverse tumour biology. It is unclear, however, whether outcome of NMIBC progressing to MIBC is adverse compared to primary MIBC and whether NMIBC of higher risk of progression to MIBC is adverse compared to NMIBC of lower risk. OBJECTIVE: Our objective was to assess cancer-specific survival (CSS) following radical cystectomy (RC) for primary MIBC and for NMIBC progressing to MIBC in dependence of EORTC risk score. MATERIALS AND METHODS: Clinical and histopathological characteristics and CSS of 150 patients were assessed. Secondary MIBCs were stratified by EORTC risk score at the last transurethral resection of bladder tumour for NMIBC. RESULTS: CSS did not differ significantly between primary and secondary MIBC (p = 0.521). Secondary MIBC with high EORTC score had significantly shorter CSS compared to secondary MIBC with intermediate EORTC score (p = 0.029). In multivariable analysis, pathological tumour stage (HR = 3.77; p = 0.020) and lymph node stage (HR = 2.34; p = 0.022) were significantly correlated with CSS. CONCLUSION: While the outcome of secondary MIBC is not generally adverse compared to primary MIBC, the EORTC risk score not only reflects high risk of progression of NMIBC to MIBC, but also worse outcome following RC for secondary MIBC. Timely RC should thus be debated in high-risk NMIBC. PMID- 23751373 TI - Detection of viruses directly from the fresh leaves of a Phalaenopsis orchid using a microfluidic system. AB - Early detection of pathogens is crucial for the effective surveillance of diseases. Many efforts have been made to explore methods which can detect these pathogens within a short period of time without requiring a tedious protocol. However, these developed methods have disadvantages such as they are relatively time-consuming or require specialized laboratory facilities. In this work, we have developed an integrated microfluidic system for rapid and automatic detection of viruses by direct analysis from fresh Phalaenopsis orchid leaves. The entire protocol, including ribonucleic acid (RNA) purification, reverse transcription loop-mediated-isothermal-amplification (RT-LAMP) and optical detection by measuring changes in turbidity was performed on a single chip. This is the first time that an integrated microfluidic system for the detection of viruses infecting the Phalaenopsis orchid has been demonstrated. The sensitivity of the developed system was also explored in this study to validate its performance. FROM THE CLINICAL EDITOR: In this study, the authors report the development of an integrated microfluidic system for rapid and automatic detection of viruses by direct analysis of fresh Phalaenopsis orchid leaves, performing the 3-step protocol using a single chip. Similar methods may find clinical application for fast and accurate detection of viral infections. PMID- 23751374 TI - An integrative approach for the large-scale identification of human genome kinases regulating cancer metastasis. AB - Kinases become one of important groups of drug targets. To identify more kinases being potential for cancer therapy, we developed an integrative approach for the large-scale screen of functional genes capable of regulating the main traits of cancer metastasis. We first employed self-assembled cell microarray to screen functional genes that regulate cancer cell migration using a human genome kinase siRNA library. We identified 81 genes capable of significantly regulating cancer cell migration. Following with invasion assays and bio-informatics analysis, we discovered that 16 genes with differentially expression in cancer samples can regulate both cell migration and invasion, among which 10 genes have been well known to play critical roles in the cancer development. The remaining 6 genes were experimentally validated to have the capacities of regulating cell proliferation, apoptosis and anoikis activities besides cell motility. Together, these findings provide a new insight into the therapeutic use of human kinases. FROM THE CLINICAL EDITOR: This team of authors have utilized a self-assembled cell microarray to screen genes that regulate cancer cell migration using a human genome siRNA library of kinases. They validated previously known genes and identified novel ones that may serve as therapeutic targets. PMID- 23751375 TI - Magnetic nanoparticle mediated transfection of neural stem cell suspension cultures is enhanced by applied oscillating magnetic fields. AB - Safe genetic modification of neural stem cell (NSC) transplant populations is a key goal for regenerative neurology. We describe a technically simple and safe method to increase transfection in NSCs propagated in the neurosphere (suspension culture) model, using magnetic nanoparticles deployed with applied oscillating magnetic fields ('magnetofection technology'). We show that transfection efficiency was enhanced over two-fold by oscillating magnetic fields (frequency=4 Hz). The protocols had no effect on cell viability, cell number, stem cell marker expression and differentiation profiles of 'magnetofected' cultures, highlighting the safety of the technique. As far as we are aware, this is the first successful application of magnetofection technology to suspension cultures of neural cells. The procedures described offer a means to augment the therapeutic potential of NSCs propagated as neurospheres - a culture model of high clinical translational relevance - by safe genetic manipulation, with further potential for incorporation into 'magneto-multifection' (repeat transfection) protocols. FROM THE CLINICAL EDITOR: This team of investigators describe a simple and safe method to increase transfection in neural stem cells using magnetic nanoparticles deployed with oscillating magnetic fields, demonstrating a greater than two-fold transfection efficiency increase by applying low frequency magnetic oscillation. PMID- 23751376 TI - Genetic and genomic interactions of animals with different ploidy levels. AB - Polyploid animals have independently evolved from diploids in diverse taxa across the tree of life. We review a few polyploid animal species or biotypes where recently developed molecular and cytogenetic methods have significantly improved our understanding of their genetics, reproduction and evolution. Mitochondrial sequences that target the maternal ancestor of a polyploid show that polyploids may have single (e.g. unisexual salamanders in the genus Ambystoma) or multiple (e.g. parthenogenetic polyploid lizards in the genus Aspidoscelis) origins. Microsatellites are nuclear markers that can be used to analyze genetic recombinations, reproductive modes (e.g. Ambystoma) and recombination events (e.g. polyploid frogs such as Pelophylax esculentus). Hom(e)ologous chromosomes and rare intergenomic exchanges in allopolyploids have been distinguished by applying genome-specific fluorescent probes to chromosome spreads. Polyploids arise, and are maintained, through perturbations of the 'normal' meiotic program that would include pre-meiotic chromosome replication and genomic integrity of homologs. When possible, asexual, unisexual and bisexual polyploid species or biotypes interact with diploid relatives, and genes are passed from diploid to polyploid gene pools, which increase genetic diversity and ultimately evolutionary flexibility in the polyploid. When diploid relatives do not exist, polyploids can interact with another polyploid (e.g. species of African Clawed Frogs in the genus Xenopus). Some polyploid fish (e.g. salmonids) and frogs (Xenopus) represent independent lineages whose ancestors experienced whole genome duplication events. Some tetraploid frogs (P. esculentus) and fish (Squaliusalburnoides) may be in the process of becoming independent species, but diploid and triploid forms of these 'species' continue to genetically interact with the comparatively few tetraploid populations. Genetic and genomic interaction between polyploids and diploids is a complex and dynamic process that likely plays a crucial role for the evolution and persistence of polyploid animals. See also other articles in this themed issue. PMID- 23751377 TI - Prostate radiotherapy clinical trial quality assurance: how real should real time review be? (A TROG-OCOG Intergroup Project). AB - BACKGROUND AND PURPOSE: Review of plans early in treatment offers the potential to reduce the chance of sub-optimal treatment delivery. We compare the use of real time reviews (RTR) either before randomization (pre-rand 3D RTR) or following randomization (post-rand 2D RTR). MATERIALS AND METHODS: PROFIT is an international randomised trial for men with prostate cancer which had credentialing via multiple dummy runs. In Australia, but not Canada, all plans were submitted for pre-rand 3D RTR using 3D software, and resubmission was requested if significant protocol deviations (PD) were seen. All plans from Canada and Australia then underwent post-rand 2D RTR using a 2D assessment. RESULTS: For 147 Australian patients, pre-rand 3D RTR was fast (median 1 day, 95% range 0-4 days). 51 minor and 5 major PD were observed and 15 of the 147 cases (10%) required resubmission. Of the 5 major PD, 4 were remedied on resubmission and 1 was withdrawn from study. For the post-rand 2D RTR, reports from 147 Australian cases and 193 Canadian cases were reviewed. No major PD were reported from Australian cases, but 3 were seen in Canadian cases (0% versus 1.5%; p=0.26). There was also no difference in the rate of minor PD (14.3% versus 15.3%; p=NS). CONCLUSIONS: In a study using relatively simple treatment volumes after comprehensive credentialing, pre-rand 3D RTR offers only modest benefits compared with post-rand 2D RTR. In the future the intensity of RTR may need to vary according to protocol and site specific factors. PMID- 23751378 TI - Frequency, outcome and prognostic factors of carotid blowout syndrome after hypofractionated re-irradiation of head and neck cancer using CyberKnife: a multi institutional study. AB - PURPOSE: Re-irradiation has attracted attention as a potential therapy for recurrent head and neck tumors. However, carotid blowout syndrome (CBS) has become a serious complication of re-irradiation because of the associated life threatening toxicity. Determining of the characteristics of CBS is important. We conducted a multi-institutional study. METHODS AND PATIENTS: Head and neck carcinoma patients (n=381) were treated with 484 re-irradiation sessions at 7 Japanese CyberKnife institutions between 2000 and 2010. RESULTS: Of these, 32 (8.4%) developed CBS, which proved fatal that median survival time after CBS onset was 0.1 month, and the 1-year survival rate was 37.5%. The median duration between re-irradiation and CBS onset was 5 months (range, 0-69 months). Elder age, skin invasion, and necrosis/infection were identified as statistically significant risk factors after CBS by univariate analysis. The presence of skin invasion at the time of treatment found only in postoperative case, is identified as only statistically significant prognostic factor after CBS in multivariate analysis. The 1-year survival rate for the group without skin invasion was 42%, whereas no patient with skin invasion survived more than 4 months (0% at 1 year, p=0.0049). CONCLUSIONS: Careful attention should be paid to the occurrence of CBS if the tumor is located adjacent to the carotid artery. The presence of skin invasion at CBS onset is ominous sign of lethal consequences. PMID- 23751379 TI - Characterization of magnetic nanoparticle systems with respect to their magnetic particle imaging performance. AB - The optimization of magnetic nanoparticles (MNPs) as markers for magnetic particle imaging (MPI) requires an understanding of the relationship between the harmonics spectrum and the structural and magnetic properties of the MNPs. Although magnetic particle spectroscopy (MPS) - carried out at the same excitation frequency as the given MPI system - represents a straightforward technique to study MNPs for their suitability for MPI, a complete understanding of the mechanisms and differences between different tracer materials requires additional measurements of the static and dynamic magnetic behavior covering additional field and time ranges. Furthermore, theoretical models are needed, which correctly account for the static and dynamic magnetic properties of the markers. In this paper, we give an overview of currently used theoretical models for the explanation of amplitude and phase of the harmonics spectra as well as of the various static and dynamic magnetic techniques, which are applied for the comprehensive characterization of MNPs for MPI. We demonstrate on two multicore MNP model systems, Resovist((r)) and FeraSpinTM Series, how a detailed picture of the MPI performance can be obtained by combining various static and dynamic magnetic measurements. PMID- 23751380 TI - Relaparotomies after cesarean sections: risk factors, indications, and management. AB - OBJECTIVE: To establish the frequency of post-cesarean relaparotomy, identify its risk factors, indications, and operative management. METHODS: This study was a retrospective matched case control study. Records of all women who underwent a cesarean section (CS) from July 2006 to March 2012 were reviewed. We identified all women who had a relaparotomy within 1 month from their CS. For each woman, two women were matched. We analyzed data regarding obstetrical history, current gestation, surgical parameters, and outcome. RESULTS: A total of 14,637 CS were performed during this period, of these, 58 cases required a relaparotomy (0.4%). In univariate analysis, female sex and duration of CS were associated with an increased risk for relaparotomy. In multivariate analysis, multiple pregnancies, general anesthesia, duration of operation, and female sex, independently increased the risk for relaparotomy. The leading indications for relaparotomy were hemodynamic shock and subcutaneous hematoma. The most common interventions during relaparotomy were cauterization of subcutaneous vessels, and ligation of large vessels. Overall, women requiring relaparotomy received, on average, 16 units of blood products. CONCLUSIONS: This study highlights risk factors associated with post-cesarean relaparotomy. Surgeons might use this important data to identify women at risk beforehand, and thus, reduce the morbidity associated with relaparotomy. PMID- 23751381 TI - The impact of route of anesthesia on maternal and fetal ischemia modified albumin levels at cesarean section: a prospective randomized study. AB - OBJECTIVE: Ischemia modified albumin has been shown to increase in ischemic situations, and has also been shown to increase in fetal cord blood in deliveries by cesarean section. The aim of this study is to reveal whether anesthesia has an impact on maternal and fetal cord ischemia modified albumin levels. METHODS: Seventy two women with uncomplicated term pregnancies were randomized to spinal (n=37) or general anesthesia (n=35) groups. The blood pressure, oxygen saturation, and pulse rate of the patients were recorded during the procedure. Maternal blood samples of ischemia modified albumin (IMA) were taken 10 min from the start of the procedure. The fetal cord blood samples of IMA were taken immediately after birth. RESULTS: Maternal (0.99 +/- 0.19 vs. 0.80 +/- 0.27) and fetal (1.00 +/- 0.21 vs. 0.70 +/- 0.26) IMA levels were significantly higher in the general anesthesia group. Fetal IMA levels were positively correlated with maternal gravidity (r=0.31; P=0.008), parity (r=0.25; P=0.028), and fetal birth weight (r=0.23, P=0.045). Also, as time from incision to delivery lengthens, fetal IMA levels increase (r=0.29, P=0.012). CONCLUSION: Fetal cord ischemia modified albumin levels were higher in the general anesthesia group, therefore, it is proposed that regional anesthesia should be the preferred route of anesthesia for an elective cesarean section, at least until the impact of high fetal cord IMA levels are manifested. PMID- 23751382 TI - Lissencephaly presenting with congenital hypothyroidism. AB - Lissencephaly is a rare brain malformation characterized by a smooth cerebral surface, thickened cortical mantle and microscopic evidence of incomplete neuronal migration. Association of congenital hypothyroidism with lissencephaly is seldom reported. We report a case of lissencephaly with congenital hypothyroidism. PMID- 23751383 TI - Treatment of hyperinsulinemic hypoglycemia because of diffuse nesidioblastosis with nifedipine after surgical therapies in a newborn. AB - Recent studies have demonstrated a role for calcium channel blocking agents in the treatment of persistent hyperinsulinemic hypoglycemia of newborns. We report a newborn infant with persistent hyperinsulinemic hypoglycemia whom we successfully treated with oral nifedipine alone after surgical therapies. A 4-day old male infant was referred with intractable hypoglycemia and seziures. Normoglycaemia could be maintained only by the intravenous infusion of glucose at a rate of 20 mg/kg per minute. Persistent hyperinsulinemic hypoglycemia of newborn was diagnosed from an inappropriately raised plasma insulin concentration (44 mU/L) at the time of hypoglycemia. Medical treatments led to only a mild reduction in the intravenous glucose requirement; an 85-90% pancreatectomy was performed and histological "diffuse nesidioblastosis" was confirmed. However, despite all the medical treatments after the first pancreatectomy, the hyperinsulinemic hypoglycemia persisted and a second 95% pancreatectomy was performed. After the second pancreatectomy, persistent hyperinsulinemic hypoglycemia was treated with somatostatin and diazoxide, but led to no reduction in the intravenous glucose requirement. We report the case of an infant who had persistent hypoglycemia after two subtotal pancreatic resections but subsequently became normoglycemic on treatment with nifedipine (2 mg/kg per day). The patient was discharged home on oral nifedipine. Calcium channel blocking agents cuold be used with efficacy and safety in recurrent persistent hyperinsulinemic hypoglycemia. PMID- 23751384 TI - Clinical characteristics and management of cranial diabetes insipidus in infants. AB - AIM: Cranial diabetes insipidus (CDI) is rare in infants with no guidelines on its management. We describe the first case series, characterizing the clinical features and treatment challenges. METHOD: Retrospective case note review of infants diagnosed with CDI between April 1992 and February 2011. RESULTS: Nineteen infants (52% male) were identified. Eight were born preterm. Median (range) age at diagnosis was 24 days (5-300); preterm babies were younger at diagnosis (21 vs. 46 days). In 58% (11/19) of infants, hypernatraemia was discovered incidentally. In 37% of cases there was associated midline anomalies, however, only four patients (21%) had absent posterior pituitary signal on a magnetic resonance imaging brain scan. The most frequent (5/19) underlying diagnosis was septo-optic dysplasia. Eight patients had isolated CDI and 11 had multiple pituitary hormone deficiencies. Isolated CDI tended to be more common in preterm, compared to term babies (p=0.11). Des-amino arginine vasopressin (DDAVP) was administered intranasally in eight and orally in 11 infants. Plasma sodium nadir following DDAVP administration was lower following intranasal compared to an oral route of administration (median: 128 vs. 133 mmol/L, p=0.022). No cases resolved on follow-up. CONCLUSIONS: CDI in infants is often diagnosed incidentally. Aetiology, clinical, and imaging features are very variable, with some differences between preterm and term infants. Oral DDAVP appears to be superior to intranasal with less pronounced serum sodium fluctuations. PMID- 23751385 TI - Prevalence of metabolic syndrome among urban Indian adolescents and its relation with insulin resistance (HOMA-IR). AB - AIM: To assess prevalence of metabolic syndrome (MS) in urban Indian adolescents. MS in adolescents is a forerunner of diabetes mellitus and cardiovascular disease in adults, therefore, its identification provides an opportunity to intervene with lifestyle changes to prevent disease progression into adulthood. We randomly selected 900 adolescents (300 for each group) to participate in the study from a total of 15,101 adolescents (10-18 years) who were grouped as normal, overweight, and obese (total population). METHODS: From the 900 adolescents, 695 consented to participate in the study and underwent a detailed anthropometric and biochemical evaluation, therefore, these adolescents constituted the study population. MS was defined by criteria proposed by the International Diabetes Federation (MS-IDF) and the Adult Treatment Panel (MS-ATP). The prevalence of MS in the study population was used to calculate the prevalence of MS in the total population based on the distribution of the different BMI categories in this larger sample (n=15,101). RESULTS: Calculated prevalence of MS in urban Indian adolescents was 4.3% and 3.0% in the total population using MS-ATP and MS-IDF criteria, respectively. Among the study population, MS was higher in girls than boys (MS ATP, G: 22.3% vs. B: 16.6%, p=0.03; MS-IDF, G: 20.5% vs. B: 13.5%, p=0.006). The most common component of MS- ATP and MS-IDF was central obesity (89.8% vs. 100.0%, p<0.00001), followed by hypertriglyceridemia (83.0% vs. 82.2%, p=0.35), low high density lipoprotein-cholesterol (71.1% vs. 71.2%, p=0.48), hypertension (44.4% vs. 44.9%, p=0.025), and dysglycemia (40.0% vs. 34.7%, p=0.94). The mean serum insulin levels and HOMA-IR progressively increased with the increasing number of components present in an individual. CONCLUSIONS: Metabolic syndrome is common in urban Indian overweight and obese adolescents. PMID- 23751386 TI - Frequency and severity of ketoacidosis at onset of autoimmune type 1 diabetes over the past decade in children referred to a tertiary paediatric care centre: potential impact of a national programme highlighted. AB - AIMS: To assess the frequency and severity of diabetic ketoacidosis (DKA) at disease onset in children newly diagnosed with autoimmune type 1 diabetes (T1D) in Istanbul in the last decade. Also, to evaluate the potential contribution of the national diabetes awareness programme (NDAP) initiated in 2010. METHODS: Four hundred and one consecutive children (mean +/- standard deviation, age 8.1 +/- 4.1 years) with a diagnosis of autoimmune T1D were evaluated retrospectively with respect to demographic, clinical, and laboratory data in relation to DKA at disease onset. The possible impact of NDAP on the rate of DKA at disease onset in the last 2 years was also evaluated by comparing the data related to the time intervals before and after the onset of the programme. The results were evaluated at 95% confidence interval and significance was granted for p <= 0.05. RESULTS: The overall frequency of DKA at disease onset was 44.2%, with a significant trend for decline in rate of DKA at disease onset in the last decade (p=0.0001). There were no significant differences in proportions of newly diagnosed T1D patients with severe or moderate DKA over time. Mean body mass index standard deviation score tended to increase in the last decade, but not significantly (p=0.09). When the time intervals before and after the onset of NDAP were evaluated, there was a more than two-fold decrease in rate of DKA (from 49.3% to 23.9%) (p<0.0001). CONCLUSIONS: The frequency of a DKA event at onset of T1D is still high in Istanbul children despite a decreasing trend in the last decade. NDAP may significantly contribute to the reduction in rate of DKA. PMID- 23751387 TI - A levothyroxine dose recommendation for the treatment of children and adolescents with autoimmune thyroiditis induced hypothyroidism. AB - OBJECTIVE: To determine a levothyroxine (T4) dose recommendation for the treatment of autoimmune thyroiditis (AIT)-induced hypothyroidism. METHODS: T4 doses in 75 children and adolescents with newly diagnosed AIT were prospectively collected and compared to T4 doses of patients with congenital hypothyroidism (CH, n=22). RESULTS: Sixty-four patients with AIT and 22 patients with CH were included in the analysis. The thyroid-stimulating hormone declined significantly from 25.8 +/- 50.1 to 2.1 +/- 1.5 MUIU/mL (AIT group; p<0.01) and from 338.7 +/- 380.7 to 1.9 +/- 1.6 MUIU/mL (CH group; p<0.01). The required T4 dose for patients with AIT was 1.5 +/- 0.5 MUg/kg per day (>= 6 to <10 years: 2.0 +/- 0.4 MUg T4/kg per day; >= 10 to <12 years: 1.6 +/- 0.4 MUg T4/kg per day; >= 12 to <14 years: 1.5 +/- 0.6 MUg T4/kg per day; >= 14 years: 1.4 +/- 0.6 MUg T4/kg per day). It deviated significantly from the CH patients' mean T4 dose of 2.8 +/- 0.7 MUg T4/kg per day, p<0.01. CH patients with athyreosis required an average dose of 3.1 +/- 0.5 MUg T4/kg per day; patients with ectopia, 2.6 +/- 0.7 MUg T4/kg per day; and patients with dyshormonogenesis, 2.5 +/- 0.6 MUg T4/kg per day. CONCLUSION: Juvenile patients with AIT require significantly lower T4 doses than patients with CH. PMID- 23751388 TI - Primary hyperparathyroidism as an extremely rare cause of secondary myelofibrosis in childhood. AB - Primary hyperparathyroidism (PHP) and myelofibrosis are rare entities in childhood. Myelofibrosis secondary to PHP is also extremely rare. We report a 15 year-old boy presented with generalized weakness, vomiting, and pallor. A parathyroid adenoma was detected on the left distal parathyroid gland. PHP was diagnosed together with hepatosplenomegaly and pancytopenia. Bone marrow biopsy revealed grade 3-4 reticulin fibrosis. As early as 2 months after the left distal parathyroidectomy, hematologic parameters improved without any other intervention. His liver and spleen also gradually decreased in size. We concluded that the pancytopenia was as a result of myelofibrosis from PHP. PMID- 23751389 TI - Application of imaging modalities for evaluating neuroblastoma. AB - Neuroblastoma are the most common extracranial solid tumor of childhood. It is a malignancy derived from embryonic neural crest cells of the peripheral sympathetic nervous system that demonstrates remarkably heterogenous clinical and biological behavior ranging from spontaneous regression to inexorable progression with fatal outcomes. Various imaging modalities, including plain radiograph, ultrasound, computed tomography (CT), magnetic resonance imaging, bone scintigraphy, metaiodobenzylguanidine scintigraphy, and positron emission tomography/CT have been used to diagnose primary and metastatic neuroblastoma. In this article, we review the application of various imaging modalities to better define and recognize their role in the diagnosis and follow-up of neuroblastoma. PMID- 23751390 TI - Nevirapine induces testicular toxicity in Wistar rats: reversal effect of kolaviron (biflavonoid from Garcinia kola seeds). AB - BACKGROUND: Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used in the treatment of HIV infections and has been reported to be toxic to the male reproductive system. This study was designed to evaluate the ameliorative effects of kolaviron (KV), a biflavonoid from Garcinia kola, on NVP-induced testicular toxicity. METHODS: The adult male Wistar rats were given two and four times therapeutic doses of NVP (NVP-2T and NVP-4T; 18 and 36 mg/kg NVP) alone or in combination with KV (200 mg/kg). NVP was given daily, whereas KV was administered five times in a week by oral gavage. RESULTS: Treatment with NVP did not alter the body weight gain and relative weight of testis of the rats. NVP-4T significantly (p<0.05) decreased the sperm motility, protein content, and live dead ratio and also increased the percentage sperm abnormalities of the rats. Although NVP-4T significantly increased sperm abnormalities, it has no effect on epididymal sperm count. Also, NVP-4T caused a significant (p<0.05) elevation of serum aminotransferases and gamma-glutamyl transferase activities. In addition, NVP-4T significantly (p<0.05) decreased the levels of testicular superoxide dismutase, catalase, glutathione S-transferase, and glutathione with marked elevation of malondialdehyde (index of lipid peroxidation) in the rats. In contrast, NVP-2T did not produce an adverse effect on the biochemical indices studied in testes and sperm of rats. Supplementation with KV significantly ameliorated the biochemical changes caused by NVP-4T. CONCLUSIONS: Taken together, KV reversed the adverse effects of NVP-4T on testicular antioxidant enzymes and markers of oxidative stress in the rats. PMID- 23751391 TI - Heat: not black, not white. It's gray!!! AB - Heat-related illness (HRI) is a broad term that includes clinical conditions ranging from heat cramps and syncope to heat exhaustion and heatstroke, which may result in death. HRIs are one of the major causes of death worldwide and continue to increase in severity with the rise in global temperature. The identification and estimation of heat-related morbidity and mortality is a major challenge. Heat stress manifests itself into respiratory, cardiovascular, and cerebrovascular disorders, leading to the attribution of the deaths caused by heat stress to these disorders. Although HRIs affect mankind in general, certain occupational workers such as soldiers and athletes are more prone. Various pharmacological and nonpharmacological strategies have been employed to combat HRIs. Despite this, heat exposure results in significant morbidity and mortality. Hence, complete understanding of HRIs at physiological as well as molecular level is required to facilitate design of more efficient preventive and treatment strategies. The impact of heat on mankind is not just restricted to HRIs. Heat treatment, i.e., thermotherapy, has been used extensively since ancient times for relieving pain, making heat a two-edged sword. This review attempts to summarize various HRIs, their physiological and molecular basis, and the state-of-the-art techniques/research initiatives to combat the same. It also illustrates the application of thermotherapy as a means for improving quality of life and morbidity associated with several disease conditions such as fibromyalgia syndrome, heart diseases, cancer, chronic pain, and depression. PMID- 23751392 TI - Component-resolved diagnostics: laboratory results are not enough. PMID- 23751393 TI - Ethnobotanical study on medicinal plants around Limu Mountains of Hainan Island, China. AB - AIM OF THE STUDY: The main objectives were to document traditional knowledge on the use of medicinal plants and compare medicinal plant traditions between Li and Hmong living around Limu Mountains of Hainan Island. MATERIAL AND METHODS: Information was obtained from semi-structured interviews, personal conversation and guided fieldtrips with herbalists. Quantitative methods, such as the coefficient of similarity (S), Chi-square analysis and the 'informant agreement ratio' were applied for the comparison of medicinal plant tradition between Li and Hmong. RESULTS: In all, 224 plant species grown in the study areas are still traditionally used for the treatment of various diseases. Euphorbiaceae (17 species), Rubiaceae (16 species), Papilionaceae and Poaceae (11 species, respectively), Verbenaceae (10 species) and Compositae (7 species) are predominant families used by herbalists. The most species were reported to be used for injuries (25.1% of all the medicinal use-reports), digestive system disorders (24.8%), infections/infestations (14.7%) and muscular-skeletal system disorders (12.3%). The coefficient of similarity (29.0%) shows a relatively high overlap of medicinal plants used by Li and Hmong. Using Chi-square analysis, it was found that habit mentions were dependent upon the culture. Infections/infestations, injuries and muscular-skeletal system disorders scored high IAR value and mention in both Li and Hmong communities. CONCLUSIONS: Medicinal plants are of importance to indigenous people around Limu Mountains who still rely on medicinal plants to treat a wide range of illnesses. There is a close relationship of medicinal plant tradition between Li and Hmong who are culturally distinct. PMID- 23751394 TI - Antimicrobial, antioxidant, mutagenic and antimutagenic activities of Distephanus angulifolius and Ormocarpum trichocarpum. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves of Distephanus angulifolius and Ormocarpum trichocarpum are used for treating stomach-related ailments in traditional medicine. AIMS OF THE STUDY: The present study evaluated the antibacterial, antioxidant, mutagenic and antimutagenic properties of extracts obtained from the leaves of Distephanus angulifolius and Ormocarpum trichocarpum. MATERIALS AND METHODS: The microtitre bioassay was used to determine the antibacterial activity against three Gram-positive and three Gram-negative bacteria. Antioxidant activity was determined using the free-radical scavenging and beta-carotene-linoleic acid model assays. The safety and possible protective properties of the extracts were investigated using Ames test. RESULTS: Dichloromethane fractions of both plants displayed a broad-spectrum antibacterial activity with minimum inhibitory concentrations ranging from 0.16 to 0.63 mg/ml. A dose-dependent antioxidant activity was recorded in both plant species. All the evaluated samples showed no mutagenic as well as weak or no antimutagenic properties in the absence of exogenous metabolic activation. CONCLUSION: The results demonstrated the antibacterial and antioxidant activities of the leaves obtained from the two plant species. Furthermore, the data provides a rationale for the use of the plant species in treating stomach-related ailments in traditional medicine. PMID- 23751395 TI - Quality assurance of rapid arc treatments: performances and pre-clinical verifications of a planar detector (MapCHECK2). AB - The purpose of this study is to evaluate the use of MapCHECK2 in a patient specific quality assurance (QA) procedure for Rapid Arc (RA) radiotherapy and to obtain reference values of gamma index (gamma) for different irradiation geometries. Dose distributions of 386 patients, optimized with Eclipse treatment planning system for RA on Varian Clinac 2300IX were exported and measured with MapCHECK2 detector array inserted in a MapPHAN dedicated phantom. Gamma index analysis was used to evaluate differences between calculated and delivered doses; collected data were analysed on the basis of complexity of plans and type of disease. Angular dependence and dose drift of detectors were estimated. The overall mean passing rate (percentage of points with gamma < 1) was equal to 97.0% +/- 3.1%; plan-specific evaluation of %gamma < 1 showed significant differences among different treatment protocols (pancreas 98.6% +/- 1.5%, prostate 96.6% +/- 2.8% and rectum 92.8% +/- 5.7%). MapCHECK2 demonstrated a strong angular dependence over a restricted range of angles (90 degrees +/- 5 degrees and 270 degrees +/- 5 degrees ); this condition affected the result of pre-treatment QA only for plans with intense lateral fluence. The drift of diode array response due to the accumulated dose was found to be comparable with the manufacturer's declaration (0.5% per 1000 Gy). MapCHECK2 proved to be a useful and accurate tool in the process of patient-specific QA for RA treatment. Excluding the irradiation geometries with a high contribution of lateral fluence, the mean percentage of cases with gamma-index > 95% equal to 90.3% was obtained instead of 81.7% including all plans. PMID- 23751396 TI - Submucosal plexitis as a predictor of postoperative surgical recurrence in Crohn's disease. AB - BACKGROUND: The presence of submucosal or myenteric plexitis was associated with clinical and endoscopic Crohn's disease (CD) recurrence after ileocolonic resection. We assessed the value of both submucosal and myenteric plexitis for predicting postoperative surgical recurrence in CD. METHODS: We performed a retrospective study using the database of the Department of Pathology of Nancy University Hospital. All patients who underwent CD-related resection between 1996 and 2008 were analyzed. The proximal resection margin was analyzed blindly by 2 expert pathologists. Plexitis was evaluated by counting each cell type (mast cell, plasmocyte, lymphocyte, eosinophil, and neutrophil) in both submucosal and myenteric plexuses. The optimal cut-off value for each cell type was determined by using receiver operating characteristic analysis. Cox proportional hazards regression analysis was used to identify independent predictors of the second CD related surgery. RESULTS: Sixty-seven patients were included in the study. Median duration of follow-up was 46 months. Using Kaplan-Meier survival analysis, the proportion of patients without second surgery was 68% at 5 years. In multivariate analysis, using Cox proportional hazards regression analysis, early surgical revision after the first ileocecal resection (hazard ratio = 9.56; 95% confidence interval, 2.02-45.19; P = 0.0046), the presence of at least one eosinophil in the submucosal plexus (hazard ratio = 8.02; 95% confidence interval, 1.87-34.47; P = 0.0054), and the presence of more than 6 lymphocytes in the submucosal plexus (hazard ratio = 5.84; 95% confidence interval, 1.23-27.65; P = 0.0269) were independently associated with risk of surgical recurrence. CONCLUSIONS: Early surgical revision and submucosal plexitis in proximal margins of ileocolonic resection specimens are independently associated with CD surgical recurrence. PMID- 23751397 TI - Isolated active ileitis: is it a mild subtype of Crohn's disease? AB - BACKGROUND: Ileal intubation is being increasingly performed at colonoscopy and has in turn lead to an increasingly recognized subgroup of patients-those with mild terminal ileal inflammation, an entity that we have coined isolated active ileitis (IAI). The aims of this study were to define the natural history of IAI and determine if IAI shares a similar genetic and serologic profile with Crohn's disease (CD). METHODS: Patients with IAI were identified from our institution's histopathology and endoscopy databases. Cases attended for repeat colonoscopy and blood were analyzed for the expression of antineutrophil cytoplasmic antibody, anti-OmpC, anti-Saccharomyces cerevisiae antigen (ASCA) IgA, ASCA IgG, and anti CBir antibodies and NOD2 genotyping. Age and sex-matched healthy controls, CD, and UC cases were also recruited. RESULTS: Sixty-three patients with IAI were recruited. There was no significant difference in the prevalence of antibodies between IAI cases and healthy controls for antineutrophil cytoplasmic antibody, OmpC, ASCA IgA, or ASCA IgG. The presence of all 5 antibodies was significantly higher in the CD group than the IAI group, P < 0.05. There were 28.6% of CD cases that carried one or more NOD2 variants, compared to 26.2% of the IAI cohort and 6.1% of healthy controls. Forty-three cases underwent follow-up ileocolonoscopy. Six of 43 cases (14%) had definite CD. CONCLUSIONS: A majority of IAI cases developed persistent symptoms and terminal ileal abnormalities; however, only 14% developed classical, histological, or radiological features of CD. Although patients with IAI have a low level of seropositivity, similar to healthy controls, they do share an excess of NOD2 mutations with CD cases. PMID- 23751398 TI - Normalization of plasma 25-hydroxy vitamin D is associated with reduced risk of surgery in Crohn's disease. AB - BACKGROUND: Vitamin D may have an immunologic role in Crohn's disease (CD) and ulcerative colitis (UC). Retrospective studies suggested a weak association between vitamin D status and disease activity but have significant limitations. METHODS: Using a multi-institution inflammatory bowel disease cohort, we identified all patients with CD and UC who had at least one measured plasma 25 hydroxy vitamin D (25(OH)D). Plasma 25(OH)D was considered sufficient at levels >=30 ng/mL. Logistic regression models adjusting for potential confounders were used to identify impact of measured plasma 25(OH)D on subsequent risk of inflammatory bowel disease-related surgery or hospitalization. In a subset of patients where multiple measures of 25(OH)D were available, we examined impact of normalization of vitamin D status on study outcomes. RESULTS: Our study included 3217 patients (55% CD; mean age, 49 yr). The median lowest plasma 25(OH)D was 26 ng/mL (interquartile range, 17-35 ng/mL). In CD, on multivariable analysis, plasma 25(OH)D <20 ng/mL was associated with an increased risk of surgery (odds ratio, 1.76; 95% confidence interval, 1.24-2.51) and inflammatory bowel disease related hospitalization (odds ratio, 2.07; 95% confidence interval, 1.59-2.68) compared with those with 25(OH)D >=30 ng/mL. Similar estimates were also seen for UC. Furthermore, patients with CD who had initial levels <30 ng/mL but subsequently normalized their 25(OH)D had a reduced likelihood of surgery (odds ratio, 0.56; 95% confidence interval, 0.32-0.98) compared with those who remained deficient. CONCLUSION: Low plasma 25(OH)D is associated with increased risk of surgery and hospitalizations in both CD and UC, and normalization of 25(OH)D status is associated with a reduction in the risk of CD-related surgery. PMID- 23751399 TI - Phylogenetic analysis of the S segment from Juquitiba hantavirus: identification of two distinct lineages in Oligoryzomys nigripes. AB - The purpose of this study was to investigate the phylogenetic relationship of the Juquitiba virus (JUQV) carried by Oligoryzomys nigripes in endemic and non endemic areas of Brazil. Wild rodents infected with the Juquitiba virus (JUQV) were sampled from a non-Hantavirus Cardiopulmonary Syndrome endemic area in Brazil. Three strains from O. nigripes were identified by the sequencing of the complete S segment and compared to previous studies of JUQV available in GenBank. The phylogenetic analysis of the complete S segment revealed two distinct clades; the first clade was composed of the JUQV from two non-endemic areas in Brazil and the second clade contained JUQV strains from Argentina, Paraguay and other Brazilian endemic areas. PMID- 23751400 TI - A fatal neuroinvasive West Nile virus infection in a traveler returning from Madagascar: clinical, epidemiological and veterinary investigations. AB - Abstract. A 58-year-old woman living in Reunion Island and returning from Madagascar was hospitalized for neuroinvasive encephalitis and died 1 month later. West Nile virus (WNV) infection was biologically confirmed by detection of immunoglobulin M (IgM) reactive with WNV antigens in both cerebrospinal fluid and serum, and weak neutralizing activity was also detected. A veterinary survey performed in her traveling area showed a seroprevalence of WNV of 28.7% (95% confidence interval [CI] = 21.1-36.3) in adult poultry, confirming an active circulation of the virus. Development of a severe form could be related to a weak antibody response, because the patient presented low IgM and IgG titers. This case report underlines the constant risk of emergence of West Nile in Indian Ocean territories, including Reunion Island where competent vectors are widely present during the whole year. PMID- 23751401 TI - Melioidosis from contaminated bore water and successful UV sterilization. AB - Two cases of melioidosis at a residence in rural northern Australia were linked to the unchlorinated domestic bore (automated well) water supply, which was found to have a high concentration of Burkholderia pseudomallei. Using multilocus sequence typing, clinical B. pseudomallei isolates from both cases were identical to an isolate from the bore water supply. A simple UV sterilizer reduced B. pseudomallei from the domestic water supply to undetectable levels. We have shown that UV treatment is highly effective for remediation of water contaminated with B. pseudomallei and recommend its consideration in households where individuals may be at heightened risk of contracting melioidosis. PMID- 23751402 TI - Knowledge and practice related to compliance with mass drug administration during the Egyptian national filariasis elimination program. AB - Lymphatic filariasis (LF) has been targeted for global elimination by 2020. The primary tool for the program is mass drug administration (MDA) with antifilarial medications to reduce the source of microfilariae required for mosquito transmission of the parasite. This strategy requires high MDA compliance rates. Egypt initiated a national filariasis elimination program in 2000 that targeted approximately 2.7 million persons in 181 disease-endemic localities. This study assessed factors associated with MDA compliance in year three of the Egyptian LF elimination program. 2,859 subjects were interviewed in six villages. The surveyed compliance rate for MDA in these villages was 85.3% (95% confidence interval = 83.9-86.5%). Compliance with MDA was positively associated with LF knowledge scores, male sex, and older age. Adverse events reported by 18.4% of participants were mild and more common in females. This study has provided new information on factors associated with MDA compliance during Egypt's successful LF elimination program. PMID- 23751403 TI - Internalization of CCR4 and inhibition of chemotaxis by K777, a potent and selective CCR4 antagonist. AB - CC chemokine receptor 4 (CCR4) is a G protein-coupled receptor that regulates the chemotaxis of Th2 lymphocytes, which are key players in allergic diseases. K777 is a small compound identified in a binding assay using a CCR4 ligand, CCL17. K777 inhibited both CCL17 binding and CCL17-induced chemotaxis in Hut78 cells (IC50: 57 and 8.9 nmol/l, respectively). The K777-mediated inhibition of chemotaxis was potent even in the presence of a 10-fold higher concentration of CCL17. The imaging and flow cytometric analyses revealed that K777 induced CCR4 internalization, with a ~50% reduction of cell surface CCR4. K777 did not inhibit CXCR4-induced chemotaxis or internalization and did not bring about Ca(2+) mobilization by itself. A Scatchard plot analysis of the binding assay using radiolabeled K777 revealed a single high-affinity binding site on the CCR4 molecule. These results indicate that K777 is a selective CCR4 antagonist featuring the potent chemotaxis inhibition, to which the internalization inducible ability of K777 to hide a part of cell surface CCR4 may contribute. PMID- 23751404 TI - Surface passivation effect on the photoluminescence of ZnO nanorods. AB - We report an investigation of the impact of surface passivation on the optical properties of ZnO nanorods. Al2O3 coating and hydrogen plasma treatment were used to passivate the surface states. It was found that Al2O3 coating led to the suppression of the deep level emissions, while hydrogen plasma treatment completely quenched the deep level emissions. It was confirmed that the surface states of the as-grown ZnO nanorod arrays indeed contributed to the deep level emissions. Evidence was also provided that shows surface states have a greater impact on the green emission than the orange emission and may cause the negative thermal quenching behavior. Moreover, the passivation effect was confirmed by the changes of the O 1s and Zn 2p spectra. PMID- 23751405 TI - Minimally invasive surgery for patients with bulky bladder stones and large benign prostatic hyperplasia simultaneously: a novel design. AB - OBJECTIVE: To determine the efficacy and safety of a novel minimally invasive design for treating bulky vesical calculi and large benign prostatic hyperplasia (BPH) simultaneously. METHODS: 76 patients with large bladder stones (>4 cm) and large BPH (>=50 cm3) were treated from August 2008 to January 2011. 38 patients (group 1) underwent transurethral cystolithotripsy followed by transurethral resection of the prostate (TURP), 38 patients (group 2) received percutaneous cystolithotripsy within a laparoscopic entrapment bag and TURP by two surgeons simultaneously. 72 patients were followed up for 1 year. Patient demographics, perioperative parameters and follow-up data were compared. RESULTS: Patient baseline characteristics were comparable in the two groups. In group 1, 3 patients converted to open surgery and received blood transfusion, 4 patients had postoperative fever, 2 had residual stones and 1 developed urethral stricture postoperatively. In group 2, the mean total operative and the operative times for stone management were 71.6 and 30.1 min, respectively, the mean hemoglobin decrease was 0.80 g/dl, no patients received blood transfusion and no complications occurred, significantly superior to group 1. CONCLUSIONS: Percutaneous cystolithotripsy using a laparoscopic entrapment bag associated with TURP by two surgeons simultaneously is a highly effective, safe and minimally invasive method for managing large vesical calculi and large BPH. PMID- 23751406 TI - Cytokines in nasal lavages and plasma and their correlation with clinical parameters in cystic fibrosis. AB - BACKGROUND: Because persistent inflammation plays a dominant role in cystic fibrosis (CF), we assessed systemic and local upper airway responses during and after pulmonary exacerbation. METHODS: We followed a cohort of Pseudomonas aeruginosa-infected adult CF patients (n=16) over time in pulmonary exacerbation and in stable disease. Interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL 10, IL-17A, IL-22, interferon-gamma and TNFalpha levels were measured in sputum, nasal lavages and plasma. RESULTS: In CF patients IL-6 and IL-10 levels in nasal lavages were significantly increased in exacerbation compared with stable disease. Systemic IL-6 significantly correlated with CRP levels and FEV1 (%predicted), independently of disease status. Systemic IL-10 also correlated significantly with CRP and FEV1 (%predicted), but only in exacerbation. Other cytokines tested did not discriminate between exacerbation and stable disease. CONCLUSIONS: Determination of IL-6 and IL-10 in nasal lavages may provide a minimally invasive tool in the assessment of an exacerbation in CF. PMID- 23751407 TI - Effects of moderate exercise over different phases on age-related physiological dysfunction in testes of SAMP8 mice. AB - Oxidative stress and chronic inflammation have been implicated in the testicular aging process. Different types and moderate-intensity of regular exercise may reduce age-related physiological dysfunction associated with inflammation and oxidative stress, but such effects of moderate-intensity of exercise over different phases of life in testes have not been reported. In this study, male SAMP8 mice, a senescence-accelerated strain, were maintained as sedentary (sed) or subjected to daily 15-min periods of swimming exercise between ages of 2-7 months (lifelong), 2-4 months (earlier) or 5-7 months (late). Age-related changes, including serum testosterone levels and biomarkers of inflammation and oxidative stress were analyzed at the end of the experiment. All exercise groups showed significantly greater serum testosterone levels and decreased age-related inflammation and oxidative stress compared with the sedentary group. Exercise also increased expression and activity of the nuclear factor erythroid 2-related factor (Nrf2), a transcriptional regulator of the cellular anti-oxidant system, and decreased expression and activity of nuclear factor kappa beta (NF-kappaB), a mediator of inflammatory molecules, in the nucleus of testicular cells. However, lifelong and earlier groups generally showed significantly better protective effects than the late group against age-related physiological dysfunction in testes. Thus, lifelong exercise and earlier phase exercise were most effective in counteracting oxidative stress and inflammation and in preserving testes function through regulation of Nrf2 and NF-kappaB. These results advocate the benefits of lifelong exercise and emphasize a greater protection against male aging by instituting exercise earlier rather than late in life. PMID- 23751408 TI - Noise-driven onset time of biodemographic aging. AB - The lifespan of each individual, even in an isogenic cohort and a uniform environment, is quite different. The genetic factors influencing the lifespan in humans as well as animal models are few. The balance is attributed to "chance" variations. In this study, we focus on a third factor, noise or chance variations, as well as on genetic and environmental factors and examine how biodemographic aging is related to stochastic fluctuations, or noise. To elucidate the third factor in relation to aging and lifespan, we employed the nematode Caenorhabditis elegans, which can provide an ideal system for analyzing the mathematical and biophysical models. An amplification of ATP noise was clearly evident from around the onset of biodemographic aging (t(0)) as if the t(0) was synchronized with or derived from the amplification of noise. Furthermore, the expression noise of the unc-54 gene, which encodes the myosin heavy chain, increased from around the t(0). In contrast, the noise of genes related to the mitochondrial respiratory chain was almost constant with aging. There is a high energy barrier between life and death. Here we propose that the transition from living to dying may be facilitated by noise amplification. The finite value (or non-zero) of t(0) is essential to the lifespan equation derived from the diffusion model. PMID- 23751409 TI - Non-selective distribution of isomeric cholesterol hydroperoxides to microdomains in cell membranes and activation of matrix metalloproteinase activity in a model of dermal cells. AB - Cholesterol hydroperoxides (ChOOHs) are included as lipid peroxidation products in the skin exposed to ultraviolet (UV) light irradiation. They may exert physicochemical actions affecting biomembrane rigidity because cholesterol is one of the major components of cell membranes. We investigated the distribution of isomeric ChOOHs in heterogeneous cell membranes with different lipid profiles using mouse fibroblast NIH-3T3 cells as a model of the dermis. Before and after UVA irradiation in the presence of hematoporphyrin, cell membranes were partitioned to microdomains (lipid rafts and caveolae) containing a higher amount of cholesterol and non-microdomains (containing a lower amount of cholesterol) by ultracentrifugation. By a combination of diphenylpyrenylphosphine-thin-layer chromatography blotting analyses and gas chromatography-electron ionization-mass spectrometry/selected ion monitoring analyses, ChOOH isomers were determined as their trimethylsilyloxyl derivatives. Cholesterol 5alpha-, 7alpha- and 7beta hydroperoxide were found as isomeric ChOOHs before irradiation. The amounts of the three ChOOH isomers increased significantly after photoirradiation for 2h. No difference was observed between microdomains and non-microdomains with regard to the ratio of the amounts of isomeric ChOOHs to that of cholesterol, suggesting that these ChOOH isomers were distributed equally in both parts depending on cholesterol content. When cells were treated with a purified mixture of ChOOH isomers, cell membranes incorporated ChOOHs into microdomains as well as non microdomains evenly. Cellular matrix metalloproteinase-9 (MMP-9) activity was elevated by treatment with the purified mixture of ChOOH isomers. These results strongly suggest that ChOOHs accumulate in cell membranes irrespective of the heterogeneous microstructure and promote MMP activity if dermal cells are exposed to photodynamic actions. PMID- 23751410 TI - Reactive macrophage activation syndrome possibly triggered by canakinumab in a patient with adult-onset Still's disease. AB - Macrophage activation syndrome (MAS) is a rare and serious complication of adult onset Still's disease. We describe a case in a 49-year-old woman with Still's disease refractory to glucocorticoids, methotrexate, and infliximab. Anakinra provided satisfactory disease control for 1 year, after which escape phenomenon occurred. After four tocilizumab injections, cutaneous melanoma developed. The persistent systemic manifestations prompted treatment with two canakinumab injections. Ten days later, she had a spiking fever, dyspnea, low back pain, abdominal pain, odynophagia, and hepatomegaly. Laboratory tests showed liver cytolysis (180 IU/L; N: 10-35), acute renal failure (creatinine, 407 MUmol/L; N:50-100), thrombocytopenia (60 G/L; N: 150-400), leukocytosis (12,200/mm(3); N: 4000-10,000), hypertriglyceridemia (5070 mmol/L; N: 0.4-1.6), lactate dehydrogenase elevation (4824 IU/L; N: 135-250), and hyperferritinemia (97 761 MUg/L; N:15-150). Examination of a bone marrow biopsy showed phagocytosis. Tests were negative for viruses and other infectious agents. Glucocorticoid therapy (1.5 mg/Kg/d) and intravenous polyvalent immunoglobulins (0.5 g/Kg/d) were given. Her condition improved despite the many factors of adverse prognostic significance (thrombocytopenia, absence of lymphadenopathy, and glucocorticoid therapy at diagnosis). This is the first reported case of MAS after canakinumab therapy in a patient with adult-onset Still's disease. PMID- 23751411 TI - Smartphone-enabled pulse rate variability: an alternative methodology for the collection of heart rate variability in psychophysiological research. AB - Heart rate variability (HRV) is widely used to assess autonomic nervous system (ANS) function. It is traditionally collected from a dedicated laboratory electrocardiograph (ECG). This presents a barrier to collecting the large samples necessary to maintain the statistical power of between-subject psychophysiological comparisons. An alternative to ECG involves an optical pulse sensor or photoplethysmograph run from a smartphone or similar portable device: smartphone pulse rate variability (SPRV). Experiment 1 determined the simultaneous accuracy between ECG and SPRV systems in n = 10 participants at rest. Raw SPRV values showed a consistent positive bias, which was successfully attenuated with correction. Experiment 2 tested an additional n = 10 participants at rest, during attentional load, and during mild stress (exercise). Accuracy was maintained, but slightly attenuated during exercise. The best correction method maintained an accuracy of +/-2% for low-frequency spectral power, and +/-5% for high-frequency spectral power over all points. Thus, the SPRV system records a pulse-to-pulse approximation of an ECG-derived heart rate series that is sufficiently accurate to perform time- and frequency-domain analysis of its variability, as well as accurately reflecting change in autonomic output provided by typical psychophysiological stimuli. This represents a novel method by which an accurate approximation of HRV may be collected for large-sample or naturalistic cardiac psychophysiological research. PMID- 23751412 TI - Serum total testosterone is a significant preoperative variable independently contributing to separating the prostate cancer population into prostatectomy Gleason score groups. AB - AIM: To investigate the potential of preoperative serum total testosterone (TT) in contributing to the definition of separate prostatectomy Gleason score (pGS) groups of the prostate cancer (PCa) population. MATERIALS AND METHODS: The data of 220 patients operated on for PCa were retrospectively reviewed. No patient had previously received 5alpha-reductase inhibitor, luteinizing hormone-releasing analogs or testosterone replacement treatment. The patient population was grouped according to the pGS as 6 = 3+3, 7 = 3+4, 7 = 4+3 and 8-10. Eight variables were simultaneously investigated in each group: prostate-specific antigen (PSA), TT, free testosterone, age, percentage of positive prostate biopsy cores (P+), biopsy Gleason score (bGS), overall cancer volume estimated as percentage of prostate volume (V+) and prostate weight (Wi). Univariate analysis of variance (ANOVA), multivariate analysis of variance (MANOVA) and multivariate discriminant analysis (MDA) were the statistical methods used for evaluating the data. RESULTS: There were 89 patients in pGS 6 = 3+3, 84 in pGS 7 = 3+4, 24 in pGS 7 = 4+3 and 23 in pGS 8-10. ANOVA showed that bGS (p < 0.0001), P+ (p < 0.0001), V+ (p < 0.0001), PSA (p = 0.0001), Wi (p = 0.0002) and TT (p = 0.01) were significantly different in the four pGS groups. MANOVA tests showed that only bGS (p < 0.0001), V+ (p = 0.0003), TT (p = 0.001) and, to a lesser extent, PSA (p = 0.06) were the significant variables that individually and independently contributed a significant amount to separation of the four pGS groups of the PCa population. MDA showed that the independent variables ranked as bGS (p < 0.0001), TT (p = 0.001), V+ (p = 0.001) and PSA (p = 0.06). CONCLUSIONS: Serum TT is a significant preoperative variable that independently contributes to separating the PCa population into pGS score groups. Pretreatment baseline serum TT levels should be measured and their inclusion in neural networks predicting PCa natural history be considered in the patient population diagnosed with PCa. PMID- 23751413 TI - Acute promyelocytic leukemia with a rare PML exon 4/ RARA exon 3 fusion transcript variant. PMID- 23751414 TI - Management strategy for small duodenal carcinoid tumors: does conservative management with close follow-up represent an alternative to endoscopic treatment? AB - BACKGROUND/AIMS: Limited data exist regarding the natural history of duodenal carcinoid tumors and the efficacy of endoscopic treatment. METHODS: A total of 27 patients with duodenal carcinoid tumors were enrolled. All tumors were located outside the periampullary region and were <=10 mm in size. 11 patients underwent endoscopic mucosal resection (EMR) and argon plasma coagulation (APC). 13 patients did not undergo any specific procedure for tumor removal and were followed clinically. RESULTS: Of 13 patients not undergoing treatment, tumors disappeared in 5 cases during follow-up with diagnostic forceps biopsy. Endoscopically visible lesions remained in the last follow-up endoscopy in 8 patients (61.5%). No lymph node or distant metastases or tumor-related deaths occurred during a median follow-up of 37 months. Of 11 cases treated with EMR, tumor-free resection margins were achieved in 10 cases and no local recurrence occurred after treatment. Two perforations occurred during EMR. Of the 3 cases treated with APC, local recurrence occurred in 1 case. CONCLUSIONS: Given the risks associated with EMR and the likely favorable natural history of small duodenal carcinoid tumors, conservative management with close follow-up may represent a viable alternative to endoscopic treatment, especially in patients with a high risk of perioperative complications. PMID- 23751415 TI - Enzymatic activity of cholesterol oxidase immobilized onto polymer nanoparticles mediated by Congo red. AB - Poly(ethylene glycol), PEG, decorated polystyrene (PS) nanoparticles were synthesized and characterized by means of dynamic light scattering (DLS), zeta (zeta) potential measurements, Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). The adsorption of Congo red (CR) onto PS/PEG particles was evidenced by the decrease of zeta potential values and increase in the particles mean diameter in comparison to bare particles. Cholesterol oxidase (ChOx), the main enzyme in the oxidation of cholesterol, adsorbed onto PS/PEG and PS/PEG/CR particles, as revealed by the increase in the particles mean size and spectrophotometry. The enzymatic activity of free and immobilized ChOx was determined as a function of time by means of a coupled reaction with horseradish peroxidase. The activity of free ChOx decreased with time, while the activity of immobilized ChOx increased with time; after 1h reaction the latter was half of the former. Freeze-drying the ChOx covered PS/PEG/CR particles allowed their storage for at least one month under room conditions without loss of enzymatic activity. Conjugation effects between CR and ChOx or cholesterol evidenced by circular dichroism and spectrophotometry rendered a conformational state of ChOx, such that the enzymatic action was favored. ChOx adsorbed onto PS/PEG presents no enzymatic activity, probably due to ChOx denaturation or unfavorable orientation. Freeze-dried and freshly prepared dispersions of ChOx immobilized onto PS/PEG/CR particles yielded linear response in the cholesterol concentration range of 100mgdL(-1) (lowest limit of normal blood concentration) to 300mgdL(-1) (high risk level). PMID- 23751416 TI - Quantification of the influence of protein-protein interactions on adsorbed protein structure and bioactivity. AB - While protein-surface interactions have been widely studied, relatively little is understood at this time regarding how protein-surface interaction effects are influenced by protein-protein interactions and how these effects combine with the internal stability of a protein to influence its adsorbed-state structure and bioactivity. The objectives of this study were to develop a method to study these combined effects under widely varying protein-protein interaction conditions using hen egg-white lysozyme (HEWL) adsorbed on silica glass, poly(methyl methacrylate), and polyethylene as our model systems. In order to vary protein protein interaction effects over a wide range, HEWL was first adsorbed to each surface type under widely varying protein solution concentrations for 2h to saturate the surface, followed by immersion in pure buffer solution for 15h to equilibrate the adsorbed protein layers in the absence of additionally adsorbing protein. Periodic measurements were made at selected time points of the areal density of the adsorbed protein layer as an indicator of the level of protein protein interaction effects within the layer, and these values were then correlated with measurements of the adsorbed protein's secondary structure and bioactivity. The results from these studies indicate that protein-protein interaction effects help stabilize the structure of HEWL adsorbed on silica glass, have little influence on the structural behavior of HEWL on HDPE, and actually serve to destabilize HEWL's structure on PMMA. The bioactivity of HEWL on silica glass and HDPE was found to decrease in direct proportion to the degree of adsorption-induce protein unfolding. A direct correlation between bioactivity and the conformational state of adsorbed HEWL was less apparent on PMMA, thus suggesting that other factors influenced HEWL's bioactivity on this surface, such as the accessibility of HEWL's bioactive site being blocked by neighboring proteins or the surface itself. The developed methods provide an effective means to characterize the influence of protein-protein interaction effects and provide new molecular-level insights into how protein-protein interaction effects combine with protein-surface interaction and internal protein stability effects to influence the structure and bioactivity of adsorbed protein. PMID- 23751417 TI - Identification and characterization of biosurfactants produced by the Arctic bacterium Pseudomonas putida BD2. AB - One hundred and thirty bacterial strains, isolated from Arctic soil on the Svalbard Archipelago, were screened for biosurfactant production. Among them, an isolate identified as Pseudomonas putida BD2 was selected as a potential biosurfactant-producer based on the surface/interfacial activity of the culture supernatant. The ability of the strain to produce simultaneously phosphatidylethanolamines and rhamnolipid, using glucose as a sole carbon source, was demonstrated. The rhamnolipid Rha-Rha-C10-C10 and two homologs of phosphatidylethanolamine were extracted from cell-free supernatant of P. putida BD2 culture with ethyl acetate and identified by UPLC-MS analysis. For Rha-Rha C10-C10 the surface tension decreased from 72 to 31mN/m and the critical micelle concentration was 0.130mg/mL. The Rha-Rha-C10-C10 was able to form stable aggregates (80-121nm). Pretreatment of a polystyrene surface with 0.5mg/mL rhamnolipid inhibited bacterial adhesion by 43-79% and that of the pathogenic fungal species C. albicans by 89-90%. The same concentration of phosphatidylethanolamines inhibited bacterial adhesion by 23-72% and that of C. albicans by 96-98%. To our knowledge, this is the first report where one type rhamnolipid and two homologs of phospholipid biosurfactants were produced by P. putida isolated from Arctic soil. PMID- 23751418 TI - Adsorption properties of biologically active derivatives of quaternary ammonium surfactants and their mixtures at aqueous/air interface. I. Equilibrium surface tension, surfactant aggregation and wettability. AB - The adsorption properties of surfactant mixtures containing two types of quaternary derivatives of lysosomotropic substances: alkyl N,N-dimethylalaninates methobromides and alkyl N,N-dimethylglycinates methobromides were studied. Quantitative and qualitative description of the adsorption process was carried out on the basis of experimentally obtained equilibrium surface tension isotherms. The results indicated that most of the systems studied revealed synergistic effect both in adsorption and wetting properties. In vitro studies on human cancer cells were undertaken and the data obtained showed that the mixtures suppressed the cancer cells' proliferation more effectively than individual components. Results of preliminary research on the interaction of catanionic mixtures with phospholipids suggested a possibility of a strong penetration of cell membranes by the mixtures investigated. PMID- 23751419 TI - pH-sensitive microparticles for oral drug delivery based on alginate/oligochitosan/Eudragit((r)) L100-55 "sandwich" polyelectrolyte complex. AB - The primary objective of this study was to investigate the influence of the oligochitosan-Eudragit((r)) L100-55 polyelectrolyte complex (OCH-EL PEC) on the pH-sensitivity of Eudragit((r)) L100-55-treated alginate-oligochitosan microparticles. In order to achieve this, three types of naproxen-loaded microparticles were prepared under mild and environmentally friendly conditions using a custom made device with coaxial air flow: Ca-alginate (Ca-ALG), alginate oligochitosan (ALG-OCH) and alginate-oligochitosan-Eudragit((r)) L100-55 (ALG-OCH EL) microparticles. After drying, the microparticles were subjected to microscopic analysis, and physicochemical and biopharmaceutical characterization. The non-covalent interaction between OCH and EL and the formation of OCH-EL PEC during the preparation procedure of the particles were verified by thermal and FT IR analysis. The obtained particles exhibited acceptable sphericity and surface roughness due to the presence of the drug crystals (Ca-ALG particles) and OCH-EL PEC (ALG-OCH-EL particles). It was found that reinforcement of the ALG-OCH particles with OCH-EL PEC had no significant effect on the relatively high encapsulation efficiencies (>74.4%). The results of drug release studies confirmed the ability of ALG-OCH PEC to sustain drug release at pH 6.8 and 7.4. However, this PEC showed enhanced sensitivity to an acidic environment and to simulated intestinal fluid (pH 6.8) after prior exposure to an acidic medium. Additional treatment of ALG-OCH particles with EL and formation of "sandwich" ALG OCH-EL PEC was essential not only to improve stability and decrease drug release in acidic medium, but also to achieve sustained release after the pH of dissolution medium was raised to 6.8. The obtained results suggested that ALG-OCH EL microparticles have promising potential as pH-sensitive multiparticulate drug carriers for oral delivery of NSAIDs. PMID- 23751420 TI - Mixed micelles of Lecithin-Tyloxapol as pharmaceutical nanocarriers for anti tubercular drug delivery. AB - The equimolar mixed micellar system of Lecithin-Tyloxapol has been explored using physicochemical and spectroscopic measurements. Thermodynamic parameters have been computed for the prepared mixed micellar system. Interaction parameter, beta, suggests synergistic interactions in the mixed systems. This has been further examined for the solubilization of anti-tuberculosis drugs (ATDs). In addition, the entrapment efficiency of the formulation has been evaluated for three ATDs. Micropolarity measurements indicate location of all the three drugs inside the mixed micellar systems. Fourier transform infrared spectroscopic and differential scanning calorimetric studies infer that the drugs are in harmony with the excipients since no visible interactions between the drugs and mixed micelles have been detected. In vitro release analyses exhibit sustained release of drugs from the formulation. Comparison of regression coefficients of different kinetic models reveal that release of ATDs from mixed micellar system follows first order exponential decay. PMID- 23751421 TI - Resistance to tenofovir-based regimens during treatment failure of subtype C HIV 1 in South Africa. AB - BACKGROUND: Tenofovir disoproxil fumarate (TDF) is increasingly available for patients infected with subtype C HIV-1. This subtype is reported to develop the principal TDF resistance mutation in the HIV reverse transcriptase, K65R, with greater propensity than other subtypes. We sought to describe K65R development during TDF use in a cohort of patients infected with subtype C HIV. METHODS: Using a prospectively followed cohort with 6 monthly HIV RNA assays, we identified virological failure (defined as an HIV RNA > 1,000 copies/ml) during treatment that included TDF. Residual serum, stored at the time of the HIV RNA assay, was used for consensus sequencing and allele-specific PCR. We assessed prevalence of resistance at failure during TDF-containing treatment and associated factors. RESULTS: Among 1,682 patients on a TDF-containing regimen, 270 developed failure of which 40 were assessed for resistance. By sequencing, the K65R was identified in 5 (12%), major non-nucleoside reverse transcriptase inhibitor mutations in 24 (57%) and the M184V/I in 12 (28%) patients. The K65R was associated with lower HIV RNA at failure (HIV RNA 3.3 versus 4.2 log10 copies/ml) and prior stavudine exposure. An additional five patients had minority K65R populations identified by allele-specific PCR. CONCLUSIONS: These data suggest that the K65R prevalence at virological failure is moderately higher in our subtype C population than some non-subtype C HIV cohorts. However, we did not find that the K65R was highly selected in HIV-1 subtype-C-infected patients with up to 6 months of failure of a TDF-containing regimen. PMID- 23751423 TI - Trapping energy of a spherical particle on a curved liquid interface. AB - We derive the trapping energy of a colloidal particle at a liquid interface with contact angle theta and principal curvatures c1 and c2. The boundary conditions at the particle surface are significantly simplified by introducing the shift epsilon of its vertical position. We discuss the undulating contact line and the curvature-induced lateral forces for a single particle and a pair of nearby particles. The single-particle trapping energy is found to decrease with the square of both the total curvature c1+c2 and the anisotropy c1-c2. In the case of non-uniform curvatures, the resulting lateral force pushes particles toward more strongly curved regions. PMID- 23751424 TI - Apoptotic toxicity of destruxin B in human non-Hodgkin lymphoma cells. AB - Destruxins are fungal toxins used as insecticides. Recent reports demonstrated the potential anti-cancer activities of destruxin B (DB). This study is to discover the effects of DB in lymphoma. Flow cytometry and Western blotting were used to analyze apoptosis and protein expression, respectively, in Toledo human non-Hodgkin lymphoma cells in response to DB. Administration of DB, induced apoptosis via death receptor pathway activating Fas associated death domain (FADD), caspase 8 and caspase 3, and suppressed the cell growth. In addition, DB alterated mitochondrial membrane potential by increasing the expressions of tBid and Bax, but decreasing the levels of Bcl-2, resulting in the release of apoptosis-inducing factor (AIF). In conclusion, apoptosis of human non-Hodgkin lymphoma cells in response to DB is induced through the death receptor pathway and involves an alteration of the mitochondrial membrane potential. These findings may aid the development of novel treatment of non-Hodgkin lymphoma. PMID- 23751422 TI - Vitamin D and cardiovascular disease: is the evidence solid? AB - Vitamin D deficiency, prevalent in 30-50% of adults in developed countries, is largely due to inadequate cutaneous production that results from decreased exposure to sunlight, and to a lesser degree from low dietary intake of vitamin D. Serum levels of 25-hydroxyvitamin D (25-OH D) <20 ng/mL indicate vitamin D deficiency and levels >30 ng/mL are considered optimal. While the endocrine functions of vitamin D related to bone metabolism and mineral ion homoeostasis have been extensively studied, robust epidemiological evidence also suggests a close association between vitamin D deficiency and cardiovascular morbidity and mortality. Experimental studies have demonstrated novel actions of vitamin D metabolites on cardiomyocytes, and endothelial and vascular smooth muscle cells. Low 25-OH D levels are associated with left ventricular hypertrophy, vascular dysfunction, and renin-angiotensin system activation. Despite a large body of experimental, cross-sectional, and prospective evidence implicating vitamin D deficiency in the pathogenesis of cardiovascular disease, a causal relationship remains to be established. Moreover, the cardiovascular benefits of normalizing 25-OH D levels in those without renal disease or hyperparathyroidism have not been established, and questions of an epiphenomenon where vitamin D status merely reflects a classic risk burden have been raised. Randomized trials of vitamin D replacement employing cardiovascular endpoints will provide much needed evidence for determining its role in cardiovascular protection. PMID- 23751425 TI - Mitochondrial response to oxidative and nitrosative stress in early stages of diabetes. AB - Diabetes mellitus (DM) is associated with increased production of reactive oxygen and nitrogen species; consequently, an increase in lipid peroxidation and a decrease in antioxidants resulting in mitochondrial dysfunction. Using a rat model of DM induced by streptozotocin, we show the opposite: an increase in NO levels, S-nitrosylation, aconitase activity, and total glutathione and a decrease in lipid peroxidation at early stages of diabetes. These data imply that the decrease in lipid peroxidation is a vital early response to hyperglycemia to prevent escalation of ROS generation in mitochondria. These results also suggest a need for novel therapeutic targets to prevent the neurological consequences of diabetes. PMID- 23751426 TI - [Nerve injuries in children]. AB - Management of peripheral nerve lesions in children does not differ fundamentally from that in adults. Nevertheless, difficulty to perform an extensive clinical examination can explain initial misdiagnosis and postoperative follow up can be tricky. The poor compliance of the children in the postoperative care makes a postoperative immobilization mandatory. If the peripheral nerve injuries involving children have a better prognosis reputation than in adults, fundamental studies results do not comfort this conventional wisdom, but rather claim for a better adaptability of the child to the relapses left by the peripheral nerves lesions. PMID- 23751427 TI - Injectable hyaluronic acid fillers for periorbital rejuvenation. PMID- 23751428 TI - Managing eyelid malpositions with hyaluronic acid gel injections. PMID- 23751429 TI - Update on botulinum toxins in oculofacial plastic surgery. PMID- 23751430 TI - Innovative laser and light techniques in facial aesthetics. PMID- 23751431 TI - Minimally invasive approaches to eyebrow lifting. PMID- 23751432 TI - Advanced techniques for midfacial rejuvenation. PMID- 23751433 TI - Minimally invasive approaches to orbital volume augmentation. PMID- 23751434 TI - Catheter-assisted conjunctivodacryocystorhinostomy (CDCR). PMID- 23751435 TI - Advances in the management of thyroid eye disease. PMID- 23751436 TI - Evaluation and treatment of pediatric orbital fractures. PMID- 23751437 TI - Innovative techniques in orbital reconstruction. PMID- 23751438 TI - Oral propranolol in the management of periocular capillary hemangiomas. PMID- 23751440 TI - Innovative advances in aesthetic & reconstructive oculofacial plastic surgery. PMID- 23751441 TI - Clinical and laboratory significance of defective P2Y(12) pathway function in patients with myeloproliferative neoplasms: a pilot study. AB - BACKGROUND: Patients with myeloproliferative neoplasms (MPN) have an increased risk for thrombosis and bleeding and show a defect in adenosine diphosphate (ADP) induced platelet aggregation. This risk of thrombosis is further increased in MPN patients bearing the JAK2V617F mutation. Two ADP receptors, P2Y1 and P2Y12, are present on platelets. Although the pattern of defective ADP-induced platelet aggregation in MPN suggests an abnormality in the P2Y12 pathway, no previous studies have specifically evaluated P2Y12 function in MPN or the relationship between P2Y12 function and the JAK2V617F mutation. METHODS: Forty-one MPN patients were enrolled, including 24 with essential thrombocythemia (ET), 16 with polycythemia vera (PV) and 1 with primary myelofibrosis. Platelet P2Y12 function in MPN was evaluated by flow-cytometric measurement of the phosphorylation of vasodilator-stimulated phosphoprotein (VASP). Clinical data were collected by review of medical records. JAK2V617F mutation was detected by allele-specific polymerase chain reaction. JAK2V617F allele burden was measured by the pyrosequencing method. RESULTS: In patients with MPN, platelet P2Y12 function determined by VASP platelet reactivity index (PRI) was inversely correlated with platelet and white blood cell (WBC) counts. In subgroup analysis, PRI was inversely correlated with platelet and WBC counts in PV. PRI was also inversely correlated with platelet counts in ET, but the correlation of PRI and WBC counts did not reach statistical significance. Eight of the 41 patients had a history of thrombosis and only 2 had a bleeding history. Neither thrombosis nor bleeding patients were found to have significantly different PRIs. JAK2V617F mutation data were available in 35 cases. PRI was not different between JAK2V617F mutation and wild-type patients but PRI had a trend towards an inverse correlation with JAK2V617F allele burden for patients with mutations. CONCLUSIONS: The present study provides the first explicit demonstration of a defect in the P2Y12 pathway in platelets of patients with MPN. Furthermore, platelet P2Y12 function, assayed by VASP, is inversely correlated with platelet and WBC counts in patients with MPN. Platelet P2Y12 function also appears to be inversely correlated with JAK2V617F allele burden. This compromised P2Y12 function may be a novel mechanism for the bleeding tendency associated with extreme thrombocytosis in MPN. PMID- 23751442 TI - Early vocabulary in full term and preterm Estonian children. AB - BACKGROUND: Preterm birth is considered to be a high risk factor for child development and early vocabulary can be used as an indicator for later development. AIMS: The aim of the present study is to compare the size of early vocabulary, proportional use of different word categories, and mean length of utterance (henceforth MLU) of preterm and full term children. METHOD: The sample consisted of 40 preterm (corrected ages 16-25 months) and two matched groups of full term children. First full term group consisted of 120 children who were matched by age and gender. Second full term group consisted of 109 children who were matched by age, gender and size of productive vocabulary. The data for this study were gathered using the Estonian adaptation of MacArthur-Bates Communicative Development Inventory: Words and Sentences. RESULTS: Full term children who were matched by age and gender had larger vocabulary as compared to the preterm children's vocabulary (U = 1758.5, p = 0.01). Poisson regression yielded that age, gender, and preterm birth explained significantly the variance in the vocabulary size. Poisson regressions showed that all three variables explained significantly variance in proportional use of social terms and predicates. Age had significant effect for proportional use of common nouns. Age and preterm birth had a significant effect on the proportional use of function words. MLU was shorter in preterm than in full term children (U = 1125.0, p = 0.002). CONCLUSIONS: Estonian preterm children's vocabulary is slightly smaller than full term children's vocabulary. There is a difference in the proportions of word categories used, as preterm children use more social terms, and less predicates, and function words. PMID- 23751443 TI - New iridium dopants forg white phosphorescent devices: enhancement of efficiency and color stability by an energy-harvesting layer. AB - A new light blue complex (fmoppy)2Ir(tfpypz) [bis(4'-fluoro-6'-methoxylphenyl pyridinato)-iridium(III)-3-(trifluoromethyl)-5-(pyridin-2-yl)-1,2,4-triazolate] and a new orange complex (dpiq)2Ir(acac) [bis(3,4-diphenylisoquinoline) iridium(III)-acetylacetonate] were synthesized. These two complexes were used as the dopants for the fabrication of two-element white phosphorescent devices. Via the introduction of a thin energy-harvesting layer (EHL) to harvest the extra energy and exciton from the emission zone, highly efficient two-element white devices with excellent color stability were created. One of the best devices shows yellow-white color emission with an extremely high external quantum efficiency (EQE) of 21.5% and a current efficiency of 68.8 cd/A. The other device gave a pure white emission with an external quantum efficiency of 19.2% and a current efficiency of 53.2 cd/A. At a high brightness of 1000 cd/m(2), the EQE still remains as high as 18.9 and 17.2%. With a brightness of 1000-10000 cd/m(2), the CIE coordinates of these two devices shift by only (0.02, <=0.01). The white phosphorescent devices with the EHL showed much higher efficiency and better color stability than the one without the EHL. PMID- 23751444 TI - Forensic aspects of insulin. AB - Insulin or, more appropriately, hypoglycaemia gives rise to a wide variety of interactions with the law. In most cases its role is not seriously open to question occasionally however, it is. This is especially true of situations in which insulin is suspected of having been used inappropriately or maliciously. The major differences between investigation of hypoglycaemia in clinical and forensic situation are that in the latter the history is often unreliable, appropriate samples for analysis were not collected, preserved or labelled correctly and analytical results are likely to be challenged on grounds of specificity, accuracy and interpretation. Immunoassay remains the mainstay of clinical investigation of hypoglycaemia but likely to become displaced by mass spectrometry in the forensic situation especially now that human insulin is being replaced by synthetic insulin analogues for the treatment of diabetes. PMID- 23751445 TI - Brain diffusion changes in obstructive sleep apnoea syndrome. AB - BACKGROUND: Obstructive sleep apnoea syndrome (OSAS) is a disorder characterized by repeated apnoeic episodes during sleep. Neurocognitive changes secondary to OSAS are likely to occur due to hypoxia in certain brain locations. Advances in magnetic resonance imaging technology, such as diffusion-weighted imaging (DWI), enable non-invasive and accurate identification of OSAS-induced changes. OBJECTIVE: We aimed to use DWI to investigate changes in the brain secondary to hypoxia in OSAS. METHODS: Eighty-eight patients underwent polysomnography and were classified as non-OSAS, mild-moderate OSAS and severe OSAS sufferers. DWI was used to evaluate 14 areas of the brain, and apparent diffusion coefficients (ADCs) were calculated. We investigated whether there were differences in the ADC values in specific areas of the brain between the non-OSAS and OSAS patients. RESULTS: We measured the ADC values of the 68 newly diagnosed OSAS patients (21 mild, 15 moderate and 32 severe) and of 20 healthy controls. There were significant increases in the ADC values in the hippocampus, amygdala and putamen in OSAS patients. Compared to the non-OSAS subjects, the ADC values of the putamen in severe OSAS patients, those of the hippocampus in moderate or severe OSAS patients and those of the amygdala in moderate OSAS patients were significantly increased. A negative correlation between the lowest oxygen saturation during sleep and the ADC values of the hippocampus and amygdala was found. CONCLUSIONS: Increased ADC levels in the hippocampus, amygdala and putamen in OSAS patients indicate hypoxia and likely cause vasogenic oedema in specific regions of the brain. PMID- 23751446 TI - Transcranial direct current stimulation changes human endowment effect. AB - To test whether the right inferior frontal gyrus (IFG) plays role in the endowment effect, we investigated the effects of transcranial direct current stimulation (tDCS) of the right IFG on the willingness to accept/willingness to pay (WTA/WTP) discrepancy. Twelve healthy subjects underwent anodal, cathodal and sham tDCS on separate days. Stimulation was applied over the right IFG for 20min at 2mA. Subjects participated in the pricing task where they evaluated the presented items under WTA and WTP framings during tDCS intervention. The results showed that the WTA/WTP ratio after anodal tDCS was significantly higher than that after cathodal one. In addition, we found that the reaction time during the cathodal tDCS condition was significantly longer compared to those during anodal or sham tDCS conditions. Our findings suggest the functional relevance of the right IFG for producing endowment effect. PMID- 23751447 TI - Protective effect of angiotensin-converting enzyme inhibitor therapy among persons with HIV and proteinuria. PMID- 23751448 TI - Nanomaterial interference with early human placenta: Sophisticated matter meets sophisticated tissues. AB - Next to nothing is known about nanoparticle and nanofiber trafficking at the feto maternal interface in early human pregnancy. As the first trimester is thought to be crucial for the further placental and fetal development, it will be important to assess the possible risks of nanomaterial exposures during this period. There are some intriguing observations in nanotoxicology, however, indicating certain differences between classical toxicology and nanotoxicology. To understand nanomaterial-biokinetics and placental toxicity in early gestation, the special architecture, the hypoxic condition, the bilayer of villous trophoblast, the plugging of spiral arteries and the contribution of intrauterine glands to nutrition, as well as the delicate immunologic situation at the implantation site, will have to be considered. Unless nano-specific biokinetics are properly understood, it will be difficult to ensure identification of potential "nano thalidomides" among all the newly engineered nanoparticles and fibers, based on the models available in reproductive toxicology. PMID- 23751449 TI - Sonic hedgehog expression is disrupted following in ovo ethanol exposure during early chick eye development. AB - The eye is particularly sensitive to ethanol's teratogenic effects. Our previous work, using a chick embryo model system, has shown that ethanol acts rapidly to perturb vital processes of early eye development producing defects of the lens and retina. Ethanol-induced disruption of the midline ventral telencephalon, a key site for expression of ocular morphogens such as sonic hedgehog (Shh), was further established. Consequently, in this study we have examined the effects of ethanol on the Shh pathway during the period of optic vesicle/optic cup formation. Chick embryos were injected in ovo with 125MUL of a 20% ethanol solution directly into the yolk-sac at HH-stage 7, resulting in peak ethanol uptake of 0.294g/dL. Subsequent molecular analysis at 12, 24 and 48h post treatment revealed that ethanol had no affect on Shh transcription, while, a significant reduction in the expression of the active signalling Shh protein was found. Surprisingly, none of the downstream Shh pathway members (Ptc, Gli1 and Gli3) were significantly altered by ethanol exposure. Overall, our results indicate that ethanol's disruption of Shh may be mediated through some alternative mechanism independent of the classical signalling pathway. However, the precise role of Shh in relation to ethanol teratogenicity continues to be debated. Thus, in conclusion, our findings are discussed in relation to the varied and often conflicting reports of ethanol-induced Shh perturbation found in the literature. PMID- 23751450 TI - Achieving the right volume of randomized controlled trials. PMID- 23751451 TI - Extending indications for islet autotransplantation in pancreatic surgery. AB - OBJECTIVE: To assess metabolic and oncologic outcomes of islet autotransplantation (IAT) in patients undergoing pancreatic surgery for either benign or malignant disease. BACKGROUND: IAT is performed to improve glycemic control after extended pancreatectomy, almost exclusively in patients with chronic pancreatitis. Limited experience is available for other indications or in patients with pancreatic malignancy. METHODS: In addition to chronic pancreatitis, indications for IAT were grade C pancreatic fistula (treated with completion or left pancreatectomy, as indicated); total pancreatectomy as an alternative to high-risk anastomosis during pancreaticoduodenectomy; and distal pancreatectomy for benign/borderline neoplasm of pancreatic body-neck. Malignancy was not an exclusion criterion. Metabolic and oncologic follow-up is presented. RESULTS: From November 2008 to June 2012, 41 patients were candidates to IAT (accounting for 7.5% of all pancreatic resections). Seven of 41 did not receive transplantation for inadequate islet mass (4 pts), patient instability (2 pts), or contamination of islet culture (1 pt). IAT-related complications occurred in 8 pts (23.5%): 4 bleeding, 3 portal thromboses (1 complete, 2 partial), and 1 sepsis. Median follow-up was 546 days. Fifteen of 34 patients (44%) reached insulin independence, 16 patients (47%) had partial graft function, 2 patients (6%) had primary graft nonfunction, and 1 patient (3%) had early graft loss. Seventeen IAT recipients had malignancy (pancreatic or periampullary adenocarcinoma in 14). Two of them had already liver metastases at surgery, 13 were disease-free at last follow-up, and none of 2 patients with tumor recurrence developed metastases in the transplantation site. CONCLUSIONS: Although larger data are needed to definitely exclude the risk of disease dissemination, the present study suggests that IAT indications can be extended to selected patients with neoplasm. PMID- 23751452 TI - Treatment of vascular Ehlers-Danlos syndrome: a systematic review. AB - OBJECTIVE: To provide the collected evidence from all literature reports. BACKGROUND: Vascular Ehlers-Danlos syndrome (EDS) is a rare connective tissue disorder with serious hemorrhagic consequences. Most experience on treatment is based on case reports and small case series. METHOD: A systematic literature review was performed. PubMed and reference lists were scrutinized. RESULTS: A total of 231 patients were identified with no gender preponderance. Aneurysms were present in 40%, often multiple. In 33%, there was an arterial rupture without an underlying aneurysm. Carotidocavernous fistula was seen in 18%. After open surgery the mortality was 30%; after endovascular procedures, it was 24%; in a group of miscellaneous cases, it was 60%; and the overall mortality was 39%. The median age of patients at death was 31 years. The median follow-up time was 12 months (5 days-7 years), but in 20% cases, it was not reported. In only 29 of the 119 recent patients (24%) the mutation was verified with molecular genetic testing. CONCLUSIONS: Vascular EDS is a serious disorder with high mortality, which does not seem to have been influenced by new treatment methods. Invasive methods should be used only when necessary, primarily to save the patients' life. Whenever possible, the genetic molecular defect should be identified. The results of this review may be affected by publications bias. Ideally, a prospective registry should be created. PMID- 23751453 TI - Reply to letter: "the role of abdominal imaging in cases with a high probability of acute left-sided colonic diverticulitis based on a clinical scoring system". PMID- 23751454 TI - Single-trial connectivity estimation for classification of motor imagery data. AB - OBJECTIVE: Many brain-computer interfaces (BCIs) use band power (BP) changes in the electroencephalogram to distinguish between different motor imagery (MI) patterns. Most current approaches do not take connectivity of separated brain areas into account. Our objective is to introduce single-trial connectivity features and apply these features to BCI data. APPROACH: We introduce a procedure for extracting single-trial connectivity estimates from vector autoregressive (VAR) models of independent components in a BCI setting. MAIN RESULTS: In a simulated BCI, we demonstrate that the directed transfer function (DTF) with full frequency normalization and the direct DTF give classification results similar to BP, while other measures such as the partial directed coherence perform significantly worse. SIGNIFICANCE: We show that single-trial MI classification is possible with connectivity measures extracted from VAR models, and that a BCI could potentially utilize such measures. PMID- 23751455 TI - Sonochemical synthesis and characterization of lead iodide hydroxide micro/nanostructures. AB - For the first time, micro/nano-sized lead iodide hydroxide; Pb(OH)I, has been successfully prepared via a simple ultrasonic method. In this method, lead nitrate and lithium iodide were applied as starting reagents to fabricate Pb(OH)I micro/nanostructures at different conditions. The effect of different surfactants like N,N-bis(salicylidene)-ethylenediamine (H2salen), sodium dodecyl sulfate (SDS) and polyvinylpyrrolidone (PVP), sonication time, and ultrasonic intensity on the morphology and particle size of the products has been investigated. The as produced micro/nanostructures were characterized with the aid of XRD, SEM, TEM, UV-vis, EDS and FT-IR. According to the SEM images, different morphologies of Pb(OH)I including micro- and nano-sized rods were formed by changing the preparation conditions. Based on the XRD results, it was found that Pb(OH)I and PbI2 have been produced with and without sonication at the same conditions, respectively. The use of the H2salen and sonication treatment were confirmed to be the crucial factors determining the formation of one-dimensional Pb(OH)I micro/nanostructures. PMID- 23751456 TI - Effect of ultrasound and high hydrostatic pressure (US/HHP) on the degradation of dextran catalyzed by dextranase. AB - In our current research work, the effect of combination of ultrasonic irradiation and high hydrostatic pressure (US/HHP) on the enzymatic activity and enzymatic hydrolysis kinetic parameters of dextran catalytic by dextranase were investigated. Furthermore, the effects of US/HHP on the structure of dextranase were also discussed with the aid of fluorescence spectroscopy and circular dichroism (CD) spectroscopy. The maximum hydrolysis of dextran was observed under US (40 W at 25 kHz for 15 min) combined with HHP (400 MPa for 25 min), in which the hydrolysis of dextran increased by 163.79% compared with the routine thermal incubation at 50 degrees C. Results also showed that, Vmax and KM values, as well as, kcat of dextranase under US/HHP treatment were higher than that under US, HHP and thermal incubation at 50 degrees C, indicated that, the substrate is converted into the product at an increased rate when compared with the incubation at 50 degrees C. Compared to the enzymatic reaction under US, HHP, and routine thermal incubation, dextranase enzymatic reaction under US/HHP treatment showed decreases in Ea, DeltaG and DeltaH, however small increase in DeltaS value was observed. In addition, fluorescence and CD spectra reflected that US/HHP treatment had increased the number of tryptophan on dextranase surface with increased alpha-helix by 19.80% and reduced random coil by 6.94% upon US/HHP treated dextranase protein compared to the control, which were helpful for the improvement of its activity. These results indicated that, the combination of US and HHP treatments could be an effective method for improving the hydrolysis of dextran in many industrial applications including sugar manufacturing processes. PMID- 23751457 TI - An Euler-Lagrange method considering bubble radial dynamics for modeling sonochemical reactors. AB - Unsteady numerical computations are performed to investigate the flow field, wave propagation and the structure of bubbles in sonochemical reactors. The turbulent flow field is simulated using a two-equation Reynolds-Averaged Navier-Stokes (RANS) model. The distribution of the acoustic pressure is solved based on the Helmholtz equation using a finite volume method (FVM). The radial dynamics of a single bubble are considered by applying the Keller-Miksis equation to consider the compressibility of the liquid to the first order of acoustical Mach number. To investigate the structure of bubbles, a one-way coupling Euler-Lagrange approach is used to simulate the bulk medium and the bubbles as the dispersed phase. Drag, gravity, buoyancy, added mass, volume change and first Bjerknes forces are considered and their orders of magnitude are compared. To verify the implemented numerical algorithms, results for one- and two-dimensional simplified test cases are compared with analytical solutions. The results show good agreement with experimental results for the relationship between the acoustic pressure amplitude and the volume fraction of the bubbles. The two-dimensional axi-symmetric results are in good agreement with experimentally observed structure of bubbles close to sonotrode. PMID- 23751458 TI - Microbial biofilm modulation by ultrasound: current concepts and controversies. AB - Biofilm elimination is often necessary during antimicrobial therapy or industrial medical manufacturing decontamination. In this context, ultrasound treatment has been frequently described in the literature for its antibiofilm effectiveness, but at the same time, various authors have described ultrasound as a formidable enhancer of bacterial viability. This discrepancy has found no solution in the current literature for around 9 years; some works have shown that every time bacteria are exposed to an ultrasonic field, both destruction and stimulation phenomena co-exist. This co-existence proves to have different final effects based on various factors such as: ultrasound frequency and intensity, the bacterial species involved, the material used for ultrasound diffusion, the presence of cavitation effects and the forms of bacterial planktonic or biofilm. The aim of this work is to analyze current concepts regarding ultrasound effect on prokaryotic cells, and in particular ultrasound activity on bacterial biofilm. PMID- 23751459 TI - Poly(4-vinylpyridine) supported acidic ionic liquid: a novel solid catalyst for the efficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones under ultrasonic irradiation. AB - A novel poly(4-vinylpyridine) supported acidic ionic liquid catalyst was synthesized by the reaction of 4-vinylpyridine with 1,3-propanesultone, followed by the polymerization and the addition of the heteropolyacid. Due to the combination of polymer features and ionic liquid, it acted as a heterogeneous catalyst to effectively catalyze the cyclocondensation reaction of anthranilamide with aldehydes under ultrasonic irradiation and afforded the corresponding 2,3 dihydro-4(1H)-quinazolinones compounds in good to excellent yields. In addition, the catalyst could be easily recovered by the filtration and reused six times without significant loss of catalytic activity. More importantly, the use of ultrasonic irradiation can obviously accelerate the reaction. PMID- 23751460 TI - The importance of disease prevalence in assessing the diagnostic value of a test: endoscopic markers in celiac disease. AB - BACKGROUND/AIMS: We evaluated the diagnostic variability and reproducibility of endoscopic signs in two populations with a different pretest likelihood of celiac disease (CD). METHODS: We recruited 289 CD patients (both adults and children) in a multicenter prospective study. Group 1 (high risk) included 111 patients referred for positive serology. Group 2 (low risk) included 178 unselected patients. Mosaic pattern, reduction/loss of Kerckring's folds, scalloping of the valvulae conniventes and a nodular pattern were the endoscopic findings looked for in the duodenum. RESULTS: In group 1, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of endoscopic findings were 100, 84.6, 94.2 and 100% in adults, and 86.8, 9.1, 82.1 and 12.5% in children. In group 2, the sensitivity, specificity, PPV and NPV of endoscopic findings were 33.3, 91.4, 7.7 and 98.5% in adults, and noncalculable, 78.3, 0.0 and 100% in children. Comparing group 1 and group 2, there was a statistically significant difference in sensitivity and PPV in adults, and in specificity, PPV and NPV in children. Concerning the reproducibility of endoscopic findings, a wide variability of kappa values was found. CONCLUSION: Endoscopic signs have low reproducibility for CD, and their diagnostic value in selecting patients for multiple intestinal biopsies is unacceptable, especially in populations with low disease prevalence. PMID- 23751461 TI - [Lifestyle-related factors and cancer incidence in men: a public health assessment based on a 'healthy lifestyle score']. AB - OBJECTIVE: To evaluate the effects of combined lifestyle-related factors and risk of cancer incidence among adult men in urban Shanghai. METHODS: Information was obtained from 60 817 men in the Shanghai Men's Health Study (2002 - 2006) program and 2033 incident cancers who were confirmed at the end of 2009. A healthy lifestyle score (HLS) system was developed, based on five lifestyle-related factors, and participants were scored one point for each of the healthy behaviour: never smoked, alcohol intake less than 1 drink/day, under normal weight range (18.5 - 27.9 kg/m(2)), physical activity (>= 54 Met-hours/week), fruit and vegetable intake >= 451 g/day, the else would score as zero. The total score would range from zero to five. Cox regression model was used to evaluate the associations between combined lifestyle-related factors and the cancer incidence. RESULTS: Compared to men having scores as zero or one, the hazard ratios (95% confidence intervals) for men with two, three, four, five health behaviour scores were 0.77 (95%CI: 0.66, 0.90), 0.67 (95%CI: 0.58, 0.78), 0.56 (95%CI: 0.47, 0.65), 0.51 (95%CI: 0.42, 0.62), respectively. The population attributable risks for cancer incidence was 10.4% for those having scores less than 3 items. CONCLUSION: Never smoked, moderate alcohol intake, maintaining normal weight, being physically fit, and having enough daily fruit and vegetable intake were associated with lower risk of total cancer incidence in men. Our data showed that healthy lifestyle could significantly benefit the public health programs of the population. PMID- 23751462 TI - [The protective effects of green tea drinking and garlic intake on lung cancer, in a low cancer risk area of Jiangsu province, China]. AB - OBJECTIVE: To understand the relationship between green tea drinking and/or garlic consumption and lung cancer. METHODS: A population-based case-control study was conducted in Ganyu county, Jiangsu province. Epidemiological data including demography, lifestyle, environmental exposures and dietary habits were collected by face-to-face interviews using a standardized questionnaire. Unconditional logistic regression was used to estimate adjusted odds ratios (OR) and their 95% confidence intervals (CI) in both univariate and multivariate analyses. RESULTS: Both green tea drinking and garlic consumption were inversely associated with lung cancer and the adjusted ORs were: 0.78 (95%CI: 0.65 - 0.95) for green tea, 0.79 (95%CI: 0.66 - 0.95) for garlic intake, and 0.69 (95%CI: 0.53 - 0.89) for both, respectively. They also modified the associations of smoking, fried food intake and cooking oil under high-temperature with lung cancer as risk factors. Potential interactions were found between garlic or green tea and the risk factors of lung cancer. CONCLUSION: Both green tea drinking and garlic consumption might serve as protective factors on lung cancer. PMID- 23751463 TI - [Contrast and efficacy of waist circumference and waist-to-height ratio in predicting central obesity]. AB - OBJECTIVE: To study the efficacy of waist circumference (WC) and waist-to-height ratio (WHtR) in predicting central obesity among the Chinese adult population. METHODS: A total of 30 630 participants aged 35 - 59 from different areas in mainland China were surveyed for the risk factors of cardiovascular diseases (CVD) in two independent cross-sectional studies that were carried out in 1992 - 1994 and 1998, respectively. In subgroups with different heights, consistency analysis for central obesity diagnosed by WHtR (>= 0.50) and WC (>= 85 cm for men, >= 80 cm for women) were conducted. Sensitivity and specificity for predicting the clustering of risk factors (number >= 2) would include hypertension, abnormal glucose, high serum total cholesterol and low serum high density lipoprotein cholesterol and they were also calculated to evaluate the efficacy of prediction, with the two indices in the different height subgroups as well. RESULTS: The consistency of diagnosis on central obesity by WC and WHtR was good in the whole population (the Kappa value was 0.805 in men and 0.816 in women), but poor (all Kappa values <= 0.6) for those with tall (men's height >= 180 cm and women's height >= 170 cm) or with short statures (men's height < 160 cm, and women's height < 150 cm). Sensitivity in the shorty subgroups and specificity in the tall subgroups appeared poor in both genders, by using WC criteria to predict the clustering of risk factors. However, the sensitivity (ranged from 56.1% to 64.1% for men and 64.7% to 73.2% for women) and specificity (from 70.0% to 74.5% for men, 59.2% to 75.9% for women) seemed good and stable in all the subgroups as well as in both genders by using the WHtR criteria. CONCLUSION: WC and WHtR could both be applied in predicting the clustering of risk factors of CVD and in evaluating the central obesity in the whole population. With satisfactory efficacy, WHtR seemed to be better than WC in the prediction of central obesity, both in men or women with tall or short statures. PMID- 23751464 TI - [Study on waist circumference and hip circumference of 7 - 18 year-old children and adolescents in Shandong province]. AB - OBJECTIVE: To study the development of waist circumference (WC) and hip circumference (HC) in children and adolescents in Shandong province, and to provide scientific data for developing related reference values for screening central obesity in Chinese children and adolescents. METHODS: Using data from 'Student physical fitness and health surveillance 2010 project' in Shandong province, a total of 42 275 students aged 7 - 18 years were selected to participate in this study. WC, HC, waist-to-hip ratio (WHR) and wrist-to-stature ratio (WSR) of subjects were measured. Comparison of data from the current study and other similar studies was made. RESULTS: The mean values of WC increased with age, and boys all significantly higher than girls in all age categories (P < 0.01). There were two crosses on gender regarding the HC curves: before the age of 11 years, with mean HC higher in boys than in girls, but girls were higher than boys between the age of 12 to 14 while boys were also higher than girls after the age of 15 years. The 50(th) percentiles (P(50)) of WC of children and adolescents aged 7 to 18 years in Shandong appeared above the figures by 1.3 - 3.1 cm (boys) and 1.2 - 2.0 cm (girls) from 15 provinces in China as well as above the data from Hong Kong by 1.9 - 5.4 cm (boys) and 2.0 - 6.5 cm (girls), respectively. Overall, 20.20% of the boys and 16.57% of the girls had a WC of >= 90(th) percentile and 15.73% and 7.38% of the boys and girls had a WHtR of >= 0.5 which both showed significant differences between genders (P < 0.01). CONCLUSION: Children and adolescents from Shandong province had a high level of WC. PMID- 23751465 TI - [Study on the risk factors of tuberculosis in four cities and provinces in China]. AB - OBJECTIVE: To investigate the influencing factors on tuberculosis (TB) in four provinces in the eastern and central parts of China. METHODS: From Nov. 2009 to Feb. 2011, three population-based field surveys were conducted among the resident population in several townships/streets in Guangdong, Hunan and Jiangsu provinces and Shanghai municipality to collect TB-related information. 474 sputum smear positive TB patients and 1896 controls were randomly selected from the population under study and each case was matched by province, age and sex using a frequency matching method. Single-variable and multiple non-conditional logistic regression modeling were applied for data analysis, and odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated. RESULTS: Data from Single-variable analysis showed that TB history, history of exposure to TB, DM history, immigrant population and per-capita living space were risk factors for TB, and high level of education was protective factors. RESULTS: from multiple logistic regression showed that the risk factors of TB would include the following items: history of having had TB (OR = 52.356, 95%CI: 18.956 - 144.607), living space over 50 m(2)per-capita (OR = 8.742, 95%CI: 1.107 - 69.064), history of exposure to TB (OR = 6.083, 95%CI: 2.336 - 15.839) and being immigrants (OR = 3.306, 95%CI: 1.907 - 5.734), while having had high degree of education as the protective factor of TB (OR = 0.284, 95%CI: 0.110 - 0.733). CONCLUSION: Control programs targeting those ever having TB patients and contacts to TB patients as well as immigrants should be strengthened. PMID- 23751466 TI - [The long term (9-year) survival of multidrug-resistant tuberculosis patients compared to non-multidrug-resistant tuberculosis patients in Henan province]. AB - OBJECTIVE: To investigate the long term survival of MDR-TB patients compared to non-MDR-TB in Henan province in 2010. METHODS: Participants were randomly selected in 2010 from a dataset generated by an anti-TB drug resistance surveillance survey conducted by the Tuberculosis Control Institute, Henan Centre for Disease Control and Prevention in 2001, supported by the World Health Organization. Information on patient's demographic profile and medical records was extracted by trained doctors and nurses at local anti-TB dispensaries. Interviews were carried out using questionnaires to collect information on the socioeconomic features and survival status. Bivariate and multivariate with logistic regression were performed for data analysis. RESULTS: The long term outcome of MDR-TB patients was much poorer when compared to non-MDR-TB patients. The case fatality was much higher among MDR-TB than non-MDR-TB patients (22.1% vs. 6.7%). The risk factors associated with the poorer outcome would include drug resistance status, disease relapse, hospitalization for treatment and long treatment period. Compared to non-MDR-TB, the survival time for MDR-TB was much shorter after having had the disease (6.7 years vs. 8.0 years). CONCLUSION: MDR TB patients had poor long term outcomes. As most of the cured TB patients were under productive age in the society, the high case fatality rate of MDR-TB would impose big burden on the related family and communities. Findings from this study suggested that the TB control programs should involve more efforts be paid on MDR TB control, in order to reduce the burden of the disease. PMID- 23751467 TI - [Survey on status of smoking, passive smoking and quitting smoking in rural areas of the midwestern provinces in China]. AB - OBJECTIVE: To study the status of smoking, passive smoking and quitting smoking in rural areas of the middle and western regions in China, and to develop strategies for improvement. METHODS: A total of 5486 residents aged 15 to 69 years in 84 villages of the 16 counties in Gansu, Qinghai, Shanxi and Xinjiang were selected through a stratified multistage cluster random sampling method to collect information through questionnaires. Data on the initiate age of smoking, and rates on smoking, passive smoking, quitting smoking as well as related knowledge were used as nutritional indicators. RESULTS: The overall smoking rate was 20.9%, with 44.8% in males and 2.0% higher than seen in females. The rate of smoking in Han nationality was higher than that in other minorities. There were significant differences seen in genders and nationalities as well the level of education received, in the rates of smoking. Smokers started to smoke at the age of 21.3 +/- 5.6 with males earlier than females. The rate of passive smoking was 37.8%, with males as 31.9%, and females as 40.4%, respectively. The rate of quitting smoking appeared as 1.9%. CONCLUSION: The status of smoking in the rural areas of middle and western regions in China faced challenges, with relatively low rate of quitting smoking. Relevant strategies need to be developed accordingly. PMID- 23751468 TI - [Present situation of congenital defects in five counties (cities) of Gansu province in 2009 - 2010]. AB - OBJECTIVE: To understand the situation of congenital defects' in five counties/cities in Gansu province so as to provide scientific evidence for the development of effective interventions. METHODS: General information was collected on all the neonates who were born in Dunhuang city, Jingchuan county, Hui county, Weiyuan county and Yongjing county in Gansu province between Oct. 1(st), 2009 to Sep. 30(th), 2010, with all of their gestational age above 28 weeks. Neonates would include live birth, dead fetus and still birth. RESULTS: The overall incidence of congenital defects was 7.490/00 in the five counties/cities in Gansu province in 2009. Ranking order in the top three showed as congenital heart disease, pigmented nevus and limb deformity. Disease with the highest mortality was congenital heart disease (0.790/00). The incidence of congenital defects was 8.350/00 in 2010 with the ranking order of the top three as congenital heart disease, neural tube defects/pigmented nevus and hydrocephalus. Diseases having the highest mortality was congenital heart disease (1.100/00). Different incidence rates on congenital defects were seen in related areas, with the highest incidence as 14.650/00 in Dunhuang city. Hui county had the lowest incidence-3.280/00. CONCLUSION: Different incidence of congenital defects were seen in respective areas in Gansu province, with the change of ranking orders. Different strategies should be developed differently depending on the current states of congenital defects in respective areas, according to the three-grade prevention model, to reduce the occurrence of congenital defects. PMID- 23751469 TI - [Depression and associated factors among migrant women of reproductive age in some areas of Wuhan]. AB - OBJECTIVE: To understand factors as social support, situation of depression and related risk factors among migrant women of reproductive age in some areas of Wuhan. METHODS: Cluster sampling method and face-to-face interview with structured questionnaire were used to investigate 316 migrant women in Wuhan. RESULTS: The overall prevalence rate of depression was 32.3%. RESULTS: from binary logistic regression analysis showed that factors as: under pressure (OR = 4.010, 95%CI: 1.672 - 9.617), having had negative life events (OR = 2.050, 95%CI: 1.170 - 3.591) or tight relations with neighbors (OR = 2.537, 95%CI: 1.053 - 6.113), not quite satisfied (OR = 4.247, 95%CI: 1.521 - 11.855) or satisfied (OR = 2.411, 95%CI: 1.111 - 5.233), on his/her own health status etc., might serve as the possible risk factors for depression. In scores related to social support, and the utilization of such support, there were statistically significant differences seen between the groups with depression and the one without. CONCLUSION: The prevalence of depression among migrant women of reproductive age appeared to be high in some areas on Wuhan. Factors as: under pressure, having had negative life events, tight relations with neighbors, status on satisfaction of one's own health situation as well as related social support, seemed to be the main risk factors for depression in this population. PMID- 23751470 TI - [Prevalence of Anaplasma spp. infection in a desert landscape region of Heshuo, Xinjiang]. AB - OBJECTIVE: To study the prevalence of Anaplasmosis among human, domestic sheep and tick population in Heshuo area, southern Xinjiang and to investigate the diversity of Anaplasma species. METHODS: Ticks were captured from wild field and blood samples were collected from healthy residents and their domestic sheep. Indirect fluorescent assay was carried out to determine the presence of Anaplasma specific IgG antibodies in blood sample of human and goats, respectively. Nested PCR and sequence alignment of Anaplasma partial 16S rDNA were used to investigate the diversity of Anaplasma species. RESULTS: 43.31% (55/127) of human beings and 27.50% (55/200) of the goats were found positive for Anaplasma specific IgG. In total, 367 ticks were captured, including 3 genus and 4 species, which mainly consisting of dominate Hyalomma (H.) asiaticum (47.41%) and Rhipicephalus (R.) pumilio (37.60%). 5.00% (18/360) of the questing ticks and 4.49% (7/156) of the goat blood samples were found to have had 16S rDNA, representing Anaplasma sp. by nested PCR, but none was found from human beings. Results from sequential alignment revealed that the positive amplicons were identified to be Anaplasma phagocytophilum (99.2% GU046565, 99.5% GU064897 and 99.5% AB196721) and Anaplasma central (99.2% GU064903). CONCLUSION: Human and zoonotic anaplasmosis, which were probably transmitted by H. asiaticum and R. pumilio, were co-circulating in the desert landscape of Heshuo area, Xinjiang. PMID- 23751471 TI - [Geographical distribution and host selection of Leptotrombidium rubellum in some parts of Yunnan province]. AB - OBJECTIVE: To investigate the geographical distribution and host selection of Leptotrombidium rubellum among different small mammal hosts in some areas of Yunnan province, China. METHODS: Field survey was carried out in 23 counties of Yunnan province between 2001 and 2011. Small mammal hosts were captured with mouse cages and traps with baits. Chigger mites on the surface of two auricles were scraped off by a bistoury, and then preserved in 70% ethanol. Every specimen of the chigger mites on the slides was finally identified into species under a microscope. Some conventional statistical methods were adopted to calculate all the collected chigger mite species and the constituent ratios of L. rubellum in different areas and on different hosts, with prevalence (P), mean intensity (MI) and mean abundance (MA) on different hosts calculated. Linear regression was used to analyze the relationship among P, MI and MA. Patch index (m*/m) was used to measure the spatial patterns of L. rubellum among different individuals of related small mammal hosts. RESULTS: A total of 108 480 chigger mites were collected from the body surface of all the captured small mammal hosts. All the collected chigger mites were identified as 3 subfamilies, 24 genera and 234 species. Of the 234 species of chigger mites, 654 individuals of L. rubellum were collected, only in 4 counties. The collected individuals of L. rubellum accounted for 0.603% of the total mites (108 480 individuals). 96.637% of L. rubellum came from flatland areas and habitats while only 3.363% of the L. rubellum were from the mountainous regions. The orderings of the hosts appeared as Rodentia and Insectivora harbored 96.296% and 2.469% respectively, of the collected while Lagomorpha and other orders there was no L. rubellum found. Of 67 species (in 34 genera and 12 families of 5 orders), Rattus tanezumi (in genus Rattus and family Muridae of Rodentia) harbored 96.788% of the collected L. rubellum with relatively low prevalence (P = 3.776%) or mean intensity (MI = 8.792 mites/per host), followed by Bandicota indica. Data from the patch index showed that L. rubellum had an aggregated distribution pattern among different individuals of their hosts. CONCLUSION: L. rubellum existed in Yunnan province with relatively rare numbers of the individuals. In Yunnan province, L. rubellum was mainly found in the flatland regions and habitats with relatively low altitude. L. rubellum could parasitize several different species of hosts with low host specificity, but it prefered to choose Rattus tanezumi and some other house-dwelling small mammals as its main hosts. PMID- 23751472 TI - [Predictors for abundance of Rattus tanezumi in households of commensal rodent plague foci]. AB - OBJECTIVE: To explore the predictors on the abundance of Rattus (R.) tanezumi in households of commensal rodent plague foci. METHODS: Thirty natural villages that experienced previous plague cases in Lianghe county, Yunnan province, were selected followed by random selection of 20 households in each village through computer technique. Live traps were set in households to capture small mammals which were then identified to species in the field according to their morphological features. Data on potential factors for abundance of R. tanezumi were collected through questionnaires and field observation and were coded and computerized using EpiData software and further analyzed by hurdle regression model under R software. RESULTS: A total of 166 rodents (133 R. tanezumi and 33 Suncus murinus) were captured. RESULTS: from final multilevel hurdle regression model showed that the likelihood of R. tanezumi captures increased by 1.67- to 2.76-fold in households belonged to Dai ethnic families that stored foodstuff in metal pail, often raising dogs, and having adjacent houses. The number of R. tanezumi captures increased by 2.18-fold in the villages where over 80% of the households would raise chickens. In the villages with communal latrine, the likelihood and the number of R. tanezumi capture increased 1.93-fold and 2.38 fold, respectively. While the likelihood of R. tanezumi captures would reduce by 45% - 61% in those households where there were cats and cattle being raised and maize grown in the village. The number of R. tanezumi captures would reduce by 63% in the households where there were outside toilet. CONCLUSION: The abundance of R. tanezumi seemed to be closely related to the ecological environment factors. Programs on plague control and prevention should relate to ecological factors that influencing the abundance of R. tanezumi. PMID- 23751474 TI - [Incidence and mortality of oral and pharyngeal cancers in China, 2003 to 2007]. AB - OBJECTIVE: To analyze the incidence and mortality of oral and pharyngeal cancers from 32 cancer registration centers, 2003 to 2007. METHODS: Data from 32 eligible cancer registries were included in this study. Both crude and age-standardized incidence and mortality of oral and pharyngeal cancers from 2003 to 2007 were calculated and stratified by area and gender. Age-stratified incidence and mortality, as well as the proportions of new and death cases of oral and pharyngeal cancer were also calculated at each site. RESULTS: Mouth, tongue and salivary gland were the most predilection sites of oral and pharyngeal cancers. The crude incidence for both oral and pharyngeal cancers was 3.15/10(5) from 2003 to 2007. The age-standardized incidence rates using the Chinese population (1982) and the World Segi's population were 1.75/10(5) and 2.26/10(5). The crude mortality of oral and pharyngeal cancer was 1.37/10(5) from 2003 to 2007; with age-standardized mortality rates, using the Chinese population (1982) and the World Segi's population were 0.69/10(5) and 0.94/10(5). Both incidence and mortality were higher in males than in females, higher in urban than in rural areas, and ascended with age. Age-standardized incidence and mortality in Zhongshan city ranked first among all the cancer registration areas. Age standardized incidences by gender and area increased slightly from 2003 to 2007, while age-standardized mortalities were stable. CONCLUSION: Although the incidence and mortality of oral and pharyngeal cancer were low in China from 2003 to 2007, attention should also be paid since the exposure of relative risk factors did not seem to have reduced and the incidence increased slightly. PMID- 23751473 TI - [Trend and prediction on the incidence of pancreatic cancer in China]. AB - OBJECTIVE: To analyze and predict the incidence trends and burden of pancreatic cancer from 2008 to 2015. METHODS: Registration data on pancreatic cancer of cancer registration in 1998 - 2007, were retrieved and utilized for analyzing the annual incidence of pancreatic cancer. Age-standardized rate by Chinese population (ASR) was calculated, using the direct method. JoinPoint software was applied for trend analysis. Bayesian Age-Period-Cohort Modeling Prediction Package was used to estimate age, period and cohort effects as well as to predict the incidence rates. RESULTS: From 1998 to 2007, the annual incidence for men and women in urban areas showed an increase of 1.86% and 2.1% per year, but the increasing trend on the age-standardized rate was not obvious in both men and women. However, the incidence rates for men and women in rural areas increased by 7.54% and 7.83% and the age-standardized rates increased by 4.82% and 5.48% per year. RESULTS: from the projection model showed that the trends were mainly caused by age, period and cohort effects. Based on the analysis, up to 2015, the annual new cases of pancreatic cancer would be 103 428 (60 500 for males and 42 928 for females), with 15 277 cases more than that of 2008. CONCLUSION: There appeared an increasing trend of pancreatic cancer incidence which was more significant in the rural areas than the slowly increasing trend in the urban areas. The increasing trend of pancreatic cancer would be slow until the year 2015. However, in the short term pancreatic cancer is still a major cancer. PMID- 23751475 TI - [Analysis on the spatial clustering of tuberculosis based on provincial level in China from 2008 to 2010]. AB - OBJECTIVE: To study the tuberculosis clustering areas and the changing trend, from 2008 to 2010, so as to provider the reference for tuberculosis control. METHODS: Global spatial autocorrelation and SaTScan methods were used to detect and analyse the spatial clustering of total tuberculosis notification rate and the new smear-positive pulmonary tuberculosis notification rate, at the provincial level from 2008 to 2010. RESULTS: The spatial clustering (SC) phenomenon was significant on total notification rate and new smear-positive pulmonary tuberculosis notification rate from 2008 to 2010 (P < 0.01). The coverages of clustering areas on total notification rate showed a reduction from 19 provinces to 14 provinces, distributed in the south, west and north-east areas of China. The coverages of clustering areas on new smear-positive pulmonary tuberculosis notification rate concentrated in 14 provinces which covered the south and north-east of China. CONCLUSION: The disease burden and the risk of transmission in the clustering areas of tuberculosis both located in the south and the north-east of China. The disease burden of tuberculosis was high in the west of China, but not the areas with high risk of transmission. PMID- 23751476 TI - [Effect of folate in modulating the expression of DNA methyltransferase 1 and methyl-CpG-binding protein 2 in cervical cancer cell lines]. AB - OBJECTIVE: To explore the effects of folate on the expression of DNA methyltransferase 1 (DNMT1) and methyl-CpG-binding protein 2 (MeCP2) in cervical cancer cell lines. METHODS: Experimental study was carried out in vitro. Human cervical cancer cell lines, including C33A cell with HPV negative and Caski cell with HPV16 positive, were treated with different concentration of folate. The expression of DNMT1 and MeCP2 protein (by Western blot) and mRNA (by real-time PCR) were then detected in the two cell lines. RESULTS: It was found that supplement of folate was able to reduce the cell proliferation in C33A cell (r = 0.984, P < 0.001) and Caski cell (r = 0.978, P = 0.002), as well as induced the cell apoptosis (C33A: r = 0.989, P < 0.001; Caski: r = 0.994, P < 0.001). RESULTS: showed that the expression levels of DNMT1 protein (C33A: r = -0.914, P < 0.001; Caski: r = -0.859, P = 0.003) and MeCP2 protein (C33A: r = -0.830, P = 0.005; Caski: r = -0.981, P < 0.001) decreased gradually with the increase of folate concentrations, but the expression of DNMT1 and MeCP2 mRNA was not observed in Caski or C33A cell. When at the same levels of folate, the expression of DNMT1 protein or mRNA was higher in Caski cell than in C33A cell. However, the expression of MeCP2 protein or mRNA was higher in C33A cell than in Caski cell. CONCLUSION: Our finding indicated that adequate folate could effectively inhibit the proliferation of cervical cancer cells and facilitate their apoptosis in vitro, thus would reverse the aberration protein expression of DNMT1 and MeCP2. That there might be a synergistic action between HPV16 infection and parafunction of DNMT1 in cervical cancer, being noticed. PMID- 23751478 TI - [Association between the interaction polymorphisms of interleukin-10 and smoking on patients with bladder cancer risk from a case-control study]. AB - OBJECTIVE: To investigate the relationship between both polymorphisms of interleukin-10 (IL-10), smoking and the susceptibility to bladder cancer. METHODS: A case-control study was conducted to study the promoter polymorphisms of IL-10 gene by allele specific PCR amplification (AS-PCR) and to explore the possible genetic and environmental factors on bladder cancer, based on data from a hospital which included 400 patients with bladder cancer and another 400 healthy controls. RESULTS: The genotypes of IL-10 gene might be associated with the susceptibility to bladder cancer. Homozygous mutant of IL-10 gene at the point of 1082, 819 and 592 could enhance the risk of bladder cancer (OR value is 2.058, 1.979, 1.979, respectively). No statistically significant correlation was found between the divergence of IL-10 genotype and the different clinical stages and pathological grade of bladder cancer (P > 0.05). Interactions were noticed between polymorphisms in IL-10 gene and their correlation with smoking on bladder cancer. The positive interaction of 1082 site homozygous variant (AA), 819 site homozygous variant (TT), 592 site homozygous variant (AA) and smoking were revealed in the occurrence rates of bladder cancer (OR = 2.264, gamma = 10.213; OR = 2.438, gamma = 6.750; OR = 2.438, gamma = 6.750). CONCLUSION: Our research findings showed that the significant interactions between IL-10 gene with homozygous mutant and smoking might increase the risk of bladder cancer. PMID- 23751477 TI - [Relationship between the expression of HBV DNA, HBV cccDNA in human ovary tissues and the HBV intrauterine infection]. AB - OBJECTIVE: To investigate the relationship between hepatitis B virus (HBV) deoxyribonucleic acid (DNA) and HBV covalently closed circular DNA (cccDNA) in the ovary and HBV intrauterine infection. METHODS: HBV DNA and HBV cccDNA were assayed in the ovaries of 33 pregnant women who were positive for HBV DNA, tested by Fluorescent quantitative polymerase chain reaction (FQ-PCR). The level of HBV mark (HBVM) and the content of HBV DNA in peripheral blood of infants were measured by chemoluminescence and FQ-PCR methods respectively. RESULTS: The overall positive rate for both HBV DNA and HBV cccDNA in ovarian samples was 51.52% (17/33). The rate on intrauterine infection among infants was 12.12% (4/33) and all the 4 infected infants were delivered from mothers with normal hepatic function. When HBV DNA and HBV cccDNA were both positive, the rate of intrauterine infection in infants was significantly higher than those who were with both negative results (P < 0.05). Levels of HBV cccDNA and the rate of positive samples were significantly higher in mothers with infants who appeared to have had intrauterine infection than those did not (P < 0.01 and < 0.05, respectively). CONCLUSION: HBV infection could be discovered in the human ovary and might be transmitted to the filial generation via ovum. PMID- 23751479 TI - [Analysis on the clinical and prognostic features of 71 male patients with breast cancer]. AB - OBJECTIVE: Male breast cancer (MBC) is a rare disease, with clinical and prognostic features still controversial. The aim of this study was to discuss the clinical characteristics and prognosis of MBC. METHODS: Clinical data related to 71 MBC patients was reviewed. RESULTS: The radio of MBC to female breast cancer (FBC) was 42:10 000. Age related to the diagnosis of MBC ranged from 43 to 84 years with the median age as 62 years old, older than the FBC patients (t = 6.355, P = 0.000). The percentage of invasive ductal carcinoma in MBC patients was much higher than in FBC patients (chi(2) = 29.875, P = 0.000). The positive rate of estrogen receptor (ER) was significantly higher than those in FBC patients and the positive rates of human epidermal growth factor receptor-2 (HER 2) were less frequently (chi(2) = 3.741, P = 0.048 and chi(2) = 12.845, P = 0.002) seen. Data from the univariate and multivariate analysis showed that the 3 , 5- and 10-year survival rates of MBC were 82.6%, 74.0% and 47.4% respectively, significantly higher than those in FBC patients (P = 0.004, P = 0.046). Patients with positive HER-2 showed worse prognosis than HER-2 negative patients in MBC patients (chi(2) = 4.219, P = 0.040). CONCLUSION: There were significant clinic pathologic and prognostic differences between FBC and MBC patients. The HER-2 positivity seemed to be an important factor for the prognosis and treatment of patients with MBC. PMID- 23751480 TI - [Comparison on the predictive values of four screening methods regarding cervical cancer]. AB - To compare the predictive values of 5% acetic acid stain and visual inspection, human papillomavirus (HPV) Self test, ThinPrep Pap and HPV direct test in screening for cervical cancer with biopsy as gold standard. Positive predictive values and negative predictive values were compared simultaneously by joint hypothesis tests and then either positive predictive values or negative predictive values of the any two screening tests were compared by marginal regression based on both GEE and weighted least square methods. Hochberg method was used for multiplicity adjustment. It was showed that HPV direct test had the highest negative predictive value and ThinPrep Pap the highest positive predictive value. 5% acetic acid stain and visual inspection had both the lowest positive predictive value and negative predictive value. Both HPV direct test and ThinPrep Pap were efficient, but the latter required compatible infrastructure and skilled caregivers to go with. Both 5% acetic acid stain and visual inspection were inexpensive, and their positive predictive value and negative predictive value were lower than HPV self-test. They also had similar positive predictive value with HPV direct test and similar negative predictive value with ThinPrep Pap. HPV self-test appeared to be efficient, suggesting that it had significant potential for screening program to be implemented in the rural areas of China since the test could be performed without speculum examination in low resource regions. PMID- 23751481 TI - [Exploratory development of automated coding software on the underlying causes of death]. AB - To develop an automated coding software related to the underlying causes of death, based on the National Registration Information System on deaths, which could improve the quality of coding on the underlying causes of death in the conventional death surveillance system. Following the coding rules of the underlying death cause of ICD-10 and the design on principles of software of underlying death cause automated coding from some other countries, as well as in accordance with the coding strategy table from the USA, we implemented the automatization of the underlying death cause coding. Based on national registration information system on cause of death, an automated coding software of underlying death cause was developed with the coding correction rate closed to 85%. The automated coding software of underlying death cause could code the death cases of underlying death cause with high rate of correction, similar to that of the same kind software developed in other countries. PMID- 23751482 TI - [The formation of toxigenic Vibrio cholerae]. PMID- 23751483 TI - Association of urinary sodium/creatinine ratio and urinary sodium/specific gravity unit ratio with blood pressure and hypertension: KNHANES 2009-2010. AB - BACKGROUND: We investigated the association between urinary sodium/creatinine ratio (U[Na(+)]/Cr) or urinary sodium/specific gravity unit ratio (U[Na(+)]/SGU), estimated from spot urine, and blood pressure (BP) and hypertension. METHODS: The study population consisted of a total of 9674 adults (4478 men, 5196 women) who participated in the Korea National Health and Nutrition Examination Surveys conducted in 2009 and 2010. Urine levels of sodium and creatinine, urine specific gravity (SG), and BP were measured along with other risk factors of hypertension. SGU is the calculated parameter of (SG-1)*100. RESULTS: There were significant trends of increasing mean systolic and diastolic BPs and prevalence of hypertension with increasing quartile of U[Na(+)]/Cr and U[Na(+)]/SGU. After adjusting for age, total cholesterol, alcohol drinking, obesity, current smoking, mild renal dysfunction, and diabetes mellitus, the odds ratios (ORs) for hypertension in the top quartile of U[Na(+)]/Cr compared with the bottom quartile were 1.40 in men and 2.68 in women. Similarly, the ORs for hypertension in the top quartile of U[Na(+)]/SGU were 1.29 in men and 3.02 in women after adjustment. CONCLUSIONS: U[Na(+)]/Cr and U[Na(+)]/SGU are associated with BP and hypertension, supporting the possible clinical value of U[Na(+)]/Cr and U[Na(+)]/SGU in general medical facilities. PMID- 23751485 TI - Metabolic syndrome, vitamin D deficiency and hypoadiponectinemia among nondiabetic patients early after kidney transplantation. AB - BACKGROUND AND AIMS: Metabolic syndrome (MetS) is common among kidney transplant patients. We studied the relationship between MetS, vitamin D deficiency/insufficiency and hypoadiponectinemia early posttransplantation and their impact on clinical outcomes. METHODS: Seventy-four previously nondiabetic kidney transplant patients were enrolled in a prospective cohort study between February and November 2008. Participants underwent a 2-hour oral glucose tolerance test and had their plasma levels of 25-hydroxyvitamin D (25[OH]D), adiponectin, insulin, intact parathyroid hormone and lipids measured at 11 weeks posttransplantation. Clinical events including cardiovascular events, new-onset diabetes after transplantation, acute rejection, graft loss and death were recorded during the follow-up to December 2012. RESULTS: Thirty-four study patients (45.9%) had MetS. Patients with MetS had lower plasma concentrations of 25[OH]D (20.5 +/- 7.2 vs. 24.8 +/- 11.1 ng/ml, p = 0.049) and adiponectin (8.2 +/ 4.5 vs. 14.6 +/- 8.0 MUg/ml, p < 0.0001) early on, and higher composite clinical event rate (61.8 vs. 27.5%, p = 0.003) during the follow-up. Multivariate analysis showed that the presence of MetS early after transplantation was independently associated with 25[OH]D deficiency/insufficiency (OR: 14.0, 95% CI: 1.8, 107.5; p = 0.011), depressed plasma adiponectin levels (beta -6.39, r(2) 0.195, p < 0.0001) and increased risk for clinical events (OR: 5.6, 95% CI: 1.9, 16.5; p = 0.002). CONCLUSION: Kidney transplant patients with MetS early after transplantation had lower levels of 25[OH]D and adiponectin, and unfavorable clinical outcomes. PMID- 23751486 TI - Influences and mechanisms of surfactants on pyrene biodegradation based on interactions of surfactant with a Klebsiella oxytoca strain. AB - Surfactant-enhanced bioremediation has been proposed as a promising technology for the treatment of organic polluted soils; however its application has been hindered by the controversial influences and mechanisms of surfactants on the biodegradation of hydrophobic organic compounds. To address this problem, effects of five surfactants on the sorption and biodegradation of pyrene by Klebsiella oxytoca PYR-1, as well as their interactions with bacterial cell surface and membrane lipids were investigated. We found that surfactants enhanced or inhibited pyrene biodegradation depending on their effects on the sorption of pyrene onto bacterial cell, which occurred mainly through modifying cell surface hydrophobicity (such as Tween series surfactants) or disrupting bacterial membrane (such as Triton X-100), respectively. A relatively high positive correlation (P<0.0001) was observed between biodegradation promotion (Bs/B0) and enhancement of sorption coefficients (Kd,s(*)/Kd,0(*)) for pyrene in the presence of surfactant, indicating that surfactant-induced sorption played the dominant role during pyrene biodegradation. PMID- 23751487 TI - Influence of microwave power, metal oxides and metal salts on the pyrolysis of algae. AB - The work was to investigate the influence of microwave power, metal oxides and metal salts onto the pyrolysis of algae (4.55 wt.% moisture). It was found that the heating rate and the final temperature would increase as enhancing the microwave power. When microwave power increased from 750 W to 2250 W, the yield of solid residue decreased by 22.05%, and gas yield increased 39.45%. After adding 5% (mass basis) CuO and MgO, the yield of solid residue and bio-oil appeared the greatest decreasing ranges of 14.35% and 11.04%, respectively. Electrical energy consumption increased by 1.44% and reduced by 40.76% after CuO and MgO was added, separately. When algae was mixed with 5% (mass basis) MgCl2, ZnCl2 and NaH2PO3, respectively, the yield of solid residue increased by 3.98%, 1.13% and 2.31%, and the bio-oil yield increased by 6.3%, 16.92% and 0.71%, respectively. The effect of microwave absorption was ZnCl2>NaH2PO3>MgCl2. PMID- 23751488 TI - Pilot-scale test of an advanced, integrated wastewater treatment process with sludge reduction, inorganic solids separation, phosphorus recovery, and enhanced nutrient removal (SIPER). AB - Sludge reduction technologies are increasingly important in wastewater treatment, but have some defects. In order to remedy them, a novel, integrated process including sludge reduction, inorganic solids separation, phosphorus recovery, and enhanced nutrient removal was developed. The pilot-scale system was operated steadily at a treatment scale of 10 m(3)/d for 90 days. The results showed excellent nutrient removal, with average removal efficiencies for NH4(+)-N, TN, TP, and COD reaching 98.2 +/- 1.34%, 75.5 +/- 3.46%, 95.3 +/- 1.65%, and 92.7 +/- 2.49%, respectively. The ratio of mixed liquor volatile suspended solids (MLVSS) to mixed liquor suspended solids (MLSS) in the system gradually increased, from 0.33 to 0.52. The process effectively prevented the accumulation of inert or inorganic solids in activated sludge. Phosphorus was recovered as a crystalline product with aluminum ion from wastewater. The observed sludge yield Yobs of the system was 0.103 gVSS/g COD, demonstrating that the system's sludge reduction potential is excellent. PMID- 23751484 TI - Calcium dysregulation and neuroinflammation: discrete and integrated mechanisms for age-related synaptic dysfunction. AB - Some of the best biomarkers of age-related cognitive decline are closely linked to synaptic function and plasticity. This review highlights several age-related synaptic alterations as they relate to Ca(2+) dyshomeostasis, through elevation of intracellular Ca(2+), and neuroinflammation, through production of pro inflammatory cytokines including interleukin-1 beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). Though distinct in many ways, Ca(2+) and neuroinflammatory signaling mechanisms exhibit extensive cross-talk and bidirectional interactions. For instance, cytokine production in glial cells is strongly dependent on the Ca(2+) dependent protein phosphatase calcineurin, which shows elevated activity in animal models of aging and disease. In turn, pro inflammatory cytokines, such as TNF, can augment the expression/activity of L type voltage sensitive Ca(2+) channels in neurons, leading to Ca(2+) dysregulation, hyperactive calcineurin activity, and synaptic depression. Thus, in addition to discussing unique contributions of Ca(2+) dyshomeostasis and neuroinflammation, this review emphasizes how these processes interact to hasten age-related synaptic changes. PMID- 23751489 TI - Partial nitrification using aerobic granules in continuous-flow reactor: rapid startup. AB - This study applied a novel strategy to rapid startup of partial nitrification in continuous-flow reactor using aerobic granules. Mature aerobic granules were first cultivated in a sequencing batch reactor at high chemical oxygen demand in 16 days. The strains including the Pseudoxanthomonas mexicana strain were enriched in cultivated granules to enhance their structural stability. Then the cultivated granules were incubated in a continuous-flow reactor with influent chemical oxygen deamnad being stepped decreased from 1,500 +/- 100 (0-19 days) to 750 +/- 50 (20-30 days), and then to 350 +/- 50 mg l(-1) (31-50 days); while in the final stage 350 mg l(-1) bicarbonate was also supplied. Using this strategy the ammonia-oxidizing bacterium, Nitrosomonas europaea, was enriched in the incubated granules to achieve partial nitrification efficiency of 85-90% since 36 days and onwards. The partial nitrification granules were successfully harvested after 52 days, a period much shorter than those reported in literature. PMID- 23751490 TI - Humanized mice for the study of infectious diseases. AB - Many of the pathogens that cause human infectious diseases do not infect rodents or other mammalian species. Small animal models that allow studies of the pathogenesis of these agents and evaluation of drug efficacy are critical for identifying ways to prevent and treat human infectious diseases. Immunodeficient mice engrafted with functional human cells and tissues, termed 'humanized' mice, represent a critical pre-clinical bridge for in vivo studies of human pathogens. Recent advances in the development of humanized mice have allowed in vivo studies of multiple human infectious agents providing novel insights into their pathogenesis that was otherwise not possible. PMID- 23751491 TI - Yukiko Yamashita: the centrosomes get there first. Interview by Caitlin Sedwick. PMID- 23751492 TI - The incredible journey: From megakaryocyte development to platelet formation. AB - Circulating blood platelets are specialized cells that prevent bleeding and minimize blood vessel injury. Large progenitor cells in the bone marrow called megakaryocytes (MKs) are the source of platelets. MKs release platelets through a series of fascinating cell biological events. During maturation, they become polyploid and accumulate massive amounts of protein and membrane. Then, in a cytoskeletal-driven process, they extend long branching processes, designated proplatelets, into sinusoidal blood vessels where they undergo fission to release platelets. Given the need for platelets in many pathological situations, understanding how this process occurs is an active area of research with important clinical applications. PMID- 23751493 TI - RNF111/Arkadia is a SUMO-targeted ubiquitin ligase that facilitates the DNA damage response. AB - Protein modifications by ubiquitin and small ubiquitin-like modifier (SUMO) play key roles in cellular signaling pathways. SUMO-targeted ubiquitin ligases (STUbLs) directly couple these modifications by selectively recognizing SUMOylated target proteins through SUMO-interacting motifs (SIMs), promoting their K48-linked ubiquitylation and degradation. Only a single mammalian STUbL, RNF4, has been identified. We show that human RNF111/Arkadia is a new STUbL, which used three adjacent SIMs for specific recognition of poly-SUMO2/3 chains, and used Ubc13-Mms2 as a cognate E2 enzyme to promote nonproteolytic, K63-linked ubiquitylation of SUMOylated target proteins. We demonstrate that RNF111 promoted ubiquitylation of SUMOylated XPC (xeroderma pigmentosum C) protein, a central DNA damage recognition factor in nucleotide excision repair (NER) extensively regulated by ultraviolet (UV)-induced SUMOylation and ubiquitylation. Moreover, we show that RNF111 facilitated NER by regulating the recruitment of XPC to UV damaged DNA. Our findings establish RNF111 as a new STUbL that directly links nonproteolytic ubiquitylation and SUMOylation in the DNA damage response. PMID- 23751494 TI - Spatiotemporal control of PopZ localization through cell cycle-coupled multimerization. AB - Bacterial cell poles constitute defined subcellular domains where numerous proteins localize, often at specific times, to affect various physiological processes. How pole recognition occurs and what governs the timing of protein localization are often unknown. In this paper, we investigate the mechanisms governing the localization of PopZ, a chromosome-anchoring protein whose unipolar to bipolar localization pattern is critical for cell cycle progression in Caulobacter crescentus. We provide evidence that polar localization of PopZ relied on its self-assembly into a higher-order structure (matrix) and that the unipolar to bipolar transition was coupled to the asymmetric distribution of ParA during the translocation of the origin-proximal ParB-parS partition complex. Collectively, our data suggest a model in which a local increase of ParA concentration promotes the assembly of a PopZ matrix precisely when and where this matrix is needed. Such coupling of protein assembly with a cell cycle associated molecular asymmetry may represent a principle of cellular organization for controlling protein localization in both time and space. PMID- 23751495 TI - A Wee1 checkpoint inhibits anaphase onset. AB - Cdk1 drives both mitotic entry and the metaphase-to-anaphase transition. Past work has shown that Wee1 inhibition of Cdk1 blocks mitotic entry. Here we show that the budding yeast Wee1 kinase, Swe1, also restrains the metaphase-to anaphase transition by preventing Cdk1 phosphorylation and activation of the mitotic form of the anaphase-promoting complex/cyclosome (APC(Cdc20)). Deletion of SWE1 or its opposing phosphatase MIH1 (the budding yeast cdc25(+)) altered the timing of anaphase onset, and activation of the Swe1-dependent morphogenesis checkpoint or overexpression of Swe1 blocked cells in metaphase with reduced APC activity in vivo and in vitro. The morphogenesis checkpoint also depended on Cdc55, a regulatory subunit of protein phosphatase 2A (PP2A). cdc55Delta checkpoint defects were rescued by mutating 12 Cdk1 phosphorylation sites on the APC, demonstrating that the APC is a target of this checkpoint. These data suggest a model in which stepwise activation of Cdk1 and inhibition of PP2A(Cdc55) triggers anaphase onset. PMID- 23751496 TI - Dynamic microtubules produce an asymmetric E-cadherin-Bazooka complex to maintain segment boundaries. AB - Distributing junctional components around the cell periphery is key for epithelial tissue morphogenesis and homeostasis. We discovered that positioning of dynamic microtubules controls the asymmetric accumulation of E-cadherin. Microtubules are oriented preferentially along the dorso-ventral axis in Drosophila melanogaster embryonic epidermal cells, and thus more frequently contact E-cadherin at dorso-ventral cell-cell borders. This inhibits RhoGEF2, reducing membrane recruitment of Rho-kinase, and increasing a specific E-cadherin pool that is mobile when assayed by fluorescence recovery after photobleaching. This mobile E-cadherin is complexed with Bazooka/Par-3, which in turn is required for normal levels of mobile E-cadherin. Mobile E-cadherin-Bazooka prevents formation of multicellular rosette structures and cell motility across the segment border in Drosophila embryos. Altogether, the combined action of dynamic microtubules and Rho signaling determines the level and asymmetric distribution of a mobile E-cadherin-Bazooka complex, which regulates cell behavior during the generation of a patterned epithelium. PMID- 23751497 TI - The netrin receptor DCC focuses invadopodia-driven basement membrane transmigration in vivo. AB - Though critical to normal development and cancer metastasis, how cells traverse basement membranes is poorly understood. A central impediment has been the challenge of visualizing invasive cell interactions with basement membrane in vivo. By developing live-cell imaging methods to follow anchor cell (AC) invasion in Caenorhabditis elegans, we identify F-actin-based invadopodia that breach basement membrane. When an invadopodium penetrates basement membrane, it rapidly transitions into a stable invasive process that expands the breach and crosses into the vulval tissue. We find that the netrin receptor UNC-40 (DCC) specifically enriches at the site of basement membrane breach and that activation by UNC-6 (netrin) directs focused F-actin formation, generating the invasive protrusion and the cessation of invadopodia. Using optical highlighting of basement membrane components, we further demonstrate that rather than relying solely on proteolytic dissolution, the AC's protrusion physically displaces basement membrane. These studies reveal an UNC-40-mediated morphogenetic transition at the cell-basement membrane interface that directs invading cells across basement membrane barriers. PMID- 23751498 TI - Liprin-alpha2 promotes the presynaptic recruitment and turnover of RIM1/CASK to facilitate synaptic transmission. AB - The presynaptic active zone mediates synaptic vesicle exocytosis, and modulation of its molecular composition is important for many types of synaptic plasticity. Here, we identify synaptic scaffold protein liprin-alpha2 as a key organizer in this process. We show that liprin-alpha2 levels were regulated by synaptic activity and the ubiquitin-proteasome system. Furthermore, liprin-alpha2 organized presynaptic ultrastructure and controlled synaptic output by regulating synaptic vesicle pool size. The presence of liprin-alpha2 at presynaptic sites did not depend on other active zone scaffolding proteins but was critical for recruitment of several components of the release machinery, including RIM1 and CASK. Fluorescence recovery after photobleaching showed that depletion of liprin alpha2 resulted in reduced turnover of RIM1 and CASK at presynaptic terminals, suggesting that liprin-alpha2 promotes dynamic scaffolding for molecular complexes that facilitate synaptic vesicle release. Therefore, liprin-alpha2 plays an important role in maintaining active zone dynamics to modulate synaptic efficacy in response to changes in network activity. PMID- 23751503 TI - Retrodialysis: a review of experimental and clinical applications of reverse microdialysis in the skin. AB - Microdialysis is a method that has been used for decades to recover endogenous mediators, metabolites and drugs from the interstitial space in several tissues of both animals and humans. The principle of microdialysis is the flux of compounds across a semipermeable membrane. The application of microdialysis as a method of drug delivery is a process referred to as retrodialysis, i.e. the introduction of a substance into the extracellular space via a microdialysis probe. Thus, microdialysis also offers opportunities to deliver mediators and drugs to target tissues by adding solutes to the perfusion medium. In this context, retrodialysis combines a method for minimally invasive delivery with a sampling method to study biological processes in health and disease. The aim of this review is to give insight into the use of retrodialysis by outlining examples of retrodialysis studies focusing on applications in skin in animal studies, human experimental investigations and clinical settings. PMID- 23751504 TI - POSS-enhanced phase separation in air-processed P3HT:PCBM bulk heterojunction photovoltaic systems. AB - Nanoparticles have been shown in some cases to improve phase separation and morphology in bulk heterojunction organic photovoltaic cells. In this study, the effect of incorporation of polyhedral oligomeric silsesquioxane (POSS) molecules of different structures in air processed poly(3-hexylthiophene-2,5-diyl) (P3HT) and [6,6]-phenyl C61 butyric acid methyl ester (PCBM) films and photovoltaic cells was evaluated. Morphology and composition of the nanoscalephase-separated domains were determined via conductive atomic force microscopy in conjunction with nanomechanical mapping and Raman imaging. UV-vis and fluorescence spectroscopy analysis of the films was performed at different stages of the process and with different levels of solvent vapor and thermal annealing. It was found that POSS molecules of selected structures provided enhancement in morphology control in films, translating to improvements in fill factor and power conversion efficiency of laboratory-scale OPV cells. The findings indicate the potential for further improvements in solar cell performance with specifically tailored POSS/polymer phase-separated systems. PMID- 23751499 TI - The adhesion protein IgSF9b is coupled to neuroligin 2 via S-SCAM to promote inhibitory synapse development. AB - Synaptic adhesion molecules regulate diverse aspects of synapse formation and maintenance. Many known synaptic adhesion molecules localize at excitatory synapses, whereas relatively little is known about inhibitory synaptic adhesion molecules. Here we report that IgSF9b is a novel, brain-specific, homophilic adhesion molecule that is strongly expressed in GABAergic interneurons. IgSF9b was preferentially localized at inhibitory synapses in cultured rat hippocampal and cortical interneurons and was required for the development of inhibitory synapses onto interneurons. IgSF9b formed a subsynaptic domain distinct from the GABAA receptor- and gephyrin-containing domain, as indicated by super-resolution imaging. IgSF9b was linked to neuroligin 2, an inhibitory synaptic adhesion molecule coupled to gephyrin, via the multi-PDZ protein S-SCAM. IgSF9b and neuroligin 2 could reciprocally cluster each other. These results suggest a novel mode of inhibitory synaptic organization in which two subsynaptic domains, one containing IgSF9b for synaptic adhesion and the other containing gephyrin and GABAA receptors for synaptic transmission, are interconnected through S-SCAM and neuroligin 2. PMID- 23751505 TI - Volatile fatty acids productivity by anaerobic co-digesting waste activated sludge and corn straw: effect of feedstock proportion. AB - Volatile fatty acids (VFAs) are the most suitable and biodegradable carbon substrates for many bioprocesses. This study explored a new approach to improve the VFAs production from anaerobic co-digesting waste activated sludge (WAS) with corn straw (CS). The effect of feedstock proportion on the acidification efficiency was investigated. The maximum VFAs yield (corresponding fermentation time) was substantially increased 69% (96 h), 45% (72 h), 13% (120 h) and 12% (120 h) with 50%, 35%, 25% and 20% CS proportion of feedstock, respectively. HAc (acetic acid) was consistently the most abundant, followed by HPr (propionic acid) and n-HBu (butyric acid) in the co-digesting tests. The increase of CS in feedstock led to more production of HAc and HPr. Moreover, the consumption of protein and carbohydrate were also improved remarkably from 2955 and 249 mg COD/L (individual WAS fermentation) to 6575 and 815 mg COD/L (50%WAS:50%CS co digestion) from 120 onward, respectively. The highest contribution of CS to additional VFAs production was1113 mg VFAs (as COD)/g CS/L in the 65%WAS:35%CS co digesting test. Our study indicated a valuable method to improve VFAs production from anaerobic co-digesting WAS and CS. PMID- 23751507 TI - No paradox: relationship between obesity and coronary atherosclerosis. PMID- 23751506 TI - Two-dimensional echocardiographic features of the inferior right atrial isthmus: the role of vestibular thickness in catheter ablation of atrial flutter. AB - OBJECTIVES: The aim of this study was to examine the feasibility of transthoracic two-dimensional (2D)-echocardiography in defining the cavo-tricuspid isthmus (CTI) anatomy and its value concerning the ease of catheter ablation of isthmic atrial flutter (AF). METHODS: CTI analysis was accomplished in 39 cases: 16 necropsy specimens and 23 patients. Sixteen were patients with isthmus-dependent AF and seven controls with other supraventricular re-entrant tachycardias. Two dimensional transthoracic echocardiography and a right atrium angiogram were performed before radiofrequency catheter ablation (RFCA). RESULTS: The measurements of the CTI with angiography were compared with those taken with echocardiography and correlation was excellent (r= 0.91; P < 0.0001). In normal patients, the dimension of the vestibular thickness was successfully compared and validated with the histological examination of the necropsy specimens: histology median 6.8 mm, range 4.4-10.5 vs. echo median 6.2 mm, range 5.4-8.7; P: NS. Vestibular thickness was greater in complex than in simple RFCA (13.6 +/- 1.9 mm vs. 10.0 +/- 2.3 mm; P = 0.01). When vestibular thickness >=11.5 mm, the ablation prone to be complex (sensitivity 83.3%, specificity 80%, positive predictive value 71.4%, and negative predictive value 88.9%). CONCLUSIONS: Two-dimensional transthoracic echocardiography clearly depicts the inferior isthmus and, displaying the thickness of the tricuspid vestibule, it was related with complexity of the ablation procedure in isthmus-dependent AF. PMID- 23751508 TI - Association among energy status, subclinical endometritis postpartum and subsequent reproductive performance in Egyptian buffaloes. AB - Sixty pluriparous, clinically normal buffalo cows (n=60) were used to investigate the relationships between metabolic status, subclinical endometritis and reproductive performance. Subclinical endometritis was diagnosed by endometrial cytology (EC) and ultrasonography (US) during weeks 4-9 postpartum (pp). A comparative assessment of these diagnostic approaches was made with respect to reproductive outcomes. Blood samples were collected on a weekly basis from weeks 4 to 9 in order to estimate some blood metabolites including blood glucose, total cholesterol, triglycerides, high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C). Reproductive tract examination was carried out weekly from weeks 4 to 9 by endometrial cytology (percentage of polymorphonuclear cells; PMN%) and Ultrasonography (detection of fluid in uterus regardless to its amount or echogenicity; FIU). The percentage of buffalo cow suffering from subclinical endometritis as diagnosed by endometrial cytology was significantly (P<0.01) higher in non-pregnant cows (80%) at weeks 4 and 5 (60%) pp when compared with pregnant animals (0). HDL-c concentration was significantly lower (P<0.05) in cytologically diagnosed ENDM group (15.4+/-0.7mg/dl) if compared to NOENDM group (25.0+/-3.1mg/dl) during week 4 pp. During week 5 pp, triglycerides concentration was significantly high (P<0.05) in ENDM group, as diagnosed by the presence of FIU (184.6+/-12.4mg/dl) if compared to NOENDM group (102.7+/-30.6mg/dl). Total cholesterol concentration was significantly lower (P<0.01) in ENDM group (51.9+/-0.5mg/dl) than that of NOENDM group (85.9+/ 2.0mg/dl) during week 6 pp. In conclusion, Weeks 4 and 5 pp are the best times to identify cytologically diagnosed endometritis. Furthermore, glucose and total cholesterol indicated that energy status is not a risk factor for cytologically diagnosed subclinical endometritis in buffalo cows. PMID- 23751509 TI - Phonon-drag thermopower and hot-electron energy-loss rate in a Rashba spin-orbit coupled two-dimensional electron system. AB - We theoretically study the phonon-drag contribution to the thermoelectric power and the hot-electron energy-loss rate in a Rashba spin-orbit coupled two dimensional electron system in the Bloch-Gruneisen (BG) regime. We assume that electrons interact with longitudinal acoustic phonons through a deformation potential and with both longitudinal and transverse acoustic phonons through a piezoelectric potential. The effect of the Rashba spin-orbit interaction on the magnitude and temperature dependence of the phonon-drag thermoelectric power and hot-electron energy-loss rate is discussed. We numerically extract the exponent of temperature dependence of the phonon-drag thermopower and the energy-loss rate. We find that the exponents are suppressed due to the presence of the Rashba spin-orbit coupling. PMID- 23751510 TI - Low nanomolar thapsigargin inhibits the replication of vascular smooth muscle cells through reversible endoplasmic reticular stress. AB - Thapsigargin (TG), an inhibitor of Ca(2+) ATPase pumps in the endoplasmic reticulum (ER), inhibits replication of human vascular smooth muscle cell (hVSMC) at low nM concentrations. TG blocks replication of other cell types through promotion of ER stress (ERS). In order to determine whether ERS may mediate the cytostatic effect of TG in hVSMCs, the effect of TG on ERS in hVSMCs was studied by assessing markers of ERS: Immunoglobulin Heavy Chain Binding Protein (BiP), growth inhibitory transcription factor, GADD153, phosphorlylated eukaryotic initiation factor 2alpha (p-eIF2alpha) and phosphorlylated protein kinase R (p PKR). hVSMCs derived from saphenous veins were rendered quiescent with serum-free medium for 96 h incubated with 10 nM TG at 37 degrees C for 24 h, then washed free of TG and incubated with 10% foetal calf serum (FCS) for a further 24 h. At selected times, BiP, GADD153, p-eIF2alpha, p-PKR and cyclin D1 expression was assessed. TG promoted a marked increase in BiP and GADD153, but suppressed cyclin D1 mRNA and protein expression. Under serum-free conditions p-eIF2alpha and p-PKR expression was not enhanced by TG. 15-24 h After removal of TG all these factors returned to levels seen in control cells. These data demonstrate that the inhibitory effect of 10nM TG on hVSMC replication is mediated through induction of ERS and associated factors that cessate replication and is reversible. These observations have implications in the aetiology and treatment of diseases that include atherogenesis, vein graft failure and restenosis. PMID- 23751511 TI - 2-Aryl- and 2-amido-benzothiazoles as multifunctional vasodilators on rat artery preparations. AB - The neuroprotective agent riluzole [2-amino-6-(trifluoromethoxy)benzothiazole] has been shown to antagonize neuronal high-voltage activated Ca(2+) currents. In the search for novel scaffolds leading to potential antihypertensive agents, a series of 2-aryl- and 2-amido-benzothiazoles (HUP) were assessed for their vasorelaxing property on rat aorta rings and for their L-type Ba(2+) currents [I(Ba(L))] blocking activity on single myocytes isolated from the rat tail artery. HUP5 and HUP30, the most potent of the series, inhibited phenylephrine induced contraction with IC50 values in the range 3-6 uM. The presence of endothelium did not modify their spasmolytic activity. Both HUP5 and HUP30 increased tissue levels of cGMP and shifted to the left the concentration response curve to sodium nitroprusside. In rings precontracted by phenylephrine, tetraethylammonium or 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) shifted to the right the concentration-relaxation curves of HUP5 and HUP30. The antispasmodic effect of HUP5 and HUP30 was more marked on rings stimulated with 25/30 mM than with 60 mM K(+). HUP5 and HUP30 antagonized both extracellular Ca(2+) influx and Ca(2+) mobilization from intracellular stores in response to phenylephrine: this effect was not modified by the presence of ODQ. I(Ba(L)) was partly inhibited by HUP5 and blocked by HUP30 in a concentration-dependent as well as ODQ-independent manner. In conclusion, HUP5 and HUP30 are vasorelaxing agents that stimulate soluble guanylyl cyclase, activate K(+) channels, and block extracellular Ca(2+) influx. The present benzothiazole derivatives form a novel class of multifunctional vasodilators which may give rise to effective antihypertensive agents. PMID- 23751512 TI - Association between dopaminergic medications and nocturnal sleep in early-stage Parkinson's disease. AB - BACKGROUND: Poor nocturnal sleep is common in Parkinson's disease (PD) and negatively impacts quality of life. There is little data on how dopaminergic drugs influence nocturnal sleep in PD, particularly in relation to medication timing. We examined the association between dopaminergic medications and subjective and objective nocturnal sleep in PD. METHODS: Individuals with PD were recruited from the outpatient clinic. Demographics and disease information were collected. Patients underwent one-night polysomnography and responded to SCOPA SLEEP, a self-administered questionnaire which includes a section on nighttime sleep and an overall measure of sleep quality; higher scores indicate worse sleep. Medication intake, including medication timing in relation to bedtime, was obtained and converted to levodopa equivalents. RESULTS: 41 Males and 21 females, median age 63.9 years, participated. Median disease duration was 5 years. After adjusting for age, sex, disease severity, and disease duration, greater total levodopa equivalent intake within 4 h of sleep was associated with higher total SCOPA-nighttime score (p = 0.009) and greater wake time after sleep onset (p = 0.049). Greater dopaminergic medication intake prior to sleep was also associated with less rapid eye movement (REM) sleep as a percent of total sleep time (p = 0.004). CONCLUSIONS: Higher amounts of dopaminergic medications taken prior to sleep were associated with poor sleep quality and less REM sleep. Although poor nocturnal sleep in PD is likely multi-factorial in etiology, our findings suggest that timing and dose of medications prior to sleep need to be considered in its management. PMID- 23751513 TI - A multi-objective programming model for assessment the GHG emissions in MSW management. AB - In this study a multi-objective mathematical programming model is developed for taking into account GHG emissions for Municipal Solid Waste (MSW) management. Mathematical programming models are often used for structure, design and operational optimization of various systems (energy, supply chain, processes, etc.). The last twenty years they are used all the more often in Municipal Solid Waste (MSW) management in order to provide optimal solutions with the cost objective being the usual driver of the optimization. In our work we consider the GHG emissions as an additional criterion, aiming at a multi-objective approach. The Pareto front (Cost vs. GHG emissions) of the system is generated using an appropriate multi-objective method. This information is essential to the decision maker because he can explore the trade-offs in the Pareto curve and select his most preferred among the Pareto optimal solutions. In the present work a detailed multi-objective, multi-period mathematical programming model is developed in order to describe the waste management problem. Apart from the bi-objective approach, the major innovations of the model are (1) the detailed modeling considering 34 materials and 42 technologies, (2) the detailed calculation of the energy content of the various streams based on the detailed material balances, and (3) the incorporation of the IPCC guidelines for the CH4 generated in the landfills (first order decay model). The equations of the model are described in full detail. Finally, the whole approach is illustrated with a case study referring to the application of the model in a Greek region. PMID- 23751514 TI - Inequalities in transplant waiting list activation across Italian dialysis centers. AB - BACKGROUND: The demand for kidney transplant exceeds organ supply; therefore, understanding patient-related and contextual factors associated with waiting list activation is key in ensuring that organ allocation is efficient and equitable. We sought to assess whether inequalities in wait-listing probability exist across centers and evaluate correlates of wait-listing in Italy. METHODS: We linked the MigliorDialisi dataset (1,238 patients enrolled in 54 Italian hemodialysis centers) to administrative data concerning the activity of each participating center and contextual information abstracted from the Italian Institute of Statistics. We modeled the odds of waiting list activation for patients on dialysis by the subjects' sociodemographic, biomedical and psychosocial factors along with center-related and contextual factors. RESULTS: The crude enlistment rate was 26% (95% CI 9-54) distributed as follows: 21, 34 and 33% in northern, central, and southern Italy, respectively (p < 0.01). Older patients with poorer health conditions and lower expectations toward transplantation outcomes were less likely to be wait-listed in multilevel multivariable logistic regression. In the fully adjusted model there was not a statistically significant variation in wait-listing across northern, central, and southern regions. However, the variance explained by center-related factors accounted for 12% (p < 0.01) of total variability in enlistment likelihood (20% in patients >65 years, p < 0.01). CONCLUSIONS: Our results showed that inter-center variation exists after adjusting for case mix. Additionally, we identified individual modifiable factors associated with wait-listing inequalities. PMID- 23751515 TI - Incidence, clinical characteristics, long-term course, and comparison of progressive and nonprogressive cases of aphthous-type Crohn's disease: a single center cohort study. AB - BACKGROUND/AIMS: In Japan, aphthous-type Crohn's disease (type A CD) is thought to represent an early phase of Crohn's disease (CD), and diagnosis of type A CD is possible in the diagnostic criteria for CD in Japan. However, the details of type A CD are not well understood. METHODS: Subjects comprised 649 CD patients diagnosed between 1985 and 2011. The incidence of type A CD over time was clarified in two periods (1985-2004 and 2005-2011). The course of type A CD was also investigated, and cases that did and did not progress to typical CD were compared. RESULTS: No significant difference was seen in the incidence of type A CD between the two periods (5.2 vs. 8.5%, p = 0.125). Type A CD patients followed at our hospital progressed to typical CD at a rate of 59.3%. In comparing progressive and nonprogressive cases, the frequency of large, densely distributed aphthous lesions in the small intestine was higher among progressive cases (p = 0.018). CONCLUSION: Type A CD is an early phase of CD, and CD diagnostic criteria including early cases are valid in Japan. PMID- 23751516 TI - Neuronal activity-regulated pentraxin expressed in medial prefrontal cortex neurons is not necessary for extinction of heroin self-administration. AB - The medial prefrontal cortex (mPFC) plays a key role in extinction learning. Previously, we found that expression of a neuronal activity-regulated pentraxin (Narp) dominant-negative construct in the mPFC of mice blocked extinction of morphine-conditioned place preference. To further investigate the role of mPFC Narp in the extinction of drug seeking, we tested whether mPFC Narp is necessary for the extinction of heroin self-administration in rats. Specifically, we injected an adeno-associated viral vector expressing a dominant-negative form of Narp (NarpN) into the infralimbic region of the mPFC of rats and compared lever presses during extinction to those of rats injected with a control virus. In contrast to our previous study, we found that injection of NarpN did not affect extinction of heroin self-administration. Our findings suggest that mPFC Narp is necessary for extinction of opiate seeking in the Pavlovian-conditioned place preference paradigm but not in the operant paradigm of drug self-administration. PMID- 23751517 TI - 2-Phenylethynyl-butyltellurium enhances learning and memory impaired by scopolamine in mice. AB - Taking into account the memory-enhancing properties of 2-phenylethynyl butyltellurium (PEBT) and the constant search for drugs that improve cognitive performance, the present study was designed to investigate the effect of PEBT on cognitive impairment induced by scopolamine in mice. PEBT (10 mg/kg, gavage) was administered to mice 1 h before the probe trial in the Morris water maze task. Memory impairment was induced by scopolamine (1 mg/kg, intraperitoneally) 30 min before the probe trial. PEBT significantly ameliorated the scopolamine-induced impairment of long-term memory, as indicated by a decrease in escape latency and an increase in the number of crossings of the platform location when compared with the amnesic mice. To evaluate the effect of PEBT on different phases of memory (acquisition, consolidation, and retrieval) impaired by scopolamine, the step-down inhibitory avoidance task was used. Scopolamine was administered 30 min before training (acquisition), test (retrieval), or immediately after training (consolidation). PEBT, administered 30 min before scopolamine, increased step down latency in memory-impaired mice, improving the consolidation and retrieval stages, but not acquisition. No significant alterations in locomotor or exploratory behaviors were found in animals treated with PEBT and/or scopolamine. PEBT improved memory deficits during consolidation and retrieval induced by scopolamine. PMID- 23751518 TI - Methylphenidate and venlafaxine attenuate locomotion in spontaneously hypertensive rats, an animal model of attention-deficit/hyperactivity disorder, through alpha2-adrenoceptor activation. AB - Recent clinical studies have shown that serotonin-norepinephrine reuptake inhibitors such as venlafaxine and duloxetine are effective against symptoms of attention-deficit/hyperactivity disorder such as inattention, oppositionality, and hyperactivity. We have recently found that these serotonin-norepinephrine reuptake inhibitors, like methylphenidate, reduced the hyperactivity in spontaneously hypertensive rats (SHR), an animal model of attention deficit/hyperactivity disorder. The present study investigated whether the alpha2 adrenoceptor and the dopamine-D1 receptor are involved in the behavioral effects of methylphenidate and venlafaxine in SHR. Adolescent male SHR showed greater horizontal locomotion in a familiar open field than male Wistar Kyoto and Wistar rats, and methylphenidate (0.3 mg/kg) and venlafaxine (30 mg/kg) reduced horizontal locomotion in SHR, but not Wistar Kyoto or Wistar rats. The effects of methylphenidate and venlafaxine were blocked by idazoxan (an alpha2-adrenoceptor antagonist), but not by SCH23390 (a dopamine-D1 receptor antagonist). These findings suggest that the alpha2-adrenoceptor plays a key role in the effects of methylphenidate and venlafaxine on enhanced locomotion in SHR. PMID- 23751519 TI - Dopamine D2 receptors modulate the expression of contextual conditioned fear: role of the ventral tegmental area and the basolateral amygdala. AB - Although dopaminergic systems are more commonly associated with the reinforcing effects of various stimuli, numerous reports have demonstrated a relationship between changes in dopaminergic transmission and aversive situations. In the present study, we examined the involvement of D1-like and D2-like receptors in the expression of conditioned freezing using the context as the conditioned stimulus. Intraperitoneal injections of the D1 agonist SKF38393 or the D1 antagonist SCH23390 did not change the conditioned freezing in rats subjected to the contextual fear paradigm. In contrast, intraperitoneal injections of the D2 agonist quinpirole and the D2 antagonist sulpiride caused a significant dose dependent reduction in the expression of contextual conditioned freezing. As these data may reflect that the systemic manipulations acted on dopaminergic receptors in different brain areas, the effects of administration of quinpirole and sulpiride into the ventral tegmental area (VTA) and the basolateral amygdala complex (BLA) on the expression of contextual conditioned freezing were also evaluated. Intra-VTA quinpirole and intra-BLA sulpiride injections reduced the conditioned freezing response; intra-VTA sulpiride and intra-BLA quinpirole injections had no significant effects. These data suggest that D2-like receptors, but not D1-like receptors, play an important role in the expression of contextual conditioned freezing. Quinpirole may act at D2 presynaptic receptors located in the VTA, decreasing dopamine levels in the terminal fields of the mesolimbic pathway. The effects of sulpiride, in contrast, appear to be triggered by an action on postsynaptic dopaminergic receptors located in the BLA. However, it cannot be totally excluded that the injected solutions did not also affect neighboring amygdalar regions. Together with previous findings, the present data suggest the need to consider dopaminergic mechanisms in the mesolimbic circuit as novel targets for the pharmacological treatment of fear-related disorders, especially post-traumatic stress disorder. PMID- 23751521 TI - Effect of caffeine on upper-body anaerobic performance in wrestlers in simulated competition-day conditions. AB - PURPOSE: Peak power (PP) and mean power (MP) attained in upper body sprint performance test are considered important factors for competitive success in wrestling. This study aimed to determine whether acute caffeine ingestion would better maintain PP and MP across a simulated competition day in wrestling. METHODS: In a double-blind, counterbalanced, crossover study, 14 trained wrestlers ingested either placebo or 5 mg/kg caffeine and completed four 6-min upper body intermittent sprint performance tests with 30-min recovery periods between consecutive tests. PP and MP were recorded during and blood lactate concentration was measured before and after each test. Ratings of perceived fatigue (RPF) and exertion (RPE) were recorded before and after each test, respectively. Heart rate (HR) was monitored across the whole testing period. RESULTS: Mean power decreased across four tests in both trials (p < .05), but the reduction in PP (from 277.2 +/- 34.6 W to 257.3 +/- 45.1 W; p < .05) only occurred in caffeine trial. Both pretest blood lactate concentration and HR were higher in caffeine than in placebo trial (p < .05) in the third and fourth tests. No between-trial differences occurred in RPF or RPE. CONCLUSIONS: Under simulated competition day conditions mimicking four consecutive wrestling matches, acute caffeine ingestion has a partially detrimental effect on upper body intermittent sprint performance in trained wrestlers. Elevated HR and blood lactate levels observed between tests after caffeine ingestion suggest that caffeine may impair recovery between consecutive maximal efforts. PMID- 23751520 TI - Nox4-generated superoxide drives angiotensin II-induced neural stem cell proliferation. AB - Reactive oxygen species (ROS) have been reported to affect neural stem cell self renewal and therefore may be important for normal development and may influence neurodegenerative processes when ROS activity is elevated. To determine if increasing production of superoxide, via activation of NADPH oxidase (Nox), increases neural stem cell proliferation, 100 nM angiotensin II (Ang II) - a strong stimulator of Nox - was applied to cultures of a murine neural stem cell line, C17.2. Twelve hours following a single treatment with Ang II, there was a doubling of the number of neural stem cells. This increase in neural stem cell numbers was preceded by a gradual elevation of superoxide levels (detected by dihydroethidium fluorescence) from the steady state at 0, 5, and 30 min and gradually increasing from 1 h to the maximum at 12 h, and returning to baseline at 24 h. Ang II-dependent proliferation was blocked by the antioxidant N-acetyl-L cysteine. Confocal microscopy revealed the presence of two sources of intracellular ROS in C17.2 cells: (i) mitochondrial and (ii) extramitochondrial; the latter indicative of the involvement of one or more specific isoforms of Nox. Of the Nox family, mRNA expression for one member, Nox4, is abundant in neural stem cell cultures, and Ang II treatment resulted in elevation of the relative levels of Nox4 protein. SiRNA targeting of Nox4 mRNA reduced both the constitutive and Ang II-induced Nox4 protein levels and attenuated Ang II-driven increases in superoxide levels and stem cell proliferation. Our findings are consistent with our hypothesis that Ang II-induced proliferation of neural stem cells occurs via Nox4-generated superoxide, suggesting that an Ang II/Nox4 axis is an important regulator of neural stem cell self-renewal and as such may fine tune normal, stress- or disease-modifying neurogenesis. PMID- 23751524 TI - [Vascular disease study in China: a review of 10 years]. PMID- 23751523 TI - Breathing and brain state: urethane anesthesia as a model for natural sleep. AB - Respiratory control differs dramatically across sleep stages. Indeed, along with rapid eye movements (REM), respiration was one of the first physiological variables shown to be modulated across sleep stages. The study of sleep stages, their physiological correlates, and neurobiological underpinnings present a challenge because of the fragility and unpredictability of individual stages, not to mention sleep itself. Although anesthesia has often substituted as a model for a unitary stage of slow-wave (non-REM) sleep, it is only recently that urethane anesthesia has been proposed to model the full spectrum of sleep given the presence of spontaneous brain state alternations and concurrent physiological correlates that appear remarkably similar to natural sleep. We describe this model, its parallels with natural sleep, and its power for studying modulation of respiration. Specifically, we report data on the EEG characteristics across brain states under urethane anesthesia, the dependence of brain alternations on neurotransmitter systems, and the observations on state dependent modulation of respiration. PMID- 23751525 TI - [Periodontal medicine: colonization and spreading of periodontal bacteria]. PMID- 23751522 TI - Activation of inspiratory muscles via spinal cord stimulation. AB - Diaphragm pacing is a clinically useful modality providing artificial ventilatory support in patients with ventilator dependent spinal cord injury. Since this technique is successful in providing full-time ventilatory support in only ~50% of patients, better methods are needed. In this paper, we review a novel method of inspiratory muscle activation involving the application of electrical stimulation applied to the ventral surface of the upper thoracic spinal cord at high stimulus frequencies (300 Hz). In an animal model, high frequency spinal cord stimulation (HF-SCS) results in synchronous activation of both the diaphragm and inspiratory intercostal muscles. Since this method results in an asynchronous pattern of EMG activity and mean peak firing frequencies similar to those observed during spontaneous breathing, HF-SCS is a more physiologic form of inspiratory muscle activation. Further, ventilation can be maintained on a long term basis with repetitive stimulation at low stimulus amplitudes (<1 mA). These preliminary results suggest that HF-SCS holds promise as a more successful method of inspiratory muscle pacing. PMID- 23751526 TI - [Progress of investigations on the effects of chronic periodontitis on diabetes]. PMID- 23751527 TI - [Practice makes perfect: in memory of periodontist Harald Loe]. PMID- 23751528 TI - [Detection of periodontal pathogens from saliva of type 2 diabetic patients in urban area of Beijing]. AB - OBJECTIVE: To investigate the prevalence of periodontal pathogens from saliva of patients with type 2 diabetes mellitus (T2DM), and to characterize the association between the glucose status and periodontal pathogens in oral cavity. METHODS: All the subjects were hypertension patients under regular care at Beijing hypertension prevention and management institute. Whole unstimulated saliva samples were collected from 45 non-diabetic subjects (non-DM group), 80 well-controlled diabetic patients (DM-well group) and 100 poor-controlled diabetic patients (DM-poor group). DNA was extracted from the salivary deposition, Porphyromonas gingivalis (Pg), Tannerella forsythia (Tf) and Treponema denticola (Td) were detected by polymerase chain reaction (PCR) method based on 16SrRNA. Prevalence and quantity of the pathogens under different glucose states were compared and logistic regression model was set to analyze the factors related to each bacterium. RESULTS: The prevalence of Tf in DM-well group and DM-poor group was significantly lower than that of non-DM group [81% (65/80), 80% (80/100) vs 91% (41/45), P = 0.048], meanwhile the quantity of Tf was also lower than that of non-DM group [1.9(2.6), 2.1(5.3) vs 3.4(6.4)] (P > 0.05). With the worsening of glucose control, the quantity of Tf was declining (P = 0.032). However, the prevalence and the quantity of Pg, Td in 3 groups had no statistical differences (P > 0.05). After adjusting age, gender, number of missing teeth and other periodontal parameters, OR of having Tf in saliva from DM-well group and DM poor group was 0.58 and 0.53, respectively. CONCLUSIONS: Abnormal blood glucose state may affect the colonization of Tf in oral cavity. PMID- 23751529 TI - [Relationship between recurrent spontaneous abortion and the level of interferon gamma and interleukin-4 in peripheral blood and gingival crevicular fluid of patients with chronic periodontitis]. AB - OBJECTIVE: To investigate the relationship between recurrent spontaneous abortion (RSA) and the level of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) in peripheral blood and gingival crevicular fluid of patients with chronic periodontitis. METHODS: Fifty pregnant women with recurrent spontaneous abortion (gestational age: 5 - 28 weeks) and 40 pregnant women (gestational age: 39 - 41 weeks) were included and their periodontal status was examined. The level of IFN gamma and IL-4 in gingival crevicular fluid and peripheral blood was detected by enzyme-linked immunosorbent assay. RESULTS: Nine RSA women and 5 in control group had periodontitis. The prevalence of periodontitis in RSA group was 18% (9/50) and 13% (5/40) in the control group (P < 0.05). The probing depth, attachment loss and bleeding index in RSA group were higher than those in the control group (P < 0.05). The level of IFN-gamma was (52.98 +/- 17.56) ng/L in gingival crevicular fluid of RSA group and (25.25 +/- 7.93) ng/L in control group (P < 0.01). The level of IL-4 was (15.43 +/- 1.77) ng/L in gingival crevicular fluid of RSA group and (19.62 +/- 4.04) ng/L in control group (P < 0.01). The content of IFN-gamma was (27.79 +/- 3.59) ng/L in peripheral blood of RSA group and (18.39 +/- 2.65) ng/L in control group (P < 0.05). The content of IL-4 was (15.88 +/- 0.95) ng/L in peripheral blood of RSA group and (22.98 +/- 4.30) ng/L in control group (P < 0.001). The content of cytokines in gingival crevicular fluid and peripheral blood in the same group was positively related (r > 0.8, P < 0.001). CONCLUSIONS: Pregnant women of RSA have a higher chance of getting periodontitis. The change in the level of cytokines in periodontal tissue could result in excursion of maternal intrauterine immune environment to T-helper 1 (Th1). Periodontitis was related to RSA. PMID- 23751530 TI - [Different expression of cytokines induced by Actinobacillus actinomycetemcomitans lipopolysaccharide in monocytes/macrophages from different organs of rabbits]. AB - OBJECTIVE: To investigate the expression of cytokines induced by Actinobacillus actinomycetemcomitans lipopolysaccharide (Aa-LPS) in monocytes/macrophages from different organs of rabbits. METHODS: The peripheral mononuclear cells (Mo), alveolar macrophages (AM), peritoneal macrophages (PM) and Kupffer cells (KC) from five New Zealand rabbits were isolated respectively. Then the cells from different organs were stimulated with Escherichia coli (Ec)-LPS or Aa-LPS at the dose of 1 mg/L. After culture for 24 hours, the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)6, IL-1beta, IL-8 mRNA and protein were determined by real-time PCR and enzyme-linked immunosorbent assay respectively. RESULTS: The monocytes/macrophages challenged by Ec-LPS or Aa-LPS expressed more cytokines both in mRNA and protein levels compared with the controls (P < 0.05). Among them, AM displayed the highest respond when encount with Aa-LPS, with the TNF-alpha, IL-6, IL-1beta, IL-8 mRNA relative levels were (0.4719 +/- 0.0171), (2.7895 +/- 0.0669), (5.1527 +/- 0.1190), (3.6785 +/- 0.1836) and the proteins concentrations were (82.2 +/- 5.4), (40.2 +/- 2.0), (50 308.3 +/- 445.0), (35 305.3 +/- 1480.9) ng/L respectively. And the inducibility of Aa-LPS was stronger than that of Ec-LPS (P < 0.05). Meanwhile the cells from different organs showed discrepant response when exposed to Aa-LPS (P < 0.05). The results showed their abilities to secrete cytokines were in the sequence of AM > Mo > KC > PM. CONCLUSIONS: Aa-LPS influenced the expression of cytokines in monocytes/macrophages from different organs of rabbits. PMID- 23751531 TI - [Assessment of quality of life of oral cancer patients after reconstruction with radial forearm free flaps]. AB - OBJECTIVE: To evaluate the quality of life in patients who had resection of oral cancer and reconstruction by radial forearm free flaps. METHODS: Quality of life of 49 patients was assessed by means of the 14-item oral health impact profile (OHIP-14) and the medical outcomes study-short form-36 (SF-36) questionnaires 12 months after operation. RESULTS: Forty-one questionnaires were collected (84%). SF-36: the highest-scoring domain were physical role (92.9 +/- 2.6) and bodily pain (82.6 +/- 5.7), the lowest-scoring domain were vitality (61.5 +/- 9.1), followed by role emotion (64.9 +/- 6.8) and social functioning (65.2 +/- 8.2). OHIP-14: the best-scoring domain were handicap (37.1 +/- 15.1) and psychological disability (45.7 +/- 11.9), the best-scoring domain were physical pain (64.2 +/- 11.7) and functional limitation (61.9 +/- 12.9). CONCLUSIONS: Radial forearm free flaps for reconstruction of oral defects after cancer resection could significantly influence the patients' quality of life. PMID- 23751532 TI - [Effect of a desensitizing polishing paste on bonding strength of two self etching adhesives to dentin]. AB - OBJECTIVE: To evaluate the effect of an 8% arginine-CaCO3 containing desensitizing polishing paste on bonding strength of two self-etching adhesives to dentin. METHODS: Thirty-six intact human premolars extracted for orthodontic reasons were collected within 1 month after extraction and randomly assigned into three groups using a table of random numbers (n = 12): specimens without any treatment served as control. In the polishing powder group specimens were polished with a slurry of pumice, and in the desensitizing polishing paste group dentin surfaces of the sample teeth were treated with 8% arginine-CaCO3 containing desensitizing polishing paste. Then each group was divided into two sub-groups using a table of random numbers in order to evaluate the bonding strength of two self-etching adhesive agents (G-Bond, GC; Fl-Bond II, Shofu). Microtensile bond strength test was conducted immediately and after 5000 thermocycling (n = 15). Scanning electron microscope (SEM) was used to evaluate the occluding effect of the desensitizing polishing paste. RESULTS: In the pre thermocycling stage, there were no significant differences in Fl-Bond II bonding strength among the three groups [control: (30.34 +/- 5.42) MPa, polishing powder group: (29.72 +/- 5.16) MPa, desensitizing polishing paste group: (31.53 +/- 4.86) MPa] (P > 0.05). However there were significant differences among the three groups in G-Bond bonding strength [control: (38.19 +/- 4.42) MPa, polishing powder group: (36.47 +/- 4.72) MPa, desensitizing polishing paste group: (46.88 +/- 7.83) MPa] (P < 0.05). After thermocycling process, there were no significant differences in bonding strength among the three groups in both G-Bond groups and Fl-Bond II groups. SEM observation showed that the desensitizing polishing paste could occlude open dentinal tubules effectively, and the application of self etching adhesives could re-open the dentinal tubular orifices. An even layer can be seen on the dentin surface treated with self-etching adhesive containing functional monomers. CONCLUSIONS: The 8% arginine-CaCO3 containing desensitizing polishing paste could effectively occlude dentinal tubules, thus may have potential benefits in preventing post-operative sensitivity. Additionally, it had no adverse effect on bonding strength of self-etching adhesives to dentin. PMID- 23751533 TI - [Metal-ceramic bond strength of Co-Cr alloy processed by selective laser melting]. AB - OBJECTIVE: To evaluate the metal-ceramic bond strength of a selective laser melting Co-Cr alloy. METHODS: Twelve Co-Cr metal bars were prepared according to the ISO 9693 standard with Vita porcelain fused onto the centre of each bar. Then the sample bars were divided into two groups of six each. The control group was made by traditional cast process (cast group), and the experimental group was processed by selective laser melting (SLM) technology (SLM group). Metal-ceramic bonding strength and fracture mode were assessed using three-point bending test. Fracture mode analysis was determined by scanning electronic microscope/energy dispersive spectroscopy. Student's t-test was used to analyze the data in SPSS 13.0. RESULTS: The metal-ceramic bond strength value of the cast group was (33.45 +/- 2.34) MPa, and that of the SLM group was (31.62 +/- 2.34) MPa (t = 0.79, P > 0.05). A mixed fracture mode on the debonding interface of all specimens was observed, while little porcelain was reserved. CONCLUSIONS: The metal-ceramic system processed by SLM exhibited a bonding strength that satisfies the requirement of clinical application. PMID- 23751534 TI - [Accuracy of different registration methods for laser-scanned dental cast data and maxillofacial cone-bean CT data]. AB - OBJECTIVE: To evaluate the accuracy of four dominant methods of three-dimensional multisource data registration. METHODS: Laser-scanned dental model and maxillofacial cone-bean CT rebuilt model were collected for one orthodontic patient before treatment. Registration process was done based on locating spheres' center, anatomic landmarks, partial characteristic region and global data separately. The registration errors were detected by the function of Geomagic Studio 12.0 software. A comparison of the registration accuracy among these four methods was done by analyzing mean error and standard deviation. RESULTS: The mean errors and standard deviations of methods of locating spheres' center, anatomic landmarks, partial characteristic region and global data were (0.082 +/- 0.221), -(0.104 +/- 0.218), -(0.047 +/- 0.138) and -(0.025 +/- 0.129) mm respectively. CONCLUSIONS: ICP registration methods had better reliability than landmark methods. The global registration was more accurate than partial characteristic region registration and the locating spheres' center method was better than anatomic landmarks method. PMID- 23751535 TI - [Effect of platelet-rich plasma on cell proliferation and osteogenic activity of pulp stem cells]. AB - OBJECTIVE: To evaluate the effects of different concentrations of platelet-rich plasma (PRP) on human dental pulp stem cells (hDPSC) proliferation and osteogenic differentiation activity so as to provide basis for future application of dental pulp stem cells and PRP in tissue engineering and bone repair therapy. METHODS: hDPSC were isolated and cultivated in vitro. Flow cytometric analysis was carried out to test the expression of STRO-1.hDPSC were cultured in various concentrations of PRP (1%, 5%, 10%, 20%). At the 2nd and 6th day 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was tested. Osteogenic differentiation of hDPSC was assessed using alkaline phosphatase (ALP) staining and Alizarin Red staining at the 7th and 14th day. RESULTS: Flow cytometric analysis demonstrated that 14.82% of hDPSC were STRO-1 positive. One percent to 20% PRP showed significant effect of promoting hDPSC proliferation. One percent to 10% PRP showed significant effect of promoting hDPSC osteogenic differentiation. CONCLUSIONS: Certain concentrations of PRP can promote hDPSC proliferate and osteogenic differentiate, and this finding suggests future application of dental pulp stem cells and PRP in bone tissue engineering. PMID- 23751536 TI - [Clinical evaluation of maxillary sinus elevation without osteotome from the top of alveolar ridge]. PMID- 23751537 TI - [Formulation and evaluation of evidence-based clinical practice guideline: II. Report of evidence-based clinical practice guidelines]. PMID- 23751538 TI - [Introduction to dental academic program in Michigan University]. PMID- 23751539 TI - Potential use of Cytisus scoparius extracts in topical applications for skin protection against oxidative damage. AB - Cytisus scoparius L. is used in folk medicine for the treatment of several ailments in which the antioxidant and anti-inflammatory effects of its carotenoid and flavonoid content is suggested to play an important role. We postulate that flavonoid- and carotenoid-rich extracts from C. scoparius may become useful in the preparation of formulations for topical application to protect the skin against oxidative damage mediated by high energy UV light radiation. The aim of this work was to apply an extraction process to obtain a bioactive extract from C. scoparius for the potential use in topical applications. Aqueous and ethanolic extracts from C. scoparius were characterized for its reducing capacity, radical scavenging capacity, and on the reactive oxygen and nitrogen species (ROS, RNS). The extracts showed activities comparable to that of synthetic antioxidants, and absence of skin-irritant effects at 1%. Those make them good candidates to be used in topical applications as active ingredients. PMID- 23751540 TI - Effect of pulsed electric fields on microbial inactivation and physico-chemical properties of whole porcine blood. AB - The objective of this study was to determine the lethal effectiveness of pulsed electric fields on the inactivation of the porcine blood endogenous microflora. Furthermore, the impact of pulsed electric field application on physico-chemical and sensory properties in this medium should be proved. Blood samples from a commercial abattoir in Germany were processed by a continuous pilot plant-pulsed electric field system at electric field strength of 11 kV/cm for treatment times of 163 and 209 us. The applied pulse frequencies of 134 and 175 Hz correspond to an energy input of 91 and 114 kJ/kg, respectively. In these conditions, the effectiveness of pulsed electric field processing on microbial inactivation was limited: 1.35 log10 CFU/mL reduction of total aerobic plate count (p < 0.05), 1.0 log10 CFU/mL for Pseudomonas spp. (p < 0.05), 0.97 and 0.66 log10 CFU/mL reduction for Enterobacteriaceae and sulfite-reducing anaerobic bacteria, respectively. However, the storage experiment (14 days at +3 ) showed a significant reduced growth of total aerobic plate count (p < 0.05) and Pseudomonas spp. (p < 0.05) in the pulsed electric field-treated blood samples. Pulsed electric field processing leads to a complete hemolysis of the red blood cells, in addition significant decreased L* (lightness), a* (redness) and b* (yellowness) values (p < 0.0001) were observed. Furthermore, changes in the sensory attributes color (changed from red to dark brown) and odor (changed from fresh to musty and tangy) were noticed. PMID- 23751541 TI - Pre-harvest treatments of pepper plants with nitrophenolates increase crop yield and enhance nutritive and bioactive compounds in fruits at harvest and during storage. AB - Pepper plants (Capsicum annuum L. cv Lamuyo) were treated with a mix of nitrophenolates either by foliar spray or in the irrigation system, and its effect on crop yield and the content of nutritive and bioactive compounds in fruit were analysed at harvest and after post-harvest storage. Treatments were applied at 2-week intervals from the development of first floral bunch (1 March) to end of August. Pepper fruits were harvested at commercial ripening stage (red surface colour) along the growth cycle (from May to September). Total yield (cumulative kilogram per plant) was increased ( 4.5% more) by nitrophenolate treatments due to significant increases in fruit mass, although the number of fruits per plant was unaffected. Pepper fruit quality (weight, firmness and pericarp thickness), its content in nutritive (sugars and organic acids) and bioactive compounds (vitamin C and total phenolics) and antioxidant activity were also enhanced by nitrophenolate treatments at the three harvested dates assayed (end May, mid July and end August). In addition, all these parameters were maintained at higher levels in treated peppers during storage, while diminutions in these parameters occurred generally in control fruit. Thus, nitrophenolate treatments were able to improve crop yield as well as the nutritional value and antioxidant properties of peppers at harvest and after fruit storage. PMID- 23751542 TI - The influence of fish age, salt level, and Mtgase addition on the quality of gels prepared from unwashed mince of farmed meagre (Argyrosomus regius). AB - The potential of using the unwashed mince of farmed meagre as raw material for the preparation of heat-induced gel products was assessed taking into account the effect of age (small size <1 kg meagre vs commercial size > 2kg meagre), lower salt levels (1.0%, w/w, vs 2.5%, w/w), and microbial transglutaminase (MTGase) incorporation (0.0%, w/w, vs 0.5%, w/w). Heat-induced gel products from > 2 kg fish were of superior quality. Salt reduction from 2.5% to 1.0% (w/w) was detrimental for textural quality, particularly, of gels prepared from >2 kg meagre mince. MTGase addition improved texture. Moreover, MTGase incorporation led to a greater importance of non-covalent hydrophobic bonding. PMID- 23751543 TI - Ultrasonic characterization of the fat source and composition of formulated dry cured meat products. AB - The aim of this work was to test the feasibility of using ultrasonic measurements to estimate the fat content and identify the fat sources used in formulated dry cured pork meat products. For that purpose, dry-cured sausages were prepared using different fat sources (two Iberian pork backfats, Iberian lard, and sunflower oil) and contents (fat content from 3% to 17% wet basis) and characterized by measuring the ultrasonic velocity (at 2 degrees C, 6 degrees C, 10 degrees C, 15 degrees C, 20 degrees C, and 25 degrees C), fatty acid profile, thermal behavior, and composition. The fatty acid composition affected the melting behavior of the sausages, which also involved different ultrasonic velocities, depending on the fat source used for the sausage formulation. Significant (p < 0.05) linear relationships were established between the ultrasonic velocity and the percentage of melted fat, by means of which the sausage batches were differentiated according to the fat source used. The ultrasonic velocity temperature dependence allowed the determination of the fat content (explained variance 96.1%) by measuring the ultrasonic velocity in the dry-cured sausages at 2 degrees C and 25 degrees C and using a semi-empirical equation. Therefore, the ultrasonic measurements could be considered as a reliable tool for the characterization and differentiation of formulated dry cured meat products with different fat sources and contents. PMID- 23751544 TI - Rheological properties of rice-blackgram batter while replacing white rice with brown rice. AB - Rice-blackgram batter is a raw material for many traditional convenience foods in Asia. Reformulation of traditional convenience food by replacing white rice with whole rice (brown rice) is a novel method to reduce the consumption of refined grain and increase the intake of whole grain in our diet. In this study, rheological properties of rice-blackgram batter was investigated while replacing white rice with brown rice at five levels (T1--0% replacement (control), T2--25% replacement, T3--50% replacement, T4--75% replacement, and T5--100% replacement). The shear stress versus shear rate plot indicates that the rice-blackgram batter exhibited non-Newtonian fluid behavior (shear thinning property) even after 100% replacement of white rice with brown rice. The rheological characteristics of rice-blackgram batters fitted reasonably well in Cassan (r2 = 0.8521-0.9856) and power law (r2 = 0.8042-0.9823) models. Brown rice replacement at all levels did not affect the flow behavior index, yield stress, consistency coefficient, and apparent viscosity of batter at 25 degrees C. However, at higher temperature, the viscosity was greater for T4 and T5 (no difference between them) than T1, T2, and T3 (no difference between them) batters. Further research is required to determine the sensory attributes and acceptability of the cooked products with brown rice-blended batter. PMID- 23751546 TI - Image analysis and green tea color change kinetics during thin-layer drying. AB - This study was conducted to investigate the effect of air temperature and air flow velocity on kinetics of color parameter changes during hot-air drying of green tea, to obtain the best model for hot-air drying of green tea, to apply a computer vision system and to study the color changes during drying. In the proposed computer vision system system, at first RGB values of the images were converted into XYZ values and then to Commission International d'Eclairage L*a*b* color coordinates. The obtained color parameters of L*, a* and b* were calibrated with Hunter-Lab colorimeter. These values were also used for calculation of the color difference, chroma, hue angle and browning index. The values of L* and b* decreased, while the values of a* and color difference (DeltaE*ab ) increased during hot-air drying. Drying data were fitted to three kinetic models. Zero, first-order and fractional conversion models were utilized to describe the color changes of green tea. The suitability of fitness was determined using the coefficient of determination (R (2)) and root-mean-square error. Results showed that the fraction conversion model had more acceptable fitness than the other two models in most of color parameters. PMID- 23751545 TI - Effects of cold storage and 1-methylcyclopropene treatments on ripening and cell wall degrading in rabbiteye blueberry (Vaccinium ashei) fruit. AB - The effect of postharvest 1-methylcyclopropene and/or cold storage application on texture quality parameters during storage was determined. The changes in fruit quality (including weight loss, firmness, total soluble solids content, and ethylene production), cell wall material (including water-soluble fraction, ethylenediaminetetraacetic acid-soluble fraction, Na2CO3-soluble fraction, 4% KOH soluble fraction, and 14% KOH-soluble fraction), and cell wall hydrolase activities (including polygalacturonase, endo-1,4-beta-D-glucanase, pectinesterase, alpha-L-arabinofuranosidase, and beta-galactosidase) were periodically measured up to 25 days after postharvest treatments. The application of cold storage reduced weight loss, ethylene production, and delayed ripening of blueberry fruit. The inhibition of senescence was associated with suppressed increase in cell wall hydrolase activities and retarded solubilization of pectins and hemicelluloses. Furthermore, no obvious differences in firmness, weight loss, ethylene production, and cell wall hydrolase activities between fruits with or without 1-methylcyclopropene application were observed, while significant lower levels of the detected parameters were found in cold storage fruit compared with fruit stored in room temperature. Thus, cold storage can be viewed as an effective means to extend the shelf life of blueberry fruit. PMID- 23751547 TI - Effect of heat treatment on.wheat dough rheology and wheat protein solubility. AB - In the present study, the influence of moisture content, temperature and time during heat treatment of wheat flour was investigated. Heat treatment was carried out on laboratory scale in a water bath at 50-90 degrees C for times up to 3 h. Flour functionality was evaluated by analysing protein solubility in acetic acid as well as by the formation of bread-like doughs, which were then analysed with dynamic oscillatory and rotational rheometry. Effects during heat treatment were explained on a molecular level using a simplified physical model describing wheat dough as a continuous gluten matrix with starch as filler particles. Heat treatment causes the formation of gluten aggregates resulting in decreased protein solubility and lower network strength of dough. Rheological data also indicate the formation of starch aggregates and modified interactions between gluten and starch. The effects were more pronounced in heat-treated flours with increased moisture content due to a higher mobility of the molecules. PMID- 23751548 TI - Effects of different fermentation methods on bacterial cellulose and acid production by Gluconacetobacter xylinus in Cantonese-style rice vinegar. AB - A strain of acidogenic bacterium was isolated from the fermentation liquid of Cantonese-style rice vinegar produced by traditional surface fermentation. 16S rDNA identification confirmed the bacterium as Gluconacetobacter xylinus, which synthesizes bacterial cellulose, and the acid productivity of the strain was investigated. In the study, the effects of the membrane integrity and the comparison of the air-liquid interface membrane with immerged membrane on total acidity, cellulose production, alcohol dehydrogenase (ADH) activity and number of bacteria were investigated. The cellulose membrane and the bacteria were observed under SEM for discussing their relationship. The correlations between oxygen consumption and total acid production rate were compared in surface and shake flask fermentation. The results showed the average acid productivity of the strain was 0.02g/(100mL/h), and the integrity of cellulose membrane in surface fermentation had an important effect on total acidity and cellulose production. With a higher membrane integrity, the total acidity after 144 h of fermentation was 3.75 g/100 mL, and the cellulose production was 1.71 g/100 mL after 360 h of fermentation. However, when the membrane was crushed by mechanical force, the total acidity and the cellulose production were as low as 0.36 g/100 mL and 0.14 g/100 mL, respectively. When the cellulose membrane was forced under the surface of fermentation liquid, the total acid production rate was extremely low, but the activity of ADH in the cellulose membrane was basically the same with the one above the liquid surface. The bacteria were mainly distributed in the cellulose membrane during the fermentation. The bacterial counts in surface fermentation were more than in the shake flask fermentation and G. xylinus consumed the substrate faster, in surface fermentation than in shake flask fermentation. The oxygen consumption rate and total acid production rate of surface fermentation were respectively 26.13 times and 2.92 times that of shake flask fermentation. PMID- 23751549 TI - Characterization of wami tilapia (Oreochromis urolepis hornorum) skin gelatin: microbiological, rheological and structural properties. AB - Gelatin was extracted from the skin of tilapia (Oreochromis urolepis hornorum) and its microbiological, rheological and structural properties were characterized. The tilapia skin gelatin presented typical molecular weight distribution of type I collagen with contents of imino acids (proline + hydroxyproline) of 21.67%. Gel strength and viscosity values were 221 +/- 5.68 g and 5.98 +/- 0.34 cP, respectively, with the maturation time of 18 +/- 1 h, and both parameters increased with the maturation time. Melting and gelling points of 25 degrees C and 21 degrees C, respectively, were obtained for tilapia skin gelatin. The gelatin presented microbiological standards in accordance with the Brazilian Legislation. PMID- 23751550 TI - The effect of combined traditional and novel treatments on oxidative status of dolphinfish (Coryphaena hippurus) and sardine (Sardina pilchardus) muscle lipids. AB - Fish is rich in polyunsaturated fatty acids with beneficial effects on human health; however, these lipids are very sensitive to auto-oxidation reactions, leading to loss of nutritional and sensory quality. The effect of traditional (brining, smoking) and novel (addition of polyphenolic extracts, high pressure) preservation processes on the antioxidant/oxidative status of muscle lipids from dolphinfish and sardine was studied. Brining with oregano or rosemary aqueous extracts, as well as smoking, gave rise to deposition of phenolic compounds (9 42, 1.5-4.5 and 0.4-2.3 ug phenol/g for smoked, oregano-brined and rosemary brined samples, respectively) in the muscle of both fish species. The antioxidant activity, as measured by ferric reducing ability, was also improved after brining with antioxidant extracts or smoking, results ranging from 8.9 to 82 mM FeSO4 . 7H2O equivalents/mg muscle depending on the treatment and the fish species. Consequently, fish lipid oxidation (as measured by thiobarbituric acid reactive substances) derived from brining and pressurizing, applied alone or in combination, was reduced between 6.6 and 69.8% depending on the treatment and the fish species. The combination of brining with oregano extract and light smoking showed an additional antioxidant effect, as compared with that obtained by smoking, on reducing sardine lipid oxidation derived from brining and pressurizing. PMID- 23751551 TI - Influence of malting conditions on sorghum (Sorghum bicolor (L.) Moench) as a raw material for fermented beverages. AB - There has been recently increased interest in sorghum to substitute the gluten containing cereals in the diet of people suffering from celiac disease. The response surface methodology was used to determine the influence of malting parameters (degree of steeping, germination temperature and time) on sorghum (Sorghum bicolor (L.) Moench). Each parameter was varied at three levels. Malting attributes, considered important to produce high quality malt for the production of lactic acid fermented beverages, were analyzed. The optimized conditions were: degree of steeping 41%, germination temperature 27C after 7 days of germination. Under these conditions, the following values of the studied attributes can be obtained: alpha-amylase 139 U/g, beta-amylase 60 U/g, extract 83.8%, free amino nitrogen 117.8 mg/100 g, Kolbach index 26.6%, water-extractable arabinoxylan 0.3 g/L and vitamin B2 114.9 ug/L. Among the tested parameters, the germination time had the highest effect on malting attributes. Although the activity of amylolytic enzymes alpha- and beta-amylase were low, the value of extract was high and comparable to that of barley malt. The obtained results showed that sorghum malt is a promising raw material for the production of lactic acid fermented beverages. PMID- 23751552 TI - The effect of high pressure at subzero temperature on proteins solubility, drip loss and texture of fish (cod and salmon) and mammal's (pork and beef) meat. AB - One of the possibilities of using high-pressure technique in inactivation of microorganism is conducting this process at subzero temperature. However, for its practical application in meat preservation the appropriate properties of meat should be maintained. Therefore, the aim of this work was to examine the effect of pressure at subzero temperature (without freezing of water) on proteins and texture of mammal's and cold-adapted fish meat. The data showed that cod and salmon meat proteins were more susceptible to pressure-induced denaturation/aggregation than beef and pork proteins. Glucose and saccharose exerted protective effect on fish meat proteins treated with pressure of 111 MPa(tc) and -10 degrees C but not at 193 MPa(tc) and -20 degrees C. The pressure treatment under the latter conditions increased cook loss of fish meat but not of mammal's meat. However, after cooking the hardness of all kinds of pressurized meat was at the same level as that for unpressurized cooked samples. PMID- 23751554 TI - Neurological manifestations of cardiac myxoma: experience in a referral hospital. AB - INTRODUCTION: Cardiac myxoma is an important but uncommon cause of stroke in younger patients. Few published case series analyse the frequency and clinical presentation of neurological complications in patients with myxoma. OBJECTIVE: To list all neurological complications from cardiac myxoma recorded in our hospital in the past 28 years. PATIENTS AND METHODS: We retrospectively reviewed the neurological manifestations of cardiac myxoma in patients treated in our hospital between December 1983 and March 2012. RESULTS: Of the 36 patients with cardiac myxoma, 8 (22%) presented neurological manifestations. Half were women and mean age of patients was 52.4 +/- 11.6 years. Sudden-onset hemiparesis was the most frequent neurological symptom (63%). Established ischaemic stroke was the most common clinical manifestation (75%), followed by transient ischemic attack. The most commonly affected territory corresponded to the middle cerebral artery. Myxoma was diagnosed by echocardiography in all cases. Mean myxoma size was 4.1cm and most of the tumours (63%) had a polypoid surface. All tumours were successfully removed by surgery. There were no in-hospital deaths. CONCLUSIONS: Cardiac myxomas frequently present with neurological symptoms, especially ischaemic events (established stroke or transient ischaemic attack), in younger patients with no cardiovascular risk factors. The anterior circulation is more frequently affected, especially the middle cerebral artery. Echocardiography can facilitate prompt diagnosis and early treatment of the lesion. PMID- 23751553 TI - A comparison of composition and emulsifying properties of MFGM materials prepared from different dairy sources by microfiltration. AB - Milk fat globule membrane (MFGM), due to its specific nature and composition, is known as material possessing advantageous nutritional as well as technological properties. In this study MFGM materials were produced from several dairy sources such as buttermilk (BM), butter serum (BS) and buttermilk whey (BMW) by microfiltration (MF). The obtained materials, depending on the sources, were called BM-MFGM, BS-MFGM and BMW-MFGM, respectively. The compositions of starting materials and the isolated MFGM materials as well as their emulsifying properties were analyzed and compared. As expected, the MF resulted in enrichment of polar lipids (PLs), major components of MFGM. On dry matter basis, BM-MFGM and BS-MFGM were about 2.5 times higher in PLs compared to their beginning materials while BMW-MFGM was about 8.3 times compared to buttermilk powder (BMP). Sodium dodecyl sulfate polyacrylamide gel electrophoresis showed that the microfiltered products still contained a high amount of non-MFGM proteins such as caseins, beta lactoglobulin, and alpha-lactalbumin. Emulsions of 35% soya oil in water were prepared with the mentioned materials using a homogenizer at various pressures. Generally, emulsions prepared with BMP and butter serum powder had significantly higher particle sizes than those prepared with the MFGM materials. This result along with microscopy observation and viscosity measurement indicated the presence of aggregated particles in the former emulsions, probably as a result of lack of surface-active components. The differences in composition, especially in content of PLs and proteins of the materials were the main reasons for the differences in their emulsifying behaviors. PMID- 23751556 TI - American Heart Association Council on Cardiovascular and Stroke Nursing. PMID- 23751557 TI - 20 Things You Didn't Know About Alcohol. PMID- 23751558 TI - Biosynthesis of silver nanoparticles by phytopathogen Xanthomonas oryzae pv. oryzae strain BXO8. AB - Extracellular biogenic synthesis of silver nanoparticles with various shapes using the rice bacterial blight bacterium Xanthomonas oryzae pv. oryzae BXO8 is reported. The synthesized silver nanoparticles were characterized by UV-Vis spectroscopy, powder X-ray diffractometry (XRD), scanning electron microscopy, energy dispersive X-ray spectrometry, and highresolution transmission electron microscopy (HR-TEM). Based on the evidence of HR-TEM, the synthesized particles were found to be spherical, with anisotropic structures such as triangles and rods, with an average size of 14.86 nm. The crystalline nature of silver nanoparticles was evident from the bright circular spots in the SAED pattern, clear lattice fringes in the high-resolution TEM images, and peaks in the XRD pattern. The FTIR spectrum showed that biomolecules containing amide and carboxylate groups are involved in the reduction and stabilization of the silver nanoparticles. Using such a biological method for the synthesis of silver nanoparticles is a simple, viable, cost-effective, and environmentally friendly process, which can be used in antimicrobial therapy. PMID- 23751559 TI - Short-term effect of elevated temperature on the abundance and diversity of bacterial and archaeal amoA genes in Antarctic Soils. AB - Global warming will have far-reaching effects on our ecosystem. However, its effects on Antarctic soils have been poorly explored. To assess the effects of warming on microbial abundance and community composition, we sampled Antarctic soils from the King George Island in the Antarctic Peninsula and incubated these soils at elevated temperatures of 5 degrees C and 8 degrees C for 14 days. The reduction in total organic carbon and increase in soil respiration were attributed to the increased proliferation of Bacteria, Fungi, and Archaea. Interestingly, bacterial ammonia monooxygenase (amoA) genes were predominant over archaeal amoA, unlike in many other environments reported previously. Phylogenetic analyses of bacterial and archaeal amoA communities via clone libraries revealed that the diversity of amoA genes in Antarctic ammonia oxidizing prokaryotic communities were temperature-insensitive. Interestingly, our data also showed that the amoA of Antarctic ammonia-oxidizing bacteria (AOB) communities differed from previously described amoA sequences of cultured isolates and clone library sequences, suggesting the presence of novel Antarctic specific AOB communities. Denitrification-related genes were significantly reduced under warming conditions, whereas the abundance of amoA and nifH increased. Barcoded pyrosequencing of the bacterial 16S rRNA gene revealed that Proteobacteria, Acidobacteria, and Actinobacteria were the major phyla in Antarctic soils and the effect of short-term warming on the bacterial community was not apparent. PMID- 23751560 TI - Influence of metal oxide particles on soil enzyme activity and bioaccumulation of two plants. AB - Particle size and metal species are important to both soil microbial toxicity and phytotoxicity in the soil ecosystem. The effects of CuO and ZnO nanoparticles (NPs) and microparticles (MPs) on soil microbial toxicity, phytotoxicity, and bioaccumulation in two crops (Cucumis sativus and Zea mays) were estimated in a soil microcosm. In the microcosm system, soil was artificially contaminated with 1,000 mg/kg CuO and ZnO NPs and MPs. After 15 days, we compared the microbial toxicity and phytotoxicity by particle size. In addition, C. sativus and Z. mays were cultivated in soils treated with CuO NPs and ZnO NPs, after which the treatment effects on bioaccumulation were evaluated. NPs were more toxic than MPs to microbes and plants in the soil ecosystem. We found that the soil enzyme activity and plant biomass were inhibited to the greatest extent by CuO NPs. However, in a Biolog test, substrate utilization patterns were more dependent upon metal type than particle size. Another finding indicated that the metal NP uptake amounts of plants depend on the plant species. In the comparison between C. sativus and Z. mays, the accumulation of Cu and Zn by C. sativus was noticeably higher. These findings show that metal oxide NPs may negatively impact soil bacteria and plants. In addition, the accumulation patterns of NPs depend on the plant species. PMID- 23751561 TI - Expression, purification, and biological characterization of the amino-terminal fragment of urokinase in Pichia pastoris. AB - Urokinase (uPA) and its receptor (uPAR) play an important role in tumor growth and metastasis. Targeting the excessive activation of this system as well as the proliferation of the tumor vascular endothelial cell would be expected to prevent tumor neovasculature and halt the tumor development. In this regard, the amino terminal fragment (ATF) of urokinase has been confirmed as effective to inhibit the proliferation, migration, and invasiveness of cancer cells via interrupting the interaction of uPA and uPAR. Previous studies indicated that ATF expressed in Escherichia coli was mainly contained in inclusion bodies and also lacked posttranslational modifications. In this study, the biologically active and soluble ATF was cloned and expressed in Pichia pastoris. The recombinant protein was purified to be homogenous and confirmed to be biologically active. The yield of the active ATF was about 30 mg/l of the P. pastoris culture medium. The recombinant ATF (rATF) could efficiently inhibit angiogenesis, endothelial cell migration, and tumor cell invasion in vitro. Furthermore, it could inhibit in vivo xenograft tumor growth and prolong the survival of tumor-bearing mice significantly by competing with uPA for binding to cell surfaces. Therefore, P. pastoris is a highly efficient and cost-effective expression system for large scale production of biologically active rATFs for potential therapeutic application. PMID- 23751562 TI - miRNA as molecular target of polyphenols underlying their biological effects. AB - Polyphenols are the most abundant antioxidants in the human diet and are widespread constituents of fruits and beverages, such as tea, coffee, and wine. Epidemiological, clinical, and animal studies support a role of polyphenols in the prevention of various chronic diseases. For a long time, their direct antioxidant effect has been reported as the mechanism responsible for the observed health properties. However, recent findings revealed that polyphenols could interact with cellular signaling cascades regulating the activity of transcription factors and consequently affecting the expression of genes. Together with this classical regulatory pathway, polyphenols have been shown to affect the expression of microRNAs (miRNA). miRNAs are small, noncoding RNAs implicated in the regulation of gene expression that control both physiological and pathological processes such as development and cancer. Furthermore, expression of miRNAs can be affected by different external stimuli including nutrients such as vitamins, lipids, and phytochemicals. In this paper, we review studies assessing modulation of miRNAs expression by dietary polyphenols that could constitute a new pathway by which these compounds may exert their health effects. Over 100 miRNAs, involved in the control of different cellular processes such as inflammation or apoptosis, were identified as modulated by polyphenols. Most of the studies were performed in vitro using different cell lines, particularly cancer cell lines, and few studies were performed in animals. From all these data, miRNAs appear as interesting mediators in regulating polyphenols' biological effects; however, further studies are needed to validate miRNA targets and particularly in physiologically relevant conditions taking into account the bioavailability of dietary polyphenols. PMID- 23751563 TI - Ischemia modified albumin and plasma oxidative stress markers in Alzheimer's disease. AB - OBJECTIVES: The objective of this study was to determine ischemia modified albumin (IMA) and oxidant status in Alzheimer's disease (AD). Therefore, we evaluated the IMA and oxidant status by measuring serum uric acid, albumin and gamma-glutamyltransferase (GGT) in AD. METHODS: The plasma albumin, uric acid, GGT and IMA levels were measured by spectrophotometric methods in 32 AD patients and 32 healthy controls. The Mini Mental Status Examination and Clinical Dementia Rating Scale were used to evaluate the cognitive functions of AD patients. RESULTS: AD patients had significantly higher IMA levels as compared to those of the controls respectively. Uric acid concentrations were significantly decreased and GGT values were significantly increased in AD when compared with control group. Albumin levels of the patients were also compared and no significant difference was detected. CONCLUSION: Oxidative stress and IMA levels rise in AD. However, large prospective studies are required to understand the mechanisms leading to increased IMA levels during AD, whether preceded or not by AD. PMID- 23751564 TI - Colon cancer mesenchymal stem cells modulate the tumorigenicity of colon cancer through interleukin 6. AB - Multipotent mesenchymal stem cells (MSCs) have been isolated from several tumors and are implicated to play critical roles to increase malignant cell growth, invasion and metastasis. Here, we show that the MSC-like cells were isolated from human colon cancer tissues. These isolated hCC-MSCs (human colon cancer-derived mesenchymal stem cells) shared similar characteristic features with bone marrow derived MSCs, which include cell morphology, surface antigens and specific gene expression. Additionally, the hCC-MSCs could differentiate into osteocytes or adipocytes under appropriate culture conditions. The conditioned medium collected from the cultured hCC-MSCs was shown to enhance the migration and invasive activity of HCT-116 colon cancer cells in vitro. Besides, transplantation of HCT 116 cells along with hCC-MSCs in nude mice increased the tumor growth and metastasis. Further study revealed that IL-6 present in the hCC-MSC-conditioned medium sufficiently induced the levels of Notch-1 and CD44 in HCT-116 and HT-29 cells, which contribute to enhance tumorigenic activity of HCT-116 and HT-29 cells. By using immunohistochemical staining, the intense co-expression of IL-6, Notch-1 and CD44 was predominantly detected in human colon cancer tissues. Taken together, our findings suggest the importance of the IL-6/Notch-1/CD44 signaling axis in the interaction between hCC-MSCs and colon cancer cells. PMID- 23751566 TI - Impairment of static vestibular function is limited in patients with sudden sensorineural hearing loss with vertigo. AB - Sudden sensorineural hearing loss with vertigo (SSNHL_V) and vestibular neuritis (VN) are common neuro-otologic disorders that cause acute spontaneous vertigo. The SSNHL_V and VN lesion sites are thought to be within the labyrinth and the vestibular nerve, respectively. Neurolabyrinthitis of a viral origin is the most commonly accepted etiology of SSNHL_V, and neural degeneration due to viral infection (predominantly in the superior vestibular nerve) is thought to be responsible for the pathophysiology of VN. The objective of this study was to compare the static vestibular imbalance between SSNHL_V and VN patients during the acute stage of the disease. We compared the results of spontaneous nystagmus (SN), subjective visual vertical (SVV), and canal paresis (CP) between SSNHL_V and VN patients within 10 days from the onset of vertigo. Significant SN was observed in 58% of SSNHL_V and 90% of VN patients (p < 0.001), and abnormal SVV was observed in 10% of SSNHL_V and 78% of VN patients (p < 0.001). However, CP values were not significantly different between the 2 groups (50.8 +/- 19.7% in SSNHL_V and 57.1 +/- 18.9% in VN). In conclusion, significant SN and abnormal SVV are less frequently encountered in SSNHL_V than in VN even though the caloric test did not reveal significant differences at the acute stage. PMID- 23751565 TI - Regulation of cell adhesion and migration by cell-derived matrices. AB - Three-dimensional in vitro extracellular matrix models provide a physiological alternative to regular two-dimensional cell culture, though they lack the full diversity of molecular composition and physical properties of whole-animal systems. Cell-derived matrices are extracellular matrices that are the product of matrix secretion and assembly by cells cultured at high density in vitro. After the removal of the cells that produced the matrix, an assembled matrix scaffold is left that closely mimics native stromal fiber organization and molecular content. Cell-derived matrices have been shown to impart in vivo-like responses to cells cultured in these matrices. In this review, we focus on mechanisms through which the distinct molecular and topographical composition of cell derived matrices directs cellular behavior, specifically through regulation of cell-matrix adhesions and subsequent contributions to the process of cell migration. PMID- 23751567 TI - Scalable method to produce biodegradable nanoparticles that rapidly penetrate human mucus. AB - Mucus typically traps and rapidly removes foreign particles from the airways, gastrointestinal tract, nasopharynx, female reproductive tract and the surface of the eye. Nanoparticles capable of rapid penetration through mucus can potentially avoid rapid clearance, and open significant opportunities for controlled drug delivery at mucosal surfaces. Here, we report an industrially scalable emulsification method to produce biodegradable mucus-penetrating particles (MPP). The emulsification of diblock copolymers of poly(lactic-co-glycolic acid) and polyethylene glycol (PLGA-PEG) using low molecular weight (MW) emulsifiers forms dense brush PEG coatings on nanoparticles that allow rapid nanoparticle penetration through fresh undiluted human mucus. In comparison, conventional high MW emulsifiers, such as polyvinyl alcohol (PVA), interrupts the PEG coating on nanoparticles, resulting in their immobilization in mucus owing to adhesive interactions with mucus mesh elements. PLGA-PEG nanoparticles with a wide range of PEG MW (1, 2, 5, and 10 kDa), prepared by the emulsification method using low MW emulsifiers, all rapidly penetrated mucus. A range of drugs, from hydrophobic small molecules to hydrophilic large biologics, can be efficiently loaded into biodegradable MPP using the method described. This readily scalable method should facilitate the production of MPP products for mucosal drug delivery, as well as potentially longer-circulating particles following intravenous administration. PMID- 23751568 TI - The effect of lauryl capping group on protein release and degradation of poly(D,L lactic-co-glycolic acid) particles. AB - The aim of this study was to investigate the effect of a specific and frequently used end group (lauryl alcohol) on the protein release and degradation kinetics of poly(DL-lactic-co-glycolic acid) particles of different sizes. Lauryl-capped PLGA and uncapped PLGA (referred to as PLGA-capped and PLGA-COOH, respectively) particles (0.3, 1 and 20 MUm) were prepared by a double emulsion solvent evaporation technique. Bovine serum albumin (BSA) was used as a model protein for release studies. During degradation (PBS buffer, pH7.4 at 37 degrees C), a slower dry mass loss was observed for 0.3 MUm particles than for particles of 1 and 20 MUm. It was further shown that PLGA-capped particles showed slower mass loss likely due to its more hydrophobic nature. It was found that the ester bond hydrolysis rate was substantially slower for PLGA-capped particles and that the rate increased with particle size. Particles showed enrichment in lactic acid content (and thus a decrease in glycolic acid content) in time, and interestingly PLGA-capped particles showed also an enrichment of the lauryl alcohol content. No difference was observed in degradation kinetics between BSA loaded and blank particles. Independent of size, PLGA-COOH based particles showed, after a small burst, a sustained and nearly complete release of BSA during 60-80 days. On the other hand, particles based on PLGA-capped showed a much slower release and exhibited incomplete release, accompanied by the presence of an insoluble residue remaining even after 180 days. FTIR analysis of this residue showed that it contained both polymer and protein. Considering the polymer enrichment in lauryl alcohol, the incomplete release observed for PLGA-capped is likely attributed to interactions between the protein and the lauryl end group. In conclusion, since PLGA-COOH, in contrast to the capped derivative, shows complete degradation as well as quantitative release of an entrapped protein, this polymer is preferred for the design of protein formulations. PMID- 23751569 TI - Worldwide trends in cervical cancer incidence: impact of screening against changes in disease risk factors. AB - BACKGROUND: Cervical cancer trends in a given country mainly depend on the existence of effective screening programmes and time changes in disease risk factors, notably exposure to human papillomavirus (HPV). Screening primarily influences variations by period of diagnosis, whereas changes in risk factors chiefly manifest themselves as variations in risk across successive birth cohorts of women. METHODS: We assessed trends in cervical cancer across 38 countries in five continents, age group 30-74 years, using age-standardised incidence rates (ASRs) and age-period-cohort (APC) models. Non-identifiability in APC models was circumvented by making assumptions based on a consistent relationship between age and cervical cancer incidence (i.e. approximately constant rates after age 45 years). FINDINGS: ASRs decreased in several countries, except in most of Eastern European populations, Thailand as well as Uganda, although the direction and magnitude of period and birth cohort effects varied substantially. Strong downward trends in cervical cancer risk by period were found in the highest income countries, whereas no clear changes by period were found in lower resourced settings. Successive generations of women born after 1940 or 1950 exhibited either an increase in risk of cervical cancer (in most European countries, Japan, China), no substantial changes (North America and Australia) or a decrease (Ecuador and India). INTERPRETATION: In countries where effective screening has been in place for a long time the consequences of underlying increases in cohort-specific risk were largely avoided. In the absence of screening, cohort-led increases or, stable, cervical cancer ASRs were observed. Our study underscores the importance of strengthening screening efforts and augmenting existing cancer control efforts with HPV vaccination, notably in those countries where unfavourable cohort effects are continuing or emerging. FUNDING: Bill and Melinda Gates Foundation (BMGF). PMID- 23751570 TI - Peripartum changes in orexigenic and anorexigenic hormones in relation to back fat thickness and feeding strategy of sows. AB - Highly prolific sows often experience peripartum hypophagia, resulting in decreased production rate. Leptin, ghrelin, and resistin are known as feed intake regulating hormones in many species, but it is yet unknown how feeding strategy and body condition will affect these hormones around parturition in sows. In the present study, a total of 63 sows, parity 2 to 7 were divided over 2 treatment groups which were fed either restricted (RESTRICT) or ad libitum (ADLIB) during the peripartum period (day 106 of gestation until day 7 of lactation). Within each treatment group, sows were assigned to 1 of 3 body condition groups based on back fat thickness at day 106 of gestation: <18 mm (LEAN), between 18 and 22 mm (MODERATE), and >22 mm (FAT). Postprandial blood samples were taken on days 107, 109, and 112 of gestation and on days 1, 3, and 5 of lactation. With RIA, leptin, ghrelin, and resistin of each sample were analyzed. For both leptin and resistin, the hormonal profile gradually increased throughout the peripartum period (P < 0.001), whereas ghrelin peaked on day 109 of gestation compared with day 107 of gestation and day 1 of lactation. Other time points were intermediate between those two (P < 0.001). The peripartum profile of leptin was significantly higher for FAT sows than for the 2 other condition groups. No effect of body condition on ghrelin and resistin concentrations was observed. None of the 3 measured hormones were affected by feeding strategy. In conclusion, during the peripartum period feed intake of sows did not affect leptin, ghrelin, or resistin profiles. Leptin was the only hormone investigated that reflected body condition. Although body condition and late gestation feed intake have been previously described as risk factors for peripartum hypophagia, they did not induce hypophagia in any of the sows or affect the profile of the observed feed intake-regulating hormones during the peripartum period. PMID- 23751571 TI - Expression of ADAMTS1 mRNA in bovine endometrium and placenta during gestation. AB - A disintegrin and metalloproteinase with thrombospondin motifs 1 (ADAMTS1) is a secreted protease. Through the regulation of extracellular matrix remodeling or developmental processes or both, ADAMTS1 is involved in several biological functions, including ovulation and embryo receptivity. However, the expression and possible role of ADAMTS1 in bovine endometrium is unknown. In this study, we analyzed ADAMTS1 mRNA expression in bovine endometrium during the estrous cycle, peri-implantation period, and at different stages of gestation by using quantitative real-time RT-PCR (qPCR) and in situ hybridization. The qPCR results indicated that the expression of ADAMTS1 mRNA was not affected by the day of the estrous cycle and was similar to cyclic levels on day 35 of gestation; however, the expression was more abundant in cotyledonary tissues of the placenta during late gestation. The in situ hybridization study showed that ADAMTS1 mRNA was detected mainly in uterine luminal epithelia and stromal cells during the estrous cycle and peri-implantation period. A disintegrin and metalloproteinase with thrombospondin motifs 1 mRNA was also expressed in the peri-implantation conceptus as well as in trophoblast cells, which include binucleate cells, and increased during late gestation. Furthermore, treatment of stromal cell with progesterone (300 nM) stimulated the expression of ADAMTS1 mRNA. This study indicates that ADAMTS1 participates in bovine endometrial remodeling, which is required for implantation and placental development in coordination with ovarian steroids. PMID- 23751572 TI - Distribution of K and L cells in the feline intestinal tract. AB - Glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide (GLP)-1 and GLP-2 are hormones secreted from specialized K cells (GIP) and L cells (GLP-1, GLP-2) in the intestinal mucosa. These hormones play major roles in health and disease by modulating insulin secretion, satiety, and multiple intestinal functions. The aim of this study was to describe the distribution of K cells and L cells in the intestines of healthy cats. Samples of duodenum, mid-jejunum, ileum, cecum, and colon were collected from 5 cats that were euthanized for reasons unrelated to this study and had no gross or histologic evidence of gastrointestinal disease. Samples stained with rabbit-anti-porcine GIP, mouse anti-(all mammals) GLP-1, or rabbit-anti-(all mammals) GLP-2 antibodies were used to determine the number of cells in 15 randomly selected 400* microscopic fields. In contrast to other mammals (eg, dogs) in which K cells are not present in the ileum and aborally, GIP-expressing cells are abundant throughout the intestines in cats (>6/high-power field in the ileum). Cells expressing GLP-1 or GLP-2 were most abundant in the ileum (>9/high-power field) as in other mammals, but, although GLP-1-expressing cells were abundant throughout the intestines, GLP-2 expressing cells were rarely found in the duodenum. In conclusion, the distribution of GIP-secreting K cells in cats is different from the distribution of K cells that is described in other mammals. The difference in distribution of GLP-2- and GLP-1-expressing cells suggests that more than 1 distinct population of L cells is present in cats. PMID- 23751573 TI - [Progress in treatment of systemic lupus erythematosus]. PMID- 23751574 TI - [Issues to address in developing evidence based clinical practice guidelines: experience from evidence-based recommendations for the diagnosis and treatment of cow's milk protein allergy in infants]. PMID- 23751575 TI - [Cohort study of 684 pairs of mother-and-child allergic diseases]. AB - OBJECTIVE: To understand allergic diseases related factors in Changzheng Town, Putuo District infants and young children. METHOD: Pregnant women registered in Putuo District, Changzheng Town Community Health Service Center Child Health Clinic within the period from January to December, 2008 were enrolled into this survey, a questionnaire survey. The infants were followed up from birth to 2 years of age. The mother and child survey was conducted for 746 pairs, and 684 pairs had complete data. SAS V9.1 statistical software was used for data processing and statistical analysis. RESULT: The survey showed that prevalence of eczema, allergic rash, and wheezing was 27.9%, 18.9%, and 3.9%, respectively. Multivariate logistic regression analysis showed that allergy in either parent and addition of foods other than milk in infants before 4 months of age were risk factors for eczema; allergy in either parent was also risk factors for allergic rash. Exclusive breastfeeding from birth to 6 months of age was a protective factor for wheezing in infants. Other factors such as parental history of asthma, vitamin supplements to the mothers during pregnancy, mothers' special diet habits, calcium level of infants, etc. had no significant correlation with allergic disorders in infants. CONCLUSION: The risk factors for allergic disorders in infants included allergy in either parent and dietary factors of the infants themselves (prematurely adding other foods). Breastfeeding (for 0 - 6 months of age) was a protective factor for infants' wheezing. PMID- 23751576 TI - [Effect of food allergy early in life on visceral hyperalgesia in the developing rats and role of substance P abnormal expression in colon]. AB - OBJECTIVE: To explore the effect of food allergy (FA) on the development of visceralgia sensibility and the substance P (SP) expression in colon of developing rats with FA. METHOD: Three-week old female Sprague-Dawley (SD) rats were randomly divided into two groups (n = 10 in each). The rats in FA group were sensitized with ovalbumin (OVA) 40 ug and Al(OH)3 1 mg suspension solution (0.2 ml) intraperitoneal (i.p.) injection on day 0, only OVA 40 ug solution i.p. on day 2, 4, 7, 9, 11, respectively, and the rats were challenged by gavage with OVA solution 30 mg (2 ml) on day 20, 24, 28, 30. The rats in non-sensitized (NS) group were not challenged except handled in the same ways. The serum OVA-IgE were determined by enzyme-linked immuno sorbent assay (ELISA) on day 0, 30. Jejunum segments were used to observe morphological structure, the expression of eosinophils, and the density and the percentage of degranulation of mast cells (MC). The rats were appraised for the pain sensibility of intestinal tract under colorectal distension irritation by the electrophysiological method on external oblique in the 18-24 hr after the last challenge. Colons were used to analyze the expression of SP through immunohistochemical staining and computer image analyzing system. RESULT: The serum OVA-IgE concentration and the eosinophils, mast cell, the percentage of mast cells degranulation in FA group were more than NS group (P < 0.01). The amplitudes of spike external oblique muscle of abdomen (EOMA, uV) of the FA group under the colorectal distension (CRD) pressures at 0, 15, 30, 45, 60, 75 mm Hg were (17.74 +/- 0.72), (18.63 +/- 1.72), (22.55 +/- 1.70), (28.63 +/- 7.00), (33.97 +/- 7.34), (37.26 +/- 8.40), and (17.43 +/- 1.18), (17.27 +/- 1.16), (17.73 +/- 1.42), (19.55 +/- 3.54), (23.29 +/- 5.46), (25.20 +/- 4.75) in NS group. With the CRD pressure increased, the amplitudes of spike EOMA increased significantly. There were significant differences between groups under the CRD pressures at 30, 45, 60, 75 mm Hg (F = 47.470, 13.367, 13.317, 15.390, P < 0.01). The expressions of colons SP in FA group and NS group are 247.12 +/- 90.83 and 103.90 +/- 58.94, respectively (t = 4.183, P < 0.01). CONCLUSION: Sensitization through i.p. pathway and challenge by gavage with OVA in early life could result in FA in young SD rats. FA in early life enabled the amplitudes of spike EOMA and the expression of colons SP increase significantly. It may be related to increase in amount and degranulation of MC and SP abnormal expression in colon, which could lead to the development of visceralgia sensibility. PMID- 23751577 TI - [WHIM syndrome: a case report and literature review]. AB - OBJECTIVE: To study the clinical and laboratory characteristics of cases with warts, hypogammaglobulinemia, infections and myelokathexis (WHIM) syndrome. METHOD: An 11-year-old boy was diagnosed as WHIM syndrome and CXCR4 gene mutation analysis was performed. RESULT: Since 3 years of age, the patient had recurrent fever and persistent cough. Since 6 years of age, he had warts on his fingers, the warts increased gradually. His complete blood count showed: white blood cell (WBC) 0.65*10(9)/L, neutrophil 0.15*10(9)/L, hemoglobin 116 g/L, platelet 200*10(9)/L, reticulocyte 0.62%. Results of serum biochemical tests: total protein (TP) 72.2 g/L (reference value 60 - 80 g/L), albumin 20.4 g/L (reference value 20 - 35 g/L), gammaglobulin 20.4 g/L (reference value 20 - 35 g/L). IgG 5.56 g/L (reference value 7.51 - 15.6 g/L), IgA 0.48 g/L (reference value 0.82 - 4.53 g/L), IgM 0.29 g/L (reference value 0.46 - 3.04 g/L). Peripheral blood lymphocyte subsets: CD3(+)T lymphocyte 43.6% (reference value 64.01% - 75.95%), CD19(+)B lymphocyte 1.00% (reference value 9.02% - 14.1%). Bone marrow smears showed that many of the neutrophils had a reactive appearance, with cytoplasmic vacuolation. Most neutrophils had hypersegmentation with four or five nuclear lobules. In some cells, the filaments connecting the nuclear lobes were long. CXCR4 mutation was detected. CONCLUSION: WHIM syndrome is a rare immunodeficiency disorder with an autosomal-dominant pattern of inheritance. The disease is less progressive, and may accompany the patients' whole life. PMID- 23751578 TI - [Evidence based recommendations for the diagnosis and management of cow's milk allergy in Chinese infants]. PMID- 23751579 TI - [Reading and interpreting evidence based recommendations for the diagnosis and management of cow's milk allergy in Chinese infants]. PMID- 23751580 TI - [Reading and interpreting the CPA-AIR recommendations for the diagnosis and management of juvenile systemic iupus erythematosus (continued)]. PMID- 23751581 TI - [Outcomes of patients with combined methylmalonic acidemia and homocystinuria after treatment]. AB - OBJECTIVE: Combined methylmalonic acidemia with homocystinuria is a common form of methylmalonic acidemia in China. Patients with this disease can progress to death without timely and effective treatment. This study aimed to analyze the treatment outcomes of patients with combined methylmalonic acidemia and homocystinuria. METHOD: From September 2004 to April 2012, 58 patients with combined methylmalonic acidemia and homocystinuria (34 males and 24 females) were diagnosed and treated in our hospital. Fifty cases were from clinical patients including 42 early-onset cases and 8 late-onset cases. Their age when they were diagnosed ranged from 18 days to 30.8 years. The other 8 cases were from newborn screening. All the patients were treated with vitamin B12, betaine, folic acid, vitamin B6, and L-carnitine. The physical and neuropsychological development, general laboratory tests, the levels of amino acids, acylcarnitines, and homocysteine in blood, and organic acids in urine were followed up. RESULT: The follow-up period ranged from 1 month to 7.1 years. Three cases died (all were early-onset cases). In the other patients after treatment, the symptoms such as recurrent vomiting, seizures, lethargy, and poor feeding disappeared, muscle strength and muscle tension were improved, and general biochemical abnormalities such as anemia and metabolic acidosis were corrected. Among the surviving 55 cases, 49 had neurological impairments such as developmental delay and mental retardation. The median levels of blood propionylcarnitine and its ratio with acetylcarnitine, serum homocysteine, and urine methylmalonic acid were significantly decreased (P < 0.01), from 7.73 umol/L (ranged from 1.5 to 18.61 umol/L), 0.74 (ranged from 0.29 to 2.06), 97.3 umol/L (ranged from 25.1 to 250 umol/L) and 168.55 (ranged from 3.66 to 1032.82) before treatment to 2.74 umol/L (ranged from 0.47 to 12.09 umol/L), 0.16 (ranged from 0.03 to 0.62), 43.8 umol/L (ranged from 17 to 97.8 umol/L) and 6.81 (ranged from 0 to 95.43) after treatment, respectively. CONCLUSION: Patients with combined methylmalonic acidemia and homocystinuria respond to a combined treatment consisting of supplementation of hydroxycobalamin, betaine, folic acid, vitamin B6 and L carnitine with clinical and biochemical improvement. But the long-term outcomes are unsatisfactory, with neurological sequelae in most patients. PMID- 23751583 TI - [Lung ultrasonography for the diagnosis of neonatal respiratory distress syndrome: a pilot study]. AB - OBJECTIVE: The diagnosis of respiratory distress syndrome (RDS) is usually based on clinical manifestations, arterial blood gas analysis and chest x-ray. Lung ultrasounds are typically not included in the diagnostic work-up of neonatal RDS. Recently, ultrasounds have been used extensively and successfully in the diagnosis of many kinds of lung diseases, but few studies have addressed neonatal RDS. This study aimed to evaluate the value of lung ultrasound in the diagnosis of neonatal RDS. METHOD: From May, 2012 to September, 2012, 45 newborn infants with RDS and 30 neonates without lung disease were enrolled into this study. Lung ultrasound was performed at bedside by a single expert physician in the first 24 h of life before exogenous pulmonary surfactant administration. The transthoracic approach was performed with longitudinal scans of the anterior, lateral and posterior chest walls. A conventional antero-posterior chest X rag was performed at bedside in the patients immediately when lung ultrasound was finished. RESULT: The ultrasound signs of lung consolidation, pleural line abnormalities, bilateral "white lung" and A-line disappearance were seen in 100% of RDS patients while they were not found in any of the controls (P < 0.001). Lung pulse was 80% in RDS patients and in 0% of controls, respectively (P = 0.001). The pleural effusion were 13.3% in RDS patients and 0% in controls, respectively (P < 0.001). B-lines existed in 4.4% of RDS patients and in 26.7% of controls (P = 0.012). Both the sensitivity and specificity were 100% when ultrasonic signs of lung consolidation, pleural line abnormalities and bilateral "white lung" coexisted or when lung consolidation, pleural line abnormalities and A-line disappearance coexisted. The presence of lung pulse demonstrated a sensitivity of 80% and a specificity of 100% in diagnosis of RDS. CONCLUSION: The main ultrasound imaging features of neonatal RDS include lung consolidation with air bronchograms, pleural line abnormalities, lung pulse and bilateral "white lung" or alveolar interstitial syndrome. It is accurate and reliable that using ultrasound to diagnose neonatal RDS, which also has many other advantages including non ionizing, can be performed at bedside, easy-operatinng, can be repeated several times in a day without hazards to the operators and the patients. Therefore, it deserves to be carried out in the neonatal ward. PMID- 23751582 TI - [Clinical study of variation and significance of the high insulin levels in critically ill children]. AB - OBJECTIVE: To analyze the variation of serum insulin levels in critically ill children and investigate the underlying mechanism and clinical significance to provide the basis for treatment. METHOD: Totally 332 critically ill children admitted in pediatric intensive care unit (PICU) of Hunan Children's Hospital from Nov., 2011 to April, 2012 were studied. The high insulin group (n = 332) was defined as insulin levels within 24 h > 11.1 mU/L and was divided into 2 groups: mildly elevated group (n = 194): 11.10 - 33.30 mU/L, increased three times group (n = 138): > 33.3 mU/L. Insulin, C-peptide and blood glucose were measured within 24 hours after admission, on day 3 and 7. Other results of inflammatory markers, lactate, cardiac enzymes, amylase, pancreatic ultrasound, hepatic and renal function as well as indicators related to severity and prognosis were recorded after admission. RESULT: The peak of insulin level was seen on day 1, then presented a downward trend and reached the normal level on day 7. The peaks of blood glucose and C-peptide level were seen on day 1 then declined, the levels on day 7 were still slightly higher than normal level. The insulin level on admission (41.47 +/- 30.85) mU/L were positively correlated with lactic acid (2.29 +/- 1.81) mmol/L and procalcitonin level (5.08 +/- 6.70) ng/ml (r = 0.370, P = 0.000; r = 0.168, P = 0.002) (P < 0.01). The insulin level on admission in children with 1 organ failure (41.24 +/- 22.60) mU/L or 2 or multiple organ failure (48.98 +/- 22.17) mU/L was higher than that in children with non-organ failure (34.11 +/- 29.84) mU/L (U = 1621.001, P = 0.000;U = 1300.000, P = 0.000) (P < 0.01). The insulin level on admission in death group (52.99 +/- 32.34) mU/L was higher than that in survival group (32.85 +/- 24.10) mU/L (U = 1585.000, P = 0.000) (P < 0.01). Ten cases in death group were complicated with pancreatic damage and the average insulin level on admission was (65.29 +/- 50.53) mU/L. CONCLUSION: The high insulin level was correlated with the degree of inflammatory response, ischemia and hypoxia. The high insulin level in critically ill children was relevant to the pancreatic damage, the severity of the disease, organ dysfunction, and evaluation of prognosis. PMID- 23751584 TI - [Chest CT features and outcome of necrotizing pneumonia caused by Mycoplasma pneumoniae in children (report of 30 cases)]. AB - OBJECTIVE: To summarize the chest CT features and outcome of necrotizing pneumonia (NP) caused by Mycoplasma pneumoniae in children and to review the changes of common inflammatory parameters in NP patients to help clinicians understand the proper timing of CT scan. METHOD: The imaging data from 30 cases of Mycoplasma pneumoniae pneumonia in NP group and 24 cases with non-necrotizing Mycoplasma penumoniae pneumonia (control group) were analyzed retrospectively. The changes of common inflammatory parameters in NP group and control group were compared. RESULT: (1) The chest CT findings of NP (30 cases): 28 cases showed unilateral pneumonia, and 20 cases showed single lobar consolidation, 10 cases had multiple lobes involvement; pulmonary cavities were seen in 27 cases. There were decreased enhancement areas in the consolidation (22 cases). (2) The dynamic changes of CT signs during follow-up: The CT scan performed during the 1 - 2 months after onset of disease (23 cases) showed that pulmonary consolidation in 2 cases (9%) were absorbed, 18 cases (78%)had cavities in lung, 16 cases (70%) had pleural thickening, 2 cases (9%) atelectasis and 1 case (4%) bronchopleural fistula;the CT scan performed during the 2 - 3 months after onset of disease (11 cases) showed pulmonary consolidation in 7 cases (64%) were absorbed, 10 cases (91%) pleural thickness, 7 cases (64%) with cavities in lung, 5 cases (45%) atelectasis, 2 cases (18%) pulmonary lobe cysts and 1 case bronchopleural fistula. The CT scan performed at 3.5 years of disease course (10 cases) showed that there were no pulmonary consolidation in any of the cases, 4 cases had atelectasis, 4 cases had pulmonary cysts, and 1 case had band-like scars. (3) There were significant differences between NP group and control group in the maximum peripheral blood WBC, proportion of neutrophil and C-reactive protein(CRP, mg/L) (P < 0.01, 0.01, 0.001, respectively), and there was significant difference between the 2 groups in the duration of fever, abnormal WBC(d) and CRP(d) (P < 0.001). CONCLUSION: The chest CT features of NP caused by Mycoplasma pneumoniae in children were single lobular consolidation in most cases, NP had decreased parenchymal enhancement and cavity in the consolidation, and recovery was slow, the outcome included recovery, atelectasis or lobar cystic degeneration. The clinicians should pay more attention to the common inflammatory parameters when they suspect the Mycoplasma pneumoniae pneumonia is progressing into necrosis and make correct decision for chest CT examination. PMID- 23751585 TI - [Analysis of clinical and genetic characteristics of 20 cases of children with Silver Russell syndrome]. AB - OBJECTIVE: To improve the accuracy of the diagnosis of the disease on the basis of the clinical features and genetic characteristics of patients with Silver Russell syndrome (SRS). METHOD: Patients diagnosed with SRS by Price criteria in 2006 to 2011 were reviewed for their clinical manifestations, physical signs, laboratory examinations and treatments. RESULT: Twenty cases with SRS were 0.08 12.17 yr old. Fifteen were male and 5 were female. The clinical characteristics included more than 80% of cases had postnatal growth retardation 100% (20/20), craniofacial dysmorphism 100% (20/20), small for gestation age 95% (19/20), asymmetry and thinning of the face and/or limbs 90% (18/20), fifth finger clinodactyly 80% (16/20), BMI < -2 SDS 80% (16/20). Their height was obviously lagging behind in the bone age. HD SDS/average of bone retardation was 3.08. The two patients with the chief complaint of external genital abnormalities would have aggressive surgical treatment and they did not use the growth hormone (GH) treatment. Only six patients had used the GH treatment. GH treatment at a dose of 0.1 IU/(kg.d) used in 2 cases achieved a growth velocity (GV) 8 - 11 cm/yr but in another 2 cases < 5 cm/yr. In genetic study, 6 patients were found to have 11p15 low methylation, 1 had low and high methylation, 1 had duplication, no relation between clinical and methylation of 11p15 was found. CONCLUSION: There were great variations of clinical features in SRS characterized by small for gestation age and/or postnatal growth retardation, craniofacial dysmorphism, asymmetry of the face and/or limbs or ultrafine limbs, fifth finger clinodactyly. Severely low BMI was seen and height was obviously lagging behind in the bone age. The findings of laboratory tests and imaging of SRS were not specific. Some of SRS had 11p15 imprinting defects. The treatment of SRS is mainly symptomatic. PMID- 23751586 TI - [Amplitude-integrated electroencephalographic changes in neonates with acute bilirubin encephalopathy]. AB - OBJECTIVE: To characterize amplitude-integrated electroencephalo graphic (aEEG) traces in neonates with acute bilirubin encephalopathy (ABE), explore the value of aEEG in early diagnosis and prediction of neurological outcome of ABE. METHOD: aEEG records of 10 cases with ABE (Oct 2009-Nov 2011) were reviewed to identify neonates with a diagnosis of ABE. Clinical data were collected. The aEEG traces were classified according to background activity (normal, moderate, or severely abnormal), presence of seizures and sleep-wake cycling (SWC). Brainstem auditory evoked potential (BAEP) and magnetic resonance imaging (MRI) were studied. The neuromotor development of survivors with ABE was assessed by using the Infant Neurological International Battery (INFANIB). RESULT: The characteristics of aEEG tracings in these infants with ABE were shown continuous normal voltage (CNV, n = 5), discontinuous voltage (DNV, n = 4), discontinuous voltage with burst suppression (BS)BS+ (n = 1); mature SWC (n = 2), immature SWC (n = 5), no SWC (n = 3); 8 infants (80%) had electrical seizures: single seizure (n = 2); repetitive seizures (n = 2), and status epilepticus (SE) (n = 4). Among the 10 infants with ABE, no infants had normal aEEG, 3 had mildly abnormal aEEG, and 7 had severely abnormal aEEG. Eight infants accepted BAEP test, 2 were mildly abnormal and 6 were severely abnormal. Six infants accepted MRI, 1 was normal and 5 were abnormal. By chi-square analysis and Spearman rank correlation analysis, the results of aEEG classification were correlated with the phase of ABE and the severity of BAEP. These infants were followed up for more than 6 months (range 6 months to 1 year). In 3 infants with mildly abnormal aEEG, 2 were normal and 1 was transit in infanib score at 6 months of age. Of 7 infants with severely abnormal aEEG, 1 died, 3 were abnormal (2 Spastic dyskinesia and 1 hypotonia), 2 were transit in infanib score at 6 months old. 1 lost to follow-up. CONCLUSION: Amplitude-integrated electroencephalography can provide important information of the status of cerebral function in neonates with ABE and help to predict its neurological outcome. PMID- 23751587 TI - [Progresses in characteristics and diagnostic methods of neonatal diffuse intravascular coagulation]. PMID- 23751588 TI - [Advances in minimal residual disease detection with flow cytometry in childhood acute myeloid leukemia]. PMID- 23751589 TI - [Progress of ATP-binding cassette transporter A3 gene and respiratory diseases of children]. PMID- 23751590 TI - [Typical WAGR syndrome in a case]. PMID- 23751591 TI - [A case of congenital subglottic hemangiomas]. PMID- 23751592 TI - Photochemically crosslinked collagen annulus plug: a potential solution solving the leakage problem of cell-based therapies for disc degeneration. AB - Intra-disc injection of mesenchymal stem cells (MSCs) to treat disc degeneration may lead to unfavorable complications, particularly osteophyte formation. Development of an effective method to block the injection portal, prevent the leakage of injected cells and materials and, hence, prevent osteophyte formation is of the utmost importance before MSC-based therapies can be applied in a clinical setting. Here we seek to alleviate the cell leakage problem and the associated complication osteophyte formation by developing an injectable annulus plug to block the injection portal during intra-disc delivery. Specifically, we fabricated a needle-shaped collagen plug by photochemical crosslinking and successfully delivered it intra-discally, in association with MSCs in collagen microsphere carriers, using a custom-made delivery device. The mechanical performance of the plug and its effectiveness in reducing cell leakage were evaluated ex vivo under compression and in torsion push-out tests. The results demonstrate that the plug survived physiologically relevant loadings and significantly reduced leakage and enhanced retention of the injected materials. Finally, a pilot in vivo study in rabbits was conducted to evaluate the performance of the plug. Microcomputed tomography imaging and histology revealed that the plug significantly reduced osteophyte formation. This work suggests the potential of the annulus plug as an adjunct or annulus closure device for intra disc delivery of cells and materials. PMID- 23751593 TI - Time between first and second transurethral resection of bladder tumors in patients with high-grade T1 tumors: is it a risk factor for residual tumor detection? AB - PURPOSE: We evaluated the risk factors for residual tumor detection after transurethral resection of bladder tumors (TURBT) in patients with newly diagnosed high-grade T1 transitional cell carcinoma of the bladder. PATIENTS AND METHODS: Overall 132 patients underwent TURBT for primary bladder tumors and were diagnosed as high-grade T1 bladder cancer. Patients with incomplete resections were excluded from the study. Clinical and pathologic characteristics of the patients were compared and multivariate analysis was performed to determine independent prognostic factors. RESULTS: Residual tumor was demonstrated in 57 (43.1%) of the patients. The residual tumor rate was significantly lower in patients with solitary tumors, tumors <3 cm in diameter, muscle presence in the initial TURBT pathologic sample and treated by an expert surgeon. In patients with solitary bladder tumors, tumors at the dome and posterior wall of the bladder exhibited higher rates of residual tumor (p < 0.0001). The time elapsed between first and second TURBT was significantly shorter in patients without residual tumor compared to patients with residual tumor at second TURBT (32.6 +/- 9.1 vs. 39.3 +/- 10.9 days, respectively, p = 0.001). Multivariate analysis demonstrated that time elapsed between first and second TURBT is the most important parameter for residual tumor detection. CONCLUSION: Our study revealed that multiple tumors, tumors >3 cm in size, absence of detrusor muscle in the initial TURBT specimen, TURBT performed by trainees and finally, as a new finding, prolonged interval between first and second TURBT are independent predictors for residual tumor detection in patients with high-grade T1 tumors. PMID- 23751594 TI - Birth preparedness and skilled attendance at birth in Nepal: implications for achieving millennium development goal 5. AB - OBJECTIVE: to assess birth preparedness in expectant mothers and to evaluate its association with skilled attendance at birth in central Nepal. DESIGN: a community-based prospective cohort study using structured questionnaires. SETTING: Kaski district of Nepal. PARTICIPANTS: a total of 701 pregnant women of more than 5 months gestation were recruited and interviewed, followed by a second interview within 45 days of delivery. MEASUREMENTS: outcome was skilled attendance at birth. Birth preparedness was measured by five indicators: identification of delivery place, identification of transport, identification of blood donor, money saving and antenatal care check-up. FINDINGS: level of birth preparedness was high with 65% of the women reported preparing for at least 4 of the 5 arrangements. It appears that the more arrangements made, the more likely were the women to have skilled attendance at birth (OR=1.51, p<0.001). For those pregnant women who intended to save money, identified a delivery place or identified a potential blood donor, their likelihood of actual delivery at a health facility increased by two to three fold. However, making arrangements for transportation and antenatal care check-up were not significantly associated with skilled attendance at birth. CONCLUSIONS: intention to deliver in a health-care facility as measured by birth preparedness indicators was associated with actual skilled attendance at birth. Birth preparedness packages could increase the proportion of skilled attendance at birth in the pathway of meeting the Millennium Development Goal 5. PMID- 23751595 TI - Transforming growth factor-beta-activated kinase 1 enhances H2O2-induced apoptosis independently of reactive oxygen species in cardiomyocytes. AB - AIMS: Heat shock protein 70 (HSP70) protects against cardiac diseases such as ischemia/reperfusion injury and myocardial infarction. However, the underlying mechanisms have not yet been fully characterized. METHODS: In this study, we investigated the effects of reactive oxygen species (ROS) and transforming growth factor-beta-activated kinase 1 (TAK1) on HSP70-regulated cardiomyocyte protection. Cultured cardiomyocytes of neonatal rats were transfected with HSP70, TAK1 or both of them before exposure to H2O2, and the ROS generation, p38 mitogen activated protein kinase (p38) activity and apoptosis were examined. RESULTS: H2O2 significantly enhanced intracellular ROS generation and apoptosis as expected, and all these cellular events were greatly abolished by overexpression of HSP70. However, H2O2-induced increments in p38 phosphorylation and cardiac cell apoptosis were largely enhanced by TAK1 overexpression, whereas the similar transfection did not affect the ROS generation in the cardiomyocytes. Moreover, inhibition of H2O2-increased ROS generation, p38 phosphorylation, and cardiomyocytes apoptosis by overexpression of HSP70 tended to disappear when the cells were cotransfected with TAK1. CONCLUSION: Our data suggest that HSP70 protects cardiomyocytes from apoptosis under oxidative stress through downregulation of intracellular ROS generation and inhibition of p38 phosphorylation. Although TAK1 itself has no effect on intracellular ROS accumulation, it may affect the inhibitory effects of HSP70 on ROS generation, p38 activity and cardiomyocyte injury. PMID- 23751596 TI - Association between genetic variations in TFR2 gene and coronary heart disease in Chinese: a case-control study. AB - AIMS: Studies indicated that body iron stores were associated with coronary heart disease (CHD). Type 2 transferrin receptor (TFR2) participates in cellular iron overload and is related to cardiovascular disease. No studies investigated the associations between variants in TFR2 gene and CHD risk. METHODS: We sought to investigate this association in a Chinese Han population and performed a case control study recruiting 1264 CHD patients and 1264 age and sex frequency matched controls. TaqMan single nucleotide polymorphisms (SNP) allelic discrimination was used to examine genotypes of the tagging single nucleotide polymorphisms (tagSNPs) of TFR2. The plasma ferritin levels were measured by ELISA. RESULTS: We did not find significant associations between variants of TFR2 gene (including tagSNPs rs2075674 and rs7385804) and the risk of CHD. After adjustment for the conventional risk factors of CHD, such as smoking and age, the results did not materially alter. Interaction analyses indicated that there were no significant interactions between conventional risk factors of CHD and these two tagSNPs on CHD risk. Among different genotypes of these two tagSNPs, no significant differences in plasma ferritin levels were found. CONCLUSION: In summary, the variants of rs2075674 and rs7385804 in TFR2 gene were not associated with CHD risk in a Chinese Han population. PMID- 23751597 TI - Left atrial myxoma: two sides of the same coin. AB - In this clinical picture we present two cases of left atrial myxoma that differed very much in their clinical presentation. PMID- 23751598 TI - Calcified apical cardiomyopathy: a rare form of endomyocardial fibrosis. AB - Endomyocardial fibrosis is a rare cardiomyopathy characterized by thickening of the endocardium, which leads to a restrictive phenotype. Differential diagnosis with other forms of cardiomyopathy may not always be straightforward and various imaging modalities are frequently necessary. In the present case, we report a patient with heart failure of uncertain origin, in whom, after an in-depth instrumental evaluation, a rare variant of endomyocardial fibrosis was diagnosed. PMID- 23751599 TI - A rare case of giant congenital left atrial appendage aneurysm in a 4-month-old child. PMID- 23751600 TI - Pressure-induced phase transitions in LnTe (Ln=La, Gd, Ho, Yb) and AmTe. AB - The structural behaviour under compression of different lanthanide (La, Gd, Ho, Yb) and actinide (Am) monochalcogenides is studied by means of in situ high pressure x-ray diffraction. All the investigated compounds crystallize at ambient conditions within a cubic (B1) NaCl-type structure but show different behaviours at high pressures. LaTe and AmTe undergo B1 to B2 (CsCl-type structure) phase transitions, starting at 9 GPa and 12 GPa, respectively. The high-pressure phase of AmTe exhibits an electronic transition, identified by an anomaly in the compression curve which is accompanied by a sample colour change. The other three monochalcogenides studied here show clear evidence of decomposition and amorphization under pressure and are, to the best of our knowledge, the first in the LnTe series to show a pressure-induced amorphization. The bulk moduli of all B1-type structure compounds are calculated using the third-order Birch-Murnaghan equation of state. PMID- 23751601 TI - Recent advances and further challenges in lyophilization. AB - While entering a new century, lyophilization in the pharmaceutical field has been subjected to ongoing development and steady expansion. This review aims to highlight recent advances but also to discuss further challenges in lyophilization. At first, the expanded range of pharmaceutical applications based on lyophilization is summarized. Moreover, novel formulation aspects and novel container systems are discussed, and the importance of the freezing step is outlined. Furthermore, the dogma of "never lyophilize above the glass transition temperature" is argued, and recent insights into novel stabilization concepts are provided. Process analytical technology (PAT) and quality by design (QbD) are now leading issues, and the design of the lyophilization equipment also might have to be reconsidered in the future. PMID- 23751602 TI - Suction lesion of finger in a woman affected by Alzheimer's disease. PMID- 23751603 TI - P2Y12 receptor gene polymorphism and antiplatelet effect of clopidogrel in patients with coronary artery disease after coronary stenting. AB - Platelets have a central role in the pathophysiology of thrombosis. Adenosine diphosphate (ADP) plays a pivotal role as an agonist of platelet activation. Genetic polymorphisms of the P2Y12 ADP receptor might influence the activation of this receptor by ADP or the response of patients to platelet inhibitors. The present study was conducted on a total number of 80 participants, 40 patients were diagnosed with acute coronary syndrome and 40 sex and aged-matched healthy volunteers were included as controls. Platelet aggregation was assessed (before and 1 week after clopidogrel administration) and genotyping of the T744C genetic polymorphism of P2Y12 receptor gene was carried out using the restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method. Platelet aggregation of the patients had a range of 54-183% before clopidogrel administration and had a range of 4-113% after its administration. Genotyping of the candidate gene revealed that 72.5% of the patients had a wild allele (TT), whereas 27.5% had a C allele (heterozygous CT, homozygous CC). On the contrary, 97.5% of controls had a wild allele (TT), whereas 2.5% had a C allele (heterozygous CT, homozygous CC). Our study elicited an association between the T744C polymorphism of the P2Y12 ADP receptor gene and platelet reactivity. Carrying the C allele at this position is associated with an increased platelet activation response to ADP. PMID- 23751604 TI - Protein C and protein S deficiency presenting as Budd-Chiari syndrome. AB - Protein C and S are vitamin K-dependent natural anticoagulants. They play a major role in hemostasis by degrading the activated factor V and factor VIII. Deficiencies of protein C and protein S are associated with increased risk of thrombotic events. The combined occurrence of protein C and S deficiency has been rarely reported. We report a 6-year-old boy with Budd-Chiari syndrome due to combined protein C and protein S deficiency. He was managed with low molecular weight heparin and discharged on long-term warfarin therapy. PMID- 23751605 TI - Comparison of local thrombolytic efficacy of plasmin and rt-PA in an in-vitro flow system; a pilot study. AB - Plasmin, a directly acting thrombolytic agent, demonstrated a very favorable safety profile upon intra-arterial delivery to the clot site; however, its thrombolytic efficacy remains to be further assessed. In this study, differences in thrombolysis between clots exposed to equimolar concentrations of plasmin and recombinant tissue-type plasminogen activator (rt-PA) after partial vessel recanalization were tested in a model system. Model blood clots were prepared in glass chambers enabling direct observation by dynamic optical microscopy. The incubation of clots with plasmin (2.4 mg/ml) or rt-PA (2.63 mg/ml), allowing for the initial biochemical clot degradation, was followed by 'flushing' the clots with tangentially directed plasma flow devoid of a thrombolytic agent, mimicking blood flow after partial vessel recanalization. The acquired images were analyzed for nondissolved blood clot area as a function of time. With both thrombolytic agents, the relative clot area decreased rapidly in the first 30 s after initiation of perfusion due to 'flushing' the degraded clot fragments (after plasmin by 0.26 +/- 0.22 and after rt-PA by 0.34 +/- 0.21, P = 0.60). In the following minutes, the clot size showed a linear time dependence: after incubation with plasmin the clot size did not change substantially any more, whereas after incubation with rt-PA the clot size continually decreased. The slopes of the regression lines differed significantly (r(pl) = -8.9 10 vs. r(rtPA) = -44.1 10/min, P < 0.01). In conclusion, the thrombolytic action of plasmin was terminated rapidly by contact with flowing blood plasma, whereas the thrombolytic action of rt-PA was prolonged. PMID- 23751606 TI - In-vitro study of methylglyoxal and aspirin effects on fibrinolysis parameters. AB - Methylglyoxal is a reactive alpha, beta dicarbonyl aldehyde compound that originates from various biochemical pathways. Some studies suggest that increased methylglyoxal in blood leads to changes in fibrinolysis; however, the precise mechanism is not clear. The aim of this study was to compare different concentrations of methylglyoxal and aspirin on fibrinolysis in the plasma of healthy individuals in vitro. Different concentrations of methylglyoxal (5, 50, 100, and 500 MUmol/l) and aspirin (1, 10, and 100 mg/l) were added to the plasma citrate. They were incubated at 37 degrees C for 24 h. Then, fibrinolysis parameters were analyzed by the turbidimetric procedure at 405 nm. The Independent Samples t-test was utilized to compare them (P < 0.05). Findings revealed that methylglyoxal at 500 MUmol/l with aspirin 100 mg/l had significant changes in the maximum lysis velocity (0.163 +/- 0.003), half-time lysis (240 +/- 10.00), the total lysis time (485 +/- 5.00), lag time in lysis (126 +/- 5.77), compared with methylglyoxal at 500 MUmol/l (0.104 +/- 0.005), (276 +/- 5.77), (570 +/- 10.00), and (186 +/- 5.77), respectively (P < 0.05). Methylglyoxal at 500 MUmol/l with aspirin 1 mg/l did not significantly change in either parameter (P > 0.05). Methylglyoxal at 100 MUmol/l with aspirin 1 mg/l did not significantly change in either fibrinolysis parameter (P > 0.05), compared with methylglyoxal at 100 MUmol/l. Methylglyoxal at 5 MUmol/l with aspirin (1, 10, 100 mg/l) changed in all fibrinolysis parameters (P < 0.05), compared with methylglyoxal at 5 MUmol/l. The other concentrations were compared in the same way. Aspirin (more than 1 mg/l) had more effect on higher concentrations of methylglyoxal. It increased the velocity of lysis of the clot and shortened clot lysis. PMID- 23751607 TI - Increased level of red blood cell distribution width is associated with deep venous thrombosis. AB - Previous studies have demonstrated a significant association between red blood cell distribution width (RDW) and acute pulmonary embolism. To the authors' knowledge no study has been reported in patients with deep venous thrombosis (DVT). A total of 431 lower extremity venous duplex examinations were included in the study. Of these, 216 examinations with the diagnosis of DVT were compared to 215 examinations with normal duplex findings with respect to RDW. The two groups were well matched. DVT group had a higher median value and the interquartile range (25th and 75th) of RDW (%) level [14.9 (14.2-16.7)] compared to control group [14.4 (13.6-15.2); P < 0.001], respectively. Patients were divided into tertiles based on RDW. DVT was detected in 42 patients (31.6%) in the lowest tertile, in 81 (53.3%) in the middle tertile, and in 93 (63.7%) in the highest tertile (P < 0.001). In multivariate analysis after adjustment for confounding variables, RDW was the only parameter to predict the presence of DVT [odds ratio (OR) 1.37; 95% confidence interval (CI) 1.21-1.55; P < 0.001]. After removing patients with chronic DVT, the interquartile range (25th and 75th) of the RDW (%) level was also higher in the DVT group [15.0 (14.2-16.7)] compared with the control group [14.4 (13.6-15.2); P < 0.001], respectively. In addition, in proximal DVT, the significant difference continued to be present, although this significance was lost in distal DVT [14.4% (13.6-15.2) vs. 16.1% (15.1-17.4), P < 0.001 and 14.4% (13.6-15.2) vs. 14.3% (14.2-14.7), P = 0.959]. In multivariate analysis, RDW was an independent predictor of risk of proximal DVT (OR 1.60; 95% CI 1.39-1.84; P < 0.001). RDW (%) level was significantly higher in patients with bilateral DVT than in patients with unilateral DVT [16.0 (14.8-17.1) vs. 14.4 (14.2-14.8), P < 0.001, respectively]. In receiver operating characteristics curve analysis, RDW more than 14.9% had 85% sensitivity and 73% specificity in predicting proximal DVT. RDW, an inexpensive and easily measurable laboratory variable, was independently and significantly associated with the presence and severity of DVT, especially nonchronic proximal DVT. The mechanism of association requires, however, further study. PMID- 23751608 TI - Fatal pulmonary embolism complicating a postoperative chylothorax despite adequate thromboprophylaxis. AB - Chylothorax is a recognized complication of intrathoracic surgery, but its occurrence after coronary artery bypass grafting (CABG) is very rare. We report a case of a fatal pulmonary embolism as a complication of chylothorax following CABG. The patient was an 82-year-old woman who presented with increasing chest pain 2 weeks after discharge after an uncomplicated CABG. A computerized tomography (CT) scan with contrast angiogram showed a left-sided pleural effusion and no concurrent pulmonary embolus. Analysis of the pleural effusion revealed a chylothorax, which was treated with chest tube drainage and total parenteral nutrition followed by an oral medium-chain fatty acid diet. The patient improved steadily but, on day 6, she developed acute hypoxemic respiratory failure and shock. A CT angiogram revealed a massive pulmonary embolus and, despite thrombolysis, the patient died. Autopsy confirmed an acute saddle embolus in the pulmonary trunk. The patient had received appropriate venous thromboembolism prophylaxis with subcutaneous unfractionated heparin during her hospital course. This is the first reported case of a fatal pulmonary embolism that occurred in the setting of a post-CABG chylothorax in adults. The occurrence of this complication despite unfractionated heparin thromboprophylaxis may suggest a role for other, more effective medications, such as low molecular weight heparin or fondaparinux in patients with chylothorax. PMID- 23751609 TI - Elevated platelet count, C-reactive protein and thromboxane analog-induced platelet aggregation in patients with Gulf War veterans' illnesses: evidence of a chronic inflammatory state? AB - A previous study of Gulf War veteran's illnesses (GWVI) observed evidence of platelet activation in a majority of patients with GWVI. To further characterize platelet function, we studied 43 patients (40 men) with GWVI (GWVI+) and 21 veterans who served concurrently in the Gulf War but who lacked criteria for GWVI (GWVI-). All participants were free of infection and known inflammatory diseases. Studies performed included platelet count, immature platelet fraction (IPF), plasma thrombopoietin (TPO), C-reactive protein (CRP), platelet aggregation and ATP secretion in response to six agonists, and spontaneous aggregation. Platelet counts and CRP were significantly elevated in GWVI+ compared to GWVI- patients without elevation in IPF or TPO. Platelet aggregation did not differ between GWVI+ and GWVI- patients except for spontaneous aggregation that was significantly greater in GWVI+ patients. Platelet ATP secretion was similar in the two groups, except the response to 50 MUmol/l thrombin receptor agonist peptide 6 (TRAP 6) was significantly greater in GWVI+ patients. When platelet aggregation was analyzed in relation to CRP, the response to 0.5 MUmol/l U46619 was significantly greater in patients whose CRP was at least 2 MUg/ml. Therefore, GWVI+ patients had elevated platelet counts, spontaneous aggregation, TRAP 6 induced secretion, and CRP, but no impairment of platelet function. The increased platelet counts and U46619-induced aggregation appear to be consequences of an underlying inflammatory state in GWVI. PMID- 23751610 TI - Topical application of ankaferd hemostat in a patient with gastroduodenal amyloidosis complicated with gastrointestinal bleeding. AB - Amyloidosis rarely manifests itself as gastrointestinal hemorrhage, especially in the absence of systemic involvement. Despite urgent endoscopic and/or pharmacological therapy, bleeding due to gastric amyloidosis usually recurs after a short period and has considerable morbidity and mortality rates, even in patients undergoing gastrointestinal surgery. For this reason, there is a need for a therapeutic armamentarium for such cases that is effective, easily applicable and has minimal side effects. In this respect, ankaferd blood stopper (ABS) offers a well tolerated and effective alternative approach for these patients. Herein we would like to report a 77-year-old man who had massive bleeding from a gastric ulcer complicating primary gastroduodenal amyloidosis, in whom topical ABS was successfully applied. PMID- 23751611 TI - Laboratory simulated duathlon performance: effects of pre-exercise meals. PMID- 23751613 TI - Contralateral implantation in children affected by postimplant meningitis. AB - This study was designed to investigate the indication and advantages of contralateral implantation after postimplant meningitis (piM). Speech perception assessment, most comfortable levels and high-resolution computer tomography were used to monitor cochlear fibrosis/ossification and clinical changes in outcomes in 5 children affected by meningitis after a variable-time post-cochlear implantation. Ipsilateral ossification was found in 3 children, 1 of whom developed delayed contralateral ossification. These children were implanted on the contralateral side as they all showed deterioration of hearing performance. Results from the present paper and literature analysis suggest that, (1) piM can induce ipsilateral and contralateral ossification, (2) meningitis-induced cochlear ossification is more prone to develop in the presence of a normal cochlear structure and (3) contralateral implantation after piM has proven to be effective in restoring performance when a full electrode insertion is accomplished. PMID- 23751612 TI - Characterization of a surrogate murine antibody to model anti-human CD3 therapies. AB - Fc-modified anti-human CD3epsilon monoclonal antibodies (mAbs) are in clinical development for the treatment of autoimmune diseases. These next generation mAbs have completed clinical trials in patients with type-1 diabetes and inflammatory bowel disease demonstrating a narrow therapeutic window. Lowered doses are ineffective, yet higher pharmacologically-active doses cause an undesirable level of adverse events. Thus, there is a critical need for a return to bench research to explore ways of improving clinical outcomes. Indeed, we recently reported that a short course of treatment affords synergy, providing long-term disease amelioration when combining anti-mouse CD3 and anti-mouse tumor necrosis factor mAbs in experimental arthritis. Such strategies may widen the window between risk and benefit; however, to more accurately assess experimentally the biology and pharmacology, reagents that mimic the current development candidates were required. Consequently, we engineered an Fc-modified anti-mouse CD3epsilon mAb, 2C11-Novi. Here, we report the functional characterization of 2C11-Novi demonstrating that it does not bind FcgammaR in vitro and elicits little cytokine release in vivo, while maintaining classical pharmacodynamic effects (CD3-TCR downregulation and T cell killing). Furthermore, we observed that oral administration of 2C11-Novi ameliorated progression of remitting-relapsing experimental autoimmune encephalitis in mice, significantly reducing the primary acute and subsequent relapse phase of the disease. With innovative approaches validated in two experimental models of human disease, 2C11-Novi represents a meaningful tool to conduct further mechanistic studies aiming at exploiting the immunoregulatory properties of Fc-modified anti-CD3 therapies via combination therapy using parenteral or oral routes of administration. PMID- 23751614 TI - Adenoid cystic carcinoma of the head and neck: a single-center analysis of 105 consecutive cases over a 30-year period. AB - BACKGROUND: Adenoid cystic carcinoma is a rare salivary gland malignancy with a poor disease free survival due to frequent distant metastases and late local recurrences. Previous single-center reports on outcome mostly encompass small series. In this report a relative large series of 105 cases is analyzed, all treated at the VU University Medical Center, Amsterdam, The Netherlands over a 30 year period in which treatment strategies remained unchanged. METHODS: All cases of ACC of the head and neck between 1979 and 2009 at our institution were analyzed through a medical chart review. Recurrence patterns and possible prognostic factors (T-stage, N-status, age, gender, type of salivary gland involved, histological grade, surgical margins, perineural invasion (PNI) and postoperative radiotherapy (RT)) were analyzed. RESULTS: One-hundred and five cases of ACC of the head and neck were identified. Five-, ten- and twenty-year survival rates for overall survival were 68%, 52% and 28%, respectively. T-stage, N-status, surgical margins, histological subtype and age were highly significant predictors for survival. PNI was not a negative prognosticator. CONCLUSIONS: T stage, N-status, surgical margins, histological grade and age are the main predictors of survival-outcome in ACC of the head and neck. Distant metastasis frequently develop, mainly in the first 5 years post treatment. Local recurrences often develop even later on, warranting long term follow up of patients treated for ACC. Grade III ACC should be considered a specific entity within the group of ACC due to its typical aggressive biological behavior and relatively poor outcome, implicating the need for an improved adjuvant treatment. PMID- 23751616 TI - [Proceedings of the Congress of the French Society of Pediatrics, 15-17 May, 2013, Clermont-Ferrand, France]. PMID- 23751615 TI - Monoclonal antibody disulfide reduction during manufacturing: Untangling process effects from product effects. AB - Manufacturing-induced disulfide reduction has recently been reported for monoclonal human immunoglobulin gamma (IgG) antibodies, a widely used modality in the biopharmaceutical industry. This effect has been tied to components of the intracellular thioredoxin reduction system that are released upon cell breakage. Here, we describe the effect of process parameters and intrinsic molecule properties on the extent of reduction. Material taken from cell cultures at the end of production displayed large variations in the extent of antibody reduction between different products, including no reduction, when subjected to the same reduction-promoting harvest conditions. Additionally, in a reconstituted model in which process variables could be isolated from product properties, we found that antibody reduction was dependent on the cell line (clone) and cell culture process. A bench-scale model using a thioredoxin/thioredoxin reductase regeneration system revealed that reduction susceptibility depended on not only antibody class but also light chain type; the model further demonstrates that the trend in reducibility was identical to DTT reduction sensitivity following the order IgG1lambda > IgG1kappa > IgG2lambda > IgG2kappa. Thus, both product attributes and process parameters contribute to the extent of antibody reduction during production. PMID- 23751726 TI - Comparability analysis of anti-CD20 commercial (rituximab) and RNAi-mediated fucosylated antibodies by two LC-MS approaches. AB - In developing biosimilar or biobetter products, comparability to the reference product is required to claim similar integrity or intended purpose. In this work, an anti-CD20 monoclonal antibody developed using RNA interference to decrease core fucosylation (RNAi-mediated) was comprehensively characterized by LC-MS and compared with the commercially-available anti-CD20 rituximab (MabThera ((r)) ). As anticipated, < 30% core fucose was found within the RNAi-produced molecule (compared with > 90% in rituximab), and the reduction in fucose resulting in a significant improvement in FcgammaRIotaIotaIotaa binding and antibody-dependent cell-mediated cytotoxicity. Two mutations, S258Y (fully mutated) and F174I/L (partially mutated), however, were detected in the production of the RNAi mediated molecule. An alternative LC-MS approach using dimethyl labeling (i.e., 2CH 2 for rituximab and 2CD 2 for the RNAi-mediated molecule) was developed to additionally compare the two mAbs and confirm the full sequence with the two mutation sites. Furthermore, disulfide linkages were found to be the same for the two antibodies, with a small portion of unpaired cysteines in both products. Disulfides were correctly linked if the samples were prepared at low pH (i.e., enzymatic digestion by pepsin at pH 2); however, trace amounts of scrambling were found by trypsin digestion at pH 6.8, and this scrambling increased significantly at pH 8. Typical modifications, such as pyro-Glu formation at the N-terminus, K clipping at the C-terminus, oxidation at Met, and deamidation at Asn, were also detected with no significant differences between the two products. Using the LC MS approaches for the comparability study, product integrity with critical structure information was revealed for confirmation of intended purpose (core fucosylation), identification of critical parameters (e.g., sample pH), and correction as needed (amino acid mutation). PMID- 23751727 TI - Effect of wearing compression stockings on recovery after mild exercise-induced muscle damage. AB - BACKGROUND: Compression garments are increasingly popular in long-distance running events where they are used to limit cumulative fatigue and symptoms associated with mild exercise-induced muscle damage (EIMD). However, the effective benefits remain unclear. OBJECTIVE: This study examined the effect of wearing compression stockings (CS) on EIMD indicators. Compression was applied during or after simulated trail races performed at competition pace in experienced off-road runners. METHODS: Eleven highly trained male runners participated in 3 simulated trail races (15.6 km: uphill section 6.6 km, average gradient 13%, and downhill section 9.0 km, average gradient -9%) in a randomized crossover trial. The effect of wearing CS while running or during recovery was tested and compared with a control condition (ie, run and recovery without CS; non- CS). Indicators of muscle function, muscle damage (creatine kinase; CK), inflammation (interleukin-6; IL-6), and perceived muscle soreness were recorded at baseline (1 h before warm-up) and 1, 24, and 48 h after the run. RESULTS: Perceived muscle soreness was likely to be lower when participants wore CS during trail running compared with the control condition (1 h postrun, 82% chance; 24 h postrun, 80% chance). A likely or possibly beneficial effect of wearing CS during running was also found for isometric peak torque at 1 h postrun (70% chance) and 24 h postrun (60% chance) and throughout the recovery period on countermovement jump, compared with non-CS. Possible, trivial, or unclear differences were observed for CK and IL-6 between all conditions. CONCLUSION: Wearing CS during simulated trail races mainly affects perceived leg soreness and muscle function. These benefits are visible very shortly after the start of the recovery period. PMID- 23751728 TI - Selecting endovascular treatment strategy according to the location of intracranial occlusion in acute stroke. AB - BACKGROUND: Selection of endovascular approaches for acute stroke patients remains unclear. The efficacy of intra-arterial therapy (IAT) has been demonstrated in the past. However, in the last years, the use of mechanical thrombectomy by retrievers (RET) is increasing at the expense of IAT. We aimed to compare several clinical outcomes between patients treated with IAT or RET. METHODS: In a 6-year period, acute stroke patients (<8 h) with confirmed internal carotid artery (ICA) occlusion or middle cerebral artery (MCA) occlusion undergoing endovascular therapy were prospectively included in our database. Patients who underwent intra-arterial tissue plasminogen activator (tPA) +/- microguidewire mechanical clot disruption (IAT group) were compared with those who underwent thrombectomy with the Solitaire(r) or Trevo(r) retrievers (RET group). Recanalization (REC) was considered if at the end of the endovascular procedure thrombolysis in cerebral infarction score was 2a-3. Dramatic clinical improvement (DCI) was defined as a decrease of >=10 NIHSSS points from baseline to discharge or 7 days. RESULTS: One hundred and eighty patients were included, 100 (55.6%) patients in the IAT group and 80 patients (44.4%) in the RET group. There were no differences in baseline characteristics (age, gender, risk factors profile, previous treatment with i.v. tPA, baseline NIHSS, extracranial ICA angioplasty and time to REC). Rates of REC, DCI and symptomatic intracranial hemorrhage were also similar between groups. Among patients with ICA occlusions (41 IAT, 34 RET), REC was significantly higher with RET (83.9 vs. 61%; p = 0.04).There was a trend towards a higher DCI rate in the RET group (32.3%) compared with the IAT group (14.6%; p = 0.06). According to MCA occlusions, there were no major differences in the main outcome variables. The number needed to treat to achieve one additional DCI with RET compared with IAT was 12 for MCA occlusions, and only 5 for ICA occlusions. CONCLUSIONS: Among acute stroke patients undergoing endovascular therapies, the benefits of RET over IAT are greater in ICA occlusions. Retrievers may be considered as the first therapeutic option in these patients. PMID- 23751729 TI - Gene structure of the two-domain taurocyamine kinase from Paragonimus westermani: evidence for a distinct lineage of trematode phosphagen kinases. AB - Taurocyamine kinase (TK) is an enzyme that catalyzes the reversible transfer of a phosphate between ATP and taurocyamine. Annelid TKs were suggested to have evolved from a CK ancestor. However, TKs from the lung fluke Paragonimus westermani comprised another lineage. Construction of phylogenetic tree and comparison of exon/intron organization showed that P. westermani TK and other trematode TKs evolved from a molluscan arginine kinase (AK) gene. Exon shuffling probably caused the changes in amino acid sequence thereby changing the affinity from AK to TK. The present study provides new insights on the evolution of phosphagen kinases found in trematodes. PMID- 23751730 TI - Trends in atmospheric deposition fluxes of sulphur and nitrogen in Czech forests. AB - We present the temporal trends and spatial changes of deposition of sulphur and nitrogen in Czech forests based on records from long-term monitoring. A statistically significant trend for sulphur was detected at most of the sites measuring for wet, dry, and total deposition fluxes and at many of these the trend was also present for the period after 2000. The spatial pattern of the changes in sulphur deposition flux between 1995 and 2011 shows the decrease over the entire forested area in a wide range of 18.1-0.2 g m(-2) year(-1) with the most pronounced improvement in formerly most impacted regions. Nitrogen still represents a considerable stress in many areas. The value of nitrogen deposition flux of 1 g m(-2) year(-1) is exceeded over a significant portion of the country. On an equivalent basis, the ion ratios of NO3(-)/SO4(2-) and NH4(+)/SO4(2-) in precipitation show significantly increasing trends in time similarly to those of pH. PMID- 23751731 TI - Body mass estimation in modern population using anthropometric measurements from computed tomography. AB - Forensic anthropologists are able to estimate the stature of a skeleton, its sex and biological age at death, with a relatively high degree of accuracy. Body mass estimation from the stature and bi-iliac (maximum pelvic) breadth and femoral head breadth can be useful in forensic investigations involving unidentified skeletal remains. Predicting the body mass of skeletal remains always involves significant inaccuracy, however when body mass extremes are disregarded average figures provide the best estimation. The aim of the study was to investigate whether the methods usually used in body mass estimation are accurate in different BMI ranges. The usefulness of these methods in forensic anthropology was discussed. The study was performed using CT images of widely differing body types of modern central European populations. Maximum pelvic breadth and anteroposterior femoral head breadth were measured directly from the appropriate CT scan slices for each individual. Body mass index was established for each individual. Four different methods of body mass estimation were applied. The statistical analysis showed that body mass prediction methods based on the bi iliac breadth with known stature and the femoral head breadth show strong correspondence. The results of body mass estimation using different methods were in high correlation with normal BMI. The accuracy of body mass prediction of underweight and obesity cases (BMI extremes) showed significant inaccuracy. Body mass estimation methods can provide important information for forensic anthropological investigation and personal identification. However, one should be aware of the discrepancies and should apply the equations carefully as they can carry significant errors. PMID- 23751732 TI - Frontomaxillary facial angle measurement at 11-14 weeks: assessment of interobserver and intraobserver agreement in 2D and 3D imaging. AB - INTRODUCTION: The primary aim of this study was to assess the interobserver and intraobserver reproducibility of the first-trimester frontomaxillary facial angle (FMFA) measurement using both 2D and 3D ultrasound. Assessment of the relationship between crown-to-rump length (CRL) and FMFA measurement was also reviewed. MATERIALS AND METHODS: Two experienced operators imaged the same 30 patients over a 1-month period collecting both 2D static images and 3D volumes during nuchal translucency assessment at 11-14 weeks' gestation. The operators were blinded to each other's images and results. RESULTS: The mean 2D FMFA measurement was 88.0 degrees and 88.4 degrees for observer 1 and 2, respectively; while the mean 3D FMFA measurement was 87.8 degrees and 88.0 degrees , respectively. Intraclass correlation suggests good intraobserver and interobserver agreement with no statistically significant difference between operators in either 2D (p = 0.14) or 3D (p = 0.11) measurements. The FMFA was unchanged with increasing CRL. DISCUSSION: Both 2D and 3D FMFA measurements have been demonstrated to be equivalent and reliable. Strict image acquisition criteria must be followed for accurate and reproducible FMFA measurements. There was no change demonstrated in FMFA measurement with increasing CRL. PMID- 23751733 TI - Validation of a scoring system to predict difficult laparoscopic cholecystectomy. AB - INTRODUCTION: Laparoscopic cholecystectomy (LC) is one of the most common laparoscopic procedures being performed by general surgeons all over the world. Preoperative prediction of the risk of conversion or difficulty of operation is an important aspect of planning laparoscopic surgery. The purpose of our prospective study was to analyze various risk factors and to predict difficulty and degree of difficulty preoperatively by the use of a scoring system. MATERIALS: This prospective study was conducted in the department of surgery, Lady Hardinge Medical College and associated Dr Ram Manohar Lohia Hospital, Delhi, India. The parameters considered in the preoperative scoring method were old age, male sex, history of hospitalization, obesity, previous abdominal surgery scar, palpable gall bladder, wall thickness of gall bladder, pericholecystic collection and impacted stone. A total of 210 patients were included in the study. RESULTS: We found that history of hospitalization, palpable gall bladder, impacted stone and gall bladder wall thickness were statistically significant factors for prediction of difficult laparoscopic cholecystectomy. Sensitivity and specificity of this preoperative scoring method were found to be 95.74% and 73.68% respectively. Positive predictive values of this scoring method were 90% and 88% for easy and difficult cases respectively. Area under ROC curve was 0.86. Conversion rate from laparoscopic to open cholecystectomy was found to be 4.28%. CONCLUSION: With the help of accurate prediction, high risk patient may be informed before hand regarding the probability of conversion and hence they may have a chance to make arrangements accordingly. On the other hand, surgeons also may have to schedule the time and team for the operation appropriately. Surgeons can also be aware about the possible complications that may arise in high risk patients. PMID- 23751734 TI - What's the 'buzz' about? The ecology and evolutionary significance of buzz pollination. AB - Many plant species have evolved floral characteristics that restrict pollen access. Some of these species are visited by insects, principally bees, which make use of vibrations to extract pollen from anthers. Buzz-pollination, as this phenomenon is generally known, is a widespread method of fertilization for thousands of species in both natural and agricultural systems. Despite its prevalence in pollination systems, the ecological and evolutionary conditions that favour the evolution of buzz-pollination are poorly known. We briefly summarize the biology of buzz-pollination and review recent studies on plant and pollinator characteristics that affect pollen removal. We suggest that buzz pollination evolves as the result of an escalation in the competition between plants and pollen-consuming floral visitors (including pollen thieves and true pollinators) to control the rate of pollen removal from flowers. PMID- 23751735 TI - Medium-term neurological complications after off-pump coronary artery bypass grafting with and without aortic manipulation. AB - BACKGROUND: This study aimed to assess the impact of aortic manipulation during off-pump coronary artery bypass (OPCAB) on neurological complications. METHODS AND RESULTS: Of 336 isolated OPCAB surgeries, the aorta was untouched in 264 cases (group A), whereas it was manipulated by a side-biting clamp in 72 (group B). The average follow-up was 2.9+/-2.5 years. One patient in each group developed postoperative stroke (P=0.38). The prevalence of triple-vessel disease (group A 40.9% vs. group B 61.1%; P=0.0003) and left main trunk disease (group A 30.7% vs. group B 47.2%; P=0.1) was lower in group A than in group B. The number of bypass grafts (group A 2.18+/-0.97 vs. group B 3.00+/-0.97; P=0.0001) was lower in group A than in group B. The prevalence of preoperative atrial fibrillation and the incidence of new-onset postoperative atrial fibrillation were not different between groups (P=0.74 and 0.86, respectively). Survival rate and freedom from major adverse cardiac events were not different between groups (P=0.87 and 0.51, respectively). However, freedom from neurological complications was significantly lower in group A (P=0.0006). The Cox hazard model showed that aortic manipulation (P=0.004; odds ratio, 6.18; 95% confidence interval, 1.8 21.6) and preoperative atrial fibrillation (P=0.001; odds ratio, 14.0; 95% confidence interval, 2.7-72.5) were risk factors for neurological complications. CONCLUSION: Although there was no difference in the incidence of immediate postoperative neurological complications, there were fewer medium-term neurological complications in OPCAB cases without aortic manipulation. PMID- 23751737 TI - [Treatment strategies for spinal cord ischemia after TEVAR]. PMID- 23751736 TI - Time course of statin-induced changes in coronary atherosclerosis using intravascular ultrasound with virtual histology. AB - OBJECTIVE: Recent trials using intravascular ultrasound (IVUS) have shown that statins induce regression and stabilization of coronary artery plaques. However, there are no reports on whether regression and stabilization in coronary artery plaques associated with statin therapy continue or not. The purpose of the present study was to examine the time course of statin-induced changes in coronary atherosclerosis. PATIENTS AND METHODS: Coronary atherosclerosis was evaluated using virtual histology-IVUS in 39 patients at the time of a percutaneous coronary intervention, 8 months after statin therapy (mid-term), and at 48-month (long-term) follow-up. IVUS images qualified for evaluation obtained from 30 of these patients at three time points. RESULTS: Significant decreases in low-density lipoprotein cholesterol and high-sensitivity C-reactive protein were observed at 8 months and these decreases continued for 48 months. A decrease in external elastic membrane volume was observed at 8 months (-1.1%) and reached significance at 48 months (-5.9%, P=0.0001). Plaque volume tended to decrease over time, but this was not statistically significant (-1.6% at 8 months and 3.8% at 48 months). An increase in the calcified plaque component was observed at 8 months (0.09+/-0.34 mm/mm) and reached significance at 48 months (0.21+/-0.33 mm/mm, P=0.002). Change in the calcified component and change in the external elastic membrane volume showed a significant negative correlation at the long term follow-up (r=-0.598, P=0.0005). CONCLUSION: Continued negative vessel remodeling associated with an increase in the calcified plaque component was observed following prolonged statin therapy by serial virtual histology-IVUS analysis. PMID- 23751738 TI - [Outcome comparison of open versus endovascular techniques in the treatment of abdominal aortic aneurysms]. AB - OBJECTIVE: To compare the efficacy, cost and safety of endovascular aortic repair (EVAR) versus open surgery in the treatment of infrarenal abdominal aortic aneurysms. METHODS: Retrospective analyses were conducted for the clinical data and follow-up information of 218 cases from January 2002 to December 2011 at our hospital. Open surgery group included 86 patients with an mean age of 65.5 years and a mean aneurysm diameter of 5.4 cm. In EVAR group, there were 132 cases with an average age of 76.8 years and a mean aneurysm diameter of 5.6 cm. RESULTS: Among 86 open cases, there were inverted "Y" type artificial graft (n = 83) and straight artificial graft (n = 3). The surgical success rate was 98.8%, perioperative period mortality rate was 2.3%, a mean volume of blood loss 450 ml and a mean transfusion volume 320 ml. The mean operative duration was 230 min, a mean hospitalization time (30 +/- 3) days and a mean hospitalization cost RMB yuan 58 000. In EVAR group, the surgical success rate was 100% and perioperative period mortality rate 0.8%. Separating stent graft (n = 121, 91.7%), straight stent graft (n = 4, 3%) and one-stent-graft (n = 7, 5.3%). The mean operative duration was 150 min, a mean volume of blood loss 140 ml, a mean hospitalization time 15.5 days and a mean hospitalization cost RMB yuan 104 800. The operative duration, volume of blood loss and length of hospital stay of EVAR group were superior to those of open surgery group (P < 0.05). But the cost of group EVAR was significantly higher than that of group open surgery (P < 0.05). In group open surgery, 80 cases (94.1%) received a mean follow-up period of 46 months. And 79 artificial grafts maintained patency (98.8%) and 8 cases died (10%). There were 125 cases in group EVAR (94.7%) with a mean time of 32.5 months; stent graft patency in 120 cases (96%), 10 death; 8 complication cases (5.6%) involved stent migration (n = 2) and iliac artery branch occlusion (n = 6). Long-term effects had no significant difference between two groups (P > 0.05). In terms of the incidence of complications, group EVAR was significantly more than group open surgery (P < 0.05). CONCLUSION: In terms of operative duration, volume of blood loss and length of hospital stay, EVAR and open surgery treatment for infrarenal abdominal aortic aneurysms group EVAR is significantly better than group open surgery. As far hospitalization cost, group EVAR is significantly higher than group open surgery. But, in terms of incidence of long-term complications, group EVAR is significantly higher than group open surgery while the latter often requires further interventions. PMID- 23751739 TI - [Acute Stanford B aortic intramural hematoma: early and midterm follow-ups and morphological changes of computed tomography]. AB - OBJECTIVE: To summarize the clinical performances and analyze the morphological characters of acute Stanford B aortic intramural hematoma (IMH) on computed tomography (CT). METHODS: From January 2010 to June 2012, a total of 28 IMH patients at General Hospital of People's Liberation Army were retrospectively reviewed. Among them, 18 patients were followed up with CT. The data of vessel wall maximum thickness (MT), aortic maximum outside diameter (OD) and aortic inner diameter (ID) at onset and 1 week, 1, 3, 6, 12 months post-onset. Statistical analysis was performed with paired t-test. RESULTS: No mortality occurred. Two patients received endovascular repair. According to the follow-ups of 18 IMH patients, MT was (12.1 +/- 2.6) mm on CT. Hematoma disappeared in 44.4% patients at 6 months post-onset. Hematoma disappeared more in the patients with MT <= 10 mm than those with > 10 mm (85.7% vs 18.2%, P < 0.01). Hematoma disappeared in 13/15 patients (86.7%) at 12 months post-onset. OD decreased (7.3 +/- 2.4) mm per year and (6.7 +/- 3.5) and (0.6 +/- 1.7) mm within the first 6 months and 6 months later respectively. OD increased (0.9 +/- 0.5) mm after the disappearance of hematoma. ID increased (6.1 +/- 2.3) mm per year and (4.7 +/- 1.8) and (1.2 +/- 1.0) mm within the first 6 months and 6 months later respectively. CONCLUSION: The early and midterm outcomes of IHM are satisfactory most of hematoma disappear 12 months after onset. Hematoma disappears more rapidly in the patients with MT <= 10 mm than those with > 10 mm. OD reduces and ID increases before the disappearance of hematoma, and both increase afterward. Aortic cavity has a trend of dilating continually. PMID- 23751740 TI - [Critical limb ischemia during perioperative period of open surgery for rupture abdominal aortic aneurysm: treatment and prognosis]. AB - OBJECTIVE: To explore the treatment and prognosis of critical limb ischemia during perioperative period of open surgery for ruptured abdominal aortic aneurysm (AAA). METHODS: Retrospective reviews were conducted for the clinical data of unstable ruptured AAA patients with open repair at our hospital from June 2002 to June 2012 to examine the characteristics and treatment regimens for associated critical limb ischemia. RESULTS: A total of 46 unstable AAAs were enrolled. There were 37 males and 9 females with an average age of 69 years. All AAAs were repaired by a bifurcated polytetrafluoroethylene graft via a transperitoneal midline incision. Critical limb ischemia was found in 8 patients during or after the procedure. Treatments included additional graft-distal iliac artery bypass (n = 2), anastomotic stoma stenting (n = 2), Fogarty catheter embolectomy plus local thrombolysis (n = 2), Fogarty catheter embolectomy (n = 1) and venous thrombolysis (n = 1). Lower limb necrosis developed in 5 patients (4 unilateral, 1 bilateral) and all of them died. CONCLUSION: Open repair of ruptured AAA may be associated with a considerate morbidity of critical limb ischemia. Early reconstruction of blood flow improves the prognosis. PMID- 23751741 TI - [Endovascular therapy for traumatic arterial injury]. AB - OBJECTIVE: To explore the clinical efficacies of endovascular therapy for traumatic arterial intima injury, arterial pseudoaneurysm and arteriovenous fistula. METHODS: From October 2009 to December 2011, 24 patients of arterial intima injury, arterial pseudoaneurysm and arteriovenous fistula underwent endovascular therapy including embolism and stent implantation, etc. RESULTS: Among them, 14 patients were punctured directly and another 10 were punctured after the exposure of arteries. The interventions included embolism (n = 3), embolism plus covered stent implantation (n = 2), covered stent implantation (n = 12) and bare stent implantation (n = 7). And the surgical success rate was 100%. After endoluminal treatment, arterial blood flow recovered, arterial pseudoaneurysm shrank, local pain relieved and venous blood pressure decreased. CONCLUSION: As an effective therapy for traumatic arterial intima injury, arterial pseudoaneurysm and arteriovenous fistula, endovascular therapy has minimal trauma, fewer complications and satisfactory outcomes. PMID- 23751742 TI - [Expression and role of glucose-regulated protein 78 in ovarian serous adenocarcinoma]. AB - OBJECTIVE: To explore the expression and role of glucose-regulated protein 78 in ovarian serous adenocarcinoma. METHODS: The surgical specimens were collected from 126 cases of serous ovarian tumors and 30 cases of normal ovarian tissue. And the mRNA and protein expressions of GRP78 were detected by immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. RESULTS: The results of immunohistochemistry showed that GRP78 positive cells in ovarian serous adenocarcinoma were significantly higher than those in normal ovarian and ovarian serous cystadenoma tissues (P < 0.05). In ovarian serous adenocarcinoma, GRP78 expression was not associated with pathological grade, age and clinical staging (P > 0.05). And the mRNA expressions of GRP78 in normal ovarian tissue, ovarian serous cystadenoma and ovarian serous cystadenocarcinoma were 0.134 +/- 0.021, 0.121 +/- 0.032 and 0.685 +/- 0.085 respectively. Protein expressions of GRP78 in normal ovarian tissue, ovarian serous cystadenoma and ovarian serous cystadenocarcinoma were 0.211 +/- 0.042, 0.193 +/- 0.032 and 0.770 +/- 0.074 respectively. GRP78 mRNA and protein expression had no difference between different pathological grades of ovarian serous cystadenocarcinoma (P > 0.05). CONCLUSION: GRP78 is highly expressed in ovarian serous adenocarcinoma. And its differential expression between ovarian benign and malignant tumors is significant and correlated with the occurrence and progression of ovarian cancer. PMID- 23751743 TI - [Clinical observation of transcatheter arterial chemoembolization plus sorafenib in the treatment of advanced hepatocellular carcinoma with different types of portal vein tumor thrombosis]. AB - OBJECTIVE: To explore the efficacy and safety of transcatheter arterial chemoembolization (TACE) plus sorafenib in the treatment of advanced hepatocellular carcinoma with different types of portal vein tumor thrombosis. METHODS: A total of 32 patients of advanced hepatocellular carcinoma with tumor thrombosis in portal vein were retrospectively analyzed. All of them took oral sorafenib after TACE. They were divided into 3 groups according to imaging examinations of tumor thrombosis in portal vein. Tumor thrombosis in main portal vein was group A, tumor thrombosis in right/left portal branch group B and tumor thrombosis in the second branch of portal vein group C. Tumor response rate, disease control rate (DCR), overall survival (OS) and time to tumor progression (TTP) was followed up. Liver functions were compared with the pre-treatment level. The occurrences of adverse events were recorded. RESULTS: DCR was 20.0% (Group A), 70.0% (Group B) and 91.7 % (Group C) at 2 months post-treatment. DCR in groups B and C had significant differences with group A (P < 0.05). The median OS was 3 (Group A), 9 (Group B) and 14 months (Group C) and the median TTP 0 (Group A), 3 (Group B) and 6 months (Group C) respectively. The median OS and median TTP were significantly longer in Groups B and C than those in Group A (P < 0.05). Liver function at 2 months post-treatment had no statistical difference with the baseline. The most common adverse effects included hand foot skin reaction (n = 23, 3 cases of grade 3), hypertension (n = 3), diarrhea (n = 25, 3 cases of grade 3), hair loss (n = 12), oral ulcers (n = 1) and gastrointestinal bleeding (n = 2). CONCLUSION: The combined use of TACE and sorafenib is both safe and efficacious in the treatment of advanced hepatocellular carcinoma with tumor thrombosis in portal vein. And it may prolong OS and TTP in hepatocellular carcinoma with tumor thrombosis in right/left portal vein and second branch of portal vein. PMID- 23751744 TI - [Long-term efficacies of sinus skeletonization plus abnormal venous reflux interruption in the treatment of parasinus dural arteriovenous fistula]. AB - OBJECTIVE: To retrospectively explore the long-term efficacies of sinus skeletonization plus abnormal venous reflux interruption in the treatment of dural arteriovenous fistula interfering major dural sinus. METHODS: Among 15 consecutively treated patients, the lesions were located in superior sagittal sinus (n = 7), medial segment of transverse sinus (n = 3) and lateral transverse and sigmoid sinus (n = 5). And 40% of them clinically presented with intracranial hypertension and 13.3% with hemorrhage. Preoperatively, Gamma knife therapy and transarterial occlusion were used in 1 case each. All underwent sinus skeletonization plus abnormal venous reflux interruption if any. Interfered sinus was preserved in 12 cases. In another 3 cases, completely occluded segment of sinus was resected after skeletonization. RESULTS: Surgical mortality was none. At discharge, the symptoms were relieved or disappeared in 12 cases. Follow-up study was available in 11 cases over a mean period of 6 years. A Karnofsky performance status (KPS) score of 90 or more was achieved in 8 cases and a KPS score of 80, 60 or 40 was found in 1 case each. Digital subtract angiography was performed in 9 cases and computed tomographic angiography in 1 case after operation. Cure was achieved in 7 cases and 3 cases had minimal residue without recurrence. CONCLUSION: Sinus skeletonization may stably block most blood supply to fistula so as to offer cure or long-term control of dural arteriovenous fistula. PMID- 23751745 TI - [Effects of supraorbital keyhole approach upon the clipping of distal basilar artery aneurysms]. AB - OBJECTIVE: To explore the feasibility and efficacy of supraorbital keyhole approach (SOKA) for the clipping of distal basilar artery (BA) aneurysms. METHODS: A total of 12 patients with distal BA aneurysms were treated with SOKA. All patients had subarachnoid hemorrhage (SAH). They underwent surgeries for an average of 7.6 days post-SAH (n = 2, within 24 hours; n = 7, 3 - 14 days; n = 2, 2 week later). Aneurysms were located on BA (n = 10), posterior cerebral artery (PCA) 1-2 segment (n = 1) and PCA 2 segment (n = 1). One-stage operations were performed in 2 cases with BA bifurcation aneurysm accompanied with anterior cerebral artery (ACA) 1 segment aneurysm and multiple middle cerebral artery (MCA) aneurysms respectively. Anterior and posterior clinoid process was drilled off in 2 patients respectively to increase the room for maneuver. Posterior communicating artery was cut in one case to expand the working space. Once a balloon catheter was put into BA, proximal artery control was implemented if immature aneurysm rupture occurred. RESULTS: All distal BA aneurysms were completely clipped; 3 accompanied aneurysms were clipped together through single supraorbital keyhole approach. One aneurysm ruptured intra-operatively and was clipped successfully with temporary parent arterial occlusion. No conscious disturbance and dyskinesia occurred post-operatively for all patients. CONCLUSION: During the procedure of SOKA, anterior and posterior clinoidectomy may be applied to increase the working space. Distal BA aneurysms located less than 15 mm higher over anterior skull base can be effectively treated via SOKA. PMID- 23751746 TI - [Ecological executive function profiles in depression patients before and after treatment]. AB - OBJECTIVE: To explore the ecological executive function profile in depression patients before and after antidepressants treatment and analyze the relationship of ecological executive function and depression symptoms and effect. METHODS: A total of 33 inpatients diagnosed as depression disorder according to ICD-10 completed the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) and Hamilton Depression Scale (HAMD) before and after a 6-week antidepressant treatment. RESULTS: (1) After treatment, they yielded lower scores significantly on most subscales of BRIEF-A (t = 2.061 - 4.229, P < 0.05), including total score [(127 +/- 27) vs (113 +/- 28)], shifting [(11.7 +/- 2.7) vs (10.3 +/- 2.6)], emotion control [(18.8 +/- 4.6) vs (15.8 +/- 4.4)], monitoring [(9.6 +/- 3.0) vs (8.8 +/- 2.7)], initiation [(15.6 +/- 3.7) vs (13.2 +/- 3.6)], working memory [(14.9 +/- 3.4) vs (13.3 +/- 3.9)], planning [(18.3 +/- 4.4) vs (16.6 +/- 4.4)], organization [(12.4 +/- 3.8) vs (11.4 +/- 3.1)], behavioral regulation index (BRI), metacognition index (MI) and global executive composite (GEC). (2) Before treatment, Person's correlation test showed that the total score of HAMD and all subscales of BRIEF-A had no significant correlation respectively (r = -0.145 - 0.220, P > 0.05). (3) After treatment, the deduction of total score of HAMD and the deduction of the scores of inhibiting belonging to behavioral regulation index (BRI) and initiation, planning belonging to metacognition index (MI) had moderate correlations respectively(r = 0.450, 0.432, 0.403, P < 0.05). (4) Multiple regression analysis showed that the scores of working memory, organization and the deduction of total score of HAMD had significantly negative correlations respectively (t = -2.295, -2.488, P < 0.05). CONCLUSION: The antidepressant treatment can improve ecological executive function of depression patients. And the improvements of ecological executive function and depression symptoms are partially correlated. PMID- 23751747 TI - [Decision-making under ambiguity condition in epileptics]. AB - OBJECTIVE: To investigate the ability of decision making under ambiguity condition in epileptics. METHODS: Twenty-five epileptics (EP) at our hospital during June 2011 to March 2012 and 25 healthy controls (HC) were surveyed by Iowa Gambling Task (IGT) with ambiguous probability. Statistical analyses were performed with analysis of variance (ANOVA) and independent sample t test. And alpha = 0.05 denoted the level of significant differences. RESULTS: As compared with HC, the epileptics were impaired in decision-making under ambiguity and scored lower in IGT (EP: -4.56 +/- 10.26; HC: 4.32 +/- 24.14; t = -2.23, P = 0.029). A comparison between the scores of subjects on 5 blocks suggested: HC subjects scored higher on block 3 (HC: 2.40 +/- 7.07; EP: -1.44 +/- 3.98) and block 5 (HC: 4.00 +/- 7.46; EP: 0.00 +/- 4.51) than the scores of EP subjects (block 3, F = 3.950, P = 0.022, block 5, F = 6.416, P = 0.027). CONCLUSION: The EP patients have significant impairment in decision-making under ambiguity. PMID- 23751748 TI - [Effects of diagnostic protocols on etiology and outcome in immunocompromised host with pulmonary infiltrate]. AB - OBJECTIVE: To explore the effects of diagnostic protocols on etiology and outcome in immunocompromised host (ICH) with pulmonary infiltrate. METHODS: For this historic control study, ICH with acute respiratory failure (ARF) were eligible as study group (n = 65) in 2009 while another ICH cohort was selected as control group (n = 45) in 2007. The protocol consisted of four parts: judgment possible site, determining probable etiology, checking and feedbacks on laboratory test in 12 hours and reassessment and adjustment treatment in 48-72 hours. The etiologies included infection, non-infection and unknown causes. RESULTS: Their average age was 45.3 years (range: 22 - 71). Causes of immune suppression were autoimmune disease (n = 69), hematological disorders (n = 21), solid cancers (n = 10) and others (n = 10). When two groups were compared, basic diseases, organ function and disease severity showed no significant difference, but etiologic diagnoses rate (73.8% vs 57.8%), time from ICU admission to diagnosis (4.0 vs 6.8 days) and 28-day mortality (38.5% vs 62.2%) had significant difference (P < 0.05). CONCLUSION: Implementation of clinical protocol in ICH with ARF is associated with improved etiologic diagnoses and decreased mortality. PMID- 23751749 TI - [Imaging reasons for periprosthetic femoral fractures during the operation of total hip arthroplasty with anatomic prosthesis]. AB - OBJECTIVE: To explore the imaging reasons for periprosthetic femoral fractures during the operation of total hip arthroplasty with anatomic prosthesis. METHODS: The fracture group consisted of 7 cases with periprosthetic femoral fracture (PPFF) and the non-fracture group 21 cases without PPFF during the operation of total hip arthroplasty (THA) among the 144 cases of primary THA with anatomic prosthesis. The preoperative plain films of hip joint were taken to calibrate the Sharp's angle, centre edge (CE) angle, femoral neck shaft angle, femoral anteversion angle of neck, bowing angle of proximal femoral shaft part, width of narrowest part in proximal femoral shaft. For each case, surgical details, age, height and weight were recorded. The results were analyzed with independent sample t test by software SPSS 17.0. RESULTS: No significant difference existed in general situation, Sharp's angle and CE's angle between two groups. And there were significant differences in femoral neck shaft angle (P = 0.040), femoral anteversion angle of neck (P = 0.026), bowing angle of proximal femoral shaft part (P = 0.024), width of narrowest part in proximal femoral shaft (P = 0.021). CONCLUSION: Dysplasia of proximal femur is a major cause of periprosthetic femoral fracture during the operation of total hip arthroplasty with anatomic prosthesis. PMID- 23751750 TI - [Effects of different fluid resuscitations on mesenteric microcirculation in rabbits of acute hemorrhagic shock]. AB - OBJECTIVE: To explore the effects of blood, crystalloid and colloid on mesenteric microcirculation in rabbits of acute hemorrhagic shock. METHODS: Hemorrhagic shock was induced in 28 anesthetized mechanically ventilated rabbits by withdrawing blood to a mean arterial blood pressure (MAP) of 40 mm Hg and maintained for 30 min. The animals were randomized into blank control group, whole blood resuscitation group, Ringer's solution resuscitation (RR) group and volume resuscitation (VR) group (n = 7 each). The data of vital signs, systemic hemodynamic parameters, arterial blood gas analysis and mesenteric microcirculation were collected at baseline, hemorrhagic shock (HS-0), resuscitation 0 min (Res-0) and resuscitation 30 min (Res-30). And side-stream dark field imaging (SDF) was employed to acquire the images of mesenteric microcirculation. RESULTS: No significant difference existed in the basic status between 4 groups. MAP decreased to around 40 mm Hg in all groups. MAP increased significantly after active fluid resuscitation (P < 0.05). In addition to blank control group, total vascular density (TVD), perfused vessel density (PVD), proportion of perfused vessels (PPV) and microvascular flow index (MFI) significantly increased after active fluid resuscitation in the other three groups. TVD and PVD were significantly lower at Res-0 in VR than in RR (P < 0.05). CONCLUSION: After acute hemorrhagic shock, fluid resuscitation with whole blood and Ringer's solution improves systemic hemodynamics. And the combined regimen of whole blood and Ringer's solution is better at restoring mesenteric microcirculation. PMID- 23751751 TI - [Preliminary clinical study of percutaneous transhepatic bipolar radiofrequency ablation catheter in the treatment for malignant biliary obstructive jaundice and biliary stent re-stenosis]. AB - OBJECTIVE: To preliminary observe the feasibility and safety of bipolar radiofrequency ablation catheter in the treatment of malignant biliary obstructive jaundice and biliary stent re-stenosis. METHODS: Four patients with malignant obstructive jaundice caused by terminal cancer received ablation therapy for biliary obstruction by percutaneous transhepatic bipolar radiofrequency ablation catheter. The normal tunnel of biliary was reconstructed rapidly to restore the outflow tract of bile. The procedural practicality, clinical safety and operative complications were analyzed. RESULTS: The ablation therapy was successful for 4 patients. The mean operating duration was 40 min without any 30-day mortality. No postoperative complications such as massive hemorrhage, biliary fistula, biliary infection, hemothorax, pneumothorax, chylothorax, chole-heart syndrome, liver penetrating wound and biliary peritonitis etc. occurred. Cholangiectasis improved markedly after biliary tract reconstruction with general declines of serum total bilirubin and direct bilirubin. One case with biliary stent re-stenosis was re-blocked postoperatively. The average patency time of biliary tract and stent was 124 (90 171) days in 4 cases. Conditions were created for further anti-tumor treatment. CONCLUSION: Percutaneous transhepatic bipolar radiofrequency ablation catheter can reestablish the canal rapidly for malignant biliary obstructive jaundice and stent re-stenosis so as to enhance the therapeutic efficacy. PMID- 23751752 TI - Influence of FCGRT gene polymorphisms on pharmacokinetics of therapeutic antibodies. AB - The neonatal Fc receptor (FcRn) encoded by FCGRT is known to be involved in the pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs). Variability in the expression of FCGRT gene and consequently in the FcRn protein level could explain differences in PK observed between patients treated with mAbs. We studied whether the previously described variable number tandem repeat (VNTR) or copy number variation (CNV) of FCGRT are associated with individual variations of PK parameters of cetuximab. VNTR and CNV were assessed on genomic DNA of 198 healthy individuals and of 94 patients treated with the therapeutic mAb. VNTR and CNV were analyzed by allele-specific PCR and duplex real-time PCR with Taqman ((r)) technology, respectively. The relationship between FCGRT polymorphisms (VNTR and CNV) and PK parameters of patients treated with cetuximab was studied. VNTR3 homozygote patients had a lower cetuximab distribution clearance than VNTR2/VNTR3 and VNTR3/VNTR4 patients (p = 0.021). We observed no affects of VNTR genotype on elimination clearance. One healthy person (0.5%) and 1 patient (1.1%) had 3 copies of FCGRT. The PK parameters of this patient did not differ from those of patients with 2 copies. The FCGRT promoter VNTR may influence mAbs' distribution in the body. CNV of FCGRT cannot be used as a relevant pharmacogenetic marker because of its low frequency. PMID- 23751753 TI - Identification and functional characterization of sex pheromone receptors in beet armyworm Spodoptera exigua (Hubner). AB - In moths, males can detect a distinct blend of several pheromone components by specialized olfactory receptor neurons (ORNs) on the antennae. Four candidate pheromone receptors (PR) with seven transmembrane domains were identified by homology cloning from the antennae of Spodoptera exigua (Sexi). Phylogenetic analyses reveal that all four odorant receptors (OR) belong to pheromone receptor subtypes. Expression patterns revealed that PRs were male-specific in the antenna except for SexiOR11, which was female antenna-biased. Functional analyses of these PRs were conducted using heterologous expression in Xenopus oocytes. SexiOR13 and SexiOR16 were all broadly activated by multiple pheromone components. SexiOR13 responded robustly to the critical pheromone component, Z9, E12-14:OAc and the minor pheromone component, Z9-14:OAc at a concentration of 10( 4) M. Dose-response studies indicate that SexiOR13 was approximately 4 times more sensitive to Z9,E12-14:OAc (EC50 = 3.158 * 10(-6) M) compared to Z9-14:OAc (EC50 = 1.203 * 10(-5) M). While, SexiOR16 responded robustly to the secondary pheromone component Z9-14:OH with high sensitivity (EC50 = 9.690 * 10(-7) M). However, similar tests of the five pheromones with SexiOR6 and SexiOR11 failed to elicit any response. These results provide basic knowledge to further advance research on the molecular mechanisms of pheromone reception. PMID- 23751754 TI - From NAFLD in clinical practice to answers from guidelines. AB - This review of the literature consists of three sections. First, papers concerning non-alcoholic fatty liver disease (NAFLD) awareness among the general population, general practitioners, and liver and non-liver specialists were retrieved and analyzed to highlight the perception of disease, verify knowledge of current recommendations, and identify the main difficulties experienced in clinical practice. Next, position papers and clinical practice guidelines issued by International and National Hepatological Scientific Societies were identified and critically assessed in order to pinpoint the areas of convergence/difference. Finally, practical suggestions on NAFLD diagnosis and management in daily practice are provided and the open questions highlighted. PMID- 23751756 TI - The WGO Train the Trainer Workshop: a participant's perspective. PMID- 23751755 TI - Impact of occult hepatitis B virus infection on the outcome of chronic hepatitis C. AB - BACKGROUND & AIMS: Occult hepatitis B virus infection (OBI) frequently occurs in patients with hepatitis C virus (HCV) related chronic hepatitis (CHC), but the influence of OBI on the CHC outcome is still uncertain. This observational cohort study evaluated the clinical evolution of CHC patients according to their OBI status. METHODS: From 1991 to 2000, 326 hepatitis B surface antigen negative CHC patients were tested for OBI by the analysis of liver biopsy DNA extracts. A total of 128/326 cases (39.2%) tested OBI positive and 198/326 (60.8%) OBI negative. Ninety-four of 326 patients (37 OBI positive, 57 OBI negative) were followed-up for a median time of 11 years (range 5-19 years). During the follow up, 79/94 patients underwent anti-HCV treatments and 25 [corrected] achieved a sustained virological response that occurred independently of their OBI status RESULTS: Eighteen patients (13/37 OBI positive, 5/57 OBI negative, p < 0.01) developed hepatocellular carcinoma (HCC). Among the 76 non-HCC individuals, 15 subjects (8/24 OBI positive, 7/52 OBI negative, p < 0.05) developed advanced forms of cirrhosis. Eighteen patients died during follow-up and 2 underwent liver transplantation. OBI positive individuals had a cumulative survival rate significantly shorter than OBI negative individuals (p = 0.003). Liver-related deaths were more frequently found in OBI positive than OBI negative patients (12/37 OBI positive vs. 6/57 OBI negative patients respectively, p < 0.01). Finally, non-response to anti-HCV therapy was significantly associated with lower survival (p = 0.02). CONCLUSIONS: Among CHC patients, occult HBV co-infected individuals are a category at high risk of progression toward cirrhosis, HCC development, and lower survival. PMID- 23751757 TI - Anomalous Nernst effect in the ferromagnetic Kondo lattice Ce3RhSi3. AB - The ferromagnetic heavy fermion compound Ce3RhSi3 was studied by means of electrical resistivity, Hall effect, thermoelectric power and Nernst coefficient measurements. Below T ~ 30 K, all the transport characteristics were found to behave anomalously as functions of temperature and magnetic field. In particular, the Hall and Nernst coefficients at low temperatures exhibit pronounced and strongly field-dependent maxima, likely possessing the same microscopic origin, which however cannot be captured by available theoretical models. PMID- 23751758 TI - A small molecule bidentate-binding dual inhibitor probe of the LRRK2 and JNK kinases. AB - Both JNK and LRRK2 are associated with Parkinson's disease (PD). Here we report a reasonably selective and potent kinase inhibitor (compound 6) that bound to both JNK and LRRK2 (a dual inhibitor). A bidentate-binding strategy that simultaneously utilized the ATP hinge binding and a unique protein surface site outside of the ATP pocket was applied to the design and identification of this kind of inhibitor. Compound 6 was a potent JNK3 and modest LRRK2 dual inhibitor with an enzyme IC50 value of 12 nM and 99 nM (LRRK2-G2019S), respectively. Compound 6 also exhibited good cell potency, inhibited LRRK2:G2019S-induced mitochondrial dysfunction in SHSY5Y cells, and was demonstrated to be reasonably selective against a panel of 116 kinases from representative kinase families. Design of such a probe molecule may help enable testing if dual JNK and LRRK2 inhibitions have added or synergistic efficacy in protecting against neurodegeneration in PD. PMID- 23751759 TI - Diagnostic imaging of a child with congenital internal jugular vein phlebectasia. PMID- 23751760 TI - Hyperbilirubinemia in black infants. PMID- 23751761 TI - Incidence of sports-related concussion among youth football players aged 8-12 years. AB - OBJECTIVE: To determine the risk of concussion among youth football players (ages 8-12 years). STUDY DESIGN: Participants included 468 male youth football players in western Pennsylvania during the 2011 youth football season. Incidence rates (IRs) and incidence density ratios (IDRs) of concussion were calculated for games and practices and for age groups. RESULTS: There was a total of 11,338 (8415 practice and 2923 game) athletic exposures (AEs) in the study period, during which 20 medically diagnosed concussions occurred. A majority of concussions were the result of head-to-head (45%) contact. The combined concussion IR for practices and games was 1.76 per 1000 AEs (95% CI 0.99-2.54). The concussion IR was 0.24 per 1000 AEs (95% CI 0.04-0.79) in practices and 6.16 per 1000 AEs (95% CI 3.76-9.54) in games. The IDR for concussions in games to practices was 25.91 (95% CI 6.01-111.70). The IDR of concussions for youth aged 11-12 years compared with youth aged 8-10 years was 2.72 (95% CI 0.66-4.78). CONCLUSIONS: The overall IR for concussion in youth football players aged 8-12 years was comparable with that reported previously for high school and collegiate samples. However, participation in games was associated with an increase in risk of concussion compared with practices, which was higher than rates previously reported for high school and collegiate athletes. Younger players were slightly less likely to incur a concussion than were older players. PMID- 23751764 TI - Lower initial central venous pressure in septic patients from long-term care facilities than in those from the community. AB - BACKGROUND/PURPOSE: The cornerstone of emergency management of severe sepsis and septic shock is early (within 6 hours) goal-directed therapy, including maintenance of central venous pressure (CVP) at 8-12 mmHg. It is unclear whether there is a difference in initial (baseline) CVP between septic patients who are referred from the community and those who come from long-term care facilities (LTCFs) in Taiwan. We designed this study to investigate the difference in hemodynamic parameters between these two groups. MATERIALS AND METHODS: Every patient with severe sepsis or septic shock who had a central venous catheter inserted via the internal jugular or subclavian vein at Kaohsiung Medical University Hospital between April 2007 and October 2007 was enrolled. CVP was measured immediately at the emergency department. Patient demographics, including residence, were retrospectively recorded and analyzed. RESULTS: There were 166 evaluable patients; 125 (75.3%) came from the community and 41 (24.7%) from LTCFs. There were no significant differences in age, sex, initial body temperature, heart rate, blood pressure, or leukocyte count between the two groups. However, patients who were referred from LTCFs had a significantly lower initial CVP than those from the community (5.0 +/- 4.5 mmHg vs. 7.0 +/- 4.8 mmHg, p = 0.023). The difference was more significant between mechanically ventilated patients from LTCFs and those from the community (5.0 +/- 3.0 mmHg vs. 8.1 +/- 5.6 mmHg, p = 0.006). CONCLUSION: Severely septic patients referred from LTCFs may require more aggressive fluid resuscitation within the first 6 hours of the diagnostic criteria met at the emergency department to achieve the CVP target of early goal-directed therapy. PMID- 23751765 TI - Burkholderia pseudomallei infection induces the expression of apoptosis-related genes and proteins in mouse macrophages. AB - BACKGROUND/PURPOSE: In this study, we addressed whether the production of apoptosis-related genes and proteins is induced in mouse macrophages infected with Burkholderia pseudomallei cells. METHODS: Mouse macrophages were infected with B. pseudomallei cells at 0.5 hours, 1 hour, 2 hours, 4 hours, and 6 hours, respectively, followed by real-time polymerase chain reaction (PCR) array analysis. The amount of apoptosis-related proteins (caspase-3, caspase -8, caspase -9, Bax, and Bcl-2) was confirmed by Western blot. RESULTS: After infection, an increase of these proteins was observed. The expression levels of other apoptosis-related genes were also determined by PCR array. Experimental results revealed that the messenger RNA levels of tumor necrosis factor ligand (e.g., tnfsf10 and tnfrs10b) and fas were increased, whereas the expression levels of some antiapoptosis genes such as Birc5, Hells, and Bnip3 were decreased. CONCLUSION: Our study results demonstrate that the apoptosis-related genes and proteins in mouse macrophages were modulated by B. pseudomallei. PMID- 23751766 TI - Tigecycline salvage therapy for necrotizing fasciitis caused by Vibrio vulnificus: Case report in a child. AB - Necrotizing fasciitis caused by Vibrio vulnificus is rarely reported in children. We describe a 12-year-old immunocompetent boy with necrotizing fasciitis caused by V. vulnificus. He was cured by radical and serial debridement and salvage therapy with intravenous cefpirome plus tigecycline. The in vitro antibacterial activity of combination regimens and a literature review of pediatric V. vulnificus infection are described. PMID- 23751767 TI - Simultaneous cryptococcal and tuberculous meningitis in a patient with systemic lupus erythematosus. AB - Simultaneous central nervous system (CNS) infection with Cryptococcus and tuberculosis (TB) is very rare. Despite improved therapeutic options, treatment of CNS cryptococcosis is still difficult and needs invasive treatment modalities, such as intrathecal or intraventricular amphotericin B, in refractory cases. We describe a patient with systemic lupus erythematosus diagnosed with simultaneous cryptococcal and TB meningitis who had a poor response to intravenous liposomal amphotericin B and fluconazole, but was successfully treated with intraventricular amphotericin B, in addition to anti-TB therapy. PMID- 23751768 TI - High prevalence of Chlamydia pneumoniae infection in an asymptomatic Jordanian population. AB - BACKGROUND/PURPOSE: The bacterium Chlamydia pneumoniae is associated with respiratory diseases and nonrespiratory illnesses like atherosclerosis. This study aims to investigate the seroprevalence of immunoglobulin G (IgG) against C. pneumoniae in an asymptomatic population in Jordan and to analyze the immunity state in relation to age and sex. METHODS: Serum samples were collected from 588 apparently healthy individuals aged 2-86 years. Using the microimmunofluorescence (MIF) test, seropositivity was defined as an anti-C. pneumoniae IgG titer >=1:16. Titers from 1:16 to 1:256 were considered indicative for a past infection, whereas 1:512 was considered diagnostic of an acute infection. RESULTS: The overall prevalence of C. pneumoniae was 54.9%. The mean seropositivity in males was slightly higher than females. The seroprevalence of infection was relatively low in children aged 2-9 years, and steadily increased to reach a plateau of 66.7% at around 30-39 years of age, which remained stable in later years. Recent infection was indicated in 14.3% of study subjects. The seropositivity was highest in males, and more frequent in adults than in children and teenagers. CONCLUSION: A high seroprevalence of C. pneumoniae in the asymptomatic population suggests that infection with this pathogen is common in Jordan. Higher seropositivity in males compared to females was observed. The primary infection is acquired during the first four decades of life, and in older ages high antibody levels are likely maintained by reinfection or persistent infection. PMID- 23751769 TI - A multicenter surveillance of antimicrobial resistance in Serratia marcescens in Taiwan. AB - BACKGROUND: Serratia marcescens is an important nosocomial pathogen and the characteristic property of resistance conferred by extended-spectrum beta lactamase or a novel AmpC cephalosporinase was not unusual in Taiwan. This study investigated the trends in antimicrobial resistance in S. marcescens from a nationwide surveillance in Taiwan. MATERIALS AND METHODS: S. marcescens isolates were collected biennially between 2002 and 2010 from medical centers and regional hospitals throughout Taiwan, as part of the Taiwan Surveillance of Antimicrobial Resistance program. Minimal inhibitory concentrations were determined by the Clinical and Laboratory Standards Institute reference broth microdilution method. RESULTS: A total of 403 nonduplicate S. marcescens isolates were collected, mostly from respiratory samples (157, 39.0%), followed by the urinary tract samples (90, 22.3%). Overall, 99.3% isolates were susceptible to imipenem, 93.8% to ceftazidime, 89.2% to minocycline, 87.8% to amikacin, 86.8% to cefepime, 82.9% to aztreonam, 73.2% to ceftriaxone, 72.7% to levofloxacin, 63.8% to ciprofloxacin, 60.8% to trimethoprim/sulfamethoxazole (TMP/SMX), and 59.6% to gentamicin. A significantly increased susceptibility rate after 2004 was observed for the following antibiotics: amikacin (73.8% vs. 97.1%), gentamicin (40.0% vs. 72.4%), ciprofloxacin (53.8% vs. 70.4%), ceftriaxone (53.8% vs. 86.0%), cefepime (74.4% vs. 95.1%), aztreonam (72.5% vs. 89.7%), and TMP/SMX (41.3% vs. 73.7%). CONCLUSION: In this 8-year study, the susceptibility of S. marcescens to ceftazidime and imipenem remained consistently high in Taiwan. S. marcescens isolates demonstrated relatively higher resistance to ciprofloxacin and levofloxacin, and therefore continued surveillance of antimicrobial resistance, especially for fluoroquinolone, is warranted. PMID- 23751770 TI - CD209 promoter -336 A/G (rs4804803) polymorphism is associated with susceptibility to pulmonary tuberculosis in Zahedan, southeast Iran. AB - INTRODUCTION: The association between -336 A/G polymorphism of CD209 and susceptibility to/protection from tuberculosis is inconsistent. AIM: The present study aimed at evaluating the possible association between CD209 rs4804803 (-336 A/G) gene polymorphism and pulmonary tuberculosis (PTB) in a sample of Iranian population. MATERIALS AND METHODS: This case-control study was performed on 156 PTB patients and 154 healthy individuals. Tetra-amplification refractory mutation system-polymerase chain reaction was used to detect the polymorphisms. RESULTS: Our findings revealed that the CD209 rs4804803 increased the risk of PTB in codominant [odds ratio (OR) = 5.16, 95% confidence interval (CI) = 1.60-16.59, p = 0.006, GG vs. AA], dominant (OR = 1.69, 95% CI = 1.07-2.66, p = 0.024, AG + GG vs. AA), and recessive (OR = 4.20, 95% CI = 1.34-13.16, p = 0.014, GG vs. AA + AG) tested inheritance models. Furthermore, the rs4804803 G allele increased the risk of PTB (OR = 1.58, 95% CI = 1.12-2.23, p = 0.011) as compared to the A allele. CONCLUSION: Our data suggest that CD209 rs4804803 polymorphism increased the risk of PTB in a sample of Iranian population. PMID- 23751771 TI - Early life exposure to antibiotics and the risk of childhood allergic diseases: an update from the perspective of the hygiene hypothesis. AB - The prevalence of allergic diseases has been growing rapidly in industrial countries during recent decades. It is postulated that growing up with less microbial exposure may render the immune system susceptible to a T helper type 2 (Th2)-predominant allergic response-also known as the hygiene hypothesis. This review delineates recent epidemiological and experimental evidence for the hygiene hypothesis, and integrates this hypothesis into the association between early life exposure to antibiotics and the development of allergic diseases and asthma. Several retrospective or prospective epidemiological studies reveal that early exposure to antibiotics may be positively associated with the development of allergic diseases and asthma. However, the conclusion is inconsistent. Experimental studies show that antibiotics may induce the Th2-skewed response by suppressing the T helper type 1 (Th1) response through inhibition of Th1 cytokines and disruption of the natural course of infection, or by disturbing the microflora of the gastrointestinal (GI) tract and therefore jeopardizing the establishment of oral tolerance and regulatory T cell immune responses. The hygiene hypothesis may not be the only explanation for the rapid increase in the prevalence of allergic diseases and asthma. Further epidemiological and experimental studies addressing the issue of the impact of environmental factors on the development of allergic diseases and the underlying mechanisms may unveil novel strategies for the prevention and treatment of allergic diseases in the future. PMID- 23751772 TI - Lower-extremity isokinetic strength profiling in professional rugby league and rugby union. AB - PURPOSE: While several studies have documented isokinetic knee strength in junior and senior rugby league players, investigations of isokinetic knee and hip strength in professional rugby union players are limited. The purpose of this study was to provide lower-extremity strength profiles and compare isokinetic knee and hip strength of professional rugby league and rugby union players. PARTICIPANTS: 32 professional rugby league and 25 professional rugby union players. METHODS: Cross-sectional analysis. Isokinetic dynamometry was used to evaluate peak torque and strength ratios of the dominant and nondominant legs during seated knee-extension/ flexion and supine hip-extension/flexion actions at 60 degrees /s. RESULTS: Forwards from both codes were taller and heavier and had a higher body-mass index than the backs of each code. Rugby union forwards produced significantly (P < .05) greater peak torque during knee flexion in the dominant and nondominant legs (ES = 1.81 and 2.02) compared with rugby league forwards. Rugby league backs produced significantly greater hip-extension peak torque in the dominant and nondominant legs (ES = 0.83 and 0.77) compared with rugby union backs. There were no significant differences in hamstring-to quadriceps ratios between code, position, or leg. Rugby union forwards and backs produced significantly greater knee-flexion-to-hip-extension ratios in the dominant and nondominant legs (ES = 1.49-2.26) than rugby union players. CONCLUSIONS: It seems that the joint torque profiles of players from rugby league and union codes differ, which may be attributed to the different demands of each code. PMID- 23751773 TI - Post-stroke apathy: an exploratory longitudinal study. AB - INTRODUCTION: Post-stroke apathy is a disturbance of motivation evidenced by low initiative, difficulties in starting, sustaining or finishing any goal-directed activity, low self-activation or self-initiated behavior and emotional indifference. Apathy is a common behavioral disturbance in stroke survivors. We aimed to analyze the relationship between post-stroke apathy at 1 year after stroke and (1) apathy in acute phase; (2) demographic, pre-stroke predisposing conditions (previous mild cognitive impairment, alcohol abuse, mood/anxiety disorder) and clinical features (stroke type and location, neurological symptoms); (3) post-stroke depression and post-stroke cognitive impairment, and (4) post-stroke functional outcome, quality of life and the perception of health. METHODS: Consecutive stroke (infarct/intracerebral hemorrhage) patients without aphasia or consciousness disturbances were included in the acute phase of stroke and assessed at 1 year after stroke. We assessed apathy with the clinically rated version of the Apathy Evaluation Scale. We also assessed post-stroke depression (Montgomery Asberg Depression Rating Scale) and post-stroke cognitive impairment (attention, mental flexibility, verbal, motor and graphomotor initiative, and non verbal and verbal abstract reasoning, and Mini-Mental State Examination), functional outcome (Barthel Index), quality of life and perception of health (EuroQol). Data were analyzed using bivariate associations (chi(2) and t test) and stepwise multivariate analysis. RESULTS: We included 76 stroke patients [32.9% women, mean age 62.9 years (SD = 10.9) and a mean of 6.9 (SD = 4.3) years of education]. Apathy was present in 17 patients in the acute phase and in 18 (23.7%) patients at 1 year after stroke. At 1 year after stroke, 41% of the acute apathetic patients remained apathetic. Sixty-one percent of new cases of post stroke apathy were detected. Post-stroke apathy was associated only with previous cognitive impairment, apathy in acute stroke, post-stroke cognitive impairment, verbal abstract reasoning and with worse Barthel Index scale scores. In the multivariate logistic regression model, verbal abstract reasoning (odds ratio, OR = 7.03) and apathy in acute stroke (OR = 3.8) were identified as independent factors for post-stroke apathy at 1 year. Apathetic patients did not report worse quality of life or health. CONCLUSION: Apathy in acute stroke phase was a reliable indicator of post-stroke apathy. Apathy should be assessed in both phases. Verbal abstract reasoning impairment was also an independent factor for post-stroke apathy impairing patients' ability to reason about goal-directed activity. Even though apathetic patients had worse post-stroke functional outcome, they did not report losing quality of life or having worse health. PMID- 23751774 TI - A modified Lund-Mackay system for radiological evaluation of chronic rhinosinusitis. AB - OBJECTIVE: The Lund-Mackay system (L-M system) is widely used for computed tomography (CT) evaluation of chronic rhinosinusitis (CRS). However, a major drawback of the L-M system is its insufficiency of gradation. To avoid this deficiency, a new staging system proposed by American societies and the Zinreich system were reported as modifications of the L-M system. The aim of this study was to investigate the efficiency of gradation and the accuracy of the visual quantification of these modified staging systems. METHODS: Preoperative CT scanning was performed on 20 adult patients with CRS. A computer workstation was used to measure the volume of each sinus and the volume of inflammatory disease in each sinus. Then the soft tissue density rate (STDR) and objective scores, which were adapted to each system, were calculated. Visual evaluation of the CT images was performed using these systems. The visual score with each staging system and STDR value were evaluated for a correlation, and the rate of agreement was determined between the visual and objective scores obtained with each staging system. RESULTS: The correlation between the visual scores and the STDR values was shown with all staging system including L-M system. The coefficients of correlation between the visual scores and the STDR values with these modified systems were higher than with the L-M system. While the agreement rates with these modified systems were significantly lower than with the L-M system, differences of 2 or greater between the subjective and objective scores were rare. CONCLUSION: We cannot conclude that one of these three staging systems is superior to the other. With this study, the simple grading system such L-M staging score was considered easy and accurate method to use the clinical level. The modified staging systems showed more efficient ability to gradate in evaluating rhinosinusitis inflammation compared with the L-M system and also showed acceptable accuracy. PMID- 23751775 TI - Peritoneal dialysis-first policy made successful: perspectives and actions. AB - Peritoneal dialysis (PD) represents an important but underused strategy for patients who are beginning dialysis treatment worldwide. The development of a health care model that encourages increased use of PD is hampered by a lack of expertise and absence of pragmatic strategies. This article provides a brief review of a PD-first initiative that was implemented in Hong Kong more than 25 years ago and issues related to this policy. Clinical studies and research by the authors' and other teams around the world have shown evidence that, as a home based dialysis therapy, PD can improve patient survival, retain residual kidney function, lower infection risk, and increase patient satisfaction while reducing financial stress to governments by addressing the burden of managing the growing number of patients with end-stage renal disease. Achieving a successful PD-first policy requires understanding inherent patient factors, selecting patients carefully, and improving technique-related factors by training physicians, nurses, patients, and caregivers better. Dialysis centers have the important role of fostering expertise and experience in PD patient management. Dialysis reimbursement policy also can be helpful in providing sufficient incentives for choosing PD. However, despite successes in improving patient survival, PD treatment has limitations, notably the shortcoming of technique failure. Potential strategies to and challenges of implementing a PD-first policy globally are discussed in this review. We highlight 3 important elements of a successful PD-first program: nephrologist experience and expertise, peritoneal dialysis catheter access, and psychosocial support for PD patients. PMID- 23751776 TI - Differential methylation of genes in the medial prefrontal cortex of developing and adult rats following exposure to maltreatment or nurturing care during infancy. AB - Quality of maternal care in infancy is an important contributing factor in the development of behavior and psychopathology. One way maternal care could affect behavioral trajectories is through environmentally induced epigenetic alterations within brain regions known to play prominent roles in cognition, emotion regulation, and stress responsivity. Whereas such research has largely focused on the hippocampus or hypothalamus, the prefrontal cortex (PFC) has only just begun to receive attention. The current study was designed to determine whether exposure to maltreatment or nurturing care is associated with differential methylation of candidate gene loci (bdnf and reelin) within the medial PFC (mPFC) of developing and adult rats. Using a within-litter design, infant male and female rats were exposed to an adverse or nurturing caregiving environment outside their home cage for 30 min per day during the first postnatal week. Additional littermates remained with their biological caregiver within the home cage during the manipulations. We observed that infant rats subjected to caregiver maltreatment emitted more audible and ultrasonic vocalizations than littermates subjected to nurturing care either within or outside of the home cage. While we found no maltreatment-induced changes in bdnf DNA methylation present in infancy, sex-specific alterations were present in the mPFC of adolescents and adults that had been exposed to maltreatment. Furthermore, while maltreated females showed differences in reelin DNA methylation that were transient, males exposed to maltreatment and both males and females exposed to nurturing care outside the home cage showed differences in reelin methylation that emerged by adulthood. Our results demonstrate the ability of infant caregiver interactions to epigenetically mark genes known to play a prominent role in cognition and psychiatric disorders within the mPFC. Furthermore, our data indicate the remarkable complexity of alterations that can occur, with both transient and later emerging DNA methylation differences that could shape developmental trajectories and underlie gender differences in outcomes. PMID- 23751779 TI - Mechanisms of carbon nanotube-induced toxicity: focus on pulmonary inflammation. AB - Carbon nanotubes have gained tremendous interest in a wide range of applications due to their unique physical, chemical, and electronic properties. Needless to say, close attention to the potential toxicity of carbon nanotubes is of paramount importance. Numerous studies have linked exposure of carbon nanotubes to the induction of inflammation, a complex protective response to harmful stimuli including pathogens, damaged or dying cells, and other irritants. However, inflammation is a double-edged sword as chronic inflammation can lead to destruction of tissues thus compromising the homeostasis of the organism. Here, we provide an overview of the process of inflammation, the key cells and the soluble mediators involved, and discuss research on carbon nanotubes and inflammation, including recent studies on the activation of the so-called inflammasome complex in macrophages resulting in secretion of pro-inflammatory cytokines. Moreover, recent work has shown that inflammatory cells i.e. neutrophils and eosinophils are capable of enzymatic degradation of carbon nanotubes, with mitigation of the pro-inflammatory and pro-fibrotic effects of nanotubes thus underscoring that inflammation is both good and bad. PMID- 23751780 TI - Genotoxicity and carcinogenicity risk of carbon nanotubes. AB - Novel materials are often commercialized without a complete assessment of the risks they pose to human health because such assessments are costly and time consuming; additionally, sometimes the methodology needed for such an assessment does not exist. Carbon nanotubes have the potential for widespread application in engineering, materials science and medicine. However, due to the needle-like shape and high durability of multiwalled carbon nanotubes (MWCNTs), concerns have been raised that they may induce asbestos-like pathogenicity when inhaled. Indeed, experiments in rodents supported this hypothesis. Notably, the genetic alterations in MWCNT-induced rat malignant mesothelioma were similar to those induced by asbestos. Single-walled CNTs (SWCNTs) cause mitotic disturbances in cultured cells, but thus far, there has been no report that SWCNTs are carcinogenic. This review summarizes the recent noteworthy publications on the genotoxicity and carcinogenicity of CNTs and explains the possible molecular mechanisms responsible for this carcinogenicity. The nanoscale size and needle like rigid structure of CNTs appear to be associated with their pathogenicity in mammalian cells, where carbon atoms are major components in the backbone of many biomolecules. Publishing adverse events associated with novel materials is critically important for alerting people exposed to such materials. CNTs still have a bright future with superb economic and medical merits. However, appropriate regulation of the production, distribution and secondary manufacturing processes is required, at least to protect the workers. PMID- 23751777 TI - Beyond gene discovery in inflammatory bowel disease: the emerging role of epigenetics. AB - In the past decade, there have been fundamental advances in our understanding of genetic factors that contribute to the inflammatory bowel diseases (IBDs) Crohn's disease and ulcerative colitis. The latest international collaborative studies have brought the number of IBD susceptibility gene loci to 163. However, genetic factors account for only a portion of overall disease variance, indicating a need to better explore gene-environment interactions in the development of IBD. Epigenetic factors can mediate interactions between the environment and the genome; their study could provide new insight into the pathogenesis of IBD. We review recent progress in identification of genetic factors associated with IBD and discuss epigenetic mechanisms that could affect development and progression of IBD. PMID- 23751778 TI - Physical energy for drug delivery; poration, concentration and activation. AB - Techniques for controlling the rate and duration of drug delivery, while targeting specific locations of the body for treatment, to deliver the cargo (drugs or DNA) to particular parts of the body by what are becoming called "smart drug carriers" have gained increased attention during recent years. Using such smart carriers, researchers have also been investigating a number of physical energy forces including: magnetic fields, ultrasound, electric fields, temperature gradients, photoactivation or photorelease mechanisms, and mechanical forces to enhance drug delivery within the targeted cells or tissues and also to activate the drugs using a similar or a different type of external trigger. This review aims to cover a number of such physical energy modalities. Various advanced techniques such as magnetoporation, electroporation, iontophoresis, sonoporation/mechnoporation, phonophoresis, optoporation and thermoporation will be covered in the review. Special emphasis will be placed on photodynamic therapy owing to the experience of the authors' laboratory in this area, but other types of drug cargo and DNA vectors will also be covered. Photothermal therapy and theranostics will also be discussed. PMID- 23751781 TI - Particulate formulations for the delivery of poly(I:C) as vaccine adjuvant. AB - Current research and development of antigens for vaccination often center on purified recombinant proteins, viral subunits, synthetic oligopeptides or oligosaccharides, most of them suffering from being poorly immunogenic and subject to degradation. Hence, they call for efficient delivery systems and potent immunostimulants, jointly denoted as adjuvants. Particulate delivery systems like emulsions, liposomes, nanoparticles and microspheres may provide protection from degradation and facilitate the co-formulation of both the antigen and the immunostimulant. Synthetic double-stranded (ds) RNA, such as polyriboinosinic acid-polyribocytidylic acid, poly(I:C), is a mimic of viral dsRNA and, as such, a promising immunostimulant candidate for vaccines directed against intracellular pathogens. Poly(I:C) signaling is primarily dependent on Toll-like receptor 3 (TLR3), and on melanoma differentiation-associated gene-5 (MDA-5), and strongly drives cell-mediated immunity and a potent type I interferon response. However, stability and toxicity issues so far prevented the clinical application of dsRNAs as they undergo rapid enzymatic degradation and bear the potential to trigger undue immune stimulation as well as autoimmune disorders. This review addresses these concerns and suggests strategies to improve the safety and efficacy of immunostimulatory dsRNA formulations. The focus is on technological means required to lower the necessary dosage of poly(I:C), to target surface-modified microspheres passively or actively to antigen-presenting cells (APCs), to control their interaction with non professional phagocytes and to modulate the resulting cytokine secretion profile. PMID- 23751784 TI - [Cellular therapy: regeneration and reprogramming]. PMID- 23751782 TI - New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations. AB - Mitochondrial HMG-CoA synthase deficiency is a rare inherited metabolic disorder that affects ketone-body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycaemia, dicarboxylic aciduria, and in severe cases, coma. This deficiency may have been under-diagnosed owing to the absence of specific clinical and biochemical markers, limitations in liver biopsy and the lack of an effective method of expression and enzyme assay for verifying the mutations found. To date, eight patients have been reported with nine allelic variants of the HMGCS2 gene. We present a new method of enzyme expression and a modification of the activity assay that allows, for first time, the functional study of missense mutations found in patients with this deficiency. Four of the missense mutations (p.V54M, p.R188H, p.G212R and p.G388R) did not produce proteins that could have been detected in soluble form by western blot; three produced a total loss of activity (p.Y167C, p.M307T and p.R500H) and one, variant p.F174L, gave an enzyme with a catalytic efficiency of 11.5%. This indicates that the deficiency may occur with partial loss of activity of enzyme. In addition, we describe a new patient with this deficiency, in which we detected the missense allelic variant, c.1162G>A (p.G388R) and the nonsense variant c.1270C>T (p.R424X). PMID- 23751783 TI - Large offspring syndrome: a bovine model for the human loss-of-imprinting overgrowth syndrome Beckwith-Wiedemann. AB - Beckwith-Wiedemann syndrome (BWS) is a human loss-of-imprinting syndrome primarily characterized by macrosomia, macroglossia, and abdominal wall defects. BWS has been associated with misregulation of two clusters of imprinted genes. Children conceived with the use of assisted reproductive technologies (ART) appear to have an increased incidence of BWS. As in humans, ART can also induce a similar overgrowth syndrome in ruminants which is referred to as large offspring syndrome (LOS). The main goal of our study is to determine if LOS shows similar loss-of-imprinting at loci known to be misregulated in BWS. To test this, Bos taurus indicus * Bos taurus taurus F1 hybrids were generated by artificial insemination (AI; control) or by ART. Seven of the 27 conceptuses in the ART group were in the > 97th percentile body weight when compared with controls. Further, other characteristics reported in BWS were observed in the ART group, such as large tongue, umbilical hernia, and ear malformations. KCNQ1OT1 (the most often misregulated imprinted gene in BWS) was biallelically-expressed in various organs in two out of seven overgrown conceptuses from the ART group, but shows monoallelic expression in all tissues of the AI conceptuses. Furthermore, biallelic expression of KCNQ1OT1 is associated with loss of methylation at the KvDMR1 on the maternal allele and with downregulation of the maternally-expressed gene CDKN1C. In conclusion, our results show phenotypic and epigenetic similarities between LOS and BWS, and we propose the use of LOS as an animal model to investigate the etiology of BWS. PMID- 23751785 TI - [Insomnia: prevalence in Cordoba city hospital]. AB - INTRODUCTION: Insomnia is a sleep disorder characterized by a deficient or poor quality sleep, with adverse daytime consequences. Prevalence is 30-50% in adults and can be associated with depression or lead to the development of this condition. Despite the high prevalence rates, is a unrecognized, misdiagnosis and undertreated. There is not much publications about its prevalence in patients with chronic diseases. OBJECTIVES: to determine prevalence and clinical characteristics of insomnia in outpatients with chronic diseases. MATERIALS AND METHODS: Prospective observational cross-sectional descriptive study. Insomnia was defined based on ICSD-2criteria. The data collection was performed by a questionnaire. RESULTS: We surveyed 100 patients who attended the consultation of various clinical specialties, mean age 50 years old, 57% were women. Sixty nine per cent of them met criteria for insomnia. The most prevalent diseases were hypertension: 57%, asthma 20%, diabetes: 18% and hypothyroidism: 17%. Among patients with insomnia, 62% were women, 35% had insomnia without another illness, and the remaining 65% had secondary conditions associated with insomnia (60% depression). 25% of patients consulting for insomnia ever. The prevalence of criteria for depression in outpatients with chronic diseases was 52%, amounting to 63% in patients suffering from insomnia. DISCUSSION: The prevalence of insomnia in patients with chronic diseases is high (in outpatients with chronic disease: 69%), higher than the average rate described in the general population. It is an undertreated condition. CONCLUSIONS: The prevalence of insomnia in patients with chronic diseases is high, it is underdiagnosed and undertreated. It is associated with depression in high rate. PMID- 23751786 TI - [Stroke. are there any difference between patients with or without patent foramen ovale in left atrial appendage systolic function?]. AB - INTRODUCTION: The aim of this study was to evaluate the systolic function of the left atrial appendage (LAA) in a group with and without patent foramen ovale (PFO) who suffered ischemic cerebrovascular events. MATERIAL AND METHODS: Between September 2010 and October 2011, 17 patients were referred for transesophageal echocardiography (TEE) after suffering a stroke. PFO was defined as the passage of at least one bubble through atrial septum with bubble test. We compared systolic velocity in the appendage between patients with and without PFO and a control group. RESULTS: Were 8 women and 9 men, mean age 54.1 +/- 19.5 years and 8 patients were under 55 years of age. All patients had suffered a ischemic cerebrovascular events, 41.2% had stroke, 52.9% transient ischemic attack and amaurosis fugax 5.9%. In the assessment of TEE, 11.8% had atrial septal aneurysm and 35.3% PFO. Mean LAA systolic velocity was 66.3 +/- 20.3 cm / sec. There was no difference in systolic velocity of the LAA between patients with and without PFO (67.5 +/- 11.8 cm / sec vs 65.7 +/- 24.3 cm / sec respectively, p = 0.87). The control group of 8 patients, 5 women and 3 men, mean age 39.5 +/- 18 years, had a LAA systolic velocity of 77.6 +/- 28.9 cm / sec, no significant differences with ischemic patients. CONCLUSION: There were no differences in systolic function of the LAA between patients with and without PFO with ischemic cerebrovascular event. PMID- 23751787 TI - [Persistence in drug therapy of hypertension among different treatment groups and comparison between fixed-dose combinations of ara II + calcium channel blockers vs ace inhibitors + calcium channel blockers]. AB - High blood pressure (HBP) is a prevalent and chronic disease, requiring pharmacologic and nonpharmacologic sustainable treatment to achieve control. "Persistence" is the continuity of pharmacological treatments. Knowing the persistence of antihypertensive therapy groups could help prioritize those with better results. The aim is to describe the persistence to antihypertensive therapy in a cohort of patients using different methods and compare the persistence of different pharmacological groups used for hypertension treatment. MATERIALS AND METHODS: Observational, retrospective cohort using secondary databases obtained during drug dispensing and electronic hospital records from the Hospital Italiano de Buenos Aires. Adult population with diagnosed hypertension and monitoring for two years. RESULTS: Diuretics, beta-blockers and first generation of angiotensin converting enzyme are the groups with the largest fall in persistence. Angiotensin antagonists in monotherapy or in combination with beta-blockers and diuretic second generation showed the best results of persistence. Persistence never reached 60% at 2 years. CONCLUSION: Despite having measure persistence through different methods the results were similar and showed low persistence to antihypertensive therapy. We found no pharmacological extra variables that could explain the persistence in different therapeutic groups. PMID- 23751788 TI - [Abpm and duration of the antihypertensive effect: a study with a new formulation of sustained release losartan (CRONOS)]. AB - Antihypertensive drugs action should last at least 24 h in order to enhance adherence, with positive impact on CV morbimortality. ABPM allow us to evaluate duration of action of drugs, against placebo, using Trough:Peak Ratio, antihypertensive effect in the last 4 h interdosis, and calculating the rate of BP morning surge. Losartan is an Antagonist At1 with good antihypertensive efficacy and renal, cardiac and cerebrovascular protection. Some studies shows less than 24 hs of action, that suggest twice a day dosing. The merge of a new formulation, Losartan Cronos, a bilayer tablet containing 50 mg of Losartan immediate release (IR) and 50 mg extended release (ER) would allow 24 h coverage, maintaining the previous advantages. OBJECTIVES: To assess antihypertensive duration of action of Losartan Cronos in patients with essential hypertension throughout a 24-h dosing interval, using ABPM and response rates, AASI and Smoothness Index. METHODS: 97 essential hypertensives, where included and received a single morning dose of Losartan Cronos (50 mg of regular release and 50 mg of controlled and retarded release) during 8 weeks. Performed valid ABPM post placebo and post active treatment. Results Mean age 58 (26-86), 60% women. 63% treatment naive. The mean reduction in BP from baseline to week 8 (end of treatment) was statistically significant for all times analyzed (24 hours, daytime, night-time, and last 4 hours monitoring). There were no significant changes in 24h heart rate. BP morning surge (mmHg/hour) decreased from 4.53 to 3,68 (p=0.03).T:P Ratio was 0.91 for SBP and 1.14 for DBP. Smoothness Index: SBP 2.86 (95% CI 1.84-3.7) - DBP 3.17 (95% CI 2.03-3.9) 19 patients had adverse events, no-one cough, all mild, without discontinuations. Conclusion Losartan Cronos demonstrated efficacy and safety, decreases BP without significant effects in heart rate, it reduces the pulse pressure, and its effect lasts for 24 hs, assessed by T:P ratio, last 4 hours effects, decreasing morning surge, also presenting homogeneous effect, since its Smoothness Index is high. Our results suggests daily monodose administration. PMID- 23751789 TI - [Mycophenolate mofetil in lupus nephritis treatment]. PMID- 23751790 TI - [Undifferentiated high grade pleomorphic sarcoma/ malignant fibrous histiocytoma associated a gouty tophus. a case report]. AB - BACKGROUND: Gout is a metabolic disease by deposition of uric acid crystals, which undertakes joint and soft tissue in both acute and chronic stages. Is a rare event the onset of a tumor in the site of the lesion. OBJECTIVE: To present a rare case of association between sarcoma and tophi. METHODS: 83 year old man who consulted for tumor in his left elbow about 40 years of evolution, which spontaneously started to hurt. With the presumptive diagnosis of tophi treated surgically. The lesion recurred after 60 days, reintervention and radiotherapy was performed for diagnosis of malignant mesenchymal tumor associated with tophi. At 10 months developed ipsilateral nodal metastases, died within 2 years of the initial consultation. RESULTS: The diagnosis of the first material resected was tophi. In the reintervention material was diagnosed mesenchymal spindle cell high grade neoplasm associated with tophi; immunohistochemistry revealed: vimentin + / +, MYO D1 - / - ASMA - / -, FVIII - / -, A1ATT - / -, CD68-/ -, S100-/ - with final diagnosis the undifferentiated high grade pleomorphic sarcoma. CONCLUSIONS: It is uncommon for gouty tophi are associated with other diseases and even fewer do so to tumors. In the literature have reported three previous cases concurrent with neoplasms, which were angiosarcoma, giant cell tumor and malignant fibrous histiocytoma. The latter have a high tendency to recur locally and have ability to distant metastases, especially lung and regional lymph nodes. PMID- 23751791 TI - [The democratization of health. The health policies during the Peronist government in Cordoba (1943-1955)]. AB - The purpose of this paper is to analyze changes produced in the public health system of Cordoba during the peronist government and the performance of the provincial state in the process. We study the increase of health services, public social spending, health agencies and bureaucracies of the state of Cordoba between 1943 and 1955. PMID- 23751792 TI - Is an account of identity necessary for bioethics? What post-genomic biomedicine can teach us. AB - Is a theory of identity necessary for bioethics? In this paper I investigate that question starting from an empirical explication of identity based on post genomics, in particular on epigenetics. After analysing whether the classic problems a theory of identity has to cope with (fictional transplants; conjoined twins; and definition of death) also affect the proposed epigenetic account of identity, I deal with three topics (the assumption of moral responsibility; decision maintenance in the case of advance directives; and the attribution of value to human beings at given developmental stages) to offer an insight on the relationship between that account and bioethics. PMID- 23751793 TI - Lemna minor exposed to fluoranthene: growth, biochemical, physiological and histochemical changes. AB - Polycyclic aromatic hydrocarbons (PAHs) represent one of the major groups of organic contaminants in the aquatic environment. Duckweed (Lemna minor L.) is a common aquatic plant widely used in phytotoxicity tests for xenobiotic substances. The goal of this study was to assess the growth and the physiological, biochemical and histochemical changes in duckweed exposed for 4 and 10 days to fluoranthene (FLT, 0.1 and 1 mgL(-1)). Nonsignificant changes in number of plants, biomass production, leaf area size, content of chlorophylls a and b and carotenoids and parameters of chlorophyll fluorescence recorded after 4 and 10 days of exposure to FLT were in contrast with considerable changes at biochemical and histochemical levels. Higher occurrence of reactive oxygen species (ROS) caused by an exposure to FLT after 10 days as compared to control (hydrogen peroxide elevated by 13% in the 0.1 mgL(-1) and by 41% in the 1 mgL(-1) FLT; superoxide anion radical by 52% and 115% respectively) reflected in an increase in the activities of antioxidant enzymes (superoxide dismutase by 3% in both treatments, catalase by 9% and 1% respectively, ascorbate peroxidase by 21% and 5% respectively, guaiacol peroxidase by 12% in the 0.1 mgL(-1) FLT). Even the content of antioxidant compounds like ascorbate (by 20% in the 1 mgL(-1) FLT) or total thiols (reduced forms by 15% in the 0.1 mgL(-1) and 8% in the 1 mgL(-1) FLT, oxidized forms by 36% in the 0.1 mgL(-1) FLT) increased. Increased amount of ROS was followed by an increase in malondialdehyde content (by 33% in the 0.1 mgL(-1) and 79% in the 1 mgL(-1) FLT). Whereas in plants treated by the 0.1 mgL( 1) FLT the contents of total proteins and phenols increased by 15% and 25%, respectively, the 1 mgL(-1) FLT caused decrease of their contents by 32% and 7%. Microscopic observations of duckweed roots also confirmed the presence of ROS and related histochemical changes at the cellular and tissue levels. The assessment of phytotoxicity of organic pollutant in duckweed based only on the evaluation of growth parameters could not fully cover the irreversible changes already running at the level of biochemical processes. PMID- 23751794 TI - Effects of the glyphosate-based herbicide Roundup WeatherMax(r) on metamorphosis of wood frogs (Lithobates sylvaticus) in natural wetlands. AB - Amphibian tadpoles develop in aquatic environments where they are susceptible to the effects of pesticides and other environmental contaminants. Glyphosate-based herbicides are currently the most commonly used herbicide in the world and have been shown to affect survival and development of tadpoles under laboratory and mesocosm conditions. In the present study, whole wetland manipulations were used to determine if exposure to an agriculturally relevant application of Roundup WeatherMax((r)), a herbicide formulation containing the potassium salt of glyphosate and an undisclosed surfactant, influences the development of wood frog tadpoles (Lithobates sylvaticus) under natural conditions. Wetlands were divided in half with an impermeable curtain so that each wetland contained a treatment and control side. Tadpoles were exposed to two pulses of this herbicide at an environmentally realistic concentration (ERC, 0.21 mg acid equivalent (a.e.)/L) and the predicted maximum environmental concentration (PMEC, 2.89 mg a.e./L), after which abundance, growth, development, and mRNA levels of genes involved in tadpole metamorphosis were measured. Results present little evidence that exposure to this herbicide affects abundance, growth and development of wood frog tadpoles. As part of the Long-term Experimental Wetlands Area (LEWA) project, this research demonstrates that typical agricultural use of Roundup WeatherMax((r)) poses minimal risk to larval amphibian development. However, our gene expression data (mRNA levels) suggests that glyphosate-based herbicides have the potential to alter hormonal pathways during tadpole development. PMID- 23751795 TI - Characterization and expression analysis of three CBF/DREB1 transcriptional factor genes from mangrove Avicennia marina. AB - Three CBF/DREB1 (C-repeat binding factor/dehydration responsive element-binding factor 1) homologues were isolated from mangrove Avicennia marina and designated AmCBF1, 2 and 3. Multiple sequence analysis showed that the three deduced proteins all contain an AP2 DNA-binding domain and two CBF signature sequences. According to the phylogenetic analysis, these proteins belong to the A-1 subgroup of the DREB subfamily. Expression analyses based on quantitative real-time PCR revealed that the AmCBF2 displayed relatively high expression under normal conditions, with the highest level in stems, while both AmCBF1 and 3 were weakly expressed without stress. The three genes also showed different responses to various environmental stimuli. The AmCBF2 was inducible by cold, drought, high salinity, heavy metals, as well as abscisic acid (ABA), and exhibited much stronger induction by cold, drought, Pb(2+) or Zn(2+) than by NaCl, ABA or Cd(2+). In contrast, both AmCBF1 and AmCBF3 displayed insignificant changes under these stimuli. These results indicate that the three AmCBF genes play different roles in A. marina and the AmCBF2 might be involved in the signaling pathway of cold, drought and heavy metal stress response. PMID- 23751796 TI - Cooperation and competition in the dynamics of tissue architecture during homeostasis and tumorigenesis. AB - The construction of a network of cell-to-cell contacts makes it possible to characterize the patterns and spatial organization of tissues. Such networks are highly dynamic, depending on the changes of the tissue architecture caused by cell division, death and migration. Local competitive and cooperative cell-to cell interactions influence the choices cells make. We review the literature on quantitative data of epithelial tissue topology and present a dynamical network model that can be used to explore the evolutionary dynamics of a two dimensional tissue architecture with arbitrary cell-to-cell interactions. In particular, we show that various forms of experimentally observed types of interactions can be modelled using game theory. We discuss a model of cooperative and non-cooperative cell-to-cell communication that can capture the interplay between cellular competition and tissue dynamics. We conclude with an outlook on the possible uses of this approach in modelling tumorigenesis and tissue homeostasis. PMID- 23751797 TI - Reentrant superconductivity in Eu(Fe(1-x)Ir(x))2As2. AB - The interplay between superconductivity and Eu(2+) magnetic ordering in Eu(Fe1 xIrx)2As2 is studied by means of electrical transport and magnetic measurements. For the near optimally doped sample Eu(Fe0.86Ir0.14)2As2, we witnessed two distinct transitions: a superconducting transition below 22.6 K which is followed by a resistivity reentrance caused by the ordering of the Eu(2+) moments. Further, the low field magnetization measurements show a prominent diamagnetic signal due to superconductivity, which is remarkable in the presence of a large moment magnetically ordered system. The electronic structure for 12.5% Ir doped EuFe1.75Ir0.25As2 is investigated along with the parent compound EuFe2As2. As compared to EuFe2As2, the doped compound has an effectively lower value of density of states throughout the energy scale with a more extended bandwidth and stronger hybridization involving Ir. Shifting of the Fermi energy and a change in band filling in EuFe1.75Ir0.25As2 with respect to the pure compound indicate electron doping in the system. PMID- 23751799 TI - Journal of Clinical Gastroenterology. Introduction. PMID- 23751800 TI - An update on clinical trials in the treatment of advanced hepatocellular carcinoma. AB - Despite the successful FDA approval of sorafenib as the standard of care therapy in patients with advanced hepatocellular carcinoma (HCC), its clinical benefits have been modest. The mortality rate remains high and prognosis poor for patients with advanced-stage HCC. The exact mechanism of sorafenib in the treatment of HCC and its resistance at the molecular levels are largely unknown. There are no other treatment options in first-line therapy and there is currently no standard of care second-line therapies available. Thus, there is a critical need for novel therapeutic approaches for the treatment of advanced HCC, and thus a clear justification for the already reported, currently ongoing, and planned clinical trials. PMID- 23751801 TI - Surgical therapy for hepatocellular carcinoma: formulating a rational approach. AB - Hepatocellular carcinoma is one of the most common malignancies worldwide, and its incidence continues to rise in the United States. Partial hepatectomy and liver transplantation remains the mainstay of treatment for localized disease and provides significant improvement in long-term survival, as well as the potential for cure. The indications and criteria for resection and transplantation are well established, but continue to undergo significant modification over time. Surgical resection is the primary therapeutic modality in patients with well-compensated liver disease, and transplantation is highly effective in early-stage tumors in patients with severe underlying liver disease. The relative role for each of these modalities must be tailored to individual patients based on a rational approach designed to balance quality of life, organ allocation, and patient survival. PMID- 23751802 TI - Hepatocellular carcinoma: perspective of an oncologist. AB - The medical oncologist's perspective on hepatocellular carcinoma (HCC) is unique compared with their view on other solid tumors. A patient's underlying liver function should be factored into the selection of treatment options; therefore, a staging system that takes into account other clinical parameters other than only tumor characteristics is important. Sorafenib is currently the only FDA-approved chemotherapy drug for patients with HCC based on the data from the SHARP trial. It is important for oncologists to anticipate and treat the side effects of sorafenib treatment in order to help the patients continue the treatment. In addition, it is important to design clinical trials for HCC that have meaningful endpoints to improve our care for patients with HCC. PMID- 23751803 TI - Surgical management of esophageal diverticulum: a review of the Nationwide Inpatient Sample database. AB - BACKGROUND: Esophageal diverticulum is rare in the United States. The mainstay treatment of symptomatic esophageal diverticulum is surgical correction. Much of the available information regarding esophageal diverticulum and its surgical management has been derived from small studies and institutional reviews. Our study objective was to investigate the demographics, perioperative conditions, and predictors of outcomes after surgical treatment of acquired esophageal diverticulum using a nationally representative database. METHODS: A retrospective review using the Nationwide Inpatient Sample database from 2000-2009 was performed for patients with acquired esophageal diverticulum. The patients were stratified into Zenker's diverticulum (ZD) or non-Zenker's diverticulum (NZD) subgroups. The covariates retrieved included age, gender, ethnicity, insurance type, and Charlson comorbidity index. A multivariate analysis was performed to determine the predictors of postoperative morbidity. Discharge-level weights were applied. RESULTS: Overall, a total of 4253 patients met our inclusion criteria, 3197 (75%) with ZD and 1056 (25%) with NZD. In the ZD group, the mean age was 73 +/- 12.3 y, and most were men (55%) and white (67%). The mean length of stay was 5.82 +/- 8.08 d, and the mortality rate was 1.2%. The most common complication was septicemia or sepsis (2.0%). The black patients had higher odds of postoperative morbidity than the white patients (odds ratio [OR] 2.29, 95% confidence interval [CI] 1.02-5.17). The risk of overall postoperative morbidity was 52% greater for women (OR 1.52, 95% CI 1.01-2.29). An increasing Charlson comorbidity index was an independent predictor of morbidity. In the NZD group, the mean age was 69 +/- 13.9 y, and most were also men (51%) and white (63%). The mean length of stay was 8.13 +/- 10.56 d, and the mortality rate was 1.6%. The most common complication was air leak (3.1%). The black and Hispanic patients had higher odds of postoperative morbidity than the white patients (OR 1.97, 95% CI 1.05-3.72 and OR 2.37, 95% CI 1.06-5.30, respectively). An increasing Charlson comorbidity index was an independent predictor of morbidity. Compared with laparoscopy, the risk of developing postoperative morbidity was higher with the thoracotomy procedure (OR 7.45, 95% CI 1.11-50.18). CONCLUSIONS: Using a nationally representative database, our study found that female gender, black race, and the presence of comorbidities were associated with increased postoperative morbidity among patients with ZD. Among the patients with NZD, black and Hispanic patients had worse postoperative morbidity than the white patients, and the presence of comorbidities was associated with increased postoperative morbidity. Thoracotomy for the correction of NZD was associated with increased postoperative morbidity compared with the laparoscopic approach. PMID- 23751804 TI - Therapeutic option for managing lung injury induced by infrarenal aortic cross clamping. AB - BACKGROUND: Operations on the infrarenal aorta can cause ischemic-reperfusion (IR) injury in local tissues, which could result in remote organ (e.g., lung) damage. Treatment of such injuries remains an unresolved problem. OBJECTIVES: Our aim was to reduce remote lung damage after lower limb IR by means of postconditioning. MATERIALS AND METHODS: Male Wistar rats were divided into three groups: Sham-operated, IR, and Postconditioned (PostC). In the latter two groups rats underwent 180 min of exclusion of the infrarenal aorta. The reperfusion time was 4 h. Serum-free radical levels, tumor necrosis factor-alpha and interleukin-6 concentrations, histologic changes in the lung, wet/dry-ratio, myeloperoxidase activity, heat shock protein 72 level and blood gas changes were investigated. RESULTS: Postconditioning reduced histological damage in the lung (P < 0.05). Free radical levels and tumor necrosis factor-alpha concentrations were significantly lower in the PostC group than in the IR group (P < 0.05 and P < 0.01, respectively). Interleukin-6 concentrations did not significantly differ in the PostC group. Compared with the IR group, lung myeloperoxidase activity was lower in the PostC group. Decreased pulmonary heat shock protein 72 level was observed in the PostC group compared with the IR group and the wet/dry-ratio was also significantly lower in the PostC group (P < 0.05). A noticeably higher arterial pO2 level was manifest in the PostC group after 2 and 4 h of reperfusion (P < 0.05). CONCLUSIONS: Postconditioning reduced lung damage under experimental conditions, in the early period of reperfusion after lower limb IR injury. PMID- 23751805 TI - Career track of Society of University Surgeons Resident Research Award recipients. AB - BACKGROUND: The Society of University Surgeons (SUS) has an ongoing competitive funding program to support research training for residents. We sought to determine the career track of award recipients. METHODS: We included in the study SUS resident awardees who completed awards from 1989-2007. Characteristics of awardees and their academic productivity were extracted from curriculum vitae provided by awardees (n = 24), or from online sources (n = 7). RESULTS: Awardees spent an average of 2.7 y (range, 1-4 y) of dedicated research time during residency. Awardees averaged 9.8 publications (range, 1-32), with 5.4 as first author (range, 1-17), with their mentor within 3 y of award completion, with an average maximum impact factor of 5.7. A total of 25 residents (81%) pursued fellowships. At an average follow-up of 11.4 y (range, 4-22 y) from the end of the award and 7.2 y (range, 0-18 y) from end of clinical training, awardees had a Hirsch index of 14.5 (range, 2-48). At the time of the study, 26 awardees (84%) were in academic surgery. Of the 23 awardees who had completed surgical training >= 3 y earlier, 11 (48%) received independent research funding, seven of whom (30%) received R01 or equivalent funding. CONCLUSIONS: The SUS resident research awardees had a productive research experience. Although our retrospective study cannot determine causation, the SUS award mechanism delivers on its promise of supporting junior surgeon-scientists who pursue academic careers and establish independent research programs. Further studies are needed to determine how rates of subsequent independent research funding can be improved. PMID- 23751806 TI - Cytogenetic analysis in the diagnosis and management of lipoblastomas: results from a single institution. AB - BACKGROUND: Lipoblastomas are rare, benign, soft tissue tumors that occur primarily in young children. Treatment includes complete excision and surveillance for recurrence. Lipoblastomas can be indistinguishable from other benign lipomatous tumors and liposarcomas. Cytogenetic analysis can provide the definitive diagnosis in questionable cases, because benign and malignant lipomatous tumors exhibit specific nonrandom cytogenetic abnormalities. The purpose of the present study was to discuss the disease management and outcomes in a large contemporary group of patients with lipoblastoma. MATERIALS AND METHODS: A retrospective chart review of patients diagnosed with lipoblastoma presenting from 2000-2011 was conducted. The data from these patients were compared with data from a previously published historical group of patients (1985 1999) from the same children's hospital. RESULTS: We identified 37 patients in the contemporary cohort group and compared them with 25 patients from the historical group. The tumor involvement sites were similar. The current cohort group had a lower recurrence rate, although this might have been underestimated owing to a shorter follow-up period (median 1.4 y, range 2 wk to 11.0 y). Preoperative imaging findings led to an incorrect diagnosis in 62% of the patients. Cytogenetic analysis was used to help determine the final diagnosis in 50% of the cases. In 39% of cases, translocations involved the long arm of chromosome 8, the most common anomaly in lipoblastoma. CONCLUSIONS: Lipoblastomas are rare tumors in young children that can be misclassified as other malignant or benign lipomatous tumors with markedly different outcomes and treatments. We recommend that cytogenetic analysis be routinely used for all pediatric lipomatous tumors to provide an accurate diagnosis and guide appropriate therapy and follow-up. PMID- 23751807 TI - Inhibitors of bacterial transcription initiation complex formation. AB - Antibiotic resistance is a growing global problem, with very few new compounds in development. Bacterial transcription is an underutilized target for antibiotics, which has been attributed to the similarity of the active site of RNA polymerases (RNAPs) across all domains of life and the ease with which resistance can arise through point mutation at multiple sites within this conserved region. In this study we have taken a rational approach to design a novel set of compounds that specifically target the formation of transcription initiation complexes by preventing the unique bacterial sigma initiation factor from binding to RNAP. We have identified the region of RNAP to which these compounds bind and demonstrate that one compound, GKL003, has an inhibition constant in the low nanomolar range. This compound has activity against both Gram-positive and -negative organisms, including a community acquired methicillin-resistant strain of the major pathogen Staphylococcus aureus. PMID- 23751808 TI - Species of phosphorus in the extracellular polymeric substances of EBPR sludge. AB - In this study, the species of extracellular phosphorus and their transformation during extracellular polymeric substances (EPS) extraction were explored by using (31)P nuclear magnetic resonance spectroscopy. Results show that the extraction methods had a substantial influence on the phosphorus species in the extracted EPS. Cation exchange resin method was more appropriate for extracting EPS from the enhanced biological phosphorus removal (EBPR) sludge. Orthophosphate, pyrophosphate and polyphosphate were the main species of phosphorus found to be present in the EPS, which together accounted for about 6.6-10.5% of the total phosphorus in the EBPR sludge. The high percentage of extracellular phosphorus and their diverse species might reveal a new insight into the characteristics of the phosphorus in EPS in EBPR system. PMID- 23751809 TI - Simultaneous nitrogen and organic carbon removal in aerobic granular sludge reactors operated with high dissolved oxygen concentration. AB - Simultaneous nitrification and denitrification (SND) together with organic removal in granules is usually carried out without Dissolved Oxygen (DO) concentration control, at "low DO" (with a DO<30-50% of the saturation value, about 3-4 mg/L) to promote anoxic conditions within the aggregates. These conditions can sometimes be in detrimental of the stability of the granules itself due to a lack of shear force. In this work, the authors achieved SND without oxygen control with big sized granules. More specifically, the paper presents a experimentation focused on the analysis of two Sequencing Batch Reactors (SBRs), in bench scale, working with different aerobic sludge granules, in terms of granule size, and high DO concentration, (with concentration varying from anoxic conditions, about DO ~0 mg/L, to values close to those of saturation, >7-8 mg/L, during feast and famine conditions respectively). In particular, different strategies of cultivation and several organic and nitrogen loading rate have been applied, in order to evaluate the efficiencies in SND process without dissolved oxygen control. The results show that, even under conditions of high DO concentration, nitrogen and organic matter can be simultaneously removed, with efficiency >90%. Nevertheless, the biological conditions in the inner layer of the granule may change significantly between small and big granules, during the feast and famine periods. From point of view of granule stability, it is also interesting that with a particle size greater than 1.5mm, after the cultivation start-up, the granules are presented stable for a long period (about 100 days) and, despite the variations of operational conditions, the granules breaking was always negligible. PMID- 23751810 TI - Improving docosahexaenoic acid productivity of Schizochytrium sp. by a two-stage AEMR/shake mixed culture mode. AB - In this work, an aeration-enhanced membrane reactor (AEMR) was built to control dissolved oxygen in Schizochytrium sp. broth. The effect of culture modes, i.e. single shake and AEMR mode, on the docosahexaenoic acid (DHA) productivity of Schizochytrium sp. was investigated. Experimental results showed that the biomass production in the AEMR mode was higher than that in the single shake mode, while the final DHA productivity in single shake mode was higher than that in the AEMR mode. A two-stage mixed culture mode was proposed, in which Schizochytrium sp. was cultured in AEMR mode at a flow rate of 0.2 L min(-1) for 60 h to first increase biomass production, and then shifted to shake mode to improve DHA productivity. Compared to the single shake mode, the DHA productivity in mixed mode costed 40% less culture time and the DHA productivity at 96 h exhibited a relative increase of 60%. PMID- 23751811 TI - The influence of age and season on fecal dehydroepiandrosterone-sulfate (DHEAS) concentrations in Japanese macaques (Macaca fuscata). AB - Dehydroepiandrosterone (DHEA) and its sulfate, DHEAS, are the most abundant steroid hormones in primates, providing a large reservoir of precursors for the production of androgens. DHEAS levels decline with age in adult humans and nonhuman primates, prompting its consideration as a biomarker of senescence. However, the mechanisms responsible for this age-related decrease and its relationship to reproduction remain elusive. This research investigated DHEAS concentrations in fecal samples in order to determine age-related changes in captive Japanese macaques, as well as to assess the possible influence of seasonality. The subjects were 25 female Japanese macaques (2weeks to 14years old) housed outdoors in social groups at the Primate Research Institute. We collected three fecal samples from each animal during the breeding season (October to December) and three additional samples from adult females during the non-breeding season (May to June). The hormonal concentrations were determined using enzyme immunoassay. DHEAS concentration was negatively correlated with age, but we did not find a significant difference between breeding and non-breeding seasons. Neonatal macaques had the highest DHEAS concentrations of all age groups. We suggest that elevated neonatal DHEAS is possibly a residue from fetal adrenal secretion and that, as in humans, it might assist in neurobiological development. PMID- 23751812 TI - The expression pattern of the glucose transporter GLUT-5 in the testis during the spermatogenic cycle of the vespertilionid bat Scotophilus heathi. AB - The aims of this study were to investigate the localization and rate of expression of GLUT-5 protein during the spermatogenic cycle of Scotophilus heathi and to determine whether the expression of testicular GLUT-5 was under androgenic control. This study showed localization of GLUT-5 mainly in the spermatogonia, spermatids, spermatozoa and Leydig cells of the testis in S. heathi. Western blot analysis showed marked variation in the rate of expression of GLUT-5 protein in the testis during the reproductive cycle, in which peak expression of GLUT-5 in the testis coincided with the period of peak spermatogenesis and mating. Treatment with flutamide (an anti-androgen) caused a dose-dependent decrease in the expression of GLUT-5 protein in the testis that suggested that the expression of GLUT-5 was under androgenic control. We propose that GLUT-5 plays an important role in the transport into spermatozoa of the fuel that is required for prolonged storage in the female genital tract in S. heathi. PMID- 23751813 TI - The Italian Register of Biological Prostheses. AB - BACKGROUND: A wide variety of meshes are available for surgical treatment of abdominal wall defects. These meshes are constructed with different materials with different biological properties. METHODS: A prospective database was instituted (January 2009-December 2010) to register biological prostheses (BPs) implanted in Italy. RESULTS: A total of 193 cases were registered. The mean age of the patients was 53.1 years (SD +/-7.4). The ratio of males to females was 1.3 to 1. The mean body mass index was 28.2 (SD +/-4.1). The breakdown of American Society of Anesthesiologists (ASA) scores was as follows: ASA I, 35.7%; ASA II, 27.5%; ASA III, 31.6%, and ASA IV, 5.2%. For ventral-incisional hernias, the mean duration of surgery was 101.1 min (SD +/-25.3), while for inguinal-femoral hernias it was 49.2 min (SD +/-19.1). The rate of urgent procedures was 36.7%. The surgical field was clean in 57.4% of cases, clean-contaminated in 21.3%, contaminated in 12.3% and dirty in 9%. Techniques used for inguinal-femoral hernias were as follows: Lichtenstein in 66.7%, plug and mesh in 3.8%, transabdominal-preperitoneal in 25.7% and intraperitoneal onlay mesh in 3.8%. The following prostheses were used: swine intestinal submucosa in 54.9%, porcine dermal collagen in 39.9% and bovine pericardium in 5.2%. In 45.1% of cases the prostheses were cross-linked. Techniques used for ventral-incisional hernias were as follows: onlay in 3.6%, inlay in 5.5%, sublay in 62.7% and underlay via laparoscopy in 28.2%. The mean overlap was 4.1 cm (SD +/-1.2). No intestinal anastomosis was necessary in 65.3% of cases; however, small/large bowel resection and anastomoses were necessary in 22.3 and 12.4% of cases, respectively. Intraoperative blood transfusion was necessary in 10.4% of procedures. The skin was completely closed in 84% of procedures. At the 1-month follow-up, there were no complications in 54.4% of cases. Among the cases with complications, 10 patients (5.8%) experienced recurrence, and the postoperative readmission rate was 12.9%. The average visual analog scale (VAS) score for pain was 2.9 (SD +/ 1.2) at rest. At the 1-year follow-up, there were no complications in 96.4% of cases. Two patients experienced recurrence, and the postoperative readmission rate was 3.6%. The average VAS score for pain was 1.8 (SD +/-0.8) at rest. CONCLUSIONS: This register shows that BPs are highly versatile and can be used in either open or laparoscopic surgery in all kinds of patients and in contaminated surgical fields. However, due to the very good outcomes of synthetic meshes and the high costs of BPs, the latter should only be used in selected cases. PMID- 23751814 TI - Effect of Recovery Interventions on Cycling Performance and Pacing Strategy in the Heat. AB - PURPOSE: To determine the effect of active recovery (AR), passive rest (PR) and cold water immersion (CWI) after 90 min intensive cycling on a subsequent 12 min time-trial (TT2) and the applied pacing strategy in TT2. METHODS: After a max test and familiarization trial, 9 trained male subjects (age: 22 +/- 3 years; VO2max: 62.1 +/- 5.3 ml.min-1.kg-1) performed 3 experimental trials in the heat (30 degrees C). Each trial consisted of two exercise tasks separated by 1h. The first was a 60min constant load trial at 55% of the maximal power output (Wmax) followed by a 30 min time trial (TT1). The second comprised a 12 min simulated time trial (TT2). After TT1 AR, PR or CWI was applied for 15min. RESULTS: No significant TT2 performance differences were observed, but a one sample t test (within each condition) revealed different pacing strategies during TT2. CWI resulted in an even pacing strategy, while AR and PR resulted in a gradual decline of power output after the onset of TT2 (p<=0.046). During recovery AR and CWI showed a trend towards faster blood lactate ([BLa]) removal, but during TT2 significantly higher [BLa] were only observed after CWI compared to PR (p=0.011). CONCLUSION: The pacing strategy during subsequent cycling performance in the heat is influenced by the application of different post-exercise recovery interventions. Although power was not significantly altered between groups, CWI enabled a different shaped power profile, likely due to decreased thermal strain. PMID- 23751815 TI - Pulmonary sequestration-differences in diagnosis and treatment in a single institution. AB - BACKGROUND: Pulmonary sequestration (PS) is a rare congenital lung malformation. In this study, we evaluated the diagnosis and treatment of PS in 31 adult patients at a single institution. METHODS: A retrospective review of all patients 16 years of age and older with PS in a single institution between January 1985 and January 2011 was conducted. The following data were analyzed for all patients: major symptoms, diagnostic procedures, operative findings, operative techniques, postoperative complications, and outcome. RESULTS: Our study involved 31 patients, 17 male and 14 female, with an average age of 32.1 (17-57) years, who underwent surgical intervention for PS. The preoperative symptoms of these patients included cough, hemoptysis, fever, pneumonia, and chest pain. Thirty (96.8%) patients were diagnosed by thoracic computed tomography. Of the 31 patients, 29 were diagnosed with intralobar pulmonary sequestration and two had extralobar pulmonary sequestration. Surgical procedures for intralobar pulmonary sequestration included lobectomy in 22 patients (including one thoracoscopic lobectomy), segmentectomy in six, and wedge resection in one of the patients. Thoracoscopic simple mass excision was performed on the two patients with extralobar pulmonary sequestration. Two patients had a postoperative complication (prolonged air leak in 1 patient and postoperative hemothorax in the other). The average hospital stay for all study patients was 6.4 (4-18) days, and there was no mortality. CONCLUSION: Diagnostic tools may enable the clinician to obtain a definitive diagnosis in patients where there is a strong suspicion of PS via a noninvasive procedure. Computed tomography angiography may be the diagnostic imaging method of choice for optimal evaluation of the sequestrated lung and its vascular supply. PMID- 23751816 TI - The relationship between repeat-dose toxicity and aromatic-ring class profile of high-boiling petroleum substances. AB - A study was undertaken within the context of the U.S. EPA HPV Chemical Challenge Program to (1) characterize relationships between PAC content and repeat-dose toxicities of high-boiling petroleum substances (HBPS) and (2) develop statistical models that could be used to predict the repeat-dose toxicity of similar untested substances. The study evaluated 47 repeat-dose dermal toxicity and 157 chemical compositional studies. The four most sensitive endpoints of repeat-dose toxicity were platelet count, hemoglobin concentration, relative liver weight and thymus weight. Predictive models were developed for the dose response relationships between the wt.% concentration of each of seven ring classes of aromatic compounds (the "ARC profile") and specific effects, with high correlations (r=0.91-0.94) between the observed and model-predicted data. The development of the mathematical models used to generate the results reported in this study is described by Nicolich et al. (2013). Model-generated dose-response curves permit the prediction of either the effect at a given dose or the dose that causes a given effect. The models generate values that are consistent with other standard measures. The models, using compositional data, can be used for predicting the repeat-dose toxicity of untested HBPS. PMID- 23751817 TI - Proteomic analysis of differences in barley (Hordeum vulgare) malts with distinct filterability by DIGE. AB - Filterability is an essential quality parameter of barley malt and significantly impacts productive efficiency and quality of beer. In the study, differences of metabolic capability, rather than of initial contents of macromolecules in barleys, were found to be the main reason for malt filterability gap between the widely used cultivars Dan'er and Metcalfe in China. Comparative proteomics based on fluorescent difference gel electrophoresis (DIGE) was employed to quantitatively analyze proteins of four commercial malts belonging to the two cultivars, and 51 cultivar-differential spots were identified to 40 metabolic proteins by MALDI-TOF/TOF mass spectrometry, mainly including hydrolases and pathogen-related proteins. According to their function analysis and abundance comparison between cultivars, filterability-beneficial and -adverse proteins were putatively proposed. Two most remarkable differential proteins, beta-amylase and serpin Z7, were further investigated to verify their effects on Dan'er malt filterability. These results provide biological markers for barley breeders and maltsters to improve malt filterability. BIOLOGICAL SIGNIFICANCE: To the best of our knowledge, this is the first report of comprehensive investigation of metabolic proteins related to wort filterability of barley malts, and sheds light on clues for filterability improvement. Visible differences in the expression level of metabolic proteins between Dan'er and Metcalfe malts using 2D-DIGE signify a valuable tool for cultivar comparison, illustration of key proteins responsible for filterability and even other qualities of barley malts. And with these explorations on biomarkers of malt filterability and other aspects, there will be higher efficiency and quality of beer brewing, less application of exogenous hydrolases and more expending market for Chinese malting barleys. This article is part of a Special Issue entitled: Translational Plant Proteomics. PMID- 23751818 TI - Exploration of magnetic fluctuations in PdFe films. AB - We investigated magnetic phase transitions, magnetic anisotropy, and magnetic domains in Pd1-xFex alloys with different Fe concentrations x = 2.2-7.2%. The Curie temperature depends linearly on the Fe concentration in the regime studied. The magnetization is dominantly in-plane with a small out-of-plane remanent contribution. Resonant magnetic small angle scattering with circularly polarized x-rays tuned to the L3 resonance edge of Fe revealed a small angle scattering ring corresponding to magnetic domain fluctuations on a length scale of 100 nm. These fluctuations are isotropically distributed in the film plane and appear to have an out-of-plane component. On increasing the transverse coherence of the incident beam, the scattering ring decomposes in a speckle pattern, indicative of magnetic correlations on a length scale smaller than the x-ray coherence length of about 4 MUm. PMID- 23751819 TI - Repeated exposure to intra-amniotic LPS partially protects against adverse effects of intravenous LPS in preterm lambs. AB - Histologic chorioamnionitis, frequently associated with preterm births and adverse outcomes, results in prolonged exposure of preterm fetuses to infectious agents and pro-inflammatory mediators, such as LPS. Endotoxin tolerance-type effects were demonstrated in fetal sheep following repetitive systemic or intra amniotic (i.a.) exposures to LPS, suggesting that i.a. LPS exposure would cause endotoxin tolerance to a postnatal systemic dose of LPS in preterm sheep. In this study, randomized pregnant ewes received either two i.a. injections of LPS or saline prior to preterm delivery. Following operative delivery, the lambs were treated with surfactant, ventilated, and randomized to receive either i.v. LPS or saline at 30 min of age. Physiologic variables and indicators of systemic and lung inflammation were measured. Intravenous LPS decreased blood neutrophils and platelets values following i.a. saline compared to that after i.a. LPS. Intra amniotic LPS prevented blood pressure from decreasing following the i.v. LPS, but also caused an increased oxygen index. Intra-amniotic LPS did not cause endotoxin tolerance as assessed by cytokine expression in the liver, lung or plasma, but increased myeloperoxidase-positive cells in the lung. The different compartments of exposure to LPS (i.a. vs i.v.) are unique to the fetal to newborn transition. Intra-amniotic LPS incompletely tolerized fetal lambs to postnatal i.v. LPS. PMID- 23751820 TI - Autophagy facilitates cytokine-induced ICAM-1 expression. AB - ICAM-1 can be induced by inflammatory cytokines such as IFN-gamma and TNF-alpha. This study investigated whether autophagy regulates ICAM-1 given that autophagy facilitates signaling of these two cytokines. Exogenous IFN-gamma induced ICAM-1 in human lung epithelial A549 cells carrying wild type p53, a transcription factor reported for ICAM-1, but not in PC14PE6/AS2 (AS2) cells carrying mutated p53. However, IFN-gamma also induced ICAM-1 in A549 cells with short hairpin RNA silenced p53. No changes in IFN-gamma receptor expression were observed in AS2 cells, but IFN-gamma-activated Jak2/STAT1/IFN regulatory factor 1 was markedly decreased. In AS2 cells, increased levels of reactive oxygen species induced the activation of Src homology domain-containing phosphatase 2 (SHP2), while SHP2 was essential for IFN-gamma resistance. AS2 cells showed autophagy resistance, and the manipulation of the autophagy pathway altered IFN-gamma resistance. Aberrant Bcl-2 expression and mammalian target of rapamycin activation contributed to both autophagy resistance and IFN-gamma resistance. Autophagy, but not p53, also modulated TNF-alpha-induced NF-kappaB activation and ICAM-1 expression. Inhibiting autophagy decreased the adhesion of human monocytic U937 cells to IFN gamma-treated A549 cells. These results demonstrated that IFN-gamma and TNF-alpha induced ICAM-1 expression through a common pathway that was regulated by autophagy, but not p53. PMID- 23751821 TI - Neuronally-expressed Sarm1 regulates expression of inflammatory and antiviral cytokines in brains. AB - Sarm1 is the fifth Toll/IL-1 receptor (TIR) domain-containing adaptor protein identified to regulate TLR downstream signaling. Unlike the other TIR domain containing adaptor proteins, Sarm1 is predominantly expressed in the brain. Our previous study indicated that Sarm1 regulates dendritic growth, axonal extension and neuronal polarity. Here, we investigated whether Sarm1 is involved in innate immunity in the brain. First, regional and cell-type distribution of Sarm1 in mouse brains was revealed using double immunostaining. Sarm1 was widely distributed in different regions of brains, including the cerebral cortex, hippocampus, amygdala, cerebellum and midbrain. Moreover, Sarm1 is present in both projection and inhibitory neurons, but, interestingly, not in microglial cells--the main immune cells in the brain. These results suggest that Sarm1 is unlikely to regulate microglial activity in a cell-autonomous manner. However, compared with wild type littermates, the RNA expression levels of several inflammatory and antiviral cytokines were altered in the embryonic and adult brains of Sarm1 knockdown transgenic mice. These data imply that Sarm1 influences cytokine expression in neurons. In conclusion, our findings suggest that Sarm1 regulates the innate immune responses of the central nervous system through regulating the inflammatory and anti-virus cytokines produced by neurons. PMID- 23751823 TI - A low recurrence rate is possible with a combination of surgery and radiosynovectomy for diffuse pigmented villonodular synovitis of the knee. AB - BACKGROUND: Diffuse pigmented villonodular synovitis (DPVNS) is an uncommon proliferative disease. After only surgery, recurrence rates are high. This study presents the efficacy of combined surgical and adjuvant radiosynovectomy (RS) in the treatment of DPVNS. MATERIALS AND METHODS: Between September 2006 and September 2012, 15 knee joints of 15 patients (10 female and 5 male) with histopathological DPVNS diagnosis with mean age 27 +/- 12 years underwent surgery. At mean 14.4 +/- 18 weeks postoperatively, RS was applied using 5 mCi (90)Y citrate colloid. Three-phase bone scintigraphy and contrast-enhanced MRI were used to evaluate residual and recurrent tumorous tissues in the joint. RESULTS: Mean follow-up was 48 +/- 22 months. Blood flow and blood pool images showed that 2 patients had marked, 4 had moderate, 6 had mild, and 3 had no uptake. Late static images showed 5 had marked, 10 had moderate (99m)Tc-HDP uptake in the related joint. MRI examination indicated that there was no progression in any of the patients. The disease was determined to be stable in 2, regressed in 9, and totally cured in 4 cases. Bremsstrahlung imaging indicated an even distribution of radionuclide in all the knee joints. There was no evidence of leakage of radioactivity in the total body scans. There was significant improvement in Lysholm knee scores after treatment. CONCLUSION: Adjuvant yttrium 90 radiosynovectomy after surgical excision in the treatment of DPVNS is a reliable and efficient treatment method with successful clinical results. RS treatment can be considered for cases with DPVNS. PMID- 23751822 TI - The interplay between the X-DING-CD4, IFN-alpha and IL-8 gene activity in quiescent and mitogen- or HIV-1-exposed PBMCs from HIV-1 elite controllers, AIDS progressors and HIV-negative controls. AB - X-DING-CD4 blocks HIV-1 long terminal repeat (LTR) and pathogen induced pro inflammatory response. Increased activity of the X-DING-CD4 gene is associated with cellular resistance to virus; therefore, HIV-1 elite controllers (ECs) should have higher X-DING-CD4 and reduced pro-inflammatory mRNA activity than viremic or uninfected individuals. Also, depending on the cell stimulating factor, expression of X-DING-CD4 mRNA in ECs might be autonomous or contingent on IFN signaling. We compared expression of X-DING-CD4, IFN-alpha and IL-8 mRNAs in naive, phytohemagglutinin- or HIV-1 exposed PBMCs from ECs, HIV progressors and negative controls; tested correlation between X-DING-CD4 and IFN-alpha expression; sensitivity of the X-DING-CD4 gene to IFN-alpha regulation; and evaluated interactions between innate and pro-inflammatory genes. We found that expression of X-DING-CD4 and IFN-alpha was up-regulated in ECs and correlated in cells stimulated with mitogen, but not HIV-1. The X-DING-CD4 gene was more sensitive to HIV-1 than rIFN-alpha stimulation. ECs had significantly less IL-8 mRNA when PBMCs were exposed to exogenous HIV-1. Two-way ANOVA showed that control of HIV-1 and virus-induced pro-inflammatory response by ECs stemmed from interactions between expression of innate immunity and pro-inflammatory genes, the state of cell stimulation and the status of virus control. Consequently, interaction of multiple host innate immune responses rather than a single mechanism regulates restriction of HIV-1 in ECs. PMID- 23751824 TI - A spectrum of SPECT/CT image fusion applications in daily clinical practice. AB - Direct multimodality image correlation optimizes interpretation and diagnostic confidence, thereby enriching the radiologist's role in guiding clinical management. The primary advantages of SPECT/CT image fusion are more accurate identification and localization of disease and improved specificity. As illustrated here, software-based SPECT/CT image fusion enhances diagnosis for a variety of clinical presentations using the armamentarium of common radiopharmaceuticals, but without the costs of hybrid systems. PMID- 23751825 TI - 99mTc-oxidronate uptake within urothelial carcinoma confirmed with SPECT/CT imaging. AB - A 63-year-old woman with recurrent urothelial carcinoma was referred for skeletal scintigraphy to evaluate for osseous metastatic disease. The bone scan showed no osseous metastatic disease, but did show intense focal radiotracer accumulation along the left aspect of the urinary bladder. SPECT/CT images localized this uptake to a calcified bladder wall mass corresponding with the biopsy-proven (via cystoscopy) recurrent tumor. This case demonstrates that (a) some tumors may accumulate radionuclide bone tracer, emphasizing the need for careful evaluation of nonosseous structures during bone scan interpretation; (b) SPECT/CT is useful for clarifying potentially confusing findings and preventing misdiagnosis. PMID- 23751826 TI - Utility of 67Ga scintigraphy in disseminated infection after BCG instillation for treatment of bladder carcinoma. AB - Intravesical instillations of bacille Calmette-Guerin (BCG), an attenuated live strain of Mycobacterium bovis, is the treatment of choice for superficial bladder cancer. Local side effects are frequent, although adverse systemic reactions are uncommon, but more serious. We present 2 patients who developed disseminated M. bovis infection with multiorgan involvement after intravesical BCG therapy. (67)Ga scintigraphy was very helpful for the diagnosis as the only imaging tool with pathological findings. PMID- 23751827 TI - Tips for a physician in getting the right job, part I: self assessment: where and what kind of job is best? AB - A doctor should try to have at least 1 year to do a job search. This allows time to learn how to find a new job, do a careful assessment of what is best for both the doctor and his family in terms of the type of job and the location, prepare an appropriate curriculum vitae, find and research the prospective employers, practice for interviews, go on multiple interviews, have successful contract negotiations, and get hospital privileges and a license in the state. Also, sometimes it is useful or required to work for a week for a prospective employer, to see if there is still mutual interest. The first part of this multi-part article focuses on the self assessment of the doctor and his family to help them determine the location and the type of job that is best for them. PMID- 23751828 TI - Comparing respiratory gated with delayed scans in the detection of colorectal carcinoma hepatic and pulmonary metastases with 18F-FDG PET-CT. AB - PURPOSE: In patients experiencing colorectal carcinoma, exhaustive analysis of indicates extent of hepatic and pulmonary surgery that prolongs survival of patients. PATIENTS AND METHODS: To localize metastasis, we compared 2 F-FDG PET CT imaging protocols, early respiratory gated scan, and delayed scan, to standard PET imaging procedure. SUVmax and lesion-to-healthy tissue ratio were measured in 60 pulmonary and 21 hepatic lesions by each of the 2 imaging protocols. RESULTS: In the liver, metastatic lesion-to-healthy tissue ratios significantly increased on delayed scans as compared with early scans (P < 0.001). Better ratios could not be obtained when using respiratory gated scans, whereas more lesions were detected on delayed scans. In the lungs, metastatic lesion- to-healthy tissue ratio increased significantly on delayed scans for largest lesions (P < 0.001). Ratios were not better when exploring smallest metastatic lesions or when using respiratory gated scans. Factors interfering with F-FDG PET-CT sensitivity are discussed, such as respiratory motion and high FDG physiological uptake in healthy liver parenchyma. CONCLUSIONS: Our studies indicate that routine acquisitions should use delayed hepatic scans for all patients referred for evaluation, recurrence check, or monitoring of colorectal adenocarcinoma. Delayed pulmonary scans are useful for the largest metastatic lesions and should be used in addition to early scan. In our experience, respiratory gated scans seem to be less convenient because of a low sensitivity in detection, as compared with the delayed technique; in addition, this technique is currently complicated by some technical issues, although these might be overcome with new gated protocols. PMID- 23751829 TI - PET/CT imaging of abdominal aorta with intramural hematomas, penetrating ulcer, and saccular pseudoaneurysm. AB - Acute aortic syndromes, encompassing intramural hematoma, penetrating ulcer, and pseudoaneurysm, are best demonstrated by angiographic CT and magnetic resonance imaging. These imaging modalities provide an accurate evaluation and allow timely therapies of these frequently symptomatic lesions, thus reducing their morbidity and mortality. The inflammatory pathogenesis of these acute aortic syndromes may exhibit positive PET findings predictive of prognosis and outcomes of these vascular events. The authors present a case of PET/CT imaging showing asymptomatic intramural hematomas with penetrating ulcer and saccular pseudoaneurysm of the proximal abdominal aorta. PMID- 23751830 TI - 18F-FDG PET for diagnosis and response assessment for aggressive NK cell leukemia. AB - Aggressive natural killer cell leukemia (ANKL) is a rare malignant disorder of mature NK cells characterized by aggressive clinical course and poor outcome. The commonly involved sites are peripheral blood, bone marrow, liver, and spleen, but any organ can show involvement. We report a case of ANKL diagnosed and assessed the clinical response with 18F-FDG PET. Pretreatment and posttreatment FDG PET/CT showed a high correlation with pathologic diagnosis and staging as well as in the follow-up assessment of the clinical response. FDG PET could be a valuable tool enabling comprehensive staging and follow-up of ANKL. PMID- 23751831 TI - Adenosquamous carcinoma of the lung: CT, FDG PET, and clinicopathologic findings. AB - PURPOSE: The aim of this study is to evaluate CT, FDG PET, and clinicopathologic features of the adenosquamous carcinoma of the lung (ASC). PATIENTS AND METHODS: Twenty-six patients (M/F = 20:6; mean age, 65.0 years) who underwent surgical resection of ASC were included. The tumors were assessed in terms of size, location, morphologic characteristics, and maximum standardized uptake value (SUVmax) on CT and FDG PET. Proportion of adenocarcinoma was determined. The central and peripheral groups were compared. The differences in disease-free survival among the groups according to the observations were analyzed by Kaplan Meier test for patients who underwent curative resection (n = 21). RESULTS: Diameter was 3.8 +/- 1.9 cm. Five tumors were located centrally (19.2%) and 21 tumors peripherally (80.8%). Internal low and heterogeneous attenuation was found in all patients. Margins were lobulated in 20 (80%) patients, spiculated in 23 (92%), and ill-defined in 23 (92%). SUVmax was 8.3 +/- 3.9. Adenocarcinoma proportion was 33 +/- 28%. Central ASC were larger than peripheral ASC (5.7 cm vs. 3.4 cm, P = 0.007). Only SUVmax >6.3 was a poor prognostic factor. CONCLUSION: ASC was more commonly peripheral than central, and showed internal low and heterogeneous attenuation and possessed lobulated, spiculated, or ill defined margin on CT. Mean SUVmax of ASC was 8.3 +/- 3.9. Central ASC was larger than peripheral ASC. Except for tumor size, central ASC and peripheral ASC showed no significant differences in pathology, FDG PET, and survival. Higher SUVmax was a poor prognostic factor. PMID- 23751832 TI - Evolving role of SPECT/CT in neuroendocrine tumors management: staging, treatment response, and follow-up. AB - The combined use of SPECT and CT strongly supports the molecular imaging of neuroendocrine tumors (NETs) with somatostatin receptor radiopharmaceuticals or with meta-iodobenzylguanidine. SPECT/CT fusion images provide potential attenuation correction, higher specificity, and accurate localization for the staging, evaluation of treatment response, and follow-up of NETs. PMID- 23751833 TI - 18F-FDG PET/CT appearances of adult pulmonary blastoma. AB - (18)F-FDG PET/CT scanning plays an important role in the management of thoracic malignancy. The authors would like to present FDG PET/CT images of a rare thoracic malignancy, pulmonary blastoma in adulthood. The patient had recurrent metastatic disease of previously resected primary pulmonary blastoma. The foci of recurrent metastases in lung, mediastinum, and subcutaneous tissue are intensely FDG-avid. PMID- 23751834 TI - Adverse functional effects of chemotherapy on whole-brain metabolism: a PET/CT quantitative analysis of FDG metabolic pattern of the "chemo-brain". AB - PURPOSE: With its unique ability to assess function through metabolism, FDG PET may provide key insight into the adverse effects of chemotherapy on the brain by shedding light on its cognitive and psychological consequences, a well-known phenomenon in cancer patients who undergo such treatments. PATIENTS AND METHODS: Twenty-one patients with untreated non-Hodgkin lymphoma and no involvement of the central nervous system were selected from an existing database for this investigation. An adaptive threshold imaging software called ROVER was used to analyze and quantify FDG PET scans for assessing whole-brain metabolism. A 3D spherical region of interest was drawn surrounding the cerebral cortex, excluding subcortical and non-cortical areas. RESULTS: We noted a mean reduction of 1308.86 +/- 394.74 SUV-cc (P = 0.03) in the whole-brain cortical glycolysis after standard chemotherapy, which translated to a decrease of 16.9 +/- 5.04% (P = 0.03) in the measured structures. CONCLUSION: These results demonstrate the potential role of such adaptive quantitative techniques in studying underlying biological effects of chemotherapy and offer a promising avenue for future research in this field. PMID- 23751835 TI - Imaging findings of inflammatory pseudotumor-like follicular dendritic cell tumor of spleen. AB - Inflammatory pseudotumor-like follicular dendritic cell tumor (IPT-like FDCT) histology is similar to that of the classical follicular dendritic cell (FDC) tumor, but, in addition, the inflammatory component is quite prominent. We report a case of IPT-like FDCT of the spleen by abdominal CT and 18F-FDG PET/CT. Abdominal CT showed a low-density, round, well-circumscribed defined mass in spleen, and the mass showed a high metabolism rate on 18F-FDG PET/CT. PMID- 23751836 TI - Long road to authenticity: establishing a nuclear medicine practice. PMID- 23751838 TI - Efficacy of probiotics in Helicobacter pylori eradication therapy. PMID- 23751837 TI - Parathyroid scintigraphy in renal hyperparathyroidism: the added diagnostic value of SPECT and SPECT/CT. AB - Secondary hyperparathyroidism (sHPT) is a major complication for patients with end-stage renal disease on long-term hemodialysis or peritoneal dialysis. When the disease is resistant to medical treatment, patients with severe sHPT are typically referred for parathyroidectomy (PTx), which usually improves biological parameters as well as clinical signs and symptoms. Unfortunately, early surgical failure with persistent disease may occur in 5%-10% of patients and recurrence reaches 20%-30% at 5 years. Presently, the use of parathyroid scintigraphy in sHPT is usually limited to the management of surgical failures after initial PTx. This review describes the strengths and limitations of typical (99m)Tc-sestamibi imaging protocols, and highlights the potential benefits of using parathyroid scintigraphy in the initial workup of surgical patients. PMID- 23751839 TI - Angiotensin converting enzyme inhibitor-induced gastrointestinal angioedema: a case series and literature review. AB - GOALS: The objective of this study was to better understand the presenting signs and symptoms of angiotensin converting enzyme (ACE) inhibitor-induced gastrointestinal angioedema, review the medical literature related to this condition, and bring this diagnosis to the attention of clinicians. BACKGROUND: Angioedema occurs in 0.1% to 0.7% of patients treated with ACE inhibitors and ACE inhibitors account for 20% to 30% of all angioedema cases presenting to emergency departments. However, only recently have ACE inhibitors been recognized as a cause of angioedema of the gastrointestinal tract. Patients with this disease present with one or more episodes of abdominal pain associated with nausea, vomiting, and/or diarrhea. STUDY: We present four cases of ACE inhibitor-induced gastrointestinal angioedema seen at a single institution and review the literature of other case reports. RESULTS: Review of the medical literature identified 27 case reports of ACE inhibitor-induced angioedema of the gastrointestinal tract. Multiple ACE inhibitors were implicated in these case reports suggesting that this disease is a class effect of ACE inhibitors. In cases where the race of the patient was stated, 50% were identified as being African American. Ascities was described as a radiographic finding in 16 of 27 cases. There were no reported cases of paracentesis or ascitic fluid analysis described in any of the identified case reports. CONCLUSIONS: This series highlights ascites as a key feature that distinguishes ACE inhibitor-induced gastrointestinal angioedema from infectious enteritis. This series also confirms the increased incidence of this condition among African American women, an unpredictable interval between medication initiation and the development of symptoms, and the heightened probability of symptom recurrence if ACE inhibitors are not discontinued. ACE inhibitor-induced gastrointestinal angioedema is a rare cause of acute abdominal complaints, but is likely underdiagnosed and should be considered in the differential diagnosis of all individuals taking ACE inhibitors with such symptoms. Early recognition of ACE inhibitor-induced gastrointestinal angioedema may avoid recurrent episodes or costly, invasive evaluations. PMID- 23751840 TI - Alcohol-related injury to peribiliary glands is a cause of peribiliary cysts: based on analysis of clinical and autopsy cases. AB - BACKGROUND AND GOAL: Peribiliary cysts, which are known to be associated with various hepatobiliary diseases including alcoholic liver disease, have been reported to originate in the peribiliary glands along the biliary tree. The causal relationship between the peribiliary cysts and alcohol-related hepatic and pancreatic disease were examined in this study. METHODS AND RESULTS: Peribiliary cysts were surveyed in the radiologic reports of out-patients and in-patients at our hospital (between 2007 and 2011), and a total of 31 patients with peribiliary cysts were found; 9 patients were associated with alcoholic liver disease and 2 patients with alcoholic pancreatitis. Among 202 consecutive autopsy cases with a history of heavy drinking (chronic alcoholics) at our Department (between 1990 and 2011), peribiliary cysts were found in 29 cases (14%), and the frequency of these cysts was correlated with the degree of alcohol-related hepatic fibrosis. Interestingly, peribiliary cysts were frequently associated with adenitis of the peribiliary glands (72%), and peribiliary adenitis and cyst formation correlated well with the degree of pancreatic fibrosis. CONCLUSIONS: These results suggest that peribiliary cysts are more likely to occur in chronic alcoholics. The frequent association of peribiliary cysts with the degree of alcohol-related hepatic fibrosis suggests the involvement of the hepatic fibrogenetic process in peribiliary cyst formation. The frequent association of peribiliary adenitis and cyst formation with the degree of pancreatic fibrosis in chronic alcoholics suggests the involvement of alcoholic injuries in the pancreas, resulting in progressive fibrosis, and peribiliary glands, resulting in adenitis and cyst formation. PMID- 23751841 TI - Decreased relative diagnostic yield of esophagogastroduodenoscopy in children with gastroparesis. AB - BACKGROUND: Esophagogastroduodenoscopy (EGD) and gastric emptying scintigraphy (GES) are commonly performed in the evaluation of children with upper gastrointestinal symptoms. It has been presumed, but not clarified, that gastroparesis increases the likelihood of identifying abnormalities on EGD. We sought to determine whether the presence of gastroparesis influenced the diagnostic yield of EGD in children. METHODS: We conducted a retrospective chart review of children who underwent both an EGD and GES within 3 months of each other for evaluation of upper gastrointestinal symptoms (eg, abdominal pain). Clinical history (symptoms, comorbidities, medications, and surgical procedures), GES results, and EGD histology reports were captured. RESULTS: A total of 125 children (46% female) were included, of whom, 70 (56%) had gastroparesis. Thirty three (26%) children had liquid meal GES (1.2 +/- 1.1 y of age, mean +/- SD) and 92 (64%) had solid meal GES (12.4 +/- 3.6 y of age). There was an overall trend toward a decreased frequency of biopsy abnormalities in those with gastroparesis (P=0.09). Those with gastroparesis identified through liquid meal GES were less likely to have reflux esophagitis on biopsy (P=0.002). Those with gastroparesis identified on solid meal GES were less likely to have gastritis (P=0.04). Symptoms, comorbidities, or medications were not predictive of GES or EGD results. CONCLUSIONS: Children with gastroparesis may be less likely to have biopsy abnormalities identified on EGD in comparison to those without gastroparesis. Further prospective, larger, and multicenter studies are needed to validate our findings. PMID- 23751842 TI - Clinical utility of sclerotherapy with a new agent for treatment of rectal prolapse in patients with risks. AB - BACKGROUND: Perineal approaches are widely applied for the treatment of rectal prolapse. Recently, less-invasive treatments such as sclerotherapy using aluminum potassium sulfate/tannic acid (ALTA) have been introduced for internal hemorrhoids. Herein, we report the results of ALTA injection for the treatment of rectal prolapse in high-risk patients. METHODS: Between January 2009 and March 2011, we performed ALTA injection sclerosing therapy in 12 female patients with high risk for preoperative complications. Using the perineal approach, 0.5 to 1 mL of ALTA was injected into the submucosa at 30 to 60 different sites. RESULTS: All patients were successfully treated without any operative or postoperative morbidity. Average operation time took 35+/-7 (mean+/-SD) minutes, and average volume of ALTA injected was 39+/-6 mL per patient. Neither complaints of bleeding nor findings of anal stenosis were noted. A slight degree of recurrence of prolapse developed in a patient after 8 months. The patient required an additional injection to be cured. CONCLUSIONS: ALTA injection could be administered for the treatment of rectal prolapse without any pain or complication and would be useful even for patients with risks due to preoperative complications and/or medical history. PMID- 23751843 TI - Large proximal serrated polyps: natural history and colorectal cancer risk in a retrospective series. PMID- 23751844 TI - Sarcopenia as a prognostic index of nutritional status in concurrent cirrhosis and hepatocellular carcinoma. AB - BACKGROUND AND AIMS: Abnormal body composition such as severe skeletal muscle depletion or sarcopenia has emerged as an independent predictor of clinical outcomes in a variety of clinical conditions. This study is the first study to report the frequency and prognostic significance of sarcopenia as a marker of nutritional status in patients with hepatocellular carcinoma (HCC). METHODS: We analyzed 116 patients with HCC who were consecutively evaluated for liver transplant. Skeletal muscle cross-sectional area was measured by CT. Sarcopenia was defined using previously established cutpoints. RESULTS: Ninety-eight patients were males (85%), and the mean age was 58+/-6 years. Sarcopenia was present in 35 patients (30%). By univariate Cox analysis, male sex (HR, 3.84; P=0.02), lumbar skeletal muscle index (HR, 0.97; P=0.04), INR (HR, 8.18; P<0.001), MELD score (HR, 1.19; P<0.001), Child-Pugh (HR, 3.95; P<0.001), serum sodium (HR, 0.84; P<0.001), TNM stage (HR, 2.59; P<0.001), treatment type (HR, 0.53; P<0.001), and sarcopenia (HR, 2.27; P=0.004) were associated with increased risks of mortality. By multivariate Cox regression analysis, only MELD score (HR, 1.08; P=0.04), Child-Pugh (HR, 2.14; P=0.005), sodium (HR, 0.89; P=0.01), TNM stage (HR, 1.92; P<0.001), and sarcopenia (HR, 2.04; P=0.02) were independently associated with mortality. Median survival for sarcopenic patients was 16+/-6 versus 28+/-3 months in nonsarcopenic (P=0.003). CONCLUSIONS: Sarcopenia is present in almost one third of patients with HCC, and constitutes a strong and independent risk factor for mortality. Our results highlight the importance of body composition assessment in clinical practice. PMID- 23751845 TI - Outcome after liver transplantation for cirrhosis due to alcohol and hepatitis C: comparison to alcoholic cirrhosis and hepatitis C cirrhosis. AB - BACKGROUND AND AIM: Data on outcome of patients after liver transplantation (LT) for cirrhosis due to hepatitis C virus (HCV+) alcohol are limited. METHODS AND RESULTS: Analysis from United Network for Organ sharing data set (1991 to 2010) for cirrhotics with first LT for HCV (group I, N=17,722), alcohol or alcoholic cirrhosis (AC; group II, N=9617), and alcohol+HCV (group III, N=6822). Five-year graft and patient survival for group III were similar to group I (73% vs. 69%; P=0.33 and 76% vs. 76%; P=0.87) and worse than group II (70% vs. 74%; P<0.0001 and 76% vs. 79%; P<0.0001). Cox regression analysis adjusted for recipient and donor characteristics showed (a) graft survival for group III similar to group I [hazard ratio (HR) 1.03 (95% confidence interval (CI), 0.97-1.09)] and worse than group II [HR 1.27 (95% CI, 1.19-1.35)] and (b) patient survival for group III worse than both groups I [HR 1.09 (95% CI, 1.02-1.15)] and II [HR 1.27 (95% CI, 1.19-1.36)]. In group III, graft failure was common for graft and patient loss and de novo malignancy more common compared with group I. CONCLUSIONS: Patients undergoing LT for cirrhosis due to combined alcohol and HCV have (a) graft survival similar to patients with HCV cirrhosis and worse than AC and (b) worse patient survival compared with AC and HCV cirrhosis. Better strategies for anti HCV treatment and screening for tumors are needed for patients undergoing LT for combined alcohol and HCV. PMID- 23751846 TI - A multidisciplinary approach to the diagnosis and treatment of gastrointestinal stromal tumor. AB - Management of patients with gastrointestinal stromal tumor (GIST) typically involves a combination of surgical, pathologic, and pharmacologic interventions. Gastroenterologists are often the first specialists to encounter patients presenting with GIST and are therefore responsible for facilitating early intervention strategies. Although patients with gastric or small-bowel GISTs typically present with symptoms, a diagnosis of GIST should be considered whenever a submucosal lesion is seen endoscopically. Visualization by standard endoscopy often can determine tumor location and size, although endoscopic ultrasound (EUS) is the most accurate imaging technique for submucosal lesions. Biopsy techniques that yield sufficient tumor samples for diagnostic studies, such as EUS-guided fine needle aspiration, are essential, although other approaches such as EUS-guided core needle biopsy may increase diagnostic yield for subepithelial lesions. Pathology assessment should include immunohistochemical staining for KIT and possibly DOG1 expression, and mutational analysis can have prognostic and predictive value for certain patients. R0 resection is the goal for patients with localized or potentially resectable tumors, which often can be accomplished by laparoscopic resection, even for larger tumors. Medical oncologists play a key role in assessing risk of recurrence after resection and optimizing tyrosine kinase inhibitor therapy in the adjuvant or metastatic setting. Cytoreductive surgery may have value for patients with recurrent or metastatic GIST who exhibit stable disease or respond to tyrosine kinase inhibitor therapy. A coordinated multidisciplinary approach over the course of the disease will serve to enhance communication among GIST team members, reduce risk of progression, and optimize outcomes. PMID- 23751848 TI - Topographical impact of hepatitis B-related hepatocellular carcinoma on local recurrence after radiofrequency ablation. AB - BACKGROUND: Radiofrequency ablation (RFA) is an efficient and safe treatment modality for early-stage hepatocellular carcinoma (HCC). However, its application is sometimes limited by several topographical factors. Whether topographical characteristics are risk factors for local recurrence after RFA is still under debate. GOALS: The aims of this study were to identify topographical risk factors for the local recurrence of solitary HCC after RFA and to evaluate their impact on long-term treatment outcomes. METHODS: The clinical and radiologic findings of patients with solitary hepatitis B virus (HBV)-related HCC<4.0 cm undergoing RFA were retrospectively reviewed. The Cox regression model was used to identify risk factors that predicted local recurrence. RESULTS: A total of 300 patients with solitary, HBV-related HCC were included in this retrospective cohort study. Seventy patients (23.3%) experienced local recurrence after RFA during the median follow-up duration of 43.0 months (range, 3.0 to 69.0 mo). Multivariate analysis showed that tumor size >=2.0 cm [hazard ratio (HR), 1.716; P=0.047], proximity to a large vessel (HR, 2.609; P=0.024), and proximity to the diaphragm (HR, 3.128; P=0.004) were independent predictors of the local recurrence of solitary HCC. Moreover, the cumulative risk of local recurrence after RFA increased with the number of risk factors. CONCLUSIONS: Proximity of HCC to a large vessel or the diaphragm as well as large tumor size may increase the risk of local recurrence after RFA. Therefore, the topographical factors of HCC should be considered to tailor therapeutic decisions for solitary, HBV-related HCC. PMID- 23751847 TI - A cross-sectional analysis of the prevalence of Barrett esophagus in otolaryngology patients with laryngeal symptoms. AB - BACKGROUND: Populations at risk for esophageal adenocarcinoma remain poorly defined. Laryngeal symptoms can be secondary to laryngopharyngeal reflux (LPR) and can occur without associated gastroesophageal reflux symptoms such as heartburn and regurgitation. GOAL: We sought to determine the prevalence of Barrett esophagus (BE) in otolaryngology patients with laryngeal symptoms+/ typical gastroesophageal reflux disease (GERD) symptoms. STUDY: We performed a cross-sectional study of otolaryngology clinic patients who reported laryngeal symptoms. Symptoms, medications, and exposure histories were obtained. Unsedated transnasal endoscopy was performed. Suspected BE was biopsied and confirmed histologically. Risk factors and prevalence of BE were assessed. RESULTS: Two hundred ninety-five patients were enrolled [73% male, median age 60 y (interquartile range 51 to 68 y)]. The overall prevalence of BE was 11.8% (n=33). Antisecretory medication use was present in 56% (n=156) of patients at enrollment. Compared with patients without BE, patients with BE were more likely to be male (P=0.01) and to report occupational lung injury (P=0.001). Duration, but not severity of laryngeal symptoms, significantly increased the odds of BE (odds ratio, 5.64; 95% confidence interval, 1.28-24.83; for a duration of symptoms >5 y). Of patients with BE, 58% (n=19) had coexisting LPR and GERD symptoms and 30% (n=10) had only LPR symptoms. Presence and size of hiatal hernia and length of columnar-lined esophagus were significant risk factors for BE. CONCLUSIONS: Long-standing laryngeal symptoms are associated with the presence of BE in otolaryngology patients. Patients with chronic laryngeal symptoms and no identifiable ear, nose, or throat etiology for those symptoms may benefit from endoscopic screening regardless of whether typical GERD symptoms are present. PMID- 23751849 TI - The utility of lower endoscopic ultrasound-guided fine needle aspiration for the diagnosis of benign and malignant pelvic diseases. AB - BACKGROUND: The utility of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for the diagnosis of pelvic masses has been suggested but limited data are available in the literature regarding its diagnostic accuracy. GOALS: To report our institutional experience with EUS-FNA for the diagnosis of a variety of pelvic diseases. METHODS: Patients who were referred for the evaluation of pelvic lesions using lower EUS-FNA were included in this retrospective analysis if they had available surgical pathology (obtained after EUS) which was considered the gold standard against which the EUS-FNA findings would have been compared. The diagnostic accuracy of EUS-FNA for pelvic masses was analyzed and any early or late complications after the procedure were reported. A pelvic mass was defined in the study as any mass seen with an imaging modality in the pelvic area including those involving the colonic wall. RESULTS: Twenty patients had EUS FNA followed by surgery for whom FNA cytology and surgical pathology findings were available. EUS-FNA reached the correct diagnosis in 19 out of 20 patients, whereas for the missing 1 malignant lymph node wherein FNA revealed benign cytology, surgical specimen confirmed metastatic colon cancer. The sensitivity and specificity of EUS-FNA were 90% and 100%, respectively, with positive and negative predictive values of 100% and 90%, respectively. No early or late complications were encountered with this procedure for the sampling of cystic and noncystic masses. CONCLUSIONS: EUS-FNA has excellent diagnostic accuracy for pelvic masses. It represents a safe procedure with excellent yield and thus may be used as a first line modality for the evaluation and diagnosis of pelvic masses within its reach. PMID- 23751850 TI - Comment on: Rifaximin in the treatment of irritable bowel syndrome. is there a high risk for development of antimicrobial resistance? PMID- 23751851 TI - Diagnostic testing for Clostridium difficile infection in patients with inflammatory bowel disease. PMID- 23751852 TI - Over the scope clip: technique and expanding clinical applications. AB - BACKGROUND: Advances in endoscopic and surgical techniques have increased the frequency and complexity of these procedures, and thus, the incidence of associated complications. AIMS: To describe the use and clinical applications of the Over the Scope Clip (OTSC) system. METHODS: An English language literature search was conducted using the key words "endoscopy" and "over the scope clip" in order to identify human studies evaluating the application of OTSC from January 2001 to August 2012. The indication, efficacy, complications, and limitations were recorded. RESULTS: Overall success rates of OTSC based on current literature range are in the range of 75% to 100% for closure of iatrogenic gastrointestinal perforations, 38% to 100% for closure of gastrointestinal fistulas, 50% to 100% for anastomotic leaks, and 71% to 100% for bleeding lesions. OTSCs have shown 100% success rates in managing postbariatric surgery weight gain secondary to dilation of the gastrojejunal pouch. CONCLUSION: OTSC is easy to use with good results, thus decreasing the morbidity and mortality associated with the complications secondary to both diagnostic and therapeutic endoscopy and avoiding surgery in many situations. PMID- 23751853 TI - Pancreatic necrosectomy using covered esophageal stents: a novel approach. AB - BACKGROUND: Endoscopic necrosectomy for necrotizing pancreatitis has been increasingly used as an alternative to surgical or percutaneous interventions. The use of fully covered esophageal self-expandable metallic stents may provide a safer and more efficient route for internal drainage. The aim of this study was to evaluate the safety and efficacy of endoscopic treatment of pancreatic necrosis with these stents. METHODS: A retrospective study at 2 US academic hospitals included patients with infected pancreatic necrosis from July 2009 to November 2012. These patients underwent transgastric placement of fully covered esophageal metallic stents draining the necrosis. After necrosectomy, patients underwent regular sessions of endoscopic irrigation and debridement of cystic contents. The efficacy endpoint was successful resolution of infected pancreatic necrosis without the need for surgical or percutaneous interventions. RESULTS: Seventeen patients were included with the mean age of 41+/-12 years. A mean of 5.3+/-3.4 sessions were required for complete drainage and the follow-up period was 237.6+/-165 days. Etiology included gallstone pancreatitis (6), alcohol abuse (6), s/p distal pancreatectomy (2), postendoscopic retrograde cholangiopancreatography pancreatitis (1), medication-induced pancreatitis (1), and hyperlipidemia (1). Mean size of the necrosis was 14.8 cm (SD 5.6 cm), ranging from 8 to 19 cm. Two patients failed endoscopic intervention and required surgery. The only complication was a perforation during tract dilation, which was managed conservatively. Fifteen patients (88%) achieved complete resolution. CONCLUSIONS: Endoscopic necrosectomy with covered esophageal metal stents is a safe and successful treatment option for infected pancreatic necrosis. PMID- 23751854 TI - Past exposure to hepatitis B: a risk factor for increase in mortality? AB - BACKGROUND: Chronic hepatitis B has been shown to increase mortality, but association of past exposure to hepatitis B and mortality has not been studied well. The aim of this study was to evaluate the risk of overall and liver-related mortality in individuals with past exposure to hepatitis B. METHODS: The National Health and Nutrition Examination Survey III (NHANES III) and its related public linked mortality files were used for this study. The participants with presence of anti-HBc +/- anti-HBs, in absence of hepatitis B surface antigen were considered to have previous exposure to hepatitis B. The overall mortality from past exposure to hepatitis B was assessed in participants without any chronic liver diseases (CLD) and in participants with chronic hepatitis C, alcoholic liver disease (ALD), and nonalcoholic fatty liver disease. The Cox proportional regression analysis was used to calculate adjusted hazard ratios. RESULTS: A total of 15,650 individuals were included in the analyses. Past exposure to hepatitis B was an independent predictor of increase in overall mortality in individuals without CLD [adjusted hazard ratio (aHR)=1.29; 95% confidence interval (CI), 1.06-1.56; P=0.012] and those with ALD (aHR=2.25; 95% CI, 1.20 4.23; P=0.013). It was also an independent predictor of liver-related mortality in ALD cohort (aHR=7.75; 95% CI, 2.56-23.48; P<0.001). Past exposure to hepatitis B did not correlate with a significant increase in overall or liver-related mortality in chronic hepatitis C or nonalcoholic fatty liver disease cohorts. CONCLUSION: Past exposure to hepatitis B is associated with significant increase in overall mortality among individuals with ALD and those without CLD. PMID- 23751855 TI - Long-term follow-up after endoscopic stent therapy for benign biliary strictures. AB - BACKGROUND AND AIMS: Endoscopic therapy holds an important role in the management of benign biliary strictures. This study compares the long-term outcome of stenting therapy depending on the underlying cause of the stricture. METHODS: In a retrospective cohort study, 228 patients with benign biliary strictures were identified using an endoscopic database, hospital charts, and cholangiograms between January 1992 and December 2008. Long-term follow-up was evaluated with cholangiograms, transabdominal ultrasound, laboratory parameters, and physical examination. The median follow-up period was 44.7 months. RESULTS: Endoscopic management showed best long-term results in patients with stone-associated biliary stricture. In this subgroup, endoscopic therapy could be successfully completed in 92% (71/77) of the patients. Patients with postoperative biliary stricture had good outcome in 83% (53/64) of cases. Idiopathic strictures presented a successful outcome in 58% (15/26). Biliary strictures caused by chronic pancreatitis had a significantly poorer outcome compared with strictures of other origin. Therapeutic success of endoscopic therapy could only be observed in 31% of patients (19/61). CONCLUSIONS: Long-term outcome of endoscopic therapy for benign strictures was significantly dependent on the underlying cause of the stricture. In particular, patients with biliary strictures due to chronic pancreatitis benefit least from endoscopic therapy, whereas patients with stone associated strictures had the highest therapeutic success rate. PMID- 23751856 TI - Safety of ornithine phenylacetate in cirrhotic decompensated patients: an open label, dose-escalating, single-cohort study. AB - AIMS: Confirm in patients with cirrhosis and gastrointestinal bleeding the safety of ornithine phenylacetate (OP) and assess the pharmacokinetic profile of OP and its effects on plasma ammonia. BACKGROUND: OP is a drug that has shown experimentally to decrease hyperammonemia and improve hepatic encephalopathy. OP is safe in healthy subjects and in stable patients with cirrhosis, but there are no data in decompensated cirrhosis. METHODS: We performed a study to assess safety and tolerance of OP in cirrhotic patients after an episode of upper gastrointestinal bleeding.Ten patients were included within 24 hours of an upper gastrointestinal bleeding. OP was administered as a continuous infusion up to a maximum of 10 g/24 h (0.42 g/h) for 5 days. The infusion was started at 33% of the target dose and increased at 12-hour intervals achieving target dose at 24 hours. Ammonia was also assessed in control group of 10 patients. RESULTS: No severe adverse events were observed. Mild adverse events were reported in 4 patients. Plasma ammonia (baseline: 80+/-43 MUmol/L) showed a progressive drop between baseline and 36 hours (42+/-15 MUmol/L), 72 hours (44+/-15 MUmol/L), 96 hours (40+/-24 MUmol/L), and 120 hours (33+/-14 MUmol/L). Plasma ammonia at 24 hours was significantly higher in the control group. Plasma glutamine showed a significant decrease (-37% at day 5) and its excretion in urine as phenylacetylglutamine, a progressive rise (52+/-35 mmol at day 5). CONCLUSIONS: OP is a safe and well-tolerated drug in decompensated cirrhotics that may decrease plasma ammonia by inducing its appearance as phenylacetylglutamine in urine. PMID- 23751857 TI - Olmesartan-associated sprue-like enteropathy. PMID- 23751858 TI - Wide spectrum of clinical manifestations in children with tuberous sclerosis complex--follow-up of 20 children. AB - TSC is a multisystem genetic disorder predisposing to multiple organ manifestations and developmental problems. Clinical follow-up of patients remains a challenge for the caring paediatrician. METHODS: We performed a retrospective analysis of clinical manifestations, diagnostic and therapeutic data in 20 children with the diagnosis of tuberous sclerosis complex (TSC) to answer the following questions: are the clinical guidelines and imaging strategies appropriate to discover complications, are there significant early predictors of long-term prognosis, what is the age range for signs and symptoms to occur. RESULTS: Cardiac rhabdomyoma were present in 18 children and occurred as earliest manifestation. 8 of these exhibited associated arrhythmia or congenital cardiac anomalies. Seizures combined with cortical tubers and subependymal nodules occurred in 18 patients and were most likely to start in infancy, which was associated with later cognitive impairment. Cutaneous manifestations (15 children) occurred in late childhood and school age, whilst renal angiomyolipomas (11) developed in puberty. DISCUSSION: The clinical course and imaging strategies are compared with data from previous studies. A review of TSC in regard to the multiple manifestations is provided. PMID- 23751859 TI - Effectiveness of single-dose fosfomycin as antimicrobial prophylaxis in transrectal ultrasound-guided biopsy of the prostate. PMID- 23751860 TI - Nlrp4g is an oocyte-specific gene but is not required for oocyte maturation in the mouse. AB - The Nlrp gene family contains 20 members and plays a pivotal role in the innate immune and reproductive systems in the mouse. The aim of the present study was to analyse the Nlrp4g gene expression pattern, protein distribution and function in mouse oocyte maturation. Quantitative real-time polymerase chain reaction and in situ hybridisation were performed on Nlrp4g mRNA. Western blotting, immunohistochemistry and immunofluorescence were used to assess expression at the protein level. Confocal and immunogold electron microscopy analyses and RNA interference approach were used to determine the location of the NLRP4G protein and inhibit Nlrp4g function specifically in mouse germinal vesicle oocytes, respectively. Nlrp4g transcripts and proteins (~85kDa) are specifically expressed in mouse ovaries, restricted to the oocytes at various follicular stages and decline with oocyte aging. There is a marked decline in transcript levels in preimplantation embryos before zygotic genome activation, but the protein remains present through to the blastocyst stage. Confocal microscopy demonstrated that this protein is localised in the cytoplasm. Immunogold electron microscopy further confirmed that NLRP4G protein was present in the cytosol rather than in oocyte cytoplasmic organelles. Furthermore, knockdown of Nlrp4g in germinal vesicle oocytes did not affect oocyte maturation. These results provide the first evidence that Nlrp4g is an oocyte-specific gene but dispensable for oocyte maturation, suggesting that this gene may play roles in mouse oogenesis and/or preimplantation development. PMID- 23751861 TI - The course of Health Related Quality of Life in postmenopausal women with breast cancer from breast surgery and up to five years post-treatment. AB - BACKGROUND: Previous studies include too few patients over 70 years to be able to assess treatment effects on Health Related Quality Of Life (HRQOL) in the older age group. We aimed to follow HRQOL in postmenopausal women (55-80 years) with breast cancer receiving adjuvant treatment, until five years post-treatment, and compare with a general population. PATIENTS AND METHODS: The patient sample included 150 women (adjuvant CT n = 75 and RT n = 75) and two reference samples from the Swedish SF-36 norm database. RESULTS: Data from baseline showed significantly higher levels of physical functioning and general health among the patients compared to the reference sample, and significantly lower levels of bodily pain, emotional role functioning and mental health. Longitudinal analyses showed significant changes in all scales, and three different patterns (a decrease-stable, a decrease-increase, and a stable- increase pattern) were identified. CONCLUSION: Postmenopausal women seem to successfully manage the effects of adjuvant treatment on HRQOL. PMID- 23751862 TI - The retention of simultaneous tones in auditory short-term memory: a magnetoencephalography study. AB - We used magnetoencephalography (MEG) to localize brain activity related to the retention of tones differing in pitch. Participants retained one or two simultaneously presented tones. After a two second interval a test tone was presented and the task was to determine if that tone was in memory. We focused on brain activity during the retention interval that increased as the number of sounds retained in auditory short-term memory (ASTM) increased. Source analyses revealed that the superior temporal gyrus in both hemispheres is involved in ASTM. In the right hemisphere, the inferior temporal gyrus, the inferior frontal gyrus, and parietal structures also play a role. Our method provides good spatial and temporal resolution for investigating neuronal correlates of ASTM and, as it is the first MEG study using a memory load manipulation without using sequences of tones, it allowed us to isolate brain regions that most likely reflect the simple retention of tones. PMID- 23751863 TI - Metabolomic approach to human brain spectroscopy identifies associations between clinical features and the frontal lobe metabolome in multiple sclerosis. AB - Proton magnetic resonance spectroscopy ((1)H-MRS) is capable of noninvasively detecting metabolic changes that occur in the brain tissue in vivo. Its clinical utility has been limited so far, however, by analytic methods that focus on independently evaluated metabolites and require prior knowledge about which metabolites to examine. Here, we applied advanced computational methodologies from the field of metabolomics, specifically partial least squares discriminant analysis and orthogonal partial least squares, to in vivo (1)H-MRS from frontal lobe white matter of 27 patients with relapsing-remitting multiple sclerosis (RRMS) and 14 healthy controls. We chose RRMS, a chronic demyelinating disorder of the central nervous system, because its complex pathology and variable disease course make the need for reliable biomarkers of disease progression more pressing. We show that in vivo MRS data, when analyzed by multivariate statistical methods, can provide reliable, distinct profiles of MRS-detectable metabolites in different patient populations. Specifically, we find that brain tissue in RRMS patients deviates significantly in its metabolic profile from that of healthy controls, even though it appears normal by standard MRI techniques. We also identify, using statistical means, the metabolic signatures of certain clinical features common in RRMS, such as disability score, cognitive impairments, and response to stress. This approach to human in vivo MRS data should promote understanding of the specific metabolic changes accompanying disease pathogenesis, and could provide biomarkers of disease progression that would be useful in clinical trials. PMID- 23751864 TI - Neural correlates of adaptation in freely-moving normal hearing subjects under cochlear implant acoustic simulations. AB - Neurobiological correlates of adaptation to spectrally degraded speech were investigated with fMRI before and after exposure to a portable real-time speech processor that implements an acoustic simulation model of a cochlear implant (CI). The speech processor, in conjunction with isolating insert earphones and a microphone to capture environment sounds, was worn by participants over a two week chronic exposure period. fMRI and behavioral speech comprehension testing were conducted before and after this two week period. After using the simulator each day for 2h, participants significantly improved in word and sentence recognition scores. fMRI shows that these improvements came accompanied by changes in patterns of neuronal activation. In particular, we found additional recruitment of visual, motor, and working memory areas after the perceptual training period. These findings suggest that the human brain is able to adapt in a short period of time to a degraded auditory signal under a natural learning environment, and gives insight on how a CI might interact with the central nervous system. This paradigm can be furthered to investigate neural correlates of new rehabilitation, training, and signal processing strategies non-invasively in normal hearing listeners to improve CI patient outcomes. PMID- 23751865 TI - High-titer heterologous production in E. coli of lyngbyatoxin, a protein kinase C activator from an uncultured marine cyanobacterium. AB - Many chemically complex cyanobacterial polyketides and nonribosomal peptides are of great pharmaceutical interest, but the levels required for exploitation are difficult to achieve from native sources. Here we develop a framework for the expression of these multifunctional cyanobacterial assembly lines in Escherichia coli using the lyngbyatoxin biosynthetic pathway, derived from a marine microbial assemblage dominated by the cyanobacterium Moorea producens. Heterologous expression of this pathway afforded high titers of both lyngbyatoxin A (25.6 mg L(-1)) and its precursor indolactam-V (150 mg L(-1)). Production, isolation, and identification of all expected chemical intermediates of lyngbyatoxin biosynthesis in E. coli also confirmed the previously proposed biosynthetic route, setting a solid chemical foundation for future pathway engineering. The successful production of the nonribosomal peptide lyngbyatoxin A in E. coli also opens the possibility for future heterologous expression, characterization, and exploitation of other cyanobacterial natural product pathways. PMID- 23751866 TI - Climatic variables are associated with the prevalence of biliary trematodes in otters. AB - Parasites with complex life cycles are expected to be disproportionately affected by climate change. Knowledge of current associations with weather and host parasite interactions is therefore essential for the inference of future distributions. The Eurasian otter, Lutra lutra, is exposed to a range of parasites due to its large home range and use of terrestrial, freshwater and marine habitats. As such, it can act as a sentinel species for generalist parasites. Here we consider two biliary parasites recently reported in the United Kingdom, Pseudamphistomum truncatum and Metorchis albidus (Trematoda, Opisthorchiidae), and ask whether there are associations between abiotic factors (season, temperature, rainfall and the North Atlantic Oscillation) and the prevalence and intensities of these parasites in otters (n = 586). To control for biotic interactions we first examined whether particular sub-groups of the otter population (grouped by sex, age-class and condition) are more prone to infection and whether any damage is associated with the presence of these parasites. Even though mean intensities of the smaller trematode, P. truncatum (28.3 worms/host), were much higher than M. albidus (4.1), both parasite species had similar impacts on the otter. The distributions of parasites on host sexes were similar, but males suffered greater damage and regardless of sex, parasite intensity increased in older hosts. The probability of infection with either parasite was negatively associated with ground frost, minimum temperatures and rainfall, but was positively associated with warm long-term average temperatures. Although it is widely accepted that multiple variables influence parasite distributions, to our knowledge this is one of only a few studies to examine the combined impact of biotic and abiotic variables on parasites with complex life cycles within their wild definitive host. Identifying such associations can give greater accuracy to predictions concerning the distribution and spread of trematodes with future climate change. PMID- 23751867 TI - Off-pump versus on-pump coronary artery bypass grafting in octogenarians: comparison of short-term outcomes and long-term survival. AB - Off-pump coronary artery bypass (OPCAB) has gained increasing acceptance with potential benefits for high-risk elderly patients. We report a surgeon's operative outcomes in octogenarians with an OPCAB program. Retrospective, intention-to-treat analysis of 97 consecutive octogenarians who underwent coronary bypass by a single surgeon between 1997 and 2001 before and after initiation of a multi-vessel OPCAB program was performed. OPCAB was attempted in all octogenarians. The OPCAB cohort had higher serum creatinine (OPCAB vs. pre OPCAB: 1.30 +/- 0.79 mg/dl vs. 1.08 +/- 0.27, p = 0.04) and ejection fractions (52 +/- 14% vs. 45 +/- 11%, p = 0.02) than the pre-OPCAB cohort. The OPCAB group was more likely to require urgent/emergency surgery (63 vs. 40%, p = 0.04) and to have chronic renal insufficiency (18 vs. 3%, p = 0.05). After programmatic change to OPCAB, significant postoperative improvements were observed in the length of hospital stay (17 +/- 19 vs. 8 +/- 4 days, p < 0.01), duration of inotropic requirement (47 +/- 70 vs. 18 +/- 39 h, p < 0.04), duration of ventilator support (51 +/- 54 vs. 16 +/- 27 h, p < 0.01) and incidence of tracheostomy (16 vs. 3%, p < 0.02). In-hospital mortalities (3.2 vs. 2.7%), strokes (3 per group) and 5-year survival did not differ significantly (57 vs. 67%, p = 0.50, NS). Despite some higher preoperative risks, the OPCAB program demonstrated clinical benefits in octogenarians but no advantage in hospital-mortality or long-term survival. PMID- 23751868 TI - Critical evaluation of a badminton-specific endurance test. AB - PURPOSE: To overcome the limitations of traditional 1-dimensional fitness tests in analyzing physiological properties of badminton players, a badminton-specific endurance test (BST) was created. This study aimed at analyzing the influence of various fitness dimensions on BST performance. METHODS: 18 internationally competing male German badminton players (22.4 +/- 3.2 y, 79.2 +/- 7.7 kg, 1.84 +/ 0.06 m, world-ranking position [WRP] 21-501) completed a straight-sprint test, a change-of-direction speed test, various jump tests (countermovement jump, drop jump, standing long jump), a multistage running test (MST), and the BST. During this on-court field test players have to respond to a computerized sign indicating direction and speed of badminton-specific movements by moving into the corresponding corners. RESULTS: Significant correlations were found between performance in MST and BST (individual anaerobic threshold [IAT], r = .63, P = .005; maximum velocity [Vmax], r = .60, P = .009). A negative correlation (r = .59, P = .014) was observed between IAT in BST and drop-jump contact time. No further associations between performance indices could be detected. Apart from a small portion explained by MST results (IAT, R2 = .40; Vmax, R2 = .36), the majority of BST performance cannot be explained by the determined physiological correlates. Moreover, it was impossible to predict the WRP of a player on the basis of BST results (r = -.15, P = .55). CONCLUSIONS: Neither discipline specific performance nor basic physiological properties were appropriately reflected by a BST in elite badminton players. This does not substantiate its validity for regular use as a testing tool. However, it may be useful for monitoring on-court training sessions. PMID- 23751869 TI - Impact of humans on long-distance communication behaviour of eastern chimpanzees (Pan troglodytes schweinfurthii) in the Northern Democratic Republic of the Congo. AB - We systematically recorded all long-distance chimpanzee vocalizations and tree drums over a 26-month study period in 13 forest regions in the Democratic Republic of the Congo. We found that the frequency of chimpanzee vocalizations and tree drums was considerably higher in the remote Gangu Forest than in other forest regions closer to human settlements and roads. We present evidence indicating that chimpanzees may reduce their levels of vocalizations in areas characterized by high levels of human hunting. The chimpanzees appear to have the behavioural flexibility necessary to modify their behaviour in areas where humans are a major threat. We discuss the possible consequences of this reduction in vocalization rate on the social system of the chimpanzees. PMID- 23751870 TI - Full-length human chromogranin-A cardioactivity: myocardial, coronary, and stimulus-induced processing evidence in normotensive and hypertensive male rat hearts. AB - Plasma chromogranin-A (CgA) concentrations correlate with severe cardiovascular diseases, whereas CgA-derived vasostatin-I and catestatin elicit cardiosuppression via an antiadrenergic/nitric oxide-cGMP mediated mechanism. Whether these phenomena are related is unknown. We here investigated whether and to what extent full-length CgA directly influences heart performance and may be subjected to stimulus-elicited intracardiac processing. Using normotensive and hypertensive rats, we evaluated the following: 1) direct myocardial and coronary effects of full-length CgA; 2) the signal-transduction pathway involved in its action mechanism; and 3) CgA intracardiac processing after beta-adrenergic [isoproterenol (Iso)]- and endothelin-1(ET-1)-dependent stimulation. The study was performed by using a Langendorff perfusion apparatus, Western blotting, affinity chromatography, and ELISA. We found that CgA (1-4 nM) dilated coronaries and induced negative inotropism and lusitropism, which disappeared at higher concentrations (10-16 nM). In spontaneously hypertensive rats (SHRs), negative inotropism and lusitropism were more potent than in young normotensive rats. We found that perfusion itself, Iso-, and endothelin-1 stimulation induced intracardiac CgA processing in low-molecular-weight fragments in young, Wistar Kyoto, and SHR rats. In young normotensive and adult hypertensive rats, CgA increased endothelial nitric oxide synthase phosphorylation and cGMP levels. Analysis of the perfusate from both Wistar rats and SHRs of untreated and treated (Iso) hearts revealed CgA absence. In conclusion, in normotensive and hypertensive rats, we evidenced the following: 1) full-length CgA directly affects myocardial and coronary function by AkT/nitric oxide synthase/nitric oxide/cGMP/protein kinase G pathway; and 2) the heart generates intracardiac CgA fragments in response to hemodynamic and excitatory challenges. For the first time at the cardiovascular level, our data provide a conceptual link between systemic and intracardiac actions of full-length CgA and its fragments, expanding the knowledge on the sympathochromaffin/CgA axis under normal and physiopathological conditions. PMID- 23751871 TI - FTO deficiency induces UCP-1 expression and mitochondrial uncoupling in adipocytes. AB - Variants in the fat mass- and obesity-associated (FTO) gene are associated with obesity and body fat mass in genome-wide association studies. However, the mechanism by which FTO predisposes individuals to obesity is not clear so far. First mechanistic evidence was shown in Fto-negative mice. These mice are resistant to obesity due to enhanced energy expenditure, whereas the mass of brown adipose tissue remains unchanged. We hypothesize that FTO is involved in the induction of white adipose tissue browning, which leads to mitochondrial uncoupling and increases energy expenditure. Uncoupling protein 1 (Ucp-1) was significantly higher expressed in both gonadal and inguinal adipose depots of Fto(-/-) compared with Fto(+/+) littermates accompanied by the appearance of multivacuolar, Ucp-1-positive adipocytes in these tissues. By using lentiviral short hairpin RNA constructs, we established FTO-deficient human preadipocytes and adipocytes and analyzed key metabolic processes. FTO-deficient adipocytes showed an adipogenic differentiation rate comparable with control cells but exhibited a reduced de novo lipogenesis despite unchanged glucose uptake. In agreement with the mouse data, FTO-deficient adipocytes exhibited 4-fold higher expression of UCP-1 in mitochondria compared with control cells. The up regulation of UCP-1 in FTO-deficient adipocytes resulted in enhanced mitochondrial uncoupling. We conclude that FTO deficiency leads to the induction of a brown adipocyte phenotype, thereby enhancing energy expenditure. Further understanding of the signaling pathway connecting FTO with UCP-1 expression might lead to new options for obesity and overweight treatment. PMID- 23751872 TI - Sustained adrenergic stimulation is required for the nuclear retention of TORC1 in male rat pinealocytes. AB - The process involved in relocation of the coactivator, transducer of regulated cAMP-regulated element-binding protein (TORC) to the cytoplasm, unlike its activation, is not well understood. Using cultured pineal cells prepared from male rats, we found that although both alpha- and beta-adrenergic stimulation could cause TORC1 dephosphorylation, only alpha-adrenergic stimulation was effective in the norepinephrine (NE)-mediated translocation of TORC1 into the nucleus. In contrast, blockade of either the alpha- or the beta-adrenergic receptor after NE stimulation was effective in causing the rephosphorylation and rapid relocation of TORC1 into the cytoplasm. Studies with phosphoprotein phosphatase (PP) inhibitors indicated that although both PP2A and PP2B could dephosphorylate TORC1, only PP2B could cause translocation into the nucleus. However, after NE stimulation, treatment with either PP2A or PP2B inhibitors could cause the rephosphorylation and cytoplasmic relocation of TORC1. These results indicate a requirement of continuous activation of both alpha- and beta adrenergic receptors as well as PP2A and PP2B activities for the nuclear retention of TORC1 during NE stimulation. Knockdown of salt-inducible kinase 1 (SIK1) had no effect on the phosphorylation or localization of TORC1. Although overexpressing SIK1 could induce TORC1 phosphorylation in the nucleus, it did not reduce TORC1 level in the nucleus, indicating that SIK1-mediated TORC1 phosphorylation may not be sufficient for its relocation into the cytoplasm. Together, these results demonstrate that, in the rat pineal gland, different mechanisms are involved in regulating the nuclear entry and exit of TORC1 and that the SIK1-mediated phosphorylation of TORC1 may not lead to its nuclear exit. PMID- 23751873 TI - Metabolic programming of puberty: sexually dimorphic responses to early nutritional challenges. AB - Body energy stores and metabolic cues influence the onset of puberty. However, the pubertal impact of early nutritional challenges has been only fragmentarily addressed. We evaluated here the consequences, in terms of pubertal timing and hormonal markers, of various nutritional manipulations during pre- or postnatal maturation in rats of both sexes. Males and females were submitted to gestational undernutrition (UNG) or peripubertal (SUB) subnutrition or were raised in large (LL; underfeeding) or small (SL; overfeeding) litters. In addition, groups of UNG, LL, and SL rats were fed on a high-fat diet (HFD) after weaning. Postnatal overfeeding resulted in higher body weights (BWs) during pubertal transition in both sexes, but only SL males displayed overtly advanced external signs of puberty. Postnatal underfeeding persistently decreased BW gain during puberty, yet the magnitude of pubertal delay was greater in LL males. In contrast, regardless of postnatal nutrition, HFD tended to advance the onset of puberty in females but did not alter pubertal timing in males. Likewise, SUB females displayed a marked delay in BW gain and puberty onset, whereas despite similar reduction in BW, SUB males showed normal timing of puberty. These sex divergences were also detected in various hormonal and metabolic indices so that postnatal overnutrition consistently increased LH, FSH, leptin, and insulin levels only in pubertal females, whereas HFD decreased gonadotropin levels in SL females but increased them in SL males. Notably, UNG rats did not show signs of delayed puberty but displayed a striking sex dimorphism in serum insulin/glucose levels, regardless of the diet, so that only UNG males had signs of presumable insulin resistance. Our data disclose important sex differences in the impact of various early nutritional challenges on the timing of puberty, which may help to explain the different trends of altered puberty and related comorbidities between sexes. PMID- 23751874 TI - Molecular characterization and transcriptional regulation of a disintegrin and metalloproteinase with thrombospondin motif 1 (ADAMTS1) in bovine preovulatory follicles. AB - The ovulatory process involves a complex remodeling of the extracellular matrix during which a desintegrin and metalloproteinase with thrombospondin motif 1 (ADAMTS1) is thought to play a key role, but its transcriptional regulation in bovine follicles remains largely unknown. The objectives of this study were to characterize the regulation of ADAMTS1 in bovine follicles before ovulation and to determine its transcriptional control in bovine granulosa cells. Regulation of ADAMTS1 was assessed using total RNA isolated from bovine preovulatory follicles obtained at various times after human chorionic gonadotropin treatment. Results from RT-PCR analyses showed that levels of ADAMTS1 mRNA were very low at 0 hours but increased at 6 to 24 hours after human chorionic gonadotropin in granulosa cells. To determine the regulatory mechanisms controlling ADAMTS1 gene expression in vitro, primary cultures of bovine granulosa cells were established, and treatment with forskolin up-regulated ADAMTS1 mRNA levels. Promoter activity assays, 5'-deletion, and site-directed mutagenesis identified a minimal region conferring full-length basal and forskolin-stimulated ADAMTS1 promoter activities, with both being dependent on Ebox cis-acting elements. EMSAs revealed upstream stimulating factor (USF) proteins as key trans-activating factors interacting with Ebox. Chromatin immunoprecipitation assays confirmed such interactions between USF and Ebox in vivo, and USF binding to Ebox elements was increased by forskolin treatment. ADAMTS1 promoter activity and mRNA expression were increased by forskolin and overexpression of the catalytic subunit of protein kinase A, but not by cotreatment with inhibitors of protein kinase A, ERK1/2, and epidermal growth factor receptor signaling pathways. Furthermore, treatment with a soluble epidermal growth factor induced ADAMTS1 mRNA expression in granulosa cells. Collectively, results from this study describe the gonadotropin/forskolin-dependent up-regulation of ADAMTS1 mRNA in granulosa cells of bovine preovulatory follicles in vivo and in vitro and identify for the first time some of the molecular mechanisms responsible for ADAMTS1 promoter activation in follicular cells of a large monoovulatory species. PMID- 23751875 TI - Teasaponin reduces inflammation and central leptin resistance in diet-induced obese male mice. AB - Chronic inflammation is involved in the pathogenesis of obesity and type 2 diabetes. Recently teasaponin, an extract from tea, has been shown to have antiinflammatory effects. We examined the effect of teasaponin on obesity, inflammation, glucose metabolism, and central leptin sensitivity in obese mice fed a high-fat (HF) diet for 16 weeks. Intraperitoneal injections of teasaponin (10 mg/kg, daily) for 21 days significantly decreased the food intake and body weight of HF diet-induced obese mice. Teasaponin treatment also reduced the protein levels of proinflammatory cytokines (TNF-alpha, IL-6, and/or IL-1beta) and nuclear factor-kappaB signaling (phosphorylated inhibitory-kappaB kinase and phosphorylated inhibitory-kappaBalpha) in adipose tissue and the liver. The antiinflammatory effects of teasaponin were associated with improved glycemic status in the treated animals, evidenced by improved glucose tolerance, homeostasis model assessment, and fasting plasma insulin. In the hypothalamus, teasaponin decreased both proinflammatory cytokines and inflammatory signaling in the mediobasal hypothalamus. Teasaponin treatment also enhanced the anorexigenic effect of central leptin administration, restored leptin phosphorylated signal transducer and activator of transcription-3 (p-STAT3) signaling in the arcuate nucleus, and increased hypothalamic expression of the anorexigenic peptide proopiomelanocortin. These results identify a potential novel application for teasaponin as an antiobesity and antiinflammatory agent. PMID- 23751877 TI - Developmental programming of offspring obesity, adipogenesis, and appetite. AB - A newly recognized primary cause of the obesity epidemic is the developmental programming effects of infants born to mothers with obesity or gestational diabetes, intrauterine growth-restricted newborns, and offspring exposed to environmental toxins including bisphenol A. The mechanisms which result in offspring obesity include the programming of the hypothalamic appetite pathway and adipogenic signals regulating lipogenesis. Processes include nutrient sensors, epigenetic modifications, and alterations in stem cell precursors of both appetite/satiety neurons and adipocytes which are modulated to potentiate offspring obesity. Future strategies for the prevention and therapy of obesity must address programming effects of the early life environment. PMID- 23751876 TI - Molecular differences between human thyroid follicular adenoma and carcinoma revealed by analysis of a murine model of thyroid cancer. AB - Mouse models can provide useful information to understand molecular mechanisms of human tumorigenesis. In this study, the conditional thyroid mutagenesis of Pten and Ras genes in the mouse, which induces very aggressive follicular carcinomas (FTCs), has been used to identify genes differentially expressed among human normal thyroid tissue (NT), follicular adenoma (FA), and FTC. Global gene expression of mouse FTC was compared with that of mouse normal thyroids: 911 genes were found deregulated +/- 2-fold in FTC samples. Then the expression of 45 deregulated genes in mouse tumors was investigated by quantitative RT-PCR in a first cohort of human NT, FA, and FTC (discovery group). Five genes were found significantly down-regulated in FA and FTC compared with NT. However, 17 genes were found differentially expressed between FA and FTC: 5 and 12 genes were overexpressed and underexpressed in FTC vs FA, respectively. Finally, 7 gene products, selected from results obtained in the discovery group, were investigated in a second cohort of human tumors (validation group) by immunohistochemistry. Four proteins showed significant differences between FA and FTC (peroxisomal proliferator-activated receptor-gamma, serum deprivation response protein, osteoglycin, and dipeptidase 1). Altogether our data indicate that the establishment of an enriched panel of molecular biomarkers using data coming from mouse thyroid tumors and validated in human specimens may help to set up a more valid platform to further improve diagnosis and prognosis of thyroid malignancies. PMID- 23751878 TI - Epigenetic basis for the development of depression in children. AB - The growing field of epigenetics and human behavior affords an unprecedented opportunity to discover molecular underpinnings of mental health disorders and pave the way for the development of preventive intervention programs. Maternal depression during pregnancy is a serious public health issue and leads to a 4 fold increase in the likelihood that the child will develop depression. We describe how mood disorders, particularly depression, may be shaped by early life stress, programming, and epigenetic processes and pathways showing how these processes could lead to depression in childhood. Implications of this approach to the study of mental health disorders for preventive interventions are discussed. PMID- 23751879 TI - The nocturnal use of complete dentures and sleep stability in edentulous elders. AB - OBJECTIVE: To evaluate the stability of sleep quality and the impact of nocturnal use of complete dentures on sleep quality in an elderly edentulous population over a one-year period. MATERIALS AND METHODS: Written informed consent was obtained from 172 edentulous elders who agreed to enrol in a longitudinal cohort study. A total of 153 participants completed the follow-up after one year. Perceived quality of sleep and daytime sleepiness were measured using the Pittsburgh Sleep Quality Index (PSQI, score 0-21) and the Epworth Sleepiness Scale (ESS, score 0-24) at baseline (T0) and at follow-up (T1). Data on oral health related quality of life, type of mandibular dentures (conventional versus implant-retained mandibular overdenture), nocturnal wear of the dentures and socio-demographic status were obtained by means of the OHIP-20 questionnaire, a clinical examination form and a socio-demographic questionnaire. RESULTS: No statistically significant differences were detected in the global PSQI mean scores and EES mean scores from baseline (PSQI 4.77 +/- 3.32; EES 5.35 +/- 3.72) to the follow-up assessment (PSQ1 5.04 +/- 3.50; EES 5.53 +/- 4.34). Edentate elders wearing prostheses at night had poorer daytime sleepiness scores than those who removed their prostheses at night (p=0.003 unadjusted model; p=0.058 adjusted for age, gender, type of prosthesis and the OHIP-20 total score). CONCLUSION: Results of this study suggest that wearing complete dentures while sleeping has little effect on sleep quality or daytime sleepiness. PMID- 23751880 TI - Magnetic domain pattern in hierarchically twinned epitaxial Ni-Mn-Ga films. AB - Magnetic shape memory alloys exhibit a hierarchically twinned microstructure, which has been examined thoroughly in epitaxial Ni-Mn-Ga films. Here we analyze the consequences of this 'twin within twins' microstructure on the magnetic domain pattern. Atomic and magnetic force microscopy are used to probe the correlation between the martensitic microstructure and magnetic domains. We examine the consequences of different twin boundary orientations with respect to the substrate normal as well as variant boundaries between differently aligned twinned laminates. A detailed micromagnetic analysis is given which describes the influence of the finite film thickness on the formation of magnetic band domains in these multiferroic materials. PMID- 23751881 TI - [Arthritis due to Paracoccus yeei]. PMID- 23751882 TI - Chlorinated compounds and polybrominated diphenyl ethers (PBDEs) in mussels (Mytilus galloprovincialis) collected from Apulia Region coasts. AB - This project was carried out to assess the levels and spatial distribution of organochlorine compounds in the coastal marine environment, using mussels as bioindicators to evaluate the coastal water quality. Levels of polychlorobiphenils (PCB), chlorinated pesticides (DDT isomers, HCH isomers, Aldrin, Dieldrin, alfa-Endosulfan, Hexachlorobenzene, Pentachlorobenzene) and polybrominated diphenyl ethers (PBDEs) were determined in tissues from mussels (Mytilus galloprovincialis) collected along the Apulia Region coasts (Mediterranean Sea). Results indicate that contamination by organochlorine compounds is higher in mussels sampled in the Ionian Sea than in those from the Adriatic Sea, with PCB levels up to seven times higher in mussels from Ionian than from the Adriatic Sea. Although PCB levels were above the maximum values indicated by both European Community (EC) and National regulation in several sample sites, the PCB concentrations were particularly high in some stations, suggesting that these locations require a much specific attention. Conversely, results on the mussel contamination by PBDEs highlight their ubiquitous environmental distribution, and underline the need to establish the maximum level for these compounds in foodstuff, according to European Regulations. PMID- 23751883 TI - ART do not increase the risk of Y-chromosome microdeletion in 19 candidate genes at AZF regions. AB - Y-chromosome microdeletions (YCMs) have been found at a much higher rate in infertile men than fertile controls. A specific deletion in the azoospermia factor locus (AZF) at Yq11 is significantly associated with male infertility. Whether assisted reproductive technology (ART) increases the risk of YCM in ART derived offspring remains unclear. In this study the occurrence of YCM in 199 fathers and their 228 sons (Chinese, Han ethnicity), including 85 offspring conceived by IVF, 73 by intra-cytoplasmic sperm injection (ICSI) and 70 by natural conception, was investigated. Nineteen candidate genes related to YCM were analysed by multiplex ligation-dependent probe amplification. We identified one de novo YCM from 70 naturally-conceived offspring and none from 158 ART conceived offspring and found no statistical significance between these two groups. There was no statistically-significant difference in the detection rate of the father's Y-chromosome microdeletion group: IVF 10.7% (8/75), ICSI 3.2% (2/63), natural conception 8.2% (5/61). These results suggest that ART does not increase the risk of YCM in male offspring. PMID- 23751884 TI - Childhood feeding difficulties: a randomized controlled trial of a group-based parenting intervention. AB - BACKGROUND: Difficulty with feeding is common during early childhood. Behavioral techniques have shown considerable utility for difficult feeding, although large scale studies of behavioral parenting interventions with typically developing young children, and in group formats, are limited. OBJECTIVE: The current study aimed to evaluate the efficacy of a group-based, behavioral family intervention for typically developing healthy children with problem eating via a fully randomized 2-group design. METHODS: : Ninety-six families of children aged 1.5 to 6 years with feeding difficulties participated in a trial of Hassle Free Mealtimes Triple P (A. Morawska and M.R. Sanders, unpublished data, 2008) in regional and metropolitan Queensland (Australia). RESULTS: Results support the utility of a group-based behavioral parenting program for childhood feeding issues, with significant improvements to the mealtime and general behavior of target children, the mealtime and general practices of parents, parental confidence and cognitions, compared with a waitlist control. Six-month follow-up data and clinical and reliable change indices support the intervention's utility. Parents were also highly satisfied with the program. CONCLUSION: The current study provides evidence of the efficacy of a group-based behavioral family intervention for mealtime difficulties, including observational and more extended outcome measures. Future directions and clinical implications of this research are discussed. PMID- 23751885 TI - Pathways from maternal distress and child problem behavior to adolescent depressive symptoms: a prospective examination from early childhood to adolescence. AB - OBJECTIVE: The main aim of this study was to identify the pathways from maternal distress and child problem behaviors (i.e., internalizing and externalizing problems) across childhood and their impact on depressive symptoms during adolescence among girls and boys. METHOD: Data from families of 921 Norwegian children in a 15-year longitudinal community sample were used. Using structural equation modeling, the authors explored the interplay between maternal-reported distress and child problem behaviors measured at 5 time points from early (ages 1.5, 2.5, and 4.5 years) and middle (age 8.5 years) childhood to early adolescence (age 12.5 years), and their prediction of self-reported depressive symptoms during adolescence (ages 14.5 and 16.5 years). RESULTS: The findings revealed paths from internalizing and externalizing problems throughout the development for corresponding problems (homotypic paths) and paths from early externalizing to subsequent internalizing problems (heterotypic paths). The findings suggest 2 pathways linking maternal-rated risk factors to self-reported adolescent depressive symptoms. There was a direct path from early externalizing problems to depressive symptoms. There was an indirect path from early maternal distress going through child problem behavior to depressive symptoms. In general, girls and boys were similar, but some gender-specific effects appeared. Problem behaviors in middle childhood had heterotypic paths to subsequent problems only for girls. CONCLUSION: The findings highlight the developmental importance of child externalizing problems, as well as the impact of maternal distress as early as age 1.5 years for the development of adolescent depressive symptoms. Findings also indicate a certain vulnerable period in middle childhood for girls. NOTE: See Supplemental Digital Content 1, at http://links.lww.com/JDBP/A45, for a video introduction to this article. PMID- 23751887 TI - Pediatric response to court-mandated Medicaid behavioral screening in Massachusetts. AB - OBJECTIVE: In 2007 in Massachusetts, a settlement of a class-action lawsuit on behalf of Medicaid beneficiaries mandated that primary care practices perform developmental, behavioral, and mental health screening using formal tools. The aim of this study was to assess perspectives from providers and practice staff about implementing developmental and mental health screening in response to the judicial ruling. METHODS: In this qualitative study, semistructured interviews were conducted with 18 physicians and staff from 11 pediatric and medicine pediatric primary care practices in Eastern Massachusetts between April 2009 and November 2010. Using an interview guide, data on barriers and facilitators to implementing developmental and mental health screening, how practices selected tools, and what processes or changes made screening routine were collected. Clinicians were asked how screening changed the quality and/or content of well child care visits. Interviews were transcribed and coded. Overarching themes were generated using thematic analysis. RESULTS: Participants were motivated to comply with the mandate, and most practices reported implementing routine screening for developmental and mental health problems over several months. Although certain aspects of screening were endorsed, many perceived that screening added little to quality of care, primarily because tools lacked sensitivity and specialty resources were too scarce to address concerns adequately. Practices' receptivity to change and physicians' sense of duty to comply facilitated implementation. No practice developed processes specifically to track and follow-up abnormal results. CONCLUSIONS: Implementation of mandated developmental and mental health screening could be facilitated by providing assistance with practice change, improving the quality of screening tools, and assuring adequate referral resources. PMID- 23751888 TI - Do politics affect prevalence? An overview and the case of cerebral palsy. AB - Many factors must be considered when assessing estimates of prevalence, including research methods and quality of the work by the research team. Broad social and political forces also influence estimates of prevalence, as seen in the case of autism and intellectual disability. Indeed, researchers themselves may be influenced by broader sociopolitical factors in ways that they do not recognize. To further explore the relationship of prevalence to sociopolitical factors, we reviewed the historical prevalence of cerebral palsy (CP) (as a proxy for physical disability) in the late 20th century. We hypothesized that increased awareness of physical impairments associated with the disability rights movement of the 1970s would increase the prevalence of CP, primarily because of changes in case definition. Although prevalence of CP did rise slightly in the 1980s, we conclude that this change is better explained by increased survival of low birth weight infants, which is only indirectly related to the disability rights movement. PMID- 23751886 TI - Maternal factors predicting cognitive and behavioral characteristics of children with fetal alcohol spectrum disorders. AB - OBJECTIVE: To provide an analysis of multiple predictors of cognitive and behavioral traits for children with fetal alcohol spectrum disorders (FASDs). METHOD: Multivariate correlation techniques were used with maternal and child data from epidemiologic studies in a community in South Africa. Data on 561 first grade children with fetal alcohol syndrome (FAS), partial FAS (PFAS), and not FASD and their mothers were analyzed by grouping 19 maternal variables into categories (physical, demographic, childbearing, and drinking) and used in structural equation models (SEMs) to assess correlates of child intelligence (verbal and nonverbal) and behavior. RESULTS: A first SEM using only 7 maternal alcohol use variables to predict cognitive/behavioral traits was statistically significant (B = 3.10, p < .05) but explained only 17.3% of the variance. The second model incorporated multiple maternal variables and was statistically significant explaining 55.3% of the variance. Significantly correlated with low intelligence and problem behavior were demographic (B = 3.83, p < .05) (low maternal education, low socioeconomic status [SES], and rural residence) and maternal physical characteristics (B = 2.70, p < .05) (short stature, small head circumference, and low weight). Childbearing history and alcohol use composites were not statistically significant in the final complex model and were overpowered by SES and maternal physical traits. CONCLUSIONS: Although other analytic techniques have amply demonstrated the negative effects of maternal drinking on intelligence and behavior, this highly controlled analysis of multiple maternal influences reveals that maternal demographics and physical traits make a significant enabling or disabling contribution to child functioning in FASD. PMID- 23751889 TI - "Media addiction" in a 10-year-old boy. AB - CASE: Bryan is a 10-year-old boy who is brought to his pediatrician by his parents with concerns about oppositional behaviors. Bryan's parents report that he has always been hyperactive and oppositional since a very young age. He has been previously diagnosed with attention-deficit hyperactivity disorder and has been treated with appropriate stimulant medications for several years; however, despite this, his parents feel increasingly unable to manage his difficult behaviors. He refuses to do chores or follow through with household routines. He refuses to go to bed at night. His family feels unable to take him to public places because he "climbs all over everything." At school, he acts up in class, is often disruptive, and requires close supervision by teachers. He was recently kicked off of the school bus. He has very few friends, and his parents state that other children do not enjoy to be around him. Bryan's parents also report that he is "obsessed" with electronics. He spends most his free time watching TV and movies and playing computer games. He has a television in his bedroom because otherwise he "monopolizes" the family television. The family also owns several portable electronic devices that he frequently uses. Bryan insists on watching TV during meals and even that the TV stays on in an adjacent room while showering. He gets up early each morning and turns on the television. He refuses to leave the house unless he can take a portable screen device with him. His parents admit to difficulty placing limits on this behavior because they feel it is the only way to keep his other behaviors under control. His mother explains "it is our only pacifier" and that attempts to place restrictions are met with explosive tantrums and have thus been short lived. These efforts have also been impeded due to the habits of his parents and older sibling, who also enjoy spending a significant amount of time watching television. PMID- 23751890 TI - Cancer and copy number variants in an autism diagnostic clinic. PMID- 23751891 TI - Fertility-sparing surgery for young women with early-stage epithelial ovarian cancer. AB - BACKGROUND/AIMS: To discuss the latest findings on oncologic and reproductive outcomes of fertility-sparing surgery in epithelial ovarian cancer (EOC) and to suggest proper indications for this treatment. METHODS: A search of Medline database was performed for articles dealing with fertility-sparing surgery for EOC published in the English literature between January 1, 1969, and October 1, 2012. RESULTS: To date, 918 patients with EOC underwent fertility-sparing surgery; 109 (11.9%) had disease recurrence and 48 (5.2%) died of disease. Retrospective studies suggest that fertility-sparing surgery may be safely performed in young women with a strong desire to preserve fertility and with nonclear cell histology, FIGO stage IA, IC and grade 1-2 disease or clear cell histology and FIGO stage IA disease. To date, 177 patients have succeeded in achieving 242 pregnancies, resulting in 214 term (88%) and 1 preterm (0.4%) births. Miscarriage rate was about 10% (25/242) and ectopic pregnancy rate was 0.8% (2/242) after fertility-sparing surgery. No congenital anomaly has been reported. CONCLUSIONS: Although randomized controlled trials have yet to be performed, many studies have suggested that fertility-sparing surgery is safe, with promising reproductive outcomes. Cautious selection of patients is important because of 5.2% mortality and 11% recurrence after this surgery. PMID- 23751892 TI - A ZMYM2-FGFR1 8p11 myeloproliferative neoplasm with a novel nonsense RUNX1 mutation and tumor lysis upon imatinib treatment. AB - The 8p11 myeloproliferative neoplasm (8p11 MPN) is a rare disorder that is molecularly characterized by fusions of diverse partners to the tyrosine kinase receptor gene FGFR1. It can rapidly transform to acute myeloid leukemia. Here we report on a case with a t(8;13)(p11.2;q12.1) ZMYM2-FGFR1 fusion, with massive tumor lysis upon tyrosine kinase inhibition with imatinib. Upon reevaluation, we detected trisomy 21 in addition to the translocation. Sequencing revealed a nonsense c.958C ->T RUNX1 mutation both at diagnosis and disease progression, resulting in a p.Arg320X carboxyl-terminal truncated RUNX1 protein. This is the first report on an 8p11 MPN with a trisomy 21 RUNX1 mutation. PMID- 23751895 TI - Tumor-induced host immunosuppression: special focus on CLL. AB - Malignant cells are able to suppress host immune responses in an effort to avoid immune detection in vivo. Tumor-induced immunosuppression can be achieved at the molecular, cellular, and/or physiological levels. Herein the contribution of immune-tolerant genes and regulatory cells to immunosuppression related to alterations of T-cells and antigen-presentation is reviewed. Furthermore, key advances in countering tumor-induced immunosuppression are described in reference to immune evasion mechanisms used by chronic lymphocytic leukemia (CLL) cells. Lastly, the challenges associated with targeting the tumor microenvironment coupled with the usefulness of immunomodulatory drugs are discussed. This review summarizes select immune evasion tactics orchestrated by the conversation between CLL cells and their microenvironment. PMID- 23751893 TI - Murine animal models for preclinical islet transplantation: No model fits all (research purposes). AB - Advances in islet transplantation research have led to remarkable improvements in the outcome in humans with type 1 diabetes. However, pitfalls, mainly linked both to early liver-specific inflammatory events and to pre-existing and transplant induced auto- and allo-specific adaptive immune responses, still remain. In this scenario research into pancreatic islet transplantation, essential to investigate new strategies to overcome open issues, needs very well-designed preclinical studies to obtain consistent and reliable results and select only promising strategies that may be translated into the clinical practice. This review discusses the main shortcomings of the mouse models currently used in islet transplantation research, outlining the main factors and variables to take into account for the design of new preclinical studies. Since several parameters concerning both the graft (i.e., islets) and the recipient (i.e., diabetic mice) may influence transplant outcome, we recommend considering several critical points in designing future bench-to-bedside islet transplantation research. PMID- 23751894 TI - Weight status in adolescence is associated with later life functional limitations. AB - OBJECTIVE: This study examines the relationship between weight status in adolescence and later life functional limitations. METHOD: We use the Wisconsin Longitudinal Study to characterize the relationship between standardized relative body mass ascertained from high school photograph portraits in 1957 and self reported functional imitations in 2004. RESULTS: Compared to individuals with normal body mass, those who were overweight in high school had poorer later life physical function, with observed gender differences. Women who were underweight in adolescence had better functioning in older adulthood than their normal weight counterparts. This relationship, however, was not found among men. CONCLUSIONS: These findings underscore the long-term consequences of being overweight in adolescence on the functional disadvantages conferred in late life. PMID- 23751896 TI - JNK activation is required for TNFalpha-induced apoptosis in human hepatocarcinoma cells. AB - BACKGROUND: A frequent distinctive feature of tumors, hepatocellular carcinomas included, is resistance to apoptosis induced by a variety of agents, among which the pleiotropic cytokine tumor necrosis factor-alpha (TNF). Compared to other cell types, hepatocytes and hepatoma-derived cell lines are poorly susceptible to TNF-induced apoptosis, which is largely ascribed to activation of the prosurvival transcription factor NF-kappaB and can be overcome by associating TNF to low doses of protein synthesis inhibitors or other drugs. AIMS: This study analyses the molecular mechanisms by which TNF, in combination with cycloheximide (CHX), induces apoptosis in human hepatoma-derived Huh7 cells, focusing on the role played by JNK. METHODS: Huh7 cell cultures were treated with TNF + CHX in the presence or in the absence of the pancaspase inhibitor zVADfmk or of the JNK inhibitor SP600125 as well as after suppression of JNK expression by RNAi. Apoptosis was assessed both by light microscopy and by flow cytometry, JNK and caspase activation by western blotting and/or enzymatic assay. RESULTS: TNF + CHX induced death of Huh7 cells involved JNK activation since it was partially prevented by suppressing JNK activity or expression. Moreover, apoptosis was significantly reduced also by zVADfmk, while SP600125 and zVADfmk combined totally abrogated cell death in an additive fashion. CONCLUSIONS: These results demonstrate a causal role for JNK and caspases in TNF+CHX-induced apoptosis of Huh7 human hepatoma cells. Therefore, strategies aimed at enhancing both pathways should provide a profitable basis to overcome the resistance of hepatocarcinoma cells to TNF-dependent apoptosis. PMID- 23751897 TI - Puerarin, isolated from Kudzu root (Willd.), attenuates hepatocellular cytotoxicity and regulates the GSK-3beta/NF-kappaB pathway for exerting the hepatoprotection against chronic alcohol-induced liver injury in rats. AB - Puerarin (PR) has been utilized as a phytomedicine to managing liver disease in China. Thus, this study aimed to evaluate the potential PR-mediated hepatoprotective role against chronic alcohol-induced liver injury in rats. The results indicated that serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and pro-inflammatory cytokines were significantly reduced following PR treatment, while the albumin (ALB) level was increased. Meanwhile, intrahepatic contents of alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH) were elevated. Pathological examination showed that alcohol-lesioned hepatocytes were mitigated through the PR treatment. In addition, the endogenous levels of glycogen synthase kinase-3beta (GSK-3beta) at the protein level and beta-catenin expression at the mRNA level were notably down regulated, whereas the tumor necrosis factor alpha (TNF-alpha) and nuclear factor kappa B (NF-kappaB) proteins in the liver tissue were effectively decreased following the PR treatment. Together, these findings demonstrate that PR mediates hepatoprotection against alcohol-induced liver injury. The mechanisms underlying the cytoprotective effects of PR are associated with inhibiting immunotoxicity in hepatocytes and regulating the GSK-3beta/NF-kappaB pathway, thereby maintaining metabolic homeostasis in the liver tissue. PMID- 23751898 TI - The origin of finches on Tristan da Cunha and Gough Island, central South Atlantic ocean. AB - The Nesospiza finches of the Tristan da Cunha archipelago and Rowettia goughensis from Gough Island, 380 km distant, are both derived from tanager-finches (Thraupidae) that colonized the islands by crossing more than 3000 km of ocean from South America. Sequences from two mitochondrial and four nuclear genes indicate that the Patagonian bridled finches Melanodera are the closest relatives of the South Atlantic finches. Melanodera typically was sister to Rowettia, although some genes linked it more closely to Nesospiza. There was no evidence that Rowettia and Nesospiza are sister taxa, suggesting that the South Atlantic finches evolved from separate colonization events, as apparently was the case for moorhens Gallinula spp. at the two island groups. Genetic divergence between the two island finch genera thus provides an estimate of the maximum period of time they have been present at the islands, some 3-5 million years. A brief review of colonization histories suggests that island hopping by passerine birds is infrequent among islands more than 100-200 km apart. PMID- 23751899 TI - Tension pneumocephalus and oxygen emboli from hydrogen peroxide irrigation. AB - Hydrogen peroxide irrigation is commonly utilised in neurosurgical and non neurosurgical procedures for its bacteriocidal and haemostatic effects, however it has been associated with devastating complications such as tension pneumocephalus, O2 embolism and even dysrhythmias. We report a patient who suffered hydrogen peroxide-related mortality due to widespread tension pneumocephalus and O2 emboli. PMID- 23751900 TI - No association between MspI allele of the ADRA2A polymorphism and ADHD: meta analysis of family-based studies. AB - There is evidence for a genetic contribution to attention-deficit hyperactivity disorder (ADHD), although no candidate genes have attained genome-wide significance to date. Given that the noradrenergic system has been implicated in ADHD, the gene for the alpha2-adrenergic receptor (ADRA2A) has been hypothesized to contribute to the pathogenesis of ADHD. The present investigation reports results from a meta-analysis of family-based studies that did not find a significant association between the MspI polymorphism of the ADRA2A gene and ADHD. PMID- 23751901 TI - Lower running performance and exacerbated fatigue in soccer played at 1600 m. AB - PURPOSE: This study investigated the decrement in running performance of elite soccer players competing at low altitude and time course for abatement of these decrements. METHODS: Twenty elite youth soccer players had their activity profile, in a sea-level (SL) and 2 altitude (Alt, 1600 m, d 4, and d 6) matches, measured with a global positioning system. Measures expressed in meters per minute of match time were total distance, low- and high-velocity running (LoVR, 0.01-4.16 m/s; HiVR, 4.17-10.0 m/s), and frequency of maximal accelerations (>2.78 m/s2). The peak and subsequent stanza for each measure were identified and a transient fatigue index calculated. Mean heart rate (HR) during the final minute of a submaximal running task (5 min, 11 km/h) was recorded at SL and for 10 d at Alt. Differences were determined between SL and Alt using percentage change and effect-size (ES) statistic with 90% confidence intervals. RESULTS: Mean HR almost certainly increased on d 1 (5.4%, ES 1.01 +/- 0.35) and remained probably elevated on both d 2 (ES 0.42 +/- 0.31) and d3 (ES 0.30 +/- 0.25), returning to baseline at d 5. Total distance was almost certainly lower than SL (ES -0.76 +/- 0.37) at d 4 and remained probably reduced on d 6 (ES -0.42 +/- 0.36). HiVR probably decreased at d 4 vs SL (-0.47 +/- 0.59), with no clear effect of altitude at d 6 (-0.08 +/- 0.41). Transient fatigue in matches was evident at SL and Alt, with a possibly greater decrement at Alt. CONCLUSION: Despite some physiological adaptation, match running performance of youth soccer players is compromised for at least 6 d at low altitude. PMID- 23751903 TI - Thrombocytopenia in an adult. PMID- 23751902 TI - Shared care obesity management in 3-10 year old children: 12 month outcomes of HopSCOTCH randomised trial. AB - OBJECTIVE: To determine whether general practice surveillance for childhood obesity, followed by obesity management across primary and tertiary care settings using a shared care model, improves body mass index and related outcomes in obese children aged 3-10 years. DESIGN: Randomised controlled trial. SETTING: 22 family practices (35 participating general practitioners) and a tertiary weight management service (three paediatricians, two dietitians) in Melbourne, Australia. PARTICIPANTS: Children aged 3-10 years with body mass index above the 95th centile recruited through their general practice between July 2009 and April 2010. INTERVENTION: Children were randomly allocated to one tertiary appointment followed by up to 11 general practice consultations over one year, supported by shared care, web based software (intervention) or "usual care" (control). Researchers collecting outcome measurements, but not participants, were blinded to group assignment. MAIN OUTCOME MEASURES: Children's body mass index z score (primary outcome), body fat percentage, waist circumference, physical activity, quality of diet, health related quality of life, self esteem, and body dissatisfaction and parents' body mass index (all 15 months post-enrolment). RESULTS: 118 (60 intervention, 56 control) children were recruited and 107 (91%) were retained and analysed (56 intervention, 51 control). All retained intervention children attended the tertiary appointment and their general practitioner for at least one (mean 3.5 (SD 2.5, range 1-11)) weight management consultation. At outcome, children in the two trial arms had similar body mass index (adjusted mean difference -0.1 (95% confidence interval -0.7 to 0.5; P=0.7)) and body mass index z score (-0.05 (-0.14 to 0.03); P=0.2). Similarly, no evidence was found of benefit or harm on any secondary outcome. Outcomes varied widely in the combined cohort (mean change in body mass index z score -0.20 (SD 0.25, range -0.97-0.47); 26% of children resolved from obese to overweight and 2% to normal weight. CONCLUSIONS: Although feasible, not harmful, and highly rated by both families and general practitioners, the shared care model of primary and tertiary care management did not lead to better body mass index or other outcomes for the intervention group compared with the control group. Improvements in body mass index in both groups highlight the value of untreated controls when determining efficacy. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12608000055303. PMID- 23751904 TI - Diabetic ketoacidosis: not always due to type 1 diabetes. PMID- 23751905 TI - Incretin therapy: should adverse consequences have been anticipated? PMID- 23751906 TI - Helping patients make sense of the risks of taking GLP-1 agonists. PMID- 23751907 TI - Pressure on public spending budgets likely to last seven more years. PMID- 23751908 TI - Incretins and risk of neoplasia. PMID- 23751909 TI - None of expected benefits of Labour's IT programme have been achieved, report says. PMID- 23751910 TI - Antihistamines and other prognostic factors for adverse outcome in hyperemesis gravidarum. AB - OBJECTIVE: The purpose of this study is to determine the frequency of adverse perinatal outcome in women with hyperemesis gravidarum and identify prognostic factors. STUDY DESIGN: This is a case-control study in which outcomes of first pregnancies were compared between 254 women with hyperemesis gravidarum treated with intravenous fluids and 308 controls. Prognostic factors were identified by comparing the clinical profile of patients with hyperemesis gravidarum with a normal and an adverse pregnancy outcome. Binary responses were analyzed using either a Chi-square or Fisher exact test and continuous responses were analyzed using a t-test. RESULTS: Women with hyperemesis gravidarum have over a 4-fold increased risk of poor outcome including preterm birth and lower birth weight (p<0.0001). Among maternal characteristics, only gestational hypertension had an influence on outcome (p<0.0001). Treatment as an outpatient and/or by alternative medicine (acupuncture/acupressure/Bowen massage) was associated with a positive outcome (p<0.0089). Poor outcomes were associated with early start of symptoms (p<0.019), and treatment with methylprednisolone (p<0.0217), promethazine (p<0.0386), and other antihistamines [diphenhydramine (Benadryl), dimenhydrinate (Gravol), doxylamine (Unisom), hydroxyzine (Vistaril/Atarax), doxylamine and pyridoxine (Diclectin/Bendectin)] (p<0.0151) independent of effectiveness. Among these medications, only the other antihistamines were prescribed independent of severity: they were effective in less than 20% of cases and were taken by almost 50% of patients with an adverse outcome. CONCLUSION: Poor outcomes are significantly greater in women with HG and are associated with gestational hypertension, early symptoms, and antihistamine use. Given these results, there is an urgent need to address the safety and effectiveness of medications containing antihistamines in women with severe nausea of pregnancy. PMID- 23751911 TI - Tbx20 promotes cardiomyocyte proliferation and persistence of fetal characteristics in adult mouse hearts. AB - While differentiated cardiomyocytes proliferate prior to birth, adult cardiomyocytes in mammals exhibit relatively little proliferative activity. The T box transcription factor Tbx20 is necessary and sufficient to promote prenatal cardiomyocyte proliferation, and Tbx20 also is required for adult cardiac homeostasis. The ability of Tbx20 to promote post-natal and adult cardiomyocyte proliferation was examined in mice with cardiomyocyte-specific Tbx20 gain-of function beginning in the fetal period. In adult hearts, increased Tbx20 expression promotes cardiomyocyte proliferation and results in increased numbers of small, cycling, mononucleated cardiomyocytes, marked by persistent expression of fetal contractile protein genes. In adult cardiomyocytes in vivo and in neonatal rat cardiomyocytes in culture, Tbx20 promotes the activation of BMP2/pSmad1/5/8 and PI3K/AKT/GSK3beta/beta-catenin signaling pathways concomitant with increased cell proliferation. Inhibition of PI3K/AKT/GSK3beta/beta-catenin signaling reduces, but does not eliminate, Tbx20-mediated increases in cell proliferation, providing evidence for parallel regulatory pathways downstream of BMP/Smad1/5/8 signaling in promoting cardiomyocyte proliferation after birth. Thus, Tbx20 overexpression beginning in the fetal period activates multiple cardiac proliferative pathways after birth and maintains adult cardiomyocytes in an immature state in vivo. PMID- 23751913 TI - Initial presentation of Brucella endocarditis in a previously healthy eighteen year-old young man. AB - Brucellosis is a reported endemic in the Middle East, Arabian Peninsula, South Asia, and Central and South America, with a high fatality rate of 80%. We present a case report of Brucella endocarditis in a young 18-year-old male who developed aortic and mitral vegetation, subaortic abscess and mitral leaflet perforation. He was started on antibiotics but his cardiac status rapidly deteriorated and eventually needed a double valve replacement. We would like to share our experience and the challenges we faced in managing this case, which is uncommon, especially in young adults. PMID- 23751912 TI - Lrrc10 is a novel cardiac-specific target gene of Nkx2-5 and GATA4. AB - Cardiac gene expression is precisely regulated and its perturbation causes developmental defects and heart disease. Leucine-rich repeat containing 10 (Lrrc10) is a cardiac-specific factor that is crucial for proper cardiac development and deletion of Lrrc10 in mice results in dilated cardiomyopathy. However, the mechanisms regulating Lrrc10 expression in cardiomyocytes remain unknown. Therefore, we set out to determine trans-acting factors and cis-elements critical for mediating Lrrc10 expression. We identify Lrrc10 as a transcriptional target of Nkx2-5 and GATA4. The Lrrc10 promoter region contains two highly conserved cardiac regulatory elements, which are functional in cardiomyocytes but not in fibroblasts. In vivo, Nkx2-5 and GATA4 endogenously occupy the proximal and distal cardiac regulatory elements of Lrrc10 in the heart. Moreover, embryonic hearts of Nkx2-5 knockout mice have dramatically reduced expression of Lrrc10. These data demonstrate the importance of Nkx2-5 and GATA4 in regulation of Lrrc10 expression in vivo. The proximal cardiac regulatory element located at around -200bp is synergistically activated by Nkx2-5 and GATA4 while the distal cardiac regulatory element present around -3kb requires SRF in addition to Nkx2-5 and GATA4 for synergistic activation. Mutational analyses identify a pair of adjacent Nkx2-5 and GATA binding sites within the proximal cardiac regulatory element that are necessary to induce expression of Lrrc10. In contrast, only the GATA site is functional in the distal regulatory element. Taken together, our data demonstrate that the transcription factors Nkx2-5 and GATA4 cooperatively regulate cardiac-specific expression of Lrrc10. PMID- 23751914 TI - Effect of beta and gamma neurofeedback on memory and intelligence in the elderly. AB - Recent research showed a correlation between cognitive decline and a decrease of EEG gamma activity. In the present double-blind randomized control study, we investigated whether gamma and beta neurofeedback protocols, that have been shown to modulate performance on cognitive control and memory in young adults, also leads to increased brain activity and cognitive performance in elderly. Twenty older adults either performed eight 30-min gamma neurofeedback session or beta neurofeedback session within a period of 21 days. Cognitive performance was determined before and after the training through an IQ and memory task and we added a subjective well-being questionnaire. Both neurofeedback training protocols resulted in a significant increase of the brain activity within each training session, suggesting that the aging brain is still trainable. However, we found no effects on cognitive performance or transfer of the feedback beyond the trainings. We discuss several possible reasons for the lack of training on rest measurements and cognition and ways to improve the feedback protocols for future studies. PMID- 23751915 TI - In search of objective components for sleep quality indexing in normal sleep. AB - The main goal of this study was to investigate to what extent polysomnographic (PSG) recordings of nocturnal human sleep can provide information about sleep quality in terms of correlation with a set of daytime measures. These measures were designed with the aim of comprising selected quality of night sleep and consist of subjective sleep quality ratings, neuropsychological tests and physiological parameters. First, a factor analysis model was applied to the large number of daytime measures of sleep quality in order to detect their latent structure. Secondly, in addition to the gold standard sleep staging method to arrive at variables about sleep architecture from PSG, we applied a recently developed continuous sleep representation by considering the probabilistic sleep model (PSM) describing the microstructure of sleep. Significant correlations between sleep architecture and daytime variables of sleep quality were found. Both the factor analysis and the PSM helped maximize the information about this relationship. PMID- 23751916 TI - Is increased blinking a form of blepharospasm? AB - OBJECTIVE: The aim of this study was to investigate whether increased blink rate (BR) is part of the clinical spectrum of primary blepharospasm (BSP). METHODS: We enrolled 40 patients (16 patients with an increased BR but without typical orbicularis oculi [OO] spasms, and 24 patients with typical involuntary OO spasms) and 18 healthy subjects. The BR, blink reflex recovery cycle, and somatosensory temporal discrimination threshold (STDT) were tested in patients and controls. RESULTS: Patients who had typical OO spasms had an altered R2 recovery cycle whereas those who had an increased BR alone had a normal blink reflex recovery cycle. STDT values were higher in patients than in healthy subjects and no difference was found in the STDT abnormalities in the 2 groups of patients. CONCLUSIONS: Our study shows that, despite the similar STDT abnormalities, the different changes in the R2 recovery cycle in patients with BSP and those with increased BR alone suggest that these disorders arise from different pathologic mechanisms. PMID- 23751917 TI - Meeting the challenges of stroke in India. AB - Worldwide, cerebrovascular diseases are responsible for 6.15 million deaths (10.8% of all deaths)(1) and are the second most common cause of mortality; 87% of stroke deaths occur in low or middle income countries.(2) With the world's second largest population, India is witnessing several adverse trends for the cardiovascular health of its population, including a rapid rise in the proportion of patients with diabetes and dyslipidemia, and the relative lack of exercise among the general population. India has the world's largest population of patients with diabetes, with over 62 million people with diabetes in 2011.(3) At the current time, the population in India is projected to have over 1 million strokes per year. This figure will surely rise in the coming decades due to longer life expectancy and the downstream influence of risk factors such as diabetes. PMID- 23751918 TI - Neurology in a globalizing world: World Congress of Neurology, Vienna, 2013. AB - The World Congress of Neurology (figure 1) theme "Neurology in a Globalizing World" acknowledges that science and increasingly medicine and neurology are becoming globalized. The best way to manage change is to shape it. It is becoming increasingly clear that brain diseases, particularly stroke and dementia, are projected to rise at a rate that could overwhelm our clinics and hospitals. Hence a new emphasis on prevention and the need to work across disciplines beyond our traditional roles. Neurologists are the guardians of the brain and need to take the lead role in advancing new approaches in stemming the tide of neurologic diseases. PMID- 23751920 TI - Unmasking a subarachnoid hemorrhage. PMID- 23751919 TI - Management of carotid stenosis in women: consensus document. AB - OBJECTIVE: Specific guidelines for management of cerebrovascular risk in women are currently lacking. This study aims to provide a consensus expert opinion to help make clinical decisions in women with carotid stenosis. METHODS: Proposals for the use of carotid endarterectomy (CEA), carotid stenting (CAS), and medical therapy for stroke prevention in women with carotid stenosis were provided by a group of 9 international experts with consensus method. RESULTS: Symptomatic women with severe carotid stenosis can be managed by CEA provided that the perioperative risk of the operators is low (<4%). Periprocedural stroke risks may be increased in symptomatic women if revascularization is performed by CAS; however, the choice of CAS vs CEA can be tailored in subgroups best fit for each procedure (e.g., women with restenosis or severe coronary disease, best suited for CAS; women with tortuous vessels or old age, best suited for CEA). There is currently limited evidence to consider medical therapy alone as the best choice for women with neurologically severe asymptomatic carotid stenosis, who should be best managed within randomized trials including a medical arm. Medical management and cardiovascular risk factor control must be implemented in all women with carotid stenosis in periprocedural period and lifelong regardless of whether or not intervention is planned. CONCLUSIONS: The suggestions provided in this article may constitute a decision-making basis for planning treatment of carotid stenosis in women. Most recommendations are of limited strength; however, it is unlikely that new robust data will emerge soon to induce relevant changes. PMID- 23751921 TI - Reliability and accuracy of skeletal muscle imaging in limb-girdle muscular dystrophies. PMID- 23751922 TI - Mystery case: frontal meningoencephalocele causing recurrent bacterial meningitis. PMID- 23751923 TI - Teaching video neuroimages: trapezius myotonia percussion sign in myotonic dystrophy type 2. PMID- 23751924 TI - Teaching NeuroImages: facial palsy due to arteriovenous malformation of the cheek. PMID- 23751925 TI - Environmental origins of congenital heart disease: the heart-placenta connection. AB - Although the mammalian embryo is well protected in the uterus, environmental chemicals, drugs, and maternal nutritional imbalances can interfere with regulatory pathways directing placental and embryonic development early in gestation. Embryonic cells are most susceptible to environmental influences during cellular specification and differentiation stages. Because biochemical differentiation precedes morphological outcome often by days, the period of susceptibility to environmental chemicals expectedly precedes visible morphogenic effects. The cellular mechanisms by which drugs and other environmental factors disrupt embryonic development and induce cardiac abnormalities have remained undefined. PMID- 23751926 TI - Fetal heart defects: potential and pitfalls of first-trimester detection. AB - Congenital heart defects (CHDs) are the leading cause of infant mortality due to birth defects. In the last 15 years, with the shift in screening for aneuploidies to the first trimester, extensive research has concentrated on early screening and detection of CHDs. Early detailed assessment of the fetal heart requires a high level of expertise in early anomaly scanning and fetal echocardiography. However, the detection of major CHDs at 11-13 weeks is influenced by their association with easily detectable markers, such as the nuchal translucency, ductus venosus blood flow and tricuspid regurgitation, and a policy decision as to the objectives of this scan and the allocation of resources necessary to achieve them. The use of transvaginal ultrasound and newer techniques are likely to improve the detection rate. However, the limitations of fetal echocardiography in the first trimester must be borne in mind, and follow-up at mid-gestational echocardiography is prudent in some cases. PMID- 23751927 TI - Comparison of visual field progression between relatively low and high intraocular pressure groups in normal tension glaucoma patients. AB - PURPOSE: To determine the risk factors of visual field (VF) progression in relatively low and high intraocular pressure (IOP) groups in normal tension glaucoma (NTG) patients and to compare progression rate of VF defects between the 2 groups. METHODS: Forty-nine eyes of 49 NTG patients with untreated IOP of <=15 mm Hg (group A) and 49 eyes of 49 NTG patients matched by age and baseline VF mean deviation (MD) who had untreated IOP of >15 mm Hg (group B) were included in this retrospective chart review study. All patients were followed >5 years. Risk factors for VF progression were evaluated using Cox proportional hazards models in each group, separately. Changes in VF indexes were compared between the 2 groups. RESULTS: Mean IOP and IOP fluctuation were significantly greater in group B than in group A (P<0.001 and P=0.016), whereas other factors did not differ between the groups. In multivariable analysis, VF progression was significantly associated with disc hemorrhage in group A (HR, 6.19; P=0.017) and mean IOP in group B (HR, 1.77; P=0.029). There was no significant difference between the groups in incidence of progression and in changes of MD, pattern SD, and VF index (P=0.942, 0.874, and 0.887, respectively). CONCLUSIONS: Although progression rate was similar, the risk factors for VF progression were different in the 2 groups. These findings may suggest that IOP-dependent and IOP-independent factors affect VF progression differently in the 2 groups. PMID- 23751928 TI - The effect of cross-link distributions in axially-ordered, cross-linked networks. AB - Cross-linking between the constituent chains of biopolymers has a marked effect on their materials' properties. In certain of these materials, such as fibrillar collagen, increases in cross-linking lead to an increase in the melting temperature. Fibrillar collagen is an axially-ordered network of cross-linked polymer chains exhibiting a broadened denaturation transition, which has been explained in terms of the successive denaturation with temperature of multiple species. We model axially-ordered, cross-linked materials as stiff chains with distinct arrangements of cross-link-forming sites. Simulations suggest that systems composed of chains with identical arrangements of cross-link-forming sites exhibit critical behavior. In contrast, systems composed of non-identical chains undergo a crossover. This model suggests that the arrangement of cross link-forming sites may contribute to the broadening of the denaturation transition in fibrillar collagen. PMID- 23751929 TI - Cost and effectiveness of therapy for wet age-related macular degeneration in routine clinical practice. AB - PURPOSE: Evaluation of the cost and effectiveness of therapy for patients with the wet form of age-related macular degeneration (AMD) in routine clinical practice. METHODS: A retrospective multicentre evaluation of changes in the best corrected visual acuity in applied kinds of therapy and a comparison with the cost of individual therapeutic procedures. RESULTS: An overall total of 788 eyes of 763 patients with an average age of 73.2 +/- 8.6 years was evaluated for a 1 year minimum period. In the ranibizumab and pegaptanib therapy groups, a reduction of 1.3 letters (p = 0.303) and 1.4 letters (p = 0.197) was found, respectively. In the group of photodynamic therapy (PDT) with verteporfin, a reduction of 5.2 letters was achieved (p < 0.001). Under the conditions of routine practice in the Czech Republic, the annual cost is highest (EUR 5,467.63/patient) in patients with pegaptanib therapy. The annual cost in patients with ranibizumab therapy is lower by EUR 1,220.16. The cost is nearly half (EUR 2,783.65) in the group treated with PDT with verteporfin. CONCLUSION: An initiation of AMD therapy by ranibizumab is cost-effective as compared to pegaptanib. Both ranibizumab and pegaptanib are significantly more efficient as compared to PDT with verteporfin. Therapy with ranibizumab and pegaptanib, as compared to PDT with verteporfin, prevents the loss of 1 line of vision on the ETDRS chart for EUR 1,225.98 and 2,286.18, respectively. PMID- 23751930 TI - The role of successful catheter ablation in patients with paroxysmal atrial fibrillation and prolonged sinus pauses: outcome during a 5-year follow-up. AB - AIMS: Although patients with paroxysmal atrial fibrillation (AF) and prolonged sinus pauses [tachycardia-bradycardia syndrome (TBS)] are generally treated by permanent pacemaker, catheter ablation has been reported to be a curative therapy for TBS without pacemaker implantation. The purpose of this study was to define the potential role of successful ablation in patients with TBS. METHODS AND RESULTS: Of 280 paroxysmal AF patients undergoing ablation, 37 TBS patients with both AF and symptomatic sinus pauses (age: 62 +/- 8 years; mean maximum pauses: 6 +/- 2 s) were analysed. During the 5.8 +/- 1.2 years (range: 5-8.7 years) follow up, both tachyarrhythmia and bradycardia were eliminated by a single procedure in 19 of 37 (51%) patients. Repeat procedures were performed in 14 of 18 patients with tachyarrhythmia recurrence (second: 12 and third: 2 patients). During the repeat procedure, 79% (45 of 57) of previously isolated pulmonary veins (PVs) were reconnected to the left atrium. Pulmonary vein tachycardia initiating the AF was found in 46% (17 of 37) and 43% (6 of 14) of patients during the initial and second procedure, respectively. Finally, 32 (86%) patients remained free from AF after the last procedure. Three patients (8%) required pacemaker implantation, one for the gradual progression of sinus dysfunction during a period of 6.5 years and the others for recurrence of TBS 3.5 and 5.5 years after ablation, respectively. CONCLUSION: Catheter ablation can eliminate both AF and prolonged sinus pauses in the majority of TBS patients. Nevertheless, such patients should be continuously followed-up, because gradual progression of sinus node dysfunction can occur after a long period of time. PMID- 23751931 TI - Radiological detection of extracapsular spread in head and neck squamous cell carcinoma (HNSCC) cervical metastases. AB - BACKGROUND: Extracapsular spread of cervical lymph nodes deteriorates the prognosis of patients with head and neck squamous cell carcinoma. Postoperative radiochemotherapy is superior to postoperative radiotherapy alone in patients with histologically proven extracapsular spread. If extracapsular spread can be detected preoperatively, patients may favor primary radiochemotherapy instead of primary surgery plus postoperative radiochemotherapy. METHODS: Computed tomography (CT) scans of nodal positive head and neck squamous cell carcinoma patients treated between 2008 and 2010 with comprehensive neck dissection as part of first line surgical treatment were retrospectively scanned for extracapsular spread by two blinded radiologists. If a positive lymph node was identified by the pathologist, CT scans were assessed for extracapsular spread retrospectively. CT criteria for Extracapsular spread were apparent fat and soft tissue infiltration or infiltration of sternocleidomastoid muscle, internal jugular vein or carotid artery. Radiologic judgment was compared with histological evidence of extracapsular spread and specificity and sensitivity of CT detection was calculated. RESULTS: Forty-nine patients with histologically proven positive lymph nodes (pN+) were included. Extracapsular spread was histologically proven in 17 cases; the number of all affected lymph nodes was not listed. Radiologist 1 found extracapsular spread in CT scans of 15/49 patients and radiologist 2 in 16/49 patients (Cohen's kappa=0.86; p<0.01). Sensitivity of radiologic extracapsular spread detection was 73% (95% confidential index (CI): 44.0-89.7%) and specificity 91% (75.0-98.0%). CONCLUSION: Extracapsular spread depicted on computed tomography using strict criteria has high specificity. PMID- 23751932 TI - Anatomic distribution of Neisseria gonorrhoeae, Chlamydia trachomatis and Mycoplasma genitalium infections in men who have sex with men. AB - BACKGROUND: New cases of gonorrhoea (Neisseria gonorrhoeae) and chlamydia (Chlamydia trachomatis) infections have been steadily increasing in Scandinavian countries over the last decade. There is a particular urgency in reducing new infections as isolation of multiple drug resistant strains of gonorrhoea is becoming more frequent. The aim of this study was to determine the prevalence and sites of infection of common sexually transmissible infections (STIs) in men who have sex with men (MSM). METHODS: We have performed a retrospective analysis of the three major STIs, gonorrhoea, chlamydia and Mycoplasma genitalium in urogenital, anorectal and oropharyngeal samples from MSM that attended two STI clinics in Oslo. RESULTS: One hundred and thirty-six men (6.0%) out of 2289 MSM tested were found to be positive for gonorrhoea using a porA gene targeted nucleic acid amplification test (NAAT). Of these, 106 (77.9%) would not have been identified through testing first-void urine alone. Two hundred and twenty eight (10.0%) patients from 2289 tested were found to be positive for chlamydia, 164 (71.9%) of which were identified through anorectal specimens. Ninety-one (5.1%) patients from 1778 tested were found to be positive for M. genitalium, with 65 (71.4%) identified through testing of anorectal specimens. CONCLUSIONS: Our results supports the European findings that the MSM population carries a high burden of STIs and that testing the anorectum and oropharynx will identify a significantly higher percentage of infected patients and reservoirs of STIs. PMID- 23751935 TI - Creatine kinase adenosine triphosphate and phosphocreatine energy supply in a single kindred of patients with hypertrophic cardiomyopathy. AB - A lethal and extensively characterized familial form of hypertrophic cardiomyopathy (HC) is due to a point mutation (Arg403Gln) in the cardiac beta myosin heavy chain gene. Although this is associated with abnormal energy metabolism and progression to heart failure in an animal model, in vivo cardiac energetics have not been characterized in patients with this mutation. Noninvasive phosphorus saturation transfer magnetic resonance spectroscopy was used to measure the adenosine triphosphate supplied by the creatine kinase (CK) reaction and phosphocreatine, the heart's primary energy reserve, in 9 of 10 patients from a single kindred with HC caused by the Arg403GIn mutation and 17 age-matched healthy controls. Systolic and diastolic function was assessed by echocardiography in all 10 patients with HC. The patients with HC had impairment of diastolic function and mild systolic dysfunction, when assessed using global systolic longitudinal strain. Myocardial phosphocreatine was significantly decreased by 24% in patients (7.1 +/- 2.3 MUmol/g) compared with the controls (9.4 +/- 1.2 MUmol/g; p = 0.003). The pseudo-first-order CK rate-constant was 26% lower (0.28 +/- 0.15 vs 0.38 +/- 0.07 s-1, p = 0.035) and the forward CK flux was 44% lower (2.0 +/- 1.4 vs 3.6 +/- 0.9 MUmol/g/s, p = 0.001) than in the controls. The contractile abnormalities did not correlate with the metabolic indexes. In conclusion, myocardial phosphocreatine and CK-ATP delivery are significantly reduced in patients with HC caused by the Arg403Gln mutation, akin to previous results from mice with the same mutation. A lack of a relation between energetic and contractile abnormalities suggests the former result from the sarcomeric mutation and not a late consequence of mechanical dysfunction. PMID- 23751937 TI - Aspirin, clopidogrel, and ticagrelor in acute coronary syndromes. AB - Dual antiplatelet therapy is the cornerstone in the management of patients with acute coronary syndromes (ACS). Ticagrelor, an oral, direct, reversibly binding, P2Y12 receptor antagonist, is approved for the prevention of atherothrombotic events in adult patients with ACS. In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor was associated with significant reductions in cardiovascular events, cardiovascular mortality, and all-cause mortality compared with clopidogrel. A subanalysis of PLATO trial data identified a geographic region interaction (p = 0.045), indicating reduced efficacy of ticagrelor versus clopidogrel in North American patients. This effect could be due to chance, but may be explained by an interaction of ticagrelor with high aspirin doses, which are commonly used in the United States. In patients taking low-dose maintenance aspirin, ticagrelor was more effective than clopidogrel in decreasing cardiovascular events regardless of the geographic region. A proposed hypothetical mechanism for the interaction between ticagrelor and higher aspirin dose is linked to the level of P2Y12 inhibition and the potential prothrombotic effects of high-dose aspirin through the suppression of prostacyclin. A review of data regarding aspirin use for secondary prevention of events in ACS demonstrated that low aspirin doses (75 to 160 mg/day) are consistently favored for short- and long-term use because of the lack of a dose-response relationship between increasing aspirin dose and improved efficacy, and a higher incidence of gastrointestinal bleeding with increasing aspirin dose. The use of low aspirin doses reflects good clinical practice and is encouraged in current guidelines. PMID- 23751936 TI - Transfemoral aortic valve implantation in patients with an annulus dimension suitable for either the Edwards valve or the CoreValve. AB - The aim of this study was to compare the outcomes of transcatheter aortic valve implantation using the Edwards SAPIEN valve and the Medtronic CoreValve in patients with annulus of intermediate size (20 to 25 mm). From October 2008 to April 2012, 662 consecutive patients who underwent transcatheter aortic valve implantation were studied at 2 French centers. After propensity score matching, a total of 192 patients with intermediate-sized aortic annulus who had received either Edwards (n = 96, mean age 82.4 +/- 7.9 years, 48% men, 61.9% receiving the 26-mm valve) or CoreValve (n = 96, mean age 82.5 +/- 7.7 years, 50% men, 64.6% receiving the 29-mm valve) prostheses through the transfemoral approach were studied. Adequate reduction in postprocedural mean pressure gradients was achieved with the Edwards valve and the CoreValve (10.9 +/- 4.7 vs 9.1 +/- 4.4 mm Hg, respectively, p <0.01). Major vascular complications (5.2% vs 3.1%, p = 0.36), device success (95.8% vs 93.8%, p = 0.52), and 30-day survival (90.6% vs 89.6%, p = 0.81) were similar. The incidence of postprocedural aortic regurgitation grade >=2/4 and new pacemaker implantation was more frequent in the CoreValve group (14.3% vs 35.5%, p <0.01, and 4.2% vs 18.8%, p <0.01, respectively). There was no significant difference in 1-year cumulative survival rates in the Edwards valve group compared with the CoreValve group (80.1 +/- 4.2% vs 75.6 +/- 4.9%, log-rank p = 0.31). In conclusion, in patients with annulus of intermediate size, similar device success and short-term and midterm outcomes were achieved with either of the valves, irrespective of the specific complications related to each valve. PMID- 23751938 TI - Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension (from the [ARIES] study 1 and 2 trials). AB - In translational models of pulmonary arterial hypertension (PAH), spironolactone improves cardiopulmonary hemodynamics by attenuating the adverse effects of hyperaldosteronism on endothelin type-B receptor function in pulmonary endothelial cells. This observation suggests that coupling spironolactone with inhibition of endothelin type-A receptor-mediated pulmonary vasoconstriction may be a useful treatment strategy for patients with PAH. We examined clinical data from patients randomized to placebo or the selective endothelin type-A receptor antagonist ambrisentan (10 mg/day) and in whom spironolactone use was reported during ARIES-1 and -2, which were randomized, double-blind, placebo-controlled trials assessing the effect of ambrisentan for 12 weeks on clinical outcome in PAH. From patients randomized to placebo (n = 132) or ambrisentan (n = 67), we identified concurrent spironolactone use in 21 (15.9%) and 10 (14.9%) patients, respectively. Compared with patients treated with ambrisentan alone (n = 57), therapy with ambrisentan + spironolactone improved change in 6-minute walk distance by 94% at week 12 (mean +/- SE, +38.2 +/- 8.1 vs +74.2 +/- 27.4 m, p = 0.11), improved plasma B-type natriuretic peptide concentration by 1.7-fold (p = 0.08), and resulted in a 90% relative increase in the number of patients improving >=1 World Health Organization functional class (p = 0.08). Progressive illness, PAH-associated hospitalizations, or death occurred as an end point for 5.3% of ambrisentan-treated patients; however, no patient treated with ambrisentan + spironolactone reached any of these end points. In conclusion, these pilot data suggest that coupling spironolactone and endothelin type-A receptor antagonism may be clinically beneficial in PAH. Prospective clinical trials are required to further characterize our findings. PMID- 23751939 TI - Accuracy and feasibility of simplified Doppler-based left ventricular ejection fraction. AB - Calculation of left ventricular (LV) ejection fraction (EF) by Doppler stroke volume and end-diastolic volume (EDV) derived from LV diastolic diameter (LVIDD) could be reliable and feasible in clinical practice. In subjects with a wide range of LV volumes and EFs, magnetic resonance imaging (MRI) was used to evaluate the accuracy of common formulas (Teichholz and Z method) to estimate EDV from LVIDD (EDVTeich; EDVZ) versus volumetric EDV. The accuracy of simplified Doppler-EF was tested in a separate study sample versus real-time 3-dimensional (RT3D) echocardiography and versus bidimensional Simpson's method. A new equation to calculate EDV from LVIDD was derived using MRI and tested in the RT3D echo samples. Feasibility of Doppler-EF was tested in a third sample of consecutive inpatients and outpatients. In the MRI sample, EDVTeich was greater whereas EDVZ was smaller than volumetric EDV (both p <0.01); however, a quadratic equation estimated EDV from LVIDD with accuracy (R2 = 0.97). In the echocardiographic sample, independent of severe segmental wall motion abnormalities, EDVTeich was greater whereas EDV using Simpson's method was smaller than RT3D EDV (all p <0.05); Doppler-EF using EDVTeich was lower compared with EF by Simpson's rule or by RT3D-EF (all p <0.01). However, RT3D-EF showed no differences compared with Doppler-EF when EDV was calculated by the novel MRI-derived equation. Feasibility was 95% for Doppler-EF and 72% using Simpson's method. In conclusion, equations estimating EDV from LVIDD affect the accuracy of simplified Doppler-EF. However, Doppler-based EF may be accurate and feasible even in the presence of LV contractile asynergy. PMID- 23751940 TI - Promising anti-growth effects of palladium(II) saccharinate complex of terpyridine by inducing apoptosis on transformed fibroblasts in vitro. AB - Fibrosarcoma is one of the fatal cancer types and there is still not satisfactory success in its treatment despite new drugs. Therefore, the search for a new compound has been going on. It is currently known that some palladium-based anti cancer compounds seem to have powerful apoptosis-inducing effects in cancer cells. For this purpose, a palladium(II)-saccharinate complex containing terpyridine which was synthesized by our research group was investigated in terms of its anti-tumor effects against mouse embryonic fibroblast NIH/3T3 (normal cell line) and rat embryonic fibroblast 5RP7 (H-ras transformed cell line) in vitro. The MTT and ATP viability assays were used to determine anti-growth/cytotoxic effects. Cytotoxic activity was confirmed by real time cytotoxicity analysis system. Flow cytometry analysis was further used to determine the mode of cell death (apoptosis/necrosis). Apoptosis was confirmed by triple-staining the cells with Hoechst 33342/PI/Calcein-AM triple and evaluated with fluorescence microscopy. It was found that the compound showed significant anti-growth activity by inducing apoptosis in a dose dependent manner. In conclusion, taking into account the cytotoxic activity of the compound at even relatively lower doses, in vivo experiments to elucidate its potential use for the treatment of fibrosarcoma are warranted. PMID- 23751941 TI - Repeated sprints, high-intensity interval training, small-sided games: theory and application to field sports. AB - Due to the broad spectrum of physical characteristics necessary for success in field sports, numerous training modalities have been used develop physical preparedness. Sports like rugby, basketball, lacrosse, and others require athletes to be not only strong and powerful but also aerobically fit and able to recover from high-intensity intermittent exercise. This provides coaches and sport scientists with a complex range of variables to consider when developing training programs. This can often lead to confusion and the misuse of training modalities, particularly in the development of aerobic and anaerobic conditioning. This review outlines the benefits and general adaptations to 3 commonly used and effective conditioning methods: high-intensity interval training, repeated-sprint training, and small-sided games. The goals and outcomes of these training methods are discussed, and practical implementations strategies for coaches and sport scientists are provided. PMID- 23751942 TI - Pachychoroid pigment epitheliopathy. AB - PURPOSE: To report nine cases of pachychoroid pigment epitheliopathy. METHODS: An observational case series of nine patients who underwent comprehensive ophthalmic examination, fundus photography, fundus autofluorescence, spectral-domain optical coherence tomography, and enhanced depth imaging optical coherence tomography. RESULTS: Eighteen eyes of 9 patients, aged 27 years to 89 years, were diagnosed with pachychoroid pigment epitheliopathy based on the characteristic funduscopic appearance of reduced fundus tessellation with overlying retinal pigment epithelial changes in one or both eyes, fundus autofluorescence abnormalities, and increased subfoveal choroidal thickness confirmed by enhanced depth imaging optical coherence tomography (mean, 460.2 MUm). The five older patients had been previously diagnosed with age-related macular degeneration, while the four younger subjects were referred for possible inflammatory chorioretinitis, pattern dystrophy, or nonspecific drusen. No subjects had a history of or subsequently developed subretinal fluid. CONCLUSION: Pachychoroid pigment epitheliopathy falls within a spectrum of diseases associated with choroidal thickening that includes central serous chorioretinopathy and polypoidal choroidal vasculopathy, and it should be suspected in eyes with a characteristic fundus appearance related to choroidal thickening and associated retinal pigment epithelial abnormalities but no history of subretinal fluid. Enhanced depth imaging optical coherence tomography confirming an abnormally thick choroid and characteristic retinal pigment epithelial changes on fundus autofluorescence support the diagnosis. Because these patients are frequently misdiagnosed, the recognition of pachychoroid pigment epitheliopathy may avoid unnecessary diagnostic testing and interventions. PMID- 23751943 TI - Role of posterior vitreous detachment on outcome of anti-vascular endothelial growth factor treatment in age-related macular degeneration. AB - PURPOSE: The aim of this study was to determine the effect of posterior vitreous detachment on outcome of anti-vascular endothelial growth factor injection. METHODS: Sixty-one eyes with age-related macular degeneration that had received intravitreal bevacizumab or ranibizumab injections were retrospectively reviewed. The vitreomacular interface was evaluated, and eyes were grouped according to the presence of posterior vitreous detachment (Group 1, n = 25) or vitreomacular adhesion (Group 2, n = 36). All patients received three loading doses of intravitreal anti-vascular endothelial growth factor injections at monthly intervals, and subsequently, pro re nata regimen was performed. Best-corrected visual acuity and central foveal thickness measurement at follow-up were evaluated. The development of posterior vitreous detachment during the follow-up was also reported. RESULTS: The best-corrected visual acuity changes at each visit compared with baseline were significantly better in Group 1 (P = 0.01, 0.02, 0.02, 0.009, 0.009, respectively at third, sixth, ninth, 12th month, and last visit). When best-corrected visual acuity was classified according to the change in visual acuity of 10 letters or more, the rate of improved or stable best-corrected visual acuity was greater in Group 1 (P = 0.02). During the follow up, 5 eyes (14.3%) developed posterior vitreous detachment. CONCLUSION: Vitreomacular adhesion seems to have an adverse effect on the visual prognosis of anti-vascular endothelial growth factor treatment for age-related macular degeneration. PMID- 23751944 TI - Potential pitfalls in measuring the thickness of small choroidal melanocytic tumors with ultrasonography. PMID- 23751945 TI - Long-shaft forceps for membrane peeling in highly myopic eyes. PMID- 23751946 TI - A methodological approach for deriving regional crop rotations as basis for the assessment of the impact of agricultural strategies using soil erosion as example. AB - Regarding increasing pressures by global societal and climate change, the assessment of the impact of land use and land management practices on land degradation and the related decrease in sustainable provision of ecosystem services gains increasing interest. Existing approaches to assess agricultural practices focus on the assessment of single crops or statistical data because spatially explicit information on practically applied crop rotations is mostly not available. This provokes considerable uncertainties in crop production models as regional specifics have to be neglected or cannot be considered in an appropriate way. In a case study in Saxony, we developed an approach to (i) derive representative regional crop rotations by combining different data sources and expert knowledge. This includes the integration of innovative crop sequences related to bio-energy production or organic farming and different soil tillage, soil management and soil protection techniques. Furthermore, (ii) we developed a regionalization approach for transferring crop rotations and related soil management strategies on the basis of statistical data and spatially explicit data taken from so called field blocks. These field blocks are the smallest spatial entity for which agricultural practices must be reported to apply for agricultural funding within the frame of the European Agricultural Fund for Rural Development (EAFRD) program. The information was finally integrated into the spatial decision support tool GISCAME to assess and visualize in spatially explicit manner the impact of alternative agricultural land use strategies on soil erosion risk and ecosystem services provision. Objective of this paper is to present the approach how to create spatially explicit information on agricultural management practices for a study area around Dresden, the capital of the German Federal State Saxony. PMID- 23751947 TI - Long-Range Gaze Tracking System for Large Movements. AB - In the vision-based remote gaze tracking systems, the most challenging topics are to allow natural movement of a user and to increase the working volume and distance of the system. Several eye gaze estimation methods considering the natural movement of a user have been proposed. However, their working volume and distance are narrow and close. In this paper, we propose a novel 2-D mapping based gaze estimation method that allows large-movement of user. Conventional 2-D mapping-based methods utilize mapping function between calibration points on the screen and pupil center corneal reflection (PCCR) vectors obtained in user calibration step. However, PCCR vectors and their associated mapping function are only valid at or near to the position where the user calibration is performed. The proposed movement mapping function, complementing the user's movement, estimates scale factors between two PCCR vector sets: one obtained at the user calibration position and another obtained at the new user position. The proposed system targets a longer range gaze tracking which operates from 1.4 to 3 m. A narrow-view camera mounted on a pan and tilt unit is used by the proposed system to capture high-resolution eye image, providing a wide and long working volume of about 100 cm * 40 cm * 100 cm. The experimental results show that the proposed method successfully compensated the poor performance due to user's large movement. Average angular error was 0.8 degrees and only 0.07 degrees of angular error was increased while the user moved around 81 cm. PMID- 23751948 TI - Head-free, remote eye-gaze detection system based on pupil-corneal reflection method with easy calibration using two stereo-calibrated video cameras. AB - We have developed a pupil-corneal reflection method-based gaze detection system, which allows large head movements and achieves easy gaze calibration. This system contains two optical systems consisting of components such as a camera and a near infrared light source attached to the camera. The light source has two concentric LED rings with different wavelengths. The inner and outer rings generate bright and dark pupil images, respectively. The pupils are detected from a difference image created by subtracting the bright and dark pupil images. The light source also generates the corneal reflection. The 3-D coordinates of the pupils are determined by the stereo matching method using two optical systems. The vector from the corneal reflection center to the pupil center in the camera image is determined as r. The angle between the line of sight and the line passing through the pupil center and the camera (light source) is denoted as theta. The relationship theta =k |r| is assumed, where k is a constant. The theory implies that head movement of the user is allowed and facilitates the gaze calibration procedure. In the automatic calibration method, k is automatically determined while the user looks around on the PC screen without fixating on any specific calibration target. In the one-point calibration method, the user is asked to fixate on one calibration target at the PC screen in order to correct the difference between the optical and visual axes. In the two-point calibration method, in order to correct the nonlinear relationship between theta and |r|, the user is asked to fixate on two targets. The experimental results show that the three proposed calibration methods improve the precision of gaze detection step by step. In addition, the average gaze error in the visual angle is less than 1 degrees for the seven head positions of the user. PMID- 23751949 TI - Long-term bilayer encapsulation performance of atomic layer deposited Al2O3 and Parylene C for biomedical implantable devices. AB - We present an encapsulation scheme that combines atomic layer deposited (ALD) Al2O3 and Parylene C for the encapsulation of implantable devices. The encapsulation performances of combining alumina and Parylene C was compared to individual layers of Parylene C or alumina and the bilayer coating had superior encapsulation properties. The alumina-Parylene coated interdigitated electrodes (IDEs) soaked in PBS for up to nine months at temperatures from 37 to 80 degrees C for accelerated lifetime testing. For 52-nm alumina and 6-MUm Parylene C, leakage current was ~20 pA at 5 VDC, and the impedance was about 3.5 MOmega at 1 kHz with a phase near -87 degrees from electrochemical impedance spectroscopy for samples soaked at 67 degrees C for equivalent lifetime of 72 months at 37 degrees C. The change of impedance during the whole soaking period (up to 70 months of equivalent soaking time at 37 degrees C) over 1 to 106 Hz was within 5%. The stability of impedance indicated almost no degradation of the encapsulation. Bias voltage effect was studied by continuously applying 5 VDC, and it reduced the lifetime of Parylene coating by ~75% while it showed no measurable effect on the bilayer coating. Lifetime of encapsulation of IDEs with topography generated by attaching a coil and surface mount device (SMD) capacitor was about half of that of planer IDEs. The stable long-term insulation impedance, low leakage current, and better lifetime under bias voltage and topography made this double-layer encapsulation very promising for chronic implantable devices. PMID- 23751950 TI - Noise Effects in Various Quantitative Susceptibility Mapping Methods. AB - Various regularization methods have been proposed for single-orientation quantitative susceptibility mapping (QSM), which is an ill-posed magnetic field to susceptibility source inverse problem. Noise amplification, a major issue in inverse problems, manifests as streaking artifacts and quantification errors in QSM and has not been comparatively evaluated in these algorithms. In this paper, various QSM methods were systematically categorized for noise analysis. Six representative QSM methods were selected from four categories: two non-Bayesian methods with alteration or approximation of the dipole kernel to overcome the ill conditioning; four Bayesian methods using a general mathematical prior or a specific physical structure prior to select a unique solution, and using a data fidelity term with or without noise weighting. The effects of noise in these QSM methods were evaluated by reconstruction errors in simulation and image quality in 50 consecutive human subjects. Bayesian QSM methods with noise weighting consistently reduced root mean squared errors in numerical simulations and increased image quality scores in the human brain images, when compared to non Bayesian methods and to corresponding Bayesian methods without noise weighting (p <= 0.001). In summary, noise effects in QSM can be reduced using Bayesian methods with proper noise weighting. PMID- 23751951 TI - Acquisition of DC component of biopotentials with body surface electrodes. AB - The dc component of biological sources is difficult to measure with body surface electrodes. This is due to the existence of an electrical polarization in the interface between the electrode and the electrolyte. A system to acquire a dc component of the biological origin is proposed by means of differentiating the polarization potential from the biological one. The acquisition system is comprised of an instrumentation amplifier, an integrated semiconductor analog switch, and ordinary silver/silver-chloride body surface electrodes. Biopotentials, electrooculograms from the eyes, were noninvasively recorded by the system with the analog switch which was inserted between the electrodes to make the two inputs electrically open following them being shorted. Asymptotes of a triple exponential function were subsequently extracted by regression model analysis on the output signals that were acquired immediately after the switch opened. One of the distinctive asymptotes of the function showed that the magnitude which corresponded to eye movements stayed stable as long as the eyes were fixed. Analysis of the time constants involved in the acquisition system elucidated that the asymptote was the biological origin. PMID- 23751952 TI - Assessing the Progression of Ventilator-Induced Lung Injury in Mice. AB - Patients with acute respiratory distress syndrome receiving mechanical ventilation typically experience repetitive closure (derecruitment) and subsequent reopening (recruitment) of airways and alveoli. This can lead, over time, to further ventilator-induced lung injury (VILI). Recruitment and derecruitment (R/D) thus reflect both the current level of lung injury and the risk for sustaining further injury. Accordingly, we investigated how the dynamics of R/D are altered as VILI develops following application of high tidal volume ventilation in initially healthy mice. R/D occurring on subsecond timescales was assessed from the shape of the pressure-volume ( PV) loop measured during a single large breath. R/D occurring on a timescale of minutes was evaluated via a derecruitability test in which we tracked the progressive increases in lung elastance occurring during periods of mechanical ventilation immediately following a recruitment maneuver. The degrees of R/D occurring on these different times scales were strongly correlated. To interpret these findings in quantitative terms, we developed a computational model of the lung in which changes in lung volume occurred both via R/D and distention of already open lung units. Fitting this model to measured PV loops indicates that VILI causes R/D both to increase and to occur at progressively higher pressures, and that the lung tissue that remains open during the breath becomes progressively more overdistended. We conclude that the dynamic PV loop in conjunction with our computational model can be used to assess the current injury state of the lung as well as its likelihood of sustaining further VILI. PMID- 23751953 TI - Anti-Xa activity supports using a simple dosing algorithm for tinzaparin for anticoagulation in hemodialysis. AB - BACKGROUND: Unfractionated heparin has been traditionally used for anticoagulation during hemodialysis (HD), but more recently low-molecular-weight heparin (LMWH) is being used as an alternative. Anti-Xa activity can be measured as a surrogate of LMWH efficacy. We present 52 patients treated with tinzaparin anticoagulation on HD, confirming that fixed dosing is safe and efficacious with sound pharmacodynamic reason in relation to anti-Xa profiling. METHODS: We undertook a prospective audit in a single dialysis unit. All patients were established on a simple anticoagulation protocol for at least 1 month prior to the audit. Blood anti-Xa activity was measured at time 0, 30, 60 and 120 min into and at the end of HD. Efficacy and safety data were collected on the study day and the two sessions before and after it. RESULTS: Fifty-two patients were included in the efficacy and safety analysis with 43 patients undergoing anti-Xa analysis (9 sampling errors). Using current consensus (an end-HD anti-Xa activity of <0.4 IU/ml), our fixed-dose protocol resulted in satisfactory safety in all patients tested. Of 260 HD sessions, 10 (4%) had reduced tinzaparin efficacy. During 105 dialysis sessions (21 patients) using an arteriovenous fistula, 4 patients had one episode of minor bleeding and there were 6 episodes (2 patients) of post-needle-compression time greater than 15 min. CONCLUSION: Tinzaparin administered thrice weekly as a fixed dose has good efficacy and is well tolerated as an anticoagulant during HD when used according to our protocol. PMID- 23751954 TI - Structure, dynamics, and specificity of endoglucanase D from Clostridium cellulovorans. AB - The enzymatic degradation of cellulose is a critical step in the biological conversion of plant biomass into an abundant renewable energy source. An understanding of the structural and dynamic features that cellulases utilize to bind a single strand of crystalline cellulose and hydrolyze the beta-1,4 glycosidic bonds of cellulose to produce fermentable sugars would greatly facilitate the engineering of improved cellulases for the large-scale conversion of plant biomass. Endoglucanase D (EngD) from Clostridium cellulovorans is a modular enzyme comprising an N-terminal catalytic domain and a C-terminal carbohydrate-binding module, which is attached via a flexible linker. Here, we present the 2.1-A-resolution crystal structures of full-length EngD with and without cellotriose bound, solution small-angle X-ray scattering (SAXS) studies of the full-length enzyme, the characterization of the active cleft glucose binding subsites, and substrate specificity of EngD on soluble and insoluble polymeric carbohydrates. SAXS data support a model in which the linker is flexible, allowing EngD to adopt an extended conformation in solution. The cellotriose-bound EngD structure revealed an extended active-site cleft that contains seven glucose-binding subsites, but unlike the majority of structurally determined endocellulases, the active-site cleft of EngD is partially enclosed by Trp162 and Tyr232. EngD variants, which lack Trp162, showed a significant reduction in activity and an alteration in the distribution of cellohexaose degradation products, suggesting that Trp162 plays a direct role in substrate binding. PMID- 23751955 TI - Outcomes of allogeneic hematopoietic cell transplantation in patients with dyskeratosis congenita. AB - We describe outcomes after allogeneic transplantation in 34 patients with dyskeratosis congenita who underwent transplantation between 1981 and 2009. The median age at transplantation was 13 years (range, 2 to 35). Approximately 50% of transplantations were from related donors. Bone marrow was the predominant source of stem cells (24 of 34). The day-28 probability of neutrophil recovery was 73% and the day-100 platelet recovery was 72%. The day-100 probability of grade II to IV acute GVHD and the 3-year probability of chronic graft-versus-host disease were 24% and 37%, respectively. The 10-year probability of survival was 30%; 14 patients were alive at last follow-up. Ten deaths occurred within 4 months from transplantation because of graft failure (n = 6) or other transplantation-related complications; 9 of these patients had undergone transplantation from mismatched related or from unrelated donors. Another 10 deaths occurred after 4 months; 6 of them occurred more than 5 years after transplantation, and 4 of these were attributed to pulmonary failure. Transplantation regimen intensity and transplantations from mismatched related or unrelated donors were associated with early mortality. Transplantation of grafts from HLA-matched siblings with cyclophosphamide-containing nonradiation regimens was associated with early low toxicity. Late mortality was attributed mainly to pulmonary complications and likely related to the underlying disease. PMID- 23751957 TI - OPG/RANK/RANKL axis as a potential therapeutic target for atrial fibrillation. PMID- 23751956 TI - Src-inducible association of CrkL with procaspase-8 promotes cell migration. AB - Procaspase-8, the zymogen form of the apoptosis-initiator caspase-8, undergoes phosphorylation following integrin-mediated cell attachment to an extracellular matrix substrate. Concordant with cell attachment to fibronectin, a population of procaspase-8 becomes associated with a peripheral insoluble compartment that includes focal complexes and lamellar microfilaments. Phosphorylation of procaspase-8 both impairs its maturation to the proapoptotic form and can promote cell migration. Here we show that the cytoskeletal adaptor protein CrkL promotes caspase-8 recruitment to the peripheral spreading edge of cells, and that the catalytic domain of caspase-8 directly interacts with the SH2 domain of CrkL. We show that the interaction is abolished by shRNA-mediated silencing of Src, in Src deficient MEFs, and by pharmacologic inhibitors of the kinase. The results provide insight into how tyrosine kinases may act to coordinate the suppression caspase-8 mediated apoptosis, while promoting cell invasion. PMID- 23751958 TI - Complex between human RNase HI and the phosphonate-DNA/RNA duplex: molecular dynamics study. AB - Our 200ns MD simulations show that even fully modified oligonucleotides bearing the 3'-O-P-CH2-O-5' (but not 3'-O-CH2-P-O-5') phosphonate linkages can be successfully attached to the surface of Human RNase H. It enables to explain that oligonucleotides consisting of the alternating 3'-O-P-CH2-O-5' phosphonate and phosphodiester linkages are capable to elicit the RNase H activity (while the 3' O-CH2-P-O-5' phosphonates are completely inactive). Stability of the binuclear active site of Human RNase H was achieved using the one-atom model for Mg(2+) in conjunction with a polarized phosphate group of the scissile bond, which is wedged between both magnesium ions. The reference MD simulation (lasting for 1000ns), which was produced using a well-established seven-point (with dummy atoms) model for Mg(2+) led to essentially the same results. The MD run (lasting for 500ns) produced for the Thermus thermophilus Argonaute enzyme shows the transferability of our approach for the stabilization of a binuclear active site. Glu512 was bound in the T. thermophilus Argonaute active site to the 2'-OH of the nucleotide adjacent to the scissile phosphate and one of the two active-site divalent metal ions in exactly the same way as Glu186 in Human RNase H. Glu512 thus completes the catalytic tetrad of Argonaute. PMID- 23751959 TI - Accelerating ordered subsets image reconstruction for X-ray CT using spatially nonuniform optimization transfer. AB - Statistical image reconstruction algorithms in X-ray computed tomography (CT) provide improved image quality for reduced dose levels but require substantial computation time. Iterative algorithms that converge in few iterations and that are amenable to massive parallelization are favorable in multiprocessor implementations. The separable quadratic surrogate (SQS) algorithm is desirable as it is simple and updates all voxels simultaneously. However, the standard SQS algorithm requires many iterations to converge. This paper proposes an extension of the SQS algorithm that leads to spatially nonuniform updates. The nonuniform (NU) SQS encourages larger step sizes for the voxels that are expected to change more between the current and the final image, accelerating convergence, while the derivation of NU-SQS guarantees monotonic descent. Ordered subsets (OS) algorithms can also accelerate SQS, provided suitable "subset balance" conditions hold. These conditions can fail in 3-D helical cone-beam CT due to incomplete sampling outside the axial region-of-interest (ROI). This paper proposes a modified OS algorithm that is more stable outside the ROI in helical CT. We use CT scans to demonstrate that the proposed NU-OS-SQS algorithm handles the helical geometry better than the conventional OS methods and "converges" in less than half the time of ordinary OS-SQS. PMID- 23751961 TI - Gait recognition using HMMs and dual discriminative observations for sub-dynamics analysis. AB - We propose a new gait recognition method that combines holistic and model-based features. Both types of features are extracted automatically from gait silhouette sequences and their combination takes place by means of a pair of hidden Markov models. In the proposed system, the holistic features are initially used for capturing general gait dynamics whereas, subsequently, the model-based features are deployed for capturing more detailed sub-dynamics by refining upon the preceding general dynamics. Furthermore, the holistic and model-based features are suitably processed in order to improve the discriminatory capacity of the final system. The experimental results show that the proposed method exhibits performance advantages in comparison with popular existing methods. PMID- 23751960 TI - Comparison of two multiplexed PCR assays for the detection of HSV-1, HSV-2, and VZV with extracted and unextracted cutaneous and mucosal specimens. AB - BACKGROUND: Several analyte specific reagents (ASRs) are available for the detection and differentiation of HSV-1, HSV-2, and VZV in clinical specimens. However, there is limited data on the test performance of these reagents used in multiplexed PCR assays. OBJECTIVE: This study compared the performance of two multiplexed ASR sets for detection of HSV-1, HSV-2, and VZV in dermal specimens. STUDY DESIGN: Two commercially available ASRs were combined to produce multiplexed PCR assays for simultaneous detection of HSV-1, HSV-2, and VZV. Seeded samples were used to determine the limit of detection (LOD) for each assay. Patient samples (n=156) were tested in duplicate and results for each method compared to the reference standard of culture. Both extracted and unextracted specimens were used in the study. RESULTS: Both multiplexed PCR assays showed similar test performance, with minimal LOD differences observed. The LOD was 10(3) copies/mL for HSV-1 and HSV-2 using the Focus assay compared to 5*10(3) copies/mL and 2*10(4) copies/mL, respectively for the EraGen assay. Both assays showed equal performance for VZV with a LOD of 5*10(3) copies/mL. Analytical specificity testing showed no cross reactivity with other selected DNA viruses. Both assays showed similar performance when clinical samples were tested using both extracted and unextracted specimens. CONCLUSION: Commercially available ASRs can be successfully multiplexed for the PCR detection of HSV-1, HSV-2, and VZV using dermal specimens. Either direct testing or nucleic acid extracted specimens can be used with similar performance in these assays. PMID- 23751962 TI - Sparse feature fidelity for perceptual image quality assessment. AB - The prediction of an image quality metric (IQM) should be consistent with subjective human evaluation. As the human visual system (HVS) is critical to visual perception, modeling of the HVS is regarded as the most suitable way to achieve perceptual quality predictions. Sparse coding that is equivalent to independent component analysis (ICA) can provide a very good description of the receptive fields of simple cells in the primary visual cortex, which is the most important part of the HVS. With this inspiration, a quality metric called sparse feature fidelity (SFF) is proposed for full-reference image quality assessment (IQA) on the basis of transformation of images into sparse representations in the primary visual cortex. The proposed method is based on the sparse features that are acquired by a feature detector, which is trained on samples of natural images by an ICA algorithm. In addition, two strategies are designed to simulate the properties of the visual perception: 1) visual attention and 2) visual threshold. The computation of SFF has two stages: training and fidelity computation, in addition, the fidelity computation consists of two components: feature similarity and luminance correlation. The feature similarity measures the structure differences between the two images, whereas the luminance correlation evaluates brightness distortions. SFF also reflects the chromatic properties of the HVS, and it is very effective for color IQA. The experimental results on five image databases show that SFF has a better performance in matching subjective ratings compared with the leading IQMs. PMID- 23751963 TI - Heart rate variability and functional outcome in ischemic stroke: a multiparameter approach. AB - BACKGROUND AND PURPOSE: Heart rate variability (HRV) as a measure of autonomic function might provide prognostic information in ischemic stroke. However, numerous difficulties are associated with HRV parameters assessment and interpretation, especially in short-term ECG recordings. For better understanding of derived HRV data and to avoid methodological bias we simultaneously recorded and analyzed heart rate, blood pressure and respiratory rate. METHODS: Seventy five ischemic stroke patients underwent short-term ECG recordings. Linear and nonlinear parameters of HRV as well as beat-to-beat blood pressure and respiratory rate were assessed and compared in patients with different functional neurological outcomes at 7th and 90th days. RESULTS: Values of Approximate, Sample and Fuzzy Entropy were significantly lower in patients with poor early neurological outcome. Patients with poor 90-day outcome had higher percentage of high frequency spectrum and normalized high frequency power, lower normalized low frequency power and lower low frequency/high frequency ratio. Low frequency/high frequency ratio correlated negatively with scores in the National Institutes of Health Stroke Scale and modified Rankin Scale (mRS) at the 7th and mRS at the 90th days. Mean RR interval, values of blood pressure as well as blood pressure variability did not differ between groups with good and poor outcomes. Respiratory frequency was significantly correlated with the functional neurological outcome at 7th and 90th days. CONCLUSION: While HRV assessed by linear methods seems to have long-term prognostic value, complexity measures of HRV reflect the impact of the neurological state on distinct, temporary properties of heart rate dynamic. Respiratory rate during the first days of the stroke is associated with early and long-term neurological outcome and should be further investigated as a potential risk factor. PMID- 23751964 TI - Twenty-four hour urinary urea excretion and 9-year risk of hypertension: the PREVEND study. AB - OBJECTIVES: It is not yet clear whether dietary protein could help maintaining a healthy blood pressure (BP). We investigated the association between total protein intake, estimated from 24-h urinary urea excretion, and incident hypertension in Dutch men and women. METHODS: We analyzed data of 3997 men and women (aged 28-75 years) who participated in the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, a prospective cohort study. Urea excretion was assessed in two consecutive 24-h urine collections at baseline and approximately 4 years later, from which total protein intake was estimated using the Maroni method. Participants were followed for 9 years for hypertension incidence, defined as BP at least 140/90 mmHg or initiation of antihypertensive medication. Hazard ratios (HR) were obtained in sex-specific quintiles of protein intake using time-dependent Cox regression, adjusted for age, sex, BMI, smoking, alcohol use, and 24-h urinary excretions of sodium and potassium. RESULTS: Baseline BP was on average 119/70 mmHg and 976 participants developed hypertension during follow-up. Mean protein intake (in g/kg ideal body weight) was 1.18 +/- 0.26 for men and 1.12 +/- 0.25 for women. Estimated protein intake was nonlinearly inversely associated with incident hypertension in the fully adjusted model, with nonsignificant HR of 0.77, 0.75, 0.82, and 0.83 in consecutive quintiles compared with the lowest quintile (P-trend: 0.52). CONCLUSION: Protein intake, as assessed by urinary urea excretion, was not significantly associated with 9-year hypertension incidence in Dutch men and women. PMID- 23751965 TI - Role of angiotensin AT2 receptors and nitric oxide in the cardiopulmonary baroreflex control of renal sympathetic nerve activity in rats. AB - OBJECTIVES: This study investigated the hypothesis that angiotensin II (type 2) (AT2) receptor activation to modulate the renal sympatho-inhibition to saline volume expansion was dependent on nitric oxide production. METHODS: Renal sympatho-inhibition to a saline volume expansion (VEP, 0.25% body weight/min i.v. for 30 min) was studied following intracerebroventricular (ICV) saline, CGP42112 (CGP, AT2 agonist), PD123319 (AT2 antagonist), and losartan (AT1 antagonist), and then in combination with N-nitro-L-arginine methyl ester (L-NAME) (nitric oxide synthase inhibitor). RESULTS: ICV saline, PD123319, CGP, and losartan did not change baseline mean arterial pressure, heart rate, or renal sympathetic nerve activity (RSNA). VEP decreased RSNA in all groups by 58-62% (P<0.05). CGP enhanced the decrease in RSNA compared to saline (74 vs. 60%; P<0.05), whereas PD123319 was without effect (58 vs. 57%). L-NAME only increased baseline RSNA when co-administered with PD123319 (P<0.05). VEP-induced reduction in RSNA following L-NAME was less than during ICV saline (46 vs. 62%; P<0.05). In the group where PD123319 preceded L-NAME, the fall in RSNA was smaller than when PD123319 was infused alone (40 vs. 63%; P<0.05), but not if PD123319 followed L NAME (52 vs. 44%). L-NAME did not change the magnitude of VEP-induced sympatho inhibition following CGP (67 vs. 60%). Losartan enhanced the renal sympatho inhibition to VEP (70 vs. 62%; P<0.05), the magnitude of which was unchanged when L-NAME was present (70 vs. 65%). CONCLUSION: AT2 receptor activation enhances the VEP-induced reduction in RSNA. Although nitric oxide is important in allowing the normal renal sympatho-inhibitory response to VEP, this is not dependent on AT2 receptors. PMID- 23751966 TI - Simulated growth trajectories and blood pressure in adolescence: Hong Kong's Chinese Birth Cohort. AB - BACKGROUND: Patterns and amounts of growth may determine adult blood pressure. Growth at different phases is correlated and affects current size, making effects on blood pressure difficult to distinguish. We decomposed growth to 13 years into independent associations with blood pressure and estimated how reaching the same size by different routes could affect adolescent blood pressure. METHODS: Using estimates from partial least squares for the associations of birth weight, height, and BMI at 3 months, growth at 3-9 months, 9-36 months, 3-8 years and 8 13 years and size at 13 years with SBP and DBP in 5247 term births (67% follow up) from Hong Kong's 'Children of 1997' Birth Cohort, we estimated SBP and DBP at 13 years for 99 simulated growth trajectories resulting in the same size using nonparametric bootstrapping. RESULTS: High birth weight followed by slower growth was associated with lower SBP in both sexes and DBP in boys. Greater height to 3 years followed by slower height growth was associated with lower SBP in boys. Higher BMI until 9 months followed by slower BMI growth was associated with lower blood pressure in boys. CONCLUSION: High birth weight or larger early size was associated with lower blood pressure if followed by slower later growth, consistent with the fetal origin hypothesis. However, whether these patterns are due to fetal and infant metabolic programming or to allowing slower growth at periods when rapid growth is harmful is unknown. PMID- 23751967 TI - Measures of carotid-femoral pulse wave velocity and augmentation index are not reliable in patients with abdominal aortic aneurysm. AB - BACKGROUND: Measures of carotid-femoral pulse wave velocity (cf-PWV) and carotid augmentation index (cAI) may be affected by the presence of an abdominal aortic aneurysm (AAA). We, therefore, investigated series of various measures of arterial stiffness and wave reflections in patients with AAA, before and 4 weeks after endovascular aneurysm repair (EVAR). METHODS: A total of 51 patients (75.2 +/- 11.6 years, 92.2% men) underwent EVAR for AAA and 51 controls with matched age, sex, SBP, and comorbidity were enrolled. Measures of aortic stiffness included cf-PWV by tonometry and brachial-ankle pulse wave velocity (ba-PWV) by plethysmography. Measures of wave reflections included cAI and the reflected pressure wave amplitude (Pb) from a decomposed carotid pressure wave. RESULTS: Patients with AAA had significantly lower cf-PWV (12.1 +/- 2.7 versus 13.6 +/- 3.5 m/s P=0.009), higher cAI (30.8 +/- 12.2 versus 23.1 +/- 23.3%, P=0.040) in comparison with controls. After EVAR for AAA, cf-PWV (14.4 +/- 3.8 ms) increased significantly (P<0.001), and cAI (24.4 +/- 14.5%) decreased significantly (P=0.004). In contrast, ba-PWV and Pb values were similar to those in controls and did not change significantly after EVAR. Furthermore, the heart rate and mean BP adjusted post-EVAR cf-PWV, ba-PWV, cAI, and Pb were similar to the corresponding values in controls. CONCLUSION: In patients with AAA, a lower cf PWV and a higher cAI are expected, which do not represent true degrees of arterial stiffness and wave reflections. EVAR may correct the impacts of AAA on cf-PWV and cAI. PMID- 23751968 TI - Guidelines and research upon which guidelines are founded. PMID- 23751969 TI - Progression of coronary artery calcification is associated with long-term cardiovascular events in hypertensive adults. AB - OBJECTIVES: Coronary artery calcification (CAC) is an independent predictor of cardiovascular (CV) events in hypertensive adults. However, the additive value of serial CAC measurements for risk stratification is unclear. The aim of the present study was to find whether CAC progression predicts long-term CV events in hypertensive patients. METHODS: The study group included 210 patients (mean age 64 +/- 5.6 years, 54% men), a subgroup of 544 participants in the calcification side arm of the INSIGHT (International Nifedipine Study Intervention as Goal for Hypertension Therapy). All were free of symptoms or known CV disease, had at least two CT scans 1 year apart, and had available long-term follow-up. Progression of CAC was defined as the absolute change in CAC score between maximal score during follow-up and baseline score. The endpoint was the first CV event after the last CT scan. Three categories of CAC progression were defined. Zero progression was defined as 'nonprogressors', and progression below and above the median of maximal progression were defined as 'slow progressors' and 'rapid progressors', respectively. RESULTS: During 15 years of follow-up (mean 11.4 +/- 4.4), 83 patients experienced a first CV event. The rate of events was higher in rapid (29/59, 49%), and slow (36/78 46%) than in nonprogressors (18/73 25%); (P=0.005). Compared with nonprogressors, the adjusted hazard ratio for CV events was 1.91 [95% confidence interval (95% CI); 1.05-3.47] in the slow, and 2.13 (95% CI; 1.12-4.03) in the rapid progressors. CONCLUSION: In hypertensive patients, progression of CAC is associated with long-term CV events. PMID- 23751970 TI - Reproducibility of peripheral arterial tonometry for the assessment of endothelial function in adults. AB - OBJECTIVES: Endothelial dysfunction is associated to cardiovascular risk factors and predicts cardiovascular events. Peripheral arterial tonometry (PAT) is a novel noninvasive method to assess endothelial function. However, there is a paucity of data about its reproducibility. The aim of this study was to assess the feasibility and reproducibility of PAT in adults. METHODS: PAT exams were performed twice in the same day in 123 participants of a cohort about the determinants of diabetes and cardiovascular diseases (Brazilian Longitudinal Study of Adult Health--ELSA-Brasil). The interval between the exams was 2-6 h (mean=4 h). Endothelial function in PAT method is measured by reactive hyperemia index (RHI), which evaluates arterial pulsatile volume changes in response to hyperemia. Agreement of RHI values was compared by Bland-Altman method, coefficient of variation and coefficient of repeatability. Reliability was assessed by intraclass correlation coefficient (ICC). RESULTS: Mean values of RHI did not differ significantly between the exams of each participant (1.92+/-0.56 vs. 1.96+/-0.58, P=0.48). There were no systematic errors between the exams (mean of differences=-0.03+/-0.5). Measurement error was 0.35, coefficient of variation was 18.0% and ICC was 0.61. Sex, age or the presence of obesity did not have a considerable influence on the reproducibility of PAT. CONCLUSION: PAT exam is feasible and has acceptable reproducibility in adults when compared with other noninvasive methods for endothelial function assessment. This performance makes PAT a promising method for future clinical and epidemiological studies. PMID- 23751971 TI - A comprehensive assessment of gait accelerometry signals in time, frequency and time-frequency domains. AB - Gait accelerometry is a promising tool to assess human walking and reveal deteriorating gait characteristics in patients and can be a rich source of clinically relevant information about functional declines in older adults. Therefore, in this paper, we present a comprehensive set of signal features that may be used to extract clinically valuable information from gait accelerometry signals. To achieve our goal, we collected tri-axial gait accelerometry signals from 35 adults 65 years of age and older. Fourteen subjects were healthy controls, 10 participants were diagnosed with Parkinson's disease, and 11 participants were diagnosed with peripheral neuropathy. The data were collected while the participants walked on a treadmill at a preferred walking speed. Accelerometer signal features in time, frequency and time-frequency domains were extracted. The results of our analysis showed that some of the extracted features were able to differentiate between healthy and clinical populations. Signal features in all three domains were able to emphasize variability among different groups, and also revealed valuable information about variability of the signals between anterior-posterior, mediolateral, and vertical directions within subjects. The current results imply that the proposed signal features can be valuable tools for the analysis of gait accelerometry data and should be utilized in future studies. PMID- 23751972 TI - Is smoking a risk factor for proliferative diabetic retinopathy in type 1 diabetes? AB - AIM: The aim was to evaluate if smoking was a risk factor for proliferative retinopathy (PDR) in a 25-year follow-up study. METHODS: 201 persons from a population-based cohort of Danish type 1 diabetic patients were examined at baseline and again 25 years later. At both examinations the patients were asked about their smoking habits. The level of retinopathy was evaluated by ophthalmoscopy at baseline and by nine 45-degree colour field fundus photos at the follow-up. RESULTS: In multivariate analyses there was a trend that current smokers at baseline were more likely to develop PDR at the follow-up (odds ratio 1.90, 95% confidence interval 0.88-4.11, p = 0.10). Neither smoking status at the follow-up nor pack-years of smoking were associated with PDR. CONCLUSIONS: We found neither a beneficial nor a harmful effect of smoking on long-term incidence. Selective mortality among smokers and patients with PDR at baseline might provide at least part of the explanation for this. PMID- 23751973 TI - A single center retrospective study on 959 excisions of non-melanoma skin cancer in 2011. PMID- 23751974 TI - Breast reconstruction using implant and acellular dermal matrix: "the trapezoidal technique". PMID- 23751975 TI - Breast implant associated anaplastic large cell lymphoma: a case report and reconstructive option. AB - Since 1995, the association between Anaplastic Large Cell Lymphoma (ALCL) and breast implant capsules has been of increasing concern. Up to 40 cases have been reported worldwide. The majority of cases favour an indolent course, similar to that of primary cutaneous ALCL, with a 10-year survival rate of greater than 90%. Many recommendations have been made for diagnosis, treatment and adjuvant therapy but the issue of reconstruction post capsulectomy and removal of implants has not yet been addressed. We present a case report and management option. PMID- 23751976 TI - Glaucoma classification based on visual pathway analysis using diffusion tensor imaging. AB - Most of the existing methods for diagnosing glaucoma analyze the eye with a main focus on the retina, despite the transsynaptic nature of the fiber degeneration caused by glaucoma. Thus, they ignore a significant part of the visual system represented by the visual pathway in the brain. The advances in neuroimaging, especially diffusion tensor imaging (DTI), enable the identification and characterization of white matter fibers. In this work, we propose a system based on DTI analysis of the visual pathway fibers in the optic radiation for detecting and discriminating different glaucoma entities. The optic radiation is identified semi-automatically. DTI provides information about the fiber orientation as well as a set of derived parameters describing the degree of diffusion anisotropy and diffusivity. Features for each DTI derived measure are extracted from a specified region of interest on the optic radiation. The features are grouped into three sets: Histogram, co-occurrence matrices, and Laws features. For feature selection, the features are ranked using a support vector machine classifier. The highest ranked features are used for classification. A support vector machine classifier is used for classification in a 10-fold cross validation setup. The system is applied to three age-matched subjects' categories containing 27 healthy, 39 primary open angle glaucoma (POAG), and 18 normal tension glaucoma (NTG) subjects. The discrimination accuracy between healthy and glaucoma (POAG and NTG) subjects is 94.1% with an area under the ROC of 0.97. Classification accuracy of 92.4% is obtained for the normal and the POAG groups while it increased to 100% in case of healthy and NTG groups. In addition, the system could differentiate between glaucoma types (POAG and NTG) with an accuracy of 98.3%. A complementary analysis was performed to estimate the selection bias in the obtained accuracy. The bias ranged from 10% to 20% depending on the group pair under consideration. The classification results indicate the high performance of the system compared to retina-based glaucoma detection systems. The proposed approach utilizes visual pathway analysis rather than the conventional eye analysis which presents a new trend in glaucoma detection. Analyzing the entire visual system could provide significant information that can improve the glaucoma examination flow and treatment. PMID- 23751977 TI - Langerhans cell histiocytosis in childhood - review, symptoms in the oral cavity, differential diagnosis and report of two cases. AB - BACKGROUND: Langerhans cell histiocytosis is a rare disease characterized by monoclonal proliferation and migration of special dendritic cells. This disease primarily affects bones, but occurs less frequently in other organ systems or may manifest as a multisystem disease. CASE REPORTS: Extraoral and intraoral symptoms of Langerhans cell histiocytosis are described in a 13-month-old female and a 5 month-old male infant. Dermatitis was found on the scalp, abdomen, flexures and in intertrigineous areas in both patients. The intraoral examination of the 13 month-old infant showed premature eruption of all maxillary deciduous molars, loosening and significant damage of periodontal tissues (gingivitis with bleeding, swelling of palatal mucosa, periodontal pockets) resembling severe periodontitis. In the oral cavity of the 5-month-old predentate infant bilateral swellings of maxillary alveolar mucosa with deep ulcerations were seen. The oral and skin symptoms in both infants were indications for biopsy. Langerhans cell histiocytosis was confirmed histologically and immunohistochemically. CONCLUSION: Oral findings in Langerhans cell histiocytosis may be the only clinical symptom of the disease; therefore the role of dentists in establishing diagnosis is very important. PMID- 23751978 TI - On the thermodynamics of multilevel evolution. AB - Biodiversity is hierarchically structured both phylogenetically and functionally. Phylogenetic hierarchy is understood as a product of branching organic evolution as described by Darwin. Ecosystem biologists understand some aspects of functional hierarchy, such as food web architecture, as a product of evolutionary ecology; but functional hierarchy extends to much lower scales of organization than those studied by ecologists. We argue that the more general use of the term "evolution" employed by physicists and applied to non-living systems connects directly to the narrow biological meaning. Physical evolution is best understood as a thermodynamic phenomenon, and this perspective comfortably includes all of biological evolution. We suggest four dynamical factors that build on each other in a hierarchical fashion and set the stage for the Darwinian evolution of biological systems: (1) the entropic erosion of structure; (2) the construction of dissipative systems; (3) the reproduction of growing systems and (4) the historical memory accrued to populations of reproductive agents by the acquisition of hereditary mechanisms. A particular level of evolution can underpin the emergence of higher levels, but evolutionary processes persist at each level in the hierarchy. We also argue that particular evolutionary processes can occur at any level of the hierarchy where they are not obstructed by material constraints. This theoretical framework provides an extensive basis for understanding natural selection as a multilevel process. The extensive literature on thermodynamics in turn provides an important advantage to this perspective on the evolution of higher levels of organization, such as the evolution of altruism that can accompany the emergence of social organization. PMID- 23751979 TI - Impact of temperature stress and validamycin A on compatible solutes and fumonisin production in F. verticillioides: role of trehalose-6-phosphate synthase. AB - Fusarium verticillioides is a pathogen of maize that causes root, stalk and ear rot and produces fumonisins, toxic secondary metabolites associated with disease in livestock and humans. Environmental stresses such as heat and drought influence disease severity and toxin production, but the effects of abiotic stress on compatible solute production by F. verticillioides have not been fully characterized. We found that decreasing the growth temperature leads to a long term reduction in polyol levels, whereas increasing the temperature leads to a transient increase in polyols. The effects of temperature shifts on trehalose levels are opposite the effects on polyols and more dramatic. Treatment with validamycin A, a trehalose analog with antifungal activity, leads to a rapid reduction in trehalose levels, despite its known role as a trehalase inhibitor. Mutant strains lacking TPS1, which encodes a putative trehalose-6-phosphate synthase, have altered growth characteristics, do not produce detectable amounts of trehalose under any condition tested, and accumulate glycogen at levels significantly higher than wild-type F. verticillioides. TPS1 mutants also produce significantly less fumonisin than wild type and are also less pathogenic than wild type on maize. These data link trehalose biosynthesis, secondary metabolism, and disease, and suggest that trehalose metabolic pathways may be a viable target for the control of Fusarium diseases and fumonisin contamination of maize. PMID- 23751980 TI - Effect of aspirin and antiplatelet drugs on the outcome of the fecal immunochemical test. AB - OBJECTIVE: To evaluate the effect of aspirin and nonaspirin antiplatelet agents (NAAAs) on the performance of the fecal immunochemical test (FIT). PARTICIPANTS AND METHODS: We performed a post hoc analysis of results from a clinical trial that involved 28,696 asymptomatic average-risk men and women aged 50 to 69 years invited to participate in a colorectal cancer screening program with FIT between November 1, 2008, and June 31, 2011. RESULTS: The test was returned by 6390 individuals (22.3%), of whom 5821 (91.1%) reported not using antiplatelet drugs (nonusers group) and 569 (8.9%) reported using these drugs at the time of testing (users group). The FIT result was positive in 48 of 569 users (8.4%) and 365 of 5821 nonusers (6.3%) (P=.05). A positive FIT result was found in 7.3% (28/384) of aspirin users, 7.1% (10/140) of NAAA users, and 22.2% (10/45) of those undergoing dual antiplatelet therapy (DAPT) (aspirin plus an NAAA). The DAPT subgroup had a significantly higher positive FIT rate than the nonuser group (odds ratio, 3.5; 95% CI, 1.7-7.3; P<.05). The positive predictive value (PPV) for advanced neoplasia (AN) in nonusers was 50.4% vs 50.0% in users (P = .40). The PPV for AN was 57.0% in aspirin users, 30.0% in NAAA users, and 50.0% in DAPT users, without statistically significant differences between the user and nonuser groups. CONCLUSION: The use of DAPT increased the rate of positive FIT results. Use of aspirin, NAAAs, or both did not modify the PPV for AN in this population-based colorectal screening program. PMID- 23751981 TI - Prevalence of skin disorders in patients seeking health care. PMID- 23751982 TI - In reply--Prevalence of skin disorders in patients seeking health care. PMID- 23751983 TI - Accelerometer-assessed physical activity and objectively determined dual sensory impairment in US adults. AB - OBJECTIVE: To examine the association between hearing and vision impairment (with the focus on dual sensory impairment) and accelerometer-assessed physical activity (PA) in a national sample of US adults because limited research has examined this association. PATIENTS AND METHODS: Data from the cross-sectional 2003-2006 National Health and Nutrition Examination Survey were used. The data were evaluated between May 28, 2012, and March 27, 2013. To assess moderate- to vigorous-intensity PA, participants wore an accelerometer for at least 4 days. Hearing and visual acuity were objectively measured in the mobile examination center. After exclusions, 1445 participants provided complete data on the study variables. A negative binomial regression was used to examine the association between PA and dual sensory impairment. RESULTS: After adjusting for age, sex, race/ethnicity, education, body mass index, comorbidity index, cotinine level, C reactive protein level, number of valid days of accelerometry, and accelerometer wear time, there was evidence of joint effects of vision and hearing on PA (incident rate ratio, 0.45; 95% CI, 0.29-0.68), indicating that participants experiencing both vision and hearing loss participated in less PA than would be expected based on their individual effects. CONCLUSION: Adults with dual sensory impairment may be at increased risk for decreased PA. Possible strategies include, but are not limited to, teaching the patient how to make modifications to their indoor and outdoor environments, encouraging patients to engage in balance and resistance training, and advocating changes to public and private institutions to address common concerns. PMID- 23751984 TI - Droplet sorting in a loop of flat microfluidic channels. AB - Motivated by recent experiments, we numerically study the droplet traffic in microfluidic channels forming an asymmetric loop with a long and a short arm. The loop is connected to an inlet and an outlet channel by two right angled T junctions. Assuming flat channels, we employ the boundary element method (BEM) to numerically solve the two-dimensional Darcy equation that governs two phase flow in the Hele-Shaw limit. The occurrence of different sorting regimes is summarized in sorting diagrams in terms of droplet size, distance between consecutive droplets in the inlet channel, and loop asymmetry for mobility ratios of the liquid phases larger and smaller than one. For large droplet distances, the traffic is regulated by the ratio of the total hydraulic resistances of the long and short arms. At high droplet densities and below a critical droplet size, droplet-droplet collisions are observed for both mobility ratios. PMID- 23751985 TI - Single-access laparoscopic cholecystectomy versus classic laparoscopic cholecystectomy: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Single-incision laparoscopic surgery has been proposed as a minimally invasive technique with the advantages of fewer scars and reduced pain. The aim of this study was to perform a systematic review and meta-analysis of prospective randomized clinical trials of single-access laparoscopic cholecystectomy (SALC) versus classic laparoscopic cholecystectomy (CLC). METHODS: All randomized controlled trials were identified through electronic searches (MEDLINE, PubMed, SAGES, and Cochrane Central Register of Controlled Trials) up to October 2011. Methodologically appropriate clinical trials identified in the search process were included in a meta-analysis to provide a pooled estimate of effect. RESULTS: Nine true randomized controlled trials were included in the analysis and reported a total of 695 patients, divided into the SALC group of 362 patients and the CLC group of 333 patients. Median operating time was longer with 57 minutes in SALC versus 45 minutes in CLC (P=0.00001). There was no significant difference in length of stay (SALC 1.36 d vs. CLC 1.15 d, P=0.18). Conversion to laparotomy in either group was similar; however, in 18 of 66 SALC patients an additional instrument was used, compared with 1 of 67 CLC patients (P=0.0003). Complications were not significant different [16% in SALC vs. 12% in the CLC group (P=0.74)]. Median postoperative pain with the visual analog scale score was 3.8 points in SALC versus 3.15 points in the CLC group (P=0.48). Cosmetic satisfaction was significantly more satisfying with 9 points favoring SALC versus 0 points favoring CLC (P=0.0005) in contrast to the quality-of-life questionnaire where there was no significant difference in patient overall satisfaction between SALC and CLC groups (P=0.0515). CONCLUSIONS: SALC required longer operative times than CLC without significant benefits in patient overall satisfaction, postoperative pain, and hospital stay. Only satisfaction with the cosmetic result showed a significantly higher preference towards SALC. PMID- 23751986 TI - Natural-orifice translumenal endoscopic surgery (NOTES): minimally invasive evolution or revolution? AB - Since the first animal experimental laparoscopy in 1902, minimal access techniques have revolutionized surgery. Using the natural orifice dates back to at least the second century when Soranus performed a vaginal hysterectomy. The main difference between traditional endolumenal surgery and the translumenal approach of natural-orifice translumenal endoscopic surgery (NOTES) is the intentional puncture of a healthy organ in NOTES to access a cavity or other organ. The aim of this review was to examine the past, present, and potential future role of NOTES in the context of other developments in minimal access surgery. NOTES is at an early stage in its development and a convincing benefit over laparoscopy has not been demonstrated. Concerns regarding complications, for example of viscerotomy closure, have limited the widespread uptake of pure NOTES. However, it is likely that technological advances for NOTES surgery will enhance conventional laparoscopic and endoscopic techniques. PMID- 23751987 TI - Diagnostic laparoscopy through deep inguinal ring: a literature-based review on the forgotten approach to visualize the abdominal cavity during emergency and elective groin hernia repair. AB - OBJECTIVE: To systematically review the published literature on the role of diagnostic laparoscopy through deep inguinal ring (DL-DR) during groin hernia repair. METHODS: Standard electronic databases were searched reporting article in any language on the role of DL-DR during groin hernia repair regardless of the age and sex of patients. RESULTS: Thirty-one articles on 5745 patients undergoing DL-DR during groin hernia repair were retrieved from the electronic databases. There was 1 randomized, controlled trial, 7 case reports and 2 case series on 58 adult patients mainly targeting assessment of bowel viability following spontaneous reduction of the strangulated groin hernia. Twenty-one articles, either retrospective or prospective case series on 5687 were reported on pediatric patients aiming to detect a contralateral patent processus vaginalis or synchronous groin hernia. Overall, the laparoscopy group had a reduced operative time, reduced length of hospital stay, lower complication rate, and earlier return to normal activity. DL-DR success rates were reported in >95% of patients. Contralateral patent processus vaginalis indicative of inguinal hernia was found in >48% of children. There was no major morbidity reported in any group. CONCLUSIONS: DL-DR during groin hernia repair may be performed safely when indicated. The routine use of DL-DR is an established practice in pediatric surgery. There is still insufficient evidence to recommend the routine use of DL DR in adults. PMID- 23751988 TI - A comparison of nonabsorbable polymeric clips and endoloop ligatures for the closure of the appendicular stump in laparoscopic appendectomy: a prospective, randomized study. AB - The aim of this prospective randomized trial was to evaluate the clinical outcomes of hem-o-lok ligation system in laparoscopic appendix stump closure by comparing the endoloop ligature. A total of 53 patients were evaluated in this study (n=26 and 27 for hem-o-lok and endoloop groups, respectively). The mean operation time were shorter in hem-o-lok group than endoloop group (64.7 +/- 19.2 vs. 75.4 +/- 23, respectively); however, the difference was not significant. Other surgical findings were similar. There was no statistically significant difference in overall nonsurgically or surgically related complications. The mean postoperative hospitalization time was also similar in both groups. Although it is not possible to make general conclusions on basis of such a limited study, in our opinion, closure of the appendix stump with polymeric nonabsorbable clips in laparoscopic appendectomy may be a cheaper and simpler alternative to other widely used methods. PMID- 23751989 TI - Fast-track surgery in real life: how patient factors influence outcomes and compliance with an enhanced recovery clinical pathway after colorectal surgery. AB - The aim of this prospective cohort study was to identify the patient factors that predict postoperative deviation from each item of a fast-track colorectal surgery protocol (FT) and these factors' influences on postoperative outcomes. A total of 606 patients with colorectal pathology from 2005 to 2011 were analyzed to assess the relationships between patient factors, the outcome variables, and the items of the FT program. The median length of stay was 5 days, and readmission rate was 2.3%. The morbidity rate was 26.7%. Independent predictors of prolonged length of stay were older than 75 years of age, ASA grade 3 and 4, and the presence of an ileostomy. Independent predictors of morbidity were age above 75 years old and ASA grade, whereas age was confirmed as an independent predictor of mortality. Male sex, age above 75 years old, and ASA 3 and 4 were identified as independent predictors of negative compliance to most of the postoperative FT items. PMID- 23751990 TI - Predictive factors of radiation dose in ERCP: a prospective study in 2 tertiary centers. AB - BACKGROUND: The use of fluoroscopy to aid endoscopic retrograde cholangiopancreatography (ERCP) places both the patient and the endoscopy staff at the risk of radiation-induced injury. Previous reports have demonstrated a linear relationship between radiation dose and fluoroscopy duration. AIM: To identify predictive factors of fluoroscopy time and radiation exposure to patients undergoing ERCP by using pulsed fluoroscopy. METHODS: Four hundred and four consecutive ERCPs performed from January 2010 to November 2010 at 2 tertiary centers in Spain were prospectively studied. Patients and procedural variables were analyzed. Philips BV Pulsera mobile fluoroscopy system was used on the endoscopy unit. Entrance surface dose, dose-area product, and fluoroscopy time were recorded for each patient. RESULTS: A total of 404 ERCPs on 404 consecutive patients were studied (mean age 73 y). The average entrance surface dose and dose area product were 12.0 mGy and 0.37 mGy/m2, respectively. Mean fluoroscopy time was 2.31 minutes. The biliary ducts were adequately visualized in 371 (92%) cases. After analysis with a univariable model, the factors found to significantly increase the radiation dose (P75>19.6 mGy) were as follows: alkaline phosphatase serum levels (P=0.047), balloon dilation (P=0.005), biliary stent placement (P=0.001), and ERCP diagnosis (P=<0.0001). In a multivariate analysis, only stent insertion significantly increased the radiation dose (risk ratio 4.75; 95% confidence interval, 1.84-7.63). CONCLUSIONS: In this prospective analysis, multiple factors affected the radiation dose. Stent insertion was the only independent predictor significantly associated with prolonged fluoroscopy. PMID- 23751991 TI - The animal model in advanced laparoscopy resident training. AB - BACKGROUND AND AIM: Laparoscopic surgery is recognized as an established technique for several abdominal disorders. Aim of the present investigation was to assess the level of expertise of senior residents and to evaluate the role of the animal model on advanced laparoscopic training. METHODS: Overall, 60 residents underwent a training session on a porcine model under the guidance of experienced laparoscopic surgeons. Of these, 30 residents underwent a box-trainer preparation before starting the surgical procedure on the animal model, while a group of 20 repeated the course 3 months after the first session. Global Operative Assessment of Laparoscopic Skills (GOALS) was used to evaluate technical proficiency. RESULTS: Senior residents presented low mean scores for all the GOALS domains for both for the minor and major surgical procedure. The box-trainer led to an improvement in suturing skills (P<0.001). Comparison of the mean GOALS scores from the first to the second laparoscopic session demonstrated a significant improvement on the duration of the procedures (P<0.05), onset of major complications (P=0.01), need of the tutor (P=0.08), and confidence in treating intraoperative bleeding (P=0.01). CONCLUSIONS: National Resident Training Programs should take into consideration the present quality of training and attempt to develop alternative methods of training for laparoscopic surgery, such as, the animal model laboratory. PMID- 23751992 TI - 2 L PEG plus ascorbic acid versus 4 L PEG plus simethicon for colonoscopy preparation: a randomized single-blind clinical trial. AB - BACKGROUND: The 2 L polyethylene glycol (PEG) lavage solution has been proved to be similarly safe and effective as 4 L PEG formulations, in spite of the reduced volume. OBJECTIVE: To compare low-volume PEG-based solution combined with ascorbic acid with high-volume PEG-based solution combined with simethicon in terms of efficacy and patient tolerability. METHODS: This was a single-blind prospective randomized trial. Patients were randomized to receive either 2 L PEG plus ascorbic acid (PEG+Asc) or 4 L PEG plus simethicon (PEG+Sim). The primary endpoint was overall colon cleansing evaluation, assessed by blinded investigators using Aronchick score. Secondary end points included patient compliance and tolerability and adverse events. RESULTS: Sixty patients received PEG+Asc and 60 received PEG+Sim. Overall bowel cleansing score was considered adequate in 81.67% of the PEG+Asc and 80% of the PEG+Sim groups, respectively. Excellent and good ratings were recorded in 11.6% and 38.3% receiving PEG+Asc as compared with 26.6% and 23.3% of patients receiving PEG+Sim. Patient tolerability and safety were similar with both the preparations. CONCLUSIONS: According to our data, low-volume PEG+Asc has comparable efficacy, safety, and tolerability as high-volume PEG+Sim; therefore, it can be considered as a good alternative solution for bowel preparation. More improvements are necessary to achieve the target of a perfect preparation. PMID- 23751993 TI - Laparoscopic floppy Nissen fundoplication: 11-year follow-up. AB - BACKGROUND: There are few published reports on the outcomes of >= 10 years after a laparoscopic floppy Nissen fundoplication (LFNF). MATERIALS AND METHODS: From April 1994 to January 2012, 567 patients underwent LFNF and the outcomes of 211 cases were determined (from April 1994 to October 2000). RESULTS: Outcomes at >= 11 years after surgery was available for 178 patients (84.3%) of which 167 (93.8%) had no heartburn or mild heartburn, 8 (4.5%) had moderate heartburn, and 3 had (1.7%) severe heartburn. Dysphagia was nonexistent or mild in 153 (85.9%), whereas the remaining 14.1% presented moderate to severe symptoms. Reports of 69.1% patients showed none or mild symptoms of abdominal bloating, that of 23% patients showed moderate discomfort, and reports of 7.8% showed severe bloating. Satisfaction score was 8.6 (of 10). A further surgical procedure was required for 7 patients (3.9%): 4 for recurrent reflux and 3 for dysphagia (2 for a tight wrap and 1 for a tight esophageal hiatus). Postoperative dysphagia sufficient for an endoscopic dilatation was observed in 4 patients (2.3%), where 3 were successfully managed with a single dilatation procedure and the last patient underwent several dilatations before adequate swallowing. CONCLUSION: LFNF is an effective long-term treatment for gastroesophageal reflux disease, yielding similar results to open fundoplication. PMID- 23751994 TI - Experience with stent implantation in malignant esophageal strictures: analysis of 1185 consecutive cases. AB - PURPOSE: The aim of this retrospective study was to analyze the experience in endoprosthesis implantation in cases of malignant esophageal strictures. METHODS: A total of 1185 consecutive patients underwent endoprosthesis implantation: through open surgery in 42 cases and by endoscopy in 1143 cases. RESULTS: Stent implantation was performed successfully in 61.2% of cases. Dysphagia was resolved temporarily in 6.2% and permanently in 93.5% of cases. The score of dysphagia decreased from 1.93 to 0.38. Complications were detected in 23.7% of patients, and 69.2% of cases were treated by endoscopy. Wound complications were seen in 21.9% of patients intubated through surgery. The mean survival time of patients with esophageal intubation was 5.4 months and that of patients not eligible for stent implantation was 3.3 months. CONCLUSIONS: Stent implantation improves the quality of life and gives an opportunity for adjuvant oncological therapy. Evaluation of morphologic anomalies is of considerable importance for achieving success in treatment through implantation. PMID- 23751995 TI - Two-year subjective, objective, quality of life, and endoscopic follow-up after laparoscopic Nissen-Rossetti in patients with columnar-lined esophagus. AB - INTRODUCTION: Barrett esophagus (BE) is a complication of gastroesophageal reflux disease. We wish to determine the effects of surgery on the histology of the esophageal mucosa and evaluate Quality of Life. MATERIALS AND METHODS: Twenty seven patients with columnar-lined esophagus (CLE) metaplasia underwent laparoscopic Nissen-Rossetti fundoplication. Patients were submitted to close follow-up. RESULTS: One patient voluntarily left follow-up after surgery. CLE was still present in 18 patients (66.6%); no patient developed dysplasia or esophageal adenocarcinoma. Two patients with gastric metaplasia and 1 patient with intestinal metaplasia had regression at 12 and 24 months after surgery (11.1%). DeMeester and Johnson score decreased from 38.69 (SD +/- 51.44) to 11.99 (SD +/- 18.08) at 6 months, 12.69 (SD +/- 12.91) at 12 months, and it was 11.38 (SD +/- 6.43) at 24 months. Preoperative gastroesophageal reflux disease-health related quality of life was 19.90 (SD +/- 18.54), 9.80 (SD +/- 8.77) at 6 months, 9.57 (SD +/- 9.14) at 12 months, and 11.53 (SD +/- 6.48) at 24 months. Short form 36 measurement showed significant improvement. CONCLUSIONS: Management of CLE requires multidisciplinary approach. Medical therapy does not prevent biliary reflux into the esophagus. Surgical therapy is effective and long lasting. It should be performed by experienced surgical teams. PMID- 23751996 TI - Endoscopic diagnosis and treatment of esophageal cavernous lymphangioma. AB - The purpose of this paper is to identify the characteristic endoscopic findings in patients with esophageal cavernous lymphangioma and assess the efficacy of endoscopic techniques in the management of this disease. We retrospectively analyzed data from 6 patients who were diagnosed with esophageal cavernous lymphangioma by endoscopy and histologic evaluation. All patients underwent endoscopic resection of the tumor at our hospital between January 2010 and June 2011. Four male and 2 female patients, with a mean age of 48.2 +/- 15.2 years (range, 35 to 77 y) with esophageal cavernous lymphangioma, who underwent endoscopy followed by endoscopic resection were included in this report. The lesions varied from 0.4 to 1.2 cm in diameter, with a mean size of 0.78 +/- 0.26 cm. Endoscopy revealed dilated lymphatic channels beneath the surface epithelium of the lesion in all patients. An endoscopic ultrasound revealed that all lesions were multicystic and located in the submucosal layer. Histologic examination confirmed the initial diagnosis in all patients. Endoscopy plays an important role in the diagnosis of esophageal cavernous lymphangioma, with dilated lymphatic channels beneath the surface epithelium of the lesion being a characteristic endoscopic feature. Endoscopic ultrasonography is a useful tool to differentiate cavernous lymphangioma from other esophageal tumors. Endoscopic resection of esophageal cavernous lymphangioma was safe and effective in all of the analyzed cases. PMID- 23751997 TI - Early outcomes of video-assisted thoracic surgery (VATS) Ivor Lewis operation for esophageal squamous cell carcinoma: the extracorporeal anastomosis technique. AB - PURPOSE: Although the use of a minimally invasive approach in esophageal cancer surgery is gradually increasing, it is generally performed using cervical anastomosis because of the difficulty of intrathoracic anastomosis. Here, we describe our technique for performing intrathoracic esophagogastrostomy using a typical video-assisted thoracic surgery (VATS) approach. METHODS: Between September 2009 and July 2011, VATS esophagectomy and intrathoracic anastomosis was performed in 31 esophageal cancer patients with a utility incision made by a segmental rib resection to enhance the extracorporeal insertion of the end-to-end stapler. We retrospectively reviewed the clinical records of these patients. RESULTS: There were no intraoperative events related to the VATS procedure. The mean VATS time was 180.2 +/- 39.2 min. The mean postoperative hospital stay was 15.2 days (range, 11 to 38 d). No significant pulmonary complications were observed. Five patients developed vocal cord palsy due to radical mediastinal lymphadenectomy. No anastomotic complications such as leaking or stricture were observed. Only 1 patient had postoperative pain requiring analgesics. CONCLUSIONS: Our technique can be safely and effectively performed for intrathoracic anastomosis in esophageal surgery with favorable early outcomes and reduced postoperative pulmonary complications. PMID- 23751998 TI - Laparoscopy-assisted small incision splenectomy and open splenectomy in the treatment of hematologic diseases: a single-institution comparative experience. AB - AIM: To compare the clinical effect of small incision-assisted laparoscopic splenectomy (LS) and open splenectomy in the treatment of hematologic disease. METHODS: The clinical data of 60 cases of small incision-assisted LS and 66 cases of splenectomy from October 1993 to May 2012 were retrospectively analyzed. RESULTS: The blood loss, enterokinesia time, off-bed activity times, hospitalization time, and incidence of complications in the laparoscopic group decreased significantly than the open group. There was no significance of difference between the 2 groups in the mean operating time and medical costs (P>0.05). CONCLUSIONS: Clinical effects of patients treated by small incision assisted LS were better than those treated by open splenectomy. Small incision assisted LS has advantages of microinvasion, safety, effectiveness, and quick recovery in the treatment of hematologic disease. PMID- 23751999 TI - Robotic thyroidectomy for benign thyroid diseases: a stepwise strategy to the adoption of robotic thyroidectomy (gasless, transaxillary approach). AB - PURPOSE: Thyroid surgery for benign diseases mainly involves young women, and thus, cosmetic considerations have motivated the development of "no scar to the neck" procedures. Endoscopic techniques are often strenuous, and therefore, discouraging to adopt. However, the recent incorporation of robotic technology proposes a feasible, safe, extracervical approach that alleviates most of the technical difficulties associated with endoscopy. Here, the authors present a series of robotic thyroidectomies performed to treat benign thyroid diseases and detail the key issues of initial patient selection. PATIENTS AND METHODS: From November 2007 to December 2010, 44 patients with benign thyroid disease were operated upon using a robotic procedure. Indications were follicular/Hurthle cell lesions smaller than 5 cm, nodules with an indefinite/suspicious cytology, or Graves disease. All patients underwent robotic gasless, transaxillary thyroidectomy using the da Vinci S system. RESULTS: Thirty-nine of the 44 patients were women, and the overall mean age was 38.2 years (range, 16 to 60 y). The most common pathology was adenomatous hyperplasia (20 lesions) followed by follicular adenoma (10 lesions). Seven patients had Graves disease. The mean tumor size was 1.68 cm (range, 0.3 to 5 cm). Thirty-nine patients underwent less than total thyroidectomy and 5 underwent total or near total thyroidectomy. The mean total operative time was 129.8 minutes (range, 75 to 242 min) and the mean duration of postoperative hospital stay was 3.1 days (range, 2 to 5 d). Postoperative complications were 1 transient hoarseness, 1 transient hypocalcemia, and 1 permanent recurrent laryngeal nerve injury. CONCLUSIONS: Robotic thyroidectomy, although novel and sophisticated, has already been used to treat over 4000 thyroid cancer patients in Korea. Female patients with a small to average build, with a follicular lesion and concerned about neck scarring, seem to be the best candidates. Patients with small suspicious nodules without severe thyroiditis are also a rational choice. In contrast, patients with Graves disease should be reserved, unless significant experience has been gained. PMID- 23752000 TI - What have we gained by performing robotic rectal resection? Evaluation of 64 consecutive patients who underwent laparoscopic or robotic low anterior resection for rectal adenocarcinoma. AB - BACKGROUND: Robotic surgery is thought to be a solution to overcome the limitations of laparoscopy in sphincter-saving resections. In this study, we present our results on patients undergoing robotic and laparoscopic low anterior resection (LAR) consecutively for rectal adenocarcinoma. MATERIALS AND METHODS: Between February 2008 and June 2011, consecutive patients who underwent laparoscopic or robotic LAR by a single surgical team for rectal cancer were evaluated. The patients' demographic, operative, postoperative short-term follow up, and histopathologic data were analyzed. RESULTS: Twenty-seven patients underwent robotic LAR, whereas 37 patients underwent laparoscopic LAR. The operation time of the laparoscopy group was significantly shorter than that of the robotic group (P=0.02). The complete total mesorectal excision rate was significantly higher in the robotic group (P=0.02). The overall complication rates were 11.11% and 21.62% in the robotic and laparoscopy groups, respectively (P=0.45). CONCLUSIONS: Good quality of resected specimens could be achieved with robotic LAR. Further prospective studies including long-term oncologic outcomes and costs with higher patient number are definitely needed to assess the benefits of robotic resection in rectal cancer treatment. PMID- 23752001 TI - Single-incision laparoscopic transabdominal preperitoneal herniorrhaphy for bilateral inguinal hernias using conventional instruments. AB - PURPOSE: Inguinal hernia repair is a common surgical procedures performed worldwide. Although surgical technology is advancing rapidly in this era, surgeons have a chance to make modifications in laparoscopic surgery by reducing the number and size of incisions. The aim of this study is to assess the safety and feasibility of a single-incision laparoscopic surgical (SILS) approach for transabdominal preperitoneal mesh hernioplasty (TAPP) of bilateral inguinal hernia. METHODS: Ten patients with bilateral inguinal hernia admitted to our department and underwent TAPP were retrospectively evaluated. Data regarding patient demographics, type of hernia, operating time, complications, and postoperative hospitalization were prospectively collected. SILS TAPP was performed using conventional instruments and, surgical techniques similar to standard 3-port TAPP were used, except that it was conducted through a single umbilical port. RESULTS: All the patients had a bilateral inguinal hernia. All patients were male, and the mean age of the patients was 45 years (range=28 to 62 y). The mean duration of surgery was 63 minutes (range=55 to 80 min). The procedures were completed successfully on all the patients without requiring conversion to the traditional laparoscopic surgery or the use of additional trocars. There was no evidence of early recurrence during a mean follow-up period of 67 days (range=30 to 105 d). CONCLUSIONS: SILS TAPP for bilateral hernia is feasible and seems to be safer. However, follow-up and analysis are required to establish long-term clinical outcomes and recurrence rate. PMID- 23752002 TI - Laparoscopic bilateral transperitoneal adrenalectomy for Cushing syndrome: surgical challenges and lessons learnt. AB - PURPOSE: Laparoscopic adrenalectomy is well established for treatment of adrenal lesions. However, bilateral adrenalectomy for Cushing syndrome is a challenging and time-consuming operation. We report our experience of laparoscopic bilateral adrenalectomy for this disease in 19 patients. MATERIALS AND METHODS: From September 2009 to August 2012, we have operated 19 patients with Cushing syndrome and performed bilateral laparoscopic adrenalectomy using the transperitoneal approach; synchronous in 15 patients and staged in 4 patients. In 15 patients, the surgery was carried out sequentially on both the sides in lateral position with intraoperative change in position. Complete adrenalectomy including periadrenal fat was carried out on both the sides. RESULTS: Nineteen patients were referred from Department of Endocrinology for bilateral adrenalectomy for adrenocorticotropin hormone (ACTH)-dependent and ACTH-independent Cushing syndrome. The indications for surgery were Cushing disease in 15 patients, occult/ectopic source of ACTH in 2 patients, and primary adrenal hyperplasia in 2 patients. Fifteen patients underwent bilateral adrenalectomy during the same operation. Four patients underwent staged procedures. All procedures were completed laparoscopically with no conversions. The mean operating time for simultaneous bilateral adrenalectomy was 210 minutes (range, 150 to 240 min). This included the repositioning and reprepping time. There were no major intraoperative complications. The average blood loss was 100 mL (range, 50 to 200 mL). None of the patients required blood transfusions in the postoperative period. The postoperative complications included minor port-site infection in 2 patients. One severely debilitated patient died on the 14th postoperative day because of hospital-acquired pneumonia. The remaining 18 patients have done well in terms of impact on the disease. CONCLUSIONS: Laparoscopic bilateral adrenalectomy for Cushing syndrome is feasible and safe. It confers all the advantages of minimally invasive approach such as less postoperative pain, shorter hospitalization, lesser wound complications, and faster recovery. The advantages of the laparoscopic approach have led to an earlier referral for bilateral adrenalectomy by endocrinologist in patients with failed pituitary surgery. PMID- 23752003 TI - Laparoscopic transumbilical single-port appendectomy: initial experience and comparison with 3-port appendectomy. PMID- 23752004 TI - Single-port laparoscopic cholecystectomy and difficulty score. PMID- 23752005 TI - Intragastric stapled pancreatic pseudocystgastrostomy under endoscopic guidance. AB - Drainage of cystic contents is the standard treatment for case of pancreatic pseudocyst (PP) with symptoms, complications, or enlargement of the cyst itself. Here, we report an intragastric stapled pancreatic pseudocystgastrostomy involving a combination of laparoscopy and transoral endoscopy. The patient was a 56-year-old man with a history of heavy alcohol intake. He complained of abdominal pain and high fever during hospitalization because of pancreatitis. Diagnostic imaging revealed a large pseudocyst expanding from the pancreatic parenchyma to the anterior abdominal wall. Intragastric stapled pancreatic pseudocystgastrostomy under endoscopic guidance was performed for relief of compression and continuous fever. A 12-mm port was inserted into the peritoneal cavity in the subumbilical region to create a pneumoperitoneum. Initially, an endoscope was inserted transorally into the stomach to identify the region of the posterior gastric wall compressed by the cyst. Two 12-mm ports were created in the stomach using a Funada-style percutaneous endoscopic gastrostomy kit. After penetrating the gastric wall and the PP with laparoscopic coagulating shears, 950 mL of cyst fluid was aspirated. A cystgastrostomy was then accomplished using an Endo-GIA linear stapler. A 5-mm port was added, and reinforcement of the connection between the posterior gastric wall and the PP was performed by hand sewing. There were no intraoperative complications, and all wounds were closed from the outside. Oral intake was started on postoperative day 3, and the postoperative course was uneventful. There was no recurrence during a follow-up period of 36 months. As intragastric stapled pancreatic pseudocystgastrostomy under endoscopic guidance is safe and effective, it can be considered a useful alternative procedure for treatment of symptomatic PP. PMID- 23752006 TI - Total extraperitoneal (TEP) hernioplasty with intestinal resection assisted by laparoscopy for a strangulated Richter femoral hernia. AB - We describe the first clinical case of a total extraperitoneal hernioplasty combined with intestinal resection assisted by laparoscopy for a strangulated Richter femoral hernia. The patient was a 94-year-old woman admitted to the emergency room with signs and symptoms of acute small bowel obstruction. Diagnosis of a strangulated left Richter femoral hernia was only possible during the initial exploratory laparoscopy. The extraperitoneal approach for mesh positioning was performed gaining access through an infraumbilical 12 mm trocar incision, and assistance of two 5 mm laparoscopic ports at the hipogastrium and right flank. Laparoscopy was resumed and segmental intestinal resection with primary anastomosis was performed. The patient recovered without complications and was discharged home at the fourth postoperative day. The total extraperitoneal approach for acute hernia repair was successful in our particular case. However, factors such as laparoscopic surgical experience, careful patient selection, and correct preoperative diagnosis must be considered before studies in the emergency setting. PMID- 23752007 TI - A hybrid endolaparoscopic therapy for the treatment of foreign bodies in the stomach with esophageal perforation. AB - Recently, the combination of a laparoscopic and endoscopic approach for surgical treatment has increased interest in minimally invasive surgery. Minimally invasive surgery has many advantages over traditional open procedures, and the management of foreign body ingestion is an interesting field in which the combination approach can be used. Herein, we describe the combined approach (laparoscopic and endoscopic) for removal of foreign bodies with the presence of esophageal perforation. PMID- 23752008 TI - Transdiaphragmatic minimally invasive lobectomy is feasible in a pig. AB - Video-assisted thoracoscopic surgery lobectomy has gained acceptance as a safe and oncologically sound alternative to the open procedure. Intercostal incisions alter chest wall mechanics and lead to postoperative pain. We postulated that performing the procedure without disruption of the intercostal spaces may lead to better outcomes because of the decreased effect on chest wall mechanics and postoperative pain. This initial experiment attempts to test the feasibility and possible changes in technique during transdiaphragmatic lobectomy and lymphadenectomy based on currently available instrumentation. Three access ports were placed beneath the costal margin of an anesthetized adult pig, and the thoracic cavity was accessed through the diaphragm. A transdiaphragmatic minimally invasive right lower lobectomy with complete lymph node dissection was performed. We report the first transdiaphragmatic minimally invasive right lower lobectomy and lymphadenectomy in a pig. The procedure is feasible using current commercially available standard instrumentation in a pig. Further, study is warranted to further refine the surgical technique. PMID- 23752009 TI - Cooperative techniques for surgical assistants in laparoscopy-assisted radical distal gastrectomy for gastric cancer. AB - Laparoscopy-assisted radical distal gastrectomy for gastric cancer is challenging to perform, particularly when conducted with D2 lymph node dissection. Successful completion of this procedure requires collaboration among all members of the surgical team. On the basis of the clinical data of 52 patients undergone laparoscopy-assisted radical distal surgery for gastric cancer from September 2009 to October 2010, we describe cooperative techniques for first and laparoscopic-holder assistants that are required to ensure successful outcomes. Precautions for surgical assistants are also described. PMID- 23752010 TI - Total laparoscopic distal gastrectomy with Roux-en Y reconstruction. AB - PURPOSE: The aim of this study was to introduce our technique and evaluate the technical efficacy of Roux-en Y (RY) reconstruction after total laparoscopic distal gastrectomy (TLDG). METHODS: We performed TLDG using our own method of RY type anastomosis in a total of 38 consecutive patients with gastric adenocarcinomas and evaluated the techniques and postoperative outcomes. RESULTS: The mean operative time was 144.5 +/- 22.4 minutes, including reconstruction time, which was 26.2 +/- 3.5 minutes. Most patients were of pathologic stage IA (76.3%) or IB (10.5%), 3 patients were of stage II, and 2 were of stage IIIA. The length of postoperative hospital stay was 8.3 +/- 3.3 days (range, 5 to 20 d). Two cases required reoperation because of internal herniation. According to our endoscopic observation, bile reflux into the gastric remnant stump was not found. CONCLUSIONS: TLDG with RY reconstruction is technically feasible in gastric cancer patients. PMID- 23752011 TI - An elusive etiology of upper gastrointestinal bleeding in a young man: testis tumor. AB - Herein, we present a case of testicular tumor in a young patient in whom the initial symptom was upper gastrointestinal bleeding secondary to duodenal invasion by retroperitoneal lymph node involvement. Although melanoma, renal, breast, bronchogenic, and gastric carcinoma are the most common metastatic tumors of the small bowel, testicular tumors should be considered in the differential diagnosis of duodenum invasion in a young man because they are the most common tumor in this age group. PMID- 23752012 TI - Intractable hiccup accompanying pleural effusion: reversible clipping of an intrathoracic phrenic nerve. AB - Hiccup is usually a self-limiting condition, and can be treated with medications and physical maneuvers. However, hiccup episodes continuing for days or weeks can be incapacitating, and disturb work, sleep, and eating. Therefore, timely therapeutic intervention is needed to achieve early resolution of this treatable condition. We report on a successful phrenic nerve block for intractable hiccups, which consisted of thoracoscopic nerve clipping under general anesthesia and reversal under local anesthesia. This method has the advantage of assured diaphragmatic functional recovery while controlling intractable hiccups. PMID- 23752013 TI - Replacement of a string jejunostomy if the suture is lost: first time a technique with no need to cut. AB - PURPOSE: The aim of the study was to present the first case of replacement of a string jejunostomy with an enteroscopic percutaneous technique after the string was lost. The replaceable string jejunostomy is a well-established method for the enteral feeding in patients where the swallowing process is impaired and gastroesophageal reflux impedes the option of a gastrostomy. In the frequent case of obstruction, rupture or malfunction of the jejunostomy, it is easily replaced in an outpatient setting without anesthesia, with the help of the string that holds the tip of the feeding tube in place. In our case the string was lost. MATERIALS AND METHODS: The jejunostomy was replaced with a fully percutaneous technique with the help of a pediatric cystoscope. RESULTS: This technique is well practicable and obviated the need for a laparotomy in a polymorbid patient. CONCLUSIONS: The technique seems promising, but we report an anecdotal case description. Further experience is needed to investigate its safety. PMID- 23752014 TI - Transtube exploration with flexible bronchoscope to extract trapped abdominal drains. AB - We herein describe the cases of 2 patients with abdominal drains trapped after surgical intervention. We were able to remove both by means of a flexible endoscope introduced through the tube, avoiding more invasive procedures. This unconventional technique could be useful before advocating surgery, provided the patient is suitable for this transtube drain removal by excluding entrapment of pelvic structure inside the tube. PMID- 23752015 TI - Clinical usefulness of endo intestinal clips during Pringle's maneuver in laparoscopic liver resection: a technical report. AB - BACKGROUND: Control of bleeding is important in parenchymal transection during laparoscopic liver resection. We suggest a new technique using Endo intestinal clips for the intestinal tract to achieve easy, safe hepatoduodenal ligament clamping during laparoscopic liver resection. METHODS: In this study, 10 consecutive patients underwent pure laparoscopic liver resection. Pringle's maneuver was performed using Endo intestinal clips directly on the hepatoduodenal ligament. RESULTS: Laparoscopic Pringle's maneuver using Endo intestinal clips is very easy and safe. In this series, Pringle's maneuver was used a mean of 3.4 times (range, 1 to 5) in each case. Mean operative time was 271.0 minutes (range, 105 to 415 min) and mean volume of intraoperative blood loss was 119.5 mL (range, 10 to 320 mL). No intraoperative or postoperative morbidity or mortality was encountered. CONCLUSIONS: Pringle's maneuver using Endo intestinal clips can be performed easily and safely during laparoscopic liver resection. PMID- 23752016 TI - Single-incision laparoscopic surgery in diagnosis and treatment for gastrointestinal bleeding of obscure origin in children. AB - In this multimedia manuscript with video presentation, we reported our experience of performing single-incision laparoscopic surgery (SILS) on 3 children who presented with gastrointestinal bleeding from congenital small bowel lesions. Preoperative investigations including endoscopy and technetium scintigraphy were all negative in the 3 patients aged 4, 7, and 10 years, respectively. SILS was performed using reusable 3- and 5-mm ports and standard straight instruments. The small bowel lesions were located by SILS and the bowel segment with the pathology was exteriorized through the umbilical wound for extracorporeal resection. The diagnoses of the 3 children were Meckel's diverticulum, ileal duplication cyst, and multiple small bowel vascular malformations. All the 3 children recovered uneventfully from surgery without any complications and required minimal postoperative analgesia. Our experience suggested that SILS is an effective alternative to conventional laparoscopy in both diagnostic and therapeutic functions for children with gastrointestinal bleeding of obscure origin. PMID- 23752017 TI - A modified technique for esophagojejunostomy or esophagogastrostomy after laparoscopic gastrectomy. AB - OBJECTIVE: Reconstruction of the digestive tract involving esophageal anastomosis after laparoscopic gastrectomy is a surgically difficult procedure. In this study, a newly developed transoral pretilted circular anvil, a "the oral to the abdomen" method, was proven to be effective. METHOD: A total of 34 consecutive patients underwent esophageal anastomosis using the OrVil in our hospital from July 2009 to February 2011. The esophagus was transected and a small hole was then made in the esophageal stump through which the nasogastric tube of the OrVil was passed to insert the anvil into the abdominal cavity. After fixation with a stapler and a glove at the jejunal loop or the remnant stomach, the abdominal cavity was entered through the minilaparotomy. Pneumoperitoneum and airtightness were reestablished after the glove edge was turned over to seal off the protector. Eventually, intracorporeal esophagojejunostomy or esophagogastrostomy was accomplished under the guidance of laparoscopy. RESULTS: There were 34 patients in the study: 1 with Zollinger-Ellison syndrome, 7 with stromal tumors in cardia, 23 with adenocarcinoma in the stomach, and 3 with cardia adenocarcinoma involving the lower esophagus. The surgical margins for all tumor patients were negative for tumor cells. The mean operative time was 175.0 minutes (90 to 240 min) and the mean intraoperative blood loss was 195.6 mL (50 to 800 mL). The 34 patients underwent successful laparoscopic surgeries with no open conversions. For 32 patients, there were no technological complications in the transoral insertion of the anvil to the esophageal stump. There were no anastomotic leaks after the surgery. CONCLUSIONS: The use of the OrVil device, a "the oral to the abdomen" method, changes the direction of the anvil insertion and significantly decreases both difficulty and duration of the laparoscopic surgery. More importantly, if the mass is at a higher position, this approach can achieve a higher surgical margin compared with the hand-sewn purse-string suture technique, thus avoiding the need to undergo a thoracotomy (Supplemental Digital Content 1, http://links.lww.com/SLE/A83). PMID- 23752018 TI - Pure laparoscopic partial hepatectomy using a newly developed vessel sealing device, BiClamp. AB - PURPOSE: The aim of the current study was to investigate whether pure laparoscopic partial hepatectomy can be safely performed using a newly developed vessel sealing device, BiClamp. METHODS: Nine cases of pure laparoscopic partial hepatectomy were performed by simply transecting liver parenchyma using the BiClamp. Four patients had a cirrhotic liver. The median tumor diameter was 1.5 cm (range, 1.0 to 2.7 cm). The tumors were located in segment (S) 3 in 3 cases, S4 in 1 case, S5 in 2 cases, S6 in 1 case, and S8 in 2 cases. Simultaneous cholecystectomy was performed in 4 cases. RESULTS: The median operation time was 187 minutes (range, 83 to 423 min) and the median estimated blood loss was little (range, little to 417 mL). All patients were discharged from the hospital without any adverse postoperative consequences. CONCLUSIONS: BiClamp is an effective device for transecting liver parenchyma during pure laparoscopic partial hepatectomy, even in cirrhotic livers. PMID- 23752019 TI - Cholecystectomy-related aberrant bile duct injuries and their endoscopic treatment. AB - Both complete transection and accidental ligation of the main bile duct because of a cholecystectomy are the injuries that are not amenable to endoscopic treatment and require an additional surgery. Leaks resulting from the severance of an aberrant bile duct may be treated endoscopically, although such injuries are difficult to be identified, thus resulting in treatment delays. Presented here are the details and follow-up results of 7 cases of patients with postcholecystectomy aberrant bile duct injuries, which were treated by endoscopic treatment. PMID- 23752020 TI - Laparoscopic prophylactic total gastrectomy with linear stapler side-to-side esophagojejunal anastomosis for hereditary diffuse gastric cancer syndrome in 2 siblings. AB - INTRODUCTION: Germ line mutations in the E-cadherin gene account for approximately 30% to 50% of cases of hereditary diffuse gastric cancer syndrome. The estimated cumulative risk of gastric cancer by the age of 80 years in hereditary diffuse gastric cancer families is 67% for men and 83% for women, both of which carry a very poor prognosis if an early diagnosis is not made. MATERIALS AND METHODS: Two siblings with a strong family history of gastric cancer over at least 2 generations, including an aunt testing positive for the E-cadherin gene mutation, presented with positive results of the same mutation. Both siblings underwent a laparoscopic total gastrectomy. The postoperative period was uneventful. A 7-trocar totally laparoscopic surgical approach was used. The esophagojejunal anastomosis was created using a linear stapler in a lateral side to-side manner. The biliopancreatic limb was 50 cm and the Roux limb was 75 cm in length. RESULTS: Both siblings recovered without complications. Histologic evaluation revealed benign gastric tissue with no evidence of malignancy. Margins were clear of gastric mucosa. Prophylactic total gastrectomy eliminates the risk of gastric cancer in individuals with E-cadherin gene mutations. This procedure can be performed safely with a laparoscopic approach, resulting in excellent recovery and prognosis. Totally laparoscopic, lateral side-to-side esophagojejunal anastomosis using linear stapler creates an emerged lumen of both the esophagus and the jejunum that carries less risk of stricture, and reflux is prevented by a 75-cm-long Roux limb. PMID- 23752021 TI - Laparoscopic surgery of the splenic artery and vein aneurysm with spontaneous arteriovenous fistula. AB - Visceral artery aneurysms are rare and important vascular entities due to the quarter of all cases presented as surgical emergency. Nevertheless, splenic artery aneurysm (SAA) is the most common visceral and third most common intra abdominal artery aneurysm after aorta and iliac artery. SAA accompany splenic vein aneurysm because arteriovenous fistula communication between them is a very rare entity. Location and size of the SAA determine the likelihood of rupture. Women of child-bearing age who have SAAs are at particularly high risk of death as a result of aneurysm rupture and should be treated with elective repair. Herein, we report a case of a splenic artery and vein aneurysm with arteriovenous fistula in a 25-year-old young female patient who presented with left upper quadrant pain. Diagnosis was established by computerized tomography angiogram. The patient underwent laparoscopic resection of splenic artery and vein, as well as with splenectomy. Laparoscopic therapy for SAA should be considered for the patient with a low periprocedural morbidity at experienced surgical clinics. PMID- 23752022 TI - Colonic obstruction as an unusual presentation of endometrioma: a case report. AB - Endometriosis usually occurs in the pelvis but can be found nearly anywhere in the body. Bowel involvement in endometriosis is uncommon and it is estimated to be present in 3.7% to 35% of women with endometriosis. It can rarely result in intestinal obstruction. Here, we present a synchronous localization of endometriosis, ovarian and intestinal, resulting in chronic gastrointestinal symptoms and colonic obstruction in a 33-year-old woman. PMID- 23752023 TI - Treatment of bleeding rectal varices with transumbilical venous obliteration of the inferior mesenteric vein. AB - A 56-year-old male with alcohol-induced liver cirrhosis developed rectal varices. He had a prior history of treatment for esophageal varices with endoscopic variceal ligation. Despite the repeated treatment for rectal varices with endoscopic variceal ligation, endoscopic injection sclerotherapy, and surgery, the bleeding from the rectal varices could not be controlled. Multidetector-row computed tomography and 3D-angiography revealed the hemodynamic profile of the rectal varices. We next approached the rectal varices through the umbilical vein on the abdominal wall, and successfully embolized the varices continuing from the inferior mesenteric vein using coils and a 5% solution of ethanolamine oleate with iopamidol. PMID- 23752024 TI - Laparoscopic resection of small bowel sarcoma. AB - A 45-year-old female who presented with nausea, vomiting, abdominal pain, and anemia was found to have an 8 * 5 * 5 cm ileal tumor on CT imaging. Laparoscopic evaluation and small bowel resection was performed with clear margins with a diagnosis of low-grade leiomyosarcoma. Small intestine leiomyosarcoma is very rare, and there are no prior reports of laparoscopic resection. PMID- 23752025 TI - Da Vinci robot-assisted anatomic left hemihepatectomy and biliary reconstruction. AB - BACKGROUND: Since the introduction of Da Vinci robotic surgery, more and more complicated surgeries can now be performed robotically, yet there have been very few on robotic hepatectomy, especially when billiary reconstruction is involved. The video shows our initial experience with an anatomic hepatectomy using Da Vinci surgical robot. In this case, we also conducted billiary reconstruction due to the anatomic abnormality of bile duct, while applying the choledochoscopy. The preoperative diagnosis is primary liver carcinoma, tumor thrombi in bile duct, and hepatitis B. METHODS: First, the gallbladder was resected, and cystic artery and duct were identified. After opening of the common bile duct above the junction, the choledochoscopy was performed. Tumor thrombi were found in common bile duct and left hepatic duct, and they were all removed. Left branches hepatic artery and portal vein were dissected, ligated, and divided. Thrombi in the left hepatic duct were removed also. After marking the cutting line along the ischemic boarder, liver parenchyma was transected using robotic harmonic scalpel. Branches of ducts were encountered and managed by either direct coagulating or dividing after clipping. The left hepatic vein was visualized, exposed, and divided during hepatectomy. Two T tubes were placed into common hepatic duct and the proximal cutting end of right anterior bile duct which was found to join the left hepatic duct, respectively. RESULTS: The operation went on successfully. The operation time was 410 minutes, the blood loss was 200 mL. The pathologic diagnosis was introductal papillary adenocarcinoma of left hepatic duct. The patient went on well postoperatively and was followed up for 22 months till now. Postoperative computed tomography examination showed no recurrence. CONCLUSIONS: Da Vinci assisted robotic hepatectomy can be performed safely in the hands of experienced hepatobilliary surgeons, and choledochoscopy can be combined for bile duct exploration. With the advantages of Da Vinci robot system, complicated billiary reconstruction can be performed (http://links.lww.com/SLE/A74). PMID- 23752026 TI - The intracorporeal knot tying using rigid instruments in single-incision laparoscopic surgery. AB - It is difficult to perform intracorporeal knot tying in a single-incision laparoscopic surgery. The instruments may not work together willingly in the limited working area. To get the proper triangulation to manipulate the instruments might be the main issue in the process of knot tying. It has been known that the knit stitch might improve knot tying in a conventional laparoscopic surgery. The modified method of knit stitch in this study was performed using a single-incision laparoscopic surgery. To use the half circle of the curved needle in the intracorporeal knot-tying procedure was effective in getting the proper angle for manipulation of rigid instruments. Spinning instrument according to the butt of the curved needle minimized the movement of working instruments. The modified method might be useful in solving the difficulty of the knot tying in a single-incision laparoscopic surgery. PMID- 23752027 TI - Laparoscopic single-stapling gastric transection for exophytic pedunculated gastrointestinal stromal tumor: is a safe procedure? AB - Gastrointestinal stromal tumors (GISTs) represent the most common mesenchymal tumors of the gastrointestinal tract. The macroscopic growth of these lesions can be intraluminal, extraluminal, or intramural, but only 6 cases in literature report a description of the pedunculated type. A 69-year-old man was admitted to our department after an echocardiographical control revealing, as an incidental consequence, an epigastric mass. Computed tomography and magnetic resonance imaging showed the presence of an oval lesion between the third segment of the liver and the front wall of the gastric antrum, measuring approximately 40 * 30 mm and suspected for pedunculated GIST. We describe the laparoscopic approach performed and the surgical technique that we suggest in similar cases. Although there are still many controversies on the use of laparoscopy in the treatment of gastric GISTs, laparoscopic resection can safely be adopted for an exophytic pedunculated GIST in an institute with experience in minimally invasive surgery. PMID- 23752028 TI - Laparoscopic pancreaticoduodenectomy assisted by mini-laparotomy. AB - PURPOSE: Pancreaticoduodenectomy (PD) is the treatment of choice for periampullary disease. Even with the increasing number of successful reports from around the globe, laparoscopic pancreaticoduodenectomy (LPD) is still not fully accepted. We report the results of our experience of LPD assisted by mini laparotomy. METHOD: This retrospective review study included 42 patients who received LPD assisted by mini-laparotomy between March 2009 and April 2012. Clinical outcomes, such as patient age, pathologic diagnosis, pancreas nature, operation time, conversion rate, hospital stay, postoperative complication, and mortality rates, were reviewed. RESULTS: A total of 42 patients (age range, 42 to 70 y ) received LPD assisted by mini-laparotomy. The mean incision length for the laparotomy was 5.2 cm. Mean operative time was 404 minutes, and 3 cases required conversion to open surgery. Mean postoperative hospital stay was 17 days. There were 3 cases of pancreaticogastrostomy leakage, 2 cases of postoperative bleeding, 4 cases of delayed gastric emptying, 1 case of bile leakage, and 5 cases of pulmonary complications. Of the 5 patients with pulmonary complications, 1 died. CONCLUSIONS: When performed by a surgeon with ample experience in laparoscopic surgery, LPD assisted by mini-laparotomy is a safe, feasible alternative to conventional PD for select cases. The method described in this study can be used to perform pancreaticoenteric anastomosis in the same manner as an open PD, while taking advantage of the merits of minimally invasive surgery. PMID- 23752029 TI - Autosomal dominant polycystic kidney disease: prevalence of renal neoplasias in surgical kidney specimens. AB - BACKGROUND: The role of autosomal dominant polycystic kidney disease (ADPKD) as a risk factor for renal cell carcinoma (RCC) is still under discussion. Data on prevalence of RCC in ADPKD are limited, especially on a large population scale. The aim of this study was to analyze the prevalence of RCC in ADPKD kidneys and characterize the clinical features of this coincidence. METHODS: Based on our histopathological registry for ADPKD and the Else Kroner-Fresenius Registry, we retrospectively reviewed malignant and benign renal lesions in patients with ADPKD who had undergone renal surgery from 1988 to 2011. RESULTS: 240 ADPKD patients underwent 301 renal surgeries. Mean age at surgery was 54 years. Overall, 16 malignant and 11 benign lesions were analyzed in 301 kidneys (5.3%; 3.7%), meaning that 12/240 (5%; 1:20) patients presented with malignant renal lesions. 66.7% (8/12) of these patients had undergone dialysis prior to surgery. We found 10/16 (63%) papillary RCC, 5/16 (31%) clear cell RCC, and 1/16 (6%) papillary noninvasive urothelial cancer. Regarding all renal lesions, 6/17 (35.3%) patients had more than one histological finding in their kidneys. In 2 cases, metachronous metastases were removed. Mean follow-up was 66.7 months. CONCLUSION: Kidney-related prevalence of RCC in ADPKD kidneys was surprisingly high. Whether or not this is due to chronic dialysis or due to the underlying disease is still speculative. Like other cystic renal diseases with an increased risk for RCC, the attending physician should be aware of the malignant potential of ADPKD, especially with concomitant dialysis. PMID- 23752030 TI - OPG/RANK/RANKL axis in atrial fibrillation. PMID- 23752031 TI - Effect of seasonal and geographical differences on skin and effect of treatment with an osmoprotectant: Sorbitol. AB - Human skin maintains an optimal permeability barrier function in a terrestrial environment that varies considerably in humidity. Cells cultured under hyperosmotic stress accumulate osmolytes including sorbitol. Epidermal keratinocytes experience similar high osmolality under dry environmental conditions because of increased transepidermal water loss (TEWL) and concomitant drying of the skin. This study was designed to determine if epidermal keratinocytes, in vitro, could be protected from high osmotic stress, with the exogenous addition of sorbitol. In addition, we evaluated the effect of a formulation containing topical sorbitol on skin barrier and moisturization of subjects living in arid and humid regions in summer as well as in winter. Results from in vitro experiments showed that 50 mM sorbitol protected epidermal keratinocytes from osmotic toxicity induced by sodium chloride. Clinical studies indicated that skin chronically exposed to hot, dry environment appeared to exhibit stronger skin barrier and a lower baseline TEWL. In addition, skin barrier was stronger in summer than in winter. Sorbitol exhibited significant improvement in both barrier repair and moisturization, especially in individuals subjected to arid environmental conditions. PMID- 23752032 TI - Menopause increases the iron storage protein ferritin in skin. AB - Menstruation and desquamation are important routes for humans to excrete iron. Because menstruation is no longer available in postmenopausal women, in the present study, we examined whether iron accumulates more in postmenopausal skin than in premenopausal skin. Skin biopsy samples were obtained from six pre- and six postmenopausal Caucasian women. Iron levels in the form of ferritin were 42% higher, but vascular endothelial growth factor and total antioxidant capacity were 45% and 34% lower in postmenopausal skin (58.8 +/- 1.3 years old) than in premenopausal skin (41.6 +/- 1.7 years old), respectively. Moreover, in vitro cultured normal human epidermal keratinocytes had surprisingly high levels of ferritin when compared to immortalized human breast epithelial MCF-10A cells or human liver HepG2 cancer cells. Our results indicate that skin is a cellular repository of iron and that menopause increases iron in skin and, thus, may contribute to the manifestation of accelerated skin aging and photo aging after menopause. PMID- 23752033 TI - Fit of fluxes of sunscreens and other compounds from propylene glycol:water (30:70) through human skin and silicone membrane to the Roberts-Sloan equation: the effect of polar vehicle (or water) solubility. AB - It would be useful to develop a surrogate for animal skin, which could be use to predict flux through human skin. The fluxes (and physicochemical properties) of sunscreens and other compounds from propylene glycol (PG):water (AQ), 30:70, through human skin have previously been reported. We measured the fluxes of several of those sunscreens and other compounds from PG:AQ, 30:70, through silicone membrane and fit both sets of data to the Roberts-Sloan (RS) equation to determine any similarities. For both sets of data, the fluxes were directly dependent on their solubilities in a lipid solvent [octanol (OCT), in this case] and in a polar solvent (PG:AQ, 30:70, or AQ in this case) and inversely on their molecular weights. The fit of the experimental (EXP) fluxes through human skin in vivo to RS was excellent: r2 = 0.92 if the vehicle (VEH) PG:AQ, 30:70 was the polar solvent (RS1) or r2 = 0.97 if water was the polar solvent (RS2). The fit of the EXP fluxes through silicone membrane to RS was good: r2 = 0.80 if the VEH PG:AQ, 30:70, was the polar solvent (RS1) or r2 = 0.81 if water was the polar solvent (RS2). The correlations between their EXP fluxes through human skin in vivo and their EXP fluxes through silicone membrane were good (r2 = 0.85). In addition, the correlation between EXP fluxes from PG:AQ, 30:70, through human skin in vivo and their fluxes calculated from the coefficients of the fit of solubilities, molecular weights and fluxes from water through silicone membranes from a previous n = 22 database to RS was even better (r2 = 0.94). These results suggest that flux through human skin can be calculated from flux through a silicone membrane. PMID- 23752034 TI - Effects of seaweed Laminaria japonica extracts on skin moisturizing activity in vivo. AB - Twelve species of edible seaweed from the coast of Korea were screened for skin moisturizing activity. We placed the lead of a Corneometer on an approximately 6 cm2 test area of the forearm and measured both untreated skin (control) and skin treated with test moisturizing creams either containing or not containing 5% water:propylene glycol (50:50) extracts of seaweeds. Over the 8-h observation period, the strongest activity of the Laminaria japonica extracts occurred at the 2-h period. For the 10% extract, hydration with the L. japonica extract increased by 14.44% compared with a placebo. Transepidermal water loss (TEWL) was also measured using a test cream with 10% L. japonica extract. For up to 8 h after applying the creams, TEWL was decreased to 4.01 g/cm2, which was approximately 20% of that seen with the control. We suggest that the L. japonica extract hydrates skin via the humectants and hydrocolloids that it contains. To confirm the safety of L. japonica extracts, we performed a patch test on human skin. The results suggested that at moderate doses humans can safely use the extracts. For commercial applications, we evaluated the physicochemical characteristics of the test cream products, including Hunter L, a, and b values; pH; refractive index; and coefficient of viscosity. L. japonica extract did not affect overall formulations of the test cream product in any of the tested aspects. These results suggest that L. japonica extract is a promising ingredient in moisturizing formulations. PMID- 23752035 TI - Kinetics of ultraviolet B irradiation-mediated reactive oxygen species generation in human keratinocytes. AB - Ultraviolet B (UVB)-mediated oxidative stress in keratinocytes has been accepted as an important factor contributing to skin damage. The present study revealed the kinetics of reactive oxygen species (ROS) production and identified the main specific ROS generated in human keratinocytes exposed to UVB. Keratinocytes were exposed to various doses of UVB, and intracellular ROS kinetics were evaluated by specific oxidant probes, namely, 2',7'-dichlorofluorescein diacetate, dihydroethidium, 10-acetyl-3,7-dihydroxyphenoxazine, and 3'-(p-hydroxyphenyl) fluorescein. Results revealed that UVB-irradiated cells exhibited significantly higher rate of ROS production in the early time period (0-2 h) compared to the nontreated control cells; however, the rate of ROS generation afterward (2-6 h) was similar to that of control cells. Specific ROS, including superoxide anion, hydrogen peroxide, and hydroxyl radical were enhanced in keratinocytes treated with UVB. Results regarding kinetics of specific ROS production revealed that superoxide anion and hydroxyl radical were the main ROS contributing to oxidative stress in the early phase (0-2 h) after UVB treatment in these cells. Further, this study showed the effect of known antioxidant, vitamin C, on ROS kinetics in UVB-exposed keratinocytes. PMID- 23752036 TI - A novel topical ingredient derived from seaweed significantly reduces symptoms of acne vulgaris: a general literature review. AB - Currently, benzoyl peroxide, antibiotics, and retinoids are the mainstay topical treatments for acne vulgaris. However, potential benefits may be offered by natural, marine-derived ingredients, such as those derived from brown seaweed (Laminaria digitata). This article will review the available literature on two ingredients; "seaweed oligosaccharides," which are those derived from the polysaccharide membrane of Laminaria digitata, and a novel seaweed oligosaccharide-zinc complex (SOZC) (Phycosaccharide AC, The Mentholatum Company, East Kilbride, UK). Findings from a recent double-blind, placebo-controlled, randomized clinical trial (RCT) will also be reported and likely mechanisms discussed. The findings taken together suggest that SOZC can significantly ameliorate symptoms of acne vulgaris, particularly in terms of reducing sebum production and populations of Propionibacterium acnes. PMID- 23752037 TI - Toward graduate medical education (GME) accountability: measuring the outcomes of GME institutions. AB - PURPOSE: Graduate medical education (GME) plays a key role in the U.S. health care workforce, defining its overall size and specialty distribution and influencing physician practice locations. Medicare provides nearly $10 billion annually to support GME and faces growing policy maker interest in creating accountability measures. The purpose of this study was to develop and test candidate GME outcome measures related to physician workforce. METHOD: The authors performed a secondary analysis of data from the American Medical Association Physician Masterfile, National Provider Identifier file, Medicare claims, and National Health Service Corps, measuring the number and percentage of graduates from 2006 to 2008 practicing in high-need specialties and underserved areas aggregated by their U.S. GME program. RESULTS: Average overall primary care production rate was 25.2% for the study period, although this is an overestimate because hospitalists could not be excluded. Of 759 sponsoring institutions, 158 produced no primary care graduates, and 184 produced more than 80%. An average of 37.9% of internal medicine residents were retained in primary care, including hospitalists. Mean general surgery retention was 38.4%. Overall, 4.8% of graduates practiced in rural areas; 198 institutions produced no rural physicians, and 283 institutions produced no Federally Qualified Health Center or Rural Health Clinic physicians. CONCLUSIONS: GME outcomes are measurable for most institutions and training sites. Specialty and geographic locations vary significantly. These findings can inform educators and policy makers during a period of increased calls to align the GME system with national health needs. PMID- 23752039 TI - Coevolution of mast seeding in trees and extended diapause of seed predators. AB - Many trees in forests show synchronized and intermittent reproduction, which is called "masting" or mast seeding. According to recent theoretical studies, the evolution of masting is promoted both by recruitment through the seedling bank and by seed predators. An important class of specialist seed predators (e.g., weevils and some moths) are parasitoids that oviposit on or in fruits from which the next generation emerges over the following several years. This staggered emergence is called "extended diapause". In this paper, we study the simultaneous evolution of tree masting and extended diapause of seed predators. If a fixed fraction of diapausing larvae matures every year, the evolution of trees results in masting (intermittent reproduction with a large fluctuation in reproductive activity) or non-masting (trees reproduce every year). The transition occurs discontinuously, showing evolutionary jumping. The range of seedling survivorship for which masting evolves is broader when the ovipositing efficiency and larval survivorship of the seed predators are large. Interestingly, the conditions for the evolution of masting are broadest for an intermediate fraction of extended diapause of seed predators. When both tree masting and the extended diapause of seed predators evolve simultaneously, the evolutionary end point of the fraction of extended diapause is clearly greater than the value that most favors masting evolution. The stochasticity caused by the finiteness of the number of trees tends to promote masting evolution. PMID- 23752038 TI - A logic model for community engagement within the Clinical and Translational Science Awards consortium: can we measure what we model? AB - The Clinical and Translational Science Award (CTSA) initiative calls on academic health centers to engage communities around a clinical research relationship measured ultimately in terms of public health. Among a few initiatives involving university accountability for advancing public interests, a small CTSA workgroup devised a community engagement (CE) logic model that organizes common activities within a university-community infrastructure to facilitate CE in research. Whereas the model focuses on the range of institutional CE inputs, it purposefully does not include an approach for assessing how CE influences research implementation and outcomes. Rather, with communities and individuals beginning to transition into new research roles, this article emphasizes studying CE through specific relationship types and assessing how expanded research teams contribute to the full spectrum of translational science.The authors propose a typology consisting of three relationship types-engagement, collaboration, and shared leadership-to provide a foundation for investigating community-academic contributions to the new CTSA research paradigm. The typology shifts attention from specific community-academic activities and, instead, encourages analyses focused on measuring the strength of relationships through variables like synergy and trust. The collaborative study of CE relationships will inform an understanding of CTSA infrastructure development in support of translational research and its goal, which is expressed in the logic model: better science, better answers, better population health. PMID- 23752040 TI - Does polarized training improve performance in recreational runners? AB - PURPOSE: To quantify the impact of training-intensity distribution on 10K performance in recreational athletes. METHODS: 30 endurance runners were randomly assigned to a training program emphasizing low-intensity, sub-ventilatory threshold (VT), polarized endurance-training distribution (PET) or a moderately high-intensity (between-thresholds) endurance-training program (BThET). Before the study, the subjects performed a maximal exercise test to determine VT and respiratory-compensation threshold (RCT), which allowed training to be controlled based on heart rate during each training session over the 10-wk intervention period. Subjects performed a 10-km race on the same course before and after the intervention period. Training was quantified based on the cumulative time spent in 3 intensity zones: zone 1 (low intensity, RCT). The contribution of total training time in each zone was controlled to have more low-intensity training in PET (+/-77/3/20), whereas for BThET the distribution was higher in zone 2 and lower in zone 1 (+/-46/35/19). RESULTS: Both groups significantly improved their 10K time (39min18s +/- 4min54s vs 37min19s +/- 4min42s, P < .0001 for PET; 39min24s +/- 3min54s vs 38min0s +/- 4min24s, P < .001 for BThET). Improvements were 5.0% vs 3.6%, ~41 s difference at post-training-intervention. This difference was not significant. However, a subset analysis comparing the 12 runners who actually performed the most PET (n = 6) and BThET (n = 16) distributions showed greater improvement in PET by 1.29 standardized Cohen effect size units (90% CI 0.31-2.27, P = .038). CONCLUSIONS: Polarized training can stimulate greater training effects than between-thresholds training in recreational runners. PMID- 23752041 TI - Aedes aegypti saliva contains a prominent 34-kDa protein that strongly enhances dengue virus replication in human keratinocytes. PMID- 23752042 TI - Efficacy of RG1-VLP vaccination against infections with genital and cutaneous human papillomaviruses. AB - Licensed human papillomavirus (HPV) vaccines, based on virus-like particles (VLPs) self-assembled from major capsid protein L1, afford type-restricted protection against HPV types 16/18/6/11 (or 16/18 for the bivalent vaccine), which cause 70% of cervical cancers (CxCas) and 90% of genital warts. However, they do not protect against less prevalent high-risk (HR) types causing 30% of CxCa, or cutaneous HPV. In contrast, vaccination with the minor capsid protein L2 induces low-level immunity to type-common epitopes. Chimeric RG1-VLP presenting HPV16 L2 amino acids 17-36 (RG1 epitope) within the DE-surface loop of HPV16 L1 induced cross-neutralizing antisera. We hypothesized that RG1-VLP vaccination protects against a large spectrum of mucosal and cutaneous HPV infections in vivo. Immunization with RG1-VLP adjuvanted with human-applicable alum-MPL (aluminum hydroxide plus 3-O-desacyl-4'-monophosphoryl lipid A) induced robust L2 antibodies (ELISA titers 2,500-12,500), which (cross-)neutralized mucosal HR HPV16/18/45/37/33/52/58/35/39/51/59/68/73/26/69/34/70, low-risk HPV6/11/32/40, and cutaneous HPV2/27/3/76 (titers 25-1,000) using native virion- or pseudovirion (PsV)-based assays, and a vigorous cytotoxic T lymphocyte response by enzyme linked immunospot. In vivo, mice were efficiently protected against experimental vaginal challenge with mucosal HR PsV types HPV16/18/45/31/33/52/58/35/39/51/59/68/56/73/26/53/66/34 and low-risk HPV6/43/44. Enduring protection was demonstrated 1 year after vaccination. RG1-VLP is a promising next-generation vaccine with broad efficacy against all relevant mucosal and also cutaneous HPV types. PMID- 23752043 TI - Lack of response to laser comb in spontaneous and graft-induced alopecia areata in C3H/HeJ mice. PMID- 23752045 TI - The effects of peritoneal dialysis on blood glutamate levels: implementation for neuroprotection. AB - BACKGROUND: Previous study has demonstrated the efficacy of hemodialysis in reducing blood glutamate levels. The purpose of the present study is to investigate whether peritoneal dialysis (PD) may be effective in lowering blood glutamate levels, which may serve as a potential tool for improving neurological function after brain injury. METHODS: Two liters of dialysis solution were infused over 10 minutes into 18 patients with stage V chronic kidney disease. Blood samples were collected immediately before initiation of PD, and hourly for a total of 5 blood samples. Blood samples were sent for determination of glutamate, creatinine, urea, glucose, glutamate oxaloacetate transaminase, and glutamate pyruvate transaminase. PD samples were collected and analyzed for glutamate, creatinine, urea, and glucose at the same time points as the blood samples. RESULTS: Blood glutamate concentrations were significantly reduced by 60 minutes after the infusion of dialysis solution (P<0.0001), whereas levels of glutamate in the dialysis solution were increased significantly by 60 minutes (P<0.0001). CONCLUSIONS: We demonstrated that PD is an effective modality in reducing blood glutamate concentrations. This method may be potentially utilized for the treatment of acute and chronic brain disorders that are accompanied by elevated glutamate in the brain's extracellular fluid. Considering the rapid saturation of the PD solution with glutamate, we recommend frequent dwelling of the PD solution in order to maintain low concentrations of blood glutamate. PMID- 23752044 TI - Mast cells are required for full expression of allergen/SEB-induced skin inflammation. AB - Atopic dermatitis (AD) is a chronic pruritic inflammatory skin disease. We recently described an animal model in which repeated epicutaneous applications of a house dust mite extract and Staphylococcal enterotoxin B induced eczematous skin lesions. In this study we showed that global gene expression patterns are very similar between human AD skin and allergen/staphylococcal enterotoxin B induced mouse skin lesions, particularly in the expression of genes related to epidermal growth/differentiation, skin barrier, lipid/energy metabolism, immune response, or extracellular matrix. In this model, mast cells and T cells, but not B cells or eosinophils, were shown to be required for the full expression of dermatitis, as revealed by reduced skin inflammation and reduced serum IgE levels in mice lacking mast cells or T cells (TCRbeta(-/-) or Rag1(-/-)). The clinical severity of dermatitis correlated with the numbers of mast cells, but not eosinophils. Consistent with the idea that T helper type 2 (Th2) cells play a predominant role in allergic diseases, the receptor for the Th2-promoting cytokine thymic stromal lymphopoietin and the high-affinity IgE receptor, FcERI, were required to attain maximal clinical scores. Therefore, this clinically relevant model provides mechanistic insights into the pathogenic mechanism of human AD. PMID- 23752046 TI - Biphasic change of progenitor proliferation in dentate gyrus after single dose of isoflurane in young adult rats. AB - BACKGROUND: Isoflurane exposure causes improvement in long-term neurocognitive function in young adult rats; this is associated with an increase in dentate gyrus (DG) progenitor proliferation 4 days after anesthesia. However, the number of new neurons that were born from cells that incorporated bromodeoxyuridine (BrdU) 4 days after anesthesia is not affected by anesthesia. We tested the hypothesis that progenitor proliferation continues to increase past 4 days, which would imply the possibility that the number of new neurons after anesthesia could be increased if BrdU labeling occurred at a later time point. METHODS: BrdU was injected at 0, 1, 2, 4, 9, 16 days after 4 hours of isoflurane exposure to 60-day old rats. Brains were harvested 2 hours later, immunohistochemically stained, and the number of BrdU+ cells in the DG was assessed microscopically. RESULTS: After 4 hours of exposure to isoflurane in 60-day old rats, the number of BrdU+ cells decreased on days 0 to 2, then increased on day 4 significantly, and regressed toward the control level on days 9 and 16. CONCLUSIONS: Anesthesia-induced progenitor proliferation in the DG was not sustained 9 days after anesthesia. We interpret these results to signify that an anesthetic effect on neurogenesis likely does not play a critical role in the previously observed isoflurane induced long-term improvement in neurocognitive function in 60-day old rats and that the transient increase in progenitor proliferation serves to replenish the pool of neural stem cells. The mechanism of anesthesia-induced improvement in cognition of young adult rats remains elusive. PMID- 23752047 TI - [Review of overlap syndromes in autoimmune liver diseases. Diagnostic and therapeutic difficulties]. AB - Overlap syndromes are biochemical, serological, histological and radiological overlaps across the classic autoimmune liver diseases in the presence of autoimmun hepatitis and primary biliary cirrhosis or primary sclerosing cholangitis. The exact prevalence of the disease is not known, but it may vary between 5% and 20%. Because it has no generally accepted diagnostic criteria, clinical signs, biochemical, serological, radiological and histological findings are evaluated together. Treatment depends on the predominant feature of the overlap syndrome; ursodeoxycholic acid and/or immunsuppressive (corticosteroid) treatment are used, based on observations from retrospective, non-randomized studies. PMID- 23752048 TI - [The history of reorientation therapy]. AB - Most scientists today agree that sexual orientation is most likely the result of a complex interaction of environmental, cognitive, and biological factors. In past decades in the United States there has been a big discourse as to the necessity and effectiveness of changing same-sex attraction. Researchers disagree on whether same-sex attraction can be changed. Position statements of the major mental health organizations state that there is not enough scientific evidence to support the reorientation therapy. In addition, there is some evidence to indicate that some individuals experienced harm or believed they had been harmed by these interventions. The aim of this article is to give a historic overview of the reorientation therapies, to review the efficacy of the therapies, motivations for seeking therapy, arguments for and against the therapy, and to overview the actual mainstream organizations' statements. PMID- 23752049 TI - [Intermittent hydronephrosis in childhood]. AB - INTRODUCTION: Intermittent pelviureteric junction obstruction, and its consequence,intermittent hydronephrosis is a difficult condition to identify. The renal collecting system is not dilated between the episodes of abdominal pain attacks and a prompt investigation is hard to carry out during the time of painful crisis. Therefore, most of the patients are initially misdiagnosed. AIM: The aim of the study was to assess the occurrence and the clinical characteristics of this phenomenon in children operated in the Department of Urological Surgery, Heim Pal Children Hospital, Budapest, Hungary. PATIENTS AND METHODS: Medical records of children operated for hydronephrosis between 2008 and 2012 were reviewed. The occurrence rate and clinical features of intermittent hydronephrosis were analyzed. RESULTS: 76 children were operated for pelviureteric junction obstruction, of which 10 met the criteria of intermittent hydronephrosis. The average interval between the onset of symptoms and the final diagnosis was 2 years and 4 months. In 7 patients pyeloplasty, and in 3 patients nephrectomy were performed. CONCLUSIONS: Intermittent hydronephrosis represents a well-defined proportion among cases operated for hydronephrosis. The delay in diagnosis led to the loss of the kidney in one third of the patients, and this finding urges for the awareness of health professionals for this phenomenon. In case of recurrent abdominal pain of unknown etiology one must suspect a urological origin, even if a previous abdominal ultrasound showed normal kidneys. PMID- 23752050 TI - [Evaluation of ambulatory antibiotic use in Hungary using drug-specific quality indicators]. AB - INTRODUCTION: Rational use of antibiotics is an important tool in combating antibiotic resistance. AIM: The aim of the authors was to evaluate the quality of ambulatory antibiotic use in Hungary. METHOD: Crude antibiotic sales data for the period between 1996 and 2010 were converted into DDD (Defined Daily Dose) per 1000 inhabitants and per year. The recently developed and validated drug-specific quality indicators were used to evaluate antibiotic use. RESULTS: Beside constant quantity (18.0+/-1.8 DDD/1000 inhabitants/day), the authors detected major changes in the composition of antibiotic use. Ratios of the consumption of broad to narrow spectrum beta-lactams and macrolides increased eight-fold (1996: 2.2 vs. 2010: 15.8) and consumption of fluoroquinolones tripled. Out of the ten surveyed drug-specific quality indicators, Hungary belonged to the European elite in case of three, while considering the remaining seven, Hungary ranked among the weak or weakest European countries. CONCLUSION: In quantity Hungary an ambulatory antibiotic use resembles to Scandinavian countries while it mimics antibiotic consumption patterns of southern countries. PMID- 23752052 TI - [Unrealized plans for medical journals before the launch of Orvosi Hetilap (Hungarian Medical Journal)]. PMID- 23752053 TI - US court lifts restrictions on some emergency contraceptives. PMID- 23752055 TI - FDA panel advises easing restrictions on rosiglitazone. PMID- 23752056 TI - Dynamic properties of liquid and undercooled aluminum. AB - First-principles molecular dynamics simulations of liquid and undercooled aluminum have been performed to study the evolution of dynamic properties across the melting point. Single-atom as well collective dynamic properties are determined and are related to the structural evolution of the liquid phase. The temperature dependence of the self-diffusion coefficient is computed from both the mean square displacement and the velocity autocorrelation function. Self diffusion coefficients follow an Arrhenius law with the single activation energy of 250 meV, consistent with experimental results for the liquid phase. Moreover, we show that the Arrhenius relation can also be applied to the undercooled state at T = 875 K. Finally, a direct calculation of the shear viscosity from the transverse current correlation function shows that the Stokes-Einstein relation can be applied over the temperature range investigated. PMID- 23752057 TI - Bronchodilator efficacy of tiotropium-formoterol via single pressurized meter dose inhaler (pMDI) versus tiotropium alone in COPD. AB - BACKGROUND: Bronchodilators form the main stay of treatment for COPD. When symptoms are not adequately controlled with one bronchodilator, addition of another bronchodilator is recommended. We have recently developed a combination of tiotropium and formoterol in a single pressurized metered dose inhaler (pMDI) (Cipla Ltd., India). The aim of this study was to compare the bronchodilator effects of a single dose of 18 mcg of tiotropium versus a single dose of a combination of 18 mcg tiotropium plus 12 mcg formoterol administered via a pMDI in subjects with moderate-to-severe COPD. STUDY DESIGN: 44 COPD subjects were enrolled in this randomized, double-blind, multi-centre, cross-over study. 18 mcg tiotropium and 18 mcg tiotropium plus 12 mcg formoterol were administered via pressurized metered dose inhalers on two separate days. FEV(1), FVC and Inspiratory capacity (IC) were measured before, 15, 30 min, 1, 2, 3, 4, 6, 8, 12 and 24 h after the study drugs were administered. RESULTS: Compared with tiotropium alone, a combination of tiotropium plus formoterol showed a faster onset of bronchodilator response (p < 0.01 for FEV(1) and FVC), a greater mean maximum change in FEV(1) (p = 0.01) and FVC (p = 0.008) and greater AUC(0-24h) values for FEV(1), FVC and IC. Trough FEV(1) and FVC values were also greater in the combination group. CONCLUSION: A combination of tiotropium plus formoterol administered via a single inhaler produced a superior bronchodilator response than tiotropium alone over a period of 24 h. PMID- 23752058 TI - Implementation of mechanical chest compression in out-of-hospital cardiac arrest in an emergency medical service system. AB - AIM: The aim of this study is to describe the outcome changes after out-of hospital cardiac arrest (OHCA) in Gothenburg, Sweden, after introduction of mechanical chest compression (MCC). METHODS: Following introduction of MCC, 1183 OHCA patients were treated from November 1, 2007, to December 31, 2011 (period 2). They were compared with 1218 OHCA patients before MCC was introduced from January 1, 1998, to May 30, 2003 (period 1). Patients in period 2 were evaluated for survival in relation to MCC use. RESULTS: The percentage of patients admitted to hospital alive increased from 25.4% to 31.9% (P < .0001). Survival to 1 month increased from 7.1% to 10.7% (P = .002) from period 1 to period 2. The proportion of ventricular fibrillation/ventricular tachycardia decreased in period 2 (P = .002). However, bystander cardiopulmonary resuscitation (P < .0001), crew witnessed cases (P = .04), percutaneous coronary intervention (P < .0001), therapeutic hypothermia (P < .0001), and implantable cardioverter-defibrillator use (P = .01) increased, as did time from call to emergency medicine service arrival (P < .0001) and to defibrillation (P = .006). In period 2, 60% of OHCA patients were treated with MCC. The percentages admitted alive to hospital (MCC vs no MCC) were 28.6% and 36.1% (P = .008). Corresponding figures for survival to 1 month were 5.6% and 17.6% (P < .0001). In the MCC group, we found increase in the delay from collapse to defibrillation (P < .0001), greater use of adrenaline (P < .0001), and fewer crew-witnessed cases (P < .0001). CONCLUSION: Survival to 1 month after implementation of MCC was higher than before introduction. However, patients receiving MCC had low survival. Although case selection might play a role, results do not support a widespread use of MCC after OHCA. PMID- 23752059 TI - Diclofenac-induced intrauterine ductal closure. PMID- 23752060 TI - Beta amyloid suppresses the expression of the vitamin d receptor gene and induces the expression of the vitamin d catabolic enzyme gene in hippocampal neurons. AB - BACKGROUND/AIMS: The beta amyloid aggregations present in Alzheimer's disease affect neurons through various toxic alterations. The aim of this study was to determine the expression of the vitamin D receptor (VDR), 25-hydroxyvitamin D3 24 hydroxylase (an accelerator of vitamin D catabolism), and the L-type voltage sensitive calcium channel A1C (LVSCC-A1C) in hippocampal neurons in response to beta amyloid and vitamin D treatments to test the protective effects of vitamin D and the probable effects of beta amyloid on vitamin D catabolism. METHODS: The expression of the VDR, 24-hydroxylase (24OHase) and LVSCC-A1C mRNAs were studied using quantitative real-time polymerase chain reaction, and the cytotoxicity levels were determined by an ELISA in primary hippocampal neuron cultures prepared from Sprague-Dawley rat embryos. RESULTS: Our results demonstrated that beta amyloid suppressed the expression of VDR mRNA and induced the expression of 24OHase and LVSCC-A1C mRNAs. CONCLUSION: Beta amyloid may disrupt the vitamin D VDR pathway and cause defective utilization of vitamin D by suppressing the level of the VDR and elevating the level of 24OHase. PMID- 23752061 TI - Relationship between body composition and glomerular filtration rate estimates in the general population. AB - BACKGROUND: Differences in body composition may lead to imprecision in estimates of glomerular filtration rate (eGFR) derived from serum creatinine. Our aims were to examine the relationship between eGFR and anthropometric and body composition measures and handgrip strength. METHODS: We analyzed data from a cross-sectional study comprising 1,630 randomly selected community-dwelling adults. The Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations were used to calculate eGFR from IMDS-standardized serum creatinine. Body mass index and body surface area were calculated from measured height and weight. Body composition was determined by dual-energy x-ray absorptiometry, handgrip strength measured by a hand-held dynamometer. Regression analysis was used to examine the association between eGFR and other factors. RESULTS: In women, eGFR determined by the MDRD equation was inversely associated with height (beta = -0.08; p = 0.012), lean mass percentage (beta = -0.06; p = 0.047) and handgrip strength (beta = -0.15; p < 0.001) and eGFR calculated using the CKD-EPI equation was inversely associated with handgrip strength (beta = -0.08; p = 0.001). In men, there was an inverse association between eGFR by the MDRD equation and lean mass percentage (beta = -0.10; p = 0.013) and handgrip strength (beta = -0.12; p = 0.022) and between eGFR by the CKD-EPI equation and lean mass percentage (beta = -0.07; p = 0.018). The R(2) for these variables was <0.02. CONCLUSIONS: The inverse relationship between eGFR and measures of lean mass percentage and handgrip strength suggests that incorporation of these variables might improve eGFR prediction from serum creatinine in the general population. This effect appears to be small however and needs to be examined in studies that include measured GFR. PMID- 23752062 TI - Descemet stripping automated endothelial keratoplasty for endothelial decompensation in buphthalmos. AB - PURPOSE: To report the results of Descemet stripping automated endothelial keratoplasty (DSAEK) to treat endothelial failure in eyes with buphthalmos. DESIGN: Prospective interventional case series. METHODS: All buphthalmic eyes with endothelial failure undergoing DSAEK by the same surgeon (M.B.) between March 2007 and January 2012 were included. Outcome measures included best spectacle-corrected visual acuity (BSCVA), refraction, and endothelial cell loss (assessed 6, 12, 24, 36, and 48 months postoperatively). Standardized DSAEK was performed in all cases, with minor modifications in phakic and aphakic eyes. Other outcomes included comparisons to penetrating keratoplasty (PK) published results and comparisons to visual outcomes in DSAEK for other indications. RESULTS: There were 14 transplants performed in 12 eyes (11 patients). Mean age was 34.9 years (range 15-54 years). The average follow-up was 21.7 +/- 13.8 months (range 6-48 months). At last follow-up examination, BSCVA had improved in 11 of 13 cases, with a logMAR average value +/- standard deviation of 0.74 +/- 0.66 from the preoperative value of 2.07 +/- 0.80. Eleven eyes reached Snellen acuity of 20/200 or better, and 5 eyes reached 20/40 or better. Mean endothelial cell loss was 40.5% +/- 8.9% (range 23.7%-53.1%). Complications included graft detachment (n = 2), glaucoma progression (n = 1), and late endothelial failure (n = 1). All complications were managed successfully either by repeat DSAEK (n = 2), rebubbling (n = 1), or cyclocryocoagulation (n = 1). CONCLUSIONS: DSAEK may be performed safely and effectively in buphthalmic eyes, with comparable results to outcomes after PK. Visual outcomes are not substantially different after DSAEK for this indication compared to DSAEK for other indications. PMID- 23752063 TI - Analysis of tear cytokines and clinical correlations in Sjogren syndrome dry eye patients and non-Sjogren syndrome dry eye patients. AB - PURPOSE: To compare concentrations of tear cytokines in 3 groups composed of Sjogren syndrome (SS) dry eye, non-Sjogren syndrome (non-SS) dry eye, and normal subjects. Correlations between ocular surface parameters and tear cytokines were also investigated. DESIGN: Prospective cross-sectional study. METHODS: SS dry eye patients (n = 24; 40 eyes) were diagnosed with primary SS according to the criteria set by the American-European Consensus Group. Non-SS dry eye patients (n = 25; 40 eyes) and normal subjects (n = 21; 35 eyes) were also enrolled. Tear concentrations of interleukin (IL)-17, IL-6, IL-10, IL-4, IL-2, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) were measured by a multiplex immunobead assay. Ocular Surface Disease Index (OSDI), tear film breakup time (TBUT), Schirmer I test, and fluorescein staining scores were obtained from dry eye patients. RESULTS: All cytokine levels except for IL-2 were highest in the SS group, followed by non-SS dry eye group and control subjects. Concentrations of IL-17, TNF-alpha, and IL-6 were significantly different among the 3 groups (IL-17: SS > control P < .001, non-SS > control P = .042, SS > non SS P < .001; TNF-alpha: SS > control P = .006, non-SS > control P = .034, SS > non-SS P = .029; IL-6: SS > control P = .002, non-SS > control P = .032, SS > non SS P = .002). IL-17 was significantly correlated with TBUT (R = -0.22, P = .012) and Schirmer I test (R = -0.36, P = .027) scores in the SS group. IL-6 was significantly correlated only with TBUT (R = -0.38, P = .02) in the non-SS group. CONCLUSIONS: Differences in tear cytokine levels and correlation patterns between SS dry eye and non-SS dry eye patients suggest the involvement of different inflammatory processes as causes of dry eye syndrome. PMID- 23752064 TI - Reversal of ER-beta silencing by chromatin modifying agents overrides acquired tamoxifen resistance. AB - The purpose of this work is to determine the molecular mechanisms underlying tamoxifen resistance. We show here that ER-beta is epigenetically silenced in a cell line with acquired tamoxifen resistance (MCF-7/TAM-R) and this could be reversed by 5-AZA-deoxycytidine (5-AZA) and trichostatin-A (TSA) pre-treatment. Subsequent treatment with 4-hydroxy-tamoxifen (4-OHT) induced ER-beta nuclear translocation, upregulated pS2 and p21 levels and reduced cell viability. Transfection with an ER-beta expression vector sensitized MCF-7/TAM-R cells to the growth inhibitory and pro-apoptotic effects of 4-OHT, indicating that ER-beta re-expression alone is sufficient to restore sensitivity to tamoxifen. This novel finding reveals that ER-beta is fundamental in overcoming acquired tamoxifen resistance and provides insights for new therapeutic protocols against breast cancer. PMID- 23752065 TI - PSMA specific single chain antibody-mediated targeted knockdown of Notch1 inhibits human prostate cancer cell proliferation and tumor growth. AB - The down-regulation of Notch1 by small interfering RNA (siRNA) can significantly inhibit human prostate cancer cell growth. The delivery of siRNA into specific cells is a key requirement for its clinical application. Recent reports have indicated that antibody-mediated siRNA delivery is an effective approach for targeted knockdown of specific genes in appropriate cells. Prostate-specific membrane antigen (PSMA) is regarded as an ideal target for the delivery of therapeutic agents to prostate cancer cells. The purpose of the present study was to evaluate whether siRNA can be efficiently delivered into PSMA-positive prostate cancer cells using two fusion proteins, s-tP and sFH-tP. These fusion proteins are composed of an anti-PSMA single chain antibody (scFv, abbreviated as an "s") and a truncated protamine (tP); and in sFH-tP a furin cleavage site and an HA2 fragment sequence (FH) were inserted between the scFv and tP domains. Our results showed that siRNA can be specifically delivered into PSMA-positive LNCaP cells by these two fusion proteins, with the sFH-tP fusion protein being more effective. Efficient knockdown of Notch1 by siNotch1 delivered by either fusion protein was observed in PSMA-positive LNCaP cells and in LNCaP xenografted nude mice. Further experiments confirmed that the fusion protein-delivered siNotch1 could efficiently inhibit PSMA-positive LNCaP cell proliferation and promote apoptosis both in vitro and in vivo. Our data describe a promising strategy for the targeted delivery of siRNA to PSMA-positive prostate cancer cells using anti PSMA scFv fusion proteins. PMID- 23752067 TI - Fate and transport of oil sand process-affected water into the underlying clay till: a field study. AB - The South Tailings Pond (STP) is a ~2300-ha tailing pond operated by Suncor Energy Inc. that has received oil sand process-affected (PA) water and mature fine tailings since 2006. The STP is underlain by a clay till, which is in turn underlain by the Wood Creek Sand Channel (WCSC). The sandy deposits of the WCSC provide greater geotechnical stability but could act as a potential flow pathway for PA water to migrate off site and into the Athabasca River. Preliminary modeling of the STP suggests that PA water from the pond will infiltrate into the underlying sand channel, but the extent and development of this impact is still poorly understood. Suncor Energy Inc. built interception wells and a cut-off-wall to control any potential seepage. Here we present the results of an investigation of the fate and transport of PA water in clay till underlying a 10 m * 10 m infiltration pond that was constructed on the southeastern portion of the STP. The geochemistry of pore water in the till underlying the infiltration pond was determined prior to filling with process-affected water (2008) and two years after the infiltration pond was filled with PA waters (2010). Pore water was analyzed for metals, cations, anions, and isotopes ((2)H and (18)O). The distribution of conservative tracers ((18)O and chloride) indicated migration of the PA waters to approximately 0.9 m, but the migrations of major ions and metals were significantly delayed relative to this depth. Uptake of Na and Mo and release of Ca, Mg, Mn, Ba, and Sr suggest that adsorption and ion exchange reactions are the foremost attenuation processes controlling inorganic solutes transport. PMID- 23752068 TI - Interleukin-23 (IL-23) deficiency disrupts Th17 and Th1-related defenses against Streptococcus pneumoniae infection. AB - Resolution of acute of infection caused by capsular Streptococcus pneumoniae infection in the absence of effective antibiotic therapy requires tight regulation of immune and inflammatory responses. To provide new mechanistic insight of the requirements needed for innate host defenses against acute S. pneumoniae infection, we examined how IL-23 deficiency mediated acute pulmonary resistance. We found that IL-23 deficient mice were more susceptible to bacterial colonization in the lungs corresponding with greater bacterial dissemination. The lack of IL-23 was found to decrease IL-6 and IL-12p70 cytokine levels in bronchiolar lavage within the initial day after infection. Pulmonary leukocytes isolated from infected IL-23 deficient mice demonstrated a dramatic decrease in IL-17A and IFN-gamma in response to heat-killed organisms. These findings corresponded with significant abrogation of neutrophilic infiltrate in the lungs compared to IL-23 competent mice. Whereas previous studies have shown opposing influences of IL-12/IL-23 regulation, our findings suggest a concordant dependency of IL-23 expression on Th1 and Th17-related responses. PMID- 23752066 TI - The natural product honokiol inhibits calcineurin inhibitor-induced and Ras mediated tumor promoting pathways. AB - Although calcineurin inhibitors (CNIs) are very useful in preventing allograft rejection, they can mediate a rapid progression of post-transplantation malignancies. The CNI cyclosporine A (CsA) can promote renal tumor growth through activation of the proto-oncogene ras and over-expression of the angiogenic cytokine VEGF; the ras activation also induces over-expression of the cytoprotective enzyme HO-1, which promotes survival of renal cancer cells. Here, we show that the natural product honokiol significantly inhibited CsA-induced and Ras-mediated survival of renal cancer cells through the down-regulations of VEGF and HO-1. Thus, honokiol treatment may help to prevent tumor-promoting effects of CsA in transplant patients. PMID- 23752069 TI - Dysembryoplastic neuroepithelial tumor: a clinical, neuroradiological, and pathological study of 15 cases. AB - Dysembryoplastic neuroepithelial tumors are rare, surgically curable, neuronal glial neoplasms affecting young patients with intractable epilepsy. Its recognition is needed to avoid unnecessary adjuvant therapy. The authors reviewed the records of 15 patients with dysembryoplastic neuroepithelial tumors who underwent epilepsy surgery using intraoperative electrocorticography monitoring, including 8 males and 7 females (mean age, 15.8 years). Neuroimaging showed a predominantly intracortical location, the presence of septations, a triangular pattern of distribution, a lack of contrast enhancement, and an absence of peritumoral edema. Eleven cases were classified as complex type, 3 as simple type, and 1 as "nonspecific" type. Associated cortical dysplasia was found in 5 cases and leptomeningeal involvement in 1 case. Its immunophenotype suggested a pluripotential neuroepithelial origin. The mean follow-up was 37.5 months; 2 patients had tumor recurrence. Although they are generally benign neoplasms, recurrences sometimes occur. Complete resection of the tumor with the epileptogenic zone is important for a favorable outcome. PMID- 23752070 TI - Episodic migraines in children: limited evidence on preventive pharmacological treatments. AB - The authors conducted a systematic literature review of preventive pharmacological treatments for episodic childhood migraines searching several databases through May 20, 2012. Episodic migraine prevention was examined in 24 publications of randomized controlled trials that enrolled 1578 children in 16 nonrandomized studies. Single randomized controlled trials provided low-strength evidence that propranolol would result in complete cessation of migraine attacks in 713 per 1000 children treated (95% confidence interval, 452-974); trazodone and nimodipine decreased migraine days, while topiramate, divalproex, and clonidine were no more effective than placebo in preventing migraines. Migraine prevention with multidisciplinary drug management was not sustained at 6 months. Divalproex resulted in treatment discontinuation due to adverse effects, and topiramate increased the risk of paresthesia, upper respiratory tract infection, and weight loss. Long-term preventive benefits and improvement in disability and quality of life are unknown. No studies examined quality of life or provided evidence for individualized treatment decisions. PMID- 23752071 TI - Neurologic complications following pediatric renal transplantation. AB - We reviewed neurologic complications after renal transplantation in children over a 20-year period. Neurologic complications were classified as early (within 3 months) and delayed (beyond 3 months). Of 115 children, 10 (8.7%) had complications. Early complications were found in 4.35% of patients: seizures in 4 (posterior reversible leukoencephalopathy syndrome due to immunosuppressant toxicity, sepsis/presumed meningitis, and indeterminate) and headaches in 1. One patient with seizures received levetiracetam for 6 months and 1 with headaches received amitriptyline prophylaxis. Late complications were noted in 4.35% of patients: seizures in 3 (posterior reversible leukoencephalopathy syndrome due to hypertension, hypertensive encephalopathy), headaches in 2, and tremors in 1. Two patients with seizures were treated with anti-epilepsy medications; 1 with migraine received cyproheptadine prophylaxis. Neurologic complications develop in children after renal transplantation. Seizures due to posterior reversible leukoencephalopathy syndrome were the commonest complication. Early detection and appropriate management of these complications is important. PMID- 23752072 TI - New revelations about Hans Berger, father of the electroencephalogram (EEG), and his ties to the Third Reich. AB - Hans Berger was a German neuropsychiatrist and head of the neurology department at the University of Jena, who discovered the human electroencephalogram (EEG). Many sources state that Berger was forced into retirement and suicide by the Nazis because he was at odds with the regime. In fact, Berger helped select his Nazi successor Berthold Kihn (complicit in "euthanasia" murders), financially supported the Nazi Schutzstaffel (SS), and was a willing participant on Nazi genetic health higher courts that reviewed appeals for forced sterilizations of neuropsychiatric patients. His motivations could be related to avoiding Nazi harassment, indoctrination by Nazi ideology, or less likely, career opportunism. His actions stand in contrast to colleagues who partially resisted the Nazis, and hopefully will serve as an example to future generations of neurologists regarding the danger of allowing one's professional standing to be used as a tool to support the policies of tyranny and oppression. PMID- 23752073 TI - Correlations of plasma citrulline levels with clinical and endoscopic score and blood markers according to small bowel involvement in pediatric Crohn disease. AB - OBJECTIVE: Several studies have indicated that plasma citrulline levels reflect the extent of mucosal injury of the small intestine. This study was performed to determine whether plasma citrulline levels correlate with the disease activity in pediatric patients with Crohn disease (CD). METHODS: A total of 63 CD and 23 ulcerative colitis (UC) patients were included in this study. Disease severity was assessed by pediatric CD activity index (PCDAI), pediatric UC activity index, simplified endoscopic activity score for CD, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). The correlations among these variables and plasma citrulline levels were evaluated. We performed subgroup analysis whether correlations between plasma citrulline levels and disease activity depend on small bowel involvement in patients with CD. RESULTS: The plasma citrulline levels correlated negatively with CRP (r = -0.332, P = 0.008), ESR (r = -0.290, P = 0.022), and PCDAI (r = -0.424, P = 0.001) in patients with CD. The plasma citrulline levels were significantly lower in patients with jejunal involvement than in those without (P = 0.027). In subgroup analysis, patients with CD with jejunal involvement showed significantly negative correlations of plasma citrulline levels with CRP (r = -0.628, P = 0.016) and PCDAI (r = -0.632, P = 0.015); however, patients with CD without jejunal involvement revealed no correlations of plasma citrulline levels with CRP and PCDAI. There were no significant correlations between plasma citrulline levels and simplified endoscopic activity score for CD. There were no significant correlations of plasma citrulline levels with CRP, ESR, and pediatric UC activity index in patients with UC. CONCLUSIONS: Plasma citrulline levels correlated with disease severity as measured by PCDAI, CRP, and ESR in pediatric patients with CD with jejunal involvement. PMID- 23752074 TI - Biliary atresia in children with aberrations involving chromosome 11q. PMID- 23752076 TI - Hemobilia caused by hepatic artery pseudoaneurysm following abdominal trauma. PMID- 23752075 TI - Medical students' conceptualizations of quality of life associated with children with IBD. AB - OBJECTIVES: The aim of the present study was to investigate second-year medical students' understanding of quality of life associated with childhood inflammatory bowel disease (IBD). METHODS: A cross-sectional study in a major teaching institution in San Francisco was carried out. A questionnaire was administered following an hour-long gastroenterology lecture, which featured 2 young patients with pediatric-onset IBD who addressed everyday life with the disease. Analyses of numerate responses to the questionnaire were paired with a content and thematic analysis of audiotape recordings of the patients' commentaries. RESULTS: Medical students' responses to the patient interviews were extremely positive. Medical students gained a new awareness of the psychosocial complexities associated with living with a pediatric chronic illness and a new way of thinking about the meaning of "healthy." Despite listening to 2 healthy young patients, however, the medical students still conceptualized pediatric IBD in mostly, although not exclusively, negative terms. CONCLUSIONS: Medical students' perceptions of pediatric IBD improved as a result of listening to the patient interviews. Although this teaching modality effectively introduced students to a complex condition, it did not overcome their unfavorable impression of the effect of IBD on children's lives. The symptoms associated with IBD have stigma attached to them, and these stereotypes influence how medical students perceive those living with this chronic illness. More research and training in this area is necessary. PMID- 23752077 TI - Psychosocial dysfunction in children and adolescents with eosinophilic esophagitis. AB - OBJECTIVE: Children with eosinophilic esophagitis (EoE) experience daily challenges related to coping with symptoms and the psychosocial effect of this chronic disease. The aim of this study was to identify features of psychosocial dysfunction experienced by children with EoE who were evaluated in a tertiary care program. METHODS: We performed a retrospective review of EoE patients and their families' psychosocial evaluations performed in a tertiary care EoE program. Consecutive evaluations were analyzed to document reports of patients' disease-related pain/discomfort; feeding/appetite symptoms; sleep, social, and school problems; depression, anxiety; and overall psychological adjustment. RESULTS: Sixty-four patients received psychosocial evaluation during an 18-month period and were analyzed. Sixty-nine percent of children evaluated experienced some form of psychosocial problems, including social difficulties (64%), anxiety (41%), sleep difficulties (33%), depression (28%), and school problems (26%). Adjustment problems were identified in 44% of the sample. Older children experienced more adjustment difficulties than younger children (P = 0.05). Sleep disturbances and feeding problems predominated in the younger children. Anxious behavior and depressive feelings increased with age. Children with gastrostomy tubes (G-tubes) had more social, school, and psychological adjustment problems than those without. CONCLUSIONS: The majority of children with EoE who underwent health and behavior evaluation in a tertiary care program experienced psychosocial adjustment and coping problems. Evaluation and management by mental health professionals would likely benefit a majority of patients with this chronic disease. PMID- 23752078 TI - Risk factors, morbidity, and treatment of thrombosis in children and young adults with active inflammatory bowel disease. AB - OBJECTIVES: Pediatric inpatients with inflammatory bowel disease (IBD) are rarely considered for thromboprophylaxis because of concerns about safety and underappreciation of thrombotic risk. We characterized thromboembolism (TE) in children and young adults with inflammatory bowel disease (IBD) at a single tertiary care hospital. METHODS: We performed a retrospective review of an inpatient billing database for all IBD admissions with colonic involvement and an anticoagulation database for thrombotic complications from 2006 to 2011. RESULTS: Of 532 patients admitted with IBD with colonic involvement, 10 (1.9%) had TE (9 venous, 1 arterial), 2 of whom had recurrent thrombosis. Many of the events resulted in considerable morbidity, including 4 cerebrovascular events and 2 pulmonary emboli. Established risk factors in IBD colitis inpatients with TE included: indwelling catheter (4/10), first-degree family member with TE (2/10), hereditary thrombophilia (3/10), smoking (1/10), oral contraceptive (1/5 females), and thalidomide (1/10). Additionally, most (8/10) patients had acquired thrombophilia, mostly elevation of factor VIII and anticardiolipin antibodies. Patients with IBD and TE received therapeutic anticoagulation without significantly increased bleeding. Thrombus resolution was documented in 7 cases, persistence in 2 cases and recurrence in 2 cases. CONCLUSIONS: Pediatric inpatients hospitalized with IBD with colonic involvement have increased risk of TE, including complications of pulmonary embolism, recurrence, persistence, and indefinite long-term anticoagulation. Therapeutic anticoagulation in patients with IBD with active colitis appears safe. We identified both inherited thrombophilias and acquired risk factors in patients with IBD and TE. We presently use risk stratification and recommend prophylactic anticoagulation in high-risk patients. PMID- 23752079 TI - Correlation of health-related quality of life in children with inflammatory bowel disease, their parents, and physician as measured by a visual analog scale. AB - BACKGROUND AND AIMS: Inflammatory bowel disease has been shown to affect children's health-related quality of life (HRQOL) through the use of lengthy questionnaires. We examined whether a pediatric patient's HRQOL, measured by a rapid visual analog scale ("feeling thermometer"), correlates with the perceptions of the HRQOL as determined by the patient's pediatric gastroenterologist and parent(s). Additionally, we attempted to determine whether the HRQOL correlates with the patient's disease activity as determined by validated activity indices. METHODS: A cross-sectional study of pediatric patients (ages 7-21 years) who were diagnosed as having Crohn disease, ulcerative colitis, or indeterminate colitis was conducted from January 2011 to May 2011. Each participant (patient, parent(s), and treating pediatric gastroenterologist) completed feeling thermometers to determine the symptom burden as well as therapeutic burden of the patient. The parent(s) and doctor were blinded to the patient's results. Pediatric Ulcerative Colitis Activity Index or a Short Pediatric Crohn Disease Activity Index (S-PCDAI) was calculated. Correlations between the participant's perceived burdens as well as their calculated disease activity were determined. RESULTS: Sixty-seven children and their families participated, resulting in 101 visits. Patients had a mean age of 15.0 years, and there were 38 boys. There was a strong significant correlation between the patient's perceived symptom burden and that of the parent's (rho 0.59, P < 0.001) and physician (rho 0.48, P < 0.001). Similarly, there was a strong significant correlation between patient's perceived treatment burden and that of the parent treatment burden (rho 0.49, P < 0.001) and, to a lesser degree, the physician (rho 0.29, P < 0.003). The correlation coefficient was strongest between the physician's perception of the patient's symptom burden against the standard disease activity indices Pediatric Ulcerative Colitis Activity Index (rho 0.69, P < 0.001) and Short Pediatric Crohn Disease Activity Index (rho 0.65, P < 0.001). CONCLUSIONS: The patient's HRQOL was highly correlated to both the physician's and parent's perceptions as well as their disease activity. The feeling thermometer is a quick, easy-to-use, visual analog scale that can be implemented in everyday practice to measure a pediatric patient's HRQOL. PMID- 23752080 TI - C-ANCA/proteinase 3-positive colitis in children: a distinctive form of inflammatory bowel disease or vasculitis with colitis as initial presentation? AB - AIM: Anti-neutrophil cytoplasmic antibodies (ANCAs) detected by indirect immunofluorescence have been found in patients with inflammatory bowel disease (IBD). Nevertheless, specific antibodies against proteinase-3 (PR3) are rare in this context. METHODS: Sera from 30 consecutive pediatric patients with IBD were evaluated for ANCA-indirect immunofluorescence and its specific antibodies to investigate whether PR3-ANCA positivity (PR3-ANCA+) identifies a distinct IBD subtype. RESULTS: The 5 PR3-ANCA+ patients (17%) showed significantly more concomitant biliary disease and severe anal blood loss (P < 0.05). None had vasculitis features at diagnosis nor during follow-up. CONCLUSIONS: This pilot study demonstrates significant clinical differences between the PR3-ANCA-positive and -negative IBD subset. PMID- 23752081 TI - Effect of Holder pasteurization and frozen storage on macronutrients and energy content of breast milk. AB - OBJECTIVES: The aim of this study was to explore the effect of Holder pasteurization and frozen storage at -20 degrees C after pasteurization on fat, total nitrogen, lactose, and energy content of breast milk. Both procedures are routinely practiced in human milk banks. METHODS: A total of 34 samples of frozen breast milk, donated by 28 women, were collected. Once thawed, an aliquot of each sample was analyzed before pasteurization; the remaining milk was pasteurized (Holder method) and split into 8 aliquots. One aliquot was analyzed after pasteurization and the remainder frozen at -20 degrees C and analyzed 30, 60, 90, 120, and 180 days later. For every aliquot, fat, total nitrogen, lactose, and energy content were determined using the device human Milk Analyzer. RESULTS: We observed a significant reduction in fat (3.5%; -0.17 (-0.29; -0.04) g/dL) and energy content (2.8%; -2.03 (-3.60; -0.46) g/dL) after pasteurization. A significant decrease over time was observed for fat, lactose and energy content. No significant changes were observed for nitrogen content. Mean differences between day 0 postpasteurization and day 180 were -0.13 (-0.21; -0.06) g/dL for fat, -0.08 (-0.13; -0.03) g/dL for lactose, and -1.55 (-2.38; -0.71) kcal/dL for energy content. The relative decreases were 2.8%, 1.7%, and 2.2%, respectively. Overall (postpasteurization + frozen storage), a 6.2% and 5% decrease were observed for fat and energy, respectively. CONCLUSIONS: Holder pasteurization decreased fat and energy content of human milk. Frozen storage at -20 degrees C of pasteurized milk significantly reduced fat, lactose, and energy content of human milk. PMID- 23752082 TI - Three main factors define changes in fecal microbiota associated with feeding modality in infants. AB - OBJECTIVES: There are many differences in the fecal infant microbiota associated with various feeding methods. The aim of this study was to examine the major differences in the fecal microbiota of breast-fed (BF) and formula-fed (FF) infants and to describe the principal bacterial components that would explain the variability in the predominant bacterial families and genus clusters. METHODS: Fecal samples from 58 infants, 31 of whom were exclusively BF and 27 of whom were exclusively FF with a standard formula in agreement with the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition recommendations, were analyzed by fluorescent in situ hybridization combined with flow cytometry. Principal component analysis was used to maximize the information gained for the predominant bacterial families and genus clusters using a minimal number of bacterial groups. RESULTS: The predominant detected group was Bifidobacterium, followed by Enterobacteriaceae and Bacteroides in both BF and FF infants. The Lactobacillus group was the only independent variable associated with FF infants. We also found that 3 principal components were sufficient to describe the association between the bacterial group, genus, and species studied in BF and FF infants; however, these components differed between BF and FF infants. For the former, the 3 factors found were Bifidobacterium/Enterobacteriaceae, Lactobacillus/Bacteroides, and Clostridium coccoides/Atopobium; for the latter, Bifidobacterium/Enterobacteriaceae, Bacteroides and C coccoides were observed. CONCLUSIONS: There is a clear clustering of components of infant microbiota based on the feeding method. PMID- 23752083 TI - Ductal carcinoma in situ: morphology-based knowledge and molecular advances. AB - Ductal carcinoma in situ (DCIS) is an established precursor of invasive breast carcinoma. Immunoperoxidase stains for selected markers can assist pathologists in the diagnosis of challenging ductal epithelial proliferations, but they cannot replace morphologic evaluation as the primary and critical assessment of this disease. Molecular studies provide further insight into how DCIS progresses to invasive carcinoma and also confirm the heterogeneity of this lesion. Morphology based knowledge, immunohistochemistry, and molecular advances in DCIS are the subjects of this review. PMID- 23752084 TI - Ras, Raf, and MAP kinase in melanoma. AB - A growing understanding of the biology and molecular mechanisms of melanoma has led to the identification of a number of driver mutations for this aggressive tumor. The most common mutations affect signaling of the Ras/Raf/MAPK (mitogen activated protein kinase) pathway. This review will focus on mutations in genes encoding proteins that play a role in the MAPK pathway and that have been implicated in melanoma biology, such as BRAF, NRAS, and MEK (MAPK kinase), and detail the current understanding of their role in melanoma progression from a molecular biology perspective. Furthermore, this review will also consider some additional mutations in genes such as KIT, GNAQ, and GNA11, which can be seen in certain subtypes of melanoma and whose gene products interact with the MAPK pathway. In addition, the association of these molecular changes with clinical and classical histopathologic characteristics of melanoma will be outlined and their role in diagnosis of melanocytic lesions discussed. Finally, a basic overview of the current targeted therapy landscape, as far as relevant to the pathologist, will be provided. PMID- 23752085 TI - Endocervical glandular lesions exhibiting gastric differentiation: an emerging spectrum of benign, premalignant, and malignant lesions. AB - A variety of benign and malignant endocervical glandular lesions exhibiting gastric differentiation has been described in the past decade that has resulted in the concept of an important category of cervical adenocarcinoma which is unrelated to human papillomavirus (HPV). Both minimal deviation adenocarcinoma (MDA), also known as adenoma malignum, and the benign lesion lobular endocervical glandular hyperplasia (LEGH), have been known for some time to exhibit a gastric phenotype and immunophenotype (HIK1083 and/or MUC6 positive). Accumulated evidence suggests that a subset of LEGH (atypical LEGH) exhibits a degree of cytologic and/or architectural atypia which, in some cases, may be associated with and be a precursor of adenocarcinomas exhibiting gastric differentiation, including MDA. Gastric-type adenocarcinoma (GAS), a recently described subtype of cervical adenocarcinoma, is an emerging clinicopathologic entity. These neoplasms exhibit a spectrum of differentiation, including MDA as its very well differentiated form, are unrelated to HPV, and exhibit aggressive clinical behavior. It is proposed that a LEGH-GAS sequence exists and, from a practical point of view, the development of optimal biomarkers is awaited to assist in early detection of GAS and atypical LEGH, as current HPV-targeted screening generally does not detect these lesions and strategies employing HPV vaccination will not prevent their occurrence. Pathologists should be familiar with the morphologic spectrum of these benign, premalignant, and malignant cervical glandular lesions exhibiting gastric differentiation. They are occasionally associated with Peutz-Jeghers syndrome or are a component of "synchronous mucinous metaplasia and neoplasia of the female genital tract." PMID- 23752086 TI - Implementing genomic medicine in pathology. AB - The finished sequence of the Human Genome Project, published 50 years after Watson and Crick's seminal paper on the structure of DNA, pushed human genetics into the public eye and ushered in the genomic era. A significant, if overlooked, aspect of the race to complete the genome was the technology that propelled scientists to the finish line. DNA sequencing technologies have become more standardized, automated, and capable of higher throughput. This technology has continued to grow at an astounding rate in the decade since the Human Genome Project was completed. Today, massively parallel sequencing, or next-generation sequencing (NGS), allows the detection of genetic variants across the entire genome. This ability has led to the identification of new causes of disease and is changing the way we categorize, treat, and manage disease. NGS approaches such as whole-exome sequencing and whole-genome sequencing are rapidly becoming an affordable genetic testing strategy for the clinical laboratory. One test can now provide vast amounts of health information pertaining not only to the disease of interest, but information that may also predict adult-onset disease, reveal carrier status for a rare disease and predict drug responsiveness. The issue of what to do with these incidental findings, along with questions pertaining to NGS testing strategies, data interpretation and storage, and applying genetic testing results into patient care, remains without a clear answer. This review will explore these issues and others relevant to the implementation of NGS in the clinical laboratory. PMID- 23752087 TI - Hereditary syndromes with associated renal neoplasia: a practical guide to histologic recognition in renal tumor resection specimens. AB - Many hereditary tumor syndromes are associated with neoplasms of the kidney. It is becoming increasingly well recognized that a given familial tumor syndrome may be very heterogenous in clinical appearance and that unrecognized patients may present initially for the treatment of a renal mass. It is therefore important for surgical pathologists to be aware of the specific gross and microscopic findings in the kidney that suggest a possible syndromic association. In this review, we detail the histologic features of syndromic-associated renal neoplasms, describe the presence of characteristic changes in the background renal parenchyma, and provide an update on associated extrarenal manifestations for each of the following syndromes: von Hippel-Lindau disease, hereditary papillary renal cell carcinoma (RCC), hereditary leiomyomatosis-RCC, Birt-Hogg Dube syndrome, tuberous sclerosis complex, germline succinate dehydrogenase mutation, hereditary nonpolyposis colorectal cancer syndrome, hyperparathyroidism jaw tumor syndrome, PTEN hamartoma syndrome, constitutional chromosome 3 translocation, and familial nonsyndromic clear cell RCC. We also include a synopsis of renal medullary carcinoma because of its association with hereditary hemoglobinopathies. PMID- 23752088 TI - Sarcoma diagnosis in the age of molecular pathology. AB - Mesenchymal neoplasia presents numerous challenges to pathologic classification. Histologic features can be deceiving, and traditional immunohistochemical markers of differentiation may be of little use in narrowing the diagnosis. Fortunately, great strides have been made in unraveling the genetic and genomic alterations associated with both sarcomagenesis and benign neoplasia. In turn, these advances have led to an expansion of the available diagnostic toolkit for sarcoma pathology. In order to assist the practicing pathologist in integrating these tools into their repertoire, this article will discuss some of the latest advances in sarcoma diagnosis, including an update on translocation-associated sarcomas, and will review a number of sarcoma-specific immunohistochemical studies developed over the past decade. Some of the potential uses and pitfalls of commonly used tests will be addressed. Finally, the discussion will briefly touch upon the impact that advances in molecular technologies, particularly targeted gene expression analysis, may have on altering the face of diagnostic pathology. PMID- 23752089 TI - Value of SOX10 immunostaining in tumor diagnosis. AB - SOX10 is a transcription factor that is essential for the generation of neural crest cells, their survival, and maintenance of pluripotency. Recent studies have shown that, among tumors, SOX10 is commonly expressed in melanomas, including desmoplastic melanomas, tumors with Schwann cell differentiation, and some salivary gland neoplasms, particularly those with myoepithelial differentiation. Because of its restricted expression, SOX10 has proved to be a useful immunohistochemical marker with a wide range of diagnostic applications in surgical pathology, some of which are briefly reviewed. PMID- 23752090 TI - Intrarater reproducibility and validity of Nintendo Wii balance testing in community-dwelling older adults. AB - The aims of the current study were to examine the intrarater intersession reproducibility of the Nintendo Wii agility and stillness tests and explore the concurrent validity in relation to gold-standard force-plate analysis. Within-day intersession reproducibility was examined in 30 older adults (age 71.8 +/- 5.1 yr). No systematic test-retest differences were found for the Wii stillness test; however, the Wii agility test scores differed systematically between test sessions (p < .05). The Wii stillness test yielded a test-retest ICC of .86 (95% CI 0.74-0.93), CV of 6.4%, LOA of 11.0, and LOA% of 17.9%. Likewise for the Wii agility test ICC was .73 (95% CI 0.50-0.86), CV 5.3%, LOA 1.8, and LOA% of 14.6%. Wii stillness scores correlated to force plate measures (r = .65-.82, p < .01), reflecting moderate to excellent validity. In conclusion, it appears that the Wii stillness test represents a low-cost, objective, reproducible, and valid test of undisturbed postural balance in community-dwelling older adults. PMID- 23752092 TI - Monocyte Chemoattractant Protein-1 upregulates GABA-induced current: evidence of modified GABAA subunit composition in cortical neurons from the G93A mouse model of Amyotrophic Lateral Sclerosis. AB - Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder that affects upper and lower motor neurons. Previous evidence has indicated that excitotoxic cell death in ALS may remarkably depend on Cl(-) ion influx through the GABA(A) receptors. In this study we have analysed the effect of Monocyte Chemoattractant Protein-1 (MCP-1), a chemokine expressed to a higher level in ALS patients, on GABAA receptors in cultured cortical neurons from a genetic model of ALS (G93A) and compared with wild type SOD1 (SOD1) and their corresponding non transgenic littermates (Control). By performing electrophysiological experiments we have observed that, in cortical neurons MCP-1 (2-150 ng/ml) induced an enhancement of GABA-evoked currents that was significantly higher in G93A neurons compared to controls. The effect of MCP-1 was not dependent on the activation of its receptor CCR2, while it was blocked by flumazenil, the antagonist of benzodiazepine sites. Analysis of GABAA receptor subunit composition has indicated an altered subunit expression level in G93A cortical neurons compared to controls. Instead, in cultured spinal neurons MCP-1 induced a significant reduction of GABA-evoked currents, also through the benzodiazepine sites, indicating a region-specific mechanism of action. However, no differences were observed in the current reduction between the three neuronal populations. These findings provide the first evidence that MCP-1, acting on benzodiazepine sites, can modulate the GABA evoked currents, depending on the subunit composition of GABA(A) receptor. In cortical neurons MCP-1 upmodulates the GABA-evoked current and this effect is exacerbated in the mutated neurons. It is reasonable to assume that the higher Cl(-) influx through GABA(A) receptors in the presence of MCP-1 in mutated cortical neurons may induce an excitotoxicity acceleration. Agents able to block the MCP-1 production may then prove useful for ALS treatment. PMID- 23752093 TI - mTORC1-dependent protein synthesis underlying rapid antidepressant effect requires GABABR signaling. AB - Administration of N-methyl-D-aspartate receptors (NMDAR) antagonists initiates a rapid anti-depressant response requiring mammalian Target of Rapamycin Complex 1 (mTORC1) kinase; however the molecular mechanism is unknown. We have determined that upon NMDAR blockade, dendritic gamma-amino-butyric acid B receptors (GABABR) facilitate dendritic calcium entry. The GABABR-mediated increase in calcium signal requires the availability of dendritic L-type calcium channels. Moreover, GABABR can activate mTOR and increase mTOR dependent expression of BDNF under the same NMDAR blocked conditions. In vivo, blocking GABABR prevents the fast-acting, anti-depressant effect of the NR2B antagonist, Ro-25-6891, decreases active mTORC1 kinase, and reduces expression of BDNF and the AMPA receptor subunit GluA1. These findings propose a novel role for GABABRs in the antidepressant action of NR2B antagonists and as an initiator/regulator of mTORC1-mediated translation. PMID- 23752094 TI - Form follows function: BDNF and its involvement in sculpting the function and structure of synapses. AB - Neurotrophins are essential for multiple aspects of neuronal development and function. Especially BDNF (brain-derived-neurotrophic-factor) has been shown to play an important role in neuronal survival and in the maintenance of several neuronal systems. In addition, BDNF has been implicated in numerous processes of functional and structural synaptic plasticity. In this review we would like to summarize what is known regarding the cellular mechanism mediating the activity of BDNF during functional and/or structural changes at neurons in order to promote synaptic plasticity. In addition, we address open questions and conflicting results. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'. PMID- 23752091 TI - Involvement of glutamatergic and GABAergic systems in nicotine dependence: Implications for novel pharmacotherapies for smoking cessation. AB - Tobacco smoking continues to be a major global health hazard despite significant public awareness of its harmful consequences. Although several treatment options are currently available for smoking cessation, these medications are effective in only a small subset of smokers, and relapse rates continue to be high. Therefore, a better understanding of the neurobiological mechanisms that mediate tobacco dependence is essential for the development of effective smoking cessation medications. Nicotine is the primary psychoactive component of tobacco that drives the harmful tobacco smoking habit. Nicotine binds to nicotinic acetylcholine receptors (nAChRs) in the brain, resulting in the release of a wide range of neurotransmitters, including glutamate and gamma-aminobutyric acid (GABA). This review article focuses on the role of the excitatory glutamate system and inhibitory GABA system in nicotine dependence. Accumulating evidence suggests that blockade of glutamatergic transmission or facilitation of GABAergic transmission attenuates the positive reinforcing and incentive motivational aspects of nicotine, inhibits the reward-enhancing and conditioned rewarding effects of nicotine, and blocks nicotine-seeking behavior. Chronic nicotine exposure produced long-term neuroadaptations that contribute to nicotine withdrawal, but the role of GABA and glutamate transmission in nicotine withdrawal is less understood. Overall, the findings presented in this review provide strong converging evidence for the potential effectiveness of glutamatergic and GABAergic medications in nicotine dependence. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23752095 TI - Transition from 'model-based' to 'model-free' behavioral control in addiction: Involvement of the orbitofrontal cortex and dorsolateral striatum. AB - Cocaine addiction is a complex and multidimensional process involving a number of behavioral and neural forms of plasticity. The behavioral transition from voluntary drug use to compulsive drug taking may be explained at the neural level by drug-induced changes in function or interaction between a flexible planning system, associated with prefrontal cortical regions, and a rigid habit system, associated with the striatum. The dichotomy between these two systems is operationalized in computational theory by positing model-based and model-free learning mechanisms, the former relying on an "internal model" of the environment and the latter on pre-computed or cached values to control behavior. In this review, we will suggest that model-free and model-based learning mechanisms appear to be differentially affected, at least in the case of psychostimulants such as cocaine, with the former being enhanced while the latter are disrupted. As a result, the behavior of long-term drug users becomes less flexible and responsive to the desirability of expected outcomes and more habitual, based on the long history of reinforcement. To support our specific proposal, we will review recent neural and behavioral evidence on the effect of psychostimulant exposure on orbitofrontal and dorsolateral striatum structure and function. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23752097 TI - Treating people with type 2 diabetes. AB - As the symposium of articles in this issue shows, there are now many options for managing type 2 diabetes. Potent new oral or injectable hypoglycaemic medications can be added to older drugs or used alone. In addition to metformin, the British National Formulary (Joint Formulary Committee, 2013) lists five sulfonylureas, two meglitinides, four dipeptidyl peptidase-4 inhibitors, two glucagon-like peptide-1 agonists, an inhibitor of intestinal alpha glucosidases, a sodium glucose co-transporter 2 inhibitor, and a thiazolidinedione. Their various formulations form a list of 30 drugs in MIMS (www.mims.co.uk/). PMID- 23752098 TI - Clinical News. AB - In 2009, the Boorman Review set a clear goal for the NHS - improve the care of staff to improve the care for patients. Dr Boorman's report identified potential savings for the NHS of L555 million a year if sickness absence among staff was tackled with early intervention occupational health services, such as physiotherapy. PMID- 23752100 TI - Tactile interactions lead to coherent motion and enhanced chemotaxis of migrating cells. AB - When motile cells come into contact with one another their motion is often considerably altered. In a process termed contact inhibition of locomotion (CIL) cells reshape and redirect their movement as a result of cell-cell contact. Here we describe a mathematical model that demonstrates that CIL alone is sufficient to produce coherent, collective cell migration. Our model illustrates a possible mechanism behind collective cell migration that is observed, for example, in neural crest cells during development, and in metastasizing cancer cells. We analyse the effects of varying cell density and shape on the alignment patterns produced and the transition to coherent motion. Finally, we demonstrate that this process may have important functional consequences by enhancing the accuracy and robustness of the chemotactic response, and factors such as cell shape and cell density are more significant determinants of migration accuracy than the individual capacity to detect environmental gradients. PMID- 23752096 TI - Amygdala and bed nucleus of the stria terminalis circuitry: Implications for addiction-related behaviors. AB - Complex motivated behavioral processes, such as those that can go awry following substance abuse and other neuropsychiatric disorders, are mediated by a distributive network of neurons that reside throughout the brain. Neural circuits within the amygdala regions, such as the basolateral amygdala (BLA), and downstream targets such as the bed nucleus of the stria terminalis (BNST), are critical neuroanatomical structures for orchestrating emotional behavioral responses that may influence motivated actions such as the reinstatement of drug seeking behavior. Here, we review the functional neurocircuitry of the BLA and the BNST, and discuss how these circuits may guide maladaptive behavioral processes such as those seen in addiction. Thus, further study of the functional connectivity within these brain regions and others may provide insight for the development of new treatment strategies for substance use disorders. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23752101 TI - Polyphenols from the bark of Rhus verniciflua and their biological evaluation on antitumor and anti-inflammatory activities. AB - Bioassay-guided fractionation and chemical investigation of the extract of Rhus verniciflua bark resulted in the identification of six polyphenols, rhusopolyphenols A-F (1-6), together with four known compounds including (2R,3S,10S)-7,8,9,13-tetrahydroxy-2-(3,4-dihydroxyphenyl)-2,3-trans-3,4-cis 2,3,10-trihydrobenzopyrano[3,4-c]-2-benzopyran-1-one (7), peapolyphenol C (8), cilicione-b (9) and (alphaR)-alpha,3,4,2',4'-pentahydroxydihydrochalcone (10). The structures of these polyphenols were elucidated by spectroscopic analysis, including 1D and 2D NMR, and HR-ESIMS, and their absolute configurations were further confirmed by a combination of chemical methods and CD data analysis. All isolates were evaluated for their antiproliferative activities against four human tumor cell lines (A549, SK-OV-3, SK-MEL-2, and HCT-15), and compounds 4-6, 9 and 10 showed antiproliferative activity against the tested cells, with IC50 values of 3.31-18.51 MUM. On the basis of the expanded understanding that inflammation is a crucial cause of tumor progression, the anti-inflammatory activities of these compounds were determined by measuring nitric oxide (NO) levels in the medium of murine microglia BV-2 cells. Compounds 5 and 10 significantly inhibited NO production in lipopolysaccharide (LPS)-stimulated murine microglia BV-2 cells with IC50 values of 28.90 and 12.70 MUM, respectively. PMID- 23752103 TI - Is tremelimumab beneficial in advanced melanoma? PMID- 23752102 TI - Adrenocortical carcinoma is a lynch syndrome-associated cancer. AB - PURPOSE: Adrenocortical carcinoma (ACC) is an endocrine malignancy with a poor prognosis. The association of adult-onset ACC with inherited cancer predisposition syndromes is poorly understood. Our study sought to define the prevalence of Lynch syndrome (LS) among patients with ACC. PATIENTS AND METHODS: One hundred fourteen patients with ACC were evaluated in a specialized endocrine oncology clinic and were prospectively offered genetic counseling and clinical genetics risk assessment (group 1). In addition, families with known mismatch repair (MMR) gene mutations that were recorded in the University of Michigan Cancer Genetics Registry were retrospectively reviewed for the presence of ACC (group 2). ACC tumors from patients with LS were tested for microsatellite instability and immunohistochemistry (IHC) to evaluate for MMR deficiency. RESULTS: Ninety-four (82.5%) of 114 patients with ACC underwent genetic counseling (group 1). Three individuals (3.2%) had family histories suggestive of LS. All three families were found to have MMR gene mutations. Retrospective review of an additional 135 MMR gene-positive probands identified two with ACC (group 2). Four ACC tumors were available (group 1, 3; group 2, 1). All four tumors were microsatellite stable; three had IHC staining patterns consistent with germline mutation status. CONCLUSION: The prevalence of LS among patients with ACC is 3.2%, which is comparable to the prevalence of LS in colorectal and endometrial cancer. Patients with ACC and a personal or family history of LS tumors should be strongly considered for genetic risk assessment. IHC screening of all ACC tumors may be an effective strategy for identifying patients with LS. PMID- 23752104 TI - Palliative radiotherapy: run with the hare and hunt with the hounds. PMID- 23752105 TI - Critical evaluation of oncology clinical practice guidelines. AB - PURPOSE: Significant concerns exist regarding the content and reliability of oncology clinical practice guidelines (CPGs). The Institute of Medicine (IOM) report "Clinical Practice Guidelines We Can Trust" established standards for developing trustworthy CPGs. By using these standards as a benchmark, we sought to evaluate recent oncology guidelines. METHODS: CPGs and consensus statements addressing the screening, evaluation, or management of the four leading causes of cancer-related mortality in the United States (lung, breast, prostate, and colorectal cancers) published between January 2005 and December 2010 were identified. A standardized scoring system based on the eight IOM standards was used to critically evaluate the methodology, content, and disclosure policies of CPGs. All CPGs were given two scores; points were awarded for eight standards and 20 subcriteria. RESULTS: No CPG fully met all the IOM standards. The average overall scores were 2.75 of 8 possible standards and 8.24 of 20 possible subcriteria. Less than half the CPGs were based on a systematic review. Only half the CPG panels addressed conflicts of interest. Most did not comply with standards for inclusion of patient and public involvement in the development or review process, nor did they specify their process for updating. CPGs were most consistent with IOM standards for transparency, articulation of recommendations, and use of external review. CONCLUSION: The vast majority of oncology CPGs fail to meet the IOM standards for trustworthy guidelines. On the basis of these results, there is still much to be done to make guidelines as methodologically sound and evidence-based as possible. PMID- 23752106 TI - Guidelines for guidelines: measuring trustworthiness. PMID- 23752107 TI - Nonimmediate hypersensitivity reaction after trastuzumab infusion: a suspected drug-virus interaction. PMID- 23752108 TI - Radiation therapy for metastatic non-small-cell lung cancer: when to bring in palliative care? PMID- 23752109 TI - Effect of age on breast cancer outcomes in women with human epidermal growth factor receptor 2-positive breast cancer: results from a herceptin adjuvant trial. AB - PURPOSE: Previous research has suggested that young age at diagnosis is an independent risk factor for breast cancer recurrence and death. No prior studies have adequately controlled for human epidermal growth factor receptor 2 (HER2) status or anti-HER2 treatment. We sought to evaluate whether age was a prognostic or predictive factor in the HERA trial. PATIENTS AND METHODS: We used 2-year median follow-up data and dichotomized age at 40 years to evaluate its prognostic effect on outcomes for women assigned to trastuzumab for 1 year or observation. RESULTS: Of the 1,703 women randomly assigned to 1 year of trastuzumab and 1,698 to observation, 722 (21%) were age <= 40 years at study entry. In separate Cox models, controlling for relevant prognostic and predictive factors, disease-free (DFS) and overall survival (OS) hazard ratios (HRs) were consistent for women age <= 40 versus > 40 years, regardless of treatment assignment (observation group: DFS HR age <= 40 v > 40 years, 1.18; 95% CI, 0.90 to 1.54; OS HR age <= 40 v > 40 years, 1.01; 95% CI, 0.60 to 1.69; trastuzumab group: DFS HR age <= 40 v > 40 years, 1.11; 95% CI, 0.81 to 1.51; OS HR age <= 40 v > 40 years, 1.18; 95% CI, 0.66 to 2.09). Interaction between age group and treatment effect was not statistically significant (DFS P = .89; OS P = .55). CONCLUSION: In a retrospective analysis of a large randomized controlled trial of women with early stage HER2-positive breast cancer, age was not strongly associated with risk of early recurrence or prediction of benefit from trastuzumab therapy. Future research should investigate whether age is a predictor of later recurrence and evaluate the impact of age within groups with other tumor subtypes. PMID- 23752110 TI - Patient preference and contraindications in measuring quality of care: what do administrative data miss? AB - PURPOSE: Prior studies report that half of patients with lung cancer do not receive guideline-concordant care. With data from a national Veterans Health Administration (VHA) study on quality of care, we sought to determine what proportion of patients refused or had a contraindication to recommended lung cancer therapy. PATIENTS AND METHODS: Through medical record abstraction, we evaluated adherence to six quality indicators addressing lung cancer-directed therapy for patients diagnosed within the VHA during 2007 and calculated the proportion of patients receiving, refusing, or having contraindications to recommended treatment. RESULTS: Mean age of the predominantly male population was 67.7 years (standard deviation, 9.4 years), and 15% were black. Adherence to quality indicators ranged from 81% for adjuvant chemotherapy to 98% for curative resection; however, many patients met quality indicator criteria without actually receiving recommended therapy by having a refusal (0% to 14%) or contraindication (1% to 30%) documented. Less than 1% of patients refused palliative chemotherapy. Black patients were more likely to refuse or bear a contraindication to surgery even when controlling for comorbidity; race was not associated with refusals or contraindications to other treatments. CONCLUSION: Refusals and contraindications are common and may account for previously demonstrated low rates of recommended lung cancer therapy performance at the VHA. Racial disparities in treatment may be explained, in part, by such factors. These results sound a cautionary note for quality measurement that depends on data that do not reflect patient preference or contraindications in conditions where such considerations are important. PMID- 23752111 TI - Case of thyroid involvement by multiple myeloma. PMID- 23752112 TI - Outcomes of critically ill patients with hematologic malignancies: prospective multicenter data from France and Belgium--a groupe de recherche respiratoire en reanimation onco-hematologique study. AB - PURPOSE Patients with hematologic malignancies are increasingly admitted to the intensive care unit (ICU) when life-threatening events occur. We sought to report outcomes and prognostic factors in these patients. PATIENTS AND METHODS Ours was a prospective, multicenter cohort study of critically ill patients with hematologic malignancies. Health-related quality of life (HRQOL) and disease status were collected after 3 to 6 months. Results Of the 1,011 patients, 38.2% had newly diagnosed malignancies, 23.1% were in remission, and 24.9% had received hematopoietic stem-cell transplantations (HSCT, including 145 allogeneic). ICU admission was mostly required for acute respiratory failure (62.5%) and/or shock (42.3%). On day1, 733 patients (72.5%) received life-supporting interventions. Hospital, day-90, and 1-year survival rates were 60.7%, 52.5%, and 43.3%, respectively. By multivariate analysis, cancer remission and time to ICU admission less than 24 hours were associated with better hospital survival. Poor performance status, Charlson comorbidity index, allogeneic HSCT, organ dysfunction score, cardiac arrest, acute respiratory failure, malignant organ infiltration, and invasive aspergillosis were associated with higher hospital mortality. Mechanical ventilation (47.9% of patients), vasoactive drugs (51.2%), and dialysis (25.9%) were associated with mortality rates of 60.5%, 57.5%, and 59.2%, respectively. On day 90, 80% of survivors had no HRQOL alterations (physical and mental health similar to that of the overall cancer population). After 6 months, 80% of survivors had no change in treatment intensity compared with similar patients not admitted to the ICU, and 80% were in remission. CONCLUSION Critically ill patients with hematologic malignancies have good survival, disease control, and post-ICU HRQOL. Earlier ICU admission is associated with better survival. PMID- 23752113 TI - Prostate cancer metastatic to the pancreas. PMID- 23752114 TI - Vemurafenib-induced cardiac tamponade: a rare but potentially life-threatening complication. PMID- 23752115 TI - Distinguishing between lymphangioleiomyomatosis and carcinomatous peritonitis in a patient with ovarian cancer. PMID- 23752116 TI - Ruxolitinib withdrawal syndrome leading to tumor lysis. PMID- 23752122 TI - Circulating levels of plasma IGF-I during recovery from size-selective harvesting in Menidia menidia. AB - Selection for growth-related traits in domesticated fishes often results in predictable changes within the growth hormone-insulin-like growth factor (GH-IGF 1) axis. Little is known about the mechanisms controlling changes in growth capacity resulting from fishery-induced evolution. We took advantage of a long term study where Menidia menidia were selected for size at age over multiple generations to mimic fisheries-induced selection. This selection regime produced three populations with significant differences in intrinsic growth rate. These growth differences partially rebounded, but persisted even after selection was relaxed, resulting in fast, intermediate, and slow-growing lines. Plasma IGF-1 was measured in these populations as a potential target of selection on growth. IGF-1 was significantly correlated with current length and mass, and was positively correlated with growth rate (g d(-1)) in two lines, indicating it may be an appropriate indicator of growth capacity. The slow-growing line exhibited higher overall IGF-1 levels relative to the depressed IGF-1 seen in the fast growing line, contrary to our prediction. We offer possible explanations for this unusual pattern and argue that somatic growth is likely to be under control of mechanism(s) downstream to IGF-1. IGF-1 provides an interesting basis for understanding endocrine control of growth in response to artificial selection and recovery. PMID- 23752123 TI - Buffer capacity of the coelomic fluid in echinoderms. AB - The increase in atmospheric CO2 due to anthropogenic activity results in an acidification of the surface waters of the oceans. The impact of these chemical changes depends on the considered organisms. In particular, it depends on the ability of the organism to control the pH of its inner fluids. Among echinoderms, this ability seems to differ significantly according to species or taxa. In the present paper, we investigated the buffer capacity of the coelomic fluid in different echinoderm taxa as well as factors modifying this capacity. Euechinoidea (sea urchins except Cidaroidea) present a very high buffer capacity of the coelomic fluid (from 0.8 to 1.8mmolkg(-1) SW above that of seawater), while Cidaroidea (other sea urchins), starfish and holothurians have a significantly lower one (from -0.1 to 0.4mmolkg(-1) SW compared to seawater). We hypothesize that this is linked to the more efficient gas exchange structures present in the three last taxa, whereas Euechinoidea evolved specific buffer systems to compensate lower gas exchange abilities. The constituents of the buffer capacity and the factors influencing it were investigated in the sea urchin Paracentrotus lividus and the starfish Asterias rubens. Buffer capacity is primarily due to the bicarbonate buffer system of seawater (representing about 63% for sea urchins and 92% for starfish). It is also partly due to coelomocytes present in the coelomic fluid (around 8% for both) and, in P. lividus only, a compound of an apparent size larger than 3kDa is involved (about 15%). Feeding increased the buffer capacity in P. lividus (to a difference with seawater of about 2.3mmolkg(-1) SW compared to unfed ones who showed a difference of about 0.5mmolkg(-1) SW) but not in A. rubens (difference with seawater of about 0.2 for both conditions). In P. lividus, decreased seawater pH induced an increase of the buffer capacity of individuals maintained at pH7.7 to about twice that of the control individuals and, for those at pH7.4, about three times. This allowed a partial compensation of the coelomic fluid pH for individuals maintained at pH7.7 but not for those at pH7.4. PMID- 23752124 TI - Hypothalamic neuropeptide Y (NPY) gene expression is not affected by central serotonin in the rainbow trout (Oncorhynchus mykiss). AB - Mammalian studies have shown a link between serotonin (5-HT) and neuropeptide Y (NPY) in the acute regulation of feeding and energy homeostasis. Taking into account that the actions of 5-HT and NPY on food intake in fish are similar to those observed in mammals, the objective of this study was to characterize a possible short-term interaction between hypothalamic 5-HT and NPY, by examining whether 5-HT regulates NPY gene expression, to help clarify the mechanism underlying the observed anorexigenic action of central 5-HT in the rainbow trout. We used qRT-PCR to determine the levels of NPY mRNA in the hypothalamus-preoptic area (HPA) of rainbow trout after intraperitoneal (i.p.) injection of a single dose of dexfenfluramine (dFF, 3mgkg(-1); 24h-fasted and fed fish) or intracerebroventricular (i.c.v.) administration of 5-HT (100MUgkg(-1); 24h-fasted fish). Significant suppression of food intake was observed after administration of 5-HT and dFF. No significant changes in NPY gene expression were obtained 150min after administration of 5-HT or dFF. However, administration of the 5HT1B receptor agonist anpirtoline did not have any significant effect on food intake in rainbow trout. The results suggest that in fish, unlike in mammals, neither the NPY neurons of the HPA nor the 5-HT1B receptor subtype participate in the neural circuitry involved in the inhibition of food intake induced by central serotoninergic activation. PMID- 23752125 TI - Renal involvement in paroxysmal nocturnal hemoglobinuria. AB - Renal involvement in paroxysmal nocturnal hemoglobinuria (PNH) is not usually apparent but in cases with clinical involvement varies from reversible acute dysfunction to chronic irreversible damage. Early diagnosis and treatment is crucial to prevent disease progression and irreversible chronic kidney disease (CKD). The ultimate outcome of CKD in many patients is the need for renal replacement therapy, which necessitates ever-growing dialysis and transplantation programs, thereby imposing a significant economic burden on the healthcare system. In a third-world country like Pakistan, increased burden due to CKD can be very hard on families. Doctor visits, hospitalization, and dialysis are all out-of-pocket expenses, therefore prevention, early detection, and timely intervention are the only cost-effective strategies. We report a case of acute kidney injury (AKI) due to PNH. This case shows AKI as one of the complications of PNH which may have a clinical course like acute tubular necrosis (ATN). This could be due to ATN or AKI superimposed on CKD due to hemosiderin deposits in the renal tubular epithelial cells. Our patient was dialyzed initially and discharged with a permanent catheter in place with advice to continue dialysis three times a week. He required dialysis for 1 week then started producing urine. His subsequent outpatient visits showed improved renal function. The permanent catheter was removed and maintenance dialysis was stopped. Here, we briefly review the literature on renal involvement in PNH, treatment options for PNH and pigment-induced nephropathy followed by a question-and-answer session at the clinicopathological conference held on March 4, 2011, at Sindh Institute of Urology and Transplantation in Karachi, Pakistan. PMID- 23752126 TI - Pulmonary CYP2A13 levels are associated with early occurrence of lung cancer-Its implication in mutagenesis of non-small cell lung carcinoma. AB - CYP2A13, a human pulmonary specific cytochrome P450 enzyme, plays an important role in susceptibility to tobacco-specific nitrosamines (TSNAs)-induced lung cancer in humans. The pattern of CYP2A13 distribution in respiratory tract affects the susceptibility of the lung to carcinogens. CYP2A13 is expressed in the epithelium of trachea and bronchi; however its pattern of expression in human lung cancer remains largely unknown. This study aimed to determine the CYP2A13 expression in specimens from human non-small cell lung carcinomas (NSCLCs), i.e., adenocarcinoma and squamous carcinoma, by immunohistochemical (IHC) analysis and to identify the potential linkage between tumor CYP2A13 levels and some clinicopathological characteristics of NSCLC patients in Taiwan. The tumor CYP2A13 IHC staining signal was strong in 76% of the 112 study subjects. Study subjects (especially non-smoking or lung adenocarcinoma patients) with higher tumor CYP2A13 levels were younger. Multiple logistic regression analysis revealed that in younger subjects (age <= 66) and heavy smokers (pack-years >= 40), the odds ratio (OR) for positive tumor CYP2A13 staining was significantly higher than that for negative tumor CYP2A13 staining. Moreover, the association of EGFR gene mutations and positive tumor CYP2A13 staining was also revealed. In conclusion, these findings suggest the potential involvement of pulmonary CYP2A13 in the early occurrence of NSCLC as well as in the development of EGFR gene mutations. PMID- 23752127 TI - Human papillomaviruses in intraepithelial neoplasia and squamous cell carcinoma of the conjunctiva: a study from Mozambique. AB - The infection with human papillomavirus (HPV) has been described as a risk factor for squamous cell carcinoma of the conjunctiva (SCCC), although the evidence is conflicting. To assess the relation between HPV infection and intraepithelial neoplasia or SCCC, we evaluated archived material from biopsies of the conjunctiva performed at the Maputo Central Hospital (Mozambique) in patients with suspected eye cancer. The quality of DNA was assessed by PCR using beta globin-specific primers. A total of 22 consecutive biopsies (intraepithelial neoplasia, SCCC, and benign conditions) positive for beta-globin were further tested for HPV infection by PCR using the general primers GP5+/GP6+ and CPI/CPII. In addition, PCR with type-specific primers HPV 16 and HPV 18 was performed. Nineteen biopsies corresponded to intraepithelial neoplasia (two low-grade and nine high-grade) or SCCC (n=8), from which 11 (57.9%) tested positive for HPV infection; nine were positive for CPI/CPII, including one case also positive for GP5+/GP6+ and HPV 18, and the remaining two tested positive only for HPV 16. HPV DNA was not detected in any of the three biopsies of benign conditions. These results suggest a stronger association between infection with cutaneous HPV and SCCC than for mucosal HPV. However, further research is required to clarify the relation between HPV and SCCC as well as to understand the potential of the HPV vaccine currently available for cervical cancer to prevent SCCC. PMID- 23752129 TI - M2-polarized tumor-associated macrophages promoted epithelial-mesenchymal transition in pancreatic cancer cells, partially through TLR4/IL-10 signaling pathway. AB - M2-polarized tumor-associated macrophages (TAMs) are key regulators of the link between inflammation and cancer. A negative correlation between infiltration intensity of M2-polarized TAMs and prognosis of pancreatic cancer has been reported. Epithelial-mesenchymal transition (EMT) is an important biological process in the progression of primary tumors toward metastasis. Inflammation induced EMT has been previously shown, therefore, we hypothesized M2-polarized TAMs could induce EMT in pancreatic cancer. Toll-like receptor 4 (TLR4) signaling has an active role in tumor progression during chronic inflammation and the receptor is primarily expressed on macrophages. Activation of TLR4 on M2 polarized TAMs stimulates an increase in the cytokine interleukin-10 (IL-10); consequently, another aim was to investigate the potential role of TLR4/IL-10 signaling in the EMT of pancreatic cancer. Treatment with IL-4 (20 ng/ml) for 24 h successfully induced the polarization of macrophage cell line RAW 264.7 to M2 phenotype, IL-10(high), IL-12(low), and IL-23(low), and high expression of CD204 and CD206. A coculture system allowed investigation of the roles of M2-polarized TAMs and TLR4/IL-10 signaling in the EMT of Panc-1 and BxPC-3 pancreatic cancer cell lines. Our results showed that coculture with M2-polarized TAMs increased fibroblastic morphology, upregulated mesenchymal markers vimentin and snail at the mRNA and protein levels, and increased proliferation, migration, and metalloproteinase (MMP)2 and MMP9 proteolytic activity in pancreatic cancer cells. Simultaneously, coculture with M2-polarized TAMs decreased the expression of the epithelial marker E-cadherin. Coculture with pancreatic cancer cells increased TLR4 mRNA and protein expression in M2-polarized TAMs. Application of TLR4 siRNA and neutralizing antibodies against TLR4 and IL-10 markedly inhibited E-cadherin reduction and the upregulation of snail and vimentin. Furthermore, activation of TLR4 signaling by lipopolysaccharide profoundly increased the EMT of pancreatic cancer cells. In conclusion, M2-polarized TAMs promoted EMT in pancreatic cancer cells partially through TLR4/IL-10 signaling, suggesting novel therapeutic strategies and enhancing our understanding of M2-polarized TAMs. PMID- 23752130 TI - Butyric acid attenuates intestinal inflammation in murine DSS-induced colitis model via milk fat globule-EGF factor 8. AB - Butyric acid, a short-chain fatty acid and one of the main metabolites of intestinal microbial fermentation of dietary fiber, has been shown to have an important role in maintaining the integrity of the intestinal mucosa, while it also has been shown to exert potent anti-inflammatory effects both in vitro and in vivo. However, the precise mechanisms underlying those effects have not been fully identified. We exposed colonic epithelial cells to butyric acid, then extracted total RNA samples, and subsequently hybridized them to microarray chips. Among the upregulated genes, milk fat globule-epidermal growth factor 8 (MFG-E8) was elevated by approximately fivefold. We previously reported that the potential therapeutic benefits of MFG-E8 in intestinal tissue injury were dependent not only on enhanced clearance of apoptotic cells but also required diverse cellular events for maintaining epithelial integrity. The influence of butyric acid on cell function is often attributed to its inhibition of histone deacetylases (HDACs). We found that acetylation on histone 3 lysine 9 (acetyl H3K9) around the MFG-E8 promoter was significantly increased with butyric acid exposure. Experimental colitis was induced by administration of dextran sodium sulfate (DSS) in C57BL/6N (MFG-E8+/+) and MFG-E8-/- mice. Although the colonic bacterial compositions in wild-type (WT) and MFG-E8-/- mice were not significantly different, intrarectal administration of butyric acid during an acute phase of colitis attenuated intestinal inflammatory parameters and inhibited body weight loss in the WT mice. Our novel findings suggest that butyric acid has significant anti-inflammatory effects partly via MFG-E8 on DSS induced murine experimental colitis. PMID- 23752131 TI - Culture and its neurofunctional correlates when death is in mind. AB - The human fear of death is marked by specific psychological reactions that affirm cultural belonging. Terror management theory explains this phenomenon with the symbolic immortality provided by collective meaning in culture. This coping has also been explained with the motive of maintaining a meaningful representation of the world. Here we show that neural patterns of activations corresponding to cultural worldview defense processes differed when images that affirmed participants' cultural heritage were preceded by death-related verbal primes versus verbal primes threatening meaning. Cultural content was drawn upon distinctly on a neural basis when facing death-related cognitions. The neural representation of cultural coping sheds light on the immediate mechanisms in compensating the human fear of death. PMID- 23752132 TI - The relationship between family and child weight status by household structure in South Korea: 2007-2010. AB - OBJECTIVE: Parental obesity has been identified as a predominant risk factor for childhood overweight and obesity. We investigated the relationship between parent and child obesity in South Korea, particularly linked with varying family structures. SUBJECTS AND METHODS: Data for households with children aged 2-18 years were taken from the pooled data of the Korea National Health and Nutrition Examination Survey (KNHANES) 2007-2010 conducted by the Korea Centers for Disease Control and Prevention (KCDC). The sample consisted of 17 453 individuals (7879 children and 9574 adults) from 5048 households with children for this study. Children's overweight and obesity prevalence was compared using both International Obesity Taskforce (IOTF) and KCDC cutoff points according to parental weight status and household structure. Logistic regression analysis was used. RESULTS: Significantly greater odds of overweight and obesity existed among children living with both parents (odds ratio (OR)=3.5, 95% confidence interval (CI): 2.71, 4.65) or one parent (mother: OR=1.6, 95% CI: 1.22, 2.12; father: OR=1.7, 95% CI: 1.37, 1.99). The adjusted ORs for overweight and obesity among children living with overweight mother only or overweight grandparent only were approximately double that of children living with normal-weight mother (OR=2.2, 95% CI: 1.22-3.82) or normal-weight grandparent (OR=2.1, 95% CI: 1.06-4.05). CONCLUSION: Children living with overweight parent(s) or grandparent(s) were positively correlated with the risk for childhood overweight and obesity. Socioeconomic status did not affect the observed relationships in this population, whereas the role of genetic, dietary and activity patterns requires further exploration. PMID- 23752133 TI - Insulin stimulation regulates AS160 and TBC1D1 phosphorylation sites in human skeletal muscle. AB - INTRODUCTION: Individuals with obesity and type 2 diabetes (T2D) are typically insulin resistant, exhibiting impaired skeletal muscle glucose uptake. Animal and cell culture experiments have shown that site-specific phosphorylation of the Rab GTPase-activating proteins AS160 and TBC1D1 is critical for GLUT4 translocation facilitating glucose uptake, but their regulation in human skeletal muscle is not well understood. METHODS: Here, lean, obese and T2D subjects underwent a euglycemic-hyperinsulinemic clamp, and vastus lateralis muscle biopsies were obtained before, and at 30 and 180 min post insulin infusion. RESULTS: Obese and T2D subjects had higher body mass indexes and fasting insulin concentrations, and T2D subjects showed insulin resistance. Consistent with the clamp findings, T2D subjects had impaired insulin-stimulated phosphorylation of AS160 Thr(642), a site previously shown to be important in glucose uptake in rodents. Interestingly, insulin-stimulated phosphorylation of TBC1D1 Thr(590), a site shown to be regulated by insulin in rodents, was only increased in T2D subjects, although the functional significance of this difference is unknown. CONCLUSION: These data show that insulin differentially regulates AS160 and TBC1D1 phosphorylation in human skeletal muscle. Impaired insulin-stimulated glucose uptake in T2D subjects is accompanied by dysregulation of AS160 and TBC1D1 phosphorylation in skeletal muscle, suggesting that these proteins may regulate glucose uptake in humans. PMID- 23752134 TI - Single cell detection using a magnetic zigzag nanowire biosensor. AB - A magnetic zigzag nanowire device was designed for single cell biosensing. Nanowires with widths of 150, 300, 500, and 800 nm were fabricated on silicon trenches by electron beam lithography, electron beam evaporation, and lift-off processes. Magnetoresistance measurements were performed before and after the attachment of a single magnetic cell to the nanowires to characterize the magnetic signal change due to the influence of the magnetic cell. Magnetoresistance responses were measured in different magnetic field directions, and the results showed that this nanowire device can be used for multi directional detection. It was observed that the highest switching field variation occurred in a 150 nm wide nanowire when the field was perpendicular to the substrate plane. On the other hand, the highest magnetoresistance ratio variation occurred in a 800 nm wide nanowire also when the field was perpendicular to the substrate plane. Besides, the trench-structured substrate proposed in this study can fix the magnetic cell to the sensor in a fluid environment, and the stray field generated by the corners of the magnetic zigzag nanowires has the function of actively attracting the magnetic cells for detection. PMID- 23752136 TI - The first purification and unequivocal characterization of the radical form of the carbon-centered quinone ketoxy radical adduct. AB - We found, unexpectedly, that the radical form of the carbon-centered quinone ketoxy radical adduct with a recently developed spin-trapping agent BMPO can not only be directly detected and identified using HPLC/high resolution MS, but can also be isolated and purified using semi-preparative HPLC, enabling direct observation of its clean 6-line ESR signal. PMID- 23752137 TI - [Flash Survey 2012: the use of self-measurement in France and its evolution since 2010]. AB - The objective of this investigation is to describe the characteristics of subjects with a self-measurement device, representative of the French population. METHODS: Auto four-page questionnaire administered by mail to 4500 individuals aged 35 years and over. RESULTS: Three thousand four hundred and sixty-two subjects aged 56 years responded to the questionnaire: 1054 subjects were treated hypertensives with a mean age 65.9 years and 2388 were untreated. Among treated subjects, 41% have one self-measurement blood pressure device (36% in 2010), 15% use one humeral device and 26% wrist device. Only 2% of treated hypertensive patients measure their blood pressure before a medical consultation, one times occasionally 49%, 11% several times a week, and 4% every day! Among 569 subjects owners of self-measure, 61% are treated hypertensive, 26% normotensive and 13% untreated hypertensive patients. Treated hypertensives are controlled with self measurement in 50% of cases (BP<135 and 85 mmHg) (49% in 2010) CONCLUSIONS: In 2012, seven million of self-measurement devices are used in France, four million in treated hypertensives. Only 2% of hypertensive patients with self-measurement device use it correctly. Better education for hypertensive subjects is required. Control in hypertensive stagnated at 50%, incite to improve our therapeutic strategy, favoring pluritherapies. PMID- 23752138 TI - Chronic kidney disease and the foot in diabetes--is inflammation the missing link? AB - Diabetes is commonly complicated by the development of chronic kidney disease (CKD). Equally prevalent is the development of diabetic foot disease and it is now recognised that there is a higher risk of the development of foot disease and major amputation in those patients with CKD. This is particularly marked in those patients with end-stage kidney disease receiving renal replacement therapy for which there are many possible mechanisms, including the effect of dialysis on tissue hypoxia. What has been recognised recently is that the risk of the development of foot disease appears to start prior to the onset of renal replacement therapy. Whilst this may be due to the fact that the emphasis of care shifts towards the requirements of the patients' renal disease, here we discuss the possibility that the presence of a foot ulcer itself may contribute to the development or progression of CKD through repeated episodes of sepsis or chronic inflammation, or both. PMID- 23752139 TI - Photophysics of 1,8-naphthalimide/Ln(III) dyads (Ln = Eu, Gd): naphthalimide -> Eu(III) energy-transfer from both singlet and triplet states. AB - Transient absorption and time resolved luminescence spectroscopy were used to study photophysical processes in the macrocycle-appended 1,8-naphthalimide compound H3L, and its Eu(III) and Gd(III) complexes Eu.L and Gd.L, in particular the naphthalimide-Eu(III) energy-transfer process. In all cases aggregation of the naphthalimide chromophores results in a low-energy emission feature in the 470-500 nm region in addition to the naphthalimide fluorescence; this lower energy emission has a lifetime longer by an order of magnitude than the monomer naphthalimide fluorescence. Transient absorption spectroscopy was used to measure the decay of the naphthalimide triplet excited state, which occurs in the range 30-50 MUs. In Eu.L, partial energy-transfer from the naphthalimide chromophore results in sensitized Eu(III)-based emission in addition to the naphthalimide based fluorescence features. Time-resolved measurements on the sensitized Eu(III) based emission reveal both fast (~10(9) s(-1)) and slow (~10(4) s(-1)) energy transfer processes from the naphthalimide energy-donor, which we ascribe to energy-transfer occurring from the singlet and triplet excited state of naphthalimide respectively. This is an unusual case of observation of sensitization of Eu(III)-based emission from the singlet state of an aromatic chromophore. PMID- 23752140 TI - Structural and spectroscopic characterization of potassium fluoroborohydrides. AB - Mechanochemical reactions between KBH4 and KBF4 result in the formation of potassium fluoroborohydrides K(BH(x)F(4-x)) (x = 0-4), as determined by (11)B and (19)F solid state NMR. The materials maintain the cubic KBH4 structure. Thermogravimetric (TG) data for a ball-milled sample with KBH4 : KBF4 = 3 : 1 are consistent with only desorption of hydrogen. PMID- 23752141 TI - Mycoplasma bovis infection in respiratory disease of dairy calves less than one month old. AB - Mycoplasma bovis is an important cause of bovine respiratory disease, especially in young calves where it can also cause arthritis, tenosynovitis and otitis. During 2009 and 2010 a survey was carried out on carcasses of calves less than one month old sent to the Diagnostic Laboratory of the Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna in Brescia, regardless of the presence of lung lesions, to detect this pathogen. PCR tests for Mycoplasma spp. and M. bovis were applied. 83 out of 224 (37%) lung tissue samples examined were positive at PCR test for Mycoplasma spp.; in 64 cases of these we observed typical respiratory lesions (P<0.001). M. bovis was identified in 26 out of 83 (31%) lung tissue samples positive at PCR test for Mycoplasma spp.; in 24 cases of these we observed typical respiratory lesions (P=0.039). Our data demonstrate that presence of Mycoplasma spp. and M. bovis positively correlates with pneumonic lung lesions in young dairy calves. PMID- 23752142 TI - Building consensus: development of a Best Practice Guideline (BPG) for surgical site infection (SSI) prevention in high-risk pediatric spine surgery. AB - BACKGROUND: Perioperative surgical site infection (SSI) after pediatric spine fusion is a recognized complication with rates between 0.5% and 1.6% in adolescent idiopathic scoliosis and up to 22% in "high risk" patients. Significant variation in the approach to infection prophylaxis has been well documented. The purpose of this initiative is to develop a consensus-based "Best Practice" Guideline (BPG), informed by both the available evidence in the literature and expert opinion, for high-risk pediatric patients undergoing spine fusion. For the purpose of this effort, high risk was defined as anything other than a primary fusion in a patient with idiopathic scoliosis without significant comorbidities. The ultimate goal of this initiative is to decrease the wide variability in SSI prevention strategies in this area, ultimately leading to improved patient outcomes and reduced health care costs. METHODS: An expert panel composed of 20 pediatric spine surgeons and 3 infectious disease specialists from North America, selected for their extensive experience in the field of pediatric spine surgery, was developed. Using the Delphi process and iterative rounds using a nominal group technique, participants in this panel were as follows: (1) surveyed for current practices; (2) presented with a detailed systematic review of the relevant literature; (3) given the opportunity to voice opinion collectively; and (4) asked to vote regarding preferences privately. Round 1 was conducted using an electronic survey. Initial results were compiled and discussed face-to-face. Round 2 was conducted using the Audience Response System, allowing participants to vote for (strongly support or support) or against inclusion of each intervention. Agreement >80% was considered consensus. Interventions without consensus were discussed and revised, if feasible. Repeat voting for consensus was performed. RESULTS: Consensus was reached to support 14 SSI prevention strategies and all participants agreed to implement the BPG in their practices. All agreed to participate in further studies assessing implementation and effectiveness of the BPG. The final consensus driven BPG for high-risk pediatric spine surgery patients includes: (1) patients should have a chlorhexidine skin wash the night before surgery; (2) patients should have preoperative urine cultures obtained; (3) patients should receive a preoperative Patient Education Sheet; (4) patients should have a preoperative nutritional assessment; (5) if removing hair, clipping is preferred to shaving; (6) patients should receive perioperative intravenous cefazolin; (7) patients should receive perioperative intravenous prophylaxis for gram-negative bacilli; (8) adherence to perioperative antimicrobial regimens should be monitored; (9) operating room access should be limited during scoliosis surgery (whenever practical); (10) UV lights need NOT be used in the operating room; (11) patients should have intraoperative wound irrigation; (12) vancomycin powder should be used in the bone graft and/or the surgical site; (13) impervious dressings are preferred postoperatively; (14) postoperative dressing changes should be minimized before discharge to the extent possible. CONCLUSIONS: In conclusion, we present a consensus-based BPG consisting of 14 recommendations for the prevention of SSIs after spine surgery in high-risk pediatric patients. This can serve as a tool to reduce the variability in practice in this area and help guide research priorities in the future. Pending such data, it is the unsubstantiated opinion of the authors of the current paper that adherence to recommendations in the BPG will not only decrease variability in practice but also result in fewer SSI in high-risk children undergoing spinal fusion. LEVEL OF EVIDENCE: Not applicable. PMID- 23752143 TI - What's the evidence? Systematic literature review of risk factors and preventive strategies for surgical site infection following pediatric spine surgery. AB - BACKGROUND: Despite relatively high rates of surgical site infections (SSIs) after pediatric spine surgery, practice guidelines are absent. We performed a systematic review of the literature, determining the level of evidence for risk factors for SSIs and prevention practices to reduce SSIs following pediatric spine surgery. METHODS: The search utilized the root search words "spine," "scoliosis," and "infection" resulting in 9594 abstracts. Following removal of duplicate abstracts, those that assessed only SSI rates, SSI treatment, nonoperative spine infections, or adult populations, 57 relevant studies were rated for level of evidence and graded using previously validated scales. RESULTS: Very few studies lead to grade A (good evidence) or grade B (fair evidence) recommendations. Ceramic bone substitute did not increase the risk of SSIs when compared with autograft (grade A). Comorbid medical conditions, particularly cerebral palsy or myelodysplasia; urinary or bowel incontinence; nonadherence to antibiotic prophylaxis protocols; and increased implant prominence increase the risk of SSIs (grade B). SSIs caused by gram-negative bacilli were more frequent in neuromuscular populations and first-generation stainless steel implants increased the risk of delayed infection compared to newer generation titanium implants (grade B). Evaluations of other risk factors for SSIs yielded conflicting or poor-quality evidence (grade C); these included malnutrition or obesity; number of levels fused or fusion extended to the sacrum/pelvis; blood loss; and use of allograft. Insufficient evidence (0 to 1 published studies) was available to recommend numerous practices shown to reduce SSI risk in other populations such as chlorhexidine skin wash the night before surgery, preoperative nasal swabs for Staphylococcus aureus, chlorhexidine skin disinfection, perioperative prophylaxis with intravenous vancomycin, vancomycin, or gentamicin powder in the surgical site or graft. CONCLUSIONS: Few studies have evaluated risk factors and preventive strategies for SSIs following pediatric spine surgery. This systematic review documents the relative lack of evidence supporting SSI prevention practices and highlights priorities for research. LEVEL OF EVIDENCE: Level III therapeutic study. PMID- 23752144 TI - Posterior spinal fusion in children with flaccid neuromuscular scoliosis: the role of noninvasive positive pressure ventilatory support. AB - BACKGROUND: Noninvasive intermittent positive pressure ventilatory assistance/support (NIV) can permit long-term survival for patients with no autonomous ability to breathe. Its role was explored in the perioperative management of children with flaccid neuromuscular scoliosis. METHODS: Vital capacity (VC), peak cough flow, and the extent of ventilator dependence were documented before and after surgical correction of scoliosis for children with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) with VCs as low as 2%. All patients and their caretakers were trained in NIV and mechanically assisted coughing preoperatively. Postoperatively, all were extubated using a specific protocol irrespective of their extent of ventilator dependence. RESULTS: Thirty-four children (16 DMD, 18 SMA) underwent posterior spinal arthrodesis for scoliosis at 11.7 (range, 6.6 to 16.6 y) years of age. The Cobb angle decreased from a mean 66 (range, 20 to 135 degrees) to 16 (range, 10 to 51 degrees) degrees. Fifteen patients (5 DMD, 10 SMA) had preoperative VC<40% of normal. All were extubated successfully by postoperative day 3 despite 14 failing preextubation and postextubation spontaneous breathing trials and requiring continuous NIV for up to 21 days after extubation. None had postoperative respiratory complications or required reintubation or readmission for pulmonary issues for at least 6 months postoperatively. CONCLUSIONS: Noninvasive positive pressure ventilator support is an alternative to invasive airway intubation in the perioperative management of children with flaccid neuromuscular scoliosis. LEVEL OF EVIDENCE: Level IV-case series. PMID- 23752145 TI - Conflict of interest in the assessment of botulinum toxin A injections in patients with cerebral palsy: a systematic review. AB - BACKGROUND: The efficacy of using botulinum toxin A injections in cerebral palsy (CP) is controversial. The financial conflict of interest related to medical research can affect the conclusion of an evidence-based review. This study was performed to determine as to what proportion of studies on botulinum toxin A injections in patients with CP was sponsored by the industry and whether the assessments of botulinum toxin injection in CP were associated with industry support. METHODS: Studies were identified with a search of the PubMed database (January 1991 to November 2011). All prospective, comparative, English language studies on the use of botulinum toxin A injections in patients with CP were included. A total of 374 articles were screened, 128 potentially eligible full articles were retrieved, and 66 studies met our inclusion criteria. The funding sources of the articles were reviewed, and qualitative conclusions regarding the effect of botulinum toxin A injection were classified as being either favorable, neutral, or unfavorable. RESULTS: Of 66 eligible articles, 28 were funded by the industry, and 25 were not. The other 13 studies did not include information on the funding source. A significant association was observed between the funding source and qualitative conclusions (P=0.042). Fifteen (53.6%) of the 28 industry sponsored studies had favorable conclusions, whereas only 5 (20%) of the 25 non industry-sponsored studies had favorable conclusions. CONCLUSIONS: About half of studies on the effect of botulinum toxin A in CP were sponsored by the industry. This systematic review revealed that the qualitative conclusions in those studies are more favorable to the use of the botulinum toxin A than the non-industry sponsored studies. Clinicians should be aware of an industry-related conflict of interest regarding reports on the efficacy of botulinum toxin A injections in patients with CP. LEVEL OF EVIDENCE: Level II-therapeutic study. PMID- 23752146 TI - Repeat hamstring lengthening for crouch gait in children with cerebral palsy. AB - BACKGROUND: Progressive crouch gait occurs in patients with cerebral palsy with increasing age. Hamstring lengthening improves crouch in these patients, but hamstring contractures can recur over time. The purpose of this study was to determine whether revision hamstring lengthening is as effective as primary lengthening in improving crouched gait. METHODS: Retrospective review was performed for 39 patients with static encephalopathy, average age 10+/-4 years, who underwent hamstring lengthening. Twenty-one subjects underwent a single hamstring lengthening (HSL group), and 18 underwent repeat HSL (rHSL group). Range of motion (ROM) and kinematic measures from preoperative and postoperative gait analysis testing were compared within and between groups using t tests, chi2 tests, and multiple regression analyses as appropriate. RESULTS: A total of 15/21 subjects in the HSL group (71%) improved stance knee extension by >=10 degrees, as compared with 5/18 (28%) in the rHSL group (P=0.007). The HSL group had improved popliteal angle, static knee and hip extension ROM, and knee flexion at initial contact and in stance phase (P<0.003). No such improvements were seen in the rHSL group. Popliteal angle, knee and hip extension ROM, and knee flexion at initial contact and in stance phase had significantly greater improvement in the HSL than the rHSL group (P<0.01). These differences persisted after adjusting for preoperative minimum hip flexion in stance, the only variable that differed between groups preoperatively. CONCLUSIONS: Repeat hamstring lengthening may delay progressive crouch, but does not result in long-term correction of crouch gait. Recurrent crouch may be caused by other factors such as quadriceps insufficiency, and may reflect the natural history of CP. Patients with recurrent crouch after hamstring lengthening are likely to benefit more from alternative surgical interventions to improve their knee position and function during gait. LEVEL OF EVIDENCE: Level IV-case series. PMID- 23752147 TI - Outcomes after salvage procedures for the painful dislocated hip in cerebral palsy. AB - BACKGROUND: The painful dislocated hip in the setting of cerebral palsy is a challenging problem. Many surgical procedures have been reported to treat this condition with varying success rates. The purpose of this study is to retrospectively evaluate and compare the outcomes of 3 different surgical procedures performed at our institution for pain relief in patients with spastic quadriplegic cerebral palsy and painful dislocated hips. METHODS: A retrospective chart review of the surgical procedures performed by 5 surgeons for spastic, painful dislocated hips from 1997 to 2010 was performed. The procedures identified were (1) proximal femoral resection arthroplasty (PFRA); (2) subtrochanteric valgus osteotomy (SVO) with femoral head resection; and (3) proximal femur prosthetic interposition arthroplasty (PFIA) using a humeral prosthesis. Outcomes based on pain and range of motion were determined to be excellent, good, fair, or poor by predetermined criteria. RESULTS: Forty-four index surgeries and 14 revision surgeries in 33 patients with an average follow up of 49 months met the inclusion criteria. Of the index surgeries, 12 hips were treated with a PFRA, 21 with a SVO, and 11 with a PFIA. An excellent or good result was noted in 67% of PFRAs, 67% of SVOs, and 73% of PFIAs. No statistical significance between these procedures was achieved. The 14 revisions were performed because of a poor result from previous surgery, demonstrating a 24% reoperation rate overall. No patients classified as having a fair result underwent revision surgery. All patients receiving revision surgery were eventually classified as having an excellent or good result. CONCLUSIONS: Surgical treatment for the painful, dislocated hip in the setting of spastic quadriplegic cerebral palsy remains unsettled. There continue to be a large percentage of failures despite the variety of surgical techniques designed to treat this problem. These failures can be managed, however, and eventually resulted in a good outcome. We demonstrated a trend toward better outcomes with a PFIA, but further study should be conducted to prove statistical significance. LEVEL OF EVIDENCE: III. PMID- 23752148 TI - Osteochondral injury after acute patellar dislocation in children and adolescents. AB - BACKGROUND: Acute patellar dislocation (APD) is a common injury in the pediatric patient population and may be associated with a spectrum of soft tissue and osteochondral injuries. This study describes the incidence of osteochondral fracture and associated injury patterns in a pediatric population after first time APD and assesses functional outcomes after treatment. METHODS: One hundred twenty-two patients, aged 11 to 18 years, who were evaluated after first-time APD over a 10-year period were identified, 46 of whom had confirmed osteochondral injury on magnetic resonance imaging (MRI). Demographic data, including knee affected, mechanism of injury, recurrent dislocation, operations performed, and condition at last follow-up, were retrieved from the medical record. Operative reports and MRI were used to characterize the location of osteochondral injury. The functional outcome of each patient with an osteochondral fracture was assessed using the Pedi-IKDC questionnaire. RESULTS: Forty-six patients, mean age 14.6 years (range, 11 to 18 y), were included. Osteochondral fracture occurred at the patella in 35 patients (76%), the lateral femoral condyle in 11 patients (24%), and at both locations in 3 patients (6.5%). In 21 patients (44%), MRI confirmed osteochondral injury despite the plain radiograph interpretation as negative for fracture. Twenty-six patients (68%) subsequently underwent surgery after injury. Injury to the medial patellofemoral ligament was identified on MRI in 97.8% of patients (45/46). Fifteen patients (32.6%) underwent a concomitant medial repair at the time of surgery. Osteochondral injury to the distal femur on average had a lower International Knee Documentation Committee score than patellar injuries (72.3+/-18 vs. 91.1+/-10.2, P<0.003). Femoral osteochondral injury involving the weight-bearing surface (75.27+/-18.19) scored lower than non weight-bearing surface injuries (93.22+/-7.47; P<0.001). CONCLUSIONS: The incidence of osteochondral injury associated with APD is high. Osteochondral fractures may initially go unrecognized on plain radiographs. Patients with weight-bearing lateral femoral condyle injuries had lower short-term functional scores, suggesting that outcomes depend on location of injury. LEVEL OF EVIDENCE: Level IV, diagnostic and therapeutic study. PMID- 23752149 TI - Comparison of submuscular and open plating of pediatric femur fractures: a retrospective review. AB - BACKGROUND: Plate osteosynthesis is an accepted method of treatment of pediatric femur fractures. Historically, open plating has been used. Submuscular bridge plating has gained recent popularity due to the theoretical advantages of decreased operative time, decreased blood loss, and decreased risk for infection. The purpose of this study was to compare submuscular bridge plating to open plating of pediatric femur fractures. METHODS: We retrospectively reviewed 79 patients (80 treated femur fractures) between 1999 and 2011 that underwent either open plating (58 femur fractures) or submuscular bridge plating (22 femur fractures). The outcome measures evaluated were operative time, estimated blood loss, malunion, leg length discrepancy, time to union, infection, unplanned return to the operating room, and length of hospital stay after surgery. RESULTS: Among our outcome measures, there was no difference between the 2 groups in terms of operative time, leg length discrepancy, time to union, infection, or length of hospital stay after surgery. There was greater estimated blood loss in the open plating group (P<=0.0001) and greater rotational asymmetry in the submuscular bridge plating group (P=0.005). There was a trend of increased unplanned return to the operating room in the open plating group (5/58 vs. 0/22) although not statistically significant (P=0.32). CONCLUSIONS: Submuscular bridge plating and open plating seem to be equally viable options for the management of pediatric diaphyseal femur fractures. In this study, open plating had an increase in estimated blood loss and a trend of more unplanned returns to the operating room, whereas submuscular bridge plating had an increase in asymptomatic rotational asymmetry. Further larger, prospective, randomized studies are necessary to further evaluate these operative techniques. LEVEL OF EVIDENCE: Therapeutic Level III. PMID- 23752150 TI - Salter-Harris II fractures of the distal tibia: does surgical management reduce the risk of premature physeal closure? AB - INTRODUCTION: Premature physeal closure (PPC) is a common complication resulting from the management of a displaced Salter-Harris II (SH II) fracture of the distal tibia. The purpose of this study was to evaluate our institution's treatment approach to assess PPC and complication rates of fractures treated both surgically and nonsurgically. METHODS: We performed a retrospective review of all patients presenting with a displaced SH II fracture between 2004 and 2010. Initial treatment was closed reduction in the emergency department. Further treatment and subsequent categorization was based on amount of residual displacement. Patients with <2 mm of postreduction displacement were treated with a non-weight-bearing long-leg cast (LLC; group 1), patients with residual displacement between 2 and 4 mm were treated with one of 2 approaches based on surgeon preference: either LLC (group 2) or open reduction and internal fixation (ORIF) with removal of any interposed tissue (group 3). Patients with >4 mm of residual displacement were treated with ORIF (group 4). Follow-up radiographs were performed for a minimum of 6 months. If there was clinical concern about PPC, computed tomography imaging was performed to assess for a bony bar. RESULTS: In total, 96 patients with a mean age of 12.6 years at presentation were included in the study. Among the 14 patients with <2 mm of postreduction displacement, 29% had a PPC and 7% had to undergo a subsequent procedure (epiphsyiodesis, osteotomy, etc.). Of the 33 patients with 2 to 4 mm of displacement who were treated with a LLC, 33% had a PPC and 15% had to undergo a subsequent procedure. Of the 11 patients with 2 to 4 mm of displacement treated with ORIF 46% had a PPC and 18% had a second procedure. Finally, 38 patients with >4 mm of displacement treated with ORIF had a PPC rate of 55% and 23% had a subsequent procedure. No statistical differences in PPC (P=0.19) or subsequent surgeries (P=0.57) were observed between groups. Among those with 2 to 4 mm of postreduction displacement, patient age (P=0.36), sex (P=0.39), mechanism of injury (P=0.13), time to fracture management (P=0.51), amount of initial displacement (P=0.34), number of reduction attempts (P=0.43), and operative treatment (P=0.47) did not significantly influence PPC. CONCLUSIONS: Patients with displaced SH II distal tibia fractures pose a challenging problem for the treating physician with a high rate of PPC (43% overall). Although surgical fixation with anatomic reduction and removal of interposed tissue may be necessary to improve joint alignment, it does not reduce the incidence of PPC and may increase the need for subsequent surgeries. PMID- 23752151 TI - High failure rate of the Pavlik harness in dislocated hips: is it bilaterality? AB - BACKGROUND: The purpose of this study was to evaluate the efficacy of Pavlik harness treatment in patients with bilaterally dislocated Graf type IV hips and compare them to cases with unilaterally dislocated hips. METHODS: Twenty-one patients (42 hips) who presented with bilaterally dislocated hips with no prior treatment were studied. The comparison group consisted of 33 patients (33 hips) with unilateral hip dislocation treated with the same protocol. Successful treatment was defined as relocation of the hips within 3 weeks of Pavlik harness application. RESULTS: Twelve of 21 patients (57%) in the bilateral group (6 failed bilaterally, 6 unilaterally) and 18/33 patients (54.5%) in the unilateral group failed harness treatment. CONCLUSIONS: The use of the Pavlik harness in dislocated hips is associated with a high failure rate. Patients presenting with bilaterally dislocated hips however, are at no greater risk for failure than patients presenting with unilateral hip dislocation. LEVEL OF EVIDENCE: Level III. PMID- 23752152 TI - Abduction bracing after Pavlik harness failure: an effective alternative to closed reduction and spica casting? AB - BACKGROUND: Previous studies have reported that the use of abduction bracing after Pavlik harness failure in patients with developmental dysplasia of the hip (DDH) is often effective in achieving hip reduction. METHODS: This is a retrospective study of consecutive patients with DDH at a single institution between 2006 and 2011. Patients in this study met all 4 inclusion criteria: (1) DDH, (2) a dislocated or dislocatable hip, (3) unsuccessful treatment with a Pavlik harness, and (4) subsequent treatment with abduction bracing. Exclusion criteria were dislocated hips associated with neurological, teratologic, syndromic, or other nonidiopathic conditions. RESULTS: Seven hips met inclusion criteria. Mean age at Pavlik harness initiation was 2.1 months (range, 1 d to 6 mo) and patients spent an average of 1.2 months (range, 0.4 to 2.7 mo) in the harness. After ultrasound demonstrated a persistently dislocated hip, patients were transitioned to an abduction brace and spent an average of 1.3 months (range, 0.1 to 3 mo) in the brace. One hundred percent (7/7) of hips treated with an abduction orthosis failed to reduce and required further treatment; 4 with closed reduction and spica casting, and 3 with open reduction. Patients were followed for an average of 33.6 months (range, 10 to 60 mo), and all patients had stable hips at latest follow-up. CONCLUSIONS: In this series of 7 patients with developmentally dislocated hips who failed Pavlik harness treatment, subsequent abduction bracing provided no benefit, in contrast to previous studies. All patients who failed Pavlik harness treatment went on to require closed or open reduction of the hip. Abduction bracing may unnecessarily prolong the time to definitive treatment. LEVEL OF EVIDENCE: Case series, level 4. PMID- 23752153 TI - Treatment of blocked elbow flexion in congenital radioulnar synostosis with radial head excision: a case series. AB - BACKGROUND: Congenital radioulnar synostosis (CRUS) causes a spectrum of presentations, most commonly a restriction of forearm rotation. Because most of these children are not treated operatively, many are not followed clinically after the diagnosis has been made. This report describes that a subset of the Cleary and Omer type IV synostoses (anterior dislocation of the radial head) can present with a progressive block to elbow flexion that worsens with growth. The location of this synostosis allows the physis of the radial head to grow untethered. The enlarged radial head can impinge upon the capitellum, blocking elbow flexion and snapping on the annular ligament. We propose excision of the radial head as a method of treating the anteriorly dislocated radial head in type IV synostoses. METHODS: We evaluated 4 patients with Cleary and Omer type IV synostoses who presented with an anteriorly dislocated radial head impinging on elbow flexion with snapping of the annular ligament. Each patient was treated with excision of the radial head. RESULTS: In 4 patients excision of the radial head was performed through a lateral Kocher approach. At follow-up, all patients showed relief from their pain and mechanical symptoms, with return of baseline range of motion. One complication which occurred was transient radial nerve neuropraxia. CONCLUSIONS: Although surgery is rarely needed for CRUS, excision of the radial head may be indicated if progressive loss of elbow flexion occurs secondary to impingement of the anteriorly dislocated radial head with the distal humerus in patients with type IV synostosis. We report that excision of the radial head can successfully treat this condition. Patients with type IV CRUS should be educated about the potential for loss of elbow flexion and/or followed until skeletal maturity to evaluate for this potential condition. LEVEL OF EVIDENCE: Case series consistent with level IV evidence; therapeutic study. PMID- 23752154 TI - Shoulder motion, strength, and functional outcomes in children with established malunion of the clavicle. AB - BACKGROUND: Recent investigations of displaced clavicle fractures in adults have demonstrated a higher prevalence of nonunion, symptomatic malunion, diminished functional outcome, and decreased strength with nonoperative treatment. Although these data have led to increased surgical management of displaced fractures, little published information is available regarding the consequences of malunion in the pediatric population. The purpose of this investigation was to assess pain, functional outcome, range of motion, and strength in children with displaced clavicle fractures treated nonoperatively. METHODS: Clinical evaluation of 16 patients with mid-diaphyseal clavicle fractures and >2 cm of initial displacement was performed; all had undergone nonoperative treatment and went on to radiographic malunion. The mean age at the time of injury was 12.2+/-3.3 years. Pain, aesthetic appearance, and satisfaction with treatment were rated by patients on a visual analog scale (VAS) (range 0 to 10 with 10 indicating the worst score). Patient-based outcomes were assessed with the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire and the Pediatric Outcomes Data Collection Instrument (PODCI). Bilateral shoulder motion was measured by a physical therapist. Isokinetic strength testing of the bilateral shoulders was performed with a Biodex dynometer. Range of motion and strength were analyzed with a multivariable regression, controlling for hand dominance. The mean follow up was 27.2 months after injury. RESULTS: All displaced fractures treated nonoperatively achieved union. Overall, there was reduced forward flexion and abduction on the injured side compared with the contralateral sides of 7.3 and 6.5 degrees, respectively, adjusted for hand dominance (P<0.05). Biodex testing did not detect any significant difference in abduction or adduction torque or power between affected and unaffected shoulders. The mean VAS score for pain was 1.6, with 4 patients reporting pain >=to 3. The mean VAS scores for satisfaction with aesthetic appearance was 2.7, with 4 patients reporting scores >5. The mean VAS scores for satisfaction with treatment was 2.0, with only 1 patient scoring >5. The mean DASH score was 4.9+/-7.5, with 3 patients scoring >=10. The mean scores on the DASH sports and performing arts module was 1.9+/-4.2, with only 1 patient scoring >=10. The mean global PODCI score was 94.5+/-6.0. The mean PODCI scores for upper extremity function, sports, and pain were 97.9+/-5.5, 95.4+/ 5.3, and 84.6+/-20.5, respectively. Only 1 patient was symptomatic enough to require corrective osteotomy. CONCLUSIONS: Skeletally immature patients with established clavicle fracture malunions do not develop clinically meaningful loss of shoulder motion or abduction/adduction strength. Routine surgical fixation for displaced, nonsegmental clavicle fractures may not be justified based upon concerns regarding shoulder motion and strength alone. Further investigation is required to determine the risk factors and causes of pain and functional compromise in the minority of pediatric patients with symptomatic malunions. LEVEL OF EVIDENCE: Level IV. PMID- 23752155 TI - Advanced bone age in children with Blount disease: a case-control study. AB - PURPOSE: Children with Blount disease are often obese and have muliplanar limb deformities including leg length discrepancy. Surgical options for these skeletally immature patients include guided growth and realignment osteotomy. Suboptimal outcomes such as persistent valgus overcorrection after proximal tibial osteotomy in children with early-onset Blount disease and undercorrection after guided growth treatment among adolescents with late-onset Blount disease can occur. Although obesity has been associated with precocious puberty, whether children with Blount disease have advanced skeletal maturity has not been previously investigated. We hypothesized that compared to their peers, children with Blount disease will have advanced skeletal (bone) age. METHODS: The relationship between skeletal and chronologic age was compared between 33 patients with Blount disease (12 early-onset, 21 late-onset) and 33 age-matched and sex-matched controls. The influence of variables such as the age of onset of Blount disease and patient's chronologic age on the discrepancy between skeletal and chronologic age was also evaluated. RESULTS: The mean body mass index was 39 kg/m2 in the Blount disease group and 23 kg/m2 in the control subjects (P<0.0001). Compared to their chronologic age, the bone age was advanced 16 months in Blount disease group (95% confidence interval, 10-22 mo) and 5 months in the control group (95% confidence interval, -1-10; P=0.003). On the basis of subgroup analysis, the bone age was advanced 26 months in early-onset and 10 months in late-onset Blount disease (P=0.01). The discrepancy between bone age and chronologic age decreased as chronologic age increased in both the control (r=-0.36, P=0.04) and Blount disease groups (r=-0.58, P=0.0004). CONCLUSION: Compared to their peers, children with Blount disease have advanced skeletal maturity. The difference between bone age and chronologic age decreases with growth. Since advanced skeletal maturity can impact the strategy for surgical realignment and magnitude of planned (over)correction of lower limb deformity, preoperative assessment of bone age should be considered when managing children with Blount disease. LEVEL OF EVIDENCE: Level III. PMID- 23752156 TI - Foot and ankle abnormalities in the Hurler syndrome: additions to the phenotype. AB - BACKGROUND: After successful hematopoietic stem cell transplantation maintaining function and mobility has become the key goal in the management of patients with mucopolysaccharoidosis type 1 (MPS-1). We detail the foot and ankle pathology in 18 patients with MPS-1 managed in our unit. METHODS: Functional assessment was performed using the Oxford Foot and Ankle Questionnaire for children (OxAFQ-C). Morphologic assessment was performed by means of a mirrored foot photograph box, the Foot Posture Index (FPI), and clinical photography. Standardized radiologic investigations were sought when clinically warranted. Average lateral talus-first metatarsal angle, anteroposterior and lateral talocalcaneal angles, and lateral distal tibial angle (LDTA) were determined. RESULTS: The average patient-reported OxAFQ-C score was 44.7 (range, 10 to 60). The average proxy-reported OxAFQ-C score was 45.7 (range, 11 to 60). Ten of the 18 patients wore customized footwear. Of the 36 feet examined 11 were found scored as "highly pronated" (FPI>+9), 12 feet had a "pronated posture" (FPI +6 to +9), and 13 feet were found to have a "normal posture" (FPI 0 to +5). Thirteen of the 18 (72%) patients studied had curly toes. The average talus-first metatarsal angle recorded was 10.7 degrees (range, -7 to 30 degrees). The average lateral and anteroposterior talocalcaneal angles were 45.8 degrees (range, 16 to 62 degrees) and 31 degrees (range, 1 to 51 degrees), respectively. The average LDTA was found to be 70.6 degrees (range, 48 to 82 degrees). A single-sample Student t test shows significant divergence of measured LDTA, OxAFQ-C, and FPI from normal populations (P<0.005). CONCLUSIONS: MPS-1 is associated with a significant degree of foot and ankle pathology that has not been previously described. We found a high incidence of curly toes, ankle valgus, functional foot, and ankle disability and a requirement for customized footwear among our cohort. We recommend that careful assessment of foot and ankle pathology should be routine in the interdisciplinary management of patients with MPS-1. LEVEL OF EVIDENCE: Level III. PMID- 23752157 TI - The use of the Ponseti method to treat clubfeet associated with congenital annular band syndrome. AB - BACKGROUND: A clubfoot deformity may be associated with congenital annular band syndrome (CABS), and has, until recently, been thought to be resistant to nonoperative management. The purpose of this report was to describe the use of the Ponseti method in the treatment of 5 patients whose clubfeet were associated with this syndrome. METHODS: All patients with a diagnosis of clubfoot, who were treated at the Orthopaedic Hospital Clubfoot Clinic, over a period of 4 years, were reviewed. During that period, a total of 131 infants with 194 clubfeet were treated. We identified 5 infants (3.8%) with 6 clubfeet associated with CABS. The patients were managed using the Ponseti method. One of the patients, with a contralateral amputation of the limb opposite to the side with a clubfoot, required the use of a unilateral foot abduction orthosis rather than a conventional foot abduction orthosis. The outcomes evaluated included: the number of casts needed to obtain correction, the percentage of patients requiring a tendo-Achilles tenotomy, the number of relapses, and the need for additional secondary procedures. RESULTS: The mean age at presentation for the 5 patients was 6.2 weeks. Four of the clubfeet had an ipsilateral band and 2 did not. None of the patients had a neurological deficit distal to a band. The mean number of casts used to correct the deformity was 6, and a percutaneous tendo-Achilles tenotomy was done in all cases. All of the feet achieved initial correction. Four patients (5 feet) experienced a relapse attributed to failure to use the postcorrective brace as prescribed. Correction of the foot in 3 of these patients was regained and maintained by another series of manipulation and cast application followed by resumption of bracing. One patient underwent an anterior tibial tendon transfer. The patients were followed for an average of 32.6 months (21 to 49 mo). All feet were supple and plantigrade at latest follow-up evaluation. CONCLUSIONS: The Ponseti method may be successfully applied to clubfeet associated with CABS. LEVEL OF EVIDENCE: Level IV. PMID- 23752158 TI - The shorthand bone age assessment: a simpler alternative to current methods. AB - BACKGROUND: Radiographic assessment of skeletal age in pediatric patients is a common practice among orthopaedic surgeons. Current methods of assessment remain labor intensive and require special resources. This study sought to investigate a novel, abridged method of bone age assessment that may serve as a simpler and more efficient alternative to the current standard. METHODS: A shorthand bone age (SBA) method developed at our institution was compared against the Greulich and Pyle method from which it was derived. Standard left hand bone age radiographs of 140 male and 120 female patients, previously assigned skeletal ages ranging from 12.5 to 16 years in males and 10 to 16 years in females by musculoskeletal radiologists using the Greulich and Pyle radiographic atlas, were read using the shorthand method by 3 attending pediatric orthopaedic surgeons and an orthopaedic surgery resident. The shorthand method utilizes a single, univariable criterion for each age, rather than a multivariable subjective comparison to a radiographic atlas. All reviewers were blinded to the original bone age determination. Interobserver reliability, intraobserver reliability, and agreement with the previous records utilizing the atlas were calculated using weighted kappa. RESULTS: The SBA method readings demonstrated substantial agreement with readings by the Greulich and Pyle atlas, demonstrating weighted kappa values ranging from 0.71 to 0.75. The SBA method also demonstrated substantial to almost perfect interobserver and intraobserver reliability, with values ranging from 0.77 to 0.87 and from 0.87 to 0.95, respectively. CONCLUSIONS: These results are comparable or superior to previous reports which investigate the validity and reliability of other skeletal age assessment tools. The SBA assessment tool offers a simple and efficient alternative to current methods. LEVEL OF EVIDENCE: Diagnostic study, level III. PMID- 23752159 TI - Risk factors for vitamin D deficiency in children with osteogenesis imperfecta. AB - BACKGROUND: The purpose of this study was to evaluate the prevalence of vitamin D deficiency and possible risk factors influencing the vitamin D serum levels in patients with osteogenesis imperfecta (OI). METHODS: Charts of all children with OI seen at Shriners Hospitals for Children in Houston, TX, between November 2008 and June 2011 were reviewed for daily milk and soda consumption, multivitamin and vitamin D supplementation, time spent outside, use of sunscreen, amount of screen time, ambulatory status, height, weight, body mass index (BMI), serum 25 hydroxyvitamin D (25OHD), parathyroid hormone levels, and history of bisphosphonate treatment. RESULTS: Of the 80 children with OI, charts of 44 children (26 female) had documentation of the variables of interest. Mean level of 25OHD was 23 ng/mL (+/-11) (range, 7 to 58) and 35 (79.5%) patients had insufficient or deficient levels. Significant correlations with low vitamin D levels were found for older age (P<0.001), African American descent (P=0.01), BMI (P<0.001), BMI percentile (P=0.30), consumption of soda (P=0.009), and pamidronate therapy (P=0.004). Evaluated together, the studied variables accounted for a large proportion of the variability of 25OHD levels in patients with OI (P=0.004). CONCLUSIONS: To optimize bone health in children with OI, health care providers need to be aware of patients' risk factors for low vitamin D levels and educate families on the modifiable risk factors of milk and soda consumption, obesity, and vitamin D supplementation. Future research is needed to address the relationship between fractures and vitamin D levels in patients with OI and on the cause and effect relationship between bisphosphonate therapy and vitamin D. LEVEL OF EVIDENCE: Level II. PMID- 23752160 TI - Cast saw noise does not reach occupational hazard levels. AB - BACKGROUND: The purpose of our study was to measure the sound level generated by selected commercially available cast saws. These levels were then compared with the level of everyday sounds and to accepted intensities by Safety Administrations to see whether the mandatory use of hearing protection should be recommended to prevent noise-induced hearing loss. METHODS: We assessed the sound levels generated by the Quiet Cast Removal System (QCR; OrthoPediatrics Corp., Warsaw, IN), Stryker 986 Cast Vac (Stryker Corp.), and the Stryker 840 Cast Cutter (Stryker Corp.). The sound generated by these saws was measured with a sound level meter at the source and at 6, 12, and 36 inches. The sound level from each device was assessed both while operating alone and while cutting casts for a total of 3 repetitions at each of the distances tested and analyzed statistically. RESULTS: The maximal mean sound intensity of the Stryker 986 and Stryker 840 saws was 90.7 and 88.6 dBA at 36 inches, respectively while cutting a cast, whereas the QCR System produced 50.1 dBA at this distance. At 6 inches, the mean sound intensity was 99.4, 96.4, and 64.5 dBA for the Stryker 840, 986, and QCR, respectively. Statistically significant differences in sound intensity between Stryker and QCR saws were noted under all testing scenarios (P<0.0001). CONCLUSIONS: None of the cast saws produced intensities exceeding recommended standards for a single exposure or intensities reaching occupational hazard levels. The QCR saw was significantly quieter than both the Stryker 840 and 986 under all scenarios. The need for a recommendation of mandatory usage of hearing protection for patients and office personal could not be demonstrated. CLINICAL RELEVANCE: Cast saw noise is common in orthopaedic clinics. Our study demonstrates sound levels from commercially available saws do not reach occupational hazards but are sufficiently high that practical methods to reduce intensity may be warranted. PMID- 23752161 TI - Growth disturbances after transphyseal ACL reconstruction in skeletally immature patients: who is more at risk? Young child or adolescent? PMID- 23752162 TI - Intraoperative anaphylaxis secondary to intraosseous gelatin administration. AB - BACKGROUND: FloSeal and SurgiFlo Hemostatic Matrices are commonly used in surgical procedures to promote coagulation and minimize blood loss. They are composed of bovine and porcine gelatin matrix, respectively, that can be injected into pedicles to stop osseous bleeding during pedicle screw insertion. METHODS: This report details 2 pediatric spinal deformity reconstructive surgery patients who experienced intraoperative cardiovascular events after the intraosseous administration of animal-derived gelatin. RESULTS: Case #1 is an 11-year-old female with adolescent idiopathic scoliosis who was undergoing routine posterior spinal instrumentation and fusion. During placement of the fourth pedicle screw, the patient developed profound hypotension, tachycardia, and elevated airway pressures requiring intravenous epinephrine and phenylephrine for hemodynamic support. Surgery was aborted. Postoperative work-up demonstrated a positive ImmunoCAP study for bovine gelatin. Surgery was repeated 1 week later, without the use of FloSeal, and no episodes of hemodynamic instability. Case #2 was a 9 year-old female with juvenile idiopathic scoliosis who was undergoing a growing spine construct. As in Case #1, SurgiFlo was placed into 2 pedicle tracts after which there was profound hypotension, tachycardia, and elevated airway pressures. Resuscitative efforts included intravenous atropine and epinephrine with resolution. Surgery was aborted. Surgery was repeated 2 weeks later, without the use of SurgiFlo, with no episodes of hemodynamic instability. CONCLUSIONS: Given that the patient's symptoms were classic for anaphylaxis, and that the timing of the anaphylaxis immediately followed the administration of FloSeal and SurgiFlo we believe that FloSeal and SurgiFlo were the causes of the reactions. These are the first known reported cases of intraoperative anaphylaxis associated with FloSeal and SurgiFlo. On the basis of our experience, in order to avoid intraoperative cardiovascular events, we obtain preoperative ImmunoCAP testing and eliciting a thorough preoperative history about bovine-derived and porcine derived gelatin products. PMID- 23752163 TI - Successful treatment of a sacral aneurysmal bone cyst with zoledronic acid. AB - BACKGROUND: Aneurysmal bone cysts (ABCs) in the sacrum pose a management challenge as their location usually means that surgical excision is not possible. Strategies such as embolization have been used previously but have the potential for significant side effects. We report the successful use of bisphosphonate treatment (zoledronic acid) in an 8-year-old boy who presented with an ABC that did not respond to embolization. METHODS: The patient presented with pain and progressive limp. After radiologic and histologic confirmation of the diagnosis, embolization therapy was trialed, which was unsuccessful. At this point, he had severe pain and extremely limited mobility, requiring the use of a wheelchair. His ability to lie flat or sit erect was limited by the pain. Zoledronic acid therapy was subsequently commenced at 0.04 mg/kg per dose by intravenous infusion, at 4 monthly intervals, for a total of 2 years (7 doses). RESULTS: The infusions were well tolerated, with rapid reduction in pain and resolution of previously severe immobility, from being bed and chair bound at baseline to normal independent ambulation over several months. This was associated with marked radiologic improvement. We postulate that the effect of treatment is a combination of the anti-inflammatory effect of zoledronic acid and the antiresorptive effect of osteoclast inhibition. CONCLUSIONS: We conclude that bisphosphonates should be considered as possible second-line agents for ABCs. Further, study of a larger cohort would help to establish their efficacy in this setting. LEVEL OF EVIDENCE: Level IV (case report, no comparator/control arm). PMID- 23752164 TI - Physical and psychosocial function in residential aged-care elders: effect of Nintendo Wii Sports games. AB - This mixed-methods, quasi-experimental pilot study examined whether the Nintendo Wii Sports (NWS) active video game (exergame) system could significantly improve the functional ability, physical activity levels, and quality of life of 34 older adults (4 men and 30 women, 83 +/- 8 yr) living in 2 residential aged-care (RAC) centers. Change score analyses indicated the intervention group had significantly greater increases in bicep curl muscular endurance, physical activity levels, and psychological quality of life than the control group (p < .05). Analysis of the quotes underlying the 3 themes (feeling silly, feeling good; having fun; and something to look forward to) suggested that intervention group participants developed a sense of empowerment and achievement after some initial reluctance and anxiousness. They felt that the games were fun and provided an avenue for greater socialization. These results add some further support to the utilization of NWS exergames in the RAC context. PMID- 23752165 TI - Plica polonica: confusion, confabulation, and the death of a disease. PMID- 23752166 TI - Postmortem high-resolution fetal magnetic resonance imaging in three cases of lower urinary tract obstruction. AB - In this manuscript we report 3 cases of severe lower urinary tract obstruction diagnosed before 20 weeks of pregnancy. All cases had a very similar prenatal presentation with a megacystis, bilateral hydro-ureteronephrosis and increased echogenicity of the kidneys. High-resolution postmortem magnetic resonance imaging (MRI), following termination of pregnancy, enabled accurate investigation of the underlying cause of the urinary tract obstruction, by depicting the presence of an urethral valve, urethral atresia and cloacal dysgenesis. Postmortem fetal MRI provides high anatomical detail and is very suitable to investigate congenital anomalies of the lower urinary tract. In case (timely or consented) conventional autopsy is not possible, MRI is an excellent alternative. PMID- 23752170 TI - Red blood cell distribution width and erythrocyte deformability in patients with acute myocardial infarction. AB - Increased RDW has been found to be a marker of adverse outcomes in cardiovascular disease (CVD), although the exact mechanism remains unclear. Recently, several authors have found that higher RDW is associated with decreased erythrocyte deformability, which can impair blood flow through microcirculation, a fact which may explain the increased risk for CVD events associated with elevated RDW. The aim of the present study was to investigate the association between RDW and erythrocyte deformability in patients with acute myocardial infarction (AMI). The study group comprised 60 AMI patients and 72 gender- and age-matched controls, in whom erythrocyte deformability was determined by means of the elongation index (EI) in a Rheodyn SSD, along with haematological, biochemical and inflammatory parameters. Patients showed higher RDW (p = 0.012) and lower EI (p < 0.05) than controls. When anaemic patients were removed from the study, AMI showed still lower EI than controls (p < 0.05), but no differences in RDW were observed (p = 0.141). RDW correlated inversely with haematimetric indices (p < 0.001), but not with inflammatory and biochemical parameters (p > 0.05). EI correlated inversely with Hb, MCHC (p < 0.001) and directly with MCV (p < 0.05). EI also correlated inversely with glucose (p < 0.05) and directly with HDL-cholesterol (p < 0.05). The multivariate regression model showed that only MCV and Hb were independent predictors of RDW (beta coefficients: -0.383, -0.208; p < 0.001, p = 0.050, respectively). In addition, MCV, MCHC and hyperlipidaemia were independent predictors of EI (beta coefficients: 0.366, -0.533, -0.192; p < 0.001, p < 0.001, p = 0.019 respectively). In AMI patients, increased RDW is not related with EI, so this mechanism does not seem to be responsible for an increased CDV risk in these patients. PMID- 23752172 TI - Fleshy asymptomatic cutaneous nodules in a young adult male-diagnosis. PMID- 23752171 TI - Patient stratification for preventive care in dentistry. AB - Prevention reduces tooth loss, but little evidence supports biannual preventive care for all adults. We used risk-based approaches to test tooth loss association with 1 vs. 2 annual preventive visits in high-risk (HiR) and low-risk (LoR) patients. Insurance claims for 16 years for 5,117 adults were evaluated retrospectively for tooth extraction events. Patients were classified as HiR for progressive periodontitis if they had >= 1 of the risk factors (RFs) smoking, diabetes, interleukin-1 genotype; or as LoR if no RFs. LoR event rates were 13.8% and 16.4% for 2 or 1 annual preventive visits (absolute risk reduction, 2.6%; 95%CI, 0.5% to 5.8%; p = .092). HiR event rates were 16.9% and 22.1% for 2 and 1 preventive visits (absolute risk reduction, 5.2%; 95%CI, 1.8% to 8.4%; p = .002). Increasing RFs increased events (p < .001). Oral health care costs were not increased by any single RF, regardless of prevention frequency (p > .41), but multiple RFs increased costs vs. no (p < .001) or 1 RF (p = .001). For LoR individuals, the association between preventive dental visits and tooth loss was not significantly different whether the frequency was once or twice annually. A personalized medicine approach combining gene biomarkers with conventional risk factors to stratify populations may be useful in resource allocation for preventive dentistry (ClinicalTrials.gov, NCT01584479). PMID- 23752173 TI - The EUTOS prognostic score: review and validation in 1288 patients with CML treated frontline with imatinib. AB - The introduction of tyrosine kinase inhibitors (TKI) in the treatment of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) has revolutionized the outcome, but the prognosis of the disease is still based on prognostic systems that were developed in the era of conventional chemotherapy and interferon (IFN)-alfa. A new prognostic score including only two variables, spleen size and basophils, was developed for the prediction of complete cytogenetic response (CCyR) and progression-free survival (PFS). The score was based on a large series of patients who were enrolled in prospective multicenter studies of first-line imatinib treatment. The prognostic value of the EUTOS (European Treatment and Outcome Study for CML) score has now been tested in an independent, multicenter, multinational series of 1288 patients who were treated first-line with imatinib outside prospective studies. It was found that also in these patients, the EUTOS prognostic score was predictive for CCyR, PFS and overall survival (OS). In addition, the prognostic value of the score was reported to be significant in seven of the eight other independent studies of almost 2000 patients that were performed in Europe, the Americas and Asia. The EUTOS risk score is a valid tool for the prediction of the therapeutic effects of TKI, particularly imatinib. PMID- 23752174 TI - Effect of graft source on mismatched unrelated donor hemopoietic stem cell transplantation after reduced intensity conditioning. AB - This retrospective report compared the results of graft source on outcome after allogeneic stem cell transplantation (allo-SCT) in patients with hematologic malignancies receiving a reduced intensity conditioning (RIC) regimen. A total of 152 patients received either a RIC allo-SCT using a 9/10 mismatched unrelated donor (MisMUD, n=42) or a double unrelated umbilical cord blood (dUCB, n=110) graft. With a median follow-up of 30.3 months, the cumulative incidence of non relapse mortality was 26% in the dUCB group versus 24% in the MisMUD group (P=0.95). Grade 3-4 acute graft-versus-host disease (GVHD) incidence was 19.7% in the dUCB group versus 21.4% in the MisMUD group (P=0.83). The cumulative incidence of extensive chronic GVHD at 2 years was 6.4% in the dUCB group versus 21.4% in the MisMUD group (P=0.02). The Kaplan-Meier estimate of overall survival at 2 years was comparable between both groups (52.3% (95% confidence interval (CI), 42.1-61.5%) in the dUCB group versus 47.9% (95% CI, 31.6-62.4%) in the MisMUD group, P=0.55). Progression-free survival at 2 years was 43.3% (95% CI, 33.7-52.5%) in the dUCB group versus 38.3% (95% CI, 23.2-53.3%) in the MisMUD group (P=0.55). These data suggest that dUCB is a valid alternative graft source with significantly less chronic GVHD compared with MisMUD in the setting of RIC allo-SCT. PMID- 23752176 TI - A Remarkable Case of Menstrual Dermatosis. K. Ruehl, p. 581. PMID- 23752175 TI - Genome-wide studies in multiple myeloma identify XPO1/CRM1 as a critical target validated using the selective nuclear export inhibitor KPT-276. AB - RNA interference screening identified XPO1 (exportin 1) among the 55 most vulnerable targets in multiple myeloma (MM). XPO1 encodes CRM1, a nuclear export protein. XPO1 expression increases with MM disease progression. Patients with MM have a higher expression of XPO1 compared with normal plasma cells (P<0.04) and to patients with monoclonal gammopathy of undetermined significance/smoldering MM (P<0.0001). The highest XPO1 level was found in human MM cell lines (HMCLs). A selective inhibitor of nuclear export compound KPT-276 specifically and irreversibly inhibits the nuclear export function of XPO1. The viability of 12 HMCLs treated with KTP-276 was significantly reduced. KPT-276 also actively induced apoptosis in primary MM patient samples. In gene expression analyses, two genes of probable relevance were dysregulated by KPT-276: cell division cycle 25 homolog A (CDC25A) and bromodomain-containing protein 4 (BRD4), both of which are associated with c-MYC pathway. Western blotting and reverse transcription-PCR confirm that c-MYC, CDC25A and BRD4 are all downregulated after treatment with KPT-276. KPT-276 reduced monoclonal spikes in the Vk*MYC transgenic MM mouse model, and inhibited tumor growth in a xenograft MM mouse model. A phase I clinical trial of an analog of KPT-276 is ongoing in hematological malignancies including MM. PMID- 23752177 TI - Deficient modulation of pain by a positive emotional context in fibromyalgia patients. AB - This study aimed to investigate the modulating effects of emotional context on pain perception in 16 patients with fibromyalgia syndrome (FMS) and 16 healthy control (HC) subjects. An infrared laser was used to apply individually adapted painful stimuli to the dorsum of the left hand. The emotional background of the painful stimuli was modulated by concurrent presentations of negative, neutral, and positive picture stimuli selected from the International Affective Picture System. As control conditions, painful stimuli and the pictures were also presented by themselves. During each of the 5 laser-picture trials, subjects received 10 painful stimuli and were asked to rate the average intensity and unpleasantness of the experienced pain. Functional magnetic resonance images were obtained, using a T2(*) sensitive echo planar sequence. HC subjects showed a linear increase in pain intensity and unpleasantness ratings when painful stimuli were presented during positive, neutral, and negative pictures. In contrast, FMS patients showed a quadratic trend for pain intensity ratings indicating a lack of pain reduction by the positive pictures. In addition, the FMS patients showed less activation in secondary somatosensory cortex, insula, orbitofrontal cortex, and anterior cingulate cortex during the positive picture pain trials. Our results suggest that fibromyalgia patients are less efficient in modulating pain by positive affect and may benefit less from appetitive events than healthy control subjects. PMID- 23752179 TI - The in vivo antitumor activity of cardiac glycosides in mice xenografted with human cancer cells is probably an experimental artifact. PMID- 23752178 TI - Utility of a bacterial infection model to study epithelial-mesenchymal transition, mesenchymal-epithelial transition or tumorigenesis. AB - DCLK1 and Lgr5 have recently been identified as markers of quiescent and cycling stem cells in the small intestinal crypts, respectively. Epithelial-mesenchymal transition (EMT) is a key development program that is often activated during cancer invasion and metastasis, and also imparts a self-renewal capability to disseminating cancer cells. Utilizing the Citrobacter rodentium (CR)-induced transmissible murine colonic hyperplasia (TMCH) model, we observed a relative decrease in DCLK1 expression in the colonic crypts, with significant shift towards stromal staining at peak (12 days post infection) hyperplasia, whereas staining for Lgr5 and Msi-1 increased several fold. When hyperplasia was regressing (days 20-34), an expansion of DCLK1+ve cells in the CR-infected crypts compared with that seen in uninfected control was recorded. Purified colonic crypt cells exhibiting epigenetic modulation of the transforming growth factor beta (TGFbeta), Wnt and Notch pathways on 12 or 34 days post infection formed monolayers in vitro, and underwent trans-differentiation into fibroblast-like cells that stained positive for vimentin, fibronectin and DCLK1. These cells when trypsinized and regrown in soft agar, formed colonospheres/organoids that developed into crypt-like structures (colonoids) in Matrigel and stained positive for DCLK1. Mice exhibiting 12 or 34 days of TMCH were given azoxymethane once for 8 h (Gp1) or weekly for 3 weeks (Gp2), and subjected to crypt isolation. Crypt cells from Gp1 animals formed monolayers as well as colonospheres in soft agar and nodules/tumors in nude mice. Crypt cells isolated from Gp2 animals failed to form the monolayers, but developed into colonospheres in soft agar and nodules/tumors in nude mice. Thus, both hyperplasia and increased presence of DCLK1+ve cells promote cellular transformation in response to a second hit. The TMCH model, therefore, provides an excellent template to study how alterations in intestinal stem cells promote trans-differentiation, crypt regeneration or colon carcinogenesis following bacterial infection. PMID- 23752180 TI - An siRNA screen identifies the GNAS locus as a driver in 20q amplified breast cancer. AB - Poor-prognosis oestrogen receptor-positive breast cancer is characterised by the presence of high-level focal amplifications. We utilised a focused small interfering RNA screen in 14 breast cancer cell lines to define genes that were pathogenic in three genomic regions focally amplified in oestrogen receptor positive breast cancer, 8p11-12, 11q13 and 20q. Silencing the GNAS locus, that encodes the G protein alpha stimulatory subunit Galphas, specifically reduced the growth of 20q amplified breast cancer cell lines. Examination of a publically available small hairpin RNA data set confirmed GNAS silencing to be selective for 20q amplified cancer cell lines. Cell lines with 20q amplification were found to overexpress specifically the extra long Galphas splice variant (XLalphas). Overexpression of XLalphas induced cAMP levels to a greater extent than Galphas, suggesting that amplification of the GNAS locus, and overexpression of the XLalphas variant in particular, enhanced cAMP signalling. GNAS silencing in amplified cell lines reduced extracellular-signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and conversely overexpression of exogenous XLalphas in a non amplified cell line increased MEK-ERK1/2 phosphorylation, identifying one potential downstream consequence of enhanced cAMP signalling. Our data indicate that amplification of the GNAS locus may contribute to the pathogenesis of breast cancer, and highlight a previously unrecognised role for the GNAS XLalphas variant in cancer. PMID- 23752181 TI - EphA2 promotes epithelial-mesenchymal transition through the Wnt/beta-catenin pathway in gastric cancer cells. AB - This study aims to investigate the significance of erythropoietin-producing hepatocellular (Eph)A2 expression and the mechanism by which EphA2 is involved in the epithelial-mensenchymal transition (EMT) of gastric cancer cells. EphA2 expression levels were upregulated and positively correlated with metastasis and EMT markers in human gastric cancer specimens. Modulation of EphA2 expression levels had distinct effects on cell proliferation, cell cycle, migration, invasion and morphology in the gastric cancer cell lines SGC7901 and AGS in vitro and in vivo. Overexpression of EphA2 resulted in the upregulation of the EMT molecular markers N-cadherin and Snail, as well as the Wnt/beta-catenin targets TCF4, Cyclin-D1 and c-Myc, while silencing EphA2 using short hairpin RNA had the opposite effect. Furthermore, inhibition of the Wnt/beta-catenin pathway by XAV939 negated the effect of EphA2 overexpression, whereas activation of the Wnt/beta-catenin pathway by LiCl impaired the effect of the EphA2 knockdown on EMT. These observations demonstrate that EphA2 upregulation is a common event in gastric cancer specimens that is closely correlated with cancer metastasis and that EphA2 promotes EMT of gastric cancer cells through activation of Wnt/beta catenin signaling. PMID- 23752182 TI - Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. AB - Prostate cancer is the second-leading cause of cancer-related mortality in men in Western societies. Androgen receptor (AR) signaling is a critical survival pathway for prostate cancer cells, and androgen-deprivation therapy (ADT) remains the principal treatment for patients with locally advanced and metastatic disease. Although a majority of patients initially respond to ADT, most will eventually develop castrate resistance, defined as disease progression despite serum testosterone levels of <20 ng/dl. The recent discovery that AR signaling persists during systemic castration via intratumoral production of androgens led to the development of novel anti-androgen therapies including abiraterone acetate and enzalutamide. Although these agents effectively palliate symptoms and prolong life, metastatic castration-resistant prostate cancer remains incurable. An increased understanding of the mechanisms that underlie the pathogenesis of castrate resistance is therefore needed to develop novel therapeutic approaches for this disease. The aim of this review is to summarize the current literature on the biology and treatment of castrate-resistant prostate cancer. PMID- 23752183 TI - Parathyroid hormone-related protein inhibits DKK1 expression through c-Jun mediated inhibition of beta-catenin activation of the DKK1 promoter in prostate cancer. AB - Prostate cancer (PCa)bone metastases are unique in that majority of them induce excessive mineralized bone matrix, through undefined mechanisms, as opposed to most other cancers that induce bone resorption. Parathyroid hormone-related protein (PTHrP) is produced by PCa cells and intermittent PTHrP exposure has bone anabolic effects, suggesting that PTHrP could contribute to the excess bone mineralization. Wnts are bone-productive factors produced by PCa cells, and the Wnt inhibitor Dickkopfs-1 (DKK1) has been shown to promote PCa progression. These findings, in conjunction with the observation that PTHrP expression increases and DKK1 expression decreases as PCa progresses, led to the hypothesis that PTHrP could be a negative regulator of DKK1 expression in PCa cells and, hence, allow the osteoblastic activity of Wnts to be realized. To test this, we first demonstrated that PTHrP downregulated DKK1 mRNA and protein expression. We then found through multiple mutated DKK1 promoter assays that PTHrP, through c-Jun activation, downregulated the DKK1 promoter through a transcription factor (TCF) response element site. Furthermore, chromatin immunoprecipitation (ChIP) and re ChIP assays revealed that PTHrP mediated this effect through inducing c-Jun to bind to a transcriptional activator complex consisting of beta-catenin, which binds the most proximal DKK1 promoter, the TCF response element. Together, these results demonstrate a novel signaling linkage between PTHrP and Wnt signaling pathways that results in downregulation of a Wnt inhibitor allowing for Wnt activity that could contribute the osteoblastic nature of PCa. PMID- 23752184 TI - Reprogramming activity of NANOGP8, a NANOG family member widely expressed in cancer. AB - NANOG is a key transcription factor for pluripotency in embryonic stem cells. The analysis of NANOG in human cells is confounded by the presence of multiple and highly similar paralogs. In particular, there are three paralogs encoding full length proteins, namely, NANOG1, NANOG2 and NANOGP8, and at least eight additional paralogs that do not encode full-length NANOG proteins. Here, we have examined NANOG family expression in human embryonic stem cells (hESCs) and in human cancer cell lines using a multi-NANOG PCR that amplifies the three functional paralogs and most of the non-functional ones. As anticipated, we found that hESCs express large amounts of NANOG1 and, interestingly, they also express NANOG2. In contrast, most human cancer cells tested express NANOGP8 and the non coding paralogs NANOGP4 and NANOGP5. Notably, in some cancer cell lines, the NANOG protein levels produced by NANOGP8 are comparable to those produced by NANOG1 in pluripotent cells. Finally, we show that NANOGP8 is as active as NANOG1 in the reprogramming of human and murine fibroblasts into induced pluripotent stem cells. These results show that cancer-associated NANOGP8 can contribute to promote de-differentiation and/or cellular plasticity. PMID- 23752185 TI - miR-27a regulates endothelial differentiation of breast cancer stem like cells. AB - Recent studies suggested that cancer stem cells (CSCs) are capable of differentiating into endothelial cells and tumor endothelium may be derived from CSCs. But the mechanism remains unclear. We showed that vascular endothelial growth factor (VEGF) induced the expression of endothelial markers in breast cancer stem like cells (BCSLCs). In addition, the VEGF-treated BCSLCs formed capillary structure in matrigel and released vWF upon histamine treatment. The miR-27a expression was significantly increased in VEGF-treated BCSLCs. Antagonizing miR-27a by miR-27a anti-sense oligos (ASOs) in VEGF-treated BCSLCs led to decreased endothelial markers and function, while increasing miR-27a in BCSLCs resulted in enhanced endothelial properties. VEGF enhanced the transcription of miR-27a by increasing RUNX1 binding to miR-27a promoter. Increased miR-27a paralleled the reduced expression of ZBTB10, a known miR-27a target. Both expression of miR-27a and knockdown of ZBTB10 in BCSLCs promoted in vivo angiogenesis and tumor metastasis. Further, we demonstrated that VEGF treated BCSLCs secreted more endogenous VEGF compared with undifferentiated BCSLCs. Thus, miR-27a promotes angiogenesis by mediating endothelial differentiation of BCSLCs and it may be a new target for anti-angiogenesis cancer therapy. PMID- 23752186 TI - EVI1 oncogene promotes KRAS pathway through suppression of microRNA-96 in pancreatic carcinogenesis. AB - Despite frequent KRAS mutation, the early molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) development have not been fully elucidated. By tracking a potential regulator of another feature of PDAC precursors, acquisition of foregut or gastric epithelial gene signature, we herein report that aberrant overexpression of ecotropic viral integration site 1 (EVI1) oncoprotein, which is usually absent in normal pancreatic duct, is a widespread marker across the full spectrum of human PDAC precursors and PDAC. In pancreatic cancer cells, EVI1 depletion caused remarkable inhibition of cell growth and migration, indicating its oncogenic roles. Importantly, we found that EVI1 upregulated KRAS expression through suppression of a potent KRAS suppressor, miR-96, in pancreatic cancer cells. Collectively, the present findings suggest that EVI1 overexpression and KRAS mutation converge on activation of the KRAS pathway in early phases of pancreatic carcinogenesis and propose EVI1 and/or miR-96 as early markers and therapeutic targets in this dismal disease. PMID- 23752187 TI - The SWI/SNF genetic blockade: effects in cell differentiation, cancer and developmental diseases. AB - Our rapidly growing knowledge about cancer genetics attests to the widespread occurrence of alterations at genes encoding different components of the SWI/SNF complex. This reveals an important new feature that sustains cancer development: the blockade of chromatin remodeling. Here, we provide an overview of our current knowledge on the gene alterations of chromatin-remodeling factors, and how they relate to cancer and human developmental diseases. We also consider the functional repercussions, particularly how the inactivation of the SWI/SNF complex impairs the appropriate cell response to nuclear receptor signaling, which, in turn, prevents cell differentiation and sustains cell growth independently of the environment. PMID- 23752188 TI - PDGFRA alterations in cancer: characterization of a gain-of-function V536E transmembrane mutant as well as loss-of-function and passenger mutations. AB - Activating mutations in the platelet-derived growth factor (PDGF) receptor alpha (PDGFRA) have been described in patients with gastrointestinal stromal tumors or myeloid malignancies associated with hypereosinophilia. These patients respond well to imatinib mesylate, raising the question as to whether patients with a PDGF receptor mutation in other tumor types should receive a tyrosine kinase inhibitor treatment. We characterized 10 novel somatic point mutations in PDGFRA that have been reported in isolated cases of glioblastoma, melanoma, acute myeloid leukemia, peripheral nerve sheath tumors and neuroendocrine carcinoma. The PDGFRA transmembrane domain mutation V536E stimulated Ba/F3 cell growth and signaling via ERK and STAT5 in the absence of ligand. This mutant, identified in glioblastoma, was strongly inhibited by imatinib. Modeling suggested that the mutation modulates the packing of the transmembrane domain helices in the receptor dimer. By contrast, two mutations in highly conserved residues affected the receptor traffic to the cell surface or kinase activity, thereby preventing the response to PDGF. The other mutations had no significant impact on the receptor activity. This functional analysis matched the predictions of SIFT and PolyPhen for only five mutations and these algorithms do not discriminate gain from loss of function. Finally, an E996K variant that had been identified in a melanoma cell line was not expressed in these cells. Altogether, several newly identified PDGFRA mutations do not activate the receptor and may therefore represent passenger mutations. Our results also underline the importance of characterizing novel kinase alterations in cancer patients. PMID- 23752190 TI - Desmoglein 3 promotes cancer cell migration and invasion by regulating activator protein 1 and protein kinase C-dependent-Ezrin activation. AB - Desmoglein 3 (Dsg3), the pemphigus vulgaris antigen, has recently been shown to be upregulated in squamous cell carcinoma (SCC) and has been identified as a good tumor-specific marker for clinical staging of cervical sentinel lymph nodes in head and neck SCC. However, little is known about its biological function in cancer. The actin-binding protein Ezrin and the activator protein 1 (AP-1) transcription factor are implicated in cancer progression and metastasis. Here, we report that Dsg3 regulates the activity of c-Jun/AP-1 as well as protein kinase C (PKC)-mediated phosphorylation of Ezrin-Thr567, which contributes to the accelerated motility of cancer cells. Ectopic expression of Dsg3 in cancer cell lines caused enhanced phosphorylation at Ezrin-Thr567 with concomitant augmented membrane protrusions, cell spreading and invasive phenotype. We showed that Dsg3 formed a complex with Ezrin at the plasma membrane that was required for its proper function of interacting with F-actin and CD44 as Dsg3 knockdown impaired these associations. The increased Ezrin phosphorylation in Dsg3-overexpressing cells could be abrogated substantially by various pharmacological inhibitors for Ser/Thr kinases, including PKC and Rho kinase that are known to activate Ezrin. Furthermore, a marked increase in c-Jun S63 phosphorylation, among others, was found in Dsg3-overexpressing cells and the activation of c-Jun/AP-1 was further supported by a luciferase reporter assay. Taken together, our study identifies a novel Dsg3-mediated c-Jun/AP-1 regulatory mechanism and PKC-dependent Ezrin phosphorylation that could be responsible for Dsg3-associated cancer metastasis. PMID- 23752189 TI - Phospholipase D (PLD) drives cell invasion, tumor growth and metastasis in a human breast cancer xenograph model. AB - Breast cancer is one of the most common malignancies in human females in the world. One protein that has elevated enzymatic lipase activity in breast cancers in vitro is phospholipase D (PLD), which is also involved in cell migration. We demonstrate that the PLD2 isoform, which was analyzed directly in the tumors, is crucial for cell invasion that contributes critically to the growth and development of breast tumors and lung metastases in vivo. We used three complementary strategies in a SCID mouse model and also addressed the underlying molecular mechanism. First, the PLD2 gene was silenced in highly metastatic, aggressive breast cancer cells (MDA-MB-231) with lentivirus-based short hairpin RNA, which were xenotransplanted in SCID mice. The resulting mouse primary mammary tumors were reduced in size (65%, P<0.05) and their onset delayed when compared with control tumors. Second, we stably overexpressed PLD2 in low invasive breast cancer cells (MCF-7) with a biscistronic MIEG retroviral vector and observed that these cells were converted into a highly aggressive phenotype, as primary tumors that formed following xenotransplantation were larger, grew faster and developed lung metastases more readily. Third, we implanted osmotic pumps into SCID xenotransplanted mice that delivered two different small-molecule inhibitors of PLD activity (5-fluoro-2-indolyl des-chlorohalopemide and N-[2-(4 oxo-1-phenyl-1,3,8-triazaspiro[4,5]dec-8-yl)ethyl]-2-naphthalenecarboxamide). These inhibitors led to significant (>70%, P<0.05) inhibition of primary tumor growth, metastatic axillary tumors and lung metastases. In order to define the underlying mechanism, we determined that the machinery of PLD-induced cell invasion is mediated by phosphatidic acid, Wiscott-Aldrich Syndrome protein, growth receptor-bound protein 2 and Rac2 signaling events that ultimately affect actin polymerization and cell invasion. In summary, this study shows for the first time that PLD2 has a central role in the development, metastasis and level of aggressiveness of breast cancer, raising the possibility that PLD2 could be used as a new therapeutic target. PMID- 23752191 TI - Downregulation of miR-140 promotes cancer stem cell formation in basal-like early stage breast cancer. AB - The major goal of breast cancer prevention is to reduce the incidence of ductal carcinoma in situ (DCIS), an early stage of breast cancer. However, the biology behind DCIS formation is not well understood. It is suspected that cancer stem cells (CSCs) are already programmed in pre-malignant DCIS lesions and that these tumor-initiating cells may determine the phenotype of DCIS. MicroRNA (miRNA) profiling of paired DCIS tumors revealed that loss of miR-140 is a hallmark of DCIS lesions. Previously, we have found that miR-140 regulates CSCs in luminal subtype invasive ductal carcinoma. Here, we find that miR-140 has a critical role in regulating stem cell signaling in normal breast epithelium and in DCIS. miRNA profiling of normal mammary stem cells and cancer stem-like cells from DCIS tumors revealed that miR-140 is significantly downregulated in cancer stem-like cells compared with normal stem cells, linking miR-140 and dysregulated stem cell circuitry. Furthermore, we found that SOX9 and ALDH1, the most significantly activated stem-cell factors in DCIS stem-like cells, are direct targets of miR 140. Currently, targeted therapies (tamoxifen) are only able to reduce DCIS risk in patients with estrogen receptor alpha (ERalpha)-positive disease. We examined a model of ERalpha-negative/basal-like DCIS and found that restoration of miR-140 via a genetic approach or with the dietary compound sulforaphane decreased SOX9 and ALDH1, and reduced tumor growth in vivo. These results support that a miR 140/ALDH1/SOX9 axis is critical to basal CSC self-renewal and tumor formation in vivo, suggesting that the miR-140 pathway may be a promising target for preventative strategies in patients with basal-like DCIS. PMID- 23752192 TI - Involvement of small ArfGAP1 (SMAP1), a novel Arf6-specific GTPase-activating protein, in microsatellite instability oncogenesis. AB - Small ArfGAP1 (stromal membrane-associated protein 1, SMAP1), a GTPase-activating protein specific for ADP-ribosylation factor 6 (Arf6), which is a small GTPase acting on membrane trafficking and actin remodeling, is frequently mutated in various tumors displaying microsatellite instability (MSI), notably in MSI colorectal cancers (CRC). Genotyping of 93 MSI CRCs (40 stage II, 32 stage III and 21 stage IV) allowed us to underscore that SMAP1 mutation frequency was inversely correlated with disease stage (P=0.01). Analysis of 46 cancer cell lines showed that SMAP1 mutations occurred only in MSI tumors, and consisted exclusively in short insertion or deletion in the coding 10-adenine repeat, generating a premature termination codon located downstream the ArfGAP domain. SMAP1 transcript levels were significant decreased (P=0.006), and truncated SMAP1 protein could not be detected in cells displaying biallelic SMAP1 mutations, owing to its sensitivity to proteasome degradation. To investigate the role of SMAP1 mutations, we used the SMAP1-null HCT116 cell line and we established three isogenic SMAP1-complemented clones. Cell proliferation was first assessed in vivo using subcutaneous xenografts into immunodeficient mice. Tumors developed in all animals regardless of the cell line injected, but tumor volumes were significantly smaller for both SMAP1-complemented clones compared with HCT116 (P<0.0001, at the time of killing). In vitro, SMAP1 mutations also increased cell clonogenicity (P=0.02-0.04), cell proliferation (P=0.008) by shortening the G2/M phase and decreased cell invasiveness (P=0.03-0.003). In keeping, SMAP1 complemented HCT116 gained several mesenchymal markers (Snail, Slug and vimentin) considered as a hallmark of epithelial-to-mesenchymal transition. These observations are reminiscent of some clinical characteristics of MSI CRCs, notably their larger size and lower rate of metastasis. Our observations suggest that SMAP1 loss-of-function mutations in MSI CRC may contribute to the emerging oncogenic pathway involving abnormal Arf6 regulation. PMID- 23752193 TI - A novel Ku70 function in colorectal homeostasis separate from nonhomologous end joining. AB - Ku70, a known nonhomologous end-joining (NHEJ) factor, also functions in tumor suppression, although this molecular mechanism remains uncharacterized. Previously, we showed that mice deficient for DNA ligase IV (Lig4), another key NHEJ factor, succumbed to aggressive lymphoma in the absence of tumor suppressor p53. However, the tumor phenotype is abrogated by the introduction of a hypomorphic mutant p53(R172P), which impaired p53-mediated apoptosis but not cell cycle arrest. However, Lig4(-/-)p53(R172P) mice succumbed to severe diabetes. To further elucidate the role of NHEJ and p53-mediated apoptosis in vivo, we bred Ku70(-/-) p53(R172P) mice. Unexpectedly, these mice were free of diabetes, although 80% of the mutant mice had abnormally enlarged colons with pronounced inflammation. Remarkably, most of these mutant mice progressed to dysplasia, adenoma and adenocarcinoma; this is in contrast to the Lig4(-/-)p53(R172P) phenotype, strongly suggesting an NHEJ-independent function of Ku70. Significantly, our analyses of Ku70(-/-)p53(R172P) colonic epithelial cells show nuclear stabilization of beta-catenin accompanied by higher expression of cyclin D1 and c-Myc in affected colon sections than in control samples. This is not due to the p53 mutation, as Ku70(-/-) mice share this phenotype. Our results not only unravel a novel function of Ku70 essential for colon homeostasis, but also establish an excellent in vivo model in which to study how chronic inflammation and abnormal cellular proliferation underlie tumorigenesis and tumor progression in the colon. PMID- 23752194 TI - ARF inhibits the growth and malignant progression of non-small-cell lung carcinoma. AB - Non-small-cell lung carcinoma (NSCLC) is among the deadliest of human cancers. The CDKN2A locus, which houses the INK4a and ARF tumor suppressor genes, is frequently altered in NSCLC. However, the specific role of ARF in pulmonary tumorigenesis remains unclear. KRAS and other oncogenes induce the expression of ARF, thus stabilizing p53 activity and arresting cell proliferation. To address the role of ARF in Kras-driven NSCLC, we compared the susceptibility of NIH/Ola strain wild-type and Arf-knockout mice to urethane-induced lung carcinogenesis. Lung tumor size, malignancy and associated morbidity were significantly increased in Arf(-/-) compared with Arf(+/+) animals at 25 weeks after induction. Pulmonary tumors from Arf-knockout mice exhibited increased cell proliferation and DNA damage compared with wild-type mice. A subgroup of tumors in Arf(-/-) animals presented as dedifferentiated and metastatic, with many characteristics of pulmonary sarcomatoid carcinoma, a neoplasm previously undocumented in mouse models. Our finding of a role for ARF in NSCLC is consistent with the observation that benign adenomas from Arf(+/+) mice robustly expressed ARF, while ARF expression was markedly reduced in malignant adenocarcinomas. ARF expression also frequently colocalized with the expression of p21(CIP1), a transcriptional target of p53, arguing that ARF induces the p53 checkpoint to arrest cell proliferation in vivo. Taken together, these findings demonstrate that induction of ARF is an early response in lung tumorigenesis that mounts a strong barrier against tumor growth and malignant progression. PMID- 23752195 TI - Evasion of p53 and G2/M checkpoints are characteristic of Hh-driven basal cell carcinoma. AB - Basal cell carcinoma (BCC), the most common type of cancer, is characterized by aberrant Hedgehog (Hh) pathway activity. Mutations in pathway components, such as PATCHED1 (PTCH1), are commonly found in BCC. While the tumor suppressor role of PTCH1 in BCC is well established, how Hh pathway activation disrupts normal skin homeostasis to promote BCC formationremains poorly understood. Like Ptc1, Sufu is a major negative regulator of the Hh pathway. Previously, we showed that inactivation of Sufu in the skin does not result in BCC formation. Why loss of Ptc1, but not Sufu, in the epidermis induces BCC formation is unclear. In this report, we utilized gene expression profiling to identify biological pathways and processes that distinguish Sufu from Ptc1 mutants, and discovered a novel role for Sufu in cell cycle regulation. We demonstrated that the Hh pathway activation inSufu and Ptc1 mutant skin is associated with abnormal cell cycle entry, ectopic expression of D-type cyclins and increasedDNA damage. However, despite the presence of DNA damage, p53 stabilization was impaired in the mutant skin. Alternative mechanism to halt genomic instability is the activation of G2/M cell cycle checkpoint, which can occur independent of p53. We found that while Ptc1 mutant cells continue to cycle, which would favor genomic instability, loss of Sufu results in G2/M cell cycle arrest.This finding may explain why inactivation of Sufu is not sufficient to drive BCC formation. Taken together, these studies revealed a unique role for Sufu in G2/M phase progression, and uncovered the molecular and cellular features associated with Hh-driven BCC. PMID- 23752197 TI - S100A4 interacts with p53 in the nucleus and promotes p53 degradation. AB - S100A4 is a small calcium-binding protein that is commonly overexpressed in a range of different tumor types, and it is widely accepted that S100A4 has an important role in the process of cancer metastasis. In vitro binding assays has shown that S100A4 interacts with the tumor suppressor protein p53, indicating that S100A4 may have additional roles in tumor development. In the present study, we show that endogenous S100A4 and p53 interact in complex samples, and that the interaction increases after inhibition of MDM2-dependent p53 degradation using Nutlin-3A. Further, using proximity ligation assay, we show that the interaction takes place in the cell nucleus. S100A4 knockdown experiments in two p53 wild type cell lines, A549 and HeLa, resulted in stabilization of p53 protein, indicating that S100A4 is promoting p53 degradation. Finally, we demonstrate that S100A4 knockdown leads to p53-dependent cell cycle arrest and increased cisplatin induced apoptosis. Thus, our data add a new layer to the oncogenic properties of S100A4 through its inhibition of p53-dependent processes. PMID- 23752198 TI - Optofluidic-tunable color filters and spectroscopy based on liquid-crystal microflows. AB - The integration of color filters with microfluidics has attracted substantial attention in recent years, for on-chip absorption, fluorescence, or Raman analysis. We describe such tunable filters based on the micro-flow of liquid crystals. The filter operation is based on the wavelength-dependent liquid crystal birefringence that can be tuned by modifying the flow velocity field in the microchannel. The latter is possible both temporally and spatially by varying the inlet pressure and the channel geometry, respectively. We explored the use of these optofluidic filters for on-chip absorption spectroscopy in poly(dimethylsiloxane) microfluidic systems; by integrating the distance dependent color filter with a dye-filled micro-channel, the absorption spectrum of a dye could be measured. Liquid crystal microflows substantially simplify the optofluidic integration, actuation and tuning of color filters for lab-on-a-chip spectroscopic applications. PMID- 23752200 TI - Funding treatment for gambling addiction in Great Britain: ethical issues. PMID- 23752196 TI - Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis. AB - The metabolic functions of androgen receptor (AR) in normal prostate are circumvented in prostate cancer (PCa) to drive tumor growth, and the AR also can acquire new growth-promoting functions during PCa development and progression through genetic and epigenetic mechanisms. Androgen deprivation therapy (ADT, surgical or medical castration) is the standard treatment for metastatic PCa, but patients invariably relapse despite castrate androgen levels (castration resistant PCa, CRPC). Early studies from many groups had shown that AR was highly expressed and transcriptionally active in CRPC, and indicated that steroids from the adrenal glands were contributing to this AR activity. More recent studies showed that CRPC cells had increased expression of enzymes mediating androgen synthesis from adrenal steroids, and could synthesize androgens de novo from cholesterol. Phase III clinical trials showing a survival advantage in CRPC for treatment with abiraterone (inhibitor of the enzyme CYP17A1 required for androgen synthesis that markedly reduces androgens and precursor steroids) and for enzalutamide (new AR antagonist) have now confirmed that AR activity driven by residual androgens makes a major contribution to CRPC, and led to the recent Food and Drug Administration approval of both agents. Unfortunately, patients treated with these agents for advanced CRPC generally relapse within a year and AR appears to be active in the relapsed tumors, but the molecular mechanisms mediating intrinsic or acquired resistance to these AR-targeted therapies remain to be defined. This review outlines AR functions that contribute to PCa development and progression, the roles of intratumoral androgen synthesis and AR structural alterations in driving AR activity in CRPC, mechanisms of action for abiraterone and enzalutamide, and possible mechanisms of resistance to these agents. PMID- 23752201 TI - The society of thoracic surgeons guidelines on the diagnosis and staging of patients with esophageal cancer. PMID- 23752202 TI - CD44 variant isoforms control experimental autoimmune encephalomyelitis by affecting the lifespan of the pathogenic T cells. AB - CD44 variant (CD44(v)) isoforms play important roles in the development of autoimmune disorders, including colitis and arthritis, but their role in multiple sclerosis (MS) has been explored only to a limited extent. We determined the functional relevance of CD44(v) isoforms in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Genetic ablation of CD44(v7) and CD44(v10) isoforms significantly reduced the clinical EAE burden, as well as the number of inflammatory infiltrates. CD44(v7) and CD44(v10) expression on both memory T and antigen-presenting cells, participated in the development of adoptive transfer EAE. Significantly reduced mRNA expression of Th1 signature genes was detected in the brains of CD44(v10-/-) mice compared with those of CD44(WT) mice. Furthermore, forkhead transcription factor 3 (Foxp3), Bcl-2, and inducible nitric oxide synthase (iNOS) levels were reduced in CD44(v10-/-) brains, whereas active caspase-3 was elevated. Brain-infiltrating CD4(hi)CD44(v10+) T cells preceded EAE onset and paralleled disease severity in wild-type but not in CD44(v7-/-) and CD44(v10-/-) mice. CD44(v7) and CD44(v10) expression contributed to EAE by increasing the longevity of autoreactive CD4(hi)panCD44(hi) T cells. Accordingly, the absence of CD44(v7) and CD44(v10) led to increased apoptosis in the inflammatory infiltrates and reduced Th1 responses, resulting in marked disease reduction. Although absent in noninflamed human brains, we detected CD44(v3), CD44(v7), and CD44(v10) isoforms on glial cells and on perivascular infiltrating cells of MS lesions. We conclude that CD44(v7) and CD44(v10), expressed on autoreactive CD4(hi)panCD44(hi) T cells, are critically involved in the pathogenesis of classic EAE by increasing their life span. Targeting these short CD44(v) isoform regions may reduce inflammatory processes and clinical symptoms in MS. PMID- 23752203 TI - Hyodeoxycholic acid improves HDL function and inhibits atherosclerotic lesion formation in LDLR-knockout mice. AB - We examined the effects of a natural secondary bile acid, hyodeoxycholic acid (HDCA), on lipid metabolism and atherosclerosis in LDL receptor-null (LDLRKO) mice. Female LDLRKO mice were maintained on a Western diet for 8 wk and then divided into 2 groups that received chow, or chow + 1.25% HDCA, diets for 15 wk. We observed that mice fed the HDCA diet were leaner and exhibited a 37% (P<0.05) decrease in fasting plasma glucose level. HDCA supplementation significantly decreased atherosclerotic lesion size at the aortic root region, the entire aorta, and the innominate artery by 44% (P<0.0001), 48% (P<0.01), and 94% (P<0.01), respectively, as compared with the chow group. Plasma VLDL/IDL/LDL cholesterol levels were significantly decreased, by 61% (P<0.05), in the HDCA group as compared with the chow diet group. HDCA supplementation decreased intestinal cholesterol absorption by 76% (P<0.0001) as compared with the chow group. Furthermore, HDL isolated from the HDCA group exhibited significantly increased ability to mediate cholesterol efflux ex vivo as compared with HDL of the chow diet group. In addition, HDCA significantly increased the expression of genes involved in cholesterol efflux, such as Abca1, Abcg1, and Apoe, in a macrophage cell line. Thus, HDCA is a candidate for antiatherosclerotic drug therapy. PMID- 23752204 TI - Sarcolipin trumps beta-adrenergic receptor signaling as the favored mechanism for muscle-based diet-induced thermogenesis. AB - Sarcolipin (SLN) regulates muscle-based nonshivering thermogenesis and is up regulated with high-fat feeding (HFF). To investigate whether other muscle-based thermogenic systems compensate for a lack of Sln and to firmly establish SLN as a mediator of diet-induced thermogenesis (DIT), we measured muscle and whole-body energy expenditure in chow- and high-fat-fed Sln(-/-) and wild-type (WT) mice. Following HFF, resting muscle metabolic rate (VO2, MUl/g/s) was increased similarly in WT (0.28+/-0.02 vs. 0.31+/-0.03) and Sln(-/-) (0.23+/-0.03 vs. 0.35+/-0.02) mice due to increased sympathetic nervous system activation in Sln( /-) mice; however, whole-body metabolic rate (VO2, ml/kg/h) was lower in Sln(-/-) compared with WT mice following HFF but only during periods when the mice were active in their cages (WT, 2894+/-87 vs. Sln(-/-), 2708+/-61). Treatment with the beta-adrenergic receptor (beta-AR) antagonist propranolol during HFF completely prevented muscle-based DIT in Sln(-/-) mice; however, it had no effect in WT mice, resulting in greater differences in whole-body metabolic rate and diet induced weight gain. Our results suggest that beta-AR signaling partially compensates for a lack of SLN to activate muscle-based DIT, but SLN is the primary and more effective mediator. PMID- 23752205 TI - Synthetic HLA-G proteins for therapeutic use in transplantation. AB - The human leukocyte antigen (HLA)-G is a tolerogenic molecule, whose expression by allografts is associated with better acceptance. An increasing interest in producing HLA-G as a clinical-grade molecule for therapy use is impaired by its complexity and limited stability. Our purpose was to engineer simpler and more stable HLA-G-derived molecules than the full-length HLA-G trimolecular complex that are also tolerogenic, functional as soluble molecules, and compatible with good manufacturing practice (GMP) production conditions. We present two synthetic molecules: (alpha3-L)x2 and (alpha1-alpha3)x2 polypeptides. We show their capability to bind the HLA-G receptor LILRB2 and their functions in vitro and in vivo. The (alpha1-alpha3)x2 polypeptide proved to be a potent tolerogenic molecule in vivo: One treatment of skin allograft recipient mice with (alpha1 alpha3)x2 was sufficient to significantly prolong graft survival, and four weekly treatments induced complete tolerance. Furthermore, (alpha1-alpha3)x2 was active as a soluble molecule and capable of inhibiting the proliferation of tumor cell lines, as does the full length HLA-G trimolecular complex. Thus, the synthetic (alpha1-alpha3)x2 polypeptide is a stable and simpler alternative to the full length HLA-G molecule. It can be produced under GMP conditions, it functions as a soluble molecule, and it is at least as tolerogenic as HLA-G in vivo. PMID- 23752206 TI - An adaptable system for improving transposon-based gene expression in vivo via transient transgene repression. AB - Transposons permit permanent cellular genome engineering in vivo. However, transgene expression falls rapidly postdelivery due to a variety of mechanisms, including immune responses. We hypothesized that delaying initial transgene expression would improve long-term transgene expression by using an engineered piggyBac transposon system that can regulate expression. We found that a 2-part nonviral Tet-KRAB inducible expression system repressed expression of a luciferase reporter in vitro. However, we also observed nonspecific promoter independent repression. Thus, to achieve temporary transgene repression after gene delivery in vivo, we utilized a nonintegrating version of the repressor plasmid while the gene of interest was delivered in an integrating piggyBac transposon vector. When we delivered the luciferase transposon and repressor to immunocompetent mice by hydrodynamic injection, initial luciferase expression was repressed by 2 orders of magnitude. When luciferase expression was followed long term in vivo, we found that expression was increased >200-fold compared to mice that received only the luciferase transposon and piggyBac transposase. We found that repression of early transgene expression could prevent the priming of luciferase-specific T cells in vivo. Therefore, transient transgene repression postgene delivery is an effective strategy for inhibiting the antitransgene immune response and improving long-term expression in vivo without using immunosuppression. PMID- 23752207 TI - Up-regulation of microRNA-142 in simian immunodeficiency virus encephalitis leads to repression of sirtuin1. AB - MicroRNA (miR)-142 is up-regulated in the brain in HIV and SIV encephalitis (SIVE). We identified the cell types where miR-142 is up-regulated and its relevant downstream target. Fluorescent in situ hybridization combined with immunofluorescent labeling revealed that miR-142-3p and -5p are expressed within hippocampal neurons and myeloid cells in SIVE. Sirtuin1 (SIRT1) was predicted as a potential miR-142 target by analysis of its 3'-UTR and bioinformatic analysis of factors linked to altered hippocampal gene expression profile in SIVE. Overexpression of pre-miR-142 in HEK293T cells led to a 3.7-fold decrease in SIRT1 protein level. Examination of the individual effects of miR-142-5p and miR 142-3p through overexpression and inhibition studies revealed that significant effects on SIRT1 occurred only with miR-142-5p. Luciferase reporter assays revealed a 2.3-fold inhibition of expression due to interaction of miR-142 with the SIRT1 3'-UTR, mutation analysis revealed that only the miR-142-5p target site was active. MiR-142 expression in primary human neurons led to a small (1.3-fold) but significant decrease in SIRT1 protein level. Furthermore, qRT-PCR revealed up regulation of miR-142-3p (6.4-fold) and -5p (3.9-fold) and down-regulation of SIRT1 (33-fold) in macrophages/microglia from animals with SIVE. We have therefore elucidated a miR-mediated mechanism of regulation of SIRT1 expression in SIVE. PMID- 23752209 TI - Randomized comparison of the Pentax AirWay Scope and Macintosh laryngoscope for tracheal intubation in patients with obstructive sleep apnoea. AB - BACKGROUND: Patients with obstructive sleep apnoea (OSA) can often present difficulties in intubation. This study aimed to compare the efficacy of the Pentax AirWay Scope (AWS) with that of the Macintosh laryngoscope for tracheal intubation in patients with OSA. METHODS: Forty-six patients undergoing uvulopalatopharyngoplasty were randomly allocated to tracheal intubation with either the Macintosh laryngoscope or the Pentax AWS. In all patients, intubation was performed by one of two anaesthetists experienced with both devices. The primary and secondary endpoints of this study were the intubation difficulty scale (IDS) score and success/failure and duration of the first successful intubation attempt. RESULTS: With the Pentax AWS, tracheal intubation was successful on the first attempt in all patients whereas four patients required repeated attempts at intubation with the Macintosh laryngoscope. The IDS score was significantly lower using the Pentax AWS and glottic exposure was better (the Cormack and Lehane grade 1 in all patients vs grade 2 or higher in all patients, P<0.0001). Average duration of successful intubation was shorter (12.9 vs 29.9 s, P=0.0002), and fewer manoeuvres were needed to improve the glottic exposure (0 in all patients vs 1 or more in 16 patients, P<0.0001) with the Pentax AWS, compared with the Macintosh laryngoscope. CONCLUSIONS: In this study of patients with OSA, tracheal intubation by experienced anaesthetists was facilitated using the Pentax AWS compared with the Macintosh laryngoscope. PMID- 23752210 TI - Acute onset of leg nodules in a sporotrichoid pattern-diagnosis. PMID- 23752208 TI - Lupus nephritis: enigmas, conflicting models and an emerging concept. AB - Autoantibodies to components of chromatin, which include double-stranded DNA (dsDNA), histones and nucleosomes, are central in the pathogenesis of lupus nephritis. How anti-chromatin autoantibodies exert their nephritogenic activity, however, is controversial. One model assumes that autoantibodies initiate inflammation when they cross-react with intrinsic glomerular structures such as components of membranes, matrices or exposed nonchromatin ligands released from cells. Another model suggests glomerular deposition of autoantibodies in complex with chromatin, thereby inducing classic immune complex-mediated tissue damage. Recent data suggest acquired error of renal chromatin degradation due to the loss of renal DNaseI enzyme activity is an important contributing factor to the development of lupus nephritis in lupus-prone (NZBxNZW)F1 mice and in patients with lupus nephritis. Down-regulation of DNaseI expression results in reduced chromatin fragmentation and in deposition of extracellular chromatin-IgG complexes in glomerular basement membranes in individuals who produce IgG anti chromatin autoantibodies. The main focus of the present review is to discuss whether exposed chromatin fragments in glomeruli are targeted by potentially nephritogenic anti-dsDNA autoantibodies or if the nephritogenic activity of these autoantibodies is explained by cross-reaction with intrinsic glomerular constituents or if both models coexist in diseased kidneys. In addition, the role of silencing of the renal DNaseI gene and the biological consequences of reduced chromatin fragmentation in nephritic kidneys are discussed. PMID- 23752211 TI - The management of a patient with chronic oedema: a case study. AB - Chronic oedema is a complex long-term condition that can have profound effects on the patient. Therefore, it is vital that the district nurse has the knowledge and skills to manage an individual to ensure a therapeutic concordant relationship. This feature seeks to consider best-practice management of a patient with chronic oedema. PMID- 23752212 TI - Treatment for lymphorrhoea in limbs and in advanced disease. AB - Supported by the NHS Lymphoedema Service Administrator, this article reports on a project undertaken by a clinical nurse specialist in Lymphoedema (CNS) and in part fulfilment of an MSc in Skin integrity skills and treatment, achieved from the University of Hertfordshire, September 2011. The need for the project was generated by the 5-day delay experienced by terminally ill patients in a hospice while waiting to receive treatment for lymphorrhoea from the community-based CNS. The training and assessment of healthcare assistants in a cost-effective treatment enabled the instigation of care within 3 hours of the development of lymphorrhoea in a patient and an evaluation of its competent delivery. PMID- 23752213 TI - Lipoedema: the first UK patient survey. AB - Lipoedema UK was founded in 2012 by women with lipoedema and clinicians working in the Lymphoedema Service at St George's Hospital in London. Its patron is Professor Peter Mortimer, the UK's leading Lipoedema expert, and its nurse consultant is Sandy Ellis, who diagnoses and treats many women with Lipoedema in the UK and is also the nurse consultant in the St George's team. The charity's objectives are to educate doctors, health professionals and the public about lipoedema and its symptoms, so it may be diagnosed and treated earlier. PMID- 23752214 TI - Getting the right fit: made-to-measure garments for lymphoedema management. AB - The purpose of this article is to discuss the use of custom made compression garments in the management of lymphoedema and chronic oedema. Patients often present to therapists with inappropriate, ill-fitting garments that can contribute to an increase in oedema and poor limb shape. Patients frequently report garments as being uncomfortable and therefore intolerable leading to a lack of concordance with wearing garments. The selection and fitting of the correct garment can affect outcomes and the patients' quality of life. The focus of this article is to increase the health professionals' knowledge and skills in the selection, measurement and fitting of custom made garments to ensure correct fit and increased concordance when compression garments are prescribed. PMID- 23752215 TI - Lymphoedema support network. AB - News. PMID- 23752216 TI - Commissioning and nursing. AB - As you read these words, the most radical overhaul in the history of the NHS will have started. Primary care trusts will have ceased to exist and newly formed clinical commissioning groups (CCGs) will have taken control of almost L70 billion of health budget. PMID- 23752217 TI - Lymphoedema management in breast cancer-related lymphoedema. AB - Due to developments in diagnosis and treatment of breast cancer, survival rates are rising. This leads to a population of mainly women, who also experience breast cancer-related lymphoedema (BCRL). Long after the cancer has been treated, lymphoedema persists at a time when individuals have returned to work. Large limb volumes can present a problem to these individuals and innovative treatments are needed, in order to retain as much normality as possible and reduce excessive limb volumes that patients can experience with lymphoedema long after treatment. It is also important that these treatments do not disrupt daily living and, for some, work-life balance. With the introduction of wrap around compression systems and collaborative working with the patient, it is possible to achieve an acceptable outcome to those patients with these issues. This approach leads to patient satisfaction and stabilisation of limb volume to within acceptable limits for these patients, in conjunction with the therapist. PMID- 23752218 TI - Digging deep: teaching hospitals and pay-for-performance. PMID- 23752219 TI - Adverse clinical events among medicare beneficiaries using antipsychotic drugs: linking health insurance benefits and clinical needs. AB - OBJECTIVE: Medicare Part D provides formulary protections for antipsychotics but does not exempt these drugs from cost-sharing. We investigated the impact of Part D coverage on antipsychotic drug spending, adherence, and clinical outcomes among beneficiaries with varying indications for use. METHODS: We conducted a historical cohort study of Medicare Advantage beneficiaries who received antipsychotic drugs, with diagnoses of schizophrenia or bipolar disorder or with no mental health diagnoses (N=10,190). Half had a coverage gap; half had no gap because of low-income subsidies. Using fixed effects regression models, we examined changes in spending and adherence as beneficiaries experienced cost sharing increases after reaching the gap. We examined changes in hospitalizations and emergency department visits using proportional hazard models. RESULTS: Across all diagnostic groups, total monthly expenditure on antipsychotic drugs decreased with cost-sharing increases in the gap compared with those with no gap (eg, schizophrenia: -$123 95% confidence interval [-$138, -$108]), and out-of-pocket spending increased (eg, schizophrenia: $104 [$98, $110]). Adherence similarly decreased, with the largest declines among those with schizophrenia (-20.6 percentage points [-22.3, -18.9] in proportion of days covered). Among beneficiaries with schizophrenia and bipolar disorder, hospitalizations and emergency department visit rates increased with cost-sharing increases (eg, schizophrenia: hazard ratio=1.32 [1.06, 1.65] for all hospitalizations), but did not among subjects without mental health diagnoses. Clinical event rates did not change among beneficiaries with low-income subsidies without gaps. CONCLUSIONS: There is evidence of interruptions in antipsychotic use attributable to Part D cost-sharing. Adverse events increased among beneficiaries with approved indications for use, but not among beneficiaries without such indications. PMID- 23752220 TI - Skew of plasma low- and high-density lipoprotein distributions to less dense subfractions in normotriglyceridemic chronic kidney disease patients on maintenance hemodialysis treatment. AB - BACKGROUND: Plasma levels of small, dense low-density lipoprotein (LDL) were reported to increase in chronic kidney disease (CKD) patients on hemodialysis (HD), but most of these patients were hypertriglyceridemic. Plasma levels of small, dense LDL are known to increase in hypertriglyceridemic subjects. Therefore, to investigate the direct effect of CKD on the distribution of LDL subfractions, we investigated the distribution of LDL subfractions in normotriglyceridemic CKD patients on HD. METHODS: The levels of plasma lipoprotein subfractions and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP), which markedly influence the distributions of plasma LDL and high-density lipoprotein (HDL) subfractions, were compared between 40 HD patients and 40 normolipidemic controls. Plasma lipoproteins were subfractionated into seven subfractions by ultracentrifugation. RESULTS: Plasma levels of cholesterol (C) in remnant-like particle, which is equivalent to the triglyceride (TG)-rich lipoprotein remnant, were twice as high in HD patients as those in controls with matched TG levels. Plasma levels of C and TG in VLDL and IDL (intermediate density lipoprotein) were slightly higher in HD patients than in controls. The C/TG ratio of VLDL was significantly higher in HD patients than in controls. In comparison with the corresponding values in controls, the C and TG levels in low-density LDL and HDL2 in HD patients were high, whereas those in medium-density LDL, high-density LDL, and HDL3 were low. Plasma LCAT activity and CETP mass were lower in HD patients than in controls. CONCLUSION: Distribution of LDL and HDL skewed toward less dense fractions in normotriglyceridemic CKD patients on HD. A decrease in reverse C transport likely played an important role in these changes in the patients. PMID- 23752221 TI - Validation of a computerized use of time recall for activity measurement in advanced-aged adults. AB - BACKGROUND: The Multimedia Activity Recall for Children and Adults (MARCA) is a computerized recall instrument that records use of time during 24 hr the previous day and has been developed to address limitations of current self-report physical activity measures for those in advanced age. METHODS: Test-retest reliability and convergent validity of the adult MARCA were assessed in a sample of 45 advanced age adults (age 84.9 SD +/- 1.62 yr) as a subsample of the Life and Living in Advanced-Age Cohort Study New Zealand (LiLACS NZ). Test-retest methods required participants to recall the previous day's activity using the MARCA twice within the same day. Convergent validity was assessed against accelerometry. RESULTS: Test-retest reliability was high, with ICCs greater than .99 for moderate to vigorous physical activity (MVPA) and physical activity level (PAL). Compared with accelerometry, the MARCA demonstrated validity comparable to other self report instruments with Spearman's coefficients of .34 and .59 for time spent in nonsedentary physical activity and PAL. CONCLUSION: The MARCA is a valid and reliable self-report tool for physical activity behaviors in advanced-age adults. PMID- 23752222 TI - Unilateral facial ulceration-quiz case. PMID- 23752223 TI - About this journal. PMID- 23752224 TI - A rapid, topographical platelet activation assay. AB - Platelets are central in maintaining normal haemostasis and are responsible for the cessation of blood loss following vascular injury. Platelet adhesion, leading to thrombus formation, involves rapid and distinct morphological changes culminating in cell aggregation. Rapid and highly specific platelet diagnostic tests are currently being developed to enable monitoring of drug response in patients with cardiovascular diseases. For a diagnostic device to be effective it needs to be rapid and simple, requiring minimal user interaction and providing results with minimal delay. This study describes the development of a rapid, label free platform for assay platelet function and demonstrates its use to monitor the influence of anti-thrombotic drugs. A rapid, single-step cell purification surface immobilises platelets from whole blood onto a protein array at specific locations used to define the assay site. Morphological changes and cell aggregation properties of activated platelets are exploited and combined within a label free, rapid, dye displacement chamber to determine cell morphology. Stimulation-dependent changes in cell morphology are described using both high resolution AFM imaging and a dye displacement platform. PMID- 23752225 TI - Top-accessed article: severe hidradenitis suppurativa treated with infliximab infusion. PMID- 23752226 TI - AP4 is a mediator of epithelial-mesenchymal transition and metastasis in colorectal cancer. AB - The basic helix-loop-helix transcription factor AP4/TFAP4/AP-4 is encoded by a c MYC target gene and displays up-regulation concomitantly with c-MYC in colorectal cancer (CRC) and numerous other tumor types. Here a genome-wide characterization of AP4 DNA binding and mRNA expression was performed using a combination of microarray, genome-wide chromatin immunoprecipitation, next-generation sequencing, and bioinformatic analyses. Thereby, hundreds of induced and repressed AP4 target genes were identified. Besides many genes involved in the control of proliferation, the AP4 target genes included markers of stemness (LGR5 and CD44) and epithelial-mesenchymal transition (EMT) such as SNAIL, E cadherin/CDH1, OCLN, VIM, FN1, and the Claudins 1, 4, and 7. Accordingly, activation of AP4 induced EMT and enhanced migration and invasion of CRC cells. Conversely, down-regulation of AP4 resulted in mesenchymal-epithelial transition and inhibited migration and invasion. In addition, AP4 induction was required for EMT, migration, and invasion caused by ectopic expression of c-MYC. Inhibition of AP4 in CRC cells resulted in decreased lung metastasis in mice. Elevated AP4 expression in primary CRC significantly correlated with liver metastasis and poor patient survival. These findings imply AP4 as a new regulator of EMT that contributes to metastatic processes in CRC and presumably other carcinomas. PMID- 23752227 TI - Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. AB - The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab results in durable responses in metastatic melanoma, though therapeutic benefit has been limited to a fraction of patients. This calls for identification of resistance mechanisms and development of combinatorial strategies. Here, we examine the inhibitory role of indoleamine 2,3-dioxygenase (IDO) on the antitumor efficacy of CTLA-4 blockade. In IDO knockout mice treated with anti-CTLA-4 antibody, we demonstrate a striking delay in B16 melanoma tumor growth and increased overall survival when compared with wild-type mice. This was also observed with antibodies targeting PD-1-PD-L1 and GITR. To highlight the therapeutic relevance of these findings, we show that CTLA-4 blockade strongly synergizes with IDO inhibitors to mediate rejection of both IDO-expressing and nonexpressing poorly immunogenic tumors, emphasizing the importance of the inhibitory role of both tumor- and host-derived IDO. This effect was T cell dependent, leading to enhanced infiltration of tumor-specific effector T cells and a marked increase in the effector-to-regulatory T cell ratios in the tumors. Overall, these data demonstrate the immunosuppressive role of IDO in the context of immunotherapies targeting immune checkpoints and provide a strong incentive to clinically explore combination therapies using IDO inhibitors irrespective of IDO expression by the tumor cells. PMID- 23752228 TI - Changes in RNA polymerase II progression influence somatic hypermutation of Ig related genes by AID. AB - Somatic hypermutation (SHM) of Ig genes is initiated by the activation-induced cytidine deaminase (AID), and requires target gene transcription. We previously proposed that AID may associate with the RNA polymerase II (Pol). Here, to determine aspects of the transcription process required for SHM, we knocked-in a transcription terminator into an Ig gene variable region in DT40 chicken B cell line. We found that the human beta-globin terminator was an efficient inhibitor of downstream transcription in these cells. The terminator reduced mutations downstream of the poly(A) signal, suggesting that the process of transcription is essential for efficient SHM and that AID has better access to its target when Pol is in the elongating rather than terminating mode. Mutations upstream of the poly(A) site were almost doubled in the active terminator clones compared with an inactivated terminator, and this region showed more single-stranded DNA, indicating that Pol pausing assists SHM. Moreover, the nontranscribed DNA strand was the preferred SHM target upstream of the active terminator. Pol pausing during poly(A) site recognition may facilitate persistence of negative supercoils, exposing the coding single strand and possibly allowing the nascent RNA intermittent reannealing with the template strand, for prolonged access of AID. PMID- 23752230 TI - Impact of body mass index on clinicopathological outcome and biochemical recurrence after radical prostatectomy. AB - BACKGROUND: Accumulating evidence suggests that obesity is associated with tumor progression in prostate cancer (PCa) patients after radical prostatectomy (RP). We conducted a retrospective multicenter study to determine the effect of body mass index (BMI) on the clinicopathological characteristics and biochemical recurrence of PCa in Japanese men who underwent RP. METHODS: The medical records of 1257 men with PCa treated by RP without neoadjuvant therapy at four medical institutes between 2001 and 2009 were retrospectively reviewed. Patients were categorized into four groups using the World Health Organization (WHO) BMI classification and BMI quartiles. Associations of the various BMI categories with clinicopathological characteristics and biochemical recurrences were statistically evaluated. Biochemical recurrence was defined as a PSA level of >0.2 ng ml(-1). RESULTS: Of the 1257 patients, 230 (18.3%) experienced biochemical recurrence during the median follow-up period of 49 months. The median BMI was 23.8 kg m(-2), and 1.4% patients were underweight, 65.4% were of normal weight, 30.9% were overweight and 2.4% were obese (WHO classification). Preoperative PSA levels and PSA density (PSAD) tended to decrease as BMI increased. Pathological characteristics did not differ significantly among BMI categories. As per the WHO classification and quartile categories, biochemical recurrence rate was comparable among the BMI groups. After adjusting for other pre- and postoperative covariables, multivariate Cox proportional hazards analysis revealed that a high BMI did not have an independent impact on biochemical recurrence-free survival. CONCLUSIONS: Underweight Japanese PCa patients treated by RP had higher preoperative PSA levels and PSAD. High BMI was not associated with adverse pathological findings or increased biochemical recurrence rate in Japanese PCa patients treated with RP. Racial differences may exist in the relationship between obesity and outcomes of RP in PCa patients. PMID- 23752231 TI - The changing landscape of higher education. PMID- 23752229 TI - The human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter. AB - Human papillomavirus type 16 (HPV16) and other oncogenic viruses have been reported to deregulate immunity by suppressing the function of the double stranded DNA innate sensor TLR9. However, the mechanisms leading to these events remain to be elucidated. We show that infection of human epithelial cells with HPV16 promotes the formation of an inhibitory transcriptional complex containing NF-kappaBp50-p65 and ERalpha induced by the E7 oncoprotein. The E7-mediated transcriptional complex also recruited the histone demethylase JARID1B and histone deacetylase HDAC1. The entire complex bound to a specific region on the TLR9 promoter, which resulted in decreased methylation and acetylation of histones upstream of the TLR9 transcriptional start site. The involvement of NF kappaB and ERalpha in the TLR9 down-regulation by HPV16 E7 was fully confirmed in cervical tissues from human patients. Importantly, we present evidence that the HPV16-induced TLR9 down-regulation affects the interferon response which negatively regulates viral infection. Our studies highlight a novel HPV16 mediated mechanism that combines epigenetic and transcriptional events to suppress a key innate immune sensor. PMID- 23752232 TI - Clinical supervision for allied health professionals: a systematic review. AB - BACKGROUND: It is recommended that allied health professionals (AHPs) participate in regular clinical supervision (CS). However, AHP understanding of CS processes and outcomes is unclear. This systematic review reports the evidence for CS for AHPs and other health professionals. METHODS: Five databases and reference lists of included articles were searched. Papers included described CS definitions, processes and outcomes of CS. Due to the paucity of CS research for AHPs, nursing and medical disciplines were included. Two reviewers critically appraised the 33 included papers. RESULTS: The majority of papers were exploratory. Definitions and processes for CS were not clearly identified. Outcomes of CS included the relationships between CS and job satisfaction and workplace stress. Proctor's model and the Manchester Clinical Supervision Scale were the most common framework and evaluation approach. Contradictory positions of which components of Proctor's model should be included in CS were reported. Methodological flaws and a lack of comparative studies were common. DISCUSSION: Although not extensively supported by evidence, CS was generally held to be a positive experience and tends to be provided without a clear definition or model, using new or untested tools. Further research to evaluate CS for AHPs, is needed. PMID- 23752233 TI - Pre-admission factors and utilization of tutoring services in health professions educational programs. AB - Pre-admission factors tend to serve as indicators of student success in health professions educational programs, but less is known about the effects that academic assistance programs have on student success. This study sought to determine whether specific pre-admission factors could help to identify students who may require academic support during their health professions education. This retrospective analysis aimed to identify differences in pre-admission variables between those students requiring tutoring and a matched sample of students who did not require tutoring. One-way ANOVA was used to assess differences for dependent variables-age, cumulative GPA (cGPA), science GPA (sGPA), verbal graduate record examination (GRE) score, quantitative GRE score, analytical GRE score and combined GRE score, community college hours, average credit hours per semester, and highest semester credit hour load-across three groups of students who received no tutoring (NT 0 hrs), some tutoring (ST <8 hrs), and more tutoring (MT >8 hrs). Total GRE and average semester hours differentiated NT from ST from MT (p<0.05). A linear regression model with these pre-admission factors found only four of the independent variables to be significant (r2=0.41; p<0.05) in predicting hours of tutoring: quantitative GRE, sGPA, cGPA and average semester hours taken. The combination of lower GRE scores and lighter average semester course load were most predictive of the need for academic assistance as defined by hours of tutoring. While the value of the GRE in admissions processes is generally accepted, the average semester hour load in college can also provide important information regarding academic preparation and the need for tutoring services. PMID- 23752234 TI - Use of a pretest strategy for physical therapist assistant programs to predict success rate on the national physical therapy exam. AB - This study investigated a pretest strategy that identified physical therapist assistant (PTA) students who were at risk of failure on the National Physical Therapy Examination (NPTE). Program assessment data from five cohorts of PTA students (2005-2009) were used to develop a stepwise multiple regression formula that predicted first-time NPTE licensure scores. Data used included the Nelson Denny Reading Test, grades from eight core courses, grade point average upon admission to the program, and scores from three mock NPTE exams given during the program. Pearson correlation coefficients were calculated between each of the 15 variables and NPTE scores. Stepwise multiple regression analysis was performed using data collected at the ends of the first, second, and third (final) semesters of the program. Data from the class of 2010 were then used to validate the formula. The end-of-program formula accounted for the greatest variance (57%) in predicted scores. Those students scoring below a predicted scaled score of 620 were identified to be at risk of failure of the licensure exam. These students were counseled, and a remedial plan was developed based on regression predictions prior to them sitting for the licensure exam. PMID- 23752235 TI - Speech-language pathology students' perceptions of a standardised patient clinic. AB - This study aimed to investigate speech-language pathology students' perceptions of a foundation clinical skills simulation program incorporating standardised patients (SPs) by determining if experiences with SPs decreased students' anxiety about interaction with real clients and increased confidence in clinical skills. In addition, it aimed to identify students' overall perceptions of the SP experience. METHODS: The study used a pre-post design. Students who were enrolled in undergraduate and graduate speech-language pathology programs (n=175) completed a survey prior to and following the SP clinic. The survey asked questions related to levels of anxiety and confidence for clinical skills. The post-clinic survey also included questions about the use of SPs and program administration. RESULTS: All participants reported decreased anxiety levels following clinic, with those of the undergraduate students at a significant level. Participants also reported significantly increased confidence in a range of clinical skills and evaluated the program positively. CONCLUSIONS: The results of this study suggest that inclusion of SPs into a foundation clinical skills program is perceived by students to be valuable. Further investigation is required to determine the relationship between students' perceived increase in confidence and their clinical competencies. These results will inform future simulation program development. PMID- 23752236 TI - Predictors of student satisfaction with allied health educational program courses. AB - Little information is available regarding the effectiveness of various teaching methods and styles on student learning and satisfaction in allied health educational programs. We used the IDEA Center's course evaluation system to determine which teaching competencies were most predictive of students' satisfaction and progress on objectives. METHODS: At the conclusion of each quarter, all students in 13 different allied health programs were asked to complete standardized course evaluations. Students responded to 20 questions grouped into five teaching competencies. Student satisfaction was assessed using survey questions to rate course and instructor excellence. All questions used a 5 point Likert scale. RESULTS: There were 2,924 student evaluations returned (72.5% response). Teaching competencies predicted 62% of the variation in course satisfaction, 67% of the variation in teacher satisfaction, and 58% of the variation in progress on relevant objectives (p<0.001. Stimulating student interest was the strongest predictor of course satisfaction and progress on relevant objectives (p<0.001. Structuring classroom experiences was the strongest predictor of teacher satisfaction (p<0.001. CONCLUSION: By developing specific teaching competencies, instructors may improve student satisfaction and progress on relevant objectives. Educational institutions may also be able to utilize this information to create faculty developments plans in an effort to improve teaching and student satisfaction levels. PMID- 23752237 TI - Seeking consensus through the use of the Delphi technique in health sciences research. AB - The purposes of this paper are to explain how the Delphi technique has been used as a research methodology for seeking consensus among experts in the health science literature and to offer a model for its future use. The authors discuss the proposed model by exploring how the Delphi technique was used to develop a survey tool to explore mentoring practices of health science faculty members. The authors' aims are to explain the use of this methodological approach in obtaining face and content validity of survey tools and to apprize the scholarly community in the health sciences of the relevance of the model. PMID- 23752238 TI - Patient safety perceptions among vascular interventional technologists. AB - OBJECTIVE: To describe perceptions of patient safety culture (PSC) among US vascular interventional technologists (VIR). METHODS: A letter to complete The Hospital Survey on Patient Safety Culture online was distributed in the US to all full-time American Registry of Radiologic Technologists (ARRT)-registered technologists with a primary discipline of cardiac-interventional or vascular interventional (n=3,184). Mean scores on each PSC dimension and overall outcome measures were calculated. RESULTS: The response rate was 13.7% (n=437) for the entire universe of ARRT-registered VIR technologists working full-time. Overall, respondents ranked the following dimensions as supporting patient safety within their respective institution: supervisor/manager promotion of patient safety, staffing, hospital handoffs/transitions, and teamwork within units. Neutral perceptions focused on teamwork across hospital units, hospital management's support for patient safety, and nonpunitive response to errors. CONCLUSION: For this population, teamwork across hospital units and administrative support for a culture of safety should be addressed. With almost 20' of respondents rating their institutions with an overall safety grade of C or below, there is clearly a need for further investigation of patient safety issues within VIR departments to confirm these findings and to expand the scope of inquiry to other radiologic science professionals. PMID- 23752239 TI - Occupational therapy admissions: professionalization and personality. AB - PURPOSE: Specific characteristics of occupational therapy students were examined before and after matriculating through a master's of occupational therapy educational program to see if any characteristics changed during the didactic portion of the program and to see how specific characteristics could be determined using noncognitive variables in occupational therapy education admissions. METHODS: This study used a quantitative pre- and post-test design, incorporating volunteer students to take the CPI 260(r) personality test. All participants signed consent forms prior to the first administration of the CPI 260(r). The final tally included 14 occupational therapy students. RESULTS: Twenty-five of the 26 characteristics on the CPI 260(r) were not found to change significantly over time. Only 1 characteristic was found to be significant (p <= 0.05), and that was a lower median score on "achievement via conformance." This was considered to be a positive result, because the profession needs less conformity and more innovation to enhance its professionalization. CONCLUSION: This pilot study provides a reasonable indicator that health care professional educational programs should consider the use of noncognitive variables for admissions if they wish to bring individuals into the professions who have specific characteristics. Admission committees can identify specific characteristics they desire and then identify activities that demonstrate that characteristic. A tool to assist in identifying core professionalization activities among OT school candidates is presented. PMID- 23752240 TI - Effect of the health mentors program on student attitudes toward team care. AB - Based on a growing body of literature documenting improved cost and quality outcomes related to good team care, interprofessional education (IPE) has been widely endorsed as critical to preparing the future healthcare workforce. This study evaluated the effect of a longitudinal team-based 2-year IPE curriculum on attitudes toward health care teams. Analyses included comparison of baseline measures to the end of the 2-year curriculum of each of the six participating disciplines (medicine, nursing, occupational therapy, pharmacy, physical therapy, and couple and family therapy). Differences between the disciplines were also analyzed. A significant improvement on a 14-item quality of care and teamwork of health professionals subscale of the Attitudes Toward Health Care Teams scale was found. Students surveyed in each of the six disciplines demonstrated significant improvements in attitudes toward quality of care and teamwork from the baseline measure at the beginning of the IPE program to the end of the 2-year program. There were no significant differences noted between disciplines. Assessment of attitudes toward health care teams assisted in evaluation and ongoing quality improvement of the IPE program and could potentially be used in other interprofessional programs that focus on health care teamwork. Next steps include longitudinal assessment of students throughout their programs and into practice to explore the sustainability of attitudes and behaviors, as well as impact on patient outcomes. PMID- 23752241 TI - Student attitudes toward a web-based interprofessional education package. AB - The objective of this study was to examine undergraduate health science students' attitudes toward interprofessional learning using a web-based interprofessional education package. METHODS: A before and after study of student attitudes toward a web-based interprofessional education package was conducted using the 17-item Readiness for Interprofessional Learning Scale (RIPLS). Students completed the RIPLS before and after the educational package. RESULTS: Forty-six students commenced the study with 2 students failing to complete. The group contained mostly females with a mean age of 22.6 yrs. A statistically significant change was found for RIPLS subscale one, "shared learning," p=0.035. CONCLUSIONS: This study demonstrated that a web-based interprofessional education package did appear to have an impact on undergraduate students' attitudes toward interprofessional learning. PMID- 23752242 TI - Video-recorded simulated patient interactions: can they help develop clinical and communication skills in today's learning environment? AB - It is difficult to provide real-world learning experiences for students to master clinical and communication skills. The purpose of this paper is to describe a novel instructional method using self- and peer-assessment, reflection, and technology to help students develop effective interpersonal and clinical skills. The teaching method is described by the constructivist learning theory and incorporates the use of educational technology. TEACHING METHOD: The learning activities were incorporated into the pre-clinical didactic curriculum. The students participated in two video-recording assignments and performed self assessments on each and had a peer-assessment on the second video-recording. ASSESSMENT: The learning activity was evaluated through the self- and peer assessments and an instructor-designed survey. This evaluation identified several themes related to the assignment, student performance, clinical behaviors and establishing rapport. Overall the students perceived that the learning activities assisted in the development of clinical and communication skills prior to direct patient care. CONCLUSION: The use of video recordings of a simulated history and examination is a unique learning activity for preclinical PT students in the development of clinical and communication skills. PMID- 23752243 TI - An interprofessional practice capability framework focusing on safe, high quality, client-centred health service. AB - This paper describes an interprofessional capability framework which builds on the existing interprofessional competency and capability frameworks from the United Kingdom, Canada, and the United States of America. Existing published frameworks generally make reference to being client-centred and to the safety and quality of care, and locate interprofessional collaborative practice as the central theme or objective. In contrast, this framework interlinks all three elements: client-centred services, safety and quality of services, and interprofessional collaborative practice. The framework is clear and succinct with an accompanying visual representation that highlights all key features. The framework has informed curriculum which incorporates a common first-year, case based educational workshops and practice placements within a large complex health sciences faculty of approximately 10,000 students from 22 disciplines. The articulation of these key elements of health practice has facilitated students, academic staff, and community health professionals to develop a shared understanding of interprofessional education and practice. The design, implementation, and evaluation of learning outcomes, learning experiences, and assessments have been transformed with the introduction of this framework, which is highly applicable to other contexts. PMID- 23752244 TI - Reelin, an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2B-NMDARs and the mTOR pathway. AB - Defective brain extracellular matrix (ECM) is a factor of vulnerability in various psychiatric diseases such as schizophrenia, depression and autism. The glycoprotein reelin is an essential building block of the brain ECM that modulates neuronal development and participates to the functions of adult central synapses. The reelin gene (RELN) is a strong candidate in psychiatric diseases of early onset, but its synaptic and behavioral functions in juvenile brain circuits remain unresolved. Here, we found that in juvenile reelin-haploinsufficient heterozygous reeler mice (HRM), abnormal fear memory erasure is concomitant to reduced dendritic spine density and anomalous long-term potentiation in the prefrontal cortex. In juvenile HRM, a single in vivo injection with ketamine or Ro25-6981 to inhibit GluN2B-N-methyl-D-aspartate receptors (NMDARs) restored normal spine density, synaptic plasticity and converted fear memory to an erasure resilient state typical of adult rodents. The functional and behavioral rescue by ketamine was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin pathway. Finally, we show that fear memory erasure persists until adolescence in HRM and that a single exposure to ketamine during the juvenile period reinstates normal fear memory in adolescent mice. Our results show that reelin is essential for successful structural, functional and behavioral development of juvenile prefrontal circuits and that this developmental period provides a critical window for therapeutic rehabilitation with GluN2B-NMDAR antagonists. PMID- 23752245 TI - Rare autosomal copy number variations in early-onset familial Alzheimer's disease. AB - Over 200 rare and fully penetrant pathogenic mutations in amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) cause a subset of early-onset familial Alzheimer's disease (EO-FAD). Of these, 21 cases of EO-FAD families carrying unique APP locus duplications remain the only pathogenic copy number variations (CNVs) identified to date in Alzheimer's disease (AD). Using high density DNA microarrays, we performed a comprehensive genome-wide analysis for the presence of rare CNVs in 261 EO-FAD and early/mixed-onset pedigrees. Our analysis revealed 10 novel private CNVs in 10 EO-FAD families overlapping a set of genes that includes: A2BP1, ABAT, CDH2, CRMP1, DMRT1, EPHA5, EPHA6, ERMP1, EVC, EVC2, FLJ35024 and VLDLR. In addition, CNVs encompassing two known frontotemporal dementia genes, CHMP2B and MAPT were found. To our knowledge, this is the first study reporting rare gene-rich CNVs in EO-FAD and early/mixed-onset AD that are likely to underlie pathogenicity in familial AD and perhaps related dementias. PMID- 23752246 TI - Exome sequence analysis of Finnish patients with clozapine-induced agranulocytosis. PMID- 23752248 TI - Paternal age, de novo mutations and schizophrenia. PMID- 23752247 TI - Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample. AB - Smoking is a major risk factor for several somatic diseases and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Previous large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed GWA analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked and ND. Our results highlight a locus on 16p12.3, with several single-nucleotide polymorphisms (SNPs) in the vicinity of CLEC19A showing association (P<1 * 10(-6)) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention-deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1 * 10(-5)) was detected between DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Recently, a significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed following chronic nicotine exposure and withdrawal in mice and an association between NRG3 SNPs and smoking cessation success was detected in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. In conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND. PMID- 23752249 TI - Dynamics of the meningeal CD4(+) T-cell repertoire are defined by the cervical lymph nodes and facilitate cognitive task performance in mice. PMID- 23752254 TI - News and products update. AB - NEWS AND PRODUCTS UPDATE. PMID- 23752253 TI - Emotion recognition in mild cognitive impairment: relationship to psychosocial disability and caregiver burden. AB - BACKGROUND: Impaired emotion recognition in dementia is associated with increased patient agitation, behavior management difficulties, and caregiver burden. Emerging evidence supports the presence of very early emotion recognition difficulties in mild cognitive impairment (MCI); however, the relationship between these impairments and psychosocial measures is not yet explored. METHODS: Emotion recognition abilities of 27 patients with nonamnestic MCI (naMCI), 29 patients with amnestic MCI (aMCI), and 22 control participants were assessed. Self-report measures assessed patient functional disability, while informants rated the degree of burden they experienced. RESULTS: Difficulties in recognizing anger was evident in the amnestic subtype. Although both the patient groups reported greater social functioning disability, compared with the controls, a relationship between social dysfunction and anger recognition was evident only for patients with naMCI. A significant association was found between burden and anger recognition in patients with aMCI. CONCLUSIONS: Impaired emotion recognition abilities impact MCI subtypes differentially. Interventions targeted at patients with MCI, and caregivers are warranted. PMID- 23752250 TI - In vitro intestinal bioavailability of arsenosugar metabolites and presystemic metabolism of thio-dimethylarsinic acid in Caco-2 cells. AB - Whereas inorganic arsenic is classified as a human carcinogen, risks to human health related to the presence of arsenosugars in marine food are still unclear. Since studies indicate that human inorganic arsenic metabolites contribute to inorganic arsenic induced carcinogenicity, a risk assessment for arsenosugars should also include a toxicological characterization of their respective metabolites. Here we assessed intestinal bioavailability of the human arsenosugar metabolites oxo-DMAA(V), thio-DMAA(V), oxo-DMAE(V), thio-DMAE(V) and thio-DMA(V) in relation to arsenite in the Caco-2 intestinal barrier model. Whereas arsenite and thio-DMA(V) caused barrier disruption at concentrations >=10 MUM, all other metabolites did not cause a barrier leakage, even when applied at 50 times higher concentrations than arsenite and thio-DMA(V). The transfer studies point to a strong intestinal bioavailability of thio-DMA(V) and thio-DMAE(V), whereas oxo DMAA(V), thio-DMAA(V) and oxo-DMAE(V) passed the in vitro intestinal barrier only to a very small extent. Detailed influx and efflux studies indicate that arsenite and thio-DMA(V) cross the intestinal barrier most likely by passive diffusion (paracellular) and facilitated (transcellular) transport. LC-ICP-QMS based arsenic speciation studies during the transfer experiments demonstrate transfer of thio-DMA(V) itself across the intestinal barrier and suggest metabolism of thio-DMA(V) using the in vitro intestinal barrier model to its oxygen-analogue DMA(V). In the case of arsenite no metabolism was observed. In summary the two arsenosugar metabolites thio-DMA(V) and thio-DMAE(V) showed intestinal bioavailability similar to that of arsenite, and about 10-fold higher than that reported for arsenosugars (Leffers et al., Mol. Nutr. Food Res., 2013, DOI: 10.1002/mnfr.201200821) in the same in vitro model. Thus, a presystemic metabolism of arsenosugars might strongly impact arsenic intestinal bioavailability after arsenosugar intake and should therefore be considered when assessing the risks to human health related to the consumption of arsenosugar containing food. PMID- 23752255 TI - Diffuse hyperkeratosis in a deaf and blind 48-year-old woman-diagnosis. PMID- 23752256 TI - Highlights of archives of facial plastic surgery. PMID- 23752257 TI - Changes in the source of unscheduled hospitalizations in the United States. AB - BACKGROUND: Hospitalizations represent a significant portion of the annual expenditures for the US health care system. Understanding recent changes in the sources of unscheduled admissions may provide opportunities to improve the quality and cost of inpatient care. OBJECTIVES: To examine sources of unscheduled hospitalization over a 10-year period and implications for inpatient mortality and length of stay (LOS). RESEARCH DESIGN: Observational study using the 2000 2009 Nationwide Inpatient Sample. SUBJECTS: We categorized unscheduled hospitalizations as those related to transfers, direct admissions from outpatient providers, and the emergency department (ED). MEASURES: Hospitalization rates by source and clinical condition with multivariable regression analyses adjusted for patient demographics, comorbid conditions, and hospital factors to evaluate associated mortality and LOS outcomes. RESULTS: Unscheduled hospitalizations arising from direct admissions and the ED changed substantially while those due to transfers remained relatively stable. The ED admitted 64.9% [95% confidence interval (CI), 62.8%-66.9%] of unscheduled hospitalizations in 2000, rising to 81.8% (95% CI, 80.5%-83.1%) by 2009, whereas direct admissions from outpatient providers correspondingly declined. In 2009, despite higher illness severity and chronic disease burden, hospitalization through the ED as compared with direct admissions was associated with an overall lower mortality adjusted odds ratio of 0.85 (95% CI, 0.77-0.93) and shorter adjusted hospital LOS of -0.84 (95% CI, 0.99 to -0.70) days. CONCLUSIONS: Sources of unscheduled hospitalization in the United States have evolved, mostly resulting from care for a variety of clinical conditions now originating in the ED. This trend does not seem to be harming patients or worsening LOS. PMID- 23752259 TI - Dabigatran and myocardial infarction: meta-illusion?-Reply. PMID- 23752258 TI - Confounding adjustment in comparative effectiveness research conducted within distributed research networks. AB - BACKGROUND: A distributed research network (DRN) of electronic health care databases, in which data reside behind the firewall of each data partner, can support a wide range of comparative effectiveness research (CER) activities. An essential component of a fully functional DRN is the capability to perform robust statistical analyses to produce valid, actionable evidence without compromising patient privacy, data security, or proprietary interests. OBJECTIVES AND METHODS: We describe the strengths and limitations of different confounding adjustment approaches that can be considered in observational CER studies conducted within DRNs, and the theoretical and practical issues to consider when selecting among them in various study settings. RESULTS: Several methods can be used to adjust for multiple confounders simultaneously, either as individual covariates or as confounder summary scores (eg, propensity scores and disease risk scores), including: (1) centralized analysis of patient-level data, (2) case-centered logistic regression of risk set data, (3) stratified or matched analysis of aggregated data, (4) distributed regression analysis, and (5) meta-analysis of site-specific effect estimates. These methods require different granularities of information be shared across sites and afford investigators different levels of analytic flexibility. CONCLUSIONS: DRNs are growing in use and sharing of highly detailed patient-level information is not always feasible in DRNs. Methods that incorporate confounder summary scores allow investigators to adjust for a large number of confounding factors without the need to transfer potentially identifiable information in DRNs. They have the potential to let investigators perform many analyses traditionally conducted through a centralized dataset with detailed patient-level information. PMID- 23752260 TI - A pilot study of a telehealth intervention for persons with spinal cord dysfunction. AB - STUDY DESIGN: Single-blind randomized controlled trial of 6 months' duration. OBJECTIVES: To evaluate the efficacy of a novel telehealth intervention, 'CareCall', on reducing pressure ulcers and depression and enhancing the use of appropriate health care. SETTING: General community, Massachusetts and Connecticut, United States METHODS: 'CareCall' is an automated, interactive voice response system that combines patient education, cognitive behavioral interventions, screening and referrals, with alerts to a nurse telerehabilitation coordinator for direct non-emergent phone follow up. Participants consisted of a convenience sample of 142 persons with multiple sclerosis or spinal cord injury using a wheelchair >6 h per day. The intervention group received CareCall (n=71) The control group received usual care (n=71). The main outcome measures were: The pressure ulcer scale for healing tool, Patient Health Questionnaire-9 depression scale, Cornell Services Index and Craig Hospital Inventory of Environmental Factors-Short Form Question 5. RESULTS: CareCall achieved a reduction in presence of pressure ulcers at 6 months in women (P<0.0001). Among those with baseline depression, CareCall reduced 6-month severity of depression, adjusting for age and gender (P<0.047). CareCall did not have a significant impact on health-care utilization (OR=1.8, P=0.07), but did significantly improve participants' report of health-care availability (OR=2.03, P<0.04). CONCLUSION: This is the first study to demonstrate the efficacy of a largely automated telehealth intervention for adults with spinal cord dysfunction. Future research needs to replicate this study in a larger, multisite trial. PMID- 23752261 TI - Traumatic epidural retroclival hematoma with odontoid fracture and cardiorespiratory arrest. AB - STUDY DESIGN: Case report. OBJECTIVES: To describe a case or traumatic retroclival hematoma with features not previously reported. SETTING: Single center. METHODS: Description of a case, in the context of relevant literature on the subject. RESULTS: Traumatic retroclival hematomas are a rare, typically pediatric, entity. Only four cases of epidural hematoma in adult patients have been reported. We describe an additional case, the first with a fatal course in the acute setting. It is also the first retroclival hematoma associated to an odontoid base fracture. CONCLUSION: Retroclival hematomas are a rare diagnosis, to be considered in pediatric patients with flexion-extension, high-energy injuries. Morphology is typically epidural. Brain stem and cranial nerve symptoms are typical. Treatment is usually conservative. Outcome is regarded as favorable, with partial recovery and neurologic sequelae. Adult cases are extremely rare. The case we describe adds new characteristics to the scarcity of cases. PMID- 23752262 TI - Compliance with clean intermittent catheterization in spinal cord injury patients: a long-term follow-up study. AB - STUDY DESIGN: Retrospective review of medical notes. OBJECTIVE: To evaluate spinal cord injury (SCI) patients' compliance with bladder emptying method at long-term period after discharge and determine the frequency of urinary tract infections (UTIs). SETTING: Inpatient rehabilitation unit of tertiary research hospital. METHODS: Bladder management method of 164 new spinal cord injured patients were noted at discharge from rehabilitation center and follow-up. Patients were questioned whether they continued the initial bladder emtying method at follow-up, reasons for discontinuation and the history of treated UTIs. RESULTS: The most common bladder management method at discharge from inpatient rehabilitation center was clean intermittent catheterization (CIC) (63.4%). At follow-up 42% of the patients who used CIC changed their bladder emptying method. Rate of reverting to urethral indwelling catheter (IC) was 21.4%. Reasons for the patients who switched to IC application were recurrent UTIs, incontinence, nephrolithiasis, dependence on care givers and urethral strictures. For all patients, the frequency of treated UTI in 1 year was 38.8%. The number of UTIs were highest in patients using IC. CONCLUSION: Many factors, including urological complications, patient's preference, living environment, life-style and level of injury should be considered in deciding the method of bladder management in SCI patients. The CIC is a reliable and effective method in selected SCI patients. Despite changes in bladder emptying method, CIC was the most preferred method at long-term follow-up. Education of patients on catheterization technique and periodic follow-up is necessary to maintain patient compliance. PMID- 23752263 TI - Medical rehabilitation of spinal cord injury following earthquakes in rehabilitation resource-scarce settings: implications for disaster research. AB - STUDY DESIGN: Narrative literature review. OBJECTIVES: To (1) summarize epidemiological and scientific research on spinal cord injury (SCI) populations from three severe earthquakes (EQs) in rehabilitation resource-scarce settings; (2) summarize SCI rehabilitation services by local and foreign providers in response to these EQs and (3) provide implications including research gaps for a supporting global scientific research agenda. SETTING: International. METHODS: A literature review was conducted using PubMed to identify epidemiological studies reporting data on SCI survivors of the 2005 Kashmir EQ in Pakistan, the Sichuan EQ of 2008 in China and the 2010 Haiti EQ. A follow-up review on the SCI rehabilitation services provided by local and foreign providers in response to these EQs was also performed. RESULTS: Review of the scientific literature revealed the qualitative trends in focused EQ victim epidemiological data, including SCI classification and types of medical complications. Selected EQ country narratives showed that post-disaster SCI rehabilitation services were expanded by adapting local resources with international assistance to manage the significant numbers of SCI survivors. The resulting SCI research was limited. CONCLUSION: A global disaster research agenda for SCI in EQs in rehabilitation resource-scarce settings is needed to strengthen the evidence base for improvement of clinical management and outcomes for SCI EQ survivors. Expansion of this limited narrative review into a systematic review to identify additional research gaps is a proposed next step. Effective disaster setting data management and research collaborations of foreign and local SCI disability and rehabilitation stakeholders will be required for agenda implementation. PMID- 23752264 TI - Optimal time window of myelotomy in rats with acute traumatic spinal cord injury: a preliminary study. AB - OBJECTIVES: Pathophysiological mechanisms underlying spinal cord injury (SCI) partially involve edema and formation of a hematoma. Myelotomy seems to be a promising intervention. However, the appropriate timing of myelotomy is still unknown in SCI. Here we aimed to determine the timing of microsurgical myelotomy in an animal model of SCI. METHODS: The SCI model was contusion-induced with a new york university impactor. Sixty-five adult female rats were randomly divided into the following groups: laminectomy alone (the 'sham group', SG), laminectomy plus contusion (the 'contusion group', CG) or laminectomy plus contusion followed by myelotomy at 8, 24 or 48 h (8 h-MTG [myelotomy-treated group], 24 h-MTG or 48 h-MTG). Functional recovery was evaluated via the open field test and the inclined plane test every week after SCI. The percentage of spared white matter area (SWMA) and ultrastructure characteristics of the injured dorsolateral spinal cord were determined on the 42nd day after SCI. RESULTS: Compared with the CG, myelotomy at 8 h-MTG or 24 h-MTG greatly improved the BASSO-BEATTIE- BRESNAHAN scores (P<0.008), whereas the 48 h-MTG showed less efficacy (P=0.023). All myelotomy groups showed higher mean angle values in an inclined plane test (P<0.005) and had greater percentages of SWMA than the CG. Rats in the 24 h-MTG showed a higher intra-axonal fraction and myelin fraction than those in 48 h-MTG (P<0.005). CONCLUSION: Myelotomy up to 48 h after SCI improves recovery in rats. The potential time window of myelotomy may be between 8 and 24 h after SCI. PMID- 23752265 TI - Dynamic proteome analysis of spinal cord injury after ischemia-reperfusion in rabbits by two-dimensional difference gel electrophoresis. AB - STUDY DESIGN: Spinal cord injury (SCI) is a devastating and common neurologic disorder that has profound influences on modern society from physical, psychosocial and socio-economic perspectives. OBJECTIVES: To analyze the dynamic changes in protein expression during SCI after ischemia-reperfusion. METHODS: We used two-dimensional difference gel electrophoresis combined with matrix-assisted laser desorption/ionization time-of-flight/time-of-flight MS to give a global analysis of protein dynamic change during SCI after ischemia-reperfusion. Dynamic changes in protein expression were investigated from 6 to 48 h in SCI after ischemia-reperfusion using a proteomics tool. RESULTS: Twenty-one proteins were identified in total, including neuronal proteins, glycometabolism enzymes, stress related proteins and cytoskeleton-related proteins. These were divided into upregulated and downregulated groups. Results identified 24 h as a key time point when all proteins were changed dramatically. In addition, changes in Fascin expression were discovered in SCI for the first time. CONCLUSION: In conclusion, we observed dynamic proteome change correlated with SCI by ischemia-reperfusion, and provided a clue to this pathological mechanism by protein identification and analysis. PMID- 23752266 TI - Postpartum hypogalactia in a woman with Brown-Sequard-plus syndrome: a case report. AB - STUDY DESIGN: A case report. OBJECTIVES: To present a case of postpartum hypogalactia in a woman with Brown-Sequard-plus syndrome (BSPS). SETTING: Outpatient spinal cord injury (SCI) clinic. CASE REPORT: A 33-year-old woman with C4 AIS D tetraplegia (American Spinal Injury Association Impairment Scale) was followed at the outpatient SCI clinic for the past 5 years. Her right side presents with increased tone, increased spasticity and decreased sensitivity to light touch. Conversely, her left side presents with minimal changes in tone and no motor function deficits, but decreased sensitivity to pinprick and temperature sensation. These findings are consistent with BSPS. After inpatient rehabilitation, she was engaged, married, and 8 months ago delivered a healthy child. After an uncomplicated delivery, breastfeeding was attempted, but a significant lack of lactation was noted the first month postpartum from the right breast. Despite the implementation of measures to increase lactation, the lack of lactation from the right breast persisted, and required initiation of formula feeding. The right breast in this case lost not only sensory proprioception, but also autonomic control, which could contribute to this instance of asymmetric lactation. CONCLUSION: In addition to motor and sensory dysfunctions following SCI, autonomic dysfunctions are commonly seen in individuals with these devastating injuries. The lactation on the right side, which had interrupted descending spinal autonomic pathways, was decreased by approximately 83%. This case provides us with interesting information regarding attention that clinicians should be paying when discussing the breastfeeding options for women with SCI. PMID- 23752267 TI - The HDAC interaction network. PMID- 23752271 TI - About this journal. PMID- 23752268 TI - The functional interactome landscape of the human histone deacetylase family. AB - Histone deacetylases (HDACs) are a diverse family of essential transcriptional regulatory enzymes, that function through the spatial and temporal recruitment of protein complexes. As the composition and regulation of HDAC complexes are only partially characterized, we built the first global protein interaction network for all 11 human HDACs in T cells. Integrating fluorescence microscopy, immunoaffinity purifications, quantitative mass spectrometry, and bioinformatics, we identified over 200 unreported interactions for both well-characterized and lesser-studied HDACs, a subset of which were validated by orthogonal approaches. We establish HDAC11 as a member of the survival of motor neuron complex and pinpoint a functional role in mRNA splicing. We designed a complementary label free and metabolic-labeling mass spectrometry-based proteomics strategy for profiling interaction stability among different HDAC classes, revealing that HDAC1 interactions within chromatin-remodeling complexes are largely stable, while transcription factors preferentially exist in rapid equilibrium. Overall, this study represents a valuable resource for investigating HDAC functions in health and disease, encompassing emerging themes of HDAC regulation in cell cycle and RNA processing and a deeper functional understanding of HDAC complex stability. PMID- 23752269 TI - Network quantification of EGFR signaling unveils potential for targeted combination therapy. AB - The epidermal growth factor receptor (EGFR) signaling network is activated in most solid tumors, and small-molecule drugs targeting this network are increasingly available. However, often only specific combinations of inhibitors are effective. Therefore, the prediction of potent combinatorial treatments is a major challenge in targeted cancer therapy. In this study, we demonstrate how a model-based evaluation of signaling data can assist in finding the most suitable treatment combination. We generated a perturbation data set by monitoring the response of RAS/PI3K signaling to combined stimulations and inhibitions in a panel of colorectal cancer cell lines, which we analyzed using mathematical models. We detected that a negative feedback involving EGFR mediates strong cross talk from ERK to AKT. Consequently, when inhibiting MAPK, AKT activity is increased in an EGFR-dependent manner. Using the model, we predict that in contrast to single inhibition, combined inactivation of MEK and EGFR could inactivate both endpoints of RAS, ERK and AKT. We further could demonstrate that this combination blocked cell growth in BRAF- as well as KRAS-mutated tumor cells, which we confirmed using a xenograft model. PMID- 23752273 TI - Expression and role of GPR87 in urothelial carcinoma of the bladder. AB - The orphan GPR87 has recently been matched with its ligand LPA, which is a lipid mediator with multiple physiological functions, including cancer cell proliferation. This study aimed to clarify the role of GPR87 in urothelial carcinoma of the bladder. GPR87 expression was assessed in seven human bladder cancer cell lines. A replication-deficient recombinant adenoviral vector expressing shRNA targeting GPR87 (Ad-shGPR87), was constructed. Gene silencing was carried out using Ad-shGPR87. Immunohistochemical analysis was performed for transurethral resection of bladder tumor samples from 71 patients with non-muscle invasive bladder cancer. We observed GPR87 expression in five of the seven cell lines, and silencing GPR87 gene expression significantly reduced cell viability. GPR87 expression was positive in 38 (54%) of 71 tumors. Ki-67 index was associated with positive GPR87 staining status (p < 0.0001). Patients with GPR87 positive tumors had shorter intravesical recurrence-free survival than those with GPR87-negative tumors (p = 0.010). Multivariate analysis revealed that GPR87 staining status was an independent prognostic parameter for intravesical recurrence (p = 0.041). Progression from non-muscle-invasive to muscle-invasive tumor was more frequently observed in patients with GPR87-positive tumors, although this trend did not reach statistical significance (p = 0.056). These results warrant further prospective studies to clarify the role of GPR87 expression in intravesical recurrence and progression in bladder cancer. PMID- 23752272 TI - Urinary bladder cancer susceptibility markers. What do we know about functional mechanisms? AB - Genome-wide association studies (GWAS) have been successful in the identification of the several urinary bladder cancer (UBC) susceptibility loci, pointing towards novel genes involved in tumor development. Despite that, functional characterization of the identified variants remains challenging, as they mostly map to poorly understood, non-coding regions. Recently, two of the UBC risk variants (PSCA and UGT1A) were confirmed to have functional consequences. They were shown to modify bladder cancer risk by influencing gene expression in an allele-specific manner. Although the role of the other UBC risk variants is unknown, it can be hypothesized-based on studies from different cancer types-that they influence cancer susceptibility by alterations in regulatory networks. The insight into UBC heritability gained through GWAS and further functional studies can impact on cancer prevention and screening, as well as on the development of new biomarkers and future personalized therapies. PMID- 23752277 TI - About this journal. PMID- 23752275 TI - Ratiometric and absolute water-soluble fluorescent tripodal zinc sensor and its application in killing human lung cancer cells. AB - A new "naked-eye" and ratiometric fluorescent zinc sensor (TAQ) of carboxamidoquinoline with 2-chloro-N-(quinol-8-yl)-acetamide as a receptor was designed and synthesized. The sensor shows good water solubility and high selectivity for sensing; about a 15-fold increase in fluorescence quantum yield and a 100 nm red-shift of fluorescence emission upon binding Zn2+ in aqueous HEPES buffer solution are observed. The human lung cancer cell line (A549) activity is also demonstrated. PMID- 23752278 TI - An inquiry from an amateur pianist. PMID- 23752274 TI - Lymphocytes of patients with Alzheimer's disease display different DNA damage repair kinetics and expression profiles of DNA repair and stress response genes. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by loss of memory and cognitive capacity. Given the limitations to analyze brain cells, it is important to study whether peripheral lymphocytes can provide biological markers for AD, an interesting approach, once they represent the overall condition of the organism. To that extent, we sought to find whether lymphocytes of AD patients present DNA damage and repair kinetics different from those found in elderly matched controls (EC group) under in vitro treatment with hydrogen peroxide. We found that AD patient cells indeed showed an altered DNA repair kinetics (comet assay). Real-time quantitative analysis of genes associated with DNA stress response also showed that FANCG and CDKN1A are upregulated in AD, while MTH1 is downregulated, compared with the control group. In contrast, the expression of ATM, ATR and FEN1 genes does not seem to differ between these groups. Interestingly, TP53 protein expression was increased in AD patients. Therefore, we found that kinetics of the stress response in the DNA were significantly different in AD patients, supporting the hypothesis that repair pathways may be compromised in AD and that peripheral lymphocytes can reveal this condition. PMID- 23752279 TI - Performance and recovery: stress profiles in professional ballroom dancers. AB - Like other athletes, ballroom dancers often compete in short time in different countries under condition of high stress, subjecting them to risk of injury and burnout. In the present study, we measured the aerobic and anaerobic capacities (both during dance and during a simulated ballroom competition), agility, hand and abdominal strength, jumping capacity, flexibility, and balance in 16 top level couples of ballroom dancers (8 males, 8 females). The in-season level of perceived stress and recovery was assessed using the Rest Q 76 questionnaire, and the relationship with aerobic and anaerobic capacity and with the other tests was studied. Our results show a very high level of aerobic/anaerobic fitness in this population, as well as a high level of stress in males. Balance and experience (age of the subjects) appear to be key characteristics linked to the position in the IDSF World Ranking (world ranking points = 8.67 x age + 5.86 x balance + 1174.65; R2 = 0.740). Emotional stress (r = 0.83, p = 0.04), social stress (r = 0.72, p = 0.032), and sleep quality (r = 0.92, p = 0.001) scales of the Rest Q appear also to be linked with balance but only in females. PMID- 23752280 TI - A bibliographic review of medicine and science research in dancesport. AB - DanceSport is the competitive form of ballroom dancing, and even though it has more participants worldwide than ballet and modern dance, there is less peer reviewed research. A review was conducted to identify all relevant literature to help researchers and clinicians gain an enhanced understanding of dancesport. Eight databases were searched, with 34 articles found in topics including participation motives, psychology, exercise physiology, fitness training, injuries and injury prevention, biomechanics, menstrual dysfunction, and substance use. Our results indicate that researchers have been inconsistently recording and reporting anthropometric and dancesport data; for example, 31 studies separated participants by gender, 21 included the competition classification of dancers, 19 reported which style of dancesport participants competed in, and 13 described the participants as a dance couple. Common injuries affected the neck, shoulder, spine, knee, lower leg, and foot. Dancesport is in the very heavy to extremely heavy category in energy expenditure (mean heart rate: male 175.2 +/- 10.7, female 178.6 +/- 8.6 bpm) and utilizes both aerobic and anaerobic energy systems. Alpha-beta and heart rate variability intervention techniques are reported to successfully enhance performance in dancers. Dancesport participants also appear less likely to smoke cigarettes, but have little knowledge about anti-doping rules. During events, professionals danced farther (30 m) and faster (0.3 m/sec) than junior dancers. Female competitors were more likely to be eumenorrheic. Dancesport is a physically and mentally demanding competitive sport, but there is a need to standardize measurements in future studies to allow comparison. PMID- 23752281 TI - Zapateado technique as an injury risk in Mexican folkloric and Spanish dance: an analysis of execution, ground reaction force, and muscle strength. AB - Zapateado is a repetitive percussive footwork in dance. This percussive movement, and the differences in technique, may be risk factors for injury. A survey on zapateado dance students found a rate of 1.5 injuries/1,000 exposures. Knee injuries are more frequent than in Spanish dancers than folkloric dancers. The aim of this research was to study the relationship between technique and ground reaction force between zapateado on Spanish and Mexican folkloric dancers. Ten female dance students (age 22.4 +/- 4 yrs), six Spanish dancers and four Mexican folkloric dancers, were considered. Each student performed zapateado with a flat foot, wearing high-heeled shoes during 5 seconds on a force platform. Videotapes were taken on a lateral plane, and knee and hip angles in each movement phase were measured with Dartfish software. Additionally, knee and ankle flexor and extensor strength was measured with a dynamometer. Ground reaction forces were lower for Spanish dancers than Mexican folkloric dancers. Spanish dancers had less knee flexion when the foot contacted to the ground than did Mexican folkloric dancers. On Spanish dancers, the working leg had more motion in relation to hip and knee angles than was seen in folkloric dancers. The ankle extensors were stronger on folkloric dancers, and there were no differences for the other muscle groups. Knee flexion at foot contact and muscle strength imbalance could be risk factors for injuries. It is suggested that the technique in Spanish dance in Mexico be reviewed, although more studies are required to define more risk factors. PMID- 23752282 TI - Contributions of muscle fatigue to a neuromuscular neck injury in female ballroom dancers. AB - OBJECTIVE: To investigate the etiology of a loss-of-control neck injury in international modern (IM) dancesport dancers. A comparison to identify if dancers with neck injury have a greater decrease in median frequency in electromyography (EMG) than non-injured dancers. SUBJECTS: Twenty female subjects (mean age 21.6 +/- 3.0 yrs, height 167.1 +/- 4.3 cm, weight 59.1 +/- 5.2 kg, mean BMI 21.1 +/- 1.2) with minimum 1-year experience in competitive IM dancesport. measurements: EMG activity from the left upper trapezius, left splenius capitius, and right sternocleidomastoid muscles before and after dancing the five IM dances. Extension, lateral flexion, and neck length were also measured. RESULTS: There was no significant difference in all measurements. CONCLUSIONS: Although we did not find the etiology of this neck injury, this was the first research into this injury. Future research could study the different IM dances, compare different competition levels, or the amount of force placed on the neck when dancing. PMID- 23752283 TI - Prevalence of musculoskeletal disorders in professional symphony orchestra musicians in Greece: a pilot study concerning age, gender, and instrument specific results. AB - This study was designed to investigate the frequency of musculoskeletal disorders among musicians in a professional-level symphony orchestra in Greece. The sample consisted of 147 musicians (97 men, 50 women) of the Athens and Thessaloniki State Symphony Orchestra. The mean age of the musicians was 38.97 years (range 24 to 67, SD 9.68), while the years of experience in the orchestra ranged from 1 to 35 (mean 14.2, SD 8.47). The data were collected with the Standardized Nordic Questionnaire, which records the frequency of musculoskeletal disorders. Our results showed a very high percentage (81.6%) of the musicians had suffered at least once, during their professional career, some kind of musculoskeletal disorder that was associated with pain or discomfort and was directly related to their profession. More than two-thirds of the musicians had also suffered a problem in the hand and neck areas during the last 12 months. Musculoskeletal disorders appeared to be related to gender, age, kind of instrument played, and duration of rehearsing/performing, along with previous experience. In summary, there is a high frequency of injury among professional-level musicians in Greece reported in our study, highlighting the obvious need to develop prevention programs. PMID- 23752284 TI - Prevalence of musculoskeletal disorders among instrumental musicians at a center for performing arts in South Africa. AB - The prevalence of playing-related musculoskeletal disorders (PRMD) is high in various countries of the world, but there is a paucity of literature in Africa. The aim of this study was to determine the prevalence of PRMDs among instrumentalists in South Africa, with specific objectives in determining the distribution, symptoms, and pain severity. The self-administered Nordic Musculoskeletal Questionnaire was used to collect information from the participants regarding the lifetime and current prevalence and the distribution of PRMD symptoms. A visual analog scale was used to collect information on the severity of pain, while the questionnaire designed by Blackie, Stone, and Tiernan (1999) was used to collect information on the symptoms of the PRMDs. Twenty participants took part in this study, and the respondents reported a lifetime prevalence (over a period of 12 months) of PRMDs as 14 out of 17 and the current prevalence (in the last 7 days) as 4. Pain severity was mostly mild, and the most affected region was in the upper extremities, with the shoulders being the most affected. Tightening and soreness were the most reported symptom of PRMDs. The prevalence of PRMDs among this population was high, although severity was mild, with the upper extremities being the most affected area. PMID- 23752285 TI - Strategies to promote health and prevent musculoskeletal injuries in students from the high conservatory of music of Salamanca, Spain. AB - OBJECTIVES: The present investigation was intended to evaluate the effectiveness of a course on health and the prevention of musculoskeletal injuries in future professional musicians, specifically designed for superior-grade students at the High Conservatory of Music of Salamanca, Spain. METHODS: Students were taught how to evaluate the possible risks associated with the practice of their instruments. They were provided with information about the most frequent medical problems of musicians, warm-up habits, postural hygiene, effective prevention strategies, and different treatment options for these pathologies. The students were randomly divided into two groups: a control group (n=56) who did not take the course and was evaluated with a questionnaire at the beginning of the academic year and 1 year later, and an experimental group (n=90) who did take the course and was evaluated with three questionnaires (at the beginning of the course, 6 months later, and 12 months after the start of the course). RESULTS: While the students in the experimental group improved their body awareness by 91% and the frequency of their injuries decreased by 78%, there was no improvement in the students from the control group at the end of the experiment. CONCLUSIONS: The results of our study have demonstrated the effectiveness of this type of course and show that such courses should be included in the academic curriculum of superior conservatories. PMID- 23752286 TI - Playing-related musculoskeletal disorders among Indian tabla players. AB - Playing a percussion instrument demands great force and effort, which may make percussionists prone to playing-related musculoskeletal disorders (PRMDs). Of all of the percussion instruments in India, tabla is the most popular. The present study was undertaken to investigate the prevalence of discomforts among professional tabla players. Eighty-five professional tabla players voluntarily participated in the study. The Nordic Musculoskeletal Questionnaire and visual analog scale were administered to all the participants. Demographic details, music-related activities, and symptoms of discomfort were also recorded. It was found that prone anatomical areas were the low back, right shoulder, neck, left shoulder, upper back, and knees. The frequency of discomfort was found to be mostly weekly for the shoulders and monthly for neck, low back, and knees. There was an association between visual analog scale and prevalence of self-reported discomforts in some body parts. It can be said that the prolonged, unsupported, folded-knee sitting posture may be the cause of discomforts. PMID- 23752287 TI - Piano technique. PMID- 23752288 TI - Prevention of scar spread on trunk excisions: a rater-blinded randomized controlled trial. AB - IMPORTANCE: Wounds that heal under tension lead to wider and more conspicuous scars and result in decreased long-term patient satisfaction. We hypothesized that prolonged intradermal suture lifetime can decrease scar spread in wounds under tension. OBJECTIVE: To determine whether prolonged intradermal support would help decrease scar spread. DESIGN Prospective, randomized, controlled, rater-blinded, split-scar trial. SETTING: Outpatient dermatology clinic at Dallas Veterans Affairs Hospital, Dallas, Texas. PATIENTS: Patients presenting with skin cancer on the trunk were considered for the trial. We included 25 distinct surgical sites on a total of 22 patients. INTERVENTION: After excision, the wounds were closed with polyglactin 910 and poly-4 hydroxybutyrate (P4HB) sutures in opposite halves of the same wound. MAIN OUTCOME MEASURES: Quantitative scar spread at 12 months and qualitative assessment using a visual analog scale and Hollander Wound Evaluation Scale. RESULTS: We found a statistically significant difference in scar width between the 2 suture materials, with a mean difference of 2.3 (95% CI, 1.0-3.6) mm (P < .001) favoring P4HB. A clinically significant difference on the visual analog and Hollander Wound Evaluation scales was not identified. Suture reactions were more common with P4HB. CONCLUSIONS AND RELEVANCE: Prolonged intradermal suture support leads to significantly decreased scar spread. However, the use of a longer-acting absorbable suture increases the rate of suture reaction noted at 3 months. Further studies into less reactive, longer-acting biomaterials are needed. In clinical practice, excisions in high tension areas that are classically known to spread over time can benefit from longer-acting intradermal sutures. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00938691. PMID- 23752289 TI - Dysphagia and quality of life. AB - Swallowing difficulties can be a symptom of many different disease processes, and are associated with adverse health outcomes; malnutrition, dehydration, pneumonia and death. The use of feeding tubes directly into the stomach as in percutaneous endoscopic gastrosomy (PEG) is an increasingly common treatment option for these patients with more and more being cared for in the community. Living with a gastrostomy tube brings physical and emotional impacts and direct consequences for quality of life. Guidance from the Royal College of Physicians recommends 'nil by mouth' should be a last resort even when swallow function is deemed unsafe. Impaired swallowing can cause increased anxiety and fear. Many patients avoid oral intake leading to malnutrition, isolation and depression. Understanding and balancing the risks and potential benefits of continuing oral intake or choosing gastrostomy makes this a complex and challenging area of health care. PMID- 23752290 TI - Improving nutrition and care for people with dementia. AB - As the number of people diagnosed with dementia rises, care services are facing a significant increase in people accessing services, be it community, hospital or long-term residential care. Maintaining wellbeing is an essential aspect of quality of life, and appropriate nutrition and hydration are essential to wellbeing. Care staff require knowledge and understanding of dementia, the impact dementia has on the individual and the challenges and issues it presents for formal and informal carers. The National Dementia Strategy and the Prime Minister's Challenge have placed emphasis on improved quality of care and education on dementia for care professionals. Nutrition is a constant need to be met, especially as the illness progresses and the person may require considerable support to meet this need. Physiological changes through the journey of the illness present many challenges and considerations, especially towards end of life. This article aims to raise awareness of dementia, diagnosis and issues faced on meeting the nutritional needs of people with dementia. PMID- 23752291 TI - Acute stroke, dysphagia and nutritional support. AB - Annually, an estimated 152000 people in the UK have a stroke, accounting for 11% of all deaths in England and Wales, but for those that survive, nutrition is key to the body's recovery. Consequences of malnutrition can include increased susceptibility to infection, delayed healing, impaired cardiovascular function, decreased muscle strength and depression. Given the complex nature of post-stroke dysphagia, it may not be possible that simple screening tools sufficiently identify those at risk of aspiration. If a patient is deemed unsafe or unable to meet their nutrition and hydration needs orally, guidelines recommend they should be considered for nasogastric feeding within 24 hours and a referral for dietetic/nutrition team input should be made accordingly. Speech and language therapists can predict early in a patient's journey whether or not prolonged dysphagia is likely. In turn, the need for long term artificial feeding can then also be anticipated. PMID- 23752294 TI - Compassionate care: at what cost? PMID- 23752292 TI - Interview with Janine Roberts by Rekha Elaswarapu. PMID- 23752295 TI - Tackling malnutrition in hospitals and nursing homes. PMID- 23752296 TI - Gastrostomy site infections: dealing with a common problem. AB - The most popular method of providing appropriate nutrition for large numbers of patients with swallowing difficulties is enteral feeding. However this treatment is not without complications, one of which is localized gastrostomy site infection. This is prevented initially by decolonisation of the oropharyngeal tract with antibiotic prophylaxis prior to insertion, and systemic antibiotics post insertion. Later complications include tracking infection, which is rare but can occur. Hypergranulation of the tissue can occur around the gastrostomy tube and this can become colonised or infected leading to further problems for the patient. A good gastrostomy site care pathway plan is required to maintain a healthy site and appropriate treatment required to minimize the infection risk. PMID- 23752297 TI - Unilateral facial ulceration-diagnosis. PMID- 23752298 TI - Specialized housing and transportation needs of adults with multiple sclerosis. AB - This study evaluated the specialized housing, transportation, and resource needs and barriers of adults with MS. Information pertaining to barriers and barrier removal strategies related to housing and transportation issues for adults with MS was gathered as part of a national survey of a randomly selected and representative sample of 5082 adults with MS, in cooperation with affiliate chapters of the National Multiple Sclerosis Society (NMSS) and the North American Research Committee on Multiple Sclerosis (NARCOMS). This article presents a qualitative analysis of participants' responses to questions addressing: (a) barriers to obtaining specialized housing and adapted transportation for individuals with MS, (b) factors contributing to maintenance of an independent lifestyle, and (c) information and referral resources pertinent to obtaining specialized housing and adapted transportation. The results provide the first assessment of these issues on a national scale and underscore the need for increased access to professional consultation, financial resources, and housing modification information and resources to enable persons with MS to obtain the specialized housing needed to maintain maximal independent lifestyles. PMID- 23752300 TI - This month in archives of dermatology. PMID- 23752299 TI - Influence of allowable interruption period on estimates of accelerometer wear time and sedentary time in older adults. AB - The criteria one uses to reduce accelerometer data can profoundly influence the interpretation of research outcomes. The purpose of this study was to examine the influence of 3 different interruption periods (i.e., 20, 30, and 60 min) on the amount of data retained for analyses and estimates of sedentary time among older adults. Older adults (N = 311, M age = 71.1) wore an accelerometer for 7 d and reported wear time on an accelerometer log. Accelerometer data were downloaded and scored using 20-, 30-, and 60-min interruption periods. Estimates of wear time, derived using each interruption period, were compared with self-reported wear time, and descriptive statistics were used to compare estimates of sedentary time. Results showed a longer interruption period (i.e., 60 min) yields the largest sample size and the closest approximation of self-reported wear time. A short interruption period (i.e., 20 min) is likely to underestimate sedentary time among older adults. PMID- 23752301 TI - Morbus europaeus: europeans naming syphilis for their enemies. PMID- 23752302 TI - Tracking the structural changes in pure and heteroatom substituted aluminophosphate, AIPO-18, using synchrotron based X-ray diffraction techniques. AB - We report the structural changes that occur during the thermal removal of organic template molecules that occlude the pores of small pore nanoporous zeolitic solids, AlPO-18, SAPO-18, CoAlPO-18, ZnAlPO-18 and CoSAPO-18. The calcination process is a necessary step in the formation of active catalysts. The studies performed using time-resolved High Resolution Powder Diffraction (HRPD) and High Energy X-ray Diffraction (HEXRD) techniques at various temperatures reveal that changes that take place are dependent on the type of heteroatom present in the nanoporous solids. While time-resolved HRPD shows clear changes in lattice parameters during the removal of physisorbed water molecules and subsequent removal of the organic template, HEXRD data show changes in various near neighbour distances in AlPO-18, SAPO-18, CoAlPO-18, CoSAPO-18 and ZnAlPO-18 during the calcination process. In particular HEXRD reveals the presence of water molecules coordinated to Al(III) ions in the as-synthesised materials. Upon removal of the template and water, these solids show contraction in the cell volume at elevated temperatures while first and second neighbour distances remained almost unchanged. PMID- 23752303 TI - Too sweet to be real?-Reply. PMID- 23752304 TI - Schistosoma antigens downmodulate the in vitro inflammatory response in individuals infected with human T cell lymphotropic virus type 1. AB - Human T cell lymphotropic virus type 1 (HTLV-1) is the causal agent of HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). While the immune response to HTLV-1 infection is polarized to the Th1-type, chronic helminth infections drive the Th2- and T regulatory-type, and are able to downregulate the inflammatory response in some autoimmune diseases. OBJECTIVE: To evaluate whether Schistosoma spp. antigens alter the in vitro cytokine response in HTLV-1 infection. METHODS: The recombinant Schistosoma antigens Sm29 and ShTSP2 (tetraspanin) and PIII, a fraction of the Schistosoma mansoni adult worm antigen were added to peripheral blood mononuclear cell (PBMC) cultures of HTLV-1 infected individuals and the levels of interferon (IFN)-gamma and interleukin (IL)-10 in the supernatants were measured using the ELISA sandwich technique. RESULTS: Compared to the levels of cytokine in nonstimulated cultures, the levels of IFN-gamma were reduced in 50, 47 and 50% of patients by the presence of Sm29, ShTsp2 and PIII, respectively. The downregulation of IFN-gamma production in the presence of Sm29 antigen was observed mainly in subjects who had lower basal levels of this cytokine. The levels of IL-10, however, increased by the addition of the three antigens in the cultures in 74, 62 and 44% of individuals, respectively. In addition, there was a decrease in the ratio of IFN-gamma/IL-10 levels in cultures stimulated with Sm29 and ShTSP2 when compared to nonstimulated ones. CONCLUSIONS: The Schistosoma spp. antigens used in this study were able to downmodulate IFN-gamma production in vitro in HTLV-1 infection. This may be associated with the increased levels of IL-10 induced by the antigens. PMID- 23752305 TI - Prospective assessment of lymphedema incidence and lymphedema-associated symptoms following lymph node surgery for melanoma. AB - We aimed to prospectively assess limb volume change (LVC) and associated symptoms in patients with melanoma undergoing sentinel lymph node biopsy and/or therapeutic lymph node dissection. Limb volume was measured preoperatively and postoperatively at 6 and 12 months using a perometer (1000 mol/l). LVC was calculated and used to define three groups: less than 5%, 5-10%, and greater than 10%. A 19-item lymphedema symptom questionnaire was administered at baseline, 6, and 12 months. One hundred and eighty-two patients were enrolled. Twelve months after axillary surgery, 9% had LVC 5-10% and 13% had LVC greater than 10%. Twelve months after inguinofemoral surgery, 10% had LVC 5-10% and 13% had LVC greater than 10%. There was a significant seven- to nine-fold increase in symptoms for patients with LVC greater than 10% compared with those with LVC less than 5% (P<0.05). On multivariate analysis, therapeutic lymph node dissection versus sentinel lymph node biopsy (odds ratio=3.18; P<0.01) and borderline significance for lower-extremity versus upper-extremity procedures (odds ratio=1.72; P=0.07) were associated with LVC greater than 5%. LVC greater than 5% is common at 12 months following nodal surgery for melanoma and is associated with symptoms. Informed consent for melanoma patients undergoing lymph node surgery should include a discussion of the risks of postoperative lymphedema. PMID- 23752307 TI - A role for opioids in chronic pain management-reply. PMID- 23752306 TI - The in-vitro spheroid culture induces a more highly differentiated but tumorigenic population from melanoma cell lines. AB - Cancer stem cells (CSCs) have been identified in various malignancies, and different properties have been examined to characterize CSCs: tumorigenicity in immunocompromised mice, stem cell surface markers, label-retaining properties, and proliferation as nonadherent spheres. This study explored the consistency and efficiency among these methods. Among the melanoma cell lines examined (A375, A875, MUM-2b, and MUM-2c), only A375 and MUM-2c grew as nonadherent spheres and continuously propagated in a defined serum-free medium in vitro. Flow cytometry and immunofluorescence analysis indicated that sphere-derived cells contained a smaller proportion of cells expressing the candidate surface markers of melanoma stem cells such as ABCB5, CD133, CD20 and CD271, and a larger proportion of cells expressing melanocytic differentiation markers such as HMB45 and S100 protein, compared with adherent cells. Surprisingly, the more highly differentiated sphere derived melanoma cells exhibited increased tumorigenic potential in vivo, as indicated by shorter tumor incubation (A375) and smaller number of cells required to initiate tumor formation (A375 and MUM-2c) compared with those of parental cells. Despite the similarity in histopathological characteristics, the expression profile indicated that xenografts derived from sphere-derived melanoma cells exhibited a more tumorigenic phenotype with respect to the stem or the differentiation markers detected by immunohistochemical analysis. Therefore, sphere formation in nonadherent cultures may not be a preferred surrogate in vitro method for enriching melanoma stem cells according to candidate markers but may be a favorable condition for activating potential CSCs. PMID- 23752308 TI - Systemic delivery of fusogenic membrane glycoprotein-expressing neural stem cells to selectively kill tumor cells. AB - Intravenously injected neural stem cells (NSCs) can infiltrate both primary and metastatic tumor sites; thus, they are attractive tumor-targeting vehicles for delivering anticancer agents. However, because the systemic distribution of the injected NSCs involves normal organs and might induce off-target actions leading to unintended side effects, clinical applications of this approach is impeded. Given that the vesicular stomatitis virus glycoprotein (VSV-G) can promote the formation of multinucleated syncytia to kill cells in a pH-dependent manner, we engineered a pH sensor of VSV-G and generated a novel VSV-G mutant that efficiently promotes syncytium formation at the tumor extracellular pH (pHe) but not at pH 7.4. Using transduced NSCs derived from induced pluripotent stem cells (iPSCs), the VSV-G mutant was delivered into mice with metastatic breast cancers in the lung through tail vein injection. Compared with the conventional stem cell based gene therapy that uses the herpes simplex virus thymidine kinase (HSVtk) suicide gene, this treatment did not display toxicity to normal non-targeted organs while retaining therapeutic effects in tumor-bearing organs. Our findings demonstrate the effectiveness of a new approach for achieving tumor-selective killing effects following systemic stem cell administration. Its potential in stem cell-based gene therapy for metastatic cancer is worthy of further exploration. PMID- 23752309 TI - NADH-dehydrogenase type-2 suppresses irreversible visual loss and neurodegeneration in the EAE animal model of MS. AB - To address mitochondrial dysfunction that mediates irreversible visual loss and neurodegeneration of the optic nerve in the experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis (MS), mice sensitized for EAE were vitreally injected with self-complementary adenoassociated virus (scAAV) containing the NADH-dehydrogenase type-2 (NDI1) complex I gene that quickly expressed in mitochondria of almost all retinal ganglion cells (RGCs). Visual function assessed by pattern electroretinograms (PERGs) reduced by half in EAE showed no significant reductions with NDI1. Serial optical coherence tomography (OCT) revealed significant inner retinal thinning with EAE that was suppressed by NDI1. Although complex I activity reduced 80% in EAE was not improved by NDI1, in vivo fluorescent probes indicated mitochondrial oxidative stress and apoptosis of the EAE retina were reduced by NDI1. Finally, the 42% loss of axons in the EAE optic nerve was ameliorated by NDI1. Targeting the dysfunctional complex I of EAE responsible for loss of respiration, mitochondrial oxidative stress and apoptosis may be a novel approach to address neuronal and axonal loss responsible for permanent disability that is unaltered by current disease modifying drugs for MS that target inflammation. PMID- 23752310 TI - Kinetics and epigenetics of retroviral silencing in mouse embryonic stem cells defined by deletion of the D4Z4 element. AB - Retroviral vectors are silenced in embryonic stem (ES) cells by epigenetic mechanisms whose kinetics are poorly understood. We show here that a 3'D4Z4 insulator directs retroviral expression with persistent but variable expression for up to 5 months. Combining an internal 3'D4Z4 with HS4 insulators in the long terminal repeats (LTRs) shows that these elements cooperate, and defines the first retroviral vector that fully escapes long-term silencing. Using FLP recombinase to induce deletion of 3'D4Z4 from the provirus in ES cell clones, we established retroviral silencing at many but not all integration sites. This finding shows that 3'D4Z4 does not target retrovirus integration into favorable epigenomic domains but rather protects the transgene from silencing. Chromatin analyses demonstrate that 3'D4Z4 blocks the spread of heterochromatin marks including DNA methylation and repressive histone modifications such as H3K9 methylation. In addition, our deletion system reveals three distinct kinetic classes of silencing (rapid, gradual or not silenced), in which multiple epigenetic pathways participate in silencing at different integration sites. We conclude that vectors with both 3'D4Z4 and HS4 insulator elements fully block silencing, and may have unprecedented utility for gene transfer applications that require long-term gene expression in pluripotent stem (PS) cells. PMID- 23752311 TI - Meganuclease-mediated virus self-cleavage facilitates tumor-specific virus replication. AB - Meganucleases can specifically cleave long DNA sequence motifs, a feature that makes them an ideal tool for gene engineering in living cells. In a proof-of concept study, we investigated the use of the meganuclease I-Sce I for targeted virus self-disruption to generate high-specific oncolytic viruses. For this purpose, we provided oncolytic adenoviruses with a molecular circuit that selectively responds to p53 activation by expression of I-Sce I subsequently leading to self-disruption of the viral DNA via heterologous I-Sce I recognition sites within the virus genome. We observed that virus replication and cell lysis was effectively impaired in p53-normal cells, but not in p53-dysfunctional tumor cells. I-Sce I activity led to effective intracellular processing of viral DNA as confirmed by detection of specific cleavage products. Virus disruption did not interfere with E1A levels indicating that reduction of functional virus genomes was the predominant cause for conditional replication. Consequently, tumor specific replication was further enhanced when E1A expression was additionally inhibited by targeted transcriptional repression. Finally, we demonstrated p53 dependent oncolysis by I-Sce I-expressing viruses in vitro and in vivo, and demonstrated effective inhibition of tumor growth. In summary, meganuclease mediated virus cleavage represents a promising approach to provide oncolytic viruses with attractive safety profiles. PMID- 23752312 TI - Managing microRNAs with vector-encoded decoy-type inhibitors. AB - A rapidly growing understanding of the complex circuitry of microRNA (miRNA) mediated gene regulation is attracting attention to miRNAs as new drug targets. Targeted miRNA suppression is achieved in a sequence-specific manner by antisense RNA "decoy" molecules. Such synthetic miRNA inhibitors have reached the clinic with remarkable pace and may soon appear as new therapeutic modalities in several diseases. Shortcomings, however, include high production costs, the requirement for repeated administration, and difficulty achieving tissue-specific delivery. With the many recent landmark achievements in clinical gene therapy, new and refined vector-encoded miRNA suppression technologies are attractive for many applications, not least as tools in innumerable daily studies of miRNA biology in laboratories worldwide. Here, we provide an overview of the strategies that have been used to adapt vector-encoded inhibitors for miRNA suppression and discuss advantages related to spatiotemporal and long-term miRNA attenuation. With the remarkable new discovery of miRNA management by naturally occurring circular RNAs, RNA circles generated by trans-splicing mechanisms may prove to be well suited carriers of decoy-type miRNA inhibitors. The community will aspire to combine circles with high-affinity miRNA decoy methodologies, and such "vectorized" RNA circles may represent new solid ways to deliver miRNA inhibitors, perhaps even with therapeutic applications. PMID- 23752313 TI - AAV genome loss from dystrophic mouse muscles during AAV-U7 snRNA-mediated exon skipping therapy. AB - In the context of future adeno-associated viral (AAV)-based clinical trials for Duchenne myopathy, AAV genome fate in dystrophic muscles is of importance considering the viral capsid immunogenicity that prohibits recurring treatments. We showed that AAV genomes encoding non-therapeutic U7 were lost from mdx dystrophic muscles within 3 weeks after intramuscular injection. In contrast, AAV genomes encoding U7ex23 restoring expression of a slightly shortened dystrophin were maintained endorsing that the arrest of the dystrophic process is crucial for maintaining viral genomes in transduced fibers. Indeed, muscles treated with low doses of AAV-U7ex23, resulting in sub-optimal exon skipping, displayed much lower titers of viral genomes, showing that sub-optimal dystrophin restoration does not prevent AAV genome loss. We also followed therapeutic viral genomes in severe dystrophic dKO mice over time after systemic treatment with scAAV9-U7ex23. Dystrophin restoration decreased significantly between 3 and 12 months in various skeletal muscles, which was correlated with important viral genome loss, except in the heart. Altogether, these data show that the success of future AAV-U7 therapy for Duchenne patients would require optimal doses of AAV-U7 to induce substantial levels of dystrophin to stabilize the treated fibers and maintain the long lasting effect of the treatment. PMID- 23752314 TI - Therapeutic DNA vaccination using in vivo electroporation followed by standard of care therapy in patients with genotype 1 chronic hepatitis C. AB - Clearance of infections caused by the hepatitis C virus (HCV) correlates with HCV specific T cell function. We therefore evaluated therapeutic vaccination in 12 patients with chronic HCV infection. Eight patients also underwent a subsequent standard-of-care (SOC) therapy with pegylated interferon (IFN) and ribavirin. The phase I/IIa clinical trial was performed in treatment naive HCV genotype 1 patients, receiving four monthly vaccinations in the deltoid muscles with 167, 500, or 1,500 MUg codon-optimized HCV nonstructural (NS) 3/4A-expressing DNA vaccine delivered by in vivo electroporation (EP). Enrollment was done with 2 weeks interval between patients for safety reasons. Treatment was safe and well tolerated. The vaccinations significantly improved IFN-gamma-producing responses to HCV NS3 during the first 6 weeks of therapy. Five patients experienced 2-10 weeks 0.6-2.4 log10 reduction in serum HCV RNA. Six out of eight patients starting SOC therapy within 1-30 months after the last vaccine dose were cured. This first-in-man therapeutic HCV DNA vaccine study with the vaccine delivered by in vivo EP shows transient effects in patients with chronic HCV genotype 1 infection. The interesting result noted after SOC therapy suggests that therapeutic vaccination can be explored in a combination with SOC treatment. PMID- 23752315 TI - Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis. AB - Food-derived exosome-like nanoparticles pass through the intestinal tract throughout our lives, but little is known about their impact or function. Here, as a proof of concept, we show that the cells targeted by grape exosome-like nanoparticles (GELNs) are intestinal stem cells whose responses underlie the GELN mediated intestinal tissue remodeling and protection against dextran sulfate sodium (DSS)-induced colitis. This finding is further supported by the fact that coculturing of crypt or sorted Lgr5+ stem cells with GELNs markedly improved organoid formation. GELN lipids play a role in induction of Lgr5+ stem cells, and the liposome-like nanoparticles (LLNs) assembled with lipids from GELNs are required for in vivo targeting of intestinal stem cells. Blocking beta-catenin mediated signaling pathways of GELN recipient cells attenuates the production of Lgr5+ stem cells. Thus, GELNs not only modulate intestinal tissue renewal processes, but can participate in the remodeling of it in response to pathological triggers. PMID- 23752316 TI - Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse. AB - Aggressive regrowth of recurrent tumors following treatment-induced dormancy represents a major clinical challenge for treatment of malignant disease. We reported previously that recurrent prostate tumors, which underwent complete macroscopic regression followed by aggressive regrowth, could be cured with a vesicular stomatitis virus (VSV)-expressed cDNA library derived from recurrent tumor cells. By screening the protective, recurrence-derived VSV-cDNA library, here we identify topoisomerase-IIalpha (TOPO-IIalpha) as a recurrence-specific tumor antigen against which tolerance can be broken. Tumor recurrences, in two different types of tumor (prostate and melanoma), which had evaded two different frontline treatments (immunotherapy or chemotherapy), significantly overexpressed TOPO-IIalpha compared with their primary tumor counterparts, which conferred a novel sensitivity to doxorubicin (DOX) chemotherapy upon the recurrent tumors. This was exploited in vivo using combination therapies to cure mice, which would otherwise have relapsed, after suboptimal primary therapy in both models. Our data show that recurrent tumors-across histologies and primary treatments-express distinct antigens compared with the primary tumor which can be identified using the VSV-cDNA library technology. These results suggest that it may be possible to design a few common second-line therapies against a variety of tumor recurrences, in some cases using agents with no obvious activity against the primary tumor. PMID- 23752317 TI - Chiral plasmonics of self-assembled nanorod dimers. AB - Chiral nanoscale photonic systems typically follow either tetrahedral or helical geometries that require four or more different constituent nanoparticles. Smaller number of particles and different chiral geometries taking advantage of the self organization capabilities of nanomaterials will advance understanding of chiral plasmonic effects, facilitate development of their theory, and stimulate practical applications of chiroplasmonics. Here we show that gold nanorods self assemble into side-by-side orientated pairs and "ladders" in which chiral properties originate from the small dihedral angle between them. Spontaneous twisting of one nanorod versus the other one breaks the centrosymmetric nature of the parallel assemblies. Two possible enantiomeric conformations with positive and negative dihedral angles were obtained with different assembly triggers. The chiral nature of the angled nanorod pairs was confirmed by 4pi full space simulations and the first example of single-particle CD spectroscopy. Self assembled nanorod pairs and "ladders" enable the development of chiral metamaterials, (bio)sensors, and new catalytic processes. PMID- 23752319 TI - eHealth: is it the panacea? PMID- 23752318 TI - Critical care in patients undergoing lumbar spine fusion: a population-based study. AB - BACKGROUND: Data on the utilization of critical care services (CCSs) among patients who underwent spine fusion are rare. Given the increasing popularity of this procedure, information regarding demographics and risk factors for the use of these advanced services is needed in order to appropriately allocate resources, educate clinical staff, and identify targets for future research. METHODS: We analyzed hospital discharge data of patients who underwent lumbar spine fusion in approximately 400 US hospitals between 2006 and 2010. Patient, procedure, and health care system-related demographics for those requiring CCS were compared to those who did not. Outcomes such as mortality, complications, disposition status, and hospital charges were compared among groups and risk factors for the utilization of CCS identified. RESULTS: A total of 95 434 entries of patients who underwent posterior lumbar spine fusion surgery between 2006 and 2010 were identified. Approximately 10% of the patients required CCS. On average, patients requiring CCS were older and had a higher comorbidity burden, developed more complications, had longer hospital stays and higher costs, and were less likely to be discharged home compared to non-CCS patients. Risk factors with increased odds for requiring CCS included advanced age, increasing comorbidity burden, increasing surgical invasiveness, and presence of postoperative complications, especially pulmonary. CONCLUSIONS: Approximately, 10% of the patients undergoing lumbar spine surgery require CCS. Utilizing the present data, critical care physicians and administrators can identify patients at risk, educate clinical staff, identify targets for intervention, and allocate resources to meet the needs of this particular patient population. PMID- 23752320 TI - Enhanced recovery, stomas and the community nurse. AB - Enhanced recovery after surgery (ERAS) is gaining interest worldwide, to improve patient care in relation to their surgery. ERAS is a set of elements that are used to guide the multidisciplinary team in caring for patients before, during and after surgery. This ERAS care challenges traditional care, but it is research based and has been shown in many settings to be effective. There are no specific recommendations for post-discharge care in the remit of the community nurse, but this is extracted from the published literature and personal experience of enhanced recovery. This article will explore issues related to ERAS and how this may affect the community nurse. Issues surrounding stoma care will be explored, including how the community nurse can aid the care of this patient group. PMID- 23752321 TI - Technology, health and the home: eHealth and the community nurse. AB - Twenty-first century methods of communication are changing. Technology and the way it is used has the potential to revolutionise health care. In the same way information technology (IT) has had a massive impact on commerce and industry, it is also having a substantial impact on the practice of community nurses and the ways in which care is delivered. In order for the impact of IT to be a positive one, community nurses and other health professionals will have to learn and develop a range of new skills. Nurses can and should be directing and becoming involved in the ways in which the IT revolution unfolds. Nurses working with systems development teams also need to make known their needs making clear what information the various IT systems have to contain and how these will fit in with their nursing practice. PMID- 23752322 TI - Group reminiscence therapy for adults with dementia: a review. AB - Dementia is an increasingly prevalent and costly condition in the UK. This review aims to explore the potential effectiveness of reminiscence group therapy as a non-pharmacological tool for reducing depressive symptoms commonly associated with dementia. The aim of this review is to explore existing literature regarding adults diagnosed with dementia, who are experiencing depressive symptoms, and the effect of reminiscence group therapy on their experience. A limited systematic search of four databases and hand search of titles, abstracts and reference lists revealed scarce evidence. A total of four original research articles, which met the inclusion and exclusion criteria, were accepted for critical appraisal. The overall quality of the studies was poor and use of multiple data collection tools made comparison difficult. All studies obtained some significant findings in favour of the effect of reminiscence group therapy. The primary recommendation of this review is for further high-quality research. PMID- 23752323 TI - Preparing for a Nursing and Midwifery Council visit in the community setting. AB - Preparing for a Nursing and Midwifery Council placement monitoring visit can appear daunting if practitioners have not previously participated in the process. This paper identifies why visits are required and how practitioners and the local higher education provider representatives can work together to prepare. Based on the experience of the authors it is proposed that the visit is an opportunity to disseminate good practice linked to the education and mentorship of students. Suggestions linked to successful preparation are also shared to assist community nurse teams who encounter the process in the future. It is advocated that feedback from the visit can be used to further strengthen the practice learning experience for both mentors and students. PMID- 23752324 TI - British Journal of Nursing Awards showcases excellence in community nursing. PMID- 23752325 TI - Assessing decision-making capacity: lessons from the Court of Protection. AB - There have now been several cases where the Court of Protection has been critical of the approach to the assessment of decision-making capacity adopted by health and social care professionals. There is concern that the rights of the frail and vulnerable to make unwise decisions about their health and residence are not being respected and that there is a return to the paternalistic, 'professional knows best' approach to care and treatment. In this article, Richard Griffith and Cassam Tengnah argue that community nurses can learn valuable lessons from recent cases in the Court of Protection that can be applied in practice when they are required to assess decision-making capacity. PMID- 23752326 TI - Reforming the NHS: an opportunity for palliative care in the community? PMID- 23752327 TI - Coordination in end-of-life care. PMID- 23752328 TI - High performance optical sensing nanocomposites for low and ultra-low oxygen concentrations using phase-shift measurements. AB - The accurate and real-time measurement of low and ultra-low concentrations of oxygen using non-invasive methods is a necessity for a multitude of applications, from brewing beer to developing encapsulating barriers for optoelectronic devices. Current optical methods and sensing materials often lack the necessary sensitivity, signal intensity, or stability for practical applications. In this report we present a new optical sensing nanocomposite resulting in an outstanding overall performance when combined with the phase-shift measurement method (determination of luminescence lifetime in the frequency domain). For the first time we have incorporated the standard PtTFPP dye (PtTFPP = platinum(II) 5,10,15,20-meso-tetrakis-(2,3,4,5,6-pentafluorophenyl)-porphyrin) into AP200/19, a nanostructured aluminium oxide-hydroxide solid support. This sensing film shows an excellent sensitivity between 0 and 1% O2 (KSV = 3102 +/- 132 bar-1) and between 0 and 10% O2 (KSV = 2568 +/- 614 bar-1) as well as Deltatau0.05% (62.53 +/- 3.66%), which makes it 62 times more sensitive than PtTFPP immobilized in polystyrene and also 8 times more sensitive than PtTFPP immobilized on silica beads. Furthermore the phase-shift measurement method results in a significant improvement (about 23 times) in stability compared to the use of intensity recording methods. The film also displays full reversibility, long shelf stability (no change observed after 12 months), and it is not affected by humidity. To establish this sensing methodology and develop sensors over the full range of the visible light, we also studied three other dye-AP200/19 nanocomposites based on phosphorescent cyclometalated iridium(III) complexes. PMID- 23752329 TI - Synthesis of pentadecaphenylenes, their inclusion properties, and nanostructure formation with C60. AB - Synthesis of macrocyclic pentadecaphenylene was carried out via electron-transfer oxidation of the corresponding Lipshutz cuprate. Pentadecaphenylene self aggregated in solution to form a gel. Furthermore, it incorporated C60 in its cavity to produce a fibrous inclusion complex which showed a high gelation ability in benzene. PMID- 23752330 TI - When can AQP4 assist transporter-mediated K+ uptake? PMID- 23752331 TI - Response to "When can AQP4 assist transporter-mediated K+ uptake?". PMID- 23752332 TI - Conformational changes in the catalytically inactive nucleotide-binding site of CFTR. AB - A central step in the gating of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel is the association of its two cytosolic nucleotide-binding domains (NBDs) into a head-to-tail dimer, with two nucleotides bound at the interface. Channel opening and closing, respectively, are coupled to formation and disruption of this tight NBD dimer. CFTR is an asymmetric adenosine triphosphate (ATP)-binding cassette protein in which the two interfacial-binding sites (composite sites 1 and 2) are functionally different. During gating, the canonical, catalytically active nucleotide-binding site (site 2) cycles between dimerized prehydrolytic (state O1), dimerized post-hydrolytic (state O2), and dissociated (state C) forms in a preferential C->O1->O2->C sequence. In contrast, the catalytically inactive nucleotide-binding site (site 1) is believed to remain associated, ATP-bound, for several gating cycles. Here, we have examined the possibility of conformational changes in site 1 during gating, by studying gating effects of perturbations in site 1. Previous work showed that channel closure is slowed, both under hydrolytic and nonhydrolytic conditions, by occupancy of site 1 by N(6)-(2-phenylethyl)-ATP (P-ATP) as well as by the site-1 mutation H1348A (NBD2 signature sequence). Here, we found that P-ATP prolongs wild-type (WT) CFTR burst durations by selectively slowing (>2*) transition O1->O2 and decreases the nonhydrolytic closing rate (transition O1->C) of CFTR mutants K1250A (~4*) and E1371S (~3*). Mutation H1348A also slowed (~3*) the O1->O2 transition in the WT background and decreased the nonhydrolytic closing rate of both K1250A (~3*) and E1371S (~3*) background mutants. Neither P-ATP nor the H1348A mutation affected the 1:1 stoichiometry between ATP occlusion and channel burst events characteristic to WT CFTR gating in ATP. The marked effect that different structural perturbations at site 1 have on both steps O1->C and O1->O2 suggests that the overall conformational changes that CFTR undergoes upon opening and coincident with hydrolysis at the active site 2 include significant structural rearrangement at site 1. PMID- 23752333 TI - Pearly penile papules: effective therapy with pulsed dye laser. AB - IMPORTANCE: Pearly penile papules (PPPs) are benign, dome-shaped lesions found around the corona of the penis. Treatments have varied in the past; however, to our knowledge, the use of the pulsed dye laser (PDL) for this condition has never been reported in the literature. Such papules are histologically analogous to angiofibromas; thus, we report PDL is an appropriate, effective, and nonablative method of treatment. OBSERVATIONS: Four patients diagnosed with PPPs were treated with PDL. Each patient reported little to no discomfort during the procedure. Minimal bruising was found in all 4 patients, which diminished over time. One patient stated slight discomfort after the procedure; this however, resolved in a weeks' time. Complete clearance of the papules was noted after 2 to 3 treatments in 2 patients and a reduction of the papules in 2 patients. CONCLUSIONS AND RELEVANCE: These 4 case reports illustrate the advantages of using PDL when treating PPP. In each patient, the appearance of the papules was either completely diminished or significantly reduced after the procedure. This result was achieved with only minimal discomfort felt by the patients. The use of PDL offers dermatologists a new treatment modality for PPPs that is safe, easily performed, and produces excellent aesthetic results. PMID- 23752334 TI - Synthesis of a novel cone-shaped CaAl-layered double hydroxide (LDH): its potential use as a reversible oil sorbent. AB - A novel cone-shaped superhydrophobic and oleophilic CaAl-LDH intercalated with dodecyl sulphate (DS(-)) anions was synthesized from calcium dodecyl sulphate as a precursor via a one-step hydrothermal method. The synthesized LDH has been successfully utilized in mopping and regeneration of oil from oil-water mixtures. PMID- 23752335 TI - Suprisingly close. PMID- 23752337 TI - Craniomaxillofacial buttresses: anatomy and repair. PMID- 23752338 TI - Morphological and functional measurements of the heart obtained by magnetic resonance imaging in Brazilians. AB - BACKGROUND: Still today, measurements used as a reference in the cardiac magnetic resonance imaging have been obtained mainly from studies carried out in North American and European populations. OBJECTIVE: To obtain measurements of the diastolic diameter, systolic diameter, end diastolic volume, end systolic volume, ejection fraction, and myocardial mass of the left and right ventricles in Brazilians. METHODS: 54 men and 53 women, with mean age of 43.4 +/- 13.1 years, asymptomatic, with no cardiomyopathies, have been subjected to the cardiac magnetic resonance imaging, using a balanced steady state free precession technique. RESULTS: The averages and the standard deviations of the parameters for the left ventricle have been: diastolic diameter = 4.8 +/- 0.5 cm; systolic diameter = 3.0 +/- 0.6 cm; end diastolic volume = 128.4 +/- 29.6 mL; end systolic volume = 45.2 +/- 16.6 mL; ejection fraction = 65.5 +/- 6.3%; mass = 95.2 +/- 30.8 g. For the right ventricle, they have been: diastolic diameter = 3.9 +/- 1.3 cm; systolic diameter = 2.5 +/- 0.5 cm; end diastolic volume = 126.5 +/- 30.7 mL; end systolic volume = 53.6 +/- 18.4 mL; ejection fraction = 58.3 +/- 8.0%, and mass = 26.1 +/- 6.1 g. The masses and the volumes were significantly greater in the men, except for the end systolic volume of the left ventricle. The ejection fraction of the right ventricle has been significantly greater in the women. There has been a significant and inverted correlation of the systolic volume of the right volume with the progression of the age. CONCLUSION: This study has described, for the first time, cardiac measurements obtained through the cardiac magnetic resonance imaging in Brazilians, asymptomatic, with no cardiomyopathies, showing differences in accordance with gender and age. PMID- 23752339 TI - Correlation between plaque composition as assessed by virtual histology and C reactive protein. AB - BACKGROUND: Previous studies have shown that coronary plaque composition plays a pivotal role in plaque instability, and imaging modalities and serum biomarkers have been investigated to identify vulnerable plaque. Virtual histology IVUS (VH IVUS) characterizes plaque components as calcified, fibrotic, fibrofatty, or necrotic core. C-reactive protein (hsCRP) is an independent risk factor and a powerful predictor of future coronary events. However, a relationship between inflammatory response indicated by CRP and plaque characteristics in ACS patients remains not well established. OBJECTIVE: To determine, by using VH-IVUS, the relation between coronary plaque components and plasma high-sensitivity CRP levels in patients with acute coronary syndromes (ACS). METHODS: 52 patients with ACS were enrolled in this prospective study. Electrocardiographically-gated VH IVUS were performed in the culprit lesion before PCI. Blood sample was drawn from all patients before the procedure and after 24 hours, and hs-CRP levels were determined. RESULTS: Mean age was 55.3+/-4.9 years, 76.9% were men and 30.9% had diabetes. Mean MLA was 3.9+/-1.3 mm2, and plaque burden was 69+/-11.3%, as assessed by IVUS. VH-IVUS analysis at the minimum luminal site identified plaque components: fibrotic (59.6+/-15.8%), fibrofatty (7.6+/-8.2%), dense calcium (12.1+/-9.2%) and necrotic core (20.7+/-12.7%). Plasma hs-CRP (mean 16.02+/-18.07 mg/L) did not correlate with necrotic core (r=-0.089, p = 0.53) and other plaque components. CONCLUSIONS: In this prospective study with patients with ACS, the predominant components of the culprit plaque were fibrotic and necrotic core. Serum hs C-reactive protein levels did not correlate with plaque composition. PMID- 23752340 TI - Comparison of diagnostic criteria for acute kidney injury in cardiac surgery. AB - BACKGROUND: There is considerable controversy regarding the diagnosis of Acute Kidney Injury (AKI), and there are over 30 different definitions. OBJECTIVE: To evaluate the incidence and risk factors for the development of AKI following cardiac surgery according to the RIFLE, AKIN and KDIGO criteria, and compare the prognostic power of these criteria. METHODS: Cross-sectional study that included 321 consecutively patients (median age 62 [53-71] years; 140 men) undergoing cardiac surgery between June 2011 and January 2012. The patients were followed for up to 30 days, for a composite outcome (mortality, need for dialysis and extended hospitalization). RESULTS: The incidence of AKI ranged from 15% - 51%, accordingly to the diagnostic criterion adopted. While age was associated with risk of AKI in the three criteria, there were variations in the remaining risk factors. During follow-up, 89 patients developed the outcome and all criteria were associated with increased risk in the univariate Cox analysis and after adjustment for age, gender, diabetes, and type of surgery. However, after further adjustment for extracorporeal circulation and the presence of low cardiac output, only AKI diagnosed by the KDIGO criterion maintained this significant association (HR= 1.89 [95% CI: 1.18 - 3.06]). CONCLUSION: The incidence and risk factors for AKI after cardiac surgery vary significantly according to the diagnostic criteria used. In our analysis, AKI the KDIGO criterion was superior to AKIN and RIFLE with regard its prognostic power. PMID- 23752341 TI - "Tailored" submaximal step test for VO2max prediction in healthy older adults. AB - The authors developed and validated a "tailored" version of the Astrand-Rhyming step test (tA-R) and a new equation for VO2max prediction in older adults (OA). Sixty subjects (age 68 +/- 4 yr, 30 male, 30 female) performed their tA-R step test (5-min, 30-cm step, tailored stepping rate) and an incremental cycling test to exhaustion. VO2max was (a) predicted using the standard A-R equation (predicted VO2max), (b) predicted based on the authors' new multiple linear equation (equation VO2max), and (c) directly measured by incremental cycling test (direct VO2max). Agreement among values of VO2max was evaluated by Bland-Altman analysis. The predicted VO2max was not significantly different from the direct VO2max, yet with relatively large imprecision. The equation VO2max allowed more precise as well as accurate predictions of VO2max compared with standard A-R prediction. The "tailored" version of the Astrand-Rhyming step test and the new prediction equation appear suitable for a rapid (5-min), safe (submaximal), accurate, and precise VO2max prediction in healthy OA. PMID- 23752343 TI - Individual dispersion of carbon nanotubes in epoxy via a novel dispersion-curing approach using ionic liquids. AB - The effective dispersion of carbon nanotubes (CNTs) in a thermoset was achieved using ionic liquid as the dispersion-curing agent. We preferentially dispersed multiwalled carbon nanotubes (MWCNTs) down to individual tube levels in epoxy resin. Here the dispersion is ruled by the depletion of physical bundles within the MWCNT networks, for which molecular ordering of ionic liquids is considered responsible. The quantitative analyses using ultra small angle X-ray scattering (USAXS) confirmed the dispersion of individual MWCNTs in the matrix. The distance between the dispersed nanotubes was calculated at different nanotube loadings using the power law fitting of the USAXS data. The fine dispersion and subsequent curing, both controlled by ionic liquid, lead to composites with substantially enhanced fracture mechanical and thermomechanical properties with no reduction in thermal properties. Merging processing techniques of nanocomposites with ionic liquid for efficient dispersion of nanotubes and preferential curing of thermosets facilitates the development of new, high performance materials. PMID- 23752342 TI - Genetic vaccine for respiratory syncytial virus provides protection without disease potentiation. AB - Respiratory syncytial virus (RSV) is a major cause of infectious lower respiratory disease in infants and the elderly. As there is no vaccine for RSV, we developed a genetic vaccine approach that induced protection of the entire respiratory tract from a single parenteral administration. The approach was based on adenovirus vectors derived from newly isolated nonhuman primate viruses with low seroprevalence. We show for the first time that a single intramuscular (IM) injection of the replication-deficient adenovirus vectors expressing the RSV fusion (F0) glycoprotein induced immune responses that protected both the lungs and noses of cotton rats and mice even at low doses and for several months postimmunization. The immune response included high titers of neutralizing antibody that were maintained >= 24 weeks and RSV-specific CD8+ and CD4+ T cells. The vectors were as potently immunogenic as a human adenovirus 5 vector in these two key respiratory pathogen animal models. Importantly, there was minimal alveolitis and granulocytic infiltrates in the lung, and type 2 cytokines were not produced after RSV challenge even under conditions of partial protection. Overall, this genetic vaccine is highly effective without potentiating immunopathology, and the results support development of the vaccine candidate for human testing. PMID- 23752345 TI - About this journal. PMID- 23752344 TI - Chronological changes of mechanical allodynia and spinal microglia activation by an intrathecal injection of MK-801. AB - The neuropathic pain that occurs after peripheral nerve injury may be related to abnormal central activity. The present experiments investigated the effects of MK 801 [N-methyl-D-aspartate (NMDA) receptor antagonist] on neuropathic pain behaviors and microglial activity in rats. Neuropathic pain was produced by L5 spinal nerve ligation of rats. MK-801 was injected to determine whether spinal microglial activation after nerve injury plays a crucial role in the development and/or maintenance of neuropathy through the NMDA receptor. Mechanical allodynia of the hind paw was examined with von Frey filaments postoperatively. Microglial activity was measured by observing changes in immunoreactivity with a microglia marker, OX-42. The MK-801, at a dose of 3 or 30 ug/5 ul, injection group showed higher neuropathic pain threshold and reduction of microglial activity. These results suggest that neuropathic pain behaviors following L5 spinal nerve ligation may be related to altered activity of the microglia involving the NMDA receptor, and chronological changes of microglial activation by MK-801 are related to maintenance of mechanical allodynia. PMID- 23752346 TI - A 26-year-old man with an eczematous lesion on the nipple-diagnosis. PMID- 23752348 TI - A green luminescent 1-D helical tubular dipyrazol-bridged cadmium(II) complex: a coordination tube included in a supramolecular tube. AB - A 1-D helical tubular cadmium coordination polymer, [Cd(H2Me4bpz)(H2bidc)2]n (1, H2Me4bpz = 3,3',5,5'-tetramethyl-4,4'-bipyrazole; H3bidc = benzimidazole-5,6 dicarboxylic acid) was hydrothermally synthesized and characterized by means of elemental analyses, PXRD, IR, 2D IR correlation spectra, solid UV, TG analysis, luminescence spectroscopy and single crystal X-ray diffraction. The crystal structure of 1 is a unique example of a 1D helical tube-in-tube structure. Interestingly, the [Cd(H2Me4bpz)] coordination helical tube is included in the [Cd(H2bidc)] supramolecular helical tube with the same handness. The compound displays a green luminescence upon excitation at 397 nm. PMID- 23752349 TI - Is sitting harmful to health? It is too early to say-reply. PMID- 23752351 TI - An international celebration of dermatology. PMID- 23752350 TI - Effects of genetically modified T2A-1 rice on the GI health of rats after 90-day supplement. AB - Bacillus thuringiensis insecticidal toxin (Bt) rice will be commercialized as a main food source. Traditional safety assessments on genetically modified products pay little attention on gastrointestinal (GI) health. More data about GI health of Bt rice must be provided to dispel public' doubts about the potential effects on human health. We constructed an improved safety assessment animal model using a basic subchronic toxicity experiment, measuring a range of parameters including microflora composition, intestinal permeability, epithelial structure, fecal enzymes, bacterial activity, and intestinal immunity. Significant differences were found between rice-fed groups and AIN93G-fed control groups in several parameters, whereas no differences were observed between genetically modified and non-genetically modified groups. No adverse effects were found on GI health resulting from genetically modified T2A-1 rice. In conclusion, this study may offer a systematic safety assessment model for GM material with respect to the effects on GI health. PMID- 23752352 TI - Quantification of tumor necrosis factor-alpha and matrix metalloproteinases-3 in synovial fluid by a fiber-optic particle plasmon resonance sensor. AB - The availability of techniques for sensitive detection of early stage osteoarthritis is critical for improving patient health. This study illustrates the feasibility of a fiber-optic particle plasmon resonance (FOPPR) sensor with gold nanoparticles on the unclad region of optical fiber probes for analysis of osteoarthritis biomarkers, tumor necrosis factor-alpha (TNF-alpha) and matrix metalloproteinases-3 (MMP-3). Results show that the sensor can achieve a refractive index resolution of 5.18 * 10-7 RIU and limits of detection for TNF alpha and MMP-3 as low as 8.22 pg ml-1 (0.48 pM) and 34.3 pg ml-1 (1.56 pM), respectively. Additionally, the FOPPR sensor shows a good correlation in determining TNF-alpha and MMP-3 in synovial fluid with the clinically accepted enzyme-linked immunosorbent assay (ELISA) method. Finally, given the FOPPR sensor's nature of being low-cost, label-free, highly sensitive, real-time, simple-to-operate, the FOPPR sensor could offer potential to monitor biomarkers of various diseases, and provide an ideal technical tool for point-of-care diagnostics. PMID- 23752353 TI - Fucoidan derived from Undaria pinnatifida induces apoptosis in human hepatocellular carcinoma SMMC-7721 cells via the ROS-mediated mitochondrial pathway. AB - Fucoidans, fucose-enriched sulfated polysaccharides isolated from brown algae and marine invertebrates, have been shown to exert anticancer activity in several types of human cancer, including leukemia and breast cancer and in lung adenocarcinoma cells. In the present study, the anticancer activity of the fucoidan extracted from the brown seaweed Undaria pinnatifida was investigated in human hepatocellular carcinoma SMMC-7721 cells, and the underlying mechanisms of action were investigated. SMMC-7721 cells exposed to fucoidan displayed growth inhibition and several typical features of apoptotic cells, such as chromatin condensation and marginalization, a decrease in the number of mitochondria, and in mitochondrial swelling and vacuolation. Fucoidan-induced cell death was associated with depletion of reduced glutathione (GSH), accumulation of high intracellular levels of reactive oxygen species (ROS), and accompanied by damage to the mitochondrial ultrastructure, depolarization of the mitochondrial membrane potential (MMP, Deltapsim) and caspase activation. Moreover, fucoidan led to altered expression of factors related to apoptosis, including downregulating Livin and XIAP mRNA, which are members of the inhibitor of apoptotic protein (IAP) family, and increased the Bax-to-Bcl-2 ratio. These findings suggest that fucoidan isolated from U. pinnatifida induced apoptosis in SMMC-7721 cells via the ROS-mediated mitochondrial pathway. PMID- 23752354 TI - Comparative analysis of glycoside hydrolases activities from phylogenetically diverse marine bacteria of the genus Arenibacter. AB - A total of 16 marine strains belonging to the genus Arenibacter, recovered from diverse microbial communities associated with various marine habitats and collected from different locations, were evaluated in degradation of natural polysaccharides and chromogenic glycosides. Most strains were affiliated with five recognized species, and some presented three new species within the genus Arenibacter. No strains contained enzymes depolymerizing polysaccharides, but synthesized a wide spectrum of glycosidases. Highly active beta-N acetylglucosaminidases and alpha-N-acetylgalactosaminidases were the main glycosidases for all Arenibacter. The genes, encoding two new members of glycoside hydrolyses (GH) families, 20 and 109, were isolated and characterized from the genomes of Arenibacter latericius. Molecular genetic analysis using glycosidase-specific primers shows the absence of GH27 and GH36 genes. A sequence comparison with functionally-characterized GH20 and GH109 enzymes shows that both sequences are closest to the enzymes of chitinolytic bacteria Vibrio furnissii and Cellulomonas fimi of marine and terrestrial origin, as well as human pathogen Elisabethkingia meningoseptica and simbionts Akkermansia muciniphila, gut and non gut Bacteroides, respectively. These results revealed that the genus Arenibacter is a highly taxonomic diverse group of microorganisms, which can participate in degradation of natural polymers in marine environments depending on their niche and habitat adaptations. They are new prospective candidates for biotechnological applications due to their production of unique glycosidases. PMID- 23752355 TI - Flexibilins A-C, new cembrane-type diterpenoids from the Formosan soft coral, Sinularia flexibilis. AB - Three new cembrane-type diterpenoids, flexibilins A-C (1-3), along with a known cembrane, (-)-sandensolide (4), were isolated from the soft coral, Sinularia flexibilis. The structures of cembranes 1-4 were elucidated by spectroscopic methods. The structure of 4, including its absolute stereochemistry, was further confirmed by single-crystal X-ray diffraction analysis. Cembrane 2 displayed a moderate inhibitory effect on the release of elastase by human neutrophils. PMID- 23752357 TI - Four new briarane diterpenoids from Taiwanese gorgonian Junceella fragilis. AB - Four new 8-hydroxybriarane diterpenoids, frajunolides P-S (1-4), together with umbraculolide A, juncenolide C, junceellonoid A and juncin R, were isolated from the acetone extract of the gorgonian Junceella fragilis, collected from the southeast coast of Taiwan. Compound 1 contains an unusual pivaloyloxy group at C 2, while 3 is a rare compound having a chlorine atom on the olefinic carbon (C 6). The structures of the isolated compounds were established by extensive spectroscopic analysis, including 1D- and 2D-NMR, as well as HRMS data. Compound 1 was further confirmed by X-ray crystallographic analysis. In the anti inflammatory test, compounds 1 and 2 exhibited moderate inhibition on superoxide anion generation and elastase release by human neutrophils in response to formylmethionylleucyl-phenylalanine/dihydrocytochalasin B (fMLP/CB). PMID- 23752359 TI - Fecal Transplant for Clostridium difficile-Reply. PMID- 23752360 TI - Editorial: cancer in plants. PMID- 23752358 TI - Bioactive phenylalanine derivatives and cytochalasins from the soft coral-derived fungus, Aspergillus elegans. AB - One new phenylalanine derivative 4'-OMe-asperphenamate (1), along with one known phenylalanine derivative (2) and two new cytochalasins, aspochalasin A1 (3) and cytochalasin Z24 (4), as well as eight known cytochalasin analogues (5-12) were isolated from the fermentation broth of Aspergillus elegans ZJ-2008010, a fungus obtained from a soft coral Sarcophyton sp. collected from the South China Sea. Their structures and the relative configurations were elucidated using comprehensive spectroscopic methods. The absolute configuration of 1 was determined by chemical synthesis and Marfey's method. All isolated metabolites (1 12) were evaluated for their antifouling and antibacterial activities. Cytochalasins 5, 6, 8 and 9 showed strong antifouling activity against the larval settlement of the barnacle Balanus amphitrite, with the EC50 values ranging from 6.2 to 37 MUM. This is the first report of antifouling activity for this class of metabolites. Additionally, 8 exhibited a broad spectrum of antibacterial activity, especially against four pathogenic bacteria Staphylococcus albus, S. aureus, Escherichia coli and Bacillus cereus. PMID- 23752356 TI - Antifreeze peptides and glycopeptides, and their derivatives: potential uses in biotechnology. AB - Antifreeze proteins (AFPs) and glycoproteins (AFGPs), collectively called AF(G)Ps, constitute a diverse class of proteins found in various Arctic and Antarctic fish, as well as in amphibians, plants, and insects. These compounds possess the ability to inhibit the formation of ice and are therefore essential to the survival of many marine teleost fishes that routinely encounter sub-zero temperatures. Owing to this property, AF(G)Ps have potential applications in many areas such as storage of cells or tissues at low temperature, ice slurries for refrigeration systems, and food storage. In contrast to AFGPs, which are composed of repeated tripeptide units (Ala-Ala-Thr)n with minor sequence variations, AFPs possess very different primary, secondary, and tertiary structures. The isolation and purification of AFGPs is laborious, costly, and often results in mixtures, making characterization difficult. Recent structural investigations into the mechanism by which linear and cyclic AFGPs inhibit ice crystallization have led to significant progress toward the synthesis and assessment of several synthetic mimics of AFGPs. This review article will summarize synthetic AFGP mimics as well as current challenges in designing compounds capable of mimicking AFGPs. It will also cover our recent efforts in exploring whether peptoid mimics can serve as structural and functional mimics of native AFGPs. PMID- 23752361 TI - Chemo-induced hair loss: prevention of a distressing side-effect. PMID- 23752362 TI - Oral care for cancer and palliative patients. PMID- 23752363 TI - The impact of national policy on the early diagnosis of cancer. AB - Since the mid-90s UK governments and other policy makers have sought to develop policy that addresses the need for improved outcomes for people diagnosed with cancer. However, the strategies for cancer in Scotland, Wales and Northern Ireland are different to the policy on cancer produced under the English government. This article will examine policy developments in the English health service aimed at achieving early diagnosis of cancer with particular reference to the Cancer Reform Strategy (2007). The role of socioeconomic factors and the need for policy to address a range of cancers due to their differences in pathology and therefore diagnosis and treatment will also be considered. PMID- 23752364 TI - As treatment options progress, so must we. PMID- 23752365 TI - Bone metastases: assessment, management and treatment options. AB - Cancer cells from a primary tumour can spread to other parts of the body through the bloodstream or the lymphatic system. Bone metastases are common in multiple myeloma, where 70-80% of patients have bone metastases at diagnosis. They are also a common feature in solid tumours such as breast, lung, prostate, thyroid and renal carcinomas. The median survival in patients with bone metastases from breast cancer is 24 months; 20% of patients survive for 5 years or more. Pain is the most common symptom of bone metastases, which can often be severe and difficult to control. This article will discuss normal bone physiology and explain the changes that occur when cancer cells spread to bone. It will outline the signs and symptoms of bone metastases and discuss patient assessment, symptom management and treatment options, including different bisphosphonates. The physical and psychological impact of bone metastases should not be underestimated and nurses are well placed to improve the quality of life of patients. PMID- 23752366 TI - Linguistic acculturation and skin cancer-related behaviors among Hispanics in the southern and western United States. AB - OBJECTIVE: To examine the association between linguistic acculturation (assessed using the Language Use and Linguistic Preference subscales from the Bidimensional Acculturation Scale for Hispanics) and skin cancer-related behaviors among US Hispanic adults to determine whether, compared with Hispanics denoted as Spanish acculturated, English-acculturated Hispanics would report less frequent shade seeking and use of sun protective clothing and higher rates of sunscreen use, sunbathing, and indoor tanning. DESIGN: Online survey study conducted in September 2011. SETTING: Five southern and western US states. PARTICIPANTS: A population-based sample of 788 Hispanic adults drawn from a nationally representative web panel. MAIN OUTCOME MEASURES: Self-reported sunscreen use, shade seeking, use of sun protective clothing, sunbathing, and indoor tanning. RESULTS: Multivariate regression analyses were conducted to examine predictors of the skin cancer-related behaviors. As hypothesized, English-acculturated Hispanics had lower rates of shade seeking and use of sun protective clothing and reported higher rates of sunbathing and indoor tanning than Spanish-acculturated Hispanics. English-acculturated Hispanics and bicultural Hispanics (ie, those with high Spanish and high English acculturation) reported comparably high rates of sunbathing and indoor tanning. Results suggested that bicultural Hispanics seek shade and wear sun protective clothing less often than Spanish-acculturated Hispanics but more often than English-acculturated Hispanics. Acculturation was not associated with sunscreen use. CONCLUSIONS: Hispanic adults do not routinely engage in behaviors that reduce their risk of skin cancer. Bicultural and English acculturated Hispanics are particularly in need of skin cancer prevention interventions. PMID- 23752367 TI - Rethinking wastewater characterisation methods for activated sludge systems - a position paper. AB - Increasingly stringent effluent limits and an expanding scope of model system boundaries beyond activated sludge has led to new modelling objectives and consequently to new and often more detailed modelling concepts. Nearly three decades after the publication of Activated Sludge Model No1 (ASM1), the authors believe it is time to re-evaluate wastewater characterisation procedures and targets. The present position paper gives a brief overview of state-of-the-art methods and discusses newly developed measurement techniques on a conceptual level. Potential future paths are presented including on-line instrumentation, promising measuring techniques, and mathematical solutions to fractionation problems. This is accompanied by a discussion on standardisation needs to increase modelling efficiency in our industry. PMID- 23752368 TI - Aeration control - a review. AB - This review covers automatic control of continuous aeration systems in municipal wastewater treatment plants. The review focuses on published research in the 21st century and describes research into various methods to decide and control the dissolved oxygen (DO) concentration and to control the aerobic volume with special focus on plants with nitrogen removal. Important aspects of control system implementation and success are discussed, together with a critical review of published research on the topic. With respect to DO control and determination, the strategies used for control span from modifications and developments of conventional control methods which have been explored since the 1970s, to advanced control such as model-based predictive and optimal controllers. The review is supplemented with a summary of comparisons between control strategies evaluated in full-scale, pilot-scale and in simulations. PMID- 23752369 TI - Sewage sludge solubilization by high-pressure homogenization. AB - The behavior of sludge solubilization using high-pressure homogenization (HPH) treatment was examined by investigating the sludge solid reduction and organics solubilization. The sludge volatile suspended solids (VSS) decreased from 10.58 to 6.67 g/L for the sludge sample with a total solids content (TS) of 1.49% after HPH treatment at a homogenization pressure of 80 MPa with four homogenization cycles; total suspended solids (TSS) correspondingly decreased from 14.26 to 9.91 g/L. About 86.15% of the TSS reduction was attributed to the VSS reduction. The increase of homogenization pressure from 20 to 80 MPa or homogenization cycle number from 1 to 4 was favorable to the sludge organics solubilization, and the protein and polysaccharide solubilization linearly increased with the soluble chemical oxygen demand (SCOD) solubilization. More proteins were solubilized than polysaccharides. The linear relationship between SCOD solubilization and VSS reduction had no significant change under different homogenization pressures, homogenization cycles and sludge solid contents. The SCOD of 1.65 g/L was solubilized for the VSS reduction of 1.00 g/L for the three experimental sludge samples with a TS of 1.00, 1.49 and 2.48% under all HPH operating conditions. The energy efficiency results showed that the HPH treatment at a homogenization pressure of 30 MPa with a single homogenization cycle for the sludge sample with a TS of 2.48% was the most energy efficient. PMID- 23752370 TI - Saturated and unsaturated flow through sloped compost filter beds of different particle sizes. AB - Little is known about the hydraulics of sloped compost beds having active free and non-flowing zones, and used for runoff erosion and volume control, and heavy metal removal. Water sorption tests on yard waste compost indicated that water transfer between the two zones would be slow (6 hr for a 0.04 m rise). The free flowing zone in ~1 m long sloped (15 degrees ) beds increased in depth (0.01-0.08 m) with decreasing particle size and increasing flow. Particle size and flow (0.08-0.3 L/s/m) affected bed stability. Drainage volume increased with flow while drainage time remained fairly constant. Saturated flow occurred depending on the particle size above 0.02-0.165 L/s/m. Data indicate that sheet runoff from low intensity storms would most likely create unsaturated but stable bed conditions. Concentrated flows as from downspouts would likely create saturated conditions and have to be managed to prevent washout. A model based on porous media theory indicated that flow regime under saturated flow is turbulent. Results can be used to design compost beds for various runoff rates and to develop a heavy metal sorption model. PMID- 23752371 TI - Inhibition effect of phosphorus-based chemicals on corrosion of carbon steel in secondary-treated municipal wastewater. AB - Secondary-treated municipal wastewater (MWW) could supply a viable alternative water resource for cooling water systems. Inorganic salts in the concentrated cooling water pose a great challenge to corrosion control chemicals. In this study, the inhibition effect of 1-hydroxy ethylidene-1,1-diphosphonic acid (HEDP), trimethylene phosphonic acid (ATMP) and 2-phosphonobutane-1,2,4 tricarboxylic acid (PBTCA) on corrosion of carbon steel in secondary-treated MWW was investigated by the means of potentiodynamic polarization and electrochemical impedance spectroscopy. The inhibition effect increased with increasing concentration of inhibitors. The corrosion rates of carbon steel were 1.5, 0.8, 0.2 and 0.5 mm a(-1) for blank, HEDP, ATMP and PBTCA samples at 50 mg L(-1), respectively. The phosphorus-based chemicals could adsorb onto the surface of the carbon steel electrode, form a coat of protective film and then protect the carbon steel from corrosion in the test solution. PMID- 23752372 TI - Investigation of UV-assisted chlorophenol congeners' degradation by organic oxidant p-nitrobenzoic acid in basic media. AB - This research specifically addressed the photodegradation of selected model chlorophenol (CP) congeners, 4-chlorophenol (4-CP), 2,4-dichlorophenol (2,4-DCP), 2,4,6-trichlorophenol (2,4,6-TCP) and pentachlorophenol (PCP), by an organic oxidant, p-nitrobenzoic acid (PNBA), in basic media. The reactions were followed by high-pressure liquid chromatography and gas chromatography-mass spectroscopy analysis for residual concentration and the identification of photodegraded products respectively. Initial degradation was confirmed by the formation of ring cleavage compounds, and subsequent mineralization was evidently marked by an increase in release of chloride ions in the time course profile. The presence of fewer/no chlorine atoms in the degraded compounds corroborated the mineralization by UV/PNBA action. The chemical oxygen demand (COD) was also observed to fall appreciably to the extent of 73% during all CP congeners' degradation. The maximum COD decrease was observed in PNBA-assisted 4-CP degradation. The overall degradation kinetics conforming to second-order reaction is observed to follow the order 4-CP > 2,4,6-TCP ~ PCP ~ 2,4-DCP. The findings of this investigation elucidated the fact that PNBA was capable of successfully degrading/mineralizing the selected CP congeners. PMID- 23752373 TI - The interaction between natural organic matter in raw waters and pesticide residues: a three dimensional excitation-emission matrix (3DEEM) fluorescence investigation. AB - This paper examines the interaction between dissolved natural organic matter and pesticide residues, both of which are found in raw water sources, using three dimensional excitation-emission matrix (3DEEM) fluorescence spectroscopy. It was observed that pesticide residue at 0.1 mg L(-1) formed a complex with humic-like fluorophores that are commonly found in raw water samples. Applying 3DEEM fluorescence to investigate the humic fractions, it was found that identification of changes in water sources was possible, and, importantly, the presence of a number of pesticides was able to be determined. In addition, the formation of this complex, and the influence of soluble cations and anions upon it, was shown to impact the efficiency of analytical extraction procedures for pesticides; however, 3DEEM fluorescence could be an approach to account for such losses. PMID- 23752374 TI - Enhancement of phosphorus removal in a low temperature A(2)/O process by anaerobic phosphorus release of activated sludge. AB - An anaerobic phosphorus release tank was introduced to an anaerobic-anoxic aerobic (A(2)/O) process treating domestic sewage to enhance the phosphorus removal at low temperature. Phosphorus release of the activated sludge from the second sedimentation tank was evaluated at 14 degrees C by batch cultures, and the nutrient removal in the modified low temperature A(2)/O process was further investigated at the same temperature. The results showed that the feasible sludge retention time was 14 h for sequencing batch reaction and 12 h for continuous flow operation. The ratio of raw sewage to activated sludge from the second sedimentation tank was 1:1 in volume to meet the demand of carbon resource for the growth of phosphorus release microbes. The feasible chemical oxygen demand (COD) loading rate of the activated sludge in the phosphorus release tank was 0.015-0.02 g COD/g MLSS (mixed liquor suspended solids) and the nitrate concentration should be less than 5 mg/L. The phosphorus release was doubled when the sludge was blended intermittently and gently. The anaerobic phosphorus release of the activated sludge improved the phosphate removal remarkably, as well as the removal of NH4(+)-N and total nitrogen (TN) in the modified low temperature A(2)/O process. The effluent COD, NH4(+)-N, TN and total phosphorus could meet a stricter discharge standard. PMID- 23752375 TI - Cysteine-modified orange peel for removal of Cu(II) from aqueous solutions. AB - In the present work, cysteine-modified orange peel (COP) for the removal of Cu(II) from aqueous solutions has been developed and comparatively studied with diethylenetriamine-modified orange peel (DOP). Both COP and DOP were systematically evaluated via their capabilities for adsorbing Cu(II), including the key influential parameters such as initial pH, contact time and initial Cu(II) concentration. Further studies suggest that the sorption of Cu(II) onto both COP and DOP fits well with the pseudo-second-order equation, and the corresponding sorption isotherm can be classified to a Langmuir isotherm model. COP appears more advantageous over DOP and far better than that of unmodified OP in removal of Cu(II) from aqueous system. The maximum capacities of COP and DOP for adsorbing Cu(II) are 95.23 and 83.68 mg/g, respectively, about three times higher than that of unmodified OP. The sorption efficiency of COP drops by merely about 3% after five cycles, implying a promising usage in the removal of Cu(II) from wastewater in practice. PMID- 23752376 TI - Electrolytic removal of ammonia from aqueous phase by Pt/Ti anode. AB - This study investigated the mechanism and kinetic modeling of electrolytic degradation of ammonia with Pt/Ti anode. The results show that ammonia oxidation from direct oxidation or indirect oxidation with hydroxyl radicals was slow but can be observed under pH 9 and high initial ammonia concentration of 1,050 mg N L(-1). Indirect oxidation with HOCl was the mechanism for the chloride-mediated electrolytic removal of ammonia. In this process, pH between 3 and 9 had little effect on the ammonia removal rate, but current density (j) and chloride concentration ([Cl(-)]) showed a linear relationship with ammonia removal rate within the range of 3.8-15.4 mA cm(-2) and 30-300 mg L(-1), respectively. The ammonia removal could be described by a pseudo-zero order kinetics with a mathematic equation of k = 0.0003 * [Cl(-)] * j - 0.076. Treatment of the actual wastewater effluent from a secondary clarifier in a local wastewater treatment plant showed an ammonia removal rate of 0.8 mg N L(-1) h(-1) and energy cost of 14 kJ per mg N ammonia. PMID- 23752377 TI - Comparison of core sampling and visual inspection for assessment of concrete sewer pipe condition. AB - Sewer systems are costly to construct and even more costly to replace, requiring proper asset management. Sewer asset management relies to a large extent on available information. In sewer systems where pipe corrosion is the dominant failure mechanism, visual inspection by closed circuit television (CCTV) and core sampling are among the methods mostly applied to assess sewer pipe condition. This paper compares visual inspection and drill core analysis in order to enhance further understanding of the limitations and potentials of both methods. Both methods have been applied on a selected sewer reach in the city of The Hague, which was reportedly subject to pipe corrosion. Results show that both methods, visual inspection and core sampling, are associated with large uncertainties and that there is no obvious correlation between results of visual inspection and results of drill core analysis. PMID- 23752378 TI - Evaluating Escherichia coli removal performance in stormwater biofilters: a preliminary modelling approach. AB - Stormwater biofilters are not currently optimised for pathogen removal since the behaviour of these pollutants within the stormwater biofilters is poorly understood. Modelling is a common way of optimising these systems, which also provides a better understanding of the major processes that govern the pathogen removal. This paper provides an overview of a laboratory-scale study that investigated how different design and operational conditions impact pathogen removal in the stormwater biofilters. These data were then used to develop a modelling tool that can be used to optimise the design and operation of the stormwater biofilters. The model uses continuous simulations where adsorption and desorption were dominant during wet weather periods and first order die-off kinetics were significant in dry periods between the wet weather events. Relatively high Nash Sutcliffe Efficiencies (>0.5) indicate that the calibrated model is in good agreement with observed data and the optimised model parameters were comparable with values reported in the literature. The model's sensitivity is highest towards the adsorption process parameter followed by the die-off and desorption rate parameters, which implies that adsorption is the governing process of the model. Vegetation is found to have an impact on the wet weather processes since the adsorption and desorption parameters vary significantly with the different plant configurations. The model is yet to be tested against field data and needs to be improved to represent the effect of some other biofilter design configurations, such as the inclusion of the submerged zone. PMID- 23752379 TI - A new disinfection system for wastewater treatment: performic acid full-scale trial evaluations. AB - To evaluate the efficiency and effect of a new disinfection technology in wastewater treatment, batch and full-scale experiments were performed between winter 2005 and summer 2011. The system, developed by Kemira Oyj, produces a disinfection solution containing performic acid (PFA) by mixing hydrogen peroxide and formic acid. A preliminary study in batch reactors established the suitability for wastewater disinfection; three subsequent full-scale plant experiments conducted at two municipal wastewater treatment plants (120,000 and 32,000 equivalent inhabitants) discharging in sensitive areas demonstrated its effectiveness and reliability in this application field. The disinfection power of the system was measured using faecal coliforms, Escherichia coli and faecal enterococci; additional water quality parameters included total organic carbon, suspended solids, eco-toxicity and disinfection by-products. Full-scale experiments indicated that PFA has a high disinfection power, always ensuring over 3 log of faecal coliforms and E. coli reductions at CT over 60 mg/L min (CT: disinfectant initial Concentration (mg/L) * contact Time (min)). The final production system yielded even better performance, with E. coli and faecal enterococci reductions ranging from 2 to 4.2 and from 0.7 to 3.2 log, respectively, at CT conditions lower than 23 mg/L min. There were no eco toxicological effects measured by Vibrio fischeri or by-product formation. PMID- 23752380 TI - Separation of metals and phosphorus from incinerated sewage sludge ash. AB - Microbial acidification of incinerated sewage sludge ash and dissolution of metals from the acidified ash were investigated using a semi-batch reactor at different solid retention times (SRTs). The average pH values ranged from 0.91 to 1.2 at SRTs longer than 10 days, whereas the reduction of SRT to 4 days resulted in an increase in the pH value to about 2. The dissolution efficiencies of Al, As, Cd, Cu and Mn were greater than 60% at a SRT of 4 days. Moreover, the effect of pH on precipitation of metals and P (dissolution of 80%) in the filtrate removed from the acidified sewage ash suspension, and the separation of phosphorus and the other metals in the filtrate using ethylenediaminetetraacetic acid (EDTA) or ferric ion, were examined. Although neutralisation of the filtrate to a pH of 5 simultaneously precipitated 100% of Al and 80% of P recovered from the acidified sewage ash, the addition of EDTA decreased their precipitation to 70 and 50%, respectively, at the same pH value, which would promote precipitation of P as calcium phosphate. Furthermore, neutralising to a pH of 2.5 after the addition of ferric ion precipitated P separately from Al and heavy metals. PMID- 23752381 TI - Nitrous oxide formation during nitritation and nitrification of high-strength wastewater. AB - The purpose of this study was to investigate the formation of nitrous oxide (N2O) in nitritation and nitrification under stable, comparable and not limiting conditions typical for treatment of high-strength wastewater. A laboratory-scale aerated chemostat was operated with reject water at different sludge retention times, achieving suppression of nitrate formation by wash-out of nitrite oxidizing bacteria for nitritation. The N2O formation factor during stable nitritation was higher (2.90% N2O-N /NH4(-)-Nox) than during nitrification (0.74%). The positive correlation of N2O formation rates and ammonium oxidation rates was linear and thus did not contribute to changes of the N2O formation factor. The dominant factor for N2O formation during stable operation was high nitrite concentration, which was positively correlated with N2O formation rates. The highest formation factors were observed during a transition phase from nitrification to nitritation with unstable process conditions (4.81%) and during a short-term experiment with increased pH of 7 (10.28%). The results indicate that even with operational conditions that are regarded favourable for the process of nitritation N2O formation can be limited but not avoided. PMID- 23752382 TI - Mobility, binding behavior and potential risks of trace metals in the sediments of the fifth largest freshwater lake, China. AB - The trace metal pollution of sediments in Chaohu Lake, one of the most highly eutrophic lakes in East China, was investigated. Surface sediment (0-5 cm) samples were collected from 35 different positions and analyzed by inductively coupled plasma optical emission spectrometry to determine trace metal contents. Results showed that the mean content of trace metals was as follows: Cr, 85.09 mg kg(-1); Cu, 34.49 mg kg(-1); Ni, 26.46 mg kg(-1); Pb, 34.17 mg kg(-1) and Zn, 107.46 mg kg(-1). The trace metal concentrations from different sampling sites displayed spatial diversity; the heavily polluted sampling sites were close to where estuaries flow in to the lake. A four-step sequential extraction was used to examine the partitioning of the trace metals. Results demonstrated that the percentage of the species bound to the oxidizable phase for all trace metals ranged from 15.6 to 37.7%, while for Cu, Cr and Ni, the main forms were residual (41.3, 62.3 and 69.8%, respectively). Trace metals in the oxidizable fraction may mainly exist in the form of sulfides. The ecological potential risks of trace metals decreased as follows: Pb > Zn > Cu > Cr > Ni. PMID- 23752383 TI - Designing domestic rainwater harvesting systems under different climatic regimes in Italy. AB - Nowadays domestic rainwater harvesting practices are recognized as effective tools to improve the sustainability of drainage systems within the urban environment, by contributing to limiting the demand for potable water and, at the same time, by mitigating the generation of storm water runoff at the source. The final objective of this paper is to define regression curves to size domestic rainwater harvesting (DRWH) systems in the main Italian climatic regions. For this purpose, the Koppen-Geiger climatic classification is used and, furthermore, suitable precipitation sites are selected for each climatic region. A behavioural model is implemented to assess inflow, outflow and change in storage volume of a rainwater harvesting system according to daily mass balance simulations based on historical rainfall observations. The performance of the DRWH system under various climate and operational conditions is examined as a function of two non dimensional parameters, namely the demand fraction (d) and the modified storage fraction (sm). This last parameter allowed the evaluation of the effects of the rainfall intra-annual variability on the system performance. PMID- 23752384 TI - The Microbial Database for Danish wastewater treatment plants with nutrient removal (MiDas-DK) - a tool for understanding activated sludge population dynamics and community stability. AB - Since 2006 more than 50 Danish full-scale wastewater treatment plants with nutrient removal have been investigated in a project called 'The Microbial Database for Danish Activated Sludge Wastewater Treatment Plants with Nutrient Removal (MiDas-DK)'. Comprehensive sets of samples have been collected, analyzed and associated with extensive operational data from the plants. The community composition was analyzed by quantitative fluorescence in situ hybridization (FISH) supported by 16S rRNA amplicon sequencing and deep metagenomics. MiDas-DK has been a powerful tool to study the complex activated sludge ecosystems, and, besides many scientific articles on fundamental issues on mixed communities encompassing nitrifiers, denitrifiers, bacteria involved in P-removal, hydrolysis, fermentation, and foaming, the project has provided results that can be used to optimize the operation of full-scale plants and carry out trouble shooting. A core microbial community has been defined comprising the majority of microorganisms present in the plants. Time series have been established, providing an overview of temporal variations in the different plants. Interestingly, although most microorganisms were present in all plants, there seemed to be plant-specific factors that controlled the population composition thereby keeping it unique in each plant over time. Statistical analyses of FISH and operational data revealed some correlations, but less than expected. MiDas-DK (www.midasdk.dk) will continue over the next years and we hope the approach can inspire others to make similar projects in other parts of the world to get a more comprehensive understanding of microbial communities in wastewater engineering. PMID- 23752385 TI - Pretreatment followed by anaerobic digestion of secondary sludge for reduction of sewage sludge volume. AB - The influence of two pretreatment methods, thermal treatment and low-pressure wet oxidation, on the sludge digestion efficiency was examined. Batch thermophilic anaerobic digestion was used to evaluate the effectiveness of the pretreatment methods in terms of volatile suspended solids (VSS) digestion efficiency and gas production. The results showed that the gas production was not proportional to the VSS degradation efficiency of either thermal treatment or low-pressure wet oxidation. Low-pressure wet oxidation treatment at 150 degrees C along with 40% of the theoretical oxygen required to oxidize organic carbon gave the highest gas production and the VSS digestion efficiency of 77% at a VSS loading rate of 8 g l(-1) d(-1). The digestion efficiency was about 30% higher than that of thermophilic anaerobic digestion without sludge pretreatment. Sewage sludge could be treated effectively at a high VSS digestion efficiency with this pretreatment followed by thermophilic anaerobic digestion. PMID- 23752386 TI - Challenges for bathing in rivers in terms of compliance with coliform standards. Case study in a large urbanized basin (das Velhas River, Brazil). AB - This paper presents a case study on the prospects of bathing in a large water course (das Velhas River, Brazil), which crosses the important metropolitan region of Belo Horizonte (25 municipalities), receiving several point and diffuse discharges. The studies were carried out based on a mathematical simulation of thermotolerant coliforms over 227 km of the river, using an adaptation of the Qual2E model (model Qual-UFMG). Simulations of intervention scenarios were made for the current conditions, with three reference flows for the das Velhas River, tributaries and direct contribution: Q7,10 (representative of low-flow conditions), Q50 (average conditions) and Q10 (rainy season). The intervention scenarios simulated were: (a) current conditions without intervention; (b) scenario with effluent disinfection in the two largest wastewater treatment plants in the basin (around 2.4 million inhabitants); (c) scenario with 95% sewage collection and treatment, with disinfection in all municipalities of the study area; (d) scenario with the calculation of values required for the coverage of sewage treatment and coliform removal efficiencies based on a mathematical optimization process. The monitoring data and results of all simulations indicated improvement in coliform concentration as the river flows downstream. However, results suggested that disinfection per se is not enough. Even under hypothetical conditions of excellent sanitary infrastructure for a developing country, coverage of collection and treatment of 95% of the generated sewage, and treatment with disinfection at all wastewater treatment plants, concentrations of thermotolerant coliforms in das Velhas River are likely to be above the maximum allowable of 1,000 MPN/100 mL for bathing purposes. The mathematical optimization indicated the need for very high percentages of sewage treatment coverage (near 100%, i.e. universality of collection and treatment) and implementation of disinfection in most treatment plants in the basin, and highlighted the fact that both items play equally important roles. PMID- 23752387 TI - A novel optical panel photobioreactor for cultivation of microalgae. AB - In this study, a novel optical panel photobioreactor (OPPBR) equipped with a V cut/or flat optical panel (OP) and a light source, i.e., light-emitting diodes (LEDs) was developed. The performance of this OPPBR was assessed using cultures of Chlorella vulgaris. Growth rates of biomass were compared in bioreactors operated separately using a V-cut OP, or a flat-plate OP both equipped with LEDs or a fluorescent light source without any OP. The experiments were conducted at neutral pH (7.2 +/- 0.3) with an initial cell concentration of 0.15 +/- 0.05 g L( 1), at 23 +/- 1 degrees C under dark and light cycles of 8 and 16 h, respectively, using LEDs and fluorescent lamps for 11 days. The results demonstrated that the amount of biomass produced using the V-cut OP was three times higher than the flat-plate OP and five times higher than without the OP. Parametric studies demonstrated that a distance of 3 mm between the OP and the LEDs produced the highest illumination uniformity, i.e., 65.7% for the flat-plate OP and 87.6% for the V-cut OP. The OPPBR system can be scaled up and could be used to enhance biomass production using an LED and OP combination. PMID- 23752388 TI - Anaerobic degradation of carbon capture reclaimer MEA waste. AB - The anaerobic biodegradation of reclaimer MEA (monoethanolamine) waste (MEAw) with easily degradable co-substrates was investigated in a laboratory-scale bioreactor at room temperature during a 160 d experimental run. The reactor that was constructed with three phases to facilitate attached biofilm and suspended biomass retention for degradation of the complex and challenging MEAw performed well. A feed strategy of step-wise increasing organic loading rate (OLR) by either increasing feed MEAw concentration or the hydraulic loading rate was applied. The system performance was evaluated by chemical oxygen demand (COD) removal efficiency, methane yield, MEA removal, and the accumulation of ammonia and volatile fatty acid (VFA). The total COD removal efficiency initially was 93% when the feed was mainly easily degradable co-substrate. The total removal dropped to 75% at the end when MEAw constituted 60% of the feed COD. Ion chromatography results show that the MEA and some unidentified feed chemicals were almost completely consumed. The main products of MEAw degradation were ammonia, VFAs and biogas. The ammonia nitrogen concentration reached about 2.0 g/L, which may explain the observed inhibition of acetoclastic methanogenesis leading to acetate accumulation. Methane accounted for up to 80% of the biogas generated. The highest methane yield was 0.34 L/g-COD while the yield was 0.16 L/g-COD at the highest load. This study shows that more than 80% reclaimer MEAw COD degradation with a co-substrate can be maintained in a hybrid anaerobic bioreactor operated in a wide loading range. PMID- 23752389 TI - Preparation of cationic waste paper and its application in poisonous dye removal. AB - Cationic paper was prepared by reaction of paper with 2,3 epoxypropyltrimethylammonium chloride in aqueous suspension, and tested as low cost adsorbent for wastewater treatment. The experimental results revealed that anionic dyes (Acid Orange 7, Acid Red 18, and Acid Blue 92) were adsorbed on the cationic paper nicely. The maximum amount of dye Acid Orange 7 adsorbed on cationic paper was 337.2 mg/g in experimental conditions. The effects of initial dye concentration, temperature, and initial pH of dye solution on adsorption capacity of cationic paper were studied. The pseudo-first-order and pseudo-second order kinetic models were applied to describe the kinetic data. The Freundlich and Langmuir adsorption models were used to describe adsorption equilibrium. The thermodynamic data indicated that the adsorption process of dye on cationic paper occurred spontaneously. PMID- 23752391 TI - Monitoring and validation of decentralised water and wastewater systems for increased uptake. AB - Decentralised water and wastewater systems are being implemented to meet growing demand for municipal services either in combination with centralised systems or as standalone systems. In Australia, there has been increased investment in decentralised water and wastewater systems in response to the capacity constraints of existing centralised systems, an extended period of below average rainfall, uncertainly in traditional water sources due to potential climate change impacts, and the need to reduce the environmental impact of urban development. The implementation of decentralised water systems as a mainstream practice at different development scales is impeded by the knowledge gaps on their actual performance in a range of development types and settings. As the wide-spread uptake of these approaches in modern cities is relatively new compared to centralised approaches, there is limited information available on their planning, design, implementation, reliability and robustness. This paper presents a number of case studies where monitoring studies are under way to validate the performance of decentralised water and wastewater systems. The results from these case studies show the yield and reliability of these decentralised systems, as well as the associated energy demand and ecological footprint. The outputs from these case studies, and other monitoring studies, are important in improving decentralised system design guidelines and developing industry wide management norms for the operation and maintenance of decentralised systems. PMID- 23752390 TI - Factors affecting microbial fuel cell acclimation and operation in temperate climates. AB - For the successful scale-up of microbial fuel cell (MFC) systems, enrichment strategies are required that not only maximise reactor performance but also allow anodic biofilms to be robust to environmental change. Cluster analysis of Denaturing Gradient Gel Electrophoresis community fingerprints showed that anodic biofilms were enriched according to substrate type and temperature. Acetate produced the highest power density of 7.2 W m(-3) and butyrate the lowest at 0.29 W m(-3), but it was also found that the trophic conditions used to acclimate the electrogenic biofilms also determined the MFC response to different substrate types, with both acetate and butyrate substrates recording power densities of 1.07 and 1.0 W m(-3) respectively in a sucrose enriched reactor. When temperature perturbations were introduced to investigate the stability of the different substrate acclimated electrogenic biofilms, the 20 degrees C acclimated acetate reactor was unaffected by 10 degrees C operation but all reactors acclimated at 35 degrees C were adversely affected. When the operating temperature was raised back to 35 degrees C both the acetate and butyrate reactors recovered electrogenic activity but the sucrose reactor did not. It is thought that this was due to the more complex syntropic interactions that are required to occur when metabolising more complex substrate types. PMID- 23752392 TI - Environmental implications and applications of carbon nanomaterials in water treatment. AB - Carbon nanomaterials have been proposed as a basis for developing new technologies for photocatalytic oxidation and disinfection, improved membrane processes, adsorbents, and biofilm-resistant surfaces. This study details recent progress towards the development of these proposed applications. We explored the use of carbon nanomaterials such as fullerene C60, single-wall carbon nanotubes (SWCNTs), and multi-wall carbon nanotubes (MWCNTs) for a range of new technologies including, degradation of a probe organic compound by in situ generation of reactive oxygen species (ROS), new strategies for microbial disinfection, and the inhibition of biofilm development on membrane surfaces. The results show that the degradation of 2-chlorophenol by ROS produced microbial inactivation, and the mobility of the nanoparticle aggregates of the carbon nanomaterials all increased as suspensions were fractionated to enrich with smaller aggregates with sonication followed by successive membrane filtration. PMID- 23752393 TI - Effect of pH and HNO2 concentration on the activity of ammonia-oxidizing bacteria in a partial nitritation reactor. AB - Ammonia-oxidizing bacteria (AOB) are very sensitive to environmental conditions and wastewater treatment plant operational parameters. One of the most important factors affecting their activity is pH. Its effect is associated with: NH3/NH4(+) and HNO2/NO2(-) chemical equilibriums and biological reaction rates. The aim of this study was to quantify and model the effect of pH and free nitrous acid (FNA) concentration on the activity of AOB present in a lab-scale partial nitritation reactor. For this purpose, two sets of batch experiments were carried out using biomass from this reactor. Fluorescent in situ hybridization analysis showed that Nitrosomona eutropha and Nitrosomona europaea species were dominant in the partial nitritation reactor (>94%). The experimental results showed that FNA inhibits the AOB activity. This inhibition was properly modelled by the non competitive inhibition function and the half inhibition constant value was determined as 1.32 mg HNO2-N L(-1). The optimal pH for these AOB was found to be in the range 7.4-7.8. The pH inhibitory effect was stronger at high pH values than at low pH values. Therefore, an asymmetric inhibition function was proposed to represent the pH effect on these bacteria. A combination of two sigmoidal functions was able to reproduce the experimental results obtained. PMID- 23752394 TI - A novel technique for evaluating foam dynamics in anaerobic digesters. AB - Foaming in anaerobic digesters has severe impacts on process efficiency and operational costs. In this study, we present an experimental method to determine foam behaviour and stability for various foaming solutions. This novel technique measured foam conductivity at different heights along a foam column allowing changes in foam composition to be monitored in time. We analysed foam stability which is primarily dependent on the foam drainage velocity, a quantity that can be determined from forced drainage experiments. The drainage velocity increased in the presence of anaerobic digester sludge, compared to simple surfactant foam. We proposed a new understanding of the effect of sludge particles on the foam stability. Both physical properties (foam physical constant, beta) of foam and bubble surface interactions by applying stable and unstable foam in addition of surfactants are also evaluated and discussed. PMID- 23752395 TI - Membrane fouling caused by sub-micron particles in a mixed liquor suspension of an MBR. AB - Membrane fouling needs to be mitigated for widespread use of membrane bioreactors (MBRs). It has been pointed out that particles with small sizes found in supernatants (sub-micron particles) of mixed liquor suspensions of MBRs are important in the evolution of membrane fouling of this technology. However, information on characteristics of sub-micron particles in MBRs is still insufficient. In this study, a pilot-scale MBR treating municipal wastewater was used to investigate and characterize sub-micron particles in an MBR and to identify the size fraction(s) responsible for irreversible fouling in an MBR. It was clearly shown that characteristics of sub-micron particles in the MBR varied considerably depending on their sizes. Results of Fourier transform infrared (FTIR) analysis and monosaccharide analysis suggested that irreversible fouling in this study was mainly caused by the specific size fraction of 0.1-0.45 MUm, which was close to the size of micropores of the membrane used. Pore plugging might explain this to some extent. PMID- 23752396 TI - pH variation and influence in an autotrophic nitrogen removing biofilm system using an efficient numerical solution strategy. AB - A pH simulator consisting of an efficient numerical solver of a system of nine nonlinear equations was constructed and implemented in the modeling software MATLAB. The pH simulator was integrated in a granular biofilm model and used to simulate the pH profiles within granules performing the nitritation-anammox process for a range of operating points. The simulation results showed that pH profiles were consistently increasing with increasing depth into the granule, since the proton-producing aerobic ammonium-oxidizing bacteria (AOB) were located close to the granule surface. Despite this pH profile, more NH3 was available for AOB than for anaerobic ammonium oxidizers, located in the center of the granules. However, operating at a higher oxygen loading resulted in steeper changes in pH over the depth of the granule and caused the NH3 concentration profile to increase from the granule surface towards the center. The initial value of the background charge and influent bicarbonate concentration were found to greatly influence the simulation result and should be accurately measured. Since the change in pH over the depth of the biofilm was relatively small, the activity potential of the microbial groups affected by the pH did not change more than 5% over the depth of the granules. PMID- 23752397 TI - Adsorption of tetracyclines on marine sediment during organic matter diagenesis. AB - The effect of decomposition and diagenesis of sediment organic matter (SOM) on the adsorption of emerging pollutants by the sediment has been seldom addressed. In the present experimental study, artificial sediment was incubated to simulate the natural organic diagenesis process and hence investigate the influence of organic diagenesis on the adsorption of tetracyclines (TCs) by marine sediment. During a period of 4 months of incubation, SOM initially added into the sediment underwent biodegradation and diagenesis. The results showed an early decrease in TC adsorption by the sediment, which was likely caused by the competition between the microbial organic products and TC molecules for the adsorption sites. Afterward, TC adsorption by the sediment increased significantly, which was mainly due to the accumulation of condensed SOM. The experimental results indicate the interactions between TCs and the sediment during the dynamic process of SOM diagenesis. Moreover, the remaining SOM is shown to have an increasing affinity with the antibiotics. PMID- 23752398 TI - Adsorption of heavy metals by road deposited solids. AB - The research study discussed in the paper investigated the adsorption/desorption behaviour of heavy metals commonly deposited on urban road surfaces, namely, Zn, Cu, Cr and Pb, for different particle size ranges of solids. The study outcomes, based on field studies and batch experiments, confirmed that road deposited solids particles contain a significantly high amount of vacant charge sites with the potential to adsorb additional heavy metals. Kinetic studies and adsorption experiments indicated that Cr is the most preferred metal element to associate with solids due to the relatively high electronegativity and high charge density of trivalent cation (Cr(3+)). However, the relatively low availability of Cr in the urban road environment could influence this behaviour. Comparing total adsorbed metals present in solids particles, it was found that Zn has the highest capacity for adsorption to solids. Desorption experiments confirmed that a low concentration of Cu, Cr and Pb in solids was present in water-soluble and exchangeable form, whilst a significant fraction of adsorbed Zn has a high likelihood of being released back into solution. Among heavy metals, Zn is considered to be the most commonly available metal among road surface pollutants. PMID- 23752399 TI - The effects of anaerobic fermentation on dehydrated sludge. AB - Dehydrated sludge with two concentrations of total suspended solids (high: 50 g/L TSS; low: 20 g/L TSS) were studied for 20 d to investigate the effects of anaerobic fermentation on sludge properties. The results showed that the soluble chemical oxygen demand (SCOD) of high-concentration sludge was 16.53 g/L, much higher than that from the low one. The SCOD/total nitrogen ratio of high concentration sludge varied from 8 to 14.29 g/g, indicating that the sludge could serve as a carbon source for biological denitrification. High-concentration sludge showed a short-chain fatty acid yield of 11.29 g COD/L, much higher than that from low-concentration sludge. The specific resistance of the sludge to filtration (SRF) increased with fermentation time. The quantity of low-speed centrifugation substances (LSCS) was the main factor that influenced the reduction of dehydration. The correlation coefficient between the SRF and protein content in the LSCS layer was significantly positive. PMID- 23752400 TI - A co-beneficial system using aquatic plants: bioethanol production from free floating aquatic plants used for water purification. AB - A co-beneficial system using constructed wetlands (CWs) planted with aquatic plants is proposed for bioethanol production and nutrient removal from wastewater. The potential for bioethanol production from aquatic plant biomass was experimentally evaluated. Water hyacinth and water lettuce were selected because of their high growth rates and easy harvestability attributable to their free-floating vegetation form. The alkaline/oxidative pretreatment was selected for improving enzymatic hydrolysis of the aquatic plants. Ethanol was produced with yields of 0.14-0.17 g-ethanol/ g-biomass in a simultaneous saccharification and fermentation mode using a recombinant Escherichia coli strain or a typical yeast strain Saccharomyces cerevisiae. Subsequently, the combined benefits of the CWs planted with the aquatic plants for bioethanol production and nutrient removal were theoretically estimated. For treating domestic wastewater at 1,100 m(3)/d, it was inferred that the anoxic-oxic activated sludge process consumes energy at 3,200 MJ/d, whereas the conventional activated sludge process followed by the CW consumes only 1,800 MJ/d with ethanol production at 115 MJ/d. PMID- 23752401 TI - Effect of sponge volume fraction on the performance of a novel fluidized bed bioreactor. AB - A novel fluidized bed bioreactor (FBBR) was designed by integration of anaerobic granular activated carbon and aerobic sponge reactors. This FBBR was evaluated at different sponge volume fractions for treating a synthetic wastewater. Polyester urethane sponge with cube size of 1 * 1 * 1 cm and density of 28-30 kg/m(3) with 90 cells per 25 mm was used as biomass carrier. The results indicate that the FBBR could remove more than 93% of dissolved organic carbon (DOC). The highest nutrient removal efficiencies (58.2% PO4-P and 75.4% NH4-N) were achieved at 40% sponge volume fraction. The system could provide a good condition for biomass growth (e.g. 186.2 mg biomass/g sponge). No significant different performance in specific oxygen uptake rate was observed between 30, 40, and 50% sponge volume fractions. PMID- 23752404 TI - This month in archives of dermatology. PMID- 23752402 TI - Towards adaptive and integrated management paradigms to meet the challenges of water governance. AB - Integrated Water Resource Management (IWRM) aims at finding practical and sustainable solutions to water resource issues. Research and practice have shown that innovative methods and tools are not sufficient to implement IWRM - the concept needs to also be integrated in prevailing management paradigms and institutions. Water governance science addresses this human dimension by focusing on the analysis of regulatory processes that influence the behavior of actors in water management systems. This paper proposes a new methodology for the integrated analysis of water resources management and governance systems in order to elicit and analyze case-specific management paradigms. It builds on the Management and Transition Framework (MTF) that allows for the examination of structures and processes underlying water management and governance. The new methodology presented in this paper combines participatory modeling and analysis of the governance system by using the MTF to investigate case-specific management paradigms. The linking of participatory modeling and research on complex management and governance systems allows for the transfer of knowledge between scientific, policy, engineering and local communities. In this way, the proposed methodology facilitates assessment and implementation of transformation processes towards IWRM that require also the adoption of adaptive management principles. A case study on flood management in the Tisza River Basin in Hungary is provided to illustrate the application of the proposed methodology. PMID- 23752405 TI - Rhinoplasty: cases and techniques. PMID- 23752406 TI - About this journal. PMID- 23752408 TI - In situ reduction study of cobalt model Fischer-Tropsch synthesis catalysts. AB - Fischer-Tropsch (FT) synthesis is an important process to manufacture hydrocarbons and oxygenated hydrocarbons from mixtures of carbon monoxide and hydrogen (syngas). The catalysis process occurs on, for example, cobalt metal surfaces at elevated temperatures and pressures. A fundamental understanding of the reduction pathway of supported cobalt oxides, and the intermediate species present during the activation, can assist in developing improved industrial supported cobalt catalysts. Hard synchrotron X-rays have the unique ability to probe atomic processes both in terms of phases present as well as the crystallographic and local structure (using the pair distribution function approach) under realistic conditions. In this manuscript we present results from measurements during in situ hydrogen activation of a model Co/alumina catalyst using in situ synchrotron X-ray powder diffraction and pair-distribution function (PDF) analysis on beam line ID31 at the ESRF in Grenoble, France. The PDF analysis showed a substantially improved understanding of the reduction of cobalt oxides, as for the first time all cobalt could be accounted for by using total scattering analysis. PMID- 23752409 TI - What price affordable access? PMID- 23752410 TI - SGLT2 inhibitors enter crowded diabetes space. PMID- 23752412 TI - Amgen announces oncolytic virus shrinks tumors. PMID- 23752413 TI - Family offices bolster early-stage financing. PMID- 23752419 TI - US Congress moves to 'protect' GM crop plantings. PMID- 23752416 TI - AstraZeneca juggernaut heads for Cambridge. PMID- 23752420 TI - $350 million in new funding for brain research. PMID- 23752421 TI - Galecto Biotech. PMID- 23752422 TI - Drug pipeline: 1Q13. PMID- 23752423 TI - Inducing translation. PMID- 23752424 TI - A personal account of translating discoveries in an academic lab. PMID- 23752425 TI - The Langer Lab's secret sauce. PMID- 23752426 TI - Startups on the menu. PMID- 23752427 TI - The cancer megafund: a catalyst for disruptive innovation. PMID- 23752428 TI - The cancer megafund: determinants of success. PMID- 23752429 TI - The cancer megafund: mathematical modeling needed to gauge risk. PMID- 23752430 TI - Publications and patents in corporate venture-backed biotech. PMID- 23752431 TI - Literature access and destruction. PMID- 23752432 TI - What the French ban of Bt MON810 maize means for science-based risk assessment. PMID- 23752433 TI - Patent portfolios for biotech inventions. PMID- 23752434 TI - Identifying the metastatic seeds of breast cancer. PMID- 23752435 TI - Cancer metabolism in breadth and depth. PMID- 23752436 TI - All charged up about implanted biomaterials. PMID- 23752447 TI - Staying happy and productive as a mid-career professional. PMID- 23752438 TI - Insect resistance to Bt crops: lessons from the first billion acres. AB - Evolution of resistance in pests can reduce the effectiveness of insecticidal proteins from Bacillus thuringiensis (Bt) produced by transgenic crops. We analyzed results of 77 studies from five continents reporting field monitoring data for resistance to Bt crops, empirical evaluation of factors affecting resistance or both. Although most pest populations remained susceptible, reduced efficacy of Bt crops caused by field-evolved resistance has been reported now for some populations of 5 of 13 major pest species examined, compared with resistant populations of only one pest species in 2005. Field outcomes support theoretical predictions that factors delaying resistance include recessive inheritance of resistance, low initial frequency of resistance alleles, abundant refuges of non Bt host plants and two-toxin Bt crops deployed separately from one-toxin Bt crops. The results imply that proactive evaluation of the inheritance and initial frequency of resistance are useful for predicting the risk of resistance and improving strategies to sustain the effectiveness of Bt crops. PMID- 23752450 TI - The voluntary sector and the NHS. PMID- 23752449 TI - Self-reported adherence to the physical activity recommendation and determinants of misperception in older adults. AB - We aimed to compare self-reported adherence to the physical activity recommendation with accelerometry in older adults and to identify determinants of misperception. The sample included 138 adults age 65-75 yr old participating in the Longitudinal Aging Study Amsterdam. Participants completed a lifestyle questionnaire and wore an accelerometer for one week. More than half (56.8%) of the participants reported to adhere to the physical activity recommendation (in 5 min bouts), however, based on accelerometry, this percentage was only 24.6%. Of those who reported to adhere, 65.3% did not do so based on accelerometry. The misperceivers were older (p < .009), more often female (p = .007), had a poorer walking performance (p = .02), reported a lower social support (p = .04), and tended to have a lower self-efficacy (p = .09) compared with those who correctly perceived their adherence to the recommendation. These results suggest that misperception of adherence to the physical activity recommendation is highly prevalent among specific subgroups of older adults. PMID- 23752451 TI - Regular observations: safe airway management. PMID- 23752452 TI - Sexuality and stroke: the effects and holistic management. AB - Since the days of the early pioneering work of authors such as Glover (1985) and Woods (1987), there has been a proliferation of research and practice guidelines related to the effects of ill health on individuals' and couples' sexuality and sexual health (Reis et al, 2010; Sadovsky et al, 2010; Royal College of Nursing, 2000). This article reviews the common difficulties experienced by individuals and couples affected by stroke regarding to their sexuality and sexual health. Furthermore, it presents and explores a possible model of care that can be used in practice to address these difficulties with people affected by stroke. PMID- 23752453 TI - Time taken to seek and receive medical attention after TIA. AB - A transient ischaemic attack (TIA) is a warning sign that a debilitating stroke could occur unless preventive action is taken. People with suspected TIAs should be seen urgently in a specialist service that provides rapid assessment, preventive care and treatment. This article highlights the importance of seeking medical attention urgently for suspected TIAs. It examines how quickly a specialist TIA clinic investigates and treats TIAs. It also identifies factors that affect how quickly patients with TIAs seek medical attention. PMID- 23752454 TI - Catheter lubrication and fixation: interventions. AB - This article looks at the indications for catheterisation, the anatomy of the urethra, the importance of asepsis and the rationale for the use of urethral lubrication for catheter insertion. The variations of lubrication available are discussed, including the use of products containing lidocaine and chlorhexidine. It then considers the problems caused by traction to the catheter and discusses the securement devices available for preventing tissue damage at the bladder neck, within the urethra and also at the meatus. The variation of devices is examined along with the potential problems associated with their use. Finally, it discusses the importance of clinicians being knowledgeable about the problems looked at and how to resolve them. PMID- 23752455 TI - Staff perceptions of respiratory rate measurement in a general hospital. AB - BACKGROUND: the National Institute for Health and Care Excellence (NICE) (2007) states that 'respiratory rate is the best marker of a sick patient and is the first observation that will indicate a problem or deterioration in condition'. It is therefore crucial that staff are confident that respiratory rates are recorded accurately. AIMS: to assess perceptions of clinical staff regarding methods of assessment and reliability of respiratory rate recordings in observation charts. METHODS: we developed a questionnaire using best practice guidelines. Some 41 ward-based clinical staff completed the questionnaires. FINDINGS: confidence in the reliability of recordings is very low. Clinical staff think recordings are often estimated with no formal measurement, with 'perceived lack of time' being the most commonly cited explanation for inappropriate assessment. CONCLUSIONS: essential clinical information is not being used, as clinical staff lack confidence that it has been assessed correctly. Furthermore, inaccurate recordings could be actively misleading clinical care. PMID- 23752456 TI - Managing passive incontinence and incomplete evacuation. AB - Both passive faecal incontinence and evacuation difficulty are distressing and demoralising conditions, resulting in physical and psychological problems including social restrictions, loss of self-esteem, altered body image and loss of skin integrity. Conservative management and biofeedback therapy has been shown to help most patients with faecal incontinence and evacuation difficulty by creating a manageable situation that can significantly improve quality of life. However, some patients may not improve their symptoms and require alternative measures. This article reports an audit of the use of the Qufora mini irrigation system in 50 patients (48 female, 2 male) with passive faecal incontinence and/or evacuation difficulty who had failed to respond to conventional biofeedback. Seventy percent found the irrigation comfortable and 74% rated the system as good or acceptable. Two-thirds believed symptoms were improved and would wish to continue using the system. Prospective studies are needed to confirm which patients are most suitable and respond well to the irrigation. PMID- 23752457 TI - Care at the end of life: how policy and the law support practice. AB - The End of Life Care Strategy was introduced in an attempt to achieve a high standard of care for patients nearing the end of life and to improve carer experience. This high standard should not depend on socioeconomic status, geographical location or diagnosis. It was to ensure that individuals felt supported, informed and empowered, and that symptoms and issues were managed by experienced staff who employ evidenced-based practice. In addition, the service provision should involve a multidisciplinary team and have the patient at the centre of all decision-making. This would be facilitated by endorsing the use of end-of-life care pathways. These recommendations are further supported by frameworks and policies, for example the Preferred Priorities for Care Gold Standards Framework in Primary Care. Health professionals must also be cognisant of the legal frameworks that protect patients and facilitate their rights to exert their autonomy, for example the Mental Capacity Act and advanced directives. The issues surrounding care at the end of life with respect to legal frameworks alongside ethical and moral dilemmas will be further explored within this discussion paper. PMID- 23752458 TI - NMC reviews registration of nurses trained outside the EU. PMID- 23752459 TI - Care Quality Commission-the second update of care services. PMID- 23752460 TI - When does life-sustaining treatment become futile? AB - The law has long recognised that providing continued life-sustaining treatment to very sick and critically ill patients may be futile. The courts have consistently rejected an absolutist approach to care and treatment that requires doctors and nurses to continue with futile treatment right up to the point of death. If it is no longer in the best interests of the patient to receive treatment, then even life-sustaining treatment may be lawfully withdrawn. It is essential that nurses know when care and treatment becomes futile to ensure they are acting lawfully if a decision is taken to withdraw that care and treatment. In this article the author considers the Court of Appeal's recent test for determining when treatment becomes futile and its impact on nursing practice. PMID- 23752461 TI - Advancing practice: from staff nurse to nurse consultant. Part 10: courses and qualifications. PMID- 23752462 TI - It's time for nurses to fight back. PMID- 23752463 TI - Generic competition in a flawed system: pill them, bill them-reply. PMID- 23752464 TI - Error in Signature Block in: The JAMA Network Journals: New Names for the Archives Journals. PMID- 23752465 TI - Water complexes of cytochrome P450: insights from energy decomposition analysis. AB - Water is a small molecule that nevertheless perturbs, sometimes significantly, the electronic properties of an enzyme's active site. In this study, interactions of a water molecule with the ferric heme and the compound I (Cpd I) intermediate of cytochrome P450 are studied. Energy decomposition analysis (EDA) schemes are used to investigate the physical origins of these interactions. Localized molecular orbital EDA (LMOEDA) implemented in the quantum chemistry software GAMESS and the EDA method implemented in the ADF quantum chemistry program are used. EDA reveals that the electrostatic and polarization effects act as the major driving force in both of these interactions. The hydrogen bonding in the Cpd I***H2O complex is similar to that in the water dimer; however, the relative importance of the electrostatic effect is somewhat larger in the water dimer. PMID- 23752466 TI - Reduction of saltiness and acrylamide levels in palm sugar-like flavouring through buffer modification and the addition of calcium chloride. AB - Palm sugar-like flavouring (PSLF) is a type of flavour product that is formed by heating amino acids and sugar under specific heating conditions. Unfortunately, PSLF has a salty taste and contains high amounts of acrylamide. Hence, the objective of this research was to reduce saltiness and acrylamide without negatively affecting the aroma properties of PSLF. A decrease in the sodium phosphate (NaHPO4) buffer concentration from 0.20 to 0.02 M was found to reduce sodium to approximately 15% of the level found in original PSLF. A further decrease (~25%) in the sodium content was achieved by removing monobasic sodium phosphate (NaH2PO4) from the buffer system. Meanwhile, the addition of CaCl2 at 20-40 mg/L reduced the acrylamide content in PSLF by as much as 58%. A CaCl2 concentration of 20 mg/mL was most favourable as it most efficiently suppressed acrylamide formation while providing an acceptably high flavour yield in PSLF. In view of the high acrylamide content in PSLF, additional work is necessary to further reduce the amount of acrylamide by controlling the asparagine concentration in the precursor mixture. PMID- 23752467 TI - Practical aspects and mechanism of asymmetric hydrogenation with chiral half sandwich complexes. AB - This review is oriented toward the asymmetric transfer hydrogenation (ATH) of imines regarding mostly fundamental, yet important topics from the practical point of view. Development of analytical methods for the monitoring of ATH (i.e., kinetics and stereoselectivity) belongs to those topics, as well as studies on the influence of reaction conditions and structural variations on the reaction performance. The second part is devoted to the reaction mechanism with the emphasis on imine ATH and catalyst behaviour under acidic conditions. The review also addresses the asymmetric hydrogenation (AH) of ketones and imines using molecular hydrogen and the application of ATH in pharmaceutical projects. The contributions of our group to each area are included. PMID- 23752468 TI - Exploring the C-X...pi halogen bonding motif: an infrared and Raman study of the complexes of CF3X (X = Cl, Br and I) with the aromatic model compounds benzene and toluene. AB - The formation of halogen bonded complexes formed between the trifluorohalomethanes CF3Cl, CF3Br and CF3I and the Lewis bases benzene and toluene at temperatures below 150K was investigated using FTIR and Raman spectroscopy. Experiments using liquid krypton as solvent show that for both CF3Br and CF3I substantial fractions of the monomers can be involved in 1:1 complexes. In addition, weak absorptions illustrating the formation of 2:1 complexes between CF3I and benzene are observed. Using spectra recorded at temperatures between 120 and 140 K, observed information on the relative stability was obtained for all complexes by determining the complexation enthalpies in solution. The resulting values for CF3Br.benzene, CF3I.benzene and (CF3I)2.benzene are -6.5(3), -7.6(2) and -14.5(9) kJ mol-1. The values for CF3Br.toluene and CF3I.toluene are -6.2(5) and -7.4(5) kJ mol-1. The experimental complexation enthalpies are compared with theoretical data obtained by combining results from MP2/aug-cc-pVDZ(-PP) and MP2/aug-cc-pVTZ(-PP) ab initio calculations, from statistical thermodynamical calculations and from Monte Carlo Free Energy Perturbation simulations. The data are also compared with results derived for other C-X...pi halogen bonded complexes involving unsaturated Lewis bases such as ethene and ethyne. PMID- 23752469 TI - Application and analysis of the folin ciocalteu method for the determination of the total phenolic content from Limonium brasiliense L. AB - Limonium brasiliense is a common plant on the southern coast of Brazil. The roots are traditionally used for treatment of premenstrual syndrome, menstrual disturbances and genito-urinary infections. Pharmaceutical preparations obtained from its roots and used for these purposes were marketed in Brazil in the 1980s and 1990s. Currently, the Brazilian Drug Agency (National Health Surveillance Agency, ANVISA) has canceled the registration of these products, and their use was discontinued because of a lack of studies to characterize the plant raw material and ensure the effectiveness and safety of its use. The aim of the present study was to develop and validate an analytical method to determine the content of total polyphenols (TP) in an extract from L. brasiliense roots, by the UV/Vis spectrophotometric method. L. brasiliense roots were extracted in acetone:water (7:3, v/v-10% w/v). The crude extract was used to develop a method for TP assay. The method was validated according to national and international guidelines. The optimum conditions for analysis time, wavelength, and standard substance were 30 min, 760 nm, and pyrogallol, respectively. Under these conditions, validation by UV/Vis spectrophotometry proved the method to be linear, specific, precise, accurate, reproducible, robust, and easy to perform. This methodology complies with the requirements for analytical application and to ensure the reliability of the results. PMID- 23752470 TI - Design, synthesis and evaluation of the antibacterial enhancement activities of amino dihydroartemisinin derivatives. AB - Artemisinin (ART) and its derivatives artesunate (AS), dihydroartemisinin (DHA) are a group of drugs containing a sesquiterpene lactone used to treat malaria. Previously, AS was shown to not have antibacterial activity but to significantly increase the antibacterial activities of beta-lactam antibiotics against E. coli. Herein, molecular docking experiments showed that ART, AS and DHA could dock into AcrB very well, especially DHA and AS; both DHA and AS had the same docking pose. The affinity between AS and AcrB seemed weaker than that of DHA, while the succinate tail of AS, which was like a "bug", could extend in the binding pocket very well. Imitating the parent nucleus of DHA and the succinate tail of AS, twenty-one DHA derivatives 4a-u were designed and synthesized. Among them, seventeen were new compounds. The synergistic effects against E. coli AG100A/pET28a-AcrB showed among the new structures 4k, 4l, 4m, 4n, and 4r exhibited significant synergism with beta-lactam antibiotics although they had no direct antibacterial activities themselves. The bacterial growth assay showed that only 4k in combination with ampicillin or cefuroxime could totally inhibit bacterial growth from 0 to 12 h, demonstrating that 4k had the best antibacterial enhancement effect. In conclusion, our results provided a new idea and several candidate compounds for antibacterial activity enhancers against multidrug resistant E. coli. PMID- 23752471 TI - Arylsulfonylamino-benzanilides as inhibitors of the apical sodium-dependent bile salt transporter (SLC10A2). AB - The apical sodium-dependent bile salt transporter (ASBT) plays a pivotal role in maintaining bile acid homeostasis. Inhibition of ASBT would reduce bile acid pool size and lower cholesterol levels. In this report, a series of novel arylsulfonylaminobenzanilides were designed and synthesized as potential inhibitors of ASBT. Most of them demonstrated great potency against ASBT's bile acid transport activity. In particular, compound 5g2 inhibited ASBT activity with an IC50 value of 0.11 MUM. These compounds represent potential cholesterol lowering drugs. PMID- 23752472 TI - Dihydrochalcones with antiinflammatory activity from leaves and twigs of Cyathostemma argenteum. AB - A new dihydrochalcone derivative, 4',6'-dihydroxy-2',4-dimethoxy-5'-(2'' hydroxybenzyl)dihydrochalcone (1) and one known dihydrochalcone, 4',6'-dihydroxy 2',4- dimethoxydihydrochalcone (2) were isolated from leaves and twigs of Cyathostemma argenteum. Their structures were established by spectral methods, mainly 2D NMR spectroscopic techniques, which involved combined applications of DEPT, COSY, HMQC and HMBC. The molecular structure of 1 was also confirmed by single crystal X-ray diffraction. The test compounds 1 and 2 displayed significant inhibitory activity at a dose of 1 mg/ear on edema formation at all determination times, with similar intensity as phenylbutazone. PMID- 23752473 TI - Preliminary biological evaluation of novel (99m)Tc-Cys-annexin A5 as a apoptosis imaging agent. AB - A novel annexin A5 derivative (cys-annexin A5) with a single cysteine residue at its C-terminal has been developed and successfully labeled in high labeling yield with (99m)Tc by a ligand exchange reaction. Like the 1st generation (99m)Tc-HYNIC annexin A5, the novel (99m)Tc-cys-annexin A5 derivative shows in normal mice mainly renal and, to a lesser extent, hepatobiliary excretion. In rat models of hepatic apoptosis there was 283% increase in hepatic uptake of (99m)Tc-cys annexin A5 as compared to normal mice. The results indicate that the novel (99m)Tc-cys-annexin A5 is a potential apoptosis imaging agent. PMID- 23752474 TI - Tuning of the Rashba effect in Pb quantum well states via a variable Schottky barrier. AB - Spin-orbit interaction (SOI) in low-dimensional systems results in the fascinating property of spin-momentum locking. In a Rashba system the inversion symmetry normal to the plane of a two-dimensional (2D) electron gas is broken, generating a Fermi surface spin texture reminiscent of spin vortices of different radii which can be exploited in spin-based devices. Crucial for any application is the possibility to tune the momentum splitting through an external parameter. Here we show that in Pb quantum well states (QWS) the Rashba splitting depends on the Si substrate doping. Our results imply a doping dependence of the Schottky barrier which shifts the Si valence band relative to the QWS. A similar shift can be achieved by an external gate voltage or ultra-short laser pulses, opening up the possibility of terahertz spintronics. PMID- 23752475 TI - Free-standing, well-aligned ordered mesoporous carbon nanofibers on current collectors for high-power micro-supercapacitors. AB - The mesoporous carbon nanofiber arrays that stand on carbon-gold double-layer current collectors are synthesized by self-assembly of a PS-b-PEO copolymer and resol in AAO templates for a high-power micro-supercapacitor at high current densities. PMID- 23752477 TI - About this journal. PMID- 23752476 TI - DFT study of intramolecular interring eta6,eta6-haptotropic rearrangements in tricarbonylchromium complexes of 2-aminobiphenyl and 4-aminobiphenyl. AB - DFT studies have been carried out to investigate the role of nitrogen participation in the interring haptotropic rearrangements of [(eta(6)-C6H5)(C6H4 4-NH2)]Cr(CO)3 and [(eta(6)-C6H5)(C6H4-2-NH2)]Cr(CO)3. For the para-substituted case, where intramolecular coordination of nitrogen to chromium is not possible, DFT modeling predicts an activation barrier of 32.5 kcal mol(-1), which is in very close agreement with the experimentally determined value of 32.57 kcal mol( 1). In the case of the ortho-substituted isomers, modeling of a mechanism that does not invoke stabilization via nitrogen coordination yields a predicted energy barrier of 32.7 kcal mol(-1), while a mechanism that does invoke nitrogen participation and accounts for interconversion of rotational isomers gives a predicted value of 30.2 kcal mol(-1). This is consistent with the experimentally determined value of 31.22 kcal mol(-1). These data provide evidence that intramolecular stabilization via nitrogen coordination to chromium is responsible for the ortho substituted isomer undergoing haptotropic rearrangement with a rate nearly five times greater than that observed for the para isomer. For the mechanism that invokes ortho-amino group participation, transition state analysis in the frame of Bader theory shows that each transition state along the proposed mechanistic pathway has a bond critical point between nitrogen and chromium. PMID- 23752478 TI - Error in Byline in: Comparative Effectiveness of Rhythm Control vs Rate Control Drug Treatment Effect on Mortality in Patients With Atrial Fibrillation. PMID- 23752479 TI - Grief in health care professionals: when screening for major depression is needed reply. PMID- 23752480 TI - Performing radical cystectomy and urinary diversion in regional anesthesia: potential risk reduction in the treatment of bladder cancer. AB - OBJECTIVE: To assess the feasibility and performance of radical cystectomy with urinary diversion using exclusively regional anesthesia (i.e. combined spinal thoracic epidural anesthesia, CSTEA), avoiding the adverse effects of general anesthesia. MATERIALS AND METHODS: In our hospital, radical cystectomy with extended pelvic and iliac lymphadenectomy and urinary diversion was performed on 28 patients using CSTEA without applying general anesthesia, in 2011 and 2012. Under maintained spontaneous breathing, the patients were awake and responsive during the entire procedure. Outcome measurements included operative time, blood loss, start of oral nutrition, start of mobilization, postoperative pain levels using numerical and visual analog scales (NAS/VAS), postoperative complications according to the Clavien-Dindo classification and length of hospital stay. RESULTS: All surgical procedures were performed without any complications and caused no anesthesiologically or surgically untoward effects. We observed no more severe complications than grade 1 according to the Clavien-Dindo classification. CONCLUSIONS: Our data show that CSTEA is an effective and safe technique for radical cystectomy, whereby spontaneous breathing and reduced interference with the cardiopulmonary system potentially lower the perioperative risks, especially for high-risk patients. We recommend practice of CSTEA for radical cystectomy to further evaluate and monitor the safety, efficacy, outcomes and complications of CSTEA. PMID- 23752481 TI - Heparin-mediated fluorescence anisotropy assay of antithrombin based on polyethyleneimine capped Mn-doped ZnS quantum dots. AB - We presented a homogeneous heparin-mediated fluorescence anisotropy (FA) assay of antithrombin (AT) based on long-lived luminescent polyethyleneimine capped Mn doped ZnS (PEI-Mn-ZnS) QDs. The PEI-Mn-ZnS QDs with long lifetime luminescence at 585 nm displayed a very low background of FA value, which was very helpful for FA assaying of large molecules. The medium heparin was crucial for AT determination, and different heparin amounts resulted in different linear range of detection and sensitivity. For example, the limit of detection (LOD) of 0.9 nM AT with a detection linear range from 8.6 nM to 21.5 nM was found when the heparin concentration was 75 MUM. The proposed method also exhibited high selectivity over the coexisting or related proteins such as human serum albumin and thrombin. PMID- 23752482 TI - Effect of laser phototherapy in the prevention and treatment of chemo-induced mucositis in hamsters. AB - The aim of this study was to investigate the effect of laser phototherapy (LPT) in the prevention and/or treatment of oral mucositis induced by 5-fluorouracil (5 FU; Eurofarma, Sao Paulo, Brazil) in hamsters. Ninety-six hamsters were divided into four groups (n=24): Control (no treatment); Preventive [LPT from day (D) D-5 to D+5]; Therapeutic (LPT from D+5 to D+15); and Combined (preventive plus therapeutic LPT from D-5 to D+15). The animals received an intraperitoneal injection of 5-FU on Days 0 and 2. The pouch mucosa was scratched on Days 3 and 4. The irradiation parameters were: indium-gallium-aluminum-phosphide (InGaAlP) diode laser (MM Optics, Sao Carlos, Brazil) (660 nm), beam area of 0.036 cm2, 40 mW, 1.11 W/cm2, 6.6 J/cm2, power density applied daily of 39.6 J/cm2, in punctual mode (six points and six seconds per point) and contact mode, one application per day. The animals were sacrificed on Days 0, 5, 10 and 15 (n=6) and weighed, and the pouch mucosa was removed for histopathological analysis. Clinical and corresponding histological scores were compared using ANOVA and Tukey's test (p<=0.05). Similar weight losses ranging from 5% to 10% occurred in all groups. The therapeutic group had significantly lower clinical and histological scores than the other groups at Day 10. This study showed that positive effects on oral mucositis management were obtained only when LPT was applied in the therapeutic protocol (from D+5 to D+15 after chemotherapy). PMID- 23752484 TI - Highlights of archives of facial plastic surgery. PMID- 23752483 TI - Survival in patients with oral and maxillofacial diffuse large B-cell lymphoma. AB - The purpose of this study was to determine the survival and prognostic factors of patients with diffuse large B-cell lymphoma (DLBCL) of the oral cavity and maxillofacial region. Retrospectively, the clinical records of patients with a primary diagnosis of DLBCL of the oral cavity and maxillofacial region treated at the A.C. Camargo Hospital for Cancer, Sao Paulo, Brazil, between January 1980 and December 2005 were evaluated to determine (A) overall survival (OS) at 2 and 5 years and the individual survival percentage for each possible prognostic factor by means of the actuarial technique (also known as mortality tables), and the Kaplan Meier product limit method (which provided the survival value curves for each possible prognostic factor); (B) prognostic factors subject to univariate evaluation with the log-rank test (also known as Mantel-Cox), and multivariate analysis with Cox's regression model (all the variables together). The data were considered significant at p<=0.05. From 1980 to 2005, 3513 new cases of lymphomas were treated, of which 151 (4.3%) occurred in the oral cavity and maxillofacial region. Of these 151 lesions, 48 were diffuse large B-cell lymphoma, with 64% for OS at 2 years and 45% for OS at 5 years. Of the variables studied as possible prognostic factors, multivariate analysis found the following variables have statistically significant values: age (p=0.042), clinical stage (p=0.007) and performance status (p=0.031). These data suggest that patients have a higher risk of mortality if they are older, at a later clinical stage, and have a higher performance status. PMID- 23752486 TI - Genome-wide hypomethylation and cancer risk--response. PMID- 23752487 TI - Genome-wide hypomethylation and cancer risk--letter. PMID- 23752489 TI - Constructing inverse opal structured hematite photoanodes via electrochemical process and their application to photoelectrochemical water splitting. AB - In this study, we constructed an inverse opal structured hematite (IOS alpha Fe2O3) as the photoanode of a photoelectrochemical (PEC) cell for efficient solar water splitting via a simple electrochemical process. At the same time, a series of affecting factors (template particle size, electrodeposition time and annealing temperature) to construct the IOS alpha-Fe2O3 photoanode on the photoelectrochemical water splitting were considered. Optimized PEC efficiency was observed for the IOS alpha-Fe2O3 photoanode annealed at 400 degrees C using the 250 nm sized-polystyrene (PS) colloid template and 9 minutes of electrodeposition time for the given specific Fe precursor solution. This resulted in the highest photocurrent density compared to other crossed conditions, which significantly achieved 3.1 mA cm(-2) at 0.5 V vs. Ag/AgCl reference electrode. The synthesis of the IOS alpha-Fe2O3 via an easy-to-control electrochemical process is described for first time that opens a possibility for constructing other oxide semiconductor photoanodes (not only well-known Si, Ti and Zr) with inverse opal structure. PMID- 23752492 TI - Errors in Text and Figure Legend in: Effect of a Single-Cycle Alternative Dosing Regimen for Rituximab for Recalcitrant Pemphigus. PMID- 23752491 TI - An essential role for the N-terminal fragment of Toll-like receptor 9 in DNA sensing. AB - Toll-like receptor 9 (TLR9) is an innate immune sensor for microbial DNA that erroneously responds to self DNA in autoimmune disease. To prevent autoimmune responses, Toll-like receptor 9 is excluded from the cell surface and silenced until the N-terminal half of the ectodomain (TLR9N) is cleaved off in the endolysosome. Truncated Toll-like receptor 9 (TLR9C) senses ingested microbial DNA, although the precise role of the truncation remains controversial. Here we show that TLR9 is expressed on the surface of splenic dendritic cells. Following the cleavage of TLR9 in the endolysosome, N-terminal half of the ectodomain remains associated with truncated TLR9, forming the complex TLR9N+C. The TLR9 dependent cytokine production by Tlr9(-/-) dendritic cells is rescued by a combination of TLR9N and TLR9C, but not by TLR9C alone. These results demonstrate that the TLR9N+C complex is a bona fide DNA sensor. PMID- 23752493 TI - Vitamin D levels are associated with cardiac autonomic activity in healthy humans. AB - Vitamin D deficiency (<=50nmol/L 25-hydroxy vitamin D) is a cardiovascular (CV) risk factor that affects approximately one billion people worldwide, particularly those affected by chronic kidney disease (CKD). Individuals with CKD demonstrate abnormal cardiac autonomic nervous system activity, which has been linked to the significant rates of CV-related mortality in this population. Whether vitamin D deficiency has a direct association with regulation of cardiac autonomic activity has never been explored in humans. METHODS: Thirty-four (34) healthy, normotensive subjects were studied and categorized based on 25-hydroxy vitamin D deficiency (deficient vs. non-deficient, n = 7 vs. 27), as well as 1,25-dihydroxy vitamin D levels (above vs. below 25th percentile, n = 8 vs. 26). Power spectral analysis of electrocardiogram recordings provided measures of cardiac autonomic activity across low frequency (LF) and high frequency (HF, representative of vagal contribution) bands, representative of the sympathetic and vagal limbs of the autonomic nervous system when transformed to normalized units (nu), respectively, as well as overall cardiosympathovagal balance (LF:HF) during graded angiotensin II (AngII) challenge (3 ng/kg/min * 30 min, 6 ng/kg/min * 30 min). RESULTS: At baseline, significant suppression of sympathovagal balance was observed in the 25-hydroxy vitamin D-deficient participants (LF:HF, p = 0.02 vs. non-deficient), although no other differences were observed throughout AngII challenge. Participants in the lowest 1,25-dihydroxy VD quartile experienced significant withdrawal of inhibitory vagal control, as well as altered overall sympathovagal balance throughout AngII challenge (HF, mean difference = -6.98 +/- 3 nu, p = 0.05; LF:HF, mean difference = 0.34 +/- 0.1, p = 0.043 vs. above 25th percentile). CONCLUSIONS: Vitamin D deficiency is associated with suppression of resting cardiac autonomic activity, while low 1,25-dihydroxy vitamin D levels are associated with unfavourable cardiac autonomic activity during an acute AngII stressor, offering a potential pathophysiological mechanism that may be acting to elevate CV risk in in populations with low vitamin D status. PMID- 23752494 TI - Flavonoids and asthma. AB - Asthma is a chronic disease, characterized by airway inflammation, airflow limitation, hyper-reactivity and airway remodeling. It is believed that asthma is caused by the interaction between genetic and environmental factors. The prevalence of allergic diseases, including asthma, has increased worldwide during the past two decades. Although the precise reasons that have caused this increase remain unknown, dietary change is thought to be one of the environmental factors. Flavonoids, which are polyphenolic plant secondary metabolites ubiquitously present in vegetables, fruits and beverages, possess antioxidant and anti allergic traits, as well as immune-modulating activities. Flavonoids are powerful antioxidants and anti-allergic nutrients that inhibit the release of chemical mediators, synthesis of Th2 type cytokines, such as interleukin (IL)-4 and IL-13, and CD40 ligand expression by high-affinity immunoglobulin E (IgE) receptor expressing cells, such as mast cells and basophils. They also inhibit IL-4 induced signal transduction and affect the differentiation of naive CD4+ T cells into effector T-cells through their inhibitory effect on the activation of the aryl hydrocarbon receptor. Various studies of flavonoids in asthmatic animal models have demonstrated their beneficial effects. The results of several epidemiological studies suggest that an increase in flavonoid intake is beneficial for asthma. Moreover, clinical trials of flavonoids have shown their ameliorative effects on symptoms related to asthma. However, these human studies are currently limited; further validation is required to clarify whether an appropriate intake of flavonoids may constitute dietary treatment and for part of a preventive strategy for asthma. PMID- 23752496 TI - A novel class of polymeric pH-responsive MRI CEST agents. AB - In this communication, we report that ionizable, tertiary amine-based block copolymers can be used as pH-responsive contrast agents for magnetic resonance imaging (MRI) through the chemical exchange saturation transfer (CEST) mechanism. The CEST signal is essentially "off" when the polymers form micelles near physiological pH but is activated to the "on" state when the micelles dissociate in an acidic environment. PMID- 23752495 TI - Impact of short term consumption of diets high in either non-starch polysaccharides or resistant starch in comparison with moderate weight loss on indices of insulin sensitivity in subjects with metabolic syndrome. AB - This study investigated if additional non-starch polysaccharide (NSP) or resistant starch (RS), above that currently recommended, leads to better improvement in insulin sensitivity (IS) than observed with modest weight loss (WL). Obese male volunteers (n = 14) were given an energy-maintenance (M) diet containing 27 g NSP and 5 g RS daily for one week. They then received, in a cross over design, energy-maintenance intakes of either an NSP-enriched diet (42 g NSP, 2.5 g RS) or an RS-enriched diet (16 g NSP, 25 g RS), each for three weeks. Finally, a high protein (30% calories) WL diet was provided at 8 MJ/day for three weeks. During each dietary intervention, endogenous glucose production (EGP) and IS were assessed. Fasting glycaemia was unaltered by diet, but plasma insulin and C-peptide both decreased with the WL diet (p < 0.001), as did EGP (-11%, p = 0.006). Homeostatis model assessment of insulin resistance improved following both WL (p < 0.001) and RS (p < 0.05) diets. Peripheral tissue IS improved only with WL (57%-83%, p < 0.005). Inclusion of additional RS or NSP above amounts currently recommended resulted in little or no improvement in glycaemic control, whereas moderate WL (approximately 3 kg fat) improved IS. PMID- 23752497 TI - Hydrodynamic instabilities provide a generic route to spontaneous biomimetic oscillations in chemomechanically active filaments. AB - Non-equilibrium processes which convert chemical energy into mechanical motion enable the motility of organisms. Bundles of inextensible filaments driven by energy transduction of molecular motors form essential components of micron-scale motility engines like cilia and flagella. The mimicry of cilia-like motion in recent experiments on synthetic active filaments supports the idea that generic physical mechanisms may be sufficient to generate such motion. Here we show, theoretically, that the competition between the destabilising effect of hydrodynamic interactions induced by force-free and torque-free chemomechanically active flows, and the stabilising effect of nonlinear elasticity, provides a generic route to spontaneous oscillations in active filaments. These oscillations, reminiscent of prokaryotic and eukaryotic flagellar motion, are obtained without having to invoke structural complexity or biochemical regulation. This minimality implies that biomimetic oscillations, previously observed only in complex bundles of active filaments, can be replicated in simple chains of generic chemomechanically active beads. PMID- 23752498 TI - Choosing an intravenous dressing. PMID- 23752499 TI - A practical guide to safe PICC placement. AB - Peripherally inserted central catheters (PICCs) are a popular device for long term vascular access. They were introduced into practice in the US in the 1970s, but only gained popularity in the UK during the 1990s (Gabriel, 1995). Many nurses now provide services for central venous access. To ensure patient safety, it is important that practitioners inserting these devices maintain up-to-date knowledge and ensure evidence-based practice. This should ultimately reduce complication and risk during insertion. The purpose of this article is to offer a guide to safe PICC insertion by providing an overview of anatomy and physiology and focusing on some of the main complications of PICC insertion and methods along with ways of reducing these. PMID- 23752500 TI - Peripheral cannulation versus peripheral inserted central catheter. PMID- 23752501 TI - Right line, right patient, right time: every choice matters. AB - The field of vascular access has developed significantly over recent decades. It has been adapted to provide a range of techniques for a range of patients much faster than a full appreciation of the risks involved has developed. Improved governance of vascular access procedures in the UK is needed. This is driven by a deeper understanding of risks such as infectious and thrombotic complications, repeated failures of peripheral intravenous (IV) access leading to poor patient experience and treatment inadequacy, and the increasing emphasis on avoiding healthcare-associated infections. The Vessel Health and Preservation (VHP) protocol, which is used to standardise vascular access practice in the US is being evaluated for adoption in the UK. A comprehensive and inclusive approach should be taken to the vascular access needs of all patients. PMID- 23752502 TI - Antimicrobial infusions in the community. PMID- 23752503 TI - Needlestick injuries and safety syringes: a review of the literature. AB - Needlestick injuries are a serious concern for nurses and other healthcare workers. One of the main clinical risks from needlestick injury is the possible infection by blood-borne diseases, such as hepatitis and HIV. A number of different measures have been introduced to minimise the risk and impact of needlestick injuries, including the use of fixed-needle safety syringes. However, some healthcare workers refuse to use such devices, for reasons that include the perceived need to change syringe needles between drawing up a medicine and its administration to a patient. This paper will explore the literature relating to needlestick injuries and the reasons commonly given for not using fixed-needle safety syringes. PMID- 23752504 TI - Subclinical hypothyroidism and cardiovascular disease-reply. PMID- 23752506 TI - Klebsiella pneumoniae sequence type 11 from companion animals bearing ArmA methyltransferase, DHA-1 beta-lactamase, and QnrB4. AB - Seven Klebsiella pneumoniae isolates from dogs and cats in Spain were found to be highly resistant to aminoglycosides, and ArmA methyltransferase was responsible for this phenotype. All isolates were typed by multilocus sequence typing (MLST) as ST11, a human epidemic clone reported worldwide and associated with, among others, OXA-48 and NDM carbapenemases. In the seven strains, armA was borne by an IncR plasmid, pB1025, of 50 kb. The isolates were found to coproduce DHA-1 and SHV-11 beta-lactamases, as well as the QnrB4 resistance determinant. This first report of the ArmA methyltransferase in pets illustrates their importance as a reservoir for human multidrug-resistant K. pneumoniae. PMID- 23752505 TI - The griffithsin dimer is required for high-potency inhibition of HIV-1: evidence for manipulation of the structure of gp120 as part of the griffithsin dimer mechanism. AB - Griffithsin (Grft) is a protein lectin derived from red algae that tightly binds the HIV envelope protein gp120 and effectively inhibits virus infection. This inhibition is due to the binding by Grft of high-mannose saccharides on the surface of gp120. Grft has been shown to be a tight dimer, but the role of the dimer in Grft's anti-HIV function has not been fully explored. To investigate the role of the Grft dimer in anti-HIV function, an obligate dimer of Grft was designed by expressing the protein with a peptide linker between the two subunits. This "Grft-linker-Grft" is a folded protein dimer, apparently nearly identical in structural properties to the wild-type protein. A "one-armed" obligate dimer was also designed (Grft-linker-Grft OneArm), with each of the three carbohydrate binding sites of one subunit mutated while the other subunit remained intact. While both constructed dimers retained the ability to bind gp120 and the viral surface, Grft-linker-Grft OneArm was 84- to 1,010-fold less able to inhibit HIV than wild-type Grft, while Grft-linker-Grft had near-wild-type antiviral potency. Furthermore, while the wild-type protein demonstrated the ability to alter the structure of gp120 by exposing the CD4 binding site, Grft linker-Grft OneArm largely lost this ability. In experiments to investigate gp120 shedding, it was found that Grft has different effects on gp120 shedding for strains from subtype B and subtype C, and this might correlate with Grft function. Evidence is provided that the dimer form of Grft is critical to the function of this protein in HIV inhibition. PMID- 23752507 TI - Pharmacokinetics of a multipurpose pod-intravaginal ring simultaneously delivering five drugs in an ovine model. AB - Multipurpose technologies that simultaneously protect from sexually transmitted infections and unintended pregnancy are urgently needed. Pod-intravaginal rings (IVRs) formulated with the antiretroviral agents (ARVs) tenofovir, nevirapine, and saquinavir and the contraceptives etonogestrel and estradiol were evaluated in sheep. Steady-state concentrations were maintained for 28 days with controlled, sustained delivery. This proof-of-principle study demonstrates that pod IVRs can deliver three ARVs from different mechanistic classes and a progestin-estrogen combination over the wide range needed for putative preventative efficacy. PMID- 23752508 TI - Correlation between Plasmodium yoelii nigeriensis susceptibility to artemisinin and alkylation of heme by the drug. AB - Evidence of artemisinin (ART) resistance in all of the Greater Mekong Region is currently of major concern. Understanding of the mechanisms of resistance developed by Plasmodium against artemisinin and its derivatives is urgently needed. We here demonstrated that ART was able to alkylate heme in mice infected by the ART-susceptible strain of Plasmodium yoelii nigeriensis, Y-control. After long-term drug pressure, the parasite strain (Y-ART3) was 5-fold less susceptible to ART than Y-control. In the blood of mice infected by Y-ART3, no heme artemisinin adducts could be detected. After release of ART drug pressure, the parasite strain obtained (Y-REL) regained both drug susceptibility to ART and increased ability to produce covalent heme-artemisinin adducts. The correlation between parasite ART susceptibility and alkylation of heme by the drug confirms that heme or hemozoin metabolism is a key target for efficacy of ART as an antimalarial. PMID- 23752509 TI - CTX-M-123, a novel hybrid of the CTX-M-1 and CTX-M-9 Group beta-lactamases recovered from Escherichia coli isolates in China. AB - The chimeric bla(CTX-M-123) gene was identified in two ceftazidime-resistant Escherichia coli isolates from animals in different Chinese provinces. Like other CTX-M-1/9 group hybrids (CTX-M-64 and CTX-M-132), the ends (amino acids 1 to 135 and 234 to 291) of CTX-M-123 match CTX-M-15 while the central part (122 to 241) matches CTX-M-14. bla(CTX-M-123) is carried on related, but not identical, ~90-kb IncI1 plasmids in the two isolates, and one isolate simultaneously carries the group 1 blaCTX-M-55 gene on an additional IncI2 plasmid. PMID- 23752510 TI - Synergistic activity of colistin plus rifampin against colistin-resistant KPC producing Klebsiella pneumoniae. AB - Infections caused by carbapenem-resistant KPC-producing Klebsiella pneumoniae are responsible for high rates of mortality and represent a major therapeutic challenge, especially when the isolates are also resistant to colistin. We used the checkerboard method to evaluate the synergistic activity of 10 antibiotic combinations against 13 colistin-resistant KPC-producing K. pneumoniae isolates (colistin MIC range of 8 to 128 mg/liter). Colistin plus rifampin was the only combination that demonstrated consistent synergistic bacteriostatic activity against 13/13 strains tested, reducing the colistin MIC below the susceptibility breakpoint (MIC <= 2 mg/liter) in 7/13 strains at rifampin concentrations ranging from 4 to 16 mg/liter. Bactericidal synergistic activity was also documented for 8/13 tested strains. Other antimicrobial combinations with carbapenems, gentamicin, and tigecycline showed variously synergistic results. Colistin plus rifampin also exhibited bacteriostatic synergistic activity against 4/4 colistin susceptible KPC-producing K. pneumoniae isolates (colistin MIC range of 0.5 to 2 mg/liter) and 4/4 ertapenem-resistant extended-spectrum beta-lactamase (ESBL) producing K. pneumoniae isolates (ertapenem MIC range of 16 to 32 mg/liter). Collectively, our data suggest that colistin plus rifampin is the most consistently synergistic combination against KPC-producing K. pneumoniae isolates, including colistin-resistant strains. Colistin-rifampin combinations may have a role in the treatment of multidrug-resistant K. pneumoniae and may possibly slow the selection of heteroresistant subpopulations during colistin therapy. PMID- 23752511 TI - Distinction between the Cfr methyltransferase conferring antibiotic resistance and the housekeeping RlmN methyltransferase. AB - The cfr gene encodes the Cfr methyltransferase that primarily methylates C-8 in A2503 of 23S rRNA in the peptidyl transferase region of bacterial ribosomes. The methylation provides resistance to six classes of antibiotics of clinical and veterinary importance. The rlmN gene encodes the RlmN methyltransferase that methylates C-2 in A2503 in 23S rRNA and A37 in tRNA, but RlmN does not significantly influence antibiotic resistance. The enzymes are homologous and use the same mechanism involving radical S-adenosyl methionine to methylate RNA via an intermediate involving a methylated cysteine in the enzyme and a transient cross-linking to the RNA, but they differ in which carbon atom in the adenine they methylate. Comparative sequence analysis identifies differentially conserved residues that indicate functional sequence divergence between the two classes of Cfr- and RlmN-like sequences. The differentiation between the two classes is supported by previous and new experimental evidence from antibiotic resistance, primer extensions, and mass spectrometry. Finally, evolutionary aspects of the distribution of Cfr- and RlmN-like enzymes are discussed. PMID- 23752512 TI - First description of KPC-2-producing Klebsiella oxytoca in Brazil. AB - The present work reports the detection of the first case of nosocomial Klebsiella oxytoca producing class A carbapenemase KPC-2 in Brazil. The isolate KPN106 carried a 65-kb IncW-type plasmid that harbors the blaKPC gene and Tn4401b. Moreover, we detected the presence of a class 1 integron containing a new allele, arr-8, followed by a 5'-truncated dhfrIIIc gene. In view of the recent results, we emphasize the high variability of the bacterial and genetic hosts of this resistance determinant. PMID- 23752513 TI - Complete sequences of two plasmids in a blaNDM-1-positive Klebsiella oxytoca isolate from Taiwan. AB - Genetic determinants of a bla(NDM-1)-positive, multidrug-resistant bacterial isolate that caused active infection was investigated by DNA sequencing. Two plasmids, pKOX_NDM1 and pKOX-R1, were identified for the Klebsiella oxytoca strain E718. Sequence annotation revealed a bla(NDM-1) gene in pKOX_NDM1 and two extended-spectrum beta-lactamase producers (bla(CTX-M-3) and blaSHV-12) and a wide array of resistance genes in pKOX-R1. These findings highlight the difficulty in treating multidrug-resistant bacterial infections and the potential danger of emerging resistant enterobacteria. PMID- 23752514 TI - Emergence of NDM-1 in association with OXA-48 in Klebsiella pneumoniae from Tunisia. PMID- 23752515 TI - A modified zinc acetate gel, a potential nonantiretroviral microbicide, is safe and effective against simian-human immunodeficiency virus and herpes simplex virus 2 infection in vivo. AB - We previously showed that a prototype gel comprising zinc acetate (ZA) in carrageenan (CG) protected mice against vaginal and rectal herpes simplex virus 2 (HSV-2) challenge as well as macaques against vaginal simian-human immunodeficiency virus reverse transcriptase (SHIV-RT) challenge. In this work, we modified buffers and cosolvents to obtain a stable, nearly iso-osmolal formulation and evaluated its safety and efficacy against SHIV-RT and HSV-2. In vitro toxicity to lactobacilli and Candida albicans was determined. Macaques were given daily doses of ZA and CG (ZA/CG) or CG alone vaginally for 14 days and challenged with SHIV-RT 24 h later. Mice were challenged vaginally or rectally with HSV-2 immediately after a single gel treatment to measure efficacy or vaginally 12 h after daily gel treatment for 7 days to evaluate the gel's impact on susceptibility to HSV-2 infection. The modified ZA/CG neither affected the viability of lactobacilli or C. albicans nor enhanced vaginal HSV-2 infection after daily ZA/CG treatment. Vaginal SHIV-RT infection of macaques was reduced by 66% (P = 0.006) when macaques were challenged 24 h after the last dose of gel. We observed 60% to 80% uninfected mice after vaginal (P < 0.0001) and rectal (P = 0.008) high-dose HSV-2 challenge. The modified ZA/CG gel is safe and effective in animal models and represents a potential candidate to limit the transmission of HIV and HSV-2. PMID- 23752517 TI - [Work and education in health in Brazil: trends in scientific output between 1990 2010]. AB - The scope of this article is to analyze the characteristics of scientific literature on work and education in health in Brazil from 1990 to 2010. A synthetic study was conducted from abstracts published in Brazilian journal articles selected from the SCIELO and LILACS databases. Five hundred and thirty two articles were selected, categorized according to their origin, year of publication, theme, and type of study. The publication of these scientific articles increased during the period analyzed, particularly from 2007 onwards. The main areas researched were education and training of health professionals, and the majority of works in these areas examine curriculum reform, methods of learning and teaching, and teaching in-service experiences. Besides these issues, others questions were addressed such as the labor market configuration and trends in health, and characteristics of the work process in several areas, like primary healthcare units. It was also observed that there are only a small number of studies related to policy, planning and management of work in public and private health institutions, as well as a scarcity of studies presenting reflections on theoretical and conceptual aspects of this theme. PMID- 23752516 TI - Epidemiology and risk factors for isolation of Escherichia coli producing CTX-M type extended-spectrum beta-lactamase in a large U.S. Medical Center. AB - A case-case-control study was conducted to identify independent risk factors for recovery of Escherichia coli strains producing CTX-M-type extended-spectrum beta lactamases (CTX-M E. coli) within a large Southeastern Michigan medical center. Unique cases with isolation of ESBL-producing E. coli from February 2010 through July 2011 were analyzed by PCR for blaCTX-M, blaTEM, and blaSHV genes. Patients with CTX-M E. coli were compared to patients with E. coli strains not producing CTX-M-type ESBLs (non-CTX-M E. coli) and uninfected controls. Of 575 patients with ESBL-producing E. coli, 491 (85.4%) isolates contained a CTX-M ESBL gene. A total of 319 (84.6%) patients with CTX-M E. coli (282 [74.8%] CTX-M-15 type) were compared to 58 (15.4%) non-CTX-M E. coli patients and to uninfected controls. Independent risk factors for CTX-M E. coli isolation compared to non-CTX-M E. coli included male gender, impaired consciousness, H2 blocker use, immunosuppression, and exposure to penicillins and/or trimethoprim sulfamethoxazole. Compared to uninfected controls, independent risk factors for isolation of CTX-M E. coli included presence of a urinary catheter, previous urinary tract infection, exposure to oxyimino-cephalosporins, dependent functional status, non-home residence, and multiple comorbid conditions. Within 48 h of admission, community-acquired CTX-M E. coli (n = 51 [16%]) and non-CTX-M E coli (n = 11 [19%]) strains were isolated from patients with no recent health care contacts. CTX-M E. coli strains were more resistant to multiple antibiotics than non-CTX-M E. coli strains. CTX-M-encoding genes, especially bla(CTX-M-15) type, represented the most common ESBL determinants from ESBL-producing E. coli, the majority of which were present upon admission. Septic patients with risk factors for isolation of CTX-M E. coli should be empirically treated with appropriate agents. Regional infection control efforts and judicious antibiotic use are needed to control the spread of these organisms. PMID- 23752518 TI - [Health professionals and workers in Brazil: where do we go from here?]. PMID- 23752519 TI - [Scientific policies and production: dialogues between work and education in health]. PMID- 23752520 TI - [Work and education in health: broadening the human resources approach]. PMID- 23752521 TI - [The authors reply]. PMID- 23752522 TI - [Productive restructuring and the reallocation of work and employment: a survey of the "new" forms of social inequality]. AB - The scope of this paper is to question the inevitability of the processes of segmentation and increased precariousness of the relations of labor and employment, which are responsible for the introduction of "new" forms of social inequality that underpin the current model of development of economies and societies. It seeks to criticize the limits of global financial and economic logic, which constitute a "new spirit of capitalism," namely a kind of reverence for the natural order of things. It is therefore necessary to conduct an analytical survey of the ongoing changes in the labor market, accompanied by epistemological vigilance which makes it possible to see neoliberal (di)visions and dominant techno-deterministic theses in context. The enunciation of scenarios on the future of work will conclude this survey and will make it possible to draw attention to both the historical and temporal constraints and to the urgent need to unveil what is ideological and political in the prevailing logic of rationalization and processes to reinstate work and employment as a "central social experience" in contemporary times. PMID- 23752523 TI - [The workforce in the Brazilian healthcare grid: advantages and challenges]. AB - This essay discusses the importance and the dimension of the workforce in the healthcare grid in the Brazilian labor market. It examines the growing occupation trend in relation to restrictions to the rise in productivity, especially in the activities in the center of the healthcare complex. In a context of recurrent governmental budget constraints, the development of the Unified Health System ultimately results in increased coverage, but with deteriorating conditions and wages. This trend has also been accompanied by tensions in resource sharing with other pillars of social policies. The essay concludes that, in order to achieve high quality treatment and adequate working conditions, public health policy requires a better solution for its funding and greater linkages with the institutional matrix of general social policies. Even with the need for greater efficiency in spending, current resources are insufficient. Furthermore, it is important to highlight the need for institutional interaction of health policy with other social policies, seeking to ensure a more comprehensive and quality service for the population. PMID- 23752524 TI - [Labor rights and the organization of workers in a context of change in labor relations: effects on health workers]. AB - This paper presents the main institutional changes in labor relations in Brazil, highlighting their impact on the organization of workers. A more recent central change is the regulation of outsourcing by the Labor Judiciary. Research into claims in the Superior Labor Court, guidelines from the Labor Prosecution Office, and trade union lawsuits, show that outsourcing and working hours are subjects which have directly affected health workers. By addressing the institutional principles of justice in contracts, it was concluded that labor reform should deal with the inequality of rights that have characterized the Brazilian labor market. PMID- 23752525 TI - [The managerial dimension of labor: aspects of care activities]. AB - The paper deals with the issue of the transformation of the worlds of work, focusing on the healthcare sector from the ergological perspective, the object of reflection and analysis of which are human activities. Initially an attempt is made to show the transformations that have occurred in performing the activity per se, emphasizing the discussions of norms and values present in healthcare situations, based on research that addressed the activities of care. Subsequently the change of values that occur in a tripolar space are discussed, in which the activity is one of the poles, indicating the tensions that impinge upon it and examining the coexistence of different temporalities that surround the worlds of work. A study is conducted to reflect on the different dimensions/poles of transformation related to work and their temporalities, opposing the idea that these originate from and are imposed solely by the market. Finally a discussion on the reserves of alternatives contained in the actual work processes is staged, seeking to point out ways that consider the viewpoint of activity and the knowledge accumulated by workers. PMID- 23752526 TI - [The contemporary relationship between work, qualification and recognition: repercussions on the Unified Health System (SUS) workers]. AB - This paper discusses the relationship between work, qualification and recognition as it occurs in the field of health today, specifically considering the employability of technical workers in the Unified Health System, the way they perceive the employment relationship with respect to their self-esteem regarding their subjectivities. Based on a review of the relevant literature, the subject is treated in the wider context of ongoing changes in the workplace, which are associated with intensification, flexibility and precariousness of labor relations, with repercussions on the specific aspects mentioned. An attempt is made to establish a critical dialogue with the analytical aspect that emphasizes daily work as a privileged forum for overcoming the contradictions that characterize the field of work and education in the SUS nowadays. The text emphasizes the following issues: analysis of the relationship between work and education from the perspective of the concept of skill; the broadening of the meaning of health work; and a critical evaluation of policies that end up making the workers liable for the quality of services rendered. PMID- 23752527 TI - [The Fernando Henrique Cardoso (FHC) and Luiz Inacio Lula da Silva (Lula) governments and the policy for the civil servant workforce of the Brazilian government]. AB - This article analyzes the configuration of the active civil servant workforce of the Brazilian government during Fernando Henrique Cardoso - FHC - (1995-2002) and Luiz Inacio Lula da Silva - Lula - (2003-2010) mandates. The article associates the condition of the workforce of the Brazilian government with the changes in the government coalition. The residual participation of the Ministry of Health (MOH) in the direct provision of public services influenced the downward trend of the federal workforce.The implementation of the Unified Health System (SUS) was strongly affected by the structural adjustment of the workforce at the federal level during the decades of 1990 and 2000. PMID- 23752528 TI - [The trajectory of the national policy for the reorientation of professional training in health in the Unified Health System (SUS)]. AB - This paper examines the national policy and its antecedents for reorientation of professional health training implemented after 2003. It highlights landmarks and transformations in the course of policies between 1980 and 2010, elements of continuity and change and the connections between past and current policy initiatives. The study involved a review of the literature on the subject and document analysis supported by theoretical analysis of public policies, particularly historical institutionalism. The results point to four different moments during the trajectory of the policy, marked by changes in the initiatives of reorientation of higher education in health: antecedents; initial experiences; university protagonism; broadening and enhancement. As an element of continuity, there is the permanence of objects in the guiding principles advocated in the policies. The evidence of implementation expresses prospects of enhancement, with diversification of mobilized actors and organizations, and more projects implemented. The accumulated experience suggests structural maturity of the structural bases of action and the main changes relate to the enhancement of decision-making bodies of the SUS and the approximation to the process of decentralization and regionalization of national health policy. PMID- 23752529 TI - [The implementation of undergraduate courses in public health: the viewpoint of the coordinators]. AB - Undergraduate courses in Public Health are now a reality in Brazil. The main goal of this article is to present the viewpoints of the coordinators of these courses on the process of their creation and implementation, emphasizing their contextual and procedural elements. Ten actors working in eight different institutions were interviewed and the interviews were submitted to content analysis as proposed by Bardin. The results showed that the creation of such courses resulted from a long process of discussion on the field of Public Health, and was hastened by some important decisions in Brazilian education, including the Program to Support Restructuring and Expansion Plans of Federal Universities. The testimonies of the coordinators enabled the researchers to understand the context prior to the proposal and the way it was developed by each university, making it possible to establish not only the aspects common to each institution, but also their specificities. Currently, these courses have the purpose of training professionals focused on the different areas of health services, especially those related to the Unified Health System (SUS), representing an irreversible advance in the field of Public Health. PMID- 23752530 TI - [Interdisciplinary Bachelor's degree in Health: an innovative proposal in higher education in Health in Brazil]. AB - This article describes and analyzes the political and institutional context and the process of implementation of the Interdisciplinary Bachelor's degree in Health (IBH) during the 2006-2011 period. The methodology included document review and analysis of personnel records of the researchers involved. By using the concepts of "window of opportunity" and "hypercomplex organization," it was revealed that managerial and organizational structures were created and master documents were prepared. In addition to this, actions for implementation of the course, related to the structure of the faculty and the academic council, preparation of the pedagogical project, planning, implementation and monitoring of the teaching-learning process in the various curriculum components offered since 2009 was conducted. Analysis of the challenges and prospects of the course indicates that the major problem is the tension between the traditional model of vocational and discipline-based higher education existing hitherto and the interdisciplinary model proposed by IBH. This tension can be overcome by the full implementation of learning cycles with the institutionalization of IBH as the first cycle of professional health education. PMID- 23752531 TI - [Pedagogical training in stricto sensu graduate programs in public health]. AB - The scope of this research is to discuss the relevance and need for pedagogical training of university lecturers in the Public Health field. The contention is that college teaching is a practice that requires specific training, since it is characterized by complex elements that transcend the mastery of given content. Considering stricto sensu graduate studies as an important stage in the training of future university lecturers, an attempt was made to identify and analyze the subjects and practices of pedagogical training in academic masters and doctorate programs in Public Health. To achieve the research aim, this work was based on Pierre Bourdieu's field theory and on Tomaz Tadeu da Silva's curriculum theory. Results indicate that the programs do not consider the aspect of teacher training as a major issue. With regard to the Public Health field approximately 61% of masters and 38% of doctorate programs have pedagogical training subjects/practices. Furthermore, there is a tendency for technical-instrumental training, which is in line with the history of the Public Health field. The conclusion is that there is a need to develop a culture that values college and graduate Public Health teaching, considering the complexity of pedagogical practice in all its dimensions. PMID- 23752532 TI - [Undergraduate students in Public Health: a socio-demographic profile and motivations]. AB - Undergraduate Courses in Public Health (UCPH) feature a new way of teaching in the Public Health field that aims to educate professionals focused on the main health needs of the Brazilian population and on the Unified Health System. Thus, it is relevant to know the students' socio-demographic profile including their interests in relation to education and professional development. Adopting a quantitative approach with these objectives, a survey was conducted with 304 UCPH students who filled out a semi-structured questionnaire in 2010 in the following federal universities: Acre, Bahia, Minas Gerais, Mato Grosso, Parana, Rio de Janeiro and Rio Grande do Norte. The overwhelming majority was female, around 26 years of age, single, living with their parents, mostly attended public school, came from lower classes with lower educational background, approved night classes, worked, and contributed to their family incomes. They aspired to work in public sector - preferably in the state capitals - and they saw UCPH as an opportunity to work in the public health field. This profile reveals challenges and advances in the intended education, reinforcing the need to monitor the UCPH development process. PMID- 23752533 TI - [Productive restructuring and its impact on labor relations in the public health services in Brazil]. AB - The restructuring of productive systems and economic globalization are directly impacting the basic social rights of workers. In the semi-peripheral countries such as Brazil, where the wage-based society and the consolidation of social rights are not completely implemented, this process of change in the world of labor contributes to aggravate the inequality in the capital-labor relationship and hampers access to employment. By means of a critical review of the scientific literature regarding changes in the world of labor and its impact on the organization and production of health services in Brazil, this article pinpoints the weakness of regulation of the labor market in Brazil, especially in the health sector. It also stresses the need to increase the debate on new forms of institutionalization of the labor relationship in order to ensure equity in the workplace and protect the rights to work and in the workplace. PMID- 23752534 TI - [Contexts, impasses and challenges for training Public Health workers in Brazil]. AB - An introductory comment is made on the historical background, institutional impasses and curriculum challenges for training Public Health workers in Brazil. Initially, a thesis is proposed, namely that the Brazilian state has not fulfilled its responsibility to ensure quality public services for the population, with access and equity, shaping "the four perversions of Brazilian education." Secondly, it analyzes the public health system, which is theoretically universal, but being underfunded and with acknowledged shortcomings, contributes to the increase in social exclusion. Lastly, it highlights the need for new models for training people who are technologically competent, suitable for teamwork, creative, autonomous, problem-solving, engaged in health promotion, open to social participation and committed to the humanization of health. PMID- 23752535 TI - [Management of financial resources of permanent education in health: challenge of the in-service learning integration committees]. AB - Despite adhering to the dynamics established in the Management Pact, the use of financial resources of Permanent Education in Health (PEH) still features as a problem in Brazil. This study analyzes how the management of these financial resources by two Permanent In-Service Learning Integration Committees (ICLS) evolves in the State of Santa Catarina, Brazil. It involves a qualitative, participatory research study adapted from Paulo Freire's Thematic Research conducted with 56 members from two ICLS between May and December 2009. After setting up the research groups, the members participated in the stages of theme generation surveys, encoding, decoding, and critical exposition of the reality. Participant observation and dialogue were the main data collection techniques. The results indicate that the two ICLS are not dissimilar in terms of issues of management of resources destined for policy, with bureaucracy, the indefinition of forms of financial management and delays that permeate regional structures responsible for resource management being the main factors detected. The participants considered the elaboration of PEH actions in the management of financial resources at state level to be the main opportunities for change. PMID- 23752536 TI - [Who teaches queer: the prospect of queer theory analysis in the health education process]. AB - The scope of this essay is to reflect on the possibilities of inclusion of a queer analytical body to the processes of education in the health field. This is because the development of the Unified Health System, with its new set of health practices has revealed challenges that include broadening the knowledge set especially required for revitalization of the notion of subject. Queer theory is needed to understand how identities and in particular gender and sexuality are incorporated, in a social and cultural process, and how, in the micro-social spaces, it can determine educational practices with the power to reinforce the status of the so-called minority sexualities. Queer theory framed in so-called post-critical theories of education is analyzed from the categories of power, resistance, transgression in the context of standardization and subjectivity. It is assumed that processes of education in health, grounded in queer teaching, working in terms of difference and not diversity, proposing processes of deconstruction of binaries such as nature/culture, reason/passion, homosexual/heterosexual, working towards shaping more assertive cultural and social subjects. PMID- 23752537 TI - [Parental stress in families of children with cerebral palsy: an integrative review]. AB - This article aims to select, evaluate and interpret critically the bibliographic production focused on the stress experienced by parents/caregivers of children with cerebral palsy. An integrative literature review was conducted. Sources for this search were the Virtual Health Library (VHL), the United States National Library of Medicine (PubMed) and manual search of references from the selected studies. It was decided to select studies published between 1998 and 2011. The sample included 13 articles. Parents of children with cerebral palsy have higher stress levels than parents of children without disabilities. Behavioral problems, psychological disorders and emotional needs of children were factors commonly associated with high levels of stress. Satisfaction with social support, satisfaction with the parental role, a good family rapport, an emotional bond between father/mother and child, spousal support and the sense of being an active participation in social life help reduce stress levels. Parents of children with cerebral palsy are likely to have their health affected by higher levels of stress. Thus, health professionals should give them special attention. PMID- 23752538 TI - Familial mental retardation: a review and practical classification. AB - Mental retardation (MR) is a definition which comprises a series of conditions whose common feature is an intellectual handicap that develops before the age of 18, afflicting 2-3% of the world's population. The classification of MR into different categories is determined by the extent of the handicap instead of its cause, which often remains unrecognized. Sometimes, MR runs in a family, characterizing familial MR, and those cases permit an in-depth look into the genetic causes and consequences of the problem. However, almost no work is available on the prevalence of familial MR among the registered MR cases, possibly because familial MR is a term with no clear definition. The scope of this work is to review the topic and discuss the implications of different genetic and environmental factors, which characterize particular categories of familial cases, suggesting a practical classification of familial MR, which is important for epidemiologic studies and also for counseling in the clinic. Some of the aspects are discussed under the perspective of a newly-developed country like Brazil. PMID- 23752539 TI - [Translational research: an interpretation]. AB - Translational Research (TR) appears to be developing into the key health research issue of the beginning of this century. Initially proposed in the United States, TR is spread rapidly throughout both the developed and the developing world. This article discusses the main topics it covers, such as its definition and scope and the reasons why it has emerged in the USA and in this century. It examines the relationship between TR and the basic principles of US scientific policy established at the end of World War II. It sees the demands of a mighty pharmaceutical industry, currently facing a major crisis, linked to scientific genomic and post-genomic output impairments in terms of real innovative products and processes as being the explanation for US government intervention in biomedical research via the NIH. It realizes that it is not easy to predict the future of TR and suggests that it is not sustained by a solid conceptual and theoretical framework. It also discusses the opportunities and possibilities of TR in countries with nascent national innovative systems, such as Brazil. Lastly, it suggests that the existence of a universal health system can be an important tool to provide potential research answers tin health for the demands of innovation on the part of society. PMID- 23752540 TI - [Reasons why pregnant women did not vaccinate against influenza A H1N1]. AB - Pregnant women constitute a risk group for any infection due to their low immunity condition. This is a descriptive study with a qualitative approach, grounded in the Theory of Social Representations that sought to understand the reasons why pregnant women did not vaccinate against influenza A (H1N1). The study included 10 women who were pregnant during the vaccination campaign of 2010. Data were collected in May 2011 through interviews and interpreted by content analysis. From the speeches it was possible to identify the various representations that the vaccine against H1N1 had for these women during their pregnancy as an element which would cause miscarriage and birth defects. The reasons why pregnant women did not vaccinate against H1N1 are associated with fear, lack of information and the myths and beliefs that people bring in their representations and their cultural values. PMID- 23752541 TI - [Hearing care and quality of life among workers exposed to pesticides]. AB - The objective of this study was to determine the relationship between exposure to pesticides and the occurrence of hearing loss among rural workers of Povoado Colonia Treze, Lagarto, State of Sergipe, Brazil. A total of 351 adult workers aged 18 to 59 years were selected, with current or past work activity in rural areas, with or without use of pesticides. The hearing evaluation included a form to record air-borne tonal thresholds using normality criteria recommended by Merluzzi 1979. The instrument used for assessing the quality of life was the Brazilian version of Short Form 36 (SF-36). Statistical analysis was performed (chi-square c2, nonparametric Kruskal-Wallis test, Cramer's V and Cohen's d) with a significance level of 95% (p <0.05). The results related the use of pesticide with the degree of toxicity in the presence of hearing loss and indices of quality of life (p <0.001). This study proved that agricultural workers, users of pesticides showed the worst levels of quality of life when compared with those who have not handled them. The use of pesticides and their toxicity class interfered in a most striking way in the classification of hearing loss presented in this group and further studies are recommended to assess other impacts on this population. PMID- 23752542 TI - [Adherence to pharmacological and non pharmacological treatment for arterial hypertension and associated factors in primary care]. AB - A cross-sectional study was conducted with 385 hypertensive patients between 20 and 79 years of age in a family health unit in Londrina, State of Parana, Brazil, to determine the adherence to pharmacological and non pharmacological treatment for arterial hypertension in primary healthcare and identify associated factors. The adherence to pharmacological treatment was 59%. Regular physical activity was reported by 68 (17.7%) hypertensive patients and 266 (69.1%) mentioned dietary changes. In the multiple regression analysis, adherence to drug treatment was associated with: increased age (50 to 79), consulting with a physician at least once a year, no regular alcohol consumption and previous myocardial infarction. Hypertensive males, with education up to 4th grade and above, who had at least one consultation per year, with diabetes or no history of high cholesterol, were more adherent to physical activity. Dietary changes were associated with education below the 4th grade and consulting with a physician at least once a year. These results show variable levels of adherence to treatment and demonstrate the importance of comprehensive actions in the care for hypertensive patients. PMID- 23752543 TI - [The use of assistive technology in the daily activities of children with disabilities]. AB - The scope of this study is to understand the use of assistive technology in the everyday life of children with disabilities, based on the concept of everyday life as a space for expression of particularity and generality of individuals. It was developed from documentary research of medical records, application of a form, observation of daily activities of children and their families and semi structured interviews. Five children were studied, representatives in age, sex, diagnosis and use of technological resources, who were attended in primary healthcare units in Sao Paulo. The resources are used in homes, schools and other environments and their use is influenced by family and social relations and by the possibility of accessing products and services. It was established that the everyday activities and the use of resources are organized according to the time, space, ways in which children and, mainly, their caregivers act, showing the presence of pragmatism, economy and spontaneity typical of everyday life. The results revealed elements that can guide the practice of professionals working with assistive technology and can contribute to enable the appraisal of providing equipment in the Unified Health System. PMID- 23752544 TI - [From guidelines to practice: evaluation of the pediatric care provided by a service of secondary reference in the north of the State of Minas Gerais]. AB - In the State of Minas Gerais, the Secondary Reference Viva Vida Centers (CVVRS) are one of the strategies deployed to tackle the problems in child health. This study sought to evaluate pediatric care provided in a CVVRS, using the guidelines defined when it was set up as a benchmark. A quantitative-qualitative approach was adopted, which included a cross-sectional study with stratified random sampling of 385 medical records of children registered with the program between 2007 and 2009, and analysis of focus groups with strategic actors of the initiative. There were divergences between the user profiles and the target audience in terms of age, hometown and clinical characteristics. Access and use of the service differed depending on the town, due to problems of misinformation concerning the proposal, difficulty of transportation and the fragility of the health network. The centers are considered an innovative and important initiative for the expansion and organization of the health network, though the intended logic is not effectively seen in practice. Interventions for articulation between the network services and adaptation of the agreed guidelines to the regional specificities are necessary. PMID- 23752545 TI - [Sexuality, reproduction and health: experiences of adolescent students living in a small city of the interior]. AB - This article aims to describe experiences of school adolescents of both sexes, living in a small city in the interior of the State of Rio de Janeiro, concerning affective-sexual life and sexual and reproductive health. A cross-sectional study was conducted with a structured questionnaire among 200 adolescents aged between 15 and 19 from public schools in Silva Jardim,. The girls' sexual initiation occurred between 15 and 19 and boys between 12 and 14. Boys started with partners from 12 to 19 years of age and girls with older partners. Girls received more information about sex than boys and talked more with partners about preventing pregnancy at the time of sexual initiation. Sources of information about sexuality and contraception are mainly from parents, with the pharmacy being the main location for the purchase of contraceptives. Information about sexually transmitted diseases is mainly received at school. The comparison of these results with those of other studies with adolescent students in large urban centers and populations that include youths outside school demonstrates similarities and dissimilarities between their experiences. Factors related to the socio-cultural and institutional context of small municipalities, gender and education help to understand them. PMID- 23752546 TI - [Prevalence of common mental disorders in recently-drafted young Brazilians to mandatory military service and associated factors]. AB - The mental health of the military enlisted in the Armed Forces is an as yet area little explored of research in Brazil. This study aimed to investigate the prevalence of common mental disorders (CMD) and associated factors among recently drafted young Brazilians to mandatory military service: the recruits. A total of 78 young adults participated in the study. The incidence of CMD (dependent variable) were evaluated by the 12-item General Health Questionnaire (GHQ-12). The tests ?2 (chi-squared) and logistic regression were used to estimate the associations between CMD and independent variables. The results showed a prevalence of CMD de 43.6% (CI 95% 33.14 to 54.64). The CMD prevalence ratios were from 4 to 5 times higher among those who reported sleep disturbances, which was the only factor associated with the occurrence of CMD. These results seem to indicate that the situations experienced by the recruits in their work environment may be causally associated with CMD. Further studies are needed, with longitudinal design, for this effect to be confirmed. PMID- 23752547 TI - [Interdisciplinarity and psychiatry: is it time not to know?]. AB - This article deals with interdisciplinarity as well as psychiatric and psychosocial care. Throughout the text, a historical account of the constitution and the crisis of scientific knowledge is presented and organized into disciplines. The theoretical difficulty of conceptualizing interdisciplinarity is analyzed and, in the concluding remarks, psychiatry and its relationship to psychosocial care is discussed. The argument is that, because of its history, psychiatry has singularities that differentiate it from other medical specialties and these singularities could initially cause psychiatry to go in the opposite direction in relation to interdisciplinarity. The conclusion is that because of their inherent characteristics psychosocial care services are privileged places for psychiatric training with interdisciplinary characteristics. PMID- 23752548 TI - [Why is environmental adaptation and acculturation relevant when seeking to conduct qualitative research in drug dependency services?]. AB - This study conducted at the Outpatient Service of Psychoactive Substances, in the University General Hospital of Campinas, sought to report on an experience of proactive participation to study the life experience of chemically dependent patients attended in a specialized university service. These observations emerged from the researcher's experiences in the environmental adaptation and acculturation period, namely through the researcher insertion in the outpatient service, during the preliminary data collection for qualitative research. This experience was important as it enabled clearer comprehension of the psycho cultural universe of the population attended and how the relation professional patient is conducted, broadening the knowledge of the field where the research was later carried out. From this initial entry in the field, it was possible to define the subject-matter and the population being studied more clearly, adapting to the needs and the reality observed in that service, as well as to reflect on the research method that serve to better understand the issues raised, and even draw up a roadmap for future interviews in the study. It was concluded that this preliminary stage is very useful as standard practice in new studies using the same methodology in clinical settings. PMID- 23752549 TI - [Social support and the frailty syndrome among elderly residents in the community]. AB - Frailty among the elderly is a result of the complex interplay between social and clinical factors involved in its genesis. However, it is still unclear whether the fraailty syndrome can be aggravated due to lack of social support. The scope of this study was to analyze the association between social support and the frailty syndrome among elderly residents in the community. It is an analytical observational cross-sectional study, with a sample of 300 elderly people. Socio demographic, economic and physical health, frailty and social support data were collected. For statistical analysis, the Pearson chi-square, the Student t and the binary logistic regression were performed, adopting a significance level of 5%. No associations were observed between frailty and the social support variables, except for the housekeeping aspect (p = 0.04). In logistic regression frailty with age (OR = 1.19), physical activity (OR = 2.56) and self-perceived health (OR = 3.33) remained associated. It is considered that more studies need to be conducted to characterize social vulnerability and health services also need to recognize the importance of social support as an integral part of care for the elderly. PMID- 23752550 TI - [Reflective portfolio: a proposal for teaching and learning geared on competencies]. AB - This article seeks to analyze the experience of collective construction of portfolios as a teaching-learning method in the discipline of Health Policy, identifying the competencies developed by students. Qualitative research, whose collection and data processing were conducted by means of documental and thematic analysis of 34 portfolios. The "Learning to be" and "Learning to live and work together" competencies were considered according to the proposals of the UNESCO report for Education. The training of critical-reflexive individuals, provided by the portfolio, was particularly observed when students reported the transformation of the negative views that they had about the health care system - an inefficient and precarious policy - to a positive vision - policy which deals with the principles of equity, integrity and universality. This process of critical transformation is the result of the practice and use of communication skills, information management (search, selection, analysis and evaluation of information), leadership, cooperation and human relationships (teamwork, ethics and recognition of diversity), and personal competencies (time management, responsibility and planning), namely important skills in the training of professionals committed to the national health policy. PMID- 23752552 TI - Proposal of the global network for the study of green tobacco sickness. PMID- 23752553 TI - Positive expiratory pressure via mask does not improve ventilation inhomogeneity more than huffing and coughing in individuals with stable chronic obstructive pulmonary disease and chronic sputum expectoration. AB - BACKGROUND: Positive expiratory pressure (PEP) has been used to promote airway clearance in individuals with chronic obstructive pulmonary disease (COPD) for many years; however, its mechanism of action and benefits are unclear. Previous authors have suggested that PEP improves collateral ventilation via changes in lung volumes. OBJECTIVES: It was the aim of this study to determine whether PEP improves ventilation inhomogeneity more than controlled huffing and coughing in individuals with stable COPD. METHODS: Twelve participants with COPD (mean forced expiratory volume in 1 s 45% predicted) and chronic sputum expectoration performed PEP therapy (10-20 cm H2O) or controlled huffing and coughing in random order on alternate study days with a 48-hour washout. Measures of acinar and conductive airway ventilation (S(acin), S(cond)), lung volumes, spirometry and sputum wet weight were recorded before, immediately after and 90 min following treatment. Ease of expectoration [visual analogue scale (VAS)] and oxyhaemoglobin saturation were assessed immediately following treatment. RESULTS: There were no significant differences between the effect of either test condition at any time point for any test parameter. Mean Sacin immediately following PEP and control conditions was 0.465 and 0.438 litre(-1), respectively (p = 0.45 for comparison between conditions) and mean S(cond) was 0.042 and 0.039 litre(-1) (p = 0.55). PEP therapy did not significantly enhance total mean sputum expectoration compared to controlled huffing and coughing (7.06 vs. 6.15 g; p = 0.51) and did not improve ease of expectoration (VAS PEP 4.8 cm vs. control 4.1 cm; p = 0.53). CONCLUSION: Any therapeutic benefits of PEP in individuals with COPD and chronic sputum expectoration are unlikely to be mediated by improvements in ventilation or lung volumes. PMID- 23752554 TI - The effectiveness of a gastrocnemius-soleus stretching program as a therapeutic treatment of plantar fasciitis. AB - CLINICAL SCENARIO: Injury to the plantar fascia, whether acute or chronic, is common among many populations. A conventional multiple-treatment approach is commonly administered by health care providers, consisting of controlling inflammation, managing pain, and promoting healing. Frequently, the initial treatment for plantar fasciitis is targeted at increasing dorsiflexion range of motion by stretching the gastroc-soleus musculature. It has been theorized that inflexibility of the gastroc-soleus complex can lead to excessive pronation and overcompensation of the plantar fascia at the first metatarsal phalangeal joint, therefore increasing the stress at the medial calcaneal insertion. Therefore, it is deemed that gastrocnemius-soleus stretches are a beneficial treatment in the initial stage of a plantar fasciitis treatment or rehabilitation program. FOCUSED CLINICAL QUESTION: Is a gastrocnemius-soleus stretching program, as a stand-alone treatment variable, effective in the treatment of plantar fasciitis? PMID- 23752556 TI - Error in Text in: Role of Intensive Glucose Control in Development of Renal End Points in Type 2 Diabetes Mellitus: Systematic Review and Meta-analysis. PMID- 23752555 TI - Scalp nodule in an elderly woman-diagnosis. PMID- 23752557 TI - A step towards the a priori design of ionic liquids. AB - A range of methods for the computational prediction of experimentally derived alpha and beta Kamlet-Taft parameters, indicators of hydrogen bond (H-bond) acidity and basicity for ionic liquids (ILs) have been explored. Most usefully, a good correlation has been established between several simple and easily computed quantities which allow for a "quick bench-top" evaluation. More accurate, but also more sophisticated methods employing TD-DFT calculations involving the Kamlet-Taft dyes have been examined and evaluated. Importantly, these techniques open up the opportunity for pre-screening and a priori prediction of properties for ILs not yet synthesised. A key fundamental insight into IL H-bonds has been the determination of an estimate for the energy associated with replacing both neutral molecules in a H-bond with ionic molecules, thus forming the "doubly ionic" H-bond found in ILs. PMID- 23752558 TI - Is hypertension overtreatment a silent epidemic?-Reply. PMID- 23752559 TI - Thermal restructuring of silica-grafted -CrO2Cl and -VOCl2 species. AB - The volatile molecular precursors CrO2Cl2 and VOCl3 were grafted to thermally dehydrated silica in order to obtain site-isolated, monopodal =SiO-MO(x)Cl(y-1) species (M = V, Cr). Thermal restructuring under dynamic vacuum was investigated up to 450 degrees C with different spectroscopic techniques (viz., NMR, UV-Vis, IR, Raman and XPS). During this thermal restructuring, VOCl3 or CrO2Cl2 is partially eliminated from the surface, whilst the remaining surface species become multiply bound to the silica surface. This restructuring increases both the chemical and thermal stability of these materials, and has significant consequences for their performance as heterogeneous catalysts. PMID- 23752560 TI - Behavioral medicine trial design: time for a change-reply. PMID- 23752561 TI - Practice gaps. Gaining insights into the relationship of obesity, weight loss, and psoriasis. PMID- 23752562 TI - Barium: an efficient cathode layer for bulk-heterojunction solar cells. AB - We report Barium (Ba) cathode layer for bulk-heterojunction solar cells which enhanced the fill factor (FF) of p-DTS(FBTTh2)2/PC71BM BHJ solar cell up to 75.1%, one of the highest value reported for an organic solar cell. The external quantum efficiency exceeds 80%. Analysis of recombination mechanisms using the current-voltage (J-V) characteristics at various light intensities in the BHJ solar cell layer reveals that Ba prevents trap assisted Shockley-Read-Hall (SRH) recombination at the interface and with different thicknesses of the Ba, the recombination shifts towards bimolecular from monomolecular. Moreover, Ba increases shunt resistance and decreases the series resistance significantly. This results in an increase in the charge collection probability leading to high FF. This work identifies a new cathode interlayer which outclasses the all the reported interlayers in increasing FF leading to high power conversion efficiency and have significant implications in improving the performance of BHJ solar cells. PMID- 23752563 TI - Early improper motion detection in golf swings using wearable motion sensors: the first approach. AB - This paper presents an analysis of a golf swing to detect improper motion in the early phase of the swing. Led by the desire to achieve a consistent shot outcome, a particular golfer would (in multiple trials) prefer to perform completely identical golf swings. In reality, some deviations from the desired motion are always present due to the comprehensive nature of the swing motion. Swing motion deviations that are not detrimental to performance are acceptable. This analysis is conducted using a golfer's leading arm kinematic data, which are obtained from a golfer wearing a motion sensor that is comprised of gyroscopes and accelerometers. Applying the principal component analysis (PCA) to the reference observations of properly performed swings, the PCA components of acceptable swing motion deviations are established. Using these components, the motion deviations in the observations of other swings are examined. Any unacceptable deviations that are detected indicate an improper swing motion. Arbitrarily long observations of an individual player's swing sequences can be included in the analysis. The results obtained for the considered example show an improper swing motion in early phase of the swing, i.e., the first part of the backswing. An early detection method for improper swing motions that is conducted on an individual basis provides assistance for performance improvement. PMID- 23752564 TI - Deployment and validation of a smart system for screening of language disorders in primary care. AB - Neuro-evolutive development from birth until the age of six years is a decisive factor in a child's quality of life. Early detection of development disorders in early childhood can facilitate necessary diagnosis and/or treatment. Primary-care pediatricians play a key role in its detection as they can undertake the preventive and therapeutic actions requested to promote a child's optimal development. However, the lack of time and little specific knowledge at primary care avoid to applying continuous early-detection anomalies procedures. This research paper focuses on the deployment and evaluation of a smart system that enhances the screening of language disorders in primary care. Pediatricians get support to proceed with early referral of language disorders. The proposed model provides them with a decision-support tool for referral actions to trigger essential diagnostic and/or therapeutic actions for a comprehensive individual development. The research was conducted by starting from a sample of 60 cases of children with language disorders. Validation was carried out through two complementary steps: first, by including a team of seven experts from the fields of neonatology, pediatrics, neurology and language therapy, and, second, through the evaluation of 21 more previously diagnosed cases. The results obtained show that therapist positively accepted the system proposal in 18 cases (86%) and suggested system redesign for single referral to a speech therapist in three remaining cases. PMID- 23752565 TI - Accurate human tissue characterization for energy-efficient wireless on-body communications. AB - The demand for Wireless Body Sensor Networks (WBSNs) is rapidly increasing due to the revolution in wearable systems demonstrated by the penetration of on-the-body sensors in hospitals, sports medicine and general health-care practices. In WBSN, the body acts as a communication channel for the propagation of electromagnetic (EM) waves, where losses are mainly due to absorption of power in the tissue. This paper shows the effects of the dielectric properties of biological tissues in the signal strength and, for the first time, relates these effects with the human body composition. After a careful analysis of results, this work proposes a reactive algorithm for power transmission to alleviate the effect of body movement and body type. This policy achieves up to 40.8% energy savings in a realistic scenario with no performance overhead. PMID- 23752566 TI - Aspects of the application of cavity enhanced spectroscopy to nitrogen oxides detection. AB - This article presents design issues of high-sensitive laser absorption spectroscopy systems for nitrogen oxides (NO(x)) detection. Examples of our systems and their investigation results are also described. The constructed systems use one of the most sensitive methods, cavity enhanced absorption spectroscopy (CEAS). They operate at different wavelength ranges using a blue- violet laser diode (410 nm) as well as quantum cascade lasers (5.27 um and 4.53 um). Each of them is configured as a one or two channel measurement device using, e.g., time division multiplexing and averaging. During the testing procedure, the main performance features such as detection limits and measurements uncertainties have been determined. The obtained results are 1 ppb NO(2), 75 ppb NO and 45 ppb N(2)O. For all systems, the uncertainty of concentration measurements does not exceed a value of 13%. Some experiments with explosives are also discussed. A setup equipped with a concentrator of explosives vapours was used. The detection method is based either on the reaction of the sensors to the nitrogen oxides directly emitted by the explosives or on the reaction to the nitrogen oxides produced during thermal decomposition of explosive vapours. For TNT, PETN, RDX and HMX a detection limit better than 1 ng has been achieved. PMID- 23752569 TI - Internal nasal valve functional surgery-reply. PMID- 23752568 TI - An iTRAQ based quantitative proteomic strategy to explore novel secreted proteins in metastatic hepatocellular carcinoma cell lines. AB - Secretomics is receiving more and more considerable attention due to the key roles of secreted proteins in cancer. Most of the potential biomarkers for clinical diagnosis and treatment of cancer are secreted proteins. However, the low concentration of secreted proteins and contaminants released from dead cells are a great challenge to secretomic profiling studies. Although some bioinformatics tools such as SecretomeP and SignalP can help to annotate or predict secreted proteins, they also cause false positive or negative rates of identification especially for nonclassical secreted proteins. Therefore, an iTRAQ based quantitative proteomics strategy was set up in this work and applied in the secretomics study of metastatic HCC cell lines. A total of 94 proteins were identified as secreted and 31 of them were newly found in our data. Compared with the known secreted proteins participating in inter-cellular signalling, most of the newly identified secreted proteins were metabolic enzymes, such as PKM2 and EHHADH, whose functions focused on the synthesis/metabolism of glucose, fatty acids and amino acids. Exploring their secretion would help to further study their bio-functions in conditioned media and the effects on the interactions of cancer cells and the microenvironment. Differences between the secretomes of the two metastatic HCC cell lines were also explored in the same experiment. This strategy showed its superiority in accurately identifying secreted proteins as well as monitoring their variation under different biological conditions. PMID- 23752570 TI - Managing urinary incontinence in adults with bronchiectasis. AB - BACKGROUND: Urinary incontinence has a negative impact on quality of life and often remains untreated due to low levels of self-reporting. Urinary incontinence is seen in cystic fibrosis associated bronchiectasis but little data are available for non-cystic fibrosis associated bronchiectasis. METHOD: In 2007 a new non-cystic fibrosis bronchiectasis service for patients aged 18 years and over was started within the Newcastle upon Tyne Hospitals NHS Foundation Trust. During the establishment of a new adult bronchiectasis service, patients were specifically asked about symptoms of incontinence, and if incontinence was identified then patients were referred for specialist continence assessment and management, in line with current good practice guidelines. The study relates only to those female patients who were referred to the continence service. RESULTS: In this audit 116 patients attended the bronchiectasis service from 2009-2010; 76 were female, of these 55% had urinary incontinence, describing dramatic effects on quality of life. Prior to intervention the duration of symptoms of urinary incontinence for more than 5 years was 87.5%, with 40% of patients describing symptoms of more than 10 years duration without seeking medical attention. Following intervention from the nurse consultant for continence care, 80% of patients who were referred were discharged with an improvement in symptoms of urinary incontinence. CONCLUSION: This audit highlights the importance of specifically asking about urinary incontinence when assessing patients with adult bronchiectasis. PMID- 23752571 TI - Schistosomiasis-an endemic parasitic waterborne disease. AB - Schistosomiasis (or bilharzia) is a chronic waterborne disease caused by parasitic worms or schistosoma in the tropics and sub tropics. Five main species exist, and common to all is its transmission to humans as a result of exposure to infested fresh water, into which the cercariae of the parasite are released by freshwater snails. With the rise of tourism and travel, more people are travelling to countries where schistosomiasis is a risk. Schistosoma haematobium is responsible for urogenital schistosomiasis, in which manifestations range from acute hypersensitivity reactions to bladder disease in the detection of which the nurse cystoscopist can have a significant role. Treatment is highly effective, and the diagnosis should be considered in individuals with possible clinical illness who have travelled to or lived in endemic areas. PMID- 23752572 TI - Painful bladder syndrome and interstitial cystitis: treatment options. AB - Painful bladder syndrome (PBS) and interstitial cystitis (IC) are associated with bladder pain, increased urinary frequency, urgency and reduced quality of life. The cause is still unknown, although there are several possible hypotheses. PBS/IC may significantly impact all areas of a patient's life as they try to manage their symptoms. Treatment options usually involve diet and fluid modifications, oral medications, intravesical therapy or as a last resort, surgery. The bladder is protected by a mucous layer known as the GAG layer and is thought to protect the underlying urothelium from coming into contact with potassium ions and other irritants contained in urine. Due to research suggesting that sufferers of PBS/IC have dysfunctional GAG layers, there is rationale for intravesical GAG replacement therapy as a treatment option in reducing PBS/IC symptoms such as pain, frequency and urgency. Early diagnosis and treatment may lead to better long-term outcomes. PMID- 23752573 TI - BAUN: protecting patients by protecting standards. PMID- 23752574 TI - Pelvic floor exercises after radical prostatectomy. AB - Prostate cancer is the most common cancer in men in the UK. Treatment with radical prostatectomy may produce risk factors that commonly include urinary incontinence and erectile dysfunction. Post-prostatectomy incontinence can be classified as either stress urinary incontinence, urge urinary incontinence or post-micturition dribble. Evidence has shown that these embarrassing conditions may be treated successfully with pre-operative and post-operative pelvic floor exercises, which include 'the knack', urge suppression, fluid advice and a post void contraction for post-micturition dribble. New evidence suggests that men with erectile dysfunction may benefit from the same pelvic floor exercises. PMID- 23752575 TI - Clean intermittent self-catheterisation: improving quality of life. AB - Clean intermittent self-catheterisation (CISC) is often a treatment option for women with urinary incontinence, particularly those with neurogenic bladder dysfunction. When used for appropriate patients it has been shown to promote continence and improve quality of life. There are a range of different products available on prescription for patients and many have been designed specifically with women in mind. Curan Lady is a new catheter that has recently been added to the UK NHS Drug Tariff. Patients suffering from limited/restricted mobility in their hands, found the Curan Lady easy to open and use. CISC can promote privacy and dignity for women with urinary incontinence and patient choice regarding product selection is important. Nurses need to keep up to date with new product availability for patients in order to offer choice to women performing CISC. PMID- 23752576 TI - [Current management in endometrial polyps]. PMID- 23752577 TI - [Endometrial polyps: still exeresis for all of them?]. PMID- 23752578 TI - Obstetric outcomes in the second birth of women with a previous caesarean delivery: a retrospective cohort study from Peru. AB - PURPOSE: To examine obstetric outcomes in the second birth of women who had undergone a previous cesarean delivery. METHODS: This was a large hospital-based retrospective cohort study. We included pregnant women who had a previous delivery (vaginal or cesarean) attending their second birth from 2001 to 2009. Main inclusion criteria were singleton pregnancies and delivery between a gestation of 24 and 41 weeks. Two cohorts were selected, being women with a previous cesarean delivery (n=7,215) and those with a vaginal one (n=23,720). Both groups were compared and logistic regression was performed to adjust for confounding variables. The obstetric outcomes included uterine rupture, placenta previa, and placental-related complications such as placental abruption, preeclampsia, and spontaneous preterm delivery. RESULTS: Women with previous cesarean delivery were more likely to have adverse outcomes such as uterine rupture (OR=12.4, 95%CI 6.8-22.3), placental abruption (OR=1.4, 95%CI 1.1-2.1), preeclampsia (OR=1.4, 95%CI 1.2-1.6), and spontaneous preterm delivery (OR=1.4, 95%CI 1.1-1.7). CONCLUSIONS: Individuals with previous cesarean section have adverse obstetric outcomes in the subsequent pregnancy, including uterine rupture, and placental-related disorders such as preeclampsia, spontaneous preterm delivery, and placental abruption. PMID- 23752579 TI - [Physical activity and body composition in menopausal women]. AB - PURPOSE: To analyze the relationship between physical activity and body composition in menopausal women. METHODS: The study included 62 menopausal women aged 50 years or more (61.2+/-7.6). The practice of physical activity was assessed with an accelerometer and is reported as minutes per week of low physical activity and moderate plus vigorous physical activity, and total physical activity in counts. Lean mass and total fat mass were assessed by dual energy X-ray absorptiometry, and are reported as percentages. The relation between body composition variables and physical activity was evaluated by Spearman and Pearson correlation. Comparisons between groups were performed using the independent t test and Mann-Whitney test. RESULTS: The age group 59 years or older had higher mean values of total physical activity in counts (1,307.081 versus 2,843.840) and of minutes per week of moderate-vigorous physical activity (273 versus 156 minutes). Women who completed 150 minutes or more of moderate vigorous physical activity had significantly lower total fat mass (43.8 versus 47.2 kg), higher lean mass (53.8 versus 49.6 kg) and lower BMI (27.7 versus 30.5 kg/m2) when compared to those with less than 150 minutes of physical activity per week. Only time spent in moderate activities showed a significant negative correlation with the percentage of total fat (r=-0.26, p<0.05), whereas total physical activity in counts correlated with the percentage of lean body mass (r=0,30), percentage of total fat (r=-0.32), trunk fat (r=-0.29), and BMI (r= 0.32); all correlations were statistically significant at p<0.05. CONCLUSION: menopausal women aged 50 years or more who spent more minutes in moderate and vigorous activity and higher total physical activity counts showed lower fat mass and higher lean mass. PMID- 23752580 TI - [Morphological aspects of the urethra in female rats after electrical stimulation of the pelvic floor]. AB - PURPOSE: To evaluate the effects of electrical stimulation (ES) of the pelvic floor on the urethra of female rats. METHODS: Forty adult rats were divided at random into four groups of ten animals each: Ctrl - without intervention; Sham - not submitted to ES, but with an electrode inserted into the vagina; Exp6 - submitted to six sessions of ES of the pelvic floor, and Exp12 - submitted to 12 sessions of ES of the pelvic floor. At the end of the experiment, all animals were anesthetized and the middle third of the urethra was removed, fixed in Bouin's fluid and processed for histomorphometric study. Sections were stained with hematoxylin and eosin for morphological and morphometric description, and others were stained with picrosirius red for the quantitation of total collagen. The thicknesses of the muscle layer and of the epithelium were determined, in 4 quadrants of the urethra, by performing 20 measurements per animal. The number of blood vessels present in the lamina propria was counted in the four quadrants over an area of 103 um2 per quadrant and the images were obtained using the image analysis program AxioVision(r) REL 4.3 (Carl Zeiss). The collagen and muscle fiber ratios in the urethrae were calculated from two images per quadrant of every slice stained with picrosirius red, employing the Imagelab(r) Program. Data were subjected to analysis of variance (ANOVA) and the Tukey-Kramer multiple comparison test (p<0.05). RESULTS: The morphometry of the collagen, number of blood vessels and thickness of the epithelium showed no significant changes; however, the thickness of the periurethral muscle tissue increased significantly in Exp12 group, compared to the other groups (Exp12*>Exp6==Ctrl==Sham; *p<0.05). CONCLUSION: Prolonged functional electric stimulation of the pelvic floor induced an increase in periurethral muscle thickness in rats. PMID- 23752581 TI - [Consultation in breast surgical pathology: interobserver diagnostic variability of atypical intraductal proliferative lesions]. AB - PURPOSE: To evaluate the agreement about the histopathological diagnosis of intraductal proliferative breast lesions between general pathologists and a specialist in breast pathology. METHODS: This was an observational, cross sectional study of 209 lesions received in consultation at the Breast Pathology Laboratory of the School of Medicine, Federal University of Minas Gerais, from 2007 to 2011, comparing the original diagnosis and the review. We included only cases with a formal request for review and cases in which the original diagnosis or reviewer's diagnosis showed proliferative lesions, pure ductal carcinoma in situ, ductal carcinoma in situ associated with microinvasion or associated with invasive carcinoma. The kappa index and percent concordance were used in the statistical analyses. RESULTS: A moderate agreement was observed between the original histopathological diagnosis and the second opinion (kappa=0.5; percentual concordance=83%). After the review, the diagnosis of malignancy was confirmed in 140/163 cases (86%) and the diagnosis of benign lesions was confirmed in 34/46 cases (74%). Regarding specific diagnosis, we observed moderate agreement between the original diagnosis and the reviewer's diagnosis (136/209 cases; kappa=0.5; percent concordance=65%). The highest disagreement was observed in cases of ductal carcinoma in situ with microinvasion (6/6 cases; 100%). Important discordance was observed in cases of atypical ductal hyperplasia (16/30 cases; 53%) and ductal carcinoma in situ (25/75 cases; 33%). Regarding the histological grade of ductal carcinoma in situ, we observed good agreement between the original diagnosis and the review (29/39 cases; kappa=0.6, percent agreement=74%). CONCLUSION: Our data confirm that intraductal proliferative breast lesions, especially atypical ductal hyperplasia, ductal carcinoma in situ and ductal carcinoma in situ with microinvasion show relevant discrepancies in the histopathological diagnoses, which may induce errors in therapeutic decisions. PMID- 23752582 TI - [Venous and lymphatic alterations in women with lymphedema after axillary lymphadenectomy in breast cancer treatment]. AB - PURPOSE: To evaluate changes in the venous axillary-subclavian and lymphatic systems of women with lymphedema after axillary lymphadenectomy for breast cancer treatment. METHODS: This was a case series involving 11 women with unilateral upper limb lymphedema after axillary lymphedenectomy for the treatment of breast cancer. The study was carried out in the Mastology Program of the Clinical Hospital of the Federal University of Goias, Goiania, GO, during the period between March 2010 and March 2011. Doppler velocimetry ultrasonography was used to detect the presence of venous changes in the subclavian and axillary veins. Lymphatic changes were evaluated by lymphoscintigraphy in both upper limbs. Fisher's exact test was used for the comparison between limbs. RESULTS: Subclavian vein flow volume in the upper limb with lymphedema was significantly different from that in the contralateral limb (p<0.001), 54.6% of the women had increased flow. In the axillary vein, 45.4% had increased flow and 45.4% had decreased flow, with a statistically significant difference (p<0.01) between limbs. Compared to the contralateral limb, significant lymphatic changes (p<0.05) were also found in the vessel route (not visualized), number of lymphatic vessels (none), axillary lymph nodes (absent) and dermal reflux (present). In the contralateral upper limb without lymphedema, no venous or lymphatic alterations were encountered. CONCLUSION: The women subjected to axillary lymphadenectomy for the treatment of breast cancer presented both venous and lymphatic changes in the upper limb with lymphedema. PMID- 23752583 TI - [Climacteric symptoms and nutritional status of women in post-menopause users and non-users of hormone therapy]. AB - PURPOSE: To analyze the climacteric symptoms, nutritional status and distribution of abdominal fat in postmenopausal women using or not hormone therapy. METHODS: exploratory analytical study of the population survey type in the urban area of Maringa, Parana, conducted on 456 postmenopausal women aged 45 to 69 years. Data collection was based on the urbanized census sector (368) of the municipality, according to the Brazilian Demographic Census. A simple random sample proportional to women residing in each census sector was used, and a questionnaire was applied during a home visit, when anthropometric measurements were performed and blood pressure was determined. The Blatt and Kupperman Menopausal Index was used for the evaluation of climacteric symptoms. The outcome variable was the use of hormone therapy. RESULTS: Mean subject age was 58.7 years. Overweight was present in 72.6% of the women and abdominal obesity in 81.4% of them. Mild climacteric symptoms were observed in 69.5% of the women. Only 18.4% of the women studied were using hormone therapy and they were white, non-smokers, had no comorbidities, and had a partner. Users of hormone therapy had a lower frequency of overweight and obesity and had a lower prevalence of severe climacteric symptoms. CONCLUSION: Overweight and obesity were prevalent in this sample. Although fewer in number, the hormone therapy users had a lower frequency of overweight and mild and severe menopausal symptoms during the postmenopausal period. PMID- 23752584 TI - [Prevalence of violence by intimate male partner among women in primary health units in Sao Paulo State]. AB - PURPOSE: To evaluate the prevalence and factors associated with intimate partner violence (IPV) among women users of Basic Health Units (BHU) in the State of Sao Paulo. METHODS: This was a cross-sectional descriptive study based on secondary data analysis of women users' interviews at 75 BHU in the State of Sao Paulo, from August/2008 to May/2009. We used a questionnaire based on the Abuse Assessment Screen and the Conflict Tactics Scales modified by the Violence Against Women Study (VAW), structured and pre-tested. The variables studied were the types of IPV (psychological, physical and sexual) and sociodemographic variables (age, education, race, paid work, religion, marital status and economic class). We interviewed 2,379 women aged 18 to 60 years. RESULTS: The prevalence of lifetime IPV was 55.7%, and the prevalences of psychological, physical and sexual IPV were 53.8, 32.2 and 12.4%, respectively. Women without a partner but previously married, with schooling <8 years and belonging to the lower economic class had a higher risk for all types of IPV, and other factors were also associated with psychological and sexual IPV. CONCLUSIONS: The prevalence of IPV is high. Healthcare professionals in primary care should make an attempt to detect IPV. PMID- 23752585 TI - On dermatologist density and melanoma mortality-reply. PMID- 23752586 TI - Atomistics of vapour-liquid-solid nanowire growth. AB - Vapour-liquid-solid route and its variants are routinely used for scalable synthesis of semiconducting nanowires, yet the fundamental growth processes remain unknown. Here we employ atomic-scale computations based on model potentials to study the stability and growth of gold-catalysed silicon nanowires. Equilibrium studies uncover segregation at the solid-like surface of the catalyst particle, a liquid AuSi droplet, and a silicon-rich droplet-nanowire interface enveloped by heterogeneous truncating facets. Supersaturation of the droplets leads to rapid one-dimensional growth on the truncating facets and much slower nucleation-controlled two-dimensional growth on the main facet. Surface diffusion is suppressed and the excess Si flux occurs through the droplet bulk which, together with the Si-rich interface and contact line, lowers the nucleation barrier on the main facet. The ensuing step flow is modified by Au diffusion away from the step edges. Our study highlights key interfacial characteristics for morphological and compositional control of semiconducting nanowire arrays. PMID- 23752588 TI - State-dependent signaling by Cav1.2 regulates hair follicle stem cell function. AB - The signals regulating stem cell activation during tissue regeneration remain poorly understood. We investigated the baldness associated with mutations in the voltage-gated calcium channel (VGCC) Cav1.2 underlying Timothy syndrome (TS). While hair follicle stem cells express Cav1.2, they lack detectable voltage dependent calcium currents. Cav1.2(TS) acts in a dominant-negative manner to markedly delay anagen, while L-type channel blockers act through Cav1.2 to induce anagen and overcome the TS phenotype. Cav1.2 regulates production of the bulge derived BMP inhibitor follistatin-like1 (Fstl1), derepressing stem cell quiescence. Our findings show how channels act in nonexcitable tissues to regulate stem cells and may lead to novel therapeutics for tissue regeneration. PMID- 23752589 TI - Protein kinase A activates the Hippo pathway to modulate cell proliferation and differentiation. AB - The Hippo tumor suppressor pathway plays an important role in tissue homeostasis that ensures development of functional organs at proper size. The YAP transcription coactivator is a major effector of the Hippo pathway and is phosphorylated and inactivated by the Hippo pathway kinases Lats1/2. It has recently been shown that YAP activity is regulated by G-protein-coupled receptor signaling. Here we demonstrate that cyclic adenosine monophosphate (cAMP), a second messenger downstream from Galphas-coupled receptors, acts through protein kinase A (PKA) and Rho GTPases to stimulate Lats kinases and YAP phosphorylation. We also show that inactivation of YAP is crucial for PKA-induced adipogenesis. In addition, PKA activation in Drosophila inhibits the expression of Yorki (Yki, a YAP ortholog) target genes involved in cell proliferation and death. Taken together, our study demonstrates that Hippo-YAP is a key signaling branch of cAMP and PKA and reveals new insight into mechanisms of PKA in regulating a broad range of cellular functions. PMID- 23752590 TI - Multivalent histone engagement by the linked tandem Tudor and PHD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation. AB - Histone post-translational modifications regulate chromatin structure and function largely through interactions with effector proteins that often contain multiple histone-binding domains. While significant progress has been made characterizing individual effector domains, the role of paired domains and how they function in a combinatorial fashion within chromatin are poorly defined. Here we show that the linked tandem Tudor and plant homeodomain (PHD) of UHRF1 (ubiquitin-like PHD and RING finger domain-containing protein 1) operates as a functional unit in cells, providing a defined combinatorial readout of a heterochromatin signature within a single histone H3 tail that is essential for UHRF1-directed epigenetic inheritance of DNA methylation. These findings provide critical support for the "histone code" hypothesis, demonstrating that multivalent histone engagement plays a key role in driving a fundamental downstream biological event in chromatin. PMID- 23752592 TI - About this journal. PMID- 23752593 TI - About this journal. PMID- 23752591 TI - The methyltransferase SMYD3 mediates the recruitment of transcriptional cofactors at the myostatin and c-Met genes and regulates skeletal muscle atrophy. AB - Elucidating the epigenetic mechanisms underlying muscle mass determination and skeletal muscle wasting holds the potential of identifying molecular pathways that constitute possible drug targets. Here, we report that the methyltransferase SMYD3 modulates myostatin and c-Met transcription in primary skeletal muscle cells and C2C12 myogenic cells. SMYD3 targets the myostatin and c-Met genes and participates in the recruitment of the bromodomain protein BRD4 to their regulatory regions through protein-protein interaction. By recruiting BRD4, SMYD3 favors chromatin engagement of the pause-release factor p-TEFb (positive transcription elongation factor) and elongation of Ser2-phosphorylated RNA polymerase II (PolIISer2P). Reducing SMYD3 decreases myostatin and c-Met transcription, thus protecting from glucocorticoid-induced myotube atrophy. Supporting functional relevance of the SMYD3/BRD4 interaction, BRD4 pharmacological blockade by the small molecule JQ1 prevents dexamethasone-induced myostatin and atrogene up-regulation and spares myotube atrophy. Importantly, in a mouse model of dexamethasone-induced skeletal muscle atrophy, SMYD3 depletion prevents muscle loss and fiber size decrease. These findings reveal a mechanistic link between SMYD3/BRD4-dependent transcriptional regulation, muscle mass determination, and skeletal muscle atrophy and further encourage testing of small molecules targeting specific epigenetic regulators in animal models of muscle wasting. PMID- 23752595 TI - Assessment of the relationship between melatonin, hormones of the pituitary ovarian, -thyroid and -adrenocortical axes, and osteoprotegerin and its ligand sRANKL in girls with anorexia nervosa. AB - BACKGROUND: It has been suggested that disturbances in melatonin (MEL) secretion might play a role in osteoporosis development in females with anorexia nervosa (AN). It might be hypothesized that changes in the levels of hormones of the pituitary-ovarian, -thyroid and -adrenocortical axes might mediate the potential relationship between MEL and bone tissue. AIM: We investigated whether a relationship existed between MEL and LH, FSH-E2, TSH-FT3, FT4 and ACTH-cortisol axes in girls with AN. We also aimed to establish whether such a relationship might adversely affect the balance of the OPG/sRANKL system. MATERIAL/METHODS: Eighty-six girls with AN and 21 healthy subjects aged 12.6 to 18.2 years participated in the study. The serum levels of hormones as well as OPG and sRANKL were determined by radioimmunoassay (RIA), immunoradiometric assay (IRMA) or enzyme-linked immunosorbent assay (ELISA) methods. DISCUSSION: Our study participants with AN showed a significant reduction in body mass and body mass index (BMI), a decrease in LH, E2 and FT3 concentrations, increased MEL concentration at 02.00 hours and increased amplitude between its nocturnal and morning levels (Delta MEL2.00/9.00) as well as an increase in cortisol concentration. These changes were associated with a significant increase of OPG and sRANKL levels and a decrease in the OPG/sRANKL ratio. BMI values correlated positively with LH, FSH, E2, FT3 and the OPG/sRANKL ratio while the correlation between BMI and cortisol was negative. Delta MEL2.00/9.00 correlated positively with cortisol and negatively with LH, FSH, E2, FT3 concentrations and the OPG/sRANKL ratio. A positive correlation was observed between LH, E2 and the OPG/sRANKL ratio as well as between cortisol and sRANKL while the correlation between LH and OPG as well as between cortisol and the OPG/sRANKL ratio was negative. E2 and LH were shown to be significant and independent predictors of Delta MEL2.00/9.00. LH turned out to be a significant and independent predictor of OPG, cortisol and FT3 were significant and independent predictors of sRANKL, while LH, E2, Delta MEL2.00/9.00 and FT3 were significant predictors of the OPG/sRANKL ratio. CONCLUSIONS: Alterations in OPG and sRANKL levels observed in girls with AN are associated with changes in nocturnal MEL secretion, the circadian rhythm of MEL, and LH, E2, FT3 and cortisol levels. Dysregulation of the relationships between MEL and LH, E2, FT3 and cortisol found in girls with AN might affect the balance of the OPG/sRANKL system. Low values of the OPG/sRANKL ratio associated with high OPG and sRANKL levels suggest some defect in the mechanism compensating for bone remodeling disturbances. PMID- 23752596 TI - [Detection of autophagy based on conversions of MAP1LC3 and p62/SQSTM1]. AB - Autophagy is a cellular process fundamental for the survival of nutrient deficiency periods and for organelle turnover. Recently much attention has been focused on autophagy as its impairment has been found in many human diseases. Unfortunately, our apparatus for study of the autophagy process is still unsatisfactory and not very well known. In this paper we would like to shed light on and discuss autophagy methods. We present the methods (fluorescence and Western blotting) based on conversions of MAP1LC3 and p62/SQSTM1 proteins, which are the most common markers of the autophagy process. PMID- 23752597 TI - [The importance of glycemic load of the diet in the development of cancer]. AB - Treatment of cancer involves not only appropriate pharmacological or psychological therapy and rehabilitation, but also diet aimed at prevention of the process of cachexia. Postprandial hyperglycemia exerts a significant effect on the growth and proliferation of tumor cells. It promotes formation of a number of metabolic changes in every tissue of the organism. Chronic postprandial hyperglycemia, occurring in type 2 diabetes, enhances all these changes. Although the results of epidemiological studies on the relationship between the overall risk of cancer development, or tumors in different parts of the organism, are heterogeneous, most of them indicate that the risk increases with an increase in glycemic load of the examined population's diets. Researchers also suggest a beneficial effect of limiting the amount of easily assimilable carbohydrate in the diet to stabilize the disease and for better tolerance of chemo or radiation therapy. However, further studies are required. PMID- 23752598 TI - IL-18 and IL-18 binding protein concentration in ovarian follicular fluid of women with "tubal factor" subjected to in vitro fertilization. AB - INTRODUCTION: Composition of follicular fluid is also regarded to be linked to quality of oocytes, fertilization and quality of the embryo. The aim of this study was to investigate the concentration of IL-18 and IL18BP in follicular fluid (FF) in a homogeneous group of women with sterility caused by "tubal factor" subjected to in vitro fertilization (IVF) and the relation between concentrate of this cytokine and IVF outcome. MATERIALS/METHODS: The study group consisted of 83 non-smoking women aged 30.9 +/- 3.2 (23.0-43.0) with confirmed (hysterosalpingography and/or laparoscopy) bilateral complete tubal impermeability. Follicular fluid levels of IL-18 and IL18BP were evaluated in 83 patients undergoing in vitro fertilization (IVF). Ovarian hormonal stimulation was conducted according to a GnRH antagonist protocol. The measurement of IL-18 and IL18BP in follicular fluid was done using the ELISA method. RESULTS: The mean follicular levels of IL-18 and IL18BP were 468.5 +/- 357.4 pg/ml and 8611.3 +/- 534 pg/ml. The biochemical pregnancy rate was 39.7% (33/83); 22 women became clinically pregnant (26.5%). The implantation rate was 26.7% (36/135). No significant correlation was found between follicular concentrations of IL-18 and age of the patients (r = 0.13 p>0.05), number of metaphase II oocytes collected (r = -0.11 p>0.05), number of 3-day embryos (r = -0.157 p>0.05), biochemical pregnancies (r = 0.03 p>0.05), or clinical pregnancies (r = -0.06 p>0.05). Also there was no significant correlation between IL18BP and age of the patients (r = 0.21 p>0.05), number of metaphase II oocytes collected (r = 0.08 p>0.05), number of 3-day embryos (r = -0.19 p>0.05), biochemical pregnancies (r = 0.11 p>0.05) and clinical pregnancies (r = -0.34 p>0.05). CONCLUSION: IL-18 and IL18BP are detectable in follicular fluid but do not determine IVF outcome in women with "tubal factor". IL-18 and IL18BP are not promising prognostic markers for IVF success in this subgroup of patients. PMID- 23752599 TI - [The dog as a model for comparative studies of lymphoma and leukemia in humans]. AB - Dogs have accompanied humankind for thousands of years. They share the same environment, and thus are exposed to the same environmental factors such as air pollution, tobacco smoke, and various chemicals. Recent development of veterinary care has led to a significant extension of dogs' lifespan and allowed the diagnosis and treatment of a growing number of different diseases in this species. Among all diseases in dogs, cancer is considered the main cause of mortality, with lymphoproliferative disorders accounting for up to 30% of all canine cancers. Some of them, such as non-Hodgkin lymphoma (NHL) and lymphocytic leukemia, are very similar in the etiology, pathogenesis and response to treatment to the diseases occurring in humans. Due to anatomical and physiological similarities to humans, the dog is a useful model for the study of new therapeutic strategies for humans. Studies on the canine neoplasia are currently limited by the lack of well-characterized and widely available cell lines; thus, recently obtained canine NHL cell lines may become a valuable model for such studies. Investigation of their sensitivity to the antiproliferative effects of different factors should allow the creation of a database similar to the existing classification of human leukemias and lymphomas. This should enable quick and accurate diagnosis and selection of appropriate treatment based on phenotypic analysis and histopathological examination of clinical samples. The cooperation between human and veterinary oncologists gives the opportunity to use the dog as a model for the study of certain types of cancers presenting a challenge for modern medicine. PMID- 23752600 TI - Epstein-Barr virus-associated lymphoproliferative disorders. AB - The Epstein-Barr virus (EBV) is one of the most common human viruses, infecting more than 90% of the world's adult population. In some individuals the interplay between EBV replication, latency and immune control can be disrupted and evokes prolonged proliferation of EBV-infected lymphocytes and their malignant transformation. Since its discovery as the first human tumor virus, EBV has been implicated in the development of a wide range of human cancers. The evidence for an association with EBV is the strongest for Burkitt's lymphoma, NK/T cell lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma and for malignant lymphomas in immune incompetent patients. Additionally, certain epithelial cell tumors, such as gastric carcinoma and breast carcinoma, have been defined as EBV related. However, the virus may be encountered in other types of malignancies. The oncogenic potential of EBV is related to its ability to infect and transform B lymphocytes into continuously growing lymphoblastoid cell lines. EBV encodes a series of products mimicking several growth, transcription and anti-apoptotic factors, to usurp control of the pathways that regulate diverse homeostatic cellular functions. However, the exact mechanism by which EBV promotes oncogenesis remains unclear. The focus of this review is to summarize the current knowledge of oncogenic potential of the Epstein-Barr virus and its role in the pathogenesis of EBV-associated lymphoproliferative disorders. PMID- 23752601 TI - [Selenium in Graves' disease]. AB - The aim of this study was to present the current state of knowledge of the role of selenium in Graves' disease. Recently, in the pathogenesis and course of this autoimmune disease, more attention has been paid to the relationship between oxidative stress and the antioxidant system, where selenium compounds play an important role. The thyroid is the organ with the highest selenium concentration in the human body. Selenium compounds, having antioxidant properties, protect thyrocytes against the destructive effects of reactive oxygen species (ROS), which are generated during the synthesis of thyroid hormones. Therefore, strengthening the body's defense mechanisms, which protect against the formation and activity of ROS during medical treatment of Graves' disease patients, may be an effective adjuvant in commonly used methods of therapy. PMID- 23752602 TI - [Components of plastic disrupt the function of the nervous system]. AB - Development of the chemical industry leads to the development of new chemical compounds, which naturally do not exist in the environment. These chemicals are used to reduce flammability, increase plasticity, or improve solubility of other substances. Many of these compounds, which are components of plastic, the new generation of cosmetics, medical devices, food packaging and other everyday products, are easily released into the environment. Many studies have shown that a major lipophilicity characterizes substances such as phthalates, BPA, TBBPA and PCBs. This feature allows them to easily penetrate into living cells, accumulate in the tissues and the organs, and affect human and animal health. Due to the chemical structures, these compounds are able to mimic some endogenous hormones such as estradiol and to disrupt the hormone homeostasis. They can also easily pass the placental barrier and the blood-brain barrier. As numerous studies have shown, these chemicals disturb the proper functions of the nervous system from the earliest moments of life. It has been proven that these compounds affect neurogenesis as well as the synaptic transmission process. As a consequence, they interfere with the formation of the sex of the brain, as well as with the learning processes, memory and behavior. Additionally, the cytotoxic and pro apoptotic effect may cause neurodegenerative diseases. This article presents the current state of knowledge about the effects of phthalates, BPA, TBBPA, and PCBs on the nervous system. PMID- 23752603 TI - Muscle activity in the course of rehabilitation of masticatory motor system functional disorders. AB - On the basis of selected cases, evaluation of the usefulness of muscular exercises in rehabilitation of patients stricken by a dysfunction of the motor system of the chewing organ was accomplished. The assessment of the electric function of chewing muscles together with the registration of mandibular movements with the axiographic Zebris JMA apparatus was made, both before and after muscular therapy. The examination has shown that regardless of micro or macro-traumatic cause, the set of muscular exercises appropriately selected and dutifully carried out is able to restore full condition of the motor system of the bone-dental structure effectively. PMID- 23752604 TI - Serum IL-10 and IL-12 levels reflect the response to chemotherapy but are influenced by G-CSF therapy and sepsis in children with soft tissue sarcomas. AB - INTRODUCTION: Pre-treatment serum IL-10/IL-12 balance has been recently found deregulated in childhood soft tissue sarcomas (STS). Its role in STS monitoring and assessment of response to therapy is unknown. OBJECTIVE: To establish whether serum IL-10 and IL-12 levels and their reciprocal ratios reflect childhood STS course and actual activity and whether G-CSF therapy and central vein catheter (CVC)-related sepsis influence the interleukins levels. MATERIALS AND METHODS: ELISA determinations of serum interleukins were performed before treatment, in remission without complications (CR), at relapse and after treatment in 59 STS patients and during G-CSF administration and CVC-related sepsis (in 18) and also in 30 healthy controls. RESULTS: In CR IL-10 declined and IL-12 increased as compared to pretreatment levels; in relapse IL-10 rose and IL-12 decreased significantly as compared to levels in CR. Also rates of IL-10, IL-12, and IL 10/IL-12 ratios recently estimated by us as of prognostic significance reflected well the STS course. During G-CSF therapy and CVC-related sepsis, IL-10 increased and IL-12 decreased significantly from levels in CR without complications. IL-10 levels and rates of IL-10 >= 11 pg/ml in sepsis could falsely suggest relapse. However, IL-12 levels, rates of IL-12 <= 60 pg/ml and/or simultaneous determination of both interleukins differed significantly from levels at relapse. CONCLUSION: Serial determinations of serum IL-10 and IL-12 reflected well the course of STS in children and enabled remission and relapse phases to be distinguished. To avoid G-CSF and sepsis influence, IL-12 and IL-10/IL-12 ratio and not IL-10 alone should be analysed. PMID- 23752605 TI - [Proteins of human milk involved in immunological processes]. AB - Human milk contains a lot of components (i.e. proteins, carbohydrates, lipids, inorganic elements) which provide basic nutrients for infants during the first period of their lives. Qualitative composition of milk components of healthy mothers is similar, but their levels change during lactation stages. Colostrum is the fluid secreted during the first days postpartum by mammary epithelial cells. Colostrum is replaced by transitional milk during 5-15 days postpartum and from 15 days postpartum mature milk is produced. Human milk, apart from nutritional components, is a source of biologically active molecules, i.e. immunoglobulins, growth factors, cytokines, acute phase proteins, antiviral and antibacterial proteins. Such components of human milk are responsible for specific biological activities of human milk. This secretion plays an important role in growth and development of newborns. Bioactive molecules present in the milk support the immature immune system of the newborn and also protect against the development of infection. In this article we describe the pathways involved in the production and secretion of human milk, the state of knowledge on the proteome of human milk, and the contents of components of milk during lactation. Moreover, some growth factors and proteins involved in innate and specific immunity, intercellular communication, immunomodulation, and inflammatory processes have been characterized. PMID- 23752606 TI - Plasma carnitine concentrations after chronic alcohol intoxication. AB - BACKGROUND: Carnitine transports fatty acids from the cytoplasm to the mitochondrial matrix, where the fatty acids are oxidized. Chronic alcohol consumption reduces the concentration of carnitine and interferes with oxidative processes occurring in the cell. AIM: The assessment of carnitine concentrations in plasma of chronically intoxicated alcohol dependent persons in a 49-day abstinence period. MATERIAL/METHODS: The study included 31 patients (5 women and 27 men) aged from 26 to 60 years (44.6 +/- 8.9) and 32 healthy subjects (15 women and 17 men) aged 22-60 years (39.8 +/- 9.4). The patients' alcohol dependence ranged from 2 to 30 years (13.6 +/- 7.5). Examined subjects consumed 75-700 g of ethanol/day (226.9 +/- 151.5). Plasma concentrations of free and total carnitine were measured three times: at the first (T0), 30th (T30) and 49th (T49) day of hospital detoxification. Free (FC) and total (TC) carnitine were determined by the spectrophotometric method. Plasma acylcarnitine (AC) concentration was calculated from the difference between TC and FC; then the AC/FC ratio was calculated. To determine statistically significant differences for related variables, Student's t-test was used. RESULTS: At T0, alcoholics had significantly lower concentration of FC and TC (p < 0.05) in plasma, as compared to the control group. In comparison to controls, at T30, plasma TC and FC (p < 0.01) as well as AC (p < 0.001) were reduced. The lowest concentration of TC, FC and AC (p < 0.001)was found at T49. The ratio of AC/FC at T0 had a tendency to be higher in alcoholics than in the control group (p = 0.05), whereas at T49 it was significantly lower in alcoholics as compared to the control subjects (p < 0.05). CONCLUSIONS: Chronic alcohol intoxication causes a plasma deficiency of carnitine. Forty-nine days of abstinence showed a significant decrease in the concentration of TC, FC and AC. Further research is necessary to clarify whether a low level of plasma carnitine after chronic alcohol intoxication is caused by the uptake of blood carnitine by tissues such as liver or muscles. In alcoholics the supplementation of carnitine is recommended in the case of a low level of plasma carnitine. PMID- 23752608 TI - Sunrise over the Persian Gulf. PMID- 23752607 TI - Expression of PIM-2 and NF-kappaB genes is increased in patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and is associated with complete remission rate and overall survival. AB - INTRODUCTION: PIM-2 is a proto-oncogene that encodes for a serine/threonine kinase that interacts with various signaling molecules. PIM-2 is highly expressed in neoplastic tissues and in leukemic and lymphoma cell lines, which is consistent with its role during oncogenic transformation. The nuclear factor kappa B (NF-kappaB) pathway appears to be deregulated in a variety of tumors, with sustained activity of NF-kappaB leading to apoptotic resistance in tumor cells. The aim of this study was to investigate whether expression of PIM-2 and NF-kappaB is altered in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: One hundred forty-three patients were included: 91 with AML and 52 with ALL, aged 18-84 (median 46.7). Eighty-three patients (51 AML and 32 ALL) reached complete remission (CR). Bone marrow samples were collected at the time of diagnosis. Control samples were obtained from 24 healthy donors. We analyzed PIM-2 and NF-kappaB expression by RQ-PCR analysis. RESULTS: Expression of both PIM-2 and NF-kappaB in all leukemia patients and subgroups was significantly higher than in controls. AML patients who reached CR expressed PIM-2 and NF-kappaB at significantly lower levels than did patients with primary resistance to chemotherapy and who did not reach CR (NCR). Survival analysis revealed that in AML patients with higher expression of PIM-2 the overall survival (OS) was significantly shorter than in patients with lower expression. CONCLUSION: Our data indicate that PIM-2 and NF-kappaB gene expression is increased in patients with AML and ALL. Moreover, high PIM-2 expression is associated with CR rate and OS in AML patients. PMID- 23752609 TI - The burden of hospitalization for atrial fibrillation-reply. PMID- 23752610 TI - Different modulation of Ptpn22 in effector and regulatory T cells leads to attenuation of autoimmune diabetes in transgenic nonobese diabetic mice. AB - Ptpn22 encodes PEST domain-enriched tyrosine phosphatase (Pep), which negatively regulates TCR proximal signaling and is strongly associated with a variety of autoimmune diseases in humans. The net effect of Pep on the balance of immunity and tolerance is uncertain because of the simultaneous inhibition of TCR-mediated signaling of effector and regulatory T cells (T(regs)). In this study, we generated transgenic NOD mice that overexpressed Pep in T cells. The transgenic mice had a significantly lower incidence of spontaneous autoimmune diabetes, which was accompanied by fewer IFN-gamma-producing T cells, and an increased ratio of CD4(+)Foxp3(+) T(regs)to CD4(+)IFN-gamma(+) or to CD8(+)IFN-gamma(+) T cells, respectively, in pancreatic islets. Transgenic T cells showed markedly decreased TCR-mediated effector cell responses such as proliferation and Th1 differentiation. By contrast, the inhibitory effect of transgenic Pep on TCR signaling did not affect the differentiation of T(regs) or their suppressive activity. Adoptive transfer experiments showed that transgenic splenocytes exhibited attenuated diabetogenic ability. To examine further the pathogenic features of transgenic T cells, we generated Ptpn22/BDC2.5 doubly transgenic mice and found reduced proliferation and Th1 differentiation in CD4(+) T lymphocytes with additional Pep in pancreatic lymph nodes but not in inguinal lymph nodes of NOD/SCID recipients. This finding indicates that transgenic Pep attenuates T cell functions in an islet Ag-driven manner. Taken together, our results demonstrate that Pep overexpression in T cells attenuates autoimmune diabetes in NOD mice by preferentially modulating TCR signaling-mediated functions in diabetogenic T cells but not in T(regs). PMID- 23752611 TI - Control of T cell fates and immune tolerance by p38alpha signaling in mucosal CD103+ dendritic cells. AB - Dendritic cells (DCs) play a crucial role in launching protective adaptive immunity against pathogens while maintaining immune tolerance to self-Ags. However, how intracellular signaling pathways program DCs to mediate tolerogenic responses remains largely unexplored. In this study, we describe that p38alpha signaling in CD103(+) mesenteric lymph node DCs reciprocally regulates the differentiation of anti-inflammatory induced regulatory T cells and proinflammatory Th1 cells from naive precursors and promotes mucosal tolerance. Deficiency of p38alpha in CD103(+) DCs inhibited the generation of induced regulatory T cells while promoting Th1 cell development in a TGF-beta2-dependent manner. Consequently, loss of p38alpha in DCs prevented induction of oral tolerance in vivo. Moreover, p38alpha in CD103(+) DCs was required for optimal expression of retinaldehyde dehydrogenase, a key enzyme for retinoic acid synthesis, which in turn imprinted gut-homing receptors on responding T cells. Consistent with a crucial role of p38alpha to program the tolerogenic activity of CD103(+) DCs, such DC subset contained constitutive activity of p38alpha and abundant expression of TGF-beta2 and retinaldehyde dehydrogenase. Our studies identify a key mechanism of DC-mediated coupling of T cell differentiation and trafficking that orchestrates mucosal immune tolerance. PMID- 23752612 TI - Contrasting effects of anti-Ly49A due to MHC class I cis binding on NK cell mediated allogeneic bone marrow cell resistance. AB - NK subsets have activating and inhibitory receptors that bind MHC-I. Ly49A is a mouse inhibitory receptor that binds with high affinity to H2(d) in both a cis- and trans-manner. Ly49A cis-associations limit trans-interactions with H2(d) expressing targets as well as mAb binding. We demonstrate that cis-interactions affect mAb effector functions. In vivo administration of anti-Ly49A depleted NK cells in H2(b) but not H2(d) mice. Despite lack of depletion, in vivo treatment with anti-Ly49A reduced NK killing capabilities and inhibited activation, partially due to its agonistic effect. These data explain the previously described in vivo effects on bone marrow allograft rejection observed with anti Ly49A treatment in H2(d)-haplotype mice. However, prior treatment of mice with poly(I:C) or mouse CMV infection resulted in increased Ly49A expression and Ly49A(+) NK cell depletion in H2(d) mice. These data indicate that, although Ly49 mAbs can exert similar in vivo effects in mice with different MHC haplotypes, these effects are mediated via different mechanisms of action correlating with Ly49A expression levels and can be altered within the same strain contingent on stimuli. This illustrates the marked diversity of mAb effector functions due to the regulation of the level of expression of target Ags and responses by stimulatory incidents such as infection. PMID- 23752613 TI - Neutrophil recruitment to the lung in both C5a- and CXCL1-induced alveolitis is impaired in vitamin D-binding protein-deficient mice. AB - Knowledge of how neutrophils respond to chemotactic signals in a complex inflammatory environment is not completely understood. Moreover, even less is known about factors in physiological fluids that regulate the activity of chemoattractants. The vitamin D-binding protein (DBP) has been shown to significantly enhance chemotaxis to complement activation peptide C5a using purified proteins in vitro, and by ex vivo depletion of DBP in physiological fluids, but this function has not been determined in vivo. DBP null ((-/-)) mice were used to investigate how a systemic absence of this plasma protein affects leukocyte recruitment in alveolitis models of lung inflammation. DBP(-/-) mice had significantly reduced (~50%) neutrophil recruitment to the lungs compared with their wild-type DBP(+/+) counterparts in three different alveolitis models, two acute and one chronic. The histology of DBP(-/-) mouse lungs also showed significantly less injury than wild-type animals. The chemotactic cofactor function of DBP appears to be selective for neutrophil recruitment, but, in contrast to previous in vitro results, in vivo DBP can enhance the activity of other chemoattractants, including CXCL1. The reduced neutrophil response in DBP( /-) mice could be rescued to wild-type levels by administering exogenous DBP. Finally, in inflammatory fluids, DBP binds to G-actin released from damaged cells, and this complex may be the active chemotactic cofactor. To our knowledge, results show for the first time that DBP is a significant chemotactic cofactor in vivo and not specific for C5a, suggesting that this ubiquitous plasma protein may have a more significant role in neutrophil recruitment than previously recognized. PMID- 23752614 TI - Viral infection of the pregnant cervix predisposes to ascending bacterial infection. AB - Preterm birth is the major cause of neonatal mortality and morbidity, and bacterial infections that ascend from the lower female reproductive tract are the most common route of uterine infection leading to preterm birth. The uterus and growing fetus are protected from ascending infection by the cervix, which controls and limits microbial access by the production of mucus, cytokines, and antimicrobial peptides. If this barrier is compromised, bacteria may enter the uterine cavity, leading to preterm birth. Using a mouse model, we demonstrate, to our knowledge for the first time, that viral infection of the cervix during pregnancy reduces the capacity of the female reproductive tract to prevent bacterial infection of the uterus. This is due to differences in susceptibility of the cervix to infection by virus during pregnancy and the associated changes in TLR and antimicrobial peptide expression and function. We suggest that preterm labor is a polymicrobial disease, which requires a multifactorial approach for its prevention and treatment. PMID- 23752616 TI - Does motivational interviewing improve medication adherence?-Reply. PMID- 23752617 TI - 5-lipoxygenase antagonist therapy: a new approach towards targeted cancer chemotherapy. AB - Leukotrienes are the bioactive group of fatty acids and major constituents of arachidonic acid metabolism molded by the catalytic activity of 5-lipoxygenase (5 LOX). Evidence is accumulating in support of the direct involvement of 5-LOX in the progression of different types of cancer including prostate, lung, colon, and colorectal cancers. Several independent studies now support the correlation between the 5-LOX expression and cancer cell viability, proliferation, cell migration, invasion through extracellular matrix destruction, metastasis, and activation of anti-apoptotic signaling cascades. The involvement of epidermal growth factor receptor and 5-oxo-ETE receptor (OXER1) is the major talking point in the downstream of the 5-LOX pathway, which relates the cancer cells to the proliferative pathways. Antisense technology approaches and use of different kinds of blocker targeted to 5-LOX, FLAP (5-LOX-activating protein), and OXER1 have shown a greater efficiency in combating different cancer cell types. Lastly, suppression of 5-LOX activity that reduces the cell proliferation activity also induces intrinsic mitochondrial apoptotic pathway in either p53-dependent or independent manner. Pharmacological agents that specifically inhibit the LOX mediated signaling pathways have been used during last few years to treat inflammatory diseases such as asthma and arthritis. Studies of these well characterized agents are therefore warranted for their use as possible candidates for chemotherapeutic studies against the killer disease cancer. PMID- 23752615 TI - Notch-regulated periphery B cell differentiation involves suppression of E protein function. AB - Notch signaling pathway plays important roles in promoting the generation of marginal zone (MZ) B cells at the expense of follicular (FO) B cells during periphery B cell maturation, but the underlying molecular mechanisms are not well understood. We hypothesize that Notch favors the generation of MZ B cells by downregulating E protein activity. In this study, we demonstrated that expression of Id2 and ankyrin-repeat SOCS box-containing protein 2 was elevated in MZ B cells and by Notch signaling. Id2 inhibits the DNA binding activity of E proteins, whereas ankyrin-repeat SOCS box-containing protein 2 facilitates E protein ubiquitination. Next, we examined the phenotypes of splenic B cells in mice expressing constitutively active Notch1 and/or two gain-of-function mutants of E proteins that counteract Id2-mediated inhibition or Notch-induced degradation. We found that upregulation of E proteins promoted the formation of FO B cells, whereas it suppressed the maturation of MZ B cells. In contrast, excessive amounts of Notch1 stimulated the differentiation of MZ B cells and inhibited the production of FO B cells. More interestingly, the effects of Notch1 were reversed by gain of E protein function. Furthermore, high levels of Bcl-6 expression in FO B cells was shown to be diminished by Notch signaling and restored by E proteins. In addition, E proteins facilitated and Notch hindered the differentiation of transitional B cells. Taken together, it appears that Notch regulates peripheral B cell differentiation, at least in part, through opposing E protein function. PMID- 23752619 TI - A new paradigm for primary care-reply. PMID- 23752618 TI - Expression and characterization of a novel highly glucose-tolerant beta glucosidase from a soil metagenome. AB - A beta-glucosidase gene unbgl1A was isolated by the function-based screening of a metagenomic library and the enzyme protein was expressed in Escherichia coli, purified, and biochemically characterized. The enzyme Unbgl1A had a Km value of 2.09 +/- 0.31 mM, and a Vmax value of 183.90 +/- 9.61 MUmol min(-1) mg(-1) under the optimal reaction conditions, which were pH 6.0 at 50 degrees C. Unbgl1A can be activated by a variety of monosaccharides, disaccharides, and NaCl, and exhibits a high level of stability at high concentration of NaCl. Two prominent features for this enzyme are: (i) high glucose tolerance. It can be tolerant to glucose as high as 2000 mM, with Ki = 1500 mM; (ii) high NaCl tolerance. Its activity is not affected by 600 mM NaCl. The enzyme showed transglucosylation activities resulting in the formation of cellotriose from cellobiose. These properties of Unbgl1A should have important practical implication in its potential applications for better industrial production of glucose or bioethanol started from lignocellulosic biomass. PMID- 23752620 TI - Caring for people who care. PMID- 23752621 TI - Quality of life for ostomates. PMID- 23752622 TI - Transition to adult care for young people with long-term conditions. AB - This study aimed to clarify how the transition from child to adult healthcare is managed in young people with two long-term conditions in the Republic of Ireland.A postal survey using an adapted questionnaire (Flume et al, 2001) with closed and open questions was sent to all physicians and nurse specialists (n=132) caring for children with cystic fibrosis (CF) and insulin dependent diabetes mellitus (IDDM)in the Republic of Ireland. Data was analysed using SPSS 16.0 for Windows and the open-ended qualitative questions were analysed using content analysis. Results showed that transition management varied depending on the service, location and resources available. Comparisons were made between CF and IDDM data. Age was found to be the criterion most commonly used to determine when to transition in all services. Healthcare professionals said transition management needed to be improved. Some services managed transition following recommended guidelines.However, the management of transition nationally needs to be more streamlined.This includes a devised cohesive strategy between adult and young people's services. PMID- 23752623 TI - Hepatitis C therapy at home: a hospital and home care partnership. AB - Hepatitis C virus (HCV) is a significant public health threat in the UK, and is both underdiagnosed and undertreated. The treatment episode takes between 12 and 48 weeks. In the UK, HCV management is undertaken in secondary and tertiary centres. This does not meet the needs of all patients; they may have to travel long distances, incur travel costs, wait a long time to be seen and negotiate time off work while not divulging their illness. Providing care at home can increase patients' access to and acceptability of treatment, especially in areas remote from specialist centres. This paper describes the feasibility, safety and efficacy of treating HCV infected patients at home by a partnership between secondary care and an clinical home care company. The home care model had a significantly higher attendance rate than the clinic model. It allowed the trust to improve care at no extra cost. This model can optimise specialist nurses' time, allowing them to focus on patients with more complex needs. PMID- 23752624 TI - NICE guidelines for new chest pain: comparison of new and old services. AB - In 2000 the National Service Framework for Coronary Artery Disease (CAD) prompted the development of rapid-access chest pain clinics (RACPCs). The aim of such clinics is to provide prompt assessment of chest pain to identify CAD with the use of an exercise tolerance test. In 2010, the National Institute for Health and Clinical Excellence (NICE) guidelines recommended using imaging studies based on CAD risk scoring and not an exercise tolerance test to exclude angina in patients with no previous history of known CAD. A comparison of the use of the 2010 NICE guidelines for the management of new-onset chest pain within a well-established exercise-based RACPC service is undocumented. The new recommendation moves the focus towards discharging low-risk patients, imaging studies/invasive procedure (angiogram) for the moderate-risk group and initiating anti-anginal treatment for the high-risk group. To phase the new recommendations into clinical practice in a district general hospital, the new guidelines were implemented in one out of three RACPC sessions per week. A retrospective assessment was carried out over a 4-month period to evaluate the new service implementation. A total of 160 patients attended the RACPC service, of which 56 (35%) were offered treatments according to the newer NICE guidelines and 104 (65%) were managed with the aim of exercising on the treadmill. This review gives an insight into the benefits of the new recommendations in practice, as well as highlighting some of the immediate limitations and barriers encountered. PMID- 23752625 TI - A year's healthcare assistant experience as a prerequisite? PMID- 23752626 TI - The results of the NHS 2012 inpatients survey. PMID- 23752627 TI - What is the Margaret Thatcher legacy for nurse education? PMID- 23752628 TI - Advancing practice: from staff nurse to nurse consultant. Part 9: conferences. PMID- 23752629 TI - From the other side. PMID- 23752630 TI - What would Florence Nightingale say? PMID- 23752631 TI - The need for additional training for nutritional management of diabetes. AB - The purpose of this study was to investigate nurses' and nursing students'knowledge and perceived role in assisting patients with the nutritional management of diabetes. Three focus groups were conducted and the results were used to modify a previously developed survey regarding the nutritional management of diabetes. The survey was administered via an online survey tool and completed by 231 nurses and students. Over 70% of respondents agreed that nurses have an important role in reinforcing patient nutritional education. Results indicated,however, that knowledge gaps in the nutritional management of diabetes exist among nurses, including not knowing the carbohydrate content of 120ml of orange juice, a common treatment for hypoglycaemia (47.5%), not knowing where to locate carbohydrate content on a food label (60%), and not identifying the correct treatment for hypoglycaemia (47.5%). These results indicate that there may be a need to improve the nutritional education of nurses with respect to diabetes management. PMID- 23752632 TI - [Complex abdominal wall hernias]. PMID- 23752633 TI - Perioperative assessment of the patients in intensive care unit. AB - OBJECTIVE: To evaluate the preoperative condition and the surgical procedure of surgical patients in a general intensive care unit of a university hospital, relating them to morbidity and mortality. METHODS: We studied the medical records of patients undergoing medium and large surgical procedures, admitted to the general intensive care unit. We analyzed: demographic data, clinical records personal history and laboratory tests, both preoperatively and on admission to the intensive care unit, imaging, operative reports, anesthetic reports and antibiotic prophylaxis. After admission, the variables studied were: length of stay, type of nutritional support, use of thromboprophylaxis, mechanical ventilation, description of complications and mortality. RESULTS: We analyzed 130 medical records. Mortality was 23.8% (31 patients), Apache II greater than 40 was observed in 57 patients undergoing major surgery (64%), ASA classification e" II was observed in 16 patients who died (51.6%), the length of stay in the intensive care unit ranged from one to nine days and was observed in 70 patients undergoing major surgery (78.5%), the use of mechanical ventilation for up to five days was observed in 36 patients (27.7%), hypertension was observed in 47 patients (47.4%), the most frequent complication was sepsis. CONCLUSION: the correct stratification of surgical patient determines their early discharge and reduced exposure to random risk. PMID- 23752634 TI - Predictors of salivary fistula after total laryngectomy. AB - OBJECTIVE: To evaluate the incidence of pharyngocutaneous fistula after total laryngectomy and try to identify its predictors. METHODS: From May 2005 to April 2010, 93 patients underwent total laryngectomy. We evaluated complications during and after surgery and compared them with the following variables: gender, nutritional status, previous tracheotomy, tumor location, type of surgery, TNM staging, prior treatment with chemotherapy and/or radiotherapy, use of flaps for reconstruction and surgical margin. All patients presented with advanced neoplastic disease according to TNM. RESULTS: 14 (15.1%) patients developed postoperative salivary fistula. The mean time to onset of salivary fistula was 3.5 days, with a standard deviation of 13.7 days. Comparing salivary fistula with TNM variables, type of operation and neck dissection, prior tracheotomy, use of flap, preoperative radio and chemotherapy and surgical margin, there was no statistically significant difference (p> 0,05). CONCLUSION: The incidence of salivary fistula was 15.1% and no predictive factor for its formation was found. PMID- 23752635 TI - Pharyngoesophageal diverticulum: evaluation of treatment results. AB - OBJECTIVE: To evaluate the postoperative outcome of patients with pharyngoesophageal diverticulum submitted to surgical and endoscopic treatments. METHODS: We retrospectively analyzed 36 patients with pharyngo-esophageal diverticulum treated at the Hospital of the Medical School of Botucatu - UNESP. Patients were divided into two groups, depending on the treatment: group 1 (n = 24): diverticulectomy associated myotomy through a left cervicotomy; group 2 (n = 12): endoscopic diverticulostomy with linear stapler. RESULTS: Operative mortality was zero in both groups. Early complications: group 1 - two patients developed cervical fistula and two, hoarseness; group 2 - none. Late complications: group 1 - none; group 2: recurrence of dysphagia in four patients (p = .01). Mean follow-up was 33 months for group 1 and 28 months for group 2. CONCLUSION: Both procedures were effective in remission of dysphagia. Surgical treatment showed superiority to endoscopy, with resolution of dysphagia with a single procedure. Endoscopic treatment should be reserved for the elderly and those with comorbidities. PMID- 23752637 TI - Spirometry evaluation in patient with tuberculosis sequelae treated by lobectomy. AB - OBJECTIVE: To evaluate pre and post-operative spirometry in patients with tuberculosis sequelae undergoing lobectomy. METHODS: We selected 20 patients, aged between 15 and 56 years, of both genders, with a history of tuberculosis treatment, with repeated infections or hemoptysis and indication of pulmonary lobectomy. The tuberculosis treatment time was six months, and onset of symptoms, between one and 32. We evaluated and compared vital capacity (VC), forced vital capacity (FVC), forced expiratory volume (FEV1), the FEV1/FVC, forced expiratory flow (FEF) and peak expiratory flow (PEF) preoperatively and after the first, third and sixth postoperative months (POM). The significance level (a) used in all tests was 5%, ie, it was considered significant when p <0.05. RESULTS: The averages found were: Vital Capacity (VC) - Preoperative: 2.83; 1st POM: 2.12; 3rd POM: 2.31; 6th POM: 2.43. Forced Vital Capacity (FVC) - Preoperative: 2.97; 1st POM: 2.21; 3rd POM: 2.35; 6th POM: 2.53. Expiratory Volume in 1 second (FEV1) - Preoperative: 2.23; 1st POM: 1.75; 3rd POM: 1.81; 6th POM 1.97. There was marked decrease in lung function in the first month after surgery, but there was an improvement of the parameters from the third month, with gradual increase up to the sixth month. CONCLUSION: There was no recovery of preoperative spirometric parameters at six months postoperatively in patients with sequelae of tuberculosis submitted to lobectomy. PMID- 23752636 TI - BRAF mutation in the elderly submitted to thyroidectomy. AB - OBJECTIVE: To evaluate the frequency of the BRAF V600E mutation in patients over 65 years of age undergoing thyroidectomy, correlating its presence or absence with the different histologic lesions, their variants and with prognostic factors of papillary carcinoma. METHODS: We evaluated 85 patients over 65 years of age who underwent thyroidectomy, analyzing the BRAF V600E mutation by RT-PCR performed after DNA extraction from the paraffin blocks. RESULTS: The study detected the presence or absence of BRAF V600E mutation in 47 patients (55.3%). Among the 17 papillary carcinomas studied, seven had the mutation (41.2%). There was a statistical association between the presence of this mutation and the classic variant of papillary carcinoma, and a trend of association with thyroid extravasation. CONCLUSION: BRAF mutation in the elderly is also exclusive of papillary carcinoma and is often significant. Furthermore, it is related to the classic variant and possibly to thyroid extravasation. PMID- 23752638 TI - Prognostic role of positive peritoneal cytology in patients with resectable gastric cancer. AB - OBJECTIVE: To evaluate the prognostic value of positive peritoneal lavage in patients with gastric cancer without signs of peritoneal or hematogenous spread. METHODS: We evaluated patients with gastric adenocarcinoma treated with curative intent operation. The peritoneal lavage was classified as positive or negative for neoplastic cells. We obtained demographics, performance status, histology and type of surgery. The results were statistically compared and were considered significant for values of p <0.05. RESULTS: We included 72 patients with gastric adenocarcinoma. During a mean follow up of 26 months (one to 39 months) we observed 20 local or distant recurrences and 21 deaths. Only the presence of lymph node metastases and the need for resection of adjacent organs were associated with a significant reduction in relapse-free survival. There was a significant reduction in overall survival in patients with angio-lymphatic invasion, lymph node metastasis, requiring resection of multiple organs, need for total gastrectomy and greater invasion of the gastric wall. The presence of tumor cells in the peritoneal cavity was associated with worse overall survival, but without statistical significance. CONCLUSION: There was no statistically significant associations between positive peritoneal citology and recurrence-free survival or overall survival among patients with resectable gastric cancer. PMID- 23752639 TI - Sentinel node biopsy should not be recommended for patients with thick melanoma. AB - OBJECTIVE: To ascertain whether there is any relationship between the state of the sentinel lymph node histopathology, recurrence and mortality from thick melanoma in patients undergoing SLNB over a long follow-up. METHODS: Eighty-six patients with thick melanoma undergoing SLNB were selected from a prospective database. Lymphoscintigraphy, lymphatic mapping and intraoperative gamma probe detection were performed in all patients. The sentinel lymph node (SLN) was analyzed by HE and immunohistochemistry. Complete lymphadenectomy was indicated for patients with positive sentinel node. The histopathological SLN status was related to the rate of recurrence and mortality from melanoma. RESULTS: One hundred and sixty-six SLNs were taken from the 86 patients. Ages ranged from 18 to 73 years. There were 47 women and 39 men. Micrometastases were found in 44 patients. Forty-two patients underwent complete lymphadenectomy. Seven other patients had positive lymph node. Among the 44 patients with positive sentinel node, there were 20 recurrences and 15 deaths. There were 18 recurrences and 12 deaths in the group with negative SLN. The Breslow thickness was not correlated with the histopathological SLN status. The histopathological SLN status did not affect the rates of recurrence and mortality (Fisher test, p = 1.00). The median follow-up was 69 months. CONCLUSION: Considering the lack of evidence of benefit, SLNB should not be indicated for patients with thick melanoma outside of clinical studies. PMID- 23752640 TI - Stable experimental model of carotid artery saccular aneurysm in swine using the internal jugular vein. AB - OBJECTIVE: To develop an experimental model of stable saccular aneurysm in carotid of pigs using the internal jugular vein. METHODS: In 12 healthy pigs, weighing between 25 and 5 0kg, five males and seven females, we made a right common carotid artery aneurysm. After elliptical arteriotomy, we carried out a terminolateral anastomosis with the distal stump of the internal jugular vein. Aneurysm volume was calculated so that the value did not exceed 27 times the area of the arteriotomy. After six days angiography and microscopic examination were performed to assess patency of the aneurysm and the presence of total or partial thrombosis. RESULTS: There was a significant weight gain of pigs in the time interval between the manufacture of the aneurysm and angiography (p = 0.04). Aneurysmal patency was observed in ten pigs (83%). Operative wound infections occurred in two animals (16.6%), both with early onset, three days after the making of the aneurysm. Histological analysis showed aneurysm thrombus partially occluding the light in nine pigs (75%). In these animals, it was observed that on average 9% of the aneurysmal diameter was filled with thrombi. CONCLUSION: It was possible to develop a stable experimental model of saccular aneurysms in pig carotid artery by use of the internal jugular vein. PMID- 23752641 TI - Hepatic repercussions of azoxymethane-induced colorectal carcinogenesis. AB - OBJECTIVE: To evaluate the hepatic effects of colonic carcinogenesis induced by azoxymethane at different doses and times of exposure in rats. METHODS: Forty four Wistar rats were divided into four groups. The animals were eight weeks at the beginning of the experiment. group 1 received 1.0 ml of saline intraperitoneally once a week for two weeks. Group 2 received 15 mg/kg of azoxymethane intraperitoneally once a week for two weeks. These animals were killed at the 15th week of the experiment. The animals of group 3 received saline intraperitoneally once a week for two weeks. Group 4 animals received 20mg/kg of azoxymethane intraperitoneally once a week for two weeks. These animals were killed at the 26th week of the experiment. The fragments of liver tissue were stained with hematoxylin and eosin and evaluated microscopically. RESULTS: Groups 1 and 2 differed significantly in relation to steatosis, no difference having been found between group 3 and group 4. However, in group 4 we observed pre neoplastic lesions (foci of altered, clear, vacuolated, basophilic, amphophilic tigroid, oncocytic, small or acidophilus cells, spongiosis and peliosis) and neoplastic lesions (adenomas and colangiomas) containing atypical hepatocytes in between, not identified in group 3. CONCLUSION: In the model of colorectal carcinogenesis, preneoplastic and neoplastic hepatic lesions appear and evolve in proportion to the time of exposure and dose of azoxymethane. PMID- 23752642 TI - [Damage control surgery: an update]. AB - The damage control surgery is a widely accepted concept today among abdominal trauma specialists when it comes to the severely traumatized. In these patients, the death is due, in most cases, to the installation of the lethal triad (hypothermia, coagulopathy and acidosis) and not the inability to repair the serious initial damage. In this review, the authors address the lethal triad in its three phases and emphasize the measures taken to prevent them, as well as discussing the indication and employment of damage control surgery in its various stages. Restoring the physiological status of the patient in the ICU, so that he/she can be submitted to final operation and closure of the abdominal cavity, another challenge in severe trauma patients, is also discussed. PMID- 23752643 TI - [Evaluation of surgical training in medical school]. AB - OBJECTIVE: To evaluate the effectiveness of training in surgical techniques in pig feet during medical school. METHODS: We conducted a cross-sectional study with 87 volunteer medical students from different graduation semesters, who attended a basic workshop for incisions, sutures, biopsies, flaps, grafts, under direct supervision. Pre and post-training self-administered questionnaires were used. RESULTS: The teaching of sutures, biopsies and ear correction was effective for learning of the minimal skills required for the proposed techniques (p <0.005), as well as excisions and flaps, except grafting (p> 0 97). CONCLUSION: The methodological approach and monitoring of techniques' reproduction were adequate. The training offered complemented cutaneous surgical skills of undergraduate medicine students. PMID- 23752644 TI - [Lymphadenectomy in gastric cancer with laparotomic hook]. AB - Gastric cancer is a common malignancy of surgical treatment. D2 lymphadenectomy is the standard procedure with curative intent. The authors report the use of laparotomic hook as an alternative technique for lymphadenectomy. PMID- 23752645 TI - [Laparoscopic hepatectomy with radiofrequency device]. AB - Laparoscopic liver resections are gaining adherents among surgeons, as they show rapid recovery, shorter hospital stay and better cosmetic results. The use of a laparoscopic radiofrequency device was first carried out successfully in Brazil for resection of hepatocellular carcinoma of the segment VI in two cirrhotic patients. Although intraoperative bleeding remains a major challenge for the surgeon during laparoscopic liver resections, in both cases the hepatic vascular exclusion was expendable and there was no need for blood transfusion. Patients were discharged on the fourth postoperative day. PMID- 23752646 TI - Classification of acute pancreatitis. AB - Based on the Atlanta Classification, acute pancreatitis is classified according to its severity in either mild or severe acute pancreatitis. In recent years, several issues regarding acute pancreatitis have been discussed in the literature. These issues include how many categories of severity should be considered; whether or not a patient with organ failure holds similar holds severity of disease and prognosis of a patient with infected necrosis; the role of transient organ failure; and how to evaluate organ failure. The"Evidence-based Telemedicine - Trauma and Acute Care Surgery" (EBT-TACS) conducted a review of the recent literature on the topic, and critically appraised its most relevant pieces of evidence.. The articles discussed suggested classifying the severity of acute pancreatitis in three or four categories, rather than mild or severe only, and addressed which is the best score to assess organ failure. The following recommendations were proposed: (1) Acute pancreatitis should be classified into four categories: mild, moderate, severe and critical, which allows a better determination of the characteristics of patients, (2) Evaluation of organ failure with a severity score that preferably evaluate directly each organ failure, such as the SOFA and MODS (Marshall). The SOFA seems to have greater accuracy, but the MODS has better applicability due to its ease of use. PMID- 23752647 TI - [A rare mediastinum tumor: hamartoma]. AB - In the present paper we report a case of mediastinal tumor which we believe has never been reported. Since surgical treatment, the patient presented good evolution. We discuss the presentation, differential diagnosis and therapy. Finally, we stress the importance of the pathologic findings. PMID- 23752648 TI - Viral and host factors required for avian H5N1 influenza A virus replication in mammalian cells. AB - Following the initial and sporadic emergence into humans of highly pathogenic avian H5N1 influenza A viruses in Hong Kong in 1997, we have come to realize the potential for avian influenza A viruses to be transmitted directly from birds to humans. Understanding the basic viral and cellular mechanisms that contribute to infection of mammalian species with avian influenza viruses is essential for developing prevention and control measures against possible future human pandemics. Multiple physical and functional cellular barriers can restrict influenza A virus infection in a new host species, including the cell membrane, the nuclear envelope, the nuclear environment, and innate antiviral responses. In this review, we summarize current knowledge on viral and host factors required for avian H5N1 influenza A viruses to successfully establish infections in mammalian cells. We focus on the molecular mechanisms underpinning mammalian host restrictions, as well as the adaptive mutations that are necessary for an avian influenza virus to overcome them. It is likely that many more viral and host determinants remain to be discovered, and future research in this area should provide novel and translational insights into the biology of influenza virus-host interactions. PMID- 23752650 TI - Single molecule kinetics of horseradish peroxidase exposed in large arrays of femtoliter-sized fused silica chambers. AB - Large arrays of femtoliter-sized chambers were etched into the surface of fused silica slides to enclose and observe hundreds of single horseradish peroxidase (HRP) molecules in parallel. Individual molecules of HRP oxidize the fluorogenic substrate Amplex Red to fluorescent resorufin in separate chambers, which was monitored by fluorescence microscopy. Photooxidation of Amplex Red and photobleaching of resorufin have previously limited the analysis of HRP in femtoliter arrays. We have strongly reduced these effects by optimizing the fluorescence excitation and detection scheme to yield accurate single molecule substrate turnover rates. We demonstrate the presence of long-lived kinetic states of single HRP molecules that are individually different for each molecule in the array. The large number of molecules investigated in parallel provides excellent statistics on the activity distribution in the enzyme population, which is similar to that reported for other enzymes such as beta-galactosidase. We have further confirmed that the product formation of HRP in femtoliter chambers is 10 fold lower than that in the bulk solution due to the particular two-step redox reaction mechanism of HRP. PMID- 23752651 TI - Experimental bound entanglement through a Pauli channel. AB - Understanding the characteristics of a quantum systems when affected by noise is one of the biggest challenges for quantum technologies. The general Pauli error channel is an important lossless channel for quantum communication. In this work we consider the effects of a Pauli channel on a pure four-qubit state and simulate the Pauli channel experimentally by studying the action on polarization encoded entangled photons. When the noise channel acting on the photons is correlated, a set spanned by four orthogonal bound entangled states can be generated. We study this interesting case experimentally and demonstrate that products of Bell states can be brought into a bound entangled regime. We find states in the set of bound entangled states which experimentally violate the CHSH inequality while still possessing a positive partial transpose. PMID- 23752649 TI - Exploiting herpes simplex virus entry for novel therapeutics. AB - Herpes Simplex virus (HSV) is associated with a variety of diseases such as genital herpes and numerous ocular diseases. At the global level, high prevalence of individuals who are seropositive for HSV, combined with its inconspicuous infection, remains a cause for major concern. At the molecular level, HSV entry into a host cell involves multiple steps, primarily the interaction of viral glycoproteins with various cell surface receptors, many of which have alternate substitutes. The molecular complexity of the virus to enter a cell is also enhanced by the existence of different modes of viral entry. The availability of many entry receptors, along with a variety of entry mechanisms, has resulted in a virus that is capable of infecting virtually all cell types. While HSV uses a wide repertoire of viral and host factors in establishing infection, current therapeutics aimed against the virus are not as diversified. In this particular review, we will focus on the initial entry of the virus into the cell, while highlighting potential novel therapeutics that can control this process. Virus entry is a decisive step and effective therapeutics can translate to less virus replication, reduced cell death, and detrimental symptoms. PMID- 23752652 TI - A sustainable two-phase procedure for V-catalyzed toluene oxidative bromination with H2O2-KBr. AB - A sustainable V(V) and Mo(VI) catalysed two-phase procedure for bromination of toluene under quite mild conditions is proposed; H2O2 is the primary oxidant and KBr is the bromine source; metal precursors are commercially available salts. The reaction is efficient without any additional solvent. By using PhCH3 as a solvent/substrate good yields, together with interesting selectivity toward the formation of PhCH2Br, are obtained with both metal ions. Recycling of the catalytic phase is also possible. Useful information on the V-peroxido chemistry was obtained. PMID- 23752653 TI - Dynamic random access memory devices based on bismuth sulfide nanoplates prepared from a single source precursor. AB - Semiconducting bismuth sulfide (Bi2S3) nanoplates with unique highly oriented {001} surfaces were prepared on a large scale using a novel organic precursor Bi(DTCA)3 (DTCA = carbazole-9-carbodithioic acid). The as-prepared Bi2S3 nanoplates were dispersed in dimethyl sulfoxide (DMSO) and spin-coated onto an indium tin oxide (ITO) coated glass substrate. With a simple ITO/Bi2S3/Al stacked structure, the fabricated sandwich-like memory device demonstrates dynamic random access memory (DRAM) characteristics with a maximum ON/OFF current ratio up to 10(6) and a long retention time. It is suggested that the volatile nature of the memory device comes from the Schottky contact between the Bi2S3 nanoplates and the Al electrodes. PMID- 23752654 TI - Psoriasis and the obesity epidemic: the effect of weight loss. PMID- 23752656 TI - This month in archives of dermatology. PMID- 23752657 TI - About this journal. PMID- 23752659 TI - An unsymmetrical pentacene derivative with ambipolar behavior in organic thin film transistors. AB - Three new unsymmetrical anthracenyl-pentacene derivatives have been synthesized, characterized using X-ray crystallography, and used as semiconductors in OTFTs. For one derivative, ambipolar charge carrier transport was observed with a hole mobility of 0.2 cm(2) V(-1) s(-1) and an electron mobility of 0.03 cm(2) V(-1) s( 1). PMID- 23752660 TI - Satisfied to death: a spurious result?-Reply. PMID- 23752661 TI - Rational design of carbon and TiO2 assembly materials: covered or strewn, which is better for photocatalysis? AB - The rational design of carbonaceous hybrid nanostructures is very important for obtaining high photoactivity. TiO2 particles strewn with an optimal quantity of carbon nanodots have a much higher photoactivity than that of TiO2 covered with a carbon layer, showing the importance of carbon morphology in the photocatalysis of carbonaceous hybrid nanostructures. PMID- 23752664 TI - Should health care systems and health care providers implement a new pathway for hospitalized patients with community-acquired pneumonia?-Reply. PMID- 23752662 TI - Fat intake after diagnosis and risk of lethal prostate cancer and all-cause mortality. AB - IMPORTANCE: Nearly 2.5 million men currently live with prostate cancer in the United States, yet little is known about the association between diet after diagnosis and prostate cancer progression and overall mortality. OBJECTIVE: To examine postdiagnostic fat intake in relation to lethal prostate cancer and all cause mortality. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 4577 men with nonmetastatic prostate cancer in the Health Professionals Follow-up Study (1986-2010). EXPOSURES: Postdiagnostic intake of saturated, monounsaturated, polyunsaturated, trans, animal, and vegetable fat. MAIN OUTCOMES AND MEASURES: Lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality. RESULTS: We observed 315 events of lethal prostate cancer and 1064 deaths (median follow-up, 8.4 years). Crude rates per 1000 person-years for lethal prostate cancer were as follows (highest vs lowest quintile of fat intake): 7.6 vs 7.3 for saturated, 6.4 vs 7.2 for monounsaturated, 5.8 vs 8.2 for polyunsaturated, 8.7 vs 6.1 for trans, 8.3 vs 5.7 for animal, and 4.7 vs 8.7 for vegetable fat. For all-cause mortality, the rates were 28.4 vs 21.4 for saturated, 20.0 vs 23.7 for monounsaturated, 17.1 vs 29.4 for polyunsaturated, 32.4 vs 17.1 for trans, 32.0 vs 17.2 for animal, and 15.4 vs 32.7 for vegetable fat. Replacing 10% of energy intake from carbohydrate with vegetable fat was associated with a lower risk of lethal prostate cancer (hazard ratio [HR], 0.71; 95% CI, 0.51-0.98; P = .04) and all-cause mortality (HR, 0.74; 95% CI, 0.61-0.88; P = .001). No other fats were associated with lethal prostate cancer. Saturated and trans fats after diagnosis (replacing 5% and 1% of energy from carbohydrate, respectively) were associated with higher all-cause mortality (HR, 1.30 [95% CI, 1.05-1.60; P = .02] and 1.25 [95% CI, 1.05-1.49; P = .01], respectively). CONCLUSIONS AND RELEVANCE: Among men with nonmetastatic prostate cancer, replacing carbohydrates and animal fat with vegetable fat may reduce the risk of all-cause mortality. The potential benefit of vegetable fat for prostate cancer specific outcomes merits further research. PMID- 23752665 TI - Raise the bar even higher for primary prevention interventions-reply. PMID- 23752663 TI - Brand-name prescription drug use among Veterans Affairs and Medicare Part D patients with diabetes: a national cohort comparison. AB - BACKGROUND: Medicare Part D and the U.S. Department of Veterans Affairs (VA) use different approaches to manage prescription drug benefits, with implications for spending. Medicare relies on private plans with distinct formularies, whereas the VA administers its own benefit using a national formulary. OBJECTIVE: To compare overall and regional rates of brand-name drug use among older adults with diabetes in Medicare and the VA. DESIGN: Retrospective cohort. SETTING: Medicare and the VA, 2008. PATIENTS: 1,061,095 Medicare Part D beneficiaries and 510,485 veterans aged 65 years or older with diabetes. MEASUREMENTS: Percentage of patients taking oral hypoglycemics, statins, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) who filled brand-name drug prescriptions and percentage of patients taking long-acting insulins who filled analogue prescriptions. Sociodemographic- and health status-adjusted hospital referral region (HRR) brand-name drug use was compared, and changes in spending were calculated if use of brand-name drugs in 1 system mirrored the other. RESULTS: Brand-name drug use in Medicare was 2 to 3 times that in the VA: 35.3% versus 12.7% for oral hypoglycemics, 50.7% versus 18.2% for statins, 42.5% versus 20.8% for ACE inhibitors or ARBs, and 75.1% versus 27.0% for insulin analogues. Adjusted HRR-level brand-name statin use ranged (from the 5th to 95th percentiles) from 41.0% to 58.3% in Medicare and 6.2% to 38.2% in the VA. For each drug group, the 95th-percentile HRR in the VA had lower brand-name drug use than the 5th-percentile HRR in Medicare. Medicare spending in this population would have been $1.4 billion less if brand-name drug use matched that of the VA. LIMITATION: This analysis cannot fully describe the factors underlying differences in brand-name drug use. CONCLUSION: Medicare beneficiaries with diabetes use 2 to 3 times more brand-name drugs than a comparable group within the VA, at substantial excess cost. PMID- 23752666 TI - Plasmonic amplification with ultra-high optical gain at room temperature. AB - Nanoplasmonic devices are promising for next generation information and communication technologies because of their capability to confine light at subwavelength scale and transport signals with ultrahigh speeds. However, ohmic losses are inherent to all plasmonic devices so that further development of integrated plasmonics requires efficient in situ loss compensation of signals with a wavelength and polarization of choice. Here we show that CdSe nanobelt/Al2O3/Ag hybrid plasmonic waveguides allow for efficient broadband loss compensation of propagating hybrid plasmonic signals of different polarizations using an optical pump and probe technique. With an internal gain coefficient of 6755 cm(-1) at ambient condition, almost 100% of the propagation loss of TM dominant plasmonic signals is compensated. From comparison with a similar photonic structure we attribute the fast-increasing gain at low pump intensity in hybrid plasmonic waveguides to the transfer across the metal-oxide-semiconductor interface of 'hot' electrons photogenerated by the pump light. PMID- 23752667 TI - Primary sensory cortices contain distinguishable spatial patterns of activity for each sense. AB - Whether primary sensory cortices are essentially multisensory or whether they respond to only one sense is an emerging debate in neuroscience. Here we use a multivariate pattern analysis of functional magnetic resonance imaging data in humans to demonstrate that simple and isolated stimuli of one sense elicit distinguishable spatial patterns of neuronal responses, not only in their corresponding primary sensory cortex, but in other primary sensory cortices. These results indicate that primary sensory cortices, traditionally regarded as unisensory, contain unique signatures of other senses and, thereby, prompt a reconsideration of how sensory information is coded in the human brain. PMID- 23752668 TI - Terms for syphilis between the 16th and the 20th centuries. PMID- 23752669 TI - Effect of weight loss on the severity of psoriasis: a randomized clinical study. AB - IMPORTANCE: Psoriasis is associated with adiposity and weight gain increases the severity of psoriasis and the risk of incident psoriasis. Therefore, we aimed to measure the effect of weight reduction on the severity of psoriasis in obese patients with psoriasis. OBJECTIVE: To assess the effect of weight reduction on the severity of psoriasis in overweight patients. DESIGN: Sixty obese patients with psoriasis from our dermatology outpatient clinic were enrolled in a prospective randomized clinical trial in which they were allocated to a control group or an intervention group. SETTING: University hospital outpatient dermatology clinic. PARTICIPANTS: We included 60 of 69 eligible overweight patients with psoriasis (body mass index [calculated as weight in kilograms divided by height in meters squared], 27-40; aged 25-71 years). INTERVENTIONS: The intervention group received a low-energy diet (LED) (800-1000 kcal/d) for 8 weeks to induce weight loss, followed by 8 weeks of reintroduction of normal food intake, reaching 1200 kcal/d. The control group was instructed to continue eating ordinary healthy foods. MAIN OUTCOMES AND MEASURES: Psoriasis Area and Severity Index (PASI) after 16 weeks, with Dermatology Life Quality Index (DLQI) as a secondary end point. RESULTS: The median PASI for all patients was 5.4 (interquartile range, 3.8-7.6) at baseline. At week 16, the mean body weight loss was 15.4 kg (95% CI, 12.3-18.5 kg; P < .001) greater in the intervention group than in the control group. The corresponding mean differences in PASI and DLQI, also in favor of the LED group, were -2.0 (95% CI, 4.1 to -0.1; P = .06) and -2.0 (95% CI, -3.6 to -0.3; P = .02), respectively. CONCLUSIONS AND RELEVANCE: Treatment with an LED showed a trend in favor of clinically important PASI improvement and a significant reduction in DLQI in overweight patients with psoriasis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01137188. PMID- 23752670 TI - Treatment of significant carotid artery stenosis in 1824 patients. AB - AIM: We report our experience of thirteen years of treatment of significant carotid artery stenosis. METHODS: Data of all consecutive patients who came to our Division for a significant carotid artery stenosis from January 1999 to January 2012 were collected about patients' demographic, cardiovascular risk factors, neurological symptoms and treatment (carotid endarterectomy, carotid artery stenting or best medical therapy). Retrospective review was performed and the occurrence of death, major cerebrovascular events (major stroke, minor stroke) and myocardial infarction (MI) were recorded both at 30-day and at long term. Analysis was performed among groups by means of JMP 5.1((r)). RESULTS: Of 1824 patients who were admitted to our Department for a significant carotid stenosis, 582 were unsuitable for surgery and underwent carotid artery stenting (CAS, Group A). Three hundred and seventy-three of them were symptomatic (64.1%). Carotid endarterectomy (CEA) was performed in 1030 patients (Group B), 741 (71.9%) of them were symptomatic. The remaining patients (Group C) were treated using best medical therapy (BMT). At 30-day CEA compared to CAS and BMT was associated with higher risk of MI (2.1% vs. 0.2%, and 0.4% respectively, P<0.05), most of all in asymptomatic patients. CEA had a higher risk of cranial nerve injuries than CAS (3.3% vs. 0%, P<0.001). Both risk of death and major neurological complications were similar among the three groups in both symptomatic and asymptomatic patients. At long-term, risk of stroke after CEA was similar to that after CAS, both for symptomatic and asymptomatic patients, while risk of 1-year stroke in Group C was higher than in Group A (P<0.001) and in Group B (P<0.001), for both symptomatic and asymptomatic patients. Risk of long term MI was similar among the three groups. Mortality at long term in symptomatic patients was higher after CAS than after CEA (P=0.001). Also long-term mortality in Group C was higher than in Group A and B (both P<0.001) but only for asymptomatic patients. A procedure that lasted for more than 60 minutes, patients who had no prior Magnetic Resonance Angiography (MRA) or Computed Tomographic Angiography (CTA) study of the aortic arch were independent risk factors for major neurological complications after CAS. Symptomatic patients were likely to have more major neurological complications in the long term if they were treated with BMT only. CONCLUSION: In our experience, CAS offered a valid alternative for both symptomatic and asymptomatic patients who were poor candidates for CEA, with results that compared favourably to those of CEA both at 30-day and at long-term. Patients who couldn't be operated on neither with CAS nor with CEA had a lower risk of MI at 30-day but a higher risk of stroke during the first year, especially if they had previously experienced neurological symptoms. PMID- 23752671 TI - Modified total arch replacement using a four-branched arch graft for acute type A aortic dissection with minimal brain and spinal cord ischemic time. AB - AIM: This study aimed to evaluate the results of modified surgical strategies of total arch replacement using a four-branched arch graft, stented elephant trunk, and innovative organ protection method for acute type A aortic dissection. METHODS: Between August 2011 and December 2011, 21 patients with acute type A aortic dissection underwent modified total arch replacement using the four branched arch graft technique. All 21 patients had emergency surgery. Five patients had undergone previous aortic or cardiac surgery. The operations were stented elephant trunk implantation in 17 patients, ascending aorta replacement in 21 patients, coronary artery bypass grafting in four patients, Bentall operation in two patients, and aortic valve replacement in one patient. Twenty one operations were performed under deep hypothermic extracorporeal circulation, modified selective cerebral perfusion, and end-organ and spinal cord protection for arch reconstruction. RESULTS: There was two in-hospital deaths (9.5%). No persisting neurologic deficits or paraplegia occurred in 21 patients. Cardiopulmonary bypass time was 177.9+/-37.8 minutes. Myocardial ischemic time was 110.3+/-29.3 minutes. ICU time was 8.8+/-6.9 days and in-hospital duration was 28.7+/-13.7 days. Ventilation time varied from 9 hours to 21 days. A tracheotomy was necessary in four patients. Mean follow-up was 7.3+/-1.7 months and all patients are still alive. CONCLUSION: Modified total arch replacement using a four-branched arch graft with stented elephant trunk and innovative organ protection is a useful and safe alternative technique for the treatment of acute type A aortic dissection and the results are encouraging. PMID- 23752673 TI - Black tea and blood pressure: did the blood pressure fall or rise?-Reply. PMID- 23752675 TI - Image processing for phase imperfections in electron holography. AB - In electron holography, an abrupt reversal of contrast from white to black may occur in a digitally reconstructed phase image, potentially resulting in inaccurate phase information. There are two types of such abrupt reversals. One is a phase jump of 2 pi during the digital reconstruction process; in this case, the phase can be unwrapped and smoothly connected for such a jump. The other is caused by the disconnection of interference fringes due to weak electron-wave amplitude in some areas of the specimen. We propose a searching technique for finding the disconnection points based on mathematical morphology and then correcting the interference fringes. Finally, a comparatively accurate phase information image is reconstructed from the corrected interference fringes. PMID- 23752676 TI - Prediction of the concentration dependence of the surface tension and density of salt solutions: atomistic simulations using Drude oscillator polarizable and nonpolarizable models. AB - Molecular simulations using Drude oscillator polarizable and nonpolarizable models for water and ions are carried out to predict the dependence of the surface tension on salt concentration. The polarizable water and ion models are based only on the classical Drude oscillators. The temperature dependence of the surface tension of water is examined for different water models. The dependence of salt densities on salt concentration is investigated through the nonpolarizable and Drude oscillator polarizable models. Finally, the reproduction of the surface tension of salt solution over a large range of concentrations is analyzed through a number of combinations between ions and water force fields. The structure of the interface is then discussed as a function of polarization effects. We establish here the inability of the Drude oscillator polarizable force fields to reproduce the salt concentration dependence of surface tension of NaCl aqueous solutions. PMID- 23752677 TI - Similar verbal fluency patterns in amnestic mild cognitive impairment and Alzheimer's disease. AB - Disproportionately greater deficits in semantic relative to phonemic verbal fluency are seen in Alzheimer's disease (AD) and have been attributed to neurodegenerative changes in the temporal lobe. Amnestic (AMN) mild cognitive impairment (MCI), which often represents incipient AD, is also characterized by early temporal lobe neuropathology, but previous comparisons of verbal fluency between AD and AMN MCI have yielded mixed results. We examined semantic and phonemic verbal fluency performance in 399 individuals (78 AD, 138 AMN MCI, 72 non-amnestic MCI, and 111 cognitively normal controls). Similar verbal fluency patterns were seen in AMN MCI and AD; both groups exhibited disproportionately poorer performance on semantic verbal fluency relative to normal controls. However, relative verbal fluency indices performed more poorly than individual semantic or phonemic verbal fluency indices for discriminating AMN MCI or AD participants from normal controls, suggesting that they are unlikely to provide additional utility for predicting progression from MCI to AD. PMID- 23752678 TI - Evidence for covalence in a N-donor complex of americium(III). AB - The molecular origin of the selectivity of N-donor ligands, such as alkylated bis triazinyl pyridines (BTPs), for actinide complexation in the presence of lanthanides is still largely unclear. NMR investigations of an Am(nPrBTP)3(3+) complex with a (15)N labelled ligand showed that it exhibits large differences in (15)N chemical shift for coordinating N-atoms in comparison to both lanthanide(III) complexes and the free ligand. The temperature dependence of NMR chemical shifts observed for this complex indicates a weak paramagnetism. This fact and the observed large chemical shift for bound nitrogen atoms allow us to conclude that metal-ligand bonding in the reported Am(III) N-donor complex has a larger share of covalence than in lanthanide complexes. This may account for the observed selectivity. PMID- 23752679 TI - How much metagenomic sequencing is enough to achieve a given goal? AB - Metagenomic studies have dramatically expanded our knowledge of the microbial world. Furthermore, the amount of sample for sequencing has significantly increased with the development of high-throughput sequencing technologies. However, fully capturing all DNA sequences carried by every microorganism in the environment is still impossible. Therefore, estimating a reasonable and practical amount for sequencing to achieve the objectives is particularly necessary. In the present study, we introduce a novel method for estimating the required minimum amount for metagenomic sequencing for a given goal. We also calculated the genomic proportion of each operational taxonomic unit and the detection efficiency of a specific gene (we have used SSU rRNA gene as an example) based on a given amount for random metagenomic sequencing. The reasonable and practical estimated amount for sequencing in metagenomic studies will provide good reference information when applying high-throughput sequencing for a given goal. PMID- 23752680 TI - Bilirubin, gallstones, and mendelian randomization. PMID- 23752682 TI - Acupuncture for dyspnea on exertion in chronic obstructive pulmonary disease: no blindness-reply. PMID- 23752681 TI - Primary care interventions to prevent child maltreatment: U.S. Preventive Services Task Force recommendation statement. AB - Chinese translation DESCRIPTION: Update of the child abuse and neglect portion of the 2004 U.S. Preventive Services Task Force (USPSTF) recommendation statement on screening for family and intimate partner violence. METHODS: The USPSTF commissioned a systematic review on interventions to prevent child maltreatment for children at risk, focusing on new studies and evidence gaps that were unresolved at the time of the 2004 recommendation. Beneficial outcomes considered include reduced exposure to maltreatment and reduced harms to physical or mental health or mortality. POPULATION: This recommendation applies to children in the general U.S. population from newborn to age 18 years who do not have signs or symptoms of maltreatment. RECOMMENDATION: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of primary care interventions to prevent child maltreatment. (I statement). PMID- 23752684 TI - Clinician Identification of Appropriate Long-term Opioid Therapy Candidacy-Reply. PMID- 23752683 TI - A tetrastable naphthalenediimide: anion induced charge transfer, single and double electron transfer for combinational logic gates. AB - Herein we demonstrate the formation of the first tetrastable naphthalenediimide (NDI, 1a) molecule having multiple distinctly readable outputs. Differential response of 1a to fluoride anions induces intramolecular charge transfer (ICT), single/double electron transfer (SET/DET) leading to a set of combinational logic gates for the first time with a NDI moiety. PMID- 23752685 TI - Strange but true moments in dermatology. PMID- 23752686 TI - A Comparison of Pemphigus Foliaceus and Dermatitis Exfoliativa Neonatorum (RITTER), With Remarks on the AETIOLOGY. PMID- 23752687 TI - Designing polyethylenes of complex chain architectures via Pd-diimine-catalyzed "living" ethylene polymerization. AB - Polymer chain architecture is a critically important chain parameter governing intrinsically the properties and applications of polymers. The rapid developments in "living"/controlled polymerization techniques, particularly the controlled radical polymerization techniques, in the past two decades have enabled the precision synthesis of novel polymers having a great variety of complex yet well defined chain architectures from various monomer stocks. For polyolefins synthesized via catalytic coordination polymerization, the design of complex chain architectures, however, has only started recently because of the relatively limited advancements in the catalytic "living" olefin polymerization technique. In this regard, the versatile Pd-diimine catalysts have provided some unprecedented opportunities, due to their outstanding features, in rendering successfully a novel class of polyethylenes of various new complex chain architectures through the "living" ethylene polymerization protocol. The complex chain architectures designed to date have included hyperbranched, hybrid hyperbranched-linear, block, gradient and block-gradient, star, telechelic, graft and comb, and surface-tethered polymer brushes. This Feature Article attempts to summarize the recent developments achieved in the area, with an emphasis on the synthetic strategies for the architectural design. These developments demonstrate the great potential for further advancements of this new exciting research area. PMID- 23752688 TI - Can upright myocardial perfusion imaging be used alone with a solid-state dedicated cardiac camera? AB - AIM: The novel solid state dedicated cardiac cameras provide fast high resolution cardiac imaging. The D-SPECT camera enables semi-reclining (upright) positioning, increasing comfort and potentially reducing movement during myocardial perfusion imaging. Physicians are generally familiar with supine imaging and the different positioning in upright imaging could potentially cause diagnostic challenges. The aim of this study was to compare the upright and supine imaging for diagnostic ability to assess Physician confidence and determine any artefacts in upright imaging. METHODS: Fifty-five patients underwent myocardial perfusion imaging on the D-SPECT camera in both upright and supine positions. Where both images showed the same defects the 2 techniques were regarded as equally diagnostic. Where only one set showed a defect this was regarded as artefact and was defined as non diagnostic. The location and cause of the artefact was recorded. RESULTS: In 13 /55 patients either form of imaging was regarded as equally diagnostic. In 24/55 the supine images revealed artefact affecting interpretation. The reasons for this were most frequently large BMI, motion and gut uptake. In 18/55 upright images were considered non-diagnostic. In 16/18 this was due to an infero-apical defect seen in female patients (14/16) with raised BMI and/or large breasts. CONCLUSION: Upright myocardial perfusion imaging on D-SPECT shows a common artefact (in up to 1/3 of cases) in the infero-apical region mainly in overweight female patients. Getting acquainted with this artefact this may increase Physician confidence in reporting, similarly as to conventional supine imaging. Indeed, some of the artefacts seen on supine imaging appear less commonly with upright imaging. Thus, upright imaging can potentially be used alone for diagnosis with D-SPECT. Performance of both supine and upright imaging can be reserved for overweight patients thereby minimizing impact on scanning time and clinical throughput in busy departments. PMID- 23752689 TI - Use of the BasGan algorithm for [123I]FP-CIT SPECT quantification: a phantom study. AB - AIM: The BasGan algorithm has been specifically developed for semi-automatic quantification of [123I]FP-CIT SPECT studies. The aim of this work was to evaluate the software linearity and its dependence on the main acquisition parameters of the SPECT study. METHODS: The anthropomorphic Striatal Phantom filled with different striatal to background activity concentration ratios was used to verify software linearity. The software response was studied with different acquisition parameters and system configurations. For this purpose, phantom studies were performed with varying radius of rotation, pixel size, number of projections and with different collimator types. For each configuration the tomographic spatial resolution was also determined using the Triple Line Source Phantom. The reconstructed SPECT images were corrected for attenuation and scatter. RESULTS: The BasGan outcome highly correlates with the real Specific Binding Ratio when fixed gamma camera configuration and reconstruction method are used. However, the software quantification depends on system configuration and decreases with increasing partial volume effect. A comparison of the BasGan output with tomographic spatial resolution data for each configuration shows that the software response highly correlates with this quantity. CONCLUSION: The BasGan algorithm is a free, easy-to-use and solid tool for quantification of [123I]FP-CIT images. The software outcome depends on system configuration, but highly correlates with tomographic spatial resolution. Then, the measurement of this quantity turns out to be a simple method to normalize the BasGan quantification for different imaging devices, making it possible the use of available reference values for normal subjects and multicentre studies. PMID- 23752692 TI - Quantitative in vivo characterization of intracellular and extracellular pH profiles in heterogeneous tumors: a novel method enabling multiparametric pH analysis. AB - Acid production and transport are currently being studied to identify new targets for efficient cancer treatment, as subpopulations of tumor cells frequently escape conventional therapy owing to their particularly acidic tumor microenvironment. Heterogeneity in intracellular and extracellular tumor pH (pHi, pHe) has been reported, but none of the methods currently available for measuring tissue pH provides quantitative parameters characterizing pH distribution profiles in tissues. To this intent, we present here a multiparametric, noninvasive approach based on in vivo (31)P nuclear magnetic resonance (NMR) spectroscopy and its application to mouse tumor xenografts. First, localized (31)P NMR spectrum signals of pHi and pHe reporter molecules [inorganic phosphate (Pi) and 3-aminopropylphosphonate (3-APP), respectively] were transformed into pH curves using established algorithms. Although Pi is an endogenous compound, 3-APP had to be injected intraperitoneally. Then, we developed algorithms for the calculation of six to eight quantitative pH parameters from the digital points of each pH curve obtained. For this purpose, each pH distribution profile was approximated as a histogram, and intensities were corrected for the nonlinearity between chemical-shift and pH. PMID- 23752694 TI - Long-standing filiform, blaschkoid papules. Porokeratotic eccrine and ostial dermal duct nevus (PEODDN). PMID- 23752695 TI - About this journal. PMID- 23752693 TI - Posttranscriptional regulation of PER1 underlies the oncogenic function of IREalpha. AB - Growing evidence supports a role for the unfolded protein response (UPR) in carcinogenesis; however, the precise molecular mechanisms underlying this phenomenon remain elusive. Herein, we identified the circadian clock PER1 mRNA as a novel substrate of the endoribonuclease activity of the UPR sensor IRE1alpha. Analysis of the mechanism shows that IRE1alpha endoribonuclease activity decreased PER1 mRNA in tumor cells without affecting PER1 gene transcription. Inhibition of IRE1alpha signaling using either siRNA-mediated silencing or a dominant-negative strategy prevented PER1 mRNA decay, reduced tumorigenesis, and increased survival, features that were reversed upon PER1 silencing. Clinically, patients showing reduced survival have lower levels of PER1 mRNA expression and increased splicing of XBP1, a known IRE-alpha substrate, thereby pointing toward an increased IRE1alpha activity in these patients. Hence, we describe a novel mechanism connecting the UPR and circadian clock components in tumor cells, thereby highlighting the importance of this interplay in tumor development. PMID- 23752696 TI - Statin use and risk of diabetes-reply. PMID- 23752697 TI - Arrhythmias: Changing indications for biventricular pacing in bradycardia. AB - The BLOCK HF trial demonstrated that, during continual cardiac pacing, adverse left ventricular remodelling and deterioration of systolic function occurred more frequently with right ventricular than with biventricular pacing. These findings will increase the role of biventricular pacing for the preservation of left ventricular function in patients with atrioventricular block. PMID- 23752698 TI - Coronary artery disease: Antidepressant treatment for mental stress-induced myocardial ischaemia. PMID- 23752701 TI - About this journal. PMID- 23752702 TI - About this journal. PMID- 23752704 TI - Intramolecular halogen-halogen bonds? AB - By analysing the properties of the electron density in the structurally simple perhalogenated ethanes, X3C-CY3 (X, Y = F, Cl), a previously overlooked non covalent attraction between halogens attached to opposite carbon atoms is found. Quantum chemical calculations extrapolated towards the full solution of the Schrodinger equation reveal the complex nature of the interaction. When at least one of the halogens is a chlorine, the strength of the interaction is comparable to that of hydrogen bonds. Further analysis shows that the bond character is quite different from standard non-covalent halogen bonds and hydrogen bonds; no bond critical points are found between the halogens, and the sigma-holes of the halogens are not utilised for bonding. Thus, the nature of the intramolecular halogen...halogen bonding studied here appears to be of an unusually strong van der Waals type. PMID- 23752699 TI - Fractional flow reserve as a surrogate for inducible myocardial ischaemia. AB - Documentation of inducible myocardial ischaemia, related to the coronary stenosis of interest, is of increasing importance in lesion selection for percutaneous coronary intervention (PCI). Fractional flow reserve (FFR) is an easily understood, routine diagnostic modality that has become part of daily clinical practice, and is used as a surrogate technique for noninvasive assessment of myocardial ischaemia. However, the application of a single, discrete, cut-off value for FFR-guided lesion selection for PCI, and its adoption in contemporary revascularization guidelines, has limited the requirement for a thorough understanding of the physiological basis of FFR. This limitation constitutes an obstacle for the adequate use and interpretation of this technique, and also for the understanding of new and future modalities of physiological functional intracoronary testing. In this Review, we revisit the fundamental elements of coronary physiology in the absence or presence of coronary artery disease. We provide insight into three essential characteristics of FFR as a diagnostic tool in contemporary clinical practice--the theoretical framework of FFR and its associated limitations; the characteristics and role of FFR as a surrogate for noninvasively assessed myocardial ischaemia; and the requirement and associated caveats of potent vasodilatory drugs to induce maximal vasodilatation of the coronary vascular bed. PMID- 23752705 TI - Towards designing robust coupled networks. AB - Natural and technological interdependent systems have been shown to be highly vulnerable due to cascading failures and an abrupt collapse of global connectivity under initial failure. Mitigating the risk by partial disconnection endangers their functionality. Here we propose a systematic strategy of selecting a minimum number of autonomous nodes that guarantee a smooth transition in robustness. Our method which is based on betweenness is tested on various examples including the famous 2003 electrical blackout of Italy. We show that, with this strategy, the necessary number of autonomous nodes can be reduced by a factor of five compared to a random choice. We also find that the transition to abrupt collapse follows tricritical scaling characterized by a set of exponents which is independent on the protection strategy. PMID- 23752706 TI - A new anti-cancer strategy of damaging mitochondria by pro-apoptotic peptide functionalized gold nanoparticles. AB - Gold nanoparticles functionalized with pro-apoptotic peptide (PAP-AuNPs) were fabricated, which were able to lead to programmed cell-death by damaging mitochondria. PMID- 23752707 TI - Effects of boron doping on the structural and optoelectronic properties of 9,10 diarylanthracenes. AB - Key structural and optoelectronic properties of 9,10-dihydro-9,10 diboraanthracene (DBA) derivatives carrying mesityl (2a), 2-methylnaphthyl- (2b) and 9-phenyl-2,7-di-tert-butylanthryl (2c) substituents at the boron atoms have systematically been compared with the properties of their all-carbon congeners 4a c. The experimental investigations have been augmented by quantum-chemical calculations. Steric repulsion leads to large dihedral angles between the aryl substituents and the DBA (2a-c) or anthrylene (4a-c) cores; as a result, the B-C bonds of 2a-c are kinetically shielded from hydrolysis and oxidative degradation. Lithium metal reduces the mesityl derivative 2a to the inverse sandwich complexes [Li(OR2)n]2[2a] (X-ray crystallography; OR2 = THF, n = 2; Et2O, n = 1). In line with the nodal structures of the LUMO of 2a/HOMO of [Li(THF)2]2[2a], the C-C bond lengths of the anionic fragment [2a](2-) show characteristic differences to those of 2a and come close to the C-C bond lengths of the isoelectronic species 4a. X ray crystallography on anti-2b * 2 C6H6 and anti-4b * 2 C6H6 reveals an essentially identical packing of the main molecules. The benzene solvate molecules, however, interact in a very different manner with anti-2b or anti-4b, which can be traced down to subtle disparities between the electron density distributions of the two compounds. 2a-c undergo a photoinduced aryl-to-DBA charge transfer; the back electron transfer results in blue (2a), green (2b) and red (2c) emission, albeit with low quantum yields. 4a-c are characterised by a local pi-pi* photoexcitation of the central 9,10-anthrylene fragments and corresponding blue emission. Each of the compounds 2a-c gives rise to two reversible DBA-centred one-electron transitions in the cyclic voltammogram. PMID- 23752708 TI - Use of acute care services among older homeless adults. PMID- 23752709 TI - Are human genes patentable? PMID- 23752710 TI - Antihypertensive drug class interactions and risk for incident diabetes: a nested case-control study. AB - BACKGROUND: We aimed to determine how single and combination antihypertensive therapy alters risk for diabetes mellitus (DM).Thiazide diuretics (TD), beta blockers (BB), and renin-angiotensin system blockers (RASB) impact DM risk while calcium channel blockers (CCB) are neutral. DM risk associated with combinations is unclear. METHODS AND RESULTS: We enrolled nondiabetic patients from Kaiser Permanente Northwest with a fasting plasma glucose (FPG) <126 mg/dL between 1997 and 2010. DM cases were defined by a FPG >= 126 mg/dL, random plasma glucose >= 200 mg/dL, HbA1c >= 7.0%, or new DM prescription (index date). We used incidence density sampling to match 10 controls per case on the date of follow-up glucose test (to reduce detection bias), in addition to age and date of cohort entry. Exposure to antihypertensive class was assessed during the 30 days prior to index date. Our cohort contained 134 967 patients and had 412 604 glucose tests eligible for matching. A total of 9097 DM cases were matched to 90 495 controls (median age 51 years). Exposure to TD (OR 1.54, 95% CI 1.41 to 1.68) or BB (OR 1.19, 95% CI 1.11 to 1.28) was associated with an increased DM risk, while CCB and RASB exposure was not. TD+BB combination resulted in the fully combined diabetogenic risk of both agents (OR 1.99, 95% CI 1.80 to 2.20; interaction OR 1.09, 95% CI 0.97 to 1.22). In contrast, combination of RASB with either TD or BB showed significant negative interactions, resulting in a smaller DM risk than TD or BB monotherapy. CONCLUSIONS: Diabetogenic potential of combination therapy should be considered when prescribing antihypertensive therapy. PMID- 23752711 TI - About this journal. PMID- 23752714 TI - Chronic hyperpigmented scaly plaques-diagnosis. PMID- 23752713 TI - Introduction to special issue: Sugars, bugs and us. PMID- 23752712 TI - Mucin-type O-glycans and their roles in intestinal homeostasis. AB - Mucin-type O-glycans are the primary constituents of mucins that are expressed on various mucosal sites of the body, especially the bacteria-laden intestinal tract. Mucins are the main components of mucus, which is secreted by goblet cells and forms a protective homeostatic barrier between the resident microbiota and the underlying immune cells in the colon. However, the specific role of mucin type O-glycans in mucus barrier function has been uncertain. Recent studies utilizing mice deficient in key glycosyltransferases involved in O-glycan biosynthesis on intestinal mucins have underscored the importance of mucin-type O glycosylation in mucus barrier function. This review will highlight recent advances in our understanding of mucin-type O-glycan function in the mucus barrier and how they promote mutualism with our resident microbiota. PMID- 23752715 TI - Comparison of three methods of diagnosis of plasma unmeasured anions in critically ill patients. AB - BACKGROUND: The measurement of plasma unmeasured anions (PUA) is paramount in assessing metabolic acid base disorders. The aim of this study was to compare the accuracy of three methods in diagnosing abnormal PUA values: standard base excess (SBE), the albumin corrected anion gap (AGc), and the Stewart-Figge approach, based on unidentified anions (XAc-). METHODS: Acid-base variables were prospectively collected in ICU patients admitted January-September 2008. Whatever the method, PUA values measured two standard deviations above or below the mean of those in control subjects were considered as abnormal. RESULTS: Of the 205 consecutives patients included, 179 had an abnormal PUA value. The accuracy of AGc and XAc- in diagnosing abnormal PUA values was comparable (AUC: 0.89+/-0.03 and 0.89+/-0.03, P=0.82) but greater than that of SBE (0.67+/-0.06, P<0.001 and P<0.001, respectively). Of the high PUA values (n=161), 96% were diagnosed by XAc , 88% by AGc (P<0.01) and 48% by SBE (P<0.001). Hyperlactatemia (n=111) was diagnosed equally by AGc and XAc-, (81% and 86%, P=0.37) but less by SBE (50%, P<0.001 and P<0.001, respectively). High PUA not associated with hyperlactatemia (N.=61) was more frequently diagnosed by XAc- (97%) than by AGc (84%, P=0.03). CONCLUSION: In ICU patients, AGc and the Stewart-Figge approach should be preferred over SBE for diagnosing abnormal PUA values and predicting hyperlactatemia. The Stewart-Figge approach based on unidentified anions, is the most efficient in diagnosing high PUA values not associated with hyperlactatemia. PMID- 23752716 TI - Comparison of acquisition of resistant microorganisms and infections in critically-ill patients with and without malignancies. AB - BACKGROUND: Patients with malignancies are often considered at risk of acquiring infections by resistant or potentially resistant microorganisms (RPRMs). However, data supporting this contention is scarce. We have compared critically ill patients with haematological malignancies (HM), solid tumours (ST) and without cancer (NC) in terms of acquisition of RPRMs, infections and mortality. METHODS: Observational, prospective cohort study of patients admitted to a medical intensive care unit (ICU). Swabbing of nares, pharynx and rectum, and culture of respiratory secretions were obtained within 48 h of admission and thrice weekly thereafter. Clinical samples were obtained as deemed necessary by the attending physician. Clinical variables, severity scores on admission and exposures during ICU stay were also collected. Multivariable logistic regression analysis was used to evaluate ICU mortality. RESULTS: Out of 969 included patients 127 (13.1%) had HM and 93 (9.6%) had ST. Patients with malignancies were more frequently exposed to central venous catheterization, methylprednisolone, and any antipseudomonal antibiotic whereas they were less commonly exposed to invasive mechanical ventilation. Patients with HM were more often admitted with an infection. There were no differences among groups in terms of RPRMs acquisition during ICU stay or prevalence of ICU-acquired infections due to any microorganism, including RPRMs. Having a HM was an independent predictor of mortality regardless of APACHE II score. CONCLUSION: Critically ill cancer patients did not show a higher rate of RPRMs acquisition nor ICU-acquired infections. Mortality was higher in the HM group and it was not accurately predicted on admission by APACHE II score. PMID- 23752717 TI - Effect of feedback content on novices' learning ultrasound guided interventional procedures. AB - BACKGROUND: Feedback, of various forms, is effective at improving performance of medical procedures in simulated and clinical settings. Our objectives were to compare the effects of two forms of feedback on i) novice learning of in-plane technique for ultrasound-guided interventional procedures and ii) to evaluate novice retention of skill 24 hours after a standard learning session. METHODS: Performance data were collected from 30 novices. All participants received training in the form of a standard training video. Participants were randomly allocated to one of three groups: Group C (Control) received no feedback; Group KR (Knowledge of Result) received feedback at the end of each series of tasks in the form of predefined performance intervals; and Group KP (Knowledge of Procedure) received feedback in the form of augmented error feedback. Each participant completed the series of tasks five times, using a standardized phantom model. Participants attempted to perform the same tasks 24 hours later using the same phantom. This performance was videotaped and assessed by two blinded assessors for predefined time and errors. RESULTS: All groups demonstrated significant learning effect in terms of imaging, needling and performance time. Error reduction was significant over time intervals measured and also in-between groups with significant difference between Control : KP (P<0.001) and KR: KP (P=0.001) but not between Control and KR groups. Marked and similar levels of skill attrition were identified in all three groups 24 hours after the learning phase CONCLUSION: When feedback was based on KP, novices acquired pre-defined skills more quickly and made fewer errors during the learning phase (compared with controls). When feedback content was based on KR novices acquired pre-defined skills more quickly but made similar numbers of errors during the learning phase (compared with controls). In conclusion, these findings should inform development of training and assessment programs for peripheral nerve blockade. PMID- 23752718 TI - Regional anesthesia in patients with significant comorbid disease. AB - An increasing body of evidence suggests that regional anesthesia does not only provide better pain control compared to systemic analgesic and anesthetic techniques but that it is associated with improved perioperative outcomes. As these benefits may be especially prominent in the patient population suffering from high comorbidity burden, anesthesiologists have to be familiar with associated factors that may complicate the decision to use regional anesthetics. This manuscript is intended to provide a brief overview of the recent literature regarding beneficial outcomes associated with the use of regional versus general anesthesia, before focusing on the discussion of the implications of specific comorbid states on the performance of regional anesthetic techniques. PMID- 23752719 TI - Is two (antibiotics) better than one? AB - The use of antibiotic therapy combining at least two drugs remains controversial in patients with severe sepsis and septic shock. Some studies have suggested an improvement in patients' outcome with combination therapy over monotherapy, especially in those patients with expected mortality exceeding 25%. Nevertheless, a recent large randomized multicentric clinical trial, comparing the effects of meropenem and moxifloxacin to meropenem alone on the occurrence of sepsis-related organ dysfunction, found no significant advantage for combination therapy. Also, mortality rates were similar at 28 days and at 90 days in both groups. Considering some opposite observations coming from other recent non-randomized studies, we aimed to discuss the raisons of these conflicting findings on antimicrobials combination in patients with severe sepsis and septic shock. PMID- 23752720 TI - ECMO in acute and chronic adult respiratory failure: recent trends and future directions. AB - Extracorporeal membrane oxygenation (ECMO) can be used to preserve or enhance systemic oxygen delivery in patients with refractory cardiac or respiratory failure. Although widely accepted as a standard of care for many indications in children and for adult cardiogenic shock, ECMO for adult respiratory failure is more controversial. This controversy arose over thirty years ago after the disappointing results of the first flawed, randomized study and is fueled by a group of non-ECMO clinicians who repeatedly criticize the methodology of more recent studies which show probable benefit. In spite of this, there is probably now more evidence to support the use of ECMO in refractory acute respiratory distress syndrome than for any other form of rescue therapy. The purpose of this review is to update clinicians regarding trends in ECMO research over the last 12 months and speculate on how the clinical use of ECMO and associated technology will evolve. PMID- 23752722 TI - Opioids use has to be considered a right for chronic pain patients. PMID- 23752721 TI - Donation after cardiocirculatory death in Italy? It is within our range. PMID- 23752726 TI - This month in archives of dermatology. PMID- 23752727 TI - Screening: CT screening for lung cancer: winner confirmed. PMID- 23752730 TI - Targeted therapies: Any surprises from selective oestrogen-receptor modulators? PMID- 23752731 TI - Biological markers: Tailoring treatment and trials to prognosis. PMID- 23752732 TI - From ASCO-targeted therapies: Anti-PD-1 approaches--important steps forward in metastatic melanoma. PMID- 23752735 TI - Errors in Byline and Text in: Primary Cutaneous Follicular Helper T-cell Lymphoma: A New Subtype of Cutaneous T-cell Lymphoma Reported in a Series of 5 Cases. PMID- 23752736 TI - About this journal. PMID- 23752738 TI - Functional characterization of 32 CYP2C9 allelic variants. AB - Genetic variations in cytochrome P450 2C9 (CYP2C9) contribute to interindividual variability in the metabolism of clinically used drugs such as warfarin and tolbutamide. We functionally characterized 32 types of allelic variant CYP2C9 proteins. Recombinant CYP2C9 proteins generated using a heterologous expression system are useful for comparing functional changes in CYP2C9 variant proteins expressed from low-frequency alleles. Wild-type CYP2C9 and its 31 variants were found to be transiently expressed in COS-7 cells, and the enzymatic activity of the CYP2C9 variants was characterized using S-warfarin as a representative substrate. Among the 32 types of CYP2C9 allelic variants tested, CYP2C9.18, CYP2C9.21, CYP2C9.24, CYP2C9.26, CYP2C9.33 and CYP2C9.35 exhibited no enzyme activity, and 12 types showed significantly decreased enzyme activity. In vitro analysis of CYP2C9 variant proteins should be useful for predicting CYP2C9 phenotypes and for application to personalized drug therapy. PMID- 23752739 TI - Gender-specific profiling in SCN1A polymorphisms and time-to-recurrence in patients with stage II/III colorectal cancer treated with adjuvant 5-fluoruracil chemotherapy. AB - This study was designed to analyze the gender-related association between SCN1A polymorphisms (voltage-gated sodium channels; alpha-subunit) and time-to recurrence (TTR) in patients with colorectal cancer (CRC) treated with 5 fluoruracil (5-FU)-based adjuvant chemotherapy. We enrolled from a prospective database patients with stage II and III CRC treated with adjuvant 5-FU-based chemotherapy. Genotypes for SCN1A rs3812718 and rs229877 were determined by direct DNA sequencing. One hundred twenty-seven males and 107 females were included in the study. In the univariate and multivariate analysis, the shortest TTR was associated with female patients carrying the rs3812718-TT genotype (hazard ratio (HR): 2.26 (95% confidence interval (CI): 0.89, 5.70), P=0.039) but with male patients carrying the rs3812718-CC genotype (HR: 0.49 (95% CI: 0.18, 1.38), P=0.048). For rs229877 the CT genotype was associated with a trend for shorter TTR in both gender populations. The study validated gender-dependent association between genomic SCN1A rs3812718 polymorphism and TTR in CRC patients treated with adjuvant 5-FU-based chemotherapy. This study confirms that voltage gated Na+ channels may be a potential therapeutic target and a useful predictive biomarker before 5-FU infusion. PMID- 23752740 TI - Cluster-derived Ir-Sn/SiO2 catalysts for the catalytic dehydrogenation of propane: a spectroscopic study. AB - Ir-Sn bimetallic silica-based materials have been prepared via deposition of the molecular organometallic clusters (NEt4)2[Ir4(CO)10(SnCl3)2] and NEt4[Ir6(CO)15(SnCl3)] or via deposition of Sn organometallic precursor Sn(n C4H9)4 onto pre-formed Ir metal particles. These solids possess promising properties, in terms of selectivity, as catalysts for propane dehydrogenation to propene. Detailed CO-adsorption DRIFTS, XANES and EXAFS characterization studies have been performed on these systems in order to compare the structural and electronic evolution of systems in relation to the nature of the Ir-Sn bonds present in the precursor compounds and to propose a structural model of the Ir-Sn species present at the silica surface of the final catalyst. PMID- 23752741 TI - Highly stable and degradable multifunctional microgel for self-regulated insulin delivery under physiological conditions. AB - The response to glucose, pH and temperature, high drug loading capacity, self regulated drug delivery and degradation in vivo are simultaneously probable by applying a multifunctional microgel under a rational design in a colloid chemistry method. Such multifunctional microgels are fabricated with N isopropylacrylamide (NIPAAm), (2-dimethylamino)ethyl methacrylate (DMAEMA) and 3 acrylamidephenylboronic acid (AAPBA) through a precipitation emulsion method and cross-linked by reductive degradable N,N'-bis(arcyloyl)cystamine (BAC). This novel kind of microgel with a narrow size distribution (~250 nm) is suitable for diabetes because it can adapt to the surrounding medium of different glucose concentrations over a clinically relevant range (0-20 mM), control the release of preloaded insulin and is highly stable under physiological conditions (pH 7.4, 0.15 M NaCl, 37 degrees C). When synthesized multifunctional microgels regulate drug delivery, they gradually degrade as time passes and, as a result, show enhanced biocompatibility. This exhibits a new proof-of-concept for diabetes treatment that takes advantage of the properties of each building block from a multifunctional micro-object. These highly stable and versatile multifunctional microgels have the potential to be used for self-regulated therapy and monitoring of the response to treatment, or even simultaneous diagnosis as nanobiosensors. PMID- 23752742 TI - Activatable fluorescent cys-diabody conjugated with indocyanine green derivative: consideration of fluorescent catabolite kinetics on molecular imaging. AB - Antibody fragments including diabodies have more desirable pharmacokinetic characteristics than whole antibodies. An activatable optical imaging probe based on a cys-diabody targeting prostate-specific membrane antigen conjugated with the near-infrared fluorophore, indocyanine green (ICG), was designed such that it can only be activated when bound to the tumor, leading to high signal-to-background ratios. We employed short polyethylene glycol (PEG) linkers between the ICG and the reactive functional group (Sulfo-OSu group), resulting in covalent conjugation of ICG to the cys-diabody, which led to lower dissociation of ICG from cys-diabody early after injection, reducing hepatic uptake. However, unexpectedly, high and long-term fluorescence was observed in the kidneys, liver, and blood pool more than 1 h after injection of the cys-diabody PEG-ICG conjugate. A biodistribution study using I125-labeled cys-diabody-ICG showed immediate uptake in the kidneys followed by a rapid decrease, while gastric activity increased due to released radioiodine during rapid cys-diabody-ICG catabolism in the kidneys. To avoid this catabolic pathway, it would be preferable to use antibody fragments large enough not to be filtered through glomerulus or to conjugate the fragments with fluorescent dyes that are readily excreted into urine when cleaved from the cys-diabody to achieve high tumor specific detection. PMID- 23752744 TI - Application of heterogeneous catalysts prepared by mechanochemical synthesis. AB - Mechanochemical synthesis has the potential to provide more sustainable preparative routes to catalysts than the current multistep solvent-based routes. In this review, the mechanochemical synthesis of catalysts is discussed, with emphasis placed on catalysts for environmental, energy and chemical synthesis applications. This includes the formation of mixed-metal oxides as well as the process of dispersing metals onto solid supports. In most cases the process involves no solvent. Encouragingly, there are several examples where the process is advantageous compared with the more normal solvent-based methods. This can be because of process cost or simplicity, or, notably, where it provides more active/selective catalysts than those made by conventional wet chemical methods. The need for greater, and more systematic, exploration of this currently unconventional approach to catalyst synthesis is highlighted. PMID- 23752745 TI - Easy activation of the aryl-sulfur bond by platinum(II). AB - The reagents 1,2-C6H4(CH=NR)(SMe), R = CH2CH2NMe2 or Ph, react with [Pt2Me4(MU SMe2)2] by oxidative addition of the aryl-sulfur bond to give the corresponding crystalline binuclear platinum(IV) compounds [Pt2Me4(MU-SMe)2(kappa(2)-C,N-C6H4-2 CH=NR)2], as the isomers with Ci (R = CH2CH2NMe2 or Ph) or C1 (R = Ph) symmetry. These first examples of C-S bond activation at platinum(II) occur easily at room temperature, and the reactions give complex equilibria of isomeric products, from which the isolated compounds crystallise. PMID- 23752746 TI - Threat or opportunity? PMID- 23752747 TI - Particulate matter in injectable drug products. AB - Clinicians have had concerns about particulate matter contamination of injectable drug products since the development of the earliest intravenous therapeutics. All parenteral products contain particulate matter, and particulate matter contamination still has the potential to cause harm to patients. With tens of millions of doses of injectable drug products administered in the United States each year, it is critical to understand the types and sources of particulate matter that contaminate injectable drug products, the possible effects of injected particulate matter on patients, and the current state of regulations and standards related to particulate matter in injectable drug products. Today, the goal of manufacturers, regulators, and standards-setting organizations should be to continue to minimize the risk of particle-induced sequelae, especially in high risk patients, without trading unnecessary manufacturing burden for minimal safety gains. LAY ABSTRACT: All injectable drug products are contaminated with some level of solid particulate matter, including, for example, fibers, dust, rubber, and silicone. These materials enter drug products primarily during the manufacturing process. The possible effects on patients of injectable drug products containing particulate matter depend on a number of factors. However, given the large number of patients receiving injectable drug products each year in the United States and the potential for particulate matter to cause harm to patients, it is critical to continue to minimize particulate matter contamination in injectable drug products. Manufacturing standards and regulations have helped improve manufacturing quality. Nevertheless, manufacturers, regulators, and standards-setting organizations must continue to work toward improving manufacturing quality and minimizing the risk of harm from particle contamination, especially in high-risk patients. PMID- 23752748 TI - Self-nanoemulsifying drug delivery system of glimepiride: design, development, and optimization. AB - The objective of the present investigation was to develop and characterize the self-nanoemulsifying drug delivery system (SNEDDS) of glimepiride, a poorly soluble drug. Solubility of glimepiride in various vehicles was determined, and ternary phase diagrams were constructed using a suitable oil, surfactant, and cosurfactant system to find out the efficient self-emulsification system. A three factor, three level Box-Behnken statistical design was employed to explore the main and interaction effect of independent variables, namely X1 (amount of Capmul MCM), X2 (amount of Acrysol K 140), and X3 (amount of Transcutol P). Percent transmittance value (Y1), droplet diameter (Y2), and percent drug released at 5 min (Y3) were the dependent variables. Formulation optimization was carried out to optimize the droplet diameter and percent drug dissolved at 5 min. The batch prepared according to the optimized formulation showed a close agreement between observed and predicted values. Box-Behnken statistical design allowed us to understand the effect of formulation variables on the rapid dissolution of drug from SNEDDS and to optimize the formulation to obtain a rapid drug dissolution at 5 min. LAY ABSTRACT: A self-nanoemulsifying drug delivery system of glimepiride has been design, developed, and optimized. A three factor, three level Box Behnken statistical design was employed to explore the main and interaction effect of independent variables, namely X1 (amount of Capmul MCM), X2 (amount of Acrysol K 140), and X3 (amount of Transcutol P). Percent transmittance value (Y1), droplet diameter (Y2), and percent drug released at 5 min (Y3) were the dependent variables. The Capmul MCM-Akcrysol K 140-Transcutol system was found to be the suitable ternary system that was able to release almost 80% of drug within the first 5 min. The improved dissolution of glimepiride might improve patient compliance. PMID- 23752749 TI - Formulation, development, and evaluation of floating pulsatile drug delivery system of atenolol. AB - The objective of this work was to develop and evaluate a floating-pulsatile drug delivery of atenolol. The floating-pulsatile concept was applied to increase the gastric residence of the dosage form by having lag phase followed by a burst release. The system was generated which consisted of three different parts: a core tablet, containing the active ingredient; an erodible outer shell; and a top cover buoyant layer. The dry, coated tablet consists in a drug-containing core, coated by a hydrophilic erodible polymer responsible for a lag phase in the onset of pulsatile release. The buoyant layer, prepared with hydroxypropyl methylcellulose (HPMC) K100 M, citric acid, and sodium bicarbonate, provides buoyancy to increase the retention of the oral dosage form in the stomach. The effect of the hydrophilic erodible polymer characteristics on the lag time and drug release was investigated. Developed formulations were evaluated for their physical properties in vitro release as well as in vivo behavior. The results showed that K3 (180 mg of HPMC K4 M) and K6 (290 mg of HPMC E15 LV) with a buoyant layer were the best formulation, with lag times of 5.2 +/- 0.1 h and 4.1 +/- 0.2 h, respectively. Floating time was controlled by the quantity and composition of the buoyant layer. In-vitro results point out the capability of the system with its prolonged residence of the tablets in the stomach and release of drug after a programmed lag time. This was confirmed by in vivo x-ray technique. LAY ABSTRACT: The objective of the present work was to develop a floating-pulsatile oral drug delivery system of atenolol with addition of hydroxylpropyl methylcellulose (HPMC) K100 M, HPMC K4 M, and HPMC E15 LV in different ratios with citric acid and sodium bicarbonate as gas-forming agents. The system consist of three different parts: a core tablet, containing the active ingredient; a bottom layer that erodes; and a top cover floating layer. Atenolol, a beta-blocker, is prescribed widely in diverse cardiovascular diseases, for example, hypertension, angina pectoris, arrhythmias, and myocardial infarction. Developed formulations were evaluated for their physical properties and vitro release as well as in vivo behavior. The results showed that K3 (180 mg HPMC K4 M) and K6 (290 mg of HPMC E15 LV) with a buoyant layer were the best formulations with the lag times of 5.2 +/- 0.1 h and 4.1 +/- 0.2 h, respectively, and were found to be the best choice for manufacturing tablets. PMID- 23752750 TI - Transformation in the pharmaceutical industry: transformation-induced quality risks--a survey. AB - This paper is the fourth in a series that explores ongoing transformation in the pharmaceutical industry and its impact on pharmaceutical quality from the perspective of risk identification. The aim of this paper is to validate proposed quality risks through elicitation of expert opinion and define the resultant quality risk model. Expert opinion was obtained using a questionnaire-based survey with participants with recognized expertise in pharmaceutical regulation, product lifecycle, or technology. The results of the survey validate the theoretical and operational evidence in support of the four main pharmaceutical transformation triggers previously identified. The quality risk model resulting from the survey indicated a firm relationship between the pharmaceutical quality risks and regulatory compliance outcomes during the marketing approval and post marketing phases of the product lifecycle and a weaker relationship during the pre-market evaluation phase. LAY ABSTRACT: In this paper through conduct of an expert opinion survey the proposed quality risks carried forward from an earlier part of the research are validated and resultant quality risk model is defined. The survey results validate the theoretical and operational evidence previously identified. The quality risk model indicates that transformation-related risks have a larger regulatory compliance impact during product approval, manufacturing, distribution, and commercial use than during the development phase. PMID- 23752751 TI - Interactions between Parenteral Lipid Emulsions and Container Surfaces. AB - OBJECTIVE: To evaluate the relationship between changes in emulsion globule size distributions and container uptake of lipid emulsions in total nutrient admixtures. METHODS: A total nutrient admixture was prepared from a commercial lipid emulsion, 20% ClinOleic(r), separated into glass (borosilicate) and ethylene vinyl acetate (EVA) plastic containers, and then stored at ambient conditions for approximately 24 h. The large globule size distribution was monitored continuously for both containers, and the quantity of triglycerides associated with both containers was measured by liquid chromatography. The changes in mass of the EVA containers were also measured gravimetrically. RESULTS: The volume percent of globules greater than 5 microns in diameter (PFAT5) levels for an emulsion admixture in EVA containers showed a 75% reduction compared to a marginal decrease of PFAT5 when in the glass container. Extraction of the containers showed that the quantity of triglycerides associated with the EVA surfaces steadily increased with emulsion exposure time, while the glass showed a significantly lower triglyceride content compared to the EVA. Gravimetric measurements confirmed that the EVA containers gained significant mass during exposure to the emulsion admixture. CONCLUSION: A time-dependent decrease in PFAT5 values for an emulsion admixture was associated with container triglyceride absorption where EVA containers had a greater uptake than glass containers. The larger globules appear to absorb preferentially, and the admixture globule size distribution fraction represented by PFAT5 accounts for 15 20% of the total triglyceride adsorption to the container. LAY ABSTRACT: The goal of this work is to evaluate how emulsions in total nutrition admixtures are affected by the containers within which they are stored. Specifically, the study examines how the emulsion globule size distribution in different containers is related to adsorption or absorption of the lipids onto or into the container. The admixtures were prepared from a commercial lipid emulsion, 20% ClinOleic(r), and the containers were either glass (borosilicate) or plastic (ethylene vinyl acetate, EVA). The large globule size distribution was monitored continuously for both containers over the course of 24 h, and the quantity of triglycerides taken up by both containers was measured by liquid chromatography. The lipid uptake by the EVA containers was also monitored by gravimetric methods. Briefly, the percent of fat globules greater than 5 micrometers (PFAT5) in EVA containers showed a 75% reduction compared to a marginal decrease of PFAT5 when in the glass container. Extraction of the lipids from the containers showed that the quantity of triglycerides associated with the EVA surfaces steadily increased with admixture exposure time, while the glass showed a significantly lower triglyceride content. Gravimetric measurements confirmed that the EVA containers gained measurable mass during exposure to the emulsion admixture. PMID- 23752752 TI - Preparation and evaluation of sustained release infliximab microspheres. AB - A sustained release microsphere system for an antibody (infliximab, molecular weight: 140 Kd) was formulated with PLGA 50:50 co-polymer using two methods of preparation: phase separation technique and double emulsion technique. Microspheres were made in triplicate using each technique and varying drug-to polymer ratios. Drug-to-polymer ratio was maintained at 1:5, 1:10, or 1:20. In vitro release profile of infliximab was studied in phosphate-buffered saline solution at 37 degrees C. The release profile and encapsulation efficiency was compared between the two methods of preparation. The releases data was modeled by the sum of squares method to isolate the dominant release mechanism. The physical attributes of the microspheres prepared were characterized. The biochemical characteristics of infliximab before and after encapsulation were also evaluated by several analytical techniques such as size exclusion chromatography, isoelectric focusing, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Biological activity of infliximab was also evaluated before and after encapsulation. The phase separation technique showed much higher entrapment efficiency than the double emulsion technique. Microspheres prepared using the double emulsion technique showed a longer release profile (~5 days) compared to microspheres prepared using the phase separation technique (~72 h). Physical and biochemical properties of infliximab did not change significantly after encapsulation into microspheres with either methods of preparation. Microspheres prepared using phase separation showed some loss in bioactivity. Based on this research it can be concluded that the microspheres can present an alternative delivery method for infliximab. LAY ABSTRACT: A sustained release microsphere system for an antibody (infliximab, molecular weight: 140 Kd) was formulated using polymers. This antibody is currently in the market for rheumatoid arthritis among various indications. Microspheres were made in triplicate using two techniques and varying drug-to-polymer ratios. Drug-to-polymer ratio was maintained at 1:5, 1:10, or 1:20. The release of drug from microsphere was studied. Biochemical properties of microspheres were also studied before and after encapsulation in microspheres. Various analytical techniques were used to study the biochemical properties of infliximab to ensure that it would be efficacious and safe after encapsulation. Sustained release of drug was observed from the microspheres. Infliximab showed no change in biochemical properties and also showed bioactivity. Based on this research it can be concluded that the microspheres can present an alternative delivery method for infliximab that is safe and efficacious and my result in cost savings for patients. PMID- 23752753 TI - Automated Solid Phase Extraction (SPE) LC/NMR Applied to the Structural Analysis of Extractable Compounds from a Pharmaceutical Packaging Material of Construction. AB - The structural analysis (i.e., identification) of organic chemical entities leached into drug product formulations has traditionally been accomplished with techniques involving the combination of chromatography with mass spectrometry. These include gas chromatography/mass spectrometry (GC/MS) for volatile and semi volatile compounds, and various forms of liquid chromatography/mass spectrometry (LC/MS or HPLC/MS) for semi-volatile and relatively non-volatile compounds. GC/MS and LC/MS techniques are complementary for structural analysis of leachables and potentially leachable organic compounds produced via laboratory extraction of pharmaceutical container closure/delivery system components and corresponding materials of construction. Both hyphenated analytical techniques possess the separating capability, compound specific detection attributes, and sensitivity required to effectively analyze complex mixtures of trace level organic compounds. However, hyphenated techniques based on mass spectrometry are limited by the inability to determine complete bond connectivity, the inability to distinguish between many types of structural isomers, and the inability to unambiguously determine aromatic substitution patterns. Nuclear magnetic resonance spectroscopy (NMR) does not have these limitations; hence it can serve as a complement to mass spectrometry. However, NMR technology is inherently insensitive and its ability to interface with chromatography has been historically challenging. This article describes the application of NMR coupled with liquid chromatography and automated solid phase extraction (SPE-LC/NMR) to the structural analysis of extractable organic compounds from a pharmaceutical packaging material of construction. The SPE-LC/NMR technology combined with micro cryoprobe technology afforded the sensitivity and sample mass required for full structure elucidation. Optimization of the SPE-LC/NMR analytical method was achieved using a series of model compounds representing the chemical diversity of extractables. This study demonstrates the complementary nature of SPE-LC/NMR with LC/MS for this particular pharmaceutical application. LAY ABSTRACT: The identification of impurities leached into drugs from the components and materials associated with pharmaceutical containers, packaging components, and materials has historically been done using laboratory techniques based on the combination of chromatography with mass spectrometry. Such analytical techniques are widely recognized as having the selectivity and sensitivity required to separate the complex mixtures of impurities often encountered in such identification studies, including both the identification of leachable impurities as well as potential leachable impurities produced by laboratory extraction of packaging components and materials. However, while mass spectrometry-based analytical techniques have limitations for this application, newer analytical techniques based on the combination of chromatography with nuclear magnetic resonance spectroscopy provide an added dimension of structural definition. This article describes the development, optimization, and application of an analytical technique based on the combination of chromatography and nuclear magnetic resonance spectroscopy to the identification of potential leachable impurities from a pharmaceutical packaging material. The complementary nature of the analytical techniques for this particular pharmaceutical application is demonstrated. PMID- 23752754 TI - Effect of resolution of measurements in the behavior of exponentially weighted moving average control charts. AB - Process behavior is known through measurement. All measurements are discrete and transform a continuous process distribution into a discrete (multinomial) measurement distribution. In this article, properties of exponentially weighted moving average control charts (EWMA charts) of measurements are studied through Monte Carlo simulations. Detection capabilities (average run length curves) are presented as a function of measurement resolution and recommendations for proper design of a measuring system are given. EWMA charts measurement resolution requirements are compared to Shewhart charts, and two examples are presented to illustrate behavior differences. LAY ABSTRACT: Industry performs quality control activities in order to control raw materials, processes, and finished products with the purpose of delivering products to market complying with quality requirements. Different statistical methods are used in chemical, physical, and biological analysis and nearly all control methods will use measurement devices. Quality control is mandatory for many industries, for example, the pharmaceutical industry, and it is a very costly activity. The selection of suitable methods of control and appropriate measurement devices acquire special relevance for obtaining efficient results. Measurement devices require a certain measurement capability and must be fit for the purpose of controlling the quality of processes and products. The equipment capability includes, among other elements, the resolution, which means the "smallest change in a quantity being measured that causes a perceptible change in the corresponding indication". Different control charts have been extensively used for statistical process control. Based on cases from the pharmaceutical industry and simulation tools, this paper studies the influence of resolution of measurement devices in exponentially weighted moving average control charts (EWMA charts). In addition, a comparison of EWMA charts and traditional Shewhart charts is presented in order to offer support to the practitioners. PMID- 23752755 TI - "Less is more" in critically ill patients: not too intensive. AB - The current view in intensive care medicine is that very sick patients need very intensive treatment. However, in this group of highly vulnerable patients, more intensive treatment may promote the chances of unwanted adverse effects and hence, iatrogenic damage. Therefore, we state that critically ill patients probably benefit from a more cautious approach. Using data from large clinical trials of previous years, we exemplify that less intensive treatment is associated with a better outcome in intensive care patients and suggest that we reappraise patient management as well as trial design in intensive care medicine while bearing in mind the "less is more" paradigm. We illustrate our case by describing the intensity of the most relevant treatment options for patients with septic shock, including mechanical ventilation, fluid management, blood pressure targeted therapy, corticosteroids, patient monitoring, sedation, and nutrition. We conclude that treatment of critically ill patients while keeping in mind the "less is more" paradigm might not only benefit the patient but could also have a notable impact on the ever-increasing intensive care-related health care costs. PMID- 23752756 TI - Flowering date of taxonomic families predicts phenological sensitivity to temperature: Implications for forecasting the effects of climate change on unstudied taxa. AB - PREMISE OF THE STUDY: Numerous long-term studies in seasonal habitats have tracked interannual variation in first flowering date (FFD) in relation to climate, documenting the effect of warming on the FFD of many species. Despite these efforts, long-term phenological observations are still lacking for many species. If we could forecast responses based on taxonomic affinity, however, then we could leverage existing data to predict the climate-related phenological shifts of many taxa not yet studied. METHODS: We examined phenological time series of 1226 species occurrences (1031 unique species in 119 families) across seven sites in North America and England to determine whether family membership (or family mean FFD) predicts the sensitivity of FFD to standardized interannual changes in temperature and precipitation during seasonal periods before flowering and whether families differ significantly in the direction of their phenological shifts. KEY RESULTS: Patterns observed among species within and across sites are mirrored among family means across sites; early-flowering families advance their FFD in response to warming more than late-flowering families. By contrast, we found no consistent relationships among taxa between mean FFD and sensitivity to precipitation as measured here. CONCLUSIONS: Family membership can be used to identify taxa of high and low sensitivity to temperature within the seasonal, temperate zone plant communities analyzed here. The high sensitivity of early flowering families (and the absence of early-flowering families not sensitive to temperature) may reflect plasticity in flowering time, which may be adaptive in environments where early-season conditions are highly variable among years. PMID- 23752757 TI - Structural and electrochemical characterization of carbon supported Pt-Pr catalysts for direct ethanol fuel cells prepared using a modified formic acid method in a CO atmosphere. AB - Pt-Pr/C electrocatalysts were prepared using a modified formic acid method, and their activity for carbon monoxide and ethanol oxidation was compared to Pt/C. No appreciable alloy formation was detected by XRD analysis. By TEM measurements it was found that Pt particle size increases with an increasing Pr content in the catalysts and with decreasing metal precursor addition time. XPS measurements indicated Pt segregation on the catalyst surface and the presence of Pr2O3 and PrO2 oxides. The addition of Pr increased the electro-catalytic activity of Pt for both CO and CH3CH2OH oxidation. The enhanced activity of Pt-Pr/C catalysts was ascribed to both an electronic effect, caused by the presence of Pr2O3, and the bi-functional mechanism, caused by the presence of PrO2. PMID- 23752758 TI - Soft subcutaneous plantar masses-diagnosis. PMID- 23752759 TI - The origin of leprosy. PMID- 23752761 TI - Error in Author Contributions Paragraph in: Patient Preference in the Decision to Place Implantable Cardioverter-Defibrillators. PMID- 23752762 TI - Electrocardiographic findings in a young man with tachycardia and hypotension discussion. PMID- 23752765 TI - Marilyn Monroe's "Lesson" on the Semantics of Dermatology. PMID- 23752766 TI - STAT6 - polymorphisms, haplotypes and epistasis in relation to atopy and asthma. AB - BACKGROUND: STAT6 has an important role in the IL-4 / IL-13 signalling pathway. Genome - wide association studies have shown that particular polymorphism (SNP) or haplotype variants of STAT6 as well as epigenetic gene modifications are associated with IgE level and asthma in childhood. METHODS: A review of the available literature was performed to map out the function and signalling pathway of STAT6, studies of STAT6 SNPs association with susceptibility to asthma and atopy, covering the years 1997 - 2012 were summarized, and the value of epigenetic and epistatic influences on STAT6 and their relevance to the development of the studied phenotype (atopy or asthma) were determined. RESULTS: There are 2 SNPs (rs71802646 and rs320411) with clinical association and proven functional effect on STAT6 expression. The effect of STAT6 SNPs cumulates in haplotypes and more potently during interaction with SNPs in the genes from the signalling pathway (IL4, IL4Ra, and IL13). Expression of STAT6 is also influenced by DNA methylation. Atopy is traditionally believed to be maternally inherited but there is one report about paternally overtransmitted STAT6 haplotype (TCA haplotype, built from rs324011, rs3024974 and rs4559 SNPs). CONCLUSIONS: STAT6 polymorphisms and their combinations have an important influence on IgE level and development of asthma. However, the interaction between SNPs in the IL-4 / IL-13 signalling pathway is of greater impact. Hypermethylation of the STAT6 promoter is also significant in the regulation of STAT6 expression and this fact opens possibilities for targeting therapy in asthma. PMID- 23752767 TI - Renal manifestations of rheumatic diseases. A review. AB - BACKGROUND: Renal manifestations of rheumatic diaseases are sometimes very discrete and mild. At others, they can present the leading symptomatology of a given disease. Systemic lupus erythematosus, systemic scleroderma, renal vasculitis, rheumatoid arthritis, mixed connective tissue disease, Sjogren's syndrome and gout can all manifest in or be accompanied by renal impairment. METHODS AND RESULTS: The authors reviewed the literature on renal manifestation of rheumatic diseases using the key words, lupus erythematosus, systemic autoimmune diseases, rheumatoid arthritis, vasculitis and gout. The review below is accompanied by their own histological findings. CONCLUSION: Diagnosis requires proper interpretation of the clinical situation, laboratory results and image analysis methods plus close interdisciplinary collaboration between nephrologist and clinical pathologist/nephropathologist. PMID- 23752768 TI - Uranyl ion coordination with rigid aromatic carboxylates and structural characterization of their complexes. AB - Uranyl complexes of rigid aromatic carboxylates were synthesized and their solid state structures characterized by X-ray crystallography. The new ligands create cavities lined with endohedral functions to encapsulate the uranyl ion. PMID- 23752769 TI - A model radiopharmaceutical agent targeted to translocator protein 18 kDa (TSPO). AB - A stable Re complex containing an imidazopyridine ligand with a high affinity for TSPO has been synthesized as a model for new (99m)Tc or (188/186)Re-based radiopharmaceuticals to be used in SPECT diagnosis or in therapy, respectively. The new complex fac-[ReBr(CO)3(TZ6)], structurally characterized, showed high affinity (nanomolar concentration) for the target protein. PMID- 23752771 TI - Testosterone therapy and cardiovascular events. PMID- 23752773 TI - Diabetes: individualized HbA(1c) targets in elderly patients with T2DM. PMID- 23752772 TI - New pharmacological approaches for obesity management. AB - Obesity, which results from an imbalance between calorie intake and expenditure, now affects over 500 million individuals worldwide. Lifestyle and behavioural interventions aimed at reducing calorie intake and/or increasing energy expenditure have limited long-term effectiveness due to complex and persistent hormonal, metabolic and neurochemical adaptations that defend against weight loss and promote weight regain. Surgical treatments for obesity, although highly effective, are unavailable or unsuitable for the majority of individuals with excess adiposity. Accordingly, few effective treatment options are available to most individuals with obesity. In the past, the use of antiobesity drugs, seemingly the logical choice to fill this therapeutic gap, has been limited because of a lack of efficacy, poor long-term adherence rates and serious adverse effects. In 2012, the FDA approved two new medications-lorcaserin and phentermine topiramate controlled release-and is currently reviewing the resubmission of naltrexone sustained release-bupropion sustained release. This Review presents the available data on the efficacy and safety of these three medications and discusses future perspectives and challenges related to pharmacological weight management. PMID- 23752777 TI - Reply. The importance of testosterone clinical trials. PMID- 23752778 TI - Diabetes: have the gut(s) to test the risk of developing type 2 diabetes mellitus. PMID- 23752779 TI - Carbon nanotube-gold nanohybrids for selective catalytic oxidation of alcohols. AB - Gold nanoparticles were deposited on carbon nanotubes to provide access to a nanohybrid structure which was involved in the aerobic oxidation of alcohols. The nanohybrid-catalyzed reaction was shown to be highly efficient under mild conditions (i.e. room temperature, air) and selective oxidation of alcohols to the corresponding acids or aldehydes could be achieved, depending on the reaction conditions. PMID- 23752780 TI - Device-guided breathing as treatment for hypertension in type 2 diabetes mellitus: a randomized, double-blind, sham-controlled trial. AB - IMPORTANCE: Biofeedback with device-guided lowering of breathing frequency could be an alternate nonpharmacologic treatment option for hypertension. Evidence from trials with high methodologic quality is lacking. OBJECTIVE: To evaluate the effects of device-guided lowering of breathing frequency on blood pressure in patients with type 2 diabetes mellitus and hypertension. DESIGN: Single-center, double-blind, sham-controlled trial. SETTING: A large nonacademic teaching hospital in the Netherlands. PARTICIPANTS: Patients with type 2 diabetes mellitus and hypertension. INTERVENTION: Fifteen-minute sessions with either the device that guides breathing through musical tones to a lower breathing frequency (aiming at <10 breaths/min) or a sham device (music without aiming at lowering of breathing frequency) for an 8-week study period. MAIN OUTCOMES AND MEASURES: Systolic and diastolic blood pressure measured in the physician's office. RESULTS: Forty-eight patients were randomized; 21 patients (88%) in the intervention group and 24 patients (100%) in the control group completed the study. There were no significant changes in systolic and diastolic blood pressure, with a difference in systolic blood pressure of 2.35 mm Hg (95% CI, 6.50 to 11.20) in favor of the control group and a difference in diastolic blood pressure of 2.25 mm Hg (95% CI, -2.16 to 6.67) in favor of the intervention group. Three patients in the intervention group experienced adverse events. CONCLUSIONS AND RELEVANCE: This high methodologic quality study shows no significant effect of device-guided lowering of breathing frequency on office measured blood pressure in patients with type 2 diabetes. On the basis of this study, together with results from all but one previous trial, device-guided lowering of breathing frequency does not appear to be a viable nonpharmacologic option for hypertension treatment. PMID- 23752781 TI - A DFT study of adsorption of perylene on clean and altered anatase (101) TiO2. AB - The adsorption of perylene equipped with a carboxylic acid anchor on a titanium dioxide anatase (101) surface was studied through density functional theory calculations. The binding of dye molecules, of which organic species are frequently modelled with perylene, is a crucial aspect in the development of efficient dye-sensitized solar cells. Two different monodentate binding modes and a bidentate mode are considered on a clean surface as well as on surfaces with a coadsorbed dissociated water molecule or an oxygen vacancy. It was concluded that monodentate adsorption is favored in all cases. Also, the modifications to the surface considered here have an additive effect on the adsorption energy. The effect of a water molecule is ~0.1 eV, while a surface oxygen vacancy increases adsorption energies by 0.6 eV-0.8 eV. Partial and complete deprotonation was discovered in some cases for non-dissociative adsorption geometries, indicating that the hydrogen atom travels between the molecule and the surface. PMID- 23752784 TI - Additional ways to diminish the deleterious effects of red meat-reply. PMID- 23752786 TI - Brook silenes: inspiration for a generation. AB - In 1981, Adrian G. Brook published his seminal work on the synthesis and characterization of the first solid, stable silene. This viewpoint summarizes the work leading up to the publication of the article and explores the significant impact it had on the field. PMID- 23752785 TI - Detection of melamine on fractals of unmodified gold nanoparticles by surface enhanced Raman scattering. AB - A simple way of detecting melamine in raw milk is demonstrated via surface enhanced Raman spectroscopy (SERS) using fractals of bare and nonfunctionalized ~30 nm gold nanoparticles (AuNP) distributed on a solid support. The technique demonstrates the formation of AuNP fractals, from a random distribution, upon exposure to melamine, that enhance the Raman scattering cross-section to enable detection by SERS. The agglomeration, which is pronounced at higher melamine concentrations, is demonstrated directly through imaging, and the red-shift of the plasmon absorption peak of the AuNP fractal away from 530 nm by finite difference time domain (FDTD) calculations. The agglomeration results in a strong plasmon field, shown by FDTD, over the interparticle sites that enhances the Raman scattering cross-section of melamine and ensures unambiguous detection. Limit of detection of 100 ppb could be achieved reproducibly. PMID- 23752787 TI - Long-term Analgesic Use: Sometimes Less Is Not More-Reply. PMID- 23752788 TI - Top-accessed article: skin markers of occult spinal dysraphism in children. PMID- 23752789 TI - Data Error in Table 2 and Typographic Errors in Text in: Use of Angiotensin Converting Enzyme Inhibitors or Angiotensin Receptor Blockers and Cardiovascular Outcomes in Chronic Dialysis Patients: A Population-Based Cohort Study. PMID- 23752792 TI - Master techniques in blepharoplasty and periorbital rejuvenation. PMID- 23752793 TI - Cumulative changes in the use of long-term medications: a measure of prescribing complexity. PMID- 23752795 TI - Sequencing studies in human genetics: design and interpretation. AB - Next-generation sequencing is becoming the primary discovery tool in human genetics. There have been many clear successes in identifying genes that are responsible for Mendelian diseases, and sequencing approaches are now poised to identify the mutations that cause undiagnosed childhood genetic diseases and those that predispose individuals to more common complex diseases. There are, however, growing concerns that the complexity and magnitude of complete sequence data could lead to an explosion of weakly justified claims of association between genetic variants and disease. Here, we provide an overview of the basic workflow in next-generation sequencing studies and emphasize, where possible, measures and considerations that facilitate accurate inferences from human sequencing studies. PMID- 23752794 TI - Genomic and epigenetic insights into the molecular bases of heterosis. AB - Heterosis, also known as hybrid vigour, is widespread in plants and animals, but the molecular bases for this phenomenon remain elusive. Recent studies in hybrids and allopolyploids using transcriptomic, proteomic, metabolomic, epigenomic and systems biology approaches have provided new insights. Emerging genomic and epigenetic perspectives suggest that heterosis arises from allelic interactions between parental genomes, leading to altered programming of genes that promote the growth, stress tolerance and fitness of hybrids. For example, epigenetic modifications of key regulatory genes in hybrids and allopolyploids can alter complex regulatory networks of physiology and metabolism, thus modulating biomass and leading to heterosis. The conceptual advances could help to improve plant and animal productivity through the manipulation of heterosis. PMID- 23752796 TI - Gene expression: Time flies thanks to Pol II pausing. PMID- 23752798 TI - Real-time optical diagnostics of graphene growth induced by pulsed chemical vapor deposition. AB - The kinetics and mechanisms of graphene growth on Ni films at 720-880 degrees C have been measured using fast pulses of acetylene and real-time optical diagnostics. In situ UV-Raman spectroscopy was used to unambiguously detect isothermal graphene growth at high temperatures, measure the growth kinetics with ~1 s temporal resolution, and estimate the fractional precipitation upon cooldown. Optical reflectivity and videography provided much faster temporal resolution. Both the growth kinetics and the fractional isothermal precipitation were found to be governed by the C2H2 partial pressure in the CVD pulse for a given film thickness and temperature, with up to ~94% of graphene growth occurring isothermally within 1 second at 800 degrees C at high partial pressures. At lower partial pressures, isothermal graphene growth is shown to continue 10 seconds after the gas pulse. These flux-dependent growth kinetics are described in the context of a dissolution/precipitation model, where carbon rapidly dissolves into the Ni film and later precipitates driven by gradients in the chemical potential. The combination of pulsed-CVD and real-time optical diagnostics opens new opportunities to understand and control the fast, sub second growth of graphene on various substrates at high temperatures. PMID- 23752800 TI - [Brain stimulation therapies for treatment-resistant depression]. AB - Treatment-resistant depression (TRD) is a major public health problem, affecting patients, their close relatives, and the society as a whole. Despite recent developments in psychopharmacotherapy, more than 50% of depressed patients fail to reach complete remission even when adequately treated. Neurostimulation therapies are an open field in research for the treatment of TRD, involving the delivery of physical interventions either through electric current or a magnetic field to target selective or generalized brain regions. In this paper we review evidences for four brain-stimulation therapies, i.e. electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), vagus nerve stimulation (VNS) and deep brain stimulation (DBS), and we enlighten several new approaches regarding ECT, rTMS and epidural cortical stimulation (EpCS). ECT is the form of neurostimulation with the most extensive evidence, rTMS and VNS have a much smaller evidence base. There is emerging evidence that DBS is effective for otherwise TRD, but this is still an investigational approach. Other approaches are anecdotal reports. ECT and rTMS can be considered as a first-line treatment under specific circumstances. Evidence supporting VNS is less consistent and DBS remains an investigational treatment. Other techniques are promising, but double-blind studies are warranted to evaluate these new approaches to TRD. PMID- 23752797 TI - Pleiotropy in complex traits: challenges and strategies. AB - Genome-wide association studies have identified many variants that each affects multiple traits, particularly across autoimmune diseases, cancers and neuropsychiatric disorders, suggesting that pleiotropic effects on human complex traits may be widespread. However, systematic detection of such effects is challenging and requires new methodologies and frameworks for interpreting cross phenotype results. In this Review, we discuss the evidence for pleiotropy in contemporary genetic mapping studies, new and established analytical approaches to identifying pleiotropic effects, sources of spurious cross-phenotype effects and study design considerations. We also outline the molecular and clinical implications of such findings and discuss future directions of research. PMID- 23752802 TI - [Tardive dyskinesia: diagnosis, assessment and treatment]. AB - Tardive dyskinesia is a potentially fatal side effect of antipsychotics. In the classic form is characterized by involuntary hyperkinetic movements, especially those affecting the mimic and mastication muscles. The main hypothesis considers that the pathophysiological basis of the disorder is an overexpression of D2 receptors in the striatum, in response to dopamine block neuroleptics-mediated, especially the older ones. Because fortunately not all patients undergo this severe adverse effects, many efforts have been conducted in trying to delineate the risk factors so as to try to prevent tardive dyskinesia by administering lower doses of neuroleptics in vulnerable groups. Advanced age, female sex, smoking habits, diabetes mellitus, alcohol abuse are known as risk factors. The instead the role of the type of psychiatric disorder, instead, is still debated. Since there was a direct relationship between cumulative dose of antipsychotic and treatment duration, recent studies are aimed at identifying factors that contribute to increased plasma concentrations of the drug, such as genetic polymorphisms of metabolizer enzymes that encode for enzymatic variants with decreased activity. PMID- 23752801 TI - [Analysis of online reports on the potential misuse of benzidamine]. AB - Benzydamine/Tantum Rosa is a drug for external use. It is typically available in Europe, without the need of a medical prescription, for the treatment of vaginal inflammatory processes. Between December 2009 and January 2010, the Milan and Pavia (I) Poison Centres have identified some 50 cases of inappropriate benzydamine ingestion. Reasons for this misuse have been attributed to an allegedly misleading television advert. However, the recreational misuse of benzydamine is a well-known phenomenon in Brazil and in some EU countries as well, notably in Poland and Romania. It is here suggested that the recent increase in benzydamine misuse reports in Italy may well be associated with a parallel increase in level of online information regarding the molecule potential for misuse. According to the online reports, benzydamine is typically taken at a dosage of 1-4 sachets, dissolved in water and ingested orally. Its intake may be associated with hallucinations (mostly visual), sleeping disorders and euphoria. Only future, prospective, studies will confirm and better describe the benzydamine misuse potential. PMID- 23752803 TI - [Risk factors associated with metabolic abnormalities in first-episode psychotic patients. A systematic review]. AB - BACKGROUND: Weight gain and metabolic abnormalities are frequent complications in first-episode psychosis (FEP) patients. Literature reviews on metabolic profile disturbances in FEP patients are however sparse and show several limitations. This review aims to fill this gap. METHODS: We identified all studies exploring risk factors for metabolic profile disturbances in FEP patients. Research focused on studies assessing the involvement of biologic, psychologic and environmental factors in the pathogenesis and maintenance of changes in glycolipid metabolism in FEP patients. Study selection was performed by searches on Medline, matching a set of key words and selecting all papers published up to October 2011. RESULTS: 37 studies were included. Literature analysis shows that FEP patients are particularly at risk for weight gain and changes in glycolipid metabolism. Major risk factors for metabolic disturbances include: increase in body weight and body mass index; abnormalities in laboratory findings; wrong lifestyle; use of antipsychotic drugs; genetic background. CONCLUSIONS: Clinical practice should be implemented with integrated care, in which psychiatric care should be strictly linked to medical care, and with early intervention programs on lifestyle habits for patients with FEP at the beginning of their psychopharmacological treatment. PMID- 23752804 TI - [Psychiatrist's professional liability for generic, brand, and off-label drug prescription]. AB - At present, drug prescription is a hot topic in terms of professional responsibility. Psychiatric-forensic criteria are provided for appropriate drug prescription, focusing on off-label and generic drug prescription. Off-label prescription should be made in accordance with current regulations, in particular with the regulatory requirements related to patient consent. Generic drug prescription is affected by several critical issues, such as drug excipients, equivalence to original drug, correspondence of therapeutic indications. The different spheres of responsibility of physicians and apothecaries in prescribing and distributing drugs, respectively, are discussed. The knowledge of these issues can be helpful for physicians in their clinical practice, allowing preservation of professional autonomy and compliance with current regulations. The explanation of the most common mistakes about drug prescription that are examined in law courts can be the starting point of an interdisciplinary debate involving all interested parties that are called upon to judge psychiatrist responsibility in drug prescription. PMID- 23752805 TI - [Obsessive-compulsive disorder with psychotic features: psychopathological and personological aspects]. AB - AIM: The aims of this study are to analyze psychopathological relations between obsessive-compulsive and psychotic symptoms in a group of patients with obsessive compulsive disorder (OCD), and to verify if the obsessive subgroup with psychotic features can be considered as a distinct OCD subtype. METHODS: The study sample included 68 patients with OCD who were divided into two different groups (OCD with and without psychotic features). All subjects completed the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Scale for the Assessment of Positive Symptoms (SAPS), the Hamilton Depression Rating Scale (HDRS), and the Structured Interview for DSM-IV Personality Disorders (SIDP-IV). RESULT: Twenty subjects (29.4%) were affected by OCD with psychotic features. They were characterized by an earlier onset of obsessive illness (p<0.05), a more frequently chronic course (p<0.01), an "atypical" obsessive-compulsive symptomatology (with poor insight and anxiety) (p<0.001), higher levels of depression (p<0.05), and a higher prevalence of schizotypal personality disorder (p<0.01). DISCUSSION: Patients affected by OCD with psychotic symptoms appear to be a distinct subtype of obsessive-compulsive disorder, characterized by a set of specific psychopathological and personological features. However, the finding that these subjects have a higher prevalence of schizotypal personality disorder seems to suggest that they can be considered as a peculiar clinical subset belonging to the schizophrenia-spectrum disorders rather than a group of obsessive individuals placed on the most serious clinical extreme of the OCD spectrum. PMID- 23752806 TI - [Italian version of Demoralization Scale: a validation study]. AB - OBJECTIVE: Demoralization and depressive symptoms are very common in chronic organic diseases. The aim of the present study is to evaluate reliability and psychometric properties of the Italian version of the Demoralization Scale (DS) in patients with advanced cancer. METHODS: The Italian version of DS was administered to a sample consisting of 100 patients affected by different forms of cancer. The following scales were also administered: Patient Health Questionnaire, Beck Depression Inventory (BDI), Mini-Mental Adjustment to Cancer (MAC) and Karnofsky Performance Status Scale. RESULTS: The total mean score of the DS was 23.9+/-14.5. The study showed a good degree of stability and internal consistency of DS total score (alpha=0.90) and the 5 factors represented by loss of meaning and purpose (alpha=0.69), dysphoria (alpha=0.72), disheartenment (alpha=0.84), helplessness (alpha=0.50) and sense of failure (alpha=0.74). Significant correlations were found between DS total score and BDI (r=0.74) and between DS factors and BDI (r=0.64 for loss of meaning and purpose; r=0.55 for dysphoria; r=0.71 for disheartenment; r=0.51 for helplessness; r=0.46 for sense of failure). Good correlations were also found between DS total score and Hopelessness scale of MAC (r=0,51). According to different cut-off values, between 28 and 32 patients were seriously demoralized and 40 had moderate levels of demoralization. Between 6 and 20 patients were seriously demoralized but not clinically depressed; between 16 and 31 patients with moderate levels of demoralization had no depression. CONCLUSION: Results provide further evidence that the DS is a valid and reliable instrument of high clinical relevance in patients with advanced cancer and confirm the hypothesis of the ontological difference between demoralization and depression. PMID- 23752807 TI - [Group cognitive-behavioral therapy for panic disorder with and without agoraphobia: an effectiveness study]. AB - OBJECTIVE: Although numerous studies have demonstrated the effectiveness of both individual and group cognitive-behavioral psychotherapy (CBT), many authors have questioned the translation of these interventions into routine clinical practice. The aim of this study was to assess the effectiveness of group CBT in patients diagnosed with panic disorder, with or without agoraphobia, in routine clinical practice. METHODS: The study involved 96 patients diagnosed according to the DSM IV criteria. Treatment consisted of 10 psychotherapy sessions of 2 hours each in a local health authority. A battery of psychometric instruments was used to assess variables including psychological symptoms, subjective well-being and psychosocial functioning before and after therapy. In addition to the evaluation of treatment outcome, final scores were compared to population norms and benchmarked against similar studies. RESULT: Almost all scores of the clinical scales used improved significantly. Only 42% of patients who were initially above the clinical cut-off on the CORE-OM showed clinically significant changes, and 20% of patients were below the clinical cut-off after treatment. Post-treatment CORE-OM scores were not significantly different from the values observed in the general population. These findings are consistent with those of comparable studies. DISCUSSION: Group CBT is effective in routine clinical practice. In addition to reducing anxiety symptoms, treatment also results in an improvement of other related variables such as subjective well-being. Owing to its better patient-therapist ratio, group CBT should be considered as an alternative to individual CBT in routine clinical care in public services. PMID- 23752808 TI - Assessment of attention network efficiency in schizophrenic patients with positive and negative symptoms. AB - AIM: The aim of the present study was to examine the anterior (Experiment 1) and posterior (Experiment 2) attention systems in schizophrenic patients with predominantly negative or positive symptoms, in order to evidence possible differences in symptomatology. MATERIALS AND METHODS: The schizophrenic sample was divided into two subgroups: negative(n=13) versus positive symptoms (n=10). The anterior and posterior attention systems in schizophrenic patients were assessed through two experiments: a dual-task paradigm evaluating executive functions, in particular planning and coordination,and a Simon task evaluating automatic shifting of visual attention. RESULTS: Our study showed specific attention deficits in the presence of negative symptoms. These findings suggest that negative schizophrenics have a deficit that affects functioning of both anterior and posterior attention systems, whereas positive schizophrenics showed a selective deficit only for the posterior attention system, with a pattern that is in the opposite direction compared to that of negative schizophrenics. DISCUSSION: Our results demonstrate that specific symptom dimensions or patterns are associated with specific cognitive impairments. Notably, negative schizophrenics exhibited clear abnormalities, whereas positive schizophrenics performed very similarly to healthy controls. PMID- 23752809 TI - Paroxetine drops versus paroxetine tablets: evaluation of compliance in a six month study. AB - AIMS: Literature data show that one third of patients discontinue antidepressant therapy within the first month of treatment. The aim of this study was to evaluate whether paroxetine liquid solution 10 mg/ml may influence adherence inpatients receiving long-term treatment. METHODS: 71 subjects affected by mood disorders or panic disorder were monitored for six months. The study sample was divided into two groups: controls (n=33) maintained their own therapy with paroxetine tablets; 38 patients maintained the same dosage of paroxetine, but shifted to liquid formulation 10 mg/ml. Compliance and general wellness were evaluated with the Medication Adherence Rating Scale (MARS) and the World Health Organization Quality of Life questionnaire (WhoQol). Data were analyzed using analysis of variance (ANOVA) and multivariate analysis of covariance (MANCOVA). RESULTS: Significant differences were found in MARS scores: patients on oral solution 10 mg/ml showed an improvement of compliance month by month. In addition, age, formulation and quality of life had a significant impacton patient compliance. Significant correlations were found between MARS and quality of life. A specific paroxetine formulation could be a variable able to influence adherence to psychopharmacological treatment. The same consideration can be made for quality of life, sex and age that showed a trend towards improved adherence when compared with controls. Inparticular, the WhoQol subscale analysis of delta scores showed a significant difference in self-perception of quality of life inpatients treated with paroxetine either in tablet or drop formulation. DISCUSSION: Formulation in drops 10 mg/ml is equally effective to tablets, but it may allow patients having a higher cognition and control on drug assumption. PMID- 23752810 TI - Nonconvulsive status epilepticus and psychotic symptoms: case report. AB - Nonconvulsive status epilepticus (NCSE) is an epileptic condition, lasting more than 30 min, characterized by continuous or recurrent epileptic activity on EEG, which is responsible for various clinical symptoms (especially in mental status or behavior) in the absence of manifest seizure activity. It includes different clinical forms, from minor confusion to complex behavioral disorders, psychosis, or coma. These psychotic symptoms can be very complex and their differential diagnosis canbe difficult. We report the case of a 31-year-old male patient without previous personal or family recorded history of epilepsy and/or schizophrenic disorder, without identifiable stressors, showing a subacute episode of anxiety with aggression. Initially,he was discharged without treatment. Seven days later he went to the emergency services accompanied by his family members reporting delusions of injury. He presented a disorganized behavior with self-harm, anxiety, dysesthesia, cenestopathy and internal field hallucinations (auditory and visual). The initial EEG study revealed a nonconvulsive status with an active temporal focus. In this patient, the psychotic symptoms and EEG abnormalities consistent with NCSE appeared simultaneously. Once the EEG returned to normal, the symptoms only persisted residually and were compatible with intraictal psychosis. PMID- 23752811 TI - Attribution of syphilis to the celts, the gauls, and the French. PMID- 23752813 TI - ST-Segment Elevation in Lead aVR on the Presenting Electrocardiogram-Reply. PMID- 23752815 TI - Error in Figure 2 and Footnote Addition for Table 2 in: Prevalence of Fracture and Fragment Embolization of Bard Retrievable Vena Cava Filters and Clinical Implications Including Cardiac Perforation and Tamponade. PMID- 23752814 TI - Spectroscopic ellipsometry of self assembled monolayers: interface effects. The case of phenyl selenide SAMs on gold. AB - This work focuses on the quantitative application of spectroscopic ellipsometry to the study of optical properties and thickness of self assembled monolayers (SAMs) of phenyl selenide deposited from the liquid phase on gold. STM, XPS and cyclic voltammetry measurements provide additional chemical and morphological characterization of the SAMs. While routine ellipsometry analysis of SAMs often relies on the film-induced deltaDelta change in the Delta ellipsometric angle and discards SAM-substrate interface effects, the present data show a distinctive behaviour of the deltaPsi data that we assign to interface effects, stronger than those previously found for densely packed alkanethiol SAMs. An inaccurate modelling of the variations in Psi related to the nano-structured SAM-substrate interface leads to a large overestimation of the film thickness. A simple model, which takes into account an effective approximation for the interface layer between the film and the substrate, and the molecular optical absorptions, provides a good agreement between the data and a reliable thickness estimate of the SAM. PMID- 23752816 TI - Synthesis, structures and luminescent properties of a series of novel Sr(II) Ln(III) (Ln = Eu, Gd, Tb) coordination polymers. AB - Eight novel Sr(II)-Ln(III) heteronuclear coordination polymers based on pyridine 2,6-dicarboxylic acid (H2pda) and imidazole (im) ligands, namely, [LnSr(pda)3(H2O)5].Him.H2O (Ln = Eu (1), Gd (2), Tb (3)), [Ln2Sr(pda)6(H2O)5].4Him.C2H5OH.nH2O (Ln = Eu (4), n = 5; Gd (5), n = 4), [LnSr(pda)3(H2O)4].Him.3H2O (Ln = Gd (6), Tb (7)), and [GdSr(pda)3(H2O)5].Him.C2H5OH.3H2O (8), have been prepared by employing different amounts of imidazole. X-ray crystal structure analysis reveals that these compounds exhibit a rich structural chemistry. Complexes 1-3 possess 2-D frameworks. Complexes 4-5, 6-7, and 8 exhibit three types of 1-D chain structure. The structures of the complexes could be rationally tuned via adding different amounts of imidazole. The luminescent properties of these complexes have been investigated. The results show that Eu(III) and Tb(III) complexes exhibit intense red and green luminescence emission which are characteristics of Tb(III) and Eu(III), respectively. Solid-state quantum yield and the lifetime of these complexes are also reported. PMID- 23752817 TI - Error in Text. in: Effect of a Single-Cycle Alternative Dosing Regimen for Rituximab for Recalcitrant Pemphigus: A Case Series of 9 Patients. PMID- 23752819 TI - Viral hepatitis: New advances in IL28B genetics. PMID- 23752821 TI - Alcoholic liver disease: ASMase implicated in alcoholic liver disease. PMID- 23752822 TI - Barrett oesophagus: Using length of Barrett oesophagus to determine risk of progression to high-grade dysplasia and adenocarcinoma. PMID- 23752820 TI - Conservative and surgical treatment of haemorrhoids. AB - The management of haemorrhoids has evolved rapidly during the past few decades. Several new treatments have been proposed with the aim of reducing patients' postoperative pain, time to return to normal life, risk of early and late complications, and recurrence rate. Although conservative treatment based on dietary and lifestyle changes can help the majority of patients, and rubber band ligation and phlebotonic drugs can effectively treat grade I and II haemorrhoids, surgery is required for the most advanced stages. Milligan-Morgan haemorrhoidectomy is considered to be the gold-standard approach for grade IV haemorrhoids. An increasing number of minimally invasive treatment options, including mucopexy with or without mucosal resection and haemorrhoid artery ligation, have now been proposed for the management of grade III haemorrhoids. These approaches aim to correct the underlying pathophysiological mechanisms involved in the aetiology of haemorrhoids. An increased risk of recurrence is the price to pay for these minimally invasive and less painful treatments, but the sparing of the sensitive anoderm and a rapid return to normal life without pain are greatly appreciated by patients. An algorithm for the management of haemorrhoids using evidence-based medicine is also presented here. PMID- 23752823 TI - Helicobacter pylori research: historical insights and future directions. AB - Helicobacter pylori leads to chronic gastritis, peptic ulcer disease and gastric cancer. With increasing issues of antibiotic resistance and changing epidemiology of this pathogen, new approaches are needed for effective management. In 1984, Dr Barry Marshall and Dr Robin Warren reported the association of Helicobacter pylori with peptic ulcers in The Lancet--a discovery that earned them the Nobel prize in Physiology or Medicine in 2005--but what progress have we made since then? Here, we have invited three international experts to give their insights into the advances in H. pylori research over the past 30 years and where research should be focused in the future. PMID- 23752824 TI - Infection: Modelling persistent giardiasis and malnutrition. PMID- 23752826 TI - Error in Byline in: Effects of Botulinum Toxin A on Cytokine Synthesis in a Cell Culture Model of Cutaneous Scarring. PMID- 23752825 TI - Liver transplantation: past, present and future. AB - The first human liver transplant operation was performed by Thomas Starzl in 1963. The next two decades were marked by difficulties with donor organ quality, recipient selection, operative and perioperative management, immunosuppression and infectious complications. Advances in each of these areas transformed liver transplantation from an experimental procedure to a standard treatment for end stage liver disease and certain cancers. From the handful of pioneering programmes, liver transplantation has expanded to hundreds of programmes in >80 countries. 1-year patient survival rates have exceeded 80% and outcomes continue to improve. This success has created obstacles. Ongoing challenges of liver transplantation include those concerning donor organ shortages, recipients with more advanced disease at transplant, growing need for retransplantation, toxicities and adverse effects associated with long-term immunosuppression, obesity and NASH epidemics, HCV recurrence and the still inscrutable biology of hepatocellular carcinoma. This Perspectives summarizes this transformation over time and details some of the challenges ahead. PMID- 23752827 TI - [Experimental base for internal connection dental implants for two-step implantation]. AB - The article contains selected results of comprehensive studies on osseointegration of small diameter internal connection dental implants made of nanostructured titanium. Fatigue tests were carried out by means of new osseointegrated metal etching method. PMID- 23752828 TI - [Biomechanics of single dental implants]. AB - Bone tissues of human skull, jawbones and hard dental tissues were formed formed by the influence of chewing loads which are functional irritants used for maintaining their physical qualities. Knowledge of tensions and deformations in bony structures allows to increase their joint work with dental implants installed. PMID- 23752829 TI - [Problems of metals biocompatibility]. AB - Bone tissues of human skull, jaws and dental hard tissues are formed under mastication loads acting as functional irritants and thus maintaining their physical qualities. Knowledge of tensions and deformations in bony structures allows creating favorable conditions for dental implant placement and function. PMID- 23752830 TI - [Experimental studies on the use of unwoven through-porous titanium material]. AB - The paper describes titanium unwoven material with a through porosity (so called metal-rubber) designed for the manufacture of the intraosseous part of dental implants. Morphological processes occurring in and around the implants were studied in animal model. PMID- 23752831 TI - [Experimental base for construction alloy choice for implant-retained restorations]. AB - The paper contains the results of experimental studies on galvanic features of "implant-construction alloy" contact pair. These results may be used as criteria for implant-retained restorations alloy choice. PMID- 23752832 TI - [Optimization of implant and teeth retained restorations by two-step dental implantation]. AB - Strength properties of provisional resin implant-retained restorations were assessed in vitro. The results were used to justify the use of combined temporary and two-step dental implantation. PMID- 23752833 TI - [Clinical experience in the use of nanohybrid composite material Filtek Z550]. AB - The paper presents the results of clinical studies on the effectiveness of nanohybrid composite Filtek Z550 (3M ESPE) for the restoration of class I cavities. PMID- 23752834 TI - [Clinical aspects of bone augmentation procedures in complex topography in patients with partial or full teeth loss]. AB - The paper concerns the problem of implant-based oral rehabilitation in complex alveolar bone topography. The study included 56 patients with partial and full teeth loss and significant alveolar bone atrophy Resonance frequency rates were used to assess intraosseous dental implants stability showing its improvement after alveolar bone augmentation procedures. PMID- 23752835 TI - [Ergonomics in oral surgery and dental implantology]. AB - The study objective was to reveal incidence, location and intensity of musculoskeletal pain in 88 dentists working in various units of Central Research Institute of Dentistry and Maxillofacial Surgery, as well as to identify pain predisposing factors and preventive measures. High rate (95.9 +/- 5.03%) of musculoskeletal pain was revealed, mostly located in cervical region. The pain occurred more often in younger dentists. High incidence of musculoskeletal pain proves the necessity for preventive measures including optical magnification devices. PMID- 23752836 TI - [Dental implants in complex oral rehabilitation in patients with class III occlusion and partial teeth loss]. AB - To prove the efficiency of dental implantation in complex treatment of patients with class III malocclusion and partial teeth loss. Nine patients aged 18-35 years with class III malocclusion and partial teeth loss were included in the study. All patients received two-step treatment involving orthodontic correction with two-step implantation and provisional restorations placement followed by orthognatic surgery procedure. The patients were followed-up for three years with no recurrent malocclusion or implant failure revealed, thus proving dental implantation to be useful tool in complex oral rehabilitation of patients with class III malocclusion and partial teeth loss. PMID- 23752837 TI - [Traumatic alveolar bone defect reconstruction by means of tissue-engineering construction with titanium mesh and one-step dental implantation]. AB - The paper presents case series of successful guided bone tissue regeneration in alveolar bone defects. In all cases osteoconductive substance was used in conjunction with platelet rich plasma and titanium mesh providing molding and barrier function. The described tactics allows dental implantation 6 months after guided tissue regeneration. PMID- 23752838 TI - [Compressive-distractive method for complex lower and upper jaw defects restoration in preparative procedures before implant placement]. AB - Distraction method in reconstructive maxillofacial surgery allows achieving optimal aesthetic and functional results. The study included 198 patients with various alveolar bone defects and 224 dental implants placed after successful alveolar bone distraction. Complex oral rehabilitation was possible after 4 month retention period. PMID- 23752839 TI - [Gingival fluid cytokine profile in patients after dental implantation and by periimplantitis]. AB - The study included 32 patients with complications which have developed 3 months to 14 years after dental implants placement. ELISA method was used to assess cytokines content in various sites of tooth alignment in patients with Herpesviridae and periodontopathogenics bacteria associated periimplantitis. The results prove the necessity for Herpesviridae and selected bacteria monitoring after dental implantation. PMID- 23752840 TI - [Use of oral fluid metabolic rates for the assessment of reparative osteogenesis after bone augmentation procedures]. AB - The use of osteoplastic materials allows extending indications for dental implants placement by considerable alveolar bone atrophy. The aim of the study was to reveal bone tissue metabolites which can be used as early bone destruction markers after bone augmentation procedure before any radiological signs occur. For this purpose the content of osteocalcinum, C-telopeptides, alkaline phosphatase and lactate dehydrogenase was examined in oral fluid. The increase of osteocalcinum and C-telopeptides and decrease activity of alkaline phosphatase and lactate dehydrogenase in comparison with control represented the pattern specific for bone destruction. PMID- 23752841 TI - [Mandible regional blood circulation peculiarities by dental implants placement]. AB - The paper presents data on regional blood circulation in mandible implant placement sites. Rheographic assessment in 50 patients divided in two groups according to implant placement protocol revealed that circulation volume and peripheral vessels tonus restored on the 14th day after implant placement with wound draining while in conventional implant placement protocol these values remained disturbed even 21 days after surgical procedure. PMID- 23752842 TI - [Mathematical planning of sandwich-plasty by osseous-muco-periosteal advancement flap]. AB - The method of mathematical planning of sandwich bone plasty is proposed. Displacement level of the bone flap is calculated in advance with regard to prosthetics size, shape and position as well as occlusal relationships. This makes it possible to accurately simulate the bone "basis" improving the prognosis of dental implantation. PMID- 23752843 TI - [Guidelines for staged maxilla bone and soft tissue augmentation]. AB - The paper contains guidelines for implant placement in case of bone and soft tissue maxilla defects. The approach is based on the possibility of staged realization of tissue regenerative potential. Using conception of "osseointegration" and "reparative regeneration" the following terms were defined: distant reparative osteogenesis, bone regenerate, structure components of bone regenerate, ortho- and heterotopic osteogenesis, regenerative macro- and microenvironment. PMID- 23752844 TI - [Long-term results of hemostatic sponge use by sinus-lift with simultaneous dental implantation]. AB - The aim of the study was to assess the long-term results of using hemostatic sponge as material of choice for sinus lift with simultaneous implant placement. The results suggest this method to be clinically successful while reducing treatment coast and length. PMID- 23752845 TI - [Use of porous titanium nickelide dental implants]. AB - The paper presents the results of 20 years clinical experience in dental prosthetics with the use of porous titanium nickelide dental implants. Implants were placed in 565 patients aged 15-17 years. Long-term results analysis showed restorations to function properly after mean follow-up period of 8 years in 435 patients (78.2%) proving this material to be clinically successful. PMID- 23752846 TI - [Clinical experience based guidelines for one-step dental implantation]. AB - The paper presents guidelines for one-step immediate implantation with simultaneous loading by means of provisional crown and subsequent ceramic restoration placement. PMID- 23752847 TI - [Alveolar bone and dental arch defects fulfillment in cleft lip and palate patients]. AB - Nine cleft lip and palate patients aged 17-32 years were included in the study, all having significant maxilla alveolar bone defects. Oral rehabilitation was possible by means of bone augmentation with iliac crest graft, soft tissue plasty and subsequent dental implantation (3 to 6 months after first-step procedures). PMID- 23752848 TI - [Preventive antibacterial treatment in oral bone augmentation procedures]. AB - The paper contains clinical and microbiological base for the use of Ceftibuten for prevention of inflammatory complications after bone augmentation and dental implant placement. PMID- 23752849 TI - [Immediate implantation after extraction of teeth with chronic apical periodontitis]. AB - The authors introduced an original method of intraoperative ozone and postoperative millimeter wave therapy which the short-term and long-term results of clinical, radiological, microbiological and immunological studies proved to enhance efficiency of immediate implantation in preliminary infected areas. PMID- 23752850 TI - [Sinus lift and dental implantation after endosurgical treatment of odontogenic maxillary sinusitis]. AB - The long-term results of dental implant placement in patients with the history of odontogenic maxillary sinusitis are assessed in retrospective study. Maxillary sinusotomy and endoscopic surgery procedures are compared in regard to complications risks after subsequent sinus lift and dental implantation, the latter proving to be method of choice in such cases. PMID- 23752851 TI - [Modern digital technologies as a useful tool for dental implantation planning]. AB - The method of implant size choice concerning mechanical properties of bone tissue surrounding an implant is proposed based on CT-assessment of anatomical and topographical conditions using MIMICS-ANSYS software. PMID- 23752852 TI - [Dental implantation options and estimation of osseous integration in patients with complete teeth loss]. AB - In 48 patients with full teeth loss 272 implants were placed with subsequent oral rehabilitation by fixed and removable dental restorations. Clinical efficiency rates after 5 years of follow-up were 99.6% for implants and 98.2% for restorations. High osseointegration values were obtained with mean "Periotest" value to be 3.6 and bone level loss of 0.7 mm. Best osseointegration features were revealed in cases of fixed restorations retained by 8 and more implants. PMID- 23752853 TI - [Comparative study of implant-retained fixed restorations with milled and casted titanium frames]. AB - The long-term results of implant retained restorations with casted and milled frames were compared in clinical and experimental settings. Electrochemical features of milled and casted titanium by contact with titanium implant were assessed. The biocompatibility of milled and casted titanium was studied in mesenchymal stem cells culture. Cross sections were used to assess the marginal fit precision of milled and casted frames. PMID- 23752854 TI - [Study of blood circulation microdynamics in gingival mucosa after dental implantation with the use of custom-made healing abutments]. AB - Microhemodynamics by gingival mucosa contour formation in implant placement sites was studied by laser doppler flowmetry. When installing healing abutment customized by Estelite Flow Quick noted reduction of tissue blood flow was revealed indicating the development of ischemia in the gingival mucosa. Conventional blood flow pattern restored in 7 days. PMID- 23752856 TI - About this journal. PMID- 23752855 TI - [The results of patients questioning regarding dental implantation procedures]. AB - Dental implantation is a widespread method of oral rehabilitation by teeth loss. The purpose of the study was to evaluate patients need and awareness of dental implantation. 486 respondents were included in survey. The low level of knowledge about dental implantation was identified among patients in Saratov. PMID- 23752857 TI - An extreme vertices mixture design approach to the optimisation of 1,2,3 trichlorobenzene specific molecularly imprinted polymers. AB - Traditional approaches to molecularly imprinted polymer (MIP) design and optimisation typically afford a template (T) : functional monomer (FM) : crosslinker (CL) ratio of 1 : 2 : 20 to 1 : 4 : 20. This approach for 1,2,3 trichlorobenzene (7) as template gave a styrene based MIP (MIP(STY)) with an imprinting factor (IF) = 1.3. An extreme vertices mixture design (EVMD) approach was applied, and in two design cycles, 15 total experimental points, the optimum composition for MIP(STY) was determined as 0.40 : 0.05 : 0.55 (T : FM : CL) with IF = 2.8. Refinements gave optimum T : FM : CL ratios for the functional monomers: 4-vinylpyridine (4VP, 0.40 : 0.02 : 0.58); 2,4,6-trimethylstyrene (TMS, 0.40 : 0.02 : 0.58) and 2,3,4,5,6-pentafluorostyrene (PFS, 0.30 : 0.12 : 0.58) with IF = 2.8, 2.8 and 3.7 respectively. These ratios deviated significantly from the traditional MIP synthesis ratio. The low levels of FM for all MIPs, except for MIP(PFS), suggest that imprinting was more consistent with T-CL, than FM-T, interactions. Analysis of the specific interactions and removal (SR) of 7 with these MIPs revealed that the SR with MIP(STY) increased from 36% at 0.02 STY to 48% at 0.13 STY; with MIP(TMS) SR increased from 38% at 0.02 TMS to 42% at 0.10 TMS; and with MIP(PFS) SR increased from 34% at 0.02 PFS to 56% at 0.14 PFS. MIP(4VP) saw a decline in SR with increasing FM, with the highest SR was 35% at 0.02 4VP. This is consistent with changes in the non-specific interactions between 7 and the MIPs. Increasing the proportion of PFS produced the largest increase in imprinting of 7 demonstrated by the highest SR (56%) and highest IF (3.7). The application of an EVMD approach resulted in the IF of MIP(STY) increased from 1.3 to 2.8. The highest IF achieved by this study was 3.7 for MIP(PFS) in proportions of 0.30 : 0.12 : 0.48 (T : FM : CL). PMID- 23752858 TI - Dietary fat and reduced prostate cancer mortality: does the type of fat matter? PMID- 23752861 TI - A new direction. PMID- 23752862 TI - Transnational history of medicine after 1950: framing and interrogation from psychiatric journals. AB - Communication amongst medical specialists helps display the tensions between localism and transnationalisation. Some quantitative sampling of psychiatric journals provides one framework for understanding the history of psychiatry and, to some extent, the history of medicine in general in the twentieth century. After World War II, extreme national isolation of psychiatric communities gave way to substantial transnationalisation, especially in the 1980s, when a remarkable switch to English-language communication became obvious. Various psychiatric communities used the new universal language, not so much as victims of Americanisation, as to gain general professional recognition and to participate in and adapt to modernisation. PMID- 23752863 TI - Appeals to autonomy and obedience: continuity and change in governing technologies in Danish and Swedish health promotion. AB - The increasingly used concept new public health indicates that a fundamental change has occurred in the goals and methods of disease prevention and health promotion. The change is often said to imply less expert-driven governing of citizens. In this article, governing technologies in the field of public health in Denmark and Sweden are analysed to investigate whether substantial changes have taken place in the governing efforts. In the endeavours unfolded in relation to health examinations for children and pregnant women during the last eighty years, no apparent evidence exists of a significant change in governing technologies. Regulatory, expert-driven and empowering technologies have been used during the whole period; additionally, appeals to autonomy, responsibility and obedience as well as to trust in authorities co-exist throughout the period. The fundamental change is the huge increase in the health authorities' governing ambitions. PMID- 23752864 TI - Bruised witness: Bernard Spilsbury and the performance of early twentieth-century English forensic pathology. AB - This article explores the status, apparatus and character of forensic pathology in the inter-war period, with a special emphasis on the 'people's pathologist', Bernard Spilsbury. The broad expert and public profile of forensic pathology, of which Spilsbury was the most prominent contemporary representative, will be outlined and discussed. In so doing, close attention will be paid to the courtroom strategies by which he and other experts translated their isolated post mortem encounters with the dead body into effective testimony. Pathologists built a high-profile practice that transfixed the popular, legal and scientific imagination, and this article also explores, through the celebrated 1925 murder trial of Norman Thorne, how Spilsbury's courtroom performance focused critical attention on the practices of pathology itself, which threatened to destabilise the status of forensic pathology. In particular, the Thorne case raised questions about the interrelation between bruising and putrefaction as sources of interpretative anxiety. Here, the question of practice is vital, especially in understanding how Spilsbury's findings clashed with those of rival pathologists whose autopsies centred on a corpse that had undergone further putrefactive changes and that had thereby mutated as an evidentiary object. Examining how pathologists dealt with interpretative problems raised by the instability of their core investigative object enables an analysis of the ways in which pathological investigation of homicide was inflected with a series of conceptual, professional and cultural difficulties stemming in significant ways from the materiality of the corpse itself. This article presents early findings of a larger study of twentieth-century English homicide investigation which focuses on the interaction between two dominant forensic regimes: the first, outlined in part here, is a body-centred forensics, associated with the lone, 'celebrity' pathologist, his scalpel and the mortuary slab; the second is a 'forensics of things' centred on the laboratory and its associated technologies of trace analysis (hair, blood, fibres), deployed in closed technician-dominated spaces and in the regimentally managed crime scene. Future work will seek to illuminate the shifting landscape of English forensics by following the historical interplay between these two powerful investigative models. PMID- 23752865 TI - 'The solution to his own enigma': connecting the life of Montague David Eder (1865-1936), socialist, psychoanalyst, Zionist and modern saint. AB - This article examines the career of pioneer British psychoanalyst David Eder (1865-1936). Credited by Freud as the first practising psychoanalyst in England, active in early British socialism and then a significant figure in Zionism in post-war Palestine, and in between an adventurer in South America, a pioneer in the field of school medicine, and a writer on shell-shock, Eder is a strangely neglected figure in existing historiography. The connections between his interest in medicine, psychoanalysis, socialism and Zionism are also explored. In doing so, this article contributes to our developing understanding of the psychoanalytic culture of early twentieth-century Britain, pointing to its shifting relationship to broader ideology and the practical social and political challenges of the period. The article also reflects on the challenges for both Eder's contemporaries and his biographers in making sense of such a life. PMID- 23752866 TI - Visual objects and universal meanings: AIDS posters and the politics of globalisation and history. AB - Drawing on recent visual and spatial turns in history writing, this paper considers AIDS posters from the perspective of their museum 'afterlife' as collected material objects. Museum spaces serve changing political and epistemological projects, and the visual objects they house are not immune from them. A recent globally themed exhibition of AIDS posters at an arts and crafts museum in Hamburg is cited in illustration. The exhibition also serves to draw attention to institutional continuities in collecting agendas. Revealed, contrary to postmodernist expectations, is how today's application of aesthetic display for the purpose of making 'global connections' does not radically break with the virtues and morals attached to the visual at the end of the nineteenth century. The historicisation of such objects needs to take into account this complicated mix of change and continuity in aesthetic concepts and political inscriptions. Otherwise, historians fall prey to seductive aesthetics without being aware of the politics of them. This article submits that aesthetics is politics. PMID- 23752867 TI - The use of mercury against pediculosis in the Renaissance: the case of Ferdinand II of Aragon, King of Naples, 1467-96. AB - The hair samples of Ferdinand II of Aragon (1467-1496), King of Naples, whose mummy is preserved in the Basilica of San Domenico Maggiore in Naples, showed a high content of mercury, with a value of 827ppm. Furthermore, examination using a stereomicroscope and a scanning electron microscope (SEM) of head and pubic hairs of Ferdinand II, revealed a lice infestation. The reasons for the massive presence of the mercury in the king's hair are discussed and contemporary literature regarding the use of this metal in medical therapies and in cosmetic practices is analysed. As a result, the high value of mercury in the hair of Ferdinand II can be attributed to antipediculosis therapy, applied as a topic medicament. This case represents an important finding for the history of medicine, because demonstrates that in the Renaissance mercury was applied locally not only to treat syphilis, as well attested by direct and indirect sources, but also to prevent or eliminate lice infestation. PMID- 23752869 TI - Highlights of archives of facial plastic surgery. PMID- 23752868 TI - Lanthanide-polyphosphonate coordination polymers combining catalytic and photoluminescence properties. AB - A rapid, mild and high-yield microwave synthesis of 1D isotypical [Ln(H4bmt)(H5bmt)(H2O)2].3H2O coordination polymers is presented. The La(3+) based material is highly active as a heterogeneous catalyst in the methanolysis of styrene oxide at nearly room temperature. Eu(3+)- and Tb(3+)-doped materials are very effective UV-to-visible light converters. PMID- 23752870 TI - Abraham buschke in ghetto terezin: a remembrance. PMID- 23752871 TI - Telehealth monitoring with nurse clinician oversight-reply. PMID- 23752872 TI - Misconstrued intentions: setting the record straight-reply. PMID- 23752873 TI - Do Angiotensin receptor blockers really hold promise for the improvement of cognitive functioning?-Reply. PMID- 23752875 TI - Distribution, clinical characteristics, and surgical treatment of lip infantile hemangiomas. AB - IMPORTANCE: Infantile hemangiomas (IHs) are the most common tumors of infancy. OBJECTIVES: To describe the patterns of occurrence of lip IHs and correlate these findings with patterns of anatomical distortion and predictable clinical outcomes and to describe the surgical management of these lesions. DESIGN: A retrospective medical record review of patients diagnosed as having facial IH of the upper or lower lips during an 8-year period (January 1, 2004, through December 31, 2011). Using clinical photographs and patient records, we mapped the 360 IHs of 342 patients on a lip schematic. Each lesion was encoded with a number reflective of its location, and this number was shared by other lesions found at the same site. Frequencies of lesion characteristics, complicating functional and aesthetic factors, and airway obstruction were documented. The treatment course was noted. SETTING: Tertiary care hospital and practice specializing in the care of congenital pediatric vascular anomalies of the head and neck. PARTICIPANTS: Three hundred forty-two patients with 360 IHs. RESULTS: A total of 1916 IHs were diagnosed. Of these, lip IHs were found in 342 patients. We reviewed those patients' medical records. Of the lesions, 59.2% were focal and 40.8% were segmental. A nonrandom distribution of lip IHs was found. The most common focal lesion occurred at the lower lip (98 of 213 lesions [46.0%]). The most common segmental lesion involved the mandibular segment (75 of 147 [51.0%]). Of the 75 patients, 30 (40.0%) had airway involvement. The most common anatomical distortions of the lip involved the vermiliocutaneous junction in 216 (61.5%). Horizontal and vertical lengthening of the lip was evident in 28.7% and 31.0% of patients, respectively. Ulceration and scarring were common findings in 137 patients overall (38.1%), with segmental mandibular IHs associated with the highest percentage (46 of 137 [33.6%]), followed by focal IHs of the lower lip (35 of 137 [25.5%]). Using previously described surgical procedures, we developed a problem-oriented solution for each of these zones. CONCLUSIONS AND RELEVANCE: The nonrandom distribution of facial hemangiomas has been documented with focal and segmental patterns of growth. Distinct anatomical patterns of occurrence for lip IHs are described. The distribution seems to be related to the embryologic development of the upper and lower lips. These anatomical patterns allow for the prediction of anatomical location, structural distortion, and possible clinical outcomes. This information is relevant when planning medical and surgical treatment for these children. LEVEL OF EVIDENCE: NA. PMID- 23752876 TI - Modeling quantification of the influence of soil moisture on subslab vapor concentration. AB - The U.S. EPA has developed a database of field data obtained from vapor intrusion sites throughout the United States. Large variations in reported subsurface contaminant vapor concentration ratios (e.g. building subslab to groundwater source) present challenges for the analysis of subsurface vapor transport processes. Meanwhile, numerical models have been used by the U.S. EPA and others to describe the transport processes governing vapor intrusion. The influence of the capillary fringe has often been ignored in these models. In this manuscript, the influence of soil moisture content on the subslab vapor concentration is analyzed in the context of mathematical models. Results are compared to those from other modeling methods that do not account for the soil moisture content. The slab capping effect is observed to interact with the effect of soil moisture in determining the subslab contaminant vapor concentration. The slab capping effect is observed to be significant when the building-source separation distance is less than half of the slab size. PMID- 23752877 TI - Serum cytokeratin-18 fragment levels are useful biomarkers for nonalcoholic steatohepatitis in children. AB - OBJECTIVES: Nonalcoholic steatohepatitis (NASH) is the most aggressive form of nonalcoholic fatty liver disease (NAFLD). Noninvasive methods to identify children with NASH are urgently needed. The aim of this study was to evaluate the use of plasma cytokeratin-18 (CK18) fragment levels, a marker of increased hepatocyte apoptosis, as a non-invasive biomarker for pediatric NASH. METHODS: Consecutive children with biopsy-proven NAFLD were included and blood samples were collected at the time of the biopsy. The diagnosis of NASH was based on Brunt's criteria. Histological features were scored: steatosis (0-3), lobular inflammation (0-3), ballooning (0-2), and portal inflammation (0-2). NAFLD activity score was calculated (0-8) and fibrosis stage was scored (0-4). We measured plasma CK18 levels using the M30-Apoptosense enzyme-linked immunosorbent assay kit. RESULTS: A total of 201 subjects were included in the study. The mean age was 10.7+/-2.5 years and 37% were male. NASH was diagnosed in 140 patients with a mean NAFLD activity scoring of 4.4+/-1.3. CK18 levels were significantly higher in subjects with NASH compared with not NASH (322.1 U/l+/-104.8 vs. 164.2 U/l+/-62, respectively; P<0.001). The risk of having NASH on liver biopsy increased with increased CK18 levels (P<0.001). For every 10 U/l increase in CK18 levels, the likelihood of having NASH increased by 70% after adjusting for multiple confounders. The performance of CK18 level for the diagnosis of NASH was excellent with an area under the receiver operating characteristics curve of 0.933. CONCLUSIONS: CK18 is a promising non-invasive biomarker for NASH in children with fatty liver disease. PMID- 23752878 TI - Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. AB - OBJECTIVES: Risk factors for hepatocellular carcinoma (HCC) include hepatitis B and C viruses (HBV, HCV), excessive alcohol consumption, rare genetic disorders and diabetes/obesity. The population attributable fractions (PAF) of these factors, however, have not been investigated in population-based studies in the United States. METHODS: Persons >=68 years diagnosed with HCC (n=6,991) between 1994 and 2007 were identified in the SEER-Medicare database. A 5% random sample (n=255,702) of persons residing in SEER locations were selected for comparison. For each risk factor, odds ratios (ORs), 95% confidence intervals (95% CI) and PAFs were calculated. RESULTS: As anticipated, the risk of HCC was increased in relationship to each factor: HCV (OR 39.89, 95% CI: 36.29-43.84), HBV (OR 11.17, 95% CI: 9.18-13.59), alcohol-related disorders (OR 4.06, 95% CI: 3.82-4.32), rare metabolic disorders (OR 3.45, 95% CI: 2.97-4.02), and diabetes and/or obesity (OR 2.47, 95% CI: 2.34-2.61). The PAF of all factors combined was 64.5% (males 65.6%; females 62.2%). The PAF was highest among Asians (70.1%) and lowest among black persons (52.4%). Among individual factors, diabetes/obesity had the greatest PAF (36.6%), followed by alcohol-related disorders (23.5%), HCV (22.4%), HBV (6.3%) and rare genetic disorders (3.2%). While diabetes/obesity had the greatest PAF among both males (36.4%) and females (36.7%), alcohol-related disorders had the second greatest PAF among males (27.8%) and HCV the second greatest among females (28.1%). Diabetes/obesity had the greatest PAF among whites (38.9%) and Hispanics (38.1%), while HCV had the greatest PAF among Asians (35.4%) and blacks (34.9%). The second greatest PAF was alcohol-related disorders in whites (25.6%), Hispanics (30.1%) and blacks (and 18.5%) and HBV in Asians (28.5%). CONCLUSIONS: The dominant risk factors for HCC in the United States among persons >=68 years differ by sex and race/ethnicity. Overall, eliminating diabetes/obesity could reduce the incidence of HCC more than the elimination of any other factor. PMID- 23752879 TI - Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and meta-analysis. AB - OBJECTIVES: There has been no definitive synthesis of the evidence for any benefit of available pharmacological therapies in opioid-induced constipation (OIC). We conducted a systematic review and meta-analysis to address this deficit. METHODS: We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials through to December 2012 to identify placebo-controlled trials of MU-opioid receptor antagonists, prucalopride, lubiprostone, and linaclotide in the treatment of adults with OIC. No minimum duration of therapy was required. Trials had to report a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Effect of pharmacological therapies was reported as relative risk (RR) of failure to respond to therapy, with 95% confidence intervals (CIs). RESULTS: Fourteen eligible randomized controlled trials (RCTs) of MU-opioid receptor antagonists, containing 4,101 patients, were identified. These were superior to placebo for the treatment of OIC (RR of failure to respond to therapy=0.69; 95% CI 0.63-0.75). Methylnaltrexone (six RCTs, 1,610 patients, RR=0.66; 95% CI 0.54 0.84), naloxone (four trials, 798 patients, RR=0.64; 95% CI 0.56-0.72), and alvimopan (four RCTs, 1,693 patients, RR=0.71; 95% CI 0.65-0.78) were all superior to placebo. Total numbers of adverse events, diarrhea, and abdominal pain were significantly commoner when data from all RCTs were pooled. Reversal of analgesia did not occur more frequently with active therapy. Only one trial of prucalopride was identified, with a nonsignificant trend toward higher responder rates with active therapy. Two RCTs of lubiprostone were found, with significantly higher responder rates with lubiprostone in both, but reporting of data precluded meta-analysis. CONCLUSIONS: MU-Opioid receptor antagonists are safe and effective for the treatment of OIC. More data are required before the role of prucalopride or lubiprostone in the treatment of OIC are clear. PMID- 23752880 TI - Endoscopically acquired pancreatic cyst fluid microRNA 21 and 221 are associated with invasive cancer. AB - OBJECTIVES: Pancreatic cysts are a group of lesions with heterogeneous malignant potential. Currently, there are no reliable biomarkers to aid in cyst diagnosis and classification. The objective of this study was to identify potential microRNA (miR) biomarkers in endoscopically acquired pancreatic cyst fluid that could be used to distinguish between benign, premalignant, and malignant cysts. METHODS: A list of candidate miRs was developed using a whole-genome expression array analysis of pancreatic cancer (pancreatic ductal adenocarcinoma) and nonmalignant samples overlapped with existing literature and predicted gene targets. Endoscopically acquired pancreatic cyst fluid samples were obtained from a group of 38 patients who underwent cyst fluid aspiration and surgical resection. Selected miR expression levels in cyst fluid samples were assessed by quantitative real-time-PCR. Additionally, in situ hybridization (ISH) on corresponding cyst tissue samples was performed to identify the source and validate the expression level of fluid miRs. RESULTS: Of the six miRs that were profiled in the study, two showed differential expression in malignant cysts. miR 221 was expressed at significantly higher levels in malignant cysts compared with benign or premalignant cysts (P=0.05). miR-21 was also expressed at significantly higher levels in malignant cysts (P<0.01). Additionally, the expression of miR-21 was significantly higher in premalignant cysts than benign cysts (P=0.03). The differential expression of miR-21 among cyst categories was confirmed by ISH. CONCLUSIONS: In this small single-center study, miRs are potential pancreatic cyst fluid diagnostic biomarkers. In particular, miR-21 is identified as a candidate biomarker to distinguish between benign, premalignant, and malignant cysts. Additionally miR-221 may be of use in the identification of more advanced malignant disease. PMID- 23752881 TI - Safety of anti-TNF agents during pregnancy and breastfeeding in women with inflammatory bowel disease. AB - OBJECTIVES: Anti-tumor necrosis factor (TNF) drugs are an effective therapeutic option in patients with inflammatory bowel disease (IBD). However, data regarding their safety during pregnancy and breastfeeding are scarce. The aim of this study was to critically review available data on the safety of anti-TNF therapy during pregnancy and breastfeeding in women with IBD. METHODS: Bibliographical searches (MEDLINE) up to January 2013. RESULTS: The studies included provided data from 462 women with IBD exposed to anti-TNF agents during pregnancy. Although these drugs cross the placenta from the end of the second trimester, they are low-risk in the short term. The use of anti-TNF agents after the second trimester leads to intra-uterine exposure. An increase in infections has recently been observed in infants exposed to immunomodulators plus anti-TNF drugs in utero, thus raising concerns about the consequences for the development of the immune system. Accordingly, it has recently been suggested that anti-TNF drugs should be stopped during the second trimester. Certolizumab is a Fab fragment of an anti-TNF monoclonal antibody, and, therefore, it may not be necessary to stop it during pregnancy. Anti-TNF drugs have been detected in breast milk, although in miniscule amounts. Case reports do not suggest toxicity; however, the effects of exposure on the neonate merit further investigation. CONCLUSIONS: Anti-TNF drugs can cross the placenta from the latter part of the second trimester of gestation, although they seem to be safe, at least in the short term. Miniscule amounts of anti-TNF drugs are transferred in breast milk; therefore, a deleterious effect of this exposure on the neonate, although unlikely, cannot be excluded. PMID- 23752882 TI - A case of psoriasis vulgaris in husband and wife. PMID- 23752886 TI - Public health: Effects of sodium and potassium intake on health outcomes. PMID- 23752887 TI - Renal involvement and the role of Notch signalling in Alagille syndrome. AB - Alagille syndrome is an autosomal dominant disorder with variable multisystem organ involvement that is caused by mutations in one of two genes in the Notch signalling pathway, JAG1 or NOTCH2. Alagille syndrome is characterized by bile duct paucity, along with at least three of the following features: cholestasis, cardiac defects, skeletal abnormalities, ocular abnormalities and characteristic facies. However, the clinical features of Alagille syndrome are highly variable, and children or adults may also present with predominantly renal findings and little or no hepatic involvement. Renal involvement occurs in 40% of JAG1 mutation-positive individuals. Renal insufficiency is common and has been specifically reported in children with Alagille syndrome who have end-stage liver disease. The role of NOTCH2 and JAG1 in formation of proximal nephron structures and podocytes might explain the observed phenotypes of renal dysplasia and proteinuria in patients with Alagille syndrome, and renal tubular acidosis may be the result of JAG1 expression in the collecting ducts. Renal vascular hypertension in patients with Alagille syndrome is explained by the widespread vasculopathy and the role of Notch signalling in vascular development. Increased awareness of Alagille syndrome amongst nephrologists may lead to more diagnoses of Alagille syndrome in patients with apparently isolated renal disease. PMID- 23752890 TI - Cardiovascular disease: Is LDL-C level a good indicator of coronary risk in people with nondialysis-dependent CKD? PMID- 23752888 TI - Biomarkers for incident CKD: a new framework for interpreting the literature. AB - Biomarkers are a useful tool for the investigation of chronic kidney disease (CKD), although the design, analytical tools and outcomes used in many biomarker studies are suboptimal. In part, this situation might reflect a lack of appreciation of the nature of different biomarkers. A particular biomarker could, for example, be implicated in the pathogenesis of CKD because it is a physiological risk factor for declining kidney function, an indicator of impaired kidney function, or a marker of ongoing injury within the kidney. Such risk factors enable us to understand the process of disease and to identify treatment targets. By contrast, risk markers enable us to distinguish persons who will or will not develop CKD, even though the markers themselves are not required to be modifiable by (or directly involved in) the disease process. Accurate prediction of CKD risk will probably require a combination of biomarkers of several types, however. This Review offers a conceptual framework for interpreting the results of studies evaluating biomarkers of declining kidney function and incident CKD. PMID- 23752892 TI - Investigation into the mechanical properties of single-walled carbon nanotube heterojunctions. AB - The mechanical properties of finite-length (6,0)/(8,0) single-walled carbon nanotube (SWCNT) heterojunctions with respect to different kinds of connection segments, either coaxial or bias, are investigated using molecular dynamics simulation calculations. It is found that the resulting significant deformation of structure and significant drop of stress under yielding strain is due to the strain localization. Moreover, the deformation is occurred below the heptagon ring in the thinner segment of the heterojunctions under tension at different temperatures, whereas under compression it occurs on the heptagon ring. The computed atomic bond number distribution and radius distribution function are applied to determine the deformed atomic structure. Finally, with increasing temperature, the yielding stresses decrease for both coaxial and bias heterojunctions under tension and compression, while the dependence of temperature on the Young's modulus of the heterojunctions is only observed in the case of tension. PMID- 23752893 TI - This month in archives of dermatology. PMID- 23752894 TI - Calf stretching prophylaxis for nocturnal cramps-reply. PMID- 23752898 TI - About this journal. PMID- 23752895 TI - Structure and biosynthesis of scabichelin, a novel tris-hydroxamate siderophore produced by the plant pathogen Streptomyces scabies 87.22. AB - Scabichelin and turgichelin, novel tris-hydroxamate siderophores, were isolated from Streptomyces antibioticus NBRC 13838/Streptomyces scabies JCM 7914 and Streptomyces turgidiscabies JCM 10429, respectively. The planar structures of scabichelin and turgichelin were elucidated by mass spectrometry, and 1- and 2-D NMR spectroscopic analyses of their gallium(III) complexes. The relative and absolute stereochemistry of the metabolites was determined by the modified Marfey's method in conjunction with computational modelling and NOESY NMR analysis of Ga-scabichelin and Ga-turgichelin. Genome sequence analysis of the plant pathogen Streptomyces scabies 87.22 identified a gene cluster containing a gene encoding a nonribosomal peptide synthetase (NRPS) that was predicted to direct the production of a pentapeptide with structural similarities to scabichelin and turgichelin. Comparative LC-MS/MS analyses of iron-deficient culture supernatants from wild type S. scabies 87.22 and a mutant in which the NRPS gene had been disrupted, and scabichelin purified from S. antibioticus, showed that scabichelin is the metabolic product of the cryptic gene cluster, strongly suggesting that it functions as a siderophore. PMID- 23752899 TI - Appropriate use of myocardial perfusion imaging in a veteran population: profit motives and professional liability concerns. PMID- 23752900 TI - The Big Ones That Got Away: Omega-3 Meta-analysis Flawed by Excluding the Biggest Fish Oil Trials-Reply. PMID- 23752901 TI - Italian renaissance: france synonymous with syphilis. PMID- 23752902 TI - Bubble master. PMID- 23752903 TI - About this journal. PMID- 23752904 TI - Molecular mechanisms of biomaterial-driven osteogenic differentiation in human mesenchymal stromal cells. AB - Calcium phosphate (CaP) based ceramics are used as bone graft substitutes in the treatment of bone defects. The physico-chemical properties of these materials determine their bioactivity, meaning that molecular and cellular responses in the body will be tuned accordingly. In a previous study, we compared two porous CaP ceramics, hydroxyapatite (HA) and beta-tricalcium phosphate (TCP), which, among other properties, differ in their degradation behaviour in vitro and in vivo, and we demonstrated that the more degradable beta-TCP induced more bone formation in a heterotopic model in sheep. This is correlated to in vitro data, where human bone marrow derived mesenchymal stromal cells (MSC) exhibited higher expression of osteogenic differentiation markers, such as osteopontin, osteocalcin and bone sialoprotein, when cultured in beta-TCP than in HA. More recently, we also showed that this effect could be mimicked in vitro by exposure of MSC to high concentrations of calcium ions (Ca(2+)). To further correlate surface physico chemical dynamics of HA and beta-TCP ceramics with the molecular response of MSC, we followed Ca(2+) release and surface changes in time as well as cell attachment and osteogenic differentiation of MSC on these ceramics. Within 24 hours, we observed differences in cell morphology, with MSC cultured in beta-TCP displaying more pronounced attachment and spreading than cells cultured in HA. In the same time frame, beta-TCP induced expression of G-protein coupled receptor (GPCR) 5A and regulator of G-protein signaling 2, revealed by DNA microarray analysis. These genes, associated with the protein kinase A and GPCR signaling pathways, may herald the earliest response of MSC to bone-inducing ceramics. PMID- 23752905 TI - Prion disease: a promising rating scale for prion disease clinical research. PMID- 23752906 TI - Decompressive craniectomy: past, present and future. AB - Decompressive craniectomy (DC)--a surgical procedure that involves removal of part of the skull to accommodate brain swelling--has been used for many years in the management of patients with brain oedema and/or intracranial hypertension, but its place in contemporary practice remains controversial. Results from a recent trial showed that early (neuroprotective) DC was not superior to medical management in patients with diffuse traumatic brain injury. An ongoing trial is investigating the clinical and cost effectiveness of secondary DC as a last-tier therapy for post-traumatic refractory intracranial hypertension. With regard to ischaemic stroke (malignant middle cerebral artery infarction), a recent Cochrane review concluded that DC improves survival compared with medical management, but that a higher proportion of DC survivors experience moderately severe or severe disability. Although many patients have a good outcome, the issue of DC-related disability raises important ethical issues. As DC and subsequent cranioplasty are associated with a number of complications, indiscriminate use of this surgery is not appropriate. Here, we review the evidence and present considerations regarding surgical technique, ethics and cost-effectiveness of DC. Prospective clinical trials and cohort studies are essential to enable optimization of patient care and outcomes. PMID- 23752907 TI - Alzheimer disease: the quest for Alzheimer disease genes--focus on CSF tau. PMID- 23752913 TI - White matter disease: aquaporin-4 antibody-positive patients may not always fulfil the clinical criteria for neuromyelitis optica. PMID- 23752914 TI - Stroke: stroke fatality on weekends--a case for organized stroke care. PMID- 23752915 TI - Weight change and depression among US young women during the transition to adulthood. AB - By using data from wave 2 (in 1996) and wave 3 (in 2000-2001) of the US-based National Longitudinal Study of Adolescent Health, we investigated the association between young women's body weight and depression during the transition to adulthood. Respondents (n = 5,243) were 13-18 years of age during wave 2 and 19 25 years of age during wave 3. We used Center for Epidemiologic Studies Depression Scale scores to classify young women as never depressed, consistently depressed, experiencing depression onset, or experiencing depression recovery from wave 2 to wave 3. Results from adjusted multinomial logistic regression models indicated that respondents who experienced significant weight gain were at risk of depression onset. Normal weight (adjusted odds ratio = 2.10, 95% confidence interval: 1.14, 3.84) and overweight (adjusted odds ratio = 1.86, 95% confidence interval: 1.15, 2.99) adolescent girls who were obese by young adulthood, as well as young women who were consistently obese during adolescence and young adulthood (adjusted odds ratio = 1.97, 95% confidence interval: 1.19, 3.26), had roughly twice the odds of depression onset as did young women who were never overweight. We concluded that weight gain and obesity are risk factors for depression onset during the transition to adulthood. Policies prioritizing healthy weight maintenance may help improve young women's mental health as they begin their adult lives. PMID- 23752908 TI - Ushering in the study and treatment of preclinical Alzheimer disease. AB - Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of, or completely prevent clinical decline. In this Review, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how advances in the field have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. PMID- 23752916 TI - Importance of adequate local spatiotemporal transmission measures in malaria cohort studies: application to the relation between placental malaria and first malaria infection in infants. AB - According to several studies, infants whose mothers had a malaria-infected placenta (MIP) at delivery are at increased risk of a first malaria infection. Immune tolerance caused by intrauterine contact with the parasite could explain this phenomenon, but it is also known that infants who are highly exposed to Anopheles mosquitoes infected with Plasmodium are at greater risk of contracting malaria. Consequently, local malaria transmission must be taken into account to demonstrate the immune tolerance hypothesis. From data collected between 2007 and 2010 on 545 infants followed from birth to age 18 months in southern Benin, we compared estimates of the effect of MIP on time to first malaria infection obtained through different Cox models. In these models, MIP was adjusted for either 1) "village-like" time-independent exposure variables or 2) spatiotemporal exposure prediction derived from local climatic, environmental, and behavioral factors. Only the use of exposure prediction improved the model's goodness of fit (Bayesian Information Criterion) and led to clear conclusions regarding the effect of placental infection, whereas the models using the village-like variables were less successful than the univariate model. This demonstrated clearly the benefit of adequately taking transmission into account in cohort studies of malaria. PMID- 23752917 TI - Prediction of cardiovascular disease mortality by proteinuria and reduced kidney function: pooled analysis of 39,000 individuals from 7 cohort studies in Japan. AB - There are limited studies addressing whether proteinuria and estimated glomerular filtration rate (eGFR) are independently associated with cardiovascular disease in Asia. Using data from 7 prospective cohorts recruited between 1980 and 1994 in Japan, we assessed the influence of proteinuria (>=1+ on dipstick) and reduced eGFR on the risk of cardiovascular disease mortality in 39,405 participants (40 89 years) without kidney failure. During a 10.1-year follow-up, 1,927 subjects died from cardiovascular disease. Proteinuria was associated with a 1.75-fold (95% confidence interval (CI): 1.44, 2.11) increased risk of cardiovascular disease mortality after adjustment for potential confounding factors. Additionally, the multivariate-adjusted hazard ratio of cardiovascular disease mortality increased linearly with lower eGFR levels (P(trend) < 0.001): Subjects with eGFR of <45 mL/minute/1.73 m2 had a 2.22-fold (95% CI: 1.60, 3.07) greater risk of cardiovascular disease mortality than those with eGFR of >=90 mL/minute/1.73 m2. Subjects with both proteinuria and eGFR of <45 mL/minute/1.73 m2 had a 4.05-fold (95% CI: 2.55, 6.43) higher risk of cardiovascular disease mortality compared with those with neither of these risk factors. There was no evidence of interaction in the relationship between proteinuria and lower eGFR (P(interaction) = 0.77). The present results suggest that proteinuria and lower eGFR are independent risk factors for cardiovascular disease mortality in the Japanese population. PMID- 23752920 TI - About this journal. PMID- 23752919 TI - Facile displacement of eta5-cyclopentadienyl ligands from half-sandwich alkyl,NHC nickel complexes: an original route to robust cis-C,C-nickel square planar complexes. AB - The eta(5)-cyclopentadienyl (Cp) ligands of 18-electron half-sandwich alkyl,NHC nickel complexes are readily displaced under acidic conditions to afford a novel class of cis-C,C-nickel square planar complexes. Remarkably, the nickel-alkyl and nickel-carbene bonds are not ruptured in these unprecedented Cp acidolysis reactions. PMID- 23752918 TI - Hypospadias and maternal intake of phytoestrogens. AB - Experimental data indicate that gestational exposures to estrogenic compounds impact risk of hypospadias. We examined whether risk of hypospadias (i.e., a congenital malformation in which the opening of the penile urethra occurs on the ventral side of the penis) was associated with maternal intake of phytoestrogens, given their potential impact on estrogen metabolism. The analysis included data on mothers of 1,250 hypospadias cases and 3,118 controls who delivered their infants from 1997 to 2005 and participated in the National Birth Defects Prevention Study, a multistate, population-based, case-control study. After adjustment for several covariates, high intakes of daidzein, genistein, glycetin, secoisolariciresinol, total isoflavones, total lignans, and total phytoestrogens were associated with reduced risks; odds ratios comparing intakes >=90th percentile with intakes between the 11th and 89th percentiles ranged from 0.6 to 0.8. For example, the odds ratio for total phytoestrogen intake was 0.7 (95% confidence interval: 0.5, 1.0). This study represents the first large-scale analysis of phytoestrogen intake and hypospadias. The observed associations merit investigation in additional populations before firm conclusions can be reached. PMID- 23752921 TI - Risk factors for young-onset advanced colorectal cancer-reply. PMID- 23752922 TI - Dermatology simplified. PMID- 23752923 TI - N-Triethylene glycol (N-TEG) as a surrogate for the N-methyl group: application to Sansalvamide A peptide analogs. AB - Here we studied the N-triethylene glycol (N-TEG) group as a surrogate for the N Me group in Sansalvamide A peptide. The five N-TEG and N-Me analogs of this cyclic pentapeptide were synthesized, and their biological activity, lipophilicity and conformational features were compared. PMID- 23752924 TI - Single molecule recordings of lysozyme activity. AB - Single molecule bioelectronic circuits provide an opportunity to study chemical kinetics and kinetic variability with bond-by-bond resolution. To demonstrate this approach, we examined the catalytic activity of T4 lysozyme processing peptidoglycan substrates. Monitoring a single lysozyme molecule through changes in a circuit's conductance helped elucidate unexplored and previously invisible aspects of lysozyme's catalytic mechanism and demonstrated lysozyme to be a processive enzyme governed by 9 independent time constants. The variation of each time constant with pH or substrate crosslinking provided different insights into catalytic activity and dynamic disorder. Overall, ten lysozyme variants were synthesized and tested in single molecule circuits to dissect the transduction of chemical activity into electronic signals. Measurements show that a single amino acid with the appropriate properties is sufficient for good signal generation, proving that the single molecule circuit technique can be easily extended to other proteins. PMID- 23752925 TI - ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages. AB - Differentiation to different types of macrophages determines their distinct functions. Tumor-associated macrophages (TAMs) promote tumorigenesis owing to their proangiogenic and immune-suppressive functions similar to those of alternatively activated (M2) macrophages. We report that reactive oxygen species (ROS) production is critical for macrophage differentiation and that inhibition of superoxide (O(2-)) production specifically blocks the differentiation of M2 macrophages. We found that when monocytes are triggered to differentiate, O(2-) is generated and is needed for the biphasic ERK activation, which is critical for macrophage differentiation. We demonstrated that ROS elimination by butylated hydroxyanisole (BHA) and other ROS inhibitors blocks macrophage differentiation. However, the inhibitory effect of ROS elimination on macrophage differentiation is overcome when cells are polarized to classically activated (M1), but not M2, macrophages. More importantly, the continuous administration of the ROS inhibitor BHA efficiently blocked the occurrence of TAMs and markedly suppressed tumorigenesis in mouse cancer models. Targeting TAMs by blocking ROS can be a potentially effective method for cancer treatment. PMID- 23752926 TI - Structure of the Ca2+-dependent PP2A heterotrimer and insights into Cdc6 dephosphorylation. AB - The B"/PR72 family of protein phosphatase 2A (PP2A) is an important PP2A family involved in diverse cellular processes, and uniquely regulated by calcium binding to the regulatory subunit. The PR70 subunit in this family interacts with cell division control 6 (Cdc6), a cell cycle regulator important for control of DNA replication. Here, we report crystal structures of the isolated PR72 and the trimeric PR70 holoenzyme at a resolution of 2.1 and 2.4 A, respectively, and in vitro characterization of Cdc6 dephosphorylation. The holoenzyme structure reveals that one of the PR70 calcium-binding motifs directly contacts the scaffold subunit, resulting in the most compact scaffold subunit conformation among all PP2A holoenzymes. PR70 also binds distinctively to the catalytic subunit near the active site, which is required for PR70 to enhance phosphatase activity toward Cdc6. Our studies provide a structural basis for unique regulation of B"/PR72 holoenzymes by calcium ions, and suggest the mechanisms for precise control of substrate specificity among PP2A holoenzymes. PMID- 23752927 TI - ALDH2, a novel protector against stroke? AB - In a recent paper published in Cell Research, an association between expression of mitochondrial aldehyde dehydrogenase (ALDH2), a mitochondrial chaperon expressed in the brain, and the prevalence of stroke is revealed. This finding indicates that ALDH2 may serve as a potential endogenous neuroprotective target and a promising therapeutic strategy for the management of stroke. PMID- 23752930 TI - Copper-catalyzed oxidative condensation of alpha-oxocarboxylic acids with formamides: synthesis of alpha-ketoamides. AB - A copper-catalyzed coupling of alpha-oxocarboxylic acids with formamides is reported. This simple method provides a practical approach toward the synthesis of alpha-ketoamides with a variety of functional groups. Mechanistic studies have shown that the reaction proceeded via a radical process and (13)C-labeled experiments proved that the amide carbon in the products comes from the corresponding carboxylic acid, not from the DMF. PMID- 23752931 TI - Numerous white papules on the vulva-diagnosis. PMID- 23752936 TI - To Sleep or Not To Sleep: Do We Forget Our Patient's Sleep?-Reply. PMID- 23752935 TI - Murder by fungus: the plot to assassinate fidel castro with madura foot. PMID- 23752937 TI - Highlights of archives of facial plastic surgery. PMID- 23752938 TI - Why physicians order tests. PMID- 23752940 TI - Error in Signature Block in: The JAMA Network Journals: New Names for the Archives Journals. PMID- 23752939 TI - Superimposed topographic and chemical cues synergistically guide neurite outgrowth. AB - Guidance of neuronal extensions is a complex process essential for linking neurons into complex functional networks underlying the workings of the neural system. Decades of research have suggested the ability of neuronal growth cones to integrate multiple types of cues during the extension process, but also have raised numerous still unanswered questions about synergy or antagonism between the superimposed chemical and mechanical signaling inputs. In this study, using a novel microfabricated analysis platform, we investigate the response of primary mouse embryonic hippocampal neurons to superimposed topographic and soluble chemical cues. We find that an optimal spatial frequency of topographic cues exists, maximizing the precision of the neurite extension. This optimal frequency can help the extending neurites navigate a topographically complex environment, providing pronounced directional selectivity. We also demonstrate that this cue can synergistically enhance attractive and suppress repulsive guidance by the bi functional soluble cue Netrin-1, and eliminate the repulsive guidance by a chemorepellent Semaphorin3A (Sema3A). These results suggest that topographic cues can provide optimal periodic input into the guidance signaling processes involved in growth cone chemoattraction and can synergistically interact with chemical gradients of soluble guidance cues, shedding light on complex events accompanying the development of the functional nervous system. PMID- 23752941 TI - Imaging: Bone erosions in rheumatoid arthritis: better to see more? PMID- 23752942 TI - Connective tissue diseases: Epigenetic silencing of Wnt inhibition in systemic sclerosis. PMID- 23752944 TI - Towards longer-lived metal-to-ligand charge transfer states of iron(II) complexes: an N-heterocyclic carbene approach. AB - A 9 ps (3)MLCT lifetime was achieved by a Fe(II) complex based on C(NHC)^N(py)^C(NHC) pincer ligands. This is the longest known so far for any kind of complexes of this abundant metal, and increased by almost two orders of magnitude compared to the reference Fe(II) bis-terpyridine complex. PMID- 23752947 TI - About this journal. PMID- 23752948 TI - Study findings hard to interpret-reply. PMID- 23752950 TI - Omissions in Acknowledgments in: Clonal T-Cell Receptor gamma-Chain Gene Rearrangements in Differential Diagnosis of Lymphomatoid Papulosis From Skin Metastasis of Nodal Anaplastic Large-Cell Lymphoma. PMID- 23752949 TI - F-doped VO2 nanoparticles for thermochromic energy-saving foils with modified color and enhanced solar-heat shielding ability. AB - F-doped VO2 (M1) nanoparticles were prepared via one-pot hydrothermal synthesis. The F-doping can minimise the size of the VO2 (M1) nanoparticles, induce a homogeneous size distribution and effectively decrease the phase transition temperature to 35 degrees C at 2.93% F in VO2. VO2 smart glass foils obtained by casting these nanoparticles exhibit excellent thermochromism in the near-infrared region, which suggests that these foils can be used for energy-efficient glass. Compared to a pure VO2 foil, the 2.93% F-doped VO2 foil exhibits an increased solar-heat shielding ability (35.1%) and a modified comfortable colour, while still retaining an excellent solar modulation ability (10.7%) and an appropriate visible transmittance (48.7%). The F-doped VO2 foils are the first to simultaneously meet the requirements of a reduced phase transition temperature, diluted colour and excellent thermochromic properties, and these properties make the further improved F-doped VO2 foils suitable for commercial applications in energy efficient glass. PMID- 23752952 TI - Long-term Nasal Plaque With Nasal Obstruction-Diagnosis. PMID- 23752953 TI - An efficient chemical synthesis of carboxylate-isostere analogs of daptomycin. AB - Herein we report a direct and efficient method for the synthesis of four new carboxylate-isostere analogs of daptomycin. The side chain carboxylic acid moieties of the aspartic acids (Asp-3, Asp-7 and Asp-9) and beta-methyl glutamic acid (MeGlu-12) were all converted into the corresponding carboxylate isosteres using direct synthetic procedures. The present study also describes an esterification protocol to overcome the possible backbone cyclization of the activated side chain carboxylic acid group of either Asp or Glu onto the backbone amide. PMID- 23752956 TI - About this journal. PMID- 23752955 TI - Transtibial versus anteromedial portal technique in single-bundle anterior cruciate ligament reconstruction: outcomes of knee joint kinematics during walking. AB - BACKGROUND: In anterior cruciate ligament (ACL) reconstruction, the transtibial (TT) technique often creates a nonanatomically placed femoral tunnel, which is a frequent cause of surgical failure and postsurgical knee instability. Several studies reported that drilling the femoral tunnel through an anteromedial portal (AMP) yields a more anatomic tunnel position compared with the TT technique. PURPOSE: To compare the effectiveness of these two surgical techniques in restoring the intact knee joint kinematics during a physiological loading situation. STUDY DESIGN: Controlled laboratory study. METHODS: Twenty-four patients (TT, n = 12; AMP, n = 12; sex, weight, and height matched, and half with dominant leg involved) who underwent unilateral single-bundle ACL reconstruction by the same surgeon were recruited. Twenty healthy patients with no history of lower limb injuries were recruited as the control group. Tibiofemoral joint motion in 6 degrees of freedom (3 translations and 3 rotations) was determined during level walking by using a least mean square-based optimization algorithm. A redundant marker set was used to improve the accuracy of the motion analysis. Knee joint kinematics as well as spatiotemporal parameters were compared between these two techniques. RESULTS: The AMP technique restored the anterior-posterior translation of the knee joint, while the TT technique resulted in significantly greater (TT, 22.2 mm vs controls, 13.2 mm; P < .01) anterior femoral translations than in the healthy controls during the swing phase. Excessive femoral external (tibial internal) rotation (3.8 degrees ; P < .05) was found at midstance in the knees that were reconstructed using the TT technique; using the AMP technique, the external rotation offset was greatly reduced during the stance phase. However, knees repaired using the AMP technique were significantly less extended (5 degrees ; P < .05) compared with the knees of the controls during the late stance phase. Neither surgical technique restored the superior-inferior femoral translation to the intact level during the swing phase. CONCLUSION: The AMP technique better restores the anterior-posterior translation during the swing phase and femoral external rotation at midstance than the TT technique does. However, the AMP technique is also correlated with an extension loss during the late stance phase. CLINICAL RELEVANCE: The AMP femoral tunnel drilling technique can improve overall knee joint stability, but the increased difficulty with full extension may need to be considered. PMID- 23752957 TI - Ustekinumab for pyoderma gangrenosum-reply. PMID- 23752962 TI - Noncommunicable diseases in developing countries: focus on research capacity building. PMID- 23752963 TI - Noncommunicable diseases in developing countries: focus on research capacity building--reply. PMID- 23752964 TI - Regarding "time to rethink screening for abdominal aortic aneurysm?". PMID- 23752965 TI - Regarding "time to rethink screening for abdominal aortic aneurysm?"--reply. PMID- 23752966 TI - End-of-round time compression in physician handoff sessions. PMID- 23752967 TI - End-of-round time compression in physician handoff sessions--reply. PMID- 23752968 TI - Comment regarding the stability of active ingredients in long-expired prescription medications. PMID- 23752969 TI - Comment regarding the stability of active ingredients in long-expired prescription medications--reply. PMID- 23752970 TI - The ability of a retrospective review of electronic health records to fully capture the frequency of supratherapeutic dosing of acetaminophen. PMID- 23752971 TI - The ability of a retrospective review of electronic health records to fully capture the frequency of supratherapeutic dosing of acetaminophen--reply. PMID- 23752972 TI - Additional considerations to precede selection of enoxaparin therapy. PMID- 23752973 TI - Additional considerations to precede selection of enoxaparin therapy--reply. PMID- 23752974 TI - Potential safety signals and their significance-reply. PMID- 23752975 TI - Role of macrophage-derived hypoxia-inducible factor (HIF)-1alpha as a mediator of vascular remodelling. AB - AIMS: Excessive vascular remodelling leads to progression of a wide range of vasculopathies, and the immune response to intimal injuries is crucial in this process. This vascular remodelling occurs in the hypoxic microenvironment and is closely related to the immune system. Macrophages play a key role in immunological-cell-mediated arterial remodelling. In this study, we clarified the role of macrophage-derived hypoxia-inducible factor (HIF-1alpha) in vascular remodelling. METHODS AND RESULTS: Wire-induced femoral arterial injury was inflicted in mice lacking the macrophage-specific HIF-1alpha gene and in their wild-type counterparts. The mutant mice showed both suppressed wire-induced neointimal thickening and decreased infiltration of inflammatory cells in the adventitia, compared with wild-type mice. Studies to clarify the mechanism of restrained vascular remodelling in the mutant mice revealed decreased production of pro-inflammatory cytokines by the activated macrophages and suppressed macrophage migration activity in the mutant mice. Gene expressions of the HIF 1alpha-deficient macrophages positively correlated with the phenotypic profile of M2 macrophages and negatively correlated with that of M1 macrophages. CONCLUSION: Our results show that HIF-1alpha in macrophages plays a crucial role in promoting vascular inflammation and remodelling. As decreasing HIF-1alpha activity in macrophages may prevent the progression of vascular remodelling, HIF-1alpha may be a possible therapeutic target in vascular diseases. PMID- 23752977 TI - Effects of peroxisome proliferator-activated receptor-beta activation in endothelin-dependent hypertension. AB - AIMS: We analysed the chronic effects of the peroxisome proliferator-activated receptor beta/delta (PPAR-beta) agonist GW0742 on the renin-independent hypertension induced by deoxycorticosterone acetate (DOCA)-salt. METHODS AND RESULTS: Rats were treated for 5 weeks with: control-vehicle, control-GW0742 (5 or 20 mg kg(-1) day(-1)), DOCA-vehicle, DOCA-GW0742 (5 or 20 mg kg(-1) day(-1)), DOCA-GSK0660 (1 mg kg(-1) day(-1)), and DOCA-GSK0660-GW0742. Rats receiving DOCA vehicle showed increased systolic blood pressure, left ventricular and kidney weight indices, endothelin-1 (ET-1), and malondialdehyde plasma levels, urinary iso-PGF2alpha excretion, impaired endothelium-dependent relaxation to acetylcholine, and contraction to ET-1 when compared with controls. Aortic reactive oxygen species content, NADPH oxidase activity, and p47(phox), p22(phox), NOX-4, glutathione peroxidase 1, hemeoxygenase-1, and preproET-1 expression were increased, whereas catalase and regulators of G protein-coupled signalling proteins (RGS)5 expression were decreased in the DOCA-vehicle group. GW0742 prevented the development of hypertension in a dose-dependent manner but the reduction of renal and cardiac hypertrophy, systemic and vascular oxidative stress markers, and improvement of endothelial dysfunction were only observed after the higher dose. GW0742, at 20 mg kg(-1) day(-1), attenuated ET-1 contraction by increasing RGS5 expression and restored the intracellular redox balance by reducing NADPH-oxidase activity, and by increasing the antioxidant genes expression. The PPAR-beta antagonist GSK0660 prevented all vascular changes induced by GW0742 but not its antihypertensive effects. CONCLUSION: Vascular protective effects of GW0742 operate via PPAR-beta by interference with the ET-1 signalling as a result of increased expression of RGS5 and up-regulation of antioxidant genes and via PPAR-beta-independent mechanisms to decrease blood pressure. PMID- 23752979 TI - Double rainbow, Voss, Norway. PMID- 23752978 TI - A frequency reconfigurable antenna based on digital microfluidics. AB - We present a novel antenna reconfiguration mechanism relying on electrowetting based digital microfluidics to implement a frequency reconfigurable antenna operating in the X-band. The antenna built on a quartz substrate (epsilonr = 3.9, tan delta = 0.0002) is a coplanar waveguide fed annular slot antenna, which is monolithically integrated with a microfluidic chip. This chip establishes an electrowetting on dielectric platform with a mercury droplet placed in it. The base contact area of the mercury droplet can be spread out by electrostatic actuation resulting in a change of loading capacitance. This in turn changes the resonant frequency of the antenna enabling a reversible reconfigurable impedance property. This reconfigurable antenna has been designed, fabricated and measured. The frequency of operation is tuned from around 11 GHz to 13 GHz as demonstrated by simulations and measurements. The design methodology, fabrication processes and the experimental results are given and discussed. PMID- 23752981 TI - Rhazes in the renaissance of Andreas Vesalius. AB - Andreas Vesalius' (1514-64) first publication was a Paraphrasis of the ninth book of the Liber ad Almansorem, written by the Arab-Persian physician and alchemist Rhazes (854-925). The role of Rhazes in Vesalius' oeuvre has thus far been much disregarded. The different ways Rhazes recurs reveal an intellectual evolution in Vesalius' work. In the Paraphrasis, Vesalius subjects Rhazes to the authority of Galen in the context of the early sixteenth-century humanist campaign for the substitution of Arab influences by Greek 'originals'. Over the years Vesalius continues his work on Rhazes, but his approach becomes more internationalistic. Ultimately, Vesalius criticises Galen while expressing sympathy for the Arab author. This may be the more significant as Rhazes could have influenced Vesalius in the act of criticising Galen - critical discussions of Galen were available to Vesalius in Latin translations of Rhazes's Liber Continens. Although Vesalius never refers to the work, it is hardly possible he was unaware of it: similarities in structure, rhetoric and form between the Continens and the De humani corporis fabrica could support this hypothesis. PMID- 23752976 TI - The arrhythmogenic consequences of increasing late INa in the cardiomyocyte. AB - This review presents the roles of cardiac sodium channel NaV1.5 late current (late INa) in generation of arrhythmic activity. The assumption of the authors is that proper Na(+) channel function is necessary to the maintenance of the transmembrane electrochemical gradient of Na(+) and regulation of cardiac electrical activity. Myocyte Na(+) channels' openings during the brief action potential upstroke contribute to peak INa and initiate excitation-contraction coupling. Openings of Na(+) channels outside the upstroke contribute to late INa, a depolarizing current that persists throughout the action potential plateau. The small, physiological late INa does not appear to be critical for normal electrical or contractile function in the heart. Late INa does, however, reduce the net repolarizing current, prolongs action potential duration, and increases cellular Na(+) loading. An increase of late INa, due to acquired conditions (e.g. heart failure) or inherited Na(+) channelopathies, facilitates the formation of early and delayed afterpolarizations and triggered arrhythmias, spontaneous diastolic depolarization, and cellular Ca(2+) loading. These in turn increase the spatial and temporal dispersion of repolarization time and may lead to reentrant arrhythmias. PMID- 23752982 TI - 'By merit raised to that bad eminence': Christopher Merrett, artisanal knowledge, and professional reform in restoration London. AB - This article examines the career and reform agenda of Christopher Merrett as a means of evaluating the changing conditions of medical knowledge production in late seventeenth-century London. This period was characterised by increasing competition between medical practitioners, resulting from the growing consumer demand for medical commodities and services, the reduced ability of elite physicians to control medical practice, and the appearance of alternative methods of producing medical knowledge - particularly experimental methods. This competition resulted in heated exchanges between physicians, apothecaries, and virtuosi, in which Merrett played an active part. As a prominent member of both the Royal Society and the Royal College of Physicians, Merrett sought to mediate between the two institutions by introducing professional reforms designed to alleviate competition and improve medical knowledge.These reforms entailed sweeping changes to medical regulation and education that integrated the traditional reliance on Galenic principles with knowledge derived from experiment and artisanal practices. The emphasis Merrett placed on the trades suggests the important role artisanal knowledge played in his efforts to reorganise medicine and improve knowledge of bodily processes. PMID- 23752983 TI - Explaining local authority choices on public hospital provision in the 1930s: a public policy hypothesis. AB - This article summarises the findings of recent work on local authority public hospital services in England and Wales in the inter-war years and identifies the lack of a robust hypothesis to explain the variations found, particularly one that would explain the actions of county councils as well as county boroughs. Using public policy techniques on a group of local authorities in the far South West it proposes that variations can be explained by an understanding of the deep core beliefs of councillors, their previous experience of 'commissioner' and 'provider' roles, and the availability or otherwise of a dedicated policy entrepreneur to promote change. PMID- 23752988 TI - About this journal. PMID- 23752984 TI - Showers, sweating and suing: Legionnaires' disease and 'new' infections in Britain, 1977-90. AB - Legionnaires' disease is now routinely discussed as an 'emerging infectious disease' (EID) and is said to be one of the earliest such diseases to be recognised. It first appeared in 1976 and its cause was identified in 1977, the same year that Ebola fever, Hantaan virus and Campylobacter jejuni arrived. The designation of Legionnaires' disease as an EID was retrospective; it was not and could not be otherwise as the category only gained currency in the early 1990s. In this article we reflect on the changing medical understanding and social profile of Legionnaires' disease in the decade or so from its recognition to the creation of EIDs, especially its ambivalent position between public health and clinical medicine. However, we question any simple opposition, between public health experts who approached Legionnaires' disease as a new and worrying environmental threat that could be prevented, and clinicians who saw it as another cause of pneumonia that could be managed by improved diagnosis and treatment. We argue that in the British context of public spending cuts and the reform of public health, the category of 'new' diseases, in which Legionnaires' disease was central, was mobilised ahead of the EID lobby of the early 1990s, by interested groups in medicine to defend infectious diseases services. PMID- 23752991 TI - Bladder cancer: second-line nab-paclitaxel for advanced urothelial carcinoma. PMID- 23752992 TI - Prostate cancer: lymph node metastases: not always the same prognosis. PMID- 23752996 TI - Infection: formalin needle disinfection reduces sepsis risk of prostate biopsy. PMID- 23752998 TI - Lonely hair sign: not specific for frontal fibrosing alopecia-reply. PMID- 23752995 TI - Ex vivo culture of human prostate tissue and drug development. AB - Although an array of new therapeutics exist for prostate cancer, the development of agents that can improve outcomes for men with prostate cancer remains inefficient, costly, and frustratingly slow. A major impediment to the clinical translation of research findings is the lack of preclinical models that can accurately predict the clinical efficacy of new drugs and, therefore, enable the selection of agents that are most suitable for clinical trials. An approach that is gaining popularity in the prostate cancer community is ex vivo culture of primary human tissues, which retains the native tissue architecture, hormone responsiveness, and cell-to-cell signalling of the tumour microenvironment in a dynamic and manipulable state. Ex vivo culture systems recapitulate the structural complexity and heterogeneity of human prostate cancers in a laboratory setting, making them an important adjunct to current cell-line-based and animal based models. When incorporated into preclinical studies, ex vivo cultured tissues enable robust quantitative evaluation of clinically relevant end points representing drug efficacy, investigation of therapy resistance, and biomarker discovery. By providing new clinically relevant insights into prostate carcinogenesis, it is likely that ex vivo culture will enhance drug development programmes and improve the translational 'hit rate' for prostate cancer research. PMID- 23753000 TI - Germanium-tin alloy nanocrystals for high-performance lithium ion batteries. AB - Germanium-tin (Ge(1-x)Sn(x)) alloy nanocrystals were synthesized using a gas phase laser photolysis reaction of tetramethyl germanium and tetramethyl tin. A composition tuning was achieved using the partial pressure of precursors in a closed reactor. For x < 0.1, cubic phase alloy nanocrystals were exclusively produced without separation of the tetragonal phase Sn metal. In the range of x = 0.1-0.4, unique Ge(1-x)Sn(x)-Sn alloy-metal hetero-junction nanocrystals were synthesized, where the Sn metal domain becomes dominant with x. Thin graphitic carbon layers usually sheathed the nanocrystals. We investigated the composition dependent electrochemical properties of these nanocrystals as anode materials of lithium ion batteries. Incorporation of Sn (x = 0.05) significantly increased the capacities (1010 mA h g(-1) after 50 cycles) and rate capabilities, which promises excellent electrode materials for the development of high-performance lithium batteries. PMID- 23753002 TI - Novel amino acids: synthesis of furoxan and sydnonimine containing amino acids and peptides as potential nitric oxide releasing motifs. AB - The incorporation of furoxan and sydnonimine ring systems into amino acid side chains is demonstrated with the preparation of four novel amino acids which carry these nitric oxide-releasing motifs. N-((4-Nitrophenoxy)carbonyl)-3 phenylsydnonimine 9 and bis(phenylsulfonyl)furoxan 10 are the key intermediates for introducing the heterocycle side chains onto appropriate amine and alcohol functionalities respectively. Furoxan 5 and 7 both displayed NO release based on determination of nitrite production. Orthogonal amino acid protecting group strategies were deployed to demonstrate that the amino acids could be incorporated into peptide frameworks. By way of demonstration the amino acids were placed centrally into several tripeptide motifs. Griess test assays showed that these amino acids released NO in the presence of gamma-glutathione (GST). PMID- 23753004 TI - Beauty tips from ancient queens. PMID- 23753006 TI - Photodecomposition of dichloromethane catalyzed by tetrachloroferrate(III) supported on a Dowex anion exchange resin. AB - The FeCl4(-) ion, heterogenized on a Dowex ion exchange resin, catalyzes the aerobic photodecomposition of neat CH2Cl2. Phosgene production was used to characterize the extent of decomposition, although it appears to be a secondary product from the decomposition of chloroform, which is suggested to arise from the reaction of dichloromethanol with hydrogen chloride. The yield of CHCl3 increases when the production of phosgene is suppressed by water or acetonitrile. CuCl4(2-), likewise heterogenized on Dowex, is photocatalytically inactive. PMID- 23753008 TI - Charge and energy transfer in a bithiophene perylenediimide based donor-acceptor donor system for use in organic photovoltaics. AB - The elementary charge and excitation energy transfer steps in a novel symmetric donor-acceptor-donor triad first described in Roland et al. Phys. Chem. Chem. Phys., 2012, 14, 273, consisting of a central perylenediimide moiety as a potential electron acceptor and two identical electron rich bithiophene compounds, have been investigated using quantum chemical methodology. These elementary processes determine the applicability of such systems in photovoltaic devices. The molecular structure, excited states and the photo-physical properties are investigated using smaller model systems and including solvation effects. The donor and acceptor pi-systems are separated by an ethyl bridge such that the molecular orbitals are either located on the donor or acceptor moiety making the identification of locally excited versus charge transfer states straightforward. Using excited state geometry optimizations, the mechanism of photo-initiated charge separation could be identified. Geometry relaxation in the excited donor state leads to a near-degeneracy with the locally excited acceptor state, entailing strong excitonic coupling and resonance energy transfer. This energy transfer process is driven by planarization and bond length alternation of the donor molecule. Geometry relaxation of the locally excited acceptor state in turn reveals a crossing with the energetically lowest charge transfer excited state. The energetic position of the latter depends in a sensitive fashion on the solvent. This provides an explanation of the sequential process observed in the experiment, favoring ultrafast (~130 fs) formation of the excited acceptor state followed by slower (~3 ps scale) formation of the charge separated state. PMID- 23753009 TI - Taj Mumbai: site of India's 9/11. PMID- 23753014 TI - Facial aesthetics: concepts & clinical diagnosis. PMID- 23753015 TI - A low sample volume particle separation device with electrokinetic pumping based on circular travelling-wave electroosmosis. AB - Particle separation is a crucial step in sample preparation processes. The preparation of low volume samples is especially important for clinical diagnosis and chemical analysis. The advantages of microfluidic techniques have lead them to become potential candidates for particle separation. However, existing microfluidic devices require external pumping sources and extensive geometric patterns to attain high separation efficiency, which is disadvantageous when handling low volume samples. This paper presents a low sample volume particle separation microfluidic device with low voltage electrokinetic pumping based on circular travelling-wave electroosmosis (TWEO). Computational numerical software was utilized to simulate two electrokinetic mechanisms: circular TWEO and dielectrophoresis (DEP). The circular TWEO shear flow generates a velocity gradient in the radial direction which causes a shear stress-induced force to drag particles into the center region of the device. In contrast, the non parallel electrodes induce negative DEP forces which push polystyrene beads towards the peripheral regions; the magnitude of the DEP forces are dependent on the sizes of the polystyrene beads. We used particles of various sizes to experimentally prove the concept of particle separation. Our experiments show that 15 MUm beads are dragged into the center region due to the shear stress induced force, and 1 MUm beads move towards the outer region because of the large negative DEP force. The results show a separation purity of 94.4% and 80.0% for 15 MUm and 1 MUm beads respectively. We further demonstrated particle isolation from a sample of containing a small proportion of 6 MUm beads mixed with 1 MUm beads at a concentration ratio of 1 : 300. Therefore, the innovative device developed in this paper provides a promising solution to allow particle separation in sample volumes as low as 50 nL. PMID- 23753016 TI - Photonic crystal fibres for chemical sensing and photochemistry. AB - In this review, we introduce photonic crystal fibre as a novel optofluidic microdevice that can be employed as both a versatile chemical sensor and a highly efficient microreactor. We demonstrate that it provides an excellent platform in which light and chemical samples can strongly interact for quantitative spectroscopic analysis or photoactivation purposes. The use of photonic crystal fibre in photochemistry and sensing is discussed and recent results on gas and liquid sensing as well as on photochemical and catalytic reactions are reviewed. These developments demonstrate that the tight light confinement, enhanced light matter interaction and reduced sample volume offered by photonic crystal fibre make it useful in a wide range of chemical applications. PMID- 23753018 TI - The hailstone spots of crazy horse. PMID- 23753017 TI - A highly porous PVA dried gel with gold nanoparticles embedded in the network as a stable and ultrasensitive SERS substrate. AB - We confirmed that the porous PVA dried gel with GNPs embedded in the network, which can be prepared very conveniently, is a stable and ultrasensitive 3D SERS substrate. The existence of the micropores within the gel is necessary for the ultrahigh sensitivity, and embedding of GNPs in the penetrable gel results in high stability. PMID- 23753020 TI - Common variable immunodeficiency and idiopathic primary hypogammaglobulinemia: two different conditions within the same disease spectrum. AB - Patients with hypogammaglobulinemia who do not fulfill all the classical diagnostic criteria for common variable immunodeficiency (reduction of two immunoglobulin isotypes and a reduced response to vaccination) constitute a diagnostic and therapeutic dilemma, because information concerning the clinical and immunological characteristics of these patients with idiopathic primary hypogammaglobulinemia is not available. In 44 common variable immunodeficiency and 21 idiopathic primary hypogammaglobulinemia patients we determined the clinical phenotypes and performed flow cytometric immunophenotyping to assess the pathophysiological B-cell patterns and memory B-cell subset counts. Age-matched B cell subset reference values of 130 healthy donors were generated. Severe pneumonia and bronchiectasis occurred at similar frequencies in idiopathic primary hypogammaglobulinemia and common variable immunodeficiency. Although IgG levels were only moderately reduced compared to common variable immunodeficiency, 12 of 21 idiopathic primary hypogammaglobulinemia patients required immunoglobulin replacement. Non-infectious disease-related clinical phenotypes (autoimmune cytopenia, polyclonal lymphocytic proliferation and persistent unexplained enteropathy) were exclusively observed in common variable immunodeficiency and were associated with early peripheral B-cell maturation defects or B-cell survival defects. T-cell dependent memory B-cell formation was more severely affected in common variable immunodeficiency. Furthermore, 14 of 21 idiopathic primary hypogammaglobulinemia patients showed normal peripheral B-cell subset counts, suggestive for a plasma cell defect. In conclusion, idiopathic primary hypogammaglobulinemia patients who do not fulfill all diagnostic criteria of common variable immunodeficiency have moderately decreased immunoglobulin levels and often a normal peripheral B-cell subset distribution, but still suffer from serious infectious complications. PMID- 23753022 TI - Omacetaxine mepesuccinate for patients with accelerated phase chronic myeloid leukemia with resistance or intolerance to two or more tyrosine kinase inhibitors. PMID- 23753021 TI - First-line treatment with rituximab-hyperCVAD alternating with rituximab methotrexate-cytarabine and followed by consolidation with 90Y-ibritumomab tiuxetan in patients with mantle cell lymphoma. Results of a multicenter, phase 2 pilot trial from the GELTAMO group. AB - The prognosis for fit patients with mantle cell lymphoma has improved with intensive strategies. Currently, the role of maintenance/consolidation approaches is being tested as relapses continue to appear. In this trial we evaluated the feasibility, safety and efficacy of rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine followed by consolidation with (90)Y ibritumomab tiuxetan. Patients received six cycles followed by a single dose of (90)Y-ibritumomab tiuxetan. Thirty patients were enrolled; their median age was 59 years. Twenty-four patients finished the induction treatment, 23 achieved complete remission (77%, 95% confidence interval 60-93) and one patient had progressive disease (3%). Eighteen patients (60%), all in complete remission, received consolidation therapy. In the intent-to-treat population, failure-free, progression-free and overall survival rates at 4 years were 40% (95% confidence interval 20.4-59.6), 52% (95% confidence interval 32.4-71.6) and 81% (95% confidence interval 67.28-94.72), respectively. For patients who received consolidation, failure-free and overall survival rates were 55% (95% confidence interval 31.48-78.52) and 87% (95% confidence interval 70-100), respectively. Hematologic toxicity was significant during induction and responsible for one death (3.3%). After consolidation, grade 3-4 neutropenia and thrombocytopenia were observed in 72% and 83% of patients, with a median duration of 5 and 12 weeks, respectively. Six (20%) patients died, three due to secondary malignancies (myelodysplastic syndrome and bladder and rectum carcinomas). In conclusion, in our experience, rituximab-hyperCVAD alternated with rituximab-methotrexate cytarabine and followed by consolidation with (90)Y-ibritumomab tiuxetan was efficacious although less feasible than expected. The unacceptable toxicity observed, especially secondary malignancies, advise against the use of this strategy. TRIAL REGISTRATION: clinical.gov identifier: NCT2005-004400-37. PMID- 23753023 TI - Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells. AB - This study investigated Polo-like kinase 1, a mitotic regulator often over expressed in solid tumors and adult hematopoietic malignancies, as a potential new target in the treatment of pediatric acute lymphoblastic leukemia. Polo-like kinase 1 protein and Thr210 phosphorylation levels were higher in pediatric acute lymphoblastic leukemia (n=172) than in normal bone marrow mononuclear cells (n=10) (P<0.0001). High Polo-like kinase 1 protein phosphorylation, but not expression, was associated with a lower probability of event-free survival (P=0.042) and was a borderline significant prognostic factor (P=0.065) in a multivariate analysis including age and initial white blood cell count. Polo-like kinase 1 was necessary for leukemic cell survival, since short hairpin-mediated Polo-like kinase 1 knockdown in acute lymphoblastic leukemia cell lines inhibited cell proliferation by G2/M cell cycle arrest and induced apoptosis through caspase-3 and poly (ADP-ribose) polymerase cleavage. Primary patient cells with a high Polo-like kinase 1 protein expression were sensitive to the Polo-like kinase 1-specific inhibitor NMS-P937 in vitro, whereas cells with a low expression and normal bone marrow cells were resistant. This sensitivity was likely not caused by Polo-like kinase 1 mutations, since only one new mutation (Ser335Arg) was found by 454-sequencing of 38 pediatric acute lymphoblastic leukemia cases. This mutation did not affect Polo-like kinase 1 expression or NMS-P937 sensitivity. Together, these results indicate a pivotal role for Polo-like kinase 1 in pediatric acute lymphoblastic leukemia and show potential for Polo-like kinase 1 inhibiting drugs as an addition to current treatment strategies for cases expressing high Polo-like kinase 1 levels. PMID- 23753024 TI - The effect of Duffy antigen receptor for chemokines on severity in sickle cell disease. PMID- 23753025 TI - Pediatric Acute Lymphoblastic Leukemia: Efficacy and safety of recombinant E. coli-asparaginase in infants (less than one year of age) with acute lymphoblastic leukemia. AB - The pharmacokinetics, pharmacodynamics, efficacy and safety of a new recombinant E. coli-asparaginase preparation were evaluated in infants (<1 year of age) with de novo acute lymphoblastic leukemia. Twelve patients were treated according to the INTERFANT-06 protocol and received up to 10,000 U/m(2) recombinant asparaginase as intravenous infusions on days 15, 18, 22, 25, 29 and 33 of remission induction treatment. The asparaginase dose was individually adjusted by protocol to 67% of the calculated dose for infants <6 months, and to 75% of the calculated dose for infants aged 6-12 months. The trough serum asparaginase activities observed were above 20, 50, and 100 U/L in 86%, 71%, and 51% of measured samples, respectively. Looking only at the data assessed 3 days after asparaginase infusion these percentages were 91%, 84%, and 74%, respectively. Asparagine was completely depleted in serum in all but one patient who was the youngest in the study. No anti-asparaginase antibodies were detected during this treatment phase. Observed adverse reactions are known to be possible and are labeled side effects of asparaginase treatment and chemotherapy. We conclude that the asparaginase dose regimen used in infants is safe and provides complete asparagine depletion for the desired time period in nearly all patients. Measured asparaginase trough serum levels justify the higher doses used in infants compared to in older children and show that 3-day intervals are preferred over 4 day intervals. (This trial was registered at www.clinicaltrialsregister.eu as EudraCT number 2008-006300-27). PMID- 23753026 TI - Hyperfibrinolysis and acquired factor XIII deficiency in newly diagnosed pediatric malignancies. PMID- 23753027 TI - Platelet interaction with von Willebrand factor is enhanced by shear-induced clustering of glycoprotein Ibalpha. AB - Initial platelet arrest at the exposed arterial vessel wall is mediated through glycoprotein Ibalpha binding to the A1 domain of von Willebrand factor. This interaction occurs at sites of elevated shear force, and strengthens upon increasing hydrodynamic drag. The increased interaction requires shear-dependent exposure of the von Willebrand factor A1 domain, but the contribution of glycoprotein Ibalpha remains ill defined. We have previously found that glycoprotein Ibalpha forms clusters upon platelet cooling and hypothesized that such a property enhances the interaction with von Willebrand factor under physiological conditions. We analyzed the distribution of glycoprotein Ibalpha with Forster resonance energy transfer using time-gated fluorescence lifetime imaging microscopy. Perfusion at a shear rate of 1,600 s(-1) induced glycoprotein Ibalpha clusters on platelets adhered to von Willebrand factor, while clustering did not require von Willebrand factor contact at 10,000 s(-1). Shear-induced clustering was reversible, not accompanied by granule release or alphaIIbbeta3 activation and improved glycoprotein Ibalpha-dependent platelet interaction with von Willebrand factor. Clustering required glycoprotein Ibalpha translocation to lipid rafts and critically depended on arachidonic acid-mediated binding of 14-3 3zeta to its cytoplasmic tail. This newly identified mechanism emphasizes the ability of platelets to respond to mechanical force and provides new insights into how changes in hemodynamics influence arterial thrombus formation. PMID- 23753028 TI - Rituximab plus gemcitabine and oxaliplatin in patients with refractory/relapsed diffuse large B-cell lymphoma who are not candidates for high-dose therapy. A phase II Lymphoma Study Association trial. AB - A previous pilot study with rituximab, gemcitabine and oxaliplatin showed promising activity in patients with refractory/relapsed B-cell lymphoma. We, therefore, conducted a phase II study to determine whether these results could be reproduced in a multi-institutional setting. This phase II study included 49 patients with refractory (n=6) or relapsing (n=43) diffuse large B-cell lymphoma. The median age of the patients was 69 years. Prior treatment included rituximab in 31 (63%) and autologous transplantation in 17 (35%) patients. International Prognostic Index at enrollment was >2 in 34 patients (71%). The primary endpoint was overall response rate after four cycles of treatment. Patients were planned to receive eight cycles if they reached at least partial remission after four cycles. After four cycles 21 patients (44%) were in complete remission and 8 (17%) in partial remission, resulting in an overall response rate of 61%. Factors significantly affecting overall response rate were early (<1 year) progression/relapse (18% versus 54%; P=0.001) and prior exposure to rituximab (23% versus 65%; P=0.004). Five-year progression-free and overall survival rates were 12.8% and 13.9%, respectively. Rituximab, gemcitabine and oxaliplatin were well tolerated with grade 3-4 infectious episodes in 22% of the cycles. These results are the first confirmation from a multicenter study that rituximab, gemcitabine and oxaliplatin provide a consistent response rate in patients with refractory/relapsed diffuse large B-cell lymphoma. This therapy can now be considered as a platform for new combinations with targeted treatments. This trial was registered at clinicaltrial.gov under #NCT00169195. PMID- 23753029 TI - In rare acute myeloid leukemia patients harboring both RUNX1 and NPM1 mutations, RUNX1 mutations are unusual in structure and present in the germline. PMID- 23753031 TI - About this journal. PMID- 23753032 TI - Sunset, kona, hawaii. PMID- 23753033 TI - Infecting the electrocardiogram-discussion. PMID- 23753030 TI - High cure rates in Burkitt lymphoma and leukemia: a Northern Italy Leukemia Group study of the German short intensive rituximab-chemotherapy program. AB - We evaluate the long-term results of a prospective clinical study enrolling more than 100 adult patients with Burkitt lymphoma/leukemia. Depending on extent of disease, treatment consisted of six to eight rituximab infusions and four to six courses of intensive chemotherapy (attenuated in patients aged >55 years) with high-dose methotrexate, fractionated ifosfamide/cyclophosphamide, other drugs in rotation, and intrathecal chemoprophylaxis. One-hundred five patients were treated (median age 47 years, range 17-78 years); 48% had Burkitt leukemia, 25% were older than 60 years, 37% had an Eastern Cooperative Oncology Group performance score >1, and 14% were positive for human immunodeficiency virus. The complete response rate and 3-year overall and disease-free survival rates were 79%, 67% and 75%, respectively, ranging from 100% to 45% for survival (P=0.000) and from 100% to 60% for disease-free survival (P=0.01) in patients with low, intermediate and high adapted International Prognostic Index scores. In multivariate analysis, only age (<= versus >60 years) and performance status (0-1 versus >1) retained prognostic significance, identifying three risk groups with overall and disease-free survival probabilities of 88% and 87.5%, 57% and 70.5%, 20% and 28.5% (P=0.0000 and P=0.0001), respectively. The relapse rate was only 7% in patients treated with an intercycle interval <= 25 days. This regimen achieved 100% curability in patients with low adapted International Prognostic Index scores (21% of total), and very close to 90% in patients aged <= 60 years with performance score 0-1 (48% of total). Rapid diagnosis of Burkitt lymphoma/leukemia with prompt referral of patients to prevent clinical deterioration, and careful supervision of treatment without chemotherapy delay can achieve outstanding therapeutic results. ClinicalTrials.gov ID, NCT01290120. PMID- 23753038 TI - Thin and flexible solid-state organic ionic plastic crystal-polymer nanofibre composite electrolytes for device applications. AB - All solid-state organic ionic plastic crystal-polymer nanofibre composite electrolytes are described for the first time. The new composite materials exhibit enhanced conductivity, excellent thermal, mechanical and electrochemical stability and allow the production of optically transparent, free-standing, flexible, thin film electrolytes (10's MUms thick) for application in electrochemical devices. Stable cycling of a lithium cell incorporating the new composite electrolyte is demonstrated, including cycling at lower temperatures than previously possible with the pure material. PMID- 23753040 TI - A cohort study of metformin exposure and survival in patients with stage I-III colorectal cancer. AB - BACKGROUND: Preclinical evidence suggests a beneficial effect of metformin in colorectal cancer. This study aimed to investigate associations between metformin exposure and colorectal cancer-specific survival using population-level data. METHODS: Adult patients with stage I-III colorectal cancer diagnosed from 2001 to 2006 were identified from the National Cancer Registry Ireland. Use of metformin and other antidiabetic medications was determined from a linked national prescription claims database. Multivariate Cox regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for associations between prediagnostic metformin exposure (versus nonmetformin antidiabetic drugs) and colorectal cancer-specific mortality. Models were stratified by antidiabetic drug coprescription and intensity of metformin exposure. RESULTS: The cohort included 207 diabetics who received metformin, 108 diabetics not exposed to metformin, and 3,501 nondiabetic patients. In multivariate analyses, a nonsignificant reduction in colorectal cancer-specific mortality was observed for metformin-exposed patients relative to other treated diabetics (HR, 0.61; 95% CI, 0.37-1.01). In stratified analyses, no significant association was observed for patients receiving low-intensity metformin or metformin in combination with other antidiabetic drugs. High-intensity exclusive metformin use was associated with a significant reduction in colorectal cancer-specific mortality (HR, 0.44; 95% CI, 0.20-0.95). CONCLUSIONS: Significant associations between metformin exposure and colorectal cancer-specific mortality were observed only for high-intensity exclusive metformin use in the diabetic cohort. IMPACT: This study provides moderate evidence of an association between metformin exposure and improved colorectal cancer survival in a diabetic population. Additional studies in larger cohorts, with detailed information on diabetes severity, are required to confirm these results. PMID- 23753039 TI - Culturally targeted patient navigation for increasing african americans' adherence to screening colonoscopy: a randomized clinical trial. AB - BACKGROUND: Patient navigation has been an effective intervention to increase cancer screening rates. This study focuses on predicting outcomes of screening colonoscopy for colorectal cancer among African Americans using different patient navigation formats. METHODS: In a randomized clinical trial, patients more than 50 years of age without significant comorbidities were randomized into three navigation groups: peer-patient navigation (n = 181), pro-patient navigation (n = 123), and standard (n = 46). Pro-patient navigations were health care professionals who conducted culturally targeted navigation, whereas peer-patient navigations were community members trained in patient navigation who also discussed their personal experiences with screening colonoscopy. Two assessments gathered sociodemographic, medical, and intrapersonal information. RESULTS: Screening colonoscopy completion rate was 75.7% across all groups with no significant differences in completion between the three study arms. Annual income more than $10,000 was an independent predictor of screening colonoscopy adherence. Unexpectedly, low social influence also predicted screening colonoscopy completion. CONCLUSIONS: In an urban African American population, patient navigation was effective in increasing screening colonoscopy rates to 15% above the national average, regardless of patient navigation type or content. IMPACT: Because patient navigation successfully increases colonoscopy adherence, cultural targeting may not be necessary in some populations. PMID- 23753042 TI - The mischievous monkey in Uluwatu, Bali. PMID- 23753045 TI - Error in Signature Block in: The JAMA Network Journals: New Names for the Archives Journals. PMID- 23753047 TI - About this journal. PMID- 23753048 TI - Pencil-on-paper: electronic devices. AB - Paper based electronics have been rapidly growing in recent years. Drawing with a pencil on paper is perhaps the simplest and easiest way of establishing graphitic circuitry in a solvent-free manner, which in the post-graphene years, has attracted an unusual interest. Here in this focus article, we highlight the recent efforts in the literature employing pencil drawings in various ways including sensors, microfluidics, energy storage and microanalytical devices. Even active devices such as piezo and chemiresistive devices as well as field effect transistors have been realised by utilizing pencil-traces. Pencil-on-paper may offer a viable route for developing lab-on-paper applications through suitable integration of the passive and active roles of the pencil-trace. PMID- 23753051 TI - White swans. PMID- 23753055 TI - Lactobacilli vs Antibiotics to Prevent Recurrent Urinary Tract Infections: An Inconclusive, Not Inferior, Outcome-Reply. PMID- 23753059 TI - A health promotion logic model to review progress in HIV prevention in China. AB - Using the theory and concepts of health promotion, this paper proposes a logic model for HIV/AIDS prevention and control which provides a structure for describing planned actions and predicted impacts/outcomes from comprehensive HIV prevention interventions. The potential usefulness of the model is examined by reviewing the evolution of HIV prevention and management in China, drawing on evidence from interventions reported from a mixture of study designs and formats. It reports that HIV interventions in China can be considered in two distinctive phases, before and after 2003 when China commenced its 'official' response to the HIV epidemic. The logic model was useful in comparing actions taken over these two periods highlighting the importance of political leadership in distinguishing between the two phases, and the continuing importance of systematic and broadly based public education and communication. We conclude that the logic model can not only be used as a planning model, but can also be applied retrospectively to assess successes and failures in national and local responses to HIV in complex social settings. PMID- 23753062 TI - Stenting vs Medical Therapy for Stable Coronary Artery Disease: A Minefield for Meta-analyses?-Reply. PMID- 23753065 TI - Boston Public Library: McKim Building. PMID- 23753064 TI - A microdevice for studying intercellular electromechanical transduction in adult cardiac myocytes. AB - Intercellular electromechanical transduction in adult cardiac myocytes plays an important role in regulating heart function. The efficiency of intercellular electromechanical transduction has so far been investigated only to a limited extent, which is largely due to the lack of appropriate tools that can quantitatively assess the contractile performance of interconnected adult cardiac myocytes. In this paper we report a microengineered device that is capable of applying electrical stimulation to the selected adult cardiac myocyte in a longitudinally connected cell doublet and quantifying the intercellular electromechanical transduction by measuring the contractile performance of stimulated and un-stimulated cells in the same doublet. The capability of applying selective electrical stimulation on only one cell in the doublet is validated by examining cell contractile performance while blocking the intercellular communication. Quantitative assessment of cell contractile performance in isolated adult cardiac myocytes is performed by measuring the change in cell length. The proof-of-concept assessment of gap junction performance shows that the device is useful in studying the efficiency of gap junctions in adult cardiac myocytes, which is most relevant to the synchronized pumping performance of native myocardium. Collectively, this work provides a quantitative tool for studying intercellular electromechanical transduction and is expected to develop a comprehensive understanding of the role of intercellular communication in various heart diseases. PMID- 23753066 TI - This month in archives of dermatology. PMID- 23753072 TI - Advance care planning of the acutely unwell patient-reply. PMID- 23753076 TI - There is nothing personal-reply. PMID- 23753079 TI - ST-Segment Elevation-Discussion. PMID- 23753085 TI - Childhood obesity: knowledge, attitudes, and practices of European pediatric care providers. AB - OBJECTIVE: To determine and compare attitudes, skills, and practices in childhood obesity management in 4 European countries with different obesity prevalence, health care systems, and economic situations. METHODS: A cross-sectional survey was distributed to primary health care providers from France, Italy, Poland, and Ukraine. The questionnaire was returned by 1119 participants with a response rate of 32.4%. RESULTS: The study revealed that most of the primary health care providers were convinced of their critical role in obesity management but did not feel sufficiently competent to perform effectively. The adherence to recommended practices such as routine weight and height measurements, BMI calculation, and plotting growth parameters on recommended growth charts was poor. Most primary health care providers recognized the need for continuing professional education in obesity management, stressing the importance of appropriate dietary counseling. CONCLUSIONS: The study underlines insufficient implementation of national guidelines for management of obesity regardless of the country and its health system. It also makes clear that the critical problem is not elaboration of guidelines but rather creating support systems for implementation of the medical standards among the primary care practitioners. PMID- 23753086 TI - Differences in characteristics of dying children who receive and do not receive palliative care. AB - OBJECTIVE: Comparing demographic and clinical characteristics associated with receipt of palliative care (PC) among children who died in children's hospitals to those who did not receive PC and understanding the trends in PC use. METHODS: This retrospective cohort study used the Pediatric Health Information System database. Children <18 years of age who died >=5 days after admission to a Pediatric Health Information System hospital between January 1, 2001, and December 31, 2011 were included. Receipt of PC services was identified by the International Classification of Diseases, Ninth Revision code for PC. Diagnoses were grouped using major diagnostic codes. International Classification of Diseases codes and clinical transaction codes were used to evaluate all interventions. RESULTS: This study evaluated 24 342 children. Overall, 4% had coding for PC services. This increased from 1% to 8% over the study years. Increasing age was associated with greater receipt of PC. Children with the PC code had fewer median days in the hospital (17 vs 21), received fewer invasive interventions, and fewer died in the ICU (60% vs 80%). Receipt of PC also varied by major diagnostic codes, with the highest proportion found among children with neurologic disease. CONCLUSIONS: Most pediatric patients who died in a hospital did not have documented receipt of PC. Children receiving PC are different from those who do not in many ways, including receipt of fewer procedures. Receipt of PC has increased over time; however, it remains low, particularly among neonates and those with circulatory diseases. PMID- 23753087 TI - Time interval between concussions and symptom duration. AB - OBJECTIVE: To test the hypothesis that children with a previous history of concussion have a longer duration of symptoms after a repeat concussion than those without such a history. METHODS: Prospective cohort study of consecutive patients 11 to 22 years old presenting to the emergency department of a children's hospital with an acute concussion. The main outcome measure was time to symptom resolution, assessed by the Rivermead Post-Concussion Symptoms Questionnaire (RPSQ). Patients and providers completed a questionnaire describing mechanism of injury, associated symptoms, past medical history, examination findings, diagnostic studies, and the RPSQ. Patients were then serially administered the RPSQ for 3 months after the concussion or until all symptoms resolved. RESULTS: A total of 280 patients were enrolled over 12 months. Patients with a history of previous concussion had a longer duration of symptoms than those without previous concussion (24 vs 12 days, P = .02). Median symptom duration was even longer for patients with multiple previous concussions (28 days, P = .03) and for those who had sustained a concussion within the previous year (35 days, P = .007) compared with patients without those risk factors. In a multivariate model, previous concussion, absence of loss of consciousness, age >=13, and initial RPSQ score >18 were significant predictors of prolonged recovery. CONCLUSIONS: Children with a history of a previous concussion, particularly recent or multiple concussions, are at increased risk for prolonged symptoms after concussion. These findings have direct implications on the management of patients with concussion who are at high risk for repeat injuries. PMID- 23753089 TI - Hermansky-Pudlak syndrome: health care throughout life. AB - Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease that displays genetic heterogeneity; there are 9 known subtypes. HPS is characterized by oculocutaneous albinism, a platelet storage pool deficiency and resultant bleeding diathesis, and lysosomal accumulation of ceroid lipofuscin. Patients with HPS, specifically those with the genotypes HPS-1, HPS-2, or HPS-4, are predisposed to interstitial lung disease. In addition, some patients with HPS develop granulomatous colitis. Optimal health care requires a thorough knowledge of the unique health risks and functional limitations associated with this syndrome. PMID- 23753088 TI - Simplified definitions of elevated pediatric blood pressure and high adult arterial stiffness. AB - OBJECTIVE: The ability of childhood elevated blood pressure (BP) to predict high pulse wave velocity (PWV), a surrogate marker for cardiovascular disease, in adulthood has not been reported. We studied whether elevated pediatric BP could predict high PWV in adulthood and if there is a difference in the predictive ability between the standard BP definition endorsed by the National High Blood Pressure Education Program and the recently proposed 2 simplified definitions. METHODS: The sample comprised 1241 subjects from the Cardiovascular Risk in Young Finns Study followed-up 27 years since baseline (1980, aged 6-15 years). Arterial PWV was measured in 2007 by whole-body impedance cardiography. RESULTS: The relative risk for high PWV was 1.5 using the simple 1 (age-specific) definition, 1.6 using the simple 2 (age- and gender-specific) definition, and 1.7 using the complex (age-, gender-, and height-specific) definition (95% confidence interval: 1.1-2.0, P = .007; 1.2-2.2, P = .001; and 1.2-2.2, P = .001, respectively). Predictions of high PWV were equivalent for the simple 1 or simple 2 versus complex definition (P = .25 and P = .68 for area under the curve comparisons, P = .13 and P = .35 for net reclassification indexes, respectively). CONCLUSIONS: Our results support the previous finding that elevated BP tracks from childhood to adulthood and accelerates the atherosclerotic process. The simplified BP tables could be used to identify pediatric patients at increased risk of high arterial stiffness in adulthood and hence to improve the primary prevention of cardiovascular diseases. PMID- 23753090 TI - Cobalamin C defect presenting with isolated pulmonary hypertension. AB - Cobalamin C (cblC) defect is the most common inborn error of vitamin B12 metabolism. Clinical features vary as does the severity of the disease. In most cases, the clinical symptoms of cblC defect tend to appear during infancy or early childhood as a multisystem disease with severe neurologic, ocular, hematologic, renal, and gastrointestinal signs. The neurologic findings are common and include hypotonia, developmental delay, microcephaly, seizures hydrocephalus, and brain MRI abnormalities. We report a case of a young boy with cblC defect, who did not undergo newborn screening, presenting at the age of 2 years with isolated pulmonary hypertension as the leading symptom. This novel way of presentation of cblC defect enlarges the spectrum of inherited diseases that must be considered in the differential diagnosis of pulmonary hypertension. PMID- 23753092 TI - Acute ovarian torsion and primary hypothyroidism. AB - A 12-year-old girl presented with acute abdominal pain due to an acute ovarian torsion. She required an oophorectomy. Clinical and laboratory assessment confirmed severe primary hypothyroidism. In this report, we review this rare complication of untreated primary hypothyroidism and the physiologic mechanisms proposed to explain this phenomenon. PMID- 23753091 TI - The RIVUR trial: profile and baseline clinical associations of children with vesicoureteral reflux. AB - BACKGROUND AND OBJECTIVE: Vesicoureteral reflux (VUR) is diagnosed in ~30% to 40% of children who have imaging studies after urinary tract infections (UTIs). Our goal is to characterize children enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial and to compare our study cohort with those from previously published studies. METHODS: RIVUR investigators from 19 pediatric sites in the United States recruited 607 children with grade I through IV VUR. Children were enrolled after a first or second UTI. This cross sectional report of baseline data includes extensive clinical, parental report, and imaging study results. RESULTS: RIVUR recruited 607 children (558 girls, 49 boys) with grade I (11%), II (42%), III (38%), or IV (8%) reflux. The median age was 12 months, and most children (91%) were enrolled after their first UTI. The UTI leading to enrollment was both febrile and symptomatic for 323 children, febrile only in 197 children, and symptomatic only in 86. Renal involvement at baseline as documented by a (99m)Tc dimercaptosuccinic acid scan was uncommon with cortical defects identified in 89 (15%) children. Bladder and bowel dysfunction was identified in 71 (56%) of 126 toilet-trained subjects assessed. CONCLUSIONS: RIVUR is the largest prospective, randomized trial for children with primary VUR to date, comparing prophylaxis with placebo. The study sample comprises patients from 19 pediatric clinical sites in the United States, whose demographic and clinical characteristics may differ from those of children enrolled in previous trials from other countries. PMID- 23753093 TI - Risk factors for urolithiasis in gastrostomy tube fed children: a case-control study. AB - BACKGROUND AND OBJECTIVE: Pediatric patients who are fed primarily via gastrostomy tube (G-tube) may be at increased risk for urolithiasis, but no studies have specifically examined risk factors for stones in this population. We aimed to determine clinical differences between G-tube fed (GTF) patients with and without stones, in hopes of identifying modifiable factors associated with increased risk of urolithiasis. METHODS: We conducted a retrospective case control study, matching GTF patients with urolithiasis (cases) to GTF children without urolithiasis (controls) based on age (+/-1 year) and gender. Bivariate comparisons and matched logistic regression modeling were used to determine the unadjusted and adjusted associations between relevant clinical factors and urolithiasis. RESULTS: Forty-one cases and 80 matched controls (mean age 12.0 +/- 6.5 years) were included. On bivariate analysis, factors associated with stone formation included: white race, urinary tract infection (UTI), topiramate administration, vitamin D use, malabsorption, dehydration, 2-year duration with G tube, and whether goal free water intake was documented in the patient chart. On regression analysis, the following factors remained significant: topiramate administration (odds ratio [OR]: 6.58 [95% confidence interval (CI): 1.76 24.59]), UTI (OR: 7.70 [95% CI: 1.59-37.17]), and <2 years with a G-tube (OR: 8.78 [95% CI: 1.27-52.50]). CONCLUSIONS: Our findings provide a preliminary risk profile for the development of urolithiasis in GTF children. Important associations identified include UTI, topiramate administration, and shorter G tube duration, which may reflect subclinical chronic dehydration. Of these, topiramate use represents the most promising target for risk reduction. PMID- 23753094 TI - Online problem-solving therapy for executive dysfunction after child traumatic brain injury. AB - OBJECTIVE: Executive dysfunction after traumatic brain injury (TBI) in children is common and leads to significant problems in functioning across multiple settings. The objective of this study was to evaluate the efficacy of a web-based counselor-assisted problem solving (CAPS) intervention compared with an Internet resource comparison (IRC) for treatment of executive dysfunction within 12 months after complicated mild to severe TBI in adolescents. We hypothesized that CAPS would significantly improve parent ratings of executive dysfunction compared with an IRC. METHODS: Participants included 132 adolescents aged 12 to 17 years who sustained a complicated mild to severe TBI within 1 to 6 months before study enrollment. Study design was a multisite, assessor-blinded, randomized controlled trial. Study sites included 3 tertiary pediatric hospitals and 2 tertiary general medical centers. The main outcome measure was primary caregiver Behavioral Rating Inventory of Executive Function Global Executive Composite at baseline and 6 month follow-up. Generalized linear models that controlled for baseline scores were used to compare the CAPS and IRC scores. RESULTS: In older teens, the CAPS group showed significant improvement in executive function behaviors at 6-month follow-up compared with the IRC group (F = 6.74, P = .01, Cohen's d = 0.63). CONCLUSIONS: Findings indicate that web-based CAPS improves primary caregiver rated executive functioning within the first 12 months after TBI in older adolescents. Future research needs to define the optimal timing after injury for delivery of CAPS and characteristics of individuals and families who are most likely to benefit from CAPS. PMID- 23753095 TI - A systematic review of home-based childhood obesity prevention studies. AB - BACKGROUND AND OBJECTIVES: Childhood obesity is a global epidemic. Despite emerging research about the role of the family and home on obesity risk behaviors, the evidence base for the effectiveness of home-based interventions on obesity prevention remains uncertain. The objective was to systematically review the effectiveness of home-based interventions on weight, intermediate (eg, diet and physical activity [PA]), and clinical outcomes. METHODS: We searched Medline, Embase, PsychInfo, CINAHL, clinicaltrials.gov, and the Cochrane Library from inception through August 11, 2012. We included experimental and natural experimental studies with >=1-year follow-up reporting weight-related outcomes and targeting children at home. Two independent reviewers screened studies and extracted data. We graded the strength of the evidence supporting interventions targeting diet, PA, or both for obesity prevention. RESULTS: We identified 6 studies; 3 tested combined interventions (diet and PA), 1 used diet intervention, 1 combined intervention with primary care and consumer health informatics components, and 1 combined intervention with school and community components. Select combined interventions had beneficial effects on fruit/vegetable intake and sedentary behaviors. However, none of the 6 studies reported a significant effect on weight outcomes. Overall, the strength of evidence is low that combined home-based interventions effectively prevent obesity. The evidence is insufficient for conclusions about home-based diet interventions or interventions implemented at home in association with other settings. CONCLUSIONS: The strength of evidence is low to support the effectiveness of home-based child obesity prevention programs. Additional research is needed to test interventions in the home setting, particularly those incorporating parenting strategies and addressing environmental influences. PMID- 23753097 TI - Mortality risks in new-onset childhood epilepsy. AB - OBJECTIVES: Estimate the causes and risk of death, specifically seizure related, in children followed from onset of epilepsy and to contrast the risk of seizure related death with other common causes of death in the population. METHODS: Mortality experiences from 4 pediatric cohorts of newly diagnosed patients were combined. Causes of death were classified as seizure related (including sudden unexpected death [SUDEP]), natural causes, nonnatural causes, and unknown. RESULTS: Of 2239 subjects followed up for >30 000 person-years, 79 died. Ten subjects with lethal neurometabolic conditions were ultimately excluded. The overall death rate (per 100 000 person-years) was 228; 743 in complicated epilepsy (with associated neurodisability or underlying brain condition) and 36 in uncomplicated epilepsy. Thirteen deaths were seizure-related (10 SUDEP, 3 other), accounting for 19% of all deaths. Seizure-related death rates were 43 overall, 122 for complicated epilepsy, and 14 for uncomplicated epilepsy. Death rates from other natural causes were 159, 561, and 9, respectively. Of 48 deaths from other natural causes, 37 were due to pneumonia or other respiratory complications. CONCLUSIONS: Most excess death in young people with epilepsy is not seizure-related. Mortality is significantly higher compared with the general population in children with complicated epilepsy but not uncomplicated epilepsy. The SUDEP rate was similar to or higher than sudden infant death syndrome rates. In uncomplicated epilepsy, sudden and seizure-related death rates were similar to or higher than rates for other common causes of death in young people (eg, accidents, suicides, homicides). Relating the risk of death in epilepsy to familiar risks may facilitate discussions of seizure-related mortality with patients and families. PMID- 23753098 TI - Outcomes of an early feeding practices intervention to prevent childhood obesity. AB - OBJECTIVE: The goal of this study was to evaluate outcomes of a universal intervention to promote protective feeding practices that commenced in infancy and aimed to prevent childhood obesity. METHODS: The NOURISH randomized controlled trial enrolled 698 first-time mothers (mean +/- SD age: 30.1 +/- 5.3 years) with healthy term infants (51% female) aged 4.3 +/- 1.0 months at baseline. Mothers were randomly allocated to self-directed access to usual care or to attend two 6-session interactive group education modules that provided anticipatory guidance on early feeding practices. Outcomes were assessed 6 months after completion of the second information module, 20 months from baseline and when the children were 2 years old. Maternal feeding practices were self-reported by using validated questionnaires and study-developed items. Study-measured child height and weight were used to calculate BMI z scores. RESULTS: Retention at follow-up was 78%. Mothers in the intervention group reported using responsive feeding more frequently on 6 of 9 subscales and 8 of 8 items (all, P <= .03) and overall less controlling feeding practices (P < .001). They also more frequently used feeding practices (3 of 4 items; all, P < .01) likely to enhance food acceptance. No statistically significant differences were noted in anthropometric outcomes (BMI z score: P = .10) nor in prevalence of overweight/obesity (control 17.9% vs intervention 13.8%; P = .23). CONCLUSIONS: Evaluation of NOURISH data at child age 2 years found that anticipatory guidance on complementary feeding, tailored to developmental stage, increased use by first-time mothers of "protective" feeding practices that potentially support the development of healthy eating and growth patterns in young children. PMID- 23753096 TI - Individual and center-level factors affecting mortality among extremely low birth weight infants. AB - OBJECTIVE: To examine factors affecting center differences in mortality for extremely low birth weight (ELBW) infants. METHODS: We analyzed data for 5418 ELBW infants born at 16 Neonatal Research Network centers during 2006-2009. The primary outcomes of early mortality (<=12 hours after birth) and in-hospital mortality were assessed by using multilevel hierarchical models. Models were developed to investigate associations of center rates of selected interventions with mortality while adjusting for patient-level risk factors. These analyses were performed for all gestational ages (GAs) and separately for GAs <25 weeks and >=25 weeks. RESULTS: Early and in-hospital mortality rates among centers were 5% to 36% and 11% to 53% for all GAs, 13% to 73% and 28% to 90% for GAs <25 weeks, and 1% to 11% and 7% to 26% for GAs >=25 weeks, respectively. Center intervention rates significantly predicted both early and in-hospital mortality for infants <25 weeks. For infants >=25 weeks, intervention rates did not predict mortality. The variance in mortality among centers was significant for all GAs and outcomes. Center use of interventions and patient risk factors explained some but not all of the center variation in mortality rates. CONCLUSIONS: Center intervention rates explain a portion of the center variation in mortality, especially for infants born at <25 weeks' GA. This finding suggests that deaths may be prevented by standardizing care for very early GA infants. However, differences in patient characteristics and center intervention rates do not account for all of the observed variability in mortality; and for infants with GA >=25 weeks these differences account for only a small part of the variation in mortality. PMID- 23753099 TI - Systematic review of community-based childhood obesity prevention studies. AB - OBJECTIVE: This study systematically reviewed community-based childhood obesity prevention programs in the United States and high-income countries. METHODS: We searched Medline, Embase, PsychInfo, CINAHL, clinicaltrials.gov, and the Cochrane Library for relevant English-language studies. Studies were eligible if the intervention was primarily implemented in the community setting; had at least 1 year of follow-up after baseline; and compared results from an intervention to a comparison group. Two independent reviewers conducted title scans and abstract reviews and reviewed the full articles to assess eligibility. Each article received a double review for data abstraction. The second reviewer confirmed the first reviewer's data abstraction for completeness and accuracy. RESULTS: Nine community-based studies were included; 5 randomized controlled trials and 4 non randomized controlled trials. One study was conducted only in the community setting, 3 were conducted in the community and school setting, and 5 were conducted in the community setting in combination with at least 1 other setting such as the home. Desirable changes in BMI or BMI z-score were found in 4 of the 9 studies. Two studies reported significant improvements in behavioral outcomes (1 in physical activity and 1 in vegetable intake). CONCLUSIONS: The strength of evidence is moderate that a combined diet and physical activity intervention conducted in the community with a school component is more effective at preventing obesity or overweight. More research and consistent methods are needed to understand the comparative effectiveness of childhood obesity prevention programs in the community setting. PMID- 23753100 TI - Access to digital technology among families coming to urban pediatric primary care clinics. AB - OBJECTIVE: Digital technologies offer new platforms for health promotion and disease management. Few studies have evaluated the use of digital technology among families receiving care in an urban pediatric primary care setting. METHODS: A self-administered survey was given to a convenience sample of caregivers bringing their children to 2 urban pediatric primary care centers in spring 2012. The survey assessed access to home Internet, e-mail, smartphone, and social media (Facebook and Twitter). A "digital technology" scale (0-4) quantified the number of available digital technologies and connections. Frequency of daily use and interest in receiving medical information digitally were also assessed. RESULTS: The survey was completed by 257 caregivers. The sample was drawn from a clinical population that was 73% African American and 92% Medicaid insured with a median patient age of 2.9 years (interquartile range 0.8 7.4). Eighty percent of respondents reported having Internet at home, and 71% had a smartphone. Ninety-one percent reported using e-mail, 78% Facebook, and 27% Twitter. Ninety-seven percent scored >=1 on the digital technology scale; 49% had a digital technology score of 4. The digital technology score was associated with daily use of digital media in a graded fashion (P < .0001). More than 70% of respondents reported that they would use health care information supplied digitally if approved by their child's medical provider. CONCLUSIONS: Caregivers in an urban pediatric primary care setting have access to and frequently use digital technologies. Digital connections may help reach a traditionally hard-to reach population. PMID- 23753101 TI - Prevention and management of infants with suspected or proven neonatal sepsis. PMID- 23753105 TI - FDR Drive. PMID- 23753102 TI - Association of fitness with vascular intima-media thickness and elasticity in adolescence. AB - OBJECTIVES: Vascular intima-media thickness (IMT) and elasticity are surrogate markers of atherosclerosis. Data on the effect of cardiorespiratory fitness on these measures of vascular health in adolescence are scarce. The aim was to examine the association of fitness with aortic and carotid artery IMT and elasticity in adolescents. METHODS: Aortic (n = 449) and carotid (n = 467) IMT and elasticity were measured ultrasonographically in 17-year-old adolescents participating in a prospective, longitudinal atherosclerosis prevention study (Special Turku Coronary Risk Factor Intervention Project). Distensibility and Young's elastic modulus (YEM) were used as measures of arterial elasticity. Cardiorespiratory fitness (maximum oxygen uptake, mL/kg/min) was measured with a maximal cycle ergometer test. Data on fitness were available for 341 of adolescents with aortic and 355 with carotid ultrasound measures. RESULTS: Fitness was inversely associated with aortic IMT (beta[SE] = -0.0029[0.0013]; P = .031) and YEM (beta[SE] = -0.012[0.0053]; P = .025) after adjusting for gender, physical activity, high-density lipoprotein/total cholesterol, triglycerides, high-sensitivity C-reactive protein, homeostasis model of assessment-insulin resistance, BMI, systolic blood pressure, and smoking. Risk of having low aortic distensibility (<=10th percentile) decreased with increasing fitness (odds ratio = 0.89, 95% confidence interval 0.82-0.98); P = .014). The increase in aortic IMT and YEM between ages 11 and 17 years was smaller in adolescents who were fit at age 17 compared with adolescents who had the lowest fitness level (P for IMT = .015, P for YEM = .0072). Fitness was not associated with carotid IMT or elasticity. Lifestyle counseling given in the Special Turku Coronary Risk Factor Intervention Project was not associated with fitness. CONCLUSIONS: Fitness was favorably associated with aortic IMT and elasticity in adolescents. No association of fitness with the respective carotid indices was found. These data suggest that fitness in part enhances vascular health in healthy adolescents. PMID- 23753114 TI - GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients. AB - STUDY QUESTION: Does a GnRH agonist (GnRHa) trigger followed by a bolus of 1.500 IU hCG in a group of patients at risk of ovarian hyperstimulation syndrome (OHSS) reduce the OHSS incidence compared with hCG trigger? SUMMARY ANSWER: A GnRHa trigger followed by early luteal hCG support with one bolus of 1.500 IU hCG appears to reduce OHSS in patients at risk of OHSS; however, in a low-risk group a second bolus of 1.500 IU hCG induced two cases of late onset OHSS. WHAT IS KNOWN ALREADY: A GnRHa trigger is an alternative to hCG in GnRH antagonist co treated cycles. STUDY DESIGN, SIZE, DURATION: Two RCTs were performed in four Danish IVF units. A total of 446 patients were assessed for eligibility and 390 patients were enrolled in the study from January 2009 until December 2011. The primary outcome of the study was OHSS incidence in the group at risk of OHSS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients received a fixed dose of recombinant human FSH for the first 4 days. On the day of triggering, patients were assessed for their risk of OHSS based on the total number of follicles >=11 mm diameter, and were classified as being at risk of OHSS when the total number of follicles >=11 mm was between 15 and 25 and at low risk of OHSS when the total number of follicles >=11 mm was <=14. Two separate randomization lists were used for each of the OHSS risk groups. Women at risk of OHSS were allocated (RCT 1) to either: Group A (n = 60), ovulation triggering with a bolus of 0.5 mg buserelin (GnRHa) s.c. followed by a single bolus of 1.500 IU hCG s.c. after the oocyte retrieval-or: Group B (n = 58): 5.000 IU hCG. Similarly, women at low risk of OHSS were allocated (RCT 2) to receive either: Group C (n = 125), a bolus of 0.5 mg buserelin s.c., followed by a bolus of 1.500 IU hCG s.c. after oocyte retrieval and a second bolus of 1.500 IU hCG on the day of oocyte retrieval +5 or: Group D (n = 141), 5.000 IU hCG. Groups C and D were included in order to obtain preliminary data. MAIN RESULTS AND THE ROLE OF CHANCE: In women at risk of OHSS (RCT 1) (15-25 follicles) no OHSS case was seen in Group A (GnRHa trigger and one bolus of 1.500 IU hCG), whereas two cases of moderate late-onset OHSS occurred in group B (3.4%), (P = 0.24). In contrast, in women at a low risk of OHSS (RCT 2) (<=14 follicles) two cases of late-onset OHSS occurred in Group C (GnRHa trigger and two boluses of 1.500 IU hCG), whereas no OHSS case was encountered in Group D (P = 0.22). LIMITATIONS, REASONS FOR CAUTION: Although the first RCT was powered to include 168 patients at risk of OHSS (15-25 follicles >=11 mm) randomized to either GnRHa trigger or hCG trigger, the trial was prematurely discontinued when a total of 118 patients at risk of OHSS were randomized. In addition the second RCT in the OHSS low-risk group was designed as a feasibility study to assess the incidence of OHSS after GnRHa trigger and dual hCG administration versus 5.000 IU hCG. No power calculation was performed for this trial. In addition, there was a lack of blinding in the RCTs. WIDER IMPLICATIONS OF THE FINDINGS: Although a non-significant result, one bolus of 1.500 IU hCG after GnRHa trigger tended to reduce the OHSS rate in patients with 15-25 follicles >=11 mm as well as secure the ongoing pregnancy rate. In contrast, in patients at low risk of OHSS the administration of two boluses of 1.500 IU hCG after GnRHa trigger should be avoided as it may induce OHSS. PMID- 23753119 TI - Freedom to innovate: the perils of centralized medical research-reply. PMID- 23753118 TI - Polycyclic aromatic hydrocarbons, particulate air pollution, and cognitive decline-reply. PMID- 23753126 TI - Shoreline of cadaques, costa brava of the mediterranean, catalonia, Spain. PMID- 23753132 TI - About this journal. PMID- 23753177 TI - Simultaneous application of heat, drought, and virus to Arabidopsis plants reveals significant shifts in signaling networks. AB - Considering global climate change, the incidence of combined drought and heat stress is likely to increase in the future and will considerably influence plant pathogen interactions. Until now, little has been known about plants exposed to simultaneously occurring abiotic and biotic stresses. To shed some light on molecular plant responses to multiple stress factors, a versatile multifactorial test system, allowing simultaneous application of heat, drought, and virus stress, was developed in Arabidopsis (Arabidopsis thaliana). Comparative analysis of single, double, and triple stress responses by transcriptome and metabolome analysis revealed that gene expression under multifactorial stress is not predictable from single stress treatments. Hierarchical cluster and principal component analyses identified heat as the major stress factor, clearly separating heat-stressed from non-heat-stressed plants. We identified 11 genes differentially regulated in all stress combinations as well as 23 genes specifically regulated under triple stress. Furthermore, we showed that virus treated plants displayed enhanced expression of defense genes, which was abolished in plants additionally subjected to heat and drought stress. Triple stress also reduced the expression of genes involved in the R-mediated disease response and increased the cytoplasmic protein response, which was not seen under single stress conditions. These observations suggested that abiotic stress factors significantly altered turnip mosaic virus-specific signaling networks, which led to a deactivation of defense responses and a higher susceptibility of plants. Collectively, our transcriptome and metabolome data provide a powerful resource to study plant responses during multifactorial stress and allow identifying metabolic processes and functional networks involved in tripartite interactions of plants with their environment. PMID- 23753178 TI - Elucidating rice cell metabolism under flooding and drought stresses using flux based modeling and analysis. AB - Rice (Oryza sativa) is one of the major food crops in world agriculture, especially in Asia. However, the possibility of subsequent occurrence of flood and drought is a major constraint to its production. Thus, the unique behavior of rice toward flooding and drought stresses has required special attention to understand its metabolic adaptations. However, despite several decades of research investigations, the cellular metabolism of rice remains largely unclear. In this study, in order to elucidate the physiological characteristics in response to such abiotic stresses, we reconstructed what is to our knowledge the first metabolic/regulatory network model of rice, representing two tissue types: germinating seeds and photorespiring leaves. The phenotypic behavior and metabolic states simulated by the model are highly consistent with our suspension culture experiments as well as previous reports. The in silico simulation results of seed-derived rice cells indicated (1) the characteristic metabolic utilization of glycolysis and ethanolic fermentation based on oxygen availability and (2) the efficient sucrose breakdown through sucrose synthase instead of invertase. Similarly, flux analysis on photorespiring leaf cells elucidated the crucial role of plastid-cytosol and mitochondrion-cytosol malate transporters in recycling the ammonia liberated during photorespiration and in exporting the excess redox cofactors, respectively. The model simulations also unraveled the essential role of mitochondrial respiration during drought stress. In the future, the combination of experimental and in silico analyses can serve as a promising approach to understand the complex metabolism of rice and potentially help in identifying engineering targets for improving its productivity as well as enabling stress tolerance. PMID- 23753185 TI - PET imaging of tumor hypoxia using 18F-fluoroazomycin arabinoside in stage III-IV non-small cell lung cancer patients. AB - Tumor hypoxia hampers the efficacy of radiotherapy because of its increased resistance to ionizing radiation. The aim of the present study was to estimate the potential added clinical value of the specific hypoxia tracer (18)F fluoroazomycin arabinoside ((18)F-FAZA) over commonly used (18)F-FDG in the treatment of advanced-stage non-small cell lung cancer (NSCLC). METHODS: Eleven patients with stage III or stage IV NSCLC underwent (18)F-FDG and (18)F-FAZA PET before chemoradiotherapy. The maximum standardized uptake value (SUVmax) was used to depict (18)F-FDG uptake, and the tumor-to-background (T/B) ratio and tumor fractional hypoxic volume (FHV) were used to quantify hypoxia. The spatial correlation between (18)F-FDG and (18)F-FAZA uptake values was investigated using voxel-based analysis. Partial-volume correction was applied. RESULTS: All 11 patients showed clear uptake of (18)F-FAZA in the primary tumor. However, different patterns of (18)F-FDG and (18)F-FAZA uptake distributions were observed and varied widely among different tumors. No significant correlation was observed between (18)F-FDG SUVmax and (18)F-FAZA T/B ratio (P = 0.055). The median FHV of 1.4 was 48.4% (range, 5.0-91.5). A significant positive correlation was found between the (18)F-FAZA T/B ratio and FHV of 1.4 (P < 0.001). There was no correlation between the lesion size and FHV or between the (18)F-FDG SUVmax and FHV. The pattern of tumoral (18)F-FDG uptake was rather homogeneous, whereas (18)F-FAZA uptake was more heterogeneous, suggesting that (18)F-FAZA identifies hypoxic areas within metabolically active areas of tumor. A significant correlation between (18)F-FDG SUVmax and lesion size (P = 0.002) was observed. CONCLUSION: (18)F-FAZA PET imaging is able to detect heterogeneous distributions of hypoxic subvolumes out of homogeneous (18)F-FDG background in a clinical setting. Therefore, (18)F-FAZA might be considered a tool for guiding dose escalation to the hypoxic fraction of the tumor. PMID- 23753186 TI - Update on appropriate use criteria for amyloid PET imaging: dementia experts, mild cognitive impairment, and education. AB - Amyloid PET imaging is a novel diagnostic test that can detect in living humans one of the two defining pathologic lesions of Alzheimer disease, amyloid-beta deposition in the brain. The Amyloid Imaging Task Force of the Alzheimer's Association and Society for Nuclear Medicine and Molecular Imaging previously published appropriate use criteria for amyloid PET as an important tool for increasing the certainty of a diagnosis of Alzheimer disease in specific patient populations. Here, the task force further clarifies and expands 3 topics discussed in the original paper: first, defining dementia experts and their use of proper documentation to demonstrate the medical necessity of an amyloid PET scan; second, identifying a specific subset of individuals with mild cognitive impairment for whom an amyloid PET scan is appropriate; and finally, developing educational programs to increase awareness of the amyloid PET appropriate use criteria and providing instructions on how this test should be used in the clinical decision-making process. PMID- 23753187 TI - 18F-FDG PET provides high-impact and powerful prognostic stratification in the staging of Merkel cell carcinoma: a 15-year institutional experience. AB - Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with limited evidence on the role of PET scanning. The primary aim of this study was to assess the impact of (18)F-FDG PET in the staging and management of MCC. METHODS: A single-institution review using clinical outcome data collected until February 2012 was performed of patients with MCC who underwent staging PET scanning between January 1997 and October 2010. Management plans were recorded prospectively at the time of the PET request, and follow-up outcomes were recorded retrospectively. The clinical impact of PET was scored using our previously published criteria: "high" if the PET scan changed the primary treatment modality or intent; "medium" if the treatment modality was unchanged but the radiation therapy technique or dose was altered. The primary objective was to test the hypothesis that the true proportion of patients who have a high- or medium-impact scan would be greater than 25%. RESULTS: The median follow-up of 102 consecutive patients was 4.8 y. The results of staging PET had an impact on patient management in 37% of patients (P < 0.003). High- and medium-impact scans were recorded for 22% and 15% of patients, respectively. PET staging results differed from conventional staging results in 22% of patients, with PET upstaging 17% and downstaging 5%. The 3- and 5-y overall survival was 60% (95% confidence interval, 50%-71%) and 51% (95% confidence interval, 41%-64%), respectively. In stratification by PET-defined stage, the 5-y overall survival was 67% for patients with stage I/II disease but only 31% for patients with stage III disease (log-rank P < 0.001). The 5-y cumulative incidence of locoregional failure, distant failure, and death was 16.6%, 22.3% and 14.3%, respectively. On multivariate analysis, only PET stage (P < 0.001) and primary treatment modality (P = 0.050) were significantly associated with overall survival. The primary treatment modality was not associated with progression-free survival when stratification was by tumor stage. CONCLUSION: The use of (18)F-FDG PET scans had a great impact on patients and may play an important role in the prognostic stratification and treatment of this disease. PMID- 23753218 TI - Necrotizing soft tissue infections. AB - Necrotising soft tissue infection (NSTI) presents unique challenges in diagnosis and management. The key to a successful outcome is a high index of suspicion in appropriate clinical settings. Type II NSTI tends to occur on an extremity in younger, healthier patients with a history of known trauma, and to be monomicrobial. Type I NSTI tends to occur on the trunk of older, less healthy patients without an obvious history of trauma, and tends to be polymicrobial. Other, rarer types exist as well. The pathophysiology of both types involves superantigen acticivty, as well as a number of microbial byproducts which collectively decrease the viscosity of pus, facilitating its spread along deep tissue planes and ultimately causing diffuse deep thrombosis and aggressive systemic sepsis. The most important physical finding is tenderness to palpation beyond the area of redness, and the lack of crepitus should not be seen as a reassuring sign. Suspected cases should undergo early surgical exploration for diagnosis, which may be performed at bedside through a small incision. Most imaging techniques are not sufficiently specific to warrant a delay in surgical exploration. The Laboratory Risk Indicator for Necrotising Fasciitis (LRINEC) shows promise as a tool for excluding suspected cases. Successful outcomes in cases of NSTI require early and aggressive serial debridement and a multidisciplinary critical care approach. PMID- 23753199 TI - Association between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus. AB - IMPORTANCE: Hypoglycemia commonly occurs in patients with diabetes mellitus (DM) and may negatively influence cognitive performance. Cognitive impairment in turn can compromise DM management and lead to hypoglycemia. OBJECTIVE: To prospectively evaluate the association between hypoglycemia and dementia in a biracial cohort of older adults with DM. DESIGN AND SETTING: Prospective population-based study. PARTICIPANTS: We studied 783 older adults with DM (mean age, 74.0 years; 47.0% of black race/ethnicity; and 47.6% female) who were participating in the prospective population-based Health, Aging, and Body Composition Study beginning in 1997 and who had baseline Modified Mini-Mental State Examination scores of 80 or higher. MAIN OUTCOME MEASURES: Dementia diagnosis was determined during the follow-up period from hospital records indicating an admission associated with dementia or the use of prescribed dementia medications. Hypoglycemic events were determined during the follow-up period by hospital records. RESULTS: During the 12-year follow-up period, 61 participants (7.8%) had a reported hypoglycemic event, and 148 (18.9%) developed dementia. Those who experienced a hypoglycemic event had a 2-fold increased risk for developing dementia compared with those who did not have a hypoglycemic event (34.4% vs 17.6%, P < .001; multivariate-adjusted hazard ratio, 2.1; 95% CI, 1.0 4.4). Similarly, older adults with DM who developed dementia had a greater risk for having a subsequent hypoglycemic event compared with participants who did not develop dementia (14.2% vs 6.3%, P < .001; multivariate-adjusted hazard ratio, 3.1; 95% CI, 1.5-6.6). Further adjustment for stroke, hypertension, myocardial infarction, and cognitive change scores produced similar results. CONCLUSION AND RELEVANCE: Among older adults with DM, there seems to be a bidirectional association between hypoglycemia and dementia. PMID- 23753219 TI - The weaning index as predictor of weaning success. AB - BACKGROUND: The quest to obtain an accurate way to predict success when weaning a patient from mechanical ventilation continues. The established parameters such as tidal volume (Vt), respiratory rate (f), negative inspiratory force (NIF), vital capacity (VC), and minute ventilation (V) have not predicted weaning accurately. The frequency-to-tidal volume ratio (f/Vt), or rapid shallow breathing index (RSBI) is a good predictor of weaning success if the value is low, but not when the value approximates 105. Because of the aforementioned, we decided to add 2 corrective factors to the RSBI. The first one was elastance index (EI = peak pressure/NIF) and the second one, the ventilatory demand index (VDI = minute ventilation/10). The result of the product of the RSBI * EI * VDI was called the weaning index (WI). METHODS: In order to assess the discriminatory power of WI, we obtained weaning parameters and calculated WI for 59 patients in our intensive care unit and extubated them if RSBI was <=105. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristics (ROC) curves were obtained. The results were compared with the previous studies involving the RSBI. RESULTS: The WI sensitivity was 98%, specificity was 89%, PPV was 95%, NPV was 94%, and area under the ROC curve was 95.9. CONCLUSIONS: The WI is a simple and reproducible parameter that integrates breathing pattern, compliance, inspiratory muscle strength, and ventilatory demand and is the most accurate predictor of weaning success. PMID- 23753220 TI - Systemic lupus-induced diffuse alveolar hemorrhage treated with extracorporeal membrane oxygenation: a case report and review of the literature. AB - OBJECTIVES: We report the case of a 28-year-old patient with systemic lupus erythematosus (SLE) with rapid onset of dyspnea and hemoptysis found to have diffuse alveolar hemorrhage (DAH) with refractory hypoxemia successfully treated with venovenous extracorporeal membrane oxygenation (ECMO). The discussion includes clinical presentation, diagnosis, management, outcome, and a review of the available adult literature on the use of ECMO in patients with DAH. DESIGN: Case report. SETTING: Froedtert Hospital and the Medical College of Wisconsin. DATA SOURCES: Data were collected from the patient's electronic medical record and the hospital radiology database. CONCLUSIONS: Diffuse alveolar hemorrhage secondary to SLE is quite rare. The adult literature on the utilization of ECMO for DAH is limited mostly to antineutrophil cytoplasmic antibody (ANCA) associated alveolar hemorrhage and a few reports of nonvasculitis DAH. Bleeding has been a contraindication to ECMO due to the need for systemic anticoagulation. Our case, along with a review of the literature, indicates that ECMO with anticoagulation can be safely utilized in patients with DAH. To our knowledge, this is the first reported adult case of DAH due to SLE successfully treated with ECMO. PMID- 23753221 TI - Fluid management in acute kidney injury. AB - Fluid management in critical illness has undergone extensive reevaluation in the past decade. Since a significant percentage of critically ill patients develop acute kidney injury (AKI), optimal fluid management is even more paramount to prevent the ill effects of either underhydration or overhydration. The concepts of early goal-directed fluid therapy (EGDT) and conservative late fluid management permeate current clinical research, and the independent association between fluid accumulation and mortality has been repeatedly demonstrated. A number of prospective randomized trials are planned to provide an adequately powered assessment of the effect of EGDT or earlier renal replacement therapy initiation in patients with, or at risk for AKI. The aim of this analytical review is to use existing clinical and physiological studies to support a 3-phase model of fluid management in the critically ill patient with AKI. PMID- 23753222 TI - Effect of normal saline and half normal saline on serum electrolytes during recovery phase of diabetic ketoacidosis. AB - OBJECTIVE: This study aims to describe the effect of 0.9% saline (NS) versus 0.45% saline (half NS) when used during recovery phase of diabetic ketoacidosis (DKA) in children. METHODS: A retrospective analysis of all children (1-18 years old) with DKA admitted in the pediatric intensive care unit (PICU) from 2005 to 2009 was undertaken. The primary end point was effect on serum electrolytes and acidosis. RESULTS: Compared to 47 patients who received only NS (group A) throughout the recovery period and 33 patients who received NS but were switched to half NS (group B) at some point during recovery, 41 who received only half NS (group C) had a significant decrease in corrected serum sodium (P < .01). Hyperchloremia leading to nonanion gap acidosis was significantly greater in NS groups A and B than in half NS group C (P < .01). This led to increased duration of insulin infusion and length of stay in the PICU in the NS groups. CONCLUSIONS: Hyperchloremia resulting in nonanion gap acidosis can occur and may prolong the duration of insulin infusion and length of PICU stay in patients receiving NS as post-bolus rehydration fluid. Alternatively, the use of half NS may result in a decrease in serum-corrected sodium. Providers need to be vigilant toward this while using higher or lower sodium chloride when managing children with DKA. Larger trials are required to study the clinical significance of the results of this study. PMID- 23753223 TI - Procedural and educational interventions to reduce ventilator-associated pneumonia rate and central line-associated blood stream infection rate. AB - BACKGROUND: Implementing best practice guidelines for ventilator-associated pneumonia (VAP) and central line-associated blood stream infection (CLA-BSI) has variable success. Our institution was concerned with high rates of VAP and CLA BSI. This retrospective study was undertaken to see whether implementation of the below practices would reduce the rates of VAP and CLA-BSI without resorting to more expensive interventions such as subglottic endotracheal (ET) tube suctioning or silver-impregnated ET tubes. We utilized easily collectable data (standardized infection ratios [SIRs]) to rapidly assess whether interventions already in place were successful. This avoided cumbersome data collection and review. METHODS: Retrospective data review calculated SIRs using National Healthcare Safety Network benchmarks. Rates and SIRs were compared using z tests with P values <.05 considered statistically significant. This data review attempted to examine the impact of education campaigns, staff meetings, in-services, physician checklist, nurse checklist, charge nurse checklist implementation, and chlorhexidine gluconate oral care addition to the VAP bundle. Additionally, central line insertion required nursing supervision, a checklist, and physician signature. RESULTS: The incidence rate of VAP went from 9.88 occurrences/1000 vent days in 2009 to 0 occurrences/1000 vent days in 2010 (P < .001). The CLA-BSI occurrences/1000 line days were 2.86 in 2009 and 0.97 in 2010 (P = .0187). The SIR for VAP was 4.12 in 2009 and 0 in 2010 (P < .001). For CLA-BSI, the SIR was 1.1 in 2009 and 0.37 in 2010 (P = .04). CONCLUSIONS: Efforts to improve physician, patient, and staff education, and checklist implementation resulted in a decrease in VAP and CLA-BSI. This study confirms the applicability of best practice guidelines and suggests a benefit to the use of checklists. We utilize a practical approach for examining the success of these changes. PMID- 23753224 TI - Subsequent infections in survivors of sepsis: epidemiology and outcomes. AB - PURPOSE: Sepsis is a devastating condition with considerable mortality. The causes of long-term mortality are poorly understood. To test the hypothesis that patients with sepsis are more susceptible to recurrent infections and death due to infectious complications, we investigated the outcomes of patients who survived sepsis, with regard to the incidence of recurrent infections and mortality. MATERIALS AND METHODS: A retrospective study of the patients admitted to the intensive care unit (ICU) for sepsis from 2001 to 2002 who achieved 30-day survival (sepsis survivors [SSs], N = 78) and a control group of patients admitted to the ICU for noninfectious conditions with a similar severity of illness (N = 50) was performed. The primary end point was the number of recurrent infections in the first year posthospitalization. RESULTS: The SSs group had higher rates of infections following hospital discharge compared to controls. Using a multivariable model, having survived sepsis was the strongest predictor of the development of subsequent infections (rate ratio [RR]: 2.83, P= .0006), the need for rehospitalization for infection in the year after the initial hospitalization (RR: 3.78, P = .0009), and postdischarge mortality (hazard ratio = 3.61, P = .003). CONCLUSIONS: Critically ill patients who survive sepsis have an increased risk of recurrent infections in the year following their septic episode that is associated with increased mortality. PMID- 23753225 TI - Management of autism in the adult intensive care unit. AB - Autism comprises a growing segment of the population and can be a management challenge in the intensive care unit (ICU). We present the case of a 22-year-old male with severe autism and intellectual disorder who developed respiratory failure and required a prolonged ICU course. This patient exhibited severe distress, aggression, and self-injurious behavior. Management challenges included sedation, weaning from sedation, and liberation from mechanical ventilation. Success was achieved with a multispecialty team and by tailoring the environment and interactions to the patient's known preferences. The use of dexmedetomidine to wean high-dose benzodiazepines and opiates also permitted successful liberation from mechanical ventilation. PMID- 23753226 TI - Plasma brain natriuretic peptide and troponin levels in severe sepsis and septic shock: relationships with systolic myocardial dysfunction and intensive care unit mortality. AB - The aim of this study was to evaluate and compare brain natriuretic peptide (BNP) and cardiac troponin I (cTnI) levels as mortality prognosticator and predictor for myocardial dysfunction in severe sepsis and septic shock. Baseline clinical and biological variables were collected from 47 patients with severe sepsis or septic shock. Ventricular systolic function assessed by echocardiography was measured over a 5-day period. Both cTnI and BNP plasmatic levels were determined at intensive care unit (ICU) admission and during the following 15 days. At admission, cTnI and BNP levels were compared to those of 12 control critically ill nonseptic patients. The plasma levels of BNP and cTnI in patients with sepsis were elevated at admission and significantly higher than in the controls. Among patients with sepsis, BNP levels were significantly more elevated in nonsurvivors compared to survivors at admission and 1 day later. The cTnI levels were also significantly more elevated in nonsurvivors compared to survivors, but only at admission. From admission to day 5, patients with sepsis with left ventricular systolic dysfunction had higher BNP plasmatic concentrations than those without; differences were significant at days 3 and 4. In contrast, plasma cTnI levels were similar between the 2 groups. In critically ill patients, sepsis induces significant increase in BNP and cTnI levels. High BNP and cTnI plasma levels during ICU admission appear to be associated with poor outcome of sepsis. Time course of BNP levels seems helpful to discriminate between surviving and nonsurviving patients with sepsis and to detect myocardial dysfunction where troponin levels fail to do so. PMID- 23753227 TI - SNAP II index: an alternative to the COMFORT scale in assessing the level of sedation in mechanically ventilated pediatric patients. AB - Sedation monitoring is essential in pediatric patients on ventilatory support to achieve comfort and safety. The COMFORT scale was designed and validated to assess the level of sedation in intubated pediatric patients. However, it remains unreliable in pharmacologically paralyzed patients. The SNAP II index is calculated using an algorithm that incorporates high-frequency (80-420 Hz) electroencephalogram (EEG) components, known to be useful in discriminating between awake and unconscious states, unlike other measurements that only include low-frequency EEG segments such as the bispectral index score. Previous studies suggested that the SNAP II index is a reliable and sensitive indicator of the level of consciousness in adult patients. Despite its potential, no data are currently available in the pediatric critically ill population on ventilatory support. This is the first pilot study assessing the potential application of the SNAP II index in critically ill pediatric patients by comparing it to the commonly used COMFORT scale. PMID- 23753228 TI - Multiorgan system dysfunction in the chylomicronemia syndrome. AB - OBJECTIVE: To describe an extreme presentation of the chylomicronemia syndrome resulting in multiorgan system dysfunction. PATIENT: A 40-year-old African American male with no past medical history presented with multiorgan system dysfunction manifested by acute respiratory failure and acute kidney injury. He was noted to have very-high triglyceride levels (>5000 mg/dL) at admission. INTERVENTIONS: An echocardiogram showed normal cardiac function. Amylase and lipase were normal. We confirmed the chylomicronemia syndrome with a triglyceride assay. The associated hyperviscosity was treated with plasmapheresis to reduce the plasma triglyceride level. RESULTS: After 3 sessions of plasmapheresis, his triglyceride levels were significantly reduced, his oxygenation improved, and his acute kidney injury resolved. He was successfully extubated on day 7 of the intensive care unit stay. His diabetes and hypertriglyceridemia were newly diagnosed and drug therapy was instituted with home discharge on day 14. CONCLUSIONS: Severe chylomicronemia can cause multiorgan system dysfunction related to hyperviscosity. Early institution of plasmapheresis to reduce the triglyceride-rich lipoproteins can improve tissue perfusion and prevent further organ damage. PMID- 23753229 TI - New drugs and strategies for management of Clostridium difficile colitis. AB - Approaches for management of Clostridium difficile infection continually evolve as research reveals shifts in epidemiology, microbial pathogenesis, disease severity states, and response to therapy. These new discoveries significantly impact diagnostic and therapeutic strategies, given the high morbidity associated with this common nosocomial infectious diarrhea. Critically ill patients are at an increased risk of developing diarrheal illness like C. difficile and succumbing to potentially fatal complications of this infection. Early diagnosis of severe disease state may improve patient outcomes. In this article, we review treatment strategies and new approaches for the management of C. difficile in critically ill patients. PMID- 23753230 TI - Patient origin is associated with duration of endotracheal intubation and PICU length of stay for children with status asthmaticus. AB - OBJECTIVE: To describe intubation practices and duration of mechanical ventilation in children with status asthmaticus admitted from emergency departments (ERs) to pediatric intensive care units (PICUs). DESIGN: Retrospective cohort study using the Virtual PICU Performance System database (VPS, LLC) of children with status asthmaticus admitted to a participating PICU between December 2003 and September 2006. The primary outcome measure was intubation prior to intensive care unit (ICU) admission. Secondary outcomes included length of intubation and medical length of stay. SETTING: Thirty-five PICUs in the United States. PATIENTS: Children who were intubated and mechanically ventilated during their ICU stay for asthma and were admitted from an ER. RESULTS: A total of 4051 patients with status asthmaticus were identified. Intubation data were available from 35 of the 53 centers. Of all, 187 children were intubated for asthma, of which 157 were admitted from an ER and had complete data. Of all, 85 patients were from community hospital ERs and 72 were from the institution's own ER. In all, 115 (73%) patients were intubated prior to ICU admission and 42 (27%) patients were intubated after PICU admission. Of patients who received mechanical ventilation for status asthmaticus and were intubated prior to PICU admission, a greater proportion were intubated at community hospital ERs than in the institutions' own ERs. Eighty-five percent of the patients from community hospital ERs were intubated prior to PICU admission as opposed to 60% from institution's own ERs (P = .0004). However, median duration of intubation and PICU stay from community hospital ERs was significantly shorter than from the hospitals' own ERs (25 vs 42 hours P = .011; 57 vs 98 hours P = .0013, respectively). Logistic regression analysis revealed that after controlling for the effects of age, race, gender, and a revised version of the Paediatric Index of Mortality score of patients who were admitted for status asthmaticus and required mechanical ventilations, patients treated in community hospital ERs represented a greater proportion of preadmission intubation. The odds ratio for preadmission intubation was 5.1 if the patients arrived from community hospital ERs (95% confidence interval 1.91-13.6). CONCLUSION: PATIENTS with status asthmaticus are more likely to be intubated when they are admitted from community hospital emergency rooms, although the duration of intubation and PICU stay is shorter. PMID- 23753232 TI - Intraabdominal infections in the intensive care unit. AB - Intraabdominal infections are frequent and dangerous entity in intensive care units. Mortality and morbidity are high, causes are numerous, and treatment options are variable. The intensivist is challenged to recognize and treat intraabdominal infections in a timely fashion to prevent complications and death. Diagnosis of intraabdominal infection is often complicated by confounding underlying disease or masked by overall comorbidity. Current research describes a wide heterogeneity of patient populations, making it difficult to suggest a general treatment regimen and stressing the need of an individualized approach to decision making. Early focus-oriented intervention and antibiotic coverage tailored to the individual patient and hospital is warranted. PMID- 23753233 TI - Letter to the editor. PMID- 23753231 TI - Cytomegalovirus pneumonia in hematopoietic stem cell recipients. AB - Cytomegalovirus (CMV) is a frequently encountered infection following hematopoietic cell transplantation, and tissue invasive pneumonia is a dreaded complication of the virus in this population. In this review of CMV pneumonia, we address epidemiology, pathogenesis, diagnostics, current therapy, and strategies to prevent the development of CMV. We also review emerging treatment and prevention options for this challenging disease. PMID- 23753234 TI - Response from the authors. PMID- 23753235 TI - Fluid resuscitation in septic shock: the effect of increasing fluid balance on mortality. AB - PURPOSE: To determine whether progressively increasing fluid balance after initial fluid resuscitation for septic shock is associated with increased mortality. METHODS: A retrospective review of the use of intravenous fluids in patients with septic shock in a large university affiliated hospital with 56 medical-surgical intensive care unit beds. We analyzed the data of 350 patients with septic shock who were managed according to the Surviving Sepsis Campaign guidelines. Based on net fluid balance at 24 hours, we examined the results of increase in positive fluid balance on the risk of in-hospital mortality. Patients were divided into 4 groups based on the amount of fluid balance by 24 hours, based on 6-L aliquots. RESULTS: At 24 hours, the average fluid balance was +6.5 L. After correcting for age and sequential organ failure assessment score, a more positive fluid balance at 24 hours significantly increased the risk of in hospital mortality. Using Cox proportional hazard analysis, excess 12-, 18-, and 24-L positive fluid balance had higher risk of mortality than those patients with a neutral to positive 6-L fluid balance (reference group). Adjusted hazard ratios, 1.519 (95% confidence interval [CI], 1.353-1.685), 1.740 (95% CI, 1.467 2.013), and 1.620 (95% CI, 1.197-2.043), respectively, P < .05. CONCLUSION: In patients with septic shock resuscitated according to current guidelines, a more positive fluid balance at 24 hours is associated with an increase in the risk of mortality. Optimal survival occurred at neutral fluid balance and up to 6-L positive fluid balance at 24 hours after the development of septic shock. PMID- 23753236 TI - Intensive care management following defibrillation of an adolescent girl after recreational inhalant use: a case report and review of the literature. AB - We report the successful out-of-hospital defibrillation and intensive care management of a 14-year-old girl who developed ventricular fibrillation following the inhalation of two 150-mL butane cigarette lighter refill canisters. Following ambulance transport to the nearest tertiary pediatric health care facility, her acute clinical course consisted of sinus tachycardia, fluctuating consciousness, and severe cerebral agitation and combativeness. Over a period of 2 weeks, her neurological function significantly improved to the point she was able to be discharged back into the community, however, not without a number of formally identified neurological deficits. Inhalant gasses, through as yet unclear mechanisms, can cause the myocardium cell membrane to become unusually sensitive to catecholamines which in turn can sometimes lead to fatal arrhythmias. This case is reported for its rarity in terms of the patient being able to be discharged back into the community and to create awareness of the sudden and potentially devastating consequences of butane inhalant use for critical care physicians and prehospital health-care personnel. PMID- 23753238 TI - Evaluation of a new index of mechanical ventilation weaning: the timed inspiratory effort. AB - PURPOSE: The performance of most indices used to predict ventilator weaning outcomes remains below expectation. The purpose of this study was to evaluate a new weaning index, the timed inspiratory effort (TIE) index, which is based on the maximal inspiratory pressure and the occlusion time required to reach it. METHODS: This observational prospective study included patients undergoing mechanical ventilation. Patients ready to be weaned had their TIE index and 6 previously reported indices recorded. The primary end point was the overall predictive performance of the studied weaning indices (area under the receiver operating characteristic curves [AUCs]). The secondary end points were sensitivity, specificity, positive predictive value, and negative predictive value. P values <.05 were considered significant. RESULTS: From the 128 initially screened patients, the 103 patients selected for the study included 45 women and 58 men (mean age 60.8 +/- 19.8 years). In all, 60 patients were weaned, 43 were not weaned, and 32 died during the study period. Tracheotomy was necessary in 61 patients. The mean duration of mechanical ventilation was 17.5 +/- 17.3 days. The AUC of 3 weaning predictors (the TIE index, the integrative weaning index, and the frequency-to-tidal volume [f/Vt] ratio index) was higher than the other indices. The TIE index had the largest AUC. CONCLUSION: The TIE index performed better than the best weaning indices used in clinical practice. PMID- 23753237 TI - Percutaneous intraperitoneal catheters in neonates following open heart surgery. AB - OBJECTIVE: Ascitic fluid in the peritoneal cavity may severely impair respiratory and renal function following neonatal heart surgery. It has been our practice to liberally insert percutaneous peritoneal catheters (PPCs) in order to manage fluid balance and thereby improve ventilatory function. We herein report our experience with PPC. METHODS: Retrospective analysis of charts of all surviving neonates that underwent PPC insertion from January 2007 through March 2010. Charts were reviewed for demographic and clinical variables from the preoperative, operative, and postoperative periods. RESULTS: A total of 1268 patients underwent surgery, 292 (23%) were neonates. 17 (5.8%) patients required PPC. Mean age and weight were 16 days and 3.1 kg, respectively. Mean amount drained upon insertion was 55 +/- 46 ml. Catheters were maintained for a mean of 5 days and drained an average of 201 ml on the first postinsertion day. Ventilatory settings did not change significantly prior to and postcatheter insertion (respiratory rate [29 +/- 3.8 vs 28.7 +/- 3.9; P = .93], inspiratory pressures [26.3 +/- 3.6 vs 26.1 +/- 3.3 cm H2O; P = .34], and fraction of inspired oxygen [0.66 +/- 0.21 vs 0.63 +/- 0.18; P = .53]). Carbon dioxide values decreased significantly (43.2 +/- 9.7 vs 37 +/- 4.9 mm Hg; P = .01), and PO2 values increased (78 +/- 69 vs 104 +/- 57 mm Hg; P = .05). CONCLUSIONS: The PPC insertion can be easily performed at the bedside with minimal complications. Fluid balance management is facilitated, and ventilation is improved. The PPC insertion is a valuable addition to the armamentarium of the physician treating neonates in the intensive care unit after complex congenital heart surgery. PMID- 23753239 TI - Chiari syndrome and respiratory failure: a literature review. AB - BACKGROUND: Patients with failed extubation requiring reintubation have increased morbidity and mortality. This situation may reflect the severity of the underlying disorder or may reflect an undiagnosed condition that was not apparent at the time of the initial intubation. METHODS: Case report and literature review. RESULTS: A 49-year-old man developed acute hypercapneic respiratory failure during an episode of community-acquired pneumonia. This patient failed extubation 4 times. Routine neurological evaluation, including computed tomography of the head, was within normal limits. A magnetic resonance imaging revealed a severe Chiari malformation type I. The patient eventually required tracheostomy and prolonged mechanical ventilation. We identified 28 cases with Chiari malformations (CM) in the medical literature, who presented with respiratory failure. The mean age was 29.5 years, 46% of the cases were male, 50% had an associated syringomyelia, and 64% required a decompressive surgery. Twenty five percent had recurrent symptoms postsurgery. CONCLUSIONS: Patients with CMs can have repeated extubation failures. Some of these patients have normal neurological examinations and studies and are not identified until they have an MRI study. Clinicians need to consider this possibility in patients who are difficult to wean. PMID- 23753240 TI - Modern trends in infection control practices in intensive care units. AB - Hospital-acquired infections (HAIs) are common in intensive care unit (ICU) patients and are associated with increased morbidity and mortality. There has been an increasing effort to prevent HAIs, and infection control practices are paramount in avoiding these complications. In the last several years, numerous developments have been seen in the infection prevention strategies in various health care settings. This article reviews the modern trends in infection control practices to prevent HAIs in ICUs with a focus on methods for monitoring hand hygiene, updates in isolation precautions, new methods for environmental cleaning, antimicrobial bathing, prevention of ventilator-associated pneumonia, central line-associated bloodstream infections, catheter-associated urinary tract infections, and Clostridium difficile infection. PMID- 23753241 TI - Common anorectal disorders for the intensive care physician. AB - Although anorectal disorders such as abscess, fissure, and hemorrhoids are typically outpatient problems, they also occur in the critically ill patient population, where their presentation and management are more difficult. This article will provide a brief review of anorectal anatomy, explain the proper anorectal examination, and discuss the current understanding and treatment concepts with regard to the most common anorectal disorders that the intensive care unit clinician is likely to face. PMID- 23753242 TI - Accuracy of noninvasive and continuous hemoglobin measurement by pulse co oximetry during preoperative phlebotomy. AB - BACKGROUND: In recent years, the continuous noninvasive hemoglobin measurement has been offered by devices using advanced pulse oximetry technology. Accuracy has been established in healthy adults as well as in surgical and intensive care unit patients but not in the setting of acute hemorrhage. In this study, we evaluated the accuracy of such a device in the clinical setting of preoperative phlebotomy thereby mimicking a scenario of acute blood loss. METHODS: This prospective study included patients undergoing surgical repair of congenital heart disease (CHD) for whom preoperative phlebotomy was planned. Blood was removed after the induction of anesthesia and prior to the start of the surgical procedure. Replacement with crystalloid was guided by hemodynamic variables and cerebral oxygenation measured by near-infrared spectroscopy. Hemoglobin was measured by bedside whole blood analysis (total hemoglobin [tHb]) before and after phlebotomy, and concurrent measurements from the pulse co-oximeter (noninvasive, continuous, or spot-check testing of total hemoglobin [SpHb]) were recorded. RESULTS: The study cohort included 45 patients ranging in age from 3 months to 50 years. Preoperative phlebotomy removed an average of 9.2 mL/kg of blood that was replaced with an average of 7.2 mL/kg of crystalloid. The pre- and postphlebotomy tHb values were 13.0 +/- 1.9 and 12.4 +/- 1.8 g/dL, respectively. The absolute difference between the tHb and SpHb (?Hb) was 1.2 +/- 0.1 g/dL. Bland-Altman analysis revealed a bias of 0.1 g/dL, a precision of 1.5 g/dL, and 95% limits of agreement of -2.8 to 3.1 g/dL. In 52.2% of the sample sets, the SpHb was within 1 g/dL of the actual hemoglobin value (tHb), and in 80% of the sample sets, the SpHb was within 2 g/dL. No variation in the accuracy of the deviation was noted based on the patient's age, weight, or type of CHD (cyanotic versus acyanotic). CONCLUSION: The current study demonstrates that the accuracy of continuous, noninvasive hemoglobin measurement was not affected by acute blood loss simulated by preoperative phlebotomy. Although the device provided a clinically acceptable correlation with the actual hemoglobin value and offers the value of a continuous trend monitor, given the precision of the device, it does not appear that actual transfusion decisions can be based on the device alone. PMID- 23753243 TI - Mutual agreement between providers in intensive care medicine on patient care after interdisciplinary rounds. AB - PURPOSE: Insights regarding the results of interdisciplinary communication about patient care are limited. We explored the perceptions of intensivists, junior physicians, and nurses about patient care directly after the interdisciplinary rounds (IDRs) in the intensive care unit (ICU) to determine mutual agreement. METHODS: A single-center survey study adapted from Pronovost "daily goal sheet" was performed in the ICUs for adults at a university medical center. Participants were intensivists, junior physicians, and ICU nurses. This survey, consisting of 14 items, was obtained directly after IDRs. Descriptive statistics of 90 observations of 30 discussed patient plans were computed. The internal consistency of the survey was measured by Cronbach alpha. RESULTS: Differences between the hypothesized agreement of 90% and the saturated agreement revealed significant differences in 12 of the 14 items between the 3 groups of ICU care providers. Results of the differing agreement between intensivist and junior physicians or ICU nurses and between ICU nurses and junior physicians revealed that intensivists tend to agree more with ICU nurses than they do with the junior physicians. Internal consistency showed alpha = .74. CONCLUSIONS: The recommendation of IDRs without mutual agreement in important aspects of patient care hampers safety in daily practice. This study demonstrates that a survey to determine this agreement between the intensivists, junior physicians, and ICU nurses has low agreement, as measured directly after the IDRs. PMID- 23753244 TI - Impact of nurse integrated rounds on self-reported comprehension, attitudes, and practices of nurses and resident physicians in a pediatric intensive care unit. AB - OBJECTIVES: To evaluate the impact of nurse integrated rounds (NIRs) on self reported comprehension, attitudes, and practices of nurses and resident physicians (RPs) in a pediatric intensive care unit (PICU). MATERIALS AND METHODS: A self-reported comprehension, attitude, and practice survey of RPs and nurses was done prior to (T0), 3 months (T3), and 15 months (T15) after initiation of NIRs in our PICU. Responses were graded on Likert-type scale from 1 to 5. The RPs, attending physicians, and nurses also ranked their overall perception of NIRs during these 3 survey time periods. RESULTS: All 3 components of the surveys showed statistically significant improvement (P < .05) from the T0 to T3 and T15 in RPs and nurses. A complete or almost complete reversal of attitude was noted for most questions in the attitude section in both RPs and nurses when T15 was compared to T0. The overall perception that NIRs was good for patient care also showed significant improvement in the survey of nurses and physicians. CONCLUSIONS: The NIRs are well accepted by nurses and physicians and are accompanied by self-reported improvements in comprehension, attitudes, and practices of nurses and RPs in the PICU. PMID- 23753245 TI - Agitation during prolonged mechanical ventilation at a long-term acute care hospital: risk factors, treatments, and outcomes. AB - INTRODUCTION: The prevalence, risk factors, treatment practices, and outcomes of agitation in patients undergoing prolonged mechanical ventilation (PMV) in the long-term acute care hospital (LTACH) setting are not well understood. We compared agitation risk factors, management strategies, and outcomes between patients who developed agitation and those who did not, in LTACH patients undergoing PMV. METHODS: Patients admitted to an LTACH for PMV over a 1-year period were categorized into agitated and nonagitated groups. The presence of agitation risk factors, management strategies, and relevant outcomes were extracted and compared between the 2 groups. RESULTS: A total of 80 patients were included, 41% (33) with agitation and 59% (47) without. Compared to the nonagitated group, the agitated group had a lower Sequential Organ Failure Assessment score (P < .0006), a greater transfer rate from an academic center (P = .05), a greater delirium frequency at both baseline (P = .04) and during admission (P < .001), and a greater rate of benzodiazepine discontinuation (P = .02). Although the use of scheduled antipsychotic (P = .0005) or restraint (P = .002) therapy was more common in the agitated group, use of benzodiazepines (P = .16), opioids (P = .11), or psychiatric evaluation (P = .90) was not. Weaning success, duration of LTACH stay, and daily costs were similar. CONCLUSION: Agitation among the LTACH patients undergoing PMV is associated with greater delirium and use of antipsychotics and restraints but does not influence weaning success or LTACH stay. Strategies focused on agitation prevention and treatment in this population need to be developed and formally evaluated. PMID- 23753246 TI - Fatal case of tension pneumothorax and subcutaneous emphysema after open surgical tracheostomy. AB - Tracheostomy tube placement remains one of the most commonly performed procedures in the intensive care unit. Its utilization permits ventilation in patients with severe compromise of the airway patency as well as facilitation of liberation of mechanical ventilation in patients with prolonged ventilatory needs. Despite its frequent use, the tracheostomy procedure, whether performed surgically or percutaneously, is not free of severe, and, in some cases devastating, complications. In fact, severe adverse events, such as pneumomediastinum, pneumothorax, hemorrhage, infections, and, occasionally, death, have been described. We report a case of a surgical tracheostomy complicated with fatal tension pneumothorax and subcutaneous emphysema secondary to an iatrogenic posterior tracheal wall laceration. This complication is barely seen in usual practice, and its recognition and aggressive therapy may avoid fatal outcomes. PMID- 23753247 TI - Hypertonic saline in elevated intracranial pressure: past, present, and future. AB - Hypertonic Saline (HS) has been a proven and effective therapy and a safe alternative to mannitol in patients with increase intracranial pressure (ICP). We hereby present a case of 25-year-old women with intracranial bleed secondary to right parietal arteriovenous malformation. Patient underwent surgery for evacuation of hematoma and resection of arteriovenous malformation. Post- operative course was complicated by recurrent episodes of elevated ICP. She received total of 17 doses of 23.4% HS and 30 doses of mannitol with good outcome. Despite reluctance from some clinicians to use HS, hypertonic saline seems to be a safe and effective therapy. PMID- 23753248 TI - Percutaneous tracheostomy at the bedside: 13 tips for improving safety and success. AB - We have developed a set of routines and practices in the course of performing a large series (n = 70) of percutaneous dilational tracheostomy (PDT). The 13 tips discussed in this review fall into 4 categories. System factors that facilitate training, patient safety, and avoidance of crises including the use of appropriate personnel, importance of timing, use of premedication, and the utility and content of a preprocedure briefing. Suggestions to prevent loss of the airway include tips on airway assessment, preparation of airway equipment, and use of exchange catheter techniques. Strategies to avoid and manage both microvascular and large-vessel bleeding are discussed. We also discuss the management of common postprocedure problems including tracheostomy tube obstruction, malposition requiring tube exchange or replacement, and air leak. The practical considerations for successful execution of PDT involve common sense, thorough planning, and structured approaches to prevent adverse effects if the procedure does not go as smoothly as expected. These strategies will aid anesthesiologists and intensivists in improving their comfort level, safety, and competence in performing this beside procedure. PMID- 23753249 TI - Umbilical cord blood transplantation: review of factors affecting the hospitalized patient. AB - The use of umbilical cord blood (UCB) as a stem cell donor source has dramatically increased over the last 2 decades. Patients undergoing UCB transplantation share medical management issues with patients receiving a hematopoietic stem cell transplantion using adult donor sources (peripheral blood stem cells or bone marrow stem cells) and may also have more complex medical issues that appear to be related to delayed immune recovery from UCB-derived stem cells. The interface with critical care providers is likely to occur in the transplant and posttransplant setting. Patients may experience UCB infusion reactions that range from mild to rarely severe. Following transplant, patients are transfusion dependent for long periods due to the prolonged engraftment of UCB cells. They are at high risk of infection, particularly viral. Once engrafted, UCB transplant patients have a lower rate of graft versus host disease compared to other donor sources. Some of the other complications that are seen in patients undergoing UCB transplant are posttransplant lymphoproliferative disease, diffuse alveolar hemorrhage, and posterior reversible encephalopathy will also be discussed. PMID- 23753250 TI - Intracerebral hemorrhage in patients receiving oral anticoagulation therapy. AB - Intracerebral hemorrhage (ICH) in patients with oral anticoagulation therapy is an increasingly prevalent problem in large part due to the aging population and the increased use of anticoagulants for patients at high risk of thrombosis. Warfarin has been virtually the only outpatient anticoagulant choice until fairly recently. The development of subcutaneously injected heparinoids, and more recently, of direct thrombin inhibitors, has made the treatment and prognostication of ICH in anticoagulated patients more difficult. In this review, we will review the current state of diagnosis, prognostication, and treatment for patients with this often-devastating type of bleeding. We will focus on warfarin therapy, because the preponderance of evidence comes from studies of warfarin treatment. Where there is evidence, we will contrast warfarin with some of the newer treatment modalities. We review the evidence of the 4 major reversal agents for warfarin, vitamin K, prothrombin complex concentrates, activated factor VII, and fresh frozen plasma as well as rational treatment choices. We offer possible treatments for the newer anticoagulants based on the limited evidence available. Finally, we review recommendations from the major societies and studies that support early and aggressive therapies in intensive care units with dedicated neurological specialists. PMID- 23753251 TI - Retrospective computed tomography mapping of intrapleural air may demonstrate optimal window for ultrasound diagnosis of pneumothorax. AB - INTRODUCTION: When a pneumothorax exists, free air should rise to the most nondependent region within the chest. Current ultrasound (US) examination methodologies may exclude visualization of these areas that may limit the sensitivity of the examination. This retrospective study uses computed tomography (CT) scans to precisely evaluate where free air within the thorax occurs and correlates this location with a presumably optimal US interrogation window. METHODS: A total of 94 CT scans of patients with a pneumothorax in a single institution from December 2006 to January 2010 were examined. The borders and volumes of each pneumothorax were precisely measured by a radiologist. Logistic regression was used to determine the relationship between volume and location of intrapleural air at specified areas of the hemithorax. Sensitivities relating location of intrapleural air at a specific landmark and side of thorax were calculated. RESULTS: All but 3 of the pneumothoraces extended to the sternum. In all, 83 patients demonstrated a pneumothorax between rib interspaces 3 and 6 (mean pneumothorax volume 300.4 mL, 95% confidence interval [CI] 217.4-383.3), and 11 patients did not (mean pneumothorax volume 4.5 mL, 95% CI 1.7-7.3; P < .0001). The cumulative sensitivity for the presence of intrapleural air at rib interspaces 3 to 6 along the sternal border was 88%. This was consistent regardless of the side of hemithorax (right 91% and left 86%). CONCLUSION: The CT scans demonstrate that intrapleural air most often collects along the mediastinum between ribs 3 and 6 on either side of the chest. Although no USs were performed in this retrospective study, one may infer that a parasternal approach along rib interspaces 3 to 6 is an easy and sensitive window to diagnose pneumothorax with US. PMID- 23753252 TI - The association of serum bilirubin levels on the outcomes of severe sepsis. AB - PURPOSE: Admission serum bilirubin levels have been incorporated into severity of illness scoring systems in critical illness as a marker of liver dysfunction. The purpose of our study is to determine the independent association of serum bilirubin with mortality in severe sepsis and septic shock. METHODS: We conducted a retrospective study of adult patients admitted with severe sepsis and septic shock. We excluded patients with a prior history of liver disease. We identified the highest serum bilirubin within 72 hours of admission and stratified bilirubin levels into <=1 mg/dL (normal), 1.1 to 2 mg/dL (abnormal up to 2 mg/dL), and >2 mg/dL. We sought to determine the independent association of hyperbilirubinemia with mortality and length of intensive care unit stay in persons with severe sepsis and septic shock. RESULTS: A total of 251 patients met criteria for severe sepsis. In all, 200 patients had a bilirubin of <1 mg/dL, and 51 had a bilirubin of >1 mg/dL. Of these 51, 12 had a bilirubin >2 mg/dL. Mortality was 12%, 24%, and 42% in persons with a bilirubin <=1, 1.1 to 2, and >2 mg/dL, respectively. Compared to those with a bilirubin <= 1 mg/dL, adjusted odds of mortality in patients were 3.85 (95% confidence interval [CI] 1.21-12.2) and 9.85 (95% CI 1.92 50.5) times higher in persons with bilirubin levels between 1.1 and 2 and >2 mg/dL, respectively. CONCLUSION: After multivariable adjustment for potential confounding factors, elevated serum bilirubin levels within 72 hours of admission are associated with an increased risk of mortality in patients with severe sepsis and septic shock. Prospective studies are warranted to further validate our findings. PMID- 23753253 TI - Potassium abnormalities in a pediatric intensive care unit: frequency and severity. AB - BACKGROUND: Potassium abnormalities are common in critically ill patients. We describe the spectrum of potassium abnormalities in our tertiary-level pediatric intensive care unit (PICU). METHODS: Retrospective observational cohort of all the patients admitted to a single-center tertiary PICU over a 1-year period. Medical records and laboratory results were obtained through a central electronic data repository. RESULTS: A total of 512 patients had a potassium measurement. Of a total of 4484 potassium measurements, one-third had abnormal values. Hypokalemia affected 40% of the admissions. Mild hypokalemia (3-3.4 mmol/L) affected 24% of the admissions. Moderate or severe hypokalemia (K <3.0 mmol/L) affected 16% of the admissions. Hyperkalemia affected 29% of the admissions. Mild hyperkalemia (5.1-6.0 mmol/L) affected 17% of the admissions. Moderate or severe hyperkalemia (>6.0 mmol/L) affected 12%. Hemolysis affected 2% of all the samples and 24% of hyperkalemic values. On univariate analysis, severity of hypokalemia was associated with mortality (odds ratio 2.2, P = .003). CONCLUSIONS: Mild potassium abnormalities are common in the PICU. Repeating hemolyzed hyperkalemic samples may be beneficial. Guidance in monitoring frequencies of potassium abnormalities in pediatric critical care is needed. PMID- 23753254 TI - The prevalence and impact of mortality of the acute respiratory distress syndrome on admissions of patients with ischemic stroke in the United States. AB - PURPOSE: To determine the epidemiology of the acute respiratory distress syndrome (ARDS) and impact on in-hospital mortality in admissions of patients with acute ischemic stroke (AIS) in the United States. METHODS: Retrospective cohort study of admissions with a diagnosis of AIS and ARDS from 1994 to 2008 identified through the Nationwide Inpatient Sample. RESULTS: During the 15-year study period, we found 55 58 091 admissions of patients with AIS. The prevalence of ARDS in admissions of patients with AIS increased from 3% in 1994 to 4% in 2008 (P < .001). The ARDS was more common among younger men, nonwhites, and associated with history of congestive heart failure, hypertension, chronic obstructive pulmonary disease, renal failure, chronic liver disease, systemic tissue plasminogen activator, craniotomy, angioplasty or stent, sepsis, and multiorgan failures. Mortality due to AIS and ARDS decreased from 8% in 1994 to 6% in 2008 (P < .001) and 55% in 1994 to 45% in 2008 (P < .001), respectively. The ARDS in AIS increased in-hospital mortality (odds ratio, 14; 95% confidence interval, 13.5-14.3). A significantly higher length of stay was seen in admissions of patients with AIS having ARDS. CONCLUSION: Our analysis demonstrates that ARDS is rare after AIS. Despite an overall significant reduction in mortality after AIS, ARDS carries a higher risk of death in this patient population. PMID- 23753256 TI - Regular self-weighing to promote weight maintenance after intentional weight loss: a quasi-randomized controlled trial. AB - BACKGROUND: Many overweight people take action to lose weight but most regain this weight. PURPOSE: To examine the effectiveness of a weight maintenance intervention focused on regular self-weighing after receiving a 12-week weight loss programme. METHODS: Quasi-randomized controlled trial of 3768 obese or overweight men and women. The intervention group (n = 3290) received two telephone calls, the offer of free weighing scales, encouragement to weigh themselves weekly and record this on a card. The main outcome was change in weight between 3 and 12 months. RESULTS: Using intention to treat analysis both groups regained weight; however, the intervention group on average regained 1.23 kg, whereas the control group regained 1.83 kg. Adjusting for covariates resulted in a mean difference of 0.68 kg (95% CI 0.12, 1.24) at 12-month follow-up. CONCLUSIONS: Encouraging people who have recently lost weight to weigh themselves regularly prevents some weight regain. PMID- 23753259 TI - Glucose control in older adults with diabetes mellitus--more harm than good? PMID- 23753274 TI - Extreme bilirubin levels as a causal risk factor for symptomatic gallstone disease. AB - IMPORTANCE: In individuals without blockage of their bile ducts, levels of plasma bilirubin likely reflect levels of biliary bilirubin; higher biliary bilirubin levels may increase the risk of gallstone disease. OBJECTIVE: To test the hypothesis that a lifelong increase in plasma bilirubin levels is a causal risk factor for symptomatic gallstone disease in the general population. DESIGN, SETTING, AND PARTICIPANTS: In a prospective study of the Danish general population (N = 61,212), we first tested whether elevated levels of plasma bilirubin predicted greater risk of symptomatic gallstone disease. Second, taking advantage of mendelian randomization, we tested whether a genetic variant in the bilirubin glucoronidating enzyme UGT1A1 (rs6742078) was associated with increased plasma bilirubin levels and, in turn, with an increased risk of symptomatic gallstone disease. MAIN OUTCOMES AND MEASURES: Plasma bilirubin level and symptomatic gallstone disease. RESULTS: During 34 years of follow-up, 3374 individuals developed symptomatic gallstone disease. In adjusted analyses, persons with plasma bilirubin levels in the 10th decile had a greater risk of symptomatic gallstone disease compared with those with plasma bilirubin levels in deciles 1 through 9; the hazard ratios (HRs) (95% CIs) were 1.57 (1.26-1.96) overall, 1.36 (1.02-1.82) in women, and 2.00 (1.41-2.83) in men. UGT1A1 genotype explained 20% of the total variation in plasma bilirubin levels and was associated with increases in the mean plasma bilirubin level overall of +16% (+0.09 mg/dL) in GT heterozygotes and +90% (+0.50 mg/dL) in TT homozygotes compared with GG homozygotes, with similar effects in women and men (P for trend <.001 for all). The corresponding HRs (95% CIs) for symptomatic gallstone disease were 1.09 (1.02-1.17) for GT heterozygotes and 1.22 (1.09-1.36) for TT homozygotes vs GG homozygotes and similar in women and men (P for trend = .04 <.001). CONCLUSIONS AND RELEVANCE: These results are compatible with a causal association between extreme levels of plasma bilirubin and increased risk of symptomatic gallstone disease. PMID- 23753295 TI - CCR5delta32 in systemic lupus erythematosus: implications for disease susceptibility and outcome in a Brazilian population. AB - The aim of this study was to analyze the allelic and genotypic frequencies of the CCR5delta32 polymorphism in systemic lupus erythematosus (SLE) patients and to investigate a possible association of this allele with SLE susceptibility and clinical outcome. A total of 367 SLE patients and 435 healthy controls were genotyped for the CCR5delta32 polymorphism. We observed that, in European-derived individuals, the frequency of the CCR5delta32 allele was smaller in patients than in controls (2.7% vs. 7.5%, OR 0.34, 95% CI 0.17-0.65, p Bonf=0.002), suggesting that this allele could be considered a protective factor for the disease. Regarding clinical manifestations, we observed that CCR5delta32 female African derived carrier patients presented a higher predisposition to class IV nephritis when compared with absent nephritis/other class group (13.8% vs. 3.8%, OR 37.1, 95% CI 2.8-1854.7, p Bonf=0.030). A multivariate analysis including all female patients and controlling for the presence or absence of anti-dsDNA antibodies, ethnicity and age at diagnosis showed an increased relative risk of 3.9 times for patients carrying the CCR5delta32 allele to develop class IV nephritis as compared with noncarriers. Our data suggest that the CCR5delta32 allele is a protective factor for the disease in European-derived patients and a susceptibility factor to class IV nephritis in African-derived female patients. PMID- 23753296 TI - Hypercalcemic crisis due to primary hyperparathyroidism in systemic lupus erythematosus (SLE). AB - Severe hypercalcemia is often caused by primary hyperparathyroidism (PHP), which is not commonly seen in patients with systemic lupus erythematosus (SLE). In this case report an adolescent girl with a history of SLE develops mild hypercalcemia secondary to unrecognized PHP that leads to a hypercalcemic crisis with a prolonged recovery. Therefore, early diagnostic evaluation of persistent hypercalcemia in patients with SLE is important for detection and appropriate treatment of PHP to avoid a hypercalcemic crisis and associated prolonged morbidity. PMID- 23753297 TI - A bibliometric study of literature on SLE research in PubMed (2002-2011). AB - OBJECTIVE: The objective of this paper is to study the distribution regularity, development tendency and research hot spots of systemic lupus erythematosus (SLE) literature published in journals indexed in PubMed over a 10-year period using the bibliometric analysis method. METHODS: Citations from 2002 to 2011 were downloaded from the PubMed database. The core of the search was the Medical Subject Headings (MeSH) "Lupus Erythematosus, Systemic." The period of study was set from 2002 to 2011. RESULTS: A total of 14,053 articles were retrieved. These articles were published in 1627 different journals, nine journals contributing to one-third of all the literature. The first three journals containing the most articles were CONCLUSION: SLE has become a field of interest over the period 2002 to 2011. However, lupus research publications in developing countries have lagged behind. PMID- 23753308 TI - Use of niacin in the United States and Canada. PMID- 23753405 TI - Heterozygous disruption of renal outer medullary potassium channel in rats is associated with reduced blood pressure. AB - The renal outer medullary potassium channel (ROMK, KCNJ1) mediates potassium recycling and facilitates sodium reabsorption through the Na(+)/K(+)/2Cl(-) cotransporter in the loop of Henle and potassium secretion at the cortical collecting duct. Human genetic studies indicate that ROMK homozygous loss-of function mutations cause type II Bartter syndrome, featuring polyuria, renal salt wasting, and hypotension; humans heterozygous for ROMK mutations identified in the Framingham Heart Study have reduced blood pressure. ROMK null mice recapitulate many of the features of type II Bartter syndrome. We have generated an ROMK knockout rat model in Dahl salt-sensitive background by using zinc finger nuclease technology and investigated the effects of knocking out ROMK on systemic and renal hemodynamics and kidney histology in the Dahl salt-sensitive rats. The ROMK(-/-) pups recapitulated features identified in the ROMK null mice. The ROMK(+/-) rats, when challenged with a 4% salt diet, exhibited a reduced blood pressure compared with their ROMK(+/+) littermates. More importantly, when challenged with an 8% salt diet, the Dahl salt-sensitive rats with 50% less ROMK expression showed increased protection from salt-induced blood pressure elevation and signs of protection from renal injury. Our findings in ROMK knockout Dahl salt-sensitive rats, together with the previous reports in humans and mice, underscore a critical role of ROMK in blood pressure regulation. PMID- 23753406 TI - Activation of neuronal transient receptor potential vanilloid 1 channel underlies 20-hydroxyeicosatetraenoic acid-induced vasoactivity: role for protein kinase A. AB - A rise in intraluminal pressure triggers vasoconstriction in resistance arteries, which is associated with local generation of the vasoconstrictor 20 hydroxyeicosatetraenoic acid (20-HETE). Importantly, dysregulation of 20-HETE synthesis and activity has been implicated in several cardiovascular disease states, including ischemic disease, hypertension, and stroke; however, the exact molecular pathways involved in mediating 20-HETE bioactivity are uncertain. We investigated whether 20-HETE activates the transient receptor potential vanilloid 1 (TRPV1) and thereby regulates vascular function and blood pressure. We demonstrate that 20-HETE causes dose-dependent increases in blood pressure, coronary perfusion pressure (isolated Langendorff), and pressure-induced constriction of resistance arteries (perfusion myography) that is substantially attenuated in TRPV1 knockout mice and by treatment with the neurokinin 1 receptor antagonist RP67580. Furthermore, we show that both channel activation (via patch clamping of dorsal root ganglion neurons) and vessel constriction are enhanced under inflammatory conditions, and our findings indicate a predominant role for protein kinase A-mediated sensitization of TRPV1 in these phenomena. Finally, we identify a prominence of these pathway in males compared with females, an effect we relate to reduced protein kinase A-induced phosphorylation of TRPV1. 20-HETE induced activation of TRPV1, in part, mediates pressure-induced myogenic constriction and underlies 20-HETE-induced elevations in blood pressure and coronary resistance. Our findings identify a novel vasoconstrictor 20-HETE/TRPV1 pathway that may offer potential for therapeutic targeting in cardiovascular diseases associated with elevated 20-HETE implicated in dysregulated organ blood flow, such as stroke or hypertension. PMID- 23753407 TI - Resveratrol improves vascular function in patients with hypertension and dyslipidemia by modulating NO metabolism. AB - Epidemiological studies have demonstrated that the Mediterranean diet, which is rich in resveratrol, is associated with a significantly reduced risk of cardiovascular disease. However, the molecular mechanisms that underlie the beneficial effects of resveratrol on cardiovascular function remain incompletely understood. Therefore, we set out to identify the molecular target(s) mediating the protective action of resveratrol on vascular function. To this end, we performed vascular reactivity studies to evaluate the effects of resveratrol on superior thyroid artery obtained from 59 patients with hypertension and dyslipidemia. We found that resveratrol evoked vasorelaxation and reduced endothelial dysfunction through the modulation of NO metabolism via (1) an 5' adenosine monophosphate-activated protein kinase-mediated increase in endothelial NO synthase activity; (2) a rise in tetrahydrobiopterin levels, which also increases endothelial NO synthase activity; and (3) attenuation of vascular oxidative stress, brought about by overexpression of manganese superoxide dismutase via an nuclear factor erythroid-derived 2-like 2-dependent mechanism. The effects of resveratrol on acetylcholine vasorelaxation were also tested in vessels from patients with nonhypertensive nondyslipidemia undergoing thyroid surgery. In this setting, resveratrol failed to exert any effect. Thus, our finding that resveratrol reduces endothelial dysfunction, an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular disease, supports the concept that the risk of vascular events could be further reduced by adherence to a set of dietary and behavioral guidelines. PMID- 23753408 TI - Cardiovascular complications associated with primary aldosteronism: a controlled cross-sectional study. AB - A higher risk of cardiovascular events has been reported in patients with primary aldosteronism (PA) than in otherwise similar patients with essential hypertension (EH). However, the evidence is limited by small sample size and potential confounding factors. We, therefore, compared the prevalence of cardiovascular events in 459 patients with PA diagnosed in our hypertension unit from 2001 to 2006 and 1290 controls with EH. PA cases and EH controls were individually matched for sex, age (+/- 2 years), and office systolic blood pressure (+/- 10 mm Hg). Patients with PA and EH differed significantly in duration of hypertension, serum potassium, plasma aldosterone and plasma renin concentrations, aldosterone to-renin ratio, and urinary aldosterone concentration (P<0.001 for all comparisons). The prevalence of electrocardiographic and echocardiographic left ventricular hypertrophy was about twice higher in patients with PA even after adjustment for hypertension duration. PA patients also had a significantly higher prevalence of coronary artery disease (adjusted odds ratio, 1.9), nonfatal myocardial infarction (adjusted odds ratio, 2.6), heart failure (adjusted odds ratio, 2.9), and atrial fibrillation (adjusted odds ratio, 5.0). The risks associated with PA were similar across levels of serum potassium and plasma aldosterone. To conclude, patients with PA are more likely to have had a cardiovascular complication at diagnosis than otherwise similar patients with EH. Target organ damage and complications disproportionate to blood pressure should be considered as an additional argument for suspecting PA in a given individual and possibly for broadening the scope of screening at the population level. PMID- 23753409 TI - Less potassium coming out, less sodium going in: phenotyping ROMK knockout rats. PMID- 23753410 TI - HO-1 induction improves the type-1 cardiorenal syndrome in mice with impaired angiotensin II-induced lymphocyte activation. AB - Type-1 cardiorenal syndrome, characterized by acute kidney dysfunction secondary to cardiac failure and renal arteriolar vasoconstriction, is mediated by the renin-angiotensin-aldosterone axis and sympathetic nervous system activation. Previous reports indicate that angiotensin II modulates immune function and causes recruitment and activation of T-lymphocytes. The goal of this study was to evaluate the effects of postischemic heart failure on renal morphology and circulation and the beneficial effects of heme oxygenase-1 (HO-1) induction in T lymphocyte-suppressed severe combined immune deficiency (SCID) mice. Mice were divided into 4 groups: sham, myocardial infarction (MI), MI treated with an HO-1 inducer, cobalt protoporphyrin, and with or without stannous mesoporphyrin, an inhibitor of HO activity. Heart and kidney function were studied 30 days after surgery. Fractional area change was reduced 30 days after surgery in both the C57 and SCID MI-groups as compared with their respective controls (P<0.01). Renal Pulsatility Index and renal injury were increased in C57 and SCID MI-groups compared with the sham group. HO-1 induction improved renal vasoconstriction as well as ameliorated renal injury in both the SCID and C57 MI-groups (P<0.01). However, improvement was more evident in SCID mice. In addition, our results showed that plasma creatinine, angiotensin II, and renin were significantly increased in the C57 and SCID MI-groups as compared with their respective controls. HO-1 induction decreased these parameters in both MI groups. Stannous mesoporphyrin reversed the beneficial effect of cobalt protoporphyrin in both mouse strains. The study demonstrates that T-lymphocyte suppression facilitated the HO-1-dependent improvement in the attenuation of type-1 cardiorenal syndrome. PMID- 23753412 TI - Measuring, analyzing, and managing drug adherence in resistant hypertension. PMID- 23753411 TI - Genomic association analysis of common variants influencing antihypertensive response to hydrochlorothiazide. AB - To identify novel genes influencing blood pressure response to thiazide diuretic therapy for hypertension, we conducted genome-wide association meta-analyses of ~1.1 million single-nucleotide polymorphisms in a combined sample of 424 European Americans with primary hypertension treated with hydrochlorothiazide from the Pharmacogenomic Evaluation of Antihypertensive Responses study (n=228) and the Genetic Epidemiology of Responses to Antihypertensive study (n=196). Polymorphisms associated with blood pressure response at P<10(-5) were tested for replication of the associations in independent samples of hydrochlorothiazide treated European hypertensives. The rs16960228 polymorphism in protein kinase C, alpha replicated for same-direction association with diastolic blood pressure response in the Nordic Diltiazem study (n=420) and the Genetics of Drug Responsiveness in Essential Hypertension study (n=206), and the combined 4-study meta-analysis P value achieved genome-wide significance (P=3.3 * 10(-8)). Systolic or diastolic blood pressure responses were consistently greater in carriers of the rs16960228 A allele than in GG homozygotes (>4/4 mm Hg) across study samples. The rs2273359 polymorphism in the GNAS-EDN3 region also replicated for same-direction association with systolic blood pressure response in the Nordic Diltiazem study, and the combined 3-study meta-analysis P value approached genome-wide significance (P=5.5 * 10(-8)). The findings document clinically important effects of genetic variation at novel loci on blood pressure response to a thiazide diuretic, which may be a basis for individualization of antihypertensive drug therapy and identification of new drug targets. PMID- 23753414 TI - Hypoadiponectinemia and endogenous nitric oxide synthase inhibitor in hypertension. PMID- 23753413 TI - P2Y1 receptors expressed by C1 neurons determine peripheral chemoreceptor modulation of breathing, sympathetic activity, and blood pressure. AB - Catecholaminergic C1 cells of the rostral ventrolateral medulla (RVLM) are key determinants of the sympathoexcitatory response to peripheral chemoreceptor activation. Overactivation of this reflex is thought to contribute to increased sympathetic activity and hypertension; however, molecular mechanisms linking peripheral chemoreceptor drive to hypertension remain poorly understood. We have recently determined that activation of P2Y1 receptors in the RVLM mimicked effects of peripheral chemoreceptor activation. Therefore, we hypothesize that P2Y1 receptors regulate peripheral chemoreceptor drive in this region. Here, we determine whether P2Y1 receptors are expressed by C1 neurons in the RVLM and contribute to peripheral chemoreceptor control of breathing, sympathetic activity, and blood pressure. We found that injection of a specific P2Y1 receptor agonist (MRS2365) into the RVLM of anesthetized adult rats increased phrenic nerve activity (~55%), sympathetic nerve activity (38 +/- 6%), and blood pressure (23 +/- 1 mm Hg), whereas application of a specific P2Y1 receptor antagonist (MRS2179) decreased peripheral chemoreceptor-mediated activation of phrenic nerve activity, sympathetic nerve activity, and blood pressure. To establish that P2Y1 receptors are expressed by C1 cells, we determine in the brain slice preparation using cell-attached recording techniques that cells responsive to MRS2365 are immunoreactive for tyrosine hydroxylase (a marker of C1 cells), and we determine in vivo that C1-lesioned animals do not respond to RVLM injection of MRS2365. These data identify P2Y1 receptors as key determinants of peripheral chemoreceptor regulation of breathing, sympathetic nerve activity, and blood pressure. PMID- 23753415 TI - Differential control of calcium homeostasis and vascular reactivity by Ca2+/calmodulin-dependent kinase II. AB - The multifunctional Ca(2+)/calmodulin-dependent kinase II (CaMKII) is activated by vasoconstrictors in vascular smooth muscle cells (VSMC), but its impact on vasoconstriction remains unknown. We hypothesized that CaMKII inhibition in VSMC decreases vasoconstriction. Using novel transgenic mice that express the inhibitor peptide CaMKIIN in smooth muscle (TG SM-CaMKIIN), we investigated the effect of CaMKII inhibition on L-type Ca(2+) channel current (ICa), cytoplasmic and sarcoplasmic reticulum Ca(2+), and vasoconstriction in mesenteric arteries. In mesenteric VSMC, CaMKII inhibition significantly reduced action potential duration and the residual ICa 50 ms after peak amplitude, indicative of loss of L type Ca(2+) channel-dependent ICa facilitation. Treatment with angiotensin II or phenylephrine increased the intracellular Ca(2+) concentration in wild-type but not TG SM-CaMKIIN VSMC. The difference in intracellular Ca(2+) concentration was abolished by pretreatment with nifedipine, an L-type Ca(2+) channel antagonist. In TG SM-CaMKIIN VSMC, the total sarcoplasmic reticulum Ca(2+) content was reduced as a result of diminished sarcoplasmic reticulum Ca(2+) ATPase activity via impaired derepression of the sarcoplasmic reticulum Ca(2+) ATPase inhibitor phospholamban. Despite the differences in intracellular Ca(2+) concentration, CaMKII inhibition did not alter myogenic tone or vasoconstriction of mesenteric arteries in response to KCl, angiotensin II, and phenylephrine. However, it increased myosin light chain kinase activity. These data suggest that CaMKII activity maintains intracellular calcium homeostasis but is not required for vasoconstriction of mesenteric arteries. PMID- 23753416 TI - The risk of congenital malformations associated with exposure to beta-blockers early in pregnancy: a meta-analysis. AB - beta-blockers are commonly used during the first trimester of pregnancy. Data about risks of congenital anomalies in offspring have not been summarized. We performed a meta-analysis to determine teratogenicity of beta-blockers in early pregnancy. A systematic literature search was performed using PubMed, EMBASE, Cochrane Clinical Trials, and hand search. Meta-analyses were performed using random-effects models based on odds ratios (ORs). Prespecified subgroup analyses were performed to explore heterogeneity. Randomized controlled trials or observational studies examining risks of congenital malformations associated with first trimester beta-blocker exposure compared with no exposure were included. Thirteen population-based case-control or cohort studies were identified. Based on meta-analyses, first-trimester oral beta-blocker use showed no increased odds of all or major congenital anomalies (OR=1.00; 95% confidence interval, 0.91 1.10; 5 studies). However, in analyses examining organ-specific malformations, increased odds of cardiovascular defects (OR=2.01; 95% confidence interval, 1.18 3.42; 4 studies), cleft lip/palate (OR=3.11; 95% confidence interval, 1.79-5.43; 2 studies), and neural tube defects (OR=3.56; 95% confidence interval, 1.19 10.67; 2 studies) were observed. The effects on severe hypospadias were nonsignificant (1 study). Causality is difficult to interpret given the small number of heterogeneous studies and possibility of biases. Given the frequency of this exposure in pregnancy, further research is needed. PMID- 23753417 TI - Oral formulation of angiotensin-(1-7) improves lipid metabolism and prevents high fat diet-induced hepatic steatosis and inflammation in mice. AB - Angiotensin (Ang)-(1-7) has been described as an important tool on treating and preventing metabolic disorders. In this study, we aimed to evaluate the effect of an oral formulation of Ang-(1-7) included in hydroxypropylbeta-cyclodextrin (HPbetaCD/Ang-[1-7]) on hepatic function, steatosis, and on liver inflammatory markers expression in mice treated with a high-fat diet. Male FVB/N mice were divided into 4 groups and fed for 60 days, with each group receiving 1 of the following diets: standard diet+HPbetaCD, standard diet+Ang-(1-7)/HPbetaCD, high fat diet+HPbetaCD, or high-fat diet+Ang-[1-7]/HPbetaCD. Body weight, food intake, and blood parameters, such as total cholesterol, triglyceride, alaninetransaminases, and aspartate transaminases, were evaluated. Immunohistochemical analyses were performed for inflammatory markers tumor necrosis factor-alpha and interleukin-6. Expression of angiotensin converting enzyme, angiotensin-converting enzyme-2, interleukin-1beta, tumor necrosis factor alpha, interleukin-6, transforming growth factor-beta, acetyl-CoA carboxylase, carbohydrate-responsive element-binding protein, peroxisome proliferator activated receptor-gamma, and sterol regulatory element-binding proteins-1c was evaluated by quantitative real-time polymerase chain reaction. The major findings of our study included reduced liver fat mass and weight, decreased plasma total cholesterol, triglyceride, and alaninetransaminase enzyme levels in the oral Ang (1-7)-treated groups compared with the control groups. These results were accompanied by a significant reduction in tumor necrosis factor-alpha and interleukin-6 mRNA expression in the liver. Analyses of liver adipogenesis related genes by quantitative real-time polymerase chain reaction showed that acetyl-CoA carboxylase, peroxisome proliferator-activated receptor-gamma, and sterol regulatory element-binding proteins-1c mRNA expression were significantly suppressed. In conclusion, we observed that treatment with Ang-(1-7) improved metabolism and decreased proinflammatory profile and fat deposition in liver of mice. PMID- 23753419 TI - Antihypertensive inorganic nitrate and nitrite: what is the underlying mechanism? PMID- 23753418 TI - Upregulation of renal D5 dopamine receptor ameliorates the hypertension in D3 dopamine receptor-deficient mice. AB - D3 dopamine receptor (D3R)-deficient mice have renin-dependent hypertension associated with sodium retention, but the hypertension is mild. To determine whether any compensatory mechanisms in the kidney are involved in the regulation of blood pressure with disruption of Drd3, we measured the renal protein expression of all dopamine receptor subtypes (D1R, D2R, D4R, and D5R) in D3R homozygous (D3(-/-)) and heterozygous (D3(+/-)) knockout mice and their wild-type (D3(+/+)) littermates. The renal immunohistochemistry and protein expression of D5R were increased (n=5/group) in D3(-/-) mice; renal D4R protein expression was decreased, whereas renal protein expressions of D1R and D2R were similar in both groups. Renal D5R protein expression was also increased in D3(+/-) (n=5/group) relative to D3(+/+) mice, whereas D1R, D2R, and D4R protein expressions were similar in D3(+/-) and D3(+/+) mice. The increase in renal D5R protein expression was abolished when D3(-/-) mice were fed a high-salt diet. Treatment with the D1 like receptor antagonist, SCH23390, increased the blood pressure in anesthetized D3(-/-) but not D3(+/+) mice (n=4/group), suggesting that the renal upregulation of D5R may have minimized the hypertension in D3(-/-) mice. The renal D5R protein upregulation was not caused by increased transcription because renal mRNA expression of D5R was similar in D3(-/-) and D3(+/+) mice. Our findings suggest that the renal upregulation of D5R may have minimized the hypertension that developed in D3(-/-) mice. PMID- 23753470 TI - Distribution of Two bioactive compounds in flowers of Trollius chinensis. AB - A comprehensive procedure was established, which combined a high-performance liquid chromatography (HPLC) assay for the simultaneous quantification of 2"-O beta-L-galactopyranosylorientin (OGA) and veratric acid and a gravimetric analysis for the determination of the mass fraction of the floral parts (calyx, corolla, stalk, stamens and pistils and ovary) of Trollius chinensis, to investigate the distribution and identify the enriched floral part(s) of these two compounds in the flowers. The calculated mean distributions of OGA in calyx, corolla, stamens and pistils, stalk and ovary were 83.62, 7.76, 4.35, 2.92 and 1.35%, respectively, whereas those of veratric acid in the corresponding floral parts were 46.41, 9.01, 18.41, 4.11 and 22.06%, respectively, indicating the uneven and noncorresponding distribution of these two compounds. This study extends the application of the HPLC assay and favors the production of OGA and veratric acid from the flowers of T. chinensis in addition to the benefits of breeding, cultivation and utilization of these flowers. PMID- 23753522 TI - 'SIT' down and relax: the interpolated twitch technique is still a valid measure of central fatigue during sustained contraction tasks. PMID- 23753523 TI - Effect of resistance exercise contraction mode and protein supplementation on members of the STARS signalling pathway. AB - The striated muscle activator of Rho signalling (STARS) pathway is suggested to provide a link between external stress responses and transcriptional regulation in muscle. However, the sensitivity of STARS signalling to different mechanical stresses has not been investigated. In a comparative study, we examined the regulation of the STARS signalling pathway in response to unilateral resistance exercise performed as either eccentric (ECC) or concentric (CONC) contractions as well as prolonged training; with and without whey protein supplementation. Skeletal muscle STARS, myocardian-related transcription factor-A (MRTF-A) and serum response factor (SRF) mRNA and protein, as well as muscle cross-sectional area and maximal voluntary contraction, were measured. A single-bout of exercise produced increases in STARS and SRF mRNA and decreases in MRTF-A mRNA with both ECC and CONC exercise, but with an enhanced response occurring following ECC exercise. A 31% increase in STARS protein was observed exclusively after CONC exercise (P < 0.001), while pSRF protein levels increased similarly by 48% with both CONC and ECC exercise (P < 0.001). Prolonged ECC and CONC training equally stimulated muscle hypertrophy and produced increases in MRTF-A protein of 125% and 99%, respectively (P < 0.001). No changes occurred for total SRF protein. There was no effect of whey protein supplementation. These results show that resistance exercise provides an acute stimulation of the STARS pathway that is contraction mode dependent. The responses to acute exercise were more pronounced than responses to accumulated training, suggesting that STARS signalling is primarily involved in the initial phase of exercise-induced muscle adaptations. PMID- 23753524 TI - Acute failure of action potential conduction in mdx muscle reveals new mechanism of contraction-induced force loss. AB - A primary feature of skeletal muscle lacking the protein dystrophin, as occurring in Duchenne muscular dystrophy, is a hypersensitivity to contraction-induced strength loss. We tested the hypothesis that the extensive strength loss results from an impairment in the electrophysiological function of the plasmalemma specifically impaired action potential development. Anterior crural muscles from mdx and wildtype mice performed a single bout of 100 electrically stimulated eccentric contractions in vivo. Electromyography, specifically the M-wave, was analysed during muscle contraction to assess the ability of the tibialis anterior muscle plasmalemma to generate and conduct action potentials. During eccentric contractions, wildtype mice exhibited a 36% loss in torque about the ankle but mdx mice exhibited a greater torque loss of 73% (P < 0.001). Despite the loss of torque, there was no reduction in M-wave root mean square (RMS) for wildtype mice, which was in stark contrast to mdx mice that had a 55% reduction in M-wave RMS (P < 0.001). This impairment resolved within 24 h and coincided with a significant improvement in strength and membrane integrity. Intracellular measurements of resting membrane potential (RMP) in uninjured and injured extensor digitorum longus muscles were made to determine if a chronic depolarization had occurred, which could lead to impaired fibre excitability and/or altered action potential conduction properties. The distributions of RMP were not different between wildtype uninjured and injured muscle cells (median: 73.2 mV vs. -72.7 mV, P = 0.46) whereas there was a significant difference between mdx uninjured and injured cells (median: -71.5 mV vs. -56.6 mV, P < 0.001). These data show that mdx muscle fibres are depolarized after an injurious bout of eccentric contractions. These findings (i) suggest a major plasmalemma based mechanism of strength loss underlying contraction-induced injury in Duchenne muscular dystrophy distinctly different from that for healthy muscle, and (ii) demonstrate dystrophin is critical for maintaining action potential generation and conduction after eccentric contractions. PMID- 23753525 TI - Long QT syndrome: beyond the causal mutation. AB - Congenital long QT syndrome (LQTS) is caused by single autosomal-dominant mutations in a gene encoding for a cardiac ion channel or an accessory ion channel subunit. These single mutations can cause life-threatening arrhythmias and sudden death in heterozygous mutation carriers. This recognition has been the basis for world-wide staggering numbers of subjects and families counselled for LQTS and treated based on finding (putative) disease-causing mutations. However, prophylactic treatment of patients is greatly hampered by the growing awareness that simple carriership of a mutation often fails to predict clinical outcome: many carriers never develop clinically relevant disease while others are severely affected at a young age. It is still largely elusive what determines this large variability in disease severity, where even within one pedigree, an identical mutation can cause life-threatening arrhythmias in some carriers while in other carriers no disease becomes clinically manifested. This suggests that additional factors modify the clinical manifestations of a particular disease-causing mutation. In this article, potential demographic, environmental and genetic factors are reviewed, which, in conjunction with a mutation, may modify the phenotype in LQTS, and thereby determine, at least partially, the large variability in disease severity. PMID- 23753526 TI - Adenylyl cyclase 6 mediates the action of cyclic AMP-dependent secretagogues in mouse pancreatic exocrine cells via protein kinase A pathway activation. AB - Both secretin and vasoactive intestinal polypeptide (VIP) receptors are responsible for the activation of adenylyl cyclases (ACs), which increase intracellular cyclic AMP (cAMP) levels in the exocrine pancreas. There are nine membrane-associated isoforms, each with its own pattern of expression and regulation. In this study we sought to establish which AC isoforms play a regulatory role in pancreatic exocrine cells. Using RT-PCR, AC3, AC4, AC6, AC7 and AC9 were found to be expressed in the pancreas. AC3, AC4, AC6 and AC9 were expressed in both pancreatic acini and ducts, whereas AC7 was expressed only in pancreatic ducts. Based on known regulation by intracellular signals, selective inhibitors and stimulators were used to suggest which isoforms play an important role in the induction of cAMP formation. AC6 appeared to be an important isoform because protein kinase A (PKA), PKC and calcium all inhibited VIP-induced cAMP formation, whereas calcineurin or calmodulin did not modify the response to VIP. Mice with genetically deleted AC6 were studied and showed reduced cAMP formation and PKA activation in both isolated pancreatic acini and duct fragments. The absence of AC6 reduced cAMP-dependent secretagogue-stimulated amylase secretion, and abolished fluid secretion in both in vivo and isolated duct fragments. In conclusion, several AC isoforms are expressed in pancreatic acini and ducts. AC6 mediates a significant part of pancreatic amylase and fluid secretion in response to secretin, VIP and forskolin through cAMP/PKA pathway activation. PMID- 23753527 TI - Classification of frequency response areas in the inferior colliculus reveals continua not discrete classes. AB - A differential response to sound frequency is a fundamental property of auditory neurons. Frequency analysis in the cochlea gives rise to V-shaped tuning functions in auditory nerve fibres, but by the level of the inferior colliculus (IC), the midbrain nucleus of the auditory pathway, neuronal receptive fields display diverse shapes that reflect the interplay of excitation and inhibition. The origin and nature of these frequency receptive field types is still open to question. One proposed hypothesis is that the frequency response class of any given neuron in the IC is predominantly inherited from one of three major afferent pathways projecting to the IC, giving rise to three distinct receptive field classes. Here, we applied subjective classification, principal component analysis, cluster analysis, and other objective statistical measures, to a large population (2826) of frequency response areas from single neurons recorded in the IC of the anaesthetised guinea pig. Subjectively, we recognised seven frequency response classes (V-shaped, non-monotonic Vs, narrow, closed, tilt down, tilt up and double-peaked), that were represented at all frequencies. We could identify similar classes using our objective classification tools. Importantly, however, many neurons exhibited properties intermediate between these classes, and none of the objective methods used here showed evidence of discrete response classes. Thus receptive field shapes in the IC form continua rather than discrete classes, a finding consistent with the integration of afferent inputs in the generation of frequency response areas. The frequency disposition of inhibition in the response areas of some neurons suggests that across-frequency inputs originating at or below the level of the IC are involved in their generation. PMID- 23753528 TI - Calcium regulation of neural rhythms, memory and Alzheimer's disease. AB - Alzheimer's disease (AD) begins with a decline in cognition followed by neuronal cell death and dementia. These changes have been linked to a deregulation of Ca(2+) signalling caused by a progressive increase in the resting level of Ca(2+), which may influence cognition by interfering with the rhythm rheostat that controls the sleep/wake cycle. The rise in resting levels of Ca(2+) may not alter the processes of memory acquisition during consciousness (gamma and theta rhythms), but may duplicate some of the events that occur during the slow oscillations responsible for the twin processes of memory consolidation and memory erasure that occur during sleep. The persistent elevation in the resting level of Ca(2+) induced by an accumulation of amyloid beta (Abeta) oligomers duplicates a similar small global elevation normally restricted to the period of slow oscillations when memories are erased during sleep. In AD, such a rapid erasure of memories soon after they are acquired during the wake period means that they are not retained for consolidation during sleep. The Abeta deregulates Ca(2+) signalling through direct effects on the neurons and indirectly by inducing inflammatory responses in the microglia and astrocytes. Some of these deleterious effects of Abeta may be alleviated by vitamin D. PMID- 23753530 TI - Interactions of enhanced urocortin 2 and mineralocorticoid receptor antagonism in experimental heart failure. AB - BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) have become established therapy in heart failure (HF). Urocortin 2 (Ucn2) is a novel peptide with potential in the treatment of this disease. The present study investigated the interactions of acute administration of Ucn2 and an MRA in experimental HF. METHODS AND RESULTS: Ucn2 and an MRA (canrenoic acid [CA]) were infused for 4 hours, both singly and together, in 8 sheeps with pacing-induced HF. Ucn2, when administered as an adjunct to CA, further improved hemodynamic indices relative to that achieved by CA alone, producing additional increases in cardiac output and decreases in left atrial pressure and peripheral resistance but without eliciting a supplementary reduction in arterial pressure. Ucn2 cotreatment reversed CA-induced rises in circulating aldosterone levels, and also significantly reduced plasma renin activity, angiotensin II, and vasopressin concentrations. Although both CA and Ucn2 infusion produced a diuresis and natriuresis, responses with Ucn2 and Ucn+CA were 2- to 3-fold greater than that elicited by separate CA. Ucn2 cotherapy additionally increased urine potassium and creatinine excretion. In contrast to the rise in plasma potassium induced by CA, Ucn2 cotreatment reduced potassium concentrations. CONCLUSIONS: Ucn2 cotreatment with an MRA in HF further improved hemodynamics relative to that achieved by CA alone, while also reducing plasma renin activity, angiotensin II, aldosterone and vasopressin levels, and enhancing renal function. Importantly, Ucn2 prevented CA-induced rises in plasma potassium. These data demonstrate a favorable profile of effects with short-term adjunct Ucn2 therapy and an MRA in HF. PMID- 23753529 TI - Tumour necrosis factor--induced loss of intestinal barrier function requires TNFR1 and TNFR2 signalling in a mouse model of total parenteral nutrition. AB - Tumour necrosis factor-alpha (TNF-alpha) has been reported to play a central role in intestinal barrier dysfunction in many diseases; however, the precise role of the TNF-alpha receptors (TNFRs) has not been well defined using in vivo models. Our previous data showed that enteral nutrient deprivation or total parenteral nutrition (TPN) led to a loss of intestinal epithelial barrier function (EBF), with an associated upregulation of TNF-alpha and TNFR1. In this study, we hypothesized that TNF-alpha plays an important role in TPN-associated EBF dysfunction. Using a mouse TPN model, we explored the relative roles of TNFR1 vs. TNFR2 in mediating this barrier loss. C57/BL6 mice underwent intravenous cannulation and were given enteral nutrition or TPN for 7 days. Tumour necrosis factor-alpha receptor knockout (KO) mice, including TNFR1KO, TNFR2KO or TNFR1R2 double KO (DKO), were used. Outcomes included small intestine transepithelial resistance (TER) and tracer permeability, junctional protein zonula occludens-1, occludin, claudins and E-cadherin expression. In order to address the dependence of EBF on TNF-alpha further, exogenous TNF-alpha and pharmacological blockade of TNF-alpha (Etanercept) were also performed. Total parenteral nutrition led to a loss of EBF, and this was almost completely prevented in TNFR1R2DKO mice and partly prevented in TNFR1KO mice but not in TNFR2KO mice. The TPN-associated downregulation of junctional protein expression and junctional assembly was almost completely prevented in the TNFR1R2DKO group. Blockade of TNF-alpha also prevented dysfunction of the EBF and junctional protein losses in mice undergoing TPN. Administration of TPN upregulated the downstream nuclear factor-B and myosin light-chain kinase (MLCK) signalling, and these changes were almost completely prevented in TNFR1R2DKO mice, as well as with TNF-alpha blockade, but not in TNFR1KO or TNFR2KO TPN groups. Tumour necrosis factor-alpha is a critical factor for TPN-associated epithelial barrier dysfunction, and both TNFR1 and TNFR2 are involved in EBF loss. Nuclear factor-B and MLCK signalling appear to be important downstream mediators involved in this TNF-alpha signalling process. PMID- 23753531 TI - A novel immunomodulator, FTY-720 reverses existing cardiac hypertrophy and fibrosis from pressure overload by targeting NFAT (nuclear factor of activated T cells) signaling and periostin. AB - BACKGROUND: Hypertension or aortic stenosis causes pressure overload, which evokes hypertrophic myocardial growth. Sustained cardiac hypertrophy eventually progresses to heart failure. Growing evidence indicates that restraining hypertrophy could be beneficial; here, we discovered that FTY-720, an immunomodulator for treating multiple sclerosis, can reverse existing cardiac hypertrophy/fibrosis. METHODS AND RESULTS: Male C57/Bl6 mice underwent transverse aortic constriction (TAC) for 1 week followed by FTY-720 treatment for 2 weeks under continuing TAC. Compared with vehicle-treated TAC hearts, FTY-720 significantly reduced ventricular mass, ameliorated fibrosis, and improved cardiac performance. Mechanistic studies led us to discover that FTY-720 appreciably inhibited nuclear factor of activated T-cells (NFAT) activity. Moreover, we found that in primary cardiomyocytes (rat and human) pertussis toxin (Gi-coupled receptor inhibitor) substantially blocked the antihypertrophic effect of FTY-720. This observation was confirmed in a mouse model of pressure overload. Interestingly, gene array analysis of TAC hearts revealed that FTY-720 profoundly decreased gene expression of a group of matricellular proteins, of which periostin was prominent. Analysis of periostin protein expression in TAC myocardium, as well as in rat and human cardiac fibroblasts, confirmed the array data. Moreover, we found that FTY-720 treatment or knockdown of periostin protein was able to inhibit transforming growth factor-beta responsiveness and decrease collagen expression. CONCLUSIONS: FTY-720 alleviates existing cardiac hypertrophy/fibrosis through mechanisms involving negative regulation of NFAT activity in cardiomyocytes and reduction of periostin expression allowing for a more homeostatic extracellular compartment milieu. Together, FTY-720 or its analogues could be a promising new approach for treating hypertrophic/fibrotic heart disease. PMID- 23753573 TI - Embryonic stem cell-derived CD166+ precursors develop into fully functional sinoatrial-like cells. AB - RATIONALE: A cell-based biological pacemaker is based on the differentiation of stem cells and the selection of a population displaying the molecular and functional properties of native sinoatrial node (SAN) cardiomyocytes. So far, such selection has been hampered by the lack of proper markers. CD166 is specifically but transiently expressed in the mouse heart tube and sinus venosus, the prospective SAN. OBJECTIVE: We have explored the possibility of using CD166 expression for isolating SAN progenitors from differentiating embryonic stem cells. METHODS AND RESULTS: We found that in embryonic day 10.5 mouse hearts, CD166 and HCN4, markers of the pacemaker tissue, are coexpressed. Sorting embryonic stem cells for CD166 expression at differentiation day 8 selects a population of pacemaker precursors. CD166+ cells express high levels of genes involved in SAN development (Tbx18, Tbx3, Isl-1, Shox2) and function (Cx30.2, HCN4, HCN1, CaV1.3) and low levels of ventricular genes (Cx43, Kv4.2, HCN2, Nkx2.5). In culture, CD166+ cells form an autorhythmic syncytium composed of cells morphologically similar to and with the electrophysiological properties of murine SAN myocytes. Isoproterenol increases (+57%) and acetylcholine decreases ( 23%) the beating rate of CD166-selected cells, which express the beta-adrenergic and muscarinic receptors. In cocultures, CD166-selected cells are able to pace neonatal ventricular myocytes at a rate faster than their own. Furthermore, CD166+ cells have lost pluripotency genes and do not form teratomas in vivo. CONCLUSIONS: We demonstrated for the first time the isolation of a nonteratogenic population of cardiac precursors able to mature and form a fully functional SAN like tissue. PMID- 23753570 TI - Optimized enzymatic dual functions of PaPrx protein by proton irradiation. AB - We investigated the effects of proton irradiation on the function and structure of the Pseudomonas aeruginosa peroxiredoxin (PaPrx). Polyacrylamide gel demonstrated that PaPrx proteins exposed to proton irradiation at several doses exhibited simultaneous formation of high molecular weight (HMW) complexes and fragmentation. Size-exclusion chromatography (SEC) analysis revealed that the number of fragments and very low molecular weight (LMW) structures increased as the proton irradiation dose increased. The peroxidase activity of irradiated PaPrx was preserved, and its chaperone activity was significantly increased by increasing the proton irradiation dose. The chaperone activity increased about 3 4 fold after 2.5 kGy proton irradiation, compared with that of non-irradiated PaPrx, and increased to almost the maximum activity after 10 kGy proton irradiation. We previously obtained functional switching in PaPrx proteins, by using gamma rays and electron beams as radiation sources, and found that the proteins exhibited increased chaperone activity but decreased peroxidase activity. Interestingly, in this study we newly found that proton irradiation could enhance both peroxidase and chaperone activities. Therefore, we can suggest proton irradiation as a novel protocol for conserved 2-Cys protein engineering. PMID- 23753600 TI - The CD11b-integrin (ITGAM) and systemic lupus erythematosus. AB - Variations at the ITGAM gene, which encodes for the CD11b chain of the Mac-1 (alphaMbeta2; CD11b/CD18; complement receptor-3) integrin, is one of the strongest genetic risk factors for systemic lupus erythematosus (SLE). More specifically, a genetic variant (rs1143679) which results in an arginine to histidine substitution at position 77 in the extracellular portion of the integrin is associated with disease. It has recently been shown that this amino acid substitution results in a dysfunctional integrin, which is deficient in mediating cell adhesion to integrin ligands, phagocytosis and in addition cannot restrict inflammatory cytokine production in macrophages. In this review, we discuss immunological functions of the Mac-1 integrin and how defects in the genetic variant of Mac-1 may relate to SLE development. PMID- 23753601 TI - Salmonella septic arthritis of the knees in a patient with systemic lupus erythematosus. AB - Hematogenous Salmonella osteomyelitis is uncommon in immunocompetent hosts, but occurs with some regularity in immunosuppressed patients affected by systemic lupus erythematosus (SLE). Surgical debridement with resection of compromised tissue is central to the surgical management of osteomyelitis. Persistence of septic arthropathy may result from inadequate debridement, areas of osteonecrosis (ON), and an abnormal cellular and humoral dysregulation characteristic of SLE. We describe a 53-year-old Hispanic female with SLE on immunosuppressive therapy, who developed acute salmonella-induced septic arthritis and osteomyelitis of both knees associated with ON and recurrent SLE synovitis. She received prolonged antibiotic therapy and an extensive surgical debridement as part of a successful two-stage bilateral total knee replacement. This report illustrates the significance of Salmonella enterica infection in SLE patients, and the role of underlying bone and joint pathology such as bone infarcts, sub-acute osteomyelitis, and SLE synovitis. PMID- 23753623 TI - Contributions of environmental signals and conserved residues to the functions of carbon storage regulator A of Borrelia burgdorferi. AB - Carbon storage regulator A of Borrelia burgdorferi (CsrABb) contributes to vertebrate host-specific adaptation by modulating activation of the Rrp2-RpoN RpoS pathway and is critical for infectivity. We hypothesized that the functions of CsrABb are dependent on environmental signals and on select residues. We analyzed the phenotype of csrABb deletion and site-specific mutants to determine the conserved and pathogen-specific attributes of CsrABb. Levels of phosphate acetyltransferase (Pta) involved in conversion of acetyl phosphate to acetyl coenzyme A (acetyl-CoA) and posttranscriptionally regulated by CsrABb in the csrABb mutant were reduced from or similar to those in the control strains under unfed- or fed-tick conditions, respectively. Increased levels of supplemental acetate restored vertebrate host-responsive determinants in the csrABb mutant to parental levels, indicating that both the levels of CsrABb and the acetyl phosphate and acetyl-CoA balance contribute to the activation of the Rrp2-RpoN RpoS pathway. Site-specific replacement of 8 key residues of CsrABb (8S) with alanines resulted in increased levels of CsrABb and reduced levels of Pta and acetyl-CoA, while levels of RpoS, BosR, and other members of rpoS regulon were elevated. Truncation of 7 amino acids at the C terminus of CsrABb (7D) resulted in reduced csrABb transcripts and posttranscriptionally reduced levels of FliW located upstream of CsrABb. Electrophoretic mobility shift assays revealed increased binding of 8S mutant protein to the CsrA binding box upstream of pta compared to the parental and 7D truncated protein. Two CsrABb binding sites were also identified upstream of fliW within the flgK coding sequence. These observations reveal conserved and unique functions of CsrABb that regulate adaptive gene expression in B. burgdorferi. PMID- 23753624 TI - Contribution of interleukin-12 p35 (IL-12p35) and IL-12p40 to protective immunity and pathology in mice infected with Chlamydia muridarum. AB - The p35 molecule is unique to interleukin-12 (IL-12), while p40 is shared by both IL-12 and IL-23. IL-12 promotes Th1 T cell responses, while IL-23 promotes Th17 T cell responses. The roles of IL-12p35- and IL-12p40-mediated responses in chlamydial infection were compared in mice following an intravaginal infection with Chlamydia muridarum. Mice deficient in either IL-12p35 or p40 both developed similar but prolonged infection time courses, confirming the roles of IL-12 mediated immune responses in clearing primary infection. However, all mice, regardless of genotype, cleared reinfection within 2 weeks, suggesting that an IL 12- or IL-23-independent adaptive immunity is protective against chlamydial infection. All infected mice developed severe oviduct hydrosalpinx despite the increased Th2 responses in IL-12p35- or IL-12p40-deficient mice, suggesting that Th2-dominant responses can contribute to Chlamydia-induced inflammatory pathology. Compared to IL-12p35 knockout mice, the IL-12p40-deficient mice exhibited more extensive spreading of chlamydial organisms into kidney tissues, leading to significantly increased incidence of pyelonephritis, which both confirms the role of IL-12 or IL-23-independent host responses in Chlamydia induced pathologies and suggests that in the absence of IL-12/IFN-gamma-mediated Th1 immunity, an IL-23-mediated response may play an important role in restricting chlamydial organisms from spreading into distal organs. These observations together provide important information for both understanding chlamydial pathogenesis and developing anti-Chlamydia vaccines. PMID- 23753625 TI - Perforin-2 restricts growth of Chlamydia trachomatis in macrophages. AB - Chlamydia trachomatis is a Gram-negative obligate intracellular bacterium that preferentially infects epithelial cells. Professional phagocytes provide C. trachomatis only a limited ability to survive and are proficient killers of chlamydiae. We present evidence herein that identifies a novel host defense protein, perforin-2, that plays a significant role in the eradication of C. trachomatis during the infection of macrophages. Knockdown of perforin-2 in macrophages did not alter the invasion of host cells but did result in chlamydial growth that closely mirrored that detected in HeLa cells. C trachomatis L2, serovar B, and serovar D and C. muridarum were all equally susceptible to perforin-2-mediated killing. Interestingly, induction of perforin-2 expression in epithelial cells is blocked during productive chlamydial growth, thereby protecting chlamydiae from bactericidal attack. Ectopic expression of perforin-2 in HeLa cells, however, does result in killing. Overall, our data implicate a new innate resistance protein in the control of chlamydial infection and may help explain why the macrophage environment is hostile to chlamydial growth. PMID- 23753626 TI - Role of Klebsiella pneumoniae type 1 and type 3 fimbriae in colonizing silicone tubes implanted into the bladders of mice as a model of catheter-associated urinary tract infections. AB - Catheter-associated urinary tract infections are biofilm-mediated infections that cause a significant economic and health burden in nosocomial environments. Using a newly developed murine model of this type of infection, we investigated the role of fimbriae in implant-associated urinary tract infections by the Gram negative bacterium Klebsiella pneumoniae, which is a proficient biofilm former and a commonly isolated nosocomial pathogen. Studies have shown that type 1 and type 3 fimbriae are involved in attachment and biofilm formation in vitro, and these fimbrial types are suspected to be important virulence factors during infection. To test this hypothesis, the virulence of fimbrial mutants was assessed in independent challenges in which mouse bladders were inoculated with the wild type or a fimbrial mutant and in coinfection studies in which the wild type and fimbrial mutants were inoculated together to assess the results of a direct competition in the urinary tract. Using these experiments, we were able to show that both fimbrial types serve to enhance colonization and persistence. Additionally, a double mutant had an additive colonization defect under some conditions, indicating that both fimbrial types have unique roles in the attachment and persistence in the bladder and on the implant itself. All of these mutants were outcompeted by the wild type in coinfection experiments. Using these methods, we are able to show that type 1 and type 3 fimbriae are important colonization factors in the murine urinary tract when an implanted silicone tube is present. PMID- 23753627 TI - Gene dosage-dependent negative regulatory role of beta-arrestin-2 in polymicrobial infection-induced inflammation. AB - beta-arrestin-2 (beta-arr2) is a scaffolding protein of the arrestin family with a wide variety of cellular functions. Recent studies have demonstrated differential roles for beta-arr2 in inflammation following endotoxemia and cecal ligation and puncture (CLP) models of sepsis. Because CLP-induced inflammation involves response to fecal contents and necrotic cecum in addition to microbial challenge, in this study, we examined the role of beta-arr2 in an exclusively polymicrobial infection (PMI) model. In addition, we examined the role of gene dosage of beta-arr2 in polymicrobial sepsis. Our studies demonstrate that beta arr2 is a negative regulator of systemic inflammation in response to polymicrobial infection and that one allele is sufficient for this process. Our results further reveal that loss of beta-arr2 leads to increased neutrophil sequestration and overt inflammation specifically in the lungs following polymicrobial infection. Consistent with this, specific NF-kappaB and mitogen activated protein kinase (MAPK) signaling pathways were differentially activated in the beta-arr2 knockout (KO) mice lungs compared to the wild type (WT) following PMI. Associated with enhanced inflammation in the KO mice, PMI-induced mortality was also significantly higher in KO mice than in WT mice. To understand the differential role of beta-arr2 in different sepsis models, we used cell culture systems to evaluate inflammatory cytokine production following endotoxin and polymicrobial stimulation. Our results demonstrate cell-type- as well as stimulus-specific roles for beta-arr2 in inflammation. Taken together, our results reveal a negative regulatory role for beta-arr2 in polymicrobial infection-induced inflammation and further demonstrate that one allele of beta arr2 is sufficient to mediate most of these effects. PMID- 23753628 TI - Enhanced susceptibility to urinary tract infection in the spinal cord-injured host with neurogenic bladder. AB - Neurogenic bladder predisposes to recurrent urinary tract infections (UTI) and renal failure, and susceptibility is commonly ascribed to urinary stasis from elevated residual urine volumes. Escherichia coli UTI was modeled in the spinal cord-injured (SCI) rat with the hypothesis that SCI animals would require fewer bacteria to establish infection, have an exaggerated inflammatory response, and have delayed clearance of infection compared to normal-voiding controls. T10 SCI rats and controls had median infectious doses (ID50) of 10(2) and 10(5) CFU, respectively. Mean residual volumes in the SCI animals did not correlate with susceptibility to initiation of UTI or outcome. In the acute infection, control and SCI rats developed acute cystitis and pyelitis without acute differences in histopathological scores of inflammation. However, in vivo imaging of infected animals revealed persistently higher levels of bacteria in the SCI urine and bladders than were seen for controls over 2 weeks. Likewise, at 2 weeks, acute and chronic inflammatory infiltrates persisted in the bladders and kidneys of SCI rats, whereas inflammation largely resolved within the controls. Together these data demonstrate that SCI rats exhibit delayed clearance of infection and exaggerated inflammatory responses in bladders and kidneys; however, the severity of residual volumes does not predict increased susceptibility to UTI. These studies suggest that host-dependent mechanisms that are discrete from alterations in bladder physiology influence UTI susceptibility with the SCI-neurogenic bladder. This model will allow elucidation of SCI-neurogenic bladder-mediated changes in host response that yield UTI susceptibility and may lead to new preventative and therapeutic options. PMID- 23753629 TI - Haemophilus ducreyi infection induces activation of the NLRP3 inflammasome in nonpolarized but not in polarized human macrophages. AB - Recognition of microbial infection by certain intracellular pattern recognition receptors leads to the formation of a multiprotein complex termed the inflammasome. Inflammasome assembly activates caspase-1 and leads to cleavage and secretion of the proinflammatory cytokines interleukin-1 beta (IL-1beta) and IL 18, which help control many bacterial pathogens. However, excessive inflammation mediated by inflammasome activation can also contribute to immunopathology. Here, we investigated whether Haemophilus ducreyi, a Gram-negative bacterium that causes the genital ulcer disease chancroid, activates inflammasomes in experimentally infected human skin and in monocyte-derived macrophages (MDM). Although H. ducreyi is predominantly extracellular during human infection, several inflammasome-related components were transcriptionally upregulated in H. ducreyi-infected skin. Infection of MDM with live, but not heat-killed, H. ducreyi induced caspase-1- and caspase-5-dependent processing and secretion of IL 1beta. Blockage of H. ducreyi uptake by cytochalasin D significantly reduced the amount of secreted IL-1beta. Knocking down the expression of the inflammasome components NLRP3 and ASC abolished IL-1beta production. Consistent with NLRP3 dependent inflammasome activation, blocking ATP signaling, K(+) efflux, cathepsin B activity, and lysosomal acidification all inhibited IL-1beta secretion. However, inhibition of the production and function of reactive oxygen species did not decrease IL-1beta production. Polarization of macrophages to classically activated M1 or alternatively activated M2 cells abrogated IL-1beta secretion elicited by H. ducreyi. Our study data indicate that H. ducreyi induces NLRP3 inflammasome activation via multiple mechanisms and suggest that the heterogeneity of macrophages within human lesions may modulate inflammasome activation during human infection. PMID- 23753630 TI - Borrelia burgdorferi linear plasmid 28-3 confers a selective advantage in an experimental mouse-tick infection model. AB - Borrelia burgdorferi, the bacterium that causes Lyme disease, has a unique segmented genome consisting of numerous linear and circular plasmids and a linear chromosome. Many of these genetic elements have been found to encode factors critical for B. burgdorferi to complete the infectious cycle. However, several plasmids remain poorly characterized, and their roles during infection with B. burgdorferi have not been elucidated. To more fully characterize the role of one of the four 28-kb linear plasmids, lp28-3, we generated strains specifically lacking lp28-3 and assayed the contribution of genes carried by lp28-3 to B. burgdorferi infection. We found that lp28-3 does not carry any genes that are strictly required for infection of a mouse or tick and that lp28-3-deficient spirochetes are competent at causing a disseminated infection. Interestingly, spirochetes containing lp28-3 were at a selective advantage compared to lp28-3 deficient spirochetes when coinjected into a mouse, and this advantage was reflected in the population of spirochetes acquired by feeding ticks. Our data demonstrate that genes carried by lp28-3, although not essential, contribute to the fitness of B. burgdorferi during infection. PMID- 23753631 TI - Agglutinating secretory IgA preserves intestinal epithelial cell integrity during apical infection by Shigella flexneri. AB - Shigella flexneri, by invading intestinal epithelial cells (IECs) and inducing inflammatory responses of the colonic mucosa, causes bacillary dysentery. Although M cells overlying Peyer's patches are commonly considered the primary site of entry of S. flexneri, indirect evidence suggests that bacteria can also use IECs as a portal of entry to the lamina propria. Passive delivery of secretory IgA (SIgA), the major immunoglobulin secreted at mucosal surfaces, has been shown to protect rabbits from experimental shigellosis, but no information exists as to its molecular role in maintaining luminal epithelial integrity. We have established that the interaction of virulent S. flexneri with the apical pole of a model intestinal epithelium consisting of polarized Caco-2 cell monolayers resulted in the progressive disruption of the tight junction network and actin depolymerization, eventually resulting in cell death. The lipopolysaccharide (LPS)-specific agglutinating SIgAC5 monoclonal antibody (MAb), but not monomeric IgAC5 or IgGC20 MAbs of the same specificity, achieved protective functions through combined mechanisms, including limitation of the interaction between S. flexneri and epithelial cells, maintenance of the tight junction seal, preservation of the cell morphology, reduction of NF-kappaB nuclear translocation, and inhibition of proinflammatory mediator secretion. Our results add to the understanding of the function of SIgA-mediated immune exclusion by identifying a mode of action whereby the formation of immune complexes translates into maintenance of the integrity of epithelial cells lining the mucosa. This novel mechanism of protection mediated by SIgA is important to extend the arsenal of effective strategies to fight against S. flexneri mucosal invasion. PMID- 23753632 TI - Characterization of intracellular growth regulator icgR by utilizing transcriptomics to identify mediators of pathogenesis in Shigella flexneri. AB - Shigella species Gram-negative bacteria which cause a diarrheal disease, known as shigellosis, by invading and destroying the colonic mucosa and inducing a robust inflammatory response. With no vaccine available, shigellosis annually kills over 600,000 children in developing countries. This study demonstrates the utility of combining high-throughput bioinformatic methods with in vitro and in vivo assays to provide new insights into pathogenesis. Comparisons of in vivo and in vitro gene expression identified genes associated with intracellular growth. Additional bioinformatics analyses identified genes that are present in S. flexneri isolates but not in the three other Shigella species. Comparison of these two analyses revealed nine genes that are differentially expressed during invasion and that are specific to S. flexneri. One gene, a DeoR family transcriptional regulator with decreased expression during invasion, was further characterized and is now designated icgR, for intracellular growth regulator. Deletion of icgR caused no difference in growth in vitro but resulted in increased intracellular replication in HCT-8 cells. Further in vitro and in vivo studies using high-throughput sequencing of RNA transcripts (RNA-seq) of an isogenic DeltaicgR mutant identified 34 genes that were upregulated under both growth conditions. This combined informatics and functional approach has allowed the characterization of a gene and pathway previously unknown in Shigella pathogenesis and provides a framework for further identification of novel virulence factors and regulatory pathways. PMID- 23753636 TI - Neurocritical care. PMID- 23753644 TI - Physical Activity and AD-Related Pathology-Reply. PMID- 23753633 TI - Induction of rapid cell death by an environmental isolate of Legionella pneumophila in mouse macrophages. AB - Legionella pneumophila, the etiological agent for Legionnaires' disease, is ubiquitous in the aqueous environment, where it replicates as an intracellular parasite of free-living protozoa. Our understanding of L. pneumophila pathogenicity is obtained mostly from study of derivatives of several clinical isolates, which employ almost identical virulent determinants to exploit host functions. To determine whether environmental L. pneumophila isolates interact similarly with the model host systems, we analyzed intracellular replication of several recently isolated such strains and found that these strains cannot productively grow in bone marrow-derived macrophages of A/J mice, which are permissive for all examined laboratory strains. By focusing on one strain called LPE509, we found that its deficiency in intracellular replication in primary A/J macrophages is not caused by the lack of important pathogenic determinants because this strain replicates proficiently in two protozoan hosts and the human macrophage U937 cell. We also found that in the early phase of infection, the trafficking of this strain in A/J macrophages is similar to that of JR32, a derivative of strain Philadelphia 1. Furthermore, infection of these cells by LPE509 caused extensive cell death in a process that requires the Dot/Icm type IV secretion system. Finally, we showed that the cell death is caused neither by the activation of the NAIP5/NLRC4 inflammasome nor by the recently described caspase 11-dependent pathway. Our results revealed that some environmental L. pneumophila strains are unable to overcome the defense conferred by primary macrophages from mice known to be permissive for laboratory L. pneumophila strains. These results also suggest the existence of a host immune surveillance mechanism differing from those currently known in responding to L. pneumophila infection. PMID- 23753649 TI - Computer programming: quality and safety for neonatal parenteral nutrition orders. AB - BACKGROUND: Computerized software programs reduce errors and increase consistency when ordering parenteral nutrition (PN). The purpose of this study was to evaluate the effectiveness of our computerized neonatal PN calculator ordering program in reducing errors and optimizing nutrient intake. MATERIALS AND METHODS: This was a retrospective study of infants requiring PN during the first 2-3 weeks of life. Caloric, protein, calcium, and phosphorus intakes; days above and below amino acid (AA) goals; and PN ordering errors were recorded. Infants were divided into 3 groups by birth weight for analysis: <=1000 g, 1001-1500 g, and >1500 g. Intakes and outcomes of infants before (2007) vs after (2009) implementation of the calculator for each group were compared. RESULTS: There were no differences in caloric, protein, or phosphorus intakes in 2007 vs 2009 in any group. Mean protein intakes were 97%-99% of goal for <=1000-g and 1001- to 1500-g infants in 2009 vs 87% of goal for each group in 2007. In 2007, 7.6 per 100 orders were above and 11.5 per 100 were below recommended AA intakes. Calcium intakes were higher in 2009 vs 2007 in <=1000-g (46.6 +/- 6.1 vs 39.5 +/- 8.0 mg/kg/d, P < .001) and >1500-g infants (50.6 +/- 7.4 vs 39.9 +/- 8.3 mg/kg/d, P < .001). Ordering errors were reduced from 4.6 per 100 in 2007 to 0.1 per 100 in 2009. CONCLUSION: Our study reaffirms that computerized ordering systems can increase the quality and safety of neonatal PN orders. Calcium and AA intakes were optimized and ordering errors were minimized using the computer-based ordering program. PMID- 23753650 TI - Pancreatic enzyme replacement therapy for enterally fed patients with cystic fibrosis. AB - Administration of pancreatic enzymes (pancrelipase) to adult patients with cystic fibrosis when receiving enteral nutrition through a feeding tube is challenging. A number of techniques for preparing and administering the drug may result in complications that include feeding tube occlusion and inadequate enzyme delivery to the patient. A series of inpatient encounters is described. PMID- 23753653 TI - Error in Data in: "Final Visual Acuity Results in the Early Treatment for Retinopathy of Prematurity Study". PMID- 23753655 TI - About this journal. PMID- 23753660 TI - Prognostic factors of acute partial transverse myelitis-reply. PMID- 23753661 TI - Molecular phylogenies support homoplasy of multiple morphological characters used in the taxonomy of Heteroscleromorpha (Porifera: Demospongiae). AB - Sponge classification has long been based mainly on morphocladistic analyses but is now being greatly challenged by more than 12 years of accumulated analyses of molecular data analyses. The current study used phylogenetic hypotheses based on sequence data from 18S rRNA, 28S rRNA, and the CO1 barcoding fragment, combined with morphology to justify the resurrection of the order Axinellida Levi, 1953. Axinellida occupies a key position in different morphologically derived topologies. The abandonment of Axinellida and the establishment of Halichondrida Vosmaer, 1887 sensu lato to contain Halichondriidae Gray, 1867, Axinellidae Carter, 1875, Bubaridae Topsent, 1894, Heteroxyidae Dendy, 1905, and a new family Dictyonellidae van Soest et al., 1990 was based on the conclusion that an axially condensed skeleton evolved independently in separate lineages in preference to the less parsimonious assumption that asters (star-shaped spicules), acanthostyles (club-shaped spicules with spines), and sigmata (C-shaped spicules) each evolved more than once. Our new molecular trees are congruent and contrast with the earlier, morphologically based, trees. The results show that axially condensed skeletons, asters, acanthostyles, and sigmata are all homoplasious characters. The unrecognized homoplasious nature of these characters explains much of the incongruence between molecular-based and morphology-based phylogenies. We use the molecular trees presented here as a basis for re interpreting the morphological characters within Heteroscleromorpha. The implications for the classification of Heteroscleromorpha are discussed and a new order Biemnida ord. nov. is erected. PMID- 23753666 TI - About this journal. PMID- 23753672 TI - April 2012 archives web quiz winner. PMID- 23753681 TI - Error in figure in "intravitreal ketorolac for chronic uveitis and macular edema: a pilot study". PMID- 23753676 TI - Hebb-based rules of neural plasticity: are they ubiquitously important for the refinement of synaptic connections in development? AB - Neuronal death and suppression of functional synaptic inputs are well-known regressive events characterizing PNS and CNS development. In the CNS, participation of activity in synapse elimination has been known ever since the pioneering studies of Hubel and Wiesel, but only recently has a Hebb-based mechanism of spike synchrony versus asynchrony received unequivocal experimental support in the visual system. At the neuromuscular junction (NMJ), where synapse elimination was discovered, the specific function of the "timing of activity" was addressed by only one group of studies and did not receive widespread attention. Here we critically review the latest NMJ investigation advocating an "activity independent" mechanism for synapse elimination and contrast it with an equally recent study demonstrating a key role for spike timing. Finally, we highlight how the striking similarities between the two mentioned studies on spike timing (visual system and NMJ) establish conclusively its role in the development of the nervous system in general. PMID- 23753682 TI - Error in Signature Block in: The JAMA Network Journals: New Names for the Archives Journals. PMID- 23753687 TI - This month in archives of neurology. PMID- 23753686 TI - Spinocerebellar ataxia types 2 and 10: more than a coincidental association? Reply. PMID- 23753691 TI - About this journal. PMID- 23753699 TI - Pathology quiz case 2: diagnosis. PMID- 23753704 TI - Systemic and Ocular Risks Associated With Therapies for Macular Degeneration: Clarification vs Confusion-Reply. PMID- 23753705 TI - Radiology quiz case 2: diagnosis. PMID- 23753708 TI - Plasma Anti-Amyloid-beta Autoantibodies in All Alzheimer Disease Types-Reply. PMID- 23753711 TI - Theme issue on genomics/genetics and epigenetics. PMID- 23753709 TI - This month in archives of pediatrics & adolescent medicine. PMID- 23753720 TI - Pathology quiz case 1: diagnosis. PMID- 23753713 TI - About this journal. PMID- 23753726 TI - About this journal. PMID- 23753728 TI - In Memoriam: Robert J. Joynt, MD, PhD (1925-2012). PMID- 23753735 TI - Radiology quiz case 1: diagnosis. PMID- 23753731 TI - Current Diagnosis and Treatment: Neurology, 2nd ed. PMID- 23753738 TI - Rural vista. PMID- 23753737 TI - Subgroup analysis in the steroids for corneal ulcers trial-reply. PMID- 23753748 TI - Radiology quiz case 2: diagnosis. PMID- 23753740 TI - This month in archives of pediatrics & adolescent medicine. PMID- 23753750 TI - Error in Figure in: Archetypal and New Families With Alexander Disease and Novel Mutations in GFAP. PMID- 23753751 TI - The JAMA Network Journals: New Names for the Archives Journals. PMID- 23753755 TI - Reflections of grand tetons, grand teton national park, wyoming. PMID- 23753756 TI - This month in archives of pediatrics & adolescent medicine. PMID- 23753760 TI - Picture of the month-diagnosis. PMID- 23753761 TI - "Blinding" empty sella-reply. PMID- 23753762 TI - About this journal. PMID- 23753767 TI - About this journal. PMID- 23753772 TI - About this journal. PMID- 23753771 TI - About this journal. PMID- 23753774 TI - Atrial fibrillation and the hachinski ischemic scale-reply. PMID- 23753776 TI - A new beginning. PMID- 23753782 TI - About this journal. PMID- 23753784 TI - Insulin and Alzheimer disease-reply. PMID- 23753781 TI - Error in Missing Journal Club Designation in: Sensitivity and Specificity of a Point-of-Care Matrix Metalloproteinase 9 Immunoassay for Diagnosing Inflammation Related to Dry Eye. PMID- 23753790 TI - This month in archives of neurology. PMID- 23753787 TI - January 2012 archives web quiz winner. PMID- 23753795 TI - Why was there no correlation between anterior chamber depth and intraocular pressure change after phacoemulsification in patients with narrow angles?-Reply. PMID- 23753797 TI - This month in archives of pediatrics & adolescent medicine. PMID- 23753799 TI - Author response: Is impaired emmetropisation related to foveal hypoplasia or is it specific to albinism? PMID- 23753804 TI - Error in Title in: Adaptive Optics and Spectral-Domain Optical Coherence Tomography of Human Photoreceptor Structure After Short Pascal Macular Grid and Panretinal Laser Photocoagulation. PMID- 23753805 TI - Is It Too Early to Predict the Failure of Natalizumab in NMO?-Reply. PMID- 23753809 TI - August in maine. PMID- 23753808 TI - Fireworks over the Hudson River. PMID- 23753810 TI - Association between district and state policies and US public elementary school competitive food and beverage environments. AB - IMPORTANCE: Given the importance of developing healthy eating patterns during early childhood, policies to improve the elementary school food and beverage environments are critical. OBJECTIVE: To examine the association between district and state policy and/or law requirements regarding competitive food and beverages and public elementary school availability of foods and beverages high in fats, sugars, and/or sodium. DESIGN AND SETTING: Multivariate, pooled, cross-sectional analysis of data gathered annually during elementary school years 2008-2009 through 2010-2011 in the United States. PARTICIPANTS: Survey respondents at 1814 elementary schools (1485 unique) in 957 districts in 45 states (food analysis) and 1830 elementary schools (1497 unique) in 962 districts and 45 states (beverage analysis). EXPOSURES Competitive food and beverage policy restrictions at the state and/or district levels. MAIN OUTCOME AND MEASURE: Competitive food and beverage availability. RESULTS Sweets were 11.2 percentage points less likely to be available (32.3% vs 43.5%) when both the district and state limited sugar content, respectively. Regular-fat baked goods were less available when the state law, alone and in combination with district policy, limited fat content. Regular fat ice cream was less available when any policy (district, state law, or both) limited competitive food fat content. Sugar-sweetened beverages were 9.5 percentage points less likely to be available when prohibited by district policy (3.6% vs 13.1%). Higher-fat milks (2% or whole milk) were less available when prohibited by district policy or state law, with either jurisdiction's policy or law associated with an approximately 15 percentage point reduction in availability. CONCLUSIONS: Both district and state policies and/or laws have the potential to reduce in-school availability of high-sugar, high-fat foods and beverages. Given the need to reduce empty calories in children's diets, governmental policies at all levels may be an effective tool. PMID- 23753811 TI - About this journal. PMID- 23753812 TI - About this journal. PMID- 23753814 TI - This month in archives of pediatrics & adolescent medicine. PMID- 23753820 TI - A pair of swans, Los Olivos, California, 2008. PMID- 23753817 TI - Effect of cataract surgery and 5-Fluorouracil on trabeculectomy function-reply. PMID- 23753823 TI - Error in Figure in: Outer Retinal Tubulation: A Novel Optical Coherence Tomography Finding. PMID- 23753829 TI - Pathology quiz case 1: diagnosis. PMID- 23753828 TI - Pathology quiz case 2: diagnosis. PMID- 23753831 TI - This month in archives of neurology. PMID- 23753830 TI - Extensive cerebral venous thrombosis. PMID- 23753832 TI - The harm in looking. PMID- 23753833 TI - About this journal. PMID- 23753838 TI - Fundus autofluorescence patterns in stargardt disease over time-reply. PMID- 23753840 TI - The Pleiades, or Seven Sisters (Messier object 45), which is an open star cluster in the constellations of Taurus. Taken at Anza, California. PMID- 23753841 TI - This month in archives of general psychiatry. PMID- 23753843 TI - Adoption of radial access and comparison of outcomes to femoral access in percutaneous coronary intervention: an updated report from the national cardiovascular data registry (2007-2012). AB - BACKGROUND: Radial access for percutaneous coronary intervention (r-PCI) is associated with reduced vascular complications; however, previous reports have shown that <2% of percutaneous coronary intervention (PCI) procedures in the United States are performed via the radial approach. Our aims were to evaluate temporal trends in r-PCI and compare procedural outcomes between r-PCI and transfemoral PCI. METHODS AND RESULTS: We conducted a retrospective cohort study from the CathPCI registry (n=2 820 874 procedures from 1381 sites) between January 2007 and September 2012. Multivariable logistic regression models were used to evaluate the adjusted association between r-PCI and bleeding, vascular complications, and procedural success, using transfemoral PCI as the reference. Outcomes in high-risk subgroups such as age >=75 years, women, and patients with acute coronary syndrome were also examined. The proportion of r-PCI procedures increased from 1.2% in quarter 1 2007 to 16.1% in quarter 3 2012 and accounted for 6.3% of total procedures from 2007 to 2012 (n=178 643). After multivariable adjustment, r-PCI use in the studied cohort of patients was associated with lower risk of bleeding (adjusted odds ratio, 0.51; 95% confidence interval, 0.49-0.54) and lower risk of vascular complications (adjusted odds ratio, 0.39; 95% confidence interval, 0.31-0.50) in comparison with transfemoral PCI. The reduction in bleeding and vascular complications was consistent across important subgroups of age, sex, and clinical presentation. CONCLUSIONS: There has been increasing adoption of r-PCI in the United States. Transradial PCI now accounts for 1 of 6 PCIs performed in contemporary clinical practice. In comparison with traditional femoral access, transradial PCI is associated with lower vascular and bleeding complication rates. PMID- 23753845 TI - New developments in cardiac pacemakers. PMID- 23753844 TI - Postural tachycardia syndrome (POTS). PMID- 23753846 TI - An egg-shaped cyst of the right interventricular septum. PMID- 23753847 TI - Eggshell-like appearance around the heart mimicking left ventricular mass. PMID- 23753849 TI - Letter by Koh regarding article, "Statins and risk of new-onset diabetes mellitus". PMID- 23753852 TI - Providing a sure start: how government discovered early childhood. PMID- 23753854 TI - Toric intraocular lens calculations-reply. PMID- 23753856 TI - Core topics in neuroanesthesia and neurointensive care. PMID- 23753857 TI - About this journal. PMID- 23753860 TI - Blood pressure and progression of brain atrophy: the SMART-MR Study. AB - IMPORTANCE: Studies have shown that both high and low blood pressure (BP) may play a role in the etiology of brain atrophy. High BP in midlife has been associated with more brain atrophy later in life, whereas studies in older populations have shown a relation between low BP and more brain atrophy. Yet, prospective evidence is limited, and the relation remains unclear in patients with manifest arterial disease. OBJECTIVE: To examine the associations of baseline BP and change in BP over time with progression of brain atrophy. DESIGN: The Secondary Manifestations of ARTerial disease-Magnetic Resonance (SMART-MR) Study is a prospective cohort study with baseline measurements in 2001-2005 and follow-up measurements in 2006-2009. The mean follow-up time was 3.9 years. SETTING: University Medical Center Utrecht, the Netherlands. PARTICIPANTS: A total of 663 patients (mean [SD] age, 57 [9] years; 81% male) with coronary artery disease, cerebrovascular disease, peripheral artery disease, or abdominal aortic aneurysm were included. MAIN OUTCOMES AND MEASURES: Using automated segmentation at baseline and follow-up, change in brain parenchymal fraction, cortical gray matter fraction, and ventricular fraction (%ICV) were quantified as indicators of progression of global, cortical, and subcortical brain atrophy. RESULTS: Multivariable adjusted regression analysis showed that patients with lower baseline diastolic BP (DBP) or mean arterial pressure had more progression of subcortical atrophy. The mean differences in the change in ventricular fraction between low and high DBP was 0.07% (95% CI, 0.01-0.14) and between low and high mean arterial pressure was 0.05% (95% CI, 0.00-0.10). Furthermore, in patients with higher baseline BP (DBP, mean arterial pressure, or systolic BP), those with declining BP levels over time had less progression of subcortical atrophy compared with those with rising BP levels. CONCLUSIONS AND RELEVANCE: In patients with manifest arterial disease, low baseline DBP was associated with more progression of subcortical atrophy, irrespective of the BP course during follow-up. Furthermore, in patients with higher baseline BP, declining BP levels over time were associated with less progression of subcortical atrophy. This could imply that BP lowering is beneficial in patients with higher BP levels, but caution should be taken with further BP lowering in patients who already have a low DBP. PMID- 23753863 TI - Pathology quiz case 2: diagnosis. PMID- 23753861 TI - This month in archives of neurology. PMID- 23753867 TI - Pathology quiz case 1: diagnosis. PMID- 23753868 TI - About this journal. PMID- 23753870 TI - Errors in Text and Conversion Factors in: Validation and Refinement of a Prediction Rule to Identify Children at Low Risk for Acute Appendicitis. PMID- 23753874 TI - Error in Data Analysis in: Adolescent Use of School-Based Health Centers and High School Dropout. PMID- 23753876 TI - Errors in the Byline, Author Affiliations, and Author Contributions in: Long-term Follow-up of Acute Partial Transverse Myelitis. PMID- 23753880 TI - The causes of epilepsy: common and uncommon causes in adults and children. PMID- 23753881 TI - El Greco's The Penitent Magdalene. PMID- 23753883 TI - Radiology quiz case 1: diagnosis. PMID- 23753877 TI - Limiting cardiac ischemic injury by pharmacological augmentation of macrophage migration inhibitory factor-AMP-activated protein kinase signal transduction. AB - BACKGROUND: Macrophage migration inhibitory factor (MIF) exerts a protective effect on ischemic myocardium by activating AMP-activated protein kinase (AMPK). Small molecules that increase the affinity of MIF for its receptor have been recently designed, and we hypothesized that such agonists may enhance AMPK activation and limit ischemic tissue injury. METHODS AND RESULTS: Treatment of cardiomyocytes with the candidate MIF agonist, MIF20, augmented AMPK phosphorylation, increased by 50% the surface localization of glucose transporter, and enhanced by 25% cellular glucose uptake in comparison with MIF alone. In mouse hearts perfused with MIF20 before no-flow ischemia and reperfusion, postischemic left ventricular function improved commensurately with an increase in cardiac MIF-AMPK activation and an augmentation in myocardial glucose uptake. By contrast, small-molecule MIF agonism was not effective in cells or tissues genetically deficient in MIF or the MIF receptor, verifying the specificity of MIF20 for MIF-dependent AMPK signaling. The protective effect of MIF20 also was evident in an in vivo regional ischemia model. Mice treated with MIF20 followed by left coronary artery occlusion and reperfusion showed a significant reduction in infarcted myocardium. CONCLUSIONS: These data support the pharmacological utility of small-molecule MIF agonists in enhancing AMPK activation and reducing cardiac ischemic injury. PMID- 23753886 TI - Radiology quiz case 1: diagnosis. PMID- 23753885 TI - Discussion of changes in intraocular pressure and anterior segment morphometry following phacoemulsification cataract surgery-reply. PMID- 23753888 TI - This month in archives of general psychiatry. PMID- 23753889 TI - May 2012 archives web quiz winner. PMID- 23753890 TI - Superficial siderosis, traumatic tap, and xanthochromia-reply. PMID- 23753892 TI - Error in Acknowledgments in: Selective Protection Against Extremes in Childhood Body Size, Abdominal Fat Deposition, and Fat Patterning in Breastfed Children. PMID- 23753893 TI - McLean Course in Electrodiagnostic Medicine. PMID- 23753900 TI - Obviating endophthalmitis after cataract surgery: the role of the paracentesis reply. PMID- 23753901 TI - BRIDGE Study Warrants Critique-Reply. PMID- 23753897 TI - Fragile X-associated tremor/ataxia syndrome: influence of the FMR1 gene on motor fiber tracts in males with normal and premutation alleles. AB - IMPORTANCE: Individuals with the fragile X premutation express expanded CGG repeats (repeats 55-200) in the FMR1 gene and elevated FMR1 messenger RNA (mRNA) levels, both of which may underlie the occurrence of the late-onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Because the core feature of FXTAS is motor impairment, determining the influence of FMR1 mRNA levels on structural connectivity of motor fiber tracts is critical for a better understanding of the pathologic features of FXTAS. OBJECTIVE: To examine the associations of CGG repeat and FMR1 mRNA with motor-related fiber tracts in males with premutation alleles. DESIGN AND SETTING: A case-control study conducted at the University of California, Davis, from April 1, 2008, through August 31, 2009. All data were collected masked to the carrier status of the FMR1 gene. PARTICIPANTS: Thirty-six male premutation carriers with FXTAS and 26 male premutation carriers without FXTAS were recruited through their family relationships with children affected by fragile X syndrome. The controls were 34 unaffected family members and healthy volunteers from the local community. MAIN OUTCOMES AND MEASURES: The CGG repeat lengths and FMR1 mRNA expression levels in peripheral blood lymphocytes, motor functioning, and white matter structural integrity that were estimated using diffusion tensor imaging. After data collection, we selected 4 motor tracts to reconstruct using diffusion tensor tractography, namely, the middle and superior cerebellar peduncles, descending motor tracts (containing the corticospinal, corticobulbar, and corticopontine tracts), and the anterior body of the corpus callosum. RESULTS: All fiber tracts exhibited weaker structural connectivity in the FXTAS group (decreased 5%-53% from controls, P <= .02). Genetic imaging correlation analysis revealed negative associations of CGG repeat length and FMR1 mRNA with connectivity strength of the superior cerebellar peduncles in both premutation groups (partial r2 = 0.23-0.33, P <= .004). In addition, the measurements from the corpus callosum and superior cerebellar peduncles revealed a high correlation with motor functioning in all 3 groups (r between partial least square predicted and actual test scores = 0.41 0.56, P <= .04). CONCLUSIONS AND RELEVANCE: Distinct pathophysiologic processes may underlie the structural impairment of the motor tracts in FXTAS. Although both the corpus callosum and superior cerebellar peduncles were of great importance to motor functioning, only the superior cerebellar peduncles exhibited an association with the elevated RNA levels in the blood of fragile X premutation carriers. PMID- 23753906 TI - Radiology quiz case 2: diagnosis. PMID- 23753905 TI - Methodological Concerns Regarding Cost-effectiveness Analysis of Palivizumab in Florida Medicaid-Reply. PMID- 23753907 TI - Error in Author's Name in: Intravitreal Bevacizumab for Peripapillary Choroidal Neovascular Membranes. PMID- 23753909 TI - About this journal. PMID- 23753911 TI - The Indian Dead Leaf Butterfly on a leaf. PMID- 23753910 TI - Cingulate epilepsy: report of 3 electroclinical subtypes with surgical outcomes. AB - IMPORTANCE: The literature on cingulate gyrus epilepsy in the magnetic resonance imaging era is limited to case reports and small case series. To our knowledge, this is the largest study of surgically confirmed epilepsy arising from the anterior or posterior cingulate region. OBJECTIVE: To characterize the clinical and electrophysiological findings of epilepsies arising from the anterior and posterior cingulate gyrus. DESIGN, SETTING, AND PARTICIPANTS: We studied consecutive cingulate gyrus epilepsy cases identified retrospectively from the Cleveland Clinic and University of Texas Southwestern Medical Center epilepsy databases from 1992 to 2009. Participants included 14 consecutive cases of cingulate gyrus epilepsies confirmed by restricted magnetic resonance image lesions and seizure freedom or marked improvement following lesionectomy. MAIN OUTCOMES AND MEASURES: The main outcome measure was improvement in seizure frequency following surgery. The clinical, video electroencephalography, neuroimaging, pathology, and surgical outcome data were reviewed. RESULTS: All 14 patients had cingulate epilepsy confirmed by restricted magnetic resonance image lesions and seizure freedom or marked improvement following lesionectomy. They were divided into 3 groups based on anatomical location of the lesion and corresponding seizure semiology. In the posterior cingulate group, all 4 patients had electroclinical findings suggestive of temporal origin of the epilepsy. The anterior cingulate cases were divided into a typical (Bancaud) group (6 cases with hypermotor seizures and infrequent generalization with the presence of fear, laughter, or severe interictal personality changes) and an atypical group (4 cases presenting with simple motor seizures and a tendency for more frequent generalization and less-favorable long-term surgical outcome). All atypical cases were associated with an underlying infiltrative astrocytoma. CONCLUSIONS AND RELEVANCE: Posterior cingulate gyrus epilepsy may present with electroclinical findings that are suggestive of temporal lobe epilepsy and can be considered as another example of pseudotemporal epilepsies. The electroclinical presentation and surgical outcome of lesional anterior cingulate epilepsy is possibly influenced by the underlying pathology. This study highlights the difficulty in localizing seizures arising from the cingulate gyrus in the absence of a magnetic resonance image lesion. PMID- 23753914 TI - Reversible postpartum cerebral vasoconstriction syndrome-reply. PMID- 23753915 TI - School-based health center use and high school dropout rates-reply. PMID- 23753918 TI - Radiology quiz case 2: diagnosis. PMID- 23753916 TI - In memoriam: charles miller fisher, MD (1913-2012). PMID- 23753923 TI - About this journal. PMID- 23753921 TI - Molecular pathways: P-Rex in cancer. AB - P-Rex proteins are Rho/Rac guanine nucleotide exchange factors that participate in the regulation of several cancer-related cellular functions such as proliferation, motility, and invasion. Expectedly, a significant portion of these actions of P-Rex proteins must be related to their Rac regulatory properties. In addition, P-Rex proteins control signaling by the phosphoinositide 3-kinase (PI3K) route by interacting with PTEN and mTOR. The interaction with PTEN inhibits its phosphatase activity, leading to AKT activation. The interaction with mTOR may be important in nutrient-stimulated Rac activation and migration. In humans, several studies have implicated P-Rex proteins in the pathophysiology of various neoplasias. Thus, overexpression of P-Rex proteins has been linked to poor patient outcome in breast cancer and may facilitate metastatic dissemination of prostate cancer cells. In addition, whole-genome sequencing described P-Rex2 as a significantly mutated gene in melanoma. Furthermore, expression in melanocytes of mutated forms of P-Rex2 found in patients with melanoma showed the protumorigenic role of these P-Rex mutations in melanoma genesis. These findings open interesting opportunities for P-Rex targeting in cancer. Moreover, the implication of P-Rex partner proteins such as Rac, mTOR, or PTEN in cancer has opened the possibility of acting on P-Rex to restrict protumorigenic signaling through these pathways. PMID- 23753926 TI - About this journal. PMID- 23753927 TI - About this journal. PMID- 23753928 TI - Pathology quiz case 1: diagnosis. PMID- 23753930 TI - Acute hypercalcemia following excessive calcium supplementation in a dehydrated patient with progressive multiple sclerosis: vitamin d supplementation is a red herring-reply. PMID- 23753934 TI - About this journal. PMID- 23753931 TI - Serotonin syndrome associated with clozapine withdrawal. AB - IMPORTANCE: We describe a case of serotonin syndrome secondary to clozapine withdrawal and concomitant use of citalopram hydrobromide, a phenomenon that has been rarely reported. OBSERVATIONS: This is a case report of a 47-year-old woman admitted to an academic medical center intensive care unit with coma, hypersalivation, hyperreflexia, and stimulus-induced clonus. The patient received a diagnosis of serotonin syndrome attributed to abrupt clozapine withdrawal with concomitant use of citalopram. She improved only minimally with supportive treatment (intravenous fluids, benzodiazapines, and withdrawal of selective serotonin-reuptake inhibitor) and received cyproheptadine hydrochloride on her third day of symptoms. Four hours after she received the loading dose of cyproheptadine, she was alert and oriented and at her baseline mental status, although some clonus remained. CONCLUSIONS AND RELEVANCE: Serotonin syndrome can result from the abrupt withdrawal of a 5-hydroxytryptamine receptor 2A antagonist from a treatment regimen that also includes a medication that increases serotonin availability. PMID- 23753936 TI - About this journal. PMID- 23753937 TI - About this journal. PMID- 23753938 TI - Picture of the month-diagnosis. PMID- 23753941 TI - Error in Figure 4F in: Spectral-Domain Optical Coherence Tomographic Assessment of Severity of Cystoid Macular Edema in Retinopathy of Prematurity. PMID- 23753943 TI - This month in archives of general psychiatry. PMID- 23753942 TI - Physical activity is not related to performance at school-reply. PMID- 23753949 TI - This month in archives of neurology. PMID- 23753951 TI - Pathology quiz case 2: diagnosis. PMID- 23753952 TI - About this journal. PMID- 23753959 TI - This month in archives of general psychiatry. PMID- 23753958 TI - This photograph overlooks the gardens and the Shrine of the Bab, in Haifa, Israel, a UNESCO World Heritage Site since 2008. PMID- 23753962 TI - Dural arteriovenous fistula at the craniocervical junction mimicking acute brainstem and spinal cord infarction. PMID- 23753963 TI - Large arteriovenous malformation in an adolescent presenting with first seizure. PMID- 23753964 TI - A variant of the anterior opercular syndrome with supranuclear gaze palsy. PMID- 23753965 TI - A complete C3-C4 spinal dislocation. PMID- 23753968 TI - Acute cervical internal carotid artery occlusion stroke. PMID- 23753969 TI - Acute cervical internal carotid artery occlusion stroke--reply. PMID- 23753975 TI - About this journal. PMID- 23753970 TI - TREM2, frontotemporal dementia-like disease, Nasu-Hakola disease, and Alzheimer dementia: a chicken and egg problem? PMID- 23753979 TI - The cradle of american neurology: the harvard neurological unit at the Boston city hospital. PMID- 23753978 TI - This month in archives of neurology. PMID- 23753980 TI - On insertion slanting strabismus surgery-reply. PMID- 23753982 TI - Radiology quiz case 1: diagnosis. PMID- 23753984 TI - Pathology quiz case 1: diagnosis. PMID- 23753989 TI - Errors in Text in: Suicide Risk in Primary Care Patients With Major Physical Diseases: A Case-Control Study. PMID- 23753993 TI - Sesame oil therapeutically ameliorates cardiac hypertrophy by regulating hypokalemia in hypertensive rats. AB - BACKGROUND: Hypokalemia and hypertension are common manifestations of preclinical cardiovascular conditions that have a predictive value for cardiovascular morbidity and mortality. Cardiac hypertrophy, an important risk factor in heart failure, is attributed to long-term hypokalemia and hypertension. Sesame oil is rich in nutrients and possesses potent antihypertensive activities. METHODS: We investigated the therapeutic potential of sesame oil using a hypertensive model created by subcutaneously injecting deoxycorticosterone acetate (DOCA; 15 mg/mL/kg in mineral oil; twice weekly for 5 weeks) and supplementing with 1% sodium chloride drinking water (DOCA/salt) to uninephrectomized rats. Sesame oil was administered by oral gavage (0.5 or 1 mL/kg/d for 7 days) after 4 weeks of DOCA/salt treatment. Systolic blood pressure (SBP) and diastolic blood pressure (DBP), electrocardiography (ECG), and K(+) and Mg(2+) levels were assessed 24 hours after the last dose of sesame oil. Heart tissue was collected for histologic analysis. RESULTS: Sesame oil effectively reduced the SBP/DBP and ECG abnormalities and increased the serum levels of K(+) and Mg(2+) while limiting the urinary excretion of K(+) in DOCA/salt-induced hypertensive rats. In addition, sesame oil decreased the heart mass, the thickness of the left ventricle, and the diameter of cardiomyocytes, indicating the regression of left ventricular hypertrophy in the hypertensive rats. CONCLUSION: We demonstrate that sesame oil therapeutically ameliorates cardiac hypertrophy by regulating hypokalemia in hypertensive rats. PMID- 23753994 TI - Vitamin D deficiency in patients with neuromuscular diseases with chronic respiratory failure. AB - BACKGROUND: The prevalence and clinical implications of vitamin D deficiency have never been studied in patients with underlying neuromuscular diseases complicated with chronic respiratory failure. The aim of this study is to demonstrate the prevalence of vitamin D deficiency, its relationship with other bone markers, and mode of nutrition. MATERIALS AND METHODS: Serum 25-hydroxyvitamin D (25[OH]D) levels along with calcium, serum albumin, and phosphorus levels were obtained from 57 patients with chronic respiratory failure due to underlying neuromuscular diseases. These levels were obtained during their first visit to a chronic respiratory diseases clinic. Data with regard to nutrition, respiratory muscle function, and level of mobility were also obtained at the same time. RESULTS: Seventy-five percent of patients had serum 25(OH)D levels <= 30 ng/mL. There is a negative correlation between parathyroid hormone and 25(OH)D levels (P = .006) and corrected calcium levels (P = .066). Serum 25(OH)D levels varied with the mode of nutrition. Patients on enteral nutrition had the highest serum levels of 25(OH)D, whereas combined oral and tube feeds had the lowest 25(OH)D levels (P = .006). CONCLUSION: Low serum 25(OH)D levels are highly prevalent in patients with neuromuscular disease and chronic respiratory failure. The route of nutrition has an impact on these levels. PMID- 23754000 TI - This month in archives of pediatrics & adolescent medicine. PMID- 23753997 TI - Picture of the month-diagnosis. PMID- 23754001 TI - Acute and emergent events in sleep disorders. PMID- 23754003 TI - Evidence-based treatment and usual care: cautions and qualifications. PMID- 23754004 TI - Age, statin use, and the risk for incident Parkinson disease-reply. PMID- 23754009 TI - About this journal. PMID- 23754005 TI - Pathology quiz case 2: diagnosis. PMID- 23754012 TI - The JAMA Network Journals: New Names for the Archives Journals. PMID- 23754016 TI - Error in Byline in: Postoperative Visual Acuity in Patients With Fuchs Dystrophy Undergoing Descemet Membrane-Stripping Automated Endothelial Keratoplasty: Correlation With the Severity of Histologic Changes. PMID- 23754019 TI - Radiology quiz case 2: diagnosis. PMID- 23754020 TI - About this journal. PMID- 23754022 TI - Primary central nervous system tumors: pathogenesis and therapy. PMID- 23754024 TI - About this journal. PMID- 23754025 TI - Pathology quiz case 3: diagnosis. PMID- 23754026 TI - Error in Tables in: Comparative Analysis of Diaphragmatic Hernia Repair Outcomes Using the Nationwide Inpatient Sample Database. PMID- 23754029 TI - March 2012 archives web quiz winner. PMID- 23754033 TI - Changing to JAMA Psychiatry. PMID- 23754034 TI - Incorrect Author Affiliation and Correspondence Address in: Intertransversalis Fascia Approach in Urologic Laparoscopic Operations. PMID- 23754036 TI - This month in archives of pediatrics & adolescent medicine. PMID- 23754039 TI - Affective-cognitive meta-bases versus structural bases of attitudes predict processing interest versus efficiency. AB - We proposed that (a) processing interest for affective over cognitive information is captured by meta-bases (i.e., the extent to which people subjectively perceive themselves to rely on affect or cognition in their attitudes) and (b) processing efficiency for affective over cognitive information is captured by structural bases (i.e., the extent to which attitudes are more evaluatively congruent with affect or cognition). Because processing speed can disentangle interest from efficiency by being manifest as longer or shorter reading times, we hypothesized and found that more affective meta-bases predicted longer affective than cognitive reading time when processing efficiency was held constant (Study 1). In contrast, more affective structural bases predicted shorter affective than cognitive reading time when participants were constrained in their ability to allocate resources deliberatively (Study 2). When deliberation was neither encouraged nor constrained, effects for meta-bases and structural bases emerged (Study 3). Implications for affective-cognitive processing and other attitudes relevant constructs are discussed. PMID- 23754040 TI - Losing one's cool: social competence as a novel inverse predictor of provocation related aggression. AB - Provocations and frustrating events can trigger an urge to act aggressively. Such behaviors can be controlled, but perhaps more so for people who can better distinguish effective from ineffective courses of action. The present three studies (total N = 285) introduce a scenario-based measure of this form of social competence (SC). In Study 1, higher levels of SC predicted lower levels of trait anger. Study 2 presented provocation scenarios and asked people whether they would engage in direct, indirect, and symbolic forms of aggression when provoked. SC was inversely predictive of all forms of aggressive responding. Study 3 focused on reactions to frustrating events in daily life. Such events were predictive of hostile behavior and cognitive failures particularly at low levels of SC. The research establishes that SC can be assessed in an objective manner and that variations in it are systematically predictive of reactive aggression. PMID- 23754041 TI - In memoriam: goodwin m. Breinin, MD (1918-2011). PMID- 23754042 TI - Picture of the month-diagnosis. PMID- 23754043 TI - About this journal. PMID- 23754046 TI - Radiology quiz case 1: diagnosis. PMID- 23754049 TI - This month in archives of neurology. PMID- 23754050 TI - About this journal. PMID- 23754053 TI - Surgical critical care workforce--are all intensivists created equal? PMID- 23754058 TI - Error in byline: in heterogeneity of coenzyme q10 deficiency: patient study and literature review. PMID- 23754061 TI - Radiology quiz case 2: diagnosis. PMID- 23754062 TI - About this journal. PMID- 23754063 TI - Something about the dance. PMID- 23754066 TI - Atlas of Inherited Metabolic Diseases, 3rd ed. PMID- 23754065 TI - Preoperative superselective mesenteric angiography and methylene blue injection for localization of obscure gastrointestinal bleeding. AB - Localizing obscure gastrointestinal bleeding can be a clinical challenge, despite the availability of various endoscopic, imaging, and visceral angiographic techniques. We reviewed the management of patients presenting with obscure gastrointestinal bleeding during the period from 2005 to 2011. Four patients had preoperative localization of the bleeding site with superselective mesenteric angiography, which was confirmed by the use of intraoperative methylene blue injection. This novel technique allowed us to identify the abnormal pathology, and, consequently, resection of the implicated segment of small bowel was performed without any postoperative complications. Final histology showed that 2 patients had arteriovenous malformations: one had a benign hemangioma of the small bowel, and the other had chronic ischemic ulceration in the ileum. Superselective mesenteric angiography combined with intraoperative localization with methylene blue is an important and innovative technique in the management of patients with unclear sources of gastrointestinal bleeding and allows for effective hemorrhage control with a focused and therefore limited bowel resection. PMID- 23754067 TI - Image of the month-diagnosis. PMID- 23754070 TI - Inhibition of proliferation, sprouting, tube formation and Tie2 signaling of lymphatic endothelial cells by the histone deacetylase inhibitor SAHA. AB - Histone deacetylase (HDAC) inhibitors exert potent inhibitory effects on various types of human cancer. The pioneer drug suberoylanilide hydroxamic acid (SAHA) is currently used in the clinic for cancer treatment. However, the effect of SAHA on tumor lymphangiogenesis is unclear. We recently showed that SAHA suppresses the expression and production of pro-lymphagenic factor vascular endothelial growth factor-C (VEGF-C) in breast cancer cells. In the present study, the effect of SAHA on lymphatic endothelial cells (LECs) was examined. We generated a lymphatic like endothelial cell line (named FP01) by overexpressing the master LEC transcription factor PROX1 in EA.hy926 endothelial cells. This cell line exhibited a gene expression pattern and phenotype similar to primarily cultured LECs. SAHA inhibited cell cycle progression and proliferation of FP01 cells. In addition, SAHA suppressed sprouting and tube formation in these cells. Moreover, SAHA attenuated the angiopoietin (Ang)/Tie signaling pathway which plays important roles in the regulation of LEC function. FP01 cells expressed Ang1, Ang2, Tie1 and Tie2, and SAHA dose-dependently reduced the expression of Tie2 in these cells. Tie2 promoter activity was attenuated by SAHA indicating a transcriptional repression. Importantly, Tie2 protein was significantly reduced by SAHA at the concentration in which no alteration of Tie2 mRNA was detected. We found that SAHA enhanced Tie2 protein degradation via the ubiquitin-proteasome pathway, and the expression of c-Cbl, the E3 ligase for Tie2 ubiquitination, rapidly increased after SAHA treatment. Knockdown of c-Cbl reversed SAHA-induced Tie2 protein degradation. Taken together, our results demonstrate that SAHA impairs the proliferation, sprouting and tube formation of LECs and attenuates Ang/Tie signaling in LECs by downregulating Tie-2 via transcriptional and post transcriptional mechanisms. PMID- 23754071 TI - About this journal. PMID- 23754072 TI - Mt Adams as seen from the shore of Takhlakh Lake, Randle, Washington. July 2010. PMID- 23754075 TI - The need for access to Medicare fee-for-service claims data. PMID- 23754077 TI - Schoolmasters on the sea star. PMID- 23754076 TI - Angle involvement and glaucoma in patients with biopsy-proven iris melanoma: a response-reply. PMID- 23754081 TI - IDEAL for CCSVI Research-Reply. PMID- 23754083 TI - This month in archives of general psychiatry. PMID- 23754086 TI - Pharmacologic and mechanical strategies for preventing venous thromboembolism after bariatric surgery: a systematic review and meta-analysis. AB - We sought to assess the comparative effectiveness and safety of pharmacologic and mechanical strategies to prevent venous thromboembolism (VTE) in patients undergoing bariatric surgery. We searched (through August 2012) for primary studies that had at least 2 different interventions. Of 30,902 citations, we identified 8 studies of pharmacologic strategies and 5 studies of filter placement. No studies randomized patients to receive different interventions. One study suggested that low-molecular-weight heparin is more efficacious than unfractionated heparin in preventing VTE (0.25% vs 0.68%, P < .001), with no significant difference in bleeding. One study suggested that prolonged therapy (after discharge) with enoxaparin sodium may prevent VTE better than inpatient treatment only. There was insufficient evidence supporting the hypothesis that filters reduce the risk of pulmonary embolism, with a point estimate suggesting increased rates with filters (pooled relative risk [RR], 1.21 95% CI, 0.57-2.56). There was low-grade evidence that filters are associated with higher mortality (pooled RR, 4.30 95% CI, 1.60-11.54) and higher deep vein thrombosis rates (2.94 1.35-6.38). There was insufficient evidence to support that augmented subcutaneous enoxaparin doses (>40 mg daily or 30 mg twice daily) are more efficacious than standard dosing, with a trend toward increased bleeding. Of note, for both filters and augmented pharmacologic dosing strategies, patients at highest risk for VTE were more likely to receive more intensive interventions, limiting our ability to attribute outcomes to prophylactic strategies used. PMID- 23754088 TI - December 2011 archives web quiz winner. PMID- 23754089 TI - Radiology quiz case 3: diagnosis. PMID- 23754091 TI - About this journal. PMID- 23754090 TI - Spatial and temporal effects of port facilities expansion on the surface area of shallow coral reefs. AB - There is a close relationship between ports and reef areas, mainly because reefs provide protection to vessels against extreme weather events like storms and hurricanes. This historical relationship has generated severe impacts on reef ecosystems. In order to identify the main impacts from the construction of port facilities in shallow coral reef areas, we analyzed and described the effects of land reclamation and coastal structure construction associated to port growth throughout a century in the Sistema Arrecifal Veracruzano National Park, Mexico. We used aerial photographs and maps of the nineteenth and early twentieth century to assess the impacts caused by port expansion activities on shallow coral reefs. Three types of impacts were identified: (a) direct reef area loss caused by landfills and perpendicular coastal structures construction leading to the loss of nearly 50 % of the fringing reef near to the port; (b) fragmentation in short- and medium-term scale, which affects two fringing reefs, and (c) long-term modification of coastal dynamics leading to sedimentation and loss of a complete reef area. On the eve of a new expansion of Veracruz Port, we used the New Port Project Plan, long-shore net drift geomorphic indicators and the port impact typology from the 100-year period assessment to evaluate a possible future scenario. The scenario describes how the new expansion project will repeat the three types of impacts affecting a whole reef area, which is currently part of the National Park. PMID- 23754092 TI - Proliferative lesions in thyroid follicular cells of dwarfs derived from Wistar Hannover GALAS rats. AB - We observed spontaneous dwarfism among Wistar Hannover GALAS rats, caused by primary hypothyroidism. The dwarf (D) rats showed markedly high serum thyroid stimulating hormone (TSH) values. In this study, we investigated the incidence and histopathological characteristics of the proliferative lesions of the thyroid follicular cells in our D rats. Gross enlargement of thyroid and histological vacuolar change of the thyroid follicular cells with age-related progression suggesting diffuse hypertrophy/hyperplasia were seen in all the D rats. In addition, focal proliferative lesions-namely hyperplasias, activated hyperplasias, adenomas, and adenocarcinomas--were seen in D rats aged over 50 weeks. Taken together, these results suggested that the sustained stimulation of elevated levels of serum TSH caused and enhanced diffuse hypertrophy of thyroid follicular cells and subsequent development of focal proliferative lesions. PMID- 23754096 TI - Effect of pantoprazole on human gastric adenocarcinoma SGC7901 cells through regulation of phospho-LRP6 expression in Wnt/beta-catenin signaling. AB - Recent studies have found that an acidic tumor microenvironment is the key to managing cancer progression and metastasis. Our previous study found that proton pump inhibitors (PPIs) inhibit the expression of vacuolar-ATPases (V-ATPases) and reverse the transmembrane pH gradient. The present study was conducted to explore the effect of pantoprazole on gastric adenocarcinoma through the regulation of Wnt/beta-catenin signaling. We used SGC7901 human gastric cancer cells as an in vitro model to study the effect of pantoprazole. The antiproliferative, pro apoptotic and anti-invasive effects of pantoprazole were examined. The effects of pantoprazole on the expression of the Wnt/beta-catenin signaling pathway were also studied by western blotting. Our study found that pantoprazole inhibited the proliferation and induced the apoptosis of SGC7901 human gastric cancer cells. The expression of V-ATPases was decreased following treatment with pantoprazole. Further study found that pantoprazole treatment caused a decrease in phospho LRP6, but not in LRP6. beta-catenin in Wnt/beta-catenin signaling and its target genes c-Myc and cyclin D1 were also decreased upon the inhibition of V-ATPases. Therefore, pantoprazole could be characterized as a V-ATPase inhibitor for treating gastric cancer by inhibiting the phosphorylation of LRP6 in Wnt/beta catenin signaling. PMID- 23754098 TI - Reading medical memoirs. PMID- 23754097 TI - Magnitude and time course of changes in maximal oxygen uptake in response to distinct regimens of chronic interval training in sedentary women. AB - PURPOSE: This study aimed to compare changes in maximal oxygen uptake (VO2max) in response to two regimens of chronic interval training. METHODS: Twenty healthy sedentary women (mean +/- SD age and VO2max = 23.0 +/- 5.7 years and 30.1 +/- 4.4 mL kg(-1) min(-1), respectively) were randomized to complete 12 weeks of one of two interval training regimes, while an additional seven women served as controls. Training was performed 3 days week(-1) on a cycle ergometer and consisted of 6-10 bouts of 1 min duration at lower (60-80 % W max = LO, n = 10) or more intense (80-90 % W max = HI, n = 10) workloads separated by a brief recovery. Every 3 weeks, measures of VO2max and W max were repeated to assign new training intensities. Changes in blood pressure and body composition were also examined. RESULTS: Data revealed significant (p < 0.001) improvements in VO2max in LO (22.3 +/- 6.9 %) and HI (21.9 +/- 11.6 %) that were similar (p > 0.05) between groups. Approximately 60 % of the increase in VO2max in HI was observed in the initial 3 weeks, compared to only 20 % in LO. No change (p > 0.05) in body weight or body composition was revealed in response to training. Results demonstrate that a relatively prolonged regimen of moderate or more intense interval training induces similar improvements in cardiorespiratory fitness, although HI induced greater increases in VO2max early on in training than LO. Completion of more intense interval training may be an effective means to expedite increases in VO2max soon after initiation of exercise training. PMID- 23754099 TI - Pathology quiz case 1: diagnosis. PMID- 23754100 TI - Selective recovery of Cu, Zn, and Ni from acid mine drainage. AB - In Korea, the heavy metal pollution from about 1,000 abandoned mines has been a serious environmental issue. Especially, the surface waters, groundwaters, and soils around mines have been contaminated by heavy metals originating from acid mine drainage (AMD) and mine tailings. So far, AMD was considered as a waste stream to be treated to prevent environmental pollutions; however, the stream contains mainly Fe and Al and valuable metals such as Ni, Zn, and Cu. In this study, Visual MINTEQ simulation was carried out to investigate the speciation of heavy metals as functions of pH and neutralizing agents. Based on the simulation, selective pH values were determined to form hydroxide or carbonate precipitates of Cu, Zn, and Ni. Experiments based on the simulation results show that the recovery yield of Zn and Cu were 91 and 94 %, respectively, in a binary mixture of Cu and Zn, while 95 % of Cu and 94 % of Ni were recovered in a binary mixture of Cu and Ni. However, the recovery yield and purity of Zn and Ni were very low because of similar characteristics of Zn and Ni. Therefore, the mixture of Cu and Zn or Cu and Ni could be recovered by selective precipitation via pH adjustment; however, it is impossible to recover selectively Zn and Ni in the mixture of them. PMID- 23754102 TI - Big alcohol catches up with adolescent girls. PMID- 23754101 TI - Incidence of breast cancer and estimates of overdiagnosis after the initiation of a population-based mammography screening program. AB - BACKGROUND: There has been growing interest in the overdiagnosis of breast cancer as a result of mammography screening. We report incidence rates in British Columbia before and after the initiation of population screening and provide estimates of overdiagnosis. METHODS: We obtained the numbers of breast cancer diagnoses from the BC Cancer Registry and screening histories from the Screening Mammography Program of BC for women aged 30-89 years between 1970 and 2009. We calculated age-specific rates of invasive breast cancer and ductal carcinoma in situ. We compared these rates by age, calendar period and screening participation. We obtained 2 estimates of overdiagnosis from cumulative cancer rates among women between the ages of 40 and 89 years: the first estimate compared participants with nonparticipants; the second estimate compared observed and predicted population rates. RESULTS: We calculated participation-based estimates of overdiagnosis to be 5.4% for invasive disease alone and 17.3% when ductal carcinoma in situ was included. The corresponding population-based estimates were -0.7% and 6.7%. Participants had higher rates of invasive cancer and ductal carcinoma in situ than nonparticipants but lower rates after screening stopped. Population incidence rates for invasive cancer increased after 1980; by 2009, they had returned to levels similar to those of the 1970s among women under 60 years of age but remained elevated among women 60-79 years old. Rates of ductal carcinoma in situ increased in all age groups. INTERPRETATION: The extent of overdiagnosis of invasive cancer in our study population was modest and primarily occurred among women over the age of 60 years. However, overdiagnosis of ductal carcinoma in situ was elevated for all age groups. The estimation of overdiagnosis from observational data is complex and subject to many influences. The use of mammography screening in older women has an increased risk of overdiagnosis, which should be considered in screening decisions. PMID- 23754103 TI - Corneal transplant wait list varies across Canada. PMID- 23754105 TI - Big data's dirty secret. PMID- 23754106 TI - Patients want access to digital health information. PMID- 23754107 TI - A 48-year-old man with a pleural-based consolidation. PMID- 23754108 TI - Eruptive xanthomas in a patient with severe hypertriglyceridemia and type 2 diabetes. PMID- 23754109 TI - BC Supreme Court begins hearing doctors' class-action lawsuit. PMID- 23754110 TI - PEI government announces catastrophic drug plan. PMID- 23754111 TI - US drug strategy runs counter to Canada's. PMID- 23754112 TI - Experts question timing of vaccination against shingles. PMID- 23754113 TI - High rates of childhood abuse, depression in Inuit suicides. PMID- 23754114 TI - Nunavut youth saturated in the realities of suicide. PMID- 23754115 TI - Cyclic tetrapeptides with -SS- bridging between amino acid side chains for potent histone deacetylases' inhibition. AB - Cyclic depsipeptide FK228 with an intramolecular disulfide bond is a potent inhibitor of histone deacetylases (HDAC). FK228 is stable in blood because of its prodrug function, whose -SS- bond is reduced within the cell. Here, cyclic peptides with -SS- bridges between a variety of amino acids were synthesized and assayed for HDAC inhibition. Cyclic peptide 3, cyclo(-L-amino acid-L-amino acid-L Val-D-Pro-), with an -SS- bridge between the first and second amino acids, was found to be a potent HDAC inhibitor. Cyclic peptide 7, cyclo(-L-amino acid-D amino acid-L-Val-D-Pro-), with an -SS- bridge between the first and second amino acids, was also a potent HDAC inhibitor. PMID- 23754116 TI - About this journal. PMID- 23754118 TI - Modification of silicone oil retention sutures in aphakic eyes with iris loss reply;. PMID- 23754120 TI - Sensory-sympathetic coupling in superior cervical ganglia after myocardial ischemic injury facilitates sympathoexcitatory action via P2X7 receptor. AB - P2X receptors participate in cardiovascular regulation and disease. After myocardial ischemic injury, sensory-sympathetic coupling between rat cervical DRG nerves and superior cervical ganglia (SCG) facilitated sympathoexcitatory action via P2X7 receptor. The results showed that after myocardial ischemic injury, the systolic blood pressure, heart rate, serum cardiac enzymes, IL-6, and TNF-alpha were increased, while the levels of P2X7 mRNA and protein in SCG were also upregulated. However, these alterations diminished after treatment of myocardial ischemic (MI) rats with the P2X7 antagonist oxATP. After siRNA P2X7 in MI rats, the systolic blood pressure, heart rate, serum cardiac enzymes, the expression levels of the satellite glial cell (SGC) or P2X7 were significantly lower than those in MI group. The phosphorylation of ERK 1/2 in SCG participated in the molecular mechanism of the sympathoexcitatory action induced by the myocardial ischemic injury. Retrograde tracing test revealed the sprouting of CGRP or SP sensory nerves (the markers of sensory afferent fibers) from DRG to SCG neurons. The upregulated P2X7 receptor promoted the activation of SGCs in SCG, resulting in the formation of sensory-sympathetic coupling which facilitated the sympathoexcitatory action. P2X7 antagonist oxATP could inhibit the activation of SGCs and interrupt the formation of sensory-sympathetic coupling in SCG after the myocardial ischemic injury. Our findings may benefit the treatment of coronary heart disease and other cardiovascular diseases. PMID- 23754122 TI - About this journal. PMID- 23754126 TI - Physical workload--a risk factor for miscarriage? PMID- 23754127 TI - This month in archives of pediatrics & adolescent medicine. PMID- 23754128 TI - Somatic hypermutations confer rheumatoid factor activity in hepatitis C virus associated mixed cryoglobulinemia. AB - OBJECTIVE: Hepatitis C virus (HCV) is the most frequent cause of mixed cryoglobulinemia (MC), which is characterized by endothelial deposition of rheumatoid factor (RF)-containing immune complexes and end-organ vasculitis. MC is a lymphoproliferative disorder in which B cells express RF-like Ig, yet its precise antigenic stimulus is unknown. We have proposed that IgG-HCV immune complexes stimulate B cell expansion and somatic hypermutation (SHM)-induced affinity maturation in part via engagement of an RF-like B cell receptor. This study was undertaken to test the hypothesis that SHM augments RF activity. METHODS: RFs cloned from single B cells from 4 patients with HCV-associated MC (HCV-MC) were expressed as IgM, IgG, or IgG Fab. Selected Ig were reverted to germline. RF activity of somatically mutated Ig and germline-reverted Ig was determined by enzyme-linked immunosorbent assay. RESULTS: Ig with SHM had RF activity, with the preference for binding being highest for IgG1, followed by IgG2 and IgG4, and lowest for IgG3, where there was no detectable binding. In contrast, reverted germline IgG exhibited markedly diminished RF activity. Competition with 1 MUg/ml of protein A abrogated RF activity, suggesting specificity for IgG Fc. Swapping of mutated heavy-chain pairs and light-chain pairs also abrogated RF activity, suggesting that context-specific pairing of appropriate IgH and Igkappa, in addition to SHM, is necessary for RF activity. CONCLUSION: SHM significantly contributes to RF activity in HCV-MC patients, suggesting that autoreactivity in these patients arises through antigen-dependent SHM, as opposed to nondeletion of autoreactive germline Ig. PMID- 23754129 TI - microRNA detection in feces, sputum, pleural effusion and urine: novel tools for cancer screening (Review). AB - microRNAs (miRNAs) are short non-coding RNA sequences that play important roles in the regulation of gene expression. They have significant regulatory functions in basic cellular processes, including differentiation, proliferation and apoptosis. miRNAs are differentially expressed in tumors, compared with normal tissues. Importantly, miRNAs are also stable and abundantly present in body fluids and feces. The high reproducibility, sensitivity and specificity of miRNAs in body fluids and feces enable miRNAs to be used as potential molecular markers for cancer screening. An increasingly large number of research studies have reported the role of miRNAs in this field. In the present review, we focused mainly on the application of detecting miRNAs in stool, sputum, pleural effusion and urine, to detect colon, lung and urological cancers, highlighting the role of miRNAs in early diagnosis and prognosis. PMID- 23754124 TI - A reappraisal of the risks and benefits of treating to target with cholesterol lowering drugs. AB - Atherosclerotic cardiovascular disease (CVD) is the number one cause of death globally, and lipid modification, particularly lowering of low density lipoprotein cholesterol (LDLc), is one of the cornerstones of prevention and treatment. However, even after lowering of LDLc to conventional goals, a sizeable number of patients continue to suffer cardiovascular events. More aggressive lowering of LDLc and optimization of other lipid parameters like triglycerides (TG) and high density lipoprotein cholesterol (HDLc) have been proposed as two potential strategies to address this residual risk. These strategies entail use of maximal doses of highly potent HMG CoA reductase inhibitors (statins) and combination therapy with other lipid modifying agents. Though statins in general are fairly well tolerated, adverse events like myopathy are dose related. There are further risks with combination therapy. In this article, we review the adverse effects of lipid modifying agents used alone and in combination and weigh these effects against the evidence demonstrating their efficacy in reducing cardiovascular events, cardiovascular mortality, and all cause mortality. For patients with established CVD, statins are the only group of drugs that have shown consistent reductions in hard outcomes. Though more aggressive lipid lowering with high dose potent statins can reduce rates of non fatal events and need for interventions, the incremental mortality benefits remain unclear, and their use is associated with a higher rate of drug related adverse effects. Myopathy and renal events have been a significant concern with the use of high potency statin drugs, in particular simvastatin and rosuvastatin. For patients who have not reached target LDL levels or have residual lipid abnormalities on maximal doses of statins, the addition of other agents has not been shown to improve clinical outcomes and carries an increased risk of adverse events. The clinical benefits of drugs to raise HDLc remain unproven. In patients without known cardiovascular disease, there is conflicting evidence as to the benefits of aggressive pursuit of numerical lipid targets, particularly with respect to all cause mortality. Certainly, in statin intolerant patients, alternative agents with a low side effect profile are desirable. Bile acid sequestrants are an effective and safe choice for decreasing LDLc, and omega-3 fatty acids are safe agents to decrease TG. There remains an obvious need to design and carry out large scale studies to help determine which agents, when combined with statins, have the greatest benefit on cardiovascular disease with the least added risk. These studies should be designed to assess the impact on clinical outcomes rather than surrogate endpoints, and require a comprehensive assessment and reporting of safety outcomes. PMID- 23754131 TI - Pathology quiz case 2: diagnosis. PMID- 23754130 TI - Image of the month-diagnosis. PMID- 23754133 TI - Recognizing speech in a novel accent: the motor theory of speech perception reframed. AB - The motor theory of speech perception holds that we perceive the speech of another in terms of a motor representation of that speech. However, when we have learned to recognize a foreign accent, it seems plausible that recognition of a word rarely involves reconstruction of the speech gestures of the speaker rather than the listener. To better assess the motor theory and this observation, we proceed in three stages. Part 1 places the motor theory of speech perception in a larger framework based on our earlier models of the adaptive formation of mirror neurons for grasping, and for viewing extensions of that mirror system as part of a larger system for neuro-linguistic processing, augmented by the present consideration of recognizing speech in a novel accent. Part 2 then offers a novel computational model of how a listener comes to understand the speech of someone speaking the listener's native language with a foreign accent. The core tenet of the model is that the listener uses hypotheses about the word the speaker is currently uttering to update probabilities linking the sound produced by the speaker to phonemes in the native language repertoire of the listener. This, on average, improves the recognition of later words. This model is neutral regarding the nature of the representations it uses (motor vs. auditory). It serve as a reference point for the discussion in Part 3, which proposes a dual-stream neuro linguistic architecture to revisits claims for and against the motor theory of speech perception and the relevance of mirror neurons, and extracts some implications for the reframing of the motor theory. PMID- 23754132 TI - Debriefing to improve outcomes from critical illness: a systematic review and meta-analysis. AB - PURPOSE: Intensive care clinicians play a central role in the co-ordination and treatment of patients that develop life-threatening emergencies. This review evaluates the effect of debriefing after life-threatening emergencies and considers the implications for intensive care training and practice. METHODS: Studies were identified by searching electronic databases, citation tracking, and contact with subject specialists. Studies evaluating the effect of debriefing after life-threatening emergencies on clinician performance (process) and/or patient outcomes were eligible for inclusion. Study quality was assessed and summarised using the GRADE system. RESULTS: The search identified 2,720 studies. After detailed review, 27 studies were included of which 20 supported the use of debriefing. Debriefing was viewed positively (n = 3), improved learning (n = 1), enhanced non-technical performance (n = 4) and technical performance (n = 16), and improved patient outcomes (n = 2). Four cardiac arrest studies were suitable for meta-analysis. This found evidence of improved resuscitation process outcomes [compression fraction (mean difference 6.80, 95 % CI 4.19-9.40, p < 0.001)] and short-term patient outcome [return of spontaneous circulation (OR 1.46, 95 % CI 1.01-2.13, p = 0.05)]. There was no effect on survival to hospital discharge (OR 0.80, 95 % CI 0.38-1.67, p = 0.55). CONCLUSIONS: This review supports the use of structured debriefing as an educational strategy to improve clinician knowledge and skill acquisition and implementation of those skills in practice. However, the effect of debriefing on long-term patient outcomes is uncertain. There remains a need for further high-quality research, which seeks to identify the optimal method for debriefing delivery and effect on patient outcomes. PMID- 23754135 TI - Commentary on special issue: CNS diseases and the immune system. AB - In an increasing number of central nervous system (CNS) diseases a pathogenic contribution of the immune system is proposed. However, the exact underlying mechanisms are often poorly understood. The collection of articles in this special issue presents a state-of-the-art review of adaptive and innate immune mechanisms and their main players in number CNS disorders. The aim of these articles is to stimulate discussion on the question whether the immune system may be a feasible target of therapy for diseases where currently no effective treatment exists. PMID- 23754137 TI - This month in archives of general psychiatry. PMID- 23754134 TI - Effects of the kappa opioid receptor antagonist, nor-binaltorphimine, on ethanol intake: impact of age and sex. AB - The kappa opioid receptor (KOR) antagonist, nor-binaltorphimine (nor-BNI), was used to investigate the role of the KOR system in mediating ethanol intake. On P25 (adolescent) or P67 (adult) male and female rats were individually housed and given ad libitum access to food and water. The experimental procedure was initiated on P28 or P70: animals were given 30 min/day access to a 10% ethanol/supersaccharin solution every other day (3 baseline exposures). On the day after the final baseline test, rats were injected with nor-BNI (0, 2.5, 5, 10 mg/kg), with testing initiated 24 hr later (30-min access every other day, 3 test exposures). Nor-BNI (10 mg/kg) increased ethanol intake in adult males, whereas the same dose decreased intake in adult females, suggesting pronounced sex differences in KOR-associated mediation of ethanol intake in adulthood. There was no impact of nor-BNI in adolescent animals of either sex, suggesting that the KOR may play less of a role in modulating ethanol intake during adolescence. PMID- 23754139 TI - Clinical pharmacology of indomethacin in preterm infants: implications in patent ductus arteriosus closure. AB - Indomethacin is a non-steroidal anti-inflammatory drug that is a potent inhibitor of prostaglandin E(2) synthesis. After birth, the ductus arteriosus closes spontaneously within 2-4 days in term infants. The major factor closing the ductus arteriosus is the tension of oxygen, which increases significantly after birth. Prostaglandin E(2) has the opposite effect to that of oxygen; it relaxes smooth muscle and tends to inhibit the closure of the ductus arteriosus. In preterm infants with respiratory distress syndrome, the ductus arteriosus fails to close (patent ductus arteriosus [PDA]) because the concentration of prostaglandin E2 is relatively high. PDA occurs in more than 70 % of neonates weighing less than 1,500 g at birth. The aim of this article was to review the published data on the clinical pharmacology of indomethacin in preterm infants in order to provide a critical analysis of the literature and a useful tool for physicians. The bibliographic search was performed electronically using the PubMed and EMBASE databases as search engines and February 2012 was the cutoff point. A remarkable interindividual variability was observed for the half-life (t(1/2)), clearance (CL), and volume of distribution (V(d)) of indomethacin. Prophylactic indomethacin consists of a continuous infusion of low levels of indomethacin and may be useful in preterm infants. Extremely preterm infants are less likely to respond to indomethacin. Infants with a postnatal age of 2 months do not respond to treatment with indomethacin. Indomethacin has several adverse effects, the most common of which is renal failure. An increase in serum creatinine of >=0.5 % mg/dL after indomethacin was observed in about 10-15 % of the patients and creatinine returns to a normal level about 1 week after cessation of therapy. Indomethacin should be administered intravenously by syringe pump for at least 30 min to minimize adverse effects on cerebral, gastrointestinal, and renal blood flow velocities. A prolonged course of indomethacin appears to reduce the risk of severe intracranial hemorrhage and renal impairment in patients with PDA. In conclusion, indomethacin is a useful drug to treat PDA. PMID- 23754138 TI - Newer treatments in the management of pediatric asthma. AB - Asthma control remains a significant challenge in the pediatric age range in which ongoing loss of lung function in children with persistent asthma has been reported, despite the use of regular preventer therapy. This has important implications for observed mortality and morbidity during adulthood. Over the past decade, there has been an emergence of other treatment adjuncts, such as anti Immunoglobulin E (IgE)-directed therapy, low dose theophylline, and the use of macrolide antibiotics, yet their exact role in asthma management remains unclear, despite omalizumab now being incorporated into several international asthma guidelines. As with many aspects of pediatric care, this is driven by a lack of appropriately designed pediatric trials. Extrapolation of data reported in adult studies may be appropriate for adolescent asthma, but is not for younger age groups, in which important pathophysiological differences exist. Novel drugs under development offer potential for benefit in the future, but to date existing data are in most cases limited to adults. Pediatric asthma also offers unique potential to prevent or modify the underlying pathophysiology. Although attempts to do so have been unsuccessful to date, advances may yet come from this approach, as our understanding about the interaction between genetics, environmental factors, and viral illness improve. This review provides an overview of the newer treatment options available for management of pediatric asthma and discusses the merits of other novel therapies in development, as we search to optimize management and improve future outcomes. PMID- 23754140 TI - Oncologic outcomes after adjuvant chemotherapy using FOLFOX in MSI-H sporadic stage III colon cancer. AB - BACKGROUND: Little is known of the oncological outcomes after adjuvant FOLFOX chemotherapy in patients with stage III colon cancer showing microsatellite instability high (MSI-H). In the present study we investigated the prognostic impact of MSI-H in patients with stage III colon cancer receiving FOLFOX chemotherapy. METHODS: We analyzed the MSI status in 127 patients with stage III colon cancer who underwent curative surgical resection followed by FOLFOX chemotherapy between January 2003 and December 2010. We assessed disease-free and overall survival (OS) in patients with MSI-H colon cancer compared with those showing microsatellite instability low or microsatellite stable (MSI-L/MSS) disease. RESULTS: Sixteen of the patients (12.6 %) were MSI-H, and 111 patients (87.4 %) were MSI-L/MSS. There was no significant difference between patients showing MSI-H and MSI-L/MSS except for age (P = 0.030), tumor location (P < 0.001), and differentiation (P = 0.031). Compared with MSI-L/MSS colon cancer, patients with MSI-H colon cancer had no significant difference in 5-year disease free and OS (72.2 vs 68.5 %, P = 0.874; 68.1 vs 71.1 %, P = 0.437). CONCLUSIONS: Our study indicates that FOLFOX chemotherapy can be considered to treat stage III colon cancer patients with MSI-H after surgery, although the study was not randomized and included only a limited number of patients. PMID- 23754141 TI - Extended lymphadenectomy in colon cancer is crucial. AB - No one doubts that lymph node dissection in colon cancer is necessary, it is just the extent of that dissection that is still under debate. As the individual steps of an oncologic operation cannot be separated from each other, analysis of the significance of lymph node dissection alone is difficult. It has been proven that the T category is directly related to the number and central spread of lymph node metastases. Micrometastases and isolated tumor cells may be detected in lymph nodes by using special staining techniques; their presence may worsen prognosis significantly and approximate it to UICC stage III. The numbers of dissected lymph nodes and the ratio of involved versus dissected lymph nodes have been used as markers for quality of surgery and histopathological evaluation. Recent results underscore the importance of technique and extent of dissection. Dissection must be performed along the embryologic planes of the mesocolon and leave them intact. A high vascular tie with preservation of the central hypogastric nerves must be applied in order to achieve the best oncologic results while preserving quality of life. Extended lymphadenectomy is oncologically relevant only when it is combined with removal of the primary tumor with adequate longitudinal clearance, an intact complete mesocolon, and high vascular tie. It is part of a concept in which the tumor-bearing specimen is harvested as an enveloped package to minimize the risk of tumor cell spillage and local recurrence. PMID- 23754144 TI - High-frequency nutrient monitoring to infer seasonal patterns in catchment source availability, mobilisation and delivery. AB - To explore the value of high-frequency monitoring to characterise and explain riverine nutrient concentration dynamics, total phosphorus (TP), reactive phosphorus (RP), ammonium (NH4-N) and nitrate (NO3-N) concentrations were measured hourly over a 2-year period in the Duck River, in north-western Tasmania, Australia, draining a 369-km(2) mixed land use catchment area. River discharge was observed at the same location and frequency, spanning a wide range of hydrological conditions. Nutrient concentrations changed rapidly and were higher than previously observed. Maximum nutrient concentrations were 2,577 MUg L(-1) TP, 1,572 MUg L(-1) RP, 972 MUg L(-1) NH4-N and 1,983 MUg L(-1) NO3-N, respectively. Different nutrient response patterns were evident at seasonal, individual event and diurnal time scales-patterns that had gone largely undetected in previous less frequent water quality sampling. Interpretation of these patterns in terms of nutrient source availability, mobilisation and delivery to the stream allowed the development of a conceptual model of catchment nutrient dynamics. Functional stages of nutrient release were identified for the Duck River catchment and were supported by a cluster analysis which confirmed the similarities and differences in nutrient responses caused by the sequence of hydrologic events: (1) a build-up of nutrients during periods with low hydrologic activity, (2) flushing of readily available nutrient sources at the onset of the high flow period, followed by (3) a switch from transport to supply limitation, (4) the accessibility of new nutrient sources with increasing catchment wetness and hydrologic connectivity and (5) high nutrient spikes occurring when new sources become available that are easily mobilised with quickly re-established hydrologic connectivity. Diurnal variations that could be influenced by riverine processes and/or localised point sources were also identified as part of stage (1) and during late recession of some of the winter high flow events. Illustrated by examples from the Duck River study, we demonstrate that the use of high frequency monitoring to identify and characterise functional stages of catchment nutrient release is a constructive approach for informing and supporting catchment management and future nutrient monitoring strategies. PMID- 23754145 TI - Comparison of compositional characteristics of amino acids between livestock wastewater and carcass leachate. AB - This study was purposed to examine the use of amino acids as an indicator to determine whether groundwater around carcass burial sites is polluted by livestock wastewater (LW) or carcass leachate (CL). The analysis of samples showed that the average amino acid concentration of carcass leachate (531.897 mg/L; 4341.784 MUmol/L) was about 300 times as high as that of livestock wastewater (1.755 mg/L; 16.283 MUmol/L). To identify distinct characteristics between LW and CL, six amino acids were paired with one another to calculate their relative composition ratios, which were found to be Leu/Trp (CL 8.39~98.6, LW 0.89~4.77), Val/Trp (CL 11.95~175.38, LW 0.73~3.62), Lys/Leu (CL 0.01~0.72, LW 0.96~8.44), Lys/Ile (CL 0.02~1.55, LW 1.64~10.99), Met/Lys (CL 0.14~0.45, LW 0.03~0.14), and Ile/Val (CL 0.38~0.73, LW 0.40~0.97). The hierarchical clustering result showed that the similarity was 0.617 among the seven LW samples and 0.563 among the seven CL samples, while the similarity between LW and CL samples was 0.198, presenting that these two sources are distinct from each other. All these results indicate that amino acids can be used as a tracer to evaluate if the contamination source is livestock wastewater or carcass leachate. To apply amino acids to tracing pollutants more effectively, however, further studies are needed to understand whether the relative abundance ratios of amino acids are maintained as they are transporting through soils as a medium. PMID- 23754146 TI - Availability of geogenic heavy metals in soils of Thiva town (central Greece). AB - Potentially toxic metals in the urban chemical environment impose risks to both ecosystem and human health. Here, we evaluate the labile pools and availabilities of non-anthropogenic Ni, Cr, Co and Mn in soil samples from Thiva town (central Greece) and investigate their associations with common soil properties and geochemical data obtained by the aqua regia and single selective dissolutions. Experimental work included the initial application of the sequential extraction protocol proposed by the European Community Bureau of Reference and chemical extractions with ethylenediamine tetraacetic acid solution and a modified physiologically based extraction test with the aim to obtain the operationally defined fractions of plant availability and human bioaccessibility, respectively. The leachate results demonstrated that despite the significant contribution of residual metal species especially for Ni and Cr, the studied serpentine soils provide chemically labile pools for all the considered elements. Nickel was found to be the most available metal with the order being Ni > Cr ~ Co ~ Mn for plant uptake and Ni > Cr > Co ~ Mn for human bioaccessibility. The aqua regia extractable concentrations are not predictors of elemental availabilities except for Ni bioaccessible data interpreting however only a moderate percentage of the total variance. The incorporation of basic soil properties (mostly total organic carbon), geochemical data for the major elements Ca, Mg and Fe and ammonium oxalate extractable Cr significantly improved the estimations for individual elements entailing the strong influence of the chemistry and mineralogy of soil materials to the release of focus metals from the soil matrix. This study provides for the first time bioaccessible data for serpentine-derived soils that are more realistic for evaluating potential adverse effects on the human health. PMID- 23754147 TI - Determination of fossil carbon content in Swedish waste fuel by four different methods. AB - This study aimed to determine the content of fossil carbon in waste combusted in Sweden by using four different methods at seven geographically spread combustion plants. In total, the measurement campaign included 42 solid samples, 21 flue gas samples, 3 sorting analyses and 2 investigations using the balance method. The fossil carbon content in the solid samples and in the flue gas samples was determined using (14)C-analysis. From the analyses it was concluded that about a third of the carbon in mixed Swedish waste (municipal solid waste and industrial waste collected at Swedish industry sites) is fossil. The two other methods (the balance method and calculations from sorting analyses), based on assumptions and calculations, gave similar results in the plants in which they were used. Furthermore, the results indicate that the difference between samples containing as much as 80% industrial waste and samples consisting of solely municipal solid waste was not as large as expected. Besides investigating the fossil content of the waste, the project was also established to investigate the usability of various methods. However, it is difficult to directly compare the different methods used in this project because besides the estimation of emitted fossil carbon the methods provide other information, which is valuable to the plant owner. Therefore, the choice of method can also be controlled by factors other than direct determination of the fossil fuel emissions when considering implementation in the combustion plants. PMID- 23754148 TI - Using sieving and pretreatment to separate plastics during end-of-life vehicle recycling. AB - Plastics continue to be a challenge for recovering materials at the end-of-life for vehicles. However, it may be possible to improve the recovery of plastics by exploiting material characteristics, such as shape, or by altering their behavior, such as through temperature changes, in relation to recovery processes and handling. Samples of a 2009 Dodge Challenger front fascia were shredded in a laboratory-scale hammer mill shredder. A 2 * 2 factorial design study was performed to determine the effect of sample shape (flat versus curved) and sample temperature (room temperature versus cryogenic temperature) on the size of the particles exiting from the shredder. It was determined that sample shape does not affect the particle size; however, sample temperature does affect the particle size. At cryogenic temperatures, the distribution of particle sizes is much narrower than at room temperature. Having a more uniform particle size could make recovery of plastic particles, such as these more efficient during the recycling of end-of-life vehicles. Samples of Chrysler minivan headlights were also shredded at room temperature and at cryogenic temperatures. The size of the particles of the two different plastics in the headlights is statistically different both at room temperature and at cryogenic temperature, and the particles are distributed narrowly. The research suggests that incremental changes in end-of-life vehicle processing could be effective in aiding materials recovery. PMID- 23754149 TI - Overview of medical device regulation in Japan as it relates to orthopedic devices. PMID- 23754150 TI - Pair of red and green macaws. PMID- 23754152 TI - Radiology quiz case 1: diagnosis. PMID- 23754151 TI - miR-708 acts as a tumor suppressor in human glioblastoma cells. AB - Glioblastoma (GBM) is one of the most lethal forms of human cancer, and new clinical biomarkers and therapeutic targets are urgently required. microRNAs (miRNAs) are small, non-coding RNAs that negatively regulate gene expression at the post-transcriptional and/or translational level by binding the 3' untranslated regions (3' UTRs) of target mRNAs. The dysregulated expression of several miRNAs has been reported to modulate glioma progression. In the present study, we defined the expression and function of miR-708, which, based on real time PCR analysis, were downregulated in GBM cells. The overexpression of miR-708 inhibited cell proliferation and invasion and induced apoptosis in the human GBM cell lines A172 and T98G. Furthermore, the overexpression of miR-708 reduced the expression of Akt1, CCND1, MMP2, EZH2, Parp-1 and Bcl2 in A172 and T98G cells. Taken together, our study suggests that miR-708 affects GBM cell proliferation and invasion, and induces apoptosis. It is suggested that miR-708 may play an important role as a tumor suppressor in GBM and it may be an attractive target for therapeutic intervention in GBM. PMID- 23754153 TI - About this journal. PMID- 23754154 TI - Robotic-assisted minimally invasive vs. thoracoscopic lung lobectomy: comparison of perioperative results in a learning curve setting. AB - PURPOSE: Minimally invasive lung lobectomy was introduced in the late 1990s. Since that time, various different approaches have been described. At our institution, two different minimally invasive approaches, a robotic and a conventional thoracoscopic one, were performed for pulmonary lobectomies. This study compares perioperative outcome of the two different techniques in a learning curve setting. METHODS: Between 2001 and 2008, 26 patients underwent lung lobectomy with a robotic-assisted thoracoscopic surgery (RATS) technique. In 2009, the minimally invasive approach was changed to a conventional video assisted thoracoscopic surgery (VATS) technique. Perioperative results of the first 26 VATS patients were compared to the results of the robotic group. RESULTS: There were significantly more patients with clinical stage >IB in the VATS group than in the robotic-assisted group (23.1 vs. 0 %). Otherwise, demographic data were equal between the groups. Operative time was significantly longer in the robotic group (215 vs. 183 min, p = 0.0362). Median difference between preoperative hemoglobin levels and levels on postoperative day 1 was higher in the RATS group, suggesting a higher blood loss. No difference was found in conversion rate, acute phase protein levels (C-reactive protein), chest drain duration, postoperative morbidity and mortality, and length of hospital stay. Procedural costs were higher for the robotic approach (difference, 770.55 , i.e., 44.4 %). CONCLUSIONS: Shorter operative times, a lower drop of postoperative hemoglobin levels indicating less blood loss, and lower procedural costs suggest a benefit of the VATS approach over the robotic approach for minimally invasive lung lobectomy. PMID- 23754155 TI - MAGI2 enhances the sensitivity of BEL-7404 human hepatocellular carcinoma cells to staurosporine-induced apoptosis by increasing PTEN stability. AB - Adaptor proteins are involved in the assembly of various intracellular complexes and the regulation of cellular functions. Membrane-associated guanylate kinase inverted 2 (MAGI2), also known as synaptic scaffolding molecule (S-SCAM), plays a critical role in signal transduction by assembling and anchoring its ligands. However, the role of MAGI2 in mediating apoptosis remains largely unknown. In the present study, BEL-7404 human hepatocellular carcinoma cells were transfected with a plasmid containing myc-MAGI2 or an empty plasmid and cell viability was then determined using the Cell Counting kit-8. Apoptosis was also detected using an Annexin V apoptosis assay. The cells were then treated with various doses of staurosporine (STS) for different periods of time. The overexpression of myc MAGI2 was found to sensitize the BEL-7404 cells to apoptosis in response to STS in a time- and dose-dependent manner. Our results demonstrated that MAGI2 enhanced STS-induced apoptosis by increasing the protein expression of cytoplasmic phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and decreasing its protein degradation. The apoptotic sensitivity of the cells caused by the overexpression of myc-MAGI2 was reversed by the silencing of PTEN expression by PTEN siRNA, thus revealing a momentous role of PTEN in the enhancement of the sensitivity of cancer cells to STS-induced apoptosis by MAGI2. Finally, we observed that the MAGI-PTEN complex triggered by MAGI2 overexpression reduced the phosphorylation levels of AKT. These results suggest that MAGI2 overexpression enhances the sensitivity of cancer cells harboring ectopic PTEN to STS-induced apoptosis. PMID- 23754159 TI - About this journal. PMID- 23754158 TI - Abstracts of ESPNIC 2013, the 24th Annual Meeting of the European Society of Paediatric and Neonatal Intensive Care. June 12-15, 2013. Rotterdam, Netherlands. PMID- 23754160 TI - The economics of the initial preventive physical examination in medicare-reply. PMID- 23754161 TI - Picture of the month-diagnosis. PMID- 23754162 TI - About this journal. PMID- 23754163 TI - Reciprocal effects of Guizhi decoction to the Guizhi decoction syndrome by toll like receptor mRNA expression and cytokines secretion. AB - OBJECTIVE: To explore the pathological mechanisms of Guizhi Decoction () syndrome and the therapeutic molecular mechanisms of the Guizhi Decoction, Mahuang Decoction (), Sangju Decoction ( ) and Yinqiao Powder (), as well as the potentially biological basis that Guizhi Decoction is most effective only for the patients with Guizhi Decoction syndrome in clinical practice. METHODS: We first got serum samples from the patients suffering from both upper respiratory tract infection and Guizhi Decoction syndrome identified by the doctors of Chinese medicine (CM) in the clinic. Four formulas with therapeutic actions of pungent warmth or pungent coolness for superficial syndromes were chosen and four kinds of rat serum samples each containing one of the above-mentioned herbal formulas were collected, then the effects of Guizhi Decoction syndromes' patient serum as well as the effects of sera containing the formulas after being stimulated by the patient serum samples on both the mRNA expression of certain toll-like receptor (TLR) subtypes and the release of some inflammatory cytokines in RAW264.7 cells were tested and analyzed in vitro. RESULTS: The expression of TLR-3, TLR-4 and TLR-9 mRNA among the 9 tested TLR subforms were up-regulated in the macrophages stimulated by the sera from untreated upper respiratory infection patients with the Guizhi Decoction syndrome (symptomcomplex). The products such as interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha and interferon (IFN)-beta from stimulated macrophages through TLR signaling pathways were also increased correspondingly. Interestingly, the changes induced by the Guizhi Decoction syndrome patients' sera were masked significantly after the macrophages were incubated with the sera from donors treated with Guizhi Decoction. Similarly, the three other exterior-releasing formulas were all effective in reversing the up regulated changes of certain TLR subforms to different degrees, but both the number of targeted TLRs and efficacy of them seemed to be inferior to that of Guizhi Decoction. CONCLUSION: Evidence from these experiments might contribute to the scientific explanation of both the pharmacological mechanisms of Guizhi Decoction and also the CM theory that Guizhi Decoction is specifically prescribed for the treatment of Guizhi Decoction syndrome (The gearing formula to the symptom-complex). PMID- 23754164 TI - Study of osteoporosis treatment principles used historically by ancient physicians in Chinese Medicine. AB - OBJECTIVE: To review the herbal drugs most often used throughout history for the treatment of osteoporosis; to study their property, flavor and meridian attribution; and to explore their compatibility. METHODS: The "Chinese Medical Classics" (upgrade) CD-ROM was used to retrieve historical prescriptions for the treatment of osteoporosis, and these were collected and sorted. Property, flavor and meridian attribution were determined, and the rules of herbal administration were determined by cluster analysis. RESULTS: A total of 389 prescriptions were found, involving 238 herbal drugs, with a total frequency of appearance of 4,236. Commonly used medications were Radix Achyranthis Bidentatae, Radix Rehmanniae praeparata, Cortex Cinnamomi, Cortex Eucommiae, Poria, Herba Cistanches, Radix Aconiti lateralis and Radix Angelicae sinensis. The herbs used included five kinds of properties, appearing a total of 2,499 times; the two most common ones were warm and plain. There were seven different drug flavors, occurring 4,151 times; sweet and bitter were the two most common ones. Eight meridian attributions were identified, appearing a total of 6,374 times; Kidney (Shen) meridian and Liver (Gan)-meridian were the two most common ones. The most common functional categories were yang-tonifying medicinal and blood-tonifying medicinal, and together these accounted for 37.8% of the total. The twenty-eight most commonly used herbal drugs formed 3 prescription clusters: C1: Cortex Eucommiae, Poria, Radix Achyranthis Bidentatae; C2: Cortex Eucommiae, Poria, Radix Achyranthis Bidentatae, Cortex Cinnamomi, Radix Rehmanniae praeparata, Herba Cistanches, Radix Angelicae sinensis, Radix Aconiti lateralis, Semen Cuscutae; C3: Os Tigris, Rhizoma Atractylodes Alba, Radix Moromdae Officinalis, Radix Angelicae pubescentis, Radix Paeoniae Alba, Herba Dendrobii, Rhizoma Alismatis, Fructus Corni, Radix Saposhnikoviae. CONCLUSIONS: Deficiency is the primary pathogenetic factor in osteoporosis, along with "stagnation" and lack of flow of water or blood. Clinical treatment of osteoporosis should be based on Kidney, Liver and Spleen (Pi) supplementation, and complemented by diuresis and dissolution of stasis, while paying attention to adjustment of the spirit. PMID- 23754165 TI - In vitro and in vivo evaluation of a self-microemulsifying drug delivery system for the poorly soluble drug fenofibrate. AB - Fenofibrate is indicated in hypercholesterolemia and hypertriglyceridemia alone or combined (types IIa, IIb, III, IV, and V dyslipidemias). However, due to its low solubility in water, it has low bioavailability after oral administration. In order to improve the dissolution rate, fenofibrate was formulated into a self microemulsifying drug delivery system (SMEDDS). We used pseudoternary phase diagrams to evaluate the area of microemulsification, and an in vitro dissolution test was used to investigate the dissolution rate of fenofibrate. The optimized formulation for in vitro dissolution and bioavailability assessment consisted of propylene glycol laurate (Lauroglycol FCC) (60 %), macrogol-15-hydroxystearate (Solutol HS 15) (27 %), and diethylene glycol monoethyl ether (Transcutol-P) (13 %). The mean droplet size of the oil phase in the microemulsion formed by the SMEDDS was 131.1 nm. The dissolution rate of fenofibrate from SMEDDS was significantly higher than that of the reference tablet. In vivo pharmacokinetics study of fenofibrate in beagles administered SMEDDS-A form resulted in a 3.7-fold increase in bioavailability as compared with the reference drug. Our studies suggested that the fenofibrate containing SMEDDS composition can effectively increase the solubility and oral bioavailability of poorly water-soluble drugs. PMID- 23754167 TI - Talia's shell, July 2008, in Bay Head, New Jersey. PMID- 23754166 TI - Rapid screening and identification of metabolites of quercitrin produced by the human intestinal bacteria using ultra performance liquid chromatography/quadrupole-time-of-flight mass spectrometry. AB - Ultra performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF MS) technique combined with MetabolynxTM software was used for analysis of the metabolites of quercitrin by the isolated human intestinal bacteria from the human feces. Four metabolites of quercitrin were detected and tentatively identified based on the characteristics of their protonated ions. The metabolites were metabolized by four main metabolic pathways including hydroxylation, demethylation, deglycosylation and ring-cleavage. Quercitrin was metabolized to the hydroxyquercitrin and desmethylquercitrin by the majority of the isolated intestinal bacteria such as Bacteroides sp. 54, and was degraded to the deglycosylated product quercetin by rhamnosidase and further ring-cleavage metabolite 3,4-dihydroxybenzoic acid by the minority of the isolated bacteria such as Bacteroides sp. 45. The metabolic pathways and most of the metabolites of quercitrin were reported for the first time. PMID- 23754171 TI - Puget sound, Seattle, washington. March 2006. PMID- 23754169 TI - Theoretical study on isomerization and peptide bond cleavage at aspartic residue. AB - Isomerization and peptide bond cleavage at aspartic residue (Asp) in peptide models have been reported. In this study, the mechanisms and energies concerning the isomerization and peptide bond cleavage at Asp residue were investigated by the density functional theory (DFT) at B3LYP/6-311++G(d,p). The integral equation formalism-polarizable continuum model (IEF-PCM) was utilized to calculate solvation effect by single-point calculation of the gas-phase B3LYP/6-311++G(d,p) optimized structure. Mechanisms and energies of the dehydration in isomerization reaction of Asp residue were comparatively analyzed with the deamidation reaction of Asn residue. The results show that the succinimide intermediate was formed preferentially through the step-wise reaction via the tetrahedral intermediate. The cleavage at C-terminus is more preferential than those at N-terminus. In comparison to isomerization, peptide bond cleavage is ~ 20 kcal mol(-1) and lower in activation barrier than the isomerization. So, in this case, the isomerization of Asp is inhibited by the peptide bond cleavage. PMID- 23754170 TI - Whole exome sequencing identifies mutation of EDNRA involved in ACTH-independent macronodular adrenal hyperplasia. AB - ACTH independent macronodular adrenal hyperplasia (AIMAH) is a rare disorder characterized by bilateral macronodular hyperplasia of the adrenal glands and increased cortisol production with subclinical or overt Cushing's syndrome. Although the family clustering of AIMAH is infrequent, we have tried our best to find such a familial affected pedigree with complete clinical information and successfully collect adrenalectomy tissue samples from two members of this family. Using whole exome sequencing and several variant prioritization strategies based on disease network analysis, we identified Endothelin receptor type A (EDNRA) Ser420Thr mutation as a causative mutation of AIMAH. EDNRA is a member of G protein coupled receptor family and is involved in cardiovascular or polycystic kidney disease. Our findings indicate that the mutation of EDNRA at S420T site should be regard as a potential AIMAH causative variation in familial and sporadic affected patients. PMID- 23754174 TI - Estrogen and estrogen receptor induce matrix metalloproteinase-26 expression in endometrial carcinoma cells. AB - The human matrix metalloproteinase (MMP)-26, also called matrilysin-2 or endometase, has been isolated as a matrilysin (MMP-7) homolog. Several reports describe that MMP-26 may be related to the development of endometrial carcinomas. Total RNAs were isolated from 51 normal endometrial tissue samples, 6 endometrial hyperplasia tissue samples and 30 endometrial carcinomas. Real-time reverse transcription-polymerase chain reaction (RT-PCR) was performed to evaluate MMP-26 mRNA expression levels. We examined the effect of estrogen and its receptor (ER) on MMP-26 expression in endometrial carcinoma cell lines by real-time RT-PCR, western blot analysis and luciferase assays. To examine protein-DNA binding between ER and MMP-26 promoter, we performed chromatin immunoprecipitation (ChIP) assay. Real-time RT-PCR analysis revealed that MMP-26 mRNA expression was significantly higher in the normal human endometria and hyperplasias compared with that in endometrial carcinomas. Estrogen not only transactivated the MMP-26 promoter activity but also enhanced endogenous MMP-26 expression. The MMP-26 promoter region contains a putative ER response element (ERE). Nuclear ER protein interacted with ERE on the MMP-26 promoter by ChIP assay. We found a significant difference in MMP-26 expression in normal and malignant endometrial tissue samples and that estrogen induced MMP-26 expression. Estrogen may induce endometrial hyperplasia but not endometrial carcinoma. Our results provide evidence that regulation of MMP-26 promoter activity by estrogen may represent a mechanism for endometrial carcinogenesis. PMID- 23754172 TI - Effects of weight-bearing exercise on bone health in girls: a meta-analysis. AB - BACKGROUND: Because growing bone possesses a greater capacity to adapt to mechanical loading than does mature bone, it is important for girls to engage in weight-bearing activities, especially since the prevalence of osteoporosis among older women is considerably higher than that of older men. In recent years, the osteogenic potential of weight-bearing activities performed by children and adolescents has received increasing attention and accumulating evidence suggests that this type of activity may improve bone health prior to adulthood and help prevent osteoporosis later in life. OBJECTIVE: Because previous interventions have varied with respect to the exercise parameters studied and sometimes produced conflicting findings, this meta-analysis was undertaken to evaluate the impact of weight-bearing exercise on the bone health of female children and adolescents and quantify the influence of key moderating variables (e.g. pubertal stage, exercise mode, intervention strategy, exercise duration, frequency of exercise, programme length and study design) on skeletal development in this cohort. METHODS: A comprehensive literature search was conducted using databases such as PubMed, MEDLINE, CINAHL, Web of Science, Physical Education Index, Science Direct and ProQuest. Search terms included 'bone mass', 'bone mineral', 'bone health', 'exercise' and 'physical activity'. Randomized- and non-randomized controlled trials featuring healthy prepubertal, early-pubertal and pubertal girls and measurement of areal bone mineral density (aBMD) or bone mineral content (BMC) using dual energy x-ray absorptiometry were examined. Comprehensive Meta-Analysis software was used to determine weighted mean effect sizes (ES) and conduct moderator analyses for three different regions of interest [i.e. total body, lumbar spine (LS), and femoral neck]. RESULTS: From 17 included studies, 72 ES values were retrieved. Our findings revealed a small, but significant influence of weight-bearing exercise on BMC and aBMD of the LS (overall ES 0.19; 95% confidence interval (CI) 0.05, 0.33 and overall ES 0.26, 95% CI 0.09, 0.43, respectively) and BMC of the femoral neck (ES 0.23; 95% CI 0.10, 0.36). For both aBMD and BMC, overall ES was not affected by any moderator variables except frequency of exercise, such that weight-bearing activity performed for more than 3 days per week resulted in a significantly greater ES value for LS aBMD compared with programmes lasting 3 or fewer days per week [Cochran's Q statistic (Qbetween) = 4.09; p < 0.05]. CONCLUSION: The impact of weight-bearing activities seems to be site specific, and a greater frequency of weight-bearing activities is related to greater aBMD of LS in growing girls. Future investigations are warranted to better understand the dose-response relationship between weight bearing activity and bone health in girls and explore the mediating role of pubertal status in promoting skeletal development among female youth. PMID- 23754175 TI - Effect of atmospheric gas plasmas on cancer cell signaling. AB - Cancer is one of the most life-threatening diseases with many forms still regarded as incurable. The conventional cancer treatments have unwanted side effects such as the death of normal cells. A therapy that can accurately target and effectively kill tumor cells could address the inadequacies of the available therapies. Atmospheric gas plasmas (AGP) that are able to specifically kill cancerous cells offer a promising alternative approach compared to conventional therapies. AGP have been shown to exploit tumor-specific genetic defects and a recent trial in mice has confirmed its antitumor effects. The mechanism by which the AGP act on tumor cells but not normal cells is not fully understood. A review of the current literature suggests that reactive oxygen species (ROS) generated by AGP induce death of cancer cells by impairing the function of intracellular regulatory factors. The majority of cancer cells are defective in tumor suppressors that interfere normal cell growth pathways. It appears that pro oncogene or tumor suppressor-dependent regulation of antioxidant/or ROS signaling pathways may be involved in AGP-induced cancer cell death. The toxic effects of ROS are mitigated by normal cells by adjustment of their metabolic pathways. On the other hand, tumor cells are mostly defective in several regulatory signaling pathways which lead to the loss of metabolic balance within the cells and consequently, the regulation of cell growth. This review article evaluates the impact of AGP on the activation of cellular signaling and its importance for exploring mechanisms for safe and efficient anticancer therapies. PMID- 23754176 TI - Hypoxia enhances the induction of human amniotic mesenchymal side population cells into vascular endothelial lineage. AB - Human amniotic mesenchymal side population (hAM-SP) cells have pluripotency and weak immunogenicity, and have promising roles in the field GAPDH of regenerative medicine. The aim of the present study was to determine whether hypoxic conditions induce the differentiation of hAM-SP cells into the vascular endothelial lineage. Mesenchymal cells were isolated from enzyme-treated amniotic membranes and stained with Hoechst 33342. The hAM-SP cells were negatively sorted by FACS and cultured in induction medium containing vascular endothelial growth factor (VEGF) under normoxic (20% O2) or hypoxic (1% O2) conditions for 1 or 2 weeks. The expression of endothelial markers such as kinase domain region (KDR), fms-like tyrosine kinase (Flt)-1, von Willebrand factor (vWF), vascular endothelial (VE)-cadherin and human vascular cell adhesion molecule (VCAM) at the gene and protein level was evaluated by real-time PCR and fluorescent immunostaining, respectively. The gene expression of KDR, Flt-1, VE-cadherin and vWF peaked after 2 weeks of culture. The protein expression of KDR and VE cadherin was also enhanced after 2 weeks of culture under hypoxic conditions. To confirm the involvement of hypoxia-inducible factor (HIF) in the induction under hypoxic conditions, the expression of genes which are known to be upregulated by HIF was analyzed by DNA microarray. The expression of these genes increased under hypoxic conditions. hAM-SP cells cultured under hypoxic conditions differentiated into the vascular endothelial lineage, probably due to upregulation of the gene expression associated with angiogenesis through activation of the HIF system. PMID- 23754177 TI - Helmet modification for soft-band bone-anchored hearing aid use during cranial orthosis. PMID- 23754179 TI - This month in archives of general psychiatry. PMID- 23754180 TI - Picture of the month-diagnosis. PMID- 23754181 TI - Issues of concern in risk assessment, genetic counseling, and genetic testing of younger breast cancer patients in Japan. AB - About 5-10 % of breast cancer cases are considered to be hereditary, and germ line mutations in the BRCA1 and BRCA2 genes have been proven to contribute to the development of hereditary breast and/or ovarian cancer syndrome (HBOC). Breast cancer diagnosed at a young age is an indication of a higher likelihood of HBOC. Risk assessment, genetic counseling, and BRCA1/BRCA2 mutation testing, especially for younger women with breast cancer, have started to be an integral element of practice due to advances in gene sequencing technologies and accumulating evidence for the clinical implications of BRCA mutation status for not only early breast cancer management, but also for the patient's own and their family's next cancer risk, and proactive steps toward a risk-reducing approach. As yet, the cancer genetic service system is immature in Japan. There are several problems to be solved to improve cancer genetic services in clinical practice for breast cancer. PMID- 23754182 TI - Moral distress reexamined: a feminist interpretation of nurses' identities, relationships, and responsibilites. AB - Moral distress has been written about extensively in nursing and other fields. Often, however, it has not been used with much theoretical depth. This paper focuses on theorizing moral distress using feminist ethics, particularly the work of Margaret Urban Walker and Hilde Lindemann. Incorporating empirical findings, we argue that moral distress is the response to constraints experienced by nurses to their moral identities, responsibilities, and relationships. We recommend that health professionals get assistance in accounting for and communicating their values and responsibilities in situations of moral distress. We also discuss the importance of nurses creating "counterstories" of their work as knowledgeable and trustworthy professionals to repair their damaged moral identities, and, finally, we recommend that efforts toward shifting the goal of health care away from the prolongation of life at all costs to the relief of suffering to diminish the moral distress that is a common response to aggressive care at end-of-life. PMID- 23754184 TI - Obturator neuropathy: an adverse outcome of a trans-obturator vaginal mesh to repair pelvic organ prolapse. AB - We report a case of obturator neuropathy induced by trans-obturator vaginal mesh surgery for symptomatic cystocele. Initial electromyography excluded genito femoral and pudendal nerve deficiency. Typical clinical arguments for severe obturator neuropathy at physical examination led to vaginal revision surgery with hemi-resection of the mesh to the ischio-pubic branch. This fully relieved obturator-induced pain and reversed adductor muscle motor deficiency. PMID- 23754186 TI - Genetic modifiers in Huntington's disease: fiction or fact? PMID- 23754185 TI - The prognostic significance of narrow fragmented QRS on admission electrocardiogram in patients hospitalized for decompensated systolic heart failure. AB - BACKGROUND: Narrow fragmented QRS (fQRS) has recently been recognized as a significant predictor of prognosis in various cardiovascular diseases. HYPOTHESIS: We hypothesized that the presence of narrow fQRS on admission electrocardiogram (ECG) in patients with decompensated systolic heart failure (HF) of any cause would be associated with long-term prognosis. METHODS: Patients hospitalized for decompensated HF due to ischemic or nonischemic dilated cardiomyopathy (left ventricular ejection fraction <35%) were retrospectively analyzed. The primary clinical end points were cardiovascular mortality, sudden cardiac death, and rehospitalization for HF. RESULTS: The mean duration of follow up was 3.73 +/- 1.41 years. Patients were classified as fQRS(+) group (n = 114; mean age, 63.49 +/- 12.04 years) and fQRS(-) group (n = 113 patients; mean age, 65.04 +/- 11.95 years). fQRS on ECG was significantly correlated with New York Heart Association (NYHA) functional class (P = 0.001). In multivariate Cox proportional hazard analysis, narrow fQRS (odds ratio [OR]: 3.130, 95% confidence interval [CI]: 1.560-2.848, P = 0.001), chronic renal failure (OR: 2.455, 95% CI: 1.120-5.381, P = 0.025), NYHA class (OR: 8.305, 95% CI: 2.568-26.855, P < 0.0001), and hypoalbuminemia (OR: 2.099, 95% CI: 1.122-3.926, P = 0.020) were independent predictors of cardiovascular mortality. In Kaplan-Meier survival analysis, narrow fQRS on admission ECG predicted worse survival rate at 84 months; survival probability significantly decreased in the fQRS(+) group compared with fQRS(-) group (P < 0.0001). CONCLUSIONS: Presence of narrow fQRS is associated with worse NYHA functional class in patients hospitalized for decompensated HF. Narrow fQRS predicts cardiovascular mortality in a specific subgroup of systolic HF patients, namely those hospitalized for decompensated HF of both ischemic and nonischemic causes. PMID- 23754187 TI - Autonomic functioning in mothers with interpersonal violence-related posttraumatic stress disorder in response to separation-reunion. AB - This study characterizes autonomic nervous system activity reactive to separation reunion among mothers with Interpersonal Violence-Related Posttraumatic Stress Disorder (IPV-PTSD). Heart-rate (HR) and high frequency heart-rate-variability (HF-HRV) were measured in 17 IPV-PTSD-mothers, 22 sub-threshold-mothers, and 15 non-PTSD mother-controls while interacting with their toddlers (12-48 months). Analyses showed IPV-PTSD-mothers having generally lower HR than other groups. All groups showed negative correlations between changes in HR and HF-HRV from sitting to standing-baseline. During initial separation, controls no longer showed a negative relationship between HR and HF-HRV. But by the second reunion, the negative relationship reappeared. IPV-PTSD- and sub-threshold-mothers retained negative HR/HF-HRV correlations during the initial separation, but stopped showing them by the second reunion. Results support that mother-controls showed a pattern of autonomic regulation suggestive of hypervigilance during initial separation that resolved by the time of re-exposure. PTSD-mothers showed delayed onset of this pattern only upon re-exposure, and were perhaps exhibiting defensive avoidance or numbing during the initial separation/reunion. PMID- 23754188 TI - Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis. AB - OBJECTIVE: To determine the long-term safety and efficacy of rilonacept, an anti interleukin-1 fusion protein, in patients with active systemic juvenile idiopathic arthritis (JIA). METHODS: In patients with systemic JIA, ages 4-20 years, the efficacy of rilonacept was evaluated using 30%, 50%, and 70% levels of improvement according to the adapted American College of Rheumatology (ACR) Pediatric 30, 50, and 70 response criteria, respectively. Efficacy and safety were evaluated during 23 months of open-label treatment (3 phases) after a 4 week, double-blind, placebo-controlled phase. Following double-blind treatment with 2.2 mg/kg or 4.4 mg/kg of rilonacept, patients were eligible to receive open label treatment at their prior dose, with adjustments. Reductions in the median daily dose of oral prednisone and improvements in laboratory parameters of disease activity (i.e., decreased levels of D-dimer and myeloid-related proteins [MRPs]) were also evaluated. RESULTS: Twenty-four patients entered the double blind study and 23 entered the open-label period. Patients were predominantly white and female, and had a median age of 14.0 years at baseline. No significant differences in efficacy were observed between the rilonacept- and placebo-treated patients during the double-blind phase, but fever and rash completely resolved by month 3 in all patients during the open-label treatment period and did not recur. Adapted ACR Pediatric 30, 50, and 70 response rates at 3 months from the start of the study were 78.3%, 60.9%, and 34.8%, respectively; these responses were generally maintained over the study duration. Levels of D-dimer and MRP-8/MRP-14 dramatically improved during the study, and in 22 of 23 patients, the prednisone dose was decreased or prednisone therapy was discontinued. No serious treatment related adverse events were observed. CONCLUSION: Sustained improvements in clinical and laboratory measures of the articular and systemic manifestations of systemic JIA were achieved in >50% of rilonacept-treated patients over 2 years. Treatment with rilonacept had a substantial steroid-sparing effect and was generally well-tolerated. PMID- 23754189 TI - Determination of the genetic architecture of seed size and shape via linkage and association analysis in soybean (Glycine max L. Merr.). AB - Seed-size traits, which are controlled by multiple genes in soybean, play an important role in determining seed yield, quality and appearance. However, the molecular mechanisms controlling the size of soybean seeds remain unclear, and little research has been done to investigate these mechanisms. In this study, we performed a genetic analysis to determine the genetic architecture of soybean seed size and shape via linkage and association analyses. We used 184 recombinant inbred lines (RILs) and 219 cultivated soybean accessions to evaluate seed length, seed width and seed height as seed-size traits, and their ratios of these values as seed-shape traits. Our results showed that all six traits had high heritability ranging from 92.46 to 98.47 %. Linkage analysis in the RILs identified 12 quantitative traits loci (QTLs), with five of these QTLs being associated with seed size, five with seed shape and two with the two first principal components of our principal component analysis (PCA). Association analysis in the 219 accessions detected 41 single nucleotide polymorphism (SNP) trait associations, with 20 of these SNPs being associated with seed-size traits, seven with seed-shape traits and 14 with the two first principal components of our PCA. This analysis reveals that seed-size and seed-shape may be controlled by different genetic factors. Our results provide a greater understanding of phenotypic structure and genetic architecture of soybean seed, and the QTLs detected in this study form a basis for future fine mapping, quantitative trait gene cloning and molecular breeding in soybean. PMID- 23754190 TI - Letter to the editor. PMID- 23754193 TI - About this journal. PMID- 23754191 TI - Safety and effectiveness of chemoembolization with drug-eluting beads for advanced-stage hepatocellular carcinoma. AB - BACKGROUND: According to the Barcelona Clinic Liver Cancer (BCLC) algorithm, patients with advanced stage (BCLC-C) hepatocellular carcinoma (HCC) are recommended for systemic treatment or palliative therapy. However, chemoembolization with drug-eluting beads (DEB-TACE) has been shown to be safe in high-risk patients. The purpose of our study was to evaluate the safety and effectiveness of DEB-TACE in patients with an advanced-stage HCC. METHODS: In this institutional review board-approved, retrospective study, 80 patients with advanced-stage HCC underwent DEB-TACE with doxorubicin. Patients were evaluated for median hospital stay, incidence of Grade 3/4 toxicities, 30-day mortality, progression-free survival (PFS), and overall survival (OS) following DEB-TACE. Univariate and multivariate analysis were performed for predictors of better OS. RESULTS: The median hospital stay following DEB-TACE was 1 day (range: 1-11). The median PFS and OS were 5.1 months [95% confidence interval (CI): 4.1-7.7] and 13.3 months (95% CI: 10.1-18.6) respectively. On multivariate analysis ECOG PS <= 1 and >2 DEB-TACE procedures were associated with better OS. Patients with ECOG PS <= 1 demonstrated a median survival of 17.7 months compared with 5.6 months for patients with ECOG PS > 1 (p = 0.025). Multiple DEB-TACE procedures (>2 procedures) were associated with improved survival (26.8 months) compared with patients with one or two procedures (11.4 months, p = 0.01). Portal vein thrombosis or extrahepatic disease had no statistically significant association with OS. CONCLUSIONS: DEB-TACE is safe and effective in patients with advanced HCC. ECOG PS <= 1 and >2 DEB-TACE procedures were associated with better OS. PMID- 23754194 TI - Patrinia scabiosaefolia induces mitochondrial-dependent apoptosis in a mouse model of colorectal cancer. AB - Disrupted apoptosis not only confers a survival advantage to cancer cells but also causes resistance to chemotherapies. Therefore, inducing cell apoptosis has become a promising strategy for anticancer treatment. Patrinia scabiosaefolia (PS) has long been used to clinically treat various types of malignancies including colorectal cancer (CRC). However, the precise mechanism of its tumoricidal activity remains largely unclear. Using a CRC mouse xenograft model and a human colon carcinoma cell line, HT-29, in the present study, we evaluated the antitumor activities of an ethanol extract of Patrinia scabiosaefolia (EEPS), and investigated the underlying molecular mechanisms. We found that EEPS inhibited CRC growth both in vivo and in vitro, without apparent adverse side effects. Moreover, EEPS treatment promoted apoptosis in CRC tumor tissues and in HT-29 cells, suggesting that the inhibitory effect of EEPS on tumor growth was due to its pro-apoptotic activity. Furthermore, EEPS treatment inhibited the expression of anti-apoptotic Bcl-2 but enhanced pro-apoptotic Bax expression at both transcriptional and translational levels. Finally, EEPS induced the loss of mitochondrial membrane potential and activation of caspase-9 and -3 in HT-29 cells. Taken together, data in this study suggest that induction of cancer cell apoptosis via the mitochondrial-dependent pathway may be one of the mechanisms whereby PS exerts anticancer activity. PMID- 23754195 TI - Picture of the month-diagnosis. PMID- 23754198 TI - Emotional, behavioral, and developmental features indicative of neglect or emotional abuse in preschool children: a systematic review. AB - IMPORTANCE: Early intervention for neglect or emotional abuse in preschoolers may mitigate lifelong consequences, yet practitioners lack confidence in recognizing these children. OBJECTIVE: To define the emotional, behavioral, and developmental features of neglect or emotional abuse in preschoolers. EVIDENCE REVIEW: A literature search of 18 databases, 6 websites, and supplementary searching performed from January 1, 1960, to February 1, 2011, identified 22 669 abstracts. Standardized critical appraisal of 164 articles was conducted by 2 independent, trained reviewers. Inclusion criteria were children aged 0 to 6 years with confirmed neglect or emotional abuse who had emotional, behavioral, and developmental features recorded or for whom the carer-child interaction was documented. FINDINGS: Twenty-eight case-control (matched for socioeconomic, educational level, and ethnicity), 1 cross-sectional, and 13 cohort studies were included. Key features in the child included the following: aggression (11 studies) exhibited as angry, disruptive behavior, conduct problems, oppositional behavior, and low ego control; withdrawal or passivity (12 studies), including negative self-esteem, anxious or avoidant behavior, poor emotional knowledge, and difficulties in interpreting emotional expressions in others; developmental delay (17 studies), particularly delayed language, cognitive function, and overall development quotient; poor peer interaction (5 studies), showing poor social interactions, unlikely to act to relieve distress in others; and transition (6 studies) from ambivalent to avoidant insecure attachment pattern and from passive to increasingly aggressive behavior and negative self-representation. Emotional knowledge, cognitive function, and language deteriorate without intervention. Poor sensitivity, hostility, criticism, or disinterest characterize maternal child interactions. CONCLUSIONS AND RELEVANCE: Preschool children who have been neglected or emotionally abused exhibit a range of serious emotional and behavioral difficulties and adverse mother-child interactions that indicate that these children require prompt evaluation and interventions. PMID- 23754197 TI - Methanolic extract of white asparagus shoots activates TRAIL apoptotic death pathway in human cancer cells and inhibits colon carcinogenesis in a preclinical model. AB - Shoots of white asparagus are a popular vegetable dish, known to be rich in many bioactive phytochemicals reported to possess antioxidant, and anti-inflammatory and antitumor activities. We evaluated the anticancer mechanisms of a methanolic extract of Asparagus officinalis L. shoots (Asp) on human colon carcinoma cells (SW480) and their derived metastatic cells (SW620), and Asp chemopreventive properties were also assessed in a model of colon carcinogenesis. SW480 and SW620 cell proliferation was inhibited by 80% after exposure to Asp (80 ug/ml). We demonstrated that Asp induced cell death through the activation of TRAIL DR4/DR5 death receptors leading to the activation of caspase-8 and caspase-3 and to cell apoptosis. By specific blocking agents of DR4/DR5 receptors we were able to prevent Asp-triggered cell death confirming the key role of DR4/DR5 receptors. We found also that Asp (80 ug/ml) was able to potentiate the effects of the cytokine TRAIL on cell death even in the TRAIL-resistant metastatic SW620 cells. Colon carcinogenesis was initiated in Wistar rats by intraperitoneal injections of azoxymethane (AOM), once a week for two weeks. One week after (post-initiation) rats received daily Asp (0.01%, 14 mg/kg body weight) in drinking water. After 7 weeks of Asp-treatment the colon of rats exhibited a 50% reduction of the number of preneoplastic lesions (aberrant crypt foci). In addition Asp induced inhibition of several pro-inflammatory mediators, in association with an increased expression of host-defense mediators. In the colonic mucosa of Asp treated rats we also confirmed the pro-apoptotic effects observed in vitro including the activation of the TRAIL death-receptor signaling pathway. Taken together, our data highlight the chemopreventive effects of Asp on colon carcinogenesis and its ability to promote normal cellular homeostasis. PMID- 23754200 TI - Fear of falling, fracture history, and comorbidities are associated with health related quality of life among European and US women with osteoporosis in a large international study. AB - We studied 7,897 women with postmenopausal osteoporosis to assess factors that influence health-related quality of life (HRQoL). An increased number of comorbidities, fear of falling, and previous vertebral fracture were associated with significant reductions in HRQoL. Understanding the factors that affect HRQoL may improve management of these patients. INTRODUCTION: HRQoL is impaired in women treated for postmenopausal osteoporosis (PMO). The objective of this study was to examine the relationship between clinical characteristics, comorbidities, medical history, patient demographics, and HRQoL in women with PMO. METHODS: Baseline data were obtained and combined from two large and similar multinational observational studies: Prospective Observational Scientific Study Investigating Bone Loss Experience in Europe (POSSIBLE EU(r)) and in the US (POSSIBLE USTM) including postmenopausal women in primary care settings initiating or switching bone loss treatment, or who had been on bone loss treatment for some time. HRQoL measured by health utility scores (EQ-5DTM) were available for 7,897 women (94 % of study participants). The relationship between HRQoL and baseline clinical characteristics, medical history and patient demographics was assessed using parsimonious, multivariable, mixed-model analyses. RESULTS: Median health utility score was 0.80 (interquartile range 0.69-1.00). In multivariable analyses, young age, low body mass index, previous vertebral fracture, increased number of comorbidities, high fear of falling, and depression were associated with reduced HRQoL. Regression-based model estimates showed that previous vertebral fracture was associated with lower health utility scores by 0.08 (10.3 %) and demonstrated the impact of multiple comorbidities and of fear of falling on HRQoL. CONCLUSIONS: In this large observational study of women with PMO, there was substantial interindividual variability in HRQoL. An increased number of comorbidities, fear of falling, and previous vertebral fracture were associated with significant reductions in HRQoL. PMID- 23754202 TI - This month in archives of general psychiatry. PMID- 23754201 TI - Stress Doppler echocardiography in systemic sclerosis: evidence for a role in the prediction of pulmonary hypertension. AB - OBJECTIVE: Patients with systemic sclerosis (SSc) in whom pulmonary hypertension (PH) is not suspected have been reported to develop an inappropriate increase of pulmonary artery systolic pressure as estimated by Doppler echocardiography under conditions of exercise (pulmonary artery systolic pressure under exercise). We undertook this study to investigate whether this increase or any other parameter detectable by stress Doppler echocardiography has utility in predicting the development of PH in SSc. METHODS: We enrolled a total of 170 patients with SSc previously investigated using standard and stress Doppler echocardiography and tissue Doppler imaging. Each patient was evaluated at baseline and yearly for skin and internal organ involvement. Right-sided heart catheterization was carried out when PH was suspected. The baseline Cochin Risk Prediction Score was calculated retrospectively. RESULTS: During followup, 6 patients (3.5%) developed PH. Compared with patients without any feature suggesting PH, the Cochin Risk Prediction Score was higher in this group (mean +/- SD 4.2 +/- 0.9 versus 3.4 +/- 0.9; P < 0.05), as was the difference between pulmonary artery systolic pressure under exercise and pulmonary artery systolic pressure (Deltapulmonary artery systolic pressure) (18.2 +/- 7 mm Hg versus 9.4 +/- 6.5 mm Hg; P < 0.001), even when adjusted for cardiac index changes. In multivariate analysis, Deltapulmonary artery systolic pressure (hazard ratio [HR] 3.4 [95% confidence interval 1.4-8], P < 0.01) and Cochin Risk Prediction Score within the fifth quintile of the values registered in our series (HR 9.3 [95% confidence interval 1.4-63.7], P < 0.05) were the only factors independently predictive of PH during followup. A Deltapulmonary artery systolic pressure cutoff of >18 mm Hg, identified by receiver operating characteristic curve analysis, had a sensitivity of 50% and a specificity of 90% for the development of PH during followup. CONCLUSION: An inappropriate response to exercise among patients with SSC is detectable by stress Doppler echocardiography. Independently of other clinical associations, increased Deltapulmonary artery systolic pressure heralds PH. Stress Doppler echocardiography may represent an additional screening tool for this severe complication. PMID- 23754203 TI - Women's intentions to receive cervical cancer screening with primary human papillomavirus testing. AB - We explored the potential impact of human papillomavirus (HPV) testing on women's intentions to be screened for cervical cancer in a cohort of Canadian women. Participants aged 25-65 years from an ongoing trial were sent a questionnaire to assess women's intentions to be screened for cervical cancer with HPV testing instead of Pap smears and to be screened every 4 years or after 25 years of age. We created scales for attitudes about HPV testing, perceived behavioral control, and direct and indirect subjective norms. Demographic data and scales that were significantly different (p < 0.1) between women who intended to be screened with HPV and those who did not intend were included in a stepwise logistic regression model. Of the 2,016 invitations emailed, 1,538 were received, and 981 completed surveys for a response rate of 63% (981/1,538). Eighty-four percent of women (826/981) responded that they intended to attend for HPV-based cervical cancer screening, which decreased to 54.2% when the screening interval was extended, and decreased further to 51.4% when screening start was delayed to age of 25. Predictors of intentions to undergo screening were attitudes (odds ratio [OR]: 1.22; 95% confidence interval [CI]: 1.15, 1.30), indirect subjective norms (OR: 1.02; 95% CI: 1.01, 1.03) and perceived behavioral control (OR: 1.16; 95% CI: 1.10; 1.22). Intentions to be screened for cervical cancer with HPV testing decreased substantially when the screening interval was extended and screening started at age of 25. Use of primary HPV testing may optimize the screening paradigm, but programs should ensure robust planning and education to mitigate any negative impact on screening attendance rates. PMID- 23754204 TI - Molar incisor hypomineralisation: prevalence and clinical presentation in school children of the northern region of India. AB - There is rarity of prevalence data on molar incisor hypomineralisation (MIH) for the Indian population and the majority of data originated from European countries. AIM: To report on prevalence and defect characteristics of MIH for school children of the northern Indian region. METHODS: A cross-sectional survey including 1,792, 6-9-year-old school children of Chandigarh, India was carried out using European Academy of Paediatric Dentistry (EAPD) 2003 criteria for diagnosis of MIH. In addition to descriptive analysis for distribution of various defects, comparative data analysis was carried out for inter-comparison of distribution and type of defect amongst two phenotypes, MH [first permanent molar (FPMs) involvement] and M + IH (simultaneous involvement of molars and incisors). Similar comparative analysis was performed for four subgroups on the basis of number of affected surfaces/subjects. RESULTS: A prevalence of 6.31% was reported. FPMs (2.83 +/- 0.874/subject) were more commonly affected than permanent incisors (1.19 +/- 1.614/subjects). White/creamy opacity without post eruptive breakdown (PEB) was the most common lesion, seen in 85% of subjects. MH phenotype was seen in 44% of subjects and 56% exhibited M + IH phenotype. A trend toward greater severity was seen in M + IH phenotype when compared to MH phenotype. A greater number of surfaces presented with white/creamy opacities without PEB (p < 0.05). With an increase in the number of surfaces involved the severity of MIH also increased with more frequent presence of brown defects with PEB. CONCLUSION: With concomitant involvement of incisors, more severe presentation of MIH was seen. Also, with increase in number of affected surfaces a parallel increase in severity as well as extent of lesions was observed. PMID- 23754205 TI - Clinical evaluation of sustained-release metronidazole gel versus metronidazole solution as an intracanal medicament in abscessed primary molars. AB - AIM: To evaluate the efficacy of metronidazole gel versus metronidazole solution against Enterococcus faecalis in abscessed primary molars. STUDY DESIGN: A clinical trial. METHOD: Twenty pulpally involved non-vital carious human primary mandibular second molars with furcal abscess were randomly allocated into two groups to evaluate the efficacy of metronidazole gel (3% w/v) and metronidazole solution (0.5% w/v) against E. faecalis. Subjects in the first experimental group were subjected to treatment with metronidazole gel (3% w/v) and subjects in the second experimental group were treated with metronidazole solution (0.5% w/v). Two microbial samples (pre-operative and post-operative samples) were obtained from the root canals of each subject from both the groups; sub cultured and efficacy of both the groups were evaluated. RESULTS: Overall percentage reduction of the mean colony forming unit (CFU) count of metronidazole gel (3% w/v) group was 96.39% and metronidazole solution (0.5 % w/v) was 90.90%. Results of intergroup t test of the percentage difference of mean CFU counts between both the groups revealed a statistically highly significant difference, i.e. p value- 0.008 (p < 0.01). CONCLUSIONS: Metronidazole gel (3% w/v) was more effective than metronidazole solution (0.5% w/v) against E. faecalis. PMID- 23754206 TI - Can rectal endoscopic sonography be used to predict infiltration depth in patients with deep infiltrating endometriosis of the rectum? AB - OBJECTIVES: To evaluate the diagnostic accuracy of rectal endoscopic sonography (RES) in the prediction of the infiltration depth of rectal endometriosis and to ascertain whether RES could be used to choose between segmental bowel resection and a more conservative approach, such as shaving or discoid resection. METHODS: In this retrospective study, 38 consecutive patients with symptomatic deep infiltrating endometriosis of the rectum who underwent laparoscopic colorectal resection were included. RES results for infiltration depth of rectal endometriosis were compared with results of pathological examination. The sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively), positive and negative likelihood ratios (LRs) and test accuracy were calculated for the presence of infiltration of the muscularis layers and submucosal/mucosal layers, as demonstrated by RES and confirmed by histopathological analysis. RESULTS: For the detection of muscularis layer infiltration by endometriosis, the PPV of RES was 100%, whereas for the detection of submucosal/mucosal layer involvement, the sensitivity was 89%, specificity was 26%, PPV was 55%, NPV was 71%, test accuracy was 58% and positive and negative LRs were 1.21 and 0.40, respectively. CONCLUSIONS: RES is a valuable tool for detecting rectal endometriosis as endometriotic infiltration of the muscularis layer can be predicted accurately. However, RES is less accurate in detecting submucosal/mucosal layer involvement and cannot, therefore, be used to choose between bowel resection and a more conservative approach. PMID- 23754207 TI - About this journal. PMID- 23754208 TI - Phenethyl isothiocyanate suppresses EGF-stimulated SAS human oral squamous carcinoma cell invasion by targeting EGF receptor signaling. AB - Phenethyl isothiocyanate (PEITC) is a natural compound that is involved in chemoprevention as well as inhibition of cell growth and induction of apoptosis in several types of cancer cells. Previous studies have revealed that PEITC suppresses the invasion of AGS gastric and HT-29 colorectal cancer cells. However, the effects of PEITC on the metastasis of SAS oral cancer cells remain to be determined. Our results showed that PEITC treatment inhibited the invasion of EGF-stimulated SAS cells in a concentration-dependent manner, but appeared not to affect the cell viability. The expression and enzymatic activities of matrix metalloprotease-2 (MMP-2) and matrix metalloprotease-9 (MMP-9) were suppressed by PEITC. Concomitantly, we observed an increase in the protein expression of both tissue inhibitor of metalloproteinase-1 (TIMP-1) and -2 (TIMP-2) in treated cells. Furthermore, PEITC treatments decreased the protein phosphorylation of epidermal growth factor receptor (EGFR) and downstream signaling proteins including PDK1, PI3K (p85), AKT, phosphorylated IKK and IkappaB to inactivate NF kappaB for the suppression of MMP-2 and MMP-9 expression. In addition, PEITC can trigger the MAPK signaling pathway through the increase in phosphorylated p38, JNK and ERK in treated cells. Our data indicate that PEITC is able to inhibit the invasion of EGF-stimulated SAS oral cancer cells by targeting EGFR and its downstream signaling molecules and finally lead to the reduced expression and enzymatic activities of both MMP-2 and MMP-9. These results suggest that PEITC is promising for the therapy of oral cancer metastasis. PMID- 23754209 TI - Cochlear pharmacokinetics of cisplatin: an in vivo study in the guinea pig. AB - OBJECTIVES/HYPOTHESIS: Cisplatin produces toxic lesions to outer hair cells (OHCs) in the cochlear base but not in the apex. The objective of this study was to compare the pharmacokinetic profile of cisplatin in scala tympani (ST) perilymph in the cochlear base and apex, respectively. STUDY DESIGN: In vivo animal study. METHODS: Forty-seven guinea pigs were given an intravenous bolus injection of an ototoxic dose of cisplatin. Ten to 240 minutes after cisplatin was given, blood, cerebrospinal fluid (CSF), and ST perilymph were aspirated within the same target time. ST perilymph was aspirated from the basal turn and from the apex of the cochlea by two different sampling techniques. Liquid chromatography with postcolumn derivatization was used for quantitative determination of the parent drug. RESULTS: Ten minutes after administration, the concentration of cisplatin in ST perilymph was 4-fold higher in the basal turn of the cochlea than in the apex. At 30 minutes, the drug concentrations did not differ. At 60 minutes, the level of cisplatin in ST perilymph and blood UF was equivalent. The perilymph-blood ratio increased thereafter with time. CONCLUSION: The pharmacokinetic findings of an early high concentration of cisplatin in the base of the cochlea and delayed elimination of cisplatin from ST perilymph compared to blood might correlate to the cisplatin-induced loss of OHCs in the base of the cochlea. PMID- 23754212 TI - Special issue on neutrophils. PMID- 23754213 TI - The use of computed tomography in pediatrics and the associated radiation exposure and estimated cancer risk. AB - IMPORTANCE: Increased use of computed tomography (CT) in pediatrics raises concerns about cancer risk from exposure to ionizing radiation. OBJECTIVES: To quantify trends in the use of CT in pediatrics and the associated radiation exposure and cancer risk. DESIGN: Retrospective observational study. SETTING: Seven US health care systems. PARTICIPANTS: The use of CT was evaluated for children younger than 15 years of age from 1996 to 2010, including 4 857 736 child-years of observation. Radiation doses were calculated for 744 CT scans performed between 2001 and 2011. MAIN OUTCOMES AND MEASURES: Rates of CT use, organ and effective doses, and projected lifetime attributable risks of cancer. RESULTS The use of CT doubled for children younger than 5 years of age and tripled for children 5 to 14 years of age between 1996 and 2005, remained stable between 2006 and 2007, and then began to decline. Effective doses varied from 0.03 to 69.2 mSv per scan. An effective dose of 20 mSv or higher was delivered by 14% to 25% of abdomen/pelvis scans, 6% to 14% of spine scans, and 3% to 8% of chest scans. Projected lifetime attributable risks of solid cancer were higher for younger patients and girls than for older patients and boys, and they were also higher for patients who underwent CT scans of the abdomen/pelvis or spine than for patients who underwent other types of CT scans. For girls, a radiation induced solid cancer is projected to result from every 300 to 390 abdomen/pelvis scans, 330 to 480 chest scans, and 270 to 800 spine scans, depending on age. The risk of leukemia was highest from head scans for children younger than 5 years of age at a rate of 1.9 cases per 10 000 CT scans. Nationally, 4 million pediatric CT scans of the head, abdomen/pelvis, chest, or spine performed each year are projected to cause 4870 future cancers. Reducing the highest 25% of doses to the median might prevent 43% of these cancers. CONCLUSIONS AND RELEVANCE: The increased use of CT in pediatrics, combined with the wide variability in radiation doses, has resulted in many children receiving a high-dose examination. Dose-reduction strategies targeted to the highest quartile of doses could dramatically reduce the number of radiation-induced cancers. PMID- 23754214 TI - On the downplay of suffering in Nordenfelt's theory of illness. AB - In his influential theory of health Nordenfelt bases the concepts of health and illness on the notions of ability and disability. A premise for this is that ability and disability provide a more promising, adequate, and useful basis than well-being and suffering. Nordenfelt uses coma and manic episodes as paradigm cases to show that this is so. Do these paradigm cases (and thus the premise) hold? What consequences does it have for the theory of health and illness if it they do not? These are the key questions in this article, which first presents the relationship between pain and disability in Nordenfelt's theory and the paradigm cases he uses to argue for the primacy of disability over pain. Then, Nordenfelt's concepts of illness are outlined, highlighting its presumptions and arguments. The main point is that if you do not have an action-theoretical perspective, it is not obvious that disability is the core concept for illness. The compelling effect of the paradigm cases presupposes that you see ability as the primary issue. To those who do not share this presumption, people in coma may not be ill. There are alternative well founded arguments for the primacy of first person experiences for the concept of illness. Hence, we need better arguments for the primacy of disability over first person experiences in illness, or first person experience should be more primarily included in the concept of illness. PMID- 23754216 TI - Huntington's disease and cell therapies: past, present, and future. AB - Huntington's disease (HD) is an inherited neurodegenerative disease that is characterized by movement abnormalities, cognitive impairment, and abnormal behavior as well as sleep and weight problems. It is an autosomal dominant disorder caused by a mutation in the huntingtin gene on the short arm of chromosome 4, which results in the progressive degeneration of the basal ganglia (caudate, putamen, and globus pallidus), cerebral cortex, brainstem, thalamus, and hypothalamus. This chapter considers four avenues of research: (a) the restoration of neurogenesis as an endogenous cell therapy in HD, (b) fetal tissue transplantation, (c) stem cell transplantation, and finally (d) the use of endogenous trophic factors such as brain derived neurotrophic factor. PMID- 23754215 TI - A brief history of triplet repeat diseases. AB - Instability of repetitive DNA sequences within the genome is associated with a number of human diseases. The expansion of trinucleotide repeats is recognized as a major cause of neurological and neuromuscular diseases, and progress in understanding the mutations over the last 20 years has been substantial. Here we provide a brief summary of progress with an emphasis on technical advances at different stages. PMID- 23754217 TI - Transcranial two-photon imaging of synaptic structures in the cortex of awake head-restrained mice. AB - Transcranial two-photon microscopy allows long-term imaging of neurons, glia, and vasculature in the intact cortex of living animals. So far, this technique has been primarily used to acquire images in anesthetized animals. Here, we describe a detailed protocol for high-resolution two-photon imaging of neuronal structures in the cortex of awake head-restrained mice. Surgery is done within 1 h in anesthetized mice. After animals recover from anesthesia, two-photon imaging can be performed multiple times over minutes to days, allowing longitudinal studies of synaptic plasticity and pathology without the complication induced by anesthesia reagents. PMID- 23754218 TI - In vivo imaging of synapse plasticity in the mouse motor cortex. AB - The mammalian motor cortex is capable of circuit reorganization driven by acquisition of novel motor skills. Time-lapse imaging of synaptic structures in the living brain provides valuable information on how motor learning rewires synaptic connections and how long-lasting memory is structurally encoded in the intact brain. Here we introduce a transcranial imaging protocol using two-photon laser scanning microscopy to follow fluorescently labeled postsynaptic dendritic spines in vivo. This protocol utilizes a thinned-skull preparation, which allows repetitive imaging of the same synapses over various intervals ranging from hours to years. Furthermore, intracortical microstimulation is performed at the end of repetitive imaging to confirm that images are taken from functionally responsive regions in the motor cortex. PMID- 23754219 TI - Pluripotent hybrid stem cells from transgenic Huntington's disease monkey. AB - Huntington's disease (HD) is a devastating disease that currently has no cure. Transgenic HD monkeys have developed key neuropathological and cognitive behavioral impairments similar to HD patients. Thus, pluripotent stem cells derived from transgenic HD monkeys could be a useful comparative model for clarifying HD pathogenesis and developing novel therapeutic approaches, which could be validated in HD monkeys. In order to create personal pluripotent stem cells from HD monkeys, here we present a tetraploid technique for deriving pluripotent hybrid HD monkey stem cells. PMID- 23754221 TI - Lentiviral-mediated gene transfer of siRNAs for the treatment of Huntington's disease. AB - This chapter describes the potential use of viral-mediated gene transfer in the central nervous system for the silencing of gene expression using RNA interference in the context of Huntington's disease (HD). Protocols provided here describe the design of small interfering RNAs, their encoding in lentiviral vectors (LVs) and viral production, as well as procedures for their stereotaxic injection in the rodent brain. PMID- 23754220 TI - Mesenchymal stem cells for trinucleotide repeat disorders. AB - Mesenchymal stem cells/marrow stromal cells (MSCs) are ideally suited for cellular therapy due to their ease of isolation, manipulation, and strong safety profile in the clinic. They can be expanded from normal qualified human donors in large quantities and can be infused without tissue matching, since they shield themselves from the immune system. The ability to be transplanted without tissue matching has allowed large multicenter trials to be conducted with direct comparison of the same batches of MSCs, without adverse events or rejection reactions. MSCs are now approved as drugs in several countries outside of the USA. MSCs can be genetically modified to provide sustained and long-term delivery of growth factors at supraphysiological levels. Gene-modified MSCs are in clinical trials for the treatment of stroke and are under consideration for the treatment of neurodegenerative disorders such as Huntington's disease. PMID- 23754222 TI - Purification of dFMR1-containing complexes using tandem affinity purification. AB - Fragile X syndrome results from the lack of FMR1 expression. To understand how the lack of FMR1 function leads to the syndrome, we are studying the Drosophila FMR1 related protein (dFMR1). We performed affinity purification of dFMR1 associated complexes from cultured Drosophila S2 cells and found that dFMR1 associates with a key component of RNA interference, AGO2. Our finding suggests cross talk between the fragile X syndrome protein and RNA interference. In this chapter, we describe a tandem affinity purification method to isolate the protein components and small RNAs in the dFMR1-associated complexes. PMID- 23754223 TI - Combined FISH and immunofluorescent staining methods to co-localize proteins and mRNA in neurons and brain tissue. AB - Combining multicolor fluorescent in situ hybridization (FISH) and immunofluorescent staining (IFS) presents a powerful method for visualizing the spatial relationship between mRNA and proteins in different neural compartments. Although seemingly straightforward, the combination of IFS/FISH and quantitative co-localization analysis of mRNA and proteins can be difficult to perform successfully, often generating variable results. Here we describe a combined method of multicolor IFS and FISH in concert with two-dimensional (2D) and three dimensional (3D) co-localization analysis for determining the expression of individual molecules in rat neurons and brain sections. Using this approach, we have analyzed interactions of the Huntington's disease protein huntingtin with select proteins and mRNA. PMID- 23754224 TI - Epigenetic modifications of the FMR1 gene. AB - The fragile X syndrome (FXS), the most common cause of heritable intellectual disability, is caused by expansion of a CGG repeat located at the 5' UTR of the FMR1 gene and subsequent epigenetic modifications of its promoter. Epigenetic modifications include both methylation of the cytosines of the CpG island in the promoter region and of the expanded CGG triplet, and posttranslational histone changes. The combination of these changes, one structural (expansion) and one epigenetic (methylation and histone modifications), results in transcriptional silencing, even though the coding region of the FMR1 gene remains intact. Here we describe the molecular methods used to study both DNA methylation and histone epigenetic modifications, namely, bisulfite sequencing and quantification of immunoprecipitated DNA after Chromatin Immunoprecipitation (ChIP). PMID- 23754225 TI - The CGG repeat and the FMR1 gene. AB - This chapter intends to provide the different DNA and protein methods for analysis of the repeat in the FMR1 gene, both in humans and in mouse models. The methods to determine the CGG repeat size include Southern blot analysis, polymerase chain reaction (PCR), and methylation status analysis, including bisulfite treatment. The methods to determine expression include analysis of RNA levels and protein levels. PMID- 23754226 TI - Study of oxidative damage and antioxidant systems in two Huntington's disease rodent models. AB - Huntington's disease (HD) is a hereditary neurodegenerative disorder, characterized by motor, psychiatric, and cognitive symptoms. The genetic defect responsible for the onset of the disease, expansion of CAG repeats in exon 1 of the gene that codes for huntingtin, has been unambiguously identified. The mechanisms by which the mutation causes the disease are not completely understood yet. However, defects in the energy metabolism of affected cells, which may cause oxidative damage, have been proposed as underlying molecular mechanisms that participate in the etiology of the disease. In this chapter, we describe biochemical methods that allow us to determine striatal oxidative damage in transgenic mice and in the quinolinic acid-induced excitotoxicity model in rat, and establish the status of protective cellular systems. The excitotoxic model is acute, easier and faster to perform than the transgenic model, and can within a short period provide valuable data to try new therapeutic strategies. The methods described in this chapter permit us to link the kynurenine pathway with the cascade of toxic and harmful reactions that cause the damage observed in HD. We consider that determining the mechanisms inducing oxidative damage in two different models of HD will allow the testing of drugs or other therapeutic strategies with antioxidant activities. PMID- 23754227 TI - Regulation of ataxin-1 phosphorylation and its impact on biology. AB - Ataxin-1 protein expression is found in the cytoplasm and nucleus of Purkinje cells, the primary site of spinocerebellar ataxia type 1 (SCA1). Phosphorylation at S776 occurs in the cytoplasm and stabilizes the protein through interaction with 14-3-3, allowing it to translocate into the nucleus where disease is initiated. Phosphorylation and stabilization are enhanced when the polyglutamine expansion is present. In this chapter, we present a model of neurodegeneration in SCA1 initiated through phosphorylation at S776 by cAMP-dependent protein kinase (PKA) and enhanced by the presence of the polyglutamine expansion. The biological methods used to uncover SCA1 pathogenesis and phosphorylation at S776 are described. PMID- 23754228 TI - Towards understanding region-specificity of triplet repeat diseases: coupled immunohistology and mass spectrometry imaging. AB - Many trinucleotide repeat disorders exhibit region-specific toxicity within tissues, the basis of which cannot be explained by traditional methods. For example, in Huntington's Disease (HD), the toxic disease-causing protein is ubiquitously expressed. However, only the medium spiny neurons in the striatum are initially targeted for death. Many changes are likely to initiate in these cells at an intracellular and microstructural level long before there is a measureable phenotype, but why some regions of the brain are more susceptible to death is unknown. This chapter describes a method to detect functional changes among brain regions and cell types, and link them directly with region-specific physiology. Due to the neurodegeneration that accompanies many triplet repeat disorders, we focus on the brain, although the methods described in this chapter can be translated to other tissue types. We integrate immunohistology and traditional mass spectrometry with a novel mass spectrometry imaging technique, called nanostructure initiated mass spectrometry (NIMS). When used together, these tools offer unique insights into region-specific physiology of the brain, and a basis for understanding the region-specific toxicity associated with triplet repeat disorders. PMID- 23754229 TI - Antibodies and intrabodies against huntingtin: production and screening of monoclonals and single-chain recombinant forms. AB - Antibodies can be extremely useful tools for the field of triplet repeats diseases. These reagents are important for localizing proteins in tissues and they can be used in the isolation and characterization of the components of protein complexes. In the context of huntingtin (Htt), antibodies can distinguish Htt with normal or an expanded polyglutamine (polyQ) repeats, and they can identify distinct conformations of Htt. Htt is the protein that, when mutated to contain an expanded polyQ motif, causes Huntington's disease (HD). Our group has produced monoclonal and recombinant single-chain antibodies (intrabodies) that can be used for these purposes and to perturb the function of Htt in living cells. Studies with anti-Htt intrabodies have led to identification of novel pathogenic epitopes. Moreover, some of the isolated intrabodies can reduce the neurotoxicity of mutant Htt in cell culture and animal models of HD. Thus, the production of antibodies and intrabodies has made a significant contribution to the understanding of HD pathogenesis and has introduced a novel strategy to treat this debilitating neurodegenerative disorder. PMID- 23754230 TI - Cell recovery from DM1 transgenic mouse tissue to study (CTG) n instability and DM1 pathogenesis. AB - Myotonic dystrophy type 1 results from an unstable expanded CTG repeat ((CTG) n ) in the 3' UTR of the DMPK gene. Transgenic mouse models have been developed to reproduce the (CTG) n instability seen in DM1 patients. These transgenic mice provide an excellent tool to study the disease mechanism as well as the molecular mechanisms underlying trinucleotide repeat instability. The propensity for somatic instability differs per tissue and cell type. Expansion of the (CTG) n over time in certain tissues is thought to underlie progression of the clinical picture. It is therefore crucial to understand what causes the (CTG) n to expand in certain cells and not in others, as well as to see possibly distinct downstream cellular effects of different (CTG) n lengths in different cell populations. We describe here an updated method to determine the genotype (homozygous, hemizygous, or non-transgenic) of the transgene, as well as length of the very long (CTG) n tracts now commonly obtained in our mouse model. Furthermore, in order to facilitate research into cell populations that show different degrees of instability, we present here a fast technique to recover cells from mouse tissues, which can serve as a basis for multiple downstream applications, including cell culture and biochemical or molecular studies. PMID- 23754231 TI - Markerless modification of trinucleotide repeat loci in BACs. AB - Transcription and splicing of human genes are regulated by nucleotide sequences encoded across large segments of our genome, and trinucleotide repeat expansion mutations can have both profound and subtle effects on these processes. In the course of our work to understand the impact of the Spinocerebellar Ataxia type 8 (SCA8) CTG repeat expansion on the transcription and splicing of the RNAs encoded near the SCA8 locus, we have developed a set of reagents and protocols for modifying large genomic BAC clones of this region. We describe the two-step procedure that allows us to precisely replace unexpanded trinucleotide repeats with expanded variants of these repeat sequences without leaving any exogenous sequences in the final constructs, and we discuss how this approach can be adapted to make other desired sequence changes to these genomic clones. PMID- 23754232 TI - DRPLA: recent advances in research using transgenic mouse models. AB - Dentatorubral-pallidoluysian atrophy (DRPLA) is one form of trinucleotide repeat disease, which has a high prevalence rate in the Japanese population. Our group established DRPLA transgenic mice harboring a single copy of a full-length human mutant DRPLA gene with 76 CAG repeats (Q76 mice). Q76 mice showed no obvious neurological phenotype but showed somatic and intergenerational instabilities of CAG repeats which closely resembled those in human DRPLA. During the breeding of Q76 mice, we serendipitously generated an additional strain with 129 repeats by "en masse" expansion of CAG repeats (Q129 mice). These two substrains are ideal models for the investigation of CAG-repeat-dependent pathogenesis of DRPLA, because they have the same genetic background except for the length of CAG repeats. Q129 mice showed a marked neurological phenotype and massive neuronal intranuclear accumulation (NIA) of mutant proteins, but showed no obvious neuronal loss. Through detailed investigations of these two substrains, we believe that "neuronal dysfunction without neuronal loss" is the key concept in the pathogenesis of DRPLA. PMID- 23754233 TI - Spinocerebellar ataxia type 2 neurodegeneration differentially affects error based and strategic-based visuomotor learning. AB - There are different types of visuomotor learning. Among the most studied is motor error-based learning where the sign and magnitude of the error are used to update motor commands. However, there are other instances where individuals show visuomotor learning even if the sign or magnitude of the error is precluded. Studies with patients suggest that the former learning is impaired after cerebellar lesions, while basal ganglia lesions disrupt the latter. Nevertheless, the cerebellar role is not restricted only to error-based learning, but it also contributes to several cognitive processes. Therefore, here, we tested if cerebellar ataxia patients are affected in two tasks, one that depends on error based learning and the other that prevents the use of error-based learning. Our results showed that cerebellar patients have deficits in both visuomotor tasks; however, while error-based learning tasks deficits correlated with the motor impairments, the motor error-dependent task did not correlate with any motor measure. PMID- 23754234 TI - Why do patients with cerebellar ataxia not use environmental cues for reducing unpredictability of sudden gait stopping? PMID- 23754236 TI - Epidemiologic evidence concerning the bereavement exclusion in major depression reply. PMID- 23754235 TI - Three-dimensional ultrasound and magnetic resonance imaging assessment of cervix and vagina in women with uterine malformations. AB - OBJECTIVES: To investigate the accuracy of three-dimensional ultrasound (3D-US) with respect to magnetic resonance imaging (MRI), and compared to clinical examination, in the assessment of cervix and vagina in women with uterine malformations. METHODS: In this prospective study, 16 patients diagnosed with uterine malformation with cervical involvement underwent 3D-US examination. The acquisition of cervical volumes was transvaginal, with four cases repeated in the peri-ovulation period, while vaginal volumes were acquired by transperineal imaging following filling of the vagina with gel. MRI was performed in 13 patients using endovaginal gel. All cases underwent clinical examination, comprising bimanual gynecological examination and speculoscopy. Diagnostic concordance of each of the methods with the gold standard was calculated. RESULTS: 3D-US cervical examinations revealed 12 cases of duplicate cervix, two of complete septate cervix and two of incomplete septate cervix. Images of the cervical canal in the peri-ovulation period were judged subjectively to be better in quality, but did not lead us to change any diagnosis. 3D-US vaginal examinations revealed four cases with a vaginal dividing wall and two with a blind hemivagina. None of the 3D-US findings contradicted the clinical findings of the cervix; however, clinically we observed two cases with vaginal dividing wall that had not been diagnosed with 3D-US. MRI diagnosed nine cases of duplicate cervix, three of complete septate cervix, one of incomplete septate cervix, five of vaginal dividing wall and two of blind hemivagina. One case diagnosed as complete septate cervix was in fact a duplicate cervix on 3D-US and on clinical examination. Compared with the gold standard, both 3D-US and MRI were highly efficient in the diagnosis of anomalies of the cervix and vagina. The overall diagnostic concordance of 3D-US with clinical examination (kappa, 0.84; 95% CI, 0.62-1) was slightly inferior to that of MRI with clinical examination (kappa, 0.9; 95% CI, 0.72-1), but this difference was not statistically significant. CONCLUSIONS: The acquisition of isolated cervical volumes, without including the uterus, defines the extent of the ectocervix and the limits of the cervical canal in uterine malformations. The use of endovaginal gel makes possible the diagnosis of associated vaginal anomalies with 3D-US. PMID- 23754237 TI - IL-15 modulates the balance between Bcl-2 and Bim via a Jak3/1-PI3K-Akt-ERK pathway to promote CD8alphaalpha+ intestinal intraepithelial lymphocyte survival. AB - IL-15 is an essential survival factor for CD8alphaalpha(+) intestinal intraepithelial lymphocytes (iIELs) in vitro and in vivo. However, the IL-15 induced survival signals in primary CD8alphaalpha(+) iIELs remains elusive. Although Bcl-2 level in CD8alphaalpha(+) iIELs positively correlates with IL 15Ralpha expression in the intestinal epithelial cells, overexpression of Bcl-2 only moderately restores CD8alphaalpha(+) gammadelta iIELs in Il15(-/-) mice. Here, we found that IL-15 promptly activated a Jak3-Jak1-PI3K-Akt pathway that led to the upregulation of Bcl-2 and Mcl-1. This pathway also induced a delayed but sustained ERK1/2 activation, which not only was necessary for the maintenance of Bcl-2 but also resulted in the phosphorylation of extra-long Bim at Ser(65) . The latter event facilitated the dissociation of Bim from Bcl-2 without affecting Bim abundance in IL-15-treated CD8alphaalpha(+) iIELs. Using an adoptive cell transfer approach, we found that either overexpression of Bcl-2 or removal of Bim from CD8alphaalpha(+) iIELs promoted their survival in Il15ra(-/-) mice. Taken together, IL-15 promotes CD8alphaalpha(+) iIEL survival by both increasing Bcl-2 levels and dissociating Bim from Bcl-2 through activation of a Jak3-Jak1-PI3K-Akt ERK1/2 pathway, which differs from a previously reported IL-15-induced survival signal. PMID- 23754239 TI - Low-frequency stimulation inhibits epileptogenesis by modulating the early network of the limbic system as evaluated in amygdala kindling model. AB - Low-frequency stimulation (LFS) is emerging as a new option for the treatment of epilepsy. The present study was designed to determine whether there is a crucial period for the treatment of epileptogenesis with LFS. LFS was delivered at different time-points to evaluate its anti-epileptogenic effect on amygdala kindling rats. (18)F-fluorodeoxyglucose small-animal positron-emission tomography (microPET) and multi-channel EEG recording (MER) were used to investigate the dynamics of brain networks during epileptogenesis and LFS treatment. Interestingly, LFS delivered in the first 7 days significantly retarded the progression of behavioral seizure stages and shortened the afterdischarge duration (ADD), LFS delivered throughout the whole process resulted in similar effects. However, if LFS was delivered at the beginning of seizure stage 2 or 3 (5 +/- 0.3 days during kindling acquisition), it had no anti-epileptogenic effect and even prolonged the ADD and enhanced synchronization of the EEGs. MicroPET study revealed a notable hypometabolism in the amygdala, piriform cortex, entorhinal cortex and other regions in the limbic system during the period from seizure stage 0 to stage 2 or 3. The glucose metabolism in those regions was specifically increased by LFS. MER further verified that an early network of afterdischarge spread was formed in those brain regions during kindling acquisition. Thus, we provided direct evidence that modulation of the early network in the limbic system is crucial for the anti-epileptogenic effect of LFS in amygdaloid-kindling rats. PMID- 23754238 TI - Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis. AB - OBJECTIVE: To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS: Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION: Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months. PMID- 23754240 TI - Role of preoperative imaging with multidetector computed tomography in the management of patients with gastroesophageal reflux disease symptoms after laparoscopic sleeve gastrectomy. AB - BACKGROUND: The aims of the study were to evaluate if multidetector computed tomography (MDCT) can be helpful and useful in the decision-making process in sleeve patients with gastroesophageal reflux disease (GERD) symptoms and to demonstrate the reproducibility and accuracy of the technique. METHODS: Twenty three patients submitted to laparoscopic sleeve gastrectomy (LSG), complaining upper gastrointestinal (GI) symptoms and/or weight regain and candidated to laparoscopic surgical revision were investigated. All patients underwent upper GI barium study, endoscopy, and MDCT for the identification of esophageal dilatation, neofundus development, thoracic sleeve migration, sleeve dilatation, and/or antrum dilatation. Selected patients underwent laparoscopic sleeve revision, cruroplasty, and/or fundectomy according to MDCT findings. Surgical findings were considered as "gold standard." Symptom persistence or resolution was investigated after 6 months with a standard clinical questionnaire. A total of 21 patients with sleeve migration or dilatation and neofundus underwent laparoscopic revision. RESULTS: A strong correlation between MDCT preoperative findings and intraoperative findings was observed. The presence of sleeve migration was significantly underestimated by both conventional radiology and upper GI endoscopy (sensitivity of 57.1 and 50 %, respectively). Symptom remission was observed in 19 out of 21 patients at 6 months. In two cases, surgical revision was not indicated on the basis of MDCT findings. CONCLUSIONS: MDCT is more accurate than the conventional radiology and endoscopy for the detection of morphological alteration causing GERD symptoms after LSG and can be considered a valid noninvasive method to guide surgery and monitoring patients following revision. PMID- 23754241 TI - Should Pneumocystis jiroveci prophylaxis be recommended with Rituximab treatment in ANCA-associated vasculitis? AB - Reports in haematology, transplantation medicine and rheumatology indicate that Rituximab, a B cell depleting therapy, increases the risk for Pneumocystis jiroveci pneumopathy. Patients with antineutrophil cytoplasmic antibodies (ANCA) associated vasculitis have an increased incidence of P. jiroveci pneumopathy compared to other autoimmune diseases and Rituximab is often used to induce and maintain remission. Herein, we present a case of a patient with granulomatosis with polyangiitis treated with Rituximab for relapse that developed P. jiroveci pneumopathy 3 months after and we review the relevant literature to assess P. jiroveci pneumopathy incidence and risks factors under Rituximab. We also discuss whether P. jiroveci screening before Rituximab and P. jiroveci pneumopathy prophylaxis under Rituximab are indicated. P. jiroveci colonisation is found in 25 % of patients with autoimmune diseases. However, the association between colonisation and P. jiroveci pneumopathy development is not very strong. P. jiroveci pneumopathy incidence in ANCA-associated vasculitis patients treated with Rituximab is found to be 1.2 %. Therefore, evidence and practice do not support the use of P. jiroveci pneumopathy chemoprophylaxis in all ANCA associated vasculitis patients receiving Rituximab. CD4 cell count cut-off does not work well in patients treated with Rituximab as it does not reflect T cell impairment following B cell depletion. To help stratify the risk of both colonisation and P. jiroveci pneumopathy development, assessment of the patient's net state of immunodeficiency before administering Rituximab-including age, renal or lung involvement, previous infections due to T cell dysfunction, blood tests (lymphocytopenia, low CD4 cell count) and concomitant therapy-is warranted. PMID- 23754242 TI - QuantiFERON testing for cell-mediated immunity to cytomegalovirus in patients with rheumatoid arthritis receiving abatacept and other DMARD therapy. PMID- 23754243 TI - Test-retest reliability of the disease activity score 28 CRP (DAS28-CRP), the simplified disease activity index (SDAI) and the clinical disease activity index (CDAI) in rheumatoid arthritis when based on patient self-assessment of tender and swollen joints. AB - Composite disease activity scores are frequently used in daily practice as tools for treatment decisions in patients with rheumatoid arthritis (RA). If reliable, patient-reported disease activity may be time saving in the busy clinic. The objective was to examine the test-retest reliability of the Disease Activity Score 28 CRP (DAS28-CRP) with four variables (4v) and three variables (3v), the Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) when based on patient self-assessment of tender and swollen joints and to examine the agreement between these scores and physician-derived scores. Thirty out-clinic RA patients with stable disease were included. A joint count was performed two times 1 week apart by the patient and by an experienced physician. Test-retest reliability was expressed as the least significant difference (LSD), as the LSD in percent of the mean score (%LSD) and as intra-individual coefficients of variation (CVi). Mean scores based on physician vs. patient joint counts (visit 1) were: DAS28-CRP(4v) 3.5 +/- 1.0 vs. 3.6 +/- 1.1 (not significant (NS)), DAS28-CRP(3v) 3.4 +/- 0.9 vs. 3.5 +/- 0.9 (NS), SDAI 14.2 +/- 9.4 vs.14.1 +/- 9.4 (NS) and CDAI 13.4 +/- 9.3 vs. 13.3 +/- 9.4 (NS). The LSDs (%LSD) for duplicate assessments of patient-derived scores (visit 2 vs. 1) were: DAS28 CRP(4v) 0.8 (23.2), DAS28-CRP(3v) 0.9 (25.2), SDAI 8.3 (59.9) and CDAI 8.4 (63.8). Similar LSDs were found for differences between duplicate assessments of physician-derived scores and for differences between physician and patient derived scores. CVis for SDAI and CDAI were significantly higher than for DAS28 CRP(4v) and DAS28-CRP(3v) (p < 0.005). Patient- and physician-derived scores agreed closely on group level. On the individual level, the LSDs between patient- and physician-derived scores were considerable but corresponded to both patient and physician intra-observer LSDs. Thus, scores based on patient-performed joint counts may be an alternative to traditional physician-derived scores in patients with stable disease. PMID- 23754244 TI - Increased expression of S100A8 and S100A9 in patients with diffuse cutaneous systemic sclerosis. A correlation with organ involvement and immunological abnormalities. AB - S100A8 and S100A9 play important roles in immune and inflammatory disorders. The role of the two proteins in systemic sclerosis (SSc) remains unknown. Fifty-seven diffuse cutaneous SSc (dcSSc) patients, 31 limited cutaneous SSc (lcSSc) patients were recruited in the present study. The expression of S100A8 and S100A9 in plasma was measured using an enzyme-linked immunosorbent assay and the mRNA levels in peripheral blood were assessed using reverse transcriptase quantitative PCR. The expression and distribution of S100A8, S100A9, and receptor for advanced glycation end products (RAGE), in skin tissues was analyzed by immunohistochemistry. The plasma concentrations of S100A8 and S100A9 were significantly higher in dcSSc patients than in normal controls and lcSSc patients. Both S100A8 and S100A9 levels were significantly increased in dcSSc patients with lung or kidney involvement. Increased plasma levels of S100A8 and S100A9 in dcSSc patients were associated with several autoantibodies. Transcription levels of S100A8 and S100A9 in peripheral blood were found elevated in both dcSSc and lcSSc patients than normal controls. Immunohistochemistry demonstrated higher S100A8 and S100A9 expression in sclerotic skin than in normal skin. The number of S100A8, S100A9, or RAGE positive fibroblasts was also significantly increased. Highly elevated expression of both S100A8 and S100A9 was found in dcSSc patients. There was close correlation with disease severity and serological abnormalities, suggesting that the two proteins may play important roles in the development of systemic sclerosis. PMID- 23754245 TI - Reduction of plasma IL-6 but not TNF-alpha by methotrexate in patients with early rheumatoid arthritis: a potential biomarker for radiographic progression. AB - OBJECTIVE: To determine the effect of methotrexate (MTX) on plasma levels of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha and to investigate their associations with clinical and radiographic responses in patients with early rheumatoid arthritis (RA). METHODS: Sixty-two untreated RA patients with the disease duration of <=36 months in whom MTX was initiated were consecutively identified in our prospective RA cohort and included in this study. Concomitant use of prednisolone and synthetic disease-modifying anti-rheumatic drugs with MTX was allowed, but patients who used biological agents were excluded. Plasma IL-6 and TNF-alpha levels were measured at the time of diagnosis (baseline) and 1 year later. The relationships of the clinical and radiographic data with plasma levels of IL-6 and TNF-alpha were analyzed. RESULTS: The median age of the patients was 57 years, 49 patients were female, and the median disease duration was 3 months. Forty-six (74.2 %) patients were anti-cyclic citrullinated protein antibody positive. Serum C-reactive protein (CRP), plasma IL-6, and DAS28 decreased significantly (p <0.001) after MTX treatment, but plasma TNF-alpha did not. Radiographic progression was significantly correlated with disease activity score and plasma IL-6 levels but not with CRP or TNF-alpha after MTX treatment. Patients with plasma IL-6 level above 4.03 pg/ml showed clinically relevant radiographic progression with a sensitivity of 91.7 % and a specificity of 88.0 %. CONCLUSION: In this early RA cohort, we demonstrated a significant (p <0.001) reduction of plasma IL-6, but not TNF-alpha, during MTX treatment. The post treatment IL-6 level was a strong indicator of radiographic progression. PMID- 23754246 TI - Mean platelet volume and amyloidosis in patients with familial Mediterranean fever. PMID- 23754248 TI - The importance of extended high viremics in models of HIV spread in South Africa. AB - Recent studies found a substantial fraction of 'extended high viremics' among HIV 1 subtype C, the most common subtype in southern Africa. Extended high viremics are HIV infected individuals who maintain a high viral load for a longer time period than usual after the initial infection. They are more infectious during this period, and their infection progresses to full-blown AIDS and death much faster than usual. This study investigates the impact of extended high viremics on the spread of the HIV epidemic in South Africa. We develop a simple deterministic compartmental model for HIV infection that includes extended high viremics. As the available data on extended high viremics are limited, we parameterize this model using only the fraction of extended high viremics among new infections and the reduced life-span of extended high viremics. We find that without extended high viremics, the HIV prevalence in South Africa would have remained close to its 1990 level, instead of increasing to the current epidemic levels. We also find that the greater the fraction of extended high viremics among susceptibles, the greater the steady-state HIV prevalence and the more sensitive the steady-state prevalence is to the HIV transmission probability. These results suggest that extended high viremics have an impact on the HIV epidemic in South Africa; justify the need for comprehensive epidemiological studies since the current data is limited; and suggest that future models of HIV for southern Africa should explicitly model extended high viremics. PMID- 23754249 TI - Differential urinary specific gravity as a molecular phenotype of the bladder cancer genetic association in the urea transporter gene, SLC14A1. AB - Genome-wide association studies (GWAS) identified associations between markers within the solute carrier family 14 (urea transporter), member 1 (SLC14A1) gene and risk of bladder cancer. SLC14A1 defines the Kidd blood groups in erythrocytes and is also involved in concentration of the urine in the kidney. We evaluated the association between a representative genetic variant (rs10775480) of SLC14A1 and urine concentration, as measured by urinary specific gravity (USG), in a subset of 275 population-based controls enrolled in the New England Bladder Cancer Study. Overnight urine samples were collected, and USG was measured using refractometry. Analysis of covariance was used to estimate adjusted least square means for USG in relation to rs10775480. We also examined the mRNA expression of both urea transporters, SLC14A1 and SLC14A2, in a panel of human tissues. USG was decreased with each copy of the rs10775480 risk T allele (p-trend = 0.011) with a significant difference observed for CC vs. TT genotypes (p-value(tukey) = 0.024). RNA-sequencing in the bladder tissue showed high expression of SLC14A1 and the absence of SLC14A2, while both transporters were expressed in the kidney. We suggest that the molecular phenotype of this GWAS finding is the genotype specific biological activity of SLC14A1 in the bladder tissue. Our data suggest that SLC14A1 could be a unique urea transporter in the bladder that has the ability to influence urine concentration and that this mechanism might explain the increased bladder cancer susceptibility associated with rs10775480. PMID- 23754252 TI - Enhanced antitumor activity of cerulenin combined with oxaliplatin in human colon cancer cells. AB - Fatty acid synthase is highly expressed in many types of human cancers. Cerulenin, a natural inhibitor of fatty acid synthase, induced apoptosis in the human colon cancer cell lines HCT116 and RKO. Oxaliplatin also induced cell death in these cell lines. Cerulenin treatment was associated with reduced levels of phosphorylated Akt, activation of p38 and induced caspase-3 cleavage and finally caused apoptosis. Oxaliplatin induced activation of the p53-p21 pathway and p38. In combination with cerulenin and oxaliplatin, activation of the p53-p21 pathway and p38 occurred in a smaller concentration and finally induced caspase-3 cleavage in a smaller concentration of cerulenin and oxaliplatin. In xenotransplanted SCID mice, the cerulenin + oxaliplatin group significantly inhibited tumor progression compared to the control, cerulenin and oxaliplatin groups. Based on these studies, inhibiting fatty acid synthase would be an effective strategy to treat unresectable colorectal cancer tumors in combination with oxaliplatin. Fatty acid synthase inhibitor would be one of the best counterparts of oxaliplatin, which reduces the dose and side-effects of oxaliplatin and would make it possible to endure the chemotherapy over a longer period. PMID- 23754253 TI - First-trimester screening for early and late small-for-gestational-age neonates using maternal serum biochemistry, blood pressure and uterine artery Doppler. AB - OBJECTIVE: To assess the effectiveness of first-trimester screening for early and late small-for-gestational-age (SGA) neonates using maternal serum biochemistry, blood pressure and uterine artery Doppler. METHODS: This was a prospective study of 4970 women with a singleton pregnancy who underwent routine first-trimester screening between 2009 and 2011. A logistic regression-based predictive model for SGA, defined as birth weight < 10(th) percentile, divided into early- or late onset based on gestational age at delivery before or after 34 weeks' gestation, was constructed. The model included maternal baseline characteristics: serum levels of pregnancy-associated plasma protein-A and free beta-human chorionic gonadotropin at 8-12 weeks and blood pressure and uterine artery Doppler at 11 + 0 to 13 + 6 weeks. RESULTS: The prevalence of early and late SGA was 0.6% and 7.9%, respectively. Association with pre-eclampsia was 67% and 8%, respectively. At a false-positive rate of 15%, the detection rate for early SGA was 73%; however it differed substantially for cases with and without pre-eclampsia (90% vs 40%). For late SGA, at false-positive rates of 15 and 50%, detection rates were 32% and 70%, respectively, and did not substantially differ between cases with and without pre-eclampsia. CONCLUSIONS: First-trimester screening predicts early SGA mainly because of its strong association with pre-eclampsia. Although prediction of late SGA was poorer, at a high false-positive rate it might be considered as part of a first-trimester strategy to select women requiring ultrasound assessment in the third trimester. PMID- 23754254 TI - Second-versus first-generation "Limus"-eluting stents in diabetic patients with coronary artery disease: a randomized comparison in setting of ISAR-TEST-4 trial. AB - BACKGROUND: Patients with diabetes mellitus remain at higher risk for adverse events following percutaneous coronary intervention and the identification of the optimum drug eluting stents (DES) in these patients is of high clinical relevance. We compared effectiveness of everolimus-eluting stents (EES; Xience) versus sirolimus-eluting stents (SES; Cypher) in patients with diabetes mellitus enrolled in the Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents (ISAR-TEST-4) trial. METHODS: In the setting of the ISAR TEST-4 trial, 1304 patients with broad inclusion criteria were randomized to treatment with EES or SES. The focus of the present analysis is on a cohort of 377 patients with diabetes mellitus assigned to receive EES (n = 184) or SES (n = 193). The primary endpoint was the composite of cardiac death, myocardial infarction (MI) related to the target vessel, or target lesion revascularization (TLR) at 3-year follow-up. Secondary endpoints were parameters of angiographic and clinical restenosis (in-stent late lumen loss, binary restenosis, and TLR), all-cause mortality and definite/probable stent thrombosis. RESULTS: EES was comparable to SES concerning the incidence of the primary endpoint (21% vs. 24%, respectively; relative risk = 0.87; 95% CI, 0.57-1.34; P = 0.53). Concerning the secondary endpoint, TLR at 3 years with EES versus SES stents was not statistically different (14.7% vs. 16.6%, respectively; relative risk = 0.85; 95% CI, 0.51-1.43; P = 0.55). In terms of angiographic outcomes patients treated with EES as compared to SES had significantly lower late lumen loss (0.22 +/- 0.46 mm vs. 0.44 +/- 0.66 mm, respectively; P < 0.001) and binary restenosis (8.4% vs. 17%, respectively; P = 0.02) at 6- to 8-month angiographic follow-up. EES was comparable to SES concerning the incidence of all-cause death (10% vs. 16%, respectively; relative risk = 0.66; 95% CI, 0.37-1.18; P = 0.16) and stent thrombosis (1.1% vs. 3.1%, respectively; P = 0.19). CONCLUSIONS: In patients with diabetes mellitus enrolled in a real-world randomized control trial, EES is comparable to SES in terms of clinical efficacy and safety out to 3 years; angiographic markers of antirestenotic efficacy favored EES. PMID- 23754256 TI - About this journal. PMID- 23754255 TI - Piloting and validation of a novel self-administered online cognitive screening tool in normal older persons: the Cognitive Function Test. AB - BACKGROUND: Subtle cognitive changes have been described that may predate the onset of clinically recognizable Alzheimer's disease (AD) and may reflect pathological changes in the brain that are detectable up to 10 years before the onset of AD. Early screening for cognitive status can have benefits in terms of early management and prevention strategies for cognitive decline. METHOD: A novel computerized cognitive screening tool, the Cognitive Function Test (CFT), was compared with established paper tests of episodic memory, executive function and processing speed, domains previously shown to be predictive of AD, with 50 normal participants, Mini Mental State Examination >=24, mean age 58.1, SD 5.6 years (range 50-65). An online version, self-administered by 195 eligible respondents without significant memory complaints or dementia, was assessed. RESULTS: Significant correlations (r = 0.75, p < 0.0001) were found between the CFT and paper tests in a pilot study, showing concurrent validity. The pilot computerized tests were compared with the online version, and no differences were found in mean scores on the total test and domain-specific scores using an algorithm derived from the pilot CFT scores, thus showing internal consistency and reliability of the online format. Norms and 1.5 SD cut-offs for the CFT are presented. CONCLUSION: The online CFT was shown to be suitable for self administration in online format (with a mouse response mode) for this midlife age group. Individuals may wish to monitor their cognitive performance before memory concerns are sufficient to warrant visiting a GP or memory clinic. PMID- 23754257 TI - Extra-esophageal reflux, NOSE score, and sleep quality in an adult clinic population. AB - OBJECTIVES/HYPOTHESIS: Gastroesophageal reflux disease and heartburn negatively impact sleep; the impact of extraesophageal reflux (EER) symptoms on sleep is unknown. This study's goal was to evaluate the association of EER and measures of nasal obstruction, mood, insomnia, hypersomnia, and obstructive sleep apnea (OSA) risk. STUDY DESIGN: Cross-sectional study. SETTING: Tertiary care hospital. SUBJECTS AND METHODS: A prospective cohort of adult patients was evaluated using validated questionnaires for insomnia (PSQI), hypersomnia (ESS), OSA risk (STOP Bang), sleep quality of life (FOSQ-10), EER reflux symptoms (RSI), nasal symptoms (NOSE), and measures of mood (HADA). Pharyngeal saliva samples underwent Western blot immunoassay for pepsin. RESULTS: Ninety-three adults (mean age 50.2 +/- 15.2 years, 43% female) were evaluated. Reflux Symptom Index (RSI) was elevated in 32% of patients and significant heartburn symptoms were reported in only 12% of patients. Prevalence of pepsin (+) was 27%. Both RSI and NOSE were significantly associated with sleep measures related to insomnia (r = 0.48 and r = 0.50; P < 0.001, respectively), Quality of Life (QOL) (r = 0.30 and r = 0.34; P < 0.001, respectively), and hypersomnolance (r = 0.18 and P < 0.04; r = 0.29 and P < 0.01, respectively), but not apnea risk (all P < 0.05). Nasal symptoms and mood were associated with all non-OSA sleep metrics (r = 0.24). In multivariate analysis, both NOSE and RSI remained significantly associated with sleep measures. CONCLUSIONS: Insomnia, hypersomnia, and sleep QOL are associated with measures of EER, nasal symptoms, and mood but not OSA risk, supporting that disrupted sleep may be associated with EER and nasal symptoms independent of sleep apnea. PMID- 23754259 TI - Conflicts of interest-reply. PMID- 23754258 TI - A historical perspective and evolution of our knowledge on the cardinal ligament. AB - AIMS: The objective of our review is to provide a critical appraisal of the literature on the anatomy, structure and roles of cardinal ligaments (CL) in pelvic organ support, in conjunction with the currently evolving evidence based mainly on imaging and biomechanical modeling studies. We aim to contribute to the understanding of the pathophysiology of pelvic organ prolapse (POP) and stimulate new insights in research and development of novel surgical approaches for POP. METHODS: PubMed, Embase, Scopus-Elsevier, and Cochrane Databases were searched in English and German. Studies from 1870 to 2012 were identified. The keywords used were "cardinal ligament," "transverse cervical ligament," "Mackenrodt ligament," "parametrium," and "paracervix." Cross check and Google search of the reference lists were used for missing articles. RESULTS: We identified 35 related articles. Located at the base of the broad ligament, the CL is a supportive structure that attaches the cervix and upper vagina to the pelvic wall. The ligament contains the uterine vessels and hypogastric plexus. It conducts most of the pelvic loading forces. On MRI, it appears as a web-like structure around the axis of the internal iliac vessels. Their clinical importance is based on the apical supportive role and lymphatic-rich structure, involved in dissemination of cervical cancer. CONCLUSIONS: The structure and role of the CL have been long studied, but remained unclear. Recent studies on imaging and biomechanics have improved our understanding and provide new insights which may enable the development of new techniques in prolapse surgery. PMID- 23754260 TI - [Neuropsychological assessment in conversion disorder]. AB - OBJECTIVE: Conversion disorder is characterized by functional impairment in motor, sensory, or neurovegetative systems that cannot be explained by a general medical condition. Diagnostic systems emphasize the absence of an organic basis for the dysfunction observed in conversion disorder. Nevertheless, there is a growing body of data on the specific functional brain correlates of conversion symptoms, particularly those obtained via neuroimaging and neurophysiological assessment. The present study aimed to determine if there are differences in measures of cognitive functioning between patients with conversion disorder and healthy controls. The hypothesis of the study was that the patients with conversion disorder would have poorer neurocognitive performance than the controls. MATERIALS AND METHODS: The patient group included 43 patients diagnosed as conversion disorder and other psychiatric comorbidities according to DSM-IV TR. Control group 1 included 44 patients diagnosed with similar psychiatric comorbidities, but not conversion diosorder, and control group 2 included 43 healthy individuals. All participants completed a sociodemographic questionnaire and were administered the SCID-I and a neuropsychological test battery of 6 tests, including the Serial Digit Learning Test (SDLT), Auditory Verbal Learning Test (AVLT), Wechsler Memory Scale, Stroop Color Word Interference Test, Benton Judgment of Line Orientation Test (BJLOT), and Cancellation Test. RESULTS: The patient group had significantly poorer performance on the SDLT, AVLT, Stroop Color Word Interference Test, and BJLOT than both control groups. CONCLUSION: The present findings highlight the differences between the groups in learning and memory, executive and visuospatial functions, and attention, which seemed to be specific to conversion disorder. PMID- 23754261 TI - [Self-efficacy and hemodialysis treatment: a qualitative and quantitative approach]. AB - BACKGROUND: The theoretically driven approach to the measurement of self-efficacy fails to capture the challenges that hemodialysis patients experience in following their dietary and fluid restrictions. AIMS: A combination of qualitative and quantitative research is necessary to identify the range of challenges associated with these restrictions and to quantify them if clinicians are to be guided in their consultations with patients. In this study the construct of self-efficacy was grounded on the basis of challenges to dietary and fluid restrictions, and the findings were used to develop a questionnaire to quantify the patients' perceptions of their ability to overcome each challenge. MATERIALS AND METHODS: The sample for the qualitative study consisted of 16 hemodialysis patients and the quantitative study included 156 hemodialysis patients. RESULTS: The qualitative findings showed that the patients experienced a range of specific challenges to dietary and fluid restrictions. Among these were practical constraints, being with others, the view of hemodialysis as compensating for dietary non-compliance, and emotional challenges including discomfort, distress, and boredom with dietary and fluid restrictions. The most common challenge to fluid restrictions was eating while not having any fluid allowance left. Boredom with diet was the most common challenge to diet. Hemodialysis treatment was a justification for a significant number of patients to neglect their dietary and fluid restrictions. CONCLUSION: The findings suggest that grounded self-efficacy is a unitary phenomenon, but that it incorporates a wide spectrum of specific challenges. The challenges identified herein have provided an evidence base for educational interventions to improve compliance with dietary and fluid restrictions. PMID- 23754262 TI - [Phenotypic features in autistic individuals: the finger length ratio (2D:4D), hair whorl, and hand dominance]. AB - OBJECTIVE: The aim of this study was to compare the finger length ratio (2D:4D), hair whorl direction, and hand, foot, and eye dominance in autistic and healthy individuals, and to investigate the phenotypic characteristics of autism. MATERIALS AND METHODS: The study included 37 males diagnosed with autistic disorder and 121 healthy males, all aged 4-18 years. The length of the index and ring fingers of both hands--from the proximal bend of the metacarpophalangeal joint to the fingertips--was measured with digital calipers and the index-ring finger (2D:4D) ratio was determined. The distance between hair whorls, their perpendicular distance from the mid-sagittal line, and their direction of rotation were calculated in the autism and control groups. Hand, foot, and eye dominance were determined in both groups. The findings were evaluated using SPSS v.15.0. RESULTS: The autism group had a greater number of hair whorls than the control group. The distance between hair whorls and the mid-sagittal line was longer in those with left hand and left eye dominance. A significant difference in the 2D:4D ratio of the right and left hands between the 2 groups was not observed. CONCLUSION: The autism group had more hair whorls than the control group and the hair whorls in the autistic individuals with left hand and left eye dominance were located further from the mid-saggital line. We think that these novel findings might contribute to the determination of the phenotypic features specific to autism. PMID- 23754263 TI - [Alterations in social reciprocity in attention-deficit hyperactivity disorder]. AB - OBJECTIVE: Social interactions in children with attention deficit-hyperactivity disorder (ADHD) are inappropriate and such social problems may originate from a failure to attend to the appropriate cues of affect. The present study aimed to determine the factors predictive of social reciprocity in ADHD and their relationship to sociodemographics. MATERIALS AND METHODS: Participants were required to interpret emotional cues depicted in pictures of facial expressions with a test that was adopted from the Reading Mind in the Eyes Test (RMET). Diagnoses were established based on the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-PL). Moreover, a detailed sociodemographic form, the Child Behavior Checklist (CBCL), and the Social Reciprocity Scale (SRS) were used for assessment. RESULTS: This study included 133 children; 64 in the ADHD group and 69 in the control group. There wasn't a significant difference in mean age between the ADHD group (13.22 +/- 1.28 years) and control group (12.97 +/- 1.27 years). In all, 50% of the ADHD group and 49.3% of the control group were male. The mean RMET score was significantly lower in the ADHD group than in the control group (ADHD group: 20.52 +/- 3.95; control group: 23.70 +/- 3.55) and the mean SRS score was significantly higher in the ADHD group than in the control group (ADHD group: 65.84 +/- 18.83; control group: 36.04 +/- 16.32). In the ADHD group attention problems and lower level of ability to interpret emotional facial expressions were predictive of impaired social reciprocity. CONCLUSION: The findings show that both the ability to decode facial expressions and social reciprocity were impaired in the ADHD group. These findings highlight the difficulty children with ADHD have with social functioning and interpretation of emotions based on facial expressions. PMID- 23754264 TI - [An investigation of the imitation skills in children with autism spectrum disorder and their association with receptive-expressive language development]. AB - AIMS: This study aimed to compare imitation skills in children with autism spectrum disorder, and age-matched typically developing children and children with developmental delay, as well as to examine the association between imitation skills, and receptive and expressive language development in children with autism spectrum disorder. MATERIALS AND METHODS: Imitation skills in children with autism spectrum disorder (n=18), and age-matched children with developmental delay (n=15) and typically developing children (n= 16) were assessed using the Motor Imitation Scale and Imitation Battery, and the differences in mean imitation scores between the groups were examined. Receptive language and expressive language development in the children with autism spectrum disorder were assessed using the Turkish Communicative Development Inventory (TCDI), and their association with imitation scores was explored. RESULTS: The children with autism spectrum disorder had significantly lower imitation scores than the children with developmental delay and typically developing children; however, there wasn't a significant difference in imitation scores between the children with developmental delay and typically developing children. A significant association between imitation scores, and receptive and expressive language development was observed in the children with autism spectrum disorder. CONCLUSION: The present findings indicate that deficient imitation skills are a distinctive feature of children with autism spectrum disorder and that imitation skills play a crucial role in children's language development. PMID- 23754265 TI - [The mediating role of anger in the relationship between automatic thoughts and physical aggression in adolescents]. AB - OBJECTIVE: This study aimed to examine the mediating role of anger in the relationship between automatic thoughts and physical aggression in adolescents. MATERIALS AND METHODS: The study included 224 adolescents in the 9th grade of 3 different high schools in central Burdur during the 2011-2012 academic year. Participants completed the Aggression Questionnaire and Automatic Thoughts Scale in their classrooms during counseling sessions. Data were analyzed using simple and multiple linear regression analysis. RESULTS: There were positive correlations between the adolescents' automatic thoughts, and physical aggression, and anger. According to regression analysis, automatic thoughts effectively predicted the level of physical aggression (b= 0.233, P < 0.001)) and anger (b= 0.325, P < 0.001). Analysis of the mediating role of anger showed that anger fully mediated the relationship between automatic thoughts and physical aggression (Sobel z = 5.646, P < 0.001). CONCLUSION: Anger fully mediated the relationship between automatic thoughts and physical aggression. Providing adolescents with anger management skills training is very important for the prevention of physical aggression. Such training programs should include components related to the development of an awareness of dysfunctional and anger triggering automatic thoughts, and how to change them. As the study group included adolescents from Burdur, the findings can only be generalized to groups with similar characteristics. PMID- 23754266 TI - [The reliability and validity of the Buss-Perry Aggression Questionnaire (BAQ) Turkish Version]. AB - OBJECTIVE: The aim of the present study was to develop, and assess the validity and reliability of the Buss-Perry Aggression Questionnaire (BAQ)-Turkish Version. METHODS: The BAQ was translated from English to Turkish by a bilingual individual, and then independently translated back to English by another bilingual individual. The study included 220 students from 2 universities. In order to determine the criterion validity of the BAQ-Turkish Version, its correlation with the Multidimensional Anger Scale anger-related behaviors subscale (Balkaya and Sahin 2003) was determined. To determine the test-retest reliability of the BAQ-Turkish Version the scale was administered twice (with a 4 week interval) to 53 of the participants. To determine the scale's reliability internal consistency (Cronbach's alpha), test-retest, and split-half methods were used. The scale's criterion validity and gender differences were examined. RESULTS: The scale was observed to have high internal consistency and appropriate stability over a 4-week period. Only 1 significant gender difference was observed -males had significantly higher physical aggression scores than females. All BAQ Turkish Version subscales were strongly inter-correlated. CONCLUSIONS: The findings support the 4-factor structure of the BAQ-Turkish Version, as originally reported (Buss and Perry 1992), and show that the BAQ-Turkish Version is a reliable and valid instrument for measuring aggression in the Turkish population. PMID- 23754267 TI - [Prevention of schizophrenia: a review]. AB - Research over the years has introduced multiple interventions for schizophrenia. Notwithstanding the nature of intervention pharmacological or psychological a complete cure for the condition remains a much-desired, yet unachieved goal. What is required is an exploration of alternative intervention strategies for treating schizophrenia a preventive approach is such an option. The chronic nature of schizophrenia and its associated disabilities have a tremendously negative affect the quality of life of patients, their families, and communities. Among the preferred approaches to reducing the negative consequences associated with the disorder is the prevention of its emergence. This review aimed to present the available data on the prevention of schizophrenia data that suggest some pharmacological and non-pharmacological interventions have a potential role in the prevention of schizophrenia. Nonetheless, the findings are restricted to a few sites and are at best preliminary; as such, the findings must be replicated in new studies that include large samples and different settings. PMID- 23754268 TI - [Clozapine-associated neuroleptic malignant syndrome followed by catatonia: a case report]. AB - OBJECTIVE: Neuroleptic malignant syndrome (NMS) is a rare life-threatening condition associated with the use of antipsychotics and other drugs that influence dopaminergic transmission. Although NMS is typically associated with classical antipsychotics, it can also be induced by atypical antipsychotics. In this paper, we report a case of NMS associated with clozapine use. CASE: A 27 year-old male was diagnosed as schizophrenia in 2006 and zuclopenthixol depot was administered parenterally. Following the second injection, NMS was diagnosed and he was switched to clozapine. After 4 years of clozapine use, one day, he suddenly stopped eating, stayed in bed all day, and had incontinence. Upon examination at our hospital the patient had muscle rigidity, high fever, leukocytosis, and a high creatine phosphokinase level, and NMS was diagnosed. He was put on bromocriptine. NMS resolved, but psychotic relapse and catatonia developed. 10 sessions of electro convulsive treatment (ECT) were administered. Quetiapine 25 mg/day was introduced and titrated up to 600 mg/day afterwards. He has been using quetiapine 600 mg/day for 18 months and at the time this manuscript was written has not had any signs of psychosis or NMS. CONCLUSION: NMS is usually induced by the use of agents with high dopaminergic affinity. Incomplete or extraordinary NMS cases have been reported due to clozapine and atypical antipsychotics. The presented case is noteworthy due to the complete and typical presentation of NMS. It should always be kept in mind that all atypical antipsychotics including clozapine have the probability to induce NMS although not common. PMID- 23754269 TI - [Editorial]. PMID- 23754270 TI - Antiangiogenic effects of oxymatrine on pancreatic cancer by inhibition of the NF kappaB-mediated VEGF signaling pathway. AB - Oxymatrine, the main alkaloid component in the traditional Chinese herbal medicine Sophora japonica (Sophora flavescens Ait), has been reported to have antitumor properties. However, the mechanisms of action in human pancreatic cancer are not well established to date. In the present study, we investigated the antiangiogenic effects of oxymatrine on human pancreatic cancer as well as the possible mechanisms involved. The results of the cell viability assay showed that treatment of PANC-1 pancreatic cancer cells with oxymatrine resulted in cell growth inhibition in a dose- and time-dependent manner. To investigate the possible mechanisms involved in these events, we performed western blotting and reverse transcription-polymerase chain reaction (RT-PCR) analysis. The results revealed that oxymatrine decreased the expression of angiogenesis-associated factors, including nuclear factor kappaB (NF-kappaB) and vascular endothelial growth factor (VEGF). Finally, the antiproliferative and antiangiogenic effects of oxymatrine on human pancreatic cancer were further confirmed in pancreatic cancer xenograft tumors in nude mice. In conclusion, our studies for the first time suggest that oxymatrine has potential antitumor effects on pancreatic cancer via suppression of angiogenesis, probably through regulation of the expression of the NF-kappaB-mediated VEGF signaling pathway. PMID- 23754271 TI - Hypersensitivity myocarditis or Kounis syndrome? PMID- 23754272 TI - Muscle depletion and the prediction of chemotherapy toxicity. PMID- 23754273 TI - Testing visual short-term memory of pigeons (Columba livia) and a rhesus monkey (Macaca mulatta) with a location change detection task. AB - Change detection is commonly used to assess capacity (number of objects) of human visual short-term memory (VSTM). Comparisons with the performance of non-human animals completing similar tasks have shown similarities and differences in object-based VSTM, which is only one aspect ("what") of memory. Another important aspect of memory, which has received less attention, is spatial short-term memory for "where" an object is in space. In this article, we show for the first time that a monkey and pigeons can be accurately trained to identify location changes, much as humans do, in change detection tasks similar to those used to test object capacity of VSTM. The subject's task was to identify (touch/peck) an item that changed location across a brief delay. Both the monkey and pigeons showed transfer to delays longer than the training delay, to greater and smaller distance changes than in training, and to novel colors. These results are the first to demonstrate location-change detection in any non-human species and encourage comparative investigations into the nature of spatial and visual short term memory. PMID- 23754274 TI - Pachydermodactyly mimicking juvenile idiopathic arthritis. PMID- 23754275 TI - Negative expectations facilitate mechanical hyperalgesia after high-frequency electrical stimulation of human skin. AB - BACKGROUND: High-frequency electrical stimulation (HFS) of human skin induces not only an increased pain sensitivity in the conditioning area but also an increased pain sensitivity to mechanical punctate stimuli in the non-conditioned surrounding skin area. The aim of the present study was to investigate whether this heterotopically increased mechanical pain sensitivity can be facilitated through the induction of negative expectations. METHODS: In two independent conditions [a nocebo (n = 15) and control condition (n = 15)], we applied mechanical pain stimuli before, directly after, 10 min and 20 min after HFS in the skin area surrounding the conditioning area, and measured the reported pain intensity [visual analogue scale (VAS)]. All subjects (of both conditions) received a written instruction about the HFS protocol, but only the instruction in the nocebo condition was extended by the following text (in Dutch): 'After the HFS, your skin will become more sensitive to the pinprick stimulation'. RESULTS: Our results clearly show that induced expectations of increased mechanical pain sensitivity after HFS facilitates the reported pain intensity after HFS more than when no information is given. CONCLUSIONS: This study shows for the first time that brain mechanisms, via the induction of negative expectations, can facilitate heterotopic mechanical hyperalgesia after HFS of human skin. PMID- 23754276 TI - UV-triggered affinity capture identifies interactions between the Plasmodium falciparum multidrug resistance protein 1 (PfMDR1) and antimalarial agents in live parasitized cells. AB - A representative of a new class of potent antimalarials with an unknown mode of action was recently described. To identify the molecular target of this class of antimalarials, we employed a photo-reactive affinity capture method to find parasite proteins specifically interacting with the capture compound in living parasitized cells. The capture reagent retained the antimalarial properties of the parent molecule (ACT-213615) and accumulated within parasites. We identified several proteins interacting with the capture compound and established a functional interaction between ACT-213615 and PfMDR1. We surmise that PfMDR1 may play a role in the antimalarial activity of the piperazine-containing compound ACT-213615. PMID- 23754277 TI - Epigallocatechin gallate (EGCG) stimulates autophagy in vascular endothelial cells: a potential role for reducing lipid accumulation. AB - Epigallocatechin gallate (EGCG) is a major polyphenol in green tea that has beneficial effects in the prevention of cardiovascular disease. Autophagy is a cellular process that protects cells from stressful conditions. To determine whether the beneficial effect of EGCG is mediated by a mechanism involving autophagy, the roles of the EGCG-stimulated autophagy in the context of ectopic lipid accumulation were investigated. Treatment with EGCG increased formation of LC3-II and autophagosomes in primary bovine aortic endothelial cells (BAEC). Activation of calmodulin-dependent protein kinase kinase beta was required for EGCG-induced LC3-II formation, as evidenced by the fact that EGCG-induced LC3-II formation was significantly impaired by knockdown of calmodulin-dependent protein kinase kinase beta. This effect is most likely due to cytosolic Ca(2+) load. To determine whether EGCG affects palmitate-induced lipid accumulation, the effects of EGCG on autophagic flux and co-localization of lipid droplets and autophagolysosomes were examined. EGCG normalized the palmitate-induced impairment of autophagic flux. Accumulation of lipid droplets by palmitate was markedly reduced by EGCG. Blocking autophagosomal degradation opposed the effect of EGCG in ectopic lipid accumulation, suggesting the action of EGCG is through autophagosomal degradation. The mechanism for this could be due to the increased co-localization of lipid droplets and autophagolysosomes. Co-localization of lipid droplets with LC3 and lysosome was dramatically increased when the cells were treated with EGCG and palmitate compared with the cells treated with palmitate alone. Collectively, these findings suggest that EGCG regulates ectopic lipid accumulation through a facilitated autophagic flux and further imply that EGCG may be a potential therapeutic reagent to prevent cardiovascular complications. PMID- 23754278 TI - The peptidyl-prolyl isomerase Pin1 up-regulation and proapoptotic function in dopaminergic neurons: relevance to the pathogenesis of Parkinson disease. AB - Parkinson disease (PD) is a chronic neurodegenerative disease characterized by a slow and progressive degeneration of dopaminergic neurons in substantia nigra. The pathophysiological mechanisms underlying PD remain unclear. Pin1, a major peptidyl-prolyl isomerase, has recently been associated with certain diseases. Notably, Ryo et al. (Ryo, A., Togo, T., Nakai, T., Hirai, A., Nishi, M., Yamaguchi, A., Suzuki, K., Hirayasu, Y., Kobayashi, H., Perrem, K., Liou, Y. C., and Aoki, I. (2006) J. Biol. Chem. 281, 4117-4125) implicated Pin1 in PD pathology. Therefore, we sought to systematically characterize the role of Pin1 in PD using cell culture and animal models. To our surprise we observed a dramatic up-regulation of Pin1 mRNA and protein levels in dopaminergic MN9D neuronal cells treated with the parkinsonian toxicant 1-methyl-4-phenylpyridinium (MPP(+)) as well as in the substantia nigra of the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced PD mouse model. Notably, a marked expression of Pin1 was also observed in the substantia nigra of human PD brains along with a high co-localization of Pin1 within dopaminergic neurons. In functional studies, siRNA-mediated knockdown of Pin1 almost completely prevented MPP(+)-induced caspase-3 activation and DNA fragmentation, indicating that Pin1 plays a proapoptotic role. Interestingly, multiple pharmacological Pin1 inhibitors, including juglone, attenuated MPP(+)-induced Pin1 up-regulation, alpha-synuclein aggregation, caspase-3 activation, and cell death. Furthermore, juglone treatment in the MPTP mouse model of PD suppressed Pin1 levels and improved locomotor deficits, dopamine depletion, and nigral dopaminergic neuronal loss. Collectively, our findings demonstrate for the first time that Pin1 is up regulated in PD and has a pathophysiological role in the nigrostriatal dopaminergic system and suggest that modulation of Pin1 levels may be a useful translational therapeutic strategy in PD. PMID- 23754279 TI - The MOV10 helicase inhibits LINE-1 mobility. AB - LINE-1 (long interspersed element 1) is an autonomous non-long terminal repeat retrotransposon. Its replication often causes mutation and rearrangement of host genomic DNA. Accordingly, host cells have evolved mechanisms to control LINE-1 mobility. Here, we report that a helicase named MOV10 effectively suppresses LINE 1 transposition. Mutating the helicase motifs impairs this function of MOV10, suggesting that MOV10 requires its helicase activity to suppress LINE-1 replication. Further studies show that MOV10 post-transcriptionally diminishes the level of LINE-1 RNA. The association of MOV10 with both LINE-1 RNA and ORF1 suggests that MOV10 interacts with LINE-1 RNP and consequently causes its RNA degradation. These data demonstrate collectively that MOV10 contributes to the cellular control of LINE-1 replication. PMID- 23754280 TI - Type 1 fibroblast growth factor receptor in cranial neural crest cell-derived mesenchyme is required for palatogenesis. AB - Cleft palate is a common congenital birth defect. The fibroblast growth factor (FGF) family has been shown to be important for palatogenesis, which elicits the regulatory functions by activating the FGF receptor tyrosine kinase. Mutations in Fgf or Fgfr are associated with cleft palate. To date, most mechanistic studies on FGF signaling in palate development have focused on FGFR2 in the epithelium. Although Fgfr1 is expressed in the cranial neural crest (CNC)-derived palate mesenchyme and Fgfr1 mutations are associated with palate defects, how FGFR1 in palate mesenchyme regulates palatogenesis is not well understood. Here, we reported that by using Wnt1(Cre) to delete Fgfr1 in neural crest cells led to cleft palate, cleft lip, and other severe craniofacial defects. Detailed analyses revealed that loss-of-function mutations in Fgfr1 did not abrogate patterning of CNC cells in palate shelves. However, it upset cell signaling in the frontofacial areas, delayed cell proliferation in both epithelial and mesenchymal compartments, prevented palate shelf elevation, and compromised palate shelf fusion. This is the first report revealing how FGF signaling in CNC cells regulates palatogenesis. PMID- 23754281 TI - Structure and function of allophanate hydrolase. AB - Allophanate hydrolase converts allophanate to ammonium and carbon dioxide. It is conserved in many organisms and is essential for their utilization of urea as a nitrogen source. It also has important functions in a newly discovered eukaryotic pyrimidine nucleic acid precursor degradation pathway, the yeast-hypha transition that several pathogens utilize to escape the host defense, and an s-triazine herbicide degradation pathway recently emerged in many soil bacteria. We have determined the crystal structure of the Kluyveromyces lactis allophanate hydrolase. Together with structure-directed functional studies, we demonstrate that its N and C domains catalyze a two-step reaction and contribute to maintaining a dimeric form of the enzyme required for their optimal activities. Our studies also provide molecular insights into their catalytic mechanism. Interestingly, we found that the C domain probably catalyzes a novel form of decarboxylation reaction that might expand the knowledge of this common reaction in biological systems. PMID- 23754283 TI - Zebrafish tyrosine hydroxylase 2 gene encodes tryptophan hydroxylase. AB - The primary pathological hallmark of Parkinson disease (PD) is the profound loss of dopaminergic neurons in the substantia nigra pars compacta. To facilitate the understanding of the underling mechanism of PD, several zebrafish PD models have been generated to recapitulate the characteristics of dopaminergic (DA) neuron loss. In zebrafish studies, tyrosine hydroxylase 1 (th1) has been frequently used as a molecular marker of DA neurons. However, th1 also labels norepinephrine and epinephrine neurons. Recently, a homologue of th1, named tyrosine hydroxylase 2 (th2), was identified based on the sequence homology and subsequently used as a novel marker of DA neurons. In this study, we present evidence that th2 co localizes with serotonin in the ventral diencephalon and caudal hypothalamus in zebrafish embryos. In addition, knockdown of th2 reduces the level of serotonin in the corresponding th2-positive neurons. This phenotype can be rescued by both zebrafish th2 and mouse tryptophan hydroxylase 1 (Tph1) mRNA as well as by 5 hydroxytryptophan, the product of tryptophan hydroxylase. Moreover, the purified Th2 protein has tryptophan hydroxylase activity comparable with that of the mouse TPH1 protein in vitro. Based on these in vivo and in vitro results, we conclude that th2 is a gene encoding for tryptophan hydroxylase and should be used as a marker gene of serotonergic neurons. PMID- 23754282 TI - Parkin-catalyzed ubiquitin-ester transfer is triggered by PINK1-dependent phosphorylation. AB - PINK1 and PARKIN are causal genes for autosomal recessive familial Parkinsonism. PINK1 is a mitochondrial Ser/Thr kinase, whereas Parkin functions as an E3 ubiquitin ligase. Under steady-state conditions, Parkin localizes to the cytoplasm where its E3 activity is repressed. A decrease in mitochondrial membrane potential triggers Parkin E3 activity and recruits it to depolarized mitochondria for ubiquitylation of mitochondrial substrates. The molecular basis for how the E3 activity of Parkin is re-established by mitochondrial damage has yet to be determined. Here we provide in vitro biochemical evidence for ubiquitin thioester formation on Cys-431 of recombinant Parkin. We also report that Parkin forms a ubiquitin-ester following a decrease in mitochondrial membrane potential in cells, and that this event is essential for substrate ubiquitylation. Importantly, the Parkin RING2 domain acts as a transthiolation or acyl transferring domain rather than an E2-recruiting domain. Furthermore, formation of the ubiquitin-ester depends on PINK1 phosphorylation of Parkin Ser-65. A phosphorylation-deficient mutation completely inhibited formation of the Parkin ubiquitin-ester intermediate, whereas phosphorylation mimics, such as Ser to Glu substitution, enabled partial formation of the intermediate irrespective of Ser 65 phosphorylation. We propose that PINK1-dependent phosphorylation of Parkin leads to the ubiquitin-ester transfer reaction of the RING2 domain, and that this is an essential step in Parkin activation. PMID- 23754284 TI - Array-assisted characterization of a fucosyltransferase required for the biosynthesis of complex core modifications of nematode N-glycans. AB - Fucose is a common monosaccharide component of cell surfaces and is involved in many biological recognition events. Therefore, definition and exploitation of the specificity of the enzymes (fucosyltransferases) involved in fucosylation is a recurrent theme in modern glycosciences. Despite various studies, the specificities of many fucosyltransferases are still unknown, so new approaches are required to study these. The model nematode Caenorhabditis elegans expresses a wide range of fucosylated glycans, including N-linked oligosaccharides with unusual complex core modifications. Up to three fucose residues can be present on the standard N,N'-diacetylchitobiose unit of these N-glycans, but only the fucosyltransferases responsible for transfer of two of these (the core alpha1,3 fucosyltransferase FUT-1 and the core alpha1,6-fucosyltransferase FUT-8) were previously characterized. By use of a glycan library in both array and solution formats, we were able to reveal that FUT-6, another C. elegans alpha1,3 fucosyltransferase, modifies nematode glycan cores, specifically the distal N acetylglucosamine residue; this result is in accordance with glycomic analysis of fut-6 mutant worms. This core-modifying activity of FUT-6 in vitro and in vivo is in addition to its previously determined ability to synthesize Lewis X epitopes in vitro. A larger scale synthesis of a nematode N-glycan core in vitro using all three fucosyltransferases was performed, and the nature of the glycosidic linkages was determined by NMR. FUT-6 is probably the first eukaryotic glycosyltransferase whose specificity has been redefined with the aid of glycan microarrays and so is a paradigm for the study of other unusual glycosidic linkages in model and parasitic organisms. PMID- 23754285 TI - ADAMDEC1 is a metzincin metalloprotease with dampened proteolytic activity. AB - ADAMDEC1 (Decysin-1) is a putative ADAM (a disintegrin and metalloprotease)-like metalloprotease with an unknown physiological role, selectively expressed in mature dendritic cells and macrophages. When compared with other members of the ADAM family, ADAMDEC1 displays some unusual features. It lacks the auxiliary cysteine-rich, EGF, and transmembrane domains, as well as the cytoplasmic tail. The active site of ADAMDEC1 is unique by being the only mammalian ADAM protease with a non-histidine zinc ligand, having an aspartic acid residue instead. Here we demonstrate that ADAMDEC1, despite these unique features, functions as an active metalloprotease. Thus, ADAMDEC1 is secreted as a mature, glycosylated, and proteolytically active metalloprotease, capable of cleaving macromolecular substrates. In the recombinant form, three of the four potential N-linked glycosylation sites are modified by carbohydrate attachment. Substitution of basic residues at the predicted proprotein convertase cleavage site blocks proprotein processing, revealing both specific ADAMDEC1-dependent and specific ADAMDEC1-independent cleavage of the prodomain. The pro-form of ADAMDEC1 does not have proteolytic activity, demonstrating that the prodomain of ADAMDEC1, like in other members of the ADAM family, confers catalytic latency. Interestingly, the proteolytic activity of mature ADAMDEC1 can be significantly enhanced when a canonical ADAM active site with three zinc-coordinating histidine residues is introduced. PMID- 23754286 TI - Lactate engages receptor tyrosine kinases Axl, Tie2, and vascular endothelial growth factor receptor 2 to activate phosphoinositide 3-kinase/Akt and promote angiogenesis. AB - Although a high level of lactate is quintessential to both tumors and wound healing, the manner by which lactate impacts endothelial cells to promote angiogenesis and thereby create or restore vascular perfusion to growing tissues has not been fully elucidated. Here we report that lactate activated the PI3K/Akt pathway in primary human endothelial cells. Furthermore, activating this signaling pathway was required for lactate-stimulated organization of endothelial cells into tubes and for sprouting of vessels from mouse aortic explants. Lactate engaged the PI3K/Akt pathway via ligand-mediated activation of the three receptor tyrosine kinases Axl, Tie2, and VEGF receptor 2. Neutralizing the ligands for these receptor tyrosine kinases, pharmacologically inhibiting their kinase activity or suppressing their expression largely eliminated the ability of cells and explants to respond to lactate. Elucidating the mechanism by which lactate communicates with endothelial cells presents a previously unappreciated opportunity to improve our understanding of the angiogenic program and to govern it. PMID- 23754287 TI - Signaling to extracellular signal-regulated kinase from ErbB1 kinase and protein kinase C: feedback, heterogeneity, and gating. AB - Many extracellular signals act via the Raf/MEK/ERK cascade in which kinetics, cell-cell variability, and sensitivity of the ERK response can all influence cell fate. Here we used automated microscopy to explore the effects of ERK-mediated negative feedback on these attributes in cells expressing endogenous ERK or ERK2 GFP reporters. We studied acute rather than chronic stimulation with either epidermal growth factor (ErbB1 activation) or phorbol 12,13-dibutyrate (PKC activation). In unstimulated cells, ERK-mediated negative feedback reduced the population-average and cell-cell variability of the level of activated ppERK and increased its robustness to changes in ERK expression. In stimulated cells, negative feedback (evident between 5 min and 4 h) also reduced average levels and variability of phosphorylated ERK (ppERK) without altering the "gradedness" or sensitivity of the response. Binning cells according to total ERK expression revealed, strikingly, that maximal ppERK responses initially occur at submaximal ERK levels and that this non-monotonic relationship changes to an increasing, monotonic one within 15 min. These phenomena occur in HeLa cells and MCF7 breast cancer cells and in the presence and absence of ERK-mediated negative feedback. They were best modeled assuming distributive (rather than processive) activation. Thus, we have uncovered a novel, time-dependent change in the relationship between total ERK and ppERK levels that persists without negative feedback. This change makes acute response kinetics dependent on ERK level and provides a "gating" or control mechanism in which the interplay between stimulus duration and the distribution of ERK expression across cells could modulate the proportion of cells that respond to stimulation. PMID- 23754288 TI - Mapping the binding region on the low density lipoprotein receptor for blood coagulation factor VIII. AB - Low density lipoprotein receptor (LDLR) was shown to mediate clearance of blood coagulation factor VIII (FVIII) from the circulation. To elucidate the mechanism of interaction of LDLR and FVIII, our objective was to identify the region of the receptor necessary for binding FVIII. Using surface plasmon resonance, we found that LDLR exodomain and its cluster of complement-type repeats (CRs) bind FVIII in the same mode. This indicated that the LDLR site for FVIII is located within the LDLR cluster. Similar results were obtained for another ligand of LDLR, alpha 2-macroglobulin receptor-associated protein (RAP), a common ligand of receptors from the LDLR family. We further generated a set of recombinant fragments of the LDLR cluster and assessed their structural integrity by binding to RAP and by circular dichroism. A number of fragments overlapping CR.2-5 of the cluster were positive for binding RAP and FVIII. The specificity of these interactions was tested by site-directed mutagenesis of conserved tryptophans within the LDLR fragments. For FVIII, the specificity was also tested using a single-chain variable antibody fragment directed against the FVIII light chain as a competitor. Both cases resulted in decreased binding, thus confirming its specificity. The mutagenic study also showed an importance of the conserved tryptophans in LDLR for both ligands, and the competitive binding results showed an involvement of the light chain of FVIII in its interaction with LDLR. In conclusion, the region of CR.2-5 of LDLR was defined as the binding site for FVIII and RAP. PMID- 23754289 TI - Molecular basis for benzodiazepine agonist action at the type 1 cholecystokinin receptor. AB - Understanding the molecular basis of drug action can facilitate development of more potent and selective drugs. Here, we explore the molecular basis for action of a unique small molecule ligand that is a type 1 cholecystokinin (CCK) receptor agonist and type 2 CCK receptor antagonist, GI181771X. We characterize its binding utilizing structurally related radioiodinated ligands selective for CCK receptor subtypes that utilize the same allosteric ligand-binding pocket, using wild-type receptors and chimeric constructs exchanging the distinct residues lining this pocket. Intracellular calcium assays were performed to determine biological activity. Molecular models for docking small molecule agonists to the type 1 CCK receptor were developed using a ligand-guided refinement approach. The optimal model was distinct from the previous antagonist model for the same receptor and was mechanistically consistent with the current mutagenesis data. This study revealed a key role for Leu(7.39) that was predicted to interact with the isopropyl group in the N1 position of the benzodiazepine that acts as a "trigger" for biological activity. The molecular model was predictive of binding of other small molecule agonists, effectively distinguishing these from 1065 approved drug decoys with an area under curve value of 99%. The model also selectively enriched for agonist compounds, with 130 agonists identified by ROC analysis when seeded in 2175 non-agonist ligands of the type 1 CCK receptor (area under curve 78%). Benzodiazepine agonists in this series docked in consistent pose within this pocket, with a key role played by Leu(7.39), whereas the role of this residue was less clear for chemically distinct agonists. PMID- 23754290 TI - Staphylococcal superantigen-like protein 10 (SSL10) inhibits blood coagulation by binding to prothrombin and factor Xa via their gamma-carboxyglutamic acid (Gla) domain. AB - The staphylococcal superantigen-like protein (SSL) family is composed of 14 exoproteins sharing structural similarity with superantigens but no superantigenic activity. Target proteins of four SSLs have been identified to be involved in host immune responses. However, the counterparts of other SSLs have been functionally uncharacterized. In this study, we have identified porcine plasma prothrombin as SSL10-binding protein by affinity purification using SSL10 conjugated Sepharose. The resin recovered the prodomain of prothrombin (fragment 1 + 2) as well as factor Xa in pull-down analysis. The equilibrium dissociation constant between SSL10 and prothrombin was 1.36 * 10(-7) M in surface plasmon resonance analysis. On the other hand, the resin failed to recover gamma carboxyglutamic acid (Gla) domain-less coagulation factors and prothrombin from warfarin-treated mice, suggesting that the Gla domain of the coagulation factors is essential for the interaction. SSL10 prolonged plasma clotting induced by the addition of Ca(2+) and factor Xa. SSL10 did not affect the protease activity of thrombin but inhibited the generation of thrombin activity in recalcified plasma. S. aureus produces coagulase that non-enzymatically activates prothrombin. SSL10 attenuated clotting induced by coagulase, but the inhibitory effect was weaker than that on physiological clotting, and SSL10 did not inhibit protease activity of staphylothrombin, the complex of prothrombin with coagulase. These results indicate that SSL10 inhibits blood coagulation by interfering with activation of coagulation cascade via binding to the Gla domain of coagulation factor but not by directly inhibiting thrombin activity. This is the first finding that the bacterial protein inhibits blood coagulation via targeting the Gla domain of coagulation factors. PMID- 23754296 TI - Diagnostic power of the noninvasive condom catheter method in patients eligible for transurethral resection of the prostate. AB - AIMS: The aim of this study was to determine the accuracy of the non-invasive condom catheter method for diagnosing B(ladder) O(utlet) O(bstruction) in patients eligible for T(rans)U(rethral) R(esection) of the P(rostate). METHODS: A group of 71 patients eligible for TURP on clinical grounds were invasively and non-invasively studied. On the basis of invasive pressure-flow studies they were stratified into obstructed, equivocal or unobstructed, according to the International Continence Society standard. Subsequently they were diagnosed non invasively on the basis of a free flowrate measurement, or on the basis of the free flowrate measurement plus the isovolumetric bladder pressure measured with the condom catheter method. R(eceiver) O(perating) C(haracteristic)s were calculated. RESULTS: The A(rea) U(nder) the (RO)C for discriminating unobstructed/equivocal patients from obstructed patients was 0.68 in our population. This improved to 0.84 for the 50 patients in whom the isovolumetric bladder pressure was not underestimated by the non-invasive method. CONCLUSIONS: In our population of TURP patients, the low flowrates affected the accuracy of the condom method to a degree that it did not perform better than a free flowrate measurement, which performed remarkably well. By excluding measurements in which the condom pressure underestimated the isovolumetric bladder pressure this method may contribute to a more accurate, patient friendly diagnosis of BOO in these patients. In the present study this exclusion was done by comparison with an invasive pressure measurement. A practical non-invasive test would necessitate a non-invasive exclusion criterion, which might be based on the risetime of the condom pressure. PMID- 23754297 TI - Normative data for uterine size according to age and gravidity and possible role of the classical golden ratio. AB - OBJECTIVES: To document normal measurements (length, width, anteroposterior (AP) diameter) and proportions of the non-pregnant uterus according to age and gravidity. We hypothesized that uterine proportions conform to the classical 'golden ratio' (1.618). METHODS: This was a retrospective study of ultrasonographic measurements of the length, width and AP diameter of non pregnant uteri recorded in our database between 1 January 2000 and 31 July 2012. All patients for whom abnormal findings were reported were excluded and only the first set of measurements for each patient was retained for analysis. Loess (local regression) analysis was performed using age and gravidity as explanatory variables. RESULTS: Measurements of 5466 non-pregnant uteri were retrieved for analysis. The mean length was found to increase to 72 mm at the age of 40 and decrease to 42 mm at the age of 80 years. Gravidity was associated with greater uterine length, width and AP diameter. Mean length/width ratio was found to be 1.857 at birth, decreasing to 1.452 at the age of 91 years. At the age of 21 years, the mean ratio was found to be 1.618, i.e. equal to the golden ratio. Increasing gravidity was associated with lower mean length/width ratio. CONCLUSIONS: Uterine size in non-pregnant women varies in relation to age and gravidity. Mean length/width ratio conformed to the golden ratio at the age of 21, coinciding with peak fertility. PMID- 23754298 TI - Ophiobolin A, a sesterterpenoid fungal phytotoxin, displays higher in vitro growth-inhibitory effects in mammalian than in plant cells and displays in vivo antitumor activity. AB - Ophiobolin A, a sesterterpenoid produced by plant pathogenic fungi, was purified from the culture extract of Drechslera gigantea and tested for its growth inhibitory activity in both plant and mammalian cells. Ophiobolin A induced cell death in Nicotiana tabacum L. cv. Bright Yellow 2 (TBY-2) cells at concentrations >=10 uM, with the TBY-2 cells showing typical features of apoptosis-like cell death. At a concentration of 5 uM, ophiobolin A did not affect plant cell viability but prevented cell proliferation. When tested on eight cancer cell lines, concentrations <1 uM of ophiobolin A inhibited growth by 50% after 3 days of culture irrespective of their multidrug resistance (MDR) phenotypes and their resistance levels to pro-apoptotic stimuli. It is, thus, unlikely that ophiobolin A exerts these in vitro growth-inhibitory effects in cancer cells by activating pro-apoptotic processes. Highly proliferative human keratinocytes appeared more sensitive to the growth-inhibitory effects of ophiobolin A than slowly proliferating ones. Ophiobolin A also displayed significant antitumor activity at the level of mouse survival when assayed at 10 mg/kg in the B16F10 mouse melanoma model with lung pseudometastases. Ophiobolin A could, thus, represent a novel scaffold to combat cancer types that display various levels of resistance to pro apoptotic stimuli and/or various MDR phenotypes. PMID- 23754299 TI - Combined intracoronary thrombolysis, thrombus aspiration and mesh-covered stent implantation for organized massive thrombus burden in ectatic coronary. AB - Organized intracoronary thrombus is associated with adverse outcomes due to distal embolization and no-reflow phenomenon during PCI, particularly in large or ectatic coronary arteries. Intracoronary thrombolysis is an underused but effective and safe strategy. We describe the case of a 56-year-old man admitted due to a subacute myocardial infarction with massive thrombus burden in a right ectatic coronary artery to present the usefulness of a sequential approach with intracoronary thrombolysis, thrombus aspiration and a novel mesh-covered stent implantation as a reasonable and effective strategy to avoid a no-reflow phenomenon during PCI, achieving an immediate successful angiographic result, and a positive long-term clinical outcome. PMID- 23754300 TI - Modalities of treatment for laryngotracheal stenosis: the EVMS experience. AB - OBJECTIVES/HYPOTHESIS: The aims of the study were to identify trends in surgical management of laryngotracheal stenosis (LTS) based on lesion location, as well as to recognize factors associated with recurrence and repeat surgical intervention. STUDY DESIGN: The study is a retrospective review of all adult patients cared for at a tertiary care laryngology practice with a diagnosis of laryngotracheal stenosis between October 2001 and July 2010, following Institutional Review Board approval. METHODS: This study collectively measured demographics, comorbidities, etiologies, sites of stenoses, treatment modalities, and recurrences. RESULTS: Incisions made with the carbon dioxide (CO2) laser were the most common modality of treatment; patients with multilevel tracheal stenosis were most likely to have undergone at least one operation in which the CO2 laser was used to make incisions (78.7%). Balloon dilation was most commonly employed in patients with multilevel tracheal stenosis (66.0%). Lowest rates of decannulation were identified in patients with a pure tracheal stenosis (23.1%). Patients presenting with multilevel tracheal stenosis underwent the most procedures (6.7). Supraglottic, glottic, and multilevel laryngeal stenosis recurred at the lowest rates. Patients suffering from diabetes mellitus recurred in an average period of 3.9 months, a shorter time frame than those without diabetes, who recurred every 10.5 months. CONCLUSIONS: Laser incision and/or balloon dilation are most effective in treatment of pure glottic, subglottic, and tracheal stenosis. Multilevel tracheal stenosis warrants closer follow-up, and is more likely to require multiple procedures. Worsening stenosis despite endoscopic management warrants an open procedure. Diabetes is associated with an earlier recurrence of stenosis. PMID- 23754301 TI - Not for turning...? PMID- 23754302 TI - Editor in chief's commentary. PMID- 23754303 TI - Serotonin transporter polymorphism is associated with increased apnea-hypopnea index in older adults. AB - RATIONALE: A functional polymorphism of the serotonin transporter gene (5-HTTLPR) has previously been related to upper airway pathology, but its contribution to obstructive sleep apnea (OSA), a highly prevalent sleep disorder in older adults, remains unclear. OBJECTIVES: We aimed to investigate the relationship between apnea-hypopnea index (AHI) and genetic variations in the promoter region of the 5 HTTLPR in older adults. METHODS: DNA samples from 94 community-dwelling older adults (57% female, mean age 72 +/- 8) were genotyped for the 5-HTTLPR polymorphism. All participants were assessed in their homes with full ambulatory polysomnography in order to determine AHI and related parameters such as hypoxia, sleep fragmentation, and self-reported daytime sleepiness. RESULTS: The 5-HTT l allele was significantly associated with AHI (p = 0.019), with l allele carriers displaying a higher AHI than s allele homozygotes. A single allele change in 5 HTTLPR genotype from s to l resulted in an increase of AHI by 4.46 per hour of sleep (95% CI, 0.75-8.17). The l allele was also associated with increased time during sleep spent at oxygen saturation levels below 90% (p = 0.014). CONCLUSIONS: The observed significant association between the 5-HTTLPR l allele and severity of OSA in older adults suggests that the l allele may be important to consider when assessing for OSA in this age group. This association may also explain some of the observed variability among serotonergic pharmacological treatment studies for OSA, and 5-HTT genotype status may have to be taken into account in future therapeutic trials involving serotonergic agents. PMID- 23754305 TI - microRNA-200c modulates the epithelial-to-mesenchymal transition in human renal cell carcinoma metastasis. AB - microRNAs (miRNAs) play essential roles in several physiological and pathological processes, including tumor metastasis. Metastasis is associated with poor prognosis in renal carcinoma patients and almost 20-30% of patients present with distant metastasis at the time of diagnosis. The aim of the present study was to investigate the possible roles of miR-200c in regulating metastasis and to identify its target genes in renal cell carcinoma (RCC). Among the miRNAs downregulated in our tissue specimen microarray, miR-200c was downregulated significantly. Functional assays demonstrated that restoration of miR-200c significantly inhibited the migration and invasion of SN12-PM6 and 786-0 cells in vitro. Genome-wide gene expression analysis and TargetScan database studies showed that ZEB1, which has been shown to promote tumor invasion and migration through E-cadherin gene silencing, is a promising candidate target gene of miR 200c. Overexpression of miR-200c in SN12-PM6 and 786-0 cells was concurrent with downregulation of ZEB1 and upregulation of E-cadherin mRNA and protein. In addition, miR-200c affected the protein expression of p-Akt and Akt. Thus, our study demonstrated that miR-200c decreases the metastatic ability of renal carcinoma cells by upregulating E-cadherin through ZEB1 and that modulating the expression of miR-200c could influence Akt protein levels. We therefore concluded that there is an Akt-miR-200c-E-cadherin axis in the epithelial-to-mesenchymal transition process in RCC. PMID- 23754304 TI - Expression differences between African American and Caucasian prostate cancer tissue reveals that stroma is the site of aggressive changes. AB - In prostate cancer, race/ethnicity is the highest risk factor after adjusting for age. African Americans have more aggressive tumors at every clinical stage of the disease, resulting in poorer prognosis and increased mortality. A major barrier to identifying crucial gene activity differences is heterogeneity, including tissue composition variation intrinsic to the histology of prostate cancer. We hypothesized that differences in gene expression in specific tissue types would reveal mechanisms involved in the racial disparities of prostate cancer. We examined 17 pairs of arrays for AAs and Caucasians that were formed by closely matching the samples based on the known tissue type composition of the tumors. Using pair-wise t-test we found significantly altered gene expression between AAs and CAs. Independently, we performed multiple linear regression analyses to associate gene expression with race considering variation in percent tumor and stroma tissue. The majority of differentially expressed genes were associated with tumor-adjacent stroma rather than tumor tissue. Extracellular matrix, integrin family and signaling mediators of the epithelial-to-mesenchymal transition (EMT) pathways were all downregulated in stroma of AAs. Using MetaCore (GeneGo) analysis, we observed that 35% of significant (p < 10(-3)) pathways identified EMT and 25% identified immune response pathways especially for interleukins-2, -4, -5, -6, -7, -10, -13, -15 and -22 as the major changes. Our studies reveal that altered immune and EMT processes in tumor-adjacent stroma may be responsible for the aggressive nature of prostate cancer in AAs. PMID- 23754306 TI - Does timing matter? How priority effects influence the outcome of parasite interactions within hosts. AB - In nature, hosts are exposed to an assemblage of parasite species that collectively form a complex community within the host. To date, however, our understanding of how within-host-parasite communities assemble and interact remains limited. Using a larval amphibian host (Pacific chorus frog, Pseudacris regilla) and two common trematode parasites (Ribeiroia ondatrae and Echinostoma trivolvis), we experimentally examined how the sequence of host exposure influenced parasite interactions within hosts. While there was no evidence that the parasites interacted when hosts were exposed to both parasites simultaneously, we detected evidence of both intraspecific and interspecific competition when exposures were temporally staggered. However, the strength and outcome of these priority effects depended on the sequence of addition, even after accounting for the fact that parasites added early in host development were more likely to encyst compared to parasites added later. Ribeiroia infection success was reduced by 14 % when Echinostoma was added prior to Ribeiroia, whereas no such effect was noted for Echinostoma when Ribeiroia was added first. Using a novel fluorescent-labeling technique that allowed us to track Ribeiroia infections from different exposure events, we also discovered that, similar to the interspecific interactions, early encysting parasites reduced the encystment success of later arriving parasites by 41 %, which could be mediated by host immune responses and/or competition for space. These results suggest that parasite identity interacts with host immune responses to mediate parasite interactions within the host, such that priority effects may play an important role in structuring parasite communities within hosts. This knowledge can be used to assess host-parasite interactions within natural communities in which environmental conditions can lead to heterogeneity in the timing and composition of host exposure to parasites. PMID- 23754307 TI - Identification of cyclopropaneoctanoic acid 2-hexyl in human adipose tissue and serum. AB - Fatty acids containing a cyclopropane ring in their structure (cyclopropane FA) have been found in a wide variety of bacteria, a number of protozoa, and Myriapoda. Little is known about cyclopropane FA in mammal, especially in human tissues. The present study deals with the identification of cyclopropane FA in adipose tissue and serum of humans and rats. Fatty acids extracted from the adipose tissue and serum obtained from obese women during bariatric surgery were methylated and analyzed on GC-MS. We have identified: cyclopropaneoctanoic acid 2 hexyl, cyclopropaneoctanoic acid 2-octyl, cyclopropanenonanoic acid, and 2-[[2 [(2-ethylcyclopropyl)methyl]cyclopropyl]methyl] acid in human adipose tissue. We confirmed the presence of cyclopropaneoctanoic acid 2-hexyl by derivatization of FA extracted from human adipose tissue to picolinyl esters. Cyclopropaneoctanoic acid 2-hexyl was the main cyclopropane FA (approximately 0.4 % of total fatty acids in human adipose tissue, and about 0.2 % of total fatty acids in the serum). In adipose tissue cyclopropaneoctanoic acid 2-hexyl was found mainly in triacylglycerols, whereas in serum in phospholipids and triacylglycerols. The cyclopropaneoctanoic acid 2-hexyl has also been found in serum, and adipose tissue of rats in amounts comparable to humans. The content of cyclopropaneoctanoic acid 2-hexyl decreased in adipose tissue of rats maintained on a restricted diet for 1 month. In conclusion, we demonstrated that cyclopropaneoctanoic acid 2-hexyl is present in human adipose tissue and serum. Adipose tissue cyclopropaneoctanoic acid 2-hexyl is stored mainly in triacylglycerols and the storage of this cyclopropane FA is affected by food restriction. PMID- 23754308 TI - Sex differences in formalin-evoked primary afferent release of substance P. AB - BACKGROUND: Sex differences in pain have been well documented; however, the mechanisms involved remain to be elucidated. The present study examined whether sex differences exist in the functioning of primary afferent fibres by assessing formalin-evoked release of substance P by way of neurokinin 1 receptor (NK1r) internalization. The study also investigated whether the observed effects would be oestradiol-sensitive. METHODS: Intact and gonadectomized male and female rats were given intraplantar formalin and then euthanized either 5 or 30 min later, representing phase 1 or 2 of the formalin response, respectively. In a subsequent experiment, ovariectomized females received oestradiol prior to formalin administration. Lastly, formalin-evoked NK1r internalization was assessed across the female oestrous cycle. RESULTS: Intraplantar formalin evoked significant NK1r internalization, during phase 1 and 2, in both males and females. During phase 1, no differences in NK1r internalization were detected between males or females, regardless of the gonadal status. In contrast, during phase 2, intact females exhibited greater NK1r internalization than intact males. Moreover, ovariectomy reduced NK1r internalization as compared to intact females, whereas castration had no effect as compared to intact males. Oestradiol supplementation in ovariectomized females increased NK1r internalization to levels observed in intact females. Formalin-evoked NK1r internalization did not differ across the oestrous cycle. CONCLUSIONS: These findings suggest that oestradiol mediates sex differences in formalin-evoked substance P release, which may contribute to a differential development of central sensitization and pain behaviours in males and females. PMID- 23754309 TI - Surgical site infections following craniotomy focusing on possible post-operative acquisition of infection: prospective cohort study. AB - Neurosurgery is characterized by a prolonged risk period for surgical site infection (SSI), mainly related to the presence of cerebrospinal fluid (CSF) drains. We aimed to examine factors associated with post-neurosurgical SSIs, focusing on post-operative factors. A prospective cohort study was conducted in a single center over a period of 18 months in Israel. Included were adult patients undergoing clean or clean-contaminated craniotomy, including craniotomies with external CSF drainage or shunts. SSIs were defined by the Centers for Disease Control and Prevention (CDC) criteria for healthcare-associated infections. All patients were followed up for 90 days and those with foreign body insertion for 1 year. We compared patients with and without SSI. A multivariable regression analysis for SSI was conducted including uncorrelated variables significantly associated with SSI. A total of 502 patients were included, with 138 (27.5%) undergoing emergent or urgent craniotomy. The overall SSI rate was 5.6% (28 patients), of which 3.2% (16 patients) were intracerebral. Non-elective surgery, external CSF drainage/monitoring devices, re-operation, and post-operative respiratory failure were independently associated with subsequent SSI. External CSF devices was the only significant risk factor for intracerebral SSIs (p < 0.001). Internal shunts or other foreign body insertions were not associated with SSIs. A phenotypically identical isolate to that causing the SSI was isolated from respiratory secretions prior to the SSI in 4/9 patients with microbiologically documented intracerebral SSIs. Patients with SSIs had longer hospital stay, poorer functional capacity on discharge, and higher 90-day mortality. We raise the possibility of post-operative infection acquisition through external CSF devices. Standard operating procedures for their maintenance are necessary. PMID- 23754310 TI - Incomplete B cell tolerance to cartilage oligomeric matrix protein in mice. AB - OBJECTIVE: Cartilage oligomeric matrix protein (COMP) is a major noncollagenous component of cartilage and is used as a biomarker in rheumatoid arthritis and experimental arthritis. Injection of COMP leads to severe inflammatory joint disease, and antibodies play a critical role in mediating arthritis. The arthritogenicity of COMP might be due to the lack of self tolerance. This study was undertaken to determine the status of COMP-specific B cell tolerance using COMP-deficient mice. METHODS: Arthritis development and antibody responses were compared between COMP-sufficient and COMP-deficient littermates after immunization with rat COMP. Serum anti-COMP antibody levels were measured using a panel of recombinant mouse COMP proteins, and antibody-secreting cells were enumerated by enzyme-linked immunospot assays. A novel sandwich enzyme-linked immunosorbent assay was developed to assess COMP molecules in serum. RESULTS: COMP-sufficient mice, but not COMP-deficient mice, developed severe arthritis following immunization with rat COMP. However, anti-COMP antibody titers to native COMP and recombinant protein domains covering the entire mouse COMP sequence, except the less immunodominant type 3 repeat domains, were decreased in COMP-sufficient mice compared to COMP-deficient mice. In addition, COMP sufficient mice had fewer B cells secreting COMP-reactive antibodies. Detectable levels of full-length COMP in arthritic COMP-sufficient B10.Q NCF-1(*/*) and healthy mice suggested systemic availability of COMP to the immune system. CONCLUSION: The lack of arthritis, together with high levels of COMP-specific antibodies, in COMP-deficient mice indicates that susceptibility to arthritis is COMP specific and that endogenous expression of COMP in wild-type mice tolerizes B cells in vivo. PMID- 23754311 TI - Pre- and postoperative evaluation of pelvic floor muscle function in POP patients using surface electromyography and digital palpation. AB - AIMS: The study aims to evaluate the pelvic floor muscle (PFM) function in patients with pelvic organ prolapse (POP) pre- and postoperatively using digital palpation and surface electromyography. METHODS: In this non-randomized prospective study, two groups of patients were recruited for assessment. The surgical group included 74 POP patients receiving the modified pelvic reconstructive surgery and the control group consisted of 30 non-POP patients. One physiotherapist conducted the digital palpation and SEMG evaluation. The scale of PFM strength, the duration and voltage of maximum voluntary contraction (MVC) as well as numbers and voltage of short, fast contractions (SFC) by SEMG were documented and compared in both groups. For statistical analysis, t-test, Mann-Whitney U test and Wilcoxon test were used with a significant level 0.05. RESULTS: A total of 68 POP patients finished the two follow-ups. Sixty-four patients were objectively cured with a 94.1% cure rate. Mesh erosions happened in three patients (4.8%). By digital palpation, the PFM strength increased significantly in POP patients after surgery but still lower than non-POP patients (P<0.001). By SEMG, the electrical activity of PFM increased significantly in the surgical group postoperatively (P 0.001). CONCLUSION: The PFM function was improved 3 months after the modified pelvic reconstructive surgery in POP patients based on digital palpation and SEMG. The evaluation of PFM function should be included in the overall assessment of pelvic reconstructive surgeries. PMID- 23754313 TI - Alternatively spliced tissue factor contributes to tumor spread and activation of coagulation in pancreatic ductal adenocarcinoma. AB - Alternatively spliced tissue factor (asTF) promotes neovascularization and monocyte recruitment via integrin ligation. While asTF mRNA has been detected in some pancreatic ductal adenocarcinoma (PDAC) cell lines and increased asTF expression can promote PDAC growth in a subcutaneous model, the expression of asTF protein in bona fide PDAC lesions and/or its role in metastatic spread are yet to be ascertained. We here report that asTF protein is abundant in lesional and stromal compartments of the five studied types of carcinoma including PDAC. Analysis of 29 specimens of PDAC revealed detectable asTF in >90% of the lesions with a range of staining intensities. asTF levels in PDAC lesions positively correlated with the degree of monocyte infiltration. In an orthotopic model, asTF overexpressing high-grade PDAC cell line Pt45P1/asTF+ produced metastases to distal lymph nodes, which stained positive for asTF. PDAC cells stimulated with and/or overexpressing asTF exhibited upregulation of genes implicated in PDAC progression and metastatic spread. Pt45P1/asTF+ cells displayed higher coagulant activity compared to Pt45P1 cells; the same effect was observed for cell-derived microparticles (MPs). Our findings demonstrate that asTF is expressed in PDAC and lymph node metastases and potentiates PDAC spread in vivo. asTF elicits global changes in gene expression likely involved in tumor progression and metastatic dissemination, and it also enhances the procoagulant potential of PDAC cells and cell-derived MPs. Thus, asTF may comprise a novel therapeutic target to treat PDAC and, possibly, its thrombotic complications. PMID- 23754314 TI - Endometrial scratching performed in the non-transfer cycle and outcome of assisted reproduction: a randomized controlled trial. AB - OBJECTIVES: To investigate the effect of endometrial scratching, performed during oral contraceptive pill (OCP) pretreatment, on reproductive outcome and on ultrasound markers of endometrial receptivity, and to assess the pain involved in the procedure, in unselected women undergoing assisted reproductive techniques (ART). METHODS: Women undergoing ART were randomly allocated to undergo either endometrial scratching with a pipelle de Cornier or a sham procedure, 7-14 days before starting controlled ovarian stimulation (COS). We evaluated subsequent rates of clinical pregnancy, live birth, implantation, miscarriage and multiple pregnancy. Pain during the procedure was evaluated using a 10-cm visual analog scale. Endometrial thickness and volume and three-dimensional power Doppler (3D PD) indices (vascularization index (VI), flow index (FI) and vascularization flow index (VFI)) were assessed during COS when there was at least one follicle >= 17 mm in diameter. RESULTS: We included 158 women. Endometrial scratching was associated with higher rates of live birth (41.8% vs 22.8%, P = 0.01) and clinical pregnancy (49.4% vs 29.1%, P = 0.01) and higher pain score (6.42 +/- 2.35 cm vs 1.82 +/- 1.52 cm, P < 0.001), endometrial VI (3.71 +/- 1.77 vs 2.95 +/ 1.56, P < 0.01) and VFI (0.97 +/- 0.51 vs 0.76 +/- 0.40, P < 0.01). There was no significant effect of endometrial scratching on rate of miscarriage (15.4% vs 21.7%, P = 0.53) or multiple pregnancy (22.5% vs 25.0%, P = 0.79), or on endometrial thickness (10.12 +/- 1.55 mm vs 9.98 +/- 1.62 mm, P = 0.59), endometrial volume (6.18 +/- 1.63 cm(3) vs 6.01 +/- 1.48 cm(3) , P = 0.51) or FI (26.12 +/- 2.82 vs 25.91 +/- 2.72, P = 0.65). CONCLUSIONS: Endometrial scratching performed once, during OCP pretreatment 7-14 days before starting COS, increases the chance of live birth and clinical pregnancy, but might cause considerable pain. PMID- 23754315 TI - Deep subsurface cavities in skin utilizing mechanical optical clearing and femtosecond laser ablation. AB - BACKGROUND AND OBJECTIVES: High precision subsurface ablation can be produced in transparent materials using femtosecond laser pulses and multiphoton absorption. Light scattering limits application of the same technique to most biological tissues. Previously, subsurface ablation was demonstrated at superficial depths (50-250 um) in highly scattering tissues including murine skin and human sclera. We report application of mechanical optical clearing to produce deeper subsurface femtosecond ablation in rodent skin. Ability to target deeper structures in skin using subsurface ablation may allow novel clinical applications for dermatological laser surgery. STUDY DESIGN/MATERIALS AND METHODS: Operation of a prototype tissue optical clearing device (TOCD) was verified with white light photography in ex vivo rodent skin. A focused femtosecond beam transmitted through the TOCD and was scanned across rodent skin to produce subsurface ablation at increasing focal depths. Histological sections with H&E staining of the laser irradiated rodent skin were examined for subsurface ablation features following laser irradiation. RESULTS: Subsurface cavities were observed as deep as 1.7 mm below the skin surface in histological tissue sections. Diameter of subsurface cavities varied from tens of microns to over 100 MUm. Subsurface cavities produced by scanning the focused femtosecond beam were contiguous and formed a continuous cut. Mechanical disruption of the overlying tissues was not observed. CONCLUSIONS: Mechanical optical clearing can be applied directly to in situ rodent skin and produces an optical clearing effect. High precision subsurface ablation can be produced at positions substantially deeper than previously demonstrated. Future studies may be targeted in in vivo human skin to investigate potential clinical applications of subsurface femtosecond ablation using mechanical optical clearing. PMID- 23754316 TI - Tetraspanin 1 promotes invasiveness of cervical cancer cells. AB - Tetraspanins are a heterogeneous group of 4-transmembrane proteins that segregate into so-called tetraspanin-enriched microdomains (TEMs) along with other cell surface proteins such as integrins. TEMs of various types are reportedly involved in the regulation of cell growth, migration and invasion of several tumour cell types, both as suppressors or supporting structures. Tetraspanin 1 (Tspan1, NET 1), a member of the transmembrane 4 superfamily (TM4SF) of tetraspanins, is overexpressed in high-grade cervical intraepithelial neoplasia (CIN) and terminal carcinomas but its precise function in the context of carcinoma of the cervix uteri is not known. Here, we present a comprehensive investigation of the role of tetraspanin 1 in the cervical cancer cell lines SiHa and HeLa. We document that tetraspanin 1 increases the invasive potential of cervical cancer cells, whereas proliferation, growth in soft agar and adhesion are largely unaffected. In line with the latter findings, our data exclude the participation of testraspanin in integrin-mediated activation of focal adhesion kinase (FAK), paxillin and phosphoinositide-3-kinase (PI3K) and in EGFR-dependent signalling to the Ras/Erk pathway. In conclusion, our data argue against a role for tetraspanin 1 as a genuine mediator of cell surface receptor signalling but rather document a role for tetraspanin 1 in the control of cervical cancer cell motility and invasion. PMID- 23754317 TI - New international advisory board members announcement. PMID- 23754318 TI - Awareness and utilization of preventive care services among the elderly under National Health Insurance. AB - This empirical study investigates the factors affecting the awareness and the utilization of preventive care among the elderly in Taiwan. We use data obtained from the 2005 National Health Interview Survey. A recursive bivariate probit model is adopted to analyze the factors affecting the awareness and the utilization of preventive care. The probability of awareness of free preventive care under the National Health Insurance is higher for those who are younger, Mainlanders, have received more education, have a spouse, exercise regularly, have better self-rated health status, and have chronic diseases; the probability of awareness is lower for those who are aborigines and who live in the south and the east. Awareness of preventive care services, having a spouse, living alone, having better health status, and the existence of chronic diseases increase the probability of preventive care utilization; working reduces the probability of preventive care utilization. Our result supports the views in Arrow (Am Econ Rev 53(5):941-973, 1963) that health information is an important factor determining the demand for medical care. Policymakers may enhance such preventive care service utilization by increasing the awareness of such services among the elderly. PMID- 23754319 TI - Autophagy enhances antitumor immune responses induced by irradiated hepatocellular carcinoma cells engineered to express hepatitis B virus X protein. AB - Hepatitis B virus X protein (HBx) plays a critical role in malignancy transformation of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). HBx sequence has been mapped with multi-epitopes which can elicit robust specific cytolytic T lymphocyte (CTL) responses. In our previous study, we developed an adenoviral vaccine against HBx oncoproteins to prevent growth of HBV-associated HCC. However, due to the weak immunogenicity of tumor antigen and pre-existing virus-neutralizing antibodies to the vaccine carrier preventing the vector from transducing target cells, the development of novel methods to enhance antigen presentation is urgently required. In the present study, we developed an adenoviral-mediated genetic engineering of hepatoma cell vaccine to express HBx and to evaluate if the novel vaccine could elicit specific immune responses. Our data showed that the irradiated tumor cells engineered to express HBx could significantly induce antitumor immune responses in vivo. The novel vaccine could induce a specific CTL response to recognize and lyse HBx-positive hepatoma cells in vitro. Both CD8+ T and CD4+ T lymphocytes are involved in the antitumor immune response induced by the novel vaccine. Furthermore, numerous autophagosomes and autolysosomes were found in the irradiated tumor cells engineered to express HBx. The results demonstrated that the irradiated HBx-modified tumor cell vaccine was a potent and promising therapeutic agent against HBx-positive HCC via induction of autophagy-enhanced CD8+ T and CD4+ T lymphocyte-mediated antitumor immune responses. The present findings have implications for the development of clinical immunotherapy against HBV-associated HCC. PMID- 23754320 TI - Mucoepidermoid carcinoma of the parotid gland treated by surgery and postoperative radiation therapy: clinicopathologic correlates of outcome. AB - OBJECTIVES/HYPOTHESIS: To determine clinical and pathological correlates of outcome among patients treated by surgery and postoperative radiation therapy for mucoepidermoid carcinoma of the parotid gland. STUDY DESIGN: Retrospective review. METHODS: The medical records of 61 patients treated by surgery and postoperative radiation therapy for localized mucoepidermoid carcinoma of the parotid gland were retrospectively reviewed in an attempt to identify clinicopathologic correlates of overall survival. Secondary endpoints included local-regional control, distant metastasis-free survival, and complications. RESULTS: The 3- and 5-year estimates of overall survival were 85% and 79%, respectively. Multivariate analysis identified high tumor grade (hazard ratio [HR] = 7.92) and T4 disease (HR = 3.35) as independent predictors of decreased survival, with the former also predicting for distant metastasis and the latter predicting for local-regional recurrence. The 5-year estimate of overall survival was 83% for patients with non-high-grade tumors, compared to 52% for those with high-grade histology (P = 0.001). Late complications included trismus (2 patients), osteoradionecrosis (1 patient), and hearing loss (1 patient). CONCLUSION: Patients with high-grade tumors and T4 disease are at increased risk for treatment failure after surgery and postoperative radiation therapy for mucoepidermoid carcinoma of the parotid gland. Investigative strategies to improve outcome should be considered for these particular patients in the future. PMID- 23754321 TI - Lung resection for lung cancer after pleural empyema. AB - BACKGROUND: The association of pleural empyema and lung cancer has traditionally been considered as a contraindication for lung resection. However, several aspects of this problem still remain controversial. MATERIALS AND METHODS: A retrospective study was conducted including 15 patients (12 pneumonectomies and 3 lobectomies) who underwent a lung resection for primary lung cancer after previous pleural empyema. RESULTS: In all but one patient, empyema was treated by chest tube for 15 to 40 days. In only two patients, the diagnosis of empyema preceded the diagnosis of lung cancer. Among patients with pneumonectomy, a good intrapleural cleavage plane existed in only one patient with no signs of infection. In each patient with a lobectomy, preoperative chest tube aspiration took 20 to 30 days and in none of them intraoperative signs of infection existed. In patients with pneumonectomy, empyema without bronchopleural fistula occurred in two patients, while in one patient, empyema was associated with fistula. The operative morbidity after pneumonectomy was 33.3%. CONCLUSION: Association of pleural empyema and lung cancer is not an absolute contraindication for surgery. Potentially curative operation is possible, provided a full control of infection is achieved. PMID- 23754322 TI - Diminution of the NMDA receptor NR2B subunit in cortical and subcortical areas of WAG/Rij rats. AB - Modulation of glutamatergic NMDA receptors affects the synchronization of spike discharges in in WAG/Rij rats, a valid genetic animal model of absence epilepsy. In this study, we describe the alteration of NR2B subunit of NMDA receptors expression in WAG/Rij rats in different somatosensory cortical layers and in hippocampal CA1 area. Experimental groups were divided into four groups of six rats of both WAG/Rij and Wistar strains with 2 and 6 months of age. The distribution of NR2B receptors was assessed by immunohistochemical staining in WAG/Rij and compared with age-matched Wistar rats. The expression of NR2B subunit was significantly decreased in different somatosensory cortical layers in 2- and 6-month-old WAG/Rij rats. In addition, the distribution of NR2B in hippocampal CA1 area was lower in 6-month-old WAG/Rij compared with age-matched Wistar rats. The reduction of NR2B receptors in different brain areas points to disturbance of glutamate receptors expression in cortical and subcortical areas in WAG/Rij rats. An altered subunit assembly of NMDA receptors may underlie cortical hyperexcitability in absence epilepsy. PMID- 23754323 TI - Oxygen mass transfer and scale-up studies in baffled roller bioreactors. AB - Oxygen mass transfer was studied in conventional, bead mill and baffled roller bioreactors. Using central composite rotational design, impacts of size, rotation speed and working volume on the oxygen mass transfer were evaluated. Baffled roller bioreactor outperformed its conventional and bead mill counterparts, with the highest k(L)a obtained in these configurations being 0.58, 0.19, 0.41 min( 1), respectively. Performances of the bead mill and baffled roller bioreactor were only comparable when a high bead loading (40%) was applied. Regardless of configuration increase in rotation speed and decrease in working volume improved the oxygen mass transfer rate. Increase in size led to enhanced mass transfer and higher k(L)a in baffled roller bioreactor (0.49 min(-1) for 2.2 L and 1.31 min( 1) for 55 L bioreactors). Finally, the experimentally determined k(L)a in the baffled roller bioreactors of different sizes fit reasonably well to an empirical correlation describing the k(L)a in terms of dimensionless numbers. PMID- 23754324 TI - P(HPMA/EGDMA) beads grafted with fibrous chains by SI-ATRP method: agmatine functionalized affinity beads for selective separation of serum albumin. AB - In this paper, novel core-shell polymeric affinity beads based on fibrous grafting and functionalization with a salt resistance affinity ligand were developed to separate and deplete serum albumin (SA) from human serum. Poly(hydroxypropyl methacrylate/ethyleneglycole dimethacrylate), p(HPMA/EGDMA), beads were prepared via suspension polymerization, and were grafted with poly(glycidyl methacrylate) (p(GMA)) via surface-initiated atom transfer radical polymerization (SI-ATRP) method. The grafted p(GMA) fibrous chains on the beads were modified with an affinity ligand (i.e., agmatine). The binding capacity of the affinity beads to SA was determined using aqueous solution of SA in a batch system. Batch adsorption studies showed that the amount of adsorbed SA was found to be 156.7 mg/g at 25 degrees C. The maximum adsorption capacity for affinity beads was observed at around pH 5.5. Adsorption of SA onto affinity beads significantly increased with increasing temperature, and reached a value 177.8 mg/g beads at 35 degrees C. The equilibrium data were found to be well described by Langmuir model, while the kinetic data were well fitted to the pseudo-second order kinetic. The degree of the purity of SA was determined by using HPLC. Before and after adsorption, the peak areas of SA were used in the calculation of separated SA. PMID- 23754325 TI - Steady-state continuous-flow purification by electrophoresis. PMID- 23754327 TI - Inhibitory role of the spinal cholinergic system in the control of urethral continence reflex during sneezing in rats. AB - AIMS: The urethral continence reflex during stress conditions such as sneezing or coughing is an important mechanism preventing stress urinary incontinence (SUI). Although the spinal noradrenergic and serotonergic pathways are known to modulate this reflex activity, the role of spinal cholinergic pathways in the control of urethral continence reflex has not been elucidated. We therefore investigated the effect of intrathecal administration of an acetylcholine esterase (AChE) inhibitor, which increases ACh in synaptic terminals, and anti-cholinergic agents on the sneeze-induced urethral reflex in rats. METHODS: Female SD rats were anesthetized with urethane. Urethral function was evaluated during sneezing induced by insertion of the rat whisker into the nostril. Effects of an AChE inhibitor, neostigmine, and muscarinic or nicotinic receptor antagonists administered at the level of L6-S1 spinal cord were examined. RESULTS: Neostigmine dose-dependently and significantly decreased the amplitude of urethral responses during sneezing (A-URS) with an approximately 70% reduction at 3 nmol, without changing urethral baseline pressure. The neostigmine-induced decrease in A-URS was significantly reversed by pretreatment with atropine (nonselective muscarinic receptor antagonist), methoctramine (M2 receptor antagonist) or 4-DAMP (M3 receptor antagonist), but not with pirenzepine (M1 receptor antagonist), tropicamide (M4 receptor antagonist), or mecamylamine (nicotinic receptor antagonist). CONCLUSIONS: These results indicate that an increase in endogenous ACh in the lumbosacral spinal cord inhibits the sneeze induced urethral continence reflex via activation of M2 and/or M3-muscarinic receptors, implying the inhibitory role of spinal cholinergic pathways in the control of urethral continence reflex under stress conditions such as sneezing. PMID- 23754326 TI - Ischemia and reactive oxygen species in sympathetic hyperactivity states: a vicious cycle that can be interrupted by renal denervation? AB - Renal denervation has developed as a new treatment strategy for patients suffering from resistant hypertension. The success of this therapy is due to the fact that sympathetic hyperactivity is involved in the pathogenesis of elevated blood pressure. However, not only the sympathetic nervous system (SNS), but also the renin angiotensin system (RAS) is known to be involved in hypertension. In addition, RAS is involved in other sympathetic hyperactivity states, such as heart failure, chronic kidney disease, insulin resistance and obstructive sleep apnea. Moreover, renal denervation has a beneficial effect on patients suffering from these disease states. Recent research suggested that the production of reactive oxygen species (ROS) is elevated in sympathetic hyperactivity states, and that ROS are able to activate the SNS and local tissue renin angiotensin system. Therefore, this review discusses the possibility of ROS as a common trigger of SNS and RAS activity in sympathetic hyperactivity states, and the effect of renal denervation on this ROS production. PMID- 23754328 TI - Suppression of glomerulonephritis in lupus-prone NZB * NZW mice by RN486, a selective inhibitor of Bruton's tyrosine kinase. AB - OBJECTIVE: Bruton's tyrosine kinase (BTK) plays a critical role in B cell development and function. We recently described a selective BTK inhibitor, RN486, that blocks B cell receptor (BCR) and Fcgamma receptor signaling and is efficacious in animal models of arthritis. The aim of this study was to examine the potential efficacy of BTK in systemic lupus erythematosus (SLE), using an NZB * NZW mouse model of spontaneous SLE. METHODS: Mice received RN486 or its vehicle (administered in chow) at a final concentration of 30 mg/kg for 8 weeks, starting at 32 weeks of age. RESULTS: The administration of RN486 completely stopped disease progression, as determined by histologic and functional analyses of glomerular nephritis. The efficacy was associated with striking inhibition of B cell activation, as demonstrated by a significant reduction in CD69 expression in response to BCR crosslinking. RN486 markedly reduced the secretion of IgG anti double-stranded DNA (anti-dsDNA) secretion, as determined by enzyme-linked immunosorbent and enzyme-linked immunospot assays. Flow cytometric analysis demonstrated depletion of CD138(high) B220(low) plasma cells in the spleen. RN486 inhibited secretion of IgG anti-dsDNA but not IgM anti-dsDNA, suggesting that pharmacologic blockade of BTK resembles the reported transgenic expression of low levels of endogenous BTK in B cells. In addition, RN486 may also impact the effector function of autoantibodies, as evidenced by a significant reduction in immune complex-mediated activation of human monocytes in vitro and down regulation of the expression of macrophage-related and interferon-inducible genes in both the kidneys and spleens of treated mice. CONCLUSION: Collectively, our data suggest that BTK inhibitors may simultaneously target autoantibody-producing and effector cells in SLE, thus constituting a promising therapeutic alternative for this disease. PMID- 23754329 TI - Male adiposity impairs clinical pregnancy rate by in vitro fertilization without affecting day 3 embryo quality. AB - OBJECTIVE: Male adiposity is detrimental for achieving clinical pregnancy rate (CPR) following assisted reproductive technologies (ART). The hypothesis that the association of male adiposity with decreased success following ART is mediated by worse embryo quality was tested. DESIGN AND METHODS: Retrospective study including 344 infertile couples undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles was performed. Cycle determinants included number of oocytes retrieved, zygote PN-score, total number of embryos available on day 3, number of embryos transferred, composite day 3 grade for transferred embryos, composite day 3 grade per cycle, and CPR. RESULTS: Couples with male body mass index (BMI) over 25 kg m(-2) (overweight and obese) exhibited significantly lower CPR compared to their normal weight counterparts (46.7% vs. 32.0% respectively, P = 0.02). No significant difference was observed for any embryo quality metrics when analyzed by male BMI: mean zygote PN-scores, mean composite day 3 grades for transferred embryos or composite day 3 grades per cycle. In a multivariable logistic regression analysis adjusting for female age, female BMI, number of embryos transferred and sperm concentration, male BMI over 25 kg m(-2) was associated with a lower chance for CPR after IVF (OR = 0.17 [95% CI: 0.04-0.65]; P = 0.01) but not after ICSI cycles (OR = 0.88 [95% CI: 0.41 1.88]; P = 0.75). In this cohort, male adiposity was associated with decreased CPR following IVF but embryo quality was not affected. CONCLUSIONS: Embryo grading based on conventional morphologic criteria does not explain the poorer clinical pregnancy outcomes seen in couples with overweight or obese male partner. PMID- 23754330 TI - Molecularly imprinted polymers as synthetic receptors for the QCM-D-based detection of L-nicotine in diluted saliva and urine samples. AB - Molecularly imprinted polymers (MIPs) are synthetic receptors that are able to specifically bind their target molecules in complex samples, making them a versatile tool in biosensor technology. The combination of MIPs as a recognition element with quartz crystal microbalances (QCM-D with dissipation monitoring) gives a straightforward and sensitive device, which can simultaneously measure frequency and dissipation changes. In this work, bulk-polymerized L-nicotine MIPs were used to test the feasibility of L-nicotine detection in saliva and urine samples. First, L-nicotine-spiked saliva and urine were measured after dilution in demineralized water and 0.1* phosphate-buffered saline solution for proof-of concept purposes. L-nicotine could indeed be detected specifically in the biologically relevant micromolar concentration range. After successfully testing on spiked samples, saliva was analyzed, which was collected during chewing of either nicotine tablets with different concentrations or of smokeless tobacco. The MIPs in combination with QCM-D were able to distinguish clearly between these samples: This proves the functioning of the concept with saliva, which mediates the oral uptake of nicotine as an alternative to the consumption of cigarettes. PMID- 23754331 TI - HPLC column-switching technique for sample preparation and fluorescence determination of propranolol in urine using fused-core columns in both dimensions. AB - A new and fast high-performance liquid chromatography (HPLC) column-switching method using fused-core columns in both dimensions for sample preconcentration and determination of propranolol in human urine has been developed. On-line sample pretreatment and propranolol preconcentration were performed on an Ascentis Express RP-C-18 guard column (5 * 4.6 mm), particle size, 2.7 MUm, with mobile phase acetonitrile/water (5:95, v/v) at a flow rate of 2.0 mL min(-1) and at a temperature of 50 degrees C. Valve switch from pretreatment column to analytical column was set at 4.0 min in a back-flush mode. Separation of propranolol from other endogenous urine compounds was achieved on the fused-core column Ascentis Express RP-Amide (100 * 4.6 mm), particle size, 2.7 MUm, with mobile phase acetonitrile/water solution of 0.5% triethylamine, pH adjusted to 4.5 by means of glacial acetic acid (25:75, v/v), at a flow rate of 1.0 mL min( 1) and at a temperature of 50 degrees C. Fluorescence excitation/emission detection wavelengths were set at 229/338 nm. A volume of 1,500 MUL of filtered urine sample solution was injected directly into the column-switching HPLC system. The total analysis time including on-line sample pretreatment was less than 8 min. The experimentally determined limit of detection of the method was found to be 0.015 ng mL(-1). PMID- 23754334 TI - Error in Byline in: Long-term and Perioperative Corticosteroids in Anastomotic Leakage: A Prospective Study of 259 Left-Sided Colorectal Anastomoses. PMID- 23754332 TI - Performance of evidence-based youth psychotherapies compared with usual clinical care: a multilevel meta-analysis. AB - IMPORTANCE: Research across more than 4 decades has produced numerous empirically tested evidence-based psychotherapies (EBPs) for psychopathology in children and adolescents. The EBPs were developed to improve on usual clinical interventions. Advocates argue that the EBPs should replace usual care, but this assumes that EBPs produce better outcomes than usual care. OBJECTIVE: To determine whether EBPs do in fact produce better outcomes than usual care in youth psychotherapy. We performed a meta-analysis of 52 randomized trials directly comparing EBPs with usual care. Analyses assessed the overall effect of EBPs vs usual care and candidate moderators; we used multilevel analysis to address the dependency among effect sizes (ES) that is common but typically unaddressed in psychotherapy syntheses. DATA SOURCES: We searched the PubMed, PsychINFO, and Dissertation Abstracts International databases for studies from January 1, 1960, through December 31, 2010. STUDY SELECTION: We identified 507 randomized youth psychotherapy trials. Of these, the 52 studies that compared EBPs with usual care were included in the meta-analysis. DATA EXTRACTION AND SYNTHESIS: Sixteen variables (participant, treatment, outcome, and study characteristics) were extracted from studies, and ESs were calculated for all comparisons of EBP vs usual care. We used an extension of the commonly used random-effects meta analytic model to obtain an overall estimate of the difference between EBP and usual care while accounting for the dependency among ESs. We then fitted a 3 level mixed-effects model to identify moderators that might explain variation in ESs within and between studies by adding study or ES characteristics as fixed predictors. MAIN OUTCOMES AND MEASURES: Primary outcomes of our meta-analysis were mean ES estimates across all studies and for levels of candidate moderators. These ES values were based on measures of symptoms, functioning, and other outcomes assessed within the 52 randomized trials. RESULTS: Evidence-based psychotherapies outperformed usual care. Mean ES was 0.29; the probability was 58% that a randomly selected youth would have a better outcome after EBP than a randomly selected youth after receiving usual care. The following 3 variables moderated treatment benefit: ESs decreased for studies conducted outside North America, for studies in which all participants were impaired enough to qualify for diagnoses, and for outcomes reported by informants other than the youths and parents in therapy. For certain key groups (eg, studies of clinically referred samples and youths with diagnoses), significant EBP effects were not demonstrated. CONCLUSIONS AND RELEVANCE: Evidence-based psychotherapies outperform usual care, but the EBP advantage is modest and moderated by youth, location, and assessment characteristics. The EBPs have room for improvement in the magnitude and range of their benefit relative to usual clinical care. PMID- 23754333 TI - Solution NMR resonance assignment strategies for beta-barrel membrane proteins. AB - Membrane proteins in detergent micelles are large and dynamic complexes that present challenges for solution NMR investigations such as spectral overlap and line broadening. In this study, multiple methods are introduced to facilitate resonance assignment of beta-barrel membrane proteins using Opa60 from Neisseria gonorrhoeae as a model system. Opa60 is an eight-stranded beta-barrel with long extracellular loops (~63% of the protein) that engage host receptors and induce engulfment of the bacterium. The NMR spectra of Opa60 in detergent micelles exhibits significant spectral overlap and resonances corresponding to the loop regions had variable line widths, which interfered with a complete assignment of the protein. To assign the beta-barrel residues, trypsin cleavage was used to remove much of the extracellular loops while preserving the detergent solubilized beta-barrel. The removal of the loop resonances significantly improved the assignment of the Opa60 beta-barrel region (97% of the resonances corresponding to the beta-barrel and periplasmic turns were assigned). For the loop resonance assignments, two strategies were implemented; modulating temperature and synthetic peptides. Lowering the temperature broadened many peaks beyond detection and simplified the spectra to only the most dynamic regions of the loops facilitating 27 loop resonances to be assigned. To further assign functionally important and unstructured regions of the extracellular loops, a synthetic 20 amino acid peptide was synthesized and had nearly complete spectral overlap with the full-length protein allowing 17 loop resonances to be assigned. Collectively, these strategies are effective tools that may accelerate solution NMR structure determination of beta-barrel membrane proteins. PMID- 23754335 TI - Expanding the differential diagnosis of fetal hydrops: an unusual prenatal presentation of megalencephaly-capillary malformation syndrome. PMID- 23754336 TI - Altered expression of MLL methyltransferase family genes in breast cancer. AB - The histone lysine methyltransferases contain a SET domain, which catalyzes the addition of methyl groups to specific lysine residues. The MLL family of genes encodes histone-modifying enzymes with histone 3-lysine 4 methyltransferase activity that can regulate gene transcription. The MLL family exists in multi protein complexes and has been implicated in a variety of processes including normal development and cell growth. Although some of the MLL family members have already been described to be involved in cancer, a clear relationship of these genes with breast cancer is not determined to date. In the present study, we used quantitative PCR to investigate the expression profile of all five MLL genes [MLL (ALL-1), MLL2, MLL3, MLL4 and MLL5] in 7 breast cancer cell lines, 8 breast tumors and adjacent non-tumor tissues and in 12 normal tissues. We observed a diminished expression of all five genes in the breast cancer cell lines when compared to normal breast tissue. We found a significantly decreased expression of MLL2 in the tumor samples compared to the non-tumor controls. In tumor samples, MLL5 also showed a clear suppression tendency. Among the normal tissues analyzed, all genes showed a markedly higher expression in skeletal muscle and brain. Although further studies are required to determine the exact role of these methyltransferases in cancer development, our results indicate that the suppression of MLL genes, especially MLL2 and 5, take part in modulating breast carcinogenesis. Our assessment of the MLL family gene expression patterns in a diverse set of breast cancer cell lines and in a multitude of tissue types and breast tumors should lead to increasingly detailed information on the involvement of these genes in cancer progression. PMID- 23754337 TI - Investigation of the effect of the uneven distribution of CYP3A4 and P glycoprotein in the intestine on the barrier function against xenobiotics: a simulation study. AB - CYP3A4 and P-glycoprotein (P-gp) have similar substrate specificities and work together to form an intestinal absorption barrier against xenobiotics. Previous reports have indicated that CYP3A4 expression decreases gradually, whereas P-gp expression increases, from the upper to lower small intestine. The physiological rationale for this uneven distribution of CYP3A4 and P-gp as a barrier against xenobiotics has not been determined. To clarify the effect of these distribution patterns on barrier function, we constructed a mathematical model that included passive membrane permeation, P-gp-mediated apical efflux, and CYP3A4-mediated metabolism, and we simulated the effects of these distribution patterns on the fraction absorbed of co-substrates without changing their overall activities. The simulation showed that the physiological distribution patterns of both CYP3A4 and P-gp result in the lowest fraction absorbed, but not for drugs with low CYP3A4 and high P-gp-mediated clearances. These results suggest that the distribution pattern of CYP3A4 is especially important for the barrier function. On the other hand, physiological distribution pattern of P-gp exerts the maximum barrier function for dual good substrates for P-gp and CYP3A4, but even distribution of P gp mostly suppresses the intestinal absorption of good P-gp, but poor CYP3A4 substrates. PMID- 23754338 TI - Isolation and characterization of reverse transcriptase fragments of LTR retrotransposons from the genome of Chenopodium quinoa (Amaranthaceae). AB - KEY MESSAGE: High heterogeneity was observed among conserved domains of reverse transcriptase ( rt ) isolated from quinoa. Only one Ty1- copia rt was highly amplified. Reverse transcriptase sequences were located predominantly in pericentromeric region of quinoa chromosomes. The heterogeneity, genomic abundance, and chromosomal distribution of reverse transcriptase (rt)-coding fragments of Ty1-copia and Ty3-gypsy long terminal repeat retrotransposons were analyzed in the Chenopodium quinoa genome. Conserved domains of the rt gene were amplified and characterized using degenerate oligonucleotide primer pairs. Sequence analyses indicated that half of Ty1-copia rt (51 %) and 39 % of Ty3 gypsy rt fragments contained intact reading frames. High heterogeneity among rt sequences was observed for both Ty1-copia and Ty3-gypsy rt amplicons, with Ty1 copia more heterogeneous than Ty3-gypsy. Most of the isolated rt fragments were present in quinoa genome in low copy numbers, with only one highly amplified Ty1 copia rt sequence family. The gypsy-like RNase H fragments co-amplified with Ty1 copia-degenerate primers were shown to be highly amplified in the quinoa genome indicating either higher abundance of some gypsy families of which rt domains could not be amplified, or independent evolution of this gypsy-region in quinoa. Both Ty1-copia and Ty3-gypsy retrotransposons were preferentially located in pericentromeric heterochromatin of quinoa chromosomes. Phylogenetic analyses of newly amplified rt fragments together with well-characterized retrotransposon families from other organisms allowed identification of major lineages of retroelements in the genome of quinoa and provided preliminary insight into their evolutionary dynamics. PMID- 23754339 TI - Parent-based sleep education for children with autism spectrum disorders. AB - This study provided sleep education to parents of children with autism spectrum disorder (ASD) to determine whether an individual or group format was more effective in improving sleep and aspects of daytime behavior and family functioning. Eighty children, ages 2-10 years, with ASD and sleep onset delay completed the study. Actigraphy and parent questionnaires were collected at baseline and 1 month after treatment. Mode of education did not affect outcomes. Sleep latency, insomnia subscales on the Children's Sleep Habits Questionnaire, and other outcomes related to child and family functioning improved with treatment. Parent-based sleep education, delivered in relatively few sessions, was associated with improved sleep onset delay in children with ASD. Group versus individualized education did not affect outcome. PMID- 23754342 TI - Design and synthesis of minimalist terminal alkyne-containing diazirine photo crosslinkers and their incorporation into kinase inhibitors for cell- and tissue based proteome profiling. PMID- 23754340 TI - Atypical neurophysiology underlying episodic and semantic memory in adults with autism spectrum disorder. AB - Individuals with autism spectrum disorder (ASD) show atypicalities in episodic memory (Boucher et al. in Psychological Bulletin, 138 (3), 458-496, 2012). We asked participants to recall the colours of a set of studied line drawings (episodic judgement), or to recognize line drawings alone (semantic judgement). Cycowicz et al. (Journal of Experimental Child Psychology, 65, 171-237, 2001) found early (300 ms onset) posterior old-new event-related potential effects for semantic judgements in typically developing (TD) individuals, and occipitally focused negativity (800 ms onset) for episodic judgements. Our results replicated findings in TD individuals and demonstrate attenuated early old-new effects in ASD. Late posterior negativity was present in the ASD group, but was not specific to this time window. This non-specificity may contribute to the atypical episodic memory judgements characteristic of individuals with ASD. PMID- 23754343 TI - Comparison of nasal sprays and irrigations in the delivery of topical agents to the olfactory mucosa. AB - OBJECTIVES/HYPOTHESIS: Sinonasal diseases are often treated with topical agents administered through various application techniques, but few prior studies have examined their distribution to the olfactory mucosa. The purpose of this study was to compare the distribution of nasal irrigations to sprays within the olfactory cleft. STUDY DESIGN: Human cadaveric study. METHODS: Eight cadaveric heads, providing a total of 15 nasal sides, underwent treatment with methylene blue solution. Application utilized a pressurized spray device followed by an irrigation squeeze bottle, both used according to manufacturer instructions. Videos and images from six standardized anatomical positions were recorded by rigid nasal endoscopy prior to and following each method of agent delivery. Using the acquired images, three reviewers blinded to the means of application scored the approximate surface area stained. An image-analysis program was additionally calibrated and used to measure pixel intensity in order to quantify surface delivery of methylene blue. RESULTS: Based on both blinded reviewer ratings and image pixel intensity measurements, irrigations demonstrated a greater extent and intensity of staining than sprays within the sphenoethmoid recess, superior turbinate, and superior olfactory cleft (all P < 0.05). Sprays and irrigations, however, were comparable in the extent of staining at the nasal vestibule (P > 0.05), inferior turbinate (P = 0.04), and middle turbinate (P > 0.05). CONCLUSIONS: Compared to sprays, irrigations provide a more effective method of delivering topical agents to the posterior and superior aspects of the nasal cavity. The thorough distribution of irrigations has important clinical implications for improving the delivery of therapeutic agents to the olfactory mucosa. PMID- 23754344 TI - Lack of association between IL-23R gene polymorphisms and systemic lupus erythematosus in a Chinese population. AB - OBJECTIVE: The aim to this study was to investigate the association between the single-nucleotide polymorphisms (SNPs) of interleukin (IL)-23 receptor gene and systemic lupus erythematosus (SLE) in a Chinese population. METHODS: A case control study was performed to investigate the associations of SNPs in IL-23R gene (rs10889677 and rs1884444) with susceptibility to SLE in 521 Chinese SLE patients and 527 normal controls. The chi-square test and unconditional Logistic regression were used to analysis by SPSS 10.1 software. RESULTS: No significant differences were detected for the distribution of allele and genotype frequencies of these two SNPs between patients and controls as well as SLE patients with nephritis (LN) and those without nephritis. CONCLUSION: The findings suggest that the polymorphisms of IL-23R gene might not contribute to the susceptibility of SLE in the Chinese population. PMID- 23754345 TI - Invited comment on Hulten et al.: Sacral nerve stimulation (SNS), posterior tibial nerve stimulation (PTNS) or acupuncture for the treatment for fecal incontinence: a clinical commentary. PMID- 23754346 TI - The role of drainage after excision and primary closure of pilonidal sinus: a meta-analysis. AB - We carried out a systematic review of the literature to identify the association between the use of drain and the incidence of infections and recurrences after surgery. MEDLINE, SCOPUS and ISI databases were searched up to September 2012. The two outcomes of this meta-analysis were wound infection and recurrence. Postoperative wound infection occurred in 50 of the 604 (8.28 %) patients who underwent drainage and in 68 of the 598 (11.4 %) patients who did not, with a resulting odds ratio (OR) of 0.71 (95 % CI: 0.48-1.03). Recurrence of pilonidal sinus occurred in 41 of the 604 (6.79 %) patients who underwent drainage and in 50 of the 598 (8.36 %) patients who did not, with a resulting OR of 0.80 (95 % CI: 0.52-1.23). The results suggest that, despite a trend toward a reduction in infectious complications and recurrence, drainage was not associated with a better outcome. However, because of the present literature's limitations, further studies are needed to address this issue. PMID- 23754347 TI - Differential allergenicity of mature and immature pollen grains in Shasta daisy (Chrysanthemum maximum Ramond). AB - Weed pollen grains belonging to the Asteraceae family contain a variety of allergens inducing type I and IV allergies in susceptible people. The aim of this research was to compare the allergenic properties of immature and mature Shasta daisy pollen grains (Chrysanthemum maximum Ramond) to define the potential role of the maturation process on the allergenicity of Asteraceae pollen grains. The immature (IP) and mature pollen (MP) grains were first studied by optical and scanning electron microscopand their protein contents were quantitatively and qualitatively analyzed. Pollen extracts were finally used to sensitize guinea pigs in order to obtain IP and MP specific antibodies. Nasal provocation tests using IP and MP crude extracts were also performed on pre-sensitized guinea pigs. The MP extract induced IgE and eosinophilia in blood and positive skin tests in sensitized guinea pigs. Moreover, high number of eosinophils was found in the nasal mucosa of MP sensitized guinea pigs. SDS-PAGE analysis of the IP and MP protein content showed seven and five apparent bands ranging from 7 to 66kDa respectively. According to immunoblot analysis, MP extract contained a single allergen of 66kDa. The overall results showed developmental processes of Shasta daisy pollen grains towards both morphological and molecular changes increasing their allergenic potency. PMID- 23754348 TI - Raised interleukin-13 levels in cord blood increases the risk of allergic sensitization at 5 years of age. AB - The identification of early markers of atopy in cord blood of newborns at delivery may offer prediction of future allergic sensitization. The aim of this study was to evaluate the relationship between cord blood interleukin-13 (IL-13) and interferon-gamma (IFN-gamma) and development of allergic diseases during the first five years of life. Umbilical cord blood samples were collected at the time of delivery from 62 newborns. The families of these newborns were asked to complete a questionnaire about age and education of parents, number of siblings, allergic diseases in family members, cigarette exposure during pregnancy and presence of pets in their house. The same subjects were evaluated when they were five years old. Venous blood samples were drawn and epidermal skin prick tests were performed. IL-13 and interferon-gamma (IFN-gamma) levels were studied from the blood samples which were taken during birth and five years later. There was no significant relationship between gender, type of delivery, educational levels of parents, exposure to cigarette smoke, atopy in parents, presence of pets in the house and IL-13 and IFN-gamma levels in cord blood and at five years. Higher levels of IL-13 in newborns and five years olds, were found significantly related to skin prick test positivity (p=0.004 and p<0.0001, respectively) and presence of allergic diseases (p= 0.008 and p= 0.001, respectively). Levels of IFN-gamma, both in cord blood and five years after, were not related with the future of allergic status of children. Higher levels of IL-13 in cord blood may be a predictor of future development of allergic sensitization. PMID- 23754349 TI - Is acetaminophen use associated with atopic eczema and other allergic diseases in adolescents? AB - Atopic Eczema (AE) is a chronic inflammatory skin disease that affects children and adults, and alters quality of life. Previous studies have suggested several socio-demographic and environmental factors related to the prevalence of AE and other allergic diseases, including acetaminophen use. In the present study, we report the rates of isolated AE, AE associated with asthma and AE associated with rhinitis among 13- to 14-year-old Spanish adolescents and the level of association of these conditions with the use of acetaminophen. We analyzed Spanish data from a cross-sectional Phase 3 study within ISAAC. A total of 28,717 adolescents completed the Phase 3 written questionnaire by answering questions for acetaminophen use and on asthma, rhinitis and AE symptoms.We observed an association between acetaminophen use and AE among the adolescents who had used acetaminophen in the previous month. Furthermore, the prevalence rate increased with the number of allergic processes: for AE alone, the adjusted Prevalence Ratio (aPR) was 1.81 and for AE associated with rhinitis or with asthma, aPRs were 2.20 and 3.03, respectively.We conclude that acetaminophen use in childhood may be an important factor associated with development and/or maintenance of AE and other allergic diseases. PMID- 23754350 TI - Remission of childhood asthma after entering the second decade of life: a hospital based cohort. AB - Asthma is the most common chronic disease in children. The natural history of asthma is often characterized by periods of remission and relapse. The aim of this study was to determine the remission rate of asthmatic children after entering the second decade of life and remission related factors in a hospital based cohort.The study population was asthmatic children who were diagnosed, registered and followed up in outpatient pediatric clinic of a university hospital in Ahvaz, Iran. Remission was assessed in the age of 11 to 15 years-old if >= 5 years passed from the time of diagnosis. Clinical remission was defined as the absence of asthma symptoms for at least one year without the use of inhaled corticosteroids and short acting beta2 agonists.In the cases with clinical remission, spirometry and exercise tests were conducted to document complete remission. The study included 197 adolescents (mean age of 13.1+/-1.9 years). Clinical remissions were found in 71 cases (%36) but according to spirometry criteria, 65 children (33%) were in complete remission. There was no significant difference between the genders. The remission rate was positively correlated with age of onset, and inversely correlated with family history of asthma, atopic dermatitis, hospitalization due to asthma, passive smoking and the need to use long-term inhaled corticosteroid.Based on this study, approximately one third of asthmatic children showed remission up to 15 years of age which is a moderate rate compared to other studies. PMID- 23754351 TI - No direct association among respiratory function, disease control and family functioning in a sample of Mexican children with intermittent asthma. AB - Asthma has been linked to family disfunctioning and poor control of the disease.This study was conducted to analyze the interactions between the level of intermittent asthma control, family functioning and respiratory function and between quality of life of asthmatic patients and their caregivers.7 to 15 years old children with intermittent asthma were included. Asthma Control Test Questionnaire, Pediatric Asthma Quality of Life Questionnaire (PAQLQ) test, and flowmetry were applied to children and Pediatric Asthma Caregiver's Quatily of Life Questionnaire (PAQCLQ) and the Family Functioning Perception Test (FF-SIL) were applied to their parents.The most affected areas of family functioning in dysfunctional families were adaptability and permeability. A medium to high strength of association was founded between the emotional function of parents and the emotional function of children, R2=0.552. The most remarkable associations were among parents' limitation of activities and parents' emotional function (r=0.837), parents' limitation of activities and child's emotional function (r=0.722), parents' emotional role and limitation of activities (r=0.837), parents' emotional role and emotional functioning of children with asthma (r=0.743) and the limitation of activities of children with asthma and the emotional function of children with asthma (r=0.870).No direct associations were founded among respiratory function, disease control and family functioning in Mexican children with intermittent asthma and emotional function of parents and children were associated in both groups. PMID- 23754352 TI - The main relaxant constituents of Nigella sativa methanolic fraction on Guinea pig tracheal chains. AB - Our previous studies demonstrated the preventive effect of Nigella sativa extract on asthma and water-soluble substances of this extract, especially its methanol fraction were responsible for this relaxation on contracted tracheal chains of guinea pigs. For the first time, the present study has been conducted to determine the main constituents of its methanolic extract. Four constituents of 20%-methanolic fraction, consisting of two flavonoids (20-20% and 21-20% fractions) and two polysaccharides (1-20% and 2-20% fractions), were purified by analytical and preparative HPLC. The relaxant effects of four cumulative concentrations of each constituent (50, 100, 150 and 200 mg/lit) in comparison with saline (1 ml) as negative control and four cumulative concentrations of theophylline (0.2, 0.4, 0.6 and 0.8 mM) as positive control were examined on methacholine-precontracted guinea pig tracheal chains (n=6). All concentrations of theophylline and most concentrations of 20-20, 21-20 fractions showed significant relaxant effects compared to that of saline. 20-20 fraction (Comferol diglucoside) was the most potent bronchodilator. Their relaxant effects were lower than that of theophylline. Polysaccharides (1-20, 2-20 fractions) did not have any relaxant effects compared to that of saline. These results revealed that two flavonoids of 20%-methanolic fraction of Nigella sativa were its main relaxant constituents. PMID- 23754353 TI - Increased expression of transforming growth factor-beta and receptors in primary human airway fibroblasts from chemical inhalation patients. AB - The widespread use of sulfur mustard (SM) as a chemical warfare agent in the past century has proved its long-lasting toxic effects. Despite a lot of research over the past decades on Iranian veterans, there are still major gaps in the SM literature. Transforming growth factor (TGF-beta), a cytokine that affects many different cell processes, has an important role in the lungs of patients with some of chronic airway diseases, especially with respect to airway remodeling in mustard lung. Primary airway fibroblasts from epibronchial biopsies were cultured, and gene expression of TGF-beta1, TGF-beta2, TbR-I and TbR-II in fibroblasts of SM injured patients and controls were investigated. Expression of TGF-betas and receptors was measured by RT-PCR. Protein level of TGF-beta1 was surveyed by western blot. Our findings revealed that expression levels of TGF beta1, TGF-beta2, TbR-I and TbR-II were upregulated in the airway fibroblasts of SM exposed patients in comparison with control samples. TGF-beta1 expression was shown to be markedly increased in primary lung fibroblasts of chemically injured patients. Our novel data, suggested that over-expression of TGF-beta molecule and receptors in primary airway fibroblasts of mustard gas injured patients may be involved in progression of airway remodeling of these patients. PMID- 23754354 TI - Downregulation of super oxide dismutase level in protein might be due to sulfur mustard induced toxicity in lung. AB - Sulfur mustard (SM) has been identified as an important chemical weapon. During the Iran-Iraq war of 1980-88, the extensive usage of SM against Iranian civilians and military forces was proven. This agent has been shown to cause severe damage mainly in the skin, eyes, lungs, and respiratory tract in Iranian veterans. The most common disease is bronchiolitis obliterans (BO)). SM increases the endogenous production of reactive oxygen species (ROS). Superoxide dismutases (SODs) are known as protective antioxidants against the harmful effects of ROS. Twenty exposed SM individuals (43.2+/-6.4 years), and 10 normal controls (41.3+/ 2.5 years) were enrolled in this study. Evaluation of SODs was performed by semiquantitative RT-PCR and immunohistochemistry. Our results demonstrated that CuZnSOD and MnSOD mRNA were up-regulated 2.79+/-1.09 and 2.49+/-1.11 folds, respectively in SM-injured patients in comparison with control levels. In contrast, Immunohistochemistry results showed downregulation of CuZnSOD protein expression in SM injured patients. Our results revealed that SODs may play an important role in cellular protection against oxidative stress due to mustard gas toxicity in airway wall of SM exposed patients. PMID- 23754355 TI - Effect of toll-like receptor 3 agonists on the functionality and metastatic properties of breast cancer cell model. AB - There exists compelling evidence that Toll-like receptor 3 (TLR3) agonists can directly affect human cancer cells. The aim of this study was to investigate anti cancer effects of TLR3 agonist in human breast cell line. We assessed potential effects of poly (A:U) on human breast cell line (MDA-MB-231) on a dose-response and time-course basis. Human breast cell line MDA-MB-231 was treated with different concentrations of poly (A:U) and lipopolysaccharide (LPS). Then, the following assays were performed on the treated cells: dose-response and time course cytotoxicity using colorimetric method; matrix metalloproteinase-2 (MMP-2) activity using gelatin zymography method; apoptosis using annexin-v flowcytometry method; and relative expression of TLR3 and MMP-2 mRNA using reverse transcriptase polymerase chain reaction (RT-PCR) method. Following treatments, dose- response and time-course cytotoxicity using a colorimetric method, (MMP-2) activity (using gelatin zymography), apoptosis (using annexin-v flowcytometry method) assays and expression of TLR3 and MMP-2 genes (using PCR method) were performed. Cytotoxicity and flowcytometry analysis of poly (A:U) showed that poly (A:U) do not have any cytotoxic and apoptotic effects in different concentrations used. MMP-2 activity analysis showed significant decrease in higher concentrations (50 and 100 MUg/ ml) between treated and untreated cells. Moreover, poly A:U treated cells demonstrated decreased expression of MMP-2 gene in higher concentrations. Collectively, our data indicated that human breast cancer cell line (MDA-MB-231) was highly responsive to poly (A:U). The antimetastatic effect of direct poly (A:U) and TLR3 interactions in MDA-MB-231 cells could provide new approaches in malignant tumor therapeutic strategy. PMID- 23754356 TI - Th1/Th2 cytokines in patients with Graves' disease with or without ophthalmopathy. AB - About 25-50% of Graves' disease (GD) patients develop thyroid eye diseases, which is associated with inflammatory process and abnormalities in the levels of several cytokines in orbital tissues in GD. The aim of this study was to determine the Th1 and Th2 serum cytokines in patients with GD with or without ophthalmopathy. Serum levels of cytokines and autoantibodies including Interferon gamma (IFN-gamma), Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-10 (IL 10), TSH receptor autoantibody (TRAb), thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody(TgAb) were measured by enzyme linked immunosorbent assay(ELISA) in 34 patients with GD and in 33 normal controls. Patients were also divided in two subgroups: 18 cases with ophthalmopathy and 16 cases without ophthalmopathy. Cytokine and antibody responses were analyzed in both groups. Compared with control subjects, patients with GD showed elevated levels of IL-2 and IL-10. IFN-gamma levels were lower in patients in comparison to the controls. No significant differences were found between patients and controls regarding the IL-4. There was no statistically significant difference in cytokine levels between those with or without ophthalmopathy. Quantitative-cytokine analysis demonstrated that a combination of Th1 and Th2 cytokines may contribute to the pathogenesis of GD. These results also indicate that IL-10, but not IL-4, is related to the moderate and severe forms of thyroid associated ophthalmophathy. PMID- 23754357 TI - Psychiatric aspects of primary immunodeficiency diseases: the parental study. AB - Primary immunodeficiency diseases (PID) consist of a group of long-term illnesses which had permanent psychiatric effects on the patients and their parents. This study was designed to find out the most important origins and aspects of stressor in parents of PID patients.To assess the impact of psychiatric aspects in parents of PID patients, a valid and reliable questionnaire was compiled based on patients' complaints and consulting professionals in PID and psychology.Fathers of 26 PID patients (17 male and 9 female) were enrolled in this study. According to the result of this study, anxiety for long duration of disease of child (mean score= 4.42), anxiety for incurable diseases of child (mean score=4.23) and anxiety for side effects and complication of treatments on child (mean score=4.08) were the most important stressors of parents.The comparison between specific PID groups showed that there were significant differences between total score of groups (XLA= 92.8+/-31.2, CVID=78.7+/-19.5 and other types of PID= 90.7+/-22.5, p-value =0.37).Survey for finding fundamental stressors and continuation of psychological counseling are necessary to achieve successful management of PID patients and their parents. PMID- 23754358 TI - The relation of multiple sclerosis with allergy and atopy: a case control study. AB - Multiple Sclerosis (MS) and Allergy are believed to up regulate T helper cell type 1 (Th1) and T helper cell type 2 (Th2) responses, respectively. It has been shown that disequilibrium in the ratio of Th1/Th2 activities may increase frequency of one disease and decrease the frequency of the other. The aim of this study was to investigate the relation of MS with allergy and atopy in new diagnosed MS patients. This case-control study was conducted on 40 new diagnosed MS patients and the same number of normal controls. All of the patients were diagnosed (according to McDonald criteria) at most 2 years prior to the study. Demographic data and clinical characteristics of both groups were recorded in a questionnaire. The total IgE and allergen specific IgE in the serum were measured in all the cases. Forty MS patients (female/male: 4.71) with mean age of 30.55+/ 9.5 years and 40 healthy controls entered in this study. History of allergy was observed in 20(50%) of MS patients (including 15 (37.5%) rhinitis, 6 (15%) conjunctivitis, 3 (7.5%) urticaria and eczema, 1 (2.5%) asthma), and 20 (50%) of the controls (including 8 (20%) rhinitis, 4 (10%) conjunctivitis, 7 (17.5%) urticaria and eczema, 1 (2.5%) asthma). The differences between the two groups were not statistically significant. Neither the serum total IgE, nor the frequency of specific IgE against Weed mix, Grass Mix, Tree mix1, Tree mix 2, Dermatophagoides Farinae, Dermatophagoides pteronyssinus and Epidermal and animal proteins mix differed statistically between the two groups. There was also no significant relationship between MS clinical manifestations and allergy prevalence and also between MS and atopy. The results of this study as some other similar studies showed the same prevalence of allergy in MS patients and controls and also demonstrated no relation between MS and atopy. PMID- 23754359 TI - Factors affecting the severity of cow's milk anaphylaxis. PMID- 23754360 TI - Immunogenicity assessment of Brucella mellitensis HSP and TF proteins by immunized rabbit serum. PMID- 23754362 TI - Gr-1(high) CD11b+ cells suppress B cell differentiation and lupus-like disease in lupus-prone male mice. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) develops much more readily in females than in males. Previous research has focused primarily on identifying mechanisms pertinent to the pathology in females. The aim of the current study was to delineate active protective mechanisms in males. We present evidence of a new male-associated mechanism of protection against the development of lupus-like disease in lupus-prone (NZB * NZW)F1 mice. METHODS: We identified previously uncharacterized cellular and functional differences in myeloid cells between male and female (NZB * NZW)F1 mice, with the use of flow cytometry, confocal imaging, in vivo antibody-mediated depletion, and in vitro cell coculture assays. RESULTS: A population of Gr-1(high) Ly-6G+CD11b+ myeloid cells was found to be constitutively increased in male (NZB * NZW)F1 mice as compared with female mice and was regulated by testosterone. The cells were located adjacent to spleen B cell follicles in vivo and were found to directly inhibit cytokine-induced differentiation of naive B cells into antibody-secreting cells in vitro. Most notably, treatment with anti-Gr-1-depleting antibodies increased the spontaneous production of antinuclear autoantibodies in male (NZB * NZW)F1 mice, while a similar approach in female mice had no effect on disease development. CONCLUSION: Male lupus-prone (NZB * NZW)F1 mice harbor elevated levels of a population of myeloid cells with pronounced immunosuppressive capacities that specifically target B cells and the production of antibodies in vivo. We suggest that these cells represent a male-driven inhibitory mechanism involved in the control of B cell pathogenesis, delaying (or preventing) lupus-like disease development in otherwise genetically predisposed male (NZB * NZW)F1 mice. PMID- 23754363 TI - Osmotic stress does not trigger brevetoxin production in the dinoflagellate Karenia brevis. AB - With the global proliferation of toxic harmful algal bloom species, there is a need to identify the environmental and biological factors that regulate toxin production. One such species, Karenia brevis, forms nearly annual blooms that threaten coastal regions throughout the Gulf of Mexico. This dinoflagellate produces brevetoxins, which are potent neurotoxins that cause neurotoxic shellfish poisoning and respiratory illness in humans, as well as massive fish kills. A recent publication reported that a rapid decrease in salinity increased cellular toxin quotas in K. brevis and hypothesized that brevetoxins serve a role in osmoregulation. This finding implied that salinity shifts could significantly alter the toxic effects of blooms. We repeated the original experiments separately in three different laboratories and found no evidence for increased brevetoxin production in response to low-salinity stress in any of the eight K. brevis strains we tested, including three used in the original study. Thus, we find no support for an osmoregulatory function of brevetoxins. The original publication also stated that there was no known cellular function for brevetoxins. However, there is increasing evidence that brevetoxins promote survival of the dinoflagellates by deterring grazing by zooplankton. Whether they have other as-yet-unidentified cellular functions is currently unknown. PMID- 23754364 TI - Osmotic stress does trigger brevetoxin production in the dinoflagellate Karenia brevis. PMID- 23754365 TI - Cultivated hay and fallow/idle cropland confound analysis of grassland conversion in the Western Corn Belt. PMID- 23754366 TI - Interpreting the evidence for middle Holocene gene flow from India to Australia. PMID- 23754367 TI - Entropic forces between fluid layers. PMID- 23754368 TI - Improved empirical tests of area-heterogeneity tradeoffs. PMID- 23754369 TI - Orientation-specific responses to sustained uniaxial stretching in focal adhesion growth and turnover. AB - Cells are mechanosensitive to extracellular matrix (ECM) deformation, which can be caused by muscle contraction or changes in hydrostatic pressure. Focal adhesions (FAs) mediate the linkage between the cell and the ECM and initiate mechanically stimulated signaling events. We developed a stretching apparatus in which cells grown on fibronectin-coated elastic substrates can be stretched and imaged live to study how FAs dynamically respond to ECM deformation. Human bone osteosarcoma epithelial cell line U2OS was transfected with GFP-paxillin as an FA marker and subjected to sustained uniaxial stretching. Two responses at different timescales were observed: rapid FA growth within seconds after stretching, and delayed FA disassembly and loss of cell polarity that occurred over tens of minutes. Rapid FA growth occurred in all cells; however, delayed responses to stretch occurred in an orientation-specific manner, specifically in cells with their long axes perpendicular to the stretching direction, but not in cells with their long axes parallel to stretch. Pharmacological treatments demonstrated that FA kinase (FAK) promotes but Src inhibits rapid FA growth, whereas FAK, Src, and calpain 2 all contribute to delayed FA disassembly and loss of polarity in cells perpendicular to stretching. Immunostaining for phospho-FAK after stretching revealed that FAK activation was maximal at 5 s after stretching, specifically in FAs oriented perpendicular to stretch. We hypothesize that orientation-specific activation of strain/stress-sensitive proteins in FAs upstream to FAK and Src promote orientation-specific responses in FA growth and disassembly that mediate polarity rearrangement in response to sustained stretch. PMID- 23754370 TI - Evolution of consciousness: phylogeny, ontogeny, and emergence from general anesthesia. AB - Are animals conscious? If so, when did consciousness evolve? We address these long-standing and essential questions using a modern neuroscientific approach that draws on diverse fields such as consciousness studies, evolutionary neurobiology, animal psychology, and anesthesiology. We propose that the stepwise emergence from general anesthesia can serve as a reproducible model to study the evolution of consciousness across various species and use current data from anesthesiology to shed light on the phylogeny of consciousness. Ultimately, we conclude that the neurobiological structure of the vertebrate central nervous system is evolutionarily ancient and highly conserved across species and that the basic neurophysiologic mechanisms supporting consciousness in humans are found at the earliest points of vertebrate brain evolution. Thus, in agreement with Darwin's insight and the recent "Cambridge Declaration on Consciousness in Non Human Animals," a review of modern scientific data suggests that the differences between species in terms of the ability to experience the world is one of degree and not kind. PMID- 23754371 TI - In vivo single branch axotomy induces GAP-43-dependent sprouting and synaptic remodeling in cerebellar cortex. AB - Plasticity in the central nervous system in response to injury is a complex process involving axonal remodeling regulated by specific molecular pathways. Here, we dissected the role of growth-associated protein 43 (GAP-43; also known as neuromodulin and B-50) in axonal structural plasticity by using, as a model, climbing fibers. Single axonal branches were dissected by laser axotomy, avoiding collateral damage to the adjacent dendrite and the formation of a persistent glial scar. Despite the very small denervated area, the injured axons consistently reshape the connectivity with surrounding neurons. At the same time, adult climbing fibers react by sprouting new branches through the intact surroundings. Newly formed branches presented varicosities, suggesting that new axons were more than just exploratory sprouts. Correlative light and electron microscopy reveals that the sprouted branch contains large numbers of vesicles, with varicosities in the close vicinity of Purkinje dendrites. By using an RNA interference approach, we found that downregulating GAP-43 causes a significant increase in the turnover of presynaptic boutons. In addition, silencing hampers the generation of reactive sprouts. Our findings show the requirement of GAP-43 in sustaining synaptic stability and promoting the initiation of axonal regrowth. PMID- 23754372 TI - Similarity in form and function of the hippocampus in rodents, monkeys, and humans. AB - We begin by describing an historical scientific debate in which the fundamental idea that species are related by evolutionary descent was challenged. The challenge was based on supposed neuroanatomical differences between humans and other primates with respect to a structure known then as the hippocampus minor. The debate took place in the early 1860 s, just after the publication of Darwin's famous book. We then recount the difficult road that was traveled to develop an animal model of human memory impairment, a matter that also turned on questions about similarities and differences between humans and other primates. We then describe how the insight that there are multiple memory systems helped to secure the animal model and how the animal model was ultimately used to identify the neuroanatomy of long-term declarative memory (sometimes termed explicit memory). Finally, we describe a challenge to the animal model and to cross-species comparisons by considering the case of the concurrent discrimination task, drawing on findings from humans and monkeys. We suggest that analysis of such cases, based on the understanding that there are multiple memory systems with different properties, has served to emphasize the similarities in memory function across mammalian species. PMID- 23754374 TI - Hypoxic survival requires a 2-on-2 hemoglobin in a process involving nitric oxide. AB - Hemoglobins are recognized today as a diverse family of proteins present in all kingdoms of life and performing multiple reactions beyond O2 chemistry. The physiological roles of most hemoglobins remain elusive. Here, we show that a 2-on 2 ("truncated") hemoglobin, termed THB8, is required for hypoxic growth and the expression of anaerobic genes in Chlamydomonas reinhardtii. THB8 is 1 of 12 2-on 2 hemoglobins in this species. It belongs to a subclass within the 2-on-2 hemoglobin class I family whose members feature a remarkable variety of domain arrangements and lengths. Posttranscriptional silencing of the THB8 gene results in the mis-regulation of several genes and a growth defect under hypoxic conditions. The latter is intensified in the presence of an NO scavenger, which also impairs growth of wild-type cells. As recombinant THB8 furthermore reacts with NO, the results of this study indicate that THB8 is part of an NO-dependent signaling pathway. PMID- 23754373 TI - From perception to pleasure: music and its neural substrates. AB - Music has existed in human societies since prehistory, perhaps because it allows expression and regulation of emotion and evokes pleasure. In this review, we present findings from cognitive neuroscience that bear on the question of how we get from perception of sound patterns to pleasurable responses. First, we identify some of the auditory cortical circuits that are responsible for encoding and storing tonal patterns and discuss evidence that cortical loops between auditory and frontal cortices are important for maintaining musical information in working memory and for the recognition of structural regularities in musical patterns, which then lead to expectancies. Second, we review evidence concerning the mesolimbic striatal system and its involvement in reward, motivation, and pleasure in other domains. Recent data indicate that this dopaminergic system mediates pleasure associated with music; specifically, reward value for music can be coded by activity levels in the nucleus accumbens, whose functional connectivity with auditory and frontal areas increases as a function of increasing musical reward. We propose that pleasure in music arises from interactions between cortical loops that enable predictions and expectancies to emerge from sound patterns and subcortical systems responsible for reward and valuation. PMID- 23754375 TI - Crystal structure of the Golgi casein kinase. AB - The family with sequence similarity 20 (Fam20) kinases phosphorylate extracellular substrates and play important roles in biomineralization. Fam20C is the Golgi casein kinase that phosphorylates secretory pathway proteins within Ser x-Glu/pSer motifs. Mutations in Fam20C cause Raine syndrome, an osteosclerotic bone dysplasia. Here we report the crystal structure of the Fam20C ortholog from Caenorhabditis elegans. The nucleotide-free and Mn/ADP-bound structures unveil an atypical protein kinase-like fold and highlight residues critical for activity. The position of the regulatory alphaC helix and the lack of an activation loop indicate an architecture primed for efficient catalysis. Furthermore, several distinct elements, including the presence of disulfide bonds, suggest that the Fam20 family diverged early in the evolution of the protein kinase superfamily. Our results reinforce the structural diversity of protein kinases and have important implications for patients with disorders of biomineralization. PMID- 23754376 TI - FIGNL1-containing protein complex is required for efficient homologous recombination repair. AB - The RAD51 recombinase plays a central role in homologous recombination (HR), which is critical for repair of DNA double-strand breaks, maintenance of genomic stability, and prevention of developmental disorders and cancer. Here, we report the identification of an RAD51-binding protein fidgetin-like 1 (FIGNL1). FIGNL1 specifically interacts with RAD51 through its conserved RAD51 binding domain. Cells depleted of FIGNL1 show defective HR repair. Interestingly, FIGNL1 is recruited to sites of DNA damage in a manner that is independent of breast cancer 2, early onset, RAD51, and probably, RAD51 paralogs. Conversely, FIGNL1 depletion does not affect the loading of RAD51 onto ssDNA. Our additional analysis uncovered KIAA0146, also known as scaffolding protein involved in DNA repair (SPIDR), as a binding partner of FIGNL1 and established that KIAA0146/SPIDR acts with FIGNL1 in HR repair. Collectively, our study uncovers a protein complex, which consists of FIGNL1 and KIAA0146/SPIDR, in DNA repair and provides potential directions for cancer diagnosis and therapy. PMID- 23754377 TI - Outsourcing CO2 within China. AB - Recent studies have shown that the high standard of living enjoyed by people in the richest countries often comes at the expense of CO2 emissions produced with technologies of low efficiency in less affluent, developing countries. Less apparent is that this relationship between developed and developing can exist within a single country's borders, with rich regions consuming and exporting high value goods and services that depend upon production of low-cost and emission intensive goods and services from poorer regions in the same country. As the world's largest emitter of CO2, China is a prominent and important example, struggling to balance rapid economic growth and environmental sustainability across provinces that are in very different stages of development. In this study, we track CO2 emissions embodied in products traded among Chinese provinces and internationally. We find that 57% of China's emissions are related to goods that are consumed outside of the province where they are produced. For instance, up to 80% of the emissions related to goods consumed in the highly developed coastal provinces are imported from less developed provinces in central and western China where many low-value-added but high-carbon-intensive goods are produced. Without policy attention to this sort of interprovincial carbon leakage, the less developed provinces will struggle to meet their emissions intensity targets, whereas the more developed provinces might achieve their own targets by further outsourcing. Consumption-based accounting of emissions can thus inform effective and equitable climate policy within China. PMID- 23754378 TI - Interplay between insulin signaling, juvenile hormone, and vitellogenin regulates maternal effects on polyphenism in ants. AB - Polyphenism is the phenomenon in which alternative phenotypes are produced by a single genotype in response to environmental cues. An extreme case is found in social insects, in which reproductive queens and sterile workers that greatly differ in morphology and behavior can arise from a single genotype. Experimental evidence for maternal effects on caste determination, the differential larval development toward the queen or worker caste, was recently documented in Pogonomyrmex seed harvester ants, in which only colonies with a hibernated queen produce new queens. However, the proximate mechanisms behind these intergenerational effects have remained elusive. We used a combination of artificial hibernation, hormonal treatments, gene expression analyses, hormone measurements, and vitellogenin quantification to investigate how the combined effect of environmental cues and hormonal signaling affects the process of caste determination in Pogonomyrmex rugosus. The results show that the interplay between insulin signaling, juvenile hormone, and vitellogenin regulates maternal effects on the production of alternative phenotypes and set vitellogenin as a likely key player in the intergenerational transmission of information. This study reveals how hibernation triggers the production of new queens in Pogonomyrmex ant colonies. More generally, it provides important information on maternal effects by showing how environmental cues experienced by one generation can translate into phenotypic variation in the next generation. PMID- 23754379 TI - Inflammatory monocytes and Fcgamma receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice. AB - Destruction of bone tissue by osteoclasts represents a severe pathological phenotype during inflammatory arthritis and results in joint pain and bone malformations. Previous studies have established the essential role of cytokines including TNFalpha and receptor-ligand interactions, such as the receptor activator of nuclear factor-kappa B-receptor activator of nuclear factor-kappa B ligand interaction for osteoclast formation during joint inflammation. Moreover, autoantibodies contribute to joint inflammation in inflammatory arthritis by triggering cellular fragment crystallizable (Fc)gamma receptors (FcgammaR), resulting in the release of proinflammatory cytokines and chemokines essential for recruitment and activation of innate immune effector cells. In contrast, little is known about the expression pattern and function of different FcgammaRs during osteoclast differentiation. This would allow osteoclasts to directly interact with autoantibody immune complexes, rather than being influenced indirectly via proinflammatory cytokines released upon immune complex binding to other FcgammaR-expressing innate immune cells. To address this question, we studied FcgammaR expression and function on osteoclasts during the steady state and during acute joint inflammation in a model of inflammatory arthritis. Our results suggest that osteoclastogenesis is directly influenced by IgG autoantibody binding to select activating FcgammaRs on immature osteoclasts, resulting in enhanced osteoclast generation and, ultimately, bone destruction. PMID- 23754380 TI - Strain history dependence of the nonlinear stress response of fibrin and collagen networks. AB - We show that the nonlinear mechanical response of networks formed from un-cross linked fibrin or collagen type I continually changes in response to repeated large-strain loading. We demonstrate that this dynamic evolution of the mechanical response arises from a shift of a characteristic nonlinear stress strain relationship to higher strains. Therefore, the imposed loading does not weaken the underlying matrices but instead delays the occurrence of the strain stiffening. Using confocal microscopy, we present direct evidence that this behavior results from persistent lengthening of individual fibers caused by an interplay between fiber stretching and fiber buckling when the networks are repeatedly strained. Moreover, we show that covalent cross-linking of fibrin or collagen inhibits the shift of the nonlinear material response, suggesting that the molecular origin of individual fiber lengthening may be slip of monomers within the fibers. Thus, a fibrous architecture in combination with constituents that exhibit internal plasticity creates a material whose mechanical response adapts to external loading conditions. This design principle may be useful to engineer novel materials with this capability. PMID- 23754381 TI - Structure and superorganization of acetylcholine receptor-rapsyn complexes. AB - The scaffolding protein at the neuromuscular junction, rapsyn, enables clustering of nicotinic acetylcholine receptors in high concentration and is critical for muscle function. Patients with insufficient receptor clustering suffer from muscle weakness. However, the detailed organization of the receptor-rapsyn network is poorly understood: it is unclear whether rapsyn first forms a wide meshwork to which receptors can subsequently dock or whether it only forms short bridges linking receptors together to make a large cluster. Furthermore, the number of rapsyn-binding sites per receptor (a heteropentamer) has been controversial. Here, we show by cryoelectron tomography and subtomogram averaging of Torpedo postsynaptic membrane that receptors are connected by up to three rapsyn bridges, the minimum number required to form a 2D network. Half of the receptors belong to rapsyn-connected groups comprising between two and fourteen receptors. Our results provide a structural basis for explaining the stability and low diffusion of receptors within clusters. PMID- 23754382 TI - Filter gate closure inhibits ion but not water transport through potassium channels. AB - The selectivity filter of K(+) channels is conserved throughout all kingdoms of life. Carbonyl groups of highly conserved amino acids point toward the lumen to act as surrogates for the water molecules of K(+) hydration. Ion conductivity is abrogated if some of these carbonyl groups flip out of the lumen, which happens (i) in the process of C-type inactivation or (ii) during filter collapse in the absence of K(+). Here, we show that K(+) channels remain permeable to water, even after entering such an electrically silent conformation. We reconstituted fluorescently labeled and constitutively open mutants of the bacterial K(+) channel KcsA into lipid vesicles that were either C-type inactivating or noninactivating. Fluorescence correlation spectroscopy allowed us to count both the number of proteoliposomes and the number of protein-containing micelles after solubilization, providing the number of reconstituted channels per proteoliposome. Quantification of the per-channel increment in proteoliposome water permeability with the aid of stopped-flow experiments yielded a unitary water permeability pf of (6.9 +/- 0.6) * 10(-13) cm(3)?s(-1) for both mutants. "Collapse" of the selectivity filter upon K(+) removal did not alter pf and was fully reversible, as demonstrated by current measurements through planar bilayers in a K(+)-containing medium to which K(+)-free proteoliposomes were fused. Water flow through KcsA is halved by 200 mM K(+) in the aqueous solution, which indicates an effective K(+) dissociation constant in that range for a singly occupied channel. This questions the widely accepted hypothesis that multiple K(+) ions in the selectivity filter act to mutually destabilize binding. PMID- 23754383 TI - Computational analysis of anti-HIV-1 antibody neutralization panel data to identify potential functional epitope residues. AB - Advances in single-cell antibody cloning methods have led to the identification of a variety of broadly neutralizing anti-HIV-1 antibodies. We developed a computational tool (Antibody Database) to help identify critical residues on the HIV-1 envelope protein whose natural variation affects antibody activity. Our simplifying assumption was that, for a given antibody, a significant portion of the dispersion of neutralization activity across a panel of HIV-1 strains is due to the amino acid identity or glycosylation state at a small number of specific sites, each acting independently. A model of an antibody's neutralization IC50 was developed in which each site contributes a term to the logarithm of the modeled IC50. The analysis program attempts to determine the set of rules that minimizes the sum of the residuals between observed and modeled IC50 values. The predictive quality of the identified rules may be assessed in part by whether there is support for rules within individual viral clades. As a test case, we analyzed antibody 8ANC195, an anti-glycoprotein gp120 antibody of unknown specificity. The model for this antibody indicated that several glycosylation sites were critical for neutralization. We evaluated this prediction by measuring neutralization potencies of 8ANC195 against HIV-1 in vitro and in an antibody therapy experiment in humanized mice. These experiments confirmed that 8ANC195 represents a distinct class of glycan-dependent anti-HIV-1 antibody and validated the utility of computational analysis of neutralization panel data. PMID- 23754384 TI - Single dose of L-dopa makes extinction memories context-independent and prevents the return of fear. AB - Traumatic events can engender persistent excessive fear responses to trauma reminders that may return even after successful treatment. Extinction, the laboratory analog of behavior therapy, does not erase conditioned fear memories but generates competing, fear-inhibitory "extinction memories" that, however, are tied to the context in which extinction occurred. Accordingly, a dominance of fear over extinction memory expression--and, thus, return of fear--is often observed if extinguished fear stimuli are encountered outside the extinction (therapy) context. We show that postextinction administration of the dopamine precursor L-dopa makes extinction memories context-independent, thus strongly reducing the return of fear in both mice and humans. Reduced fear is accompanied by decreased amygdala and enhanced ventromedial prefrontal cortex activation in both species. In humans, ventromedial prefrontal cortex activity is predicted by enhanced resting-state functional coupling of the area with the dopaminergic midbrain during the postextinction consolidation phase. Our data suggest that dopamine-dependent boosting of extinction memory consolidation is a promising avenue to improving anxiety therapy. PMID- 23754385 TI - Use of mutant 125I-perfringolysin O to probe transport and organization of cholesterol in membranes of animal cells. AB - Animal cells strictly control the distribution of cholesterol in their organelle membranes. This regulation requires an efficient machinery to transport insoluble cholesterol between organelles. In the present study, we generate an (125)I labeled mutant version of Perfringolysin O (PFO), a cholesterol-binding protein, and use it to measure cholesterol in the plasma membrane of intact cells. We also purify plasma membranes from the same cells, which allows us to directly relate cholesterol concentration to (125)I-PFO binding. We show that cholesterol is organized in the plasma membrane in a manner that makes it inaccessible to PFO until its concentration exceeds a threshold of 35 mol% of total lipids. This 35% threshold is in striking contrast to the 5% threshold previously found for PFO binding to endoplasmic reticulum membranes. The (125)I-PFO probe also proved useful in monitoring the movement of LDL-derived cholesterol from lysosomes to plasma membranes. Using three different mutant cell lines, we show that this transport requires receptor-mediated uptake of LDL, hydrolysis of LDL-cholesteryl esters in lysosomes, and transfer of the liberated cholesterol to the plasma membrane. PMID- 23754386 TI - Effects of oncogenic mutations on the conformational free-energy landscape of EGFR kinase. AB - Activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase are frequently found in many cancers. It has been suggested that changes in the equilibrium between its active and inactive conformations are linked to its oncogenic potential. Here, we quantify the effects of some of the most common single (L858R and T790M) and double (T790M-L858R) oncogenic mutations on the conformational free-energy landscape of the EGFR kinase domain by using massive molecular dynamics simulations together with parallel tempering, metadynamics, and one of the best force-fields available. Whereas the wild-type EGFR catalytic domain monomer is mostly found in an inactive conformation, our results show a clear shift toward the active conformation for all of the mutants. The L858R mutation stabilizes the active conformation at the expense of the inactive conformation and rigidifies the alphaC-helix. The T790M gatekeeper mutant favors activation by stabilizing a hydrophobic cluster. Finally, T790M with L858R shows a significant positive epistasis effect. This combination not only stabilizes the active conformation, but in nontrivial ways changes the free-energy landscape lowering the transition barriers. PMID- 23754387 TI - Metabolic signatures of amyotrophic lateral sclerosis reveal insights into disease pathogenesis. AB - Metabolic dysfunction is an important modulator of disease course in amyotrophic lateral sclerosis (ALS). We report here that a familial mouse model (transgenic mice over-expressing the G93A mutation of the Cu/Zn superoxide dismutase 1 gene) of ALS enters a progressive state of acidosis that is associated with several metabolic (hormonal) alternations that favor lipolysis. Extensive investigation of the major determinants of H(+) concentration (i.e., the strong ion difference and the strong ion gap) suggests that acidosis is also due in part to the presence of an unknown anion. Consistent with a compensatory response to avert pathological acidosis, ALS mice harbor increased accumulation of glycogen in CNS and visceral tissues. The altered glycogen is associated with fluctuations in lysosomal and neutral alpha-glucosidase activities. Disease-related changes in glycogen, glucose, and alpha-glucosidase activity are also found in spinal cord tissue samples of autopsied patients with ALS. Collectively, these data provide insights into the pathogenesis of ALS as well as potential targets for drug development. PMID- 23754388 TI - Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model. AB - Glioblastoma (World Health Organization grade IV) is an aggressive adult brain tumor that is inevitably fatal despite surgery, radiation, and chemotherapy. Treatment failures are attributed to combinations of cellular heterogeneity, including a subpopulation of often-resistant cancer stem cells, aberrant vasculature, and noteworthy immune suppression. Current preclinical models and treatment strategies do not incorporate or address all these features satisfactorily. Herein, we describe a murine glioblastoma stem cell (GSC) model that recapitulates tumor heterogeneity, invasiveness, vascularity, and immunosuppressive microenvironment in syngeneic immunocompetent mice and should prove useful for a range of therapeutic studies. Using this model, we tested a genetically engineered oncolytic herpes simplex virus that is armed with an immunomodulatory cytokine, interleukin 12 (G47-mIL12). G47Delta-mIL12 infects and replicates similarly to its unarmed oncolytic herpes simplex virus counterpart in mouse 005 GSCs in vitro, whereas in vivo, it significantly enhances survival in syngeneic mice bearing intracerebral 005 tumors. Mechanistically, G47-mIL12 targets not only GSCs but also increases IFN-gamma release, inhibits angiogenesis, and reduces the number of regulatory T cells in the tumor. The increased efficacy is dependent upon T cells, but not natural killer cells. Taken together, our findings demonstrate that G47Delta-mIL12 provides a multifaceted approach to targeting GSCs, tumor microenvironment, and the immune system, with resultant therapeutic benefit in a stringent glioblastoma model. PMID- 23754389 TI - Stabilization of a protein conferred by an increase in folded state entropy. AB - Entropic stabilization of native protein structures typically relies on strategies that serve to decrease the entropy of the unfolded state. Here we report, using a combination of experimental and computational approaches, on enhanced thermodynamic stability conferred by an increase in the configurational entropy of the folded state. The enhanced stability is observed upon modifications of a loop region in the enzyme acylphosphatase and is achieved despite significant enthalpy losses. The modifications that lead to increased stability, as well as those that result in destabilization, however, strongly compromise enzymatic activity, rationalizing the preservation of the native loop structure even though it does not provide the protein with maximal stability or kinetic foldability. PMID- 23754390 TI - BACE2 processes PMEL to form the melanosome amyloid matrix in pigment cells. AB - Amyloids are often associated with pathologic processes such as in Alzheimer's disease (AD), but can also underlie physiological processes such as pigmentation. Formation of pathological and functional amyloidogenic substrates can require precursor processing by proteases, as exemplified by the generation of Abeta peptide from amyloid precursor protein (APP) by beta-site APP cleaving enzyme (BACE)1 and gamma-secretase. Proteolytic processing of the pigment cell-specific Melanocyte Protein (PMEL) is also required to form functional amyloid fibrils during melanogenesis, but the enzymes involved are incompletely characterized. Here we show that the BACE1 homologue BACE2 processes PMEL to generate functional amyloids. BACE2 is highly expressed in pigment cells and Bace2(-/-) but not Bace1(-/-) mice display coat color defects, implying a specific role for BACE2 during melanogenesis. By using biochemical and morphological analyses, combined with RNA silencing, pharmacologic inhibition, and BACE2 overexpression in a human melanocytic cell line, we show that BACE2 cleaves the integral membrane form of PMEL within the juxtamembrane domain, releasing the PMEL luminal domain into endosomal precursors for the formation of amyloid fibrils and downstream melanosome morphogenesis. These studies identify an amyloidogenic substrate of BACE2, reveal an important physiological role for BACE2 in pigmentation, and highlight analogies in the generation of PMEL-derived functional amyloids and APP derived pathological amyloids. PMID- 23754391 TI - Engineering of regulated stochastic cell fate determination. AB - Both microbes and multicellular organisms actively regulate their cell fate determination to cope with changing environments or to ensure proper development. Here, we use synthetic biology approaches to engineer bistable gene networks to demonstrate that stochastic and permanent cell fate determination can be achieved through initializing gene regulatory networks (GRNs) at the boundary between dynamic attractors. We realize this experimentally by linking a synthetic GRN to a natural output of galactose metabolism regulation in yeast. Combining mathematical modeling and flow cytometry, we show that our engineered systems are bistable and that inherent gene expression stochasticity does not induce spontaneous state transitioning at steady state. Mathematical analysis predicts that stochastic cell fate determination in this case can only be realized when gene expression fluctuation occurs on or near attractor basin boundaries (the points of instability). Guided by numerical simulations, experiments are designed and performed with quantitatively diverse gene networks to test model predictions, which are verified by both flow cytometry and single-cell microscopy. By interfacing rationally designed synthetic GRNs with background gene regulation mechanisms, this work investigates intricate properties of networks that illuminate possible regulatory mechanisms for cell differentiation and development that can be initiated from points of instability. PMID- 23754392 TI - Ca2+/calmodulin-dependent protein kinase kinase beta phosphorylation of Sirtuin 1 in endothelium is atheroprotective. AB - Atheroprotective flow exerts antioxidative and anti-inflammatory effects on vascular endothelial cells (ECs), in part through the induction of Sirtuin 1 (SIRT1), a class III histone deacetylase. The role of Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK)beta in flow induction of SIRT1 both in vitro and in vivo was investigated. Pulsatile shear stress mimicking atheroprotective flow increased the level of SIRT1 in cultured ECs by enhancing its stability, and this effect was abolished by inhibition or knockdown of CaMKKbeta. Flow-enhanced SIRT1 stability was primarily mediated by CaMKKbeta phosphorylation of SIRT1 at Ser-27 and Ser-47, as evidenced by in vitro kinase assay, mass spectrometry, and experiments using loss- or gain-of-function SIRT1 mutants. Flow-induced CaMKKbeta phosphorylation of SIRT1 Ser-27 and Ser-47 increased antioxidative and anti inflammatory capacities. Ablation of CaMKKbeta or SIRT1 in mice with an apolipoprotein E-null background showed increased atherosclerosis both in athero prone and in athero-protective areas. The results suggest that the CaMKKbeta SIRT1 axis in ECs is mechanosensitive, antioxidative, and anti-inflammatory. PMID- 23754393 TI - Genome of Phaeocystis globosa virus PgV-16T highlights the common ancestry of the largest known DNA viruses infecting eukaryotes. AB - Large dsDNA viruses are involved in the population control of many globally distributed species of eukaryotic phytoplankton and have a prominent role in bloom termination. The genus Phaeocystis (Haptophyta, Prymnesiophyceae) includes several high-biomass-forming phytoplankton species, such as Phaeocystis globosa, the blooms of which occur mostly in the coastal zone of the North Atlantic and the North Sea. Here, we report the 459,984-bp-long genome sequence of P. globosa virus strain PgV-16T, encoding 434 proteins and eight tRNAs and, thus, the largest fully sequenced genome to date among viruses infecting algae. Surprisingly, PgV-16T exhibits no phylogenetic affinity with other viruses infecting microalgae (e.g., phycodnaviruses), including those infecting Emiliania huxleyi, another ubiquitous bloom-forming haptophyte. Rather, PgV-16T belongs to an emerging clade (the Megaviridae) clustering the viruses endowed with the largest known genomes, including Megavirus, Mimivirus (both infecting acanthamoeba), and a virus infecting the marine microflagellate grazer Cafeteria roenbergensis. Seventy-five percent of the best matches of PgV-16T-predicted proteins correspond to two viruses [Organic Lake phycodnavirus (OLPV)1 and OLPV2] from a hypersaline lake in Antarctica (Organic Lake), the hosts of which are unknown. As for OLPVs and other Megaviridae, the PgV-16T sequence data revealed the presence of a virophage-like genome. However, no virophage particle was detected in infected P. globosa cultures. The presence of many genes found only in Megaviridae in its genome and the presence of an associated virophage strongly suggest that PgV-16T shares a common ancestry with the largest known dsDNA viruses, the host range of which already encompasses the earliest diverging branches of domain Eukarya. PMID- 23754394 TI - Genetic and archaeological perspectives on the initial modern human colonization of southern Asia. AB - It has been argued recently that the initial dispersal of anatomically modern humans from Africa to southern Asia occurred before the volcanic "supereruption" of the Mount Toba volcano (Sumatra) at ~74,000 y before present (B.P.)-possibly as early as 120,000 y B.P. We show here that this "pre-Toba" dispersal model is in serious conflict with both the most recent genetic evidence from both Africa and Asia and the archaeological evidence from South Asian sites. We present an alternative model based on a combination of genetic analyses and recent archaeological evidence from South Asia and Africa. These data support a coastally oriented dispersal of modern humans from eastern Africa to southern Asia ~60-50 thousand years ago (ka). This was associated with distinctively African microlithic and "backed-segment" technologies analogous to the African "Howiesons Poort" and related technologies, together with a range of distinctively "modern" cultural and symbolic features (highly shaped bone tools, personal ornaments, abstract artistic motifs, microblade technology, etc.), similar to those that accompanied the replacement of "archaic" Neanderthal by anatomically modern human populations in other regions of western Eurasia at a broadly similar date. PMID- 23754395 TI - Key ornamental innovations facilitate diversification in an avian radiation. AB - Patterns of biodiversity are often explained by ecological processes, where traits that promote novel ways of interacting with the environment (key innovations) play a fundamental role in promoting diversification. However, sexual selection and social competition can also promote diversification through rapid evolution of ornamental traits. Because selection can operate only on existing variation, the tendency of ornamental traits to constrain or enable the production of novel phenotypes is a crucial but often overlooked aspect of diversification. Starlings are a speciose group characterized by diverse iridescent colors produced by nanometer-scale arrays of melanin-containing organelles (melanosomes) that play a central role in sexual selection and social competition. We show that evolutionary lability of these colors is associated with both morphological and lineage diversification in African starlings. The solid rod-like melanosome morphology has evolved in a directional manner into three more optically complex forms that can produce a broader range of colors than the ancestral form, resulting in (i) faster color evolution, (ii) the occupation of novel, previously unreachable regions of colorspace, and ultimately (iii) accelerated lineage diversification. As in adaptive radiations, key innovations in ornament production can provide high phenotypic trait variability, leading to dramatic effects on the tempo and mode of diversification. PMID- 23754396 TI - Candidate phylum TM6 genome recovered from a hospital sink biofilm provides genomic insights into this uncultivated phylum. AB - The "dark matter of life" describes microbes and even entire divisions of bacterial phyla that have evaded cultivation and have yet to be sequenced. We present a genome from the globally distributed but elusive candidate phylum TM6 and uncover its metabolic potential. TM6 was detected in a biofilm from a sink drain within a hospital restroom by analyzing cells using a highly automated single-cell genomics platform. We developed an approach for increasing throughput and effectively improving the likelihood of sampling rare events based on forming small random pools of single-flow-sorted cells, amplifying their DNA by multiple displacement amplification and sequencing all cells in the pool, creating a "mini metagenome." A recently developed single-cell assembler, SPAdes, in combination with contig binning methods, allowed the reconstruction of genomes from these mini-metagenomes. A total of 1.07 Mb was recovered in seven contigs for this member of TM6 (JCVI TM6SC1), estimated to represent 90% of its genome. High nucleotide identity between a total of three TM6 genome drafts generated from pools that were independently captured, amplified, and assembled provided strong confirmation of a correct genomic sequence. TM6 is likely a Gram-negative organism and possibly a symbiont of an unknown host (nonfree living) in part based on its small genome, low-GC content, and lack of biosynthesis pathways for most amino acids and vitamins. Phylogenomic analysis of conserved single-copy genes confirms that TM6SC1 is a deeply branching phylum. PMID- 23754398 TI - Anisotropic growth shapes intestinal tissues during embryogenesis. AB - Embryogenesis offers a real laboratory for pattern formation, buckling, and postbuckling induced by growth of soft tissues. Each part of our body is structured in multiple adjacent layers: the skin, the brain, and the interior of organs. Each layer has a complex biological composition presenting different elasticity. Generated during fetal life, these layers will experience growth and remodeling in the early postfertilization stages. Here, we focus on a herringbone pattern occurring in fetal intestinal tissues. Common to many mammalians, this instability is a precursor of the villi, finger-like projections into the lumen. For avians (chicks' and turkeys' embryos), it has been shown that, a few days after fertilization, the mucosal epithelium of the duodenum is smooth, and then folds emerge, which present 2 d later a pronounced zigzag instability. Many debates and biological studies are devoted to this specific morphology, which regulates the cell renewal in the intestine. After reviewing experimental results about duodenum morphogenesis, we show that a model based on simplified hypothesis for the growth of the mesenchyme can explain buckling and postbuckling instabilities. Being completely analytical, it is based on biaxial compressive stresses due to differential growth between layers and it predicts quantitatively the morphological changes. The growth anisotropy increasing with time, the competition between folds and zigzags, is proved to occur as a secondary instability. The model is compared with available experimental data on chick's duodenum and can be applied to other intestinal tissues, the zigzag being a common and spectacular microstructural pattern of intestine embryogenesis. PMID- 23754397 TI - Bach2 maintains T cells in a naive state by suppressing effector memory-related genes. AB - The transcriptional repressor BTB and CNC homology 2 (Bach2) is thought to be mainly expressed in B cells with specific functions such as class switch recombination and somatic hypermutation, but its function in T cells is not known. We found equal Bach2 expression in T cells and analyzed its function using Bach2-deficient (-/-) mice. Although T-cell development was normal, numbers of peripheral naive T cells were decreased, which rapidly produced Th2 cytokines after TCR stimulation. Bach2(-/-) naive T cells highly expressed genes related to effector-memory T cells such as CCR4, ST-2 and Blimp-1. Enhanced expression of these genes induced Bach2(-/-) naive T cells to migrate toward CCR4-ligand and respond to IL33. Forced expression of Bach2 restored the expression of these genes. Using Chromatin Immunoprecipitation (ChIP)-seq analysis, we identified S100 calcium binding protein a, Heme oxigenase 1, and prolyl hydroxylase 3 as Bach2 direct target genes, which are highly expressed in effector-memory T cells. These findings indicate that Bach2 suppresses effector memory-related genes to maintain the naive T-cell state and regulates generation of effector-memory T cells. PMID- 23754399 TI - Powering up with indirect reciprocity in a large-scale field experiment. AB - A defining aspect of human cooperation is the use of sophisticated indirect reciprocity. We observe others, talk about others, and act accordingly. We help those who help others, and we cooperate expecting that others will cooperate in return. Indirect reciprocity is based on reputation, which spreads by communication. A crucial aspect of indirect reciprocity is observability: reputation effects can support cooperation as long as peoples' actions can be observed by others. In evolutionary models of indirect reciprocity, natural selection favors cooperation when observability is sufficiently high. Complimenting this theoretical work are experiments where observability promotes cooperation among small groups playing games in the laboratory. Until now, however, there has been little evidence of observability's power to promote large scale cooperation in real world settings. Here we provide such evidence using a field study involving 2413 subjects. We collaborated with a utility company to study participation in a program designed to prevent blackouts. We show that observability triples participation in this public goods game. The effect is over four times larger than offering a $25 monetary incentive, the company's previous policy. Furthermore, as predicted by indirect reciprocity, we provide evidence that reputational concerns are driving our observability effect. In sum, we show how indirect reciprocity can be harnessed to increase cooperation in a relevant, real-world public goods game. PMID- 23754400 TI - Double deletion of melanocortin 4 receptors and SAPAP3 corrects compulsive behavior and obesity in mice. AB - Compulsive behavior is a debilitating clinical feature of many forms of neuropsychiatric disease, including Tourette syndrome, obsessive-compulsive spectrum disorders, eating disorders, and autism. Although several studies link striatal dysfunction to compulsivity, the pathophysiology remains poorly understood. Here, we show that both constitutive and induced genetic deletion of the gene encoding the melanocortin 4 receptor (MC4R), as well as pharmacologic inhibition of MC4R signaling, normalize compulsive grooming and striatal electrophysiologic impairments in synapse-associated protein 90/postsynaptic density protein 95-associated protein 3 (SAPAP3)-null mice, a model of human obsessive-compulsive disorder. Unexpectedly, genetic deletion of SAPAP3 restores normal weight and metabolic features of MC4R-null mice, a model of human obesity. Our findings offer insights into the pathophysiology and treatment of both compulsive behavior and eating disorders. PMID- 23754401 TI - Ptr-miR397a is a negative regulator of laccase genes affecting lignin content in Populus trichocarpa. AB - Laccases, as early as 1959, were proposed to catalyze the oxidative polymerization of monolignols. Genetic evidence in support of this hypothesis has been elusive due to functional redundancy of laccase genes. An Arabidopsis double mutant demonstrated the involvement of laccases in lignin biosynthesis. We previously identified a subset of laccase genes to be targets of a microRNA (miRNA) ptr-miR397a in Populus trichocarpa. To elucidate the roles of ptr-miR397a and its targets, we characterized the laccase gene family and identified 49 laccase gene models, of which 29 were predicted to be targets of ptr-miR397a. We overexpressed Ptr-MIR397a in transgenic P. trichocarpa. In each of all nine transgenic lines tested, 17 PtrLACs were down-regulated as analyzed by RNA-seq. Transgenic lines with severe reduction in the expression of these laccase genes resulted in an ~40% decrease in the total laccase activity. Overexpression of Ptr MIR397a in these transgenic lines also reduced lignin content, whereas levels of all monolignol biosynthetic gene transcripts remained unchanged. A hierarchical genetic regulatory network (GRN) built by a bottom-up graphic Gaussian model algorithm provides additional support for a role of ptr-miR397a as a negative regulator of laccases for lignin biosynthesis. Full transcriptome-based differential gene expression in the overexpressed transgenics and protein domain analyses implicate previously unidentified transcription factors and their targets in an extended hierarchical GRN including ptr-miR397a and laccases that coregulate lignin biosynthesis in wood formation. Ptr-miR397a, laccases, and other regulatory components of this network may provide additional strategies for genetic manipulation of lignin content. PMID- 23754402 TI - TLR-independent neutrophil-derived IFN-gamma is important for host resistance to intracellular pathogens. AB - IFN-gamma is a major cytokine that is critical for host resistance to a broad range of intracellular pathogens. Production of IFN-gamma by natural killer and T cells is initiated by the recognition of pathogens by Toll-like receptors (TLRs). In an experimental model of toxoplasmosis, we have identified the presence of a nonlymphoid source of IFN-gamma that was particularly evident in the absence of TLR-mediated recognition of Toxoplasma gondii. Genetically altered mice lacking all lymphoid cells due to deficiencies in Recombination Activating Gene 2 and IL 2Rgammac genes also produced IFN-gamma in response to the protozoan parasite. Flow-cytometry and morphological examinations of non-NK/non-T IFN-gamma(+) cells identified neutrophils as the cell type capable of producing IFN-gamma. Selective elimination of neutrophils in TLR11(-/-) mice infected with the parasite resulted in acute susceptibility similar to that observed in IFN-gamma-deficient mice. Similarly, Salmonella typhimurium infection of TLR-deficient mice induces the appearance of IFN-gamma(+) neutrophils. Thus, neutrophils are a crucial source for IFN-gamma that is required for TLR-independent host protection against intracellular pathogens. PMID- 23754403 TI - Staphylococcus aureus LukAB cytotoxin kills human neutrophils by targeting the CD11b subunit of the integrin Mac-1. AB - Staphylococcus aureus causes diseases ranging from superficial wound infections to more invasive manifestations like osteomyelitis and endocarditis. The evasion of host phagocytes recruited to the site of infection is essential to the success of S. aureus as a pathogen. A single S. aureus strain can produce up to five different bicomponent pore-forming leukotoxins that lyse immune cells by forming pores in the cellular plasma membrane. Although these leukotoxins have been considered redundant due to their cytotoxic activity toward human neutrophils, each toxin displays varied species and cell-type specificities. This suggests that cellular factors may influence which cells each toxin targets. Here we describe the identification of CD11b, the alpha subunit of the alphaM/beta2 integrin (CD11b/CD18), macrophage-1 antigen, or complement receptor 3, as a cellular receptor for leukocidin A/B (LukAB), an important toxin that contributes to S. aureus killing of human neutrophils. We demonstrate that CD11b renders human neutrophils susceptible to LukAB-mediated killing by purified LukAB as well as during S. aureus infection ex vivo. LukAB directly interacts with human CD11b by binding to the I domain, a property that determines the species specificity exhibited by this toxin. Identification of a LukAB cellular target has broad implications for the use of animal models to study the role of LukAB in S. aureus pathogenesis, explains the toxin's tropism toward human neutrophils and other phagocytes, and provides a cellular therapeutic target to block the effect of LukAB toward human neutrophils. PMID- 23754404 TI - Learning where to look for a hidden target. AB - Survival depends on successfully foraging for food, for which evolution has selected diverse behaviors in different species. Humans forage not only for food, but also for information. We decide where to look over 170,000 times per day, approximately three times per wakeful second. The frequency of these saccadic eye movements belies the complexity underlying each individual choice. Experience factors into the choice of where to look and can be invoked to rapidly redirect gaze in a context and task-appropriate manner. However, remarkably little is known about how individuals learn to direct their gaze given the current context and task. We designed a task in which participants search a novel scene for a target whose location was drawn stochastically on each trial from a fixed prior distribution. The target was invisible on a blank screen, and the participants were rewarded when they fixated the hidden target location. In just a few trials, participants rapidly found the hidden targets by looking near previously rewarded locations and avoiding previously unrewarded locations. Learning trajectories were well characterized by a simple reinforcement-learning (RL) model that maintained and continually updated a reward map of locations. The RL model made further predictions concerning sensitivity to recent experience that were confirmed by the data. The asymptotic performance of both the participants and the RL model approached optimal performance characterized by an ideal-observer theory. These two complementary levels of explanation show how experience in a novel environment drives visual search in humans and may extend to other forms of search such as animal foraging. PMID- 23754405 TI - SlmA forms a higher-order structure on DNA that inhibits cytokinetic Z-ring formation over the nucleoid. AB - The spatial and temporal control of Filamenting temperature sensitive mutant Z (FtsZ) Z-ring formation is crucial for proper cell division in bacteria. In Escherichia coli, the synthetic lethal with a defective Min system (SlmA) protein helps mediate nucleoid occlusion, which prevents chromosome fragmentation by binding FtsZ and inhibiting Z-ring formation over the nucleoid. However, to perform its function, SlmA must be bound to the nucleoid. To deduce the basis for this chromosomal requirement, we performed biochemical, cellular, and structural studies. Strikingly, structures show that SlmA dramatically distorts DNA, allowing it to bind as an orientated dimer-of-dimers. Biochemical data indicate that SlmA dimer-of-dimers can spread along the DNA. Combined structural and biochemical data suggest that this DNA-activated SlmA oligomerization would prevent FtsZ protofilament propagation and bundling. Bioinformatic analyses localize SlmA DNA sites near membrane-tethered chromosomal regions, and cellular studies show that SlmA inhibits FtsZ reservoirs from forming membrane-tethered Z rings. Thus, our combined data indicate that SlmA DNA helps block Z-ring formation over chromosomal DNA by forming higher-order protein-nucleic acid complexes that disable FtsZ filaments from coalescing into proper structures needed for Z-ring creation. PMID- 23754406 TI - Connectivity profiles reveal the relationship between brain areas for social cognition in human and monkey temporoparietal cortex. AB - The human ability to infer the thoughts and beliefs of others, often referred to as "theory of mind," as well as the predisposition to even consider others, are associated with activity in the temporoparietal junction (TPJ) area. Unlike the case of most human brain areas, we have little sense of whether or how TPJ is related to brain areas in other nonhuman primates. It is not possible to address this question by looking for similar task-related activations in nonhuman primates because there is no evidence that nonhuman primates engage in theory-of mind tasks in the same manner as humans. Here, instead, we explore the relationship by searching for areas in the macaque brain that interact with other macaque brain regions in the same manner as human TPJ interacts with other human brain regions. In other words, we look for brain regions with similar positions within a distributed neural circuit in the two species. We exploited the fact that human TPJ has a unique functional connectivity profile with cortical areas with known homologs in the macaque. For each voxel in the macaque temporal and parietal cortex we evaluated the similarity of its functional connectivity profile to that of human TPJ. We found that areas in the middle part of the superior temporal cortex, often associated with the processing of faces and other social stimuli, have the most similar connectivity profile. These results suggest that macaque face processing areas and human mentalizing areas might have a similar precursor. PMID- 23754407 TI - Justice- and fairness-related behaviors in nonhuman primates. AB - A distinctive feature across human societies is our interest in justice and fairness. People will sometimes invest in extremely costly behavior to achieve fair outcomes for themselves and others. Why do people care so much about justice? One way to address this is comparatively, exploring behaviors related to justice and fairness in other species. In this paper, I review work exploring responses to inequity, prosocial behavior, and other relevant behaviors in nonhuman primates in an effort to understand both the potential evolutionary function of these behaviors and the social and ecological reasons for the individual differences in behavior. I also consider how these behaviors relate to human behavior, particularly in the case of experimental studies using games derived from experimental economics to compare nonhuman primates' responses to those of humans in similar experimental conditions. These results emphasize the importance of a comparative approach to better understand the function and diversity of human behavior. PMID- 23754409 TI - Directing exocrine secretory vesicles to the apical membrane by actin cables generated by the formin mDia1. AB - The final stage in exocrine secretion involves translocation of vesicles from their storage areas to the apical membrane. We show that actin-coated secretory vesicles of the exocrine pancreas travel this distance over bundles of specialized actin cables emanating from the apical plasma membrane. These bundles are stable structures that require constant G-actin incorporation and are distinct from the actin web that surrounds the exocrine lumen. The murine mammalian Diaphanous-related formin 1 (mDia1) was identified as a generator of these cables. The active form of mDia1 localized to the apical membrane, and introduction of an active form of mDia1 led to a marked increase in bundle density along the lumen perimeter. Compromising formation of the cables does not prevent secretion, but results in disorganized trafficking and fusion between secretory vesicles. Similar apical secretory tracks were also found in the submandibular salivary glands. Together with previous results that identified a role for Diaphanous in apical secretion in tubular organs of Drosophila, the role of Diaphanous formins at the final stages of secretion appears to be highly conserved. PMID- 23754408 TI - Impact of contour on aesthetic judgments and approach-avoidance decisions in architecture. AB - On average, we urban dwellers spend about 90% of our time indoors, and share the intuition that the physical features of the places we live and work in influence how we feel and act. However, there is surprisingly little research on how architecture impacts behavior, much less on how it influences brain function. To begin closing this gap, we conducted a functional magnetic resonance imaging study to examine how systematic variation in contour impacts aesthetic judgments and approach-avoidance decisions, outcome measures of interest to both architects and users of spaces alike. As predicted, participants were more likely to judge spaces as beautiful if they were curvilinear than rectilinear. Neuroanatomically, when contemplating beauty, curvilinear contour activated the anterior cingulate cortex exclusively, a region strongly responsive to the reward properties and emotional salience of objects. Complementing this finding, pleasantness--the valence dimension of the affect circumplex--accounted for nearly 60% of the variance in beauty ratings. Furthermore, activation in a distributed brain network known to underlie the aesthetic evaluation of different types of visual stimuli covaried with beauty ratings. In contrast, contour did not affect approach-avoidance decisions, although curvilinear spaces activated the visual cortex. The results suggest that the well-established effect of contour on aesthetic preference can be extended to architecture. Furthermore, the combination of our behavioral and neural evidence underscores the role of emotion in our preference for curvilinear objects in this domain. PMID- 23754410 TI - Neuroethology of primate social behavior. AB - A neuroethological approach to human and nonhuman primate behavior and cognition predicts biological specializations for social life. Evidence reviewed here indicates that ancestral mechanisms are often duplicated, repurposed, and differentially regulated to support social behavior. Focusing on recent research from nonhuman primates, we describe how the primate brain might implement social functions by coopting and extending preexisting mechanisms that previously supported nonsocial functions. This approach reveals that highly specialized mechanisms have evolved to decipher the immediate social context, and parallel circuits have evolved to translate social perceptual signals and nonsocial perceptual signals into partially integrated social and nonsocial motivational signals, which together inform general-purpose mechanisms that command behavior. Differences in social behavior between species, as well as between individuals within a species, result in part from neuromodulatory regulation of these neural circuits, which itself appears to be under partial genetic control. Ultimately, intraspecific variation in social behavior has differential fitness consequences, providing fundamental building blocks of natural selection. Our review suggests that the neuroethological approach to primate behavior may provide unique insights into human psychopathology. PMID- 23754412 TI - Oxidation of nanoscale Au-In alloy particles as a possible route toward stable Au based catalysts. AB - The oxidation of bimetallic alloy nanoparticles comprising a noble and a nonnoble metal is expected to cause the formation of a single-component surface oxide of the nonnoble metal, surrounding a core enriched with the noble metal. Studying the room temperature oxidation of Au-In nanoparticles, we show that this simple picture does not apply to an important class of bimetallic alloys, in which the oxidation proceeds via predominant oxygen diffusion. Instead of a crystalline In2O3 shell, such oxidation leads to an amorphous shell of mixed Au-In oxide that remains stable to high temperatures and whose surface layer is enriched with Au. The Au-rich mixed oxide is capable of adsorbing both CO and O2 and converting them to CO2, which desorbs near room temperature. The oxidation of Au-In alloys to a mixed Au-In oxide shows significant promise as a viable approach toward Au based oxidation catalysts, which do not require any complex synthesis processes and resist deactivation up to at least 300 degrees C. PMID- 23754411 TI - Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium. AB - Vascular endothelium offers a variety of therapeutic targets for the treatment of cancer, cardiovascular diseases, inflammation, and oxidative stress. Significant research has been focused on developing agents to target the endothelium in diseased tissues. This includes identification of antibodies against adhesion molecules and neovascular expression markers or peptides discovered using phage display. Such targeting molecules also have been used to deliver nanoparticles to the endothelium of the diseased tissue. Here we report, based on in vitro and in vivo studies, that the specificity of endothelial targeting can be enhanced further by engineering the shape of ligand-displaying nanoparticles. In vitro studies performed using microfluidic systems that mimic the vasculature (synthetic microvascular networks) showed that rod-shaped nanoparticles exhibit higher specific and lower nonspecific accumulation under flow at the target compared with their spherical counterparts. Mathematical modeling of particle surface interactions suggests that the higher avidity and specificity of nanorods originate from the balance of polyvalent interactions that favor adhesion and entropic losses as well as shear-induced detachment that reduce binding. In vivo experiments in mice confirmed that shape-induced enhancement of vascular targeting is also observed under physiological conditions in lungs and brain for nanoparticles displaying anti-intracellular adhesion molecule 1 and anti transferrin receptor antibodies. PMID- 23754413 TI - In the light of evolution VII: The human mental machinery. PMID- 23754414 TI - Identification of transferrin receptor 1 as a hepatitis C virus entry factor. AB - Hepatitis C virus (HCV) is a liver tropic pathogen that affects ~170 million people worldwide and causes liver pathologies including fibrosis, cirrhosis, steatosis, iron overload, and hepatocellular carcinoma. As part of a project initially directed at understanding how HCV may disrupt cellular iron homeostasis, we found that HCV alters expression of the iron uptake receptor transferrin receptor 1 (TfR1). After further investigation, we found that TfR1 mediates HCV entry. Specifically, functional studies showed that TfR1 knockdown and antibody blocking inhibit HCV cell culture (HCVcc) infection. Blocking cell surface TfR1 also inhibited HCV pseudoparticle (HCVpp) infection, demonstrating that TfR1 acts at the level of HCV glycoprotein-dependent entry. Likewise, a TfR1 small-molecule inhibitor that causes internalization of surface TfR1 resulted in a decrease in HCVcc and HCVpp infection. In kinetic studies, TfR1 antibody blocking lost its inhibitory activity after anti-CD81 blocking, suggesting that TfR1 acts during HCV entry at a postbinding step after CD81. In contrast, viral spread assays indicated that HCV cell-to-cell spread is less dependent on TfR1. Interestingly, silencing of the TfR1 trafficking protein, a TfR-1 specific adaptor protein required for TfR1 internalization, also inhibited HCVcc infection. On the basis of these results, we conclude that TfR1 plays a role in HCV infection at the level of glycoprotein-mediated entry, acts after CD81, and possibly is involved in HCV particle internalization. PMID- 23754416 TI - Theory of mind and Darwin's legacy. AB - We do not have an adequate theory of consciousness. Both dualism and materialism are mistaken because they deny consciousness is part of the physical world. False claims include (i) behaviorism, (ii) computationalism, (iii) epiphenomenalism, (iv) the readiness potential, (v) subjectivity, and (vi) materialism. Ontological subjectivity does not preclude epistemic objectivity. Observer relative phenomena are created by consciousness, but consciousness is not itself observer relative. Consciousness consists of feeling, sentience, or awareness with (i) qualitativeness, (ii) ontological subjectivity, (iii) unified conscious field, (iv) intentionality, and (v) intentional causation. All conscious states are caused by lower level neurobiological processes in the brain, and they are realized in the brain as higher level features. Efforts to get a detailed scientific account of how brain processes cause consciousness are disappointing. The Darwinian revolution gave us a new form of explanation; two levels were substituted: a causal level, where we specify the mechanism by which the phenotype functions, and a functional level, where we specify the selectional advantage that the phenotype provides. Sociobiology attempted to explain general features of human society, ethics, etc. It failed. For the incest taboo, it confuses inhibition with prohibition. It did not explain the moral force of the taboo. To explain the function of consciousness we cannot ask, "What would be subtracted if we subtracted consciousness but left everything else the same?" We cannot leave everything else the same because consciousness is necessary for higher functions of human and animal life. The unified conscious field gives the organism vastly increased power. PMID- 23754415 TI - Differential control of seed primary dormancy in Arabidopsis ecotypes by the transcription factor SPATULA. AB - Freshly matured seeds exhibit primary dormancy, which prevents germination until environmental conditions are favorable. The establishment of dormancy occurs during seed development and involves both genetic and environmental factors that impact on the ratio of two antagonistic phytohormones: abscisic acid (ABA), which promotes dormancy, and gibberellic acid, which promotes germination. Although our understanding of dormancy breakage in mature seeds is well advanced, relatively little is known about the mechanisms involved in establishing dormancy during seed maturation. We previously showed that the SPATULA (SPT) transcription factor plays a key role in regulating seed germination. Here we investigate its role during seed development and find that, surprisingly, it has opposite roles in setting dormancy in Landsberg erecta and Columbia Arabidopsis ecotypes. We also find that SPT regulates expression of five transcription factor encoding genes: ABA-INSENSITIVE4 (ABI4) and ABI5, which mediate ABA signaling; REPRESSOR-OF-GA (RGA) and RGA-LIKE3 involved in gibberellic acid signaling; and MOTHER-OF-FT-AND TFL1 (MFT) that we show here promotes Arabidopsis seed dormancy. Although ABI4, RGA, and MFT are repressed by SPT, ABI5 and RGL3 are induced. Furthermore, we show that RGA, MFT, and ABI5 are direct targets of SPT in vivo. We present a model in which SPT drives two antagonistic "dormancy-repressing" and "dormancy promoting" routes that operate simultaneously in freshly matured seeds. Each of these routes has different impacts and this in turn explains the opposite effect of SPT on seed dormancy of the two ecotypes analyzed here. PMID- 23754417 TI - Discovery of positive allosteric modulators and silent allosteric modulators of the MU-opioid receptor. AB - MU-Opioid receptors are among the most studied G protein-coupled receptors because of the therapeutic value of agonists, such as morphine, that are used to treat chronic pain. However, these drugs have significant side effects, such as respiratory suppression, constipation, allodynia, tolerance, and dependence, as well as abuse potential. Efforts to fine tune pain control while alleviating the side effects of drugs, both physiological and psychological, have led to the development of a wide variety of structurally diverse agonist ligands for the MU opioid receptor, as well as compounds that target kappa- and delta-opioid receptors. In recent years, the identification of allosteric ligands for some G protein-coupled receptors has provided breakthroughs in obtaining receptor subtype-selectivity that can reduce the overall side effect profiles of a potential drug. However, positive allosteric modulators (PAMs) can also have the specific advantage of only modulating the activity of the receptor when the orthosteric agonist occupies the receptor, thus maintaining spatial and temporal control of receptor signaling in vivo. This second advantage of allosteric modulators may yield breakthroughs in opioid receptor research and could lead to drugs with improved side-effect profiles or fewer tolerance and dependence issues compared with orthosteric opioid receptor agonists. Here, we describe the discovery and characterization of MU-opioid receptor PAMs and silent allosteric modulators, identified from high-throughput screening using a beta-arrestin recruitment assay. PMID- 23754418 TI - Paternally expressed genes predominate in the placenta. AB - The discovery of genomic imprinting through studies of manipulated mouse embryos indicated that the paternal genome has a major influence on placental development. However, previous research has not demonstrated paternal bias in imprinted genes. We applied RNA sequencing to trophoblast tissue from reciprocal hybrids of horse and donkey, where genotypic differences allowed parent-of-origin identification of most expressed genes. Using this approach, we identified a core group of 15 ancient imprinted genes, of which 10 were paternally expressed. An additional 78 candidate imprinted genes identified by RNA sequencing also showed paternal bias. Pyrosequencing was used to confirm the imprinting status of six of the genes, including the insulin receptor (INSR), which may play a role in growth regulation with its reciprocally imprinted ligand, histone acetyltransferase-1 (HAT1), a gene involved in chromatin modification, and lymphocyte antigen 6 complex, locus G6C, a newly identified imprinted gene in the major histocompatibility complex. The 78 candidate imprinted genes displayed parent-of origin expression bias in placenta but not fetus, and most showed less than 100% silencing of the imprinted allele. Some displayed variability in imprinting status among individuals. This variability results in a unique epigenetic signature for each placenta that contributes to variation in the intrauterine environment and thus presents the opportunity for natural selection to operate on parent-of-origin differential regulation. Taken together, these features highlight the plasticity of imprinting in mammals and the central importance of the placenta as a target tissue for genomic imprinting. PMID- 23754419 TI - Functional interplay between a virus and the ESCRT machinery in archaea. AB - Recently it has been discovered that a number of eukaryotic viruses, including HIV, coopt the cellular Endosomal Sorting Complex Required for Transport (ESCRT) machinery to affect egress from infected cells. Strikingly, the ESCRT apparatus is conserved in a subset of Archaea, including members of the genus Sulfolobus where it plays a role in cytokinesis. In the current work, we reveal that the archaeal virus Sulfolobus turreted icosahedral virus isolated from Yellowstone National Park's acidic hot springs also exploits the host ESCRT machinery in its replication cycle. Moreover, perturbation of normal ESCRT function abrogates viral replication and, thus, prevents establishment of a productive Sulfolobus turreted icosahedral virus infection. We propose that the Sulfolobus ESCRT machinery is involved in viral assembly within the cytoplasm and in escape from the infected cell by using a unique lysis mechanism. Our results support an ancient origin for viruses "hijacking" ESCRT proteins to complete their replication cycle and thus identify a critical host-virus interaction conserved between two domains of life. PMID- 23754420 TI - Affiliation, empathy, and the origins of theory of mind. AB - To understand the evolution of a Theory of Mind, we need to understand the selective factors that might have jumpstarted its initial evolution. We argue that a subconscious, reflexive appreciation of others' intentions, emotions, and perspectives is at the roots of even the most complex forms of Theory of Mind and that these abilities may have evolved because natural selection has favored individuals that are motivated to empathize with others and attend to their social interactions. These skills are adaptive because they are essential to forming strong, enduring social bonds, which in turn enhance reproductive success. We first review evidence from both humans and other animals indicating that reflexive and reflective mental state attributions are inextricably linked and play a crucial role in promoting affiliative social bonds. We next describe results from free-ranging female baboons showing that individuals who show high rates of affiliative behavior form stronger social bonds with other females. These bonds, in turn, are linked to fitness. We then provide data from three different types of social challenges (male immigration, changes in grooming behavior after the death of a close relative, and responses during playback experiments), suggesting that females who manifest high rates of affiliative behavior may also be more motivated to anticipate challenges, react adaptively to setbacks, and respond appropriately to social interactions. PMID- 23754421 TI - Chemical and cytokine features of innate immunity characterize serum and tissue profiles in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) arises from inappropriate activation of the mucosal immune system resulting in a state of chronic inflammation with causal links to colon cancer. Helicobacter hepaticus-infected Rag2(-/-) mice emulate many aspects of human IBD, and our recent work using this experimental model highlights the importance of neutrophils in the pathology of colitis. To define molecular mechanisms linking colitis to the identity of disease biomarkers, we performed a translational comparison of protein expression and protein damage products in tissues of mice and human IBD patients. Analysis in inflamed mouse colons identified the neutrophil- and macrophage-derived damage products 3 chlorotyrosine (Cl-Tyr) and 3-nitrotyrosine, both of which increased with disease duration. Analysis also revealed higher Cl-Tyr levels in colon relative to serum in patients with ulcerative colitis and Crohn disease. The DNA chlorination damage product, 5-chloro-2'-deoxycytidine, was quantified in diseased human colon samples and found to be present at levels similar to those in inflamed mouse colons. Multivariate analysis of these markers, together with serum proteins and cytokines, revealed a general signature of activated innate immunity in human IBD. Signatures in ulcerative colitis sera were strongly suggestive of neutrophil activity, and those in Crohn disease and mouse sera were suggestive of both macrophage and neutrophil activity. These data point to innate immunity as a major determinant of serum and tissue profiles and provide insight into IBD disease processes. PMID- 23754422 TI - Synaptogenesis and development of pyramidal neuron dendritic morphology in the chimpanzee neocortex resembles humans. AB - Neocortical development in humans is characterized by an extended period of synaptic proliferation that peaks in mid-childhood, with subsequent pruning through early adulthood, as well as relatively delayed maturation of neuronal arborization in the prefrontal cortex compared with sensorimotor areas. In macaque monkeys, cortical synaptogenesis peaks during early infancy and developmental changes in synapse density and dendritic spines occur synchronously across cortical regions. Thus, relatively prolonged synapse and neuronal maturation in humans might contribute to enhancement of social learning during development and transmission of cultural practices, including language. However, because macaques, which share a last common ancestor with humans ~ 25 million years ago, have served as the predominant comparative primate model in neurodevelopmental research, the paucity of data from more closely related great apes leaves unresolved when these evolutionary changes in the timing of cortical development became established in the human lineage. To address this question, we used immunohistochemistry, electron microscopy, and Golgi staining to characterize synaptic density and dendritic morphology of pyramidal neurons in primary somatosensory (area 3b), primary motor (area 4), prestriate visual (area 18), and prefrontal (area 10) cortices of developing chimpanzees (Pan troglodytes). We found that synaptogenesis occurs synchronously across cortical areas, with a peak of synapse density during the juvenile period (3-5 y). Moreover, similar to findings in humans, dendrites of prefrontal pyramidal neurons developed later than sensorimotor areas. These results suggest that evolutionary changes to neocortical development promoting greater neuronal plasticity early in postnatal life preceded the divergence of the human and chimpanzee lineages. PMID- 23754423 TI - Histone deacetylase inhibitors are neuroprotective and preserve NGF-mediated cell survival following traumatic brain injury. AB - Acute traumatic brain injury (TBI) is associated with long-term cognitive and behavioral dysfunction. In vivo studies have shown histone deacetylase inhibitors (HDACis) to be neuroprotective following TBI in rodent models. HDACis are intriguing candidates because they are capable of provoking widespread genetic changes and modulation of protein function. By using known HDACis and a unique small-molecule pan-HDACi (LB-205), we investigated the effects and mechanisms associated with HDACi-induced neuroprotection following CNS injury in an astrocyte scratch assay in vitro and a rat TBI model in vivo. We demonstrate the preservation of sufficient expression of nerve growth factor (NGF) and activation of the neurotrophic tyrosine kinase receptor type 1 (TrkA) pathway following HDACi treatment to be crucial in stimulating the survival of CNS cells after TBI. HDACi treatment up-regulated the expression of NGF, phospho-TrkA, phospho-protein kinase B (p-AKT), NF-kappaB, and B-cell lymphoma 2 (Bcl-2) cell survival factors while down-regulating the expression of p75 neurotrophin receptor (NTR), phospho JNK, and Bcl-2-associated X protein apoptosis factors. HDACi treatment also increased the expression of the stem cell biomarker nestin, and decreased the expression of reactive astrocyte biomarker GFAP within damaged tissue following TBI. These findings provide further insight into the mechanisms by which HDACi treatment after TBI is neuroprotective and support the continued study of HDACis following acute TBI. PMID- 23754424 TI - Symmetry breaking in self-assembled M4L6 cage complexes. AB - Here we describe the phenomenon of symmetry breaking within a series of M4L6 container molecules. These containers were synthesized using planar rigid bis bidentate ligands based on 2,6-substituted naphthalene, anthracene, or anthraquinone spacers and Fe(II) ions. The planarity of the ligand spacer favors a stereochemical configuration in which each cage contains two metal centers of opposite handedness to the other two, which would ordinarily result in an S4 symmetric, achiral configuration. Reduction of symmetry from S4 to C1 is achieved by the spatial offset between each ligand's pair of binding sites, which breaks the S4 symmetry axis. Using larger Cd(II) or Co(II) ions instead of Fe(II) resulted, in some cases, in the observation of dynamic motion of the symmetry breaking ligands in solution. NMR spectra of these dynamic complexes thus reflected apparent S4 symmetry owing to rapid interconversion between energetically degenerate, enantiomeric C1-symmetric conformations. PMID- 23754425 TI - Evidence for glycoprotein transport into complex plastids. AB - Diatoms are microalgae that possess so-called "complex plastids," which evolved by secondary endosymbiosis and are surrounded by four membranes. Thus, in contrast to primary plastids, which are surrounded by only two membranes, nucleus encoded proteins of complex plastids face additional barriers, i.e., during evolution, mechanisms had to evolve to transport preproteins across all four membranes. This study reveals that there exist glycoproteins not only in primary but also in complex plastids, making transport issues even more complicated, as most translocation machineries are not believed to be able to transport bulky proteins. We show that plastidal reporter proteins with artificial N glycosylation sites are indeed glycosylated during transport into the complex plastid of the diatom Phaeodactylum tricornutum. Additionally, we identified five endogenous glycoproteins, which are transported into different compartments of the complex plastid. These proteins get N-glycosylated during transport across the outermost plastid membrane and thereafter are transported across the second, third, and fourth plastid membranes in the case of stromal proteins. The results of this study provide insights into the evolutionary pressure on translocation mechanisms and pose unique questions on the operating mode of well-known transport machineries like the translocons of the outer/inner chloroplast membranes (Toc/Tic). PMID- 23754426 TI - Distributed cortical adaptation during learning of a brain-computer interface task. AB - The majority of subjects who attempt to learn control of a brain-computer interface (BCI) can do so with adequate training. Much like when one learns to type or ride a bicycle, BCI users report transitioning from a deliberate, cognitively focused mindset to near automatic control as training progresses. What are the neural correlates of this process of BCI skill acquisition? Seven subjects were implanted with electrocorticography (ECoG) electrodes and had multiple opportunities to practice a 1D BCI task. As subjects became proficient, strong initial task-related activation was followed by lessening of activation in prefrontal cortex, premotor cortex, and posterior parietal cortex, areas that have previously been implicated in the cognitive phase of motor sequence learning and abstract task learning. These results demonstrate that, although the use of a BCI only requires modulation of a local population of neurons, a distributed network of cortical areas is involved in the acquisition of BCI proficiency. PMID- 23754427 TI - Langerin(neg) conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice. AB - Psoriasis is an autoinflammatory skin disease of unknown etiology. Topical application of Aldara cream containing the Toll-like receptor (TLR)7 agonist Imiquimod (IMQ) onto patients induces flares of psoriasis. Likewise, in mice IMQ triggers pathological changes closely resembling psoriatic plaque formation. Key cytokines like IL-23 and type-I IFN (IFN-I), both being produced mainly by dendritic cells (DCs), have been implicated in psoriasis. Although plasmacytoid DCs (pDCs) are the main source of IFNalpha and thought to initiate disease, conventional DCs (cDCs) appear to maintain the psoriatic lesions. Any role of cDCs during lesion formation remains elusive. Here, we report that selective activation of TLR7 signaling specifically in CD11c(+) DCs was sufficient to induce psoriasiform skin disease in mice. Intriguingly, both pDCs and the IFN-I pathway were dispensable for the development of local skin inflammation. Selective TLR7 triggering of Langerin(+) DCs resulted in attenuated disease, whereas their depletion did not alter the severity of skin lesions. Moreover, after IMQ-painting, IL-23 was exclusively produced by Langerin(neg) DCs in vivo. In conclusion, TLR7-activated Langerin(neg) cDCs trigger psoriatic plaque formation via IL-23-mediated activation of innate IL-17/IL-22-producing lymphocytes, independently of pDCs or IFN-I. These results suggest therapeutic targeting of IL-23 production by cDCs to refine current treatment strategies for psoriasis. PMID- 23754428 TI - Evolution of working memory. AB - Working memory (WM) is fundamental to many aspects of human life, including learning, speech and text comprehension, prospection and future planning, and explicit "system 2" forms of reasoning, as well as overlapping heavily with fluid general intelligence. WM has been intensively studied for many decades, and there is a growing consensus about its nature, its components, and its signature limits. Remarkably, given its central importance in human life, there has been very little comparative investigation of WM abilities across species. Consequently, much remains unknown about the evolution of this important human capacity. Some questions can be tentatively answered from the existing comparative literature. Even studies that were not intended to do so can nonetheless shed light on the WM capacities of nonhuman animals. However, many questions remain. PMID- 23754429 TI - MitoBK(Ca) is encoded by the Kcnma1 gene, and a splicing sequence defines its mitochondrial location. AB - The large-conductance Ca(2+)- and voltage-activated K(+) channel (BK(Ca), MaxiK), which is encoded by the Kcnma1 gene, is generally expressed at the plasma membrane of excitable and nonexcitable cells. However, in adult cardiomyocytes, a BK(Ca)-like channel activity has been reported in the mitochondria but not at the plasma membrane. The putative opening of this channel with the BK(Ca) agonist, NS1619, protects the heart from ischemic insult. However, the molecular origin of mitochondrial BK(Ca) (mitoBK(Ca)) is unknown because its linkage to Kcnma1 has been questioned on biochemical and molecular grounds. Here, we unequivocally demonstrate that the molecular correlate of mitoBK(Ca) is the Kcnma1 gene, which produces a protein that migrates at ~140 kDa and arranges in clusters of ~50 nm in purified mitochondria. Physiological experiments further support the origin of mitoBK(Ca) as a Kcnma1 product because NS1619-mediated cardioprotection was absent in Kcnma1 knockout mice. Finally, BKCa transcript analysis and expression in adult cardiomyocytes led to the discovery of a 50-aa C-terminal splice insert as essential for the mitochondrial targeting of mitoBK(Ca). PMID- 23754430 TI - Roles of different pools of the mitotic checkpoint complex and the mechanisms of their disassembly. AB - The mitotic (or spindle assembly) checkpoint system prevents premature separation of sister chromatids in mitosis. When the checkpoint is turned on, the mitotic checkpoint complex (MCC) inhibits the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C). MCC is composed of the checkpoint proteins BubR1, Bub3, and Mad2 associated with the APC/C activator Cdc20. The mechanisms of the assembly of MCC when the checkpoint is turned on, and of its disassembly when the checkpoint is inactivated, are not sufficiently understood. Previous reports indicated that APC/C-mediated polyubiquitylation of Cdc20 in MCC is required for the dissociation of APC/C-associated MCC, but not of free MCC. The pool of free MCC is disassembled by an ATP-dependent process stimulated by the Mad2-binding protein p31(comet). It remained unknown whether free MCC is the precursor or the dissociation product of APC/C-bound MCC. By characterizing the mechanisms of the disassembly of APC/C-bound MCC in a purified system, we find that it cannot be the source of free MCC, because it is bound at high affinity and is released only in ubiquitylated or partially disassembled forms. By the use of a cell-free system from Xenopus eggs that reproduces the mitotic checkpoint, we show that MCC can be assembled in the absence of APC/C in a checkpoint-dependent manner. We propose that when the checkpoint is turned on, free MCC is the precursor of APC/C bound MCC. When the mitotic checkpoint is extinguished, both APC/C-bound and free MCC pools have to be disassembled to release APC/C from inhibition. PMID- 23754431 TI - Quantifying the topography of the intrinsic energy landscape of flexible biomolecular recognition. AB - Biomolecular functions are determined by their interactions with other molecules. Biomolecular recognition is often flexible and associated with large conformational changes involving both binding and folding. However, the global and physical understanding for the process is still challenging. Here, we quantified the intrinsic energy landscapes of flexible biomolecular recognition in terms of binding-folding dynamics for 15 homodimers by exploring the underlying density of states, using a structure-based model both with and without considering energetic roughness. By quantifying three individual effective intrinsic energy landscapes (one for interfacial binding, two for monomeric folding), the association mechanisms for flexible recognition of 15 homodimers can be classified into two-state cooperative "coupled binding-folding" and three state noncooperative "folding prior to binding" scenarios. We found that the association mechanism of flexible biomolecular recognition relies on the interplay between the underlying effective intrinsic binding and folding energy landscapes. By quantifying the whole global intrinsic binding-folding energy landscapes, we found strong correlations between the landscape topography measure Lambda (dimensionless ratio of energy gap versus roughness modulated by the configurational entropy) and the ratio of the thermodynamic stable temperature versus trapping temperature, as well as between Lambda and binding kinetics. Therefore, the global energy landscape topography determines the binding-folding thermodynamics and kinetics, crucial for the feasibility and efficiency of realizing biomolecular function. We also found "U-shape" temperature-dependent kinetic behavior and a dynamical cross-over temperature for dividing exponential and nonexponential kinetics for two-state homodimers. Our study provides a unique way to bridge the gap between theory and experiments. PMID- 23754432 TI - The evolution of episodic memory. AB - One prominent view holds that episodic memory emerged recently in humans and lacks a "(neo)Darwinian evolution" [Tulving E (2002) Annu Rev Psychol 53:1-25]. Here, we review evidence supporting the alternative perspective that episodic memory has a long evolutionary history. We show that fundamental features of episodic memory capacity are present in mammals and birds and that the major brain regions responsible for episodic memory in humans have anatomical and functional homologs in other species. We propose that episodic memory capacity depends on a fundamental neural circuit that is similar across mammalian and avian species, suggesting that protoepisodic memory systems exist across amniotes and, possibly, all vertebrates. The implication is that episodic memory in diverse species may primarily be due to a shared underlying neural ancestry, rather than the result of evolutionary convergence. We also discuss potential advantages that episodic memory may offer, as well as species-specific divergences that have developed on top of the fundamental episodic memory architecture. We conclude by identifying possible time points for the emergence of episodic memory in evolution, to help guide further research in this area. PMID- 23754433 TI - Conserved microRNA pathway regulates developmental timing of retinal neurogenesis. AB - Most regions of the vertebrate central nervous system develop by the sequential addition of different classes of neurons and glia. This phenomenon has been best characterized in laminated structures like the retina and the cerebral cortex, in which the progenitor cells in these structures are thought to change in their competence as development proceeds to generate different types of neurons in a stereotypic sequence that is conserved across vertebrates. We previously reported that conditional deletion of Dicer prevents the change in competence of progenitors to generate later-born cell types, suggesting that specific microRNAs (miRNAs) are required for this developmental transition. In this report, we now show that three miRNAs, let-7, miR-125, and miR-9, are key regulators of the early to late developmental transition in retinal progenitors: (i) members of these three miRNA families increase over the relevant developmental period in normal retinal progenitors; (ii) inhibiting the function of these miRNAs produces changes in retinal development similar to Dicer CKO; (iii) overexpression of members of these three miRNA families in Dicer-CKO retinas can rescue the phenotype, allowing their progression to late progenitors; (iv) overexpression of these miRNAs can accelerate normal retinal development; (v) microarray and computational analyses of Dicer-CKO retinal cells identified two potential targets of the late-progenitor miRNAs: Protogenin (Prtg) and Lin28b; and (vi) overexpression of either Lin28 or Prtg can maintain the early progenitor state. Together, these data demonstrate that a conserved miRNA pathway controls a key step in the progression of temporal identity in retinal progenitors. PMID- 23754434 TI - Concepts and implications of altruism bias and pathological altruism. AB - The profound benefits of altruism in modern society are self-evident. However, the potential hurtful aspects of altruism have gone largely unrecognized in scientific inquiry. This is despite the fact that virtually all forms of altruism are associated with tradeoffs--some of enormous importance and sensitivity--and notwithstanding that examples of pathologies of altruism abound. Presented here are the mechanistic bases and potential ramifications of pathological altruism, that is, altruism in which attempts to promote the welfare of others instead result in unanticipated harm. A basic conceptual approach toward the quantification of altruism bias is presented. Guardian systems and their over arching importance in the evolution of cooperation are also discussed. Concepts of pathological altruism, altruism bias, and guardian systems may help open many new, potentially useful lines of inquiry and provide a framework to begin moving toward a more mature, scientifically informed understanding of altruism and cooperative behavior. PMID- 23754436 TI - Random fluctuation of selection coefficients and the extent of nucleotide variation in human populations. AB - It is well known that the selection coefficient of a mutant allele varies from generation to generation, and the effect of this factor on genetic variation has been studied by many theoreticians. However, no consensus has been reached. One group of investigators believes that fluctuating selection has an effect of enhancing genetic variation, whereas the other group contends that it has a diversity-reducing effect. In recent years, it has become possible to study this problem by using single nucleotide polymorphisms (SNPs) as well as exome sequence data. In this article we present the theoretical distributions of mutant nucleotide frequencies for the two models of fluctuating selection and then compare the distributions with the empirical distributions obtained from SNP and exome sequence data in human populations. Interestingly, both SNP and exome sequence data showed that the neutral mutation model fits the empirical distribution quite well. Furthermore, the mathematical models with diversity enhancing and diversity-reducing effects also fit the empirical distribution reasonably well. This result implies that there is no need of distinguishing between the diversity-enhancing and diversity-reducing models of fluctuating selection and the nucleotide polymorphism in human populations can be explained largely by neutral mutations when long-term evolution is considered. PMID- 23754435 TI - APE2 is required for ATR-Chk1 checkpoint activation in response to oxidative stress. AB - The base excision repair pathway is largely responsible for the repair of oxidative stress-induced DNA damage. However, it remains unclear how the DNA damage checkpoint is activated by oxidative stress at the molecular level. Here, we provide evidence showing that hydrogen peroxide (H2O2) triggers checkpoint kinase 1 (Chk1) phosphorylation in an ATR [ataxia-telangiectasia mutated (ATM) and Rad3-related]-dependent but ATM-independent manner in Xenopus egg extracts. A base excision repair protein, Apurinic/apyrimidinic (AP) endonuclease 2 (APE2, APN2, or APEX2), is required for the generation of replication protein A (RPA) bound single-stranded DNA, the recruitment of a checkpoint protein complex [ATR, ATR-interacting protein (ATRIP), and Rad9] to damage sites, and H2O2-induced Chk1 phosphorylation. A conserved proliferating cell nuclear antigen interaction protein box of APE2 is important for the recruitment of APE2 to H2O2-damaged chromatin. APE2 3'-phosphodiesterase and 3'-5' exonuclease activity is essential for single-stranded DNA generation in the 3'-5' direction from single-stranded breaks, referred to as single-stranded break end resection. In addition, APE2 associates with Chk1, and a serine residue (S86) in the Chk1-binding motif of APE2 is essential for Chk1 phosphorylation, indicating a Claspin-like but distinct role for APE2 in ATR-Chk1 signaling. Our data indicate that APE2 plays a vital and previously unexpected role in ATR-Chk1 checkpoint signaling in response to oxidative stress. Thus, our findings shed light on a distinct mechanism of how an ATR-Chk1-dependent DNA damage checkpoint is mediated by APE2 in the oxidative stress response. PMID- 23754437 TI - Dynamics of brain networks in the aesthetic appreciation. AB - Neuroimage experiments have been essential for identifying active brain networks. During cognitive tasks as in, e.g., aesthetic appreciation, such networks include regions that belong to the default mode network (DMN). Theoretically, DMN activity should be interrupted during cognitive tasks demanding attention, as is the case for aesthetic appreciation. Analyzing the functional connectivity dynamics along three temporal windows and two conditions, beautiful and not beautiful stimuli, here we report experimental support for the hypothesis that aesthetic appreciation relies on the activation of two different networks, an initial aesthetic network and a delayed aesthetic network, engaged within distinct time frames. Activation of the DMN might correspond mainly to the delayed aesthetic network. We discuss adaptive and evolutionary explanations for the relationships existing between the DMN and aesthetic networks and offer unique inputs to debates on the mind/brain interaction. PMID- 23754439 TI - Valley Chern numbers and boundary modes in gapped bilayer graphene. AB - Electronic states at domain walls in bilayer graphene are studied by analyzing their four- and two-band continuum models, by performing numerical calculations on the lattice, and by using quantum geometric arguments. The continuum theories explain the distinct electronic properties of boundary modes localized near domain walls formed by interlayer electric field reversal, by interlayer stacking reversal, and by simultaneous reversal of both quantities. Boundary mode properties are related to topological transitions and gap closures, which occur in the bulk Hamiltonian parameter space. The important role played by intervalley coupling effects not directly captured by the continuum model is addressed using lattice calculations for specific domain wall structures. PMID- 23754438 TI - Mammalian Exo1 encodes both structural and catalytic functions that play distinct roles in essential biological processes. AB - Mammalian Exonuclease 1 (EXO1) is an evolutionarily conserved, multifunctional exonuclease involved in DNA damage repair, replication, immunoglobulin diversity, meiosis, and telomere maintenance. It has been assumed that EXO1 participates in these processes primarily through its exonuclease activity, but recent studies also suggest that EXO1 has a structural function in the assembly of higher-order protein complexes. To dissect the enzymatic and nonenzymatic roles of EXO1 in the different biological processes in vivo, we generated an EXO1-E109K knockin (Exo1(EK)) mouse expressing a stable exonuclease-deficient protein and, for comparison, a fully EXO1-deficient (Exo1(null)) mouse. In contrast to Exo1(null/null) mice, Exo1(EK/EK) mice retained mismatch repair activity and displayed normal class switch recombination and meiosis. However, both Exo1 mutant lines showed defects in DNA damage response including DNA double-strand break repair (DSBR) through DNA end resection, chromosomal stability, and tumor suppression, indicating that the enzymatic function is required for those processes. On a transformation-related protein 53 (Trp53)-null background, the DSBR defect caused by the E109K mutation altered the tumor spectrum but did not affect the overall survival as compared with p53-Exo1(null) mice, whose defects in both DSBR and mismatch repair also compromised survival. The separation of these functions demonstrates the differential requirement for the structural function and nuclease activity of mammalian EXO1 in distinct DNA repair processes and tumorigenesis in vivo. PMID- 23754440 TI - Solid surface tension measured by a liquid drop under a solid film. AB - We show that a drop of liquid a few hundred microns in diameter placed under a solid, elastic, thin film (~10 MUm thick) causes it to bulge by tens of microns. The deformed shape is governed by equilibrium of tensions exerted by the various interfaces and the solid film, a form of Neumann's triangle. Unlike Young's equation, which specifies the contact angles at the junction of two fluids and a (rigid) solid, and is fundamentally underdetermined, both tensions in the solid film can be determined here if the liquid-vapor surface tension is known independently. Tensions in the solid film have a contribution from elastic stretch and a constant residual component. The residual component, extracted by extrapolation to films of vanishing thickness and supported by analysis of the elastic deformation, is interpreted as the solid-fluid surface tension, demonstrating that compliant thin-film structures can be used to measure solid surface tensions. PMID- 23754442 TI - Reversible 2D/3D coatings from zipper-assembly of block copolymer micelles. AB - A zipper-assembly of micelles into 2D/3D coatings is reported. Block copolymer micelles that incorporate a poly(n-octadecyl methacrylate) block are zipped and unzipped on demand onto a PMMA surface. The mechanism implies an interdigitation of molecular brushes enabling 15 nm micelles to be assembled into monolayers or multilayers. PMID- 23754443 TI - Trefoil factor family member 2 (Tff2) KO mice are protected from high-fat diet induced obesity. AB - INTRODUCTION: Trefoil factor family member 2 (Tff2) is a small gut peptide, mainly known for its protective and healing functions. As previously demonstrated, high-fat (HF) feeding can rapidly and specifically modulate Tff2 transcription in key tissues of mice, including the duodenum and mesenteric adipose tissue, therefore suggesting a novel role for this gene in energy balance. DESIGN AND METHODS: To explore whether and how Tff2 can influence feeding behavior and energy metabolism, Tff2 knock-out (KO) mice were challenged with HF diet for 12 weeks, hence food and energy intakes, body composition, as well as energy excretion and serum lipid and hormonal levels were analyzed. Finally, energy efficiency was estimated. RESULTS: Tff2 KO mice showed a greater appetite and higher energy intake compared to wild-type (WT). Consistently, they presented lower levels of serum leptin, and increased transcription of agouti related protein (Agrp) in the hypothalamus. Though energy and triglyceride fecal excretion were augmented in Tff2 KO mice, digestible energy intake was superior. However, KO mice were finally protected from HF diet-induced obesity, and accumulated less weight and fat depots than WT animals, while keeping a normal lean mass. Energy efficiency was lower in HF-KO mice, while energy expenditure and locomotor activity were globally increased. CONCLUSIONS: The present work demonstrates previously unsuspected roles for Tff2 and suggests it to be a mastermind in the control of energy balance and a promising therapeutic target for obesity. PMID- 23754441 TI - Making lasting memories: remembering the significant. AB - Although forgetting is the common fate of most of our experiences, much evidence indicates that emotional arousal enhances the storage of memories, thus serving to create, selectively, lasting memories of our more important experiences. The neurobiological systems mediating emotional arousal and memory are very closely linked. The adrenal stress hormones epinephrine and corticosterone released by emotional arousal regulate the consolidation of long-term memory. The amygdala plays a critical role in mediating these stress hormone influences. The release of norepinephrine in the amygdala and the activation of noradrenergic receptors are essential for stress hormone-induced memory enhancement. The findings of both animal and human studies provide compelling evidence that stress-induced activation of the amygdala and its interactions with other brain regions involved in processing memory play a critical role in ensuring that emotionally significant experiences are well-remembered. Recent research has determined that some human subjects have highly superior autobiographic memory of their daily experiences and that there are structural differences in the brains of these subjects compared with the brains of subjects who do not have such memory. Understanding of neurobiological bases of such exceptional memory may provide additional insights into the processes underlying the selectivity of memory. PMID- 23754444 TI - Urinary and ejaculatory dysfunction induced by denervation of specific striated muscles anatomically related to the urethra in male rats. AB - AIMS: The purpose of the present study was to determine the contribution of the external urethral sphincter (EUS), the ischiocavernous (IC), or the bulbospongiosus (BS) on the control of micturition, copulatory behavior and semen expulsion in male rats. We hypothesized that the EUS contributes to maintain urinary continence, while all three muscles participate in expulsive urethral functions. METHODS: In Experiment 1, it was analyzed the effects of bilateral denervation of IC, BS or EUS, or sham surgery, on voiding behavior and urinary parameters measured before surgery and 2 and 10 days post-surgery. In Experiment 2, copulatory behavior and the weight of the seminal plug expelled during ejaculation were recorded before and after sham surgery or bilateral denervation of the aforementioned muscles. Immediately after ejaculation, the animals were anesthetized to confirm the denervation and determine whether seminal material had accumulated in the lower urinary tract. RESULTS: In IC-denervated animals, voiding duration and the number of mounts was increased, and intromission or ejaculation patterns were absent. Denervation of BS induced signs of post micturition dribble, decreased voiding frequency, increased urine volume and reduced the amount of semen ejaculated. Denervation of EUS induced signs of post micturition dribble and urinary incontinence, as well as retrograde ejaculation. CONCLUSIONS: Striated muscles anatomically related to the urethra contribute differentially to the control of continence and expulsive urethral functions. Damages to the muscles or to their innervation, as may occur during pelvic surgery, would result in sexual and urinary dysfunctions. PMID- 23754445 TI - Controlling the diameter, monodispersity, and solubility of ApoA1 nanolipoprotein particles using telodendrimer chemistry. AB - Nanolipoprotein particles (NLPs) are nanometer-scale discoidal particles that feature a phospholipid bilayer confined within an apolipoprotein "scaffold," which are useful for solubilizing hydrophobic molecules such as drugs and membrane proteins. NLPs are synthesized either by mixing the purified apolipoprotein with phospholipids and other cofactors or by cell-free protein synthesis followed by self-assembly of the nanoparticles in the reaction mixture. Either method can be problematic regarding the production of homogeneous and monodispersed populations of NLPs, which also currently requires multiple synthesis and purification steps. Telodendrimers (TD) are branched polymers made up of a dendritic oligo-lysine core that is conjugated to linear polyethylene glycol (PEG) on one end, and the lysine "branches" are terminated with cholic acid moieties that enable the formation of nanomicelles in aqueous solution. We report herein that the addition of TD during cell-free synthesis of NLPs produces unique hybrid nanoparticles that have drastically reduced polydispersity as compared to NLPs made in the absence of TD. This finding was supported by dynamic light scattering, fluorescence correlation spectroscopy, and cryo transmission electron microscopy (Cryo-EM). These techniques demonstrate the ability of TDs to modulate both the NLP size (6-30 nm) and polydispersity. The telodendrimer NLPs (TD-NLPs) also showed 80% less aggregation as compared to NLPs alone. Furthermore, the versatility of these novel nanoparticles was shown through direct conjugation of small molecules such as fluorescent dyes directly to the TD as well as the insertion of a functional membrane protein. PMID- 23754446 TI - Biowaiver monographs for immediate-release solid oral dosage forms: Zidovudine (azidothymidine). AB - Literature data on the properties of zidovudine relevant to waiver of in vivo bioequivalence (BE) testing requirements for the approval of immediate-release (IR) solid oral dosage forms containing zidovudine alone or in combination with other active pharmaceutical ingredients (APIs) are reviewed. Solubility, dissolution, and permeability data for zidovudine, along with its dosing schedule, therapeutic index and pharmacokinetic properties, and reports related to BE/bioavailability were all taken into consideration. Data for solubility and permeability suggest that zidovudine belongs to Class I according to the Biopharmaceutics Classification System. Also, zidovudine is not a narrow therapeutic index drug. Although five out of 13 formulations tested in vivo (mostly of unreported composition) failed to show BE, it appears that in vitro studies performed according to biowaiver methods could predict in vivo behavior. Nevertheless, it is highly recommended that if a biowaiver is to be applied, excipient choices be limited to those found in IR drug products approved in International Conference on Harmonisation (ICH) or associated countries in the same dosage form (Table 2 of this monograph), in their usual amounts. These conclusions apply to products containing zidovudine as the only API and also to fixed combination products containing zidovudine with respect to the zidovudine component of the formulation. PMID- 23754447 TI - Quantitative assessment of the influence of cytochrome P450 2C19 gene polymorphisms and digestive tract cancer risk. AB - Cytochrome P450 (CYP) 2C19 metabolizes many promutagens and procarcinogens to biologically active metabolites, which strongly promote proliferation of cancer cells in vitro and in vivo. The CYP2C19 gene exhibits several genetic polymorphisms that are thought to play a major role in inter-individual variability in drug response, drug-xenobiotic interactions, and in cancer susceptibility. Two polymorphisms of the CYP2C19 gene (CYP2C19*2, CYP2C19*3) which was associated with reduced enzyme activity have been investigated extensively digestive tract cancer; however, these studies have yielded contradictory results. To clarify this inconsistency, we performed this meta analysis including 15 case-control studies with a total of 3,252 cases and 6,269 controls. Overall, we found significant association between CYP2C19*2 and digestive tract cancer (OR = 1.27, 95 % CI, 1.07-1.51, P = 0.007) while no significant results were found for CYP2C19*3. Potential sources of heterogeneity including cancer types, ethnicity, source of control, and sample size of study were assessed. In the subgroup analyses by cancer types, significant association was detected only in esophagus cancer for CYP2C19*2. When stratified by ethnicity, significantly increased risks were found for the CYP2C19*2 polymorphism among Asians. This meta-analysis demonstrated that the CYP2C19*2 polymorphism is a risk factor for developing digestive tract cancer. However, additional very large-scale studies are warranted to provide conclusive evidence on the effects of the CYP2C19 gene on risk of digestive tract cancer. PMID- 23754448 TI - LEP gene variant is associated with prostate cancer but not with colorectal cancer. AB - The leptin (LEP) gene has been considered to be implicated in the development of cancer. However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the association of LEP rs7799039 variant with colorectal and prostate cancer risk. Published literatures from PubMed and Embase were retrieved. Pooled odds ratio (OR) with 95 % confidence interval (CI) was calculated using fixed or random effects model. A total of five studies (2,596 colorectal cancer cases and 3,240 controls) for association of LEP rs7799039 variant with colorectal cancer, and three studies (1,343 prostate cancer cases and 1,238 controls) for association with prostate cancer were included in the meta-analysis. For colorectal cancer, there was no significant association of LEP rs7799039 variant with this disease under homogeneous co-dominant model (OR = 0.88, 95 % CI = 0.75-1.02), heterogeneous co-dominant model (OR = 1.00, 95 % CI = 0.89-1.13) and dominant model (OR = 0.97, 95 % CI = 0.87-1.08); however, there was a marginal association under recessive model (OR = 0.87, 95 % CI = 0.76 0.99). For prostate cancer, there was significant association of LEP rs7799039 variant with this disease under homogeneous co-dominant model (OR = 1.33, 95 % CI = 1.06-1.67) and recessive model (OR = 1.26, 95 % CI = 1.05-1.51), but not under heterogeneous co-dominant model (OR = 1.24, 95 % CI = 0.87-1.77) and dominant model (OR = 1.30, 95 % CI = 1.84). The present meta-analysis demonstrated that the LEP rs7799039 variant was associated with prostate cancer, but not with colorectal cancer. PMID- 23754449 TI - Human papillomavirus is independent prognostic factor on outcome of oropharyngeal squamous cell carcinoma. AB - The primary aim of this study is to assess differences in patients' clinicopathological characteristics based on human papillomavirus (HPV) status and the effect of HPV status on outcome in oropharyngeal squamous cell carcinoma (OSCC). The medical registry of 81 patients who were treated for OSCC was retrospectively analyzed. Factors that are found to be predictive of poor overall survival and event risk by univariate Cox's regression analysis included age greater than 60 years (hazard ratio (HR), 1.2, p = 0.02, and HR, 1.12, p = 0.05), poor Eastern Cooperative Oncology Group performance (HR,1.6, p = 0.01, and HR,1.32, p = 0.001), advanced T stage (HR,1.38, p = 0.01, and HR,1.4, p = 0.02), advanced N stage(HR, 1.6, p = 0.03, and HR,1.5, p = 0.03), smoking history (HR,1.4, p = 0.04, and HR, 1.6, p = 0.03), and HPV-negative patients (HR, 2.4, p = 0.012, and HR, 1.8, p = 0.01). HPV-positive tumors were estimated to have a 36 % reduction in risk of death and 32% reduction in event risk. HPV status had independent prognostic effects on survival and event-free survival. PMID- 23754450 TI - Long noncoding RNA AC096655.1-002 has been officially named as gastric cancer associated transcript 1, GACAT1. PMID- 23754451 TI - Novel challenges of multi-society investigator-initiated studies: a paradigm shift for technique and technology evaluation. AB - The introduction of innovative techniques and novel technologies into clinical practice is a challenge that confronts all aspects of healthcare delivery. Upheaval from shrinking research funding and declining healthcare reimbursements now forces patients, doctors, hospitals, payers, regulators, and even health systems into conflict as new therapies struggle to find a place in the therapeutic armamentarium. The escalating costs of healthcare force all parties to consider both the medical risks/benefits as well as the economic efficiency of proposed tools and therapies. We highlight these challenges by examining the process of initiating and conducting a "society-as-investigator" clinical trial to assess the safety of the natural orifice translumenal endoscopic surgery (NOTES) approach to cholecystectomy in the context of the issues that confront technology diffusion today. PMID- 23754452 TI - Suction test to demonstrate the peritoneal edge during laparoscopic extraperitoneal inguinal hernia repair. AB - INTRODUCTION: Inadequate peritoneal dissection from retroperitoneal structures may account for a large number of hernia recurrences amongst surgeons and trainees who are new to totally extraperitoneal (TEP) laparoscopic inguinal hernia repair. In this paper, we describe a simple dynamic test that allows surgeons to better appreciate the peritoneal edge during the initial dissection phase of TEP inguinal hernia repair, allowing for more adequate dissection of the peritoneum from retroperitoneal structures before placement of mesh. METHODS: Data from a single surgeon was collected on 113 consecutive patients who underwent laparoscopic TEP inguinal hernia repair at the Royal North Shore Hospital in Sydney. The data was retrospectively reviewed to determine the number of cases in which the suction test led to further peritoneal dissection prior to mesh placement. OPERATIVE TECHNIQUE: After balloon dissection of the pre peritoneal space and initial dissection of peritoneum and sac from retroperitoneal structures, a laparoscopic suction device is used to aspirate the insufflated gas from the pre-peritoneal space to cause the peritoneum to bulge anteriorly, thus demonstrating the edge of the peritoneal reflection. Further dissection is performed if deemed necessary at this point, and the mesh is placed over the hernia defect. RESULTS: 136 TEP hernia repairs were performed in 113 patients. In 26 (23 %) of patients, the abovementioned technique was of particular value resulting in further dissection of peritoneum prior to mesh placement. There were no complications as a direct result of the test. CONCLUSION: This dynamic suction test is a risk-free and useful operative tool for surgeons and trainees who are new to TEP inguinal hernia repair, and provides a definitive way of identifying the peritoneal reflection to ensure the peritoneum has been dissected adequately prior to mesh placement. PMID- 23754453 TI - C20H4(C4F8)3: a fluorine-containing annulated corannulene that is a better electron acceptor than C60. AB - At sixes and sevens: The reaction of corannulene with 35 equivalents of 1,4 C4F8I2 is an efficient and a relatively selective process that yields two main products in which six H atoms are substituted with three C4F8 moieties that form six- and seven-membered rings. Low-temperature photoelectron spectroscopy showed the electron affinity of the major isomer (shown) exceeds that of C60 (2.74+/ 0.02 and 2.689+/-0.008 eV, respectively). PMID- 23754454 TI - Cranial morphological variation among contemporary Mexicans: Regional trends, ancestral affinities, and genetic comparisons. AB - Genetic research has documented geographical variation within Mexico that corresponds to trends in ancestry admixture from postcolonial times on. The purpose of this study is to determine whether craniometric variation among contemporary Mexicans is comparable to that reported in genetic studies. Standard osteometric measurements were taken on 82 male crania derived from forensic cases, with geographic origins of the specimens spanning over two-thirds of Mexico's states. To study similarities in regional clustering patterns with genetic data, k-means clustering analyses were performed, followed by chi-square tests of association between cluster assignments and geographic region of origin. Normal mixtures analyses were performed, centered on three "ancestral" sample proxies to estimate classification probability to each ancestry. The results demonstrate that the cranial morphological sample data cluster similarly to the regional groupings inferred from the genetic data. Additionally, the results indicate a gradient trend in population structure for contemporary Mexicans, with the proportion of Amerindian ancestry increasing from North to South while, conversely, European ancestry proportion estimates increase from South to North. Furthermore, the probabilities for classification of African ancestry remained low across the regions, again reflecting the results for the genetic data. Cranial morphological variation is well aligned with the genetic data for describing broad trends among Mexican populations, as well as yielding comparable estimates of general ancestry affiliations that reflect Mexico's history of Spanish contact and colonialism. PMID- 23754455 TI - Management of MRSA/GISA, VISA Endocarditis. AB - Infective endocarditis is a worrisome disease, with no significant decrease of the incidence and mortality in the last decade. Despite a changing epidemiology over the last few years, S. aureus remains the leading causative organism in Canada, the U.S., and Europe. Experimental animal models of endocarditis have been extensively used to evaluate the activity of new drugs or new regimens. Although vancomycin has shown satisfactory in vivo activity against MRSA, the drug has failed to demonstrate a bactericidal activity against isolates with reduced susceptibility to glycopeptides. Among the new, recently available antimicrobial agents, experimental data strongly support daptomycin and ceftaroline fosamil as effective options. In clinical practice, vancomycin continues to be recommended for the treatment of IE caused by MRSA. However, its use is more and more debated, especially with the availability of new effective therapeutic options. Further studies are needed to define the role of these new antimicrobials in the treatment of MRSA and GISA endocarditis. PMID- 23754456 TI - Concentration of tissue angiotensin II increases with severity of experimental pancreatitis. AB - Necrotizing pancreatitis is a serious condition that is associated with high morbidity and mortality. Although vasospasm is reportedly involved in necrotizing pancreatitis, the underlying mechanism is not completely clear. In addition, the local renin-angiotensin system has been hypothesized to be involved in the progression of pancreatitis and trypsin has been shown to generate angiotensin II under weakly acidic conditions. However, to the best of our knowledge, no studies have reported elevated angiotensin II levels in tissue with pancreatitis. In the present study, the concentration of pancreatic angiotensin II in rats with experimentally induced acute pancreatitis was measured. Acute pancreatitis was induced by retrograde injection of 6% sodium taurocholate into the biliopancreatic duct. Control rats were sacrificed without injection into the biliopancreatic duct. The concentration of tissue angiotensin II was measured using the florisil method. Angiotensin II concentration in tissues with acute pancreatitis measured at 3, 6, 12 and 24 h following taurocholate injection were significantly higher than that of normal pancreatic tissue. In addition, the concentration of angiotensin II increased in a time-dependent manner. The results demonstrated that the angiotensin II generating system is involved in the transition from edematous to necrotizing pancreatitis in experimental animals. We hypothesize that locally formed angiotensin II affects the microenvironment in pancreatitis. PMID- 23754458 TI - Stimulant medication and substance use outcomes: a meta-analysis. AB - IMPORTANCE: Psychostimulant medication is an efficacious treatment for childhood attention-deficit/hyperactivity disorder, yet controversy remains regarding potential iatrogenic effects of stimulant medication, particularly with respect to increasing susceptibility to later substance use disorders. However, stimulant treatment was previously reported to reduce the risk of substance problems. OBJECTIVE: To meta-analyze the longitudinal association between treatment with stimulant medication during childhood and later substance outcomes (ie, lifetime substance use and substance abuse or dependence). DATA SOURCES: Studies published between January 1980 and February 2012 were identified using review articles, PubMed, and pertinent listservs. STUDY SELECTION: Studies with longitudinal designs in which medication treatment preceded the measurement of substance outcomes. DATA EXTRACTION AND SYNTHESIS: Odds ratios were extracted or provided by the study authors. Odds ratios were obtained for lifetime use (ever used) and abuse or dependence status for alcohol, cocaine, marijuana, nicotine, and nonspecific drugs for 2565 participants from 15 different studies. MAIN OUTCOMES AND MEASURES: Random-effects models estimated the overall association, and potential study moderators were examined. RESULTS: Separate random-effects analyses were conducted for each substance outcome, with the number of studies ranging from 3 to 11 for each outcome. Results suggested comparable outcomes between children with and without medication treatment history for any substance use and abuse or dependence outcome across all substance types. CONCLUSIONS: These results provide an important update and suggest that treatment of attention deficit/hyperactivity disorder with stimulant medication neither protects nor increases the risk of later substance use disorders. PMID- 23754459 TI - Stochastic method for determination of the organ-specific averaged SAR in realistic environments at 950 MHz. AB - The organ-specific averaged specific absorption rate (SARosa ) in a heterogeneous human body phantom, the Virtual Family Boy, is determined for the first time in five realistic electromagnetic environments at the Global System for Mobile Communications downlink frequency of 950 MHz. We propose two methods based upon a fixed set of finite-difference time-domain (FDTD) simulations for generating cumulative distribution functions for the SARosa in a certain environment: an accurate vectorial cell-wise spline interpolation with an average error lower than 1.8%, and a faster scalar linear interpolation with a maximal average error of 14.3%. These errors are dependent on the angular steps chosen for the FDTD simulations. However, it is demonstrated that both methods provide the same shape of the cumulative distribution function for the studied organs in the considered environments. The SARosa depends on the considered organ and the environment. Two factors influencing the SARosa are investigated for the first time: conductivity over the density ratio of an organ, and the distance of the organ's center of gravity to the body's surface and exterior of the phantom. A non-linear regression with our model provides a correlation of 0.80. The SARosa due to single plane-wave exposure is also investigated; a worst-case single plane-wave exposure is determined for all studied organs and has been compared with realistic SARosa values. There is no fixed worst-case polarization for all organs, and a single plane-wave exposure condition that exceeds 91% of the SARosa values in a certain environment can always be found for the studied organs. PMID- 23754460 TI - Tracking of fluorescence nanoparticles with nanometre resolution in a biological system: assessing local viscosity and microrheology. AB - The aim of the study was to establish a user-friendly approach for single fluorescence particle 3D localization and tracking with nanometre precision in a standard fluorescence microscope using a point spread function (PSF) approach, and to evaluate validity and precision for different analysis methods and optical conditions with particular application to microcirculatory flow dynamics and cell biology. Images of fluorescent particles were obtained with a standard fluorescence microscope equipped with a piezo positioner for the objective. Whole pattern (WP) comparison with a PSF recorded for the specific set-up and measurement of the outermost ring radius (ORR) were used for analysis. Images of fluorescent particles were recorded over a large range (about 7MUm) of vertical positions, with and without distortion by overlapping particles as well as in the presence of cultured endothelial cells. For a vertical range of 6.5MUm the standard deviation (SD) from the predicted value, indicating validity, was 9.3/8.7 nm (WP/ORR) in the vertical and 8.2/11.7 nm in the horizontal direction. The precision, determined by repeated measurements, was 5.1/3.8 nm in the vertical and 2.9/3.7 nm in the horizontal direction. WP was more robust with respect to underexposure or overlapping images. On the surface of cultured endothelial cells, a layer with 2.5 times increased viscosity and a thickness of about 0.8MUm was detected. With a validity in the range of 10 nm and a precision down to about 3-5 nm obtained by standard fluorescent microscopy, the PSF approach offers a valuable tool for a variety of experimental investigations of particle localizations, including the assessment of endothelial cell microenvironment. PMID- 23754461 TI - Thoracic periaortic and visceral adipose tissue and their cross-sectional associations with measures of vascular function. AB - OBJECTIVE: Perivascular fat may have a local adverse effect on the vasculature. We evaluated whether thoracic periaortic adipose tissue (TAT), a type of perivascular fat, and visceral adipose tissue (VAT) were associated with vascular function. DESIGN AND METHODS: TAT and VAT were quantified in Framingham Heart Study participants using multidetector-computed tomography; vascular function was assessed using brachial artery vasodilator function, peripheral arterial tone, and arterial tonometry (n = 2,735; 48% women; mean age, 50 years; mean body mass index [BMI], 27.7 kg/m(2) ). Using multiple linear regression, the relationships between TAT, VAT, and vascular measures was examined while adjusting for cardiovascular risk factors. RESULTS: Mean TAT and VAT volumes were 13.2 and 1763 cm(3) . TAT and VAT were associated with multiple vascular function measures after multivariable adjustment. After BMI adjustment, TAT and VAT remained negatively associated with peripheral arterial tone and inverse carotid femoral pulse wave velocity (P < 0.02); TAT was negatively associated with hyperemic mean flow velocity (P = 0.03). Associations of TAT with vascular function were attenuated after VAT adjustment (all P > 0.06). CONCLUSIONS: Thoracic periaortic and visceral fat are associated with microvascular function and large artery stiffness after BMI adjustment. These findings support the growing recognition of associations between ectopic fat and vascular function. PMID- 23754462 TI - Proton magnetic resonance spectroscopy in the evaluation of patients with acute Charcot neuro-osteoarthropathy. AB - OBJECTIVE: To evaluate whether bone marrow proton magnetic resonance spectroscopy (MRS) might provide a quantitative parameter able to assess disease activity in acute Charcot neuro-osteoarthropathy (CN). METHODS: Ten diabetic patients with stage 0 CN were prospectively evaluated at clinical onset and during treatment follow-up. The MRS lipid spectrum was analysed and a lipid polyunsaturation index (PUI) was calculated. Disease recovery was defined as the disappearance of bone marrow oedema as demonstrated on MRI short-tau-inversion-recovery (STIR) images. A 3-T MRI was used. RESULTS: Inter- and intra-individual PUI measurements generated reproducible results with approximately 7 % and 6 % variation respectively. Baseline PUI values were significantly higher in patients with acute CN compared with controls. Also, a significant positive correlation was observed between baseline PUI values and serum levels of IL-6 and TNF-alpha. During follow-up a gradual decrease in PUI was observed. The percentage reduction of PUI values at 3 months' follow-up with respect to baseline values showed a negative correlation with recovery time. CONCLUSIONS: Bone marrow MRS may provide a measurable index that allows progressive evaluation of disease activity in acute CN. MRS may be a complementary tool that can be used to guide clinicians in the management of acute CN patients. KEY POINTS: * Bone marrow MRS demonstrates lipid alterations in acute Charcot neuro-osteoarthropathy (CN). * Bone marrow MRS allows disease activity in acute CN to be evaluated. * MRS could become a new tool in the management of CN. PMID- 23754463 TI - ESUR prostate MR guidelines. Author reply. PMID- 23754465 TI - Image of the month-diagnosis. PMID- 23754464 TI - Estimation of relative binding free energy based on a free energy variational principle for the FKBP-ligand system. AB - Predicting an accurate binding free energy between a target protein and a ligand can be one of the most important steps in a drug discovery process. Often, many molecules must be screened to find probable high potency ones. Thus, a computational technique with low cost is highly desirable for the estimation of binding free energies of many molecules. Several techniques have thus far been developed for estimating binding free energies. Some techniques provide accurate predictions of binding free energies but high large computational cost. Other methods give good predictions but require tuning of some parameters to predict them with high accuracy. In this study, we propose a method to predict relative binding free energies with accuracy comparable to the results of prior methods but with lower computational cost and with no parameter needing to be carefully tuned. Our technique is based on the free energy variational principle. FK506 binding protein (FKBP) with 18 ligands is taken as a test system. Our results are compared to those from other widely used techniques. Our method provides a correlation coefficient (r2) of 0.80 between experimental and calculated relative binding free energies and yields an average absolute error of 0.70 kcal/mol compared to experimental values. These results are comparable to or better than results from other techniques. We also discuss the possibility to improve our method further. PMID- 23754466 TI - Time-dependent changes and gender differences in urinary dysfunction in patients with multiple system atrophy. AB - AIMS: Because time-dependent changes and gender differences in urinary dysfunction in patients with multiple system atrophy (MSA) are yet unknown, we aimed to determine these parameters through a combination of urodynamic examination and the results of a questionnaire on urinary symptoms. METHODS: We retrospectively reviewed 66 patients with MSA who responded to a urinary symptoms questionnaire and underwent urodynamic examination more than twice. The participants' mean age was 62 years and mean disease duration at the first urodynamic examination was 3.2 years. Mean duration between the first and second urodynamic examination was 441 days. RESULTS: With regard to overall (both genders) time-dependent change, none of the urinary symptoms showed significant differences. In the urodynamic examination there were significant differences in reduced urine flow, increased post-void residuals, and decreased detrusor contractility at the second examination. With regard to gender differences, at the first examination, night-time urinary frequency, and voiding symptoms were significantly more severe in male than in female patients; however, at the second examination, except for urinary urgency, gender differences were not observed for any other symptoms. In urodynamic examination, the degree of detrusor contraction was significantly less in male patients at the first examination. However, no significant differences were found in urodynamic examination at the second examination. CONCLUSIONS: The present study indicates that voiding dysfunction progressed without significant worsening of voiding symptoms. In addition, gender differences are important in evaluating urinary dysfunction being basically less severe in female than in male patients, at least during the early stage. Neurourol. Urodynam. 33:516-523, 2014. (c) 2013 Wiley Periodicals, Inc. PMID- 23754467 TI - Elucidation of release characteristics of highly soluble drug trimetazidine hydrochloride from chitosan-carrageenan matrix tablets. AB - The aim of this study was to better understand the underlying drug release characteristics from matrix tablets based on the combination of chitosan (CS) and different types of carrageenans [kappa (kappa)-CG, iota (iota)-CG, and lambda (lambda)-CG]. Highly soluble trimetazidine hydrochloride (TH) was used as a model drug. First, characteristics of drug release from different formulations were investigated, and then in situ complexation capacity of CG with TH and CS was studied by differential scanning calorimetry and Fourier transform infrared spectroscopy. Erosion and swelling of matrix were also characterized to better understand the drug-release mechanisms. Effects of pH and ionic strength on drug release were also studied. It was found that not only iota-CG and lambda-CG could reduce the burst release of TH by the effect of TH-CG interaction, CS-iota-CG- and CS-lambda-CG-based polyelectrolyte film could further modify the controlled release behavior, but not CS-kappa-CG. High pH and high ionic strength resulted in faster drug release from CS-kappa-CG- and CS-iota-CG-based matrix, but drug release from CS-lambda-CG-based matrix was less sensitive to pH and ionic strength. In conclusion, CS-lambda-CG-based matrix tablets are quite promising as controlled-release drug carrier based on multiple mechanisms. PMID- 23754468 TI - Thermodynamic signature of substrates and substrate analogs binding to human blood group B galactosyltransferase from isothermal titration calorimetry experiments. AB - It has been observed earlier that human blood group B galactosyltransferase (GTB) hydrolyzes its donor substrate UDP-Galactose (UDP-Gal) in the absence of acceptor substrate, and that this reaction is promoted by the presence of an acceptor substrate analog, alpha-L-Fuc-(1,2)-beta-D-3-deoxy-Gal-O-octyl (3DD). This acceleration of enzymatic hydrolysis of UDP-Gal was traced back to an increased affinity of GTB toward the donor substrate in the presence of 3DD. Herein, we present new thermodynamic data from isothermal titration calorimetry (ITC) on the binding of donor and acceptor substrates and analogs to GTB. ITC data are supplemented by surface plasmon resonance and STD-NMR titration experiments. These new data validate mutual allosteric control of binding of donor and acceptor substrates to GTB. It is of note that ITC experiments reveal significant differences in enthalpic and entropic contributions to binding of the natural donor substrate UDP-Gal, when compared with its analog UDP-Glucose (UDP-Glc). This may reflect different degrees of ordering of an internal loop (amino acids 176-194) and the C-terminus (amino acids 346-354), which close the binding pocket on binding of UDP-Gal or UDP-Glc. As both ligands have rather similar dissociation constants KD and almost identical modes of binding this finding is unexpected. Another surprising finding is that an acceptor analog, alpha-L-Fuc (1,2)-beta-D-3-amino-3-deoxy-Gal-O-octyl (3AD) as well as the constituent monosaccharide beta-D-3-amino-3-deoxy-Gal-O-octyl (3AM) effectively inhibit enzymatic hydrolysis of UDP-Gal. This is unexpected, too, because in analogy to the effects of 3DD one would have predicted acceleration of enzymatic hydrolysis of UDP-Gal. It is difficult to explain these observations based on structural data alone. Therefore, our results highlight that there is an urgent need of experimental studies into the dynamic properties of GTB. PMID- 23754469 TI - Prospective clinical trial of gelatin-thrombin matrix as first line treatment of posterior epistaxis. AB - OBJECTIVES/HYPOTHESIS: To evaluate the effectiveness of gelatin-thrombin matrix for first line treatment of posterior epistaxis. Secondarily, we evaluated discomfort during treatment and the cost savings of treatment with gelatin thrombin matrix compared to posterior packing, endoscopic, or endovascular treatment at our institution. STUDY DESIGN: Prospective pilot, nonblinded, noncontrolled registered clinical trial (NCT01098578). METHODS: Twenty patients with posterior epistaxis were enrolled into this study. Gelatin-thrombin matrix was used for posterior epistaxis treatment with simultaneous ipsilateral choanal occlusion. Patients were discharged within 2 hours of being successfully treated. A visual analog scale (range 0-10) was used to assess treatment discomfort. Patients were evaluated in clinic 5 and 30 days after treatment to assess for intranasal complications and recurrent epistaxis. RESULTS: Gelatin-thrombin matrix successfully treated epistaxis in 80% of the patients. The procedure was associated with a mean discomfort of 3.6 (range 0-9.7). The institutional per case cost of treatment of patients with posterior epistaxis with gelatin-thrombin matrix is 80.3%, 87.4%, and 89.4% less than with endoscopic surgery, posterior packing, or embolization, respectively. There were no complications. CONCLUSION: This pilot study demonstrated that gelatin-thrombin matrix is a safe and both a clinically effective and cost-saving means of treating posterior epistaxis. In this study, its use is associated with a low level of discomfort. This treatment method may improve the quality of care for patients with posterior epistaxis. PMID- 23754470 TI - Dose-dependent alterations in gene expression and testosterone production in fetal rat testis after exposure to di-n-hexyl phthalate. AB - In utero exposure to the phthalate ester plasticizer di-n-hexyl phthalate (DnHP) is known to affect the development of the male reproductive system and induce alterations in androgen-dependent tissues of male rat offspring. Male reproductive malformations produced by several phthalates have been causally linked to decreased testosterone production during the gestational period. This study was designed to evaluate the dose-response relationship for the effects of DnHP on the synthesis and production of testosterone in the fetal rat testis. Pregnant Sprague-Dawley rats were administered the vehicle (olive oil) and either DnHP (5 to 625 mg kg(-1) per day) or diethylhexyl phthalate (DEHP) (50 or 625 mg kg(-1) per day), by gavage, from gestation day (GD) 12 to19. Fetal testes were assessed on GD 19. DnHP reduced ex vivo testosterone production and down regulated the expression of several genes required for cholesterol transport and steroid synthesis (i.e. SR-B1, StAR, P450scc, 3betaHSD and P450c17). These inhibitions were dose dependent. A no-effect level was established at 5 mg kg(-1) per day and a lowest-effect level at 20 mg kg(-1) per day. mRNA levels of SR-B1, StAR, P450scc and 3betaHSD were not similarly decreased in the adrenals. In conclusion, DnHP shares the same mode of action as DEHP in disrupting fetal testicular androgen synthesis. Alterations in testosterone production and in key steroidogenic gene expressions were apparent at lower doses than those causing postnatal reproductive malformations after gestational exposure during the critical period of male sexual differentiation. This suggests that they can be considered early biomarkers of DnHP-induced fetal testicular effects in rats. PMID- 23754472 TI - Jury panel member perceptions of interpersonal-affective traits of psychopathy predict support for execution in a capital murder trial simulation. AB - Recent research with college undergraduate mock jurors suggests that how psychopathic they perceive a criminal defendant to be is a powerful predictor of whether they will support a death verdict in simulated capital murder trials. Perceived affective and interpersonal traits of psychopathy are especially predictive of support for capital punishment, with perceived remorselessness explaining a disproportionate amount of variance in these attitudes. The present study attempted to extend these findings with a more representative sample of community members called for jury duty (N = 304). Jurors reviewed a case vignette based on an actual capital murder trial, provided sentencing verdicts, and rated the defendant on several characteristics historically associated with the construct of psychopathy. Consistent with prior findings, remorselessness predicted death verdicts, as did the affective and interpersonal features of psychopathy - though the latter effect was more pronounced among jurors who were Caucasian and/or who described their political beliefs as moderate rather than conservative or liberal. Results are discussed in terms of the potentially stigmatizing effects of psychopathy evidence in capital cases. PMID- 23754471 TI - Neisseria meningitidis expresses a single 3-deoxy-d-arabino-heptulosonate 7 phosphate synthase that is inhibited primarily by phenylalanine. AB - Neisseria meningitidis is the causative agent of meningitis and meningococcal septicemia is a major cause of disease worldwide, resulting in brain damage and hearing loss, and can be fatal in a large proportion of cases. The enzyme 3-deoxy d-arabino-heptulosonate 7-phosphate synthase (DAH7PS) catalyzes the first reaction in the shikimate pathway leading to the biosynthesis of aromatic metabolites including the aromatic acids l-Trp, l-Phe, and l-Tyr. This pathway is absent in humans, meaning that enzymes of the pathway are considered as potential candidates for therapeutic intervention. As the entry point, feedback inhibition of DAH7PS by pathway end products is a key mechanism for the control of pathway flux. The structure of the single DAH7PS expressed by N. meningitidis was determined at 2.0 A resolution. In contrast to the other DAH7PS enzymes, which are inhibited only by a single aromatic amino acid, the N. meningitidis DAH7PS was inhibited by all three aromatic amino acids, showing greatest sensitivity to l-Phe. An N. meningitidis enzyme variant, in which a single Ser residue at the bottom of the inhibitor-binding cavity was substituted to Gly, altered inhibitor specificity from l-Phe to l-Tyr. Comparison of the crystal structures of both unbound and Tyr-bound forms and the small angle X-ray scattering profiles reveal that N. meningtidis DAH7PS undergoes no significant conformational change on inhibitor binding. These observations are consistent with an allosteric response arising from changes in protein motion rather than conformation, and suggest ligands that modulate protein dynamics may be effective inhibitors of this enzyme. PMID- 23754473 TI - Craniospinal irradiation with concurrent temozolomide and nimotuzumab in a child with primary metastatic diffuse intrinsic pontine glioma. A compassionate use treatment. AB - Primary metastatic diffuse intrinsic pontine glioma (DIPG) is relatively rare and associated with a dismal prognosis. Combining craniospinal irradiation (CSI) with concurrent temozolomide and nimotuzumab therapy may slightly improve tumor control and overall survival. However, little is known about the feasibility and toxicity of this treatment approach. Here, we describe the case of an 8-year-old girl with primary metastatic DIPG who received craniospinal radiotherapy, a local boost, and concurrent temozolomide and nimotuzumab treatment based on an individual therapy recommendation. Radiotherapy could be completed without any interruption. However, concurrent temozolomide had to be disrupted several times due to considerable acute myelotoxicity (grade III-IV).Maintenance immunochemotherapy could be started with a delay of 5 days and was performed according to treatment schedule. The disease could be stabilized for a few months. A routine MRI scan finally depicted disease progression 5.7 months after the start of irradiation. The patient died 1.9 months later. PMID- 23754474 TI - Maternal admixture and population structure in Mexican-Mestizos based on mtDNA haplogroups. AB - The maternal ancestry (mtDNA) has important applications in different research fields, such as evolution, epidemiology, identification, and human population history. This is particularly interesting in Mestizos, which constitute the main population in Mexico (~93%) resulting from post-Columbian admixture between Spaniards, Amerindians, and African slaves, principally. Consequently, we conducted minisequencing analysis (SNaPshot) of 11 mitochondrial single nucleotide polymorphisms in 742 Mestizos of 10 populations from different regions in Mexico. The predominant maternal ancestry was Native American (92.9%), including Haplogroups A, B, C, and D (47, 23.7, 15.9, and 6.2%, respectively). Conversely, European and African ancestries were less frequent (5.3 and 1.9%, respectively). The main characteristics of the maternal lineages observed in Mexican-Mestizos comprised the following: 1) contrasting geographic gradient of Haplogroups A and C; 2) increase of European lineages toward the Northwest; 3) low or absent, but homogeneous, African ancestry throughout the Mexican territory; 4) maternal lineages in Mestizos roughly represent the genetic makeup of the surrounding Amerindian groups, particularly toward the Southeast, but not in the North and West; 5) continuity over time of the geographic distribution of Amerindian lineages in Mayas; and 6) low but significant maternal population structure (FST = 2.8%; P = 0.0000). The average ancestry obtained from uniparental systems (mtDNA and Y-chromosome) in Mexican-Mestizos was correlated with previous ancestry estimates based on autosomal systems (genome-wide single nucleotide polymorphisms and short tandem repeats). Finally, the comparison of paternal and maternal lineages provided additional information concerning the gender bias admixture, mating patterns, and population structure in Mestizos throughout the Mexican territory. PMID- 23754475 TI - Connecting molecular structure and exciton diffusion length in rubrene derivatives. AB - Connecting molecular structure and exciton diffusion length in rubrene derivatives demonstrates how the diffusion length of rubrene can be enhanced through targeted functionalization aiming to enhance self-Forster energy transfer. Functionalization adds steric bulk, forcing the molecules farther apart on average, and leading to increased photoluminescence efficiency. A diffusion length enhancement greater than 50% is realized over unsubstituted rubrene. PMID- 23754476 TI - Palladium-catalyzed migratory insertion of isocyanides: an emerging platform in cross-coupling chemistry. AB - Isocyanides have been important building blocks in organic synthesis since the discovery of the Ugi reaction and related isocyanide-based multicomponent reactions. In the past decade isocyanides have found a new application as versatile C1 building blocks in palladium catalysis. Palladium-catalyzed reactions involving isocyanide insertion offer a vast potential for the synthesis of nitrogen-containing fine chemicals. This Minireview discusses all the achievements in this emerging field. PMID- 23754477 TI - microRNAs and cartilage. AB - microRNAs are small non-coding RNAs that in the last decade have emerged as overarching regulators of gene expression. Their abundance, ability to repress a large number of target genes and overlapping target specificity indicate a complex network of interactions that is still being defined. A number of studies focused on the role of microRNAs in cartilage have identified a small number, including miR-140 and -675 as playing important roles in regulation of cartilage homeostasis and together with the broader description of the activity of microRNAs in other tissues are beginning to define the function of microRNAs in cartilage development and homeostasis. PMID- 23754478 TI - Can high-spatial resolution T2-weighted endorectal MRI rule out clinically significant prostate cancer? AB - PURPOSE: To evaluate whether clinically significant prostate cancer (PCa) can be ruled out by high-spatial resolution T2-weighted endorectal MRI (eMRI) in a cohort of patients with biopsy-proven PCa. PATIENTS AND METHODS: A retrospective analysis was carried out for consecutive patients who underwent 1.5 Tesla eMRI for local staging before open radical prostatectomy. The cohort was dichotomized into patients with apparent or inapparent tumour on eMRI. The results were compared with final histopathology, and an analysis for presence of clinically significance PCa was performed. RESULTS: A total of 385 patients were included in the study; in 85 patients (22 %), no apparent lesion suspicious for PCa was detected on eMRI, still final pathology revealed clinically significant PCa in 61 of these patients (72 %). In contrast, 256 (85 %) of the 300 patients with apparent tumour in eMRI harboured clinically significant PCa. eMRI could not differentiate clinically significant from insignificant PCa in neither of the groups (p > 0.6). CONCLUSIONS: Presence of clinically significant cancer cannot be excluded by high-resolution 1.5 Tesla T2-weighted eMRI. The results of the study suggest that the role of T2-weighted eMRI for selecting patients suitable for AS is limited. PMID- 23754479 TI - DSF method optimization and its application in predicting protein thermal aggregation kinetics. AB - Differential scanning fluorimetry (DSF) has gained wide acceptance in the therapeutic protein development. However, the effects of dyes and surfactants that may affect structural transitions have not been studied thoroughly to date. We therefore first optimized the DSF method by studying surfactant-containing formulations and found that the presence of surfactants generally required medium to-high protein concentrations and that high SYPRO(r) Orange concentration in a DSF experiment may lower protein thermal transitions. We also benchmarked DSF against differential scanning calorimetry (DSC) and evaluated the capability of thermal parameters (from DSF/DSC) to predict real-time thermal aggregation kinetics monitored by size exclusion chromatography (SEC) and analytical ultracentrifugation (AUC) in different scenarios. For monoclonal antibody (MAb) fragment, both DSF and DSC were predictive of thermal aggregation rate. For MAb3, a good correlation was observed between DSF and DSC, none of which was, however, indicative of protein aggregation kinetics. In a surfactant ranging study, DSF did not agree with DSC and was not predictive of the aggregation kinetics of the MAb fragment. The concentration-dependent thermal behavior was also studied by DSF. Although higher concentration, in general, tends to lower protein transition temperature, case where it was independent of protein concentration was also presented. PMID- 23754480 TI - Image of the month-diagnosis. PMID- 23754482 TI - [Therapy limitations in intensive care medicine]. PMID- 23754481 TI - [Postoperative complaints : gender differences in expectations, prevalence and appraisal]. AB - OBJECTIVE: Women report more severe postoperative complaints than men (e.g. nausea and pain) and expectations of complaints prior to surgery influence the postoperative complaints. Therefore, the aim of this study was to explore if gender differences in complaint expectation can account for differences in postoperative complaints. A further objective was to investigate the effective load of complaints and to look for gender differences. METHODS: In total 281 patients (128 men and 153 women) were included in the study and all patients underwent elective general surgery. Patients were asked for symptom expectations and symptom experiences prior to surgery. After surgery they answered the Anesthesiological Questionnaire (ANP) a validated self-rating method for the assessment of postoperative symptoms and complaints. The symptoms referred to in the questionnaire included sensation of cold, sensation of heat, nausea and vomiting, tickly throat, croakiness, dry mouth and thirst, difficulty in breathing, sore throat, pain in the area of surgery, pain in the area of infusion, muscle pain, back pain, headache, difficulties in urination, difficulty in awakening and feeling of somatic discomfort. In addition patients rated the affective load of the postoperative complaints. RESULTS: In previous surgery women reported experiencing more postoperative somatic complaints than men. Sex related differences were significant (p < 0.05) for sensation of cold, nausea and vomiting, tickly throat, croakiness, sore throat, pain and the feeling of somatic discomfort. Likewise, women expected more intensive postoperative complaints following the forthcoming operation. After surgery women reported significantly more severe complaints in negative symptoms of the ANP (e.g. nausea and vomiting, pain and somatic discomfort). Effect sizes of sex-related differences varied according to the symptom (e.g. for pain effect strength d = 0.50, for nausea d = 0.60 and for thirst d = 0.13). Effect sizes decreased when the effect of expectation was statistically controlled. Logistic regression revealed that expectation was an independent predictor for the sensation of severe nausea (odds ratio OR 4.3] and intensive postoperative pain (OR 2.6). Regardless of gender, postoperative pain, nausea and dry mouth/thirst were symptoms with the highest affective load. CONCLUSIONS: Preoperative expectations increase gender differences in somatic complaints following surgery. Anesthesiological education of patients should influence dysfunctional expectations. Postoperative pain, nausea and thirst should be the main targets of interventions to improve patient complaints. PMID- 23754483 TI - [Breakthrough pain and short-acting opioids]. AB - Conventional opioid therapy consists of the regular administration of extended release opioids following fixed time intervals and, as needed, the supplemental use of an immediate-release formulation. For the patient needs of such rescue medication, recent studies distinguished different scenarios, such as an inadequate daily opioid dose or time interval (end-of-dose failure) from so called breakthrough pain where the attacks can suddenly occur either spontaneously (idiopathic pain) or due to certain provocations (incident pain) despite optimal dose adjustment. In line with this time course, a fast and short lasting elevation of the opioid plasma concentration seems to be reasonable. Although in a recent European survey breakthrough pain attacks in the majority of cancer pain patients were sufficiently treated with immediate-release opioids, currently running clinical trials examine whether the application of transmucosal or intranasal fentanyl with their known reduced time to maximum plasma concentrations show a possible advantage in comparison to immediate-release opioids. In these clinical trials the pain intensity and number of pain episodes were significantly reduced following transmucosal or intranasal fentanyl; however, the magnitude of these effects does not convincingly appear to be clinically relevant. Among other reasons this may be related to the fact that those patients who would perhaps benefit from such treatment have not yet been identified. PMID- 23754484 TI - Characterization of the allergenic potential of proteins: an assessment of the kiwifruit allergen actinidin. AB - Assessment of the potential allergenicity (IgE-inducing properties) of novel proteins is an important challenge in the overall safety assessment of foods. Resistance to digestion with pepsin is commonly measured to characterize allergenicity, although the association is not absolute. We have previously shown that specific IgE antibody production induced by systemic [intraperitoneal (i.p.)] exposure of BALB/c strain mice to a range of proteins correlates with allergenic potential for known allergens. The purpose of the present study was to explore further the utility of these approaches using the food allergen, actinidin. Recently, kiwifruit has become an important allergenic foodstuff, coincident with its increased consumption, particularly as a weaning food. The ability of the kiwifruit allergen actinidin to stimulate antibody responses has been compared with the reference allergen ovalbumin, and with the non-allergen bovine haemoglobin. Haemoglobin was rapidly digested by pepsin whereas actinidin was resistant unless subjected to prior chemical reduction (reflecting intracellular digestion conditions). Haemoglobin stimulated detectable IgG antibody production at relatively high doses (10%), but failed to provoke detectable IgE. In contrast, actinidin was both immunogenic and allergenic at relatively low doses (0.25% to 1%). Vigorous IgG and IgG1 antibody and high titre IgE antibody responses were recorded, similar to those provoked by ovalbumin. Thus, actinidin displays a marked ability to provoke IgE, consistent with allergenic potential. These data provide further encouragement that in tandem with analysis of pepsin stability, the induction of IgE after systemic exposure of BALB/c strain mice provides a useful approach for the prospective identification of protein allergens. PMID- 23754486 TI - Delayed mobilization after microsurgical reconstruction: an independent risk factor for pneumonia. AB - OBJECTIVES/HYPOTHESIS: Large defects secondary to oral cancer resection are reconstructed with microsurgical free flaps. Pulmonary complications in these patients are common. Postoperative mobilization is recommended to decrease respiratory complications; however, many microsurgeons are reluctant to adopt early mobilization protocols due to the perceived risk of flap compromise. The purpose of this study was to determine the incidence of pneumonia among patients undergoing oral cancer resection and immediate free flap reconstruction and to compare the incidence of this complication between patients mobilized early (<4 days postoperative) versus later. A secondary goal was to determine whether early postoperative mobilization affected microvascular flap outcome. STUDY DESIGN: Retrospective cohort study. METHODS: Sixty-two consecutive patients treated between 2005 and 2009 with oral carcinoma resection and free flap reconstruction were studied. Information pertaining to comorbidities, postoperative care, and complications were collected. Risk factors for development of pulmonary and flap complications were analyzed. RESULTS: The incidence of pneumonia was 30.6%. Longer intensive care unit stay (P = 0.01), tracheostomy decannulation later than 10 days (P = 0.04), and longer operative times (P = 0.04) were significantly associated with pneumonia. Delayed mobilization (after day 4 postoperative) was an independent risk factor for pneumonia (OR = 4.2, 95% CI: 1.1, 17.1). Early mobilization (before day 4 postoperative) was not associated with an increased incidence of secondary flap procedures or flap failure. CONCLUSION: Late mobilization of free flap patients is an independent risk factor for developing postoperative pneumonia. Earlier mobilization does not increase flap failure rates, is safe, and should be strongly considered in all free flap patients to reduce pulmonary complications. PMID- 23754487 TI - The adolescent and young adult with cancer: state of the art--epithelial cancer. AB - The adolescent and young adult (AYA) is defined as a patient of 15 to 39 years of age at initial cancer diagnosis, and this group has particular medical needs and age-related issues. Excluding violent deaths, cancer is the leading cause of death among the AYA population. Lymphomas, melanoma, testicular cancer, female genital tract malignancies, thyroid cancer, bone and soft tissue sarcomas, leukemias, central nervous system tumors, breast cancer, and nongonadal germ cell tumors account for 95 % of the cancers in this group. Among those, the epithelial cancer of AYA comprehends the minimum amount and its incidence rates tend to increase with age. This review presents information about epidemiology, biologic peculiarities, as well as standard treatment strategies for epithelial cancers in AYA. PMID- 23754489 TI - Acidosis inhibits mineralization in human osteoblasts. AB - Osteoblasts and osteoclasts maintain bone volume. Acidosis affects the function of these cells including mineral metabolism. We examined the effect of acidosis on the expression of transcription factors and mineralization in human osteoblasts in vitro. Human osteoblasts (SaM-1 cells) derived from the ulnar periosteum were cultured with alpha-MEM containing 50 MUg/ml ascorbic acid and 5 mM beta-glycerophosphate (calcifying medium). Acidosis was induced by incubating the SaM-1 cells in 10 % CO2 (pH approximately 7.0). Mineralization, which was augmented by the calcifying medium, was completely inhibited by acidosis. Acidosis depressed c-Jun mRNA and increased osteoprotegerin (OPG) production in a time-dependent manner. Depressing c-Jun mRNA expression using siRNA increased OPG production and inhibited mineralization. In addition, depressing OPG mRNA expression with siRNA enhanced mineralization in a dose-dependent manner. Acidosis or the OPG protein strongly inhibited mineralization in osteoblasts from neonatal mice. The present study was the first to demonstrate that acidosis inhibited mineralization, depressed c-Jun mRNA expression, and induced OPG production in human osteoblasts. These results suggest that OPG is involved in mineralization via c-Jun in human osteoblasts. PMID- 23754488 TI - Molecular mechanisms of osteoblast/osteocyte regulation by connexin43. AB - Osteoblasts, osteocytes, and osteoprogenitor cells are interconnected into a functional network by gap junctions formed primarily by connexin43 (Cx43). Over the past two decades, it has become clear that Cx43 is important for the function of osteoblasts and osteocytes. This connexin contributes to the acquisition of peak bone mass and is a major modulator of cortical modeling. We review key data from human and mouse genetics on the skeletal consequences of ablation or mutation of the Cx43 gene (Gja1) and the molecular mechanisms by which Cx43 regulates the differentiation, function, and survival of osteogenic lineage cells. We also discuss putative second messengers that are communicated by Cx43 gap junctions, the role of hemichannels, and the function of Cx43 as a scaffold for signaling molecules. Current knowledge demonstrates that Cx43 is more than a passive channel; rather, it actively participates in the generation and modulation of cellular signals that drive skeletal development and homeostasis. PMID- 23754490 TI - Treatment thresholds for osteoporosis and reimbursability criteria: perspectives associated with fracture risk-assessment tools. AB - The definition of osteoporosis was based for several years on bone mineral density values, which were used by most guidelines for defining treatment thresholds. The availability of tools for the estimation of fracture risk, such as FRAXTM or its adapted Italian version, DeFRA, is providing a way to grade osteoporosis severity. By applying these new tools, the criteria identified in Italy for treatment reimbursability (e.g., "Nota 79") are confirmed as extremely conservative. The new fracture risk-assessment tools provide continuous risk values that can be used by health authorities (or "payers") for identifying treatment thresholds. FRAX estimates the risk for "major osteoporotic fractures," which are not counted in registered fracture trials. Here, we elaborate an algorithm to convert vertebral and nonvertebral fractures to the "major fractures" of FRAX, and this allows a cost-effectiveness assessment for each drug. PMID- 23754491 TI - Fast and accurate fitting of relaxation dispersion data using the flexible software package GLOVE. AB - Relaxation dispersion spectroscopy is one of the most widely used techniques for the analysis of protein dynamics. To obtain a detailed understanding of the protein function from the view point of dynamics, it is essential to fit relaxation dispersion data accurately. The grid search method is commonly used for relaxation dispersion curve fits, but it does not always find the global minimum that provides the best-fit parameter set. Also, the fitting quality does not always improve with increase of the grid size although the computational time becomes longer. This is because relaxation dispersion curve fitting suffers from a local minimum problem, which is a general problem in non-linear least squares curve fitting. Therefore, in order to fit relaxation dispersion data rapidly and accurately, we developed a new fitting program called GLOVE that minimizes global and local parameters alternately, and incorporates a Monte-Carlo minimization method that enables fitting parameters to pass through local minima with low computational cost. GLOVE also implements a random search method, which sets up initial parameter values randomly within user-defined ranges. We demonstrate here that the combined use of the three methods can find the global minimum more rapidly and more accurately than grid search alone. PMID- 23754492 TI - Recombinant human decorin upregulates p57KIP2 expression in HepG2 hepatoma cell lines. AB - Increasing the expression of cyclin-cyclin-dependent kinase inhibitors (cyclin CDK) using small molecule inhibitors is a therapeutic strategy used to suppress cancer cell growth. Decorin (DCN), a functional component of the extracellular matrix, has been implicated in the suppression of cell proliferation by upregulating p21, a cyclin-CDK inhibitor. The purpose of this study was to examine the effect of recombinant decorin on the reactivation of p57KIP2, whose expression is silenced in hepatocellular carcinoma (HCC). Cell viability assay, cell cycle analysis, apoptosis assay and quantitative real time-PCR experiments were performed in three groups of HepG2 human cells: Uninfected HepG2 cells (control group), pcDNA3.1 vector-infected HepG2 cells (pcDNA3.1 group) and pcDNA3.1-DCN-infected HepG2 cells (pcDNA3.1-DCN group). Our results revealed that recombinant human decorin inhibited cell proliferation, induced G0/G1 phase arrest and induced apoptosis by increasing the expression of caspase-3 in the pcDNA3.1-DCN group. The expression of p57KIP2 mRNA in the pcDNA3.1-DCN group was higher than in the pcDNA3.1 and control groups (P<0.05); however, there was no statistically significant difference between the control and pcDNA3.1 groups (P>0.05). In conclusion, recombinant human decorin reactivated p57KIP2 expression in HepG2 cells. As the expression level of p57KIP2 is downregulated in HCC, our finding may serve as a basis for the therapy and prognosis of HCC, although further studies are required. PMID- 23754493 TI - Under-folded proteins: Conformational ensembles and their roles in protein folding, function, and pathogenesis. AB - For decades, protein function was intimately linked to the presence of a unique, aperiodic crystal-like structure in a functional protein. The two only places for conformational ensembles of under-folded (or partially folded) protein forms in this picture were either the end points of the protein denaturation processes or transiently populated folding intermediates. Recent years witnessed dramatic change in this perception and conformational ensembles, which the under-folded proteins are, have moved from the shadow. Accumulated to date data suggest that a protein can exist in at least three global forms-functional and folded, functional and intrinsically disordered (nonfolded), and nonfunctional and misfolded/aggregated. Under-folded protein states are crucial for each of these forms, serving as important folding intermediates of ordered proteins, or as functional states of intrinsically disordered proteins (IDPs) and IDP regions (IDPRs), or as pathology triggers of misfolded proteins. Based on these observations, conformational ensembles of under-folded proteins can be classified as transient (folding and misfolding intermediates) and permanent (IDPs and stable misfolded proteins). Permanently under-folded proteins can further be split into intentionally designed (IDPs and IDPRs) and unintentionally designed (misfolded proteins). Although intrinsic flexibility, dynamics, and pliability are crucial for all under-folded proteins, the different categories of under foldedness are differently encoded in protein amino acid sequences. PMID- 23754494 TI - ADAMTS5 is required for biomechanically-stimulated healing of murine tendinopathy. AB - A recently developed murine model of tendinopathy, induced by TGF-beta1 injection, has been used to examine the reparative capacity of tendinopathic Achilles in Adamts5(-/-) mice. After TGF-beta1 injection and 2 weeks of treadmill exercise, the Achilles from Adamts5(-/-) mice exhibited a reduction in maximum tensile stress of approximately 60%. However, in contrast to wild type mice previously characterized by this model, Adamts5(-/-) mice subjected to further treadmill exercise were unable to reverse this biomechanical deficit. This nonreparative phenotype was accompanied by a major deficiency, relative to wild type, in expression of Col1a1 and Col3a1 and an abnormally elevated expression of a wide range of integrins. In addition, the tendinopathic Adamts5(-/-) mice showed a persistent accumulation of chondrogenic cells in the tendon body and an aggrecan-rich fibrocartilaginous matrix within disorganized collagen fiber bundles. Moreover, consistent with the compromised biomechanical properties of the Achilles in the Adamts5(-/-) mice, in vivo gait analysis revealed a strong trend (p = 0.07) towards increased swing time of the injected limb in Adamts5(-/ ) relative to wild-type mice. These findings demonstrate that a deficiency in ADAMTS5 promotes a chondrogenic response to TGF-beta1 injection that is not reversed by treadmill exercise. Hence, repair of biomechanically compromised tendons exhibiting midsubstance chondroid accumulation requires ADAMTS5. PMID- 23754495 TI - Identification of Annexin A1 interacting proteins in chronic myeloid leukemia KCL22 cells. AB - In the present study, we used a functional proteomic approach to identify Annexin A1 (Anxa1) interacting proteins in the Philadelphia-positive KCL22 cell line. We focused on Anxa1 because it is one of the major proteins upregulated in imatinib sensitive KCL22S cells versus imatinib-resistant KCL22R. Our proteomic strategy revealed 21 interactors. Bioinformatic analysis showed that most of these proteins are involved in cell death processes. Among the proteins identified, we studied the interaction of Anxa1 with two phosphatases, Shp1 and Shp2, which were recently identified as biomarkers of imatinib sensitivity in patients affected by chronic myeloid leukemia. Our data open new perspectives in the search for annexin-mediated signaling pathways and may shed light on mechanisms of resistance to imatinib that are unrelated to Bcr-Abl activity. All mass spectrometry data have been deposited in the ProteomeXchange with identifier PXD000030. PMID- 23754496 TI - A review on functional results of sphincter-saving surgery for rectal cancer: the anterior resection syndrome. AB - The aim of this review is to characterize the functional results and "anterior resection syndrome" (ARS) after sphincter-saving surgery for rectal cancer. The purpose of sphincter-saving operations is to save the anal sphincters by avoiding the need for rectal abdomino-perineal resection with a permanent stoma. A variety of alternative techniques have been proposed and, today, ultra-low anterior resections of the rectum are commonplace. Inevitably rectal resections modify anorectal physiology. The backdrop of the functional asset for ultralow anterior resections is related to a small neorectal capacity with high endo-neorectal pressures that act together on a weakened sphincteric mechanism. Sometimes a defecation disorder called ARS may be induced and the patient experiences an extremely low quality of life. Impaired bowel function is usually provoked either by colonic dysmotility, neorectal reservoir dysfunction, anal sphincter damage or by a combination of these factors. Surgical technique defects can contribute to these possible causes: anastomotic ischemia, short length of the descending colon and stretching of neorectal mesentery may play a role. Unfortunately, there is no therapeutic algorithm or gold standard treatment that may be used for ARS. Nevertheless, it is rational to use conservative therapy first and then resort to surgery. Drugs, rehabilitative treatment and sacral neuromodulation may be used; after failure of conservative methods, surgical treatment can be considered. PMID- 23754497 TI - Modeling multisystem biological risk in later life: allostatic load in the Lothian birth cohort study 1936. AB - OBJECTIVES: To investigate and replicate a multisystem model of biological risk, or allostatic load, in a sample of generally healthy older adults. METHODS: Multigroup confirmatory factor analysis (MG-CFA) was applied to data from the Lothian Birth Cohort 1936 (n = 726). Blood samples were taken at a physical examination. Three markers of inflammation (fibrinogen, interleukin-6, and C reactive protein), five metabolic markers (high- and low-density lipoprotein, body mass index, glycated hemoglobin, and triglyceride), and blood pressure (mean sitting systolic and diastolic blood pressure) were used to estimate a second order CFA model of allostatic load. Our sample was split into those taking antihypertensive, anti-inflammatory, lipid-lowering, and diabetes medications (n = 470), and those who were not (n = 256), in order to test the stability of the CFA model across groups. RESULTS: In the nonmedicated sample, a second-order allostatic load model showed good fit to the data. However, the second-order model failed to estimate in the medicated group. The factor correlations between blood pressure and inflammation and metabolism were smaller in magnitude in the medicated group. Invariance analysis on the first-order measurement model suggested significant differences across groups in the associations of low density lipoprotein and HbA1c with metabolism. CONCLUSIONS: Reliable measurement of allostatic load is possible in ageing samples free of medications but is complicated in the presence of medications. MG-CFA represents a highly versatile method for the analysis of allostatic load. PMID- 23754498 TI - Tryptamine and dimethyltryptamine inhibit indoleamine 2,3 dioxygenase and increase the tumor-reactive effect of peripheral blood mononuclear cells. AB - Indoleamine 2,3-dioxygenase (IDO) is an interferon-gamma (IFN-gamma)-induced tryptophan-degrading enzyme, producing kynurenine (KYN) that participates in the mechanism of tumor immune tolerance. Thus, IDO inhibition has been considered a strategy for anticancer therapy. The aim of this study was to identify whether the metabolites originated from the competitive routes of tryptophan metabolism, such as the serotonergic or N, N-dimethyltryptamine (DMT) pathways, have inhibitory effects on recombinant human IDO (rhIDO) activity. Serotonin and melatonin had no effect; on the other hand, tryptamine (TRY) and DMT modulated the activity of rhIDO as classical non-competitive inhibitors, with Ki values of 156 and 506 MUM, respectively. This inhibitory effect was also observed on constitutively expressed or IFN-gamma-induced IDO in the A172 human glioma cell line. TRY and DMT increased the cytotoxic activity of peripheral blood mononuclear cells (PBMCs) in co-culture assays. We conclude that the IDO inhibition by TRY and DMT contributed to a more effective tumor-reactive response by the PBMCs. PMID- 23754499 TI - A validated silver-nanoparticle-enhanced chemiluminescence method for the determination of citalopram in pharmaceutical preparations and human plasma. AB - A simple and sensitive chemiluminescence (CL) method was developed for the determination of citalopram in pharmaceutical preparations and human plasma. The method is based on the enhancement of the weak CL signal of the luminol-H2 O2 system. It was found that the CL signal arising from the reaction between alkaline luminol and H2 O2 was greatly increased by the addition of silver nanoparticles in the presence of citalopram. Prepared silver nanoparticles (AgNPs) were characterized by UV-visible spectroscopy and transmission electron microscopy (TEM). Various experimental parameters affecting CL intensity were studied and optimized for the determination of citalopram. Under optimized experimental conditions, CL intensity was found to be proportional to the concentration of citalopram in the range 40-2500 ng/mL, with a correlation coefficient of 0.9997. The limit of detection (LOD) and limit of quantification (LOQ) of the devised method were 3.78 and 12.62 ng/mL, respectively. Furthermore, the developed method was found to have excellent reproducibility with a relative standard deviation (RSD) of 3.65% (n = 7). Potential interference by common excipients was also studied. The method was validated statistically using recovery studies and was successfully applied to the determination of citalopram in the pure form, in pharmaceutical preparations and in spiked human plasma samples. Percentage recoveries were found to range from 97.71 to 101.99% for the pure form, from 97.84 to 102.78% for pharmaceutical preparations and from 95.65 to 100.35% for spiked human plasma. PMID- 23754500 TI - Sex determination of human skeletal populations using latent profile analysis. AB - Accurately estimating biological sex from the human skeleton can be especially difficult for fragmentary or incomplete remains often encountered in bioarchaeological contexts. Where typical anatomically dimorphic skeletal regions are incomplete or absent, observers often take their best guess to classify biological sex. Latent profile analysis (LPA) is a mixture modeling technique which uses observed continuous data to estimate unobserved categorical group membership using posterior probabilities. In this study, sex is the latent variable (male and female are the two latent classes), and the indicator variables used here were eight standard linear measurements (long bone lengths, diaphyseal and articular breadths, and circumferences). Mplus (Muthen and Muthen: Mplus user's guide, 6th ed. Los Angeles: Muthen & Muthen, 2010) was used to obtain maximum likelihood estimates for latent class membership from a known sample of individuals from the forensic data bank (FDB) (Jantz and Moore-Jansen: Database for forensic anthropology in the United States 1962-1991, Ann Arbor, MI: Interuniversity Consortium for Political and Social Research, 2000) (n = 1,831), yielding 87% of correct classification for sex. Then, a simulation extracted 5,000 different random samples of 206 complete cases each from the FDB (these cases also had known sex). We then artificially imposed patterns of missing data similar to that observed in a poorly preserved bioarchaeological sample from Medieval Asturias, Spain (n = 206), and ran LPA on each sample. This tested the efficacy of LPA under extreme conditions of poor preservation (missing data, 42%). The simulation yielded an average of 82% accuracy, indicating that LPA is robust to large amounts of missing data when analyzing incomplete skeletons. PMID- 23754503 TI - Alcohol use does not equal abuse-reply. PMID- 23754501 TI - Trehalose limits BSA aggregation in spray-dried formulations at high temperatures: implications in preparing polymer implants for long-term protein delivery. AB - Polymer implants are promising systems for sustained release applications but their utility for protein delivery has been hindered because of concerns over drug stability at elevated temperatures required for processing. Using bovine serum albumin (BSA) as a model, we have assessed whether proteins can be formulated for processing at elevated temperatures. Specifically, the effect of trehalose and histidine-HCl buffer on BSA stability in a spray-dried formulation has been investigated at temperatures ranging from 80 degrees C to 110 degrees C. When both the sugar and buffer are present, aggregation is suppressed even when exposed to 100 degrees C, the extrusion temperature of poly(lactide-co-glycolide) (PLGA), a bioresorbable polymer. Estimation of aggregation rate constants (k) indicate that though both trehalose and histidine-HCl buffer contribute to BSA stability, the effect because of trehalose alone is more pronounced. BSA-loaded PLGA implants were prepared using hot-melt extrusion process and in vitro release was conducted in phosphate buffered saline at 37 degrees C. Comparison of drug released from implants prepared using four different formulations confirmed that maximal release was achieved from the formulation in which BSA was least aggregated. These studies demonstrate that when trehalose and histidine-HCl buffer are included in spray-dried formulations, BSA stability is maintained both during processing at 100 degrees C and long-term residence within implants. PMID- 23754504 TI - Clinical significance of IgA anti-cardiolipin and IgA anti-beta2glycoprotein I antibodies. AB - IgA antiphospholipid antibodies (aPL) are not currently recognized as formal laboratory criteria for the Antiphospholipid Syndrome (APS). This is mainly due to methodological issues (different study designs, use of various non standardized IgA assays). However, there are experimental data showing the pathogenic role of IgA anti-cardiolipin antibodies (aCL) and IgA anti beta2glycoprotein I antibodies (anti-beta2GPI). Isolated IgA aCL are not very common, therefore their testing could be useful in the case of strong suspicion of APS but negative results for other aPL tests. IgA anti-beta2GPI seem to be the most prevalent isotype in patients with Systemic Lupus Erythematosus (SLE), with a significant association with thrombotic events. Such a clinical relevance has been recently recognized by the inclusion of these autoantibodies among the aPL tests in the novel SLICC classification criteria for SLE. Emerging interest has been raised by IgA anti-beta2GPI against domain 4/5 as a novel subgroup of clinically relevant aPL. PMID- 23754505 TI - Mechanochromic photonic gels. AB - Polymer gels are remarkable materials with physical structures that can adapt significantly and quite rapidly with changes in the local environment, such as temperature, light intensity, electrochemistry, and mechanical force. An interesting phenomenon observed in certain polymer gel systems is mechanochromism - a change in color due to a mechanical deformation. Mechanochromic photonic gels are periodically structured gels engineered with a photonic stopband that can be tuned by mechanical forces to reflect specific colors. These materials have potential as mechanochromic sensors because both the mechanical and optical properties are highly tailorable via incorporation of diluents, solvents, nanoparticles, or polymers, or the application of stimuli such as temperature, pH, or electric or strain fields. Recent advances in photonic gels that display strain-dependent optical properties are discussed. In particular, this discussion focuses primarily on polymer-based photonic gels that are directly or indirectly fabricated via self-assembly, as these materials are promising soft material platforms for scalable mechanochromic sensors. PMID- 23754506 TI - What's the harm? Genetic counselor perceptions of adverse effects of genetics service provision by non-genetics professionals. AB - Anecdotal accounts suggest some patients have experienced negative outcomes as a result of receiving genetics services from non-genetics providers, but empirical evidence of these incidents and their outcomes is limited. This study examined genetic counselors' perceptions of the occurrence of such incidents in the state of Minnesota. Twenty-five genetic counselors completed an on-line survey and 20 also participated in a semi-structured telephone interview. The interviewees recalled and described 37 specific incidents they perceived as having negative outcomes for patients and/or their families. Inductive and cross-case analysis revealed common themes including: adverse psychosocial effects, inadequate genetic counseling, genetic testing and screening errors, medical mismanagement, negative shifts in attitudes toward medical providers, and unnecessary use of health care resources. Commonly mentioned strategies for preventing/mitigating negative outcomes included: educational outreach and awareness programs for medical providers and the general public, standardized testing and screening processes, and implementing mechanisms for reporting and addressing adverse events. Additional findings, practice and policy implications, and research recommendations are discussed. PMID- 23754508 TI - Vocal fold hemorrhage: factors predicting recurrence. AB - OBJECTIVES/HYPOTHESIS: Vocal fold hemorrhage is an acute phonotraumatic injury treated with voice rest; recurrence is a generally accepted indication for surgical intervention. This study aims to identify factors predictive of recurrence based on outcomes of a large clinical series. STUDY DESIGN: Retrospective cohort. METHODS: Retrospective review of cases of vocal fold hemorrhage presenting to a university laryngology service. Demographic information was compiled. Videostroboscopic exams were evaluated for hemorrhage extent, presence of varix, mucosal lesion, and/or vocal fold paresis. Vocal fold hemorrhage recurrence was the main outcome measure. Follow-up telephone survey was used to complement clinical data. RESULTS: Forty-seven instances of vocal fold hemorrhage were evaluated (25M:22F; 32 professional voice users). Twelve of the 47 (26%) patients experienced recurrence. Only the presence of varix demonstrated significant association with recurrence (P = 0.0089) on multivariate logistic regression. CONCLUSION: Vocal fold hemorrhage recurred in approximately 26% of patients. Varix was a predictor of recurrence, with 48% of those with varix experiencing recurrence. Monitoring, behavioral management and/or surgical intervention may be indicated to treat patients with such characteristics. PMID- 23754507 TI - Distal attachment of flexor tendon allograft: a biomechanical study of different reconstruction techniques in human cadaver hands. AB - We compared the mechanical force of tendon-to-bone repair techniques for flexor tendon reconstruction. Thirty-six flexor digitorum profundus (FDP) tendons were divided into three groups based upon the repair technique: (1) suture/button repair using FDP tendon (Pullout button group), (2) suture bony anchor using FDP tendon (Suture anchor group), and (3) suture/button repair using FDP tendon with its bony attachment preserved (Bony attachment group). The repair failure force and stiffness were measured. The mean load to failure and stiffness in the bony attachment group were significantly higher than that in the pullout button and suture anchor groups. No significant difference was found in failure force and stiffness between the pullout button and suture anchor groups. An intrasynovial flexor tendon graft with its bony attachment has significantly improved tensile properties at the distal repair site when compared with a typical tendon-to-bone attachment with a button or suture anchor. The improvement in the tensile properties at the repair site may facilitate postoperative rehabilitation and reduce the risk of graft rupture. PMID- 23754510 TI - Mechanistic investigation of immunosuppression in patients with condyloma acuminata. AB - Condyloma acuminatum (CA) is a common sexually transmitted disease caused by human papillomavirus (HPV) infection. Previous studies have identified that the occurrence, relapse and cancerization of CA is relevant to immune imbalance caused by immune hypofunction or immunoregulatory dysfunction. However, to date, the specific mechanisms accounting for immune imbalance in CA patients have remained elusive. In the present study, changes in the expression levels of myeloid differentiation factor 88 (MyD88) and toll-like receptors (TLRs) were determined in lesion tissues and peripheral blood samples obtained from CA patients by fluorescence quantitative PCR and western blot analysis. The results indicated that TLRs and MyD88 expression was upregulated in the lesion tissues only. In addition, the expression of forkhead box P3, a characteristic marker of regulatory T cells (Tregs), transforming growth factor-beta1 and interleukin (IL) 10, inhibitory factors secreted by Tregs and inhibitory costimulatory molecules, cytotoxic T-lymphocyte antigen 4, glucocorticoid-induced TNFR-related protein and programmed cell death protein 1 was observed to be upregulated, indicating that immunosuppression of Tregs was enhanced significantly. However, the expression levels of NKG2D and NKp46, natural killer (NK) cell activation receptors located on the surface of NK cells, decreased markedly indicating that HPV infection inhibits the activation of NK cells. The secretion levels of various cytokines in the peripheral blood of CA patients were detected by enzyme-linked immunosorbent assay revealing that IL-2, IL-12 and interferon-gamma levels were markedly lower than that of healthy subjects. By contrast, the expression levels of tumor necrosis factor-alpha, IL-4 and IL-10 were markedly increased in CA samples compared with the control, with the exception of IL-6. Taken together, these results are consistent with the hypothesis of immunosuppression in CA patients. Increased expression of MyD88 and TLRs is likely to enhance immunosuppression of Tregs, leading to the imbalance of Th1/Th2, cytotoxic T cell type 1 (Tc1)/Tc2 cells and secreted cytokines. PMID- 23754511 TI - Prevalence of serum celiac antibody in patients with IBD in Japan. AB - BACKGROUND: Although the incidence of inflammatory bowel diseases (IBD) in Japan has increased, the prevalence of celiac disease is considered very low with the lowest genetic disposition. IBD is reported as the most common comorbidity because of the high positive rate of serological celiac markers. The aim of this study was to examine the current incidence of celiac disease, especially in IBD patients in Japan, where both wheat consumption and incidence of IBD have increased. METHODS: A total of 172 patients with IBD and 190 controls in Japan were screened for serum antibody of tissue transglutaminase and deaminated gliadin peptide. In sero-positive patients, HLA testing and upper gastrointestinal endoscopy with duodenal biopsy was performed. Some of the sero positive patients started a gluten-restricted or unrestricted diet, and serological change was determined. RESULTS: The positivity of both serum antibodies was significantly higher in IBD and correlated with disease activity. However, no biopsy-defined or HLA-defined true celiac disease was found. A decrease in serum antibody titers was observed with a gluten-restricted diet. CONCLUSIONS: Despite the increased incidence of IBD and high positivity for serum celiac antibody in Japanese IBD patients, no true-positive celiac disease was noted, suggesting the presence of gluten intolerance in these populations. PMID- 23754513 TI - Oxygen nano-bubble water reduces calcium oxalate deposits and tubular cell injury in ethylene glycol-treated rat kidney. AB - Renal tubular cell injury induced by oxalate plays an important role in kidney stone formation. Water containing oxygen nano-bubbles (nanometer-sized bubbles generated from oxygen micro-bubbles; ONB) has anti-inflammatory effects. Therefore, we investigated the inhibitory effects of ONB water on kidney stone formation in ethylene glycol (EG)-treated rats. We divided 60 rats, aged 4 weeks, into 5 groups: control, the water-fed group; 100 % ONB, the 100 % ONB water-fed group; EG, the EG treated water-fed group; EG + 50 % ONB and EG + 100 % ONB, water containing EG and 50 % or 100 % ONB, respectively. Renal calcium oxalate (CaOx) deposition, urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG), and renal expression of inflammation-related proteins, oxidative stress biomarkers, and the crystal-binding molecule hyaluronic acid were compared among the 5 groups. In the control and 100 % ONB groups, no renal CaOx deposits were detected. In the EG + 50 % ONB and EG + 100 % ONB groups, ONB water significantly decreased renal CaOx deposits, urinary NAG excretion, and renal monocyte chemoattractant protein-1, osteopontin, and hyaluronic acid expression and increased renal superoxide dismutase-1 expression compared with the EG group. ONB water substantially affected kidney stone formation in the rat kidney by reducing renal tubular cell injury. ONB water is a potential prophylactic agent for kidney stones. PMID- 23754515 TI - Image of the month-diagnosis. PMID- 23754514 TI - Darexaban (YM150), an oral direct factor Xa inhibitor, has no effect on the pharmacokinetics of digoxin. AB - To investigate the impact of the direct Factor Xa inhibitor darexaban administered in a modified-release formulation (darexaban-MR) on the pharmacokinetic (PK) profile of digoxin. In this Phase I, randomized, double blind, two-period crossover study (8 days for each treatment, 10 days washout), 24 healthy subjects received darexaban-MR 120 mg once/day (qd) + digoxin 0.25 mg qd in one treatment period, and placebo + digoxin 0.25 mg qd in the other treatment period. Blood for PK assessment of digoxin and darexaban was obtained in serial profile on day 8, as well as pre-dose on day 6-7; urinary PK samples were obtained up to 24 h after the last dose on day 8. A lack of interaction was determined if 90 % confidence intervals (CIs) for the geometric mean ratios (GMR) of digoxin C max,ss and AUC0-24h,ss with and without darexaban-MR co administration were within 0.80-1.25 limits. Pharmacodynamic activity was assessed by international normalized ratio and activated partial thromboplastin time. Twenty-three subjects completed the study. The GMR (90 % CI) for C max,ss and AUC0-24h,ss of digoxin plus darexaban versus digoxin plus placebo was 1.03 (90 % CI: 0.94-1.12) and 1.11 (90 % CI: 1.05-1.17), respectively. The 90 % CI for the GMRs fell within the limits of 0.80-1.25, indicating a lack of drug-drug interaction. Co-administration of digoxin with darexaban-MR was well tolerated, with no unexpected treatment-emergent adverse events or safety concerns. Co administration of darexaban-MR did not impact the steady-state PK profile of digoxin. PMID- 23754517 TI - Hole-shell microparticles from controllably evolved double emulsions. PMID- 23754516 TI - Atrial endothelial impairment through Toll-like receptor 4 signaling causes atrial thrombogenesis. AB - Low-grade inflammation associated with heart failure (HF) is known to deteriorate cardioembolic stroke in patients with atrial fibrillation (AF). Little is known about the relationship between atrial endothelial impairment induced by innate immunity and thrombus formation. We examined whether atrial endothelial impairment through Toll-like receptor (TLR) 4 signaling causes atrial thrombogenesis. TLR4, heat shock protein 60, and vascular cell adhesion molecule (VCAM)-1 expression were higher in the atrium of AF patients who underwent valve replacement surgery with HF compared with those without it (p < 0.05). We created thoracic transverse aortic constriction (TAC) in TLR4 knock-out (KO) and wild type (WT) mice. Atrial thrombosis was observed less frequently in TLR4 KO mice (4/15) than in WT mice (16/20) 4 weeks after TAC despite similar severity of heart failure. The decrease in endothelial nitric oxide synthase (eNOS) phosphorylation and increase in VCAM-1 and plasminogen activator inhibitor (PAI) 1 expression, observed in the atrium of WT mice following TAC, were significantly attenuated in TLR4 KO mice (p < 0.05). Nuclear factor-kappaB (NF-kappaB) activation after TAC was attenuated in TLR4 KO mice compared with WT mice. Activation of mitogen-activated protein kinase p38 (p38) after TAC was also attenuated in TLR4 KO mice (p < 0.05). Thus, increased VCAM-1 and PAI-1, and decreased eNOS phosphorylation through the TLR4/NFkappaB/p38 pathway, may be associated with atrial thrombogenesis in the heart failure mice model. Atrial endothelial impairment through the TLR4 signaling may play a role in atrial thrombogenesis in AF patients with HF. PMID- 23754519 TI - [Rotating physician in CHIR-Net. Evaluation of the curriculum]. AB - BACKGROUND: Conduction of and participation in clinical trials is a major challenge for surgical departments especially as job performance in hospitals has increased immensely during the last few years due to economic aspects. Only 11.7 % of published clinical studies are randomized controlled trials. As more and more treatment procedures in medicine have an evidence-based design the aim must be to present randomized controlled trials with an evidence level 1 for an increasing number of surgical therapies. Since 2006 the German National Surgical Trial Network (CHIR-Net) has been established and funded by the Federal Ministry of Education and Research (BMBF) in order to promote the realization of clinical trials in surgery. Thus the basis for the execution of high quality clinical studies in surgery has been extended further. In the individual CHIR-Net centers clinical trials are planned, organized and supervised which requires extensive knowledge of prevalent international standards. Teaching them to rotating physicians is one of the tasks of CHIR-Net. Therefore, a special curriculum for physicians has been developed which is evaluated in this study. MATERIALS AND METHODS: From December 2010 to March 2011 an online survey of physicians who had previously rotated in the CHIR-Net was conducted, starting from the Surgical Regional Center (CRZ) Witten-Herdecke/Cologne. A total of 19 partly open and partly closed questions concerning the person, training, duration of the rotation, the funding applied for and the generated scientific output were surveyed. In addition, the curriculum for physicians and rotation time was checked by means of 17 questions in an evaluation matrix. RESULTS: In this article the results of the rotating physician evaluation are presented. The satisfaction of physicians with the training during the rotation is presented as well as an analysis of how many of the submitted publications were directly supported by CHIR-Net. It was also evaluated how many rotating physicians requested funding and what the type of funding was. CONCLUSION: With the rotating physician model of CHIR-Net a working concept for the training of surgeons in clinical research and the realization of randomized surgical trials was established as a viable solution for the difficult situation of clinical research in the surgical disciplines with the double burden of research and clinical practice. PMID- 23754520 TI - [Laparoscopic vs open colectomy for acute colitis refractive to medicinal therapy]. PMID- 23754521 TI - When 2D is not enough, go for an extra dimension. AB - The use of an extra SDS separation in a different buffer system provide a technique for deconvoluting 2D gel spots made of several proteins (Colignon et al. Proteomics, 2013, 13, 2077-2082). This technique keeps the quantitative analysis of the protein amounts and combines it with a strongly improved identification process by mass spectrometry, removing identification ambiguities in most cases. In some favorable cases, posttranslational variants can be separated by this procedure. This versatile and easy to use technique is anticipated to be a very valuable addition to the toolbox used in 2D gel-based proteomics. PMID- 23754522 TI - Editorial. PMID- 23754512 TI - Risk factor profiles, drug usage, and prevalence of aspirin-associated gastroduodenal injuries among high-risk cardiovascular Japanese patients: the results from the MAGIC study. AB - BACKGROUND: Low-dose aspirin is widely used for the prevention of cardiovascular events. The prevalence of gastroduodenal injuries and the risk factor profile including gastroprotective drug therapy needs to be clarified in Japanese patients taking daily aspirin for cardioprotection. METHODS: This Management of Aspirin-induced Gastro-Intestinal Complications (MAGIC) study was conducted with a prospective nationwide, multicenter, real-world registry of Japanese patients at high-risk of cardiovascular diseases who were taking regular aspirin (75-325 mg) for 1 month or more. All patients underwent endoscopic examination for detection of gastroduodenal ulcer and mucosal erosion. The risk factor profiles including the concurrent drug therapy were compared for those patients with gastroduodenal problems and those without. RESULTS: Gastroduodenal ulcer and erosion were detected in 6.5, and 29.2% of the 1,454 patients receiving aspirin, respectively. H. pylori infection was associated with an increased risk for ulcer: OR 1.83 (1.18-2.88 p = 0.0082). Risk of erosion was lower with enteric coated aspirin than with buffered aspirin: odds ratio (OR) 0.47 (0.32-0.70, p = 0.0002). Patients receiving proton pump inhibitors had lower risks for both gastroduodenal ulcer and erosion: OR 0.34 (0.15-0.68, p = 0.0050) and 0.32 (0.22 0.46, p < 0.0001), respectively. However, those receiving histamine 2-receptor antagonists had reduced risks for erosion but not for ulcer: OR 0.49 (0.36-0.68, p < 0.0001). CONCLUSION: Gastroduodenal ulcer and erosion are common in Japanese patients taking low dose aspirin for cardioprotection. Proton pump inhibitors reduce the risk of gastroduodenal mucosal injury. PMID- 23754523 TI - Little effect of gestation at 3,100 m on fetal fat accretion or the fetal circulation. AB - OBJECTIVE: While chronic hypoxia has been recognized as the principal causative factor for decreasing birth weight at high altitude, unknown is whether fetal fat accretion and vascular function are affected. METHODS: Colorado women with normal singleton pregnancies (18 Denver residents, 1,600 m; 24 Leadville residents, 3,100 m) were studied longitudinally from 20 to 36 weeks gestation. Fetal biometry was used to obtain axial images for assessing mid-upper arm and mid thigh subcutaneous tissue mass (MUA and MUL SQ) and Doppler waveform analysis conducted to measure indices of vascular function in the fetal umbilical arteries (UmbA), umbilical vein (UmbV), middle cerebral artery (MCA), and ductus venosus (DV). SAS PROC MIXED was used to compare altitudes with P < 0.05 considered significant and trends present when 0.05 < P < 0.10. RESULTS: The 3,100 m vs. 1,600 m babies weighed less at birth. Third trimester fetal biometry, MUA SQ and MUL SQ were somewhat lower, but neither the biometry nor the SQ altitudinal differences attained statistical significance. Greater prepregnant maternal BMI tended to decrease MUA SQ (P = 0.07) and increase MUL SQ (P = 0.07). UmbA S/D ratios decreased and UmbV flow increased with advancing gestation (both P < 0.001). Altitude did not affect the UmbA or MCA systolic/diastolic ratios (S/D), MCA peak-systolic velocity, UmbV flow, or the DV systolic/atrial flow ratio. CONCLUSION: The hypoxia of residence at high compared to moderate altitude lowered birth weight but did not significantly alter MUA or mid-thigh fetal subcutaneous tissue mass or Doppler indices of vascular function. PMID- 23754525 TI - Contribution of radixin to P-glycoprotein expression and transport activity in mouse small intestine in vivo. AB - The ERM proteins, ezrin, radixin, and moesin, are membrane-cytoskeleton cross linkers with multiple physiological functions. We previously showed that radixin is involved in posttranslational regulation of P-glycoprotein (P-gp) in human hepatoblastoma HepG2 cells. Here, we investigated the physiological role of radixin in regulating P-gp expression and activity in the small intestine by comparing wild-type- and radixin knockout (Rdx) mice. In intestinal tissue homogenates, P-gp protein levels increased markedly from the upper part to the lower part of the small intestine in both wild-type- and Rdx(-/-) mice. In the membrane fractions, a similar pattern was seen in wild-type mice. However, the membrane expression of P-gp protein remained at the same level from the upper to the lower part of the small intestine in Rdx(-/-) mice. When rhodamine123 (Rho123), a substrate of P-gp, was orally administered to Rdx(-/-) and wild-type mice, the absorption phase of Rho123 was greater in Rdx(-/-) than in wild-type mice, whereas the elimination phase in Rdx(-/-) mice was not different from that of wild-type mice. Our results indicate that radixin plays an important role in regulating P-gp localization and P-gp functional activity at the intestinal membrane. PMID- 23754524 TI - A personal perspective on chemistry-driven RNA research. AB - In this mini review, we discuss how our understanding of ribonucleic acid (RNA) properties becomes significantly deepened when a broad range of modern chemical and biophysical methods is applied. We span our perspective from RNA solid-phase synthesis and site-specific labeling to single-molecule fluorescence-resonance energy-transfer imaging and NMR spectroscopy approaches to explore the dynamics of RNA over a broad timescale. We then move on to Fourier-transform-ion-cyclotron resonance mass spectrometry (FT-ICR-MS) as a powerful technique for RNA sequencing and modification analysis. The novel methodological developments are discussed for selected biological systems that include the thiamine-pyrophosphate riboswitch, HIV and ribosomal A-site RNA, and transfer RNA. PMID- 23754526 TI - Bite force and occlusal stress production in hominin evolution. AB - Maximum bite force affects craniofacial morphology and an organism's ability to break down foods with different material properties. Humans are generally believed to produce low bite forces and spend less time chewing compared with other apes because advances in mechanical and thermal food processing techniques alter food material properties in such a way as to reduce overall masticatory effort. However, when hominins began regularly consuming mechanically processed or cooked diets is not known. Here, we apply a model for estimating maximum bite forces and stresses at the second molar in modern human, nonhuman primate, and hominin skulls that incorporates skeletal data along with species-specific estimates of jaw muscle architecture. The model, which reliably estimates bite forces, shows a significant relationship between second molar bite force and second molar area across species but does not confirm our hypothesis of isometry. Specimens in the genus Homo fall below the regression line describing the relationship between bite force and molar area for nonhuman anthropoids and australopiths. These results suggest that Homo species generate maximum bite forces below those predicted based on scaling among australopiths and nonhuman primates. Because this decline occurred before evidence for cooking, we hypothesize that selection for lower bite force production was likely made possible by an increased reliance on nonthermal food processing. However, given substantial variability among in vivo bite force magnitudes measured in humans, environmental effects, especially variations in food mechanical properties, may also be a factor. The results also suggest that australopiths had ape-like bite force capabilities. PMID- 23754527 TI - Trends of human papillomavirus-related head and neck cancers in Korea: national cancer registry data. AB - OBJECTIVES/HYPOTHESIS: The incidence of human papillomavirus (HPV)-positive head and neck cancers (HNCs) is increasing sharply worldwide, while their HPV-negative counterparts are showing a decreased frequency. However, epidemiologic data related to these changes are sparse in Korea, which is rapidly adopting more westernized lifestyles. STUDY DESIGN: Data from the Korea Central Cancer Registry, a nationwide population-based cancer registry, from 1999 to 2009 were retrieved. METHODS: Age-standardized rates (ASRs), their annual percent changes (APC) and male-to-female incidence rate ratios (IRRs) were analyzed and compared between HPV-related and HPV-unrelated primary sites. RESULTS: HPV-related sites (oropharynx) had increased significantly over the period 1999 to 2009 (APC = 2.35%, P = 0.017), particularly in young men (30-59 years, APC = 2.65%, P = 0.031), whereas HPV-unrelated sites such as larynx and hypopharynx decreased markedly in both sexes. Interestingly, tongue cancer was found to have increased gradually (APC = 2.35%, P = 0.003) in both sexes. The male-to-female IRRs and the median age of occurrence remained stable. CONCLUSIONS: Although the cultural and ethnic background differs from the United States, cancers of HPV-related sites are increasing in Korea, whereas cancers of HPV-unrelated sites are decreasing, which is similar to the trends observed in the United States. Greater public awareness in Korea of HPV-related HNCs is therefore warranted. PMID- 23754528 TI - PASylation: a biological alternative to PEGylation for extending the plasma half life of pharmaceutically active proteins. AB - A major limitation of biopharmaceutical proteins is their fast clearance from circulation via kidney filtration, which strongly hampers efficacy both in animal studies and in human therapy. We have developed conformationally disordered polypeptide chains with expanded hydrodynamic volume comprising the small residues Pro, Ala and Ser (PAS). PAS sequences are hydrophilic, uncharged biological polymers with biophysical properties very similar to poly-ethylene glycol (PEG), whose chemical conjugation to drugs is an established method for plasma half-life extension. In contrast, PAS polypeptides offer fusion to a therapeutic protein on the genetic level, permitting Escherichia coli production of fully active proteins and obviating in vitro coupling or modification steps. Furthermore, they are biodegradable, thus avoiding organ accumulation, while showing stability in serum and lacking toxicity or immunogenicity in mice. We demonstrate that PASylation bestows typical biologics, such as interferon, growth hormone or Fab fragments, with considerably prolonged circulation and boosts bioactivity in vivo. PMID- 23754529 TI - Engineered DNA ligases with improved activities in vitro. AB - The DNA ligase from bacteriophage T4 is one of the most widely used enzymes in molecular biology. It has evolved to seal single-stranded nicks in double stranded DNA, but not to join double-stranded fragments with cohesive or blunt ends. Its poor activity in vitro, particularly with blunt-ended substrates, can lead to failed or sub-optimal experimental outcomes. We have fused T4 DNA ligase to seven different DNA-binding proteins, including eukaryotic transcription factors, bacterial DNA repair proteins and archaeal DNA-binding domains. Representatives from each of these classes improved the activity of T4 DNA ligase, by up to 7-fold, in agarose gel-based screens for cohesive- and blunt ended fragment joining. Overall, the most active variants were p50-ligase (i.e. NF-kappaB p50 fused to T4 DNA ligase) and ligase-cTF (T4 DNA ligase fused to an artificial, chimeric transcription factor). Ligase-cTF out-performed T4 DNA ligase by ~160% in blunt end 'vector + insert' cloning assays, and p50-ligase showed an improvement of a similar magnitude when it was used to construct a library for Illumina sequencing. The activity of the Escherichia coli DNA ligase was also enhanced by fusion to p50. Together, these results suggest that our protein design strategy is a generalizable one for engineering improved DNA ligases. PMID- 23754530 TI - The indistinguishability of epitopes from protein surface is explained by the distinct binding preferences of each of the six antigen-binding loops. AB - General protein-protein interfaces are known to be enriched, compared with other surface patches, with amino acids that can form stabilizing interactions. However, several studies reported that there are hardly any differences between the amino acid composition of B-cell epitopes and that of antigen surface residues. If the amino acid composition of epitopes is indistinguishable from other surface patches, how do antibodies (Abs) identify epitopes? Here, we analyze the antigen binding regions (ABRs, roughly corresponding to the complementarity determining regions) and the epitopes in a non-redundant set of all known Ab-antigen complexes. We find that the ABRs differ significantly from each other in their amino acid composition and length. Analysis of the energetic contribution of each ABR to antigen binding reveals that, while H3 often plays a key role in antigen binding, in many antibodies other ABRs are more important. Moreover, each ABR has a distinct propensity to bind different amino acids on the antigen. The combined binding preferences of the ABRs yield a total preference to amino acids with a composition that is virtually identical to that of surface residues. These results suggest that antibodies evolved to recognize protein surfaces. They may help in improving Ab engineering and B-cell epitope prediction. PMID- 23754531 TI - Flexible, transparent contacts for inorganic nanostructures and thin films. AB - A transparent, flexible contact is developed using Ni nanoparticles and Ag nanowires and demonstrated on free-standing, polymer embedded, Si microwire solar cells. Contact yields of over 99% and a series resistance of 14 Omega cm2 are demonstrated. PMID- 23754532 TI - Prediagnostic circulating markers of inflammation and risk of prostate cancer. AB - Accruing evidence suggests that inflammation plays a role in prostate carcinogenesis. However, studies evaluating this association using C-reactive protein (CRP) and interleukin-6 as markers of inflammation have reported conflicting results. We investigated the associations of three common markers of inflammation (CRP, fibrinogen and leukocyte count) with the risk of prostate cancer in a prospective cohort of 2,571 men from Finland. During an average follow-up period of 24 years (21-26 years), 203 men from the cohort who developed prostate cancer were identified via linkage to the nationwide Finnish Cancer Registry. We investigated the associations between the markers and the risk of prostate cancer using Cox proportional hazards model, adjusting for potential confounders. Elevated prediagnostic leukocyte count was associated with an increased risk of prostate cancer. In multivariable adjusted model, the relative risk of prostate cancer among men in the highest tertile of leukocyte count compared to men in the lowest tertile was 1.60 (95% confidence interval [CI] = 1.10-2.29, p-trend = 0.01). Circulating CRP and fibrinogen were not associated with increased risk. The corresponding relative risks for elevated CRP and fibrinogen concentrations were 1.08 (95% CI: 0.74-1.60, p-trend = 0.56) and 1.25 (95% CI: 0.87-1.81, p-trend = 0.14), respectively. Men with elevated leukocyte counts had a 2.57-fold (95% CI: 0.99-6.79) increased risk of prostate cancer mortality. The increased risk associated with elevated leukocyte counts warrants confirmation in other studies. Larger studies should consider combining at least two markers or using an inflammation score derived from many inflammatory markers to evaluate prostate cancer risk. PMID- 23754533 TI - Varicocele and hypogonadism. AB - Accumulating evidence suggests that varicocele, long associated with male infertility, is also a risk factor for low testosterone levels. The exact pathophysiology of the negative effects of varicocele on testicular function is not well understood, but theories include venous stasis, increased testicular temperature, oxidative stress, and resulting toxic environment. While prior studies report conflicting effects of non-microsurgical varicocelectomy on testosterone level, recent literature demonstrates that microsurgical varicocelectomy improves testosterone levels in men with varicocele and low testosterone preoperatively. PMID- 23754534 TI - Are right-sided colectomy outcomes different from left-sided colectomy outcomes?: study of patients with colon cancer in the ACS NSQIP database. AB - IMPORTANCE: Optimization of surgical outcomes after colectomy continues to be actively studied, but most studies group right-sided and left-sided colectomies together. OBJECTIVE: To determine whether the complication rate differs between right-sided and left-sided colectomies for cancer. As a secondary analysis, we investigated hospital length of stay. DESIGN: We identified patients who underwent colectomy for colon cancer in the 2005-2008 American College of Surgeons National Surgical Quality Improvement Program database and stratified cases by right and left side. Preoperative, intraoperative, and postoperative factors were compared. Multivariable techniques were used to assess the impact of the side of colectomy on operative outcome measures, adjusting for covariates. SETTING: Hospitals within the American College of Surgeons National Surgical Quality Improvement Program database. PATIENTS: We identified 4875 patients who underwent elective laparoscopic or open colectomy for right-sided or left-sided colon cancer in the database. MAIN OUTCOMES AND MEASURES: Major complications and surgical site infection (SSI) rates. RESULTS: In the 4875 colectomies studied, a laparoscopic approach was used in 42% of cases and at similar frequency in right sided and left-sided colectomies. Thirty-day mortality (1.5%) was similar in both groups. Major complications were seen in 17% of patients in each group. Superficial SSI was more likely to occur in patients who underwent left-sided colectomy (8.2% vs 5.9%). Among patients with postoperative sepsis or deep or organ space SSIs, more patients in the left-sided colectomy group underwent reoperation compared with the right-sided colectomy group (56% vs 30%). Laparoscopic right-sided colectomy patients were more likely to have a prolonged hospital length of stay than laparoscopic left-sided colectomy patients (odds ratio, 1.39; 95% CI, 1.09-1.78). CONCLUSIONS AND RELEVANCE: The outcomes after colectomy for cancer are comparable in right-sided and left-sided resections, except for in the case of superficial SSI, which is less common in right-sided resections. Further research on SSI after colectomy should incorporate right vs left side as a potential preoperative risk factor. PMID- 23754535 TI - Outcome expectancies, descriptive norms, and alcohol use: American Indian and white adolescents. AB - This study examined the relationships between adolescent alcohol use and outcome expectancies and descriptive norms for a sample of American Indian and white youth living on or near reservations. Three outcome expectancies proposed by the theory of normative social behavior (perceived benefits to self, perceived benefits to others, and anticipatory socialization) were examined. Survey data were collected from high school students in the 2009-2010, 2010-2011, and 2011 2012 school years. Stronger descriptive norms for use and higher perceived benefits to self from use were associated with alcohol use in the last month, drunkenness in the last month, and binge drinking. Perceived benefits to self also moderated the relationship between descriptive norms and both alcohol use in the last month and binge drinking, and the effect of descriptive norms on use became more robust as perceived benefits to self increased. Outcome expectancies of perceived benefits to others and anticipatory socialization did not moderate the relationship between norms and alcohol use. Implications for prevention are discussed. PMID- 23754537 TI - About this journal. PMID- 23754536 TI - Oxymatrine ameliorates non-alcoholic fatty liver disease in rats through peroxisome proliferator-activated receptor-alpha activation. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common type of liver disease worldwide. Recent studies have reported that oxymatrine (OMT), an active monomer isolated from Sophora flavescens Ait. (kushen), ameliorates NAFLD in rats. In order to explore the possible molecular mechanism involved, we used an NAFLD rat model with hyperlipidemia, which had been established by feeding a high fructose diet (HFD) for eight weeks, and the model rats were subsequently treated with OMT (80 mg/kg/day) for a further four weeks. We evaluated the expression of genes and proteins regulating fatty acid oxidation and lipid export in the liver using quantitative (q)PCR and western blot analysis. The NAFLD model rats developed dyslipidaemia, hepatic steatosis and insulin resistance (IR). OMT administration for four weeks reduced body weight gain and visceral fat weight, decreased serum triglyceride (TG), total cholesterol (TC), free fatty acid (FFA) and fasting serum insulin (FinS) levels and lowered liver TG contents. It also increased the glucose infusion rate (GIR), indicative of a reduction in IR. Moreover, OMT treatment markedly increased the mRNA and protein levels of peroxisome proliferator-activated receptor-alpha (PPARalpha), carnitine palmitoyltransferase 1A (CPT1A) and microsomal triglyceride transfer protein (MTTP). The beneficial effects of OMT were further confirmed by the observation of a decrease in lipid accumulation in the histology of the liver. Our results indicate that OMT may be used to treat NAFLD. PMID- 23754538 TI - Tendon mineralization is accelerated bilaterally and creep of contralateral tendons is increased after unilateral needle injury of murine achilles tendons. AB - Heterotopic mineralization may result in tendon weakness, but effects on other biomechanical responses have not been reported. We used a needle injury, which accelerates spontaneous mineralization of murine Achilles tendons, to test two hypotheses: that injured tendons would demonstrate altered biomechanical responses; and that unilateral injury would accelerate mineralization bilaterally. Mice underwent left hind (LH) injury (I; n = 11) and were euthanized after 20 weeks along with non-injured controls (C; n = 9). All hind limbs were examined by micro computed tomography followed by biomechanical testing (I = 7 and C = 6). No differences were found in the biomechanical responses of injured tendons compared with controls. However, the right hind (RH) tendons contralateral to the LH injury exhibited greater static creep strain and total creep strain compared with those LH tendons (p <= 0.045) and RH tendons from controls (p <= 0.043). RH limb lesions of injured mice were three times larger compared with controls (p = 0.030). Therefore, despite extensive mineralization, changes to the responses we measured were limited or absent 20 weeks postinjury. These results also suggest that bilateral occurrence should be considered where tendon mineralization is identified clinically. This experimental system may be useful to study the mechanisms of bilateral new bone formation in tendinopathy and other conditions. PMID- 23754539 TI - Large and variable genome size unrelated to serpentine adaptation but supportive of cryptic sexuality in Cenococcum geophilum. AB - Estimations of genome size and its variation can provide valuable information regarding the genetic diversity of organisms and their adaptation potential to heterogeneous environments. We used flow cytometry to characterize the variation in genome size among 40 isolates of Cenococcum geophilum, an ectomycorrhizal fungus with a wide ecological and geographical distribution, obtained from two serpentine and two non-serpentine sites in Portugal. Besides determining the genome size and its intraspecies variation, we wanted to assess whether a relationship exists between genome size and the edaphic background of the C. geophilum isolates. Our results reveal C. geophilum to have one of the largest genome sizes so far measured in the Ascomycota, with a mean haploid genome size estimate of 0.208 pg (203 Mbp). However, no relationship was found between genome size and the edaphic background of the sampled isolates, indicating genetic and demographic processes to be more important for shaping the genome size variation in this species than environmental selection. The detection of variation in ploidy level among our isolates, including a single individual with both presumed haploid and diploid nuclei, provides supportive evidence for a possible cryptic sexual or parasexual cycle in C. geophilum (although other mechanisms may have caused this variation). The existence of such a cycle would have wide significance, explaining the high levels of genetic diversity and likelihood of recombination previously reported in this species, and adds to the increasing number of studies suggesting sexual cycles in previously assumed asexual fungi. PMID- 23754540 TI - Arbuscular mycorrhizal fungal communities along a pedo-hydrological gradient in a Central Amazonian terra firme forest. AB - Little attention has been paid to plant mutualistic interactions in the Amazon rainforest, and the general pattern of occurrence and diversity of arbuscular mycorrhizal fungi (AMF) in these ecosystems is largely unknown. This study investigated AMF communities through their spores in soil in a 'terra firme forest' in Central Amazonia. The contribution played by abiotic factors and plant host species identity in regulating the composition, abundance and diversity of such communities along a topographic gradient with different soils and hydrology was also evaluated. Forty-one spore morphotypes were observed with species belonging to the genera Glomus and Acaulospora, representing 44 % of the total taxa. Soil texture and moisture, together with host identity, were predominant factors responsible for shaping AMF communities along the pedo-hydrological gradient. However, the variability within AMF communities was largely associated with shifts in the relative abundance of spores rather than changes in species composition, confirming that common AMF species are widely distributed in plant communities and all plants recruited into the forest are likely to be exposed to the dominant sporulating AMF species. PMID- 23754541 TI - Ellis-van Creveld syndrome: its history. AB - The story of Ellis-van Creveld syndrome is one of serendipity. By chance, Simon van Creveld and Richard Ellis purportedly met on a train and combined their independently encountered patients with short stature, dental anomalies and polydactyly into one landmark publication in 1940. They included a patient used in work published previously by Rustin McIntosh without naming McIntosh as a coauthor. This patient was followed radiologically by Caffey for nearly two decades. In 1964, Victor McKusick felt compelled to investigate a brief report in an obscure pharmaceutical journal on an unusual geographic cluster of short statured Amish patients in Pennsylvania. This review highlights the lives of the individuals involved in the discovery of Ellis-van Creveld syndrome in their historic context. PMID- 23754542 TI - Discontinuous splenogonadal fusion: new sonographic findings. AB - Splenogonadal fusion is an uncommon cause of scrotal mass in children that is rarely diagnosed before surgery. Occasionally it leads to unnecessary orchiectomy. We report a case highlighting US findings that could help with correct diagnosis. PMID- 23754543 TI - Number of events and reliability in fMRI. AB - Relatively early in the history of fMRI, research focused on issues of power and reliability, with an important line concerning the establishment of optimal procedures for experimental design in order to maximize the various statistical properties of such designs. However, in recent years, tasks wherein events are defined only a posteriori, on the basis of behavior, have become increasingly common. Although these designs enable a much wider array of questions to be answered, they are not amenable to the tight control afforded by designs with events defined entirely a priori, and little work has assessed issues of power and reliability in such designs. We demonstrate how differences in numbers of events-as can occur with a posteriori event definition-affect reliability, both through simulation and in real data. PMID- 23754544 TI - Bacteriocin activity against various pathogens produced by Pediococcus pentosaceus VJ13 isolated from Idly batter. AB - Bacteriocins, an antimicrobial peptide, is known to have wide spectrum antimicrobial activity against various pathogens. Because they are easily digested in the intestine, they are considered as safe and are widely used as food preservatives. Hence their purification and characterization have attracted considerable attraction, especially for those having activity against human pathogens. In this study, the bacteriocin produced by Pediococcus pentosaceus VJ13 was precipitated with cold acetone and purified by gel permeation chromatography and hydrophobic interaction chromatography. The bacteriocin exhibited antimicrobial activity against various pathogens, like Mycobacterium smegmatis, Klebsiella pneumonia, Clostridium perfringens and Staphylococcus epidermidis. The activity of bacteriocin was lost completely after treatment with protease, which revealed its proteinaceous nature. The bacteriocin was stable up to 100 degrees C and exhibited antilisterial property which is a characteristic feature of class IIa bacteriocins. It was active within the pH range of 2-8 and stable against various chemicals and denaturants. Tricine SDS-PAGE revealed its molecular weight to be 4.0 kDa, where the corresponding activity against Listeria monocytogenes was also noted. Treatment of L. monocytogenes with bacteriocin decreased the viable cell count, and scanning electron microscope analysis revealed membrane pore formation that resulted in the release of intracellular content, suggesting its bactericidal effect. PMID- 23754546 TI - A multi-stopband photonic-crystal microchip for high-performance metal-ion recognition based on fluorescent detection. PMID- 23754545 TI - Intermittent treatment with mesalazine in the prevention of diverticulitis recurrence: a randomised multicentre pilot double-blind placebo-controlled study of 24-month duration. AB - BACKGROUND AND AIM: Recurrence of diverticulitis is frequent within 5 years from the uncomplicated first attack, and its prophylaxis is still unclear. We have undertaken a multicentre, randomised, double-blind, placebo-controlled pilot study in order to evaluate the role of mesalazine in preventing diverticulitis recurrence as well as its effects on symptoms associated to diverticular disease. METHODS: Ninety-six patients with the recent first episode of uncomplicated diverticulitis were randomised to receive mesalazine 800 mg twice daily for 10 days every month or placebo for 24 months. The primary efficacy end point was the diverticulitis recurrence at intention to treat analysis. Clinical evaluations were performed using the Therapy Impact Questionnaire (TIQ) for physical condition and quality of life at admission and at 3-month intervals. Treatment tolerability and routine biochemistry parameters as well as the use of additional drugs were also evaluated. RESULTS: Ninety-two patients (mean age, 61.5) completed the study, 45 of whom received mesalazine, and 47, placebo. Diverticulitis relapse incidence in mesalazine-treated group was 5/45 (11%) at the 12th month and 6/45 (13%) at the 24th month; in the placebo-treated group, the correspondent rates were 13% (6/47) and 28% (13/47), respectively. Mean values of TIQ at 24 months were significantly better in mesalazine-treated group than in placebo-treated group (p = 0.02); in addition, average additional drug consumption was significantly lower (-20.4%, p < 0.03) in mesalazine than in placebo. CONCLUSIONS: Diverticulitis recurrence occurred in as many as 28% of patients under placebo within 24 months from the initial episode. Intermittent prophylaxis with mesalazine did not significantly reduce the risk of relapse but induced a significant improvement of patients' physical conditions and significantly lowered the additional consumption of other gastrointestinal drugs. PMID- 23754547 TI - Prognosis in women with breast cancer and private extra insurance coverage. AB - BACKGROUND: Many women covered by the Spanish public health system also have an extra private insurance policy for gynecological examinations and routine annual mammography. We retrospectively analyzed the long-term survival rates in these patients when diagnosed with breast cancer. METHODS: We analyzed the survival and prognostic factors in patients diagnosed with breast cancer who were referred to a medical oncology unit for multidisciplinary treatment covered by private health insurance. RESULTS: Between 1994 and 2009, a total of 434 patients with breast tumor were analyzed: 33 in situ and 401 infiltrating. Among the infiltrating carcinomas, 38 were stage IV and 363 were stage I, II, or III. With a median follow-up of 62 months, the 5-year global survival rate was 91%: 97% for stage I, 94% for stage II, and 77% for stage III tumors. In the patients diagnosed by routine mammography, the 5-year survival rate was 96%, compared with 86% in those consulting their gynecologist after breast self-examination or for other symptoms (p=0.0159). Seventy-four percent were treated conservatively and experienced better survival than the 26% who underwent mastectomy (p=0.0024). Patients with disease with positive hormone receptors had a better survival rate (p=0.0264); hormone receptor status was the only independent prognostic factor in the Cox multivariate analysis. Postmenopausal patients who received adjuvant tamoxifen plus exemestane had a better prognosis than those who received tamoxifen alone (p=0.0203). CONCLUSIONS: Long-term survival rate was high in breast cancer patients with extra private insurance coverage. This is probably because disease was diagnosed at an early stage. PMID- 23754549 TI - Mechanism of protein stabilization by trehalose during freeze-drying analyzed by in situ micro-raman spectroscopy. AB - Raman investigations were performed in situ during freeze-drying of two model proteins, lysozyme and chymotrypsinogen. The structures of proteins dissolved in 0-30 wt % solutions of trehalose in D2 O were monitored with the fingerprint (800 1800 cm(-1) ) spectrum, simultaneously with freezing, ice sublimation, and water desorption analyzed in the O-D stretching (2200-2700 cm(-1) ) region. In the absence of trehalose, the main changes were detected at the end of primary drying, and correspond to distortion and disordering of secondary structures. A stabilizing effect of trehalose was evidenced in primary and secondary drying stages. Raman images were calculated after freezing and primary drying, providing the distributions of trehalose, water, and protein which occur during the first two stages of the lyophilization cycle. Raman images show a slight heterogeneity in the degree of protein denaturation at the end of primary drying, in relation with the structure of the frozen product observed during freezing. The ability of trehalose to make the protein more rigid was determined as responsible for the protein stabilization during a lyophilization cycle. PMID- 23754550 TI - [Dislocation of double-threaded screws after stabilization of the odontoid process with the Knoringer technique]. AB - A type III fracture of the odontoid process according to Anderson-D'Alonzo in a 92-year-old patient was stabilized anteriorly with two double-threaded screws using the technique of Knoringer. Postoperatively, cranial dislocation of the screws was evident and attempts to correct the screw position failed resulting in screw proximity to the brain stem. In a second revision the screws could be removed by an anterior approach and fusion was achieved by a posterior approach. Type III fractures of the odontoid process are usually stable and should be treated conservatively. In case of instability posterior stabilization techniques should be selected. Anterior osteosynthesis of the odontoid process with double threaded screws in osteoporotic bone carries the risk of screw dislocation. PMID- 23754551 TI - [Treatment of isolated fractures of the olecranon: percutaneous double-screw fixation versus conventional tension band wiring]. AB - BACKGROUND: Isolated fractures of the olecranon account for 7-10% of all osseous injuries in adults. These fractures are usually treated surgically by conventional tension band wiring. The percutaneous double-screw fixation is an optional treatment in patients with two fragment olecranon fractures with some postoperative advantages. PATIENTS AND METHODS: A total of 13 patients with isolated fractures of the olecranon (Schatzker-Schmelling type A) treated by percutaneous double-screw fixation were included in this prospective study. The mean age of patients was 43.6 +/- 11.0 years. Intraoperative and postoperative complications were recorded. Functional results were assessed after a mean follow up of 38.2 +/- 11.5 months using the Quick-DASH score. The results were compared with those obtained in the control group including 26 patients treated by conventional tension band wiring. RESULTS: No intraoperative complications were observed in both groups. In the group with percutaneous double-screw fixation the scar length was significantly shorter (2.4 +/- 0.4 cm vs. 11.0 +/- 1.8 cm, p < 0.001) and the hardware removal was substantially less frequent that in the group with conventional tension band wiring with 38.5 % and 73.1 %, respectively. At the minimum follow-up of 2 years comparable functional results were obtained in both groups (Quick-DASH score 2.3 vs. 0.0 points, respectively, p = 0.155); however, the range of elbow motion was significantly higher in the group with percutaneous double-screw fixation (extension/flexion 145 degrees vs. 130 degrees , p < 0.001; pronation/supination 165 degrees vs. 155 degrees , p < 0.001). CONCLUSIONS: The percutaneous double-screw fixation is a safe and viable treatment option in patients with isolated fractures of the olecranon (Schatzker Schmelling type A). The functional results regarding DASH scores obtained using this technique were comparable with those observed in patients with conventional tension band wiring; however, range of elbow motion and cosmetic results were significantly better in the patient group with percutaneous double-screw fixation. PMID- 23754552 TI - [Evisceration of intestines following abdominal stab wounds: epidemiology and clinical aspects of emergency room management]. AB - STUDY AIM: The aim of the study was an estimation of the incidence and clinical aspects of emergency room (ER) parameters of penetrating abdominal injury patients with bowel evisceration. STUDY DESIGN AND METHODS: The study involved a retrospective cohort analysis of ER data from the Chris Hani Baragwanath Academic Hospitals, Soweto, Johannesburg, South Africa between September 2000 to May 2005. RESULTS: Out of 9,010 ER patients, 4,390 suffered penetrating injuries with 8 out of 71 eviscerations due to a single gunshot wound, 60 out of 71 eviscerations due to single stab wounds and 3 further patients suffered multiple injuries. The ER mortality was 1 out of 71(1.6 %) with an average ER mortality of 4.2 %. The only death seen was a single abdominal gunshot wound with vascular injury. The causative mortality due to abdominal stab wounds with evisceration of the bowels was therefore zero. The heart rate in patients with abdominal stab wounds with and without bowel evisceration showed no significant difference, thus mesentery tearing or vagal overstimulation could not be seen, neither with bradycardia nor hypotension. CONCLUSION: Evisceration itself is not a cause for increased mortality or cardiovascular instability seen in the ER. There is ample time for diagnostic procedures before laparotomy is performed. PMID- 23754553 TI - Obesity is associated with sensorineural hearing loss in adolescents. AB - OBJECTIVES/HYPOTHESIS: Childhood obesity, defined as body mass index (BMI) >= 95%, is a significant health problem associated with a variety of disorders, and in adults it has been found to be a risk factor for hearing loss. We investigated the hypothesis that obese children are at increased risk of sensorineural hearing loss (SNHL). STUDY DESIGN: A complex, multistage, stratified geographic area design for collecting representative data from noninstitutionalized U.S. population. METHODS: Relevant cross-sectional data from the National Health and Nutrition Examination Survey, 2005 to 2006, for 1,488 participants 12 to 19 years of age was examined. Subjects were classified as obese if their BMI >= 95 th percentile. SNHL was defined as average pure-tone level greater than 15 dB for 0.5, 1, and 2 kHz (low frequency) and 3, 4, 6, and 8 kHz (high frequency). RESULTS: Compared to normal weight participants (BMI 5%-85%), obesity in adolescents was associated with elevated pure tone hearing thresholds and greater prevalence of unilateral low-frequency SNHL (15.2 vs. 8.3%, P = 0.01). In multivariate analyses, obesity was associated with a 1.85 fold increase in the odds of unilateral low-frequency SNHL (95% CI: 1.10-3.13) after controlling for multiple hearing-related covariates. CONCLUSIONS: We demonstrate for the first time that obesity in childhood is associated with higher hearing thresholds across all frequencies and an almost 2-fold increase in the odds of unilateral low-frequency hearing loss. These results add to the growing literature on obesity-related health disturbances and also add to the urgency in instituting public health measures to reduce it. PMID- 23754554 TI - Dietary zinc intake is inversely associated to metabolic syndrome in male but not in female urban adolescents. AB - OBJECTIVE: To evaluate the relationship of copper and zinc dietary intakes with metabolic syndrome (MetS) in adolescents. METHODS: The sample consisted of 1,311 adolescents aged 11-16 years, and MetS definition by de Ferranti et al. was used. Nutritional intakes, anthropometrical and biochemical markers were measured. RESULTS: In males, highest quartile of zinc intake was inversely associated with MetS without and with adjustment by covariables. Without adjustment, highest quartile of copper intake was inversely associated (marginal significance) with MetS, but with adjustment, the relationship was not maintained. Likewise in male gender, elevated waist circumference was the only MetS component inversely associated with highest quartiles of zinc (without and with adjustment) and copper (significant in crude analysis and marginal significant in adjustment by covariables) intakes. In the girls, only waist circumference was significant and inversely associated with highest quartiles of zinc and copper intakes but the association did not remain significant after adjustments. DISCUSSION: In the adolescents of this study, zinc intake could be more associated to a clustering of anthropometric, vascular, and metabolic alterations than to these alterations separately, and also it is inversely related to this clustering (MetS). However, studies in other populations are necessary to confirm and explain the finding of exclusive association zinc intake-MetS in male gender adolescents. Further research is required to explore biomarkers of physiological processes (antioxidant function, blood flow regulation, and epigenetic modulation dependent of zinc) in relation to zinc intake and MetS in pediatric and adult populations. PMID- 23754555 TI - Insecticide susceptibilities in populations of two rice planthoppers, Nilaparvata lugens and Sogatella furcifera, immigrating into Japan in the period 2005-2012. AB - BACKGROUND: The brown planthopper Nilaparvata lugens and the whitebacked planthopper Sogatella furcifera are both important pests on rice throughout Asia. The major cause of recent outbreaks is thought to be the development of insecticide resistance. Thus, the authors monitored insecticide susceptibilities in populations of these two insects immigrating into Japan in the period 2005 2012. Ten insecticides were tested, including members of the organophosphate, carbamate, pyrethroid, neonicotinoid and phenylpyrazole groups. RESULTS: The LD50 values of N. lugens against imidacloprid increased from 2005 (0.7 ug g(-1)) to 2012 (98.5 ug g(-1)). The resistance ratio (LD50 value in 2012/baseline LD50 value in 1992) was 615.5. In contrast, LD50 values of N. lugens against fipronil were <1.0 ug g(-1) up to 2012, suggesting that N. lugens had developed no insecticide resistance to this insecticide. However, S. furcifera exhibited resistance against fipronil up to 2012. Except for the case of malathion, the resistances of N. lugens against members of the organophosphate and carbamate groups were closely similar in the period 2005-2012 to earlier determinations in 1984 and 1985. CONCLUSION: Species-specific insecticide resistance (imidacloprid resistance in N. lugens and fipronil resistance in S. furcifera) is ongoing in populations of the two planthoppers immigrating into Japan. PMID- 23754556 TI - Rabbit muscle proteomics: a great leap forward. AB - The rabbit is an important species as both a production animal and as a model organism in physiology, pharmaceutical, and numerous other studies. Similar to other species, the rabbit skeletal muscle proteome has been characterized, first using 2DE mapping and more recently using high-throughput shotgun proteomics. This article is a commentary on "Shotgun proteomics analysis of the sarcoplasmic reticulum preparations from rabbit skeletal muscle" (Z. Liu et al., Proteomics, 2013, 13, 2335-2338). Herein, we present the reasons why the manuscript is of high relevance to three major fields: farm animal, rabbit, and muscle/meat proteomics. PMID- 23754557 TI - In situ biphasic extractive fermentation for hexanoic acid production from sucrose by Megasphaera elsdenii NCIMB 702410. AB - Hexanoic acid production by a bacterium using sucrose as an economic carbon source was studied under conditions in which hexanoic acid was continuously extracted by liquid-liquid extraction. Megasphaera elsdenii NCIMB 702410, selected from five M. elsdenii strains, produced 4.69 g l-1 hexanoic acid in a basal medium containing sucrose. Production increased to 8.19 g l-1 when the medium was supplemented by 5 g l-1 sodium butyrate. A biphasic liquid-liquid extraction system with 10 % (v/v) alamine 336 in oleyl alcohol as a solvent was evaluated in a continuous stirred-tank reactor held at pH 6. Over 90 % (w/w) of the hexanoic acid in a 0.5 M aqueous solution was transferred to the extraction solvent within 10 h. Cell growth was not significantly inhibited by direct contact of the fermentation broth with the extraction solvent. The system produced 28.42 g l-1 of hexanoic acid from 54.85 g l-1 of sucrose during 144 h of culture, and 26.52 and 1.90 g l-1 of hexanoic acid was accumulated in the extraction solvent and the aqueous fermentation broth, respectively. The productivity and yield of hexanoic acid were 0.20 g l-1 h-1 and 0.50 g g-1 sucrose, respectively. PMID- 23754558 TI - Efficient production of ethanol from empty palm fruit bunch fibers by fed-batch simultaneous saccharification and fermentation using Saccharomyces cerevisiae. AB - The concentration of ethanol produced from lignocellulosic biomass should be at least 40 g l(-1) [about 5 % (v/v)] to minimize the cost of distillation process. In this study, the conditions for the simultaneous saccharification and fermentation (SSF) at fed-batch mode for the production of ethanol from alkali pretreated empty palm fruit bunch fibers (EFB) were investigated. Optimal conditions for the production of ethanol were identified as temperature, 30 degrees C; enzyme loading, 15 filter paper unit g(-1) biomass; and yeast (Saccharomyces cerevisiae) loading, 5 g l(-1) of dry cell weight. Under these conditions, an economical ethanol concentration was achieved within 17 h, which further increased up to 62.5 g l(-1) after 95 h with 70.6 % of the theoretical yield. To our knowledge, this is the first report to evaluate the economic ethanol production from alkali-pretreated EFB in fed-batch SSF using S. cerevisiae. PMID- 23754559 TI - Predicting the impact of deleterious mutations in the protein kinase domain of FGFR2 in the context of function, structure, and pathogenesis--a bioinformatics approach. AB - Fibroblast growth factor receptor 2 (FGFR2) controls a wide range of biological functions by regulating the cellular proliferation, survival, migration and differentiation. A growing body of preclinical data demonstrated that deregulation of the FGFR signalling through genetic modification was observed in various types of cancers. However, the extent to which genetic modifications interfere with gene regulation and their involvement in cancer susceptibility remains largely unknown. In this work, we performed in silico profiling of harmful non-synonymous single nucleotide polymorphisms (SNPs) in the protein kinase domain of FGFR2. Tolerance index, position-specific independent count score, change in free energy score (DeltaDeltaG), Eris and FoldX indicated that seven mutations were found to be deleterious and may alter the protein function and structure. Furthermore, based on physico-chemical properties, two mutations K659N and R747H were found to be most deleterious in protein kinase domain and taken for further structural analysis. Docking study showed a complete loss of binding affinity followed by interference in hydrogen bonding and surrounding residues due to K659N and R747H mutations. In order to elucidate the mechanism behind the impact of mutation that can generate a ripple effect throughout the protein structure and ultimately affect the function, in-depth molecular dynamics simulation and principal component analysis were performed. The obtained results indicate that K659N and R747H mutations have a distinct effect on the dynamic behaviour of FGFR2 protein. Our strategy may be helpful for understanding SNP effects on proteins with function and their role in human genetic diseases and for the development of novel pharmacological strategies. PMID- 23754560 TI - A new metal-chelated cryogel for reversible immobilization of urease. AB - Poly(2-hydroxyethyl methacrylate-co-glycidyl methacrylate) [poly(HEMA-GMA)] cryogel was synthesized by cryopolymerization technique at frozen temperature. Iminodiacetic acid (IDA) was then attached covalently to the cryogel as a chelating agent. Then, poly(HEMA-GMA)-IDA cryogel was chelated with Ni(II) ions and this novel metal affinity support was used for adsorption of urease from its aqueous solution. Urease adsorption experiments were carried out in a continuous system by using a peristaltic pump. Maximum urease adsorption onto poly(HEMA-GMA) IDA-Ni(II) cryogel was found to be 11.30 mg/g cryogel at pH 5.0 acetate buffer and in 25 degrees C medium temperature. Urease adsorption capacity decreased with increasing ionic strength and increasing chromatographic flow rate. Adsorption kinetics of urease onto poly(HEMA-GMA)-IDA-Ni(II) cryogel was also investigated and it was found that Langmuir adsorption model is applicable for this adsorption study. This novel immobilized metal affinity chromatography support was used 10 times without any decrease at their adsorption capacity. It was also observed that urease enzyme was repeatedly adsorbed and desorbed without significant lost in enzymatic activity. PMID- 23754561 TI - A simple technique of preparing stable CLEAs of phenylalanine ammonia lyase using co-aggregation with starch and bovine serum albumin. AB - Cross-linked enzyme aggregates (CLEAs) have been recently proposed as an alternative to conventional immobilization methods on solid carriers. However, the low cross-linking efficiency causes the major activity loss and instability in the conventional protocol for CLEA preparation. Herein, the effects of bovine serum albumin and starch addition on the cross-linking efficiency of CLEAs of phenylalanine ammonia lyase (PAL) from Rhodotorula glutinis were evaluated. A co aggregation strategy was developed to improve cross-linking efficiency by adding starch and bovine serum albumin (BSA). CLEAs of PAL prepared in the presence of BSA and starch (PSB-CLEAs) retained 36 % activity, whereas CLEAs prepared without BSA and starch (PAL-CLEAs) retained only 8 % activity of the starting enzyme preparation. Compared with PAL-CLEAs, the thermal stability of PSB-CLEAs has improved considerably, maintaining 30 % residual activity after 4 h of incubation at 70 degrees C, whereas the PAL-CLEAs have only 13 % residual activity. PSB CLEAs also exhibited the expected increased stability of PAL against hydrophilic organic solvents, superior operability, and higher storage stability. The proposed technique of preparing CLEAs using co-aggregation with starch and BSA would rank among the potential strategies for efficiently preparing robust and highly stable enzyme aggregates. PMID- 23754562 TI - Fermentation of biologically pretreated wheat straw for ethanol production: comparison of fermentative microorganisms and process configurations. AB - The pretreatment of lignocellulosic biomass with white-rot fungi to produce bioethanol is an environmentally friendly alternative to the commonly used physico-chemical processes. After biological pretreatment, a solid substrate composed of cellulose, hemicellulose and lignin, the two latter with a composition lower than that of the initial substrate, is obtained. In this study, six microorganisms and four process configurations were utilised to ferment a hydrolysate obtained from wheat straw pretreated with the white-rot fungus Irpex lacteus. To enhance total sugars utilisation, five of these microorganisms are able to metabolise, in addition to glucose, most of the pentoses obtained after the hydrolysis of wheat straw by the application of a mixture of hemicellulolytic and cellulolytic enzymes. The highest overall ethanol yield was obtained with the yeast Pachysolen tannophilus. Its application in combination with the best process configuration yielded 163 mg ethanol per gram of raw wheat straw, which was between 23 and 35 % greater than the yields typically obtained with a conventional bioethanol process, in which wheat straw is pretreated using steam explosion and fermented with the yeast Saccharomyces cerevisiae. PMID- 23754563 TI - One set system for the synthesis and purification of glycosaminoglycan oligosaccharides reconstructed using a hyaluronidase-immobilized column. AB - Using the transglycosylation reaction as a reverse reaction for the hydrolysis of hyaluronidase, new artificial oligosaccharides may be synthesized by reconstructing natural glycosaminoglycans (GAGs) according to preliminary planned arrangements. However, as some problems have been associated with the method, including the low yields of reaction products and complicated processes of separation and purification, improvements in this method were investigated. Transglycosylation reactions were carried out using bovine testicular hyaluronidase-immobilized resin packed in a column. For the transglycosylation reaction, pyridylaminated (PA) GAG hexasaccharides, which were the minimum size for hydrolysis sensitivity and the transglycosylation reaction, were used as acceptors, whereas large size GAGs were used as donors. The reaction mixture was pooled after incubation in the hyaluronidase-immobilized resin column and was then introduced into continuously joined HPLC columns constructed from three steps: the first step of ion-exchange HPLC for concentrating newly synthesized GAG oligosaccharides as reaction products, the second step of reverse phase HPLC for separating PA oligosaccharides from non-PA oligosaccharides, and the third step of size fractionation HPLC for fractionating newly synthesized oligosaccharides. Newly synthesized oligosaccharides were obtained by one complete cycle of the transglycosylation reaction and separation. PMID- 23754565 TI - Effects of bilingualism and trilingualism in L2 production: evidence from errors and self-repairs in early balanced bilingual and trilingual adults. AB - Through analyzing response latencies, errors, and self-repairs in Mandarin, this investigation explores how monolingual, bilingual, and trilingual adults process their speech production differently using cognitive control mechanisms. In this study we conducted two experiments involving speech production in Mandarin. In the two experiments, 81 adults participated and were categorized into three groups: Mandarin monolingual, Hakka-Mandarin bilingual, and Hakka-Mandarin-Minnan trilingual. In Experiment 1 (unpreprogrammed task), each subject read 250 targets that were presented on a computer screen, one at a time, using E-prime; in Experiment 2 (preprogrammed task), each subject read 466 targets printed on A4 paper. Experiment 1 showed that bilinguals and trilinguals outperformed monolinguals in every aspect examined in this research, revealing the presence of bilingual and trilingual advantages in inhibitory control. Interestingly, in Experiment 2, we found a more complex pattern of results: a trilingual advantage in attentional control occurred during L2 production in terms of the number of errors and error correction; however, the bilingual group did not maintain this advantage in the task requiring attentional control. These experimental results revealed that the differences between the language groups became clearer when the inhibitory control demands increased and that compared with the trilingual advantage, the bilingual advantage in inhibitory control emerged in more limited contexts. PMID- 23754567 TI - Errors in text and legend to Figure 3 in: Risk Factors for Anastomotic Leak and Mortality in Diabetic Patients Undergoing Colectomy: Analysis From a Statewide Surgical Quality Collaborative. PMID- 23754566 TI - Spain is not Greece: how metaphors are understood. AB - Metaphoric expressions are pervasive and powerful communication tools. The present report sheds light on two questions: how do we extract meaning from metaphors and similes, and are these two tropes interchangeable? Existing models propose different mechanisms for metaphor comprehension: comparison, categorization, and a shift from comparison to categorization as metaphors become conventionalized. While the categorization model allows for the possibility that metaphors and similes are not always interchangeable, all the variants of the comparison model assume equivalence of meaning between the two tropes. The findings reported here rule out this assumption: they show that metaphors and similes may express different, and even incompatible meanings. Aptness, rather than conventionalization, seems to determine processing mechanisms: apt metaphors, both novel and conventionalized, are understood as categorizations, while similes and inapt metaphors are understood as comparisons. PMID- 23754568 TI - The modern surgery department chairman: the job description as identified by chairmen. AB - IMPORTANCE: The role of the chairman of a surgery department is critical in academic surgery. However, little is known about the variability of job responsibilities. OBJECTIVE: To evaluate chairmen's responsibilities, methods of support, determinants of job performance success, and concerns. DESIGN: Internet based survey. SETTING: Electronic survey system. PARTICIPANTS: Seventy-two chairmen. MAIN OUTCOMES AND MEASURES: Survey data on job responsibilities, methods of support, determinants of job performance success, and concerns. RESULTS: Of 168 chairmen who received the survey, 72 (43%) responded. The mean age of chairmen was 57 years (range, 44-78 years). Of 72 chairmen who responded, 69 (96%) were men, 67 (93%) were white, 65 (90%) were professors, 11 (15%) held a previous chair, 35 (49%) have advanced degrees, and 19 (26%) are program directors. Respondents are responsible for an average of 8.7 divisions, 60 (83%) spent 1 to 10 hours per week in the clinic, 45 (63%) performed surgery 1 to 10 hours per week, 54 (75%) took less than 6 call days per month, 44 (61%) published 1 to 6 papers per year and attended a mean (SD) of 4.3 (1.7) essential meetings per year, and 48 (67%) took 1 to 3 weeks of vacation annually. Chair salary support includes (from least to most) faculty tax, grants, endowment, school, and hospital. Compensation correlates with age, additional degree, specialty, location, contract, and tenure but not clinical hours. Reported compensation was consistent with data from the Association of American Medical Colleges, but 24 (33%) felt undercompensated. Incentives for job performance were given for clinical productivity (34 chairmen [47%]), department performance (50 [70%]), institutional performance (27 [38%]), and personal accomplishment (14 [19%]). Of 72 chairmen, 30 (42%) were concerned about personal liability related to the job, 15 (21%) had purchased personal liability insurance, and 20 (28%) have defended a lawsuit related to nonclinical responsibilities. CONCLUSIONS AND RELEVANCE: Academic surgery department chairmen have a wide array of responsibilities that have changed from historic standards. Success in the role of chairman may improve by appreciating the responsibilities, time allocation, methods of support, and concerns of other chairmen. PMID- 23754569 TI - Taxonomic attribution of the La Grive hominoid teeth. AB - The two hominoid teeth--a central upper incisor (NMB G.a.9.) and an upper molar (FSL 213981)--from the Middle Miocene site of La Grive-Saint-Alban (France) have been traditionally attributed to Dryopithecus fontani (Hominidae: Dryopithecinae). However, during the last decade discoveries in the Valles Penedes Basin (Spain) have shown that several hominoid genera were present in Western Europe during the late Middle Miocene. As a result, the attribution of the dryopithecine teeth from La Grive is not as straightforward as previously thought. In fact, similarities with the upper incisor of Pierolapithecus have led to suggestions that either the latter taxon is present at La Grive, or that it is a junior synonym of Dryopithecus. Here, we re-describe the La Grive teeth and critically revise their taxonomic assignment based on metrical and morphological comparisons with other Middle to Late Miocene hominoids from Europe and Turkey, with particular emphasis on those from the Valles-Penedes Basin. Our results suggest that the I(1) differs in several respects from those of Pierolapithecus and Hispanopithecus, so that an attribution to either Dryopithecus or Anoiapithecus (for which this tooth is unknown) seems more likely. The molar, in turn, most likely corresponds to the M(1) of a female individual. Compared to other Middle Miocene taxa, its occlusal morphology enables its distinction from Pierolapithecus, whereas relative crown height agrees well with Dryopithecus. Therefore, based on available evidence, we support the traditional attribution of the La Grive hominoid to D. fontani. PMID- 23754571 TI - Curcumin as a regulator of epigenetic events. AB - Epigenetic alterations correspond to changes in DNA methylation, covalent modifications of histones, or altered miRNA expression patterns. These three mechanisms are interconnected and appear to be key players in tumor progression and failure of conventional chemotherapy. Dietary components emerged as a promising source of new epigenetically active compounds able to reverse these alterations and to actively regulate gene expression as well as molecular targets implicated in tumorigenesis. The polyphenolic compound curcumin (diferuloylmethane), a yellow spice that enters into the composition of curry, already described for its diverse and broad biological activities, is nowadays well described as an inhibitor of DNA methyltransferase so that it is considered as a DNA hypomethylating agent. It reestablishes the balance between histone acetyl transferase and histone deacetylase (HDAC 1, 3, 4, 5, 8) activity to selectively activate or inactivate the expression of genes implicated in cancer death and progression, respectively. Finally curcumin modulates miRNAs (miR-15a, miR-16, miR-21, miR-22, miR-26, miR-101, miR-146, miR-200, miR-203, and let-7) and their multiple target genes. In conclusion, this dietary compound is able to restore the epigenetic regulation balance and appears as an attractive preventive and/or therapeutic approach against human cancer. PMID- 23754570 TI - Grape seed extract suppresses MDA-MB231 breast cancer cell migration and invasion. AB - BACKGROUND AND AIM: Breast cancer remains a leading cause of mortality among women. In metastasis, cascade migration of cancer cells and invasion of extracellular matrix (ECM) represent critical steps. Urokinase-type plasminogen activator (uPA), as well as metalloproteinases MMP-2 and MMP-9, strongly contribute to ECM remodelling, thus becoming associated with tumour migration and invasion. In addition, the high expression of cytoskeletal (CSK) proteins, as fascin, has been correlated with clinically aggressive metastatic tumours, and CSK proteins are thought to affect the migration of cancer cells. Consumption of fruits and vegetables, characterized by high procyanidin content, has been associated to a reduced mortality for breast cancer. Therefore, we investigated the biological effect of grape seed extract (GSE) on the highly metastatic MDA MB231 breast cancer cell line, focusing on studying GSE ability in inhibiting two main metastatic processes, i.e., cell migration and invasion. METHODS: After MDA MB231 breast cancer cells stimulated with GSE migration and invasion were evaluated by means of trans-well assays and uPA as well as MMPs activity was detected by gelatin zymography. Fascin, beta-catenin and nuclear factor-kappaB (NF-kappaB) expression were determined using western blot technique. beta-Catenin localization was observed by confocal microscopy. RESULTS: We observed that high concentrations of GSE inhibited cell proliferation and apoptosis. Conversely, low GSE concentration decreased cell migration and invasion, likely by hampering beta catenin expression and localization, fascin and NF-kappaB expression, as well as by decreasing the activity of uPA, MMP-2 and MMP-9. CONCLUSIONS: These results make GSE a powerful candidate for developing preventive agents against cancer metastasis. PMID- 23754572 TI - Downregulation of T-cell lymphoma invasion and metastasis-inducing factor 1 induces cytoskeletal rearrangement and inhibits the invasive capacity of gastric cancer cells. AB - T-cell lymphoma invasion and metastasis-inducing factor 1 (Tiam-1) is an important member of the diffuse B-cell lymphoma (Dbl) oncogene family. In a previous study, the overexpression of Tiam-1 protein was identified by immunohistochemistry in human gastric cancer tissues, indicating that Tiam-1 may represent a candidate biomarker of the invasive and metastatic capacity of gastric cancer and for patient prognosis. In the present study, in vitro adhesion selection was used to separate two subpopulations with high (MH) or low (ML) invasive and metastatic potential from the MKN-45 human gastric cancer cell line (M0). A positive correlation was observed between Tiam-l mRNA and protein expression levels and the invasive capacity of the cells using RT-PCR and quantitative cellular-ELISA, respectively. To determine the mechanism by which Tiam-1 affects the invasive capacities of gastric cancer cells, Tiam-1 expression was downregulated in the MH subclone by liposomal transfection of antisense oligodeoxynucleotides (ASODNs). Following 48 h of treatment with ASODNs (0.43 uM), Tiam-1 mRNA transcription and protein expression levels in MH cells was decreased by 80 and 24%, respectively, compared with untreated controls. In addition, the in vitro invasive potential of MH cells was suppressed by 60%. Morphological and ultrastructural observations also demonstrated that ASODN treated MH cells exhibited a smooth surface with markedly reduced filopodia and microspikes, which resembled M0 and ML cells. In addition, cytoskeletal distribution was markedly altered from disordered to regular with reduced long filament-like structures, projections, pseudopodia on the cell surface and decreased actin bodies in the cytoplasm. Results of the current study indicate that the overexpression of Tiam-1 contributes to the invasive phenotypes of gastric cancer cells. These observations are likely to provide an improved insight into the biological mechanisms of Tiam-1 and promote the development of novel treatment strategies in gastric cancer. PMID- 23754573 TI - [Image post-processing, part 1: visualization and segmentation]. AB - Image post-processing of large thin-slice radiological datasets relies on increasingly diverse and complex algorithms. Basic techniques of visualization, segmentation and data analysis will be presented in this article focusing on methods which are integrated into the majority of current viewing and reporting tools, such as multiplanar reformation, volume rendering or basic segmentation. Subsequently, more complex methods and a possible role of post-processing algorithms in the radiology of the future will be discussed. PMID- 23754574 TI - Fetal growth and childhood acute lymphoblastic leukemia: findings from the childhood leukemia international consortium. AB - Positive associations have been reported between the measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual-level data from 12 case control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth-weight-for-gestational-age and proportion of optimal birth weight (POBW)-were analysed. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta-analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta-analyses were 1.24 (95% CI: 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one-standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small-for gestational-age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI: 0.77, 0.95), respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin-like growth factors. (c) 2013 UICC. PMID- 23754576 TI - Phi-square Lexical Competition Database (Phi-Lex): an online tool for quantifying auditory and visual lexical competition. AB - A widely agreed-upon feature of spoken word recognition is that multiple lexical candidates in memory are simultaneously activated in parallel when a listener hears a word, and that those candidates compete for recognition (Luce, Goldinger, Auer, & Vitevitch, Perception 62:615-625, 2000; Luce & Pisoni, Ear and Hearing 19:1-36, 1998; McClelland & Elman, Cognitive Psychology 18:1-86, 1986). Because the presence of those competitors influences word recognition, much research has sought to quantify the processes of lexical competition. Metrics that quantify lexical competition continuously are more effective predictors of auditory and visual (lipread) spoken word recognition than are the categorical metrics traditionally used (Feld & Sommers, Speech Communication 53:220-228, 2011; Strand & Sommers, Journal of the Acoustical Society of America 130:1663-1672, 2011). A limitation of the continuous metrics is that they are somewhat computationally cumbersome and require access to existing speech databases. This article describes the Phi-square Lexical Competition Database (Phi-Lex): an online, searchable database that provides access to multiple metrics of auditory and visual (lipread) lexical competition for English words, available at www.juliastrand.com/phi-lex . PMID- 23754575 TI - CYP3A-mediated drug-drug interaction potential and excretion of brentuximab vedotin, an antibody-drug conjugate, in patients with CD30-positive hematologic malignancies. AB - Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E (MMAE) into CD30-expressing cells. This study evaluated the CYP3A-mediated drug-drug interaction potential of brentuximab vedotin and the excretion of MMAE. Two 21-day cycles of brentuximab vedotin (1.2 or 1.8 mg/kg intravenously) were administered to 56 patients with CD30-positive hematologic malignancies. Each patient also received either a sensitive CYP3A substrate (midazolam), an effective inducer (rifampin), or a strong inhibitor (ketoconazole). Brentuximab vedotin did not affect midazolam exposures. ADC exposures were unaffected by concomitant rifampin or ketoconazole; however, MMAE exposures were lower with rifampin and higher with ketoconazole. The short-term safety profile of brentuximab vedotin in this study was generally consistent with historic clinical observations. The most common adverse events were nausea, fatigue, diarrhea, headache, pyrexia, and neutropenia. Over a 1-week period, ~23.5% of intact MMAE was recovered after administration of brentuximab vedotin; all other species were below the limit of quantitation. The primary excretion route is via feces (median 72% of the recovered MMAE). These results suggest that brentuximab vedotin (1.8 mg/kg) and MMAE are neither inhibitors nor inducers of CYP3A; however, MMAE is a substrate of CYP3A. PMID- 23754578 TI - Image of the month-diagnosis. PMID- 23754579 TI - Biomimetic synthesis of santalin A,B and santarubin A,B, the major colorants of red sandalwood. PMID- 23754577 TI - Imaging mass spectrometry for assessing temporal proteomics: analysis of calprotectin in Acinetobacter baumannii pulmonary infection. AB - Imaging MS is routinely used to show spatial localization of proteins within a tissue sample and can also be employed to study temporal protein dynamics. The antimicrobial S100 protein calprotectin, a heterodimer of subunits S100A8 and S100A9, is an abundant cytosolic component of neutrophils. Using imaging MS, calprotectin can be detected as a marker of the inflammatory response to bacterial challenge. In a murine model of Acinetobacter baumannii pneumonia, protein images of S100A8 and S100A9 collected at different time points throughout infection aid in visualization of the innate immune response to this pathogen. Calprotectin is detectable within 6 h of infection as immune cells respond to the invading pathogen. As the bacterial burden decreases, signals from the inflammatory proteins decrease. Calprotectin is no longer detectable 96-144 h post infection, correlating to a lack of detectable bacterial burden in lungs. These experiments provide a label-free, multiplexed approach to study host response to a bacterial threat and eventual clearance of the pathogen over time. PMID- 23754580 TI - Religion and United States physicians' opinions and self-predicted practices concerning artificial nutrition and hydration. AB - This study surveyed 1,156 practicing US physicians to examine the relationship between physicians' religious characteristics and their approaches to artificial nutrition and hydration (ANH). Forty percent of physicians believed that unless a patient is imminently dying, the patient should always receive nutrition and fluids; 75 % believed that it is ethically permissible for doctors to withdraw ANH. The least religious physicians were less likely to oppose withholding or withdrawing ANH. Compared to non-evangelical Protestant physicians, Jews and Muslims were significantly more likely to oppose withholding ANH, and Muslims were significantly more likely to oppose withdrawing ANH. PMID- 23754581 TI - Aging and religious participation in late life. AB - The aim of the study is to evaluate the relationship between two dimensions of religiosity and the process of aging. Secondary analysis of longitudinal data from the Florida Retirement Study was used to assess the trajectories of religious development over time. We analyzed data from six interview waves with 1,000 older adults aged 72 or over. A baseline model of growth processes only indicated significant variation and mean decline in religious attendance, but no significant variation nor mean change in religious beliefs over time. A final model including a set of 17 covariates was estimated, and the model fit statistics indicated very good fit for this latent growth curve model. The decline in mean religious attendance across time did not accompany a mean increase in religious beliefs as expected. There were numerous individual differences in the trajectory of decline for religious attendance, as well as in the initial levels of attendance and religious beliefs. PMID- 23754582 TI - Comparison of recurrence patterns between <=5 years and >5 years after curative operations in colorectal cancer patients. AB - BACKGROUND AND OBJECTIVES: To identify characteristics of recurrent colorectal cancer in terms of follow-up periods, that is, <=5 years and >5 years after curative operations METHODS: This study enrolled 4,023 patients. Of them, 835 patients showed recurrence after primary curative resection for colorectal cancer. Recurrence occurred <=5 years (n = 799) or >5 years (n = 36) after curative surgery. Variables and recurrence patterns were compared between the groups. RESULTS: Among the 835 patients who experienced recurrence, only 4.3% recurred >5 years after surgery. This group showed lower preoperative serum carcinoembryonic antigen levels, more tumors with expanding growth, well differentiated histology, and no lymph node metastasis (all P < 0.05). In terms of haematogenous metastasis, lung or liver was the most prevalent site in patients who recurred after >5 years or <=5 years, respectively (P = 0.005). In rectal cancer patients, recurrence patterns revealed the same results. In colon cancer patients, the liver was the most prevalent site in both groups. CONCLUSIONS: After 5 years of follow-up, routine surveillance for detecting other malignancies seems to be sufficient. However, the possibility of late (particularly late pulmonary) recurrence should be considered. Radiologic examination to detect pulmonary metastasis should be considered in the follow-up program. PMID- 23754583 TI - The Professionalism Assessment of Clinical Teachers (PACT): the reliability and validity of a novel tool to evaluate professional and clinical teaching behaviors. AB - Physicians function as clinicians, teachers, and role models within the clinical environment. Negative learning environments have been shown to be due to many factors, including the presence of unprofessional behaviors among clinical teachers. Reliable and valid assessments of clinical teacher performance, including professional behaviors, may provide a foundation for evidence-based feedback to clinical teachers, enable targeted remediation or recognition, and help to improve the learning environment. However, few tools exist for the evaluation of clinical teachers that include a focus on both professional and clinical teaching behaviors. The Professionalism Assessment of Clinical Teachers (PACT) was developed and implemented at one Canadian institution and was assessed for evidence of reliability and validity. Following each clerkship rotation, students in the 2009-2010 third-year undergraduate clerkship cohort (n = 178) anonymously evaluated a minimum of two clinical teachers using the PACT. 4,715 forms on 567 faculty members were completed. Reliability, validity, and free text comments (present in 45 % of the forms) were examined. An average of 8.6 PACT forms were completed per faculty (range 1-60), with a reliability of 0.31 for 2.9 forms (harmonic mean); 12 forms were necessary for a reliability of 0.65. Global evaluations of teachers aligned with ratings of free-text comments (r = 0.77, p < 0.001). Comment length related negatively with overall rating (r = -0.19, p < 0.001). Mean performance related negatively with variability of performance (r = 0.72, p < 0.001), although this may be related to a ceiling effect. Most faculty members were rated highly; however 'provided constructive feedback' was the least well-rated item. Respectful interactions with students appeared to be the most influential item in the global rating of faculty performance. The PACT is a moderately reliable tool for the assessment of professional behaviors of clinical teachers, with evidence supporting its validity. PMID- 23754584 TI - Intersubject local SAR variation for 7T prostate MR imaging with an eight-channel single-side adapted dipole antenna array. AB - PURPOSE: Surface transmit arrays used in ultra-high field body MRI require local specific absorption rate (SAR) assessment. As local SAR cannot be measured directly, local SAR is determined by simulations using dielectric patient models. In this study, the inter-patient local SAR variation is investigated for 7T prostate imaging with the single-side adapted dipole antenna array. METHOD: Four dedicated dielectric models were created by segmenting Dixon water-fat separated images that were obtained from four subjects with a 1.5T scanner and the surface array in place. Electromagnetic simulations were performed to calculate the SAR distribution for each model. Radio frequency (RF) exposure variations were determined by analyzing the SAR(10g) distributions (1) with one element active, (2) using a Q-matrix eigenvalue/eigenvector approach, (3) with the maximum potential SAR in each voxel, and (4) for a phase shimmed prostate measurement. RESULTS: Maximum potential local SAR levels for 1 W time-averaged accepted power per transmit channel range from 4.1 to 7.1 W/kg. CONCLUSION: These variations show that one model is not sufficient to determine safe scan settings. For the operation of the surface array conservative power settings were derived based on a worst-case SAR evaluation and the most SAR-sensitive body model. PMID- 23754585 TI - Mechanistic insight into the Staudinger reaction catalyzed by N-heterocyclic carbenes. AB - Four zwitterions were prepared by treating 1,3-dimesitylimidazolin-2-ylidene (SIMes) or 1,3-dimesitylimidazol-2-ylidene (IMes) with either N-tosyl benzaldimine or diphenylketene. They were isolated in high yields and characterized by IR and NMR spectroscopy. The molecular structures of three of them were determined by using X-ray crystallography and their thermal stability was monitored by using thermogravimetric analysis. The imidazol(in)ium-2-amides were rather labile white solids that did not show any tendency to tautomerize into the corresponding 1,2,2-triaminoethene derivatives. They displayed a mediocre catalytic activity in the Staudinger reaction of N-tosyl benzaldimine with diphenylketene. In contrast, the imidazol(in)ium-2-enolates were orange-red crystalline materials that remained stable over extended periods of time. Despite their greater stability, these zwitterions turned out to be efficient promoters for the model cycloaddition under scrutiny. As a matter of fact, their catalytic activity matched those recorded with the free carbenes. Altogether, these results provide strong experimental insight into the mechanism of the Staudinger reaction catalyzed by N-heterocyclic carbenes. They also highlight the superior catalytic activity of the imidazole-based carbene IMes compared with its saturated analogue SIMes in the reaction under consideration. PMID- 23754586 TI - Mycobacterial spindle cell pseudotumor: atypical mycobacterial infection mimicking malignancy on fine needle aspiration. PMID- 23754587 TI - Masculinization of the eruption pattern of permanent mandibular canines in opposite sex twin girls. AB - The aim of this study is to explore the effect of prenatal androgenization on the clinical eruption of permanent teeth expressing dimorphism and bimaturism. The eruption curves of permanent teeth (except third molars), including those that make up the canine complex (permanent canines, lower first premolars), are compared among opposite sex twins (OS twins) relative to single-born boys and girls. The comparisons are made with regard to three phases of eruption (pierced mucosa, half- erupted, and completely erupted) from a cross-sectional sample of dental casts, using Kaplan-Meier survival and Cox regression analyzes. The casts were collected from 2159 school children from the US Collaborative Perinatal Project, including 39 pairs of OS-twins, of which 12 pairs (30.8%) were Euro Americans and 27 pairs (69.2%) were of African-American ancestry. The eruption patterns of the incisors, upper first molars, and lower canines were found to be significantly masculinized (delayed) among OS twin girls. The differences in most other teeth were either not significant, or the number of observations of active eruption phases were too few, such as in the upper first molars and incisors, to yield strong evidence and meaningful results. The masculinization of the tooth eruption pattern in OS twin girls is intriguing because of the lower canine responses during puberty, as well as canine primordial formation during early fetal androgenization of their co-twin during the 8th to 14th gestational weeks. The present results offer a challenge for future research exploring tooth eruption mechanisms, and may also highlight some cases of delayed or ectopic canines, which are biased toward females. PMID- 23754588 TI - [GSTCVS certificate for cardiac pacemaker, ICD and CRT therapy]. AB - Medical qualifications to perform operations with cardiac electronic implantable devices as well as for preoperative and postoperative therapy, including follow up in this patient population are not well defined. Based on recommendations which have been worked out and published by an interdisciplinary consensus of cardiac surgeons, cardiologists and electrophysiologists, a certificate with three modules has been developed by the Working Group for Electrophysiologic Surgery of the German Society for Thoracic and Cardiovascular Surgery (GSTCVS, Deutsche Gesellschaft fur Thorax-, Herz- und Gefabetachirurgie, DGTHG). First examinations for this certificate will be held in 2013 and transitional regulations apply until 1st April 2014. Further details are available on the homepage of the GSTCVS. PMID- 23754589 TI - The shape of the placental surface at birth and colorectal cancer in later life. AB - OBJECTIVES: Many chronic diseases, including certain cancers, may originate through variations in the supply of nutrients to the fetus. These variations change gene expression and permanently set the structure and function of the body, a process known as programming. Fetal nutrition depends on the mother's metabolism and nutritional reserves, and on the placenta's ability to transfer nutrients from mother to baby. In this study, we examine how colorectal cancer is related to maternal and placental characteristics. METHODS: We ascertained 275 cases of colorectal cancer among the 20,431 people in the Helsinki Birth Cohort, who were born during 1924-1944 and whose body size at birth was recorded, together with the shape and size of the placenta. RESULTS: Hazard ratios for colorectal cancer increased as the placental surface became longer and more oval. The hazard ratio was 2.3 (95% CI 1.2-4.7) among people in whom the difference between the length and breadth of the surface exceeded 6 cm, compared with those in whom there was no difference. Colorectal cancer was unrelated to other placental measurements or to body size at birth. CONCLUSION: An oval placental surface at birth is associated with later colorectal cancer. The shape of the placental surface is determined by events at around 8-12 weeks gestation. We speculate that, if the spiral arteries open prematurely, the surface becomes more oval and the fetus is at risk of oxidative damage at a time when the colon is differentiating. PMID- 23754590 TI - Selenium supplementation alters gene expression profiles associated with innate immunity in whole-blood neutrophils of sheep. AB - Footrot (FR) is a common, contagious bacterial disease of sheep that results in lameness and significant economic losses for producers. We previously reported that sheep affected with FR have lower whole-blood (WB) selenium (Se) concentrations and that Se supplementation in conjunction with routine control practices accelerates recovery from FR. To determine whether oral Se-yeast administered at supranutritional levels (>4.9 mg Se/week) alters the ability of sheep to resist or recover from FR infection, 60 ewes with and 60 ewes without FR were drenched once weekly for 62.5 weeks with 0, 4.9, 14.7, or 24.5 mg organic Se yeast (30 ewes per treatment group). Footrot prevalence and severity were measured at 0, 20, 28, 40, and 60 weeks of Se supplementation. Genomic expression of eight WB-neutrophil genes for selenoproteins and seven WB-neutrophil genes for proteins involved in innate immunity was determined at the end of the treatment period using SYBR Green and quantitative polymerase chain reaction methodology. Supranutritional Se-yeast supplementation successfully increased Se status in sheep but did not prevent FR. Supranutritional Se-yeast supplementation increased WB-neutrophil expression of genes involved in innate immunity: L-selectin, interleukin-8 receptor, and toll-like receptor 4, which were or tended to be lower in ewes affected with FR. Furthermore, supranutritional Se-yeast supplementation altered the expression of selenoprotein genes involved in innate immunity, increasing selenoprotein S and glutathione peroxidase 4 and decreasing iodothyronine deiodinases 2 and 3. In conclusion, supranutritional Se-yeast supplementation does not prevent FR, but does alter WB-neutrophil gene expression profiles associated with innate immunity, including reversing those impacted by FR. PMID- 23754591 TI - Comparative analysis of serum zinc, copper, manganese, iron, calcium, and magnesium level and complexity of interelement relations in generalized anxiety disorder patients. AB - The purpose of the study was to determine the concentration of serum trace and other essential elements of generalized anxiety disorder patients and to find out the relationship between element levels and nutritional status or socioeconomic factors. The study was conducted among 50 generalized anxiety disorder patients and 51 healthy volunteers. Patients were selected and recruited in the study with the help of a clinical psychologist by random sampling. The concentrations of serum trace elements (Zn, Cu, Mn, and Fe) and other two essential elements (Ca and Mg) were determined by graphite furnace and flame atomic absorption spectroscopy. Data were analyzed by independent t test, Pearson's correlation analysis, regression analysis, and analysis of variance. The serum concentrations of Zn, Cu, Mn, Fe, Ca, and Mg in generalized anxiety disorder patients were 1.069 +/- 0.40, 1.738 +/- 0.544, 1.374 +/- 0.750, 3.203 +/- 2.065, 108.65 +/- 54.455, and 21 +/- 4.055 mg/L, while those were 1.292 +/- 0.621, 0.972 +/- 0.427, 0.704 +/- 0.527, 1.605 +/- 1.1855, 101.849 +/- 17.713, and 21.521 +/- 3.659 mg/L in control subjects. Significantly decreased (p < 0.05) serum Zn concentration was found in the patient group compared to the control group while serum level of Cu, Mn, and Fe was significantly (p < 0.05) higher, but the differences of the concentration of Ca and Mg between the patient and control groups were not significant (p > 0.05). Socioeconomic data revealed that most of the patients were in the lower middle class group and middle-aged. Mean BMI of the control group (23.63 +/- 3.91 kg/m(2)) and the patient group (23.62 +/- 3.77 kg/m(2)) was within the normal range (18.5-25.0 kg/m(2)). The data obtained from different interelement relations in the generalized anxiety disorder patients and control group strongly suggest that there is a disturbance in the element homeostasis. So changes in the serum trace element level in generalized anxiety disorder patients occur independently and they may provide a prognostic tool for the diagnosis and treatment of this disease. PMID- 23754592 TI - Feasibility of dasatinib in children and adolescents with new or recurrent central nervous system germinoma. AB - Germinomas and embryonal carcinomas are central nervous system (CNS) germ cell tumors (GCT) that may overexpress the proto-oncogene c-KIT, a receptor tyrosine kinase, of which dasatinib is a potent inhibitor. This retrospective review presents the feasibility and tolerability of dasatinib administration in select patients with CNS germinoma. Between November 2008 and April 2010, six patients with newly diagnosed (n = 3) or recurrent (n = 3) CNS GCT were treated in an effort to avoid irradiation and/or delay recurrence. The daily doses administered were 100-170 mg/m(2) with mostly grade 1-2 toxicities. Dasatinib may play a role in future treatment strategies for CNS GCT. PMID- 23754593 TI - Insight into the redox partner interaction mechanism in cytochrome P450BM-3 using molecular dynamics simulations. AB - Flavocytochrome P450BM-3 is a soluble bacterial reductase composed of two flavin (FAD/FMN) and one HEME domains. In this article, we have performed molecular dynamics simulations on both the isolated FMN and HEME domains and their crystallographic complex, with the aim to study their binding modes and to garner insight into the interdomain electron transfer (ET) mechanism. The results evidenced an interdomain conformational rearrangement that reduces the average distance between the FMN and HEME cofactors from 1.81 nm, in the crystal structure, to an average value of 1.41+/-0.09 nm along the simulation. This modification is in agreement with previously proposed hypotheses suggesting that the crystallographic FMN/HEME complex is not in the optimal arrangement for favorable ET rate under physiological conditions. The calculation of the transfer rate along the simulation, using the Pathways Path method, demonstrated the occurrence of seven ET pathways between the two redox centers, with three of them providing ET rates (KET ) comparable with the experimental one. The sampled ET pathways comprise the amino acids N319, L322, F390, K391, P392, F393, A399, C400, and Q403 of the HEME domain and M490 of the FMN domain. The values of KET closer to the experiment were found along the pathways FMN(C7)->F390->K391->P392 >HEME(Fe) and FMN(C8)->M490->F393->HEME(Fe). Finally, the analysis of the collective modes of the protein complex evidences a clear correlation of the first two essential modes with the activation of the most effective ET pathways along the trajectory. PMID- 23754594 TI - Involvement of patients with cancer in patient safety: a qualitative study of current practices, potentials and barriers. AB - BACKGROUND: Patient involvement in patient safety is widely advocated but knowledge regarding implementation of the concept in clinical practice is sparse. OBJECTIVE: To investigate existing practices for patient involvement in patient safety, and opportunities and barriers for further involvement. DESIGN: A qualitative study of patient safety involvement practices in patient trajectories for prostate, uterine and colorectal cancer in Denmark. Observations from four hospital wards and interviews with 25 patients with cancer, 11 hospital doctors, 10 nurses, four general practitioners and two private practicing gynaecologists were conducted using ethnographic methodology. FINDINGS: Patient safety was not a topic of attention for patients or dominant in communication between patients and healthcare professionals. The understanding of patient safety in clinical practice is almost exclusively linked to disease management. Involvement of patients is not systematic, but healthcare professionals and patients express willingness to engage. Invitation and encouragement of patients to become involved could be further systematised and developed. Barriers include limited knowledge of patient safety, of specific patient safety involvement techniques and concern regarding potential negative impact on doctor-patient relationship. CONCLUSIONS: Involvement of patients in patient safety must take into account that despite stated openness to the idea of involvement, patients and health professionals may not in practice show immediate concern. Lack of systematic involvement can also be attributed to limited knowledge about how to implement involvement beyond the focus of self-monitoring and compliance and a concern about the consequences of patient involvement for treatment outcomes. To realise the potential of patients' and health professionals' shared openness towards involvement, there is a need for more active facilitation and concrete guidance on how involvement can be practiced by both parties. PMID- 23754595 TI - The real job: recruit, mentor, and protect: Comment on "The modern surgery department chairman". PMID- 23754596 TI - Pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of Delta(9) -THC in cannabis users. AB - Oral Delta(9) -tetrahydrocannabinol (Delta(9) -THC) has been evaluated as a medication for cannabis dependence, but repeated administration of acute oral doses up to 40 mg has not been effective at reducing drug-taking behavior. Larger doses might be necessary to affect cannabis use. The purpose of the present study was therefore to determine the physiological and behavioural effects of oral Delta(9) -THC at acute doses higher than those tested previously. The pharmacokinetic and pharmacodynamic profile of oral Delta(9) -THC, administered in ascending order in 15 mg increments across separate sessions, up to a maximum of 90 mg, was determined in seven cannabis users. Five subjects received all doses and two experienced untoward side effects at lower doses. Delta(9) -THC produced a constellation of effects consistent with previous clinical studies. Low cannabinoid concentrations were associated with significant effects on drug sensitive measures, although progressively greater levels did not lead to proportionately larger drug effects. Considerable variability in Cmax and tmax was observed. Doses of oral Delta(9) -THC larger than those tested previously can be administered to individuals with a history of cannabis use, although given the pharmacokinetic variability of oral Delta(9) -THC and individual differences in sensitivity, individualized dose adjustment is needed to avoid side effects and maximize therapeutic response. PMID- 23754597 TI - Favorable effect of moderate dose caffeine on the skeletal system in ovariectomized rats. AB - SCOPE: Caffeine, a methylxanthine present in coffee, has been postulated to be responsible for an increased risk of osteoporosis in coffee drinkers; however, the data are inconsistent. The aim of the present study was to investigate the effects of a moderate dose of caffeine on the skeletal system of rats with normal and decreased estrogen level (developing osteoporosis due to estrogen deficiency). METHODS AND RESULTS: The experiments were carried out on mature nonovariectomized and ovariectomized Wistar rats, divided into control rats and rats receiving caffeine once daily, 20 mg/kg p.o., for 4 wk. Serum bone turnover markers, bone mass, mass of bone mineral, calcium and phosphorus content, histomorphometric parameters, and bone mechanical properties were examined. Caffeine favorably affected the skeletal system of ovariectomized rats, slightly inhibiting the development of bone changes induced by estrogen deficiency (increasing bone mineralization, and improving the strength and structure of cancellous bone). Moreover, it favorably affected mechanical properties of compact bone. There were no significant effects of caffeine in rats with normal estrogen levels. CONCLUSION: In conclusion, results of the present study indicate that low-to-moderate caffeine intake may exert some beneficial effects on the skeletal system of mature organisms. PMID- 23754598 TI - Validated LC-MS method for simultaneous quantitation of catalpol and harpagide in rat plasma: application to a comparative pharmacokinetic study in normal and diabetic rats after oral administration of Zeng-Ye-Decoction. AB - A simple and efficient liquid chromatography-mass spectrometry (LC-MS) method was developed and validated for simultaneous quantitation of catalpol and harpagide in normal and diabetic rat plasma. Protein precipitation extraction with acetonitrile was carried out using salidroside as the internal standard (IS). The LC separation was performed on an Elite C18 column (150 * 4.6 mm, 5 um) with the mobile phase consisting of acetonitrile and water within a runtime of 12.0 min. The analytes were detected without endogenous interference in the selected ion monitoring mode with positive electrospray ionization. Calibration curves offered satisfactory linearity (r > 0.99) at linear range of 0.05-50.0 ug/mL for catalpol and 0.025-5.0 ug/mL for harpagide with the lower limits of quantitation of 0.05 and 0.025 ug/mL, respectively. Intra- and inter-day precisions (RSD) were <9.4%, and accuracy (RE) was in the -6.6 to 4.9% range. The extraction efficiencies of catalpol, harpagide and IS were all >76.5% and the matrix effects of the analytes ranged from 86.5 to 106.0%. The method was successfully applied to the pharmacokinetic study of catalpol and harpagide after oral administration of Zeng Ye-Decoction to normal and diabetic rats, respectively. PMID- 23754599 TI - The "malignant truth" about the recurrence of pancreatic intraductal papillary mucinous neoplasms-reply. PMID- 23754600 TI - Electrospun antibacterial chitosan-based fibers. AB - Chitosan is non-toxic, biocompatible, and biodegradable polysaccharide from renewable resources, known to have inherent antibacterial activity, which is mainly due to its polycationic nature. The combining of all assets of chitosan and its derivatives with the unique properties of electrospun nanofibrous materials is a powerful strategy to prepare new materials that can find variety of biomedical applications. In this article the most recent studies on different approaches for preparation of antibacterial fibrous materials from chitosan and its derivatives such as electrospinning, coating, and electrospinning electrospraying, loading of drugs or bioactive nanoparticles are summarized. PMID- 23754601 TI - Loss of heterozygosity at 13q13 and 14q32 predicts BRCA2 inactivation in luminal breast carcinomas. AB - BRCA2 is the major high-penetrance predisposition gene for luminal (estrogen receptor [ER] positive) breast cancers. However, many BRCA2 mutant carriers lack family history of breast/ovarian cancers and do not benefit from genetic testing. Specific genomic features associated with BRCA2 inactivation in tumors could help identify patients for whom a genetic test for BRCA2 may be proposed. A series of ER-positive invasive ductal carcinomas (IDCs) including 30 carriers of BRCA2 mutations and 215 control cases was studied by single-nucleotide polymorphism (SNP) arrays. Cases and controls were stratified by grade and HER2 status. Independently, 7 BRCA2 and 51 control cases were used for validation. Absolute copy number and Loss of heterozygosity (LOH) profiles were obtained from SNP arrays by the genome alteration print (GAP) method. BRCA2 tumors were observed to display a discriminatively greater number of chromosomal breaks calculated after filtering out and smoothing <3 Mb variations. This argues for a BRCA2-associated genomic instability responsible for long-segment aberrations. Co-occurrence of two genomic features-LOH of 13q13 and 14q32-was found to predict BRCA2 status with 90% of sensitivity and 87% of specificity in discovery series of high-grade HER2-negative IDCs and 100% of sensitivity and 88% of specificity in an independent series of 58 IDCs. Estimated positive predictive value was 17.2% (confidence interval: 6.7-33.5) in the whole series. In conclusion, the simplified BRCA2 classifier based on the co-occurrence of LOH at 13q13 and 14q32 could provide an indication to test for BRCA2 mutation in patients with ER positive IDC. PMID- 23754602 TI - Optimisation of supercritical carbon dioxide extraction of essential oil of flowers of tea (Camellia sinensis L.) plants and its antioxidative activity. AB - BACKGROUND: To extract natural volatile compounds from tea (Camellia sinensis) flowers without thermal degradation and residue of organic solvents, supercritical fluid extraction (SFE) using carbon dioxide was employed to prepare essential oil of tea flowers in the present study. Four important parameters- pressure, temperature, static extraction time, and dynamic extraction time--were selected as independent variables in the SFE. RESULTS: The optimum extraction conditions were the pressure of 30 MPa, temperature of 50 degrees C, static time of 10 min, and dynamic time of 90 min. Based on gas chromatography-mass spectrometry analysis, 59 compounds, including alkanes (45.4%), esters (10.5%), ketones (7.1%), aldehydes (3.7%), terpenes (3.7%), acids (2.1%), alcohols (1.6%), ethers (1.3%) and others (10.3%) were identified in the essential oil of tea flowers. Moreover, the essential oil of tea flowers showed relatively stronger DPPH radical scavenging activity than essential oils of geranium and peppermint, although its antioxidative activity was weaker than those of essential oil of clove, ascorbic acid, tert-butylhydroquinone, and butylated hydroxyanisole. CONCLUSION: Essential oil of tea flowers using SFE contained many types of volatile compounds and showed considerable DPPH scavenging activity. The information will contribute to the future application of tea flowers as raw materials in health-care food and food flavour industries. PMID- 23754603 TI - Exiting root injury in transforaminal endoscopic discectomy: preoperative image considerations for safety. AB - PURPOSE: To evaluate the clinical and radiological risk factors for exiting root injuries during transforaminal endoscopic discectomy. METHODS: We retrospectively examined cohort data from 233 patients who underwent percutaneous endoscopic lumbar discectomy for lumbar disc herniation between January 1st, 2010 and December 31st, 2011. We divided the patients into the two groups: those who presented a postoperative exiting root injury, such as postoperative dysesthesia or motor weakness (Group A, n = 20), and those who did not suffer from a root injury (Group B, n = 213). We examined the clinical and radiological factors relating exiting root injuries. We measured the active working zone with the exiting root to the upper facet distance (Distance A), the exiting root to disc surface distance at the lower facet line (Distance B) and the exiting root to the lower facet distance (Distance C) in magnetic resonance imaging (MRI). RESULTS: Group A exhibited a shorter Distance C (6.4 +/- 1.5 versus 4.4 +/- 0.8 mm, p < 0.001) and a longer operation time (67.9 +/- 21.8 versus 80.3 +/- 23.7 min, p = 0.017) relative to Group B. The complication rate decreased by 23% per each 1-mm increase in Distance C (p = 0.000). In addition, the complication rate increased 1.027-fold per each 1-min increase in the operation time (p = 0.027). CONCLUSION: We recommend measuring the distance from the exiting root to the facet at the lower disc level according to a preoperative MRI scan. If the distance is narrow, an alternative surgical method, such as microdiscectomy or conventional open discectomy, should be considered. PMID- 23754605 TI - A palladium-catalyzed enantioselective addition of arylboronic acids to cyclic ketimines. AB - Sly as Nicox: A palladium-catalyzed addition of arylboronic acids to ketimines has been developed to efficiently provide products in up to 99 % yield and 96 % ee. The reactions could be run under aerobic conditions and with unpurified trifluoroethanol (TFE). A pyrrolidine compound bearing a chiral alpha-tertiary amine was synthesized in several steps without loss of enantioselectivity. TFA = trifluoroacetate. PMID- 23754606 TI - Commentary on: predictive value of health-related quality of life in progression of disability and depression in persons with multiple sclerosis: a 3-year study. PMID- 23754607 TI - Dynamic gadobutrol-enhanced MRI predicts early response to antivascular but not to antiproliferation therapy in a mouse xenograft model. AB - PURPOSE: Dynamic contrast-enhanced magnetic resonance imaging has been described as a method to assess tumor vascularity and, therefore, is discussed as a noninvasive biomarker for drug response prediction in tumor therapies. Because antiangiogenic and antiproliferative drugs are frequently combined for therapy, the aim was to investigate (1) the early response predictability and (2) the extent to which these therapy types influence dynamic contrast-enhanced magnetic resonance imaging with gadobutrol soon after therapy initiation. METHODS: Mice bearing a KPL-4 tumor were treated with either bevacizumab as an antiangiogenic drug or trastuzumab as a cytotoxic anti-tumor drug. The gadobutrol-contrast agent exposure of the tumor was recorded before and at several time points after therapy initiation to examine the response prediction by dynamic contrast enhanced magnetic resonance imaging. RESULTS: Both therapies resulted in significant tumor growth attenuation over 30 days of therapy, but the individual response to each therapy was different. Specifically, bevacizumab affected the dynamic gadobutrol-enhanced MRI-derived area under the curve at early time points (<=8 days), while trastuzumab did not. CONCLUSION: The area under the curve obtained from dynamic gadobutrol-enhanced MRI predicted early tumor response to the antiangiogenic drug bevacizumab, but not to the anti-tumor cell drug trastuzumab. This indicates that the area under the curve may be useful for assessing early antiangiogenic but not antiproliferative drug effects. PMID- 23754608 TI - [Stress incontinence after prostatectomy in treatment reality: results from a rehabilitation clinic]. AB - BACKGROUND: In the current discussion on the operative therapy of prostate cancer, not only"if" but also"how" play a major role. Both questions are closely related as, e.g. a possible excessive therapy will result in additional suffering due to stress incontinence. For the most common, troublesome and expensive consequences of prostatectomy it is of interest to know which factors play a role in treatment reality and which could possibly be avoided. PATIENTS AND METHODS: The hospital records of all patients who underwent follow-up treatment after prostatectomy in 2009 at the clinic in the spa park in Bad Wildungen Reinhardshausen were evaluated with respect to relevant data on outcome and clinical endpoints. RESULTS: Of the 1,750 patients 405 (23.1 %) were continent on admission and discharge and a further 189 (10.8 %) were continent on discharge so that a total of 594 patients (33.9 %) were continent on discharge. Of the 1,155 patients (66.0 %) who were incontinent on admission and discharge, this remained the same during the rehabilitation period for 727 (62.9 %) who were diurnally incontinent and 659 (57.1 %) who were nocturnally incontinent. For 387 patients (33.5 %) the incontinence decreased during the day and for 370 (32.0 %) during the night, for 34 (3.4 %) the incontinence increased during the day and for 45 (3.9 %) during the night. An age < 60 years was advantageous for maintaining continence and in contrast > 70 years was disadvantageous. Retention of nerves showed a significant effect on maintaining continence. Statistically significant differences between the results of operative procedures and the results of the type of clinic (KKP communal, confessional and private or UK university clinic) were not observed. However, the results of maintaining continence (up to termination of rehabilitation treatment) for the 594 patients (33.9 %) was only achieved by 94 (51 %) of all 183 clinics, i.e. 78 (49.7 %) of the KKP clinics and 14 (53.9 %) of UK clinics. For the certified prostate centers of KKP and UK clinics this amounted to 17 (81 %) and 5 (83.3 %), respectively. CONCLUSIONS: In treatment reality of follow-up treatment of patients after prostatectomy in rehabilitation clinics approximately one third (33.9 %) achieved retention of continence up to discharge. An age < 60 years was advantageous and > 70 years disadvantageous. Bilateral and unilateral retention of nerves significantly improved retention of continence. The operative procedure and type of clinic did not significantly affect the results. However, in approximately one third of patients (33.9 %) retention of continence was achieved by only approximately one half (51.4 %) of all clinics. This shows that in treatment reality, stress incontinence following prostatectomy is avoidably underdeveloped and can be demonstrably increased by suitable operative techniques for sphincter protection. PMID- 23754609 TI - [Testosterone deficiency - an underestimated risk for men? Prevalence of hypogonadism]. AB - BACKGROUND: Testosterone deficiency represents a significant health risk factor for men but the importance has so far been underestimated. Besides physiological and age-related reduction, acquired testosterone deficiency may also occur. Testosterone deficiency is a possible result of commonly occurring diseases or is itself the basis for development of different diseases. The scope of the present investigation was measurement of serum testosterone levels in different age groups. MATERIALS AND METHODS: Serum testosterone levels were determined in samples from 5,735 healthy men at the LADR laboratory MVZ Dr. Kramer & colleagues, Geesthacht under routine conditions. The frequency of testosterone deficiency was calculated in different age groups and compared using SPSS 19.0 software. RESULTS: Pathologically low testosterone levels (< 2.5 ng/ml) were found in 15.2 % of subjects while 37.4 % had a testosterone level lower than 3.5 ng/ml. Decreased testosterone levels were not associated with age. In addition the proportion of men with decreased serum testosterone levels was comparable in all age groups. The average serum testosterone level decreased slightly in all age groups during the period before midday. CONCLUSIONS: The data reveal high rates of testosterone deficiency in men independent of patient age. As decreased serum testosterone levels may be the consequence of several diseases and can be causally involved in the pathogenesis of further diseases, it is strongly recommended that serum testosterone measurement should be included in the diagnostic arsenal especially when symptoms, such as loss of libido, erectile dysfunction, lack of concentration, depression, lethargy, irritability and sleep disturbance are present. PMID- 23754610 TI - [Traditional Chinese medicine in urology]. AB - Traditional Chinese medicine (TCM) is an ancient holistic medicine based on the doctrine of Tao and Qi. Tao represents an alteration from which the polarity of Yin and Yang arises and Qi is the vitality which circulates through the body. Therapeutic concepts of TCM include acupuncture, herbal therapy, nutrition and Tuina, a form of manual therapy. TCM is now gaining increased acceptance in the Western society as a complementary therapy. Acupuncture and herbal therapy are the main forms of implementation of TCM in urology. PMID- 23754611 TI - [T1 bladder cancer: role of documentation for bladder tumor findings and targeted second resection]. AB - BACKGROUND: For control resection of T1 bladder tumors an exact relocalization of the previously infiltrating tumor spread can be complicated by postreactive alterations, multiple scar tissue or change of surgeons. In this study the results of control transurethral resection of the bladder (TURB) after T1 high grade bladder tumors with the focus on localization and importance of standardized exact documentation were analyzed. PATIENTS AND METHODS: From July to February 2012 a control resection was performed in 167 patients due to a T1 high grade bladder cancer. The rates of residual tumor tissue and localization were investigated with standardized tumor documentation. RESULTS: Out of 167 patients with T1 bladder cancer who underwent a control resection tumor tissue was found in 58.1 % (97 out of 167) and in 85.6 % (83 out of 97) the primary site was affected (41.2 % only at primary site and 44.3 % additionally at other locations). In 11 patients (11.3 %) residual tumor tissue at the initial site was only detected histologically. CONCLUSIONS: Our results indicate that T1 high grade bladder cancers show a relevant rate of residual tumor tissue at control resection which confirms the clinical guidelines of the European Association of Urology (EAU) on mandatory resection. In most cases the primary tumor site is affected. The standardized bladder tumor documetation allows well-directed control resection also in patients with multiple scars and post-TUR alterations, even when performed by a different surgeon. PMID- 23754612 TI - Birth weight, season of birth and postnatal growth do not predict levels of systemic inflammation in Gambian adults. AB - OBJECTIVES: Studies testing whether systemic inflammation might lie on the causal pathway between aberrant fetal and post-natal growth patterns and later cardiovascular disease have been inconclusive, possibly due to the use of single markers of unknown predictive value. We used repeated measures of a comprehensive set of inflammatory markers to investigate the relationship between early life measures and systemic inflammation in an African population. METHODS: Individuals born in three rural villages in The Gambia, and for whom early life measurements were recorded, were traced (n = 320). Fasting levels of eight inflammatory markers (C-reactive protein, serum amyloid A, orosomucoid, fibrinogen, alpha 1 antichymotrypsin, sialic acid, interleukin-6 and neopterin) were measured, and potential confounding factors recorded. The association between early life measurements and systemic inflammation was assessed using regression analysis. RESULTS: Levels of most markers were unrelated to early growth patterns. In analyses adjusted for age and sex, more rapid growth between birth and 3 months of age was associated with higher levels of fibrinogen, orosomucoid, and sialic acid. These relationships persisted after further adjustment for body mass index but after full adjustment only the association with fibrinogen remained. CONCLUSIONS: This study provides little evidence that size at birth or growth in early infancy determine levels of inflammatory markers in young Gambian adults. PMID- 23754613 TI - Law enforcement practices associated with HIV infection among injection drug users in Odessa, Ukraine. AB - Despite HIV prevention efforts over the past 10 years in Odessa, Ukraine, HIV rates among injection drug users (IDUs) remain high. We explored whether IDUs' experiences with the police and court system in Odessa were associated with HIV serostatus, after controlling for other factors. Qualitative methods, including semi-structured interviews with the police and members of court (N = 19), and focus groups with IDUs (N = 42), were employed to aid in developing a survey instrument for a larger quantitative phase and to assist in interpreting the findings from the quantitative phase, which included 200 participants who were interviewed and tested for HIV. Overall, 55 % tested positive for HIV. Negative experiences with the police were noted by 86 % and included having preloaded syringes taken (66 %), rushed injections due to fear of the police (57 %), police planting drugs (18 %), paying police to avoid arrest (61 %) and threatened by the police to inform on other IDUs (23 %). HIV positive participants were more likely than those who were negative to report these experiences. In a multiple logistic regression, the most significant correlate of HIV infection was rushed injections due to fear of the police. Police actions in Odessa may be contributing to the continued escalation of HIV among IDUs, underscoring the need for structural interventions. PMID- 23754614 TI - HIV infection among young pregnant women in Brazil: prevalence and associated risk factors. AB - Our goal was to estimate prevalence of HIV among young women in labor. A national, probability-based, cross-sectional study was performed among pregnant women, aged 15-24 years, who were attending Brazilian public hospitals. The study included 2,071 of 2,400 women selected (86.3 % participation). Mean age was 20.2 years (SD = 2.7). HIV prevalence was 0.7 % (95 % CI, 0.4-1.1 %). Living in the North region of the country and having previous sexually transmitted infections were associated with HIV infection. Our survey of young pregnant women found higher prevalence than expected for women of all ages in Brazil (0.42 %), indicating that the epidemic persists among heterosexuals. PMID- 23754615 TI - Eps8 vaccine exerts prophylactic antitumor effects in a murine model: a novel vaccine for breast carcinoma. AB - Cancer vaccines are an effective way to prevent the occurrence of cancer. Epidermal growth factor receptor pathway substrate 8 (Eps8) is a novel tumor associated antigen, which is overexpressed in the majority of tumor types. In the present study, the Eps8 protein was cloned and characterized, and its feasibility as an antitumor agent in murine breast carcinoma was investigated. The results revealed that the Eps8 protein increased the secretion of interleukin (IL)-12 in the culture supernatant of dendritic cells (DCs). The Eps8 protein-pulsed DCs induced significant cytotoxic T lymphocyte (CTL) responses, T-cell proliferation and a higher level of interferon (IFN)-gamma in the culture supernatant of the splenocytes ex vivo. Additionally, when the mice were immunized with the Eps8 vaccine, this resulted in a regression of 4T1 breast tumors and significantly prolonged survival time in the tumor-bearing mice compared with that in the phosphate-buffered saline (PBS) control group. The Eps8 vaccine induced higher CTL responses in the splenocytes of mice vaccinated against the 4T1 cells; the ratio of CD4+/CD8+ T cells was increased in the Eps8 group; and the percentage of CD4+CD25+ FoxP3+ regulatory T (Treg) cells in the Eps8 group was significantly lower compared with that of the PBS group. The results suggested that the Eps8 vaccine was able to stimulate antitumor effects against 4T1 breast cancer cells in vitro and in vivo, and it may provide a potential immunotherapeutic agent for the treatment of breast cancer. PMID- 23754616 TI - Experimental diabetes treated with trigonelline: effect on key enzymes related to diabetes and hypertension, beta-cell and liver function. AB - Type 2 diabetes is quite diverse, including the improvement of insulin sensitivity by dipeptidylpeptidase-4 (DPP-4) inhibitor, alpha-glucosidase inhibitors, and the protection of beta-cells islet. The aim of this study was to search the effect of trigonelline (Trig) on DPP-4, alpha-glucosidase and angiotensin converting enzyme (ACE) activities as well as beta-cells architecture, and starch and glucose tolerance test. In surviving diabetic rats, the supplement of Trig potentially inhibited DPP-4 and alpha-glucosidase activities in both plasma and small intestine. The pancreas islet and less beta cells damage were observed after the administration of trig to diabetic rats. The increase of GLP-1 in surviving diabetic rats suppressed the increase of blood glucose level and improved results in the oral glucose and starch tolerance test. Trig also normalized key enzyme related to hypertension as ACE and improved the hemoglobin A1c and lipid profiles (plasma triglyceride, HDL-cholesterol, LDL cholesterol, and total cholesterol), and liver indices toxicity. Therefore, these results revealed that Trig was successful in improving glycemic control, metabolic parameters, and liver function in diabetic rats. It is therefore suggested that Trig may be a potential agent for the treatment of type 2 diabetes. PMID- 23754617 TI - siRNA-mediated knockdown of SMC1A expression suppresses the proliferation of glioblastoma cells. AB - SMC1A is a member of cohesin complex which has essential functions in cell cycle progression and DNA repair. Therefore, we choose SMC1A as a target gene therapy of glioblastoma. It is well known that glioblastoma has very low survival rate because of ineffectiveness of conventional treatments. This study was designed to explore the possibilities of small interfering RNA (siRNA)-mediated SMC1A silencing as alternative method of treatment. We found that the lentivirus mediated RNAi system efficiently decreased the expression level of SMC1A. Inhibiting SMC1A expression efficiently (P < 0.001) resulted in inhibiting the proliferation and colony formation of U251 and U87MG cells. Moreover, we found that SMC1A silencing led to S cell-cycle arresting. Collectively, these results demonstrated the possibility of siRNA-mediated silencing of SMC1A as a therapeutic tool for the treatment of glioblastoma. PMID- 23754619 TI - Solvent responsive magnetic dynamics of a dinuclear dysprosium single-molecule magnet. AB - A new dysprosium(III) phosphonate dimer {Dy(notpH4)(NO3)(H2O)}2.8H2O (1) [notpH6=1,4,7-triazacyclononane-1,4,7-triyl-tris(methylenephosphonic acid)] that contains two equivalent Dy(III) ions with a three-capped trigonal prism environment is reported. Complex 1 can be transformed into {Dy(notpH4)(NO3)(H2O)}2 (2) in a reversible manner by desorption and absorption of solvent water at ambient temperature. This process is accompanied by a large dielectric response. Magnetic studies reveal that both 1 and 2 show thermally activated magnetization relaxation as expected for single-molecule magnets. Moreover, the magnetic dynamics of the two compounds can be manipulated by controlling the number of solvent molecules at room temperature. PMID- 23754618 TI - Expression of angiotensin II and its receptors in activated microglia in experimentally induced cerebral ischemia in the adult rats. AB - Expression of angiotensin II (Ang II) and its receptors (AT1/AT2) is undetected in the mature microglia in normal brain. We report here that the immunoexpression of Ang II and AT1/AT2 was altered in activated microglia notably at 1 week in rats subjected to middle cerebral artery occlusion (MCAO). Immunolabeled activated microglia were widely distributed in the infarcted cerebral tissue after MCAO. By enzyme immunoassay, Ang II protein expression levels of the ischemic tissues were decreased drastically at 12 h after ischemia, then rose rapidly at 3 days and 1 week after MCAO when compared with the control. On the other hand, AT1 and AT2 receptor mRNA and protein levels were up-regulated after MCAO, peaking at 12 h, but declined thereafter. Expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mRNA and protein levels was concomitantly increased. Edaravone significantly suppressed Ang II and AT1/AT2 receptor expression as well as that of TNF-alpha and IL-1beta suggesting that microglia-derived Ang II can act through an autocrine manner via its receptor that may be linked partly to the production of proinflammatory cytokines. We conclude that neuroinflammation in MCAO may be attenuated by Edaravone which acts through suppression of expression of Ang II and its receptors and proinflammatory cytokines in activated microglia. PMID- 23754620 TI - Ubiquitin and drug discovery: challenges and opportunities. PMID- 23754621 TI - Absolute quantification of E1, ubiquitin-like proteins and Nedd8-MLN4924 adduct by mass spectrometry. AB - Ubiquitin (Ub) and ubiquitin-like (Ubl) proteins regulate a variety of important cellular processes by forming covalent conjugates with target proteins or lipids. Ubl conjugation is catalyzed by a cascade of proteins including activating enzymes (E1), conjugating enzymes (E2), and in many cases ligation enzymes (E3). The discovery of MLN4924 (Brownell et al., Mol Cell 37: 102-111, 1), an investigational small molecule that is a mechanism-based inhibitor of NEDD8 activating enzyme (NAE), reveals a promising strategy of targeting E1/Ubl pathway for therapeutic purposes. In order to better understand, the biochemical dynamics of Ubl conjugation in cells and tissues, we have developed a mass spectrometry based method to quantify E1 and Ubls using isotope-labeled proteins as internal standards. Furthermore, we have used the described method to quantify levels of the covalent Nedd8-inhibitor adduct formed in MLN4924 treated cells and tissues. The Nedd8-MLN4924 adduct is a tight-binding inhibitor of NAE, and its cellular concentration represents an indirect pharmacodynamic readout of NAE/Nedd8 pathway inhibition. PMID- 23754623 TI - New lipid-producing, cold-tolerant yellow-green alga isolated from the Rocky Mountains of Colorado. AB - A new strain of yellow-green algae (Xanthophyceae, Heterokonta), tentatively named Heterococcus sp. DN1 (UTEX accession number UTEX ZZ885), was discovered among snow fields in the Rocky Mountains. Axenic cultures of H. sp. DN1 were isolated and their cellular morphology, growth, and composition of lipids were characterized. H. sp. DN1 was found to grow at temperatures approaching freezing to accumulate large intracellular stores of lipids. H. sp. DN1 produces the highest quantity of lipids when grown undisturbed with high light in low temperatures. Of particular interest was the accumulation of eicosapentaenoic acid, known to be important for human nutrition, and palmitoleic acid, known to improve biodiesel feedstock properties. PMID- 23754622 TI - MicroRNA-124 protects against focal cerebral ischemia via mechanisms involving Usp14-dependent REST degradation. AB - MicroRNAs (miRNAs) are highly conserved non-coding RNAs modulating gene expression via mRNA binding. Recent work suggests an involvement of miRNAs in cardiovascular diseases including stroke. As such, the brain-abundant miR-124 and its transcriptional repressor RE1-silencing transcription factor (REST) do not only have elementary roles in the developing and the adult brain, but also alter expression upon cerebral ischemia. However, the therapeutic potential of miR-124 against stroke and the mechanisms involved remain elusive. Here, we analyzed the therapeutic potential of ectopic miR-124 against stroke and its underlying mechanisms with regard to the interaction between miR-124 and REST. Our results show that viral vector-mediated miR-124 delivery increased the resistance of cultured oxygen-glucose-deprived cortical neurons in vitro and reduced brain injury as well as functional impairment in mice submitted to middle cerebral artery occlusion. Likewise, miR-124 induced enhanced neurovascular remodeling leading to increased angioneurogenesis 8 weeks post-stroke. While REST abundance increased upon stroke, the increase was prevented by miR-124 despite a so far unknown negative feedback loop between miR-124 and REST. Rather, miR-124 decreased the expression of the deubiquitinating enzyme Usp14, which has two conserved miR-124-binding sites in the 3'UTR of its mRNA, and thereby mediated reduced REST levels. The down-regulation of REST by miR-124 was also mimicked by the Usp14 inhibitor IU-1, suggesting that miR-124 promotes neuronal survival under ischemic conditions via Usp14-dependent REST degradation. Ectopic miR-124 expression, therefore, appears as an attractive and novel tool in stroke treatment, mediating neuroprotection via a hitherto unknown mechanism that involves Usp14-dependent REST degradation. PMID- 23754624 TI - "Intertransversalis" approach for laparoscopic urology: surgical anatomy concerns reply. PMID- 23754625 TI - Amphipatic molecules affect the kinetic profile of Pseudomonas putida chlorocatechol 1,2-dioxygenase. AB - Dioxygenases are nonheme iron enzymes that biodegrade recalcitrant compounds, such as catechol and derivatives, released into the environment by modern industry. Intradiol dioxygenases have attracted much attention due to the interest in their use for bioremediation, which has demanded efforts towards understanding their action mechanism and also how to control it. The role of unexpected amphipatic molecules, observed in crystal structures of intradiol dioxygenases, during catalysis has been poorly explored. We report results obtained with the intradiol enzyme chlorocatechol 1,2-dioxygenase (1,2-CCD) from Pseudomonas putida subjected to delipidation. The delipidated enzyme is more stable and shows more cooperative thermal denaturation. The kinetics changes from Michaelis-Menten to a cooperative scheme, indicating that conformational changes propagate between monomers in the absence of amphipatic molecules. Furthermore, these molecules inhibit catalysis, yielding lower v(max) values. To the best of our knowledge, this is the first report concerning the effects of amphipatic molecules on 1,2-CCD function. PMID- 23754626 TI - Living with advanced heart failure or COPD: experiences and goals of individuals nearing the end of life. AB - The last phase of life of patients with end-stage heart failure (HF) or chronic obstructive pulmonary disease (COPD) is marked by high symptom burden and uncertainty about the future. Few enroll in hospice, and their preferences for care remain unknown. The purpose of this qualitative study was to describe the experiences and goals for care of patients with end-stage HF and COPD who were recently discharged from the hospital. Forty semi-structured interviews were completed with 20 participants. Despite conditions considered life-threatening by clinicians, participants believed they still had time. They hoped that their illnesses would remain stable, although specific experiences made them think they might be worsening. All expected that their doctors would tell them when their illnesses became life-threatening. PMID- 23754628 TI - Baseline predictors of systemic lupus erythematosus flares: data from the combined placebo groups in the phase III belimumab trials. AB - OBJECTIVE: To identify predictors of moderate-to-severe systemic lupus erythematosus (SLE) flare in 562 patients treated with standard therapy alone in phase III belimumab trials, and to evaluate the impact of standard therapies on preventing flares. METHODS: Post hoc analysis assessed baseline demographics, disease activity, and biomarkers in patients with and those without flare at treatment weeks 24 and 52. Severe flare was defined by the modified SLE Flare Index (SFI) and the development of any new British Isles Lupus Assessment Group (BILAG) A domain score. Severe and moderate flare was defined by development of 1 new BILAG A domain score or 2 new BILAG B domain scores. Baseline characteristics associated with a >=10% absolute difference or a >=50% increase in flare rates were considered predictive. RESULTS: Frequencies of flares over 52 weeks according to the SFI, any new BILAG A domain score, and 1 new BILAG A domain score or 2 new BILAG B domain scores were 23.7%, 23.1%, and 32.0%, respectively. Flare predictors by univariate analysis on all 3 indices at weeks 24 and 52 were a score >=12 on the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI); anti-double stranded DNA (anti-dsDNA) positivity; proteinuria (>=0.5 gm/24 hours); BILAG renal, vasculitic, and hematologic scores; elevated C-reactive protein levels; and B lymphocyte stimulator (BLyS) levels >=2 ng/ml. Independent predictors by multivariate analysis at week 52 were SELENA-SLEDAI and/or BILAG renal involvement and anti-dsDNA >=200 IU/ml (on all 3 indices); SELENA-SLEDAI and/or BILAG neurologic and vasculitic involvement (on 2 indices: any new BILAG A domain score and 1 new BILAG A domain score or 2 new BILAG B domain scores); BLyS levels >=2 ng/ml (on 2 indices: the SFI and 1 new BILAG A domain score or 2 new BILAG B domain scores); and low C3 level (on the SFI). Baseline medications did not significantly decrease or increase moderate-to-severe SLE flare risk. CONCLUSION: Patients who were receiving standard SLE therapy and had renal, neurologic, or vasculitic involvement, elevated anti-dsDNA or BLyS levels, or low C3 had increased risk of clinically meaningful flare over 1 year. Hydroxychloroquine use was not predictive. PMID- 23754627 TI - Non-mRNA 3' end formation: how the other half lives. AB - The release of nascent RNA from transcribing RNA polymerase complexes is required for all further functions carried out by RNA molecules. The elements and processing machinery involved in 3' end formation therefore represent key determinants in the biogenesis and accumulation of cellular RNA. While these factors have been well-characterized for messenger RNA, recent work has elucidated analogous pathways for the 3' end formation of other important cellular RNA. Here, we discuss four specific cases of non-mRNA 3' end formation metazoan small nuclear RNA, Saccharomyces cerevisiae small nuclear RNA, Schizosaccharomyces pombe telomerase RNA, and the mammalian MALAT1 large noncoding RNA-as models of alternative mechanisms to generate RNA 3' ends. Comparison of these disparate processing pathways reveals an emerging theme of evolutionary ingenuity. In some instances, evidence for the creation of a dedicated processing complex exists; while in others, components are utilized from the existing RNA processing machinery and modified to custom fit the unique needs of the RNA substrate. Regardless of the details of how non-mRNA 3' ends are formed, the lengths to which biological systems will go to release nascent transcripts from their DNA templates are fundamental for cell survival. PMID- 23754629 TI - 10-Hydroxy-2-decenoic acid, a unique medium-chain fatty acid, activates 5'-AMP activated protein kinase in L6 myotubes and mice. AB - SCOPE: 10-Hydroxy-2-decenoic acid (10H2DA) is one of the unique medium-chain fatty acids (MCFAs) specifically found in royal jelly. We hypothesize that 10H2DA has multiple biological functions and may aid in 5'-AMP-activated protein kinase (AMPK) activation and affect the glucose transport system in skeletal muscle. METHODS AND RESULTS: We examined whether various MCFAs present in royal jelly activated AMPKalpha. Treatment of L6 myotubes with various MCFAs showed that 10H2DA administration resulted in a significant increase in phosphorylated AMPKalpha. 10H2DA activates AMPK independently of insulin and significantly increased glucose uptake into L6 myotubes following translocation of glucose transporter 4 (Glut4) to the plasma membrane (PM). The activation was induced by the upstream kinase Ca2+/calmodulin-dependent kinase kinase beta, but was independent of changes in AMP:ATP ratio and the liver kinase B1 pathway. Oral administration of 10H2DA significantly stimulated phosphorylation of AMPK and Glut4 translocation to the PM in mouse skeletal muscle. CONCLUSION: These findings indicate that (i) 10H2DA activates AMPK, and insulin independently enhances glucose uptake following translocation of Glut4 to PM, (ii) activation of AMPKalpha by 10H2DA is mediated via extracellular Ca2+-dependent Ca2+/calmodulin-dependent kinase kinase beta, without alteration in the AMP:ATP ratio, and liver kinase B1 was not involved in the activation. PMID- 23754630 TI - Association between circulating concentrations of 25(OH)D and colorectal adenoma: a pooled analysis. AB - The relationship between the biomarker of vitamin D status, 25(OH)D, and the risk for colorectal neoplasia is suggestive but equivocal. Questions remain regarding whether there are differential associations between 25(OH)D and colorectal adenoma by gender, colorectal subsite or features of baseline and recurrent adenomas. We sought to investigate the relationship between 25(OH)D and both baseline and recurrent adenoma characteristics. Our study was conducted among 2,074 participants in a pooled population of two clinical intervention trials of colorectal adenoma recurrence. A cross-sectional analysis of 25(OH)D and baseline adenoma characteristics and a prospective study of recurrent adenomas and their characteristics were conducted. There was a statistically significant inverse association between the concentrations of 25(OH)D and the presence of three or more adenomas at baseline. Compared to participants with 25(OH)D levels of <20 ng/mL, the adjusted odds ratios (ORs) (95% condifdence intervals [CIs]) were 0.99 (0.70-1.41) for those with concentrations of >=20 and <30 ng/mL, and 0.73 (0.50 1.06) among participants with levels of >=30 ng/mL (p-trend = 0.05). Baseline villous histology was also significantly inversely related to 25(OH)D levels (p trend = 0.04). Conversely, 25(OH)D concentrations were not associated with overall colorectal adenoma recurrence, with ORs (95% CIs) of 0.91 (0.71-1.17) and 0.95 (0.73-1.24; p-trend = 0.85). These findings support the concept that the relationship between vitamin D and colorectal neoplasia may vary by stage of adenoma development. PMID- 23754631 TI - The hypolipidaemic effects of Spirulina (Arthrospira platensis) supplementation in a Cretan population: a prospective study. AB - BACKGROUND: Spirulina (Arthrospira platensis) is a filamentous cyanobacterium used as a food supplement. The objective of the study was to determine the lipid lowering effects of Spirulina in Cretan Greek dyslipidaemic patients, and to document its effectiveness as a possible alternative treatment for dyslipidaemia. Fifty-two adultCretan outpatients (32 men, 20 women), median age 47 (range, 37 61) years, with recently diagnosed dyslipidaemia, consumed orally 1 g Spirulina (Greek production) per day for 12 weeks. The full lipid profile was measured in fasting blood samples at the beginning and end of the study period. Anthropometric measurements including systolic and diastolic blood pressure, height, weight and body mass index were also recorded. RESULTS: At the end of the 3-month intervention period the mean levels of triglycerides, low density lipoprotein-cholesterol, total cholesterol, non-high density lipoprotein cholesterol levels, and the ratio of total cholesterol to high-density lipoproteincholesterol were significantly decreased: 16.3% (P < 0.0001), 10.1% (P < 0.0001), 8.9% (P < 0.0001), 10.8% (P < 0.0001) and 11.5% (P = 0.0006) respectively, whereas the mean high-density lipoprotein-cholesterol levels were not significantly increased (3.5%). Blood pressure, weight and body mass index remained almost unchanged. CONCLUSIONS: Spirulina supplementation at a dose of 1 g daily has powerful hypolipidaemic effects, especially on the triglyceride concentration in dyslipidaemic Cretan outpatients. PMID- 23754632 TI - Surgical site infection after open reduction and internal fixation of tibial plateau fractures. AB - OBJECTIVE: The aim of this study was to identify risk factors for surgical site infections and to quantify the contribution of independent risk factors to the probability of developing infection after definitive fixation of tibial plateau fractures in adult patients. METHODS: A retrospective analysis was performed at a level I trauma center between January 2004 and December 2010. Data were collected from a review of the patient's electronic medical records. A total of 251 consecutive patients (256 cases) were divided into two groups, those with surgical site infections and those without surgical site infections. Preoperative and perioperative variables were compared between these groups, and risk factors were determined by univariate analyses and multivariate logistic regression. Variables analyzed included age, gender, smoking history, diabetes, presence of an open fracture, presence of compartment syndrome, Schatzker classification, polytrauma status, ICU stay, time from injury to surgery, use of temporary external fixation, surgical approach, surgical fixation, operative time, and use of a drain. RESULTS: The overall rate of surgical site infection after ORIF of tibial plateau fractures during the 7 years of this study was 7.8% (20 of 256). The most common causative pathogens was Staphylococcus aureus (n=15, 75%). Independent predictors of surgical site infection identified by multivariate analyses were open tibial plateau fracture (odds ratio=3.9; 95% CI=1.3-11.6; p=0.015) and operative time (odds ratio=2.7; 95% CI=1.6-4.4; p<0.001). The presence of compartment syndrome (odds ratio=3.4; 95% CI=0.7-15.9; p=0.119), use of temporary external fixation (odds ratio=0.5; 95% CI=0.2-1.7; p=0.298), and ICU stay (odds ratio=1.0; 95% CI=1.0-1.1; p=0.074) were not determined to be independent predictors of surgical site infection. CONCLUSIONS: Both open fracture and operative time are independent risks factors for postoperative infection. PMID- 23754633 TI - Atlantoaxial rotatory fixation in a child after bilateral otoplastic surgery. AB - Atlantoaxial rotatory fixation (AARF), which is a dislocation or subluxation of the atlantoaxial joint, is a well-recognized condition in children. We present a case of AARF after otoplastic surgery for bilateral cryptotia performed by plastic surgeons. The pediatric patient presented with neck pain and torticollis after the surgery, and an orthopedic surgeon diagnosed AARF. The patient was treated successfully with conservative treatment incorporating mild manual manipulation, neck traction, and a collar for 1.5 months. Physicians should consider the possibility of AARF when a patient presents with neck pain and torticollis after otoplastic surgery; diagnosis and treatment should be started immediately. PMID- 23754634 TI - B1 mapping of short T2 * spins using a 3D radial gradient echo sequence. AB - PURPOSE: To develop a method to acquire a radiofrequency (B1 ) field map when the signal has a short T2 *. THEORY AND METHODS: The method is based on the actual flip angle imaging (AFI) technique and a radial 3D gradient-echo sequence known as COncurrent Dephasing and Excitation (CODE), which preserves short T2 (*) signals. CODE was implemented with Gradient-modulated Offset-Independent Adiabaticity (GOIA) pulses to obtain high estimation sensitivity with AFI. The correlation method, which removes the quadratic phase from the frequency modulated pulse excitation, was modified to handle gradient-modulated pulses. Validity of the modified correlation procedure was tested by Bloch simulations. CODE experiments with sinc, hyperbolic secant, and GOIA pulses were performed in order to see effects from the frequency and gradient modulation. Finally, GOIA CODE AFI was conducted and compared with conventional AFI with 3D gradient echo (GRE). RESULTS: The modified correlation method developed to accommodate frequency and gradient modulations of GOIA performed well as judged by the minimal impact on reconstructed image quality. GOIA-CODE AFI provided flip angle maps consistent with those measured by GRE AFI when the T2 * was long (>2 ms) and continued to perform well for short T2 * signals. CONCLUSION: The proposed technique provides a means to obtain a 3D B1 field map when imaging spins with short T2 (*) . PMID- 23754635 TI - Natural selection in utero: evidence from the Great East Japan Earthquake. AB - OBJECTIVES: Controversy remains over whether declines in male births reported after population stressors result from either or both reduced conception of males or increased selection in utero against male fetuses. We use monthly birth cohorts to determine if Japanese male births following the Great East Japan Earthquake of 2011 fell below levels expected from female births and from history (i.e., autocorrelation) among cohorts exposed to the Earthquake at or after conception. METHODS: We apply interrupted time-series methods to 69 months (i.e., April, 2006 through December, 2011) of birth data from the most and least affected prefectures as well as from the remainder of Japan. We estimate expected male births from female births and from autocorrelation. RESULTS: Findings varied by distance from the greatest damage but suggest sensitive periods both early and late in gestation when population stressors may induce selection against males in utero. Support for reduced conception of males appeared only in the prefectures most damaged by the Earthquake. CONCLUSIONS: Results align with the claim that natural selection has conserved mechanisms that reduce the odds of a male live birth during stressful times by reducing the conception of males and by increasing the rate of spontaneous abortion among male fetuses. PMID- 23754636 TI - Cutaneous dermatomyositis: an updated review of treatment options and internal associations. AB - Dermatomyositis is a specific type of inflammatory myopathy with characteristic cutaneous findings. Patients may have skin disease without clinically apparent muscle disease, but this disorder is best thought of as a systemic process. Therefore, all patients with dermatomyositis skin lesions need appropriate evaluation for muscle disease, esophageal dysfunction, cardiopulmonary disease, and potential internal malignancy. There are many therapies that have been used for patients with dermatomyositis, but most are based upon case series or expert opinion rather than meta-analyses or randomized, placebo-controlled trials. Even those therapies that have been subjected to randomized, blinded, placebo controlled trials include a mixture of patients with idiopathic inflammatory myopathy and do not utilize a validated assessment tool for measuring cutaneous disease responses. In this review, we discuss the therapies available as well as the internal associations with dermatomyositis. PMID- 23754637 TI - Genetic mapping of a novel gene for soybean aphid resistance in soybean (Glycine max [L.] Merr.) line P203 from China. AB - The soybean aphid (SA: Aphis glycines Matsumura) is a worldwide pest of soybean (Glycine max [L.] Merr.). The objectives of this study were to identify the type of aphid resistance and the resistance phenotype in soybean line 'P203', and to map the relative position of the gene involved. Compared with cultivars 'P746' and 'Dongnong 47', P203 was demonstrated to possess antixenosis resistance. P203 prevented aphids from reproducing in a choice test, but the resistance level decreased significantly in a no-choice test at 11 and 21 days after infestation. Analysis of 273 Dongnong 47/P203 F2 plants and confirmed using 260 F2:3 families revealed that a single dominant gene from P203 was positioned between marker loci Sat_377 and Satt409 on chromosome 8. The gene was further mapped to a 1.57 Mb interval flanked by marker loci BARCSOYSSR_08_1451 and BARCSOYSSR_08_1527. We developed five new SSR markers in the target interval and the resistance locus mapped between new markers SSR_08_75 and SSR_08_88 with the genetic distance of 1.1 and 1.0 cM corresponding to a physical distance of 192 kb on the Williams 82 8X draft genome assembly (Glyma1.01). A single serine/threonine protein kinase gene is present in this region, suggesting that the SA resistance mechanism in P203 may be different from those previously reported. Therefore, the resistance gene could very well be novel, and could be valuable in soybean aphid resistance breeding programs. PMID- 23754638 TI - Rational for statin use in psoriatic patients. AB - Psoriasis represents a common skin disease which is clinically manifested by chronic cutaneous lesions. It has been observed that psoriasis is associated with an increased risk of cardiovascular diseases, which is contributed to the inappropriate lipid metabolism. Statins are commonly used in clinical practice to lower cholesterol concentration and, accordingly, decrease the individual risk of developing a cardiovascular episode. There have been reports that statin administration could also result in better management of psoriasis. The observed beneficial effects are contributed to the effects on lipid metabolism, including that in skin, as well as anti-inflammatory and immunomodulatory properties of statins. Simvastatin and atorvastatin were found to improve the clinical outcome in patients with psoriatic skin lesions. Clinically, the effectiveness of this novel treatment was confirmed by the significant reduction in PASI score. To date several cases have been reported in which atorvastatin or pravastatin worsened psoriasis. Based on these results, it seems that statins represent a promising class of medications which could be extensively used in psoriasis. PMID- 23754639 TI - Multi-targeted DATS prevents tumor progression and promotes apoptosis in ectopic glioblastoma xenografts in SCID mice via HDAC inhibition. AB - Glioblastoma, the most lethal brain tumor, remains incurable despite aggressive chemotherapy and surgical interventions. New chemotherapeutics for glioblastoma have been explored in preclinical models and some agents have reached the clinical setting. However, success rates are not significant. Previous investigations involving diallyl trisulfide (DATS), a garlic compound, indicated significant anti-cancer effects in glioblastoma in vitro. DATS has also been shown to inhibit histone deacetylase activity and impede glioblastoma tumor progression. We hypothesized that DATS would block ectopic U87MG tumor by multiple pro-apoptotic pathways via inhibiting histone deacetylase (HDAC). To prove this, we developed ectopic U87MG tumors in SCID mice and treated them daily with intraperitoneal injections of DATS for 7 days. Results indicated that DATS (10 MUg/kg-10 mg/kg) dose-dependently reduced tumor mass and number of mitotic cells within tumors. Histological and biochemical assays demonstrated that DATS reduced mitosis in tumors, decreased HDAC activity, increased acetylation of H3 and H4, inhibited cell cycle progression, decreased pro-tumor markers (e.g., survivin, Bcl-2, c-Myc, mTOR, EGFR, VEGF), promoted apoptotic factors (e.g., bax, mcalpian, active caspase-3), and induced DNA fragmentation. Our data also demonstrated an increase in p21Waf1 expression, which correlated with increased p53 expression and MDM2 degradation following DATS treatment. Finally, histological assessment and enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function. Collectively, our results clearly demonstrated that DATS could be an effective therapeutic agent in preventing tumor progression and inducing apoptosis in human glioblastoma in vivo, without impairing hepatic function. PMID- 23754641 TI - Dental implants from functionally graded materials. AB - Functionally graded material (FGM) is a heterogeneous composite material including a number of constituents that exhibit a compositional gradient from one surface of the material to the other subsequently, resulting in a material with continuously varying properties in the thickness direction. FGMs are gaining attention for biomedical applications, especially for implants, owing to their reported superior composition. Dental implants can be functionally graded to create an optimized mechanical behavior and achieve the intended biocompatibility and osseointegration improvement. This review presents a comprehensive summary of biomaterials and manufacturing techniques researchers employ throughout the world. Generally, FGM and FGM porous biomaterials are more difficult to fabricate than uniform or homogenous biomaterials. Therefore, our discussion is intended to give the readers about successful and obstacles fabrication of FGM and porous FGM in dental implants that will bring state-of-the-art technology to the bedside and develop quality of life and present standards of care. PMID- 23754640 TI - Identification of new HLA-A*0201-restricted cytotoxic T lymphocyte epitopes from neuritin. AB - Identification of cytotoxic T lymphocyte (CTL) epitopes from additional tumor antigens is essential for the development of specific immunotherapy of malignant tumors. Neuritin, a recently discovered antigen overexpressed in astrocytoma, is considered to be a promising target for biological therapy. In the present study, we predicted and identified HLA-A2-restricted CTL epitopes from neuritin by using the following four-step procedure: (1) computer-based epitope prediction from the amino acid sequence of neuritin; (2) peptide-binding assay to determine the affinity of the predicted peptide with HLA-A2.1 molecule; (3) stimulation of primary T cell response against the predicted peptides in vitro; and (4) testing of the induced CTLs toward target cells expressing neuritin and HLA-A2.1. The results demonstrated that effectors induced by peptides of neuritin containing residues 13-21, 121-129 and 4-12 could specifically-secrete interferon-gamma and lyse target cells. Our results indicate that these peptides are new HLA-A2.1 restricted CTL epitopes, and may serve as valuable tools for astrocytoma immunotherapy. PMID- 23754642 TI - Venous thromboembolism. PMID- 23754643 TI - Systematic review and meta-analysis of hypothermic machine perfusion versus static cold storage of kidney allografts on transplant outcomes. AB - BACKGROUND: Adequate preservation of renal allografts for transplantation is important for maintaining and improving transplant outcomes. There are two prevalent methods: hypothermic machine perfusion and static cold storage. The preferred method of storage, however, remains controversial. The objective was to review systematically the evidence comparing outcomes from these two modalities. METHODS: A literature search was performed using MEDLINE, Embase, the Cochrane Library, the Transplant Library and the International Clinical Trials Registry Platform. The final date for searches was 30 November 2012. Studies were assessed for methodological quality. Summary effects were calculated as relative risk (RR) with 95 per cent confidence interval (c.i.). Randomized clinical trials (RCTs) and non-RCTs were included, but evaluated separately. Results from RCTs alone were used for meta-analysis. RESULTS: Eighteen studies met the inclusion criteria, including seven RCTs (1475 kidneys) and 11 non-RCTs (728 kidneys). The overall risk of delayed graft function was lower with hypothermic machine perfusion than static cold storage (RR 0.81, 95 per cent c.i. 0.71 to 0.92; P = 0.002). There was no difference in the rate of primary non-function (RR 1.15, 0.46 to 2.90; P = 0.767). There was a faster initial fall in the level of serum creatinine with hypothermic machine perfusion in two RCTs, but not in another. There was no relationship between rates of acute rejection or patient survival and the method of preservation. CONCLUSION: Data from the included studies suggest that hypothermic machine perfusion reduces delayed graft function compared with static cold storage. There was no difference in primary non function, acute rejection, long-term renal function or patient survival. A difference in renal graft survival is uncertain. PMID- 23754644 TI - Raised haematocrit concentration and the risk of death and vascular complications after major surgery. AB - BACKGROUND: Preoperative anaemia is associated with adverse postoperative outcomes. Data on raised preoperative haematocrit concentration are limited. This study aimed to evaluate the effect of raised haematocrit on 30-day postoperative mortality and vascular events in patients undergoing major surgery. METHODS: This was a cohort study using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Thirty-day mortality and vascular events, demographics and perioperative risk factors were obtained for adults undergoing major surgery. The adjusted effect of raised (over 0.50) compared with normal (0.41-0.50, American Medical Association reference range) preoperative haematocrit concentration on postoperative outcomes was assessed. Separate sex-specific analyses were also conducted, using haematocrit concentration thresholds commonly used in the diagnosis and management of apparent or absolute erythrocytosis. RESULTS: Some 3961 (2.0 per cent) of 197 469 patients had a raised haematocrit concentration before surgery. After adjustment, the 30-day postoperative mortality rate was higher in patients with raised haematocrit than in those without (odds ratio (OR) 2.23, 95 per cent confidence interval 1.77 to 2.80). Thirty-day rates of deep vein thrombosis (OR 1.95, 1.44 to 2.64) and pulmonary embolism (OR 1.79, 1.17 to 2.73), but not myocardial infarction or stroke, were also higher in patients with a raised haematocrit concentration. The effect on mortality was noted beyond the haematocrit thresholds of 0.48 in women and 0.52 in men; the effect estimates were considerably higher for values exceeding 0.54. Values between 0.41 and 0.45 were not associated with increased mortality risk. Similar observations were noted for venous thrombosis, although with apparent sex differences. CONCLUSION: A raised haematocrit concentration was associated with an increased risk of 30-day mortality and venous thrombosis following major surgery. PMID- 23754645 TI - Surgical delay is a critical determinant of survival in perforated peptic ulcer. AB - BACKGROUND: Morbidity and mortality following perforated peptic ulcer (PPU) remain substantial. Surgical delay is a well established negative prognostic factor, but evidence derives from studies with a high risk of bias. The aim of the present nationwide cohort study was to evaluate the adjusted effect of hourly surgical delay on survival after PPU. METHODS: This was a cohort study including all Danish patients treated surgically for PPU between 1 February 2003 and 31 August 2009. Medically treated patients and those with a malignant ulcer were excluded. The associations between surgical delay and 30-day survival are presented as crude and adjusted relative risks (RRs) with 95 per cent confidence intervals (c.i.). RESULTS: A total of 2668 patients were included. Their median age was 70.9 (range 16.2-104.2) years and 55.4 per cent (1478 of 2668) were female. Some 67.5 per cent of the patients (1800 of 2668) had at least one of six co-morbid diseases and 45.6 per cent had an American Society of Anesthesiologists fitness grade of III or more. A total of 708 patients (26.5 per cent) died within 30 days of surgery. Every hour of delay from admission to surgery was associated with an adjusted 2.4 per cent decreased probability of survival compared with the previous hour (adjusted RR 1.024, 95 per cent c.i. 1.011 to 1.037). CONCLUSION: Limiting surgical delay in patients with PPU seems of paramount importance. PMID- 23754646 TI - Snapshot quiz. PMID- 23754647 TI - Proximal margin length with transhiatal gastrectomy for Siewert type II and III adenocarcinomas of the oesophagogastric junction. AB - BACKGROUND: A gross proximal oesophageal margin greater than 5 cm is considered to be necessary for curative surgery of adenocarcinoma of the oesophagogastric junction. This study investigated whether a shorter proximal margin might suffice in the context of total gastrectomy for Siewert type II and III tumours. METHODS: The gross proximal margin was measured on stretched specimens just after resection. Relationships between gross proximal margin lengths and clinicopathological features were investigated in patients with Siewert type II and III adenocarcinoma of the oesophagogastric junction treated by R0-1 surgical resection. For survival analyses, only patients who had undergone R0 resection for pathological (p) T2-4N0-3M0 tumour via a transhiatal approach were evaluated. RESULTS: Of the 140 patients, 120 had a total gastrectomy. Two patients (1.4 per cent) had histologically positive proximal margins and another two (1.4 per cent) developed anastomotic recurrence. Of 100 patients with pT2-4N0-3M0 tumours who underwent gastrectomy via a transhiatal approach, those with gross proximal margins larger than 20 mm appeared to have better survival than those with shorter margins (P = 0.027). Multivariable analysis demonstrated that a gross proximal margin of 20 mm or less was an independent prognostic factor (hazard ratio (HR) 3.56, 95 per cent confidence interval 1.39 to 9.14; P = 0.008), as was pathological node status (HR 1.76, 1.08 to 2.86; P = 0.024). CONCLUSION: Gross proximal margin lengths of more than 20 mm in resected specimens seem satisfactory for patients with type II and III adenocarcinoma of the oesophagogastric junction treated by transhiatal gastrectomy. PMID- 23754648 TI - Partial hepatectomy for ruptured hepatocellular carcinoma. AB - BACKGROUND: Improvements in surgical technique and perioperative care have made partial hepatectomy a safe and effective treatment for hepatocellular carcinoma (HCC), even in the event of spontaneous HCC rupture. METHODS: A consecutive cohort of patients who underwent partial hepatectomy for HCC between 2000 and 2009 was divided into a ruptured group and a non-ruptured group. Patients with ruptured HCC were further divided into emergency and staged hepatectomy subgroups. Mortality and morbidity, overall survival and recurrence-free survival (RFS) were compared. Prognostic factors for overall survival and RFS were identified by univariable and multivariable analyses. RESULTS: A total of 1233 patients underwent partial hepatectomy for HCC, of whom 143 had a ruptured tumour. The morbidity and mortality rates were similar in the ruptured and non ruptured groups, as well as in the emergency and staged subgroups. In univariable analyses, overall survival and RFS were lower in the ruptured group than in the non-ruptured group (both P < 0.001), and also in the emergency subgroup compared with the staged subgroup (P = 0.016 and P = 0.025 respectively). In multivariable analysis, spontaneous rupture independently predicted poor overall survival after hepatectomy (hazard ratio 1.54, 95 per cent confidence interval 1.24 to 1.93) and RFS (HR 1.75, 1.39 to 2.22). Overall survival and RFS after hepatectomy for ruptured HCC in the emergency and staged subgroups were not significantly different in multivariable analyses. CONCLUSION: Spontaneous rupture predicted poor long-term survival after hepatectomy for HCC, but surgical treatment seems possible, safe and appropriate in selected patients. PMID- 23754649 TI - Error rating tool to identify and analyse technical errors and events in laparoscopic surgery. AB - BACKGROUND: Surgical error analysis is essential for investigating mechanisms of errors, events and adverse outcomes. Furthermore, it provides valuable information for formative feedback and quality control. The aim of the present study was to design and validate a technical error rating tool in laparoscopic surgery. METHODS: The framework consisted of nine task groups and four error modes. Unedited videos of laparoscopic Roux-en-Y gastric bypass procedures were rated and analysed. The Objective Structured Assessment of Technical Skill (OSATS) global rating scale was used to assess technical skills. The incidence of errors and of injuries (events) were the main outcome measures, and were used to calculate the reliability, and construct and concurrent validity of the instrument. RESULTS: Two observers analysed 25 procedures. Inter-rater reliability was high regarding total number of errors (intraclass correlation coefficient (ICC) 0.90) and events (ICC 0.85). The median (interquartile range) error rate was 35 (26-44) and the event rate 3 (2-3) per procedure. Error frequencies and OSATS scores correlated significantly in all operative steps (rs = -0.75 to -0.40, P = <0.001-0.046). Surgeons demonstrating high OSATS scores had lower median (i.q.r.) error rates than surgeons with low scores in three of four steps: measuring bowel (4 (2-7) versus 10 (9-11); P = 0.004), jejunojejunostomy formation (5 (2-6) versus 10 (9-11); P = 0.001) and pouch formation (4 (3-6) versus 9 (5-12); P = 0.004). CONCLUSION: The proposed error rating tool allows an objective and reliable assessment of operative performance in laparoscopic gastric bypass procedures. PMID- 23754650 TI - Cost-effectiveness of the implementation of an enhanced recovery protocol for colorectal surgery. AB - BACKGROUND: Enhanced recovery protocols may reduce postoperative complications and length of hospital stay. However, the implementation of these protocols requires time and financial investment. This study evaluated the cost effectiveness of enhanced recovery implementation. METHODS: The first 50 consecutive patients treated during implementation of an enhanced recovery programme were compared with 50 consecutive patients treated in the year before its introduction. The enhanced recovery protocol principally implemented preoperative counselling, reduced preoperative fasting, preoperative carbohydrate loading, avoidance of premedication, optimized fluid balance, standardized postoperative analgesia, use of a no-drain policy, as well as early nutrition and mobilization. Length of stay, readmissions and complications within 30 days were compared. A cost-minimization analysis was performed. RESULTS: Hospital stay was significantly shorter in the enhanced recovery group: median 7 (interquartile range 5-12) versus 10 (7-18) days (P = 0.003); two patients were readmitted in each group. The rate of severe complications was lower in the enhanced recovery group (12 versus 20 per cent), but there was no difference in overall morbidity. The mean saving per patient in the enhanced recovery group was ?1651. CONCLUSION: Enhanced recovery is cost-effective, with savings evident even in the initial implementation period. PMID- 23754651 TI - Author's reply: Prophylactic central neck dissection for papillary thyroid cancer (Br J Surg 2013; 100: 410-418). PMID- 23754652 TI - Prophylactic central neck dissection for papillary thyroid cancer (Br J Surg 2013; 100: 410-418). PMID- 23754654 TI - Consensus statement on the multidisciplinary management of patients with recurrent and primary rectal cancer beyond total mesorectal excision planes. AB - BACKGROUND: The management of primary rectal cancer beyond total mesorectal excision planes (PRC-bTME) and recurrent rectal cancer (RRC) is challenging. There is global variation in standards and no guidelines exist. To achieve cure most patients require extended, multivisceral, exenterative surgery, beyond conventional total mesorectal excision planes. The aim of the Beyond TME Group was to achieve consensus on the definitions and principles of management, and to identify areas of research priority. METHODS: Delphi methodology was used to achieve consensus. The Group consisted of invited experts from surgery, radiology, oncology and pathology. The process included two international dedicated discussion conferences, formal feedback, three rounds of editing and two rounds of anonymized web-based voting. Consensus was achieved with more than 80 per cent agreement; less than 80 per cent agreement indicated low consensus. During conferences held in September 2011 and March 2012, open discussion took place on areas in which there is a low level of consensus. RESULTS: The final consensus document included 51 voted statements, making recommendations on ten key areas of PRC-bTME and RRC. Consensus agreement was achieved on the recommendations of 49 statements, with 34 achieving consensus in over 95 per cent. The lowest level of consensus obtained was 76 per cent. There was clear identification of the need for referral to a specialist multidisciplinary team for diagnosis, assessment and further management. CONCLUSION: The consensus process has provided guidance for the management of patients with PRC-bTME or RRC, taking into account global variations in surgical techniques and technology. It has further identified areas of research priority. PMID- 23754655 TI - Genetic analysis of the leucine-rich repeat and lg domain containing Nogo receptor-interacting protein 1 gene in essential tremor. AB - Variants in the leucine-rich repeat and lg domain containing nogo receptor interacting protein 1 gene (LINGO1) have been identified to be associated with the increased risk of essential tremor (ET), especially among Caucasians. To explore whether the LINGO1 gene plays a role in ET susceptibility, we performed a systematic genetic analysis of the coding region in the LINGO1 gene. Four nucleotide variants have been genotyped, including three known variants (rs2271398, rs2271397, and rs3743481), and a novel G -> C transition (ss491228439). Extended analysis showed no significant difference in genotypic and allelic distributions between 151 patients and 301 control subjects for these four variants (all P > 0.05). However, further sex-stratified analysis revealed that the C allele of rs2271397 and ss491228439 contributed the risk of ET in female (P = 0.017, OR = 2.139, 95 % CI 1.135 ~ 4.030 for rs2271397 and P = 0.038, OR = 1.812, 95 % CI 1.027 ~ 3.194 for ss491228439). Haplotype analysis indicated that A465-C474-C714 haplotype was significantly associated with increased risk of ET in female (P = 0.041, OR = 1.800, 95 % CI 1.020 ~ 3.178). Our results indicate that the LINGO1 variants are associated with ET in Chinese Han female patients. PMID- 23754656 TI - MicroRNA-1 inhibits the proliferation of Chinese sika deer-derived cartilage cells by binding to the 3'-untranslated region of IGF-1. AB - Insulin-like growth factor-1 (IGF-1) is critical in the proliferation and regeneration of Chinese sika deer antler cells. The regulation of IGF-1 is complex and remains unclear. In the present study, miRNA GeneChip(r) and TargetScan Human software were used to identify microRNA-1 (miR-1), which binds to the 3'-untranslated region (3'UTR) of IGF-1. An miR-1 mimic was transfected into antler cartilage cells in order to induce the overexpression of miR-1. The expression levels of miR-1 in antler cartilage cells were determined by quantitative polymerase chain reaction (qPCR). A high-throughput luciferase reporter screen was used to demonstrate the potential regulation of IGF-1 by miR 1. miR-1 suppressed the luciferase activity of the pmiR-IGF-1 by ~50% compared with the negative control (NC). An MTT assay and cell cycle analyses confirmed that the overexpression of miR-1 significantly inhibited the proliferation of cartilage cells (P<0.05). Furthermore, western blot analysis revealed that overexpressed miR-1 downregulated the protein levels of IGF-1. The 3'UTR of IGF-1 was found to have an miR-1 combining site, which allowed the inhibition of IGF-1 protein expression, as demonstrated by a luciferase reporter assay, and miR-1 was shown to be an important and effective means of regulating IGF-1. In conclusion, miR-1 downregulated the protein expression of IGF-1 by directly targeting the 3'UTR of IGF-1. miR-1 may be crucial for inhibiting the proliferation of deer antler cartilage cells. Our findings provided the evidence for the first time that miR-1 directly regulates the expression of IGF-1 by directly targeting its 3'UTR. PMID- 23754658 TI - About this journal. PMID- 23754657 TI - Structure and function of the T-loop structural motif in noncoding RNAs. AB - The T-loop is a frequently occurring five-nucleotide motif found in the structure of noncoding RNAs where it is commonly assumed to play an important role in stabilizing the tertiary RNA structure by facilitating long-range interactions between different regions of the molecule. T-loops were first identified in tRNA(Phe) and a formal consensus sequence for this motif was formulated and later revised based on analyses of the crystal structures of prokaryotic ribosomal RNAs and RNase P and the corresponding primary sequence of their orthologues. In the past decade, several new structures of large RNA molecules have been added to the RCSB Protein Data Bank, including the eukaryotic ribosome, a self-splicing group II intron, numerous synthetases in complex with their cognate transfer RNAs (tRNAs), transfer-messenger RNA (tmRNA) in complex with SmpB, several riboswitches, and a complex of bacterial RNase P bound to its tRNA substrate. In this review, the search for T-loops is extended to these new RNA molecules based on the previously established structure-based criteria. The review highlights and discusses the function and additional roles of T-loops in four broad categories of RNA molecules, namely tRNAs, ribosomal RNAs (rRNAs), P RNAs, and RNA genetic elements. Additionally, the potential application for T-loops as interaction modules is also discussed. PMID- 23754659 TI - Local selection of human populations shapes complex evolution patterns of CXCL10 gene. AB - CXC motif chemokine 10 (CXCL10) is a small cytokine belonging to the CXC chemokine family, and it is secreted by several cell types in response to IFN gamma and regulates immune responses through the recruitment and activation of lymphocytes. As CXCL10 is very important in T-cell immunity and infectious diseases, we studied the effect of natural selection on the CXCL10 locus. By sequencing 74 individuals from three human populations, we found a complex pattern of natural selection acting on the CXCL10 locus. We discovered a signature of balancing selection in the European population with a significant positive Tajima's D value (2.57, P=0.005) and an excess of intermediate frequency alleles. However, we observed an excess of high frequency-derived alleles and a significant Fay and Wu's test statistics (P=0.015) in the Chinese population, which suggests that recent selective sweeps under positive selection had occurred. Also, there are a lot of alleles showing great frequency difference among populations. These results demonstrate that local selection has shaped CXCL10 evolution and indicates that there exist different actions of natural selection on the CXCL10 locus in different populations. This study provides insights into the likely relative roles of natural selection and population history in shaping today's genetic variation at the CXCL10 locus, indicates the relationship between adaptation to past infection and predisposition to autoimmunity in modern populations, improves our understanding of CXCL10 evolution, and motivates further investigations of the role of CXCL10 in infectious diseases and autoimmune diseases. PMID- 23754660 TI - Waste nitrogen metabolism and excretion in zebrafish embryos: effects of light, ammonia, and nicotinamide. AB - Bony fish primarily excrete ammonia as adults however the persistence of urea cycle genes may reflect a beneficial role for urea production during embryonic stages in protecting the embryo from toxic effects of ammonia produced from a highly nitrogenous yolk. This study aimed to examine the dynamic scope for changes in rates of urea synthesis and excretion in one such species (zebrafish, Danio rerio) by manipulating the intrinsic developmental rate (by alteration of light:dark cycles), as well as by direct chemical manipulation via ammonia injection (to potentially activate urea production) and nicotinamide exposure (to potentially inhibit urea production). Continuous dark exposure delayed development in embryos as evidenced by delayed appearance of hallmark anatomical features (heartbeat, eye pigmentation, body pigmentation, lateral line, fin buds) at 30 and 48 hr post-fertilization, as well by a lower hatching rate compared to embryos reared in continuous light. Both ammonia and urea excretion were similarly effected and were generally higher in embryos continuously exposed to light. Ammonia injection resulted in significant increases (up to fourfold) of urea N excretion and no changes to ammonia excretion rates along with modest increases in yolk ammonia content during 2-6 hr post-injection. Nicotinamide (an inhibitor of urea synthesis in mammals) reduced the ammonia-induced increase in urea excretion and led to retention of ammonia in the yolk and body of the embryo. Our results indicate that there is a relatively rapid and large scope for increases in urea production/excretion rates in developing embryos. Potential mechanisms for these increases are discussed. PMID- 23754661 TI - Actinopolyspora righensis sp. nov., a novel halophilic actinomycete isolated from Saharan soil in Algeria. AB - A novel halophilic actinomycete strain, H23(T), was isolated from a Saharan soil sample collected in Djamaa (Oued Righ region), El-Oued province, South Algeria. Strain H23(T) was identified as a member of the genus Actinopolyspora by a polyphasic approach. Phylogenetic analysis showed that strain H23(T) had 16S rRNA gene sequence similarities ranging from 97.8 % (Actinopolyspora xinjiangensis TRM 40136(T)) to 94.8 % (Actinopolyspora mortivallis DSM 44261(T)). The strain grew optimally at pH 6.0-7.0, 28-32 degrees C and in the presence of 15-25 % (w/v) NaCl. The substrate mycelium was well developed and fragmented with age. The aerial mycelium produced long, straight or flexuous spore chains with non-motile, smooth-surfaced and rod-shaped spores. Strain H23(T) had MK-10 (H4) and MK-9 (H4) as the predominant menaquinones. The whole micro-organism hydrolysates mainly consisted of meso-diaminopimelic acid, galactose and arabinose. The diagnostic phospholipid detected was phosphatidylcholine. The major cellular fatty acids were anteiso-C17:0 (37.4 %), iso-C17:0 (14.8 %), iso-C15:0 (14.2 %), and iso C16:0 (13.9 %). The genotypic and phenotypic data show that the strain represents a novel species of the genus Actinopolyspora, for which the name Actinopolyspora righensis sp. nov. is proposed, with the type strain H23(T) (=DSM 45501(T) = CCUG 63368(T) = MTCC 11562(T)). PMID- 23754662 TI - Salegentibacter echinorum sp. nov., isolated from the sea urchin Hemicentrotus pulcherrimus. AB - A novel Gram-negative, strictly aerobic, heterotrophic, non-motile and yellow pigmented bacterial strain, designated HD4(T), was isolated from the sea urchin Hemicentrotus pulcherrimus collected from the Yellow Sea in China. Optimal growth of the strain was observed at 28-30 degrees C, pH 6.8-7.3, and in the presence of 3-5 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequence revealed that strain HD4(T) exhibited high similarity with the members of Salegentibacter (92.3-95.4 %). The DNA G+C content was 37.0 mol%, MK-6 was the main respiratory quinone and summed feature 3 (comprising iso-C15:0 2 OH/C16:1omega7c), iso-C15:0, iso-C17:0 3-OH and anteiso-C15:0 were the major cellular fatty acids. The predominant polar lipids in strain HD4(T) were phosphatidylethanolamine and two unknown lipids (L2, L4). Based on the phylogenetic, physiological and biochemical characteristics, strain HD4(T) should be classified as a novel species within the genus Salegentibacter, for which the name Salegentibacter echinorum sp. nov. is proposed. The type strain is HD4(T) (=CICC 10466(T) = NRRL B-59666(T)). PMID- 23754663 TI - Observation and visualization: reflections on the relationship between science, visual arts, and the evolution of the scientific image. AB - The connections between biological sciences, art and printed images are of great interest to the author. She reflects on the historical relevance of visual representations for science. She argues that the connection between art and science seems to have diminished during the twentieth century. However, this connection is currently growing stronger again through digital media and new imaging methods. Scientific illustrations have fuelled art, while visual modeling tools have assisted scientific research. As a print media artist, she explores the relationship between art and science in her studio practice and will present this historical connection with examples related to evolution, microbiology and her own work. Art and science share a common source, which leads to scrutiny and enquiry. Science sets out to reveal and explain our reality, whereas art comments and makes connections that don't need to be tested by rigorous protocols. Art and science should each be evaluated on their own merit. Allowing room for both in the quest to understand our world will lead to an enriched experience. PMID- 23754664 TI - An end-on-coordinated As4 tetrahedron. AB - One time only: The reaction of [Cp*Ru(dppe)Cl] with the potent As4 transfer reagent [Ag(eta(2)-As4)2](+)[pftb](-) leads to [Cp*Ru(dppe)(eta(1) As4)](+)[pftb](-) with an unprecedented end-on-coordinated As4 tetrahedron. Reaction with a second cationic ruthenium complex fragment does not lead to a second end-on coordination but to the cleavage of one basal As-As bond. This behavior, which differs from its phosphorus analogues, is rationalized by DFT calculations. PMID- 23754665 TI - Emotion dysregulation and symptoms of anorexia nervosa: the unique roles of lack of emotional awareness and impulse control difficulties when upset. AB - OBJECTIVE: Extant research suggests that individuals with anorexia nervosa (AN) have deficits in emotion regulation across a variety of domains. The current study investigated associations between specific difficulties with emotion regulation and the core symptoms of AN. METHOD: Participants were 192 patients with AN presenting to an intensive eating disorder treatment facility. Emotion regulation was assessed using the multidimensional Difficulties in Emotion Regulation Scale, and associations with body mass index (BMI) at admission, eating disorder cognitions, objective binge eating, subjective binge eating, and purging were examined. RESULTS: Eating disorder cognitions were significantly associated with multiple forms of emotion dysregulation; however, only lack of emotional awareness was independently related to these symptoms. In contrast, impulse control difficulties when upset was the only emotion regulation impairment associated with the presence of recurrent objective binge eating and recurrent purging in AN. No significant relationships between emotion regulation and BMI or subjective binge eating were detected. DISCUSSION: Results point to differential associations between specific emotion regulation deficits and core symptoms of AN. These findings suggest that parsing the construct of emotion regulation as well as the AN phenotype can help to identify the unique ways in which eating disorder symptoms may function to regulate emotions. PMID- 23754666 TI - The value of quantitative real-time myocardial contrast echocardiography for detection of angiographically significant coronary artery disease. AB - BACKGROUND: Real-time (RT) myocardial contrast echocardiography (MCE) is a novel method for the assessment of regional myocardial perfusion. We sought to evaluate the feasibility and diagnostic accuracy of quantitative RT-MCE in predicting significant coronary stenosis, with reference to quantitative coronary angiography. HYPOTHESIS: RT-MCE can identify anatomically significant coronary artery stenosis in selected patients. RT-MCE is probably an effective method for detection of angiographically significant coronary artery stenosis. METHODS: Thirty-five patients (mean age, 59.94 +/- 10.63 years; 25 males) scheduled for coronary angiography underwent RT-MCE at rest, and shortly afterward underwent gated single-photon emission computed tomography (gated-SPECT). Coronary angiography was performed within 1 week after RT-MCE in all patients. The observing indexes included the images of RT-MCE that were analyzed quantitatively from microbubble replenishment curves for myocardial perfusion by using the Q-Lab software. The sensitivity and specificity of RT-MCE for quantitative detection of coronary artery disease (CAD) were obtained. The receiver operator characteristic (ROC) curves were used to assess the differences of accuracy in ischemic segments with A, beta and A * beta respectively. The sensitivity and specificity of gated SPECT and RT-MCE for assessment of CAD were calculated using a 4-score method. RESULTS: A total of 513 segments among 595 segments in 35 patients were obtained. The cutoffs for A, beta and A * beta were 4.58, 0.64, and 2.73, and the sensitivity and specificity of quantitative RT-MCE for detection of CAD were 86.0%, 80.2%, 88.9%, and 84.1%, 64.6%, 79.9%, respectively. Meanwhile, the sensitivity and specificity of semiquantitative analysis for assessment of CAD were 66.7% and 61.8%. The ROC curve area of A and A * beta was 0.91 and 0.90 in the middle segments. The ROC area of A was 0.52 in the base segments. The sensitivity and specificity of gated-SPECT for assessment of CAD were 84.8% and 82.7%, respectively. The sensitivity of multi-indexes RT-MCE increased. The sensitivity was 89.1%, 90.4%, and 96.3% by A + beta, A + A * beta, and beta + A * beta. CONCLUSIONS: Quantitative RT-MCE is an effective method for the detection of coronary artery stenosis. Quantitative RT-MCE is segmented for assessment to ischemic myocardium. RT-MCE with multi-indexes has a valuable application for assessment of CAD surpassing SPECT. PMID- 23754667 TI - Methionine-induced hyperhomocysteinemia impairs the antioxidant ability of high density lipoproteins without reducing in vivo macrophage-specific reverse cholesterol transport. AB - SCOPE: High plasma homocysteine concentrations have been associated with increased risk of cardiovascular disease both in humans and experimental animal models, whereas plasma HDL-cholesterol concentration is inversely correlated with such disorders. This work aimed to study the impact of methionine-induced hyperhomocysteinemia (HHcy) on two major antiatherogenic functions of HDL, namely their capacity to prevent LDL oxidation and induce in vivo macrophage-specific reverse cholesterol transport. METHODS AND RESULTS: Methionine-induced HHcy in mice resulted in an approximately 20% decreased concentration of HDL-cholesterol and HDL main protein component, apolipoprotein A-I. The HDL potential to resist oxidation as well as to prevent LDL oxidative modification was impaired in hyperhomocysteinemic mice. Activities of paraoxonase-1 and platelet activation factor acetylhydrolase, two of the main HDL-associated enzymes with antioxidant activity, were reduced. The ability of HDL to efflux cholesterol from macrophages was decreased in hyperhomocysteinemic mice; however, the in vivo macrophage specific reverse cholesterol transport measured as the output of labeled cholesterol into feces did not significantly differ between groups. CONCLUSION: Our data indicate that the HDL from methionine-induced hyperhomocysteinemic mice was more prone to oxidation and displayed lower capacity to protect LDL against oxidative modification than that of control mice, highlighting a mechanism by which a diet-induced HHcy may facilitate progression of atherosclerosis. PMID- 23754668 TI - TPO genetic variants and risk of differentiated thyroid carcinoma in two European populations. AB - Thyroid cancer risk involves the interaction of genetic and environmental factors. The thyroperoxidase (TPO) has a key role in the iodine metabolism, being essential for the thyroid function. Mutations in the TPO gene are common in congenital hypothyroidism, and there are also signs of the implication of TPO in thyroid cancer. We performed a case-control association study of genetic variants in TPO and differentiated thyroid carcinoma (DTC) in 1,586 DTC patients and 1,769 controls including two European populations (Italy: 1,190 DTC and 1,290 controls; Spain: 396 DTC and 479 controls). Multivariate logistic regression analyses were performed separately for each population and each single-nucleotide polymorphism (SNP). From the three studied polymorphisms, significant associations were detected between DTC and rs2048722 and rs732609 in both populations (p < 0.05). In the Italian population, both SNPs showed a negative association (rs2048722, odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.63-1.00, p = 0.045; rs732609, OR = 0.72, 95% CI = 0.55-0.94, p = 0.016), whereas in the Spanish population, these SNPs showed a positive association (rs2048722, OR = 1.39, 95% CI = 1.03-1.89, p = 0.033; rs732609, OR = 1.41, 95% CI = 1.06-1.87, p = 0.018). The corresponding associations for papillary or follicular thyroid cancer were similar to those for all DTC, within population. No association was detected for the third TPO polymorphism in the Italian and the Spanish populations. Our results, for the first time, point to TPO as a gene involved in the risk of DTC, and suggest the importance of interactions between TPO variants and other unidentified population-specific factors in determining thyroid cancer risk. PMID- 23754669 TI - Biofunctionalization of multiwalled carbon nanotubes by irradiation of electropolymerized poly(pyrrole-diazirine) films. AB - A photoactivatable poly(pyrrole-diazirine) film was synthesized and electropolymerized as a versatile tool for covalent binding of laccase and glucose oxidase on multiwalled carbon nanotube coatings and Pt, respectively. Irradiation of the functionalized nanotubes allowed photochemical grafting of laccase and its subsequent direct electrical wiring, as illustrated by the electrocatalytic reduction of oxygen. Moreover, covalent binding of glucose oxidase as model enzyme, achieved by UV activation of electropolymerized pyrrole diazirine, allowed a glucose biosensor to be realized. This original method to graft biomolecules combines electrochemical and photochemical techniques. The simplicity of this new method allows it to be extended easily to other biological systems. PMID- 23754670 TI - Long-distance translocation of photosynthates: a primer. AB - The storage of light energy in chemical form through photosynthesis is the key process underlying life as we know it. To utilize photosynthates efficiently as structural materials or as fuel to drive endergonic processes, they have to be transported from where they are produced to where they are needed. In this primer, we provide an overview of basic biophysical concepts underlying our current understanding of the mechanisms of photosynthate long-distance transport, and briefly discuss current developments in the field. PMID- 23754671 TI - Effect of renal disease on the standardized mortality ratio and life expectancy of patients with systemic lupus erythematosus. AB - OBJECTIVE: To study the effect of renal disease on the standardized mortality ratio (SMR) and life expectancy of patients with systemic lupus erythematosus (SLE). METHODS: Patients whose diagnosis met >=4 American College of Rheumatology criteria for SLE were longitudinally followed up from 1995 to 2011. The cumulative survival rate, SMR, and life expectancy were calculated, and the effect of renal involvement, histologic class of lupus nephritis, renal damage, and end-stage renal disease (ESRD) on these parameters was evaluated. RESULTS: Of the 694 SLE patients studied, 368 (53%) had renal disease, and the distribution of histologic classes (among 285 patients) was class I (1%), class II (6%), class III (19%), class IV (47%), class III/IV + class V (10%), and class V (16%). Renal damage was present in 79 patients (11%), and 24 (3%) developed ESRD. The age- and sex-adjusted hazard ratios (HRs) of mortality in SLE patients with renal disease, those with renal damage, and those with ESRD, as compared to those without, were 2.23 (95% confidence interval [95% CI] 1.29-3.85), 3.59 (95% CI 2.20-5.87), and 9.20 (95% CI 4.92-17.2), respectively. Proliferative lupus nephritis (adjusted HR 2.28, 95% CI 1.22-4.24), but not the pure membranous type (adjusted HR 1.09, 95% CI 0.38-3.14), was associated with a significant increase in mortality. The age- and sex-adjusted SMRs of SLE patients without renal involvement, those with lupus nephritis, those with proliferative nephritis, those with pure membranous nephritis, those with renal damage, and those with ESRD were 4.8 (95% CI 2.8 7.5), 9.0 (95% CI 6.7-11.9), 9.8 (95% CI 6.5-14.1), 6.1 (95% CI 2.0-14.1), 14.0 (95% CI 9.1-20.5), and 63.1 (95% CI 33.6-108.0), respectively. The life expectancy of SLE patients with renal disease and those with renal damage was reduced by 15.1 years and 23.7 years, respectively, compared to the general population. CONCLUSION: The presence of renal disease, in particular proliferative nephritis causing renal insufficiency, significantly reduces the survival and life expectancy of SLE patients. PMID- 23754672 TI - "Normoalbuminuric" diabetic nephropathy: tubular damage and NGAL. AB - The aim of this study was to demonstrate that neutrophil gelatinase-associated lipocalin (NGAL) increased before the onset of microalbuminuria in patients with type 1 diabetes mellitus (T1DM), representing an important biochemical parameter with high sensitivity and specificity to make a precocious diagnosis of "normoalbuminuric" diabetic nephropathy (DN). Serum NGAL (sNGAL) and urinary NGAL (uNGAL) levels were evaluated in a cohort of fifty patients affected by T1DM. They had no signs of clinical nephropathy. Thirty-five healthy subjects (HS) were recruited. sNGAL levels were significantly higher compared with those measured in HS [193.7 (103.2-405.4) vs. 46.4 (39.8-56.2) ng/ml; p < 0.0001], as were uNGAL levels [25.5 (14.2-40.2) vs. 6.5 (2.9-8.5) ng/ml; p < 0.0001]. sNGAL was found to be directly correlated with glycated hemoglobin. uNGAL also positively correlated with albuminuria, whereas an inverse correlation was found with uric acid. After multivariate analysis, significance was maintained for the correlation between uNGAL and microalbuminuria. In ROC analysis, sNGAL showed a good diagnostic profile such as uNGAL. NGAL increases in patients with T1DM, even before diagnosis of microalbuminuria representing an early biomarker of "normoalbuminuric" DN with a good sensitivity and specificity. NGAL measurement could be useful for the evaluation of early renal involvement in the course of diabetes. PMID- 23754673 TI - Independent glucose and weight-reducing effects of Liraglutide in a real-world population of type 2 diabetic outpatients. AB - The GLP-1 receptor agonist Liraglutide is effective in reducing HbA1c in type 2 diabetic (T2D) patients. In addition, treatment with Liraglutide is associated with significant weight loss. In this study, we analyzed the inter-relationships between glycemic and weight effects of Liraglutide treatment in a population of type 2 diabetic outpatients. T2D patients initiating Liraglutide therapy since September 2010 to July 2012 at 3 outpatient clinics were enrolled and followed up. We collected baseline information about anthropometric data, cardiovascular risk factors, diabetes duration, prevalence of complications and history of anti diabetic medications. We collected HbA1c and body weight at baseline and every 4 months. A total of 166 patients were included, who were on average 56.6 +/- 8.9 (mean +/- SD) years old and had a baseline HbA1c of 8.7 +/- 1.3 % and BMI 36.3 +/ 6.4 kg/m(2). Mean follow-up was 9.4 +/- 4.2 months (range 4-16). Patients lost on average 1.5 +/- 1.3 % HbA1c and 4.0 +/- 5.0 kg body weight. Most patients (73.5 %) improved HbA1c and loosed weight. Significant independent determinants of HbA1c drop were baseline HbA1c (r = 0.673; p < 0.001) and previous insulin therapy (r = -0.251; p < 0.001). The only independent determinant of weight loss was baseline BMI (r = 0.429; p < 0.001). Drop in HbA1c was unrelated to baseline BMI or weight loss. Weight loss was unrelated to baseline HbA1c or drop in HbA1c. Glycemic improvement and weight reduction obtained with Liraglutide treatment in T2D patients in a real-world setting are independent and possibly mediated by different mechanisms. PMID- 23754674 TI - Iterative 3D projection reconstruction of (23) Na data with an (1) H MRI constraint. AB - PURPOSE: To increase the signal-to-noise ratio (SNR) and to reduce artifacts in non-proton magnetic resonance imaging (MRI) by incorporation of a priori information from (1) H MR data in an iterative reconstruction. METHODS: An iterative reconstruction algorithm for 3D projection reconstruction (3DPR) is presented that combines prior anatomical knowledge and image sparsity under a total variation (TV) constraint. A binary mask (BM) is used as an anatomical constraint to penalize non-zero signal intensities outside the object. The BM&TV method is evaluated in simulations and in MR measurements in volunteers. RESULTS: In simulated BM&TV brain data, the artifact level was reduced by 20% while structures were well preserved compared to gridding. SNR maps showed a spatially dependent SNR gain over gridding reconstruction, which was up to 100% for simulated data. Undersampled 3DPR (23) Na MRI of the human brain revealed an SNR increase of 29 +/- 7%. Small anatomical structures were reproduced with a mean contrast loss of 14%, whereas in TV-regularized iterative reconstructions a loss of 66% was found. CONCLUSION: The BM&TV algorithm allows reconstructing images with increased SNR and reduced artifact level compared to gridding and performs superior to an iterative reconstruction using an unspecific TV constraint only. PMID- 23754675 TI - Providing care for critically ill surgical patients: challenges and recommendations. AB - Providing optimal care for critically ill and injured surgical patients will become more challenging with staff shortages for surgeons and intensivists. This white paper addresses the historical issues behind the present situation, the need for all intensivists to engage in dedicated critical care per the intensivist model, and the recognition that intensivists from all specialties can provide optimal care for the critically ill surgical patient, particularly with continuing involvement by the surgeon of record. The new acute care surgery training paradigm (including trauma, surgical critical care, and emergency general surgery) has been developed to increase interest in trauma and surgical critical care, but the number of interested trainees remains too few. Recommendations are made for broadening the multidisciplinary training and practice opportunities in surgical critical care for intensivists from all base specialties and for maintaining the intensivist model within acute care surgery practice. Support from academic and administrative leadership, as well as national organizations, will be needed. PMID- 23754676 TI - Dosage schedule for antipyretic combination formulations: experts' reply I. PMID- 23754677 TI - Changes in the utilization of venlafaxine after the introduction of generics in Sweden. AB - BACKGROUND: There has been an appreciable increase in the prescribing efficiency of proton pump inhibitors, statins, and renin-angiotensin inhibitor drugs in Sweden in recent years. This has been achieved through multiple reforms encouraging the prescription of generics at low prices versus patented drugs in the same class. Generic venlafaxine also presents an opportunity to save costs given the prevalence of depression. However, depression is more complex to treat, with physicians reluctant to change prescriptions if patients are responding to a particular antidepressant. OBJECTIVES: We assessed (a) changes in the utilization pattern of venlafaxine versus other newer antidepressants before and after the availability of generic venlafaxine and before and after the initiation of prescription restrictions for duloxetine limiting its prescription to refractory patients, (b) utilization of generic versus original venlafaxine after its availability, and (c) price reductions for generic venlafaxine and the subsequent influence on total expenditure on newer antidepressants over time. METHODOLOGY: We performed interrupted time series analysis of changes in monthly reimbursed prescriptions using defined daily doses (DDDs) of patients dispensed at least one newer antidepressant from January 2007 to August 2011. DDDs was defined as the average maintenance dose of a drug when used in its major indication in adults. This included 19 months after the availability of generic venlafaxine and before initiation of prescription restrictions for duloxetine to 13 months after prescription restrictions. Total expenditure and expenditure/DDD for venlafaxine were measured over time. RESULTS: No appreciable change in the utilization pattern for venlafaxine was observed after generic availability when no appreciable demand-side activities by the regions (counties) were implemented to encourage its use. The utilization of venlafaxine significantly increased after prescription restrictions for duloxetine. Generic venlafaxine was dispensed once available, reaching 99.6 % of total venlafaxine (DDD basis) by August 2011. There was an appreciable fall in expenditure for newer antidepressants in Sweden after generic venlafaxine despite increased utilization, helped by a 90 % reduction in expenditure/DDD for venlafaxine by the end of the study versus prepatent loss prices. CONCLUSION: Multiple demand-side measures are needed to change physician prescribing habits. Authorities should not rely on a spillover effect between drug classes to effect change. Limited influence of prescription restrictions on the subsequent utilization of duloxetine reflects the complexity of this disease area. This is exacerbated by heterogeneous indications for duloxetine. PMID- 23754678 TI - Tri-planar computed tomographic projection of three segments of the middle turbinate in a Chinese population. AB - To investigate the exact anatomical characteristics and variations of three segments of middle turbinate bones in a Chinese population using Tri-planar computed tomographic (CT) projections. The axial, sagittal, and coronal thin slice reconstructed CT images of the middle turbinate were obtained from 200 bones of 100 normal adult Chinese subjects (54 males and 46 females). The middle turbinate bones were divided into three segments: vertical, basal lamella, and horizontal. The anterior vertical segment is a sagittal plane best seen on coronal images. Forty-eight bones of the vertical segment were pneumatized on both sides, 14 bones were pneumatized on one side and 21 bones had paradoxical curvature. The distribution of pneumatized concha bullosa bones (based on shape) was as follows: 41 lamellar, 5 bulbous, and 7 extensive types. The basal lamella of the middle turbinate (an L-shaped bony plate) was easily observed on axial and sagittal imaging. On the axial images, the anterior vertical portion of the bones was classified according to shape: 44 linear, 116 curved, and 40 angular. On the sagittal images, it was apparent that most of the horizontal portion was not at a real horizontal plane but on a slope, with an average angle of 127 degrees in the anterior direction. Racial differences may cause the discrepancy between our results and those of other studies. The present study describes the anatomical characteristics and variations of the middle turbinate in the Chinese in Asia, knowledge of which is essential to avoid complications during surgery. PMID- 23754679 TI - Computed tomographic colonography for colorectal cancer screening: risk factors for the detection of advanced neoplasia. AB - BACKGROUND: The objective of this study was to determine whether age, sex, a positive family history of colorectal cancer, and body mass index (BMI) are important predictors of advanced neoplasia in the setting of screening computed tomographic colonography (CTC). METHODS: Consecutive patients who were referred for first-time screening CTC from 2004 to 2011 at a single medical center were enrolled. Results at pathology were recorded for all patients who underwent polypectomy. Logistic regression was used to identify significant predictor variables for advanced neoplasia (any adenoma >= 10 mm or with villous component, high-grade dysplasia, or adenocarcinoma). Odds ratios (ORs) were used to express associations between the study variables (age, sex, BMI, and a positive family history of colorectal cancer) and advanced neoplasia. RESULTS: In total, 7620 patients underwent CTC screening. Of these, 276 patients (3.6%; 95% confidence interval [CI], 3.2%-4.1%) ultimately were diagnosed with advanced neoplasia. At multivariate analysis, age (mean OR per 10-year increase, 1.8; 95% CI, 1.6-2.0) and being a man (OR, 1.7; 95% CI, 1.3-2.2) were independent predictors of advanced neoplasia, whereas BMI and a positive family history of colorectal cancer were not. The number needed to screen to detect 1 case of advanced neoplasia varied from 51 among women aged <= 55 years to 10 among men aged >65 years. The number of post-CTC colonoscopies needed to detect 1 case of advanced neoplasia varied from 2 to 4. CONCLUSIONS: Age and sex were identified as important independent predictors of advanced neoplasia risk in individuals undergoing screening CTC, whereas BMI and a positive family history of colorectal cancer were not. These results have implications for appropriate patient selection. PMID- 23754680 TI - What is the perioperative antibiotic prophylaxis in adult oncologic head and neck surgery? PMID- 23754681 TI - The societal cost of bipolar disorder in Sweden. AB - PURPOSE: There is a lack of comprehensive cost-of-illness studies in bipolar disorder, in particular studies based on patient-level data. The purpose of this study was to estimate the societal cost of bipolar disorder and to relate costs to disease severity, depressive episodes, hospitalisation and patient functioning. METHODS: Retrospective resource use data in inpatient and outpatient care during 2006-2008, as well as ICD-10 diagnoses and Global Assessment of Functioning (GAF) scores, were obtained from the Northern Stockholm psychiatric clinic with a catchment area including 47% of the adult inhabitants in Stockholm. This dataset was combined with national register data on prescription pharmaceuticals and sick leave to estimate the societal cost of bipolar disorder. The study was conducted from a societal perspective, with indirect costs valued according to the human capital method. RESULTS: The average annual cost per patient was 28,011 in 2008 (n = 1,846). Indirect costs due to sick leave and early retirement represented 75%, inpatient costs 13%, outpatient costs 8%, pharmaceuticals 2% and community care another 2% of the total cost. Total costs were considerably higher during mood episodes (six times higher than in remission), for hospitalised patients (55,500 vs. 22,200) and for patients with low GAF scores. CONCLUSIONS: The high cost of bipolar disorder is driven primarily by indirect costs. Costs were strongly associated with mood episodes, hospitalisations and low GAF scores. This suggests that treatment that reduces the risk for relapses and hospitalizations and improve functioning may decrease both the societal cost of bipolar disorder and patient suffering. PMID- 23754682 TI - Neighborhood disadvantage in context: the influence of urbanicity on the association between neighborhood disadvantage and adolescent emotional disorders. AB - PURPOSE: Inconsistent evidence of a relationship between neighborhood disadvantage and adolescent mental health may be, in part, attributable to heterogeneity based on urban or rural residence. Using the largest nationally representative survey of US adolescent mental health available, we estimated the association between neighborhood disadvantage and adolescent emotional disorders and the extent to which urbanicity modified this association. METHODS: The National Comorbidity Survey Replication Adolescent Supplement (NCS-A) sampled adolescents aged 13-17 years (N = 10,123). Households were geocoded to Census tracts. Using a propensity score approach that addresses bias from non-random selection of individuals into neighborhoods, logistic regression models were used to estimate the relative odds of having a DSM-IV emotional disorder (any past year anxiety disorder, major depressive disorder or dysthymia) comparing similar adolescents living in disadvantaged versus non-disadvantaged neighborhoods in urban center, urban fringe, and non-urban areas. RESULTS: The association between neighborhood disadvantage and emotional disorder was more than twice as large for adolescents living in urban centers versus non-urban areas. In urban centers, living in a disadvantaged neighborhood was associated with 59% (95% confidence interval 25-103) increased adjusted odds of emotional disorder. CONCLUSIONS: Urbanicity modifies the relationship between neighborhood disadvantage and emotional disorder in adolescents. This effect modification may explain why evidence of a relationship between neighborhood disadvantage and adolescent mental health has been inconsistent. Recognizing the joint influence of neighborhood socioeconomic context and urbanicity may improve specificity in identifying relevant neighborhood processes. PMID- 23754683 TI - cDNA microarray profiling of rat cholangiocarcinoma induced by thioacetamide. AB - Cholangiocarcinoma (CCA) is a malignant neoplasm affecting thousands of individuals worldwide. CCA develops through a multistep process. In the current study, an oral thioacetamide (TAA)-induced model of rat CCA was established which generates the histological progression of human CCA, particularly the mass forming type. Seven male Sprague-Dawley rats were treated with TAA for 24 weeks to induce CCA. Following the generation of the rat CCA model, whole rat genomic oligo microarray was performed to examine gene expression profiles in CCA and non cancerous liver samples. In brief, 10,427 genes were found to be differentially expressed (8,318 upregulated and 3,489 downregulated) in CCA compared with non tumor liver tissue. The top 50 genes (upregulated or downregulated) were selected and their functional involvement in various pathways associated with cancer progression was analyzed, including cell proliferation, apoptosis, metabolism and the cell cycle. In addition, increased expression of CLCA3, COL1A2, DCN, GLIPr2 and NID1, and decreased expression of CYP2C7 and SLC10A1 were validated by quantitative real-time PCR. Immunohistochemical analysis was performed to determine the protein expression levels of GLIPr2 and SLC10A1. The gene expression profiling performed in this study provides a unique opportunity for understanding the carcinogenesis of TAA-induced CAA. In addition, expression profiling of a number of specific genes is likely to provide important novel biomarkers for the diagnosis of CCA and the development of novel therapeutic strategies for CCA. PMID- 23754684 TI - Replacement of fractured reconstruction plate with customized mandible implant: a novel technique. PMID- 23754685 TI - Necessary and sufficient causes of participation post-stroke: practical and philosophical perspectives. AB - INTRODUCTION: Participation, a construct within the disability/functioning framework, is evaluated on a person's involvement in life situations including family, community, work, social, and civic life. In the context of recovering from a major health event, participation is a treatment goal and it is known to correlate with the quality of life. OBJECTIVE: The purpose of this study is to track the dynamics of participation post-stroke in relationship to the dynamics of walking capacity, social support, and mood. METHODS: An inception cohort was followed over the first post-stroke year. Group-based trajectory analysis, a form of latent class analysis, was used to identify distinctive groups of individuals with similar trajectories. Dual trajectories were used to estimate concordance between participation trajectory and trajectories for each of the three constructs under study. RESULTS: From the sample of 102 persons (mean age 70), four trajectories of participation were identified, two of which were qualified as excellent and very good, and two qualified as fair and poor. All those with excellent walking showed excellent participation. However, people with excellent (and very good) community participation had a range of walking capacities. Most (82%) people with normal mood showed excellent participation. People with good mood but not meeting norms for age showed the complete range of participation trajectories from excellent to poor. The higher proportion of people with excellent or good social support (57%) showed excellent participation. CONCLUSION: Two treatable component causes of participation, walking capacity and mood, were identified; of these, only excellent walking capacity could be considered a sufficient cause. PMID- 23754686 TI - Barriers and solutions to implementing dialectical behavior therapy in a public behavioral health system. AB - Dialectical behavior therapy (DBT) is an evidence-based treatment that is considered to be the standard of care in treating individuals with BPD, however there have been few published studies to identify the challenges and solutions for implementing DBT in community-based settings. The current study identified the barriers and solutions within a system-wide roll-out of DBT within a large, urban public health system encompassing both mental health and substance abuse treatment settings. Qualitative interviews were conducted with 19 clinicians receiving DBT training over a period of 13 months. A content analysis revealed three themes that were identified as challenges to the DBT implementation process including program development and recruitment of patients, a lack of administrative support or organizational investment in DBT, and time commitment of DBT. In order to transfer DBT into a public behavioral health system, investment from both clinic- and system-level administrators is required. Strategies to prevent drift, such as incorporating a train-the-trainer model, are discussed. PMID- 23754687 TI - How the development of handedness could contribute to the development of language. AB - We propose a developmental process which may link the development of handedness with the development of hemispheric specialization for speech processing. Using Arbib's proposed sequence of sensorimotor development of manual skills and gestures (that he considers to be the basis of speech gestures and proto language), we show how the development of hand-use preferences in proto-reaching skills concatenate into object acquisition skills and eventually into role differentiated bimanual manipulation skills (that reflect interhemispheric communication and coordination). These latter sensorimotor skills might facilitate the development of speech processing via their influence on the development of tool-using and object management abilities. PMID- 23754688 TI - Spatial moving average risk smoothing. AB - This paper introduces spatial moving average risk smoothing (SMARS) as a new way of carrying out disease mapping. This proposal applies the moving average ideas of time series theory to the spatial domain, making use of a spatial moving average process of unknown order to define dependence on the risk of a disease occurring. Correlation of the risks for different locations will be a function of m values (m being unknown), providing a rich class of correlation functions that may be reproduced by SMARS. Moreover, the distance (in terms of neighborhoods) that should be covered for two units to be found to make the correlation of their risks 0 is a quantity to be fitted by the model. This way, we reproduce patterns that range from spatially independent to long-range spatially dependent. We will also show a theoretical study of the correlation structure induced by SMARS, illustrating the wide variety of correlation functions that this proposal is able to reproduce. We will also present three applications of SMARS to both simulated and real datasets. These applications will show SMARS to be a competitive disease mapping model when compared with alternative proposals that have already appeared in the literature. Finally, the application of SMARS to the study of mortality for 21 causes of death in the Comunitat Valenciana will allow us to identify some qualitative differences in the patterns of those diseases. PMID- 23754690 TI - Presence of angina pectoris is related to extensive coronary artery disease in diabetic patients. AB - BACKGROUND: Due to sensorial autonomic neuropathy, the type and severity of angina pectoris in patients with diabetes mellitus (DM) may be rather different from the type and severity of angina pectoris in patients without DM. HYPOTHESIS: The aim of the study was to understand if angina pectoris is related to extensive coronary artery disease (CAD) in patients with DM. METHODS: The study included 530 patients with DM who underwent coronary angiography at our center in 2009 and 2010. Patients were divided into 4 groups according to type of chest pain: group 1, noncardiac chest pain or no pain; group 2, angina equivalent; group 3, atypical angina; and group 4, typical angina. All angiograms were re-evaluated and Gensini scores were calculated. Three-vessel disease was diagnosed in the presence of stenosis >50% in all 3 coronary artery systems. RESULTS: There were no statistically significant differences between the groups with regard to age, sex, systolic or diastolic blood pressures, body mass index, creatinine clearance, or lipid profile. Fasting blood glucose was significantly higher in group 4 than in group 2. Gensini scores were not statistically different between groups 1 and 2 or between groups 3 and 4; however, the scores for groups 3 and 4 were higher than the score for either group 1 or group 2. Prevalence of 3-vessel disease was significantly higher in groups 3 and 4 compared with the other groups. CONCLUSIONS: The presence of angina pectoris was related to extensive CAD in patients with DM. The extent of CAD was not correlated with the type of angina (typical or atypical). PMID- 23754689 TI - Posttranscriptional regulation of retroviral gene expression: primary RNA transcripts play three roles as pre-mRNA, mRNA, and genomic RNA. AB - After reverse transcription of the retroviral RNA genome and integration of the DNA provirus into the host genome, host machinery is used for viral gene expression along with viral proteins and RNA regulatory elements. Here, we discuss co-transcriptional and posttranscriptional regulation of retroviral gene expression, comparing simple and complex retroviruses. Cellular RNA polymerase II synthesizes full-length viral primary RNA transcripts that are capped and polyadenylated. All retroviruses generate a singly spliced env mRNA from this primary transcript, which encodes the viral glycoproteins. In addition, complex viral RNAs are alternatively spliced to generate accessory proteins, such as Rev, which is involved in posttranscriptional regulation of HIV-1 RNA. Importantly, the splicing of all retroviruses is incomplete; they must maintain and export a fraction of their primary RNA transcripts. This unspliced RNA functions both as the major mRNA for Gag and Pol proteins and as the packaged genomic RNA. Different retroviruses export their unspliced viral RNA from the nucleus to the cytoplasm by either Tap-dependent or Rev/CRM1-dependent routes. Translation of the unspliced mRNA involves frame-shifting or termination codon suppression so that the Gag proteins, which make up the capsid, are expressed more abundantly than the Pol proteins, which are the viral enzymes. After the viral polyproteins assemble into viral particles and bud from the cell membrane, a viral encoded protease cleaves them. Some retroviruses have evolved mechanisms to protect their unspliced RNA from decay by nonsense-mediated RNA decay and to prevent genome editing by the cellular APOBEC deaminases. PMID- 23754691 TI - Developmental changes in morphine clearance across the entire paediatric age range are best described by a bodyweight-dependent exponent model. AB - BACKGROUND AND OBJECTIVE: Morphine clearance has been successfully scaled from preterm neonates to 3-year-old children on the basis of a bodyweight-based exponential (BDE) function and age younger or older than 10 days. The aim of the current study was to characterize the developmental changes in morphine clearance across the entire paediatric age range. METHODS: Morphine and morphine-3 glucuronide (M3G) concentration data from 358 (pre)term neonates, infants, children and adults, and morphine concentration data from 117 adolescents were analysed using NONMEM 7.2. Based on available data, two models were developed: I. using morphine data; II. using morphine and M3G data. RESULTS: In model I, morphine clearance across the paediatric age range was very well described by a BDE function in which the allometric exponent decreased in a sigmoidal manner with bodyweight (BDE model) from 1.47 to 0.88, with half the decrease in exponent reached at 4.01 kg. In model II, the exponent for the formation and elimination clearance of M3G was found to decrease from 1.56 to 0.89 and from 1.06 to 0.61, with half the decrease reached at 3.89 and 4.87 kg, respectively. Using the BDE model, there was no need to use additional measures for size or age. CONCLUSION: The BDE model was able to scale both total morphine clearance and glucuronidation clearance through the M3G pathway across all age ranges between (pre)term neonates and adults by allowing the allometric exponent to decrease across the paediatric age range from values higher than 1 for neonates to values lower than 1 for infants and children. PMID- 23754693 TI - Multidrug and heavy metal-resistant Raoultella planticola isolated from surface water. AB - A surface water isolate of Raoultella sp. having both multidrug- and multimetal resistant ability was isolated and identified as Raoultella planticola. R. planticola displayed resistance to 15 drugs like ampicillin, amoxicillin/clavulanic acid, aztreonam, erythromycin, imipenem, oxacillin, pefloxacin, penicillin, piperacillin, piperacillin/tazobactam, rifampin, sulbactam/cefoperazone, ticarsillin, ticarsillin/clavulanic acid, vancomycin, and to 11 heavy metals like aluminum, barium, copper, iron, lead, lithium, manganese, nickel, silver, strontium, and tin. The multidrug and multi-metal-resistant R. planticola may remain present in the environment for a long time. Due to a possible health risk of these pathogenic bacteria, a need exists for an accurate assessment of their acquired resistance to multiple drugs and metals. PMID- 23754692 TI - Layering PLGA-based electrospun membranes and cell sheets for engineering cartilage-bone transition. AB - It is now widely acknowledged that implants that have been designed with an effort towards reconstructing the transition between tissues might improve their functionality and integration in vivo. This paper contributes to the development of improved treatment for articular cartilage repair by exploring the potential of the combination of electrospinning technology and cell sheet engineering to create cartilage tissue. Poly(lactic-co-glycolic acid) (PLGA) was used to create the electrospun membranes. The focus being on the cartilage-bone transition, collagen type I and hydroxyapatite (HA) were also added to the scaffolds to increase the histological biocompatibility. Human mesenchymal stem cells (hMSCs) were cultured in thermoresponsive dishes to allow non-enzymatic removal of an intact cell layer after reaching confluence. The tissue constructs were created by layering electrospun membranes with sheets of hMSCs and were cultured under chondrogenic conditions for up to 21 days. High viability was found to be maintained in the multilayered construct. Under chondrogenic conditions, reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry have shown high expression levels of collagen type X, a form of collagen typically found in the calcified zone of articular cartilage, suggesting an induction of chondrocyte hypertrophy in the PLGA-based scaffolds. To conclude, this paper suggests that layering electrospun scaffolds and cell sheets is an efficient approach for the engineering of tissue transitions, and in particular the cartilage-bone transition. The use of PLGA-based scaffold might be particularly useful for the bone-cartilage reconstruction, since the differentiated tissue constructs seem to show characteristics of calcified cartilage. PMID- 23754694 TI - Identification of optimal concentrations and incubation times for the study of in vitro effects of Pb in ram spermatozoa. AB - In vitro effects of lead (Pb) on ram (Ovis aries) spermatozoa were studied to establish a threshold level that affects sperm function. Spermatozoa were incubated between 15 and 180 min with Pb concentrations ranging from 0 to 5,000 ng/mL. Sperm motility, acrosome integrity, membrane functionality and sperm viability were all negatively affected by Pb and incubation time. Acrosome integrity was linearly affected by Pb levels at an incubation time of 30 min, and 50 ng/mL was the lowest Pb level producing such effect. These experimental conditions can be appropriate for in vitro studies of the mechanisms of action of Pb on spermatozoa. PMID- 23754695 TI - Grey and white matter abnormalities in temporal lobe epilepsy with and without mesial temporal sclerosis. AB - Temporal lobe epilepsy with (TLE-mts) and without (TLE-no) mesial temporal sclerosis display different patterns of cortical neuronal loss, suggesting that the distribution of white matter damage may also differ between the sub-groups. The purpose of this study was to examine patterns of white matter damage in TLE mts and TLE-no and to determine if identified changes are related to neuronal loss at the presumed seizure focus. The 4 T diffusion tensor imaging (DTI) and T1 weighted data were acquired for 22 TLE-mts, 21 TLE-no and 31 healthy controls. Tract-based spatial statistics (TBSS) was used to compare fractional anisotropy (FA) maps and voxel-based morphometry (VBM) was used to identify grey matter (GM) volume atrophy. Correlation analysis was conducted between the FA maps and neuronal loss at the presumed seizure focus. In TLE-mts, reduced FA was identified in the genu, body and splenium of the corpus callosum, bilateral corona radiata, cingulum, external capsule, ipsilateral internal capsule and uncinate fasciculus. In TLE-no, FA decreases were identified in the genu, the body of the corpus callosum and ipsilateral anterior corona radiata. The FA positively correlated with ipsilateral hippocampal volume. Widespread extra-focal GM atrophy was associated with both sub-groups. Despite widespread and extensive GM atrophy displaying different anatomical patterns in both sub-groups, TLE-mts demonstrated more extensive FA abnormalities than TLE-no. The microstructural organization in the corpus callosum was related to hippocampal volume in both patients and healthy subjects demonstrating the association of these distal regions. PMID- 23754696 TI - Vitamin D deficiency in myotonic dystrophy type 1. AB - Myotonic dystrophy type 1 (DM1) is a multisystemic disorder affecting, among others, the endocrine system, with derangement of steroid hormones functions. Vitamin D is a steroid recognized for its role in calcium homeostasis. In addition, vitamin D influences muscle metabolism by genomic and non-genomic actions, including stimulation of the insulin-like-growth-factor 1 (IGF1), a major regulator of muscle trophism. To verify the presence of vitamin D deficit in DM1 and its possible consequences, serum 25-hydroxyvitamin D (25(OH)D), calcium, parathormone (PTH), and IGF1 levels were measured in 32 DM1 patients and in 32 age-matched controls. Bone mineral density (BMD) and proximal muscle strength were also measured by DXA and a handheld dynamometer, respectively. In DM1 patients, 25(OH)D levels were reduced compared to controls, and a significant decrease of IGF1 was also found. 25(OH)D levels inversely correlated with CTG expansion size, while IGF1 levels and muscle strength directly correlated with levels of 25(OH)D lower than 20 and 10 ng/ml, respectively. A significantly higher percentage of DM1 patients presented hyperparathyroidism as compared to controls. Calcium levels and BMD were comparable between the two groups. Oral administration of cholecalciferol in 11 DM1 patients with severe vitamin D deficiency induced a normal increase of circulating 25(OH)D, ruling out defects in intestinal absorption or hepatic hydroxylation. DM1 patients show a reduction of circulating 25(OH)D, which correlates with genotype and may influence IGF1 levels and proximal muscle strength. Oral supplementation with vitamin D should be considered in DM1 and might mitigate muscle weakness. PMID- 23754697 TI - A strategy to prepare wafer scale bismuth compound superstructures. AB - Epitaxial wafer scale superstructures of bismuth compounds are synthesized. Single crystalline beta-Bi2O3 films are obtained by sputtering amorphous BiOx onto (001)-oriented strontium titanate with a buffer layer, followed by thermal crystallization. This is used as the precursor for the growth of the superstructures. The superstructures of bismuth compounds reveal anisotropic physical properties that are related to their unique morphology. PMID- 23754698 TI - Structure elucidation of antiproliferative bisbenzylisoquinoline alkaloids from Anisocycla grandidieri from the Madagascar dry forest. AB - Antiproliferative bioassay-guided fractionation of the ethanol extract of the stems of Anisocycla grandidieri led to the isolation of the known alkaloids stebisimine (1), (+)-1,2-dehydrotelobine (2), (+)-2'-norcocsuline (3) and puetogaline B (4). Herein, we report the full NMR assignments of all compounds and the X-ray crystallography of single crystals of compounds 1 and 3. Compounds 2 and 3 showed moderate antiproliferative activity against the A2780 human ovarian cancer cell line with IC50 values of 4.1 +/- 0.3 and 2.7 +/- 0.3 MUM, respectively, and they also displayed selective activity toward the H460 (large cell lung cancer), MCF-7 (breast ductal carcinoma), and UACC-257 (melanoma) cell lines. PMID- 23754699 TI - 1H, 13C and 15N backbone and side-chain resonance assignments of the N-terminal ubiquitin-binding domains of the human deubiquitinase Usp28. AB - Deubiquitinases (DUBs) reversibly remove ubiquitin tags from polypeptides and play crucial regulatory roles in multiple cellular processes. Ubiquitin-specific protease 28 (Usp28), a member of the DUB family, exerts its deubiquitination function on key protein molecules in a couple of cancer-associated pathways, likely acting as an oncogenic factor in vivo. The N-terminal ubiquitin-binding domains (UBDs) of Usp28 are potentially required for the full catalytic capacity of Usp28 toward ubiquitin chains. Here we report the expression, purification and (1)H, (13)C and (15)N backbone and side-chain resonance assignments of the N terminal UBDs of Usp28. The BMRB accession number is 19077. PMID- 23754700 TI - 1H, 13C and 15N backbone and side-chain resonance assignments of the N-terminal ubiquitin-binding domains of USP25. AB - Ubiquitin Specific Protease 25 (USP25), a member of the deubiquitinase family, is involved in several disease-related signal pathways including myogenesis, immunity and protein degradation. It specially catalyzes the hydrolysis of the K48-linked and K63-linked polyubiquitin chains. USP25 contains one ubiquitin associated domain and two ubiquitin-interacting motifs (UIMs) in its N-terminal region, which interact with ubiquitin and play a role in substrate recognition. Besides, it has been shown that the catalysis activity of USP25 is either impaired by sumoylation or enhanced by ubiquitination within its UIM. To elucidate the structural basis of the cross-regulation of USP25 function by non covalent binding and covalent modifications of ubiquitin and SUMO2/3, a systematic structural biology study of USP25 is required. Here, we report the (1)H, (13)C and (15)N backbone and side-chain resonance assignments of the N terminal ubiquitin binding domains (UBDs) of USP25 with BMRB accession number of 19111, which is the first step of the systematic structural biology study of the enzyme. PMID- 23754701 TI - Chemical shift assignments of the C-terminal Eps15 homology domain-3 EH domain. AB - The C-terminal Eps15 homology (EH) domain 3 (EHD3) belongs to a eukaryotic family of endocytic regulatory proteins and is involved in the recycling of various receptors from the early endosome to the endocytic recycling compartment or in retrograde transport from the endosomes to the Golgi. EH domains are highly conserved in the EHD family and function as protein-protein interaction units that bind to Asn-Pro-Phe (NPF) motif-containing proteins. The EH domain of EHD1 was the first C-terminal EH domain from the EHD family to be solved by NMR. The differences observed between this domain and proteins with N-terminal EH domains helped describe a mechanism for the differential binding of NPF-containing proteins. Here, structural studies were expanded to include the EHD3 EH domain. While the EHD1 and EHD3 EH domains are highly homologous, they have different protein partners. A comparison of these structures will help determine the selectivity in protein binding between the EHD family members and lead to a better understanding of their unique roles in endocytic regulation. PMID- 23754702 TI - Relatives without rheumatoid arthritis show reactivity to anti-citrullinated protein/peptide antibodies that are associated with arthritis-related traits: studies of the etiology of rheumatoid arthritis. AB - OBJECTIVE: To examine reactivity to anti-citrullinated protein/peptide antibodies (ACPAs) and determine associations between ACPAs and other rheumatoid arthritis (RA)-related autoantibodies and clinically assessed swollen or tender joints in unaffected first-degree relatives of RA patients. METHODS: Serum samples were obtained from first-degree relatives without RA according to the 1987 American College of Rheumatology (ACR) and the 2010 ACR/European League Against Rheumatism classification criteria. A bead-based assay was used to measure 16 separate ACPAs in sera from 111 antibody-positive first-degree relatives who were positive on at least 1 visit for any of 5 RA-related autoantibodies (rheumatoid factor [RF], anti-cyclic citrullinated peptide 2 [anti-CCP-2], and RF isotypes), and sera from 99 antibody-negative first-degree relatives who were never autoantibody positive. Cutoffs for positivity for each ACPA were determined using receiver operating characteristic curves derived from data on 200 RA patients and 98 blood donor controls, in which positivity for >=9 ACPAs had 92% specificity and 62% sensitivity for RA. In first-degree relatives, ACPA reactivity was assessed, and associations between ACPAs (number positive, and positivity for >=9 ACPAs) and RA related characteristics were examined. RESULTS: Fifty-seven percent of anti-CCP-2 positive first-degree relatives and 8% of anti-CCP-2- negative first-degree relatives were positive for >=9 ACPAs. After adjusting for age, sex, ethnicity, and pack-years of smoking, an increasing number of ACPAs was directly associated with the presence of >=1 tender joint on examination (odds ratio [OR] 1.18, 95% confidence interval [95% CI] 1.04-1.34), with the greatest risk of having >=1 tender joint seen in first-degree relatives positive for >=9 ACPAs (OR 5.00, 95% CI 1.37-18.18). CONCLUSION: RA-free first-degree relatives (even those negative for RF and anti-CCP-2) demonstrate reactivity to multiple ACPAs, and the presence of an increasing number of ACPAs may be associated with signs of joint inflammation. Prospective evaluation of the relationship between these findings and the progression of classifiable RA is warranted. PMID- 23754703 TI - A charge-stabilizing, multimodular, ferrocene-bis(triphenylamine)-zinc-porphyrin fullerene polyad. AB - A novel multimodular donor-acceptor polyad featuring zinc porphyrin, fullerene, ferrocene, and triphenylamine entities was designed, synthesized, and studied as a charge-stabilizing, photosynthetic-antenna/reaction-center mimic. The ferrocene and fullerene entities, covalently linked to the porphyrin ring, were distantly separated to accomplish the charge-separation/hole-migration events leading to the creation of a long-lived charge-separated state. The geometry and electronic structures of the newly synthesized compound was deduced by B3LYP/3-21G(*) optimization, while the energy levels for different photochemical events was established using data from the optical absorption and emission, and electrochemical studies. Excitation of the triphenylamine entities revealed singlet-singlet energy transfer to the appended zinc porphyrin. As predicted from the energy levels, photoinduced electron transfer from both the singlet and triplet excited states of the zinc porphyrin to fullerene followed by subsequent hole migration involving ferrocene was witnessed from the transient absorption studies. The charge-separated state persisted for about 8.5 MUs and was governed by the distance between the final charge-transfer product, that is, a species involving a ferrocenium cation and a fullerene radical anion, with additional influence from the charge-stabilizing triphenylamine entities located on the zinc porphyrin macrocycle. PMID- 23754704 TI - Microbial production of glucosamine and N-acetylglucosamine: advances and perspectives. AB - Glucosamine (GlcN), an amino sugar, is a compound derived from substitution of a hydroxyl group of a glucose molecule with an amino group. GlcN and its acetylated derivative, N-acetylglucosamine (GlcNAc), have been widely used in food, cosmetics, and pharmaceutical industries and are currently produced by acid hydrolysis of chitin (a linear polymer of GlcNAc) extracted from crab and shrimp shells. Microbial fermentation by filamentous fungi or recombinant Escherichia coli, as an alternative method for the production of GlcN and GlcNAc, is attracting increasing attention because it is an environmentally friendly process. Although the microbial production of GlcN and GlcNAc is hampered by low yield and high production cost, considerable advances have been made in recent years. Here we review the applications, commercial market, and production of GlcN and GlcNAc, with emphasis on the metabolic and process engineering strategies used to improve GlcN and GlcNAc production by recombinant microbes. PMID- 23754706 TI - Stereoselective synthesis of tetrasubstituted olefins through a halogen-induced 1,2-silyl migration. AB - Migrating through Si valley: The highly stereoselective formation of alpha-silyl beta- haloenones by way of silicon group migration is described. Electrophilic activation of the alkyne by N-halosuccinimides induced an anti-selective migration to give highly substituted enones (see scheme). These enone products can be readily converted to the all-carbon tetrasubstituted alkenes while maintaining their geometry. PMID- 23754705 TI - Worldwide trend of increasing primary adenocarcinoma of the lung. AB - The four major histological types of lung cancer are adenocarcinoma, squamous cell carcinoma (SQ), large cell carcinoma and small cell carcinoma. Over the past few decades, the incidence of lung adenocarcinoma has increased gradually in most countries as the most frequently occurring histological type, displacing SQ. Adenocarcinoma is the predominant type of lung cancer among lifelong non-smokers and among females. Especially in East Asian countries, the cause(s) of the increase in adenocarcinomas are not clear. Several genetic mutations specific to lung adenocarcinomas have been found, representing attractive targets for molecular therapy. Recently, the pathological classification of lung adenocarcinoma was revised by integrating the newer clinical and biological knowledge concerning this prevailing type. Additional epidemiological, pathological and genetic studies are required to better understand this type of lung cancer. PMID- 23754707 TI - Patients undergoing lymphadenectomy for stage III melanomas of known or unknown primary site do not differ in outcome. AB - The outcome of patients with palpable melanoma metastases in lymph nodes in the presence (metastatic melanoma of known primary site, MKP) or absence (metastatic melanoma of unknown primary site, MUP) of an identifiable primary tumour remains controversial. Some of the previous studies contained large case series that included historical patients. We aimed to compare outcomes of those with MUPs versus MKPs with palpable lymph node invasion, after staging with modern imaging technology. Aprospective study of patients from a single tertiary institution who were undergoing lymph node dissection for palpable metastatic melanoma between 2000 and 2011 was conducted. All patients were ascertained by computerised tomography scanning and most diagnosed after 2004 had positron emission tomography scanning also. Clinicopathological details about the primary melanoma and lymph node dissections were gathered. Factors associated with recurrence and melanoma-specific mortality in those with MKP and with MUP were assessed using univariate and multivariate analyses. Out of 485 patients studied, 82 had MUP and 403 had MKP. Patients were followed up for a median of 17.4 and 19.0 months, for MKP and MUP, respectively. Five-year adjusted melanoma-specific survival was 58% for MUPs versus 49% for MKPs and was not significantly different between the two groups (adjusted Cox proportional Hazard ratio = 0.88 95% confidence interval [0.58, 1.33] p = 0.54). Previously established prognostic factors such as number of positive nodes and extracapsular extension were confirmed in both sets of patients. We conclude that among melanoma patients presenting with clinically detectable nodes, when accurately staged, those without an identifiable primary lesion have similar outcomes to patients with MKP. PMID- 23754708 TI - Demographic trends and disease-specific survival in salivary acinic cell carcinoma: an analysis of 1129 cases. AB - OBJECTIVE/HYPOTHESIS: Acinic cell carcinoma (AciCC) is a rare salivary gland malignancy that most commonly arises in the parotid gland. Characteristics of AciCC are slow growth and a long clinical course. As a rare tumor, population based studies are limited. We analyzed the incidence and survival for AciCC using a national population-based database. STUDY DESIGN: Retrospective analysis. METHODS: The United States National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry was utilized to calculate incidence and disease-specific survival trends for AciCC between 1973 and 2009. Patient data were stratified according to age, gender, race, grade, and extent of disease. Incidence trends were studied across the last 30 years and long-term disease-specific survival outcomes were compared across the different demographic parameters. RESULTS: A total of 1,129 cases of AciCC were identified, comprising of 672 (59.52%) females. Incidence trend analysis revealed significant changes in yearly incidence rates from 1973 to 2009 for male gender and white and "others" races. Overall 5-year survival was 97.15%, 10-year survival was 93.81%, and 20 year survival was 89.74%. Significant differences in survival outcomes were noted for extent of disease. Patients exhibiting distant metastasis displayed the worse long-term prognosis at 21.99% 20-year disease-specific survival. Hazard ratios demonstrated a significant increase in mortality in patients with poorly differentiated, undifferentiated, and metastatic disease. CONCLUSION: Trends in incidence of AciCC are influenced by gender, race and age. Long-term survival of this rare malignant tumor is influenced by gender, grade, race, and extent of disease. Future studies need to be conducted to investigate these dynamic trends related to AciCC. PMID- 23754709 TI - Development of a DNA macroarray for simultaneous detection of multiple foodborne pathogenic bacteria in fresh chicken meat. AB - A DNA macroarray was developed to provide the ability to detect multiple foodborne pathogens in fresh chicken meat. Probes targeted to the 16S rRNA and genus- and species-specific genes, including fimY, ipaH, prfA, and uspA, were selected for the specific detection of Salmonella spp., Shigella spp., Listeria monocytogenes, and Escherichia coli, respectively. The combination of target gene amplification by PCR and a DNA macroarray in our system was able to distinguish all target bacteria from pure cultures with a detection sensitivity of 105 c.f.u. ml-1. The DNA macroarray was also applied to 10 fresh chicken meat samples. The assay validation demonstrated that by combining the enrichment steps for the target bacteria and the DNA macroarray, all 4 target bacteria could be detected simultaneously from the fresh chicken samples. The sensitivity of L. monocytogenes and Shigella boydii detection in the fresh chicken samples was at least 10 and 3 c.f.u. of the initial contamination in 25 g samples, respectively. The advantages of our developed protocol are high accuracy and time reduction when compared to conventional culture. The macroarray developed in our investigation was cost effective compared to modern oligonucleotide microarray techniques because there was no expensive equipment required for the detection of multiple foodborne pathogens. PMID- 23754710 TI - Causal inference in paired two-arm experimental studies under noncompliance with application to prognosis of myocardial infarction. AB - Motivated by a study about prompt coronary angiography in myocardial infarction, we propose a method to estimate the causal effect of a treatment in two-arm experimental studies with possible noncompliance in both treatment and control arms. We base the method on a causal model for repeated binary outcomes (before and after the treatment), which includes individual covariates and latent variables for the unobserved heterogeneity between subjects. Moreover, given the type of noncompliance, the model assumes the existence of three subpopulations of subjects: compliers, never-takers, and always-takers. We estimate the model using a two-step estimator: at the first step, we estimate the probability that a subject belongs to one of the three subpopulations on the basis of the available covariates; at the second step, we estimate the causal effects through a conditional logistic method, the implementation of which depends on the results from the first step. The estimator is approximately consistent and, under certain circumstances, exactly consistent. We provide evidence that the bias is negligible in relevant situations. We compute standard errors on the basis of a sandwich formula. The application shows that prompt coronary angiography in patients with myocardial infarction may significantly decrease the risk of other events within the next 2 years, with a log-odds of about - 2. Given that noncompliance is significant for patients being given the treatment because of high-risk conditions, classical estimators fail to detect, or at least underestimate, this effect. PMID- 23754711 TI - Impact of atorvastatin treatment in first-degree relatives of patients with premature coronary artery disease with endothelial dysfunction: a double-blind, randomized, placebo-controlled crossover trial. AB - BACKGROUND: A family history of premature coronary artery disease (CAD) is a well known risk factor for cardiovascular events. HYPOTHESIS: Atorvastatin may improve endothelial dysfunction (ED) in the first-degree relatives (FDRs) of patients with premature CAD with ED. METHODS: Thirty-five FDRs (median age, 52 years [interquartile range (IQR), 46-57 years], 21 male) of patients with premature CAD with ED were recruited in a prospective trial with a crossover double-blind design: 6 weeks of treatment with atorvastatin 40 mg/day followed by placebo, or vice versa. After each treatment, the digital pulse wave amplitude was determined by EndoPAT to obtain the reactive hyperemia index (RHI), a measure for endothelial function. The primary outcome was the difference of RHI between atorvastatin and placebo treatment. RESULTS: Low-density lipoprotein cholesterol was lower after atorvastatin compared with placebo treatment (124 [102-145] mg/dL vs 67 [50-73] mg/dL, P < 0.001). However, RHI was not different after atorvastatin compared with placebo treatment (1.9 [1.5-2.4] vs 1.9 [1.6-2.2], P = 0.902). Also, the augmentation index was similar after each treatment. These results were observed both in subjects who had indications for statin treatment (31%) and those who did not (69%) according to National Cholesterol Education Program Adult Treatment Panel III guidelines. CONCLUSIONS: Despite improvement in the lipid profile, atorvastatin failed to improve ED in the FDRs of patients with premature CAD with ED. Although we identified those with ED in FDRs of patients with premature CAD as a high-risk group for future cardiovascular events, atorvastatin treatment may not be a beneficial primary prevention strategy for this population. PMID- 23754712 TI - Age and sex differences in reward behavior in adolescent and adult rats. AB - Compared to adults, adolescents are at heightened risk for drug abuse and dependence. One of the factors contributing to this vulnerability may be age dependent differences in reward processing, with adolescents approaching reward through stimulus-directed, rather than goal-directed, processes. However, the empirical evidence for this in rodent models of adolescence, particularly those that investigate both sexes, is limited. To address this, male and female rats that were adolescents (P30) or adults (P98) at the start of the experiment were trained in a Pavlovian approach (PA) task and were subsequently tested for the effects of reward devaluation, extinction, and re-acquisition. We found significant interactions between age and sex: females had enhanced acquisition of PA and poorer extinction, relative to males, while adolescents and females were less sensitive to reward devaluation than male adults. These results suggest that females and adolescents exhibit reward behavior that is more stimulus-directed, rather than goal-directed. PMID- 23754713 TI - Validation of asthma and eczema in population-based Swedish drug and patient registers. AB - PURPOSE: Validated measures of asthma and eczema at the population level remain a challenge. Our aim was to ascertain if register-based information on asthma/eczema medication can function as a proxy for an asthma/eczema diagnosis and to validate register-based asthma diagnoses. METHODS: Information was requested on all 0-45-year-old individuals with reported asthma/eczema medication and/or diagnoses in the Swedish Prescribed Drug Register and National Patient Register, between July 2005 and December 2009 (N = 250 691). Medical records for 1952 randomly selected individuals were reviewed to estimate the proportion of individuals with the following: (1) asthma/eczema medication that fulfilled predefined criteria of asthma/eczema (positive predictive value (PPV)) and (2) a register-based asthma diagnosis verified as asthma by predefined criteria. RESULTS: Positive predictive value for asthma by predefined criteria ranged between 0.75 (95%CI: 0.70-0.78) to 0.94 (95%CI: 0.91-0.96), depending on age group. In pre-school children, PPV for asthma in combination with obstructive bronchitis was 0.87 (95%CI: 0.83-0.90), and PPV for eczema was estimated to 0.45 (95%CI: 0.38-0.51). Eighty percent of children 0-4.5 years and 99% of children >4.5-17 years with a register-based diagnosis of asthma were verified as asthmatics. CONCLUSION: Asthma medication is a suitable proxy for asthma in older children and adults; the same approach is insufficient for eczema. This validation study of two Swedish registers opens for future large nation-wide register-based studies on asthma. PMID- 23754714 TI - Conceptualizing functional traits and ecological characteristics of methane oxidizing bacteria as life strategies. AB - Methane-oxidizing bacteria (MOB) possess the ability to use methane for energy generation and growth, thereby, providing a key ecosystem service that is highly relevant to the regulation of the global climate. MOB subgroups have different responses to key environmental controls, reflecting on their functional traits. Their unique features (C1-metabolism, unique lipids and congruence between the 16S rRNA and pmoA gene phylogeny) have facilitated numerous environmental studies, which in combination with the availability of cultured representatives, yield the most comprehensive ecological picture of any known microbial functional guild. Here, we focus on the broad MOB subgroups (type I and type II MOB), and aim to conceptualize MOB functional traits and observational characteristics derived primarily from these environmental studies to be interpreted as microbial life strategies. We focus on the functional traits, and the conditions under which these traits will render different MOB subgroups a selective advantage. We hypothesize that type I and type II MOB generally have distinct life strategies, enabling them to predominate under different conditions and maintain functionality. The ecological characteristics implicated in their adopted life strategies are discussed, and incorporated into the Competitor-Stress tolerator Ruderal functional classification framework as put forward for plant communities. In this context, type I MOB can broadly be classified as competitor-ruderal while type II MOB fit more within the stress tolerator categories. Finally, we provide an outlook on MOB applications by exemplifying two approaches where their inferred life strategies could be exploited thereby, putting MOB into the context of microbial resource management. PMID- 23754715 TI - A quest for indigenous truffle helper prokaryotes. AB - Tuber aestivum is the most common European truffle with significant commercial exploitation. Its production originates from natural habitats and from artificially inoculated host tree plantations. Formation of Tuber ectomycorrhizae in host seedling roots is often inefficient. One possible reason is the lack of indigenous associative microbes. Here we aimed at metagenetic characterization and cultivation of indigenous prokaryotes associated with T. aestivum in a field transect cutting through the fungus colony margin. Several operational taxonomic units (OTUs) showed close association with the T. aestivum in the ectomycorrhizae and in the soil, but there was no overlap between the associative prokaryotes in the two different habitats. Among those positively associated with the ectomycorrhizae, we identified several bacterial genera belonging to Pseudonocardineae. Extensive isolation efforts yielded many cultures of ectomycorrhizae-associative bacteria belonging to Rhizobiales and Streptomycineae, but none belonging to the Pseudonocardineae. The specific unculturable Tuber-associated prokaryotes are likely to play important roles in the biology of these ectomycorrhizal fungi, including modulation of competition with other symbiotic and saprotrophic microbes, facilitation of root penetration and/or accessing mineral nutrients in the soil. However, the ultimate proof of this hypothesis will require isolation of the microbes for metabolic studies, using novel cultivation approaches. PMID- 23754716 TI - LbNrt RNA silencing in the mycorrhizal symbiont Laccaria bicolor reveals a nitrate-independent regulatory role for a eukaryotic NRT2-type nitrate transporter. AB - Fungal nitrogen metabolism plays a fundamental role in function of mycorrhizal symbiosis and consequently in nutrient cycling of terrestrial ecosystems. Despite its global ecological relevance the information on control and molecular regulation of nitrogen utilization in mycorrhizal fungi is very limited. We have extended the nitrate utilization RNA silencing studies of the model mycorrhizal basidiomycete, Laccaria bicolor, by altering the expression of LbNrt, the sole nitrate transporter-encoding gene of the fungus. Here we report the first nutrient transporter mutants for mycorrhizal fungi. Silencing of LbNrt results in fungal strains with minimal detectable LbNrt transcript levels, significantly reduced growth capacity on nitrate and altered symbiotic interaction with poplar. Transporter silencing also creates marked co-downregulation of whole Laccaria fHANT-AC (fungal high-affinity nitrate assimilation cluster). Most importantly, this effect on the nitrate utilization pathway appears independent of extracellular nitrate or nitrogen status of the fungus. Our results indicate a novel and central nitrate uptake-independent regulatory role for a eukaryotic nitrate transporter. The possible cellular mechanisms behind this regulation mode are discussed in the light of current knowledge on NRT2-type nitrate transporters in different eukaryotes. PMID- 23754717 TI - Epiphytic cyanobacteria of the seagrass Cymodocea rotundata: diversity, diel nifH expression and nitrogenase activity. AB - Seagrasses are photoautotrophic, ecologically important components of many globally widespread coastal ecosystems, in which combined nitrogen may limit their production. We examined the biodiversity and diazotrophic capacity of microbial epiphytes associated with the phyllosphere of the seagrass Cymodocea rotundata of the Western Indian Ocean. Light microscopy, 16S rRNA and nifH gene analysis revealed the dominance of cyanobacteria in the epiphytic microbial community. Most phylotypes were related to free-living uncultured benthic cyanobacteria, while some to cyanobacterial endosymbionts of marine diatoms. Novel and potentially diazotrophic species, some of known pantropical distribution, were also discovered. Significant diel nitrogenase activities (acetylene reduction assay) were recorded (up to 358 +/- 232 nmol C2H4 g(-1) of seagrass FW h(-1)). The nifH gene expression patterns showed that heterocystous phylotypes may be the dominant diazotrophs during the day and non-heterocystous at night. These data show that C. rotundata is colonized by diverse diazotrophic cyanobacteria species and suggest that these may be beneficial partners of seagrasses in nitrogen-depleted waters. PMID- 23754718 TI - Characterization of the SPI-1 and Rsp type three secretion systems in Pseudomonas fluorescens F113. AB - Pseudomonas fluorescens F113 is a plant growth-promoting rhizobacterium (PGPR) isolated from the sugar beet rhizosphere. The recent annotation of the F113 genome sequence has revealed that this strain encodes a wide array of secretion systems, including two complete type three secretion systems (T3SSs) belonging to the Hrp1 and SPI-1 families. While Hrp1 T3SSs are frequently encoded in other P. fluorescens strains, the presence of a SPI-1 T3SS in a plant-beneficial bacterial strain was unexpected. In this work, the genetic organization and expression of these two T3SS loci have been analysed by a combination of transcriptional reporter fusions and transcriptome analyses. Overexpression of two transcriptional activators has shown a number of genes encoding putative T3 effectors. In addition, the influence of these two T3SSs during the interaction of P. fluorescens F113 with some bacterial predators was also assessed. Our data revealed that the transcriptional activator hilA is induced by amoeba and that the SPI-1 T3SS could potentially be involved in resistance to amoeboid grazing. PMID- 23754719 TI - Single-cell versus population-level reproductive success of bacterial immigrants to pre-colonized leaf surfaces. AB - We assessed how preemptive inoculation of plant leaves with bacteria affected the establishment of secondary colonizers. We quantified the latter in two ways: (i) at the population level, i.e. as counts of colony-forming units and (ii) at the level of single cells by tracking the reproductive success of individual bacteria. Both analyses showed that the ability of secondary immigrants to establish on the leaf was negatively correlated with the level of pre-population by primary colonizers. This effect was best described by an inverse dose-response curve with an apparent half-point inhibition efficacy of approximately 10(6) cells of primary colonizers per gram leaf. This efficacy was the same whether calculated from population- or average single-cell data. However, single-cell data revealed that even under conditions of heavy pre-population with primary colonizers, a small fraction of secondary immigrants still produced offspring, although the corresponding population measurement showed no increase in total population size. This observation has direct relevance for biocontrol strategies that are based on the principle of preemptive exclusion of foliar bacterial pathogens: even at seemingly saturating levels of primary inoculum, some secondary colonizers may still be able to reproduce and possibly reach a quorum to trigger behaviours that enhance survival or virulence. PMID- 23754720 TI - Genomic analysis of the biocontrol strain Pseudomonas fluorescens Pf29Arp with evidence of T3SS and T6SS gene expression on plant roots. AB - Several bacterial strains of the Pseudomonas genus provide plant growth stimulation, plant protection against pests or bioremediation. Among these bacteria, P. fluorescens Pf29Arp reduces the severity of take-all, a disease caused by the pathogenic fungus Gaeumannomyces graminis var. tritici (Ggt) on wheat roots. In this study, we obtained a draft genome of Pf29Arp and subsequent comparative genomic analyses have revealed that this bacterial strain is closely related to strains of the 'P. brassicacearum-like' subgroup including P. brassicacearum ssp. brassicacearum NFM421 and P. fluorescens F113. Despite an overall chromosomal organization similar to these strains, a number of features including antibiotic synthesis gene clusters from secondary metabolism are not found in the Pf29Arp genome. But Pf29Arp possesses different protein secretion systems including type III (T3SS) and type VI (T6SS) secretion systems. Pf29Arp is the first Pseudomonas sp. strain described with four T6SS clusters (cluster I, II, III and IV). In addition, some protein-coding genes involved in the assembly of these secretion systems are basally expressed during Pf29Arp colonization of healthy wheat roots and display different expression patterns on necrotized roots caused by Ggt. These data suggest a role of T3SS and T6SS in the Pf29Arp adaptation to different root environments. PMID- 23754721 TI - Soil phosphorus depletion and shifts in plant communities change bacterial community structure in a long-term grassland management trial. AB - Agricultural systems rely on healthy soils and their sustainability requires understanding the long-term impacts of agricultural practices on soils, including microbial communities. We examined the impact of 17 years of land management on soil bacterial communities in a New Zealand randomized-block pasture trial. Significant variation in bacterial community structure related to mowing and plant biomass removal, while nitrogen fertilizer had no effect. Changes in soil chemistry and legume abundance described 52% of the observed variation in the bacterial community structure. Legumes (Trifolium species) were absent in unmanaged plots but increased in abundance with management intensity; 11% of the variation in soil bacterial community structure was attributed to this shift in the plant community. Olsen P explained 10% of the observed heterogeneity, which is likely due to persistent biomass removal resulting in P limitation; Olsen P was significantly lower in plots with biomass removed (14 mg kg(-1) +/- 1.3SE) compared with plots that were not mown, or where biomass was left after mowing (32 mg kg(-1) +/- 1.6SE). Our results suggest that removal of plant biomass and associated phosphorus, as well as shifts in the plant community, have greater long-term impacts on soil bacterial community structure than application of nitrogen fertilizers. PMID- 23754722 TI - Abundance and distribution of diverse membrane-bound monooxygenase (Cu-MMO) genes within the Costa Rica oxygen minimum zone. AB - Diverse copper-containing membrane-bound monooxygenase-encoding sequences (Cu MMOs) have recently been described from the marine environment, suggesting widespread potential for oxidation of reduced substrates. Here, we used the well defined oxygen and methane gradients associated with the Costa Rican oxygen minimum zone (OMZ) to gain insight into the physico-chemical parameters influencing the distribution and abundance of Cu-MMO-encoding marine microorganisms. Two Methylococcales-related Cu-MMO-encoding lineages, termed groups OPU1 and OPU3, demonstrated differences in their relative abundance, with both pmoA and candidate 16S rRNA genes correlating significantly with reduced environmental oxygen concentrations and depth. In contrast, a newly identified Cu MMO-encoding lineage, Group C, was primarily associated with the oxygenated euphotic zone. An updated phylogenetic analysis including these sequences, a marine pxmABC gene cluster, ethylene-utilizing Cu-MMO-encoding lineages and previously reported planktonic Cu-MMOs (Groups W, X, Z and O) demonstrates the breadth of diversity of Cu-MMO-encoding marine microorganisms. Groups C and X affiliated phylogenetically with ethane- and ethylene-oxidizing Cu-MMOs, Groups W and O affiliated phylogenetically with the recently described Cu-MMO 'pXMO', and Group Z clustered with Cu-MMOs recovered from soils. Collectively, these data demonstrate widespread genetic potential in ocean waters for the oxidation of small, reduced molecules and advance our understanding of the microorganisms involved in methane cycling in the OMZ environment. PMID- 23754723 TI - Identification of biomass utilizing bacteria in a carbon-depleted glacier forefield soil by the use of 13C DNA stable isotope probing. AB - As Alpine glaciers are retreating rapidly, bare soils with low organic C and N contents are becoming exposed. Carbon availability is a key factor regulating microbial diversity and ecosystem functioning in these soils. The aim of this study was to investigate how bacterial activity, community structure and composition are influenced by organic carbon availability. Bare soils were supplied with (13)C-labelled fungal (Penicillium sp.) and green algal (Chlorella sp.) biomass and the CO2 evolution and its delta(13)C signature were monitored up to 60 days. These organisms have previously been isolated near the glacier terminus. DNA stable isotope probing followed by T-RFLP profiling and sequencing of 16S rRNA genes was employed to identify consumers able to assimilate carbon from these biomass amendments. Higher respiration and higher bacterial activity indicated a more efficient utilization of algal cells than fungal cells. Flavobacterium sp. predominantly incorporated fungal-derived C, whereas the algal derived C was mainly incorporated by Acidobacteria and Proteobacteria. This study emphasizes the important role of both fungal and algal biomass in increasing the carbon pool in recently deglaciated bare soils, as only 20% of the added C was respired as CO2, and the rest, we presume, remained in the soil. PMID- 23754724 TI - A cadherin-like protein influences Bacillus thuringiensis Cry1Ab toxicity in the oriental armyworm, Mythimna separata. AB - Cadherins comprise a family of calcium-dependent cell adhesion proteins that act in cell-cell interactions. Cadherin-like proteins (CADs) in midguts of some insects act as receptors that bind some of the toxins produced by the Bacillus thuringiensis (Bt). We cloned a CAD gene associated with larval midguts prepared from Mythimna separata. The full-length cDNA (MsCAD1, GenBank Accession No. JF951432) is 5642 bp, with an open reading frame encoding a 1757 amino acid and characteristics typical of insect CADs. Expression of MsCAD1 is predominantly in midgut tissue, with highest expression in the 3rd- to 6th-instars and lowest in newly hatched larvae. Knocking-down MsCAD1 decreased Cry1Ab susceptibility, indicated by reduced developmental time, increased larval weight and reduced larval mortality. We expressed MsCAD1 in E. coli and recovered the recombinant protein, rMsCAD1, which binds Cry1Ab toxin. Truncation analysis and binding experiments revealed that a contiguous 209-aa, located in CR11 and CR12, is the minimal Cry1Ab binding region. These results demonstrate that MsCAD1 is associated with Cry1Ab toxicity and is one of the Cry1Ab receptors in this insect. The significance of this work lies in identifying MsCAD1 as a Cry1Ab receptor, which helps understand the mechanism of Cry1Ab toxicity and of potential resistance to Bt in M. separata. PMID- 23754725 TI - The transition from freshwater to marine iron-oxidizing bacterial lineages along a salinity gradient on the Sheepscot River, Maine, USA. AB - Oxygen-dependent, neutrophilic iron-oxidizing bacteria (FeOB) are important drivers of iron transformations in marine and freshwater environments. Despite remarkable similarities in physiology and morphotype, known freshwater and marine FeOB are clustered in different classes of Proteobacteria; freshwater FeOB in the Betaproteobacteria and marine FeOB in the Zetaproteobacteria. To determine effects of salinity on these microbes, we examined the mineral biosignatures and molecular ecology of bacteria in FeOB mats collected along an estuarine salinity gradient. Light microscopy and scanning electron microscopy analyses showed the presence of iron oxide stalk and sheath structures in both freshwater and saline iron mats. Results of tagged pyrosequencing, quantitative PCR and fluorescent in situ hybridization, all based on the small subunit rRNA gene, confirmed Zetaproteobacteria were not present in freshwater mats, but were in saline mats at salinities down to 50/00. Among the Betaproteobacteria, Leptothrix spp. were only found in the freshwater mat. Gallionella spp. were limited to freshwater and low salinity mats (< 50/00). Sideroxydans sp. were salt tolerant; however, their relative abundance decreased with increasing salinity. These results suggest salinity is important in shaping the population biology of iron mat communities, and some coexistence between marine and freshwater populations occurs in brackish waters. PMID- 23754726 TI - Habitat species pools for phylogenetic structure in microbes. AB - The processes underlying the phylogenetic structure of the biotic communities are typically scale-dependent and thus often poorly resolved. Illustrated by the study of macroorganisms, it is suggested that the relative influence of ecological processes on the phylogenetic structure of the communities can be inferred by the geographical definition of the species pools. However, given the high dispersal ability of microbes, the spatial delineation of the species pool may not be that practical for microbial taxa. This idea is supported by the observational data on bacteria along an elevational gradient. Significant negative values of standardized effect size of the mean nearest taxon distance were consistently observed for different sized species pools considered. Reviewing the reports on microbial phylogenetic structure so far, we suggested that the 'habitat species pools' are perhaps more important for microbes than spatial delineated 'regional species pools'. PMID- 23754727 TI - Growth temperatures of archaeal communities can be estimated from the guanine plus-cytosine contents of 16S rRNA gene fragments. AB - Prokaryote growth temperatures in environmental samples are difficult to measure because it is hard to culture viable prokaryotes in natural environments. We comprehensively surveyed growth temperatures and 16S rRNA sequences of prokaryotes to estimate their growth temperatures based on guanine-plus-cytosine contents (P(GC)) of their 16S rRNA sequences. We focused on archaea because of the wide range of growth temperatures within this group. Their minimum (Tmin), optimum (Topt) and maximum (Tmax) growth temperatures correlated strongly with PGC of their 16S rRNA genes. Linear regression equations were established to approximate Tmin, Topt and Tmax from P(GC). We also established a linear regression equation for calculating P(GC) of 16S rRNA genes based on the melting temperatures (Tm) of PCR fragments, without using a clone library or sequencing. Environmental samples were obtained from a wide variety of microbial natural habitats. Tm of archaeal 16S rRNA genes amplified by real-time PCR were determined by melting curve analysis. Based on those values, P(GC) of 16S rRNA genes and mean Tmin, Topt and Tmax were calculated using the linear regression equations. These temperatures correlated strongly with the in situ temperatures. Tmax agreed particularly well with these temperatures, suggesting many archaea live at their maximum growth temperatures. PMID- 23754728 TI - Bacterial, archaeal and viral-like rhodopsins from the Red Sea. AB - The Gulf of Aqaba, extending north to the Red Sea, is an oligotrophic basin with typical open ocean gyre characteristics. Here we report on the existence of diverse microbial rhodopsins in the Gulf of Aqaba, based on 454-pyrosequencing generated metagenome and metatranscriptome data sets, obtained from the microbial fraction smaller than 1.6 MUm. Bacterial SAR11, SAR86 and archaeal proteorhodopsins as well as viral-like rhodopsins were detected on the DNA level. On the RNA level, only SAR11 and SAR86 proteorhodopsin transcripts were detected. Our results add to the growing evidence that microbial rhodopsins are a diverse, abundant and widespread protein family. PMID- 23754729 TI - Enrichment of an anammox bacterial community from a flooded paddy soil. AB - This study describes the enrichment of anammox bacteria in a column simulating oxygen limited flooded paddy soils, which are important man-made ecosystems that receive substantial amounts of fixed nitrogen. The upper 50 cm of the paddy soil, containing a high amount of ammonium [1.6-10.4 mmol N kg (dry weight)(-1)], was selected as the inoculum for anammox enrichment. After 18 months of incubation with freshwater from the paddy soil ecosystem, the enrichment culture consumed approximately 4 mmol ammonium l(-1) day(-1) and 5 mmol nitrite l(-1) day(-1). The maximum specific anammox activity of the culture was 35.7 MUmol N g (dry weight)( 1) h(-1). Fluorescence in situ hybridization indicated that anammox cells constituted 50% +/- 10% of the enrichment culture. The phylogenetic analyses of 16S rRNA and the diagnostic hydrazine synthase (hzsA) genes showed that two dominant anammox species were enriched from paddy soil. The enriched Candidatus Anammoxoglobus-like organisms showed a 16S rRNA gene similarity of 97.5-99.2% to Candidatus Anammoxoglobus propionicus and the Candidatus Jettenia-like organisms showed 92.1-93.1% 16S rRNA gene identity to Candidatus Jettenia asiatica. Real time quantitative PCR of hzsA gene suggested that up to 10(10) copies g (dry weight)(-1) of soil anammox bacteria were present in the enrichment culture. PMID- 23754731 TI - A case report: radiological findings in an unusual case of calciphylaxis 16 years after renal transplantation. AB - Calciphylaxis is a serious and potentially life-threatening disorder characterized by medial calcification of arterioles leading to subcutaneous ischemia and skin necrosis. It is most commonly seen in patients with end-stage renal disease or shortly after renal transplantation. We report an unusual case of calciphylaxis occurring 16 years after renal transplantation in a 48-year-old female with a failing graft, along with histological and striking radiological findings. PMID- 23754732 TI - Perineural spread of cervical cancer to the sciatic nerve. AB - In this report we present a patient with a recent diagnosis of cervical adenocarcinoma with progressive left lower extremity pain and weakness. MR imaging of the pelvis and subsequent FDG CT/PET were complementary in demonstrating abnormalities worrisome for perineural spread of malignancy, which was confirmed with an open fascicular biopsy of the sciatic nerve. We review the imaging and propose a mechanism of perineural spread to the sciatic nerve, which we believe is supported by the imaging in this case. PMID- 23754733 TI - SPECT/CT in patients with painful knee arthroplasty-what is the evidence? AB - SPECT/CT is increasingly recognized as a promising imaging modality for the investigation of patients with a painful knee after knee arthroplasty. In this review article, we give an overview of the clinical value and current and future applications of SPECT/CT for patients with knee pain following joint arthroplasty. A detailed evidence-based literature review is performed and presented. PMID- 23754734 TI - The temporal characterization of marrow lipids and adipocytes in a rabbit model of glucocorticoid-induced osteoporosis. AB - OBJECTIVE: To characterize the temporal changes in marrow lipids content and adipocytes in the development of glucocorticoid-induced osteoporosis (GIOP) in rabbits using MR spectroscopy. SUBJECTS AND METHODS: Twenty 20-week-old female rabbits were randomized to a control group and a GIOP group equally. Marrow lipids fraction and bone mineral density at the left proximal femur and L3-L4 vertebrae were measured by MR spectroscopy and dual-energy X-ray absorptiometry at week 0, 4, 8, and 12. Marrow adipocytes were quantitatively evaluated by histopathology. RESULTS: Marrow adiposity in the GIOP group showed a significant increase over time, with a variation of marrow lipids fraction (+35.9 %) at week 4 from baseline and it was maintained until week 12 (+75.2 %, p < 0.001 for all). The GIOP group demonstrated continuous deterioration of bone with significant difference between the two groups at week 8, followed by increased marrow fat with significant difference at week 4 (p < 0.05 for all). In comparison with the controls, marrow adipocyte density in the GIOP group increased by 57.1 % at week 8 and 35.4 % at week 12, respectively. A reduction (-13.3 %) in adipocyte mean diameter at week 8 (but an increase (+22.7 %) at week 12) were observed in the GIOP group compared with the control group (p < 0.05 for all). There was significant difference between two periods (p = 0.023) in adipocyte mean diameter in the GIOP group. The percentage area of marrow adipocytes in the GIOP group was 62.8 +/- 8.7 % at week 8 and 79.2 +/- 7.7 % at week 12, both of which were significantly higher than those of the controls (p < 0.05 for all). CONCLUSIONS: Marrow adipogenesis is synchronized with bone loss in the development of GIOP, which was characterized by a significant increase in the number of small-sized marrow adipocytes in the relatively early stage and concomitant volume increase later on. MR spectroscopy appears to be the most powerful tool for detecting the sequential changes in marrow lipid content. PMID- 23754735 TI - Population pharmacokinetics of JNJ-37822681, a selective fast-dissociating dopamine D2-receptor antagonist, in healthy subjects and subjects with schizophrenia and dose selection based on simulated D2-receptor occupancy. AB - BACKGROUND AND OBJECTIVES: JNJ-37822681 is a selective, fast-dissociating dopamine D2-receptor antagonist currently in development as a candidate antipsychotic. The aim of the analyses was to develop a population pharmacokinetic model to describe the pharmacokinetics of JNJ-37822681 in healthy subjects and patients with schizophrenia and to identify covariates of interest. The model was then used to simulate D2-receptor occupancy in support of dose selection for subsequent studies. METHODS: Data were obtained from 378 subjects enrolled in three phase I and two phase II studies. Nonlinear mixed effects modeling of pooled data was conducted using NONMEM((r)) to estimate population pharmacokinetic parameters and the effect of covariates on these parameters. The model was evaluated on a subset of data that was not used for model building and was subsequently used to simulate steady-state exposure for each subject in the phase IIb study. Striatal D2-receptor occupancy was predicted using simulated exposure combined with pharmacodynamic parameters from a sigmoid maximum effect model established from previous [(11)C]raclopride positron emission tomography studies. RESULTS: A two-compartment disposition model with zero-order input in a depot compartment followed by first-order absorption into and first-order elimination from the central compartment combined with a transit compartment provided the best fit to the data. Significant covariates were sex and bioavailability on apparent clearance and food intake on the absorption rate constant. Clearance was 11 % higher in females compared with males. The model passed external evaluation. The estimated pharmacokinetic parameters for the phase IIb study were similar to those observed in the phase IIa study. D2 receptor occupancy was predicted to be in the 65-80 % range at 10 mg twice daily and partially or fully reaching the 80 % threshold at doses of 20 and 30 mg twice daily. CONCLUSION: The population pharmacokinetic model of JNJ-37822681 successfully described the pharmacokinetics of JNJ-37822681 and allowed the reliable determination of individual exposure parameters in a phase IIb study. It was concluded that 5 or 7.5 mg twice daily would likely be minimal- or no-effect doses, whereas 10 mg twice daily was expected to provide an optimal balance of efficacy and tolerability. PMID- 23754737 TI - Selective alpha-metalation of THF by a cationic zirconium complex supported by an (NNNN)-type macrocyclic ligand. PMID- 23754738 TI - Stereoelectronic effect of curved aromatic structures: favoring the unexpected endo conformation of benzylic-substituted sumanene. PMID- 23754736 TI - Population pharmacokinetics of sifalimumab, an investigational anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus. AB - BACKGROUND AND OBJECTIVES: Sifalimumab is a fully human immunoglobulin G1kappa monoclonal antibody that binds to and neutralizes a majority of the subtypes of human interferon-alpha. Sifalimumab is being evaluated as a treatment for systemic lupus erythematosus (SLE). The primary objectives of this analysis were (a) to develop a population pharmacokinetic model for sifalimumab in SLE; (b) to identify and quantitate the impact of patient/disease characteristics on pharmacokinetic variability; and (c) to evaluate fixed versus body weight (WT) based dosing regimens. METHODS: Sifalimumab serum concentration-time data were collected from a phase Ib study (MI-CP152) designed to evaluate the safety and tolerability of sifalimumab in adult patients with SLE. Sifalimumab was administered every 14 days as a 30- to 60-minute intravenous infusion with escalating doses of 0.3, 1.0, 3.0, and 10 mg/kg and serum concentrations were collected over 350 days. A total of 120 patients provided evaluable pharmacokinetic data with a total of 2,370 serum concentrations. Sifalimumab serum concentrations were determined using a validated colorimetric enzyme-linked immunosorbent assay (ELISA) with a lower limit of quantitation of 1.25 MUg/mL. Population pharmacokinetic modeling of sifalimumab was performed using a non linear mixed effects modeling approach with NONMEM VII software. Impact of patient demographics, clinical indices, and biomarkers on pharmacokinetic parameters were explored using a stepwise forward selection and backward elimination approach. The appropriateness of the final model was tested using visual predictive check (VPC). The impact of body WT-based and fixed dosing of sifalimumab was evaluated using a simulation approach. The final population model was utilized for phase IIb dosing projections. RESULTS: Sifalimumab pharmacokinetics were best described using a two-compartment linear model with first order elimination. Following intravenous dosing, the typical clearance (CL) and central volume of distribution (V 1) were estimated to be 176 mL/day and 2.9 L, respectively. The estimates (coefficient of variation) of between-subject variability for CL and V 1 were 28 and 31 %, respectively. Patient baseline body WT, interferon gene signature from 21 genes, steroid use, and sifalimumab dose were identified as significant covariates for CL, whereas only baseline body WT was a significant covariate for V 1 and peripheral volume of distribution (V 2). Although the above-mentioned covariates were statistically significant, they did not explain variability in pharmacokinetic parameters to any relevant extent (<7 %). Thus, no dosing adjustments are necessary. VPC confirmed good predictability of the final population pharmacokinetic model. Simulation results demonstrate that both fixed and body WT-based dosing regimens yield similar median steady state concentrations and overall variability. Fixed sifalimumab doses of 200, 600, and 1,200 mg monthly (with a loading dose at Day 14) were selected for a phase IIb clinical trial. CONCLUSION: A two-compartment population pharmacokinetic model adequately described sifalimumab pharmacokinetics. The estimated typical pharmacokinetic parameters were similar to other monoclonal antibodies without target mediated elimination. Although the population pharmacokinetic analysis identified some statistically significant covariates, they explained <7 % between-subject variability in pharmacokinetic parameters indicating that these covariates are not clinically relevant. The population pharmacokinetic analysis also demonstrated the feasibility of switching to fixed doses in phase IIb clinical trials of sifalimumab. PMID- 23754739 TI - Systemic polyarteritis nodosa in the young: a single-center experience over thirty-two years. AB - OBJECTIVE: Polyarteritis nodosa (PAN) is a rare disease of childhood. The aims of this study were to describe the clinical features, treatment, and outcome of systemic childhood PAN and to identify predictors of relapse. METHODS: A single center retrospective medical records review of children with PAN fulfilling the European League Against Rheumatism (EULAR)/Paediatric Rheumatology European Society (PRES)/Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria who were seen over a 32-year period was performed. Data on demographic and clinical features, treatments, relapses (recurrence of clinical signs/symptoms or occurrence of new symptoms after initial remission requiring escalation or resumption of immunosuppressive therapy), and deaths were recorded. A disease activity score was retrospectively assigned using the Paediatric Vasculitis Activity Score (PVAS) instrument. Cox regression analysis was used to identify significant predictors of relapse. RESULTS: Sixty-nine children with PAN were identified; 55% were male, and their median age was 8.5 years (range 0.9-15.8 years). Their clinical features at presentation were fever (87%), myalgia (83%), skin (88%), renal (19%), severe gastrointestinal (GI) (10%), and neurologic (10%) involvement. The PVAS at presentation was 9 of 63 (range 4-24). Histopathologic analysis of the skin showed necrotizing vasculitis in biopsy samples from 40 of 50 children. Results of selective visceral arteriography suggested the presence of PAN in 96% of patients. Treatment included cyclophosphamide and corticosteroids (83%), plasma exchange (9%), and biologic agents (after 2002; 13%). The relapse rate was 35%, and the mortality rate was 4%. Severe GI involvement was associated with increased risk of relapse (P = 0.031), while longer time to induce remission (P = 0.022) and increased cumulative dose of cyclophosphamide (P = 0.005) were associated with lower relapse risk. CONCLUSION: Childhood PAN is a severe inflammatory disease of insidious onset and variable clinical presentation. Relapses occurred more frequently in those with severe GI involvement. A higher cumulative dose of cyclophosphamide was associated with a lower risk of relapse. PMID- 23754740 TI - Tumor stroma and differentiated cancer cells can be originated directly from polyploid giant cancer cells induced by paclitaxel. AB - Paclitaxel is widely used to treat cancer patients through the blocking of mitosis and result in formation of polyploidy giant cancer cells (PGCCs), which are generally believed to be nondividing cells or in mitotic catastrophe. Here, we showed that PGCCs following the treatment of paclitaxel of MCF-7 breast cancer cell line have capability to generate regular-sized progeny cells through budding. The PGCCs not only grew into well-differentiated cancer cells that formed cancer organotypic structures in vitro but also trans-differentiated into multiple tumor stromal cells including myoepithelial, endothelial and erythroid cells. PGCCs formed glandular and vessel-like cancer organotypic structures that expressed normal stem cell markers. These progeny cells generated from PGCCs showed decreased ability of proliferation, invasion and tumor growth and became more resistant to paclitaxel than parental MCF-7 cells. These results demonstrated that paclitaxel-induced PGCCs have properties of cancer stem cells that can generate both epithelial cancer cells and multilineage of stromal cells. PGCCs are not only the morphogenic determinant to tumor histogenesis and but also contribute to paclitaxel resistance. PMID- 23754741 TI - Evaluation of single and dual siRNAs targeting rabies virus glycoprotein and nucleoprotein genes for inhibition of virus multiplication in vitro. AB - Small interfering RNAs (siRNAs) targeting rabies virus (RV) glycoprotein (G) and nucleoprotein (N) genes were evaluated as antiviral agents against rabies virus in vitro in BHK-21 cells. To select effective siRNAs targeting RV-G, a plasmid based transient co-transfection approach was used. In this, siRNAs were expressed as short hairpin RNAs (shRNAs), and their ability to inhibit RV-G gene expression was evaluated in cells transfected with a plasmid expressing RV-G. The nine different siRNAs designed to target RV-G exhibited varying degrees of knockdown of RV-G gene expression. One siRNA (si-G7) with considerable effect in knockdown of RV-G expression also demonstrated significant inhibition of RV multiplication in BHK-21 cells after in vitro challenge with the RV Pasteur virus-11 (PV-11) strain. A decrease in the number of fluorescent foci in siRNA-treated cells and a reduction (86.8 %) in the release of RV into infected cell culture supernatant indicated the anti-rabies potential of siRNA. Similarly, treatment with one siRNA targeting RV-N resulted in a decrease in the number of fluorescent foci and a reduction (85.9 %) in the release of RV. As a dual gene silencing approach where siRNAs targeting RV-G and RV-N genes were expressed from single construct, the anti-rabies-virus effect was observed as an 87.4 % reduction in the release of RV. These results demonstrate that siRNAs targeting RV-G and N, both in single and dual form, have potential as antiviral agent against rabies. PMID- 23754743 TI - Clinical and molecular epidemiology of norovirus infection in adults with acute gastroenteritis in Ji'nan, China. AB - Acute gastroenteritis caused by human noroviruses (NoVs) has become an important public health problem worldwide. This study was carried out to investigate the rates of NoV infections and the genetic characteristics of NoVs in adult outpatients with acute gastroenteritis in Ji'nan, a large eastern city in China. A total of 480 fecal samples were collected from outpatients at the Shandong University Qilu Hospital between June 2010 and May 2011. Of the collected samples, 42 (42/480, 8.75 %) were positive for NoVs by RT-PCR, and seven different genotypes were identified: GI-1, GI-4, GII-1, GII-3, GII-4, GII-6 and GII-13, of which GII-4 was the most prevalent (29/42, 69.0 %). Phylogenetic and Simplot analyses showed that three recombinant strains were detected: two GII-4 polymerase/GII-3 capsid recombinants and one GII-6 polymerase/GII-4 capsid recombinant. This study indicated that NoV was a common causative agent of sporadic acute gastroenteritis in adults in Ji'nan, China, and that NoV GII-4 was the predominant strain during this period. Three recombinant strains were identified in which GII-6 polymerase/GII-4 capsid was detected for the first time in China. PMID- 23754744 TI - ATM mediates pRB function to control DNMT1 protein stability and DNA methylation. AB - The retinoblastoma tumor suppressor gene (RB) product has been implicated in epigenetic control of gene expression owing to its ability to physically bind to many chromatin modifiers. However, the biological and clinical significance of this activity was not well elucidated. To address this, we performed genetic and epigenetic analyses in an Rb-deficient mouse thyroid C cell tumor model. Here we report that the genetic interaction of Rb and ATM regulates DNMT1 protein stability and hence controls the DNA methylation status in the promoters of at least the Ink4a, Shc2, FoxO6, and Noggin genes. Furthermore, we demonstrate that inactivation of pRB promotes Tip60 (acetyltransferase)-dependent ATM activation; allows activated ATM to physically bind to DNMT1, forming a complex with Tip60 and UHRF1 (E3 ligase); and consequently accelerates DNMT1 ubiquitination driven by Tip60-dependent acetylation. Our results indicate that inactivation of the pRB pathway in coordination with aberration in the DNA damage response deregulates DNMT1 stability, leading to an abnormal DNA methylation pattern and malignant progression. PMID- 23754745 TI - Molecular basis of the essential s phase function of the rad53 checkpoint kinase. AB - The essential yeast kinases Mec1 and Rad53, or human ATR and Chk1, are crucial for checkpoint responses to exogenous genotoxic agents, but why they are also required for DNA replication in unperturbed cells remains poorly understood. Here we report that even in the absence of DNA-damaging agents, the rad53-4AQ mutant, lacking the N-terminal Mec1 phosphorylation site cluster, is synthetic lethal with a deletion of the RAD9 DNA damage checkpoint adaptor. This phenotype is caused by an inability of rad53-4AQ to activate the downstream kinase Dun1, which then leads to reduced basal deoxynucleoside triphosphate (dNTP) levels, spontaneous replication fork stalling, and constitutive activation of and dependence on S phase DNA damage checkpoints. Surprisingly, the kinase-deficient rad53-K227A mutant does not share these phenotypes but is rendered inviable by additional phosphosite mutations that prevent its binding to Dun1. The results demonstrate that ultralow Rad53 catalytic activity is sufficient for normal replication of undamaged chromosomes as long as it is targeted toward activation of the effector kinase Dun1. Our findings indicate that the essential S phase function of Rad53 is comprised by the combination of its role in regulating basal dNTP levels and its compensatory kinase function if dNTP levels are perturbed. PMID- 23754746 TI - Epigenetic functions of smchd1 repress gene clusters on the inactive X chromosome and on autosomes. AB - The Smchd1 gene encodes a large protein with homology to the SMC family of proteins involved in chromosome condensation and cohesion. Previous studies have found that Smchd1 has an important role in CpG island (CGI) methylation on the inactive X chromosome (Xi) and in stable silencing of some Xi genes. In this study, using genome-wide expression analysis, we showed that Smchd1 is required for the silencing of around 10% of the genes on Xi, apparently independent of CGI hypomethylation, and, moreover, that these genes nonrandomly occur in clusters. Additionally, we found that Smchd1 is required for CpG island methylation and silencing at a cluster of four imprinted genes in the Prader-Willi syndrome (PWS) locus on chromosome 7 and genes from the protocadherin-alpha and -beta clusters. All of the affected autosomal loci display developmentally regulated brain specific methylation patterns which are lost in Smchd1 homozygous mutants. We discuss the implications of these findings for understanding the function of Smchd1 in epigenetic regulation of gene expression. PMID- 23754747 TI - Program specificity for Ptf1a in pancreas versus neural tube development correlates with distinct collaborating cofactors and chromatin accessibility. AB - The lineage-specific basic helix-loop-helix transcription factor Ptf1a is a critical driver for development of both the pancreas and nervous system. How one transcription factor controls diverse programs of gene expression is a fundamental question in developmental biology. To uncover molecular strategies for the program-specific functions of Ptf1a, we identified bound genomic regions in vivo during development of both tissues. Most regions bound by Ptf1a are specific to each tissue, lie near genes needed for proper formation of each tissue, and coincide with regions of open chromatin. The specificity of Ptf1a binding is encoded in the DNA surrounding the Ptf1a-bound sites, because these regions are sufficient to direct tissue-restricted reporter expression in transgenic mice. Fox and Sox factors were identified as potential lineage specific modifiers of Ptf1a binding, since binding motifs for these factors are enriched in Ptf1a-bound regions in pancreas and neural tube, respectively. Of the Fox factors expressed during pancreatic development, Foxa2 plays a major role. Indeed, Ptf1a and Foxa2 colocalize in embryonic pancreatic chromatin and can act synergistically in cell transfection assays. Together, these findings indicate that lineage-specific chromatin landscapes likely constrain the DNA binding of Ptf1a, and they identify Fox and Sox gene families as part of this process. PMID- 23754748 TI - Splicing functions and global dependency on fission yeast slu7 reveal diversity in spliceosome assembly. AB - The multiple short introns in Schizosaccharomyces pombe genes with degenerate cis sequences and atypically positioned polypyrimidine tracts make an interesting model to investigate canonical and alternative roles for conserved splicing factors. Here we report functions and interactions of the S. pombe slu7(+) (spslu7(+)) gene product, known from Saccharomyces cerevisiae and human in vitro reactions to assemble into spliceosomes after the first catalytic reaction and to dictate 3' splice site choice during the second reaction. By using a missense mutant of this essential S. pombe factor, we detected a range of global splicing derangements that were validated in assays for the splicing status of diverse candidate introns. We ascribe widespread, intron-specific SpSlu7 functions and have deduced several features, including the branch nucleotide-to-3' splice site distance, intron length, and the impact of its A/U content at the 5' end on the intron's dependence on SpSlu7. The data imply dynamic substrate-splicing factor relationships in multiintron transcripts. Interestingly, the unexpected early splicing arrest in spslu7-2 revealed a role before catalysis. We detected a salt stable association with U5 snRNP and observed genetic interactions with spprp1(+), a homolog of human U5-102k factor. These observations together point to an altered recruitment and dependence on SpSlu7, suggesting its role in facilitating transitions that promote catalysis, and highlight the diversity in spliceosome assembly. PMID- 23754749 TI - Transactivation of Atg4b by C/EBPbeta promotes autophagy to facilitate adipogenesis. AB - Autophagy is a highly conserved self-digestion pathway involved in various physiological and pathophysiological processes. Recent studies have implicated a pivotal role of autophagy in adipocyte differentiation, but the molecular mechanism for its role and how it is regulated during this process are not clear. Here, we show that CCAAT /enhancer-binding protein beta (C/EBPbeta), an important adipogenic factor, is required for the activation of autophagy during 3T3-L1 adipocyte differentiation. An autophagy-related gene, Atg4b, is identified as a de novo target gene of C/EBPbeta and is shown to play an important role in 3T3-L1 adipocyte differentiation. Furthermore, autophagy is required for the degradation of Klf2 and Klf3, two negative regulators of adipocyte differentiation, which is mediated by the adaptor protein p62/SQSTM1. Importantly, the regulation of autophagy by C/EBPbeta and the role of autophagy in Klf2/3 degradation and in adipogenesis are further confirmed in mouse models. Our data describe a novel function of C/EBPbeta in regulating autophagy and reveal the mechanism of autophagy during adipocyte differentiation. These new insights into the molecular mechanism of adipose tissue development provide a functional pathway with therapeutic potential against obesity and its related metabolic disorders. PMID- 23754750 TI - Caspase activity is required for engulfment of apoptotic cells. AB - Clearance of apoptotic cells by phagocytic neighbors is crucial for normal development of multicellular organisms. However, how phagocytes discriminate between healthy and dying cells remains poorly understood. We focus on glial phagocytosis of apoptotic neurons during development of the Drosophila central nervous system. We identified phosphatidylserine (PS) as a ligand on apoptotic cells for the phagocytic receptor Six Microns Under (SIMU) and report that PS alone is not sufficient for engulfment. Our data reveal that, additionally to PS exposure, caspase activity is required for clearance of apoptotic cells by phagocytes. Here we demonstrate that SIMU recognizes and binds PS on apoptotic cells through its N-terminal EMILIN (EMI), Nimrod 1 (NIM1), and NIM2 repeats, whereas the C-terminal NIM3 and NIM4 repeats control SIMU affinity to PS. Based on the structure-function analysis of SIMU, we discovered a novel mechanism of internal inhibition responsible for differential affinities of SIMU to its ligand which might prevent elimination of living cells exposing PS on their surfaces. PMID- 23754751 TI - Dual phosphorylation of Btk by Akt/protein kinase b provides docking for 14-3 3zeta, regulates shuttling, and attenuates both tonic and induced signaling in B cells. AB - Bruton's tyrosine kinase (Btk) is crucial for B-lymphocyte activation and development. Mutations in the Btk gene cause X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Using tandem mass spectrometry, 14-3-3zeta was identified as a new binding partner and negative regulator of Btk in both B-cell lines and primary B lymphocytes. The activated serine/threonine kinase Akt/protein kinase B (PKB) phosphorylated Btk on two sites prior to 14-3-3zeta binding. The interaction sites were mapped to phosphoserine pS51 in the pleckstrin homology domain and phosphothreonine pT495 in the kinase domain. The double-alanine, S51A/T495A, replacement mutant failed to bind 14-3-3zeta, while phosphomimetic aspartate substitutions, S51D/T495D, caused enhanced interaction. The phosphatidylinositol 3-kinase (PI3-kinase) inhibitor LY294002 abrogated S51/T495 phosphorylation and binding. A newly characterized 14-3-3 inhibitor, BV02, reduced binding, as did the Btk inhibitor PCI-32765 (ibrutinib). Interestingly, in the presence of BV02, phosphorylation of Btk, phospholipase Cgamma2, and NF-kappaB increased strongly, suggesting that 14 3-3 also regulates B-cell receptor (BCR)-mediated tonic signaling. Furthermore, downregulation of 14-3-3zeta elevated nuclear translocation of Btk. The loss-of function mutant S51A/T495A showed reduced tyrosine phosphorylation and ubiquitination. Conversely, the gain-of-function mutant S51D/T495D exhibited intense tyrosine phosphorylation, associated with Btk ubiquitination and degradation, likely contributing to the termination of BCR signaling. Collectively, this suggests that Btk could become an important new candidate for the general study of 14-3-3-mediated regulation. PMID- 23754752 TI - MAVS regulates apoptotic cell death by decreasing K48-linked ubiquitination of voltage-dependent anion channel 1. AB - The mitochondrial antiviral signaling protein MAVS (IPS-1, VISA, or Cardif) plays an important role in the host defense against viral infection by inducing type I interferon. Recent reports have shown that MAVS is also critical for virus induced apoptosis. However, the mechanism of MAVS-mediated apoptosis induction remains unclear. Here, we show that MAVS binds to voltage-dependent anion channel 1 (VDAC1) and induces apoptosis by caspase-3 activation, which is independent of its role in innate immunity. MAVS modulates VDAC1 protein stability by decreasing its degradative K48-linked ubiquitination. In addition, MAVS knockout mouse embryonic fibroblasts (MEFs) display reduced VDAC1 expression with a consequent reduction of the vesicular stomatitis virus (VSV)-induced apoptosis response. Notably, the upregulation of VDAC1 triggered by VSV infection is completely abolished in MAVS knockout MEFs. We thus identify VDAC1 as a target of MAVS and describe a novel mechanism of MAVS control of virus-induced apoptotic cell death. PMID- 23754754 TI - A case report of intraoperative retroorbital fluid dissection after frontal mini trephine placement. AB - OBJECTIVES/HYPOTHESIS: We report a case of a 24-year-old male with a history of allergic fungal sinusitis, who experienced an intraoperative retro-orbital fluid dissection after frontal mini-trephine placement. Although mini-trephination of the frontal sinus is a useful technique that is frequently employed during endoscopic sinus surgery, it has potential complications. The purpose of this report is to discuss a previously unreported complication of frontal mini trephination and its management. PMID- 23754753 TI - A network of transcription factors operates during early tooth morphogenesis. AB - Improving the knowledge of disease-causing genes is a unique challenge in human health. Although it is known that genes causing similar diseases tend to lie close to one another in a network of protein-protein or functional interactions, the identification of these protein-protein networks is difficult to unravel. Here, we show that Msx1, Snail, Lhx6, Lhx8, Sp3, and Lef1 interact in vitro and in vivo, revealing the existence of a novel context-specific protein network. These proteins are all expressed in the neural crest-derived dental mesenchyme and cause tooth agenesis disorder when mutated in mouse and/or human. We also identified an in vivo direct target for Msx1 function, the cyclin D-dependent kinase (CDK) inhibitor p19(ink4d), whose transcription is differentially modulated by the protein network. Considering the important role of p19(ink4d) as a cell cycle regulator, these results provide evidence for the first time of the unique plasticity of the Msx1-dependent network of proteins in conferring differential transcriptional output and in controlling the cell cycle through the regulation of a cyclin D-dependent kinase inhibitor. Collectively, these data reveal a novel protein network operating in the neural crest-derived dental mesenchyme that is relevant for many other areas of developmental and evolutionary biology. PMID- 23754755 TI - Physical activity and other lifestyle factors in relation to the prevalence of colorectal adenoma: a colonoscopy-based study in asymptomatic Koreans. AB - PURPOSE: To evaluate physical activity and other lifestyle risk factors in relation to the prevalence of colorectal adenomas in asymptomatic Koreans. METHODS: A total of 1,526 asymptomatic subjects who underwent a colonoscopy were enrolled. Lifestyle factors such as physical activity and smoking data were obtained using a questionnaire. The subjects were grouped into three exposure levels by tertiles of metabolic equivalent hours per week. We evaluated the risk factors in subjects with adenomas by risk stratification (low-risk adenoma group vs. high-risk adenoma group) and by anatomic location (proximal colon, distal colon, rectum, and multiple locations). The high-risk adenoma group was defined as subjects with advanced adenomas or multiple (>= 3) adenomas. RESULTS: A total of 456 participants had colorectal adenomas, and 861 had no polyps. In multivariate analyses, higher levels of physical activity were associated with a significantly decreased risk of colorectal adenomas (OR = 0.56, 95% CI 0.40 0.79). This inverse association was stronger for the risk of high-risk adenomas (OR = 0.39, 95% CI 0.21-0.73) than for low-risk adenomas (OR = 0.62, 95% CI 0.43 0.89). The negative relation of physical activity was significant for distal colon adenomas (OR = 0.54, 95% CI 0.30-0.95) and the adenomas with multiple locations (OR = 0.39, 95% CI 0.21-0.72). CONCLUSIONS: Increased physical activity is associated with a reduced prevalence of colorectal adenomas. The inverse association between physical activity and adenoma was stronger for the risk of advanced or multiple adenomas. PMID- 23754756 TI - Mixture randomized item-response modeling: a smoking behavior validation study. AB - Misleading response behavior is expected in medical settings where incriminating behavior is negatively related to the recovery from a disease. In the present study, lung patients feel social and professional pressure concerning smoking and experience questions about smoking behavior as sensitive and tend to conceal embarrassing or threatening information. The randomized item-response survey method is expected to improve the accuracy of self-reports as individual item responses are masked and only randomized item responses are observed. We explored the validation of the randomized item-response technique in a unique experimental study. Therefore, we administered a new multi-item measure assessing smoking behavior by using a treatment-control design (randomized response (RR) or direct questioning). After the questionnaire, we administered a breath test by using a carbon monoxide (CO) monitor to determine the smoking status of the patient. We used the response data to measure the individual smoking behavior by using a mixture item-response model. It is shown that the detected smokers scored significantly higher in the RR condition compared with the directly questioned condition. We proposed a Bayesian latent variable framework to evaluate the diagnostic test accuracy of the questionnaire using the randomized-response technique, which is based on the posterior densities of the subject's smoking behavior scores together with the breath test measurements. For different diagnostic test thresholds, we obtained moderate posterior mean estimates of sensitivity and specificity by observing a limited number of discrete randomized item responses. PMID- 23754757 TI - Motherless quail mothers display impaired maternal behavior and produce more fearful and less socially motivated offspring. AB - Early maternal deprivation impairs the behavioral development of young individuals. Recently, strong differences between mothered and maternally deprived chicks have been reported concerning their emotionality, sociality, and spatial skills. Here we investigated long-term and cross-generational impacts of maternal deprivation by comparing the characteristics of the non-reproductive and the maternal behavior of 22 mothered and 22 non-mothered adult female Japanese quail (Coturnix c. japonica) and by comparing the behavior of their respective fostered chicks. We reveal that non-brooded mothers were more fearful and less competent in spatial tasks and expressed impaired maternal care, characterized by more aggression towards chicks, higher activity rates, and more abnormal pacing during the first days of the care period. Chicks' behavior was clearly affected by maternal care inducing strong differences in their fearfulness and social motivation. Our results show both long-term and cross-generational impacts of early maternal deprivation in precocial birds. PMID- 23754758 TI - Discordant association of C-reactive protein with clinical events and coronary luminal narrowing in postmenopausal women: data from the Women's Angiographic Vitamin and Estrogen (WAVE) study. AB - BACKGROUND: The incidence of cardiovascular events had been shown to be associated with C-reactive protein (CRP). However, it is unclear that the cardiovascular risk associated with CRP is due to progressive coronary narrowing or to other factors such as formation of unstable plaque. This study was designed to determine the effect of baseline CRP on cardiovascular events and on the progression of atherosclerotic narrowing among 423 postmenopausal women with angiographic stenosis between 15% and 75%. HYPOTHESIS: Baseline CRP levels may affect cardiovascular events and progression of atherosclerotic coronary artery narrowing among postmenopausal women. METHODS: Baseline and follow-up (2.8 years) angiographic data were analyzed among 320 women. Women were stratified into 4 quartiles according to baseline CRP levels. The changes in lumen diameter and clinical events in each quartile were compared. RESULTS: The annualized changes in minimal and average lumen diameter in diseased and nondiseased coronary segments were not significantly associated with baseline CRP levels. The composite end point of all-cause mortality and myocardial infarction (MI) increased from 3% (3/107) in the first CRP quartile to 14% (14/98) in fourth CRP quartile (P < 0.001). Similar results were found for cardiovascular death and MI (increased from 1% (2/107) in the first quartile to 11% (11/98) in fourth quartile). The difference remained significant even after adjustment for baseline differences and cardiovascular risk factors. CONCLUSIONS: Higher baseline CRP was associated with increased risk of clinical events but was not associated with annualized change in luminal diameters. Thus, increased risk of adverse events among patients with higher baseline CRP events was independent of progression of atherosclerosis as measured by change in minimal or average luminal diameter. PMID- 23754759 TI - Choosing thresholds for statistical signal detection with the proportional reporting ratio. AB - BACKGROUND: Identification of potential drug safety problems using statistical screening algorithms in routinely collected databases of adverse drug reactions (ADRs) requires decision rules based on thresholds of the chosen parameters. Choosing higher or lower thresholds changes both the sensitivity of the screening and the number of false alarms produced, and thus has an impact on the effectiveness of the detection process. OBJECTIVE: The aim of this study was to evaluate the impact on the effectiveness of signal detection activities of choosing different warning thresholds for the proportional reporting ratio (PRR) and for the count of reports of any drug-event combination. METHODS: Signal detection methods were tested within the EudraVigilance database of suspected ADRs. Using an established set of known ADRs, the number that could be detected and the changes in time gained for earlier investigation of the signal were calculated over a range of signal detection thresholds. These figures were set against the number of false positive signals produced by the statistical signal detection algorithms. RESULTS: Higher thresholds for the lower confidence bound of the PRR produced fewer false positives but this benefit was offset by important losses of sensitivity in the detection of ADRs. By contrast, increases in the threshold for the count of a specific drug-event combination produced fewer false positives with little loss of either sensitivity or time gained for investigation of adverse events. A threshold of five compared with the current European Medicines Agency threshold of three gave a reduction of 25 % in false positive signals in return for a loss of 12 % in true signals detected early. CONCLUSION: Changes in the standard threshold for the count of drug-event combinations can result in a substantial improvement in efficiency of the signal detection process. Initially this change might be applied only to products with a well-established safety profile. PMID- 23754760 TI - In vivo bioluminescence reporter gene imaging for the activation of neuronal differentiation induced by the neuronal activator neurogenin 1 (Ngn1) in neuronal precursor cells. AB - PURPOSE: Facilitation of the ability of neuronal lineages derived from transplanted stem cells to differentiate is essential to improve the low efficacy of neuronal differentiation in stem cell therapy in vivo. Neurogenin 1 (Ngn1), a basic helix-loop-helix factor, has been used as an activator of neuronal differentiation. In this study, we monitored the in vivo activation of neuronal differentiation by Ngn1 in neuronal precursor cells using neuron-specific promoter-based optical reporters. METHODS: The NeuroD promoter coupled with the firefly luciferase reporter system (pNeuroD-Fluc) was used to monitor differentiation in F11 neuronal precursor cells. In vitro luciferase activity was measured and normalized by protein content. The in vivo-jetPEI(TM) system was used for in vivo transgene delivery. The IVIS 100 imaging system was used to monitor in vivo luciferase activity. RESULTS: The Ngn1-induced neuronal differentiation of F11 cells generated neurite outgrowth within 2 days of Ngn1 induction. Immunofluorescence staining demonstrated that early and late neuronal marker expression (betaIII-tubulin, NeuroD, MAP2, NF-M, and NeuN) was significantly increased at 3 days after treatment with Ngn1. When Ngn1 and the pNeuroD-Fluc vector were cotransfected into F11 cells, we observed an approximately 11-fold increase in the luciferase signal. An in vivo study showed that bioluminescence signals were gradually increased in Ngn1-treated F11 cells for up to 3 days. CONCLUSION: In this study, we examined the in vivo tracking of neuronal differentiation induced by Ngn1 using an optical reporter system. This reporter system could be used effectively to monitor the activation efficiency of neuronal differentiation in grafted stem cells treated with Ngn1 for stem cell therapy. PMID- 23754761 TI - Non-invasive imaging of glioma vessel size and densities in correlation with tumour cell proliferation by small animal PET and MRI. AB - PURPOSE: Angiogenesis is a key event in the progression of glioblastomas (GBM). Our goal was to measure different anatomical and physiological parameters of GBM vessels using steady-state contrast-enhanced magnetic resonance imaging (SSCE MRI), together with the assessment of biochemical parameters on GBM proliferation and angiogenesis using [(11)C]methyl-L-methionine (MET) and 3'-deoxy-3' [(18)F]fluorothymidine (FLT) and positron emission tomography (PET). We focused on how these anatomical and biochemical read-outs correlate with one another and with immunohistochemistry. METHODS: SSCE-MRI together with (11)C-MET and (18)F FLT PET were performed 3 weeks after intracranial implantation of human GBM spheroids in nude rats (n = 8). Total cerebral blood volume (tCBV), blood volume present in microvessels (MUCBV), vessel density and size were calculated. Rats were treated with bevacizumab (n = 4) or vehicle (n = 4) for 3 weeks. Imaging was repeated at week 6, and thereafter immunohistochemistry was performed. RESULTS: Three weeks after implantation, MRI showed an increase of vessel density and MUCBV in the tumour compared to the contralateral brain. At week 6, non-treated rats showed a pronounced increase of (11)C-MET and (18)F-FLT tumour uptake. Between weeks 3 and 6, tCBV and vessel size increased, whereas vessel density and MUCBV decreased. In rats treated with bevacizumab MUCBV values were significantly smaller at week 6 than in non-treated rats, whereas the mean vessel size was higher. Accumulation of both radiotracers was lower for the treated versus the non-treated group. Most importantly, non-invasive measurement of tumour vessel characteristics and tumour proliferation correlated to immunohistochemistry findings. CONCLUSION: Our study demonstrates that SSCE-MRI enables non-invasive assessment of the anatomy and physiology of the vasculature of experimental gliomas. Combined SSCE-MRI and (11)C-MET/(18)F-FLT PET for monitoring biochemical markers of angiogenesis and proliferation in addition to vessel anatomy could be useful to improve our understanding of therapy response of gliomas. PMID- 23754762 TI - Evaluation of strategies towards harmonization of FDG PET/CT studies in multicentre trials: comparison of scanner validation phantoms and data analysis procedures. AB - PURPOSE: PET quantification based on standardized uptake values (SUV) is hampered by several factors, in particular by variability in PET acquisition settings and data analysis methods. Quantitative PET/CT studies acquired during a multicentre trial require harmonization of imaging procedures to maximize study power. The aims of this study were to determine which phantoms are most suitable for detecting differences in image quality and quantification, and which methods for defining volumes of interest (VOI) are least sensitive to these differences. METHODS: The most common accreditation phantoms used in oncology FDG PET/CT trials were scanned on the same scanner. These phantoms were those used by the Society of Nuclear Medicine Clinical Trials Network (SNM-CTN), the European Association of Nuclear Medicine/National Electrical Manufacturers Association (EANM/NEMA) and the American College of Radiology (ACR). In addition, tumour SUVs were derived from ten oncology whole-body examinations performed on the same PET/CT system. Both phantom and clinical data were reconstructed using different numbers of iterations, subsets and time-of-flight kernel widths. Subsequently, different VOI methods (VOI(A50%), VOI(max), VOI(3Dpeak), VOI(2Dpeak)) were applied to assess the impact of changes in image reconstruction settings on SUV and recovery coefficients (RC). RESULTS: All phantoms demonstrated sensitivity for detecting changes in SUV and RC measures in response to changes in image reconstruction settings and VOI analysis methods. The SNM-CTN and EANM/NEMA phantoms showed almost equal sensitivity in detecting RC differences with changes in image characteristics. Phantom and clinical data demonstrated that the VOI analysis methods VOI(A50%) and VOI(max) gave SUV and RC values with large variability in relation to image characteristics, whereas VOI(3Dpeak) and VOI(2Dpeak) were less sensitive to these differences. CONCLUSION: All three phantoms may be used to harmonize parameters for data acquisition, processing and analysis. However, the SNM-CTN and EANM/NEMA phantoms are the most sensitive to parameter changes and are suitable for harmonizing SUV quantification based on 3D VOIs, such as VOI(A50%) and VOI(3Dpeak), and VOImax. Variability in SUV quantification after harmonization could be further minimized using VOI(3Dpeak) analysis, which was least sensitive to residual variability in image quality and quantification. PMID- 23754763 TI - Freehand SPECT for image-guided sentinel lymph node biopsy in breast cancer. AB - PURPOSE: Sentinel lymph node biopsy (SLNB) is standard of care in early-stage breast cancer. Freehand SPECT (FhSPECT) is a system generating 3-D images for intraoperative visual detection of radioactivity in the body. The aim of our study was to evaluate the sensitivity of this technology for sentinel lymph node (SLN) detection and SLNB guidance. METHODS: In 40 patients, FhSPECT was additionally used after planar imaging and probe localization for SLNB. The number of SLNs detected was compared with the number detected by planar scintigraphy (reference method) and the conventional acoustic gamma probe (standard alternative). The sensitivity of FhSPECT was compared with that of the conventional gamma probe (McNemar's test). RESULTS: FhSPECT mapped the SLNs in 92.3 % of the basins (36/39) intraoperatively in identical positions to those seen on planar scintigrams. The conventional gamma probe correctly detected the SLNs in 35 of 39 basins (89.7 %). After SLNB, remaining radioactivity was detected by FhSPECT in nine patients, resulting in additional resection of SLNs in four patients. CONCLUSION: FhSPECT is a highly sensitive modality for intraoperative detection of SLNs, resulting in the identification of a higher number of SLNs than conventional gamma probe detection. PMID- 23754764 TI - Reply to: Area under the cumulative SUV-volume histogram is not a viable metric of intratumoral metabolic heterogeneity. PMID- 23754765 TI - A new dynamic covalent bond of Se-N: towards controlled self-assembly and disassembly. AB - A new kind of Se-N dynamic covalent bond has been found that can form between the Se atom of a phenylselenyl halogen species and the N atom of a pyridine derivative, such as polystyrene-b-poly(4-vinylpyridine). This Se-N dynamic covalent bond can be reversibly and rapidly formed or cleaved under acidic or basic conditions, respectively. Furthermore, the bond can be dynamically cleaved by heating or treatment with stronger electron-donating pyridine derivatives. The multiple responses of Se-N bond to external stimuli has enriched the existing family of dynamic covalent bonds. It can be used for controlled and reversible self-assembly and disassembly, which may find potential applications in a number of areas, including self-healing materials and responsive assemblies. PMID- 23754767 TI - Atypical chronic myeloid leukemia harboring NUP98-HOXA9. PMID- 23754766 TI - Autologous peripheral blood stem cell transplantation with granulocyte colony stimulating factor combined conditioning regimen as a postremission therapy for acute myelogenous leukemia in first complete remission. AB - We retrospectively analyzed the outcomes of 81 patients with non-M3 acute myelogenous leukemia (AML) in first complete remission (CR1) who were treated with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (Auto-PBSCT) by the Fukuoka Blood and Marrow Transplantation Group between 1989 and 2005. Cytogenetically, 16 patients were defined as good risk, 56 as intermediate risk, and nine as poor risk, following the Southwest Oncology Group criteria. The pre-transplant conditioning regimen consisted of high-dose busulfan, etoposide, and cytarabine (BEA regimen), combined with priming by granulocyte colony-stimulating factor (G-CSF). Disease-free survival (DFS) and overall survival at 5 years were 64.0 % (95 % CI 52.5-73.4) and 66.4 % (95 % CI 54.9-75.6) after Auto-PBSCT at a median follow-up time of 103 months (range 3-240 months), respectively. Two patients died of transplant-related pulmonary complications 6 months after Auto-PBSCT without relapse. The 5-year DFS rates of patients in the genetically good-, intermediate-, and poor-risk groups were 80.8, 64.3, and 33.3 %, respectively, but there was no significant difference statistically among the risk groups (log-rank p = 0.0579). These observations suggest that HDCT supported by Auto-PBSCT with the BEA regimen combined with G-CSF priming is a therapeutic option for postremission therapy of AML in CR1. PMID- 23754768 TI - Shaping micelles: the interplay between hydrogen bonds and dispersive interactions. AB - A subtle interplay: In the formation of a 1.6 nm micelle containing up to six molecules of propofol, a hydrogen-bond network is shown to influence the structure of the micelle, whereas the nonpolar groups arrange in such a way that the remaining noncovalent interactions are maximized. Such globular structures present a characteristic signature in the IR spectrum that will allow their identification in more complex media. PMID- 23754769 TI - Stress echocardiography and Cochin Risk Prediction Score for the prediction of pulmonary arterial hypertension in scleroderma: not yet ready for prime time. PMID- 23754771 TI - Quality of case reports of adverse drug reactions with psychotropic drugs: a 25 year review. AB - Case reports of adverse reactions with psychotropic drugs can be useful in raising hypotheses, to be tested with more rigorous study designs. However such reports have significant methodological drawbacks, making it hard to determine causality. We undertook a systematic assessment of the quality of case reports and small case series published within Human Psychopharmacology over 25 years. For reports of adverse drug reactions, modified Bradford Hill criteria for causality (for consistency, strength, specificity, temporal relationship and plausibility) were used to ascertain the quality of the account. Reports which had been cited at least 10 times by December 2010 were examined in detail, to assess their overall contribution in extending understanding and influencing clinical practice. Of 40 reports of adverse drug reactions, only seven were sufficiently robust for confidence in probable or possible causality. Nine reports had been cited more than 10 times: the five most frequently cited reports of adverse drug reactions described movement disorders, suicidal thoughts and discontinuation symptoms with SSRIs: clinical relevance was high, but their quality was not markedly greater than less frequently cited reports. Nearly all reports of adverse drug reactions, published in a single journal over 25 years, were insufficiently robust to demonstrate probable causality. Reports that are cited frequently become influential because of their potential clinical relevance, rather than due to their methodological quality. PMID- 23754772 TI - Enhanced antitumor activity mediated by human 4-1BB-engineered T cells. AB - 4-1BB (CD137) is a costimulatory molecule transiently expressed on the T-cell surface after TCR engagement, whereas its ligand 4-1BBL can be found on professional antigen-presenting cells, but more importantly, also on tumor cells. As the role of the 4-1BB/4-1BBL pathway has emerged central to CD8(+) T-cell responses and survival, we sought to test its relevance in the context of genetically modified human T cells. To that end, T cells purified from healthy donors and from vaccinated-melanoma patients were transduced to express high levels of constitutive 4-1BB. 4-1BB-transduced T cells were cocultured with melanoma tumor lines and exhibited enhanced cytokine secretion, upregulation of activation markers as well as increased cytotoxicity in a chick-chorioallantoic membrane model of human melanoma tumors. In addition, these cells expanded and proliferated at a higher rate, expressed heightened levels of the antiapoptotic molecule Bcl(XL) and were also relatively insensitive to immunosuppression mediated by transforming growth factor-beta, compared to control cells. We also show that 4-1BBL expression on the target cell is essential to 4-1BB-mediated functional improvement. Overall, we conclude that the modification of human T cells with 4-1BB yields enhanced antitumor function which may have important applications in therapies based on the genetic modification of patient lymphocytes. PMID- 23754773 TI - Asymptomatic subjects with zero coronary calcium score: coronary CT angiographic features of plaques in event-prone patients. AB - The aims of this study were: (a) to assess clinical predictors and coronary computed tomography angiography (CCTA) characteristics of noncalcified coronary plaques (NCP) in subjects who had cardiac events despite a zero coronary artery calcium score (CACS), and (b) to describe computed tomography (CT) plaque characteristics in subjects with cardiac events. A total of 7,961 subjects with zero CACS were evaluated; 6,531 subjects underwent CCTA as part of a health check up. Those who had zero CACS were included in our mid-term follow-up study. Cardiac events included cardiac death, acute coronary syndrome or revascularization with stable angina. More than one NCP was identified in 441 subjects with zero CACS, including 48 subjects with obstructive coronary artery disease (CAD) caused by NCPs. Age, male gender, hypertension, diabetes and low density lipoprotein were independent predictors of obstructive CAD. Among subjects with obstructive CAD, young adults were classified into low (79.2 %) or moderate (72.9 %) risk groups by the National Centers for Environmental Prediction III guidelines. Approximately 0.2 % of subjects had cardiac events during our follow-up period. All patients with cardiac events had NCPs with significantly lower mean CT numbers, higher remodeling indexes and worse degree of stenosis. In asymptomatic subjects with zero CACS, NCP was associated with cardiac events. CCTA might be useful for risk stratification among select populations with CAD and zero CACS who have certain plaque characteristics associated with cardiac events. PMID- 23754774 TI - Merkel cell carcinoma of the head and neck: potential histopathologic predictors. AB - OBJECTIVES/HYPOTHESIS: To identify or confirm any new or suggested independent histopathological predictors in Merkel cell carcinoma (MCC) of the head and neck (HN) correlated with outcome. STUDY DESIGN: Retrospective chart and pathology review. METHODS: Between 1990 and 2010, 58 patients with Merkel cell carcinoma of the head and neck HNMCC were identified for study. Pathologic specimens were reviewed and evaluated for independent prognostic factors and correlated with locoregional recurrence and disease-specific survival. RESULTS: The 2- and 5-year disease-specific survival (DSS) rates were 72.7% and 63.6%, respectively. The local and regional recurrence rates were 12.0% and 24.1%, respectively. A total of 25.9% of the patients developed distant metastases during follow-up. Tumor size (< 1 cm vs. > 1 cm) and the presence of a positive deep resection margin were independently found to be significantly associated with regional recurrence (P = 0.01 and P = 0.04, respectively). No other prognostic factors could be identified. CONCLUSION: Adjuvant radiotherapy cannot remediate a positive resection margin. Given these results, consideration for revision surgery should be considered for a positive deep margin. Frozen section analysis may help to define the margins in this invasive and aggressive disease. PMID- 23754775 TI - [4-tBu-2,6-{P(O)(OiPr)2}2C6H2SnL]+: an NHC-stabilized organotin(II) cation and related derivatives. PMID- 23754776 TI - Sharp bounds on causal effects using a surrogate endpoint. AB - This paper considers a problem of evaluating the causal effect of a treatment X on a true endpoint Y using a surrogate endpoint S, in the presence of unmeasured confounders between S and Y. Such confounders render the causal effect of X on Y unidentifiable from the causal effect of X on S and the joint probability of S and Y. To evaluate the causal effect of X on Y in such a situation, this paper derives closed-form formulas for the sharp bounds on the causal effect of X on Y based on both the causal effect of X on S and the joint probability of S and Y under various assumptions. In addition, we show that it is not always necessary to observe Y to test the null causal effect of X on Y under the monotonicity assumption between X and S. These bounds enable clinical practitioners and researchers to assess the causal effect of a treatment on a true endpoint using a surrogate endpoint with minimum computational effort. PMID- 23754777 TI - Predicting readmission or death after acute ST-elevation myocardial infarction. AB - BACKGROUND: Risk factors for emergent readmissions or death after acute myocardial infarction (AMI) are important in identifying patients at risk for major adverse events. However, there has been limited investigation conducted of prospective clinical registries to determine relevant risk factors. HYPOTHESIS: We hypothesize 30-day readmission or death could be predicted using patient, procedural, and process factors. METHODS: Patients presenting with ST-elevation myocardial infarction (STEMI) from 2006 to 2011 were prospectively enrolled in a STEMI registry (1271 patients). Thirty-day readmission was ascertained by administrative claims data. Death was determined by linking to the Social Security Death Master File. Univariate and stepwise multivariate logistic regression was conducted with Hosmer-Lemeshow goodness-of-fit statistics for model calibration and receiver operating characteristic (ROC) curve for model discrimination. RESULTS: The combined end point of 30-day readmission or postdischarge death included 135 patients (10.6%), including 109 emergent readmissions and 26 deaths. Factors associated with an increase risk of 30-day readmission or postdischarge death included age >= 80 years, diabetes, chest pain or cardiac arrest at presentation, and 3-vessel disease found at initial angiography. Factors associated with a decreased risk of 30-day readmission or postdischarge death included transfer to the catheterization lab from another emergency department, clopidogrel given during the procedure hypercholesterolemia, and receiving aspirin, beta-blockers, and angiotensin converting enzyme or angiotensin receptor blocker inhibitors at discharge. Index admission outcomes indicative of readmission or death postdischarge only included a new diagnosis of congestive heart failure. The model discriminated well with an ROC of 0.71 (95% confidence interval: 0.66-0.76). CONCLUSIONS: Prehospitalization factors are overlooked and are important factors to incorporate in routine risk prediction models for readmission or death within 30 days following an AMI. PMID- 23754778 TI - Noisy spit: parental noncompliance with child salivary cortisol sampling. AB - Studies assessing hypothalamic-pituitary-adrenal (HPA) axis functioning in young children commonly involve parental collection of salivary cortisol in ambulatory settings. However, no data are available on the compliance of parents in collecting ambulatory measures of children's salivary cortisol. This study examined the effects of parental compliance on the cortisol awakening response (CAR) and diurnal cortisol slopes in a sample of preschool-age children (ages 3 5). Eighty-one parents were instructed to collect their child's salivary cortisol samples upon their child's waking, 30 and 45 min post-waking and before bedtime on two weekdays. Subjective parental compliance was assessed using parent-report, and objective parental compliance was assessed using an electronic monitoring device. Rates of compliance were higher based on parent-report than electronic monitoring. Parental noncompliance as indicated by electronic monitoring was associated with higher waking cortisol and lower CAR. Findings suggest the need to incorporate electronic monitoring of parental compliance into developmental neuroendocrine research, especially when assessing the CAR. PMID- 23754779 TI - Precise nail tip positioning after tibial intramedullary nailing prevents anterior knee pain. AB - PURPOSE: Anterior knee pain (AKP) is a common complication following intramedullary nailing of tibial shaft fractures. Our aim was, by analysing the postoperative lateral knee X-rays and clinical status (VAS score), to find the best intramedullary tip position of a non protruded nail that will provide the best postoperative outcome avoiding AKP. METHODS: We evaluated the postoperative outcome of 221 patients, from the last four years, with healed fractures initially treated with intramedullary reamed nails with two or three interlocking screws proximally and distally through a medial paratendinous incision for nail entry portal. Our aim was to analyse a possible relationship between AKP according to the VAS scale, and nail position marked as a distance from tip of nail to tibial plateau (NP) and to tibial tuberosity (NT), measured postoperatively on lateral knee X-rays. RESULTS: Two groups of patients were formed on the basis of presence of pain related to AKP (the level of pain was neglected): group A were patients with pain and group B without pain. The difference between the two groups concerning NP and NT measurements appeared to be statistically significant concerning NT measurement (p < 0.05), with high accuracy according to the classification tree. CONCLUSIONS: We presume that the position of the proximal tip of the nail and its negative influence on the innervation pattern of the area dorsal to patellar tendon could be the key factor of AKP. We conclude that the symptoms of AKP will not appear if the tip of the nail position is more than 5.5 mm from the tibial plateau (NP) and more than 2.5 mm from the tibial tuberosity (NT). PMID- 23754780 TI - Metacognition-oriented social skills training for individuals with long-term schizophrenia: methodology and clinical illustration. AB - PURPOSE: There is much evidence indicating the presence of social deficits in schizophrenia and the detrimental effect of these deficits on global functioning in this population. As a result, social skills training (SST) has emerged as a legitimate psychosocial treatment, although effectiveness research has revealed small effect sizes and limited generalizability regarding the benefits of this treatment. METHODS: In light of the strong evidence of metacognitive deficits in schizophrenia and the importance of metacognition to successful social functioning, we propose a novel therapeutic intervention wherein metacognitive remediation is integrated into SST: metacognition-oriented social skills training (MOSST). In the current paper, we present MOSST, an adapted SST programme wherein clients are also encouraged to have mindful contact with their own thoughts and to better consider and understand the mental states of others as well as the connection between mental states and behaviour. RESULTS: We present a case wherein an individual with schizophrenia successfully completed the MOSST programme. CONCLUSION: We outline directions for future research, starting with the logical next step of empirically testing the efficacy of MOSST. KEY PRACTITIONER MESSAGE: Currently social skills training is considered to be the elected psychosocial treatment for people affected by schizophrenia, although evidence indicates limited benefits. People with schizophrenia have metacognitive deficits, which interfere with proper social functioning. A metacognitive oriented social skills training (MOSST) intervention has been developed by the authors.A treatment such as MOSST, which integrates social skills training and metacognitive training, promises to improve social skills through improving the metacognition. PMID- 23754781 TI - Science on the market: what does competition do to research? PMID- 23754782 TI - Childhood obesity prevention and control in city recreation centres and family homes: the MOVE/me Muevo Project. AB - BACKGROUND: Interventions to prevent and control childhood obesity have shown mixed results in terms of short- and long-term changes. OBJECTIVES: 'MOVE/me Muevo' was a 2-year family- and recreation centre-based randomized controlled trial to promote healthy eating and physical activity among 5- to 8-year-old children. It was hypothesized that children in the intervention group would demonstrate lower post-intervention body mass index (BMI) values and improved obesity-related behaviours compared with the control group children. METHODS: Thirty recreation centres in San Diego County, California, were randomized to an intervention or control condition. Five hundred forty-one families were enrolled and children's BMI, diet, physical activity and other health indicators were tracked from baseline to 2 years post-baseline. Analyses followed an intent-to treat approach using mixed-effects models. RESULTS: No significant intervention effects were observed for the primary outcomes of child's or parent's BMI and child's waist circumference. Moderator analyses, however, showed that girls (but not boys) in the intervention condition reduced their BMI. At the 2-year follow up, intervention condition parents reported that their children were consuming fewer high-fat foods and sugary beverages. CONCLUSIONS: Favourable implementation fidelity and high retention rates support the feasibility of this intervention in a large metropolitan area; however, interventions of greater intensity may be needed to achieve effects on child's BMI. Also, further research is needed to develop gender-specific intervention strategies so that both genders may benefit from such efforts. PMID- 23754783 TI - Genome-wide methylation analyses identify a subset of mantle cell lymphoma with a high number of methylated CpGs and aggressive clinicopathological features. AB - Mantle cell lymphoma (MCL) is a B-cell neoplasm with an aggressive clinical behavior characterized by the t(11;14)(q13;q32) and cyclin D1 overexpression. To clarify the potential contribution of altered DNA methylation in the development and/or progression of MCL, we performed genome-wide methylation profiling of a large cohort of primary MCL tumors (n = 132), MCL cell lines (n = 6) and normal lymphoid tissue samples (n = 31), using the Infinium HumanMethylation27 BeadChip. DNA methylation was compared to gene expression, chromosomal alterations and clinicopathological parameters. Primary MCL displayed a heterogeneous methylation pattern dominated by DNA hypomethylation when compared to normal lymphoid samples. A total of 454 hypermethylated and 875 hypomethylated genes were identified as differentially methylated in at least 10% of primary MCL. Annotation analysis of hypermethylated genes recognized WNT pathway inhibitors and several tumor suppressor genes as frequently methylated, and a substantial fraction of these genes (22%) showed a significant downregulation of their transcriptional levels. Furthermore, we identified a subset of tumors with extensive CpG methylation that had an increased proliferation signature, higher number of chromosomal alterations and poor prognosis. Our results suggest that a subset of MCL displays a dysregulation of DNA methylation characterized by the accumulation of CpG hypermethylation highly associated with increased proliferation that may influence the clinical behavior of the tumors. PMID- 23754784 TI - Targeted identification of glycosylated proteins in the gastric pathogen Helicobacter pylori (Hp). AB - Virulence of the gastric pathogen Helicobacter pylori (Hp) is directly linked to the pathogen's ability to glycosylate proteins; for example, Hp flagellin proteins are heavily glycosylated with the unusual nine-carbon sugar pseudaminic acid, and this modification is absolutely essential for Hp to synthesize functional flagella and colonize the host's stomach. Although Hp's glycans are linked to pathogenesis, Hp's glycome remains poorly understood; only the two flagellin glycoproteins have been firmly characterized in Hp. Evidence from our laboratory suggests that Hp synthesizes a large number of as-yet unidentified glycoproteins. Here we set out to discover Hp's glycoproteins by coupling glycan metabolic labeling with mass spectrometry analysis. An assessment of the subcellular distribution of azide-labeled proteins by Western blot analysis indicated that glycoproteins are present throughout Hp and may therefore serve diverse functions. To identify these species, Hp's azide-labeled glycoproteins were tagged via Staudinger ligation, enriched by tandem affinity chromatography, and analyzed by multidimensional protein identification technology. Direct comparison of enriched azide-labeled glycoproteins with a mock-enriched control by both SDS-PAGE and mass spectrometry-based analyses confirmed the selective enrichment of azide-labeled glycoproteins. We identified 125 candidate glycoproteins with diverse biological functions, including those linked with pathogenesis. Mass spectrometry analyses of enriched azide-labeled glycoproteins before and after cleavage of O-linked glycans revealed the presence of Staudinger ligation-glycan adducts in samples only after beta-elimination, confirming the synthesis of O-linked glycoproteins in Hp. Finally, the secreted colonization factors urease alpha and urease beta were biochemically validated as glycosylated proteins via Western blot analysis as well as by mass spectrometry analysis of cleaved glycan products. These data set the stage for the development of glycosylation-based therapeutic strategies, such as new vaccines based on natively glycosylated Hp proteins, to eradicate Hp infection. Broadly, this report validates metabolic labeling as an effective and efficient approach for the identification of bacterial glycoproteins. PMID- 23754786 TI - Fast synthesis of complex enantiopure heterocyclic scaffolds by a tandem sequence of simple transformations on alpha-hydroxyaldehydes. PMID- 23754785 TI - Multimolecular analysis of stable immunological synapses reveals sustained recruitment and sequential assembly of signaling clusters. AB - The formation of the immunological synapse between T cells and antigen-presenting cells (APC) begins within minutes of contact and can take hours for full T-cell activation. Although early phases of the synapse have been extensively studied for a select number of proteins, later phases have not yet been examined in detail. We studied the signaling network in stable synapses by measuring the simultaneous localization of 25 signaling and structural molecules over 2 h at the level of individual synapses using multi-epitope ligand cartography (MELC). Signaling proteins including phospho(p)ZAP70, pSLP76, pCD3zeta, and pLAT, along with proteins that influence synapse structure such as F-actin, tubulin, CD45, and ICAM-1, were localized in images of synapses and revealed the multidimensional construction of a mature synapse. The construction of the stable synapse included intense early TCR signaling, a phase of recruitment of structural proteins, and a sustained increase in signaling molecules and colocalization of TCR and pLAT signaling clusters in the center of the synapse. Consolidation of TCR and associated proteins resulted in formation of a small number of discrete synaptic microclusters. Development of synapses and cSMAC composition was greatly affected by the absence of Vav1, with an associated loss in PLCgamma1 recruitment, pSLP76, and increased CXCR4. Together, these data demonstrate the use of multi-epitope ligand cartography to quantitatively analyze synapse formation and reveal successive recruitment of structural and signaling proteins and sustained phosphorylation at the mature synapse. PMID- 23754787 TI - Association between C-reactive protein and atrial fibrillation recurrence after catheter ablation: a meta-analysis. AB - BACKGROUND: Atrial fibrillation (AF) is associated with inflammation. Increased serum C-reactive protein (CRP) levels are important representatives of an inflammatory state of AF. A variety of studies have evaluated whether increased CRP levels have an association with AF recurrence after catheter ablation. However, the results remain inconsistent, therefore, this meta-analysis was conducted to offer suggestions. HYPOTHESIS: Increased baseline CRP have an association with AF recurrence after catheter ablation. METHODS: Electronic databases including PubMed, Embase, Medline, ISI Web of Knowledge, and ScienceDirect were searched until December 31, 2012 for any CRP-associated studies. Overall and subgroup analyses were performed. Standardized mean difference (SMD) and 95% confidence interval (CI) were used to evaluate the associations between CRP levels and postablation AF recurrence. Statistical analysis was performed with Review Manager 5.2 and Stata 11.0. RESULTS: Seven available studies were identified, which included 526 patients (179 recurrence vs 347 no recurrence). Overall, increased baseline CRP levels had significant positive association with postablation AF recurrence. The SMD in the CRP levels was 0.65 units (95% CI: 0.30-0.99), and the z-score for overall effect was 3.70 (P = 0.0002). The heterogeneity test showed that there were moderate differences between individual studies (P = 0.006, I(2) = 67%). Metaregression revealed that different sample sizes of studies possibly accounted for the heterogeneity. Positive associations were also found in subgroup analyses based on sample size. When stratifying for ethnicity, similarly significant associations were found in both European (Caucasian) and Asian populations. CONCLUSIONS: Investigations demonstrate that baseline CRP levels are greater in patients with postablation AF recurrence. Further studies with larger sample size and delicate design for CRP should be conducted. PMID- 23754788 TI - Direct syn insertion of alkynes and allenes into Au-Si bonds. PMID- 23754789 TI - Injectable tumor necrosis factor alpha inhibitors and outpatient antimicrobial use in children with rheumatic diseases: analyses of prescription claims from a pharmacy benefit manager database. AB - OBJECTIVE: To estimate the incidence and rate of outpatient antibiotic and antiviral medication use among children receiving methotrexate and/or an injectable tumor necrosis factor alpha (iTNFalpha) inhibitor (etanercept and/or adalimumab)and to compare these rates with those of a control population. METHODS: Data were obtained from a pharmacy benefit manager (PBM) database. Children were included if they had >1 prescription claim for an iTNFalpha inhibitor or methotrexate prescribed by a pediatric or adult rheumatologist between 2008 and 2010 and if they were age <18 years at the time of the claim. A control cohort of randomly selected children was generated from the PBM database. Poisson regression was used to compare antimicrobial rate ratios (RRs). Incidence rates and RRs were adjusted for age, sex, and prednisone exposure. RESULTS: In total, 4,312 children were included. The adjusted RRs for antibiotic prescriptions among children receiving methotrexate monotherapy or iTNFalpha inhibitor and methotrexate combination therapy compared with the control cohort were 2.18 (95% confidence interval [95% CI] 1.92-2.47) and 2.12 (95% CI 1.79 2.50), respectively. The adjusted RRs for antiviral prescriptions among children receiving methotrexate monotherapy or iTNFalpha inhibitor and methotrexate combination therapy compared with the control cohort were 3.67 (95% CI 1.98-6.78) and 4.34 (95% CI 1.86-10.14), respectively. The RRs for the iTNFalpha inhibitor group were similar in magnitude. There was no significant difference in RRs between the medication exposure categories for either antibiotic or antiviral prescriptions. CONCLUSION: Children receiving methotrexate and/or an iTNFalpha inhibitor had higher rates of antibiotic and antiviral use compared with the control cohort. Data sets with additional patient-level and disease-specific data are required to assess this association in more detail. PMID- 23754790 TI - Water-soluble nitric-oxide-releasing acetylsalicylic acid (ASA) prodrugs. AB - A series of water-soluble (benzoyloxy)methyl esters of acetylsalicylic acid (ASA), commonly known as aspirin, are described. The new derivatives each have alkyl chains containing a nitric oxide (NO)-releasing nitrooxy group and a solubilizing moiety bonded to the benzoyl ring. The compounds were synthesized and evaluated as ASA prodrugs. After conversion to the appropriate salt, most of the derivatives are solid at room temperature and all possess good water solubility. They are quite stable in acid solution (pH 1) and less stable at physiological pH. In human serum, these compounds are immediately metabolized by esterases, producing a mixture of ASA, salicylic acid (SA), and of the related NO donor benzoic acids, along with other minor products. Due to ASA release, the prodrugs are capable of inhibiting collagen-induced platelet aggregation of human platelet-rich plasma. Simple NO-donor benzoic acids 3-hydroxy-4-(3 nitrooxypropoxy)benzoic acid (28) and 3-(morpholin-4-ylmethyl)-4-[3 (nitrooxy)propoxy]benzoic acid (48) were also studied as representative models of the whole class of benzoic acids formed following metabolism of the prodrugs in serum. These simplified derivatives did not trigger antiaggregatory activity when tested at 300 MUM. Only 28 displays quite potent NO-dependent vasodilatatory action. Further in vivo evaluation of two selected prodrugs, {[2 (acetyloxy)benzoyl]oxy}methyl-3-[(3-[aminopropanoyl)oxy]-4-[3 (nitrooxy)propoxy]benzoate?HCl (38) and {[2-(acetyloxy)benzoyl]oxy}methyl 3 (morpholin-4-ylmethyl)-4-[3-(nitrooxy)propoxy]benzoate oxalate (49), revealed that their anti-inflammatory activities are similar to that of ASA when tested in the carrageenan-induced paw edema assay in rats. The gastrotoxicity of the two prodrugs was also determined to be lower than that of ASA in a lesion model in rats. Taken together, these results indicated that these NO-donor ASA prodrugs warrant further investigation for clinical application. PMID- 23754791 TI - Expression of core 3 synthase in human pancreatic cancer cells suppresses tumor growth and metastasis. AB - Core 3-derived glycans, a major type of O-glycan expressed by normal epithelial cells of the gastrointestinal tract, are downregulated during malignancy because of loss of expression of functional beta3-N-acetylglucosaminyltransferase-6 (core 3 synthase). We investigated the expression of core 3 synthase in normal pancreas and pancreatic cancer and evaluated the biological effects of re-expressing core 3 synthase in pancreatic cancer cells that had lost expression. We determined that pancreatic tumors and tumor cell lines have lost expression of core 3 synthase. Therefore, we re-expressed core 3 synthase in human pancreatic cancer cells (Capan-2 and FG) to investigate the contribution of core 3 glycans to malignant progression. Pancreatic cancer cells expressing core 3 synthase showed reduced in vitro cell proliferation, migration and invasion compared to vector control cells. Expression of core 3 O-glycans induced altered expression of beta1 integrin, decreased activation of focal adhesion kinase, led to the downregulation of expression of several genes including REG1alpha and FGFR3 and altered lamellipodia formation. The addition of a GlcNAc residue by core 3 synthase leads to the extension of the tumor-associated Tn structure on MUC1. Orthotopic injection of FG cells expressing core 3 synthase into the pancreas of nude mice produced significantly smaller tumors and decreased metastasis to the surrounding tissues compared to vector control FG cells. These findings indicate that expression of core 3-derived O-glycans in pancreatic cancer cells suppresses tumor growth and metastasis through modulation of glycosylation of mucins and other cell surface and extracellular matrix proteins. PMID- 23754793 TI - On the similarity and dissimilarity between photocatalytic water splitting and photocatalytic degradation of pollutants. AB - The last four decades have shown a remarkable increase in scientific interest in photocatalysis as a tool for tackling the world's energy and waste problems. The apparent similarity between photocatalytic water splitting and photocatalytic degradation of pollutants, which have been studied so far by two different scientific communities, raises the question regarding the extent to which one may utilize knowledge obtained in one field for the benefit of the other. This review examines the common features and differences between the two areas. The main similarities stem from the common dependence on the absorption of photons and on subsequent charge-carrier dynamics. The main dissimilarities are linked to thermodynamics, the type of reactants and end products, and to the role of adsorption and desorption. At present the fundamental differences between storing energy and using it to solve environmental issues affect practical solutions. Yet, easy transfer of knowledge, research resources, and personnel between the two is not only possible but should be encouraged. PMID- 23754792 TI - Tongkat Ali as a potential herbal supplement for physically active male and female seniors--a pilot study. AB - Tongkat Ali (Eurycoma longifolia; TA) is known to increase testosterone levels and alleviate aging males' symptoms. This study aimed at investigating TA as an ergogenic supplement for elderly people. Thirteen physically active male and 12 physically active female seniors (57-72 years) were supplemented with 400-mg TA extract daily for 5 weeks. Standard hematological parameters were taken. In addition, the concentrations of total and free testosterone, dihydroepiandrosterone, cortisol, insulin-like growth factor-1, and sex hormone binding globulin were analyzed. As additional biochemical parameters, blood urea nitrogen and creatine kinase as parameters of kidney function and muscle damage, respectively, as well as the muscle strength by a simple handgrip test were determined. After treatment, hemoglobin, testosterone, and dihydroepiandrosterone concentrations, and the ratio of total testosterone/cortisol and muscle force remained significantly lower in female seniors than in male seniors. Hematocrit and erythrocyte count in male seniors increased slightly but were significantly higher than in female seniors. Treatment resulted in significant increases in total and free testosterone concentrations and muscular force in men and women. The increase in free testosterone in women is thought to be due to the significant decline in sex hormone-binding globulin concentrations. The study affirms the ergogenic benefit of TA through enhanced muscle strength. PMID- 23754794 TI - Reliability of widefield nailfold capillaroscopy and video capillaroscopy in the assessment of patients with Raynaud's phenomenon. AB - OBJECTIVE: To analyze the diagnostic performance and reliability of different parameters evaluated by widefield nailfold capillaroscopy (NFC) with those obtained by video capillaroscopy in patients with Raynaud's phenomenon (RP). METHODS: Two hundred fifty-two individuals were assessed, including 101 systemic sclerosis (SSc; scleroderma) patients,61 patients with undifferentiated connective tissue disease, 37 patients with primary RP, and 53 controls. Widefield NFC was performed using a stereomicroscope under 10-25 x magnification and direct measurement of all parameters. Video capillaroscopy was performed under 200 x magnification, with the acquirement of 32 images per individual (4 fields per finger in 8 fingers). The following parameters were analyzed in 8 fingers of the hands (excluding thumbs) by both methods: number of capillaries/mm, number of enlarged and giant capillaries, microhemorrhages, and avascular score.Intra- and interobserver reliability was evaluated by performing both examinations in 20 individuals on 2 different days and by 2 long-term experienced observers. RESULTS: There was a significant correlation (P < 0.000) between widefield NFC and video capillaroscopy in the comparison of all parameters. Kappa values and intraclass correlation coefficient analysis showed excellent intra- and interobserver reproducibility for all parameters evaluated by widefield NFC and video capillaroscopy. Bland-Altman analysis showed high agreement of all parameters evaluated in both methods. According to receiver operating characteristic curve analysis, both methods showed a similar performance in discriminating SSc patients from controls. CONCLUSION: Widefield NFC and video capillaroscopy are reliable and accurate methods and can be used equally for assessing peripheral microangiopathy in RP and SSc patients. Nonetheless, the high reliability obtained may not be similar for less experienced examiners. PMID- 23754795 TI - Preparation of glycerol carbonate esters by using hybrid Nafion-silica catalyst. AB - Glycerol carbonate esters (GCEs), which are valuable biomass-derivative compounds, have been prepared through the direct esterification of glycerol carbonate and long organic acids with different chain lengths, in the absence of solvent, and with heterogeneous catalysts, including acidic-organic resins, zeolites, and hybrid organic-inorganic acids. The best results, in terms of activity and selectivity towards GCEs, were obtained using a Nafion-silica composite. A full reaction scheme has been established, and it has been demonstrated that an undesired competing reaction results in the generation of glycerol and esters derived from a secondary hydrolysis of the endocyclic ester group, which is attributed to water formed during the esterification reaction. The influence of temperature, substrate ratio, catalyst-to-substrate ratio, and the use of solvent has been studied and, under optimized reaction conditions and with the adequate catalyst, it was possible to achieve 95% selectivity for the desired product at 98% conversion. It was demonstrated that the reaction rate decreased as the number of carbon atoms in the linear alkyl chain of the carboxylic acid increased for both p-toluenesulfonic acid and Nafion-silica nanocomposite (Nafion SAC-13) catalysts. After fitting the experimental data to a mechanistically based kinetic model, the reaction kinetic parameters for Nafion SAC-13 catalysis were determined and compared for reactions involving different carboxylic acids. A kinetic study showed that the reduced reactivity of carboxylic acids with increasing chain lengths could be explained by inductive as well as steric effects. PMID- 23754796 TI - Sampling strategy and analysis of trace element concentrations by inductively coupled plasma mass spectrometry on medieval human bones--the concept of chemical life history. AB - RATIONALE: Medieval human bones have the potential to reveal diet, mobility and treatment of diseases in the past. During the last two decades trace element chemistry has been used extensively in archaeometric investigations revealing such data. Many studies have reported the trace element inventory in only one sample from each skeleton - usually from the femur or a tooth. It cannot a priori be assumed that all bones or teeth in a skeleton will have the same trace element concentrations. METHODS: Six different bone and teeth samples from each individual were carefully decontaminated by mechanical means. Following dissolution of ca. 20 mg sample in nitric acid and hydrogen peroxide the assays were performed using inductively coupled plasma mass spectrometry (ICPMS) with quadropole detection. We describe the precise sampling technique as well as the analytical methods and parameters used for the ICPMS analysis. RESULTS: The places of sampling in the human skeleton did exhibit varying trace element concentrations. Although the samples are contaminated by Fe, Mn and Al from the surrounding soil where the bones have been residing for more than 500 years, other trace elements are intact within the bones. It is shown that the elemental ratios Sr/Ca and Ba/Ca can be used as indicators of provenance. CONCLUSIONS: The differences in trace element concentrations can be interpreted as indications of varying diet and provenance as a function of time in the life of the individual - a concept which can be termed chemical life history. A few examples of the results of such analyses are shown, which contains information about provenance and diagenesis. PMID- 23754797 TI - Laser ablation synthesis of new gold tellurides using tellurium and nanogold as precursors. Laser desorption ionisation time-of-flight mass spectrometry. AB - RATIONALE: Only a few gold tellurides are known. However, Laser Ablation Synthesis (LAS) using Laser Desorption Ionisation (LDI) time-of-flight mass spectrometry (TOF MS) has high potential for the generation of new compounds. METHODS: LDI of nanogold-Te conjugate using a nitrogen laser 337 nm was applied while the mass spectra were recorded in positive and negative ion modes using a quadrupole ion trap-TOF mass spectrometer equipped with a reflectron. Diffuse coplanar surface barrier discharge was applied for the plasma treatment of glass and silicon surfaces. RESULTS: A form of nanogold-Te conjugate was prepared and found suitable for LAS of gold tellurides. Several new Au(m)Te(n) (m = 1-11; n = 1-4) clusters were identified. An excess of nanogold and chloride or an excess of auric acid caused the formation of mixed Au(m)Te(n)Cl(x) clusters. The nanogold Te conjugate can be deposited from an aqueous suspension onto glass while the deposition is strongly enhanced if the surface is modified by plasma. CONCLUSIONS: LDI of nanogold-Te conjugate is a suitable procedure for the generation of new gold telluride clusters. Treatment of borosilicate glass with a diffuse coplanar surface barrier discharge strongly enhances the deposition of gold tellurides on glass while limited adsorption on a silicon surface was observed. PMID- 23754798 TI - Fragmentation of deprotonated polyethylene glycols, [PEG-H]-. AB - RATIONALE: Polyethylene glycols (PEGs) are soluble molecules utilized in a wide range of applications. Mass spectrometry and fragmentation patterns of positively charged PEG oligomers are well-known, but decomposition mechanisms of the deprotonated ions have not been studied. METHODS: Deprotonated PEGs were generated by electrospray ionization of PEG in water/acetonitrile. Collision induced dissociation (CID) experiments were carried out in a tandem mass spectrometer. The anions were studied using a tandem mass spectrometer to carry out CID experiments. A series of small PEG oligomers, with 1 to 8 monomer units, were studied in order to monitor size-dependent effects on fragmentation reactions. RESULTS: Because deprotonated PEG ions have a unique charge site, their dissociation pathways can easily be monitored. The ions fragment by loss of C2H4O monomer units, with an alternating intensity pattern that suggests the loss of an even number of monomer units is favored. Smaller oligomers and oligomer fragments also yielded fragments corresponding to H2 elimination and H2O loss. H2 elimination occurs by the generation of a hydride ion which deprotonates an alcohol upon leaving, while dehydration appears to be a charge-remote process. CONCLUSIONS: The fragmentation of deprotonated PEG is dominated by intramolecular S(N)2 reactions involving the terminal oxide anion. PMID- 23754799 TI - Gaseous byproducts from high-temperature thermal conversion elemental analysis of nitrogen- and sulfur-bearing compounds with considerations for delta2H and delta18O analyses. AB - RATIONALE: High-temperature, conversion-reduction (HTC) systems convert hydrogen and oxygen in materials into H2 and CO for delta(2)H and delta(18)O measurements by isotope ratio mass spectrometry. HTC of nitrogen- and sulfur-bearing materials produces unintended byproduct gases that could affect isotope analyses by: (1) allowing isotope exchange reactions downstream of the HTC reactor, (2) creating isobaric or co-elution interferences, and (3) causing deterioration of the chromatography. This study characterizes these HTC byproducts. METHODS: A HTC system (ThermoFinnigan TC/EA) was directly connected to a gas chromatograph/quadrupole mass spectrometer in scan mode (m/z 8 to 88) to identify the volatile products generated by HTC at conversion temperatures of 1350 degrees C and 1450 degrees C for a range of nitrogen- and sulfur-bearing solids [keratin powder, horse hair, caffeine, ammonium nitrate, potassium nitrate, ammonium sulfate, urea, and three nitrated organic explosives (PETN, RDX, and TNT)]. RESULTS: The prominent HTC byproduct gases include carbon dioxide, hydrogen cyanide, methane, acetylene, and water for all nitrogen-bearing compounds, as well as carbon disulfide, carbonyl sulfide, and hydrogen sulfide for sulfur-bearing compounds. The 1450 degrees C reactor temperature reduced the abundance of most byproduct gases, but increased the significant byproduct, hydrogen cyanide. Inclusion of a post-reactor chemical trap containing Ascarite II and Sicapent, in series, eliminated the majority of byproducts. CONCLUSIONS: This study identified numerous gaseous HTC byproducts. The potential adverse effects of these gases on isotope ratio analyses are unknown but may be mitigated by higher HTC reactor temperatures and purifying the products with a purge-and trap system or with chemical traps. PMID- 23754800 TI - Ultraviolet laser-induced cross-linking in peptides. AB - RATIONALE: The aim of this study was to demonstrate, and to characterize by high resolution mass spectrometry that it is possible to preferentially induce covalent cross-links in peptides by using high-energy femtosecond ultraviolet (UV) laser pulses. The cross-link is readily formed only when aromatic amino acids are present in the peptide sequence. METHODS: Three peptides, xenopsin, angiotensin I, and interleukin, individually or in combination, were exposed to high-energy femtosecond UV laser pulses, either alone or in the presence of spin trapping molecules, the reaction products being characterized by high resolution mass spectrometry. RESULTS: High-resolution mass spectrometry and spin trapping strategies showed that cross-linking occurs readily, proceeds via a radical mechanism, and is the highly dominant reaction, proceeding without causing significant photo-damage in the investigated range of experimental parameters. CONCLUSIONS: High-energy femtosecond UV laser pulses can be used to induce covalent cross-links between aromatic amino acids in peptides, overcoming photo oxidation processes, that predominate as the mean laser pulse intensity approaches illumination conditions achievable with conventional UV light sources. PMID- 23754801 TI - Adult pituitary cell maintenance: lineage-specific contribution of self duplication. AB - The identification of a stable pool of progenitor/stem cells in the adult pituitary has renewed the interest of identifying mechanisms for maintenance of pituitary cells throughout life. Whereas developmental studies have shown that progenitor expansion is the major source of new differentiated cells during pituitary organogenesis, the contribution of these progenitors for maintenance of the adult tissue is not clear although progenitors were clearly involved in cell expansion following end-organ ablation, notably after adrenalectomy and/or gonadectomy. We have used a genetic trick that eliminates dividing cells by apoptosis in order to assess the contribution of differentiated corticotropes and melanotropes for maintenance of their population in the adult pituitary. The system relies on chromosome instability created by the action of the Cre recombinase on inverted loxP sites. Expression of Cre recombinase in corticotropes and melanotropes led to progressive loss of corticotropes whereas melanotropes were unaffected. Because the Cre transgene is not expressed in progenitors, the data indicate that maintenance of the adult corticotrope pool is primarily due to self-duplication of differentiated cells. In contrast, melanotropes do not divide. Maintenance of corticotropes by self-duplication contrasts with the reported proliferative response of undifferentiated cells observed after adrenalectomy. If corticotrope reentry into cell cycle constitutes a normal mechanism to maintain the adult corticotrope pool, this same mechanism may also be perturbed during corticotrope adenoma development in Cushing's disease. PMID- 23754803 TI - Robust NMR approaches for the determination of homonuclear dipole-dipole coupling constants in studies of solid materials and biomolecules. AB - This review addresses the NMR spectroscopy study of molecular structure and dynamics by way of homonuclear dipole-dipole couplings by relying on their orientation and direct distance dependence. The study of homonuclear couplings as opposed to heteronuclear couplings poses specific challenges. On the one hand, two like spins cannot be independently manipulated easily, which means that simple shift-refocusing concepts by using hard pi pulses cannot be used to cope with potentially large chemical-shift dispersions at the high fields used today. On the other hand, the noncommutativity of the different pair Hamiltonians in a multispin system leads to complications associated with the isolation of specific pair couplings while minimizing the influence of the other spins. In particular, the so-called dipolar-truncation effect challenges the observation of weak couplings of interest in the presence of stronger ones. Recent advances in determining homonuclear dipole-dipole coupling constants are reviewed, stressing the use of double-quantum spectroscopy approaches and their similarity to the popular heteronuclear rotational-echo double-resonance experiment. Particular emphasis is put on corrections for the influence of transverse relaxation effects on the measured data, and the handling of distribution effects as well as potential dynamic heterogeneities in complex substances. PMID- 23754802 TI - Lhcgr expression in granulosa cells: roles for PKA-phosphorylated beta-catenin, TCF3, and FOXO1. AB - Ovarian follicles lacking FSH or FSH receptors fail to progress to a preovulatory stage, resulting in infertility. One hallmark of the preovulatory follicle is the presence of luteinizing hormone/choriogonadotropin receptors (LHCGR) on granulosa cells (GCs). However, the mechanisms by which FSH induces Lhcgr gene expression are poorly understood. Our results show that protein kinase A (PKA) and phosphoinositide 3-kinase (PI3K)/AKT pathways are required for FSH to activate both the murine Lhcgr-luciferase reporter and expression of Lhcgr mRNA in rat GCs. Based on results showing that an adenovirus (Ad) expressing a steroidogenic factor 1 (SF1) mutant that cannot bind beta-catenin abolished FSH-induced Lhcgr mRNA, we evaluated the role of beta-catenin in the regulation of Lhcgr gene expression. FSH promoted the PKA-dependent, PI3K-independent phosphorylation of beta-catenin on Ser552 and Ser665. FSH activated the beta-catenin/T-cell factor (TCF) artificial promoter-reporter TOPFlash via a PKA-dependent, PI3K-independent pathway, and dominant-negative (DN) TCF abolished FSH-activated Lhcgr-luciferase reporter and induction of Lhcgr mRNA. Microarray analysis of GCs treated with Ad DN-TCF and FSH identified the Lhcgr as the most down-regulated gene. Chromatin immunoprecipitation results placed beta-catenin phosphorylated on Ser552 and Ser675 and SF1 on the Lhcgr promoter in FSH-treated GCs; TCF3 was constitutively associated with the Lhcgr promoter. Transduction with an Ad-phospho-beta-catenin mutant (Ser552/665/Asp) enhanced Lhcgr mRNA expression in FSH-treated cells greater than 3-fold. Finally, we identified a recognized PI3K/AKT target, forkhead box O1, as a negative regulator of Lhcgr mRNA expression. These results provide new understanding of the complex regulation of Lhcgr gene expression in GCs. PMID- 23754804 TI - Trends in the use of biologic agents among rheumatoid arthritis patients enrolled in the US medicare program. AB - OBJECTIVE: Self-injectable biologic agents have been covered by Medicare Part D since 2006. We hypothesized that this coverage benefit and related financial considerations would lead to increased use of self-injectable biologic agents overtime and would be influential in determining which rheumatoid arthritis (RA) patients received infusion versus self injected biologic agents. METHODS: We used 100% of US Medicare data (2006-2009) to calculate the prevalence of use of different RA biologic agents and evaluated factors associated with receipt of infliximab versus etanercept or adalimumab among patients starting their first anti-tumor necrosis factor (anti-TNF) agent. RESULTS: Through 2009, the prevalence of biologic agent use overall (~ 27%) and via infusion (16-17%) or self-injection(10-11%) remained unchanged among Medicare beneficiaries with RA. After adjusting for patient characteristics,stronger physician preference for infused biologic agents was related to physician reimbursement and associated with an increased likelihood of using infliximab as the first anti-TNF agent (odds ratio [OR] comparing the highest to lowest quartile of physician preference 7.3, 95% confidence interval [95% CI] 6.4-8.3). Lower-income patients who received state assistance for Medicare coverage had lower out-of-pocket payments for injectable biologic agents ($4.10/prescription) and were less likely to use infliximab (OR 0.41, 95% CI 0.37-0.45) compared with etanercept or adalimumab. CONCLUSION: The prevalence of injection and infusion biologic agents in RA remained stable in the Medicare program through 2009. The choice between an intravenous infusion versus an injectable anti-TNF agent as first-line treatment appeared to be strongly influenced by financial considerations affecting both patients and physicians. PMID- 23754805 TI - Production of dimethylfuran from hydroxymethylfurfural through catalytic transfer hydrogenation with ruthenium supported on carbon. AB - RuC ees' transfer: Transfer hydrogenation using alcohols as hydrogen donors and supported ruthenium catalysts results in the selective conversion of hydroxymethylfurfural to dimethylfuran (>80% yield). During transfer hydrogenation, the hydrogen produced from alcohols is utilized in the hydrogenation of hydroxymethylfurfural. PMID- 23754807 TI - Energy, genes and evolution: introduction to an evolutionary synthesis. AB - Life is the harnessing of chemical energy in such a way that the energy harnessing device makes a copy of itself. No energy, no evolution. The 'modern synthesis' of the past century explained evolution in terms of genes, but this is only part of the story. While the mechanisms of natural selection are correct, and increasingly well understood, they do little to explain the actual trajectories taken by life on Earth. From a cosmic perspective-what is the probability of life elsewhere in the Universe, and what are its probable traits? a gene-based view of evolution says almost nothing. Irresistible geological and environmental changes affected eukaryotes and prokaryotes in very different ways, ones that do not relate to specific genes or niches. Questions such as the early emergence of life, the morphological and genomic constraints on prokaryotes, the singular origin of eukaryotes, and the unique and perplexing traits shared by all eukaryotes but not found in any prokaryote, are instead illuminated by bioenergetics. If nothing in biology makes sense except in the light of evolution, nothing in evolution makes sense except in the light of energetics. This Special Issue of Philosophical Transactions examines the interplay between energy transduction and genome function in the major transitions of evolution, with implications ranging from planetary habitability to human health. We hope that these papers will contribute to a new evolutionary synthesis of energetics and genetics. PMID- 23754808 TI - The inevitable journey to being. AB - Life is evolutionarily the most complex of the emergent symmetry-breaking, macroscopically organized dynamic structures in the Universe. Members of this cascading series of disequilibria-converting systems, or engines in Cottrell's terminology, become ever more complicated-more chemical and less physical-as each engine extracts, exploits and generates ever lower grades of energy and resources in the service of entropy generation. Each one of these engines emerges spontaneously from order created by a particular mother engine or engines, as the disequilibrated potential daughter is driven beyond a critical point. Exothermic serpentinization of ocean crust is life's mother engine. It drives alkaline hydrothermal convection and thereby the spontaneous production of precipitated submarine hydrothermal mounds. Here, the two chemical disequilibria directly causative in the emergence of life spontaneously arose across the mineral precipitate membranes separating the acidulous, nitrate-bearing CO2-rich, Hadean sea from the alkaline and CH4/H2-rich serpentinization-generated effluents. Essential redox gradients-involving hydrothermal CH4 and H2 as electron donors, CO2 and nitrate, nitrite, and ferric iron from the ambient ocean as acceptors were imposed which functioned as the original 'carbon-fixing engine'. At the same time, a post-critical-point (milli)voltage pH potential (proton concentration gradient) drove the condensation of orthophosphate to produce a high energy currency: 'the pyrophosphatase engine'. PMID- 23754809 TI - The energetics of organic synthesis inside and outside the cell. AB - Thermodynamic modelling of organic synthesis has largely been focused on deep-sea hydrothermal systems. When seawater mixes with hydrothermal fluids, redox gradients are established that serve as potential energy sources for the formation of organic compounds and biomolecules from inorganic starting materials. This energetic drive, which varies substantially depending on the type of host rock, is present and available both for abiotic (outside the cell) and biotic (inside the cell) processes. Here, we review and interpret a library of theoretical studies that target organic synthesis energetics. The biogeochemical scenarios evaluated include those in present-day hydrothermal systems and in putative early Earth environments. It is consistently and repeatedly shown in these studies that the formation of relatively simple organic compounds and biomolecules can be energy-yielding (exergonic) at conditions that occur in hydrothermal systems. Expanding on our ability to calculate biomass synthesis energetics, we also present here a new approach for estimating the energetics of polymerization reactions, specifically those associated with polypeptide formation from the requisite amino acids. PMID- 23754810 TI - Discovering the electronic circuit diagram of life: structural relationships among transition metal binding sites in oxidoreductases. AB - Oxidoreductases play a central role in catalysing enzymatic electron-transfer reactions across the tree of life. To first order, the equilibrium thermodynamic properties of these proteins are governed by protein folds associated with specific transition metals and ligands at the active site. A global analysis of holoenzyme structures and functions suggests that there are fewer than approximately 500 fundamental oxidoreductases, which can be further clustered into 35 unique groups. These catalysts evolved in prokaryotes early in the Earth's history and are largely responsible for the emergence of non-equilibrium biogeochemical cycles on the planet's surface. Although the evolutionary history of the amino acid sequences in the oxidoreductases is very difficult to reconstruct due to gene duplication and horizontal gene transfer, the evolution of the folds in the catalytic sites can potentially be used to infer the history of these enzymes. Using a novel, yet simple analysis of the secondary structures associated with the ligands in oxidoreductases, we developed a structural phylogeny of these enzymes. The results of this 'composome' analysis suggest an early split from a basal set of a small group of proteins dominated by loop structures into two families of oxidoreductases, one dominated by alpha-helices and the second by beta-sheets. The structural evolutionary patterns in both clades trace redox gradients and increased hydrogen bond energy in the active sites. The overall pattern suggests that the evolution of the oxidoreductases led to decreased entropy in the transition metal folds over approximately 2.5 billion years, allowing the enzymes to use increasingly oxidized substrates with high specificity. PMID- 23754811 TI - Beating the acetyl coenzyme A-pathway to the origin of life. AB - Attempts to draft plausible scenarios for the origin of life have in the past mainly built upon palaeogeochemical boundary conditions while, as detailed in a companion article in this issue, frequently neglecting to comply with fundamental thermodynamic laws. Even if demands from both palaeogeochemistry and thermodynamics are respected, then a plethora of strongly differing models are still conceivable. Although we have no guarantee that life at its origin necessarily resembled biology in extant organisms, we consider that the only empirical way to deduce how life may have emerged is by taking the stance of assuming continuity of biology from its inception to the present day. Building upon this conviction, we have assessed extant types of energy and carbon metabolism for their appropriateness to conditions probably pertaining in those settings of the Hadean planet that fulfil the thermodynamic requirements for life to come into being. Wood-Ljungdahl (WL) pathways leading to acetyl CoA formation are excellent candidates for such primordial metabolism. Based on a review of our present understanding of the biochemistry and biophysics of acetogenic, methanogenic and methanotrophic pathways and on a phylogenetic analysis of involved enzymes, we propose that a variant of modern methanotrophy is more likely than traditional WL systems to date back to the origin of life. The proposed model furthermore better fits basic thermodynamic demands and palaeogeochemical conditions suggested by recent results from extant alkaline hydrothermal seeps. PMID- 23754812 TI - Requirements of the cytosolic iron-sulfur cluster assembly pathway in Arabidopsis. AB - The assembly of iron-sulfur (Fe-S) clusters requires dedicated protein factors inside the living cell. Striking similarities between prokaryotic and eukaryotic assembly proteins suggest that plant cells inherited two different pathways through endosymbiosis: the ISC pathway in mitochondria and the SUF pathway in plastids. Fe-S proteins are also found in the cytosol and nucleus, but little is known about how they are assembled in plant cells. Here, we show that neither plastid assembly proteins nor the cytosolic cysteine desulfurase ABA3 are required for the activity of cytosolic aconitase, which depends on a [4Fe-4S] cluster. In contrast, cytosolic aconitase activity depended on the mitochondrial cysteine desulfurase NFS1 and the mitochondrial transporter ATM3. In addition, we were able to complement a yeast mutant in the cytosolic Fe-S cluster assembly pathway, dre2, with the Arabidopsis homologue AtDRE2, but only when expressed together with the diflavin reductase AtTAH18. Spectroscopic characterization showed that purified AtDRE2 could bind up to two Fe-S clusters. Purified AtTAH18 bound one flavin per molecule and was able to accept electrons from NAD(P)H. These results suggest that the proteins involved in cytosolic Fe-S cluster assembly are highly conserved, and that dependence on the mitochondria arose before the second endosymbiosis event leading to plastids. PMID- 23754813 TI - Evolutionary rewiring: a modified prokaryotic gene-regulatory pathway in chloroplasts. AB - Photosynthetic electron transport regulates chloroplast gene transcription through the action of a bacterial-type sensor kinase known as chloroplast sensor kinase (CSK). CSK represses photosystem I (PS I) gene transcription in PS I light and thus initiates photosystem stoichiometry adjustment. In cyanobacteria and in non-green algae, CSK homologues co-exist with their response regulator partners in canonical bacterial two-component systems. In green algae and plants, however, no response regulator partner of CSK is found. Yeast two-hybrid analysis has revealed interaction of CSK with sigma factor 1 (SIG1) of chloroplast RNA polymerase. Here we present further evidence for the interaction between CSK and SIG1. We also show that CSK interacts with quinone. Arabidopsis SIG1 becomes phosphorylated in PS I light, which then specifically represses transcription of PS I genes. In view of the identical signalling properties of CSK and SIG1 and of their interactions, we suggest that CSK is a SIG1 kinase. We propose that the selective repression of PS I genes arises from the operation of a gene-regulatory phosphoswitch in SIG1. The CSK-SIG1 system represents a novel, rewired chloroplast-signalling pathway created by evolutionary tinkering. This regulatory system supports a proposal for the selection pressure behind the evolutionary stasis of chloroplast genes. PMID- 23754814 TI - Controlling the delicate balance of tetrapyrrole biosynthesis. AB - Tetrapyrroles are a family of compounds that contain four pyrrole rings. They are involved in many fundamental biological processes such as photoreception, electron transport, gas transport and also as cofactors for enzymatic reactions. As regulators of protein activity, tetrapyrroles mediate cellular response to light, oxygen and nutrient levels in the surrounding environment. Biosynthesis of haem tetrapyrroles shares, conserved pathways and enzymes among all three domains of life. This is contrasted by chlorophyll biosynthesis that is only present in eubacteria and chloroplasts, or cobalamin biosynthesis that is only present in eubacteria and archaea. This implicates haem as the most ancient, and chlorophyll as the most recent, of the common tetrapyrroles that are currently synthesized by existing organisms. Haem and chlorophyll are both toxic when synthesized in excess over apo-proteins that bind these tetrapyrroles. Accordingly, the synthesis of these tetrapyrroles has to be tightly regulated and coordinated with apo-protein production. The mechanism of regulating haem and chlorophyll synthesis has been studied intensively in Rhodobacter species and will be discussed. PMID- 23754815 TI - Energy, ageing, fidelity and sex: oocyte mitochondrial DNA as a protected genetic template. AB - Oxidative phosphorylation couples ATP synthesis to respiratory electron transport. In eukaryotes, this coupling occurs in mitochondria, which carry DNA. Respiratory electron transport in the presence of molecular oxygen generates free radicals, reactive oxygen species (ROS), which are mutagenic. In animals, mutational damage to mitochondrial DNA therefore accumulates within the lifespan of the individual. Fertilization generally requires motility of one gamete, and motility requires ATP. It has been proposed that oxidative phosphorylation is nevertheless absent in the special case of quiescent, template mitochondria, that these remain sequestered in oocytes and female germ lines and that oocyte mitochondrial DNA is thus protected from damage, but evidence to support that view has hitherto been lacking. Here we show that female gametes of Aurelia aurita, the common jellyfish, do not transcribe mitochondrial DNA, lack electron transport, and produce no free radicals. In contrast, male gametes actively transcribe mitochondrial genes for respiratory chain components and produce ROS. Electron microscopy shows that this functional division of labour between sperm and egg is accompanied by contrasting mitochondrial morphology. We suggest that mitochondrial anisogamy underlies division of any animal species into two sexes with complementary roles in sexual reproduction. We predict that quiescent oocyte mitochondria contain DNA as an unexpressed template that avoids mutational accumulation by being transmitted through the female germ line. The active descendants of oocyte mitochondria perform oxidative phosphorylation in somatic cells and in male gametes of each new generation, and the mutations that they accumulated are not inherited. We propose that the avoidance of ROS-dependent mutation is the evolutionary pressure underlying maternal mitochondrial inheritance and the developmental origin of the female germ line. PMID- 23754816 TI - Interactions of photosynthesis with genome size and function. AB - Photolithotrophs are divided between those that use water as their electron donor (Cyanobacteria and the photosynthetic eukaryotes) and those that use a different electron donor (the anoxygenic photolithotrophs, all of them Bacteria). Photolithotrophs with the most reduced genomes have more genes than do the corresponding chemoorganotrophs, and the fastest-growing photolithotrophs have significantly lower specific growth rates than the fastest-growing chemoorganotrophs. Slower growth results from diversion of resources into the photosynthetic apparatus, which accounts for about half of the cell protein. There are inherent dangers in (especially oxygenic) photosynthesis, including the formation of reactive oxygen species (ROS) and blue light sensitivity of the water spitting apparatus. The extent to which photolithotrophs incur greater DNA damage and repair, and faster protein turnover with increased rRNA requirement, needs further investigation. A related source of environmental damage is ultraviolet B (UVB) radiation (280-320 nm), whose flux at the Earth's surface decreased as oxygen (and ozone) increased in the atmosphere. This oxygenation led to the requirements of defence against ROS, and decreasing availability to organisms of combined (non-dinitrogen) nitrogen and ferrous iron, and (indirectly) phosphorus, in the oxygenated biosphere. Differential codon usage in the genome and, especially, the proteome can lead to economies in the use of potentially growth-limiting elements. PMID- 23754817 TI - Why did eukaryotes evolve only once? Genetic and energetic aspects of conflict and conflict mediation. AB - According to multi-level theory, evolutionary transitions require mediating conflicts between lower-level units in favour of the higher-level unit. By this view, the origin of eukaryotes and the origin of multicellularity would seem largely equivalent. Yet, eukaryotes evolved only once in the history of life, whereas multicellular eukaryotes have evolved many times. Examining conflicts between evolutionary units and mechanisms that mediate these conflicts can illuminate these differences. Energy-converting endosymbionts that allow eukaryotes to transcend surface-to-volume constraints also can allocate energy into their own selfish replication. This principal conflict in the origin of eukaryotes can be mediated by genetic or energetic mechanisms. Genome transfer diminishes the heritable variation of the symbiont, but requires the de novo evolution of the protein-import apparatus and was opposed by selection for selfish symbionts. By contrast, metabolic signalling is a shared primitive feature of all cells. Redox state of the cytosol is an emergent feature that cannot be subverted by an individual symbiont. Hypothetical scenarios illustrate how metabolic regulation may have mediated the conflicts inherent at different stages in the origin of eukaryotes. Aspects of metabolic regulation may have subsequently been coopted from within-cell to between-cell pathways, allowing multicellularity to emerge repeatedly. PMID- 23754818 TI - Bioenergetics in human evolution and disease: implications for the origins of biological complexity and the missing genetic variation of common diseases. AB - Two major inconsistencies exist in the current neo-Darwinian evolutionary theory that random chromosomal mutations acted on by natural selection generate new species. First, natural selection does not require the evolution of ever increasing complexity, yet this is the hallmark of biology. Second, human chromosomal DNA sequence variation is predominantly either neutral or deleterious and is insufficient to provide the variation required for speciation or for predilection to common diseases. Complexity is explained by the continuous flow of energy through the biosphere that drives the accumulation of nucleic acids and information. Information then encodes complex forms. In animals, energy flow is primarily mediated by mitochondria whose maternally inherited mitochondrial DNA (mtDNA) codes for key genes for energy metabolism. In mammals, the mtDNA has a very high mutation rate, but the deleterious mutations are removed by an ovarian selection system. Hence, new mutations that subtly alter energy metabolism are continuously introduced into the species, permitting adaptation to regional differences in energy environments. Therefore, the most phenotypically significant gene variants arise in the mtDNA, are regional, and permit animals to occupy peripheral energy environments where rarer nuclear DNA (nDNA) variants can accumulate, leading to speciation. The neutralist-selectionist debate is then a consequence of mammals having two different evolutionary strategies: a fast mtDNA strategy for intra-specific radiation and a slow nDNA strategy for speciation. Furthermore, the missing genetic variation for common human diseases is primarily mtDNA variation plus regional nDNA variants, both of which have been missed by large, inter-population association studies. PMID- 23754819 TI - Energy, ecology and the distribution of microbial life. AB - Mechanisms that govern the coexistence of multiple biological species have been studied intensively by ecologists since the turn of the nineteenth century. Microbial ecologists in the meantime have faced many fundamental challenges, such as the lack of an ecologically coherent species definition, lack of adequate methods for evaluating population sizes and community composition in nature, and enormous taxonomic and functional diversity. The accessibility of powerful, culture-independent molecular microbiology methods offers an opportunity to close the gap between microbial science and the main stream of ecological theory, with the promise of new insights and tools needed to meet the grand challenges humans face as planetary engineers and galactic explorers. We focus specifically on resources related to energy metabolism because of their direct links to elemental cycling in the Earth's history, engineering applications and astrobiology. To what extent does the availability of energy resources structure microbial communities in nature? Our recent work on sulfur- and iron-oxidizing autotrophs suggests that apparently subtle variations in the concentration ratios of external electron donors and acceptors select for different microbial populations. We show that quantitative knowledge of microbial energy niches (population-specific patterns of energy resource use) can be used to predict variations in the abundance of specific taxa in microbial communities. Furthermore, we propose that resource ratio theory applied to micro-organisms will provide a useful framework for identifying how environmental communities are organized in space and time. PMID- 23754821 TI - Evaluation of an innovative computer-assisted sagittal split ramus osteotomy to reduce neurosensory alterations following orthognathic surgery: a pilot study. AB - BACKGROUND: Sagittal split ramus osteotomy (SSRO) can be associated with postoperative neurosensory disturbances. This study aimed to evaluate the effectiveness of computer-assisted SSRO in reducing the incidence and severity of neurosensory alterations, using a surgical guide fabricated by computer-aided design and rapid prototyping (to guide bone cutting lateral to the inferior alveolar nerve). METHODS: A prospective double-blind, randomized controlled, clinical trial of computer-assisted SSRO vs conventional SSRO (assigned in a split-mouth design) in eight patients, mean age 23 (range 18-30) years, who participated in one session preoperatively and three sessions at 1 week and 1, 3 and 6 months postoperatively. At each session, subjective oral sensation was scored and quantitative sensory tests were performed. Neurosensory changes were compared between the two sides. RESULTS: The results showed that on the computer assisted SSRO sides, patients had lower postoperative abnormal thresholds for the Semmes-Weinstein monofilaments on lower lip and chin (p < 0.05 at 3 months) and for the two-point discrimination on lower lip (p < 0.05 at 1 week) and chin (p < 0.05 at 6 months), with fewer abnormal self-reported changes in lower lip sensation (p < 0.05 at 1 week) after surgery. CONCLUSIONS: These findings imply that computer-assisted SSRO is associated with better levels of neurosensory function after surgery. PMID- 23754822 TI - Safety of surgery after rituximab therapy in 133 patients with rheumatoid arthritis: data from the autoimmunity and rituximab registry. AB - OBJECTIVE: We used data from the AutoImmunity and Rituximab (AIR) registry to investigate the safety of surgery for patients with rheumatoid arthritis receiving rituximab (RTX) in routine care. METHODS: Data for patients included in the AIR registry and undergoing surgery during the year following an infusion of RTX were reviewed to describe the frequency of postsurgical complications, compare patients with and without complications, and identify factors associated with complications. RESULTS: We examined data for 133 patients with a known date of surgery and at least 1 followup visit, corresponding to 140 procedures, including 94 orthopedic surgeries (67%) and 23 abdominal surgeries (16.5%). The median delay between surgery and the last RTX infusion was 6.4 months (interquartile range 4.3- 8.7 months), without any difference between patients with and without complications. Nine patients (6.7%) experienced 12 complications (8.5%), including 8 surgical site infections (5.7%) and 1 death due to septic shock. Postoperative complications occurred after 4.3% of abdominal surgeries (1 of 23) and 7.4% of orthopedic surgeries (7 of 95). On univariate analysis, spine surgery was associated with postoperative complications (P = 0.048). CONCLUSION: In common practice, the risk of complications may be more important in case of spine surgery, but does not seem to be linked to the time between the last RTX infusion and surgery. PMID- 23754823 TI - Crown-rump length discordance in the first trimester: a predictor of adverse outcome in twin pregnancies? AB - OBJECTIVES: To evaluate the usefulness of first-trimester crown-rump length (CRL) discordance in predicting adverse outcome in twin pregnancies. METHODS: This retrospective study included a large cohort retrieved from local ultrasound databases at 14 obstetric departments in Denmark, comprising all twin pregnancies with two live fetuses scanned between 11 and 14 weeks' gestation during the period 1 January 2004 to 31 December 2006. The association between CRL discordance >= 10 % and adverse outcome was evaluated. RESULTS: Among 1993 twin pregnancies, 1733 were dichorionic (156 (9%) discordant; 1577 (91%) concordant) and 260 were monochorionic (32 (12%) discordant; 228 (88%) concordant). In dichorionic twin pregnancies we found an association between CRL discordance >= 10% and preterm delivery before 34 weeks' gestation (P=0.007), birth weight discordance (P=0.001) and mean birth weight (P=0.033). In monochorionic twin pregnancies we found an association between CRL discordance >= 10% and birth weight discordance (P=0.02) and mean birth weight (P=0.03). To evaluate CRL discordance as a predictor of fetal loss and preterm delivery before 34 weeks' gestation, receiver-operating characteristics curves were created for each outcome. For CRL discordance >= 10% as a predictor of fetal loss and preterm delivery in dichorionic twin pregnancies, sensitivity was 0.17 (95% CI, 0.06 0.28) and 0.14 (95% CI, 0.10-0.18), respectively, and in monochorionic twin pregnancies it was 0.10 (95% CI, 0.03-0.22) and 0.16 (95% CI, 0.06-0.26), respectively. CONCLUSIONS: CRL discordance in twin pregnancies is associated with, but is not a strong predictor of, adverse outcome. PMID- 23754820 TI - Early bioenergetic evolution. AB - Life is the harnessing of chemical energy in such a way that the energy harnessing device makes a copy of itself. This paper outlines an energetically feasible path from a particular inorganic setting for the origin of life to the first free-living cells. The sources of energy available to early organic synthesis, early evolving systems and early cells stand in the foreground, as do the possible mechanisms of their conversion into harnessable chemical energy for synthetic reactions. With regard to the possible temporal sequence of events, we focus on: (i) alkaline hydrothermal vents as the far-from-equilibrium setting, (ii) the Wood-Ljungdahl (acetyl-CoA) pathway as the route that could have underpinned carbon assimilation for these processes, (iii) biochemical divergence, within the naturally formed inorganic compartments at a hydrothermal mound, of geochemically confined replicating entities with a complexity below that of free-living prokaryotes, and (iv) acetogenesis and methanogenesis as the ancestral forms of carbon and energy metabolism in the first free-living ancestors of the eubacteria and archaebacteria, respectively. In terms of the main evolutionary transitions in early bioenergetic evolution, we focus on: (i) thioester-dependent substrate-level phosphorylations, (ii) harnessing of naturally existing proton gradients at the vent-ocean interface via the ATP synthase, (iii) harnessing of Na(+) gradients generated by H(+)/Na(+) antiporters, (iv) flavin-based bifurcation-dependent gradient generation, and finally (v) quinone-based (and Q-cycle-dependent) proton gradient generation. Of those five transitions, the first four are posited to have taken place at the vent. Ultimately, all of these bioenergetic processes depend, even today, upon CO2 reduction with low-potential ferredoxin (Fd), generated either chemosynthetically or photosynthetically, suggesting a reaction of the type 'reduced iron -> reduced carbon' at the beginning of bioenergetic evolution. PMID- 23754824 TI - Food reinforcement partially mediates the effect of socioeconomic status on body mass index. AB - OBJECTIVE: Low socioeconomic status (low SES), as defined by income or educational attainment, has been associated with obesity in industrialized nations. Low SES persons have limited resources and may experience food insecurity that increases food reinforcement. Food reinforcement has been positively related to energy intake and weight status, and increased food reinforcement may explain the higher prevalence of obesity among low SES individuals who have restricted access to low-energy-dense foods and nonfood reinforcers. DESIGN AND METHODS: Annual household income, highest education level completed and food reinforcement in 166 adults of varying body mass index (BMI, kg m(-2) ) was measured. RESULTS: Multivariate linear regression analyses controlling for age, sex, minority status, session hunger, and the reinforcing value of nonfood alternatives showed that household income was related to food reinforcement (P = 0.048) and BMI (P = 0.019), and that food reinforcement was related to BMI (P = 0.0017). Path analyses revealed a significant indirect effect of household income on BMI through food reinforcement, suggesting that the relationship between lower household income and greater BMI was mediated in part by increased food reinforcement. A similar pattern of results was observed when education level was used as the proxy for SES. CONCLUSIONS: These findings support the hypothesis that deprivation and restricted food choice associated with low SES enhance food reinforcement, increasing the risk for obesity. PMID- 23754825 TI - Liquid-based cytology improves preoperative diagnostic accuracy of the tall cell variant of papillary thyroid carcinoma. AB - The tall cell variant (TCV) of papillary thyroid carcinoma (PTC) is the most common among the aggressive variants of the disease. We aimed to investigate the clinicopathologic characteristics of TCV, and evaluate the diagnostic efficacy of liquid-based cytology (LBC) in TCV detection compared with conventional smear in thyroid fine needle aspiration (FNA). A total of 266 consecutive patients (220 women and 46 men) with PTC were enrolled. We analyzed tumor characteristics according to histologic growth patterns as classic, classic PTC with tall cell features, and TCV. The cytomorphologic features of these subtypes were investigated according to the preparation methods of conventional smear and LBC. TCV and classic PTC with tall cell features comprised 4.9% and 6.0% of all tumors, respectively, and were significantly associated with older age at presentation, larger tumor size, high frequency of extrathyroid extension, and BRAF mutation in comparison with classic PTC. However, there was no statistically significant difference in clinicopathologic features between TCV and classic PTC with tall cell features. Tall cells were more easily detected by LBC than by conventional smear. The percentage of tall cells identified using LBC was well correlated with three histologic subtypes. Our results demonstrate that TCV is more common than previously recognized in Korea and any PTC containing tall cells may have identical biological behavior regardless of the precise proportions of tall cells. It is possible to make a preoperative diagnosis of TCV using LBC. PMID- 23754826 TI - Activation of adipose tissue macrophages in obese mice does not require lymphocytes. AB - OBJECTIVE: Macrophages which infiltrate adipose tissue and secrete proinflammatory cytokines may be responsible for obesity-induced insulin resistance. However, the reason why macrophages migrate into adipose tissue and become activated remains unknown though some studies suggest that this may be regulated by T and B lymphocytes. In this study, it has been tested whether T and B lymphocytes and natural killer (NK) cells were necessary for the obesity induced activation of macrophages in adipose tissue. DESIGN AND METHODS: NOD/SCID/IL2-receptor gamma-chain knockout (NSG) mice, which lack mature T and B lymphocytes and NK cells, were made obese by selectively reducing litters and weaning onto a high-fat diet. Mice were then maintained on the diet for 10-11 weeks. RESULTS: Adipose tissue from obese NSG mice had more activated macrophages than nonobese mice. These macrophages were found in "crown-like structures" surrounding adipocytes, and expressed higher levels of the inflammatory cytokine TNF-alpha. However, obesity did not impair glucose tolerance in the NSG mice. CONCLUSIONS: These studies demonstrated that T and B lymphocytes and NK cells are not necessary for adipose tissue macrophage activation in obese mice. T and B lymphocytes and/or NK cells may be necessary for the development of obesity induced impaired glucose tolerance. PMID- 23754827 TI - Cognitive enhancers. PMID- 23754828 TI - A1C screening less expensive? PMID- 23754829 TI - An evaluation of the diagnostic and prognostic significance of p16(INK4a) /p21(WAF1/Cip1) immunostaining in squamous intraepithelial lesions of the uterine cervix using liquid-based cytology specimens. AB - Human papillomavirus (HPV) infection frequently causes squamous intraepithelial lesions (SIL) of the uterine cervix and consequently gives rise to squamous cell carcinoma. It is therefore important to identify cases that potentially develop higher grades of SIL at an early stage of the disease. In this study, we thus investigated whether immunocytochemistry for p21(WAF1/Cip1) and p16(INK4a) could be applicable in the diagnosis and the prognostic prediction of SIL in combination with genomic analyses of HPV. The genomic analysis of high-risk HPV (hrHPV), which was done by reversed dot blotting and by in situ hybridization, and immunocytochemistry were performed on liquid-based cytological specimens. A cross-sectional study comprising 145 cases of NILM, ASC-US, LSIL, and HSIL indicated that the incidence of the positive cases for p16(INK4a) and p21(WAF1/Cip1) and hrHPV increased with the grade of SIL. A double positive status for p16(INK4a) and p21(WAF1/Cip1) was a significant discriminator between HSIL and LSIL/NILM, even when applied in conjunction with the genomic test for hrHPV (P = 0.006 by logistic regression analysis). However, a prospective study employing 61 NILM/ASC-US cases, revealed that the p16(INK4a) /p21(WAF1/Cip1) immunostaining was not a significant predictor for the progression of SIL, whereas the cytological diagnosis (NILM vs. ASC-US) and the infection status of hrHPV conferred significant effects on the prognosis. Immunostaining of p16(INK4a) and p21(WAF1/Cip1) provides additional information on the cytological diagnosis of SIL. A further analysis using a larger population is warranted to obtain a conclusive result regarding the prognostic significance of p16(INK4a) /p21(WAF1/Cip1) immunocytochemistry in the diagnosis of SIL. PMID- 23754830 TI - Coincident Merkel cell carcinoma and B-cell lymphoma: a report of two cases evaluated by cytology. PMID- 23754831 TI - Transfer of 238U and 232Th from soil to plant in a high background radiation area of the southwestern region of Cameroon. AB - In order to estimate the soil-to-plant transfer factors (TFs) of some natural radionuclides, the activity of 238U and 232Th was measured in the soil and in agricultural crop samples collected from identified high background radiation areas in the southwestern region of Cameroon. The results showed that the 238U and 232Th TFs values were in the ranges 1.0*10-2-12.2*10-1 kg kg-1 and 5.0*10-2 9.7*10-1 kg kg-1, respectively. These computed TFs values were found to be globally higher than those proposed by the International Atomic Energy Agency. PMID- 23754832 TI - Measurement of 238U,232Th and 40K in boreholes at Gosa and Lugbe, Abuja, north central Nigeria. AB - The purpose of this project is to evaluate the suitability of different sites as locations for obtaining underground water for consumption. The analysis of 238U, 232Th and 40K from rock samples from each layer of borehole at a depth of ~50 m at Site A borehole, S3L1-S3L6 in Gosa and 40 m at Site B borehole, S4L1-S4L5 in Lugbe, Abuja, north central Nigeria is presented. The gamma-ray spectrometry was carried out using a high-purity germanium detector coupled to a computer-based high-resolution multichannel analyzer. The activity concentrations at Site A borehole for 238U have a mean value of 26 +/- 3, ranging from 23 +/- 2 to 30 +/- 3 Bq kg-1, 232Th a mean value of 63 +/- 5, ranging from 48 +/- 4 to 76 +/- 6 Bq kg-1 and 40K a mean value of 573 +/- 72, ranging from 437 +/- 56 to 821 +/- 60 Bq kg-1. The activity concentrations at Site B borehole for 238U have a mean value of 20 +/- 2, ranging from 16 +/- 2 to 23 +/- 2 Bq kg-1, 232Th a mean value of 46 +/- 4, ranging from 43 +/- 4 to 49 +/- 4 Bq kg-1, 40K a mean value of 915 +/- 116 and ranging from 817 +/- 103 Bq kg-1 to 1011 +/- 128 Bq kg-1. It is noted that the higher activity concentrations of 232Th and 238U are found in Site A at Gosa. Site B has lower radioactivity, and it is recommended that both sites are suitable for underground water consumption. PMID- 23754833 TI - Estimation of (41)Ar production in 0.1-1.1.0-GeV proton accelerator vaults using FLUKA Monte Carlo code. AB - The FLUKA Monte Carlo simulations are carried out to estimate the (41)Ar concentration inside accelerator vaults of various sizes when proton beams of energy 0.1-1.0 GeV are incident on thick copper and lead targets. Generally (41)Ar concentration is estimated using an empirical formula suggested in the NCRP 144, which assumes the activation is caused only by thermal neutrons alone. It is found that while the analytical and Monte Carlo techniques give similar results for the thermal neutron fluence inside the vault, the (41)Ar concentration is under-predicted by the empirical formula. It is also found that the thermal neutrons contribute ~41 % to the total (41)Ar production while 56 % production is caused by neutrons between 0.025 and 1 eV. A modified factor is suggested for the use in the empirical expression to estimate the (41)Ar activity 0.1-1.0-GeV proton accelerator enclosures. PMID- 23754834 TI - Conversion factors for estimation of effective dose in paediatric chest tomosynthesis. AB - For chest tomosynthesis in adults, a conversion factor of 0.26 mSv/Gy cm2 has been reported for calculating the effective dose from the registered dose-area product. The aim of this study was to determine conversion factors for chest tomosynthesis in children. Using the Monte Carlo-based computer software PCXMC 2.0, simulations were performed on modified phantoms for males and females aged 8 19 y, in the posteroanterior and anteroposterior projection, with energies 80-140 kV and copper filtration 0.1-0.3 mm. Resulting conversion factors ranged between 0.23 and 1.09 mSv/Gy cm2, decreased with patient age, were significantly higher in the anteroposterior projection and increased with increased energy or copper filtration. To avoid an underestimation of effective dose in children, it is recommended to use age-dependent conversion factors. As a simplified approach, three conversion factors might be used for posteroanterior chest tomosynthesis and radiography in children, namely 0.6 (8-10 y), 0.4 (11-14 y) and 0.3 mSv/Gy cm2 (15-19 y). PMID- 23754835 TI - Relevance of microscopic indicators of chromosomal instability in routine reporting of malignancies. AB - Chromosomal instability (CIN) is the defining feature of most human cancers. The role of CIN has been suggested in diagnosis and prognostication of the tumors since long. However, the molecular methods used for its identification are costly, require expertise and may not be available in many of the laboratories. Therefore, this article tries to revisit the already described morphological indicators of CIN like multipolar mitoses, chromatin bridges, chromatin strings, nuclear heterogeneity, laggards, nuclear buds, micronuclei, and multinucleated micronucleated cells. The role of above as morphological biomarkers in diagnosis and prognosis of various cancers has been reviewed and the possibility of their inclusion in day to day reporting of malignancies is also discussed. PMID- 23754837 TI - Prognostic Value of the Neutrophil-Lymphocyte Ratio in Patients With ST-Elevated Acute Myocardial Infarction. AB - The predictive value of leukocyte counts has been reported in patients with acute myocardial infarction (AMI). We aimed to evaluate the predictive value of the total leukocyte count and neutrophil-lymphocyte (N/L) ratio for mortality due to AMI. A total of 522 patients with acute ST-elevated MI were included in the study. The study population was divided into tertiles based on admission N/L ratio values. High (n = 174) and low N/L (n = 348) ratio groups were defined as patients having values in the third tertile (>5.77) and lower 2 tertiles (<= 5.77), respectively. The high N/L ratio group had a significantly higher incidence of in-hospital cardiovascular mortality (13.8% vs 4.6%, P < .001). An N/L ratio >5.77 was found to be an independent predictor of in-hospital cardiovascular mortality (hazard ratio: 3.78, 95% confidence interval: 1.71-8.30, P = .001). A high N/L ratio is a strong and independent predictor of in-hospital cardiovascular mortality of AMI with ST elevation. PMID- 23754836 TI - Did I do that? Abnormal predictive processes in schizophrenia when button pressing to deliver a tone. AB - Motor actions are preceded by an efference copy of the motor command, resulting in a corollary discharge of the expected sensation in sensory cortex. These mechanisms allow animals to predict sensations, suppress responses to self generated sensations, and thereby process sensations efficiently and economically. During talking, patients with schizophrenia show less evidence of pretalking activity and less suppression of the speech sound, consistent with dysfunction of efference copy and corollary discharge, respectively. We asked if patterns seen in talking would generalize to pressing a button to hear a tone, a paradigm translatable to less vocal animals. In 26 patients [23 schizophrenia, 3 schizoaffective (SZ)] and 22 healthy controls (HC), suppression of the N1 component of the auditory event-related potential was estimated by comparing N1 to tones delivered by button presses and N1 to those tones played back. The lateralized readiness potential (LRP) associated with the motor plan preceding presses to deliver tones was estimated by comparing right and left hemispheres' neural activity. The relationship between N1 suppression and LRP amplitude was assessed. LRP preceding button presses to deliver tones was larger in HC than SZ, as was N1 suppression. LRP amplitude and N1 suppression were correlated in both groups, suggesting stronger efference copies are associated with stronger corollary discharges. SZ have reduced N1 suppression, reflecting corollary discharge action, and smaller LRPs preceding button presses to deliver tones, reflecting the efference copy of the motor plan. Effects seen during vocalization largely extend to other motor acts more translatable to lab animals. PMID- 23754838 TI - Oral anticoagulation therapy for elderly patients with atrial fibrillation: utility of bleeding risk covariates to better understand and moderate risks. AB - Elderly individuals are prone to nonvalvular atrial fibrillation (AF) with associated risks of arterial thromboembolic disease. Despite definitive guidelines, oral anticoagulant therapy (OAC) is notoriously underutilized in patients with AF. Physicians cite excessive bleeding risk as one reason they omit OAC for their older patients with AF. Improved understanding of the pathophysiology of age-related bleeding may improve risk-benefit assessments for warfarin and newer antithrombotic agents. We reviewed the literature to identify age-related pathophysiological elements that can exacerbate the likelihood of bleeding. In the context of the Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs/alcohol concomitantly (HAS-BLED) bleeding risk framework, we highlight age-related physiological dynamics that predispose to hemorrhage. The combination of increased age (>65 years) with the other elements of the risk factor stratification model identifies patients with AF who are especially susceptible to OAC-related bleeding, irrespective of the agent used. Empirically adjusting OAC dose relative to these common bleeding risks may help to achieve an improved risk-benefit therapeutic ratio. PMID- 23754839 TI - A relational understanding of sibling experiences of children with rare life limiting conditions: findings from a qualitative study. AB - Mucopolysaccharidoses (MPS) and Batten disease are rare life-limiting conditions (LLCs) characterised by progressive and permanent physical and cognitive decline. The impact of such conditions on families, and notably on siblings, has not yet been described or documented. This paper presents data from a UK-wide study that sought to understand the family experience of supporting a child with the rare degenerative LLCs of MPS and Batten disease. The aim of this paper is to report sibling experiences related to these rare degenerative and progressive conditions, in order to inform the future development of supportive interventions. Eight siblings of children with MPS (n = 7) and Batten Disease (n = 1) participated in semi-structured qualitative interviews. A card sort technique was utilised to support and engage the children. Siblings are clearly impacted emotionally, pragmatically and relationally by the ill health of another child in the family. The data indicate four key themes which demonstrate impacts on siblings: perceptions of the condition and its symptoms, impact on daily life, emotional consequences and ways of coping. Siblings often had considerable knowledge of the condition and took on important roles in symptom management. However, these experiences were in the context of managing relationships within the family (often protecting parents from an awareness of how much they knew) and relationships at school (including distraction from learning and being bullied by peers). The data highlight how sibling experiences are generated through a combination of negative disability discourses and support through peers and family members. The data indicate how these features shift as a consequence of witnessing the advancement of their brother's or sister's condition and the emotional sequelae of disease progression. Exploration of siblings' experiences of living with such rare progressive and degenerative LLCs suggest the focus of interventions to support this group should address their emotional health and ways to overcome isolation and build connections with other siblings who share their unique experiences. Critically, the data suggest that sibling support should be cognisant of the trajectory of the illness as well as the family, school and peer relational contexts that siblings inhabit. PMID- 23754840 TI - Reduced cognitive function predicts functional decline in patients with heart failure over 12 months. AB - BACKGROUND: Occurrences of impaired activities of daily living (ADL) are common in heart failure (HF) patients and contribute to the elevated mortality and hospitalization rates in this population. Cognitive impairment is also prevalent in HF, though its ability to predict functional decline over time is unknown. AIMS: This study examined the longitudinal pattern of activities of daily living (ADL) in HF persons and whether reduced baseline cognitive status predicts functional decline in this population. METHODS: Altogether 110 persons with HF completed the Lawton-Brody Instrumental Activities of Daily Living (IADL) scale and were administered the Modified Mini-Mental Status Examination (3MS) at baseline and a 12-month follow-up. Three composite scores were derived from the Lawton-Brody scale, including total, instrumental, and basic ADL. RESULTS: HF patients reported high rates of baseline impairments in instrumental ADL, including shopping, food preparation, housekeeping duties, laundry, among others. Repeated measures analyses showed significant declines in total and instrumental ADL from baseline to the 12-month follow-up in HF (p<0.05). Hierarchical regression analyses showed that poorer baseline performance on the 3MS predicted worse total ADL performance at 12-months (beta=0.15, p=0.049), including greater dependence in shopping, driving, feeding, and physical ambulation (p<0.05 for all). CONCLUSION: The current results show that HF patients report significant functional decline over a 12-month period and brief cognitive tests can identify those patients at highest risk for decline. If replicated, such findings encourage the use of cognitive screening measures to identify HF patients most likely to require assistance with ADL tasks. PMID- 23754841 TI - A delayed-control trial examining the impact of body mass index recognition on obesity-related counseling. AB - BACKGROUND: Rates of body mass index (BMI) calculation and plotting remain low. We examined whether providing a BMI wheel and brief education to pediatric residents and attendings would increase rates of "BMI recognition" and obesity related counseling. METHODS: A delayed-control design was used to evaluate a 20 minute intervention. A total of 1640 records of well-child visits were reviewed to determine the proportion of records in which BMI was calculated and plotted and counseling provided. RESULTS: In clinic A, there was a significant increase in the proportion of records in which BMI was recognized from pre- to postintervention (P < .01). No changes in clinic B occurred until after the delayed intervention. Obesity-related counseling was more likely to occur if BMI was recognized. CONCLUSION: Brief education and BMI wheel increased rates of BMI recognition. BMI recognition was associated with increased obesity management. Additional efforts should be incorporated to further increase BMI recognition and assist providers in treating these children. PMID- 23754842 TI - Transcriptional analysis of the F0F1 ATPase operon of Corynebacterium glutamicum ATCC 13032 reveals strong induction by alkaline pH. AB - This article has been retracted at the request of Microbiology because identical bands for the 16S rRNA probe controls in the Northern blots were reported to correspond to experiments using different strains and experimental conditions in articles published in this journal and in Journal of Bacteriology over a period of 5 years. PMID- 23754843 TI - Microarray studies reveal a 'differential response' to moderate or severe heat shock of the HrcA- and HspR-dependent systems in Corynebacterium glutamicum. AB - This article has been retracted at the request of Microbiology because identical bands for the 16S rRNA probe controls in the Northern blots were reported to correspond to experiments using different strains and experimental conditions in articles published in this journal and in Journal of Bacteriology over a period of 5 years. PMID- 23754844 TI - Dynamic chemotherapy-induced upregulation of CXCR4 expression: a mechanism of therapeutic resistance in pediatric AML. AB - Cure rates in pediatric acute leukemias remain suboptimal. Overexpression of the cell-surface chemokine receptor CXCR4 is associated with poor outcome in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Certain nonchemotherapeutic agents have been shown to modulate CXCR4 expression and alter leukemia interactions with stromal cells in the bone marrow microenvironment. Because chemotherapy is the mainstay of AML treatment, it was hypothesized that standard cytotoxic chemotherapeutic agents induce dynamic changes in leukemia surface CXCR4 expression, and that chemotherapy-induced upregulation of CXCR4 represents a mechanism of acquired therapeutic resistance. Here, it was shown that cell lines variably upregulate CXCR4 with chemotherapy treatment. Those that showed upregulation were differentially protected from chemotherapy-induced apoptosis when cocultured with stroma. The functional effects of chemotherapy induced CXCR4 upregulation in an AML cell line (MOLM-14, which harbors consistent upregulated CXCR4) and clinical specimens were explored. Importantly, enhanced stromal-cell derived factor-1alpha (SDF1A/CXCL12)-mediated chemotaxis and stromal protection from additional chemotherapy-induced apoptosis was found. Furthermore, treatment with plerixafor, a CXCR4 inhibitor, preferentially decreased stromal protection with higher chemotherapy-induced upregulation of surface CXCR4. Thus, increased chemokine receptor CXCR4 expression after treatment with conventional chemotherapy may represent a mechanism of therapeutic resistance in pediatric AML. IMPLICATIONS: CXCR4 may be a biomarker for the stratification and optimal treatment of patients using CXCR4 inhibitors. PMID- 23754845 TI - Serum 25-hydroxyvitamin D level is associated with aortic distensibility and left ventricle hypertrophy in newly diagnosed type 2 diabetes mellitus. AB - We aimed to evaluate the association between serum vitamin D status and elastic properties of aorta in patients with diabetes mellitus (DM). We studied 136 patients with newly diagnosed DM (mean age: 62.9 +/- 10.6 years). Serum 25 hydroxyvitamin D was measured using a direct competitive chemiluminescent immunoassay. Aortic distensibility was calculated from the echocardiographically derived ascending aorta diameters and haemodynamic pressure measurements. Left ventricle mass index (LVMI) was determined according to the Devereux formula. Multiple linear regression analysis showed that vitamin D level is independently associated with LVMI (beta = -0.259, p = 0.001), aortic distensibility (beta = 0.369, p < 0.001), high-sensitive C-reactive protein (hs-CRP) (beta = -0.220, p = 0.002) and body mass index (beta = -0.167, p = 0.015) in patients with DM. In diabetic patients, serum 25-hydroxyvitamin D level is independently associated with aortic distensibility. Vitamin D may play a role on pathogenesis of impaired elastic properties of aorta in type 2 DM. PMID- 23754846 TI - High-glucose levels and elastin degradation products accelerate osteogenesis in vascular smooth muscle cells. AB - Diabetes mellitus (DM) is a chronic disease in which the body either does not use or produce the glucose metabolising hormone insulin efficiently. Calcification of elastin in the arteries of diabetics is a major predictor of cardiovascular diseases. It has been previously shown that elastin degradation products work synergistically with transforming growth factor-beta 1 (TGF-beta1) to induce osteogenesis in vascular smooth muscle cells. In this study, we tested the hypothesis that high concentration of glucose coupled with elastin degradation products and TGF-beta1 (a cytokine commonly associated with diabetes) will cause a greater degree of osteogenesis compared to normal vascular cells. Thus, the goal of this study was to analyse the effects of high concentration of glucose, elastin peptides and TGF-beta1 on bone-specific markers like alkaline phosphatase (ALP), osteocalcin (OCN) and runt-related transcription factor 2 (RUNX2). We demonstrated using relative gene expression and specific protein assays that elastin degradation products in the presence of high glucose cause the increase in expression of the specific elastin-laminin receptor-1 (ELR-1) and activin receptor-like kinase-5 (ALK-5) present on the surface of the vascular cells, in turn leading to overexpression of typical osteogenic markers like ALP, OCN and RUNX2. Conversely, blocking of ELR-1 and ALK-5 strongly suppressed the expression of the osteogenic proteins. In conclusion, our results indicate that glucose plays an important role in amplifying the osteogenesis induced by elastin peptides and TGF-beta1, possibly by activating the ELR-1 and ALK-5 signalling pathways. PMID- 23754847 TI - The Psychometric Properties of the Simple Screening Instrument for Substance Abuse. AB - The Simple Screening Instrument for Substance Abuse (SSI-SA) is gaining widespread use as a self-report measure of substance abuse; yet, little information exists regarding the instrument's psychometric properties. This study examined the SSI's psychometric properties within a population of 6,664 adult Medicaid enrollees in Florida, who responded to a survey conducted as part of a statewide evaluation of Medicaid services. The SSI-SA had excellent internal consistency (.85). Evidence of the SSI's validity was strong; SSI-SA scores distinguished among individuals with and without substance abuse needs and were significantly correlated with a measure of functioning in daily living. Using the recommended SSI-SA cutoff score of 4 or higher to indicate the presence of a substance abuse problem, the SSI-SA had respectable sensitivity (.82) and specificity (.90). PMID- 23754848 TI - The effect of an organizational network for patient safety on safety event reporting. AB - Health care organizations continue to implement organization-wide educational approaches to enhance patient safety with less attention on evaluating the impact of these approaches. In this context, a study was conducted to measure the impact of an organization-wide patient safety network approach on patient safety event reporting. A time-series analysis with reported rates of adverse events (major and moderate), near misses, sentinel events, and incidents from 2 years prior through 13 months following implementation was conducted. Study findings include a significant increase in reporting of patient safety events (an approximately 50% increase in overall reporting of safety events was observed; p < .001), especially near misses (an approximately 100% increase following implementation; p = .002). Study findings suggest that a multifaceted networked approach does contribute to improving patient safety event reporting. PMID- 23754850 TI - FIDEA: a server for the functional interpretation of differential expression analysis. AB - The results of differential expression analyses provide scientists with hundreds to thousands of differentially expressed genes that need to be interpreted in light of the biology of the specific system under study. This requires mapping the genes to functional classifications that can be, for example, the KEGG pathways or InterPro families they belong to, their GO Molecular Function, Biological Process or Cellular Component. A statistically significant overrepresentation of one or more category terms in the set of differentially expressed genes is an essential step for the interpretation of the biological significance of the results. Ideally, the analysis should be performed by scientists who are well acquainted with the biological problem, as they have a wealth of knowledge about the system and can, more easily than a bioinformatician, discover less obvious and, therefore, more interesting relationships. To allow experimentalists to explore their data in an easy and at the same time exhaustive fashion within a single tool and to test their hypothesis quickly and effortlessly, we developed FIDEA. The FIDEA server is located at http://www.biocomputing.it/fidea; it is free and open to all users, and there is no login requirement. PMID- 23754851 TI - The genetic code constrains yet facilitates Darwinian evolution. AB - An important goal of evolutionary biology is to understand the constraints that shape the dynamics and outcomes of evolution. Here, we address the extent to which the structure of the standard genetic code constrains evolution by analyzing adaptive mutations of the antibiotic resistance gene TEM-1 beta lactamase and the fitness distribution of codon substitutions in two influenza hemagglutinin inhibitor genes. We find that the architecture of the genetic code significantly constrains the adaptive exploration of sequence space. However, the constraints endow the code with two advantages: the ability to restrict access to amino acid mutations with a strong negative effect and, most remarkably, the ability to enrich for adaptive mutations. Our findings support the hypothesis that the standard genetic code was shaped by selective pressure to minimize the deleterious effects of mutation yet facilitate the evolution of proteins through imposing an adaptive mutation bias. PMID- 23754853 TI - RBPmotif: a web server for the discovery of sequence and structure preferences of RNA-binding proteins. AB - RBPmotif web server (http://www.rnamotif.org) implements tools to identify binding preferences of RNA-binding proteins (RBPs). Given a set of sequences that are known to be bound and unbound by the RBP of interest, RBPmotif provides two types of analysis: (i) de novo motif finding when there is no a priori knowledge on RBP's binding preferences and (ii) analysis of structure preferences when there is a previously identified sequence motif for the RBP. De novo motif finding is performed with the previously published RNAcontext algorithm that learns discriminative motif models to identify both sequence and structure preferences. The results of this analysis include the inferred binding preferences of the RBP and the added predictive value of incorporating structure preferences. Second type of analysis investigates whether the instances of the previously identified sequence motif are enriched in a particular structure context in bound sequences, relative to its instances in unbound sequences. On completion, the results page shows the comparison of structure contexts of the motif instances between bound and unbound sequences and an assessment of statistical significance of detected preferences. In summary, RBPmotif web server enables the concurrent analysis of sequence and structure preferences of RBPs through a user-friendly interface. PMID- 23754852 TI - Structure-function analysis of the 5' end of yeast U1 snRNA highlights genetic interactions with the Msl5*Mud2 branchpoint-binding complex and other spliceosome assembly factors. AB - Yeast pre-mRNA splicing initiates via formation of a complex comprising U1 snRNP bound at the 5' splice site (5'SS) and the Msl5*Mud2 heterodimer engaged at the branchpoint (BP). Here, we present a mutational analysis of the U1 snRNA, which shows that although enlarging the 5' leader between the TMG cap and the (3)ACUUAC(8) motif that anneals to the 5'SS is tolerated, there are tight constraints on the downstream spacer between (3)ACUUAC(8) and helix 1 of the U1 fold. We exploit U1 alleles with 5' extensions, variations in the (3)ACUUAC(8) motif, downstream mutations and a longer helix 1 to discover new intra-snRNP synergies with U1 subunits Nam8 and Mud1 and the trimethylguanosine (TMG) cap. We describe novel mutations in U1 snRNA that bypass the essentiality of the DEAD-box protein Prp28. Structure-guided mutagenesis of Msl5 distinguished four essential amino acids that contact the BP sequence from nine other BP-binding residues that are inessential. We report new synthetic genetic interactions of the U1 snRNP with Msl5 and Mud2 and with the nuclear cap-binding subunit Cbc2. Our results fortify the idea that spliceosome assembly can occur via distinct genetically buffered microscopic pathways involving cross-intron-bridging interactions of the U1 snRNP*5'SS complex with the Mud2*Msl5*BP complex. PMID- 23754854 TI - Climate change: global challenges for the chiropractic profession. PMID- 23754855 TI - Knowledge Transfer within the Canadian Chiropractic Community. Part 1: Understanding Evidence-Practice Gaps. PMID- 23754856 TI - Transient osteoporosis of the hip: A case report. AB - We report a case of transient osteoporosis of the hip (TOH) in a 59-year-old man including the clinical presentation, diagnostic studies, management and clinical progress. TOH is a rare self-limiting condition that typically affects middle aged men or, less frequently, women in the third trimester of pregnancy. Affected individuals present clinically with acute hip pain, limping gait, and limited ranges of hip motion. TOH may begin spontaneously or after a minor trauma. Radiographs are typically unremarkable but MR imaging studies yield findings consistent with bone marrow edema. TOH is referred to as regional migratory osteoporosis if it travels to other joints or the contralateral hip. TOH often resembles osteonecrosis but the two conditions must be differentiated due to different prognoses and management approaches. The term TOH is often used interchangeably and synonymously with transient bone marrow edema. PMID- 23754857 TI - Insufficiency fracture of the tibial plateau after anterior cruciate ligament reconstructive surgery: a case report and review of the literature. AB - Peri-articular fractures after anterior cruciate ligament (ACL) reconstructive surgery are rare. To our knowledge, this case documents the first insufficiency fracture of the tibial plateau after ACL reconstruction, which presented three weeks after the procedure. A 25-year-old female recreational soccer player suffered an insufficiency fracture of the tibial plateau, extending 1.5 mm into the anterior wall of tibial tunnel and medial compartment under the anterior horn of medial meniscus, which presented as a diagnostic challenge. Clinically, the fracture mimicked a low-grade infection of the surgical site, while radiographically, the fracture resembled an avulsion fracture, later confirmed as a tibial tunnel fracture with computed tomography. With the ACL graft integrity not in jeopardy, four weeks of non-weightbearing and a delayed post-operative rehabilitation program was effective in allowing the fracture to heal. Good functional outcome was achieved after conservative management, with minimal loss of terminal knee extension and minimal pain at 22-month follow-up. PMID- 23754858 TI - Therapeutic interventions employed by Greater Toronto Area chiropractors on pregnant patients: results of a cross-sectional online survey. AB - INTRODUCTION: Due to different biomechanical, nutritional, and hormonal considerations, it is possible that chiropractors may employ different therapeutic interventions and recommendations for pregnant patients than non pregnant ones. The objective of this study was to determine the therapeutic interventions that chiropractors who are members of the Ontario Chiropractic Association in the Greater Toronto Area most commonly provide to pregnant patients. METHODS: An introductory e-mail was sent in October 2011 to 755 members of the Ontario Chiropractic Association within the Greater Toronto Area five days prior to a 15 question survey being distributed via e-mail. Reminder e-mails were sent 13 days and 27 days later. Using descriptive statistics, demographic information was reported along with reported use of different treatments and recommendations for pregnant patients. RESULTS: A response rate of 23% was obtained. The majority of the respondents (90%) reported using the Diversified technique on pregnant patients, followed by soft tissue therapy (62%) and Activator (42%). The most common adjunctive therapy recommended to pregnant patients was referral to massage therapy (90%). Most of the respondents (92%) indicated that they prescribe stretching exercises to pregnant patients and recommend a multivitamin (84%) or folic acid (81%) to pregnant patients. CONCLUSION: In agreement with previous research on chiropractic technique usage on non-pregnant patients, the majority of respondents indicated treating pregnant patients with the Diversified technique, with other chiropractic techniques being utilized at varying rates on pregnant patients. Most respondents indicated prescribing exercise, and making adjunctive and nutritional recommendations frequently for their pregnant patients. PMID- 23754859 TI - Straight Back Syndrome: positive response to spinal manipulation and adjunctive therapy - A case report. AB - Straight Back Syndrome (SBS) has been recognized for over 50 years. Not to be confused with flat back syndrome in the lumbar spine, SBS patients present with an obvious loss of the thoracic kyphosis accompanied by apparent heart symptoms. The main purpose of this article is to describe a patient diagnosed with SBS, whose symptoms were successfully managed using spinal manipulative therapy as well as ancillary modalities. The use of diagnostic and laboratory tests are essential to differentially diagnose cardiac disease from SBS. Genesis and incidence of this condition is also discussed as well as roentgenometric analysis. A suggested diagnostic algorithm is presented as well. PMID- 23754860 TI - Myxopapillary ependymoma as a cause of back pain in a young male - A case report. AB - OBJECTIVE: Primary spinal cord tumours are rare causes of low back pain but can be a significant cause of morbidity if undiagnosed and untreated. The following is a case of a young male patient presenting with low back pain and radicular symptoms caused by myxopapillary ependymoma. CLINICAL FEATURES: A nineteen year old male presented to an orthopaedic surgeon with a long history of back pain. He was initially diagnosed with soft tissue injuries and discharged. He began to experience erectile and bowel dysfunction two years later and was re-referred to the orthopaedic surgeon by his family physician but was lost to follow-up. The patient did not present to the surgeon until two years after his symptom profile changed. At that point, MRI examinations revealed a large myxopapillary ependymoma extending from T12 to L4 that was confirmed by a pathologist. INTERVENTION AND OUTCOME: The tumour was surgically resected with subsequent adjuvant radiotherapy. After one year, the patient required continued catheterization and had poor anal tone. His back and leg complaints were almost normal. Follow-up MRI examinations revealed no disease progression or new spinal lesions at 4 years after the initial diagnosis. CONCLUSION: The clinical presentation of primary spinal cord tumours is non-specific and can easily be missed. In cases of chronic back pain, signs and symptoms should be regularly monitored for changes indicative of progressive neurological compromise such as sensory, motor and bowel/bladder dysfunction. If there is deterioration of clinical signs and symptoms, a spinal tumour should be considered in the list of differential diagnoses. Delayed diagnosis and treatment of these rare causes of back pain could lead to poor outcomes; therefore, a referral to a surgeon should be done immediately with proper follow up to ensure continuity of care. PMID- 23754861 TI - Interexaminer reliability of cervical motion palpation using continuous measures and rater confidence levels. AB - INTRODUCTION: Motion palpators usually rate the movement of each spinal level palpated, and their reliability is assessed based upon discrete paired observations. We hypothesized that asking motion palpators to identify the most fixated cervical spinal level to allow calculating reliability at the group level might be a useful alternative approach. METHODS: Three examiners palpated 29 asymptomatic supine participants for cervical joint hypomobility. The location of identified hypomobile sites was based on their distance from the T1 spinous process. Interexaminer concordance was estimated by calculating Intraclass Correlation Coefficient (ICC) and mean absolute differences (MAD) values, stratified by degree of examiner confidence. RESULTS: For the entire participant pool, ICC [2,1] = 0.61, judged "good." MAD=1.35 cm, corresponding to mean interexaminer differences of about 75% of one cervical vertebral level. Stratification by examiner confidence levels resulted in small subgroups with equivocal results. DISCUSSION AND CONCLUSION: A continuous measures study methodology for assessing cervical motion palpation reliability showed more examiner concordance than was usually the case in previous studies using discrete methodology. PMID- 23754862 TI - Frequency of use of diagnostic and manual therapeutic procedures of the spine currently taught at the Canadian Memorial Chiropractic College: A preliminary survey of Ontario chiropractors. Part 2 - procedure usage rates. AB - OBJECTIVE: The purpose of this study was to determine which diagnostic and therapeutic procedures of the spine are most commonly utilized by chiropractors practicing in Ontario, based on a list of currently taught procedures at CMCC. In Part 1 of this study (published previously), the demographics and practice patterns of the respondents were presented. Part 2 of this study (presented here) reports on the utilization rates of spinal diagnostic and therapeutic procedures by the respondents. METHODS: The study consisted of a paper-based survey that was sent to 500 randomly selected Ontario chiropractors who responded confidentially. Survey questions inquired into demographic and practice style characteristics as well as the frequency with which spinal diagnostic and therapeutic procedures were performed. RESULTS: There were 108 respondents to the survey, giving a response rate of 22.4%. Frequency of use of diagnostic procedures fell into three broad categories: (i) those tests that are almost always performed, (ii) those tests that are almost always performed by two-thirds to one-half of patients, and (iii) those tests that are virtually never used. By comparison, respondents utilized the same therapeutic procedures for patients care less consistently. CONCLUSIONS: Despite a low response rate, respondents reported mostly relying on static and motion palpation, joint play, neurological tests, and ranges of motion when assessing their patients. Due to a low response rate, the results of this study may not be generalizable to all Ontario chiropractors. PMID- 23754863 TI - Comminuted scapular body fractures: A report of three cases managed conservatively in chiropractic settings. AB - Fractures of the scapula are relatively uncommon. Fractures specific to the scapular body comprise 35-65% of these fractures. Currently, 99% of all isolated scapular body fractures are being treated nonoperatively with an immobilizing sling or brace and some form of manual therapy with an 86% success rate. We present the conservative management of three patients with comminuted fractures involving the scapular body that were managed in chiropractic settings. Residual disabilities in these three patients as measured by a standardized outcome tool were 2%, 5% and 23% after 3 years, 2 years, and 6 years respectively. PMID- 23754864 TI - Erratum to: Thin layer drying of tomato slices. PMID- 23754865 TI - Green symphonies: a call for studies on acoustic communication in plants. AB - Sound and its use in communication have significantly contributed to shaping the ecology, evolution, behavior, and ultimately the success of many animal species. Yet, the ability to use sound is not a prerogative of animals. Plants may also use sound, but we have been unable to effectively research what the ecological and evolutionary implications might be in a plant's life. Why should plants emit and receive sound and is there information contained in those sounds? I hypothesize that it would be particularly advantageous for plants to learn about the surrounding environment using sound, as acoustic signals propagate rapidly and with minimal energetic or fitness costs. In fact, both emission and detection of sound may have adaptive value in plants by affecting responses in other organisms, plants, and animals alike. The systematic exploration of the functional, ecological, and evolutionary significance of sound in the life of plants is expected to prompt a reinterpretation of our understanding of these organisms and galvanize the emergence of novel concepts and perspectives on their communicative complexity. PMID- 23754866 TI - A case of 25 gauge vitrectomy for malignant glaucoma with microphthalmos. AB - We report the first case report of pars plana lensectomy (PPL) and pars plana vitrectomy using a 25 gauge vitrectomy system for microphthalmos. RESULTS: A 45 year-old woman reported repeated pain in her left eye, despite the use of medications. Ultrasound biomicroscopy revealed a narrow angle and thickened sclera. The lens and the iris showed anterior displacement with a flattening of the ciliary body. The axial length was 15.16 mm in the right eye and 15.04 mm in the left eye. She was diagnosed with a malignant glaucoma with microphthalmos. The patient underwent PPL and pars plana vitrectomy, using a 25 gauge vitrectomy system. The intraocular pressure was well controlled after surgery without medication. CONCLUSION: We considered the PPL and 25 gauge vitrectomy effective in microphthalmos when performed safely. PMID- 23754867 TI - Prompt versus delayed amniotic membrane application in a patient with acute Stevens-Johnson syndrome. AB - BACKGROUND: Stevens-Johnson syndrome is often associated with blinding ocular surface cicatricial sequelae. Recent reports have described markedly improved clinical outcomes with the application of amniotic membrane to the ocular surface during the acute phase. Here we describe the clinical outcome of a patient with acute Stevens-Johnson syndrome and severe ocular surface involvement in whom the evolving medical condition and family consent resulted in amniotic membrane application to each eye at differing intervals from disease onset. METHODS: We undertook a retrospective chart review of a woman with Stevens-Johnson syndrome who presented within hours of disease onset. She underwent application of amniotic membrane to the ocular surface of the left eye during the hyperacute phase (<72 hours after disease onset) and to the right eye at a later time point during the acute phase (six days after disease onset). The clinical outcomes of the two eyes, as well as associated ocular symptoms, were compared over a one year postoperative period. RESULTS: The right eye, treated later in the course of the disease, required additional surgical procedures and ultimately exhibited significantly more advanced ocular surface pathology than the left. Further, the patient reported more pronounced issues of chronic eye pain and visual difficulties in the right eye. CONCLUSION: Earlier intervention with application of amniotic membrane to the ocular surface in this patient with severe ocular involvement secondary to Stevens-Johnson syndrome proved superior. Application of amniotic membrane as soon as possible after disease onset, preferably in the hyperacute phase, appears to result in a significantly better clinical outcome than application later in the disease course. PMID- 23754868 TI - Histologically proven epithelial ingrowth in failed Descemet stripping automated endothelial keratoplasty (DSAEK) managed by repeat DSAEK. AB - PURPOSE: To report a case of corneal graft failure due to epithelial ingrowth after an uneventful combined Descemet stripping automated endothelial keratoplasty (DSAEK) and phacoemulsification cataract surgery with intraocular lens implant treated successfully with a repeat DSAEK. METHODS: A 77-year-old male patient underwent combined DSAEK and phacoemulsification with intraocular lens implant implantation for Fuchs' endothelial dystrophy plus cataract in the right eye. The donor cornea was cut on the Moria ALTK system and introduced using a suture pull-through technique. After an episode of endothelial rejection, the graft failed, with signs suggesting epithelial ingrowth. It was stripped from the host cornea using a Descemet's membrane stripper, and a Simcoe irrigation aspiration cannula was used to remove all traces of interface material. The excised lenticule was examined histologically using a hematoxylin and eosin stain. RESULT: The patient regained and maintained excellent visual acuity with no sign of recurrence of epithelial ingrowth. Histopathological evaluation of the donor tissue of the first graft showed epithelial ingrowth on the stromal surface of the graft and very few endothelial cells, in keeping with the diagnosis of graft failure. CONCLUSION: Epithelial ingrowth is a possible cause of endothelial graft failure, but histologically proven cases are rare. Surgical intervention can achieve successful clearance, with the potential for cure and an excellent outcome. PMID- 23754869 TI - Scleral buckling for retinal detachment in Ibadan, Sub-Saharan Africa: anatomical and visual outcome. AB - BACKGROUND: Scleral buckle surgery is not a commonly performed surgical procedure in Sub-Saharan Africa due to a paucity of trained vitreo retinal surgeons. The aim of the study was to review sclera buckle procedures with a view to evaluating the anatomical and visual outcomes. METHODS: Case records of patients that had scleral buckle surgery at the Retina Unit of the University College Hospital, Ibadan, Nigeria, between 2007 and 2010 were reviewed. Information retrieved included patients' demographics, duration of symptoms, and presenting vision. Other information included site of retinal break, extent of retinal detachment, involvement of the fellow eye, and macular involvement. Postoperative retina reattachment and postoperative visual acuity were also recorded. Proportions and percentages were used to analyze data. RESULTS: Forty five eyes of 42 patients were studied with a male to female ratio of 1.6:1. The mean age was 47.7 years (+/-17.6 years). The median duration before presentation was 3 months (range: 5 days - 156 months). Subtotal retinal detachment was found in 35 eyes (77.8%) while total retinal detachment occurred in ten eyes (22.2%). Thirty four eyes (75.6%) had "macular off " detachments. At 6 weeks, there was an improvement in visual acuity in 23 eyes (51.1%), while visual acuity remained the same in nine eyes (20%) and was worse in 13 eyes (28.9%). Anatomical attachment was seen in 43 eyes (95.6%) on the operation table, in 40 eyes (90.9%) at first day postoperatively and in 32 eyes (86.5%) at 6 weeks after surgery. CONCLUSION: Outcome of sclera buckle surgery for rhegmatogenous retinal detachment may be improved in developing countries of Sub Sahara Africa if adequate awareness is created to educate the populace on early presentation. PMID- 23754870 TI - A comparison of three multidimensional indices of COPD severity as predictors of future exacerbations. AB - BACKGROUND: Prediction of future exacerbations of chronic obstructive pulmonary disease (COPD) is a major concern for long-term management of this disease. AIM: To determine which of three multidimensional assessment systems (the body mass index, obstruction, dyspnea, and exercise capacity [BODE] index; dyspnea, obstruction, smoking, exacerbations [DOSE] index; or age, dyspnea, obstruction [ADO] index) is superior for predicting exacerbations. METHODS: This was a 2-year prospective cohort study of COPD patients. Pulmonary function tests, the 6-minute walk distance (6MWD), Modified Medical Respiratory Council (MMRC) dyspnea scores, chest computed-tomography measurements, and body composition were analyzed, and predictions of exacerbation by the three assessment systems were compared. RESULTS: Among 183 patients who completed the study, the mean annual exacerbation rate was 0.57 events per patient year, which correlated significantly with lower predicted forced expiratory volume in 1 second (FEV1) (P < 0.001), lower transfer coefficient of the lung for carbon monoxide (%DLco/VA) (P = 0.021), lesser 6MWD (P = 0.016), higher MMRC dyspnea score (P = 0.001), higher DOSE index (P < 0.001), higher BODE index (P = 0.001), higher ADO index (P = 0.001), and greater extent of emphysema (P = 0.002). For prediction of exacerbation, the areas under the curves were larger for the DOSE index than for the BODE and ADO indices (P < 0.001). Adjusted multiple logistic regression identified the DOSE index as a significant predictor of risk of COPD exacerbation. CONCLUSION: In this study, the DOSE index was a better predictor of exacerbations of COPD when compared with the BODE and ADO indices. PMID- 23754871 TI - Seasonal skin darkening in Chinese women: the Shanghaiese experience of daily sun protection. AB - The facial skin tone of two groups of Chinese women from Shanghai was compared using standard colorimetric space techniques during a 6-month interval between January and July 2011. During the study period, one group of women (n = 40) applied a potent sun-protective cosmetic product daily, while the other group (n = 40) did not use any sun protection. The results, based on images taken using a standardized digital camera coupled to a spectroradiometer, showed that sun protection largely mitigated changes in the components of skin tone, ie, lightness, melanization, and individual typology angle parameters. The skin darkening process appeared to be reduced or prevented in the sun-protected group when compared with the control group. The sun-protected women had participated in an earlier study in 2008, which confirmed that seasonal skin darkening occurs from winter through summer in Shanghaiese women. Comparing the data obtained in the winters of 2008 and 2011, we were able to identify better the impact of 3 years of aging on the components of skin tone. Comparing data between seasons on the same women with (2011 study) and without (2008 study) sun protection highlights the role of the test product in preventing skin darkening. PMID- 23754872 TI - Minocycline-induced hyperpigmentation: comparison of 3 Q-switched lasers to reverse its effects. AB - Minocycline is a tetracycline derivative antibiotic commonly prescribed for acne, rosacea, and other inflammatory skin disorders. Minocycline turns black when oxidized, leading to discoloration of the skin, nails, bulbar conjunctiva, oral mucosa, teeth, bones, and thyroid gland. Hyperpigmentation has been reported after long-term minocycline therapy with at least 100 mg/day. Three types of minocycline-induced cutaneous hyperpigmentation can result. Type I is the most common, and is associated with blue-black discoloration in areas of previous inflammation and scarring. Type II most commonly affects the legs and is characterized by blue-gray pigmentation of previously normal skin. Type III is the least common and is characterized by diffuse muddy-brown discoloration predominantly on sun exposed skin. Minocycline-induced hyperpigmentation may be cosmetically disfiguring and prompt identification is essential. Without treatment, symptoms may take several months, to years to resolve, after discontinuation of the drug. However, the pigmentation may never completely disappear. In fact, there have been few reports of complete resolution associated with any therapeutic intervention. We report a case of a patient on long-term minocycline therapy utilized as an anti-inflammatory agent to control symptoms of rheumatoid arthritis, which led to minocycline-induced hyperpigmentation of the face. To remove the blue-gray cutaneous deposits, 3 Q-switched lasers (Neodymium: yttrium aluminum garnet (Nd:YAG) 1064 nm, Alexandrite 755 nm, and Ruby 694 nm) were used in test areas. The Alexandrite 755 nm laser proved to provide effective clearing of the minocycline hyperpigmentation requiring just 2 treatments, with minimal treatment discomfort and down time. PMID- 23754873 TI - Postoperative pulmonary embolism in a three year old with Klippel-Trenaunay syndrome. AB - Massive pulmonary embolism (PE) in a small child is a rare event and unified guidelines for its treatment are missing. Timely diagnosis and management of massive pulmonary embolism is of crucial importance for a good outcome. We describe a unique management of PE causing oxygenation failure using a combination of catheter extraction technique, and regional thrombolysis on top of systemic heparin administration and inferior vena cava filter placement. Pulmonary hypertension was treated with inhaled nitric oxide. We believe that catheter extraction technique and regional thrombolysis is an option to consider provided that resources and expertise are available. Preoperative placement of an inferior vena cava filter should be contemplated in such high risk situations. PMID- 23754874 TI - Primary omental hydatid cyst. AB - Hydatid disease is still a frequently seen disease in endemic area like South America, Middle Asia and South Europe as well as Turkey. Although the disease occurs more frequently in liver and lungs, it can be seen in any part of the body. In this report we present a case of isolated omental hydatid disease which is a rare entity in the English literature. PMID- 23754875 TI - Myopathy following postoperative ablative radioiodine for follicular carcinoma of the thyroid. AB - We highlight a case of disabling myopathy following radioablative iodine treatment for follicular carcinoma of the thyroid. A 34-year-old man presented with a tender neck swelling, ultrasound and biopsy were suggestive of thyroid malignancy. Thyroidectomy was undertaken and histology confirmed follicular carcinoma of the thyroid. Treatment with ablative radioiodine followed and within days the patient developed disabling myopathy. Investigations to date do not reveal any other cause for the myopathy and there is no evidence to suggest that this is a paraneoplastic phenomenon. We believe this is the first reported case of ablative radioiodine-induced mypoathy. PMID- 23754876 TI - A case of endobronchial lipoma mimicking bronchial asthma. AB - Endobronchial lipoma is a rare neoplasm of the tracheobronchial tree and it may cause irreversible pulmonary damage due to recurrent pneumonia. Rarely, it may mimic bronchial asthma. We present a 53-year-old woman with an endobronchial lipoma, which had been treated as a bronchial asthma for four years. She also had developed recurrent pneumonia three times. PMID- 23754877 TI - Penile metastasis as a first sign of lung cancer. AB - Lung cancer does not generally produce any symptoms at the early stages and it rapidly metastasizes. Although lung cancer has a potential of metastasis to all organs and tissues, metastasis to the penis from lung cancer is very rare. We present a case with a penile lesion as the first sign of lung cancer. PMID- 23754878 TI - Polyostotic fibrous dysplasia of the ribs: An unusual cause of chest pain and dyspnea. AB - Fibrous dysplasia is a benign bony abnormality that may be monostotic or polyostotic and is not included in the differential diagnosis of chest pain and dyspnea, since it is typically asymptomatic. A 36-year-old man presented with left-sided chest pain and dsypnea for three months. Chest X-ray and chest computed tomography scan revealed a large solid mass arising from the anterior parts of the left fourth, fifth, and sixth ribs and compressing the adjacent lung parenchyma. The tumor was completely removed surgically and histopathologic examination was consistent with fibrous dysplasia without malignant transformation. This report demonstrates that polyostotic dysplasia of the ribs may cause chest pain and dyspnea and present radiographically as a large mass. PMID- 23754879 TI - Cholecystectomy in situs inversus totalis: a laparoscopic approach. AB - PURPOSE: To report and describe a safe approach to laparoscopic cholecystectomy in patients with situs inversus totalis. METHODS: We present the case of a 61 year-old male who was diagnosed with gallstones and situs inversus totalis during work-up for epigastric pain. Laparoscopic cholecystectomy was performed in mirror image to the standard approach, with the surgeon standing on the patient's right side. In order to maintain orientation and safety during the operation, anatomical structures were spatially related to each other in a "medial" and "lateral" manner, which are preserved in situs inversus; rather than "left" and "right" which are reversed. RESULTS: The duration of the operation was 85 minutes, which is slightly longer than our standard laparoscopic cholecystectomy. Nonetheless, the patient was discharged on the morning following surgery, which is comparable to other patients undergoing laparoscopic cholecystectomy. He was seen in follow-up on postoperative day 14 and was doing very well. There were no postoperative complications. CONCLUSION: Laparoscopic cholecystectomy can be performed safely in patients with situs inversus totalis. Careful attention to unfamiliar anatomic relationships is important. Approaching the anatomy in terms of medial and lateral structures, a relationship that is preserved, is helpful to complete the procedure safely. PMID- 23754880 TI - Cardiac lymphoma with first manifestation of recurrent syncope-a case report and literature review. AB - Cardiac involvement, as an initial presentation of malignant lymphoma is rare. We report a 42-year-old Taiwanese man with frequent syncope. Routine electrocardiography disclosed complete atrioventricular block. Before permanent pacemaker implantation was undertaken, transthoracic echocardiography revealed a solid mass infiltrating the left atrium and interatrial septum. Transesophageal echocardiography proved cardiac neoplasm with biatrial infiltration. Endomyocardial tissue biopsy was performed under angiography guide. Pathology diagnosis unraveled large B-cell lymphoma. Despite aggressive chemotherapy, the patient's condition worsened and he died 2 months later. PMID- 23754881 TI - Obstructive jaundice at the initial presentation in small-cell lung cancer. AB - Obstructive jaundice sometimes may develop in association with advanced small cell lung cancer (SCLC); however, SCLC initially presenting with obstructive jaundice is rare. This report presents the cases of two SCLC patients with obstructive jaundice at the initial diagnosis. A 64-year-old male presented with obstructive jaundice due to a tumor at the head of the pancreas. He was diagnosed with SCLC by transbronchial biopsy from a lung tumor in the left upper lobe. Another 74-year-old male was admitted with jaundice due to a tumor in the porta hepatis. He was also diagnosed with SCLC by a fine-needle aspiration biopsy of a lung tumor in the left lower lobe. Both cases were successfully treated with systemic chemotherapy after endoscopic retrograde biliary drainage. PMID- 23754882 TI - Large gastrointestinal stromal tumor size does not imply early recurrence. AB - A 28-year-old female presented with a huge intra-abdominal mass. Initially a mesenteric mass was diagnosed, but her tumor was found to be a gastrointestinal stromal tumor (GIST). Laparotomy was performed. The mass was resected en bloc with clear surgical margins in January 2007. It was found to be 20 * 18 * 16 cm. In order to remove the tumor, the left half of transverse colon with its mesocolon, spleen, body and tail of pancreas, and a part of the small intestine had to be removed. The mass was tightly attached to these viscera. The tumor was surgically removed three years ago. The pathology report of the case presented places the tumor in the high-risk category. The tumor had a relatively high mitotic index. It was positive for CD117 and CD34 stains and also positive for smooth muscle actin. Although the patient did not receive adjuvant chemotherapy, no signs of local recurrence or distant metastasis could be recognized on follow up. Surgery remains the standard initial management for all localized GISTs. The tumor should be removed en bloc, with clear surgical margin. The case presented indicates no association of tumor size with early local recurrence of the tumor or early distant metastasis. PMID- 23754883 TI - Wandering spleen: Report of two cases. AB - Wandering spleen is a rare clinical condition which presents with a variety of symptoms with abdominal pain, abdominal mass, and acute abdomen. It may also remain silent until diagnosed by a routine imaging study. Treatment options may differ depending on the presenting clinical picture. Herein we present two cases of wandering spleen treated by splenectomy, with one of them admitted to our emergency clinic with torsion. PMID- 23754884 TI - Intercavernous portion of internal carotid artery occlusion resulting from snowboarding. AB - A 33-year-old gentleman who was otherwise fit and healthy suffered repetitive low impact head injuries while snowboarding in Austria over a period of one week. During the fall he had several hyperextension injuries and presented with headache, nausea, vomiting, drowsiness (felt 'drunk' on Friday night despite not being drunk), diplopia, abnormal pupillary signs. A Horner's syndrome was diagnosed and on investigation, the left intercavernous portion of internal carotid artery (ICA) was found to be thrombosed. The symptoms gradually settled after conservative treatment for a month. Blunt head trauma is a recognized cause of carotid dissection and thrombosis and many neuromechanics studies have attempted to calculate the wall shear stress involved. Physicians treating snowboarders should be aware of the condition and should look for Horner's syndrome and consider the possibility of carotid occlusion. With a thorough PubMed, Ovid, EMBASE search using 'snowboarding', 'carotid dissection', 'Horner's syndrome' no such case was found to be reported. Proper training for such sport activities is essential to avoid serious consequences. PMID- 23754885 TI - Fulminate anaerobic bacteremia after chemotherapy for metastatic breast cancer despite the prophylactic use of GCSF. AB - Chemotherapy-induced neutropenia often occurs in our routine work and presents an obstacle for adequate (dose and continuance) treatment, which may affect patients' outcome. Granulocyte colony-stimulating factors (GCSFs) effectively prevent myelosuppression and thus improve the standard treatment. Through their application cases of chemotherapy-induced neutropenia have been reduced. Still these factors cannot remove entirely the danger of encountering neutropenia, which can cause dangerous complications. We present a case of a fulminate anaerobic infection with unknown origin in a patient with metastatic breast cancer after standard treatment with chemotherapy supported by GCSFs. PMID- 23754886 TI - Marked leukocytosis in response to estramustine phosphate in a hormone-refractory prostate cancer patient. AB - A 67-year-old man was refered to our institution with a complaint of elevated serum prostate-specific antigen (PSA) level (54 ng/mL). Diagnosis was adenocarcinoma of the prostate with a Gleason score of 9, with bone metastasis (stageD2). He was treated with maximal androgen blockade followed by estramustine phosphate (EMP) because of the progression to hormone-refractory prostate cancer (HRPC). Leukocytosis over 20000/MUL was repeatedly observed at each administration of EMP. This is the first case report of leukocytosis in response to EMP in an HRPC patient. The present case suggests that EMP could modulate leukocyte differentiation in HRPC patients. PMID- 23754888 TI - Isolated pulmonary veno-occlusive disease and pulmonary arterial thrombosis in systemic sclerosis - a lethal combination. AB - BACKGROUND: Isolated pulmonary hypertension secondary to systemic sclerosis is not uncommon. Our patient with systemic sclerosis presented with a very aggressive form of pulmonary hypertension due to a lethal combination of pulmonary veno-occlusive disease (PVOD) and pulmonary arterial thrombosis. This combined presentation has never before been reported in medical literature. CASE REPORT: A 75-year-old woman with a 4-month history of atypical chest pains was admitted with a 3-week history of worsening symptoms of shortness of breath, reduced exercise tolerance, and bilateral pitting edema. On examination she had thickened skin in her hands, telangiectasia on her face, maculopapular rash in her legs, raised jugular venous pressure, and bilateral pitting edema. Her autoimmune profile revealed positive anticentromere antibodies, and her echocardiogram showed right ventricular systolic pressure of 91 mmHg. She also had renal impairment secondary to hypoperfusion. A diagnosis of isolated pulmonary hypertension secondary to limited systemic sclerosis was made. As she was clinically improving on slow diuretic infusion and awaiting transfer to a specialist center for management of pulmonary hypertension, our patient died due to cardiopulmonary arrest. Her postmortem revealed that she died of a combination of PVOD and pulmonary arteriopathy due to thrombosis. CONCLUSION: This is clearly a unique case both in presentation and difficulty of management. Pulmonary vasodilators used in therapy of pulmonary arteriopathy can be detrimental in patients with PVOD. There is no definitive investigation, curative treatment, or management, that exists for a combination of PVOD and pulmonary arteriopathy due to thrombosis secondary to systemic sclerosis. PMID- 23754887 TI - Nonischemic ST segment elevation in hypertrophic cardiomyopathy due to chest wall deformity from kyphoscoliosis. AB - A 57-year-old male was admitted with suspected acute coronary syndrome. He reported experiencing moderate chest pain when walking during the day prior to admission, but had very prominent ST segment elevations in the precordial electrocardiography (EKG) leads. A physical examination revealed remarkable severe kyphoscoliosis with chest deformity. The patient's cardiac troponin levels remained normal, while cardiac ultrasound and magnetic resonance imaging of the chest confirmed hypertrophic cardiomyopathy (HCM) with severe thickening of the interventricular septum. Ischemic heart disease was ruled out by myocardial perfusion imaging with (99m)Tc-MIBI during rest and dipyridamole-induced stress without showing irreversible or reversible myocardial ischemia. Our diagnosis was that the chest pain was noncardiac in origin and that the pronounced ST segment elevations in the precordial EKG leads reflected the severely hypertrophic interventricular septum through the normally thick left ventricular free wall. The patient's chest wall deformity brought his septum and the ventricular free wall nearly parallel to the left side of the chest wall, allowing for complete expression of the reciprocal EKG pattern of septal hypertrophy. We suggest that EKG findings should always be interpreted with the chest wall shape being kept in mind. PMID- 23754889 TI - Sorafenib in metastatic MTC - a case report and minireview of the literature. AB - Medullary thyroid cancer (MTC) is a rare and only surgically treatable disease with early development of metastases and bad prognosis. Due to the lack of efficient systemic treatment, new strategies and approaches are needed to better the patients' outcome. One of the most promising treatment options is the use of tyrosine multikinase inhibitors, which appear to have some effect on the disease progression with tolerable toxicity. Most of them affect many key pathways in the cancer genesis and have proven their effect in different malignancies. We report a case of a young patient with metastatic MTC treated successfully for two months with sorafenib. PMID- 23754890 TI - Temporomandibular joint dislocation due to acute propranolol intoxication. AB - Temporomandibular joint (TMJ) dislocation has not previously been reported as a complication of beta-blocker toxicity. We are reporting two cases of TMJ dislocation resulted from acute severe intoxication with pure propranolol (PPL) for the first time. Bilateral TMJ dislocation happened in two patients who were admitted to intensive care unit with diagnosis of severe acute PPL toxicity. Clinical diagnosis of TMJ dislocation was obtained by physical examination. Successful reduction was performed for both patients without subsequent recurrence in two weeks following hospital discharge. Both of our subjects had no previous history of lower jaw dislocation. There was not any risk factor for dislocation such as convulsion during admission period, recent face trauma, or oral manipulation by the medical team. This study showed that TMJ dislocation may occur after severe acute PPL toxicity probably due to spastic contraction of the lateral pterygoid muscle. This is against previously mentioned hypothesis that stated masseteric muscles contraction as the main cause of a bilateral dislocated TMJ. PMID- 23754891 TI - Asymptomatic double aortic arch. AB - A 51-year-old male patient with a past history of lung tuberculosis was referred to our clinic for routine control. The patient reported no complaints and chest X ray was normal. Three-dimensional thoracic computed tomography revealed a balanced-type double aortic arch with no compression of trachea or esophagus. PMID- 23754892 TI - Primary epiploic appendagitis: from A to Z. AB - Epiploic appendagitis is a rare and uncommon diagnosis that is frequently unknown to clinicians. Inflammation is usually acute and causes abrupt symptoms, but once the diagnosis is accurately made, most patients respond to pain control and conservative management. We report the case of a young woman presenting with acute primary epiploic appendagitis of the right colon. The inflammatory mass was unusually large and occurred a few months after surgery for gastric bypass. This case will give us the opportunity to discuss the clinical presentation of this disease, as well as the potential associations and risk factors and the means for adequate diagnosis and treatment. PMID- 23754893 TI - Brief, recurrent, and spontaneous episodes of loss of consciousness in a healthy young male. AB - INTRODUCTION: Lyme disease is caused by bacterial spirochete Borrelia burgdorferi and is transmitted by Ixodes scapularis and Ixodes pacificus ticks, which get infected while feeding on the reservoir host of the bacteria.1 About 248,074 cases of Lyme disease were reported by the US Centers for Disease Control and Prevention from 1992-2006.2 Over 95% of these cases are reported from the Northeastern and upper Midwestern United States.3 Carditis is usually a clinical manifestation/complication of Lyme disease and is seen in approximately 5% of untreated cases.4. CASE PRESENTATION: A 32-year-old male Hispanic from Chile presented with brief episodes of loss of consciousness and awareness of irregular heart beat, and denied any history of tick bite. The patient was found to have a heart rate of 40 beats per minute and fluctuating variable atrioventricular blocks. A transvenous pacemaker was placed with good capture. The diagnosis was made with serological testing and gallium scanning. Treatment with antibiotics and continuous cardiac monitoring resulted in remarkable symptomatic improvement of the patient. CONCLUSION: Absence of history or evidence of tick bite must not rule out the possibility of Lyme carditis in a patient with a transient heart block. Prompt recognition of this reversible cause of heart block is essential for avoiding implantation of an unnecessary, permanent pacemaker. PMID- 23754894 TI - Acute pyogenic discitis in a degenerative intervertebral disc in an adult. AB - A 35-year-old male who had been receiving conservative treatment for L4 isthmic spondylolisthesis suffered from pyogenic spondylodiscitis in the degenerative L4/L5 intervertebral disc space, which could be identified by comparison with previous images. Symptoms improved with conservative antibiotic treatment. Neovascularization may occur in the annulus fibrosus of a degenerative intervertebral disc, which may increase the risk of hematogenous infection, leading to "discitis" even in adults. PMID- 23754895 TI - A retroperitoneal cyst with unusual urinary histogenesis: clinical and immunomorphological characteristics. AB - Primary retroperitoneal cysts are rare benign lesions which often present as an incidental radiological finding and also cause abdominal symptoms. A 47-year-old woman was admitted to the surgery unit because of right-sided abdominal pain. Computed tomographic scan investigation confirmed a circumscribed, oval, dishomogeneous mass in the right anterior pararenal space. The final diagnosis was obtained after laparotomy excision and pathological evaluation. Immunohistochemical profile was characterized by positive expression of epithelial cystic cells for CKAE1/AE3, CK7, CK8, and CK18, with EMA sustaining the diagnosis of a benign retroperitoneal cyst of urinary system origin. PMID- 23754896 TI - Small bowel intussusception due to metastatic intestinal carcinosarcoma from a pulmonary primary. AB - Metastatic small bowel tumors are rarely encountered. They usually present with small bowel obstruction, perforation, bleeding, or, rarely, intestinal intussusception. Only a few case reports have mentioned bowel symptoms due to metastatic malignancies. We report a seldom encountered clinical condition of intestinal intussusception from metastatic lung malignancy. Pathology demonstrated both epithelial and mesenchymal content, and the final diagnosis was carcinosarcoma. This case report indicates that intestinal metastases should be considered in the differential diagnosis for patients with lung malignancy and abdominal symptoms. PMID- 23754897 TI - Importance of early audiologic assessment in distal renal tubular acidosis. AB - Autosomal recessive distal renal tubular acidosis is usually a severe disease of childhood, often presenting as failure to thrive in infancy. It is often, but not always, accompanied by sensorineural hearing loss, the clinical severity and age of onset of which may be different from the other clinical features. Mutations in either ATP6V1B1 or ATP6V0A4 are the chief causes of primary distal renal tubular acidosis with or without hearing loss, although the loss is often milder in the latter. We describe a kindred with compound heterozygous alterations in ATP6V0A4, where hearing loss was formally diagnosed late in both siblings such that they missed early opportunities for hearing support. This kindred highlights the importance of routine audiologic assessments of all children with distal renal tubular acidosis, irrespective either of age at diagnosis or of which gene is mutated. In addition, when diagnostic genetic testing is undertaken, both genes should be screened irrespective of current hearing status. A strategy for this is outlined. PMID- 23754898 TI - Chryseobacterium indologenes peritonitis in a patient with malignant ascites. AB - Chryseobacterium indologenes is an uncommon pathogen of human disease and is usually associated with indwelling devices or immunocompromised hosts. We report here an unusual case of C. indologenes peritonitis in an oncological patient with malignant ascites. The patient was treated successfully by trimethoprim sulfamethoxazole without removal of the catheter. PMID- 23754899 TI - Homozygous N396T mutation in Gaucher disease: Portuguese sisters with markedly different phenotypes. AB - Gaucher disease (GD) is characterized by reduced activity of glucocerebrosidase leading to complications in the reticuloendothelial system. N396T, a rarer mutation of the glucocerebrosidase gene, has been encountered in Portuguese populations and has generally been associated with milder phenotypes. This report presents brief histories of two Portuguese sisters, both with homozygous N396T mutations. These patients are phenotypically very different despite the fact that in both patients residual enzyme activity is very low. The case of patient 1 is complicated by comorbid diabetes mellitus and human immunodeficiency virus (HIV) infection. Enzyme replacement therapy (ERT) improved this patient's clinical picture sufficiently to enable antiretroviral treatment to proceed for the HIV. This report demonstrates the poor correlation of clinical GD with genotype as well as with residual enzyme activity. It further illustrates how treatment of the underlying GD with ERT improved symptoms allowing for antiretroviral therapy thereby improving both the GD and HIV. PMID- 23754900 TI - Extralobar pulmonary sequestration. AB - Prevalence of pulmonary sequestration accounts for up to 6.4% of all congenital pulmonary malformations. We report on a 40-year-old woman who underwent excision of an aberrant solid retroperitoneal mass in the left subdiaphragmatic area. The mass was identified to be an extralobar pulmonary sequestration. The diagnosis could be made without surgery by percutaneous tissue biopsy and imaging. We encourage keeping in mind pulmonary sequestration anomaly presenting as an aberrant retroperitoneal mass. The aim of this case report is to increase awareness about the condition and review the criteria for its definitive diagnosis and treatment. PMID- 23754901 TI - An unusual presentation of osteogenesis imperfecta type I. AB - Osteogenesis imperfecta (OI) is a rare inherited disorder with a broad spectrum of clinical and genetic variability. The genetic diversity involves, in the majority of the cases, mutations in one of the genes that encodes the type 1 collagen protein (COL1 A1 and COL1 A2), but it is not a requirement for the diagnosis. The most benign form is OI type I. The authors present a case report of a 25-year-old woman who had severe low back pain associated with incapacity to walk and breast-feed post-partum. Symptoms developed 2 weeks after delivery. The radiological examination revealed severe osteoporosis with no abnormalities in the laboratory findings. The clinical signs and a positive personal and family history of multiple fractures in childhood suggested OI type I, although other diagnosis, such as pregnancy-associated osteoporosis, was also considered. The atypical presentation of this rare disorder in adulthood calls attention to the need for early diagnosis for prompt treatment. Treatment of OI is never curative, but it improves the quality of the patient's life. PMID- 23754902 TI - Anti-Factor V inhibitor in patients with autoimmune diseases: case report and literature review. AB - Acquired anti-Factor V deficiency caused by inhibitor production is a rare coagulation disorder. Although this is a well known entity in the literature, choice of optimal treatment for an individual patient is difficult, given that no standard therapeutic measures are available because of rare incidence and various underlying diseases occurring in the elderly. An 88 year-old man treated for Hashimoto's disease was found to exhibit prolongation of both prothrombin time and activated partial thromboplastin time. Detailed study of coagulation factors revealed a deficiency of Factor V. Our patient's coagulation disorder resolved in two weeks with intravenous administration of prednisolone 20 mg/day. Clinical features of autoimmune disease-related Factor V deficiency are discussed, along with eight previously reported cases over the past 20 years. PMID- 23754903 TI - Intravesical foreign bodies: a case report and a review of the literature. AB - AIM: We report a case of intravesical polyvinyl-coated electric wire in the urinary bladder. CASE REPORT: A 34-year-old man presented in our clinic with irritative lower urinary tract symptoms. Three weeks earlier he had seen and felt a wire in his urethra of which he was unaware of the origin. Radiologic evaluation revealed an electric wire completely coiled up in the urinary bladder. It was removed through a suprapubic cystotomy. DISCUSSION: Patients are usually too ashamed to admit the cause of an intravesical foreign body, which is often sexual or erotic in origin. Radiologic evaluation usually reveals the nature and size of the foreign body in the bladder of patients evaluated for recurrent urinary tract infection. Open surgery or an endoscopic approach may be used for their extraction. PMID- 23754904 TI - Controversial treatment of a victim of severe head injury complicated by septic shock and acute respiratory distress syndrome. AB - Pneumonia, severe sepsis, and acute respiratory distress syndrome (ARDS) are frequent complications after head trauma. Recombinant human activated protein C (APC) reportedly improves circulation and respiration in severe sepsis, but is contraindicated after head injury because of increased risk of intracranial bleeding. A 21-year-old man with severe head injury after a car accident was endotracheally intubated, mechanically ventilated, and hemodynamically stabilized before transfer to our university hospital. His condition became complicated with pneumonia, septic shock, ARDS, coagulation dysfunction, and renal failure. In spite of intensive therapy, oxygenation and arterial blood pressure fell to critically low values. Simultaneously, his intracranial pressure peaked and his pupils dilated, displaying no reflexes to light. His antibiotic regimen was changed and ventilation was altered to high frequency oscillations, and despite being ethically problematic, we added APC to his treatment. The patient recovered with modest neurological sequelae. PMID- 23754905 TI - Chondroma of the hand with osteoid formation: first case report. AB - Chondroma is the most common neoplasia of the hand. Histologically, it consists of lobules of normal-appearing hyaline cartilage showing a lobular arrangement. To the best of our knowledge, this is the first reported case of chondroma of the hand in which, interestingly, osteoid production was observed. PMID- 23754906 TI - Association of aortic coarctation and malignant right coronary artery anomaly: an unusual cause of angina pectoris. AB - A 53-year-old man with exercise-induced ischemia was referred for investigation. Coronary angiography revealed a right coronary artery originating from the trunk of the left coronary artery, and an aortic coarctation was observed on aortography. A CT angiogram confirmed these findings. Resection of the aortic coarctation and reimplantation of the ostial portion of right coronary artery into its native site was performed, and resulted in a satisfactory outcome. The association of an anomalous right coronary artery with aortic coarctation has rarely been described and represents a critical situation where early diagnosis and prompt intervention are essential. PMID- 23754907 TI - Cytomegalovirus infection presenting as a colonic mass in a patient with acquired immunodeficiency syndrome. AB - Cytomegalovirus (CMV) infection of the gastrointestinal tract occurs in both immunocompromised and immunocompetent hosts. Often presenting as ulcerative lesions, CMV infection rarely presents as a mass lesion in the gastrointestinal tract. We present a case of a discrete colonic mass caused by CMV infection in a patient with acquired immunodeficiency syndrome (AIDS). This case illustrates that an infectious process such as CMV should be considered along with malignancy as the etiology of a mass lesion present in the gastrointestinal tract of patients with AIDS. PMID- 23754908 TI - Management and surgical treatment of parathyroid crisis secondary to parathyroid tumors: report of four cases. AB - Parathyroid crisis, also known as a parathyroid storm, is a rare and serious complication of primary hyperparathyroidism. Four cases are reported here in which patients presented to hospital with general complaints due to hypercalcemia secondary to hyperparathyroidism. Blood test results upon admission showed high levels of serum calcium and parathyroid hormone, and medical treatment initiated to lower the calcium level was ineffective. After relevant investigations, each patient underwent surgical exploration of the parathyroid glands, followed by excision of a pathological parathyroid tumor. There was a prompt decrease in parathyroid hormone level immediately after surgery. Histology reports revealed that patients had parathyroid adenoma. All patients recovered after surgery, with serum calcium levels restored back to normal and with resolution of all symptoms of hypercalcemia. This report illustrates how often this disease is initially misdiagnosed, and how prompt appropriate surgical treatment provides the best outcome for the patient. PMID- 23754909 TI - Behcet's disease presenting with Budd-Chiari syndrome and intracardial thrombus: a case report. AB - Budd-Chiari syndrome has been described as a late complication of Behcet's disease. Although the mortality rate associated with Behcet's disease is low, it can escalate in the presence of Budd-Chiari syndrome and may be further complicated by intracardial thrombus formation. It is therefore important to detect and initiate management early in the disease course. The imaging modalities of choice should be minimally invasive as certain procedures may aggravate Behcet's disease by initiating a thrombosis or aggravating an existing one. In Behcet's disease-induced Budd-Chiari syndrome, cardiac investigation is crucial in the work-up in order to identify any cardiac involvement and determine the etiology of intracardial thrombus. Furthermore, the treatment should ultimately focus on controlling the activity of Behcet's disease. We report an unusual case of Behcet's disease presenting with Budd-Chiari syndrome complicated by intracardial thrombus in a young Korean man. PMID- 23754910 TI - Diagnostic dilemma; report of a bizarre case of advanced scalp and face angiosarcoma and literature review. AB - A 36-year-old male painter presented to our service in 2007 with an ulcerated solitary scalp swelling of 8 months' duration. The mass was a dormant, painless, pea-sized growth, which he had had since childhood and which he bruised in a passenger motorcycle road traffic accident 8 months prior to presentation. The accident caused it to flare up and progressively increase in size, with associated pain, contact bleeding, and ulceration. A work-up for excision biopsy was proposed, but the patient defaulted and presented 2 years later with an increased number of lesions all around the scalp and face and in an obviously deteriorating clinical status with regional lymph node involvement at this stage. An incisional biopsy was then carried out and the histological reports came out with three different diagnoses of glioblastoma multiforme, poorly differentiated angiosarcoma, and squamous cell carcinoma, constituting a major diagnostic dilemma for our service. PMID- 23754911 TI - Effectiveness of a combination of cyclosporine A, suplatast tosilate and prednisolone on periodic oscillating hypereosinophilia. AB - We report the treatment course of a 29-year-old man who has had unique oscillating FIP1L1-PDGFRA fusion gene-negative hypereosinophilic syndrome (HES) for nearly 6 years. His periodic oscillating pattern of eosinophilia associated with angioedematous soft tissue swelling has shown two to three seasonal peaks (>15,000/MUL absolute eosinophil counts [AEC]) a year. Initially, the patient, who was thought to have distinct HES not compatible with previously described cases, did not respond to treatment except for a temporary response to imatinib mesylate. For 6 years, from 2005 to 2010, he was treated with a combination of oral cyclosporine A, suplatast tosilate, and a small dose of prednisolone, which significantly reduced the peak heights of AEC as well as blunting the oscillating patterns. PMID- 23754912 TI - A pregnant Japanese woman returning from Africa with recurrent fevers. AB - Certain clinical aspects of vivax malaria are no longer defined as benign. We present a case of vivax malaria with three relapses in a pregnant Japanese woman who had returned to Japan from the Comoros Islands in East Africa. Data on the successful delivery, examination of Duffy-blood group antigen, and microscopic findings of growing stages of Plasmodium vivax are thought to be of considerable interest. PMID- 23754913 TI - Relaxation incisions of venomous snake "Japanese mamushi" bites to the hand. AB - Gloydius blomhoffii, commonly known as Japanese mamushi, is a venomous viper species found widely in Japan. The most frequently bitten regions are the fingers and toes, and severe swelling causes compression of peripheral arteries and/or compartment syndrome of the extremities. We experienced four cases of mamushi bites to the hand, and undertook relaxation incision in the hands of three of these patients. As a result, the patients who underwent relaxation incision did not show any skin necrosis or permanent sensory disturbance in the affected fingers. Relaxation incision can be useful to not only decompress subcutaneous and compartment pressure of the hand, but also to wash out the venom from the bitten region by improving venous and lymphatic drainage. PMID- 23754914 TI - Successful management of aortic thrombi resulting in spinal cord infarction in a patient with antiphospholipid antibody syndrome and acute cholecystitis. AB - A 74-year-old man with coronary artery disease was suffering from acute nonobstructive cholecystitis and was admitted to a nearby hospital. Dual antiplatelet (aspirin and ticlopidine) therapy was discontinued before preparation for surgical resection of the gall bladder. During his time in hospital he was aware of lumbar pain and weakness in both legs. He was transferred to our hospital for further evaluation and therapy. Diffuse intra aortic thrombi were revealed by computed tomography with contrast media, and magnetic resonance imaging showed spinal cord infarction. However, computed tomography scans of the descending aorta obtained 4 months before admission exhibited no signs of atherosclerotic plaques or intra-aortic thrombi. Laboratory data suggest that antiphospholipid antibody syndrome might have caused these acute multiple intra-arterial thrombi. By restarting dual antiplatelet therapy and increasing the dose of heparin (from 10,000 IU/day to 15,000 IU/day) we successfully managed the patient's clinical condition and symptoms. It is important to understand that stopping antiplatelet therapy may rapidly grow thrombi in patients with a hypercoagulative state. PMID- 23754915 TI - McArdle disease: a case report and review. AB - McArdle disease (glycogen storage disease type V) is a pure myopathy caused by an inherited deficit of myophosphorylase. The disease exhibits clinical heterogeneity, but patients typically experience exercise intolerance, acute crises of early fatigue, and contractures, sometimes with rhabdomyolysis and myoglobinuria, triggered by static muscle contractions or dynamic exercise. We present the case of a 54-year-old man with a lifelong history of fatigability, worsening on exertion. Laboratory evaluation revealed significant elevations in levels of creatine kinase (7924 U/L), lactate dehydrogenase (624 U/L), and myoglobulin (671 ng/mL). A muscle biopsy confirmed the presence of McArdle disease. This case report illustrates how, due to embarrassment, the patient hid his symptoms for many years and was eventually extremely relieved and "liberated" once McArdle disease was diagnosed 40 years later. PMID- 23754916 TI - Neurosyphilis with optical involvement in an immunocompetent patient: a case report. AB - BACKGROUND: Neurosyphilis became a rare disease after the introduction of antibiotics. The resurgence of syphilis in association with human immunodeficiency virus infection in the past decades increased the incidence of this tertiary form of the disease. However, in immunocompetent patients neurosyphilis remains uncommon and accurate diagnosis is challenging as the clinical presentation is unspecific and the validity of supportive laboratory tests is unclear. CASE REPORT: We describe the case of a 60-year-old man who presented with a 6-month clinical picture of depression-like symptoms and recent sudden unilateral blindness. Medical history uncovered a primary syphilitic event 20 years before. The investigation led to the diagnosis of neurosyphilis with optical involvement in a patient who did not present with any signs of secondary syphilis. Treatment with penicillin G and topical steroids resulted in significant clinical improvement and resolution of the visual loss. CONCLUSION: In the well-established natural history of syphilis, primary syphilis is almost always followed by manifestation of the secondary form, which in turn precedes a period of latency. This case emphasizes the need for a high index of suspicion of neurosyphilis in an immunocompetent patient with nonspecific neuropsychiatric manifestations and an atypical course of syphilis infection. PMID- 23754917 TI - Percutaneous vertebral augmentation for painful osteolytic vertebral metastasis: a case report. AB - INTRODUCTION: Vertebral metastases are associated with significant pain, disability, and morbidity. Open surgery for fracture stabilization is often inappropriate in this population due to a poor risk-benefit profile, particularly if life expectancy is short. Percutaneous vertebroplasty and kyphoplasty are appealing adjunctive procedures in patients with malignancy for alleviation of intractable pain. However, these patients have higher risk of serious complications, notably cement extravasation. Described in this report is a case of a painful osteolytic vertebral metastasis that was successfully treated by a novel percutaneous vertebral augmentation system. CASE PRESENTATION: A 42-year old Caucasian female presented with a history of metastatic lung cancer unresponsive to radiation and chemotherapy with symptoms inadequately controlled by opiates over the previous 6 months. Magnetic resonance imaging and spiral computed tomography with two-dimensional reconstruction showed an osteolytic vertebral metastasis with complete involvement of the T10 vertebral body, extending to the cortical vertebral wall anteriorly and posteriorly. The patient was treated with percutaneous vertebral augmentation (Kiva(r) VCF Treatment System, Benvenue Medical, Inc, Santa Clara, CA) utilizing a novel coil-shaped polyetheretherketone implant designed to minimize the risk of cement extravasation. After the minimally invasive procedure, bone cement distribution within the vertebral body was ideal, with no observed cement extravasation. No complications were reported, pain completely resolved within 24 hours, and use of intravenous narcotics was progressively diminished within 1 week. Complete pain relief was maintained throughout 4 months of follow-up. CONCLUSION: The Kiva System represents a novel and effective minimally invasive treatment option for patients suffering from severe pain due to osteolytic vertebral metastasis. PMID- 23754918 TI - A case of mitochondrial cardiomyopathy with restrictive transmitral filling pattern. AB - A 61-year-old diabetic woman with a mitochondrial A3243G mutation was hospitalized for evaluation of breathlessness, general fatigue, and leg edema. Chest radiography revealed cardiomegaly with massive pleural effusion. Serum lactate, pyruvate, and brain natriuretic peptide concentrations were elevated. Transthoracic echocardiography revealed a restrictive pattern of transmitral flow, although systolic function of the left ventricle was only mildly impaired. Based on these findings and her clinical course, the patient was diagnosed with right-sided heart failure caused by mitochondrial cardiomyopathy associated with a restrictive transmitral filling pattern. Treatment with furosemide, enalapril, and eplerenone was effective, and improvement in her symptoms was associated with amelioration of transthoracic echocardiographic findings and a reduction in serum brain natriuretic peptide levels. Previous reports have indicated heterogeneity in the clinical features of mitochondrial cardiomyopathy in patients carrying the A3243G mutation; the present case highlights the substantial variability in the clinical features of this disease. PMID- 23754919 TI - A case of traumatic intracranial vertebral artery injury presenting with life threatening symptoms. AB - Traumatic intracranial vertebral artery injury is a relatively rare but potentially fatal disease. We present a case of a 63-year-old man who presented with sudden onset of loss of consciousness after hitting his head. After immediate resuscitation, he showed quadriplegia and absence of spontaneous breathing. Brain and cervical spine magnetic resonance imaging revealed an atlantoaxial subluxation, fractured C2 odontoid process, left vertebral artery occlusion, and bilateral extensive ischemia in the medulla oblongata and high cervical spinal cord. Digital subtraction angiography demonstrated left vertebral artery dissection just below the level of vertebral body C2. PMID- 23754920 TI - Topical cyclosporin as an alternative treatment for vision threatening blepharokeratoconjunctivitis: a case report. AB - Here, a case of vision threatening blepharokeratoconjunctivitis that responded well to topical cyclosporin is reported. A 9-year-old Malay girl with a history of bilateral blepharokeratoconjunctivitis was regularly treated with lid scrubbing using diluted baby shampoo, fusidic acid gel, and topical steroids as well as an intermittent course of oral doxycycline for the past year. She developed acute onset bilateral eye redness associated with poor vision in her right eye. Both eyes showed marked diffuse hyperemic conjunctiva with corneal vascularization. The presence of corneal vascularization obscured the visual axis in the right eye. The condition did not improve with regular intensive lid hygiene using diluted baby shampoo, fusidic acid gel, and topical steroids. She was started on topical cyclosporin A 0.5% every 6 hours. There was a dramatic regression of corneal vascularization after 3 days on topical cyclosporin, with marked improvement in visual acuity. This is a single case in which cyclosporin improved the status of the ocular surface. A large cohort study is required to justify its effectiveness in treating blepharokeratoconjunctivitis and to test its potential as an alternative immunosuppressive agent in comparison to conventional corticosteroids. PMID- 23754921 TI - Therapeutic effect of bortezomib for primary plasma cell leukemia followed by auto/allo stem cell transplantation. AB - Plasma cell leukemia (PCL) is a rare disease that represents approximately 4% of plasma cell malignant disorders. PCL consists of two variants: primary PCL presents in patients with no previous history of multiple myeloma, while secondary PCL consists of a leukemic transformation in a previously recognized multiple myeloma. Primary PCL is an extremely resistant, rapidly progressive, fatal disease, with a median overall survival of 6.8 months. There is no standard therapeutic strategy, because no treatment option has been prospectively evaluated. We describe a successful case of newly diagnosed primary PCL, treated with a regimen that included bortezomib, followed by auto stem cell transplantation and nonmyeloablative allogeneic stem cell transplantation. Our patient has maintained remission status for over 12 months since undergoing the allogeneic stem cell transplantation. This strategy is promising for PCL, which, though an extremely resistant disease, may become curable. PMID- 23754922 TI - Metastatic syringoid eccrine carcinoma of the nipple. AB - Syringoid eccrine carcinoma is a very rare skin tumor. Herein we describe a 72 year-old male patient presenting with a syringoid eccrine carcinoma of the nipple with associated axillary lymph node metastases. Surgery associated with adjuvant radiotherapy was performed. To the best of our knowledge, this is the first case of syringoid eccrine carcinoma of the nipple ever reported. PMID- 23754923 TI - Pseudohypoparathyroidism type Ia manifesting as intractable epilepsy in a 23-year old female. AB - Pseudohypoparathyroidism is a rare disorder of calcium metabolism that involves target organ resistance to the action of the parathyroid hormone. As a result, calcium levels may become dangerously low, sometimes leading to seizures and other symptoms. We present a case of a 23-year-old Somalian female on antiepileptic therapy presenting with intractable epilepsy. She was subsequently found to have pseudohypoparathyroidism type Ia. She had multiple reasons accounting for loss of seizure control, including worsening hypocalcemia from resistance to the parathyroid hormone; vitamin D deficiency, which could have resulted from lack of exposure to direct sunlight and her antiepileptic medication; and extensive calcium deposition in the brain due to pseudohypoparathyroidism. The patient was stabilized with intravenous therapy and oral calcium, vitamin D, and calcitriol. Her antiepileptic therapy was changed to a medication that did not interfere with vitamin D metabolism or contribute to worsening hypocalcemia. PMID- 23754924 TI - Anesthetic management of schwannoma mimicking carotid body tumor. AB - Schwannomas are rare and slow-growing neurogenic tumors for which surgery is the standard of care. However, the anesthetic management of these tumors can be challenging. This case report describes the anesthetic management of a patient who underwent carotid endarterectomy and excision of a presumed carotid body tumor. Histopathologic examination showed that the excised tissue was a schwannoma, which in this location can mimic a carotid body tumor. The relevant literature is also reviewed. PMID- 23754925 TI - Rhabdomyolysis secondary to drug interaction between atorvastatin, omeprazole, and dexamethasone. AB - Concomitant administration of atorvastatin, omeprazole, and dexamethasone has been shown to increase the serum concentration of serum hydroxymethylglutaryl coenzyme A which can be associated with elevation of creatine kinase and an increased risk of severe myopathy and rhabdomyolysis. In this paper, we report a case of a 60-year-old female patient with stage IV colon cancer and compromised hepatic function receiving palliative care who developed rhabdomyolysis while taking atorvastatin, omeprazole, and dexamethasone. Atorvastatin was stopped, and the dexamethasone dose was decreased. Her case was complicated by urosepsis cultures revealing an extended spectrum beta-lactamase-producing strain of Escherichia coli, and she died on the second day after admission. Physicians should evaluate the risk/benefit ratio of continuing statins in palliative care patients, and pay special attention to the monitoring of patients on statins and P-glycoprotein inhibitors regardless of hepatic function. PMID- 23754926 TI - The antiphospholipid antibody syndrome: a case report. AB - Antiphospholipid antibody syndrome is defined by the presence of thromboembolic complications and/or pregnancy morbidity in the presence of persistently increased titers of antiphospholipid antibodies. Its clinical presentation can be diverse and any organ can be involved, with a current impact in most surgical and medical specialties. The authors present the case of a 43-year-old man who, over a 13-year period of follow-up, presented with thrombosis of the mesenteric vein, inferior vena cava, and axillary and subclavian veins in a setting where diagnostic and therapeutic options are limited and costly. Through this case report, the authors aim to describe the evolution of this complex pathology, which to date has not been described in the authors' milieu - probably because of its challenging diagnosis and the limited treatment options available. The authors conclude that clinicians need to have a high index of suspicion of APS in patients who present with a thrombotic episode - clinicians should investigate for the presence of antiphospholipid antibodies, as early diagnosis may influence the course of the disease. Furthermore, resources for the detection of antiphospholipid antibodies should be made readily available in resource-limited settings. Finally, patient education on the importance of drug compliance, periodic monitoring, and prevention of thrombosis is indispensable, especially as mortality could be associated with the effects of vascular thrombosis and/or the effects of bleeding due to anticoagulants. PMID- 23754927 TI - Bleeding from gastric body varices effectively treated with endoscopic band ligation. AB - A 55-year-old man with alcoholic liver cirrhosis was admitted to hospital with tarry stools. Videoendoscopy examination on admission revealed blood oozing from the greater curvature of the gastric body (ectopic varices). Endoscopic ultrasonography and computed tomography were used in making the diagnosis. Endoscopic band ligation (EBL) was performed for the bleeding site of these varices. The patient experienced no further episodes of bleeding during the 6 months following treatment with EBL. EBL was very effective in treating the bleeding from gastric body varices. PMID- 23754928 TI - Collision tumors in the gastrointestinal tract: a rare case series. AB - A collision tumor is one where histology shows the presence of two distinct primaries involving the same organ without intermixture of individual cell types, ie, a side by side pattern. Here we present three rare cases of collision tumors involving the stomach and transverse colon. There were two cases of collision tumors involving the stomach, one of which was a combination of adenocarcinoma and low-grade non-Hodgkin's (mucosa-associated lymphoid tissue) lymphoma, and the other showed the presence of non-Hodgkin's lymphoma involving the entire stomach wall along with adenocarcinoma infiltrating the muscle layer. The third case comprised a mucinous adenocarcinoma and carcinoid tumor in the large gut. PMID- 23754929 TI - Churg-Strauss syndrome associated with antiphospholipid antibodies in a patient with recurrent myocardial and cerebral ischemia. AB - We report on a case of Churg-Strauss syndrome (CSS) associated with the presence of antiphospholipid antibodies. The patient had a history of recurrent myocardial infarction and presented with acute ischemic cerebral disease. Eosinophilia with typical lung and skin lesions led us to diagnose the patient with CCS. We hypothesize that the presence of antiphospholipid antibodies significantly contributed to the ischemic events. We suggest that the search for antiphospholipid antibodies should be included in the laboratory work-up in CSS patients and patients affected by primary systemic vasculitides in general. Moreover, anticoagulant treatment appears to be warranted in all CSS patients and antiphospholipid antibodies to counteract this thrombosis-favoring association. PMID- 23754930 TI - Solitary synovial osteochondroma of the knee: mimicking a giant loose body. AB - Solitary synovial osteochondromas are rarely seen. Usually arising from the juxta articular soft tissues without attaching to the bone, these lesions can be large and show clinical and radiological features of a malignant process. This report is about a 64-year-old woman with no history of trauma. She had a history of dull pain and a progressive limited range of motion that had been ongoing for 3 years. An unusual presentation of an uncommon disease that is not widely known by orthopedic surgeons is reported. PMID- 23754931 TI - Acute small bowel obstruction due to chicken bone bezoar. AB - Acute intestinal obstruction due to foreign bodies, or bezoar, is a rare occurrence in an adult with a normal intestinal tract. We report an unusual case of a 43-year-old black man with no previous abdominal surgery and no significant medical history who presented with an acute episode of small bowel obstruction due to an impacted undigested chicken bone. PMID- 23754932 TI - Successful two-stage revision of a KineSpring(r) joint unloading implant: a case study. AB - Few nonsurgical treatment options are available to the patient with debilitating knee osteoarthritis (OA) that is refractory to conservative care. The KineSpring(r) System joint unloading implant is a unique device that reduces the load carried by the medial compartment of the knee joint by up to 13 kilograms during the stance phase of gait. We report a case of a male patient who underwent implant with the KineSpring System for symptomatic knee OA but subsequently required revision due to local infection. We performed a novel two-stage revision procedure where the absorber unit was removed in the first phase and a new absorber was placed 3 months later after the infection resolved. A key finding of this case was that knee OA pain resolved with the KineSpring System, returned following explant of the absorber unit, and resolved again following implant of the new absorber. Another important aspect of this case was that the femoral and tibial bases of the KineSpring System remained in situ, which simplified each phase of the revision procedure. PMID- 23754933 TI - Clinical trial registration in physiotherapy journals: recommendations from the international society of physiotherapy journal editors. PMID- 23754934 TI - Facilitators and barriers to implementation of the ankle brachial index in outpatient physical therapy practice: a qualitative study. AB - INTRODUCTION: The ankle brachial index (ABI) is a valid and reliable measurement of lower extremity circulation and can be used as a screening tool for peripheral arterial disease (PAD), but the usage pattern in physical therapy practice is virtually unknown. PURPOSE: This study was performed to describe the phenomenon of using the ABI in outpatient physical therapy practice. METHODS: Nine participants from 3 different outpatient physical therapy clinics were provided with a hand held Doppler and education on how to accurately perform an ABI. Over a 3-month period, participants performed the ABI on any patient presenting with age > 50 with at least two risk factors for PAD. Immediately following the 3 month data collection period, two focus group interviews were performed to examine the therapist's experience using the ABI. Transcripts were analyzed to identify facilitators and barriers to implementation. RESULTS: Facilitators identified include familiarity, ease of use, accuracy, and confidence with results. Barriers included flow and routine disruption, patient did not want/refused, and issues related to direct access. CONCLUSION: Although some barriers to use of the ABI in an outpatient clinical setting need to be considered, most participants found the experience of using the ABI positive and feasible. PMID- 23754935 TI - Improving the validity and reliability of a health promotion survey for physical therapists. AB - PURPOSE: Physical therapists (PTs) have a unique opportunity to intervene in the area of health promotion. However, no instrument has been validated to measure PTs' views on health promotion in physical therapy practice. The purpose of this study was to evaluate the content validity and test-retest reliability of a health promotion survey designed for PTs. METHODS: An expert panel of PTs assessed the content validity of "The Role of Health Promotion in Physical Therapy Survey" and provided suggestions for revision. Item content validity was assessed using the content validity ratio (CVR) as well as the modified kappa statistic. Therapists then participated in the test-retest reliability assessment of the revised health promotion survey, which was assessed using a weighted kappa statistic. RESULTS: Based on feedback from the expert panelists, significant revisions were made to the original survey. The expert panel reached at least a majority consensus agreement for all items in the revised survey and the survey CVR improved from 0.44 to 0.66. Only one item on the revised survey had substantial test-retest agreement, with 55% of the items having moderate agreement and 43% poor agreement. CONCLUSIONS: All items on the revised health promotion survey demonstrated at least fair validity, but few items had reasonable test-retest reliability. Further modifications should be made to strengthen the validity and improve the reliability of this survey. PMID- 23754936 TI - A pilot study exploring the role of physical therapists and transition in care of pediatric patients with cystic fibrosis to the adult setting. AB - BACKGROUND: Cystic fibrosis (CF) is a disease that requires intensive multidisciplinary care, including care by physical therapists (PTs). People with CF are now living well into adulthood, necessitating a transfer of care from the pediatric setting to an adult one. Physical therapists play a large role in the care of the person with CF; however, there is little known about the PT role in transition of care. PURPOSE: To explore transition issues for people with CF from the perspective of PTs. METHODS: An 18-question online survey was sent to PTs via an electronic CF listserv. Questions were derived from an analysis of transition literature in CF and other chronic childhood conditions. Physical therapists who reported treating people with CF gave their opinions on issues impacting transition from their perspective as well as their perception of patient and parent concerns. Descriptive statistics were used for data analysis. RESULTS: A total of 26 PTs completed the survey. A majority, 61.5%, reported that there was a transition program at their facility, with 42.3% involving physical therapy. Common themes for patients and parents included feeling uncertain about: knowledge of the adult physician, acquiring pulmonary infections in the adult setting, and pace of the adult clinic. Physical therapists were concerned about adherence with airway clearance and exercise following transfer to the adult clinic. CONCLUSIONS: The role of PT in transition programs is quite varied. Physical therapists should address common concerns of their patients and families to improve the transition process and possibly impact adherence to the PT plan of care. PMID- 23754938 TI - Are v1 simple cells optimized for visual occlusions? A comparative study. AB - Simple cells in primary visual cortex were famously found to respond to low-level image components such as edges. Sparse coding and independent component analysis (ICA) emerged as the standard computational models for simple cell coding because they linked their receptive fields to the statistics of visual stimuli. However, a salient feature of image statistics, occlusions of image components, is not considered by these models. Here we ask if occlusions have an effect on the predicted shapes of simple cell receptive fields. We use a comparative approach to answer this question and investigate two models for simple cells: a standard linear model and an occlusive model. For both models we simultaneously estimate optimal receptive fields, sparsity and stimulus noise. The two models are identical except for their component superposition assumption. We find the image encoding and receptive fields predicted by the models to differ significantly. While both models predict many Gabor-like fields, the occlusive model predicts a much sparser encoding and high percentages of 'globular' receptive fields. This relatively new center-surround type of simple cell response is observed since reverse correlation is used in experimental studies. While high percentages of 'globular' fields can be obtained using specific choices of sparsity and overcompleteness in linear sparse coding, no or only low proportions are reported in the vast majority of studies on linear models (including all ICA models). Likewise, for the here investigated linear model and optimal sparsity, only low proportions of 'globular' fields are observed. In comparison, the occlusive model robustly infers high proportions and can match the experimentally observed high proportions of 'globular' fields well. Our computational study, therefore, suggests that 'globular' fields may be evidence for an optimal encoding of visual occlusions in primary visual cortex. PMID- 23754937 TI - Reliability and responsiveness of gait speed, five times sit to stand, and hand grip strength for patients in cardiac rehabilitation. AB - PURPOSE: Following a cardiac event patients are at risk for deficits in mobility and function. However, measures of physical performance are not commonly used and have not been extensively studied in patients enrolled in cardiac rehabilitation. The purpose of this study was to determine the reliability and the minimal detectable change (MDC) of gait speed, 5 times sit to stand (5 STS) and hand grip strength for individuals enrolled in cardiac rehabilitation. METHODS: Forty-nine individuals enrolled in phase II or III cardiac rehabilitation participated in the study. Gait speed, 5 STS, and hand grip strength were measured over two sessions held on the same day. Intraclass correlation coefficient was used to determine reliability and MDC95 was calculated to measure responsiveness. RESULTS: All 3 measures showed high reliability (ICC for gait speed = 0.96, 5 STS = 0.87, right hand grip strength = 0.97, left hand grip strength = 0.97). The MDC95 for gait speed was 0.16 meters/second, 3.12 seconds for 5 STS, 5.2 kilograms for right and 5.1 kilograms for left hand grip strength. CONCLUSION: Gait speed, 5 STS, and hand grip strength are reliable and responsive measures for patients in cardiac rehabilitation. Findings support their use in clinical practice and future cardiac rehabilitation studies. PMID- 23754939 TI - Combinatorial clustering of residue position subsets predicts inhibitor affinity across the human kinome. AB - The protein kinases are a large family of enzymes that play fundamental roles in propagating signals within the cell. Because of the high degree of binding site similarity shared among protein kinases, designing drug compounds with high specificity among the kinases has proven difficult. However, computational approaches to comparing the 3-dimensional geometry and physicochemical properties of key binding site residue positions have been shown to be informative of inhibitor selectivity. The Combinatorial Clustering Of Residue Position Subsets (ccorps) method, introduced here, provides a semi-supervised learning approach for identifying structural features that are correlated with a given set of annotation labels. Here, ccorps is applied to the problem of identifying structural features of the kinase atp binding site that are informative of inhibitor binding. ccorps is demonstrated to make perfect or near-perfect predictions for the binding affinity profile of 8 of the 38 kinase inhibitors studied, while only having overall poor predictive ability for 1 of the 38 compounds. Additionally, ccorps is shown to identify shared structural features across phylogenetically diverse groups of kinases that are correlated with binding affinity for particular inhibitors; such instances of structural similarity among phylogenetically diverse kinases are also shown to not be rare among kinases. Finally, these function-specific structural features may serve as potential starting points for the development of highly specific kinase inhibitors. PMID- 23754940 TI - Scrutinizing MHC-I binding peptides and their limits of variation. AB - Designed peptides that bind to major histocompatibility protein I (MHC-I) allomorphs bear the promise of representing epitopes that stimulate a desired immune response. A rigorous bioinformatical exploration of sequence patterns hidden in peptides that bind to the mouse MHC-I allomorph H-2K(b) is presented. We exemplify and validate these motif findings by systematically dissecting the epitope SIINFEKL and analyzing the resulting fragments for their binding potential to H-2K(b) in a thermal denaturation assay. The results demonstrate that only fragments exclusively retaining the carboxy- or amino-terminus of the reference peptide exhibit significant binding potential, with the N-terminal pentapeptide SIINF as shortest ligand. This study demonstrates that sophisticated machine-learning algorithms excel at extracting fine-grained patterns from peptide sequence data and predicting MHC-I binding peptides, thereby considerably extending existing linear prediction models and providing a fresh view on the computer-based molecular design of future synthetic vaccines. The server for prediction is available at http://modlab-cadd.ethz.ch (SLiDER tool, MHC-I version 2012). PMID- 23754941 TI - Gag-Pol processing during HIV-1 virion maturation: a systems biology approach. AB - Proteolytic processing of Gag and Gag-Pol polyproteins by the viral protease (PR) is crucial for the production of infectious HIV-1, and inhibitors of the viral PR are an integral part of current antiretroviral therapy. The process has several layers of complexity (multiple cleavage sites and substrates; multiple enzyme forms; PR auto-processing), which calls for a systems level approach to identify key vulnerabilities and optimal treatment strategies. Here we present the first full reaction kinetics model of proteolytic processing by HIV-1 PR, taking into account all canonical cleavage sites within Gag and Gag-Pol, intermediate products and enzyme forms, enzyme dimerization, the initial auto-cleavage of full length Gag-Pol as well as self-cleavage of PR. The model allows us to identify the rate limiting step of virion maturation and the parameters with the strongest effect on maturation kinetics. Using the modelling framework, we predict interactions and compensatory potential between individual cleavage rates and drugs, characterize the time course of the process, explain the steep dose response curves associated with PR inhibitors and gain new insights into drug action. While the results of the model are subject to limitations arising from the simplifying assumptions used and from the uncertainties in the parameter estimates, the developed framework provides an extendable open-access platform to incorporate new data and hypotheses in the future. PMID- 23754942 TI - Crosstalk between the circadian clock and innate immunity in Arabidopsis. AB - The circadian clock integrates temporal information with environmental cues in regulating plant development and physiology. Recently, the circadian clock has been shown to affect plant responses to biotic cues. To further examine this role of the circadian clock, we tested disease resistance in mutants disrupted in CCA1 and LHY, which act synergistically to regulate clock activity. We found that cca1 and lhy mutants also synergistically affect basal and resistance gene-mediated defense against Pseudomonas syringae and Hyaloperonospora arabidopsidis. Disrupting the circadian clock caused by overexpression of CCA1 or LHY also resulted in severe susceptibility to P. syringae. We identified a downstream target of CCA1 and LHY, GRP7, a key constituent of a slave oscillator regulated by the circadian clock and previously shown to influence plant defense and stomatal activity. We show that the defense role of CCA1 and LHY against P. syringae is at least partially through circadian control of stomatal aperture but is independent of defense mediated by salicylic acid. Furthermore, we found defense activation by P. syringae infection and treatment with the elicitor flg22 can feedback-regulate clock activity. Together this data strongly supports a direct role of the circadian clock in defense control and reveal for the first time crosstalk between the circadian clock and plant innate immunity. PMID- 23754943 TI - The stable association of virion with the triple-gene-block protein 3-based complex of Bamboo mosaic virus. AB - The triple-gene-block protein 3 (TGBp3) of Bamboo mosaic virus (BaMV) is an integral endoplasmic reticulum (ER) membrane protein which is assumed to form a membrane complex to deliver the virus intracellularly. However, the virus entity that is delivered to plasmodesmata (PD) and its association with TGBp3-based complexes are not known. Results from chemical extraction and partial proteolysis of TGBp3 in membrane vesicles revealed that TGBp3 has a right-side-out membrane topology; i.e., TGBp3 has its C-terminal tail exposed to the outer surface of ER. Analyses of the TGBp3-specific immunoprecipitate of Sarkosyl-extracted TGBp3 based complex revealed that TGBp1, TGBp2, TGBp3, capsid protein (CP), replicase and viral RNA are potential constituents of virus movement complex. Substantial co-fractionation of TGBp2, TGBp3 and CP, but not TGBp1, in the early eluted gel filtration fractions in which virions were detected after TGBp3-specific immunoprecipitation suggested that the TGBp2- and TGBp3-based complex is able to stably associate with the virion. This notion was confirmed by immunogold labeling transmission electron microscopy (TEM) of the purified virions. In addition, mutational and confocal microscopy analyses revealed that TGBp3 plays a key role in virus cell-to-cell movement by enhancing the TGBp2- and TGBp3 dependent PD localization of TGBp1. Taken together, our results suggested that the cell-to-cell movement of potexvirus requires stable association of the virion cargo with the TGBp2- and TGBp3-based membrane complex and recruitment of TGBp1 to the PD by this complex. PMID- 23754944 TI - The systemic immune state of super-shedder mice is characterized by a unique neutrophil-dependent blunting of TH1 responses. AB - Host-to-host transmission of a pathogen ensures its successful propagation and maintenance within a host population. A striking feature of disease transmission is the heterogeneity in host infectiousness. It has been proposed that within a host population, 20% of the infected hosts, termed super-shedders, are responsible for 80% of disease transmission. However, very little is known about the immune state of these super-shedders. In this study, we used the model organism Salmonella enterica serovar Typhimurium, an important cause of disease in humans and animal hosts, to study the immune state of super-shedders. Compared to moderate shedders, super-shedder mice had an active inflammatory response in both the gastrointestinal tract and the spleen but a dampened T(H)1 response specific to the secondary lymphoid organs. Spleens from super-shedder mice had higher numbers of neutrophils, and a dampened T cell response, characterized by higher levels of regulatory T cells (T(regs)), fewer T-bet(+) (T(H)1) T cells as well as blunted cytokine responsiveness. Administration of the cytokine granulocyte colony stimulating factor (G-CSF) and subsequent neutrophilia was sufficient to induce the super-shedder immune phenotype in moderate-shedder mice. Similar to super-shedders, these G-CSF-treated moderate-shedders had a dampened T(H)1 response with fewer T-bet(+) T cells and a loss of cytokine responsiveness. Additionally, G-CSF treatment inhibited IL-2-mediated TH1 expansion. Finally, depletion of neutrophils led to an increase in the number of T-bet(+) T(H)1 cells and restored their ability to respond to IL-2. Taken together, we demonstrate a novel role for neutrophils in blunting IL-2-mediated proliferation of the TH1 immune response in the spleens of mice that are colonized by high levels of S. Typhimurium in the gastrointestinal tract. PMID- 23754945 TI - Shigella IpaH0722 E3 ubiquitin ligase effector targets TRAF2 to inhibit PKC-NF kappaB activity in invaded epithelial cells. AB - NF-kappaB plays a central role in modulating innate immune responses to bacterial infections. Therefore, many bacterial pathogens deploy multiple mechanisms to counteract NF-kappaB activation. The invasion of and subsequent replication of Shigella within epithelial cells is recognized by various pathogen recognition receptors as pathogen-associated molecular patterns. These receptors trigger innate defense mechanisms via the activation of the NF-kappaB signaling pathway. Here, we show the inhibition of the NF-kappaB activation by the delivery of the IpaH E3 ubiquitin ligase family member IpaH0722 using Shigella's type III secretion system. IpaH0722 dampens the acute inflammatory response by preferentially inhibiting the PKC-mediated activation of NF-kappaB by ubiquitinating TRAF2, a molecule downstream of PKC, and by promoting its proteasome-dependent degradation. PMID- 23754946 TI - Cryotomography of budding influenza A virus reveals filaments with diverse morphologies that mostly do not bear a genome at their distal end. AB - Influenza viruses exhibit striking variations in particle morphology between strains. Clinical isolates of influenza A virus have been shown to produce long filamentous particles while laboratory-adapted strains are predominantly spherical. However, the role of the filamentous phenotype in the influenza virus infectious cycle remains undetermined. We used cryo-electron tomography to conduct the first three-dimensional study of filamentous virus ultrastructure in particles budding from infected cells. Filaments were often longer than 10 microns and sometimes had bulbous heads at their leading ends, some of which contained tubules we attribute to M1 while none had recognisable ribonucleoprotein (RNP) and hence genome segments. Long filaments that did not have bulbs were infrequently seen to bear an ordered complement of RNPs at their distal ends. Imaging of purified virus also revealed diverse filament morphologies; short rods (bacilliform virions) and longer filaments. Bacilliform virions contained an ordered complement of RNPs while longer filamentous particles were narrower and mostly appeared to lack this feature, but often contained fibrillar material along their entire length. The important ultrastructural differences between these diverse classes of particles raise the possibility of distinct morphogenetic pathways and functions during the infectious process. PMID- 23754947 TI - Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy. AB - Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies. PMID- 23754949 TI - Impact of natural genetic variation on gene expression dynamics. AB - DNA sequence variation causes changes in gene expression, which in turn has profound effects on cellular states. These variations affect tissue development and may ultimately lead to pathological phenotypes. A genetic locus containing a sequence variation that affects gene expression is called an "expression quantitative trait locus" (eQTL). Whereas the impact of cellular context on expression levels in general is well established, a lot less is known about the cell-state specificity of eQTL. Previous studies differed with respect to how "dynamic eQTL" were defined. Here, we propose a unified framework distinguishing static, conditional and dynamic eQTL and suggest strategies for mapping these eQTL classes. Further, we introduce a new approach to simultaneously infer eQTL from different cell types. By using murine mRNA expression data from four stages of hematopoiesis and 14 related cellular traits, we demonstrate that static, conditional and dynamic eQTL, although derived from the same expression data, represent functionally distinct types of eQTL. While static eQTL affect generic cellular processes, non-static eQTL are more often involved in hematopoiesis and immune response. Our analysis revealed substantial effects of individual genetic variation on cell type-specific expression regulation. Among a total number of 3,941 eQTL we detected 2,729 static eQTL, 1,187 eQTL were conditionally active in one or several cell types, and 70 eQTL affected expression changes during cell type transitions. We also found evidence for feedback control mechanisms reverting the effect of an eQTL specifically in certain cell types. Loci correlated with hematological traits were enriched for conditional eQTL, thus, demonstrating the importance of conditional eQTL for understanding molecular mechanisms underlying physiological trait variation. The classification proposed here has the potential to streamline and unify future analysis of conditional and dynamic eQTL as well as many other kinds of QTL data. PMID- 23754950 TI - Global DNA hypermethylation in down syndrome placenta. AB - Down syndrome (DS), commonly caused by an extra copy of chromosome 21 (chr21), occurs in approximately one out of 700 live births. Precisely how an extra chr21 causes over 80 clinically defined phenotypes is not yet clear. Reduced representation bisulfite sequencing (RRBS) analysis at single base resolution revealed DNA hypermethylation in all autosomes in DS samples. We hypothesize that such global hypermethylation may be mediated by down-regulation of TET family genes involved in DNA demethylation, and down-regulation of REST/NRSF involved in transcriptional and epigenetic regulation. Genes located on chr21 were up regulated by an average of 53% in DS compared to normal villi, while genes with promoter hypermethylation were modestly down-regulated. DNA methylation perturbation was conserved in DS placenta villi and in adult DS peripheral blood leukocytes, and enriched for genes known to be causally associated with DS phenotypes. Our data suggest that global epigenetic changes may occur early in development and contribute to DS phenotypes. PMID- 23754951 TI - Histone acetyl transferase 1 is essential for mammalian development, genome stability, and the processing of newly synthesized histones H3 and H4. AB - Histone acetyltransferase 1 is an evolutionarily conserved type B histone acetyltransferase that is thought to be responsible for the diacetylation of newly synthesized histone H4 on lysines 5 and 12 during chromatin assembly. To understand the function of this enzyme in a complex organism, we have constructed a conditional mouse knockout model of Hat1. Murine Hat1 is essential for viability, as homozygous deletion of Hat1 results in neonatal lethality. The lungs of embryos and pups genetically deficient in Hat1 were much less mature upon histological evaluation. The neonatal lethality is due to severe defects in lung development that result in less aeration and respiratory distress. Many of the Hat1(-/-) neonates also display significant craniofacial defects with abnormalities in the bones of the skull and jaw. Hat1(-/-) mouse embryonic fibroblasts (MEFs) are defective in cell proliferation and are sensitive to DNA damaging agents. In addition, the Hat1(-/-) MEFs display a marked increase in genome instability. Analysis of histone dynamics at sites of replication-coupled chromatin assembly demonstrates that Hat1 is not only responsible for the acetylation of newly synthesized histone H4 but is also required to maintain the acetylation of histone H3 on lysines 9, 18, and 27 during replication-coupled chromatin assembly. PMID- 23754952 TI - Inferring demographic history from a spectrum of shared haplotype lengths. AB - There has been much recent excitement about the use of genetics to elucidate ancestral history and demography. Whole genome data from humans and other species are revealing complex stories of divergence and admixture that were left undiscovered by previous smaller data sets. A central challenge is to estimate the timing of past admixture and divergence events, for example the time at which Neanderthals exchanged genetic material with humans and the time at which modern humans left Africa. Here, we present a method for using sequence data to jointly estimate the timing and magnitude of past admixture events, along with population divergence times and changes in effective population size. We infer demography from a collection of pairwise sequence alignments by summarizing their length distribution of tracts of identity by state (IBS) and maximizing an analytic composite likelihood derived from a Markovian coalescent approximation. Recent gene flow between populations leaves behind long tracts of identity by descent (IBD), and these tracts give our method power by influencing the distribution of shared IBS tracts. In simulated data, we accurately infer the timing and strength of admixture events, population size changes, and divergence times over a variety of ancient and recent time scales. Using the same technique, we analyze deeply sequenced trio parents from the 1000 Genomes project. The data show evidence of extensive gene flow between Africa and Europe after the time of divergence as well as substructure and gene flow among ancestral hominids. In particular, we infer that recent African-European gene flow and ancient ghost admixture into Europe are both necessary to explain the spectrum of IBS sharing in the trios, rejecting simpler models that contain less population structure. PMID- 23754948 TI - Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits. AB - Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5*10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits. PMID- 23754953 TI - Network topologies and convergent aetiologies arising from deletions and duplications observed in individuals with autism. AB - Autism Spectrum Disorders (ASD) are highly heritable and characterised by impairments in social interaction and communication, and restricted and repetitive behaviours. Considering four sets of de novo copy number variants (CNVs) identified in 181 individuals with autism and exploiting mouse functional genomics and known protein-protein interactions, we identified a large and significantly interconnected interaction network. This network contains 187 genes affected by CNVs drawn from 45% of the patients we considered and 22 genes previously implicated in ASD, of which 192 form a single interconnected cluster. On average, those patients with copy number changed genes from this network possess changes in 3 network genes, suggesting that epistasis mediated through the network is extensive. Correspondingly, genes that are highly connected within the network, and thus whose copy number change is predicted by the network to be more phenotypically consequential, are significantly enriched among patients that possess only a single ASD-associated network copy number changed gene (p = 0.002). Strikingly, deleted or disrupted genes from the network are significantly enriched in GO-annotated positive regulators (2.3-fold enrichment, corrected p = 2*10(-5)), whereas duplicated genes are significantly enriched in GO-annotated negative regulators (2.2-fold enrichment, corrected p = 0.005). The direction of copy change is highly informative in the context of the network, providing the means through which perturbations arising from distinct deletions or duplications can yield a common outcome. These findings reveal an extensive ASD-associated molecular network, whose topology indicates ASD-relevant mutational deleteriousness and that mechanistically details how convergent aetiologies can result extensively from CNVs affecting pathways causally implicated in ASD. PMID- 23754954 TI - USF1 and hSET1A mediated epigenetic modifications regulate lineage differentiation and HoxB4 transcription. AB - The interplay between polycomb and trithorax complexes has been implicated in embryonic stem cell (ESC) self-renewal and differentiation. It has been shown recently that WRD5 and Dpy-30, specific components of the SET1/MLL protein complexes, play important roles during ESC self-renewal and differentiation of neural lineages. However, not much is known about how and where specific trithorax complexes are targeted to genes involved in self-renewal or lineage specification. Here, we report that the recruitment of the hSET1A histone H3K4 methyltransferase (HMT) complex by transcription factor USF1 is required for mesoderm specification and lineage differentiation. In undifferentiated ESCs, USF1 maintains hematopoietic stem/progenitor cell (HS/PC) associated bivalent chromatin domains and differentiation potential. Furthermore, USF1 directed recruitment of the hSET1A complex to the HoxB4 promoter governs the transcriptional activation of HoxB4 gene and regulates the formation of early hematopoietic cell populations. Disruption of USF or hSET1A function by overexpression of a dominant-negative AUSF1 mutant or by RNA-interference mediated knockdown, respectively, led to reduced expression of mesoderm markers and inhibition of lineage differentiation. We show that USF1 and hSET1A together regulate H3K4me3 modifications and transcription preinitiation complex assembly at the hematopoietic-associated HoxB4 gene during differentiation. Finally, ectopic expression of USF1 in ESCs promotes mesoderm differentiation and enforces the endothelial-to-hematopoietic transition by inducing hematopoietic-associated transcription factors, HoxB4 and TAL1. Taken together, our findings reveal that the guided-recruitment of the hSET1A histone methyltransferase complex and its H3K4 methyltransferase activity by transcription regulator USF1 safeguards hematopoietic transcription programs and enhances mesoderm/hematopoietic differentiation. PMID- 23754955 TI - The RNA export factor, Nxt1, is required for tissue specific transcriptional regulation. AB - The highly conserved, Nxf/Nxt (TAP/p15) RNA nuclear export pathway is important for export of most mRNAs from the nucleus, by interacting with mRNAs and promoting their passage through nuclear pores. Nxt1 is essential for viability; using a partial loss of function allele, we reveal a role for this gene in tissue specific transcription. We show that many Drosophila melanogaster testis-specific mRNAs require Nxt1 for their accumulation. The transcripts that require Nxt1 also depend on a testis-specific transcription complex, tMAC. We show that loss of Nxt1 leads to reduced transcription of tMAC targets. A reporter transcript from a tMAC-dependent promoter is under-expressed in Nxt1 mutants, however the same transcript accumulates in mutants if driven by a tMAC-independent promoter. Thus, in Drosophila primary spermatocytes, the transcription factor used to activate expression of a transcript, rather than the RNA sequence itself or the core transcription machinery, determines whether this expression requires Nxt1. We additionally find that transcripts from intron-less genes are more sensitive to loss of Nxt1 function than those from intron-containing genes and propose a mechanism in which transcript processing feeds back to increase activity of a tissue specific transcription complex. PMID- 23754956 TI - Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. AB - Genome-wide association studies have mainly relied on common HapMap sequence variations. Recently, sequencing approaches have allowed analysis of low frequency and rare variants in conjunction with common variants, thereby improving the search for functional variants and thus the understanding of the underlying biology of human traits and diseases. Here, we used a large Icelandic whole genome sequence dataset combined with Danish exome sequence data to gain insight into the genetic architecture of serum levels of vitamin B(12) (B12) and folate. Up to 22.9 million sequence variants were analyzed in combined samples of 45,576 and 37,341 individuals with serum B(12) and folate measurements, respectively. We found six novel loci associating with serum B(12) (CD320, TCN2, ABCD4, MMAA, MMACHC) or folate levels (FOLR3) and confirmed seven loci for these traits (TCN1, FUT6, FUT2, CUBN, CLYBL, MUT, MTHFR). Conditional analyses established that four loci contain additional independent signals. Interestingly, 13 of the 18 identified variants were coding and 11 of the 13 target genes have known functions related to B(12) and folate pathways. Contrary to epidemiological studies we did not find consistent association of the variants with cardiovascular diseases, cancers or Alzheimer's disease although some variants demonstrated pleiotropic effects. Although to some degree impeded by low statistical power for some of these conditions, these data suggest that sequence variants that contribute to the population diversity in serum B(12) or folate levels do not modify the risk of developing these conditions. Yet, the study demonstrates the value of combining whole genome and exome sequencing approaches to ascertain the genetic and molecular architectures underlying quantitative trait associations. PMID- 23754957 TI - Distinct neuroblastoma-associated alterations of PHOX2B impair sympathetic neuronal differentiation in zebrafish models. AB - Heterozygous germline mutations and deletions in PHOX2B, a key regulator of autonomic neuron development, predispose to neuroblastoma, a tumor of the peripheral sympathetic nervous system. To gain insight into the oncogenic mechanisms engaged by these changes, we used zebrafish models to study the functional consequences of aberrant PHOX2B expression in the cells of the developing sympathetic nervous system. Allelic deficiency, modeled by phox2b morpholino knockdown, led to a decrease in the terminal differentiation markers th and dbh in sympathetic ganglion cells. The same effect was seen on overexpression of two distinct neuroblastoma-associated frameshift mutations, 676delG and K155X - but not the R100L missense mutation - in the presence of endogenous Phox2b, pointing to their dominant-negative effects. We demonstrate that Phox2b is capable of regulating itself as well as ascl1, and that phox2b deficiency uncouples this autoregulatory mechanism, leading to inhibition of sympathetic neuron differentiation. This effect on terminal differentiation is associated with an increased number of phox2b(+), ascl1(+), elavl3(-) cells that respond poorly to retinoic acid. These findings suggest that a reduced dosage of PHOX2B during development, through either a heterozygous deletion or dominant negative mutation, imposes a block in the differentiation of sympathetic neuronal precursors, resulting in a cell population that is likely to be susceptible to secondary transforming events. PMID- 23754958 TI - A genome-wide, fine-scale map of natural pigmentation variation in Drosophila melanogaster. AB - Various approaches can be applied to uncover the genetic basis of natural phenotypic variation, each with their specific strengths and limitations. Here, we use a replicated genome-wide association approach (Pool-GWAS) to fine-scale map genomic regions contributing to natural variation in female abdominal pigmentation in Drosophila melanogaster, a trait that is highly variable in natural populations and highly heritable in the laboratory. We examined abdominal pigmentation phenotypes in approximately 8000 female European D. melanogaster, isolating 1000 individuals with extreme phenotypes. We then used whole-genome Illumina sequencing to identify single nucleotide polymorphisms (SNPs) segregating in our sample, and tested these for associations with pigmentation by contrasting allele frequencies between replicate pools of light and dark individuals. We identify two small regions near the pigmentation genes tan and bric-a-brac 1, both corresponding to known cis-regulatory regions, which contain SNPs showing significant associations with pigmentation variation. While the Pool GWAS approach suffers some limitations, its cost advantage facilitates replication and it can be applied to any non-model system with an available reference genome. PMID- 23754959 TI - Juvenile hormone and insulin regulate trehalose homeostasis in the red flour beetle, Tribolium castaneum. AB - Insulin/IGF-1 signaling (IIS) has been well studied for its role in the control of life span extension and resistance to a variety of stresses. The Drosophila melanogaster insulin-like receptor (InR) mutant showed extended life span due to reduced juvenile hormone (JH) levels. However, little is known about the mechanism of cross talk between IIS and JH in regulation of life span extension and resistance to starvation. In the current study, we investigated the role of IIS and JH signaling in regulation of resistance to starvation. Reduction in JH biosynthesis, JH action, or insulin-like peptide 2 (ILP2) syntheses by RNA interference (RNAi)-aided knockdown in the expression of genes coding for juvenile hormone acid methyltransferase (JHAMT), methoprene-tolerant (Met), or ILP2 respectively decreased lipid and carbohydrate metabolism and extended the survival of starved beetles. Interestingly, the extension of life span could be restored by injection of bovine insulin into JHAMT RNAi beetles but not by application of JH III to ILP2 RNAi beetles. These data suggest that JH controls starvation resistance by regulating synthesis of ILP2. More importantly, JH regulates trehalose homeostasis, including trehalose transport and metabolism, and controls utilization of stored nutrients in starved adults. PMID- 23754960 TI - Mutations in CERS3 cause autosomal recessive congenital ichthyosis in humans. AB - Autosomal recessive congenital ichthyosis (ARCI) is a rare genetic disorder of the skin characterized by abnormal desquamation over the whole body. In this study we report four patients from three consanguineous Tunisian families with skin, eye, heart, and skeletal anomalies, who harbor a homozygous contiguous gene deletion syndrome on chromosome 15q26.3. Genome-wide SNP-genotyping revealed a homozygous region in all affected individuals, including the same microdeletion that partially affects two coding genes (ADAMTS17, CERS3) and abolishes a sequence for a long non-coding RNA (FLJ42289). Whereas mutations in ADAMTS17 have recently been identified in autosomal recessive Weill-Marchesani-like syndrome in humans and dogs presenting with ophthalmologic, cardiac, and skeletal abnormalities, no disease associations have been described for CERS3 (ceramide synthase 3) and FLJ42289 so far. However, analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients. Functional analysis of patient skin and in vitro differentiated keratinocytes demonstrated that mutations in CERS3 lead to a disturbed sphingolipid profile with reduced levels of epidermis-specific very long-chain ceramides that interferes with epidermal differentiation. Taken together, these data present a novel pathway involved in ARCI development and, moreover, provide the first evidence that CERS3 plays an essential role in human sphingolipid metabolism for the maintenance of epidermal lipid homeostasis. PMID- 23754961 TI - SPO11-independent DNA repair foci and their role in meiotic silencing. AB - In mammalian meiotic prophase, the initial steps in repair of SPO11-induced DNA double-strand breaks (DSBs) are required to obtain stable homologous chromosome pairing and synapsis. The X and Y chromosomes pair and synapse only in the short pseudo-autosomal regions. The rest of the chromatin of the sex chromosomes remain unsynapsed, contains persistent meiotic DSBs, and the whole so-called XY body undergoes meiotic sex chromosome inactivation (MSCI). A more general mechanism, named meiotic silencing of unsynapsed chromatin (MSUC), is activated when autosomes fail to synapse. In the absence of SPO11, many chromosomal regions remain unsynapsed, but MSUC takes place only on part of the unsynapsed chromatin. We asked if spontaneous DSBs occur in meiocytes that lack a functional SPO11 protein, and if these might be involved in targeting the MSUC response to part of the unsynapsed chromatin. We generated mice carrying a point mutation that disrupts the predicted catalytic site of SPO11 (Spo11(YF/YF)), and blocks its DSB inducing activity. Interestingly, we observed foci of proteins involved in the processing of DNA damage, such as RAD51, DMC1, and RPA, both in Spo11(YF/YF) and Spo11 knockout meiocytes. These foci preferentially localized to the areas that undergo MSUC and form the so-called pseudo XY body. In SPO11-deficient oocytes, the number of repair foci increased during oocyte development, indicating the induction of S phase-independent, de novo DNA damage. In wild type pachytene oocytes we observed meiotic silencing in two types of pseudo XY bodies, one type containing DMC1 and RAD51 foci on unsynapsed axes, and another type containing only RAD51 foci, mainly on synapsed axes. Taken together, our results indicate that in addition to asynapsis, persistent SPO11-induced DSBs are important for the initiation of MSCI and MSUC, and that SPO11-independent DNA repair foci contribute to the MSUC response in oocytes. PMID- 23754962 TI - Enterococcus faecalis prophage dynamics and contributions to pathogenic traits. AB - Polylysogeny is frequently considered to be the result of an adaptive evolutionary process in which prophages confer fitness and/or virulence factors, thus making them important for evolution of both bacterial populations and infectious diseases. The Enterococcus faecalis V583 isolate belongs to the high risk clonal complex 2 that is particularly well adapted to the hospital environment. Its genome carries 7 prophage-like elements (V583-pp1 to -pp7), one of which is ubiquitous in the species. In this study, we investigated the activity of the V583 prophages and their contribution to E. faecalis biological traits. We systematically analyzed the ability of each prophage to excise from the bacterial chromosome, to replicate and to package its DNA. We also created a set of E. faecalis isogenic strains that lack from one to all six non-ubiquitous prophages by mimicking natural excision. Our work reveals that prophages of E. faecalis V583 excise from the bacterial chromosome in the presence of a fluoroquinolone, and are able to produce active phage progeny. Intricate interactions between V583 prophages were also unveiled: i) pp7, coined EfCIV583 for E. faecalis chromosomal island of V583, hijacks capsids from helper phage 1, leading to the formation of distinct virions, and ii) pp1, pp3 and pp5 inhibit excision of pp4 and pp6. The hijacking exerted by EfCIV583 on helper phage 1 capsids is the first example of molecular piracy in Gram positive bacteria other than staphylococci. Furthermore, prophages encoding platelet-binding-like proteins were found to be involved in adhesion to human platelets, considered as a first step towards the development of infective endocarditis. Our findings reveal not only a role of E. faecalis V583 prophages in pathogenicity, but also provide an explanation for the correlation between antibiotic usage and E. faecalis success as a nosocomial pathogen, as fluoriquinolone may provoke release of prophages and promote gene dissemination among isolates. PMID- 23754963 TI - Methylation of histone H3 on lysine 79 associates with a group of replication origins and helps limit DNA replication once per cell cycle. AB - Mammalian DNA replication starts at distinct chromosomal sites in a tissue specific pattern coordinated with transcription, but previous studies have not yet identified a chromatin modification that correlates with the initiation of DNA replication at particular genomic locations. Here we report that a distinct fraction of replication initiation sites in the human genome are associated with a high frequency of dimethylation of histone H3 lysine K79 (H3K79Me2). H3K79Me2 containing chromatin exhibited the highest genome-wide enrichment for replication initiation events observed for any chromatin modification examined thus far (23.39% of H3K79Me2 peaks were detected in regions adjacent to replication initiation events). The association of H3K79Me2 with replication initiation sites was independent and not synergistic with other chromatin modifications. H3K79 dimethylation exhibited wider distribution on chromatin during S-phase, but only regions with H3K79 methylation in G1 and G2 were enriched in replication initiation events. H3K79 was dimethylated in a region containing a functional replicator (a DNA sequence capable of initiating DNA replication), but the methylation was not evident in a mutant replicator that could not initiate replication. Depletion of DOT1L, the sole enzyme responsible for H3K79 methylation, triggered limited genomic over-replication although most cells could continue to proliferate and replicate DNA in the absence of methylated H3K79. Thus, prevention of H3K79 methylation might affect regulatory processes that modulate the order and timing of DNA replication. These data are consistent with the hypothesis that dimethylated H3K79 associates with some replication origins and marks replicated chromatin during S-phase to prevent re-replication and preserve genomic stability. PMID- 23754964 TI - RSR-2, the Caenorhabditis elegans ortholog of human spliceosomal component SRm300/SRRM2, regulates development by influencing the transcriptional machinery. AB - Protein components of the spliceosome are highly conserved in eukaryotes and can influence several steps of the gene expression process. RSR-2, the Caenorhabditis elegans ortholog of the human spliceosomal protein SRm300/SRRM2, is essential for viability, in contrast to the yeast ortholog Cwc21p. We took advantage of mutants and RNA interference (RNAi) to study rsr-2 functions in C. elegans, and through genetic epistasis analysis found that rsr-2 is within the germline sex determination pathway. Intriguingly, transcriptome analyses of rsr-2(RNAi) animals did not reveal appreciable splicing defects but instead a slight global decrease in transcript levels. We further investigated this effect in transcription and observed that RSR-2 colocalizes with DNA in germline nuclei and coprecipitates with chromatin, displaying a ChIP-Seq profile similar to that obtained for the RNA Polymerase II (RNAPII). Consistent with a novel transcription function we demonstrate that the recruitment of RSR-2 to chromatin is splicing-independent and that RSR-2 interacts with RNAPII and affects RNAPII phosphorylation states. Proteomic analyses identified proteins associated with RSR-2 that are involved in different gene expression steps, including RNA metabolism and transcription with PRP-8 and PRP-19 being the strongest interacting partners. PRP-8 is a core component of the spliceosome and PRP-19 is the core component of the PRP19 complex, which interacts with RNAPII and is necessary for full transcriptional activity. Taken together, our study proposes that RSR-2 is a multifunctional protein whose role in transcription influences C. elegans development. PMID- 23754965 TI - Negative regulation of notch signaling by xylose. AB - The Notch signaling pathway controls a large number of processes during animal development and adult homeostasis. One of the conserved post-translational modifications of the Notch receptors is the addition of an O-linked glucose to epidermal growth factor-like (EGF) repeats with a C-X-S-X-(P/A)-C motif by Protein O-glucosyltransferase 1 (POGLUT1; Rumi in Drosophila). Genetic experiments in flies and mice, and in vivo structure-function analysis in flies indicate that O-glucose residues promote Notch signaling. The O-glucose residues on mammalian Notch1 and Notch2 proteins are efficiently extended by the addition of one or two xylose residues through the function of specific mammalian xylosyltransferases. However, the contribution of xylosylation to Notch signaling is not known. Here, we identify the Drosophila enzyme Shams responsible for the addition of xylose to O-glucose on EGF repeats. Surprisingly, loss- and gain-of function experiments strongly suggest that xylose negatively regulates Notch signaling, opposite to the role played by glucose residues. Mass spectrometric analysis of Drosophila Notch indicates that addition of xylose to O-glucosylated Notch EGF repeats is limited to EGF14-20. A Notch transgene with mutations in the O-glucosylation sites of Notch EGF16-20 recapitulates the shams loss-of-function phenotypes, and suppresses the phenotypes caused by the overexpression of human xylosyltransferases. Antibody staining in animals with decreased Notch xylosylation indicates that xylose residues on EGF16-20 negatively regulate the surface expression of the Notch receptor. Our studies uncover a specific role for xylose in the regulation of the Drosophila Notch signaling, and suggest a previously unrecognized regulatory role for EGF16-20 of Notch. PMID- 23754966 TI - Comparative polygenic analysis of maximal ethanol accumulation capacity and tolerance to high ethanol levels of cell proliferation in yeast. AB - The yeast Saccharomyces cerevisiae is able to accumulate >=17% ethanol (v/v) by fermentation in the absence of cell proliferation. The genetic basis of this unique capacity is unknown. Up to now, all research has focused on tolerance of yeast cell proliferation to high ethanol levels. Comparison of maximal ethanol accumulation capacity and ethanol tolerance of cell proliferation in 68 yeast strains showed a poor correlation, but higher ethanol tolerance of cell proliferation clearly increased the likelihood of superior maximal ethanol accumulation capacity. We have applied pooled-segregant whole-genome sequence analysis to identify the polygenic basis of these two complex traits using segregants from a cross of a haploid derivative of the sake strain CBS1585 and the lab strain BY. From a total of 301 segregants, 22 superior segregants accumulating >=17% ethanol in small-scale fermentations and 32 superior segregants growing in the presence of 18% ethanol, were separately pooled and sequenced. Plotting SNP variant frequency against chromosomal position revealed eleven and eight Quantitative Trait Loci (QTLs) for the two traits, respectively, and showed that the genetic basis of the two traits is partially different. Fine mapping and Reciprocal Hemizygosity Analysis identified ADE1, URA3, and KIN3, encoding a protein kinase involved in DNA damage repair, as specific causative genes for maximal ethanol accumulation capacity. These genes, as well as the previously identified MKT1 gene, were not linked in this genetic background to tolerance of cell proliferation to high ethanol levels. The superior KIN3 allele contained two SNPs, which are absent in all yeast strains sequenced up to now. This work provides the first insight in the genetic basis of maximal ethanol accumulation capacity in yeast and reveals for the first time the importance of DNA damage repair in yeast ethanol tolerance. PMID- 23754967 TI - H3.3-H4 tetramer splitting events feature cell-type specific enhancers. AB - Previously, we reported that little canonical (H3.1-H4)(2) tetramers split to form "hybrid" tetramers consisted of old and new H3.1-H(4) dimers, but approximately 10% of (H3.3-H4)2 tetramers split during each cell cycle. In this report, we mapped the H3.3 nucleosome occupancy, the H3.3 nucleosome turnover rate and H3.3 nucleosome splitting events at the genome-wide level. Interestingly, H3.3 nucleosome turnover rate at the transcription starting sites (TSS) of genes with different expression levels display a bimodal distribution rather than a linear correlation towards the transcriptional activity, suggesting genes are either active with high H3.3 nucleosome turnover or inactive with low H3.3 nucleosome turnover. H3.3 nucleosome splitting events are enriched at active genes, which are in fact better markers for active transcription than H3.3 nucleosome occupancy itself. Although both H3.3 nucleosome turnover and splitting events are enriched at active genes, these events only display a moderate positive correlation, suggesting H3.3 nucleosome splitting events are not the mere consequence of H3.3 nucleosome turnover. Surprisingly, H3.3 nucleosomes with high splitting index are remarkably enriched at enhancers in a cell-type specific manner. We propose that the H3.3 nucleosomes at enhancers may be split by an active mechanism to regulate cell-type specific transcription. PMID- 23754969 TI - Digital Inverter Amine Sensing via Synergistic Responses by n and p Organic Semiconductors. AB - Chemiresistors and sensitive OFETs have been substantially developed as cheap, scalable, and versatile sensing platforms. While new materials are expanding OFET sensing capabilities, the device architectures have changed little. Here we report higher order logic circuits utilizing OFETs sensitive to amine vapors. The circuits depend on the synergistic responses of paired p- and n-channel organic semiconductors, including an unprecedented analyte-induced current increase by the n-channel semiconductor. This represents the first step towards 'intelligent sensors' that utilize analog signal changes in sensitive OFETs to produce direct digital readouts suitable for further logic operations. PMID- 23754968 TI - Negative regulation of the novel norpA(P24) suppressor, diehard4, in the endo lysosomal trafficking underlies photoreceptor cell degeneration. AB - Rhodopsin has been used as a prototype system to investigate G protein-coupled receptor (GPCR) internalization and endocytic sorting mechanisms. Failure of rhodopsin recycling upon light activation results in various degenerative retinal diseases. Accumulation of internalized rhodopsin in late endosomes and the impairment of its lysosomal degradation are associated with unregulated cell death that occurs in dystrophies. However, the molecular basis of rhodopsin accumulation remains elusive. We found that the novel norpA(P24) suppressor, diehard4, is responsible for the inability of endo-lysosomal rhodopsin trafficking and retinal degeneration in Drosophila models of retinal dystrophies. We found that diehard4 encodes Osiris 21. Loss of its function suppresses retinal degeneration in norpA(P24), rdgC(306), and trp(1), but not in rdgB(2), suggesting a common cause of photoreceptor death. In addition, the loss of Osiris 21 function shifts the membrane balance between late endosomes and lysosomes as evidenced by smaller late endosomes and the proliferation of lysosomal compartments, thus facilitating the degradation of endocytosed rhodopsin. Our results demonstrate the existence of negative regulation in vesicular traffic between endosomes and lysosomes. We anticipate that the identification of additional components and an in-depth description of this specific molecular machinery will aid in therapeutic interventions of various retinal dystrophies and GPCR-related human diseases. PMID- 23754970 TI - Attention-deficit hyperactivity disorder (ADHD) stimulant medications as cognitive enhancers. AB - Recent increases in attention deficit hyperactivity disorder (ADHD) diagnoses, and the escalation of stimulant prescriptions, has raised concern about diversion and abuse of stimulants, as well as the ethics of using these drugs as "cognitive enhancers."Such concern appears misplaced in the face of substantial evidence that stimulant drugs do not improve the academic performance of ADHD-diagnosed students. Moreover, numerous studies have found little or no benefit of stimulants on neuropsychological tests of ADHD-diagnosed as well as normal, individuals. This paper examines the apparent paradox: why don't drugs that improve "attention," produce better academic outcomes in ADHD-diagnosed students? We found that stimulant drugs significantly improved impairment of episodic memory in ADHD-diagnosed undergraduate students. Nevertheless, we also found consistent academic deficits between ADHD students and their non-ADHD counterparts, regardless of whether or not they used stimulant medications. We reviewed the current literature on the behavioral effects of stimulants, to try to find an explanation for these conflicting phenomena. Across a variety of behavioral tasks, stimulants have been shown to reduce emotional reactions to frustration, improve the ability to detect errors, and increase effortful behavior. However, all of these effects would presumably enhance academic performance. On the other hand, the drugs were also found to promote "risky behavior" and to increase susceptibility to environmental distraction. Such negative effects, including the use of drugs to promote wakefulness for last minute study, might explain the lack of academic benefit in the "real world," despite their cognitive potential. Like many drugs, stimulants influence behavior in multiple ways, depending on the environmental contingencies. Depending on the circumstances, stimulants may, or may not, enhance cognition. PMID- 23754971 TI - GHS-R1a constitutive activity and its physiological relevance. AB - Abundant evidences have shown that ghrelin, by its binding to GHS-R1a, plays an important role for fundamental physiological functions. Increasing attention is given to the GHS-R1a unusually high constitutive activity and its contribution to downstream signaling and physiological processes. Here, we review recent lines of evidences showing that the interaction between ligand-binding pocket TM domains and the ECL2 could be partially responsible for this high constitutive activity. Interestingly, GHSR-1a constitutive activity activates in turn the downstream PLC, PKC, and CRE signaling pathways and this activation is reversed by the inverse agonist [D-Arg(1), D-Phe(5), D-Trp(7,9), Leu(11)]-substance P (MSP). Noteworthy, GHSR-1a exhibits a C-terminal-dependent constitutive internalization. Non-sense GHS-R1a mutation (Ala204Glu), first discovered in Moroccan patients, supports the role of GHSR-1a constitutive activity in physiological impairments. Ala204Glu-point mutation, altering exclusively the GHSR-1a constitutive activity, was associated with familial short stature syndrome. Altogether, these findings suggest that GHS-R1a constitutive activity could contribute to GH secretion or body weight regulation. Consequently, future research on basic and clinical applications of GHS-R1a inverse agonists will be challenging and potentially rewarding. PMID- 23754972 TI - Expression of three GnRH receptors in specific tissues in male and female sea lampreys Petromyzon marinus at three distinct life stages. AB - Two recently cloned gonadotropin-releasing hormone (GnRH) receptors (lamprey GnRH R-2 and lamprey GnRH-R-3) along with lamprey (l) GnRH-R-1 were shown to share similar structural features and amino acid motifs common to other vertebrate receptors. Here we report on our findings of RNA expression of these three GnRH receptors in the three major life stages (larval, parasitic, and adult phases) of the sea lamprey, Petromyzon marinus, a basal vertebrate. For each stage, we examined the expression of messenger RNA encoding the receptors in the brain, pituitary, gonad, heart, muscle, liver, eye, intestine, kidney, skin, thyroid, gill, and endostyle by RT-PCR. In adult lampreys, the spatial expression of the three receptors in the brain and pituitary was investigated by in situ hybridization. In general, the receptors were more widely expressed in adult tissues as compared to parasitic-phase tissues and least widely expressed in the larval tissues. There were noted differences in male and female lampreys in the adult and parasitic phases for all three receptors. The data showed the presence of all three receptor transcripts in brain tissues for adult and parasitic phases and all three receptor transcripts were expressed in the adult pituitaries, but not in the parasitic pituitaries. However, in the larval phase, only lGnRH-R-1 was expressed in the larval brain and pituitary. In situ hybridization revealed that lGnRH-R-2 and -3 were expressed in the pineal tissue of adult female lampreys while lGnRH-R-1 was expressed in the pineal in adult male lampreys, all restricted to the pineal pellucida. In summary, these data provide an initial comparative analysis of expression of three lamprey GnRH receptors suggesting differential regulation within males and females at three different life/reproductive stages. PMID- 23754974 TI - Regulation of feeding behavior and psychomotor activity by corticotropin releasing hormone (CRH) in fish. AB - Corticotropin-releasing hormone (CRH) is a hypothalamic neuropeptide belonging to a family of neuropeptides that includes urocortins, urotensin I, and sauvagine in vertebrates. CRH and urocortin act as anorexigenic factors for satiety regulation in fish. In a goldfish model, intracerebroventricular (ICV) administration of CRH has been shown to affect not only food intake, but also locomotor and psychomotor activities. In particular, CRH elicits anxiety-like behavior as an anxiogenic neuropeptide in goldfish, as is the case in rodents. This paper reviews current knowledge of CRH and its related peptides derived from studies of teleost fish, as representative non-mammals, focusing particularly on the role of the CRH system, and examines its significance from a comparative viewpoint. PMID- 23754973 TI - Animal models of post-traumatic stress disorder: face validity. AB - Post-traumatic stress disorder (PTSD) is a debilitating condition that develops in a proportion of individuals following a traumatic event. Despite recent advances, ethical limitations associated with human research impede progress in understanding PTSD. Fortunately, much effort has focused on developing animal models to help study the pathophysiology of PTSD. Here, we provide an overview of animal PTSD models where a variety of stressors (physical, psychosocial, or psychogenic) are used to examine the long-term effects of severe trauma. We emphasize models involving predator threat because they reproduce human individual differences in susceptibility to, and in the long-term consequences of, psychological trauma. PMID- 23754975 TI - The CRF system and social behavior: a review. AB - The corticotropin-releasing factor (CRF) system plays a key role in a diversity of behaviors accompanying stress, anxiety and depression. There is also substantial research on relationships between social behaviors and the CRF system in a variety of taxa including fish, birds, rodents, and primates. Some of these relationships are due to the broad role of CRF and urocortins in stress and anxiety, but these peptides also modulate social behavior specifically. For example, the social interaction (SI) test is often used to measure anxiety-like behavior. Many components of the CRF system including CRF, urocortin1, and the R1 receptor have been implicated in SI, via general effects on anxiety as well as specific effects depending on the brain region. The CRF system is also highly responsive to chronic social stressors such as social defeat and isolation. Animals exposed to these stressors display a number of anxiety- and stress related behaviors, accompanied by changes in specific components the CRF system. Although the primary focus of CRF research on social behavior has been on the deleterious effects of social stress, there are also insights on a role for CRF and urocortins in prosocial and affiliative behaviors. The CRF system has been implicated in parental care, maternal defense, sexual behavior, and pair bonding. Species differences in the ligands and CRF receptors have been observed in vole and bird species differing in social behavior. Exogenous administration of CRF facilitates partner preference formation in monogamous male prairie voles, and these effects are dependent on both the CRF R1 and R2 receptors. These findings are particularly interesting as studies have also implicated the CRF and urocortins in social memory. With the rapid progress of social neuroscience and in understanding the complex structure of the CRF system, the next challenge is in parsing the exact contribution of individual components of this system to specific social behaviors. PMID- 23754977 TI - Roles of FGF20 in dopaminergic neurons and Parkinson's disease. AB - The fibroblast growth factor (FGF) family comprises 22 members with diverse functions in development and metabolism. Fgf20 was originally identified as a new Fgf preferentially expressed in the substantia nigra pars compacta (SNpc). Fgf20, which acts on proximal cells, significantly enhanced the survival of cultured dopaminergic neurons by activating the mitogen-activated protein kinase (MAPK) pathway through Fgf receptor 1c. In the rat model of Parkinson's disease, Fgf20 afforded significant protection against the loss of dopaminergic neurons. The significant correlation of Parkinson's disease with single-nucleotide polymorphisms in FGF20 indicates that the genetic variability of FGF20 can be a Parkinson's disease risk. Neural and embryonic stem (ES) cells have been considered as cell resources for restorative transplantation strategies in Parkinson's disease. Fgf20 promoted the differentiation of these stem cells into dopaminergic neurons, which attenuated neurological symptoms in animal models of Parkinson's disease. These findings indicate the importance of FGF20 for the differentiation and survival of dopaminergic neurons and the etiology and therapy of Parkinson's disease. PMID- 23754976 TI - Alcohol and NMDA receptor: current research and future direction. AB - The brain is one of the major targets of alcohol actions. Most of the excitatory synaptic transmission in the central nervous system is mediated by N-methyl-D aspartate (NMDA) receptors. However, one of the most devastating effects of alcohol leads to brain shrinkage, loss of nerve cells at specific regions through a mechanism involving excitotoxicity, oxidative stress. Earlier studies have indicated that chronic exposure to ethanol both in vivo and in vitro, increases NR1 and NR2B gene expression and their polypeptide levels. The effect of alcohol and molecular changes on the regulatory process, which modulates NMDAR functions including factors altering transcription, translation, post-translational modifications, and protein expression, as well as those influencing their interactions with different regulatory proteins (downstream effectors) are incessantly increasing at the cellular level. Further, I discuss the various genetically altered mice approaches that have been used to study NMDA receptor subunits and their functional implication. In a recent countable review, epigenetic dimension (i.e., histone modification-induced chromatin remodeling and DNA methylation, in the process of alcohol related neuroadaptation) is one of the key molecular mechanisms in alcohol mediated NMDAR alteration. Here, I provide a recount on what has already been achieved, current trends and how the future research/studies of the NMDA receptor might lead to even greater engagement with many possible new insights into the neurobiology and treatment of alcoholism. PMID- 23754978 TI - Developing BACE-1 inhibitors for FXS. AB - Fragile X syndrome (FXS) is a debilitating genetic disorder with no cure and few therapeutic options. Excessive signaling through metabotropic glutamate receptor 5 in FXS leads to increased translation of numerous synaptic proteins and exaggerated long-term depression. Two of the overexpressed proteins are amyloid beta protein precursor (APP) and its metabolite amyloid-beta, which have been well-studied in Alzheimer's disease (AD). Here we discus the possibility that pharmaceuticals under study for the modulation of these proteins in AD might be viable therapeutic strategies for FXS. Specifically, a recently identified acetyltransferase inhibitor that reduces the levels and activity of beta-site APP cleaving enzyme (BACE-1) has strong potential to attenuate BACE-1 activity and maintain homeostatic levels APP catabolites in FXS. PMID- 23754979 TI - Dopamine prevents lipid peroxidation-induced accumulation of toxic alpha synuclein oligomers by preserving autophagy-lysosomal function. AB - The formation of Lewy bodies containing alpha-synuclein (alpha-syn), prominent loss of dopaminergic neurons and dopamine (DA) deficiency in substantia nigra and striatum are histopathological and biochemical hallmarks of Parkinson's disease (PD). Multiple lines of evidence have indicated that a critical pathogenic factor causing PD is enhanced production of reactive oxygen species (ROS), which reacts readily with polyunsaturated fatty acids to cause lipid peroxidation (LPO). LPO products have been shown to facilitate assembly of toxic alpha-syn oligomers in in vitro studies. Since DA is prone to autoxidation and cause ROS, it has been suggested that interactions among DA, LPO, and alpha-syn play an important role in neuronal loss in PD. However, the exact mechanism(s) remains unclear. We addressed this issue using a neuronal cell model which inducibly expresses human wild-type alpha-syn by the tetracycline off (Tet-Off) mechanism and stably expresses high levels of DA transporter. Under retinoic acid elicited neuronal differentiation, cells with or without overexpressing alpha-syn and with or without exposure to LPO inducer-arachidonic acid (AA), plus 0-500 MUM of DA were assessed for the levels of LPO, alpha-syn accumulation, cell viability, and autophagy. AA exposure elicited similar LPO levels in cells with and without alpha-syn overexpression, but significantly enhanced the accumulation of alpha syn oligomers and monomers only in cultures with Tet-Off induction and decreased cell survival in a LPO-dependent manner. Surprisingly, DA at low concentrations (<50 MUM) protected cells from AA cytotoxicity and alpha-syn accumulation. Such effects were attributed to the ability of DA to preserve autophagic-lysosomal function compromised by the AA exposure. At high concentrations (>100 MUM), DA exposure enhanced the toxic effects of AA. To our knowledge, this is the first report showing biphasic effects of DA on neuronal survival and alpha-syn accumulation. PMID- 23754980 TI - LRRK2: an eminence grise of Wnt-mediated neurogenesis? AB - The importance of leucine-rich repeat kinase 2 (LRRK2) to mature neurons is well established, since mutations in PARK8, the gene encoding LRRK2, are the most common known cause of Parkinson's disease. Nonetheless, despite the LRRK2 knockout mouse having no overt neurodevelopmental defect, numerous lines of in vitro data point toward a central role for this protein in neurogenesis. Roles for LRRK2 have been described in many key processes, including neurite outgrowth and the regulation of microtubule dynamics. Moreover, LRRK2 has been implicated in cell cycle control, suggesting additional roles in neurogenesis that precede terminal differentiation. However, we contend that the suggested function of LRRK2 as a scaffolding protein at the heart of numerous Wnt signaling cascades provides the most tantalizing link to neurogenesis in the developing brain. Numerous lines of evidence show a critical requirement for multiple Wnt pathways in the development of certain brain regions, not least the dopaminergic neurons of the ventral mid-brain. In conclusion, these observations indicate a function of LRRK2 as a subtle yet critical mediator of the action of Wnt ligands on developing neurons. We suggest that LRRK2 loss- or gain-of-function are likely modifiers of developmental phenotypes seen in animal models of Wnt signaling deregulation, a hypothesis that can be tested by cross-breeding relevant genetically modified experimental strains. PMID- 23754981 TI - Cell-attached recordings of responses evoked by photorelease of GABA in the immature cortical neurons. AB - We present a novel non-invasive technique to measure the polarity of GABAergic responses based on cell-attached recordings of currents activated by laser uncaging of GABA. For these recordings, a patch pipette was filled with a solution containing RuBi-GABA, and GABA was released from this complex by a laser beam conducted to the tip of the patch pipette via an optic fiber. In cell attached recordings from neocortical and hippocampal neurons in postnatal days P2 5 rat brain slices in vitro, we found that laser-uncaging of GABA activates integral cell-attached currents mediated by tens of GABA(A) channels. The initial response was inwardly directed, indicating a depolarizing response to GABA. The direction of the initial response was dependent on the pipette potential and analysis of its slope-voltage relationships revealed a depolarizing driving force of +11 mV for the currents through GABA channels. Initial depolarizing responses to GABA uncaging were inverted to hyperpolarizing in the presence of the NKCC1 blocker bumetanide. Current-voltage relationships of the currents evoked by RuBi GABA uncaging using voltage-ramps at the peak of responses not only revealed a bumetanide-sensitive depolarizing reversal potential of the GABA(A) receptor mediated responses, but also showed a strong voltage-dependent hysteresis. Upon desensitization of the uncaged-GABA response, current-voltage relationships of the currents through single GABA(A) channels revealed depolarizing responses with the driving force values similar to those obtained for the initial response. Thus, cell-attached recordings of the responses evoked by local intrapipette GABA uncaging are suitable to assess the polarity of the GABA(A)-Rs mediated signals in small cell compartments. PMID- 23754982 TI - Local connections of excitatory neurons in motor-associated cortical areas of the rat. AB - In spite of recent progress in brain sciences, the local circuit of the cerebral neocortex, including motor areas, still remains elusive. Morphological works on excitatory cortical circuitry from thalamocortical (TC) afferents to corticospinal neurons (CSNs) in motor-associated areas are reviewed here. First, TC axons of motor thalamic nuclei have been re-examined by the single-neuron labeling method. There are middle layer (ML)-targeting and layer (L) 1-preferring TC axon types in motor-associated areas, being analogous to core and matrix types, respectively, of Jones (1998) in sensory areas. However, the arborization of core-like motor TC axons spreads widely and disregards the columnar structure that is the basis of information processing in sensory areas, suggesting that motor areas adopt a different information-processing framework such as area-wide laminar organization. Second, L5 CSNs receive local excitatory inputs not only from L2/3 pyramidal neurons but also from ML spiny neurons, the latter directly processing cerebellar information of core-like TC neurons (TCNs). In contrast, basal ganglia information is targeted to apical dendrites of L2/3 and L5 pyramidal neurons through matrix TCNs. Third, L6 corticothalamic neurons (CTNs) are most densely innervated by ML spiny neurons located just above CTNs. Since CTNs receive only weak connections from L2/3 and L5 pyramidal neurons, the TC recurrent circuit composed of TCNs, ML spiny neurons and CTNs appears relatively independent of the results of processing in L2/3 and L5. It is proposed that two circuits sharing the same TC projection and ML neurons are embedded in the neocortex: one includes L2/3 and L5 neurons, processes afferent information in a feedforward way and sends the processed information to other cortical areas and subcortical regions; and the other circuit participates in a dynamical system of the TC recurrent circuit and may serve as the basis of autonomous activity of the neocortex. PMID- 23754983 TI - Role of the olivo-cerebellar complex in motor learning and control. AB - How is the cerebellum capable of efficient motor learning and control despite very low firing of the inferior olive (IO) inputs, which are postulated to carry errors needed for learning and contribute to on-line motor control? IO neurons form the largest electrically coupled network in the adult human brain. Here, we discuss how intermediate coupling strengths can lead to chaotic resonance and increase information transmission of the error signal despite the very low IO firing rate. This increased information transmission can then lead to more efficient learning than with weak or strong coupling. In addition, we argue that a dynamic modulation of IO electrical coupling via the Purkinje cell-deep cerebellar neurons - IO triangle could speed up learning and improve on-line control. Initially strong coupling would allow transmission of large errors to multiple functionally related Purkinje cells, resulting in fast but coarse learning as well as significant effects on deep cerebellar nucleus and on-line motor control. In the late phase of learning decreased coupling would allow desynchronized IO firing, allowing high-fidelity transmission of error, resulting in slower but fine learning, and little on-line motor control effects. PMID- 23754984 TI - Comparing development of synaptic proteins in rat visual, somatosensory, and frontal cortex. AB - Two theories have influenced our understanding of cortical development: the integrated network theory, where synaptic development is coordinated across areas; and the cascade theory, where the cortex develops in a wave-like manner from sensory to non-sensory areas. These different views on cortical development raise challenges for current studies aimed at comparing detailed maturation of the connectome among cortical areas. We have taken a different approach to compare synaptic development in rat visual, somatosensory, and frontal cortex by measuring expression of pre-synaptic (synapsin and synaptophysin) proteins that regulate vesicle cycling, and post-synaptic density (PSD-95 and Gephyrin) proteins that anchor excitatory or inhibitory (E-I) receptors. We also compared development of the balances between the pairs of pre- or post-synaptic proteins, and the overall pre- to post-synaptic balance, to address functional maturation and emergence of the E-I balance. We found that development of the individual proteins and the post-synaptic index overlapped among the three cortical areas, but the pre-synaptic index matured later in frontal cortex. Finally, we applied a neuroinformatics approach using principal component analysis and found that three components captured development of the synaptic proteins. The first component accounted for 64% of the variance in protein expression and reflected total protein expression, which overlapped among the three cortical areas. The second component was gephyrin and the E-I balance, it emerged as sequential waves starting in somatosensory, then frontal, and finally visual cortex. The third component was the balance between pre- and post-synaptic proteins, and this followed a different developmental trajectory in somatosensory cortex. Together, these results give the most support to an integrated network of synaptic development, but also highlight more complex patterns of development that vary in timing and end point among the cortical areas. PMID- 23754987 TI - KCC2-dependent subcellular E(Cl) difference of ON-OFF retinal ganglion cells in larval zebrafish. AB - Subcellular difference in the reversal potential of Cl(-) (ECl) has been found in many types of neurons. As local ECl largely determines the action of nearby GABAergic/glycinergic synapses, subcellular ECl difference can effectively regulate neuronal computation. The ON-OFF retinal ganglion cell (RGC) processes both ON and OFF visual signals via its ON and OFF dendrites, respectively. It is thus interesting to investigate whether the ON and OFF dendrites of single RGCs exhibit different local ECl. Here, using in vivo gramicidin-perforated patch recording in larval zebrafish ON-OFF RGCs, we examine local ECl at the ON and OFF dendrites, and soma through measuring light-evoked ON and OFF inhibitory responses, and GABA-induced response at the soma, respectively. We find there are subcellular ECl differences between the soma and dendrite, as well as between the ON and OFF dendrites of single RGCs. These somato-dendritic and inter-dendritic ECl differences are dependent on the Cl(-) extruder, K(+)/Cl(-) co-transporter (KCC2), because they are largely diminished by down-regulating kcc2 expression with morpholino oligonucleotides (MOs) or by blocking KCC2 function with furosemide. Thus, our findings indicate that there exists KCC2-dependent ECl difference between the ON and OFF dendrites of individual ON-OFF RGCs that may differentially affect visual processing in the ON and OFF pathways. PMID- 23754985 TI - Cellular dissection of the spinal cord motor column by BAC transgenesis and gene trapping in zebrafish. AB - Bacterial artificial chromosome (BAC) transgenesis and gene/enhancer trapping are effective approaches for identification of genetically defined neuronal populations in the central nervous system (CNS). Here, we applied these techniques to zebrafish (Danio rerio) in order to obtain insights into the cellular architecture of the axial motor column in vertebrates. First, by using the BAC for the Mnx class homeodomain protein gene mnr2b/mnx2b, we established the mnGFF7 transgenic line expressing the Gal4FF transcriptional activator in a large part of the motor column. Single cell labeling of Gal4FF-expressing cells in the mnGFF7 line enabled a detailed investigation of the morphological characteristics of individual spinal motoneurons, as well as the overall organization of the motor column in a spinal segment. Secondly, from a large scale gene trap screen, we identified transgenic lines that marked discrete subpopulations of spinal motoneurons with Gal4FF. Molecular characterization of these lines led to the identification of the ADAMTS3 gene, which encodes an evolutionarily conserved ADAMTS family of peptidases and is dynamically expressed in the ventral spinal cord. The transgenic fish established here, along with the identified gene, should facilitate an understanding of the cellular and molecular architecture of the spinal cord motor column and its connection to muscles in vertebrates. PMID- 23754986 TI - Acute ethanol treatment upregulates Th1, Th2, and Hdc in larval zebrafish in stable networks. AB - Earlier studies in zebrafish have revealed that acutely given ethanol has a stimulatory effect on locomotion in fish larvae but the mechanism of this effect has not been revealed. We studied the effects of ethanol concentrations between 0.75 and 3.00% on 7-day-old larval zebrafish (Danio rerio) of the Turku strain. At 0.75-3% concentrations ethanol increased swimming speed during the first minute. At 3% the swimming speed decreased rapidly after the first minute, whereas at 0.75 and 1.5% a prolonged increase in swimming speed was seen. At the highest ethanol concentration dopamine levels decreased significantly after a 10 min treatment. We found that ethanol upregulates key genes involved in the biosynthesis of histamine (hdc) and dopamine (th1 and th2) following a short 10 min ethanol treatment, measured by qPCR. Using in situ hybridization and immunohistochemistry, we further discovered that the morphology of the histaminergic and dopaminergic neurons and networks in the larval zebrafish brain was unaffected by both the 10-min and a longer 30-min treatment. The results suggest that acute ethanol rapidly decreases dopamine levels, and activates both forms or th to replenish the dopamine stores within 30 min. The dynamic changes in histaminergic and dopaminergic system enzymes occurred in the same cells which normally express the transcripts. As both dopamine and histamine are known to be involved in the behavioral effects of ethanol and locomotor stimulation, these results suggest that rapid adaptations of these networks are associated with altered locomotor activity. PMID- 23754988 TI - Morphology and connections of intratrigeminal cells and axons in the macaque monkey. AB - Trigeminal primary afferent fibers have small receptive fields and discrete submodalities, but second order trigeminal neurons often display larger receptive fields with complex, multimodal responses. Moreover, while most large caliber afferents terminate exclusively in the principal trigeminal nucleus, and pars caudalis (sVc) of the spinal trigeminal nucleus receives almost exclusively small caliber afferents, the characteristics of second order neurons do not always reflect this dichotomy. These surprising characteristics may be due to a network of intratrigeminal connections modifying primary afferent contributions. This study characterizes the distribution and morphology of intratrigeminal cells and axons in a macaque monkeys. Tracer injections centered in the principal nucleus (pV) and adjacent pars oralis retrogradely labeled neurons bilaterally in pars interpolaris (sVi), but only ipsilaterally, in sVc. Labeled axons terminated contralaterally within sVi and caudalis. Features of the intratrigeminal cells in ipsilateral sVc suggest that both nociceptive and non-nociceptive neurons project to principalis. A commissural projection to contralateral principalis was also revealed. Injections into sVc labeled cells and terminals in pV and pars oralis on both sides, indicating the presence of bilateral reciprocal connections. Labeled terminals and cells were also present bilaterally in sVi and in contralateral sVc. Interpolaris injections produced labeling patterns similar to those of sVc. Thus, the rostral and caudal poles of the macaque trigeminal complex are richly interconnected by ipsilateral ascending and descending connections providing an anatomical substrate for complex analysis of oro-facial stimuli. Sparser reciprocal crossed intratrigeminal connections may be important for conjugate reflex movements, such as the corneal blink reflex. PMID- 23754989 TI - How do you wire a brain? PMID- 23754990 TI - Cross-frequency phase synchrony around the saccade period as a correlate of perceiver's internal state. AB - In active vision, eye-movements depend on perceivers' internal state. We investigated peri-fixation brain activity for internal state-specific tagging. Human participants performed a task, in which a visual object was presented for identification in lateral visual field, to which they moved their eyes as soon as possible from a central fixation point. Next, a phrase appeared in the same location; the phrase could either be an easy or hard question about the object, answered by pressing one of two alternative response buttons, or it could be an instruction to simply press one of these two buttons. Depending on whether these messages were blocked or randomly mixed, one of two different internal states was induced: either the task was known in advance or it wasn't. Eye movements and electroencephalogram (EEG) were recorded simultaneously during task performance. Using eye-event-time-locked averaging and independent component analysis, saccade and fixation-related components were identified. Coss-frequency phase-synchrony was observed between the alpha/beta1 ranges of fixation-related and beta2/gamma1 ranges of saccade-related activity 50 ms prior to fixation onset in the mixed phrase condition only. We interpreted this result as evidence for internal state specific tagging. PMID- 23754991 TI - Language, writing, and activity disorder in the autistic spectrum. PMID- 23754992 TI - Heterogeneity in threat extinction learning: substantive and methodological considerations for identifying individual difference in response to stress. AB - Pavlovian threat (fear) conditioning (PTC) is an experimental paradigm that couples innate aversive stimuli with neutral cues to elicit learned defensive behavior in response to the neutral cue. PTC is commonly used as a translational model to study neurobiological and behavioral aspects of fear and anxiety disorders including Posttraumatic Stress Disorder (PTSD). Though PTSD is a complex multi-faceted construct that cannot be fully captured in animals PTC is a conceptually valid model for studying the development and maintenance of learned threat responses. Thus, it can inform the understanding of PTSD symptomatology. However, there are significant individual differences in posttraumatic stress that are not as of yet accounted for in studies of PTC. Individuals exposed to danger have been shown to follow distinct patterns: some adapt rapidly and completely (resilience) others adapt slowly (recovery) and others failure to adapt (chronic stress response). Identifying similar behavioral outcomes in PTC increases the translatability of this model. In this report we present a flexible methodology for identifying individual differences in PTC by modeling latent subpopulations or classes characterized by defensive behavior during training. We provide evidence from a reanalysis of previously examined PTC learning and extinction data in rats to demonstrate the effectiveness of this methodology in identifying outcomes analogous to those observed in humans exposed to threat. By utilizing Latent Class Growth Analysis (LCGA) to test for heterogeneity in freezing behavior during threat conditioning and extinction learning in adult male outbred rats (n = 58) three outcomes were identified: rapid extinction (57.3%), slow extinction (32.3%), and failure to extinguish (10.3%) indicating that heterogeneity analogous to that in naturalistic human studies is present in experimental animal studies strengthening their translatability in understanding stress responses in humans. PMID- 23754993 TI - Spatial learning of female mice: a role of the mineralocorticoid receptor during stress and the estrous cycle. AB - Corticosterone facilitates behavioral adaptation to a novel experience in a coordinate manner via mineralocorticoid (MR) and glucocorticoid receptors (GR). Initially, MR mediates corticosterone action on appraisal processes, risk assessment and behavioral flexibility and then, GR activation promotes consolidation of the new information into memory. Here, we studied on the circular holeboard (CHB) the spatial performance of female mice with genetic deletion of MR from the forebrain (MR(CaMKCre)) and their wild type littermates (MR(flox/flox) mice) over the estrous cycle and in response to an acute stressor. The estrous cycle had no effect on the spatial performance of MR(flox/flox) mice and neither did the acute stressor. However, the MR(CaMKCre) mutants needed significantly more time to find the exit and made more hole visit errors than the MR(flox/flox) mice, especially when in proestrus and estrus. In addition, stressed MR(CaMKCre) mice in estrus had a shorter exit latency than the control estrus MR(CaMKCre) mice. About 70% of the female MR(CaMKCre) and MR(flox/flox) mice used a hippocampal (spatial, extra maze cues) rather than the caudate nucleus (stimulate-response, S-R, intra-maze cue) strategy and this preference did neither change over the estrous cycle nor after stress. However, stressed MR(CaMKCre) mice using the S-R strategy needed significantly more time to find the exit hole as compared to the spatial strategy using mice suggesting that the MR could be needed for the stress-induced strategy switch toward a spatial strategy. In conclusion, the results suggest that loss of MR interferes with performance of a spatial task especially when estrogen levels are high suggesting a strong interaction between stress and sex hormones. PMID- 23754994 TI - Visual avoidance in phobia: particularities in neural activity, autonomic responding, and cognitive risk evaluations. AB - We investigated the neural mechanisms and the autonomic and cognitive responses associated with visual avoidance behavior in spider phobia. Spider phobic and control participants imagined visiting different forest locations with the possibility of encountering spiders, snakes, or birds (neutral reference category). In each experimental trial, participants saw a picture of a forest location followed by a picture of a spider, snake, or bird, and then rated their personal risk of encountering these animals in this context, as well as their fear. The greater the visual avoidance of spiders that a phobic participant demonstrated (as measured by eye tracking), the higher were her autonomic arousal and neural activity in the amygdala, orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and precuneus at picture onset. Visual avoidance of spiders in phobics also went hand in hand with subsequently reduced cognitive risk of encounters. Control participants, in contrast, displayed a positive relationship between gaze duration toward spiders, on the one hand, and autonomic responding, as well as OFC, ACC, and precuneus activity, on the other hand. In addition, they showed reduced encounter risk estimates when they looked longer at the animal pictures. Our data are consistent with the idea that one reason for phobics to avoid phobic information may be grounded in heightened activity in the fear circuit, which signals potential threat. Because of the absence of alternative efficient regulation strategies, visual avoidance may then function to down-regulate cognitive risk evaluations for threatening information about the phobic stimuli. Control participants, in contrast, may be characterized by a different coping style, whereby paying visual attention to potentially threatening information may help them to actively down-regulate cognitive evaluations of risk. PMID- 23754996 TI - Comprehension of action negation involves inhibitory simulation. AB - Previous research suggests that action language is comprehended by activating the motor system. We report a study, investigating a critical question in this research field: do negative sentences activate the motor system? Participants were exposed to sentences in the affirmation and negation forms while the zygomatic muscle activity on the left side of the face was continuously measured (Electromyography technique: EMG). Sentences were descriptions of emotional expressions that mapped either directly upon the zygomatic muscle (e.g., "I am smiling") or did not (e.g., "I am frowning"). Reading sentences involving the negation of the activity of a specific muscle (zygomatic major-"I am not smiling") is shown to lead to the inhibition of this muscle. Reading sentences involving the affirmative form instead ("I am smiling") leads to the activation of zygomatic mucle. In contrast, sentences describing an activity that is irrelevant to the zygomatic muscle (e.g., "I am frowning" or "I am not frowning") produce no muscle activity. These results extend the range of simulation models to negation and by implication to an abstract domain. We discuss how this research contributes to the grounding of abstract and concrete concepts. PMID- 23754995 TI - Men perform comparably to women in a perspective taking task after administration of intranasal oxytocin but not after placebo. AB - Oxytocin (OT) is thought to play an important role in human interpersonal information processing and behavior. By inference, OT should facilitate empathic responding, i.e., the ability to feel for others and to take their perspective. In two independent double-blind, placebo-controlled between-subjects studies, we assessed the effect of intranasally administered OT on affective empathy and perspective taking, whilst also examining potential sex differences (e.g., women being more empathic than men). In study 1, we provided 96 participants (48 men) with an empathy scenario and recorded self-reports of empathic reactions to the scenario, while in study 2, a sample of 120 individuals (60 men) performed a computerized implicit perspective taking task. Whilst results from Study 1 showed no influence of OT on affective empathy, we found in Study 2 that OT exerted an effect on perspective taking ability in men. More specifically, men responded faster than women in the placebo group but they responded as slowly as women in the OT group. We conjecture that men in the OT group adopted a social perspective taking strategy, such as did women in both groups, but not men in the placebo group. On the basis of results across both studies, we suggest that self-report measures (such as used in Study 1) might be less sensitive to OT effects than more implicit measures of empathy such as that used in Study 2. If these assumptions are confirmed, one could infer that OT effects on empathic responses are more pronounced in men than women, and that any such effect is best studied using more implicit measures of empathy rather than explicit self-report measures. PMID- 23754997 TI - Pupil dilation in the Simon task as a marker of conflict processing. AB - Cognitive demands in response conflict paradigms trigger negative affect and avoidance behavior. However, not all response conflict studies show increases in physiological indices of emotional arousal, such as pupil diameter. In contrast to earlier null-results, this study shows for the first time that small (about 0.02 mm) conflict-related pupil dilation can be observed in a Simon task when stimuli do not introduce a light reflex. Results show that response-conflict in Simon trials induces both pupil dilation and reaction-time costs. Moreover, sequential analyses reveal that pupil dilation mirrors the conflict-adaptation pattern observed in reaction time (RT). Although single-trial regression analyses indicated that pupil dilation is likely to reflect more than one process at the same time, in general our findings imply that pupil dilation can be used as an indirect marker of conflict processing. PMID- 23754998 TI - Statistical learning as a tool for rehabilitation in spatial neglect. AB - We propose that neglect includes a disorder of representational updating. Representational updating refers to our ability to build mental models and adapt those models to changing experience. This updating ability depends on the processes of priming, working memory, and statistical learning. These processes in turn interact with our capabilities for sustained attention and precise temporal processing. We review evidence showing that all these non-spatial abilities are impaired in neglect, and we discuss how recognition of such deficits can lead to novel approaches for rehabilitating neglect. PMID- 23754999 TI - Mirror-like brain responses to observed touch and personality dimensions. AB - The last years have shown a growing interest in research on the neural mechanisms for perceiving and understanding social interactions. Only very recently, a role for somatosensation in social perception has been suggested. Numerous studies reported vicarious responses in the primary somatosensory cortex (SI) and other areas merely when seeing others being touched. Moreover, it has been demonstrated that these vicarious somatosensory responses can be linked with inter-individual differences in empathy. However, beyond empathy other personality traits have been shown to interact with social perception and behavior. Here we tested if personality traits according to the Five-Factor-Model interact with vicarious activation in somatosensory brain regions. We conducted a functional magnetic resonance imaging (fMRI) study in which subjects viewed video clips showing simple non-painful touch to a hand and a control condition including the same visual and motion parts. Results revealed vicarious somatosensory activation when viewing the touched hand, as expected. Vicarious activation in SI showed a trend for a positive correlation with the personality trait openness to experience. Moreover, mirror-like responses in the insula were strongly correlated with the personality trait conscientiousness, suggesting links to processes of self control. We conclude that vicarious brain responses to seen touch seem to interact with personality traits. PMID- 23755001 TI - Segregation of the human medial prefrontal cortex in social cognition. AB - While the human medial prefrontal cortex (mPFC) is widely believed to be a key node of neural networks relevant for socio-emotional processing, its functional subspecialization is still poorly understood. We thus revisited the often assumed differentiation of the mPFC in social cognition along its ventral-dorsal axis. Our neuroinformatic analysis was based on a neuroimaging meta-analysis of perspective-taking that yielded two separate clusters in the ventral and dorsal mPFC, respectively. We determined each seed region's brain-wide interaction pattern by two complementary measures of functional connectivity: co-activation across a wide range of neuroimaging studies archived in the BrainMap database and correlated signal fluctuations during unconstrained ("resting") cognition. Furthermore, we characterized the functions associated with these two regions using the BrainMap database. Across methods, the ventral mPFC was more strongly connected with the nucleus accumbens, hippocampus, posterior cingulate cortex, and retrosplenial cortex, while the dorsal mPFC was more strongly connected with the inferior frontal gyrus, temporo-parietal junction, and middle temporal gyrus. Further, the ventral mPFC was selectively associated with reward related tasks, while the dorsal mPFC was selectively associated with perspective-taking and episodic memory retrieval. The ventral mPFC is therefore predominantly involved in bottom-up-driven, approach/avoidance-modulating, and evaluation-related processing, whereas the dorsal mPFC is predominantly involved in top-down-driven, probabilistic-scene-informed, and metacognition-related processing in social cognition. PMID- 23755002 TI - Combination of Resting State fMRI, DTI, and sMRI Data to Discriminate Schizophrenia by N-way MCCA + jICA. AB - Multimodal brain imaging data have shown increasing utility in answering both scientifically interesting and clinically relevant questions. Each brain imaging technique provides a different view of brain function or structure, while multimodal fusion capitalizes on the strength of each and may uncover hidden relationships that can merge findings from separate neuroimaging studies. However, most current approaches have focused on pair-wise fusion and there is still relatively little work on N-way data fusion and examination of the relationships among multiple data types. We recently developed an approach called "mCCA + jICA" as a novel multi-way fusion method which is able to investigate the disease risk factors that are either shared or distinct across multiple modalities as well as the full correspondence across modalities. In this paper, we applied this model to combine resting state fMRI (amplitude of low-frequency fluctuation, ALFF), gray matter (GM) density, and DTI (fractional anisotropy, FA) data, in order to elucidate the abnormalities underlying schizophrenia patients (SZs, n = 35) relative to healthy controls (HCs, n = 28). Both modality-common and modality-unique abnormal regions were identified in SZs, which were then used for successful classification for seven modality-combinations, showing the potential for a broad applicability of the mCCA + jICA model and its results. In addition, a pair of GM-DTI components showed significant correlation with the positive symptom subscale of Positive and Negative Syndrome Scale (PANSS), suggesting that GM density changes in default model network along with white matter disruption in anterior thalamic radiation are associated with increased positive PANSS. Findings suggest the DTI anisotropy changes in frontal lobe may relate to the corresponding functional/structural changes in prefrontal cortex and superior temporal gyrus that are thought to play a role in the clinical expression of SZ. PMID- 23755003 TI - Social behavior in the "Age of Empathy"?-A social scientist's perspective on current trends in the behavioral sciences. AB - Recently, several behavioral sciences became increasingly interested in investigating biological and evolutionary foundations of (human) social behavior. In this light, prosocial behavior is seen as a core element of human nature. A central role within this perspective plays the "social brain" that is not only able to communicate with the environment but rather to interact directly with other brains via neuronal mind reading capacities such as empathy. From the perspective of a sociologist, this paper investigates what "social" means in contemporary behavioral and particularly brain sciences. It will be discussed what "social" means in the light of social neuroscience and a glance into the history of social psychology and the brain sciences will show that two thought traditions come together in social neuroscience, combining an individualistic and an evolutionary notion of the "social." The paper concludes by situating current research on prosocial behavior in broader social discourses about sociality and society, suggesting that to naturalize prosocial aspects in human life is a current trend in today's behavioral sciences and beyond. PMID- 23755004 TI - Auditory verbal hallucinations result from combinatoric associations of multiple neural events. AB - While Auditory Verbal Hallucinations (AVH) refer to specific experiences shared by all subjects who have AVH-the perception of auditory speech without corresponding external stimuli, the characteristics of these experiences differ from one subject to another. These characteristics include aspects such as the location of AVH (inside or outside the head), the linguistic complexity of AVH (hearing words, sentences, or conversations), the range of content of AVH (repetitive or systematized content), and many other variables. In another word, AVH are phenomenologically heterogeneous experiences. After decades of research focused on a few explanatory mechanisms for AVH, it is apparent that none of these mechanisms alone explains the wide phenomenological range of AVH experiences. To date, our phenomenological understanding of AVH remains largely disjointed from our understanding of the mechanisms of AVH. For a cohesive understanding of AVH, I review the phenomenology and the cognitive and neural basis of AVH. This review indicates that the phenomenology of AVH is not a pointless curiosity. How a subject describes his AVH experiences could inform about the neural events that resulted in AVH. I suggest that a subject-specific combinatoric associations of different neural events result in AVH experiences phenomenologically diverse across subjects. PMID- 23755006 TI - The benefits of cholinergic enhancement during perceptual learning are long lasting. AB - The neurotransmitter acetylcholine (ACh) regulates many aspects of cognition, including attention and memory. Previous research in animal models has shown that plasticity in sensory systems often depends on the behavioral relevance of a stimulus and/or task. However, experimentally increasing ACh release in the cortex can result in experience-dependent plasticity, even in the absence of behavioral relevance. In humans, the pharmacological enhancement of ACh transmission by administration of the cholinesterase inhibitor donepezil during performance of a perceptual task increases the magnitude of perceptual learning (PL) and its specificity to physical parameters of the stimuli used for training. Behavioral effects of PL have previously been shown to persist for many months. In the present study, we tested whether enhancement of PL by donepezil is also long-lasting. Healthy human subjects were trained on a motion direction discrimination task during cholinergic enhancement, and follow-up testing was performed 5-15 months after the end of training and without additional drug administration. Increases in performance associated with training under donepezil were evident in follow-up retesting, indicating that cholinergic enhancement has beneficial long-term effects on PL. These findings suggest that cholinergic enhancement of training procedures used to treat clinical disorders should improve long-term outcomes of these procedures. PMID- 23755005 TI - Neural masses and fields in dynamic causal modeling. AB - Dynamic causal modeling (DCM) provides a framework for the analysis of effective connectivity among neuronal subpopulations that subtend invasive (electrocorticograms and local field potentials) and non-invasive (electroencephalography and magnetoencephalography) electrophysiological responses. This paper reviews the suite of neuronal population models including neural masses, fields and conductance-based models that are used in DCM. These models are expressed in terms of sets of differential equations that allow one to model the synaptic underpinnings of connectivity. We describe early developments using neural mass models, where convolution-based dynamics are used to generate responses in laminar-specific populations of excitatory and inhibitory cells. We show that these models, though resting on only two simple transforms, can recapitulate the characteristics of both evoked and spectral responses observed empirically. Using an identical neuronal architecture, we show that a set of conductance based models-that consider the dynamics of specific ion-channels present a richer space of responses; owing to non-linear interactions between conductances and membrane potentials. We propose that conductance-based models may be more appropriate when spectra present with multiple resonances. Finally, we outline a third class of models, where each neuronal subpopulation is treated as a field; in other words, as a manifold on the cortical surface. By explicitly accounting for the spatial propagation of cortical activity through partial differential equations (PDEs), we show that the topology of connectivity-through local lateral interactions among cortical layers-may be inferred, even in the absence of spatially resolved data. We also show that these models allow for a detailed analysis of structure-function relationships in the cortex. Our review highlights the relationship among these models and how the hypothesis asked of empirical data suggests an appropriate model class. PMID- 23755007 TI - Set-size effects for sampled shapes: experiments and model. AB - The location of imperfections or heterogeneities in shapes and contours often correlates with points of interest in a visual scene. Investigating the detection of such heterogeneities provides clues as to the mechanisms processing simple shapes and contours. We determined set-size effects (e.g., sensitivity to single target detection as distractor number increases) for sampled contours to investigate how the visual system combines information across space. Stimuli were shapes sampled by oriented Gabor patches: circles and high-amplitude RF4 and RF8 radial frequency patterns with Gabor orientations tangential to the shape. Subjects had to detect a deviation in orientation of one element ("heterogeneity"). Heterogeneity detection sensitivity was measured for a range (7-40) of equally spaced (2.3-0.4 degrees ) elements. In a second condition, performance was measured when elements sampled a part of the shapes. We either varied partial contour length for a fixed (7) set-size, co-varying inter-element spacing, or set-size for a fixed spacing (0.7 degrees ), co-varying partial contour length. Surprisingly, set-size effects (poorer performance with more elements) are rarely seen. Set-size effects only occur for shapes containing concavities (RF4 and RF8) and when spacing is fixed. When elements are regularly spaced, detection performance improves with set-size for all shapes. When set size is fixed and spacing varied, performance improves with decreasing spacing. Thus, when an increase in set-size and a decrease in spacing co-occur, the effect of spacing dominates, suggesting that inter-element spacing, not set-size, is the critical parameter for sampled shapes. We propose a model for the processing of simple shapes based on V4 curvature units with late noise, incorporating spacing, average shape curvature, and the number of segments with constant sign of curvature contained in the shape, which accurately accounts for our experimental results, making testable predictions for a variety of simple shapes. PMID- 23755008 TI - Consolidated learning can be susceptible to gradually-developing interference in prolonged motor learning. AB - When multiple items are learned in sequential order, learning for one item tends to be disrupted by subsequently learned items. Such retrograde interference has been studied with paradigms conducted over a relatively short term. Resistance to interference is generally believed to be a measure of learning or consolidation. Here, we used a finger-tapping motor sequence paradigm to examine interference in prolonged motor learning. Three groups of nine subjects participated in training sessions for 16 days, and practiced three different sequences in different orders and combinations. We found that a well-trained motor sequence was subject to a gradual interference when the subsequent learning was paired in a particular order. The results suggest that a well-learned motor memory is still susceptible to interference, and that resistance to interference in one condition does not necessarily imply full, permanent consolidation. PMID- 23755009 TI - Biological oscillations for learning walking coordination: dynamic recurrent neural network functionally models physiological central pattern generator. AB - The existence of dedicated neuronal modules such as those organized in the cerebral cortex, thalamus, basal ganglia, cerebellum, or spinal cord raises the question of how these functional modules are coordinated for appropriate motor behavior. Study of human locomotion offers an interesting field for addressing this central question. The coordination of the elevation of the 3 leg segments under a planar covariation rule (Borghese et al., 1996) was recently modeled (Barliya et al., 2009) by phase-adjusted simple oscillators shedding new light on the understanding of the central pattern generator (CPG) processing relevant oscillation signals. We describe the use of a dynamic recurrent neural network (DRNN) mimicking the natural oscillatory behavior of human locomotion for reproducing the planar covariation rule in both legs at different walking speeds. Neural network learning was based on sinusoid signals integrating frequency and amplitude features of the first three harmonics of the sagittal elevation angles of the thigh, shank, and foot of each lower limb. We verified the biological plausibility of the neural networks. Best results were obtained with oscillations extracted from the first three harmonics in comparison to oscillations outside the harmonic frequency peaks. Physiological replication steadily increased with the number of neuronal units from 1 to 80, where similarity index reached 0.99. Analysis of synaptic weighting showed that the proportion of inhibitory connections consistently increased with the number of neuronal units in the DRNN. This emerging property in the artificial neural networks resonates with recent advances in neurophysiology of inhibitory neurons that are involved in central nervous system oscillatory activities. The main message of this study is that this type of DRNN may offer a useful model of physiological central pattern generator for gaining insights in basic research and developing clinical applications. PMID- 23755010 TI - Finding neural assemblies with frequent item set mining. AB - Cell assemblies, defined as groups of neurons exhibiting precise spike coordination, were proposed as a model of network processing in the cortex. Fortunately, in recent years considerable progress has been made in multi electrode recordings, which enable recording massively parallel spike trains of hundred(s) of neurons simultaneously. However, due to the challenges inherent in multivariate approaches, most studies in favor of cortical cell assemblies still resorted to analyzing pairwise interactions. However, to recover the underlying correlation structures, higher-order correlations need to be identified directly. Inspired by the Accretion method proposed by Gerstein et al. (1978) we propose a new assembly detection method based on frequent item set mining (FIM). In contrast to Accretion, FIM searches effectively and without redundancy for individual spike patterns that exceed a given support threshold. We study different search methods, with which the space of potential cell assemblies may be explored, as well as different test statistics and subset conditions with which candidate assemblies may be assessed and filtered. It turns out that a core challenge of cell assembly detection is the problem of multiple testing, which causes a large number of false discoveries. Unfortunately, criteria that address individual candidate assemblies and try to assess them with statistical tests and/or subset conditions do not help much to tackle this problem. The core idea of our new method is that in order to cope with the multiple testing problem one has to shift the focus of statistical testing from specific assemblies (consisting of a specific set of neurons) to spike patterns of a certain size (i.e., with a certain number of neurons). This significantly reduces the number of necessary tests, thus alleviating the multiple testing problem. We demonstrate that our method is able to reliably suppress false discoveries, while it is still very sensitive in discovering synchronous activity. Since we exploit high-speed computational techniques from FIM for the tests, our method is also computationally efficient. PMID- 23755011 TI - An intrinsic value system for developing multiple invariant representations with incremental slowness learning. AB - Curiosity Driven Modular Incremental Slow Feature Analysis (CD-MISFA;) is a recently introduced model of intrinsically-motivated invariance learning. Artificial curiosity enables the orderly formation of multiple stable sensory representations to simplify the agent's complex sensory input. We discuss computational properties of the CD-MISFA model itself as well as neurophysiological analogs fulfilling similar functional roles. CD-MISFA combines 1. unsupervised representation learning through the slowness principle, 2. generation of an intrinsic reward signal through learning progress of the developing features, and 3. balancing of exploration and exploitation to maximize learning progress and quickly learn multiple feature sets for perceptual simplification. Experimental results on synthetic observations and on the iCub robot show that the intrinsic value system is essential for representation learning. Representations are typically explored and learned in order from least to most costly, as predicted by the theory of curiosity. PMID- 23755012 TI - Glucose and lactate metabolism in the awake and stimulated rat: a (13)C-NMR study. AB - Glucose is the major energetic substrate for the brain but evidence has accumulated during the last 20 years that lactate produced by astrocytes could be an additional substrate for neurons. However, little information exists about this lactate shuttle in vivo in activated and awake animals. We designed an experiment in which the cortical barrel field (S1BF) was unilaterally activated during infusion of both glucose and lactate (alternatively labeled with (13)C) in rats. At the end of stimulation (1 h) both S1BF areas were removed and analyzed by HR-MAS NMR spectroscopy to compare glucose and lactate metabolism in the activated area vs. the non-activated one. In combination with microwave irradiation HR-MAS spectroscopy is a powerful technical approach to study brain lactate metabolism in vivo. Using in vivo (14)C-2-deoxyglucose and autoradiography we confirmed that whisker stimulation was effective since we observed a 40% increase in glucose uptake in the activated S1BF area compared to the ipsilateral one. We first determined that lactate observed on spectra of biopsies did not arise from post-mortem metabolism. (1)H-NMR data indicated that during brain activation there was an average 2.4-fold increase in lactate content in the activated area. When [1-(13)C]glucose + lactate were infused (13)C-NMR data showed an increase in (13)C-labeled lactate during brain activation as well as an increase in lactate C3-specific enrichment. This result demonstrates that the increase in lactate observed on (1)H-NMR spectra originates from newly synthesized lactate from the labeled precursor ([1-(13)C]glucose). It also shows that this additional lactate does not arise from an increase in blood lactate uptake since it would otherwise be unlabeled. These results are in favor of intracerebral lactate production during brain activation in vivo which could be a supplementary fuel for neurons. PMID- 23755013 TI - Targeting potassium channels for increasing delivery of imaging agents and therapeutics to brain tumors. AB - Every year in the US, 20,000 new primary and nearly 200,000 metastatic brain tumor cases are reported. The cerebral microvessels/capillaries that form the blood-brain barrier not only protect the brain from toxic agents in the blood but also pose a significant hindrance to the delivery of small and large therapeutic molecules. Different strategies have been employed to circumvent the physiological barrier posed by blood-brain tumor barrier (BTB). Studies in our laboratory have identified significant differences in the expression levels of certain genes and proteins between normal and brain tumor capillary endothelial cells (ECs). In this study, we validated the non-invasive and clinically relevant dynamic contrast enhancing-magnetic resonance imaging (DCE-MRI) method with invasive, clinically irrelevant but highly accurate quantitative autoradiography method using rat glioma model. We also showed that DCE-MRI metric of tissue vessel perfusion-permeability is sensitive to changes in blood vessel permeability following administration of calcium-activated potassium (BKCa) channel activator NS-1619. Our results show that human gliomas and brain tumor ECs that overexpress BKCa channels can be targeted for increased BTB permeability for MRI enhancing agents to brain tumors. We conclude that monitoring the outcome of increased MRI enhancing agents' delivery to microsatellites and leading tumor edges in glioma patients would lead to beneficial clinical outcome. PMID- 23755014 TI - Does the use of an electronic reminder device with or without counseling improve adherence to lipid-lowering treatment? The results of a randomized controlled trial. AB - BACKGROUND: Lipid-lowering treatment with statins has proven to be effective in reducing cardiovascular events and mortality. In daily practice, however, adherence to medication is often low and this compromises the therapeutic effect. The aim of this study was to assess the effectiveness of an electronic reminder device (ERD) with or without counseling to improve refill adherence and persistence for statin treatment in non-adherent patients. METHODS: A multicenter, community pharmacy-based, randomized controlled trial was conducted in 24 pharmacies in the Netherlands among patients with pre-baseline refill adherence rates between 50 and 80%. Eligible patients aged 65 years or older were randomly assigned to 1 of 3 groups: (1) counseling with an ERD (n = 134), (2) ERD with a written instruction (n = 131), and a (3) control group that received the usual treatment (n = 134). MAIN OUTCOME MEASURE: refill adherence to statin treatment for a 360-day period after inclusion (PDC360). Patients with a refill rate >=80% were considered adherent. The effect among subgroups was also assessed. RESULTS: There were no relevant differences at baseline. In the counseling with ERD group 54 of 130 eligible patients received the counseling with ERD. In the ERD group, 117 of 123 eligible patients received the ERD. The proportions of adherent patients in the counseling with ERD-group (69.2%) and in the ERD group (72.4%) were not higher than in the control group (64.8%). Among women using statins for secondary prevention, more patients were adherent in the ERD group (86.1%) than in the control group (52.6%) (p < 0.005). In men using statins for secondary prevention the ERD was found to have no effect. CONCLUSION: In this randomized controlled trial, no statistically significant improvement of refill adherence was found if an ERD was used with or without counseling. However, in a subgroup of women using statins for secondary prevention the ERD did improve adherence significantly. PMID- 23755015 TI - From the ultrasonic to the infrared: molecular evolution and the sensory biology of bats. AB - Great advances have been made recently in understanding the genetic basis of the sensory biology of bats. Research has focused on the molecular evolution of candidate sensory genes, genes with known functions [e.g., olfactory receptor (OR) genes] and genes identified from mutations associated with sensory deficits (e.g., blindness and deafness). For example, the FoxP2 gene, underpinning vocal behavior and sensorimotor coordination, has undergone diversification in bats, while several genes associated with audition show parallel amino acid substitutions in unrelated lineages of echolocating bats and, in some cases, in echolocating dolphins, representing a classic case of convergent molecular evolution. Vision genes encoding the photopigments rhodopsin and the long-wave sensitive opsin are functional in bats, while that encoding the short-wave sensitive opsin has lost functionality in rhinolophoid bats using high-duty cycle laryngeal echolocation, suggesting a sensory trade-off between investment in vision and echolocation. In terms of olfaction, bats appear to have a distinctive OR repertoire compared with other mammals, and a gene involved in signal transduction in the vomeronasal system has become non-functional in most bat species. Bitter taste receptors appear to have undergone a "birth-and death" evolution involving extensive gene duplication and loss, unlike genes coding for sweet and umami tastes that show conservation across most lineages but loss in vampire bats. Common vampire bats have also undergone adaptations for thermoperception, via alternative splicing resulting in the evolution of a novel heat-sensitive channel. The future for understanding the molecular basis of sensory biology is promising, with great potential for comparative genomic analyses, studies on gene regulation and expression, exploration of the role of alternative splicing in the generation of proteomic diversity, and linking genetic mechanisms to behavioral consequences. PMID- 23755016 TI - Multiscale analysis of heart rate variability in non-stationary environments. AB - Heart rate variability (HRV) is highly non-stationary, even if no perturbing influences can be identified during the recording of the data. The non stationarity becomes more profound when HRV data are measured in intrinsically non-stationary environments, such as social stress. In general, HRV data measured in such situations are more difficult to analyze than those measured in constant environments. In this paper, we analyze HRV data measured during a social stress test using two multiscale approaches, the adaptive fractal analysis (AFA) and scale-dependent Lyapunov exponent (SDLE), for the purpose of uncovering differences in HRV between chronic fatigue syndrome (CFS) patients and their matched-controls. CFS is a debilitating, heterogeneous illness with no known biomarker. HRV has shown some promise recently as a non-invasive measure of subtle physiological disturbances and trauma that are otherwise difficult to assess. If the HRV in persons with CFS are significantly different from their healthy controls, then certain cardiac irregularities may constitute good candidate biomarkers for CFS. Our multiscale analyses show that there are notable differences in HRV between CFS and their matched controls before a social stress test, but these differences seem to diminish during the test. These analyses illustrate that the two employed multiscale approaches could be useful for the analysis of HRV measured in various environments, both stationary and non stationary. PMID- 23755017 TI - Inflammatory markers associated with osteoarthritis after destabilization surgery in young mice with and without Receptor for Advanced Glycation End-products (RAGE). AB - HtrA1, Ddr-2, and Mmp-13 are reliable biomarkers for osteoarthritis (OA), yet the exact mechanism for the upregulation of HtrA-1 is unknown. Some have shown that chondrocyte hypertrophy is associated with early indicators of inflammation including TGF-beta and the Receptor for Advanced Glycation End-products (RAGE). To examine the correlation of inflammation with the expression of biomarkers in OA, we performed right knee destabilization surgery on 4-week-old-wild type and RAGE knock-out (KO) mice. We assayed for HtrA-1, TGF-beta1, Mmp-13, and Ddr-2 in articular cartilage at 3, 7, 14, and 28 days post-surgery by immunohistochemistry on left and right knee joints. RAGE KO and wild type mice both showed staining for key OA biomarkers. However, RAGE KO mice were significantly protected against OA compared to controls. We observed a difference in the total number of chondrocytes and percentage of chondrocytes staining positive for OA biomarkers between RAGE KO and control mice. The percentage of cells staining for OA biomarkers correlated with severity of cartilage degradation. Our results indicate that the absence of RAGE did protect against the development of advanced OA. We conclude that HtrA-1 plays a role in lowering TGF-beta1 expression in the process of making articular cartilage vulnerable to damage associated with OA progression. PMID- 23755018 TI - YKL-40 acts as an angiogenic factor to promote tumor angiogenesis. AB - A secreted glycoprotein YKL-40 also named chitinase-3-like-1 is normally expressed by multiple cell types such as macrophages, chondrocytes, and vascular smooth muscle cells. However, a prominently high level of YKL-40 was found in a wide spectrum of human diseases including cancers and chronic inflammatory diseases where it was strongly expressed by cancerous cells and infiltrating macrophages. Here, we summarized recent important findings of YKL-40 derived from cancerous cells and smooth muscle cells during tumor angiogenesis and development. YKL-40 is a potent angiogenic factor capable of stimulating tumor vascularization mediated by endothelial cells and maintaining vascular integrity supported by smooth muscle cells. In addition, YKL-40 induces FAK-MAPK signaling and up-regulates VEGF receptor 2 in endothelial cells; but a neutralizing antibody (mAY) against YKL-40 inhibits its angiogenic activity. While YKL-40 is essential for angiogenesis, little is known about its functional role in tumor associated macrophage (TAM)-mediated tumor development. Therefore, significant efforts are urgently needed to identify pathophysiological function of YKL-40 in the dynamic interaction between tumor cells and TAMs in the tumor microenvironment, which may offer substantial mechanistic insights into tumor angiogenesis and metastasis, and also point to a therapeutic target for treatment of cancers and other diseases. PMID- 23755019 TI - Echolocation in Oilbirds and swiftlets. AB - The discovery of ultrasonic bat echolocation prompted a wide search for other animal biosonar systems, which yielded, among few others, two avian groups. One, the South American Oilbird (Steatornis caripensis: Caprimulgiformes), is nocturnal and eats fruit. The other is a selection of diurnal, insect-eating swiftlets (species in the genera Aerodramus and Collocalia: Apodidae) from across the Indo-Pacific. Bird echolocation is restricted to lower frequencies audible to humans, implying a system of poorer resolution than the ultrasonic (>20 kHz) biosonar of most bats and toothed whales. As such, bird echolocation has been labeled crude or rudimentary. Yet, echolocation is found in at least 16 extant bird species and has evolved several times in avian lineages. Birds use their syringes to produce broadband click-type biosonar signals that allow them to nest in dark caves and tunnels, probably with less predation pressure. There are ongoing discrepancies about several details of bird echolocation, from signal design to the question about whether echolocation is used during foraging. It remains to be seen if bird echolocation is as sophisticated as that of tongue clicking rousette bats. Bird echolocation performance appears to be superior to that of blind humans using signals of notable similarity. However, no apparent specializations have been found so far in the birds' auditory system (from middle ear to higher processing centers). The advent of light-weight recording equipment and custom software for examining signals and reconstructing flight paths now provides the potential to study the echolocation behavior of birds in more detail and resolve such issues. PMID- 23755020 TI - Muscle fatigue and muscle weakness: what we know and what we wish we did. PMID- 23755021 TI - Mitochondrial reactive oxygen species (ROS) as signaling molecules of intracellular pathways triggered by the cardiac renin-angiotensin II-aldosterone system (RAAS). AB - Mitochondria represent major sources of basal reactive oxygen species (ROS) production of the cardiomyocyte. The role of ROS as signaling molecules that mediate different intracellular pathways has gained increasing interest among physiologists in the last years. In our lab, we have been studying the participation of mitochondrial ROS in the intracellular pathways triggered by the renin-angiotensin II-aldosterone system (RAAS) in the myocardium during the past few years. We have demonstrated that acute activation of cardiac RAAS induces mitochondrial ATP-dependent potassium channel (mitoKATP) opening with the consequent enhanced production of mitochondrial ROS. These oxidant molecules, in turn, activate membrane transporters, as sodium/hydrogen exchanger (NHE-1) and sodium/bicarbonate cotransporter (NBC) via the stimulation of the ROS-sensitive MAPK cascade. The stimulation of such effectors leads to an increase in cardiac contractility. In addition, it is feasible to suggest that a sustained enhanced production of mitochondrial ROS induced by chronic cardiac RAAS, and hence, chronic NHE-1 and NBC stimulation, would also result in the development of cardiac hypertrophy. PMID- 23755022 TI - The prevalence of electrocardiographic early repolarization in an adult cohort with chronic kidney disease and its impact upon all-cause mortality and progression to dialysis. AB - BACKGROUND: Electrocardiographic early repolarization (ER) occurring in <5% of general/atherosclerotic populations, is a marker of sudden cardiac death (SCD). The prevalence of ER in chronic kidney disease (CKD) patients, in whom SCD is common, is unknown. We aimed to determine the prevalence, contributing factors, and relationship of ER to all-cause mortality and progression to dialysis in CKD patients. METHODS: A retrospective study of 197 patients with stage 3-5 CKD. Full demographic data were collected including cardiovascular risk factors and history. All patients underwent a 12-lead ECG, analysed for the presence of ER and other ECG findings. ER was defined as elevation of the QRS-ST junction (J point) by at least 0.1 mV from baseline with slurring/notching of the QRS complex. The primary and secondary endpoints were all cause mortality and progression to dialysis respectively at 1 year. To control for the effects of CKD, we evaluated the ECGs of 39 healthy renal transplant donors (RTD). RESULTS: CKD patients had a mean age of 61.5 (+/-16.1). Prevalence of ER in pre-dialysis patients with CKD stage 4 and 5 was higher than in RTD (26.4 vs. 7.7%, p = 0.02). ER frequency increased with CKD stage (stage 3: 7.7%, stage 4: 29.7%, and pre dialysis stage 5: 24.6%), but decreased in dialysis patients (13%). On multivariate analysis only the QRS duration was a significant independent predictor of ER (OR 0.97, 95% CI, 0.94-0.99, p = 0.01). At 1-year follow-up, there were 24 (12%) deaths in the patients with CKD of whom 5 (21%) had ER. ER was not a predictor of all cause mortality (p = 1.00) and had no effects on the rate of progression to dialysis (p = 0.67). CONCLUSIONS: ER is more common in pre dialysis CKD patients, compared to healthy RTD but is not associated with increased 1-year mortality or entry onto dialysis programs. Further longitudinal studies are indicated to determine whether this increased prevalence of ER is associated with the rate of SCD seen in this population. PMID- 23755024 TI - Diagnostic Criteria in Attention Deficit Hyperactivity Disorder - Changes in DSM 5. PMID- 23755025 TI - Legalization of marijuana: unraveling quandaries for the addiction professional. PMID- 23755023 TI - Emerging role for corticotropin releasing factor signaling in the bed nucleus of the stria terminalis at the intersection of stress and reward. AB - Stress and anxiety play an important role in the development and maintenance of drug and alcohol addiction. The bed nucleus of the stria terminalis (BNST), a brain region involved in the production of long-term stress-related behaviors, plays an important role in animal models of relapse, such as reinstatement to previously extinguished drug-seeking behaviors. While a number of neurotransmitter systems have been suggested to play a role in these behaviors, recent evidence points to the neuropeptide corticotropin releasing factor (CRF) as being critically important in BNST-mediated reinstatement behaviors. Although numerous studies indicate that the BNST is a complex brain region with multiple afferent and efferent systems and a variety of cell types, there has only been limited work to determine how CRF modulates this complex neuronal system at the circuit level. Recent work from our lab and others have begun to unravel these BNST neurocircuits and explore their roles in CRF-related reinstatement behaviors. This review will examine the role of CRF signaling in drug addiction and reinstatement with an emphasis on critical neurocircuitry within the BNST that may offer new insights into treatments for addiction. PMID- 23755026 TI - Reexamining the validity and reliability of the clinical version of the iowa gambling task: evidence from a normal subject group. AB - Over past decade, the Iowa gambling task (IGT) has been utilized to test various decision deficits induced by neurological damage or psychiatric disorders. The IGT has recently been standardized for identifying 13 different neuropsychological disorders. Neuropsychological patients choose bad decks frequently, and normal subjects prefer good expected value (EV) decks. However, the IGT has several validity and reliability problems. Some research groups have pointed out that the validity of IGT is influenced by the personality and emotional state of subjects. Additionally, several other studies have proposed that the "prominent deck B phenomenon" (PDB phenomenon) - that is, normal subjects preferring bad deck B - may be the most serious problem confronting IGT validity. Specifically, deck B offers a high frequency of gains but negative EV. In the standard IGT administration, choice behavior can be understood with reference to gain-loss frequency (GLF) rather than inferred future consequences (EV, the basic assumption of IGT). Furthermore, using two different criteria (basic assumption vs. professional norm) results in significantly different classification results. Therefore, we recruited 72 normal subjects to test the validity and reliability of IGT. Each subject performed three runs of the computer-based clinical IGT version. The PDB phenomenon has been observed to a significant degree in the first and second stages of the clinical IGT version. Obviously, validity, reliability, and the practice effect were unstable between two given stages. The present form of the clinical IGT version has only one stage, so its use should be reconsidered for examining normal decision makers; results from patient groups must also be interpreted with great care. GLF could be the main factor to be considered in establishing the constructional validity and reliability of the clinical IGT version. PMID- 23755028 TI - Autistic trait interactions underlie sex-dependent facial recognition abilities in the normal population. AB - Autistic face processing difficulties are either uniquely social or due to a piecemeal cognitive "style." Co-morbidity of social deficits and piecemeal cognition in autism makes teasing apart these accounts difficult. These traits vary normally, and are more separable in the general population, suggesting another way to compare accounts. Participants completed the Autism Quotient survey of autistic traits, and one of three face recognition tests: full-face, eyes-only, or mouth-only. Social traits predicted performance in the full-face condition in both sexes. Eyes-only males' performance was predicted by a social * cognitive trait interaction: attention to detail boosted face recognition in males with few social traits, but hindered performance in those reporting many social traits. This suggests social/non-social Autism Spectrum Conditions (ASC) trait interactions at the behavioral level. In the presence of few ASC-like difficulties in social reciprocity, an ASC-like attention to detail may confer advantages on typical males' face recognition skills. On the other hand, when attention to detail co-occurs with difficulties in social reciprocity, a detailed focus may exacerbate such already present social difficulties, as is thought to occur in autism. PMID- 23755027 TI - On disturbed time continuity in schizophrenia: an elementary impairment in visual perception? AB - Schizophrenia is associated with a series of visual perception impairments, which might impact on the patients' every day life and be related to clinical symptoms. However, the heterogeneity of the visual disorders make it a challenge to understand both the mechanisms and the consequences of these impairments, i.e., the way patients experience the outer world. Based on earlier psychiatry literature, we argue that issues regarding time might shed a new light on the disorders observed in patients with schizophrenia. We will briefly review the mechanisms involved in the sense of time continuity and clinical evidence that they are impaired in patients with schizophrenia. We will then summarize a recent experimental approach regarding the coding of time-event structure in time, namely the ability to discriminate between simultaneous and asynchronous events. The use of an original method of analysis allowed us to distinguish between explicit and implicit judgments of synchrony. We showed that for SOAs below 20 ms neither patients nor controls fuse events in time. On the contrary subjects distinguish events at an implicit level even when judging them as synchronous. In addition, the implicit responses of patients and controls differ qualitatively. It is as if controls always put more weight on the last occurred event, whereas patients have a difficulty to follow events in time at an implicit level. In patients, there is a clear dissociation between results at short and large asynchronies, that suggest selective mechanisms for the implicit coding of time event structure. These results might explain the disruption of the sense of time continuity in patients. We argue that this line of research might also help us to better understand the mechanisms of the visual impairments in patients and how they see their environment. PMID- 23755029 TI - Degraded stimulus visibility and the effects of perceptual load on distractor interference. AB - In this study we examined whether effects of perceptual load on the attentional selectivity are modulated by degradation of the visual input. According to the perceptual load theory, increasing task difficulty via degradation of stimulus visibility should not alter the typical effect of perceptual load. In previous studies only the target was degraded, resulting in increased distractor saliency. Here we combined manipulation of perceptual load with a more systematic degradation of visual information. Experiment 1 included five conditions. Three conditions involved low perceptual load + contrast reduction of: (A) only the target; (B) only the distractor; (C) both target and distractor. The other two conditions included non-degraded stimuli with low or high perceptual load. In Experiment 2 visibility degradation was established via manipulation of exposure duration. It included two exposure durations-100 and 150 ms-for each load level (low vs. high). The results of both experiments demonstrated reliable distractor interference of a similar magnitude with both degraded and non-degraded stimuli. This finding suggests that task difficulty, when manipulated via degradation of stimulus visibility, does not play a critical role in determining the efficiency of the attentional selectivity. However, contrary to the predictions of the perceptual load theory, in both experiments distractor interference emerged under the high load condition. In Experiment 2 the high-load interference was of the same magnitude as that of the low load condition. This high-load interference is not due to the presence of a mask (Experiment 3) or a mixed design (Experiment 4). These findings suggest that perceptual load may also play a lesser role in attentional selectivity than that assigned to it by the perceptual load theory. PMID- 23755030 TI - Individual Differences in Discriminatory Fear Learning under Conditions of Ambiguity: A Vulnerability Factor for Anxiety Disorders? AB - Complex fear learning procedures might be better suited than the common differential fear-conditioning paradigm for detecting individual differences related to vulnerability for anxiety disorders. Two such procedures are the blocking procedure and the protection-from-overshadowing procedure. Their comparison allows for the examination of discriminatory fear learning under conditions of ambiguity. The present study examined the role of individual differences in such discriminatory fear learning. We hypothesized that heightened trait anxiety would be related to a deficit in discriminatory fear learning. Participants gave US-expectancy ratings as an index for the threat value of individual CSs following blocking and protection-from-overshadowing training. The difference in threat value at test between the protected-from-overshadowing conditioned stimulus (CS) and the blocked CS was negatively correlated with scores on a self-report tension-stress scale that approximates facets of generalized anxiety disorder (GAD), the Depression Anxiety Stress Scale-Stress (DASS-S), but not with other individual difference variables. In addition, a behavioral test showed that only participants scoring high on the DASS-S avoided the protected-from-overshadowing CS. This observed deficit in discriminatory fear learning for participants with high levels of tension-stress might be an underlying mechanism for fear overgeneralization in diffuse anxiety disorders such as GAD. PMID- 23755031 TI - A new measure of interpersonal exploitativeness. AB - Measures of exploitativeness evidence problems with validity and reliability. The present set of studies assessed a new measure [the Interpersonal Exploitativeness Scale (IES)] that defines exploitativeness in terms of reciprocity. In Studies 1 and 2, 33 items were administered to participants. Exploratory and Confirmatory Factor Analysis demonstrated that a single factor consisting of six items adequately assess interpersonal exploitativeness. Study 3 results revealed that the IES was positively associated with "normal" narcissism, pathological narcissism, psychological entitlement, and negative reciprocity and negatively correlated with positive reciprocity. In Study 4, participants competed in a commons dilemma. Those who scored higher on the IES were more likely to harvest a greater share of resources over time, even while controlling for other relevant variables, such as entitlement. Together, these studies show the IES to be a valid and reliable measure of interpersonal exploitativeness. The authors discuss the implications of these studies. PMID- 23755032 TI - When speaking of the experience, do not leave out the experiencer: on self and magnitude. PMID- 23755034 TI - Repeated Activation of a CS-US-Contingency Memory Results in Sustained Conditioned Responding. AB - Individuals seem to differ in conditionability, i.e., the ease by which the contingent presentation of two stimuli will lead to a conditioned response. In contemporary learning theory, individual differences in the etiology and maintenance of anxiety disorders are, among others, explained by individual differences in temperamental variables (Mineka and Zinbarg, 2006). One such individual difference variable is how people process a learning experience when the conditioning stimuli are no longer present. Repeatedly thinking about the conditioning experience, as in worry or rumination, might prolong the initial (fear) reactions and as such, might leave certain individuals more vulnerable to developing an anxiety disorder. However, in human conditioning research, relatively little attention has been devoted to the processing of a memory trace after its initial acquisition, despite its potential influences on subsequent performance. Post-acquisition processing can be induced by mental reiteration of a conditioned stimulus-unconditioned stimulus (CS-US)-contingency. Using a human conditioned suppression paradigm, we investigated the effect of repeated activations of a CS-US-contingency memory on the level of conditioned responding at a later test. Results of three experiments showed more sustained responding to a "rehearsed" CS+ as compared to a "non-rehearsed" CS+. Moreover, the second experiment showed no effect of rehearsal when only the CS was rehearsed instead of the CS-US-contingency. The third experiment demonstrated that mental CS-US rehearsal has the same effect regardless of whether it was cued by the CS and a verbal reference to the US or by a neutral signal, making the rehearsal "purely mental." In sum, it was demonstrated that post-acquisition activation of a CS-US contingency memory can impact conditioned responding, underlining the importance of post-acquisition processes in conditioning. This might indicate that individuals who are more prone to mentally rehearse information condition more easily. PMID- 23755033 TI - Conscious experience and episodic memory: hippocampus at the crossroads. AB - If an instance of conscious experience of the seemingly objective world around us could be regarded as a newly formed event memory, much as an instance of mental imagery has the content of a retrieved event memory, and if, therefore, the stream of conscious experience could be seen as evidence for ongoing formation of event memories that are linked into episodic memory sequences, then unitary conscious experience could be defined as a symbolic representation of the pattern of hippocampal neuronal firing that encodes an event memory - a theoretical stance that may shed light into the mind-body and binding problems in consciousness research. Exceedingly detailed symbols that describe patterns of activity rapidly self-organizing, at each cycle of the theta rhythm, in the hippocampus are instances of unitary conscious experience that jointly constitute the stream of consciousness. Integrating object information (derived from the ventral visual stream and orbitofrontal cortex) with contextual emotional information (from the anterior insula) and spatial environmental information (from the dorsal visual stream), the hippocampus rapidly forms event codes that have the informational content of objects embedded in an emotional and spatiotemporally extending context. Event codes, formed in the CA3-dentate network for the purpose of their memorization, are not only contextualized but also allocentric representations, similarly to conscious experiences of events and objects situated in a seemingly objective and observer-independent framework of phenomenal space and time. Conscious perception, creating the spatially and temporally extending world that we perceive around us, is likely to be evolutionarily related to more fleeting and seemingly internal forms of conscious experience, such as autobiographical memory recall, mental imagery, including goal anticipation, and to other forms of externalized conscious experience, namely dreaming and hallucinations; and evidence pointing to an important contribution of the hippocampus to these conscious phenomena will be reviewed. PMID- 23755036 TI - Subthreshold Depressive Symptoms have a Negative Impact on Cognitive Functioning in Middle-Aged and Older Males. AB - INTRODUCTION: Cognitive aging is associated with a decline on measures of fluid intelligence (gF), whereas crystallized intelligence (gC) tends to remain stable. In the present study we asked if depressive symptoms might contribute to explain the decline on gF in a sample of healthy middle-aged and older adults. METHOD: The Norwegian sample included 83 females and 42 males (M = 60, SD = 7.9 years). gF was calculated from factor-analysis, including tests of matrix reasoning (WASI), memory function (CVLT-II), processing speed and executive function (CDT; CWIT). gC was derived from a Vocabulary subtest (WASI). Depressive symptoms were assessed by self-reports on Beck's Depression Index (BDI) and ranged from 0 to 21 (M = 6, SD = 4.5). RESULTS: Increased age was correlated with a decline on gF (r = -0.436, p < 0.001), but not gC (r=-0.103, p = ns.). The BDI score in the whole sample was correlated with gF (r = -0.313, p < 0.001). A more detailed analysis showed that the BDI score correlated with measures of both gF and gC in males. The correlations were non-significant for females on all measures, with the exception of a measure of processing speed/executive function. A regression analysis including age and sex in the first step, showed that symptoms of depression significantly contributed to explain decline on gF, F(3, 124) = 16.653, p < 0.001, R? = 0.292, DeltaR? = 0.054. DISCUSSION: The results showed that symptoms of depression were negatively correlated with cognitive functioning in males even when the symptom-level was below clinical threshold. This indicates that minimal symptoms of depression in older men are clinically relevant to address. PMID- 23755037 TI - Grasp posture modulates attentional prioritization of space near the hands. AB - Changes in visual processing near the hands may assist observers in evaluating items that are candidates for actions. If altered vision near the hands reflects adaptations linked to effective action production, then positioning the hands for different types of actions could lead to different visual biases. I examined the influence of hand posture on attentional prioritization to test this hypothesis. Participants placed one of their hands on a visual display and detected targets appearing either near or far from the hand. Replicating previous findings, detection near the hand was facilitated when participants positioned their hand on the display in a standard open palm posture affording a power grasp (Experiments 1 and 3). However, when participants instead positioned their hand in a pincer grasp posture with the thumb and forefinger resting on the display, they were no faster to detect targets appearing near their hand than targets appearing away from their hand (Experiments 2 and 3). These results demonstrate that changes in visual processing near the hands rely on the hands' posture. Although hands positioned to afford power grasps facilitate rapid onset detection, a pincer grasp posture that affords more precise action does not. PMID- 23755038 TI - Clinical neuropsychologists need a standard preliminary observational examination of cognitive functions. PMID- 23755035 TI - The coherent organization of mental life depends on mechanisms for context sensitive gain-control that are impaired in schizophrenia. AB - There is rapidly growing evidence that schizophrenia involves changes in context sensitive gain-control and probabilistic inference. In addition to the well-known cognitive disorganization to which these changes lead, basic aspects of vision are also impaired, as discussed by other papers on this Frontiers Research Topic. The aim of this paper is to contribute to our understanding of such findings by examining five central hypotheses. First, context-sensitive gain-control is fundamental to brain function and mental life. Second, it occurs in many different regions of the cerebral cortex of many different mammalian species. Third, it has several computational functions, each with wide generality. Fourth, it is implemented by several neural mechanisms at cellular and circuit levels. Fifth, impairments of context-sensitive gain-control produce many of the well known symptoms of schizophrenia and change basic processes of visual perception. These hypotheses suggest why disorders of vision in schizophrenia may provide insights into the nature and mechanisms of impaired reality testing and thought disorder in psychosis. They may also cast light on normal mental function and its neural bases. Limitations of these hypotheses, and ways in which they need further testing and development, are outlined. PMID- 23755040 TI - Diabetes and change in bone mineral density at the hip, calcaneus, spine, and radius in older women. AB - Older women with type 2 diabetes mellitus (DM) have higher bone mineral density (BMD) but also have higher rates of fracture compared to those without DM. Limited evidence suggests that DM may also be associated with more rapid bone loss. To determine if bone loss rates differ by DM status in older women, we analyzed BMD data in the Study of Osteoporotic Fractures (SOF) between 1986 and 1998. SOF participants were women >=65 years at baseline who were recruited from four regions in the U.S. DM was ascertained by self-report. BMD was measured with dual-energy x-ray absorptiometry (DXA) at baseline and at least one follow-up visit at the hip (N = 6624) and calcaneus (N = 6700) and, on a subset of women, at the spine (N = 396) and distal radius (N = 306). Annualized percent change in BMD was compared by DM status, using random effects models. Of 6,867 women with at least one follow-up DXA scan, 409 had DM at baseline. Mean age was 70.8 (SD 4.7) years. Baseline BMD was higher in women with DM at all measured sites. In models adjusted for age and clinic, women with prevalent DM lost bone more rapidly than those without DM at the femoral neck (-0.96 vs. -0.59%/year, p < 0.001), total hip (-0.98 vs. -0.70%/year, p < 0.001), calcaneus (-1.64 vs. 1.40%/year, p = 0.005), and spine (-0.33 vs. +0.33%/year, p = 0.033), but not at the distal radius (-0.97 vs. -0.90%/year, p = 0.91). These findings suggest that despite higher baseline BMD, older women with DM experience more rapid bone loss than those without DM at the hip, spine, and calcaneus, but not the radius. Higher rates of bone loss may partially explain higher fracture rates in older women with DM. PMID- 23755039 TI - Mathematical Models of Blast-Induced TBI: Current Status, Challenges, and Prospects. AB - Blast-induced traumatic brain injury (TBI) has become a signature wound of recent military activities and is the leading cause of death and long-term disability among U.S. soldiers. The current limited understanding of brain injury mechanisms impedes the development of protection, diagnostic, and treatment strategies. We believe mathematical models of blast wave brain injury biomechanics and neurobiology, complemented with in vitro and in vivo experimental studies, will enable a better understanding of injury mechanisms and accelerate the development of both protective and treatment strategies. The goal of this paper is to review the current state of the art in mathematical and computational modeling of blast induced TBI, identify research gaps, and recommend future developments. A brief overview of blast wave physics, injury biomechanics, and the neurobiology of brain injury is used as a foundation for a more detailed discussion of multiscale mathematical models of primary biomechanics and secondary injury and repair mechanisms. The paper also presents a discussion of model development strategies, experimental approaches to generate benchmark data for model validation, and potential applications of the model for prevention and protection against blast wave TBI. PMID- 23755041 TI - Hatching the cleidoic egg: the role of thyroid hormones. AB - A major life stage transition in birds and other oviparous sauropsids is the hatching of the cleidoic egg. Not unlike amphibian metamorphosis, hatching in these species can be regarded as a transition from a relatively well-protected "aqueous" environment to a more hazardous and terrestrial life outside the egg, a transition in which thyroid hormones (THs) (often in concert with glucocorticoids) play an important role. In precocial birds such as the chicken, the perihatch period is characterized by peak values of THs. THs are implicated in the control of muscle development, lung maturation and the switch from chorioallantoic to pulmonary respiration, yolk sac retraction, gut development and induction of hepatic genes to accommodate the change in dietary energy source, initiation of thermoregulation, and the final stages of brain maturation as well as early post-hatch imprinting behavior. There is evidence that, at least for some of these processes, THs may have similar roles in non-avian sauropsids. In altricial birds such as passerines on the other hand, THs do not rise significantly until well after hatching and peak values coincide with the development of endothermy. It is not known how hatching-associated processes are regulated by hormones in these animals or how this developmental mode evolved from TH-dependent precocial hatching. PMID- 23755042 TI - Metagenome sequence analysis of filamentous microbial communities obtained from geochemically distinct geothermal channels reveals specialization of three aquificales lineages. AB - The Aquificales are thermophilic microorganisms that inhabit hydrothermal systems worldwide and are considered one of the earliest lineages of the domain Bacteria. We analyzed metagenome sequence obtained from six thermal "filamentous streamer" communities (~40 Mbp per site), which targeted three different groups of Aquificales found in Yellowstone National Park (YNP). Unassembled metagenome sequence and PCR-amplified 16S rRNA gene libraries revealed that acidic, sulfidic sites were dominated by Hydrogenobaculum (Aquificaceae) populations, whereas the circum-neutral pH (6.5-7.8) sites containing dissolved sulfide were dominated by Sulfurihydrogenibium spp. (Hydrogenothermaceae). Thermocrinis (Aquificaceae) populations were found primarily in the circum-neutral sites with undetectable sulfide, and to a lesser extent in one sulfidic system at pH 8. Phylogenetic analysis of assembled sequence containing 16S rRNA genes as well as conserved protein-encoding genes revealed that the composition and function of these communities varied across geochemical conditions. Each Aquificales lineage contained genes for CO2 fixation by the reverse-TCA cycle, but only the Sulfurihydrogenibium populations perform citrate cleavage using ATP citrate lyase (Acl). The Aquificaceae populations use an alternative pathway catalyzed by two separate enzymes, citryl-CoA synthetase (Ccs), and citryl-CoA lyase (Ccl). All three Aquificales lineages contained evidence of aerobic respiration, albeit due to completely different types of heme Cu oxidases (subunit I) involved in oxygen reduction. The distribution of Aquificales populations and differences among functional genes involved in energy generation and electron transport is consistent with the hypothesis that geochemical parameters (e.g., pH, sulfide, H2, O2) have resulted in niche specialization among members of the Aquificales. PMID- 23755043 TI - Enzymes and genes involved in aerobic alkane degradation. AB - Alkanes are major constituents of crude oil. They are also present at low concentrations in diverse non-contaminated because many living organisms produce them as chemo-attractants or as protecting agents against water loss. Alkane degradation is a widespread phenomenon in nature. The numerous microorganisms, both prokaryotic and eukaryotic, capable of utilizing alkanes as a carbon and energy source, have been isolated and characterized. This review summarizes the current knowledge of how bacteria metabolize alkanes aerobically, with a particular emphasis on the oxidation of long-chain alkanes, including factors that are responsible for chemotaxis to alkanes, transport across cell membrane of alkanes, the regulation of alkane degradation gene and initial oxidation. PMID- 23755044 TI - Sterol C-22 Desaturase ERG5 Mediates the Sensitivity to Antifungal Azoles in Neurospora crassa and Fusarium verticillioides. AB - Antifungal azoles inhibit ergosterol biosynthesis by interfering with lanosterol 14alpha-demethylase. In this study, seven upregulated and four downregulated ergosterol biosynthesis genes in response to ketoconazole treatment were identified in Neurospora crassa. Azole sensitivity test of knockout mutants for six ketoconazole-upregulated genes in ergosterol biosynthesis revealed that deletion of only sterol C-22 desaturase ERG5 altered sensitivity to azoles: the erg5 mutant was hypersensitive to azoles but had no obvious defects in growth and development. The erg5 mutant accumulated higher levels of ergosta 5,7-dienol relative to the wild type but its levels of 14alpha-methylated sterols were similar to the wild type. ERG5 homologs are highly conserved in fungal kingdom. Deletion of Fusarium verticillioides erg5 also increased ketoconazole sensitivity, suggesting that the roles of ERG5 homologs in azole resistance are highly conserved among different fungal species, and inhibition of ERG5 could reduce the usage of azoles and thus provide a new target for drug design. PMID- 23755045 TI - Causes, consequences, and perspectives in the variations of intestinal density of colonization of multidrug-resistant enterobacteria. AB - The intestinal microbiota is a complex environment that hosts 10(13) to 10(14) bacteria. Among these bacteria stand multidrug-resistant enterobacteria (MDRE), which intestinal densities can substantially vary, especially according to antibiotic exposure. The intestinal density of MDRE and their relative abundance (i.e., the proportion between the density of MDRE and the density of total enterobacteria) could play a major role in the infection process or patient-to patient transmission. This review discusses the recent advances in understanding (i) what causes variations in the density or relative abundance of intestinal colonization, (ii) what are the clinical consequences of these variations, and (iii) what are the perspectives for maintaining these markers at low levels. PMID- 23755046 TI - Reclaimed water as a reservoir of antibiotic resistance genes: distribution system and irrigation implications. AB - Treated wastewater is increasingly being reused to achieve sustainable water management in arid regions. The objective of this study was to quantify the distribution of antibiotic resistance genes (ARGs) in recycled water, particularly after it has passed through the distribution system, and to consider point-of-use implications for soil irrigation. Three separate reclaimed wastewater distribution systems in the western U.S. were examined. Quantitative polymerase chain reaction (qPCR) was used to quantify ARGs corresponding to resistance to sulfonamides (sul1, sul2), macrolides (ermF), tetracycline [tet(A), tet(O)], glycopeptides (vanA), and methicillin (mecA), in addition to genes present in waterborne pathogens Legionella pneumophila (Lmip), Escherichia coli (gadAB), and Pseudomonas aeruginosa (ecfx, gyrB). In a parallel lab study, the effect of irrigating an agricultural soil with secondary, chlorinated, or dechlorinated wastewater effluent was examined in batch microcosms. A broader range of ARGs were detected after the reclaimed water passed through the distribution systems, highlighting the importance of considering bacterial re growth and the overall water quality at the point of use (POU). Screening for pathogens with qPCR indicated presence of Lmip and gadAB genes, but not ecfx or gyrB. In the lab study, chlorination was observed to reduce 16S rRNA and sul2 gene copies in the wastewater effluent, while dechlorination had no apparent effect. ARGs levels did not change with time in soil slurries incubated after a single irrigation event with any of the effluents. However, when irrigated repeatedly with secondary wastewater effluent (not chlorinated or dechlorinated), elevated levels of sul1 and sul2 were observed. This study suggests that reclaimed water may be an important reservoir of ARGs, especially at the POU, and that attention should be directed toward the fate of ARGs in irrigation water and the implications for human health. PMID- 23755047 TI - The antibiotic resistance "mobilome": searching for the link between environment and clinic. AB - Antibiotic resistance is an ancient problem, owing to the co-evolution of antibiotic-producing and target organisms in the soil and other environments over millennia. The environmental "resistome" is the collection of all genes that directly or indirectly contribute to antibiotic resistance. Many of these resistance determinants originate in antibiotic-producing organisms (where they serve to mediate self-immunity), while others become resistance determinants only when mobilized and over-expressed in non-native hosts (like plasmid-encoded beta lactamases). The modern environmental resistome is under selective pressure from human activities such as agriculture, which may influence the composition of the local resistome and lead to gene transfer events. Beyond the environment, we are challenged in the clinic by the rise in both frequency and diversity of antibiotic resistant pathogens. We assume that clinical resistance originated in the environment, but few examples of direct gene exchange between the environmental resistome and the clinical resistome have been documented. Strong evidence exists to suggest that clinical aminoglycoside and vancomycin resistance enzymes, the extended-spectrum beta-lactamase CTX-M and the quinolone resistance gene qnr have direct links to the environmental resistome. In this review, we highlight recent advances in our understanding of horizontal gene transfer of antibiotic resistance genes from the environment to the clinic. Improvements in sequencing technologies coupled with functional metagenomic studies have revealed previously underappreciated diversity in the environmental resistome, and also established novel genetic links to the clinic. Understanding mechanisms of gene exchange becomes vital in controlling the future dissemination of antibiotic resistance. PMID- 23755048 TI - Interrelated influence of light and Ni on Trichodesmium growth. AB - Our previous laboratory study revealed that insufficient Ni supply can limit nitrogen fixation in Trichodesmium, a primary diazotrophic phytoplankton in the tropical and subtropical oceans. Here we show that light intensity and Ni availability interrelate to influence Trichodesmium growth. Trichodesmium growth is severely inhibited under high light (670 MUE m(-2) s(-1)) and insufficient Ni condition. On the contrary, the sufficient supply of Ni in seawater can sustain the growth of Trichodesmium under either high or low light conditions. We also observed elevated intracellular Ni uptake in Trichodesmium grown under relatively high light condition, supporting that the Ni requirement is used for removing superoxide generated through photosynthetic electron transport. This study shows that light saturation condition for Trichodesmium growth is Ni concentration dependent. This finding may exhibit implications for interpreting temporal and spatial distributions and activities of Trichodesmium in both modern and ancient oceans when light intensity and Ni concentrations have significantly varied. PMID- 23755049 TI - Brief Exercise Increases Peripheral Blood NK Cell Counts without Immediate Functional Changes, but Impairs their Responses to ex vivo Stimulation. AB - Physical as well as psychological stress increases the number of circulating peripheral blood NK cells. Whereas some studies found a positive correlation between exercise and NK cell counts and cytotoxic activity, others showed that, for example, heavy training leads to a decrease in per cell NK cytotoxicity. Thus, the impact of exercise on NK cell function and eventually on altered immunocompetence remains to be elucidated. Here, we investigated whether a single bout of brief exercise, consisting in running up and down 150 stair-steps, affects the number and function of circulating NK cells. NK cells, obtained from 29 healthy donors, before and immediately after brief exercise, were assessed for numbers, phenotype, IFNgamma production, degranulation, cytotoxicity, and in vitro response to stimulation with IL-2, IL-2/IL-12, or TLR2 agonists. Running resulted in a sixfold increase in the number of CD3(-)/CD56(+) NK cells, but decreased the frequency of CD56(bright) NK cells about twofold. Brief exercise did not significantly interfere with baseline IFNgamma secretion or NK cell cytotoxicity. In vitro stimulation with IL-2 and TLR2 agonists (lipoteichoic acid, and synthetic triacylated lipopeptide Pam3CSK4) enhanced IFNgamma secretion, degranulation, and cytotoxicity mediated by NK cells isolated pre exercise, but had less effect on NK cells isolated following exercise. There were no differences in response to combined IL-2/IL-12 stimulation. In conclusion, having no obvious impact on baseline NK functions, brief exercise might be used as a simple method to significantly increase the number of CD56(dim) NK cell available for in vitro experiments. Nevertheless, the observed impaired responses to stimulation suggest an alteration of NK cell-mediated immunity by brief exercise which is at least in part explained by a concomitant decrease of the circulating CD56(bright) NK cell fraction. PMID- 23755050 TI - Pentraxin 3: an immuno-regulator in the lungs. AB - Pentraxin 3 (PTX3) is a soluble pattern recognition receptor that is a humoral component of the innate immune system. It interacts with pathogenic moieties, infected and dying host cells and facilitates their removal through activation of appropriate innate and adaptive mechanisms. PTX3 is secreted by a diverse variety of cells, ranging from immune cells to structural cells, in response to Toll like receptor (TLR) engagement, inflammatory stimuli, and physical and chemical stress. Further, PTX3 plays an essential role in female fertility as it facilitates the organization of extracellular matrix in the cumulus oophorus. Such activity is also implicated in post-inflammation tissue repair. PTX3 is a multifunctional protein and plays a non-redundant role in providing immunity against potential immunological dangers. Thus, we assessed its role in lung immunity, as lungs are at a constant risk of infections and tissue damage that is attributable to perpetual exposure to foreign agents. PMID- 23755051 TI - Prime-boost strategies in mucosal immunization affect local IgA production and the type of th response. AB - Combinations of different delivery routes for priming and boosting represent vaccination strategies that can modulate magnitude, quality, and localization of the immune response. A murine model was used to study T cell clonal expansion following intranasal (IN) or subcutaneous (SC) priming, and secondary immune responses after boosting by either homologous or heterologous routes. T cell primary activation was studied by using the adoptive transfer model of ovalbumin specific transgenic CD4(+) T cells. Both IN and SC immunization efficiently elicited, in the respective draining lymph nodes, primary clonal expansion of antigen-specific CD4(+) T cells that disseminated toward distal lymph nodes (mesenteric and iliac) and the spleen. After boosting, a significant serum IgG response was induced in all groups independent of the combination of immunization routes used, while significant levels of local IgA were detected only in mice boosted by the IN route. Mucosal priming drove a stronger Th1 polarization than the systemic route, as shown by serum IgG subclass analysis. IFN-gamma production was observed in splenocytes of all groups, while prime-boost vaccine combinations that included the mucosal route, yielded higher levels of IL-17. Memory lymphocytes were identified in both spleen and draining lymph nodes in all immunized mice, with the highest number of IL-2 producing cells detected in mice primed and boosted by the nasal route. This work shows the critical role of immunization routes in modulating quality and localization of immune responses in prime-boost vaccine strategies. PMID- 23755053 TI - The Brassica genome. PMID- 23755054 TI - Nicotianamine synthase overexpression positively modulates iron homeostasis related genes in high iron rice. AB - Nearly one-third of the world population, mostly women and children, suffer from iron malnutrition and its consequences, such as anemia or impaired mental development. Biofortification of rice, which is a staple crop for nearly half of the world's population, can significantly contribute in alleviating iron deficiency. NFP rice (transgenic rice expressing nicotianamine synthase, ferritin and phytase genes) has a more than six-fold increase in iron content in polished rice grains, resulting from the synergistic action of nicotianamine synthase (NAS) and ferritin transgenes. We investigated iron homeostasis in NFP plants by analyzing the expression of 28 endogenous rice genes known to be involved in the homeostasis of iron and other metals, in iron-deficient and iron-sufficient conditions. RNA was collected from different tissues (roots, flag leaves, grains) and at three developmental stages during grain filling. NFP plants showed increased sensitivity to iron-deficiency conditions and changes in the expression of endogenous genes involved in nicotianamine (NA) metabolism, in comparison to their non-transgenic siblings (NTS). Elevated transcript levels were detected in NFP plants for several iron transporters. In contrast, expression of OsYSL2, which encodes a member of yellow stripe like protein family, and a transporter of the NA-Fe(II) complex was reduced in NFP plants under low iron conditions, indicating that expression of OsYSL2 is regulated by the endogenous iron status. Expression of the transgenes did not significantly affect overall iron homeostasis in NFP plants, which establishes the engineered push-pull mechanism as a suitable strategy to increase rice endosperm iron content. PMID- 23755052 TI - Regulation of adaptive immunity; the role of interleukin-10. AB - Since the discovery of interleukin-10 (IL-10) in the 1980s, a large body of work has led to its recognition as a pleiotropic immunomodulatory cytokine that affects both the innate and adaptive immune systems. IL-10 is produced by a wide range of cell types, but for the purposes of this review we shall focus on IL-10 secreted by CD4(+) T cells. Here we describe the importance of IL-10 as a mediator of suppression used by both FoxP3(+) and FoxP3(-) T regulatory cells. Moreover, we discuss the molecular events leading to the induction of IL-10 secretion in T helper cell subsets, where it acts as a pivotal negative feedback mechanism. Finally we discuss how a greater understanding of this principle has allowed for the design of more efficient, antigen-specific immunotherapy strategies to exploit this natural phenomenon clinically. PMID- 23755055 TI - Progress toward the tomato fruit cell wall proteome. AB - The plant cell wall (CW) compartment, or apoplast, is host to a highly dynamic proteome, comprising large numbers of both enzymatic and structural proteins. This reflects its importance as the interface between adjacent cells and the external environment, the presence of numerous extracellular metabolic and signaling pathways, and the complex nature of wall structural assembly and remodeling during cell growth and differentiation. Tomato fruit ontogeny, with its distinct phases of rapid growth and ripening, provides a valuable experimental model system for CW proteomic studies, in that it involves substantial wall assembly, remodeling, and coordinated disassembly. Moreover, diverse populations of secreted proteins must be deployed to resist microbial infection and protect against abiotic stresses. Tomato fruits also provide substantial amounts of biological material, which is a significant advantage for many types of biochemical analyses, and facilitates the detection of lower abundance proteins. In this review, we describe a variety of orthogonal techniques that have been applied to identify CW localized proteins from tomato fruit, including approaches that: target the proteome of the CW and the overlying cuticle; functional "secretome" screens; lectin affinity chromatography; and computational analyses to predict proteins that enter the secretory pathway. Each has its merits and limitations, but collectively they are providing important insights into CW proteome composition and dynamics, as well as some potentially controversial issues, such as the prevalence of non-canonical protein secretion. PMID- 23755056 TI - Examining strategies to facilitate vitamin B1 biofortification of plants by genetic engineering. AB - Thiamin (vitamin B1) is made by plants and microorganisms but is an essential micronutrient in the human diet. All organisms require it as a cofactor in its form as thiamin pyrophosphate (TPP) for the activity of key enzymes of central metabolism. In humans, deficiency is widespread particularly in populations where polished rice is a major component of the diet. Considerable progress has been made on the elucidation of the biosynthesis pathway within the last few years enabling concrete strategies for biofortification purposes to be devised, with a particular focus here on genetic engineering. Furthermore, the vitamin has been shown to play a role in both abiotic and biotic stress responses. The precursors for de novo biosynthesis of thiamin differ between microorganisms and plants. Bacteria use intermediates derived from purine and isoprenoid biosynthesis, whereas the pathway in yeast involves the use of compounds from the vitamin B3 and B6 groups. Plants on the other hand use a combination of the bacterial and yeast pathways and there is subcellular partitioning of the biosynthesis steps. Specifically, thiamin biosynthesis occurs in the chloroplast of plants through the separate formation of the pyrimidine and thiazole moieties, which are then coupled to form thiamin monophosphate (TMP). Phosphorylation of thiamin to form TPP occurs in the cytosol. Therefore, thiamin (or TMP) must be exported from the chloroplast to the cytosol for the latter step to be executed. The regulation of biosynthesis is mediated through riboswitches, where binding of the product TPP to the pre-mRNA of a biosynthetic gene modulates expression. Here we examine and hypothesize on genetic engineering approaches attempting to increase the thiamin content employing knowledge gained with the model plant Arabidopsis thaliana. We will discuss the regulatory steps that need to be taken into consideration and can be used a prerequisite for devising such strategies in crop plants. PMID- 23755057 TI - Regulation of cell division and expansion by sugar and auxin signaling. AB - Plant growth and development are modulated by concerted actions of a variety of signaling molecules. In recent years, evidence has emerged on the roles of sugar and auxin signals network in diverse aspects of plant growth and development. Here, based on recent progress of genetic analyses and gene expression profiling studies, we summarize the functional similarities, diversities, and their interactions of sugar and auxin signals in regulating two major processes of plant development: cell division and cell expansion. We focus on roles of sugar and auxin signaling in both vegetative and reproductive tissues including developing seed. PMID- 23755058 TI - The plant-specific dof transcription factors family: new players involved in vascular system development and functioning in Arabidopsis. AB - In higher plants phloem and xylem are responsible for long-distance transport of water, nutrients, and signals that act systemically at short or long-distance to coordinate developmental processes. The formation of the plant vascular system is a complex process that integrates signaling events and gene regulation at transcriptional and posttranscriptional levels. Thanks to transcriptomic and proteomic analysis we start to better understand the mechanisms underlying the formation and the functioning of the vascular system. The role of the DNA-binding with one finger (Dof TFs), a group of plant-specific transcription factors, recently emerged as part of the transcriptional regulatory networks acting on the formation and functioning of the vascular tissues. More than half of the members of this TF family are expressed in the vascular system. In addition some of them have been proposed to be mobile proteins, suggesting a possible role in the control of short- or long-distance signaling as well. This review summarizes the current knowledge on Dof TFs family in Arabidopsis with a special focus on their role in vascular development and functioning. PMID- 23755059 TI - The rhizosphere revisited: root microbiomics. AB - The rhizosphere was defined over 100 years ago as the zone around the root where microorganisms and processes important for plant growth and health are located. Recent studies show that the diversity of microorganisms associated with the root system is enormous. This rhizosphere microbiome extends the functional repertoire of the plant beyond imagination. The rhizosphere microbiome of Arabidopsis thaliana is currently being studied for the obvious reason that it allows the use of the extensive toolbox that comes with this model plant. Deciphering plant traits that drive selection and activities of the microbiome is now a major challenge in which Arabidopsis will undoubtedly be a major research object. Here we review recent microbiome studies and discuss future research directions and applicability of the generated knowledge. PMID- 23755060 TI - Searching iron sensors in plants by exploring the link among 2'-OG-dependent dioxygenases, the iron deficiency response and metabolic adjustments occurring under iron deficiency. AB - Knowledge accumulated on the regulation of iron (Fe) homeostasis, its intracellular trafficking and transport across various cellular compartments and organs in plants; storage proteins, transporters and transcription factors involved in Fe metabolism have been analyzed in detail in recent years. However, the key sensor(s) of cellular plant "Fe status" triggering the long-distance shoot-root signaling and leading to the root Fe deficiency responses is (are) still unknown. Local Fe sensing is also a major task for roots, for adjusting the internal Fe requirements to external Fe availability: how such sensing is achieved and how it leads to metabolic adjustments in case of nutrient shortage, is mostly unknown. Two proteins belonging to the 2'-OG-dependent dioxygenases family accumulate several folds in Fe-deficient Arabidopsis roots. Such proteins require Fe(II) as enzymatic cofactor; one of their subgroups, the HIF-P4H (hypoxia-inducible factor-prolyl 4-hydroxylase), is an effective oxygen sensor in animal cells. We envisage here the possibility that some members of the 2'-OG dioxygenase family may be involved in the Fe deficiency response and in the metabolic adjustments to Fe deficiency or even in sensing Fe, in plant cells. PMID- 23755061 TI - Effect of normalization on statistical and biological interpretation of gene expression profiles. AB - An under-appreciated aspect of the genetic analysis of gene expression is the impact of post-probe level normalization on biological inference. Here we contrast nine different methods for normalization of an Illumina bead-array gene expression profiling dataset consisting of peripheral blood samples from 189 individual participants in the Center for Health Discovery and Well Being study in Atlanta, quantifying differences in the inference of global variance components and covariance of gene expression, as well as the detection of variants that affect transcript abundance (eSNPs). The normalization strategies, all relative to raw log2 measures, include simple mean centering, two modes of transcript-level linear adjustment for technical factors, and for differential immune cell counts, variance normalization by interquartile range and by quantile, fitting the first 16 Principal Components, and supervised normalization using the SNM procedure with adjustment for cell counts. Robustness of genetic associations as a consequence of Pearson and Spearman rank correlation is also reported for each method, and it is shown that the normalization strategy has a far greater impact than correlation method. We describe similarities among methods, discuss the impact on biological interpretation, and make recommendations regarding appropriate strategies. PMID- 23755062 TI - Integrative genomics: quantifying significance of phenotype-genotype relationships from multiple sources of high-throughput data. AB - Given recent advances in the generation of high-throughput data such as whole genome genetic variation and transcriptome expression, it is critical to come up with novel methods to integrate these heterogeneous datasets and to assess the significance of identified phenotype-genotype relationships. Recent studies show that genome-wide association findings are likely to fall in loci with gene regulatory effects such as expression quantitative trait loci (eQTLs), demonstrating the utility of such integrative approaches. When genotype and gene expression data are available on the same individuals, we and others developed methods wherein top phenotype-associated genetic variants are prioritized if they are associated, as eQTLs, with gene expression traits that are themselves associated with the phenotype. Yet there has been no method to determine an overall p-value for the findings that arise specifically from the integrative nature of the approach. We propose a computationally feasible permutation method that accounts for the assimilative nature of the method and the correlation structure among gene expression traits and among genotypes. We apply the method to data from a study of cellular sensitivity to etoposide, one of the most widely used chemotherapeutic drugs. To our knowledge, this study is the first statistically sound quantification of the overall significance of the genotype phenotype relationships resulting from applying an integrative approach. This method can be easily extended to cases in which gene expression data are replaced by other molecular phenotypes of interest, e.g., microRNA or proteomic data. This study has important implications for studies seeking to expand on genetic association studies by the use of omics data. Finally, we provide an R code to compute the empirical false discovery rate when p-values for the observed and simulated phenotypes are available. PMID- 23755063 TI - Bridging the Gap between Genotype and Phenotype via Network Approaches. AB - In the last few years we have witnessed tremendous progress in detecting associations between genetic variations and complex traits. While genome-wide association studies have been able to discover genomic regions that may influence many common human diseases, these discoveries created an urgent need for methods that extend the knowledge of genotype-phenotype relationships to the level of the molecular mechanisms behind them. To address this emerging need, computational approaches increasingly utilize a pathway-centric perspective. These new methods often utilize known or predicted interactions between genes and/or gene products. In this review, we survey recently developed network based methods that attempt to bridge the genotype-phenotype gap. We note that although these methods help narrow the gap between genotype and phenotype relationships, these approaches alone cannot provide the precise details of underlying mechanisms and current research is still far from closing the gap. PMID- 23755064 TI - Exploiting gene expression variation to capture gene-environment interactions for disease. AB - Gene-environment interactions have long been recognized as a fundamental concept in evolutionary, quantitative, and medical genetics. In the genomics era, study of how environment and genome interact to shape gene expression variation is relevant to understanding the genetic architecture of complex phenotypes. While genetic analysis of gene expression variation focused on main effects, little is known about the extent of interaction effects implicating regulatory variants and their consequences on transcriptional variation. Here we survey the current state of the concept of transcriptional gene-environment interactions and discuss its utility for mapping disease phenotypes in light of the insights gained from genome-wide association studies of gene expression. PMID- 23755065 TI - Mapping Novel Pathways in Cardiovascular Disease Using eQTL Data: The Past, Present, and Future of Gene Expression Analysis. AB - Genome-wide association studies (GWAS) have identified genetic variants associated with numerous cardiovascular and metabolic diseases. Newly identified polymorphisms associated with myocardial infarction, dyslipidemia, hypertension, diabetes, and insulin resistance suggest novel mechanistic pathways that underlie these and other complex diseases. Working out the connections between the polymorphisms identified in GWAS and their biological mechanisms has been especially challenging given the number of non-coding variants identified thus far. In this review, we discuss the utility of expression quantitative trait locus (eQTL) databases in the study of non-coding variants with respect to cardiovascular and metabolic phenotypes. Recent successes in using eQTL data to link variants with functional candidate genes will be reviewed, and the shortcomings of this approach will be outlined. Finally, we discuss the emerging next generation of eQTL studies that take advantage of the ability to generate induced pluripotent stem cell lines from population cohorts. PMID- 23755066 TI - eQTL Epistasis - Challenges and Computational Approaches. AB - The determination of expression quantitative trait loci (eQTL) epistasis - a form of functional interaction between genetic loci that affect gene expression - is an important step toward the thorough understanding of gene regulation. Since gene expression has emerged as an "intermediate" molecular phenotype eQTL epistasis might help to explain the relationship between genotype and higher level organismal phenotypes such as diseases. A characteristic feature of eQTL analysis is the big number of tests required to identify associations between gene expression and genetic loci variability. This problem is aggravated, when epistatic effects between eQTLs are analyzed. In this review, we discuss recent algorithmic approaches for the detection of eQTL epistasis and highlight lessons that can be learned from current methods. PMID- 23755068 TI - LIM Protein Ajuba Participates in the Repression of the ATR-Mediated DNA Damage Response. AB - LIM proteins constitute a superfamily characterized by the presence of a LIM domain, known to be involved in protein-protein interactions. Our previous work has implicated members of the Zyxin family of LIM proteins, namely TRIP6 and LPP, in the repression of the DNA damage response (DDR) at telomeres. Here, we describe a role for Ajuba, a closely related LIM molecule, in repressing the ATR mediated DDR. We found that depletion of Ajuba led to apparent delays in the cell cycle, accompanied with increased Rb phosphorylation, Chk1 phosphorylation, induction of p53, and cell death. Ajuba could be found in a complex with replication protein A (RPA), and its depletion led to RPA phosphorylation, known to be an early event in ATR activation. We propose that Ajuba protects against unscheduled ATR signaling by preventing inappropriate RPA phosphorylation. PMID- 23755067 TI - Detection and impact of rare regulatory variants in human disease. AB - Advances in genome sequencing are providing unprecedented resolution of rare and private variants. However, methods which assess the effect of these variants have relied predominantly on information within coding sequences. Assessing their impact in non-coding sequences remains a significant contemporary challenge. In this review, we highlight the role of regulatory variation as causative agents and modifiers of monogenic disorders. We further discuss how advances in functional genomics are now providing new opportunity to assess the impact of rare non-coding variants and their role in disease. PMID- 23755069 TI - The possible roles of human Alu elements in aging. PMID- 23755070 TI - Heterogeneity of expression of epithelial-mesenchymal transition markers in melanocytes and melanoma cell lines. AB - The epithelial-mesenchymal transition (EMT) describes a reversible switch from an epithelial-like to a mesenchymal-like phenotype. It is essential for the development of the normal epithelium and also contributes to the invasive properties of carcinomas. At the molecular level, the EMT transition is characterized by a series of coordinated changes including downregulation of the junctional protein E-cadherin (CDH1), up-regulation of transcriptional repressors of E-cadherin such as Snail (SNAI1) and Slug (SNAI2), and up-regulation of N cadherin. We wished to determine whether cultured normal melanocytes and melanoma cell lines, which are derived from the neural crest, showed signs of a similarly coordinated phenotypic switch. We investigated normal melanocytes and 25 cell lines derived from New Zealand patients with metastatic melanoma. Most lines had been previously genotyped for common mutations such as BRAF, NRAS, PIK3CA (phosphatidylinositol-3-kinase), TP53 (p53), and CDKN2A (p16). Expression of E cadherin, N-cadherin, microphthalmia-associated transcription factor (MITF), Snail, Slug, Axl, p53, and Hdm2 was compared by western blotting. Normal melanocytes expressed each of these proteins except for Snail, while normal melanocytes and almost every melanoma line expressed Slug. Expression of individual markers among different melanoma lines varied from high to low or undetectable. Quantitation of western blots showed that expression of MITF-M, the melanocyte-specific isoform of MITF, was positively related to that of E-cadherin but inversely related to that of N-cadherin and Axl. There was also no apparent relationship between expression of any particular marker and the presence of BRAF, NRAS, PIK3CA, TP53, or CDKN2A mutations. The results suggest that melanomas do not show the classical epithelial and mesenchymal phenotypes but rather display either high E-cadherin/high MITF-M expression on one hand, or high N cadherin/high Axl expression on the other. These may correspond to differentiated and invasive phenotypes in vivo. PMID- 23755071 TI - An overview of STRUCTURE: applications, parameter settings, and supporting software. AB - OBJECTIVES: We present an up-to-date review of STRUCTURE software: one of the most widely used population analysis tools that allows researchers to assess patterns of genetic structure in a set of samples. STRUCTURE can identify subsets of the whole sample by detecting allele frequency differences within the data and can assign individuals to those sub-populations based on analysis of likelihoods. The review covers STRUCTURE's most commonly used ancestry and frequency models, plus an overview of the main applications of the software in human genetics including case-control association studies (CCAS), population genetics, and forensic analysis. The review is accompanied by supplementary material providing a step-by-step guide to running STRUCTURE. METHODS: With reference to a worked example, we explore the effects of changing the principal analysis parameters on STRUCTURE results when analyzing a uniform set of human genetic data. Use of the supporting software: CLUMPP and distruct is detailed and we provide an overview and worked example of STRAT software, applicable to CCAS. CONCLUSION: The guide offers a simplified view of how STRUCTURE, CLUMPP, distruct, and STRAT can be applied to provide researchers with an informed choice of parameter settings and supporting software when analyzing their own genetic data. PMID- 23755073 TI - Long-term anticoagulation in the extreme elderly with the newer antithrombotics: safe or sorry? AB - BACKGROUND AND OBJECTIVES: The prevalence of atrial fibrillation (AF) doubles in the extreme elderly and is higher than in the rest of the population. Warfarin therapy to prevent thromboembolic events secondary to AF is often underutilized and under-prescribed in this subgroup, due to the fear of bleeding and other complications. Newer oral anticoagulants such as rivaroxaban and dabigatran offer alternative therapeutic options for the extreme elderly. We review the clinical trial data of these newer agents in the extreme elderly population. SUBJECTS AND METHODS: THE PRIMARY LITERATURE WAS IDENTIFIED THROUGH PUBMED, USING THE FOLLOWING SEARCH TERMS: anticoagulation, rivaroxaban, dabigatran, warfarin, elderly, AF, bleeding, stroke, and aging. Additional references were identified through the review of references from the articles obtained. We included clinical studies evaluating anticoagulation therapies in AF. Selection emphasis was placed on those evaluating anticoagulation in the elderly population. RESULTS: Dabigatran and rivaroxaban have predictable, dose-proportional pharmacokinetic and pharmacodynamic properties, which make them favorable options for the elderly. Fewer monitoring parameters and drug interactions allow for the greater ease of use. A landmark trial shows that the rate of intracranial hemorrhage with dabigatran is lower in this population compared to warfarin. However, the data is based on a small number of subjects enrolled in the clinical trials. As such, the real-world use of these agents may not replicate the published rates of bleeding and thrombosis in the study populations. CONCLUSION: More research is needed in this area, specifically in this population, before newer agents such as rivaroxaban and dabigatran are widely recommended for use in the extreme elderly patients. PMID- 23755074 TI - Comparison of Two Different Strategies of Intravascular Ultrasound Guidance during Percutaneous Coronary Intervention; Routine versus Selective. PMID- 23755072 TI - Using eQTL weights to improve power for genome-wide association studies: a genetic study of childhood asthma. AB - Increasing evidence suggests that single nucleotide polymorphisms (SNPs) associated with complex traits are more likely to be expression quantitative trait loci (eQTLs). Incorporating eQTL information hence has potential to increase power of genome-wide association studies (GWAS). In this paper, we propose using eQTL weights as prior information in SNP based association tests to improve test power while maintaining control of the family-wise error rate (FWER) or the false discovery rate (FDR). We apply the proposed methods to the analysis of a GWAS for childhood asthma consisting of 1296 unrelated individuals with German ancestry. The results confirm that eQTLs are enriched for previously reported asthma SNPs. We also find that some SNPs are insignificant using procedures without eQTL weighting, but become significant using eQTL-weighted Bonferroni or Benjamini-Hochberg procedures, while controlling the same FWER or FDR level. Some of these SNPs have been reported by independent studies in recent literature. The results suggest that the eQTL-weighted procedures provide a promising approach for improving power of GWAS. We also report the results of our methods applied to the large-scale European GABRIEL consortium data. PMID- 23755075 TI - Impact of chronic emotional stress on myocardial function in postmenopausal women and its relationship with endothelial dysfunction. AB - BACKGROUND AND OBJECTIVES: An association between chronic stress and cardiovascular diseases has been described, but the underlying mechanisms have not been fully elucidated. We investigate the impact of perceived stress on the left ventricular (LV) and endothelial functions in postmenopausal women. SUBJECTS AND METHODS: We investigated 64 consecutive postmenopausal women (mean age 56.7+/ 9.7 years) with atypical chest pain and chronic stress. Patients with coronary heart disease were excluded. Global and segmental longitudinal deformation parameters of LV were used as parameters to assess myocardial function and brachial flow-mediated dilatation (FMD) was used to assess the endothelial function, and patients were analyzed by the Symptom Checklist 90 Revised (SCL-90 R) to determine emotional stress. The study participants were divided into two groups, based on global severity index (GSI): >=50 (group A, n=27) or <50 (group B, n=37). RESULTS: Although there were no significant differences in LV geometry or myocardial performance indices between the groups, global LV strain was significantly reduced in group A compared to group B (-16.6+/-2.7% vs. -19.1+/ 1.9%, p=0.001). There were also significant differences in the value of reactive FMD (6.6+/-2.2% vs. 9.5+/-2.9%, p<0.001), and same result was observed for nitroglycerine-induced dilatation (14.6+/-4.7% vs. 18.0+/-5.8%, p=0.016). Multivariate linear regression analysis showed that GSI was the only significant attributor to global LV strain (beta=0.149, p=0.008) and reactive FMD (beta= 0.200, p=0.041). CONCLUSION: Chronic emotional stress may exert negative effects on the LV and endothelial functions, which may be associated with the severity of stress. This study provides a possible mechanism by which stress is associated with an increased risk of cardiovascular dysfunction. PMID- 23755076 TI - Comparison of Two Different Strategies of Intravascular Ultrasound Guidance during Percutaneous Coronary Intervention; Routine versus Selective. AB - BACKGROUND AND OBJECTIVES: Intravascular ultrasound (IVUS) is helpful during percutaneous coronary intervention (PCI), because it can be used to confirm good apposition or optimal expansion of stents. In this study, we compared angiographic result as well as clinical outcomes between two different strategies of IVUS-guidance, the selective vs. the routine. SUBJECTS AND METHODS: The study population consisted of 279 patients undergoing electric and emergency intracoronary implatation of TAXUS stent from August 2003 through September 2006. For this study, we divided physicians into two groups; doctors to perform PCI under 'routine' IVUS-guidance vs. PCI under 'selective' IVUS-guidance. Among a total of 279 patients (384 lesions) who underwent PCI with TAXUS stent, 87 patients underwent the procedure under the strategy of 'routine' IVUS-guidance, whereas 192 patients under 'selective' IVUS-guidance. RESULTS: The baseline clinical features of the patients are similar between the two groups. The actual rate of IVUS usage was 89.2% in the routine group and 68.2% in the selective group (p<0.01). A high rate of adjunctive ballooning was determined as a remarkable procedure-related parameter which was comparable between the two groups (72.5% vs. 76.1% in routine vs. selective, p=0.57). The minimal lumen diameter at immediate post-PCI was significantly larger in the routine IVUS group than that in the selective group (2.58 mm vs. 2.48 mm, p=0.03). However, the difference disappeared during the follow-up period (1.98 mm vs. 1.98 mm, p=0.94). Clinical outcomes at 1 year were not different between the two groups. CONCLUSION: PCI under the strategy of 'selective' IVUS-guidance was comparable to PCI under 'routine' IVUS-guidance in terms of angiographic and clinical outcomes in circumstances with frequent use of adjunctive ballooning after stenting. PMID- 23755077 TI - Prediction of Fractional Flow Reserve without Hyperemic Induction Based on Resting Baseline Pd/Pa. AB - BACKGROUND AND OBJECTIVES: The purposes of this study are 1) to investigate the relationship between resting baseline Pd/Pa, determined by the ratio of the pressures proximal (Pa) and distal (Pd) to the target lesion before, inducing hyperemia and fractional flow reserve (FFR) and 2) to identify a resting baseline Pd/Pa range that might reliably preclude the need for hyperemic induction. SUBJECTS AND METHODS: A total of 622 pressure wire data sets obtained from intermediate stenotic lesions were analyzed. RESULTS: There was a good linear relationship between resting baseline Pd/Pa and FFR (r=0.746, p<0.001). Receiver operating characteristic curves of the resting baseline Pd/Pa with FFR <=0.80 as the reference variable showed an area under the curve of 0.89 (95% confidence intervals 0.863-0.914, p<0.001) with a diagnostic accuracy of 82.3% when the resting baseline Pd/Pa was <=0.92. These results showed that certain cutoff values can reliably predict FFR, whether positive or negative. The resting baseline Pd/Pa >0.95 (n=257, 41.3%) had a negative predictive value (NPV) of 98.1% and a sensitivity of 97.3%. the resting baseline Pd/Pa <=0.88 (n=65, 10.5%) had a positive predictive value (PPV) of 96.2% and a specificity of 99.8%. These were consistent regardless of coronary vessel, lesion location, lesion length, or degree of stenosis. CONCLUSION: In intermediate lesions, the resting baseline Pd/Pa was linearly related to FFR. A certain range of the resting baseline Pd/Pa values had an excellent NPV with high sensitivity or excellent PPV with high specificity for determining the lesion significance. PMID- 23755078 TI - Comparison of cardiovascular risk factors for peripheral artery disease and coronary artery disease in the korean population. AB - BACKGROUND AND OBJECTIVES: The objective of this study was to analyze and compare risk factors for peripheral artery disease (PAD) and coronary artery disease (CAD). SUBJECTS AND METHODS: The sample included 7936 Korean patients aged >=20 years who were hospitalized from 1994 to 2004. Of the 7936 subjects, PAD (n=415), CAD (n=3686), and normal controls (Control) (n=3835) were examined at the Health Promotion Center, Samsung Medical Center. RESULTS: The mean age (years) of PAD subjects was 64.4 (+/-9.3), while CAD subjects was 61.2 (+/-9.9), and Control subjects was 59.9 (+/-9.1) (p<0.01). The proportion of males was 90.6% for PAD, 71.4% for CAD, and 75.5% for Control subjects (p<0.01). The adjusted odds ratios (ORs) for hypertension, diabetes mellitus, hypercholesterolemia, smoking, metabolic syndrome and chronic kidney disease were significantly higher in subjects with PAD or CAD compared to those in Control. However, the ORs for high density lipoprotein, being overweight, and being obese were significantly lower in PAD subjects compared to those in Control. CONCLUSION: We found that cardiovascular risk factors were in fact risk factors for both PAD and CAD. PMID- 23755079 TI - Comparison of the average of five readings with averages from fewer readings for automated oscillometric blood pressure measurement in an outpatient clinic. AB - BACKGROUND AND OBJECTIVES: The optimal number of consecutive measurements for obtaining an average blood pressure (BP) reading in clinical practice is yet undefined by research. This study aimed to compare readings obtained from an average of 5 with averages of 2, 3, and 4, sequential measurements. SUBJECTS AND METHODS: Using an automated oscillometric device (BpTRU), BP measurement was conducted on 410 consenting adults attending a general outpatients clinic. Comparison of an average of 5 readings with averages of 2, 3, and 4 readings involved evaluation of correlations, Bland-Altman analysis, comparison of means and distribution of readings, and determination of the proportion of differences between compared readings which were clinically non-significant. RESULTS: 397 (96.8%) sets of complete BP readings were suitable for analysis. Clinically non significant differences (<=5 mm Hg) were found between at least 79.3% (n=315) and 96.5% (n=383) of compared systolic and diastolic readings, respectively. Bland Altman's analysis revealed that the 95% limits of agreement for the differences between compared readings were approximately 2-4, 3-7, and 4-11 mm Hg for 2, 3 and 4 readings' systolic comparisons while those for diastolic comparisons were 2 3, 3-5, and 4-7 mm Hg, respectively. Statistically non-significant differences were observed in all comparisons of the distributions of readings that were classified as <140 mm Hg or >=140 mm Hg and <90 mm Hg or >=90 mm Hg for systolic and diastolic readings, respectively. Strong positive correlations were found between 5 average readings and each of 2, 3, and 4 average readings, respectively. CONCLUSION: An average of 5 readings may be excessive for routine BP measurement using this device at outpatient clinics. PMID- 23755080 TI - A case of riata(r) dual coil defibrillator lead failure in a patient with ventricular fibrillation. AB - A 50-year-old man, who underwent a procedure for an implantable cardioverter defibrillator (ICD), visited the outpatient department of our clinic after suffering multiple ICD shocks. The ICD interrogation revealed recurrent shock due to a high frequency of noise that is sensed by the device as ventricular fibrillation. Chest radiography revealed a significant split in the insulation of the lead allowing the inner wire to protrude. We considered the removal of the failed lead, but the removal of ICD lead is potentially a high risk procedure, so we cut and capped a proximal part of the failed lead and inserted a new lead. This is the first report of a St. Jude Riata(r) dual coil defibrillator lead failure with clinical and radiologic evidence of a defect in lead insulation in Korea. PMID- 23755081 TI - Acquired Long QT Syndrome Manifesting with Torsades de Pointes in a Patient with Panhypopituitarism due to Radiotherapy. AB - We describe a 64-year-old male patient with panhypopituitarism who experienced polymorphic ventricular tachycardia (VT) associated with long QT intervals. The panhypopituitarism developed as a sequelae of radiation therapy administered 20 years prior to his current presentation and was recently aggravated by urinary tract infection with sepsis. In this case, polymorphic VT was resistant to conventional therapy (including magnesium infusion), and QT prolongation and T wave inversion were normalized after the administration of steroid and thyroid hormones. Thyroid hormone is generally known to be associated with torsades de pointes (TdP), but steroid or other hormones may also provoke TdP. Hormonal disorders should be considered as a cause of polymorphic VT with long QT intervals. Some arrhythmias can be life-threatening, and they can be prevented with supplementation of the insufficient hormone. PMID- 23755082 TI - Successful prasugrel rescue therapy in clopidogrel resistant patients who had recurrent stent thrombosis of drug-eluting-stent: the role of prasugrel in clopidogrel nonresponders. AB - Stent thrombosis is a very serious problem after drug-eluting stent (DES) implantation even though its incidence is about or less than 1%. As the clopidogrel resistance is expected to play an important role in the occurrence of stent thrombosis, new anti-platelet agents overcoming this issue can give us another choice. We experienced a case of a 58-year-old male with successful prasugrel rescue therapy in a patient with clopidogrel resistance who had recurrent stent thrombosis following DES implantation. PMID- 23755083 TI - A case of sheathless transradial coronary intervention for complex coronary lesions with a standard guiding catheter. AB - One of the major limitations of transradial coronary intervention is the inability to use large guiding system, which leads to the development of dedicated sheathless guide catheter system. However, these devices are not available in the Republic of Korea. We present a case in which conventional guiding catheter was used for sheathless transradial coronary intervention in the treatment of complex coronary anatomy. PMID- 23755084 TI - Spontaneous partial regression of coronary artery fistula following optimal medical therapy in a patient who had combined significant coronary artery spasm. AB - Coronary artery fistulas (CAFs) are one of the most rare cardiac anomalies. Some patients with CAF may suffer from ischemic chest pain that originates from combined significant coronary artery spasm (CAS). Spontaneous regression of CAF has been reported in a few cases, almost all of which were infants. We report an adult patient who presented with ischemic chest pain due to multiple coronary arteries to pulmonary artery fistulas and combined significant CAS induced by intracoronary acetylcholine provocation test. Spontaneous regression of one of the fistulas was observed at 2-year angiography follow-up. PMID- 23755085 TI - A rare combination of the left circumflex coronary artery fistula connecting a dilated coronary sinus with persistent left superior vena cava and multiple arteriovenous fistulae. AB - Coronary artery fistula (CAF) is an abnormal communication between an epicardial coronary artery and a cardiac chamber, major vessel or other vascular structures. This report presents a rare case of CAF in which a dilated left main trunk and proximal circumflex coronary artery are connected to a dilated coronary sinus. There were also two other fistulae and persistent left superior vena cava. The coronary fistula was managed conservatively. PMID- 23755086 TI - Incidental visualization of the septal vein of the left atrium. PMID- 23755087 TI - Diagnosing Alzheimer's disease: are we any nearer to useful biomarker-based, non invasive tests? AB - BACKGROUND: Alzheimer's disease (AD) accounts for 60-80% of cases of dementia and causes significant morbidity in patients and carers, and expense for health and social services. There is a need for a validated, non-invasive and cheap test to diagnose early AD, as diagnosis may enable prompt treatment and service planning. AIM: To identify emerging biomarker-based tests for the early diagnosis of AD which could be available for use in primary or generalist care in the near future. DESIGN: Horizon scanning review. METHODS: We searched online sources to identify emerging non-invasive, biomarker-based tests. Tests were included if they used blood, saliva or urine; and there was evidence of use in trials in patients with AD. For tests licensed for use in clinical or research settings we requested information from the developer on the intended place of use and plans for availability in Europe. RESULTS: We identified 6 biomarker-based tests of which 5 are available for research or clinical use. The closest to market were AclarusDXTM (ExonHit Therapeutics) a gene signature test, and INNO-BIA plasma Abeta forms assay (Innogenetics N.V.) which may be CE marked for clinical use in 2015. We found no evidence of clinical utility or cost. CONCLUSION: Although biomarker-based tests are nearing clinical availability and may have a future role to help target AD-specific treatment and guide prognosis, they are not yet ready for trials of clinical utility in primary care. PMID- 23755088 TI - Medical specialist attendance in nursing homes. AB - The care in nursing homes was examined based on scientific studies. The analysis focuses on dementia and type II diabetes. There is evidence for deficits in the supply of medical specialist attendance to nursing home residents with these diseases in Germany. Compared with corresponding guidelines the medical care for nursing home residents may be too low or inadequate. PMID- 23755089 TI - Efficacy and efficiency of psychological, psychiatric, sociomedical and complementary medical interventions for excessive crying in primary care services ("Schreiambulanzen"). AB - There are different approaches to reduce excessive crying of babies. Studies prove positive effects of single measures, e. g. certain diets, acupuncture or psychological approaches improve the crying behaviour. No evaluation data support the effectiveness of the examined crying ambulances. PMID- 23755090 TI - Orthopaedic manifestations and diagnostic clues in children with Guillain-Barre syndrome. AB - INTRODUCTION: Guillain-Barre syndrome (GBS) is an acute inflammatory demyelinating polyneuropathy characterized by symmetric limb weakness. Children with GBS sometimes consult the orthopaedists because of limb pain and gait disturbance. The orthopaedists, however, are unfamiliar with GBS, since it has rarely been delineated in detail in the orthopaedic literature. In the present study, we specifically describe orthopaedic manifestations and diagnostic clues in pediatric GBS. METHODS: We reviewed seven patients with pediatric GBS in regard to age, gender, clinical symptoms, department at the first medical consultation, initial diagnosis, physical and laboratory findings, medical interventions, and the latest clinical outcome. RESULTS: There were five boys and two girls, with a mean age at presentation of 7.2 years. Gait disturbance associated with lower limb pain and weakness was the most frequent early clinical symptom. Among the five patients who presented initially at the orthopaedic department, three were misdiagnosed. Loss of deep tendon reflexes was seen in all patients. Anti-ganglioside antibodies were positive in three and protein levels of cerebrospinal fluid were elevated in five patients. Six patients recovered completely after intravenous immunoglobulin (IVIG) treatment, while one patient who had not undergone IVIG treatment showed minor residual disability. CONCLUSIONS: Acute symmetrical limb pain and gait disturbance associated with loss of tendon reflexes were important clinical manifestations of pediatric GBS. Early diagnosis is essential to prevent delayed recovery, long-term weakness, and permanent functional disabilities. PMID- 23755093 TI - The stroke oxygen pilot study: a randomized controlled trial of the effects of routine oxygen supplementation early after acute stroke--effect on key outcomes at six months. AB - INTRODUCTION: Post-stroke hypoxia is common, and may adversely affect outcome. We have recently shown that oxygen supplementation may improve early neurological recovery. Here, we report the six-month outcomes of this pilot study. METHODS: Patients with a clinical diagnosis of acute stroke were randomized within 24 h of admission to oxygen supplementation at 2 or 3 L/min for 72 h or to control treatment (room air). Outcomes (see below) were assessed by postal questionnaire at 6 months. Analysis was by intention-to-treat, and statistical significance was set at p <= 0.05. RESULTS: Out of 301 patients randomized two refused/withdrew consent and 289 (148 in the oxygen and 141 in the control group) were included in the analysis: males 44%, 51%; mean (SD) age 73 (12), 71 (12); median (IQR) National Institutes of Health Stroke Scale score 6 (3, 10), 5 (3, 10) for the two groups respectively. At six months 22 (15%) patients in the oxygen group and 20 (14%) in the control group had died; mean survival in both groups was 162 days (p = 0.99). Median (IQR) scores for the primary outcome, the modified Rankin Scale, were 3 (1, 5) and 3 (1, 4) for the oxygen and control groups respectively. The covariate-adjusted odds ratio was 1.04 (95% CI 0.67, 1.60), indicating that the odds of a lower (i.e. better) score were non-significantly higher in the oxygen group (p = 0.86). The mean differences in the ability to perform basic (Barthel Index) and extended activities of daily living (NEADL), and quality of life (EuroQol) were also non-significant. CONCLUSIONS: None of the key outcomes differed at 6 months between the groups. Although not statistically significant and generally of small magnitude, the effects were predominantly in favour of the oxygen group; a larger trial, powered to show differences in longer-term functional outcomes, is now on-going. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN12362720; Eudract.ema.europa.eu 2004-001866-41. PMID- 23755094 TI - Muller cell reactivity in response to photoreceptor degeneration in rats with defective polycystin-2. AB - BACKGROUND: Retinal degeneration in transgenic rats that express a mutant cilia gene polycystin-2 (CMV-PKD2(1/703)HA) is characterized by initial photoreceptor degeneration and glial activation, followed by vasoregression and neuronal degeneration (Feng et al., 2009, PLoS One 4: e7328). It is unknown whether glial activation contributes to neurovascular degeneration after photoreceptor degeneration. We characterized the reactivity of Muller glial cells in retinas of rats that express defective polycystin-2. METHODS: Age-matched Sprague-Dawley rats served as control. Retinal slices were immunostained for intermediate filaments, the potassium channel Kir4.1, and aquaporins 1 and 4. The potassium conductance of isolated Muller cells was recorded by whole-cell patch clamping. The osmotic swelling characteristics of Muller cells were determined by superfusion of retinal slices with a hypoosmotic solution. FINDINGS: Muller cells in retinas of transgenic rats displayed upregulation of GFAP and nestin which was not observed in control cells. Whereas aquaporin-1 labeling of photoreceptor cells disappeared along with the degeneration of the cells, aquaporin-1 emerged in glial cells in the inner retina of transgenic rats. Aquaporin-4 was upregulated around degenerating photoreceptor cells. There was an age-dependent redistribution of Kir4.1 in retinas of transgenic rats, with a more even distribution along glial membranes and a downregulation of perivascular Kir4.1. Muller cells of transgenic rats displayed a slight decrease in their Kir conductance as compared to control. Muller cells in retinal tissues from transgenic rats swelled immediately under hypoosmotic stress; this was not observed in control cells. Osmotic swelling was induced by oxidative-nitrosative stress, mitochondrial dysfunction, and inflammatory lipid mediators. INTERPRETATION: Cellular swelling suggests that the rapid water transport through Muller cells in response to osmotic stress is altered as compared to control. The dislocation of Kir4.1 will disturb the retinal potassium and water homeostasis, and osmotic generation of free radicals and inflammatory lipids may contribute to neurovascular injury. PMID- 23755095 TI - Ectopic overexpression of SsCBF1, a CRT/DRE-binding factor from the nightshade plant Solanum lycopersicoides, confers freezing and salt tolerance in transgenic Arabidopsis. AB - The C-repeat (CRT)/dehydration-responsive element (DRE) binding factor (CBF/DREB1) transcription factors play a key role in cold response. However, the detailed roles of many plant CBFs are far from fully understood. A CBF gene (SsCBF1) was isolated from the cold-hardy plant Solanum lycopersicoides. A subcellular localization study using GFP fusion protein indicated that SsCBF1 is localized in the nucleus. We delimited the SsCBF1 transcriptional activation domain to the C-terminal segment comprising amino acid residues 193-228 (SsCBF1(193-228)). The expression of SsCBF1 could be dramatically induced by cold, drought and high salinity. Transactivation assays in tobacco leaves revealed that SsCBF1 could specifically bind to the CRT cis-elements in vivo to activate the expression of downstream reporter genes. The ectopic overexpression of SsCBF1 conferred increased freezing and high-salinity tolerance and late flowering phenotype to transgenic Arabidopsis. RNA-sequencing data exhibited that a set of cold and salt stress responsive genes were up-regulated in transgenic Arabidopsis. Our results suggest that SsCBF1 behaves as a typical CBF to contribute to plant freezing tolerance. Increased resistance to high-salinity and late flowering phenotype derived from SsCBF1 OE lines lend more credence to the hypothesis that plant CBFs participate in diverse physiological and biochemical processes related to adverse conditions. PMID- 23755096 TI - Prolactin-induced protein (PIP) regulates proliferation of luminal A type breast cancer cells in an estrogen-independent manner. AB - Prolactin-induced Protein (PIP), an aspartyl protease unessential for normal mammalian cell function, is required for the proliferation and invasion of some breast cancer (BCa) cell types. Because PIP expression is particularly high in the Luminal A BCa subtype, we investigated the roles of PIP in the related T47D BCa cell line. Nucleic acid and antibody arrays were employed to screen effects of PIP silencing on global gene expression and activation of receptor tyrosine kinases (RTKs), respectively. Expression of PIP-stimulated genes, as defined in the T47D cell culture model, was well correlated with the expression of PIP itself across a cohort of 557 mRNA profiles of diverse BCa tumors, and bioinformatics analysis revealed cJUN and cMYC as major nodes in the PIP dependent gene network. Among 71 RTKs tested, PIP silencing resulted in decreased phosphorylation of focal adhesion kinase (FAK), ephrin B3 (EphB3), FYN, and hemopoietic cell kinase (HCK). Ablation of PIP also abrogated serum-induced activation of the downstream serine/threonine kinases AKT, ERK1/2, and JNK1. Consistent with these results, PIP-depleted cells exhibited defects in adhesion to fibronectin, cytoskeletal stress fiber assembly and protein secretion. In addition, PIP silencing abrogated the mitogenic response of T47D BCa cells to estradiol (E2). The dependence of BCa cell proliferation was unrelated, however, to estrogen signaling because: 1) PIP silencing did not affect the transcriptional response of estrogen target genes to hormone treatment, and 2) PIP was required for the proliferation of tamoxifen-resistant BCa cells. Pharmacological inhibition of PIP may therefore serve the bases for both augmentation of existing therapies for hormone-dependent tumors and the development of novel therapeutic approaches for hormone-resistant BCa. PMID- 23755097 TI - The application of the Ten Group classification system (TGCS) in caesarean delivery case mix adjustment. A multicenter prospective study. AB - BACKGROUND: Caesarean delivery (CD) rates are commonly used as an indicator of quality in obstetric care and risk adjustment evaluation is recommended to assess inter-institutional variations. The aim of this study was to evaluate whether the Ten Group classification system (TGCS) can be used in case-mix adjustment. METHODS: Standardized data on 15,255 deliveries from 11 different regional centers were prospectively collected. Crude Risk Ratios of CDs were calculated for each center. Two multiple logistic regression models were herein considered by using: Model 1- maternal (age, Body Mass Index), obstetric variables (gestational age, fetal presentation, single or multiple, previous scar, parity, neonatal birth weight) and presence of risk factors; Model 2- TGCS either with or without maternal characteristics and presence of risk factors. Receiver Operating Characteristic (ROC) curves of the multivariate logistic regression analyses were used to assess the diagnostic accuracy of each model. The null hypothesis that Areas under ROC Curve (AUC) were not different from each other was verified with a Chi Square test and post hoc pairwise comparisons by using a Bonferroni correction. RESULTS: Crude evaluation of CD rates showed all centers had significantly higher Risk Ratios than the referent. Both multiple logistic regression models reduced these variations. However the two methods ranked institutions differently: model 1 and model 2 (adjusted for TGCS) identified respectively nine and eight centers with significantly higher CD rates than the referent with slightly different AUCs (0.8758 and 0.8929 respectively). In the adjusted model for TGCS and maternal characteristics/presence of risk factors, three centers had CD rates similar to the referent with the best AUC (0.9024). CONCLUSIONS: The TGCS might be considered as a reliable variable to adjust CD rates. The addition of maternal characteristics and risk factors to TGCS substantially increase the predictive discrimination of the risk adjusted model. PMID- 23755098 TI - The IPV-GBM scale: a new scale to measure intimate partner violence among gay and bisexual men. AB - OBJECTIVES: The paper describes the creation of a new scale to measure intimate partner violence (IPV) among gay and bisexual men. METHODS: Seven focus group discussions were held with gay and bisexual men, focusing on defining intimate partner violence: 30 forms of IPV were identified. A venue-recruited sample of 912 gay and bisexual men was surveyed, examining definitional understanding and recent experiences of each of the 30 forms of IPV. Participants were also asked questions from the CDC definition of intimate partner violence and the short-form of the Conflicts Tactics Scale (CTS2S). Factor analysis of responses to the definitional questions was used to create the IPV-GBM scale, and the prevalence of intimate partner violence was compared with that identified by the CDC and CTS2S measures of intimate partner violence. RESULTS: A 23-item scale, with 5 unique domains, was created, with strong internal reliability (Cronbach Alpha >.90). The IPV-GBM scale mirrored both the CDC and CTS2S definitions of intimate partner violence, but contained additional domains such as controlling violence, monitoring behaviors, emotional violence, and HIV-related violence. The new scale identified a significantly higher prevalence of IPV than either of the more commonly used measures. CONCLUSIONS: The results presented here provide encouraging evidence for a new, more accurate measure of intimate partner violence among gay and bisexual men in the U.S. PMID- 23755099 TI - The skeletal phenotype of chondroadherin deficient mice. AB - Chondroadherin, a leucine rich repeat extracellular matrix protein with functions in cell to matrix interactions, binds cells via their alpha2beta1 integrin as well as via cell surface proteoglycans, providing for different sets of signals to the cell. Additionally, the protein acts as an anchor to the matrix by binding tightly to collagens type I and II as well as type VI. We generated mice with inactivated chondroadherin gene to provide integrated studies of the role of the protein. The null mice presented distinct phenotypes with affected cartilage as well as bone. At 3-6 weeks of age the epiphyseal growth plate was widened most pronounced in the proliferative zone. The proteome of the femoral head articular cartilage at 4 months of age showed some distinct differences, with increased deposition of cartilage intermediate layer protein 1 and fibronectin in the chondroadherin deficient mice, more pronounced in the female. Other proteins show decreased levels in the deficient mice, particularly pronounced for matrilin-1, thrombospondin-1 and notably the members of the alpha1-antitrypsin family of proteinase inhibitors as well as for a member of the bone morphogenetic protein growth factor family. Thus, cartilage homeostasis is distinctly altered. The bone phenotype was expressed in several ways. The number of bone sialoprotein mRNA expressing cells in the proximal tibial metaphysic was decreased and the osteoid surface was increased possibly indicating a change in mineral metabolism. Micro CT revealed lower cortical thickness and increased structure model index, i.e. the amount of plates and rods composing the bone trabeculas. The structural changes were paralleled by loss of function, where the null mice showed lower femoral neck failure load and tibial strength during mechanical testing at 4 months of age. The skeletal phenotype points at a role for chondroadherin in both bone and cartilage homeostasis, however, without leading to altered longitudinal growth. PMID- 23755100 TI - cGMP-dependent protein kinase Ibeta interacts with p44/WDR77 to regulate androgen receptor-driven gene expression. AB - The androgen receptor (AR) pathway plays critical roles in controlling differentiation and proliferation of prostate epithelial cells. We previously identified a novel AR cofactor, p44/WDR77, which specifically enhances AR transcriptional activity in the prostate gland and prostate cancer. To further elucidate p44/WDR77's role in the AR signaling pathway, we conducted a yeast two hybrid screening and identified cGMP-dependent protein kinase (PKG) as a p44/WDR77-interacting protein. Further investigation by lusiferase assay and kinase assay demonstrated that PKG-Ibeta physically interacted with and phosphorylated both p44 and AR and enhanced AR transactivity in synergy with p44 in an androgen- and cGMP-dependent manner. Furthermore, PKG1beta expression promoted p44/WDR77 nuclear translocation and inhibited prostate cancer cell growth via G1 cell cycle arrest. Our findings characterize PKG as a novel regulator of AR-mediated transcription by enhancing AR cofactor p44/WDR77's function, which provide a novel mechanism for the growth regulation of prostate cancer cells by the androgen signaling. PMID- 23755101 TI - In TCR-stimulated T-cells, N-ras regulates specific genes and signal transduction pathways. AB - It has been recently shown that N-ras plays a preferential role in immune cell development and function; specifically: N-ras, but not H-ras or K-ras, could be activated at and signal from the Golgi membrane of immune cells following a low level T-cell receptor stimulus. The goal of our studies was to test the hypothesis that N-ras and H-ras played distinct roles in immune cells at the level of the transcriptome. First, we showed via mRNA expression profiling that there were over four hundred genes that were uniquely differentially regulated either by N-ras or H-ras, which provided strong evidence in favor of the hypothesis that N-ras and H-ras have distinct functions in immune cells. We next characterized the genes that were differentially regulated by N-ras in T cells following a low-level T-cell receptor stimulus. Of the large pool of candidate genes that were differentially regulated by N-ras downstream of TCR ligation, four genes were verified in qRT-PCR-based validation experiments (Dntt, Slc9a6, Chst1, and Lars2). Finally, although there was little overlap between individual genes that were regulated by N-ras in unstimulated thymocytes and stimulated CD4(+) T-cells, there was a nearly complete correspondence between the signaling pathways that were regulated by N-ras in these two immune cell types. PMID- 23755102 TI - A sensitive and selective liquid chromatography/tandem mass spectrometry method for quantitative analysis of efavirenz in human plasma. AB - A selective and a highly sensitive method for the determination of the non nucleoside reverse transcriptase inhibitor (NNRTI), efavirenz, in human plasma has been developed and fully validated based on high performance liquid chromatography tandem mass spectrometry (LC-MS/MS). Sample preparation involved protein precipitation followed by one to one dilution with water. The analyte, efavirenz was separated by high performance liquid chromatography and detected with tandem mass spectrometry in negative ionization mode with multiple reaction monitoring. Efavirenz and 13C6-efavirenz (Internal Standard), respectively, were detected via the following MRM transitions: m/z 314.20243.90 and m/z 320.20249.90. A gradient program was used to elute the analytes using 0.1% formic acid in water and 0.1% formic acid in acetonitrile as mobile phase solvents, at a flow-rate of 0.3 mL/min. The total run time was 5 min and the retention times for the internal standard (13C6-efavirenz) and efavirenz was approximately 2.6 min. The calibration curves showed linearity (coefficient of regression, r>0.99) over the concentration range of 1.0-2,500 ng/mL. The intraday precision based on the standard deviation of replicates of lower limit of quantification (LLOQ) was 9.24% and for quality control (QC) samples ranged from 2.41% to 6.42% and with accuracy from 112% and 100-111% for LLOQ and QC samples. The inter day precision was 12.3% and 3.03-9.18% for LLOQ and quality controls samples, and the accuracy was 108% and 95.2-108% for LLOQ and QC samples. Stability studies showed that efavirenz was stable during the expected conditions for sample preparation and storage. The lower limit of quantification for efavirenz was 1 ng/mL. The analytical method showed excellent sensitivity, precision, and accuracy. This method is robust and is being successfully applied for therapeutic drug monitoring and pharmacokinetic studies in HIV-infected patients. PMID- 23755104 TI - Differences help recognition: a probabilistic interpretation. AB - This paper presents a computational model to address one prominent psychological behavior of human beings to recognize images. The basic pursuit of our method can be concluded as that differences among multiple images help visual recognition. Generally speaking, we propose a statistical framework to distinguish what kind of image features capture sufficient category information and what kind of image features are common ones shared in multiple classes. Mathematically, the whole formulation is subject to a generative probabilistic model. Meanwhile, a discriminative functionality is incorporated into the model to interpret the differences among all kinds of images. The whole Bayesian formulation is solved in an Expectation-Maximization paradigm. After finding those discriminative patterns among different images, we design an image categorization algorithm to interpret how these differences help visual recognition within the bag-of-feature framework. The proposed method is verified on a variety of image categorization tasks including outdoor scene images, indoor scene images as well as the airborne SAR images from different perspectives. PMID- 23755105 TI - Challenges of culturing human norovirus in three-dimensional organoid intestinal cell culture models. AB - Human noroviruses are the most common cause of acute gastroenteritis worldwide. Recently, cell culture systems have been described using either human embryonic intestinal epithelial cells (Int-407) or human epithelial colorectal adenocarcinoma cells (Caco-2) growing on collagen-I porous micro carrier beads in a rotating bioreactor under conditions of physiological fluid shear. Here, we describe the efforts from two independent laboratories to implement this three dimensional (3D) cell culture system for the replication of norovirus. Int-407 and Caco-2 were grown in a rotating bioreactor for up to 28 days. Prior to infection, cells were screened for the presence of microvilli by electron microscopy and stained for junction proteins (zonula occludens-1, claudin-1, and beta-catenin). Differentiated 3D cells were transferred to 24-well plates and infected with bacteria-free filtrates of various norovirus genotypes (GI.1, GI.3, GI.8, GII.2, GII.4, GII.7, and GII.8). At 12 h, 24 h, and 48 h post inoculation, viral RNA from both cells and supernatants were collected and analyzed for norovirus RNA by real-time reverse transcription PCR. Despite observations of high expression of junction proteins and microvilli development in stained thin sections, our data suggest no significant increase in viral titer based on norovirus RNA copy number during the first 48 h after inoculation for the different samples and virus culture conditions tested. Our combined efforts demonstrate that 3D cell culture models using Int-407 or Caco-2 cells do not support norovirus replication and highlight the complexity and difficulty of developing a reproducible in vitro cell culture system for human norovirus. PMID- 23755103 TI - Sequencing of candidate chromosome instability genes in endometrial cancers reveals somatic mutations in ESCO1, CHTF18, and MRE11A. AB - Most endometrial cancers can be classified histologically as endometrioid, serous, or clear cell. Non-endometrioid endometrial cancers (NEECs; serous and clear cell) are the most clinically aggressive of the three major histotypes and are characterized by aneuploidy, a feature of chromosome instability. The genetic alterations that underlie chromosome instability in endometrial cancer are poorly understood. In the present study, we used Sanger sequencing to search for nucleotide variants in the coding exons and splice junctions of 21 candidate chromosome instability genes, including 19 genes implicated in sister chromatid cohesion, from 24 primary, microsatellite-stable NEECs. Somatic mutations were verified by sequencing matched normal DNAs. We subsequently resequenced mutated genes from 41 additional NEECs as well as 42 endometrioid ECs (EECs). We uncovered nonsynonymous somatic mutations in ESCO1, CHTF18, and MRE11A in, respectively, 3.7% (4 of 107), 1.9% (2 of 107), and 1.9% (2 of 107) of endometrial tumors. Overall, 7.7% (5 of 65) of NEECs and 2.4% (1 of 42) of EECs had somatically mutated one or more of the three genes. A subset of mutations are predicted to impact protein function. The co-occurrence of somatic mutations in ESCO1 and CHTF18 was statistically significant (P = 0.0011, two-tailed Fisher's exact test). This is the first report of somatic mutations within ESCO1 and CHTF18 in endometrial tumors and of MRE11A mutations in microsatellite-stable endometrial tumors. Our findings warrant future studies to determine whether these mutations are driver events that contribute to the pathogenesis of endometrial cancer. PMID- 23755106 TI - Fish assemblages on estuarine artificial reefs: natural rocky-reef mimics or discrete assemblages? AB - If the primary goal of artificial reef construction is the creation of additional reef habitat that is comparable to adjacent natural rocky-reef, then performance should be evaluated using simultaneous comparisons with adjacent natural habitats. Using baited remote underwater video (BRUV) fish assemblages on purpose built estuarine artificial reefs and adjacent natural rocky-reef and sand-flat were assessed 18 months post-deployment in three south-east Australian estuaries. Fish abundance, species richness and diversity were found to be greater on the artificial reefs than on either naturally occurring reef or sand-flat in all estuaries. Comparisons within each estuary identified significant differences in the species composition between the artificial and natural rocky-reefs. The artificial reef assemblage was dominated by sparid species including Acanthopagrus australis and Rhabdosargus sarba. The preference for a range of habitats by theses sparid species is evident by their detection on sand-flat, natural rocky reef and artificial reef habitats. The fish assemblage identified on the artificial reefs remained distinct from the adjacent rocky-reef, comprising a range of species drawn from naturally occurring rocky-reef and sand flat. In addition, some mid-water schooling species including Trachurus novaezelandiae and Pseudocaranx georgianus were only identified on the artificial reef community; presumably as result of the reef's isolated location in open water. We concluded that estuarine artificial reef assemblages are likely to differ significantly from adjacent rocky-reef, potentially as a result of physical factors such as reef isolation, coupled with species specific behavioural traits such as the ability of some species to traverse large sand flats in order to locate reef structure, and feeding preferences. Artificial reefs should not be viewed as direct surrogates for natural reef. The assemblages are likely to remain distinct from naturally occurring habitat comprised of species that reside on a range of adjacent natural habitats. PMID- 23755107 TI - Efficacy of new generation antidepressants: differences seem illusory. AB - BACKGROUND: Recently, Cipriani and colleagues examined the relative efficacy of 12 new-generation antidepressants on major depression using network meta-analytic methods. They found that some of these medications outperformed others in patient response to treatment. However, several methodological criticisms have been raised about network meta-analysis and Cipriani's analysis in particular which creates the concern that the stated superiority of some antidepressants relative to others may be unwarranted. MATERIALS AND METHODS: A Monte Carlo simulation was conducted which involved replicating Cipriani's network meta-analysis under the null hypothesis (i.e., no true differences between antidepressants). The following simulation strategy was implemented: (1) 1000 simulations were generated under the null hypothesis (i.e., under the assumption that there were no differences among the 12 antidepressants), (2) each of the 1000 simulations were network meta-analyzed, and (3) the total number of false positive results from the network meta-analyses were calculated. FINDINGS: Greater than 7 times out of 10, the network meta-analysis resulted in one or more comparisons that indicated the superiority of at least one antidepressant when no such true differences among them existed. INTERPRETATION: Based on our simulation study, the results indicated that under identical conditions to those of the 117 RCTs with 236 treatment arms contained in Cipriani et al.'s meta-analysis, one or more false claims about the relative efficacy of antidepressants will be made over 70% of the time. As others have shown as well, there is little evidence in these trials that any antidepressant is more effective than another. The tendency of network meta-analyses to generate false positive results should be considered when conducting multiple comparison analyses. PMID- 23755108 TI - Development of the hearts of lizards and snakes and perspectives to cardiac evolution. AB - Birds and mammals both developed high performance hearts from a heart that must have been reptile-like and the hearts of extant reptiles have an unmatched variability in design. Yet, studies on cardiac development in reptiles are largely old and further studies are much needed as reptiles are starting to become used in molecular studies. We studied the growth of cardiac compartments and changes in morphology principally in the model organism corn snake (Pantherophis guttatus), but also in the genotyped anole (Anolis carolinenis and A. sagrei) and the Philippine sailfin lizard (Hydrosaurus pustulatus). Structures and chambers of the formed heart were traced back in development and annotated in interactive 3D pdfs. In the corn snake, we found that the ventricle and atria grow exponentially, whereas the myocardial volumes of the atrioventricular canal and the muscular outflow tract are stable. Ventricular development occurs, as in other amniotes, by an early growth at the outer curvature and later, and in parallel, by incorporation of the muscular outflow tract. With the exception of the late completion of the atrial septum, the adult design of the squamate heart is essentially reached halfway through development. This design strongly resembles the developing hearts of human, mouse and chicken around the time of initial ventricular septation. Subsequent to this stage, and in contrast to the squamates, hearts of endothermic vertebrates completely septate their ventricles, develop an insulating atrioventricular plane, shift and expand their atrioventricular canal toward the right and incorporate the systemic and pulmonary venous myocardium into the atria. PMID- 23755109 TI - Extracellular modulation of the silkmoth sex pheromone receptor activity by cyclic nucleotides. AB - Odorants and pheromones are essential to insects as chemical cues for finding food or an appropriate mating partner. These volatile compounds bind to olfactory receptors (Ors) expressed by olfactory sensory neurons. Each insect Or functions as a ligand-gated ion channel and is a heteromeric complex that comprises one type of canonical Or and a highly conserved Orco subunit. Because there are many Or types, insect Ors can recognize with high specificity a myriad of chemical cues. Cyclic nucleotides can modulate the activity of insect Or-Orco complexes; however, the mechanism of action of these nucleotides is under debate. Here, we show that cyclic nucleotides, including cAMP and cGMP, interact with the silkmoth sex pheromone receptor complex, BmOr-1-BmOrco, from the outside of the cell and that these nucleotides act as antagonists at low concentrations and weak agonists at high concentrations. These cyclic nucleotides do not compete with the sex pheromone, bombykol, for binding to the BmOr-1 subunit. ATP and GTP also weakly inhibited BmOr-1-BmOrco activity, but D-ribose had no effect; these findings indicated that the purine moiety was crucial for the inhibition. Only the bombykol receptors have been so far shown to be subject to modulation by nucleotide-related compounds, indicating that this responsiveness to these compounds is not common for all insect Or-Orco complexes. PMID- 23755110 TI - Double-stranded RNA attenuates the barrier function of human pulmonary artery endothelial cells. AB - Circulating RNA may result from excessive cell damage or acute viral infection and can interact with vascular endothelial cells. Despite the obvious clinical implications associated with the presence of circulating RNA, its pathological effects on endothelial cells and the governing molecular mechanisms are still not fully elucidated. We analyzed the effects of double stranded RNA on primary human pulmonary artery endothelial cells (hPAECs). The effect of natural and synthetic double-stranded RNA (dsRNA) on hPAECs was investigated using trans-endothelial electric resistance, molecule trafficking, calcium (Ca(2+)) homeostasis, gene expression and proliferation studies. Furthermore, the morphology and mechanical changes of the cells caused by synthetic dsRNA was followed by in-situ atomic force microscopy, by vascular-endothelial cadherin and F-actin staining. Our results indicated that exposure of hPAECs to synthetic dsRNA led to functional deficits. This was reflected by morphological and mechanical changes and an increase in the permeability of the endothelial monolayer. hPAECs treated with synthetic dsRNA accumulated in the G1 phase of the cell cycle. Additionally, the proliferation rate of the cells in the presence of synthetic dsRNA was significantly decreased. Furthermore, we found that natural and synthetic dsRNA modulated Ca(2+) signaling in hPAECs by inhibiting the sarco-endoplasmic Ca(2+) ATPase (SERCA) which is involved in the regulation of the intracellular Ca(2+) homeostasis and thus cell growth. Even upon synthetic dsRNA stimulation silencing of SERCA3 preserved the endothelial monolayer integrity. Our data identify novel mechanisms by which dsRNA can disrupt endothelial barrier function and these may be relevant in inflammatory processes. PMID- 23755112 TI - Analysis of multiple B-value diffusion-weighted imaging in pediatric acute encephalopathy. AB - Acute encephalopathy is a disease group more commonly seen in children. It is often severe and has neurological sequelae. Imaging is important for early diagnosis and prompt treatment to ameliorate an unfavorable outcome, but insufficient sensitivity/specificity is a problem. To overcome this, a new value (fraction of high b-pair (FH)) that could be processed from clinically acceptable MR diffusion-weighted imaging (DWI) with three different b-values was designed on the basis of a two-compartment model of water diffusion signal attenuation. The purpose of this study is to compare FH with the apparent diffusion coefficient (ADC) regarding the detectability of pediatric acute encephalopathy. We retrospectively compared the clinical DWI of 15 children (1-10 years old, mean 2.34, 8 boys, 7 girls) of acute encephalopathy with another 16 children (1-11 years old, mean 4.89, 9 boys, 7 girls) as control. A comparison was first made visually by mapping FH on the brain images, and then a second comparison was made on the basis of 10 regions of interest (ROIs) set on cortical and subcortical areas of each child. FH map visually revealed diffusely elevated FH in cortical and subcortical areas of the patients with acute encephalopathy; the changes seemed more diffuse in FH compared to DWI. The comparison based on ROI revealed elevated mean FH in the cortical and subcortical areas of the acute encephalopathy patients compared to control with significant difference (P<0.05). Similar findings were observed even in regions where the findings of DWI were slight. The reduction of mean ADC was significant in regions with severe findings in DWI, but it was not constant in the areas with slighter DWI findings. The detectability of slight changes of cortical and subcortical lesions in acute encephalopathy may be superior in FH compared to ADC. PMID- 23755111 TI - Physicochemical characterization of a thermostable alcohol dehydrogenase from Pyrobaculum aerophilum. AB - In this work we characterize an alcohol dehydrogenase (ADH) from the hyperthermophilic archaeon Pyrobaculum aerophilum (PyAeADHII). We have previously found that PyAeADHII has no activity when standard ADH substrates are used but is active when alpha-tetralone is used as substrate. Here, to gain insights into enzyme function, we screened several chemical libraries for enzymatic modulators using an assay employing alpha-tetralone. The results indicate that PyAeADHII activity in the presence of alpha-tetralone was inhibited by compounds such as flunarizine. We also examined metal coordination of the enzyme in solution by performing metal substitution of the enzyme-bound zinc (Zn2+) with cobalt. The solution-based absorption spectra for cobalt substituted PyAeADHII supports substitution at the structural Zn2+ site. To gain structural insight, we obtained the crystal structure of both wild-type and cobalt-substituted PyAeADHII at 1.75 A and 2.20 A resolution, respectively. The X-ray data confirmed one metal ion per monomer present only at the structural site with otherwise close conservation to other ADH enzymes. We next determined the co-crystal structure of the NADPH-bound form of the enzyme at 2.35 A resolution to help define the active site region of the enzyme and this data shows close structural conservation with horse ADH, despite the lack of a catalytic Zn2+ ion in PyAeADHII. Modeling of alpha tetralone into the NADPH bound structure suggests an arginine as a possible catalytic residue. The data presented here can yield a better understanding of alcohol dehydrogenases lacking the catalytic zinc as well as the structural features inherent to thermostable enzymes. PMID- 23755113 TI - Predicting species cover of marine macrophyte and invertebrate species combining hyperspectral remote sensing, machine learning and regression techniques. AB - In order to understand biotic patterns and their changes in nature there is an obvious need for high-quality seamless measurements of such patterns. If remote sensing methods have been applied with reasonable success in terrestrial environment, their use in aquatic ecosystems still remained challenging. In the present study we combined hyperspectral remote sensing and boosted regression tree modelling (BTR), an ensemble method for statistical techniques and machine learning, in order to test their applicability in predicting macrophyte and invertebrate species cover in the optically complex seawater of the Baltic Sea. The BRT technique combined with remote sensing and traditional spatial modelling succeeded in identifying, constructing and testing functionality of abiotic environmental predictors on the coverage of benthic macrophyte and invertebrate species. Our models easily predicted a large quantity of macrophyte and invertebrate species cover and recaptured multitude of interactions between environment and biota indicating a strong potential of the method in the modelling of aquatic species in the large variety of ecosystems. PMID- 23755114 TI - Mastication and risk for diabetes in a Japanese population: a cross-sectional study. AB - BACKGROUND: Associations between mastication and insufficient nutrient intake, obesity, and glucose metabolism have been shown in previous studies. However, the association between mastication and diabetes has not been clarified. Our objective was to examine the association between mastication, namely masticatory performance or rate of eating, and diabetes in a population-based cohort. METHODS: We conducted a cross-sectional study of the association between mastication and diabetes in the Nagahama Prospective Cohort Study, an ongoing study which recruits citizens of Nagahama City in Shiga Prefecture, central Japan. 2,283 male and 4,544 female residents aged 40-74 years were enrolled from July 2009 to November 2010. Masticatory performance was evaluated by spectrophotometric measurement of color changes after masticating color changeable chewing gum. Categorical rate of eating (fast, intermediate or slow) was self-assessed using a questionnaire. RESULTS: 177 males (7.7%) and 112 (2.4%) females were diagnosed with diabetes. We divided participants into four groups by quartile of masticatory performance, namely Q1 (lowest), 2, and 3 and 4 (highest). Compared to the lowest performance group, the multivariable adjusted odds ratio (OR) of diabetes was 0.91 (95% confidence interval (CI), 0.58-1.4) in Q2, 0.77 (95% CI, 0.48-1.2) in Q3, and 0.53 (95% CI, 0.31-0.90) in the highest group in males, and 1.2 (95% CI, 0.73-2.0), 0.95 (95% CI, 0.54-1.6) and 0.56 (95% CI, 0.30-1.0) in females. We also estimated ORs of diabetes by rate of eating. Compared to the fast eating group, ORs in males were 0.87 (95% CI, 0.61-1.2) in the intermediate group and 0.38 (95% CI, 0.16-0.91) in the slow group, and ORs in females were 0.92 (95% CI, 0.59-1.4) and 1.5 (95% CI, 0.73-3.0). CONCLUSIONS: These findings support the hypothesis that higher masticatory performance and slow eating prevent the occurrence of diabetes. PMID- 23755115 TI - Development and evaluation of a pseudovirus-luciferase assay for rapid and quantitative detection of neutralizing antibodies against enterovirus 71. AB - The level of neutralizing antibodies (NtAb) induced by vaccine inoculation is an important endpoint to evaluate the efficacy of EV71 vaccine. In order to evaluate the efficacy of EV71 vaccine, here, we reported the development of a novel pseudovirus system expression firefly luciferase (PVLA) for the quantitative measurement of NtAb. We first evaluated and validated the sensitivity and specificity of the PVLA method. A total of 326 serum samples from an epidemiological survey and 144 serum specimens from 3 clinical trials of EV71 vaccines were used, and the level of each specimen's neutralizing antibodies (NtAb) was measured in parallel using both the conventional CPE-based and PVLA based assay. Against the standard neutralization assay based on the inhibition of the cytopathic effect (CPE), the sensitivity and specificity of the PVLA method are 98% and 96%, respectively. Then, we tested the potential interference of NtAb against hepatitis A virus, Polio-I, Polio-II, and Polio-III standard antisera (WHO) and goat anti-G10/CA16 serum, the PVLA based assay showed no cross reactivity with NtAb against other specific sera. Importantly, unlike CPE based method, no live replication-competent EV71 is used during the measurement. Taken together, PVLA is a rapid and specific assay with higher sensitivity and accuracy. It could serve as a valuable tool in assessing the efficacy of EV71 vaccines in clinical trials and disease surveillance in epidemiology studies. PMID- 23755116 TI - The expression of GHS-R in primary neurons is dependent upon maturation stage and regional localization. AB - Ghrelin is a hormone with a crucial role in the regulation of appetite, regulation of inflammation, glucose metabolism and cell proliferation. In the brain ghrelin neurons are located in the cortex (sensorimotor area, cingular gyrus), and the fibres of ghrelin neurons in hypothalamus project directly to the dorsal vagal complex (DVC). Ghrelin binds the growth hormone secretagogue receptor (GHS-R) a G-protein-coupled receptor with a widespread tissue distribution, indeed these receptors are localized both in nonnervous, organs/tissues (i.e. adipose tissue, myocardium, adrenals, gonads, lung, liver, arteries, stomach, pancreas, thyroid, and kidney) as well as in central nervous system (CNS) and higher levels of expression in the pituitary gland and the hypothalamus and lower levels of expression in other organs, including brain. A GHS-R specific monoclonal antibody has been developed and characterized and through it we demonstrate that GHS-R is expressed in primary neurons and that its expression is dependent upon their developmental stage and shows differences according to the brain region involved, with a more pronounced expression in hippocampal rather than cortical neurons. A characterization of GHS-R within the central nervous system is of extreme importance in order to gain insights on its role in the modulation of neurodegenerative events such as Alzheimer's disease. PMID- 23755117 TI - A leafhopper-transmissible DNA virus with novel evolutionary lineage in the family geminiviridae implicated in grapevine redleaf disease by next-generation sequencing. AB - A graft-transmissible disease displaying red veins, red blotches and total reddening of leaves in red-berried wine grape (Vitis vinifera L.) cultivars was observed in commercial vineyards. Next-generation sequencing technology was used to identify etiological agent(s) associated with this emerging disease, designated as grapevine redleaf disease (GRD). High quality RNA extracted from leaves of grape cultivars Merlot and Cabernet Franc with and without GRD symptoms was used to prepare cDNA libraries. Assembly of highly informative sequence reads generated from Illumina sequencing of cDNA libraries, followed by bioinformatic analyses of sequence contigs resulted in specific identification of taxonomically disparate viruses and viroids in samples with and without GRD symptoms. A single stranded DNA virus, tentatively named Grapevine redleaf-associated virus (GRLaV), and Grapevine fanleaf virus were detected only in grapevines showing GRD symptoms. In contrast, Grapevine rupestris stem pitting-associated virus, Hop stunt viroid, Grapevine yellow speckle viroid 1, Citrus exocortis viroid and Citrus exocortis Yucatan viroid were present in both symptomatic and non symptomatic grapevines. GRLaV was transmitted by the Virginia creeper leafhopper (Erythroneura ziczac Walsh) from grapevine-to-grapevine under greenhouse conditions. Molecular and phylogenetic analyses indicated that GRLaV, almost identical to recently reported Grapevine Cabernet Franc-associated virus from New York and Grapevine red blotch-associated virus from California, represents an evolutionarily distinct lineage in the family Geminiviridae with genome characteristics distinct from other leafhopper-transmitted geminiviruses. GRD significantly reduced fruit yield and affected berry quality parameters demonstrating negative impacts of the disease. Higher quantities of carbohydrates were present in symptomatic leaves suggesting their possible role in the expression of redleaf symptoms. PMID- 23755118 TI - Differential response of the cynomolgus macaque gut microbiota to Shigella infection. AB - Little is known about the role of gut microbiota in response to live oral vaccines against enteric pathogens. We examined the effect of immunization with an oral live-attenuated Shigella dysenteriae 1 vaccine and challenge with wild type S. dysenteriae 1 on the fecal microbiota of cynomolgus macaques using 16 S rRNA analysis of fecal samples. Multi-dimensional cluster analysis identified different bacterial community types within macaques from geographically distinct locations. The fecal microbiota of Mauritian macaques, observed to be genetically distinct, harbored a high-diversity community and responded differently to Shigella immunization, as well as challenge compared to the microbiota in non Mauritian macaques. While both macaque populations exhibited anti-Shigella antibody responses, clinical shigellosis was observed only among non-Mauritian macaques. These studies highlight the importance of further investigation into the possible protective role of the microbiota against enteric pathogens and consideration of host genetic backgrounds in conducting vaccine studies. PMID- 23755119 TI - A modified MELD model for Chinese pre-ACLF and ACLF patients and it reveals poor prognosis in pre-ACLF patients. AB - BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is one of the most deadly, prevalent, and costly diseases in Asia. However, no prognostic model has been developed that is based specifically on data gathered from Asian patients with ACLF. The aim of the present study was to quantify the survival time of ACLF among Asians and to develop a prognostic model to estimate the probability of death related to ACLF. METHODS: We conducted a retrospective observational cohort study to analyze clinical data from 857 patients with ACLF/pre-ACLF who did not undergo liver transplantation. Kaplan-Meier and Cox proportional hazards regression model were used to estimate survival rates and survival affected factors. The area under the receiver operating characteristic curve (auROC) was used to evaluate the performance of the models for predicting early mortality. RESULTS: The mortality rates among patients with pre-ACLF at 12 weeks and 24 weeks after diagnosis were 30.5% and 33.2%, respectively. The mortality rates among patients with early-stage ACLF at 12 weeks and 24 weeks after diagnosis were 33.9% and 37.1%, respectively. The difference in survival between pre-ACLF patients and patients in the early stage of ACLF was not statistically significant. The prognostic model identified 5 independent factors significantly associated with survival among patients with ACLF and pre-ACLF: the model for end stage liver disease (MELD) score; age, hepatic encephalopathy; triglyceride level and platelet count. CONCLUSION: The findings of the present study suggest that the Chinese diagnostic criteria of ACLF might be broadened, thus enabling implementation of a novel model to predict ACLF-related death after comprehensive medical treatment. PMID- 23755120 TI - Scope and Limits of an anamnestic questionnaire in a control-induced low endemicity helminthiasis setting in south-central Cote d'Ivoire. AB - BACKGROUND: Schistosomiasis and soil-transmitted helminthiasis are two high burden neglected tropical diseases. In highly endemic areas, control efforts emphasize preventive chemotherapy. However, as morbidity, infection, and transmission begin to decrease, more targeted treatment is likely to become more cost-effective, provided that comparatively cheap diagnostic methods with reasonable accuracy are available. METHODOLOGY: Adults were administered an anamnestic questionnaire in mid-2010 during a cross-sectional epidemiological survey in the Taabo health demographic surveillance system in south-central Cote d'Ivoire. Questions pertaining to risk factors and signs and symptoms for schistosomiasis and soil-transmitted helminthiasis were included. The individuals' helminth infection status and their belonging to three different anthelmintic treatment groups were compared with the questionnaire results (i) to inform the local health authorities about the epidemiological and clinical footprint of locally prevailing helminthiases, and (ii) to explore the scope and limits of an anamnestic questionnaire as monitoring tool, which eventually could help guiding the control of neglected tropical diseases in control-induced low endemicity settings. PRINCIPAL FINDINGS: Our study sample consisted of 195 adults (101 males, 94 females). We found prevalences of hookworm, Trichuris trichiura, Schistosoma haematobium, and Schistosoma mansoni of 39.0%, 2.7%, 2.1%, and 2.1%, respectively. No Ascaris lumbricoides infection was found. Helminth infection intensities were generally very low. Seven, 74 and 79 participants belonged to three different treatment groups. Multivariable logistic regression models revealed statistically significant (p<0.05) associations between some risk factors, signs, and symptoms, and the different helminth infections and treatment groups. However, the risk factors, signs, and symptoms showed weak diagnostic properties. CONCLUSIONS/SIGNIFICANCE: The generally low prevalence and intensity of helminth infection in this part of south-central Cote d'Ivoire indicates that recent control efforts have turned our study area into a low endemicity setting. Our anamnestic questionnaire had low sensitivity and specificity to identify infected individuals or treatment groups. PMID- 23755121 TI - Natural killer cells generated from cord blood hematopoietic progenitor cells efficiently target bone marrow-residing human leukemia cells in NOD/SCID/IL2Rg(null) mice. AB - Natural killer (NK) cell-based adoptive immunotherapy is an attractive adjuvant treatment option for patients with acute myeloid leukemia. Recently, we reported a clinical-grade, cytokine-based culture method for the generation of NK cells from umbilical cord blood (UCB) CD34+ hematopoietic progenitor cells with high yield, purity and in vitro functionality. The present study was designed to evaluate the in vivo anti-leukemic potential of UCB-NK cells generated with our GMP-compliant culture system in terms of biodistribution, survival and cytolytic activity following adoptive transfer in immunodeficient NOD/SCID/IL2Rg(null) mice. Using single photon emission computed tomography, we first demonstrated active migration of UCB-NK cells to bone marrow, spleen and liver within 24 h after infusion. Analysis of the chemokine receptor expression profile of UCB-NK cells matched in vivo findings. Particularly, a firm proportion of UCB-NK cells functionally expressed CXCR4, what could trigger BM homing in response to its ligand CXCL12. In addition, high expression of CXCR3 and CCR6 supported the capacity of UCB-NK cells to migrate to inflamed tissues via the CXCR3/CXCL10-11 and CCR6/CCL20 axis. Thereafter, we showed that low dose IL-15 mediates efficient survival, expansion and maturation of UCB-NK cells in vivo. Most importantly, we demonstrate that a single UCB-NK cell infusion combined with supportive IL-15 administration efficiently inhibited growth of human leukemia cells implanted in the femur of mice, resulting in significant prolongation of mice survival. These preclinical studies strongly support the therapeutic potential of ex vivo generated UCB-NK cells in the treatment of myeloid leukemia after immunosuppressive chemotherapy. PMID- 23755122 TI - Treatment response and mortality among patients starting antiretroviral therapy with and without Kaposi sarcoma: a cohort study. AB - BACKGROUND: Improved survival among HIV-infected individuals on antiretroviral therapy (ART) has focused attention on AIDS-related cancers including Kaposi sarcoma (KS). However, the effect of KS on response to ART is not well-described in Southern Africa. We assessed the effect of KS on survival and immunologic and virologic treatment responses at 6- and 12-months after initiation of ART. METHODS: We analyzed prospectively collected data from a cohort of HIV-infected adults initiating ART in South Africa. Differences in mortality between those with and without KS at ART initiation were estimated with Cox proportional hazard models. Log-binomial models were used to assess differences in CD4 count response and HIV virologic suppression within a year of initiating treatment. RESULTS: Between January 2001-January 2008, 13,847 HIV-infected adults initiated ART at the study clinics. Those with KS at ART initiation (n = 247, 2%) were similar to those without KS (n = 13600,98%) with respect to age (35 vs. 35yrs), presenting CD4 count (74 vs. 85cells/mm3) and proportion on TB treatment (37% vs. 30%). In models adjusted for sex, baseline CD4 count, age, treatment site, tuberculosis and year of ART initiation, KS patients were over three times more likely to have died at any time after ART initiation (hazard ratio[HR]: 3.62; 95% CI: 2.71-4.84) than those without KS. The increased risk was highest within the first year on ART (HR: 4.05; 95% CI: 2.95-5.55) and attenuated thereafter (HR: 2.30; 95% CI: 1.08-4.89). Those with KS also gained, on average, 29 fewer CD4 cells (95% CI: 7 52cells/mm3) and were less likely to increase their CD4 count by 50 cells from baseline (RR: 1.43; 95% CI: 0.99-2.06) within the first 6-months of treatment. CONCLUSIONS: HIV-infected adults presenting with KS have increased risk of mortality even after initiation of ART with the greatest risk in the first year. Among those who survive the first year on therapy, subjects with KS demonstrated a poorer immunologic response to ART than those without KS. PMID- 23755123 TI - Two-year results of an open-label randomized comparison of everolimus-eluting stents and sirolimus-eluting stents. AB - BACKGROUND: Second generation drug-eluting stents were developed to improve the safety and efficacy of first generation stents. So far, limited long term randomized data exist comparing the second generation everolimus-eluting stents (EES) with first generation sirolimus-eluting stents (SES). METHODS: A prospective, open-label, randomized, single center trial comparing EES and SES in all-comer patients. The primary endpoint was a composite of cardiac mortality, myocardial infarction and target vessel revascularization. Secondary endpoints included individual components of the composite, along with target lesion revascularization and stent thrombosis. RESULTS: In total, 977 patients were randomized, of which 498 patients to EES and 479 to SES. Average age was 65.2 +/- 11.2 years and 71.6% of the population was male. Fifty percent of patients were treated for acute coronary syndrome, more often for ST-elevation myocardial infarctions in EES patients (13.7% vs. 9.2% in SES). In contrast, SES patients more often had prior interventions and showed more calcified lesions. Two-year follow-up was available in 98% of patients. The primary endpoint occurred in 10.7% of EES patients compared to 10.6% of SES patients (HR 1.00, 95% CI 0.68 1.48). Additionally, secondary endpoints were similar between groups. The rate of stent thrombosis was low for both stent types. CONCLUSION: In this all-comer population, there were no differences in endpoints between EES and SES during two year follow-up. Stent thrombosis rates were low, supporting the safety of drug eluting stent appliance in clinical practice. TRIAL REGISTRATION: TrialRegister.nl NTR3170. PMID- 23755124 TI - Inhalation toxicity of humidifier disinfectants as a risk factor of children's interstitial lung disease in Korea: a case-control study. AB - BACKGROUND: The occurrence of numerous cases of interstitial lung disease in children (chILD) every spring in Korea starting in 2006 raised suspicion about a causal relationship with the use of humidifier disinfectants (HDs). The aim of this study was to evaluate the association between HD use and the risk of chILD. METHODS: This retrospective, 1?3 matched case-control study consisted of 16 cases of chILD that had developed between 2010 and 2011. The three groups of parallel controls (patients with acute lobar pneumonia, asthma, and healthy children) were matched by age, gender, and index date. Indoor/outdoor environmental risk factors, including HD use, were investigated by asking the guardians to complete a questionnaire. RESULTS: The median age of the affected children (43.8% male) was 26 months (18.25-36.25). The chILD group did not differ significantly from the control groups with respect to socio-demographic and clinical variables. Indoor and outdoor environmental factors were not associated with a risk of chILD. However, the previous use of HDs (OR; 2.73. 95% CI; 1.41-5.90, P = 0.00) were independently associated with an increased risk. CONCLUSIONS: This study showed that HDs, which are widely used in South Korea in the winter season, independently increased the risk of chILD in spring. Therefore, continuous monitoring and, if needed, changes in policy are essential to prevent and control pediatric diseases caused by toxic chemicals. PMID- 23755125 TI - Automated segmentation tool for brain infusions. AB - This study presents a computational tool for auto-segmenting the distribution of brain infusions observed by magnetic resonance imaging. Clinical usage of direct infusion is increasing as physicians recognize the need to attain high drug concentrations in the target structure with minimal off-target exposure. By co infusing a Gadolinium-based contrast agent and visualizing the distribution using real-time using magnetic resonance imaging, physicians can make informed decisions about when to stop or adjust the infusion. However, manual segmentation of the images is tedious and affected by subjective preferences for window levels, image interpolation and personal biases about where to delineate the edge of the sloped shoulder of the infusion. This study presents a computational technique that uses a Gaussian Mixture Model to efficiently classify pixels as belonging to either the high-intensity infusate or low-intensity background. The algorithm was implemented as a distributable plug-in for the widely used imaging platform OsiriX(r). Four independent operators segmented fourteen anonymized datasets to validate the tool's performance. The datasets were intra-operative magnetic resonance images of infusions into the thalamus or putamen of non-human primates. The tool effectively reproduced the manual segmentation volumes, while significantly reducing intra-operator variability by 67+/-18%. The tool will be used to increase efficiency and reduce variability in upcoming clinical trials in neuro-oncology and gene therapy. PMID- 23755126 TI - Fibrous dysplasia in a 120,000+ year old Neandertal from Krapina, Croatia. AB - We describe the first definitive case of a fibrous dysplastic neoplasm in a Neandertal rib (120.71) from the site of Krapina in present-day Croatia. The tumor predates other evidence for these kinds of tumor by well over 100,000 years. Tumors of any sort are a rare occurrence in recent archaeological periods or in living primates, but especially in the human fossil record. Several studies have surveyed bone diseases in past human populations and living primates and fibrous dysplasias occur in a low incidence. Within the class of bone tumors of the rib, fibrous dysplasia is present in living humans at a higher frequency than other bone tumors. The bony features leading to our diagnosis are described in detail. In living humans effects of the neoplasm present a broad spectrum of symptoms, from asymptomatic to debilitating. Given the incomplete nature of this rib and the lack of associated skeletal elements, we resist commenting on the health effects the tumor had on the individual. Yet, the occurrence of this neoplasm shows that at least one Neandertal suffered a common bone tumor found in modern humans. PMID- 23755127 TI - Birth weight, growth and feeding pattern in early infancy predict overweight/obesity status at two years of age: a birth cohort study of Chinese infants. AB - OBJECTIVES: To investigate the early determinants of overweight and obesity status at age two years. METHODS: A total of 1098 healthy neonates (563 boys and 535 girls) were involved in this community-based prospective study in China. Data on body weight and length were collected at birth, the 3(rd) and 24(th) month. A self-administered questionnaire was used to collect data on social demography and feeding patterns of children, etc. Three multivariable logistic regression models were employed to make various comparisons of weight status, i.e., model 1 (obesity vs. non-obesity), model 2 (combined overweight and obesity vs. normal weight, and model 3 (obesity, overweight and normal weight). RESULTS: Prevalences of overweight/obesity (95(th) >BMI >=85(th) p and BMI >=95(th) p, referring to WHO BMI standards) at 2 years of age are 15.8%/11.2% for boys and 12.9%/9.0% for girls, respectively. Being born with macrosomia (OR: 1.80-1.88), relatively greater BMI increment in the first 3 months (OR: 1.15-1.16) and bottle emptying by encouragement at age two (OR: 1.30-1.57) were found in all three models to be significant risk factors for higher BMI status at 2 years. Pre-pregnancy maternal BMI (OR: 1.09-1.12), paternal BMI (OR: 1.06), and mixed breastfeeding (OR: 1.54 1.57) or formula feeding (OR: 1.90-1.93) in the first month were identified as significant in models 2 and 3. Child-initiated bottle emptying at age two was observed to increase the risk of obesity by 1.31 times but only in model 1. CONCLUSION: Fetal and early postnatal growth and feeding pattern appear to have significant impacts on early childhood overweight and obesity status independent of parental BMI. Policy-based and multidisciplinary approaches to promote breastfeeding and enhancement of feeding skills of care takers may be promising intervention strategies. PMID- 23755128 TI - Connectivity-based parcellation of the thalamus explains specific cognitive and behavioural symptoms in patients with bilateral thalamic infarct. AB - A novel approach based on diffusion tractography was used here to characterise the cortico-thalamic connectivity in two patients, both presenting with an isolated bilateral infarct in the thalamus, but exhibiting partially different cognitive and behavioural profiles. Both patients (G.P. and R.F.) had a pervasive deficit in episodic memory, but only one of them (R.F.) suffered also from a dysexecutive syndrome. Both patients had an MRI scan at 3T, including a T1 weighted volume. Their lesions were manually segmented. T1-volumes were normalised to standard space, and the same transformations were applied to the lesion masks. Nineteen healthy controls underwent a diffusion-tensor imaging (DTI) scan. Their DTI data were normalised to standard space and averaged. An atlas of Brodmann areas was used to parcellate the prefrontal cortex. Probabilistic tractography was used to assess the probability of connection between each voxel of the thalamus and a set of prefrontal areas. The resulting map of corticothalamic connections was superimposed onto the patients' lesion masks, to assess whether the location of the thalamic lesions in R.F. (but not in G. P.) implied connections with prefrontal areas involved in dysexecutive syndromes. In G.P., the lesion fell within areas of the thalamus poorly connected with prefrontal areas, showing only a modest probability of connection with the anterior cingulate cortex (ACC). Conversely, R.F.'s lesion fell within thalamic areas extensively connected with the ACC bilaterally, with the right dorsolateral prefrontal cortex, and with the left supplementary motor area. Despite a similar, bilateral involvement of the thalamus, the use of connectivity-based segmentation clarified that R.F.'s lesions only were located within nuclei highly connected with the prefrontal cortical areas, thus explaining the patient's frontal syndrome. This study confirms that DTI tractography is a useful tool to examine in vivo the effect of focal lesions on interconnectivity brain patterns. PMID- 23755129 TI - Courtship sounds advertise species identity and male quality in sympatric Pomatoschistus spp. gobies. AB - Acoustic signals can encode crucial information about species identity and individual quality. We recorded and compared male courtship drum sounds of the sand goby Pomatoschistus minutus and the painted goby P. pictus and examined if they can function in species recognition within sympatric populations. We also examined which acoustic features are related to male quality and the factors that affect female courtship in the sand goby, to determine whether vocalisations potentially play a role in mate assessment. Drums produced by the painted goby showed significantly higher dominant frequencies, higher sound pulse repetition rates and longer intervals between sounds than those of the sand goby. In the sand goby, male quality was predicted by visual and acoustic courtship signals. Regression analyses showed that sound amplitude was a good predictor of male length, whereas the duration of nest behaviour and active calling rate (i.e. excluding silent periods) were good predictors of male condition factor and fat reserves respectively. In addition, the level of female courtship was predicted by male nest behaviour. The results suggest that the frequency and temporal patterns of sounds can encode species identity, whereas sound amplitude and calling activity reflects male size and fat reserves. Visual courtship duration (nest-related behaviour) also seems relevant to mate choice, since it reflects male condition and is related to female courtship. Our work suggests that acoustic communication can contribute to mate choice in the sand goby group, and invites further study. PMID- 23755130 TI - Impact of cagPAI and T4SS on the inflammatory response of human neutrophils to Helicobacter pylori infection. AB - Helicobacter pylori contains a pathogenicity island, cagPAI, with genes homologous to components of the type IV secretion system (T4SS) of Agrobacterium tumefaciens. The T4SS components assemble a structure that transfers CagA protein and peptidoglycan into host epithelial cells, causing the increased release of interleukin 8 (IL8) from the cells. The Toll-like receptors on neutrophils recognize H. pylori, initiating signaling pathways that enhance the activation of NF-kappaB. However, the roles of cagPAI and T4SS in the inflammatory response of neutrophils are unknown. We evaluated the participation of cagPAI and T4SS in the response of human neutrophils to H. pylori infection. Neutrophils were isolated from the blood of healthy donors and infected with H. pylori cagPAI(+), cagPAI( ), and cagPAI mutant strains virB4 (-) and virD4 (-). Whereas cagPAI(+) strain 26695 induced the greatest IL8 production, a proinflammatory response, cagPAI(-) strain 8822 induced the greatest IL10 production, an anti-inflammatory response. In contrast, the virB4 (-) and virD4 (-) mutant strains produced significantly more of the two proinflammatory cytokines IL1beta and tumor necrosis factor alphathan the cagPAI(+) strain 26695. We observed that H. pylori downregulated the expression of TLRs 2 and 5 but upregulated TLR9 expression in a cagPAI and T4SS-independent manner. These results show for the first time that the response of human neutrophils to H. pylori may vary from a pro-inflammatory to an anti inflammatory response, depending on cagPAI and the integrity of T4SS. PMID- 23755131 TI - Complex multi-block analysis identifies new immunologic and genetic disease progression patterns associated with the residual beta-cell function 1 year after diagnosis of type 1 diabetes. AB - The purpose of the present study is to explore the progression of type 1 diabetes (T1D) in Danish children 12 months after diagnosis using Latent Factor Modelling. We include three data blocks of dynamic paraclinical biomarkers, baseline clinical characteristics and genetic profiles of diabetes related SNPs in the analyses. This method identified a model explaining 21.6% of the total variation in the data set. The model consists of two components: (1) A pattern of declining residual beta-cell function positively associated with young age, presence of diabetic ketoacidosis and long duration of disease symptoms (P = 0.0004), and with risk alleles of WFS1, CDKN2A/2B and RNLS (P = 0.006). (2) A second pattern of high ZnT8 autoantibody levels and low postprandial glucagon levels associated with risk alleles of IFIH1, TCF2, TAF5L, IL2RA and PTPN2 and protective alleles of ERBB3 gene (P = 0.0005). These results demonstrate that Latent Factor Modelling can identify associating patterns in clinical prospective data--future functional studies will be needed to clarify the relevance of these patterns. PMID- 23755132 TI - Systemic blockade of dopamine D2-like receptors increases high-voltage spindles in the globus pallidus and motor cortex of freely moving rats. AB - High-voltage spindles (HVSs) have been reported to appear spontaneously and widely in the cortical-basal ganglia networks of rats. Our previous study showed that dopamine depletion can significantly increase the power and coherence of HVSs in the globus pallidus (GP) and motor cortex of freely moving rats. However, it is unclear whether dopamine regulates HVS activity by acting on dopamine D1 like receptors or D2-like receptors. We employed local-field potential and electrocorticogram methods to simultaneously record the oscillatory activities in the GP and primary motor cortex (M1) in freely moving rats following systemic administration of dopamine receptor antagonists or saline. The results showed that the dopamine D2-like receptor antagonists, raclopride and haloperidol, significantly increased the number and duration of HVSs, and the relative power associated with HVS activity in the GP and M1 cortex. Coherence values for HVS activity between the GP and M1 cortex area were also significantly increased by dopamine D2-like receptor antagonists. On the contrary, the selective dopamine D1 like receptor antagonist, SCH23390, had no significant effect on the number, duration, or relative power of HVSs, or HVS-related coherence between M1 and GP. In conclusion, dopamine D2-like receptors, but not D1-like receptors, were involved in HVS regulation. This supports the important role of dopamine D2-like receptors in the regulation of HVSs. An siRNA knock-down experiment on the striatum confirmed our conclusion. PMID- 23755134 TI - Central nervous system pathology progresses independently of KC and CXCR2 in globoid-cell leukodystrophy. AB - Globoid-cell Leukodystrophy (GLD; Krabbe's disease) is a rapidly progressing inherited demyelinating disease caused by a deficiency of the lysosomal enzyme Galactosylceramidase (GALC). Deficiency of GALC leads to altered catabolism of galactosylceramide and the cytotoxic lipid, galactosylsphingosine (psychosine). This leads to a rapidly progressive fatal disease with spasticity, cognitive disability and seizures. The murine model of GLD (Twitcher; GALC-/-) lacks the same enzyme and has similar clinical features. The deficiency of GALC leads to oligodendrocyte death, profound neuroinflammation, and the influx of activated macrophages into the CNS. We showed previously that keratinocyte chemoattractant factor (KC) is highly elevated in the CNS of untreated Twitcher mice and significantly decreases after receiving a relatively effective therapy (bone marrow transplantation combined with gene therapy). The action of KC is mediated through the CXCR2 receptor and is a potent chemoattractant for macrophages and microglia. KC is also involved in oligodendrocyte migration and proliferation. Based on the commonalities between the disease presentation and the functions of KC, we hypothesized that KC and/or CXCR2 contribute to the pathogenesis of GLD. Interestingly, the course of the disease is not significantly altered in KC- or CXCR2-deficient Twitcher mice. There is also no alteration in inflammation or demyelination patterns in these mice. Furthermore, transplantation of CXCR2 deficient bone marrow does not alter the progression of the disease as it does in other models of demyelination. This study highlights the role of multiple redundant cytokines and growth factors in the pathogenesis of GLD. PMID- 23755135 TI - Whole-exome sequencing enables rapid determination of xeroderma pigmentosum molecular etiology. AB - Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by extreme sensitivity to actinic pigmentation changes in the skin and increased incidence of skin cancer. In some cases, patients are affected by neurological alterations. XP is caused by mutations in 8 distinct genes (XPA through XPG and XPV). The XP-V (variant) subtype of the disease results from mutations in a gene (XPV, also named POLH) which encodes for Poleta, a member of the Y-DNA polymerase family. Although the presence and severity of skin and neurological dysfunctions differ between XP subtypes, there are overlapping clinical features among subtypes such that the sub-type cannot be deduced from the clinical features. In this study, in order to overcome this drawback, we undertook whole-exome sequencing in two XP sibs and their father. We identified a novel homozygous nonsense mutation (c.897T>G, p.Y299X) in POLH which causes the disease. Our results demonstrate that next generation sequencing is a powerful approach to rapid determination of XP genetic etiology. PMID- 23755136 TI - A novel approach for lie detection based on F-score and extreme learning machine. AB - A new machine learning method referred to as F-score_ELM was proposed to classify the lying and truth-telling using the electroencephalogram (EEG) signals from 28 guilty and innocent subjects. Thirty-one features were extracted from the probe responses from these subjects. Then, a recently-developed classifier called extreme learning machine (ELM) was combined with F-score, a simple but effective feature selection method, to jointly optimize the number of the hidden nodes of ELM and the feature subset by a grid-searching training procedure. The method was compared to two classification models combining principal component analysis with back-propagation network and support vector machine classifiers. We thoroughly assessed the performance of these classification models including the training and testing time, sensitivity and specificity from the training and testing sets, as well as network size. The experimental results showed that the number of the hidden nodes can be effectively optimized by the proposed method. Also, F score_ELM obtained the best classification accuracy and required the shortest training and testing time. PMID- 23755137 TI - Mother to Mother (M2M) peer support for women in Prevention of Mother to Child Transmission (PMTCT) programmes: a qualitative study. AB - INTRODUCTION: Mother-to-Mother (M2M) or "Mentor Mother" programmes utilise HIV positive mothers to provide support and advice to HIV positive pregnant women and mothers of HIV exposed babies. Medecins Sans Frontieres (MSF) supported a Mentor Mother programme in Bulawayo, Zimbabwe from 2009 to 2012; with programme beneficiaries observed to have far higher retention at 6-8 weeks (99% vs 50%, p<0.0005) and to have higher adherence to Prevention of Mother to Child Transmission (PMTCT) guidelines, compared to those not opting in. In this study we explore how the M2M progamme may have contributed to these findings. METHODS: In this qualitative study we used thematic analysis of in-depth interviews (n = 79). This study was conducted in 2 urban districts of Bulawayo, Zimbabwe's second largest city. RESULTS: Interviews were completed by 14 mentor mothers, 10 mentor mother family members, 30 beneficiaries (women enrolled both in PMTCT and M2M), 10 beneficiary family members, 5 women enrolled in PMTCT but who had declined to take part in the M2M programme and 10 health care staff members. All beneficiaries and health care staff reported that the programme had improved retention and provided rich information on how this was achieved. Additionally respondents described how the programme had helped bring about beneficial behaviour change. CONCLUSIONS: M2M programmes offer great potential to empower communities affected by HIV to catalyse positive behaviour change. Our results illustrate how M2M involvement may increase retention in PMTCT programmes. Non disclosure to one's partner, as well as some cultural practices prevalent in Zimbabwe appear to be major barriers to participation in M2M programmes. PMID- 23755138 TI - Serum resistin, cardiovascular disease and all-cause mortality in patients with type 2 diabetes. AB - BACKGROUND: High serum resistin has been associated with increased risk of cardiovascular disease in the general population, Only sparse and conflicting results, limited to Asian individuals, have been reported, so far, in type 2 diabetes. We studied the role of serum resistin on coronary artery disease, major cardiovascular events and all-cause mortality in type 2 diabetes. METHODS: We tested the association of circulating resistin concentrations with coronary artery disease, major cardiovascular events (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) and all-cause mortality in 2,313 diabetic patients of European ancestry from two cross-sectional and two prospective studies. In addition, the expression of resistin gene (RETN) was measured in blood cells of 68 diabetic patients and correlated with their serum resistin levels. RESULTS: In a model comprising age, sex, smoking habits, BMI, HbA1c, and insulin, antihypertensive and antidyslipidemic therapies, serum resistin was associated with coronary artery disease in both cross-sectional studies: OR (95%CI) per SD increment = 1.35 (1.10-1.64) and 1.99 (1.55-2.55). Additionally, serum resistin predicted incident major cardiovascular events (HR per SD increment = 1.31; 1.10-1.56) and all-cause mortality (HR per SD increment = 1.16; 1.06-1.26). Adjusting also for fibrinogen levels affected the association with coronary artery disease and incident cardiovascular events, but not that with all cause-mortality. Finally, serum resistin was positively correlated with RETN mRNA expression (rho = 0.343). CONCLUSIONS: This is the first study showing that high serum resistin (a likely consequence, at least partly, of increased RETN expression) is a risk factor for cardiovascular disease and all-cause mortality in diabetic patients of European ancestry. PMID- 23755139 TI - Mortality attributable to seasonal and pandemic influenza, Australia, 2003 to 2009, using a novel time series smoothing approach. AB - BACKGROUND: Official statistics under-estimate influenza deaths. Time series methods allow the estimation of influenza-attributable mortality. The methods often model background, non-influenza mortality using a cyclic, harmonic regression model based on the Serfling approach. This approach assumes that the seasonal pattern of non-influenza mortality is the same each year, which may not always be accurate. AIM: To estimate Australian seasonal and pandemic influenza attributable mortality from 2003 to 2009, and to assess a more flexible influenza mortality estimation approach. METHODS: We used a semi-parametric generalized additive model (GAM) to replace the conventional seasonal harmonic terms with a smoothing spline of time ('spline model') to estimate influenza-attributable respiratory, respiratory and circulatory, and all-cause mortality in persons aged <65 and >= 65 years. Influenza A(H1N1)pdm09, seasonal influenza A and B virus laboratory detection time series were used as independent variables. Model fit and estimates were compared with those of a harmonic model. RESULTS: Compared with the harmonic model, the spline model improved model fit by up to 20%. In <65 year-olds, the estimated respiratory mortality attributable to pandemic influenza A(H1N1)pdm09 was 0.5 (95% confidence interval (CI), 0.3, 0.7) per 100,000; similar to that of the years with the highest seasonal influenza A mortality, 2003 and 2007 (A/H3N2 years). In >= 65 year-olds, the highest annual seasonal influenza A mortality estimate was 25.8 (95% CI 22.2, 29.5) per 100,000 in 2003, five-fold higher than the non-statistically significant 2009 pandemic influenza estimate in that age group. Seasonal influenza B mortality estimates were negligible. CONCLUSIONS: The spline model achieved a better model fit. The study provides additional evidence that seasonal influenza, particularly A/H3N2, remains an important cause of mortality in Australia and that the epidemic of pandemic influenza A (H1N1)pdm09 virus in 2009 did not result in mortality greater than seasonal A/H3N2 influenza mortality, even in younger age groups. PMID- 23755133 TI - Transcriptomic analysis of cadmium stress response in the heavy metal hyperaccumulator Sedum alfredii Hance. AB - The Sedum alfredii Hance hyperaccumulating ecotype (HE) has the ability to hyperaccumulate cadmium (Cd), as well as zinc (Zn) and lead (Pb) in above-ground tissues. Although many physiological studies have been conducted with these plants, the molecular mechanisms underlying their hyper-tolerance to heavy metals are largely unknown. Here we report on the generation of 9.4 gigabases of adaptor trimmed raw sequences and the assembly of 57,162 transcript contigs in S. alfredii Hance (HE) shoots by the combination of Roche 454 and Illumina/Solexa deep sequencing technologies. We also have functionally annotated the transcriptome and analyzed the transcriptome changes upon Cd hyperaccumulation in S. alfredii Hance (HE) shoots. There are 110 contigs and 123 contigs that were up regulated (Fold Change >= 2.0) and down-regulated (Fold Change 120 PWID per 10,000 youth in 2006-2007. CONCLUSIONS: Overall, PWID rates remained constant since 2002, but increased for two subpopulations: non-Hispanic black PWID and young PWID. Estimates of PWID are important for planning and evaluating public health programs to reduce harm among PWID and for understanding related trends in social and health outcomes. PMID- 23755144 TI - High levels of asymmetric dimethylarginine are strongly associated with low HDL in patients with acute myocardial infarction. AB - OBJECTIVES: Low levels of high-density lipoprotein (HDL) cholesterol are associated with an increased risk of acute myocardial infarction possibly through impaired endothelial atheroprotection and decreased nitric oxide (NO) bioavailability. Asymmetric dimethylarginine (ADMA) mediates endothelial function by inhibiting nitric oxide synthase activity. In patients with acute myocardial infarction, we investigated the relationship between serum levels of HDL and ADMA. APPROACH AND RESULTS: Blood samples from 612 consecutive patients hospitalized for acute MI <24 hours after symptom onset were taken on admission. Serum levels of ADMA, its stereoisomer, symmetric dimethylarginine (SDMA) and L arginine were determined using high-performance liquid chromatography. Patients with low HDL (<40 mg/dL for men and <50 mg/dL for women) were compared with patients with higher HDL. Most patients (59%) had low HDL levels. Median ADMA levels were markedly higher in the low HDL group (0.69 vs. 0.50 umole/L, p<0.001). In contrast, SDMA and L-arginine levels were similar for the two groups (p = 0.120 and p = 0.064). Notably, ADMA, but not SDMA or L-arginine, was inversely correlated with HDL (r = -0.311, p<0.001). In stratified analysis, this relationship was only found for low HDL levels (r = -0.265, p<0.001), but not when HDL levels were higher (r = -0.077, p = 0.225). By multivariate logistic regression analysis, ADMA level was strongly associated with low HDL levels (OR(95%CI):6.06(3.48-10.53), p<0.001), beyond traditional confounding factors. CONCLUSIONS: Our large population-based study showed for the first time a strong inverse relationship between HDL and ADMA in myocardial infarction patients, suggesting a functional interaction between HDL and endothelium, beyond metabolic conditions associated with low HDL levels. PMID- 23755146 TI - Foraging ecology predicts learning performance in insectivorous bats. AB - Bats are unusual among mammals in showing great ecological diversity even among closely related species and are thus well suited for studies of adaptation to the ecological background. Here we investigate whether behavioral flexibility and simple- and complex-rule learning performance can be predicted by foraging ecology. We predict faster learning and higher flexibility in animals hunting in more complex, variable environments than in animals hunting in more simple, stable environments. To test this hypothesis, we studied three closely related insectivorous European bat species of the genus Myotis that belong to three different functional groups based on foraging habitats: M. capaccinii, an open water forager, M. myotis, a passive listening gleaner, and M. emarginatus, a clutter specialist. We predicted that M. capaccinii would show the least flexibility and slowest learning reflecting its relatively unstructured foraging habitat and the stereotypy of its natural foraging behavior, while the other two species would show greater flexibility and more rapid learning reflecting the complexity of their natural foraging tasks. We used a purposefully unnatural and thus species-fair crawling maze to test simple- and complex-rule learning, flexibility and re-learning performance. We found that M. capaccinii learned a simple rule as fast as the other species, but was slower in complex rule learning and was less flexible in response to changes in reward location. We found no differences in re-learning ability among species. Our results corroborate the hypothesis that animals' cognitive skills reflect the demands of their ecological niche. PMID- 23755145 TI - Effects of chronic swimming training and oestrogen therapy on coronary vascular reactivity and expression of antioxidant enzymes in ovariectomized rats. AB - The aim of this study was to evaluate the effects of swimming training (SW) and oestrogen replacement therapy (ERT) on coronary vascular reactivity and the expression of antioxidant enzymes in ovariectomized rats. Animals were randomly assigned to one of five groups: sham (SH), ovariectomized (OVX), ovariectomized with E2 (OE2), ovariectomized with exercise (OSW), and ovariectomized with E2 plus exercise (OE2+SW). The SW protocol (5*/week, 60 min/day) and/or ERT were conducted for 8 weeks; the vasodilator response to bradykinin was analysed (Langendorff Method), and the expression of antioxidant enzymes (SOD-1 and 2, catalase) and eNOS and iNOS were evaluated by Western blotting. SW and ERT improved the vasodilator response to the highest dose of bradykinin (1000 ng). However, in the OSW group, this response was improved at 100, 300 and 1000 ng when compared to OVX (p<0,05). The SOD-1 expression was increased in all treated/trained groups compared to the OVX group (p<0,05), and catalase expression increased in the OSW group only. In the trained group, eNOS increased vs. OE2, and iNOS decreased vs. SHAM (p<0,05). SW may represent an alternative to ERT by improving coronary vasodilation, most likely by increasing antioxidant enzyme and eNOS expression and augmenting NO bioavailability. PMID- 23755147 TI - Effect of single amino acid substitution observed in cancer on Pim-1 kinase thermodynamic stability and structure. AB - Pim-1 kinase, a serine/threonine protein kinase encoded by the pim proto oncogene, is involved in several signalling pathways such as the regulation of cell cycle progression and apoptosis. Many cancer types show high expression levels of Pim kinases and particularly Pim-1 has been linked to the initiation and progression of the malignant phenotype. In several cancer tissues somatic Pim 1 mutants have been identified. These natural variants are nonsynonymous single nucleotide polymorphisms, variations of a single nucleotide occurring in the coding region and leading to amino acid substitutions. In this study we investigated the effect of amino acid substitution on the structural stability and on the activity of Pim-1 kinase. We expressed and purified some of the mutants of Pim-1 kinase that are expressed in cancer tissues and reported in the single nucleotide polymorphisms database. The point mutations in the variants significantly affect the conformation of the native state of Pim-1. All the mutants, expressed as soluble recombinant proteins, show a decreased thermal and thermodynamic stability and a lower activation energy values for kinase activity. The decreased stability accompanied by an increased flexibility suggests that Pim 1 variants may be involved in a wider network of protein interactions. All mutants bound ATP and ATP mimetic inhibitors with comparable IC50 values suggesting that the studied Pim-1 kinase mutants can be efficiently targeted with inhibitors developed for the wild type protein. PMID- 23755148 TI - Sex-biased sound symbolism in english-language first names. AB - Sexual selection has resulted in sex-based size dimorphism in many mammals, including humans. In Western societies, average to taller stature men and comparatively shorter, slimmer women have higher reproductive success and are typically considered more attractive. This size dimorphism also extends to vocalisations in many species, again including humans, with larger individuals exhibiting lower formant frequencies than smaller individuals. Further, across many languages there are associations between phonemes and the expression of size (e.g. large /a, o/, small /i, e/), consistent with the frequency-size relationship in vocalisations. We suggest that naming preferences are a product of this frequency-size relationship, driving male names to sound larger and female names smaller, through sound symbolism. In a 10-year dataset of the most popular British, Australian and American names we show that male names are significantly more likely to contain larger sounding phonemes (e.g. "Thomas"), while female names are significantly more likely to contain smaller phonemes (e.g. "Emily"). The desire of parents to have comparatively larger, more masculine sons, and smaller, more feminine daughters, and the increased social success that accompanies more sex-stereotyped names, is likely to be driving English-language first names to exploit sound symbolism of size in line with sexual body size dimorphism. PMID- 23755149 TI - alphanu and beta1 Integrins mediate Abeta-induced neurotoxicity in hippocampal neurons via the FAK signaling pathway. AB - alphanu and beta1 integrins mediate Abeta-induced neurotoxicity in primary hippocampal neurons. We treated hippocampal neurons with 2.5 ug/mL 17E6 and 5 ug/mL ab58524, which are specific alphanu and beta1 integrin antagonists, respectively, for 42 h prior to 10 uM Abeta treatment. Next, we employed small interfering RNA (siRNA) to silence focal adhesion kinase (FAK), a downstream target gene of integrins. The siRNAs were designed with a target sequence, an MOI of 10 and the addition of 5 ug/mL polybrene. Under these conditions, the neurons were transfected and the apoptosis of different cell types was detected. Moreover, we used real-time PCR and Western blotting analyses to detect the expression of FAK and rhoFAK genes in different cell types and investigated the underlying mechanism and signal pathway by which alphanu and beta1 integrins mediate Abeta-induced neurotoxicity in hippocampal neurons. An MTT assay showed that both 17E6 and ab58524 significantly increased cell viability compared with the Abeta-treated neurons (P<0.01 and P<0.05, respectively). However, this protective effect was markedly attenuated after transfection with silencing FAK (siFAK). Moreover, TUNEL immunostaining and flow cytometry indicated that both 17E6 and ab58524 significantly protected hippocampal neurons against apoptosis induced by Abeta (P<0.05) compared with the Abeta-treated cells. However, this protective effect was reversed with siFAK treatment. Both the gene and protein expression of FAK increased after Abeta treatment. Interestingly, as the gene and protein levels of FAK decreased, the rhoFAK protein expression markedly increased. Furthermore, both the gene and protein expression of FAK and rhoFAK were significantly diminished. Thus, we concluded that both alphanu and beta1 integrins interfered with Abeta-induced neurotoxicity in hippocampal neurons and that this mechanism partially contributes to the activation of the Integrin-FAK signaling pathway. PMID- 23755150 TI - Kidney specific protein-positive cells derived from embryonic stem cells reproduce tubular structures in vitro and differentiate into renal tubular cells. AB - Embryonic stem cells and induced pluripotent stem cells have the ability to differentiate into various organs and tissues, and are regarded as new tools for the elucidation of disease mechanisms as well as sources for regenerative therapies. However, a method of inducing organ-specific cells from pluripotent stem cells is urgently needed. Although many scientists have been developing methods to induce various organ-specific cells from pluripotent stem cells, renal lineage cells have yet to be induced in vitro because of the complexity of kidney structures and the diversity of kidney-component cells. Here, we describe a method of inducing renal tubular cells from mouse embryonic stem cells via the cell purification of kidney specific protein (KSP)-positive cells using an anti KSP antibody. The global gene expression profiles of KSP-positive cells derived from ES cells exhibited characteristics similar to those of cells in the developing kidney, and KSP-positive cells had the capacity to form tubular structures resembling renal tubular cells when grown in a 3D culture in Matrigel. Moreover, our results indicated that KSP-positive cells acquired the characteristics of each segment of renal tubular cells through tubular formation when stimulated with Wnt4. This method is an important step toward kidney disease research using pluripotent stem cells, and the development of kidney regeneration therapies. PMID- 23755151 TI - Platelet activation determines angiopoietin-1 and VEGF levels in malaria: implications for their use as biomarkers. AB - INTRODUCTION: The angiogenic proteins angiopoietin (Ang)-1, Ang-2 and vascular endothelial growth factor (VEGF) are regulators of endothelial inflammation and integrity. Since platelets store large amounts of Ang-1 and VEGF, measurement of circulation levels of these proteins is sensitive to platelet number, in vivo platelet activation and inadvertent platelet activation during blood processing. We studied plasma Ang-1, Ang-2 and VEGF levels in malaria patients, taking the necessary precautions to avoid ex vivo platelet activation, and related plasma levels to platelet count and the soluble platelet activation markers P-selectin and CXCL7. METHODS: Plasma levels of Ang-1, Ang-2, VEGF, P-selectin and CXCL7 were measured in CTAD plasma, minimizing ex vivo platelet activation, in 27 patients with febrile Plasmodium falciparum malaria at presentation and day 2 and 5 of treatment and in 25 healthy controls. RESULTS: Levels of Ang-1, Ang-2 and VEGF were higher at day 0 in malaria patients compared to healthy controls. Ang-2 levels, which is a marker of endothelial activation, decreased after start of antimalarial treatment. In contrast, Ang-1 and VEGF plasma levels increased and this corresponded with the increase in platelet number. Soluble P-selectin and CXCL7 levels followed the same trend as Ang-1 and VEGF levels. Plasma levels of these four proteins correlated strongly in malaria patients, but only moderately in controls. CONCLUSION: In contrast to previous studies, we found elevated plasma levels of Ang-1 and VEGF in patients with malaria resulting from in vivo platelet activation. Ang-1 release from platelets may be important to dampen the disturbing effects of Ang-2 on the endothelium. Evaluation of plasma levels of these angiogenic proteins requires close adherence to a stringent protocol to minimize ex vivo platelet activation. PMID- 23755152 TI - Higher isolation of NDM-1 producing Acinetobacter baumannii from the sewage of the hospitals in Beijing. AB - Multidrug resistant microbes present in the environment are a potential public health risk. In this study, we investigate the presence of New Delhi metallo-beta lactamase 1 (NDM-1) producing bacteria in the 99 water samples in Beijing City, including river water, treated drinking water, raw water samples from the pools and sewage from 4 comprehensive hospitals. For the bla NDM-1 positive isolate, antimicrobial susceptibility testing was further analyzed, and Pulsed Field Gel Electrophoresis (PFGE) was performed to determine the genetic relationship among the NDM-1 producing isolates from sewage and human, as well as the clinical strains without NDM-1. The results indicate that there was a higher isolation of NDM-1 producing Acinetobacter baumannii from the sewage of the hospitals, while no NDM-1 producing isolates were recovered from samples obtained from the river, drinking, or fishpond water. Surprisingly, these isolates were markedly different from the clinical isolates in drug resistance and pulsed field gel electrophoresis profiles, suggesting different evolutionary relationships. Our results showed that the hospital sewage may be one of the diffusion reservoirs of NDM-1 producing bacteria. PMID- 23755153 TI - The effect of antineoplastic drugs in a male spontaneous mammary tumor model. AB - Male breast cancer is a rare disease. The limited number of clinical cases has led to the primary treatments for men being derived from female breast cancer studies. Here the transgenic strain FVB/N-Tg(MMTV-PyVT)634Mul/J (also known as PyVT) was used as a model system for measuring tumor burden and drug sensitivity of the antineoplastic drugs tamoxifen, cisplatin, and paclitaxel on tumorigenesis at an early stage of mammary carcinoma development in a male mouse model. Cisplatin treatment significantly reduced tumor volume, while paclitaxel and tamoxifen did not attenuate tumor growth. Cisplatin treatment was shown to induce apoptosis, grossly observed by reduced tumor formation, through reduced Bcl-2 and survivin protein expression levels with an increase in caspase 3 expression compared to control tumors. Tamoxifen treatment significantly altered the hormone receptor expression levels of the tumor, while additionally upregulating Bcl-2 and Cyclin D1. This suggests an importance in hormonal signaling in male breast cancer pathogenesis. The results of this study provide valuable information toward the better understanding of male breast cancer and may help guide treatment decisions. PMID- 23755155 TI - Genetically modified crops and food security. AB - The role of genetically modified (GM) crops for food security is the subject of public controversy. GM crops could contribute to food production increases and higher food availability. There may also be impacts on food quality and nutrient composition. Finally, growing GM crops may influence farmers' income and thus their economic access to food. Smallholder farmers make up a large proportion of the undernourished people worldwide. Our study focuses on this latter aspect and provides the first ex post analysis of food security impacts of GM crops at the micro level. We use comprehensive panel data collected over several years from farm households in India, where insect-resistant GM cotton has been widely adopted. Controlling for other factors, the adoption of GM cotton has significantly improved calorie consumption and dietary quality, resulting from increased family incomes. This technology has reduced food insecurity by 15-20% among cotton-producing households. GM crops alone will not solve the hunger problem, but they can be an important component in a broader food security strategy. PMID- 23755154 TI - The cell wall-targeting antibiotic stimulon of Enterococcus faecalis. AB - Enterococcus faecalis is an opportunistic nosocomial pathogen that is highly resistant to a variety of environmental insults, including an intrinsic tolerance to antimicrobials that target the cell wall (CW). With the goal of determining the CW-stress stimulon of E. faecalis, the global transcriptional profile of E. faecalis OG1RF exposed to ampicillin, bacitracin, cephalotin or vancomycin was obtained via microarrays. Exposure to the beta-lactams ampicillin and cephalotin resulted in the fewest transcriptional changes with 50 and 192 genes differentially expressed 60 min after treatment, respectively. On the other hand, treatment with bacitracin or vancomycin for 60 min affected the expression of, respectively, 377 and 297 genes. Despite the differences in the total number of genes affected, all antibiotics induced a very similar gene expression pattern with an overrepresentation of genes encoding hypothetical proteins, followed by genes encoding proteins associated with cell envelope metabolism as well as transport and binding proteins. In particular, all drug treatments, most notably bacitracin and vancomycin, resulted in an apparent metabolic downshift based on the repression of genes involved in translation, energy metabolism, transport and binding. Only 19 genes were up-regulated by all conditions at both the 30 and 60 min time points. Among those 19 genes, 4 genes encoding hypothetical proteins (EF0026, EF0797, EF1533 and EF3245) were inactivated and the respective mutant strains characterized in relation to antibiotic tolerance and virulence in the Galleria mellonella model. The phenotypes obtained for two of these mutants, DeltaEF1533 and DeltaEF3245, support further characterization of these genes as potential candidates for the development of novel preventive or therapeutic approaches. PMID- 23755156 TI - Enhancing protein adsorption simulations by using accelerated molecular dynamics. AB - The atomistic modeling of protein adsorption on surfaces is hampered by the different time scales of the simulation ([Formula: see text][Formula: see text]s) and experiment (up to hours), and the accordingly different 'final' adsorption conformations. We provide evidence that the method of accelerated molecular dynamics is an efficient tool to obtain equilibrated adsorption states. As a model system we study the adsorption of the protein BMP-2 on graphite in an explicit salt water environment. We demonstrate that due to the considerably improved sampling of conformational space, accelerated molecular dynamics allows to observe the complete unfolding and spreading of the protein on the hydrophobic graphite surface. This result is in agreement with the general finding of protein denaturation upon contact with hydrophobic surfaces. PMID- 23755157 TI - Inhibition of UII/UTR system relieves acute inflammation of liver through preventing activation of NF-kappaB pathway in ALF mice. AB - Urotensin II (UII) is implicated in immune inflammatory diseases through its specific high-affinity UT receptor (UTR). Enhanced expression of UII/UTR was recently demonstrated in the liver with acute liver failure (ALF). Here, we analysed the relationship between UII/UTR expression and ALF in lipopolysaccharide (LPS)/D-galactosamine (GalN)-challenged mice. Thereafter, we investigated the effects produced by the inhibition of UII/UTR system using urantide, a special antagonist of UTR, and the potential molecular mechanisms involved in ALF. Urantide was administered to mice treated with LPS/GalN. Expression of UII/UTR, releases of proinflammatory cytokines including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta) and interferon gamma (IFN-gamma), and activation of nuclear factor kappaB (NF-kappaB) signaling pathway were assessed in the lethal ALF with or without urantide pretreatment. We found that LPS/GalN-challenged mice showed high mortality and marked hepatic inflammatory infiltration and cell apoptosis as well as a significant increase of UII/UTR expression. Urantide pretreatment protected against the injury in liver following downregulation of UII/UTR expression. A close relationship between the acutely flamed hepatic injury and UII/UTR expression was observed. In addition, urantide prevented the increases of proinflammatory cytokines such as TNF-alpha, IL-1beta and IFN-gamma, and activation of NF-kappaB signaling pathway induced by LPS/GalN in mice. Thus, we conclude that UII/UTR system plays a role in LPS/GalN induced ALF. Urantide has a protective effect on the acutely inflamed injury of liver in part through preventing releases of proinflammatory cytokines and activation of NF-kappaB pathway. PMID- 23755159 TI - Credibility analysis of putative disease-causing genes using bioinformatics. AB - BACKGROUND: Genetic studies are challenging in many complex diseases, particularly those with limited diagnostic certainty, low prevalence or of old age. The result is that genes may be reported as disease-causing with varying levels of evidence, and in some cases, the data may be so limited as to be indistinguishable from chance findings. When there are large numbers of such genes, an objective method for ranking the evidence is useful. Using the neurodegenerative and complex disease amyotrophic lateral sclerosis (ALS) as a model, and the disease-specific database ALSoD, the objective is to develop a method using publicly available data to generate a credibility score for putative disease-causing genes. METHODS: Genes with at least one publication suggesting involvement in adult onset familial ALS were collated following an exhaustive literature search. SQL was used to generate a score by extracting information from the publications and combined with a pathogenicity analysis using bioinformatics tools. The resulting score allowed us to rank genes in order of credibility. To validate the method, we compared the objective ranking with a rank generated by ALS genetics experts. Spearman's Rho was used to compare rankings generated by the different methods. RESULTS: The automated method ranked ALS genes in the following order: TARDBP, FUS, ANG, SPG11, NEFH, OPTN, ALS2, SETX, FIG4, VAPB, DCTN1, TAF15, VCP, DAO. This compared very well to the ranking of ALS genetics experts, with Spearman's Rho of 0.69 (P = 0.009). CONCLUSION: We have presented an automated method for scoring the level of evidence for a gene being disease-causing. In developing the method we have used the model disease ALS, but it could equally be applied to any disease in which there is genotypic uncertainty. PMID- 23755158 TI - Assessing SNP-SNP interactions among DNA repair, modification and metabolism related pathway genes in breast cancer susceptibility. AB - Genome-wide association studies (GWASs) have identified low-penetrance common variants (i.e., single nucleotide polymorphisms, SNPs) associated with breast cancer susceptibility. Although GWASs are primarily focused on single-locus effects, gene-gene interactions (i.e., epistasis) are also assumed to contribute to the genetic risks for complex diseases including breast cancer. While it has been hypothesized that moderately ranked (P value based) weak single-locus effects in GWASs could potentially harbor valuable information for evaluating epistasis, we lack systematic efforts to investigate SNPs showing consistent associations with weak statistical significance across independent discovery and replication stages. The objectives of this study were i) to select SNPs showing single-locus effects with weak statistical significance for breast cancer in a GWAS and/or candidate-gene studies; ii) to replicate these SNPs in an independent set of breast cancer cases and controls; and iii) to explore their potential SNP SNP interactions contributing to breast cancer susceptibility. A total of 17 SNPs related to DNA repair, modification and metabolism pathway genes were selected since these pathways offer a priori knowledge for potential epistatic interactions and an overall role in breast carcinogenesis. The study design included predominantly Caucasian women (2,795 cases and 4,505 controls) from Alberta, Canada. We observed two two-way SNP-SNP interactions (APEX1-rs1130409 and RPAP1-rs2297381; MLH1-rs1799977 and MDM2-rs769412) in logistic regression that conferred elevated risks for breast cancer (P(interaction)<7.3 * 10(-3)). Logic regression identified an interaction involving four SNPs (MBD2-rs4041245, MLH1-rs1799977, MDM2-rs769412, BRCA2-rs1799943) (P(permutation) = 2.4 * 10(-3)). SNPs involved in SNP-SNP interactions also showed single-locus effects with weak statistical significance, while BRCA2-rs1799943 showed stronger statistical significance (P(correlation/trend) = 3.2 * 10(-4)) than the others. These single locus effects were independent of body mass index. Our results provide a framework for evaluating SNPs showing statistically weak but reproducible single locus effects for epistatic effects contributing to disease susceptibility. PMID- 23755160 TI - Differences in the pathogenicity of the p.H723R mutation of the common deafness associated SLC26A4 gene in humans and mice. AB - Mutations in the SLC26A4 gene are a common cause of human hereditary hearing impairment worldwide. Previous studies have demonstrated that different SLC26A4 mutations have different pathogenetic mechanisms. By using a genotype-driven approach, we established a knock-in mouse model (i.e., Slc26a4(tm2Dontuh/tm2Dontuh) mice) homozygous for the common p.H723R mutation in the East Asian population. To verify the pathogenicity of the p.H723R allele in mice, we further generated mice with compound heterozygous mutations (i.e., Slc26a4(tm1Dontuh/tm2Dontuh) ) by intercrossing Slc26a4(+/tm2Dontuh) mice with Slc26a4(tm1Dontuh/tm1Dontuh) mice, which segregated the c.919-2A>G mutation with an abolished Slc26a4 function. Mice were then subjected to audiologic assessments, a battery of vestibular evaluations, inner ear morphological studies, and noise exposure experiments. The results were unexpected; both Slc26a4(tm2Dontuh/tm2Dontuh) and Slc26a4(tm1Dontuh/tm2Dontuh) mice showed normal audiovestibular phenotypes and inner ear morphology, and they did not show significantly higher shifts in hearing thresholds after noise exposure than the wild-type mice. The results indicated not only the p.H723R allele was non pathogenic in mice, but also a single p.H723R allele was sufficient to maintain normal inner ear physiology in heterozygous compound mice. There might be discrepancies in the pathogenicity of specific SLC26A4 mutations in humans and mice; therefore, precautions should be taken when extrapolating the results of animal studies to humans. PMID- 23755161 TI - Remote sensing the phytoplankton seasonal succession of the Red Sea. AB - The Red Sea holds one of the most diverse marine ecosystems, primarily due to coral reefs. However, knowledge on large-scale phytoplankton dynamics is limited. Analysis of a 10-year high resolution Chlorophyll-a (Chl-a) dataset, along with remotely-sensed sea surface temperature and wind, provided a detailed description of the spatiotemporal seasonal succession of phytoplankton biomass in the Red Sea. Based on MODIS (Moderate-resolution Imaging Spectroradiometer) data, four distinct Red Sea provinces and seasons are suggested, covering the major patterns of surface phytoplankton production. The Red Sea Chl-a depicts a distinct seasonality with maximum concentrations seen during the winter time (attributed to vertical mixing in the north and wind-induced horizontal intrusion of nutrient rich water in the south), and minimum concentrations during the summer (associated with strong seasonal stratification). The initiation of the seasonal succession occurs in autumn and lasts until early spring. However, weekly Chl-a seasonal succession data revealed that during the month of June, consistent anti cyclonic eddies transfer nutrients and/or Chl-a to the open waters of the central Red Sea. This phenomenon occurs during the stratified nutrient depleted season, and thus could provide an important source of nutrients to the open waters. Remotely-sensed synoptic observations highlight that Chl-a does not increase regularly from north to south as previously thought. The Northern part of the Central Red Sea province appears to be the most oligotrophic area (opposed to southern and northern domains). This is likely due to the absence of strong mixing, which is apparent at the northern end of the Red Sea, and low nutrient intrusion in comparison with the southern end. Although the Red Sea is considered an oligotrophic sea, sporadic blooms occur that reach mesotrophic levels. The water temperature and the prevailing winds control the nutrient concentrations within the euphotic zone and enable the horizontal transportation of nutrients. PMID- 23755162 TI - Altered regional homogeneity with short-term simulated microgravity and its relationship with changed performance in mental transformation. AB - In order to further the insight into the explanation of changed performance in mental transformation under microgravity, we discuss the change of performance in mental transformation and its relationship with altered regional homogeneity (ReHo) in resting-state brain by using simulated weightlessness model. Twelve male subjects with age between 24 and 31 received resting-state fMRI scan and mental transformation test both in normal condition and immediately after 72 hours -6 degrees head down tilt (HDT). A paired sample t-test was used to test the difference of behavior performance and brain activity between these two conditions. Compare with normal condition, subjects showed a changed performance in mental transformation with short term simulated microgravity and appeared to be falling. Meanwhile, decreased ReHo were found in right inferior frontal gyrus (IFG) and left inferior parietal lobule (IPL) after 72 hours -6 degrees HDT, while increased ReHo were found in bilateral medial frontal gyrus (MFG) and left superior frontal gyrus (SFG) (P<0.05, corrected). Particularly, there was a significant correlation between ReHo values in left IPL and velocity index of mental transformation. Our findings indicate that gravity change may disrupt the function of right IFG and left IPL in the resting-state, among of which functional change in left IPL may contribute to changed abilities of mental transformation. In addition, the enhanced activity of the bilateral MFG and decreased activity of right IFG found in the current study maybe reflect a complementation effect on inhibitory control process. PMID- 23755163 TI - Reduced CTGF expression promotes cell growth, migration, and invasion in nasopharyngeal carcinoma. AB - BACKGROUND: The role of CTGF varies in different types of cancer. The purpose of this study is to investigate the involvement of CTGF in tumor progression and prognosis of human nasopharyngeal carcinoma (NPC). EXPERIMENTAL DESIGN: CTGF expression levels were examined in NPC tissues and cells, nasopharynx (NP) tissues, and NP69 cells. The effects and molecular mechanisms of CTGF expression on cell proliferation, migration, invasion, and cell cycle were also explored. RESULTS: NPC cells exhibited decreased mRNA expression of CTGF compared to immortalized human nasopharyngeal epithelial cell line NP69. Similarly, CTGF was observed to be downregulated in NPC compared to normal tissues at mRNA and protein levels. Furthermore, reduced CTGF was negatively associated with the progression of NPC. Knocking down CTGF expression enhanced the colony formation, cell migration, invasion, and G1/S cell cycle transition. Mechanistic analysis revealed that CTGF suppression activated FAK/PI3K/AKT and its downstream signals regulating the cell cycle, epithelial-mesenchymal transition (EMT) and MMPs. Finally, DNA methylation microarray revealed a lack of hypermethylation at the CTGF promoter, suggesting other mechanisms are associated with suppression of CTGF in NPC. CONCLUSION: Our study demonstrates that reduced expression of CTGF promoted cell proliferation, migration, invasion and cell cycle progression through FAK/PI3K/AKT, EMT and MMP pathways in NPC. PMID- 23755164 TI - Direct look from a predator shortens the risk-assessment time by prey. AB - Decision making process is an important component of information use by animals and has already been studied in natural situations. Decision making takes time, which is expressed as a cost in evolutionary explanations of decision making abilities of animals. However, the duration of information assessment and decision making process has not been measured in a natural situation. Here, we use responses of wild magpies (Pica pica) to predictably approaching humans to demonstrate that, regardless of whether the bird perceived high (decided to fly away) or low (resumed foraging) threat level, the bird assessed the situation faster when approaching humans looked directly at it than when the humans were not directly looking at it. This indicates that prey is able to extract more information about the predator's intentions and to respond sooner when the predator is continuously ("intently") looking at the prey. The results generally illustrate how an increase of information available to an individual leads to a shorter assessment and decision making process, confirming one of central tenets of psychology of information use in a wild bird species in its natural habitat. PMID- 23755165 TI - Dilemma in differentiating between acute osteomyelitis and bone infarction in children with sickle cell disease: the role of ultrasound. AB - BACKGROUND: Distinguishing between acute presentations of osteomyelitis (OM) and vaso-occlusive crisis (VOC) bone infarction in children with sickle cell disease (SCD) remains challenging for clinicians, particularly in culture-negative cases. We examined the combined role of ultrasound scan (USS), C - reactive protein and White blood counts (WCC) in aiding early diagnosis in children with SCD presenting acutely with non-specific symptoms such as bone pain, fever or swelling which are common in acute osteomyelitis or VOC. METHODS: We reviewed the records of all children with SCD who were discharged from our department from October 2003 to December 2010 with a diagnosis of osteomyelitis based on clinical features and the results of radiological and laboratory investigations. A case control group with VOC who were investigated for OM were identified over the same period. RESULTS: In the osteomyelitis group, USS finding of periosteal elevation and/or fluid collection was reported in 76% cases with the first scan (day 0-6). Overall 84% were diagnosed with USS (initial +repeat). 16% had negative USS. With VOC group, USS showed no evidence of fluid collection in 53/58 admissions (91%), none of the repeated USS showed any fluid collection. Mean C-reactive protein (CRP), and white cell count (WCC) were significantly higher in the OM. CONCLUSION: The use of Ultrasound in combination with CRP and WCC is a reliable, cost-effective diagnostic tool for differentiating osteomyelitis from VOC bone infarction in SCD. A repeat ultrasound and/or magnetic resonance imaging (MRI) scan may be is necessary to confirm the diagnosis. PMID- 23755166 TI - Nitrogen cycling responses to mountain pine beetle disturbance in a high elevation whitebark pine ecosystem. AB - Ecological disturbances can significantly affect biogeochemical cycles in terrestrial ecosystems, but the biogeochemical consequences of the extensive mountain pine beetle outbreak in high elevation whitebark pine (WbP) (Pinus albicaulis) ecosystems of western North America have not been previously investigated. Mountain pine beetle attack has driven widespread WbP mortality, which could drive shifts in both the pools and fluxes of nitrogen (N) within these ecosystems. Because N availability can limit forest regrowth, understanding how beetle-induced mortality affects N cycling in WbP stands may be critical to understanding the trajectory of ecosystem recovery. Thus, we measured above- and belowground N pools and fluxes for trees representing three different times since beetle attack, including unattacked trees. Litterfall N inputs were more than ten times higher under recently attacked trees compared to unattacked trees. Soil inorganic N concentrations also increased following beetle attack, potentially driven by a more than two-fold increase in ammonium (NH4+) concentrations in the surface soil organic horizon. However, there were no significant differences in mineral soil inorganic N or soil microbial biomass N concentrations between attacked and unattacked trees, implying that short-term changes in N cycling in response to the initial stages of WbP attack were restricted to the organic horizon. Our results suggest that while mountain pine beetle attack drives a pulse of N from the canopy to the forest floor, changes in litterfall quality and quantity do not have profound effects on soil biogeochemical cycling, at least in the short-term. However, continuous observation of these important ecosystems will be crucial to determining the long-term biogeochemical effects of mountain pine beetle outbreaks. PMID- 23755167 TI - Oral perceptions of fat and taste stimuli are modulated by affect and mood induction. AB - This study examined the impact of three clinical psychological variables (non pathological levels of depression and anxiety, as well as experimentally manipulated mood) on fat and taste perception in healthy subjects. After a baseline orosensory evaluation, 'sad', 'happy' and 'neutral' video clips were presented to induce corresponding moods in eighty participants. Following mood manipulation, subjects rated five different oral stimuli, appearing sweet, umami, sour, bitter, fatty, which were delivered at five different concentrations each. Depression levels were assessed with Beck's Depression Inventory (BDI) and anxiety levels were assessed via the Spielberger's STAI-trait and state questionnaire. Overall, subjects were able to track the concentrations of the stimuli correctly, yet depression level affected taste ratings. First, depression scores were positively correlated with sucrose ratings. Second, subjects with depression scores above the sample median rated sucrose and quinine as more intense after mood induction (positive, negative and neutral). Third and most important, the group with enhanced depression scores did not rate low and high fat stimuli differently after positive or negative mood induction, whereas, during baseline or during the non-emotional neutral condition they rated the fat intensity as increasing with concentration. Consistent with others' prior observations we also found that sweet and bitter stimuli at baseline were rated as more intense by participants with higher anxiety scores and that after positive and negative mood induction, citric acid was rated as stronger tasting compared to baseline. The observation that subjects with mild subclinical depression rated low and high fat stimuli similarly when in positive or negative mood is novel and likely has potential implications for unhealthy eating patterns. This deficit may foster unconscious eating of fatty foods in sub clinical mildly depressed populations. PMID- 23755168 TI - Patients' insight of interpreting prescriptions and drug labels--a cross sectional study. AB - BACKGROUND: Errors in consuming drugs are associated with significant morbidity and mortality, besides an impact on the already overburdened health-care system. Misunderstanding drug labels and prescriptions plays an important role in contributing to adverse drug events. OBJECTIVE: To evaluate abilities to understand prescriptions and drug labels among patients attending tertiary care hospital in Karachi. METHODS: A cross sectional study was conducted at the Aga Khan University Hospital (AKUH), from January to March 2009. After informed consent, 181 adult patients and their healthy attendants were interviewed at AKUH using a standardized questionnaire, which ascertained patient demographics, factors that might increase exposure to health-care personnel as well as the basic knowledge and understanding of prescriptions and drug labels. RESULTS: Out of 181, majority 137(76%) had received graduate or post-graduate degrees. 16 (9%) had received no formal education; of which all were females and 89(84%) of the total females were housewives. Overall, 130(72%) followed only a single doctor's prescription. Majority failed to understand various medical terminologies related to dosage. In the high literacy group, 45(33%) understood once daily OD (p = 0.003), 27(20%) thrice daily TID (p = 0.05), 29(21%) twice daily BD (p = 0.01), 31(23%) thrice daily TDS (p = 0.002) and 43(31%) as needed SOS (p = 0.003) as compared to the group with no formal education, who were unable to comprehend the terms. The most common reason for using more than one prescription was decreased satisfaction with the doctor in 19(39%) and multiple co-morbids as responded by 17(35%) of patients. Knowledge regarding various medical terminologies used for dosage and routes of drug administration were also understood more frequently among the English medium respondents. The elderly identified medicine through color (47%, p<0.001), and were less likely to understand drug indications (p = 0.05) compared to younger subjects. CONCLUSION: Understanding of drug prescriptions is alarmingly low in the community, even amongst the educated. Care givers need to revisit this often ignored aspect of patient care. PMID- 23755169 TI - Inhibition of nuclear factor of activated T-cells (NFAT) suppresses accelerated atherosclerosis in diabetic mice. AB - OBJECTIVE OF THE STUDY: Diabetic patients have a much more widespread and aggressive form of atherosclerosis and therefore, higher risk for myocardial infarction, peripheral vascular disease and stroke, but the molecular mechanisms leading to accelerated damage are still unclear. Recently, we showed that hyperglycemia activates the transcription factor NFAT in the arterial wall, inducing the expression of the pro-atherosclerotic protein osteopontin. Here we investigate whether NFAT activation may be a link between diabetes and atherogenesis. METHODOLOGY AND PRINCIPAL FINDINGS: Streptozotocin (STZ)-induced diabetes in apolipoprotein E(-/-) mice resulted in 2.2 fold increased aortic atherosclerosis and enhanced pro-inflammatory burden, as evidenced by elevated blood monocytes, endothelial activation- and inflammatory markers in aorta, and pro-inflammatory cytokines in plasma. In vivo treatment with the NFAT blocker A 285222 for 4 weeks completely inhibited the diabetes-induced aggravation of atherosclerosis, having no effect in non-diabetic mice. STZ-treated mice exhibited hyperglycemia and higher plasma cholesterol and triglycerides, but these were unaffected by A-285222. NFAT-dependent transcriptional activity was examined in aorta, spleen, thymus, brain, heart, liver and kidney, but only augmented in the aorta of diabetic mice. A-285222 completely blocked this diabetes-driven NFAT activation, but had no impact on the other organs or on splenocyte proliferation or cytokine secretion, ruling out systemic immunosuppression as the mechanism behind reduced atherosclerosis. Instead, NFAT inhibition effectively reduced IL-6, osteopontin, monocyte chemotactic protein 1, intercellular adhesion molecule 1, CD68 and tissue factor expression in the arterial wall and lowered plasma IL-6 in diabetic mice. CONCLUSIONS: Targeting NFAT signaling may be a novel and attractive approach for the treatment of diabetic macrovascular complications. PMID- 23755170 TI - Ketogenic diet improves core symptoms of autism in BTBR mice. AB - Autism spectrum disorders share three core symptoms: impaired sociability, repetitive behaviors and communication deficits. Incidence is rising, and current treatments are inadequate. Seizures are a common comorbidity, and since the 1920's a high-fat, low-carbohydrate ketogenic diet has been used to treat epilepsy. Evidence suggests the ketogenic diet and analogous metabolic approaches may benefit diverse neurological disorders. Here we show that a ketogenic diet improves autistic behaviors in the BTBR mouse. Juvenile BTBR mice were fed standard or ketogenic diet for three weeks and tested for sociability, self directed repetitive behavior, and communication. In separate experiments, spontaneous intrahippocampal EEGs and tests of seizure susceptibility (6 Hz corneal stimulation, flurothyl, SKF83822, pentylenetetrazole) were compared between BTBR and control (C57Bl/6) mice. Ketogenic diet-fed BTBR mice showed increased sociability in a three-chamber test, decreased self-directed repetitive behavior, and improved social communication of a food preference. Although seizures are a common comorbidity with autism, BTBR mice fed a standard diet exhibit neither spontaneous seizures nor abnormal EEG, and have increased seizure susceptibility in just one of four tests. Thus, behavioral improvements are dissociable from any antiseizure effect. Our results suggest that a ketogenic diet improves multiple autistic behaviors in the BTBR mouse model. Therefore, ketogenic diets or analogous metabolic strategies may offer novel opportunities to improve core behavioral symptoms of autism spectrum disorders. PMID- 23755171 TI - The clinical characteristics, carbapenem resistance, and outcome of Acinetobacter bacteremia according to genospecies. AB - BACKGROUND: Few clinical data are available on the relationship between genospecies and outcome of Acinetobacter bacteremia, and the results are inconsistent. We performed this study to evaluate the relationship between genospecies and the outcome of Acinetobacter bacteremia. METHODS: Clinical data from 180 patients who had Acinetobacter bacteremia from 2003 to 2010 were reviewed retrospectively. The genospecies were identified by rpoB gene sequence analysis. The clinical features and outcomes of 90 patients with A. baumannii bacteremia were compared to those of 90 patients with non-baumannii Acinetobacter bacteremia (60 with A. nosocomialis, 17 with Acinetobacter species "close to 13 TU", 11 with A. pittii, and two with A. calcoaceticus). RESULTS: A. baumannii bacteremia was associated with intensive care unit-onset, mechanical ventilation, pneumonia, carbapenem resistance, and higher APACHE II scores, compared to non baumannii Acinetobacter bacteremia (P<0.05). In univariate analyses, age, pneumonia, multidrug resistance, carbapenem resistance, inappropriate empirical antibiotics, higher APACHE II scores, and A. baumannii genospecies were risk factors for mortality (P<0.05). Multivariate analysis revealed A. baumannii genospecies (OR, 3.60; 95% CI, 1.56-8.33), age, pneumonia, and higher APACHE II scores to be independent risk factors for mortality (P<0.05). CONCLUSION: A. baumannii genospecies was an independent risk factor for mortality in patients with Acinetobacter bacteremia. Our results emphasize the importance of correct species identification of Acinetobacter blood isolates. PMID- 23755173 TI - Sleep promotes the extraction of grammatical rules. AB - Grammar acquisition is a high level cognitive function that requires the extraction of complex rules. While it has been proposed that offline time might benefit this type of rule extraction, this remains to be tested. Here, we addressed this question using an artificial grammar learning paradigm. During a short-term memory cover task, eighty-one human participants were exposed to letter sequences generated according to an unknown artificial grammar. Following a time delay of 15 min, 12 h (wake or sleep) or 24 h, participants classified novel test sequences as Grammatical or Non-Grammatical. Previous behavioral and functional neuroimaging work has shown that classification can be guided by two distinct underlying processes: (1) the holistic abstraction of the underlying grammar rules and (2) the detection of sequence chunks that appear at varying frequencies during exposure. Here, we show that classification performance improved after sleep. Moreover, this improvement was due to an enhancement of rule abstraction, while the effect of chunk frequency was unaltered by sleep. These findings suggest that sleep plays a critical role in extracting complex structure from separate but related items during integrative memory processing. Our findings stress the importance of alternating periods of learning with sleep in settings in which complex information must be acquired. PMID- 23755174 TI - Fishers' behaviour in response to the implementation of a Marine Protected Area. AB - Marine Protected Areas (MPAs) have been widely proposed as a fisheries management tool in addition to their conservation purposes. Despite this, few studies have satisfactorily assessed the dynamics of fishers' adaptations to the loss of fishing grounds. Here we used data from before, during and after the implementation of the management plan of a temperate Atlantic multiple-use MPA to examine the factors affecting the spatial and temporal distribution of different gears used by the artisanal fishing fleet. The position of vessels and gear types were obtained by visual surveys and related to spatial features of the marine park. A hotspot analysis was conducted to identify heavily utilized patches for each fishing gear and time period. The contribution of individual vessels to each significant cluster was assessed to better understand fishers' choices. Different fisheries responded differently to the implementation of protection measures, with preferred habitats of target species driving much of the fishers' choices. Within each fishery, individual fishers showed distinct strategies with some operating in a broader area whereas others kept preferred territories. Our findings are based on reliable methods that can easily be applied in coastal multipurpose MPAs to monitor and assess fisheries and fishers responses to different management rules and protection levels. This paper is the first in depth empirical study where fishers' choices from artisanal fisheries were analysed before, during and after the implementation of a MPA, thereby allowing a clearer understanding of the dynamics of local fisheries and providing significant lessons for marine conservation and management of coastal systems. PMID- 23755172 TI - Green tea polyphenols stimulate mitochondrial biogenesis and improve renal function after chronic cyclosporin a treatment in rats. AB - Our previous studies showed that an extract from Camellia sinenesis (green tea), which contains several polyphenols, attenuates nephrotoxicity caused by cyclosporine A (CsA). Since polyphenols are stimulators of mitochondrial biogenesis (MB), this study investigated whether stimulation of MB plays a role in green tea polyphenol protection against CsA renal toxicity. Rats were fed a powdered diet containing green tea polyphenolic extract (0.1%) starting 3 days prior to CsA treatment (25 mg/kg, i.g. daily for 3 weeks). CsA alone decreased renal nuclear DNA-encoded oxidative phosphorylation (OXPHOS) protein ATP synthase beta (AS-beta) by 42%, mitochondrial DNA (mtDNA)-encoded OXPHOS protein NADH dehydrogenase-3 (ND3) by 87% and their associated mRNAs. Mitochondrial DNA copy number was also decreased by 78% by CsA. Immunohistochemical analysis showed decreased cytochrome c oxidase subunit IV (COX-IV), an OXPHOS protein, in tubular cells. Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha, the master regulator of MB, and mitochondrial transcription factor-A (Tfam), the transcription factor that regulates mtDNA replication and transcription, were 42% and 90% lower, respectively, in the kidneys of CsA-treated than in untreated rats. These results indicate suppression of MB by chronic CsA treatment. Green tea polyphenols alone and following CsA increased AS-beta, ND3, COX-IV, mtDNA copy number, PGC-1alpha mRNA and protein, decreased acetylated PGC-1alpha, and increased Tfam mRNA and protein. In association with suppressed MB, CsA increased serum creatinine, caused loss of brush border and dilatation of proximal tubules, tubular atrophy, vacuolization, apoptosis, calcification, and increased neutrophil gelatinase-associated lipocalin expression, leukocyte infiltration, and renal fibrosis. Green tea polyphenols markedly attenuated CsA-induced renal injury and improved renal function. Together, these results demonstrate that green tea polyphenols attenuate CsA-induced kidney injury, at least in part, through the stimulation of MB. PMID- 23755175 TI - Predator-prey interactions shape thermal patch use in a newt larvae-dragonfly nymph model. AB - Thermal quality and predation risk are considered important factors influencing habitat patch use in ectothermic prey. However, how the predator's food requirement and the prey's necessity to avoid predation interact with their respective thermoregulatory strategies remains poorly understood. The recently developed 'thermal game model' predicts that in the face of imminent predation, prey should divide their time equally among a range of thermal patches. In contrast, predators should concentrate their hunting activities towards warmer patches. In this study, we test these predictions in a laboratory setup and an artificial environment that mimics more natural conditions. In both cases, we scored thermal patch use of newt larvae (prey) and free-ranging dragonfly nymphs (predators). Similar effects were seen in both settings. The newt larvae spent less time in the warm patch if dragonfly nymphs were present. The patch use of the dragonfly nymphs did not change as a function of prey availability, even when the nymphs were starved prior to the experiment. Our behavioral observations partially corroborate predictions of the thermal game model. In line with asymmetric fitness pay-offs in predator-prey interactions (the 'life-dinner' principle), the prey's thermal strategy is more sensitive to the presence of predators than vice versa. PMID- 23755176 TI - Proper microtubule structure is vital for timely progression through meiosis in fission yeast. AB - Cells of the fission yeast Schizosaccharomyces pombe normally reproduce by mitotic division in the haploid state. When subjected to nutrient starvation, two haploid cells fuse and undergo karyogamy, forming a diploid cell that initiates meiosis to form four haploid spores. Here, we show that deletion of the mal3 gene, which encodes a homolog of microtubule regulator EB1, produces aberrant asci carrying more than four spores. The mal3 deletion mutant cells have a disordered cytoplasmic microtubule structure during karyogamy and initiate meiosis before completion of karyogamy, resulting in twin haploid meiosis in the zygote. Treatment with anti-microtubule drugs mimics this phenotype. Mutants defective in karyogamy or mutants prone to initiate haploid meiosis exaggerate the phenotype of the mal3 deletion mutant. Our results indicate that proper microtubule structure is required for ordered progression through the meiotic cycle. Furthermore, the results of our study suggest that fission yeast do not monitor ploidy during meiosis. PMID- 23755177 TI - Distinct transcriptional networks in quiescent myoblasts: a role for Wnt signaling in reversible vs. irreversible arrest. AB - Most cells in adult mammals are non-dividing: differentiated cells exit the cell cycle permanently, but stem cells exist in a state of reversible arrest called quiescence. In damaged skeletal muscle, quiescent satellite stem cells re-enter the cell cycle, proliferate and subsequently execute divergent programs to regenerate both post-mitotic myofibers and quiescent stem cells. The molecular basis for these alternative programs of arrest is poorly understood. In this study, we used an established myogenic culture model (C2C12 myoblasts) to generate cells in alternative states of arrest and investigate their global transcriptional profiles. Using cDNA microarrays, we compared G0 myoblasts with post-mitotic myotubes. Our findings define the transcriptional program of quiescent myoblasts in culture and establish that distinct gene expression profiles, especially of tumour suppressor genes and inhibitors of differentiation characterize reversible arrest, distinguishing this state from irreversibly arrested myotubes. We also reveal the existence of a tissue-specific quiescence program by comparing G0 C2C12 myoblasts to isogenic G0 fibroblasts (10T1/2). Intriguingly, in myoblasts but not fibroblasts, quiescence is associated with a signature of Wnt pathway genes. We provide evidence that different levels of signaling via the canonical Wnt pathway characterize distinct cellular states (proliferation vs. quiescence vs. differentiation). Moderate induction of Wnt signaling in quiescence is associated with critical properties such as clonogenic self-renewal. Exogenous Wnt treatment subverts the quiescence program and negatively affects clonogenicity. Finally, we identify two new quiescence-induced regulators of canonical Wnt signaling, Rgs2 and Dkk3, whose induction in G0 is required for clonogenic self-renewal. These results support the concept that active signal-mediated regulation of quiescence contributes to stem cell properties, and have implications for pathological states such as cancer and degenerative disease. PMID- 23755178 TI - Prognostic significance of C-reactive protein polymorphism and KRAS/BRAF in synchronous liver metastasis from colorectal cancer. AB - BACKGROUND: The liver is the most common target organ in the metastasis of colorectal cancer (CRC). Synchronous liver metastases may confer a poorer prognosis than metachronous metastases, and genetic alterations and an inflammatory response have also been associated with a poor prognosis in cases of a liver metastasis arising from CRC. However, few studies have examined the relationship between KRAS mutations and inflammatory status in CRC, especially with respect to liver metastases. METHODS: The effect of the activated mitogen activated protein kinase pathway and another protein involved in inflammation, C reactive protein, in liver metastases were examined. We aimed to determine the impact of the CRP-specific single nucleotide polymorphism (SNP) rs7553007 in liver metastasis on the CRC-specific survival (CSS) of patients after colorectal liver metastasectomy. RESULTS: We found no significant differences in genotype distributions and allele frequencies at the CRP SNP rs7553007 between CRC patients with liver metastasis and the control group. CSS rates were low in the subgroup of patients with synchronous metastasis with the A-allele (A/A and A/G) at rs7553007 or mutated KRAS/BRAF in liver metastatic specimens. Furthermore, the CRP SNP rs7553007 (hazard ratio [HR] = 1.101; 95% confidence interval [CI] = 1.011-1.200; P = 0.027) and KRAS/BRAF mutations (HR = 2.377; 95% CI = 1.293 4.368; P = 0.005) remained predictive for the CSS of CRC patients with synchronous liver metastasis in multivariate analysis. CONCLUSIONS: Both the CRP SNP rs7553007 and KRAS/BRAF mutations were independent prognostic factors for CRC patients with synchronous liver metastasis. PMID- 23755179 TI - Heterogeneous effects of calorie restriction on in vivo glucose uptake and insulin signaling of individual rat skeletal muscles. AB - Calorie restriction (CR) (consuming ~60% of ad libitum, AL, intake) improves whole body insulin sensitivity and enhances insulin-stimulated glucose uptake by isolated skeletal muscles. However, little is known about CR-effects on in vivo glucose uptake and insulin signaling in muscle. Accordingly, 9-month-old male AL and CR (initiated when 3-months-old) Fischer 344 x Brown Norway rats were studied using a euglycemic-hyperinsulinemic clamp with plasma insulin elevated to a similar level (~140 uU/ml) in each diet group. Glucose uptake (assessed by infusion of [(14)C]-2-deoxyglucose, 2-DG), phosphorylation of key insulin signaling proteins (insulin receptor, Akt and Akt substrate of 160 kDa, AS160), abundance of GLUT4 and hexokinase proteins, and muscle fiber type composition (myosin heavy chain, MHC, isoform percentages) were determined in four predominantly fast-twitch (epitrochlearis, gastrocnemius, tibialis anterior, plantaris) and two predominantly slow-twitch (soleus, adductor longus) muscles. CR did not result in greater GLUT4 or hexokinase abundance in any of the muscles, and there were no significant diet-related effects on percentages of MHC isoforms. Glucose infusion was greater for CR versus AL rats (P<0.05) concomitant with significantly (P<0.05) elevated 2-DG uptake in 3 of the 4 fast-twitch muscles (epitrochlearis, gastrocnemius, tibialis anterior), without a significant diet-effect on 2-DG uptake by the plantaris or either slow-twitch muscle. Each of the muscles with a CR-related increase in 2-DG uptake was also characterized by significant (P<0.05) increases in phosphorylation of both Akt and AS160. Among the 3 muscles without a CR-related increase in glucose uptake, only the soleus had significant (P<0.05) CR-related increases in Akt and AS160 phosphorylation. The current data revealed that CR leads to greater whole body glucose disposal in part attributable to elevated in vivo insulin-stimulated glucose uptake by fast twitch muscles. The results also demonstrated that CR does not uniformly enhance either insulin signaling or insulin-stimulated glucose uptake in all muscles in vivo. PMID- 23755180 TI - Socioeconomic status, functional recovery, and long-term mortality among patients surviving acute myocardial infarction. AB - OBJECTIVES: To examine the relationship between socio-economic status (SES), functional recovery and long-term mortality following acute myocardial infarction (AMI). BACKGROUND: The extent to which SES mortality disparities are explained by differences in functional recovery following AMI is unclear. METHODS: We prospectively examined 1368 patients who survived at least one-year following an index AMI between 1999 and 2003 in Ontario, Canada. Each patient was linked to administrative data and followed over 9.6 years to track mortality. All patients underwent medical chart abstraction and telephone interviews following AMI to identify individual-level SES, clinical factors, processes of care (i.e., use of, and adherence, to evidence-based medications, physician visits, invasive cardiac procedures, referrals to cardiac rehabilitation), as well as changes in psychosocial stressors, quality of life, and self-reported functional capacity. RESULTS: As compared with their lower SES counterparts, higher SES patients experienced greater functional recovery (1.80 ml/kg/min average increase in peak V02, P<0.001) after adjusting for all baseline clinical factors. Post-AMI functional recovery was the strongest modifiable predictor of long-term mortality (Adjusted HR for each ml/kg/min increase in functional capacity: 0.91; 95% CI: 0.87-0.94, P<0.001) irrespective of SES (P = 0.51 for interaction between SES, functional recovery, and mortality). SES-mortality associations were attenuated by 27% after adjustments for functional recovery, rendering the residual SES mortality association no longer statistically significant (Adjusted HR: 0.84; 95% CI:0.70-1.00, P = 0.05). The effects of functional recovery on SES-mortality associations were not explained by access inequities to physician specialists or cardiac rehabilitation. CONCLUSIONS: Functional recovery may play an important role in explaining SES-mortality gradients following AMI. PMID- 23755182 TI - The importance of demonstratively restoring order. AB - Contrary to what is often assumed, order is not the strongest context for encouraging normative behavior. The strongest context effect on normative behavior comes from cues that clearly convey other people's respect for norms. Ironically, this show of respect necessitates some contrasting disrespect that is being restored. Using civic virtues (such as helping behavior) as a prototype of normative behavior, the three field experiments described in this paper reveal the impact of normative cues on civic virtues. Results show that the strongest effect on making people follow prosocial norms in public places emanates from seeing order being restored, rather than just order being present. The robust and surprisingly large effects show that observing other people's respect for one particular norm (as evidenced in their restoring physical order) makes it more likely that the onlooker follows other norms as well. This implies that prosocial behavior has the highest chance of spreading when people observe order being restored. There are clear policy implications: create low cost "normative respect cues" wherever it is desirable to increase conformity to norms. PMID- 23755181 TI - Pectin methylesterase and pectin remodelling differ in the fibre walls of two gossypium species with very different fibre properties. AB - Pectin, a major component of the primary cell walls of dicot plants, is synthesized in Golgi, secreted into the wall as methylesters and subsequently de esterified by pectin methylesterase (PME). Pectin remodelling by PMEs is known to be important in regulating cell expansion in plants, but has been poorly studied in cotton. In this study, genome-wide analysis showed that PMEs are a large multi gene family (81 genes) in diploid cotton (Gossypium raimondii), an expansion over the 66 in Arabidopsis and suggests the evolution of new functions in cotton. Relatively few PME genes are expressed highly in fibres based on EST abundance and the five most abundant in fibres were cloned and sequenced from two cotton species. Their significant sequence differences and their stage-specific expression in fibres within a species suggest sub-specialisation during fibre development. We determined the transcript abundance of the five fibre PMEs, total PME enzyme activity, pectin content and extent of de-methylesterification of the pectin in fibre walls of the two cotton species over the first 25-30 days of fibre growth. There was a higher transcript abundance of fibre-PMEs and a higher total PME enzyme activity in G. barbadense (Gb) than in G. hirsutum (Gh) fibres, particularly during late fibre elongation. Total pectin was high, but de esterified pectin was low during fibre elongation (5-12 dpa) in both Gh and Gb. De-esterified pectin levels rose thereafter when total PME activity increased and this occurred earlier in Gb fibres resulting in a lower degree of esterification in Gb fibres between 17 and 22 dpa. Gb fibres are finer and longer than those of Gh, so differences in pectin remodelling during the transition to wall thickening may be an important factor in influencing final fibre diameter and length, two key quality attributes of cotton fibres. PMID- 23755183 TI - Simulation of left atrial function using a multi-scale model of the cardiovascular system. AB - During a full cardiac cycle, the left atrium successively behaves as a reservoir, a conduit and a pump. This complex behavior makes it unrealistic to apply the time-varying elastance theory to characterize the left atrium, first, because this theory has known limitations, and second, because it is still uncertain whether the load independence hypothesis holds. In this study, we aim to bypass this uncertainty by relying on another kind of mathematical model of the cardiac chambers. In the present work, we describe both the left atrium and the left ventricle with a multi-scale model. The multi-scale property of this model comes from the fact that pressure inside a cardiac chamber is derived from a model of the sarcomere behavior. Macroscopic model parameters are identified from reference dog hemodynamic data. The multi-scale model of the cardiovascular system including the left atrium is then simulated to show that the physiological roles of the left atrium are correctly reproduced. This include a biphasic pressure wave and an eight-shaped pressure-volume loop. We also test the validity of our model in non basal conditions by reproducing a preload reduction experiment by inferior vena cava occlusion with the model. We compute the variation of eight indices before and after this experiment and obtain the same variation as experimentally observed for seven out of the eight indices. In summary, the multi-scale mathematical model presented in this work is able to correctly account for the three roles of the left atrium and also exhibits a realistic left atrial pressure-volume loop. Furthermore, the model has been previously presented and validated for the left ventricle. This makes it a proper alternative to the time-varying elastance theory if the focus is set on precisely representing the left atrial and left ventricular behaviors. PMID- 23755185 TI - Empathy as a function of clinical exposure--reading emotion in the eyes. AB - BACKGROUND: Evidence based largely on self-report data suggests that factors associated with medical education erode the critical human quality of empathy. These reports have caused serious concern among medical educators and clinicians and have led to changes in medical curricula around the world. This study aims to provide a more objective index of possible changes in empathy across the spectrum of clinical exposure, by using a behavioural test of empathic accuracy in addition to self-report questionnaires. Moreover, non-medical groups were used to control for maturation effects. METHODS: Three medical groups (N = 3*20) representing a spectrum of clinical exposure, and two non-medical groups (N = 2*20) matched for age, sex and educational achievements completed self-report measures of empathy, and tests of empathic accuracy and interoceptive sensitivity. RESULTS: Between-group differences in reported empathy related to maturation rather than clinical training/exposure. Conversely, analyses of the "eyes" test results specifically identified clinical practice, but not medical education, as the key influence on performance. The data from the interoception task did not support a link between visceral feedback and empathic processes. CONCLUSIONS: Clinical practice, but not medical education, impacts on empathy development and seems instrumental in maintaining empathetic skills against the general trend of declining empathic accuracy with age. PMID- 23755184 TI - Polycyclic aromatic hydrocarbon-induced signaling events relevant to inflammation and tumorigenesis in lung cells are dependent on molecular structure. AB - Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and occupational toxicants, which are a major human health concern in the U.S. and abroad. Previous research has focused on the genotoxic events caused by high molecular weight PAHs, but not on non-genotoxic events elicited by low molecular weight PAHs. We used an isomeric pair of low molecular weight PAHs, namely 1 Methylanthracene (1-MeA) and 2-Methylanthracene (2-MeA), in which only 1-MeA possessed a bay-like region, and hypothesized that 1-MeA, but not 2-MeA, would affect non-genotoxic endpoints relevant to tumor promotion in murine C10 lung cells, a non-tumorigenic type II alveolar pneumocyte and progenitor cell type of lung adenocarcinoma. The non-genotoxic endpoints assessed were dysregulation of gap junction intercellular communication function and changes in the major pulmonary connexin protein, connexin 43, using fluorescent redistribution and immunoblots, activation of mitogen activated protein kinases (MAPK) using phosphospecific MAPK antibodies for immunoblots, and induction of inflammatory genes using quantitative RT-PCR. 2-MeA had no effect on any of the endpoints, but 1-MeA dysregulated gap junctional communication in a dose and time dependent manner, reduced connexin 43 protein expression, and altered membrane localization. 1-MeA also activated ERK1/2 and p38 MAP kinases. Inflammatory genes, such as cyclooxygenase 2, and chemokine ligand 2 (macrophage chemoattractant 2), were also upregulated in response to 1-MeA only. These results indicate a possible structure-activity relationship of these low molecular weight PAHs relevant to non-genotoxic endpoints of the promoting aspects of cancer. Therefore, our novel findings may improve the ability to predict outcomes for future studies with additional toxicants and mixtures, identify novel targets for biomarkers and chemotherapeutics, and have possible implications for future risk assessment for these PAHs. PMID- 23755186 TI - Refractive errors affect the vividness of visual mental images. AB - The hypothesis that visual perception and mental imagery are equivalent has never been explored in individuals with vision defects not preventing the visual perception of the world, such as refractive errors. Refractive error (i.e., myopia, hyperopia or astigmatism) is a condition where the refracting system of the eye fails to focus objects sharply on the retina. As a consequence refractive errors cause blurred vision. We subdivided 84 individuals according to their spherical equivalent refraction into Emmetropes (control individuals without refractive errors) and Ametropes (individuals with refractive errors). Participants performed a vividness task and completed a questionnaire that explored their cognitive style of thinking before their vision was checked by an ophthalmologist. Although results showed that Ametropes had less vivid mental images than Emmetropes this did not affect the development of their cognitive style of thinking; in fact, Ametropes were able to use both verbal and visual strategies to acquire and retrieve information. Present data are consistent with the hypothesis of equivalence between imagery and perception. PMID- 23755187 TI - Paracrine effects of IGF-1 overexpression on the functional decline due to skeletal muscle disuse: molecular and functional evaluation in hindlimb unloaded MLC/mIgf-1 transgenic mice. AB - Slow-twitch muscles, devoted to postural maintenance, experience atrophy and weakness during muscle disuse due to bed-rest, aging or spaceflight. These conditions impair motion activities and can have survival implications. Human and animal studies demonstrate the anabolic role of IGF-1 on skeletal muscle suggesting its interest as a muscle disuse countermeasure. Thus, we tested the role of IGF-1 overexpression on skeletal muscle alteration due to hindlimb unloading (HU) by using MLC/mIgf-1 transgenic mice expressing IGF-1 under the transcriptional control of MLC promoter, selectively activated in skeletal muscle. HU produced atrophy in soleus muscle, in terms of muscle weight and fiber cross-sectional area (CSA) reduction, and up-regulation of atrophy gene MuRF1. In parallel, the disuse-induced slow-to-fast fiber transition was confirmed by an increase of the fast-type of the Myosin Heavy Chain (MHC), a decrease of PGC 1alpha expression and an increase of histone deacetylase-5 (HDAC5). Consistently, functional parameters such as the resting chloride conductance (gCl) together with ClC-1 chloride channel expression were increased and the contractile parameters were modified in soleus muscle of HU mice. Surprisingly, IGF-1 overexpression in HU mice was unable to counteract the loss of muscle weight and the decrease of fiber CSA. However, the expression of MuRF1 was recovered, suggesting early effects on muscle atrophy. Although the expression of PGC-1alpha and MHC were not improved in IGF-1-HU mice, the expression of HDAC5 was recovered. Importantly, the HU-induced increase of gCl was fully contrasted in IGF-1 transgenic mice, as well as the changes in contractile parameters. These results indicate that, even if local expression does not seem to attenuate HU induced atrophy and slow-to-fast phenotype transition, it exerts early molecular effects on gene expression which can counteract the HU-induced modification of electrical and contractile properties. MuRF1 and HDAC5 can be attractive therapeutic targets for pharmacological countermeasures and then deserve further investigations. PMID- 23755188 TI - Lymphoid to myeloid cell trans-differentiation is determined by C/EBPbeta structure and post-translational modifications. AB - The transcription factor C/EBPbeta controls differentiation, proliferation, and functionality of many cell types, including innate immune cells. A detailed molecular understanding of how C/EBPbeta directs alternative cell fates remains largely elusive. A multitude of signal-dependent post-translational modifications (PTMs) differentially affect the protean C/EBPbeta functions. In this study we apply an assay that converts primary mouse B lymphoid progenitors into myeloid cells in order to answer the question how C/EBPbeta regulates (trans-) differentiation and determines myeloid cell fate. We found that structural alterations and various C/EBPbeta PTMs determine the outcome of trans differentiation of lymphoid into myeloid cells, including different types of monocytes/macrophages, dendritic cells, and granulocytes. The ability of C/EBPbeta to recruit chromatin remodeling complexes is required for the granulocytic trans-differentiation outcome. These novel findings reveal that PTMs and structural plasticity of C/EBPbeta are adaptable modular properties that integrate and rewire epigenetic functions to direct differentiation to diverse innate immune system cells, which are crucial for the organism survival. PMID- 23755189 TI - The miR-30 microRNA family targets smoothened to regulate hedgehog signalling in zebrafish early muscle development. AB - The importance of microRNAs in development is now widely accepted. However, identifying the specific targets of individual microRNAs and understanding their biological significance remains a major challenge. We have used the zebrafish model system to evaluate the expression and function of microRNAs potentially involved in muscle development and study their interaction with predicted target genes. We altered expression of the miR-30 microRNA family and generated phenotypes that mimicked misregulation of the Hedgehog pathway. Inhibition of the miR-30 family increases activity of the pathway, resulting in elevated ptc1 expression and increased numbers of superficial slow-muscle fibres. We show that the transmembrane receptor smoothened is a target of this microRNA family. Our results indicate that fine coordination of smoothened activity by the miR-30 family allows the correct specification and differentiation of distinct muscle cell types during zebrafish embryonic development. PMID- 23755190 TI - Long-term effects of early overnutrition in the heart of male adult rats: role of the renin-angiotensin system. AB - To analyze the long-term effects of early overfeeding on the heart and coronary circulation, the effect of ischemia-reperfusion (I/R) and the role of the renin angiotensin system (RAS) was studied in isolated hearts from control and overfed rats during lactation. On the day of birth litters were adjusted to twelve pups per mother (controls) or to three pups per mother (overfed). At 5 months of age, the rats from reduced litters showed higher body weight and body fat than the controls. The hearts from these rats were perfused in a Langendorff system and subjected to 30 min of ischemia followed by 15 min of reperfusion (I/R). The myocardial contractility (dP/dt) and the coronary vasoconstriction to angiotensin II were lower, and the expression of the apoptotic marker was higher, in the hearts from overfed rats compared to controls. I/R reduced the myocardial contractily, the coronary vasoconstriction to angiotensin II and the vasodilatation to bradykinin, and increased the expression of (pro)renin receptor and of apoptotic and antiapoptotic markers, in both experimental groups. I/R also increased the expression of angiotensinogen in control but not in overfed rats. In summary, the results of this study suggest that early overnutrition induces reduced activity of the RAS and impairment of myocardial and coronary function in adult life, due to increased apoptosis. Ischemia-reperfusion produced myocardial and coronary impairment and apoptosis, which may be related to activation of RAS in control but not in overfed rats, and there may be protective mechanisms in both experimental groups. PMID- 23755191 TI - Persistent inflammation and endothelial activation in HIV-1 infected patients after 12 years of antiretroviral therapy. AB - OBJECTIVE: The study investigated markers of inflammation and endothelial activation in HIV infected patients after 12 years of successful combination antiretroviral treatment (cART). METHODS: Inflammation and endothelial activation were assessed by measuring levels of immunoglobulins, beta2-microglobulin, interleukin (IL) 8, tumor necrosis factor alpha (TNFalpha), vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), sE Selectin, and sP-Selectin. RESULTS: HIV infected patients had higher levels of beta2-microglobulin, IL-8, TNFalpha, and sICAM-1 than uninfected controls, and HIV infected patients lacked correlation between platelet counts and sP-Selectin levels found in uninfected controls. CONCLUSION: Discrete signs of systemic and vascular inflammation persist even after very long term cART. PMID- 23755192 TI - Evolutionary relationship and structural characterization of the EPF/EPFL gene family. AB - EPF1-EPF2 and EPFL9/Stomagen act antagonistically in regulating leaf stomatal density. The aim of this study was to elucidate the evolutionary functional divergence of EPF/EPFL family genes. Phylogenetic analyses showed that AtEPFL9/Stomagen-like genes are conserved only in vascular plants and are closely related to AtEPF1/EPF2-like genes. Modeling showed that EPF/EPFL peptides share a common 3D structure that is constituted of a scaffold and loop. Molecular dynamics simulation suggested that AtEPF1/EPF2-like peptides form an additional disulfide bond in their loop regions and show greater flexibility in these regions than AtEPFL9/Stomagen-like peptides. This study uncovered the evolutionary relationship and the conformational divergence of proteins encoded by the EPF/EPFL family genes. PMID- 23755193 TI - A comparison of 100 human genes using an alu element-based instability model. AB - The human retrotransposon with the highest copy number is the Alu element. The human genome contains over one million Alu elements that collectively account for over ten percent of our DNA. Full-length Alu elements are randomly distributed throughout the genome in both forward and reverse orientations. However, full length widely spaced Alu pairs having two Alus in the same (direct) orientation are statistically more prevalent than Alu pairs having two Alus in the opposite (inverted) orientation. The cause of this phenomenon is unknown. It has been hypothesized that this imbalance is the consequence of anomalous inverted Alu pair interactions. One proposed mechanism suggests that inverted Alu pairs can ectopically interact, exposing both ends of each Alu element making up the pair to a potential double-strand break, or "hit". This hypothesized "two-hit" (two double-strand breaks) potential per Alu element was used to develop a model for comparing the relative instabilities of human genes. The model incorporates both 1) the two-hit double-strand break potential of Alu elements and 2) the probability of exon-damaging deletions extending from these double-strand breaks. This model was used to compare the relative instabilities of 50 deletion-prone cancer genes and 50 randomly selected genes from the human genome. The output of the Alu element-based genomic instability model developed here is shown to coincide with the observed instability of deletion-prone cancer genes. The 50 cancer genes are collectively estimated to be 58% more unstable than the randomly chosen genes using this model. Seven of the deletion-prone cancer genes, ATM, BRCA1, FANCA, FANCD2, MSH2, NCOR1 and PBRM1, were among the most unstable 10% of the 100 genes analyzed. This algorithm may lay the foundation for comparing genetic risks posed by structural variations that are unique to specific individuals, families and people groups. PMID- 23755194 TI - Microbial communities in pre-columbian coprolites. AB - The study of coprolites from earlier cultures represents a great opportunity to study an "unaltered" composition of the intestinal microbiota. To test this, pre Columbian coprolites from two cultures, the Huecoid and Saladoid, were evaluated for the presence of DNA, proteins and lipids by cytochemical staining, human and/or dog-specific Bacteroides spp. by PCR, as well as bacteria, fungi and archaea using Terminal Restriction Fragment analyses. DNA, proteins and lipids, and human-specific Bacteroides DNA were detected in all coprolites. Multidimensional scaling analyses resulted in spatial arrangements of microbial profiles by culture, further supported by cluster analysis and ANOSIM. Differences between the microbial communities were positively correlated with culture, and SIMPER analysis indicated 68.8% dissimilarity between the Huecoid and Saladoid. Proteobacteria, Bacteroidetes and methanogens were found in all coprolite samples. Propionebacteria, Shewanella and lactic acid bacteria dominated in the Huecoid samples, while Acidobacteria, and peptococci were dominant in Saladoid samples. Yeasts, including Candida albicans and Crypotococcus spp. were found in all samples. Basidiomycetes were the most notable fungi in Huecoid samples while Ascomycetes predominated in Saladoid samples, suggesting differences in dietary habits. Our study provides an approach for the study of the microbial communities of coprolite samples from various cultures. PMID- 23755195 TI - Zn(II)-Chlorido complexes of phytohormone kinetin and its derivatives modulate expression of inflammatory mediators in THP-1 cells. AB - Kinetin (N6-furfuryladenine) belongs to a group of plant growth hormones involved in cell division, differentiation and other physiological processes. One of the possible ways to obtain biologically active compounds is to complex biologically relevant natural compounds to suitable metal atoms. In this work, two structural groups of Zn(II) complexes [Zn(L(n))2Cl2].Solv (1-5) and [Zn(HL(n))Cl3] . xL(n) (6-7); n=1-5, Solv=CH3OH for 1 and 2H2O for 2; x =1 for 6 and 2 for 7; involving a phytohormone kinetin and its derivatives (L(n)) were evaluated for their ability to modulate secretion of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and matrix metalloproteinase (MMP)-2 in a lipopolysaccharide (LPS) activated macrophage-like THP-1 cell model. The penetration of the complexes to cells was also detected. The mechanism of interactions of the zinc(II) complexes with a fluorescent sensor N-(6-methoxy-8-quinolyl)-p-toluene sulphonamide (TSQ) and sulfur-containing biomolecules (l-cysteine and reduced glutathione) was studied by electrospray-ionization mass spectrometry and flow-injection analysis with fluorescence detection. The present study showed that the tested complexes exhibited a low cytotoxic effect on the THP-1 cell line (IC50>40 uM), apart from complex 4, with an IC50=10.9 +/- 1.1 uM. Regarding the inflammation-related processes, the Zn(II) complexes significantly decreased IL-1beta production by a factor of 1.47-2.22 compared with the control (DMSO), but did not affect TNF alpha and MMP-2 secretions. However, application of the Zn(II) complexes noticeably changed the pro-MMP-2/MMP-2 ratio towards a higher amount of maturated MMP-2, when they induced a 4-times higher production of maturated MMP-2 in comparison with the vehicle-treated cells under LPS stimulation. These results indicated that the complexes are able to modulate an inflammatory response by influencing secretion and activity of several inflammation-related cytokines and enzymes. PMID- 23755196 TI - An ethanolic extract of Lindera obtusiloba stems, YJP-14, improves endothelial dysfunction, metabolic parameters and physical performance in diabetic db/db mice. AB - Lindera obtusiloba is a medicinal herb traditionally used in Asia for improvement of blood circulation, treatment of inflammation, and prevention of liver damage. A previous study has shown that an ethanolic extract of Lindera obtusiloba stems (LOE) has vasoprotective and antihypertensive effects. The possibility that Lindera obtusiloba improves endothelial function and metabolic parameters in type 2 diabetes mellitus (T2DM) remains to be examined. Therefore, the aim of the present study was to determine the potential of LOE to prevent the development of an endothelial dysfunction, and improve metabolic parameters including hyperglycemia, albuminuria and physical exercise capacity in db/db mice, an experimental model of T2DM. The effect of LOE (100 mg/kg/day by gavage for 8 weeks) on these parameters was compared to that of an oral antidiabetic drug, pioglitazone (30 mg/kg/day by gavage). Reduced blood glucose level, body weight and albumin-creatinine ratio were observed in the group receiving LOE compared to the control db/db group. The LOE treatment improved endothelium-dependent relaxations, abolished endothelium-dependent contractions to acetylcholine in the aorta, and normalized the increased vascular oxidative stress and expression of NADPH oxidase, cyclooxygenases, angiotensin II, angiotensin type 1 receptors and peroxynitrite and the decreased expression of endothelial NO synthase in db/db mice. The angiotensin-converting enzyme (ACE) activity was reduced in the LOE group compared to that in the control db/db group. LOE also inhibited the activity of purified ACE, COX-1 and COX-2 in a dose-dependent manner. In addition, LOE improved physical exercise capacity. Thus, the present findings indicate that LOE has a beneficial effect on the vascular system in db/db mice by improving endothelium-dependent relaxations and vascular oxidative stress most likely by normalizing the angiotensin system, and also on metabolic parameters, and these effects are associated with an enhanced physical exercise capacity. PMID- 23755197 TI - Monitoring dolphins in an urban marine system: total and effective population size estimates of Indo-Pacific bottlenose dolphins in Moreton Bay, Australia. AB - Moreton Bay, Queensland, Australia is an area of high biodiversity and conservation value and home to two sympatric sub-populations of Indo-Pacific bottlenose dolphins (Tursiops aduncus). These dolphins live in close proximity to major urban developments. Successful management requires information regarding their abundance. Here, we estimate total and effective population sizes of bottlenose dolphins in Moreton Bay using photo-identification and genetic data collected during boat-based surveys in 2008-2010. Abundance (N) was estimated using open population mark-recapture models based on sighting histories of distinctive individuals. Effective population size (Ne ) was estimated using the linkage disequilibrium method based on nuclear genetic data at 20 microsatellite markers in skin samples, and corrected for bias caused by overlapping generations (Ne c). A total of 174 sightings of dolphin groups were recorded and 365 different individuals identified. Over the whole of Moreton Bay, a population size N of 554 +/- 22.2 (SE) (95% CI: 510-598) was estimated. The southern bay sub population was small at an estimated N = 193 +/- 6.4 (SE) (95% CI: 181-207), while the North sub-population was more numerous, with 446 +/- 56 (SE) (95% CI: 336-556) individuals. The small estimated effective population size of the southern sub-population (Ne c = 56, 95% CI: 33-128) raises conservation concerns. A power analysis suggested that to reliably detect small (5%) declines in size of this population would require substantial survey effort (>4 years of annual mark recapture surveys) at the precision levels achieved here. To ensure that ecological as well as genetic diversity within this population of bottlenose dolphins is preserved, we consider that North and South sub-populations should be treated as separate management units. Systematic surveys over smaller areas holding locally-adapted sub-populations are suggested as an alternative method for increasing ability to detect abundance trends. PMID- 23755199 TI - Random effects models and multistage estimation procedures for statistical population reconstruction of small game populations. AB - Recently, statistical population models using age-at-harvest data have seen increasing use for monitoring of harvested wildlife populations. Even more recently, detailed evaluation of model performance for long-lived, large game animals indicated that the use of random effects to incorporate unmeasured environmental variation, as well as second-stage Horvitz-Thompson-type estimators of abundance, provided more reliable estimates of total abundance than previous models. We adapt this new modeling framework to small game, age-at-harvest models with only young-of-the-year and adult age classes. Our Monte Carlo simulation results indicate superior model performance for the new modeling framework, evidenced by lower bias and proper confidence interval coverage. We apply this method to male wild turkey harvest in the East Ozarks turkey productivity region, Missouri, USA, where statistical population reconstruction indicates a relatively stationary population for 1996-2010. PMID- 23755198 TI - Mechanisms that enhance sustainability of p53 pulses. AB - The tumor suppressor p53 protein shows various dynamic responses depending on the types and extent of cellular stresses. In particular, in response to DNA damage induced by gamma-irradiation, cells generate a series of p53 pulses. Recent research has shown the importance of sustaining repeated p53 pulses for recovery from DNA damage. However, far too little attention has been paid to understanding how cells can sustain p53 pulses given the complexities of genetic heterogeneity and intrinsic noise. Here, we explore potential molecular mechanisms that enhance the sustainability of p53 pulses by developing a new mathematical model of the p53 regulatory system. This model can reproduce many experimental results that describe the dynamics of p53 pulses. By simulating the model both deterministically and stochastically, we found three potential mechanisms that improve the sustainability of p53 pulses: 1) the recently identified positive feedback loop between p53 and Roralpha allows cells to sustain p53 pulses with high amplitude over a wide range of conditions, 2) intrinsic noise can often prevent the dampening of p53 pulses even after mutations, and 3) coupling of p53 pulses in neighboring cells via cytochrome-c significantly reduces the chance of failure in sustaining p53 pulses in the presence of heterogeneity among cells. Finally, in light of these results, we propose testable experiments that can reveal important mechanisms underlying p53 dynamics. PMID- 23755200 TI - Faster cognitive and functional decline in Dysexecutive versus amnestic Alzheimer's subgroups: a longitudinal analysis of the National Alzheimer's Coordinating Center (NACC) database. AB - OBJECTIVE: To compare the rate of cognitive and functional decline in dysexecutive, typical and amnestic subgroups of Alzheimer's disease. METHODS: 943 participants from the National Alzheimer's Coordinating Center (NACC) database who had a diagnosis of probable AD were followed for a mean of 2.3 years. A dysexecutive subgroup (n = 165) was defined as having executive performance >1.5 SD worse than memory performance, an amnestic subgroup (n = 157) was defined as having memory performance >1.5 SD worse than executive performance and a typical subgroup (n = 621) was defined as having a difference in executive and memory performance of <1.5 SD. Generalized estimating equations (GEE) were used to model decline on the Folstein Mini Mental Status Exam (MMSE), rise on the Clinical Dementia Rating (CDR) sum of boxes and rise on the total Functional Assessment Questionnaire (FAQ). RESULTS: Compared with the amnestic subgroup, the dysexecutive subgroup declined 2.2X faster on the Folstein MMSE (p<.001), rose 42% faster on the CDR sum of boxes (p = .03) and rose 33% faster on the total FAQ (p = .01). Rate of change for the typical subgroup fell between that of the amnestic and dysexecutive subgroups for the MMSE, CDR sum of boxes and total FAQ. Among a subset of participants (n = 129) who underwent autopsy, the dysexecutive, amnestic and typical subgroups did not differ in odds of having an AD pathologic diagnosis, suggesting that variation in non-AD pathologies across subtypes did not lead to the observed differences. CONCLUSIONS: A dysexecutive subgroup of AD has a unique disease course in addition to cognitive phenotype. PMID- 23755201 TI - Tumor necrosis factor-alpha promotes cholestasis-induced liver fibrosis in the mouse through tissue inhibitor of metalloproteinase-1 production in hepatic stellate cells. AB - Tumor necrosis factor (TNF)-alpha, which is a mediator of hepatotoxicity, has been implicated in liver fibrosis. However, the roles of TNF-alpha on hepatic stellate cell (HSC) activation and liver fibrosis are complicated and remain controversial. To explore this issue, the role of TNF-alpha in cholestasis induced liver fibrosis was examined by comparing between TNF-alpha(-/-) mice and TNF-alpha(+/+) mice after bile duct ligation (BDL). Serum TNF-alpha levels in mice were increased by common BDL combined with cystic duct ligation (CBDL+CDL). TNF-alpha deficiency reduced liver fibrosis without affecting liver injury, inflammatory cell infiltration, and liver regeneration after CBDL+CDL. Increased expression levels of collagen alpha1(I) mRNA, transforming growth factor (TGF) beta mRNA, and alpha-smooth muscle actin (alphaSMA) protein by CBDL+CDL in the livers of TNF-alpha(-/-) mice were comparable to those in TNF-alpha(+/+) mice. Exogenous administration of TNF-alpha decreased collagen alpha1(I) mRNA expression in isolated rat HSCs. These results suggest that the reduced fibrosis in TNF-alpha(-/-) mice is regulated in post-transcriptional level. Tissue inhibitor of metalloproteinase (TIMP)-1 plays a crucial role in the pathogenesis of liver fibrosis. TIMP-1 expression in HSCs in the liver was increased by CBDL+CDL, and the induction was lower in TNF-alpha(-/-) mice than in TNF alpha(+/+) mice. Fibrosis in the lobe of TIMP-1(-/-) mice with partial BDL was also reduced. These findings indicate that TNF-alpha produced by cholestasis can promote liver fibrosis via TIMP-1 production from HSCs. Thus, targeting TNF-alpha and TIMP-1 may become a new therapeutic strategy for treating liver fibrosis in cholestatic liver injury. PMID- 23755202 TI - The influence of dengue virus serotype-2 infection on Aedes aegypti (Diptera: Culicidae) motivation and avidity to blood feed. AB - BACKGROUND: Dengue virus (DENV) is transmitted by Aedes aegypti, a species that lives in close association with human dwellings. The behavior of DENV-infected mosquitoes needs further investigation, especially regarding the potential influence of DENV on mosquito biting motivation and avidity. METHODOLOGY/PRINCIPAL FINDINGS: We orally challenged 4-5 day-old Ae. aegypti females with a low passage DENV serotype -2 (DENV-2) to test whether the virus influences motivation to feed (the likelihood that a mosquito obtains a blood meal and the size of its blood meal) and avidity (the likelihood to re-feed after an interrupted first blood-meal). To assay motivation, we offered mosquitoes an anesthetized mouse for 2, 3, 4 or 5 minutes 7 or 14 days after the initial blood meals and measured the time they started feeding. 60.5% of the unexposed mosquitoes fed on the mouse, but only 40.5% of the positive ones did. Exposed but negative mosquitoes behaved similarly to unexposed ones (55.0% feeding). Thus DENV-2 infection decreased the mosquitoes' motivation to feed. To assay avidity, we offered the same mosquitoes a mouse two hours after the first round of feeding, and we measured the time at which they started probing. The exposed (positive or negative) mosquitoes were more likely to re-feed than the unexposed ones and, in particular, the size of the previous blood-meal that kept mosquitoes from re-feeding was larger in the exposed than in the unexposed mosquitoes. Thus, DENV-2 infection increased mosquito avidity. CONCLUSIONS/SIGNIFICANCE: DENV-2 significantly decreased the mosquitoes' motivation to feed, but increased their avidity (even after taking account the amount of blood previously imbibed). As these are important components of transmission, we expect that the changes of the blood-feeding behaviour impact the vectorial capacity Ae. aegypti for dengue. PMID- 23755203 TI - Lower cerebrospinal fluid/plasma fibroblast growth factor 21 (FGF21) ratios and placental FGF21 production in gestational diabetes. AB - OBJECTIVES: Circulating Fibroblast Growth Factor 21 (FGF21) levels are increased in insulin resistant states such as obesity, type 2 diabetes mellitus and gestational diabetes mellitus (GDM). In addition, GDM is associated with serious maternal and fetal complications. We sought to study human cerebrospinal fluid (CSF) and corresponding circulating FGF21 levels in women with gestational diabetes mellitus (GDM) and in age and BMI matched control subjects. We also assessed FGF21 secretion from GDM and control human placental explants. DESIGN: CSF and corresponding plasma FGF21 levels of 24 women were measured by ELISA [12 GDM (age: 26-47 years, BMI: 24.3-36.3 kg/m(2)) and 12 controls (age: 22-40 years, BMI: 30.1-37.0 kg/m(2))]. FGF21 levels in conditioned media were secretion from GDM and control human placental explants were also measured by ELISA. RESULTS: Glucose, HOMA-IR and circulating NEFA levels were significantly higher in women with GDM compared to control subjects. Plasma FGF21 levels were significantly higher in women with GDM compared to control subjects [234.3 (150.2-352.7) vs. 115.5 (60.5-188.7) pg/ml; P<0.05]. However, there was no significant difference in CSF FGF21 levels in women with GDM compared to control subjects. Interestingly, CSF/Plasma FGF21 ratio was significantly lower in women with GDM compared to control subjects [0.4 (0.3-0.6) vs. 0.8 (0.5-1.6); P<0.05]. FGF21 secretion into conditioned media was significantly lower in human placental explants from women with GDM compared to control subjects (P<0.05). CONCLUSIONS: The central actions of FGF21 in GDM subjects maybe pivotal in the pathogenesis of insulin resistance in GDM subjects. The significance of FGF21 produced by the placenta remains uncharted and maybe crucial in our understanding of the patho physiology of GDM and its associated maternal and fetal complications. Future research should seek to elucidate these points. PMID- 23755204 TI - Regional assessment of urban impacts on landcover and open space finds a smart urban growth policy performs little better than business as usual. AB - Assessment of landscape change is critical for attainment of regional sustainability goals. Urban growth assessments are needed because over half the global population now lives in cities, which impact biodiversity, ecosystem structure and ecological processes. Open space protection is needed to preserve these attributes, and provide the resources humans need. The San Francisco Bay Area, California, is challenged to accommodate a population increase of 3.07 million while maintaining the region's ecosystems and biodiversity. Our analysis of 9275 km2 in the Bay Area links historic trends for three measures: urban growth, protected open space, and landcover types over the last 70 years to future 2050 projections of urban growth and open space. Protected open space totaled 348 km2 (3.7% of the area) in 1940, and expanded to 2221 km2 (20.2%) currently. An additional 1038 km2 of protected open space is targeted (35.1%). Urban area historically increased from 396.5 km2 to 2239 km2 (24.1% of the area). Urban growth during this time mostly occurred at the expense of agricultural landscapes (62.9%) rather than natural vegetation. Smart Growth development has been advanced as a preferred alternative in many planning circles, but we found that it conserved only marginally more open space than Business-as-usual when using an urban growth model to portray policies for future urban growth. Scenarios to 2050 suggest urban development on non-urban lands of 1091, 956, or 179 km2, under Business-as-usual, Smart Growth and Infill policy growth scenarios, respectively. The Smart Growth policy converts 88% of natural lands and agriculture used by Business-as-usual, while Infill used only 40% of those lands. Given the historic rate of urban growth, 0.25%/year, and limited space available, the Infill scenario is recommended. While the data may differ, the use of an historic and future framework to track these three variables can be easily applied to other metropolitan areas. PMID- 23755205 TI - "Like throwing a bowling ball at a battle ship" audience responses to Australian news stories about alcohol pricing and promotion policies: a qualitative focus group study. AB - INTRODUCTION: Policies affecting alcohol's price and promotion are effective measures to reduce harms. Yet policies targeting populations are unpopular with the public, whose views can be influenced by news framings of policy narratives. In Australia, alcohol taxation receives high news coverage, while advertising restrictions have not until recently, and narratives are highly contested for each. However, research specifically examining how audiences respond to such news stories is scant. We sought to explore audience understanding of news reports about two alcohol policy proposals. METHOD: From June to August 2012, 46 participants were recruited for 8 focus groups in age-brackets of young people aged 18-25 years, parents of young people, and adults aged 25 or older. Groups were split by education. Participants were asked their prior knowledge of alcohol policies, before watching and discussing four news stories about alcohol taxation and advertising. RESULTS: Participants were clear that alcohol poses problems, yet thought policy solutions were ineffective in a drinking culture they viewed as unamenable to change and unaffected by alcohol's price or promotion. Without knowledge of its actual effect on consumption, they cited the 2008 alcopops tax as a policy failure, blaming cheaper substitution. Participants had low knowledge of advertising restrictions, yet were concerned about underage exposure. They offered conditional support for restrictions, while doubting its effectiveness. There was marked distrust of statistics and news actors in broadcasts, yet discussions matched previous research findings. CONCLUSIONS: News coverage has resulted in strong audience understanding of alcohol related problems but framed solutions have not always provided clear messages, despite audience support for policies. Future advocacy will need to continue recent moves to address the links between alcohol's price and promotion with the drinking culture, as well as facilitate understandings of how this culture is amenable to change through the use of evidence-based policies. PMID- 23755206 TI - Small molecule R1498 as a well-tolerated and orally active kinase inhibitor for hepatocellular carcinoma and gastric cancer treatment via targeting angiogenesis and mitosis pathways. AB - Protein kinases play important roles in tumor development and progression. Lots of kinase inhibitors have entered into market and show promising clinical benefits. Here we report the discovery of a novel small molecule, well-tolerated, orally active kinase inhibitor, R1498, majorly targeting both angiogenic and mitotic pathways for the treatment of hepatocellular carcinoma (HCC) and gastric cancer (GC). A series of biochemical and cell-based assays indicated that the target kinase cluster of R1498 included Aurora kinases and VEGFR2 et al. R1498 showed moderate in vitro growth inhibition on a panel of tumor cells with IC50 of micromole range. The in vivo anti-tumor efficacy of R1498 was evaluated on a panel of GC and HCC xenografts in a parallel comparison with another multikinase inhibitor sorafenib. R1498 demonstrated superior efficacy and toxicity profile over sorafenib in all test models with >80% tumor growth inhibition and tumor regression in some xenogratfts. The therapeutic potential of R1498 was also highlighted by its efficacy on three human GC primary tumor derived xenograft models with 10-30% tumor regression rate. R1498 was shown to actively inhibit the Aurora A activity in vivo, and decrease the vascularization in tumors. Furthermore, R1498 presented good in vivo exposure and therapeutic window in the pharmacokinetic and dose range finding studies. Theses evidences indicate that R1498 is a potent, well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic and antiproliferative profile, and provide strong confidence for further development for HCC and GC therapy. PMID- 23755207 TI - Two distinct calmodulin binding sites in the third intracellular loop and carboxyl tail of angiotensin II (AT(1A)) receptor. AB - In this study, we present data that support the presence of two distinct calmodulin binding sites within the angiotensin II receptor (AT(1A)), at juxtamembrane regions of the N-terminus of the third intracellular loop (i3, amino acids 214-231) and carboxyl tail of the receptor (ct, 302-317). We used bioluminescence resonance energy transfer assays to document interactions of calmodulin with the AT(1A) holo-receptor and GST-fusion protein pull-downs to demonstrate that i3 and ct interact with calmodulin in a Ca2+-dependent fashion. The former is a 1-12 motif and the latter belongs to 1-5-10 calmodulin binding motif. The apparent Kd of calmodulin for i3 is 177.0+/-9.1 nM, and for ct is 79.4+/-7.9 nM as assessed by dansyl-calmodulin fluorescence. Replacement of the tryptophan (W219) for alanine in i3, and phenylalanine (F309 or F313) for alanine in ct reduced their binding affinities for calmodulin, as predicted by computer docking simulations. Exogenously applied calmodulin attenuated interactions between G protein betagamma subunits and i3 and ct, somewhat more so for ct than i3. Mutations W219A, F309A, and F313A did not alter Gbetagamma binding, but reduced the ability of calmodulin to compete with Gbetagamma, suggesting that calmodulin and Gbetagamma have overlapping, but not identical, binding requirements for i3 and ct. Calmodulin interference with the Gbetagamma binding to i3 and ct regions of the AT(1A) receptor strongly suggests that calmodulin plays critical roles in regulating Gbetagamma-dependent signaling of the receptor. PMID- 23755208 TI - Hepatitis C viral entry inhibitors prolong viral suppression by replication inhibitors in persistently-infected Huh7 cultures. AB - Efforts to treat HCV patients are focused on developing antiviral combinations that lead to the eradication of infection. Thus, it is important to identify optimal combinations from the various viral inhibitor classes. Based on viral dynamic models, HCV entry inhibitors are predicted to reduce viral load in a monophasic manner reflecting the slow death rate of infected hepatocytes (t1/2 = 2-70 days) and the protection of naive, un-infected cells from HCV infection. In contrast, replication inhibitors are predicted to reduce viral load in a biphasic manner. The initial rapid reduction phase is due to the inhibition of virus production and elimination of plasma virus (t1/2~3 hours). The second, slower reduction phase results from the elimination of infected hepatocytes. Here we sought to compare the ability of HCV entry and replication inhibitors as well as combinations thereof to reduce HCV infection in persistently-infected Huh7 cells. Treatment with 5 * EC50 of entry inhibitors anti-CD81 Ab or EI-1 resulted in modest (<= 1 log10 RNA copies/ml), monophasic declines in viral levels during 3 weeks of treatment. In contrast, treatment with 5 * EC50 of the replication inhibitors BILN-2016 or BMS-790052 reduced extracellular virus levels more potently (~2 log10 RNA copies/ml) over time in a biphasic manner. However, this was followed by a slow rise to steady-state virus levels due to the emergence of resistance mutations. Combining an entry inhibitor with a replication inhibitor did not substantially enhance the rate of virus reduction. However, entry/replication inhibitor and replication/replication inhibitor combinations reduced viral levels further than monotherapies (up to 3 log10 RNA copies/ml) and prolonged this reduction relative to monotherapies. Our results demonstrated that HCV entry inhibitors combined with replication inhibitors can prolong antiviral suppression, likely due to the delay of viral resistance emergence. PMID- 23755209 TI - Acute toxicity, respiratory reaction, and sensitivity of three cyprinid fish species caused by exposure to four heavy metals. AB - Using 3 cyprinid fish species zebra fish, rare minnow, and juvenile grass carp, we conducted assays of lethal reaction and ventilatory response to analyze sensitivity of the fish to 4 heavy metals. Our results showed that the 96 h LC50 of Hg(2+) to zebra fish, juvenile grass carp, and rare minnow were 0.14 mg L(-1), 0.23 mg L(-1), and 0.10 mg L(-1), respectively; of Cu(2+)0.17 mg L(-1), 0.09 mg L(-1), and 0.12 mg L(-1) respectively; of Cd(2+)6.5 mg L(-1), 18.47 mg L(-1), 5.36 mg L(-1), respectively; and of Zn(2+)44.48 mg L(-1), 31.37 mg L(-1), and 12.74 mg L(-1), respectively. Under a 1-h exposure, the ventilatory response to the different heavy metals varied. Ventilatory frequency (Vf) and amplitude (Va) increased in zebra fish, juvenile grass carp, and rare minnows exposed to Hg(2+) and Cu(2+) (P<0.05), and the Vf and Va of the 3 species rose initially and then declined when exposed to Cd(2+). Zn(2+) had markedly different toxic effects than the other heavy metals, whose Vf and Va gradually decreased with increasing exposure concentration (P<0.05). The rare minnow was the most highly susceptible of the 3 fish species to the heavy metals, with threshold effect concentrations (TEC) of 0.019 mg L(-1), 0.046 mg L(-1), 2.142 mg L(-1), and 0.633 mg L(-1) for Hg(2+), Cu(2+), Cd(2+), and Zn(2+), respectively. Therefore, it is feasible to use ventilatory parameters as a biomarker for evaluating the pollution toxicity of metals and to recognize early warning signs by using rare minnows as a sensor. PMID- 23755210 TI - Effect of sodium bicarbonate administration on mortality in patients with lactic acidosis: a retrospective analysis. AB - BACKGROUND: Lactic acidosis is a common cause of high anion gap metabolic acidosis. Sodium bicarbonate may be considered for an arterial pH <7.15 but paradoxically depresses cardiac performance and exacerbates acidosis by enhancing lactate production. This study aimed to evaluate the cause and mortality rate of lactic acidosis and to investigate the effect of factors, including sodium bicarbonate use, on death. METHODS: We conducted a single center analysis from May 2011 through April 2012. We retrospectively analyzed 103 patients with lactic acidosis among 207 patients with metabolic acidosis. We used SOFA and APACHE II as severity scores to estimate illness severity. Multivariate logistic regression analysis and Cox regression analysis models were used to identify factors that affect mortality. RESULTS: Of the 103 patients with a mean age of 66.1+/-11.4 years, eighty-three patients (80.6%) died from sepsis (61.4%), hepatic failure, cardiogenic shock and other causes. The percentage of sodium bicarbonate administration (p = 0.006), catecholamine use, ventilator care and male gender were higher in the non-survival group than the survival group. The non-survival group had significantly higher initial and follow-up lactic acid levels, lower initial albumin, higher SOFA scores and APACHE II scores than the survival group. The mortality rate was significantly higher in patients who received sodium bicarbonate. Sodium bicarbonate administration (p = 0.016) was associated with higher mortality. Independent factors that affected mortality were SOFA score (Exp (B) = 1.72, 95% CI = 1.12-2.63, p = 0.013) and sodium bicarbonate administration (Exp (B) = 6.27, 95% CI = 1.10-35.78, p = 0.039). CONCLUSIONS: Lactic acidosis, which has a high mortality rate, should be evaluated in patients with metabolic acidosis. In addition, sodium bicarbonate should be prescribed with caution in the case of lactic acidosis because sodium bicarbonate administration may affect mortality. PMID- 23755211 TI - Cupric ions induce the oxidation and trigger the aggregation of human superoxide dismutase 1. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS), partly caused by the mutations and aggregation of human copper, zinc superoxide dismutase (SOD1), is a fatal degenerative disease of motor neurons. Because SOD1 is a major copper-binding protein present at relatively high concentration in motor neurons and copper can be a harmful pro-oxidant, we want to know whether aberrant copper biochemistry could underlie ALS pathogenesis. In this study, we have investigated and compared the effects of cupric ions on the aggregation of ALS-associated SOD1 mutant A4V and oxidized wild-type SOD1. METHODOLOGY/PRINCIPAL FINDINGS: As revealed by 90 degrees light scattering, dynamic light scattering, SDS-PAGE, and atomic force microscopy, free cupric ions in solution not only induce the oxidation of either apo A4V or Zn2-A4V and trigger the oligomerization and aggregation of oxidized A4V under copper-mediated oxidative conditions, but also trigger the aggregation of non-oxidized form of such a pathogenic mutant. As evidenced by mass spectrometry and SDS-PAGE, Cys-111 is a primary target for oxidative modification of pathological human SOD1 mutant A4V by either excess Cu(2+) or hydrogen peroxide. The results from isothermal titration calorimetry show that A4V possesses two sets of independent binding sites for Cu(2+): a moderate-affinity site (10(6) M(-1)) and a high-affinity site (10(8) M(-1)). Furthermore, Cu(2+) binds to wild-type SOD1 oxidized by hydrogen peroxide in a way similar to A4V, triggering the aggregation of such an oxidized form. CONCLUSIONS/SIGNIFICANCE: We demonstrate that excess cupric ions induce the oxidation and trigger the aggregation of A4V SOD1, and suggest that Cu(2+) plays a key role in the mechanism of aggregation of both A4V and oxidized wild-type SOD1. A plausible model for how pathological SOD1 mutants aggregate in ALS-affected motor neurons with the disruption of copper homeostasis has been provided. PMID- 23755212 TI - Self-rated health and cardiovascular disease incidence: results from a longitudinal population-based cohort in Norfolk, UK. AB - INTRODUCTION: Self-rated health (SRH) predicts chronic disease morbidity including cardiovascular disease (CVD). In a population-based cohort, we examined the association between SRH and incident CVD and whether this association was independent of socio-demographic, clinical and behavioural participant characteristics. METHODS: Population-based prospective cohort study (European Prospective Investigation of Cancer-Norfolk). 20,941 men and women aged 39-74 years without prevalent CVD attended a baseline health examination (1993-1998) and were followed for CVD events/death until March 2007 (mean 11 years). We used a Cox proportional hazards model to quantify the association between baseline SRH (reported on a four point scale--excellent, good, fair, poor) and risk of developing CVD at follow-up after adjusting for socio-demographic, clinical and behavioural risk factors. RESULTS: Baseline SRH was reported as excellent by 17.8% participants, good by 65.1%, fair by 16.0% and poor by 1.2%. During 225,508 person-years of follow-up, there were 55 (21.2%) CVD events in the poor SRH group and 259 (7.0%) in the excellent SRH group (HR 3.7, 95% CI 2.8-4.9). The HR remained significant after adjustment for behavioural risk factors (HR 2.6, 95% CI 1.9-3.5) and after adjustment for all socio-demographic, clinical and behavioural risk factors (HR 3.3, 95% CI 2.4-4.4). Associations were strong for both fatal and non-fatal events and remained strong over time. CONCLUSIONS: SRH is a strong predictor of incident fatal and non-fatal CVD events in this healthy, middle-aged population. Some of the association is explained by lifestyle behaviours, but SRH remains a strong predictor after adjustment for socio demographic, clinical and behavioural risk factors and after a decade of follow up. This easily accessible patient-centred measure of health status may be a useful indicator of individual and population health for those working in primary care and public health. PMID- 23755213 TI - PCR-based molecular characterization of Toxocara spp. using feces of stray cats: a study from Southwest Iran. AB - Feces of stray cat are potential sources of gastrointestinal parasites and play a crucial role in spreading and transmitting parasite eggs, larvae, and oocysts through contamination of soil, food, or water. In this study, we investigated the prevalence of Toxocara spp. infection in stray cats in Ahvaz city, southwest Iran. Eggs of Toxocara spp. in feces of stray cats were detected by the sucrose flotation method, and identification was conducted by polymerase chain reaction (PCR) and DNA sequencing. Of the 140 fecal samples that were randomly collected from public environments during the months of January to May 2012, 45% were found to harbour Toxocara spp. eggs. The highest prevalence of Toxocara spp. eggs was found in the central area of Ahvaz city (28.6%). T. canis eggs were found in 4 (6.34%) of the 63 positive samples. Stray cats are found in parks, playgrounds, and other public places and may be a potential contamination risk. Identification of Toxocara spp. using molecular methods is sufficiently sensitive to detect low levels of parasites and identify the different Toxocara spp. in feces. The relatively high prevalence of Toxocara spp. infection may continue to increase due to lack of effective environmental hygiene control in Iran. Consequently, there is a need to plan adequate programs to detect, identify, and control this infection as well as stray cats in the region. PMID- 23755214 TI - Role of miR-142-3p in the post-transcriptional regulation of the clock gene Bmal1 in the mouse SCN. AB - MicroRNAs (miRNAs) are small non-coding RNAs that function as post transcriptional modulators by regulating stability or translation of target mRNAs. Recent studies have implicated miRNAs in the regulation of mammalian circadian rhythms. To explore the role of miRNAs in the post-transcriptional modulation of core clock genes in the master circadian pacemaker, we examined miR 142-3p for evidence of circadian expression in the suprachiasmatic nuclei (SCN), regulation of its putative clock gene target Bmal1 via specific binding sites in the 3' UTR and overexpression-induced changes in the circadian rhythm of BMAL1 protein levels in SCN cells. In mice exposed to constant darkness (DD), miR-142 3p levels in the SCN were characterized by circadian rhythmicity with peak expression during early subjective day at CT 3. Mutagenesis studies indicate that two independent miRNA recognition elements located at nucleotides 1-7 and 335-357 contribute equally to miR-142-3p-induced repression of luciferase-reported Bmal1 3' UTR activity. Importantly, overexpression of miR-142-3p in immortalized SCN cells abolished circadian variation in endogenous BMAL1 protein levels in vitro. Collectively, our results suggest that miR-142-3p may play a role in the post transcriptional modulation of Bmal1 and its oscillatory regulation in molecular feedback loops mediating SCN circadian function. PMID- 23755215 TI - Anthropometric differences between HIV-infected individuals prior to antiretroviral treatment and the general population from 1998-2007: the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) cohort and NHANES. AB - OBJECTIVE: To assess differences in body circumferences and body mass index (BMI, kg/m(2)) between antiretroviral treatment (ART) naive HIV-infected and HIV uninfected persons. METHODS: Waist, arm, and thigh circumferences and BMI were measured within the ALLRT and NHANES cohorts between 1998 and 2007. ALLRT is a prospective, longitudinal study of U.S. participants enrolled in randomized HIV treatment studies conducted by the AIDS Clinical Trials Group (ACTG). NHANES is a representative group of the US population. The cohorts were analyzed in two time periods, to account for trends towards increased adiposity. Anthropometrics were displayed in percentiles by age and sex. Multiple linear regression models examined differences between cohorts. RESULTS: ALLRT had more males (82% versus 48%, p<0.0001), more black participants (32% versus 23%, p<0.0001), and less Hispanics (21% versus 30%, p<0.0001) than NHANES. Mean BMI was smaller in ALLRT males and females compared to NHANES by 1.6-2.4 kg/m(2) (p<0.0001). Mean waist and arm circumferences in both sexes and time periods were significantly smaller in ALLRT than in NHANES (p<0.0001). Mean thigh circumference in ALLRT was also smaller than NHANES among males (p<0.0001 in both time periods) and females (p = 0.01 in the early time period). CONCLUSIONS: Differences in anthropometrics existed prior to ART initiation, in this large national cohort of HIV-infected individuals, compared to a representative HIV-uninfected cohort, indicating that HIV and its complications have important effects on body shape. Further longitudinal examination of anthropometrics in this HIV-infected cohort may provide additional insight into disease risk. TRIAL REGISTRATION: NCT00001137 at www.clinicaltrials.gov. PMID- 23755216 TI - Differential mechanisms of activation of the Ang peptide receptors AT1, AT2, and MAS: using in silico techniques to differentiate the three receptors. AB - The renin-angiotensin system is involved in multiple conditions ranging from cardiovascular disorders to cancer. Components of the pathway, including ACE, renin and angiotensin receptors are targets for disease treatment. This study addresses three receptors of the pathway: AT1, AT2, and MAS and how the receptors are similar and differ in activation by angiotensin peptides. Combining biochemical and amino acid variation data with multiple species sequence alignments, structural models, and docking site predictions allows for visualization of how angiotensin peptides may bind and activate the receptors; allowing identification of conserved and variant mechanisms in the receptors. MAS differs from AT1 favoring Ang-(1-7) and not Ang II binding, while AT2 recently has been suggested to preferentially bind Ang III. A new model of Ang peptide binding to AT1 and AT2 is proposed that correlates data from site directed mutagenesis and photolabled experiments that were previously considered conflicting. Ang II binds AT1 and AT2 through a conserved initial binding mode involving amino acids 111 (consensus 325) of AT1 (Asn) interacting with Tyr (4) of Ang II and 199 and 256 (consensus 512 and 621, a Lys and His respectively) interacting with Phe (8) of Ang II. In MAS these sites are not conserved, leading to differential binding and activation by Ang-(1-7). In both AT1 and AT2, the Ang II peptide may internalize through Phe (8) of Ang II propagating through the receptors' conserved aromatic amino acids to the final photolabled positioning relative to either AT1 (amino acid 294, Asn, consensus 725) or AT2 (138, Leu, consensus 336). Understanding receptor activation provides valuable information for drug design and identification of other receptors that can potentially bind Ang peptides. PMID- 23755217 TI - Environmental influences on kelp performance across the reproductive period: an ecological trade-off between gametophyte survival and growth? AB - Most kelps (order Laminariales) exhibit distinct temporal patterns in zoospore production, gametogenesis and gametophyte reproduction. Natural fluctuations in ambient environmental conditions influence the intrinsic characteristics of gametes, which define their ability to tolerate varied conditions. The aim of this work was to document seasonal patterns in reproduction and gametophyte growth and survival of Ecklonia radiata (C. Agardh) J. Agardh in south-western Australia. These results were related to patterns in local environmental conditions in an attempt to ascertain which factors explain variation throughout the season. E. radiata was fertile (produced zoospores) for three and a half months over summer and autumn. Every two weeks during this time, gametophytes were grown in a range of temperatures (16-22 degrees C) in the laboratory. Zoospore densities were highly variable among sample periods; however, zoospores released early in the season produced gametophytes which had greater rates of growth and survival, and these rates declined towards the end of the reproductive season. Growth rates of gametophytes were positively related to day length, with the fastest growing recruits released when the days were longest. Gametophytes consistently survived best in the lowest temperature (16 degrees C), yet exhibited optimum growth in higher culture temperatures (20-22 degrees C). These results suggest that E. radiata releases gametes when conditions are favourable for growth, and E. radiata gametophytes are tolerant of the range of temperatures observed at this location. E. radiata releases the healthiest gametophytes when day length and temperature conditions are optimal for better germination, growth, and sporophyte production, perhaps as a mechanism to help compete against other species for space and other resources. PMID- 23755218 TI - Frailty in old age is associated with decreased interleukin-12/23 production in response to toll-like receptor ligation. AB - Aging is associated with progressive alterations of immune functions, leading to higher susceptibility to bacterial and viral infections and reduced vaccine responses. Data concerning cytokine production in response to Toll-like receptor (TLR) ligands are highly variable in old people, reflecting the heterogeneity of the geriatric population. The aim of our study was to define the relative contribution of age and clinical status on TLR-induced interleukin (IL)-12p70 and IL-23 production as these cytokines play an important role in the protection against intracellular and extracellular pathogens, respectively. For this purpose, we recruited 100 subjects (aged 23-96 years) in the general population or hospitalized for chronic diseases. We collected information on clinical status (medical history, ongoing comorbidities, treatments and geriatric scales), biological parameters (biochemical and hematological tests, telomere length determination, cytomegalovirus serology). Whole blood samples were stimulated with a combination of TLR4 and TLR7/8 ligands. We performed univariate and stepwise backward multivariate analyses regression to define which set of clinical variables could be predictive for IL-12p70 and IL-23 production in these conditions. Our results indicated that age was not correlated with TLR-mediated IL-12p70 and IL-23 production. In contrast, poor nutritional status and frailty in subjects >75 years were associated with decreased IL-12p70 and IL-23 production. By intracytoplasmic staining, we confirmed that production of IL 12/23p40 by conventional dendritic cells (DCs) upon TLR ligation was decreased in frail patients. However, proportion of DCs and monocytes subsets, phenotypic maturation and proximal signaling events were found to be comparable in frail and healthy old subjects. These results suggest the importance of age-associated clinical parameters and not age by itself in the alteration of innate immune responses in old individuals and emphasis the importance of innate immune responses in the susceptibility of frail geriatric patients to infections. PMID- 23755219 TI - Scanning a DNA molecule for bound proteins using hybrid magnetic and optical tweezers. AB - The functional state of the genome is determined by its interactions with proteins that bind, modify, and move along the DNA. To determine the positions and binding strength of proteins localized on DNA we have developed a combined magnetic and optical tweezers apparatus that allows for both sensitive and label free detection. A DNA loop, that acts as a scanning probe, is created by looping an optically trapped DNA tether around a DNA molecule that is held with magnetic tweezers. Upon scanning the loop along the lambda-DNA molecule, EcoRI proteins were detected with ~17 nm spatial resolution. An offset of 33 +/- 5 nm for the detected protein positions was found between back and forwards scans, corresponding to the size of the DNA loop and in agreement with theoretical estimates. At higher applied stretching forces, the scanning loop was able to remove bound proteins from the DNA, showing that the method is in principle also capable of measuring the binding strength of proteins to DNA with a force resolution of 0.1 pN/[Formula: see text]. The use of magnetic tweezers in this assay allows the facile preparation of many single-molecule tethers, which can be scanned one after the other, while it also allows for direct control of the supercoiling state of the DNA molecule, making it uniquely suitable to address the effects of torque on protein-DNA interactions. PMID- 23755220 TI - Prognostic and clinicopathological significance of survivin in colorectal cancer: a meta-analysis. AB - Survivin/BIRC5 is a potentially interesting prognostic marker and therapeutic target in colorectal cancer (CRC). However, the available data on survivin expression in CRC are heterogeneous. Thus, to clarify the prognostic relevance of survivin in patients with CRC and its association with clinicopathological parameters we performed a meta-analysis. We screened PubMed and EMBASE for those studies that investigated the prognostic value of survivin and its association with clinicopathological parameters in CRC. Data from eligible studies were extracted and included into the meta-analyses using a random effects model. Electronical literature search identified 15 studies including 1934 patients with CRC mostly detecting survivin by immunohistochemistry (IHC). Pooled hazard ratios of 11 studies that performed survival analysis revealed a positive correlation between survivin expression and poor prognosis (HR 1.93; 95% CI: 1.55-2.42; P<0.00001; I(2) = 23%). Subgroup analyses with respect to the detection method, HR estimation, global quality score and the country of origin in which the study was conducted supported the stability of this observation. In addition, meta analyses revealed a significant association between expression of survivin and the presence of lymph node metastases (OR: 0.37; 95% CI: 0.19-0.75; I(2) = 61%) or blood vessel invasion (OR: 0.50; 95% CI: 0.28-0.90; I(2) = 0%). Expression of survivin indicates poor prognosis and a pro-metastatic phenotype and may be useful in identifying a subgroup of patients that could benefit from a targeted therapy against survivin in CRC. PMID- 23755221 TI - Oxygen and air nanobubble water solution promote the growth of plants, fishes, and mice. AB - Nanobubbles (<200 nm in diameter) have several unique properties such as long lifetime in liquid owing to its negatively charged surface, and its high gas solubility into the liquid owing to its high internal pressure. They are used in variety of fields including diagnostic aids and drug delivery, while there are no reports assessing their effects on the growth of lives. Nanobubbles of air or oxygen gas were generated using a nanobubble aerator (BUVITAS; Ligaric Company Limited, Osaka, Japan). Brassica campestris were cultured hydroponically for 4 weeks within air-nanobubble water or within normal water. Sweetfish (for 3 weeks) and rainbow trout (for 6 weeks) were kept either within air-nanobubble water or within normal water. Finally, 5 week-old male DBA1/J mice were bred with normal free-chaw and free-drinking either of oxygen-nanobubble water or of normal water for 12 weeks. Oxygen-nanobubble significantly increased the dissolved oxygen concentration of water as well as concentration/size of nanobubbles which were relatively stable for 70 days. Air-nanobubble water significantly promoted the height (19.1 vs. 16.7 cm; P<0.05), length of leaves (24.4 vs. 22.4 cm; P<0.01), and aerial fresh weight (27.3 vs. 20.3 g; P<0.01) of Brassica campestris compared to normal water. Total weight of sweetfish increased from 3.0 to 6.4 kg in normal water, whereas it increased from 3.0 to 10.2 kg in air-nanobubble water. In addition, total weight of rainbow trout increased from 50.0 to 129.5 kg in normal water, whereas it increased from 50.0 to 148.0 kg in air-nanobubble water. Free oral intake of oxygen-nanobubble water significantly promoted the weight (23.5 vs. 21.8 g; P<0.01) and the length (17.0 vs. 16.1 cm; P<0.001) of mice compared to that of normal water. We have demonstrated for the first time that oxygen and air-nanobubble water may be potentially effective tools for the growth of lives. PMID- 23755222 TI - Antioxidant and anti-inflammatory effects in RAW264.7 macrophages of malvidin, a major red wine polyphenol. AB - BACKGROUND: Red wine polyphenols can prevent cardiovascular and inflammatory diseases. Resveratrol, the most extensively studied constituent, is unlikely to solely account for these beneficial effects because of its rather low abundance and bioavailability. Malvidin is far the most abundant polyphenol in red wine; however, very limited data are available about its effect on inflammatory processes and kinase signaling pathways. METHODS FINDINGS: The present study was carried out by using RAW 264.7 macrophages stimulated by bacterial lipopolysaccharide in the presence and absence of malvidin. From the cells, activation of nuclear factor-kappaB, mitogen-activated protein kinase, protein kinase B/Akt and poly ADP-ribose polymerase, reactive oxygen species production, mitogen-activated protein kinase phosphatase-1 expression and mitochondrial depolarization were determined. We found that malvidin attenuated lipopolysaccharide-induced nuclear factor-kappaB, poly ADP-ribose polymerase and mitogen-activated protein kinase activation, reactive oxygen species production and mitochondrial depolarization, while upregulated the compensatory processes; mitogen-activated protein kinase phosphatase-1 expression and Akt activation. CONCLUSIONS: These effects of malvidin may explain the previous findings and at least partially account for the positive effects of moderate red wine consumption on inflammation-mediated chronic maladies such as obesity, diabetes, hypertension and cardiovascular disease. PMID- 23755223 TI - The importance of coral larval recruitment for the recovery of reefs impacted by cyclone Yasi in the central Great Barrier Reef. AB - Cyclone Yasi, one of the most severe tropical storms on record, crossed the central Great Barrier Reef (GBR) in February 2011, bringing wind speeds of up to 285 km hr-1 and wave heights of at least 10 m, and causing massive destruction to exposed reefs in the Palm Island Group. Following the cyclone, mean (+/- S.E.) hard coral cover ranged from just 2.1 (0.2) % to 5.3 (0.4) % on exposed reefs and no reproductively mature colonies of any species of Acropora remained. Although no fragments of Acropora were found at impacted exposed sites following the cyclone, small juvenile colonies of Acropora (<10 cm diameter) were present, suggesting that their small size and compact morphologies enabled them to survive the cyclone. By contrast, sheltered reefs appeared to be unaffected by the cyclone. Mean (+/- S.E.) hard coral cover ranged from 18.2 (2.4) % to 30.0 (1.0) % and a large proportion of colonies of Acropora were reproductively mature. Macroalgae accounted for 8 to 16% of benthic cover at exposed sites impacted by cyclone Yasi but were absent at sheltered sites. Mean (+/- S.E.) recruitment of acroporids to settlement tiles declined from 25.3 (4.8) recruits tile-1 in the pre-cyclone spawning event (2010) to 15.4 (2.2) recruits tile-1 in the first post cyclone spawning event (2011). Yet, post-cyclone recruitment did not differ between exposed (15.2+/-2.1 S.E.) and sheltered sites (15.6+/-2.2 S.E.), despite the loss of reproductive colonies at the exposed sites, indicating larval input from external sources. Spatial variation in impacts, the survival of small colonies, and larval replenishment to impacted reefs suggest that populations of Acropora have the potential to recover from this severe disturbance, provided that the Palm Islands are not impacted by acute disturbances or suffer additional chronic stressors in the near future. PMID- 23755224 TI - Effects of sample size on differential gene expression, rank order and prediction accuracy of a gene signature. AB - Top differentially expressed gene lists are often inconsistent between studies and it has been suggested that small sample sizes contribute to lack of reproducibility and poor prediction accuracy in discriminative models. We considered sex differences (69?, 65 ?) in 134 human skeletal muscle biopsies using DNA microarray. The full dataset and subsamples (n = 10 (5 ?, 5 ?) to n = 120 (60 ?, 60 ?)) thereof were used to assess the effect of sample size on the differential expression of single genes, gene rank order and prediction accuracy. Using our full dataset (n = 134), we identified 717 differentially expressed transcripts (p<0.0001) and we were able predict sex with ~90% accuracy, both within our dataset and on external datasets. Both p-values and rank order of top differentially expressed genes became more variable using smaller subsamples. For example, at n = 10 (5 ?, 5 ?), no gene was considered differentially expressed at p<0.0001 and prediction accuracy was ~50% (no better than chance). We found that sample size clearly affects microarray analysis results; small sample sizes result in unstable gene lists and poor prediction accuracy. We anticipate this will apply to other phenotypes, in addition to sex. PMID- 23755225 TI - alpha-Lipoic acid antioxidant treatment limits glaucoma-related retinal ganglion cell death and dysfunction. AB - Oxidative stress has been implicated in neurodegenerative diseases, including glaucoma. However, due to the lack of clinically relevant models and expense of long-term testing, few studies have modeled antioxidant therapy for prevention of neurodegeneration. We investigated the contribution of oxidative stress to the pathogenesis of glaucoma in the DBA/2J mouse model of glaucoma. Similar to other neurodegenerative diseases, we observed lipid peroxidation and upregulation of oxidative stress-related mRNA and protein in DBA/2J retina. To test the role of oxidative stress in disease progression, we chose to deliver the naturally occurring, antioxidant alpha-lipoic acid (ALA) to DBA/2J mice in their diet. We used two paradigms for ALA delivery: an intervention paradigm in which DBA/2J mice at 6 months of age received ALA in order to intervene in glaucoma development, and a prevention paradigm in which DBA/2J mice were raised on a diet supplemented with ALA, with the goal of preventing glaucoma development. At 10 and 12 months of age (after 4 and 11 months of dietary ALA respectively), we measured changes in genes and proteins related to oxidative stress, retinal ganglion cell (RGC) number, axon transport, and axon number and integrity. Both ALA treatment paradigms showed increased antioxidant gene and protein expression, increased protection of RGCs and improved retrograde transport compared to control. Measures of lipid peroxidation, protein nitrosylation, and DNA oxidation in retina verified decreased oxidative stress in the prevention and intervention paradigms. These data demonstrate the utility of dietary therapy for reducing oxidative stress and improving RGC survival in glaucoma. PMID- 23755226 TI - Urea synthesis and excretion in Aedes aegypti mosquitoes are regulated by a unique cross-talk mechanism. AB - Aedes aegypti mosquitoes do not have a typical functional urea cycle for ammonia disposal such as the one present in most terrestrial vertebrates. However, they can synthesize urea by two different pathways, argininolysis and uricolysis. We investigated how formation of urea by these two pathways is regulated in females of A. aegypti. The expression of arginase (AR) and urate oxidase (UO), either separately or simultaneously (ARUO) was silenced by RNAi. The amounts of several nitrogen compounds were quantified in excreta using mass spectrometry. Injection of mosquitoes with either dsRNA-AR or dsRNA-UO significantly decreased the expressions of AR or UO in the fat body (FB) and Malpighian tubules (MT). Surprisingly, the expression level of AR was increased when UO was silenced and vice versa, suggesting a cross-talk regulation between pathways. In agreement with these data, the amount of urea measured 48 h after blood feeding remained unchanged in those mosquitoes injected with dsRNA-AR or dsRNA-UO. However, allantoin significantly increased in the excreta of dsRNA-AR-injected females. The knockdown of ARUO mainly led to a decrease in urea and allantoin excretion, and an increase in arginine excretion. In addition, dsRNA-AR-injected mosquitoes treated with a specific nitric oxide synthase inhibitor showed an increase of UO expression in FB and MT and a significant increase in the excretion of nitrogen compounds. Interestingly, both a temporary delay in the digestion of a blood meal and a significant reduction in the expression of several genes involved in ammonia metabolism were observed in dsRNA-AR, UO or ARUO-injected females. These results reveal that urea synthesis and excretion in A. aegypti are tightly regulated by a unique cross-talk signaling mechanism. This process allows blood fed mosquitoes to regulate the synthesis and/or excretion of nitrogen waste products, and avoid toxic effects that could result from a lethal concentration of ammonia in their tissues. PMID- 23755227 TI - Soil temperature triggers the onset of photosynthesis in Korean pine. AB - In forest ecosystems, the onset of spring photosynthesis may have an important influence on the annual carbon balance. However, triggers for the onset of photosynthesis have yet to be clearly identified, especially for temperate evergreen conifers. The effects of climatic factors on recovery of photosynthetic capacity in a Korean pine forest were investigated in the field. No photosynthesis was detectable when the soil temperature was below 0 degrees C even if the air temperature was far beyond 15 degrees C. The onset of photosynthesis and sap flow was coincident with the time of soil thawing. The rates of recovery of photosynthetic capacity highly fluctuated with air temperature after onset of photosynthesis, and intermittent frost events remarkably inhibited the photosynthetic capacity of the needles. The results suggest that earlier soil thawing is more important than air temperature increases in triggering the onset of photosynthesis in Korean pine in temperate zones under global warming scenarios. PMID- 23755228 TI - The influence of socioeconomic factors on health parameters in overweight and obese adults. AB - The prevalence of being overweight and of obesity is increasing worldwide, and is associated with a high risk to health. Therefore, the aim of our study was to investigate whether normal weight, overweight and obese subjects of low, middle or high socioeconomic status (SES) differ with regard to their health behavior, health, quality of life, and the use of medical care. Data from the Austrian Health Interview Survey (ATHIS) 2006/07, comprising 3 groups of 1,077 individuals, each of whom were normal weight, overweight, or obese, respectively, and matched according to their age, sex and SES, were analyzed concerning health outcomes. The results show that subjects with a low SES differ significantly from those of high SES in terms of their health behavior, self-perceived health, levels of impairment, chronic conditions, quality of life, and health care. Additionally, obesity in adults is associated with sub-optimal dietary practices and worse health, poorer quality of life and medical care than normal weight and overweight individuals. A significant interaction between the weight class and SES was found concerning physical exercise, impairment due to health problems and chronic diseases. A low SES has a strong negative impact on health, especially in obese individuals. Therefore a continuous target group-oriented, non discriminatory public health program is required, prioritizing obese subjects with low SES. PMID- 23755229 TI - Redox factor-1 activates endothelial SIRTUIN1 through reduction of conserved cysteine sulfhydryls in its deacetylase domain. AB - Apurinic/Apyrmidinic Endonuclease 1/Redox Factor-1 (APE1/Ref-1) is a reductant which is important for vascular homeostasis. SIRTUIN1 (SIRT1) is a lysine deacetylase that also promotes endothelium-dependent vasorelaxation. We asked if APE1/Ref-1 governs the redox state and activity of SIRT1, and whether SIRT1 mediates the effect of APE1/Ref-1 on endothelium-dependent vascular function. APE1/Ref-1 maintains sulfhydryl (thiol) groups of cysteine residues in SIRT1 in the reduced form and promotes endothelial SIRT1 activity. APE1/Ref-1 stimulates SIRT1 activity by targeting highly conserved vicinal thiols 371 and 374 which form a zinc tetra-thiolate motif in the deacetylase domain of SIRT1. Cysteine residues in the N-terminal redox domain of APE1/Ref-1 are essential for reducing SIRT1 and stimulating its activity. APE1/Ref-1 protects endothelial SIRT1 from hydrogen peroxide-induced oxidation of sulfhydryls and from inactivation. APE1/Ref-1 also promotes lysine deacetylation of the SIRT1 target endothelial nitric oxide synthase (eNOS). SIRT1 mutated at cysteines 371 and 374, which renders it non-reducible by APE1/Ref-1, prevents lysine deacetylation of eNOS by APE1/Ref-1. SIRT1 free thiol (reduced sulfhydryl) content and deacetylase activity are diminished in all examined tissues of APE1/Ref-1(+/-) mice, including the vasculature. Overexpression of SIRT1 in aortas of APE1/Ref-1(+/-) mice restores endothelium-dependent vasorelaxation and bioavailable nitric oxide (NO) to levels similar to those observed in wild-type mice. Thus, APE1/Ref-1, by maintaining functionally important cysteine sulfhydryls in SIRT1 in the reduced form, promotes endothelial SIRT1 activity. This reductive activation of endothelial SIRT1 by APE1/Ref-1 mediates the effect of APE1/Ref-1 on eNOS acetylation, promoting endothelium-derived NO and endothelium-dependent vasorelaxation. PMID- 23755231 TI - Synthetic-type control charts for time-between-events monitoring. AB - This paper proposes three synthetic-type control charts to monitor the mean time between-events of a homogenous Poisson process. The first proposed chart combines an Erlang (cumulative time between events, Tr ) chart and a conforming run length (CRL) chart, denoted as Synth-Tr chart. The second proposed chart combines an exponential (or T) chart and a group conforming run length (GCRL) chart, denoted as GR-T chart. The third proposed chart combines an Erlang chart and a GCRL chart, denoted as GR-Tr chart. By using a Markov chain approach, the zero- and steady-state average number of observations to signal (ANOS) of the proposed charts are obtained, in order to evaluate the performance of the three charts. The optimal design of the proposed charts is shown in this paper. The proposed charts are superior to the existing T chart, Tr chart, and Synth-T chart. As compared to the EWMA-T chart, the GR-T chart performs better in detecting large shifts, in terms of the zero- and steady-state performances. The zero-state Synth T4 and GR-Tr (r = 3 or 4) charts outperform the EWMA-T chart for all shifts, whereas the Synth-Tr (r = 2 or 3) and GR-T 2 charts perform better for moderate to large shifts. For the steady-state process, the Synth-Tr and GR-Tr charts are more efficient than the EWMA-T chart in detecting small to moderate shifts. PMID- 23755230 TI - Complete genome sequence analysis of Nocardia brasiliensis HUJEG-1 reveals a saprobic lifestyle and the genes needed for human pathogenesis. AB - Nocardia brasiliensis is an important etiologic agent of mycetoma. These bacteria live as a saprobe in soil or organic material and enter the tissue via minor trauma. Mycetoma is characterized by tumefaction and the production of fistula and abscesses, with no spontaneous cure. By using mass sequencing, we determined the complete genomic nucleotide sequence of the bacteria. According to our data, the genome is a circular chromosome 9,436,348-bp long with 68% G+C content that encodes 8,414 proteins. We observed orthologs for virulence factors, a higher number of genes involved in lipid biosynthesis and catabolism, and gene clusters for the synthesis of bioactive compounds, such as antibiotics, terpenes, and polyketides. An in silico analysis of the sequence supports the conclusion that the bacteria acquired diverse genes by horizontal transfer from other soil bacteria, even from eukaryotic organisms. The genome composition reflects the evolution of bacteria via the acquisition of a large amount of DNA, which allows it to survive in new ecological niches, including humans. PMID- 23755232 TI - Lung myofibroblasts are characterized by down-regulated cyclooxygenase-2 and its main metabolite, prostaglandin E2. AB - BACKGROUND: Prostaglandin E2 (PGE2), the main metabolite of cyclooxygenase (COX), is a well-known anti-fibrotic agent. Moreover, myofibroblasts expressing alpha smooth muscle actin (alpha-SMA), fibroblast expansion and epithelial-mesenchymal transition (EMT) are critical to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our aim was to investigate the expression of COX-2 and PGE2 in human lung myofibroblasts and establish whether fibroblast-myofibroblast transition (FMT) and EMT are associated with COX-2 and PGE2 down-regulation. METHODS: Fibroblasts obtained from IPF patients (n = 6) and patients undergoing spontaneous pneumothorax (control, n = 6) and alveolar epithelial cell line A549 were incubated with TGF-beta1 and FMT and EMT markers were evaluated. COX-2 and alpha-SMA expression, PGE2 secretion and cell proliferation were measured after IL-1beta and PGE2 incubation. RESULTS: Myofibroblasts from both control and IPF fibroblast cultures stimulated with IL-1beta showed no COX-2 expression. IPF fibroblasts showed increased myofibroblast population and reduced COX-2 expression in response to IL-1beta. TGF-beta1 increased the number of myofibroblasts in a time-dependent manner. In contrast, TGF-beta1 induced slight COX-2 expression at 4 h (without increase in myofibroblasts) and 24 h, but not at 72 h. Both IPF and control cultures incubated with TGF-beta1 for 72 h showed diminished COX-2 induction, PGE2 secretion and alpha-SMA expression after IL 1beta addition. The latter decreased proliferation in fibroblasts but not in myofibroblasts. A549 cells incubated with TGF-beta1 for 72 h showed down regulated COX-2 expression and low basal PGE2 secretion in response to IL-1beta. Immuno-histochemical analysis of IPF lung tissue showed no COX-2 immuno reactivity in myofibroblast foci. CONCLUSIONS: Myofibroblasts are associated with COX-2 down-regulation and reduced PGE2 production, which could be crucial in IPF development and progression. PMID- 23755233 TI - Sunscreen products as emerging pollutants to coastal waters. AB - A growing awareness of the risks associated with skin exposure to ultraviolet (UV) radiation over the past decades has led to increased use of sunscreen cosmetic products leading the introduction of new chemical compounds in the marine environment. Although coastal tourism and recreation are the largest and most rapidly growing activities in the world, the evaluation of sunscreen as source of chemicals to the coastal marine system has not been addressed. Concentrations of chemical UV filters included in the formulation of sunscreens, such as benzophehone 3 (BZ-3), 4-methylbenzylidene camphor (4-MBC), TiO2 and ZnO, are detected in nearshore waters with variable concentrations along the day and mainly concentrated in the surface microlayer (i.e. 53.6-577.5 ng L-1 BZ-3; 51.4 113.4 ng L-1 4-MBC; 6.9-37.6 ug L-1 Ti; 1.0-3.3 ug L-1 Zn). The presence of these compounds in seawater suggests relevant effects on phytoplankton. Indeed, we provide evidences of the negative effect of sunblocks on the growth of the commonly found marine diatom Chaetoceros gracilis (mean EC50 = 125+/-71 mg L-1). Dissolution of sunscreens in seawater also releases inorganic nutrients (N, P and Si forms) that can fuel algal growth. In particular, PO43- is released by these products in notable amounts (up to 17 umol PO43-g-1). We conservatively estimate an increase of up to 100% background PO43- concentrations (0.12 umol L-1 over a background level of 0.06 umol L-1) in nearshore waters during low water renewal conditions in a populated beach in Majorca island. Our results show that sunscreen products are a significant source of organic and inorganic chemicals that reach the sea with potential ecological consequences on the coastal marine ecosystem. PMID- 23755234 TI - Pre- and early-postnatal nutrition modify gene and protein expressions of muscle energy metabolism markers and phospholipid Fatty Acid composition in a muscle type specific manner in sheep. AB - We previously reported that undernutrition in late fetal life reduced whole-body insulin sensitivity in adult sheep, irrespective of dietary exposure in early postnatal life. Skeletal muscle may play an important role in control of insulin action. We therefore studied a range of putative key muscle determinants of insulin signalling in two types of skeletal muscles (longissimus dorsi (LD) and biceps femoris (BF)) and in the cardiac muscle (ventriculus sinister cordis (VSC)) of sheep from the same experiment. Twin-bearing ewes were fed either 100% (NORM) or 50% (LOW) of their energy and protein requirements during the last trimester of gestation. From day-3 postpartum to 6-months of age (around puberty), twin offspring received a high-carbohydrate-high-fat (HCHF) or a moderate-conventional (CONV) diet, whereafter all males were slaughtered. Females were subsequently raised on a moderate diet and slaughtered at 2-years of age (young adults). The only long-term consequences of fetal undernutrition observed in adult offspring were lower expressions of the insulin responsive glucose transporter 4 (GLUT4) protein and peroxisome proliferator-activated receptor gamma, coactivator 1alpha (PGC1alpha) mRNA in BF, but increased PGC1alpha expression in VSC. Interestingly, the HCHF diet in early postnatal life was associated with somewhat paradoxically increased expressions in LD of a range of genes (but not proteins) related to glucose uptake, insulin signalling and fatty acid oxidation. Except for fatty acid oxidation genes, these changes persisted into adulthood. No persistent expression changes were observed in BF and VSC. The HCHF diet increased phospholipid ratios of n-6/n-3 polyunsaturated fatty acids in all muscles, even in adults fed identical diets for 11/2 years. In conclusion, early postnatal, but not late gestation, nutrition had long-term consequences for a number of determinants of insulin action and metabolism in LD. Tissues other than muscle may account for reduced whole body insulin sensitivity in adult LOW sheep. PMID- 23755235 TI - Mitofusin 2 protects hepatocyte mitochondrial function from damage induced by GCDCA. AB - Mitochondrial impairment is hypothesized to contribute to the pathogenesis of chronic cholestatic liver diseases. Mitofusin 2 (Mfn2) regulates mitochondrial morphology and signaling and is involved in the development of numerous mitochondrial-related diseases; however, a functional role for Mfn2 in chronic liver cholestasis which is characterized by increased levels of toxic bile acids remain unknown. Therefore, the aims of this study were to evaluate the expression levels of Mfn2 in liver samples from patients with extrahepatic cholestasis and to investigate the role Mfn2 during bile acid induced injury in vitro. Endogenous Mfn2 expression decreased in patients with extrahepatic cholestasis. Glycochenodeoxycholic acid (GCDCA) is the main toxic component of bile acid in patients with extrahepatic cholestasis. In human normal hepatocyte cells (L02), Mfn2 plays an important role in GCDCA-induced mitochondrial damage and changes in mitochondrial morphology. In line with the mitochondrial dysfunction, the expression of Mfn2 decreased significantly under GCDCA treatment conditions. Moreover, the overexpression of Mfn2 effectively attenuated mitochondrial fragmentation and reversed the mitochondrial damage observed in GCDCA-treated L02 cells. Notably, a truncated Mfn2 mutant that lacked the normal C-terminal domain lost the capacity to induce mitochondrial fusion. Increasing the expression of truncated Mfn2 also had a protective effect against the hepatotoxicity of GCDCA. Taken together, these findings indicate that the loss of Mfn2 may play a crucial role the pathogenesis of the liver damage that is observed in patients with extrahepatic cholestasis. The findings also indicate that Mfn2 may directly regulate mitochondrial metabolism independently of its primary fusion function. Therapeutic approaches that target Mfn2 may have protective effects against hepatotoxic of bile acids during cholestasis. PMID- 23755236 TI - Predictive validation of an influenza spread model. AB - BACKGROUND: Modeling plays a critical role in mitigating impacts of seasonal influenza epidemics. Complex simulation models are currently at the forefront of evaluating optimal mitigation strategies at multiple scales and levels of organization. Given their evaluative role, these models remain limited in their ability to predict and forecast future epidemics leading some researchers and public-health practitioners to question their usefulness. The objective of this study is to evaluate the predictive ability of an existing complex simulation model of influenza spread. METHODS AND FINDINGS: We used extensive data on past epidemics to demonstrate the process of predictive validation. This involved generalizing an individual-based model for influenza spread and fitting it to laboratory-confirmed influenza infection data from a single observed epidemic (1998-1999). Next, we used the fitted model and modified two of its parameters based on data on real-world perturbations (vaccination coverage by age group and strain type). Simulating epidemics under these changes allowed us to estimate the deviation/error between the expected epidemic curve under perturbation and observed epidemics taking place from 1999 to 2006. Our model was able to forecast absolute intensity and epidemic peak week several weeks earlier with reasonable reliability and depended on the method of forecasting-static or dynamic. CONCLUSIONS: Good predictive ability of influenza epidemics is critical for implementing mitigation strategies in an effective and timely manner. Through the process of predictive validation applied to a current complex simulation model of influenza spread, we provided users of the model (e.g. public-health officials and policy-makers) with quantitative metrics and practical recommendations on mitigating impacts of seasonal influenza epidemics. This methodology may be applied to other models of communicable infectious diseases to test and potentially improve their predictive ability. PMID- 23755237 TI - Specific and evolving resting-state network alterations in post-concussion syndrome following mild traumatic brain injury. AB - Post-concussion syndrome has been related to axonal damage in patients with mild traumatic brain injury, but little is known about the consequences of injury on brain networks. In the present study, our aim was to characterize changes in functional brain networks following mild traumatic brain injury in patients with post-concussion syndrome using resting-state functional magnetic resonance imaging data. We investigated 17 injured patients with persistent post-concussion syndrome (under the DSM-IV criteria) at 6 months post-injury compared with 38 mild traumatic brain injury patients with no post-concussion syndrome and 34 healthy controls. All patients underwent magnetic resonance imaging examinations at the subacute (1-3 weeks) and late (6 months) phases after injury. Group-wise differences in functional brain networks were analyzed using graph theory measures. Patterns of long-range functional networks alterations were found in all mild traumatic brain injury patients. Mild traumatic brain injury patients with post-concussion syndrome had greater alterations than patients without post concussion syndrome. In patients with post-concussion syndrome, changes specifically affected temporal and thalamic regions predominantly at the subacute stage and frontal regions at the late phase. Our results suggest that the post concussion syndrome is associated with specific abnormalities in functional brain network that may contribute to explain deficits typically observed in PCS patients. PMID- 23755238 TI - Shyness in early infancy: approach-avoidance conflicts in temperament and hypersensitivity to eyes during initial gazes to faces. AB - 'Infant shyness', in which infants react shyly to adult strangers, presents during the third quarter of the first year. Researchers claim that shy children over the age of three years are experiencing approach-avoidance conflicts. Counter-intuitively, shy children do not avoid the eyes when scanning faces; rather, they spend more time looking at the eye region than non-shy children do. It is currently unknown whether young infants show this conflicted shyness and its corresponding characteristic pattern of face scanning. Here, using infant behavioral questionnaires and an eye-tracking system, we found that highly shy infants had high scores for both approach and fear temperaments (i.e., approach avoidance conflict) and that they showed longer dwell times in the eye regions than less shy infants during their initial fixations to facial stimuli. This initial hypersensitivity to the eyes was independent of whether the viewed faces were of their mothers or strangers. Moreover, highly shy infants preferred strangers with an averted gaze and face to strangers with a directed gaze and face. This initial scanning of the eye region and the overall preference for averted gaze faces were not explained solely by the infants' age or temperament (i.e., approach or fear). We suggest that infant shyness involves a conflict in temperament between the desire to approach and the fear of strangers, and this conflict is the psychological mechanism underlying infants' characteristic behavior in face scanning. PMID- 23755239 TI - Frequency of regulatory T-cells in the peripheral blood of patients with pulmonary tuberculosis from shanxi province, china. AB - BACKGROUND: Tuberculosis (TB) is a disease caused by the chronic and continuous infection of the pathogen Mycobacterium tuberculosis (M. tuberculosis). M. tuberculosis is an intracellular bacterial pathogen and is eliminated mainly through CD4(+) effector Th cells. M. tuberculosis induces regulatory T lymphocytes (Tregs) that mediate immune suppression by cell-to-cell contact or by secreting cytokines such as transforming growth factor-beta (TGF-beta). To understand the role of regulatory T-cells in the pathogenesis of TB, we have measured the in vivo frequency of regulatory T-cells and associated in vivo cytokine production in pulmonary tuberculosis patients. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we analyzed blood samples from 3 different populations (Group 1: patients with active TB, Group 2: patients recovered from TB and Group 3: healthy controls). We measured natural regulatory T-cell expression in peripheral blood using flow cytometry, and levels of blood serum IFN-gamma and TGF-beta1 using ELISA. The in vivo function of inductive regulatory T cells was mainly indicated by the expression of IFN-gamma, TGF-beta1, etc. Frequencyof natural regulatory T cells and inductive regulatory T cells in the peripheral blood samples from Group 1 patients were all significantly higher (P<0.05) than those from Groups 2 and 3. CONCLUSION/SIGNIFICANCE: Our results indicate that frequency of natural regulatory T cells and inductive regulatory T cells are significantly higher in the peripheral blood of patients with active pulmonary tuberculosis. These findings have potential application in improving TB diagnostic methods. PMID- 23755240 TI - Milligram production and biological activity characterization of the human chemokine receptor CCR3. AB - Human chemokine receptor CCR3 (hCCR3) belongs to the G protein-coupled receptors (GPCRs) superfamily of membrane proteins and plays major roles in allergic diseases and angiogenesis. In order to study the structural and functional mechanism of hCCR3, it is essential to produce pure protein with biological functions on a milligram scale. Here we report the expression of hCCR3 gene in a tetracycline-inducible stable mammalian cell line. A cell clone with high hCCR3 expression was selected from 46 stably transfected cell clones and from this cell line pure hCCR3 on a milligram scale was obtained after two-step purification. Circular dichroism spectrum with a characteristic shape and magnitude for alpha helix indicated proper folding of hCCR3 after purification. The biological activity of purified hCCR3 was verified by its high binding affinity with its endogenous ligands CCL11 and CCL24, with K D in the range of 10(-8) M to 10(-6) M. PMID- 23755241 TI - Co-registering kinematics and evoked related potentials during visually guided reach-to-grasp movements. AB - BACKGROUND: In non-human primates grasp-related sensorimotor transformations are accomplished in a circuit involving the anterior intraparietal sulcus (area AIP) and both the ventral and the dorsal sectors of the premotor cortex (vPMC and dPMC, respectively). Although a human homologue of such a circuit has been identified, the time course of activation of these cortical areas and how such activity relates to specific kinematic events has yet to be investigated. METHODOLOGY/PRINCIPAL FINDINGS: We combined kinematic and event-related potential techniques to explicitly test how activity within human grasping-related brain areas is modulated in time. Subjects were requested to reach towards and grasp either a small stimulus using a precision grip (i.e., the opposition of index finger and thumb) or a large stimulus using a whole hand grasp (i.e., the flexion of all digits around the stimulus). Results revealed a time course of activation starting at the level of parietal regions and continuing at the level of premotor regions. More specifically, we show that activity within these regions was tuned for specific grasps well before movement onset and this early tuning was carried over--as evidenced by kinematic analysis--during the preshaping period of the task. CONCLUSIONS/SIGNIFICANCE: Data are discussed in terms of recent findings showing a marked differentiation across different grasps during premovement phases which was carried over into subsequent movement phases. These findings offer a substantial contribution to the current debate about the nature of the sensorimotor transformations underlying grasping. And provide new insights into the detailed movement information contained in the human preparatory activity for specific hand movements. PMID- 23755242 TI - Engineering human T cells for resistance to methotrexate and mycophenolate mofetil as an in vivo cell selection strategy. AB - Gene transfer and drug selection systems that enforce ongoing transgene expression in vitro and in vivo which are compatible with human pharmaceutical drugs are currently underdeveloped. Here, we report on the utility of incorporating human enzyme muteins that confer resistance to the lymphotoxic/immunosuppressive drugs methotrexate (MTX) and mycophenolate mofetil (MMF) in a multicistronic lentiviral vector for in vivo T lymphocyte selection. We found that co-expression of human dihydrofolate reductase (DHFR(FS); L22F, F31S) and inosine monophosphate dehydrogenase II (IMPDH2(IY); T333I, S351Y) conferred T cell resistance to the cytocidal and anti-proliferative effects of these drugs at concentrations that can be achieved clinically (up to 0.1 uM MTX and 1.0 uM MPA). Furthermore, using a immunodeficient mouse model that supports the engraftment of central memory derived human T cells, in vivo selection studies demonstrate that huEGFRt(+)DHFR(FS+)IMPDH2(IY+) T cells could be enriched following adoptive transfer either by systemic administration of MTX alone (4.4 fold), MMF alone (2.9-fold), or combined MTX and MMF (4.9-fold). These findings demonstrate the utility of both DHFR(FS)/MTX and IMPDH2(IY)/MMF for in vivo selection of lentivirally transduced human T cells. Vectors incorporating these muteins in combination with other therapeutic transgenes may facilitate the selective engraftment of therapeutically active cells in recipients. PMID- 23755243 TI - The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. AB - INTRODUCTION: Abnormal cancer metabolism creates a glycolytic-dependency which can be exploited by lowering glucose availability to the tumor. The ketogenic diet (KD) is a low carbohydrate, high fat diet which decreases blood glucose and elevates blood ketones and has been shown to slow cancer progression in animals and humans. Abnormal tumor vasculature creates hypoxic pockets which promote cancer progression and further increase the glycolytic-dependency of cancers. Hyperbaric oxygen therapy (HBO2T) saturates tumors with oxygen, reversing the cancer promoting effects of tumor hypoxia. Since these non-toxic therapies exploit overlapping metabolic deficiencies of cancer, we tested their combined effects on cancer progression in a natural model of metastatic disease. METHODS: We used the firefly luciferase-tagged VM-M3 mouse model of metastatic cancer to compare tumor progression and survival in mice fed standard or KD ad libitum with or without HBO2T (2.5 ATM absolute, 90 min, 3x/week). Tumor growth was monitored by in vivo bioluminescent imaging. RESULTS: KD alone significantly decreased blood glucose, slowed tumor growth, and increased mean survival time by 56.7% in mice with systemic metastatic cancer. While HBO2T alone did not influence cancer progression, combining the KD with HBO2T elicited a significant decrease in blood glucose, tumor growth rate, and 77.9% increase in mean survival time compared to controls. CONCLUSIONS: KD and HBO2T produce significant anti-cancer effects when combined in a natural model of systemic metastatic cancer. Our evidence suggests that these therapies should be further investigated as potential non-toxic treatments or adjuvant therapies to standard care for patients with systemic metastatic disease. PMID- 23755244 TI - Pan-HSV-2 IgG antibody in vaccinated mice and guinea pigs correlates with protection against herpes simplex virus 2. AB - We lack a correlate of immunity to herpes simplex virus 2 (HSV-2) that may be used to differentiate whether a HSV-2 vaccine elicits robust or anemic protection against genital herpes. This gap in knowledge is often attributed to a failure to measure the correct component of the adaptive immune response to HSV-2. However, efforts to identify a correlate of immunity have focused on subunit vaccines that contain less than 3% of HSV-2's 40,000-amino-acid proteome. We were interested to determine if a correlate of immunity might be more readily identified if 1. animals were immunized with a polyvalent immunogen such as a live virus and/or 2. the magnitude of the vaccine-induced immune response was gauged in terms of the IgG antibody response to all of HSV-2's antigens (pan-HSV-2 IgG). Pre-challenge pan-HSV-2 IgG levels and protection against HSV-2 were compared in mice and/or guinea pigs immunized with a gD-2 subunit vaccine, wild-type HSV-2, or one of several attenuated HSV-2 ICP0 (-) viruses (0Delta254, 0Delta810, 0DeltaRING, or 0DeltaNLS). These six HSV-2 immunogens elicited a wide range of pan-HSV-2 IgG levels spanning an ~500-fold range. For 5 of the 6 immunogens tested, pre challenge levels of pan-HSV-2 IgG quantitatively correlated with reductions in HSV-2 challenge virus shedding and increased survival frequency following HSV-2 challenge. Collectively, the results suggest that pan-HSV-2 IgG levels may provide a simple and useful screening tool for evaluating the potential of a HSV 2 vaccine candidate to elicit protection against HSV-2 genital herpes. PMID- 23755245 TI - Can healthy fetuses show facial expressions of "pain" or "distress"? AB - BACKGROUND: With advances of research on fetal behavioural development, the question of whether we can identify fetal facial expressions and determine their developmental progression, takes on greater importance. In this study we investigate longitudinally the increasing complexity of combinations of facial movements from 24 to 36 weeks gestation in a sample of healthy fetuses using frame-by-frame coding of 4-D ultrasound scans. The primary aim was to examine whether these complex facial movements coalesce into a recognisable facial expression of pain/distress. METHODOLOGY/FINDINGS: Fifteen fetuses (8 girls, 7 boys) were observed four times in the second and third trimester of pregnancy. Fetuses showed significant progress towards more complex facial expressions as gestational age increased. Statistical analysis of the facial movements making up a specific facial configuration namely "pain/distress" also demonstrates that this facial expression becomes significantly more complete as the fetus matures. CONCLUSIONS/SIGNIFICANCE: The study shows that one can determine the normal progression of fetal facial movements. Furthermore, our results suggest that healthy fetuses progress towards an increasingly complete pain/distress expression as they mature. We argue that this is an adaptive process which is beneficial to the fetus postnatally and has the potential to identify normal versus abnormal developmental pathways. PMID- 23755246 TI - The type III secreted effector DspE is required early in solanum tuberosum leaf infection by Pectobacterium carotovorum to cause cell death, and requires Wx(3 6)D/E motifs. AB - Pectobacterium species are enterobacterial plant-pathogens that cause soft rot disease in diverse plant species. Unlike hemi-biotrophic plant pathogenic bacteria, the type III secretion system (T3SS) of Pectobacterium carotovorum subsp. carotovorum (P. carotovorum) appears to secrete only one effector protein, DspE. Previously, we found that the T3SS regulator HrpL and the effector DspE are required for P. carotovorum pathogenesis on leaves. Here, we identified genes up regulated by HrpL, visualized expression of dspE in leaves, and established that DspE causes host cell death. DspE required its full length and WxxxE-like motifs, which are characteristic of the AvrE-family effectors, for host cell death. We also examined expression in plant leaves and showed that hrpL is required for the expression of dspE and hrpN, and that the loss of a functional T3SS had unexpected effects on expression of other genes during leaf infection. These data support a model where P. carotovorum uses the T3SS early in leaf infection to initiate pathogenesis through elicitation of DspE-mediated host cell death. PMID- 23755247 TI - Different expression patterns and functions of acetylated and unacetylated Klf5 in the proliferation and differentiation of prostatic epithelial cells. AB - KLF5 is a basic transcription factor that regulates multiple biological processes. While it was identified as a putative tumor suppressor in prostate cancer, likely due to its function as an effector of TGF-beta in the inhibition of cell proliferation, KLF5 is unacetylated and promotes cell proliferation in the absence of TGF-beta. In this study, we evaluated the expression and function of KLF5 in prostatic epithelial homeostasis and tumorigenesis using mouse prostates and human prostate epithelial cells in 3-D culture. Histological and molecular analyses demonstrated that unacetylated-Klf5 was expressed in basal or undifferentiated cells, whereas acetylated-Klf5 was expressed primarily in luminal and/or differentiated cells. Androgen depletion via castration increased both the level of Klf5 expression and the number of Klf5-positive cells in the remaining prostate. Functionally, knockdown of KLF5 in the human RWPE-1 prostate cell line decreased the number of spheres formed in 3-D culture. In addition, knockout of Klf5 in prostate epithelial cells, mediated by probasin promoter driven Cre expression, did not cause neoplasia but promoted cell proliferation and induced hyperplasia when one Klf5 allele was knocked out. Knockout of both Klf5 alleles however, caused apoptosis rather than cell proliferation in the epithelium. In castrated mice, knockout of Klf5 resulted in more severe shrinkage of the prostate. These results suggest that KLF5 plays a role in the proliferation and differentiation of prostatic epithelial cells, yet loss of KLF5 alone is insufficient to induce malignant transformation in epithelial cells. PMID- 23755248 TI - Granulin exacerbates lupus nephritis via enhancing macrophage M2b polarization. AB - BACKGROUND AND AIMS: Lupus nephritis (LN), with considerable morbidity and mortality, is one of the most severe manifestations of systemic lupus erythematosus (SLE). Yet, the pathogenic mechanisms of LN have not been clearly elucidated, and efficient therapies are still in great need. Granulin (GRN), a multifunctional protein linked to inflammatory diseases, has recently been reported to correlate with the disease activity of autoimmune diseases. However, the role of GRN in the pathogenic process of LN still remains obscure. In this study, we explored its potential role and underlying mechanism in the pathogenesis of LN. METHODOLOGY/PRINCIPAL FINDINGS: We found that serum GRN levels were significantly up-regulated and were positively correlated with the severity of LN. Overexpression of GRN in vivo by transgenic injection remarkably exacerbated LN, whereas down-regulation of GRN with shRNA ameliorated LN, firmly demonstrating the critical role of GRN in the pathogenesis of LN. Notably, macrophage phenotype analysis revealed that overexpression of GRN could enhance macrophage polarization to M2b, a key mediator of the initiation and progression of LN. On the contrary, down-regulation of GRN resulted in impaired M2b differentiation, thus ameliorating LN. Moreover, we found that MAPK signals were necessary for the effect of GRN on macrophage M2b polarization. CONCLUSION/SIGNIFICANCE: We first demonstrated that GRN could aggravate lupus nephritis (LN) via promoting macrophage M2b polarization, which might provide insights into the pathogenesis of LN as well as potential therapeutic strategies against LN. PMID- 23755249 TI - Signal peptide cleavage from GP5 of PRRSV: a minor fraction of molecules retains the decoy epitope, a presumed molecular cause for viral persistence. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is the major pathogen in the pig industry. Variability of the antigens and persistence are the biggest challenges for successful control and elimination of the disease. GP5, the major glycoprotein of PRRSV, is considered an important target of neutralizing antibodies, which however appear only late in infection. This was attributed to the presence of a "decoy epitope" located near a hypervariable region of GP5. This region also harbors the predicted signal peptide cleavage sites and (dependent on the virus strain) a variable number of potential N-glycosylation sites. Molecular processing of GP5 has not been addressed experimentally so far: whether and where the signal peptide is cleaved and (as a consequence) whether the "decoy epitope" is present in virus particles. We show that the signal peptide of GP5 from the American type 2 reference strain VR-2332 is cleaved, both during in vitro translation in the presence of microsomes and in transfected cells. This was found to be independent of neighboring glycosylation sites and occurred in a variety of porcine cells for GP5 sequences derived from various type 2 strains. The exact signal peptide cleavage site was elucidated by mass spectrometry of virus-derived and recombinant GP5. The results revealed that the signal peptide of GP5 is cleaved at two sites. As a result, a mixture of GP5 proteins exists in virus particles, some of which still contain the "decoy epitope" sequence. Heterogeneity was also observed for the use of glycosylation sites in the hypervariable region. Lastly, GP5 mutants were engineered where one of the signal peptide cleavage sites was blocked. Wildtype GP5 exhibited exactly the same SDS-PAGE mobility as the mutant that is cleavable at site 2 only. This indicates that the overwhelming majority of all GP5 molecules does not contain the "decoy epitope". PMID- 23755250 TI - Evaluating baculovirus as a vector for human prostate cancer gene therapy. AB - Gene therapy represents an attractive strategy for the non-invasive treatment of prostate cancer, where current clinical interventions show limited efficacy. Here, we evaluate the use of the insect virus, baculovirus (BV), as a novel vector for human prostate cancer gene therapy. Since prostate tumours represent a heterogeneous environment, a therapeutic approach that achieves long-term regression must be capable of targeting multiple transformed cell populations. Furthermore, discrimination in the targeting of malignant compared to non malignant cells would have value in minimising side effects. We employed a number of prostate cancer models to analyse the potential for BV to achieve these goals. In vitro, both traditional prostate cell lines as well as primary epithelial or stromal cells derived from patient prostate biopsies, in two- or three dimensional cultures, were used. We also evaluated BV in vivo in murine prostate cancer xenograft models. BV was capable of preferentially transducing invasive malignant prostate cancer cell lines compared to early stage cancers and non malignant samples, a restriction that was not a function of nuclear import. Of more clinical relevance, primary patient-derived prostate cancer cells were also efficiently transduced by BV, with robust rates observed in epithelial cells of basal phenotype, which expressed BV-encoded transgenes faster than epithelial cells of a more differentiated, luminal phenotype. Maximum transduction capacity was observed in stromal cells. BV was able to penetrate through three-dimensional structures, including in vitro spheroids and in vivo orthotopic xenografts. BV vectors containing a nitroreductase transgene in a gene-directed enzyme pro-drug therapy approach were capable of efficiently killing malignant prostate targets following administration of the pro-drug, CB1954. Thus, BV is capable of transducing a large proportion of prostate cell types within a heterogeneous 3-D prostate tumour, can facilitate cell death using a pro-drug approach, and shows promise as a vector for the treatment of prostate cancer. PMID- 23755251 TI - How well can centenarians hear? AB - With advancements in modern medicine and significant improvements in life conditions in the past four decades, the elderly population is rapidly expanding. There is a growing number of those aged 100 years and older. While many changes in the human body occur with physiological aging, as many as 35% to 50% of the population aged 65 to 75 years have presbycusis. Presbycusis is a progressive sensorineural hearing loss that occurs as people get older. There are many studies of the prevalence of age-related hearing loss in the United States, Europe, and Asia. However, no audiological assessment of the population aged 100 years and older has been done. Therefore, it is not clear how well centenarians can hear. We measured middle ear impedance, pure-tone behavioral thresholds, and distortion-product otoacoustic emission from 74 centenarians living in the city of Shaoxing, China, to evaluate their middle and inner ear functions. We show that most centenarian listeners had an "As" type tympanogram, suggesting reduced static compliance of the tympanic membrane. Hearing threshold tests using pure tone audiometry show that all centenarian subjects had varying degrees of hearing loss. More than 90% suffered from moderate to severe (41 to 80 dB) hearing loss below 2,000 Hz, and profound (>81 dB) hearing loss at 4,000 and 8,000 Hz. Otoacoustic emission, which is generated by the active process of cochlear outer hair cells, was undetectable in the majority of listeners. Our study shows the extent and severity of hearing loss in the centenarian population and represents the first audiological assessment of their middle and inner ear functions. PMID- 23755252 TI - Counting on beta-diversity to safeguard the resilience of estuaries. AB - Coastal ecosystems are often stressed by non-point source and cumulative effects that can lead to local-scale community homogenisation and a concomitant loss of large-scale ecological connectivity. Here we investigate the use of beta diversity as a measure of both community heterogeneity and ecological connectivity. To understand the consequences of different environmental scenarios on heterogeneity and connectivity, it is necessary to understand the scale at which different environmental factors affect beta-diversity. We sampled macrofauna from intertidal sites in nine estuaries from New Zealand's North Island that represented different degrees of stress derived from land-use. We used multiple regression models to identify relationships between beta-diversity and local sediment variables, factors related to the estuarine and catchment hydrodynamics and morphology and land-based stressors. At local scales, we found higher beta-diversity at sites with a relatively high total richness. At larger scales, beta-diversity was positively related to gamma-diversity, suggesting that a large regional species pool was linked with large-scale heterogeneity in these systems. Local environmental heterogeneity influenced beta-diversity at both local and regional scales, although variables at the estuarine and catchment scales were both needed to explain large scale connectivity. The estuaries expected a priori to be the most stressed exhibited higher variance in community dissimilarity between sites and connectivity to the estuary species pool. This suggests that connectivity and heterogeneity metrics could be used to generate early warning signals of cumulative stress. PMID- 23755253 TI - Exploring the influence of carbon nanoparticles on the formation of beta-sheet rich oligomers of IAPP22-28 peptide by molecular dynamics simulation. AB - Recent advances in nanotechnologies have led to wide use of nanomaterials in biomedical field. However, nanoparticles are found to interfere with protein misfolding and aggregation associated with many human diseases. It is still a controversial issue whether nanoparticles inhibit or promote protein aggregation. In this study, we used molecular dynamics simulations to explore the effects of three kinds of carbon nanomaterials including graphene, carbon nanotube and C60 on the aggregation behavior of islet amyloid polypeptide fragment 22-28 (IAPP22 28). The diverse behaviors of IAPP22-28 peptides on the surfaces of carbon nanomaterials were studied. The results suggest these nanomaterials can prevent beta-sheet formation in differing degrees and further affect the aggregation of IAPP22-28. The pi-pi stacking and hydrophobic interactions are different in the interactions between peptides and different nanoparticles. The subtle differences in the interaction are due to the difference in surface curvature and area. The results demonstrate the adsorption interaction has competitive advantages over the interactions between peptides. Therefore, the fibrillation of IAPP22-28 may be inhibited at its early stage by graphene or SWCNT. Our study can not only enhance the understanding about potential effects of nanomaterials to amyloid formation, but also provide valuable information to develop potential beta-sheet formation inhibitors against type II diabetes. PMID- 23755254 TI - Increased prefrontal cortical thickness is associated with enhanced abilities to regulate emotions in PTSD-free women with borderline personality disorder. AB - Previous studies suggest that amygdala, insula and prefrontal cortex (PFC) disintegrity play a crucial role in the failure to adequately regulate emotions in Borderline Personality Disorder (BPD). However, prior results are confounded by the high rate of comorbidity with Posttraumatic Stress Disorder (PTSD), which itself has been associated with changes in frontolimbic circuitry. We thus scrutinized the link between PFC, amygdala, insula, and the ability to regulate emotions, contrasting 17 women with BPD without comorbid PTSD to 27 non-clinical control women and in addition to those with BPD and PTSD (n = 14). BPD women without PTSD, but not those with comorbid PTSD, had increased cortical thickness in the dorsolateral PFC (DLPFC) in comparison to control women. Furthermore, cortical thickness in the DLPFC of BPD women without PTSD positively correlated with emotion regulation scores and furthermore was positively associated with amygdala volume, as well as cortical thickness of the insula. Our findings highlight the importance of disentangling the impact of BPD and PTSD on the brain and suggest possible compensatory mechanisms for the impaired emotion regulation in BPD women without PTSD. PMID- 23755255 TI - Two challenges for U.S. irrigation due to climate change: increasing irrigated area in wet states and increasing irrigation rates in dry states. AB - Agricultural irrigation practices will likely be affected by climate change. In this paper, we use a statistical model relating observed water use by U.S. producers to the moisture deficit, and then use this statistical model to project climate changes impact on both the fraction of agricultural land irrigated and the irrigation rate (m3 ha-1). Data on water withdrawals for US states (1985 2005) show that both quantities are highly positively correlated with moisture deficit (precipitation--PET). If current trends hold, climate change would increase agricultural demand for irrigation in 2090 by 4.5-21.9 million ha (B1 scenario demand: 4.5-8.7 million ha, A2 scenario demand: 9.1-21.9 million ha). Much of this new irrigated area would occur in states that currently have a wet climate and a small fraction of their agricultural land currently irrigated, posing a challenge to policymakers in states with less experience with strict regulation of agriculture water use. Moreover, most of this expansion will occur in states where current agricultural production has relatively low market value per hectare, which may make installation of irrigation uneconomical without significant changes in crops or practices by producers. Without significant increases in irrigation efficiency, climate change would also increase the average irrigation rate from 7,963 to 8,400-10,415 m3 ha-1 (B1 rate: 8,400-9,145 m3 ha-1, A2 rate: 9,380-10,415 m3 ha-1). The irrigation rate will increase the most in states that already have dry climates and large irrigation rates, posing a challenge for water supply systems in these states. Accounting for both the increase in irrigated area and irrigation rate, total withdrawals might increase by 47.7-283.4 billion m3 (B1 withdrawal: 47.7-106.0 billion m3, A2 withdrawal: 117.4-283.4 billion m3). Increases in irrigation water-use efficiency, particularly by reducing the prevalence of surface irrigation, could eliminate the increase in total irrigation withdrawals in many states. PMID- 23755256 TI - The Sm complex is required for the processing of non-coding RNAs by the exosome. AB - A key question in the field of RNA regulation is how some exosome substrates, such as spliceosomal snRNAs and telomerase RNA, evade degradation and are processed into stable, functional RNA molecules. Typical feature of these non coding RNAs is presence of the Sm complex at the 3'end of the mature RNA molecule. Here, we report that in Saccharomyces cerevisiae presence of intact Sm binding site is required for the exosome-mediated processing of telomerase RNA from a polyadenylated precursor into its mature form and is essential for its function in elongating telomeres. Additionally, we demonstrate that the same pathway is involved in the maturation of snRNAs. Furthermore, the insertion of an Sm binding site into an unstable RNA that is normally completely destroyed by the exosome, leads to its partial stabilization. We also show that telomerase RNA accumulates in Schizosaccharomyces pombe exosome mutants, suggesting a conserved role for the exosome in processing and degradation of telomerase RNA. In summary, our data provide important mechanistic insight into the regulation of exosome dependent RNA processing as well as telomerase RNA biogenesis. PMID- 23755257 TI - The amyloid-beta-SDR5C1(ABAD) interaction does not mediate a specific inhibition of mitochondrial RNase P. AB - The amyloid-beta peptide (Abeta) is suggested to cause mitochondrial dysfunction in Alzheimer's disease. The mitochondrial dehydrogenase SDR5C1 (also known as ABAD) was shown to bind Abeta and was proposed to thereby mediate mitochondrial toxicity, but the molecular mechanism has not been clarified. We recently identified SDR5C1 as an essential component of human mitochondrial RNase P and its associated tRNA:m1R9 methyltransferase, the enzymes responsible for tRNA 5' end processing and methylation of purines at tRNA position 9, respectively. With this work we investigated whether SDR5C1's role as a subunit of these two tRNA maturation activities represents the mechanistic link between Abeta and mitochondrial dysfunction. Using recombinant enzyme components, we tested RNase P and methyltransferase activity upon titration of Abeta. Micromolar concentrations of monomeric or oligomerized Abeta were required to inhibit tRNA 5'-end processing and position 9 methylation catalyzed by the SDR5C1-containing enzymes, yet similar concentrations of Abeta also inhibited related RNase P and methyltransferase activities, which do not contain an SDR5C1 homolog. In conclusion, the proposed deleterious effect of Abeta on mitochondrial function cannot be explained by a specific inhibition of mitochondrial RNase P or its tRNA:m1R9 methyltransferase subcomplex, and the molecular mechanism of SDR5C1 mediated Abeta toxicity remains unclear. PMID- 23755258 TI - Identification of subunit-subunit interaction sites in alphaA-WT crystallin and mutant alphaA-G98R crystallin using isotope-labeled cross-linker and mass spectrometry. AB - Cataract is characterized by progressive protein aggregation and loss of vision. alpha-Crystallins are the major proteins in the lens responsible for maintaining transparency. They exist in the lens as highly polydisperse oligomers with variable numbers of subunits, and mutations in alpha-crystallin are associated with some forms of cataract in humans. Because the stability of proteins is dependent on optimal subunit interactions, the structural transformations and aggregation of mutant proteins that underlie cataract formation can be understood best by identifying the residue-specific inter- and intra-subunit interactions. Chemical crosslinking combined with mass spectrometry is increasingly used to provide structural insights into intra- and inter-protein interactions. We used isotope-labeled cross-linker in combination with LC-MS/MS to determine the subunit-subunit interaction sites in cataract-causing mutant alphaA-G98R crystallin. Peptides cross-linked by isotope-labeled (heavy and light forms) cross-linkers appear as doublets in mass spectra, thus facilitating the identification of cross-linker-containing peptides. In this study, we cross linked wild-type (alphaA-WT) and mutant (alphaA-G98R) crystallins using the homobifunctional amine-reactive, isotope-labeled (d0 and d4) cross-linker-BS2G (bis[sulfosuccinimidyl]glutarate). Tryptic in-solution digest of cross-linked complexes generates a wide array of peptide mixtures. Cross-linked peptides were enriched using strong cation exchange (SCX) chromatography followed by both MS and MS/MS to identify the cross-linked sites. We identified a distinct intermolecular interaction site between K88-K99 in the beta5 strand of the mutant alphaA-G98R crystallin that is not found in wild-type alphaA-crystallin. This interaction could explain the conformational instability and aggregation nature of the mutant protein that results from incorrect folding and assembly. PMID- 23755259 TI - Patterns and Outcomes of Induction of Labour in Africa and Asia: a secondary analysis of the WHO Global Survey on Maternal and Neonatal Health. AB - BACKGROUND: Labour induction should be performed where benefit outweighs potential harm, however epidemiology of induction in lower-income countries is not well described. We used the WHO Global Survey dataset to describe the epidemiology and outcomes of labour induction in 192,538 deliveries in 253 facilities across 16 countries in Africa and Asia. METHODS: Data was analyzed separately for Africa and Asia. Prevalence of indications, methods, success and characteristics associated with labour induction were determined. Multilevel logistic regression was used to determine the relationship between induction (with medical indication and elective) and maternal/perinatal outcomes. RESULTS: Induction accounted for 4.4% (Africa) and 12.1% (Asia) of deliveries. Oxytocin alone was the most common method (45.9% and 37.5%) and success rates were generally over 80%. Medically indicated inductions were associated with increased adjusted odds of Apgar <7 at 5 minutes, low birthweight, NICU admission and fresh stillbirth in both regions. The odds of caesarean section in Africa were reduced (Adj OR 0.61, 95%CI 0.42-0.88). Elective induction was associated with increased adjusted odds of NICU (Africa) and ICU (Asia) admissions. DISCUSSION: Induction was generally less common than in higher-income countries. Prostaglandin use was uncommon despite evidence supporting use. Induction for medical indications may be associated with poorer outcomes due to maternal baseline risks. Despite one third of elective inductions occurring at <39 weeks, the risk of maternal, fetal and neonatal mortality was not elevated following elective inductions. PMID- 23755260 TI - A biomathematical model of human erythropoiesis under erythropoietin and chemotherapy administration. AB - Anaemia is a common haematologic side effect of dose-dense multi-cycle cytotoxic polychemotherapy requiring erythrocyte transfusions or erythropoietin (EPO) administration. To simulate the effectiveness of different EPO application schedules, we performed both modelling of erythropoiesis under chemotherapy and pharmacokinetic and dynamic modelling of EPO applications in the framework of a single comprehensive biomathematical model. For this purpose, a cell kinetic model of bone marrow erythropoiesis was developed that is based on a set of differential compartment equations describing proliferation and maturation of erythropoietic cell stages. The system is regulated by several feedback loops comprising those mediated by EPO. We added a model of EPO absorption after injection at different sites and a pharmacokinetic model of EPO derivatives to account for the effects of external EPO applications. Chemotherapy is modelled by a transient depletion of bone marrow cell stages. Unknown model parameters were determined by fitting the predictions of the model to data sets of circulating erythrocytes, haemoglobin, haematocrit, percentage of reticulocytes or EPO serum concentrations derived from the literature or cooperating clinical study groups. Parameter fittings resulted in a good agreement of model and data. Depending on site of injection and derivative (Alfa, Beta, Delta, Darbepoetin), nine groups of EPO applications were distinguished differing in either absorption kinetics or pharmacokinetics. Finally, eight different chemotherapy protocols were modelled. The model was validated on the basis of scenarios not used for parameter fitting. Simulations were performed to analyze the impact of EPO applications on the risk of anaemia during chemotherapy. We conclude that we established a model of erythropoiesis under chemotherapy that explains a large set of time series data under EPO and chemotherapy applications. It allows predictions regarding yet untested EPO schedules. Prospective clinical studies are needed to validate model predictions and to explore the feasibility and effectiveness of the proposed schedules. PMID- 23755261 TI - Laccase versus laccase-like multi-copper oxidase: a comparative study of similar enzymes with diverse substrate spectra. AB - Laccases (EC 1.10.3.2) are multi-copper oxidases that catalyse the one-electron oxidation of a broad range of compounds including substituted phenols, arylamines and aromatic thiols to the corresponding radicals. Owing to their broad substrate range, copper-containing laccases are versatile biocatalysts, capable of oxidizing numerous natural and non-natural industry-relevant compounds, with water as the sole by-product. In the present study, 10 of the 11 multi-copper oxidases, hitherto considered to be laccases, from fungi, plant and bacterial origin were compared. A substrate screen of 91 natural and non-natural compounds was recorded and revealed a fairly broad but distinctive substrate spectrum amongst the enzymes. Even though the enzymes share conserved active site residues we found that the substrate ranges of the individual enzymes varied considerably. The EC classification is based on the type of chemical reaction performed and the actual name of the enzyme often refers to the physiological substrate. However, for the enzymes studied in this work such classification is not feasible, even more so as their prime substrates or natural functions are mainly unknown. The classification of multi-copper oxidases assigned as laccases remains a challenge. For the sake of simplicity we propose to introduce the term "laccase-like multi copper oxidase" (LMCO) in addition to the term laccase that we use exclusively for the enzyme originally identified from the sap of the lacquer tree Rhus vernicifera. PMID- 23755262 TI - Increased risk of sudden cardiac arrest in obstructive pulmonary disease: a case control study. AB - BACKGROUND: We aimed to determine whether (1) patients with obstructive pulmonary disease (OPD) have an increased risk of sudden cardiac arrest (SCA) due to ventricular tachycardia or fibrillation (VT/VF), and (2) the SCA risk is mediated by cardiovascular risk-profile and/or respiratory drug use. METHODS: A community based case-control study was performed, with 1310 cases of SCA of the ARREST study and 5793 age, sex and SCA-date matched non-SCA controls from the PHARMO database. Only incident SCA cases, age older than 40 years, that resulted from unequivocal cardiac causes with electrocardiographic documentation of VT/VF were included. Conditional logistic regression analysis was used to assess the association between SCA and OPD. Pre-specified subgroup analyses were performed regarding age, sex, cardiovascular risk-profile, disease severity, and current use of respiratory drugs. RESULTS: A higher risk of SCA was observed in patients with OPD (n = 190 cases [15%], 622 controls [11%]) than in those without OPD (OR adjusted for cardiovascular risk-profile 1.4 [1.2-1.6]). In OPD patients with a high cardiovascular risk-profile (OR 3.5 [2.7-4.4]) a higher risk of SCA was observed than in those with a low cardiovascular risk-profile (OR 1.3 [0.9-1.9]) The observed SCA risk was highest among OPD patients who received short-acting beta2-adrenoreceptor agonists (SABA) or anticholinergics (AC) at the time of SCA (SABA OR: 3.9 [1.7-8.8], AC OR: 2.7 [1.5-4.8] compared to those without OPD). CONCLUSIONS: OPD is associated with an increased observed risk of SCA. The most increased risk was observed in patients with a high cardiovascular risk-profile, and in those who received SABA and, possibly, those who received AC at the time of SCA. PMID- 23755263 TI - Patterns of genetic and reproductive traits differentiation in Mainland vs. Corsican populations of bumblebees. AB - Populations on islands often exhibit lower levels of genetic variation and ecomorphological divergence compared to their mainland relatives. While phenotypic differentiation in characters, such as size or shape among insular organisms, has been well studied, insular differentiation in quantitative reproductive traits involved in chemical communication has received very little attention to date. Here, we investigated the impact of insularity on two syntopic bumblebee species pairs: one including species that are phylogenetically related (Bombus terrestris and B. lucorum), and the other including species that interact ecologically (B. terrestris and its specific nest inquiline B. vestalis). For each bumblebee species, we characterized the patterns of variation and differentiation of insular (Corsican) vs. mainland (European) populations (i) with four genes (nuclear and mitochondrial, 3781 bp) and (ii) in the chemical composition of male marking secretions (MMS), a key trait for mate attraction in bumblebees, by gas chromatography-mass spectrometry (GC-MS). Our results provide evidence for genetic differentiation in Corsican bumblebees and show that, contrary to theoretical expectations, island populations of bumblebees exhibit levels of genetic variation similar to the mainland populations. Likewise, our comparative chemical analyses of MMS indicate that Corsican populations of bumblebees are significantly differentiated from the mainland yet they hold comparative levels of within-population MMS variability compared to the mainland. Therefore, insularity has led Corsican populations to diverge both genetically and chemically from their mainland relatives, presumably through genetic drift, but without a decrease of genetic diversity in island populations. We hypothesize that MMS divergence in Corsican bumblebees was driven by a persistent lack of gene flow with mainland populations and reinforced by the preference of Corsican females for sympatric (Corsican) MMS. The impoverished Corsican bumblebee fauna has not led to relaxation of stabilizing selection on MMS but to consistent differentiation chemical reproductive traits on the island. PMID- 23755264 TI - Using temporal sampling to improve attribution of source populations for invasive species. AB - Numerous studies have applied genetic tools to the identification of source populations and transport pathways for invasive species. However, there are many gaps in the knowledge obtained from such studies because comprehensive and meaningful spatial sampling to meet these goals is difficult to achieve. Sampling populations as they arrive at the border should fill the gaps in source population identification, but such an advance has not yet been achieved with genetic data. Here we use previously acquired genetic data to assign new incursions as they invade populations within New Zealand ports and marinas. We also investigated allelelic frequency change in these recently established populations over a two-year period, and assessed the effect of temporal genetic sampling on our ability to assign new incursions to their population of source. We observed shifts in the allele frequencies among populations, as well as the complete loss of some alleles and the addition of alleles novel to New Zealand, within these recently established populations. There was no significant level of genetic differentiation observed in our samples between years, and the use of these temporal data did alter the assignment probability of new incursions. Our study further suggests that new incursions can add genetic variation to the population in a single introduction event as the founders themselves are often more genetically diverse than theory initially predicted. PMID- 23755265 TI - Female putty-nosed monkeys use experimentally altered contextual information to disambiguate the cause of male alarm calls. AB - Many animal vocal signals are given in a wide range of contexts which can sometimes have little in common. Yet, to respond adaptively, listeners must find ways to identify the cause of a signal, or at least rule out alternatives. Here, we investigate the nature of this process in putty-nosed monkeys, a forest primate. In this species, adult males have a very restricted repertoire of vocalizations which are given in response to a wide variety of events occurring under conditions of limited visibility. We carried out a series of field playback experiments on females (N = 6) in a habituated group in Gashaka Gumti National Park, Nigeria, in which male alarm/loud calls were presented either alone, or following acoustic information that simulated the occurrence of natural disturbances. We demonstrate that listeners appear to integrate contextual information in order to distinguish among possible causes of calls. We conclude that, in many cases, pragmatic aspects of communication play a crucial role in call interpretation and place a premium on listeners' abilities to integrate information from different sources. PMID- 23755266 TI - The body size-dependent diet composition of north american sea ducks in winter. AB - Daily food requirements scale with body mass and activity in animals. While small species of birds have higher mass-specific field metabolic rates than larger species, larger species have higher absolute energy costs. Under energy balance, we thus expect the small species to have a higher energy value diet. Also the weight and time constraints for flighted and diurnal foragers should set a maximum to the amount of prey items taken in one meal and to the daily number of meals, respectively. Further, avoidance of competition causes the species to reduce the amount of shared prey in their diet. Some diet segregation is therefore to be expected between species. We tested these hypotheses and investigated the role of body mass in the diet composition of 12 sea duck species (Somateria mollissima, Somateria spectabilis, Somateria fischeri, Polysticta stelleri, Bucephala clangula, Bucephala islandica, Bucephala albeola, Melanitta nigra, Melanitta perspicillata, Melanitta deglandi, Histrionicus histrionicus and Clangula hyemalis) wintering in North America. This study was based on a literature survey with special emphasis given to the diet data from the former US Bureau of Biological Survey. The data supported our hypothesis that the energy value of winter diet of sea ducks scales negatively with body mass. Diet diversity also scaled negatively with body mass. Our results suggest the existence of a minimum for the energy value of avian diets. PMID- 23755267 TI - Metabonomic profiling of serum and urine by (1)H NMR-based spectroscopy discriminates patients with chronic obstructive pulmonary disease and healthy individuals. AB - Chronic obstructive pulmonary disease (COPD) has seriously impacted the health of individuals and populations. In this study, proton nuclear magnetic resonance ((1)H NMR)-based metabonomics combined with multivariate pattern recognition analysis was applied to investigate the metabolic signatures of patients with COPD. Serum and urine samples were collected from COPD patients (n = 32) and healthy controls (n = 21), respectively. Samples were analyzed by high resolution (1)H NMR (600 MHz), and the obtained spectral profiles were then subjected to multivariate data analysis. Consistent metabolic differences have been found in serum as well as in urine samples from COPD patients and healthy controls. Compared to healthy controls, COPD patients displayed decreased lipoprotein and amino acids, including branched-chain amino acids (BCAAs), and increased glycerolphosphocholine in serum. Moreover, metabolic differences in urine were more significant than in serum. Decreased urinary 1-methylnicotinamide, creatinine and lactate have been discovered in COPD patients in comparison with healthy controls. Conversely, acetate, ketone bodies, carnosine, m hydroxyphenylacetate, phenylacetyglycine, pyruvate and alpha-ketoglutarate exhibited enhanced expression levels in COPD patients relative to healthy subjects. Our results illustrate the potential application of NMR-based metabonomics in early diagnosis and understanding the mechanisms of COPD. PMID- 23755268 TI - Repositioning of Verrucosidin, a purported inhibitor of chaperone protein GRP78, as an inhibitor of mitochondrial electron transport chain complex I. AB - Verrucosidin (VCD) belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78) expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential. We therefore sought to characterize VCD's anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose), but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin). However, VCD's strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin) might act in a similar GRP78-independent fashion will be discussed. PMID- 23755269 TI - Lepr(db/db) Mice with senescence marker protein-30 knockout (Lepr(db/db)Smp30(Y/ )) exhibit increases in small dense-LDL and severe fatty liver despite being fed a standard diet. AB - BACKGROUND/AIMS: The senescence marker protein-30 (SMP30) is a 34 kDa protein originally identified in rat liver that shows decreased levels with age. Several functional studies using SMP30 knockout (Smp30(Y/-) ) mice established that SMP30 functions as an antioxidant and protects against apoptosis. To address the potential role of SMP30 in nonalcoholic fatty liver disease (NAFLD) pathogenesis, we established Smp30(Y/-) mice on a Lepr(db/db) background (Lepr(db/db)Smp30(Y/-) mice). RESEARCH DESIGN/PRINCIPAL FINDINGS: Male Lepr(db/db)Smp30(Y/-) mice were fed a standard diet (340 kcal/100 g, fat 5.6%) for 16 weeks whereupon the lipid/lipoprotein profiles, hepatic expression of genes related to lipid metabolism and endoplasmic reticulum stress markers were analyzed by HPLC, quantitative RT-PCR and western blotting, respectively. Changes in the liver at a histological level were also investigated. The amount of SMP30 mRNA and protein in livers was decreased in Lepr(db/db)Smp30(Y/+) mice compared with Lepr(db/+)Smp30(Y/+) mice. Compared with Lepr(db/db)Smp30(Y/+) mice, 24 week old Lepr(db/db)Smp30(Y/-) mice showed: i) increased small dense LDL-cho and decreased HDL-cho levels; ii) fatty liver accompanied by numerous inflammatory cells and increased oxidative stress; iii) decreased mRNA expression of genes involved in fatty acid oxidation (PPARalpha) and lipoprotein uptake (LDLR and VLDLR) but increased CD36 levels; and iv) increased endoplasmic reticulum stress. CONCLUSION: Our data strongly suggest that SMP30 is closely associated with NAFLD pathogenesis, and might be a possible therapeutic target for NAFLD. PMID- 23755270 TI - ADAM17 is critical for multipolar exit and radial migration of neuronal intermediate progenitor cells in mice cerebral cortex. AB - The radial migration of neuronal progenitor cells is critical for the development of cerebral cortex layers. They go through a critical step transforming from multipolar to bipolar before outward migration. A Disintegrin and Metalloprotease 17 (ADAM17) is a transmembrane protease which can process many substrates involved in cell-cell interaction, including Notch, ligands of EGFR, and some cell adhesion molecules. In this study, we used in utero electroporation to knock down or overexpress ADAM17 at embryonic day 14.5 (E14.5) in neuronal progenitor cells to examine the role of ADAM17 in cortical embryonic neurogenesis. Our results showed that the radial migration of ADAM17-knocked down cells were normal till E16.5 and reached the intermediate zone (IZ). Then most transfected cells stopped migration and stayed at the IZ to inner cortical plate (CP) layer at E18.5, and there was higher percentage of multipolar cells at IZ layer in the ADAM17-knocked down group compared to the cells in control group. Marker staining revealed that those ADAM17-knocked down cells differentiated normally from neural stem cells (NSCs) to neuronal intermediate progenitor cells (nIPCs) but did not differentiate into mature neurons. The migration and multipolar exit defects caused by ADAM17 knockdown could be partially rescued by over-expressing an shRNA resistant ADAM17, while overexpressing ADAM17 alone did not affect the radial migration. Taken together, our results showed for the first time that, ADAM17 is critical in regulating the multipolar-stage exit and radial migration of the nIPCs during telencephalon cortex development in mice. PMID- 23755271 TI - Zinc oxide nanoparticles induce necrosis and apoptosis in macrophages in a p47phox- and Nrf2-independent manner. AB - In view of the steadily increasing use of zinc oxide nanoparticles in various industrial and consumer applications, toxicological investigations to evaluate their safety are highly justified. We have investigated mechanisms of ZnO nanoparticle-induced apoptosis and necrosis in macrophages in relation to their important role in the clearance of inhaled particulates and the regulation of immune responses during inflammation. In the murine macrophage RAW 264.7 cell line, ZnO treatment caused a rapid induction of nuclear condensation, DNA fragmentation, and the formation of hypodiploid DNA nuclei and apoptotic bodies. The involvement of the essential effector caspase-3 in ZnO-mediated apoptosis could be demonstrated by immunocytochemical detection of activated caspase-3 in RAW 264.7 cells. ZnO specifically triggered the intrinsic apoptotic pathway, because Jurkat T lymphocytes deficient in the key mediator caspase-9 were protected against ZnO-mediated toxicity whereas reconstituted cells were not. ZnO also caused DNA strand breakage and oxidative DNA damage in the RAW 264.7 cells as well as p47(phox) NADPH oxidase-dependent superoxide generation in bone marrow derived macrophages. However, ZnO-induced cell death was not affected in bone marrow-derived macrophages of mice deficient in p47(phox) or the oxidant responsive transcription factor Nrf2. Taken together, our data demonstrate that ZnO nanoparticles trigger p47(phox) NADPH oxidase-mediated ROS formation in macrophages, but that this is dispensable for caspase-9/3-mediated apoptosis. Execution of apoptotic cell death by ZnO nanoparticles appears to be NADPH oxidase and Nrf2-independent but rather triggered by alternative routes. PMID- 23755272 TI - Agp2, a member of the yeast amino acid permease family, positively regulates polyamine transport at the transcriptional level. AB - Agp2 is a plasma membrane protein of the Saccharomyces cerevisiae amino acid transporter family, involved in high-affinity uptake of various substrates including L-carnitine and polyamines. The discovery of two high affinity polyamine permeases, Dur3 and Sam3, prompted us to investigate whether Agp2 directly transports polyamines or acts instead as a regulator. Herein, we show that neither dur3Delta nor sam3Delta single mutant is defective in polyamine transport, while the dur3Delta sam3Delta double mutant exhibits a sharp decrease in polyamine uptake and an increased resistance to polyamine toxicity similar to the agp2Delta mutant. Studies of Agp2 localization indicate that in the double mutant dur3Delta sam3Delta, Agp2-GFP remains plasma membrane-localized, even though transport of polyamines is strongly reduced. We further demonstrate that Agp2 controls the expression of several transporter genes including DUR3 and SAM3, the carnitine transporter HNM1 and several hexose, nucleoside and vitamin permease genes, in addition to SKY1 encoding a SR kinase that positively regulates low-affinity polyamine uptake. Furthermore, gene expression analysis clearly suggests that Agp2 is a strong positive regulator of additional biological processes. Collectively, our data suggest that Agp2 might respond to environmental cues and thus regulate the expression of several genes including those involved in polyamine transport. PMID- 23755273 TI - A new functional site W115 in CdtA is critical for Aggregatibacter actinomycetemcomitans cytolethal distending toxin. AB - Aggregatibacter actinomycetemcomitans, a specific pathogen of localized aggressive periodontitis, produces a cytolethal distending toxin (CDT) that arrests eukaryotic cells irreversibly in G0/G1 or G2/M phase of the cell cycle. Although structural studies show that the aromatic patch region of CdtA plays an important role in its biological activity, the functional sites of CdtA have not been firmly established. In this study, site-specific mutagenesis strategy was employed for cdtA point mutations construction so as to examine the contributions of individual amino acids to receptor binding and the biological activity of holotoxin. The binding ability was reduced in CdtA(Y181A)BC holotoxin and the biological function of CDT was not weaken in CdtA(Y105A)BC, CdtA(Y125A)BC, CdtA(F109A)BC and CdtA(S106N)BC holotoxin suggesting that these sites were not critical to CDT. But the binding activity and cell cycle arrest ability of holotoxin complexes were inhibited in CdtA(W115G)BC. And this site did not affect the holotoxin assembly by size exclusion chromatography. Therefore, W115 might be a critical site of CdtA binding ability. These findings suggest that the functional sites of CdtA are not only in the aromatic patch region. W115, the new functional site is critical for receptor binding and cell cycle arrest, which provides potential targets for pharmacological disruption of CDT activity. PMID- 23755274 TI - Influence of a short-term iron-deficient diet on hepatic gene expression profiles in rats. AB - Iron is an essential mineral for the body, and iron deficiency generally leads to anemia. However, because non-anemic iron deficiency can exist, we performed a comprehensive transcriptome analysis of the liver to define the effects of this condition on the body. Four-week-old male rats were fed a low-iron diet (approximately 3 ppm iron) for 3 days and compared with those fed a normal diet (48 ppm iron) by pair feeding as a control. The rats in the iron-deficient diet group developed a non-anemic iron-deficient state. DNA microarray analysis revealed that during this short time, this state conferred a variety of effects on nutrient metabolism in the liver. In comparison with long-term (17 days) iron deficiency data from a previous study, some of the changed genes were found to be common to both short- and long-term iron deficiency models, some were specific to the short-term iron deficiency model, and the others were oppositely regulated between the two feeding terms. Taken together, these data suggest that although the blood hemoglobin level itself remains unchanged during non-anemic iron deficiency, a variety of metabolic processes involved in the maintenance of the energy balance are altered. PMID- 23755275 TI - Digital gene expression analysis of corky split vein caused by boron deficiency in 'Newhall' Navel Orange (Citrus sinensis Osbeck) for selecting differentially expressed genes related to vascular hypertrophy. AB - Corky split vein caused by boron (B) deficiency in 'Newhall' Navel Orange was studied in the present research. The boron-deficient citrus exhibited a symptom of corky split vein in mature leaves. Morphologic and anatomical surveys at four representative phases of corky split veins showed that the symptom was the result of vascular hypertrophy. Digital gene expression (DGE) analysis was performed based on the Illumina HiSeqTM 2000 platform, which was applied to analyze the gene expression profilings of corky split veins at four morphologic phases. Over 5.3 million clean reads per library were successfully mapped to the reference database and more than 22897 mapped genes per library were simultaneously obtained. Analysis of the differentially expressed genes (DEGs) revealed that the expressions of genes associated with cytokinin signal transduction, cell division, vascular development, lignin biosynthesis and photosynthesis in corky split veins were all affected. The expressions of WOL and ARR12 involved in the cytokinin signal transduction pathway were up-regulated at 1(st) phase of corky split vein development. Furthermore, the expressions of some cell cycle genes, CYCs and CDKB, and vascular development genes, WOX4 and VND7, were up-regulated at the following 2(nd) and 3(rd) phases. These findings indicated that the cytokinin signal transduction pathway may play a role in initiating symptom observed in our study. PMID- 23755276 TI - Multi-targeted mechanisms underlying the endothelial protective effects of the diabetic-safe sweetener erythritol. AB - Diabetes is characterized by hyperglycemia and development of vascular pathology. Endothelial cell dysfunction is a starting point for pathogenesis of vascular complications in diabetes. We previously showed the polyol erythritol to be a hydroxyl radical scavenger preventing endothelial cell dysfunction onset in diabetic rats. To unravel mechanisms, other than scavenging of radicals, by which erythritol mediates this protective effect, we evaluated effects of erythritol in endothelial cells exposed to normal (7 mM) and high glucose (30 mM) or diabetic stressors (e.g. SIN-1) using targeted and transcriptomic approaches. This study demonstrates that erythritol (i.e. under non-diabetic conditions) has minimal effects on endothelial cells. However, under hyperglycemic conditions erythritol protected endothelial cells against cell death induced by diabetic stressors (i.e. high glucose and peroxynitrite). Also a number of harmful effects caused by high glucose, e.g. increased nitric oxide release, are reversed. Additionally, total transcriptome analysis indicated that biological processes which are differentially regulated due to high glucose are corrected by erythritol. We conclude that erythritol protects endothelial cells during high glucose conditions via effects on multiple targets. Overall, these data indicate a therapeutically important endothelial protective effect of erythritol under hyperglycemic conditions. PMID- 23755277 TI - When the rule becomes the exception. no evidence of gene flow between two Zerynthia cryptic butterflies suggests the emergence of a new model group. AB - There is increasing evidence that most parapatric cryptic/sister taxa are reproductively compatible across their areas of contact. Consequently, the biological species concept, which assumes absence of interbreeding, is becoming a not so effective criterion in evolutionary ecology. Nevertheless, the few parapatric sister taxa showing complete reproductive barriers represent interesting models to study speciation processes and the evolution of reproductive isolation. In this study, we examined contact populations in northwestern Italy of two butterfly species, Zerynthia polyxena and Z. cassandra, characterized by different genitalic morphotypes. We studied levels of divergence among 21 populations distributed from Sicily to France using three genetic markers (the mitochondrial COI and ND1 genes and the nuclear wingless gene) and genitalic geometric morphometrics. Moreover, we performed species distribution modelling to estimate different climatic requirements of Z. polyxena and Z. cassandra. We projected climatic data into glacial maximum scenarios in order to verify if and to which extent glacial cycles could have contributed to speciation processes. Genetic and morphometric analyses identified two main groups. All specimens showed a concordant pattern of diversification, including those individuals sampled in the contact area. Haplotype distribution and climatic models showed that during glacial maxima both species experienced a strong range contraction and presumably remained separated into different microrefugia in southern France, in the Italian Peninsula and on the islands of Elba and Sicily. Long term separation was probably favoured by reduced dispersal ability and high phylopatry, while genitalic diversification probably favoured interbreeding avoidance. Conversely, the aposematic wing pattern remained almost identical. We compared our results with those obtained in other species and concluded that Z. polyxena and Z. cassandra represent a valuable model in the study of speciation. PMID- 23755278 TI - Biomaterial constructs for delivery of multiple therapeutic genes: a spatiotemporal evaluation of efficacy using molecular beacons. AB - Gene therapy is emerging as a potential therapeutic approach for cardiovascular pathogenesis. An appropriate therapy may require multiple genes to enhance therapeutic outcome by modulating inflammatory response and angiogenesis in a controlled and time-dependent manner. Thus, the aim of this research was to assess the spatiotemporal efficacy of a dual-gene therapy model based on 3D collagen scaffolds loaded with the therapeutic genes interleukin 10 (IL-10), a potent anti-inflammatory cytokine, and endothelial nitric oxide synthase (eNOS), a promoter of angiogenesis. A collagen-based scaffold loaded with plasmid IL-10 polyplexes and plasmid eNOS polyplexes encapsulated into microspheres was used to transfect HUVECs and HMSCs cells.The therapeutic efficacy of the system was monitored at 2, 7 and 14 days for eNOS and IL-10 mRNA expression using RT-PCR and live cell imaging molecular beacon technology. The dual gene releasing collagen based scaffold provided both sustained and delayed release of functional polyplexes in vitro over a 14 day period which was corroborated with variation in expression levels seen using RT-PCR and MB imaging. Maximum fold increases in IL 10 mRNA and eNOS mRNA expression levels occurred at day 7 in HMSCs and HUVECs. However, IL-10 mRNA expression levels seemed dependent on frequency of media changes and/or ease of transfection of the cell type. It was demonstrated that molecular beacons are able to monitor changes in mRNA levels at various time points, in the presence of a 3D scaffolding gene carrier system and the results complemented those of RT-PCR. PMID- 23755280 TI - Spray nozzles, pressures, additives and stirring time on viability and pathogenicity of entomopathogenic nematodes (nematoda: rhabditida) for greenhouses. AB - The objective of this study was to evaluate different strategies for the application of entomopathogenic nematodes (EPN). Three different models of spray nozzles with air induction (AI 11003, TTI 11003 and AD-IA 11004), three spray pressures (207, 413 and 720 kPa), four different additives for tank mixtures (cane molasses, mineral oil, vegetable oil and glycerin) and the influence of tank mixture stirring time were all evaluated for their effect on EPN (Steinernema feltiae) viability and pathogenicity. The different nozzles, at pressures of up to 620 kPa, were found to be compatible with S. feltiae. Vegetable oil, mineral oil and molasses were found to be compatible adjuvants for S. feltiae, and stirring in a motorized backpack sprayer for 30 minutes did not impact the viability or pathogenicity of this nematode. Appropriate techniques for the application of nematodes with backpack sprayers are discussed. PMID- 23755279 TI - Modulation of apoptotic pathways of macrophages by surface-functionalized multi walled carbon nanotubes. AB - Biomedical applications of carbon nanotubes (CNTs) often involve improving their hydrophilicity and dispersion in biological media by modifying them through noncovalent or covalent functionalization. However, the potential adverse effects of surface-functionalized CNTs have not been well characterized. In this study, we functionalized multi-walled CNTs (MWCNTs) via carboxylation, to produce MWCNTs COOH, and via poly (ethylene glycol) linking, to produce MWCNTs-PEG. We used these functionalized MWCNTs to study the effect of surface functionalization on MWCNTs-induced toxicity to macrophages, and elucidate the underlying mechanisms of action. Our results revealed that MWCNTs-PEG were less cytotoxic and were associated with less apoptotic cell death of macrophages than MWCNTs-COOH. Additionally, MWCNTs-PEG induced less generation of reactive oxygen species (ROS) involving less activation of NADPH oxidase compared with MWCNTs-COOH, as evidenced by membrane translocation of p47(phox) and p67(phox) in macrophages. The less cytotoxic and apoptotic effect of MWCNTs-PEG compared with MWCNTs-COOH resulted from the lower cellular uptake of MWCNTs-PEG, which resulted in less activation of oxidative stress-responsive pathways, such as p38 mitogen-activated protein kinases (MAPK) and nuclear factor (NF)-kappaB. These results demonstrate that surface functionalization of CNTs may alter ROS-mediated cytotoxic and apoptotic response by modulating apoptotic signaling pathways. Our study thus provides new insights into the molecular basis for the surface properties affecting CNTs toxicity. PMID- 23755281 TI - Association between cannabinoid CB1 receptor expression and Akt signalling in prostate cancer. AB - BACKGROUND: In prostate cancer, tumour expression of cannabinoid CB1 receptors is associated with a poor prognosis. One explanation for this association comes from experiments with transfected astrocytoma cells, where a high CB receptor expression recruits the Akt signalling survival pathway. In the present study, we have investigated the association between CB1 receptor expression and the Akt pathway in a well-characterised prostate cancer tissue microarray. METHODOLOGY/PRINCIPAL FINDINGS: Phosphorylated Akt immunoreactivity (pAkt-IR) scores were available in the database. CB1 receptor immunoreactivity (CB1IR) was rescored from previously published data using the same scale as pAkt-IR. There was a highly significant correlation between CB1IR and pAkt-IR. Further, cases with high expression levels of both biomarkers were much more likely to have a more severe form of the disease at diagnosis than those with low expression levels. The two biomarkers had additive effects, rather than an interaction, upon disease-specific survival. CONCLUSIONS/SIGNIFICANCE: The present study provides data that is consistent with the hypothesis that at a high CB1 receptor expression, the Akt signalling pathway becomes operative. PMID- 23755282 TI - Operant self-stimulation of dopamine neurons in the substantia nigra. AB - We examined the contribution of the nigrostriatal DA system to instrumental learning and behavior using optogenetics in awake, behaving mice. Using Cre inducible channelrhodopsin-2 (ChR2) in mice expressing Cre recombinase driven by the tyrosine hydroxylase promoter (Th-Cre), we tested whether selective stimulation of DA neurons in the substantia nigra pars compacta (SNC), in the absence of any natural rewards, was sufficient to promote instrumental learning in naive mice. Mice expressing ChR2 in SNC DA neurons readily learned to press a lever to receive laser stimulation, but unlike natural food rewards the lever pressing did not decline with satiation. When the number of presses required to receive a stimulation was altered, mice adjusted their rate of pressing accordingly, suggesting that the rate of stimulation was a controlled variable. Moreover, extinction, i.e. the cessation of action-contingent stimulation, and the complete reversal of the relationship between action and outcome by the imposition of an omission contingency, rapidly abolished lever pressing. Together these results suggest that selective activation of SNC DA neurons can be sufficient for acquisition and maintenance of a new instrumental action. PMID- 23755283 TI - Polyamines inhibit porin-mediated fluoroquinolone uptake in mycobacteria. AB - Polyamines decrease the permeability of the outer membrane of Escherichia coli to fluoroquinolones and beta-lactams. In this study, we tested the effect of four polyamines (spermidine, spermine, cadaverine and putrescine) on fluoroquinolone uptake in Mycobacterium bovis BCG. Our results show that polyamines are also capable of reducing the permeability of the mycobacterial outer membrane to fluoroquinolones. Spermidine was most effective and demonstrated reversible dose- and pH-dependent inhibition of ciprofloxacin accumulation. The extent of this inhibition was demonstrated across the fluoroquinolone compound class to varying degrees. Furthermore, we have shown that the addition of spermidine increases the survival of M. bovis BCG after a 5-day exposure to ciprofloxacin by up to 25 times. The treatment of actively-replicating Mycobacterium tuberculosis with spermidine reduced ciprofloxacin accumulation by half while non-replicating nutrient-starved M. tuberculosis cultures lacked similar sensitivity to polyamines. Gene expression studies showed that several outer membrane proteins are significantly down-regulated during the shift to non-replication. Collectively, these characteristics of fluoroquinolone uptake in M. bovis BCG are consistent with facilitated transport by porin-like proteins and suggest that a reduction in intracellular uptake contributes to the phenotypic drug resistance demonstrated by M. tuberculosis in the non-replicating state. PMID- 23755284 TI - High resolution imaging of temporal and spatial changes of subcellular ascorbate, glutathione and H2O2 distribution during Botrytis cinerea infection in Arabidopsis. AB - In order to study the mechanisms behind the infection process of the necrotrophic fungus Botrytis cinerea, the subcellular distribution of hydrogen peroxide (H2O2) was monitored over a time frame of 96 h post inoculation (hpi) in Arabidopsis thaliana Col-0 leaves at the inoculation site (IS) and the area around the IS which was defined as area adjacent to the inoculation site (AIS). H2O2 accumulation was correlated with changes in the compartment-specific distribution of ascorbate and glutathione and chloroplast fine structure. This study revealed that the severe breakdown of the antioxidative system, indicated by a drop in ascorbate and glutathione contents at the IS at later stages of infection correlated with an accumulation of H2O2 in chloroplasts, mitochondria, cell walls, nuclei and the cytosol which resulted in the development of chlorosis and cell death, eventually visible as tissue necrosis. A steady increase of glutathione contents in most cell compartments within infected tissues (up to 600% in chloroplasts at 96 hpi) correlated with an accumulation of H2O2 in chloroplasts, mitochondria and cell walls at the AIS indicating that high glutathione levels could not prevent the accumulation of reactive oxygen species (ROS) which resulted in chlorosis. Summing up, this study reveals the intracellular sequence of events during Botrytis cinerea infection and shows that the breakdown of the antioxidative system correlated with the accumulation of H2O2 in the host cells. This resulted in the degeneration of the leaf indicated by severe changes in the number and ultrastructure of chloroplasts (e.g. decrease of chloroplast number, decrease of starch and thylakoid contents, increase of plastoglobuli size), chlorosis and necrosis of the leaves. PMID- 23755285 TI - Role of the adiponectin binding protein, T-cadherin (cdh13), in pulmonary responses to subacute ozone. AB - Adiponectin, an adipose derived hormone with pleiotropic functions, binds to several proteins, including T-cadherin. We have previously reported that adiponectin deficient (Adipo(-/-)) mice have increased IL-17A-dependent neutrophil accumulation in their lungs after subacute exposure to ozone (0.3 ppm for 72 hrs). The purpose of this study was to determine whether this anti inflammatory effect of adiponectin required adiponectin binding to T-cadherin. Wildtype, Adipo(-/-) , T-cadherin deficient (T-cad(-/-) ), and bideficient (Adipo(-/-)/T-cad(-/-) ) mice were exposed to subacute ozone or air. Compared to wildtype mice, ozone-induced increases in pulmonary IL-17A mRNA expression were augmented in T-cad(-/-) and Adipo(-/-) mice. Compared to T-cad(-/-) mice, there was no further increase in IL-17A in Adipo(-/-)/T-cad(-/-) mice, indicating that adiponectin binding to T-cadherin is required for suppression of ozone-induced IL 17A expression. Similar results were obtained for pulmonary mRNA expression of saa3, an acute phase protein capable of inducing IL-17A expression. Comparison of lung histological sections across genotypes also indicated that adiponectin attenuation of ozone-induced inflammatory lesions at bronchiolar branch points required T-cadherin. BAL neutrophils and G-CSF were augmented in T-cad(-/-) mice and further augmented in Adipo(-/-)/T-cad(-/-) mice. Taken together with previous observations indicating that augmentation of these moieties in ozone exposed Adipo(-/-) mice is partially IL-17A dependent, the results indicate that effects of T-cadherin deficiency on BAL neutrophils and G-CSF are likely secondary to changes in IL-17A, but that adiponectin also acts via T-cadherin independent pathways. Our results indicate that T-cadherin is required for the ability of adiponectin to suppress some but not all aspects of ozone-induced pulmonary inflammation. PMID- 23755286 TI - Outpatient therapeutic feeding program outcomes and determinants in treatment of severe acute malnutrition in tigray, northern ethiopia: a retrospective cohort study. AB - BACKGROUND: Outpatient Therapeutic feeding Program (OTP) brings the services for management of Severe Acute Malnutrition (SAM) closer to the community by making services available at decentralized treatment points within the primary health care settings, through the use of ready-to-use therapeutic foods, community outreach and mobilization. Little is known about the program outcomes. This study revealed the levels of program outcome indictors and determinant factors to recovery rate. METHODS: A retrospective cohort study was conducted on 628 children who had been managed for SAM under OTP from April/2008 to January/2012. The children were selected using systematic random sampling from 12 health posts and 4 health centers. The study relied on information of demographic characteristics, anthropometries, Plumpy'Nut, medical problems and routine medications intakes. The results were estimated using Kaplan-Meier survival curves, log-rank test and Cox-regression. RESULTS: The recovery, defaulter, mortality and weight gain rates were 61.78%, 13.85%, 3.02% and 5.23 gm/kg/day, respectively. Routine medications were administered partially and children with medical problems were managed inappropriately under the program. As a child consumed one more sachet of Plumpy'Nut, the recovery rate from SAM increased by 4% (HR = 1.04, 95%-CI = 1.03, 1.05, P<0.001). The adjusted hazard ratios to recovery of children with diarrhea, appetite loss with Plumpy'Nut and failure to gain weight were 2.20 (HR = 2.20, 95%-CI = 1.31, 3.41, P = 0.001), 4.49 (HR = 1.74, 95%-CI = 1.07, 2.83, P = 0.046) and 3.88 (HR = 1.95, 95%-CI = 1.17, 3.23, P<0.001), respectively. Children who took amoxicillin and de-worming had 95% (HR = 1.95, 95%-CI = 1.17, 3.23) and 74% (HR = 1.74, 95%-CI = 1.07, 2.83) more probability to recover from SAM as compared to those who didn't take them. CONCLUSIONS: The OTP was partially successful. Management of children with comorbidities under the program and partial administration of routine drugs were major threats for the program effectiveness. The stakeholders should focus on creating the capacity of the OTP providers on proper management of SAM to achieve fully effective program. PMID- 23755287 TI - Assessment of intratumoral micromorphology for patients with clear cell renal cell carcinoma using susceptibility-weighted imaging. AB - BACKGROUND: Multiple treatment options exist for the management of renal cell carcinomas. Preoperative evaluation of clear cell renal cell carcinoma (CRCC) grades is important for deciding upon the appropriate method of therapy. We hypothesize that susceptibility weighted imaging (SWI) is sensitive enough to detect intratumoral microvessles and microbleeding in renal cell carcinoma, which can be used to grade CRCC. MATERIAL AND METHODS: Retrospective reviews of 37 patients with pathologically proven CRCCs were evaluated. All patients underwent SWI examinations. The characteristics of intratumoral susceptibility signal intensity (ITSS) includes the likelihood of the presence of ITSS, morphology of ITSS, dominant structure of ITSS and ratio of ITSS area to tumor area, which were all assessed on SWI. The results were compared using the nonparametric Mann Whitney test. RESULTS: ITSS was seen in all patients except 4 patients with low grade CRCCs. There was no significant difference between low and high-grade CRCCs when looking at the likelihood of the presence of ITSS. There was a significant difference in the mean score of dominant structures between low and high-grade CRCCs. Specifically, more dominant vascular structures and less hemorrhage were seen in low-grade tumors (2.15+/-1.05) compared to high-grade tumors (1.27+/ 0.47) (P<0.005). The ratio of ITSS area to tumor area was also significantly higher for the high-grade group (1.55+/-0.52) than that for the low-grade group (0.88+/-0.43) on SWI (P<0.005). CONCLUSION: SWI is useful for grading CRCCs. PMID- 23755288 TI - Spatio-temporal variation in contrasting effects of resident vegetation on establishment, growth and reproduction of dry grassland plants: implications for seed addition experiments. AB - Successful establishment of plants is limited by both biotic and abiotic conditions and their interactions. Seedling establishment is also used as a direct measure of habitat suitability, but transient changes in vegetation might provide windows of opportunity allowing plant species to colonize sites which otherwise appear unsuitable. We aimed to study spatio-temporal variability in the effects of resident vegetation on establishment, growth and reproduction of dry grassland species in abandoned arable fields representing potentially suitable habitats. Seeds were sown in disturbed (bare of vegetation and roots) and undisturbed plots in three fields abandoned in the last 20 years. To assess the effects of temporal variation on plant establishment, we initiated our experiments in two years (2007 and 2008). Seventeen out of the 35 sown species flowered within two years after sowing, while three species completely failed to become established. The vegetation in the undisturbed plots facilitated seedling establishment only in the year with low spring precipitation, and the effect did not hold for all species. In contrast, growth and flowering rate were consistently much greater in the disturbed plots, but the effect size differed between the fields and years of sowing. We show that colonization is more successful when site opening by disturbance coincide with other suitable conditions such as weather or soil characteristics. Seasonal variability involved in our study emphasizes the necessity of temporal replication of sowing experiments. Studies assessing habitat suitability by seed sowing should either involve both vegetation removal treatments and untreated plots or follow the gradient of vegetation cover. We strongly recommend following the numbers of established individuals, their sizes and reproductive success when assessing habitat suitability by seed sowing since one can gain completely different results in different phases of plant life cycle. PMID- 23755289 TI - Cooperative anti-diabetic effects of deoxynojirimycin-polysaccharide by inhibiting glucose absorption and modulating glucose metabolism in streptozotocin induced diabetic mice. AB - We had previously shown that deoxynojirimycin-polysaccharide mixture (DPM) not only decreased blood glucose but also reversed the damage to pancreatic beta cells in diabetic mice, and that the anti-hyperglycemic efficacy of this combination was better than that of 1-deoxynojirimycin (DNJ) or polysachharide alone. However, the mechanisms behind these effects were not fully understood. The present study aimed to evaluate the therapeutic effects of DPM on streptozotocin (STZ)-induced diabetic symptoms and their potential mechanisms. Diabetic mice were treated with DPM (150 mg/kg body weight) for 90 days and continued to be fed without DPM for an additional 30 days. Strikingly, decrease of blood glucose levels was observed in all DPM treated diabetic mice, which persisted 30 days after cessation of DPM administration. Significant decrease of glycosylated hemoglobin and hepatic pyruvate concentrations, along with marked increase of serum insulin and hepatic glycogen levels were detected in DPM treated diabetic mice. Results of a labeled (13)C6-glucose uptake assay indicated that DPM can restrain glucose absorption. Additionally, DPM down-regulated the mRNA and protein expression of jejunal Na(+)/glucose cotransporter, Na(+)/K(+) ATPase and glucose transporter 2, and enhanced the activities as well as mRNA and protein levels of hepatic glycolysis enzymes (glucokinase, phosphofructokinase, private kinase and pyruvate decarboxylas E1). Activity and expression of hepatic gluconeogenesis enzymes (phosphoenolpyruvate carboxykinase and glucose-6 phosphatase) were also found to be attenuated in diabetic mice treated with DPM. Purified enzyme activity assays verified that the increased activities of glucose glycolysis enzymes resulted not from their direct activation, but from the relative increase in protein expression. Importantly, our histopathological observations support the results of our biochemical analyses and validate the protective effects of DPM on STZ-induced damage to the pancreas. Thus, DPM has significant potential as a therapeutic agent against diabetes. PMID- 23755290 TI - Tacrolimus (FK506) prevents early stages of ethanol induced hepatic fibrosis by targeting LARP6 dependent mechanism of collagen synthesis. AB - Tacrolimus (FK506) is a widely used immunosuppressive drug. Its effects on hepatic fibrosis have been controversial and attributed to immunosuppression. We show that in vitro FK506, inhibited synthesis of type I collagen polypeptides, without affecting expression of collagen mRNAs. In vivo, administration of FK506 at a dose of 4 mg/kg completely prevented development of alcohol/carbon tetrachloride induced liver fibrosis in rats. Activation of hepatic stellate cells (HSCs) was absent in the FK506 treated livers and expression of collagen alpha2(I) mRNA was at normal levels. Collagen alpha1(I) mRNA was increased in the FK506 treated livers, but this mRNA was not translated into alpha1(I) polypeptide. No significant inflammation was associated with the fibrosis model used. FK506 binding protein 3 (FKBP3) is one of cellular proteins which binds FK506 with high affinity. We discovered that FKBP3 interacts with LARP6 and LARP6 is the major regulator of translation and stability of collagen mRNAs. In the presence of FK506 the interaction between FKBP3 and LARP6 is weakened and so is the pull down of collagen mRNAs with FKBP3. We postulate that FK506 inactivates FKBP3 and that lack of interaction of LARP6 and FKBP3 results in aberrant translation of collagen mRNAs and prevention of fibrosis. This is the first report of such activity of FK506 and may renew the interest in using this drug to alleviate hepatic fibrosis. PMID- 23755291 TI - Dengue in travelers: kinetics of viremia and NS1 antigenemia and their associations with clinical parameters. AB - Despite the increasing numbers of travel-acquired dengue, few studies have assessed virologic markers of the disease in non-endemic populations. We examined the kinetics of diagnostic markers and their associations with clinical parameters in 93 patients with travel-acquired dengue fever. Kinetics analyses suggested a longer average duration for viremia (9 days, CI95%: 8-10) and non structural protein 1 (NS1) antigenemia (15 days, CI95%: 12-20) than reported in endemic populations. While none of the tests sufficed alone, the best diagnostic coverage was achieved by combining antibody detection with RNA or NS1 testing. Studied by regression models, early relative levels of viremia and NS1 antigenemia proved to be significantly associated with several clinical parameters: high viremia predicted greater likelihood and increased length of hospitalization, the degree of NS1 antigenemia correlated positively with hematocrit and liver transaminases, and both viremia and NS1 antigenemia levels negatively with platelet counts in follow-up. Levels of viremia and NS1 antigenemia may serve as predictors of the clinical manifestations in travel acquired dengue. PMID- 23755292 TI - Protein expressions and their immunogenicity from Riemerella anatipestifer cultured in iron restriction medium. AB - Riemerella anatipestifer was cultured in both iron restriction media and normal media. Two-dimensional gel electrophoresis identified 23 proteins that significantly increased in the iron restriction media. Of them 12 proteins were analyzed with mass spectrography. Nine of 12 proteins belong to 6 different protein families: fibronectin type iii domain protein, secreted subtilase family protein, phosphoglycerate kinase, translation elongation factor, leucine-rich repeat-containing protein, and Galactose-binding domain-like protein. Other 3 proteins were novel with unknown function. Two novel proteins (Riean_1750 and Riean_1752) were expressed in prokaryotic expression systems. The specificities of these 2 novel proteins to R. anatipestifer were confirmed by western-blotting analysis. The ducks immunized with either protein had low mortality challenged by R. anatipestifer, 33.3% and 16.7%, respectively. The ducks developed 100% immunity when immunized with combined Riean_1750 and Riean_1752 proteins. The data suggested 2 novel proteins play important roles in the bacterial survival in the iron restricted environment. They could be used as subunit vaccines of R. anatipestifer. PMID- 23755293 TI - Osthole attenuates hepatic injury in a rodent model of trauma-hemorrhage. AB - Recent evidences show that osthole possesses anti-inflammatory properties and protective effects following shock-like states, but the mechanism of these effects remains unknown. The p38 mitogen-activated protein kinase (p38 MAPK) pathway exerts anti-inflammatory effects in injury. The aim of this study was to investigate whether p38 MAPK plays any role in the osthole-mediated attenuation of hepatic injury after trauma-hemorrhage. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35-40 mmHg for 90 minutes), followed by fluid resuscitation. During resuscitation, a single dose of osthole (3 mg/kg, intravenously) with and without a p38 MAPK inhibitor SB 203580 (2 mg/kg, intravenously), SB-203580 or vehicle was administered. Plasma alanine aminotransferase (ALT) with aspartate aminotransferase (AST) concentrations and various hepatic parameters were measured (n = 8 rats/group) at 24 hours after resuscitation. The results showed that trauma-hemorrhage increased hepatic myeloperoxidase activity, intercellular adhesion molecule-1 and interleukin-6 levels, and plasma ALT and AST concentrations. These parameters were significantly improved in the osthole-treated rats subjected to trauma hemorrhage. Osthole treatment also increased hepatic phospho-p38 MAPK expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of SB 203580 with osthole abolished the osthole-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of osthole administration on alleviation of hepatic injury after trauma hemorrhage, which is, at least in part, through p38 MAPK-dependent pathway. PMID- 23755294 TI - Age distribution of influenza like illness cases during post-pandemic A(H3N2): comparison with the twelve previous seasons, in France. AB - In France, the 2011-2012 influenza epidemic was characterized by the circulation of antigenically drifted influenza A(H3N2) viruses and by an increased disease severity and mortality among the elderly, with respect to the A(H1N1)pdm09 pandemic and post-pandemic outbreaks. Whether the epidemiology of influenza in France differed between the 2011-2012 epidemic and the previous outbreaks is unclear. Here, we analyse the age distribution of influenza like illness (ILI) cases attended in general practice during the 2011-2012 epidemic, and compare it with that of the twelve previous epidemic seasons. Influenza like illness data were obtained through a nationwide surveillance system based on sentinel general practitioners. Vaccine effectiveness was also estimated. The estimated number of ILI cases attended in general practice during the 2011-2012 was lower than that of the past twelve epidemics. The age distribution was characteristic of previous A(H3N2)-dominated outbreaks: school-age children were relatively spared compared to epidemics (co-)dominated by A(H1N1) and/or B viruses (including the 2009 pandemic and post-pandemic outbreaks), while the proportion of adults over 30 year-old was higher. The estimated vaccine effectiveness (54%, 95% CI (48, 60)) was in the lower range for A(H3N2) epidemics. In conclusion, the age distribution of ILI cases attended in general practice seems to be not different between the A(H3N2) pre-pandemic and post-pandemic epidemics. Future researches including a more important number of ILI epidemics and confirmed virological data of influenza and other respiratory pathogens are necessary to confirm these results. PMID- 23755295 TI - Label-free detection of breast masses using multiphoton microscopy. AB - Histopathology forms the gold standard for the diagnosis of breast cancer. Multiphoton microscopy (MPM) has been proposed to be a potentially powerful adjunct to current histopathological techniques. A label-free imaging based on two- photon excited fluorescence and second-harmonic generation is developed for differentiating normal breast tissues, benign, as well as breast cancer tissues. Human breast biopsies (including human normal breast tissues, benign as well as breast cancer tissues ) that are first imaged (fresh, unfixed, and unstained) with MPM and are then processed for routine H-E histopathology. Our results suggest that the MPM images, obtained from these unprocessed biopsies, can readily distinguish between benign lesions and breast cancers. In the tissues of breast cancers, MPM showed that the tumor cells displayed marked cellular and nuclear pleomorphism. The tumor cells, characterized by irregular size and shape, enlarged nuclei, and increased nuclear-cytoplasmic ratio, infiltrated into disrupted connective tissue, leading to the loss of second-harmonic generation signals. For breast cancer, MPM diagnosis was 100% correct because the tissues of breast cancers did not have second-harmonic generation signals in MPM imaging. On the contrary, in benign breast masses, second-harmonic generation signals could be seen easily in MPM imaging. These observations indicate that MPM could be an important potential tool to provide label-free noninvasive diagnostic impressions that can guide surgeon in biopsy and patient management. PMID- 23755297 TI - Molecular characterization and functions of fatty acid and retinoid binding protein gene (Ab-far-1) in Aphelenchoides besseyi. AB - Rice white tip nematode, Aphelenchoides besseyi, is a kind of plant parasitic nematodes that cause serious losses in rice and many other crops. Fatty acid and retinoid binding protein (FAR) is a specific protein in nematodes and is related to development, reproduction, infection to the host, and disruption of plant defense reactions, so the inhibition of FAR function is the potential approach to control A. besseyi. The full-length of Ab-far-1 cDNA is 805 bp, including 546 bp of ORF that encodes 181 amino acids. Software analysis revealed that the Ab-FAR-1 was rich in alpha-helix structure, contained a predicted consensus casein kinase II phosphorylation site and a hydrophobic secretory signal peptide, but did not have glycosylation sites. The Ab-FAR-1 had 52% homology to Gp-FAR-1 protein. The Ab-FAR-1 and Gp-FAR-1 were grouped in the same branch according to the phylogenetic tree. Fluorescence-based ligand binding analysis confirmed that the recombinant Ab-FAR-1 (rAb-FAR-1) bound with the fluorescent analogues 11-((5 dimethylaminonaphthalene-1-sulfonyl) amino) undecannoic acid (DAUDA), cis parinaric acid and retinol, but the oleic acid would compete with the binding site. Quantitative PCR (qPCR) was used to assess the expression level of Ab-far-1 at different development stages of A. besseyi, the highest expression was found in the females, followed by eggs, juveniles and males. Using in situ hybridization technique, Ab-far-1 mRNA was present in the hypodermis of juveniles and adults, the ovaries of females and the testes of males. When A. besseyi was treated with Ab-far-1 dsRNA for 48 h, the silencing efficiency of Ab-far-1 was the best and the number of nematodes on the carrot was the least. Thus FAR plays important roles in the development and reproduction of nematodes. This study is useful and helpful to figure out a new way to control the plant parasitic nematodes. PMID- 23755296 TI - Barrelettes without barrels in the American water shrew. AB - Water shrews (Sorex palustris) depend heavily on their elaborate whiskers to navigate their environment and locate prey. They have small eyes and ears with correspondingly small optic and auditory nerves. Previous investigations have shown that water shrew neocortex is dominated by large representations of the whiskers in primary and secondary somatosensory cortex (S1 and S2). Flattened sections of juvenile cortex processed for cytochrome oxidase revealed clear borders of the whisker pad representation in S1, but no cortical barrels. We were therefore surprised to discover prominent barrelettes in brainstem of juvenile water shrews in the present investigation. These distinctive modules were found in the principal trigeminal nucleus (PrV), and in two of the three spinal trigeminal subnuclei (interpolaris--SpVi and caudalis--SpVc). Analysis of the shrew's whisker pad revealed the likely relationship between whiskers and barrelettes. Barrelettes persisted in adult water shrew PrV, but barrels were also absent from adult cortex. Thus in contrast to mice and rats, which have obvious barrels in primary somatosensory cortex and less clear barrelettes in the principal nucleus, water shrews have clear barrelettes in the brainstem and no barrels in the neocortex. These results highlight the diverse ways that similar mechanoreceptors can be represented in the central nervous systems of different species. PMID- 23755298 TI - Chronic intermittent fasting improves cognitive functions and brain structures in mice. AB - Obesity is a major health issue. Obesity started from teenagers has become a major health concern in recent years. Intermittent fasting increases the life span. However, it is not known whether obesity and intermittent fasting affect brain functions and structures before brain aging. Here, we subjected 7-week old CD-1 wild type male mice to intermittent (alternate-day) fasting or high fat diet (45% caloric supplied by fat) for 11 months. Mice on intermittent fasting had better learning and memory assessed by the Barnes maze and fear conditioning, thicker CA1 pyramidal cell layer, higher expression of drebrin, a dendritic protein, and lower oxidative stress than mice that had free access to regular diet (control mice). Mice fed with high fat diet was obese and with hyperlipidemia. They also had poorer exercise tolerance. However, these obese mice did not present significant learning and memory impairment or changes in brain structures or oxidative stress compared with control mice. These results suggest that intermittent fasting improves brain functions and structures and that high fat diet feeding started early in life does not cause significant changes in brain functions and structures in obese middle-aged animals. PMID- 23755299 TI - Individual differences in the attentional blink: the temporal profile of blinkers and non-blinkers. AB - BACKGROUND: When two targets are presented in close temporal succession, the majority of people frequently fail to report the second target. This phenomenon, known as the 'attentional blink' (AB), has been a major topic in attention research for the past twenty years because it is informative about the rate at which stimuli can be encoded into consciously accessible representations. An aspect of the AB that has long been ignored, however, is individual differences. METHODOLOGY/PRINCIPAL FINDINGS: Here we compare a group of blinkers (who show an AB) and non-blinkers (who show little or no AB), and investigate the boundary conditions of the non-blinkers' remarkable ability. Second, we directly test the properties of temporal selection by analysing response errors, allowing us to uncover individual differences in suppression, delay, and diffusion of selective attention across time. Thirdly, we test the hypothesis that information concerning temporal order is compromised when an AB is somehow avoided. Surprisingly, compared to earlier studies, only a modest amount of suppression was found for blinkers. Non-blinkers showed no suppression, were more precise in selecting the second target, and made less order reversals than blinkers did. In contrast, non-blinkers made relatively more intrusions and showed a selection delay when the second target immediately followed the first target (at lag 1). CONCLUSION/SIGNIFICANCE: The findings shed new light on the mechanisms that may underlie individual differences in selective attention. The notable ability of non-blinkers to accurately perceive targets presented in close temporal succession might be due to a relatively faster and more precise target selection process compared to large blinkers. PMID- 23755300 TI - Treponema denticola major outer sheath protein impairs the cellular phosphoinositide balance that regulates neutrophil chemotaxis. AB - The major outer sheath protein (Msp) of Treponema denticola inhibits neutrophil polarization and directed chemotaxis together with actin dynamics in vitro in response to the chemoattractant N-formyl-methionine-leucine-phenylanine (fMLP). Msp disorients chemotaxis through inhibition of a Rac1-dependent signaling pathway, but the upstream mechanisms are unknown. We challenged murine bone marrow neutrophils with enriched native Msp to determine the role of phospholipid modifying enzymes in chemotaxis and actin assembly downstream of fMLP stimulation. Msp modulated cellular phosphoinositide levels through inhibition of phosphatidylinositol 3-kinase (PI3-kinase) together with activation of the lipid phosphatase, phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Impaired phosphatidylinositol[(3,4,5)]-triphosphate (PIP3) levels prevented recruitment and activation of the downstream mediator Akt. Release of the actin capping proteins gelsolin and CapZ in response to fMLP was also inhibited by Msp exposure. Chemical inhibition of PTEN restored PIP3 signaling, as measured by Akt activation, Rac1 activation, actin uncapping, neutrophil polarization and chemotaxis in response to fMLP-stimulation, even in the presence of Msp. Transduction with active Rac1 also restored fMLP-mediated actin uncapping, suggesting that Msp acts at the level of PIP3 in the hierarchical feedback loop of PIP3 and Rac1 activation. Taken together, Msp alters the phosphoinositide balance in neutrophils, impairing the cell "compass", which leads to inhibition of downstream chemotactic events. PMID- 23755301 TI - Identification of cisplatin-binding proteins using agarose conjugates of platinum compounds. AB - Cisplatin is widely used as an antineoplastic drug, but its ototoxic and nephrotoxic side-effects, as well as the inherent or acquired resistance of some cancers to cisplatin, remain significant clinical problems. Cisplatin's selectivity in killing rapidly proliferating cancer cells is largely dependent on covalent binding to DNA via cisplatin's chloride sites that had been aquated. We hypothesized that cisplatin's toxicity in slowly proliferating or terminally differentiated cells is primarily due to drug-protein interactions, instead of drug-DNA binding. To identify proteins that bind to cisplatin, we synthesized two different platinum-agarose conjugates, one with two amino groups and another with two chlorides attached to platinum that are available for protein binding, and conducted pull-down assays using cochlear and kidney cells. Mass spectrometric analysis on protein bands after gel electrophoresis and Coomassie blue staining identified several proteins, including myosin IIA, glucose-regulated protein 94 (GRP94), heat shock protein 90 (HSP90), calreticulin, valosin containing protein (VCP), and ribosomal protein L5, as cisplatin-binding proteins. Future studies on the interaction of these proteins with cisplatin will elucidate whether these drug-protein interactions are involved in ototoxicity and nephrotoxicity, or contribute to tumor sensitivity or resistance to cisplatin treatment. PMID- 23755302 TI - Screen-based sedentary behavior, physical activity, and muscle strength in the English longitudinal study of ageing. AB - BACKGROUND: Sarcopenia is associated with loss of independence and ill-health in the elderly although the causes remain poorly understood. We examined the association between two screen-based leisure time sedentary activities (daily TV viewing time and internet use) and muscle strength. METHODS AND RESULTS: We studied 6228 men and women (aged 64.9 +/- 9.1 yrs) from wave 4 (2008-09) of the English Longitudinal Study of Ageing, a prospective study of community dwelling older adults. Muscle strength was assessed by a hand grip test and the time required to complete five chair rises. TV viewing and internet usage were inversely associated with one another. Participants viewing TV >= 6 hrs/d had lower grip strength (Men, B = -1.20 kg, 95% CI, -2.26, -0.14; Women, -0.75 kg, 95% CI, -1.48, -0.03) in comparison to <2 hrs/d TV, after adjustment for age, physical activity, smoking, alcohol, chronic disease, disability, depressive symptoms, social status, and body mass index. In contrast, internet use was associated with higher grip strength (Men, B = 2.43 kg, 95% CI, 1.74, 3.12; Women, 0.76 kg, 95% CI, 0.32, 1.20). These associations persisted after mutual adjustment for both types of sedentary behaviour. CONCLUSIONS: In older adults, the association between sedentary activities and physical function is context specific (TV viewing vs. computer use). Adverse effects of TV viewing might reflect the prolonged sedentary nature of this behavior. PMID- 23755303 TI - A simple method for estimating informative node age priors for the fossil calibration of molecular divergence time analyses. AB - Molecular divergence time analyses often rely on the age of fossil lineages to calibrate node age estimates. Most divergence time analyses are now performed in a Bayesian framework, where fossil calibrations are incorporated as parametric prior probabilities on node ages. It is widely accepted that an ideal parameterization of such node age prior probabilities should be based on a comprehensive analysis of the fossil record of the clade of interest, but there is currently no generally applicable approach for calculating such informative priors. We provide here a simple and easily implemented method that employs fossil data to estimate the likely amount of missing history prior to the oldest fossil occurrence of a clade, which can be used to fit an informative parametric prior probability distribution on a node age. Specifically, our method uses the extant diversity and the stratigraphic distribution of fossil lineages confidently assigned to a clade to fit a branching model of lineage diversification. Conditioning this on a simple model of fossil preservation, we estimate the likely amount of missing history prior to the oldest fossil occurrence of a clade. The likelihood surface of missing history can then be translated into a parametric prior probability distribution on the age of the clade of interest. We show that the method performs well with simulated fossil distribution data, but that the likelihood surface of missing history can at times be too complex for the distribution-fitting algorithm employed by our software tool. An empirical example of the application of our method is performed to estimate echinoid node ages. A simulation-based sensitivity analysis using the echinoid data set shows that node age prior distributions estimated under poor preservation rates are significantly less informative than those estimated under high preservation rates. PMID- 23755304 TI - Modified whole effluent toxicity test to assess and decouple wastewater effects from environmental gradients. AB - Environmental gradients and wastewater discharges produce aggregated effects on marine populations, obscuring the detection of human impact. Classical assessment methods do not include environmental effects in toxicity tests designs, which could lead to incorrect conclusions. We proposed a modified Whole Effluent Toxicity test (mWET) that includes environmental gradients in addition to effluent dilutions, together with the application of Generalized Linear Mixed Models (GLMM) to assess and decouple those effects. We tested this approach, analyzing the lethal effects of wastewater on a marine sandy beach bivalve affected by an artificial canal freshwater discharge used for rice crops irrigation. To this end, we compared bivalve mortality between canal water dilutions (CWd) and salinity controls (SC: without canal water). CWd were prepared by diluting the water effluent (sampled during the pesticide application period) with artificial marine water. The salinity gradient was included in the design by achieving the same final salinities in both CWd and SC, allowing us to account for the effects of salinity by including this variable as a random factor in the GLMM. Our approach detected significantly higher mortalities in CWd, indicating potential toxic effects of the effluent discharge. mWET represents an improvement over the internationally standardized WET tests, since it considers environmental variability and uses appropriate statistical analyses. PMID- 23755305 TI - Suppression of gluconeogenic gene expression by LSD1-mediated histone demethylation. AB - Aberrant gluconeogenic gene expression is associated with diabetes, glycogen storage disease, and liver cancer. However, little is known how these genes are regulated at the chromatin level. In this study, we investigated in HepG2 cells whether histone demethylation is a potential mechanism. We found that knockdown or pharmacological inhibition of histone demethylase LSD1 causes remarkable transcription activation of two gluconeogenic genes, FBP1 and G6Pase, and consequently leads to increased de novo glucose synthesis and decreased intracellular glycogen content. Mechanistically, LSD1 occupies the promoters of FBP1 and G6Pase, and modulates their H3K4 dimethylation levels. Thus, our work identifies an epigenetic pathway directly governing gluconeogenic gene expression, which might have important implications in metabolic physiology and diseases. PMID- 23755306 TI - CO2 efflux from shrimp ponds in Indonesia. AB - The conversion of mangrove forest to aquaculture ponds has been increasing in recent decades. One of major concerns of this habitat loss is the release of stored 'blue' carbon from mangrove soils to the atmosphere. In this study, we assessed carbon dioxide (CO2) efflux from soil in intensive shrimp ponds in Bali, Indonesia. We measured CO2 efflux from the floors and walls of shrimp ponds. Rates of CO2 efflux within shrimp ponds were 4.37 kg CO2 m-2 y-1 from the walls and 1.60 kg CO2 m-2 y-1 from the floors. Combining our findings with published data of aquaculture land use in Indonesia, we estimated that shrimp ponds in this region result in CO2 emissions to the atmosphere between 5.76 and 13.95 Tg y-1. The results indicate that conversion of mangrove forests to aquaculture ponds contributes to greenhouse gas emissions that are comparable to peat forest conversion to other land uses in Indonesia. Higher magnitudes of CO2 emission may be released to atmosphere where ponds are constructed in newly cleared mangrove forests. This study indicates the need for incentives that can meet the target of aquaculture industry without expanding the converted mangrove areas, which will lead to increased CO2 released to atmosphere. PMID- 23755307 TI - Decreased tumor progression and invasion by a novel anti-cell motility target for human colorectal carcinoma cells. AB - We have previously described a novel modulator of the actin cytoskeleton that also regulates Ras and mitogen-activated protein kinase activities in TGFbeta sensitive epithelial cells. Here we examined the functional role of this signaling regulatory protein (km23-1) in mediating the migration, invasion, and tumor growth of human colorectal carcinoma (CRC) cells. We show that small interfering RNA (siRNA) depletion of km23-1 in human CRC cells inhibited constitutive extracellular signal-regulated kinase (ERK) activation, as well as pro-invasive ERK effector functions that include phosphorylation of Elk-1, constitutive regulation of c-Fos-DNA binding, TGFbeta1 promoter transactivation, and TGFbeta1 secretion. In addition, knockdown of km23-1 reduced the paracrine effects of CRC cell-secreted factors in conditioned medium and in fibroblast co cultures. Moreover, km23-1 depletion in human CRC cells reduced cell migration and invasion, as well as expression of the ERK-regulated, metastasis-associated scaffold protein Ezrin. Finally, km23-1 inhibition significantly suppressed tumor formation in vivo. Thus, our results implicate km23-1 as a novel anti-metastasis target for human colon carcinoma cells, capable of decreasing tumor growth and invasion via a mechanism involving suppression of various pro-migratory features of CRC. These include a reduction in ERK signaling, diminished TGFbeta1 production, decreased expression of the plasma membrane-cytoskeletal linker Ezrin, as well as attenuation of the paracrine effects of colon carcinoma secreted factors on fibroblast migration and mitogenesis. As such, km23-1 inhibitors may represent a viable therapeutic strategy for interfering with colon cancer progression and invasion. PMID- 23755308 TI - Intestinal parasite prevalence in an area of ethiopia after implementing the SAFE strategy, enhanced outreach services, and health extension program. AB - BACKGROUND: The SAFE strategy aims to reduce transmission of Chlamydia trachomatis through antibiotics, improved hygiene, and sanitation. We integrated assessment of intestinal parasites into large-scale trachoma impact surveys to determine whether documented environmental improvements promoted by a trachoma program had collateral impact on intestinal parasites. METHODOLOGY: We surveyed 99 communities for both trachoma and intestinal parasites (soil-transmitted helminths, Schistosoma mansoni, and intestinal protozoa) in South Gondar, Ethiopia. One child aged 2-15 years per household was randomly selected to provide a stool sample of which about 1 g was fixed in sodium acetate-acetic acid formalin, concentrated with ether, and examined under a microscope by experienced laboratory technicians. PRINCIPAL FINDINGS: A total of 2,338 stool specimens were provided, processed, and linked to survey data from 2,657 randomly selected children (88% response). The zonal-level prevalence of Ascaris lumbricoides, hookworm, and Trichuris trichiura was 9.9% (95% confidence interval (CI) 7.2 12.7%), 9.7% (5.9-13.4%), and 2.6% (1.6-3.7%), respectively. The prevalence of S. mansoni was 2.9% (95% CI 0.2-5.5%) but infection was highly focal (range by community from 0-52.4%). The prevalence of any of these helminth infections was 24.2% (95% CI 17.6-30.9%) compared to 48.5% as found in a previous study in 1995 using the Kato-Katz technique. The pathogenic intestinal protozoa Giardia intestinalis and Entamoeba histolytica/E. dispar were found in 23.0% (95% CI 20.3 25.6%) and 11.1% (95% CI 8.9-13.2%) of the surveyed children, respectively. We found statistically significant increases in household latrine ownership, use of an improved water source, access to water, and face washing behavior over the past 7 years. CONCLUSIONS: Improvements in hygiene and sanitation promoted both by the SAFE strategy for trachoma and health extension program combined with preventive chemotherapy during enhanced outreach services are plausible explanations for the changing patterns of intestinal parasite prevalence. The extent of intestinal protozoa infections suggests poor water quality or unsanitary water collection and storage practices and warrants targeted intervention. PMID- 23755309 TI - Safety, pharmacokinetic, and efficacy studies of oral DB868 in a first stage vervet monkey model of human African trypanosomiasis. AB - There are no oral drugs for human African trypanosomiasis (HAT, sleeping sickness). A successful oral drug would have the potential to reduce or eliminate the need for patient hospitalization, thus reducing healthcare costs of HAT. The development of oral medications is a key objective of the Consortium for Parasitic Drug Development (CPDD). In this study, we investigated the safety, pharmacokinetics, and efficacy of a new orally administered CPDD diamidine prodrug, 2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868; CPD-007-10), in the vervet monkey model of first stage HAT. DB868 was well tolerated at a dose up to 30 mg/kg/day for 10 days, a cumulative dose of 300 mg/kg. Mean plasma levels of biomarkers indicative of liver injury (alanine aminotransferase, aspartate aminotransferase) were not significantly altered by drug administration. In addition, no kidney-mediated alterations in creatinine and urea concentrations were detected. Pharmacokinetic analysis of plasma confirmed that DB868 was orally available and was converted to the active compound DB829 in both uninfected and infected monkeys. Treatment of infected monkeys with DB868 began 7 days post infection. In the infected monkeys, DB829 attained a median C(max) (dosing regimen) that was 12-fold (3 mg/kg/day for 7 days), 15-fold (10 mg/kg/day for 7 days), and 31-fold (20 mg/kg/day for 5 days) greater than the IC50 (14 nmol/L) against T. b. rhodesiense STIB900. DB868 cured all infected monkeys, even at the lowest dose tested. In conclusion, oral DB868 cured monkeys with first stage HAT at a cumulative dose 14-fold lower than the maximum tolerated dose and should be considered a lead preclinical candidate in efforts to develop a safe, short course (5-7 days), oral regimen for first stage HAT. PMID- 23755311 TI - Replacing a native Wolbachia with a novel strain results in an increase in endosymbiont load and resistance to dengue virus in a mosquito vector. AB - Wolbachia is a maternally transmitted endosymbiotic bacterium that is estimated to infect up to 65% of insect species. The ability of Wolbachia to both induce pathogen interference and spread into mosquito vector populations makes it possible to develop Wolbachia as a biological control agent for vector-borne disease control. Although Wolbachia induces resistance to dengue virus (DENV), filarial worms, and Plasmodium in mosquitoes, species like Aedes polynesiensis and Aedes albopictus, which carry native Wolbachia infections, are able to transmit dengue and filariasis. In a previous study, the native wPolA in Ae. polynesiensis was replaced with wAlbB from Ae. albopictus, and resulted in the generation of the transinfected "MTB" strain with low susceptibility for filarial worms. In this study, we compare the dynamics of DENV serotype 2 (DENV-2) within the wild type "APM" strain and the MTB strain of Ae. polynesiensis by measuring viral infection in the mosquito whole body, midgut, head, and saliva at different time points post infection. The results show that wAlbB can induce a strong resistance to DENV-2 in the MTB mosquito. Evidence also supports that this resistance is related to a dramatic increase in Wolbachia density in the MTB's somatic tissues, including the midgut and salivary gland. Our results suggests that replacement of a native Wolbachia with a novel infection could serve as a strategy for developing a Wolbachia-based approach to target naturally infected insects for vector-borne disease control. PMID- 23755312 TI - Schistosomiasis control using piplartine against Biomphalaria glabrata at different developmental stages. AB - BACKGROUND: Schistosomiasis is one of the most significant diseases in tropical countries and affects almost 200 million people worldwide. The application of molluscicides to eliminate the parasite's intermediate host, Biomphalaria glabrata, from infected water supplies is one strategy currently being used to control the disease. Previous studies have shown a potent molluscicidal activity of crude extracts from Piper species, with extracts from Piper tuberculatum being among the most active. METHODS AND FINDINGS: The molluscicidal activity of P. tuberculatum was monitored on methanolic extracts from different organs (roots, leaves, fruit and stems). The compounds responsible for the molluscicidal activity were identified using (1)H NMR and ESIMS data and multivariate analyses, including principal component analysis and partial least squares. These results indicated that the high molluscicidal activity displayed by root extracts (LC50 20.28 ug/ml) was due to the presence of piplartine, a well-known biologically active amide. Piplartine was isolated from P. tuberculatum root extracts, and the molluscicidal activity of this compound on adults and embryos of B. glabrata was determined. The compound displayed potent activity against all developmental stages of B. glabrata. Next, the environmental toxicity of piplartine was evaluated using the microcrustacean Daphnia similis (LC50 7.32 ug/ml) and the fish Danio rerio (1.69 ug/ml). The toxicity to these organisms was less compared with the toxicity of niclosamide, a commercial molluscicide. CONCLUSIONS: The development of a new, natural molluscicide is highly desirable, particularly because the commercially available molluscicide niclosamide is highly toxic to some organisms in the environment (LC50 0.25 ug/ml to D. similis and 0.12 ug/ml to D. rerio). Thus, piplartine is a potential candidate for a natural molluscicide that has been extracted from a tropical plant species and showed less toxic to environment. PMID- 23755310 TI - A systematic review of the epidemiology of echinococcosis in domestic and wild animals. AB - BACKGROUND: Human echinococcosis is a neglected zoonosis caused by parasites of the genus Echinococcus. The most frequent clinical forms of echinococcosis, cystic echinococcosis (CE) and alveolar echinococcosis (AE), are responsible for a substantial health and economic burden, particularly to low-income societies. Quantitative epidemiology can provide important information to improve the understanding of parasite transmission and hence is an important part of efforts to control this disease. The purpose of this review is to give an insight on factors associated with echinococcosis in animal hosts by summarising significant results reported from epidemiological studies identified through a systematic search. METHODOLOGY AND PRINCIPAL FINDINGS: The systematic search was conducted mainly in electronic databases but a few additional records were obtained from other sources. Retrieved entries were examined in order to identify available peer-reviewed epidemiological studies that found significant risk factors for infection using associative statistical methods. One hundred studies met the eligibility criteria and were suitable for data extraction. Epidemiological factors associated with increased risk of E. granulosus infection in dogs included feeding with raw viscera, possibility of scavenging dead animals, lack of anthelmintic treatment and owners' poor health education and indicators of poverty. Key factors associated with E. granulosus infection in intermediate hosts were related to the hosts' age and the intensity of environmental contamination with parasite eggs. E. multilocularis transmission dynamics in animal hosts depended on the interaction of several ecological factors, such as hosts' population densities, host-prey interactions, landscape characteristics, climate conditions and human-related activities. CONCLUSIONS/SIGNIFICANCE: Results derived from epidemiological studies provide a better understanding of the behavioural, biological and ecological factors involved in the transmission of this parasite and hence can aid in the design of more effective control strategies. PMID- 23755313 TI - Schistosoma japonicum soluble egg antigens attenuate invasion in a first trimester human placental trophoblast model. AB - BACKGROUND: Schistosomiasis affects nearly 40 million women of reproductive age, and is known to elicit a pro-inflammatory signature in the placenta. We have previously shown that antigens from schistosome eggs can elicit pro-inflammatory cytokine production from trophoblast cells specifically; however, the influence of these antigens on other characteristics of trophoblast function, particularly as it pertains to placentation in early gestation, is unknown. We therefore sought to determine the impact of schistosome antigens on key characteristics of first trimester trophoblast cells, including migration and invasion. METHODS: First trimester HTR8/SVneo trophoblast cells were co-cultured with plasma from pregnant women with and without schistosomiasis or schistosome soluble egg antigens (SEA) and measured cytokine, cellular migration, and invasion responses. RESULTS: Exposure of HTR8 cells to SEA resulted in a pro-inflammatory, anti invasive signature, characterized by increased pro-inflammatory cytokines (IL-6, IL-8, MCP-1) and TIMP-1. Additionally, these cells displayed 62% decreased migration and 2.7-fold decreased invasion in vitro after treatment with SEA. These results are supported by increased IL-6 and IL-8 in the culture media of HTR8 cells exposed to plasma from Schistosoma japonica infected pregnant women. CONCLUSIONS: Soluble egg antigens found in circulation during schistosome infection increase pro-inflammatory cytokine production and inhibit the mobility and invasive characteristics of the first trimester HTR8/SVneo trophoblast cell line. This is the first study to assess the impact of schistosome soluble egg antigens on the behavior of an extravillous trophoblast model and suggests that schistosomiasis in the pre-pregnancy period may adversely impact placentation and the subsequent health of the mother and newborn. PMID- 23755315 TI - Estimates of dengue force of infection in children in Colombo, Sri Lanka. AB - Dengue is the most important vector-borne viral disease worldwide and a major cause of childhood fever burden in Sri Lanka, which has experienced a number of large epidemics in the past decade. Despite this, data on the burden and transmission of dengue virus in the Indian Subcontinent are lacking. As part of a longitudinal fever surveillance study, we conducted a dengue seroprevalence survey among children aged <12 years in Colombo, Sri Lanka. We used a catalytic model to estimate the risk of primary infection among seronegative children. Over 50% of children had IgG antibodies to dengue virus and seroprevalence increased with age. The risk of primary infection was 14.1% per year (95% CI: 12.7%-15.6%), indicating that among initially seronegative children, approximately 1 in 7 experience their first infection within 12 months. There was weak evidence to suggest that the force of primary infection could be lower for children aged 6 years and above. We estimate that there are approximately 30 primary dengue infections among children <12 years in the community for every case notified to national surveillance, although this ratio is closer to 100:1 among infants. Dengue represents a considerable infection burden among children in urban Sri Lanka, with levels of transmission comparable to those in the more established epidemics of Southeast Asia. PMID- 23755314 TI - Dengue virus activates membrane TRAIL relocalization and IFN-alpha production by human plasmacytoid dendritic cells in vitro and in vivo. AB - BACKGROUND: Dengue displays a broad spectrum of clinical manifestations that may vary from asymptomatic to severe and even fatal features. Plasma leakage/hemorrhages can be caused by a cytokine storm induced by monocytes and dendritic cells during dengue virus (DENV) replication. Plasmacytoid dendritic cells (pDCs) are innate immune cells and in response to virus exposure secrete IFN-alpha and express membrane TRAIL (mTRAIL). We aimed to characterize pDC activation in dengue patients and their function under DENV-2 stimulation in vitro. METHODS FINDINGS: Flow cytometry analysis (FCA) revealed that pDCs of mild dengue patients exhibit significantly higher frequencies of mTRAIL compared to severe cases or healthy controls. Plasma levels of IFN-alpha and soluble TRAIL are increased in mild compared to severe dengue patients, positively correlating with pDC activation. FCA experiments showed that in vitro exposure to DENV-2 induced mTRAIL expression on pDC. Furthermore, three dimension microscopy highlighted that TRAIL was relocalized from intracellular compartment to plasma membrane. Chloroquine treatment inhibited DENV-2-induced mTRAIL relocalization and IFN-alpha production by pDC. Endosomal viral degradation blockade by chloroquine allowed viral antigens detection inside pDCs. All those data are in favor of endocytosis pathway activation by DENV-2 in pDC. Coculture of pDC/DENV-2 infected monocytes revealed a dramatic decrease of antigen detection by FCA. This viral antigens reduction in monocytes was also observed after exogenous IFN-alpha treatment. Thus, pDC effect on viral load reduction was mainly dependent on IFN alpha production. CONCLUSIONS: This investigation characterizes, during DENV-2 infection, activation of pDCs in vivo and their antiviral role in vitro. Thus, we propose TRAIL-expressing pDCs may have an important role in the outcome of disease. PMID- 23755316 TI - Atmospheric moisture variability and transmission of hemorrhagic fever with renal syndrome in Changsha City, Mainland China, 1991-2010. AB - BACKGROUND: The transmission of hemorrhagic fever with renal syndrome (HFRS) is influenced by environmental determinants. This study aimed to explore the association between atmospheric moisture variability and the transmission of hemorrhagic fever with renal syndrome (HFRS) for the period of 1991-2010 in Changsha, China. METHODS AND FINDINGS: Wavelet analyses were performed by using monthly reported time series data of HFRS cases to detect and quantify the periodicity of HFRS. A generalized linear model with a Poisson distribution and a log link model were used to quantify the relationship between climate and HFRS cases, highlighting the importance of moisture conditions. There was a continuous annual oscillation mode and multi-annual cycle around 3-4 years from 1994 to 1999. There was a significant association of HFRS incidence with moisture conditions and the Multivariate El Nino-Southern Oscillation Index (MEI). Particularly, atmospheric moisture has a significant effect on the propagation of HFRS; annual incidence of HFRS was positively correlated with annual precipitation and annual mean absolute humidity. CONCLUSIONS: The final model had good accuracy in forecasting the occurrence of HFRS and moisture condition can be used in disease surveillance and risk management to provide early warning of potential epidemics of this disease. PMID- 23755318 TI - Entangled Valence Electron-Hole Dynamics Revealed by Stimulated Attosecond X-ray Raman Scattering. AB - We show that broadband x-ray pulses can create wavepackets of valence electrons and holes localized in the vicinity of a selected atom (nitrogen, oxygen or sulfur in cysteine) by stimulated resonant Raman scattering. The subsequent dynamics reveals highly correlated motions of entangled electrons and hole quasiparticles. This information goes beyond the time-dependent total charge density derived from x-ray diffraction. PMID- 23755317 TI - Plague circulation and population genetics of the reservoir Rattus rattus: the influence of topographic relief on the distribution of the disease within the Madagascan focus. AB - BACKGROUND: Landscape may affect the distribution of infectious diseases by influencing the population density and dispersal of hosts and vectors. Plague (Yersinia pestis infection) is a highly virulent, re-emerging disease, the ecology of which has been scarcely studied in Africa. Human seroprevalence data for the major plague focus of Madagascar suggest that plague spreads heterogeneously across the landscape as a function of the relief. Plague is primarily a disease of rodents. We therefore investigated the relationship between disease distribution and the population genetic structure of the black rat, Rattus rattus, the main reservoir of plague in Madagascar. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a comparative study of plague seroprevalence and genetic structure (15 microsatellite markers) in rat populations from four geographic areas differing in topology, each covering about 150-200 km(2) within the Madagascan plague focus. The seroprevalence levels in the rat populations mimicked those previously reported for humans. As expected, rat populations clearly displayed a more marked genetic structure with increasing relief. However, the relationship between seroprevalence data and genetic structure differs between areas, suggesting that plague distribution is not related everywhere to the effective dispersal of rats. CONCLUSIONS/SIGNIFICANCE: Genetic diversity estimates suggested that plague epizootics had only a weak impact on rat population sizes. In the highlands of Madagascar, plague dissemination cannot be accounted for solely by the effective dispersal of the reservoir. Human social activities may also be involved in spreading the disease in rat and human populations. PMID- 23755319 TI - Revision of the instructions to authors to require a structured abstract, digital object identifier of each reference, and author's voice recording may increase journal access. PMID- 23755320 TI - Psychotraumatology: rich in international and cross-cultural collaboration. AB - Although European countries differ widely in their approach to psychotrauma and its consequences, with 20 years of European psychotraumatology in the form of the European Society for Traumatic Studies (ESTSS) there is now increasing dissemination of evidence-based care reaching more and more professionals and scholars in Europe. The society has moved forward to become a European umbrella organization serving many different European countries and cultures. This article describes the process of the restructuring and how ESTSS has grown from collaboration with other traumatic stress partners inside and outside Europe. The knowledge generated by The European Network for Traumatic Stress (TENTS) project has helped this process as well as the creation of an international open-access journal, the European Journal of Psychotraumatology (EJPT), for optimal dissemination of knowledge. PMID- 23755321 TI - European psychotraumatology - alongside the recent European history. AB - This article outlines a personal reflection of experiences within the field of traumatic stress, especially in relation to specific events, which affected the author's professional life. Conclusions for further challenges for European Society for Traumatic Stress Studies (ESTSS) are delineated. ESTSS's role in the global network of traumatic stress societies is discussed. This is a personal view of Brigitte Lueger-Schuster, president of ESTSS on behalf of the 20th birthday of ESTSS. PMID- 23755322 TI - Mutual learning globally. AB - This article is about the development of the trauma field over the last 20 years from an organizational perspective, and about trauma from a global, culture sensitive perspective. My professional career is very closely linked to the development of the European Society for Traumatic Stress Studies (ESTSS) in the 1990s. Later on, I was fortunate enough to witness, and contribute to, the International Society for Traumatic Stress Studies' (ISTSS) increasing focus on trauma as a global issue. I am trying to demonstrate how important the ESTSS and the ISTSS have been for me, how serving these societies has shaped my thinking, both as a clinician and a researcher, and how much I learned from these experiences. PMID- 23755323 TI - ESTSS and ISTSS: "heterozygous twins". AB - The development of traumatic stress studies during the past decades has much profited from professionals from the United States and from Europe. However, these professional societies, the International Society for Traumatic Stress Studies and the European Society for Traumatic Stress Studies (ESTSS) still struggle to find an equal common pathway. This is a personal retrospective view of Berthold Gersons, past president of ESTSS on behalf of the 20th anniversary of ESTSS. PMID- 23755324 TI - The first president's pathway into ESTSS: memories and ideas for future issue. Patients as partners. AB - This article addresses Wolter De Loos' pathway into ESTSS that ended on 6th January 2004. His footsteps are still printed in the field of psychotraumatology as he showed the field how a physician was trying to integrate his working field with that of psychiatry, with a great passion for his patients. Erica M. Van der Schrieck-De Loos outlines the perspectives of her father as funding president of the ESTSS by using his Opening Address of the Fourth ESTSS Conference in 1995. This address emphasized that the mixture of righteousness and offence in warfare is ubiquitious and everlasting. The perspective of the first president's pathway has been integrated with the current vision of the author to show that the patient can be a partner of the healthcare team. A suggestion for ESTSS main objective number (8), contained within the ESTSS mission statement, is to involve patients as partners of the traumatic stress care team into accelerating traumatic stress care across Europe and beyond. PMID- 23755325 TI - Disseminating and implementing evidence-based practice. AB - The inconsistent implementation of evidence-based practice has become a significant concern in the traumatic stress field. The European Society for Traumatic Stress Studies (ESTSS) has played a major role in highlighting this issue and has contributed to a number of European initiatives to improve dissemination and implementation. Key initiatives include the introduction of the ESTSS General Certificate in Psychotrauma Psychotraumatology and the European Network for Traumatic Stress (TENTS); these are discussed in this paper. PMID- 23755326 TI - Introducing the notion of social context of collective trauma to ESTSS. AB - Living amidst war and mass suffering while grasping the opportunity for professional growth, intertwined into my life perspective. Along the years, ESTSS provided a backdrop for my contacts with mental health colleagues from whom I learned, and among whom many became my friends. These rich experiences guided me towards promoting awareness within ESTSS of the importance of social context in which healing of traumatized populations is expected to progress. Each incident of organized violence leaves behind new scores of traumatized individuals and family members, among whom many will need support that may stretch their resources beyond reasonable limits. We need to acknowledge the hindering effects of living in such a social context and that many people that we meet as professionals may carry the burden of unresolved trauma, which should not go by unattended. PMID- 23755327 TI - 20 years of European society for traumatic stress. PMID- 23755328 TI - ESTSS at 20 years: "a phoenix gently rising from a lava flow of European trauma". AB - Roderick J. Orner, who was President between 1997 and 1999, traces the phoenix like origins of the European Society for Traumatic Stress Studies (ESTSS) from an informal business meeting called during the 1st European Conference on Traumatic Stress (ECOTS) in 1987 to its emergence into a formally constituted society. He dwells on the challenges of tendering a trauma society within a continent where trauma has been and remains endemic. ESTSS successes are noted along with a number of personal reflections on activities that give rise to concern for the present as well as its future prospects. Denial of survivors' experiences and turning away from survivors' narratives by reframing their experiences to accommodate helpers' theory-driven imperatives are viewed with alarm. Arguments are presented for making human rights, memory, and ethics core elements of a distinctive European psycho traumatology, which will secure current ESTSS viability and future integrity. PMID- 23755329 TI - Psychotraumatology in Europe: a personal history. AB - This paper outlines a personal account of the growth of the field of traumatic stress in Europe, especially with the history of major disasters in the 1980s, the first European Conference in Lincoln in 1988, the formation of European Society for Traumatic Stress Studies and its subsequent development, for example, with a federal structure and its own journal, and most important of all the way that the field as a whole has matured. PMID- 23755330 TI - Color stability of thermochromic pigment in maxillofacial silicone. AB - PURPOSE: Maxillofacial silicone elastomer is usually colored intrinsically with color pigments to match skin colors. The purpose of this study was to investigate the color stability of a maxillofacial silicone elastomer, colored with a thermochromic, color changing pigment. MATERIALS AND METHODS: Disc-shaped maxillofacial silicone specimens were prepared and divided into 3 groups: a conventionally colored control group, one group additionally colored with 0.2 wt% thermochromic pigment , and one group with 0.6 wt% thermochromic pigment. Half of the surface of each specimen was covered with an aluminium foil. All of the specimens were exposed to UV radiation in 6 hour cycles over 46 days. In between the UV exposures, half of the specimens were stored in darkness, at room temperature, and the other half was stored in an incubator, at a humidity of 97% and a temperature of +37C. Color measurements were made with a spectrophotometer and registered according to the CIELAB L(*)a(*)b(*) color model system. The changes in L(*), a(*) and b(*) values during artificial aging were statistically analyzed by using paired samples t-test and repeated measures ANOVA. P-values <.05 were considered as statistically significant. RESULTS: The UV exposure resulted in visually noticeable and statistically significant color changes in the L(*), a(*) and b(*) values in both of the test groups containing thermochromic pigment. Storage in the incubator lead to statistically significant color changes in the a(*) and b(*) values of the specimens containing thermochromic pigment, compared to those stored at room temperature. CONCLUSION: The specimens containing thermochromic pigment were very sensitive to UV radiation, and the thermochromic pigment is not suitable, as such, to be used in maxillofacial prostheses. PMID- 23755331 TI - Physical stability of arginine-glycine-aspartic acid peptide coated on anodized implants after installation. AB - PURPOSE: The aim of this study was to evaluate the stability of arginine-glycine aspartic acid (RGD) peptide coatings on implants by measuring the amount of peptide remaining after installation. MATERIALS AND METHODS: Fluorescent isothiocyanate (FITC)-fixed RGD peptide was coated onto anodized titanium implants (width 4 mm, length 10 mm) using a physical adsorption method (P) or a chemical grafting method (C). Solid Rigid Polyurethane Foam (SRPF) was classified as either hard bone (H) or soft bone (S) according to its density. Two pieces of artificial bone were fixed in a customized jig, and coated implants were installed at the center of the boundary between two pieces of artificial bone. The test groups were classified as: P-H, P-S, C-H, or C-S. After each installation, implants were removed from the SRPF, and the residual amounts and rates of RGD peptide in implants were measured by fluorescence spectrometry. The Kruskal-Wallis test was used for the statistical analysis (alpha=0.05). RESULTS: Peptide-coating was identified by fluorescence microscopy and XPS. Total coating amount was higher for physical adsorption than chemical grafting. The residual rate of peptide was significantly larger in the P-S group than in the other three groups (P<.05). CONCLUSION: The result of this study suggests that coating doses depend on coating method. Residual amounts of RGD peptide were greater for the physical adsorption method than the chemical grafting method. PMID- 23755332 TI - Comparative fracture strength analysis of Lava and Digident CAD/CAM zirconia ceramic crowns. AB - PURPOSE: All-ceramic crowns are subject to fracture during function. To minimize this common clinical complication, zirconium oxide has been used as the framework for all-ceramic crowns. The aim of this study was to compare the fracture strengths of two computer-aided design/computer-aided manufacturing (CAD/CAM) zirconia crown systems: Lava and Digident. MATERIALS AND METHODS: Twenty Lava CAD/CAM zirconia crowns and twenty Digident CAD/CAM zirconia crowns were fabricated. A metal die was also duplicated from the original prepared tooth for fracture testing. A universal testing machine was used to determine the fracture strength of the crowns. RESULTS: THE MEAN FRACTURE STRENGTHS WERE AS FOLLOWS: 54.9 +/- 15.6 N for the Lava CAD/CAM zirconia crowns and 87.0 +/- 16.0 N for the Digident CAD/CAM zirconia crowns. The difference between the mean fracture strengths of the Lava and Digident crowns was statistically significant (P<.001). Lava CAD/CAM zirconia crowns showed a complete fracture of both the veneering porcelain and the core whereas the Digident CAD/CAM zirconia crowns showed fracture only of the veneering porcelain. CONCLUSION: The fracture strengths of CAD/CAM zirconia crowns differ depending on the compatibility of the core material and the veneering porcelain. PMID- 23755333 TI - Shear bond strength of resin cement to an acid etched and a laser irradiated ceramic surface. AB - PURPOSE: To evaluate the effects of hydrofluoric acid etching and Er,Cr:YSGG laser irradiation on the shear bond strength of resin cement to lithium disilicate ceramic. MATERIALS AND METHODS: Fifty-five ceramic blocks (5 mm * 5 mm * 2 mm) were fabricated and embedded in acrylic resin. Their surfaces were finished with 1000-grit silicon carbide paper. The blocks were assigned to five groups: 1) 9.5% hydrofluoric-acid etching for 60 s; 2-4), 1.5-, 2.5-, and 6-W Er,Cr:YSGG laser applications for 60 seconds, respectively; and 5) no treatment (control). One specimen from each group was examined using scanning electron microscopy. Ceramic primer (Rely X ceramic primer) and adhesive (Adper Single Bond) were applied to the ceramic surfaces, followed by resin cement to bond the composite cylinders, and light curing. Bonded specimens were stored in distilled water at 37C for 24 hours. Shear bond strengths were determined by a universal testing machine at 1 mm/min crosshead speed. Data were analyzed using Kruskal Wallis and Mann-Whitney U-tests (alpha=0.05). RESULTS: Adhesion was significantly stronger in Group 2 (3.88 +/- 1.94 MPa) and Group 3 (3.65 +/- 1.87 MPa) than in Control group (1.95 +/- 1.06 MPa), in which bonding values were lowest (P<.01). No significant difference was observed between Group 4 (3.59 +/- 1.19 MPa) and Control group. Shear bond strength was highest in Group 1 (8.42 +/- 1.86 MPa; P<.01). CONCLUSION: Er,Cr:YSGG laser irradiation at 1.5 and 2.5 W increased shear bond strengths between ceramic and resin cement compared with untreated ceramic surfaces. Irradiation at 6 W may not be an efficient ceramic surface treatment technique. PMID- 23755334 TI - Effect of silane activation on shear bond strength of fiber-reinforced composite post to resin cement. AB - PURPOSE: Among the surface treatment methods suggested to enhance the adhesion of resin cement to fiber-reinforced composite posts, conflicting results have been obtained with silanization. In this study, the effects of silanization, heat activation after silanization, on the bond strength between fiber-reinforced composite post and resin cement were determined. MATERIALS AND METHODS: Six groups (n=7) were established to evaluate two types of fiber post (FRC Postec Plus, D.T. Light Post) and three surface treatments (no treatment; air drying; drying at 38C). Every specimen were bonded with dual-curing resin cement (Variolink N) and stored in distilled water for 24 hours at 37C. Shear-bond strength (MPa) between the fiber post and the resin cement were measured using universal testing device. The data were analyzed with 1-way ANOVA and by multiple comparisons according to Tukey's HSD (alpha=0.05). The effect of surface treatment, fiber post type, and the interactions between these two factors were analyzed using 2-way ANOVA and independent sample T-tests. RESULTS: Silanization of the FRC Postec Plus significantly increased bond strength compared with the respective non-treated control, whereas no effect was determined for the D.T. Light Post. Heat drying the silane coupling agent on to the fiber-reinforced post did not significantly improve bond strength compared to air-syringe drying. CONCLUSION: The bond strength between the fiber-reinforced post and the resin cement was significantly increased with silanization in regards to the FRC Postec Plus post. Bond strength was not significantly improved by heat activation of the silane coupling agent. PMID- 23755335 TI - The effect of acrylamide incorporation on the thermal and physical properties of denture resins. AB - PURPOSE: Polymethyl methacrylate (PMMA) is the most commonly used denture base material despite typically low in strength. The purpose of this study was to improve the physical properties of the PMMA based denture base resins (QC-20, Dentsply Ltd., Addlestone, UK; Stellon, AD International Ltd, Dentsply, Switzerland; Acron MC; GC Lab Technologies Inc., Alsip, Japan) by copolymerization mechanism. MATERIALS AND METHODS: Control group specimens were prepared according to the manufacturer recommendations. In the copolymer groups; resins were prepared with 5%, 10%, 15% and 20% acrylamide (AAm) (Merck, Hohenbrunn, Germany) content according to the moleculer weight ratio, respectively. Chemical structure was characterized by a Bruker Vertex-70 Fourier transform infrared spectroscopy (FTIR) (Bruker Optics Inc., Ettlingen, Germany). Hardness was determined using an universal hardness tester (Struers Duramin, Struers A/S, Ballerup, Denmark) equipped with a Vickers diamond penetrator. The glass transition temperature (Tg) of control and copolymers were evaluated by Perkin Elmer Diamond DSC (Perkin Elmer, Massachusetts,USA). Statistical analyses were carried out using the statistical package SPSS for Windows, version 15.0 (SPSS, Chicago, IL, USA). The results were tested regarding the normality of distribution with the Shapiro Wilk test. Data were analyzed using ANOVA with post hoc Tukey test (P<.01). RESULTS: The copolymer synthesis was confirmed by FTIR spectroscopy. Glass transition temperature of the copolymer groups were higher than the control groups of the resins. The 10%, 15% and 20% copolymer groups of Stellon presented significantly higher than the control group in terms of hardness. 15% and 20% copolymer groups of Acron MC showed significantly higher hardness values when compared to the control group of the resin. Acrylamide addition did not affect the hardness of the QC-20 resin significantly. CONCLUSION: Within the limitation of this study, it can be concluded that copolymerization of PMMA with AAm increased the hardness value and glass transition temperature of PMMA denture base resins. PMID- 23755336 TI - Effect of span length on the fit of zirconia framework fabricated using CAD/CAM system. AB - PURPOSE: The purpose of this study was to evaluate the effect of the span length on the fit of zirconia framework fabricated using CAD/CAM system. MATERIALS AND METHODS: Abutments for single, 4-unit and 6-unit fixed partial prostheses were fabricated. Ten zirconia frameworks were fabricated for each group. The marginal and internal gap were presented by means of replica technique and measured by measuring microscope (AXIO(r), Carl Zeiss, Rochester, NY) and software (I solution(r), IMT i-solution Inc., Vancouver, BC, Canada). The results were statistically analyzed by multivariate analysis test and Dunnett T3 test for post hoc test (alpha=.05). RESULTS: There were statistically significant differences at 2, 4, 7, 8 points (mesio-distal section) and b, d, e, f, g (labio-lingual section). In some marginal reference points of 6-unit group (P<.05), the marginal gap were larger than 120 um. CONCLUSION: Span length of zirconia core may have an influence on marginal and internal fit. Within the limitation of this study, the increase of span length of zirconia framework of 6 or more-unit fixed partial denture may decrease the marginal and internal fit. PMID- 23755337 TI - Effects of post surface conditioning before silanization on bond strength between fiber post and resin cement. AB - PURPOSE: Post surface conditioning is necessary to expose the glass fibers to enable bonding between fiber post and resin cement. The purpose of the present study was to evaluate the effect of different surface conditioning on tensile bond strength (TBS) of a glass fiber reinforced post to resin cement. MATERIALS AND METHODS: In this in vitro study, 40 extracted single canal central incisors were endodontically treated and post spaces were prepared. The teeth were divided into four groups according to the methods of post surface treatment (n=10): 1) Silanization after etching with 20% H2O2, 2) Silanization after airborne-particle abrasion, 3) Silanization, and 4) No conditioning (Control). Adhesive resin cement (Panavia F 2.0) was used for cementation of the fiber posts to the root canal dentin. Three slices of 3 mm thick were obtained from each root. A universal testing machine was used with a cross-head speed of 1 mm/minute for performing the push-out tests. Two-way ANOVA and Tukey post hoc tests were used for analyzing data (alpha=0.05). RESULTS: It is revealed that different surface treatments and root dentin regions had significant effects on TBS, but the interaction between surface treatments and root canal regions had no significant effect on TBS. There was significant difference among H2O2 + Silane Group and other three groups. CONCLUSION: There were significant differences among the mean TBS values of different surface treatments. Application of hydrogen peroxide before silanization increased the bond strength between resin cements and fiber posts. The mean TBS mean values was significantly greater in the coronal region of root canal than the middle and apical thirds. PMID- 23755338 TI - Effect of solution temperature on the mechanical properties of dual-cure resin cements. AB - PURPOSE: This study was to evaluate the effect of the solution temperature on the mechanical properties of dualcure resin cements. MATERIALS AND METHODS: For the study, five dual-cure resin cements were chosen and light cured. To evaluate the effect of temperature on the specimens, the light-cured specimens were immersed in deionized water at three different temperatures (4, 37 and 60C) for 7 days. The control specimens were aged in a 37C dry and dark chamber for 24 hours. The mechanical properties of the light-cured specimens were evaluated using the Vickers hardness test, three-point bending test, and compression test, respectively. Both flexural and compressive properties were evaluated using a universal testing machine. The data were analyzed using a two way ANOVA with Tukey test to perform multiple comparisons (alpha=0.05). RESULTS: After immersion, the specimens showed significantly different microhardness, flexural, and compressive properties compared to the control case regardless of solution temperatures. Depending on the resin brand, the microhardness difference between the top and bottom surfaces ranged approximately 3.3-12.2%. Among the specimens, BisCem and Calibra showed the highest and lowest decrease of flexural strength, respectively. Also, Calibra and Multilink Automix showed the highest and lowest decrease of compressive strength, respectively compared to the control case. CONCLUSION: The examined dual-cure resin cements had compatible flexural and compressive properties with most methacrylate-based composite resins and the underlying dentin regardless of solution temperature. However, the effect of the solution temperature on the mechanical properties was not consistent and depended more on the resin brand. PMID- 23755339 TI - Effect of biofilm formation, and biocorrosion on denture base fractures. AB - PURPOSE: The aim of this study was to investigate the destructive effects of biofilm formation and/or biocorrosive activity of 6 different oral microorganisms. MATERIALS AND METHODS: Three different heat polymerized acrylic resins (Ivocap Plus, Lucitone 550, QC 20) were used to prepare three different types of samples. Type "A" samples with "V" type notch was used to measure the fracture strength, "B" type to evaluate the surfaces with scanning electron microscopy and "C" type for quantitative biofilm assay. Development and calculation of biofilm covered surfaces on denture base materials were accomplished by SEM and quantitative biofilm assay. According to normality assumptions ANOVA or Kruskal-Wallis was selected for statistical analysis (alpha=0.05). RESULTS: Significant differences were obtained among the adhesion potential of 6 different microorganisms and there were significant differences among their adhesion onto 3 different denture base materials. Compared to the control groups after contamination with the microorganisms, the three point bending test values of denture base materials decreased significantly (P<.05); microorganisms diffused at least 52% of the denture base surface. The highest median quantitative biofilm value within all the denture base materials was obtained with P. aeruginosa on Lucitone 550. The type of denture base material did not alter the diffusion potential of the microorganisms significantly (P>.05). CONCLUSION: All the tested microorganisms had destructive effect over the structure and composition of the denture base materials. PMID- 23755340 TI - Mouthguard use in Korean Taekwondo athletes - awareness and attitude. AB - PURPOSE: A survey was performed to identify the level of mouthguard use, awareness, wearability issues and attitude toward mouthguard among elite Korean Taewondo athletes. MATERIALS AND METHODS: Survey questionnaires were given to 152 athletes participating in the Korea National Taekwondo team selection event for the 2010 Guangzhou Asian Games. Questionnaires consisted of three sections, mouthguard awareness, reasons for not wearing mouthguard and the last section to test the level of acceptance on current mouthguard and when the identified problems were resolved. For analyzing difference among response, chi(2) test was used and significant level (alpha) was set up as 0.05. RESULTS: Responses in each of items showed significant difference (P<.001). Majority of response regarding each question: Majority of respondents believed that mouthguard were effective in preventing injuries (36.4%) but the result suggested that the provision of information on mouthguard to athletes was inadequate (44.0%) and the result showed that respondents were not greatly interested or concerned in relation to the mandatory mouthguard rule (31.6%). Although the responses on the level of comfort and wearability of mouthguard were negative (34.8%), athletes were positively willing to wear mouthguard if the problems rectified (51.2%). CONCLUSION: Considering the high level of willingness to wear mouthguard if the problems rectified, it is thought that together with efforts in providing more mouthguard information, the work of sports dentistry to research and improve mouthguard will be invaluable in promoting mouthguard to more athletes. PMID- 23755341 TI - Mechanical and thermal properties of polyamide versus reinforced PMMA denture base materials. AB - PURPOSE: This in vitro study intended to investigate the mechanical and thermal characteristics of Valplast, and of polymethyl methacrylate denture base resin in which different esthetic fibers (E-glass, nylon 6 or nylon 6.6) were added. MATERIALS AND METHODS: FIVE GROUPS WERE FORMED: control (PMMA), PMMA-E glass, PMMA-nylon 6, PMMA-nylon 6.6 and Valplast resin. For the transverse strength test the specimens were prepared in accordance with ANSI/ADA specification No.12, and for the impact test ASTM D-256 standard were used. With the intent to evaluate the properties of transverse strength, the three-point bending (n=7) test instrument (Lloyd NK5, Lloyd Instruments Ltd, Fareham Hampshire, UK) was used at 5 mm/min. A Dynatup 9250 HV (Instron, UK) device was employed for the impact strength (n=7). All of the resin samples were tested by using thermo-mechanical analysis (Shimadzu TMA 50, Shimadzu, Japan). The data were analyzed by Kruskal Wallis and Tukey tests for pairwise comparisons of the groups at the 0.05 level of significance. RESULTS: IN ALL MECHANICAL TESTS, THE HIGHEST VALUES WERE OBSERVED IN VALPLAST GROUP (TRANSVERSE STRENGTH: 117.22 +/- 37.80 MPa, maximum deflection: 27.55 +/- 1.48 mm, impact strength: 0.76 +/- 0.03 kN). Upon examining the thermo-mechanical analysis data, it was seen that the E value of the control sample was 8.08 MPa, higher than that of the all other samples. CONCLUSION: Although Valplast denture material has good mechanical strength, its elastic modulus is not high enough to meet the standard of PMMA materials. PMID- 23755342 TI - Effects of the sintering conditions of dental zirconia ceramics on the grain size and translucency. AB - PURPOSE: This study aimed to identify the effects of the sintering conditions of dental zirconia on the grain size and translucency. MATERIALS AND METHODS: Ten specimens of each of two commercial brands of zirconia (Lava and KaVo) were made and sintered under five different conditions. Microwave sintering (MS) and conventional sintering (CS) methods were used to fabricate zirconia specimens. The dwelling time was 20 minutes for MS and 20 minutes, 2, 10, and 40 hours for CS. The density and the grain size of the sintered zirconia blocks were measured. Total transmission measurements were taken using a spectrophotometer. Two-way analysis of variance model was used for the analysis and performed at a type-one error rate of 0.05. RESULTS: There was no significant difference in density between brands and sintering conditions. The mean grain size increased according to sintering conditions as follows: MS-20 min, CS-20 min, CS-2 hr, CS-10 hr, and CS-40 hr for both brands. The mean grain size ranged from 347-1,512 nm for Lava and 373-1,481 nm for KaVo. The mean light transmittance values of Lava and KaVo were 28.39-34.48% and 28.09-30.50%, respectively. CONCLUSION: Different sintering conditions resulted in differences in grain size and light transmittance. To obtain more translucent dental zirconia restorations, shorter sintering times should be considered. PMID- 23755343 TI - Guided bone regeneration using demineralized allogenic bone matrix with calcium sulfate: case series. AB - PURPOSE: The purpose of this case series was to evaluate the effect of guided bone regeneration using demineralized allogenic bone matrix with calcium sulfate. MATERIALS AND METHODS: Guided bone regeneration using Demineralized Allogenic Bone Matrix with Calcium Sulfate (AlloMatrixTM, Wright. USA) was performed at the time of implant placement from February 2010 to April 2010. At the time of the second surgery, clinical evaluation of bone healing and histologic evaluation were performed. The study included 10 patients, and 23 implants were placed. The extent of bony defects around implants was determined by measuring the horizontal and vertical bone defects using a periodontal probe from the mesial, distal, buccal, and lingual sides and calculating the mean and standard deviation of these measurements. Wedge-shaped tissue samples were obtained from 3 patients and histologic examination was performed. RESULTS: In clinical evaluation, it was observed that horizontal bone defects were completely healed with new bones, and in the vertical bone defect area, 15.1% of the original defect area remained. In 3 patients, histological tests were performed, and 16.7-41.7% new bone formation was confirmed. Bone graft materials slowly underwent resorption over time. CONCLUSION: AlloMatrixTM is an allograft material that can be readily manipulated. It does not require the use of barrier membranes, and good bone regeneration can be achieved with time. PMID- 23755344 TI - Evaluation on the efficacy and safety of calcium metaphosphate coated fixture. AB - PURPOSE: The purpose of this study was to assess the difference in efficacy between calcium metaphosphate (CMP)-coated implant fixtures and conventional resorbable blasted media (RBM) processed implant fixtures. MATERIALS AND METHODS: This study targeted 50 implants from 44 patients who visited Dankook University Dental Hospital. Implantations were done separately for RBM treated and CMP coated implants, although their design was the same. Calcium metaphosphate has a quicker biodegradation process through hydrolysis compared to other phosphate calcium groups. For the first year of the implantation, the resorption volume of marginal bone analyzed via radiography and perio-test value were measured, under the check plan. Their analyses were composed of a non-inferiority trials test. A 95% level of reliability was used. RESULTS: In the comparative analysis of the resorption volume of marginal bone and the perio-test value, no statistically significant difference was found between the CMP-coated implants and RBM implants. CONCLUSION: One year after the implant placement, CMP-coated implants were found not to be inferior to the conventional RBM implants. PMID- 23755345 TI - Evaluation of the marginal and internal gap of metal-ceramic crown fabricated with a selective laser sintering technology: two- and three-dimensional replica techniques. AB - PURPOSE: One of the most important factors in evaluating the quality of fixed dental prostheses (FDPs) is their gap. The purpose of this study was to compare the marginal and internal gap of two different metal-ceramic crowns, casting and selective laser sintering (SLS), before and after porcelain firing. Furthermore, this study evaluated whether metal-ceramic crowns made using the SLS have the same clinical acceptability as crowns made by the traditional casting. MATERIALS AND METHODS: The 10 study models were produced using stone. The 20 specimens were produced using the casting and the SLS methods; 10 samples were made in each group. After the core gap measurements, 10 metal-ceramic crowns in each group were finished using the conventional technique of firing porcelain. The gap of the metal-ceramic crowns was measured. The marginal and internal gaps were measured by two-dimensional and three-dimensional replica techniques, respectively. The Wilcoxon signed-rank test, the Wilcoxon rank-sum test and nonparametric ANCOVA were used for statistical analysis (alpha=.05). RESULTS: In both groups, the gap increased after completion of the metal-ceramic crown compared to the core. In all measured areas, the gap of the metal cores and metal ceramic crowns produced by the SLS was greater than that of the metal cores and metal-ceramic crowns produced using the casting. Statistically significant differences were found between cast and SLS (metal cores and metal-ceramic crown). CONCLUSION: Although the gap of the FDPs produced by the SLS was greater than that of the FDPs produced by the conventional casting in all measured areas, none exceeded the clinically acceptable range. PMID- 23755346 TI - The influence of various core designs on stress distribution in the veneered zirconia crown: a finite element analysis study. AB - PURPOSE: The purpose of this study was to evaluate various core designs on stress distribution within zirconia crowns. MATERIALS AND METHODS: Three-dimensional finite element models, representing mandibular molars, comprising a prepared tooth, cement layer, zirconia core, and veneer porcelain were designed by computer software. The shoulder (1 mm in width) variations in core were incremental increases of 1 mm, 2 mm and 3 mm in proximal and lingual height, and buccal height respectively. To simulate masticatory force, loads of 280 N were applied from three directions (vertical, at a 45 degrees angle, and horizontal). To simulate maximum bite force, a load of 700 N was applied vertically to the crowns. Maximum principal stress (MPS) was determined for each model, loading condition, and position. RESULTS: In the maximum bite force simulation test, the MPSs on all crowns observed around the shoulder region and loading points. The compressive stresses were located in the shoulder region of the veneer-zirconia interface and at the occlusal region. In the test simulating masticatory force, the MPS was concentrated around the loading points, and the compressive stresses were located at the 3 mm height lingual shoulder region, when the load was applied horizontally. MPS increased in the shoulder region as the shoulder height increased. CONCLUSION: This study suggested that reinforced shoulder play an essential role in the success of the zirconia restoration, and veneer fracture due to occlusal loading can be prevented by proper core design, such as shoulder. PMID- 23755347 TI - The effect of resin cements and primer on retentive force of zirconia copings bonded to zirconia abutments with insufficient retention. AB - PURPOSE: The purpose of this study was to investigate the effect of resin cements and primer on the retentive force of zirconia copings bonded to zirconia abutments with insufficient retention. MATERIALS AND METHODS: Zirconia blocks (Lava, 3M ESPE, St. Paul, MN, USA) were obtained and forty sets of zirconia abutments and copings were fabricated using CAD/CAM technology. They were grouped into 4 categories as follows, depending on the types of resin cements used, and whether the primer is applied or not:Panavia F2.0 (P), Panavia F2.0 using Primer (PRIME Plus, Bisco Inc, Schaumburg, IL, USA) (PZ), Superbond C&B (S), and Superbond C&B using Primer (SZ). For each of the groups, the cementation was conducted. The specimens were kept in sterilized water (37C) for 24 hours. Retentive forces were tested and measured, and a statistical analysis was carried out. The nature of failure was recorded. RESULTS: The means and standard deviations of retentive force in Newton for each group were 265.15 +/- 35.04 N (P), 318.21 +/- 22.24 N (PZ), 445.13 +/- 78.54 N (S) and 508.21 +/- 79.48 N (SZ). Superbond C&B groups (S & SZ) showed significantly higher retentive force than Panavia F2.0 groups (P & PZ). In Panavia F2.0 groups, the use of primer was found to contribute to the increase of retentive force. On the other hand, in Superbond C&B groups, the use of primer did not influence the retention forces. Adhesive failure was observed in all groups. CONCLUSION: This study suggests that cementation of the zirconia abutments and zirconia copings with Superbond C&B have a higher retentive force than Panavia F2.0. When using Panavia F2.0, the use of primer increases the retentive force. PMID- 23755348 TI - Recruitment and enrollment in a randomized clinical trial of mandibular two implant overdenture. AB - PURPOSE: The purpose of this study was to evaluate the effectiveness of a promotion campaign for subject recruitment and selection, and reasons of withdrawal from a prospective clinical trial of mandibular two-implant supported overdenture. MATERIALS AND METHODS: The subjects of this study were participants in a randomized controlled clinical trial for investigating prognosis of implants and overdentures with attachments. Recruited subjects were classified by gender, age, and participation motives. Withdrawal rate of the participants before and after enrollment were evaluated. RESULTS: 177 patients were recruited and 51 patients were enrolled for the trial. Among them, 40 participants eventually took part in the trial. 116 subjects (65.5%) were recruited by advertisement and 61 (34.5%) were referred by patients of the hospital or local clinics. Regarding recruitment effectiveness, newspaper recruited the largest number of participants. With respect to referral patients, the proportion of our hospital patients was higher (37/61). Subjects in their 70s comprised the largest proportion (22/51). The male to female ratio was similar (25:26). Final withdrawal rate of all subjects were 74.0%. Among the reasons for withdrawal from enrollment (n=126) presence of remaining teeth and lack of motivation were the most common reasons. CONCLUSION: To facilitate recruitment of clinical trial subjects and improve enrollment rate, it is important to obtain a sufficient number of researchers, perform promotion activity with diverse strategies, cooperate with local dentists, increase the research funding, and alleviate subjects' fear against clinical trials by thorough consultation. PMID- 23755349 TI - Maxillary cement retained implant supported monolithic zirconia prosthesis in a full mouth rehabilitation: a clinical report. AB - This clinical report presents the reconstruction of a maxillary arch with a cement retained implant supported fixed prosthesis using a monolithic zirconia generated by CAD/CAM system on eight osseointegrated implants. The prosthesis was copy milled from an interim prosthesis minimizing occlusal adjustments on the definitive prosthesis at the time of delivery. Monolithic zirconia provides high esthetics and reduces the number of metal alloys used in the oral cavity. PMID- 23755350 TI - Intraspecific diversity in Sinningia speciosa (Gesneriaceae: Sinningieae), and possible origins of the cultivated florist's gloxinia. AB - BACKGROUND AND AIMS: The florist's gloxinia is a familiar houseplant in the Gesneriaceae, the botanical family that includes the African violet (Saintpaulia) and other ornamental species. The gloxinia's wild progenitor is Sinningia speciosa (Lodd.) Hiern, a Brazilian endemic. Although it has been cultivated for almost 200 years, little is known about the genetic diversity in S. speciosa, how the wild populations relate to one another or even where the cultivated forms originated. Using available wild collections, preliminary phenetic and phylogenetic investigations were conducted to elucidate the interspecific relationships within S. speciosa and to infer the origins of the cultivars. METHODOLOGY: Amplified fragment length polymorphism (AFLP) analysis was applied to 24 accessions of S. speciosa (17 wild collections, seven cultivars) and one accession each of Sinningia guttata and Sinningia macrophylla. A maximum likelihood (ML) tree was also calculated from an alignment of the nuclear ribosomal internal transcribed spacer sequence from the same 26 accessions. PRINCIPAL RESULTS: Dice/UPGMA and principal coordinates analysis of the AFLP data partitioned S. speciosa into several distinct clusters, one of which included S. macrophylla. All cultivated 'gloxinias' grouped together in a major cluster with plants from Rio de Janeiro. The AFLP results were compared with a phylogenetic analysis of the ribosomal spacer region, which was informative in S. speciosa. The ML tree generally supported the AFLP results, although several clades lacked strong statistical support. CONCLUSIONS: Independent analyses of two different data sets show that S. speciosa is a diverse species comprised of several lineages. Genetic distance estimates calculated from the AFLP data were positively correlated with geographic distances between populations, indicating that reproductive isolation could be driving speciation in this taxon. Molecular markers are under development for population genetic studies in S. speciosa, which will make it possible to define evolutionarily significant units for purposes of conservation. PMID- 23755351 TI - Moving from a regional to a continental perspective of Phragmites australis invasion in North America. AB - AIMS: We use a regional comparison of Phragmites australis (common reed) subsp. americanus, P. australis subsp. berlandieri and introduced P. australis (possibly five sublineages) in the Chesapeake Bay, the St Lawrence River, Utah and the Gulf Coast to inform a North American perspective on P. australis invasion patterns, drivers, impacts and research needs. FINDINGS AND RESEARCH NEEDS: Our regional assessments reveal substantial diversity within and between the three main lineages of P. australis in terms of mode of reproduction and the types of environment occupied. For introduced P. australis, the timing of introduction also differed between the regions. Nevertheless, a common finding in these regions reinforces the notion that introduced P. australis is opportunistic and thrives in disturbed habitats. Thus, we expect to see substantial expansion of introduced P. australis with increasing anthropogenic disturbances in each of these regions. Although there have been some studies documenting the negative impacts of introduced P. australis, it also plays a beneficial role in some regions, and in some cases, the purported negative impacts are unproven. There is also a broader need to clarify the genetic and ecological relationships between the different introduced sublineages observed in North America, and their relative competitive ability and potential for admixture. This may be done through regional studies that use similar methodologies and share results to uncover common patterns and processes. To our knowledge, such studies have not been performed on P. australis in spite of the broad attention given to this species. Such research could advance theoretical knowledge on biological invasion by helping to determine the extent to which the patterns observed can be generalized or are sublineage specific or region specific. SYNTHESIS: Given what appears to be sometimes idiosyncratic invasion patterns when interpreted in isolation in the regions that we analysed, it may be time to consider initiatives on a continental (if not intercontinental) scale to tackle unresolved issues about P. australis. PMID- 23755352 TI - Spotting fruit versus picking fruit as the selective advantage of human colour vision. AB - The spatiochromatic properties of the red-green dimension of human colour vision appear to be optimized for picking fruit in leaves at about arms' reach. However, other evidence suggests that the task of spotting fruit from a distance might be more important. This discrepancy may arise because the task a system (e.g. human trichromacy) is best at is not necessarily the same task where the largest advantage occurs over the evolutionary alternatives (dichromacy or anomalous trichromacy). We tested human dichromats, anomalous trichromats and "normal" trichromats in a naturalistic visual search task in which they had to find fruit pieces in a bush at 1, 4, 8 or 12 m viewing distance. We found that the largest advantage (in terms of either performance ratio or performance difference) of normal trichromacy over both types of colour deficiency was for the largest viewing distance. We infer that in the evolution of human colour vision, spotting fruit from a distance was a more important selective advantage than picking fruit at arms' reach. PMID- 23755353 TI - Weak priors versus overfitting of predictions in autism: Reply to Pellicano and Burr (TICS, 2012). AB - Pellicano and Burr (2012) argue that a Bayesian framework can help us understand the perceptual peculiarities in autism. We agree, but we think that their assumption of uniformly flat or equivocal priors in autism is not empirically supported. Moreover, we argue that any full account has to take into consideration not only the nature of priors in autism, but also how these priors are constructed or learned. We argue that predictive coding provides a more constrained framework that very naturally explains how priors are constructed in autism leading to strong, but overfitted, and non-generalizable predictions. PMID- 23755354 TI - Inferred motion perception of light sources in 3D scenes is color-blind. AB - In everyday scenes, the illuminant can vary spatially in chromaticity and luminance, and change over time (e.g. sunset). Such variation generates dramatic image effects too complex for any contemporary machine vision system to overcome, yet human observers are remarkably successful at inferring object properties separately from lighting, an ability linked with estimation and tracking of light field parameters. Which information does the visual system use to infer light field dynamics? Here, we specifically ask whether color contributes to inferred light source motion. Observers viewed 3D surfaces illuminated by an out-of-view moving collimated source (sun) and a diffuse source (sky). In half of the trials, the two sources differed in chromaticity, thereby providing more information about motion direction. Observers discriminated light motion direction above chance, and only the least sensitive observer benefited slightly from the added color information, suggesting that color plays only a very minor role for inferring light field dynamics. PMID- 23755355 TI - The binocular advantage in visuomotor tasks involving tools. AB - We compared performance on three manual-dexterity tasks under monocular and binocular viewing. The tasks were the standard Morrisby Fine Dexterity Test, using forceps to manipulate the items, a modified version of the Morrisby test using fingers, and a "buzz-wire" task in which subjects had to guide a wire hoop around a 3D track without bringing the hoop into contact with the track. In all three tasks, performance was better for binocular viewing. The extent of the binocular advantage in individuals did not correlate significantly with their stereoacuity measured on the Randot test. However, the extent of the binocular advantage depended strongly on the task. It was weak when fingers were used on the Morrisby task, stronger with forceps, and extremely strong on the buzz-wire task (fivefold increase in error rate with monocular viewing). We suggest that the 3D buzz-wire game is particularly suitable for assessing binocularly based dexterity. PMID- 23755356 TI - Perception of length to width relations of city squares. AB - In this paper, we focus on how people perceive the aspect ratio of city squares. Earlier research has focused on distance perception but not so much on the perceived aspect ratio of the surrounding space. Furthermore, those studies have focused on "open" spaces rather than urban areas enclosed by walls, houses and filled with people, cars, etc. In two experiments, we therefore measured, using a direct and an indirect method, the perceived aspect ratio of five city squares in the historic city center of Delft, the Netherlands. We also evaluated whether the perceived aspect ratio of city squares was affected by the position of the observer on the square. In the first experiment, participants were asked to set the aspect ratio of a small rectangle such that it matched the perceived aspect ratio of the city square. In the second experiment, participants were asked to estimate the length and width of the city square separately. In the first experiment, we found that the perceived aspect ratio was in general lower than the physical aspect ratio. However, in the second experiment, we found that the calculated ratios were close to veridical except for the most elongated city square. We conclude therefore that the outcome depends on how the measurements are performed. Furthermore, although indirect measurements are nearly veridical, the perceived aspect ratio is an underestimation of the physical aspect ratio when measured in a direct way. Moreover, the perceived aspect ratio also depends on the location of the observer. These results may be beneficial to the design of large open urban environments, and in particular to rectangular city squares. PMID- 23755357 TI - The role of binocular disparity in rapid scene and pattern recognition. AB - We investigated the contribution of binocular disparity to the rapid recognition of scenes and simpler spatial patterns using a paradigm combining backward masked stimulus presentation and short-term match-to-sample recognition. First, we showed that binocular disparity did not contribute significantly to the recognition of briefly presented natural and artificial scenes, even when the availability of monocular cues was reduced. Subsequently, using dense random dot stereograms as stimuli, we showed that observers were in principle able to extract spatial patterns defined only by disparity under brief, masked presentations. Comparing our results with the predictions from a cue-summation model, we showed that combining disparity with luminance did not per se disrupt the processing of disparity. Our results suggest that the rapid recognition of scenes is mediated mostly by a monocular comparison of the images, although we can rely on stereo in fast pattern recognition. PMID- 23755358 TI - On why music changes what (we think) we taste. AB - A pair of recently published studies demonstrate that what we happen to be listening to can sometimes change our perception (or, at the very least, our rating) of what we are eating or drinking. In one recent study, North (2012) showed that the emotional attributes (or connotation) of a piece of music could influence people's perception of red or white wine. Meanwhile, Crisinel et al. (2012) reported that listening to a lower-pitched soundscape can help to emphasize the bitter notes in a bittersweet toffee while listening to a soundscape with a higher pitch tends to bring out its sweetness. Although the most appropriate psychological and neuroscientific explanations for such crossmodal effects are still uncertain, we outline a number of possible alternatives for such intriguing, not to mention surprising, phenomena. PMID- 23755359 TI - A short line segment squirms along a zigzag line. AB - When a short straight line segment moves across a zigzag line and is viewed in one's peripheral vision, it appears to exhibit nonrigid squirming motion (the squirm effect). This phenomenon demonstrates that the form, orientation, and motion direction of a short line are influenced by those of a longer one when they are viewed in one's peripheral vision. PMID- 23755360 TI - Cryo-EM visualization of the ribosome in termination complex with apo-RF3 and RF1. AB - Termination of messenger RNA translation in Bacteria and Archaea is initiated by release factors (RFs) 1 or 2 recognizing a stop codon in the ribosomal A site and releasing the peptide from the P-site transfer RNA. After release, RF dissociation is facilitated by the G-protein RF3. Structures of ribosomal complexes with RF1 or RF2 alone or with RF3 alone-RF3 bound to a non-hydrolyzable GTP-analog-have been reported. Here, we present the cryo-EM structure of a post termination ribosome containing both apo-RF3 and RF1. The conformation of RF3 is distinct from those of free RF3*GDP and ribosome-bound RF3*GDP(C/N)P. Furthermore, the conformation of RF1 differs from those observed in RF3-lacking ribosomal complexes. Our study provides structural keys to the mechanism of guanine nucleotide exchange on RF3 and to an L12-mediated ribosomal recruitment of RF3. In conjunction with previous observations, our data provide the foundation to structurally characterize the complete action cycle of the G protein RF3. DOI:http://dx.doi.org/10.7554/eLife.00411.001. PMID- 23755361 TI - Passive and active DNA methylation and the interplay with genetic variation in gene regulation. AB - DNA methylation is an essential epigenetic mark whose role in gene regulation and its dependency on genomic sequence and environment are not fully understood. In this study we provide novel insights into the mechanistic relationships between genetic variation, DNA methylation and transcriptome sequencing data in three different cell-types of the GenCord human population cohort. We find that the association between DNA methylation and gene expression variation among individuals are likely due to different mechanisms from those establishing methylation-expression patterns during differentiation. Furthermore, cell-type differential DNA methylation may delineate a platform in which local inter individual changes may respond to or act in gene regulation. We show that unlike genetic regulatory variation, DNA methylation alone does not significantly drive allele specific expression. Finally, inferred mechanistic relationships using genetic variation as well as correlations with TF abundance reveal both a passive and active role of DNA methylation to regulatory interactions influencing gene expression. DOI:http://dx.doi.org/10.7554/eLife.00523.001. PMID- 23755362 TI - Stapled Golgi cisternae remain in place as cargo passes through the stack. AB - We have designed a membrane 'staple', which consists of membrane-anchored repeats of the trans-aggregating FM domain that face the lumen of the secretory pathway. In the presence of the disaggregating drug these proteins transit the secretory pathway. When the drug is removed these proteins form electron-dense plaques which we term staples. Unexpectedly, when initially positioned within the cis Golgi, staples remained at the cis face of the Golgi even after many hours. By contrast, soluble FM-aggregates transited the Golgi. Staples and soluble aggregates placed in cis-Golgi cisternae therefore have different fates. Whereas the membrane staples are located in the flattened, stacked central regions of the cisternae, the soluble aggregates are in the dilated rims. This suggests that while the cisternae are static on the time scale of protein traffic, the dilated rims are mobile and progress in the cis -> trans direction via a mechanism that we term 'Rim Progression'. DOI:http://dx.doi.org/10.7554/eLife.00558.001. PMID- 23755363 TI - MCU encodes the pore conducting mitochondrial calcium currents. AB - Mitochondrial calcium (Ca(2+)) import is a well-described phenomenon regulating cell survival and ATP production. Of multiple pathways allowing such entry, the mitochondrial Ca(2+) uniporter is a highly Ca(2+)-selective channel complex encoded by several recently-discovered genes. However, the identity of the pore forming subunit remains to be established, since knockdown of all the candidate uniporter genes inhibit Ca(2+) uptake in imaging assays, and reconstitution experiments have been equivocal. To definitively identify the channel, we use whole-mitoplast voltage-clamping, the technique that originally established the uniporter as a Ca(2+) channel. We show that RNAi-mediated knockdown of the mitochondrial calcium uniporter (MCU) gene reduces mitochondrial Ca(2+) current (I MiCa ), whereas overexpression increases it. Additionally, a classic feature of I MiCa , its sensitivity to ruthenium red inhibition, can be abolished by a point mutation in the putative pore domain without altering current magnitude. These analyses establish that MCU encodes the pore-forming subunit of the uniporter channel. DOI:http://dx.doi.org/10.7554/eLife.00704.001. PMID- 23755365 TI - Metabolic phenotyping and systems biology approaches to understanding neurological disorders. AB - The development of high-throughput metabolic profiling and the study of the metabolome are particularly important in brain research where small molecules or metabolites play fundamental signalling roles: neurotransmitters, signalling lipids, osmolytes and even ions. Metabolic profiling has shown that metabolic perturbations in the brain go beyond alterations of neurotransmission and that variations in brain metabolic homeostasis are associated with neurological disorders. In this report, we will focus on recent developments in the field of metabolic phenotyping that have contributed to unravelling the pathophysiology of neurological diseases. Also, we will highlight the necessity of implementing systems biology approaches to integrate metabolic data and tackle the structural and functional complexity of the brain in normal and pathological conditions. PMID- 23755364 TI - Signal integration in TGF-beta, WNT, and Hippo pathways. AB - Complete sequences of animal genomes have revealed a remarkably small and conserved toolbox of signalling pathways, such as TGF-beta and WNT that account for all biological diversity. This raises the question as to how such a limited set of cues elaborates so many diverse cell fates and behaviours. It is now clear that components of signalling pathways are physically assembled into higher order networks that ultimately dictate the biological output of pathway activity. Intertwining of pathways is thus emerging as a key feature of a large, integrated and coordinated signalling network that allows cells to read a limited set of extrinsic cues, but mount the diverse responses that underpin successful development and homeostasis. Moreover, this design principle confounds the development of effective therapeutic interventions in complex diseases, such as cancer. PMID- 23755366 TI - Measurement of disease severity in cutaneous autoimmune diseases. AB - The development of disease-specific outcome instruments for several autoimmune skin diseases including cutaneous lupus erythematosus (CLE), dermatomyositis, vitiligo, pemphigus and alopecia areata has facilitated the objective assessment of disease in clinical trials. Validation of these instruments provides reliable tools to measure disease severity and therapeutic effect in clinical studies. However, the existence of multiple outcome measures for each disease and the lack of uniformity between studies has created a challenge in comparing results across trials. Efforts to address this issue include the Core Outcome Measures in Effectiveness Trials (COMET) initiative and international meetings directed at reaching a consensus. Other challenges with the use of outcome measures include difficulties measuring change in mild disease, measuring response in topical studies, and capturing disease activity in skin with extensive post-inflammatory hyperpigmentation. PMID- 23755367 TI - Pathoetiology of multiple sclerosis: are we barking up the wrong tree? AB - Despite a century of intensive investigation, the underlying cause of multiple sclerosis has eluded us. It is clear that there exists a prominent progressive degenerative phenotype together with an important autoimmune inflammatory component, and careful histopathological examination always shows, to a greater or lesser degree, concomitant degeneration/demyelination and adaptive T cell dependent immune responses. Given this picture, it is difficult, if not impossible, to definitively say whether degeneration or autoimmunity is the initiator of the disease. In this review, I put forward the evidence for and against both models and speculate that, in contrast to the accepted view, it is equally likely that multiple sclerosis may be a degenerative disease that secondarily elicits an autoimmune response, and suggest how this might influence therapeutic approaches. PMID- 23755368 TI - Duodenal epithelial transport in functional dyspepsia: Role of serotonin. AB - AIM: To investigate functional duodenal abnormalities in functional dyspepsia (FD) and the role of serotonin (5-hydroxytryptamine, 5-HT) in mucosal ion transport and signalling. METHODS: Duodenal mucosal biopsies were obtained from 15 patients with FD and 18 healthy controls. Immunohistochemistry was used to study the number of 5-HT-containing cells and real-time polymerase chain reaction for expression of 5-HT receptors 1A, 1B, 2A, 2B, 3A, 3B, 3C, 3D, 3E, 4 and 7, as well as expression of the serotonin re-uptake transporter (SERT) gene SLC6A4 and tryptophan hydroxylase 1 (TPH1). Biopsies were mounted in Ussing chambers for evaluation of basal and 5-HT-stimulated short-circuit current (SCC). RESULTS: Conductance was lower in FD [42.4 +/- 4.7 mS/cm(2) (n = 15) vs 62.5 +/- 4.5 mS/cm(2) (n = 18), P = 0.005]. 5-HT induced a dose dependent rise in SCC in both FD (n = 8) and controls (n = 9), the rise was lower in FD (P < 0.001). Mean number of 5-HT stained cells per high power field was the same [34.4 +/- 8.4 in FD (n = 15) and 30.4 +/- 3.7 in controls (n = 18), P = 0.647]. The following genes were highly expressed: 5-HT receptor HTR3E, HTR4, HTR7, SERT gene (SLC6A4) and TPH1. Differences in expression levels were observed for HTR3E (higher expression in FD, P = 0.008), HTR7 (lower expression in FD, P = 0.027), SLC6A4 (higher expression in FD, P = 0.033) and TPH1 (lower expression in FD, P = 0.031). CONCLUSION: Duodenal ion transport in response to exogenous 5-HT is abnormal in FD patients and associated with high expression of the HTR3E receptor and the serotonin transporter. PMID- 23755369 TI - Impact of body mass index for patients undergoing pancreaticoduodenectomy. AB - AIM: To evaluate the impact of body mass index (BMI) on short and long term results after pancreaticoduodenectomies (PD). METHODS: A consecutive series of PDs performed at the Karolinska University Hospital from 2004 till 2010 were retrieved from our prospective database. The patients were divided by BMI into overweight/obese (O; BMI >= 25 kg/m(2)) and controls (C; BMI < 25 kg/m(2)). Demographics, peri-operative data, morbidity, mortality, pancreatic fistula (PF) rate, length of stay (LOS), hospital costs, histology, and survival were analyzed. An additional sub analysis of survival was performed in patients with a diagnosis of pancreatic ductal adenocarcinoma (PDAC) and divided in underweight, normal-weight, overweight and obese. RESULTS: A total of 367 PDs were included (O = 141/C = 226). No differences were found between O and C regarding demographics, peri-operative data, costs, morbidity or mortality. O was associated with higher intra-operative blood loss (1392 +/- 115 mL vs 1121 +/- 83 mL; P = 0.01), rate of PF (20% vs 9.5%; P = 0.006) and marginally longer LOS (18 +/- 0.9 d vs 15 +/- 1.1 d; P = 0.05). An increasing risk for PF was observed with increasing BMI. The 1, 3 and 5 years survival rate was similar in O and C in PDAC (68.7%, 26.4% and 8.8% vs 66.1%, 30.9% and 17.9% respectively; P = 0.9). When the survival was analyzed using 4 different categories of BMI (underweight, normal, overweight and obese), a trend was seen toward a difference in survival, with a worse prognosis for the underweight and obese patients compared to normal weight and overweight patients. CONCLUSION: Overweight increases the risk for intra-operative bleeding and PF, but do not otherwise alter short or long term outcome after PD for pancreatic cancer. PMID- 23755371 TI - Single cell functional proteomics for assessing immune response in cancer therapy: technology, methods, and applications. AB - In the past decade, significant progresses have taken place in the field of cancer immunotherapeutics, which are being developed for most human cancers. New immunotherapeutics, such as Ipilimumab (anti-CTLA-4), have been approved for clinical treatment; cell-based immunotherapies such as adoptive cell transfer (ACT) have either passed the final stage of human studies (e.g., Sipuleucel-T) for the treatment of selected neoplastic malignancies or reached the stage of phase II/III clinical trials. Immunotherapetics has become a sophisticated field. Multimodal therapeutic regimens comprising several functional modules (up to five in the case of ACT) have been developed to provide focused therapeutic responses with improved efficacy and reduced side-effects. However, a major challenge remains: the lack of effective and clinically applicable immune assessment methods. Due to the complexity of antitumor immune responses within patients, it is difficult to provide comprehensive assessment of therapeutic efficacy and mechanism. To address this challenge, new technologies have been developed to directly profile the cellular immune functions and the functional heterogeneity. With the goal to measure the functional proteomics of single immune cells, these technologies are informative, sensitive, high-throughput, and highly multiplex. They have been used to uncover new knowledge of cellular immune functions and have been utilized for rapid, informative, and longitudinal monitoring of immune response in clinical anti-cancer treatment. In addition, new computational tools are required to integrate high-dimensional data sets generated from the comprehensive, single cell level measurements of patient's immune responses to guide accurate and definitive diagnostic decision. These single cell immune function assessment tools will likely contribute to new understanding of therapy mechanism, pre-treatment stratification of patients, and ongoing therapeutic monitoring and assessment. PMID- 23755370 TI - A review of targeted therapies evaluated by the pediatric preclinical testing program for osteosarcoma. AB - Osteosarcoma, the most common malignant bone tumor of childhood, is a high-grade primary bone sarcoma that occurs mostly in adolescence. Standard treatment consists of surgery in combination with multi-agent chemotherapy regimens. The development and approval of imatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia in children and the fully human monoclonal antibody, anti GD2, as part of an immune therapy for high-risk neuroblastoma patients have established the precedent for use of targeted inhibitors along with standard chemotherapy backbones. However, few targeted agents tested have achieved traditional clinical endpoints for osteosarcoma. Many biological agents demonstrating anti-tumor responses in preclinical and early-phase clinical testing have failed to reach response thresholds to justify randomized trials with large numbers of patients. The development of targeted therapies for pediatric cancer remains a significant challenge. To aid in the prioritization of new agents for clinical testing, the Pediatric Preclinical Testing Program (PPTP) has developed reliable and robust preclinical pediatric cancer models to rapidly screen agents for activity in multiple childhood cancers and establish pharmacological parameters and effective drug concentrations for clinical trials. In this article, we examine a range of standard and novel agents that have been evaluated by the PPTP, and we discuss the preclinical and clinical development of these for the treatment of osteosarcoma. We further demonstrate that committed resources for hypothesis-driven drug discovery and development are needed to yield clinical successes in the search for new therapies for this pediatric disease. PMID- 23755372 TI - Epigenetic therapy in lung cancer. AB - Epigenetic deregulation of gene function has been strongly implicated in carcinogenesis and is one of the mechanisms contributing to the development of lung cancer. The inherent reversibility of epigenetic alterations makes them viable therapeutic targets. Here, we review the therapeutic implications of epigenetic changes in lung cancer, and recent advances in therapeutic strategies targeting DNA methylation and histone acetylation. PMID- 23755373 TI - Improvement of cancer immunotherapy by combining molecular targeted therapy. AB - In human cancer cells, a constitutive activation of MAPK, STAT3, beta-catenin, and various other signaling pathways triggers multiple immunosuppressive cascades. These cascades result in the production of immunosuppressive molecules (e.g., TGF-beta, IL-10, IL-6, VEGF, and CCL2) and induction of immunosuppressive immune cells (e.g., regulatory T cells, tolerogenic dendritic cells, and myeloid derived suppressor cells). Consequently, immunosuppressive conditions are formed in tumor-associated microenvironments, including the tumor and sentinel lymph nodes. Some of these cancer-derived cytokines and chemokines impair immune cells and render them immunosuppressive via the activation of signaling molecules, such as STAT3, in the immune cells. Thus, administration of signal inhibitors may inhibit the multiple immunosuppressive cascades by acting simultaneously on both cancer and immune cells at the key regulatory points in the cancer-immune network. Since common signaling pathways are involved in manifestation of several hallmarks of cancer, including cancer cell proliferation/survival, invasion/metastasis, and immunosuppression, targeting these shared signaling pathways in combination with immunotherapy may be a promising strategy for cancer treatment. PMID- 23755374 TI - Nano-curcumin inhibits proliferation of esophageal adenocarcinoma cells and enhances the T cell mediated immune response. AB - In Western countries the incidence of the esophageal adenocarcinoma (EAC) has risen at a more rapid rate than that of any other malignancy. Despite intensive therapies this cancer is associated with extreme high morbidity and mortality. For this reason, novel effective therapeutic strategies are urgently required. Dendritic Cell (DC)-based immunotherapy is a promising novel treatment strategy, which combined with other anti-cancer strategies has been proven to be beneficial for cancer patients. Curcumin (diferuloylmethane), is a natural polyphenol that is known for its anti-cancer effects however, in it's free form, curcumin has poor bioavailability. The aim of this study was to investigate whether using a highly absorptive form of curcumin, dispersed with colloidal nano-particles, named Theracurmin would be more effective against EAC cells and to analyze if this new compound affects DC-induced T cell response. As a result, we show efficient uptake of nano-curcumin by the EAC cell lines, OE33, and OE19. Moreover, nano-curcumin significantly decreased the proliferation of the EAC cells, while did not affect the normal esophageal cell line HET-1A. We also found that nano-curcumin significantly up-regulated the expression of the co stimulatory molecule CD86 in DCs and significantly decreased the secretion of pro inflammatory cytokines from in vitro activated T cells. When we combined T cells with nano-curcumin treatment in OE19 and OE33, we found that the basic levels of T cell induced cytotoxicity of 6.4 and 4.1%, increased to 15 and 13%, respectively. In conclusion, we found that nano-curcumin is effective against EAC, sensitizes EAC cells to T cell induced cytotoxicity and decreases the pro inflammatory signals from T cells. Combining DC immunotherapy with nano-curcumin is potentially a promising approach for future treatment of EAC. PMID- 23755375 TI - Peripheral T-cell lymphomas: a review of current approaches and hopes for the future. AB - Peripheral T-cell lymphomas (PTCL) are a diverse group of lymphoproliferative disorders, which share a common denominator of overall poor prognosis, with few exceptions. In this article, the authors review current standard of care approaches for the treatment of PTCLs, the role of stem-cell/bone marrow transplantation, and current developments in novel targeted therapies. PMID- 23755376 TI - What Makes You Can Also Break You, Part II: Mitochondrial Permeability Transition Pore Formation by Dimers of the F1FO ATP-Synthase? PMID- 23755377 TI - [Refractory ascites: which is the current treatment: paracentesis or transjugular portosystemic shunts?]. PMID- 23755378 TI - [Clinical guidelines for diagnosis and treatment of ascites. Therapeutic aspects of complicated ascites and hepatorenal syndrome]. PMID- 23755379 TI - [General surgery subspecialization: evolution of the practice and teaching of gastrointestinal surgery]. PMID- 23755380 TI - [Not Available]. PMID- 23755381 TI - Quantum dots as probes in biology. PMID- 23755382 TI - [Decision makers must be legally competent]. PMID- 23755383 TI - [The Faroese population will be genome sequenced--democratic project?]. PMID- 23755384 TI - [Flying High]. PMID- 23755386 TI - China's skies: a complex recipe for pollution with no quick fix. PMID- 23755387 TI - US sequester hits health and science programmes. PMID- 23755388 TI - [Reporting system for implant failure: "We need a new No-Blame Culture"]. PMID- 23755389 TI - [Implant failure--prosthesis registry--examples elsewhere]. PMID- 23755390 TI - [Amendment to the Infection Protection Act: new opportunities against nosocomial infections]. PMID- 23755391 TI - [Training documentation -- making transparent and efficient training with the WDoku]. PMID- 23755392 TI - [Achilles tendon rupture--surgical or conservative therapy?]. PMID- 23755393 TI - [Periprosthetic joint infections--what is the current state of diagnosis?]. PMID- 23755394 TI - [Knee arthroplasty--no increased risk for kinematic alignment]. PMID- 23755395 TI - [Knee arthroplasty--higher BMI: contraindication for sliding prosthesis?]. PMID- 23755396 TI - 10 Years on, the world still learns from SARS. PMID- 23755397 TI - Implications of narcolepsy link with swine-influenza vaccine. PMID- 23755398 TI - Highlights from the ESCMID conference on vaccines. PMID- 23755399 TI - Infectious Disease/CDC Update: Update on emerging infections: news from the Centers for Disease Control and Prevention. Evaluation of 11 commercially available rapid influenza diagnostic tests-United States, 2011-2012. PMID- 23755400 TI - Minimum data set for mass-gatherings health research and evaluation: the beginning of an international dialogue. Author reply. PMID- 23755401 TI - [Depression in schizophrenia: diagnosis and treatment]. PMID- 23755402 TI - [Efficacy of aripiprazole (amdoal) in the long-term treatment of schizophrenia]. PMID- 23755403 TI - From the desk of the Editor: journal introduction. PMID- 23755404 TI - [Autosomal recessive polycystic kidney disease (ARPKD)]. PMID- 23755405 TI - Artemisia herba alba: a popular plant with potential medicinal properties. AB - Artemisia herba alba (Asteraceae), commonly known as desert or white wormwood, is used in folk medicine for treatment of various diseases. Phytochemical studies of this plant revealed the existence of many beneficial compounds such as herbalbin, cis-chryanthenyl acetate, flavonoids (hispidulin and cirsilineol), monoterpenes, sesquiterpene. The aerial parts are characterized by a very low degree of toxicity. This study reviews the main reports of the pharmacological and toxicological properties of Artemisia herba alba in addition to the main constituents. It would appear that this plant exhibits many beneficial properties. Further studies are warranted to more integrate this popular plant in human health care system. PMID- 23755406 TI - Effect of Allium sativum and fish collagen on the proteolytic and angiotensin-I converting enzyme-inhibitory activities in cheese and yogurt. AB - There is an increasing demand of functional foods in developed countries. Yogurt plays an important role in the management of blood pressure. Several bioactive peptides isolated from Allium sativum or fish collagen have shown antihypertensive activity. Thus, in the present study the effects of A. sativum and/or Fish Collagen (FC) on proteolysis and ACE inhibitory activity in yogurt (0, 7 and 14 day) and cheese (0, 14 and 28 day) were investigated. Proteolytic activities were the highest on day 7 of refrigerated storage in A. sativum-FC yogurt (337.0 +/- 5.3 microg g(-1)) followed by FC-yogurt (275.3 +/- 2.0 microg g(-1)), A. sativum-yogurt (245.8 +/- 4.2 microg g(-1)) and plain-yogurt (40.4 +/- 1.2 microg g(-1)). On the other hand, proteolytic activities in cheese ripening were the highest (p < 0.05) on day 14 of storage for plain and A. sativum-cheeses (411.4 +/- 4.3 and 528.7 +/- 1.6 microg g(-1), respectively). However, the presence of FC increased the proteolysis to the highest level on day 28 of storage for FC- and A. sativum-FC cheeses (641.2 +/- 0.1 and 1128.4 +/- 4.5 microg g(-1), respectively). In addition, plain- and A. sativum-yogurts with or without FC showed maximal inhibition of ACE on day 7 of storage. Fresh plain- and A. sativum-cheeses showed ACE inhibition (72.3 +/- 7.8 and 50.4 +/- 1.6 % respectively), the presence of FC in both type of cheeses reduced the ACE inhibition to 62.9 +/- 0.8 and 44.5 +/- 5.0%, respectively. However, refrigerated storage increased ACE inhibition in cheeses (p < 0.05 on day 28) in the presence of FC more than in the absence. In conclusion, the presence of FC in A. sativum yogurt or cheese enhanced the proteolytic activity. Thus, it has potential in the development of an effective dietary strategy for hypertension associated cardiovascular diseases. PMID- 23755407 TI - Effects of maternal nicotine exposure on expression of laminin alpha 5 in lung tissue of newborn. AB - Maternal smoking has been clearly demonstrated to be associated with increased health problems in infants and children. Nicotine is the chemical substance with high level of toxicity. It crosses through the placenta and accumulates in the developing organs of fetus. Previous investigation indicated that maternal nicotine exposures induce decreased fibronectin expression in lung parenchyma. In this study, the effect of maternal nicotine exposure on laminin expression of the newborn mice lungs has been evaluated. Female pregnant Balb/C mice were divided randomly in to four groups as fallow: Experimental group 1 (Exp D1); was received 3 mg kg(-1) nicotine intra peritoneal injection (IP) from gestational day 7 (GD7) to the last day of pregnancy, Experimental group 2 (Exp D14); was received 3 mg kg(-1) nicotine from GD7 to postnatal day 14, Groups 3 and 4; as sham control groups (Sha-Con) were received the same volume (3 mg kg(-1)) of normal saline parallel to experimental groups. At the end of exposure times, all of newborns were anesthetized; their lungs were removed and prepared for immunohistochemical method and real-time polymerase chain reaction. The finding indicated that laminin alpha 5 (Lama5) mRNA expressions in the lung of newborn in the nicotine treated Exp D1 decreased by 0.63 fold but increased in Exp D14 by 1.57 fold comparing to Sh-Con groups. Lama5 immunoreactivity was not similar in different parts of the lungs including alveoli and bronchiole, having a significant increase in the experimental groups in contrast to the Sh-Con groups. However, increase in immunoreactivity observed more in Exp D14. Immunoreactivity intensity in small vessels of all experimental groups was not significantly different. These data also indicate that maternal nicotine exposure may induce abnormal laminin expression which may cause defects in lung function during life time. PMID- 23755408 TI - Macro-biophysical properties of candidate novel feedstuffs for poultry feeding. AB - Information on the proximate composition and sometimes the toxicology of novel feedstuffs has been used routinely in determining the suitability of feedstuffs in poultry feeding, especially during animal feeding trials. Limited information however exists on the biophysical characteristics of such novel feedstuffs. The Bulk Density (BD), Water-holding Capacity (WHC) and Specific Gravity (SG) of three novel feedstuffs {Leaf Meal (LEM), Rumen Digesta (RD) and Poultry Dung (PD)}, were evaluated. Available published and unpublished results on the proximate compositions of the materials were related to the physical characteristics results. LEM had significantly (p > 0.05) lower BD and SG than RD and PD while RD recorded the highest WHC value although the value was similar (p > 0.05) to that of LEM. Particle Size (PS) effects showed that BD of RD and PD were lower at the > or = 1.00 mm PS than at the unmodified and < 1.00 mm PS, indicating that materials of similar Crude Fiber (CF) could be manipulated to yield different BD with possible ultimate effects on the performance of birds. The WHC of LEM at < 1.00 mm PS level was seven times higher than that of unmodified and =1.00 mm PS while RD value at the same < 1.00 mm PS level was 2 and 4 times higher than those recorded at the unmodified and > or = 1.00 mm PS levels, respectively. This is evidence that grinding increased the surface area of the LEM, thus improving the ability of its Non-starch Polysaccharides (NSP) to bind water. Information on the feed physical characteristics could be used together with proximate and toxicological information to determine the nutritional and intake potentials of a novel feedstuff even before a feeding trial. PMID- 23755409 TI - Astaxanthin production by freshwater microalgae Chlorella sorokiniana and marine microalgae Tetraselmis sp. AB - There are numerous commercial applications of microalgae nowadays owing to their vast biotechnological and economical potential. Indisputably, astaxanthin is one of the high value product synthesized by microalgae and is achieving commercial success. Astaxanthin is a keto-carotenoid pigment found in many aquatic animals including microalgae. Astaxanthin cannot be synthesized by animals and provided in the diet is compulsory. In this study, the production of astaxanthin by the freshwater microalgae Chlorella sorokiniana and marine microalgae Tetraselmis sp. were studied. The relationship between growth and astaxanthin production by marine and freshwater microalgae cultivated under various carbon sources and concentrations, environmental conditions and nitrate concentrations was investigated in this study. Inorganic carbon source and low nitrate concentration favored the growth and production of astaxanthin by the marine microalgae Tetraselmis sp. and the freshwater microalgae Chlorella sorokiniana. Outdoor cultivation enhanced the growth of microalgae, while indoor cultivation promoted the formation of astaxanthin. The results indicated that supplementation of light, inorganic carbon and nitrate could be effectively manipulated to enhance the production of astaxanthin by both microalgae studied. PMID- 23755410 TI - Molecular characterization of the leptin receptor gene as a candidate gene in the pulmonary hypertension syndrome in broiler chickens. AB - Leptin Receptor Gene (LEPR) is a candidate gene in understanding the genetic basis of the Pulmonary Hypertension Syndrome (PHS) in broilers. Identification and evaluation of genetic polymorphisms in LEPR may provide a link between traits like Body Weight (BW) and Total Ventricle weight (TV) to the development of PHS. In this study, primers were designed in exons, upstream and downstream sequences to identify mutations in the LEPR on four broilers selected with respect to the PHS-related traits. About 77% of the 11,820 bp of the LEPR gene covered by the primers were sequenced. No mutations were found between the chickens associating the traits to the occurrence of PHS. However, 42 single nucleotide polymorphisms and four Indels were found between the reference sequences of the red jungle fowl and the experimental population. Ten of these mutations were not previously reported in LEPR at the genomic and transcript sequences (NP_989654.1, ENSGALT00000018009). The 10 mutations include six SNPs in intron regions, two Indels and two non-synonymous SNPs. The two new non-synonymous SNPs; G301A and A1637G, led to amino acid change A89T and N534S, respectively. PMID- 23755411 TI - Feasibility study on the culture of mud crab Scylla serrata in the mid coast region of Bangladesh. AB - A study was conducted at Hatiya and Nijhum Island, Noakhali in the mid coastal region of Bangladesh to identify feasibility of mud crab culture for a study period of six months from January 2010 to June 2010. Data were collected through questionnaire interviews, focus group discussions and cross check interviews. Average yearly collection of mud crabs in this area was about 890.36 tons where lower grade crabs 45.16% and these can be brought under culture practice. It has observed that saline water intrusion was evident 670 Ha. In Hatiya and vast inundated area with saline water was found in Nijhum Island. Overall waiter salinity range was between 2-10 ppt., pH range of 7.8-8.6 and the soil was silt loamy. The average temperature of the last three years was approximately 26.10 degrees C and rainfall was almost 10.85 mm. It was observed that natural feeds were available in this study area and there was existed a small potential marketing channel with 3-4 middlemen. Also there was a good transportation system both water and road way. So, present study revealed that the area is suitable for crab culture during April to October. PMID- 23755412 TI - [Morbidly healthy]. PMID- 23755413 TI - [Adieu Providence, hello indecent]. PMID- 23755414 TI - [Between delusion and reason]. PMID- 23755415 TI - [Fresh air in the nursing home thanks to Kneipp]. PMID- 23755416 TI - [Strong nursing career with significant autonomy]. PMID- 23755417 TI - [Washing without water]. PMID- 23755418 TI - [Supporting mentally ill parents]. PMID- 23755419 TI - ["Without you we cannot do much"]. PMID- 23755420 TI - [For me, nursing represents the human element (interview by Urs Luthi)]. PMID- 23755421 TI - [Emerging stronger out of the crisis]. PMID- 23755422 TI - [Inevitable disappointments]. PMID- 23755423 TI - [Secrets of the family disclosed]. PMID- 23755424 TI - [It's not your fault (interview by Francoise Taillens)]. PMID- 23755425 TI - [The most time!]. PMID- 23755426 TI - [Aroma therapy]. PMID- 23755427 TI - [The best years]. PMID- 23755428 TI - Declassifying doctors' notes. PMID- 23755429 TI - Personal check. PMID- 23755430 TI - How can I help you? PMID- 23755431 TI - First steps for synergizing health IT projects. PMID- 23755432 TI - HIPAA changes call for revising BA agreements. PMID- 23755433 TI - Providing patients with meaningful choices. PMID- 23755434 TI - Preparing for patient-generated documents. PMID- 23755435 TI - Getting serious about information governance. PMID- 23755436 TI - Rules for handling and maintaining metadata in the EHR. PMID- 23755437 TI - Mitigating coding risks in the EHR. PMID- 23755438 TI - Coding root operations with ICD-10-PCS. PMID- 23755439 TI - Case management insider. Managing length of stay using patient flow--Part 4. AB - Managing patient flow is a complex process that includes the daily management of patient throughput and capacity issues, and also the measurement and management of monthly data indicators. These indicators touch on every department and discipline in the hospital and should be readily shared and discussed. Because patient flow management is so complicated, it will require the active participation of a steering committee as well. The department of case management cannot manage patient flow alone. No department can. It is an interdisciplinary issue and the solutions must come from the interdisciplinary team. Be sure to keep track of your daily admissions and discharges, available beds and daily bottlenecks. At the same time, look for patterns and opportunities in the data you collect to continuously improve flow over time. Stay current with The Joint Commission standards on patient flow which can be found in the leadership section of the standards. Patient flow is an old problem with a new name. Reductions in payment, and the need to continuously manage length of stay require a deep dive look at all the elements affecting your hospital's flow. PMID- 23755440 TI - [They were lucky!?]. PMID- 23755441 TI - [Nursing care of heart patients with temporary pacemaker]. PMID- 23755442 TI - [The potentials of stem cell therapy]. PMID- 23755443 TI - [Sunscreening agents as an important pillar of modern sun management]. PMID- 23755444 TI - [The healthy vitamin myth. What you are guaranteed to not know about vitamins: 10 vitamin myths and what is really true]. PMID- 23755445 TI - [Knives with point down in the silverware based of the dishwasher]. PMID- 23755446 TI - [Infections in pediatrics: rapid diagnosis and new vaccines]. PMID- 23755447 TI - [Margaret Sanger - advocate of birth control]. PMID- 23755448 TI - [Reporting work overload: legal liability basis of relief for employees in health care and nursing facilities]. PMID- 23755449 TI - [Nutrition education. Children need examples]. PMID- 23755450 TI - ["Preventing eating disorders". Updated reference for pedagogic professionals]. PMID- 23755451 TI - [Hearing in deafness - living with a cochlear implant (interview by Angelika Staub)]. PMID- 23755452 TI - [Google and co. replace grandparents. 90 percent of children search the web for answers]. PMID- 23755453 TI - [Spitzer: no computer until 9th grade - students should write applications by hand]. PMID- 23755454 TI - [Clinics cover up problems in newborn infants. Patient advocate and health experts demand disclosure]. PMID- 23755455 TI - [Lack of morning light delay sleep. Early school opening turns adolescents into night owls]. PMID- 23755456 TI - [Mycotoxins in food - how to minimize the burden]. PMID- 23755458 TI - [German Society of Social Pediatrics and Adolescent Medicine]. PMID- 23755459 TI - [Appendectomy is often unnecessary]. PMID- 23755460 TI - [Many unnecessary tests before minor operations]. PMID- 23755461 TI - [Simultaneous bachelor studies during employment "nursing science/nursing management" successfully re-accredited]. PMID- 23755462 TI - Safety, cost savings, simplicity back broader use of bloodless surgery. PMID- 23755463 TI - Has your checklist effort stalled? Some advice on how to restart it. PMID- 23755464 TI - Health care reform and the 'golden age' of nursing. PMID- 23755465 TI - 'Second victim' rapid-response team helps fellow clinicians recover from trauma. PMID- 23755466 TI - Stryker's Neptune recall raises stakes for compliance. PMID- 23755467 TI - Higher awareness may lower the odds of retained surgical items. PMID- 23755468 TI - The right strategies can help increase OR utilization. PMID- 23755469 TI - Starting in the office to improve postop outcome. PMID- 23755470 TI - [Soil aggregate stability and soil organic carbon characteristics in Quercus variabilis and Pinus tabulaeformis plantations in Beijing area]. AB - Based on the field survey and laboratory analysis, this paper studied the soil aggregate stability and soil organic carbon characteristics in Quercus variabilis and Pinus tabulaeformis plantations in Beijing area. In the two plantations, the contents of soil macro-aggregates decreased with soil depth. In P. tabulaeformis plantation, soil macro-aggregates (>0.25 mm) occupied the majority, accounting for 71% -77% of the total; whereas in Q. variabilis plantation, no significant difference was observed in the contents of soil macro-aggregates and micro aggregates (< or =0.25 mm), which accounted for 51% -58% and 42% -49%, respectively. Both the mean mass diameter and the geometrical mean mass diameter of the soil aggregates in P. tabulaeformis plantation were significantly higher than those in Q. variabilis plantation, and the fractal dimension (D) of the soil water-stable aggregates in P. tabulaeformis plantation was lower than that in Q. variabilis plantation, suggesting that P. tabulaeformis plantation was more favorable for the soil aggregate stability than Q. variabilis plantation. Also in the two plantations, the organic carbon content in soil water-stable aggregates decreased with soil depth. The organic carbon content in soil macro-aggregates was significantly higher in P. tabulaeformis plantation (58% -83%) than in Q. variabilis plantation (49% -66% ). It was suggested that in Beijing area, P. tabulaeformis plantation was more beneficial to the soil organic carbon protection, as compared with Q. variabilis plantation. PMID- 23755471 TI - [Effects of forest gap size and light intensity on herbaceous plants in Pinus koraiensis-dominated broadleaved mixed forest]. AB - 1 m x 1 m fixed quadrats were parallelly arranged with a space of 2 m in each of six forest gaps in Pinus koraiensis-dominated broadleaved mixed forest, taking the gap center as the starting point and along east-west and south-north directions. In each quadrat, the coverage and abundance of herbaceous plants at different height levels were investigated by estimation method in June and September 2011, and the matrix characteristics within the quadrats were recorded. Canopy analyzer was used to take fish-eye photos in the selected overcast days in each month from June to September, 2011, and the relative light intensity was calculated by using Gap Light Analyzer 2.0 software. The differences in the relative light intensity and herbaceous plants coverage and richness between different gaps as well as the correlations between the coverage of each species and the direct light, diffuse light, and matrix were analyzed. The results showed that in opening areas and under canopy, the relative light intensity in large gaps was higher than that in small gaps, and the variation ranges of diffuse light and direct light from gap center to gap edge were bigger in large gaps than in small gaps. The direct light reaching at the ground both in large gaps and in small gaps was higher in the north than in the south direction. In the Z1, Z2, Z3, and Z4 zones, both the coverage and the richness of herbaceous plants were larger in large gaps than in small gaps, and the differences of species richness between large and small gaps reached significant level. The coverage of the majority of the herbaceous plants had significant correlations with diffuse light and matrix, and only the coverage of a few herbaceous plants was correlated with direct light. PMID- 23755472 TI - [Topographic distribution patterns of forest gap within an evergreen broad-leaved forest in Tiantong region of Zhejiang Province, Eastern China]. AB - To explore the effects of multi-dimensional topographic factors on forest gap distribution, the forest gaps in a 20 hm2 dynamic monitoring plot of an evergreen broad-leaved forest in Tiantong region of Zhejiang were taken as the objects to study the distribution patterns of the gap fraction, gap density, and gap area under the effects of altitude, slope degree, slope shape, slope aspect, and slope position by using a geographic information system (GIS) software. In the plot, the gap fraction was 13.1% , gap density was 9.5 ind.hm-2, and average gap area was 137.82 m2. Because of the greater intensity of typhoon disturbance at high altitudes, the gap fraction and gap density at the high altitude (> or =500 m) sections were significantly larger than those at the medium and low altitude (<500 m) sections. The heavy precipitation produced by typhoon could easily cause small scale landslide, and thus, lead to the gap fraction and gap density being larger in valley area than in side-slope and ridge. It was suggested that typhoon and its produced heavy precipitation could be the main causes of the significant differences in the forest gaps along the gradients of altitude and slope position. PMID- 23755473 TI - [Fine root biomass of four main vegetation types in Daluo Mountain of Ningxia, Northwest China]. AB - By the method of soil core sampling, this paper studied the fine root biomass, soil water content, and soil bulk density in 0-40 cm soil layer of four main vegetation types (Picea crassifolia forest, Pinus tabulaeformis forest, deciduous shrubs, and desert grassland) in Daluo Mountain of Ningxia, and the fine root biomass in the 0-40 cm soil layer of P. crassifolia forests with the ages of 50-, 70-, and 100 a. The fine root biomass of the four vegetation types was mainly distributed in 0-20 cm soil layer, with the rank of P. tabulaeformis forest > P. crassifolia forest > deciduous shrubs > desert grassland, and the fine root biomass of P. tabulaeformis forest was significantly higher than that of the other three vegetation types. The fine root biomass of the P. crassifolia forests with different ages was 70 a > 100 a > 50 a, and there were no significant differences in the live fine root biomass ratio and dead fine root biomass ratio among the three P. crassifolia forests. The soil water content in the 0-40 cm soil layer of the four vegetation types was P. crassifolia forest > P. tabulaeformis forest > deciduous shrubs > desert grassland, while the soil bulk density followed an opposite pattern, and was significantly negatively correlated with the fine root biomass. PMID- 23755474 TI - [Microsite characteristics of pit and mound and their effects on the vegetation regeneration in Pinus koraiensis-dominated broadleaved mixed forest]. AB - Abstract: An investigation was conducted in a 2.55 hm2 plot of Pinus koraiensis dominated broad-leaved mixed forest to study the microsite characteristics of pit and mound formed by 42 treefalls and the status of vegetation regeneration on the microsites. The soil water content, soil temperature, relative air humidity, and photosynthetically active radiation (PAR) on five microsites (mound top, mound face, pit wall, pit bottom, and intact forest floor) were measured. Among the five mirosites, mound top had the highest PAR (527.9 micromol.m-2.s-1 ) while intact forest floor had the lowest one (58.7 micromol.m-2.s-), mound top had the highest soil temperature (16.0 degrees C) but pit bottom had the lowest one (13.3 degrees C), pit bottom had the highest soil water content (34.6%) but mound face had the lowest one (0.5%), and intact forest floor had the highest relative air humidity (75.9%) but mound top had the lowest one (68.0%). The frequency of forming pit/ mound complex by the tree species was decreased in the order of Pinus koraiensis (42. 9%) >Picea asperata (31.0%) > Betula platyphylla (16.7%) > Abies fabri (7. 1%) > Prunus padus (2.4%). Among the 42 treefalls, two-thirds of them were in northwest direction. The treefalls volume had significant positive correlations with pit depth, pit length, mound height, and mound width, but negative correlation with mound thickness. The treefall mean diameter at breast height had significant positive correlations with pit width (r=0.328, P=0.017) and pit length (r=0.527, P= 0). The tree species richness at the microsites decreased in the order of intact forest floor > pit > mound, and the tree species coverage was in the sequence of intact forest floor > pit > mound. PMID- 23755475 TI - [Physiological responses of mycorrhizal Pinus massoniana seedlings to drought stress and drought resistance evaluation]. AB - A greenhouse pot experiment was conducted to study the effects of inoculating Pisolithus tinctorius, Cenococcum geophilum, Cantharellus cibarius, and Suillus luteus on the physiological characteristics of Pinus massoniana seedlings under the conditions of drought stress and re-watering, with the drought resistance of the mycorrhizal seedlings evaluated. Under drought stress, the MDA content and membrane' s relative permeability of P. massoniana seedlings increased, but these two indices in the inoculated (mycorrhizal) seedlings were significantly lower than these in the un-inoculated (control) seedlings. After re-watering, the MDA content and membrane's relative permeability of mycorrhizal seedlings had a rapid decrease, as compared with the control. In the first 21 days of drought stress, the production rate of superoxide radical of the seedlings increased, and the SOD, POD and NR activities of mycorrhizal seedlings increased significantly. With the extending of drought stress, the seedlings after re-watering had different recovery ability. Under the re-watering after 14 days drought stress, the SOD, POD and NR activities recovered. The drought resistance of the mycorrhizal seedlings was in the order of Suillus luteus 1 > Suillus luteus 7 > Cantharellus cibarius > Cenococcum geophilum > Pisolithus tinctorius. The SOD and MDA activities had a greater correlation with the mycorrhizal seedlings drought resistance, being able to be used as the indicators to evaluate the drought resistance of mycorrhizal seedlings. PMID- 23755476 TI - [Relationships between nitric oxide response signal and external factors during the early interaction between Pinus thunbergii and Bursaphelenchus xylophilus]. AB - In the interaction between Pinus thunbergii and Bursaphelenchus xylophilus, nitric oxide (NO) is an important signaling molecule involving in the early response of P. thunbergii to the invasion of B. xylophilus. However, it is unclear that whether the NO production by P. thunbergii is triggered by the invaded B. xylophilus or its secreted metabolites. In the present study, the P. thunbergii was inoculated with living B. xylophilus, its secretion, and the suspension of grinded B. xylophilus, respectively, and the nitric oxide synthase (NOS) activity and NO content in the P. thunbergii were detected at the early stage. In all treatments, the inoculated P. thunbergii appeared disease symptoms, and the NOS activity and NO content in the P. thunbergii inoculated with B. xylophilus secretion and grinded B. xylophilus suspension increased, suggesting that besides living B. xylophilus, its contents or secretion could also trigger the expression of NO response signal in P. thunbergii, inducing the downstream response and causing the disease development of P. thunbergi. With the increasing temperature at 15-25 degrees C, both the NOS activity and the NO content in inoculated P. thunbergii increased, and the disease symptoms appeared earlier. The same patterns of NOS activity, NO content, and disease symptoms were also observed under increasing drought stress. It was suggested that within a definite range, increased. temperature and drought stress could enhance the NO signal expression in inoculated P. thunbergii and accelerate its disease development, and thus, the disease development of inoculated P. thunbergii under high temperature and drought condition could be related to the enhancement of the NO response signal in the host. PMID- 23755477 TI - [Ecological effect of hygroscopic and condensate water on biological soil crusts in Shapotou region of China]. AB - By the method of field experiment combined with laboratory analysis, this paper studied the ecological significance of hygroscopic and condensate water on the biological soil crusts in the vegetation sand-fixing area in Shapotou region of China. In the study area, 90% of hygroscopic and condensate water was within the 3 cm soil depth, which didn' t affect the surface soil water content. The hygroscopic and condensate water generated at night involved in the exchange process of soil surface water and atmosphere water vapor, made up the loss of soil water due to the evaporation during the day, and made the surface soil water not reduced rapidly. The amount of the generated hygroscopic and condensate water had a positive correlation with the chlorophyll content of biological soil crusts, indicating that the hygroscopic and condensate water could improve the growth activity of the biological soil crusts, and thus, benefit the biomass accumulation of the crusts. PMID- 23755478 TI - [Effects of biological soil crust at different succession stages in hilly region of Loess Plateau on soil CO2 flux]. AB - Biological soil crust (biocrust) is a compact complex layer of soil, which has photosynthetic activity and is one of the factors affecting the CO2flux of soil atmosphere interface. In this paper, the soil CO, flux under the effects of biocrust at different succession stages on the re-vegetated grassland in the hilly region of Loess Plateau was measured by a modified LI-8100 automated CO, flux system. Under light condition, the soil CO2 flux under effects of cyanobacteria crust and moss crust was significantly decreased by 92% and 305%, respectively, as compared with the flux without the effects of the biocrusts. The decrement of the soil CO, flux by the biocrusts was related to the biocrusts components and their biomass. Under the effects of dark colored cyanobacteria crust and moss crust, the soil CO2 flux was decreased by 141% and 484%, respectively, as compared with that in bare land. The diurnal curve of soil CO2 flux under effects of biocrusts presented a trend of 'drop-rise-drop' , with the maximum carbon uptake under effects of cyanobacteria crust and moss crust being 0.13 and -1.02 micromol CO2.m-2.s-1 and occurred at about 8:00 and 9:00 am, respectively, while that in bare land was unimodal. In a day (24 h) , the total CO2 flux under effects of cyanobacteria crust was increased by 7.7% , while that under effects of moss crust was decreased by 29.6%, as compared with the total CO2 flux in bare land. This study suggested that in the hilly region of Loess Plateau, biocrust had significant effects on soil CO2 flux, which should be taken into consideration when assessing the carbon budget of the 'Grain for Green' eco project. PMID- 23755479 TI - [Effects of exogenous phenolic acid on soil nutrient availability and enzyme activities in a poplar plantation]. AB - By using ion exchange resin membrane as a plant root simulator, this paper studied the variations of soil nutrient availability and enzyme activities in a poplar plantation after applying phenolic acid. The exogenous phenolic acid had significant effects on the soil nutrient availability and enzyme activities, and the effects were concentration- and time dependent. With increasing phenolic acid concentration, the extraction mass of soil NH4+ -N and NO3- -N decreased significantly. At high concentration phenolic acid, soil PO4(3-) and Mn2+ availability increased significantly while soil K+ and Fe3+ availability was in adverse, and soil urease and phosphatase activities had a significant decrease while soil catalase and polyphenol oxidase activities increased significantly. With the elongation of incubation time, the availability of soil NH4+-N, PO4(3-), and Mn2+ increased gradually, while that of soil NO3- -N, K+, Fe3+, and Zn2+ decreased significantly. The correlation analysis showed that the availability of soil NO3- -N, K , Fe2+, and Mn2+ had close correlations with the activities of soil urease, polyphenol oxidase, and phosphatase. PMID- 23755480 TI - [Effects of flooding on the photosynthetic physiology characteristics of Pterocarya stenoptera seedlings]. AB - Three water treatments (control, CK; continuous flooding, CF; and periodic flooding, PF) were installed to simulate the soil moisture change of the riparian zone in the Three Gorges Reservoir (TGR) region of China to study the physiological and ecological adaptation mechanisms of the native plant species Pterocarya stenoptera seedlings to the soil moisture change. All the water treatments had significant effects on the photosynthesis, biomass accumulation, and growth of the P. stenoptera seedlings. As compared with those in CK, the seedling's net photosynthetic rate (Pn) and stomatal conductance (gs) in treatments CF and PF were significantly lower while the intercellular carbon dioxide concentration was significantly higher, and the Pn and gs in CF and PF declined initially followed by a gradual recovery or tended to be stable. With the extension of treatment time, the total biomass and root-, stem-, and leaf biomass, plant height, and basal diameter in CF and PF all presented an increasing trend. Throughout the experimental period, the total biomass, root- and leaf biomass, and plant height in CF and PF and the stem biomass in PF were significantly lower than those in CK, whereas the stem biomass in CF had no significant difference with that in CK, though the basal diameter in CF was significantly higher than that in CK. It was suggested that the P. stenoptera seedlings had the physiological and ecological characteristics of tolerating flooding rather than flooding-drought alteration. PMID- 23755481 TI - [Estimation of soil organic carbon density and storage in Zhejiang Province of East China by using 1:50000 soil database]. AB - As an important component of the carbon pool of terrestrial ecosystem, soil carbon pool plays a key role in the studies of greenhouse effect and global change. By using a 1:50000 soil database, the organic carbon density in the 0-100 cm layer of 277 soil species in Zhejiang Province was estimated, and the soil organic carbon (SOC) density and storage in the whole Province as well as the spatial distribution of the SOC density and storage in the main soil types of the Province were analyzed. In the whole Province, the SOC density ranged from 5 kg.m 2 to 10 kg.m-2. Among the main soil types in the Province, humic mountain yellow soil had the highest SOC density (52.80 kg.m-2), whereas fluvio-sand ridge soil had the lowest one (1.82 kg.m-2). Red soil and paddy soil had the largest SOC storages, with the sum accounting for 63.8% of the total SOC storage in the Province. The total area of the soils in the Province was 100784.19 km2, the estimated SOC storage was 875. 42 x 10(6) t, and the estimated SOC density was averagely 8.69 kg.m-2. The analysis with the superposition digital elevation model showed that the SOC density presented an obvious variation trend with the changes of elevation, slope gradient, and aspect. PMID- 23755482 TI - [Effects of farming managements on the global warming potentials of CH4 and N2O from a rice-wheat rotation system based on the analysis of DNDC modeling]. AB - Taking a rice-wheat rotation system in the suburb of Nanjing, Jiangsu Province of East China as test object, this paper studied the fluxes of CH4 and N2O and their annual dynamics under different farming managements in 2010-2011, and the field observation data were applied to validate the process-based model, denitrification-decomposition (DNDC) model, aimed to approach the applicability of the model to this rotation system, and to use this model to simulate the effects of different environmental factors and farming managements on the global warming potentials (GWPs) of CH4 and N2O. The results showed that except in the treatment control and during wheat growth season, the simulated cumulative emissions of CH4 and N2O from the rotation system in all treatments were basically in coincide with the observed data, the relative deviations being from 7. 1% to 26.3%, and thus, the DNDC model could be applied to simulate the GWPs of cumulative emissions of CH4 and N2O as affected by various environmental factors or management practices. The sensitivity test showed that the GWPs of CH4 and N2O varied significantly with the changes of environmental factors such as the mean annual air temperature, soil bulk density, soil organic carbon, soil texture, and soil pH. Farming managements such as N fertilization, straw returning, and duration of mid-season drainage also had significant effects on the GWPs of CH4 and NO20. Therefore, the above-mentioned environmental factors and farming managements should be taken into account to estimate the greenhouse gases emission from the rice-wheat cropping system on site-specific or regional scale. PMID- 23755483 TI - [Multi-scenario simulation and prediction of ecosystem services as affected by urban expansion: A case study in coastal area of Tianjin, North China]. AB - Based on the modified Logistic-CA model, and taking the coastal area of Tianjin as a case, this paper simulated the spatial evolution patterns of ecosystem services as affected by the urban expansion in 2011-2020 under the scenarios of historical extrapolation, endogenous development, and exogenous development. Overall, the total ecosystem services of the study area under the three scenarios were generally the same, and the functional region with the lowest level ecosystem services had the identical spatial pattern. However, the spatial evolution patterns of the ecosystem services of the study area under the three scenarios had a great difference. The functional regions with lower-level ecosystem services grew in a cross-shaped pattern, with the Tanggu downtown as a center, and finally formed a full connectivity area along the Haihe River and coastal zone. PMID- 23755484 TI - [Ecological risk assessment of rural-urban ecotone based on landscape pattern: A case study in Daiyue District of Tai' an City, Shandong Province of East China]. AB - Based on the remote sensing data in 2000, 2005, and 2010, this paper analyzed the variation trends of the land use type and landscape pattern in Daiyue District of Tai' an City from 2000 to 2010. The ecological risk index was built, that of the District was re-sampled and spatially interpolated, and the spatiotemporal pattern of the ecological risk in the rural-urban ecotone of the District was analyzed. In 2000-2010, the main variation trend of the land use type in the District was the shift from natural landscape to artificial landscape. The intensity of human disturbance was larger in cultivated land, garden plot, and forestland than in other landscape types, while the human disturbance in water area was smaller. The ecological loss degree of cultivated land and water area decreased somewhat, while that of the other land use types presented an increasing trend. The ecological risk distribution in the District was discrete in 2000 and 2010, but most centralized in 2005. The ecological risk of each ecological risk sub-area had an increasing trend in 2000-2005, but was in adverse in 2005-2010. In 2000-2010, the ecological risk of the District was mainly at medium level. Spatially, the distribution of the ecological risk in the District had an obvious differentiation, with an overall diffusive increasing from forestland as the center to the surrounding areas. In the District, the ecological risk was mainly at medium and higher levels, the area with lower ecological risk had an obvious dynamic change, while that with the lowest and highest ecological risk had less change. PMID- 23755485 TI - [Simulation model of the development stages of flue-cured tobacco based on physiological development period and growing degree days]. AB - Based on the 2010-2011 experimental data of planting flue-cured tobacco in its representative production counties of Yunnan Province, Southwest China, the models of the tobacco plant physiological development period and growing degree days were established, and validated by the observation data from local agro meteorological stations. The two models had good performance at pre-transplanting stage, and the errors of the estimated dates were smaller. After transplanting stage, the errors of the estimated dates were larger, because of the disturbances from farming activities such as transplanting and topping. The simulated values based on the tobacco plant physiological development period had a higher coincidence with the observed values, especially at the pretransplanting stage, with the errors of the estimated dates being smaller than two days. As affected by the photoperiod effect, the model of tobacco plant physiological development period fitted better in high latitude regions than in low latitude regions. PMID- 23755486 TI - [Distribution characteristics of aggregates organic carbon in a paddy soil chronosequence]. AB - By the method of physical fractionation of organic matter, this paper studied the distribution characteristics of organic carbon in different particle size aggregates in a paddy soil chronosequence on the south bank of Hangzhou Bay, East China. In the plow layers of the paddy soil chronosequence, micro-aggregates (<0. 25 mm) dominated, and the proportion of large micro-aggregates (0.053-0.25 mm) decreased with increasing rice cultivation year. In the micro-aggregates (<0. 053 mm and 0. 053-0. 25 mm), the organic carbon content increased with increasing rice cultivation time; and in the aggregates (0. 053-2 mm), the ratio of the organic carbon in different particle size fractions to the bulk soil organic carbon increased with decreasing particle size, and the organic carbon mainly distributed in large micro-aggregates (0. 053 -0. 25 mm). With increasing rice cultivation time, soil particulate organic carbon decreased, indicating that the paddy soil with a longer rice cultivation history had a stronger capability of carbon sequestration than the soil with a shorter rice cultivation history, and the early cultivated paddy soil still had great potential for carbon sequestration. PMID- 23755487 TI - [Effects of different planting modes on the soil permeability of sloping farmlands in purple soil area]. AB - Taking bare land as the control, this paper studied the effects of different planting modes on the soil permeability of sloping farmlands in purple soil area. For the test six planting modes, the soil permeability was in the order of Eriobotrya japonica > Citrus limon > Vetiveria zizanioides hedgerows +corn >Leucaena leucocephala hedgerows + corn> Hemerocallis fulva > corn> bare land, and decreased with increasing depth. The eigenvalues of soil infiltration were in the order of initial infiltration rate> average infiltration rate> stable infiltration rate. The soil permeability had significant positive linear correlations with soil total porosity, non-capillary porosity, initial moisture content, water holding capacity, and organic matter content, and significant negative linear correlation with soil bulk density. The common empirical infiltration model could well fit the soil moisture infiltration processes under the six planting modes, while the Kostiakov equation could not. PMID- 23755488 TI - [Effects of long-term fertilization on soil organic carbon pool and carbon sequestration under double rice cropping]. AB - This paper studied the effects of 30 years (1981-2010) fertilization with chemical N, P, and K, pig manure (PM), and rice straw (RS) on the soil organic carbon (SOC) and its components contents under intensive double rice cropping. The experiment was established on a typic Hapli-Stagnic Anthrosols in Hunan in 1981, and the soil samples were collected in November 2010. In treatment NPK, the contents of SOC, particulate organic C (POC), and KMnO4-oxidizable C (KMnO4-C) were higher than those in treatments NP and NK. The combined application of chemical and organic fertilizers (treatments NK+PM, NP+RS, and NPK+RS) made the contents of SOC, POC, and KMnO4-C have a significant increase, as compared with chemical fertilizations. Treatment NK+PM had the highest contents of SOC (84.71 t C.hm-2), POC (8.94 t C.hm-2), and KMnO4-C (21.09 t C.hm-2) in top soil (0-45 cm), followed by treatment NPK+RS. Treatment NK+PM had the highest C sequestration (485 kg C.hm-2.a-1) , followed by treatment NPK+RS (375 kg C.hm-2.a-1). The C sequestration efficiency (CSE) of SOC in the treatments of chemical fertilizers plus pig manure or rice straw was obviously higher than that in the treatments of chemical fertilizations, and the CSE of the POC in fertilization treatments (ranging from 0.4% and 1.2%) was lower than that of the KMnO4-C (ranging from 3.0% to 8.3%). By using the values of humification constant (h) and the decay constant (k) in Jenkinson' s equation, it was possible to predict the SOC storages in different treatments in the year 2010; and by using Jenkinson' s equation, it was possible to calculate the C input required to maintain the SOC storages in the year 1981 (AE). The increase of the SOC in treatments NK+PM, NP+RS, and NPK+RS was due to the annual C input being higher than the AE. It was considered that in the double rice cropping areas in subtropical region of China, long-term application of chemical fertilizers combined with pig manure or rice straw could promote the organic carbon sequestration in paddy soils. PMID- 23755489 TI - [Effects of soil compaction stress on respiratory metabolism of cucumber root]. AB - A pot experiment with cucumber cultivar "Jingchun 4" was conducted to study the effects of soil compaction stress on the respiratory metabolism of cucumber root. Two treatments were installed, i.e. , soil bulk densities 1.20 and 1.55 g . cm-3. Under soil compaction stress, the activities of root pyruvate decarboxylase, alcohol dehydrogenase, and lactate dehydrogenase and the contents of root anaerobic respiration products alcohol, acetaldehyde, and lactate increased significantly, while the activities of the key enzymes involved in root aerobic respiration, including malate dehydrogenase, succinate dehydrogenase, and isocitrate dehydrogenase, decreased significantly, root pyruvate and succinate contents had significant increase, whereas root malate content decreased significantly. All the results illustrated that under soil compaction stress, the aerobic respiration of cucumber root was inhibited, while its anaerobic respiration was promoted. PMID- 23755490 TI - [Effects of different cultivation modes on the leaf photosynthetic characteristics and yield of summer-sowing peanut]. AB - Taking the Arachis hypogaea cv. 'Qinghua 7' as test material, a field experiment was conducted to study the effects of different cultivation modes on the leaf photosynthetic characteristics and yield of summer-sowing peanut after wheat harvest. As compared with conventional cultivation mode, high-yield protective cultivation mode promoted the leaf growth, significantly improved the leaf area index (LAI), and maintained a longer time of high LAI and chlorophyll content. Meanwhile, the net photosynthetic rate, stomatal conductance, and transpiration rate of functional leaves under high-yield protective cultivation mode were higher while the intercellular CO2 concentration was lower, which induced the photosynthetic efficiency of functional leaves being significantly improved. Therefore, under high-yield protective cultivation mode, the yield per peanut plant was higher, the pod yield increased significantly, and the economic coefficient improved obviously. Both film mulching and straw returning could also improve the leaf photosynthesis of summer-sowing peanut, and increase the peanut yield. It was suggested that high-yield protective cultivation mode could effectively alleviate the adverse factors of summer-sowing peanut, such as the short growth period and lower productivity per plant, being a practical high yield cultivation mode of summer-sowing peanut. PMID- 23755491 TI - [Effects of outer type and built-in type straw bio-reactors on tomato growth and photosynthetic performance]. AB - Taking the tomato (Solanum lycopersicum) cultivar "Kuiguan108" as test object, a comparative study was made on the effects of outer type and built-in type straw bio-reactors on the CO2 concentration, air relative humidity , air vapor pressure deficit in the solar greenhouse during the tomato growth over autumn-delayed cultivation as well as the effects of the bio-reactors on the tomato growth and photosynthetic performance. As compared with that in CK, the average CO2 concentration in the greenhouse with outer type straw bio-reactor at 9:30-11:30 and 14:30-15:00 on sunny days was increased significantly by 207. 3 and 103 micromol . mol-1 , respectively, and the ave-rage CO2 concentration in the greenhouse with built-in straw bio-reactor at 9:30-11:30 on sunny days was raised by 19.0 micromol . mol-1. Both the outer type and the built-in type straw bio reactors promoted the tomato plant height growth and early flowering, enhanced the plant net photosynthetic rate and the yield per plant and per unit area significantly, and decreased the plant transpiration rate at the stages of vegetative growth and fruit- bearing significantly. Nevertheless, as compared with built-in type straw bio-reactor, outer type straw bio-reactor was more suitable for the autumn- delayed cultivation of tomato in solar greenhouse. PMID- 23755492 TI - [Effects of potassium fertilization period on photosynthetic characteristics and storage root starch accumulation of edible sweetpotato]. AB - Abstract: In this study, same amount of potassium (240 kg . hm-2) was applied as basal dressing (treatment 1) and as 1/2 basal dressing + 1/2 top-dressing at day 75 after planting (treatment 2), aimed to investigate the effects of potassium fertilization period on the photosynthetic characteristics of edible sweetpotato and the starch accumulation in storage root. As compared with treatment 1, treatment 2 improved the leaf photosynthetic rate and sucrose-phosphate synthase activity and the storage root's adenosine diphosphate glucose pyrophosphortlase activity, enhanced the starch accumulation rate in storage root (with an average increment of 6. 7%), and increased the root tuber yield significantly by 8. 2%. Both of the potassium fertilization treatments improved the synthesis of sucrose in leaf and the transformation from sucrose to starch in storage root, as compared with no potassium fertilization. PMID- 23755493 TI - [Characteristics of DNA adsorption on different sizes red soil colloidal particles]. AB - By using balance reaction method, this paper studied the adsorption characteristics and thermodynamic properties of DNA on four kinds of red soil colloids (organic matter-contained coarse clay, organic matter-removed coarse clay, organic matter-contained fine clay, and organic matter-removed fine clay). The DNA adsorption on the four red soil colloids was a process of fast reaction, and the adsorption isotherms were conformed to the Langmuir equation, with the corresponding correlation coefficient (r2) being 0.974, 0. 991, 0. 958, and 0. 975, respectively. The maximum adsorption amount of DNA on the colloidal particles followed the order of organic matter-contained fine clay > organic matter-removed fine clay > organic matter-contained coarse clay > organic matter removed coarse clay, implying that the size and organic matter content of colloidal particles played an important role in DNA adsorption. Electrolyte concentration and type and adsorption system pH were the main factors affecting the DNA adsorption on the four soil colloids. Within a definite electrolyte concentration range (NaCl < 60 mmol . L-1 and CaCl2 <10 mmol L-1) , the adsorption amount of DNA on the red soil colloids increased significantly with the increase of electrolyte concentration. As compared with sodium ion, calcium ion had a greater promotion effect on the DNA adsorption, but the effect decreased significantly with the increase of adsorption system pH. The DNA adsorption on the organic matter-contained red soil colloids was an endothermic reaction, while the DNA adsorption on the organic matter-removed red soil colloids was an exothermic reaction. The DNA adsorption on the red soil colloids was a process of entropy increase. PMID- 23755494 TI - [Ecological regionalization of cotton varieties based on GGE biplot]. AB - By using the heritability-adjusted GGE biplot analysis method, and taking the trial sites Anqing, Nanyang, Huanggang, Jingzhou, Wuhan, Xiangyang, Changde, Yueyang, Nanjing, Nantong, Yancheng, Jiujiang, Jianyang, Shehong, and Cixi as the representative cotton-planting areas in the Yangtze River basin, the ecological regionalization of cotton varieties in the basin was made based on the lint cotton yield, and the regionalization results were adjusted by the information ratio (IR) method, aimed to provide scientific basis for the selection of cotton varieties in the cotton-planting areas of the basin. The cotton-planting areas in the Yangtze River basin could be divided into three ecological regions, i.e., the "Sichuan basin cotton region" with Jianyang and Shehong as the representative, the "Nan-Xiang basin cotton region" with Xiangyang and Nanyang as the representative, and the "majority complex cotton region in the Yangtze River basin" including all the other sites in the basin. PMID- 23755495 TI - [Effects of different soil and water loss control measures on the dung beetle assemblages in Huangfuchuan watershed, Inner Mongolia of North China]. AB - By using pitfall trap method, and taking the croplands and natural grasslands under different soil and water loss control measures as sampling plots, an investigation was conducted on the dung beetle assemblages in the Huangfuchuan watershed of Inner Mongolia from September 2007 to September 2008, aimed to understand the effects of different soil and water loss control measures on the dung beetle assemblages in the watershed. A total of 6169 dung beetles were captured, belonging to 15 species, 5 genus, and 2 families. The dominant species were Aphodius rectus and Onthophagus gibbulus, accounting for 66. 54% and 13. 26% of the total captured beetles, respectively. A lack of the species suitable for living in woodland habitats was the basic feature of the dung beetle assemblages. As compared with the control, all test soil and water loss control measures did not cause an obvious increase of species richness, biomass, and abundance of the dung beetle assemblages. The biomass and species richness of the assemblages as well as the abundance of the functional groups II and III had a significant negative correlation with the average tree (grass) height. Under the effects of long-term agricultural cultivation and the lack of large herbivores, the species richness and abundance of the functional group I (larger paracoprids and telocoprids) were lower than those of the functional groups II (relatively smaller paracoprids) and II (endocoprids), the main components of the dung beetle assemblages in the watershed. The faeces of the residents and livestock in the study region provided abundant foods for the dung beetle assemblages, inducing the relatively high abundance and spices richness of the assemblages occurred in the croplands nearby the villages. Our results suggested that natural grasslands were the suitable habitats for the dung beetles in Huangfuchuan watershed. At regional scale, to popularize the successful experiences of comprehensive soil and water loss control, preserve natural grasslands, and feed appropriate number of livestock (especially larger herbivores) could be the effective approaches for maintaining the diversity of dung beetles and the ecosystem functions. PMID- 23755496 TI - [CaCl2-heat shock preparation of competent cells of three Pseudomonas strains and related transformation conditions]. AB - Pseudomonas, due to its diversity in habitat and metabolic type, makes it have broad prospects applying in bioremediation, bioconversion, and biocontrol, while the introduction of exogenous gene is the key link to genetically modified Pseudomonas. The preparation and transformation of competent cells are the important methodological basis of the introduction of exogenous gene. In this paper, three Pseudomonas strains (P. putida TS11, P. stutzeri DNB, and P. mendocina JJ12) isolated from a petroleum-contaminated soil were taken as the recipient strains, and a three-factor and four-level orthogonal experiment was conducted to investigate the effects of CaCl2 concentration, heat shock duration, and recovery duration on the preparation and transformation efficiency of the strains competent cells. The results showed that CaCl2 concentration was the most important factor affecting the transformation efficiency (P<0.05), and the transformation efficiency was improved markedly when the Pseudomonas cells were repeatedly washed with sterile distilled water before the preparation of competent cells. When the P. putida TS11 cells were treated with 100 mmol L-1 of CaC12, heat-shocked for 3 minutes at 42 degrees, and incubated for 1.5 hours at 30 degrees C, the P. stutzeri DNB cells were treated with 50 mmol . L-1 of CaCl2, heat-shocked for 6 minutes, and incubated for 1.5 hours, and the P. mendocina JJ12 cells were treated with 75 mmol . L-1 of CaCl2, heat-shocked for 4. 5 minutes, and incubated for 0. 5 hours, the transformation efficiency of exogenous plasmids in the three strains all achieved 10(5) cells . microg-1 DNA. PMID- 23755497 TI - [Effects of different treatment methods of housefly pupae for the reproduction of Pachycrepoideus vindemmiae Rondani]. AB - It is an important way to massively rear parasitoid wasps by using appropriate methods to treat the wasps' hosts and preserve them for a long duration. Pachycrepoideus vindemmiae Rondani is a pupal parasitoid of several dipteral pests, being of significance for the biological control of the pests. In this paper, housefly pupae were frozen at -20 degrees C, cold storage-preserved at 6 degrees C, and CO2-asphyxiated for 1-, 3-, and 30 days, respectively, and some pupae were heat-killed and cold storage-preserved for 30 days, aimed to approach the effects of these treatment methods on the reproduction of P. vindemmiae on the pupae. The results showed that P. vindemmiae could reproduce on the pupae treated with the above-mentioned methods, and the tibia length of the offspring had less difference with that on the fresh pupae. However, the reproduction of P. vindemmiae on the pupae treated with the above-mentioned methods except frozen decreased with the increasing preserving duration of the pupae. At the prerequisite of preserving for 30 days, frozen pupae had the highest P. vindemmiae offspring reproduction, suggesting that P. vindemmiae could be massively reared when the housefly pupae were treated by frozen and cold storage preserved. PMID- 23755498 TI - [Soil seed bank and its correlations with aboveground vegetation and environmental factors in water level fluctuating zone of Danjiangkou Reservoir, Central China]. AB - Taking the water level fluctuating zone of the Danjiangkou Reservoir as a case, and by the method of hierarchical cluster analysis, the soil seed banks at 37 sampling plots within the areas of 140-145 m elevation were divided into 6 groups, and the species composition, density, and diversity of the soil seed banks among the groups were compared. The differences between the soil seed banks and the aboveground vegetations were analyzed by S0rensen similarity coefficient, and the correlations among the soil seed banks, aboveground vegetations, and environmental factors were explored by principal component analysis (PCA) and multivariable regression analysis. At the same altitudes of the water level fluctuating zone, the species composition of the soil seed banks had obvious heterogeneity, and the density and diversity indices of the soil seed banks among different groups were great. The similarity coefficient between the soil seed banks and aboveground vegetations was low, and the species number in the soil seed banks was obviously lesser than that in the aboveground vegetations. The density of the soil seed banks was highly positively correlated with the aboveground vegetations coverage and species number and the soil texture, but highly negatively correlated with the soil water-holding capacity and soil porosity. PMID- 23755499 TI - [Effects of Three Gorges Reservoir impoundment on the wetland ecosystem service value of Dongting Lake, South-central China]. AB - Based on the field investigation and measurement, and by using the monetary method, this paper estimated the wetland ecosystem service value of Dongting Lake before and after the impoundment of Three Gorges Reservoir (in 1996 and 2010, respectively). After the impoundment, the total ecosystem service value increased from 156.69x10(8) yuan in 1996 to 177.11x10(8) yuan in 2010. The main services value in 1996 was in the order of flood storage and regulation > water storage and supply > air regulation > scientific research and education, while that in 2010 was leisure tourism > shipping transportation > air regulation > water storage and supply. In the total service value of the wetland ecosystem, the direct value associated with water decreased from 110. 85x10(8) in 1996 to 27.47x10(8) in 2010, with a decrement of 75.2%. Though the proportion of the direct value in the production and supply of material products had somewhat increase, the indirect value in ecological environment regulation and maintenance and in culture and society still maintained at about 80% of the total value. In addition to climate factors, the impoundment of Three Gorges Reservoir and the reduction of water and sediment from Yangtze River to the Lake were the crucial reasons leading to the changes of the wetland ecosystem service value of Dongting Lake. PMID- 23755500 TI - [Spatial niches of dominant zooplankton species in Sanmen Bay, Zhejiang Province of East China]. AB - Ecological niche has close relations with inter-species competition and resources utilization, and thus, can be used as an indicator to symbolize the resources utilization capability of certain groups of related species. In this paper, the niche breadth and overlap of the dominant zooplankton species in the Sanmen Bay of Zhejiang were determined by Shannon's formula and Petraitis index, respectively, and the differentiation of the niche was studied by canonical correspondence analysis (CCA), aiming to approach the distribution features of coastal zooplankton and related affecting factors in the Bay. In the study area, some coastal species such as Zonosagitta bedoti, Centropages dorsispinatus, and brachyuran larvae had wider niche breadth than the pelagic species such as Flaccisagitta enflata and Pseudeuphausia sinica, and the species of different groups with prey-predator relation had a greater niche overlap than those of the same groups without this relation. The CCA analysis showed that the spatial distribution of the zooplankton was more affected by water temperature, salinity, and chlorophyll a content rather than nutrients. The spatial niche of the zooplankton species was correlated with their living habit, inter-species competition, and prey- predator relationship. PMID- 23755501 TI - [Eco-environmental quality assessment of Luoyuan Bay, Fujian province of East China based on biotic indices]. AB - In this paper, two types of eco-environmental quality assessment indices that have been successively applied abroad, i.e., the AZTI marine biotic index (AMBI) and BENTIX index based on the ecological sensitivity of benthos and the multivariate-AMBI (M-AMBI), a multivariate index integrating AMBI, Shannon Index H', and species richness, were applied to assess the eco-environmental quality of Luoyuan Bay, Fujian Province of East China, and the assessment results were compared with those by the H', an index based on community structure, which is often applied in China, aimed to test the applicability of these indices to the Bay, and to provide reference in selecting the indices for assessing our coastal eco-environment quality. Similar assessment results were obtained by applying AMBI and BENTIX index, and M-AMBI and H'. At most stations (13 of 16), the assessment results by applying AMBI and BENTIX index, M-AMBI and H' were coincident, respectively; while at the other 3 stations, the assessment grade was high or good based on AMBI and BENTIX index, but moderate based on M-AMBI and H'. Taking account of the richness, individual abundance, and ecological group composition of the benthos in Luoyuan Bay, the assessment results based on M-AMBI and H' could be more reasonable. It was suggested that for the Luoyuan Bay which has a high level of eutrophication and low organic matter enrichment in sediment and is dominated by sensitive benthos species, M-AMBI and H' could be more applicative and objective than AMBI and BENTIX index in assessing its eco environmental quality. PMID- 23755502 TI - [Using kenaf (Hibiscus cannabinus) to reclaim multi-metal contaminated acidic soil]. AB - A five-year field trial was conducted at the surrounding area of Dabao Mountain Mine to explore the feasibility and availability of using kenaf (Hibiscus cannabinus) , a fiber crop with strong heavy metals tolerance and potential economic value, to reclaim the multi-metal contaminated acidic farmland soil. Different amendments were applied prior to the kenaf planting to evaluate their effects on the soil properties and kenaf growth. After the amendments application, the kenaf could grow well on the heavy metals contaminated soil with the Pb, Zn, Cu, Cd, and As concentrations being 1600, 440, 640, 7. 6, and 850 mg . kg-1, respectively. Among the amendments, dolomite and fly ash had better effects than limestone and organic fertilizer. With the application of dolomite and fly ash, the aboveground dry mass production of kenaf reached 14-15 t . hm-2, which was similar to that on normal soils, and the heavy metal concentrations in the bast fiber and stem of kenaf decreased significantly, as compared with the control. The mass of the bast fiber accounted for 32% -38% of the shoot production, and the extractable heavy metal concentrations in the bast fiber could meet the standard of 'technical specifications of ecological textiles' in China, suggesting that the bast fiber had potential economic value. It was suggested that planting kenaf combining with dolomite/fly ash application could be an effective measure to reclaim the multi-metal contaminated acidic farmland soil. PMID- 23755503 TI - [Effects of enhanced CO2 fertilization on phytoremediation of DEHP-polluted soil]. AB - Low efficiency of remediation is one of the key issues to be solved in phytoremediation technology. Based on the necessity of reducing CO2 emission in China and the significance of CO2 in plant photosynthesis, this paper studied the effects of enhanced CO2 fertilization on the phytoremediation of polluted soil, selecting the C3 plant mung bean (Vigna radiate) and the C4 plant maize (Zea mays) as test plants for phytoremediation and the DEHP as the target pollutant. DEHP pollution had negative effects on the growth and rhizosphere micro environment of the two plants. After enhanced CO2 fertilization, the aboveground dry mass of the two plants and the alkaline phosphatase activity in the rhizosphere soils of the two plants increased, the COD activity in the leaves of the two plants decreased, the microbial community in the rhizosphere soils shifted, and the numbers of the microbes with DEHP-tolerance in the rhizosphere soils increased. These changes indicated that enhanced CO2 fertilization could promote the plant growth and the plant tolerance to DEHP stress, and improve the rhizosphere micro-environment. Enhanced CO2 fertilization also increased the DEHP uptake by the two plants, especially their underground parts. All these effects induced the residual DEHP concentration in the rhizospheres of the two plants, especially that of mung bean, decreased obviously, and the phytoremediation efficiency increased. Overall, enhanced CO2 fertilization produced greater effects on C3 plant than on C4 plant. It was suggested that enhanced CO2 fertilization could be a useful measure to enhance the efficiency of phytoremediation. PMID- 23755504 TI - [Molecular identification and detection of moon jellyfish (Aurelia sp.) based on partial sequencing of mitochondrial 16S rDNA and COI]. AB - Taking the moon jellyfish Aurelia sp. commonly found in our coastal sea areas as test object, its genome DNA was extracted, the partial sequences of mt-16S rDNA (650 bp) and mt-COI (709 bp) were PCR-amplified, and, after purification, cloning, and sequencing, the sequences obtained were BLASTn-analyzed. The sequences of greater difference with those of the other jellyfish were chosen, and eight specific primers for the mt-16S rDNA and mt-COI of Aurelia sp. were designed, respectively. The specificity test indicated that the primer AS3 for the mt-16S rDNA and the primer AC3 for the mt-COI were excellent in rapidly detecting the target jellyfish from Rhopilema esculentum, Nemopilema nomurai, Cyanea nozakii, Acromitus sp., and Aurelia sp., and thus, the techniques for the molecular identification and detection of moon jellyfish were preliminarily established, which could get rid of the limitations in classical morphological identification of Aurelia sp. , being able to find the Aurelia sp. in the samples more quickly and accurately. PMID- 23755505 TI - [Factors affecting the vegetation restoration after fires in cold temperate wetlands: A review]. AB - Cold temperate wetland plays an important role in maintaining regional ecological balance. Fire is an important disturbance factor in wetland ecosystem. Severe burning can induce the marked degradation of the ecological functions of wetland ecosystem. The vegetation restoration, especially the early vegetation restoration, after fires, is the premise and basis for the recovery of the ecological functions of the ecosystem. This paper reviewed the research progress on the factors affecting the vegetation restoration after fires in wetlands. The vegetation restoration after fires in cold temperate wetlands was controlled by the fire intensity, fire size, vegetation types before fires, regeneration characteristics of plant species, and site conditions. It was considered that the long-term monitoring on the post-fire vegetation restoration in cold temperate wetland, the key factors affecting the vegetation restoration, the roles of frozen soil layer on the post-fire vegetation restoration, and the theories and technologies on the vegetation restoration would be the main research directions in the future. PMID- 23755506 TI - [Nitrogen metabolism and translocation in arbuscular mycorrhizal symbiote and its ecological implications]. AB - Arbuscular mycorrhizal fungi (AMF) can form mutually beneficial relations with more than 80% of vascular plants, and the existence of the symbiote is of significance in promoting the growth and stress tolerance of host plants. AMF can obtain the photosynthate carbohydrates from host plants, and in the meantime, effectively promote the nitrogen (N) uptake by host plants via the absorption of various N sources by mycorrhiza mycelia, resulting in the N exchange at population or community level, the improvement of host plants nutrition and metabolism, and the strengthening of the stress tolerance of host plants. However, there are still in debates in which ways the symbiote absorbs and transfers N and what the mechanisms the N metabolism and translocation from AMF to host plants. This paper reviewed the mechanisms of N metabolism and translocation in the symbiote and the effects of carbon and phosphorous on the N metabolism and translocation. The roles of AMF in the N allocation in host plants and the related ecological significance at community and ecosystem levels were briefly elucidated, and some issues to be further studied on the N metabolism in the symbiote were addressed. PMID- 23755507 TI - [Inhalable particulate matter and fine particulate matter: their basic characteristics, monitoring methods, and forest regulation functions]. AB - Both inhalable particulate matter (PM10) and fine particulate matter (PM2.5) are not only one of the main causes of air pollution, but also the primary pollutants in most cities. Based on the analysis of the impacts of PM10 and PM2.5 on the environment and human health, this paper summarized the components, sources, and mass concentration variations of PM10 and PM2.5 and related affecting factors, and introduced the network layout of PM10 and PM2.5 monitoring and its principles and features. The research methods on the removal of PM10 and PM2.5 by forests, the removal rates of PM10 and PM2.5 by different forests, and the related affecting mechanisms were summed up at regional and individual scales, and the existed problems in this research field were discussed. Due to the lack of the comparable observation studies on the atmospheric PM10 and PM2.5 along different gradients and in background areas, the joint effects of multiple factors on the PM10 and PM2.5 concentrations are not revealed. It was suggested that to make a rational network layout of PM10 and PM2.5 monitoring, to correctly select proper monitoring methods, and to compare and calibrate the observed results from classical manual methods would be the bases to guarantee the validity of PM10 and PM2.5 monitoring data. At present, there are few reports about the PM2.5 removal by forests, and it's not clear about the physiological processes and ecological mechanisms of PM10 and PM2.5 removal at cell, tissue, organ, and individual level. PMID- 23755508 TI - [Effects of extracellular protein on the formation and properties of microbial assemblages: A review]. AB - Extracellular polymeric substance (EPS) , as a major component of microbial assemblages, e.g. , activated sludge, biofilm and particulate sludge, etc., plays a crucial role in the formation and structural maintenance of microbial assemblages. Extracellular protein is a main constituent of EPS, and its functioning in microbial flocculation and aggregation has being paid more and more attention. The development and application of protein analytical techniques provide a good platform for the further study of extracellular protein. The paper reviewed the kind and distribution of extracellular protein in microbial assemblages and the roles of the extracellular protein in flocculation, sedimentation, adsorption, mass transferring, and dewatering. The prospects of the future study and applications of extracellular protein were also put forward. PMID- 23755509 TI - [Eco-toxicological effect of metal-based nanoparticles on plants: Research progress]. AB - The rapid development of nanotechnology and the potential environmental risk of wide application of artificial nanoparticles (NPs) have raised considerable concerns. Metal-based nanoparticles (MB NPs) have dual-toxicity of metal and NPs, and thus, their bio-toxicity and ecological risk are the hotspots in the studies of nanotoxicology. Plant, as a main component of ecosystem, is a potential pathway for NPs bioaccumulation and entering into food chain. This paper discussed the MB NPs absorption, translocation, and accumulation by plants, and summarized the eco-toxicological effect of MB NPs on plants and related mechanisms. The factors affecting the phytotoxicity of MB NPs were approached, and the research progress on the eco-toxicological effect of MB NPs on plants, especially on food crops, was reviewed. Also, the existing problems in present MB NPs phytotoxicity studies were analyzed, and the future research directions were proposed. PMID- 23755510 TI - [Genetic implications and therapeutic possibilities in the course of hereditary macular pathology and vitreoretinopathies]. AB - There are many hereditary diseases in ophthalmology including retinal dystrophies -diseases of great heterogeneity requiring genetic determination, individual or in entire family. PMID- 23755511 TI - [Screening in open angle glaucoma]. AB - Primary open angle glaucoma (POAG) represents the second cause of mondial cecity, after retinal diabetes complications, with extremely severe implications in quality of life. Screening testing for glaucoma is justified, because only the diagnosis in very incipient stage will preserve the visual function; any treatment will not assure the reversibility of pre-existent optic nerve lesions. Screening of glaucoma, will take into a consideration the costs, the time of investigation, the adverse effects, and the sensitivity and specificity of tests; the last parameter also will strongly influence the positive predictive value. An ideal screening identifies all subjects that present the disease (sensitivity) and will exclude all healthy subjects (specificity). In this moment, in Dolj district, the diagnosis is based on active diagnosis of new cases of glaucoma on the high risk level population, therefore in a 210000 habitants. 4723 patients with glaucoma are diagnosed, screened and follow-up on medical cabinets and on Center of Glaucoma, which coordinates their activity. To better monitored patients, automatized programs with acquisition and storage for different types of medical imaging facilities had become indispensable to any routine practice. PMID- 23755512 TI - [Genotyping in progressive age-related macular degeneration]. AB - After presenting both the prevalence and the staging of the age-related macular degeneration (AMD), the disease progression is discussed; it is determined primarily by genetic factors but is also influenced by environmental, demographic and behavioral factors. The genes working by means of the high-density lipoprotein cholesterol (HDL) pathway have critical roles in the drusen initiation in the early AMD stages. After the drusen have accumulated between retinal pigment epithlium (RPE) and Bruch's membrane, the genes acting in the alternative complement pathway are activated so influencing in this way the progression from the intermediate and large drusen to the advanced AMD stages (e.g. the geographic atrophy of the RPE and neovascular stages). PMID- 23755513 TI - [Hypopyon]. AB - The hypopyon represents an anterior chamber exudative syndrome which has important clinical and prognostic implications. It is very important to be able to differentiate between the sterile and infectiouos hypopyon and also to separate it by pseudohypopyon. A clear view over the etiology is strongly correlated with the therapeutical approach and the patient evolution. PMID- 23755514 TI - [General anesthesia in ophthalmology]. AB - General anesthesia is less utilized in ophthalmology. There are some criteria that lead to general anesthesia: patients with auditive debility, aged and senile patients, allergic patients, children and young patients, and subjects who totally refuse loco-regional procedures. General anesthesia utilizes as basic products: narcotic substances, analgesic substances, or neuroleptic substances utilized separately or associated, with posology adaptated to several factors: patients' pulse, physical statement, age, duration. The type of anesthetic substance depends also of specialist anesthetist experience. PMID- 23755515 TI - [Aspects of molecular immunology and immunogenetics in autoimmune uveitis]. AB - Generally speaking, the uveitis comprises a relative complex group of autoimmune diseases or other autoimmune associated illness. Until now, a little from molecular and cellular mechanisms are known in the autoimmunity of uveitis. The uveitis may cause a visual handicap as well, leading even to blindness. This paper tries to bring into focus some of the molecular mechanisms and immunogenetic features of the disease. PMID- 23755516 TI - [Lens prescription for rigid contact lenses in keratoconus]. AB - Rigid Gas-Permeable contact lenses is a less risky option for improving the quality of vision in corneal ectasias such as keratoconus. They reshape the corneal surface (flattens the cornea) so that in most cases, with a proper lens, the patient can reach a visual acuity of 20/20. PMID- 23755517 TI - [Clinical and functional considerations in some cases of postoperative endophthalmitis]. AB - We present 3 cases of postsurgery endophthalmitis, with good initial operatory technique, which were admitted in our hospital within variable time, to which a second surgery was performed, with good postoperative evolution, without any inflamatory signs and preserving the eye. We analyse the pre and post-operative treatment of endophthalmitis, but also the ways to prevent the appearance of this post-operative complication. PMID- 23755518 TI - [Contusive ocular trauma--case report]. AB - We present the case of a 48 year old man who was admitted for the decreased visual acuity of the left eye for about 20 years, when a left sided facial trauma had occured. Clinical examination and lab exams revealed the cause of this change: ocular contusive posttraumatic status for about 20 years (anamnestic), iridodialysis, corectopie, traumatic cataract, PVR, tractional retinal detachment. Surgical treatment was warranted. We performed cataract extraction, posterior vitrectomy with laser fotocoagulation and injection of silicon oil 1000. We followed the pacient's post-operative evolution and we extracted of the silicone oil six months later. The evolution was favorable. PMID- 23755519 TI - [Normal tension glaucoma or syndrome of chronic ocular ischemia]. AB - Chronic ischemia related to a manifest ophthalmic artery stenosis, determines extremely rare ischemic chronic modifications at the level of the optic nerve, with progressive optic atrophy and visual fun ction alteration. It is presented the case of a 59 years patient, who was hospitalized in Clinic of Ophthalmology, Emergency Clinic Districtual Hospital, for decreased vision of the left eye. Fundus eye examination reveals normal aspect of papilla of the right eye and glaucomatous like modification of the left eye, confirmed by perimetry and OCT exams, which present typical glaucomatous lesions. Doppler examination revealed an enormous thrombus at the level of the left internal carotid, with more than 90% stenosis. In this context the diagnosis was chronic ocular ischemia, atypical form. lschemic ocular syndrome presents polymorphic clinic aspects, the most frequent are the ischemic lesions of posterior pole of the eye: retinal hemorrhages, neovascularization, ischemic edema, red cherry macula, cotton-wool spots. lschemic optic neuropathy is less frequent presented, and pseudo glaucomatous lesion of optic nerve with papillary excavation is exceptional. PMID- 23755520 TI - [Mobius syndrome]. AB - Mobius syndrom, an anomaly in cranial nerve developement, presents with a remarkable clinical polymorphism. The rare occurence of this pathology and the questions raised by the diagnosis and treatment determined us to make this presentation. PMID- 23755521 TI - [Intraocular hypertension after retinal detachment surgery]. AB - This papers presents a case of a patient with retinal detachment, 3 days ago operated (posterior vitrectomy, internal tamponament with silicon oil 1000) who developed increased ocular pressure following silicon oil output in the anterior chamber. PMID- 23755522 TI - [Amniotic membrane in conjunctivoplasty]. AB - The basic principles of conjunctival reconstruction are similar in all pathologies that inflict conjunctival tissue loss. Large conjunctival defects are difficult to treat, with little conjunctival reserve that can be used to close the defect. The study had the objective to find alternatives to conjunctival autograft. Frozen amniotic membrane was investigated. From 27 cases, 22 cases were reconstructed using amniotic membrane alone, but in 5 cases conjunctival autograft was also needed. Bulbar conjunctiva was reconstructed in 23 cases, of which 19 with pterygium, 3 with conjunctival tumors, one operatory plague. Fornix reconstruction was carried out in 4 cases, one tumor and 3 symblepharons (2 after conjunctival burns and one pemfigus). The rate of pterygium recurrence was 7,14%. Amniotic membrane can heal large defects of the conjunctiva, either bulbar or forniceal. PMID- 23755523 TI - [Computer-assisted phacoemulsification for hard cataracts]. AB - PURPOSE: to evaluate the efficiency of new torsional phacoemulsification software (Ozil IP system) in hard nucleus cataract extraction. METHODS: 45 eyes with hard senile cataract (degree III and IV) underwent phacoemulsification performed by the same surgeon, using the same technique (stop and chop). Infiniti (Alcon) platform was used, with Ozil IP software and Kelman phaco tip miniflared, 45 degrees. The nucleus was split into two and after that the first half was phacoemulsificated with IP-on (group 1) and the second half with IP-off (group 2). For every group we measured: cumulative dissipated energy (CDE), numbers of tip closure that needed manual desobstruction the amount of BSS used. RESULTS: The mean CDE was the same in group 1 and in group 2 (between 6.2 and 14.9). The incidence of occlusion that needed manual desobstruction was lower in group 1 (5 times) than in group 2 (13 times). Group 2 used more BSS compared to group 1. CONCLUSION: The new torsional software (IP system) significantly decreased occlusion time and balanced salt solution use over standard torsional software, particularly with denser cataracts. PMID- 23755524 TI - [Unexpected effects of genes--tumor suppressors in fruit fly ontogenesis]. AB - Many of well-known genes-suppressors, beside protecting tissues against unlimited cells division and forming neoplastic tumors, cause various effects on animals development, vital functions, and fitness. Pleiotropic effects of these genes are due to their primary functions related with controlling of key cell processes. By making up complex compounds with other proteins, the products of genes suppressors form cell contacts and polarity; take part in transmission of molecular signals that govern vitally important processes in a developing organism; control the cell cycle, growth, and proliferation; modulate signal paths of cell survival and preprogrammed death that protect an organism against defective structures in critical situations. Despite of tumor suppressors' vital importance, their lethal mutations are widespread in animal populations, while ensuring higher fitness under natural conditions when being in a heterozygous state. PMID- 23755525 TI - [The puzzle of Wolbachia spreading out through natural populations of Drosophila melanogaster]. AB - The endosymbiotic bacteria Wolbachia are widely spread in natural populations of arthropods all over the world. This phenomenon, according to the current views, may be due either to so called reproductive parasitism (modification of sexual reproduction) or to mutualistic interrelationships with the host organism, since the bacteria are transmitted transovarially. Wolbachia are extremely widespread in natural populations and laboratory lineages of Drosophila melanogaster though they do not cause any known modifications of this insect sexual reproduction that could influence the bacteria frequency in the populations. It is found out that Wolbachia effects on drosophila reproductive processes can only consist in low level of cytoplasmic incompatibility within laboratory lineages; in natural drosophila populations even such an effect has not been detected. The attempts to explain the wide spread of Wolbachia among representatives of D. melanogaster through fitness increasing of infected individuals were not successful either. Data obtained thereupon are contradictive and the results are not versatile. Meanwhile, there are some incomplete data on the bacteria affecting drosophila sexual behavior, expression of certain genes, ferrum metabolism. It is shown that the bacteria enhance individual resistance to RNA-viruses that, under natural conditions, infect fruit flies rather frequently, but the mechanisms of the phenomenon remain uncertain as well as the commonness of the phenomenon itself. Thus, at the one hand, it can be stated that infection by Wolbachia leads to a rather complex effect on D. melanogaster while, at the other hand, the reasons behind the wide spread of Wolbachia in natural populations of D. melanogaster still remain unclear. PMID- 23755526 TI - [Network structures in biological systems]. AB - Network structures (networks) that have been extensively studied in the humanities are characterized by cohesion, a lack of a central control unit, and predominantly fractal properties. They are contrasted with structures that contain a single centre (hierarchies) as well as with those whose elements predominantly compete with one another (market-type structures). As far as biological systems are concerned, their network structures can be subdivided into a number of types involving different organizational mechanisms. Network organization is characteristic of various structural levels of biological systems ranging from single cells to integrated societies. These networks can be classified into two main subgroups: (i) flat (leaderless) network structures typical of systems that are composed of uniform elements and represent modular organisms or at least possess manifest integral properties and (ii) three dimensional, partly hierarchical structures characterized by significant individual and/or intergroup (intercaste) differences between their elements. All network structures include an element that performs structural, protective, and communication-promoting functions. By analogy to cell structures, this element is denoted as the matrix of a network structure. The matrix includes a material and an immaterial component. The material component comprises various structures that belong to the whole structure and not to any of its elements per se. The immaterial (ideal) component of the matrix includes social norms and rules regulating network elements' behavior. These behavioral rules can be described in terms of algorithms. Algorithmization enables modeling the behavior of various network structures, particularly of neuron networks and their artificial analogs. PMID- 23755527 TI - [Duration of the pre-nesting period and its relation with social organization in sandpipers (Charadrii, Aves) nesting in north-east Yakutia]. AB - Investigations were carried out at two stations of Ornithological Unit, IBPN FEB RAS, located in Nizhnekolymsk District, Yakutia, starting from May 18-20 in 1984, 1985, 1987, 1988 and 1990. Duration of the pre-nesting period in 11 sandpiper species with different social organization was studied and compared with each other by allometric equations. As a characteristic of bird size the body mass was selected. Sandpipers come flying to the tundra at almost critical temperatures, to begin breeding as early as possible. Tining of breeding depends on birds feeding manner and the proximity to sites of overwintering. Duration of the pre nesting period is invariable for every bird species and sex. There are sexual distinctions in time spent for the pre-nesting period in jointly-nesting sandpipers. The exponents in allometric equations that relate duration of the pre nesting period with body mass are constant within a particular sex and differ between males and females. In different sexes, time spent for the pre-nesting period depends on mating, parental, and territorial systems. In sandpipers' males and females, this time is determined by the type of social organization. Relatively large sandpiper species seek to shortening of the pre-nesting period calendar time, which constrains their social organization. Monogamy and pair parental care lead to a necessity for spatial population structure to be controlled more strictly and maintained for a longer time. This, in turn, causes the increasing of males' time expenditures for such a behavior. PMID- 23755528 TI - [Embryonic development of whitefishes (Coregonidae) as representatives of the "pagophilous" ecological group]. AB - Studies of reproduction and embryonic development in six species of coregonid fishes have revealed the possibility of their fertilized eggs to develop normally while being embedded in the ice of a spawning water body (optionally). Such ability is facilitated by extremely low respiratory activity of embryos at early stages of embryogenesis (from the stage of fission to the stage of organogenesis). Low level of oxygen consumption and carbon dioxide emission is an adaptation to low diffusion gas permeability of the ice. The main factor controlling the rate of coregonids embryonic development is not temperature, but intensity and periodicity of insolation. Without the sunlight--an obligatory external factor--normal development is just not possible. Under experimental conditions, when developing in the water at near zero temperature or in the ice, normal morphogenesis of Arctic cisco and Sevan whitefish embryos was observed at the illumination of 50-300 lux. Hemoproteid cytochrome beta560, the pigment that has been discovered in water-soluble part of coregonids oocyte yolk and is treated as a biochemical marker for eggs of the family Coregonidae, in all likelihood performs protective (antioxidant) functions preventing spontaneous oxidation of embryo's fatty inclusions. Under the oxygen shortage inside the ice envelope, cytochrome beta560 probably sets conditions for oxidation processes of embryo's tissue respiration. Spherome, being kept till the time of hatching, acts as a temporary hydrostatic organ and ensures larvae buoyancy at the stage of postembryonic metamorphosis. It also serves as an energy store after downstream migration of larvae from the spawning areas till their shift to exogenous feeding on zooplankton. Conforming to ecological traits of reproduction and development, and also to revealed morphogenetic, physiological, and biochemical features, it is proposed to ascribe all of the currently known 26 species of whitefishes to "pagophilous" ecological group. PMID- 23755529 TI - [Actual problems of genetic toxicology]. AB - The review deals with current issues of genetic toxicology and aims to develop this science at the contemporary stage. We study general approaches to assessing the genotoxic and mutagenic activity of environmental factors; to constructing a regulatory system of chemical compounds that considers the mutagenic effect in Russia and abroad; and to determining modem methods for assessing the organ specificity of mutagens, alternative methods of genetic toxicology, the mutagenic action of various factors in the survey of population, and the abilities of toxicogenomics to identify the mutagenic properties of the environment. PMID- 23755530 TI - The origin of the B-genome of bread wheat (Triticum aestivum L.). AB - Understanding the origin of cultivated wheats would further their genetic improvement. The hexaploid bread wheat (Triticum aestivum L., AABBDD) is believed to have originated through one or more rare hybridization events between Aegilops tauschii (DD) and the tetraploid T. turgidum (AABB). Progenitor of the A-genome of the tetraploid and hexaploid wheats has generally been accepted to be T. urartu. In spite of the large number of attempts and published reports about the origin of the B-genome in cultivated wheats, the donor of the B-genome is still relatively unknown and controversial and, hence, remains open. This genome has been found to be closely related to the S-genome of the Sitopsis section (Ae. speltoides, Ae. longissima, Ae. sharonensis, Ae. searsii, and Ae. bicornis) of the genus Aegilops L. Among Sitopsis species, the most positive evidence has been accumulated for Ae. speltoides as the progenitor of the B-genome. Therefore, one or more of the Sitopsis species were proposed frequently as the B-genome donor. Although several reviews have been written on the origin of the genomes of wheat over the years, this paper will attempt for the first time to review the immense literature on the subject, with a particular emphasis on the B-genome which has attracted a huge attention over some 100 years. The ambiguity and conflicting results in most of the methods employed in deducing the precise B-genome donor/s to bread wheat are also discussed. PMID- 23755531 TI - [Distribution of genes of toxin-antitoxin systems of mazEF and relBE families in bifidobacteria from human intestinal microbiota]. AB - The in silico analysis of 36 sequenced genomes of bacteria of the Bifidobacterium genus determined the presence of 19 genes of toxin-antitoxin (TA) systems that belong to the MazEF and RelBE families, including five mazF and two relE genes that encode toxins and 12 relB genes that encode antitoxins. A high level ofgene (at the level of nucleotide changes) and genomic (presence or absence of genes in distinct genomes) polymorphism in the investigated genes was revealed. The highest level of polymorphism was observed in strains of the Bifidobacterium longum species, primarily in relB1-10 genes. Gene and genomic polymorphism might be used to identify the strain of B. longum species. PCR analysis ofgenomic DNA of 30 bifidobacteria strains belonging to the three species, B. longum, B. adolscentis, and B. bifidum, isolated from the intestinal microbiota of astronauts demonstrated the presence of mazF and relB genes. The observed polymorphism of TA genes indicates the presence of differences in bifidobacteria strains isolated from the intestinal microbiota of astronauts before and after space flight and the control group. PMID- 23755532 TI - [HSM6 gene is identical to PSY4 gene in Saccharomyces cerevisiae yeasts]. AB - Previously, we isolated mutant yeasts Saccharomyces cerevisiae with an increased rate of spontaneous mutagenesis. Here, we studied the properties of HSM6 gene, the hsm6-1 mutation of which increased the frequency of UV-induced mutagenesis and decreased the level of UV-induced mitotic crossover at the centromere gene region, ADE2. HSM6 gene was mapped on the left arm of chromosome 11 in the region where the PSY4 gene is located. The epistatic analysis has shown that the hsm6-1 mutation represents an allele of PSY4 gene. Sequencing of hsm6-1 mutant allele has revealed a frameshift mutation, which caused the substitution of Lys218Glu and the generation of a stop codon in the next position. The interactions of hsm6 1 and rad52 mutations were epistatic. Our data show that the PSY4 gene plays a key role in the regulation of cell withdrawal from checkpoint induced by DNA disturbances. PMID- 23755533 TI - [Characterization of puroindolines in the control of endosperm texture in common wheat lines with substitutions of homeologous group-5 chromosomes]. AB - The genetic control of grain hardness and its association with the specific friabilin content on starch granules of common wheat cultivars and lines with intervarietal substitutions of homeologous group-5 chromosomes were studied. A significant correlation was revealed between the technological parameters of grain hardness (mean size of flour particles) and the specific content of puroindolines on the starch surface estimated in terms of starch doses. The results obtained allowed the method of starch doses to be used to identify soft and hard wheat cultivars and lines based on an analysis of a single grain. The biochemical analysis confirmed the previously obtained estimates of flour grinding properties of wheat cultivars and substitution lines, which allowed specific genotypes to be characterized according to the composition of puroindolines. The influence of chromosomes 5D and 5A of donor wheat cultivars on the activity of the Ha loci of recipient cultivars was revealed and found to be associated with the composition of PIN products and with the expression of the Pina-D1 and Pinb-D1 genes. PMID- 23755534 TI - [Sibling species of rein orchid (Gymnadenia:Orchidaceae, Magnoliophyta) in Russia]. AB - Recent molecular phylogenetic studies of the genus Gymnadenia have demonstrated that it contains sibling taxa, i.e., species that are hardly distinguishable according to morphological traits, yet are phylogenetically rather distant and distinctly distinguishable by molecular methods, which is a rare phenomenon for angiosperms. The sequencing of the ITS 1-5.8S rDNA-ITS2 fragment allowed us the presence of the species G. densiflora to be demonstrated in Russia. The Russian specimens have confirmed a high degree of genetic differentiation between G. conopsea s. str. and G. densiflora, which proves their taxonomic status rank of species. Morphological analysis has shown that the features that allow for the best discrimination between these two species in Northwestern Russia are the length of the lower bract, length of the mid-lobe of the lip, and width of leaves. The ecological and phenological discrimination between G. conopsea s. str. and G. densiflora is briefly reviewed. The ITS sequence variation in these species has been analyzed; the molecular genetic distinctions of the G. conopsea individuals from the eastern part of the distribution area have been discovered for the first time. Different taxonomic interpretations of the Gymnadenia phylogenetic tree topology taking into account the presence sibling species are discussed in general. PMID- 23755535 TI - [Comparative analysis of mitochondrial DNA variation in four species of far eastern redfins of the genus Tribolodon (Pisces, Cyprinidae)]. AB - MtDNA variations were examined in four endemic species of the Far Eastern redfins of the genus Tribolodon across considerable parts of their ranges. No close correlation was revealed between the lifespan of the species and the level of mtDNA variations. An association was revealed between the degree of manifestation of the genetic structure population and the degree ofamphidromy in the species. The presence of differing mtDNA phylogroups in three out of four species indicates that the history of these species included long period of independent intraspecific divergent evolution. This period occurred at approximately the same historical time and was probably caused by the same factors. The period appeared to be not long enough and ended with the association of genetically independent units into single species. PMID- 23755536 TI - [Methylation profile of group of miRNA genes in clear cell renal cell carcinoma; involvement in cancer progression]. AB - MicroRNA regulates gene expression, is involved in many cellular processes, and plays an important role in the development of cancer. The regulation of the expression of miRNA genes can be achieved by methylating their CpG islands, which is shown in different types of tumors. The methylation of miRNA genes in clear cell renal cell carcinoma (CCRCC) has mainly been studied for the miR-9 and miR 34 families. The methylation of six miRNA genes (miR-124a-2, -124a-3, -9-1, -9-3, -34b/c, -129-2) was investigated with the use of representative set of CCRCC samples (46 cases). Methylation of three genes miR-124a-2, -124a-3, and -129-2 was studied in kidney tumors for the first time. Methylation analysis was performed using methyl specific PCR. It is shown that the frequency of methylation of six genes (miR-124a-2, -124a-3, -9-1, -9-3, -34b/c and -129-2) was significantly higher in tumor samples than in samples of histologically normal tissue (P < 3 x 10(-5) by Fisher's exact test). These results suggest the properties of tumor suppressors for the six miRNA genes indicated in CCRCC. We also found correlations between the methylation frequency of some miRNA genes and signs of the progression of CCRCC (tumor size, clinical stage, loss of differentiation, and metastasis). PMID- 23755537 TI - [Haplotype diversity in mtDNA and Y-chromosome in populations of Altai-Sayan region]. AB - Polymorphism of mtDNA was examined in five ethnic populations that belong to the Turkic language group and inhabit the territory of the Altai-Sayan upland (N = 1007). Most of the haplogroups identified in the examined populations belonged to East Eurasian lineages. In all five populations, only three haplogroups, C, D, and F, were prevailing. The frequencies of the other six haplogroups (A, B, G, M, Y, and Z) varied in the range from 1.1 to 6.5%. Among West Eurasian haplogrous, the most common were haplogroups H, J, T, and U. An analysis of Y-chromosome haplogroups in 407 individuals showed that only two haplogroups, N* and R1a1, were present in all five populations examined. Moreover, in different ethnic groups, the highest frequencies were observed for C-M130, N-P43, and N-Tat haplogroups. The differences in the distribution patterns of ancient West Eurasian and East Eurasian haplotypes from Gorny Altai in the present-day populations from the northern part of Eurasia revealed can be explained in terms of the multistage expansion of humans across these territories. The ubiquity of haplotypes from haplogroup H and cluster U across the wide territory from the Yenisei River basin to the Atlantic Ocean can indicate directional human expansion, which most likely occurred out of Central Asia as early as in the Paleolithic era, and took place in several waves with the glacier retreat. PMID- 23755538 TI - [On the problems of the evolutionary optimization of life history. I. A Markov model of the Leslie life history and optimization of fertility]. AB - The paper considers the properties of individual life history corresponding to the Leslie model of age-structured population. The life history is simulated as a finite Markov chain with absorption at a death state of individual. In this model, individual longevity, average number of offspring R(L) (produced by an individual over the entire life), and some other known parameters of the life history have been derived using simple probability methods that do not involve matrix calculus and their individual components have been interpreted. In the Leslie linear population model (derived by simple modification of a Markov chain), R(L) determines the growth or decline of a population. Individuals with higher R(L) values have evolutionary advantages in the population due to accelerated growth in their number The selection of fertility as a factor of the increase in R(L) is considered. In the Leslie model, fertility is a set of correlated quantitative traits, where the age-specific fertility components determined both by multipl loci and the environment. According to the genetic theory of quantitative trait selection, they evolve towards an increase in R(L). Taking into account the limited resources for reproduction, selection optimizes the fertility distribution according to age. Optimal distribution corresponds to the attainment of the maximum R(L). This complies with the maximization of the rate of population growth (r-selection), which is characteristic of linear population models. The search for the RL maximum and optimal distribution of fertility belongs to the field of linear programming. PMID- 23755539 TI - [On the problems of the evolutionary optimization of life history. II. To justification of optimization criterion for nonlinear Leslie model]. AB - The paper considers the problems in the adaptive evolution of life-history traits for individuals in the nonlinear Leslie model of age-structured population. The possibility to predict adaptation results as the values of organism's traits (properties) that provide for the maximum of a certain function of traits (optimization criterion) is studied. An ideal criterion of this type is Darwinian fitness as a characteristic of success of an individual's life history. Criticism of the optimization approach is associated with the fact that it does not take into account the changes in the environmental conditions (in a broad sense) caused by evolution, thereby leading to losses in the adequacy of the criterion. In addition, the justification for this criterion under stationary conditions is not usually rigorous. It has been suggested to overcome these objections in terms of the adaptive dynamics theory using the concept of invasive fitness. The reasons are given that favor the application of the average number of offspring for an individual, R(L), as an optimization criterion in the nonlinear Leslie model. According to the theory of quantitative genetics, the selection for fertility (that is, for a set of correlated quantitative traits determined by both multiple loci and the environment) leads to an increase in R(L). In terms of adaptive dynamics, the maximum R(L) corresponds to the evolutionary stability and, in certain cases, convergent stability of the values for traits. The search for evolutionarily stable values on the background of limited resources for reproduction is a problem of linear programming. PMID- 23755540 TI - [Association between 242C > T polymorphism of NADPH oxidase p22phox gene (CYBA) and longevity in Russian population]. AB - Life span depends on many factors, including the level of reactive oxygen species, like superoxide radical. Superoxide radical is produced from oxygen in the course of the oxidation of NADPH to NADP+. The process is catalyzed by NADPH oxidase. In this study, genotype and allele distributions of the C242T polymorphism in the CYBA gene, which encodes the alpha subunit ofNADPH oxidase (p22phox), were examined in the sample of long livers and in the population sample of the city of Tomsk. Statistically significantly higher frequency of T allele among female long livers (34.62%), compared to the females from Russian population (26.32%) was demonstrated (chi2 = 5.226; p = 0.022; OR = 1.48). Thus, the T allele is associated with a high life expectancy in females from the Russian population. No such association was observed for males from the same population. PMID- 23755541 TI - [On the role of gene of SER-4 serotonin receptor in thermotolerance of Caenorhabditis elegans behavior]. AB - Serotonin reduces the behavior tolerance of Caenorhabditis elegans of the N2 wild type strain (swimming induced by the mechanical stimulus) to a temperature of 36 degrees C. The sensitivity to the serotonin influence on the behavior thermotolerance remains intact in strains with null mutations of mod-1 (ok103) and ser-1 (ok345) serotonin receptor genes, and is almost completely lost in the ser-4 (ok512) strain with null mutation in the gene of the SER-4 serotonin receptor, which is a homologue of 5-HT1 mammalian serotonin receptor. In addition, nematodes of the ser-4 (ok512) strain have high behavior thermotolerance in the absence of the exogenous serotonin compared to the N2 strain. These data indicate the involvement of the ser-4 gene in the serotonin regulation of the tolerance of C. elegance nervous system functions to hyperthermia. PMID- 23755542 TI - [Intra- and interspecific polymorphism of (AAT)n in microsatellite locus du47D in parthenogenetic species of the genus Darevskia]. AB - The molecular structure of the allelic variants of (AAT)n of the Du47D microsatellite locus was determined in parthenogenetic lizards Darevskia dahli, D. armeniaca, and D. rostombekovi. Comparative analysis of these alleles showed that they were characterized by perfect structure of microsatellite cluster, and were different in the number of (AAT) monomeric units, as well as in the combinations of species-specific substitutions and deletions in the microsatellite flanking regions. Molecular structure of microsatellite cluster, species-specific single nucleotide polymorphism (SNP), and different representation of alleles Du47 in the samples of parthenogenetic species examined point to the origin of the alleles from different bisexual species, which is consistent with the hybrid nature of unisexual species of the genus Darevskia. In addition, these data reflect different combination patterns of interspecific hybridization events with the participation of the same bisexual species upon the formation of hybrid genomes of parthenogenetic species. Possible application of the allelic variants of microsatellite loci of parthenogenetic lizards as the genetic markers for the analysis of the genomes of parthenogenetic species in the light of evolution, ecology, and parthenogenetic type of reproduction in vertebrates is discussed. PMID- 23755543 TI - [Estimation of the quality of global alignment of amino acid sequences based on evolution criterion]. AB - The aim of the work is to develop the common method for estimating the pairwise alignment quality versus the evolution distance (a degree of homology) between the sequences being comparing, and the type of the alignment procedure. 3D alignments as well as any data on 3D protein structure are not used in the study. Based on the accepted protein sequences evolution model it is possible to estimate the capability of the concrete alignment algorithm to recover the genuine alignment. In this study a classical Needleman and Wunsch global alignment algorithm has been tested on a set of sequences from the Prefab database. Dependences of accuracy and confidence of a global alignment procedure were calculated as consequences of insertions/deletions and mutations shares. PMID- 23755544 TI - [Statistical methods of comparative genomic analysis based on diffusion processes]. AB - Comparative genomics is a powerful tool of genome functional specificity predictions and investigation of evolution specificity. Background of a large field of bioinformatics investigations is a computation of different scores of sequences and comparing them with a threshold. Comparative genomic analysis involves scores comparing for orthological groups of genetic objects. In this paper we represent a statistical approach to comparative genomic analysis, that based on investigation of diffusion in sequence space determined by neutral evolution of sequences. Using this approach we represent several statistics for selection pressure estimation and analyze statistics for several biological problems. We formulate technology of statistics applying to obtain new biological information. This approach is represented as Java-class library. PMID- 23755545 TI - [Linear clusters of gold nanoparticles in quasinematic layers of DNA liquid crystalline dispersion particles]. AB - The effects of small size (approximately 2 nm) gold nanoparticles on the properties of particles of cholesteric liquid-crystalline dispersions formed by double-stranded DNA molecules were analyzed. It has been shown that gold nanoparticles induce two different processes. First, they facilitate reorganization of the spatial cholesteric structure of dispersion particles to nematic one. This process is accompanied by the fast decrease in the amplitude of abnormal band in the CD spectrum. Second, they can form ensembles consisting of gold nanoparticles. This process is accompanied by the development and displacement of surface plasmon resonance band in the visible region of the absorption spectrum. The appearance of this band is analyzed by considering two different models of the formation of ensembles consisting of gold nanoparticles. By small-angle X-ray scattering we performed structural analysis of phases formed by DNA cholesteric liquid-crystalline dispersion particles treated with gold nanoparticles. As a result of this study it was possible to prove the formation of linear clusters of gold nanoparticles in the "free space" between the adjacent DNA molecules fixed in the quasinematic layers of liquid-crystalline particles. It has been hypothesized that the formation of linear clusters of gold nanoparticles is most likely related to DNA molecules, ordered in the spatial structure of quasinematic layers, and the toxicity of these nanoparticles in biological systems hypothesized. PMID- 23755546 TI - [A method for solution of the multi-objective inverse problems under uncertainty]. AB - We describe a method to solve multi-objective inverse problems under uncertainty. The method was tested on non-linear models of dynamic series and population dynamics, as well as on the spatiotemporal model of gene expression in terms of non-linear differential equations. We consider how to identify model parameters when experimental data contain additive noise and measurements are performed in discrete time points. We formulate the multi-objective problem of optimization under uncertainty. In addition to a criterion of least squares difference we applied a criterion which is based on the integral of trajectories of the system spatiotemporal dynamics, as well as a heuristic criterion CHAOS based on the decision tree method. The optimization problem is formulated using a fuzzy statement and is constrained by penalty functions based on the normalized membership functions of a fuzzy set of model solutions. This allows us to reconstruct the expression pattern of hairy gene in Drosophila even-skipped mutants that is in good agreement with experimental data. The reproducibility of obtained results is confirmed by solution of inverse problems using different global optimization methods with heuristic strategies. PMID- 23755547 TI - [Phosphorus-containing iminoxy and nitroxy free radicals as perspective spin labels]. AB - A structure and magnetic parameters of a series of nitroxy and iminoxy radicals with different position of the phosphorus atom with respect to the radical center were established by means of EPR. Free radicals were obtained in the course of chemical and electrochemical reactions and also through UV-radiation with the use of "spin traps". The studied phosphorylated nitroxy and iminoxy radicals are revealed to be highly sensitive to the medium and temperature that makes them perspective "spin labels" in biological objects. PMID- 23755548 TI - [Formation of a new type of dinitrosyl iron complexes bound to cysteine modified with methylglyoxal]. AB - It has been shown that interaction of cysteine dinitrosyl iron complexes with methylglyoxal leads to the formation of a new type of dinitrosyl iron complexes., EPR spectrum of these complexes essentially differs from spectra of dinitrosyl iron complexes containing unmodified thiol. The products of the cysteine reaction with methylglyoxal are hemithioacetals, Schiff bases and thiazolidines, which most likely serve as ligands for the new type of dinitrosyl iron complexes. It has been shown that the new type of dinitrosyl iron complexes as cysteine dinitrosyl iron complexes, which are physiological donors of nitric oxide, exert a vasodilator effect. It has also been found that the oxidative destruction of the new type of dinitrosyl iron complexes occurs at normal oxygen partial pressure, but these dinitrosyl iron complexes remain rather stable under hypoxia modeling. An assumption that the destruction of the new type of dinitrosyl iron complexes is caused by the formation of a bound peroxynitrite-containing intermediate is made. PMID- 23755549 TI - [Photoinduced production of reactive oxygen species by retinal derivatives and conjugates]. AB - The formation of reactive oxygen species (ROS) during all trans-retinal illumination was studied by ESR. The quantity of ROS was estimated by the ESR signal of a spin adduct of DEPMPO (5-dietoxyphosphoryl-5 methyl-1-pirroline-N oxide). The ESR signal was found to be a superposition of the adducts: 80%- superoxide anion radical, 15%--hydroxyl radical and 5%--an unknown radical. It was shown that the addition of an equimolar albumin concentration resulted in the 5-fold decrease of the relative quantum yield for ROS generation, and a 4-fold albumin excess led to decreased ROS production by 30-fold. It is supposed that ATR and A2E in the photoreceptor membrane are the sources of photodamage induced by ROS. ATR in the cell is known to be transported by interphotoreceptor retinal binding proteins that belong to the albumin family. The ATR binding with proteins is supposed to prevent the ROS production in the photoreceptor cell and thus produces the light damage protection action. PMID- 23755550 TI - [Investigation of changes in fluidity of brain membranes in mice bearing experimental Alzheimer's disease using spin labeling electron paramagnetic resonance]. AB - Changes in fluidity of membranes isolated from the microsomal and crude synaptosomal fractions which were obtained from forebrain tissue of mice bearing experimental Alzheimer's disease induced with olfactory bulbectomy were studied. Membrane microviscosity was measured by electron paramagnetic resonance with 2,2,6,6-tetramethyl-4-capryloyl-oxypiperidine-1-oxyl and 5,6-benzo-2,2,6,6 tetramethyl-1,2,3,4-tetrahydro-gamma-carboline-3-oxyl as spin labeling. Phasic alterations in relative fluidity were found during the development of experimental Alzheimer's disease pathology. These changes correlate with the stages of "clinical" features. Main abnormalities were related to structural changes in near-protein region of the lipid bilayer. PMID- 23755551 TI - [Nuclear spin catalysis in nanoreactors of living cells]. AB - There is a great variety of chemical elements with magnetic and nonmagnetic isotopes in living cells. The question arises as to whether living cells can perceive the difference between magnetic and non-magnetic isotopes of chemical elements. It has been shown that bacteria Escherichia coli, which were previously enriched with the magnetic isotope of magnesium, 25Mg, essentially faster adapt to the new growth media in comparison with the cells, which were enriched with the nonmagnetic isotopes, 24Mg or 26Mg. In the experiments with another commonly accepted cell model, yeast Saccharomyces cerevisiae, it has been shown that the magnetic 25Mg, in comparison with the nonmagnetic 24Mg, essentially better stimulates recovery of the cells after short wave UV irradiation. Thus, for the first time, the magnetic isotope effects in vivo have been discovered. These findings reveal the novel, based on the stable magnetic isotopes, ways of control over efficiency and reliability of biological systems. PMID- 23755552 TI - [Study of the relationship between shape and aggregation change in human erythrocytes]. AB - The relationship between shape and spontaneous and fibrinogen-induced aggregation change in human erythrocytes was studied. Spontaneous and fibrinogen-induced erythrocyte aggregation was investigated using a rheoscope designed according to the method of H. Schmid-Schonbein et al. (1973). The erythrocyte shape was studied by means of light microscopy. It was shown that plasma enriched with lysophosphatidic acid and ATP depletion of erythrocytes led to the change of erythrocyte shape: discocytes transformed into echinocytes. It was found that spontaneous aggregation of such cells was considerably decreased. Aggregation of erythrocytes, treated with lysophosphatidic acid, was diminished more markedly. Fibrinogen-induced aggregation of echinocytes, obtained after treatment with lysophosphatidic acid and produced by ATP depletion, was also greatly reduced. PMID- 23755553 TI - [Respiratory and olfactory cilia molecular machines of locomotor apparatus]. AB - Physical activity of respiratory and olfactory cilia of animals and humans in the context of L.A. Blumenfeld concept, according to which protein molecules are "machines that perform chemical transformation" and create "a meaningful order", has been investigated and analyzed. PMID- 23755554 TI - [Electron paramagnetic resonance study of nitric oxide production in rat heart during hypokinesia]. AB - By the method of EPR spectroscopy we studied the intensity of nitric oxide (NO) production after modeling of hypokinesia in rats (limitation of moving activity) through analyses of the amount of NO-containing paramagnetic complexes in tissues of heart and liver. Experimental animals were kept during 60 day protracted hypokinesia. NO amount was assessed by the intensity of EPR spectra of complex (DEDTC)2-Fe(2+)-NO. It was established that after 60 day hypokinesia the 2-3 fold increase of NO quantity occured in heart and liver tissues. The application of a nonspecific inhibitor of NO-synthases, L-NAME, in suspended rats led to a decreased NO quantity up to the value more lower than in control. The obtained results show that the main contribution to the increase in the intensity of NO production during hypokinesia belongs to the fermentative pathway of NO production and the formation of NO by nitrite-reductase activity is not enhanced during hypokinesia. PMID- 23755555 TI - [Transformations of dinitrosyl iron complexes in an isolated rat heart after introduction of this substance into perfusion medium]. AB - The objective of the present research was to study transformations of various physiological NO forms in an isolated rat heart, perfused with the medium, containing dinitrosyl iron complexes with glutathione ligand (DNIC-GH). We showed that such aerobic perfusion resulted in accumulation of mostly diamagnetic NO physiological forms (S-nitrosothiols) in myocardial tissue. They were transformed into protein-bound mononuclear dinitrosyl iron complexes during subsequent total ischemia. Meantime, DNIC-GH injection on the onset of ischemia resulted in the changes in the state of mitochondrial respiratory state, characterized by the increase in myocardial concentration of flavosemiquinones. PMID- 23755556 TI - [Electron paramagnetic resonance study of blood of anemic patients with urological cancer]. AB - Changes in Fe(3+)-transferrin (Fe(3+)-Tf) and Cu(2+)-ceruloplasmin (Cu(2+)-Cp) concentrations in venous blood sampled from anemic patients with urinary bladder and kidney cancer in I-IV stages were investigated using electron paramagnetic resonance spectroscopy. It was established that at malignancy-associated anemia the paramagnetic Fe3+ ion concentration in transferrin is below a norm, while in anemic non-oncology patients the Tf iron saturation is normal. Moreover, in patients with malignancy-associated anemia the Cu(2+)-Cp average value is nearly twice as large as that for healthy volunteers (confidence probability P). It was shown that simultaneous EPR measuring of paramagnetic centers (such as Fe(3+)-Tf and Cu(2+)-Cp) in blood of anemic patients can be used as a biomarker for urological cancer diagnosis even at early stages of the growth of a malignant tumor. PMID- 23755557 TI - [Introduction of dinitrosyl iron complexes with thiol-containing ligands into animal organism by inhalation method]. AB - The possibility of water-soluble dinitrosyl iron complexes (DNIC) with thiol containing ligands introduction into lungs and other tissues of mice by free inhalation of little drops (2-3 microns diameter) of the solutions of these complexes was investigated. Little drops of 2-20 mM solutions of the complexes were obtained by using an inhalation apparatus (compressor nebulizer). A cloud of these little drops was then inhaled by animals in a closed chamber. A maximal amount of protein-bound DNICs formed in mouse lungs was 0.6 micromoles per kilogram of tissue weight. The amount of DNIC in lungs, liver and blood decreased to the undetected level within 2-3 hours after inhalation. No cytotoxic effect of DNIC formed in lungs on Mycobacterium tuberculosis was found in mice infected with these mycobacteria. PMID- 23755558 TI - [Dinitrosyl iron complexes with glutathione recover rats with experimental endometriosis]. AB - The effect of binuclear dinitrosyl iron complexes (DNIC) with glutathione on endometrioid tumors in rats with experimental endometriosis has been studied. The latter was induced by an autotransplantation model, where two fragments of endometrium with myometrium (2 x 2 mm) from the left uterine horn was grafted to the inner surface of the anterior abdominal wall. The test animals received intraperitoneal injections of 0.5 ml DNIC-glutathione at the dose of 12.5 micromole per kg daily for 12 days 28 days after operation. The injections resulted in more than a 2-fold decrease in the total volume of both large tumors formed from grafts and small additive tumors formed nearby grafts. The disappearance of the additive tumors was also observed in test animals. The EPR signal with g(av) = 2.03 characteristic of protein bound DNIC with thiol containing ligands was recorded in livers, graft and additive tumors of test and control animals pointing out intensive generation of nitric oxide in rats with experimental endometriosis. Ribonucleotide reductase activation discovered by doublet the EPR signal at g = 2.0 with 2.3 mT hyperfine structure splitting was found in small tumors. The cytotoxic effect of DNIC-glutathione on endometrioid tumors was suggested to be due to DNIC degradation nearby the tumors induced by iron chelating compounds released from the tumors. The degradation resulted in release of a high amount of nitric oxide molecules and nitrosonium ions from DNICs affecting the tumors by way of the cytotoxic effect. PMID- 23755559 TI - [Biophysical methods of ecological monitoring. Photosynthetic characteristics of tree plants growing in Moscow city]. AB - In this work, we studied an influence of ecological factors (a distance from the highway) on photosynthetic characteristics of leaves of four species of tree plants growing in Moscow city. Photosynthetic activity of leaves was assayed by instrumental methods of probing the functional state of photosynthetic apparatus, using electron paramagnetic resonance method for measuring the kinetics of photooxidation of P700 centers, thermoluminescence, and slow induction of chlorophyll fluorescence. It has been shown that kinetic parameters of the induction curves, as measured from the kinetics of photooxidation of P700 and slow induction of chlorophyll fluorescence in dark-adapted leaves, are sensible to variations of plant growing conditions. These parameters can be used as informative characteristics for ecological monitoring of the environment. PMID- 23755560 TI - [Luminescence characteristics of strawberry leaves in early stages of their injury by arachnoidal mite]. AB - In this work, we have investigated how the luminescence characteristics and a total content of antioxidants in leaves of strawberry (Fragaria x ananassa Duch.) change after infestation of plants by spider mite (Tetranychus atlanticus McGregor). At the earlier stage of plant injury, the chlorophyll concentration remained unchanged. However, the total amount of antioxidants decreased and the intensity of high-temperature band (60 divided by 100 degrees C) of thermoluminescence increased, indicating a degradation of membrane lipids caused by oxidative stress. In infected leaves, the light-induced rise of non photochemical quenching of chlorophyll fluorescence was slower, while the relaxation of non-photochemical quenching in the dark was faster than in control samples of leaves. These data might indicate that the thylakoid membranes in infested leaves were more permeable for ions than in control leaves. PMID- 23755561 TI - [Biomonitoring of indicator species of lichen by EPR spectroscopy]. AB - EPR spectroscopy is beginning to occupy a key position in the field of quality control environment. The analysis of the number of paramagnetic centers in the thallus of indicator species of lichen (in a tolerant and sensitive species) was carried out. The number of paramagnetic centers in the lichen thallus was found to depend on the intensity of human impact on habitats of the species studied and their taxonomic affiliation. Possible mechanisms of resistance to atmospheric pollution for tolerant species df lichens were discussed. PMID- 23755562 TI - [Long-period endogenous oscillations in fish population size: mathematical modeling]. AB - We present a mathematical model of an aquatic community, where the size-and-age structure of hydrobiont populations is taken into account and the corresponding trophic interactions between zooplankton, peaceful fish and predatory fish are described. We show that the interactions between separate components of the aquatic community can lead to long-period oscillations in fish population size. The period of these oscillations is of the order of dozen years. With the use of the model we show also that an increase in the zooplankton growth rate can be followed by a set of the fish population dynamical bifurcations: stationary states --> regular oscillations --> quasicycles --> the dynamical chaos. PMID- 23755563 TI - [Mechanistic model for the allee effect and interference in predator population]. AB - Simulation results obtained with an individual-based model describing spatial movement and interactions of predators and prey within a closed rectangular habitat are represented. Movement of each individual animal is determined by local conditions only, thus any collective behaviour emerges due to self organization. It is shown that the pursuit of the prey by predators leads to the emergence of predator interference manifesting itself at the population level as the dependence of the trophic function on predator abundance (predator dependence). The stabilizing effect of predator dependence on the dynamics of a predator-prey system has been discussed. The inclusion of prey evasion induces predators' cooperation that further distorts the functional response (the trophic function), leading to a strong Allee effect, i.e. extinction of predator population dropping below a critical threShold. Thus, we propose a simple mechanistic explanation of important but still poorly understood behavioural phenomena that underlie functioning of natural trophic systems. PMID- 23755564 TI - [Fractality, "coast line of the universe", movement of the earth and "macroscopic fluctuations"]. AB - The evolution of views on the nature of "macroscopic fluctuations" phenomenon, discovered about sixty years ago as an "anomalous scattering of results" of actomyosin enzyme activity measurement, is traced in the paper. Ever since the general character of this phenomenon was stated because it was found in measurements of processes of different nature and caused by movement of the Earth in heterogeneous and anisotropic space-time. The paper is dedicated to the memory of L.A. Blumenfeld: a many-decade discussion with him favoured these investigations. PMID- 23755565 TI - [Fractal dimension and histogram method: algorithm and some preliminary results of noise-like time series analysis]. AB - In the present work a methodological background for the histogram method of time series analysis is developed. Connection between shapes of smoothed histograms constructed on the basis of short segments of time series of fluctuations and the fractal dimension of the segments is studied. It is shown that the fractal dimension possesses all main properties of the histogram method. Based on it a further development of fractal dimension determination algorithm is proposed. This algorithm allows more precision determination of the fractal dimension by using the "all possible combination" method. The application of the method to noise-like time series analysis leads to results, which could be obtained earlier only by means of the histogram method based on human expert comparisons of histograms shapes. PMID- 23755566 TI - Preparation and biomedical applications of gold-coated magnetic nanocomposites. AB - Gold-coated magnetic nanocomposites with unique physical and chemical properties have recently been subjected to extensive researches since the gold shells could improve their biocompatibility, functionality and stability further, which endue them with great application potentials in various fields. Several main approaches have been studied for the synthesis of gold-coated magnetic nanocomposites, including microemulsion, sonochemical synthesis, self assembly, seed-mediated growth method, and laser irradiation. This review is focused on describing various strategies for the preparation of gold-coated magnetic nanocomposites. Furthermore, we also introduce main applications of gold-coated magnetic nanocomposites in biomedical fields and point out some challenges in the synthesis of high-quality gold-coated magnetic nanocomposites. PMID- 23755567 TI - Surface tunable polymersomes loaded with magnetic contrast agent and drug for image guided cancer therapy. AB - Polymersomes with different surface charges were synthesized from polysuccinimide (p) by introducing positively charged polyethylenimine (PEI-P), neutrally charged polyethylene glycol (PEG-P), and negatively charged glycine (GLY-P) to the polymer backbone polysuccinimide (P). Then, the polymersomes were prepared with super paramagnetic iron nanoparticles (SPIONs) to obtain PEI-P encapsulating SPIONs (PEI-PS), PEG-P encapsulating SPIONs (PEG-PS), and GLY-P encapsulating SPIONs (GLY-PS), respectively. The average particle sizes of GLY-PS, PEG-PS, and PEI-PS were analyzed by dynamic light scattering, and it was around 163.nm, 105 nm, and 285 nm, respectively. The surface charges of GLY-PS, PEG-PS, and PEI-PS was found to be -29.5, -18.9, and +44, respectively. The presence of PEI, PEG, and GLY in the polymer backbone was confirmed with nuclear magnetic resonance (NMR). The GLY-PS, PEG-PS, and PEI-PS were loaded with the anticancer drug paclitaxel during the preparation. The drug release from the PEG-PS was faster compared to GLY-PS and PEI-PS. An in vivo hemi-spleen mouse metastatic liver model was established and imaged with MRI after intravenous administration of GLY PS, PEG-PS, and PEI-PS. From the T2-weighted imaging, it was evident that PEG-PS accumulated in the spleen and liver more efficiently than the other charged formulations of GLY-PS and PEI-PS. From this study, the nanoparticle-based delivery and imaging of anti-cancer drugs could be effectively demonstrated simultaneously. PMID- 23755568 TI - Preparation and characterization of nano-hydroxyapatite nanomaterials for liver cancer cell treatment. AB - Nano-hydroxyapatite was synthesized by means of the hydrothermal treatment. The effects of nano-hydroxyapatite material on the behaviour of G2 liver cancer cells were explored. About 50% of cell viability was lost in nHAp material treated cells at 200 degrees C @ 5 h, followed by -30% in nHAp treated cells at 100 degrees C @ 5 h. Compared with control, nHAp material treated cells at 200 degrees C @ 5 h showed 60% and nHAp material treated cells at 100 degrees C @ 5 h showed 15% morphological change. Moreover, 50% of cell death was observed at 24 h incubation with nHAp material treated at 200 degrees C @ 5 h cells and 56% cell death at 48 h incubation and hence alters and disturbs the growth of cancer cells. In contrast, the nHAp material treated at 100 degrees C @ 5 h protects the cells and could be used for liver cancer cell treatment. PMID- 23755569 TI - Fabrication and photocatalytic properties of self-assembled in(OH)3 and In2O3 nano/micro-cubes. AB - This article reports a novel fabrication method for In(OH)3 from indium oxalate by hydrothermal process. Hydrothermal decomposition of indium oxalate at 180 degrees C for 10 h results in In(OH)3. The influence of hydrothermal experimental conditions such as temperature, time on the formation of indium hydroxide was investigated. The self-assembly process was strongly influenced the experimental conditions. The thermal decomposition of In(OH)3 at 400 degrees C results In2O3. The synthesized In(OH)3 and In2O3 were characterized using X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), high resolution transmission electron microscopy (HR-TEM), thermal analysis (TGA and DTA), diffuse reflectance spectra (DRS), and nitrogen adsorption analysis. The XRD patterns indicated the formation of well crystallized cubic phase In(OH)3 and In2O3. The FE-SEM results indicated formation of In(OH)3 and porous In2O3 nano/micro-cubes. The photocatalytic activity of the synthesized In(OH)3 was studied under UV light irradiation and results showed that the In(OH)3 photocatalyst was efficient for dye degradation. We proposed a plausible mechanism for the formation of In(OH)3, and In2O3 self-assembly. PMID- 23755570 TI - Bio-synthesis of gold nanoparticles using English ivy (Hedera helix). AB - Gold nanoparticles (AuNPs) have drawn significant interest in recent years due to unique properties that make them advantageous in biomedical applications, including drug delivery and tissue engineering. In this paper, we have developed multiple methods for the synthesis of AuNPs using English ivy as the substrate. In the first method, we have used actively growing English ivy shoots to develop a sustainable system for the production of ivy nanoparticles. The second method was developed using the extract from the adventitious roots of English ivy. The nanoparticles formed using both methods were compared to determine the size distribution, morphology, and chemical structure of the nanoparticles. Characterization of the AuNPs was conducted using ultraviolet-visible (UV-Vis) spectroscopy, dynamic light scattering (DLS), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDS). In addition to the structural differences between the AuNPs formed from the different methods, details of the methods in terms of yield, duration, and speed of AuNP formation are also discussed. Further, this paper will show that AuNPs formed using both methods demonstrated efficient uptake in mammalian cells, which provides the potential for biomedical applications. The two methods developed through this research for eco-friendly synthesis of AuNPs present an alternative to traditional chemical synthesis methods. PMID- 23755571 TI - In vivo interaction of gold nanoparticles after acute and chronic exposures in experimental animal models. AB - With emerging use of gold nanopaticles (GNP) in biomedical science now concern lies upon the fact that how this nonanparticles interact with biological systems both in vivo and in vitro. In this study effects of GNP (50 nm) were investigated in animal models after acute and chronic exposure. For acute studies GNP was administered intravenously at three doses and urine and blood samples were collected for urinary and haematological analysis at regular time intervals. For chronic studies GNP was administered intra-peritoneally at two dose levels and urine, blood, serum and tissue samples were collected for urinary, haematological, serum biochemical and histo-pathological analysis at regular intervals. Acute exposure revealed significant increase in WBC count at all the three dose levels and significant dose-dependent increase in RBC count and Hb%. Chronic exposure at 2 mg/kg dose level showed high toxicity. Significant changes in physical, morphological, WBC count and Hb% were observed after chronic exposure for multiple days. Histo-pathological studies indicated detrimental tissue histological changes in chronic animal models. Therefore, the above studies indicate that both acute and chronic GNP exposure exhibits potential physiological changes within animal system. PMID- 23755572 TI - Tin oxide quantum dot based DNA sensor for pathogen detection. AB - We report the application of nano crystalline tin oxide quantum dots (SnO2-QDs) for electrochemical detection of Vibrio cholerae based on DNA hybridization technique. SnO2-QDs (- 1-5 nm) have been synthesized by laser ablation technique in liquid (LAL) and electrophoretically deposited onto hydrolyzed surface of indium tin oxide (ITO) coated glass electrode. A single stranded oligonucleotide probe (23 bases) have been designed form the virulent gene sequence of V. cholerae and has been immobilized onto SnO2-QDs/ITO surface for the fabrication of ssDNA/SnO2-QDs/ITO bioelectrode and these bioelectrode have been further used for DNA hybridization (dsDNA/SnO2-QDs/ITO). The electrochemical response studies have been carried out with different concentration genomic DNA (100-500 ng/microL), which indicated that SnO2 provides an effective surface to bind with the phosphate group of DNA, thus resulting in an enhanced electron transport. The hybridized electrode exhibits linear response with regression coefficient (R) 0.974, high sensitivity 35.20 nA/ng/cm2, low detection limit (31.5 ng/microL), faster response time (3 s) and high stability of 0-120 days when stored under refrigerated conditions. PMID- 23755573 TI - Surface phenomena of hydroxyapatite film on the nanopore formed Ti-29Nb-xZr alloy by anodization for bioimplants. AB - In this study, surface phenomena of hydroxyapatite (HA) film on the nanopore formed Ti-29Nb-xZr alloy by anodization for bioimplants have been investigated by electron beam physical vapor deposition (EB-PVD), field emission scanning electron microscope (FE-SEM), X-ray diffractometer (XRD), potentiostat and contact angle. The microstructure of Ti-29Nb-xZr alloys exhibited equiaxed structure and alpha" phase decreased, whereas beta phase increased as Zr content increased. The increment of Zr contents in HA coated nanotubular Ti-29Nb-xZr alloys showed good corrosion potential in 0.9% NaCI solution. The wettability of HA coated nanotubular surface was higher than that of non-coated samples. PMID- 23755574 TI - Development and evaluation of a paramagnetic nanoparticle based immunochromatographic strip for specific detection of 2009 H1N1 influenza virus. AB - Influenza A/H1N1 virus spreads worldwide and has been a threat to human health and the poultry industry. Although H1N1 lateral-flow immunoassay strips are available for the detection of 2009/A/H1N1 antigens, the specificity and sensitivity of these strips are limited. Because of the monodispersity, the strong magnetic signal and the stable brown color of superparamagnetic nanoparticles, which were employed in this study as label instead of commonly used colloidal gold particles. Two different monoclonal anti-HA (hemagglutinin) and anti-HA-tag mAbs were paired for conjugating with paramagnetic beads and immobilizing on the surface of nitrocellulose (NC) membrane as capture antibody respectively. After optimizing the experimental condition, we generated a superparamagnetic bead-based immunochromatographic strip. The strip could detect HA antigen from H1N1 influenza A virus sample sensitively, its detection limit was 100 pg/mL. It had low cross reactivity with H3N2 influenza A virus and did not detect influenza B virus. It had no false positive detection in all of the tested control samples. With the help of magnetic assay reader (MAR), the magnetic intensity on test lines could be recorded and quantified proportionally with the amount of antigens captured. Those properties were indeed superior to the colloidal gold-based strips. More importantly, the strip was affordable and easy to use. Conceivably, superparamagnetic bead-based immunochromatographic strip should be a valuable point-of-care test for the rapid and specific detection of influenza A virus. PMID- 23755575 TI - Enhanced attachment of human osteoblasts on NH3-treated poly(L-lactic acid) membranes for guided bone regeneration. AB - Barrier membranes for guided bone regeneration (GBR) were prepared by a solvent casting method using solutions of poly(L-lactic acid) (PLLA) and chitosan. PLLA and PLLA/chitosan membranes were treated with ammonia gas plasma. PLLA/chitosan membranes were successfully fabricated, and the surface of the PLLA/chitosan membrane was clearly modified by NH3 plasma treatment according to attenuated total reflectance (ATR-FTIR), X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM) analyses. Additionally, water contact angle testing indicated that the hydrophilicity of these membranes was significantly increased. MG-63 cells were cultured on each type of membrane, and cell viability was examined using an MTT assay. After one week of culturing, MG-63 cells were more abundant on PLLA/chitosan membranes than on PLLA membranes. The cell viability of PLLA/chitosan membranes with plasma treatment was significantly higher than that of PLLA membranes. These results suggest that this plasma-treated membrane is suitable for GBR and is a promising source of bioactive membrane material for bone regeneration. PMID- 23755576 TI - Surface modification and bioactivity of anodic Ti6Al4V alloy. AB - The present study deals with surface modification of Ti6Al4V alloy via anodization technique. The morphology, structure, adhesion and bioactivity of Ti6Al4V alloy after anodization process were investigated in detail. The influence of fluoride content and direct circuit (DC) applied voltage during anodization of Ti6Al4V alloy in a bath with electrolytes composed of ethylene glycol (EG) and ammonium fluoride (NH4F) were considered. It was found that the average pore sizes and length of nanoporous or nanotubes were increasing with the fluoride content and applied voltage. A minimum of 3 wt% of NH4F is required to grow a self-organized nanotube arrays. As the fluoride content was increased to 5 wt%, TiO2 nanotubes with average diameter of 110 nm and 3.4 microm lengths were successfully synthesized. It is noteworthy to point out that the rate of the nanotube formation was increasing up to 9 microm thick bioactive TiO2 nanotubes layer as anodization time was increased to 3 h. Based on the results obtained, the PA6 cells cultured on anodic Ti6Al4V alloy showed highest level of cell viability and greater cell adhesion compared to the flat Ti6Al4V foil substrate. In fact, highly ordered nanotubes structure on Ti6Al4V alloy can provide beneficial effects for PA6 cells in attachment and proliferation. PMID- 23755577 TI - Surface observation of nanotube/micropit formed Ti-Nb-xZr alloy for biocompatibility. AB - To improve bone tissue integration on implant surfaces, nanotube formation and laser texturing techniques have been used to increase the roughness of the implant surfaces. In this study, surface film of nanotube/micropit formed Ti-3ONb xZr and Ti-30Ta-xZr alloy with low elastic modulus have been investigated using field emission scanning electron microscope (FE-SEM) and energy dispersive X-ray spectroscope (EDS). The alloying elements can play role in controlling the nanotube shape and micropit shape, the highly ordered nanostructure, and contact angle for biocompatibility. PMID- 23755578 TI - Preparation and characterization of glucose oxidase nanoparticles and their application in dissolved oxygen metric determination of serum glucose. AB - The nanoparticle (NP) aggregates of commercial glucose oxidase (GOD) from A. niger with 117 nm diameter, were prepared by desolvation method. The formation and characterization of GOD-NP aggregates was studied by UV, transmission electron microscopic (TEM) and Fourier transform infrared (FTIR) spectra. GOD-NP aggregates were more stable, active and had a higher shelf life than that of free enzyme. These GOD-NP aggregates were immobilized onto chitosan activated nitrocellulose (NC) membrane through glutaraldehyde coupling with 55.15% retention of initial activity of free enzyme and 5.9 microg protein/cm2 yield. The membrane bound GOD-NP aggregates showed optimum response within 60 s, at pH 6.0, temperature range 30-45 degrees C with a peak at 35 degrees C and a hyperbolic relationship with glucose upto 250 mg/dl. Apparent K(m) and V(max) were 75 mg/dl and 0.06 mg/l respectively. The NC membrane bound GOD-NP aggregates were employed for dissolved O2 (DO) metric determination of serum glucose in apparently healthy and diabetic adults. The present method of serum glucose determination was evaluated. PMID- 23755579 TI - Preparation, characterization and antibacterial activity of poly(epsilon caprolactone) electrospun fibers loaded with amoxicillin for controlled release in biomedical applications. AB - Amoxicillin (AMOX) was successfully encapsulated at different concentrations into poly(epsilon-caprolactone) (PCL) by the electrospinning technique, and mats of non-woven fibers were obtained and characterized in terms of morphology, in vitro release and antibacterial properties. The scanning electron microscopy evidenced the nanofibrous structure of the pristine PCL, composed of individual, uniform, and randomly oriented fibres with an average diameter ranging around 0.8 micron. The addition of amoxicillin at different concentrations (3, 5 and 7 wt%) did not evidence change in the fiber morphology. The release curves, for all samples, present mainly two stages: a first stage, quick as a "burst," is followed by a second slow stage. The burst was analyzed as a function of amoxicillin concentration and thickness of the membranes, and values corresponding to absence of burst were individuated. In the second stage the release was found very slow extending up to months for the most concentrated sample. The antibacterial activity of the electrospun fibers was effective to inhibit in different proportions Staphylococcus aureus, Enterococcus faecalis and Escherichia coli. The properties of the filled membranes and their capability for local delivery of antibiotics make them suitable for biomedical applications. PMID- 23755581 TI - Polarity reversion of the operation mode of HfO2-based resistive random access memory devices by inserting Hf metal layer. AB - The reversion of polarity within bipolar resistive switching operation occurs in Pt/HfO2/TiN and Pt/Hf/HfO2/TiN resistive random access memory devices. This reversion of voltage polarity is the result of interface generation which induces a conduction mechanism transformation from Poole-Frenkel emission to space charge limited current mechanism. To prove the reversion of polarity, this study uses curve fitting of I-V relations to verify the conduction mechanism theoretically and physical analysis to verify the oxygen ion distribution practically. The proposed Pt/Hf/HfO2/TiN devices exhibit good resistive switching characteristics, such as good uniformity, low voltage operation, robust endurance (10(3) dc sweep), and long retention (3 x 10(4) s at 85 degrees C). PMID- 23755580 TI - Liposomes composed of dioleoylphosphatidylethanolamine and 2 (hexadecyloxy)cinnamic acid: effects of UV irradiation and pH value on release. AB - Novel liposomes composed of dioleoylphosphatidylethanolamine (DOPE) and 2 (hexadecyloxy) cinnamic acid (HOCA) were prepared by a detergent removal method. When the molar ratio of DOPE to HOCA was 4:1, 3:2, and 2:3, the florescence quenching degree of 5(6)-carboxylic fluorescein (CF, a fluorescence marker) loaded in the assemblies was 62.4%, 68.9%, and 72.5%, respectively. The quenching degree was fairly high, indicating the assemblies were closed bilayer vesicles (liposomes). The release degree in 60 min of CF from the DOPE/HOCA liposomes was 9.6% to 15.7%, when the liposomes were subjected to the irradiation of a UV light (e.g., lambda = 254 nm). The photo-dimerization of the cinnamic acid residue of HOCA may destabilize the liposomal membrane, leading to a significant release. In addition, DOPE/HOCA (4/1) liposome exhibited a pH-sensitive release. It showed almost 100% of release degree in a few seconds under an acidic condition (e.g., pH 5.0), but it was stable at neutral and alkali conditions. PMID- 23755582 TI - Reduction of gate leakage current on AlGaN/GaN high electron mobility transistors by electron-beam irradiation. AB - This study examined the effect of electron-beam (E-beam) irradiation on the AIGaN/GaN HEMTs for the reduction of gate leakage. After E-beam irradiation, the gate leakage current significantly decreased from 2.68 x 10(-8) A to 4.69 x 10( 9) A at a drain voltage of 10 V. The maximum drain current density of the AIGaN/GaN HEMTs with E-beam irradiation increased 14%, and the threshold voltage exhibited a negative shift, when compared to that of the AIGaN/GaN HEMTs before E beam irradiation. These results strongly suggest that the reduction of gate leakage current resulted from neutralization nitrogen vacancies and removing of oxygen impurities. PMID- 23755583 TI - Electrical properties of magnesium incorporated zinc tin oxide thin film transistors by solution process. AB - Zinc tin oxide (ZTO) films were fabricated on SiO2/Si substrate as a function of Mg concentration (the ratio of 3 to 10 atomic%) using a spin-coating process. For the characterization of thin film transistors (TFTs), Zn0.3Sn0.70 channel TFT exhibited a higher on/off ratio compared to Zn0.5 Sn.0.5O channel TFT because the higher Sn concentration can induce more charge carriers. 3 atomic% Mg incorporated Zn0.3Sn0.7O channel TFTs showed stable electrical performances such as I(on/off) - 1 x 10(7), micro(sat) = 1.40 cm2 V(-1) s(-1), and S = 0.39 V/decade. However, 10 atomic% Mg incorporated Zn0.3Sn0.7O channel TFTs deteriorated their electrical performances due to Mg segregation. The Mg incorporated Zn0.3Sn0.7O channel TFTs effectively suppress off-current and threshold voltage change during positive gate bias stress due to their strong bonding with oxygen. PMID- 23755584 TI - Phosphorus-doped exfoliated graphene for supercapacitor electrodes. AB - Graphene, a single atom thick carbon material with high surface area and electrical conductivity provides an ideal platform for designing high performance electrochemical devices. This paper reports the synthesis of phosphorous doped graphene from reduced graphene sheets, its characterization by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy and its use for supercapacitor applications. The specific capacitance was found to be 367 Fg(-1) from electrochemical measurements. These samples show a high power density of 9 kW kg(-1) and energy density of 59 Wh kg( 1) in an aqueous electrolyte solution, which is much higher than other graphene based supercapacitors. The phosphorus-doped graphene showed a high potential for use in low cost energy storage devices. PMID- 23755585 TI - Study of the structure and electrical properties of chemically reduced graphene/polyvinyl alcohol composite films. AB - Thin films of composites of chemically reduced graphene oxide (rGO) and polyvinyl alcohol (PVA) were prepared by simple solution-mixing technique followed by filtration or evaporation. The as-obtained composite rGO/PVA films were characterized by using optical microscope, gloss meter, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The different glossiness of the upper and lower surface of the films prepared by filtration and evaporation, combined with the section SEM images indicated that the thin films have a gradient layered structure, and the distance between the layers increases from the bottom to the top surface of the thin film obtained by filtration, and decreases for the film obtained by evaporation. Such a structure gives the films anisotropic swelling and electrical conduction properties which may find practical applications in electrodes and multifunctional composites. PMID- 23755586 TI - Mechanical and electromagnetic interference shielding Properties of poly(vinyl alcohol)/graphene and poly(vinyl alcohol)/multi-walled carbon nanotube composite nanofiber mats and the effect of Cu top-layer coating. AB - We report the mechanical property and electromagnetic interference shielding effectiveness (EMI SE) of poly(vinyl alcohol) (PVA)/graphene and PVA/multi-walled carbon nanotube (MWCNT) composite nanofibers prepared by electrospinning. The metal (Cu) was deposited on the resultant PVA composite nanofibers using metal deposition technique in order to improve the mechanical properties and EMI shielding properties. The resulting PVA composite nanofibers and Cu-deposited corresponding nanofibers were characterized by field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM) and wide angle X-ray diffraction (WAXD). Tensile tests were performed on the PVA/graphene and PVA/MWCNT composite nanofibers. The tensile strength of the PVA/graphene and PVA/MWCNT composite nanofibers was found to be 19.2 +/- 0.3 MPa at graphene content - 6.0 wt% and 12.2 +/- 0.2 MPa at MWCNT content - 3.0 wt%, respectively. The EMI SE of the Cu-deposited PVA/graphene composite nanofibers was significantly improved compared to pure PVA/graphene composite nanofibers, and also depended on the thickness of Cu metal layer deposited on the PVA composite nanofibers. PMID- 23755587 TI - Amorphous carbon nanotube/MnO2/graphene oxide ternary composite electrodes for electrochemical capacitors. AB - Ternary composites of amorphous carbon nanotube/MnO2/graphene oxide (a CNT/MnO2/GO) were synthesized by a facile direct redox reaction between potassium permanganate and a-CNT, which was prepared by anodic aluminum oxide template method following co-filtration with GO. Needle-like, 100-nm-thick, MnO2 crystals were homogeneously coated on the a-CNT surface, which was then covered with GO. The electrochemical performance of the resulting MnO2-coated a-CNTs exhibited a specific capacitance of 473 F/g at a scan rate of 5 mV/s, and excellent charge/discharge stability after 500 cycles. PMID- 23755588 TI - Nanocomposites of polystyrene/polystyrene-grafted graphene oxides synthesized by in-situ bulk polymerization. AB - In this study, polystyrene-grafted graphene oxide (GO-g-PS) nanocomposites with different PS chain lengths were prepared by in-situ polymerization, and their reinforcing effect on the PS matrix was investigated. The glass transition (T(g)) and the thermal degradation (T(d)) temperatures of the PS/GO-g-PS nanocomposites were increased up to 2.8 degrees C and 23.9 degrees C, respectively. The addition of only 0.1 wt% of the GO-g-PS to the PS/GO-g-PS nanocomposites increased the tensile strength and Young's modulus by around 20.5% and 71.4%, respectively. These results showed that the thermal and mechanical properties of the PS/GO-g-PS nanocomposites gradually improved with increasing length of the PS chain grafted onto the GO surface. These differences in reinforcing effects were attributed to differences in interfacial interaction between the graphene and PS matrix. PMID- 23755589 TI - Synthesis and electrochemical properties of stannous oxide clinopinacoid as anode material for lithium ion batteries. AB - Tin monoxide is a significant functional semiconductor material which employed to a wide area of applications especially optical and energy storage devices. Presently, template free hydrothermal technique has been employing to synthesize stannous oxide (SnO) clinopinacoid type controlled morphology using SnCl2 x 2H2O, NH3, and H2O as raw materials. The crystalline phase, morphology, particle size and component were characterized by X-ray diffraction (XRD), energy-dispersive X ray spectroscopy (EDS) and field-emission scanning electron microscopy (FESEM). FESEM results exhibited the large scale homogeneous growth of clinopinacoid architecture with the obvious size of 5 - 7 micrometers. The XRD results showed that the average crystallite size of the tetragonal phase romarchite SnO was about 29 nm calculated from the FWHM of X-ray diffraction pattern. The dominant Raman active modes A(1g) = 205 cm(-1), B(1g) = 105-107 cm(-1) and about 6 cm(-1) redshift were observed by the Raman spectroscopy, which further confirmed the existence of the nano tetragonal phase SnO. The electrochemical performance of as synthesized SnO clinopinacoid structure as the anode material for lithium ion batteries was investigated. It was observed that the first discharge capacity of the two samples could reach a very high value of 1502 mA h g(-1) and 1422 mA h g( 1) respectively. The effect of nitrogen concentration on morphology as well as cyclic performance of Li-Ion-batteries was also discussed. PMID- 23755590 TI - Synthesis and characterizations of MnO2/multi-wall carbon nanotubes nanocomposites for lithium-air battery. AB - In this work, rechargeable lithium-air battery using MnO2/MWNTs nanocomposites as a catalyst was studied. MnO2/MWNTs nanocomposites were synthesized by a hydrothermal method, and their physical and chemical properties were investigated. X-ray diffraction (XRD) was used to examine crystallinity and morphology was investigated by transmission electron microscopy (TEM). Charge discharge behavior and cell impedance with electrolyte replacement were investigated, and charge-discharge capacity decreased with cycles mainly due to the decomposition of carbonate-based electrolyte. PMID- 23755591 TI - Nanocrystals encapsulated in SiO2 particles: silanization and homogenous coating for bio applications. AB - Sol-gel procedures have been developed to encapsulate inorganic nanocrystals including metallic Au and II-VI semiconductor materials (CdSe/Cd(1-x)Zn(x)S) in SiO2 particles by using tetraethyl orthosilicate. The key strategy was the control of a sol-gel procedure. The anisotropic deposition of SiO2 monomers occurs because well-developed crystal facets having different affinity to SiO2 monomers. SiO2 monomers were not homogeneously deposited on nonspherical Au and CdSe/Cd(1-x)Zn(x)S nanocrystals. A surface silanization process, partly hydrolyzed tetraethyl orthosilicate were attached to the nanocrystals instead of initial ligands, plays an important role for the nanocrystals coated homogeneously with a SiO2 layer. Furthermore, CdSe/Cd(1-x)Zn(x)S nanocrystals were homogeneously coated with a thin SiO2 layer by the surface silanization process and a subsequent reverse micelle route. Colloidal Au nanocrystals were homogeneously coated with a SiO2 shell by the surface silanization process and subsequent Stober synthesis without using a silane coupling agent or bulk polymer as the surface primer to render the Au surface vitreophilic. These results indicated partly hydrolyzed tetraethyl orthosilicate has an ability to replace the ligand on nanocrystals. After surface modification, the SiO2 particles with nanocrystals were conjugated with antibody for bioapplications. PMID- 23755592 TI - Phosphorescence white organic light-emitting diodes with single emitting layer based on isoquinolinefluorene-carbazole containing host. AB - We have demonstrated a stable phosphorescent white organic light-emitting diodes (WOLEDs) using an orange emitter, Bis(5-benzoyl-2-(4-fluorophenyl)pyridinato-C,N) iridium(III)acetylacetonate [(Bz4Fppy)2Ir(III)acac] doped into a newly synthesized blue host material, 2-(carbazol-9-yl)-7-(isoquinolin-1-yl)-9,9 diethylfluorene (CzFliq). When 1 wt.% (Bz4Fppy)2Ir(III)acac was doped into emitting layer, it was realized an improved EL performance and a pure white color in the OLED. The optimum WOLED showed maximum values as a luminous efficiency of 10.14 cd/A, a power efficiency of 10.24 Im/W, a peak external quantum efficiency 4.07%, and Commission Internationale de L'Eclairage coordinates of (0.34, 0.39) at 8 V. PMID- 23755593 TI - Effect of BaF2 on crystal structure and luminescent properties of Sr2SiO4:Eu2+ for light emitting diode lighting. AB - Divalent europium-activated strontium silicate (Sr2SiO4:Eu2+) phosphors were prepared at relatively low temperature via a conventional solid-state reaction method, in which BaF2 was used as both flux and component. The effect of BaF2 on XRD patterns and luminescent properties of Sr2SiO4:Eu2+ was investigated. BaF2 could enhance the emission intensity and change the wavelength of emission peaks. These phosphors showed yellow to green emission bands with the amounts of BaF2. With a combination of blue LED chip, these phosphors are still more efficient in the amount used than commercial phosphors when they are doped on the chips, indicating that they may become promising phosphor candidates for white LEDs. PMID- 23755594 TI - Time-resolved ultraviolet near-field scanning optical microscope for characterizing photoluminescence lifetime of light-emitting devices. AB - We developed a instrument consisting of an ultraviolet (UV) near-field scanning optical microscope (NSOM) combined with time-correlated single photon counting, which allows efficient observation of temporal dynamics of near-field photoluminescence (PL) down to the sub-wavelength scale. The developed time resolved UV NSOM system showed a spatial resolution of 110 nm and a temporal resolution of 130 ps in the optical signal. The proposed microscope system was successfully demonstrated by characterizing the near-field PL lifetime of InGaN/GaN multiple quantum wells. PMID- 23755595 TI - Double-gate junctionless transistor for analog applications. AB - In this paper, analog performance of short channel symmetric double-gate junctionless transistor (DGJLT) is reported for the first time. The analog performance parameters, namely drain current (I(D)), transconductance (G(m)), transconductance/drain current ratio (G(m)/I(D)), early voltage (V(EA)), drain output conductance (G(D)), output resistance (R(o)), intrinsic gain (G(m)R(o)), gate to source capacitance (C(GS)), gate to drain capacitance (C(GD)) and unity gain cut-off frequency (f(T)) for the n-type DGJLT are systematically investigated with the help of extensive device simulations and are compared with conventional inversion mode symmetric double-gate transistor (DGMOS) of similar dimensions. DGJLT offers superior transconductance/drain current ratio and intrinsic gain in the subthreshold region than its inversion mode counterpart having same dimensions. However, DGMOS presents higher unity gain cut-off frequency which makes it suitable for high speed applications as compared to a DGJLT transistor. PMID- 23755596 TI - N,N-(diphenylamino)fluorenylstyrene derivatives with the various heteroatom containing moieties for blue organic light-emitting diodes. AB - A series of blue fluorescent materials 1-6 based on N, N-diphenyl aminofluorene styryl derivatives with six heteroatoms (PhOPh, PhSPh, PhSePh, PhPPh2, thiophene and dibenzothiophene), were synthesized and multilayer devices were fabricated. Interestingly, the EL efficiencies were very sensitive to the structural features of dopants in the emitting layers. Particularly, by using 1 as a dopant in emitting layer, a high-efficiency blue OLED was fabricated, showing the maximum luminance of 10420 cd/m2 at 11 V, the luminous efficiency of 8.6 cd/A at 20 mA/cm2, the power efficiency of 3.4 Im/W at 20 mA/cm2 and had a blue color with the CIE coordinates of (0.147, 0.156) at 8.0 V. PMID- 23755597 TI - Structural, magnetic and dielectric properties of Ni(1_x)Zn(x)Fe2O4 (x = 0,0.5 and 1) nanoparticles synthesized by chemical co-precipitation method. AB - Ni(1-x)Zn(x)Fe2O4 (x = 0, 0.5 and 1) ferrite nanoparticles were synthesized by chemical co-precipitation method. X-ray diffraction technique and Rietveld refinement were used to investigate the structural characteristics and determination of the particle size which was found to decrease from 4.9 to 4.1 nm as a function of increasing Zn from 0 to 1.0. Vibrating sample magnetometer was used to study magnetic properties of nickel zinc ferrite nanoparticles. Field dependent magnetization measurements (M-H curve) at 300 K revealed that Zn substitutions on inverse spinel nickel ferrites enhance the magnetic properties. Magnetization as a function of temperature showed the superparamagnetic behavior of Ni(1-x)Zn(x)Fe2O4 (x = 0,0.5 and 1) nanoparticles. Dielectric permittivity and a.c. conductivity were measured as a function of frequency from 100 kHz to 1 MHz at certain temperatures. The observed response in a.c. conductivity as a function of log of frequency of these nickel zinc ferrite systems was believed to be due to the presence of Maxwell-Wagner type interfacial polarization and hopping of electron by means of quantum mechanical tunneling. PMID- 23755598 TI - Synthesis of Fe3O4-ZnS/AgInS2 composite nanoparticles using a hydrophobic interaction. AB - Magnetic nanoparticles and fluorescent quantum dots (QDs) can make many effective applications in biomedical system. Here, we demonstrated one way of synthetic method and its surface modification to use for biomedical applications. Fe3O4 nanoparticles are well known as magnetic materials and its magnetic property can be used in magnetic resonance imaging (MRI), cell detection. QDs as a fluorescent probes, make cell labeling and in vivo imaging possible. ZnS/AgInS2 QDs have a lower toxicity than other QDs (CdSe, CdTe, CdS). We combined two nanoparticles by hydrophobic interaction in their ligands. The prepared fluorescent magnetic composite particles were modified with CTAB-TEOS. The surface modified composite has a low cytotoxicity and these biocompatible particles will provide many possibilities in biomedical system. PMID- 23755599 TI - Dielectric properties of polyaniline-montmorillonite clay hybrids. AB - Polyaniline (PANI)-montmorillonite clay (MMT) hybrid (PANI-MMT) was prepared by mechanical grinding of ANI and MMT in the presence of potassium perdisulphate (KPS) followed by soaking the mass in 0.1 (M) HCI for 24 h. The formation of PANI MMT hybrid was confirmed by Fourier transform infrared spectroscopic analyses. XRD studies revealed the intercalation of PANI into two-dimensional silicate galleries of MMT HRTEM analyses indicated particle size distribution to be in the range of 40-55 nm. The real part of the dielectric constant reached values as high as 4500 at frequency - 10(2) Hz for a MMT:PANI = 1:1 weight ratio, the value decreasing with increasing frequency up to 25 kHz, and also with increasing MMT loading in the hybrids. This dispersion was indicative of the interfacial space charge polarization (Maxwell Wagner type). Grain boundary resistance and capacitance of the hybrid along with the conductivity-relaxation time for the hybrid at several PANI:MMT weight ratios were evaluated from the complex impedance plot considering the Maxwell-Wagner Two-Layered Model AC conductivity was independent of frequency in the range 0.1-1 kHz and thereafter found to rise in the range 1-25 kHz due to trapped charges. DC conductivity values of the hybrids were lower than the PANI homopolymer. PMID- 23755600 TI - Fabrication of nanosized Al2O3 coated reinforcing particle using electrostatic force. AB - Titanium carbide (TiC) particles have been coated with aluminum (Al) phase to enhance the compatibility with a metal matrix based on Al, expecting the homogenous dispersion of TiC particles into the matrix. The TiC particles were uniformly dispersed in the aqueous solution of pH 12. The aluminum nitrate as a precursor of Al phase was added to the solution dispersed with the TiC particles. The coating of Al phase onto the TiC particle was driven by the attractive force between the TiC particle with a negative charge and the Al cation in the aqueous solution. The TiC was not oxidized after heat treatment at 500 degrees C, whereas titanium dioxide peaks are detected after heat treatment at 1000 degrees C. In addition, the Al phase coated on the TiC surface was converted to amorphous alumina (Al2O3) and crystallized into alpha-Al2O3 during heat treatment at 500 and 1000 degrees C, respectively. The heat treatment condition such as atmosphere and temperature was an important factor in fabricating the reinforcing particles without degradation such as oxidation and phase transformation. The nano-sized Al2O3 coated reinforcing particles could be well fabricated using electrostatic force in the aqueous solution and by controlling the heat treatment condition. PMID- 23755601 TI - Mossbauer and magnetic studies of surfactant mediated Ca-Mg doped ferrihydrite nanoparticles. AB - Ultrafine (2-5 nm) particles of amorphous Ca-Mg co-doped ferrihydrite have been synthesized by surfactant mediated co-precipitation method. The evolution of the amorphous ferrihydrite by Ca-Mg co-doping is quite different from our earlier investigations on individual doping of Ca and Mg. Amorphous phase of ferrihydrite for the present study has been confirmed by X-ray diffraction (XRD) and Mossbauer spectroscopy at room temperature and low temperatures (40 K and 20 K). Hematite nanoparticles with crystallite size about 8, 38 and 70 nm were obtained after annealing the as-prepared samples at 400, 600 and 800 degrees C respectively in air atmosphere. Superparamagnetism has been found in 8 nm sized hematite nanoparticles which has been confirmed from the magnetic hysteresis loop with zero remanent magnetization and coercive field and also from the superparamagnetic doublet of its room temperature Mossbauer spectrum. The magnetic properties of the 38 and 70 nm sized particles have been studied by room temperature magnetic hysteresis loop measurements and Mossbauer spectroscopy. The coercive field in these hematite nanoparticles increases with increasing particle size. Small amount of spinel MgFe2O4 phase has been detected in the 800 degrees C annealed sample. PMID- 23755602 TI - Rapid synthesis and consolidation of nanostructured 4Fe-Al2O3 composite by pulsed current activated sintering. AB - Nanocrystalline 4Fe-Al2O3 composite was simultaneously synthesized and consolidated by pulsed current activated sintering (PCAS) method within 5 min from mechanically activated powders of Fe2O3 and 2FeAl. The average grain size and mechanical properties of the composite were investigated. The average grain sizes of Fe and Al2O3 prepared by PCAS were about 75 nm and 54 nm, respectively. The average hardness and fracture toughness values obtained were 770 kg/mm2 and 9.3 MPa x m1/2, respectively. PMID- 23755603 TI - Synthesis and optical characterization of SrHfO3 nano-crystals synthesized by using the combustion method. AB - We synthesized SrHfO3 nano-crystals (NCs) by using the combustion method, and investigated their emission property using 325 nm photo-excitation. The as-grown SrHfO3 NCs were annealed at different temperatures from 700 degrees C to 1450 degrees C. The X-ray diffraction analysis revealed that all the samples are of a single phase, and the grain size increases with the higher temperature annealing. Interestingly, it is found that in contrast to the bulk case, the SrHfO3 NCs show a strong blue emission even at room temperature. The strong dependence of the visible emission on annealing temperatures and grain sizes indicated that the effects of grain size and oxygen vacancies may play a role in forming the observed visible emission band for SrHfO3 NCs. We also compare our findings with the case of similar material, SrZrO3. PMID- 23755604 TI - Room temperature ferromagnetism in Fe-doped CuO nanoparticles. AB - The pure and Fe-doped CuO nanoparticles of the series Cu(1-x)Fe(x)O (x = 0.00, 0.02, 0.04, 0.06 and 0.08) were successfully prepared by a simple low temperature sol-gel method using metal nitrates and citric acid. Rietveld refinement of the X ray diffraction data showed that all the samples were single phase crystallized in monoclinic structure of space group C2/c with average crystallite size of about 25 nm and unit cell volume decreases with increasing iron doping concentration. TEM micrograph showed nearly spherical shaped agglomerated particles of 4% Fe-doped CuO with average diameter 26 nm. Pure CuO showed weak ferromagnetic behavior at room temperature with coercive field of 67 Oe. The ferromagnetic properties were greatly enhanced with Fe-doping in the CuO matrix. All the doped samples showed ferromagnetism at room temperature with a noticeable coercive field. Saturation magnetization increases with increasing Fe-doping, becomes highest for 4% doping then decreases for further doping which confirms that the ferromagnetism in these nanoparticles are intrinsic and are not resulting from any impurity phases. The ZFC and FC branches of the temperature dependent magnetization (measured in the range of 10-350 K by SQUID magnetometer) look like typical ferromagnetic nanoparticles and indicates that the ferromagnetic Curie temperature is above 350 K. PMID- 23755605 TI - Microbially induced synthesis of cubic and hexagonal selenium nanoparticles. AB - Nanobiotechnology represents an economic alternative for chemical and physical methods of nanoparticles formation. The objectives of this study were to synthesize selenium nanoparticles by microbial processes using anaerobic metal reducing bacteria as well as to characterize mineralogical properties of the nanoparticles. The selenium nanoparticles were about 200 nm in size and ball shaped. Microbial processes for elemental selenium synthesis may be useful for recovery of natural selenate in the natural environments and immobilization of selenium isotope in the high level nuclear waste disposal sites. PMID- 23755606 TI - Effect of Ce3+ and Pd2+ doping on coral-like nanostructured SnO2 as acetone gas sensor. AB - SnO2 nanocrystals with coral-like porous structure were prepared with sol-gel method combining with an annealing process. The crystallite size and structure of SnO2 were characterized with X-ray diffraction and scanning electron microscope. The average coral-like nanostructrured SnO2 crystallite size is about 13 nm. The acetone gas sensors were obtained by sintering the mixture of coral-like porous nanostructured SnO2 and PdCl2, Ce(NO3)3 respectively. The acetone gas sensing properties of the mixed solid powder were measured by the commercial gas-sensing measurement system. Pd-doped sensors show decreased sensitivity to acetone, compared to that of the undoped sensor. On the other hand, the sensor based on 0.5 mol% Ce-doped shows the highest response to acetone at 190 degrees C. It exhibits a good linear relationship with the acetone concentration (10 - 1000 ppm) in logarithmic forms, which can provide potential applications for acetone detecting. PMID- 23755607 TI - Annealing effect on the microstructure and electrochemical properties of Fe2O3/H TiNT/FTO thin film. AB - A layer of titanate nanotubular (H-TiNT) particles between Fe2O3 film and FTO substrate was inserted and heat-treated to improve electrochemical property of Fe2O3 for water splitting. Heat-treatment of the synthesized F2O3/H-TiNT/FTO thin film was found to significantly affect photoelectrochemical properties of the film through electrochemical impedance analysis. The film showed larger oxidation reduction peaks of I-V characteristics and capacitive properties under UV-Vis light illumination with heat treatment temperatures during transformation of H TiNT into anatase TiO2 phase. The overall results showed an appropriate heat treatment was a promising way to improve the electrochemical property of the photoanode film. PMID- 23755608 TI - A novel synthetic method of Sr2Si5N8:Eu2+ from SrSi2O2N2:Eu2+ by carbo-thermal reduction and nitridation. AB - We demonstrated a novel synthetic route from Eu(2+)-doped oxy-nitride phosphors to prepare Eu(2+)-doped nitride phosphors. The Eu(2+)-doped Sr2Si5N8 phosphor was prepared by carbo-thermal reduction and nitridation from Eu(2+)-doped SrSi2O2N2 mixed with carbon. Eu(2+)-doped SrSi2O2N2 phosphor was prepared at 1350-1500 degrees C, and subsequently Eu(2+)-doped Sr2Si5N8 phosphor was synthesized at 1550-1700 degrees C. When over 4 wt% of carbon was added, the phase of SrSi2O2N2:Eu2+ changed to the one of Sr2Si5N8:Eu2+. The data of photoluminescent spectra and X-ray powder diffraction (XRD) patterns proved the phase transition. The product showed a red emission of 616 nm at the blue excitation of 450 nm. The shape of phosphor changed from a plate type to a rod one. We also prepared some red phosphors of SrSi(x)O(o)N(n):Eu2+ according to the different ratio of Si. Although the Si content was different from each other, there was no change in XRD patterns. PMID- 23755609 TI - A study on the fabrication of nanostructures with high aspect ratio and large area uniformity. AB - Nanoimprint lithography (NIL), as a promising next generation lithography method, has the advantages of high throughput, sub-10-nm feature and low cost. However, the requirements, such as the structure with high aspect ratio, large area uniformity, and pattern transfer on nonflat surface, have barely been satisfied at the same time. In this study, the authors present a novel fabrication process by introducing a three-mask-layer (TML) Soft UV NIL technique which proves to be a simple and effective method. The initial mold with low aspect ratio can guarantee the imprint uniformity on large area under a high pressure in NIL. Meanwhile, high aspect ratio structure can be easily obtained due to a high etching selectivity of SiO2 to resist in O2 plasma dry etching. Using the proposed technique to fabricate 40 nm gratings with the aspect ratio as high as 6 is proved successful. Uniform photonic crystal (PC) structures with micrometer scale nonflat steps are obtained on large area. The photoluminescence enhancements of the PC light-emitting diode (LED) fabricated by the proposed method to the one with conventional process and un-patterned LED are 1.6 fold and 2.2 fold, respectively. PMID- 23755610 TI - Surface morphology of highly ordered nanotube formed and laser textured beta titanium alloys. AB - The aim of the present study is to produce and characterize a well-controlled surface texture on Ti-35Nb-xHf alloys to promote osseointegration. Ti-35Nb-xHf (x = 0, 3, 7 and 15 wt.%) alloys were prepared by arc melting and heat treated for 12 hr at 1000 degrees C in an argon atmosphere and then water quenching. For surface texturing, an amplified Ti: sapphire laser system was used for generating 184 femtosecond (FS, 10(-15) sec) laser pulses with the pulse energy over 30 mJ at a 1 kHz repetition rate with a central wavelength of 800 nm. The nanotube formation was achieved by anodizing a Ti-35Nb-xHf alloy in H3PO4 electrolytes containing 0.8 wt.% NaF at room temperature. The surface morphology of nano/micro structure will enhance osseointegration and cell adhesion. PMID- 23755611 TI - Orientation-dependent local structural properties of Zn(1-x)Mg(x)O nanorods studied by extended X-ray absorption fine structure. AB - The orientation-dependent structural properties of Zn(1-x)Mg(x)O nanorods with different Mg concentrations were investigated quantitatively using polarization dependent extended X-ray absorption fine structure (EXAFS) measurements at the Zn K edge. Vertically-aligned Zn(1-x)Mg(x)O nanorods were synthesized on Si substrates using catalyst free metal organic chemical vapor deposition. Polarization-dependent EXAFS measurements showed that Mg ions mainly occupied the Zn sites of the nanorods. EXAFS revealed that the distance between Zn-Mg pairs in all directions is - 0.2 angstroms shorter than that of Zn-Zn pairs and that there is a substantial amount of disorder in the Mg sites of the nanorods, independent of Mg concentrations. PMID- 23755612 TI - Low cost fabrication of a superhydrophobic V-grooved polymer surface. AB - Engineering of polymer surfaces to control their wetting properties has shown a wide range of potential applications. In this paper we show low cost fabrication of a superhydrophobic polymer surface via a hierarchical combination of hot embossing, O2 reactive ion etching (RIE) and deposition of a hydrophobic silane. The hot embossing and O2 RIE were used to produce respective micro and nanoscale surface roughness which is a requirement for obtaining superhydrophobic surfaces, while the deposition of a hydrophobic silane modified surface chemistry. In order to increase the water/air interface in the Cassie-Baxter composite wetting model, a brass mold with microscale V-grooves was used for hot embossing. Images of droplets in both static water contact angles and dynamic impact tests with the surface clearly show that the wetting state follows the Cassie-Baxter wetting model. The results of this study indicate that our design of the dual level surface roughness and the fabrication process allow for low cost and easy production of a highly superhydrophobic surface. PMID- 23755613 TI - Effect of anodic aluminum oxide template imprinting on TiO2 blocking layer of flexible dye-sensitized solar cell. AB - In this paper, we have proposed a new flexible dye-sensitized solar cell (DSSC) structure that employs an Anodic Aluminum Oxide (AAO) template imprinted TiO2 blocking layer, in which the AAO template creates TiO2 nano-particle aggregated islands on the TiO2 blocking layer. The TiO2 blocking layer prevents charge recombination between the metal foil and the liquid electrolyte. TiO2 nano particle aggregated islands improve the scattering of incident light during back illumination and provide the wider surface area, yielding enhanced power conversion efficiency (PCE). All the flexible DSSC structure with TiO2 nano particle aggregated islands on the TiO2 blocking layer exhibited higher photocurrent than did conventional DSSC because light that passed through the photoanode was scattered, thereby giving it improved PCE that was as much as 23% higher than that of a conventional DSSC. This proposed method is an effective manufacturing process for flexible DSSC. PMID- 23755614 TI - Fabrication of isolated CoGdTb magnetic nanodots with perpendicular magnetic anisotropy. AB - The authors report that a closely-packed hybrid nanostructure can be fabricated by using simple sputtering deposition and anodized aluminum oxide (AAO) templates. In order to isolate CoGdTb magnetic materials with the AAO template, carbon nanotubes (CNTs) were incorporated into the AAO template. Scanning electron microscopy reveals that the nanodots are formed exactly on the top of CNTs, which are placed in a regular arrangement over a wide range area. This indicates that magnetic nanodots, well-arranged over a large area, can be formed using simple sputtering deposition. Isothermal magnetization shows that the CoGdTb nanodots have perpendicular magnetic anisotropy and the strength of the dipolar interaction between the magnetic nanodots can be also controlled by adjusting the spacing between the dots. PMID- 23755615 TI - Electronic structure of Zn doped Fe3O4 thin films. AB - We investigated the effect of Zn doping on the electronic property of magnetite by using optical spectroscopy. The (Zn(x)Fe(1-x))Fe2O4 (ZFFO) (x = 0, 0.2, 0.4, and 0.5) samples were prepared by PLD technique. The XRD measurement revealed that all the samples have an inverse spinel-type of crystalline structure. The M H curves indicate that the saturation magnetization reduces with the increasing x. From the spectroscopic ellipsometry and infrared spectroscopy, we found that the doping of nonmagnetic Zn2+ ions leads to the dramatic change in the electronic structure of the ZFFO films. We discuss the correlation of our spectra with the electric and magnetic properties of the ZFFO films. PMID- 23755616 TI - Growth of aluminum catalyzed AlGaAs nanowires on silicon substrate. AB - Aluminum catalyzed AlGaAs nanowires were fabricated on Si (111) substrates using metal-organic chemical vapor deposition (MOCVD) technique at a low growth temperature of 450 degrees C. Grown structures were characterized by field emission scanning electron microscope (FE-SEM), energy-dispersive X-ray spectroscopy (EDS) and photoluminescence (PL) techniques. Nanowire clusters were observed all over the substrate. Multiprong root-grown AlGaAs nanowire clusters as well as catalyst particle terminated growth was observed. The growth is explained by Vapor-Solid-Solid (VSS) and Vapor-Solid (VS) growth mechanisms using Al-Si binary phase diagram. EDS and PL measurement confirm the formation of AlGaAs nanowires. PMID- 23755617 TI - Thermoresponsive wettability of photonic crystals fabricated by core-shell poly(styrene-acrylamide) nano/microspheres. AB - The photonic crystals (PCs) films with tunable wettability were fabricated from self-assembly of an amphiphilic latex nano/microspheres poly(styrene-acrylamide) at different temperatures. The results demonstrate that the surface wettability of the PCs film can be tuned from high hydrophilic (CA, 17 degrees) to high hydrophobic (CA, 127.8 degrees) by controlling the assembly temperature from 30 degrees C to 90 degrees C, while the position of the photonic stopbands of the PCs films unchanged virtually. The obvious wettability transition is due to the change of the surface chemical component of the latex spheres, which mainly derives from the phase separation of polymer segments driven toward minimum interfacial energy. The facile method could open new application fields of PCs in diverse environments. PMID- 23755618 TI - Photoelectrochemical properties of vertically oriented hematite/gold multi-block nanorod arrays and their comparison to pure hematite nanorod arrays. AB - Vertically oriented hematite/gold (alpha-Fe2O3/Au) multi-block nanorod arrays are prepared with the goal of achieving enhanced photocatalytic ability to produce hydrogen from water. The effects of the insertion of the Au block in the pure alpha-Fe2O3 nanorod on the photocurrent generation are firstly characterized by photocurrent-voltage. The insertion of Au is expected to play an important role in the enhancement of the transport of electrons generated in the alpha-Fe2O3. The multi-block nanorod arrays show an improved photocurrent density and negative shift of the onset potential under 100 mW cm(-2) simulated solar light illumination. PMID- 23755619 TI - Asymmetric angular dependence of domain wall motion in magnetic nanowires. AB - An angular dependence of domain wall (DW) motion is studied in a magnetic wire consisting of a giant-magnetoresistance spin-valve. A DW pinning site is formed by a single notch, where a conventional linear one and a specially designed tilted one are compared. The asymmetric angular dependence was found in the DW depinning behavior with the tilted notch. The geometry control of the pinning site can be useful for DW diode devices using a rotating magnetic field. PMID- 23755620 TI - Nanometer-scale fabrication of hydrogen silsesquioxane (HSQ) films with post exposure baking. AB - A nanometer-scale grating structure with a 60-nm-wide gap and 200-nm-wide ridge has been successfully demonstrated on a silicon-on-insulator substrate by using a 220-nm-thick hydrogen silsesquioxane (HSQ) negative tone electron beam resist. A post exposure baking (PEB) process and hot development process with low concentration (3.5 wt%) of tetramethylammonium hydroxide (TMAH) solution were introduced to realize the grating pattern. To study the effects of post exposure baking on the HSQ resist, Fourier transform infrared spectroscopy (FT-IR) and X ray photoelectron spectroscopy (XPS) analyses were carried out. From the FT-IR and XPS analyses, it was verified that a thin SiO2 with high cross-linked network structure was formed on the HSQ surface during the PEB step. This SiO2 layer prevents the formation of unwanted bonds on the HSQ surface, which results in clearly defined grating structures with a 60-nm-gap and 200-nm-wide-ridge on the 220-nm-thick HSQ resist. The nanometer-scale grating pattern was successfully transfered to the 280-nm-thick silicon layer of a silicon-on-insulator (SOI) substrate by using inductively-coupled-plasma-reactive-ion-etching (ICP-RIE). PMID- 23755621 TI - Amidation of multiwalled carbon nanotubes in mild and efficient conditions. AB - Functionalization of Multi Walled Carbon Nanotubes (MWCNTs) with amines under a two step reaction is studied. In the first step, maleic anhydride graft to the MWCNT (Mah-g-MWCNTs) surfaces via a polymerization process with benzoylproxide as initiator. Active anhydride groups on the surfaces of MWCNTs, react with amines to give a polyamido chain attached to the MWCNTs surfaces. The reaction products have high solubility and disperse stability in organic solvents. FTIR, TGA and elemental analysis (CHN) were used to characterization of the achieved products. PMID- 23755622 TI - Magnetic nanoparticle decorated multi-walled carbon nanotubes for removing copper ammonia complex from water. AB - A kind of novel magnetic carbon nanotube composite was prepared and designed for wastewater treatment. Multi-walled carbon nanotubes were decorated with magnetic iron oxide nanoparticles, with an uniform distribution on the nanotube surface. The functionalized carbon nanotubes exhibit superparamagnetic behavior and can be easily and rapidly separated from the dispersion via a magnetic process. The carbon nanotube-iron oxide composites might serve as adsorbent for contaminant adsorption in water, especially for copper ammonia complex removal. The adsorption of copper ammonia complex to carbon nanotube-iron oxide composites is time dependent, and they can be quickly and efficiently removed together through a magnetic separation process. This novel magnetic composites might serve as an efficient and proper adsorbent in wastewater treatment applications. PMID- 23755623 TI - Template based synthesis of mesoporous silica material and its application in removal of fluorescent dyes. AB - Dye encapsulated uniform mesoporous silica particles have been synthesized using the surfactant assisted sol gel method. The release profile of the dye in different solvents (water and ethanol) has been studied. It is observed that the release of dye is controlled by the type of solvent chosen. When dispersed in ethanol the concentration of dye molecules released is much higher than what we observe when the release is carried out under aqueous conditions. The initial increase in the fluorescence intensity in both ethanol and water is a contribution from the initial burst of dye molecules present on the outer surface. Apart from the in-situ encapsulation of the fluorescent dye, mesoporous silica particles were also used as nanocontainers for storing dye molecules. The post synthesis adsorption of the dye on mesoporous silica was also carried out and the effective concentration of the dye molecule was found to decrease with increase in time. This study shows that mesoporous silica particles can be used for the in-situ encapsulation of organic molecules and also as a host for dye molecules by employing the simple post adsorption technique. PMID- 23755624 TI - Pulsed laser deposition and ferroelectric characterization of nanostructured perovskite lead zirconate titanate (52/48) thin films. AB - Perovskite lead zirconate titanate nanostructured (PZT) thin films with Zr/Ti ratio of 52/48 were deposited on Pt/TiO2/SiO2/Si(100) substrate using pulsed laser deposition method. A metal/ ferroelectric/metal (MFM) structure was used for ferroelectric property measurements, formed by depositing gold electrode on top of the film. A Nd:YAG UV laser having a wavelength of 355 nm and an energy fluence of -2.7 J/cm2 was used to deposit the film. The film was deposited on platinum (Pt) coated silicon substrate at the substrate temperature of 600 degrees C and the base vacuum of 10(-6) mbar. The scanning electron microscopy (SEM) images revealed well-crystallized films with a fine microstructure and an average grain size of - 50 nm. The ferroelectric properties of the film were studied and the results were discussed. The voltage dependent Polarization versus Electric field hysteresis measurements of PZT (52/48) pellet showed a well defined hysteresis loop with a fairly high remnant polarization (P(r)) and low coercive field (E(c)). PMID- 23755625 TI - Self assembled growth of GaSb nano triangles on GaN/sapphire substrate. AB - Self-assembled GaSb nano structures were grown on GaN/sapphire. GaSb nano triangles as well as quantum dots were obtained under controlled growth conditions. Nano triangles were grown at 580 degrees C due to the growth rate anisotropy among the (1100) planes. The size of nano triangle was 87 nm in width, 5 nm in height, and the density was 5 x 10(8) cm(-2), when the growth time was 30 s. This is the first report on the self assembled growth of nano triangles within a highly strained material system. PMID- 23755626 TI - Hybrid nanocomposites containing carboxymethylcellulose and silver nanoparticles. AB - Silver nanoparticles have high temperature stability and low volatility, and at the nanoscale are known to be an effective antifungal and antimicrobial agent. The present investigation involves the synthesis of silver nanoparticle/carboxymethylcellulose nanocomposites. The nanoparticles synthesised in this study had sizes in the range of 100 and 40 nm. The nanocomposites formed by a combination of metallic nanoparticles and carboxymethylcellulose were characterised by contact angle measurements, solubility tests, thermal and mechanical analyses, and morphological images. Improvements in the hydrophobic properties were observed with inclusion of the nanoparticles in the nanocomposites, with the best results occurring after the addition of 40 nm nanoparticles in a carboxymethylcellulose matrix. The silver nanoparticles tend to occupy the empty spaces in the pores of the carboxymethylcellulose matrix, inducing the collapse of these pores and thereby improving the tensile and barrier properties of the film. PMID- 23755627 TI - Improvement of optical properties of TiO2 thin film treated with electron beam. AB - Nanocrystalline titanium dioxide (TiO2) thin films on silicon wafer substrates were prepared by sol-gel spin coating process. The prepared thin films were treated with electron beam (1.1 MeV, 300 kGy) at air atmosphere. The effects of electron-beam (EB) irradiation on the structural and optical properties of the TiO2 thin films were investigated. The structures of all the TiO2 thin films by XRD analysis showed an anatase phase, and the phase remained unchanged within the investigating range of EB treatment. The thickness of the titania thin film decreased slightly with EB treatment whereas the porosity increased. The EB treatment of TiO2 thin film can increase the proportion of Ti3+ in Ti2p at the thin film surface. The optical transmittance of the film in the wavelength ranges of above 380 nm increased after the EB treatment while its refractive index decreased with increasing EB dose. Therefore, improvement of the optical properties could be due to the change in both surface chemistry and morphology of the TiO2 thin films affected by EB irradiation. PMID- 23755628 TI - Synthesis of vertically aligned carbon nanofibers-carbon nanowalls by plasma enhanced chemical vapor deposition. AB - Vertically aligned carbon nanofibers (VA-CNFs)-carbon nanowalls (CNWs) have been prepared on a silicon (Si) substrate by plasma-enhanced chemical vapor deposition. The VA-CNFs-CNWs were formed at bias voltage of - 185 V, whereas conventional VA-CNFs were synthesized under conditions of high bias voltages. Degenerated CNWs with turbostratic graphite structure were created on amorphous carbon layer around CNFs like a flag attached to a pole, which is evidenced by scanning electron microscopy, transmission electron microscopy, electron diffraction, and micro-Raman spectroscopy. Electron field emission characteristics of VA-CNFs-CNWs with unique microstructure, fabricated on the Si substrate, were primarily investigated. As a result, the VA-CNFs-CNWs showed the turn-on and the threshold fields of 1.7 V x microm(-1) and 3.35 V x microm(-1) with current densities of 10 nA x cm(-2) and 1 microA x cm(-2), respectively. The field enhancement factor beta was estimated to be 1059 by using Fowler-Nordheim theory. PMID- 23755629 TI - Influence of a surfactant and reducing agent on preparation of palladium. AB - We investigated the influence of a surfactant and reducing agent on the preparation of palladium nanoparticles, characterizing the prepared palladium nanoparticles by Transmission Electron Microscopy (TEM), and X-ray diffractometer (XRD). Colloidal palladium nanoparticles are prepared using PdCl2 as a precursor and polyvinylpyrrolidone (PVP) as a surfactant. In addition, hydrogen and sodium borohydride are used as reducing agents are used to characterize the prepared palladium nanoparticles. The concentrations of a precursor, a surfactant and its molecular weight affect the size of palladium nanoparticles, while the reducing agents influence the morphologies and structures of palladium nanoparticles. PMID- 23755630 TI - Bipolar pulsed electrical discharge for decomposition of methylene blue in aqueous TiO2 nanoparticle dispersions. AB - The objective of this paper is to investigate the decomposition process of organic pollutants by liquid phase plasma. A bipolar pulsed power supply was used to generate discharges in the aqueous TiO2 nanoparticle dispersions. The applied voltage, pulse width, and frequency were 250 V, 5 micros, and 30 kHz, respectively. Properties of generated plasma were investigated by electrical and optical emission spectroscopy methods. The comparison of properties of the discharge operated with and without oxygen gas bubbling is shown. The results of electrical-discharge degradation of methylene blue showed that the decomposition rate increased with the TiO2 particle dosages. Addition of oxygen gas bubbles also increased the degradation rate of methylene blue. PMID- 23755631 TI - Chemical modification of polyhedral oligomeric silsesquioxanes by functional polymer via azide-alkyne click reaction. AB - A series of poly(methylmethacrylate-co-2-hydroxyethylmethacrylate)/polyhedral oligomeric silsesquioxanes (P(MMA-co-HEMA)/POSS) nanocomposites were synthesized by the combination of ATRP and click chemistry. The hybrid nanocomposites were characterized by FT-IR, 1H-NMR, GPC, SEM, XRD, DSC, and TGA analyses. The loading of POSS in the nanocomposites was calculated using 1H-NMR data. TGA measurements suggested that the incorporation of POSS into polymer matrices enhanced decomposition temperature as well as char yield of the polymeric materials. The glass transition temperature linearly increased with the increase of POSS loading plausibly because of the aggregation of POSS nanoparticles and the dipole-dipole interaction between POSS and P(MMA-co-HEMA) segments. PMID- 23755632 TI - Fabricating superamphiphobic surface with fluorosilane glued carbon nanospheres films. AB - A stable superamphiphobic surface was successfully prepared with the carbon nanospheres film by means of a two steps method. Carbon nanosphere film was deposited by soot of burning cooking oil followed by fluorosilane modification. The results showed that the fluorosilane adopted for the surface modification can glue the loose carbon nanospheres, and make the surface energy decreased. The method reported here is suitable for the large-scale preparation of superamphiphobic surface. The scanning electron microscopy confirmed the synergistic binary geometric structures at micro- and nanometer scale. Transmission electron microscope examination demonstrated that all the carbon nanospheres have uniform diameter of about 50 nm. This method is cheap, time saving and easy to control. This result will open a new avenue in the superamphiphobic coating research with utilizing carbon nanospheres in the near future. PMID- 23755633 TI - Morphological and structural properties of electrospun Sm0.5Sr0.5CoO3-delta nanofibers. AB - Strontium-doped samarium cobaltite (Sm0.5Sr0.5CoO3-delta, SSC) fibers were successfully fabricated by electrospinning of a precursor gel derived from polyvinyl alcohol (PVA) and aqueous metal nitrate. After calcination of the as spun SSC fibers in microwave furnace at above 500 degrees C, SSC fibers of 100 +/ 20 nm in diameter with well-developed cubic-perovskite structure were successfully obtained. The crystal structure morphology, and grain structure of the fibers were influenced by the calcination temperature and the grain structure was evolved to "bamboo" structured polycrystalline SSC at above 700 degrees C. PMID- 23755634 TI - Fabrication of WS2 nanofibers from WO3 nanofibers prepared by an electrospinning method. AB - This paper describes a procedure of synthesizing long WS2 nanofibers. WO3 nanofibers were prepared as precursors by electrospinning of ammonium meta tungstate (AMT), polyvinyl alcohol (PVA) and alcohol solution followed by calcination at 550 degrees C in air. WS2 nanofibers were obtained by sulfurization of the WO3 nanofibres at 800 degrees C in an argon atmosphere, with sulfur powder acting as sulfuration reducer. The nanofibres were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive X-ray (EDX), and transmission electron microscopy (TEM). The results show that the final products are pure WS2 nanofibres, which have high aspect ratio. The WS2 nanofibers with rough surface were formed of nanoparticles, while some nanoflakes appeared on the surface of WS2 nanofibres. The diameters of the WS2 nanofibers were between 200 and 300 nm, which is similar to WO3 nanofibers. In addition, the WS2 nanofibers were polycrystalline. PMID- 23755635 TI - Catalytic characteristics of titanium oxide/MCM-41 synthesized by liquid phase atomic layer deposition. AB - Titanium oxide on MCM-41 was synthesized using the atomic layer deposition (ALD) method. BET, XRD, NH3-TPD and EDS were used to study the structural properties of the supported titanium oxides. The surface area of catalysts decreased with increasing of the amount of titanium in precursor solution. However, unique characteristics of 2-D hexagonal structure of mesopores in MCM-41 were maintained. The Ti/MCM-41 catalyst with titanium loading of 12.6 wt% showed the highest activity in the dehydration of 2-butanol, which was attributed to the highest overall amount of acid sites among the Ti/MCM-41 catalysts. PMID- 23755636 TI - The structure and properties of pulsed dc magnetron sputtered nanocrystalline TiN films for electrodes of alkali metal thermal-to-electric conversion systems. AB - Titanium nitride films used as an important electrode material for the design of alkali metal thermal-to-electric conversion (AMTEC) system have been prepared using dc (direct current) and asymmetric-bipolar pulsed dc magnetron sputtering. The pulse frequency and the duty cycle were varied from 5 to 50 kHz and 50 to 95%, respectively. The deposition rate, grain size and resistivity of pulsed dc sputtered films were decreased when the pulse frequency increased, while the nano hardness of titanium nitride films increased. We present in detail coatings (e.g., deposition rate, grain size, prefer-orientation, resistivity and hardness). Our studies show that titanium nitride coatings with superior properties can be prepared using asymmetric-bipolar pulsed dc sputtering. PMID- 23755637 TI - The synthesis of nickel nanoparticles by liquid phase plasma processing. AB - In this work, the liquid phase plasma reduction method was applied to prepare the spherical nickel nanoparticles from the solution of nickel chloride. A bipolar pulsed power supply was used to generate discharges in the aqueous solutions. Nickel nanoparticle peaks produced by surface plasmon absorption were observed around 381 nm with electrical discharge. Spherical nickel nanoparticles were mostly observed in this study, pentagonal nanoparticles were also observed occasionally. The TEM image showed that the average particle size varied from 10 to 200 nm in diameter as discharge time was increased. Many spots could be seen in the ED pattern for polycrystalline particles. PMID- 23755638 TI - Kinetics of phase transformation in nanostructured Ga-Se-Te glasses. AB - Bulk samples of Ga25Se(F5-x)Te(x) chalcogenides were prepared by melt quenching technique. The glassy nature of these alloys was verified by X-ray diffraction. The morphology of these as-prepared alloys was studied using field emission scanning electron microscopy. Kinetics of crystallization in these glassy alloys was studied under non-isothermal conditions at different heating rates (5, 10, 15, 20 and 25 K/min) using differential scanning calorimetry. The value of glass transition and crystallization temperature was found to be composition and heating-rate dependent. The value of order parameter indicates that the crystallization was due to volume nucleation with two dimensional growths. The activation energy of crystallization and activation energy of glass transition were determined from the heating rate dependence of glass transition and crystallization temperature. Both the activation energy for glass transition and the activation energy of crystallization were found to decrease from 130.05 to 102.99 kJ/mole and from 130.05 to 102.99 kJ/mole respectively with increasing Te content in Ga-Se system. PMID- 23755639 TI - Development of a moment model for condensational obliteration of nanoparticle aggregates. AB - A new method of simulating condensational obliteration in the framework of the moment method is presented. The nanoparticle size distribution was assumed to be represented by a time-evolving log-normal function during the particle growth. The rate of change in the primary particle size due to obliteration was expressed as a function of the surface growth rate and three size distribution moments. Model validation was carried out by comparing with sectional model simulations. Compared to the sectional model, the new moment model was shown to provide similar results for primary and aggregate particle growth with much less computing time. PMID- 23755640 TI - Improvement of quantum efficiency of P3HT:PCBM-based organic photovoltaic cells using DMDCNQI as an N-type dopant and buffer layer. AB - In previous work, we have reported that a P3HT:PCBM-based organic photovoltaic cell using a thermally evaporated DMDCNQI buffer layer shows a high power conversion efficiency. In the present work, we have fabricated organic photovoltaic cells consisting of ITO/PEDOT:PSS/P3HT:PCBM:DMDCNQI/DMDCNQI/Al using an all-solution process. A thin, uniform DMDCNQI film was obtained in a methanol solution with high solubility and low viscosity. The prepared device shows a high power conversion efficiency of 2.9%. In particular, a maximum external quantum efficiency of 81% was obtained. PMID- 23755641 TI - Preparation and electrocatalytic activity of nanocrystalline Ni-Mo-Co alloy electrode for hydrogen evolution. AB - Ni-Mo-Co alloy electrodes were prepared by electrodeposition technique with citric acid as a complexing agent. The influence of the main technical parameters such as the concentration of CoSO4 7H2O, the current density and the bath temperature on the component content in the Ni-Mo-Co alloy electrode were investigated by electron dispersive spectrometer (EDS), the microstructure and surface morphology of Ni-Mo-Co alloy electrodes were characterized by employing X ray diffractometer (XRD) and scanning electron microscope (SEM), and the electrocatalytic activity of Ni-Mo-Co alloy electrode for hydrogen evolution was investigated by the method of the cathode polarization curves. The results showed that the excellent Ni-Mo-Co alloy electrode with 41.39 wt% Ni, 53.82 wt% Mo and 4.79 wt% Co was obtained when the concentration of CoSO4 x 7H2O was 8 g/L, the current density was 12 A/dm2 and the bath temperature was 25 degrees C. The mircostructure of the Ni-Mo-Co alloy was nanocrystalline and the average grain size was about 25 nm by calculating using Scherrer Equation. The electrocatalytic activity of Ni-Mo-Co alloy electrode for hydrogen evolution was better than that of Ni-Mo alloy electrode. PMID- 23755642 TI - Nanosize-controlled titanium nitride films in pulsed dc magnetron sputtering. AB - Titanium nitride films with different nano-grain size deposited by direct current (dc) and pulsed dc magnetron sputtering have been investigated for various target frequencies ranging from 0 to 50 kHz. The crystal grain size, surface and cross sectional microstructure and the surface roughness of the coatings were analyzed using grazing incidence X-ray diffraction (GIXRD), field-emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM). Pulsed prepared TiN films showed higher hardness and Young's modulus, and smaller grain size and the roughness than dc prepared TiN films. The effects of target frequency on film structure and properties is more remarkable at high target frequency exhibited a nano-grain size and a dense microstructure and smooth surface roughness with superhard hardness, which are the results of the high ion energy and high ion flux bombardment from the high frequency pulsed plasma. PMID- 23755643 TI - Increase the reliability and applicability of quartz crystal resonator coupled with other instruments. AB - The principle and applications of quartz-crystal resonator systems and the methods to increase their reliability and applicability coupled with other instruments were reported. The principle of quartz-crystal resonator system was documented with based on the three basic concepts for mass, viscosity, and viscoelastic changes. In the preliminary discussion, the realization of a resonant frequency-resonant resistance diagram was described in detail. As the examples of quartz-crystal resonator applications with introducing the resonant resistance concept and the resonant frequency, the fabrication of a carbon-coated quartz crystal sensor and monitoring changes in the viscoelastic properties of thin polymer films were carefully discussed. Examples for increasing their reliability and applicability of quartz crystal resonator systems combined with UV-visible spectroscopy, Atomic Force Microscope (AFM), Surface Plasmon Resonance (SPR), or Charge Coupled Device (CdCD) camera were described. PMID- 23755644 TI - Production of green fluorescent protein in transgenic rice seeds. AB - Immature embryos from immature seeds of rice (Oryza sativa L.) were transformed by biolistic bombardment with the plasmid carrying the coding region of the hygromycin phosphotransferase gene under the control of the 5' region of the cauliflower mosaic virus 35S promoter and the synthetic green fluorescence protein gene (sgfp) under the control of the maize ubiquitine promoter. Southern blot analysis confirmed the stable integration of hpt and sgfp genes in transformants. Subsequently leaves from regenerated plants were resistant to hygromycin, and microscopic observation of the green fluorescence and immunoblotting analysis revealed that green fluorescence protein was not only detected in the leaf and pollen of primary transformants but also in mature seeds. The results bear out the importance of the suitability of GFP as an in vivo marker to follow the processes of selection of somatic hybrid embryos and plants. PMID- 23755645 TI - Antioxidant properties of biohybrids based on liposomes and sage silver nanoparticles. AB - This paper is aimed to describe a simple and rapid eco-friendly bottom-up approach for the preparation of antioxidant silver bionanostructures using a leaf extract from sage (Salvia officinalis L.). The bioreduction property of sage in the synthesis of silver nanoparticles was investigated by UV-VIS and Attenuated Total Reflectance Fourier Transform Infrared spectroscopy. During their preparation, the particle size analysis was performed by using Dynamic Light Scattering technique. Ultrasonic irradiation was used to obtain sage silver nanoparticles. The morphology (size and shape) of the herbal silver nanoparticles was evaluated by Scanning Electron Microscopy that revealed the formation of spherical phytonanoparticles with size less than 80 nm. In order to increase their stability and their biocompatibility, the sage silver nanoparticles were introduced in two types of liposomes: soybean lecithin- and Chla-DPPC-lipid vesicles which were prepared by thin film hydration method. X-Ray Fluorescence analysis confirmed the silver presence in liposomes/sage-AgNPs biohybrids. The stability of liposomes/herbal AgNPs bioconstructs was checked by zeta potential measurements. The most stable biohybrids: Chla-DPPC/sage-AgNPs with zeta potential value of -34.2 mV, were characterized by Atomic Force Microscopy revealing the spherical and quasi-spherical shaped profiles of these nanobiohybrids with size less than 96 nm. The antioxidant activity of the silver bionanostructures was evaluated using chemiluminescence assay. The developed eco friendly silver phytonanostructures based on lipid membranes, nanosilver and sage extract, manifest strong antioxidant properties (between 86.5% and 98.6%). PMID- 23755646 TI - Peptide nucleic acids (PNAs) patterning by an automated microarray synthesis system through photolithography. AB - Peptide nucleic acids (PNA) microarray assembled with hundreds of unique PNA oligomers has been regarded as a new and mighty competitor of DNA chip in gene analyzing. However, PNA microarray is still a luxury art due to the difficult and laborious chemical synthesis. Herein, we have developed a fully-automated synthesizer for PNA microarray through photolithography. A preactivation mixer was designed and integrated into the synthesizer in order to get rid of the annoying manual process and increase the coupling efficiency of PNA monomers. The PNA patterning model was carried out to check the performance of the automated synthesizer, revealing that an exposure time of 3 min was sufficient for the complete removal of o-nitroveratryloxycarbonyl (NVOC) groups from the synthetic sites with the help of photosensitizer isopropylthioxanthone and the stepwise yield was measured to be about 98.0%, which is comparable with that from conventional fluorenyl-methyloxycarbonyl (FMOC) chemistry. Those results have definitely demonstrated the possibility and capability of this fully-automated synthesizer to fabricate high-quality PNA microarrays. PMID- 23755647 TI - Green synthesis and nanotopography of heparin-reduced gold nanoparticles with enhanced anticoagulant activity. AB - This paper reports on the green synthesis of heparin-reduced gold nanoparticles and their nanotopography as studied with atomic force microscopy. The study also evaluated the anticoagulant activity of the newly prepared gold nanoparticles. The heparin-reduced gold nanoparticles were homogeneous, showing characteristic surface plasmon resonance bands of approximately 523-527 nm, and their shapes were mostly spherical and amorphous. The average diameter of the nanoparticles measured from atomic force microscopic images was either 20.26 +/- 3.35 nm or 40.85 +/- 8.95 nm depending on the different precursor salts and heparin concentrations. Atomic force microscopic images revealed that the topography of the heparin polymer aggregated when deposited onto mica, resembling a chain of mountains. This characteristic nanotopography of the heparin disappeared after the synthesis of the gold nanoparticles was performed. Interestingly, prolonged prothrombin time, thrombin time, and activated partial thromboplastin time were observed in the heparin-reduced gold nanoparticles when compared to a control heparin, suggesting the enhancement of anticoagulant activity in heparin-reduced gold nanoparticles. Hence, the green synthesis of gold nanoparticles with heparin using a simple reaction step could be a viable procedure for enhancing heparin's anticoagulant activity. PMID- 23755648 TI - Development of flowing automatic quartz crystal microbalance system for DNA detection. AB - A novel flowing automatic QCM (Quartz Crystal Microbalance) system for DNA detection was fabricated in this paper. The system included a multi-channel flowing system, a flow cell and a constant temperature controlling system, which integrated multi-functions such as flowing detection, temperature controlling and automatic analysis. Moreover, this system was utilized for DNA immobilization and hybridization detection. The results showed that the system is of good stability and validity. PMID- 23755649 TI - Comparative evaluation of interaction force between cofilin protein and peptide probe to actin protein. AB - In current study, we report the direct interaction force comparison for a synthesized peptide probe to actin and cofilin protein to actin using atomic force microscopy. The peptide probe was synthesized following the actin binding module of cofilin protein. Thus, the functionality of the peptide probe was similar with that of the cofilin protein. The difference between the peptide probe and cofilin protein was the molecular size. The small peptide probe enables highly dense surface modification, thus produces different interaction force curves compared with that of original cofilin protein to actin. The results showed the peptide probe was possible to measure many numbers of the interaction force though the measurement of single molecular order interaction force was a weak point. These imply that the peptide probe has a merit when that was applied surface related applications such as protein sensor and protein-protein interaction separation. PMID- 23755650 TI - Real-time monitoring of changes in microtubule mechanical properties in response to microtubule-destabilizing drug treatment. AB - Microtubules are cylindrical protein polymers that play important roles in a number of cellular functions. The properties of microtubules are dynamically changed by interacting with many microtubule-related proteins and drugs. In this study, we used atomic force microscopy to evaluate the changes in microtubule mechanical properties induced by treatment with nocodazole, which is a microtubule-destabilizing drug. The average spring constant of the microtubules, which was used as a measure of microtubule lateral stiffness, was drastically decreased by treatment with nocodazole within 30 min from 0.052 +/- 0.014 N/m to 0.029 +/- 0.015 N/m. Our findings will aid in the understanding of microtubule dynamics, protein interactions in response to drug treatment, microtubule-related diseases, and drug development. PMID- 23755651 TI - An environmentally friendly approach to the reduction of graphene oxide by Escherichia fergusoni. AB - Graphene has attracted a great deal of scientific interest due to its unique properties and its various prospective applications. However, the use of graphene in technological purposes depends on the development of suitable methodologies for its mass production. Several environmentally safe methods have been emerging for the production of graphene from graphite oxide which are based on the solvothermal and the electrochemical processes. Herein, we developed a green, simple and cost effective approach to produce graphene by using an Escherichia fergusoni as a reducing agent. This reduction method avoids the use of environmentally harmful reagents such as hydrazine and hydrazine hydrate. The resulting reduced graphene oxide (rGO) was characterized by a wide range of analytical techniques. UV-Vis spectra of the samples confirm the transition of graphene oxide (GO) into graphene. Fourier transform infra-red spectroscopy (FT IR) spectrum of the rGO indicates a significant reduction of the intensity of all oxygen containing moieties suggesting efficient conversion of GO to rGO. X-ray diffraction (XRD) was used to investigate the crystalline of graphene nanosheets, whereas high resolution scanning electron microscopy (SEM) and atomic force microscopy (AFM) were employed to investigate the morphologies of prepared graphene. Raman spectroscopy images provide clear evidence for the formation of graphene. All these findings clearly indicate that GO could be reduced by simple, eco-friendly method by using E. fergusoni to produce water dispersible graphene. PMID- 23755652 TI - Authentication and recovery of medical diagnostic image using dual reversible digital watermarking. AB - This paper proposes a new region-based tampering detection and recovering method that utilizes both reversible digital watermarking and quad-tree decomposition for medical diagnostic image's authentication. Firstly, the quad-tree decomposition is used to divide the original image into blocks with high homogeneity, and then we computer pixels' linear interpolation as each block's recovery feature. Secondly, these recovery features as the first layer watermarking information is embedded by using simple invertible integer transformation. In order to enhance the proposed method's security, the logistic chaotic map is exploited to choose each block's reference pixel. The second layer watermark comprises by the quad-tree information and essential parameters for extraction are embedded by LSB replacement. In the authentication phase, the embedded watermark is extracted and the source image is recovered, and the similar linear interpolation technique is utilized to get each block's feature. Therefore, the tampering detection and localization can be achieved through comparing the extracted feature with the recomputed one, and the extracted feature can be used to recover those tampered regions with high similarity to their original state. Experimental results show that, compared with previous similar existing scheme, the proposed method not only achieves high embedding capacity and good visual quality of marked and restored image, but also has more accuracy for tampering detection. PMID- 23755653 TI - A novel lossless robust watermarking method for copyright protection of biomedical image. AB - Nanoscience and Nanotechnology promotes the development of biomedical imaging devices, more and more valuable biomedical images are transmitted through the open network, and their copyright suffers a major challenge. This paper proposes a new lossless robust watermarking method to realize biomedical image's copyright protection. For high-resolution biomedical images, the redundant theory and histogram shifting method based on image block's difference are utilized to repeatedly embed copyright watermark into different color channels. In the extracting procedure, each layer's watermark information can be extracted from watermarked image respectively, and the final watermark is judged by the voting theory. The redundant scheme and voting theory guarantees the watermark can resist against random noise's attack well. Besides, in order to reduce the watermark overhead in embedding procedure, the histogram narrowing down technique is used to tackle with those image blocks would overflows and underflows. Experimental results showed that the proposed method outperformed the existing semi-fragile reversible watermarking scheme and provided a great robustness against moderate JPEG compression and salt-pepper and Gaussian noise. PMID- 23755654 TI - Engineering of the growth environment of microalgae with high biomass and lipid productivity. AB - Pure cultures of Botryococcus sp. microalgae have great potential for generating huge amounts of algae lipid that can be further converted into biodiesel. Lipids with nanometer in size can be applied to medicine and pharmacy recently. In this study, the effects of light intensity and CO2 concentration on the biomass productivity, lipid content, and lipid productivity of Botryococcus braunii were examined in 21-day intervals. The optimum cultivating conditions for biomass accumulation were 6,000 lux with 0.04% CO2 and 21 days of culturing; this provided the highest biomass productivity of 140.46 mg L(-1) d(-1). The highest lipid productivity of 44.46 mg L(-1) d(-1) occurred at 6,000 lux with 5% CO2 and 21 days of culturing. The maximum specific growth rate (micro(max)) was similar among different concentrations of CO2 (0.682 d(-1) under 12,000 lux at 10% CO2; 0.585 d(-1) under 6,000 lux at 5% CO2). Culturing at 5% or 10% CO2 has been shown to enhance the accumulation of lipids, introducing the possibility of using flue gas as a carbon source. The nanotechnology in this study will be helpful towards research in green science and engineering such as bio-fixation of CO2 and drug delivery systems. PMID- 23755655 TI - Observation of interaction force in large area between actin modified surface and actin antibody modified microsphere probe. AB - In order to observe the force interaction in large areas, a novel force detection probe was fabricated by two-photon absorbed photopolymerization (TPAP) techniques. The probe was based on a commercial cantilever, and a docking structure for adopting a microsphere immobilized with actin antibody was fabricated by the TPAP techniques. The commercial AFM tip was also modified with the antibody for comparison. Using force curve measurement, the interaction force was compared between the modified probes and the sample surface which was immobilized with actin using a spotting system. The adhesive force of 1.3 nN was measured applying the commercial cantilever. The value was comparable to the measured interaction force of 130 nN applying the microsphere modified cantilever. The measured adhesive force of the novel probe was 100-fold larger than that obtained by the sharp AFM cantilever tip. This strong adhesive force of the microsphere modified cantilever to actin is explainable by the large contact area between the microsphere and the sample surface. PMID- 23755657 TI - A novel fast responsive thermo-sensitive poly(N-isopropylacrylamide)-clay nanocomposites hydrogels modified by nanosized octavinyl polyhedral oligomeric silsesquioxane. AB - The preparation of a novel fast response thremosensitive hydrogel was investigated by incorporating nanosized octavinyl polyhedral oligomeric silsesquioxane (OvPOSS) particles into inorganic clay-crosslinked poly(N isopropylacrylamide) (PNIPA) nanocomposites hydrogels (NC gels). The resulting hydrogels named as P-NC gels involving both the strategies of NC gels and double network gels (DN gels) were successfully synthesized via a two-step technique. The second PNIPA network crosslinked by OvPOSS were polymerized in the presence of the first clay-PNIPA network. The P-NC gels were characterized by FTIR, X-ray, DSC, UV/vis,spectra, SEM, mechanical properties and swelling behaviors measurements. The key factor for preparing homogenous P-NC gels with good transparency was the low concentration of OvPOSS (c(OvPOSS)) dispersed uniformly in polymer as a cross-linker. On the contrary, the high c(OvPOSS) led to the significant aggregation of the OvPOSS particles and thus resulted in the heterogeneity of gels. The SEM images of freeze-dried P-NC gels exhibited a highly interconnected microporous network structure, which could be adjusted by varying the amount of OvPOSS. The special porous morphology brought about an attractive faster swelling/deswelling rate than that of normal NC gels. All properties of P-NC gels displayed an obvious dependence on the concentration of incorporated OvPOSS. The excellent mechanical properties, tunable LCST, especially the fast deswelling rate make these hydrogels potential candidates for applications in drug release and other biological fields. PMID- 23755656 TI - Dendrimer-encapsulated silver nanoparticles and antibacterial activity on cotton fabric. AB - Silver-dendrimer nanocomposites are synthesized in the presence low generation poly(amido amine) dendrimers with terminal amine groups employing silver nitrate as the precursor and sodium borohydride as the reduction agent. The parameters including the addition of oxalic acid and the generation of the dendrimer that influence the particle size of the synthesized silver nanoparticles are discussed. Under the optimized conditions, a series of silver-dendrimer nanocomposites with the average diameter of silver nanoparticles ranging from 7.6 nm to 16.2 nm are synthesized by varying the molar ratio of dendrimer to silver nitrate. The synthesized silver-dendrimer nanocomposites are utilized as the antibacterial agents in fabrication of antibacterial cotton fabrics. The antimicrobial properties of the prepared antibacterial cotton fabrics against E. coli and S. aureus are evaluated by the inhibition zone method. The results demonstrate that the antimicrobial activity of the silver-dendrimer composites treated cotton fabric enhances with the decrease of the silver nanoparticle size. PMID- 23755658 TI - Time-resolved polymer propagation for acrylic acid-mediated nanolatexes containing magnetic Fe3O4 cores. AB - This study reports on the time-resolved polymer propagation of thermal-sensitive latex nanoparticles containing Fe3O4 cores. The latex shells are made with poly(N isopropylacrylamide-co-acrylic acid) (Fe3O4/P(NIPAAm-co-AAc)) at different reaction times. The Fe3O4 particles are first modified using AAc monomers. The AAc-modified Fe3O4 cores are then copolymerized with NIPAAm to form the latex shell. The Fe3O4 cores in the latex nanoparticles are confirmed using X-ray photoelectron spectroscopy (XPS), X-ray diffraction spectroscopy (XRD), and thermo gravimetric analyzer (TGA). As the reaction time is increased from 0.5 h to 2 h, the particle size enlarges from 100 to 250 nm and the Fe3O4 content decreases from 46.4% to 2.6%. The thermal responses are more pronounced in the 2 h sample with the phase transition temperature (lower critical solution temperature, LCST) about 35 degrees C. The nanoparticles show a gradient concentration distribution of AAc as the particles propagate. A higher AAc concentration is observed near'the Fe3O4 core and the AAc content deceases as the degree of polymerization increases in the latex particles. This declining AAc concentration is beneficial for profound thermal responses in the synthesized nanoparticle. PMID- 23755659 TI - Green approach to synthesize multi-walled carbon nanotubes by using metal formate as catalyst precursors. AB - The multi-walled nanotubes (MWNTs) have been synthesized in large scale by using metal formate as catalyst precursors. The calcium carbonate is used as catalyst support, it is chosen because of its non toxic and easily soluble nature. The synthesis was carried out by chemical vapor deposition method for 15 min under optimized conditions. The products were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Raman spectroscopy and X-ray diffraction (XRD) method. The purity of the as grown products and purified products were determined by thermal analysis. The obtained yield of MWNTs was about 8300 wt% relative to the nickel catalyst. This synthesis route avoids the lengthy process of calcination and reduction for the preparation of catalysts hence this method is more economical. This economical and environmental friendly synthesis route can be used for synthesizing MWNTs in large scale. PMID- 23755660 TI - Enhanced photochemical stability of CdSe/CdS quantum dots capped by imidazolium based ionic liquids. AB - The novel thiol-functionalized ionic liquids (ILs), 1-(10-mercaptodecyl)-3 methylimidazolium chloride ([HS-C10mim]Cl) and 1-(4-mercaptobutyl)-3 methylimidazolium chloride ([HS-C4mim]Cl), were synthesized by introducing thiol groups onto the alkyl chains in imidazolium-based ILs. The ILs exhibit strong affinity toward CdSe/CdS quantum dots (QDs), and can readily transfer the QDs from organic phases to aqueous phase. The IL-capped CdSe/CdS QDs are extremely soluble in water, and their photochemical stability was measured by absorption spectra. It is shown that the [HS-C10mim]Cl-capped QDs in water present much better anti-photooxidation than [HS-C4mim]Cl-capped those. The measurements of Zeta potential and hydrodynamic diameter reveal that the enhanced mechanism of [HS-C10mim]Cl depends mainly on the specific physico-chemical properties of the ILs. In particular, CdSe/CdS QDs with high surface potential, small hydrodynamic diameter, and optimal photochemical stability can be harvested by the solubilization of free [HS-C10mim]Cl in ligand shells of the QDs. PMID- 23755661 TI - Enhanced performance of organic light emitting device by incorporating 4,4 bis(2,2-diphenylvinyl)-1,1-biphenyl as an efficient hole-injection nano-layer. AB - Here we reported that 4,4-bis(2,2-diphenylvinyl)-1,1-biphenyl (DPVBi), known as blue emitting host material, could effectively manipulate the Schottky energy barrier between the indium tin oxide (ITO) and the emitting layer and thus significantly enhanced hole injection property. As a result, we could greatly improve the current and luminance efficiencies of organic light emitting diodes (OLEDs) as well as their stability. We attributed the enhanced performance of hole injection layer (HIL)-modified OLEDs to the lowered hole injection barrier. By analyzing the J-V characteristics of hole only devices as a function of temperature, we could show that the interfacial energy barrier between ITO and emitting layer was reduced by more than 0.2 eV by insertion of DPVBi HIL. PMID- 23755662 TI - Catalytic combustion of toluene on Pd/CeO2-TiO2 catalysts. AB - Pd/TiO2 and Pd/CeO2 were reported to be very active to destruct toluene. Combination of TiO2 and CeO2 is an interesting candidate to achieve a catalyst with higher activity. In this study, a series of Pd/CeO2-TiO2 catalysts with various Pd loadings were prepared. CeO2-TiO2 was prepared by impregnation of aqueous solution of cerium nitrate into TiO2 support. It was then calcined at 400 degrees C. Pd was loaded by incipient-wetness impregnation method. The Pd loadings in all samples were fixed at 0.5 wt.%. The catalysts were characterized by powder X-ray diffraction, transmission electron microscopy, high resolution transmission electron microscopy, temperature-programmed reduction of hydrogen, and X-ray photoelectron spectroscopy. The catalysts were tested for total oxidation of toluene. The feed concentration of toluene was 8.564 g/m3 (2085 ppm), with GHSV = 10,000 h(-1). Pd particle sizes were 3-5 nm and well-dispersed on the support. CeO2 on TiO2 was easier to reduce than the bulk CeO2, therefore it could enhance the activity of VOC destruction. Pd/CeO2-TiO2 was more active than Pd/CeO2 and Pd/TiO2. Pd/CeO2-TiO2 with Ce/Ti ratio of 2/8 was very active for toluene destruction, due to its lower oxygen reduction temperature of ceria and higher concentration of Pd(0). PMID- 23755663 TI - Characteristics of styrene-butadiene rubber/silica/Nanoprene compounds for application in tire tread. AB - Nanoprene is made from chemically cross-linked rubber particles, and has many hydroxyl groups on the surface of the particles. It is speculated that the Nanoprene could reduce the silica-silica network formation by introducing hydrogen bonding between the silanol group of silica and the hydroxyl group of Nanoprene. In this study, the styrene-butadiene rubber (SBR)/silica compounds with two types of the Nanoprene (BM75OH, BM15OH) were evaluated and it could be well explained by the concept of the volume fraction of filler or the volume fraction of rubber. If the Nanoprene applied to the compound is considered as a kind of filler, the minimum torque values and bound rubber contents of the un vulcanized compounds, the swelling ratio and the stress-strain relationship of the vulcanized compounds could be well explained by the volume fraction of filler (phi(F)). If Nanoprene is considered as a kind of rubber such as SBR, the properties such as peak tan delta, Payne effect, tan delta at 0 degrees C and 60 degrees C, and abrasion resistance could be well explained by the volume fraction of rubber (phi'(R)). However, the improvement of silica dispersion by addition of the Nanoprene particles in the compounds was not significant. The application of BM75OH as a polymer to the tread compound will be suitable for winter tires. In addition, the compound with BM15OH as an additive will be suitable as a tread compound for summer tires. PMID- 23755664 TI - Environmentally benign synthesis of Bi2S3 quantum dot using microwave-assisted approach. AB - Oleic acid (OA) capped Bi2S3 quantum dots were successfully synthesized using 180 watt microwave power for 5 minutes in water-ethanol mixed solvents containing oleic acid as capping agent. In this approach, the reaction was conducted in ambient air and a much lower temperature than hot injection approach. The OA capped Bi2S3 QDs were characterized by using XRD, TEM, FTIR, UV-Vis and PL. The OA capped Bi2S3 QDs can be readily modified with sodium dodecyl sulfate (SDS) via hydrophobic interaction to improve their solubility in aqueous solution. According to optical properties of the QDs, the modified QD revealed the additional features, such as photothermal therapeutic agent and fluorescent probe. PMID- 23755665 TI - Effects of compound carboxylate-urea system on nano Ni-Cr/SiC composite coatings from trivalent chromium baths. AB - The effects of compound carboxylate-urea system on the nano Ni-Cr/SiC composite coatings from trivalent chromium baths have been investigated in ultrasonic field. These results indicated that the SiC and Cr contents and the thickness of the Ni-Cr/SiC composite coatings could be obviously improved by the compound carboxylate-urea system. The steady-state polarization curves showed that the hydrogen evolution reaction (HER) could be significantly inhibited by the compound carboxylate-urea system, which was benefit to increase the SiC and Cr contents and the thickness of the composite coatings. The cyclic voltammetry (CV) curves showed that both of the Cr(III) and Ni(II) cathodic polarization could be increased in the bath containing the compound carboxylate-urea system. Thus, a compact Ni-Cr/SiC composite coating could be obtained using this technique. The surface morphology of the Ni-Cr/SiC composite coatings checked with the scanning electron micrographs (SEM) showed that the surface smoothness could be also improved and the microcracks and pinholes could be decreased due to the presence of the compound carboxylate-urea system. The phase composition of the as-posited coating was measured by the X-ray diffraction. XRD data showed that the as posited coating was Ni-Cr/SiC composite coating. The chemical composition of the coating was investigated by energy dispersive spectrum (EDS) analysis. The result showed the Ni-Cr/SiC composite coatings with 3.8 wt.% SiC and 24.68 wt.% Cr were obtained in this study, which had best corrosion resistance according to the results of the typical potentiodynamic polarization curves of the Ni-Cr/SiC composite coatings. PMID- 23755666 TI - Selective detection of calcium cations on macromolecular Langmuir monolayer and Langmuir-Schaefer films. AB - In this study, we report the interfacial Langmuir monolayer behavior and surface morphological features of a dendronic terthiophene linked via a tetraethylene glycol moiety (3T5O3T) and its complexation with calcium cations. Surface pressure-mean molecular area (pi-A) isotherms show distinct behavior due to the secondary interaction of cations with the ionophore units. Furthermore, two Langmuir-Schaefer (LS) films with and without calcium cations exhibited significantly different surface morphological features from atomic force microscopy (AFM) imaging. Quartz crystal microbalance (QCM) measurements reveal changes in frequency and resistance enabling selective sensing of calcium cations on the LS films. Thus, well-organized 3T5O3T LS films on the solid substrates are potential candidates for highly selective chemosensing. PMID- 23755667 TI - A fully integrated prothrombin time test on the microfluidic disk analyzer. AB - A fully integrated prothrombin time test, which is capable of measuring the time required for blood to coagulate, is presented in this study. The microfluidic functions integrated on the microfluidic disk were able to extract the plasma from whole blood samples and conduct rapid mixing within 1 second. The factors which affected the plasma decanting mechanism were investigated. The complete fluidic design was applied to prothrombin time tests. Ninety-two whole blood clinical samples were tested by the microfluidic disk analyzer and the Sysmex CA1500 coagulation analyzer, which is the instrument used in medical centers. The test results from these two instruments showed good correlation and agreement. PMID- 23755668 TI - Reduction procedure effect on the electrochemical properties of conductive carbon black supported Pt-Pd electrocatalysts. AB - Conductive carbon black supported Pt-Pd nanocomposites were prepared to study a difference of simultaneously and sequentially reduced Pt-Pd nanocomposites using polyol method. The concentration of Pt-Pd alloyed metals on carbon blacks (CB) was adjusted to 20 wt%. The catalysts could be characterized by transmission electron microscopy, X-ray diffraction and thermogravimetric analysis. The electrochemical activities of Pt-Pd were measured by cyclic voltammograms. As a result, electrochemical active surface area (ESA) value of sequentially deposited Pt-Pd/CB was shown to 66 m2/g, which was higher than 55 m2/g of simultaneously deposited Pt-Pd/CB. Besides, average particle size of sequentially deposited Pt Pd/CB was calculated to 1.7 nm which was smaller than 2.2 nm of simultaneously deposited Pt-Pd/CB. PMID- 23755669 TI - Adsorption equilibria and kinetics for the adsorption of p-nitrophenol on a phenoxy groups modified hypercrosslinked polystyrene resin. AB - Adsorption equilibria and kinetics of p-nitrophenol adsorbed on HJ-01 were investigated in this study. The result indicated that phenoxy groups were uploaded on the skeleton of HJ-01 successfully, the Friedel-Crafts reaction brought on prodigious changes for the Brunauer-Emmett-Teller (BET) specific surface area and pore structure while the nucleophilic substitution reaction had few effects. The adsorption experiments revealed that the acidic solution was suitable for p-nitrophenol adsorption, the adsorption isotherms could be characterized by the Freundlich isotherm equation and the adsorption thermodynamic parameters were all negative, the adsorption kinetic curves obeyed the pseudo-second-order rate equation. PMID- 23755670 TI - Effect of dispersion stability on the deposition of citrate-capped silver nanoparticles in natural soils. AB - Although little is known about the behavior of engineered nanomaterials after exposure to terrestrial areas, recent studies indicate that silver nanoparticles (AgNPs) can perturb the soil environment due to their biocidal and catalytic properties. The fundamental evaluation of the environmental fate of AgNPs would be a significant step toward a comprehensive understanding of the harmful effects of such particles on ecosystems. Therefore, from an eco-toxicological perspective, the estimation of AgNP behavior in soil should be investigated. Among the various environmental characteristics, the deposition of nanoparticles in the soil constitute is a critical step in their migration into surface or groundwater and interaction with organisms, which is determined by the stability of aqueous dispersions in a soil micro-environment. In the present study, we observed the aggregation and deposition of AgNPs to natural soil surfaces by comparing the partitioning of AgNPs in a soil/water interface with that of Ag+ ion. Both AgNPs and Ag+ ion were selectively quantified by means of inductively coupled plasma (ICP) spectrometry and an ion-selective electrode (ISE). We interpreted the partitioning of AgNPs and Ag+ ion using the Freundlich isotherm and the findings indicate that AgNPs with reduced dispersion stability in a soil micro-environment were aggregated and deposited on the surface of natural soil. This study provides a fundamental basis for understanding the deposition of AgNPs, which will enable their accumulation and mobility in a soil environment to be predicted. PMID- 23755671 TI - Hybrid inorganic-organic framework as efficient heterogeneous catalyst for the synthesis of allyl glycidyl carbonate from CO2 and allyl glycidyl ether. AB - A mixed-linker nanoporous coordination polymer Zn2(HIP)2(bipy)(H2O)2 x H2O (ZnHipBipy) constructed from polyfunctional linker 5-hydroxy isophthalic acid (HIP) and exo-bidentate ligand 4,4'-bipyridyl (bipy) was employed as heterogeneous catalyst for allyl glycidyl carbonate (AGC) synthesis from CO2 and allyl glycidyl ether (AGE) under solventless conditions. Besides being the organic linker, 5-hydroxy isophthalic acid enriches the functionality of the material through accessible hydroxyl group capable of contributing extensive hydrogen bonding interactions. The cycloaddition of CO2 and epoxide was catalyzed through a synergistic pathway offered by inherent hydroxyl group together with the catalytically active metal centre. Method of synthesis and texture of the catalyst were key factors in determining the conversion and selectivity. The effects of reaction parameters like catalyst amount, temperature, CO2 pressure and reaction time on the yield of AGC were also studied. PMID- 23755672 TI - Highly efficient hybrid energy generator: coupled organic photovoltaic device and randomly oriented electrospun poly(vinylidene fluoride) nanofiber. AB - A hybrid architecture consisting of an inverted organic photovoltaic device and a randomly-oriented electrospun PVDF piezoelectric device was fabricated as a highly-efficient energy generator. It uses the inverted photovoltaic device with coupled electrospun PVDF nanofibers as tandem structure to convert solar and mechanical vibrations energy to electricity simultaneously or individually. The power conversion efficiency of the photovoltaic device was also significantly improved up to 4.72% by optimized processes such as intrinsic ZnO, MoO3 and active layer. A simple electrospinning method with the two electrode technique was adopted to achieve a high voltage of - 300 mV in PVDF piezoelectric fibers. Highly-efficient HEG using voltage adder circuit provides the conceptual possibility of realizing multi-functional energy generator whenever and wherever various energy sources are available. PMID- 23755673 TI - The preparation and degradation performance of CdS photocatalysts to methyl orange solution. AB - In this paper, the CdS samples were prepared using thiourea or sodium sulfide as sulfur source by hydrothermal or solvothermal synthesis method, the results of XRD, TEM and SEM showed all the samples belong to hexagonal CdS nano-material with different morphologies. Using the degradation of methyl orange solution as a model reaction, the photocatalytic performance of different CdS samples was measured, and the samples prepared using thiourea as sulfur source exhibited better photocatalytic activity than those using sodium sulfide as sulfur source. The factors on degradation effect were discussed including the pH value of degradation system and the type of light source. The degradation effect of CdS samples increased with the pH value decreased, and the degradation effect was better when the methyl orange solution was irradiated under sunlight than under 250 W mercury lamp. PMID- 23755674 TI - Tunable wettability and rewritable wettability-gradient in self-cleaning composites containing nanoscale photocatalysts. AB - The photo induced properties of self-cleaning materials can be attributed to the synergy of two fundamental photochemical phenomena, oxidation-reduction reaction of adsorbed substances and photo induced superhydrophilicity, which occur on the surface of photo catalysts. The photo-induced properties make these materials able to mimic the tunable wettability of the Nepenthes-Rafflesiana leaf and tune their wettability while decomposing the air pollution. In this study the effects of UV radiation and dark storage on reversibility of the surface wettability in cement-based composites containing tin oxide nanoparticles, were investigated. In addition the self-cleaning properties of these composites were determined by measuring the decomposition of Methylene blue (MB). PMID- 23755675 TI - Preparation of anatase/rutile mixed-phase titania nanoparticles for dye sensitized solar cells. AB - Acid-labile high surface mesoporous ZnO/Zn(OH)2 composite material is used as a novel hard template for the preparation of mesoporous amorphous TiO2. The template-free amorphous TiO2 material is then thermally crystallized at suitable temperature to control the relative ratio of anatase and rutile phases in a particle. Four different anatase/rutile (AR) mixed-phase TiO2 nanoparticles (AR 3, AR-15, AR-20, and AR-23 denoted for the samples of 3%, 15%, 20%, and 23% rutile phase, respectively) are prepared and characterized by powder X-ray diffraction (PXRD) and transmission electron microscopy (TEM). The coexistence of anatase and rutile phases in a TiO2 nanoparticle is visually confirmed by HRTEM analysis. These mixed-phase TiO2 nanoparticles are examined as candidates for photoelectrodes of dye-sensitized solar cells (DSSCs). The J-V curves and IPCE spectra for the DSSCs prepared from the mixed-phase TiO2 nanoparticles are obtained, and their photovoltaic properties are investigated. The photo conversion efficiency (eta) indicates the highest value of 5.07% for AR-20. The synergistic effect of coexisting anatase and rutile phases with an optimal ratio in a TiO2 nanoparticle of AR-20 for an efficient interfacial transfer of photo generated electrons is likely to lead to the highest efficiency among the AR-n samples. PMID- 23755676 TI - Syntheses of LiMn2O4 nanoparticles with nano-size precursor and its electrochemistry performance. AB - LiMn2O4 nanoparticles were prepared by solid state reaction with nano-size Mn3O4 precursor. Mn3O4 nanoparticles with the size of about 200 nm were prepared via controlled crystallization method, which were used as the precursor to prepare LiMn2O4 in nanometer size. The size of LiMn2O4 synthesized by the route is about 300 nm. Cyclic voltammetry shows two pairs of clearly-separated oxidation peaks, located at 4.07 and 4.19 V, and reduction peaks, located at 3.91 and 4.07 V. The as-synthesized LiMn2O4 nanoparticles exhibit good electrochemical performance with an initial discharge capacity of 125.9 mAh x g(-1) at a current density of 14.8 mA x g(-1). The LiMn2O4 nanoparticles show wonderful cycle ability and the capacity retention ratio is 92.1% after 650 cycles at the current density of 296 mA x g(-1). PMID- 23755677 TI - Nanoimmobilization of marine epoxide hydrolase of Mugil cephalus for repetitive enantioselective resolution of racemic styrene oxide in aqueous buffer. AB - We developed two nanoimmobilized biocatalyst systems of thermally unstable Mugil cephalus epoxide hydrolase (McEH) for enantioselective resolution of racemic styrene oxide in aqueous buffer. The recombinant and purified McEH enzyme was immobilized onto magnetic nanoparticles (Mag-NPs) via a two step process of enzyme precipitation and crosslinking. McEH enzyme was also adsorbed, precipitated, and cross-linked in/on polyaniline nanofibers (PANFs). The residual relative activity of free McEH, defined as the ratio of residual activity to the initial activity, was 8% after incubation at 30 degrees C for 80 h while those of McEH immobilized onto Mag-NPs and in/on PANFs were 15% and 33% in the same condition, respectively. McEH immobilizations onto Mag-NPs and in/on PANFs could be reused in seven repetitive batch reactions for enantioselective hydrolysis of racemic styrene oxide to prepare (S)-styrene oxide with 98% enantiomeric excess (ee) while retaining greater than 40-50% of their initial activity. PMID- 23755678 TI - Preparation of mesoporous Si-C-O fibers with a narrow mesopore size distribution. AB - Mesoporous Si-C-O fibers were fabricated by air activation of a kind of carbon rich SiC-C fibers at 600 degrees C. The SiC-C fibers were prepared from the hybrid precursor of polycarbosilane and pitch through melt-spinning, air curing and pyrolysis in nitrogen. The carbon content of the SiC-C fibers was 54.4 wt%, and decreased to lower than 25 wt% after activation for more than 5 hours. Meanwhile, the surface area increased up to 260 m2/g, with a narrow mesopore size distribution mainly in the range of 2-5 nm. The SiC-phase derived from the polycarbosilane and the C-phase derived from the pitch form a bicontinuous interpenetrating network, which plays an important role for the narrow pore size distribution. PMID- 23755679 TI - Pore size reduction in directional crystallization processing of porous polymeric membranes. AB - Although various prep technologies of porous polymeric materials have evolved, the versatile control of pore morphology still remains as the most demanding subject. Herein, we applied the engineering principles of crystal habit by directional crystallization to the fabrication of porous PVDF (polyvinylidene fluoride) membranes. Pores of low tortuosity and relatively high porosity (80 90%) were successfully fabricated by the directional crystallization of DMSO (dimethyl sulfoxide) under a temperature gradient imposed by the controlled movement of a sample toward a liquid nitrogen reservoir followed by subsequent solvent removal. Pore size was controlled across a wide range by mixing DMSO with dioxane. Notably, nanoporous structures could be prepared at a 1:1 mixing ratio, in which the multi-step crystallization of solvents restricted by highly concentrated solutes enabled the preparation of nanomembranes. The homogeneous dispersion of TiO2 nanoparticles into PVDF, which are often used to improve hydrophilicity and antifouling performance, was easily achieved by this method. This novel prep technology based on the directional crystallization of solvent mixtures is a potentially viable solution to the limitations of current porous materials research. PMID- 23755680 TI - Synthesis and characterization of hollow silica particles from tetraethyl orthosilicate and sodium silicate. AB - We herein introduce an effective method to synthesize hollow silica particles (HSPs) from tetraethyl orthosilicate (TEOS) and sodium silicate (Na2SiO3) as silica sources using a sacrificial template method with a simple modification. The advantage of the method is that it can be applied to synthesize HSPs from not only TEOS but also Na2SiO3 silica sources without changing the method adopted to obtain the sacrificial polymeric templates. Polystyrene particles are adopted as sacrificial templates to synthesize the HSPs, and a conventional dispersion polymerization method is used to synthesis polystyrene particles in an oil medium. Size control of HSPs is enabled by modulation of the polymerization initiator content (2,2'-Azoisobutyronitrile). The particle size, shell thickness, and morphology are analyzed. Light reflection spectra are measured to obtain the light reflection properties of the HSPs. The results indicate that the hollow architecture is the most important factor in determining the light reflection properties of the particles. Such particles are potential candidates for use in light reflectors and heat insulators, as they may reduce energy consumption in heating and cooling applications. PMID- 23755681 TI - Gripe water as reducing and stabilizing agent for synthesis of size controlled gold nanoparticles. AB - Green synthesis techniques are emerging as more facile and eco-friendly approach for the synthesis of metal nanoparticles compared to chemical reduction methods. Herein we report a new approach to synthesize gold nanoparticles (AuNPs) using gripe water as a reducing as well as stabilizing agent. Good control over the size of the nanoparticles from 3.2 nm to 25 nm has been achieved with this method by simply varying the experimental conditions. The Surface Plasmon Resonance bands of tunable gold nanospheres with high monodispersity and polydispersity have been obtained by this technique and monitored using UV-Visible spectrum. The morphology and the size of these AuNPs are determined using High Resolution Transmission Electron Microscope (HR-TEM). X-Ray Diffraction (XRD) analysis confirms the crystalline nature and the phase of the AuNPs. The as-synthesized AuNPs exhibit good optical nonlinearity. The nonlinear optical studies have been carried out by Z-scan technique to demonstrate its optical limiting property. The threshold limit of the AuNPs is obtained at a input intensity of 30 mW. The nonlinear refractive index of the nanoparticles is in the order of 10(-9) cm2/W and the third-order nonlinearity is estimated to be 7 x 10(-5) esu. PMID- 23755682 TI - Influence of external factors on the production and morphology of biogenic silver nanocrystallites. AB - Naturally existing biological materials have been garning considerable attention as environmentally benign green-nanofactories for the fabrication of diverse nanomaterials, and with desired size and shape distributions. In the present investigation, we report the size and shape controllable biofabrication of silver nanocrystallites using the growth extract of the fungus, Rhizoctonia solani. Influence of various factors such as growth medium; radiation, in the form of sun light; and seeding duration on the production of silver nanoparticles using aqueous 1 mm silver nitrate solution under ambient conditions is presented. Our results demonstrate that these factors can significantly influence the production, size and shape transformation, and the rate of nanoparticles formation. Multiple characterization techniques involving UV-visible and Fourier transform infrared spectroscopy, X-ray diffraction, energy dispersive X-ray spectroscopy and transmission electron microscopy measurements confirmed the production, surface and structural characteristics, purity and crystalline nature of the biosynthesized silver nanoparticles. Our biogenic synthesis process provides a simple, ecologically friendly, cost-effective synthesis route, and most importantly the ability to have control over the size and shape distributions that lends itself for various biomedical and opto-electronic applications. PMID- 23755683 TI - The influences of reaction conditions on magnetic porous pseudo-carbon paste electrode for schistosoma egg antigen detection. AB - A novel and sensitive electrochemical sensor based on magnetic porous pseudo carbon paste electrode (MPPCPE) for schistosoma egg antigen (SEA) detection was described. The influences of immune reaction conditions such as time, pH and temperature on the detection current were investigated, and the influences of the blocking times of mercaptoethanol and ethanolamine on the background current were investigated. The experimental results shown that the high detection current and low background current could be obtained when the immune reaction temperature was 30 degrees C, the immune reaction time was 40 min, the immune reaction pH was 7.2, the blocking time of ethanolamine was 40 min, and the blocking time of mercaptoethanol was 60 min. At the optimum reaction conditions, a limit of detecting SEA as low as 0.01 microg/mL was obtained using MPPCPE. PMID- 23755684 TI - Functionalized IRMOF-3: an efficient heterogeneous catalyst for the cycloaddition of allyl glycidyl ether and CO2. AB - Functionalized metal organic framework F-IRMOF-3 having quaternary ammonium group was prepared by a fast precipitation and solvothermal method. They showed good catalytic performance for the cycloaddition of allyl glycidyl ether (AGE) and carbon dioxide without any solvent. F-IRMOF-3 with a larger alkyl chain structure and more nucleophilic anion exhibited better reactivity for the cycloaddition reaction. The introduction of a defective ZnO to F-IRMOF-3 by the fast precipitation method becomes more advantageous than the conventional solvothermal method for the cycloaddition reaction due to acid-base bifunctional active sites. The F-IRMOF-3 can be easily recovered and reused without any considerable loss of initial activity. PMID- 23755685 TI - Functional display of active tetrameric beta-galactosidase using Bacillus subtilis spore display system. AB - For the functional bacterial surface display of active enzyme of multimeric form, which is generally impossible due to molecular assembly of the monomer subunit subsequent to the secretion of displayed target protein outside the cell, a new surface display system based on B. subtilis spore was developed. Using cotE and cotG of B. subtilis as anchoring motives, beta-galactosidase, which is active in tetrameric form, was functionally displayed on the surface of B. subtilis spore. The surface localization of beta-galactosidase was verified by Miller assay of purified spore, protease accessibility test of purified spore, and flow cytometric analysis of spore expressing beta-galactosidase. While B. subtilis spore wall integrity, examined by lysozyme and heat treatments, was affected by the incorporation of CotE-LacZ fusion protein, it was not affected by the incorporation of CotG-lacZ fusion. Heat stability of displayed protein was similar with that of free enzyme. PMID- 23755686 TI - Photocatalytic decomposition of methyl orange over nanosized perovskite-type oxides under visible light irradiation. AB - In this study, we have investigated the photocatalytic activity for the decomposition of methyl orange on the LaCoO3 perovskite-type oxides prepared using sol-gel method at different conditions. From the results of UV-Vis DRS, all the catalysts have the similar absorption spectrum up to visible region. The LaCoO3 catalyst prepared at 1.5 mol of malic acid and calcined at 350 degrees C shows the highest activity. The amount of photo absorption in the visible region is correlated with the photocatalytic activity. In addition, the chemisorbed oxygen plays an important role on the photocatalytic decomposition of methyl orange and the higher are the contents of chemisorbed oxygen, the better shows the performance of photocatalyst. PMID- 23755687 TI - Rheological behaviors of nylon 6/silica modified melamine cyanurate non-halogen flame retardant composites. AB - Nylon 6 (PA 6)/silica modified melamine cyanurate (MCA) flame retardant (FR) composites were prepared by melt blending method. The morphology and rheological behaviors of composites were characterized using scanning electron microscopy and capillary rheometer. The results show that the presence of silica can improve the dispersion of mMCA in PA 6. The rheological behaviors are significantly affected by temperature, shear rate and the structure of composites. With increase of temperature and shear rate the apparent viscosities of composites decrease. All composites are pesudoplastic fluids. At same temperature and shear rate PA 6 composites, which contain different flame retardants (FRs) and different loadings, exhibit different viscosities. The presence of MCA can enhance the non Newtonian index of composites. The flow activation energies (E) of PA 6/silica modified MCA (S-mMCA) composites are larger than that of PA 6/pure MCA composites, and, with the increasing shear rate the flow activation energies of composites decrease. At a fixed FRs content, with the increase of silica loading, E of PA 6/S-mMCA composites increases firstly and then decreases. These results would be useful for the processing of FR PA 6 composites and for further understanding their flame retardant mechanisms. PMID- 23755688 TI - A novel recovery of silicon nanoparticles from a waste silicon sludge. AB - As the semiconductor and photovoltaic industry undergo rapid growth, a large amount of silicon sludge is generated from the cutting process of silicon ingots. However, it is not effectively recycled. Recovery of nanometer-sized silicon (Si) particles from the sludge has become an important concern because the silicon sludge contains valuable resources including high purity silicon. In the present study, we investigated the novel recovery of Si nanoparticles from waste silicon sludge. The waste silicon sludge also contained surfactant, silicon carbide particles and metallic fragments. After removal of the surfactant by distillation, the Si nanoparticles were recovered by applying controlled ultrasonic waves and centrifugation in series. Metallic impurities in the recovered Si nanoparticles were purified by HCl treatment. The overall maximum yield and purity of the Si nanoparticles were about 80% and 99.7%, respectively. PMID- 23755689 TI - Remarkable pH-responsive polypropylene microfiltration membrane through surface entrapment of poly(2-(diethylamino) ethyl methacrylate)-containing macromolecules by ATRP method. AB - Polypropylene (PP) microfiltration membrane were functionalized with an adsorption/surface entrapment process, using block copolymers with poly(n-butyl acrylate) (PBA) as anchor block being capable to tether the pH-responsive block poly(2-(diethylamino) ethyl methacrylate) (PDEA) to the surface, Homopolymer and Block copolymer synthesis was investigated by atom transfer radical polymerization (ATRP) using PMDETA, CuBr and ethyl acetate. These polymers were characterized by 1H NMR and GPC. Copolymer of PDEA with polybutylacrylate (PBA) was selected as best suitable modifier. Models related to the underlying deswelling/entrapment process which leads to fixation of the modifier were considered. Surface properties were analyzed by ATR-FTIR spectroscopy and water contact angle measurements, which confirmed the presence of modifier and a strong improvement of surface and pore wettability. The structure of membranes was evaluated using Polarized Optical Microscopy. Furthermore the pH-sensitive properties of modified PP membranes were verified by pH-dependence of water permeability which due to protonation/deprotonation and volume phase transition of PDEA around the pH 6-6.9. PMID- 23755690 TI - Estimating the solubility of amorphous ibuprofen using nanoporous anodic aluminum oxide as a solidification template. AB - Amorphous phases of active pharmaceutical ingredients (APIs) generally possess greater solubility than the crystalline counterparts. This presents them as attractive candidates for enhancing the bioavailability of the sparingly soluble drugs, while the unstable nature of them makes it challenging to reliably evaluate their potential improvement in solubility and utilize them in drug formulations. We have investigated the anodic aluminum oxide (AAO) substrates with nanopores to establish a simple system to examine the solubility increase accompanied by the decrease of the API crystallinity, using ibuprofen (IBU) as a model compound. The fabricated AAO substrates had the average pore diameters: 25, 55, and 370 nm. The AAO substrates with nanopores allowed the solidification of IBU with lower crystallinity. Also, the release behavior directly from the AAO substrates made it possible to estimate the accompanying solubility increase. The amorphous IBU in the 25-nm pores possessed solubility about 6 times higher than the bulk crystalline phase. The present study demonstrated that the nanoporous AAO substrates could be utilized as a straightforward tool to investigate the solubility and stability of the amorphous phases of APIs. PMID- 23755691 TI - Green method to form iron oxide nanorods in orange peels for chromium(VI) reduction. AB - A green method for synthesizing iron oxide nanorods within orange peel pith has been developed. Orange peel pith functions as both a support and a reducing agent for iron ions. The nanorods were characterized using scanning electron microscopy, energy dispersive X-ray spectroscopy, transmission electron microscopy and X-ray photoelectron spectroscopy. Results of the characterization indicate that iron is deposited on the surface of orange peel primarily in the form of iron, iron(II) oxide and magnetite. The nanoparticles grow to form nanorods in the range of 20-40 nm of diameter. The biocomposite was then tested for Cr(VI) reduction and removal from aqueous solutions, exhibiting removals as high as 96% for concentrations of 10 mg/L and 76% for 50 mg/L, which is almost 4 times the removal capacity of orange peel alone. PMID- 23755692 TI - Fabrication of the micro/nano-structure superhydrophobic surface on aluminum alloy by sulfuric acid anodizing and polypropylene coating. AB - The preparation of the superhydrophobic surface on aluminum alloy by anodizing and polypropylene (PP) coating was reported. Both the different anodizing process and different PP coatings of aluminum alloy were investigated. The effects of different anodizing conditions, such as electrolyte concentration, anodization time and current on the superhydrophobic surface were discussed. By PP coating after anodizing, a good superhydrophobic surface was facilely fabricated. The optimum conditions for anodizing were determined by orthogonal experiments. After the aluminium-alloy was grinded with 600# sandpaper, pretreated by 73 g/L hydrochloric acid solution at 1 min, when the concentration of sulfuric acid was 180 g/L, the concentration of oxalic acid was 5 g/L, the concentration of potassium dichromate was 10 g/L, the concentration of chloride sodium was 50 g/L and 63 g/L of glycerol, anodization time was 20 min, and anodization current was 1.2 A/dm2, anodization temperature was 30-35 degrees C, the best micro nanostructure aluminum alloy films was obtained. On the other hand, the PP with different concentrations was used to the PP with different concentrations was used to coat the aluminum alloy surface after anodizing. The results showed that the best superhydrophobicity was achieved by coating PP, and the duration of the superhydrophobic surface was improved by modifying the coat the aluminum alloy surface after anodizing. The results showed that the best superhydrophobicity was surface with high concentration PP. The morphologies of micro/nano-structure superhydrophobic surface were further confirmed by scanning electron microscope (SEM). The material of PP with the low surface free energy combined with the micro/nano-structures of the surface resulted in the superhydrophobicity of the aluminum alloy surface. PMID- 23755693 TI - Development of green nanotechnology and factors influencing it in China. AB - The rise of nanotechnology brings an unprecedented change to us, but its uncertainty may also causes unforeseen hazards to human health and the environment. Many countries around the world are actively researching and developing green nanotechnology which is non-toxic, environmentally friendly for the interests of humanity, and this systematic project needs the collaboration and efforts of government, research institutions, enterprises and public groups. PMID- 23755694 TI - Low temperature synthesis of N-doped TiO2 nanocatalysts for photodegradation of methyl orange. AB - N-doped TiO2 nanoparticles were synthesized using a hydrazine-assisted liquid method at low temperatures, owing to the additional heat provided by the decomposition of hydrazine nitrate, which was formed by reaction of hydrazine with nitric acid. Different crystal phases of N-doped TiO2 were studied by varying the nitric acid concentration, and calcination temperature and time. These photocatalysts were characterized using a transmission electron microscope, UV-vis photometer, X-ray diffractometer, and nitrogen adsorption. Photocatalytic performance of the N-doped TiO2 was studied by testing the degradation of methyl orange under visible irradiation. It was observed that N-doped TiO2 demonstrated much higher photocatalytic performance than commercial TiO2 (P-25) and exhibited excellent reusability. PMID- 23755695 TI - The controlled preparation of polypyrrole nanostructures via tuning the concentration of acrylic acid. AB - Two types of nanostructures, nanowires and nanoribbons were prepared with polypyrrole (PPy) by controlling the concentration of acrylic acid (AA) in systems containing cationic surfactant, cetyltrimethylammonium bromide (CTAB) at about 12 degrees C. The effect of reaction conditions involving the concentration of AA, CTAB, pyrrole as well as the reaction temperature was systematically studied on the final structures of prepared PPy. The results revealed that the polymerization of AA, resulting in PAA, played a key role in the evolution of PPy nanostructures. A possible mechanism was briefly discussed on the formation of these two nanostructures, nanowires and nanoribbons. PMID- 23755696 TI - Copper(L) selenide thin films deposited by a solution-based method for photovoltaic applications. AB - Polycrystalline Cu(2-x)Se thin films for solar cell application were deposited by a solution-based continuous flow reactor (CFR) process. In order to study the influence of reaction time on the physical, structural, and optical properties of the Cu(2-x)Se thin films, the deposition time for impinging varied from 2 min to 15 min. Based on X-ray diffraction (XRD), scanning electron microscopy (SEM), and UV-visible spectrophotometry, the optimum time to deposit the Cu(2-x)Se thin films using the CFR process was 10 min. The X-ray diffraction analysis revealed the cubic structure of the Cu(2-x)Se thin films annealed at 400 degrees C. The estimated band gap of the film was approximately 2.20 eV and its average grain size was around 150 nm with a film thickness of 1.8 microm. Energy dispersive analysis by X-ray (EDAX) showed that the atomic weight ratio of Cu to Se in the Cu(2-x)Se film deposited for 10 min was 1.8:1, i.e., x = 0.2. The chemical binding information of the Cu(2-x)Se thin film was also studied using X-ray photoelectron spectroscopy (XPS). PMID- 23755697 TI - George Emil Palade centenary (1912-2012). PMID- 23755698 TI - Considerations on the isolation of Listeria monocytogenes and other Listeria spp. in food products. AB - Listeria monocytogenes, a Gram positive bacillus, is well adapted for survival as a saprophyte in soil and decaying vegetation, but also able to cause serious infections, due to its ability of intracellular multiplication and meningeal and placental dissemination. A total number of 43 Listeria spp. strains isolated from food were investigated. Bacterial identification was performed according to standard methodology, based on: Gram staining affinity, morphology, culture aspects on blood agar (examined in oblique light), catalase test, beta/hemolysis (on sheep blood agar), CAMP test and carbohydrates breakdown, i.e., trehalose, mannitol, mannose, rhamnoze, xylose. Out of the 43 analyzed strains, the biochemical and serological assay evidenced: 10 strains of L.monocytogenes (8 belonging to serotype la and 2 strains to the serotype 4 b), 27 of L. innocua, 2 of L. grayi and 4 of L. welshimeri. L. innoqua was the most frequently identified species. L. monocytogenes strains typing confirms that the serotype la is most commonly found in food and serotype 4b was detected in imported foods. This observation has an epidemiological importance for our country. PMID- 23755699 TI - Comparative analysis of biofilm development among MRSA and MSSA strains. AB - As the recalcitrance of biofilm-mediated infections to the anti-infective treatment has an adverse effect on patient's health, the main objective of this study was to investigate the capacity of clinical isolates of Staphylococcus aureus with different resistance patterns to form biofilms. S. aureus strains are among the most representative etiology of infections in the health-care environment of Milad hospital in Iran. The results showed that out of 80 analyzed strains, 27 methicillin resistant S. aureus (MRSA) and 29 methicillin susceptible S. aureus (MSSA) were positive for biofilm development ability, without any significant correlation observed between MRSA and biofilm production. PMID- 23755700 TI - Correlations among different markers determined by immunochemical methods used for the diagnosis and monitoring of intact immunoglobulin multiple myeloma cases. AB - The purpose of this study was to determine the correlations between the concentration of free light chains (kappa, lambda and ratio kappa/lambda) and two other markers, M- protein and pathological total intact immunoglobulin in four groups of patients with intact immunoglobulin multiple myeloma (IIMM) at the diagnosis and during the treatment. In this study 354 samples coming from 46 patients with IIMM were assayed, out of which: 19, IgGkappa; 13, IgGlambda; 7, IgAkappa; 7, IgAlambda. At the diagnosis, immunofixation was positive in all samples and serum protein electrophoresis quantified M- protein for all patients. Free light chains concentrations were abnormal in 92.25% of patients with concentrations above the reference ranges in all patients with IgGkappa and IgAkappa MM. The intact immunoglobulins were elevated in 83.12% of cases. Pearson correlation coefficient showed correlations among the free light chains serum levels (kappa, lambda and ratio kappa/lambda), M- protein and intact immunoglobulins in two groups with IIMM (IgGlambda, IgAlambda). Spearman correlation coefficient values analysis showed that there is a good correlation between M-protein and FLCs (kappa, lambda and ratio kappa/lambda) in three patient groups (IgGkappa, IgGlambda and IgAlambda), excepting IgAkappa myeloma group where the correlation was insignificant. Regarding the intact immunoglobulin, Spearman coefficient showed significant correlations with FLCs concentrations in two groups (IgGlambda and IgAlambda) and an insignificant correlation in the group with IgGkappa MM. For the group of patients with IgAkappa myeloma, the Spearman coefficient showed that IgA concentrations did not correlate with the concentrations of FLCs. The individual correlation (for each patient) among FLCs, M- protein and intact immunoglobulins in 8 patients with IgGkappa IIMM proved to be more significant as compared with the degree of correlation established for the entire group of patients among these markers. Since the values obtained for the studied markers were not homogeneous, we have taken into account the Spearman coefficient values, which indicated the existence ofa correlation between the M-protein, FLCs and intact immunoglobulin. PMID- 23755701 TI - Double transgenic mice--a suitable model for studying oxidative stress in type 1 diabetes mellitus. AB - Type 1 diabetes mellitus (T1DM), one of the most prevalent chronic diseases is characterized by the progressive destruction of pancreatic beta cells, leading to insulin deficiency and hyperglycemia. Studies performed on diabetic subjects with prolonged hyperglycemia showed the oxidative stress occurrence followed by molecular, cellular and tissue damage. Currently, reducing the oxidative stress represents a therapeutic target, in order to reduce its complications in diabetic patients. An adequate experimental model of type 1 diabetes represents a prerequisite in oxidative stress study, therefore, we assessed oxidative status in polymorphonuclear cells (PMNs) and peritoneal macrophages using a double transgenic (dTg) mouse model of type 1 diabetes. Our results revealed the increased production of reactive oxygen species (superoxide anion and H2O2) and nitrogen (nitric oxide) species in diabetic mice leading to the idea of oxidative stress model for the study of its complications in type 1 diabetes. PMID- 23755702 TI - Capsaicin short term administration effect on different immune parameters. AB - Type 1 diabetes is an autoimmune disease affecting a higher and higher number of persons; for this reason, the study of diabetes, and its complications, has shown a major interest. In order to highlight the modifications appeared in this disease, it is essential to use a suitable model. In "Cantacuzino" NIRDMI there is a double transgenic murine model which develops a fulminating form of type 1 diabetes. Previous studies indicate the usefulness of this diabetic murine model in order to study neuropathy. Capsaicin treatment is one method to reduce neuropathic pain. This study was based on the assumption that intraperitoneal administration of a low dose of capsaicin, on a short period of time, can decrease pain sensations generation and transmission. If from the neurological point of view, capsaicin effects are known, its effects on the immune system are not clear yet. Therefore, in this study we have investigated capsaicin effects on oxygen and nitrogen free radicals generation by phagocytic immune cells, in lymphocyte populations, and also capsaicin effects on plasmatic protein oxidation. Our results point to minor modifications in oxygen reactive species production, simultaneous with a significantly decrease in nitric oxide generation, without affecting lymphocyte populations. Therefore, capsaicin short term administration can be used to reduce pain sensations, without the impairment of immune parameters. PMID- 23755703 TI - [Clinical case of the month. Tetanus still exists!]. AB - We report the dramatic story of a 81 year old patient admitted to the intensive care unit following the development of tetanus. This man, perfectly autonomous, used to workin his garden without anti-tetanus immunization coverage. In this article, we report the therapeutic management of tetanus. We emphasize the importance of vaccination which permits to avoid the disease, the mortality and morbidity of which remain high. PMID- 23755704 TI - [Adenomyosis]. AB - Adenomyosis is a medical benign condition of the endometrium-myometrium interface that is histopathologically characterized by the presence of ectopic tissue (endometrial glands and stroma) in myometrium. The diagnosis is complicated by the low specificity of its symptoms and the frequent associations with others gynaecologic pathologies. Consequently, paraclinic investigations are essential to make the diagnosis. PMID- 23755705 TI - [Orthostatic hypotension: 2nd part. Epidemiology, complications and treatments]. AB - Orthostatic hypotension (OH) is a rather common phenomenon in clinical practice. It may occur in 5-10 % of normal individuals, but its prevalence increases with age and various pathologies, so that it may rise above 35 % in certain subgroups of patients. OH is associated with various comorbidities, in particular cardio cerebro-vascular accidents and falls (especially in the elderly), and may even increase mortality. It is, however, difficult to determine whether OH is simply a marker of frailty or whether it is really a risk factor. OH treatment involves physical manoeuvres or medications, which aim at inducing a peripheral vasoconstriction (midodrine, etilefrine) or an increase of circulating blood volume (9-alpha-fluohydrocortisone). However, their use should be cautious, because of a risk of arterial hypertension in supine position. PMID- 23755706 TI - [Cerebrotendinous xanthomatosis, a rare, severe, but treatable metabolic disorder]. AB - Cerebrotendinous xanthomatosis (CTX) is a rare and treatable autosomal recessive disease. The diagnosis should be suspected in the presence of a suggestive clinical triad characterized by early-onset cataract, tendinous xanthomata and neurological symptoms and signs, notably cerebellar ataxia, mental retardation and pyramidal syndrome.The diagnosis is confirmed by demonstrating an increased blood level of cholestanol, or/and by molecular genetic analysis.In typical cases, brain MRI shows bilateral hyperintensity of the cerebellar nucleus dentatus together with cerebral atrophy and leukoencephalopathy. The treatment is based on the administration of chenodeoxycholic acid. The aim is to restore the negative feedback on the enzymatic cascade altered by mutation in the gene CYP27 which induces a 27-hydroxylase deficiency PMID- 23755707 TI - [Hooping cough in adults, think about it!]. AB - We report the case of a 47 year old patient who had been suffering from persistent cough for more than three weeks. Patient coughed predominantly during night time, without fever. The amoxicillin-clavulanic acid initially prescribed was not effective. A series of complementary investigations were performed before serology finally identified Bordetella pertussis infection after two months of symptoms which improved slowly without evident benefit of macrolide treatment. The diagnosis of whooping cough was also established for the wife of the patient with fast resolution of the symptoms after rapid unset of treatment with macrolides. PMID- 23755708 TI - [Epidemiology and characteristics of febrile seizures in children]. AB - Febrile Seizures (FS), despite their usual benign clinical course, are still subject of controversies regarding the need for further investigation and treatment with anti-epileptic drugs (AEDs). Our study aimed to inventory the clinical findings, laboratory and imaging data associated with FS and eventually influencing their management. 275 episodes admitted with FS at the emergency ward of the Liege CHR over a 5 year period were retrospectively analyzed regarding precipitating factors; clinical features; laboratory, electroencephalographic, and imaging studies; as well as treatment response. FS represented 1.4% of admissions to the pediatric service. 31.3% of patients had a family history of seizure disorder. 9% percent of seizures were focal, 11.7% recurrent, and 12.3% prolonged (greater than 10 minutes). Upper respiratory tract and otorhinolaryngologic viral infections were the most often implicated provoking factors, occurring in 69.5% of patients. Laboratory, electroencephalographic and radiographic studies were normal in more than 90% of cases. 73.8% of seizures resolved without intervention. An AED was required to manage the remaining 26.2%. This study confirms the favorable outcomes of FS as demonstrated in previous studies. This happens without requiring AEDs for resolution, and without recurrence. Laboratory, electroencephalographic and imaging studies, as well as initiation of AEDs should be based primarily on clinical severity. PMID- 23755709 TI - [How to cope with the bad reputation of depression]. AB - Today, the term depression has lost its meaning. Recent scientific data suggests a change in our classifications of mental disorders. Depression is frequently used to refer to "normal" sadness, anxiety disorders, personality disorders or adjustment disorders... Moreover, in our society, this diagnosis remains badly accepted. It is really time to be aware of the deterioration of the image of psychiatry, and particularly the bad image of depression and its treatment with antidepressants. This paper is a reflexion inviting general practicioners and psychiatrists to progressively avoid the term depression and rather use the diagnosis of unipolar mood disorder, a broader concept, more adapted to new scientific data, less stigmatizing, and closer to the evolution of our society. PMID- 23755710 TI - [How I treat ... with metformin a diabetic patient with moderate renal insufficiency]. AB - Numerous patients with type 2 diabetes have renal impairment, especially in the elderly population. Metformin, the first choice oral glucose-lowering agent, is classically contraindicated in case of chronic kidney disease of stages 3-5 (creatinine clearance < 60 ml/min/1.73 m2), because of a risk of accumulation of the biguanide that may lead to lactic acidosis. Hence numerous patients with some degree of renal impairment are being treated with metformin in clinical practice, apparently without any harm. In contrast, several observational studies have shown that they may clinically benefit from this therapy, including with a significant reduction of all-cause mortality when compared to patients not receiving metformin. Thus, an increasing number of physicians plea for revisiting the official criteria of contraindication to the use of metformin in case of renal insufficiency. The present paper discusses this controversy and insists upon the mandatory cautions to be taken when using metformin in a diabetic patient with moderate (stage 3) chronic kidney disease (metformin being contraindicated in case of severe renal impairment - stages 4-5). PMID- 23755711 TI - [Medication of the month. asenapine (Sycrest]. AB - Asenapine is a new atypical antipsychotic. Like other atypicals, asenapine acts as an antagonist at both dopamine D2 and serotonin 5-HT2A receptors. The efficacy of asenapine monotherapy in the treatment of bipolar disorder manic episodes in adults has been demonstrated in two similarly designed randomized placebo controlled flexible-dose trials of 3 weeks' duration, using olanzapine as active reference. Asenapine is associated with a good tolerability profile. In particular, asenapine induces a moderate weight gain, and does not increase serum levels of lipids or fasting glucose. PMID- 23755712 TI - [Diagnosis of gestational diabetes]. AB - Gestational diabetes (GD) is a common complication of pregnancy. Its prevalence depends on the strategy used for screening and the studied population. Pregnant women with GD are at increased risk for maternal and fetal complications. The relationship between maternal blood sugar and complications is linear, without a clear threshold defining GD. Therefore, the diagnostic criteria for GD have been the subject of several controversies since many years. The choice of the one-step or two-step method, the test to be used and the cut-off levels validated to define GD are still debated. The same is true regarding a universal versus a at risk population screening. International experts have recently proposed the use of a one-step approach with a 2-hour oral glucose tolerance test for a universal screening. The need for a better harmonization regarding the diagnosis of GD is indeed mandatory. The present article discusses both the advantages and disadvantages of the various approaches used for GD screening. PMID- 23755713 TI - [Clinical examination of children with cerebral palsy: is there a consensus between clinicians?]. AB - Diagnosis and most of all classification of children with cerebral palsy (CP) remain a challenge for clinicians. To help them in this process, clinicians can rely on several clinical testing procedures as well as complementary investigations. The goal of this study was to determine which clinical tests found in the literature are the most frequently used in common practice in Belgium. Forty tests have been found in the literature. They have been sorted into five different categories: quantitative evaluation of motor function, spasticity evaluation, orthopaedic testing, upper limb evaluation and complementary investigations. Seven clinicians (five medical doctors and two physiotherapists) with a mean experience of sixteen years with CP children answered the questionnaire. Concerning the quantitative evaluation of motor function the most used tests are: Gross Motor Function Classification System, Manual Ability Classification System and the Pediatric Evaluation of Disability Inventory (PEDI). As regards spasticity, Ashworth scale is more frequently used than Tardieu test. No trend currently exist for the upper limb evaluation, but it was noted that these tests are rarely used in clinical practice. We observed a significant use of gait analysis at diagnosis and follow-up of CP children. We conclude that there are large differences between clinicians for clinical examination of CP children. This lack of consensus makes patient data comparison difficult between clinical centers. This seems to indicate that a homogenization effort should be organized if one wishes to better stimulate collaborations between centers. PMID- 23755714 TI - [Implementation of the therapeutic hypothermia recommendation after resuscitated cardiac arrest caused by ventricular fibrillation and tachycardia without pulse: a retrospective study in Saint-Pierre Hospital]. AB - INTRODUCTION: Therapeutic hypothermia is an essential step for the neurological protection of comatose individuals after cardiorespiratory arrest (CA) and ventricular fibrillation (VF). The evaluation of the application of the Protocol thereto within the C.H.U. Saint-Pierre (SPH) is the subject of this study. METHOD: Retrospective analyzes of the SPH computerized records from 01/01/2005 to 31/12/2010 whose inclusion criteria are out-of-hospital CA admitted alive to the hospital with VF as initial rythm. Transferred patients or NTBR status are excluded. RESULTS: Of the 72 patients studied, 68% were discharged alive from the hospital, 84% of which has no neurologic sequelae. Hypothermia was used for 44 people, unduly in 5 cases and there were also 5 other cases for which it was needed, but not applied. Hypothermia (32-34 degrees C) was reached in 11 h 23 (+/ 144 min) and lasted an average of 19 h 51 (+/- 249 min). Hypothermic patient survival amounted to 72.4%, including 81% with good neurological outcome. CONCLUSION: The results of the protocol application are superior to those of several other studies. Few errors of inclusion and exclusion are present. The implementing of a common protocol for IC--Emergency Units--EMS to accelerate obtaining the target temperature and improve performance seems beneficial. The creation and implementation of a specific register with patients who had AC and were cooled seem interesting for a better medical follow-up, an assessment of the management and an enhancement of the current knowledge related to this technique. PMID- 23755715 TI - [Evaluation of DCA vantage for rapid in-clinic measurement of HbA1c on capillary blood in young type 1 diabetic patients]. AB - Rapid in clinic measurement of glycated hemoglogin (HbA1c) allows to determine the level of metabolic control within a few minutes on capillary blood. We have evaluated the new DCA Vantage (Siemens) based on an immunological technique, replacing the DCA 2000+ (Siemens). The study included 120 unselected young type 1 diabetic patients, with different degrees of metabolic control. The DCA Vantage was compared with the HPLC system (Menarini HA 8160) whose deviation from the DCCT was < 0.1% across the clinical range. The mean underestimation of the DCA Vantage was -0.40%. The agreement limits (+/- 1.96 SD) were between 0.14% and 0.93%; this means +/- 0.53% around -0.40%. In conclusion, the DCA Vantage underestimates HbA1c levels; however it met the acceptance criteria of having a coefficient of variation < 3%. PMID- 23755716 TI - [The contribution of neuroscience research to the study of empathy]. AB - The study of the cerebral mechanisms underlying empathy lies currently at the heart of neuroscience research. This process which can be defined as "the ability to put oneself into other's shoes in order to feel his emotions and feelings", constitutes a basic skill in any interpersonal relationship, particularly in the caregiver-patient relationship. In addition, the study of empathy impairements offers new ways to approach diverse mental disorders such as autism or psychopathy. However, it is essential to identify how the brain processes empathy in healthy subjects before studying its impairements. The purpose of this paper will then be to synthesize what the neuroscience research already identified thanks to the numerous works in neurophysiology, neuroimaging and lesion studies. We will also mention some limitations of this field of research and end the paper with its future perspectives. PMID- 23755717 TI - [Thoracic oncology: annual review]. AB - The objective of this paper is to review the literature published in 2011-12 in the field of thoracic oncology. Are discussed because of new original publications: epidemiology, screening, pulmonary nodule, diagnosis and assessment, treatment of lung cancer non-small cell, small cell lung cancer, prognosis, palliative care and end of life, organization of care, mesothelioma. PMID- 23755718 TI - [Intracranial Rosai-Dorfman disease mimicking multiple meningiomas]. AB - A 38 years-old man, who had olfactive schwannoma totally removed, with favorable clinical evolution and no radiological recurrence, suffered from headache and frontal syndrome, seven years after surgery. MRI of the brain showed multiple extra-axial lesions, disseminated, mimicking multiple meningiomas. The surgical strategy consisted in primary removal of the most symptomatic lesion. Histopathological examination after immunohistochemical tests permitted the definitive diagnosis of Rosai-Dorfman disease of the central nervous system. Evolution was still favorable 6 months after surgical removal of the whole lesions. PMID- 23755719 TI - [Maurice Herlant (1887-1920), a shooting star of embryology]. AB - Maurice Herlant (1887-1920) was a Belgian embryologist who worked at the Universite libre de Bruxelles during his brief career. He was the assistant of Professor Albert Brachet and was interested by polyspermia and experimental parthenogenesis. His promising career was interrupted by an early death at 33 years of age. PMID- 23755720 TI - A facile one-pot synthesis of functionalized 1,3-oxathiolan-2-yliden derivatives: multicomponent reaction of oxiranes in water. AB - An efficient synthesis of 1,3-oxathiolan-2-yliden derivatives is described via a simple reactions between CHacids, CS2 and oxiranes in the presence of triethylamine at 70 degrees C in water as the solvent. The mild reaction conditions and high yields of the products exhibit the good synthetic advantage of this method. PMID- 23755721 TI - Pharmacokinetics of 3'-O-retinoyl-5-fluoro-2'-deoxyuridine (RFUdR), a dual acting mutually masking prodrug, and its metabolites in tumor bearing mice. AB - 3'-O-Retinoyl-5-fluoro-2'-deoxyuridine (RFUdR) is a putative dual-acting, mutually-masking (DAMM) prodrug for the treatment of cancer. As part of the proof of principle for the DAMM concept, the concentrations of RFUdR and its post hydrolysis active metabolites, 5-fluoro-2'-deoxyuridine (FUdR) and all-trans retinoic acid (RA), were determined in plasma and selected tissues following either bolus intravenous (i.v.; 12.5 MUmol/kg) or oral (p.o.; 13.7 MUmol/kg) doses of RFUdR to mice bearing EMT6 murine mammary tumors. The concentrations of RFUdR and its primary metabolites were measured by high-performance liquid chromatography. A three compartment model provided the best fit for plasma RFUdR after an i.v. bolus, whereas FUdR and RA data were best fit by a one compartment model. The terminal half-life of RFUdR in plasma was 9 hours. The AUC of RFUdR in tumor (3400 MUmol/L.min) was estimated to be about 4- fold higher than its AUC in the plasma (809 +/- 241 MUmol/L.min). A short-duration, saturated elimination phase for RFUdR was observed in both liver and kidney following an i.v. bolus. Neither unchanged RFUdR nor RA was detected in urine. The high bioavailability (~90%) following oral dosing with RFUdR indicates that this DAMM prodrug may be suitable for oral dosing to deliver FUdR and RA for cancer chemotherapy. PMID- 23755722 TI - Comparative pharmacokinetic studies of fast dissolving film and oral solution of ondansetron in rats. AB - Ondansetron, selective serotonin (5-HT3) receptor blocker, is used in treating chemotherapy induced nausea and vomiting in cancer patients. Mouth dissolving films containing ondansetron were developed to have better onset and patient compliances. The drug content of prepared films was within 85%-115%. The films were found to be stable for 4 months when stored at 40 % degrees C and 75% RH. In vitro dissolution studies suggested a rapid disintegration, in which most of ondansetron was released (91.5+/-3.4%) within 90 sec. Subsequently, Sprague Dawley rats were used to compare pharmacokinetic parameters of the formulated films with oral administration of pure drug solution. Pharmacokinetic parameters were similar between the two groups in which AUC0-t (ng h/ml), AUC0-infinity (ng h/ml), Cmax (ng/ml), Tmax (min), Kel (h(-1)) and t1/2 (h) of reference was 109.091+/-15.73, 130.32+/-18.56, 28.5+/-4.053, 60, 0.1860+/-0.0226, and 3.771+/ 0.498 respectively; and for formulated film 113.663+/-16.64, 151.79+/-16.54, 30+/ 3.51, 60, 0.1521+/-0.0310 and 4.755+/-0.653 respectively. These results suggest that the fast dissolving film containing ondansetron is likely to become one of the choices to treat chemotherapy induced nausea and vomiting. PMID- 23755723 TI - Reacting to stress: radical cellular pathways for novel drug development. PMID- 23755725 TI - Stable gastric pentadecapeptide BPC 157-NO-system relation. AB - We reviewed stable gastric pentadecapeptide BPC 157-NO-system-relation, its close participation in Moncada's (maintained vascular integrity, platelets control) homeostatic healing response of NO-system to injury. Namely, BPC 157's particular healing effect also affects all events after vascular integrity loss (dependent on circumstances, it reduces either thrombosis (abdominal aorta anastomosis) or bleeding/thrombocytopenia (amputation, heparin, warfarin, aspirin)) and in a series of different injurious models, acute and chronic, BPC 157 consistently advances healing after severe injuries in various tissues spontaneously unable to heal; stimulates egr-1 and naB2 genes; exhibits high safety (LD1 not achieved)). Hypothesis, that BPC 157 (since formed constitutively in the gastric mucosa, stable in human gastric juice, along with significance of NO-synthase and the basal formation of NO in stomach mucosa, greater than that seen in other tissues) exhibits a general, effective competing both with L-arginine analogues (i. e., L NAME) and L-arginine, and that this has some physiologic importance (NO generation), later, practically supports its beneficial effects illustrating BPC 157 and NOsystem mutual (with L-NAME/L-arginine; alone and together) relations in (i) gastric mucosa and mucosal protection, following alcohol lesions, in cytoprotection course, NO-generation, and blood pressure regulation; (ii) alcohol acute/chronic intoxication, and withdrawal; (iii) cardiovascular disturbances, chronic heart failure, pulmonary hypertension, and arrhythmias; (iv) disturbances after hypokalemia and hyperkalemia, and potassium-cell membrane dysfunction; and finally, in (v) complex healing failure, proved by the fistulas healing, colocutaneous and esophagocutaneous. However, how this advantage of modulating NO system (i. e., particular effect on eNOS gene), may be practically translated into an enhanced clinical performance remains to be determined. PMID- 23755726 TI - Probiotics in the mechanism of protection against gut inflammation and therapy of gastrointestinal disorders. AB - A growing body of experimental and clinical evidence supports the hypothesis that the intestinal microbiota markedly influences function and the structure of the mucosal lining. Intestinal microbiota can potentially cause damage to the mucosa either directly by releasing toxins or indirectly by causing a detrimental immune response. Probiotic bacteria have been defined as live microorganisms, which when consumed in adequate amounts, confer a health benefit for the host. In recent years, the therapeutic and preventive application of probiotics for several gastrointestinal and liver disorders has received increasing attention. Probiotics appear to be beneficial for premature infants who suffer necrotizing enterocolitis. The effectiveness of certain probiotics as treatment for infectious and antibioticassociated diarrhea in adults and for allergic disorders in children has been supported by clinical studies; however, the potential mechanism( s) remains to be studied. Experimental studies and clinical trials for probiotic treatment of inflammatory bowel diseases (IBD) have yielded conflicting results. Daily intake of selected probiotics was effective in the prevention of ulcerative colitis and the attenuation of the active onset of Crohn's disease or ulcerative colitis but others failed to show a beneficial effect. The combination of Lactobacillus, Bifidobacterium, Saccharomyces boulardi and the treatment with Escherichia coli Nissle were found beneficial in inducing and maintaining remission of disease activity of gut inflammation and moderately severe ulcerative colitis. Probiotic bacteria were considered in some studies as a safe adjuvant when added to triple eradication therapy against the symptoms induced by the major gastric pathogen, Helicobacter pylori. This review attempted to overview these new exciting advances in the role of these microbes in the pathogenesis, management and treatment of gastrointestinal disorders. PMID- 23755727 TI - VEGF and colon cancer growth beyond angiogenesis: does VEGF directly mediate colon cancer growth via a non-angiogenic mechanism? AB - In this article we review the role of vascular endothelial growth factor (VEGF) in colon cancer growth and the underlying mechanisms. Angiogenesis, the growth of new capillary blood vessels in the body, is critical for tissue injury healing and cancer growth. In 1971, Judah Folkman proposed the concept that tumor growth beyond 2 mm is critically dependent on angiogenesis. Tumors including colon cancers release angiogenic growth factors that stimulate blood vessels to grow into the tumors thus providing oxygen and nutrients that enable exponential growth. VEGF is the most potent angiogenic growth factor. Several studies have highlighted the role of VEGF in colon cancer, specifically in the stimulation of angiogenesis. This role of VEGF is strongly supported by studies showing that inhibition of VEGF using the blocking antibody, bevacizumab, results in decreased angiogenesis and abrogation of cancer growth. In the United States, bevacizumab in combination with chemotherapy is FDA approved for the treatment of metastatic colon cancer. However, the source of VEGF in colon cancer tissue, the mechanisms of VEGF generation in colon cancer cells and the molecular pathways involved in VEGF mediated angiogenesis in colon cancer are not fully known. The possibility that VEGF directly stimulates cancer cell growth in an autocrine manner has not been explored in depth. PMID- 23755728 TI - Chondrogenic potential of two hASCs subpopulations loaded onto gellan gum hydrogel evaluated in a nude mice model. AB - Cells constitute one of the fundamental components of any cartilage tissue engineering approach. Adipose tissue derived stem cells (ASCs) have a promising future considering the abundance of this tissue in the human body, ease of harness, and the high number of stem cells that can be isolated from small amounts of tissue. However the stromal vascular fraction of the adipose tissue that is isolated upon digestion by collagenase followed by a rough selection of the adherent cells, is composed of many different types of cells, some of which may compromise the proliferation and the differentiation of the ASCs. This manuscript reports a study on the in vivo chondrogenic potential of two ASCs specific subpopulations isolated using a method based on immunomagnetic beads coated with specific antibodies. These ASCs subpopulations, isolated using immunomagnetic beads coated with CD29 and CD105 antibodies, were subsequently transfected with green fluorescent protein (GFP), expanded, and pre differentiated into the chondrogenic lineage, before being encapsulated in a novel hydrogel based on gellan gum, that has recently been showed to promote in vitro and in vivo cartilage tissue formation. The two ASCs subpopulations encapsulated in the gellan gum hydrogel and in vitro pre-differentiated, were then subcutaneously implanted in nude mice for 6 weeks. Explants were analyzed by various techniques, namely histology, immunohistology and real time RT-PCR that demonstrated the different behaviour of the two ASCs subpopulations under study, namely their potential to differentiate into the chondrogenic lineage and to form new cartilage tissue. PMID- 23755729 TI - Utility of cryopreserved umbilical cord tissue for regenerative medicine. AB - MSCs can be isolated from adult sources such as bone marrow and adipose tissue. In contrast to these adult tissue sources, harvesting MSCs from cord tissue is a non-invasive procedure and poses no risk to the donor. Stem cell banks offer the opportunity to cryopreserve cord tissue as a source of MSCs for future autologous or allogeneic stem cell based regenerative medicine applications. There is little published data however, characterizing MSCs isolated from cryopreserved cord tissue. The goal of this study was to determine if MSCs isolated from cryopreserved cord tissue are functionally equivalent to MSCs isolated from fresh cord tissue. Umbilical cords were collected from 10 donors. Cords were segmented into 4-6 inch pieces and either cryopreserved or used immediately. Fresh and thawed cord segments were cultured in 7-14 days for outgrowth of MSCs. MSCs were analyzed by FACS for CD45, CD73, CD90 and CD105 expression. FACs analysis confirmed cells isolated from both fresh and frozen tissue expressed MSC markers. Adherent cells were obtained from both fresh and cryopreserved cord tissue segments at a similar plating efficiency. There was no difference in either the number or time of population doublings. MSCs isolated from fresh and frozen tissue were capable of differentiating along adipogenic, chondrogenic, osteogenic and neurogenic pathways, as confirmed by histology and RT-PCR analysis of tissue specific mRNAs. No significant functional differences were observed between MSCs from frozen cord tissue as compared to fresh cord tissue. Cryopreserving cord tissue allows for isolation of MSCs at the point of care when the specific clinical application is known. This may be advantageous as MSC isolation protocols continue to be optimized dependent on intended use. PMID- 23755730 TI - Relation of eggs with incident cardiovascular disease and diabetes: friends or foes? PMID- 23755731 TI - Moving beyond warfarin-are we ready? A Review of the efficacy and safety of novel anticoagulant agents compared to warfarin for the management of atrial fibrillation in older adults. AB - Atrial fibrillation (AF) is one of the most common cardiac arrhythmias seen in clinical practice. Stroke risk in patients diagnosed with AF increases from 1.5% in the fifth decade of life to 23.5% in patients older than 80, emphasizing the need for effective and appropriate therapies. Over the past 50 years, vitamin K antagonists-namely warfarin (Coumadin((r)))-have been the mainstay for stroke prevention. The introduction of dabigatran (Pradaxa((r))), rivaroxaban (Xarelto((r))), and apixaban (Eliquis((r))) has caused both patients and providers to question whether better alternatives to warfarin therapy exist. These agents have shown to be at least as effective as warfarin in stroke risk reduction with no need for international normalized ratio monitoring. This review will examine these newer anticoagulant agents' safety and efficacy and provide clinical considerations for treating older adults with AF. Clinicians with patients unable to tolerate warfarin or with difficulty managing therapy will need to consider patient characteristics, cost, adherence, lack of a reversal agent, and long-term efficacy before prescribing these agents. PMID- 23755733 TI - Graphene as a long-term metal oxidation barrier: worse than nothing. AB - Anticorrosion and antioxidation surface treatments such as paint or anodization are a foundational component in nearly all industries. Graphene, a single-atom thick sheet of carbon with impressive impermeability to gases, seems to hold promise as an effective anticorrosion barrier, and recent work supports this hope. We perform a complete study of the short- and long-term performance of graphene coatings for Cu and Si substrates. Our work reveals that although graphene indeed offers effective short-term oxidation protection, over long time scales it promotes more extensive wet corrosion than that seen for an initially bare, unprotected Cu surface. This surprising result has important implications for future scientific studies and industrial applications. In addition to informing any future work on graphene as a protective coating, the results presented here have implications for graphene's performance in a wide range of applications. PMID- 23755732 TI - Symptom communication during critical illness: the impact of age, delirium, and delirium presentation. AB - Symptom communication is integral to quality patient care. Communication between patients and nurses in the intensive care unit (ICU) is complicated by oral or endotracheal intubation and fluctuating neurocognitive status or delirium. We report the (a) prevalence of delirium and its subtypes in non-vocal, mechanically ventilated, critically ill patients; (b) impact of age on delirium; and (c) influence of delirium and age on symptom communication. Videorecorded interactions between patients (N = 89) and nurses (N = 30) were analyzed for evidence of patient symptom communication at four time points across 2 consecutive days. Delirium was measured at enrollment and following sessions. Delirium prevalence was 23.6% at enrollment and 28.7% across sessions. Participants age >60 were more likely to be delirious on enrollment and during observational sessions. Delirium was associated with self-report of pain, drowsiness, and feeling cold. Patients were significantly less likely to initiate symptom communication when delirious. Symptom identification should be carefully undertaken in older adults with or without delirium. PMID- 23755735 TI - Activation of Wnt5a-Ror2 signaling associated with epithelial-to-mesenchymal transition of tubular epithelial cells during renal fibrosis. AB - Activation of Wnt5a-Ror2 signaling has been shown to be associated with epithelial-to-mesenchymal transition (EMT) of epidermoid carcinoma cells via induction of matrix metalloproteinase-2 (MMP-2). Because EMT has also been implicated in the progression of tissue fibrosis, we examined the possible association of Wnt5a-Ror2 signaling with renal fibrosis. Here, we show that expression of Wnt5a and Ror2 is induced in a damaged mouse kidney after unilateral ureteral obstruction (UUO) treatment. Immunofluorescent analysis showed that Ror2 expression is clearly induced in tubular epithelial cells during renal fibrosis, and these Ror2-expressing cells also express Snail and vimentin, markers of mesenchymal cells, suggesting that Ror2 might be induced in epithelial cells undergoing EMT. We also found that MMP-2 expression is induced at Ror2 positive epithelium adjacent to significantly disrupted tubular basement membrane (TBM). Interestingly, reduced expression of MMP-2 is detected at epithelium in damaged kidneys from Ror2(+/-) mice compared with those from wild-type Ror2(+/+) mice. Importantly, extents of TBM disruption are apparently reduced in damaged kidneys from Ror2(+/-) mice compared with those from wild-type mice. Collectively, these findings indicate that activation of Wnt5a-Ror2 signaling in epithelial cells undergoing EMT may play an important role in disrupting TBM via MMP-2 induction during renal fibrosis. PMID- 23755736 TI - [Use of physical restraints on the elderly: attitudes, knowledge and practice among nursing staff]. AB - OBJECTIVES: To investigate the attitudes, knowledge and practice on the use of physical restraints by nursing staff working with the elderly, as well as the relationship existing between these variables. MATERIAL AND METHODS: A cross sectional descriptive and correlational study was conducted among professionals from eight nursing homes. Three questionnaires asking about the mentioned variables were used. RESULTS: A total of 378 questionnaires were finally included (94 nurses and 284 auxiliary nurses). The professionals' attitude was generally against the use of restraints, although they were in favour of using them to avoid falls. With regard to knowledge, they obtained 66% of the correct answers; only 32% believed that there were alternatives to restraints, and 69.1% were unaware that these procedures could cause the death of patients. A total of 69.8% said that their training regarding restraint was limited. The practice could be considered acceptable, although the 61.9% thought it was not necessary to get informed consent from the family, and only 47.1% of the nurses always recorded its use in the patient's history. Differences between attitudes, knowledge and practice were found among the two groups. A relationship between the variables was confirmed; less knowledge and more favourable attitude towards physical restraints correlate with a worst practice. CONCLUSIONS: The attitude of the staff to physical restraints is ambiguous, and erroneous concepts have been detected in their knowledge and practice. Given the influence of knowledge on the rest of the variables, the training of the professionals needs to be improved. PMID- 23755737 TI - Comprehensive structural, surface-chemical and electrochemical characterization of nickel-based metallic foams. AB - Nickel-based metallic foams are commonly used in electrochemical energy storage devices (rechargeable batteries) as both current collectors and active mass support. These materials attract attention as tunable electrode materials because they are available in a range of chemical compositions, pore structures, pore sizes, and densities. This contribution presents structural, chemical, and electrochemical characterization of Ni-based metallic foams. Several materials and surface science techniques (transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive spectrometer (EDS), focused ion beam (FIB), and X-ray photoelectron spectroscopy (XPS)) and electrochemical methods (cyclic voltammetry (CV)) are used to examine the micro-, meso-, and nanoscopic structural characteristics, surface morphology, and surface-chemical composition of these materials. XPS combined with Ar-ion etching is employed to analyze the surface and near-surface chemical composition of the foams. The specific and electrochemically active surface areas (As, Aecsa) are determined using CV. Though the foams exhibit structural robustness typical of bulk materials, they have large As, in the range of 200-600 cm(2) g(-1). In addition, they are dual porosity materials and possess both macro- and mesopores. PMID- 23755738 TI - Phosphoramidite-Cu(OTf)2 complexes as chiral catalysts for 1,3-dipolar cycloaddition of iminoesters and nitroalkenes. AB - Chiral complexes formed by phosphoramidites such as (Sa,R,R)-9 and Cu(OTf)2 are excellent catalysts for the general 1,3-dipolar cycloaddition between azomethine ylides and nitroalkenes affording the corresponding tetrasubstituted proline esters mainly as exo-cycloadducts in high er at room temperature. The exo cycloadducts can be obtained in enantiomerically pure form just after simple recrystallization. DFT calculations support the stereochemical results. PMID- 23755739 TI - Epidemiology of suicide in bipolar disorders: a systematic review of the literature. AB - OBJECTIVE: Suicidal behavior is a major public health problem worldwide, and its prediction and prevention represent a challenge for everyone, including clinicians. The aim of the present paper is to provide a systematic review of the existing literature on the epidemiology of completed suicides in adult patients with bipolar disorder (BD). METHODS: We performed a Pubmed/Medline, Scopus, PsycLit, PsycInfo, and Cochrane database search to identify all relevant papers published between 1980 and 2011. A total of 34 articles meeting our inclusion criteria were included in the present review. RESULTS: Several prospective follow up contributions, many retrospective analyses, and a few psychological autopsy studies and review articles investigated the epidemiology of completed suicides in patients with BD. The main finding of the present review was that the risk for suicide among BD patients was up to 20-30 times greater than that for the general population. CONCLUSION: Special attention should be given to the characteristics of suicides in patients with BD. Better insight and understanding of suicide and suicidal risk in this very disabling illness should ultimately help clinicians to adequately detect, and thus prevent, suicidal acts in patients with BD. PMID- 23755740 TI - Suicide risk in people with epilepsy taking antiepileptic drugs. AB - OBJECTIVES: The standardized mortality ratio for suicide in people with epilepsy is reported as 5.1 [95% confidence interval (CI): 3.9-6.6], but this is only partially explained by the high rates of psychiatric comorbidity. This issue was revived when, in 2008, the Food and Drug Administration (FDA) issued an alert on an increased risk of suicide in people taking antiepileptic drugs (AEDs). We discuss and elaborate on available evidence on the interplay among epilepsy, suicide, and AEDs, taking into account the phenomenology of mood disorders in people with epilepsy and the psychotropic potential of AEDs. METHODS: Articles were identified by searches of Medline/PubMed using the terms epilepsy, antiepileptic drugs, and suicide. Only papers published in English in international peer-reviewed journals were considered. The reference lists of relevant articles were hand-searched for additional publications (e.g., book chapters or review papers) if relevant to the discussion. RESULTS: The results of studies supporting or opposing the FDA conclusions have been inconsistent. This may be due to a number of methodological limitations, such as the failure to adjust for past suicidality and the confounding effect of epilepsy. CONCLUSIONS: A subgroup of people with epilepsy appears to be at risk of developing treatment emergent psychiatric adverse effects of AEDs independently of the specific mechanism of action of the drug. Clinicians need to pay attention not only to seizure patterns when choosing the appropriate AED but also to a number of different parameters, not least the mental state of the individual patient. PMID- 23755741 TI - Declines in state teen birth rates by race and Hispanic origin. AB - Teen birth rates fell steeply in the United States from 2007 through 2011, resuming a decline that began in 1991 but was briefly interrupted in 2006 and 2007. The overall rate declined 25% from 41.5 per 1,000 teenagers aged 15-19 in 2007 to 31.3 in 2011--a record low. The number of births to teenagers aged 15-19 also fell from 2007 to 2011, by 26% to 329,797 in 2011. Births to teenagers are at elevated risk of low birthweight, preterm birth, and of dying in infancy compared with infants born to women aged 20 and over, and they are associated with significant public costs, estimated at $10.9 billion annually. Recent trends by state and race and Hispanic origin are illustrated using the most current available data from the National Vital Statistics System. PMID- 23755742 TI - Use of media technology to enhance the learning of student nurses in regards to auditory hallucinations. AB - The aim of this study was to determine if simulation aided by media technology contributes towards an increase in knowledge, empathy, and a change in attitudes in regards to auditory hallucinations for nursing students. A convenience sample of 60 second-year undergraduate nursing students from an Australian university was invited to be part of the study. A pre-post-test design was used, with data analysed using a paired samples t-test to identify pre- and post-changes on nursing students' scores on knowledge of auditory hallucinations. Nine of the 11 questions reported statistically-significant results. The remaining two questions highlighted knowledge embedded within the curriculum, with therapeutic communication being the core work of mental health nursing. The implications for practice are that simulation aided by media technology increases the knowledge of students in regards to auditory hallucinations. PMID- 23755743 TI - Vaccines and autoimmunity. AB - Vaccines have eradicated or controlled many infectious diseases, saving each year millions of lives and quality of life of many other millions of people. In spite of the success of vaccines over the last two centuries, parents (and also some health care workers) gloss over the devastating consequences of diseases, which are now avoided thanks to vaccines, and direct their attention to possible negative effects of immunization. Three immunological objections are raised: vaccines cause antigenic overload, natural immunity is safer and better than vaccine-induced immunity, and vaccines induce autoimmunity. The last point is examined in this review. Theoretically, vaccines could trigger autoimmunity by means of cytokine production, anti-idiotypic network, expression of human histocompatibility leukocyte antigens, modification of surface antigens and induction of novel antigens, molecular mimicry, bystander activation, epitope spreading, and polyclonal activation of B cells. There is strong evidence that none of these mechanisms is really effective in causing autoimmune diseases. Vaccines are not a source of autoimmune diseases. By contrast, absolute evidence exists that infectious agents can trigger autoimmune mechanisms and that they do cause autoimmune diseases. PMID- 23755744 TI - Treatment effects in prostate cancer following traditional and emerging therapies. AB - Treatment options for prostate cancer consist of radical prostatectomy, hormonal therapy and radiation therapy. Hormonal and radiation therapy have well-known, often profound, effects on the histological appearance of benign and malignant prostate tissue. Novel therapies including focal ablative treatments, chemotherapies and targeted molecular therapies are beginning to emerge and pathologists will play a central role in documenting the effects of these treatments at the tissue level. As such, knowledge of treatment-related changes and access to clinical information are essential to ensure accurate interpretation and reporting of post-treatment prostate specimens by pathologists. PMID- 23755745 TI - Is there a role for agomelatine in the treatment of anxiety disorders?A review of published data. AB - Anxiety disorders (Ads) are the most common type of psychiatric disorders, Pharmacologic options studied for treating ADs may include benzodiazepines, tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRIs), noradrenergic and specific serotonergic antidepressants (NaSSA) and serotonin and noradrenaline reuptake inhibitors (SNRIs). Agomelatine, a new melatonergic antidepressant, has been shown effective in various types of mood disorders. Moreover, some evidence points towards a possible efficacy of such a drug in the treatment of ADs. Therefore, the aim of this review was to elucidate current (facts and views) data on the role of agomelatine in the treatment of ADs. The trials evaluating agomelatine in the treatment of generalized anxiety disorder are few but, overall, encouraging in regards to its efficacy. However, further randomized, placebo-controlled studies on larger samples use are needed. Apart from some interesting case reports, no large studies are, to date, present in literature regarding agomelatine in the treatment of other ADs, such as panic disorder, social anxiety disorder, obsessive-compulsive disorder and post traumatic stress disorder. Therefore, the clinical efficacy and the relative good tolerability of agomelatine in generalized anxiety (GAD) warrants further investigation in ADs. PMID- 23755746 TI - Immunopathogenesis of sarcoidosis and risk of malignancy: a lost truth? AB - The hypothesis of a relationship between sarcoidosis and malignancy was firstly formulated in 1972 by Brincker. He documented an association of sarcoid reactions or sarcoidosis with 19 lymphomas and associated malignancies. Based on various epidemiological studies, for more than 20 years sarcoidosis has been considered as a condition at increased risk for cancer, particularly lymphoproliferative disorders. The existence of a sarcoidosis-lymphoma syndrome was therefore proposed, highlighting, as a potential mechanism, the uncontrolled lymphocyte proliferation and mitotic activity. A reduced ability to eliminate an antigen and chronic inflammation have been suggested as triggering events. Leading to a reduced tumor immune surveillance, a diminished myeloid dendritic cells (mDC) function, despite up-regulated co-stimulatory and maturation markers, was also raised as potential mechanism. However, some subsequent studies have questioned the presence of a close association between the two entities and have explained those previously published as the result of selection bias and misclassification. Recently, a Swedish population-based cohort study documented a significant overall excess incidence of cancer among sarcoidosis patients, especially those with multiple hospitalizations or admission in older age, emphasizing again a potential neoplastic risk. Therefore, currently, whether these patients have an increased risk of developing malignant lesions is still debated. Larger and unbiased studies are needed before drawing definite conclusions. PMID- 23755747 TI - A roadmap for fever of unknown origin in children. AB - Fever of unknown origin (FUO) in adults is conventionally defined by the occurrence of body temperatures above 38.3 degrees C (101 degrees F) for a period of 3 weeks without any identified etiology after a period of 1-week hospitalization. The issue of FUO in pediatrics is rather hazy and still represents a challenging diagnostic dilemma. Most of the available data are limited to nationwide cohorts of patients of any age. The major difficulty in establishing a diagnosis is that the characteristic features rendering specific disorders clinically recognizable are absent or subtle, hence only a painstaking questioning on family background may elicit the correct investigative path. No diagnostic algorithms are actually available and clinicians must rely on a very careful step-by-step evaluation of the single patient. The need for invasive diagnostic techniques should be closely taken into consideration when laboratory tests or simple imaging procedures fail to discern the origin of FUO. Fevers with no reasonable explanation and no localizing signs often conceal different common diseases in children, which tend to display an unusual or atypical pattern. The principal causes behind FUO in pediatric age remain infections, followed by collagen vascular diseases and neoplastic disorders, although most children with malignancies present other systemic signs or suggestive laboratory abnormalities. The possibility of autoinflammatory syndromes, drug fever, and factitious fever should also be taken into account. PMID- 23755748 TI - Vascular endothelial growth factor (VEGF), mast cells and inflammation. AB - Vascular endothelial growth factor (VEGF) is one of the most important inducers of angiogenesis, therefore blocking angiogenesis has led to great promise in the treatment of various cancers and inflammatory diseases. VEGF, expressed in response to soluble mediators such as cytokines and growth factors, is important in the physiological development of blood vessels as well as development of vessels in tumors. In cancer patients VEGF levels are increased, and the expression of VEGF is associated with poor prognosis in diseases. VEGF is a mediator of angiogenesis and inflammation which are closely integrated processes in a number of physiological and pathological conditions including obesity, psoriasis, autoimmune diseases and tumor. Mast cells can be activated by anti-IgE to release potent mediators of inflammation and can also respond to bacterial or viral antigens, cytokines, growth factors and hormones, leading to differential release of distinct mediators without degranulation. Substance P strongly induces VEGF in mast cells, and IL-33 contributes to the stimulation and release of VEGF in human mast cells in a dose-dependent manner and acts synergistically in combination with Substance P. Here we report a strong link between VEGF and mast cells and we depict their role in inflammation and immunity. PMID- 23755749 TI - Reduced expression of insulin-like growth factor 1 receptor leads to accelerated intervertebral disc degeneration in mice. AB - Insulin-like growth factor 1 (IGF-1) and its receptor (insulin-like growth factor 1 receptor, IGF1R) can regulate the extracellular matrix synthesis and play a crucial role in maintaining the normal functions of the intervertebral disc (IVD). The objective of this study was to investigate whether there would be accelerated IVD degeneration (IVDD) in IGF1R+/- mice. Three IGF1R+/- male mice and three wild-type male mice were sacrificed respectively at 6, 12, and 18 weeks after birth. Six lumbar disc samples were harvested from each mouse, with a total of 54 disc samples taken from each genotype. Histomorphological analysis for the IVD was performed to assess the degenerative extent according to the classification system proposed by Boos et al. Quantitative real-time PCR and semi quantitative histologic scoring (HScore) for immunohistochemical staining were used to evaluate the expression level of type-II collagen, aggrecan and matrix metallopeptidase 13 (MMP-13). Histomorphological analysis for the discs revealed significantly less amounts of proteoglycan and type-II collagen, and significantly higher total degenerative score in IGF1R+/- mice than in wild-type mice. Real-time PCR showed that the mRNA expressions of type-II collagen and aggrecan in the discs were significantly lower, while MMP-13 was significantly higher in IGF1R+/- mice than in wild-type mice. The results of HScore analysis were similar to those obtained from the quantitative real-time PCR. Taken together, our study indicates that reduced expression of IGF1R would lead to accelerated degeneration of IVD. IGF1R+/- mice could be regarded as a good animal model to study IVD degeneration (IVDD), and studies on the IVD of IGF1R+/- mice could provide further insight into the pathogenesis of IVDD. PMID- 23755750 TI - Heparin protects BALB/c mice from mite-induced airway allergic inflammation. AB - More and more studies have demonstrated the anti-inflammatory effects of heparin. However, in the aspect of allergic airway inflammation, data about its daily use in animal model is scarce. To evaluate the efficacy of 22-day intranasal heparin administration in mite-induced airway allergic inflammation in BALB/c mice, the murine model of house dust-mite allergen-induced asthma was used to assess the effect of heparin (h) and low molecular weight heparin (l mwh) administered intra nasally (IN) throughout the full study period (22 days). Effects were monitored by histopathology, cell counts in broncho-alveolar lavage fluid (BALF), local cytokine production, serum, specific antibody levels, and airway resistance measurements. Compared to the positive control group, both hIN and lmwhIN groups had lower peri-bronchiolar/alveolar inflammatory pathology score and lower goblet cell scores (p less than 0.01); lower eosinophil and neutrophil counts in BALF (p less than 0.0001); and lower cytokine levels including IL-17A/F, IL-5, IL-13, IL 8 and eotaxin in lung tissue (p less than 0.001). Serum Der p-specific IgE level was also lower in heparin-treated groups (p less than 0.004). The two heparin treated groups also revealed lower value of Penh after Mch stimulation. In conclusion, heparin and lmw heparin decrease serum Der p-specific IgE level and possess anti-inflammatory effects on mite-induced airway allergic inflammation model in BALB/c mice. PMID- 23755751 TI - Knockdown of MMP11 inhibits proliferation and invasion of gastric cancer cells. AB - Matrix metalloproteinase 11 (MMP11 or stromelysin-3) has recently been reported to play a crucial role in the development and progression of multiple malignancies. The aim of this study was to investigate the function of MMP11 expression in human gastric adenocarcinoma (GAC). Using immunohistochemistry assay, we studied the expression level of MMP11 in GAC and adjacent non-cancerous tissues (ANCT). The association between MMP11 expression and tumor size and pathological grade, as well as metastatic potential was analyzed. Through small hairpin RNA (shRNA)-mediated MMP11 knockdown in SGC-7901 GAC cells, we observed the changes of the biological behaviors of GAC cells. Our results indicated that the rate of positive expression of MMP11 was higher in GAC tissues than in ANCT (55.0 vs 30.0 percent, P=0.025). MMP11 expression had no association with the factors of age or gender of the GAC patients, or the size, pathological staging and lymph node metastases of the tumors (each P greater than 0.05). Furthermore, MMP11 knockdown inhibited the proliferative activities and invasive potential of SGC-7901 GAC cells with decreased expression of IGF-1, PCNA and VEGF. Taken together, our findings demonstrated that MMP11 expression was increased in GAC tissues, but did not correlate with the clinicopathologic features. Knockdown of MMP11 expression could inhibit the proliferation and invasion of GAC cells probably through down-regulation of the IGF-1 signaling pathway, suggesting that MMP11 might be a potential therapeutic target for the treatment of gastric cancer. PMID- 23755752 TI - Histone modifications of Notch1 promoter affect lung CD4+ T cell differentiation in asthmatic rats. AB - Asthma is an inflammatory disease of the airways, and the current treatment in managing asthma is the control of inflammation. Notch signaling pathway has been linked to T-cell imbalance. The present study aimed to explore the histone modifications of Notch1 promoter in normal and asthmatic lung CD4+ T cells. Chromatin immunoprecipitation analysis showed that the acetylation levels of total H3, H4, site-specific H3K9, H3K14, H3K27, H3K18, H4K16, and the trimethylation levels of H3K4, H3K79 of Notch1 gene promoter were increased significantly in asthmatic lung CD4+ T cells compared to the control group, which correlated with increased P300, PCAF activity and decreased HDAC1, HDAC2 activity. After intervention of garcinol, a potent inhibitor of histone acetyltransferases, in asthmatic lung CD4+ T cells, HAT activity decreased significantly and the increased Notch1 and hes-1 expression was reversed. The total H3ac, H4ac, site-specific H3K9ac, H3K14ac, H3K27ac, H3K18ac, H4K16ac and H3K79me3 levels of Notch1 gene promoter decreased significantly, and the H3K4me3, H3K9me3, H4K20me3 levels had no significant difference. We further investigated the suppressive effects of GAR on asthmatic parameters. Results showed that the levels of IL-4, IL-5 and IL-13 were significantly reduced and a small reverse trend was found in the level of IFN-g after GAR treatment. Furthermore, the expression of NF-κB and AP-1 reduced significantly. These results suggest that asthma is associated with changes in the epigenetic status of Notch1 promoter, including abnormal histone acetylation and methylation, and GAR may have applications in the treatment of asthma. PMID- 23755753 TI - S100B induces the release of pro-inflammatory cytokines in alveolar type I-like cells. AB - S100B, a 21kDa cytosolic calcium-binding protein of the EF-hand type, present in high abundance in the brain, stimulates inflammatory responses in different cellular types inside and outside the central nervous system. Most of extracellular S100B effects are mediated by Receptor for Advanced Glycation End products (RAGE). RAGE is highly expressed in lung by Alveolar Type-I (AT-I) cells and its activation contributes to ALI/ARDS pathogenesis. In this in-vitro study, we tested the hypothesis that S100B stimulates an ATI-derived cell line (R3/1) to secrete inflammatory mediators involved in lung inflammation. Our main result is that S100B stimulates R3/1 cells to secrete TNF-alpha and IL-6 (well-known pro inflammatory cytokines in lung inflammation and neurogenic pulmonary edema), but not sICAM-1, CINC-1 or CINC-3. Soluble RAGE (sRAGE) reduced S100B-dependent secretion of TNF-alpha but did not decrease S100B-dependent secretion of IL-6. Moreover, in absence of S100B, sRAGE enhanced IL-6 release. This study demonstrates that in vitro S100B dose-dependently stimulated R3/1 cells, to enhance the secretion of TNF-alpha and IL-6; S100B pro-inflammatory activity might be mediated at least in part by RAGE. Besides acting as decoy receptor, sRAGE could have pro-inflammatory properties. PMID- 23755754 TI - A novel report of apoptosis in human lung carcinoma cells using selective agonist of D2-like dopamine receptors: a new approach for the treatment of human non small cell lung cancer. AB - In our previous study, a relationship between low expression of D2-like dopamine receptor genes and non-small cell lung cancer (NSCLC) disease was found. In this new research, by using selective agonist of these receptors, Bromocriptine (BR), we attempted to activate D2-like expression and apoptotic induction in a selective cell line of NSCLC. In addition, the relationship of apoptotic response of human lung carcinoma cells to BR and D2- dopamine receptor genes is investigated. Human lung cancer (QU-DB) cells were treated by five doses of BR at 48 h and cell viability was determined by MTT assay. The gene expression pattern of D2-like dopamine receptor Genes was studied by Real Time PCR. Nuclear morphology of cells was monitored by DAPI flourescent staining then induction of DNA fragmentation by BR was shown in an agarose gel. Finally, the detection and quantification of apoptosis and its differentiation from necrosis was carried out by using Annecxin-V-Fluos Staining. In this study, it is demonstrated that BR inhibited the proliferation of human lung cancer cells and induced apoptosis in them. In addition, the probable relationship between D2-dopamine receptor genes expression and the development of apoptosis was found. In conclusion, BR is responsible for induction of apoptosis in human lung cancer cells and can be used in treatment of these tumoric cells. In addition, normal expression of D2 dopamine receptors was associated with apoptotic effect of BR on these cells. PMID- 23755755 TI - Clinical pharmacology of cyclooxygenase inhibition and pharmacodynamic interaction with aspirin by floctafenine in Thai healthy subjects. AB - Floctafenine, a hydroxyquinoline derivative with analgesic properties, is widely used in Thailand and many other countries. The objectives of this study were to evaluate in Thai healthy volunteers: i) the inhibition of whole blood cyclooxygenase(COX)-2 and COX-1 activity by floctafenine and its metabolite floctafenic acid in vitro and ex vivo after dosing with floctafenine; ii) the possible interference of floctafenine administration with aspirin antiplatelet effects. We performed an open-label, cross-over, 3-period study, on 11 healthy Thai volunteers, who received consecutively floctafenine(200mg/TID), low-dose aspirin(81mg/daily) or their combination for 4 days, separated by washout periods. Floctafenine and floctafenic acid resulted potent inhibitors of COX-1 and COX-2 in vitro (floctafenic acid was more potent than floctafenine) showing a slight preference for COX-1. After dosing with floctafenine alone, whole blood COX-1 and COX-2 activities were inhibited ex vivo in a time-dependent fashion which paralleled floctafenic acid plasma concentrations. Aspirin alone inhibited profoundly and persistently platelet COX-1 activity and AA-induced platelet aggregation throughout 24-h dosing interval which was affected by the co administration of floctafenine. At 24 h after dosing with aspirin and floctafenine, the inhibition of platelet thromboxane(TX)B2 generation and aggregation were significantly(P less than 0.05) lower than that caused by aspirin alone. Therapeutic dosing with floctafenine profoundly inhibited prostanoid biosynthesis through the rapid conversion to floctafenic acid. Floctafenine interfered with the antiplatelet effect of aspirin. Our results suggest that floctafenine should be avoided in patients with cardiovascular disease under treatment with low-dose aspirin. PMID- 23755756 TI - Comparison of antibody-conjugated magnetic immunoassay and liquid chromatography tandem mass spectrometry for the measurement of cyclosporine and tacrolimus in whole blood. AB - The aim of this work is to compare the results of a commercially available liquid chromatography tandem mass spectrometry (LC-MS/MS) method in a clinical pathology laboratory for routine Therapeutic Drug Monitoring (TDM) of cyclosporine (CsA) and tacrolimus (Tacr) in pediatric patients with those obtained with the current antibody-conjugated magnetic immunoassay (ACMIA). Whole blood levels of CsA (n= 135) and Tacr (n=100) were sequentially analyzed by using ACMIA and LC-MS/MS on pediatric transplanted patients. The differences were analyzed by using the Passing Bablok regression analysis and the Bland and Altman test. The LC-MS/MS method showed excellent reproducibility and lower limits of quantification compared to the ACMIA. A linear relationship between ACMIA and LC-MS/MS was obtained for both CsA Tacr. No significant inter-method biases were observed. The analytical performances of the LC-MS/MS method make it suitable for the accurate measurement of CsA and Tacr in pediatric transplanted patients. However ACMIA results are also accurate and reliable. For this reason the choice of the method to be used in a routine clinical pathology laboratory can be made on the bases of non-analytical considerations such as costs, organization, availability of skilled personnel. PMID- 23755757 TI - Behaviour of perioperative values of haemoglobin, haematocrit and red blood cells in elderly patients undergoing lower limb arthroplasty: a retrospective cohort study on non-transfused patients. AB - Little is known on how elderly patients recover pre-operative haemoglobin, haematocrit and red blood cell levels after total hip and knee arthroplasties. In this study we aimed to evaluate blood loss and recovery blood levels in relation to gender, type of surgery and preoperative haemoglobin values. We conducted a retrospective cohort study on 187 patients over 65 years of age who underwent total knee or total hip arthroplasty between January 2008 and December 2009. Preoperative blood analysis was carried out within 40 days prior to intervention followed by a 15-day postoperative follow-up. Haemoglobin recovery values in anaemic patients versus healthy patients was also estimated. All tested values decreased significantly during the first 3-5 postoperative days. Haemoglobin levels decreased statistically significantly more in males than in females, while no significant differences were observed for haematocrit and erythrocytes. Recovery of haemoglobin values did not differ significantly between healthy patients and patients with preoperative haemoglobin below 120 g/L. Furthermore, our data showed a higher blood loss in total hip arthroplasty, whilst recovery rates showed to be higher after a total knee arthroplasty procedure. In conclusion, the type of intervention and gender played an important role in blood loss and recovery rates in total joint arthroplasty. PMID- 23755758 TI - Detection of bovine alpha-S1-casein in term and preterm human colostrum with proteomic techniques. AB - Due to increased social awareness of allergens and population hyper sensitization, the reported incidence of allergic reactions to food allergens has increased over the past two decades. Cow's milk proteins (CMPs) are among the most common food allergens. The aim of this study was to use proteomics techniques to investigate cow's milk allergens in both full-term human colostrum and in preterm newborns mothers where both groups showed no prior allergen detection -- in order to understand whether cows milk allergens could be a cause of sensitization established through lactation. The most relevant finding was the detection of the intact bovine alpha-S1-casein in both term and preterm colostrum. Using techniques detailed in this paper and which allowed for direct protein identification, beta-lactoglobulin was not detected in any of the colostrum samples. According to our results, bovine alpha 1 casein is considered a major cow's milk allergen, is readily secreted in human milk, and so could be considered a possible cause of sensitization in exclusively breastfed infants. PMID- 23755759 TI - Comparison of subjective and objective tools in transoral laser cordectomy for early glottic cancer: importance of voice handicap index. AB - Several studies in recent years have already reported good oncologic results with laser microsurgery in the treatment of early glottic carcinoma. We conducted a longitudinal voice evaluation, in patients with early glottic cancer who underwent transoral laser cordectomy, in order to assess the voice quality outcome and its relationship with objective and subjective (voice handicap index questionnaire and GIRBAS scale) means. Twenty-four previously untreated patients underwent transoral laser cordectomy for early glottic cancer. All patients underwent subjective and objective voice assessment according to the multidimensional voice protocol recommended by the European Laryngological Society including acoustic, perceptual and stroboscopic analysis combined to patient self assessment of voice (voice handicap index-VHI). These evaluations were performed before treatment and 6 months after the treatment. Vocal fold healing was complete in all cases by 6 months following surgery. Main voice parameters (subjective and objective) resulted improved at the 6-month control after surgery. In particular, voice handicap index (VHI) and GIRBAS scale resulted reliable for voice assessment and for the postoperative follow-up. In conclusion, VHI, GIRBAS, multidimensional voice program (MDVP) and spectroacoustic parameters showed a close trend in the present study, and this confirms the validity of the voice analysis performed by each tool. PMID- 23755760 TI - In vitro adhesion of commensal and pathogenic bacteria to commercial titanium implants with different surfaces. AB - Although dental implants have undergone impressive evolution in recent years, periimplantitis still remains a relevant problem and information on the susceptibility of commercial implants to bacterial colonization is insufficient. This work evaluated the susceptibility of different commercial implants to bacterial colonization, to identify key features for good performances. Twenty four implants, produced with different technologies, were colonized with 9 bacterial strains following pre-conditioning with culture medium, or saliva or serum proteins and adherent bacteria were enumerated by Real Time quantitative PCR. The studied implants differed significantly for susceptibility to bacterial adhesion. Pre-conditioning of surfaces affected adhesion assays in a species specific manner. Although surface topography influenced bacterial adhesiveness, implants produced by different manufacturers with comparable technologies showed great variability of results. These data demonstrate that susceptibility of implants to bacterial colonization is influenced by productive technologies (in a surface topography proportional manner) and by the productive environment. In choosing an implant the clinician should rely upon specific experimental studies, because surface characteristics alone cannot predict susceptibility to colonization by pathogenic bacteria. Tests should include assays performed in the medium of culture and in the presence of serum proteins. PMID- 23755761 TI - Microbial tracking of multidrug-resistant Klebsiella pneumoniae isolates in a pediatric hospital setting. AB - We investigated the clonal relatedness of seven multi-drug-resistant (MDR) Klebsiella pneumoniae isolates, as well as three susceptible K. pneumoniae isolates collected during hospital outbreaks and outbreak-related microbiological surveillance, respectively. The relatedness among K. pneumoniae isolates was assessed by pulsed field gel electrophoresis (PFGE) and automated repetitive sequence-based PCR (rep-PCR) genotyping and the results were compared to a proteomic phenotyping performed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). All typing methods agreed on the generation of three different clusters of K. pneumoniae isogenetic/related MDR strains. After strengthening hospital infection control measures, no other spreading events involving MDR-K. pneumoniae were reported until the end of the observation period. This preliminary investigation suggests that, in a hierarchical approach to bacterial typing, MALDI-TOF MS proteome profiling might offer a fast and valuable preliminary screening tool able to support microbiologists during nosocomial outbreak surveys. PMID- 23755762 TI - STAT4 is a genetic risk factor for systemic sclerosis in a Chinese population. AB - Systemic sclerosis (SSc) is an immune-mediated and complex genetic disease. An association of single-nucleotide polymorphisms (SNPs) in the STAT4 gene with SSc has been reported in European Caucasians, North Americans and Japanese. We undertook the current study to examine whether the STAT4 SNPs are also associated with susceptibility to SSc and SSc subsets in a Han Chinese population. A total of 453 Han Chinese patients with SSc and 534 healthy controls were examined in the study. The SNPs rs7574865, rs10168266 and rs3821236 of the STAT4 gene were examined with SNP TaqMan assays. The T-allele carriers of rs7574865 and rs10168266 were strongly associated with the presence of anti-topoisomerase I (ATA) and pulmonary fibrosis in SSc patients, as well as with diffuse cutaneous SSc (dcSSc). The presence of anti-centromere (ACA) and limited cutaneous SSc (lcSSc) did not show significant association with any of the examined SNPs. The results were consistent with previous reports in other ethnic populations in supporting the notion that polymorphisms of STAT4 may play an important role in susceptibility to SSc. It also revealed different genetic aspects of SSc subsets in a Han Chinese population. PMID- 23755763 TI - An approach for plasma cell myeloma diagnosis by two-color flow cytometry based on kappa/lambda ratios of CD38-gated plasma cells. AB - Criteria from the World Health Organization (WHO) are commonly used to diagnose plasma cell myeloma (PCM), but they are complex and require several laboratory parameters. To differentiate reactive plasmacytosis from clonal plasma cell neoplasms, such as PCM, it is important to accurately determine the expression of the cytoplasmic immunoglobulin (cIg) light chain (LC). Through retrospective analyses, we selected the patients with PCM, and analyzed records of 52 PCM patients, who underwent bone biopsies, and final diagnosis of PCM was established according to WHO criteria, and 22 controls. In the present study, all samples were analyzed by flow cytometry (FC) in the side scatter vs CD38 histogram mode, and the CD38-gated plasma cell population was identified. The positive cell ratios of kappa and lambda to plasma cell populations were analyzed. PCM cells were distinguished from normal plasma cells by a cut-off level between 0.80 and 3.3, a sensitivity of 90.3 percent, and a specificity of 81.1 percent. Two-color FC analysis is simple to perform, inexpensive, and clinically relevant data are obtained soon after completion of the FC measurements. It could be one of the helpful tools in the diagnosis of PCM. The correct diagnosis of PCM can be achieved more simply, efficiently, and rapidly by combining this method. PMID- 23755764 TI - Clinical significance of immunogenic cell death biomarker rage and early growth response 1 in human primary gastric adenocarcinoma. AB - The receptor for advanced glycation end products (RAGE), a pattern recognition receptor that binds multiple ligands derived from a damaged cell environment, contributes to multiple pathologies including cancer. Early growth response 1 (EGR1) is a tumor suppressor gene or a tumor promoter involved in tumorigenesis and progression of some cancers. However, there is some lack of knowledge about the expression and clinical significance of RAGE and EGR1 in human primary gastric adenocarcinoma (GAC). The present study was aimed to investigate the expression and clinical significance of RAGE and EGR1 in human GAC. One hundred and twenty cases of GAC tissues, adjacent non-cancer tissues (ANCT) and metastatic lymph node (MLN) tissues were collected. The expression of RAGE and EGR1 was assessed using immunohistochemistry (IHC) through tissue microarray procedure. The clinicopathologic characteristics of all patients were analyzed. As a result, the expression of RAGE in GAC and MLN tissues showed the positive staining mainly in the cytoplasm, with lower reactivity rate compared with the ANCT (P less than 0.001), while EGR1 expression had no significant difference between GAC, MLN tissues and ANCT (P=0.565). Moreover, the positive expression of RAGE was closely associated with the N stage of GAC patients, but did not correlate with their age, gender, tumor size, tumor sites, T stage, and metastatic lymph node (each P>0.05). In addition, Spearman Rank correlation analysis showed the positive correlation of RAGE expression with EGR1 in GAC tissues (r=0.658). Taken together, the expression of RAGE is decreased in GAC and MLN tissues, and is associated with the N stage of GAC patients, suggesting that RAGE may represent a potential therapeutic target for the treatment of GAC. PMID- 23755765 TI - Clinical, pathological and immunohistochemical effects of arsenical-ferruginous spa waters on mild-to-moderate psoriatic lesions: a randomized placebo-controlled study. AB - Thermalism and spa treatments are traditionally considered effective in a number of dermatologic inflammatory conditions, yet there is scarce evidence about spring water effectiveness on psoriasis in a daily setting. We enrolled 34 patients with mild-to-moderate psoriasis in a double-blind, randomized, placebo contralaterally-controlled trial, to evaluate Levico and Vetriolo arsenical ferruginous water effectiveness on psoriatic lesions by daily 20-minute wet packing for 12 consecutive days. Clinical, histopathologic and immunohistochemical parameters were considered. A statistically significant difference between spa water-treated lesions and placebo-treated lesions in the same patients was demonstrated for histopathologic and immunohistochemical parameters. Since iron ions have an antiproliferative effect on epithelia, and magnesium ions have an anti-inflammatory effect, Levico and Vetriolo water effectiveness on psoriasis could be addressed to their content of these ions. PMID- 23755766 TI - Development and validation of an enzyme linked immunosorbent assay for palivizumab serum determination. AB - Palivizumab (Synagis) is a humanized monoclonal antibody (IgG1K) composed of 95 percent human and 5 percent murine sequences. It is directed to an epitope in the A antigenic site of the F protein of respiratory syncytial virus (RSV). Palivizumab is used for prevention of serious lower respiratory tract disease caused by RSV in pediatric patients who are at increased risk of severe disease and is administered intramuscularly (IM) for a total of 5 monthly doses. Herein, we report on the development and validation of a very sensitive enzyme-linked immunosorbent assay (ELISA) to measure serum concentrations of palivizumab by a rabbit polyclonal antibody specifically produced against the murine sequence. The method was developed and validated according to the guidelines "Guidance for Industry" (1998) and has proved suitable for the determination of palivizumab serum levels in the target infant population. The ELISA assay was successfully applied to test the serum samples in an infant population who received palivizumab intramuscularly; thus, the assay could be used to determine serum levels in palivizumab-treated infants to optimize dosing and scheduling and to study the relationship between dose and clinical response. PMID- 23755767 TI - Bcgitis and vaccine-derived poliovirus infection in a patient with a novel deletion in RAG1 binding site. AB - A girl who developed severe BCGitis and vaccine-derived poliovirus infection was discovered to have a novel deletion of RAG1. A neonatal screening program for SCID would identify affected infants at birth, before live vaccines are administered. PMID- 23755768 TI - Evaluation by environmental monitoring of pesticide absorption in farm workers of 18 Italian tomato cultivations. AB - Tomato cultivation farms of Southern Italy were investigated in order to evaluate the general working conditions and the levels of exposure of farm workers to pesticides, during the mixing/loading and the application of pesticides on fields. Information on working modalities, personal protective equipment, etc. was collected using a questionnaire. Inhaling and cutaneous exposure levels were measured, and the estimated pesticide total absorbed dose was compared with Admissible Daily Intakes (ADIs). Field treatments were mainly carried out by using sprayers with open cab tractors, and, in 57.9 percent of cases, the pesticide mixture was manually prepared by mixing pesticides in a pail, often without using gloves (59.5 percent). The estimated pesticides absorbed doses varied in the range 0.56-2630.31 mg (mean value, 46.9 mg), and 20 percent of the measured absorbed doses exceeded ADIs. The findings obtained in the 18 examined farms show a worrying situation, suggesting the investigation of many more farms, so that a statistically significant picture of tomato cultivations in Southern Italy could be formed. Besides, the planning of training courses aimed to increase workers consciousness about health risks and how they can be prevented is advisable. PMID- 23755769 TI - New insights into Chlamydiae persistence: an energy metabolism strategy? AB - Chlamydiaceae is a family of obligate intracellular bacteria generally considered energy parasites. Several studies have suggested that Chlamydiae are capable of independently producing energy and, more importantly, several genes involved in the energy metabolism are up-regulated during the persistent state. Thus, it has been suggested that chlamydial persistence could be a complex and flexible metabolic strategy designed to favor a lengthy survival in the host cell by evading the immune response. In conclusion, more detailed studies on the shift in the chlamydial energy metabolism, from the active to the persistent form, may be helpful in future to determine whether chlamydial persistence observed in vitro does occur in vivo and whether chronic sequelae of chlamydial diseases may be related to the persistence. PMID- 23755770 TI - Inhaled mucoactive drugs for treating non-cystic fibrosis bronchiectasis in children. AB - Non-cystic fibrosis bronchiectasis (nCFb) is an acquired condition of variable etiology. Medical treatment basically involves antibiotics and chest physiotherapy. An impaired mucociliary clearance seems to be one of the mechanisms behind nCFb, and inhaled therapy with mucoactive agents has frequently been used to try to correct it. The most often used mucoactive agents in this setting are N-acetylcysteine, hypertonic saline solution (HS), mannitol powder and recombinant human DNase (rhDNase). Reviewing the international medical literature on the use of these drugs for patients with nCFb from 1992 to the present day, we retrieved 88 articles, only 12 of which met our selection criteria for this analysis. We found only 2 papers and 2 reviews on the use of rhDNase in children, and in adults 3 trials on HS, 5 on mannitol powder and 2 on rhDNase. In conclusion, no observational or randomized controlled trials (RCT) have been published on the use of these drugs in children with nCFb, while the few conducted on adult patients report some evidence of their effects. Further studies are needed on inhaled mucoactive drugs for the treatment of children with nCFb. PMID- 23755771 TI - Macrophage activation syndrome in a child affected by malaria: the choice of steroid. AB - Macrophage activation syndrome is a potentially fatal clinical syndrome caused by an excessive activation and proliferation of macrophages and T cells, leading to an exaggerated inflammatory reaction. It is well known that it can complicate the course of different conditions, especially autoimmune, lympho-proliferative, infectious diseases and drugs. Many infective pathogens can trigger the syndrome but the association with malaria has rarely been described, especially in children. We report a child with severe malaria complicated by MAS, in whom the clinical appearance of this syndrome could be considered as worsening of malaria itself. Furthermore, the use of steroids as first choice drugs in this complication, but arguable in malaria, has been highlighted. Clinicians should be aware of this syndrome when malaria does not respond to conventional therapy, since early diagnosis and prompt treatment may dramatically reduce the mortality associated with this condition. PMID- 23755772 TI - Histopathological features of tissue alterations induced by low frequency ultrasound with cavitational effects on human adipose tissue. AB - Low frequency, high energy level ultrasound (US) induces physical effects on tissues called ultrasonic cavitation (UC). Endermic US therapy has recently been proposed as a method to reduce non-invasively the amount of adipose tissue. Very few published studies have dealt with the biological effects of such therapies on human adipose tissue. The aim of this study is to evaluate, through histopathological examination, the effects of various levels of ultrasonic radiation on supravital human adipose tissue. Four ex vivo human tissue samples were treated as follows: sample 1: no US radiation; sample 2: US radiation 2,5 W/cm2 for 15 minutes; sample 3: US radiation 5 W/cm2 for 15 minutes; sample 4: infiltration of 30 ml physiological saline and US radiation, 5 W/cm2 for 15 minutes. For lower levels of ultrasonic energy, interruption of the adipocytic membranes was evident both in the surface and in the deeper cutaneous and subcutaneous layers, with focal dissolution and homogenization of the surface dermal fascia. For higher levels of ultrasonic energy, alterations of the adipocytes and of the collagen fibers were greater, resulting in the dissolution of the cells and of the interlobular fibrous septa. Both effects were amplified by tumescent saline infiltration. The histological lesions demonstrated in adipocytes confirm the theoretical premises of a possible usefulness in the treatment of localized adiposis. The alterations observed in the connective stroma could have positive effects on the structural re-organization and consequently on the in vivo external appearance of the treated areas. PMID- 23755773 TI - The use of cortical heterologous sheets for sinus lift bone grafting: a modification of Tulasne's technique with 7-year follow-up. AB - In this article, the authors describe their experience with using cortical deantigenated equine bone sheets in sinus lift grafting procedures performed on 23 patients. The technique employed resembles that described by Tulasne but avoids the need for using harvested calvaria bone and introduces some additional operating variants. The use of heterologous cortical bone sheets effectively managed even large lacerations of the Schneiderian membrane and allowed for immediate stabilization of the heterologous bone granules. Average histomorphometric values for bone cores collected six months after grafting, at the time of implant placement, were: newly formed bone tissue, residual bone substitute, medullary spaces. At seven year follow-up, clinical and radiographic examination indicated that the use of the bone sheets preserved the regenerated bone volume. In conclusion, the use of heterologous cortical bone sheets in association with granular bone graft material enabled long-term stabilization of the graft material and effective management of intra-surgical complications. PMID- 23755774 TI - Antibacterial efficacy and drug-induced tooth discolouration of antibiotic combinations for endodontic regenerative procedures. AB - Elimination of microbial contamination from the root canal system is a precondition for successful root canal treatment. Teeth with immature root development, necrotic pulps and apical periodontitis present multiple challenges for successful treatment. Disinfection is achieved by irrigation followed by the placement of an intracanal medicament. A mixture of ciprofloxacin, metronidazole and minocycline (3-MIX S) has been shown to be very effective in eliminating endodontic pathogens in vitro and in vivo. Among the components of the mixture, minocycline can induce tooth discolouration after long-term oral use. Therefore, the elimination of minocycline from the above-mentioned combination has been suggested to prevent the occasion of this undesirable effect. The aim of this study was to investigate the potential antimicrobial efficacy of alternative antibiotic combinations [3-MIX C (clarithromycin); 3-MIX F (fosfomycin)] against bacteria from infected root canals. An additional objective was to evaluate their discolouration potential as possible alternatives to minocycline-based intracanal medicaments. Our in vitro results clearly demonstrated that 3-MIX C and 3-MIX F had a greater antimicrobial activity than 3-MIX S, underlying that clarithromycin still had a higher capacity to kill endodontic pathogens in vitro compared to fosfomycin. Both 3-MIX C and 3-MIX F were able to avoid the permanent staining effect of the crown. PMID- 23755775 TI - Habitual snoring in children with previous allergic sensitization. AB - Previous studies have reported a high prevalence of allergy in children with Habitual Snoring (HS), but the relationship between allergy in the early years of life and the subsequent development of this Sleep Disordered Breathing (SDB) is yet to be elucidated. The purpose of the present study was to determine the role of early, under 36 months of age, allergic sensitization to food (with or without sensitization to airborne allergens) in determining the development of HS 8-10 years after. One hundred and forty-eight children (10-14 years, mean age 12 years) with a history of food allergy were selected. Under the age of 36 months, atopic status was assessed by skin prick test for a panel of airborne and food allergens. Questionnaires filled in by parents were used to collect information on children's snoring and associated symptoms. HS was defined as snoring three or more times per week. At 1-3 years of age 54 children were positive to food allergens alone, and 94 were positive also to airborne allergens. After 8-10 years of life, when patients were aged between 10 and 14 years, habitual snoring was reported in 37 children. Furthermore, among the 54 children under three years of age sensitized only to food, 8 became HS while of the 94 children sensitized to both food and inhalants allergens 29 developed HS. The difference between those two groups was statistically significant (p=0.04). We reported a significant risk of developing HS in children with early allergic sensitization. Specifically this risk was higher when food allergy was associated with inhalant allergy. The onset of upper airway inflammation due to allergic triggers in subjects under three years of age may be related to the subsequent development of SDB after 8-10 years. PMID- 23755776 TI - IgG4: not only for allergists. AB - We describe herein a case of IgG4-related disease with the isolated clinical presentation of malabsorption due to pancreatic failure. Histology of an abdominal lymph node was critical for diagnosis. IgG4-related disease is increasingly recognized as an immunological disorder that can mimic various clinical entities. PMID- 23755777 TI - Systemic complications of esophageal lichen planus. AB - Lichen planus is an uncommon inflammatory mucocutaneous disorder affecting the skin and its appendages, as well as oral and genital mucosa. Involvement of the esophageal mucosa is rare and causes significant morbidity, with dysphagia and risk of long-term complications, such as esophageal strictures and stenosis. Esophageal lichen planus is an underreported condition in the spectrum of lichenoid tissue reactions, presenting the risk of systemic manifestations. We describe a patient with severe, long-standing esophageal lichen planus, which had led to marked weight-loss, malnutrition syndrome and chronic respiratory distress due to recurrent aspiration pneumonia. Diagnosis was confirmed by the presence of concomitant muco-cutaneous lesions and characteristic endoscopic and histological findings. Systemic therapy with cyclosporine A and micronutrient supplementation led to rapid clinical improvement. Early diagnosis of esophageal lichen planus as well as effective systemic immunosuppressive treatment is crucial in order to prevent short- and long-term complications. PMID- 23755778 TI - [Suggestion of diagnosis and treatment for pediatric sinusitis]. PMID- 23755779 TI - [Guidelines of endoscopic surgery of tumors in nasal cavity and sinus]. PMID- 23755780 TI - [Recurrence and surgical salvage of sinonasal squamous cell carcinoma]. AB - OBJECTIVE: To analyze the significant clinicopathologic factors related to tumor recurrence in patients with sinonasal squamous cell carcinomas (SCC) and to evaluate the effectiveness and plausibility of surgical salvage in the recurrent cases. METHODS: The clinicopatholgic data of 107 patients with primary sinonasal SCC treated from 1996 to 2007 were analyzed retrospectively. Univariate and multivariate logistic regression analyses were used to define the risk factors related to tumor recurrence. Salvage surgery with was selectively carried out in the recurrent sinonasal SCC using different surgical approaches, including lateral rhinotomy midfacial degloving or combined craniofacial approach. Immediate reconstruction of major surgical defects were performed with latissimus dorsi flap, pectoralis major myocutanneous flap, temperalis fasciomuscular flap, free rectus abdominis flap and free radial forearm flap. All patients were routinely follwed up and 5-year survival were calculated using directly calculating method and Kaplan-Meier's method. RESULTS: The 5-year survival rate of 107 cases was 52.3% (56/107). Local recurrence was the most common pattern of tumor relapse. Forty-four of the 107 cases had recurrence. Logistic regression analysis showed the T stag was the most important impacting factor for tumor recurrence (OR = 0.258, P = 0.001). Of 44 cases with recurrence, 33 cases underwent salvage surgery and the 5-year survival rate after salvage surgery was 29.1%. CONCLUSIONS: T stag is the most important impacting factor for tumor recurrence. Salvage surgery with immediate reconstruction of major surgical defects should be carried out in the selective cases of recurrent sinonasal SCC. PMID- 23755781 TI - [Clinical effect of Le Fort I osteotomy approach associated with endoscope for the resection of juvenile nasopharyngeal angiofibroma]. AB - OBJECTIVE: To analyze the clinical effect of Le Fort I osteotomy approach associated with endoscope for the resection of juvenile nasopharyngeal angiofibroma. METHODS: Three patients with juvenile nasopharyngeal angiofibroma, stage II b, were retrospectively analyzed. All of them underwent Le Fort I osteotomy approach associated with endoscope between 2004 and 2009. All patients were followed up at first, third, sixth months and one year after surgery. Two years later, endoscopic examination and CT scan were performed, to analyze the clinical effect. RESULT: All three patients had total removal of tumor and no postoperative complications. No tumor recurrence was found 2 years after operation, and no face deformity. The tooth articulation was recovered, these patients could eat hard diet, although one patient had lose a little teeth sensation. CONCLUSION: Le Fort I osteotomy had good clinical effect, if associated with endoscope, it could get a good surgical exposure, and can do well in the treatment on juvenile nasopharyngeal angiofibroma, even intruded into pterygopalatine and infratemporal fossa. PMID- 23755782 TI - [Radiobiological characteristics and MRN complex expression of human nasopharyngeal carcinoma cell lines]. AB - OBJECTIVE: To study the radiobiological characteristic of human nasopharyngeal carcinoma cell lines CNE1 and CNE2 and the changes in expression MRN (Mre11-Rad50 Nbs1) complex in the cell lines exposed to irradiation. METHODS: CNE1 and CNE2 were irradiated by a linear accelerator. Radiobiological characteristics were detected by colony assay and MTT assay. MRN complex expression were examined by Western blot. RESULTS: Surviving fraction at 2 Gy (SF2), quasi-threshold Dose (Dq), and mean lethal dose (Do) of CNE1 were 0.56, 1.449 Gy and 1.480 Gy; SF2, Dq, and Do of CNE2 were 0.44, 0.776 Gy and 1.685 Gy, respectively. Survival fraction of CNE1 at the day 6 after 4 Gy irradiation was 0.59 and that of CNE2 was 0.79 when compared with control, with the up-regulated expressions of Rad50 in CNE1 and Mre11, Rad50 and Nbs1 in CNE2 (P < 0.05). CONCLUSIONS: CNE1 and CNE2 were sensitive to radiation, but there were radioresistance cells in CNE2. The expressions of some components of MRN complex were up-regulated to repair DNA lesions induced by radiation. PMID- 23755783 TI - [Relationship between the Mandarin acceptable noise level and the personality traits in normal hearing adults]. AB - OBJECTIVE: To evaluate the relationship between the Mandarin acceptable noise level (ANL) and the personality trait for normal-hearing adults. METHODS: Eighty five Mandarin speakers, aged from 21 to 27, participated in this study. ANL materials and the Eysenck Personality Questionnaire (EPQ) questionnaire were used to test the acceptable noise level and the personality trait for normal-hearing subjects. SPSS 17.0 was used to analyze the results. RESULTS: ANL were (7.8 +/- 2.9) dB in normal hearing participants. The P and N scores in EPQ were significantly correlated with ANL (r = 0.284 and 0.318, P < 0.01). No significant correlations were found between ANL and E and L scores (r = -0.036 and -.167, P > 0.05). CONCLUSION: Listeners with higher ANL were more likely to be eccentric, hostile, aggressive, and instabe, no ANL differences were found in listeners who were different in introvert-extravert or lying. PMID- 23755784 TI - [Transnasal endoscopic removal of orbital apex cavernous hemangioma]. AB - OBJECTIVE: To explore the strategy and indications of endoscopic transnasal resection of orbital apex cavernous hemangiomas (OACH). METHODS: Eleven patients aged from 30 to 62 years-old diagnosed as OACH bypostoperative histopathology were reviewed retrospectively. Four males and 7 females were included. Both ophthalmological examination and rhinologic evaluation were adopted preoperatively. The surgeries were carried out under general anesthesia endoscopically by the same senior surgeon. After ethmoidectomy, the orbital lamina papyracea was opened, and the orbital fat and muscles were pushed back into the orbit by using the brain cotton, and then the orbital tumor was removed. The patients were kept follow-up both in ophthalmologic and rhinologic departments. RESULTS: As suggested by preoperative imagings, 4 lesions located in the extraconal space (nasal side), 6 between the optic nerve and the internal rectus muscle of the intraconal space, and 1 outside the optic nerve in the intraconal space. Total resection was achieved in 9 cases, and orbital decompressions were done in 2 cases. Meanwhile, orbital wall reconstruction was done in 7 cases. The follow up ranged from 6 to 47 months. Seven patients achieved visual acuity improvement and no deteriorations were found in other 4 patients. Defects of vision field in 3 patients disappeared after 2 weeks. No operative or postoperative complications occurred. CONCLUSIONS: The OACH located in the nasal side of extraconal space and between the optic nerve and the internal rectus muscle of the intraconal space can be accessed endoscopically by intranasal approach. Using the brain cotton to push the orbital fat and muscles back into the orbit and an experienced endoscopic surgeon are important to access a successful intranasal endoscopic removal of orbital apex tumor. PMID- 23755785 TI - [Transsphenoidal endoscopic endonasal approach for the resection of Rathke cleft cysts]. AB - OBJECTIVE: To evaluate the effectiveness of transsphenoidal endoscopic endonasal approach for the resection of Rathke cleft cysts (RCC). METHODS: Thirty-five pathologically diagnosed RCCs were resected throuth transsphenoidal endoscopic endonasal approach at the HuanHu hospital between January 2000 and December 2011. The clinical data were retrospectively analysed. There were 12 male and 23 female. The average age was 45.7 years and the average disease course was 4.6 years. The typical clinical manifestations included headache (26 cases), visual interference (11 cases) and pituitary dysfunction (8 cases). The postoperative symptoms and follow-up results were recorded. RESULTS: All of the patients underwent complete removal of the cyst contents, complete removal of the cyst wall in 20, fenestration and aspiration of the RCC with partial excision of the cyst wall in 15. The mean cyst volume was (1145.3 +/- 12.1) mm(3) [range (121 - 4586) mm(3)]. One patient had cerebrospinal fluid leak, which was repaired using artificial dura mate of brain and gelatin sponge intraoperatively. No postoperative complications were found. Follow-up time ranged from half a year to 11 years. Headache resolved in 100% (26/26), visual interference resolved in 90.9% (10/11), pituitary dysfunction resolved in 62.5% (5/8). No patient recurred. CONCLUSION: It is concluded that the transsphenoidal endoscopic endonasal approach is microinvasive, safe and effective in the treatment of RCC. PMID- 23755786 TI - [Impact in response control, attention and hyperactivity behavior on children with obstructive sleep apnea hypopnea syndrome by integrated visual and auditory continuous performance test]. AB - OBJECTIVE: To study the impact in response control, attention and hyperactivity behavior on children with obstructive sleep apnea hypopnea syndrome (OSAHS) by the integrated visual and auditory continuous performance test (IVA-CPT). METHODS: Fifty-one children aged between 5 and 12 years were diagnosed as OSAHS by polysomnography (PSG), and received adenotonsillectomy and adenoidectomy or only adenoidectomy. Then received IVA-CPT and PSG before surgery, 3 months after surgery and 6 months after surgery (named as first, second and third time point). These children were divided into two groups according to the disease course (group A: course of disease < 5 years; group B: course of disease >= 5 years). The SPSS 19.0 was used for statistical analysis. RESULTS: By balanced test, there were no differences in gender, body mass index (BMI) and disease severity among the two groups before surgery (P > 0.05). The numbers of children with abnormal psychological behavior at three time points were 32 (62.7%), 25 (49.0%) and 8 (15.7%). The abnormal rate did not show statistical difference between the first and second time point (chi(2) = 1.49, P = 0.163), but did show statistical difference between the second and third time point (chi(2) = 12.95, P < 0.001). Repetitive measurement and analysis of variance showed that there were statistical differences in means of FRCQ, FAQ and HYP between three time points in two groups (F were 342.15, 263.12, 380.57, P < 0.001), and all the means improved with time. It also showed that there were statistical differences in means of FRCQ, FAQ and HYP between two groups at every time point (F were 167.05, 126.47, 117.683, P < 0.001). FRCQ and HYP all showed interation effect between two groups (P < 0.001). Means of apnea hypopnea index (AHI) and lowest arterial (LaSO2) were compared between three time points in two groups and all showed statistical differences (F were 99.057, 70.742, P < 0.001). Means of AHI and LaSO2 were compared between two groups at every time point. AHI and LaSO2 did not show statistical difference (P > 0.05). AHI and LaSO2 did not exist interation effect of disease course and time. CONCLUSIONS: OSAHS obviously affect the children's response control, attention and hyperactivity behavior, but can recover gradually after adenotonsillectomy and adenoidectomy or only adenoidectomy. Therefore, Children with OSAHS should receive treatment as early as possible so as to reduce the influence on psychology. PMID- 23755787 TI - [Surgery and function reconstruction of laryngeal cancer involved supraglottic and glottis area]. AB - OBJECTIVE: To investigate the surgery preserving epiglottis, the repair and the postoperative functions in laryngeal carcinoma involving supraglottic and glottic areas. METHODS: A total of 97 cases with laryngeal cancer involving both supraglottic and glottic areas with normal epiglottis underwent surgery between June 2005 and December 2010 was reviewed. Of them 37 cases were stage II, 41 cases were stage III, and 19 cases were stage IV. Vertical partial laryngectomy (VPL) or extended VPL with the repair and functional reconstruction was carried out in 86 cases and cricohyoidoepiglottopexy (CHEP) in 11 cases. Postoperative survival rate, laryngeal functions and quality of life were evaluated. RESULTS: The 3-year and 5-year total cumulative survival rate (Kaplan-Meire survival analysis) were 87.1% and 69.6% in the 97 cases; 86.6% and 68.3% in VPL/EVPL group; 90.0% and 78.8% in CHEP group, respectively, with no significant difference between VPL/EVPL and CHEP groups (P > 0.05). Of 97 cases, 86(88.7%) cases were decannulated postoperatively. The rates of decannulation were 87.2% (75/86) in VPL/EVPL group and 100% (11/11) in CHEP group, with no significant difference (P > 0.05). Average oral diet recovery time of VPL/EVPL group and CHEP group was (5.2 +/- 1.3) and (15.7 +/- 5.2) days, respectively, with a significant difference (P < 0.01). Voice evaluation showed the mean maximum phonation time of VPL/EVPL group was shorter than that of CHEP group (P < 0.01) and the S/Z ratio of VPL/EVPL group was higher than that of CHEP group (P < 0.01). Perceptual voice evaluation GRBAS ratings showed patients in VPL/EVPL group had higher G and B ratings compared to patients in CHEP group (P < 0.01), but no significant difference in R-rating between two groups (P > 0.05). Voice handicap index-10 (VHI-10) scores of VPL/EVPL and CHEP groups were 29.5 +/- 4.7 and 31.6 +/- 6.3, respectively, no significant difference (P > 0.05). CONCLUSIONS: For patients with the laryngeal carcinoma involving both supraglottic and glottic areas, VPL has better anatomical and functional outcomes than CHEP. The preservation of at least 2/3 of the lamina of thyroid cartilage on one side and shift-down of epiglottis were key to successful VPL and postoperative decannulation. PMID- 23755788 TI - [Development of allergic airway disease model in mice]. AB - OBJECTIVE: To investigate the method of development of allergic airway disease model in mice. METHODS: Ten BALB/c mice were devided into the model group and the control group. Each group contained 5 mice. Ovalbumin (OVA) was used as allergen. OVA was emulsified with aluminum hydroxide and injected intraperitoneally for sensitization. Afterwards the mice from model group were challenged with aerosolized 5% OVA and subsequently instilled with OVA intranasally. For the blank control group the mice were sensitized and challenged with phosphate buffer saline (PBS). After final challenge, the nasal symptoms were scored, and mice were sacrificed for evaluation of eosinophilia of nasal septum, peribronchial inflammation and goblet cell hyperplasia. Mice serum was collected for measurement of OVA-specific IgE concentration, and levels of IL-4 and IL-5 from bronchoalveolar fluids were also tested. RESULTS: Compared with blank control mice, mice from model group displayed typical sneezing and nasal scratching symptoms. The histopathological changes, such as eosinophilia of nasal septum mucosa, infiltration of peribronchial inflammatory cells and hyperplasia of goblet cells were successfully induced by OVA sensitization and challenge. Moreover, mice in model group showed higher level of OVA-specific IgE in serum and IL-4 and IL-5 cytokines in bronchoalveolar fluids[mice from model group: IgE (1237.00 +/- 153.20) pg/ml, IL-4 (46.50 +/- 10.15) pg/ml, IL-5 (50.81 +/- 11.41) pg/ml; mice from control group: IgE (191.90 +/- 43.20) pg/ml, IL-4 (7.96 +/- 1.80) pg/ml, IL-5 (7.53 +/- 2.23) pg/ml;t value were 6.569, 3.738 and 3.724, respectively, all P < 0.05]. CONCLUSION: The method using OVA as allergen could effectively develop a mouse model of allergic airway disease which could be used for pathogenesis study and drug effect evaluation. PMID- 23755789 TI - [EphA2 mediated vascular endothelial growth factor expression via the p38 MAPK signaling pathway in squamous cell carcinoma of the head and neck]. AB - OBJECTIVE: To investigate the regulatory effect of erythropoietin-producing hepatocellular receptor (EphA2) on the expression of VEGF protein, a pro angiogenic factor, via p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway in squamous cell carcinoma of the head and neck(SCCHN) in vitro. METHODS: SCCHN Tu686 cells were transfected with EphA2 overexpression vector pEGFP-N1 EphA2. Western blot was used to detect the expression of p38 MAPK and enzyme linked immunosorbent assay (ELISA) was applied to assay of VEGF. SB203580 as a inhibitor of p38 MAPK signaling pathway was used. RESULTS: The expression of VEGF protein was significantly up-regulated in Tu686 cells transfected with EphA2 overexpression vector (535.31 +/- 45.71) pg/ml, when compared with Tu686 cells transfected with empty vector (400.99 +/- 33.50) pg/ml and Tu686 cells with no transfection (385.30 +/- 33.50) pg/ml (F = 17.091, P < 0.01). The expression of phosphorylated p38 MAPK was obviously increased in Tu686 cells with EphA2 overexpression. SB203580 inhibited the expressions of VEGF and phosphorylated p38 MAPK proteins in Tu686 cells with EphA2 overexpression. CONCLUSION: EphA2 can regulate the expression of VEGF protein and stimulate p38 MAPK signaling pathway. PMID- 23755790 TI - [The model of aged-hearing monitoring under the hospital information system]. AB - OBJECTIVE: To study the oldly people's hearing screening and dynamic monitoring mode, and to discuss the new diseases and health management mode in current information network era. METHODS: To establish the network connection between the hospital and the communities in the internet through the function expansion of the Hospital Information Systems and to realize "dual systems, double platforms" integrated management modes and establish the audiology workstation. The routine physical examination, pure tone hearing threshold tests and middle ear analysis were performed on four hundred and twenty elderly people from the fourteen communities every three months, and the changes of hearing and related symptoms were observed. RESULTS: Resources sharing was established between the hospital and these fourteen communities. Health records were established for all the aged people, the hearing screening lasted only half a day each time. Fourteen hearing loss cases were found during one year. A statistically significant difference (P < 0.01) were found, the ratio of hearing loss with diabetes, high blood pressure and other diseases were much higher than people without concomitant. CONCLUSION: The advantage of disease management mode under the Hospital Information System is convenient, the work efficiency and qualities are improved, which is worthy of popularizing. PMID- 23755791 TI - [Effects of laser-assisted cochleostomy on inner hair cell ribbon synapse in rats]. AB - OBJECTIVE: To investigate the effects on ribbon synapse of inner hair cells after superpulsed CO2 laser-assisted cochleostomy in SD rats. METHODS: Eighteen SD rats were randomly divided into laser-assisted surgery groups (2 W group and 5 W group), sham-operated group and control group. Ten of those were performed a cochleostomy using superpulsed CO2 laser with a corresponding power. Auditory brainstem responses (ABR) were measured pre-and postoperatively. The ribbon synapses at apical and middle cochlear turns were observed under laser scanning confocal microscope and then were quantified with 3ds Max software. RESULTS: The postoperative ABR thresholds of the 2 W and 5 W groups were larger than the preoperative case (t = -5.65, P < 0.01; t = -4.97, P < 0.01). The synapse number at the middle turn decreased significantly in 5 W group (F = 17.15, P < 0.01), while no significant changes were noted at the apical turn (P > 0.05). There was no statistical difference in 2 W group (P > 0.05). CONCLUSIONS: The superpulsed CO2 laser-assisted cochleostomy with high-power is accompanied by a synaptic injury, while no obvious effects after the low-power laser surgery, which might be a safe strategy to preform cochleostomy. PMID- 23755792 TI - [Clinical manifestation of Kaposi sarcoma in otorhinolaryngology head and neck surgery]. AB - OBJECTIVE: To improve the knowledge of Kaposi sarcoma and the relationship between Kaposi sarcoma and human immunodeficiency virus (HIV) infection, and to improve the ability to diagnose and treat Kaposi sarcoma and acquired immune deficiency syndrome (AIDS). METHODS: Symptoms, signs and results of 121 patients encountered in the department of otorhinolaryngology head and neck surgery in Tanzania, who was diagnosed as Kaposi sarcoma actually with HIV infection and AIDS, were retrospectively analyzed in this study. RESULTS: There were 46 males and 75 females with age ranged from 5 to 65 years, medium 30 year. The mucous membranes and skin lesions was the most commonly seen clinical manifestation in 121 cases, these lesions appeared as raised blotches or lumps that might be purple, brown, or red, early stages typical lesions began as flat or slightly raised colored spots. Among the cases reported here, 25 patients (20.66%) showed progressive nose blockage and nose bleeding and the purple-red new-grows were found in the nose of these patients. Fifteen patients (12.40%) had flat or slightly raised colored spots in their mucous membrane of mouth (palate or tongue), and in other 7 patients, purple small lumps were found in the gums of the patients. There were same lesions in their pharynx in 9 cases. In 10 patients (8.26%), Kaposi sarcoma was found in tonsil looked like tonsillitis with enlarged tonsils by two to three degree. Twelve patients (9.92%) had masses in the neck with no pain. Thirty-five patients (28.92%)had lesions of purple black nodules, including 10 patients who had the same lesions with ulcer formation in the nodules. All patients had been followed-up for at least two-years. Eighty-five patients passed away in one year, survival rate of one year was 21.48% (26/121), only 12 patients survived from the disease over two years, two years' survival rate was 9.92% (12/121). CONCLUSIONS: Kaposi sarcoma is the characteristic disease for AIDS, mainly found on the membranes and skin. These lesions appears as raised blotches or lumps that may be purple, brown, or red, early stages typical lesions begin as flat or slightly raised colored spots. Patients who had kaposi sarcoma often died in a short-time without treatment. PMID- 23755793 TI - [Clinical significance of pulmonary function test in patients with chronic rhinosinusitis with nasal polyps]. AB - OBJECTIVE: To investigate the incidence and severity of pulmonary function impairment in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: In this prospective study, fifty-six patients with bilateral CRSwNP who were scheduled for functional endoscopic sinus surgery during a period from March to June 2010 in the Department of Otolaryngology of Qilu Hospital, were recruited in this study. Routine medical and rhinological examinations such as nasal endoscopy, sinus CT scan, and skin prick tests (SPT) for common inhalant and food allergens, and cytological examination of the paraffin-embedded NP tissues were performed together with a full assessment of the pulmonary functions. RESULTS: Based on the pulmonary function tests, the rate of patients showing bronchial hyperresponsiveness (BHR), asthma, and abnormal pulmonery functions were 37.5%, 44.6%, and 53.6%. In patients who did not have a history of lower airway symptoms, the rate of abnormal pulmonary functions was 50.0%, the rate of BHR was 43.2%. There was an increased rate of BHR, asthma and abnormal pulmonary functions in patients with a higher polyp grading score or Lund Mackay CT scan score (polyp grading score: chi(2) were 8.077, 3.989 and 7.445, P < 0.01 or < 0.05. CT scan score: chi(2) were 3.863, 5.380 and 4.309; 4.293, 4.293 and 4.572; 10.572, 13.504 and 13.295, P < 0.01 or < 0.05). The rate of BHR and asthma in patients with positive SPT were higher (P < 0.05). In patients with eosinophils hyperplasia in nasal polyps, the rate of BHR, asthma and abnormal pulmonary functions were higher (chi(2) were 4.065, 5.217 and 3.376, P < 0.05 or P < 0.01). CONCLUSIONS: There is a high risk of developing lower airway diseases in patients with CRSwNP. PMID- 23755794 TI - [A case of refractory maxillary osteomyelitis with fistula formation in gingival sulcus]. PMID- 23755795 TI - [A case report of pterygopalatine fossa communication arachnoid cyst]. PMID- 23755796 TI - [Platysma myofascial flap combined with acellular dermal matrix in the repair of oropharyngeal carcinoma of the buccal defects after cancer resection]. PMID- 23755797 TI - [A case of huge thyroglossal duct cyst blocking throat and the piriform fossa]. PMID- 23755798 TI - [Research progress of separation screening and oncogenes correlation in nasopharyngeal carcinoma cancer stem cells]. PMID- 23755799 TI - [Surgical treatment of sinonasal carcinoma]. PMID- 23755800 TI - [Effects of drugs on nasal mucociliary clearance]. PMID- 23755801 TI - Duration of upper and lower extremity peripheral nerve blockade is prolonged with dexamethasone when added to ropivacaine: a retrospective database analysis. AB - BACKGROUND: Dexamethasone, when added to local anesthetics, has been shown to prolong the duration of peripheral nerve blocks; however, there are limited studies utilizing large numbers of patients. The purpose of this study was to examine the effect of adding dexamethasone to ropivacaine on duration of nerve blocks of the upper and lower extremity. METHODS: We reviewed 1,040 patient records collected in an orthopedic outpatient surgery center that had received an upper or lower extremity peripheral nerve block with ropivacaine 0.5% with or without dexamethasone and/or epinephrine. The primary outcome was duration of analgesia in upper or lower extremity blocks containing dexamethasone as an adjunct. Secondary outcomes included postoperative patient pain scores, satisfaction, and the incidence of block related complications. Linear and ordinal logistic regression models were used to examine the independent effect of dexamethasone on outcomes. RESULTS: Dexamethasone was observed to increase median block duration by 37% (95% confidence interval: 31-43%). The increased block duration persisted within body regions (upper and lower) and across a range of block types. Dexamethasone was also observed to reduce pain scores on the day of surgery (P = 0.001) and postoperative day 1 (P < 0.001). There was no significant difference in duration of nerve blocks when epinephrine (1:400,000) was added to 0.5% ropivacaine with or without dexamethasone. CONCLUSION: The addition of dexamethasone to 0.5% ropivacaine prolongs the duration of peripheral nerve blocks of both the upper and lower extremity. PMID- 23755802 TI - FasL-induced apoptosis in bovine oocytes via the Bax signal. AB - The factor associated suicide (Fas) and its ligand (FasL) signaling is an important regulatory pathway of apoptosis in mammalian follicles. However, whether apoptosis in bovine oocytes is regulated by the Fas-FasL signaling pathway remains unknown. In this study, localization of Fas and FasL in immature oocytes and FasL in cumulus cells were examined using immunofluorescence staining. In addition, exogenous FasL was added to an in vitro culture system to investigate apoptotic changes in bovine oocytes, using annexin-V and terminal uridine nick-end labeling staining, and real-time quantitative polymerase chain reaction. In this study, Fas was expressed in immature oocytes, whereas FasL was expressed in cumulus cells, but not in immature oocytes; annexin-V- and terminal uridine nick-end labeling-positive rates of oocytes treated with 2, 10, or 50 ng/mL FasL were higher than those of control oocytes (P < 0.05); and oocytes from the three treatment groups had higher expression levels of Fas and B cell lymphoma/leukemia-2 associated X than those in the control group (P < 0.05). Taken together, we concluded that the Fas-FasL signaling pathway was involved in regulation of bovine oocyte apoptosis, perhaps related to B cell lymphoma/leukemia-2 associated X upregulation. PMID- 23755803 TI - [Medical professionalism research and its implications to China]. PMID- 23755804 TI - [Surgeon and the surgical safety]. PMID- 23755805 TI - [Challenges to medical professionalism: perspectives from the United States]. PMID- 23755806 TI - [Theory and best practices of medical professionalism as well as the policy recommendations for healthcare reform in China]. PMID- 23755807 TI - [Implementation of medical students' whole person education, shaping physician occupation spirit]. PMID- 23755808 TI - [Scientific research accomplishment of medical staff]. PMID- 23755809 TI - [How to improve the game situation in doctor-patient relationship]. PMID- 23755810 TI - [Expression and role of vascular endothelial growth inhibitor in sporadic clear cell renal cell carcinoma]. AB - OBJECTIVE: To evaluate the expression of vascular endothelial growth inhibitor (VEGI) in sporadic clear cell renal cell carcinoma (CCRCC) and explore its relationships between VEGI expression, pathologic grade and tumor staging. METHODS: Western blot and immunohistochemical staining were used to detect the expression of VEGI in CCRCC cell line (786-O cells), CCRCC and paired normal kidney tissues. A total of 50 CCRCC cases were recruited. There were 37 males and 13 females with an average age of 53 +/- 12 years. The tumor sizes were < 7 cm (n = 33) and >= 7 cm (n = 17). Their pathologic grades were G1 (n = 14), G2 (n = 22) and G3 (n = 14) and pathologic stages pT1 (n = 32), 10 pT2 (n = 10) and pT3 (n = 8). RESULTS: VEGI protein was predominantly located in cytoplasm. Compared with normal kidney tissues(mean optic density (MOD) of VEGI staining: 0.40 +/- 0.16), it was lower in CCRCC tissues (MOD: 0.11 +/- 0.06, P < 0.01). In addition, the positive rate of VEGI expression, the expression intensity and the MOD of VEGI protein were negatively correlated with the pathologic grade of CCRCC (r = 0.640, P < 0.01; r = -0.831, P < 0.01; r = -0.781, P < 0.01 respectively). The MOD of VEGI expression in >= 7 cm tumors (MOD, 0.08 +/- 0.04) was significantly lower than that in < 7 cm tumors (MOD: 0.12 +/- 0.06, P < 0.05). However, there was no correlations between the VEGI protein level and age, gender and pathologic stage of patients (P > 0.05). CONCLUSION: VEGI protein is predominantly located in cytoplasm. Compared with CCRCC tissues, VEGI protein level is higher in normal ones. In consideration of negative correlations between VEGI expression, pathologic grade and tumor size, it is implied that VEGI may play a negative regulatory role in the occurrence and development of CCRCC. PMID- 23755811 TI - [Expression and clinicopathological significance of serine-257/threonine-261 phosphorylated MKK4 in colorectal carcinoma]. AB - OBJECTIVE: As an activator of JNK and p38, phosphorylated MKK4 is considered to be associated with tumor progression and prognosis. This study was to examine the expression of pMKK4 and evaluate its prognostic significance in colorectal carcinoma. METHODS: A total of 343 cases of colorectal cancer were followed up to analyze the associations between the expression of pMKK4 and various clinicopathological factors. The expression of Serine-257/Threonine-261 pMKK4 was detected immunohistochemically by tissue microarray. RESULTS: The staining of pMKK4 was present in cytoplasm of colorectal carcinoma. And the expression of pMKK4 was correlated with invasion depth (P = 0.003), differentiation (P = 0.018), lymph node metastasis (P < 0.001), metastasis (P < 0.001), hepatic metastasis (P = 0.039) and TNM stage (P < 0.001). The patients with strong pMKK4 staining had a better overall survival than those with lowered levels (Log rank = 4.531, P = 0.033). Univariate analysis indicated that the expression of pMKK4 was correlated with either overall survival (HR = 0.785, P = 0.035) or relapse-free survival (HR = 0.788, P = 0.044). In multivariate analysis, there was no prognostic significance of pMKK4 after adjusting for invasion depth, differentiation, lymph node metastasis, metastasis, liver metastasis and TNM stage. CONCLUSIONS: The down-regulation of S257/T261 pMKK4 is associated with more advanced stages and it plays an important role in tumor progression. A high level expression of pMKK4 indicates favorable clinical outcomes, but it is not an independent predictor. PMID- 23755812 TI - [Clinical characteristics in adult acute myeloid leukemia with isocitrate dehydrogenase gene mutation]. AB - OBJECTIVE: To explore the prevalence and clinical characteristics of isocitrate dehydrogenase (IDH)1 R132 and IDH2 R140/R172 gene mutations in acute myeloid leukemia (AML) patients. METHODS: Polymerase chain reaction (PCR) and direct sequencing were used to sequence exon 4 of IDH gene in 570 AML patients from 2005 to 2011. RESULTS: In a cohort of 570 patients, AML IDH gene mutation was found in 90 (15.79%) patients. IDH1 and IDH2 mutations were detected in 27 (4.74%) patients and 63 (11.05%) patients respectively. None of them had the combined mutations of IDH1 and IDH2. The highest frequency of IDH mutations was found in AML M1 (according to the FAB scheme) compared with all other subtypes (P < 0.01). The median age was 53 years in mutated group versus 40 years in wild-type group (P = 0.010). Mutated and wild-type groups had no significant difference in gender, white blood cell count at diagnosis, hemoglobin count and bone marrow blast percentage, excepting for blood platelets level (median 52*10(9)/L vs 31*10(9)/L, P < 0.01). IDH gene mutations were associated with cytogenetically normal (CN)-AML, NPM1 mutations and particularly with the genotype of mutated NPM1 without FLT3-ITD. IDH gene mutations had no significant correlation with WT1, FLT3-TKD and MLL-PTD mutations. IDH mutated patients had a lower complete remission rate than unmutated in non-M3 patients (58.1% vs 77.9%, P < 0.05). And the patients with mutant IDH gene were associated with a shorter overall survival (28.4% vs 51.3%, P < 0.01). CONCLUSION: IDH gene mutations are more prevalent in elder AML patients and it may constitute a molecular marker for a poor prognosis in AML. PMID- 23755813 TI - [Clinical application of transport distraction osteogenesis arthroplasty in the treatment of temporomandibular joint bony ankylosis]. AB - OBJECTIVE: To explore the clinical application of transport distraction osteogenesis arthroplasty (TDOAP) in the treatment of temporomandibular joint (TMJ) bony ankylosis. METHODS: From December 1999 to December 2011, a total of 73 patients (89 sides of TMJ) underwent TDOAP were included. There were 39 males and 34 females with a mean age of 19.6 years (range: 3 - 60). Among them, 27 patients were recurrence cases and 30 cases were accompanied with micrognathia and obstructive sleep apnea-hypopnea syndrome (OSAHS). The mean preoperative degree of mouth opening was 6.6 mm (range: 1 - 20). After a release of ankylosis, a transport disc was performed and fixed to ramus with a distractor. Distraction began at Days 4 - 8 postoperation. The distraction rhythm and rate were 0.25 mm four times daily. Distraction stopped when planning distance was achieved. And a distractor was maintained in place for 3-6 months after completion of distraction and then removed. Active postoperative training of mouth opening was implemented. RESULTS: The mean distance of distraction was 15.3 mm (range: 12 - 23). The range of mouth opening of 65 patients increased to normal and bone formation in gaps were perfect. The mean follow-up period was 44.8 months (range: 18 - 102). Eight cases were recurrent. And 1/37 over 15 years old and 7/36 under 15 years old had recurrence. CONCLUSIONS: TDOAP is an effective treatment for TMJ ankylosis. A pediatric patient, especially recurrent, should be operated after adolescence to decrease recurrence. Micrognathia and OSAHS should be also considered during the treatment of ankylosis. PMID- 23755814 TI - [Comparison of non-glucose versus glucose stimulation test in estimating islet beta-cell function in individuals with differential glucose tolerance]. AB - OBJECTIVE: To explore the values of arginine stimulation, oral glucose-insulin release and intravenous glucose tolerance tests to assess the function of islet beta-cell in individuals with differential glucose tolerance. METHODS: Healthy subjects (n = 38) and those with impaired glucose regulation (IGR) without a family history of diabetes (n = 31), 32 normal glucose tolerance (NGT, n = 32) and impaired glucose regulation as first-degree relatives of type 2 diabetes mellitus (DM) (IGR, n = 36) and 35 newly-diagnosed type 2 DM (n = 35) were recruited. All of them received arginine C-peptide releasing test (AST), oral glucose-insulin release test (OG-IRT) and intravenous glucose tolerance test (IVGTT). ACRARG was used to reflect non-glucose stimulated insulin secretion function, AIR0-10 for first-phase insulin secretion function and DeltaI30/DeltaG30 for early insulin secretion function. The changes of islet-beta cell function indicators were detected in individuals with different glucose tolerance. RESULTS: (1) No significant differences existed in ACRARG among five groups (all P > 0.05). (2) In terms of AIR0-10, the patients of type 2 DM had lower levels than those with IGR and NGT with or without a family history of DM (all P < 0.01). No significant difference existed among the subjects of IGR regardless of a family history of DM (P > 0.05). However, the subjects of IGR with or without a family history of DM had lower levels than those with NGT regardless of a family history of DM (P < 0.01 or P < 0.05). The subjects of NGT with a family history of DM had lower levels than those with NGT without a family history of DM (50.0 (24.3 - 85.1) vs 69.4 (46.1 - 94.8), P < 0.05). (3) DeltaI30/DeltaG30: no significant difference existed between the patients of type 2 DM and IGT with a family history of DM (P > 0.05). However, the subjects of type 2 DM had lower levels than those of IGR without a family history of DM and NGT with or without a family history of DM (all P < 0.01). The subjects of IGR with or without a family history of DM had lower levels than those with NGT regardless of a family history of DM (all P < 0.01). No significant difference existed among the subjects of NGT with or without a family history of DM (P > 0.05). And it was the same with IGR group. CONCLUSION: The acute C-peptide response to arginine stimulation test may not be used to evaluate the early phase insulin secretion among the subjects of early-stage DM, impaired glucose regulation and high diabetic risks. PMID- 23755815 TI - [Costimulatory molecule CD40 expression in thyroid tissue of Graves' disease patients and its immune pathogenetic significance]. AB - OBJECTIVE: To explore the expression of costimulatory molecule CD40 in thyroid tissue of Graves' disease patients and understand its immune pathogenetic significance. METHODS: From January 2008 to December 2011, 8 patients undergoing partial thyroidectomy for Graves' disease (n = 3) or non-toxic goiter (n = 5) at Affiliated Suzhou Hospital of Nanjing Medical University and Third Affiliated Hospital of Soochow University were enrolled. Using the method of immunohistochemistry, the expression of CD40 was detected in their thyroid tissues. Variation in CD40 expression on thyroid follicular (TFC) in primary cultures was analyzed in the absence (no stimulation group) or presence of inflammatory cytokines including interleukin interferon-gamma (IFN-gamma) (IFN gamma stimulation group), interferon-6 (IL-6) (IL-6 stimulation group)and tumor necrosis factor (TNF)-alpha (TNF-alpha stimulation group) with flow cytometry. IFN-gamma-stimulated TFC were cultured with agonist CD40 monoclonal antibody (5C11) (IFN-gamma + CD40 group) or isotypic mouse IgG (mIgG) antibody (IFN-gamma + mIgG group). And the proliferation of TFC was assessed by 3-(4,5)-dimethyl thiazolyl-3,5-di-phenytetrazoliumromide (MTT) assays for each donor. The production of free triiodothyronine (FT3) and free thyroxine (FT4) and the release of thyroglobulin (Tg) were measured with radioimmunoassays. RESULTS: The expression of CD40 on infiltrated lymphocytes and TFC were detected in Graves' disease but not in non-toxic goiter patient tissues. Compared with no stimulation group (23.7% +/- 7.3%), the expression of CD40 on TFC increased in IFN-gamma stimulation group (86.4% +/- 4.6%), IL-6 stimulation group (90.0% +/- 4.2%) and TNF-alpha stimulation group (87.3% +/- 4.2%). Compared with the IFN-gamma + mIgG group (0.75 +/- 0.06), the TFC proliferation of IFN-gamma + CD40 group (1.14 +/- 0.14) significantly increased (P < 0.01). The levels of FT3, FT4 and Tg secretion of IFN-gamma + CD40 group were (1.10 +/- 0.15) pmol/L, (0.80 +/- 0.14) pmol/L and (30.23 +/- 1.60) ug/L respectively. They were all significantly increased compared with the IFN-gamma + mIgG group, of which the FT3, FT4 and Tg production were (0.76 +/- 0.07) pmol/L, (0.63 +/- 0.09) pmol/L and (21.37 +/- 3.22) ug/L respectively (all P < 0.05). CONCLUSIONS: CD40 is abnormally expressed in thyroid tissue of Graves' disease patients. And its costimulatory signal may take part in the immunopathologic mechanism of Graves' disease. PMID- 23755816 TI - [Value of detecting epidermal growth factor receptor mutations in non-small cell lung cancer tissue by TaqMan-amplification refractory mutation system]. AB - OBJECTIVE: To explore the value of detecting mutations on epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) tissue by TaqMan amplification refractory mutation system (TaqMan-ARMS). METHODS: TaqMan-ARMS and DNA sequencing were used to detect the EGFR exon 19 and 21 mutations in tumor tissues and the samples collected from 199 patients at 4 different 3A hospitals in Beijing from January 2008 to March 2011. RESULTS: The rate of mutations in EGFR exon 19 and 21 was 19.1% (38/199), according to their different pathological types. Based upon TaqMan-ARMS, the classification was as followed: adenocarcinoma (35.0% (36/103)), squamous carcinoma (2.2% (2/93)) and adenosquamous carcinoma (0). According to DNA sequencing, they were 19.6% (39/199), 35.9% (37/103), 2.2% (2/93) and 0 respectively. Thus, no statistically significant difference existed between two methods (McNemar Test, P = 1.000, kappa = 0.984). The mutation rate of adenocarcinoma was higher than those of squamous and adenosquamous carcinoma. CONCLUSION: The detection of EGFR mutations is highly consistent in the NSCLC tissue by the methods of TaqMan-ARMS and DNA sequencing. PMID- 23755817 TI - [Valuable experiences and analysis of causes of urine-induced sepsis]. AB - OBJECTIVE: To explore the characteristics, early symptoms and valuable experiences in the diagnosis and treatment of urine-induced sepsis. METHODS: The clinical data of 30 cases of urine-induced sepsis between August 2008 and April 2012 were reviewed retrospectively. Among them, YAG laser lithotripsy (n = 3) and transurethral prostatic resection (TURP) (n = 2) were performed. One case was after transurethral resection of bladder (TURB). There were 3 cases after cystectomy and Bricker and another 18 during and after percutaneous nephrolithotomy (PCNL). RESULTS: A total of 12 PCNL cases have significant drop in blood pressure during operation with non-bleed causes. A total of 26 cases developed symptoms of chills and high fever after 2 hours of surgery. The earliest symptoms of urine-induced sepsis were decline in blood pressure and high fever. After resistance to infection and symptomatic treatment actively, 27 patients were rescued successful (90%), 3 patients died (10%). Among the 3 deceased patients, 1 case was after YAG laser lithotripsy under ureteroscope, 1 case was after PCNL, 1 case was after TURP. CONCLUSIONS: The onset of urine induced sepsis onset may be insidious. But this condition deteriorates rapidly and it is rather difficult to reverse. Most cases could be managed when the onset characteristics were recognized early. Prevention and early treatment are keys of lowering the mortality. PMID- 23755818 TI - [Role of PI3K-AKT signaling pathway in CD40-mediated proliferation and invasiveness of lung cancer cell]. AB - OBJECTIVE: To analyze the CD40-mediated in vitro proliferation and invasiveness of lung cancer cell H1299, and explore the role of phosphatidylinositol-3-kinase protein kinase B (PI3K-AKT) signaling pathway in the above-mentioned process. METHODS: Cell counting kit-8 (CCK-8) assay was used to detect the proliferation of tumor cells. And scratch test and Transwell chambers were applied to detect the migration and invasiveness of H1299. Western blot was utilized to examine the expressions of AKT and p-AKT and enzyme-linked immunosorbent assay (ELISA) for the CD40-mediated secretion of MMP-9. RESULTS: According to the CCK-8 test, the absorbance of 5C11 groups at different timepoints was significantly higher than the control group (1.72 +/- 0.18), especially when the concentration was 10 mg/L at 96 hour (2.75 +/- 0.35, P < 0.05). In scratch test, the scratching width of 5C11 groups was significantly shorter than control group (1.62 +/- 0.32 mm), especially when the concentration was 10 mg/L (0.05 +/- 0.01 mm, P < 0.05). Western blot showed that the level of p-AKT protein increased at 10 minutes after activating by the signal of CD40 on H1299 cells. It was higher (0.65 +/- 0.28) than the un-activating group (0.33 +/- 0.16) at 30 min (P < 0.05). Upon the addition of LY294002, 5C11-mediated up-regulation of p-AKT was inhibited. In Transwell invasion assay, the number of cells on membranes in 5C11 group (168 +/- 31) were significantly higher than the control group (105 +/- 19, P < 0.05) and there was no significant difference between the 5C11-added LY294002 group (118 +/ 21) and the control group (P < 0.05). The expression of MMP-9 of 5C11 group (192 +/- 31 ng/L) was higher than that of the control group (110 +/- 23 ng/L, P < 0.05) and no significant difference existed between the 5C11-added LY294002 group (120 +/- 21 ng/L) and the control group (P < 0.05). CONCLUSION: The in vitro proliferation and invasiveness of lung cancer H1299 may be regulated by the CD40 mediated activation of PI3K-AKT signaling pathway. PMID- 23755819 TI - [Effects of leflunomide on high glucose-induced podocyte cytoskeleton and its mechanism]. AB - OBJECTIVE: To explore the effects of leflunomide active metabolite A771726 on high glucose-induced podocyte cytoskeleton and its possible signaling pathway. METHODS: The conditionally immortal human glomerular podocytes were divided into normal glucose (NG), mannitol (MA), high glucose (HG), high glucose with PDTC (pyrrolidine dithiocarbamate, a NF-kappaBp65 inhibitor) and high glucose with active leflunomide metabolite A771726 groups. Western blot was used to measure the ratio of p-NF-kappaBp65 to total NF-kappaBp65. And the protein and mRNA expressions of NF-kappaBp65, TRPC6 and nephrin were detected by Western blot and reverse transcription polymerase chain reaction (PCR). Immunofluorescence staining was used to detect the changes in the skeleton of podocyte. RESULTS: (1) Podocytes with high glucose could activate the NF-kappaBp65 signaling pathway. There was a significant increase of p-NF-kappaBp65 protein at 60 min versus 0 min (1.20 +/- 0.04 vs 0.79 +/- 0.02, P < 0.01). Little activation of the pathways was observed in groups NG and MA. The up-regulated protein expression of p-NF kappaBp65 induced with high glucose was significantly inhibited by PDTC and A771726 (both P < 0.05). The difference of NF-kappaBp65 mRNA expression was not statistically significant between the groups (all P > 0.05). (2) High glucose induced podocyte activated the NF-kappaBp65 signaling path. Its downstream TRPC6 mRNA and protein expression significantly increased than NG while nephrin became down-regulated more than NG. PDTC and A771726 inhibited the high expression of TRPC6 while the expression of nephrin was elevated (all P < 0.05). (3) Immunofluorescent assay of high glucose-induced podocyte cytoskeleton showed disorderly F-actin and a disappearance of tensile fiber after 72 h. CONCLUSION: Active leflunomide metabolite A771726 may protect podocytes through blocking the high glucose-induced signaling pathway of NF-kappaBp65. PMID- 23755820 TI - [Shock modeling of large area third-degree burn in miniature swine]. AB - OBJECTIVE: To report a novel method of establishing a stable shock model of swine. METHODS: A total of 12 Guangxi BA-MA female miniature swines (aged 4-6 months) into A and B groups according to a random number table. Total body surface area (TBSA) was calculated according to the Meeb-Rubner formula. After intravenous anesthesia and other steps, solidified gasoline was used as burns material to establish TBSA 40% skin burn (Group A: 45 s, Group B: 50 s). Burn depth by was judged by visual and histopathological examination. Fluid resuscitation was instituted at 2 h post injury. At the same time, the hourly and pre-injury data of heart rate (HR), blood pressure (BP), urinary volume, central venous pressure (CVP) and pulmonary arterial wedge pressure (PAWP) were recorded. The actual input quantities of fluid resuscitation were assessed at the 1st and 2nd 24 h post injury. And shock condition was estimated by shock index at 2 h post injury. RESULTS: All miniature swines were successfully modeled without any mortality. The burn wound observed by visual examination and light microscope showed that Group A was of deep II burn and Group B III burn. Compared with the pre-injury data, HR (111 +/- 6 vs 74 +/- 9, 119 +/- 13 vs 75 +/- 13 beats/min) increased, urinary volume (0.99 +/- 0.06 vs 1.45 +/- 0.05, 0.82 +/- 0.04 vs 1.47 +/- 0.06 ml*kg(-1)*h(-1)), CVP and PAWP decreased at 2nd 24 h post-injury in two groups (P < 0.01, P < 0.05). But the changes of BP (120 +/- 6/93 +/- 9 vs 120 +/- 6/94 +/- 6, 121 +/- 15/90 +/- 11 vs 124 +/- 10/91 +/- 8 mm Hg) had no statistical significance (P > 0.05). The average value of HP in 48 h post-injury had no statistical significance in two groups (P > 0.05). The recovery liquid quantity in the first 24 h of Group B (1.66 +/- 0.10 ml*kg(-1)*1%(-1) TBSA) was significantly more than Group A (1.53 +/- 0.05 ml*kg(-1)*1%(-1) TBSA) (P < 0.05). The ratio between liquid input and output of Groups A and B showed that the comparison had no statistical significance (P > 0.05). In the second 24 h post injury, the recovery liquid quantity (0.69 +/- 0.17, 0.65 +/- 0.16 ml*kg(-1)*1%( 1) TBSA) and the ratio between liquid in and out (1.48 +/- 0.28, 1.52 +/- 0.27)% between Groups A and B had no statistical significance (P > 0.05). The shock index at 2 h post-injury showed that Groups A and B were in shock compensatory period (0.92 +/- 0.07) and mild shock state (1.00 +/- 0.16) respectively (P > 0.05). CONCLUSION: Such a shock model is stable and dependable. PMID- 23755821 TI - A cross-sectional exploratory survey of knowledge, attitudes and daily self reported pain assessment practice among nurses in Mainland China. AB - AIMS AND OBJECTIVES: To describe the level of knowledge, attitudes, and self reported quality of practice in pain assessment among nurses of Mainland China and explore links with current hospital pain policy and continuing education. BACKGROUND: Knowledge is necessary for skilled pain assessment among nurses. Little is currently known regarding knowledge, attitude toward, and self reported pain assessment by nurses from Mainland China. METHODS: Quantitative research and cross-sectional convenience sampling assessed nursing knowledge, attitude, and practice among 101 nurses working in high-level hospitals in Mainland China. RESULTS: 81.2% of nurses participating in the survey were from high-level (level three) hospitals in Mainland China. 24.8% of the nurses attended continuing education in pain assessment. No nurses from the 76 hospital staffs surveyed were able to recall any hospital policy regarding pain assessment. Knowledge regarding pain assessment was rated at 1.9 (SD = 1.6) on a (0-7) scale. 27.7% of nurses possessed a positive attitude toward pain assessment. Pain assessment was not routine in most of the hospitals surveyed. Nurses who attended continuing education showed greater knowledge and more positive attitudes regarding pain assessment but did not show improvement in their quality of practice. CONCLUSIONS: This study identified inadequate knowledge and low level of self reported pain assessment practice among nurses working in high-level hospitals in Mainland China. Current education did not influence nursing self-reported pain assessment practice. Knowledge of pain evaluation should be improved through newer approaches to education. A better policy framework for pain evaluation may also contribute to improvement. PMID- 23755822 TI - Interaction of the antimicrobial peptide gomesin with model membranes: a calorimetric study. AB - Gomesin is a potent cationic antimicrobial peptide (z = +6) isolated from the Brazilian spider Acanthoscurria gomesiana . The interaction of gomesin with large unilamellar vesicles composed of a 1:1 mixture of zwitterionic (1-palmitoyl-2 oleoyl-sn-glycero-3-phosphocholine) and anionic (1-palmitoyl-2-oleoyl-sn-glycero 3-phospho-(1'-rac-glycerol) phospholipids is studied with isothermal titration calorimetry (ITC). In parallel, light scattering and optical microscopy are used to assess peptide-induced vesicle aggregation. The ability of gomesin to permeabilize the membrane is examined with fluorescence spectroscopy of the leakage of 5,6-carboxyfluorescein (CF). Vesicles coated with 3 mol % 1,2 dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol) 2000] (PE-PEG) lipids are also investigated to assess the influence of peptide induced vesicle aggregation in the activity of gomesin. The ITC and light scattering titrations are done in two ways: lipid into peptide and peptide into lipid injections. Although some differences arise between the two setups, the basic interaction of gomesin with anionic vesicles is preserved. A surface partition model combined with the Gouy-Chapman theory is put forward to fit the ITC results. The intrinsic binding constant of gomesin is found to be K ~ 10(3) M(-1). The interaction of gomesin with anionic membranes is highly exothermic and enthalpy-driven. Binding of gomesin is virtually always accompanied by vesicle aggregation and changes in membrane permeability, leading to CF leakage. Addition of PE-PEG to the membrane strongly attenuates vesicle aggregation but does not significantly change the mode of action of gomesin. The results point to a strong interaction of gomesin with the membrane surface, causing membrane rupture without a deep penetration into the bilayer core. PMID- 23755823 TI - Surface modification of several dental substrates by non-thermal, atmospheric plasma brush. AB - OBJECTIVE: The purpose of this study was to reveal the effectiveness of non thermal atmospheric plasma brush in surface wettability and modification of four dental substrates. METHODS: Specimens of dental substrates including dentin, enamel, and two composites Filtek Z250, Filtek LS Silorane were prepared (~2mm thick, ~10mm diameter). The prepared surfaces were treated for 5-45s with a non thermal atmospheric plasma brush working at temperatures from 36 to 38 degrees C. The plasma-treatment effects on these surfaces were studied with contact-angle measurement, X-ray photoemission spectroscopy (XPS) and scanning electron microscopy (SEM). RESULTS: The non-thermal atmospheric argon plasma brush was very efficient in improving the surface hydrophilicity of four substrates studied. The results indicated that water contact angle values decreased considerably after only 5s plasma treatment of all these substrates. After 30s treatment, the values were further reduced to <5 degrees , which was close to a value for super hydrophilic surfaces. XPS analysis indicated that the percent of elements associated with mineral in dentin/enamel or fillers in the composites increased. In addition, the percent of carbon (%C) decreased while %O increased for all four substrates. As a result, the O/C ratio increased dramatically, suggesting that new oxygen-containing polar moieties were formed on the surfaces after plasma treatment. SEM surface images indicated that no significant morphology change was induced on these dental substrates after exposure to plasmas. SIGNIFICANCE: Without affecting the bulk properties, a super-hydrophilic surface could be easily achieved by the plasma brush treatment regardless of original hydrophilicity/hydrophobicity of dental substrates tested. PMID- 23755824 TI - Identifying culturally appropriate strategies for coronary heart disease secondary prevention in a regional Aboriginal Medical Service. AB - Aboriginal Australians experience high rates of coronary heart disease (CHD) at an early age, highlighting the importance of effective secondary prevention. This study employed a two-stage process to evaluate CHD management in a regional Aboriginal Medical Service. Stage 1 involved an audit of 94 medical records of clients with documented CHD using the Audit and Best Practice in Chronic Disease approach to health service quality improvement. Results from the audit informed themes for focus group discussions with Aboriginal Medical Service clients (n=6) and staff (n=6) to ascertain barriers and facilitators to CHD management. The audit identified that chronic disease management was the focus of appointments more frequently than in national data (P<0.05), with brief interventions for lifestyle modification occurring at similar or greater frequency. However, referrals to follow-up support services for secondary prevention were lower (P<0.05). Focus groups identified psychosocial factors, systemic shortcomings, suboptimal medication use and variable awareness of CHD signs and symptoms as barriers to CHD management, whereas family support and culturally appropriate education promoted health care. To optimise CHD secondary prevention for Aboriginal people, health services require adequate resources to achieve best practice systems of follow up. Routinely engaging clients is required to ensure services meet diverse community needs. PMID- 23755825 TI - Pd(II)-catalyzed phosphorylation of aryl C-H bonds. AB - A Pd(II)-catalyzed C-H phosphorylation reaction has been developed using heterocycle-directed ortho-palladation. Both H-phosphonates and diaryl phosphine oxides are suitable coupling partners for this reaction. PMID- 23755826 TI - Consumption of bovine spongiform encephalopathy (BSE) contaminated beef and the risk of variant Creutzfeldt-Jakob disease. AB - To date, the variant Creutzfeldt-Jakob disease (vCJD) risk assessments that have been performed have primarily focused on predicting future vCJD cases in the United Kingdom, which underwent a bovine spongiform encephalopathy (BSE) epidemic between 1980 and 1996. Surveillance of potential BSE cases was also used to assess vCJD risk, especially in other BSE-prevalent EU countries. However, little is known about the vCJD risk for uninfected individuals who accidentally consume BSE-contaminated meat products in or imported from a country with prevalent BSE. In this article, taking into account the biological mechanism of abnormal prion PrP(res) aggregation in the brain, the probability of exposure, and the expected amount of ingested infectivity, we establish a stochastic mean exponential growth model of lifetime exposure through dietary intake. Given the findings that BSE agents behave similarly in humans and macaques, we obtained parameter estimates from experimental macaque data. We then estimated the accumulation of abnormal prions to assess lifetime risk of developing clinical signs of vCJD. Based on the observed number of vCJD cases and the estimated number of exposed individuals during the BSE epidemic period from 1980 to 1996 in the United Kingdom, an exposure threshold hypothesis is proposed. Given the age-specific risk of infection, the hypothesis explains the observations very well from an extreme value distribution fitting of the estimated BSE infectivity exposure. The current BSE statistics in the United Kingdom are provided as an example. PMID- 23755827 TI - Rhodium(III)-catalyzed intermolecular direct amidation of aldehyde C-H bonds with N-chloroamines at room temperature. AB - A Rh(III)-catalyzed direct aldehyde C-H amidation from aldehydes and N chloroamines, prepared in situ from amines, has been developed via C-H bond activation under very mild reaction conditions. A variety of primary and secondary amines were used to afford the corresponding amides in moderate to excellent yields. PMID- 23755828 TI - Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study. AB - BACKGROUND: VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. METHODS: We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged >=18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 -1639G->A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5*10(-8) in the discovery cohort and p<0.0038 in the replication cohort. FINDINGS: The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1.51*10(-8)). This association was confirmed in the replication cohort (p=5.04*10(-5)); analysis of the two cohorts together produced a p value of 4.5*10(-12). Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6.92 mg/week and those homozygous 9.34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). INTERPRETATION: A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3. Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population. FUNDING: National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust. PMID- 23755829 TI - Genetics of warfarin dosing--one polymorphism at a time. PMID- 23755830 TI - Enhancement of electrical signaling in neural networks on graphene films. AB - One of the key challenges for neural tissue engineering is to exploit supporting materials with robust functionalities not only to govern cell-specific behaviors, but also to form functional neural network. The unique electrical and mechanical properties of graphene imply it as a promising candidate for neural interfaces, but little is known about the details of neural network formation on graphene as a scaffold material for tissue engineering. Therapeutic regenerative strategies aim to guide and enhance the intrinsic capacity of the neurons to reorganize by promoting plasticity mechanisms in a controllable manner. Here, we investigated the impact of graphene on the formation and performance in the assembly of neural networks in neural stem cell (NSC) culture. Using calcium imaging and electrophysiological recordings, we demonstrate the capabilities of graphene to support the growth of functional neural circuits, and improve neural performance and electrical signaling in the network. These results offer a better understanding of interactions between graphene and NSCs, also they clearly present the great potentials of graphene as neural interface in tissue engineering. PMID- 23755831 TI - Doxorubicin-loaded porous PLGA microparticles with surface attached TRAIL for the inhalation treatment of metastatic lung cancer. AB - Inhalable highly porous large PLGA microparticles with incorporated doxorubicin and surface-attached with TRAIL (TRAIL/Dox PLGA MP) were fabricated using a w/o/w double emulsification method using ammonium bicarbonate as a gas-foaming agent for the treatment of lung cancer. The TRAIL/Dox PLGA MP produced were highly porous and 11.5 +/- 0.4 MUm in diameter, and the loading efficiencies of Dox and TRAIL were 86.5 +/- 6.5% and 91.8 +/- 2.4%, respectively. TRAIL and doxorubicin were gradually released by TRAIL/Dox PLGA over 7 days, and pulmonary administration resulted in the deposition of TRAIL/Dox PLGA MP in mouse lungs, and they remained in situ for up to a week. The anti-tumor efficacy of pulmonary administered TRAIL/Dox PLGA MP was evaluated in a BALB/c nu/nu mice mouse model of H226 cell metastasis. Tumors in H226-implanted mice treated with TRAIL/Dox PLGA MP were markedly smaller and fewer in number than mice treated with TRAIL or Dox PLGA MP alone. Furthermore, this improved performance was found to be due to the synergistic apoptotic effects of the two drugs. We believe that TRAIL/Dox PLGA MP offer a promise of a sustained-release, long-acting, inhalable anti-lung cancer agent. Furthermore, the synergism observed between TRAIL and doxorubicin suggests that the doxorubicin dosage could be substantially reduced and its side effects minimized. PMID- 23755832 TI - Cancer cell-specific photoactivity of pheophorbide a-glycol chitosan nanoparticles for photodynamic therapy in tumor-bearing mice. AB - We designed a cancer-cell specific photosensitizer nano-carrier by synthesizing pheophorbide a (PheoA) conjugated glycol chitosan (GC) with reducible disulfide bonds (PheoA-ss-GC). The amphiphilic PheoA-ss-GC conjugates self-assembled in aqueous condition to form core-shell structured nanoparticles (PheoA-ss-CNPs) with good colloidal stability and switchable photoactivity. The photoactivity of PheoA-ss-CNPs in an aqueous environment was greatly suppressed by the self quenching effect, which enabled the PheoA-ss-CNPs to remain photo-inactive and in a quenched state. However, after the cancer cell-specific uptake, the nanoparticular structure instantaneously dissociated by reductive cleavage of the disulfide linkers, followed by an efficient dequenching process. Compared to non reducible PheoA-conjugated GC-NPs with stable amide linkages (PheoA-CNPs), PheoA ss-CNPs rapidly restored their photoactivity in response to intracellular reductive conditions, thus presenting higher cytotoxicity with light treatment. In addition, the PheoA-ss-CNPs presented prolonged blood circulation in vivo compared to free PheoA, demonstrating enhanced tumor specific targeting behavior through the enhanced permeation and retention (EPR) effect. The enhanced tumor accumulation of PheoA-ss-CNPs enabled tumor therapeutic efficacy that was more efficient than free PheoA in tumor-bearing mice. Based on the enhanced intracellular release for cytosolic high dose and switchable photoactivity mechanism for reduced side effects, these results suggest that PheoA-ss-CNPs have good potential for photodynamic therapy (PDT) in cancer treatment. PMID- 23755833 TI - Selectively targeting the toll-like receptor 9 (TLR9)--IRF 7 signaling pathway by polymer blend particles. AB - Signaling through toll-like receptor 9 (TLR9) has been exploited for cancer therapy. The stimulation of TLR9 leads to two bifurcating signaling pathways - NF kappaB-dependent pro-inflammatory cytokines pathway and IRF-7-dependent type I interferons (IFNs) pathway. In this study, we employ polymer blend particles to present the synthetic ligand, CpG oligonucleotides (CpG ODNs), to TLR9. The polymer blend particles are made from the blend of pH-insensitive and pH sensitive copolymer. By tailoring the composition of the pH-sensitive polymer, CpG ODNs are presented to TLR9 in a way that only activates the IRF-7 signaling pathway. CpG ODNs have been used for cancer therapy in both preclinical and clinical studies. The selective activation of IRF-7 could potentially enhance the apoptosis of tumor cells and immunological control of tumor progression without inadvertently activating NF-kappaB-dependent oncogenesis. PMID- 23755834 TI - Control of the size, shape and composition of highly uniform, non-agglomerated, sub-micrometer beta-tricalcium phosphate and dicalcium phosphate platelets. AB - Calcium phosphates (CaPs) are widely used as bone graft substitutes but are inherently brittle, hence restricting their use to mechanically protected environments. Combining them with a tough polymer matrix could potentially lead to a composite with load-bearing properties. However, the highest mechanical properties can only be achieved if the CaP particles possess very precise features: they should be uniform in size and shape, non-agglomerated, elongated and thin. The aim of the present study therefore was to assess a novel method to produce such particles. This involved the precipitation of CaP particles in ethylene glycol at moderate temperatures (90-170 degrees C) and the variation of different reaction parameters (temperature, concentration, pH, etc) to study their influence on particle composition, size, shape and dispersion was studied. As a result, two main CaP phases were obtained as well-dispersed and highly uniform platelets in the form of: (i) beta-tricalcium phosphate (beta-TCP) hexagonal prisms and (ii) monetite (DCP) flat parallelepipeds. The size dispersion was the narrowest for beta-TCP (standard deviation/mean < 5%) whereas the aspect ratio was the highest for DCP (up to 25). In both cases, the thickness of the platelets was below 300 nm which should be ideal for the synthesis of strong CaP-based composites. PMID- 23755835 TI - The effect of the physicochemical properties of bioactive electroconductive hydrogels on the growth and proliferation of attachment dependent cells. AB - The physicochemical properties of soft electrode materials for the abio-bio interface of advanced biosensors and next generation bionic devices in the form of electroconductive hydrogels (ECH) of interpenetrating networks of polypyrrole formed within poly(hydroxyethylmethacrylate)-based hydrogels were examined. The 1.5 mol% UV-crosslinked tetraethyleneglycol diacrylate (TEGDA) (step 1) poly(HEMA) and the electropolymerized (step 2) polypyrrole co-networks were covalently joined by the inclusion of a bifunctional monomer (1.5 mol%), 2 methacryloyloxyethyl-4(3-pyrrolyl)butanate (MPB) that served to covalently link the two networks. The optical absorbance, degree of hydration, the frequency dependent electrical impedance and the elastic modulus were examined as a function of electropolymerization charge density (step 2) (1-900 mC/cm(2)) used to prepare the linked, interpenetrating co-networks. The absorption at 430 nm showed a monotonic increase with electropolymerization charge density and correlated with the increase in elastic modulus [56 (+/- 32)-499 (+/- 293) kPa], the decrease in % hydration (68-0%) and the decrease in membrane electrical resistance. Polypyrrole (PPy) grows initially from the gel-electrode interface to fill voids within the hydrogel and ultimately onto the surface of the hydrogel. Growth of attachment dependent Rhabdomyosarcoma (RMS13) and pheochromocytoma (PC 12) cells reflects this evolution, showing an increase to a maximal value and then to decrease again at high electropolymerization charge density. PMID- 23755836 TI - The use of a near-infrared RNA fluorescent probe with a large Stokes shift for imaging living cells assisted by the macrocyclic molecule CB7. AB - A near-infrared fluorescent dye Hsd was designed and synthesized, which absorbed as hemicyane and emitted as Cy7 and therefore produced a Stokes shift as large as 224 nm. Quantum chemistry calculation demonstrated that the large Stokes shift was produced by the combination of intramolecular charge transfer (ICT) and internal conversion. Significantly, Hsd showed selectively response to RNA in aqueous solution and fixed cells. Moreover, Hsd could be uptaken into the cells under the assistance of cucurbit[7]uril (CB7) and selectively stain RNA in living cells. The introducing of CB7 provides a platform to amplify the application of some cell-impermeant fluorescent stains through the supramolecular chemistry methods. PMID- 23755837 TI - Supervising undergraduate research: a collective approach utilising groupwork and peer support. AB - BACKGROUND: Nursing education now requires graduate entry for professional registration. The challenge is to ensure that students develop independence and team working in a resource effective manner. The dissertation is one opportunity for this. AIM: To evaluate changing from individual dissertation supervision to group peer supervision. METHODS: Group supervision was implemented for one cohort. Dissertation outcomes were compared with two previous cohorts. Student evaluative data was assessed. FINDINGS: Group supervision did not adversely affect dissertation outcomes (p=0.85). 88% of students reported peer supervision to be helpful, with themes being 'support and sharing', and 'progress and moving forward'. CONCLUSIONS: Peer group support provided consistent supervision harnessing the energy and resources of the students and Faculty, without adversely affecting outcomes. PMID- 23755838 TI - Single-crystal apatite nanowires sheathed in graphitic shells: synthesis, characterization, and application. AB - Vertically aligned one-dimensional hybrid structures, which are composed of apatite and graphitic structures, can be beneficial for orthopedic applications. However, they are difficult to generate using the current method. Here, we report the first synthesis of a single-crystal apatite nanowire encapsulated in graphitic shells by a one-step chemical vapor deposition. Incipient nucleation of apatite and its subsequent transformation to an oriented crystal are directed by derived gaseous phosphorine. Longitudinal growth of the oriented apatite crystal is achieved by a vapor-solid growth mechanism, whereas lateral growth is suppressed by the graphitic layers formed through arrangement of the derived aromatic hydrocarbon molecules. We show that this unusual combination of the apatite crystal and the graphitic shells can lead to an excellent osteogenic differentiation and bony fusion through a programmed smart behavior. For instance, the graphitic shells are degraded after the initial cell growth promoted by the graphitic nanostructures, and the cells continue proliferation on the bare apatite nanowires. Furthermore, a bending experiment indicates that such core-shell nanowires exhibited a superior bending stiffness compared to single crystal apatite nanowires without graphitic shells. The results suggest a new strategy and direction for bone grafting materials with a highly controllable morphology and material conditions that can best stimulate bone cell differentiation and growth. PMID- 23755839 TI - Gastrointestinal stromal tumors in children and young adults: a clinicopathologic and molecular genetic study of 22 Korean cases. AB - Studies on gastrointestinal stromal tumors (GISTs) in young patients are limited due to their rarity, and none have been conducted in Asian populations. GISTs from patients under the age of 30 were retrospectively reviewed and were analyzed for clinicopathologic features, immunohistochemistry for SDHB (succinate dehydrogenase subunit B), and mutations for exon 9, 11, 13, and 17 of KIT gene and exon 12, 14, and 18 of PDGFRA gene. We found two pediatric (<18 years old) and 20 young adult (18-30 years old) GIST cases. Pediatric GISTs occurred in two girls, both as solitary masses with epithelioid histology in the stomach. Both GISTs were wild type for KIT and PDGFRA genes, were negative for SDHB, and there was no recurrence during follow-up. Of the 20 GISTs in young adults, 12 (60%) were from extra-gastric locations (six duodenum, five jejunum, and one esophagus), and 16 (80%) showed a spindle cell morphology. Mutations of KIT or PDGFRA genes were identified in 14 (78%) of the 18 cases. One patient with multiple gastric GISTs with perigastric lymph node metastases at presentation developed multiple distant metastases and died of the disease 7.3 years after diagnosis. Of the 19 R0-resected young adult patients, one patient with small intestinal GIST harboring KIT exon 11 deletion mutation developed recurrence and showed partial responses for imatinib. In summary, compared with pediatric GIST cases, young adult GISTs are heterogeneous and share the characteristics of both pediatric and adult GISTs. When a mesenchymal tumor is clinically suspected in the small intestine of young adults, a GIST should be included in the differential diagnoses. Further mutation studies and extensive treatments are recommended for these cases. PMID- 23755840 TI - Zinc enhancement of LLC-PK(1) renal epithelial barrier function. AB - BACKGROUND AND AIMS: Earlier work by our group and others has documented improvement of epithelial barrier function in human gastrointestinal models. Here we tested zinc's ability to improve a renal epithelial model. Our aim was to compare the functional and structural effects of zinc on the tight junctional (TJ) complexes of these two very distinct epithelial cell types. Zinc's ability to achieve barrier enhancement in very different epithelial cell types by action upon distinct molecular targets in each epithelial model may suggest a fundamental general role for supplemental zinc in epithelial barrier improvement throughout the body. METHODS: Cell layers were exposed to 50 or 100 MUM zinc on both cell surfaces for 48 h followed by measurement of transepithelial electrical resistance (Rt) and transepithelial (14)C-mannitol flux (Jm). TJ proteins in cell layers were analyzed by Western immunoblot. RESULTS AND CONCLUSIONS: Zinc supplementation improved the basal TJ barrier function of LLC-PK1 renal cell layers, exemplified by increased Rt and decreased Jm. These zinc-induced changes were also accompanied by decreased NaCl dilution potentials. Of the tight junctional proteins that were tested (occludin, claudins 1, 2, 3, 4, and 5, and tricellulin), we did not observe a zinc-induced change in abundance of any of them, in detergent-soluble fractions of lysates of confluent differentiated cell layers. However, examination of cytosolic fractions showed concentration dependent increases in the levels of claudins -2 and -4 in this compartment as a result of supplemental zinc. The effects of supplemental zinc on the tight junctional complexes and barrier properties of this renal epithelial model are contrasted with zinc effects on the CACO-2 gastrointestinal model. PMID- 23755841 TI - Subjective global assessment: a reliable nutritional assessment tool to predict outcomes in critically ill patients. AB - BACKGROUND & AIMS: Nutritional assessment of critically ill patients has created controversy. However, it is well established that malnourished patients who are severely ill have worse outcomes than well-nourished patients. Therefore, assessing patients' nutritional status may be useful in predicting which patients may experience increased morbidity and mortality. METHOD: One hundred eighty-five consecutively admitted patients were followed until discharge or death, and their nutritional status was evaluated using Subjective Global Assessment (SGA) as well as anthropometric and laboratory methods. Agreement between the methods was measured using the Kappa coefficient. RESULTS: Malnutrition was highly prevalent (54%), according to SGA. Malnourished patients had significantly higher rates of readmission to the intensive care unit (ICU) (OR 2.27; CI 1.08-4.80) and mortality (OR 8.12; CI 2.94-22.42). The comparison of SGA with other tests used to assess nutritional status showed that the correlation between the methods ranged from poor to superficial. CONCLUSION: SGA, an inexpensive and quick nutritional assessment method conducted at the bedside, is a reliable tool for predicting outcomes in critically ill patients. PMID- 23755842 TI - Prevalence and determinants for malnutrition in geriatric outpatients. AB - BACKGROUND & AIMS: Few data is available on the nutritional status of geriatric outpatients. The aim of this study is to describe the nutritional status and its clinical correlates of independently living geriatric older individuals visiting a geriatric outpatient department. METHODS: From 2005 to 2010, all consecutive patients visiting a geriatric outpatient department in the Netherlands were screened for malnutrition. Nutritional status was assessed by the Mini Nutritional Assessment (MNA). Determinants of malnutrition were categorized into somatic factors (medicine use, comorbidity, walking aid, falls, urinary incontinence), psychological factors (GDS-15 depression scale, MMSE cognition scale), functional status (Activities of Daily Life (ADL), Instrumental ADL (IADL)), social factors (children, marital status), and life style factors (smoking, alcohol use). Univariate and multivariate logistic regression analyses, adjusted for age and sex and all other risk factors were performed to identify correlates of malnutrition (MNA < 17). RESULTS: Included were 448 outpatients, mean (SD) age was 80 (7) years and 38% was men. Prevalence of malnutrition and risk for malnutrition were 17% and 58%. Depression, being IADL dependent, and smoking were independently associated with an increased risk of malnutrition with OR's (95%CI) of 2.6 (1.3-5.3), 2.8 (1.3-6.4), 5.5 (1.9-16.4) respectively. Alcohol use was associated with a decreased risk (OR 0.4 (0.2-0.9)). CONCLUSION: Malnutrition is highly prevalent among geriatric outpatients and is independently associated with depressive symptoms, poor functional status, and life style factors. Our results emphasize the importance of integrating nutritional assessment within a comprehensive geriatric assessment. Future longitudinal studies should be performed to examine the effects of causal relationships and multifactorial interventions. PMID- 23755844 TI - Differential effect of coal combustion products on the bioavailability of phosphorus between inorganic and organic nutrient sources. AB - In farming systems, all the applied phosphorus (P) is not available to plants because they are either adsorbed in soil or lost to the environment through leaching or runoff. The effect of coal combustion products (CCPs) for enhancing the bioavailability of applied phosphorus (P) in soil was examined separately for inorganic (KH2PO4 - PP) and organic (poultry manure - PM) P treatments, where fluidised bed combustion (FBC) ash emerged as the most effective amendment. Greenhouse study was conducted by growing mustard plants on FBC amended soils under leaching and non-leaching setups. The FBC increased the biomass yield for organic P treatments in the first crop and increased for both inorganic and organic P in the second cropping. The increase in cumulative yield was highest in leached PP and unleached PM treatments. Field experiment assessed the effectiveness of FBC on inorganic (single super phosphate - SSP) and organic P (biosolids - BS) uptake by mustard and sunflower plants. In the first cropping, the yield was higher in crops treated with SSP alone. In the second crop, yields were higher in the presence than absence of FBC, as reflected by the high relative agronomic effectiveness (RAE) exhibited by BS+FBC (462%) combination. Overall, FBC used in these experiments enhanced bioavailability of P in soil through adsorption and mineralisation of inorganic and organic P, respectively as evident from phosphatase activity and Olsen P relationship. Hence the differential effect of CCPs has not only decreased the loss of applied P (from inorganic and organic sources) to the environment, but also enhanced the P bioavailability in the soil. Among the three CCPs used in the preliminary experiments, FBC proved to perform better than the other two and hence can be recommended for agricultural and environmental applications targeting P issues. PMID- 23755843 TI - Coffee consumption delays the hepatitis and suppresses the inflammation related gene expression in the Long-Evans Cinnamon rat. AB - BACKGROUND AND AIMS: Large-scale epidemiological studies have shown that drinking more than two cups of coffee per day reduces the risks of hepatitis and liver cancer. However, the heterogeneity of the human genome requires studies of experimental animal models with defined genetic backgrounds to evaluate the coffee effects on liver diseases. We evaluated the efficacy of coffee consumption with one of experimental animal models for human disease. METHOD: We used the Long Evans Cinnamon (LEC) rat, which onsets severe hepatitis and high incidence of liver cancer, due to the accumulation of copper and iron in livers caused by the genetic mutation in Atp7B gene, and leading to the continuous oxidative stress. We determined the expression of inflammation related genes, and amounts of copper and iron in livers, and incidence of the pre-neoplastic foci in the liver tissue of LEC rats. RESULTS: Coffee administration for 25 weeks delayed the occurrence of hepatitis by two weeks, significantly improved survival, reduced the expression of inflammatory cytokines, and reduced the incidence of small pre neoplastic liver foci in LEC rats. There was no significant difference in the accumulation of copper and iron in livers, indicating that coffee administration does not affect to the metabolism of these metals. These findings indicate that drinking coffee potentially prevents hepatitis and liver carcinogenesis through its anti-inflammatory effects. CONCLUSION: This study showed the efficacy of coffee in the prevention of hepatitis and liver carcinogenesis in the LEC model. PMID- 23755845 TI - Size fraction effect on phthalate esters accumulation, bioaccessibility and in vitro cytotoxicity of indoor/outdoor dust, and risk assessment of human exposure. AB - Indoor and outdoor dusts from two urban centers in the Pearl River Delta, China, were analyzed and phthalate esters varied from 4.95 to 2,220 MUg g(-1) in indoor dust, significantly higher than outdoor dust (1.70-869 MUg g(-1)). Di-2 ethylhexyl phthalate (DEHP) was the dominant phthalate found and the highest distribution factor (DF) (1.56 +/- 0.41) was noted in the <63 MUm fraction (p<0.05). In vitro cytotoxicity of dust extract on human T cell lymphoblast leukemic cell line (CCRF-CEM) indicated by Lethal Concentration 50 (LC50) decreased with particle size. The power model was found as a better fit for explaining the relationship between LC50 and phthalates (R(2)=0.46, p<0.01). Bioaccessibility of phthalates in dust varied with different particle sizes, with the greatest bioaccessible fraction (2.49-38.6%) obtained in <63 MUm. Risk assessment indicated that indoor dust ingestion accounted for the major source for DEHP exposure (81.4-96.4% of non-dietary exposure and 36.5% of total exposure), especially for toddlers. The cancer risks associated with DEHP via home dust were high (10(-6)-10(-4)), with 10% of houses estimated with unacceptable risks (>10(-4)). After corrected with the bioaccessibility of phthalates, the cancer risks of dust exposure were moderate (10(-7)-10(-5)). PMID- 23755846 TI - Total nasal reconstruction using composite radial forearm free flap and forehead flap as a one-stage procedure with minor revision. AB - The refashioning of the many distinct structures necessary for successful anatomical and aesthetic reconstruction of the nose after total rhinectomy is difficult. Several significant operations are needed to produce good aesthetic results with functional patency of the nasal airway. We describe a method using autologous grafts that has produced good results on both occasions when it was done. It has the advantage of only one major operation and one subsequent minor revision. PMID- 23755847 TI - Excellent toluene sensing properties of SnO2-Fe2O3 interconnected nanotubes. AB - SnO2-Fe2O3 interconnected nanotubes were obtained by combining the single nozzle electrospinning and thermal treatment methods. The results of scanning electron microscopy revealed the special structure of ruptures and interconnected nanotubes in the as-prepared materials. The toluene sensing test results of SnO2 Fe2O3 interconnected nanotubes show that SnO2-Fe2O3 interconnected nanotubes possess excellent toluene gas-sensing properties. The sensitivity of detecting limit (50 ppb) is 2.0 at the optimum operating temperature of 260 degrees C. The response and recovery times to 1 ppm toluene are about 5 and 11 s, respectively. Moreover, the SnO2-Fe2O3 interconnected nanotube gas sensors exhibit the remarkable selectivity to toluene, and good long-term stability. PMID- 23755848 TI - Pyridone-conjugated monobactam antibiotics with gram-negative activity. AB - Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa , Klebsiella pneumoniae , and Escherichia coli . Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1. PMID- 23755849 TI - Gamma-aminobutyric acid(C) (GABAC) selective antagonists derived from the bioisosteric modification of 4-aminocyclopent-1-enecarboxylic acid: amides and hydroxamates. AB - Series of compounds were generated via the bioisosteric replacement of the carboxylate of 4-ACPCA (2) with hydroxamate or amide groups. All compounds from this study exhibited increased selectivity for GABAC, the most potent being 4 ACPHA (10a, IC50 = 13 MUM) and 4-ACPAM (11a, IC50 = 10 MUM). This provides evidence that a zwitterionic structure is not essential for GABAC antagonists, rather the emphasis lies in appropriate heteroatoms to participate in hydrogen bonding. PMID- 23755850 TI - Guaiane-type sesquiterpenes from Curcuma phaeocaulis and their inhibitory effects on nitric oxide production. AB - Ten new guaiane-type sesquiterpenes (1-10), phaeocaulisins A-J, and 18 known guaiane derivatives were isolated from rhizomes of Curcuma phaeocaulis. Their structures were established on the basis of extensive spectroscopic analyses, X ray crystallographic analysis, and comparison with literature data. Compound 10 is the first example of a norsesquiterpene with this unusual skeleton isolated from the genus Curcuma. All of the isolated compounds were tested for inhibitory activity against LPS-induced nitric oxide production in RAW 264.7 macrophages. Compounds 1, 2, 20, and 22-24 inhibited nitric oxide production with IC50 values less than 2 MUM. Preliminary structure-activity relationships for these compounds are discussed. PMID- 23755851 TI - Abietane diterpenoids and a sesquiterpene pyridine alkaloid from Euonymus lutchuensis. AB - Four new abietane diterpenoids (1-4), a new 9(10->20)-abeo-abietane diterpenoid (5), and a new sesquiterpene pyridine alkaloid (6) were isolated from the roots of Euonymus lutchuensis along with 19 known compounds. The structures of the new compounds were elucidated by interpretation of the spectroscopic data. PMID- 23755852 TI - Perpendicular blood vessel seals are stronger than those made at an angle. AB - Vessel sealing devices effectively produce hemostatic seals with minimal thermal damage, but the strength of seals decreases as vessel diameter increases. Because vessels sealed at an angle to the vessel require a greater functional seal diameter than those sealed perpendicularly to the vessel, it was hypothesized that perpendicular seals would have comparably higher burst pressures. Ex vivo, porcine carotid arteries of nominal diameters of 5, 6, and 7 mm were sealed perpendicularly to and at a 45 degrees angle to the longitudinal axis of the vessels, and burst pressures of the sealed vessels were measured. Overall burst pressures were 51% greater for perpendicular seals than for angled seals (P<.001). Mean burst pressures for the 5-mm angled and 7-mm perpendicular groups, which have similar seal lengths, were not significantly different (P=.959). Analysis using the functional diameter as a covariate indicated that the seal length is the primary variable in determining burst pressure, and not some other inherent characteristic of angled versus perpendicular sealing. These results suggest that at least for vessels >=5 mm in diameter, surgeons should approach vessels perpendicularly and not at an angle, for the highest possible seal strength. The development of articulated sealing and cutting devices would provide greater seal strength, in addition to improved maneuverability, especially in laparoscopic surgery, where angles of approach may be limited by the fixed location of surface cannulas. PMID- 23755853 TI - Systematic review of studies investigating sentinel node navigation surgery and lymphatic mapping for gastric cancer. AB - Evolutions in minimally invasive surgical techniques and advances in sentinel node navigation surgery (SNNS) have had considerable impact on current insights into surgical treatment of gastric cancer. Extensive data on this method of surgical application have accumulated but have been principally derived from single-institute studies. Isosulfan blue and patent blue violet have been the most frequently used dye tracers in the past; however, indocyanine green has now is increasingly popular. The double-tracer method, where dye and radioisotope tracers are used together, seems to be more effective than any single tracer. Among newly emerging adjunct techniques and promising alternative in particular are infrared ray electronic endoscopy, florescence imaging, nanoparticles, and near-infrared technology. Hematoxylin and eosin (H&E) staining is still the method of choice for the detection of sentinel lymph node (SLN) metastases. Immunohistochemical staining can be used to support H&E findings, but the equipment costs of ultrarapid processing systems are currently slowing down their worldwide spread. We believe minimally invasive function-preserving resection of the stomach, together with lymphatic basin dissection navigated by SLNs, can represent the ideal approach for SNNS to detect clinically node-negative early gastric cancer, although this remains to be elucidated. Patients with cT3 or more advanced disease should still be treated by means of standard D2 dissection. PMID- 23755854 TI - Pure NOTES rectosigmoid resection: transgastric endoscopic IMA dissection and transanal rectal mobilization in animal models. AB - BACKGROUND: We report a pure natural orifice translumenal endoscopic surgery (NOTES((r)); American Society for Gastrointestinal Endoscopy [Oak Brook, IL] and the Society of American Gastrointestinal and Endoscopic Surgeons [Los Angeles, CA]) rectosigmoidectomy in animal models using transgastric endoscopic inferior mesenteric artery (IMA) dissection and transanal rectal mobilization. MATERIALS AND METHODS: Ten live animals (2 pigs weighing 35-40 kg each and 8 dogs weighing 25-30 kg each) were used. A gastrotomy was made using a needle-knife puncture and the balloon dilatation technique or following the creation of a submucosal tunnel. A circular stapler shaft was transanally inserted up to the sigmoid colon for spatial orientation and traction of the mesocolon. The IMA was endoscopically dissected using a CoagrasperTM (Olympus, Tokyo, Japan) and then clipped. Endoscopic division of the sigmoid mesocolon was conducted laterally toward the marginal artery. Transanal full-thickness circumferential rectal and mesorectal dissections were performed, and a colorectal anastomosis was performed using a circular stapler with a single stapling technique. During the transanal approach, the gastrotomy was closed using four endoscopic clips. RESULTS: Endoscopic dissection of the IMA was successful in all cases, but minor bleedings occurred in 3 cases. The mean time from dissection and clipping to division of the IMA was 36.7 minutes (range, 25-45 minutes). The mean operation time was 180.5 minutes (range, 145-210 minutes). There were no intraoperative complications or hemodynamic instability. The mean length of the resected specimen was 11.2 cm (range, 9-17 cm). CONCLUSIONS: A pure NOTES approach to rectosigmoid resection using transgastric endoscopic IMA dissection is technically feasible in animal models. PMID- 23755855 TI - Development of a needle driver with multiple degrees of freedom for neonatal laparoscopic surgery. AB - AIMS: The aims of this study were to develop a thin needle driver with multiple degrees of freedom and to evaluate its efficacy in multidirectional suturing compared with a conventional needle driver. MATERIALS AND METHODS: The tip (15 mm) of the novel user-friendly needle driver (3.5 mm in diameter) has three degrees of freedom for grasping, rotation, and deflection. Six pediatric surgeons performed two kinds of suturing tasks in a dry box: three stitches in continuous suturing that were perpendicular or parallel to the insertion direction of the instrument, first using the novel instrument, then using a conventional instrument, and finally using the novel instrument again. The accuracy of insertion and exit compared with the target points and the procedure time were measured. RESULTS: In the conventional and novel procedures the mean gaps from the insertion point to the target in perpendicular suturing were 0.8 mm and 0.7 mm, respectively; in parallel suturing they were 0.8 mm and 0.6 mm, respectively. The mean gaps from the exit point to the target in perpendicular suturing were 0.6 mm and 0.6 mm for conventional and novel procedures, respectively; in parallel suturing they were 0.6 mm and 0.8 mm, respectively. The procedure time for perpendicular suturing was 33 seconds and 64 seconds for conventional and novel procedures, respectively (P=.02); for parallel suturing it was 114 seconds and 91 seconds, respectively. CONCLUSIONS: Our novel needle driver maintained accuracy of suturing; parallel suturing with the novel driver may be easier than with the conventional one. PMID- 23755856 TI - Laparoscopic management of pyloric atresia in a neonate with epidermolysis bullosa. AB - Pyloric atresia (PA) is rare and may be associated with epidermolysis bullosa (EB). This is the first case report of a successful laparoscopic treatment of PA in a full-term 7-day-old neonate with EB. The laparoscopic approach consists of a longitudinal pyloromyotomy and excision of the thick obstructing pyloric membrane with a Heineke-Mickulicz pyloroplasty closure. Oral feeding was resumed at postoperative Day 7, and the child was discharged 5 days later with satisfactory follow-up at 8 months. Recommendations are provided for the management of the neonate with PA/EB. PMID- 23755857 TI - Factors associated with loss to clinic among HIV patients not yet known to be eligible for antiretroviral therapy (ART) in Mozambique. AB - INTRODUCTION: Retention in HIV care prior to ART initiation is generally felt to be suboptimal, but has not been well-characterized. METHODS: We examined data on 37,352 adult pre-ART patients (ART ineligible or unknown eligibility) who enrolled in care during 2005-2008 with >1 clinical visit at 23 clinics in Mozambique. We defined loss to clinic (LTC) as >12 months since the last visit among those not known to have died/transferred. Cox proportional-hazards models were used to examine factors associated with LTC, accounting for clustering within sites. RESULTS: Of 37,352 pre-ART patients, 61% had a CD4 count within three months of enrolment (median CD4: 452, IQR: 345-611). 17,598 (47.1%) were ART ineligible and 19,754 (52.9%) were of unknown eligibility status at enrolment because of missing information on CD4 count and/or WHO stage. Kaplan-Meier estimates for LTC at 12 months were 41% (95% CI: 40.2-41.8) and 48% (95% CI: 47.2 48.8), respectively. Factors associated with LTC among ART ineligible patients included male sex (AHR(men_vs_non-pregnant women): 1.5; 95% CI: 1.4-1.6) and being pregnant at enrolment (AHR(pregnant_vs_non-pregnant women): 1.3; 95% CI: 1.1-1.5). Older age, more education, higher weight and more advanced WHO stage at enrolment were independently associated with lower risks of LTC. Similar findings were observed among patients whose ART eligibility status was unknown at enrolment. CONCLUSIONS: Substantial LTC occurred prior to ART initiation among patients not yet known to be eligible for ART, including nearly half of patients without documented ART eligibility assessment. Interventions are needed to target pre-ART patients who may be at higher risk for LTC, including pregnant women and patients with less advanced HIV disease. PMID- 23755858 TI - Nonaqueous atomic layer deposition of aluminum phosphate. AB - Aluminum phosphate was deposited onto bundles of carbon fibers and flat glassy carbon substrates using atomic layer deposition by exposing them to alternating pulses of trimethylaluminum and triethylphosphate vapors. Energy dispersive X-ray spectroscopy (EDXS) and solid state nuclear magnetic resonance (SS-NMR) spectra confirmed that the coating comprises aluminum phosphate (orthophosphate as well as other stoichiometries). Scanning electron microscopic (SEM) images revealed that the coatings are uniform and conformal. After coating, the fibers are still separated from each other like the uncoated fibers. Thermogravimetric analysis (TGA) indicates an improvement of oxidation resistance of the coated fibers compared to uncoated fibers. PMID- 23755859 TI - Respiratory infection caused by Bordetella hinzii. PMID- 23755860 TI - Noise characteristics of nanoscaled redox-cycling sensors: investigations based on random walks. AB - We investigate noise effects in nanoscaled electrochemical sensors using a three dimensional simulation based on random walks. The presented approach allows the prediction of time-dependent signals and noise characteristics for redox cycling devices of arbitrary geometry. We demonstrate that the simulation results closely match experimental data as well as theoretical expectations with regard to measured currents and noise power spectra. We further analyze the impact of the sensor design on characteristics of the noise power spectrum. Specific transitions between independent noise sources in the frequency domain are indicative of the sensor-reservoir coupling and can be used to identify stationary design features or time-dependent blocking mechanisms. We disclose the source code of our simulation. Since our approach is highly flexible with regard to the implemented boundary conditions, it opens up the possibility for integrating a variety of surface-specific molecular reactions in arbitrary electrochemical systems. Thus, it may become a useful tool for the investigation of a wide range of noise effects in nanoelectrochemical sensors. PMID- 23755861 TI - (3-aminopropyl)-4-methylpiperazine end-capped poly(1,4-butanediol diacrylate-co-4 amino-1-butanol)-based multilayer films for gene delivery. AB - Biodegradable polyelectrolyte surfaces for gene delivery were created through electrospinning of biodegradable polycations combined with iterative solution based multilayer coating. Poly(beta-amino ester) (PBAE) poly(1,4-butanediol diacrylate-co-4-amino-1-butanol) end-capped with 1-(3-aminopropyl)-4 methylpiperazine was utilized because of its ability to electrostatically interact with anionic molecules like DNA, its biodegradability, and its low cytotoxicity. A new DNA release system was developed for sustained release of DNA over 24 h, accompanied by high exogenous gene expression in primary human glioblastoma (GB) cells. Electrospinning a different PBAE, poly(1,4-butanediol diacrylate-co-4,4'-trimethylenedipiperidine), and its combination with polyelectrolyte 1-(3-aminopropyl)-4-methylpiperazine end-capped poly(1,4 butanediol diacrylate-co-4-amino-1-butanol)-based multilayers are promising for DNA release and intracellular delivery from a surface. PMID- 23755862 TI - Physiological and morphological responses of the root system of Indian mustard (Brassica juncea L. Czern.) and rapeseed (Brassica napus L.) to copper stress. AB - Copper (Cu) is an essential microelement for growth and development, but in excess it can cause toxicity in plants. In this comparative study, the uptake and accumulation of Cu as well as the morphological and physiological responses of Indian mustard (Brassica juncea L. Czern.) and rapeseed (Brassica napus L.) roots to Cu treatment were investigated. The possible involvement of redox active molecules (reactive oxygen species and nitric oxide) and modification in cell wall structure associated with Cu-induced morphological responses were also studied. In short- and long-term treatments, B. juncea suffered more pronounced growth inhibition as compared with B. napus. In addition to the shortening of primary and lateral roots, the number and the density of the laterals were also decreased by Cu. Exposure to copper induced nitric oxide generation in the root tips and this event proved to be dependent on the duration of the exposure and on the plant species. In short- and long-term treatments, Indian mustard showed more significant activation of superoxide dismutase (SOD), inhibition of ascorbate peroxidase (APX) and oxidation of ascorbate (AsA) than B. napus. Moreover, H2O2 dependent lignification was also observed in the Cu-exposed plants. In longer term, significant AsA accumulation and callose deposition were observed, reflecting serious oxidative stress in B. juncea. Based on the morphological and physiological results, we conclude that rapeseed tolerates Cu excess better than Indian mustard. PMID- 23755863 TI - Cytoprotective and antioxidant effects of the edible halophyte Sarcocornia perennis L. (swampfire) against lead-induced toxicity in renal cells. AB - Lead (Pb) exposure is considered as a risk factor responsible for renal impairment in humans. On the other hand, the halophyte Sarcocornia perennis is a fresh vegetable crop suitable for leafy vegetable production. This study was designed to evaluate the in vitro protective activity of S. perennis against lead induced damages in HEK293 kidney cells. Morphological and biochemical indicators were used to assess cytotoxicity and oxidative damages caused by Pb treatment on the cells. Our results showed that lead induced (1) a decrease in cell viability (MTT), (2) cell distortion and cohesion loss, (3) superoxide anion production and lipid peroxidation. Conversely, addition of S. perennis extract to the lead containing medium alleviated every above syndrome. Thus, cell survival was increased and the production of reactive oxygen species caused by Pb treatment was inhibited. Taken together, our study revealed that S. perennis has potent cytoprotective effect against Pb-induced toxicity in HEK 293 cell. Such action would proceed through the decrease in ROS levels and resulting oxidative stress, which suggests a potential interest of this halophyte in the treatment of oxidative-stress related diseases. PMID- 23755864 TI - Dose-dependent reactions of Aporrectodea caliginosa to perfluorooctanoic acid and perfluorooctanesulfonic acid in soil. AB - As a consequence of their widespread use, e.g. as protective coatings for fabrics, and their resistance to thermal and biological breakdown, perfluorinated compounds are increasingly found in the environment, but little is known about their ecotoxicological properties. A 40-day microcosm experiment was carried out to examine the effects of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) on the endogeic geophagus earthworm Aporrectodea caliginosa, its survival and feeding on soil organic C and microbial biomass C. Three levels of concentration (1, 100, and 500 mg kg(-1)) were chosen. The lowest represented the maximum found in sediments and soils and the other two are extreme concentrations that might occur in pollution hotspots and that have been shown to poison organisms. Earthworms promoted the production of CO2 and decreased microbial biomass C in soil, regardless of the presence of PFOA or PFOS. Both compounds significantly decreased the surviving numbers and dry weight of earthworms at concentrations of 100 mg kg(-1). No earthworms survived at PFOA and PFOS concentrations of 500 mg kg(-1). At concentrations of 1 mg kg(-1), no negative effects were observed. The delta(13)C values of A. caliginosa did not differ between treatments. In contrast, the delta(15)N values were significantly increased after adding 1 mg kg(-1) of PFOA, reflecting elevated portions of soil derived N in the earthworm tissue. In contrast, these portions of soil-derived N were lower in the earthworms after addition of 100 mg kg(-1) of PFOA and PFOS. In conclusion, extreme concentrations of PFOA and PFOS negatively affected endogeic A. caliginosa, whereas a concentration of 1 mg kg(-1) of PFOA and PFOS was related to an increased uptake of soil N by the earthworms. PMID- 23755865 TI - Preface: Forum on conjugated polymer materials for sensing and biomedical applications. PMID- 23755866 TI - Interfacial adhesive properties between a rigid-rod pyromellitimide molecular layer and a covalent semiconductor via atomistic simulations. AB - We conducted a comprehensive atomistic simulation study of the adhesive properties of aromatic rigid-rod poly-[(4,4'diphenylene) pyromellitimide] on a dimer-reconstructed silicon surface. We describe the structural developments within the adherent's interfacial region at the atomistic scale, and evaluate the energetics of the adhesive interactions between bimaterial constituents. In particular, we observe a transition between noncontact and contact adhesion regimes as a function of the interfacial bonding strength between the polyimide repeat units and the silicon substrate. This transition is manifest by a three- to four-fold increase in adhesive energy, which is entirely attributable to structural relaxation in the organic layer near the interface, revealing the importance of accurately describing structural details at interfaces for reliable interfacial strength predictions. The underlying molecular reconfigurations in the pyromellitimide layer include preferred orientation of the rigid-rod molecules, molecular stacking, ordering, and the local densification. The role of each of these factors in the adhesive behavior is analyzed and conclusively described. Where possible, simulation results are compared with theoretical model predictions or experimental data. PMID- 23755867 TI - Evaluation of pharmacokinetic and pharmacodynamic profiles and tolerability after single (2.5, 5, or 10 mg) and repeated (2.5, 5, or 10 mg bid for 4.5 days) oral administration of ivabradine in healthy male Korean volunteers. AB - BACKGROUND: Ivabradine, a selective inhibitor of the pacemaker current in the sinoatrial node, has shown pure heart rate (HR)-reducing effects with anti ischemic efficacy as well as improvement in heart failure outcomes. OBJECTIVE: The purpose of this study was to explore pharmacokinetic (PK) and pharmacodynamic (PD) characteristics and tolerability in healthy male Korean volunteers, as well as to compare them with PK/PD profiles of white subjects. METHODS: This was a randomized, double-blind, placebo-controlled Phase I study conducted in healthy male subjects. For each of the 3 dosing groups, 9 subjects were randomized to receive ivabradine and 3 to receive placebo. Subjects received a single oral dose of ivabradine 2.5, 5, or 10 mg and after a 3-day washout period, repeat doses of 2.5, 5, or 10 mg BID for 4.5 days. Blood and urine samples were collected over 72 hours during each period, and levels of ivabradine and its metabolite S18982 were determined by using validated LC-MS/MS, followed by noncompartmental PK analysis. For PD properties and tolerability, 24-hour Holter recordings were obtained: at baseline, after a single dose, after repeated doses, and after the last dose. Serial resting 12-lead ECG assessments were also performed throughout the study. RESULTS: Forty-eight subjects were enrolled, and 45 completed the study. After single doses of 2.5, 5, and 10 mg, respective mean Cmax levels of ivabradine were 9, 15, and 39 ng/mL, and mean AUC0-last values were 30, 52, and 121 ng h/mL. At steady state, mean Cmax,ss levels were 11, 19, and 42 ng/mL, reached at a median Tmax of 0.67 hour for all 3 doses. The mean AUC0-tau levels were 43, 58, and 139 ng h/mL, respectively. The PK findings were linear with dose and time. Decreases in mean HR on both the Holter recordings and ECGs were observed in all of the ivabradine groups compared with placebo. After the repeated doses, mean decreases in HR were greater than those for the single doses for the same period. Statistically significant differences were observed between the 5- and 10-mg ivabradine groups and placebo. A total of 3 adverse events were reported in 2 subjects receiving ivabradine; both fully recovered without sequelae. CONCLUSIONS: Single and repeated administration of ivabradine were generally well tolerated in these healthy male Korean volunteers. Ivabradine induced significant reductions in HR, especially at doses of 5 and 10 mg. PK/PD characteristics were similar to those found in white subjects, suggesting that the dose concentration response relationship of ivabradine is similar between Korean and white subjects. PMID- 23755869 TI - Efficiency of noncoherent photon upconversion by triplet-triplet annihilation: the C60 plus anthanthrene system and the importance of tuning the triplet energies. AB - As part of a continuing effort to find noncoherent photon upconversion (NCPU) systems with improved energy conversion efficiencies, the photophysics of the blue emitter, anthanthrene (An), and the fullerene absorber-sensitizer, C60, have been examined by both steady-state and pulsed laser techniques. An is a promising candidate for NCPU by homomolecular triplet-triplet annihilation (TTA) because its triplet state lies ~800 cm(-1) below the triplet energy of the C60 donor (thereby improving efficiency by reducing back triplet energy transfer), and its fluorescent singlet state lies in near resonance with double its triplet energy (thus minimizing thermal energy losses in the annihilation process). In fluid solution, efficient triplet-triplet donor-acceptor energy transfer is observed, and rate constants for homomolecular TTA in the An acceptor are estimated to approach the diffusion limit. NCPU is also observed in An + C60 in poly(methylmethacrylate) thin films. PMID- 23755870 TI - Free impinging jet microreactors: controlling reactive flows via surface tension and fluid viscoelasticity. AB - We investigate the use of impinging free liquid jets as wall-free continuous microreactors. The collision of two reactant jets forming a free-standing thin liquid sheet allows us to perform rapid precipitation reactions to form colloidal particles, enhance micromixing, and master challenging reactions with very fast kinetics. To control the shape, size, and hydrodynamics of the impingement zone between the two liquid streams, it is crucial to understand the interplay among surface tension, fluid viscoelasticity, and reaction kinetics. Here, we study these aspects using model fluids, each illustrating a different physical effect of surface and bulk fluid properties. First, solutions of sodium dodecyl sulfate below, near, and above the critical micelle concentration are used to assess the role of static and dynamic surface tension. Second, we demonstrate how dilute solutions of high-molecular-weight polymers can be used to control the morphology of the free surface flow. If properly controlled, these effects can enhance the micromixing time scales to the extent that very rapid reactions can be performed with outstanding selectivity. We quantitatively assess the interplay between the free surface flow and reaction kinetics using parallel-competitive reactions and demonstrate how these results can be used to control the particle size in precipitation processes. PMID- 23755871 TI - Outcome of ABCA4 disease-associated alleles in autosomal recessive retinal dystrophies: retrospective analysis in 420 Spanish families. AB - OBJECTIVE: To provide a comprehensive overview of all detected mutations in the ABCA4 gene in Spanish families with autosomal recessive retinal disorders, including Stargardt's disease (arSTGD), cone-rod dystrophy (arCRD), and retinitis pigmentosa (arRP), and to assess genotype-phenotype correlation and disease progression in 10 years by considering the type of variants and age at onset. DESIGN: Case series. PARTICIPANTS: A total of 420 unrelated Spanish families: 259 arSTGD, 86 arCRD, and 75 arRP. METHODS: Spanish families were analyzed through a combination of ABCR400 genotyping microarray, denaturing high-performance liquid chromatography, and high-resolution melting scanning. Direct sequencing was used as a confirmation technique for the identified variants. Screening by multiple ligation probe analysis was used to detect possible large deletions or insertions in the ABCA4 gene. Selected families were analyzed further by next generation sequencing. MAIN OUTCOME MEASURES: DNA sequence variants, mutation detection rates, haplotypes, age at onset, central or peripheral vision loss, and night blindness. RESULTS: Overall, we detected 70.5% and 36.6% of all expected ABCA4 mutations in arSTGD and arCRD patient cohorts, respectively. In the fraction of the cohort where the ABCA4 gene was sequenced completely, the detection rates reached 73.6% for arSTGD and 66.7% for arCRD. However, the frequency of possibly pathogenic ABCA4 alleles in arRP families was only slightly higher than that in the general population. Moreover, in some families, mutations in other known arRP genes segregated with the disease phenotype. CONCLUSIONS: An increasing understanding of causal ABCA4 alleles in arSTGD and arCRD facilitates disease diagnosis and prognosis and also is paramount in selecting patients for emerging clinical trials of therapeutic interventions. Because ABCA4-associated diseases are evolving retinal dystrophies, assessment of age at onset, accurate clinical diagnosis, and genetic testing are crucial. We suggest that ABCA4 mutations may be associated with a retinitis pigmentosa-like phenotype often as a consequence of severe (null) mutations, in cases of long-term, advanced disease, or both. Patients with classical arRP phenotypes, especially from the onset of the disease, should be screened first for mutations in known arRP genes and not ABCA4. PMID- 23755872 TI - A randomized trial of increasing patching for amblyopia. AB - OBJECTIVE: After treatment with refractive correction and patching, some patients have residual amblyopia resulting from strabismus or anisometropia. We conducted a clinical trial to evaluate the effectiveness of increasing prescribed daily patching from 2 to 6 hours in children with stable residual amblyopia. DESIGN: Prospective, randomized, multicenter clinical trial. PARTICIPANTS: A total of 169 children aged 3 to <8 years (mean, 5.9 years) with stable residual amblyopia (20/32-20/160) after 2 hours of daily patching for at least 12 weeks. INTERVENTION: Random assignment to continue 2 hours of daily patching or increase patching time to an average of 6 hours/day. MAIN OUTCOME MEASURES: Best-corrected visual acuity (VA) in the amblyopic eye after 10 weeks. RESULTS: Baseline VA was 0.44 logarithm of the minimum angle of resolution (logMAR) (20/50(-2)). Ten weeks after randomization, amblyopic eye VA had improved an average of 1.2 lines in the 6-hour group and 0.5 line in the 2-hour group (difference in mean VA adjusted for acuity at randomization = 0.6 line; 95% confidence interval, 0.3-1.0; P = 0.002). Improvement of 2 or more lines occurred in 40% of participants patched for 6 hours versus 18% of those who continued to patch for 2 hours (P = 0.003). CONCLUSIONS: When amblyopic eye VA stops improving with 2 hours of daily patching, increasing the daily patching dosage to 6 hours results in more improvement in VA after 10 weeks compared with continuing 2 hours daily. PMID- 23755874 TI - Weak ion-molecule interactions in the gas phase: a high-pressure mass spectrometry and computational study of chloride-alkane interactions. AB - High-pressure mass spectrometric equilibrium experiments and electronic structure calculations have been carried out to investigate the energetics of the interactions of chloride ion with a series of normal alkanes and cycloalkanes in the gas phase. The structures of the complexes obtained from the electronic structure calculations provide considerable insight into the nature of the interaction between the negatively charged ion and the alkanes, which has the character of a purely ion-induced dipole interaction. The structural information also shows how the charged species affect the confirmation of the normal alkanes. PMID- 23755873 TI - Reproducibility of a long-range swept-source optical coherence tomography ocular biometry system and comparison with clinical biometers. AB - OBJECTIVE: To demonstrate a novel swept source optical coherence tomography (SS OCT) imaging device using a vertical cavity surface-emitting laser (VCSEL) capable of imaging the full eye length and to introduce a method using this device for noncontact ocular biometry. To compare the measurements of intraocular distances using this SS-OCT instrument with commercially available optical and ultrasound biometers. To evaluate the intersession reproducibility of measurements of intraocular distances using SS-OCT. DESIGN: Evaluation of technology. PARTICIPANTS: Twenty eyes of 10 healthy subjects imaged at the New England Eye Center at Tufts Medical Center and Massachusetts Institute of Technology between May and September 2012. METHODS: Averaged central depth profiles were extracted from volumetric SS-OCT datasets. The intraocular distances, such as central corneal thickness (CCT), aqueous depth (AD), anterior chamber depth (ACD), crystalline lens thickness (LT), vitreous depth (VD), and axial length (AL), were measured and compared with a partial coherence interferometry device (IOLMaster; Carl Zeiss Meditec, Inc., Dublin, CA) and an immersion ultrasound (IUS) A-scan biometer (Axis-II PR; Quantel Medical, Inc., Cournon d'Auvergne Cedex, France). MAIN OUTCOME MEASURES: Reproducibility of the measurements of intraocular distances, correlation coefficients, and intraclass correlation coefficients. RESULTS: The standard deviations of the repeated measurements of intraocular distances using SS-OCT were 6 MUm (CCT), 16 MUm (ACD), 14 MUm (AD), 13 MUm (LT), 14 MUm (VD), and 16 MUm (AL). Strong correlations among all 3 biometric instruments were found for AL (r > 0.98). The AL measurement using SS-OCT correlates better with the IOLMaster (r=0.998) than with IUS (r=0.984). The SS-OCT and IOLMaster measured higher AL values than ultrasound (175 and 139 MUm, respectively). No statistically significant difference in ACD between the optical (SS-OCT or IOLMaster) and ultrasound methods was detected. High intersession reproducibility of SS-OCT measurements of all intraocular distances was observed with intraclass correlation coefficients >0.99. CONCLUSIONS: The SS-OCT using VCSEL technology enables full eye length imaging and high-precision, noncontact ocular biometry. The measurements with the prototype SS-OCT instrument correlate well with commercial biometers. The SS-OCT biometry has the potential to provide clinically useful comprehensive biometric parameters for pre- and postoperative eye evaluation. PMID- 23755875 TI - Siderocalin outwits the coordination chemistry of vibriobactin, a siderophore of Vibrio cholerae. AB - The human protein siderocalin (Scn) inhibits bacterial iron acquisition by binding catechol siderophores. Several pathogenic bacteria respond by making stealth siderophores that are not recognized by Scn. Fluvibactin and vibriobactin, respectively of Vibrio fluvialis and Vibrio cholerae , include an oxazoline adjacent to a catechol. This chelating unit binds iron either in a catecholate or a phenolate-oxazoline coordination mode. The latter has been suggested to make vibriobactin a stealth siderophore without directly identifying the coordination mode in relation to Scn binding. We use Scn binding assays with the two siderophores and two oxazoline-substituted analogs and the crystal structure of Fe-fluvibactin:Scn to show that the oxazoline does not prevent Scn binding; hence, vibriobactin is not a stealth siderophore. We show that the phenolate-oxazoline coordination mode is present at physiological pH and is not bound by Scn. However, Scn binding shifts the coordination to the catecholate mode and thereby inactivates this siderophore. PMID- 23755876 TI - Ab initio chemical kinetics for H + NCN: prediction of NCN heat of formation and reaction product branching via doublet and quartet surfaces. AB - The reaction of NCN with H atoms has been investigated by ab initio MO and RRKM theory calculations. The mechanisms for formation of major products on the doublet and quartet potential energy surfaces have been predicted at the CCSD(T) level of theory with the complete basis set limit. In addition, the heat of formation for NCN predicted at this rigorous level and those from five isogyric reactions are in close agreement with the best value based on the isodesmic process, (3)CCO + N2 = (3)NCN + CO, 109.4 kcal/mol, which lies within the two existing experimental values. The rate constants for the three possible reaction channels, H + NCN -> CH + N2 (k(P1)), HCN + (4)N (k(QP1)), and HNC + (4)N (k(QP2)), have been calculated in the temperature range 298-3000 K. The results show that k(P1) is significantly higher than k(QP1) and k(QP2) and that the total rate constant agrees well with available experimental values in the whole temperature range studied. The kinetics of the reverse CH + N2 reaction has also been revisited at the CCSD(T)/CBS level; the predicted total rate constants at 760 Torr Ar pressure can be represented by kr = 4.01 * 10(-15) T(0.90) exp(-17.42 kcal mol(-1)/RT) cm(3) molecule(-1) s(-1) at T = 800-4000 K. The result agrees closely with the most recent experimental data and the best theoretical result of Harding et al. (J. Phys. Chem. A 2008, 112, 522) as well as that of Moskaleva and Lin (Proc. Combust. Inst. 2000, 28, 2393) evaluated with a steady-state approximation after a coding error correction made in this study. PMID- 23755877 TI - Liquid crystalline and shear-induced properties of an aqueous solution of graphene oxide sheets. AB - We demonstrated here the lyotropic liquid crystalline behavior of an aqueous solution of graphene oxide (GO) sheets. Scanning electron microscope experiments revealed GO sheets self-assembled into fiber-like or sheet-like structures at different concentrations under flow conditions. As a result, the solution viscosity decreased dramatically with increasing shear stress. PMID- 23755879 TI - [Reply]. PMID- 23755878 TI - Structural studies of an A2-type modular polyketide synthase ketoreductase reveal features controlling alpha-substituent stereochemistry. AB - Modular polyketide synthase ketoreductases often set two stereocenters when reducing intermediates in the biosynthesis of a complex polyketide. Here we report the 2.55-A resolution structure of an A2-type ketoreductase from the 11th module of the amphotericin polyketide synthase that sets a combination of l-alpha methyl and l-beta-hydroxyl stereochemistries and represents the final catalytically competent ketoreductase type to be structurally elucidated. Through structure-guided mutagenesis a double mutant of an A1-type ketoreductase was generated that functions as an A2-type ketoreductase on a diketide substrate analogue, setting an alpha-alkyl substituent in an l-orientation rather than in the d-orientation set by the unmutated ketoreductase. When the activity of the double mutant was examined in the context of an engineered triketide lactone synthase, the anticipated triketide lactone was not produced even though the ketoreductase-containing module still reduced the diketide substrate analogue as expected. These findings suggest that re-engineered ketoreductases may be catalytically outcompeted within engineered polyketide synthase assembly lines. PMID- 23755880 TI - Asthma exacerbation in children: relationship among pollens, weather, and air pollution. AB - BACKGROUND: Asthma exacerbation is an episode of (sub)acute worsening of asthmatic symptoms. Exacerbation may depend on environmental factors. OBJECTIVE: The present study investigated emergency calls for asthma exacerbation in children, analysing: i) their trend over the course of time; and ii) their possible relationship with environmental factors, including pollen count, meteorological parameters, and air pollution. METHODS: Emergency calls for exacerbation were recorded for 10 years (from 2002 to 2011) in Genoa (Italy). Betulaceae, Urticaceae, Gramineae, and Oleaceae pollen counts were measured. Meteorological parameters and air pollutants were also measured in the same area and for the same period. RESULTS: The number of emergency calls did not significantly modify during the time studied. Two main peaks were detected: during the autumn and the spring. Wind speed significantly diminished as did most air pollutants. There were significant and relevant relationships between emergency calls and: pollens during the spring (r = 0.498), rainfall (r = 0.818), wind speed (r = 0.727), and air pollutants (r = 0.622 for SO2; r = 0.699 for NO; r = 0.58 for NO2). CONCLUSIONS: This 10-year survey demonstrates that: (i) asthma exacerbations did not diminish over the time; (ii) there were seasonal peaks (autumn and spring); (iii) pollens (mainly Parietaria), wind speed and rainfall, SO2, NO, O3 and NO2 were strongly associated with asthma exacerbations in children in this area. Therefore, asthma exacerbations may significantly depend on environmental variations. PMID- 23755881 TI - Effects of microhydration on the electronic properties of ortho-aminobenzoic acid. AB - High-level density functional electronic structure calculations have been performed to analyze the effect of microsolvation with water on the electronic properties of ortho-aminobenzoic acid (o-Abz). The hydrogen-bonded interaction of the o-Abz molecule with one to three water molecules, o-Abz...(H2O)n (n = 1-3), has been considered in two different situations, once the solvent water molecules are placed close to the carboxyl (-COOH) group of o-Abz producing the o Abz...[H2O]nCOOH complexes and when the water molecules are placed close to the amino (-NH2) group producing the o-Abz...[H2O]nNH2 clusters. Variation of the vibrational spectra and energetics upon hydrogen-bond formation are analyzed and compared with available experimental data. The effect of cooperativity is also analyzed. Overall, the hydrogen-bonded o-Abz...[H2O]nCOOH clusters are found to be more stable than the o-Abz...[H2O]nNH2 clusters. PMID- 23755882 TI - Performance characteristics of qPCR assays targeting human- and ruminant associated bacteroidetes for microbial source tracking across sixteen countries on six continents. AB - Numerous quantitative PCR assays for microbial fecal source tracking (MST) have been developed and evaluated in recent years. Widespread application has been hindered by a lack of knowledge regarding the geographical stability and hence applicability of such methods beyond the regional level. This study assessed the performance of five previously reported quantitative PCR assays targeting human-, cattle-, or ruminant-associated Bacteroidetes populations on 280 human and animal fecal samples from 16 countries across six continents. The tested cattle associated markers were shown to be ruminant-associated. The quantitative distributions of marker concentrations in target and nontarget samples proved to be essential for the assessment of assay performance and were used to establish a new metric for quantitative source-specificity. In general, this study demonstrates that stable target populations required for marker-based MST occur around the globe. Ruminant-associated marker concentrations were strongly correlated with total intestinal Bacteroidetes populations and with each other, indicating that the detected ruminant-associated populations seem to be part of the intestinal core microbiome of ruminants worldwide. Consequently tested ruminant-targeted assays appear to be suitable quantitative MST tools beyond the regional level while the targeted human-associated populations seem to be less prevalent and stable, suggesting potential for improvements in human-targeted methods. PMID- 23755883 TI - A method to differentiate the causes of stiff-knee gait in stroke patients. AB - Stiff-knee gait (SKG) is a common abnormal gait pattern in patients after stroke characterized by insufficient knee flexion (KF) during swing. Overactivity of the rectus femoris (RF) is considered the primary cause of SKG. Inadequate push-off has been indicated as an additional cause in the recent literature, as KF depends on knee flexion velocity in preswing (KFV). We used the peak of vertical acceleration of the malleolus (PMVA) as a kinematic-based indirect measure of push-off and studied its relationship with KF and KFV in a sample of 20 healthy subjects walking fast (v = 95 +/- 5%heights(-1)), at self-selected speed (v = 74 +/- 5%heights(-1)), slow (v = 54 +/- 6%heights(-1)) and very slow (v = 38 +/- 5%heights(-1)) and in a sample of 52 stroke patients with SKG (age 60 +/- 11, v = 20 +/- 11%heights(-1)). In healthy subjects PMVA occurred before knee flexion acceleration (p<0.001) and hip flexion acceleration (p<0.001). KF appeared as a bottom-up mechanism driven by the ankle push-off. From a regression analysis, the PMVA-KFV cause-effect relationship resulted strictly linear, with R(2) = 0.967, KFV = 0+7.1*PMVA, P<0.0001. Data from SKG patients were compared to this normal cause-effect model. For 44/52 patients the reduced KFV was combined with lack of push-off. Data from 8/52 patients only were statistically outside the 95%CI of the model, thus requiring for a braking mechanism to explain KFV reduction. In stroke adults of our sample the push-off impairment (85% of cases) and not the inappropriate knee extension moment produced by the thigh muscles was the primary cause of SKG. This result could explain the low average efficacy (<10 degrees ) of focal and surgical treatments at the quadriceps. The presented model could be used to differentiate the primary cause of SKG between inadequate push-off and braking activity of the thigh muscles, thus increasing the effectiveness of the selected treatment. PMID- 23755884 TI - Design, synthesis, and evaluation of novel VEGFR2 kinase inhibitors: discovery of [1,2,4]triazolo[1,5-a]pyridine derivatives with slow dissociation kinetics. AB - For the purpose of discovering novel type-II inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) kinase, we designed and synthesized 5,6-fused heterocyclic compounds bearing a anilide group. A co-crystal structure analysis of imidazo[1,2-b]pyridazine derivative 2 with VEGFR2 revealed that the N1 nitrogen of imidazo[1,2-b]pyridazine core interacts with the backbone NH group of Cys919. To retain this essential interaction, we designed a series of imidazo[1,2 a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, thiazolo[5,4-b]pyridine, and 1,3 benzothiazole derivatives maintaining a ring nitrogen as hydrogen bond acceptor (HBA) at the corresponding position. All compounds thus designed displayed strong inhibitory activity against VEGFR2 kinase, and the [1,2,4]triazolo[1,5-a]pyridine 13d displayed favorable physicochemical properties. Furthermore, 13d inhibited VEGFR2 kinase with slow dissociation kinetics and also inhibited platelet-derived growth factor receptor (PDGFR) kinases. Oral administration of 13d showed potent anti-tumor efficacy in DU145 and A549 xenograft models in nude mice. PMID- 23755885 TI - Assessment of the cellular internalization of thermolytic phosphorothioate DNA oligonucleotide prodrugs. AB - The bioactivity of a CpG-containing phosphorothioate DNA oligonucleotide with thermolytic 2-(N-formyl-N-methylamino)ethyl (fma) thiophosphate groups in mice led us to investigate the parameters affecting the internalization of these thermosensitive DNA prodrugs in various cell lines. Flow cytometry and confocal microscopy analyses indicate that 5'-fluoresceinated fma-phosphorothioate DNA sequences are poorly internalized in Vero, HeLa and GC-2 cells. However, when four fma-thiophosphate groups of a 15-nucleotide long oligothymidylate prodrug are replaced with 3-(N,N-dimethylamino)prop-1-yl thiophosphate functions, internalization of the positively charged prodrug, under physiological conditions, increased fourfold in HeLa and 40-fold in Vero or GC-2 cells. No cytotoxic effects are observed in Vero cells even at an extracellular prodrug concentration of 50 MUM over a period of 72 h. Confocal microscopy studies show that internalization of the positively charged oligothymidylate prodrug in Vero cells is time-dependent with early trafficking of the DNA sequence through endosomal vesicles and, eventually, to the nucleus of the cells. Thus, the incorporation of four 3-(N,N-dimethylamino)prop-1-yl thiophosphate groups into thermosentive fma-phosphorothioate DNA prodrugs is an attractive strategy for efficient cellular internalization of these nucleic acid-based drugs for potential therapeutic indications. PMID- 23755886 TI - Temporal trends of polybrominated diphenyl ethers (PBDEs) in the blood of newborns from New York State during 1997 through 2011: analysis of dried blood spots from the newborn screening program. AB - Polybrominated diphenyl ethers (PBDEs) are ubiquitous environmental pollutants, and on a global basis, North American populations are exposed to the highest doses of PBDEs. In response to the exponential increase in human exposure to PBDEs during the late 1990s, some PBDE formulations were phased out from production in the early 2000s. The effectiveness of the phase-out of commercial penta-BDE and octa-BDE mixtures in 2004 in the U.S. on human exposure levels is not known. Dried blood spots (DBSs), collected for the newborn screening program (NSP) in the U.S., are a valuable resource for the elucidation of trends in exposure to environmental pollutants in newborns. In this study, seven PBDE congeners were determined by gas chromatography-high resolution mass spectrometry (GC-HRMS) in archived DBS samples (in total, 51 blood spot composites from 1224 newborns) collected from newborns in New York State (NYS) from 1997 to 2011. The most frequently detected PBDE congener was BDE-47, with a detection rate (DR) of 86%, followed by BDE-99 (DR: 45%) and BDE-100 (DR: 43%). The mean concentrations determined during 1997 through 2011 in the whole blood of newborns were 0.128, 0.040, and 0.012 ng/mL for BDE-47, -99, and -100, respectively. A significant correlation was found among the concentrations of three major congeners (p < 0.001). PBDE concentrations were similar during 1997 through 2002 and, thereafter, decreased significantly, which was similar to the trends observed for perfluorinated compounds (PFCs) in DBS samples. Occurrence of PBDEs in the whole blood of newborns confirms that these compounds do cross the placental barrier. PMID- 23755887 TI - Contaminants in tracked seabirds showing regional patterns of marine pollution. AB - Ocean-scale monitoring of pollution is challenging. Seabirds are useful indicators because they travel over a broad foraging range. Nevertheless, this coarse spatial resolution is not fine enough to discriminate pollution in a finer scale. Previous studies have demonstrated that pollution levels are higher in the Sea of Japan and South and East China Seas than the Northen Pacific Ocean. To test these findings in a wide-ranging animal, we tracked streaked shearwaters (Calonectris leucomelas) from four islands in Japan using global positioning system (GPS) and measured persistent organic pollutants (POPs) in the oil of their preen glands. The POPs did not change during 6 to 21 days when birds from Awashima were foraging only in the Sea of Japan, while it increased when they crossed to the Pacific through the Tsugaru Strait and foraged along the eastern coast of Hokkaido where industrial cities occur. These results indicate that POPs in the oil reflect relatively short-term exposure. Concentrations of POPs displayed greater variation among regions. Total polychlorinated biphenyls were highest in birds foraging in a small area of the semiclosed Seto Inland Sea surrounded by urbanized coast, p,p'-dichlorodiphenyltrichloroethane (DDT) was highest in birds foraging in the East China Sea, and total hexachlorocyclohexanes were highest in birds foraging in the Sea of Japan. All were lowest in birds foraging in the Pacific. This distribution of POPs concentration partly agrees with previous findings based on mussels, fish, and seawater and possibly reflects the mobility and emission sources of each type of POP. These results highlight the importance of information on the foraging area of highly mobile top predators to make them more effective monitors of regional marine pollution. PMID- 23755888 TI - Comparative toxicokinetics of organic micropollutants in freshwater crustaceans. AB - Exposure and depuration experiments for Gammarus pulex and Daphnia magna were conducted to quantitatively analyze biotransformation products (BTPs) of organic micropollutants (tramadol, irgarol, and terbutryn). Quantification for BTPs without available standards was performed using an estimation method based on physicochemical properties. Time-series of internal concentrations of micropollutants and BTPs were used to estimate the toxicokinetic rates describing uptake, elimination, and biotransformation processes. Bioaccumulation factors (BAF) for the parents and retention potential factors (RPF), representing the ratio of the internal amount of BTPs to the parent at steady state, were calculated. Nonlinear correlation of excretion rates with hydrophobicity indicates that BTPs with lower hydrophobicity are not always excreted faster than the parent compound. For irgarol, G.pulex showed comparable elimination, but greater uptake and BAF/RPF values than D.magna. Further, G. pulex had a whole set of secondary transformations that D. magna lacked. Tramadol was transformed more and faster than irgarol and there were large differences in toxicokinetic rates for the structurally similar compounds irgarol and terbutryn. Thus, predictability of toxicokinetics across species and compounds needs to consider biotransformation and may be more challenging than previously thought because we found large differences in closely related species and similar chemical structures. PMID- 23755889 TI - Larynx preservation: what is the best non-surgical strategy? AB - The concept of larynx preservation in locally advanced laryngeal or hypopharyngeal squamous cell carcinoma has evolved during the last three decades, especially with the advancement of nonsurgical strategies. These nonsurgical strategies include: (1) radiotherapy alone; (2) concomitant chemoradiotherapy (CCRT); and (3) induction chemotherapy followed by radiotherapy or CCRT and concurrent anti-epidermal growth factor receptor (EGFR). To date, the best approach for larynx preservation has yet to be defined. In this article, we review and discuss important recent randomized phase II/III trials investigating larynx preservation in order to facilitate the selection of an appropriate strategy in the clinical setting. However, the decision of larynx preservation should always be a multidisciplinary approach. PMID- 23755890 TI - Dendritic cell sarcoma: a pooled analysis including 462 cases with presentation of our case series. AB - Dendritic cell tumors are extremely rare and current knowledge on these tumors is limited. The characteristics of three dendritic cell sarcoma subtypes and their optimal treatment approaches are not fully clarified. We aimed to make a systematic review of the literature and enrich the current data with five new cases. Pooled analysis of 462 reported cases revealed that the tumor had no age, gender or racial predilection. Our analysis suggests that the young age, advanced stage, intraabdominal involvement and unfavorable histological features (i.e. large tumor size, absence of lymphoplasmacytic infiltration, coagulative necrosis, high mitotic count) may predict poor prognosis. Subtypes of this tumor have different clinical behaviors with interdigitating dendritic cell sarcoma being the most aggressive form. In general, surgery is the most effective treatment modality and adjuvant radiotherapy has no significant effect on overall survival of patients. The role of chemotherapy for the management of advanced disease is controversial. PMID- 23755891 TI - P53 mutations in triple negative breast cancer upregulate endosomal recycling of epidermal growth factor receptor (EGFR) increasing its oncogenic potency. AB - There is no available targeted therapy for triple-negative or its more aggressive subtype, basal-like breast cancer. Multiple therapeutic strategies based on translational knowledge have not improved the treatment options for triple negative patients. As understanding of molecular pathways that drive tumor development is rapidly increasing, it is imperative to adapt our treatment strategies to perturbations in molecular pathways driving the malignant process. Basal-like breast cancers over-express EGFR (without mutations or EGFR gene amplifications) and have p53 mutations. While EGFR drives the malignant behavior in triple negative breast cancer (TNBC), anti-EGFR therapies have fallen short of the expected results in clinical trials. Here we bring evidence that the less than optimal results of the anti-EGFR therapies may be explained in part by the increased potency of the EGFR signaling due to increased endosomal recycling. The functional connection between EGFR and endosomal trafficking in TNBC is mutant p53 found in the most aggressive forms of TNBC. Mutant p53 acquires oncogenic functions and binds p63 protein, a member of p53 family with tumor suppressor activities. In the absence of functional p63 there is an upregulation of endosomal recycling EGFR and integrin to the membrane with increased proinvasive abilities of cancer cells. Blocking endosomal trafficking combined with anti-EGFR treatments may result in better clinical outcomes in TNBC. PMID- 23755892 TI - Pond-derived organic carbon driving changes in arsenic hazard found in Asian groundwaters. AB - Microbially mediated reductive processes involving the oxidation of labile organic carbon are widely considered to be critical to the release of arsenic into shallow groundwaters in South and Southeast Asia. In areas where there is significant pumping of groundwater for irrigation the involvement of surface derived organic carbon drawn down from ponds into the underlying aquifers has been proposed but remains highly controversial. Here we present isotopic data from two sites with contrasting groundwater pumping histories that unequivocally demonstrate the ingress of surface pond-derived organic carbon into arsenic containing groundwaters. We show that pond-derived organic carbon is transported to depths of up to 50 m even in an arsenic-contaminated aquifer in Cambodia thought to be minimally disturbed by groundwater pumping. In contrast, in the extensively exploited groundwaters of West Bengal, we show that pond-derived organic carbon is transported in shallow groundwater to greater depths, in excess of 100 m in the aquifer. Intensive pumping of groundwaters may potentially drive secular increases in the groundwater arsenic hazard in this region by increasing the contribution of bioavailable pond-derived dissolved organic carbon drawn into these aquifer systems and transporting it to greater depths than would operate under natural flow conditions. PMID- 23755894 TI - Targeting phosphatidylinositol 3-kinase signaling in acute myelogenous leukemia. AB - INTRODUCTION: Despite continuous advances in our knowledge of the biology of acute myelogenous leukemia (AML), the prognosis of AML patients treated with standard chemotherapy is still poor, especially in the elderly. Therefore, there is a need for novel targeted and less toxic therapies, particularly for patients who develop resistance to traditional chemotherapeutic drugs. Constitutively active phosphatidylinositol 3-kinase (PI3K) signaling characterizes many types of tumors, including AML, where it negatively influences response to therapeutic treatments. AREAS COVERED: The literature data showed that small inhibitor molecules targeting PI3K signaling induced cell cycle arrest, apoptosis and decreased drug-resistance in AML cells. PI3K inhibitors were also capable of targeting leukemic initiating cells (LICs), the most relevant target for leukemia eradication, whereas they tended to spare healthy hematopoietic stem cells. EXPERT OPINION: Data emerging from pre-clinical settings suggest that the PI3K pathway is critically involved in regulating proliferation, survival and drug resistance of AML cells. Therefore, we propose that novel drugs targeting this signaling pathway may offer a novel and less toxic treatment option for AML patients, most likely in combination with a lower dosage of traditional chemotherapeutic agents or other innovative therapeutic agents. PMID- 23755895 TI - Current trends in detecting non-O157 Shiga toxin-producing Escherichia coli in food. AB - Non-O157 Shiga toxin-producing Escherichia coli (non-O157 STEC) strains are increasingly recognized as important foodborne pathogens worldwide. Together with E. coli O157:H7, six additional STEC serogroups (O26, O45, O103, O111, O121, and O145) are now regulated as adulterants in certain raw beef products in the United States. However, effective detection and isolation of non-O157 STEC strains from food matrices remain challenging. In the past decade, great attention has been paid to developing rapid and reliable detection methods for STEC in general (targeting common virulence factors) and specific STEC serogroups in particular (targeting serogroup-specific traits). This review summarizes current trends in detecting non-O157 STEC in food, including culture, immunological, and molecular methods, as well as several novel technologies. PMID- 23755893 TI - Vaccinomics, adversomics, and the immune response network theory: individualized vaccinology in the 21st century. AB - Vaccines, like drugs and medical procedures, are increasingly amenable to individualization or personalization, often based on novel data resulting from high throughput "omics" technologies. As a result of these technologies, 21st century vaccinology will increasingly see the abandonment of a "one size fits all" approach to vaccine dosing and delivery, as well as the abandonment of the empiric "isolate-inactivate-inject" paradigm for vaccine development. In this review, we discuss the immune response network theory and its application to the new field of vaccinomics and adversomics, and illustrate how vaccinomics can lead to new vaccine candidates, new understandings of how vaccines stimulate immune responses, new biomarkers for vaccine response, and facilitate the understanding of what genetic and other factors might be responsible for rare side effects due to vaccines. Perhaps most exciting will be the ability, at a systems biology level, to integrate increasingly complex high throughput data into descriptive and predictive equations for immune responses to vaccines. Herein, we discuss the above with a view toward the future of vaccinology. PMID- 23755897 TI - Propranolol treatment of portal hypertension in cirrhosis patients is better the higher the untreated pressure: a single-centre prospective experience. AB - OBJECTIVE: To assess the effect of propranolol treatment on the hepatic venous pressure gradient (HVPG) and the relationship between native HVPG and the effect of propranolol in patients with cirrhosis and portal hypertension in a prospective, observational, single-center study. MATERIAL AND METHODS: The HVPG was registered prospectively in 124 consecutive cirrhosis patients with and without treatment with propranolol 80 mg daily. Results. 41% of the patients responded to the treatment with the intended reduction of HVPG to <12 mm Hg and/or by >20%. The HVPG reduction was larger for higher native HVPG values (p < 0.001). There was no significant relation between changes in heart rate and changes in HVPG (p = 0.8). CONCLUSIONS: The high fraction of hemodynamic non responders supports the rationale of measuring the HVPG with and without propranolol treatment to assist the clinical assessment and avoid meaningless and potentially harmful treatment. The positive association between a high native HVPG and propranolol-induced HVPG reduction indicates that pharmacological treatment also benefits patients with advanced portal hypertension. PMID- 23755896 TI - Genetic modification of hypertension by sGCalpha1. AB - Hypertension is an important modifiable risk factor for coronary heart disease, congestive heart failure, stroke, end-stage renal disease, and peripheral vascular disease, but many of the molecular mechanisms and genetic factors underlying the development of the most common forms of human hypertension remain to be defined. Abundant evidence suggests that nitric oxide (NO) and one of its primary targets, the cyclic guanosine monophosphate (cGMP)-generating enzyme soluble guanylate cyclase (sGC), have a critical role in regulating blood pressure. The availability of murine models of hypertension and the revolution in human genetics research (e.g., genome-wide association studies [GWAS]), resulting in the identification of dozens of genetic loci that affect normal variation in blood pressure and susceptibility to hypertension, provide a unique opportunity to dissect the mechanisms by which NO-cGMP signaling regulates blood pressure and to gain important insights into the pathogenesis of hypertension. In this review, we will give an overview of the current knowledge relating to the role of sGC in the regulation of blood pressure, discussing data obtained from genetically modified mouse models as well as from human genetic studies. PMID- 23755898 TI - The significance of heat-shock protein gp96 and its receptors' CD91 and Toll-like receptor 4 expression at the maternal foetal interface. AB - PROBLEM: Differences in the expression of gp96 and its receptors were analysed in normal and pathological human pregnancy. MATERIAL AND METHODS: Immunohistology and immunofluorescence of sections from decidual part of term placenta, first trimester normal decidua, missed abortion and blighted ovum decidua were performed together with reverse transcriptase-quantitative polymerase chain reaction and flow cytometry. RESULTS: In missed abortion, gp96 was intensively stained, when compared to normal early pregnancy. The intensity of CD91 and TLR4 was higher in the first trimester pregnancy and blighted ovum, when compared to missed abortion. Decidual part of the term placenta is invaded with gp96+ , CD91+ and TLR4+ trophoblast. Progesterone-induced blocking factor (PIBF) decreased the frequency of TLR4+ T lymphocytes, CD91+ T, natural killer (NK) and mature dendritic cells after an 18-h culture. Decidual mononuclear cells (DMCs) treated with PIBF down-regulated CD91, TLR4 and gp96 gene expression. CONCLUSION: The presence of gp96, CD91 and TLR4 at the maternal-foetal interface provides a molecular basis for their interaction, particularly in the absence of PIBF. PMID- 23755899 TI - Impact of medication non-adherence on survival after pediatric heart transplantation in the U.S.A. AB - BACKGROUND: Medication non-adherence (NA) can result in life-threatening illness in children after solid-organ transplantation. Little is known about the incidence, risk factors and outcomes of NA in large numbers of pediatric heart transplant (HT) recipients. METHODS: Organ Procurement Transplant Network (OPTN) data were used to identify all children <18 years of age in the U.S.A. who underwent HT from October 1999 to January 2007. Cox proportional hazards analysis was used to identify risk factors for NA and the effect on graft survival. RESULTS: Of 2,070 pediatric heart transplants performed the median age at transplant was 6 years (interquartile range [IQR] 0 to 13 years); 40% had congenital heart disease (CHD), 7% were re-transplants, 42% were non-white and 43% had Medicaid insurance. Overall, 186 (9%) children had a report of NA at a median age of 15 years with more than two-thirds of NA episodes occurring after 12 years of age. Factors independently associated with NA were: adolescent age at transplant (hazard ratio [HR] 7.0, 95% confidence interval [CI] 4.1 to 12, compared with infants); black race (HR 2.3, 95% CI 1.7 to 3.3, compared with white); Medicaid insurance (HR 2.0, 95% CI 1.5 to 2.7, compared with non-Medicaid insurance); and ventilator or ventricular assist device (VAD) support at transplant. The risk of mortality conditional upon report of NA was 26% at 1 year and 33% at 2 years. CONCLUSIONS: Medication NA is an important problem in pediatric HT recipients and is associated with high mortality. Adolescent age, black race, Medicaid insurance and invasive hemodynamic support at transplant were associated with NA, whereas time on the wait list and gender were not. Targeted interventions among at-risk populations may be warranted. PMID- 23755900 TI - Non-adherence: time for action--not evaluation. PMID- 23755901 TI - Survival in the environment is a possible key factor for the expansion of Escherichia coli strains producing extended-spectrum beta-lactamases. AB - Acquired resistance to cephalosporins in Enterobacteriaceae is a global problem. After an outbreak at Uppsala University Hospital of extended-spectrum beta lactamase (ESBL)-positive Klebsiella pneumoniae producing CTX-M-15, there was a shift from AmpC to ESBL production among Escherichia coli isolates. To explore the basis for this epidemiological shift, 46 E. coli isolates (ESBLs, n = 23; AmpC, n = 23) were characterized with regard to genetic relatedness, beta lactamase, replicon and integron types, antibiotic resistance profiles, and genes encoding virulence factors. In addition, the survival in the environment and on hospital-associated materials was analysed. CTX-M-15 was the most frequent ESBL (78%). Only three (13%) of the AmpC enzymes were harboured on plasmids (CMY-2, DHA-1). Independent of plasmid-mediated beta-lactamase, IncF plasmids predominated and only class I integrons were detected. The ESBL producers carried more virulence genes (p = 0.04), exhibited a broader resistance phenotype (p = 0.01) and survived significantly longer (p = 0.03) on different materials than the AmpC-producing isolates. In conclusion, ESBL-producing isolates had properties which are likely to augment their competitiveness. Apart from antibiotic resistance and virulence factors, extended survival in the environment could be a selective trait for successful ESBL-producing E. coli strains. PMID- 23755902 TI - Evaluation of metal ion release from Ti6Al4V and Co-Cr-Mo casting alloys: in vivo and in vitro study. AB - PURPOSE: The aim of this study was to evaluate the amount of ions released from Ti6Al4V and Co-Cr-Mo alloys both in vivo and in vitro. MATERIALS AND METHODS: Twenty-one discs of each alloy were constructed and divided into seven groups. Three specimens from each group were immersed in a buffered saline solution over a period of 1, 3, 5, 7, 14, 21, and 28 days. Twenty-eight participants were also included in the study, where the study group consisted of 14 mandibular partially edentulous patients, and the control group consisted of 14 volunteers. The study group was further divided into two equal groups: the first group received removable partial dentures (RPDs) constructed from Co-Cr-Mo alloy, while the second group received RPDs constructed from Ti6Al4V alloy. Saliva samples were collected from each participant over the same study period. The conditioning media and saliva samples were analyzed using a spectrophotometer. One-way ANOVA and Tukey tests were used for statistical analysis (p < 0.05). RESULTS: The concentrations of metal ions released from the studied alloys were significantly higher in the in vitro than in the in vivo study group during the follow-up periods. A statistically significant increase in ion concentrations of the different elements for both alloys was found with time (p < 0.05). CONCLUSION: The amounts of released metallic ions from Co-Cr-Mo and Ti6Al4V alloys were higher in the buffered saline solutions than in the studied saliva samples and control groups; however, these amounts were still within the physiological limit of trace elements in the human body. PMID- 23755903 TI - Patient satisfaction surveys and treatment of pain in the emergency department (ED) setting. PMID- 23755904 TI - Low cdc27 and high securin expression predict short survival for breast cancer patients. AB - Cell cycle regulators cdc27 and securin participate in control of the mitotic checkpoint and survey the mitotic spindle to maintain chromosomal integrity. This is achieved by their functions in metaphase-anaphase transition, DNA damage repair, enhancement of mitotic arrest and apoptosis. We report on the roles of cdc27 and securin in aneuploidy and prognosis of breast cancer. The study comprises 429 breast cancer patients with up to 22 years of follow-up. DNA content was determined by image cytometry, and immunopositivity for cdc27 and securin was based on tissue microarrays. An inverse association between cdc27 and securin expression was observed in both image cytometric and immunohistochemical analyses. Low cdc27 and high securin expression identified patients with significant difference in disease outcome. Cdc27 and securin immunoexpression identified patients at risk of early cancer death within five years from diagnosis. In multivariate analysis, the combination of cdc27 and securin immunohistochemistry was the strongest predictor of cancer death after lymph node status. We demonstrate, for the first time in human breast cancer, the prognostic value of cdc27 and securin immunohistochemistry. Cdc27 and securin appear promising biomarkers for applications in predicting disease progression, prognostication of individual patients and potential in anti-mitotic drug development. PMID- 23755905 TI - Molecular angiogenic events of a two-herb wound healing formula involving MAPK and Akt signaling pathways in human vascular endothelial cells. AB - The emergence of electric cell-substrate impedance sensing (ECIS) technology has provided new insight in advanced cell behavioral study by its nanometer sensitivity, precise electrical wounds generation, and high reproducibility that can be monitored in real time in a noninvasive way. However, little is known regarding pro-angiogenic agents in wound healing studies using endothelial cells evaluated with ECIS technology. Our previous studies showed a prominent wound healing effect of a two-herb formula (NF3) comprising of Astragali Radix and Rehmanniae Radix in a rat chronic wound model through actions including angiogenesis. Here we further investigated the angiogenic effect and its underlying molecular mechanism through proliferation, motility, and tubule formation of human vascular endothelial cells (HECV) using ECIS technology. It was first shown that HECV treated with NF3 had a higher resistance than that of control using ECIS cell attachment and cell migration model (p < 0.01). We further validated in a scratch assay that NF3 treatment significantly stimulated HECV cell migration (p < 0.01-0.05). Also, NF3-treated HECV were observed to develop into a significantly more branched tubular structure when compared with control (p < 0.05-0.01). Meanwhile, Western blot analysis of NF3-treated HECV revealed the activated expression of p-Akt, and mitogen-activated protein (MAP) kinases for p-ERK, p-p38, and p-JNK. We propose that the effect of NF3 in the promotion of endothelial cell migration and tubule formation could be mediated through pathways involving p-Akt and activated MAP kinases. Hence, we demonstrated the complexity of the angiogenic effect activated by NF3 molecularly and functionally. NF3 treatment could offer therapeutic value to chronic wound healing for its pro-angiogenic efficacy. PMID- 23755906 TI - Relationship between type-2 diabetes and use of metformin with risk of colorectal adenoma in an American population receiving colonoscopy. AB - The aim of this study is to explore the relationship between type-2 diabetes, its treatments (Use of metformin) and the development of colorectal adenoma. Colonoscopy reports from a total of 66 endoscopists in one big hospital in midwest during 2008-2009 were reviewed. Colonoscopy findings including quality of preparation, polyp size, location, morphology, pathology and history of diabetes and metformin treatment were retrieved. Of the 7382 colonoscopy reports were reviewed, 3465 average risk patients were included in our final analysis. The pathologically proven Adenoma detection rate (ADR) in total population was 24.6 % (30.2% in Men and 19.2% in Women). Old age and male sex were significantly associated with increasing risk of colorectal adenoma. Type-2 diabetes was associated increased risk of colorectal adenoma (OD 1.35, 95% confidence interval 1.08-1.70, p=0.009). A total of 426 subjects (12.29%) had diabetes and 405 of these subjects (11.7%) had type-2 diabetes. Within diabetic patient group, people who were taking metformin have significantly lower risk of colorectal adenoma (OD 0.55, 95% confidence interval 0.34-0.87, p=0.011). Diabetic subjects have increased risk of developing colorectal adenoma. Our study also supports the beneficial effect of metformin in development of colorectal adenoma. PMID- 23755907 TI - Occupational exposure to polychlorinated dibenzo-p-dioxins and dibenzofurans, dioxin-like polychlorinated biphenyls, and polychlorinated naphthalenes in workplaces of secondary nonferrous metallurgical facilities in China. AB - The concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), dioxin-like polychlorinated biphenyls (dl-PCBs), and polychlorinated naphthalenes (PCNs) were determined in workplace air from eight secondary nonferrous metal processing plants to investigate occupational exposure to these toxic compounds. The total estimated daily intakes of PCDD/Fs and dl-PCBs for workers by inhalation in the workplace were in the range of 0.15-9.91 and 0.13 8.59 pg of WHO-TEQ/kg of body weight (bw) for moderate and light activities, respectively. The daily inhalation doses for workers in the workplaces of three investigated plants exceeded the tolerable daily intake recommended by the World Health Organization. These results indicate that the risk of occupational exposure to dioxins by inhalation in the workplace of plants investigated was considerably high. For PCNs, the daily inhalation doses for workers in the workplace were in the range of 0.005-4.46 and 0.004-3.87 pg of TEQ/kg of bw for moderate and light activities, respectively, which were lower than those of dioxins. To identify the source of PCDD/Fs, PCBs, and PCNs in workplace air, their homologue profiles were compared with those in stack gas from the plants investigated. It was found that significant dioxin contamination in workplace air was mainly attributed to the emission of fugitive gas from smelting furnaces during reclamation processes. PMID- 23755908 TI - Press Ganey scores and patient satisfaction in the emergency department (ED): the patient perspective. PMID- 23755909 TI - Lower mannose-binding lectin contributes to deleterious H1N1 2009 infection in children. AB - Mannose-binding lectin (MBL) has broad range of activity against viruses through the mechanisms of neutralization, opsonization, and complement activation. Prior studies have demonstrated that MBL inactivated the season's influenza virus. Due to the fact that children have no neutralizing antibody against H1N1 2009 virus, innate immunity may be crucial in the defense against influenza. Therefore, we studied whether MBL levels played a role in H1N1 2009 infection in children. In a prospective survey, we revealed that MBL levels in ICU influenza cases were significantly lower than in children with influenza from infection disease ward. MBL may be involved in innate immune responses to H1N1 2009 infection in children. PMID- 23755910 TI - Wound healing potential of topical bacteriophage therapy on diabetic cutaneous wounds. AB - Chronic wounds that fail to heal are a common complication of diabetes mellitus and the most common precipitating reason for nontraumatic lower limb amputation. Unfortunately, the bacterial species that cause these infections are becoming more resistant to antibiotics, making them increasingly difficult to treat. We assessed the feasibility of combating chronic bacterial infections with a topically delivered bacteriophage cocktail in two animal models of diabetes mellitus. Microbiological, planimetric, and histological parameters were compared in debrided infected wounds with or without topical bacteriophage treatment. We determined that bacteriophage treatment effectively decreased bacterial colony counts and improved wound healing, as indicated by smaller epithelial and dermal gaps, in Staphylococcus aureus and Pseudomonas aeruginosa infections but was not as effective against Acinetobacter baumannii. Although the improvements were more significant in the rodent model than in the porcine model, our results suggest that topically administered bacteriophage treatment may be effective in resolving chronic infections, especially when applied in conjunction with wound debridement. These findings have important implications for the feasibility of using topical antimicrobial therapies to safely treat chronic infections in diabetes mellitus patients. PMID- 23755911 TI - The association between BsmI polymorphism and risk factors for atherosclerosis in patients with epilepsy taking valproate. AB - PURPOSE: To evaluate the association between the BsmI polymorphism and vascular risk factors or metabolic syndrome in patients with epilepsy treated with valproate. METHODS: We performed a cross-sectional study to determine glucose homeostasis, lipid profile, and evidence of metabolic syndrome, as well as the BsmI polymorphism in seizure free adults with epilepsy. RESULTS: We recruited 75 patients with epilepsy to the current study. The frequency of the BsmI polymorphism was 22.7%. We found that patients with BsmI polymorphism had significantly higher total levels of triglycerides, total cholesterol, HDL-C and LDL-C. There were no differences in terms of fasting blood glucose level and fasting insulin levels between patients with the BsmI polymorphism and those with the wild type vitamin D receptor (VDR) gene. Insulin resistance was identified in 6 of 17 patients with the BsmI polymorphism, and 18 of 58 patients with the wild type VDR gene. We calculated the homeostasis model assessment (HOMA) index and found no difference in HOMA levels between the groups. Systolic blood pressure was higher in patients with the BsmI polymorphism. There was a higher prevalence of metabolic syndrome in patients with the BsmI polymorphism than in patients with the wild type gene. The prevalence of metabolic syndrome in BsmI polymorphism carriers was 64.7% compared with 41.4% in patients with the wild type VDR gene. CONCLUSION: Young patients with epilepsy taking valproate who carry the BsmI polymorphism are at an increased risk of having vascular risk factors. PMID- 23755912 TI - Chlorinated solvent transformation by palladized zerovalent iron: mechanistic insights from reductant loading studies and solvent kinetic isotope effects. AB - Palladized nanoscale zerovalent iron (Pd/NZVI) has been utilized for source zone control, yet the reductant responsible for pollutant transformation and the optimal conditions for subsurface application remain poorly understood. Here, trends in Pd/Fe reactivity toward 1,1,1,2-tetrachloroethane (1,1,1,2-TeCA) and cis-dichloroethene (cis-DCE) were compared in H2O and D2O batch systems as a function of pH, chlorinated solvent concentration, Pd surface loading, Pd/Fe mass loading, Pd/Fe aging time, and zerovalent iron [Fe(0)] particle size. For Pd/NZVI, the solvent kinetic isotope effect [i.e., kobs(H2O)/kobs(D2O) or SKIE] for 1,1,1,2-TeCA and cis-DCE reduction increased substantially with Pd loading and Pd/NZVI concentration, evidence that multiple pathways exist for chlorinated solvent reduction. At low Pd loadings and Pd/NZVI concentrations with relatively small SKIEs (less than ~5), we propose that modest reactivity enhancements (<= 10 fold) reflect more efficient electron transfer to 1,1,1,2-TeCA from Fe(0) facilitated by Pd nanodeposits. Much larger SKIEs (e.g., exceeding 100 for cis DCE) imply the involvement of atomic hydrogen in more reactive systems with high Pd loadings and Pd/NZVI concentrations. Generally, evidence of SKIEs supporting a dominant role for atomic hydrogen was not observed for Pd/Fe prepared from micrometer-sized Fe(0), or for any size of nonpalladized Fe(0). During anaerobic aging of Pd/NZVI, decreases in the SKIE for 1,1,1,2-TeCA reduction suggest that atomic hydrogen will contribute to reactivity for only approximately 1 week after application. PMID- 23755913 TI - Expression of urocortin in pancreatic ductal adenocarcinoma and pancreatic intraepithelial neoplasia. AB - Urocortin (UCN) is a 40-amino acid neuropeptide that regulates angiogenesis and inhibits cell proliferation. Our aim was to examine the relationship of UCN expression to the clinicopathological parameters of pancreatic ductal adenocarcinoma (PDAC) and histological grade of pancreatic intraepithelial neoplasia (PanIN). Tissue microarray was used to analyze UCN protein expression in 89 surgical specimens including 21 PanIN, 3 PDAC arising from PanIN, and 65 PDAC without PanIN. UCN immunoscores ranging from 0 to 12 were obtained by multiplying intensity (scored on a 3-point scale) by the percentage of stained cells (scored on a 4-point scale). Strong expression of UCN was detected in 5 specimens of non-neoplastic pancreatic ductal epithelia. UCN immunoscore was significantly higher in PanIN-1 than in PanIN-2 and PanIN-3 (p = 0.038) and significantly higher in well-differentiated PDAC or early American Joint Committee on Cancer (AJCC) stage PDAC than in poorly differentiated or advanced stage PDAC (p = 0.025, p = 0.018). Higher expression of UCN correlates with PDAC tumor grade and AJCC pathologic stage as well as PanIN grade. Immunohistochemical assessment of UCN may help clinicians predict tumor recurrence rate and help pathologists make a proper diagnosis. PMID- 23755914 TI - Seasonal variation in the antifouling defence of the temperate brown alga Fucus vesiculosus. AB - The important role of marine epibiotic biofilms in the interactions of the host with its environment has been acknowledged recently. Previous studies with the temperate brown macroalga Fucus vesiculosus have identified polar and non-polar compounds recovered from the algal surface that have the potential to control such biofilms. Furthermore, both the fouling pressure and the composition of the epibiotic bacterial communities on this macroalga varied seasonally. The extent to which this reflects a seasonal fluctuation of the fouling control mechanisms of the host is, however, unexplored in an ecological context. The present study investigated seasonal variation in the anti-settlement activity of surface extracts of F. vesiculosus against eight biofilm-forming bacteria isolated from rockweed-dominated habitats, including replication of two populations from two geographically distant sites. The anti-settlement activity at both sites was found to vary temporally, reaching a peak in summer/autumn. Anti-settlement activity also showed a consistent and strong difference between sites throughout the year. This study is the first to report temporal variation of antifouling defence originating from ecologically relevant surface-associated compounds. PMID- 23755915 TI - Undermining incision and healing of deep pressure ulcers: a prospective cohort study of pressure ulcers by the Japanese national hospital organization. AB - Undermining is one of the most challenging complications of deep pressure ulcers. Recommendations in most guidelines are based only on expert opinions. Here, we examined the relationship between surgical incision of the undermined space and pressure ulcer healing through a Japanese multicenter prospective cohort study. A total of 162 patients with undermining in 40 national hospitals in Japan were enrolled from July 2007 to June 2009. The incision group included 39 patients (24.1%) whose undermining was surgically incised during the observational period. Their 4-week follow-up data on pressure ulcer severity and areas of healthy granulation tissue were recorded as outcome variables using the DESIGN-R pressure ulcer assessment tool. The 4-week follow-up was restarted after the incision in the incision group. The outcome variables over time were compared between the two groups using a linear mixed model with or without adjustment for demographic and other variables. The incision group showed more rapid improvement in the total and granulation DESIGN-R scores compared with the nonincision group (p < 0.001 and p = 0.007, respectively, in the crude models). This study may provide the first considerable evidence to support that surgical incision of undermining may promote healing of deep pressure ulcers. PMID- 23755916 TI - Delivery outcomes for nulliparous women at the extremes of maternal age - a cohort study. AB - OBJECTIVE: To examine the associations between extremes of maternal age (<=17 years or >=40 years) and delivery outcomes. DESIGN: Retrospective cohort study. SETTING: Urban maternity hospital in Ireland. POPULATION: A total of 36 916 nulliparous women with singleton pregnancies who delivered between 2000 and 2011. METHODS: The study population was subdivided into five maternal age groups based on age at first booking visit: <=17 years, 18-19 years, 20-34 years, 35-39 years and women aged >=40 years. Logistic regression analyses were performed to examine the associations between extremes of maternal age and delivery outcomes, adjusting for potential confounding factors. MAIN OUTCOME MEASURES: Preterm birth, admission to the neonatal unit, congenital anomaly, caesarean section. RESULTS: Compared with maternal age 20-34 years, age <=17 years was a risk factor for preterm birth (adjusted odds ratio [adjOR] 1.83, 95% confidence interval [95% CI] 1.33-2.52). Babies born to mothers >=40 years were more likely to require admission to the neonatal unit (adjOR 1.35, 95% CI 1.06-1.72) and to have a congenital anomaly (adjOR 1.71, 95% CI 1.07-2.76). The overall caesarean section rate in nulliparous women was 23.9% with marked differences at the extremes of maternal age; 10.7% at age <=17 years (adjOR 0.46, 95% CI 0.34-0.62) and 54.4% at age >=40 years (adjOR 3.24, 95% CI 2.67-3.94). CONCLUSIONS: Extremes of maternal age need to be recognised as risk factors for adverse delivery outcomes. Low caesarean section rates in younger women suggest that a reduction in overall caesarean section rates may be possible. PMID- 23755917 TI - The significance of peroxisome function in chronological aging of Saccharomyces cerevisiae. AB - We studied the chronological lifespan of glucose-grown Saccharomyces cerevisiae in relation to the function of intact peroxisomes. We analyzed four different peroxisome-deficient (pex) phenotypes. These included Deltapex3 cells that lack peroxisomal membranes and in which all peroxisomal proteins are mislocalized together with Deltapex6 in which all matrix proteins are mislocalized to the cytosol, whereas membrane proteins are still correctly sorted to peroxisomal ghosts. In addition, we analyzed two mutants in which the peroxisomal location of the beta-oxidation machinery is in part disturbed. We analyzed Deltapex7 cells that contain virtually normal peroxisomes, except that all matrix proteins that contain a peroxisomal targeting signal type 2 (PTS2, also including thiolase), are mislocalized to the cytosol. In Deltapex5 cells, peroxisomes only contain matrix proteins with a PTS2 in conjunction with all proteins containing a peroxisomal targeting signal type 1 (PTS1, including all beta-oxidation enzymes except thiolase) are mislocalized to the cytosol. We show that intact peroxisomes are an important factor in yeast chronological aging because all pex mutants showed a reduced chronological lifespan. The strongest reduction was observed in Deltapex5 cells. Our data indicate that this is related to the complete inactivation of the peroxisomal beta-oxidation pathway in these cells due to the mislocalization of thiolase. Our studies suggest that during chronological aging, peroxisomal beta-oxidation contributes to energy generation by the oxidation of fatty acids that are released by degradation of storage materials and recycled cellular components during carbon starvation conditions. PMID- 23755918 TI - An age-related numerical and functional deficit in CD19(+) CD24(hi) CD38(hi) B cells is associated with an increase in systemic autoimmunity. AB - Autoimmunity increases with aging indicative of reduced immune tolerance, but the mechanisms involved are poorly defined. In recent years, subsets of B cells with immunoregulatory properties have been identified in murine models of autoimmune disorders, and these cells downregulate immune responses via secretion of IL10. In humans, immature transitional B cells with a CD19(+) CD24(hi) CD38(hi) phenotype have been reported to regulate immune responses via IL10 production. We found the frequency and numbers of CD19(+) CD24(hi) CD38(hi) cells were reduced in the PBMC pool with age. IL10 expression and secretion following activation via either CD40, or Toll-like receptors was also impaired in CD19(+) CD24(hi) CD38(hi) B cells from healthy older donors. When investigating the mechanisms involved, we found that CD19(+) CD24(hi) CD38(hi) B-cell function was compromised by age-related effects on both T cells and B cells: specifically, CD40 ligand expression was lower in CD4 T cells from older donors following CD3 stimulation, and signalling through CD40 was impaired in CD19(+) CD24(hi) CD38(hi) B cells from elders as evidenced by reduced phosphorylation (Y705) and activation of STAT3. However, there was no age-associated change in expression of costimulatory molecules CD80 and CD86 on CD19(+) CD24(hi) CD38(hi) cells, suggesting IL10 dependent immune suppression is impaired, but contact-dependent suppressive capacity is intact with age. Finally, we found a negative correlation between CD19(+) CD24(hi) CD38(hi) B-cell IL10 production and autoantibody (Rheumatoid factor) levels in older adults. We therefore propose that an age-related decline in CD19(+) CD24(hi) CD38(hi) B cell number and function may contribute towards the increased autoimmunity and reduced immune tolerance seen with aging. PMID- 23755919 TI - Ligamentous influence in pelvic load distribution. AB - BACKGROUND CONTEXT: The influence of the posterior pelvic ring ligaments on pelvic stability is poorly understood. Low back pain and sacroiliac joint (SIJ) pain are described being related to these ligaments. Computational approaches involving finite element (FE) modeling may aid to determine their influence. Previous FE models lacked in precise ligament geometries and material properties, which might have influence on the results. PURPOSE AND STUDY DESIGN: The aim of this study is to investigate ligamentous influence in pelvic stability by means of FE using precise ligament material properties and morphometries. METHODS: An FE model of the pelvis bones was created from computer tomography, including the pubic symphysis joint (PSJ) and the SIJ. Ligament data were used from 55 body donors: anterior (ASL), interosseous (ISL), and posterior (PSL) sacroiliac ligaments; iliolumbar (IL), inguinal (IN), pubic (PL), sacrospinous (SS), and sacrotuberous (ST) ligaments; and obturator membrane (OM). Stress-strain data were gained from iliotibial tract specimens. A vertical load of 600 N was applied. Pelvic motion related to altered ligament and cartilage stiffness was determined in a range of 50% to 200%. Ligament strain was investigated in the standing and sitting positions. RESULTS: Tensile and compressive stresses were found at the SIJ and the PSJ. The center of sacral motion was at the level of the second sacral vertebra. At the acetabula and the PSJ, higher ligament and cartilage stiffnesses decrease pelvic motion in the following order: SIJ cartilage>ISL>ST+SS>IL+ASL+PSL. Similar effects were found for the sacrum (SIJ cartilage>ISL>IL+ASL+PSL) but increased ST+SS stiffnesses increased sacral motion. The influence of the IN, OM, and PL was less than 0.1%. Compared with standing, total ligament strain was reduced to 90%. Increased strains were found for the IL, ISL, and PSL. CONCLUSIONS: Posterior pelvic ring cartilage and ligaments significantly contribute to pelvic stability. Their effects are region- and stiffness dependent. While sitting, load concentrations occur at the IL, ISL, and PSL, which goes in coherence with the clinical findings of these ligaments serving as generators of low back pain. PMID- 23755920 TI - Quantification and minimization of uncertainties of internal target volume for stereotactic body radiation therapy of lung cancer: in regard to Ge et al. PMID- 23755921 TI - Oncogenic radiation abscopal effects in vivo: interrogating mouse skin. AB - PURPOSE: To investigate the tissue dependence in transmission of abscopal radiation signals and their oncogenic consequences in a radiosensitive mouse model and to explore the involvement of gap junction intercellular communication (GJIC) in mediating radiation tumorigenesis in off-target mouse skin. METHODS AND MATERIALS: Patched1 heterozygous (Ptch1(+/-)) mice were irradiated at postnatal day 2 (P2) with 10 Gy of x-rays. Individual lead cylinders were used to protect the anterior two-thirds of the body, whereas the hindmost part was directly exposed to radiation. To test the role of GJICs and their major constituent connexin43 (Cx43), crosses between Ptch1(+/-) and Cx43(+/-) mice were similarly irradiated. These mouse groups were monitored for their lifetime, and skin basal cell carcinomas (BCCs) were counted and recorded. Early responses to DNA damage - Double Strand Breaks (DSBs) and apoptosis - were also evaluated in shielded and directly irradiated skin areas. RESULTS: We report abscopal tumor induction in the shielded skin of Ptch1(+/-) mice after partial-body irradiation. Endpoints were induction of early nodular BCC-like tumors and macroscopic infiltrative BCCs. Abscopal tumorigenesis was significantly modulated by Cx43 status, namely, Cx43 reduction was associated with decreased levels of DNA damage and oncogenesis in out-of-field skin, suggesting a key role of GJIC in transmission of oncogenic radiation signals to unhit skin. CONCLUSIONS: Our results further characterize the nature of abscopal responses and the implications they have on pathologic processes in different tissues, including their possible underlying mechanistic bases. PMID- 23755922 TI - Epidermal growth factor receptor expression as prognostic marker in patients with anal carcinoma treated with concurrent chemoradiation therapy. AB - PURPOSE: To investigate the prognostic value of epidermal growth factor receptor (EGFR) expression in pretreatment tumor biopsy specimens of patients with anal cancer treated with concurrent 5-fluorouracil and mitomycin C-based chemoradiation therapy (CRT). METHODS AND MATERIALS: Immunohistochemical staining for EGFR was performed in pretreatment biopsy specimens of 103 patients with anal carcinoma. EGFR expression was correlated with clinical and histopathologic characteristics and with clinical endpoints, including local failure-free survival (LFFS), colostomy-free survival (CFS), distant metastases-free survival (DMFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: EGFR staining intensity was absent in 3%, weak in 23%, intermediate in 36% and intense in 38% of the patients. In univariate analysis, the level of EGFR staining was significantly correlated with CSS (absent/weak vs intermediate/intense expression: 5-year CSS, 70% vs 86%, P=.03). As a trend, this was also observed for DMFS (70% vs 86%, P=.06) and LFFS (70% vs 87%, P=.16). In multivariate analysis, N stage, tumor differentiation, and patients' sex were independent prognostic factors for CSS, whereas EGFR expression only reached borderline significance (hazard ratio 2.75; P=.08). CONCLUSION: Our results suggest that elevated levels of pretreatment EGFR expression could be correlated with favorable clinical outcome in anal cancer patients treated with CRT. Further studies are warranted to elucidate how EGFR is involved in the response to CRT. PMID- 23755923 TI - Prognostic utility of cell cycle progression score in men with prostate cancer after primary external beam radiation therapy. AB - PURPOSE: To evaluate the prognostic utility of the cell cycle progression (CCP) score, a RNA signature based on the average expression level of 31 CCP genes, for predicting biochemical recurrence (BCR) in men with prostate cancer treated with external beam radiation therapy (EBRT) as their primary curative therapy. METHODS AND MATERIALS: The CCP score was derived retrospectively from diagnostic biopsy specimens of men diagnosed with prostate cancer from 1991 to 2006 (n=141). All patients were treated with definitive EBRT; approximately half of the cohort was African American. Outcome was time from EBRT to BCR using the Phoenix definition. Median follow-up for patients without BCR was 4.8 years. Association with outcome was evaluated by Cox proportional hazards survival analysis and likelihood ratio tests. RESULTS: Of 141 patients, 19 (13%) had BCR. The median CCP score for patient samples was 0.12. In univariable analysis, CCP score significantly predicted BCR (P=.0017). The hazard ratio for BCR was 2.55 for 1-unit increase in CCP score (equivalent to a doubling of gene expression). In a multivariable analysis that included Gleason score, prostate-specific antigen, percent positive cores, and androgen deprivation therapy, the hazard ratio for CCP changed only marginally and remained significant (P=.034), indicating that CCP provides prognostic information that is not provided by standard clinical parameters. With 10-year censoring, the CCP score was associated with prostate cancer-specific mortality (P=.013). There was no evidence for interaction between CCP and any clinical variable, including ethnicity. CONCLUSIONS: Among men treated with EBRT, the CCP score significantly predicted outcome and provided greater prognostic information than was available with clinical parameters. If validated in a larger cohort, CCP score could identify high-risk men undergoing EBRT who may need more aggressive therapy. PMID- 23755924 TI - Results of a 5-week schedule of modern total skin electron beam radiation therapy. AB - PURPOSE: To report the outcomes of a 5-week schedule of total skin electron beam radiation therapy (TSEB) for mycosis fungoides (MF). METHODS: Over 5 years, 41 patients with confirmed MF were treated with a modern TSEB technique delivering 30 Gy in 20 fractions over 5 weeks to the whole skin surface. Data were collected prospectively and entered into the skin tumor unit research database. Skin modified skin weighted assessment tool score data were collected to determine response, duration of response, survival, and toxicity. The outcomes were analyzed according to the patient's stage before TSEB, prognostic factors, and adjuvant treatments. RESULTS: Seventeen patients were stage 1B, 19 were stage IIB, 3 were stage III, and 2 were stage IV. The overall response rate was 95%, with a complete response rate of 51%. Seventy-six percent of patients had relapsed at median follow-up of 18 months. The median time to relapse was 12 months, to systemic therapy was 15 months, and to modified skin weighted assessment tool progression above baseline was 44 months. The complete response rate was 59% in stage IB and 47% in stage IIB patients. The median time to skin relapse was longer in stage IB compared with stage IIB, 18 months versus 9 months. The median time to systemic therapy was longer in stage IB compared with stage IIB, >56 months versus 8 months. The median overall survival was 35 months: >56 months for stage IB, 25 months for stage IIB, 46 months for stage III, and 23.5 months for stage IV. Fifteen patients received adjuvant psoralen + ultraviolet A treatment with no difference seen in the time to relapse. CONCLUSIONS: This 5-week schedule of TSEB for MF has a high response rate with comparable duration of response to other regimens. Future studies are needed to find adjuvant and combination treatments to improve the duration of response. PMID- 23755925 TI - Discordance of KRAS mutational status in a single colonic resection specimen in a patient with colorectal cancer: a case report and review of the literature. PMID- 23755926 TI - Couplers in arterial and venous repairs. PMID- 23755927 TI - The art and science of photography in hand surgery. AB - High-quality medical photography plays an important role in teaching and demonstrating the functional capacity of the hands as well as in medicolegal documentation. Obtaining standardized, high-quality photographs is now an essential component of many surgery practices. The importance of standardized photography in facial and cosmetic surgery has been well documented in previous studies, but no studies have thoroughly addressed the details of photography for hand surgery. In this paper, we provide a set of guidelines and basic camera concepts for different scenarios to help hand surgeons obtain appropriate and informative high-quality photographs. A camera used for medical photography should come equipped with a large sensor size and an optical zoom lens with a focal length ranging anywhere from 14 to 75 mm. In a clinic or office setting, we recommend 6 standardized views of the hand and 4 views for the wrist; additional views should be taken for tendon ruptures, nerve injuries, or other deformities of the hand. For intraoperative pictures, the camera operator should understand the procedure and pertinent anatomy in order to properly obtain high-quality photographs. When digital radiographs are not available and radiographic film must be photographed, it is recommended to reduce the exposure and change the color mode to black and white to obtain the best possible pictures. The goal of medical photography is to present the subject in an accurate and precise fashion. PMID- 23755928 TI - A MAOA gene*cocaine severity interaction on impulsivity and neuropsychological measures of orbitofrontal dysfunction: preliminary results. AB - BACKGROUND: Based on previous evidence of a MAOA gene*cocaine use interaction on orbitofrontal cortex volume attrition, we tested whether the MAOA low activity variant and cocaine use severity are interactively associated with impulsivity and behavioral indices of orbitofrontal dysfunction: emotion recognition and decision-making. METHODS: 72 cocaine dependent individuals and 52 non-drug using controls (including healthy individuals and problem gamblers) were genotyped for the MAOA gene and tested using the UPPS-P Impulsive Behavior Scale, the Iowa Gambling Task and the Ekman's Facial Emotions Recognition Test. To test the main hypothesis, we conducted hierarchical multiple regression analyses including three sets of predictors: (1) age, (2) MAOA genotype and severity of cocaine use, and (3) the interaction between MAOA genotype and severity of cocaine use. UPPS P, Ekman Test and Iowa Gambling Task's scores were the outcome measures. We computed the statistical significance of the prediction change yielded by each consecutive set, with 'a priori' interest in the MAOA*cocaine severity interaction. RESULTS: We found significant effects of the MAOA gene*cocaine use severity interaction on the emotion recognition scores and the UPPS-P's dimensions of Positive Urgency and Sensation Seeking: Low activity carriers with higher cocaine exposure had poorer emotion recognition and higher Positive Urgency and Sensation Seeking. CONCLUSION: Cocaine users carrying the MAOA low activity show a greater impact of cocaine use on impulsivity and behavioral measures of orbitofrontal cortex dysfunction. PMID- 23755929 TI - Efficacy of extended-release tramadol for treatment of prescription opioid withdrawal: a two-phase randomized controlled trial. AB - BACKGROUND: Tramadol is an atypical analgesic with monoamine and modest mu opioid agonist activity. The purpose of this study was to evaluate: (1) the efficacy of extended-release (ER) tramadol in treating prescription opioid withdrawal and (2) whether cessation of ER tramadol produces opioid withdrawal. METHODS: Prescription opioid users with current opioid dependence and observed withdrawal participated in this inpatient, two-phase double blind, randomized placebo controlled trial. In Phase 1 (days 1-7), participants were randomly assigned to matched oral placebo or ER tramadol (200 or 600 mg daily). In Phase 2 (days 8 13), all participants underwent double blind crossover to placebo. Breakthrough withdrawal medications were available for all subjects. Enrollment continued until 12 completers/group was achieved. RESULTS: Use of breakthrough withdrawal medication differed significantly (p<0.05) among groups in both phases; the 200mg group received the least amount in Phase 1, and the 600 mg group received the most in both phases. In Phase 1, tramadol 200mg produced significantly lower peak ratings than placebo on ratings of insomnia, lacrimation, muscular tension, and sneezing. Only tramadol 600 mg produced miosis in Phase 1. In Phase 2, tramadol 600 mg produced higher peak ratings of rhinorrhea, irritable, depressed, heavy/sluggish, and hot/cold flashes than placebo. There were no serious adverse events and no signal of abuse liability for tramadol. CONCLUSIONS: ER tramadol 200mg modestly attenuated opioid withdrawal. Mild opioid withdrawal occurred after cessation of treatment with 600 mg tramadol. These data support the continued investigation of tramadol as a treatment for opioid withdrawal. PMID- 23755931 TI - What happened to our technical component? PMID- 23755930 TI - Gender differences in the relationship between gambling problems and the incidence of substance-use disorders in a nationally representative population sample. AB - BACKGROUND: Cross-sectional studies have demonstrated gender-related differences in the associations between problem-gambling severity and substance-use disorders; however, these associations have not been examined longitudinally. We aimed to examine the prospective associations between problem-gambling severity and incident substance-use disorders in women versus men. METHODS: Analyses were conducted using Wave-1 and Wave-2 NESARC data focusing on psychiatric diagnoses from 34,006 non-institutionalized US adults. Inclusionary criteria for pathological gambling were used to categorize Wave-1 participants as at risk/problem gambling (ARPG) and non-ARPG (i.e. non-gambling/low-frequency gambling/low-risk gambling). Dependent variables included the three-year incidence of any substance-use disorder, alcohol-use disorders, nicotine dependence, drug-use disorders, prescription drug-use disorders, and illicit drug use disorders. RESULTS: Significant gender-by-ARPG status interactions were observed with respect to the three-year incidence of nicotine dependence and prescription drug-use disorders, and approached significance with respect to incident alcohol-use disorders. ARPG (relative to non-ARPG) was positively associated with nicotine dependence among women (OR=2.00; 95% CI=1.24-3.00). ARPG was negatively associated with incident prescription drug-use disorders among men (OR=0.30; 95% CI=0.10-0.88)). Finally, ARPG was positively associated with incident alcohol-use disorders among men (OR=2.20; 95% CI=1.39-3.48). CONCLUSIONS: Gambling problems were associated with an increased 3-year incidence of nicotine dependence in women and alcohol dependence in men. These findings highlight the importance of considering gender in prevention and treatment initiatives for adults who are experiencing gambling problems. Moreover, the specific factors underlying the differential progressions of specific substance use disorders in women and men with ARPG warrant identification. PMID- 23755932 TI - Survival of transferred ileum after ischemia time longer than 1 hour: a clinical result different from animal studies. AB - BACKGROUND: The aim of this study was to identify the ischemic tolerance of the ileum. In microvascular transfer of autologous bowel segments, the most critical factor for survival is ischemic time. In earlier animal studies, the tolerance of ischemic time was shorter for the ileum than for the jejunum, and an ischemic time of <1 hour was suggested for microvascular transfer of the ileum. It was believed that there are more bacteria in the ileum than in the jejunum and therefore autolysis and necrosis will be triggered sooner after the initiation of ischemia. However, in a clinical scenario, the tolerance for ischemic time of the ileum has not yet been clarified. STUDY DESIGN: From 1998 to 2011, eight-four cases of microvascular transfer of intestine containing a segment of the ileum were reviewed. Data collected included the ischemia time during surgery, re exploration, survival, complications, and postoperative functions. Multivariate analysis with exact logistic regression was used to identify the correlation between the ischemic time and necrosis of the transferred segment, as well as other complications. RESULTS: For segmental ileum transfer, the ischemic time >1 hour (but within 2 hours) at room temperature is not a risk factor for flap loss or complications. This contradicts data from animal studies in the literature. CONCLUSIONS: Clinically, the ileum segments can tolerate ischemia well within 2 hours. Segmental ileum transfer can be more widely applied in other fields. Care in each step of transfer is mandatory for functional success. PMID- 23755933 TI - Response to "patients with obstructive sleep apnea after laparoscopic bariatric surgery: oxygen and continuous positive pressure could always be enough?". PMID- 23755934 TI - Japanese encephalitis virus non-coding RNA inhibits activation of interferon by blocking nuclear translocation of interferon regulatory factor 3. AB - Noncoding RNA (ncRNA) plays a critical role in modulating a broad range of diseases. All arthropod-borne flaviviruses produce short fragment ncRNA (sfRNA) collinear with highly conserved regions of the 3'-untranslated region (UTR) in the viral genome. We show that the molar ratio of sfRNA to genomic RNA in Japanese encephalitis virus (JEV) persistently infected cells is greater than that in acutely infected cells, indicating an sfRNA role in establishing persistent infection. Transfecting excess quantities of sfRNA into JEV-infected cells reduced interferon-beta (IFN-beta) promoter activity by 57% and IFN-beta mRNA levels by 52%, compared to mock-transfected cells. Transfection of sfRNA into JEV-infected cells also reduced phosphorylation of interferon regulatory factor-3 (IRF-3), the IFN-beta upstream regulator, and blocked roughly 30% of IRF 3 nuclear localization. Furthermore, JEV-infected sfRNA transfected cells produced 23% less IFN-beta-stimulated apoptosis than mock-transfected groups did. Taken together, these results suggest that sfRNA plays a role against host-cell antiviral responses, prevents cells from undergoing apoptosis, and thus contributes to viral persistence. PMID- 23755935 TI - Effects of Tinospora cordifolia supplementation on semen quality and hormonal profile in rams. AB - The present study was undertaken to assess the effect of dietary supplementation of Tinospora cordifolia on physico-morphological, biochemical, antioxidant profiles and serum testosterone concentration in Muzzafarnagari rams. Twelve rams were randomly divided into two groups, control (n=6) and supplemental (n=6) group. The control group was fed with a diet satisfying NRC recommendations whereas the supplemental group was fed with T. cordifolia at the rate of 1g/kg body weight for 6 months. The semen samples were collected 60 days post-feeding. The result revealed that T. cordifolia supplementation did not have a significant effect on physico-morphological, biochemical attributes of semen and serum testosterone concentrations in rams. The concentration of cholesterol, superoxide dismutase (SOD) and catalase were, however, increased (P<0.05) in seminal plasma. It was concluded that the possible protective effects of T. cordifolia supplementation were enhancing antioxidant enzymes and cholesterol concentrations in semen which may be protected the spermatozoa during cryopreservation and thus enhancing fertility in farm animals. PMID- 23755936 TI - How do different concentrations of Clostridium perfringens affect the quality of extended boar spermatozoa? AB - Bacteriospermia in boar fresh and extended semen is a frequent finding that produces alterations on sperm quality and, consequently, causes economic losses in artificial insemination (AI) centres. The present study sought to evaluate the effect of different infective concentrations of Clostridium perfringens on boar sperm quality, assessed as sperm motility (CASA), morphology and viability, through 11 days of storage at 15 degrees C (experiment 1), and after 96h of incubation at 37 degrees C (experiment 2). With this purpose, different seminal doses were artificially inoculated with different infective concentrations of C. perfringens, ranging from 10(2) to 10(8)cfumL(-1). The negative controls were non inoculated doses. Sperm quality was checked after 0, 1, 2, 3, 4, 7, 8, 9, 10 and 11 days of storage at 15 degrees C in experiment 1, and after 0, 24, 48, 72 and 96h at 37 degrees C in the second experiment. Moreover, the presence/absence of bacteria was detected by PCR analyses during both experiments at different time points. In both experiments, sperm morphology of inoculated samples did not differ from the negative control. Conversely, detrimental effects on sperm viability and motility were observed after 24h of incubation/storage at the highest infective concentrations in both experiments. The deleterious effects observed because of the presence of C. perfringens in semen emphasise the relevance of detecting bacteria in extended doses destined to AI. So, this study suggests that the evaluation of bacterial contamination in semen is a procedure that should be routinely applied while assessing sperm quality in AI centres to avoid the use of doses with low sperm quality and the possible spread of bacterial contaminants. PMID- 23755937 TI - Venous sinus volume in the caudal cranial fossa in Cavalier King Charles spaniels with syringomyelia. AB - Syringomyelia (SM) in Cavalier King Charles spaniels (CKCS) has a complex pathophysiology. Recent studies support a relationship between altered venous drainage and cerebrospinal fluid flow dynamics. The aim of this study was to evaluate the relationship between venous sinus and parenchymal volume within the caudal cranial fossa (CCF) in CKCS with SM (n=22) and without SM (n=12) using magnetic resonance venography (MRV). MRI and MRV images were used to obtain volumetric calculations of CCF volume, as well as the percentage of this volume occupied by parenchyma (CCFP%) and venous sinuses (CCFV%). In CKCS with SM, CCFP% was significantly higher (P<0.001), whilst CCFV% was significantly lower (P=0.001) than in CKCS without SM. These results support a role for reduced venous drainage and parenchymal 'overcrowding' of the CCF in the pathophysiology of SM. PMID- 23755938 TI - Elaborating the phenotypic spectrum associated with mutations in ARFGEF2: case study and literature review. AB - BACKGROUND: The BIG2 protein, coded by ARFGEF2 indirectly assists neuronal proliferation and migration during cortical development. Mutations in ARFGEF2 have been reported as a rare cause of periventricular heterotopia. METHODS: The presence of periventricular heterotopia, acquired microcephaly and suspected recessive inheritance led to mutation analysis of ARFGEF2 in two affected siblings and their healthy consanguineous parents, after mutations in FLNA had been ruled out. RESULTS: A homozygous c.242_249delins7 (p.Pro81fs) mutation in exon 3 of ARFGEF2 was identified in the siblings. The alteration is a combination of 2 missense mutations (c.242C > A and c.247G > T) and a frameshift mutation (c.249delA) resulting in a premature stop codon. The clinical phenotype was characterized by dystonic quadriplegia, marked developmental delay, obstructive cardiomyopathy, recurrent infections and feeding difficulties. Degenerative features included early regression, acquired microcephaly and cerebral atrophy. Brain MRI revealed bilateral periventricular heterotopia, small corpus callosum, cerebral and hippocampal atrophy and hyperintensity in the putamen. CONCLUSION: Mutations in ARFGEF2 can be anticipated based on characteristic clinical and imaging features. PMID- 23755939 TI - Lower limb functioning and its impact on quality of life in ambulatory children with cerebral palsy. AB - BACKGROUND: Children with cerebral palsy (CP) are confronted on a daily basis with their motor problems affecting gait, which might impact on their quality of life (QOL). AIM: The goal of this study was to evaluate the impact of gross motor and gait function on QOL in ambulatory children with CP attending regular school. METHODS: A condition-specific questionnaire (CP QOL-Child), including a parent/proxy and child self-report, was used to assess the relation between patient characteristics, lower limb impairments and functioning, and the different aspects of the child's QOL. Data on therapy management, lower limb impairments, and gross motor and gait function was collected for 81 children with CP (10.5 +/- 3.0 years). CP QOL-Child questionnaires were completed by a parent/proxy for all 81 children and by 39 of the children over 9 years. RESULTS: The mean self-reported QOL score (78.2 +/- 9.6) was significantly higher than the mean parent/proxy reported score (73.9 +/- 10.2). Lower limb spasticity and higher frequency of BTX-A injections correlated with worse scores for the pain and impact of disability domain. Results further showed the adverse impact of the severity of gait pathology on QOL perception for the parents/proxy and the child self-report. Gait speed was an important factor for the parents/proxy, though correlated less with self-perceived QOL for the children. CONCLUSIONS: Children and parents identified similar factors that adversely affect QOL, whereby the amount of gait pathology was shown to play a crucial role. Only gait speed seemed to be of higher importance for the parents compared to the children. PMID- 23755940 TI - Improving lives using multidisciplinary education: partnering to benefit community, innovation, health, and technology. AB - University students are trained in specific disciplines, which can benefit disabled individuals in a variety of ways, including education, health promotion, assistive technologies, logistics, or design improvement. However, collaboration with other disciplines can have a greater impact on improving the health of disabled individuals than can training in one discipline alone. The University of Detroit Mercy Colleges of Engineering and Nursing have partnered to develop and provide assistive devices to disabled individuals while teaching innovation, technology, and collaboration to students. After 4 years of developing and implementing our multidisciplinary program, numerous unique and helpful assistive devices have been designed, created, and delivered to individuals in our community. More nursing schools should initiate multidisciplinary programs to train and prepare students for workplaces where such innovative, collaborative skills are increasingly sought. Nurses need to be at the forefront of such collaborative work. PMID- 23755941 TI - Thinking inside the box: the tele-intensive care unit as a new clinical site. AB - The tele-intensive care unit (ICU) offers students an opportunity to observe the decision-making process of nurses working in consultative teams in a high-acuity environment, providing a unique opportunity for novices to "see" into the thinking and the communication of expert nurses. Students are often overwhelmed by the physical environment of an ICU--specifically, its noise, technology, and pace--and often are relegated to the sidelines when a patient becomes unstable. Clinical education in the tele-ICU allows students to participate safely in the care of complex, unstable patients. Nurse educators, as experienced tele-ICU nurses, can help students to process complex information and can model intradisciplinary and interdisciplinary communication about patient concerns. The experience moves the students from engagement in tasks and a linear process of thinking to engagement in decision making and a more complex understanding of the nurse's role in patient care. PMID- 23755942 TI - Virtual worlds in nursing education: a synthesis of the literature. AB - Although the literature has highlighted the use of virtual worlds in teaching learning, little is known about the concepts associated with this technology in nursing education. Moreover, the application of virtual worlds to education has been underdeveloped theoretically, with much of the work being exploratory. Thus, the aim of this integrative review was to identify the current evidence on the use of virtual worlds in the education of nursing and other health professional students and to describe emerging themes surrounding this phenomenon. We searched seven electronic databases for relevant articles and used Whittemore's and Knafl's integrative review method to synthesize the literature. Twelve articles met the selection criteria for this review, from which three overarching themes emerged: (a) critical reasoning skills, (b) student-centered learning, and (c) instructional design considerations. This integrative review extends our understanding of virtual worlds in nursing education and the potential barriers and facilitators of their use. PMID- 23755943 TI - [Interests of advanced systematic evaluation of dialysis session]. AB - In order to rationalize the cost of care for dialysis patients in Centre, regulatory authorities urge establishments to favor the orientation of the patients in Medical Dialysis Unit where the medical presence is not permanent. This involves clinical skills for nurses in the conduct of the dialysis session. Faced with this changing work patterns, we present two security tools of the dialysis session. The first is a "check-list", simple, quick and easy to use, it enables secure connection phase of the patient. It was quickly integrated practice of all professionals. The second tool developed is a combination of indicators "DEAUP" for Pain, Purification, Blood access, Ultrafiltration and other Problems for assessing the quality of the course of the dialysis session. The aim is to reduce the occurrence of adverse events, the DEAUP rating certain criteria depending on the occurrence of incidents, from 0 to 2, 2 corresponding to the appearance of an incident having required the call of the doctor and constitute a precious tool of evaluation of the session for all the professionals. All nurses have joined the practice of evaluation, 98% of the realized sessions are informed and quoted; 8.4% of sessions required call nephrologists before or at the connection. The evaluation at the end of dialysis session found 15% of the sessions listed 2. Calls have resulted in an adjustment to the prescription of the sessions. PMID- 23755944 TI - [Satisfaction and quality of life evaluation in patients with type 1 diabetes mellitus treated using continuous subcutaneous insulin infusion compared with multiple daily injections]. AB - OBJECTIVE: To assess the quality of life (QOL) and satisfaction (SF) in patients with type 1 diabetes mellitus (T1DM) treated with continuous subcutaneous insulin infusion (CSII) compared with multiple daily insulin injections (MDI). METHOD: A descriptive study was conducted to assess the QOL and SF of 68 patients on CSII or MDI treatment (1:2). The instruments used were, the Spanish version of the Diabetes Quality of Life (EsDQOL) specific for diabetes related QOL, SF-36 for general QOL, and the Diabetes Treatment Satisfaction Questionnaire (DTSQ) for SF evaluation. RESULTS: The EsDQOL scores for patients on CSII therapy were similar to those treated with MDI (87.20+/-21.11 vs 86.83+/-20.7, P=.86), with lower scores in the SF-36 questionnaire (66.91+/-15.76 vs 75.90+/-14.56, P=.03) except in Health Transition section, where patients treated with CSII showed higher scores (68.75+/-19.66 vs 57.93+/-17.18, p=.02). The values obtained in the DTSQ questionnaire were higher in CSII patients compared with the MDI group in last weeks (31.50+/-4.66 vs 27.83+/-6.06, p=.01) and last three months periods (13.2+/ 6.73 vs 8.77+/-7.40, p=.01). CONCLUSIONS: Patients with T1DM on CSII therapy showed a poorer global QOL, although they felt more satisfied with their treatment than those treated with MDI. No differences in diabetes related QOL were detected between groups. PMID- 23755945 TI - [Prevalence of extrapyramidal effects by neuroleptics in admitted people with schizophrenia]. AB - OBJECTIVE: The aim of the study was to detect and determine the prevalence of extrapyramidal effects (akathisia, parkinsonism and tardive dyskinesias) in admitted people with schizophrenia who have been treated with typical and atypical neuroleptics. METHOD: Descriptive and cross-sectional study on Zaldibar's Hospital, with a sample of 28 admitted persons over 18 years diagnosed with schizophrenia, treated with typical and atypical neuroleptics for a period longer than 6 months. The variables studied were sex, age, treatment with neuroleptics, treatment duration and extrapyramidal effects (akathisia, parkinsonism and tardive dyskinesias). To measure extrapyramidal effects were used: the Simpson-Angus Scale for parkinsonism, the Barnes Scale for akathisia and Abnormal Involuntary Movement Scale for tardive dyskinesias. RESULTS: In the study the 21.4% of patients had extrapyramidal effects (akathisia, parkinsonism and tardive dyskinesias). Depending on the type of extrapyramidal effects 14.3% of patients had parkinsonism, 7.1% of patients had akathisia and 3.6% of patients had tardive dyskinesias. CONCLUSIONS: The clinical assessment of adverse effects is an important aspect. Encourage the use of specific assessment scales for these adverse effects may be useful as a guarantee of the quality of care and improved patient safety. Nurses have an important role in the assessment of adverse effects. PMID- 23755946 TI - Botulism with Unusual Rapid Progression to Complete Paralysis in a Child. AB - Botulism is a severe neuroparalytic illness which is difficult to diagnose accurately, especially in children. We report a child with type A botulism intoxication, with very rapid progression to coma-like consciousness and respiratory failure. Careful physical examinations led to the suspicion of botulism, and electrophysiologic examinations, including electroencephalogram and repetitive nerve stimulation tests, further supported the diagnosis. Hospitalization due to botulism had a great emotional impact on the patient and psychological support was crucial. PMID- 23755947 TI - Poincare plot indexes of heart rate variability: relationships with other nonlinear variables. AB - The Poincare plot for heart rate variability analysis is a technique considered geometrical and non-linear, that can be used to assess the dynamics of heart rate variability by a representation of the values of each pair of R-R intervals into a simplified phase space that describes the system's evolution. The aim of the present study was to verify if there is some correlation between SD1, SD2 and SD1/SD2 ratio and heart rate variability nonlinear indexes either in disease or healthy conditions. 114 patients with arterial coronary disease and 65 healthy subjects underwent 30 minute heart rate registration, in supine position and the analyzed indexes were as follows: SD1, SD2, SD1/SD2, Sample Entropy, Lyapunov Exponent, Hurst Exponent, Correlation Dimension, Detrended Fluctuation Analysis, SDNN, RMSSD, LF, HF and LF/HF ratio. Correlation coefficients between SD1, SD2 and SD1/SD2 indexes and the other variables were tested by the Spearman rank correlation test and a regression analysis. We verified high correlation between SD1/SD2 index and HE and DFA (alpha1) in both groups, suggesting that this ratio can be used as a surrogate variable. PMID- 23755949 TI - Histone deacetylase inhibitors down-regulate G-protein-coupled estrogen receptor and the GPER-antagonist G-15 inhibits proliferation in endometriotic cells. AB - OBJECTIVE: To investigate whether histone deacetylase inhibitors reduce the expression of the G-protein-coupled estrogen receptor (GPER) and whether the functional inhibition of GPER by the antagonist G-15 decreases the proliferation of endometriotic cells. DESIGN: In vitro study. SETTING: University hospital. PATIENT(S): Immortalized epithelial endometriotic cells. INTERVENTION(S): Treatment with the histone deacetylase inhibitor romidepsin or suberoylanilide hydroxamic acid (SAHA), or with the GPER antagonist G-15. MAIN OUTCOME MEASURE(S): Western blot analysis and quantitative real-time polymerase chain reaction (PCR) were used to monitor the expression of GPER in response to drug treatment. Effects of GPER stimulation and inhibition on cell proliferation were investigated by the 93-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (Sigma) (MTT) assay. RESULT(S): Our results demonstrate that romidepsin and SAHA reduce GPER expression in a concentration-dependent manner. This reduction correlated with the accumulation of acetylated histones. No decreased expression of the estrogen receptor (ER)-alpha and ERbeta was found under comparable experimental conditions. Pretreatment of endometriotic cells with the GPER agonist G-1 stimulated cell proliferation accompanied by rapid Akt phosphorylation. G-15 reversed this stimulation and inhibited cell proliferation, which was accompanied by Akt dephosphorylation. CONCLUSION(S): G-protein-coupled estrogen receptor is proposed as a potential therapeutic target in endometriosis. The down-regulation of GPER and/or the impairment of its function may reduce the estrogen responsiveness in endometriosis, and therefore might be considered a possible treatment option of endometriosis. PMID- 23755948 TI - Adipokines, adiposity, and vasomotor symptoms during the menopause transition: findings from the Study of Women's Health Across the Nation. AB - OBJECTIVE: To test relationships between adipokines, adiposity, and vasomotor symptoms (VMS), including how these associations vary by menopause stage. DESIGN: A subcohort of the longitudinal cohort Study of Women's Health Across the Nation completed questionnaires, physical measures, and a fasting blood draw annually for 8 years. Associations between a poorer adipokine profile (lower adiponectin, lower high-molecular-weight [HMW] adiponectin, higher leptin, lower soluble leptin receptor, higher monocyte chemoattractant protein 1 [MCP-1]) and VMS were tested with the use of generalized estimating equations adjusting for potential confounders. Interactions by menopause stage (pre-/early perimenopause, late peri /postmenopause) were tested. SETTING: Community. PATIENT(S): A total of 536 women ages 42-52 at baseline. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S) VMS RESULT(S): Associations between adipokines and hot flashes varied by menopause stage, with a poorer adipokine profile associated with higher odds of hot flashes early in the transition (adiponectin(log): odds ratio [OR] 0.68, 95% confidence interval [CI] 0.51-0.90; HMW adiponectin(log): OR 0.70, 95% CI 0.58-0.85; leptin(log): OR 1.23, 95% CI 0.99-1.54; multivariable models including body mass index [BMI]), but not later in the transition. The direction of associations between BMI and VMS also varied by menopausal stage. Higher MCP-1 was associated with more night sweats (OR 1.37, 95% CI 1.06-1.76) across menopausal stages. CONCLUSION(S): An adverse adipokine profile was associated with more VMS, particularly early in the menopause transition. PMID- 23755950 TI - Endometrial integrin expression in women with recurrent implantation failure after in vitro fertilization and its relationship to pregnancy outcome. AB - OBJECTIVE: To determine expression of integrins alpha1, alpha4, and alphaVbeta3 in the glandular and luminal epithelium, stroma, and cells in the blood vessel walls of the endometrium from women with recurrent implantation failure (RIF) and to determine if they are of prognostic value in determining pregnancy outcome. DESIGN: Prospective nonrandomized study. SETTING: Department of reproductive medicine. PATIENT(S): Forty-five women with RIF and six healthy fertile women were recruited. RIF was defined as the failure to conceive after the transfer of four good-quality embryos in three or more fresh or frozen cycles. INTERVENTION(S): Endometrial biopsy samples were obtained from women with RIF and control women on days LH+7-LH+9 of the cycle. Expression of integrins alpha1, alpha4, and alphaVbeta3 was determined by immunohistochemistry. MAIN OUTCOME MEASURE(S): A semiquantitative measurement of expression of each integrin protein in the luminal and glandular epithelium, stroma, and cells in the blood vessel walls was determined by H-score analysis. RESULT(S): Expression of integrins alpha1 and alpha4 was greatest in the luminal and glandular epithelial cells and the cells in the blood vessel wall, and significantly higher expression of integrins alpha1 and alpha4 was seen in the glandular epithelium compared with the luminal epithelium (H-scores: alpha1 293 +/- 15 and 180 +/- 12, alpha4 287 +/ 14 and 191 +/- 11, respectively). Expression of alphaVbeta3 in the epithelium and blood vessels was also greater than in the stroma but there was no significant difference in expression of alphaVbeta3 in glandular and luminal epithelium. No significant difference in H-scores was seen for alpha1, alpha4, and alphaVbeta3 expression in any of the endometrial compartments in tissue from women with RIF and control women. No significant difference in alpha1, alpha4, and alphaVbeta3 expression in any compartment was observed between those who achieved a clinical pregnancy after subsequent assisted conception treatment (n = 21) and those who were unsuccessful (n = 24). CONCLUSION(S): RIF, when defined as failure to achieve a clinical pregnancy after the transfer of at least four good quality embryos in three transfer cycles, is not associated with abnormal endometrial integrin expression. In addition, the expression of integrins alpha1, alpha4, and alphaVbeta3 appears to have no prognostic value in subsequent IVF treatment. PMID- 23755951 TI - Reduced hemopexin levels in peritoneal fluid of patients with endometriosis. AB - OBJECTIVE: To study altered hemopexin concentrations in peritoneal fluid (PF) samples from patients with endometriosis. Recent data implicate a role of altered iron metabolism in endometriosis patients. Hemopexin is the major transport protein for heme. Like iron, heme exposure to the epithelial surface can provoke oxidative stress on the peritoneal epithelium. Therefore, altered hemopexin concentrations and heme scavenging in PF might play a role in the pathophysiology of endometriosis. DESIGN: Prospective explorative study. SETTING: Academic tertiary care center. PATIENT(S): Eighty symptomatic patients scheduled for laparoscopy for the diagnosis and/or therapy of endometriosis. INTERVENTION(S): Aspiration of PF samples during laparoscopy. MAIN OUTCOME MEASURE(S): Hemopexin and heme concentration in PF. RESULT(S): At laparoscopy, 47 of 80 (58.8%) patients exhibited endometriosis, and 33 (41.2%) were proven disease-free (CO). By means of ELISA significantly lower concentrations of hemopexin in the samples from patients with endometriosis (endometriosis 0.377 +/- 0.16 mg/mL) compared with controls (disease-free 0.479 +/- 0.20 mg/mL) could be demonstrated. Heme levels in the samples were not significantly different between groups (endometriosis 9.130 +/- 6.124 MUM and disease-free 9.990 +/- 4.485 MUM). There was no significant correlation between heme and hemopexin levels (Pearson's correlation coefficient r = -0.146). Demographic data between the groups were comparable. CONCLUSION(S): These data provide further evidence that hemopexin is significantly down-regulated in PF samples from patients with endometriosis compared with controls. This study confirms recent findings in two-dimensional gel electrophoresis demonstrating a down-regulation of hemopexin in PF from patients with endometriosis in a larger series of samples. PMID- 23755952 TI - Antimullerian hormone as predictor of reproductive outcome in subfertile women with elevated basal follicle-stimulating hormone levels: a follow-up study. AB - OBJECTIVE: To investigate the role of serum antimullerian hormone (AMH) as a predictor of live birth and reproductive stage in subfertile women with elevated basal FSH levels. DESIGN: A prospective observational cohort study conducted between February 2005 and June 2009. SETTING: Tertiary fertility center. PATIENT(S): Subfertile women with [1] a regular menstrual cycle (mean cycle length 25-35 days); [2] basal FSH concentrations >=12.3 IU/L; and [3] younger than 40 years (n = 96). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth and reproductive stage according to the Stages of Reproductive Aging Workshop. RESULT(S): A cumulative live birth rate of 63.5% was observed during a median follow-up of 3.3 years (n = 85). The AMH level was significantly associated with live birth. There was evidence of a nonlinear prediction pattern, with an increase in chances of live birth until an AMH level of 1 MUg/L. Other ovarian reserve tests and chronological age appeared of limited value in predicting live birth. In addition, AMH was significantly associated with the timing of reproductive stages (n = 68) (i.e., the occurrence of menopausal transition or menopause during follow-up). CONCLUSION(S): The present findings suggest applicability of AMH determination as a marker for actual fertility in subfertile women with elevated basal FSH levels. PMID- 23755953 TI - Impact of chemotherapy and radiotherapy for testicular germ cell tumors on spermatogenesis and sperm DNA: a multicenter prospective study from the CECOS network. AB - OBJECTIVE: To determine the consequences of adjuvant testicular germ cell tumor treatment (TGCT) on sperm characteristics and sperm DNA, and to evaluate the predictors of sperm recovery. DESIGN: Multicenter prospective longitudinal study of patients analyzed before treatment and after 3, 6, 12, and 24 months. SETTING: University hospitals. PATIENT(S): One hundred twenty-nine volunteer TGCT patients and a control group of 257 fertile men. INTERVENTION(S): Routine semen analyses, sperm DNA, and chromatin assessments. MAIN OUTCOME MEASURE(S): Comparisons of mean sperm characteristics before and after treatment, with sperm recovery analyzed by the Kaplan-Meier method. RESULT(S): The quantitative and qualitative sperm characteristics decreased after treatment, with lowest values at 3 and 6 months and with variations according to treatment type. The mean total sperm count recovered to pretreatment values at 12 months after treatment after two or fewer bleomycin, etoposide, and cisplatin (BEP) cycles, but not after radiotherapy or more than two BEP cycles. Only the treatment modalities and pretreatment sperm production were related to recovery of the World Health Organization reference sperm values. An increased proportion of patients had elevated high sperm DNA stainability at 6 months after radiotherapy. CONCLUSION(S): Adjuvant treatments for testicular germ cell tumor have drastic effects on spermatogenesis and sperm chromatin quality. These new data on both the recovery period according to treatment modalities and the post-treatment chromatin status of sperm are useful tools for counseling patients wishing to conceive. PMID- 23755954 TI - Bed rest after embryo transfer negatively affects in vitro fertilization: a randomized controlled clinical trial. AB - OBJECTIVE: To evaluate the influence of 10 minutes of bed rest after ET on the achievement of a live-born infant (LBI) in patients undergoing IVF treatment with oocyte donation (OD). DESIGN: Prospective, randomized, parallel assignment, controlled trial. SETTING: Private IVF center. PATIENT(S): A total of 240 patients undergoing a first IVF cycle with OD in our center. INTERVENTION(S): Ten minutes of bed rest after ET or no bed rest, that is, allowing patients to ambulate immediately after the ET. MAIN OUTCOME MEASURE(S): The primary outcome was LBI rate per randomized patient. Secondary outcomes were implantation rate and biochemical and clinical miscarriage rates. RESULT(S): LBI rates (56.7% vs. 41.6%) were observed to be significantly higher in the no rest (NR) group than in the rest (R) group. And lower miscarriage rates (18.3% vs. 27.5%) were shown in the NR when compared with the R group, but the difference did not reach statistical significance. Neonatal characteristics like height, weight, and Apgar score were similar in both the groups. Comparable implantation rates were obtained with or without BR after ET. CONCLUSION(S): The statistically significant higher LBI rate shown in our NR group confirms that 10 minutes of bed rest immediately after ET has no positive effect and in fact can be negative for the outcome of IVF with OD. The anatomical/physiological or psychological reasons for this should be explored in future research. CLINICAL TRIAL REGISTRATION NUMBER: NCT01343992. PMID- 23755955 TI - Genotoxicity assessment of mouse oocytes by comet assay before vitrification and after warming with three vitrification protocols. AB - OBJECTIVE: To assess the genotoxicity of three oocyte vitrification protocols. DESIGN: Murine assay. SETTING: Biogenotoxicology research laboratory. ANIMAL(S): CD1 female mice. INTERVENTION(S): Three mouse oocyte groups were exposed to three commercialized human oocyte vitrification protocols. Protocols 1 and 2 contained dimethyl sulfoxide and ethylene glycol (EG), and protocol 3 contained EG and 1,2 propanediol (PrOH). DNA damage was first evaluated by comet assay after oocyte exposure to the three different equilibration and vitrification solutions. Comet assay was also performed after full vitrification and warming procedure and compared with a negative control group (oocytes stored in medium culture only) and a positive control group (oocytes exposed to hydrogen peroxide just before comet assay). MAIN OUTCOME MEASURE(S): DNA damage was quantified as Olive tail moment (OTM). Statistical analysis consisted of a Shapiro-Wilk test. Then, median protocol OTM was compared with the negative control group with the Mann-Whitney U test. The difference was considered to be statistically significant if the P value was <.05. RESULT(S): In both parts of our study, protocols 1 and 2 did not induce significant DNA damage, whereas protocol 3 induced statistically higher DNA damage compared with the negative control group. CONCLUSION(S): Vitrification protocols containing PrOH induced significant DNA damage on mouse oocytes, both before cooling and after warming. Therefore, for the moment, we prefer vitrification techniques without PrOH while we await more studies on PrOH toxicity and long-term evaluation. PMID- 23755956 TI - The status of public reporting of clinical outcomes in assisted reproductive technology. AB - OBJECTIVE: To assess the transparency of assisted reproductive technology (ART) surveillance reports published by the Centers for Disease Control and Prevention (CDC) and by the Society for Assisted Reproductive Technologies (SART). DESIGN: Retrospective analysis. SETTING: Private clinical ART and research center. PATIENT(S): We analyzed ART data for the years 2005-2010, which were reported under federal mandate to the CDC (818,927 completed cycles) and voluntarily to SART (812,400 initiated cycles). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Initiated cycles excluded from final outcome reporting were used to evaluate transparency. RESULT(S): Only SART, but not CDC, reported initiated cycles, allowing analysis of excluded cycles. Excluded cycles increased significantly from 3.3% to 7.4% between 2005 and 2010. By 2010, 13/341 (3.8%) ART centers accounted for 50% of excluded cycles, representing an average of 37.3% of their cycles. These 13 clinics reported significantly better pregnancy and cancellations rates than national averages and collectively increased by 19.9% their share of U.S. ART cycles. CONCLUSION(S): Our data indicate decreasing transparency in public ART reporting in the United States, likely due to changes in practice and reporting patterns. A few clinics accounted for the majority of excluded cycles, leading to improved reported clinical outcomes and increasing market share. CDC and SART should ensure that all ART clinics publicly report the outcomes of all initiated cycles including embryo-banking cycles. ART surveillance and quality of care may be improved by prospectively tracking the total reproductive potential of each initiated cycle. PMID- 23755957 TI - Remodeling of estrogen-dependent sympathetic nerve fibers seems to be disturbed in adenomyosis. AB - OBJECTIVE: To investigate neuronal remodeling processes in the uterine innervation, particularly a remodeling of sympathetic nerve fibers, as well as the role of estrogen in this modulation in adenomyosis. DESIGN: Retrospective case-control study. SETTING: University hospital endometriosis center. PATIENT(S): Forty-two patients with histologically proven adenomyosis and 19 patients without adenomyosis. INTERVENTION(S): Endometrial and myometrial tissue were immunohistochemically analyzed to further characterize the uterine innervation. MAIN OUTCOME MEASURE(S): Immunohistochemical analysis was used to identify PGP 9.5-, substance P-, and tyrosine hydroxylase-positive nerve fibers. The expression of the aromatase cytochrome P450 was evaluated in uterine tissue, and the expression of the estrogen receptor (ER) -alpha and ERbeta in uterine nerve fibers was analyzed. RESULT(S): Adenomyotic lesions are not innervated. The density of sympathetic nerve fibers in the myometrium of women with adenomyosis is reduced when compared with the nonadenomyosis group. The aromatase expression in the myometrium of women with adenomyosis was increased when compared with the control group. The ERalpha/ERbeta ratio is in trend shifted to the ERalpha side in the myometrial tyrosine hydroxylase-positive nerve fibers in adenomyosis compared to the controls. CONCLUSION(S): The disruption of the modulation of the uterine sympathetic innervation seems to be an important aspect in the pathogenesis of adenomyosis. Estrogen and its receptors seem to play a crucial role in the depletion of myometrial sympathetic nerve fibers. PMID- 23755958 TI - Promising results after the treatment of simple and complex distal humerus type C fractures by angular-stable double-plate osteosynthesis. AB - INTRODUCTION: The aim of this study was to evaluate the functional results and complications following open reduction and internal fixation of distal humerus type C fractures (AO classification) using an anatomically precontoured, angular stable double-plate system. PATIENTS AND METHODS: The study is a retrospective analysis of 45 patients with 46 type C fractures. There was one C1, eight C2 and 31 C3 fractures. Twelve fractures were open (Gustilo classification). Follow-up was performed on 38 patients with 39 fractures (84%) after 14 months (range, 12 22). The mean age was 50 years (range, 14-87). Functional results were evaluated using the Mayo Elbow Performance Score (MEPS); the Disabilities of the Arm, Shoulder and Hand score (DASH); and range-of motion (ROM) measurements. Complications were classified as minor or major, and the postoperative and follow up X-rays were analyzed. RESULTS: Thirty-four fractures were considered stable to allow early physical therapy. With a mean MEPS of 85 points, 36 results (36/39 [92%]) were rated as excellent or good. The mean DASH was 22.5 points, and the ROM for extension-flexion was 105 degrees (range, 50-145). Sixteen major complications (eventually coexistent: 6 * implant failure, 3 * non-union, 6 * stiffness, 2 * necrosis capitulum, 4 * failure olecranon osteotomy refixation) and two minor complications were recorded in 17 patients. These adverse events led to 14 revision surgeries (14/39 [36%]). Except for extension deficit, no statistically significant differences were found between the articular simple and articular complex fractures and when comparing the results between patients with and without a major complication. CONCLUSION: The anatomically precontoured and angular-stable double-plate system provides sufficient immediate postoperative stability to allow early physiotherapy, even in C3-type fractures. Excellent or good results could be achieved in the vast majority of patients, independent on having suffered a complication or not. Complication rates were remarkably high, emphasizing the difficulties associated with this rare type of fracture. LEVEL OF EVIDENCE: Level IV Retrospective study. PMID- 23755959 TI - Intra-individual variability in gait and in cognitive performance are not related in the elderly. AB - As humans age, the amount of intra-individual variability (IIV) present in both their gait and their cognitive performance tends to increase. Both gait and cognitive IIV are associated with attentional control and with cerebrovascular disease, suggesting that the IIV in gait and cognitive function should be strongly correlated in the elderly. In this study temporal gait variability was determined from a 60-second period of walking. Cognitive variability was determined from two decision-time tasks assessing inhibition. Despite the presence of substantial amounts of gait and cognitive IIV in 71 elderly individuals, there were no significant correlations between measures of cognitive and gait IIV, suggesting that different factors drive IIV in the motor and cognitive performance of older individuals. These results are not consistent with the common cause theory of aging, which predicts that cognitive and sensorimotor performance should show related declines due to age-related disruption of a common neurological substrate. PMID- 23755960 TI - Abecedarium: Who am I? J'.... PMID- 23755961 TI - Canalplasty for congenital atresia of the external auditory canal. AB - Canalplasty for congenital atresia of the external auditory canal is associated with a high postoperative stenosis rate in the literature. The authors describe an original surgical and stenting technique that has been used systematically since 2000 in the paediatric otolaryngology department of Trousseau hospital in Paris. After minimal endaural canalplasty, possibly combined with lining of the external auditory canal by skin graft, a stent is sutured to the opening of the ear canal and left in place for 4 weeks. This stenting technique can be used for a shorter duration after tympanoplasty in children with behavioural disorders. PMID- 23755962 TI - meso-Tetraphenylbenzoporphyrin-2(2),2(3)-dicarboxylic anhydride: a platform to benzoporphyrin derivatives. AB - A method to synthesize meso-tetraphenylbenzoporphyrin-2(2),2(3)-dicarboxylic anhydride is reported. This compound reacts with alkylamines and arylamines to afford the corresponding "phthalimides" in moderate to excellent yields. The reaction of the title compound with benzene-1,4-diamine or with benzene-1,3 diamine yields the corresponding N,N'-(phenylene)bisphthalimides, whereas with benzene-1,2-diamine or naphthalene-1,8-diamine it affords heterocyclic-fused porphyrins. Molecular mechanics simulations elucidates the multiplicity of signals observed in the NMR spectra of the N,N'-(1,4-phenylene)bisphthalimide 11. This molecule exhibits two preferential conformations corresponding to a coplanar and an almost perpendicular arrangement of the benzoporphyrin units relative to the central benzenic ring. PMID- 23755963 TI - Interference control in adolescents with mild-to-borderline intellectual disabilities and/or behavior disorders. AB - The aim of this study was to investigate interference control in adolescents with Mild to Borderline Intellectual Disability (MBID) by addressing two key questions. First, as MBID is often associated with comorbid behavior disorders (BD), we investigated whether MBID and BD both affect interference control. Second, we studied whether interference control deficits are associated to problems in everyday executive functioning. Four groups of adolescents with and without MBID and/or BD performed the Eriksen flanker task, requiring participants to respond to a central target while ignoring interfering flanking stimuli. Their teachers rated behavior on the Behavior Rating Inventory Executive Function (BRIEF). We found pronounced effects of MBID but not BD on flanker interference control. In contrast, we observed pronounced effects of BD, but not MBID, on the BRIEF. In addition, flanker interference scores and BRIEF scores did not correlate. These results are taken to suggest that adolescents with MBID are characterized by deficits in interference control that do not become manifest in ratings of everyday executive functioning. In contrast, adolescents with BD are not characterized by deficits in interference control but do show elevated ratings of deficits in everyday executive function. PMID- 23755964 TI - Human NEIL3 is mainly a monofunctional DNA glycosylase removing spiroimindiohydantoin and guanidinohydantoin. AB - Base excision repair is the major pathway for removal of oxidative DNA base damage. This pathway is initiated by DNA glycosylases, which recognize and excise damaged bases from DNA. In this work, we have purified the glycosylase domain (GD) of human DNA glycosylase NEIL3. The substrate specificity has been characterized and we have elucidated the catalytic mechanisms. GD NEIL3 excised the hydantoin lesions spiroiminodihydantoin (Sp) and guanidinohydantoin (Gh) in single-stranded (ss) and double-stranded (ds) DNA efficiently. NEIL3 also removed 5-hydroxy-2'-deoxycytidine (5OHC) and 5-hydroxy-2'-deoxyuridine (5OHU) in ssDNA, but less efficiently than hydantoins. Unlike NEIL1 and NEIL2, which possess a beta,delta-elimination activity, NEIL3 mainly incised damaged DNA by beta elimination. Further, the base excision and strand incision activities of NEIL3 exhibited a non-concerted action, indicating that NEIL3 mainly operate as a monofunctional DNA glycosylase. The site-specific NEIL3 mutant V2P, however, showed a concerted action, suggesting that the N-terminal amino group in Val2 is critical for the monofunctional modus. Finally, we demonstrated that residue Lys81 is essential for catalysis. PMID- 23755965 TI - Dento-facial relationships in individuals with normal occlusion. AB - The aim of this study was to evaluate the relationships of selected facial measurements with mesio-distal crown widths and dental arch dimensions in individuals with normal occlusions. A cross-sectional study was conducted on 276 subjects with Angle's Class I normal occlusions. Three-dimensional images of the face and dental casts were captured and analyzed using stereophotogrammetric systems. Significant correlations were found between the sagittal facial variables and both upper and lower dental arch dimensions and to lesser degree with the horizontal and vertical variables. The values of correlation coefficients calculated between facial and dental crown measurements ranged from .01 to .50 for upper teeth and .01 to .49 for lower teeth. The values of correlation coefficients between facial and upper dental arch dimensions ranged from .01 to .55 and those between facial and lower dental arch dimensions ranged from .01 to .60. A principal components analysis showed that the sagittal dimensions, face height, nose, labial fissure, binocular widths were positively associated with dental arch dimensions and mesio-distal crown diameters in males. On the other hand, only the sagittal variables were associated with dental dimensions in females. The results of this study confirm that positive associations exist between facial and dental arch dimensions. These relationships should be taken into consideration when attempts are made to modify dental arch size as part of orthodontic treatment. Moreover, these relationships are also relevant to prosthodontists involved with selecting tooth sizes that display optimal functional balance with the craniofacial structures. PMID- 23755966 TI - Identification and antiviral activity of common polymorphisms in the APOBEC3 locus in human populations. AB - There are seven members of the APOBEC3 family in humans (APOBEC3A through APOBEC3H) that have antiviral activity against retroviruses and/or retroelements. To determine whether variants in APOBEC3 genes in human populations have altered antiviral activity, we identified and functionally tested novel single nucleotide variants (SNVs) in APOBEC3 genes present in the 1000 Genome Project dataset. We found that common variants minor allele frequency (> 1%) of APOBEC3A, C, F, and G do not affect protein function. However, we found that two common novel polymorphisms in APOBEC3D decrease antiviral activity against HIV-1, and one polymorphism decreases activity against Alu retrotransposons. We characterized the diversity of APOBEC3 genes in three human populations and find significant evidence that APOBEC3D has evolved under purifying selection in recent human history. These data suggest that the activity of APOBEC3D has been maintained in human populations for a cellular function in host defense. PMID- 23755967 TI - Safety analysis of a Russian phage cocktail: from metagenomic analysis to oral application in healthy human subjects. AB - Phage therapy has a long tradition in Eastern Europe, where preparations are comprised of complex phage cocktails whose compositions have not been described. We investigated the composition of a phage cocktail from the Russian pharmaceutical company Microgen targeting Escherichia coli/Proteus infections. Electron microscopy identified six phage types, with numerically T7-like phages dominating over T4-like phages. A metagenomic approach using taxonomical classification, reference mapping and de novo assembly identified 18 distinct phage types, including 7 genera of Podoviridae, 2 established and 2 proposed genera of Myoviridae, and 2 genera of Siphoviridae. De novo assembly yielded 7 contigs greater than 30 kb, including a 147-kb Myovirus genome and a 42-kb genome of a potentially new phage. Bioinformatic analysis did not reveal undesired genes and a small human volunteer trial did not associate adverse effects with oral phage exposure. PMID- 23755968 TI - Wilcox molecular torsion balance with rigid side arm and separable atropisomers for investigating CH-pi interactions. AB - A new variant of the Wilcox molecular torsion balance featuring a naphthyl-alkyl side arm was synthesized. The energy barrier for axial isomerization in the new balance was sufficiently high to allow for separation of the two rotamers and to observe their isomerization kinetics. The CH-pi interaction energies in derivatives of the new and the original ester balance were in close agreement, suggesting that the motion in ester linkage is not an important factor in folding in the ester balance. PMID- 23755970 TI - Making rational treatment decisions in rheumatoid arthritis when methotrexate fails. PMID- 23755972 TI - Whipple's disease with gastrointestinal involvement and multiple abdominal adenopathies. PMID- 23755971 TI - Changes in personal networks of women in residential and outpatient substance abuse treatment. AB - Changes in personal network composition, support and structure over 12 months were examined in 377 women from residential (n=119) and intensive outpatient substance abuse treatment (n=258) through face-to-face interviews utilizing computer based data collection. Personal networks of women who entered residential treatment had more substance users, more people with whom they had used alcohol and/or drugs, and fewer people from treatment programs or self- help groups than personal networks of women who entered intensive outpatient treatment. By 12 months post treatment intake, network composition improved for women in residential treatment; however, concrete support was still lower and substance users are still more prevalent in their networks. Network composition of women in outpatient treatment remained largely the same over time. Both groups increased cohesiveness within the network over 12 months. Targeting interventions that support positive changes in personal networks may heighten positive long term outcomes for women entering treatment. PMID- 23755973 TI - Superior outcome of strut allograft-augmented plate fixation for the treatment of periprosthetic fractures around a stable femoral stem. AB - PURPOSE: This study was designed to compare the outcome of two surgical approaches for treating femoral periprosthetic fractures around a stable femoral stem. The hypothesis was that plate fixation alone might be associated with a higher complication rate due to insufficient mechanical stability. We also considered that the addition of a strut allograft would contribute to fracture healing by means of osteoconduction. METHODS: We retrospectively assessed the outcome of 21 patients who sustained periprosthetic fractures around a total hip replacement system (Vancouver type B1 and type C fractures) and who were treated in our department (January 2006 and August 2011) either by plate fixation alone or by plate fixation and a strut allograft. The mean postoperative follow-up was 23 months (range 9-69 months). Eleven patients were treated by plate fixation alone (Plate Group), and 10 patients were treated by plate fixation and a deep frozen cortical strut allograft (AG Group). Functional outcome was rated by the Harris Hip scoring system. Postoperative radiographs were assessed for evidence of fracture union. Surgical failure was defined as any complication requiring surgical revision. RESULTS: The 21 patients included 17 females and 4 males. The average age was 79 years (range, 73-88) for the Plate Group and 82 years (range, 53-94) for the AG Group, and the average time to fracture union was 12 weeks (range, 2.5-6 months) and 12.95 weeks (range, 1.5-3) respectively. The overall failure rate was significantly higher in the Plate Group: 5 of them required revision surgery compared to none in the AG Group (p=0.014). CONCLUSION: The results of this analysis indicate that a strut allograft augmentation approach to Vancouver type B1 and type C periprosthetic fractures results in a better outcome than plate fixation alone by apparently adding mechanical stability and enhancing the biological healing process. PMID- 23755969 TI - Therapies for active rheumatoid arthritis after methotrexate failure. AB - BACKGROUND: Few blinded trials have compared conventional therapy consisting of a combination of disease-modifying antirheumatic drugs with biologic agents in patients with rheumatoid arthritis who have active disease despite treatment with methotrexate--a common scenario in the management of rheumatoid arthritis. METHODS: We conducted a 48-week, double-blind, noninferiority trial in which we randomly assigned 353 participants with rheumatoid arthritis who had active disease despite methotrexate therapy to a triple regimen of disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, and hydroxychloroquine) or etanercept plus methotrexate. Patients who did not have an improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy. The primary outcome was improvement in the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) at week 48. RESULTS: Both groups had significant improvement over the course of the first 24 weeks (P=0.001 for the comparison with baseline). A total of 27% of participants in each group required a switch in treatment at 24 weeks. Participants in both groups who switched therapies had improvement after switching (P<0.001), and the response after switching did not differ significantly between the two groups (P=0.08). The change between baseline and 48 weeks in the DAS28 was similar in the two groups ( 2.1 with triple therapy and -2.3 with etanercept and methotrexate, P=0.26); triple therapy was noninferior to etanercept and methotrexate, since the 95% upper confidence limit of 0.41 for the difference in change in DAS28 was below the margin for noninferiority of 0.6 (P=0.002). There were no significant between group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications. CONCLUSIONS: With respect to clinical benefit, triple therapy, with sulfasalazine and hydroxychloroquine added to methotrexate, was noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy. (Funded by the Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, and others; CSP 551 RACAT ClinicalTrials.gov number, NCT00405275.) PMID- 23755974 TI - Choosing the best first line oral drug agent in patients with pulmonary hypertension: evidence from a network meta-analysis. PMID- 23755975 TI - Zinc finger protein 191 deficiency attenuates vascular smooth muscle cell proliferation, migration, and intimal hyperplasia after endovascular arterial injury. AB - OBJECTIVE: Restenosis engenders surgical vascular intervention failure. Zinc finger protein 191 (ZFP191) is a novel member of the SCAN domain family of Kruppel-like zinc finger transcription factors. Previous work reveals that ZFP191 is a pleiotropic factor that plays important roles in hematopoiesis, brain development, and tumor growth. Here, we sought to determine whether intimal hyperplasia was affected by the activity of ZFP191 and to investigate the molecular mechanisms that may underpin the process. METHODS: Intimal hyperplasia was induced by guidewire injury in mouse femoral arteries. The arteries were harvested for morphometric assessment and determination of ZFP191 expression. Next, ZFP191 knockdown in cultured mouse aortic vascular smooth muscle cells (VSMCs) was achieved by lentiviral transduction of short-hairpin RNA. MTT (3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, [(3)H]thymidine incorporation assay, scratch assay, and transwell migration assay were used to evaluate the effects of ZFP191 knockdown on VSMC growth and migration. In addition, beta-catenin, c-myc, cyclin D1, matrix metalloproteinase (MMP) 9, MMP2, and MMP7 were measured by Western blotting in the absence of ZFP191 in vitro and in vivo. Zymography was used to evaluate MMP activity in cell culture-conditioned media. Lastly, artery injury was performed in wild-type (WT) and heterozygous ZFP191 knockout (KO) mice, and morphometric analysis of the arteries was determined. RESULTS: Guidewire injury was associated with development of intimal hyperplasia, and ZFP191 expression was enhanced by 51% in the injured arteries. Cultured primary VSMCs transfected with lentiviral shZFP191 displayed reduced proliferation and migration compared with controls. Mechanically, ZFP191 knockdown potently decreased the level of beta-catenin and its downstream targets c-myc and cyclin D1. ZFP191 knockdown downregulated the expression of MMP9, MMP2, and MMP7, and zymography confirmed that ZFP191 knockdown reduced the activity of MMPs. Consistent with the in vitro data, elevated expression of beta-catenin, c myc, cyclin D1, MMP9, MMP2, and MMP7 accompanied upregulation of ZFP191 after injury in the femoral arteries of mice, and these levels were downregulated in ZFP191 KO vessels. Finally, intimal hyperplasia was greatly blocked in heterozygous ZFP191 KO mice compared with WT mice (intima/media ratio, 0.124 vs 0.412; P < .05). CONCLUSIONS: ZFP191 played an essential role in aggressive proliferation and migration of VSMCs, which in turn facilitated intimal hyperplasia. Our findings offer the first genetic evidence of ZFP191 as a potential therapeutic target to prevent restenosis. PMID- 23755976 TI - Expression of neuropeptides and cytokines in a rabbit model of diabetic neuroischemic wound healing. AB - OBJECTIVE: The present study is designed to understand the contribution of peripheral vascular disease and peripheral neuropathy to the wound-healing impairment associated with diabetes. Using a rabbit model of diabetic neuroischemic wound healing, we investigated rate of healing, leukocyte infiltration, and expression of cytokines, interleukin-8 and interleukin-6, and neuropeptides, substance P, and neuropeptide Y. METHODS: Diabetes was induced in New Zealand White rabbits by administering alloxan while control rabbits received saline. Ten days later, animals in both groups underwent surgery. One ear served as a sham, and the other was made ischemic (ligation of central+rostral arteries) or neuroischemic (ischemia+ resection of central+rostral nerves). Four 6-mm punch biopsy wounds were created in both ears and wound healing was followed for 10 days using computerized planimetry. RESULTS: Nondiabetic sham and ischemic wounds healed significantly more rapidly than diabetic sham and ischemic wounds. Healing was slowest in neuroischemic wounds, irrespective of diabetic status. A high M1/M2 macrophage ratio and a high proinflammatory cytokine expression, both indicators of chronic proinflammatory state, and low neuropeptide expression were seen in preinjury diabetic skin. Postinjury, in diabetic wounds, the M1/M2 ratio remained high, the reactive increase in cytokine expression was low, and neuropeptide expression was further decreased in neuroischemic wounds. CONCLUSIONS: This rabbit model illustrates how a combination of a high M1/M2 ratio, a failure to mount postinjury cytokine response as well as a diminished neuropeptide expression, contribute to wound-healing impairment in diabetes. The addition of neuropathy to ischemia leads to equivalently severe impaired wound healing irrespective of diabetes status, suggesting that in the presence of ischemia, loss of neuropeptide function contributes to the impaired healing associated with diabetes. PMID- 23755977 TI - Drug-coated balloon angioplasty after directional atherectomy improves outcome in restenotic femoropopliteal arteries. AB - BACKGROUND: Restenosis remains an unresolved problem despite different treatment modalities and new stent technology in femoropopliteal arteries. No standard therapy has proven to provide acceptable outcome data for this entity. Directional atherectomy alone did not result in satisfactory long-term patency rates. The outcome might be improved in conjunction with drug-coated balloon angioplasty. METHODS: In this retrospective study, restenotic lesions of the femoropopliteal arteries were treated with directed atherectomy in 89 lesions of consecutive patients (58% male; mean age, 69 +/- 11 years). All patients received adjunctive treatment with conventional balloon percutaneous angioplasty (PTA; n = 60) or drug-coated balloon angioplasty (DCB; n = 29). RESULTS: Lesion location was in the stent (DCB [n = 27] vs PTA [n = 36]) and in native restenotic vessels (DCB [n = 2] vs PTA [n = 25]). The 1-year Kaplan-Meier freedom from restenosis estimates (95% confidence intervals) in the DCB and PTA groups were 84.7% (70.9% 98.5%) and 43.8% (30.5%-57.1%), respectively. In a multivariable Cox model for restenosis, DCB treatment had a hazard ratio (95% confidence interval) of 0.28 (0.12-0.66; P = .0036) compared with the PTA group. In the multivariable model for procedural success, the effect of treatment did not differ between PTA and DCB (P = .134). CONCLUSIONS: The combination of directed atherectomy with adjunctive DCB is associated with a better event-free survival at 12 months of follow-up compared with PTA after directed atherectomy. PMID- 23755978 TI - Atherectomy offers no benefits over balloon angioplasty in tibial interventions for critical limb ischemia. AB - BACKGROUND: Endovascular adjuncts, like atherectomy, were developed to improve outcomes of endovascular arterial interventions. The true impact of atherectomy on endovascular outcomes remains to be determined, and little data exist on the influence of atherectomy on tibial interventions. Our study compares early and late outcomes of tibial intervention with angioplasty vs atherectomy-assisted interventions. METHODS: We completed a retrospective review of all tibial interventions between 2008 and 2010. Outcomes were analyzed using single and multivariate analysis, Cox regression, and Kaplan-Meier curves. Primary outcomes were primary, primary assisted, and secondary patency rates, as well as limb salvage and survival rates. RESULTS: Over a 2-year period, 480 tibial interventions were completed for 421 patients. Eighty-seven percent (n = 418) of interventions were performed for critical limb ischemia (CLI) and 13% (n = 62) for claudication. The CLI cohort of 418 interventions was analyzed. These patients had a mean age of 71 years with a mean follow-up time of 16 +/- 15 months (range, 0-59 months). Of the 418 interventions, 339 underwent percutaneous transluminal angioplasty (PTA): 333 PTA alone, six PTA + stent. The remaining 79 interventions received atherectomy: 33 laser, 13 directional, and 33 orbital either alone or in conjunction with PTA (11 atherectomy only, 68 atherectomy + PTA). The groups did not differ significantly in terms of demographics, risk factors, or technical success. The atherectomy group had more TASC B lesions (54% vs 38%; P = .013), while the PTA-alone group had more TASC D lesions (25% vs 13%; P = .004). TASC A and C lesions did not differ significantly between the groups. No significant differences existed with respect to the early (30-day) outcomes of loss of patency (11% vs 13%; P = .699), complications (8% vs 13%; P = .292), or major amputation (17% vs 13%; P = .344) in the PTA-alone group vs the atherectomy assisted group. Kaplan-Meier analysis revealed no difference for all primary outcomes of PTA alone vs the atherectomy-assisted group at 12 and 36 months: primary patency (69%, 55% vs 61%, 46%; P = .158), primary assisted patency (83%, 71% vs 85%, 67%; P = .801), secondary patency (94%, 89% vs 95%, 89%; P = .892), limb salvage (79%, 70% vs 81%, 77%; P = .485), or survival (77%, 56% vs 80%, 50%; P = .944). CONCLUSIONS: The adjunctive use of atherectomy offered no improvement in primary outcomes over PTA alone in either early or late outcomes in CLI patients who underwent endovascular tibial interventions. Considering the additional cost and increased procedural time, these findings put into question the routine use of adjunctive atherectomy. PMID- 23755979 TI - Nickel-cobalt hydroxide nanosheets coated on NiCo2O4 nanowires grown on carbon fiber paper for high-performance pseudocapacitors. AB - A series of flexible nanocomposite electrodes were fabricated by facile electro deposition of cobalt and nickel double hydroxide (DH) nanosheets on porous NiCo2O4 nanowires grown radially on carbon fiber paper (CFP) for high capacity, high energy, and power density supercapacitors. Among different stoichiometries of CoxNi1-xDH nanosheets studied, Co0.67Ni0.33 DHs/NiCo2O4/CFP hybrid nanoarchitecture showed the best cycling stability while maintaining high capacitance of ~1.64 F/cm(2) at 2 mA/cm(2). This hybrid composite electrode also exhibited excellent rate capability; the areal capacitance decreased less than 33% as the current density was increased from 2 to 90 mA/cm(2), offering excellent specific energy density (~33 Wh/kg) and power density (~41.25 kW/kg) at high cycling rates (up to150 mA/cm(2)). PMID- 23755980 TI - Unraveling the effects of siRNA carrier systems on cell physiology: a multiparametric approach demonstrated on dextran nanogels. AB - AIM: The extent of cell-nanoparticle interactions between a polycationic siRNA nanocarrier system (dextran nanogels) and cultured cells was analyzed. MATERIALS & METHODS: A multiparametric methodology is introduced to examine the cytotoxic effects of a model siRNA carrier (dextran nanogels) on different cell types, including primary human cells. Using this methodology, the nontoxic concentration of nanogels could be defined and the mechanisms contributing to their toxic profile were unraveled. RESULTS: Above the toxicity threshold, nanogels were found to induce oxidative stress and destabilize the plasma membrane. Furthermore, nanogel-induced cellular stress led to DNA damage, impeded cell functionality and intracellular signaling, resulting in unspecific regulation of gene expression. CONCLUSION: This methodology shows that current toxicity assays such as the 3-(4,5-dimethylthiazol-2yl-)-2,5-diphenyl tetrazolium bromide assay are not adequate to assess the full spectrum of cell-nanoparticle interactions and more in-depth studies are required. PMID- 23755981 TI - Body mass index, waist circumference and employment: evidence from older Irish adults. AB - Data from the first wave of the Irish Longitudinal Study on Ageing are used to examine the relationship between fatness and obesity and employment status among older Irish adults. Employment status is regressed on one of the following measures of fatness: BMI and waist circumference entered linearly as continuous variables and obesity as a categorical variable defined using both BMI and waist circumference. Controls for demographic and socioeconomic characteristics, socioeconomic characteristics in childhood and physical, mental and behavioural health are also included. The regression results for women indicate that all measures of fatness are negatively associated with the probability of being employed and that the employment elasticity associated with waist circumference is larger than the elasticity associated with BMI. The results for men indicate that employment is not significantly associated with BMI and waist circumference when these are entered linearly in the regression, but it is significantly and negatively associated with obesity defined either using BMI or waist circumference as categorical variables. The results also indicate that the negative association between obesity and employment status is larger among women. For example, the probability of being employed for the obese category defined using BMI is around 8 percentage points lower for women and 5 percentage points lower for men. PMID- 23755982 TI - Facile fabrication of reduced graphene oxide-encapsulated silica: a sorbent for solid-phase extraction. AB - In this study, a facile hydrothermal reduction strategy was developed for the preparation of reduced graphene oxide-encapsulated silica (SiO2@rGO). Compared with other conventional methods for the synthesis of SiO2@rGO, the proposed strategy endowed the obtained SiO2@rGO with larger amount of immobilized rGO. The prepared functionalized silica shows remarkable adsorption capacity toward chlorophenols (CPs) and peptides. When it was used as solid-phase extraction (SPE) sorbent, a superior recovery could be obtained compared to commercial sorbents, such as C18 silica, graphitized carbon black and carbon nanotubes. Based on these, the prepared material was used as SPE sorbent for the enrichment of CPs, and a method for the analysis of CPs in water samples was established by coupling SPE with high performance liquid chromatography-ultra violet detection (SPE-HPLC/UV). In addition, the obtained SiO2@rGO was further successfully extended to the enrichment of peptides in bovine serum albumin (BSA) digests. PMID- 23755983 TI - Determination of antibiotics (tetracyclines and sulfonamides) in biosolids by pressurized liquid extraction and liquid chromatography-tandem mass spectrometry. AB - A robust and sensitive analytical method is developed to quantitatively determine tetracyclines and sulfonamides, two major antibiotic classes, in sewage sludge. The antibiotic agents, oxytetracycline, tetracycline, dioxycycline, chlorotetracycline, sulfathiazole, sulfapyridine, sulfamethazine and sulfamethoxazole, were extracted using pressurized liquid extraction (PLE) with citric acid at pH 3 and methanol (1:1 v/v). Clean-up of the extracts was performed by solid phase extraction (SPE) with hydrophilic-lipophilic balance cartridges. Identification and quantification of the compounds is by liquid chromatography-tandem mass spectrometry in multiple reaction monitoring (MRM) mode. High recoveries ranging from 90.4 to 99.9% for sulfonamides and 96.2 to 100.9% for the tetracyclines are obtained. Method detection limits (MDLs) range from 0.6 to 4.2 ng/g for sulfonamides and 3.2 to 13 ng/g for tetracyclines. After validation, the method is applied to the analysis of sludges collected from different WWTPs in Spain. PMID- 23755984 TI - Study of stereomeric peptoid chiral stationary phases containing different chiral side chains. AB - In this study, we investigated six stereomeric peptoid chiral stationary phases (CSPs) successively combining N'-phenyl-proline amide, alpha-phenylethyl amine, 2 aminocyclohexyl phenylcarbamate and another alpha-phenylethyl amine under normal phase mode. CSPs 1-4 with R-S-(R,R)-S, R-S-(S,S)-S, R-R-(R,R)-R and R-R-(S,S)-R configuration exhibited much different enantiorecognition abilities. Overall, CSPs 1 and 2 performed better for the 55 analytes tested. CSP 5 with mixed selectors combined partial selectivities of CSPs 1 and 2. CSP 6 as enantiomeric counterpart of CSP 2 exhibited similar enantioseparation ability and reversal elution orders for analytes resolved. For several biaryl type analytes, CSP 6 even outperformed commercial Chiralpak AD-H and Chiralcel OD-H. Excellent resolution of 3,3'-diphenyl-2,2'-bi-1-naphthalol (VANOL) on CSP 6 illustrated its potential application in preparative enantioseparation. Eluting orders of enantiomers on stereomeric CSPs also provided us further insight into enantiorecognition of some analytes. PMID- 23755985 TI - Effects of aqueous stable fullerene nanocrystal (nC60) on copper (trace necessary nutrient metal): Enhanced toxicity and accumulation of copper in Daphnia magna. AB - Our focus herein is to evaluate the potential interaction between nC60 and copper, a trace necessary metal, in light of the impact on toxicity. The non observable effects concentration (NOEC) of nC60 was confirmed as 100MUgL(-1) before. When Daphnia magna was exposed to the mixture of copper solution and nC60 suspension (100MUgL(-1)), LC50 of 48h was lower than that when they were exposed to copper solution alone. This result clearly showed the decrease in NOEC of copper at the presence of nC60. Cu(2+)-ATPase activity was enhanced at the presence of nC60, indicating that copper transport involved with the uptake, distribution and depuration in body was increased. We further conducted experiments on accumulation of copper in D. magna. The observed equilibrium copper concentration in D. magna in the mixture of 100MUgL(-1) nC60 and 1MUgL(-1) copper solution reached 131MUg (kg wet weight)(-1), which was more than twice that in copper solution only: 60MUg (kg wet weight)(-1). This result demonstrated that the accumulation of copper in D. magna was significantly enhanced at the presence of even low nC60 concentration. Experiments also showed that copper was quickly adsorbed onto nC60. The absorption of copper onto D. magna was statistically correlated to the absorption of nC60 onto D. magna; this might be caused by nC60 facilitating the transfer of copper into D. magna. The absorption and desorption of copper to nC60 (pH=5.0) reached equilibrium quickly, which may be involved with the co-bioaccumulation and decrease in NOEC of Cu(2+) and nC60. PMID- 23755986 TI - The mitigating effect of calcification-dependent of utilization of inorganic carbon of Chara vulgaris Linn on NH4-N toxicity. AB - Increased ammonium (NH4-N) concentrations in water bodies have been reported to adversely affect the dominant species of submersed vegetation in meso-eutrophic waters worldwide. However calcareous plants were lowly sensitive to NH4-N toxicity. In order to make clear the function of calcification in the tolerance of calcareous plants to NH4-N stress, we studied the effects of increased HCO3(-) and additional NH4-N on calcification and utilization of dissolve inorganic carbon (DIC) in Chara vulgaris Linn in a 7-d sub-acute experiment (light:dark 12:12h) carried out in an open experimental system in lab. Results revealed that calcification was dependent of utilization of dissolve inorganic carbon. Additional HCO3(-) significantly decreased the increase of pH while additional NH4-N did not. And additional HCO3(-) significantly improved calcification while NH4-N did in versus in relation to the variation of DIC concentration. However, addition of both HCO3(-) and NH4-N increased utilization of DIC. This resulted in calcification to utilization of DIC ratio decreased under additional NH4-N condition while increased under additional HCO3(-) conditions in response to the variation of solution pH. In the present study, external HCO3(-) decreased the increase of solution pH by increasing calcification, which correspondingly mitigated the toxic effect of high NH4-N. And we argue that the mitigating effect of increased HCO3(-) on NH4-N toxicity is dependent of plant calcification, and it is a positive feedback mechanism, potentially leading to the dominance of calcareous plants in meso-eutrophic water bodies. PMID- 23755987 TI - Mixed arbuscular mycorrhizal (AM) fungal application to improve growth and arsenic accumulation of Pteris vittata (As hyperaccumulator) grown in As contaminated soil. AB - A greenhouse pot experiment was conducted to study the effects of three types of single inoculum [indigenous mycorrhizas (IM) isolated from As mine, Glomus mosseae (GM) and Glomus intraradices (GI)] and two types of mixed inoculum (mixed with IM and either GM or GI) on the growth response of Pteris vittata (hyperaccumulator) and Cynodon dactylon (non-hyperaccumulator) at three levels of As concentrations (0, 100 and 200mgkg(-1)). Both mycorrhizal plants exhibited significantly higher biomass, and N and P accumulation in its tissue than the control. Among the mycorrhizal inoculum, the mixed inoculum IM/GM promoted substantially higher mycorrhizal colonization and arsenate reductase activity in P. vittata than C. dactylon, among all As levels. The portion of Paris arbuscular mycorrhizal structure (observed in colonized roots) together with the highest As translocation factor of 10.2 in P. vittata inoculated with IM/GM was also noted. It was deduced that IM/GM inoculum may be the best choice for field inoculation at any contaminated lands as the inoculum exhibited better adaptation to variable environmental conditions and hence benefited the host plants. PMID- 23755988 TI - Occurrence of glucocorticogenic activity in various surface waters in The Netherlands. AB - Considering the important role that surface waters serve for drinking water production, it is important to know if these resources are under the impact of contaminants. Apart from environmental pollutants such as pesticides, compounds such as (xeno)estrogens have received al lot of research attention and several large monitoring campaigns have been carried out to assess estrogenic contamination in the aquatic environment. The introduction of novel in vitro bioassays enables researchers to study if - and to what extent - water bodies are under the impact of less-studied (synthetic) hormone active compounds. The aim of the present study was to carry out an assessment on the presence and extent of glucocorticogenic activity in Dutch surface waters that serve as sources for drinking water production. The results show glucocorticogenic activity in the range of16 in different time periods looking at their 48-hour mortality, hematocrit (HCT), base deficit (BD), oxygen saturation (SpO2), and physiological parameters on arrival to the CSH. RESULTS: The CCFP group had better HCT [36.5 (8.8)] than the EMT-B group [33.1 (11.4); p <= 0.001]. BD and SpO2 were better in the CCFP group [-3.2 (4.7)]/[97.8 (4.8)] than the EMT-B group [-4.4 (5.5)]/[96.3 (10.9)] [p <= 0.014]. The CCFP group had a 72% lower estimated risk ratio of mortality with an associated improvement in 48-hour survivability of 4.9% versus 15.8% for the EMT-B-group. CONCLUSIONS: There is a statistically significant improvement in the HCT, BD, SpO2, and 48 hour survivability at the CSH in the cohort transported by the CCFP group when compared to the cohort transported by the EMT-B group. PMID- 23756013 TI - Humanitarian and civic assistance health care training and cultural awareness promoting health care pluralism. AB - Integration between traditional and contemporary health care in a host nation can be beneficial to nation- and capacity-building and, subsequently, to the overall health of the society. "Traditional" health care in this sense refers to the indigenous health care system in the host nation, which includes characteristic religious or cultural practices, whereas "contemporary" health care is also known as "conventional" or "Westernized"; integration is a synchronization of these two health care forms. However, the choice of integration depends on the political and cultural situation of the nation in which the Department of Defense health care personnel are intervening. Thus, cultural awareness training is essential to ensure the success of missions related to global health and in promoting a health care system that is most beneficial to the society. The present study attempts to show the benefits of both cultural training and health care integration, and how adequately evaluating their efficacy has been problematic. The author proposes that determinants of this efficacy are better documentation collection, extensive predeployment cultural awareness and sensitivity training, and extensive after action reports for future development. PMID- 23756014 TI - Comparison of chronic disease prevalence between U.S. Navy ships without medical doctors and a similar shore-based population. AB - OBJECTIVE: Most U.S. Navy ships operate without embarked physicians, employing Independent Duty Corpsmen to provide primary and emergency medical care to crewmembers. We sought to characterize the burden of chronic disease faced by Independent Duty Corpsmen aboard Navy ships and compare it to that of a similar shore-based population. METHODS: We conducted cross-sectional analyses of shipboard and shore-based samples using 1,305 records from Norfolk, Virginia based U.S. Navy ships without doctors between March and May 2007, and records for Norfolk shore-based sailors from the same time frame matched 3:1 on age, sex, and race against the shipboard sample. RESULTS: Asthma prevalence was 2.0% and 5.9% for the shipboard and shore-based samples, respectively (p < 0.0001). Cervical dysplasia among women was 16.2% and 23.1% (p = 0.3687). Depression was 4.6% and 8.4% (p < 0.0001). Diabetes was 1.0% and 2.3% (p = 0.0096). Hyperlipidemia was 20.6% and 21.4% (p = 0.5597). Hypertension was 25.5% and 36.1% (p < 0.0001). Total prevalence for any of the above conditions was 42.5% and 50.9% (p = 0.0001). CONCLUSION: Over 42% of shipboard sailors have one or more chronic health conditions. Even though the studied conditions were significantly less prevalent aboard ship than in the comparable shore-based sample, nonphysician practitioners aboard ships must be prepared to diagnose and treat chronic diseases. PMID- 23756015 TI - Predictors of completing compulsory military service among men who have received a temporary exemption from service. AB - Military or alternative civilian service is obligatory for all Finnish male citizens. About 70% of each annual age cohort carry out this service. The rest are given either a permanent or temporary exemption from military or civil service. The aim of this study was to investigate predictors associated with completing military service after having once been given a temporary exemption from service. The study sample consisted of 245 men who were exempted temporarily from service. The data were collected through questionnaires and register data. During the 5-year follow-up, only 21 men had completed the service following a previous temporary exemption. Completing military service was associated with an exemption based on a somatic diagnosis, having no suicidal ideation in the past, no history of parental divorce, and having physical exercise at least once a week. The results of this study support the idea of preferring to give a permanent exemption instead of a temporary exemption. However, this trend runs the risk of discharging men who could be capable of later completing the service successfully. PMID- 23756016 TI - Clara Maass, yellow fever and human experimentation. AB - Clara Louise Maass, a 25-year-old American nurse, died of yellow fever on August 24, 1901, following experimental inoculation by infected mosquitoes in Havana, Cuba. The human yellow fever experiments were initially conducted by MAJ Walter Reed, who first used written informed consent and proved the validity of Finlay's mosquito-vector hypothesis. Despite informed consent form and an incentive of $100 in U.S. gold, human subjects were exposed to a deadly virus. The deaths of Clara Maass and two Spanish immigrants resulted in a public outcry and the immediate cessation of yellow fever human experiments in Cuba. PMID- 23756017 TI - Cigarette prices in military retail: a review and proposal for advancing military health policy. AB - Tobacco use is the leading cause of preventable death in the United States and has been shown to significantly harm the combat readiness of military personnel. Unfortunately, recent research showed that cigarettes are sold at substantial discounts in military retail outlets. In fact, the military is the only retailer that consistently loses money on tobacco. Cheap tobacco prices have been identified by enlisted personnel and Department of Defense health policy experts as promoting a culture of tobacco use in the U.S. Military. This article provides an analysis of why current military tobacco pricing policy has failed to eliminate cheap tobacco prices as an incentive for use. A rationale for increasing tobacco prices also is presented along with recommendations for improved military tobacco control policy. PMID- 23756018 TI - Effects of top-loading a zero-link bovine hemoglobin, OxyVita, on systemic and microcirculatory variables. AB - This study was designed to test the effect of top-load infusions of increasing doses of two versions of the novel, high molecular weight hemoglobin-based oxygen carrier, OxyVita and OxyVita C solution ([Hb] = 6 g/dL), on mean arterial pressure (MAP), arteriolar diameter, and tissue oxygenation. Experiments were carried out on 18 anesthetized male Sprague-Dawley rats in which microcirculatory observations were made on the spinotrapezius muscle. Intravenous infusions of four increasing doses of the OxyVita solutions (2, 22, 230, and 780 mg/kg) were made for each group, and a separate group of animals was used for volume control. Tissue oxygenation was measured as interstitial fluid (ISF) PO2 using phosphorescence quenching microscopy. Increasing doses of either OxyVita solution or Lactated Ringer's solution (LRS, volume control) were associated with increasing MAP. For LRS infusions, MAP returned to baseline between each incremental dose injected, whereas there was an incomplete return for either of the OxyVita solutions. ISF PO2 for OxyVita was significantly lower than that for either LRS or OxyVita C, whereas ISF PO2 for OxyVita C was never statistically different from LRS. There were no significant changes in arteriolar diameters for LRS and either of the OxyVita solutions. PMID- 23756019 TI - Tourniquets and occlusion: the pressure of design. AB - Nerve injuries result from tourniquet pressure. The objective was to determine arterial occlusion and completion pressures with the 3.8-cm-wide windlass Combat Application Tourniquet (CAT) and the 10.4-cm-wide Stretch, Wrap, and Tuck Tourniquet (SWAT-T). METHODS: Sixteen volunteers self-applied and had tourniquets applied to their thighs and arms (CAT and SWAT-T, random order, then blood pressure cuffs). RESULTS: Occlusion (Doppler signal elimination) pressures were higher than predicted (p < 0.0001), highest with the CAT (p < 0.0001), and often lower than completion pressures (completion median, range: CAT 360, 147-745 mm Hg; SWAT-T 290, 136-449 mm Hg; cuff 184, 108-281 mm Hg). Three CAT thigh and 9 CAT arm completion pressures were >500 mm Hg. Pressure decreases and occlusion losses occurred over 1 minute (pressure decrease: CAT 44 +/- 33 mm Hg; SWAT-T 6 +/- 8 mm Hg; cuff 14 +/- 19 mm Hg; p < 0.0001; loss/initially occluded: CAT 17 of 61, SWAT-T 5 of 61, cuff 40 of 64, p < 0.01). CAT pressures before turn did not have a clear relationship with turns to occlusion. CONCLUSIONS: Limb circumference/tourniquet width occlusion pressure predictions are not good substitutes for measurements. The wider SWAT-T has lower occlusion and completion pressures than the CAT. Decreases in muscle tension lead to decreases in tourniquet pressure, especially with the nonelastic CAT, which can lead to occlusion loss. PMID- 23756020 TI - Diagnostic accuracy of a point-of-care blood typing kit conducted by potential end users. AB - The usability of a rapid point-of-care ABO-Rh blood typing kit was determined by comparing the performance of individuals with extensive medical training/experience to those with a lesser extent. Subjects were asked to use the blood typing kit with their own blood. These outcomes were compared to that listed in the subject's medical record, stamped on their dog tag, and the result interpreted by a laboratorian. For all participants, there was ~80% consistency between the result interpreted by the subject and that stated in their medical record. The participant's level of formal education (P <= 0.05) affected the accuracy of the blood typing kit. When comparing the subject's outcome to that stated in their medical record, the performance of individuals in the Medical Corps was approximately 10% and 25% higher (P < 0.05) than that observed with Hospital Corpsman or Medical Service Corps members, respectively. To remove bias that can occur when interpreting the blood type of oneself, the subjects also interpreted the result from cards prepared by the investigator. Taken together, a discrepancy between the potential diagnostic accuracy of the kit and that observed with potential end users was identified. PMID- 23756021 TI - Di-, tri-, and tetra(pentafluorophenyl) derivatives for oligotopic anion-pi interactions. AB - The present study describes a series of pentafluorobenzyl ammonium salts with two, three, or four C6F5 units in order to investigate simultaneous interactions of several perfluorinated arenes with anions in the crystalline state. Most of the structures show multiple anion-pi contacts. However, only 6.2HI reveals an effective encapsulation of the iodide ion by the aromatic units. For comparison, the structure of 4b is investigated because it offers two pi-systems with inverse charge distribution to a bromide anion. Only the electron-deficient pi-system of the pentafluorophenyl group interacts with the anion. PMID- 23756022 TI - Dynamic expression of MEIS1 homeoprotein in E14.5 forebrain and differentiated forebrain-derived neural stem cells. AB - Central nervous system development is controlled by highly conserved homeoprotein transcription factors including HOX and TALE (Three Amino acid Loop Extension). TALE proteins are primarily known as HOX-cofactors and play key roles in cell proliferation, differentiation and organogenesis. MEIS1 is a TALE member with established expression in the developing central nervous system. MEIS1 is essential for embryonic development and Meis1 knockout mice dies at embryonic day (E) 14.5. However, Meis1/MEIS1 expression in the devolving forebrain, at this critical time-point has not been studied. Here, for the first time we characterize the region-specific expression of MEIS1 in E14.5 mouse forebrain, filling the gap of MEIS1 expression profile between E12.5 and E16.5. Previously, we reported MEIS1 transcriptional regulatory role in neuronal differentiation and established forebrain-derived neural stem cells (NSC) for gene therapy application of neuronal genes. Here, we show the dynamic expression of Meis1/MEIS1 during the differentiation of forebrain-derived NSC toward a glial lineage. Our results show that Meis1/MEIS1 expression is induced during NSC differentiation and is expressed in both differentiated neurons and astrocytes. Confirming these results, we detected MEIS1 expression in primary cultures of in vivo differentiated cortical neurons and astrocytes. We further demonstrate Meis1/MEIS1 expression relative to other TALE family members in the forebrain derived NSC in the absence of Hox genes. Our data provide evidence that forebrain derived NSC can be used as an accessible in vitro model to study the expression and function of TALE proteins, supporting their potential role in modulating NSC self-renewal and differentiation. PMID- 23756023 TI - The role of prostaglandin E2 in human vascular inflammation. AB - Prostaglandins (PG) are the product of a cascade of enzymes such as cyclooxygenases and PG synthases. Among PG, PGE2 is produced by 3 isoforms of PGE synthase (PGES) and through activation of its cognate receptors (EP1-4), this PG is involved in the pathophysiology of vascular diseases. Some anti-inflammatory drugs (e.g. glucocorticoids, nonsteroidal anti-inflammatory drugs) interfere with its metabolism or effects. Vascular cells can initiate many of the responses associated with inflammation. In human vascular tissue, PGE2 is involved in many physiological processes, such as increasing vascular permeability, cell proliferation, cell migration and control of vascular smooth muscle tone. PGE2 has been shown to contribute to the pathogenesis of atherosclerosis, abdominal aortic aneurysm but also in physiologic/adaptive processes such as angiogenesis. Understanding the roles of PGE2 and its cognate receptors in vascular diseases could help to identify diagnostic and prognostic biomarkers. In addition, from these recent studies new promising therapeutic approaches like mPGES-1 inhibition and/or EP4-antagonism should be investigated. PMID- 23756024 TI - [Computerized three-dimensional reconstruction of the retrohepatic segment of inferior vena cava of a 20 mm human embryo]. AB - The subdiaphragmatic venous drainage of the embryo is provided by the two caudal cardinal veins to which is added the subcardinal vein system, draining the mesonephros, the perispinal supracardinal veins and the umbilical and vitelline venous system. The anastomosis of certain segments of the embryonic venous structures and the disappearance of others are at the origin of the inferior vena cava. Since the 19th century, three-dimensional reconstruction of solid models from histological sections were developed. At present, the development of computerized three-dimensional reconstruction techniques allowed to operate a multitude of techniques of image processing and modeling in space. Three dimensional reconstruction is a tool for teaching and research very useful in embryological studies because of the obvious difficulty of dissection and the necessity of introducing time as the fourth dimension in the study of organogenesis. This method represents a promising alternative compared to previous three-dimensional reconstruction techniques including Born technique. The aim of our work was to create a three-dimensional computer reconstruction of the retrohepatic segment of the inferior vena cava of a 20mm embryo from the embryo collection of Saints-Peres institute of anatomy (Paris Descartes university, Paris, France) to specify the path relative to the liver and initiate a series of computerized three-dimensional reconstruction that will follow the evolution of this segment of the inferior vena cava and this in a pedagogical and morphological research introducing the time as the fourth dimension. PMID- 23756025 TI - [Incarceration of the retroverted uterus in the third trimester: report of 2 cases]. AB - Incarceration of the retroverted gravid uterus in the third trimester is a rare but distinctive diagnosis. Initial symptoms are more frequently urinary and digestive symptoms which became more acute at the third trimester. Severe abdominal pain associated with bleeding in early labor leads to make the diagnosis during an emergency cesarean section. However, the typical features of the clinical transvaginal exam and the abdominal ultrasound exam can confirm easily this diagnosis. We report two additional cases where Joel-Cohen incision for cesarean section was possible after manual reposition of the uterus. We discuss the diagnostic approach and the management regarding a literature review. PMID- 23756026 TI - [Surgery training of trainees in obstetrics and gynecology is insufficient?]. PMID- 23756027 TI - [Propensity score: A method for reducing measurement bias]. PMID- 23756028 TI - [D. Torrejon, J. Cortes, D. Serpico, S. Di Cosimo in reply to the article by F. Vasseur et al.: Ki67 in young patients with breast cancer. Gynecol Obstet Fertil 2013; 41(1):16-9]. PMID- 23756029 TI - [Which quality measure for maternity services?]. PMID- 23756030 TI - Atypical hemolytic uremic syndrome: from the rediscovery of complement to targeted therapy. AB - Atypical hemolytic uremic syndrome (aHUS) is a devastating form of renal thrombotic microangiopathy. In the last five years, we have finally witnessed a dramatic improvement in the management of aHUS patients, and three breakthroughs in our understanding of aHUS have led to such an improvement. The first breakthrough was the emergence of a new clinical picture of aHUS (frequency of adult cases, and overall poor renal prognosis despite plasma therapy). The second breakthrough was the identification of complement alternative pathway dysregulation as a major risk factor for aHUS. The third breakthrough was the availability in clinical practice of the first complement inhibitor, the anti-C5 monoclonal antibody, eculizumab. Available data from case series and prospective studies indicate that eculizumab use has dramatically improved the renal prognosis of aHUS. These breakthroughs have prompted the French working group on aHUS to propose a new algorithm for the management of aHUS in children and in adults. This algorithm will evolve as we gain new insights in the pathogenesis and evolution of aHUS in the eculizumab era. PMID- 23756031 TI - Myofascial trigger point therapy for triceps surae dysfunction: a case series. AB - AIMS: The main aim of the case series was to inform further experimental research to determine the effectiveness of myofascial trigger point (MTrP) therapy for the treatment of triceps surae dysfunction. PARTICIPANTS: Ten participants with triceps surae dysfunction were recruited (4 females and 6 males); mean age+/ standard deviation=43+/-7.1 years. METHODS: Participants were screened for inclusion/exclusion criteria and the following outcomes measures were assessed at baseline and discharge; lower extremity functional scale (LEFS), verbal numerical rating scale (NRS), MTrP prevalence, ankle dorsiflexion range of movement (ROM) and pressure pain threshold (PPT). Intervention involved trigger point (TrP) pressure release, self MTrP release and a home stretching programme. RESULTS: There was a high prevalence of active/latent MTrPs and possible myofascial pain syndrome (MPS) for all 10 participants at baseline. Active MTrP prevalence decreased to 0%, while latent MTrPs were still present at discharge. There were positive changes in most outcome measures (LEFS, NRS, ROM and PPT) for all 10 participants. Short term to medium term treatment outcomes (6 week post discharge) showed an overall mean LEFS increase of 11 points from 61/80 at baseline to 72/80 at discharge. CONCLUSION: This case series suggests that a brief course of multimodal MTrP therapy would be helpful for some patients with sub-acute or chronic calf pain. Important preliminary data was gathered, that will inform more rigorous research in this under investigated area. PMID- 23756032 TI - The influence of forefoot varus on eccentric hip torque in adolescents. AB - Hip strength impairments have been established as risk factors for lower limb injuries. Hip muscles strength might be influenced by foot misalignments, however this has not yet been verified. Forefoot varus (FV) has been shown to cause subtalar joint hyperpronation. Subtalar hyperpronation has been associated with excessive lower limb internal rotation in weight-bearing activities. Also, subtalar hyperpronation might result in greater ground reaction force dissipation at the foot. Consequently, there would be less demand for force dissipation at the hip joint, which could reduce the capacity for hip eccentric torque in these subjects. Therefore, the purpose of this study was to determine if FV influences the eccentric hip torque generation of young subjects. Forty-four sedentary, healthy adolescents were divided into 2 groups: subjects with FV (VG, n = 22) and subjects with neutral forefoot alignment (CG, n = 22). An isokinetic dynamometer was used to assess the eccentric torque generated in hip extension and external rotation in these subjects. Group differences were assessed using a one-way multivariate analysis of variance. The VG presented smaller eccentric torque for hip extension (P = 0.014) when compared to the CG, with no difference between groups in external rotation torque (P = 0.433). These results indicate that FV influences hip eccentric torque generation of young subjects. Considering that the muscles involved in hip extension are related to the stabilization of the lumbar spine, hip and knee, these findings bring further enlightenment to the role of foot misalignments as risk factors for injuries in the lower limbs and lumbo-pelvic complex in young subjects. PMID- 23756033 TI - Emotional processing and its relationship to chronic low back pain: results from a case-control study. AB - Chronic low back pain (CLBP) is a common, yet challenging condition for both patients and clinicians. Several studies have demonstrated a strong association between CLBP and psychological factors such as anxiety, fear-avoidance, self efficacy, catastrophizing and depression. These factors are closely linked with emotional states; however, it is unknown whether CLBP patients process their emotions differently from asymptomatic individuals. The aim of this case-control study was to investigate the relationship between CLBP and emotional processing. A sample of 110 participants comprising of 55 patients with chronic back pain and 55 individuals without a history of CLBP were assessed using the Emotional Processing Scale (EPS-25). The EPS-25 generates an overall score, and also scores pertaining to five individual emotional processing factors--avoidance, suppression, unregulated emotion, impoverished emotional experience and signs of unprocessed emotion. Chronic back pain patients scored significantly higher in the overall EPS-25 score (p < 0.001) with an effect size of 0.33. In addition, there were significant differences in four factors--impoverished emotional experience, unregulated emotion, unprocessed emotion, and suppression, with effect sizes ranging from 0.20 to 0.44. The results suggest that dysfunctional emotional processing, particularly with regard to the suppression of emotions, is associated with CLBP. Clinicians should critically consider the role of emotional processing in their patients' evaluation and management. Future research using a prospective cohort should assess the role of emotional processing as a predictor in the development of chronic back pain. PMID- 23756034 TI - Lumbar repositioning error in sitting: healthy controls versus people with sitting-related non-specific chronic low back pain (flexion pattern). AB - Studies examining repositioning error (RE) in non-specific chronic low back pain (NSCLBP) demonstrate contradictory results, with most studies not correlating RE deficits with measures of pain, disability or fear. This study examined if RE deficits exist among a subgroup of patients with NSCLBP whose symptoms are provoked by flexion, and how such deficits relate to measures of pain, disability, fear-avoidance and kinesiophobia. 15 patients with NSCLBP were matched (age, gender, and body mass index) with 15 painfree participants. Lumbo pelvic RE, pain, functional disability, fear-avoidance and kinesiophobia were evaluated. Participants were asked to reproduce a target position (neutral lumbo pelvic posture) after 5 s of slump sitting. RE in each group was compared by evaluating constant error (CE), absolute error (AE) and variable error (VE). Both AE (p = 0.002) and CE (p = 0.006) were significantly larger in the NSCLBP group, unlike VE (p = 0.165) which did not differ between the groups. There were significant, moderate correlations in the NSCLBP group between AE and functional disability (r = 0.601, p = 0.018), and between CE and fear-avoidance (r = -0.577, p = 0.0024), but all other correlations were weak (r < 0.337, rs < 0.377) or non significant (p > 0.05). The results demonstrate increased lumbo-pelvic RE in a subgroup of NSCLBP patients, with the selected subgroup undershooting the target position. Overall, RE was only weakly to moderately correlated with measures of pain, disability or fear. The deficits observed are consistent with findings of altered motor control in patients with NSCLBP. The mechanisms underlying these RE deficits, and the most effective method of addressing these deficits, require further study. PMID- 23756035 TI - Risk factors for methicillin-resistant Staphylococcus aureus in patients with community-onset and hospital-onset pneumonia. AB - OBJECTIVES: The risk factors for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia have not been fully characterized and are likely to be different depending on whether infection is acquired in the community or the hospital. METHODS: We conducted a case-control study of 619 adults hospitalized between 2005 and 2010 with either MRSA or methicillin-sensitive S. aureus (MSSA) pneumonia. Patients with a respiratory culture within 48 h of hospitalization had community-onset pneumonia whereas patients with a culture collected after this time point had hospital-onset pneumonia. RESULTS: Among patients with community onset disease, the risk for MRSA was increased by tobacco use (OR 2.31, CI 1.23 4.31), chronic obstructive pulmonary disease (OR 3.76, CI 1.74-8.08), and recent antibiotic exposure (OR 4.87, CI 2.35-10.1) in multivariate analysis while patients with hospital-onset disease had an increased MRSA risk with tobacco use (OR 2.66, CI 1.38-5.14), illicit drug use (OR 3.52, CI 2.21-5.59), and recent antibiotic exposure (OR 2.04, CI 3.54-13.01). Hospitalization within the prior three months was associated with decreased risk (OR 0.64, CI 0.46-0.89) in multivariate analysis. CONCLUSIONS: This study suggests there are common and distinct risk factors for MRSA pneumonia based on location of onset. The decreased risk for MRSA pneumonia associated with recent hospitalization is unexpected and warrants further investigation. SUMMARY: This case-control study showed that there are common and distinct risk factors associated with MRSA pneumonia depending on whether the infection onset is in the hospital or in the community. Recent hospitalization was unexpectedly shown to be associated with decreased risk for MRSA pneumonia and warrants further investigation. PMID- 23756036 TI - A trait-based framework to understand life history of mycorrhizal fungi. AB - Despite the growing appreciation for the functional diversity of arbuscular mycorrhizal (AM) fungi, our understanding of the causes and consequences of this diversity is still poor. In this opinion article, we review published data on AM fungal functional traits and attempt to identify major axes of life history variation. We propose that a life history classification system based on the grouping of functional traits, such as Grime's C-S-R (competitor, stress tolerator, ruderal) framework, can help to explain life history diversification in AM fungi, successional dynamics, and the spatial structure of AM fungal assemblages. Using a common life history classification framework for both plants and AM fungi could also help in predicting probable species associations in natural communities and increase our fundamental understanding of the interaction between land plants and AM fungi. PMID- 23756037 TI - Access to treatment for substance-using women in the Republic of Georgia: socio cultural and structural barriers. AB - BACKGROUND: In the Republic of Georgia, women comprise under 2% of patients in substance use treatment and to date there has been no empirical research to investigate what factors may facilitate or hinder their help-seeking behaviour or access to treatment services. METHODS: This study included secondary analysis of in-depth interviews with 55 substance-using women and 34 providers of health related services. RESULTS: The roles and norms of women in Georgian society were identified as major factors influencing their help-seeking behaviour. Factors that had a negative impact on use of drug treatment services included an absence of gender-specific services, judgmental attitudes of service providers, the cost of treatment and a punitive legal position in regard to substance use. Having a substance-using partner served as an additional factor inhibiting a woman's willingness to seek assistance. CONCLUSION: Within the context of orthodox Georgian society, low self-esteem, combined with severe family and social stigma play a critical role in creating barriers to the use of both general health and substance-use-treatment services for women. Education of the public, including policy makers and health care providers is urgently needed to focus on addiction as a treatable medical illness. The need for more women centred services is also critical to the provision of effective treatment for substance-using women. PMID- 23756038 TI - Attention flexibly alters tuning for object categories. AB - Using functional MRI (fMRI) and a sophisticated forward encoding and decoding approach across the cortical surface, a new study examines how attention alternates tuning functions across a large set of semantic categories. The results suggest a dynamic attention mechanism that allocates greater resources to the attended and related semantic categories at the expense of unattended ones. PMID- 23756039 TI - Alkali activation processes for incinerator residues management. AB - Incinerator bottom ash (BA) is produced in large amount worldwide and in Italy, where 5.1 millionstons of municipal solid residues have been incinerated in 2010, corresponding to 1.2-1.5 millionstons of produced bottom ash. This residue has been used in the present study for producing dense geopolymers containing high percentage (50-70 wt%) of ash. The amount of potentially reactive aluminosilicate fraction in the ash has been determined by means of test in NaOH. The final properties of geopolymers prepared with or without taking into account this reactive fraction have been compared. The results showed that due to the presence of both amorphous and crystalline fractions with a different degree of reactivity, the incinerator BA geopolymers exhibit significant differences in terms of Si/Al ratio and microstructure when reactive fraction is considered. PMID- 23756040 TI - Interactions between climatic and production factors on returns of female pigs to service during summer in Japanese commercial breeding herds. AB - The objectives of this study were to determine the associations between climatic factors and production factors for returns to service of female pigs during summer and to quantify the associations between these factors and occurrences of returns to service. The factors that were assessed were as follows: maximum temperature (HT), relative humidity, age of gilts at first mating, parity, weaning-to-first-mating interval (WMI), and lactation length. The study analyzed records of 18,307 gilts in 99 herds and 78,135 parity records of 56,322 sows in 103 herds; all the females were first-serviced between June and September, 2007 to 2009. Average daily HT and relative humidity for 15 days post-service of a female were obtained from 21 local weather stations and coordinated with the performance data of the respective local herds. The returns to service were categorized into three groups: regular returns (RRs: 18-24 days), irregular returns (IRs: 25-38 days), and late returns to service (LRs: 39 days or later). Two-level mixed-effects models were applied to the data by using a herd at level 2 and an individual record at level 1. In mated gilts, the occurrences (%) of RRs, IRs, and LRs were 4.8%, 1.8%, and 5.3%, respectively. In mated sows, the respective occurrences were 3.3%, 1.8%, and 4.2%. Mean values (ranges) of HT and relative humidity were 28.4 degrees C (13.6 degrees C-39.8 degrees C) and 73.4% (35.0%-98.0%), respectively. In gilts, as HT increased from 25 degrees C to 30 degrees C, the occurrence of RR increased from 3.7% to 4.4% (P < 0.05). However, there was no association between the occurrence of RR and either relative humidity (P = 0.17) or age at first mating (P = 0.23). In addition, there were no associations between the occurrences of either gilt IR or LR and HT (P >= 0.05), relative humidity (P >= 0.46), or age at first mating (P >= 0.32). In sows, greater occurrences of RRs, IRs, and LRs were associated with higher HT, lower parity, and a WMI of 7 days or longer (P < 0.05), but they were not associated with relative humidity (P >= 0.62) or lactation length (P >= 0.13). The occurrence of RRs in sows of all WMI groups increased 1.22 (1.04(5)) times for each 5 degrees C increase in HT. For sows with WMI 0 to 6 days, each 5 degrees C rise in HT increased the occurrence of IRs and LRs by 1.36 (1.06(5)) and 1.27 (1.05(5)) times, respectively. However, there was no association between increased HT and occurrences of IRs or LRs for sows with WMI 7 days or longer (P >= 0.38). Therefore, in order to prevent returns to service, it is recommended that producers apply cooling management for females during the post-service periods in summer. PMID- 23756041 TI - Microorganisms in cryopreserved semen and culture media used in the in vitro production (IVP) of bovine embryos identified by matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS). AB - Commercial cattle breeders produce their own herd offspring for the dairy and beef market using artificial insemination. The procedure involves sanitary risks associated with the collection and commercialization of the germplasm, and the in vitro production and transfer of the bovine embryos must be monitored by strict health surveillance. To avoid the spreading of infectious diseases, one must rely on using controlled and monitored germplasm, media, and reagents that are guaranteed free of pathogens. In this article, we investigated the use of a new mass spectrometric approach for fast and accurate identification of bacteria and fungi in bovine semen and in culture media employed in the embryo in vitro production process. The microorganisms isolated from samples obtained in a commercial bovine embryo IVP setting were identified in a few minutes by their conserved peptide/protein profile, obtained applying matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS), matched against a commercial database. The successful microorganisms MS identification has been confirmed by DNA amplification and sequencing. Therefore, the MS technique seems to offer a powerful tool for rapid and accurate microorganism identification in semen and culture media samples. PMID- 23756042 TI - Two-way coupling between FSH and the dominant follicle in heifers. AB - Follicular Wave 1 and 2 and the associated FSH Surge 1 and 2 were used to designate the first two waves and surges of the interovulatory interval in two experiments in heifers. In experiment 1, a group with early (group E, N = 9) and late (group L, N = 5) development of the dominant follicle of Wave 1 were used as natural models to study FSH/follicle coupling. The day of wave emergence and the day of deviation in diameters between the two largest follicles were not different between groups. Emergence of Wave 2 and maximal FSH concentration in Surge 2 was approximately 1 day later (P < 0.03) in group L. Diameter of the dominant follicle of wave 1 (13.8 +/- 0.3 mm vs. 12.0 +/- 0.3 mm) and FSH concentrations in Surge 2 (0.29 +/- 0.02 ng/mL vs. 0.21 +/- 0.03 ng/mL) were first greater (P < 0.05) in group E than in group L at 4 and 5 days, respectively, after wave emergence. In experiment 2, treatment with estradiol (N = 8) when the dominant follicle of Wave 1 was >= 11 mm (Hour 0) resulted in a decrease (P < 0.02) in FSH and slower (P < 0.05) growth rate of the follicle between Hours 0 and 4. Results supported the following hypotheses: (1) the FSH surge that stimulates emergence of a follicular wave is associated with final growth of the dominant follicle of the previous anovulatory wave; and (2) suppression of FSH Surge 2 when the dominant follicle of Wave 1 is >= 11 mm is associated with a decrease in diameter. It is concluded for the first time that two-way FSH/follicle coupling in heifers continues during final growth of the dominant follicle of Wave 1 and that Surge 2 is the FSH source. PMID- 23756043 TI - Seminal plasma applied post-thawing affects boar sperm physiology: a flow cytometry study. AB - Cryopreservation induces extensive biophysical and biochemical changes in the sperm. In the present study, we used flow cytometry to assess the capacitation like status of frozen-thawed boar spermatozoa and its relationship with intracellular calcium, assessment of membrane fluidity, modification of thiol groups in plasma membrane proteins, reactive oxygen species (ROS) levels, viability, acrosomal status, and mitochondrial activity. This experiment was performed to verify the effect of adding seminal plasma on post-thaw sperm functions. To determine these effects after cryopreservation, frozen-thawed semen from seven boars was examined after supplementation with different concentrations of pooled seminal plasma (0%, 10%, and 50%) at various times of incubation from 0 to 4 hours. Incubation caused a decrease in membrane integrity and an increase in acrosomal damage, with small changes in other parameters (P > 0.05). Although 10% seminal plasma showed few differences with 0% (ROS increase at 4 hours, P < 0.05), 50% seminal plasma caused important changes. Membrane fluidity increased considerably from the beginning of the experiment, and ROS and free thiols in the cell surface increased by 2 hours of incubation. By the end of the experiment, viability decreased and acrosomal damage increased in the 50% seminal plasma samples. The addition of 50% of seminal plasma seems to modify the physiology of thawed boar spermatozoa, possibly through membrane changes and ROS increase. Although some effects were detrimental, the stimulatory effect of 50% seminal plasma could favor the performance of post-thawed boar semen, as showed in the field (Garcia JC, Dominguez JC, Pena FJ, Alegre B, Gonzalez R, Castro MJ, Habing GG, Kirkwood RN. Thawing boar semen in the presence of seminal plasma: effects on sperm quality and fertility. Anim Reprod Sci 2010;119:160-5). PMID- 23756044 TI - A potential molecular target for morphological defects of fetal alcohol syndrome: Kir2.1. AB - Fetal alcohol spectrum disorder (FASD) is a developmental disorder that affects up to 0.2% of births. FASD comprises severe cognitive and structural birth defects including cleft lip/palate, small jaw, wide-set eyes, dental abnormalities, digit abnormalities, small head, and short stature. Strict counseling guidelines stress abstaining from alcohol during pregnancy, but the prevalence of FASD persists. The lack of a convincing molecular target has hindered FASD research and treatment. Interestingly, mutations in an inwardly rectifying potassium channel, Kir2.1, cause a similar constellation of birth defects as in FASD. In other words, FASD phenocopies the traits conveyed by Kir2.1 mutations. Furthermore, alcohol directly binds to and modulates Kir2.1. Substantial evidence now suggests that alcohol targets Kir2.1 to cause the birth defects associated with FASD. This review compiles clinical, genetic, biochemical, electrophysiological, and molecular evidence that identifies Kir2.1 as a molecular target for FASD development and possibly therapeutic treatment. PMID- 23756047 TI - A role for clock genes in sleep homeostasis. AB - The timing and quality of both sleep and wakefulness are thought to be regulated by the interaction of two processes. One of these two processes keeps track of the prior sleep-wake history and controls the homeostatic need for sleep while the other sets the time-of-day that sleep preferably occurs. The molecular pathways underlying the latter, circadian process have been studied in detail and their key role in physiological time-keeping has been well established. Analyses of sleep in mice and flies lacking core circadian clock gene proteins have demonstrated, however, that besides disrupting circadian rhythms, also sleep homeostatic processes were affected. Subsequent studies revealed that sleep loss alters both the mRNA levels and the specific DNA-binding of the key circadian transcriptional regulators to their target sequences in the mouse brain. The fact that sleep loss impinges on the very core of the molecular circadian circuitry might explain why both inadequate sleep and disrupted circadian rhythms can similarly lead to metabolic pathology. The evidence for a role for clock genes in sleep homeostasis will be reviewed here. PMID- 23756045 TI - Skeletal muscle programming and re-programming. AB - The discovery of the transcription factor MyoD and its ability to induce muscle differentiation was the first demonstration of genetically programmed cell transdifferentiation. MyoD functions by activating a feed-forward circuit to regulate muscle gene expression. This requires binding to specific E-boxes throughout the genome, followed by recruitment of chromatin modifying complexes and transcription machinery. MyoD binding can be modified by both cooperative factors and inhibitors, including microRNAs that may serve as important developmental switches. Recent studies indicate that epigenetic regulation of MyoD binding sites is another important mechanism for controlling MyoD activity, which may ultimately limit its ability to induce transdifferentiation to cells with permissive epigenetic 'landscapes.' PMID- 23756048 TI - Estimation of hydrocarbon biodegradation rates in marine environments: a critical review of the Q10 approach. AB - Offshore oil & gas industry is moving exploration and production activities into Arctic and deep water regions. Governmental regulations require environmental impact assessments before operations to evaluate the possible effects of accidental oil releases. These are often performed by numerical fate models, like the Oil Spill Contingency and Response (OSCAR) model, which has become an industry standard in Norway. In this model, biodegradation rates are adjusted to local conditions by temperature compensation according to a Q10 approach. Q10 is the multiplier by which rates of enzymatic reactions increase at a 10 degrees C temperature rise. Herein, this Q10 approach implemented in the OSCAR model is investigated based on published data and novel obtained results. Overall, biodegradation rate predictions calculated by temperature compensation are found to be questionable, and choosing one universal Q10 value is considered not feasible. The high variation in Q10 values is herein attributed to indirect effects of temperature. PMID- 23756046 TI - Pediatric traumatic brain injury: language outcomes and their relationship to the arcuate fasciculus. AB - Pediatric traumatic brain injury (TBI) may result in long-lasting language impairments alongside dysarthria, a motor-speech disorder. Whether this co morbidity is due to the functional links between speech and language networks, or to widespread damage affecting both motor and language tracts, remains unknown. Here we investigated language function and diffusion metrics (using diffusion weighted tractography) within the arcuate fasciculus, the uncinate fasciculus, and the corpus callosum in 32 young people after TBI (approximately half with dysarthria) and age-matched healthy controls (n=17). Only participants with dysarthria showed impairments in language, affecting sentence formulation and semantic association. In the whole TBI group, sentence formulation was best predicted by combined corpus callosum and left arcuate volumes, suggesting this "dual blow" seriously reduces the potential for functional reorganisation. Word comprehension was predicted by fractional anisotropy in the right arcuate. The co morbidity between dysarthria and language deficits therefore seems to be the consequence of multiple tract damage. PMID- 23756049 TI - Hepatogenesis of murine induced pluripotent stem cells in 3D micro-cavitary hydrogel system for liver regeneration. AB - The discovery of induced pluripotent stem cell (iPSC) technology has raised hopes in circumventing the current limitations in cell-based therapies where autologous stem cells could be generated from terminally differentiated somatic cells. Given the relatively short history of iPSC research, most of the studies are scientific exploratory in nature and hence have minimal practical usage. In this study, we aimed to combine existing knowledge on iPSC differentiation with three dimensional (3D) scaffold platform so as to fabricate implantable constructs for liver regeneration. A micro-cavitary hydrogel (MCG) platform was employed as a continuous system for both colonies and/or EBs formation and differentiation. The advantage of MCG system is that it further enhances nutrient exchange and also permits greater living space for the encapsulated pluripotent stem cells to rapidly grow into colonies and/or EBs compared to typical non-MCG system. Murine iPSCs and embryonic stem cells (ESCs) were encapsulated respectively in alginate MCG system and after culturing for 10 days; colonies/EBs were formed spontaneously. Differentiation conditions were then introduced to direct the cells toward endodermal lineage and subsequently hepatic lineage and maturation. Up-regulation of endoderm markers and hepatic markers was observed in both iPSCs and ESCs suggesting that iPSC as effectively as the ESCs in MCG system. Urea and albumin production were significantly higher compared to monolayer culture, demonstrating the beneficial effects of MCG system. The results from this work provide foundation in understanding of iPSC differentiation in 3D engineered environment and aid in future biomedical research of iPSC technology. PMID- 23756050 TI - Striking a balance: fungal commensalism versus pathogenesis. AB - The environment is suffused with nearly countless types of fungi, and our immune systems must be tuned to cope with constant exposure to them. In addition, it is becoming increasingly clear that many surfaces of our bodies are colonized with complex populations of fungi (the mycobiome) in the same way that they are colonized with complex populations of bacteria. The immune system must tolerate colonization with commensal fungi but defend against fungal invasion. Truly life threatening fungal infections are common only when this balance is disrupted through, for example, profound immunosuppression or genetic mutation. Recent studies have begun to shed light on how this balance is established and maintained, and suggest future studies on the role of fungi in homeostatic conditions. PMID- 23756051 TI - 2D-Ultrasound and endocrinologic evaluation of placentation in early pregnancy and its relationship to fetal birthweight in normal pregnancies and pre eclampsia. AB - OBJECTIVES: To study the relationships between 2D ultrasound measurements of placentation and maternal serum (MS) levels of PAPP-A, inhibin A and fbetahCG in early pregnancy and subsequent fetal growth in pregnancies with a normal and abnormal outcome. STUDY DESIGN: Prospective population-based cohort study of 301 pregnancies with a normal outcome, 18 with a pregnancy complicated by pre-term delivery (PTD) and 14 with subsequent pre-eclampsia (PE). MAIN OUTCOME MEASURES: Basal placental surface area, placental thickness, ellipsivity and volume; MS PAPP-A and fbetahCG at 11-13 + 6 weeks, MS inhibin A at 15-22 weeks and birthweight centile at delivery. RESULTS: In the normal group, the basal surface area showed a significantly (P < 0.001) positive correlation with placental thickness and placental ellipsivity. With the exception of placental ellipsivity, all other placental ultrasound parameters were significantly related with birthweight centile. Inhibin A showed a significant (P < 0.005) correlation with birthweight centiles. The basal plate surface area and MS PAPP-A were significantly (P < 0.01 and P < 0.001, respectively) lower and MS inhibin A significantly (P < 0.01) higher in PE than in controls. No changes were found in pregnancies complicated by PTD. CONCLUSION: The basal plate surface area at 11-14 weeks reflects indirectly normal and abnormal placentation and development of the definitive placenta. Combined with MS PAPP-A and/or inhibin A levels this parameter could be useful in identifying from the end of the first trimester, pregnancies subsequently complicated with PE. PMID- 23756052 TI - Rikkunshito and isoliquiritigenin counteract 5-HT-induced 2C receptor-mediated activation of pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus. AB - Anorexia deteriorates the quality of life in patients with anorexia nervosa, stress disorders, gastrointestinal disorders, and cancer. Pro-opiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC), serotonin (5-HT) and its 2C receptor (5-HT2CR) are implicated in anorexia. Rikkunshito, a traditional Japanese medicine, has been used to treat anorexia and gastrointestinal disorders. The present study aimed to clarify whether rikkunshito influences the 5-HT action on ARC POMC neurons. We isolated single neurons from the ARC of adult rats and measured cytosolic Ca2+ concentration ([Ca2+](i)) by fura-2 microfluorometry combined with immunocytochemical identification of POMC neurons. Administration of 5-HT increased [Ca2+](i) in ARC neurons, and 80% of the 5-HT responsive neurons were immunoreactive to POMC. Rikkunshito concentration dependently and 5-HT2CR antagonist SB242084 significantly suppressed 5-HT-induced [Ca2+](i) increases. The rikkunshito-suppressed neurons highly overlapped SB242084-suppressed neurons. Isoliquiritigenin, an ingredient of rikkunshito, suppressed 5-HT-induced [Ca2+](i) increases to a lesser extent than rikkunshito. These results demonstrate that rikkunshito counteracts 5-HT-induced 5-HT2CR mediated Ca2+ signaling in ARC POMC neurons, and that isoliquiritigenin may serve as an active component of rikkunshito. The ability of rikkunshito to antagonize 5 HT action in ARC POMC neurons could underlie the rikkunshito's action to attenuate anorexia induced by excessive 5-HT release and/or action associated with psychiatric diseases, gastrointestinal disorders, cancer, and anti-cancer medicines. PMID- 23756053 TI - Ab initio potential energy and dipole moment surfaces of the F(-)(H2O) complex. AB - We present full-dimensional, ab initio potential energy and dipole moment surfaces for the F(-)(H2O) complex. The potential surface is a permutationally invariant fit to 16,114 coupled-cluster single double (triple)/aVTZ energies, while the dipole surface is a covariant fit to 11,395 CCSD(T)/aVTZ dipole moments. Vibrational self-consistent field/vibrational configuration interaction (VSCF/VCI) calculations of energies and the IR-spectrum are presented both for F( )(H2O) and for the deuterated analog, F(-)(D2O). A one-dimensional calculation of the splitting of the ground state, due to equivalent double-well global minima, is also reported. PMID- 23756054 TI - Latent class analysis identifies three subtypes of aggressive end-of-life care: a population-based study in Taiwan. AB - The aggressiveness of end-of-life (EOL) cancer care has often been analysed by the occurrence of several indicators, separately or aggregately. Whether aggressive EOL cancer care has different subtypes is unknown. This study sought to identify distinct subtypes of aggressive EOL care based on usage patterns of aggressive EOL-care indicators and to explore demographic, disease and treatment factors associated with the identified subtypes. This retrospective study linked data from 2001 to 2006 from three Taiwanese databases: National Registration of Death Database, Cancer Registration System and National Health Insurance claims database. Adult cancer patients (N=203,642) who died in 2001-2006 were selected. For these cancer patients' last month of life, we analysed eight indicators of aggressive EOL care: receiving chemotherapy, >1 emergency room visit, >1 hospitalisation, hospitalisation for >14 days, intensive care unit admission, received cardiopulmonary resuscitation, received intubation and received mechanical ventilation. Subtypes of aggressive EOL care were identified by latent class analysis. Among the study population, only 22.3% were treated by medical oncologists. Based on their profiles of EOL care, deceased cancer patients were classified into three subgroups: 'not aggressive' (45%), 'intent to sustain life' (33%) and 'symptom crisis' group (22%). Patients assigned to the 'intent to sustain life' group were less likely to have metastatic disease and to receive hospice care in the last year of life, but more likely to be cared for by non medical oncologists, to die within 2 months after diagnosis and to die in hospital. EOL cancer care may be improved by understanding factors related to different subtypes of aggressive EOL care. PMID- 23756055 TI - Acyclovir-resistant varicella-zoster virus keratitis in an immunocompetent patient. AB - Varicella-zoster virus (VZV) resistance to acyclovir (ACV) has only been reported in rare cases of immunocompromised patients. We report the first case of an immunocompetent patient with ACV-resistant VZV keratitis associated with a nucleotide deletion in the VZV thymidine kinase gene, leading to production of a truncated protein. PMID- 23756056 TI - Increased osteopontin expression in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patient cells is associated with IL-17 expression. AB - BACKGROUND: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological inflammatory disease associated with a predominant infiltration of CD4+ T lymphocytes, which are the main subset of HTLV-1-infected cells. It has been demonstrated that in cell line the viral Tax protein transcriptionnally regulate expression of osteopontin, an inflammatory cytokine associated with Th17 related pathologies. OBJECTIVES: The aim of the study was to explore osteopontin expression in HTLV-1 asymptomatic carriers and in HAM/TSP patients and consequences on IL17 expression. STUDY DESIGN: We quantified Tax, osteopontin, RORgamma, IL17 and IL22 mRNA expressions in cells from 10 HAM/TSP patients, 6 asymptomatic HTLV-1 carriers (ASY) and 4 HTLV-1-negative healthy donors during ex vivo culture. RESULTS: We observed that the expression of osteopontin was higher in HAM/TSP patients and correlated with Tax expression levels. Positive regulation of RORgamma, IL17 and IL22 were also observed during cell culture. CONCLUSIONS: Our results propose a new mechanism which could contribute to HAM/TSP pathogenesis. PMID- 23756057 TI - Special issue on International Conference on Industrial Bioprocesses, IFIB-2012: October 7-10, 2012, Taipei, Taiwan. PMID- 23756058 TI - Imidacloprid induced alterations in enzyme activities and energy reserves of the land snail, Helix aspersa. AB - The in vivo sublethal toxic effects (0.2 and 0.6 LD50) of topically applied imidacloprid on biochemical biomarkers in the land snail, Helix aspersa was examined. Biochemical perturbations were assessed by measuring the three enzymatic (Acetylcholinesterase, AChE; catalase, CAT and glutathione-S transferase, GST) activities and three energy reserves (protein, glycogen and lipids) in the snails. Snail samples were taken from each sublethal dose and control groups at 1, 3 and 7 days after treatment. The results revealed that there were overall decrease in AChE activity as well as depletion of lipids and glycogen contents in the imidacloprid-treated snails compared to control groups. The CAT and GST activities of treated snails with the sublethal doses of imidacloprid were significantly higher than those of untreated controls along the three times of exposure. Moreover, an increase in the level of total proteins was observed in animals treated with 0.6 LD50 imidacloprid compared to control groups. The alterations in all tested biochemical perturbations were most pronounced with the 0.6 LD50 than 0.2 LD50. This study suggests that alterations of the enzyme activities and energy reserves in this species that could be useful as biomarkers of imidacloprid exposure in the evaluation of terrestrial impacts of this insecticide. PMID- 23756059 TI - Primary headache pathophysiology in children: the contribution of clinical neurophysiology. AB - Although primary headaches are very prevalent also in pediatric age, most neurophysiologic studies in these diseases concerned only the adulthood. The neurophysiologic investigation of the pathophysiological mechanisms subtending migraine and tension-type headache in children and adolescents could be particularly interesting, since during the developmental age the migrainous phenotype is scarcely influenced by many environmental factors that can typically act on adult headache patients. The neurophysiologic abnormality most frequently found in adult migraineurs, that is the reduced habituation of evoked potentials, was confirmed also in migraine children, although it was shown to involve also children with tension-type headache. Some studies showed abnormalities in the maturation of brain functions in migraine children and adolescents. While the visual system maturation seems slowed in young migraineurs, the psychophysiological mechanisms subtending somatosensory spatial attention in migraine children are more similar to those of healthy adults than to those of age-matched controls. There are some still unexplored fields that will have to be subjects of future studies. The nociceptive modality, which has been investigated in adult patients with primary headaches, should be studied also in pediatric migraine. Moreover, the technique of transcranial magnetic stimulation, not yet used in young migraineurs, will possibly provide further elements about brain excitability in migraine children. PMID- 23756060 TI - Time-varying inter-hemispheric coherence during corpus callosotomy. AB - OBJECTIVE: Corpus callosotomy limits the bilateral synchrony of epileptic discharges. However, the instantaneous changes in bilateral synchrony during corpus callosotomy are unclear. The present study investigated how and when bilateral synchrony is suppressed in the anterior and then posterior steps of corpus callosotomy. METHODS: Intra-operative scalp electroencephalography (EEG) was recorded simultaneously with surgical video for six patients who underwent total corpus callosotomy for medically intractable drop attacks. The time-varying EEG inter-hemispheric coherence was quantified by wavelet transform coherence and trend analysis. RESULTS: The 4-13 Hz coherence decreased after corpus callosotomy in five patients. Significant decrease in coherence was observed only during the posterior step of callosal sectioning in three patients, but throughout both steps in two patients. CONCLUSIONS: Decrease in inter-hemispheric coherence is not always correlated with the stages of callosal sectioning. Inter-hemispheric coherence is decreased during the final stage of corpus callosotomy and the effect is maximized after sectioning is completed. SIGNIFICANCE: Various patterns of coherence decrease suggest individual variations in the participation of the corpus callosum in the genesis of bilateral synchrony. Time-varying inter hemispheric EEG coherence is useful to monitor the physiological completeness of corpus callosotomy. PMID- 23756061 TI - Structure-cytotoxic activity relationship of 3-arylideneflavanone and chromanone (E,Z isomers) and 3-arylflavones. AB - The E,Z-isomers of 3-arylidene substituted flavanone, chromanone and 3-aryl substituted flavone derivatives were tested in vitro for their cytotoxic activity against three cancer cell lines (HL-60, NALM-6, WM-115) and normal cell line (HUVEC). It was observed that substitution at C3 position led to significant enhance in cytotoxicity. Isomeric configuration of 3-arylideneflavanones had an influence on the cytotoxic potential. Multiple regression analysis combined with variable selection by genetic algorithm was used to model relationships between molecular descriptors and the cytotoxic activity. The most accurate QSAR models were based on a combination between energy of LUMO, experimental value of logP and partial charge on carbonyl oxygen (deltaO2). PMID- 23756062 TI - Discovery of TD-8954, a clinical stage 5-HT(4) receptor agonist with gastrointestinal prokinetic properties. AB - The discovery of a series of 5-HT4 receptor agonists based on a novel 2 alkylbenzimidazole aromatic core is described. Optimization of the 2-substituent of the benzimidazole ring led to a series of agonists with subnanomolar binding affinity and moderate-to-high intrinsic activity relative to that of 5-HT. Consistent with our previously described multivalent design approach to this target, subsequent optimization of the linker and secondary binding group regions of the series afforded compound 18 (TD-8954), a potent and selective 5-HT4 receptor agonist in vitro with demonstrated prokinetic activity in multiple species. PMID- 23756063 TI - The discovery of potent selective NPY Y(2) antagonists. AB - A series of small molecules with a piperidinyl core were synthesized and tested for binding affinity (IC50) at human Neuropeptide Y Y2 receptor. Various amide related analogs (ureas, reversed amides, and sulfonamides) were evaluated. Several potent and selective NPY Y2 antagonists were identified. PMID- 23756064 TI - Navy medicine's solution to chronic pain. PMID- 23756065 TI - A conceptual model of the psychological health system for U.S. active duty service members: an approach to inform leadership and policy decision making. AB - The influence of individual-level factors such as pretraumatic risk and protective factors and the availability of unit-level and enterprise-level factors on psychological health outcomes have been previously considered individually, but have not been considered in tandem across the U.S. Military psychological health system. We use the existing literature on military psychological health to build a conceptual system dynamics model of the U.S. Military psychological health system "service-cycle" from accession and deployment to future psychological health screening and treatment. The model highlights a few key observations, challenges, and opportunities for improvement for the system that relate to several topics including the importance of modeling operational demand combined with the population's psychological health as opposed to only physical health; the role of resilience and post-traumatic growth on the mitigation of stress; the positive and negative effects of pretraumatic risk factors, unit support, and unit leadership on the service-cycle; and the opportunity to improve the system more rapidly by including more feedback mechanisms regarding the usefulness of pre- and post-traumatic innovations to medical leaders, funding authorities, and policy makers. PMID- 23756066 TI - The Army Selected Reserve Dental Readiness System: overview, assessment, and recommendations. AB - The Army Selected Reserve Dental Readiness System (ASDRS) is a key dental program directed by the Assistant Secretary of the Army (Manpower & Reserve Affairs) starting in fiscal year 09. The Army National Guard and Army Reserve have steadily implemented ASDRS over the past 3 years as a means to improve the historically abysmal dental readiness of the Army Reserve Component (RC). Dental readiness is essential for sustaining an Army RC Operational Force. ASDRS is a tool for RC commanders to provide contract dental readiness care in support of over 558 thousand nonmobilized Selected Reserve Citizen-Soldiers dispersed throughout the 54 states and U.S. territories, at home station before alert, and if necessary after alert (throughout the Army force generation cycle). This article examines the status of ASDRS implementation, assesses its effectiveness in improving Army RC Dental Readiness, and provides Army leadership recommendations regarding the following focus areas: (1) command emphasis, (2) program execution, and (3) synergy with the Military Health System and Department of Veterans Affairs. PMID- 23756067 TI - Developing physical capability standards that are predictive of success on Special Forces selection courses. AB - This study aimed to develop minimum standards for physical capability assessments (vertical jump, sit and reach, push-ups, seven-stage sit-ups, heaves, agility, 20 m shuttle run, loaded 5-km pack march, and 400-m swim) that candidates must pass before they can commence Australian Army Special Forces (SF) selection courses. Soldiers (Part A: n = 104; Part B: n = 92) completed the physical capability assessments before commencing a SF selection course. At the beginning of these selection courses, participants attempted two barrier assessments (3.2-km battle run and 20-km march). Statistical analysis revealed several physical capability assessments were associated with performance on the barrier assessments and selection course outcome (Part A); however, these statistical models were unable to correctly classify all candidates as likely to pass or fail the selection course. Alternatively, manual analysis identified a combination of physical capability standards that correctly classified 14% to 18% of candidates likely to fail, without excluding any candidates able to pass (Part A). The standards were applied and refined through Part B and included completing the 5-km pack march in <=45:45 minutes : seconds, achieving >=level five on the sit-up test, or completing >=66 push-ups. Implementation of these standards may reduce attrition rates and enhance the efficiency of the SF recruitment process. PMID- 23756068 TI - Accession medical waivers and deployment duration in the U.S. Army. AB - To examine the performance of active duty U.S. Army personnel with accession medical waivers during combat deployments, the deployment duration and likelihood of early return from theater for medically waived (n = 18,093) and medically qualified (n = 250,209) personnel deploying between September 2001 and March 2011 were determined. The mean and median deployment duration for waived men (309.4 +/ 107.5 and 346) and for waived women (291.8 +/- 115.3 and 341) was not shorter than for medically qualified men (304.6 +/- 112.1 and 346) and women (289.5 +/- 116.3 and 337). When adjusted for other accession factors in a multivariate linear regression model, neither waived men (p = 1.00) nor women (p = 0.7713) had significantly shorter deployments. In a case-control analysis, 24,369 men and 3,094 women were defined as having a short deployment. Multivariate logistic regression found that medically waived men (odds ratio [OR] = 0.87, 95% confidence interval [CI] = 0.82-0.92) and women (OR = 1.02, 95% CI = 0.87-1.19) were not more likely to have shorter deployments compared to medically qualified individuals. These findings show that those with an accession medical waiver were not more likely to have shorter deployments or more likely to return early from deployment than those without waivers. PMID- 23756069 TI - Cross-cultural communication capabilities of U.S. military trainers: host nation perspective. AB - A survey was conducted to assess trainee perception of the cross-cultural communication competency of U.S. military trainers and their satisfaction with the training they received. Findings from the survey show that U.S. military trainers rely significantly on local interpreters. This indicates variability in the ability of the trainers to communicate effectively with host nation partners, the variability being dependent on the capabilities of the individual interpreter. The findings illustrate the importance of providing military health personnel with training on how to work effectively with interpreters. The use of supplementary resources such as electronic translation devises when the interpreter is not capable of conveying health-related training information with the desired level of accuracy is recommended. Expanding the availability of general cultural training, which provides baseline information on local values, traditions, and customs in addition to health-specific cultural orientation, is also recommended to help military health trainers customize their training content and methods to fit the local environment. PMID- 23756070 TI - Professional quality of life and associated factors among VHA chaplains. AB - Chaplains play a unique role in the Veterans Affairs (VA) health care systems and have numerous responsibilities. Compassion satisfaction (CS), compassion fatigue (CF), and burnout (BO) are three major phenomenons that have been documented in other helping professions, but little is known about VA Chaplains' professional quality of life. This study examines a national sample of VA Chaplains and their professional quality of life along with associated factors. Two-hundred and seventeen VA Chaplains completed an anonymous Internet survey, and regression analyses were conducted to determine which variables affect professional quality of life. On average, participants report high levels of CS and low levels of CF and BO. Gender, perceived support from VA administration, and mental health (MH) integration were significant predictors for CS. MH integration and perceived support significantly affected CF. Age, MH integration, and perceived support affected BO. Significant interaction effects were found for CF and BO. In summary, younger Chaplains and Chaplains who report low levels of collaboration with MH professionals are most likely to develop CF and BO. This supports continued support from the VA for interdisciplinary initiatives and mentorship of younger Chaplains. PMID- 23756071 TI - Psychometric evaluation of the Moral Injury Events Scale. AB - Literature describing the phenomenology of the stress of combat suggests that war zone experiences may lead to adverse psychological outcomes such as post traumatic stress disorder not only because they expose persons to life threat and loss but also because they may contradict deeply held moral and ethical beliefs and expectations. We sought to develop and validate a measure of potentially morally injurious events as a necessary step toward studying moral injury as a possible adverse consequence of combat. We administered an 11-item, self-report Moral Injury Events Scale to active duty Marines 1 week and 3 months following war-zone deployment. Two items were eliminated because of low item-total correlations. The remaining 9 items were subjected to an exploratory factor analysis, which revealed two latent factors that we labeled perceived transgressions and perceived betrayals; these were confirmed via confirmatory factor analysis on an independent sample. The overall Moral Injury Events Scale and its two subscales had favorable internal validity, and comparisons between the 1-week and 3-month data suggested good temporal stability. Initial discriminant and concurrent validity were also established. Future research directions were discussed. PMID- 23756072 TI - Impact of the 2009 influenza (H1N1) pandemic on the United States military health care system. AB - BACKGROUND: During public health emergencies, the Military Health System experiences challenges similar to those across the U.S. public and private health systems. This study explored how 1 such event, the 2009/2010 influenza (H1N1) pandemic, impacted health care utilization and associated costs in the Military Health System. METHODS: Data from the Military Data Repository were used to examine diagnoses, claims data, and dates of services with respect to military or civilian care during 2004-2009/2010 influenza seasons. Comparison analysis was conducted through two-tailed t-tests and regression models. RESULTS: There was a significant increase in inpatient and outpatient health care utilization during the 2009/2010 H1N1 pandemic year, most markedly for emergency department visits. The 2009/2010 H1N1 pandemic cost the Department of Defense $100 million compared to influenza-related health care costs incurred in previous influenza seasons. Highest health care utilization costs were found in children less than age 5. The greatest cost burden was attributed to immunizations for active duty personnel delivered at military facilities. CONCLUSION: Annual trend analysis of costs and health care utilization would be helpful to plan and resource emerging influenza pandemics and to identify subgroups at greatest risk for contracting influenza. PMID- 23756073 TI - Patterns and perceptions of supplement use by U.S. Marines deployed to Afghanistan. AB - Dietary supplements are implicated in an increasing number of minor and serious adverse events, including death. A series of adverse events in deployed Marines using multiple supplements prompted medical officers to investigate the prevalence of supplement use among Marines stationed on Camp Leatherneck, Afghanistan. The investigators developed a survey to identify the types of supplements used, patterns of supplement use, reasons for taking supplements, perceived benefits from using supplements, and self-reported adverse effects. Marines were invited to complete an anonymous 17-question survey while visiting recreational and athletic facilities. A total of 329 active duty Marines completed the survey. The prevalence of supplement use was 72% for males and 42% for females (p = 0.009). Of the 12% of Marines reporting side effects, 79% were taking multiple supplements and 89% were using stimulants. Deployment was significantly associated with new supplement use (p < 0.001). Of users, 81% noted an improvement in physical performance. The majority of deployed Marines use multiple dietary supplements and perceive a high benefit. Given the high prevalence of supplement use and recent deaths associated with supplement use, recommendations are needed to guide the use of certain supplements by U.S. Marines in the deployed environment. PMID- 23756074 TI - What is the real cost of an overnight stay after an ambulatory general surgical procedure? AB - INTRODUCTION: Outpatient surgery is performed widely throughout the Army Medical Command (MEDCOM). It is common practice throughout Medical Command to admit barracks dwelling active duty service members (ADSMs) undergoing ambulatory surgical procedures for overnight observation. We hypothesized that overnight observation of these individuals has not prevented adverse outcomes that would have otherwise occurred if the patient had been discharged to the barracks. METHODS: We reviewed the postoperative course of all ADSMs undergoing ambulatory surgery with subsequent overnight hospital stay because of primary barracks residence. Procedures included hernia repair, lipoma excisions, and pilonidal cystectomies. Inclusion criteria were ADSMs who stayed overnight purely on the basis of their military barracks residence. RESULTS: 145 patients met our inclusion criteria. Their mean age was 23 +/- 3.2, 90.9% were males. The mean hospital length of stay was 24 +/- 11.4 hours. There were four (2.78%) postoperative complications, three patients with postoperative urinary retention, and one patient with mild bleeding from a pilonidal excision site, all within 8 hours postoperatively. No adverse outcomes were noted during the period of their hospitalization. CONCLUSION: Barracks dwelling ADSMs do not have adverse outcomes during their inpatient observational hospitalization. An outpatient escort would be sufficient to ensure adequate observation. PMID- 23756075 TI - Re-evaluating the field tourniquet for the Canadian Forces. AB - OBJECTIVE: To determine the best field tourniquet for Medical Technician (Med Tech) use in the Canadian Forces (CF). METHODS: We conducted a prospective controlled trial, comparing the efficacy and ease of applicability of 3 types of commercially available windlass tourniquets in 4 tactical situations on simulated patients. The primary outcome was time to tourniquet application with secondary outcomes including effectiveness and Med Tech satisfaction. RESULTS: The overall finding of this study indicates that the Combat Application Tourniquet (C-A-T) was applied the fastest in each scenario and was also significantly the most effective in occluding distal blood flow. The survey results show that the 3 tourniquet types are similar in many of the measures of ease of learning and application, with the C-A-T scoring highest in self-application and the Special Operations Forces Tactical Tourniquet Wide having the lowest scores for both durability and effectiveness. CONCLUSION: When tested on a group of CF Med Techs, the C-A-T remained the CF field tourniquet of choice, based on the assessed criteria. Although there is inherent bias in the approach of this study, it reflects the process required to determine if a new piece of kit is superior to what is already considered the standard to a trained and equipped military. PMID- 23756076 TI - Risk factors for soft tissue knee injuries in active duty U.S. Army soldiers, 2000-2005. AB - BACKGROUND: There is a scarcity of analytic research on active duty Army (ADA) knee injuries (KI), such as soft tissue knee injuries (STKI), which are the predominant ADA KI pattern. PURPOSE: To quantify the independent adjusted association of significant ADA STKI risk factors, 2000-2005. MATERIALS/METHODS: Using the Total Army Injury and Health Outcomes Database, we (1) captured absolute STKI numbers and rates (N = 83,323) and (2) developed regression models to determine significant STKI risk factors. Models included STKI overall and subcategories: meniscus, patella, anterior/posterior cruciate ligament, and medial/lateral cruciate ligament. RESULTS: Eight risk factors significantly increased STKI. They are: (1) prior KI (within 2 years) (odds ratio [OR] 9.83, 95% confidence interval [CI] 9.67-10.00); (2) increasing length of service (OR 1.83, 95% CI 1.76-1.90); (3) increasing age (OR 1.57, 95% CI 1.50-1.65); (4) prior deployment (OR 1.39, 95% CI 1.36-1.41); (5) prior ankle injury (OR 1.16, 95% CI 1.14-1.19); (6) Infantry occupation (OR 1.12, 95% CI 1.04-1.21); (7) marital status (OR 1.10, 95% CI 1.08-1.12); (8) and prior hip injury (OR 1.08, 95% CI 1.03-1.12). MAJOR CONCLUSION: Soldiers with a prior KI have nearly a 10 fold increased relative risk of developing a subsequent STKI. PMID- 23756077 TI - Shock-absorbing insoles reduce the incidence of lower limb overuse injuries sustained during Royal Marine training. AB - This study was undertaken to determine whether the incidence of lower limb overuse injuries (LLOIs) sustained during Royal Marine training could be reduced by issuing the recruits with shock-absorbing insoles (SAIs) to wear in their military boots. This was a retrospective longitudinal trial conducted in two phases. Injury data from 1,416 recruits issued with standard Saran insoles and 1,338 recruits issued with SAI were compared. The recruits in the two groups were of similar height, body mass, and aerobic fitness and followed the same training course. The incidence of LLOI sustained by the recruits was lower (p < 0.05) in the SAI Group (19.0%) compared to the Saran Insole Group (31.7%). The incidences of lower limb stress fractures, tibial periostitis, tenosynovitis of foot, achilles tendonopathy, other tendonopathy and anterior knee pain were lower (p < 0.05) in the SAI Group. Tibial stress fracture incidence was lower (p < 0.05) in the SAI Group but metatarsal and femoral stress fracture incidences were the same for the two insole groups. Thus, issuing SAIs to military recruits undertaking a sustained, arduous physical training program with a high incidence of LLOI would provide a beneficial reduction in the incidence of LLOI. PMID- 23756078 TI - Computed tomography can improve the selection of fragment simulating projectiles from which to test future body armor materials. AB - INTRODUCTION: Ballistic protective materials used in body armor are tested with fragment simulating projectiles (FSPs). The type of FSP used has historically been made by choosing fragments representative of those produced by controlled explosions, which may not be representative of those fragments actually injuring soldiers. METHOD: 75 cylindrical FSPs of three different sizes were fired into six euthanized pigs, imaged using computed tomography (CT) and the wound tracks dissected. Skin entry wound locations, as determined by surface-shaded CT, were compared to clinical photographs. FSP dimensions and depth of penetration derived from CT were compared to surgical dissection using a Mann-Whitney U test. RESULTS: Skin entry wound locations derived from CT were identical to that seen clinically. FSP dimensions were consistently 15% to 19% larger than the true measurements, reflecting the magnifying effect associated with metallic artifact. No statistical difference (p = 0.26) was found between depth of penetration measured radiologically compared to dissection when a projectile did not hit bone but there was a statistical difference when bone was hit (p < 0.05). CONCLUSIONS: CT has the potential to accurately ascertain values required to improve the selection of representative FSPs from which future ballistic protective materials are tested. PMID- 23756079 TI - A rabbit osteomyelitis model to simulate multibacterial war wound infections. AB - A challenge facing military caregivers is the presence of multidrug-resistant infection in extremity wounds. Most frequently identified resistant strains are methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae (KP), Pseudomonas aeruginosa (PA), and Acinetobacter baumannii (AB). We adapted an existing osteomyelitis model to simulate an infected extremity wound for antibiotic testing. New Zealand White Rabbits (n = 95) were divided into 6 inoculation groups for infection with MRSA, KP, PA, and AB alone, and in multibacteria infections. Sodium morrhuate was injected into the left tibia to simulate blast wound trauma, then the respective bacteria or combination of pathogens, and finally sterile saline were injected. Colony-forming units for the mono-organism groups showed that AB, KP, or PA alone at 10(7) colony-forming units per mL (CFUs/mL) was effective for rabbit osteomyelitis induction. Colony forming units for the multiorganism groups showed that the combination of AB (10(7) CFUs/mL)/KP (10(7) CFUs/mL)/PA (10(7) CFUs/mL)/MRSA (10(5) CFUs/mL) yielded a 100% osteomyelitis induction rate. At 8 weeks, however, only one mono bacterial group and one multibacterial group showed significant radiographic improvement (p < 0.05). The rabbit model of osteomyelitis can be adapted to study infected blast wounds typical of those seen in veterans. To our knowledge, this is the first demonstration of the model simulating multibacterial infections with multidrug-resistant organisms. PMID- 23756080 TI - Methemoglobinemia in patients undergoing esophagogastroduodenoscopy: a randomized controlled trial. AB - BACKGROUND: Methemoglobinemia is a potentially life-threatening complication of local anesthetic sprays employed in upper endoscopy. There is limited information available on the incidence of this complication, and no prospective trial has ever undertaken to evaluate subclinical levels of methemoglobinemia. OBJECTIVE: To evaluate the incidence of subclinical methemoglobinemia in patients exposed to anesthetic spray. METHODS: Subjects were randomized to a "spray" or "no-spray" group. Subjects in the "spray" group received a 1-second benzocaine spray before upper endoscopy. All subjects in both groups were monitored with a noninvasive co oximetry device capable of detecting methemoglobin levels in real time. RESULTS: 401 subjects were enrolled (209 in the study group, 192 in the control group); mean peak methemoglobin concentrations were 0.82% (CI 0.74-0.90%, SD 0.57%) and 0.80% (CI 0.73-0.86%, SD 0.46%) respectively. There was no statistically significant difference between the two groups (p = 0.69). Only 3 (1.4%) subjects in the study group and 2 (1%) subjects in the control group had a peak methemoglobin concentration >2%. CONCLUSIONS: In this randomized clinical trial, no significant elevation of methemoglobin concentration was observed in any subject. Final analysis failed to demonstrate any statistically significant difference between the two groups. PMID- 23756081 TI - Frontotemporal hypoactivity during a reality monitoring paradigm is associated with delusions in patients with schizophrenia spectrum disorders. AB - INTRODUCTION: Impaired monitoring of internally generated information has been proposed to be one component in the development and maintenance of delusions. The present study investigated the neural correlates underlying the monitoring processes and whether they were associated with delusions. METHODS: Twenty healthy controls and 19 patients with schizophrenia spectrum disorders were administrated a reality monitoring paradigm during functional magnetic resonance imaging. During encoding participants were instructed to associate a statement with either a presented (viewed condition) or an imagined picture (imagined condition). During the monitoring session in the scanner, participants were presented with old and new statements and their task was to identify whether a given statement was associated with the viewed condition, imagined condition, or if it was new. RESULTS: Patients showed significantly reduced accuracy in the imagined condition with performance negatively associated with degree of delusions. This was accompanied with reduced activity in the left dorsolateral prefrontal cortex and left hippocampus in the patient group. The severity of delusions was negatively correlated with the blood-oxygenation-level dependent response in the left hippocampus. CONCLUSIONS: The results suggest that weakened monitoring is associated with delusions in patients with schizophrenia spectrum disorder, and that this may be mediated by a frontotemporal dysfunction. PMID- 23756082 TI - Motivational interviewing as a way to promote physical activity in obese adolescents: a randomised-controlled trial using self-determination theory as an explanatory framework. AB - Using self-determination theory (SDT) as an explanatory framework, this randomised-controlled study evaluates the effect of a motivational interviewing (MI)-based intervention as an addition to a standard weight loss programme (SWLP) on physical activity (PA) practice in obese adolescents over a six-month period. Fifty-four obese adolescents (mean age = 13 years, mean BMI = 29.57 kg/m2) were randomly assigned to an SWLP group (n = 28) or SWLP + MI group (n = 26). Both groups received two SWLP sessions, supplemented for the SWLP + MI group, by six MI sessions. Perceived autonomy support, perceived competence, motivational regulations, PA and BMI were assessed at baseline, three and six months (i.e. the end of the programme). MLM analyses revealed that compared to SWLP, the SWLP + MI group had a greater BMI decrease and a greater PA practice increase over time. Moreover, the SWLP + MI group reported greater autonomy support from medical staff at the end of the programme, greater increase in integrated and identified regulations and a stronger decrease in amotivation. MI appears as an efficient counselling method as an addition to an SWLP to promote PA in the context of pediatric obesity. PMID- 23756083 TI - Homocysteine, vitamin B12 and folate levels in Iranian patients with Multiple Sclerosis: a case control study. AB - BACKGROUND: Recently, homocysteine (Hcy), folate, and vitamin B12 have been proposed to have several roles on MS pathogenesis. OBJECTIVE: We performed this study to determine the role of serum levels of Hcy, vitamin B12, and folate in patients with relapsing remitting MS (RRMS) and compared them with healthy controls. METHODS: We recruited 75 RRMS patients and 75 subjects as controls with the same age and sex. Homocysteine was measured using fluorimetric high performance liquid chromatography. Plasma folate and vitamin B12 levels were measured through ion-capture method. RESULTS: Mean plasma levels of vitamin B12, folate, and Hcy in cases were 342.64 +/- 210.66 pg/ml, 9.74 +/- 4.77 ng/ml, and 22.73 +/- 11.63 MUM/L, respectively, which showed significant difference in comparison with the controls. In addition, there were significant correlations between mean serum Hcy levels and duration of disease (r=0.2, p=0.05) and treatment with interferon (r=0.21, p=0.01). In cases, Hcy level was higher among those on beta interferon (24.56 +/- 11.87 vs. 19.71 +/- 10.75, p=0.01). CONCLUSIONS: We concluded that serum levels of vitamin B12 and folate decreased in RRMS patients, but Hcy levels increased significantly. It seems necessary to conduct prospective trials to determine whether the treatment with supplements and correct biomarker levels in the early stage of the disease can change the course of the disease. We recommend regular checking of the serum level of Hcy in patients who use disease-modifying drugs. PMID- 23756084 TI - Cryptococcal encephalopathy without persisting cerebrospinal fluid pleocytosis, a diagnostic challenge: case report and review of the literature. PMID- 23756085 TI - Genetic variants of eNOS gene may modify the susceptibility to idiopathic male infertility. AB - In testis, eNOS is responsible for synthesis of nitric oxide (NO) which is an essential gas message regulator in spermatogenesis, suggesting that eNOS gene plays a role in normal spermatogenesis and the genetic variants of eNOS gene may be potential genetic risk factors of spermatogenesis impairment. In this study, the polymorphic distributions of three common polymorphism loci including T-786C, 4A4B and G894T in eNOS gene were investigated in 355 Chinese infertile patients with azoospermia or oligozoospermia and 246 healthy fertile men and a meta analysis was carried in order to explore the possible relationship between the three loci of eNOS gene and male infertility with spermatogenesis impairment. As a result, allele -786C of T-786C (11.4% versus 6.5%, p = 0.004) and 4A of 4A4B (11.0% versus 6.3%, p = 0.005) as well as genotype TC of T-786C (22.8% versus 13.0%, p = 0.002) and AB of 4A4B (18% versus 11%, p = 0.015) were significantly associated with idiopathic male infertility. The haplotypes T-4A-G (7.4% versus 4.1%, p = 0.015) and C-4B-G (7.6% versus 4.4%, p = 0.028) could increase the susceptibility to male infertility, whereas haplotype T-4B-G (67.0% versus 75.2%, p = 0.002) might be a protective factor for male infertility. The results of meta analysis revealed that the polymorphism of T-786C was associated with male infertility. These findings suggested that the variants of eNOS gene may modify the susceptibility to male infertility with impaired spermatogenesis. PMID- 23756086 TI - Mitochondrial disorders: aetiologies, models systems, and candidate therapies. AB - It has become evident that many human disorders are characterised by mitochondrial dysfunction either at a primary level, due to mutations in genes whose encoded products are involved in oxidative phosphorylation, or at a secondary level, due to the accumulation of mitochondrial DNA (mtDNA) mutations. This has prompted keen interest in the development of cell and animal models and in exploring innovative therapeutic strategies to modulate the mitochondrial deficiencies observed in these diseases. Key advances in these areas are outlined in this review, with a focus on Leber hereditary optic neuropathy (LHON). This exciting field is set to grow exponentially and yield many candidate therapies to treat this class of disease. PMID- 23756087 TI - Mixed polarity in polarization-induced p-n junction nanowire light-emitting diodes. AB - Polarization-induced nanowire light emitting diodes (PINLEDs) are fabricated by grading the Al composition along the c-direction of AlGaN nanowires grown on Si substrates by plasma-assisted molecular beam epitaxy (PAMBE). Polarization induced charge develops with a sign that depends on the direction of the Al composition gradient with respect to the [0001] direction. By grading from GaN to AlN then back to GaN, a polarization-induced p-n junction is formed. The orientation of the p-type and n-type sections depends on the material polarity of the nanowire (i.e., Ga-face or N-face). Ga-face material results in an n-type base and a p-type top, while N-face results in the opposite. The present work examines the polarity of catalyst-free nanowires using multiple methods: scanning transmission electron microscopy (STEM), selective etching, conductive atomic force microscopy (C-AFM), and electroluminescence (EL) spectroscopy. Selective etching and STEM measurements taken in annular bright field (ABF) mode demonstrate that the preferred orientation for catalyst-free nanowires grown by PAMBE is N-face, with roughly 10% showing Ga-face orientation. C-AFM and EL spectroscopy allow electrical and optical differentiation of the material polarity in PINLEDs since the forward bias direction depends on the p-n junction orientation and therefore on nanowire polarity. Specifically, C-AFM reveals that the direction of forward bias for individual nanowire LEDs changes with the polarity, as expected, due to reversal of the sign of the polarization-induced charge. Electroluminescence measurements of mixed polarity PINLEDs wired in parallel show ambipolar emission due to the mixture of p-n and n-p oriented PINLEDs. These results show that, if catalyst-free III-nitride nanowires are to be used to form polarization-doped heterostructures, then it is imperative to understand their mixed polarity and to design devices using these nanowires accordingly. PMID- 23756088 TI - Cell-free epstein-barr viral loads in childhood hodgkin lymphoma: a study from South India. AB - Cell-free Epstein-Barr viral (EBV) DNA is detectable in plasma of patients with EBV-related lymphomas. The aim of this study was to evaluate the utility of plasma EBV DNA as a biomarker of EBV association in childhood Hodgkin lymphoma (HL). Furthermore, an attempt was made to evaluate the effectiveness of viral quantitation for assessing response to chemotherapy. Thirteen cases of childhood HL were included in this study. All 13 cases were EBV associated as reflected by expression of EBV LMP1 in the tumor specimen. Eighty-five percent had detectable EBV DNA levels; viral loads ranging from 2.9 to 156.2 * 103 copies/ml (mean 29 * 103 copies/ml); while in 2 patients and 30 controls tested, viral DNA was undetectable. In four patients, follow-up samples were available after three cycles of chemotherapy; all had EBV DNAemia prior to chemotherapy but undetectable EBV DNA posttherapy. This corroborated with complete response in these four patients. Plasma EBV viral load quantification maybe a useful tool for detecting EBV association with lymphomas and in monitoring response to treatment in childhood HL in centers with limited resources, more so in India where majority of childhood HL is likely to be EBV associated. This is the first Indian study estimating plasma EBV viral loads in HL. PMID- 23756089 TI - Detection of PAX2 deletions and duplications using multiplex ligation-dependent probe amplification. AB - BACKGROUND: Renal coloboma syndrome (RCS) is a rare inherited disorder caused by mutations in the PAX2 gene. Clinical testing is currently performed by bidirectional Sanger sequencing of all 12 coding exons of the PAX2 gene, which detects point mutations or small insertion/deletion mutations. Large genomic deletions of PAX2 have been identified in 3/90 known RCS families, accounting for approximately (3%) of RCS cases. In these cases, the deletion was detected by cytogenetic techniques such as G-banding or array comparative genomic hybridization. While these methods would be sufficient to identify whole gene deletions, they may not be able to identify smaller rearrangements affecting single exons. Similarly, such deletions would not be detected by Sanger sequencing. AIM: The aim of this study was to determine whether mutation-negative RCS probands harbor a genomic deletion or duplication involving one or more exons of the PAX2 gene. We evaluated this hypothesis in 46 patients with a clinical suspicion of RCS in whom no mutations were identified. RESULTS: We developed a multiplex ligation-dependent probe amplification assay to detect gene deletion/duplication in all 12 exons of the PAX2 gene. Of the 46 PAX2 mutation negative samples tested, none demonstrated deletions or duplications in the PAX2 gene. This suggests that deletions or duplications in PAX2 are unlikely to significantly contribute to the pathogenesis of RCS, beyond the known 3% of cases that have been attributed to whole gene deletions. Given these results, we hypothesize that other genes and/or locus control regions regulating PAX2 may be involved in the pathogenesis of PAX2 mutation-negative cases of RCS. PMID- 23756090 TI - Glucose-insulin regulation model with subcutaneous insulin injection and evaluation using diabetic inpatients data. AB - Closed-loop insulin delivery systems often implement glucose measurement and insulin administration in the subcutis. However some existing models for glucose insulin system ignored the dynamics of subcutaneous glucose and subcutaneously injected insulin. This paper reports a two-compartment model that includes glucose and insulin dynamics in subcutis, and its evaluation using patient data. Clinical information such as glucose level, insulin dosage, insulin injection time and meals of anonymous diabetes inpatients was collected. Measured glucose level of the diabetic inpatients agrees with that of computer simulation. Due to the lack of glucose-insulin model with subcutaneously-injected insulin for type 2 diabetic patients, our model was compared with existing model for type 1 subjects. The new glucose-insulin model can mimic dynamics of glucose and insulin under the disturbance of insulin injections and meals. Model parameters were estimated using nonlinear least square method and their effect on pathology and physiology of diabetes were analyzed. PMID- 23756092 TI - Clinical significance of survivin and VEGF mRNA detection in the cell fraction of the peripheral blood in non-small cell lung cancer patients before and after surgery. AB - PURPOSE: The aim of this study was to evaluate the predictive and prognostic value of peripheral blood survivin and VEGF mRNA expression levels in non-small cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Fifty-eight patients with stage I-IIIA NSCLC who underwent surgical resection were enrolled in this study. Thirty-six patients with benign lung disease (BLD) entered this study as control group. Quantitative real-time PCR was used to detect survivin and VEGF mRNA levels in the cell fraction of peripheral blood in NSCLC patients before and after surgery and BLD patients. The relationship between blood survivin and VEGF mRNA levels and patients clinicopathologic parameters and prognostic factors were investigated. RESULTS: The levels of survivin and VEGF mRNA were decreased significantly after surgery in NSCLC patients (P = 0.024 and P = 0.012 respectively). Tumor recurrence was significantly more frequent in NSCLC patients with survivin and VEGF mRNA positivity postoperation than in patients without (P = 0.003 and P = 0.006, respectively). Patients with survivin or VEGF mRNA positivity postoperation had markedly shorter disease-free survival (DFS) and overall survival (OS) than patients without (P = 0.023 and P = 0.016 for survivin; P = 0.031 and P = 0.025 for VEGF, respectively). Multivariate analysis showed that survivin positivity preoperation (P = 0.026, P = 0.041, respectively) and postoperation (P = 0.003, P = 0.005, respectively) and VEGF mRNA positivity postoperation (P = 0.007, P = 0.009, respectively) were independently associated with DFS and OS. CONCLUSION: Although the levels of surviving and VEGF mRNA were decreased significantly after surgery, postoperative detections of survivin and VEGF mRNA by quantitative real-time PCR could be used as tools to monitor tumor recurrence and predict prognosis. PMID- 23756093 TI - Metabolism in physiological cell proliferation and differentiation. AB - Stem and progenitor cells proliferate and give rise to other types of cells through differentiation. Deregulation of this process can lead to many diseases including cancer. Recent evidence suggests that an extensive metabolic reconfiguration of cancer cells allows them to sustain pathological growth by providing anabolic intermediates for biosynthesis. This raises the question of the physiological role of metabolic pathways during normal cell growth and differentiation. Metabolism changes with differentiation, and metabolic pathways may be controlled by the same signals that control cell proliferation and differentiation. However, metabolism could also reciprocally influence these signals. The role of metabolic regulation may extend beyond the provision of intermediates for the biosynthetic needs of proliferation, to affect cell differentiation. Here we bring together a large number of recent studies that support this suggestion and illustrate some of the mechanisms by which metabolism is linked to cell proliferation and differentiation. PMID- 23756095 TI - A call for institutional policies on postmortem sperm retrieval. PMID- 23756096 TI - New insights in aneuploidy screening: old principles, new approaches. PMID- 23756094 TI - Emerging roles for ribonucleoprotein modification and remodeling in controlling RNA fate. AB - In the cell, mRNAs and non-coding RNAs exist in association with proteins to form ribonucleoprotein (RNP) complexes. Regulation of RNP stability and function is achieved by alterations to the RNP through poorly understood mechanisms into which recent studies have now begun to provide insight. This emerging body of work points to chemical modification of RNPs at the RNA or protein level and ATP dependent RNP remodeling by RNA helicases/RNA-dependent ATPases as central events that dictate RNA fate. Some RNP modifications serve as tags for recruitment of regulatory proteins, with RNP modifiers and recruited proteins analogous to the writers and readers of chromatin modification, respectively. This review highlights examples in which RNP modification and ATP-dependent remodeling play key roles in the control of eukaryotic RNA fate, suggesting that we are only at the beginning of uncovering the multitude of ways in which RNP modification and remodeling impact RNA regulation. PMID- 23756097 TI - The nasal epithelium provides an easier alternative than the oviduct for the study of ciliary beating. PMID- 23756098 TI - Prevalence of polycystic ovary syndrome in adolescents. AB - OBJECTIVE: To investigate the prevalence of polycystic ovary syndrome (PCOS) in adolescents and its association with obesity. DESIGN: Cross-sectional study using electronic medical records. SETTING: Not applicable. PATIENT(S): Adolescents aged 15-19 years (n = 137,502). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): PCOS diagnosed or defined according to National Institutes of Health (NIH) criteria. RESULT(S): The prevalence of a confirmed diagnosis of PCOS was 0.56%, which increased to 1.14% when undiagnosed cases with documented symptoms qualifying for PCOS according to NIH criteria were included. Compared with normal/underweight girls, the odds ratios (OR and 95% confidence interval [CI]) for confirmed PCOS diagnosis were 3.85 (3.04-4.88), 10.25 (8.16-12.84), and 23.10 (18.66-28.61) for overweight, moderately obese, and extremely obese adolescents, respectively, after adjusting for potential confounders. When adolescents with two or more supportive diagnoses were included (diagnosed and undiagnosed PCOS-NIH), the ORs (95% CI) for PCOS-NIH by weight class were significantly attenuated to 2.95 (2.53 3.44), 6.73 (5.78-7.83), and 14.65 (12.73-16.86) for overweight, moderately obese, and extremely obese adolescents, respectively. CONCLUSION(S): Overweight and obesity were associated with higher odds of PCOS in adolescents. Studies based solely on diagnosis codes may underestimate the prevalence of PCOS and overestimate the magnitude of the association between obesity and PCOS. PMID- 23756099 TI - The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. AB - OBJECTIVE: To demonstrate the clinical value of the endometrial receptivity array (ERA) in patients with repeated implantation failure (RIF), for guiding their personalized embryo transfer (pET) as a novel therapeutic strategy. DESIGN: Prospective interventional multicenter clinical trial. SETTING: University affiliated infertility and private clinics. PATIENT(S): Eighty-five RIF patients and 25 comparison patients. INTERVENTION(S): Endometrial sampling and pET guided by ERA. MAIN OUTCOME MEASURE(S): A receptive (R) or nonreceptive (NR) endometrial status according to ERA. Pregnancy (PR) and implantation (IR) rates after pET. RESULT(S): The ERA test gave an R result of 74.1% in RIF patients versus 88% in control subjects. Clinical follow-up was possible in 29 RIF patients, in whom pET was performed, resulting in 51.7% PR and 33.9% IR. The IRs and PRs in the 6 months after the biopsy showed that pregnancy was not related to the local injury. Twenty-two RIF patients (25.9%) were NR, and in 15 of them a second ERA validated a displacement of the window of implantation (WOI). In eight of them, pET was performed on the day designated by the ERA, resulting in 50.0% PR and 38.5% IR. These results should be considered as preliminary. CONCLUSION(S): There is an increased percentage of WOI displacement in RIF patients compared with comparison group patients, leading to the concept of pET as a therapeutic strategy. Rescue of NR patients by pET in a displaced WOI results in similar PR and IR. PMID- 23756100 TI - Dentinal tubules sealing by means of diode lasers (810 and 980 nm): a preliminary in vitro study. AB - OBJECTIVE: The aim of this study was to evaluate the effect on dentinal surfaces of diode lasers (810 and 980 nm) at different parameters. MATERIALS AND METHODS: Twenty-four caries-free human impacted wisdom teeth were used. The crowns were sectioned transversely in order to expose the dentin. The smear layer was removed by a 1 min application of ethylenediaminetetraacetic acid (EDTA). Each surface was divided into four quadrants irradiated at a different output power setting for each kind of laser: 0.8, 1, 1.6, and 2 W (energy densities: 2547, 3184, 5092, and 6366 J/cm(2), irradiation speed 1 mm/sec; optical fiber diameter: 200 MUm; continuous and noncontact mode). Half of the samples were stained with a graphite paste. All specimens were sent for scanning electron microscopic (SEM) analysis. Pulp temperature increases in additional 20 teeth were measured by a thermocouple. RESULTS: Diode laser irradiations at 0.8 and 1 W led to occlusion or narrowing of dentin tubules without provoking fissures or cracks. The application of graphite paste increased the thermal effects in dentin. Measurements of pulp temperature showed that irradiations at 0.8 and 1 W for a period of 10 sec in continuous mode increased pulp temperature (T <=2 degrees C). CONCLUSIONS: Diode lasers (810 and 980 nm) used at 0.8 and 1 W for 10 sec in continuous mode were able to seal the dentin tubules. These parameters can be considered harmless for pulp vitality, and may be effective in the treatment of dentinal hypersensitivity. PMID- 23756091 TI - Preexposure prophylaxis (PrEP) of HIV infection in France: a nationwide cross sectional study (PREVIC study). AB - Although preliminary studies showed that preexposure prophylaxis (PrEP) lowers the HIV transmission in individuals with HIV, confirmative trials are ongoing and PrEP is not routinely recommended. The aim of this study was to assess whether individuals with HIV share antiretroviral (ARV) drugs for PrEP and to describe awareness and discussion on PrEP in this population. A cross-sectional survey was conducted in France in 23 representative departments of infectious diseases and internal medicine. Physicians administered an anonymous standardized questionnaire to all individuals with HIV receiving ARVs and followed between 24 and 31 October 2011. The questionnaire included items regarding PrEP (awareness; discussion with their close circle, physician or patients' association; experience), personal sociodemographic characteristics, risk behaviors and HIV status of the participants. Five hundred and ninety three participants were recruited: male 74.2% (men who have sex with men 52.4%, heterosexuals 21.6%), member of patient's association 9.8%. Half of them (50.6%) lived with a stable partner and 35.2% with an HIV-negative partner. Almost half (41.8%) were aware and 29.5% had had discussion about PrEP. In logistic regression, awareness and discussion on PrEP were more frequent: (1) among males, in patients' association members (p< 0.001 for both) and in nonheterosexuals (p=0.023 and 0.057, respectively); (2) among women, in those not living with a stable partner (p=0.035 and p=0.03, respectively) or living with an HIV-negative partner (p=0.049 and p=0.083, respectively). One percent of the participants declared having shared ARVs with someone and 8.3% reported PrEP in their close circle. Men reporting PrEP in their close circle shared ARVs more frequently than those who did not (10.3% vs. 0.2%, p < 0.001). Today, individuals with HIV do not seem to widely share personal ARVs for PrEP with seronegative people. A significant number of individuals with HIV are aware of and commonly discuss PrEP. PMID- 23756101 TI - Push-out bond strength between composite core buildup and fiber-reinforced posts after different surface treatments. AB - OBJECTIVE: The aim of this study was to evaluate the effects of different surface treatments on the pushout bond strength of fiber-reinforced posts to composite resin cores. MATERIALS AND METHODS: Twenty-five translucent glass fiber posts were divided into five groups according to surface treatment methods as follows: an untreated control group, a group coated with silicated alumina particles (Co Jet system, 3M ESPE, St. Paul, MN), and three groups undergoing surface preparation with erbium:yttrium-aluminum-garnet (Er:YAG) laser under three different power settings (150, 300, and 450 mJ at 10 Hz for 60 sec at 100 MUs duration). After surface treatment, fiber posts were built up to a dual cure composite resin core. All of the specimens were set and sectioned perpendicularly along the long axis of the post using a saw. Two discs (thickness of 2 mm) were obtained from each post-core sample; finally, each group consisted of 10 samples. For artificial aging, the specimens were stored in water (37 degrees C) for 24 h and subjected to thermal cycling (5000 cycles, 5-55 degrees C, and 30 sec dwell time). Pushout tests were performed using a universal testing machine at a crosshead speed of 0.5 mm/min. The pushout pressure values were measured in MPa and analyzed using one way analysis of variance (ANOVA) and Tukey's honestly significant difference (HSD) post-hoc test (p<0.05). Fiber post surface images were obtained using a scanning electron microscope (SEM). RESULTS: The bond strength values ranged between 14,949 and 23,879 MPa. The lowest values were observed in the groups treated with the Er:YAG laser at 150 mJ. Irradiation by the Er:YAG laser at 450 mJ affected the bond strength significantly (p<0.05). After Co-Jet sandblasting, the bond strength increased relatively (19,184 MPa). CONCLUSIONS: Er:YAG laser irradiation enhanced the bond strength of fiber reinforced posts to composite resin cores depending upon the power applied; Co Jet sandblasting also increased the bond strength. PMID- 23756102 TI - The impact of neurobehavioral features on medication adherence in HIV: evidence from longitudinal models. AB - Effective antiretroviral therapy has led to substantial improvements in health related outcomes among individuals with HIV. Despite advances in HIV pharmacotherapy, suboptimal medication adherence remains a significant barrier to successful treatment. Although several factors have been associated with medication adherence in the extant literature, study assessing the effects of some of the neurobehavioral features specific to HIV has been limited. Moreover, although there is a growing body of literature measuring medication adherence in HIV prospectively, few employ advanced statistical methodologies suited to handle advanced models with multiple predictors that would strengthen our understanding of medication adherence trajectories in HIV. This study sought to integrate traditionally assessed predictors of medication adherence with neurobehavioral features of HIV in a longitudinal study of medication adherence to combined antiretroviral therapy (cART). The current study used multilevel modeling to examine a wide arrangement of categories of factors - demographic, medication related, psychosocial, and neurobehavioral - on medication adherence. The sample consisted of 235 HIV+ individuals whose medication adherence was monitored over the course of six months using electronic monitoring devices. After controlling for the effects of demographic, medication, and psychosocial factors, neurobehavioral features added predictive validity to the model. In the final model, simultaneously controlling for the effects of each of the predictors within all the categories, age, self-efficacy, executive functioning, apathy, and frequency of stimulant use emerged as unique individual predictors of average medication adherence across the 6-month study. Self-efficacy and irritability predicted changes in medication adherence over time. Adherence behavior is multidetermined. Adequate assessment of these factors, combined with timely intervention, appears to be warranted in order to boost adherence rates. PMID- 23756103 TI - Screening for obstructive sleep apnea: is overnight oximetry the best solution? PMID- 23756104 TI - Ecological novelty and the emergence of evolutionary traps. AB - Human-induced rapid environmental change (HIREC; e.g., climate change or exotic species) has caused global species declines. Although behavioral plasticity has buffered some species against HIREC, maladaptive behavioral scenarios called 'evolutionary traps' are increasingly common, threatening the persistence of affected species. Here, we review examples of evolutionary traps to identify their anthropogenic causes, behavioral mechanisms, and evolutionary bases, and to better forecast forms of HIREC liable to trigger traps. We summarize a conceptual framework for explaining the susceptibility of animals to traps that integrates the cost-benefit approach of standard behavioral ecology with an evolutionary approach (reaction norms) to understanding cue-response systems (signal detection). Finally, we suggest that a significant revision of conceptual thinking in wildlife conservation and management is needed to effectively eliminate and mitigate evolutionary traps. PMID- 23756105 TI - Biodiversity data should be published, cited, and peer reviewed. AB - Concerns over data quality impede the use of public biodiversity databases and subsequent benefits to society. Data publication could follow the well established publication process: with automated quality checks, peer review, and editorial decisions. This would improve data accuracy, reduce the need for users to 'clean' the data, and might increase data use. Authors and editors would get due credit for a peer-reviewed (data) publication through use and citation metrics. Adopting standards related to data citation, accessibility, metadata, and quality control would facilitate integration of data across data sets. Here, we propose a staged publication process involving editorial and technical quality controls, of which the final (and optional) stage includes peer review, the most meritorious publication standard in science. PMID- 23756106 TI - Environmental stressors alter relationships between physiology and behaviour. AB - Although correlations have frequently been observed between specific physiological and behavioural traits across a range of animal taxa, the nature of these associations has been shown to vary. Here we argue that a major source of this inconsistency is the influence of environmental stressors, which seem capable of revealing, masking, or modulating covariation in physiological and behavioural traits. These effects appear to be mediated by changes in the observed variation of traits and differential sensitivity to stressors among phenotypes. Considering that wild animals routinely face a range of biotic and abiotic stressors, increased knowledge of these effects is imperative for understanding the causal mechanisms of a range of ecological phenomena and evolutionary responses to stressors associated with environmental change. PMID- 23756107 TI - Investigating the association of vitamin D seasonality on inflammatory and hemostatic markers. AB - Seasonal variations in health outcomes are commonly used to hypothesize a link with nutritional vitamin D (25-hydroxyvitamin D, 25(OH)D) status. The majority of vitamin D intake is from skin exposure to sunlight and varies seasonally in countries at a distance away from the Equator. However, despite the strong seasonality of vitamin D intake, no statistical method using cyclical patterns has been proposed to deduce an association between 25(OH)D and health indicators. Our motivation was to overcome the influence of related confounders, such as obesity, between 25(OH)D and health indicators: obesity would be expected to have little or no effect on the seasonal variations in 25(OH)D and in five inflammatory/hemostatic health outcomes (fibrinogen, tissue plasminogen activator [tPA], von Willebrand factor [vWF], C-reactive protein [CRP], and D-dimer). The data analyzed was from the 1958 British birth cohort biomedical survey (n = 6195) and the biomarkers were ascertained from blood drawn over an 18-mo period. We used mediation analysis to determine whether the seasonal variations of the outcomes were mediated by 25(OH)D to infer an association. The assumptions of mediation analysis fit naturally into the study's cross-sectional setting, where day of year of blood collection is the independent variable transformed by the harmonic function, and 25(OH)D is the mediator of the seasonal variation of the outcomes. The harmonic terms were tested to establish the presence of seasonal variation in the outcomes and 25(OH)D in order to determine whether the statistical mediation test could be applied. The data were collected over an 18 mo period and assayed in multiple batches to measure the serum biomarkers. When the assay batches were modeled as fixed effects, significant correlation was found with date of when blood was drawn. Thus, variation in assay batches was accounted for as random effects terms on the intercept in linear mixed-effects models. Inferences were based on tests from mediation analysis defined by the product of regression coefficients; we extended this test to allow for harmonic functions with multiple frequencies in order to statistically test the mediated effect through 25(OH)D. This was done using parametric bootstrap when the models were run in the Frequentist setting. We also replicated the analyses in the Bayesian setting to ascertain the change in amplitude of the seasonal variation that was due to 25(OH)D. Out of the five health outcomes, three (tPA, D-dimer, and fibrinogen) had significant seasonal associations that were partially mediated through 25(OH)D, one (vWF) had a seasonal pattern not mediated through 25(OH)D, and finally another (CRP) had no significant seasonal pattern. The association of 25(OH)D was strongest for tPA, and less so for D-dimer and fibrinogen. Our results and adaption of the mediation test show that there is broad potential in using seasonal variations of health indicators to deduce an association that may have not been affected by nonseasonal confounding. PMID- 23756108 TI - Clinical evaluation of microRNA expression profiling in non small cell lung cancer. AB - Deregulation of miRNAs expression levels has been detected in many human tumor types, and recent studies have demonstrated the critical roles of miRNAs in cancer pathogenesis. Numerous recent studies have shown that miRNAs are rapidly released from tissues into the circulation in many pathological conditions. The high relative stability of miRNAs in biofluids such as plasma and serum, and the ability of miRNA expression profiles to accurately classify discrete tissue types and disease states have positioned miRNAs as promising non-invasive new tumor biomarkers. In this study, we used liquid bead array technology (Luminex) to profile the expression of 320 mature miRNAs in a pilot testing group of 19 matched fresh frozen cancerous and non-cancerous tissues from NSCLC patients. We further validated our results by RT-qPCR for differentially expressed miRNAs in an independent group of 40 matched fresh frozen tissues, 37 plasma samples from NSCLC patients and 28 healthy donors. We found that eight miRNAs (miR-21, miR 30d, miR-451, miR-10a, miR-30e-5p and miR-126*, miR-126, miR-145) were differentially expressed by three different statistical analysis approaches. Two of them (miR-10a and miR-30e-5p) are reported here for the first time. Bead-array results were further verified in an independent group of 40 matched fresh frozen tissues by RT-qPCR. According to RT-qPCR miR-21 was significantly up-regulated (P = 0.010), miR-126* (P = 0.002), miR-30d (P = 0.012), miR-30e-5p (P < 0.001) and miR-451 (P < 0.001) were down-regulated, while miR-10a was not differentiated (P = 0.732) in NSCLC tissues. However, in NSCLC plasma samples, only three of these miRNAs (miR-21, miR-10a, and miR-30e-5p) displayed differential expression when compared to plasma of healthy donors. High expression of miR-21 was associated with DFI and OS both in NSCLC tissues (P = 0.022 and P = 0.037) and plasma (P = 0.045 and P = 0.065), respectively. Moreover, we report for the first time that low expression of miR-10a in NSCLC plasma samples was associated with worse DFI (P = 0.050) and high expression of miR-30e-5p was found to be associated with shorter OS (P = 0.048). In conclusion, circulating miR-21, miR-10a and miR-30e-5p in plasma should be further evaluated as potential non-invasive biomarkers in NSCLC. PMID- 23756109 TI - Bone mineral density differences between femurs of scoliotic patients undergoing dual-energy X-ray absorptiometry. AB - AIM: To investigate whether a difference exists in the bone mineral density (BMD) between femurs in scoliotic patients undergoing dual-energy X-ray absorptiometry (DXA) and whether this difference is related to spine convexity. MATERIALS AND METHODS: Of 1080 consecutive patients who underwent DXA, 127 had lumbar scoliosis seen at DXA. Further, after excluding 30 patients with previous osteoporotic fractures, metallic/image artefacts, soft-tissue calcifications, the BMD differences between femurs of 97 scoliotic patients (94 females; mean age 67 +/- 11 years) were analysed. Femurs were classified as ipsilateral or contralateral to the spine convexity. Least significant change was used as a threshold of measurement precision. Differences between femoral neck BMD in respect of and regardless of spine convexity were calculated for each patient. Student's t-test and Wilcoxon's signed-rank test were used to assess significance. RESULTS: Fifty nine of 97 patients (61%) had left-sided scoliosis. Osteoporosis was found in 32/97 patients (33%), osteopenia in 54/97 (56%), and 11/97 (11%) had a normal T score. Of 97 patients, 46 (47%) had ipsilateral BMD < contralateral BMD. Regardless of spine convexity, 66/97 patients (68%) had different BMD values between femurs. Among them, variation of densitometric diagnosis was seen in 29/66 patients (44%), and in 29/97 patients overall (30%). CONCLUSION: Differences in the femoral neck BMD exist between femurs of scoliotic patients undergoing DXA. Thus, bilateral femoral DXA acquisition is recommended. PMID- 23756110 TI - A five-item screening version of the Eating Disorder Inventory (EDI-3). AB - OBJECTIVE: The Eating Disorder Inventory (EDI) is used worldwide in research and treatment of eating disorders (EDs). Using the latest version (EDI-3: 91 items), we extracted the best screening items for a diagnosis of anorexia (AN) and bulimia (BN) nervosa. METHOD: A patient sample of 561 women was recruited from an ED treatment centre in Denmark, and a comparison group of 878 women was randomly selected from the general population. An ED diagnosis was determined according to the Eating Disorder Examination Interview, yielding 84 AN and 202 BN patients. RESULTS: Only two EDI items (Cronbach's alpha = .79) were needed to achieve a superior screening capability of BN (sensitivity = .94, specificity = .94). An adequate screening of AN was possible by using three items (alpha = .71; sensitivity = .91, specificity = .86). DISCUSSION: The present study provides an even more economical and reliable screening of AN and BN compared with existing screening instruments. Implications for DSM-5 are also discussed. PMID- 23756111 TI - Evaluation of equivalence between different methods for enumeration of fecal indicator bacteria before and after adoption of the new Bathing Water Directive and risk assessment of pollution. AB - The quality of bathing water is of considerable public importance due to the possibility of fecal contamination. In 2009, Croatia implemented the new European Bathing Water Directive (BWD, 2006/7/EC) establishing stricter microbiological standards for new parameters with new reference methods. This study aims to evaluate the equivalence of different methods according to the old and revised BWD and to provide the possibility of data comparison. Furthermore, the directive requires the establishment of the bathing water profile (BWP) for pollution risk assessment. The estimation of consistency of pollution risk assessment with obtained microbiological results was also performed. Six marine beaches of the Municipality of Rijeka (Croatia) were examined during the 2009 season. Statistical analysis showed equivalence between determination methods for fecal contamination indicators. Based on the current water classification results, the need for correction of estimated pollution risks and recommendations for inclusion of historical microbiological data during BWP enactment was noticed. PMID- 23756112 TI - Can the combination of decreased pH and increased temperature values induce oxidative stress in the clam Chamelea gallina and the mussel Mytilus galloprovincialis? AB - The combined effects of decreased pH and increased temperature values on antioxidant enzyme activities and lipid peroxidation were evaluated for the first time in the clam Chamelea gallina and the mussel Mytilus galloprovincialis, two bivalve species that are widespread along the northwestern coast of the Adriatic Sea. For 7 days, bivalves were exposed to three pH values (8.1, 7.7 and 7.4) at two temperatures (22 and 28 degrees C). Three independent experiments were carried out at salinity values of 28, 34 and 40 psu. Superoxide dismutase, catalase and glutathione S-transferase activities as well as lipid peroxidation were measured in the gills and digestive gland of the bivalves. The results demonstrated that the experimental conditions significantly influenced the biochemical parameters of the bivalves, although the variation pattern varied depending on the species and tissues analysed. PMID- 23756113 TI - Marine dispersion assessment of 137Cs released from the Fukushima nuclear accident. AB - Radionuclides were released into the atmosphere and ocean due to an accident in the Fukushima Daiichi Nuclear Power Plant (NPP) in March 2011. Numerical simulations were carried out to evaluate the distribution of (137)Cs in the ocean considering both direct releases to the sea and deposition from the atmosphere as source terms. A significant amount of atmospheric deposition occurred on the sea surface in the northeast direction from the Fukushima NPP, due to westerly winds and precipitations on March 15-31, 2011. In a previous study using local scale modeling, no significant differences in resulting (137)Cs patterns in water and sediments with and without atmospheric deposition were found. However, this new research, on a regional scale, has pointed out meaningful differences in seabed sediment radionuclide concentrations in the Fukushima northeast area with and without atmospheric deposition. PMID- 23756114 TI - Interruption of nonviable pregnancies of 24-28 weeks' gestation using medical methods: release date June 2013 SFP guideline #20133. AB - The need to interrupt a pregnancy between 24 and 28 weeks of gestation is uncommon and is typically due to fetal demise or lethal anomalies. Nonetheless, treatment options become more limited at these gestations, when access to surgical methods may not be available in many circumstances. The efficacy of misoprostol with or without mifepristone has been well studied in the first and earlier second trimesters of pregnancy, but its use beyond 24 weeks' gestation is less well described. This document attempts to synthesize the existing evidence for the use of misoprostol with or without mifepristone to induce labor for nonviable pregnancies at gestations of 24-28 weeks. The composite evidence suggests that a regimen combining mifepristone and misoprostol may shorten the time to expulsion, though the overall success rates are similar to those seen with misoprostol-only regimens. PMID- 23756115 TI - [Tetra-saccharide glucose as a diagnostic biomarker for Pompe disease: a study with 35 patients]. AB - BACKGROUND AND OBJECTIVES: Pompe disease is a disorder originating from an acid alpha-glycosidase (AAG) enzyme deficiency. This disease produces an accumulation of lysosomal glycogen in different tissues, whereby the skeletal and heart muscles are especially involved. The established diagnosis is achieved through the identification of the AAG deficiency. There are also other secondary diagnostic biomarkers, such as tetra-saccharide glucose (Glc4), which shows high levels in the urine of these patients. In this study it is highlighted the usefulness of Glc4 as a diagnostic biomarker for Pompe disease in its different forms of presentation, using a high-performance liquid chromatography with ultraviolet detection (HPLC/UV) adapted to the study. PATIENTS AND METHODS: A total of 75 individuals have been analyzed: 40 healthy controls and 35 patients diagnosed with Pompe disease. Twenty-four hour samples of urine were collected from all of the patients and their Glc4 levels were determined by means of HPLC/UV. RESULTS: The evaluation of the urinary Glc4 shows a high discrimination ability between healthy/sick individuals. In addition, the results obtained have allowed to establish the most appropriate level of decision or cut-off point for the identification of sick people. CONCLUSIONS: Glc4 urinary levels are found to be high in patients suffering from Pompe disease and even though increased levels are also found in other conditions, the existence of a AAG deficiency together with a compatible clinical symptoms, prove very helpful for a correct diagnosis of this serious disease. PMID- 23756116 TI - [Cognitive complaints in people with human immunodeficiency virus in Spain: prevalence and related variables]. AB - BACKGROUND AND OBJECTIVE: Cognitive complaints have been scarcely studied in people with HIV in Spain. The aim of this research was to know the prevalence of cognitive complaints in HIV-infected people, as well as its potential relationships with demographic, clinical and psychological variables, in the era of combination antiretroviral therapies. PATIENTS AND METHOD: Observational multicenter study developed in 4 hospitals and 10 NGOs, in which 791 people with HIV in Spain participated. A self-reported questionnaire was used to evaluate demographic and clinical variables, and an assessment of cognitive complaints, emotional status and quality of life variables was also included. Descriptive and inferential tests were used for statistical analyses. RESULTS: Almost half of the sample (49.8%) referred cognitive complaints, in 72.1% of them an association with interference on daily living activities was found. Memory and attention were the areas most prevalently perceived as affected. The existence of cognitive complaints correlated with a longer HIV infection, lower CD4+ cell count, undetectable viral load and worse quality of life. A discriminant analysis determined that depression, anxiety, older age, living with no partner and low education level allowed to classify optimally HIV-infected people with cognitive complaints. CONCLUSIONS: Self-reported cognitive complaints are frequent in people infected with HIV in the current era of combination antiretroviral therapies. This fact is related to emotional disturbances and poor quality of life, but also to impaired immunological and virological status. PMID- 23756117 TI - [Fulminant giant cell myocarditis]. PMID- 23756118 TI - Protected from torsades de pointes? What psychiatrists need to know about pacemakers and defibrillators. AB - BACKGROUND: Consultation-liaison (C-L) psychiatrists are frequently asked to initiate and manage psychotropic drugs, some of which can delay cardiac repolarization, prolong the QT interval, and increase the risk of torsades de pointes (TdP). This task is complicated by the growing number of patients with cardiovascular implantable electronic devices (CIED) [i.e., permanent pacemakers (PPM), implantable cardioverter defibrillators (ICD), and cardiac resynchronization therapy devices (CRT)]. The precise protective role of CIEDs in the prevention and treatment of TdP is not well-defined. METHODS: We review practical tips for assessment of the QT interval in patients with paced rhythms, as well as the basic operative principles of CIEDs. We examine the available clinical evidence for the use of CIEDs in patients at risk for TdP. RESULTS: Most CIEDs have a pacing function that, when utilized appropriately, can offer partial protection against TdP by prevention of bradycardia. Defibrillators deliver shocks and are reasonably effective at terminating TdP; however, recurrent shocks are common and are associated with significant physical and psychological morbidity. CONCLUSIONS: CIEDs are important tools in the management of drug induced ventricular arrhythmias in spite of significant limitations. The C-L psychiatrist should remain vigilant in recognizing and managing patients at risk for TdP, and refrain from over-reliance on CIEDs regardless of type or settings. Ultimately, the presence of a CIED should serve as a marker of increased risk of TdP. PMID- 23756119 TI - Musical hallucinations successfully treated with antipsychotic medications: three case reports. PMID- 23756120 TI - Vertigo "in the pink": The impact of female gender on psychiatric-psychosomatic comorbidity in benign paroxysmal positional vertigo patients. AB - BACKGROUND: Comorbidity between vestibular and psychiatric disorders in predisposed individuals is underestimated, untreated, and may result in chronicization and poor quality of life. There are few studies concerning the type and the prevalence of psychiatric-psychosomatic distress in patients with benign paroxysmal positional vertigo (BPPV). OBJECTIVE: The aim of this study was to evaluate psychiatric-psychosomatic comorbidities, in particular anxiety, depression, somatization symptoms, and alexithymia, in a group of BPPV patients compared with healthy subjects, and according to gender. METHODS: Case-control study comparing 92 BPPV patients recruited at the ENT Unit of Modena General Hospital between November 2007 and December 2010, and 141 healthy controls. The Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), Diagnostic Criteria for Psychosomatic Research (DCPR), Brief Symptom Inventory (BSI), and Toronto Alexithymia Scale (TAS-20) were used to perform psychometric assessment. RESULTS: BPPV patients scored higher than controls, with statistical significance, at BDI, BSI somatization, anxiety, and phobic anxiety subscales, and STAI state anxiety; a larger proportion of BPPV patients suffered from clinically significant BDI depressive symptomatology; DCPR disease phobia, functional somatic symptoms secondary to a psychiatric disorder, and demoralization were more common among BPPV subjects. High levels of symptomatology were still found among BPPV female patients, but not among males, even after controlling for symptom severity. CONCLUSIONS: Affective symptomatology, such as depression, demoralization, phobia and anxiety, and somatization, were significantly prevalent in BPPV patients, and female gender may be a predisposing factor. PMID- 23756121 TI - Levamisole: a common cocaine adulterant with life-threatening side effects. PMID- 23756122 TI - Depression and fatigue in chronic hepatitis C patients with and without HIV co infection. AB - BACKGROUND: Depression and fatigue are common in chronic hepatitis C (CHC). OBJECTIVE: We report clinical predictors of these conditions in patients seen in a university clinic. METHODS: A total of 167 CHC patients completed the Patient Health Questionnaire-9 (PHQ-9) and Fatigue Severity Scale (FSS). Major depressive disorder (MDD) suggested by PHQ-9 was confirmed by clinical interview. FSS scores >=41 were considered clinically significant fatigue. Logistic and multiple regression models were employed for analysis. RESULTS: Thirty-three percent of patients had MDD and 52% had clinically significant fatigue. Sixty-one percent were HIV-infected, among whom both MDD and clinically significant fatigue were significantly less prevalent (OR = 0.47 and 0.46, respectively). MDD was least common in patients without a history of IV drug use (OR = 0.28), and highest in methadone users (OR = 3.57). Compared with methadone users, patients with no history of IV drug use and former IV drug users had less severe fatigue (coefficients = -31.0, -34.0, respectively). Lack of a history of hepatitis treatment was also associated with less severe fatigue (coefficient= -7.6). CONCLUSION: Our study confirms high prevalence of fatigue and depression in CHC. HIV-positivity was associated with lower rates of MDD and clinically significant fatigue, arguably due to support systems for people living with HIV. Higher rates of depression in methadone users might be due to intrinsically higher rates of psychopathology in this group. Being on hepatitis treatment was associated with higher rates of fatigue, probably due to the adverse effects of interferon. Our findings emphasize the importance of routine screening and evaluation of depression and fatigue in CHC populations. PMID- 23756123 TI - Panic disorder prevalence among patients referred for an electrocardiogram in a Nigerian teaching hospital. AB - BACKGROUND: Panic disorder is a common chronic illness that is often unrecognized, misdiagnosed, and untreated because it often presents to the physicians with symptoms that are similar to those of emergency medical conditions. One study of the prevalence of panic disorder in the general population in Nigeria has been published, but no studies have examined the prevalence of panic disorder in a sample of Nigerian patients with cardiac symptoms. This study investigated the 12-month prevalence of panic disorder among patients who were referred for an electrocardiogram in a Nigerian teaching hospital. METHODS: Three hundred consecutive patients who were referred for an electrocardiogram were assessed for panic disorder using the Structured Clinical Interview for DSM-IV (SCID). RESULTS: The prevalence of panic attacks and panic disorder were 10.0% and 7.0%, respectively. Age was associated with the presence of both panic attacks and panic disorder. CONCLUSIONS: This study suggests that panic disorder is common among patients who are referred for an electrocardiogram. It is recommended that patients whose cardiovascular or respiratory symptoms are not well explained by the diseases of such systems be evaluated for mental illness. PMID- 23756124 TI - Depression and death in diabetes; 10-year follow-up of all-cause and cause specific mortality in a diabetic cohort. AB - BACKGROUND: When depression co-occurs with type 2 diabetes, adverse bidirectional interactions increase the burden of both illnesses. In addition to affecting patient's health, functioning, and quality of life, this relationship also results in increased mortality compared with those with depression or diabetes alone. OBJECTIVE: The purpose of this study was to examine the relationship between depression and all-cause as well as cause-specific mortality in patients with type 2 diabetes by extending findings from our 5-year mortality study. Specifically, we re-examined the risk of depression and all-cause, cardiovascular, cancer, and non-cardiovascular, non-cancer related deaths. METHOD: We used an ICD-10 algorithm combined with death certificate data to classify mortality types among type 2 diabetic patients who participated in the Pathways Epidemiologic Study. Cox proportional hazard modeling was used to examine the relationships between depression status and mortality over a 10-year period. RESULTS: We found a significant positive relationship between depression and all-cause as well as non-cardiovascular, non-cancer mortality in this sample (n = 4128). Cardiovascular mortality failed to reach significance in fully adjusted models and, in contrast to the 5-year data, no trend or significant relationship was observed between depression status and cancer related deaths. CONCLUSIONS: Our study confirmed a significant positive relationship between depression and mortality in patients with type 2 diabetes. Major depression demonstrated a stronger relationship than did minor depression, and among cause specific groups, non-cardiovascular, non-cancer death types demonstrated the largest magnitude of association with depression status. PMID- 23756125 TI - Psychiatric outcome after severe cardio-respiratory failure treated with extracorporeal membrane oxygenation: a case-series. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is increasingly used to save patients with severe cardiopulmonary failure at high risk of dying, but the long-term psychiatric outcome of the treatment has not been studied. METHODS: Twenty-eight adults who survived ECMO were subjected to psychiatric assessment 5 years after ECMO by means of interviews (MINI-Neuropsychiatric Interview and Montgomery-Asberg Depression Rating Scale) and psychometrics [Neuroticism and social conformity (EPQ-N+L); General Health Questionnaire (GHQ), Hospital Anxiety Depression Scale; Aggression Questionnaire, Toronto Alexithymia Scale, and Giessener somatic symptom checklist (GBB)]. RESULTS: Fifteen patients (54%) suffered lifetime psychiatric disorders prior to ECMO. After ECMO, 11 subjects (39%) developed new psychiatric disorders, mostly organic mental (18%), obsessive compulsive disorders (OCD) 15%, and/or post-traumatic stress disorders (PTSD) 11%. These 11 patients reported higher scores on Montgomery-Asberg Depression Rating Scale (MADRS), GHQ, EPQ-N, and GBB. Disregarding the presence of psychiatric disorders at follow-up, ECMO patients reported high levels of distress, physical aggression, anger, and alexithymic traits. CONCLUSIONS: Severe life-threatening cardiovascular or pulmonary failure with subsequent ECMO is associated with an increased prevalence of long-term psychiatric disorders and distress. Studies addressing the etiology and prevalence of psychiatric consequences after ECMO are needed. PMID- 23756126 TI - Galactofuranosyl glycosides: immunomodulatory effects on macrophages and in vivo enhancement of lethality on sepsis. AB - Galactofuranoside derivatives were synthesised by the classic Fischer glycosydation method, and their immune modulation properties were studied in vitro and in vivo. NMR spectroscopic and ESI-MS analyses confirmed the purity and authenticity of all derivatives. Their phagocyte capacities were tested in resident macrophages. Methyl beta-galactofuranoside (GFB-Me) and n-octyl beta galactofuranoside (GFB-O) had an immune stimulant effect at 25MUmolml(-1) with an enhancement of 35.12%+/-0.06 SD and 17.49%+/-0.11 SD, respectively, but Methyl alpha-galactofuranoside (GFA-Me) and n-octyl alpha-galactofuranoside (GFA-O) gave a low immune response. Methyl alpha-galactofuranoside 5,6-O-isopropylidene (GFA IP) and Methyl beta-galactofuranoside 5,6-O-isopropylidene (GFB-IP) had negative values relative to the control group of minus 4.96%+/-0.10 SD and -40.72%+/-0.07 SD, respectively. Furthermore, GFB-Me and GFB-Me-IP were evaluated in vivo on the lethality induced by cecal ligation and puncture. Cytokine levels and iNOS expression were determined and correlated to mortality data. The results showed that the free HO-5 and HO-6 and the beta-configuration are essential for the induction of phagocytic activity by the galactofuranosyl units. The methyl beta galactofuranosides also enhanced lethality during sepsis, increasing the levels of pro-inflammatory cytokines and iNOS expression. PMID- 23756127 TI - Comparison of self-processing of foot-and-mouth disease virus leader proteinase and porcine reproductive and respiratory syndrome virus leader proteinase nsp1alpha. AB - The foot-and-mouth disease virus leader proteinase (Lb(pro)) cleaves itself off the nascent viral polyprotein. NMR studies on the monomeric variant Lb(pro) L200F provide structural evidence for intramolecular self-processing. (15)N-HSQC measurements of Lb(pro) L200F showed specifically shifted backbone signals in the active and substrate binding sites compared to the monomeric variant sLb(pro), lacking six C-terminal residues. This indicates transient intramolecular interactions between the C-terminal extension (CTE) of one molecule and its own active site. Contrastingly, the porcine reproductive and respiratory syndrome virus (PRRSV) leader proteinase nsp1alpha, with a papain-like fold like Lb(pro), stably binds its own CTE. Parts of the beta-sheet domains but none of the alpha helical domains of Lb(pro) and nsp1alpha superimpose; consequently, the alpha helical domain of nsp1alpha is oriented differently relative to its beta-sheet domain. This provides a large interaction surface for the CTE with the globular domain, stabilising the intramolecular complex. Consequently, self-processing inactivates nsp1alpha but not Lb(pro). PMID- 23756128 TI - Plasma lipoprotein-associated phospholipase A2 mass is elevated in STEMI compared to non-STEMI patients but does not discriminate between myocardial infarction and non-cardiac chest pain. AB - BACKGROUND: Plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) mass predicts future cardiovascular events in the non-acute setting. We tested the extent to which Lp-PLA2 is elevated in patients with acute coronary syndrome. METHODS: A total of 231 consecutive patients referred for acute chest pain participated. Of this number, 144 were diagnosed with myocardial infarction (MI; 100 were classified as MI with ST-elevation (STEMI) and 44 as MI without ST elevation (non-STEMI)). Eighty-seven patients had non-cardiac chest pain. Plasma Lp-PLA2 mass was measured using turbidimetric immunoassay. RESULTS: Lp-PLA2 mass was not different between MI patients and patients with non-cardiac chest pain (231+/-72 MUg/l vs.243+/-88 MUg/l, p=0.29), and did not relate to MI in age- and sex-adjusted logistic regression analysis (odds ratio per SD increment, 0.92 (95% CI, 0.69-1.23), p=0.58). However, Lp-PLA2 mass was elevated in STEMI compared to non-STEMI patients (246+/-73 vs. 198+/-58 ng/ml, p<0.001), and independently predicted STEMI (odds ratio, 2.35 (95% CI, 1.46-3.79), p<0.001). Among MI patients maximal creatine kinase was correlated positively with Lp-PLA2 (r=0.183, p=0.034). CONCLUSIONS: In the acute setting, plasma Lp-PLA2 mass is not elevated in MI patients, although Lp-PLA2 mass appears to relate to the severity of myocardial damage. PMID- 23756129 TI - Inflammatory biomarkers for predicting cardiovascular disease. AB - The pathology of cardiovascular disease (CVD) is complex; multiple biological pathways have been implicated, including, but not limited to, inflammation and oxidative stress. Biomarkers of inflammation and oxidative stress may serve to help identify patients at risk for CVD, to monitor the efficacy of treatments, and to develop new pharmacological tools. However, due to the complexities of CVD pathogenesis there is no single biomarker available to estimate absolute risk of future cardiovascular events. Furthermore, not all biomarkers are equal; the functions of many biomarkers overlap, some offer better prognostic information than others, and some are better suited to identify/predict the pathogenesis of particular cardiovascular events. The identification of the most appropriate set of biomarkers can provide a detailed picture of the specific nature of the cardiovascular event. The following review provides an overview of existing and emerging inflammatory biomarkers, pro-inflammatory cytokines, anti-inflammatory cytokines, chemokines, oxidative stress biomarkers, and antioxidant biomarkers. The functions of each biomarker are discussed, and prognostic data are provided where available. PMID- 23756130 TI - Demonstration of long-term increases in tropospheric O3 levels: causes and potential impacts. AB - Ground-level ozone (O3) is a well-known atmospheric pollutant with its adverse impacts on the environment and human health. Here, the tropospheric O3 concentrations monitored in seven major cities in Korea at monthly intervals over a 22-year period (1989-2010) are presented, and their long-term variability examined. The analysis of annual mean values of O3 (in nmolmol(-1), or ppb) showed a noticeable increase of 118+/-69% in all seven cities over the two decades (p<0.01). Changes in O3 levels are closely associated with both environmental (e.g., NOx (NO+NO2), SO2, CO, and total suspended particles (TSPs) (p<0.01), temperature, and sunshine hours) and common anthropogenic variables (e.g., population density and number of vehicles). Evidence collected in this study suggests that the atmospheric conditions in most major cities of Korea should be volatile organic compounds (VOCs) sensitive or NOx saturated with respect to O3 formation. As such, establishment of a proper management strategy seems a sensible approach to control tropospheric ozone concentrations in densely populated cities. PMID- 23756131 TI - The role of alpha2-adrenoceptors in the anti-convulsant effects of cannabinoids on pentylenetetrazole-induced seizure threshold in mice. AB - Cannabinoid system plays a pivotal role in the seizure threshold modulation which is mainly mediated through activation of the cannabinoid CB1 receptor. There is also several evidence of interaction between cannabinoid system and alpha2 adrenoceptors in different paradigms. Using model of clonic seizure induced by intravenous pentylenetetrazole (PTZ) in male mice, we investigated whether alpha2 adrenoceptors is involved in the effects of cannabinoids on the seizure threshold. Injection of the selective cannabinoid CB1 agonist ACEA (2 mg/kg) significantly (P<0.01) increased the seizure threshold which was prevented by pretreatment with the selective CB1 antagonist AM251 (1 mg/kg, i.p.). The highest doses of clonidine, a alpha2 receptor agonist, (1 and 5 mg/kg) showed anticonvulsant effects while yohimbine, a alpha2 receptor antagonist, (0.01, 0.1, 1, and 10 mg/kg) did not induce any significant effect on PTZ seizure threshold. Pretreatment with clonidine (0.1 and 0.5 mg/kg) significantly reversed the anticonvulsant effect of ACEA (2 mg/kg). Yohimbine (0.1, 1, and 10 mg/kg) pretreatment of mice enhanced the clonic seizure threshold of ACEA (1 mg/kg), significantly. Combination of non-effective doses of AM251 (0.1 mg/kg) and clonidine (0.01 mg/kg) showed additive effect in blocking the anticonvulsant effect of ACEA (2 mg/kg). In conclusion, our findings demonstrated that alpha2 adrenoceptors could be involved in the anticonvulsant properties of the specific cannabinoid CB1 agonist ACEA, suggesting that CB1 cannabinoid and alpha2 receptors have functional interactions in modulation of clonic seizure threshold. PMID- 23756132 TI - Pharmacologic manipulation of coronary vascular physiology for the evaluation of coronary artery disease. AB - During the last forty years tremendous progress has been made in our understanding of coronary atherosclerosis and in the development of methods to characterize atherosclerotic disease burden and risk. Stress testing is designed to elucidate abnormalities in myocardial perfusion during stress due to abnormal coronary vasomotor response. We summarize the underlying determinants of normal coronary vasomotor tone as well as its responsiveness to both exercise and pharmacologic stressors. We introduce the various methods of assessing the presence of myocardial ischemia. A detailed discussion of the most commonly used stress agents as well as their clinical advantages and limitations follows. PMID- 23756133 TI - Regulation of metabolism by cGMP. AB - The second messenger cyclic guanosine monophosphate (cGMP) mediates the physiological effects of nitric oxide and natriuretic peptides in a broad spectrum of tissues and cells. So far, the major focus of research on cGMP lay on the cardiovascular system. Recent evidence suggests that cGMP also plays a major role in the regulation of cellular and whole-body metabolism. Here, we focus on the role of cGMP in adipose tissue. In addition, other organs important for the regulation of metabolism and their regulation by cGMP are discussed. Targeting the cGMP signaling pathway could be an exciting approach for the regulation of energy expenditure and the treatment of obesity. PMID- 23756135 TI - Prepulse inhibition modulation by contextual conditioning of dopaminergic activity. AB - When a neutral stimulus is repeatedly paired with a drug, an association is established between them that can induce two different responses: either an opponent response that counteracts the effect of the drug, or a response that is similar to that induced by the drug. In this paper, we focus on the analysis of the associations that can be established between the contextual cues and the administration of dopamine agonists or antagonists. Our hypothesis suggests that repeated administration of drugs that modulate dopaminergic activity in the presence of a specific context leads to the establishment of an association that subsequently results in a conditioned response to the context that is similar to that induced by the drug. To test this hypothesis, we conducted two experiments that revealed that contextual cues acquired the property to modulate pre-pulse inhibition by prior pairings of such context with the dopamine antagonist haloperidol (Experiment 1), and with the dopamine agonist d-amphetamine (Experiment 2). The implications of these results are discussed both at a theoretical level, and attending to the possibilities that could involve the use of context cues for the therapeutic administration of dopaminergic drugs. PMID- 23756134 TI - Deletion of retinoic acid receptor beta (RARbeta) impairs pancreatic endocrine differentiation. AB - All-trans retinoic acid (RA) signals via binding to retinoic acid receptors (RARs alpha, beta, and gamma). RA directly influences expression of Pdx1, a transcription factor essential for pancreatic development and beta-cell (beta cell) maturation. In this study we follow the differentiation of cultured wild type (WT) vs. RARbeta knockout (KO) embryonic stem (ES) cells into pancreatic islet cells. We found that RARbeta KO ES cells show greatly reduced expression of some important endocrine markers of differentiated islet cells, such as glucagon, islet amyloid polypeptide (Iapp), and insulin 1 (Ins1) relative to WT. We conclude that RARbeta activity is essential for proper differentiation of ES cells to pancreatic endocrine cells. PMID- 23756136 TI - Exercise-induced rescue of tongue function without striatal dopamine sparing in a rat neurotoxin model of Parkinson disease. AB - Unilateral lesions to the medial forebrain bundle with 6-hydroxydopamine (6-OHDA) lead to force and timing deficits during a complex licking task. We hypothesized that training targeting tongue force generation during licking would improve timing and force measures and also lead to striatal dopamine sparing. Nine month old male Fisher344/Brown Norway rats were used in this experiment. Sixteen rats were in the control condition and received tongue exercise (n=8) or no exercise (n=8). Fourteen rats were in the 6-OHDA lesion condition and underwent tongue exercise (n=7) and or no exercise (n=7). Following 4 weeks of training and post training measures, all animals underwent bilateral stimulation of the hypoglossal nerves to measure muscle contractile properties and were then transcardially perfused and brain tissues collected for immunohistochemistry to examine striatal dopamine content. Results demonstrated that exercise animals performed better for maximal force, average force, and press rate than their no-exercise counterparts, and the 6-OHDA animals that underwent exercise performed as well as the Control No Exercise group. Interestingly, there were no group differences for tetanic muscle force, despite behavioral recovery of forces. Additionally, behavioral and neurochemical analyses indicate that there were no differences in striatal dopamine. Thus, targeted exercise can improve tongue force and timing deficits related to 6-OHDA lesions and this exercise likely has a central, versus peripheral (muscle strength) mechanism. However, this mechanism is not related to sparing of striatal dopamine content. PMID- 23756137 TI - A large scale (N=102) functional neuroimaging study of response inhibition in a Go/NoGo task. AB - We report a functional magnetic resonance imaging (fMRI) study of healthy adult participants who completed a demanding Go/NoGo task. The primary purpose of this study was to delineate the neural systems underlying successful and unsuccessful response inhibition using a large sample (N=102). We identified a number of regions uniquely engaged during successful response inhibition, including a fronto-parietal network involving the anterior cingulate, supplementary motor areas, lateral and inferior prefrontal regions, and the inferior parietal lobule. Unique hemodynamic activity was also noted in the amygdala and in frontostriatal regions including the inferior frontal gyrus and portions of the basal ganglia. Also, contrasts were defined to explore three variants of hemodynamic response allowing for more specificity in identifying the underlying cognitive mechanisms of response inhibition. Addressing issues raised by prior small sample studies, we identified a stable set of regions involved in successful response inhibition. The present results help to incrementally refine the specificity of the neural correlates of response inhibition. PMID- 23756138 TI - Chronic testosterone propionate supplement could activated the Nrf2-ARE pathway in the brain and ameliorated the behaviors of aged rats. AB - Aging is usually associated with a progressive disruption of the redox balance leading to recurrent damage resulting from oxidative stress. Oxidative stress resulting from excessive free-radical release is likely implicated in the initiation and progression of motor behavior disorders. Therefore, antioxidant therapies have received considerable attention in motor behavior defects treatment. The nuclear factor erythroid 2-related factor 2 (Nrf2) binds to antioxidant response element (ARE) to induce antioxidant and phase II detoxification enzymes under conditions of oxidative stress, which reduces oxidative stress and accumulation of toxic metabolites. Testosterone has many physiological and behavioral effects throughout the lifespan and shown to affect motor behavior in adult male rats and gonadectomized rats. However, whether Nrf2 ARE pathway is activated after testosterone administration has not been studied in aged rats. The tilting-plane test and the horizontal-wire test as well as the oxidative stress parameters, the expression of Nrf2, heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1) and the number of tyrosine hydroxylase immunoreactive (TH-ir) cells in brain were examined in aged rats following chronic subcutaneous injections of testosterone propionate (TP). Our study showed that chronic TP supplement significantly ameliorated the decline of balancing reactions and muscular strength associated with aging. Oxidative stress parameters were ameliorate, the expression of Nrf2, HO-1 and NQO1 at protein or gene levels and the number of TH-ir cells significantly increased in substantia nigra or caudate putamen after TP treatment in aged rats. Our findings demonstrated that chronic TP treatment activated Nrf2-ARE pathway may influence the maintenance of the balancing reactions and muscular strength and reduce TH-ir cells death in aged rats. Therefore, TP supplement have shown for therapeutic strategies in the treatment and modification of motor behavior disorders. PMID- 23756139 TI - Age of exposure-dependent effects of amphetamine on behavioral flexibility. AB - Drug use typically begins during adolescence, which is a period of ongoing neurobiological development that may confer heightened vulnerability to develop drug dependence. Previously, our lab has shown that amphetamine (AMPH)-induced deficits in a medial prefrontal cortex (mPFC)-sensitive working memory task are greater in rats exposed to the drug during adolescence compared to adulthood. Here, we examine potential age-dependent effects of AMPH exposure on behavioral flexibility tasks that are sensitive to disruptions in mPFC and orbitofrontal cortex (OFC) function. Male Sprague-Dawley rats were injected (i.p.) with saline or 3mg/kg AMPH every other day between postnatal days (PNDs) 27-45 and PNDs 85 103. Starting around PND 125, rats were tested in an attentional set-shifting task and a subset of those was then tested in an operant strategy shifting task. Following completion of the operant task, rats were challenged with 3mg/kg AMPH and monitored in open field chambers. Our results demonstrate that AMPH-exposed rats were faster to acquire simple and compound discriminations, but were impaired during the first stimulus-reward reversal when compared to controls. In the operant strategy shifting task, adolescent-exposed rats shifted more rapidly between strategies and completed reversals faster than adult-exposed and control rats, respectively. The final AMPH challenge revealed evidence for sensitization in drug pre-exposed rats, with adult-exposed animals exhibiting the most significant effects. Together, these results suggest that AMPH induces long lasting changes in behavioral flexibility that are at least partially dependent on age of exposure and may be due to adaptations in OFC function. PMID- 23756141 TI - Behavioral effects of alpha-alkylated amino acid analogs in the C57BL/6J mouse. AB - Although a series of amino acid analogs have been shown to modulate brain function, information on the pharmacology of alpha-alkylated amino acids (AAAA) is limited. In particular there is no information on the effect of these amino acid analogs (AAA) on the elevated plus maze, the tail suspension test and the forced swim test. It was therefore the aim of the study to test a series of AAAA in these paradigms in order to explore behavioral activities of this compound class. 10 male mice per group aged between 10 and 14 weeks were used. Vehicle treated controls were used in addition to intraperitoneal injections of 1, 10 and 100mg/kg body weight of each, alpha-amino-isobutyic acid (AIB), isovaline (IVA), alpha-propyl-alanine (APA), alpha-butyl-alanine (ABA), alpha-pentyl-alanine (APnA), alpha-ethylphenylglycine (AEPG) and alpha-methyl-valine (AMV). The elevated plus maze (EPM), the tail suspension test (TST) and forced swim test (FST) were used for behavioral testing. There were dose-dependent results: all compounds increased time and pathlength in the open arm of the EPM at least at one dose administered. In the TST and in the FST only the 100mg dose was showing an effect. The results show pharmacological activity modifying the EPM in low doses suggesting the use in treatment of behavioral traits and symptoms represented by or linked to the EPM including anxiety-related behavior including depression. Compounds acting at higher doses may be used to induce behavioral changes and thus serve as neurobiological-neuropharmacological tools. PMID- 23756140 TI - Post-stroke protection from maladaptive effects of learning with the non-paretic forelimb by bimanual home cage experience in C57BL/6 mice. AB - Behavioral experience, in the form of skilled limb use, has been found to impact the structure and function of the central nervous system, affecting post-stroke behavioral outcome in both adaptive and maladaptive ways. Learning to rely on the less-affected, or non-paretic, body side is common following stroke in both humans and rodent models. In rats, it has been observed that skilled learning with the non-paretic forelimb following ischemic insult leads to impaired or delayed functional recovery of the paretic limb. Here we used a mouse model of focal motor cortical ischemic injury to examine the effects of non-paretic limb training following unilateral stroke. In addition, we exposed some mice to increased bimanual experience in the home cage following stroke to investigate the impact of coordinated dexterous limb use on the non-paretic limb training effect. Our results confirmed that skilled learning with the non-paretic limb impaired functional recovery following stroke in C56BL/6 mice, as it does in rats. Further, this effect was avoided when the skill learning of the non-paretic limb was coupled with increased dexterous use of both forelimbs in the home cage. These findings further establish the mouse as an appropriate model in which to study the neural mechanisms of recovery following stroke and extend previous findings to suggest that the dexterous coordinated use of the paretic and non paretic limb can promote functional outcome following injury. PMID- 23756142 TI - Time-course of behavioural changes induced by ethanol in zebrafish (Danio rerio). AB - The zebrafish has been proposed for the study of the effects of ethanol on the vertebrate brain. Behavioural tests have been successfully employed in the phenotypical characterization of these effects. However, the short scale (minute to minute) time course of ethanol induced changes of zebrafish behaviour has not been analyzed. The current study alleviates this need using a 2*3 chronic*acute ethanol exposure experimental design. We first expose zebrafish to ethanol chronically using a dose escalation procedure in which fish are kept in a final concentration of 0.5% vol/vol ethanol for 10 days while control fish receive identical dosing procedures but no ethanol. Subsequently, we expose zebrafish for 1h to an acute dose of ethanol (0.00, 0.50, or 1.00% vol/vol) and monitor their behaviour throughout this period. We quantify the mean and within-individual temporal variance of distance travelled, distance from bottom and angular velocity using video-tracking, and establish temporal trajectories of ethanol induced behavioural changes in zebrafish. For example, we find fish of the highest acute dose group previously not exposed to chronic ethanol to exhibit an inverted U shaped temporal trajectory in distance travelled (biphasic alcohol effect). We find this response to be blunted after chronic ethanol exposure (development of tolerance). We also describe an acute ethanol withdrawal induced increase in angular velocity. We conclude that temporal analysis of zebrafish behaviour is a sensitive method for the study of chronic and acute ethanol exposure induced functional changes in the vertebrate brain. PMID- 23756143 TI - Early gestational exposure to moderate concentrations of ethanol alters adult behaviour in C57BL/6J mice. AB - Alcohol consumption during pregnancy has deleterious effects on the developing foetus ranging from subtle physical deficits to severe behavioural abnormalities and is encompassed under a broad umbrella term, foetal alcohol spectrum disorders (FASD). High levels of exposure show distinct effects, whereas the consequences of moderate exposures have been less well studied. The aim of this study was to examine the effects of a moderate dose ethanol exposure using an ad libitum drinking procedure during the first eight days of gestation in mice on the behavioural phenotype of adult offspring. Adult female C57Bl/6J mice were mated and exposed to either 10% (v/v) ethanol or water for the first 8 days of gestation (GD 0-8), and then offered water for the rest of gestation. Early developmental milestone achievement was assessed in offspring at postnatal days (P) 7, 14 and 21. Adult offspring underwent a comprehensive battery of behavioural tests to examine a range of behavioural domains including locomotion, exploration, anxiety, social behaviour, learned helplessness, sensorimotor gating, and nociception, as well as spatial memory in a water maze. Ethanol exposed mice had similar postnatal developmental trajectories to water-exposed mice. However, the ethanol-exposed mice showed increased hyperlocomotion at P 14, 21 and 70 (p<0.05). Increased exploration and heightened motivation were also observed in adult mice. Furthermore, ethanol-exposed mice showed a significant improvement in memory in the water maze. The main findings were that mice had persistent and long lasting alterations in behaviour, including hyperactivity and enhanced spatial memory. These data suggest that even moderate dose ethanol exposure in early gestation has long term consequences on brain function and behaviour in mice. PMID- 23756144 TI - Endogenous descending facilitation and inhibition differ in control of formalin intramuscularly induced persistent muscle nociception. AB - In conscious rats, intramuscular injection of 2.5% formalin into the gastrocnemius muscle, at volumes between 25 and 200 MUl, evoked dose-dependent biphasic persistent flinching activities: phase 1 (0-10 min) and phase 2 (10-60 min). During this intramuscular formalin-induced ipsilateral muscle nociception, bilateral secondary mechanical hyperalgesia and heat hypoalgesia assessed by measuring thresholds of paw withdrawal reflex to noxious mechanical and heat stimuli were observed (P<0.05). Lesion of either the ipsilateral dorsal funiculus (DF) or contralateral thalamic mediodorsal (MD) nucleus significantly alleviated the formalin-induced flinches in both phase 1 and phase 2 of the behavioral response, and blocked the occurrence of secondary mechanical hyperalgesia, but not heat hypoalgesia. By contrast, lesion of the ipsilateral dorsal lateral funiculus (DLF) or contralateral thalamic ventromedial (VM) nucleus markedly enhanced the formalin induced flinching behavior in the late part (30-60 min) of phase 2 alone; phase 1 and early part (10-30 min) of phase 2 response were unaffected. Heat hypoalgesia, but not mechanical hyperalgesia, was markedly attenuated by this treatment (P<0.05). Microinjection of GABA (0.1 MUg/0.5 MUl) into the thalamic MD nucleus significantly depressed the intramuscular formalin induced biphasic persistent nociception, and the occurrence of bilateral secondary mechanical hyperalgesia was significantly delayed (P<0.05). By contrast, microinjection of GABA into the thalamic VM nucleus significantly enhanced the formalin-induced nociceptive behavior in the late part (30-60 min) of phase 2, and the bilateral secondary heat hypoalgesia was temporarily prevented (P<0.05). The present study demonstrates that intramuscular formalin evokes biphasic muscle nociception, and that bilateral secondary mechanical hyperalgesia and heat hypoalgesia are differentially controlled by endogenous descending facilitation and inhibition respectively. It is further suggested that thalamic MD nucleus and VM nucleus constitute an endogenous discriminative, modulatory system that exerts, via pathways in the DF and DLF, descending facilitatory and inhibitory actions on responses to peripheral afferent activity evoked by noxious mechanical and heat stimulation. PMID- 23756145 TI - Simple, time saving pulsed-field gel electrophoresis protocol for the typing of Stenotrophomonas maltophilia. AB - We developed a time-saving and cost-efficient Pulsed Field Gel Electrophoresis (PFGE) method for the typing of Stenotrophomonas maltophilia by modifying the conventional procedures. Our modifications related to the cell suspension preparation, lysis of bacterial cells in plugs, washing steps, and consumption of restriction enzyme. Although few rapid PFGE protocols on Gram-negative bacteria are available, the use of comparatively large amounts of costly reagents prompted us to look for other alternative. Hence, by considering the speed, simplicity, and relatively low cost, the modified protocol may be of more practical value than other established protocols in investigating S. maltophilia nosocomial outbreaks. PMID- 23756146 TI - Cloning and characterization of a bone morphogenetic protein homologue of Schistosoma japonicum. AB - Bone morphogenetic proteins (BMPs) are known to play an important role in the regulation of cell proliferation, survival, differentiation and apoptosis in many vertebrates and invertebrates through the TGF-beta signaling pathway. Although the TGF-beta signaling pathway exists in schistosomes, BMP homologue, a ligand of TGF-beta in Schistosoma japonicum, has not yet been identified. In this study, a BMP homologue of S. japonicum was cloned and characterized. The full length SjBMP cDNA is 3,020 bp and encodes 928 amino acids, which include a TGF-beta superfamily conserved domain at the C-terminus. BLAST analysis showed that, SjBMP has 68%, 51% and 43% homology with BMP from Schistosoma mansoni, Schmidtea mediterranea and Dugesia japonica at the amino acid level, respectively. According to data from real-time PCR, SjBMP was expressed in lung-stage schistosomula, 21-day liver-stage schistosomula, 50-day adult worms (the male and female), and eggs. The PCR data also indicated that, there was a ~ 27- and ~ 37 fold increase of SjBMP transcripts in the lung-stage schistosomula and eggs, respectively, and that there was relatively more SjBMP transcript in the adult male worm than in the adult female, in which the hepatic schistosomula was set as the calibrator for calculation. In situ hybridization based on FITC-labeled specific antisense oligonucleotide probes showed that SjBMP mRNA localized to the ovary of female worms and the integument and epithelium of female and male worms. After treatment with double-stranded RNA (dsRNA) at a concentration of 8 * 10(-2) MUg/ml, which was added to the culture medium every other day for a week, the level of SjBMP mRNA in the cultured adult mixed-sex S. japonicum decreased at a range of ~ 25-98% within 7 days compared with the level of SjBMP mRNA in the blank control group. On the 2nd day, the number of eggs produced per pair of worms decreased 28.7%, and the percent of normal eggs also decreased (12.7% vs. 4.3%) in the SjBMP dsRNA-treated group when compared with the eggs laid by the blank control group. No difference was detected between the two groups on the 7th day of treatment, because the eggs of the untreated worms were also mostly abnormal, similar to the eggs laid by the treated group. In addition, no significant difference in the morphological structure of the adult worms was observed. Thus, the preliminary in vitro experiment indicated that SjBMP may be involved in the oviposition behavior of S. japonicum, and further studies based on the recombinant virus vector-induced steady knockdown of SjBMP or in vivo experiments are required for more in-depth investigation. PMID- 23756147 TI - Is blunted cardiovascular reactivity in depression mood-state dependent? A comparison of major depressive disorder remitted depression and healthy controls. AB - Prior work has repeatedly demonstrated that people who have current major depression exhibit blunted cardiovascular reactivity to acute stressors (e.g., Salomon et al., 2009). A key question regards the psychobiological basis for these deficits, including whether such deficits are depressed mood-state dependent or whether these effects are trait-like and are observed outside of depression episodes in vulnerable individuals. To examine this issue, we assessed cardiovascular reactivity to a speech stressor task and a forehead cold pressor in 50 individuals with current major depressive disorder (MDD), 25 with remitted major depression (RMD), and 45 healthy controls. Heart rate (HR), blood pressure and impedance cardiography were assessed and analyses controlled for BMI and sex. Significant group effects were found for SBP, HR, and PEP for the speech preparation period and HR, CO, and PEP during the speech. For each of these parameters, only the MDD group exhibited attenuated reactivity as well as impaired SBP recovery. Reactivity and recovery in the RMD group more closely resembled the healthy controls. Speeches given by the MDD group were rated as less persuasive than the RMD or healthy controls' speeches. No significant differences were found for the cold pressor. Blunted cardiovascular reactivity and impaired recovery in current major depression may be mood-state dependent phenomena and may be more reflective of motivational deficits than deficits in the physiological integrity of the cardiovascular system. PMID- 23756148 TI - Do mirror neuron areas mediate mu rhythm suppression during imitation and action observation? AB - Mu rhythm is an EEG measure of resting motor neurons, which is normally suppressed by input because of action observation or movement execution. This characteristic has caused mu suppression to be used as proxy marker for mirror neuron activation. However, there is little direct evidence that fluctuations in mu rhythm suppression reflect concurrent fluctuations in mirror neuron activity. A manual imitation paradigm was used to look at correlations between mu rhythm and BOLD response, by recording sequential EEG and fMRI measures to allow within subject correlation analyses. Participants were instructed to imitate or observe actions involving the movement of a handle with their right hand. Mu power modulation, defined as mu power changes between conditions, correlated negatively with BOLD response in right inferior parietal lobe, premotor cortex and inferior frontal gyrus; putative mirror neuron areas. Clusters were also identified in bilateral cerebellum, left medial frontal gyrus, right temporal lobe and thalamus. This suggests that mu suppression involves a range of structures that modulate motor preparation activities and are sensitive to visual input, including but not restricted to the human analogue of the mirror neuron system. PMID- 23756149 TI - Complex-forming proteins escape the robust regulations of miRNA in human. AB - Most proteins carry out their functions by participating in protein complexes. Recently, miRNAs were identified as promising post-transcriptional regulators that influence a large proportion of genes in higher eukaryotes. We aim to understand the role of miRNAs in the regulation of human proteins that are present in protein complexes. Here, we show that robust regulation by miRNA is absent in human complex-forming proteins. Moreover, the numbers of miRNA hits cannot direct the evolutionary fate of complex-forming proteins independently. However, the duplicated complex-forming proteins having a severe effect on organismal fitness are profoundly targeted by miRNA, probably to reduce the chances of dosage imbalance. PMID- 23756150 TI - Magnetic field intensified bi-enzyme system with in situ cofactor regeneration supported by magnetic nanoparticles. AB - Efficient dynamic interactions among cofactor, enzymes and substrate molecules are of primary importance for multi-step enzymatic reactions with in situ cofactor regeneration. Here we showed for the first time that the above dynamic interactions could be significantly intensified by exerting an external alternating magnetic field on magnetic nanoparticles-supported multi-enzymatic system so that the inter-particle collisions due to Brownian motion of nanoparticles could be improved. To that end, a multienzyme system including glutamate dehydrogenase (GluDH), glucose dehydrogenase (GDH) and cofactor NAD(H) were separately immobilized on silica coated Fe3O4 magnetic nanoparticles with an average diameter of 105 nm, and the effect of magnetic field strength and frequency on the kinetics of the coupled bi-enzyme reaction was investigated. It was found that at low magnetic field frequency (25 Hz and 100 Hz), increasing magnetic field strength from 9.8 to 161.1 Gs led to only very slight increase in reaction rate of the coupled bi-enzyme reaction expressed by glucose consumption rate. At higher magnetic field of 200 Hz and 500 Hz, reaction rate increased significantly with increase of magnetic field strength. When the magnetic field frequency was kept at 500 Hz, the reaction rate increased from 3.89 MUM/min to 8.11 MUM/min by increasing magnetic field strength from 1.3 to 14.2 Gs. The immobilized bi-enzyme system also showed good reusability and stability in the magnetic field (500 Hz, 14.2 Gs), that about 46% of original activity could be retained after 33 repeated uses, accounting for totally 34 days continuous operation. These results demonstrated the feasibility in intensifying molecular interactions among magnetic nanoparticle-supported multienzymes by using nano magnetic stirrer for efficient multi-step transformations. PMID- 23756151 TI - Reproductive neuropeptides: prevalence of GnRH and KNDy neural signalling components in a model avian, gallus gallus. AB - Diverse external and internal environmental factors are integrated in the hypothalamus to regulate the reproductive system. This is mediated through the pulsatile secretion of GnRH into the portal system to stimulate pituitary gonadotrophin secretion, which in turn regulates gonadal function. A single subpopulation of neurones termed 'KNDy neurones' located in the hypothalamic arcuate nucleus co-localise kisspeptin (Kiss), neurokinin B (NKB) and dynorphin (Dyn) and are responsive to negative feedback effects of sex steroids. The co ordinated secretion from KNDy neurones appears to modulate the pulsatile release of GnRH, acting as a proximate pacemaker. This review briefly describes the neuropeptidergic control of reproduction in the avian class, highlighting the status of reproductive neuropeptide signalling systems homologous to those found in mammalian genomes. Genes encoding the GnRH system are complete in the chicken with similar roles to the mammalian counterparts, whereas genes encoding Kiss signalling components appear missing in the avian lineage, indicating a differing set of hypothalamic signals controlling avian reproduction. Gene sequences encoding both NKB and Dyn signalling components are present in the chicken genome, but expression analysis and functional studies remain to be completed. The focus of this article is to describe the avian complement of neuropeptidergic reproductive hormones and provide insights into the putative mechanisms that regulate reproduction in birds. These postulations highlight differences in reproductive strategies of birds in terms of gonadal steroid feedback systems, integration of metabolic signals and seasonality. Also included are propositions of KNDy neuropeptide gene silencing and plasticity in utilisation of these neuropeptides during avian evolution. PMID- 23756152 TI - Co-delivery of a hydrophobic small molecule and a hydrophilic peptide by porous silicon nanoparticles. AB - Nanoparticulate drug delivery systems offer remarkable opportunities for clinical treatment. However, there are several challenges when they are employed to deliver multiple cargos/payloads, particularly concerning the synchronous delivery of small molecular weight drugs and relatively larger peptides. Since porous silicon (PSi) nanoparticles (NPs) can easily contain high payloads of drugs with various properties, we evaluated their carrier potential in multi-drug delivery for co-loading of the hydrophobic drug indomethacin and the hydrophilic human peptide YY3-36 (PYY3-36). Sequential loading of these two drugs into the PSi NPs enhanced the drug release rate of each drug and also their amount permeated across Caco-2 and Caco-2/HT29 cell monolayers. Regardless of the loading approach used, dual or single, the drug permeation profiles were in good correlation with their drug release behaviour. Furthermore, the permeation studies indicated the critical role of the mucus intestinal layer and the paracellular resistance in the permeation of the therapeutic compounds across the intestinal wall. Loading with PYY3-36 also greatly improved the cytocompatibility of the PSi NPs. Conformational analysis indicated that the PYY3-36 could still display biological activity after release from the PSi NPs and permeation across the intestinal cell monolayers. These results are the first demonstration of the promising potential of PSi NPs for simultaneous multi-drug delivery of both hydrophobic and hydrophilic compounds. PMID- 23756153 TI - Modulation of the arcuate nucleus-medial preoptic nucleus lordosis regulating circuit: a role for GABAB receptors. AB - Estradiol rapidly activates a microcircuit in the arcuate nucleus of the hypothalamus (ARH) that is needed for maximal female sexual receptivity. Membrane estrogen receptor-alpha complexes with and signals through the metabotropic glutamate receptor-1a stimulating NPY release within the ARH activating proopiomelanocortin (POMC) neurons. These POMC neurons project to the medial preoptic nucleus (MPN) and release beta-endorphin. Estradiol treatment induces activation/internalization of MPN MU-opioid receptors (MOR) to inhibit lordosis. Estradiol membrane action modulates ARH gamma-aminobutyric acid receptor-B (GABAB) activity. We tested the hypothesis that ARH GABAB receptors mediate estradiol-induced MOR activation and facilitation of sexual receptivity. Double label immunohistochemistry revealed expression of GABAB receptors in NPY, ERalpha and POMC expressing ARH neurons. Approximately 70% of POMC neurons expressed GABAB receptors. Because estradiol initially activates an inhibitory circuit and maintains activation of this circuit, the effects of blocking GABAB receptors were evaluated before estradiol benzoate (EB) treatment and after at the time of lordosis testing. Bilateral infusions of the GABAB receptor antagonist, CGP52432, into the ARH prior to EB treatment of ovariectomized rats prevented estradiol induced activation/internalization of MPN MOR, and the rats remained unreceptive. However, in EB-treated rats, bilateral CGP52432 infusions 30 min before behavior testing attenuated MOR internalization and facilitated lordosis. These results indicated that GABAB receptors were located within the lordosis-regulating ARH microcircuit and are necessary for activation and maintenance of the estradiol inhibition of lordosis behavior. Although GABAB receptors positively influence estradiol signaling, they negatively regulate lordosis behavior since GABAB activity maintains the estradiol-induced inhibition. PMID- 23756156 TI - CCN2 plays a key role in extracellular matrix gene expression in severe hypertrophic cardiomyopathy and heart failure. AB - Hypertrophic cardiomyopathy (HCM) is the most common inherited primary myocardial disorder. HCM is characterized by interstitial fibrosis and excessive accumulation of extracellular matrix (ECM) proteins. Fibrosis in HCM has been associated with impaired cardiac function and heart failure, and has been considered a key substrate for ventricular arrhythmias and sudden death. The molecular triggers underpinning ECM production are not well established. We have previously developed a double-mutant mouse model of HCM that recapitulates the phenotype seen in humans with multiple mutations, including earlier onset of the disease, progression to a dilated phenotype, severe heart failure and premature mortality. The present study investigated the expression of ECM-encoding genes in severe HCM and heart failure. Significant upregulation of structural Fn1, regulatory Mmp14, Timp1, Serpin3A, SerpinE1, SerpineE2, Tgfbeta1, and Tgfbeta2; and matricellular Ccn2, Postn, Spp1, Thbs1, Thbs4, and Tnc was evident from the early, pre-phenotype stage. Non-myocytes expressed ECM genes at higher levels than cardiomyocytes in normal and diseased hearts. Synchronous increase of secreted CCN2 and TIMP1 plasma levels and decrease of MMP3 levels were observed in end-stage disease. CCN2 protein expression was increased from early disease in double-mutant hearts and played an important role in ECM responses. It was a powerful modulator of ECM regulatory (Timp1 and SerpinE1) and matricellular protein-encoding (Spp1, Thbs1, Thbs4 and Tnc) gene expression in cardiomyocytes when added exogenously in vitro. Modulation of CCN2 (CTGF, connective tissue growth factor) and associated early ECM changes may represent a new therapeutic target in the treatment and prevention of heart failure in HCM. PMID- 23756154 TI - The amygdala: an agent of change in adolescent neural networks. AB - This article is part of a Special Issue "Puberty and Adolescence". A unique component of adolescent development is the need to master new developmental tasks in which peer interactions become primary (for the purposes of becoming autonomous from parents, forming intimate friendships, and romantic/sexual partnerships). Previously, it has been suggested that the ability to master these tasks requires an important re-organization in the relation between perceptual, motivational, affective, and cognitive systems in a very general and broad way that is fundamentally influenced by the infusion of sex hormones during pubertal development (Scherf et al., 2012). Herein, we extend this argument to suggest that the amygdala, which is vastly connected with cortical and subcortical regions and contains sex hormone receptors, may lie at the heart of this re organization. We propose that during adolescent development there is a shift in the attribution of relevance to existing stimuli and contexts that is mediated by the amygdala (e.g., heightened relevance of peer faces, reduced relevance of physical distance from parents). As a result, amygdala inputs to existing stable neural networks are re-weighted (increased or decreased), which destabilizes the functional interactions among regions within these networks and allows for a critical restructuring of the network functional organization. This process of network re-organization enables processing of qualitatively new kinds of social information and the emergence of novel behaviors that support mastery of adolescent-specific developmental tasks. PMID- 23756158 TI - Effect of neuropeptide Y on food intake in bullfrog larvae. AB - Neuropeptide Y (NPY) is a potent orexigenic neuropeptide implicated in appetite regulation in mammals. However, except for teleost fish such as the goldfish and zebrafish, the involvement of NPY in the regulation of feeding in non-mammalian vertebrates has not been well studied. Anuran amphibian larvae feed and grow during the pre- and pro-metamorphic stages, but, thereafter they stop feeding as the metamorphic climax approaches. Therefore, orexigenic factors seem to play important roles in pre- and pro-metamorphic larvae. We investigated the role of NPY in food intake using bullfrog larvae including pre- and pro-metamorphic stages, and examined the effect of feeding status on the expression level of the NPY transcript in the hypothalamus. NPY mRNA levels in hypothalamus specimens obtained from larvae that had been fasted for 3 days were higher than those in larvae that had been fed normally. We then investigated the effect of intracerebroventricular (ICV) administration of NPY on food intake in the larvae. Cumulative food intake was significantly increased by ICV administration of NPY (5 and 10 pmol/g body weight, BW) during a 15-min observation period. The NPY induced orexigenic action (10 pmol/g BW) was blocked by treatment with a NPY Y1 receptor antagonist, BIBP-3226 (100 pmol/g BW). These results indicate that NPY acts as an orexigenic factor in bullfrog larvae. PMID- 23756157 TI - Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes. AB - Endothelin receptors are present on the nuclear membranes in adult cardiac ventricular myocytes. The objectives of the present study were to determine 1) which endothelin receptor subtype is in cardiac nuclear membranes, 2) if the receptor and ligand traffic from the cell surface to the nucleus, and 3) the effect of increased intracellular ET-1 on nuclear Ca(2+) signaling. Confocal microscopy using fluorescently-labeled endothelin analogs confirmed the presence of ETB at the nuclear membrane of rat cardiomyocytes in skinned-cells and isolated nuclei. Furthermore, in both cardiac myocytes and aortic endothelial cells, endocytosed ET:ETB complexes translocated to lysosomes and not the nuclear envelope. Although ETA and ETB can form heterodimers, the presence or absence of ETA did not alter ETB trafficking. Treatment of isolated nuclei with peptide: N glycosidase F did not alter the electrophoretic mobility of ETB. The absence of N glycosylation further indicates that these receptors did not originate at the cell surface. Intracellular photolysis of a caged ET-1 analog ([Trp-ODMNB(21)]ET 1) evoked an increase in nucleoplasmic Ca(2+) ([Ca(2+)]n) that was attenuated by inositol 1,4,5-trisphosphate receptor inhibitor 2-aminoethoxydiphenyl borate and prevented by pre-treatment with ryanodine. A caged cell-permeable analog of the ETB-selective antagonist IRL-2500 blocked the ability of intracellular cET-1 to increase [Ca(2+)]n whereas extracellular application of ETA and ETB receptor antagonists did not. These data suggest that 1) the endothelin receptor in the cardiac nuclear membranes is ETB, 2) ETB traffics directly to the nuclear membrane after biosynthesis, 3) exogenous endothelins are not ligands for ETB on nuclear membranes, and 4) ETB associated with the nuclear membranes regulates nuclear Ca(2+) signaling. PMID- 23756160 TI - Defective expression and function of the ILT2/CD85j regulatory receptor in dendritic cells from patients with systemic lupus erythematosus. AB - Dendritic cells (DCs) play an important role in inducing immune tolerance. Inhibitory receptors, such as ILT2/CD85j, are involved in the tolerogenic effect of DCs and previous studies have indicated the important role of these receptors on the pathogenesis of autoimmune diseases. The aim of this study was to evaluate the expression and function of ILT2 in DCs from SLE patients. Peripheral blood from fifty patients with SLE and 38 healthy volunteers was obtained. ILT2 expression was assessed by flow cytometry. DCs were generated in the absence or presence of an anti-ILT2 antibody. The effect of ILT2 in the immunogenic ability of SLE DCs was also evaluated. We observed that SLE patients had significant higher levels of circulating plasmacytoid DCs (pDCs), and that these levels correlated with disease activity. In contrast, the expression of ILT2 was diminished in both pDCs and myeloid DCs (mDCs) from these patients. However, under our experimental conditions, the in vitro differentiation of DCs was not apparently affected by ILT2 engagement. In contrast, the immunogenic capability of monocyte-derived DCs was not down-regulated by ILT2 cross-linking in a significant proportion of SLE patients. Our results suggest that ILT2 participates in the defective immune-regulation observed in patients with SLE. PMID- 23756159 TI - Crystal structures of the first condensation domain of CDA synthetase suggest conformational changes during the synthetic cycle of nonribosomal peptide synthetases. AB - Nonribosomal peptide synthetases (NRPSs) are large modular macromolecular machines that produce small peptide molecules with wide-ranging biological activities, such as antibiotics and green chemicals. The condensation (C) domain is responsible for amide bond formation, the central chemical step in nonribosomal peptide synthesis. Here we present two crystal structures of the first condensation domain of the calcium-dependent antibiotic (CDA) synthetase (CDA-C1) from Streptomyces coelicolor, determined at resolutions 1.8A and 2.4A. The conformations adopted by CDA-C1 are quite similar in these two structures yet distinct from those seen in other NRPS C domain structures. HPLC-based reaction assays show that this CDA-C1 construct is catalytically active, and small-angle X ray scattering experiments suggest that the conformation observed in these crystal structures could faithfully represent the conformation in solution. We have performed targeted molecular dynamics simulations, normal mode analyses and energy-minimized linear interpolation to investigate the conformational changes required to transition between the observed structures. We discuss the implications of these conformational changes in the synthetic cycle and of the observation that the "latch" that covers the active site is consistently formed in all studied C domains. PMID- 23756162 TI - HLA-DO increases bacterial superantigen binding to human MHC molecules by inhibiting dissociation of class II-associated invariant chain peptides. AB - HLA-DO (H2-O in mice) is an intracellular non-classical MHC class II molecule (MHCII). It forms a stable complex with HLA-DM (H2-M in mice) and shapes the MHC class II-associated peptide repertoire. Here, we tested the impact of HLA-DO and H2-O on the binding of superantigens (SAgs), which has been shown previously to be sensitive to the structural nature of the class II-bound peptides. We found that the binding of staphylococcal enterotoxin (SE) A and B, as well as toxic shock syndrome toxin 1 (TSST-1), was similar on the HLA-DO(+) human B cell lines 721.45 and its HLA-DO(-) counterpart. However, overexpressing HLA-DO in MHC class II(+) HeLa cells (HeLa-CIITA-DO) improved binding of SEA and TSST-1. Accordingly, knocking down HLA-DO expression using specific siRNAs decreased SEA and TSST-1 binding. We tested directly the impact of the class II-associated invariant chain peptide (CLIP), which dissociation from MHC class II molecules is inhibited by overexpressed HLA-DO. Loading of synthetic CLIP on HLA-DR(+) cells increased SEA and TSST-1 binding. Accordingly, knocking down HLA-DM had a similar effect. In mice, H2-O deficiency had no impact on SAgs binding to isolated splenocytes. Altogether, our results demonstrate that the sensitivity of SAgs to the MHCII associated peptide has physiological basis and that the effect of HLA-DO on SEA and TSST-1 is mediated through the inhibition of CLIP release. PMID- 23756161 TI - HLA class II DQA and DQB epitopes: recognition of the likely binding sites of HLA DQ alloantibodies eluted from recombinant HLA-DQ single antigen cell lines. AB - Donor-specific antibodies (DSA) in sera of sensitized transplant patients are often produced against the specific epitopes on mismatched HLA antigens. In this study, we selected sera from 30 kidney transplant patients with DSA and AMR to define DQ epitopes. Using adsorption and elution assays, we identified 18 antibody reaction patterns to define 6 new epitopes and to confirm 12 previously defined epitopes. In one patient case, one mismatched antigen produced 3 different antibodies and, in another, antibodies were produced against the alpha and beta chains of the same antigen. For some sera, a single epitope can explain reactions for 27 of the 29 DQ beads in the single antigen panel. Several studies highlighted the prevalence of anti-DQ antibodies. In 2011, Almeshari et al. observed DQ DSA in 34/46 (74%) of rejection episodes - 44 patients had DSA and 20 lost their graft due to AMR. Other studies have shown a high prevalence of anti DQ antibodies and an association with adverse effects on the graft. We conclude that analysis of the epitopes of the DQ antibodies using Adsorption/Elution and testing on single antigen DQ beads helps to better understand the specificities and cross-reactions of DQ antibodies in transplant patients. PMID- 23756163 TI - Absence of activating killer immunoglobulin-like receptor genes combined with hepatitis C viral genotype is predictive of hepatocellular carcinoma. AB - Killer immunoglobulin-like receptors and their human leukocyte antigen class I ligands have a critical role in natural killer cell response to viral pathogens and tumors. To investigate whether killer immunoglobulin-like receptor genes could influence the chronic course of hepatitis C virus infection and/or progression to hepatocellular carcinoma we retrospectively analyzed a cohort of 228 patients transplanted for hepatitis C virus-induced cirrhotic end stage liver disease, combined or not with hepatocellular carcinoma. We found that patients completely lacking activating killer immunoglobulin-like receptor genes had a high risk of developing hepatocellular carcinoma. Hepatitis C viral genotype and viral load are other risk factors that can influence the course of chronic hepatitis C virus infection. In our study, the risk conferred by hepatitis C viral genotypes was enhanced in patients lacking activating killer immunoglobulin like receptors. These results point to an important role for activating killer immunoglobulin-like receptors in the control of hepatitis C virus infection and progression to hepatocellular carcinoma. In clinical practice, assessment of killer immunoglobulin-like receptor and hepatitis C viral genotype combinations should allow for more accurate monitoring of patients with chronic hepatitis C virus infection. PMID- 23756164 TI - Kinetics of the CTLA-4 isoforms expression after T-lymphocyte activation and role of the promoter polymorphisms on CTLA-4 gene transcription. AB - Cytotoxic T lymphocyte antigen 4 (CTLA-4) plays a key inhibitory role during T lymphocyte activation. The CTLA4 gene is translated into two proteic isoforms: a full-length protein (flCTLA-4) and a soluble counterpart. We explored the expression of both isoforms on healthy subjects. Whereas in non-stimulated cells the flCTLA-4 isoform is predominant, after stimulation the expression of the soluble form rapidly increases, reaching its maximum 24h after and falling again to the basal levels 72 h after stimulation. In contrast, the flCTLA-4 mRNA levels increase is slower, reaching the maximum level 72 h after stimulation. The presence of the T allele in the promoter positions -1722 and -318 is associated with an increased transcriptional activity and this effect seems to be synergic. We conclude that the kinetics of CTLA-4 isoform expression are sequential, and that the promoter polymorphisms -1722(C/T) and -318(C/T) are involved in the control of the CTLA4 transcription. PMID- 23756165 TI - Defensins: natural component of human innate immunity. AB - The widespread use of antibiotics has contributed to a huge increase in the number of resistant bacteria. New classes of drugs are therefore being developed of which defensins are a potential source. Defensins are a group of antimicrobial peptides found in different living organisms, involved in the first line of defense in their innate immune response against pathogens. This review summarizes the results of studies of this family of human antimicrobial peptides (AMPs). There is a special emphasis on describing the entire group and individual peptides, history of their discovery, their functions and expression sites. The results of the recent studies on the use of the biologically active peptides in human medicine are also presented. The pharmaceutical potential of human defensins cannot be ignored, especially considering their strong antimicrobial activity and properties such as low molecular weight, reduced immunogenicity, broad activity spectrum and resistance to proteolysis, but there are still many challenges and questions regarding the possibilities of their practical application. PMID- 23756166 TI - Regulatory T cells in cancer: an overview and perspectives on cyclooxygenase-2 and Foxp3 DNA methylation. AB - Epigenetics has been gaining great attention as a therapeutic target in cancer. The cancer genome usually contains both hyper- and hypo-methylated genes to increase invasion, proliferation and metastasis. These cells not only operate their own growth, but also develop various strategies to escape from immune surveillance, and for this aim, regulatory T (Treg) cells support the cancer mediated immune suppression. The fate of Treg cells is mainly controlled by DNA methylation within the promoter and intronic regions of Foxp3 gene. Foxp3 transcription factor is involved in the development, differentiation and function of Treg cells. COX-2 is also an epigenetically controlled gene in these processes. This enzyme and its product PGE2 plays essential roles in Treg functionality in cancer. Here, we discuss the effects of DNA methylation on cancer and nTreg cells. We also summarize the mechanisms related with COX-2/PGE2 and Foxp3 on inhibitory function of Treg cells in cancer. PMID- 23756167 TI - Association of interleukin (IL)-4 gene intron 3 VNTR polymorphism with multiple sclerosis in Turkish population. AB - OBJECTIVE: Genetic risk factors are known to contribute to the etiology of multiple sclerosis (MS). Interleukin (IL)-4 gene polymorphisms have been associated with immune-mediated diseases. The aim of this study was to explore the frequency of IL-4 gene intron 3 VNTR (variable number tandem repeat) polymorphism in a cohort of Turkish patients with MS. METHODS: The study included 125 patients with MS and 160 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) analyses for the IL-4 gene intron 3 VNTR polymorphism. RESULTS: The distribution of genotype and allele frequencies of IL-4 gene intron 3 VNTR polymorphism was statistically different between MS patients and control group (p = 0.003 and p = 0.002, respectively). There were no statistically significant association between IL-4 VNTR polymorphism and clinical and demographical characteristics of MS patients. CONCLUSION: The results of this study suggest that intron 3 VNTR polymorphism of the IL-4 gene was positively associated with predisposition to develop MS in Turkish population. PMID- 23756168 TI - Chronic treatment with MPEP, an mGlu5 receptor antagonist, normalizes basal ganglia glutamate neurotransmission in L-DOPA-treated parkinsonian monkeys. AB - Metabotropic glutamate 5 (mGlu5) receptor antagonists reduce L-3,4 dihydroxyphenylalanine (L-DOPA)-induced dyskinesias (LID) in Parkinson's disease (PD). The aim of this study was to investigate the long-term effect of the prototypal mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) on glutamate receptors known to be involved in the development of LID in the de novo chronic treatment of monkeys lesioned with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). MPTP monkeys were treated for one month with L-DOPA and developed dyskinesias while those treated with L-DOPA and MPEP (10 mg/kg) developed significantly less. Normal control and saline-treated MPTP monkeys were also included. All MPTP monkeys were extensively and similarly denervated. The basal ganglia [(3)H]ABP688 specific binding (mGlu5 receptors) was elevated in L DOPA-treated MPTP monkeys compared to controls but not in those treated with L DOPA and MPEP; dyskinesia scores of these monkeys correlated positively with their [(3)H]ABP688 specific binding. Striatal density (B(max)) of [(3)H]ABP688 specific binding increased in L-DOPA-treated MPTP monkeys compared to other groups and affinity (Kd) remained unchanged. Striatal mGlu5 receptor mRNA remained unchanged following treatments. Elevated basal ganglia specific binding of [(3)H]Ro 25-6981 (NMDA NR1/NR2B receptors), [(3)H]Ro 48-8587 (AMPA receptors) but not [(3)H]CGP-39653 (NMDA NR1/NR2A receptors) was observed only in L-DOPA treated MPTP monkeys; dyskinesias scores correlated with binding. By contrast, basal ganglia [(3)H]LY341495 specific binding (mGlu2/3 receptors) decreased in L DOPA-treated MPTP monkeys compared to controls, saline and L-DOPA + MPEP treated MPTP monkeys; dyskinesias scores correlated negatively with this binding. Hence, chronic MPEP treatment reduces the development of LID and is associated with a normalization of glutamate neurotransmission. PMID- 23756169 TI - Behavioral endophenotypes of drug addiction: Etiological insights from neuroimaging studies. AB - This article reviews recent advances in the elucidation of neurobehavioral endophenotypes associated with drug addiction made possible by the translational neuroimaging techniques magnetic resonance imaging (MRI) and positron emission tomography (PET). Increasingly, these non-invasive imaging approaches have been the catalyst for advancing our understanding of the etiology of drug addiction as a brain disorder involving complex interactions between pre-disposing behavioral traits, environmental influences and neural perturbations arising from the chronic abuse of licit and illicit drugs. In this article we discuss the causal role of trait markers associated with impulsivity and novelty-/sensation-seeking in speeding the development of compulsive drug administration and in facilitating relapse. We also discuss the striking convergence of imaging findings from these behavioural traits and addiction in rats, monkeys and humans with a focus on biomarkers of dopamine neurotransmission, and highlight areas where further research is needed to disambiguate underlying causal mechanisms. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. PMID- 23756170 TI - Glyphosate induces human breast cancer cells growth via estrogen receptors. AB - Glyphosate is an active ingredient of the most widely used herbicide and it is believed to be less toxic than other pesticides. However, several recent studies showed its potential adverse health effects to humans as it may be an endocrine disruptor. This study focuses on the effects of pure glyphosate on estrogen receptors (ERs) mediated transcriptional activity and their expressions. Glyphosate exerted proliferative effects only in human hormone-dependent breast cancer, T47D cells, but not in hormone-independent breast cancer, MDA-MB231 cells, at 10-12 to 10-6M in estrogen withdrawal condition. The proliferative concentrations of glyphosate that induced the activation of estrogen response element (ERE) transcription activity were 5-13 fold of control in T47D-KBluc cells and this activation was inhibited by an estrogen antagonist, ICI 182780, indicating that the estrogenic activity of glyphosate was mediated via ERs. Furthermore, glyphosate also altered both ERalpha and beta expression. These results indicated that low and environmentally relevant concentrations of glyphosate possessed estrogenic activity. Glyphosate-based herbicides are widely used for soybean cultivation, and our results also found that there was an additive estrogenic effect between glyphosate and genistein, a phytoestrogen in soybeans. However, these additive effects of glyphosate contamination in soybeans need further animal study. PMID- 23756171 TI - Tumor cell growth inhibitory activity and structure-activity relationship of polyoxygenated steroids from the gorgonian Menella kanisa. AB - Fourteen new polyoxygenated steroids (6, 9, 14-18, 20-23, 25-27) having carbon skeletons of cholestane, ergostane, and 24-norcholestane, were isolated together with thirteen known analogues (1-5, 7, 8, 10-13, 19, 24) from the South China Sea gorgonian Menella kanisa. The structures of the new compounds were elucidated by detailed analysis of spectroscopic data and comparisons with reported data. This is the first report of chemical investigation on the title gorgonian. Compounds 12 and 13 were reported for the first time from natural sources. These compounds exhibited different levels of growth inhibition activity against A549 and MG-63 cell lines in bioassay in vitro. Preliminary structure-activity analysis revealed an important role of side chain in the activity. A substitution of a 5alpha hydroxy or an oxidation of 6beta-hydroxy to a ketone carbonyl group may decrease the activity whereas the contribution of the 1-ketone group remains uncertain. PMID- 23756172 TI - Synthesis and structure of 16,22-diketocholesterol bound to oxysterol-binding protein Osh4. AB - We have synthesized 16,22-diketocholesterol, a novel ligand for oxysterol-binding protein Osh4, and determined X-ray structure of the diketocholesterol in complex with Osh4. The X-ray structure shows that alpha7 helix of Osh4 assumes open conformation while the rest of Osh4, closed conformation, implying this diketocholesterol-bound Osh4 structure may represent a structural intermediate between the two conformations. PMID- 23756173 TI - Exploitation or cooperation? Evolution of a host (ciliate)-benefiting alga in a long-term experimental microcosm culture. AB - Controversy persists as to whether the acquisition of beneficial metabolic functions via endosymbiosis can occur suddenly on an evolutionary time scale. In this study, an early stage of endosymbiotic associations, which evolved from previously unassociated auto (photo)- and heterotrophic unicellular organisms was analyzed using an experimental ecosystem model, called CET microcosm. This ecosystem model was composed of a green alga (Micractinium sp.; formerly described as Chlorella vulgaris), a bacterium (Escherichia coli), and a ciliate (Tetrahymena thermophila). Our previous study using a CET microcosm that was cultured 3-5 years revealed that fitness of the ciliate increased by harboring algal cells within its own cells. This fact suggested three possibilities: (i) the ciliate evolved the ability to exploit intracellular algal cells ("exploiter ciliate hypothesis"), (ii) the alga evolved the ability to benefit the host ciliate by providing photosynthates ("cooperator alga hypothesis"), and (iii) a combination of (i) and (ii). To test these hypotheses, two-by-two co-cultures were conducted between the ancestral or derived ciliate and the ancestral or derived alga. The experimental results demonstrated that a cooperative alga evolved in the microcosm, although the possibility remains that an exploitative genotype of the ciliate might also exist in the population as a polymorphism. Remarkably, an algal isolate prolonged the longevity of not only the isolated ciliate, but also the ancestral ciliate. This result suggests that once a cooperative algal genotype evolves in a local population, it can then be transmitted to other individuals of the prospective host species and spread rapidly beyond the local range due to its positive effect on the host fitness. Such transmission suggests the possibility of a sudden acquisition of beneficial autotrophic function by the pre-associated host. PMID- 23756174 TI - (4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone inhibits tubulin polymerization, induces G2/M arrest, and triggers apoptosis in human leukemia HL 60 cells. AB - (4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) is a known cytotoxic compound belonging to the phenstatin family. However, the exact mechanism of action of PHT-induced cell death remains to be determined. The aim of this study was to investigate the mechanisms underlying PHT-induced cytotoxicity. We found that PHT displayed potent cytotoxicity in different tumor cell lines, showing IC50 values in the nanomolar range. Cell cycle arrest in G2/M phase along with the augmented metaphase cells was found. Cells treated with PHT also showed typical hallmarks of apoptosis such as cell shrinkage, chromatin condensation, phosphatidylserine exposure, increase of the caspase 3/7 and 8 activation, loss of mitochondrial membrane potential, and internucleosomal DNA fragmentation without affecting membrane integrity. Studies conducted with isolated tubulin and docking models confirmed that PHT binds to the colchicine site and interferes in the polymerization of microtubules. These results demonstrated that PHT inhibits tubulin polymerization, arrests cancer cells in G2/M phase of the cell cycle, and induces their apoptosis, exhibiting promising anticancer therapeutic potential. PMID- 23756175 TI - Statins attenuate the development of atherosclerosis and endothelial dysfunction induced by exposure to urban particulate matter (PM10). AB - Exposure to ambient air particulate matter (particles less than 10MUm or PM10) has been shown to be an independent risk factor for the development and progression of atherosclerosis. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have well-established anti-inflammatory properties. The aim of this study was to determine the impact of statins on the adverse functional and morphological changes in blood vessels induced by PM10. New Zealand White rabbits fed with a high fat diet were subjected to balloon injury to their abdominal aorta followed by PM10/saline exposure for 4weeks+/ lovastatin (5mg/kg/day) treatment. PM10 exposure accelerated balloon catheter induced plaque formation and increased intimal macrophages and lipid accumulation while lovastatin attenuated these changes and promoted smooth muscle cell recruitment into plaques. PM10 impaired vascular acetylcholine (Ach) responses and increased vasoconstriction induced by phenylephrine as assessed by wire myograph. Supplementation of nitric oxide improved the impaired Ach responses. PM10 increased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in blood vessels and increased the plasma levels of endothelin-1 (ET-1). Incubation with specific inhibitors for iNOS, COX-2 or ET-1 in the myograph chambers significantly improved the impaired vascular function. Lovastatin decreased the expression of these mediators in atherosclerotic lesions and improved endothelial dysfunction. However, lovastatin was unable to reduce blood lipid levels to the baseline level in rabbits exposed to PM10. Taken together, statins protect against PM10-induced cardiovascular disease by reducing atherosclerosis and improving endothelial function via their anti-inflammatory properties. PMID- 23756176 TI - C-terminals in the mouse branchiomotor nuclei originate from the magnocellular reticular formation. AB - Large cholinergic synaptic boutons called "C-terminals" contact motoneurons and regulate their excitability. C-terminals in the spinal somatic motor nuclei originate from cholinergic interneurons in laminae VII and X that express a transcription factor Pitx2. Cranial motor nuclei contain another type of motoneuron: branchiomotor neurons. Although branchiomotor neurons receive abundant C-terminal projections, the neural source of these C-terminals remains unknown. In the present study, we first examined whether cholinergic neurons express Pitx2 in the reticular formation of the adult mouse brainstem, as in the spinal cord. Although Pitx2-positive cholinergic neurons were observed in the magnocellular reticular formation and region around the central canal in the caudal medulla, none was present more rostrally in the brainstem tegmentum. We next explored the origin of C-terminals in the branchiomotor nuclei by using biotinylated dextran amine (BDA). BDA injections into the magnocellular reticular formation of the medulla and pons resulted in the labeling of numerous C terminals in the branchiomotor nuclei: the ambiguous, facial, and trigeminal motor nuclei. Our results revealed that the origins of C-terminals in the branchiomotor nuclei are cholinergic neurons in the magnocellular reticular formation not only in the caudal medulla, but also at more rostral levels of the brainstem, which lacks Pitx2-positive neurons. PMID- 23756177 TI - A comparison of neuroplastic responses to non-invasive brain stimulation protocols and motor learning in healthy adults. AB - Non-invasive brain stimulation (NBS) techniques can induce neuroplastic changes similar to those associated with motor learning and there is evidence for the involvement of common mechanisms. Whether there are correlations between the changes induced by NBS and those associated with motor learning remains unclear. We investigated whether there was any relationship between an individual's neuroplastic responses to several different NBS protocols (continuous theta-burst stimulation (cTBS); intermittent theta-burst stimulation (iTBS); facilitatory paired associative stimulation (PAS: inter-stimulus interval 25ms)) and whether these responses correlated with the neuroplastic response associated with a motor training (MT) task involving repeated fast-as-possible thumb abductions. Changes in motor evoked potential (MEP) amplitude were used to assess the neuroplastic response to each protocol. MEP amplitude decreased significantly following cTBS, however there was no significant change in MEP amplitude following iTBS, PAS or MT. There were no significant correlations between individuals' neuroplastic responses to any of the NBS protocols tested or between individuals' neuroplastic responses to the NBS protocols and motor learning. These results provide no support for an association between individuals' neuroplastic responses to several plasticity-inducing protocols. Although there is evidence for involvement of common mechanisms in the neuroplastic changes induced by NBS and motor learning, the results of this study suggest (1) the mechanisms mediating TBS-, PAS-, and MT induced plasticity may only partially overlap, and (2) additional factors, including large intra and inter-subject response variability, may make the demonstration of associations between neuroplastic responses to the various protocols difficult. PMID- 23756178 TI - Meta-analysis confirms a functional polymorphism (5-HTTLPR) in the serotonin transporter gene conferring risk of bipolar disorder in European populations. AB - The serotonin transporter (5-HTT) is a candidate risk gene for bipolar disorder, and a functional polymorphism of 44-bp insertion/deletion (5-HTTLPR) located in the promoter region of this gene has been investigated for the association with the illness extensively among worldwide populations, but overall results were inconsistent and its role in the disorder remains unclear. The present study attempts to find its potential association with bipolar disorder using meta analyzes that maximize the statistical power. We applied meta-analysis techniques by combining all available case-control studies of 5-HTTLPR and bipolar disorder in samples of European ancestry (with a total of 3778 cases and 4997 controls), and we assessed the evidence for allelic associations, heterogeneity among different studies, influence of each single study, and potential publication bias. The short allele (S allele) of 5-HTTLPR showed a significant association with bipolar disorder in our meta-analysis (odds ratio=1.10, p-value=0.005), suggesting it is likely a risk polymorphism for the illness, and the observed OR is consistent with other susceptibility loci identified through recent large scale genetic association studies on bipolar disorder, which could be regarded simply as a small but detectable effects. PMID- 23756179 TI - Radiation-inducible protein RbAp48 contributes to radiosensitivity of cervical cancer cells. AB - OBJECTIVE: Retinoblastoma-associated protein 48 (RbAp48) has been recently discovered as a radiosensitive gene. We aimed to investigate the role of RbAp48 in radiosensitivity of cervical cancer cells in vivo and in vitro. METHODS: We used real-time RT-PCR and Western blot assay to examine the expression of RbAp48 in irradiated cervical cancer cell lines, including SiHa, Caski, and HeLa cells. The role of RbAp48 in radiosensitivity of cervical cancer cells was assessed by cell proliferation, counting, survival, and apoptosis as well as cell cycle and tumor growth assays with RbAp48 overexpression or gene silencing. RESULTS: The expression of RbAp48 was increased in irradiated cervical cancer cell lines. Overexpression of RbAp48 induced G2/M arrest and apoptosis in irradiated cells, which was related to upregulation of p53, Rb and caspase-8 expression. Adenovirus RbAp48 infection and irradiation synergistically inhibited tumor growth in nude mice. CONCLUSIONS: RbAp48 is a radiation-inducible gene in cervical cancer cells because of enhanced radiosensitivity of cervical cancer cells in vivo and in vitro. RbAp48 may be a potential target to improve the results of radiation therapy for patients with cervical cancer. PMID- 23756180 TI - A phase I clinical trial of Ad5/3-Delta24, a novel serotype-chimeric, infectivity enhanced, conditionally-replicative adenovirus (CRAd), in patients with recurrent ovarian cancer. AB - OBJECTIVE: The conditionally replicative adenovirus Ad5/3-Delta24 has a type-3 knob incorporated into the type-5 fiber that facilitates enhanced ovarian cancer infectivity. Preclinical studies have shown that Ad5/3-Delta24 achieves significant oncolysis and anti-tumor activity in ovarian cancer models. The purpose of this study was to evaluate in a phase I trial the feasibility and safety of intraperitoneal (IP) Ad5/3-Delta24 in recurrent ovarian cancer patients. METHODS: Eligible patients were treated with IP Ad5/3-Delta24 for 3 consecutive days in one of three dose cohorts ranging 1 * 10(10)-1 * 10(12)vp. Toxicity was assessed utilizing CTC grading and efficacy with RECIST. Ascites, serum, and other samples were obtained to evaluate gene transfer, generation of wildtype virus, viral shedding, and antibody response. RESULTS: Nine of 10 patients completed treatment per protocol. A total of 15 vector-related adverse events were experienced in 5 patients. These events included fever or chills, nausea, fatigue, and myalgia. All were grades 1-2 in nature, transient, and medically managed. Of the 8 treated patients evaluable for response, six patients had stable disease and 2 patients had progressive disease. Three patients had decreased CA-125 from pretreatment levels one month after treatment. Ancillary biologic studies indicated Ad5/3-Delta24 replication in patients in the higher dose cohorts. All patients experienced an anti-adenoviral neutralizing antibody effect. CONCLUSIONS: This study suggests the feasibility and safety of a serotype chimeric infectivity-enhanced CRAd, Ad5/3-Delta24, as a potential therapeutic option for recurrent ovarian cancer patients. PMID- 23756181 TI - Protein tyrosine phosphatases as novel targets in breast cancer therapy. AB - Breast cancer is linked to hyperactivation of protein tyrosine kinases (PTKs), and recent studies have unveiled that selective tyrosine dephosphorylation by protein tyrosine phosphatases (PTPs) of specific substrates, including PTKs, may activate or inactivate oncogenic pathways in human breast cancer cell growth related processes. Here, we review the current knowledge on the involvement of PTPs in breast cancer, as major regulators of breast cancer therapy-targeted PTKs, such as HER1/EGFR, HER2/Neu, and Src. The functional interplay between PTKs and PTK-activating or -inactivating PTPs, and its implications in novel breast cancer therapies based on targeting of specific PTPs, are discussed. PMID- 23756182 TI - Granulocyte colony stimulating factor (GCSF) improves memory and neurobehavior in an amyloid-beta induced experimental model of Alzheimer's disease. AB - GCSF is an endogenous neuronal hematopoietic factor that displays robust in vitro and in vivo neuroprotective activity. The present study aimed to evaluate the effect of GCSF on Abeta-induced memory loss in an Alzheimer's disease model of rats. A total of 42 male adult Wistar rats weighing 200-250 g were used in the study and were divided into 7 experimental groups. Animals were subjected to intracerebroventricular (ICV) injection stereotaxically at day 0 to instill amyloid-beta(1-42) (Abeta(1-42)) or PBS (sham operated group) at 10 MUl (5 MUl bilaterally). GCSF treatment was given from day 7 to 12 of Abeta injection. On day 21, behavioral tests (short term memory, exploratory behavior and motor coordination) in all groups were evaluated. Biochemical parameters and RNA expression were measured to ensure the efficacy of GCSF. GCSF (35 and 70 MUg/kg, s.c.) showed statistically significant improvement in memory as compared to control and sham operated groups (p<0.05). Mean time spent in the platform placed quadrant was found to be significantly increased in the GCSF (70 MUg/kg, s.c.) as compared to GCSF (35 MUg/kg, s.c.) and GCSF (10 MUg/kg, s.c.) groups (p<0.001). GCSF (35 and 70 MUg/kg, s.c.) also improved motor coordination and exploratory behavior significantly as compared to naive sham operated and GCSF (10 MUg/kg, s.c.) groups (p<0.05). Improvement in memory by GCSF (35 and 70 MUg/kg, s.c.) was coupled with marked reduction of lipid peroxidation, acetylcholinesterase levels and a significant increase in antioxidant enzymes as well as total RNA expression in the brain. Additionally, GCSF (35 and 70 MUg/kg, s.c.) significantly increased progenitor cells (iPSCs) and surface marker CD34+ in the brain and hence induced neurogenesis. The present findings demonstrate an improvement of memory and neurobehavioral function with GCSF in Abeta-induced Alzheimer's disease model in rats. PMID- 23756183 TI - Evidence that the anxiolytic-like effects of the beta3 receptor agonist amibegron involve serotoninergic receptor activity. AB - Anxiety disorders are the most common behavioral disorders, and they exhibit high comorbidity rates. The aim of the present study was to confirm the effects of Amibegron, the first selective beta 3 adrenergic agent, on anxiety and to demonstrate that different serotoninergic receptor subtypes are involved in this effect. We administered the serotonin 5-HT1A receptor antagonist WAY-100635, the serotonin 5-HT2A receptor antagonist Ketanserin and the serotonin 5-HT3 receptor antagonist Ondansetron in mice and evaluated their performance in the elevated plus-maze test. Mice administered with Amibegron (5 and 10 mg/kg) showed a dose dependent prolonged time spent in the open arms and an increase in the number of entries into the open arms during the elevated plus-maze (EPM) test. However, in the control mice, administration of WAY, Ketanserin and Ondansetron demonstrated no effect on the time spent in the open arms and the number of entries into the open arms. In addition, these treatments all significantly reversed the effect of the Amibegron-induced (10 mg/kg) increase in the time spent in the open arms. However, only WAY and Ketanserin treatments reversed the Amibegron-induced increase in the number of entries into the open arms. In conclusion, Amibegron exerted a significant anxiolytic effect, which was as effective as Diazepam, in mice during the EPM test. This effect of Amibegron may be mediated by interactions with the serotonin 5-HT1A, 5-HT2A and 5-HT3 receptors. PMID- 23756184 TI - Hippocampal development - old and new findings. AB - The hippocampus, derived from medial regions of the telencephalon, constitutes a remarkable brain structure. It is part of the limbic system, and it plays important roles in information encoding, related to short-term and long-term memory, and spatial navigation. It has also attracted the attention of many clinicians and neuroscientists for its involvement in a wide spectrum of pathological conditions, including epilepsy, intellectual disability, Alzheimer disease and others. Here we address the topic of hippocampal development. As well as original landmark findings, modern techniques such as large-scale in situ hybridizations, in utero electroporation and the study of mouse mutants with hippocampal phenotypes, add further detail to our knowledge of the finely regulated processes which form this intricate structure. Molecular signatures are being revealed related to field, intra-field and laminar cell identity, as well as, cell compartments expressing surface proteins instrumental for connectivity. We summarize here old and new findings, and highlight elegant tools used to fine study hippocampal development. PMID- 23756185 TI - Globular adiponectin elicits neuroprotection by inhibiting NADPH oxidase-mediated oxidative damage in ischemic stroke. AB - Recent studies indicate that adiponectin can attenuate cerebral ischemic lesions via its functional area located in the C-terminal globular domain, which is called globular adiponectin (gAD). However, the mechanisms underlying this action remain unclear. In this study, we investigated the antioxidant properties of gAD during cerebral ischemia. Adult male C57BL/6 mice received an intracerebral injection of gAD with or without tetrabromocinnamic acid (TBCA, a NADPH oxidase activator). Mice were subjected to middle cerebral artery occlusion (MCAO) after gAD injection. Infarct volume, neurological function, the activity of antioxidant enzymes (superoxide dismutase [SOD], catalase), the content of malondialdehyde (MDA), and the expression of Bax, Bcl-2, cleaved caspase-3 and NADPH oxidase 2 (NOX2) were examined at 24h after MCAO. Infarct volume was attenuated in gAD transduced mice when compared with mice in the MCAO group, with significant improvement in neurological function. In addition, neuronal apoptosis was attenuated, along with the expression of Bax/Bcl-2 and cleaved caspase 3. Furthermore, the activities of SOD and catalase increased, and the content of MDA reduced. However, TBCA blocked the effect of gAD on cerebral protection and its antioxidant abilities. Taken together, these results demonstrate that the neuroprotective action of gAD may result from the promotion of antioxidant capacity by inhibiting the NOX2 signaling system. PMID- 23756186 TI - Primary prevention of metabolic syndrome in the community using an evidence-based exercise program. AB - OBJECTIVES: The purpose of the present study was to examine the effectiveness of a community-based exercise program to lower metabolic syndrome (MetS) risk factors. METHODS: MetS components were retrospectively analyzed in 332 adults (190 women, 142 men) before and after a 14-week supervised community exercise program between January 2007 and May 2012 at the University of Wisconsin-Eau Claire. RESULTS: Except for total cholesterol, all health outcome variables, including the 5 MetS components, improved following community exercise. Individuals having MetS decreased from 22.3% before participation to 13.5% at end (p<0.05), while prevalence of participants with no MetS components increased 56% (from 65 to 102; p<0.05). Compared to the lowest quartile of relative energy expenditure, participants with the highest quartile were 6.4 (95% CI 1.8-23.2; p<0.05), 7 (95% CI 2.5-20.0; p<0.05) and 9.3 (95% CI 2.6-34.0; p<0.05) times more likely to eliminate low-HDL cholesterol, impaired fasting glucose, and low cardiorespiratory fitness as MetS risk factors, respectively. CONCLUSION: A community exercise program is an effective method to reduce cardiovascular risk in adults by substantially decreasing the prevalence of MetS and its components. Greater volumes of exercise may increase the likelihood of MetS risk factor elimination. PMID- 23756187 TI - Shape Up Somerville two-year results: a community-based environmental change intervention sustains weight reduction in children. AB - OBJECTIVE: The objective of this study was to test the hypothesis that community based environmental change intervention prevents undesirable weight gain in children. METHOD: The method used in this study was a two-year, non-randomized, controlled trial (2003-2005) using community-based participatory methodology in three diverse cities in Massachusetts: one intervention and two socio demographically-matched control communities (pooled for analysis). Children (n=1028), with a mean age=7.61+1.04years participated. Interventions were made to improve energy balance by increasing physical activity options and availability of healthful foods (Year 1). To firmly secure sustainability, the study team supported policies and shifted intervention work to community members (Year 2). RESULTS: Change in body mass index z-score (BMIz) was assessed by multiple regression, accounting for clustering within communities and adjusting for baseline covariates. Sex-specific overweight/obesity prevalence, incidence and remission were assessed. Over the two-year period, BMIz of children in the intervention community decreased by -0.06 [p=0.005, 95% confidence interval: 0.08 to -0.04] compared to controls. Prevalence of overweight/obesity decreased in males (OR=0.61, p=0.01) and females (OR=0.78, p=0.01) and remission increased in males (OR 3.18, p=0.03) and females (OR 1.93, p=0.03) in intervention compared to controls. CONCLUSION: Results demonstrate promise for preventing childhood obesity using a sustainable multi-level community-based model and reinforce the need for wide-reaching environmental and policy interventions. PMID- 23756188 TI - Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases. AB - Long noncoding RNAs (lncRNAs) have been attracting immense research interest, while only a handful of lncRNAs have been characterized thoroughly. Their involvement in the fundamental cellular processes including regulate gene expression at epigenetics, transcription, and post-transcription highlighted a central role in cell homeostasis. However, lncRNAs studies are still at a relatively early stage, their definition, conservation, functions, and action mechanisms remain fairly complicated. Here, we give a systematic and comprehensive summary of the existing knowledge of lncRNAs in order to provide a better understanding of this new studying field. lncRNAs play important roles in brain development, neuron function and maintenance, and neurodegenerative diseases are becoming increasingly evident. In this review, we also highlighted recent studies related lncRNAs in central nervous system (CNS) development and neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), and elucidated some specific lncRNAs which may be important for understanding the pathophysiology of neurodegenerative diseases, also have the potential as therapeutic targets. PMID- 23756190 TI - Three new secoiridoids, swermacrolactones A-C and anti-hepatitis B virus activity from Swertia macrosperma. AB - Three new secoiridoids, swermacrolactones A-C (1-3), together with fourteen known compounds were isolated from Swertia macrosperma. Their structures were elucidated based on extensive spectroscopic analyses (IR, UV, MS, 1D and 2D NMR). By anti-HBV assay on the Hep G 2.2.15 cell line in vitro, the most active compound, luteolin (9), inhibited the secretion of hepatitis B virus surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg) with IC50 values of 0.02 and 0.02 mM, respectively. PMID- 23756189 TI - Characterizations of two grass carp Ctenopharyngodon idella HMGB2 genes and potential roles in innate immunity. AB - High-mobility group box 2 (HMGB2) protein is a chromatin-associated nonhistone protein, involved in transcriptional regulation and nucleic-acid-mediated innate immune responses in mammalian. However, the function of piscine HMGB2 in innate immune responses is still unknown. In the present study, two HMGB2 homologue genes (CiHMGB2a, CiHMGB2b) were identified and characterized in grass carp (Ctenopharyngodon idella). Both CiHMGB2a and CiHMGB2b genes encode proteins with 213 amino acids, sharing 71.4% identities and containing two basic HMG boxes and an acidic tail. The deduced protein sequences showed the most identities to HMGB2a (93%) and HMGB2b (86.4%) of zebrafish (Danio rerio), respectively. Quantitative real-time RT-PCR (qRT-PCR) analysis showed that CiHMGB2a and CiHMGB2b were constitutively expressed in all the 15 tested tissues. Post grass carp reovirus (GCRV) infection, mRNA levels of CiHMGB2a and CiHMGB2b were strongly up-regulated in spleen and head kidney and mildly modulated in C. idella kidney (CIK) cells. Meanwhile, mRNA expressions of CiHMGB2a and CiHMGB2b were significantly regulated by viral pathogen associated molecular patterns (PAMPs) polyinosinic-polycytidylic potassium salt (poly(I:C)) and bacterial PAMPs lipopolysaccharide (LPS), peptidoglycan (PGN) challenge in CIK cells. In CiHMGB2a and CiHMGB2b over-expression cells, expressions of CiHMGB2a and CiHMGB2b facilitated each other; transcription levels of CiTRIF, CiMyD88, CiIPS-1 and CiMx1 were remarkably enhanced, whereas CiIFN-I was inhibited, compared with those in cells transfected with pCMV (control plasmid); after GCRV challenge, all those tested genes were up-regulated with divergent expression profiles. Antiviral activities of CiHMGB2a and CiHMGB2b were manifested by the delayed appearance of cytopathic effect (CPE) and inhibition of GCRV yield. All those results demonstrate that CiHMGB2a and CiHMGB2b not only mediate antiviral immune responses but also involve in responding to viral/bacterial PAMPs challenge, which provides novel insights into the essential role of HMGB2 in innate immunity. PMID- 23756191 TI - Daphmacromines K-O, alkaloids from Daphniphyllum macropodum. AB - Five new yuzurimine-type Daphniphyllum alkaloids, daphmacromines K-O (1-5), were isolated from the leaves and stems of Daphniphyllum macropodum. Their structures were elucidated by extensive spectroscopic techniques, including 2D NMR spectroscopy and mass spectrometry. Daphmacromine O (5) showed moderate cytotoxic activity against brine shrimp. PMID- 23756192 TI - Association between interleukin 4 gene intron 3 VNTR polymorphism and recurrent aphthous stomatitis in a cohort of Turkish patients. AB - OBJECTIVE: Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal diseases, with a multifactorial etiopathogenesis, an interaction between predisposing factors and/or systemic conditions and immunological components in genetically predisposed subjects. Although there is no clear genetic mode of inheritance, there is evidence that inheritance of specific gene polymorphisms may predispose individuals to RAS. The purpose of the present study was to investigate a possible association between the functional interleukin 4 (IL4) VNTR genetic polymorphism and RAS in a sample of Turkish patients. METHODS: The study included 145 unrelated patients with a clinical diagnosis of RAS and 150 unrelated healthy controls. Genomic DNA was isolated and IL4 gene 70 bp VNTR polymorphism determined by using polymerase chain reaction (PCR) with specific primers. RESULTS: The distribution of genotype and allele frequencies of IL4 gene intron 3 VNTR polymorphism was statistically different between RAS patients and control group (p<0.0001 and p<0.0001, respectively) P2P2 genotype and P2 allele were also found to be protective with a lower risk for susceptibility to RAS (p<0.0001). CONCLUSION: The results of this study suggest that intron 3 VNTR polymorphism in the IL4 gene is associated with RAS susceptibility in Turkish population. PMID- 23756193 TI - Analysis of the Dendrobium officinale transcriptome reveals putative alkaloid biosynthetic genes and genetic markers. AB - Dendrobium officinale Kimura et Migo (Orchidaceae) is a traditional Chinese medicinal plant. The stem contains an alkaloid that is the primary bioactive component. However, the details of alkaloid biosynthesis have not been effectively explored because of the limited number of expressed sequence tags (ESTs) available in GenBank. In this study, we analyzed RNA isolated from the stem of D. officinale using a single half-run on the Roche 454 GS FLX Titanium platform to generate 553,084 ESTs with an average length of 417 bases. The ESTs were assembled into 36,407 unique putative transcripts. A total of 69.97% of the unique sequences were annotated, and a detailed view of alkaloid biosynthesis was obtained. Functional assignment based on Kyoto Encyclopedia of Genes and Genomes (KEGG) terms revealed 69 unique sequences representing 25 genes involved in alkaloid backbone biosynthesis. A series of qRT-PCR experiments confirmed that the expression levels of 5 key enzyme-encoding genes involved in alkaloid biosynthesis are greater in the leaves of D. officinale than in the stems. Cytochrome P450s, aminotransferases, methyltransferases, multidrug resistance protein (MDR) transporters and transcription factors were screened for possible involvement in alkaloid biosynthesis. Furthermore, a total of 1061 simple sequence repeat motifs (SSR) were detected from 36,407 unigenes. Dinucleotide repeats were the most abundant repeat type. Of these, 179 genes were associated with a metabolic pathway in KEGG. This study is the first to produce a large volume of transcriptome data from D. officinale. It extends the foundation to facilitate gene discovery in D. officinale and provides an important resource for the molecular genetic and functional genomic studies in this species. PMID- 23756194 TI - Screening for Fabry disease in patients undergoing dialysis for chronic renal failure in Turkey: identification of new case with novel mutation. AB - BACKGROUND: Chronic renal failure (CRF) is a serious complication of Fabry disease (FD). The aims of the present study were to determine the prevalence of unrecognized FD in Turkish hemodialysis population and to investigate the molecular background. METHOD: Primarily, alpha-galactosidase A (alpha-Gal A) activity was investigated on DBS in 1136 patients of both sexes who underwent dialysis for CRF in Turkey. The disease was confirmed by analyzing enzyme activity in leukocyte and GLA gene sequencing in all patients in whom alpha-Gal A level was 40% of normal or less. RESULTS: Mean age of the patients (44.5% female, 52.5% male) was 56.46+/-15.85 years. Enzyme activity was found low with DBS method in 12 patients (four males, eight females). Two men, but no women, were diagnosed with FD by enzymatic and molecular analysis. In consequence of genetic analysis of a case, a new mutation [hemizygote c.638C>T (p.P214S) missense mutation in exon 5] was identified, which was not described in literature. Family screening of cases identified six additional cases. CONCLUSION: As a result of this initial screening study performed on hemodialysis patients for the first time with DBS method in Turkey, the prevalence of FD was detected as 0.17%. Although the prevalence seems to be low, screening studies are of great importance for detecting hidden cases as well as for identifying other effected family members. PMID- 23756195 TI - Klotho gene polymorphism of rs3752472 is associated with the risk of urinary calculi in the population of Han nationality in Eastern China. AB - BACKGROUND/AIMS: The incidence of urolithiasis has considerably increased throughout the world in the last two decades. Clinical researches have showed an association between oxidative stress and stone formation. Emerging evidence indicated a novel function for klotho protein in anti-oxidative stress. In this study, we aimed at investigating a possible relationship between klotho gene polymorphisms and the risk of calcium oxalate urolithiasis in the population of Han nationality in Eastern China. METHODS: Klotho gene polymorphisms rs3752472 in exon3, rs650439 in intron 4 and rs577912 in intron 1 were investigated in 426 patients with calcium oxalate stones compared with 282 age-matched healthy volunteers with no history of stone formation, using TaqMan SNP Genotyping Assays. RESULTS: Significant differences were found between rs3752472 and the risk of nephrolithiasis as CC genotype of rs3752472 klotho polymorphism had almost 2-fold increased stone risk compared with the heterozygote genotype CT and homozygous genotype TT(95% CI=1.013-2.255, OR=1.512,p=0.043). CONCLUSION: Our results showed that the rs3752472 polymorphism of klotho gene is associated with the risk of calcium oxalate urolithiasis and may act as a risk factor during stone formation in our study population. PMID- 23756196 TI - Major cis-regulatory elements for rice bidirectional promoter activity reside in the 5'-untranslated regions. AB - Bidirectional promoters are defined as those that regulate adjacent genes organized in a divergent fashion (head to head orientation) and separated by <1 kb. In order to dissect bidirectional promoter activity in a model plant, deletion analysis was performed for seven rice promoters using promoter-reporter gene constructs, which identified three promoters to be bidirectional. Regulatory elements located in or close to the 5'-untranslated regions (UTR) of one of the genes (divergent gene pair) were found to be responsible for their bidirectional activity. DNA footprinting analysis identified unique protein binding sites in these promoters. Deletion/alteration of these motifs resulted in significant loss of expression of the reporter genes on either side of the promoter. Changes in the motifs at both the positions resulted in a remarkable decrease in bidirectional activity of the reporter genes flanking the promoter. Based on our results, we propose a novel mechanism for the bidirectionality of rice bidirectional promoters. PMID- 23756197 TI - Oxidized low density lipoprotein enhanced RANKL expression in human osteoblast like cells. Involvement of ERK, NFkappaB and NFAT. AB - BACKGROUND: Receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cell ligand/osteoprotegerin ratio is of crucial importance in osteoclast differentiation and thus in bone dysregulation diseases. METHODS: Receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cell ligand and osteoprotegerin were determined under oxidized low density lipoprotein treatment of human osteoblast-like cells. The involvement of oxidative stress, of the extracellular signal regulated kinase and of the transcription factors nuclear factor kappa-light-chain-enhancer of activated B cells and nuclear factor of activated T cells was demonstrated. RESULTS: Cu(2+) oxidized low density lipoprotein increased cell-associated and extracellular receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cell ligand levels whereas osteoprotegerin levels were not affected. The increase in receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cell ligand was parallel to the generation of reactive oxygen species provoked by Cu(2+)-oxidized low density lipoprotein. The lipid extract of Cu(2+)-oxidized low density lipoprotein, together with other forms of oxidized low density lipoproteins such as smooth muscle cell-oxidized low density lipoprotein and myeloperoxidase-oxidized low density lipoprotein, also induced an increase in reactive oxygen species and cell-associated receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cell ligand. The effect of Cu(2+) oxidized low density lipoprotein was prevented by the antioxidant vitamin E, and mimicked by the prooxidant compounds hydrogen peroxide and buthionine sulfoximine. Inhibitors of mitogen activated protein kinase/extracellular signal regulated kinase (PD 98059), nuclear factor kappa-light-chain-enhancer of activated B cells (Ro 106-9920) and nuclear factor of activated T cells (Vivit) reduced the effect of Cu(2+)-oxidized low density lipoprotein on receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cell ligand expression. Cu(2+)-oxidized low density lipoprotein signaling was also reduced by vitamin E. GENERAL SIGNIFICANCE: This work describes a new molecular mechanism and elucidates the signaling pathway whereby oxidized low density lipoprotein, by means of its lipid moiety, can modulate the crosstalk between osteoblasts/osteoclasts and bone remodeling, leading to an eventual risk of osteoporosis. PMID- 23756198 TI - Sucrose lyophiles: a semi-quantitative study of residual water content by total X ray diffraction analysis. AB - Total X-ray Powder Diffraction Analysis (TXRPD) using transmission geometry was able to observe significant variance in measured powder patterns for sucrose lyophilizates with differing residual water contents. Integrated diffraction intensity corresponding to the observed variances was found to be linearly correlated to residual water content as measured by an independent technique. The observed variance was concentrated in two distinct regions of the lyophilizate powder pattern, corresponding to the characteristic sucrose matrix double halo and the high angle diffuse region normally associated with free-water. Full pattern fitting of the lyophilizate powder patterns suggested that the high angle variance was better described by the characteristic diffraction profile of a concentrated sucrose/water system rather than by the free-water diffraction profile. This suggests that the residual water in the sucrose lyophilizates is intimately mixed at the molecular level with sucrose molecules forming a liquid/solid solution. The bound nature of the residual water and its impact on the sucrose matrix gives an enhanced diffraction response between 3.0 and 3.5 beyond that expected for free-water. The enhanced diffraction response allows semi-quantitative analysis of residual water contents within the studied sucrose lyophilizates to levels below 1% by weight. PMID- 23756199 TI - Enhanced Ca(2+)-dependent glutamate release from astrocytes of the BACHD Huntington's disease mouse model. AB - Huntington's disease (HD) causes preferential loss of a subset of neurons in the brain although the huntingtin protein is expressed broadly in various neural cell types, including astrocytes. Glutamate-mediated excitotoxicity is thought to cause selective neuronal injury, and brain astrocytes have a central role in regulating extracellular glutamate. To determine whether full-length mutant huntingtin expression causes a cell-autonomous phenotype and perturbs astrocyte gliotransmitter release, we studied cultured cortical astrocytes from BACHD mice. Here, we report augmented glutamate release through Ca(2+)-dependent exocytosis from BACHD astrocytes. Although such release is usually dependent on cytosolic Ca(2+) levels, surprisingly, we found that BACHD astrocytes displayed Ca(2+) dynamics comparable to those in wild type astrocytes. These results point to a possible involvement of other factors in regulating Ca(2+)-dependent/vesicular release of glutamate from astrocytes. We found a biochemical footprint that would lead to increased availability of cytosolic glutamate in BACHD astrocytes: i) augmented de novo glutamate synthesis due to an increase in the level of the astrocyte specific mitochondrial enzyme pyruvate carboxylase; and ii) unaltered conversion of glutamate to glutamine, as there were no changes in the expression level of the astrocyte specific enzyme glutamine synthetase. This work identifies a new mechanism in astrocytes that could lead to increased levels of extracellular glutamate in HD and thus may contribute to excitotoxicity in this devastating disease. PMID- 23756200 TI - NESS06SM reduces body weight with an improved profile relative to SR141716A. AB - We have recently synthesized a new series of 4,5-dihydrobenzo-oxa cycloheptapyrazole derivatives with the aim to discover novel CB1 antagonist agents characterized by anti-obesity activity comparable to that of SR141716A but with reduced adverse effects such as anxiety and depression. Within the novel class, the CB1 antagonist 8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5 dihydrobenzo-1H-6-oxa-cyclohepta(1,2-c)pyrazole-3-carboxamide (NESS06SM) has been selected as lead compound. We found that NESS06SM is a CB1 neutral antagonist, characterized by poor blood-brain barrier permeability. Moreover, NESS06SM chronic treatment determined both anti-obesity effect and cardiovascular risk factor improvement in C57BL/6N Diet Induced Obesity (DIO) mice fed with fat diet (FD mice). In fact, the mRNA gene expression in Central Nervous System (CNS) and peripheral tissues by real time PCR, showed a significant increase of orexigenic peptides and a decrease of anorexigenic peptides elicited by NESS06SM treatment, compared to control mice fed with the same diet. Moreover, in contrast to SR141716A treatment, the chronic administration of NESS06SM did not change mRNA expression of both monoaminergic transporters and neurotrophins highly related with anxiety and mood disorders. Our results suggest that NESS06SM reduces body weight and it can restore the disrupted expression profile of genes linked to the hunger-satiety circuit without altering monoaminergic transmission probably avoiding SR141716A side effects. Therefore the novel CB1 neutral antagonist could represent a useful candidate agent for the treatment of obesity and its metabolic complications. PMID- 23756201 TI - Hyperoxia causes reduced density of retinal astrocytes in the central avascular zone in the mouse model of oxygen-induced retinopathy. AB - The mouse model of oxygen-induced retinopathy (OIR) is commonly used to investigate various aspects of the pathogenesis of the retinopathy of prematurity (ROP) as well as angiogenesis in general. Retinal astrocytes were suggested to be involved in retinal angiogenesis. This study aimed to describe their localization and cell density during the course of physiological vascularization and pathological revascularization. Mice expressing H2B-GFP (green fluorescent protein fused to histone 2B) from the endogenous Pdgfra promoter were kept in 75% oxygen from P7 (post natal day 7) to P12 (mouse model of OIR). Retinal flatmounts or cryosections were immunostained for glial fibrillary acidic protein (Gfap), glutamine synthetase (Glul), collagen IV (Col IV), desmin (Des), caspase 3 (Casp3), paired box 2 (Pax2), or Ki67. Astrocytic nuclei were counted with the ImageJ macro AuTOCellQuant. The hypoxic state of the retina was investigated by Hypoxyprobe. The GFP signal of the Pdgfra reporter mice co-localized with Pax2, a nuclear marker for retinal astrocytes. This bright label was much easier to quantify than Gfap or Pax2 staining. Quantification of the cell density of astrocytes during physiological development specified the spreading of astrocytes in a concentrical wave from the optic nerve head towards the periphery. Astrocyte density was reduced during the remodelling of the primary vascular plexus into a hierarchical vascular tree (maximal astrocyte density at P1: 2800 astrocytes/mm2, final astrocyte density: 800 astrocytes/mm2). In the OIR model, cell density of astrocytes was elevated in the peripheral vascularized zone. In contrast, astrocyte density dropped to a half (400 astrocytes/mm2) of the normal value in the central avascular zone during the hyperoxic phase between P8 and P10 by apoptosis and rose only after P17 as the retinal network normalized. An additional drop of astrocyte density was observed within the angles between the large vessels of the central avascular zone during hypoxia between P12 and P17. Astrocyte density was not altered at vascular tufts. The hyperoxia effect on astrocytes including the reduced astrocyte density is not the reason for vascular tuft formation. Hypoxia-affected astrocytes in combination with a reduced astrocytic network in the central avascular zone during the hypoxic phase are important determinants in the formation of pathological features during retinal revascularization. PMID- 23756202 TI - Antibody conjugation via one and two C-terminal selenocysteines. AB - Conventional antibody conjugation methods generate antibody-drug conjugates that are heterogeneous mixtures with undefined stoichiometry and variable pharmacokinetic and pharmacodynamic properties. We have previously described a strategy to generate site-specific antibody conjugates by genetic engineering of an antibody with a single C-terminal selenocysteine, the 21st natural amino acid, which displays unique chemical reactivity allowing selective conjugation in the presence of all other natural amino acids. In the present work, we describe a method for expanding this technology to higher drug-to-antibody ratios by genetically engineering an antibody with two C-terminal selenocysteines. Both selenocysteines effectively conjugate to a fluorescent iodoacetamide derivative and the resulting conjugate fully retains its antigen binding capability. Our method provides a platform for creating stoichiometrically defined antibody-drug conjugates for therapeutic intervention. PMID- 23756203 TI - Using high-resolution quantitative mapping of R1 as an index of cortical myelination. AB - A fundamental tenet of neuroscience is that cortical functional differentiation is related to the cross-areal differences in cyto-, receptor-, and myeloarchitectonics that are observed in ex-vivo preparations. An ongoing challenge is to create noninvasive magnetic resonance (MR) imaging techniques that offer sufficient resolution, tissue contrast, accuracy and precision to allow for characterization of cortical architecture over an entire living human brain. One exciting development is the advent of fast, high-resolution quantitative mapping of basic MR parameters that reflect cortical myeloarchitecture. Here, we outline some of the theoretical and technical advances underlying this technique, particularly in terms of measuring and correcting for transmit and receive radio frequency field inhomogeneities. We also discuss new directions in analytic techniques, including higher resolution reconstructions of the cortical surface. We then discuss two recent applications of this technique. The first compares individual and group myelin maps to functional retinotopic maps in the same individuals, demonstrating a close relationship between functionally and myeloarchitectonically defined areal boundaries (as well as revealing an interesting disparity in a highly studied visual area). The second combines tonotopic and myeloarchitectonic mapping to localize primary auditory areas in individual healthy adults, using a similar strategy as combined electrophysiological and post-mortem myeloarchitectonic studies in non-human primates. PMID- 23756204 TI - Mapping registration sensitivity in MR mouse brain images. AB - Nonlinear registration algorithms provide a way to estimate structural (brain) differences based on magnetic resonance images. Their ability to align images of different individuals and across modalities has been well-researched, but the bounds of their sensitivity with respect to the recovery of salient morphological differences between groups are unclear. Here we develop a novel approach to simulate deformations on MR brain images to evaluate the ability of two registration algorithms to extract structural differences corresponding to biologically plausible atrophy and expansion. We show that at a neuroanatomical level registration accuracy is influenced by the size and compactness of structures, but do so differently depending on how much change is simulated. The size of structures has a small influence on the recovered accuracy. There is a trend for larger structures to be recovered more accurately, which becomes only significant as the amount of simulated change is large. More compact structures can be recovered more accurately regardless of the amount of simulated change. Both tested algorithms underestimate the full extent of the simulated atrophy and expansion. Finally we show that when multiple comparisons are corrected for at a voxelwise level, a very low rate of false positives is obtained. More interesting is that true positive rates average around 40%, indicating that the simulated changes are not fully recovered. Simulation experiments were run using two fundamentally different registration algorithms and we identified the same results, suggesting that our findings are generalizable across different classes of nonlinear registration algorithms. PMID- 23756205 TI - Anticancer drug delivery of PEG based micelles with small lipophilic moieties. AB - Herein, we reported a new type of self-assembly micelles based on amphiphilic polymers of cinnamate and coumarin derivatives modified PEG for drug delivery applications. Lipophilic cinnamic acid (CIN) and 7-carboxyl methoxycoumarin (COU) were immobilized on the terminal groups of poly(ethylene glycol) (PEG) to prepare amphiphiles. The amphiphiles self-assembled into micelles. The amphiphiles and micelles were characterized by (1)H NMR, FT-IR, DLS and TEM. Doxorubicin (DOX) was used as a model drug to investigate the lipophilic moieties effects on the drug release behaviors. The DOX loaded micelles were incubated with HepG2 liver cancer cells to study the in vitro anticancer activities. The results showed that DOX could be encapsulated in the micelles efficiently. The mean diameter of the drug loaded micelles was around 100 nm. Drug release profile revealed that the release rate of DOX loaded COU-PEG-COU micelles was significantly slower than that of CIN-PEG-CIN micelles. The DOX loaded micelles could be internalized in HepG2 cells. Both CLSM and flow cytometry results showed that the DOX loaded CIN PEG-CIN micelles exhibited better anticancer efficacy. PMID- 23756206 TI - Invasive African Salmonella Typhimurium induces bactericidal antibodies against O antigens. AB - Nontyphoidal Salmonella are a major and emerging cause of fatal invasive disease in Africa, and are genetically distinct from those found elsewhere in the world. Understanding the targets of protective immunity to these African Salmonellae is key to vaccine development. We immunized mice and rabbits with heat-inactivated wild-type African invasive Salmonella Typhimurium D23580 and rough mutants lacking O-antigen. Wild-type Salmonella, unlike rough bacteria, induced a large bactericidal antibody response mainly against O-antigen. Bactericidal ability of anti-O-antigen antibodies was confirmed following purification by affinity chromatography. The current findings support the development of an O-antigen conjugate vaccine against invasive nontyphoidal Salmonellae for Africa. PMID- 23756207 TI - The role of birds and insects in pollination shifts of Scrophularia (Scrophulariaceae). AB - The mixed vertebrate-insect pollination system is rare in Holarctic plants. Phylogenetic relationships of 116 Scrophularia taxa were investigated based on two plastid (ndhF and trnL-trnF) and one nuclear (ITS) DNA regions. A wider time calibrated analysis of ndhF sequences of the Lamiales revealed that Scrophularia diverged as early as in the Miocene (<22 Ma). Results of maximum-likelihood optimizations supported wasp pollination as the ancestral pollination system from which other systems derived (hoverfly, mixed vertebrate-insect and bird systems). Four origins for a mixed vertebrate-insect (MVI) pollination system were inferred, in which two western Mediterranean species (S. sambucifolia and S. grandiflora) and two island species (the Tirrenian S. trifoliata and the Canarian S. calliantha) were involved. S. calliantha is the only species in which a more complex MVI system, including pollination by the lizard Gallotia stehlini, has evolved. In addition, bird (hummingbird) floral traits found in the New Mexican S. macrantha appear to have been independently acquired. In contrast, we failed to find evidence for an ancient role of hummingbirds in the evolution of European Scrophularia. Indeed, paleontological data revealed that extinction of European hummingbirds (30-32 Ma) occurred earlier than the divergence of European MVI lineages of Scrophularia. In conclusion, our results showed that a role of birds in pollination of Scrophularia may not have been effective in the Miocene Pliocene, but bird pollination that shows its origin in the Pliocene-Pleistocene is still operating independently in different islands and continents. PMID- 23756208 TI - Heterozygosity for an inactivating mutation in low-density lipoprotein-related receptor 6 (Lrp6) increases osteoarthritis severity in mice after ligament and meniscus injury. AB - OBJECTIVE: Wnt/beta-catenin signaling plays an integral and complex role in cartilage development and maintenance. beta-catenin signaling has been linked to osteoarthritis (OA), but the role of Lrp6-mediated Wnt/beta-catenin signaling during OA remains unexplored. Mutations in the Wnt/beta-catenin co-receptors LRP5 and LRP6 (low-density lipoprotein-related receptors 5 and 6) result in skeletal abnormalities, which tend to be more severe in Lrp6 mutant mice. We examined OA development, chondrocyte and osteoblast behavior, and beta-catenin signaling after ligament and meniscus damage in mice with global heterozygous deletion of Lrp6. DESIGN: Ligament and meniscus damage was surgically induced in Lrp6(+/-) and wild-type (WT) mice, and evidence of joint disease was assessed by Microcomputed tomography (micro-CT) and histology. Wnt/beta-catenin signaling, proliferation, apoptosis, chondrogenesis, osteogenesis, and catabolic enzyme activity were measured. RESULTS: Relative to WT mice, Lrp6(+/-) mice had lower nuclear beta-catenin signaling within articular cartilage. After surgery, osteophytes and reduced articular cartilage were apparent in WT mice, but more severe in Lrp6(+/-) animals. Impairments to trabecular bone geometry occurred for WT and Lrp6(+/-) mice after surgery. Relative to WT mice, Lrp6(+/-) mice had reduced trabecular BMD and thickness, and Cyclin D1 and Lrp6 gene expression after surgery. There was an increase in apoptotic cells and serum matrix metalloproteinase-9 (MMP9) for Lrp6(+/-) mice after surgery, but no differences in cell proliferation occurred. CONCLUSIONS: Heterozygous loss-of-function mutation in Lrp6 leads to less beta-catenin signaling within articular cartilage and to increased degenerative joint disease after ligament and meniscus injury. Modulation of Lrp6 function could attenuate joint disease after damage to ligaments and the meniscus. PMID- 23756209 TI - Enhanced sensitivity to learning fearful associations during adolescence. AB - The majority of anxiety disorders emerge during adolescence, yet there is a paucity of research examining factors that contribute to the "storm and stress" of this period. Understanding how juvenile (P23), adolescent (P35), and adult (P90) rats differ on basic fear conditioning tasks may shed light on this issue. In Experiment 1, P23, P35, and P90 rats were given 6 CS-US presentations. There were four training conditions: Delay (i.e., CS co-terminating with the US), Trace 20 and Trace 40 (i.e., an interval of 20s and 40s between the CS and US, respectively), and Unpaired (i.e., explicitly Unpaired presentations of the CS and US). Twenty-four hours after conditioning, freezing was measured to assess fear of the CS in a novel context. At test, there were no age differences in CS elicited freezing in group Delay, and this condition exhibited significantly higher levels of freezing compared to group Unpaired. However, the adolescent rats were the only age group to exhibit higher levels of freezing following training with the 20s and 40s trace intervals, compared to Unpaired controls. Experiment 2 replicated the finding that adolescent but not adult rats exhibit fear following conditioning with a 20s trace interval, while also demonstrating that both age groups display learning with a shorter trace interval of 5s. Experiment 3 showed that exposure to corticosterone (200 MUg/ml) in the drinking water for 1 week prior to conditioning selectively disrupts Trace 20 but not Delay conditioning during adolescence. Lastly, in Experiment 4 the test procedures were changed such that freezing was measured both during the CS and during a stimulus free trace interval. Once again, P35 but not P90 rats exhibited fear following training with a 20s trace interval. Taken together, these findings demonstrate that adolescent rats show a heightened propensity to learn fearful associations, and that this is disrupted following exposure to corticosterone. PMID- 23756210 TI - Multicenter analyses demonstrate significant clinical effects of minor histocompatibility antigens on GvHD and GvL after HLA-matched related and unrelated hematopoietic stem cell transplantation. AB - The effect of minor H antigen mismatching on the occurrence of graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) after HLA-matched hematopoietic stem cell transplantation (HSCT) has mainly been demonstrated in single-center studies. Yet, the International Histocompatibility and Immunogenetics Workshops (IHIW) provide a collaborative platform to execute crucial large studies. In collaboration with 20 laboratories of the IHIW, the roles of 10 autosomal and 10 Y chromosome-encoded minor H antigens were investigated on GvHD and relapse incidence in 639 HLA-identical related donor (IRD) and 210 HLA-matched unrelated donor (MUD) HSCT recipients. Donor and recipient DNA samples were genotyped for the minor H antigens HA-1, HA-2, HA-3, HA-8, HB-1, ACC-1, ACC-2, SP110, PANE1, UGT2B17, and HY. The correlations with the primary outcomes GvHD (acute or chronic GvHD), survival, and relapse were statistically analyzed. The results of these multicenter analyses show that none of the HLA class I-restricted HY antigens were found to be associated with any of the primary outcomes. Interestingly, of the HLA class II-restricted HY antigens analyzed, HLA-DQ5 positive recipients showed a significantly increased GvHD-free survival in female to-male HSCT compared with male-to-female HSCT (P = .013). Yet, analysis of the overall gender effect, thus independent of the known HY antigens, between the gender groups demonstrated an increased GvHD incidence in the female-to-male transplantations (P < .005) and a decreased GvHD-free survival in the female-to male transplantations (P < .001). Of all autosomally encoded minor H antigens, only mismatching for the broadly expressed minor H antigen HA-8 increased the GvHD incidence in IRD HSCT (Hazard ratio [HR] = 5.28, P < .005), but not in MUD HSCT. Most striking was the influence of hematopoietic restricted minor H antigens on GvL as mismatching for hematopoietic minor H antigens correlated with lower relapse rates (P = .078), higher relapse-free survival (P = .029), and higher overall survival (P = .032) in recipients with GvHD, but not in those without GvHD. In conclusion, the significant GvHD effect of the broadly expressed minor H antigen HA-8 favors matching for HA-8 in IRD, but not in MUD, patient/donor pairs. The GvHD-GvL association demonstrating a significant lower relapse in hematopoietic minor H antigen mismatched patient/donor pairs underlines their clinical applicability for adoptive immunotherapy, enhancing the GvL effect in a GvHD controllable manner. PMID- 23756211 TI - Fractioned exhaled nitric oxide (FE(NO)) is not a sufficiently reliable test for monitoring asthma in pregnancy. AB - It has been reported that fractioned exhaled nitric oxide (FENO) can be used for monitoring airway inflammation and for asthma management but conclusions drawn by different researchers are controversial. The aim of our study was to evaluate the clinical usefulness of FENO assessment for monitoring asthma during pregnancy. We monitored 72 pregnant asthmatics aged 18-38years (Me=29 years) who underwent monthly investigations including: the level of asthma control according to GINA (Global Initiative for Asthma), the occurrence of exacerbations, ACT (Asthma Control Test), as well as FENO and spirometry measurements. In 50 women, during all visits, asthma was well-controlled. In the remaining 22 women, asthma was periodically uncontrolled. FENO measured at the beginning of the study did not show significant correlation with retrospectively evaluated asthma severity (r=0.07; p=0.97). An analysis of data collected during all 254 visits showed that FENO correlated significantly but weakly with ACT scores (r=0.25; p=0.0004) and FEV1 (r=0.21; p=0.0014). FENO at consecutive visits in women with well-controlled asthma (N=50) showed large variability expressed by median coefficient of variation (CV)=32.0% (Min 2.4%, Max 121.9%). This concerned both: atopic and nonatopic groups (35.5%; and 26.7%, respectively). Large FENO variability (35.5%) was also found in a subgroup of women (N=11) with ACT=25 constantly throughout the study. FENO measured at visits when women temporarily lost control of asthma (N=22; 38 visits), showed an increasing tendency (64.2 ppb; 9.5 ppb-188.3 ppb), but did not differ significantly (p=0.13) from measurements taken at visits during which asthma was well-controlled (27.6 ppb; 6.2 ppb-103.4 ppb). The comparison of FENO in consecutive months of pregnancy in women who had well controlled asthma did not show significant differences in FENO values during the time of observation. The assessment of asthma during pregnancy by means of monitoring FENO is of limited practical value due to this parameter's considerable intrasubject variability, regardless of the degree of asthma control. PMID- 23756212 TI - Effect of body mass and activity on the metabolic rate and ammonia-N excretion of the spiny lobster Sagmariasus verreauxi during ontogeny. AB - Intraspecific analyses of the relationship between metabolic rate and mass have rarely been considered during complete ontogeny. Spiny lobsters are fascinating candidates to examine metabolic changes during ontogeny because their life cycle includes an extended planktonic, nektonic, and benthic life stages. The effect of body mass on metabolic rates, aerobic scope, and ammonia-N excretion of Sagmariasus verreauxi juveniles were examined to determine energetic demands through juvenile development. Mass-independent routine oxygen consumption increased allometrically during juvenile development with a mass scaling exponent of 0.83. The mass scaling exponent of active metabolism (0.81) was reduced compared to standard metabolism (0.91) of juvenile lobsters. The aerobic scope of juvenile lobsters decreased with larger body mass. To examine if the mass scaling exponent varies with ontogeny, we compared our data with previous measurements made with larvae of the same species. Comparison between mass scaling exponents showed they were higher for phyllosoma (0.97) compared to juvenile (0.83) development. Higher scaling exponents for phyllosoma may be attributed to increased growth rates of phyllosoma compared to juveniles, which increase oxygen consumption due to the higher energy cost of growth. The mass scaling exponent for complete ontogeny (0.91) of S. verreauxi was larger than the commonly cited 0.67 (1/3) and 0.75 (3/4) mass scaling exponents, indicating that species specific differences can be a large factor affecting allometric relationships of animals. PMID- 23756213 TI - Integrated modelling to assess long-term water supply capacity of a meso-scale Mediterranean catchment. AB - Assessing water supply capacity is crucial to meet stakeholders' needs, notably in the Mediterranean region. This region has been identified as a climate change hot spot, and as a region where water demand is continuously increasing due to population growth and the expansion of irrigated areas. The Herault River catchment (2500 km(2), France) is a typical example and a negative trend in discharge has been observed since the 1960s. In this context, local stakeholders need first to understand the processes controlling the evolution of water resources and demands in the past to latter evaluate future water supply capacity and anticipate the tensions users could be confronted to in the future. A modelling framework is proposed at a 10-day time step to assess whether water resources have been able to meet water demands over the last 50 years. Water supply was evaluated using hydrological modelling and a dam management model. Water demand dynamics were estimated for the domestic and agricultural sectors. A water supply capacity index is computed to assess the extent and the frequency to which water demand has been satisfied at the sub-basin scale. Simulated runoff dynamics were in good agreement with observations over the calibration and validation periods. Domestic water demand has increased considerably since the 1980s and is characterized by a seasonal peak in summer. Agricultural demand has increased in the downstream sub-basins and decreased upstream where irrigated areas have decreased. As a result, although most water demands were satisfied between 1961 and 1980, irrigation requirements in summer have sometimes not been satisfied since the 1980s. This work is the first step toward evaluating possible future changes in water allocation capacity in the catchment, using future climate change, dam management and water use scenarios. PMID- 23756214 TI - Assessing the tolerance of the terrestrial moss Pseudoscleropodium purum to high levels of atmospheric heavy metals: a reciprocal transplant study. AB - We measured the concentrations of Cd, Cu, Hg, Pb and Zn in samples of the terrestrial moss Pseudoscleropodium purum reciprocally transplanted between an unpolluted and two polluted sampling sites. At the beginning of the experiment, the concentrations of all these elements differed significantly between mosses from the unpolluted site and mosses from the polluted sites. In general, the concentrations of the heavy metals in mosses from both polluted sites transplanted to the unpolluted site decreased until they reached the same levels as in autotransplants at this site (after 480-840 days). However, the concentrations of all heavy metals in mosses transplanted from the unpolluted site to both polluted sites increased to higher levels than in the autotransplants (except for Cu, Hg and Pb at one of the sampling sites). These results led us to conclude that mosses that have been continuously exposed to high atmospheric deposition of heavy metals undergo an adaptive response (probably genotypic) to such conditions. We therefore recommend active rather than passive biomonitoring of air quality in industrial environments because atmospheric deposition could be underestimated, and also recommend further investigation into the mechanisms involved in this response. PMID- 23756215 TI - Comparative studies of multi-walled carbon nanotubes (MWNTs) and octadecyl (C18) as sorbents in passive sampling devices for biomimetic uptake of polycyclic aromatic hydrocarbons (PAHs) from soils. AB - To avoid overestimating the risk of polycyclic aromatic hydrocarbons (PAHs), research is needed to evaluate the bioavailable portion of PAHs in the environment. However, limited PSDs were developed for a terrestrial soil system. In this study, two sorbents, octadecyl (C18) and multi-walled carbon nanotubes (MWNTs), were individually evaluated as sorbents in passive sampling devices (PSDs) as biomimetic samplers to assess the uptake of PAHs from soil. C18-PSDs were an excellent biomimetic tool for PAHs with a low molecular weight in complex exposure conditions with different soil types, types of PAHs, aging periods, and initial PAH concentrations in soil. The utility of MWNT-PSDs was limited by extraction efficiencies of PAHs from MWNTs. However, when compared to C18-PSDs, they had higher adsorption capacities and were less expensive. This study provides data regarding useful techniques that can be used in risk assessment to assess the bioavailability of PAHs in soil. PMID- 23756216 TI - Vertical distribution profiles and diagenetic fate of synthetic surfactants in marine and freshwater sediments. AB - This manuscript deals with the presence and degradation of the most commonly-used surfactants, including anionic (linear alkylbenzene sulfonates, LAS, and alkyl ethoxysulfates, AES) and non-ionic (alcohol polyethoxylates, AEOs, and nonylphenol polyethoxylates, NPEOs) compounds, in sediments and pore water from several aquatic environments (Southwest, Spain). Different vertical distributions were observed according to the respective sources, uses, production volumes and physicochemical properties of each surfactant. Levels of nonionics (up to 10 mg kg(-1)) were twice as high as anionics in industrial areas and harbors, whereas the opposite was found near urban wastewater discharge outlets. Sulfophenyl carboxylic acids (SPCs), LAS degradation products, were identified at anoxic depths at some sampling stations. Their presence was related to in situ anaerobic degradation of LAS in marine sediments, whereas the occurrence of these metabolites in freshwater sediments was attributed to the existence of wastewater sources nearby. No significant changes in the average length of AEO and NPEO ethoxylated chains were observed along the sediment cores, suggesting that their biodegradation was very limited in the sampling area. This may be directly related to their lower bioavailability, as their calculated sediment-pore water distribution coefficients (log K(sw)), which showed that non-ionic surfactants examined in this study had greater sorption affinity than the anionic surfactants (e.g., 2.3+/-0.3 for NPEOs). PMID- 23756217 TI - NOEC and LOEC as merely concessive expedients: two unambiguous alternatives and some criteria to maximize the efficiency of dose-response experimental designs. AB - NOEC and LOEC (no and lowest observed effect concentrations, respectively) are toxicological concepts derived from analysis of variance (ANOVA), a not very sensitive method that produces ambiguous results and does not provide confidence intervals (CI) of its estimates. For a long time, despite the abundant criticism that such concepts have raised, the field of the ecotoxicology is reticent to abandon them (two possible reasons will be discussed), adducing the difficulty of clear alternatives. However, this work proves that a debugged dose-response (DR) modeling, through explicit algebraic equations, enables two simple options to accurately calculate the CI of substantially lower doses than NOEC. Both ANOVA and DR analyses are affected by the experimental error, response profile, number of observations and experimental design. The study of these effects--analytically complex and experimentally unfeasible--was carried out using systematic simulations with realistic data, including different error levels. Results revealed the weakness of NOEC and LOEC notions, confirmed the feasibility of the proposed alternatives and allowed to discuss the--often violated--conditions that minimize the CI of the parametric estimates from DR assays. In addition, a table was developed providing the experimental design that minimizes the parametric CI for a given set of working conditions. This makes possible to reduce the experimental effort and to avoid the inconclusive results that are frequently obtained from intuitive experimental plans. PMID- 23756218 TI - Local landscape predictors of maximum stream temperature and thermal sensitivity in the Columbia River Basin, USA. AB - Stream temperature regimes are important determinants of the health of lotic ecosystems, and a proper understanding of the landscape factors affecting stream temperatures is needed for water managers to make informed decisions. We analyzed spatial patterns of thermal sensitivity (response of stream temperature to changes in air temperature) and maximum stream temperature for 74 stations in the Columbia River basin, to identify landscape factors affecting these two indices of stream temperature regimes. Thermal sensitivity (TS) is largely controlled by distance to the Pacific Coast, base flow index, and contributing area. Maximum stream temperature (Tmax) is mainly controlled by base flow index, percent forest land cover, and stream order. The analysis of four different spatial scales- relative contributing area (RCA) scale, RCA buffered scale, 1 km upstream RCA scale, and 1 km upstream buffer scale--yield different significant factors, with topographic factors such as slope becoming more important at the buffer scale analysis for TS. Geographically weighted regression (GWR), which takes into account spatial non-stationary processes, better predicts the spatial variations of TS and Tmax with higher R(2) and lower residual values than ordinary least squares (OLS) estimates. With different coefficient values over space, GWR models explain approximately up to 62% of the variation in TS and Tmax. Percent forest land cover coefficients had both positive and negative values, suggesting that the relative importance of forest changes over space. Such spatially varying GWR coefficients are associated with land cover, hydroclimate, and topographic variables. OLS estimated regression residuals are positively autocorrelated over space at the RCA scale, while the GWR residuals exhibit no spatial autocorrelation at all scales. GWR models provide useful additional information on the spatial processes generating the variations of TS and Tmax, potentially serving as a useful tool for managing stream temperature across multiple scales. PMID- 23756219 TI - Recommendations for the management of candidemia in neonates in Latin America. Latin America Invasive Mycosis Network. AB - Candidemia is one of the most frequent opportunistic mycoses worldwide. Limited epidemiological studies in Latin America indicate that incidence rates are higher in this region than in the Northern Hemisphere. Diagnosis is often made late in the infection, affecting the initiation of antifungal therapy. A more scientific approach, based on specific parameters, for diagnosis and management of candidemia in Latin America is warranted. 'Recommendations for the diagnosis and management of candidemia' are a series of manuscripts that have been developed by members of the Latin America Invasive Mycosis Network. They aim to provide a set of best-evidence recommendations for the diagnosis and management of candidemia. This publication, 'Recommendations for the management of candidemia in neonates in Latin America', was written to provide guidance to healthcare professionals on the management of neonates who have, or who are at risk of, candidemia. Computerized searches of existing literature were performed by PubMed. The data were extensively reviewed and analyzed by members of the group. The group also met on two occasions to pose questions, discuss conflicting views, and deliberate on a series of management recommendations. 'Recommendations for the management of candidemia in neonates in Latin America' includes prophylaxis, empirical therapy, therapy for proven candidemia, patient work-up following diagnosis of candidemia, central venous catheter management, and management of complications. This manuscript is the fourth of this series that deals with diagnosis and treatment of invasive candidiasis. Other publications in this series include: 'Recommendations for the diagnosis of candidemia in Latin America', 'Recommendations for the management of candidemia in adults in Latin America', and 'Recommendations for the management of candidemia in children in Latin America'. PMID- 23756220 TI - Intake of coffee, decaffeinated coffee, or tea does not affect risk for pancreatic cancer: results from the European Prospective Investigation into Nutrition and Cancer Study. AB - BACKGROUND & AIMS: Few modifiable risk factors have been implicated in the etiology of pancreatic cancer. There is little evidence for the effects of caffeinated coffee, decaffeinated coffee, or tea intake on risk of pancreatic cancer. We investigated the association of total coffee, caffeinated coffee, decaffeinated coffee, and tea consumption with risk of pancreatic cancer. METHODS: This study was conducted within the European Prospective Investigation into Nutrition and Cancer cohort, comprising male and female participants from 10 European countries. Between 1992 and 2000, there were 477,312 participants without cancer who completed a dietary questionnaire and were followed up to determine pancreatic cancer incidence. Coffee and tea intake was calibrated with a 24-hour dietary recall. Adjusted hazard ratios (HRs) were computed using multivariable Cox regression. RESULTS: During a mean follow-up period of 11.6 y, 865 first incidences of pancreatic cancers were reported. When divided into fourths, neither total intake of coffee (HR, 1.03; 95% confidence interval [CI], 0.83-1.27; high vs low intake), decaffeinated coffee (HR, 1.12; 95% CI, 0.76 1.63; high vs low intake), nor tea were associated with risk of pancreatic cancer (HR, 1.22, 95% CI, 0.95-1.56; high vs low intake). Moderately low intake of caffeinated coffee was associated with an increased risk of pancreatic cancer (HR, 1.33; 95% CI, 1.02-1.74), compared with low intake. However, no graded dose response was observed, and the association attenuated after restriction to histologically confirmed pancreatic cancers. CONCLUSIONS: Based on an analysis of data from the European Prospective Investigation into Nutrition and Cancer cohort, total coffee, decaffeinated coffee, and tea consumption are not related to the risk of pancreatic cancer. PMID- 23756221 TI - Celiac disease patients presenting with anemia have more severe disease than those presenting with diarrhea. AB - BACKGROUND & AIMS: Anemia is considered to be an atypical or silent presentation of celiac disease, compared with the classic presentation with diarrhea. However, little information is available about how these groups compare in terms of disease severity. We compared the severity of celiac disease between patients who present with anemia vs those who present with diarrhea. METHODS: The study cohort was selected from a database of patients with celiac disease who were evaluated at a tertiary referral center between 1990 and 2011. Severity of celiac disease was assessed by the degree of villous atrophy and clinical and serologic parameters. Patients were compared according to mode of presentation and sex. Multivariable analyses, adjusting for age and sex, were conducted to assess the association between the mode of celiac disease presentation and cholesterol level, bone density, severity of villous atrophy, erythrocyte sedimentation rate, and level of anti-tissue transglutaminase. RESULTS: Of 727 patients, 77% presented with diarrhea and 23% with anemia (92% iron deficient). On multiple regression analysis, presentation with anemia was associated with lower levels of total cholesterol (P = .02) and high-density lipoprotein (P = .002) and a higher erythrocyte sedimentation rate (P = .001) and level of anti-tissue transglutaminase (P = .01). Presentation with anemia was associated with lower level of cholesterol only in women. Anemic patients were more than 2-fold more likely to have severe villous atrophy and a low bone mass density at the time they were diagnosed with celiac disease than patients who presented with diarrhea. CONCLUSIONS: Celiac disease patients who present with anemia have more severe disease than those who present with diarrhea. There also appear to be sex specific differences with regard to the association between anemia and the different features of celiac disease. PMID- 23756222 TI - Collagenous sprue, an enigma in the spectrum of celiac disease. PMID- 23756223 TI - Fat polyp, thin blood: think clip! PMID- 23756224 TI - Colorectal dysplasia in inflammatory bowel disease: a clinicopathologic perspective. AB - Surveillance for neoplasia in colitis is the most challenging diagnostic colonoscopic procedure. The detection and treatment of colorectal dysplasia in inflammatory bowel disease remain problematic to the point that unsuspected colorectal cancers (CRCs) are still identified. Excellent bowel preparation and use of high-resolution colonoscopes with chromoendoscopy facilitate the detection and characterization of subtle neoplasia. This approach is superior to taking random biopsy specimens and should be the standard of care for surveillance but requires adequate training. Suspicious lesions should be assessed carefully and described using objective terminology. The terms dysplasia-associated lesions/masses and flat dysplasia are best avoided because they may be open to misinterpretation. Most suspicious lesions detected during surveillance can be removed endoscopically, precluding the need for surgery. Nevertheless, endotherapy in colitis can be difficult as a result of underlying inflammation and scarring. Lesions that are not endoscopically resectable need to be removed surgically, although the possibility that some lesions might be amenable to local resection (including lymphadenectomy) rather than subtotal colectomy may need to be re-evaluated. Despite surveillance programs, patients still present clinically with CRC. This may occur because lesions are missed (possibly because of the failure to use optimal techniques), lesions are not adequately removed, patients fail to return for colonoscopy, or CRCs arise rapidly in mucosa that is minimally dysplastic and the CRCs are not recognized as being potentially invasive even on biopsy. Future advances in, for example, stool DNA assays, use of confocal endomicroscopy, or use of endoscopic ultrasound, may help in the identification of high-risk patients and the assessment of dysplastic lesions. PMID- 23756225 TI - Social referencing in infants of mothers with symptoms of depression. AB - The present study examined the acquisition of social referencing skills in infants of mothers with symptoms of depression (n = 44). We aimed to determine if a short discrimination training could facilitate infants' social referencing. Mothers were instructed to pose either joyful or fearful facial expressions to cue infants' approach/avoidance responses toward an ambiguous object. Maternal expressions were correlated with pleasant or unpleasant events occurring after the infant's response. The results showed that after the intervention, infants looked at their mothers more frequently and reached or avoided the ambiguous object based on the preceding maternal expression. The results suggest that discrimination training procedures can establish social referencing in infants of mothers with symptoms of depression. PMID- 23756226 TI - Positive selection along the evolution of primate mitogenomes. AB - The mitochondrial genomes of four neotropical primates, Aotus infulatus, Chiropotes israelita, Callimico goeldii and Callicebus lugens were sequenced and annotated. Phylogenetic reconstructions with mitochondrial genes of other 66 primates showed a similar arrangement to a topology based on nuclear genes. Screening for positive selection identified 15 codons in 7 genes along 9 independent lineages, three with two or more genes and five in internal nodes, ruling out false positive estimates. Mitochondrial genes of the electron transport chain (ETC.) complexes evolved with high substitution rates. A study of nuclear ETC. genes might elucidate whether they co-evolved with their mitochondrial counterparts. PMID- 23756227 TI - Silk microgels formed by proteolytic enzyme activity. AB - The proteolytic enzyme alpha-chymotrypsin selectively cleaves the amorphous regions of silk fibroin protein (SFP) and allows the crystalline regions to self assemble into silk microgels (SMGs) at physiological temperature. These microgels consist of lamellar crystals in the micrometer scale, in contrast to the nanometer-scaled crystals in native silkworm fibers. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and zeta potential results demonstrated that alpha-chymotrypsin utilized only the non-amorphous domains or segments of the heavy chain of SFP to form negatively charged SMGs. The SMGs were characterized in terms of size, charge, structure, morphology, crystallinity, swelling kinetics, water content and thermal properties. The results suggest that the present technique of preparing SMGs by alpha-chymotrypsin is simple and efficient, and that the prepared SMGs have useful features for studies related to biomaterial and pharmaceutical needs. This process is also an easy way to obtain the amorphous peptide chains for further study. PMID- 23756228 TI - Elucidating the fungal stress response by proteomics. AB - Fungal species need to cope with stress, both in the natural environment and during interaction of human- or plant pathogenic fungi with their host. Many regulatory circuits governing the fungal stress response have already been discovered. However, there are still large gaps in the knowledge concerning the changes of the proteome during adaptation to environmental stress conditions. With the application of proteomic methods, particularly 2D-gel and gel-free, LC/MS-based methods, first insights into the composition and dynamic changes of the fungal stress proteome could be obtained. Here, we review the recent proteome data generated for filamentous fungi and yeasts. This article is part of a Special Issue entitled: Trends in Microbial Proteomics. PMID- 23756229 TI - Osteoclast-induced Foxp3+ CD8 T-cells limit bone loss in mice. AB - Osteoimmunology is the crosstalk between the skeletal and immune systems. We have previously shown in vitro that osteoclasts (OC) crosspresent antigens to induce FoxP3 in CD8 T-cells (OC-iTc(REG)), which then suppress osteoclast activity. Here we assessed the ability of OC-iTc(REG) to limit bone resorption in vivo. Mice lacking CD8 T-cells lose more bone in response to RANKL (Tnfsf11) administration. Using adoptive transfer experiments we demonstrate that FoxP3(+) CD8 T-cells limit bone loss by RANKL administration. In ovariectomized mice, a murine model of postmenopausal osteoporosis, OC-iTc(REG) limited bone loss and increased bone density as assessed by serum markers, micro computed tomography (MUCT) and histomorphometry. Indeed, OC-iTc(REG)-treated ovariectomized mice had decreased levels of effector T-cells in the bone marrow compared to untreated mice, and increased bone formation rates relative to bisphosphonate-treated mice. Our results provide the first in vivo evidence that OC-iTc(REG) have anti-resorptive activity and repress the immune system, thus extending the purview of osteoimmunology. PMID- 23756230 TI - Characterization of the effect of chronic administration of a calcium-sensing receptor antagonist, ronacaleret, on renal calcium excretion and serum calcium in postmenopausal women. AB - Ronacaleret is an orally-active calcium-sensing receptor (CaSR) antagonist that has the potential for therapeutic utility in the stimulation of PTH release, notably as a bone anabolic agent comparable to recombinant human PTH(1-34) (rhPTH(1-34)). A recent study has shown that, despite the ability to increase circulating PTH levels in postmenopausal women in a dose-dependent manner, minimal effects of ronacaleret on bone mineral density have been observed. Therefore, the purpose of this study was to characterize the PTH profile as well as calcium metabolism parameters as a marker of PTH biological activity following the administration of ronacaleret or rhPTH(1-34). Administration of ronacaleret led to lower peak levels of PTH than were observed with rhPTH(1-34), however, greater total PTH exposure was observed. Further, chronic administration of either agent was associated with increases in urinary calcium excretion and serum calcium levels, with the magnitude of the changes following ronacaleret significantly greater than that for rhPTH(1-34). The greater magnitude of effects observed with ronacaleret is likely due to the greater total PTH exposure, and is potentially reflective of a state comparable to mild hyperparathyroidism. It is not clear whether the administration of all calcilytics would lead to a similar result, or is due to characteristics specific to ronacaleret. PMID- 23756231 TI - MicroRNA-133a, downregulated in osteosarcoma, suppresses proliferation and promotes apoptosis by targeting Bcl-xL and Mcl-1. AB - Deregulated microRNAs and their roles in cancer development have attracted much attention. Although miR-133a has been shown to be important in osteogenesis, its roles in osteosarcoma carcinogenesis and progression remain unknown. Hence, we focused on the expression and mechanisms of miR-133a in osteosarcoma development in this study. We found that miR-133a was downregulated in osteosarcoma cell lines and primary human osteosarcoma tissues, and its decrease was significantly correlated with tumor progression and prognosis of the patients. Functional studies revealed that restoration of miR-133a could reduce cell proliferation, promote cell apoptosis, and suppress tumorigenicity in osteosarcoma cell lines. Furthermore, bioinformatic prediction and experimental validation were applied to identify target genes of miR-133a, and the results revealed that the anti-tumor effect of miR-133a was probably due to targeting and repressing of Bcl-xL and Mcl 1 expression. Taken together, our data elucidate the roles of miR-133a in osteosarcoma pathogenesis and implicate its potential in cancer therapy. PMID- 23756232 TI - Biomechanical properties and microarchitecture parameters of trabecular bone are correlated with stochastic measures of 2D projection images. AB - It is well known that loss of bone mass, quantified by areal bone mineral density (aBMD) using DXA, is associated with the increasing risk of bone fractures. However, bone mineral density alone cannot fully explain changes in fracture risks. On top of bone mass, bone architecture has been identified as another key contributor to fracture risk. In this study, we used a novel stochastic approach to assess the distribution of aBMD from 2D projection images of Micro-CT scans of trabecular bone specimens at a resolution comparable to DXA images. Sill variance, a stochastic measure of distribution of aBMD, had significant relationships with microarchitecture parameters of trabecular bone, including bone volume fraction, bone surface-to-volume ratio, trabecular thickness, trabecular number, trabecular separation and anisotropy. Accordingly, it showed significantly positive correlations with strength and elastic modulus of trabecular bone. Moreover, a combination of aBMD and sill variance derived from the 2D projection images (R2=0.85) predicted bone strength better than using aBMD alone (R2=0.63). Thus, it would be promising to extend the stochastic approach to routine DXA scans to assess the distribution of aBMD, offering a more clinically significant technique for predicting risks of bone fragility fractures. PMID- 23756233 TI - Chronic low dose tumor necrosis factor-alpha (TNF) suppresses early bone accrual in young mice by inhibiting osteoblasts without affecting osteoclasts. AB - The inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) is known to cause bone resorption and inhibit bone formation in arthritis and aging but less is known about TNF effects in the young growing skeleton. While investigating the mechanism of bone loss in TNF transgenic mice, we identified an early TNF sensitive period marked by suppression of osteoblasts and bone accrual as the sole mechanism of TNF action, without an effect on osteoclasts or bone resorption. TgTNF mice express low concentrations of hTNFalpha (<=5 pg/ml). Osteoblasts cultured from TgTNF mice express reduced levels of RUNX2, Osx, alkaline phosphatase, bone sialoprotein, and osteocalcin and have delayed formation of mineralized nodules. Early accrual of bone in TgTNF mice is suppressed until 6 weeks of age, after which the rate of bone accrual normalizes without catch up. Histomorphometry revealed that TgTNF mice fail to generate a transient surge in osteoblast number that is seen in wild type (WT) mice at 4 weeks. Osteoclasts, TRAP staining, erosive surfaces, serum CTx, and OPG/RANKL expression did not differ between young TgTNF and WT mice. Canonical Wnts and signaling through beta-catenin were reduced in TgTNF mice at 4 weeks and partially recovered by 12 weeks, associated with reduced cytoplasm to nuclear transfer of beta-catenin and Wnt regulated genes. TgTNF mice were crossed with BatGal Wnt reporter mice. Active Wnt signaling in tibial trabecular lining cells was reduced in TgTNF mice at 4 weeks compared to control littermates. Our results demonstrate that a low dose inflammatory stimulus is sufficient to inhibit the early surge in osteoblasts and optimal bone formation of young mice independent of changes in osteoclasts. TNF inhibition of the Wnt pathway contributes to the suppression of osteoblasts. PMID- 23756234 TI - Vertebral fractures and abdominal aortic calcification in postmenopausal women. A cohort study. AB - INTRODUCTION: Vertebral fracture assessment (VFA) imaging with a bone densitometer can simultaneously detect prevalent vertebral fractures (VFs) and abdominal aortic calcification (AAC). OBJECTIVE: To study the relation between the prevalence of VFs using VFA in asymptomatic women and the prevalence and severity of AAC. DESIGN: This is a cross-sectional study. SETTINGS: Subjects were recruited in a third care center from asymptomatic women selected from the general population. PARTICIPANTS: We enrolled 908 post-menopausal women with a mean age of 60.9 years +/- 7.7 (50 to 91) with no prior known diagnosis of osteoporosis or taking medication interfering with bone metabolism. PRIMARY AND SECONDARY OUTCOME MEASURES: Lateral VFA images and scans of the lumbar spine and proximal femur were obtained using a GE Healthcare Lunar Prodigy densitometer. VFs were defined using a combination of Genant semiquantitative (SQ) approach and morphometry. VFA images were scored for AAC using a validated 24 point scale. RESULTS: VFA images showed that 179 of the participants (19.7%) had at least one grade 2/3 VF, 81% did not have any detectable AAC whereas the prevalence of significant atherosclerotic burden, defined as AAC score of 5 or higher, was 12%. The group of women with 2/3 VFs had a statistically significant higher AAC score and higher proportion of subjects with extended AAC, and lower weight, height, and lumbar spine and hip BMD and T-scores than those without VFA-identified VFs. Multiple regression analysis showed that the presence of grade 2/3 VFs was significantly associated with age, BMI, history of peripheral fracture, AAC score >= 5 and densitometric osteoporosis. CONCLUSION: In post-menopausal women, extended AAC is independently associated with prevalent VFs regardless of age, BMI, history of fractures, and BMD. PMID- 23756235 TI - Predictive thermal inactivation model for the combined effect of temperature, cinnamaldehyde and carvacrol on starvation-stressed multiple Salmonella serotypes in ground chicken. AB - We investigated the combined effect of three internal temperatures (60, 65 and 71.1 degrees C) and four concentrations (0.0, 0.1, 0.5 and 1% vol/wt) of two natural antimicrobials on the heat resistance of an eight-strain cocktail of Salmonella serovars in chicken meat. A complete factorial design (3*4*4) was used to assess the effects and interactions of heating temperature and the two antimicrobials, carvacrol and cinnamaldehyde. The 48 variable combinations were replicated to provide a total of 96 survivor curves from the experimental data. Mathematical models were then developed to quantify the combined effect of these parameters on heat resistance of starved Salmonella cells. The theoretical analysis shows that the addition of plant-derived antimicrobials overcomes the heat resistance of starvation-stressed Salmonella in ground chicken meat. The influence of the antimicrobials allows reduced heat treatments, thus reducing heat-induced damage to the nutritional quality of ground-chicken products. Although the reported omnibus log-linear model with tail and the omnibus sigmoid model could represent the experimental survivor curves, their discrepancy only became apparent in the present study when lethality times (D-values and t7.0) from each of the models were calculated. Given the concave nature of the inactivation curves, the log-linear model with tail greatly underestimates the times needed to obtain 7.0 log lethality. Thus, a polynomial secondary model, based on the sigmoid model, was developed to accurately predict the 7.0-log reduction times. The three-factor predictive model can be used to estimate the processing times and temperatures required to achieve specific log reductions, including the regulatory recommendation of 7.0-log reduction of Salmonella in ground chicken. PMID- 23756236 TI - Yeast dynamics during spontaneous fermentation of mawe and tchoukoutou, two traditional products from Benin. AB - Mawe and tchoukoutou are two traditional fermented foods largely consumed in Benin, West Africa. Their preparations remain as a house art and they are the result of spontaneous fermentation processes. In this study, dynamics of the yeast populations occurring during spontaneous fermentations of mawe and tchoukoutou were investigated using both culture-dependent and -independent approaches. For each product, two productions were followed. Samples were taken at different fermentation times and yeasts were isolated, resulting in the collection of 177 isolates. They were identified by the PCR-DGGE technique followed by the sequencing of the D1/D2 domain of the 26S rRNA gene. The predominant yeast species identified were typed by rep-PCR. Candida krusei was the predominant yeast species in mawe fermentation followed by Candida glabrata and Kluyveromyces marxianus. Other yeast species were detected in lower numbers. The yeast successions that took place during mawe fermentation lead to a final population comprising Saccharomyces cerevisiae, C. krusei and K. marxianus. The yeast populations dominating the fermentation of tchoukoutou were found to consist of S. cerevisiae, almost exclusively. Other yeast species were detected in the early stages of fermentation. For the predominant species a succession of biotypes was demonstrated by rep-PCR for the fermentation of both products. The direct analysis at DNA and RNA levels in the case of mawe did not reveal any other species except those already identified by culture-based analysis. On the other hand, for tchoukoutou, four species were identified that were not detected by the culture-based approach. The spontaneous fermentation of mawe and tchoukoutou in the end were dominated by a few autochthonous species. PMID- 23756237 TI - Effect of household and commercial processing on acetamiprid, azoxystrobin and methidathion residues during crude rapeseed oil production. AB - Rape crops with residues of acetamiprid, azoxystrobin and methidathion incurred from field trials were used to evaluate the effect of household and commercial crude rapeseed oil processing on the transfer of pesticide residues. The pesticides were applied at exaggerated dosage to quantify residue levels in processed samples. The processing procedure was conducted as closely as possible to the actual conditions in practice. The conditioning step removed at least 30% of pesticides, while azoxystrobin and methidathion were concentrated by at least 15% at the single pressing step. The residue level of methidathion was concentrated with a processing factor (PF) of 1.07, while azoxystrobin and acetamiprid decreased with PFs of 0.67 and 0.04, respectively, after all processing procedures. The overall magnitudes of acetamiprid, azoxystrobin and methidathion in rapeseed oil and meal were all decreased after processing compared with the magnitude of those in raw rapeseed. PMID- 23756238 TI - Fusariotoxins in asparagus - their biosynthesis and migration. AB - Asparagus is often infected by fungi of the Fusarium genus, a causal agent of crown and root rot, which decreases the quantity and quality of spears. Fusarium oxysporum and Fusarium proliferatum are the most severe asparagus pathogens, well known as mycotoxin producers, mainly fumonisins and moniliformin. The present study was undertaken to estimate fumonisin B1, moniliformin and ergosterol concentrations in asparagus tissue. Moreover, the possibility of toxin transport to the edible asparagus part during the inoculation by F. oxysporum and F. proliferatum of different plant parts (root, crown and stem base) and the potential risk for consumers were assessed. Our studies showed that the highest capability of producing fumonisin B1 and moniliformin was demonstrated from isolates of F. proliferatum. The highest level of fumonisin B1 in edible spears was detected when the asparagus crown was inoculated with F. oxysporum and F. proliferatum. The lowest concentration was found in the case of storage root inoculation, which corresponds with mycelium absence and the long distance from the roots to the stem. Similar results were demonstrated for moniliformin. The mycotoxin content was confirmed even in healthy spears (without disease symptoms and mycelium presence), which might indicate that the transport of mycotoxins is possible from the soil through the root system to the top part of the plants. PMID- 23756239 TI - Telemedicine screening for cytomegalovirus retinitis using digital fundus photography. AB - BACKGROUND: Screening for cytomegalovirus retinitis (CMVR) is important in patients with acquired immune deficiency syndrome and low CD4(+) counts. However, many human immunodeficiency virus (HIV) patients lack access to specialist ophthalmological care. Telemedicine screening is a cost-effective method for screening these patients. We aimed to report the use of composite nine-field digital fundus photography (DFP) images for CMVR screening. We report its sensitivity and specificity in detecting CMVR and the level of agreement with gold-standard binocular indirect ophthalmoscopy. MATERIALS AND METHODS: An audit was performed on our national CMVR screening program that screened all HIV patients referred to the Ophthalmology Department at Tan Tock Seng Hospital, Singapore. All patients underwent retinal screening with DFP. Images were categorized as CMVR-positive, CMVR-negative, suspicious, or unreadable by blinded retinal specialists. Patients subsequently underwent dilated gold-standard indirect ophthalmoscopy by a different retinal specialist. Diagnoses were categorized as CMVR-positive, CMVR-negative, or unreadable. Sensitivity and specificity of retinal findings on DFP and kappa values for level of agreement between the two screening methods were calculated. RESULTS: Three hundred seventy screenings on 188 patients were performed. Twenty-three eyes diagnosed with CMVR on indirect ophthalmoscopy were also identified on DFP (100% sensitivity). A 99.9% specificity was achieved. The fundus photograph of one eye without CMVR was read as CMVR-positive because of an artifact, accounting for a false-positive. Kappa values ranged from 0.739 to 0.987. CONCLUSIONS: DFP is a sensitive and specific method of screening HIV patients for CMVR and has a high level of agreement with indirect ophthalmoscopy. PMID- 23756240 TI - Geomapping telehealth access to developmental-behavioral pediatrics. AB - BACKGROUND: Geographic information systems (GIS) mapping is fairly novel in describing utilization of health services. Our study is the first to use GIS to demonstrate that telehealth pediatric specialty service access would create substantial savings in travel time and distance compared with accessing a tertiary-care center for similar service. MATERIALS AND METHODS: A retrospective chart review of telehealth encounters and geocoding of patients' address were done with actual travel along road calculations to estimate travel time and distance for a visit, compared with a hypothetical visit to the nearest tertiary care site for the similar service. RESULTS: Over a 2-year period, 255 telehealth visits by 171 patients with a variety of developmental and behavioral diagnoses were made to five telehealth sites. The median travel time and distance saved by accessing a telehealth site were 66.9 min and 63.8 miles, respectively. Of these patients, 12.3% had a median negative estimated savings of 52.7 min and 39.0 miles, which was associated with longer travel burden. Using the straight-line method underestimated the total time and distance traveled by approximately one quarter of the actual distance (median distance of 20.5 miles underestimate relative to the median distance of 100.7 miles). CONCLUSIONS: Telehealth patients experienced significant reduction in travel times and distances. Patients/families would accept an increased burden of spatial accessibility in exchange for reduced burdens in other aspects of access, such as accommodation or acceptability when engaging telehealth services. Using a road network-based method is more accurate than previously used straight-line methods in calculating distance impedance. PMID- 23756242 TI - Metabolic detoxification pathways for 5-methoxy-sterigmatocystin in primary tracheal epithelial cells. AB - 1. The health effects of inhaled mycotoxins remain poorly documented despite their presence in bioaerosols. 5-methoxy-sterigmatocystin is produced in association with sterigmatocystin by some Aspergillus spp., sometimes in larger amounts than sterigmatocystin. Whereas sterigmatocystin can be metabolized through cytochromes P450 (CYP), UDP-glucuronosyltransferases and sulfotransferases in airway epithelial cells, little is known about 5-methoxy sterigmatocystin. 2. The 5-methoxy-sterigmatocystin metabolites were analyzed using human recombinant CYP and porcine tracheal epithelial cell (PTEC) primary cultures at an air-liquid interface. The induction of xenobiotic-metabolizing enzymes was examined by real-time quantitative PCR for mRNA expression and 7 ethoxyresorufin O-deethylation activity. 3. CYP1A1 metabolized 5-methoxy sterigmatocystin into hydroxy-nor-methoxy-sterigmatocystin, nor-methoxy sterigmatocystin and dihydroxy-methoxy-sterigmatocystin. CYP1A2 led to monohydroxy-methoxy-sterigmatocystin. In PTEC, 5-methoxy-sterigmatocystin metabolism resulted into a glucuroconjugate of 5-methoxy-sterigmatocystin, a sulfoconjugate and a glucuroconjugate of monohydroxy-methoxy-sterigmatocystin. The exposure of PTEC for 24 h to 1 uM 5-methoxy-sterigmatocystin induced a significant increase in the mRNA levels of CYP1A1, without significant induction of the 7-ethoxyresorufin O-deethylation activity. 4. These data suggest that 5 methoxy-sterigmatocystin is mainly detoxified in airway cells through conjugation, as sterigmatocystin. However, while CYP produced a reactive metabolite of sterigmatocystin, no such metabolite was detected with 5-methoxy sterigmatocystin. Nevertheless, 5-methoxy-sterigmatocystin increases the CYP1A1 mRNA levels. The long-term consequences remain unknown. PMID- 23756243 TI - Glucocorticoid-induced apoptosis in animal models of multiple sclerosis. AB - Glucocorticoids (GCs) are highly potent anti-inflammatory and immunosuppressive agents. They exert influence on many cell types of the immune system and impact a plethora of processes such as cytokine production, leukocyte differentiation, migration and adhesion, apoptosis induction, and changes in morphology. Those that are most relevant for the modulation of neuroinflammatory diseases, however, are still under debate. In this review, we will elaborate on how GCs impact inflammatory responses in general and revisit the ambivalent role that apoptosis plays in animal models of multiple sclerosis. Furthermore, we will discuss arguments that speak in favor or against an essential function of GC-induced apoptosis in neuroinflammation. We anticipate that a better knowledge of the mechanisms that GCs employ will eventually find its way into clinical practice for the future benefit of afflicted patients. PMID- 23756244 TI - The yin-yang of KIR3DL1/S1: molecular mechanisms and cellular function. AB - Killer Immunoglobulin-like Receptors (KIR) are a family of receptors expressed on natural killer (NK) and T-cell subsets. KIR3DL1 is a highly polymorphic receptor that binds to groups of HLAA and HLA-B allotypes that express the Bw4 epitope. The variation in KIR3DL1 allotypes manifests at a number of levels. Most dramatically, a common allelic variant encodes an activating rather than an inhibitory receptor (KIR3DS1). In addition, sequence variants can affect both the frequency of expression within the NK cell population and the intensity of expression on a given cell. KIR3DL1 polymorphism also influences the interaction with HLA-Bw4 molecules, due to contacts with the HLA molecule itself and sensitivity to the presented peptide. A body of evidence from genetic association studies supports the biological significance not only of the interaction of KIR3DL1 with HLA-Bw4 but also the functional variation seen with different KIR3DL1 and HLA allotypes. In this review, we discuss our current understanding of KIR3DL1 function and our recent insights from the structure of the KIR3DL1 in complex with HLA. In addition, we will summarize our current understanding of KIR3DS1, including its ligand specificity and its role in immune responses. PMID- 23756246 TI - Immunotherapeutic treatment of autoimmune diabetes. AB - Type 1 diabetes is a prototypic, organ-specific autoimmune disease. Diverse antigen-specific immunotherapy using insulin or glutamic acid decarboxylase peptides and other immunotherapies, such as antibodies, fusion proteins, cytokines, regulatory T cells, small-molecule inhibitors, nonspecific immune modulators, or dietary modifications, have been attempted in human type 1 diabetes. Some of these immunotherapies delay the onset of diabetes or reduce insulin requirements or blood glucose level in patients with established type 1 diabetes. However, most of these immunotherapies failed to induce complete remission of established type 1 diabetes, which could be due to 1) technical difficulties in the achievement of immune tolerance to diabetic autoantigens or in the inhibition of autoimmune responses to those antigens that can be applied to human patients without significant adverse effects, and 2) markedly reduced beta-cell mass at the time of disease onset that should be replenished. This review focuses on the immunological aspects of the disease and its treatment, and data from previous or ongoing human clinical trials using immune-logical measures, and recent results from immunological studies employing animal models are discussed. PMID- 23756247 TI - Comparison between ultrasound-guided supraclavicular and infraclavicular approaches for subclavian venous catheterization in children--a randomized trial. AB - BACKGROUND: Ultrasound (US)-guided subclavian vein (SCV) catheterization via the supraclavicular (SC) or infraclavicular (IC) approaches can be useful in children. The purpose of this study was to compare the efficacy of these approaches. METHODS: This prospective, randomized study included 98 children who were <3 years old, and who were divided into two groups: the SC group (n=49) and the IC group (n=49). All SCV catheterizations were guided by US and performed by a single experienced anaesthesiologist. Data regarding puncture time, number of attempts, successful guidewire insertion, catheter insertion time, and complications were analysed. RESULTS: The median puncture time was longer in the IC group than the SC group (48 vs 36 s, P=0.02). Multiple attempts (number of attempts >3) were more frequently required in the IC group than the SC group (24.5 vs 6.1%, P=0.01). The incidence of guidewire misplacement was higher in the IC group than that of the SC group [10 (20.4%) vs 0 (0%), P=0.001]. Catheterization was successfully performed in all patients. No pneumothoraces or arterial punctures occurred in either group. CONCLUSION: During SCV catheterization under US guidance in paediatric patients, the SC approach yielded a shorter puncture time and decreased the incidence of guidewire misplacement when compared with the IC approach. PMID- 23756245 TI - The role of CARMA1 in T cells. AB - Caspase recruitment domain-containing membrane-associated guanylate kinase protein-1 (CARMA1), a member of the membrane associated guanylate kinase (MAGUK) family of kinases, is essential for T lymphocyte activation and proliferation via T-cell receptor (TCR) mediated NF-kappaB activation. Recent studies suggest a broader role for CARMA1 regulating other T-cell functions as well as a role in non-TCR-mediated signaling pathways important for lymphocyte development and functions. In addition, CARMA1 has been shown to be an important component in the pathogenesis of several human diseases. Thus, comprehensively defining its mechanisms of action and regulation could reveal novel therapeutic targets for T cell-mediated diseases and lymphoproliferative disorders. PMID- 23756248 TI - Combined dysfunctions of immune cells predict nosocomial infection in critically ill patients. AB - BACKGROUND: Nosocomial infection occurs commonly in intensive care units (ICUs). Although critical illness is associated with immune activation, the prevalence of nosocomial infections suggests concomitant immune suppression. This study examined the temporal occurrence of immune dysfunction across three immune cell types, and their relationship with the development of nosocomial infection. METHODS: A prospective observational cohort study was undertaken in a teaching hospital general ICU. Critically ill patients were recruited and underwent serial examination of immune status, namely percentage regulatory T-cells (Tregs), monocyte deactivation (by expression) and neutrophil dysfunction (by CD88 expression). The occurrence of nosocomial infection was determined using pre defined, objective criteria. RESULTS: Ninety-six patients were recruited, of whom 95 had data available for analysis. Relative to healthy controls, percentage Tregs were elevated 6-10 days after admission, while monocyte HLA-DR and neutrophil CD88 showed broader depression across time points measured. Thirty three patients (35%) developed nosocomial infection, and patients developing nosocomial infection showed significantly greater immune dysfunction by the measures used. Tregs and neutrophil dysfunction remained significantly predictive of infection in a Cox hazards model correcting for time effects and clinical confounders {hazard ratio (HR) 2.4 [95% confidence interval (CI) 1.1-5.4] and 6.9 (95% CI 1.6-30), respectively, P=0.001}. Cumulative immune dysfunction resulted in a progressive risk of infection, rising from no cases in patients with no dysfunction to 75% of patients with dysfunction of all three cell types (P=0.0004). CONCLUSIONS: Dysfunctions of T-cells, monocytes, and neutrophils predict acquisition of nosocomial infection, and combine additively to stratify risk of nosocomial infection in the critically ill. PMID- 23756249 TI - Association of living alone with the presence of undiagnosed diabetes in Japanese men: the role of modifiable risk factors for diabetes: Toranomon Hospital Health Management Center Study 13 (TOPICS 13). AB - AIMS: To investigate whether living alone was associated with the presence of undiagnosed diabetes and whether this association could be attenuated by modifiable lifestyle habits. METHODS: This cross-sectional study included 6400 Japanese men without a history of diagnosed diabetes. Individuals with currently undiagnosed diabetes were identified through fasting glucose concentration >=7.0 mmol/l or HbA1c concentration >= 48 mmol/mol (>= 6.5%). Effect modification was examined using body mass index, hypertension, history of dyslipidaemia, drinking habits, smoking habits, physical activity, vegetable intake, emotional stress and depressed mood. RESULTS: Men who lived alone (n = 1098) had a significantly elevated odds ratio for having undiagnosed diabetes in an age-adjusted model (odds ratio 1.45, 95% CI 1.07, 1.96; P = 0.018). After adjustment for lifestyle factors, the association was slightly attenuated (odds ratio 1.40, 95% CI 1.02, 1.91; P = 0.036). After further adjustment for all factors mentioned above, living alone was still marginally significantly associated with the presence of undiagnosed diabetes (odds ratio 1.38, 95% CI 1.003, 1.90; P = 0.048). A significant association of living alone with the presence of undetected diabetes was particularly observed among men who were overweight, currently smoked and were physically inactive, or had any one of those three factors. CONCLUSIONS: The association between undiagnosed diabetes and living alone can be partially influenced by modifiable lifestyle factors. Men who lived alone, especially those who did not engage in favourable lifestyle habits, were more likely to have undiagnosed diabetes. Such individuals have a higher probability of having undetected diabetic hyperglycaemia and would need to undergo glucose tests to identify the disease. PMID- 23756250 TI - Diurnal temporal patterns of hypoglycaemia in hospitalized people with diabetes may reveal potentially correctable factors. AB - AIM: To determine whether diurnal temporal variations in hypoglycaemic frequency occur in hospitalized patients. METHODS: Hypoglycaemic events were identified in a snapshot bedside audit of capillary blood glucose results from diabetes charts of all inpatients receiving insulin or a sulphonylurea (with or without insulin) on 2 days separated by 6 weeks. Additionally, capillary blood glucose measurements were remotely captured over 2 months, in the same category of patients, and analysed for temporal patterns. Hypoglycaemia was defined as 'severe' when the capillary blood glucose was < 3.0 mmol/l and 'mild' when the capillary blood glucose was between 3.0 and 3.9 mmol/l. RESULTS: The bedside audit found that 74% of those audited experienced a hypoglycaemia event. Eighty three per cent of all hypoglycaemic events and 70% of severe events were recorded between 21.00 and 09.00 h. This was confirmed in the longer duration remote monitoring study where 70% of all hypoglycaemic events and 66% of severe events occurred between 21.00 and 09.00 h. CONCLUSION: Hypoglycaemia occurs more frequently between 21.00 and 09.00 h in hospitalized patients receiving treatments that can cause hypoglycaemia. This may be related to insufficient carbohydrate intake during this period, and is potentially preventable by changes in catering practice. PMID- 23756251 TI - Association between serum ferritin and microalbuminuria in Type 2 diabetes in Taiwan. AB - AIMS: Serum ferritin has been found closely related with diabetes and glucose metabolism, but its impact on diabetic nephropathy remains unknown. This study aimed to explore the association between serum ferritin and microalbuminuria in Type 2 diabetes. METHODS: Eight hundred and fifty-one subjects with Type 2 diabetes were selected from a cohort participating in a glycaemic control study in Taiwan in 2008. We used urine albumin:creatinine ratio to define microalbuminuria; serum ferritin was divided into quartiles for analysis. Logistic regression and trend tests were used to delineate the association between serum ferritin and microalbuminuria. RESULTS: Subjects with diabetes with higher ferritin tended to have more metabolic disorders, higher high-sensitivity C-reactive protein and higher prevalence of microalbuminuria. Compared with those in the lowest quartile, subjects with diabetes in the highest ferritin quartile were 55% (P = 0.029) more likely to have microalbuminuria. After controlling for demographics, metabolic profiles and other inflammatory markers, the association between serum ferritin levels and microalbuminuria remained significant (P for trend < 0.001). This independent relationship was not changed either for those who had better glycaemic control or those who had not used an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. CONCLUSIONS: The current study shows hyperferritinemia may be an independent risk factor of nephropathy in patients with Type 2 diabetes. PMID- 23756252 TI - Abstracts of the 2013 Convention Proceedings of the AWHONN (Association of Women's Health, Obstetric and Neonatal Nurses). June 15-19, 2013. Nashville, Tennessee, USA. PMID- 23756254 TI - The effects of VEGF-A on atherosclerosis, lipoprotein profile, and lipoprotein lipase in hyperlipidaemic mouse models. AB - AIMS: The role of vascular endothelial growth factor (VEGF-A) in atherogenesis has remained controversial. We addressed this by comparing the effects of adenoviral VEGF-A gene transfer on atherosclerosis and lipoproteins in ApoE(-/-), LDLR(-/-), LDLR(-/-)ApoE(-/-), and LDLR(-/-)ApoB(100/100) mice. METHODS AND RESULTS: After 4 weeks on western diet, systemic adenoviral gene transfer was performed with hVEGF-A or control vectors. Effects on atherosclerotic lesion area and composition, lipoprotein profiles, and plasma lipoprotein lipase (LPL) activity were examined. On day 4, VEGF-A induced alterations in lipoprotein profiles and a significant negative correlation was observed between plasma LPL activity and VEGF-A levels. One month after gene transfer, no changes in atherosclerosis were observed in LDLR(-/-) and LDLR(-/-)ApoB(100/100) models, whereas both ApoE(-/-) models displayed increased en face lesion areas in thoracic and abdominal aortas. VEGF-A also reduced LPL mRNA in heart and white adipose tissue, whereas Angptl4 was increased, potentially providing further mechanistic explanation for the findings. CONCLUSION: VEGF-A gene transfer induced pro-atherogenic changes in lipoprotein profiles in all models. As a novel finding, VEGF-A also reduced LPL activity, which might underlie the observed changes in lipid profiles. However, VEGF-A was observed to increase atherosclerosis only in the ApoE(-/-) background, clearly indicating some mouse model-specific effects. PMID- 23756255 TI - Frequent overexpression of ErbB--receptor family members in brain metastases of non-small cell lung cancer patients. AB - The ErbB receptor family has been implicated in brain metastases (BM) formation in various cancer types and specific targeted therapies are available. We investigated the overexpression of EGFR, HER2 and HER3 in BM of non-small cell lung cancer (NSCLC) patients to get a better insight on pathobiology of BM and potential drugable targets. We performed immunohistochemical analysis of EGFR, HER2 and HER3 on tissue microarrays of 131 NSCLC-BM. Fifty-one of 131 (38.9%) specimens were considered as positive for EGFR overexpression, 12/131 (9.2%) for HER2 and 27/131 (20.6%) for HER3 respectively. Sixty-nine of 131 (52.7%) of the cases showed overexpression of at least one marker. Four of 131 (3.1%) were positive for all three markers. Strong correlation was observed between HER2 and HER3 overexpression (p = 0.009; Chi-square test after Bonferroni-Holmes correction). No statistically significant correlation of EGFR, HER2 or HER3 overexpression with clinico-pathological parameters including overall survival times was observed. We observed overexpression of ErbB receptor family members, which represent established therapeutic targets in various primary tumours, in approximately half of NSCLC-BM. Further studies should investigate the role of the ErbB pathway in development of and as a therapeutic target in BM of NSCLC patients. PMID- 23756257 TI - Dispersive liquid-liquid microextraction of thiram followed by microvolume UV-vis spectrophotometric determination. AB - A novel and simple method for the sensitive determination of trace amounts of fungicide thiram is developed by combination of dispersive liquid-liquid microextraction (DLLME) and microvolume UV-vis spectrophotometry. The method is based on the conversion of thiram to a yellow product in the presence of ethanolic potassium hydroxide and copper sulfate, and its extraction into CCL4 using DLLME technique. In this method the ethanol existing in ethanolic KOH plays as disperser solvent and a cloudy solution is formed by injection of only CCl4 as extractant solvent into sample solution. Under the optimum conditions, the calibration graph was linear over the range of 25-1000 ng mL(-1) of thiram with limit of detection of 11.5 ng mL(-1). The relative standard deviation (RSD) for 100 and 500 ng mL(-1) of thiram was 2.7 and 1.1% (n=8), respectively. The proposed method was successfully applied to determination of thiram in water and plant seed samples. PMID- 23756256 TI - Significance of COX-2 and VEGF expression in histopathologic grading and invasiveness of meningiomas. AB - Meningiomas are slow-growing neoplasms that recur locally. Their morphologic grading does not always correlate with patient outcome. We evaluated the status of several immunohistochemical markers with histopathologic parameters in various grades of meningioma.Eighty-eight meningioma specimens were examined immunohistochemically to determine the status of Ki-67, cyclin D1, epidermal growth factor receptor (EGFR), cyclooxygenase-2 (COX-2), vascular endothelial growth factor (VEGF), and bcl-2. Several clinical and pathological parameters were investigated.Forty-nine Grade I, 33 Grade II, and 6 Grade III meningiomas were observed. VEGF and Ki-67 expression was correlated with higher tumor grade. The association between grade and other immunohistochemical markers expression was not significant. A correlation was observed between COX-2 expression and invasiveness to the brain or adjacent soft tissue. Tumor recurrence was correlated with brain or adjacent soft tissue invasion. We also observed a relationship between VEGF level and COX-2 expression, and they were both correlated with necrosis.Immunohistochemical evaluation of VEGF, COX-2, and Ki-67 expression can provide information regarding the behavior of meningiomas, particularly for cases in which histological grading is not straightforward. PMID- 23756258 TI - The P-branch and R-branch emission spectral lines in the d1Sigma(+)-A3Sigma0(-) system of NbN. AB - The P and R-branch spectral lines of high-lying rotational quantum states of (0,0), (1,1) bands in d(1)Sigma(+)-A(3)Sigma0(-) electronic transition of NbN are obtained in this work by using the analytical formula proposed recently by Sun et al. The formula have generated unknown P and R-branch emission spectral lines up to J=80 those may not be available experimentally for these bands of NbN molecule. PMID- 23756259 TI - Characterization of the sulphate mineral amarantite - Fe2(3+)(SO4)O.7H2O using infrared, Raman spectroscopy and thermogravimetry. AB - The mineral amarantite Fe2(3+)(SO4)O.7H2O has been studied using a combination of techniques including thermogravimetry, electron probe analyses and vibrational spectroscopy. Thermal analysis shows decomposition steps at 77.63, 192.2, 550 and 641.4 degrees C. The Raman spectrum of amarantite is dominated by an intense band at 1017 cm(-1) assigned to the SO4(2-) nu1 symmetric stretching mode. Raman bands at 1039, 1054, 1098, 1131, 1195 and 1233 cm(-1) are attributed to the SO4(2-) nu3 antisymmetric stretching modes. Very intense Raman band is observed at 409 cm(-1) with shoulder bands at 399, 451 and 491 cm(-1) are assigned to the nu2 bending modes. A series of low intensity Raman bands are found at 543, 602, 622 and 650 cm(-1) are assigned to the nu4 bending modes. A very sharp Raman band at 3529 cm( 1) is assigned to the stretching vibration of OH units. A series of Raman bands observed at 3025, 3089, 3227, 3340, 3401 and 3480 cm(-1) are assigned to water bands. Vibrational spectroscopy enables aspects of the molecular structure of the mineral amarantite to be ascertained. PMID- 23756260 TI - Synthesis, spectroscopic and structural characterization of 5-benzoyl-4-phenyl-2 methylthio-1H-pyrimidine with theoretical calculations using density functional theory. AB - In this paper, we will report a combined experimental and theoretical investigation of the molecular structure and spectroscopic parameters (FT-IR, (1)H NMR, (13)C NMR) of 5-benzoyl-4-phenyl-2-methylthio-1H-pyrimidine. The compound crystallizes in the triclinic space group P-1 with Z=2. The molecular geometry was also optimized using density functional theory (DFT/B3LYP) method with the 6-311G(d,p) and 6-311++G(d,p) basis sets in ground state and compared with the experimental data. All the assignments of the theoretical frequencies were performed by potential energy distributions using VEDA 4 program. Information about the size, shape, charge density distribution and site of chemical reactivity of the molecules has been obtained by mapping electron density isosurface with electrostatic potential (ESP). Also, non-linear optical properties of the title compound were performed at B3LYP/6-311++G(d,p) level. The theoretical results showed an excellent agreement with the experimental values. PMID- 23756261 TI - IR, Raman and SERS spectral analysis and DFT calculations on the Herbicide O,S Dimethyl phosphoramidothioate, metamidophos. AB - Infrared, Raman and SERS spectra of O,S-Dimethyl phosphoramidothioate, metamidophos, MAP, have been recorded. Density Functional Theory, DFT, with the B3LYP functional was used for the optimization of the ground state geometry and simulation of the infrared and Raman spectra of this molecule. Calculated geometrical parameters fit very well with the experimental ones. Combining the recorded data, the DFT results and a Normal Coordinate Analysis based on a scaled quantum mechanical (SQM) force field approach, a complete vibrational assignment was made for the first time. The comparison of SERS spectra obtained by using colloidal silver nanoparticles, with the corresponding Raman spectrum reveals enhancement and shifts in bands as well as information about the orientation of MAP on the nm-sized metal structures and the importance of the S atom on the SERS effect. DFT modelling of the SERS effect and Molecular Electrostatic Potentials (MEP) confirms the experimental information. PMID- 23756262 TI - FT-IR, dispersive Raman, NMR, DFT and antimicrobial activity studies on 2 (Thiophen-2-yl)-1H-benzo[d]imidazole. AB - 2-(Thiophen-2-yl)-1H-benzo[d]imidazole (TBI) was synthesized under microwave conditions and was characterized by FT-IR, dispersive Raman, (1)H-, (13)C-, DEPT , HETCOR-NMR spectroscopies and density functional theory (DFT) computations. The FT-IR and dispersive Raman spectra of TBI were recorded in the regions 4000-400 cm(-1) and 4000-100 cm(-1). The experimental vibrational spectra were interpreted with the help of normal coordinate analysis based on DFT/B3LYP/6-311++G(d,p) theory level for the more stable tautomeric form (Tautomer 1). The complete vibrational assignments were performed on the basis of the potential energy distribution (PED) of the vibrational modes, calculated with scaled quantum mechanical (SQM) method. A satisfactory consistency between the experimental and theoretical findings was obtained. The frontier molecular orbitals (FMOs), atomic charges and NMR shifts of the two stable tautomeric forms were also obtained at the same theory level without any symmetry restrictions. In addition, the title compound was screened for its antimicrobial activity and was found to be exhibit antifungal and antibacterial effects. PMID- 23756263 TI - Randomised trial of blood transfusion versus a restrictive transfusion policy after hip fracture surgery. AB - BACKGROUND: Debate exists as to what should be the transfusion threshold for patients with anaemia after hip fracture surgery. METHODS: A total of 200 patients aged 60 years and above with a haemoglobin level of between 8.0 and 9.5gdl(-1) after hip fracture surgery were randomised to receive a transfusion to raise the haemoglobin to at least 10.0gdl(-1) or not to have a transfusion unless definite symptoms of anaemia became apparent. Patients were followed up for 1 year. RESULTS: There was no statistically significant difference in the outcomes of mortality, hospital stay, regain of mobility or complications between the two groups. CONCLUSIONS: This study confirms other recent research studies which found that reducing the transfusion threshold to 8.0gdl(-1) appears to be a safe practice for this group of patients. PMID- 23756264 TI - In vitro temperature evaluation during cement augmentation of proximal humerus plate screw tips. AB - BACKGROUND: The treatment of proximal humerus fractures in patients with poor bone quality remains a challenge in trauma surgery. Augmentation with polymethylmethacrylate (PMMA) cement is a possible method to strengthen the implant anchorage in osteoporotic bone and to avoid loss of reduction and reduce the cut-out risk. The polymerisation of PMMA during cement setting leads, however, to an exothermic reaction and the development of supraphysiological temperatures may harm the bone and cartilage. This study addresses the issue of heat development during augmentation of subchondrally placed proximal humerus plate screws with PMMA and the possible risk of bone and cartilage necrosis and apoptosis. METHODS: Seven fresh frozen humeri from geriatric female donors were instrumented with the proximal humerus interlocking system (PHILOS) plate and placed in a 37 degrees C water bath. Thereafter, four proximal perforated screws were augmented with 0.5 ml PMMA each. During augmentation, the temperatures in the subchondral bone and on the articular surface were recorded with K-type thermocouples. The measured temperatures were compared to threshold values for necrosis and apoptosis of bone and cartilage reported in the literature. RESULTS: The heat development was highest around the augmented tips of the perforated screws and diminished with growing distance from the cement cloud. The highest temperature recorded in the subchondral bone reached 43.5 degrees C and the longest exposure time above 42 degrees C was 86s. The highest temperature measured on the articular surface amounted to 38.6 degrees C and the longest exposure time above 38 degrees C was 5 min and 32s. CONCLUSION: The study shows that augmentation of the proximal screws of the PHILOS plate with PMMA leads to a locally limited development of supraphysiological temperatures in the cement cloud and closely around it. The critical threshold values for necrosis and apoptosis of cartilage and subchondral bone reported in the literature, however, are not reached. In order to avoid cement extravasation, special care should be taken in detecting perforations or intra-articular cracks in the humeral head. PMID- 23756265 TI - The Human UDP-glucuronosyltransferase UGT2A1 and UGT2A2 enzymes are highly active in bile acid glucuronidation. AB - Bile acids (BA) are essential modulators of lipid, glucose, and cholesterol homeostasis, but they exert cytotoxic effects in the cholestatic liver. Glucuronidation, catalyzed by the UDP-glucuronosyltransferase (UGT) enzymes is a pharmacologically relevant BA detoxification process. The present study characterized the BA-conjugating activity of the little-studied human UGTs of subfamily 2A: UGT2A1, 2A2, and 2A3. Recombinant UGT2As, expressed in baculovirus infected insect cells, were assayed for the glucuronidation of six major bile acids: chenodeoxycholic acid (CDCA), cholic acid (CA), lithocholic acid (LCA), deoxycholic acid (DCA), hyocholic acid (HCA) and hyodeoxycholic acid (HDCA). UGT2A3 exhibited detectable but very low activity with all the tested BA substrates. UGT2A1 was highly efficient in forming LCA-3 and LCA-24G, CDCA-24, DCA-24, HCA-24, and HDCA-24G, whereas UGT2A2 was the most active enzyme for CA 24G and CDCA-24G formation and also was able to generate HDCA-6G, HDCA-24G, LCA 24G, and HCA-24G. The Km values of UGT2A1 varied between 102.2 +/- 14.3 uM and 2.4 +/- 1.2 mM. With the exception of CA-24G, a low affinity substrate for UGT2A2, all the Km values for UGT2A2 were in the 100 to 400 uM range. We demonstrate the high reactivity of the human UGT2A1 and UGT2A2 for bile acid glucuronidation. The physiologic importance of these reactions to BA disposition remains, however, to be clarified in vivo. PMID- 23756266 TI - Role of plasma exchange in autoimmune hyperthyroidism complicated by severe tiamazol-induced cholestatic jaundice. AB - Therapeutic plasma exchange (TPE) is an alternative treatment for hyperthyroidism, resulting in a rapid decline in plasma thyroid hormones and anti thyroid antibodies. TPE has also been used both in primary liver disease and in drug-induced cholestasis. Data on thyrotoxic patients with severe hepatic complications are scarce. Cholestasis induced by imidazol-derived anti-thyroid drugs is extremely rare. The use of TPE for treating this complication was not previously reported. We report the experience of one such patient with a favorable response to TPE. A 45-year-old male patient with Graves' disease, presented with severe jaundice and extremely high serum bilirubin levels due to hepatotoxicity induced by tiamazol. Through extensive investigation primary liver disease, including viral, metabolic, neoplastic and autoimmune disease, as a cause of cholestasis were all ruled out. The patient underwent total of 6 TPEs which in combination with low dose of glucocorticoids and standard supportive measures, resulted in normalization of thyroid hormones and normal liver function tests. TPE provided a safe, rapid and effective treatment of severe drug-induced cholestasis and auto immune hyperthyroidism. From this case we conclude that TPE should be considered as a valuable alternative therapeutic option in thyrotoxic patients with severe complications. Guidelines and indication criteria for TPE treatment in patients with hyperthyroidism are still lacking. PMID- 23756267 TI - Assessing the frequencies of GP.Mur (Mi.III) in several Southeast Asian populations by PCR typing. PMID- 23756268 TI - Many more reasons behind difficulties in recruiting patients to randomized controlled trials in psychiatry. PMID- 23756269 TI - Internal herniation through a broad ligament defect found at laparoscopy. PMID- 23756270 TI - All for one. PMID- 23756271 TI - Comparative evaluation of 50 microgram oral misoprostol and 25 microgram intravaginal misoprostol for induction of labour at term: a randomized trial. AB - OBJECTIVES: To assess and compare the efficacy and safety of 50 ug oral misoprostol and 25 ug intravaginal misoprostol for induction of labour at term. METHODS: This non-blinded, randomized clinical trial included 228 pregnant women at term with obstetric or medical indications for induction of labour. Women either took 50 ug misoprostol orally (two 25 ug tablets) or had one 25 ug tablet of misoprostol inserted in the posterior vaginal fornix. In each group, misoprostol administration was repeated every four hours in the same dose until regular uterine contractions were established or to a maximum of five doses. Time to delivery and outcome data for each group were compared. RESULTS: Of the 228 women, eight (3.5%) were excluded from the analysis as they withdrew their consent after randomization. Mean induction-to-delivery interval was similar in both groups (21.22 hours in the oral group vs. 20.15 hours in the vaginal group; P = 0.58). There was no significant difference between the groups with respect to the number of women who delivered within 24 hours or who required oxytocin augmentation of labour, the mode of delivery, and neonatal outcomes (P > 0.05). Uterine hyperstimulation occurred in two women who received misoprostol vaginally, but not in any of the women in the oral misoprostol group. CONCLUSION: Oral misoprostol in a dose of 50 ug every four hours, to a maximum of five doses, has the potential to induce labour as safely and effectively as 25 ug misoprostol administered vaginally every four hours. PMID- 23756272 TI - Multidisciplinary management of invasive placenta previa. AB - OBJECTIVE: To assess the effectiveness of a multidisciplinary team approach to reduce severe maternal morbidity in women with invasive placenta previa. METHODS: We conducted a prospective study of 33 women with placenta previa and increta percreta (diagnosed by ultrasound and/or magnetic resonance imaging) delivering at Mount Sinai Hospital, Toronto, following the introduction in January 2008 of a team-based approach to women with this condition. We included women who delivered by June 2012. We reviewed antenatal outpatient and inpatient records for use of six pre-defined team components by the attending staff obstetrician: (1) antenatal maternal-fetal medicine consultation, (2) surgical gynaecology consultation, (3) antenatal MRI, (4) interventional radiology consultation and preoperative placement of balloon catheters in the anterior divisions of the internal iliac arteries, (5) pre-planned surgical date, and (6) surgery performed by members of the invasive placenta surgical team. Antenatal course, delivery, and postpartum details were recorded to derive a five-point composite severe maternal morbidity score based on the presence or absence of: (1) ICU admission following delivery, (2) transfusion > 2 units of blood, (3) general anaesthesia start or conversion, (4) operating time in highest quartile (> 125 minutes), and (5) significant postoperative complications (readmission, prolonged postpartum stay, and/or pulmonary embolism). RESULTS: All 33 women survived during this time period. Two thirds (22/33) had either five or six of the six components of multidisciplinary care. Increasing use of multidisciplinary team components was associated with a significant reduction in composite morbidity (R2 = 0.228, P = 0.005). CONCLUSION: Team-based assessment and management of women with invasive placenta previa is likely to improve maternal outcomes and should be encouraged on a regional basis. PMID- 23756273 TI - A randomized controlled trial of early versus delayed skin staple removal following caesarean section in the obese patient. AB - OBJECTIVE: To compare wound complications after Caesarean section in the obese patient, following early versus delayed skin staple removal. METHODS: We conducted a single-centre, non-inferiority, randomized controlled trial. Following Caesarean section, obese women (BMI >= 30 kg/m(2)) with subcutaneous wound depth >= 2.0 cm and skin staple closure of a transverse incision were randomized to staple removal on postoperative day 3 (early) or between postoperative day 7 and postoperative day 10 (delayed). The primary outcome was superficial wound dehiscence; a rate of 8% or higher in the early group was defined as inferior. Secondary outcomes were seroma/hematoma, surgical site infection, and visual analogue pain score. The planned sample size was 250 patients per group. RESULTS: The study was halted after 295 patients were randomized because of slow enrolment and exhaustion of funding. The rate of superficial wound dehiscence was 15.2% in the early group (n = 145) versus 11.5% in the delayed group (n = 148). The point estimate for this difference (3.7 %; 95% CI -4.4 to 12.4) favours delayed removal. However, because the 95% CI includes zero and the upper CI exceeds the predefined limit for non-inferiority (8%), non-inferiority was not demonstrated. The rates of all secondary outcomes were similar in the early group and the delayed group: seroma/hematoma (6.9% vs. 4.7%; RR 1.4, 95% CI 0.6 to 3.7, P = 0.4); surgical site infection (9.7% vs. 4.8%; RR 2.0, 95% CI 0.8 to 4.9, P = 0.1); and composite (superficial wound dehiscence, seroma/hematoma, and surgical site infection) wound complication (17.2% vs. 12.8%; RR 1.3, 95% CI 0.8 to 2.3, P = 0.3). CONCLUSION: The non inferiority of early skin staple removal was not demonstrated. Delayed removal of staples should remain the accepted standard in the obese patient following Caesarean section. PMID- 23756274 TI - Preventable obstetrical interventions: how many caesarean sections can be prevented in Canada? AB - Public health authorities have been alarmed by the progressive rise in rates of Caesarean section in Canada, approaching one birth in three in several provinces. We aimed therefore to consider what were preventable obstetrical interventions in women with a low-risk pregnancy and to propose an analytic framework for the reduction of the rate of CS. We obtained statistical variations of CS rates over time, across regions, and within professional practices from MED-ECHO, the Quebec hospitalization database, from 1969 to 2009. Data were extracted from a recent systematic review of the cascade of obstetrical interventions to calculate the population-attributable fractions for each intervention associated with an increased probability of CS. We thereby identified expectant management (as an alternative to labour induction) and planned vaginal birth after CS as the leading strategies for potentially reducing rates of CS in women at low risk. For vaginal birth after CS, an increase to its 1995 level could lower the current CS rate of 23.2% (2009 to 2010) to 21.0%. Other alternatives to obstetrical interventions with a potential for lowering CS rates included non-pharmacological pain control methods (such as continuous support during childbirth) in addition to usual care, intermittent auscultation of the fetal heart (instead of electronic fetal monitoring), and multidisciplinary internal quality assessment audits. We believe, therefore, that the concept of preventable CS is supported by empirical evidence, and we identified realistic strategies to maintain a CS rate in Quebec near 20%. PMID- 23756275 TI - Assessing the impact of the SOGC recommendations to increase access to prenatal screening on overall use of health resources in pregnancy. AB - OBJECTIVES: The recommendation by the Society of Obstetricians and Gynaecologists of Canada that prenatal screening for fetal aneuploidy be offered to all pregnant women is an important change in clinical obstetrics. However, it is unknown how this recommendation might affect the use of other health resources during pregnancy. METHODS: Twelve clinical and administrative databases were linked, and care paths outlining typical service use in pregnancy were created based on the type of prenatal screening accessed (first trimester screening [FTS], maternal serum screening [MSS], invasive testing only, or no screening and/or diagnosis). Logistic, Poisson, and negative binomial models were applied to the data to examine the association between use of prenatal screening/diagnosis and other health services during pregnancy. RESULTS: Women who accessed prenatal screening/diagnosis were significantly more likely to have a consultation with a medical geneticist (FTS OR 2.42; 95% CI 1.75 to 3.33; MSS OR 4.84; 95% CI 2.92 to 8.03; and invasive testing OR 8.58; 95% CI 5.28 to 13.94), and women who accessed FTS had more prenatal visits (FTS incidence rate ratio 1.03; 95% CI 1.01 to 1.05) than women who did not access prenatal screening/diagnosis. Uptake of invasive tests did not differ between women who accessed FTS and those who accessed MSS. Use of prenatal screening/diagnosis was not significantly associated with use of most other health resources CONCLUSION: In a publicly funded health care system, understanding the impact of recommendations to increase access to a specific service on other services is important. Recommendations to increase access to prenatal screening services may have some unanticipated downstream effects on the use of other services during pregnancy. However, most aspects of health resource use in pregnancy do not appear to be influenced by the use of prenatal screening services. PMID- 23756276 TI - Social gradients in surgical sterilization rates: opposing patterns for males and females. AB - OBJECTIVE: The purpose of this study was to analyze population-based rates of surgical sterilization by sex, income, age group, and location of residence (urban, rural, or remote) among a universally insured population. METHODS: The study included all 1.2 million residents of Manitoba. Data from comprehensive hospital and medical visit records were used to calculate rates of vasectomy and tubal ligation among the population aged 20 to 55 years. Analyses were carried out with generalized linear modelling, using administrative data housed at the Manitoba Centre for Health Policy. RESULTS: There were significant income-related gradients in sterilization rates for both sexes (P < 0.001), but the trends were in opposite directions for males and females. Tubal ligation rates were highest in low-income areas, and decreased with income, whereas vasectomy rates were lowest in low-income areas and increased with income. Rates also varied considerably by age and area of residence (urban, rural, or remote). CONCLUSION: These results are potentially worrying because tubal ligation is more invasive, associated with higher risks, and more costly than vasectomy. It would therefore be expected to be less common than vasectomy among all groups, not just those in higher income areas. The results contribute unique population-based procedure rates, which are not subject to biases that can affect survey-based studies. The findings may reflect underlying differences across income groups in decision making regarding reproductive health issues. PMID- 23756277 TI - Sacral colpopexy versus transvaginal mesh colpopexy in obese patients. AB - OBJECTIVES: Obesity can predispose women to pelvic organ prolapse and can also affect the success of pelvic organ prolapse surgery. The purpose of this study was to compare the postoperative anatomical outcomes following sacral colpopexy (SC) and transvaginal mesh colpopexy in a group of obese women with pelvic organ prolapse. METHODS: We conducted a retrospective cohort study of obese women who underwent SC (n = 56) or transvaginal mesh colpopexy (n = 35). Follow-up ranged from 6 to 12 months. Preoperative, perioperative, and postoperative variables were compared using Student t, Mann-Whitney U, and Fisher exact tests, and by analysis of covariance. RESULTS: The women in the SC group had significantly higher mean apical vaginal measurements (P < 0.05), and significantly fewer stage II recurrences than women in the transvaginal mesh colpopexy group. There were no significant differences between the groups for other postoperative outcomes, including mesh erosion, recurrent prolapse symptoms, dyspareunia, and surgical satisfaction (P > 0.05). CONCLUSION: In these 91 obese patients with pelvic organ prolapse, SC resulted in better anatomical outcomes than transvaginal mesh colpopexy. However, the two procedures had similar outcomes with regard to recurrent symptoms and surgical satisfaction. PMID- 23756278 TI - Minimally invasive surgical management of a second trimester pregnancy in a rudimentary uterine horn. AB - BACKGROUND: Pregnancy in a rudimentary uterine horn is a rare form of ectopic pregnancy with a high risk of rupture. Management usually involves excision of the rudimentary horn. If diagnosed after the first trimester, it has been managed in the past by laparotomy. CASE: A primigravid woman was found on routine ultrasound to have a rudimentary horn pregnancy. The diagnosis was confirmed on MRI, and a thin uterine wall was demonstrated. Management comprised fetal injection of potassium chloride followed by complete laparoscopic excision of the rudimentary horn at 16 weeks' gestation. CONCLUSION: Laparoscopic management of a mid-trimester rudimentary horn pregnancy is feasible, but expert radiological characterization is required for optimal surgical planning. PMID- 23756279 TI - Abnormal uterine bleeding in pre-menopausal women. AB - BACKGROUND: Abnormal uterine bleeding is the direct cause of a significant health care burden for women, their families, and society as a whole. Up to 30% of women will seek medical assistance for this problem during their reproductive years. This guideline replaces previous clinical guidelines on the topic and is aimed to enable health care providers with the tools to provide the latest evidence-based care in the diagnosis and the medical and surgical management of this common problem. OBJECTIVE: To provide current evidence-based guidelines for the diagnosis and management of abnormal uterine bleeding (AUB) among women of reproductive age. OUTCOMES: Outcomes evaluated include the impact of AUB on quality of life and the results of interventions including medical and surgical management of AUB. METHODS: Members of the guideline committee were selected on the basis of individual expertise to represent a range of practical and academic experience in terms of location in Canada, type of practice, subspecialty expertise, and general gynaecology background. The committee reviewed relevant evidence in the English medical literature including published guidelines. Recommendations were established as consensus statements. The final document was reviewed and approved by the Executive and Council of the SOGC. RESULTS: This document provides a summary of up-to-date evidence regarding diagnosis, investigations, and medical and surgical management of AUB. The resulting recommendations may be adapted by individual health care workers when serving women with this condition. CONCLUSIONS: Abnormal uterine bleeding is a common and sometimes debilitating condition in women of reproductive age. Standardization of related terminology, a systematic approach to diagnosis and investigation, and a step-wise approach to intervention is necessary. Treatment commencing with medical therapeutic modalities followed by the least invasive surgical modalities achieving results satisfactory to the patient is the ultimate goal of all therapeutic interventions. EVIDENCE: Published literature was retrieved through searches of MEDLINE and the Cochrane Library in March 2011 using appropriate controlled vocabulary (e.g. uterine hemorrhage, menorrhagia) and key words (e.g. menorrhagia, heavy menstrual bleeding, abnormal uterine bleeding). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies written in English and published from January 1999 to March 2011. Searches were updated on a regular basis and incorporated in the guideline to February 2013. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table). BENEFITS, HARMS, AND COSTS: Implementation of the guideline recommendations will improve the health and well-being of women with abnormal uterine bleeding, their families, and society. The economic cost of implementing these guidelines in the Canadian health care system was not considered. PMID- 23756280 TI - Nutritional approaches in the risk reduction and management of Alzheimer's disease. AB - Alzheimer's disease (AD) is a heterogeneous and devastating neurodegenerative disease with increasing socioeconomic burden for society. In the past 30 y, notwithstanding advances in the understanding of the pathogenesis of the disease and consequent development of therapeutic approaches to novel pathogenic targets, no cure has so far emerged. This contribution focuses on recent nutritional approaches in the risk reduction and management of AD with emphasis on factors providing a rationale for nutritional approaches in AD, including compromised nutritional status, altered nutrient uptake and metabolism, and nutrient requirements for synapse formation. Collectively these factors are believed to result in specific nutritional requirement in AD. The chapter also emphasizes investigated nutritional interventions in patients with AD, including studies with single nutrients and with the specific nutrient combination Fortasyn Connect and discusses the current shift of paradigm to intervene in earlier stages of AD, which offers opportunities for investigating nutritional strategies to reduce the risk for disease progression. Fortasyn Connect was designed to enhance synapse formation and function in AD by addressing the putative specific nutritional requirements and contains docosahexaenoic acid, eicosapentaenoic acid, uridine-5' mono-phosphate, choline, phospholipids, antioxidants, and B vitamins. Two randomized controlled trials (RCTs) with the medical food Souvenaid, containing Fortasyn Connect, showed that this intervention improved memory performance in mild, drug-naive patients with AD. Electroencephalography outcome in one of these clinical studies suggests that Souvenaid has an effect on brain functional connectivity, which is a derivative of changed synaptic activity. Thus, these studies suggest that nutritional requirements in AD can be successfully addressed and result in improvements in behavioral and neuro-physiological alterations that are characteristic to AD. The recent advance of methodologies and techniques for early diagnosis of AD facilitates the investigation of strategies to reduce the risk for AD progression in the earliest stages of the disease. Nutrition-based approaches deserve further investigation as an integral part of such strategies due to their low risk for side effects and their potential to affect pathological processes of very early AD. PMID- 23756281 TI - Branched-chain amino acids and ammonia metabolism in liver disease: therapeutic implications. AB - The rationale for recommendation of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) in treatment of liver failure is based on their unique pharmacologic properties, stimulatory effect on ammonia detoxification to glutamine (GLN), and decreased concentrations in liver cirrhosis. Multiple lines of evidence have shown that the main cause of the BCAA deficiency in liver cirrhosis is their consumption in skeletal muscle for synthesis of glutamate, which acts as a substrate for ammonia detoxification to GLN and that the BCAA administration to patients with liver failure may exert a number of positive effects that may be more pronounced in patients with marked depression of BCAA levels. On the other hand, due to the stimulatory effect of BCAA on GLN synthesis, BCAA supplementation may lead to enhanced ammonia production from GLN breakdown in the intestine and the kidneys and thus exert harmful effects on the development of hepatic encephalopathy. Therefore, to enhance therapeutic effectiveness of the BCAA in patients with liver injury, their detrimental effect on ammonia production, which is negligible in healthy people and/or patients with other disorders, should be avoided. In treatment of hepatic encephalopathy, simultaneous administration of the BCAA (to correct amino acid imbalance and promote ammonia detoxification to GLN) with alpha-ketoglutarate (to inhibit GLN breakdown to ammonia in enterocytes) and/or phenylbutyrate (to enhance GLN excretion by the kidneys) is suggested. Attention should be given to the type of liver injury, gastrointestinal bleeding, signs of inflammation, and the dose of BCAA. PMID- 23756282 TI - A high-fat diet supplemented with fish oil improves metabolic features associated with type 2 diabetes. AB - OBJECTIVE: The goal of this study was to investigate the effects of a high-fat diet supplemented with fish oil or olive oil, fed to C57BL/6J mice for an extended period, on metabolic features associated with type 2 diabetes. METHODS: Mice were fed one of four diets for 30 wk: a low-fat diet, a high-fat diet supplemented with lard, a high-fat diet supplemented with fish oil, or a high-fat diet supplemented with olive oil. Phenotypic and metabolic analysis were determined at 15 and 25 to 30 wk, thereby providing comparative analysis for weight gain, energy consumption, fat distribution, glucose and insulin tolerance, and hepatic/plasma lipid analysis. RESULTS: Mice fed a high-fat diet supplemented with fish oil had improved glucose tolerance after an extended period compared with mice fed a high-fat diet supplemented with lard. Moreover, mice fed a high fat diet supplemented with fish oil had significantly decreased concentrations of liver cholesterol, cholesteryl ester, and triacylglycerol compared with mice fed a high-fat diet supplemented with either lard or olive oil. CONCLUSION: Mice fed a high-fat diet supplemented with fish oil improved metabolic features associated with type 2 diabetes such as impaired glucose tolerance and hepatic steatosis. PMID- 23756283 TI - Use of gastric residual volume to guide enteral nutrition in critically ill patients: a brief systematic review of clinical studies. AB - OBJECTIVE: In critically ill patients, the optimal procedure to monitor upper gastrointestinal function is controversial. Several authors have proposed gastric residual volume (GRV) as a tool to guide enteral nutrition. The aim of this contribution is to briefly discuss corresponding studies. METHODS: We electronically searched MEDLINE, EMBASE, and CINAHL for studies relevant to the subject. RESULTS: Six randomized controlled trials (RCTs) and six prospective observational studies were identified. Each analyzed different thresholds of GRV to guide enteral nutrition and to avoid complications (e.g., vomiting, aspiration, nosocomial pneumonia) in artificially ventilated patients. Due to heterogeneity in outcome measures, patient populations, type and diameter of feeding tubes, and randomization procedures, combination of the results of the six RCTs into a meta-analysis was not appropriate. High-quality RCTs studying medical patients could not demonstrate an association between complication rate and the magnitude of GRV. The only observational study that adjusted results to potential confounders and that studied surgical patients found, however, that the frequency of aspiration increased significantly if a GRV > 200 mL was registered more than once. CONCLUSION: For mechanically ventilated patients with a medical diagnosis at admission to the intensive care unit, monitoring of GRV appears unnecessary to guide nutrition. Surgical patients might profit, however, from a low GRV threshold (200 mL). PMID- 23756284 TI - Behavioural addictions as a way to classify behaviours. PMID- 23756285 TI - Phenomenology and treatment of behavioural addictions. AB - Behavioural addictions are characterized by an inability to resist an urge or drive resulting in actions that are harmful to oneself or others. Behavioural addictions share characteristics with substance and alcohol abuse, and in areas such as natural history, phenomenology, and adverse consequences. Behavioural addictions include pathological gambling, kleptomania, pyromania, compulsive buying, compulsive sexual behaviour, Internet addiction, and binge eating disorder. Few studies have examined the efficacy of pharmacological and psychological treatment for the various behavioural addictions, and therefore, currently, no treatment recommendations can be made. PMID- 23756287 TI - Sex differences in suicides among children and youth: the potential impact of help-seeking behaviour. AB - OBJECTIVE: To describe sex differences in health service use among children and youth who died by suicide. METHOD: This is a retrospective study of children and youth (aged 10 to 25 years) living in Ontario who died by suicide between April 1, 2003, and December 31, 2007. Coroner records were individually linked to outpatient physician visit, emergency department (ED) presentation, and inpatient stay administrative health care records for 724 people (192 girls and 532 boys). Only 77 (10.6%) were aged 10 to 15 years. The health services types used, number of contacts made, and the last contact were compared in boys and girls. RESULTS: About 80% of subjects had contact with the health care system in the year before their death, typically to an outpatient physician and (or) the ED. However, not all were seen for mental health reasons. Girls had more outpatient physician and ED contact than boys and closer in time to their death. Further, girls were more likely than boys to have contact in more than one setting. Still, boys and girls did not differ in their use of an outpatient psychiatrist, some ED presentations, and in the nature and number of inpatient stays. CONCLUSIONS: While most people were seen by an outpatient physician and (or) in the ED in the year before their death, not all received mental health care. Further research is needed to determine whether boys and girls who died by suicide differ from their peers in their health service use to guide preventive interventions. PMID- 23756288 TI - Effects of age and subtype on emotional recognition in children with anxiety disorders: implications for cognitive-behavioural therapy. AB - OBJECTIVE: It remains unclear whether an anxiety diagnosis is associated with children's emotional recognition. We considered children's age and types of primary anxiety diagnosis, which have been neglected, to elucidate this relationship. METHODS: Sixty-three referred children with anxiety disorder(s) and 59 volunteer children without anxiety disorder(s), aged between 6 and 11 years, were presented with animated characters, displaying a range of simple and complex emotions, for identification. Statistical analyses examined identification accuracy based on presence or absence of anxiety disorder, age, and types of primary diagnoses. RESULTS: Children with anxiety disorder(s) as a group performed comparably to children without anxiety disorder(s) in identifying emotions (z = -0.72, P = 0.47). In both groups, accuracy for disgust increased significantly each year of age ([anxiety group] OR 2.6; 95% CI 1.6 to 4.3, P < 0.001, [control group] OR 2.1; 95% CI 1.3 to 3.3, P = 0.002). When primary anxiety types were considered, while controlling for age, children with separation anxiety disorder (SAD) showed deficits in overall emotional recognition, compared with children with other subtypes or without anxiety (P = 0.004). Further regression analyses showed that children with generalized anxiety disorder (GAD) presented significantly lower accuracy than children without anxiety disorder(s) at a young age, but the deficit disappeared with increased age. CONCLUSION: Children with anxiety disorder(s) as a group may not appear to be impaired in emotional recognition. However, when age and subtypes are considered, children with SAD and young children with GAD appear to have difficulty, compared with children without anxiety disorder(s). PMID- 23756286 TI - A targeted review of the neurobiology and genetics of behavioural addictions: an emerging area of research. AB - This review summarizes neurobiological and genetic findings in behavioural addictions, draws parallels with findings pertaining to substance use disorders, and offers suggestions for future research. Articles concerning brain function, neurotransmitter activity, and family history and (or) genetic findings for behavioural addictions involving gambling, Internet use, video game playing, shopping, kleptomania, and sexual activity were reviewed. Behavioural addictions involve dysfunction in several brain regions, particularly the frontal cortex and striatum. Findings from imaging studies incorporating cognitive tasks have arguably been more consistent than cue-induction studies. Early results suggest white and grey matter differences. Neurochemical findings suggest roles for dopaminergic and serotonergic systems, but results from clinical trials seem more equivocal. While limited, family history and genetic data support heritability for pathological gambling and that people with behavioural addictions are more likely to have a close family member with some form of psychopathology. Parallels exist between neurobiological and genetic and family history findings in substance and nonsubstance addictions, suggesting that compulsive engagement in these behaviours may constitute addictions. To date, findings are limited, particularly for shopping, kleptomania, and sexual behaviour. Genetic understandings are at an early stage. Future research directions are offered. PMID- 23756289 TI - Longitudinal associations of importance of religion and frequency of service attendance with depression risk among adolescents in Nova Scotia. AB - OBJECTIVE: To examine the directionality of associations between self-reported religious importance or worship attendance and depression among adolescents, and to determine whether social supports or general self-efficacy are mechanisms of observed associations. METHOD: A cohort (n = 976) of Canadian high school students were surveyed in Grade 10 (2000 to 2001) and 2 years later (2002 to 2003). Logistic regression was conducted separately among adolescents with and without elevated depressive symptoms to examine associations between baseline religious attendance and religious importance with later depression, adjusting for confounding factors. Effects of reverse causation were also assessed, determining associations between baseline depression and follow-up religious attendance and importance. RESULTS: Girls who were not depressed at baseline and who attended religious services had lower odds of later depression (adjusted odds ratio [AOR] 0.46; 95% CI 0.22 to 0.95, P < 0.05), which was accounted for by general self-efficacy. Boys who were depressed at baseline who attended religious services had lower odds of still being depressed at follow-up (AOR 0.23; 95% CI 0.06 to 0.80, P < 0.01). Depression at baseline predicted lower attendance at follow-up among boys (AOR 0.26; 95% CI 0.09 to 0.75, P < 0.01). CONCLUSIONS: Religious attendance independently predicts lower depression at follow- up among girls, and may do so by increasing self-efficacy. Among boys with depression, religious attendance predicts a lower likelihood of still being depressed at follow-up. The relation between religious attendance and depression in boys is bidirectional. PMID- 23756290 TI - [Barriers to treatment access reported by people with anxiety disorders]. AB - OBJECTIVES: Our study examined the barriers to treatment experienced by people with anxiety disorders (ADs) who had not received services for their problems. Recommendations to improve treatment access made by participants are reported. METHOD: A web-based questionnaire on treatment accessibility for anxiety disorders was completed by 610 people living in Quebec reporting an anxiety problem. Chi-square tests were used to compare answers from people who received services (n = 151) with answers from people who had not (n = 434 ). RESULTS: Treatment wait times that were too long (X2 = 29.66, df = 1, P < 0.001 ), difficulties reaching a professional by phone (X2 = 13. 75, df = 1, P < 0.001 ), and geographical distance from service sites (X2 = 4.34, df = 1, P = 0.04) were obstacles that hindered participants who had not received the services they were seeking, more than those who had received services. CONCLUSIONS: Participant reported barriers and recommendations highlight the need to increase access to health care professionals in terms of wait times, to train and inform primary care professionals about screening and treating ADs, and to develop psychotherapeutic services availability in the public health network. PMID- 23756291 TI - Interforaminal implant placement in oral cancer patients: during ablative surgery or delayed? A 5-year retrospective study. PMID- 23756292 TI - Children with psychogenic non-epileptic seizures (PNES): a detailed semiologic analysis and modified new classification. AB - PURPOSE: To analyze children with psychogenic non epileptic seizures and propose a modified new classification. METHODS: This retrospective analysis included 56 children aged <18 years (M:F=26:30; mean age: 12.3+/-4.0 years) diagnosed PNES on video-EEG monitoring. The semiological characteristics like pattern of bodily movements, emotional signs, stereotypy, ictal vocalization, responsiveness, delay in diagnosis etc. were recorded. We analyzed our data as per previous adult classifications and proposed a modified classification. RESULTS: There were 190 recorded attacks (range: 1-9, median: 3) recorded. The age at onset of PNES was 8.9+/-4.1 years (range: 0.4-15.8 years; median: 9 years), age at diagnosis: 11.9+/-4.1 years (range: 2-17; median: 12.0 years), delay in diagnosis: 3.2+/-3.7 years (range: 0-15; median: 2.0 years). Anxiety disorder was seen in 9 (16.1%), stress in 6 (10.7%) children. Flexion/extension bodily movements were seen in 40 (70.1%), negative emotional signs in 17 (30.4%) and tremors in 14 (25%) cases. Thirty-three (58.9%) patients diagnosed as having true seizures initially and were on anti-epileptic drugs (AEDs), 14 patients (25.0%) initially diagnosed of PNES which remained unchanged after VEEG, nine patients (16.1%) had both PNES and true seizures. Twenty-six (46.4%) of our patients into the existing classifications. We then classified our patients into categories of a modified new classification: Hypermotor: 13 (23.2%), partial motor: 8 (14.3%), affective/emotional behaviour phenomena: 2 (3.6%), dialeptic: 8 (14.3%), 'aura': 3 (5.4%), mixed: 22 (39.3%). CONCLUSION: Incorrect diagnosis of epilepsy leads to unnecessary drug treatment. A detailed analysis of semiology and classification helps in early diagnosis of PNES. A modified systematic classification of PNES is proposed which would help in better standardization of PNES. PMID- 23756293 TI - Outpatient screening of Japanese children with epilepsy for attention deficit/hyperactivity disorder (AD/HD). AB - The significance of the Strengths and Difficulties Questionnaire (SDQ) score for AD/HD (attention-deficit/hyperactivity disorder) screening was assessed in Japanese epileptic children. SUBJECTS AND METHODS: Sixty-eight epileptic children were enrolled in this study. Parents were asked to fill out both the SDQ and AD/HD-rating scale (AD/HD-RS) simultaneously. RESULTS: The SDQ subscale of hyperactivity showed the highest score. The AD/HD-RS showed higher scores for both inattention and hyperactivity-impulsivity. Twenty-two (32.4%) of these subjects were diagnosed as having AD/HD. The SDQ subscale for hyperactivity showed 86.4% sensitivity and 95% specificity, respectively, for detection of AD/HD. All SDQ subscales correlated significantly with inattention and hyperactivity-impulsivity scores of the AD/HD-RS. CONCLUSIONS: The SDQ is a good screening tool which can contribute to the detection of AD/HD, not only of the hyperactive/impulsive but also the inattentive subtype. Furthermore, the SDQ can elucidate more complicated behavioral problems than the core symptoms of AD/HD that are not noticed in the epilepsy clinic. PMID- 23756294 TI - Utilization of a benchmarking database to inform NICHE implementation. AB - An integral part of NICHE (Nurses Improving Care for Healthsystem Elders) is a benchmarking service that provides member sites with the ability to evaluate staff perceptions of the care environment compared with other NICHE sites. The NICHE Database includes more than 100,000 surveys (Geriatric Institutional Assessment Profile). This study aimed to explain how secondary analyses of this aggregate database can inform effective geriatric programming in hospitals. We found that nurse age and experience influence nurse perceptions of organizational alignment to NICHE guiding principles and that those perceptions improve following NICHE implementation. The NICHE Database addresses knowledge generation in key areas of geriatric nursing practice and assists hospitals' systemic capacity to effectively embed NICHE Guiding Principles: evidence-based geriatric knowledge, patient-family centered care, healthy and productive practice environment, and multidimensional metrics of quality. It contributes to the growing field of implementation science that seeks to promote the uptake of research findings into clinical practice. PMID- 23756295 TI - Primary cutaneous CD4+ small to medium-size pleomorphic T-cell lymphoma in a 12 year-old girl. AB - Primary cutaneous CD4+ small to medium-size pleomorphic T-cell lymphoma (PCSM TCL) is a rare disease that has been added as a provisional entity to the World Health Organization European Organization for Research and Treatment of Cancer (WHO-EORTC) classification of lymphomas with primary cutaneous manifestations. Patients commonly present with a solitary nodule or plaque on the head or upper trunk, but are usually otherwise in good health. The prognosis is favorable, but the optimal treatment has not been defined. Recent publications have described the expression of programmed death-1 in PCSM-TCL and T-cell pseudolymphoma, suggesting a diagnostic value of this marker in the differential diagnosis of PCSM-TCL in contrast to other types of cutaneous T-cell lymphoma. We present the case of a 12-year-old girl with a tumor of the right supraorbital area. She was treated as an outpatient four times with intralesional triamcinolone acetonide at intervals of 3 to 4 weeks. In addition to the case history, this report includes the clinical and histologic findings and a review of the current literature. PMID- 23756296 TI - Visual aids to medical data and computational diagnostics: new frontiers in pediatric neurology. PMID- 23756297 TI - Adapting and evaluating a social cognitive remediation program for schizophrenia in Arabic. AB - Although growing evidence supports the efficacy of social cognitive training interventions for schizophrenia, nearly all studies to date have been conducted in Westernized countries. In the current study, we translated and adapted an existing social cognitive skills training (SCST) program into Arabic and conducted a preliminary efficacy evaluation in schizophrenia outpatients in Egypt. Twenty-two patients were randomized to 16 sessions of group-based SCST and 20 were randomized to a format- and time-matched illness management training control condition. Pre- and post-intervention assessments included a primary social cognition outcome measure that assessed four branches of emotional intelligence and a battery of neurocognitive tests. The SCST group demonstrated significant treatment effects on total emotional intelligence scores (F=24.31, p<.001), as well as the sub-areas of Identifying Emotions (F=11.77, p<.001) and Managing Emotions (F=23.27, p<.001), compared with those in the control condition. There were no treatment benefits for neurocognition for either condition, and both interventions were well-tolerated by patients. These initial results demonstrate the feasibility of implementing social cognitive interventions in different cultural settings with relatively minor modifications. The findings are encouraging regarding further efforts to maximize the benefits of social cognitive interventions internationally. PMID- 23756298 TI - The evidence for illness progression after relapse in schizophrenia. AB - It has long been suspected that relapse in schizophrenia is associated with disease progression in so far as time to response is longer, negative and other symptoms persist, some patients become treatment refractory and neuroprogression in terms of structural brain changes may occur. This article examines the evidence for illness progression after relapse in patients with schizophrenia. It reports on indirect evidence obtained from retrospective, naturalistic and brain imaging studies, as well as a few prospective studies examining pre- and post relapse treatment response. Findings suggest that the treatment response after relapse is variable, with many patients responding rapidly, others exhibiting protracted impairment of response and a subgroup displaying emergent refractoriness. This subgroup comprises about 1 in 6 patients, irrespective of whether it is the first or a subsequent relapse, and even when the delay between onset of first symptoms of relapse and initiation of treatment is brief. While there is a lack of well-designed studies investigating the post-relapse treatment outcome, available evidence gives sufficient cause for concern that, in addition to the considerable psychosocial risks, an additional risk of biological harm may be associated with relapse. PMID- 23756299 TI - Oxygen and wound care: a review of current therapeutic modalities and future direction. AB - While the importance of oxygen to the wound healing process is well accepted, research and technological advances continue in this field and efforts are ongoing to further utilize oxygen as a therapeutic modality. In this paper, the authors briefly review the role of oxygen in wound healing and discuss the distinct mechanism of action as well as the advantages and disadvantages of the three major oxygen-based therapies currently in clinical use (Hyperbaric Oxygen and Topical Oxygen and Continuous Diffusion of Oxygen), as well as review the existing literature regarding these distinct therapeutic modalities. PMID- 23756300 TI - Oral health status of children with craniofacial anomalies. AB - As a key component of the craniofacial team in caring for children with craniofacial anomalies, pediatric dentists play a vital role in the treatment and prevention of dental disease. The purpose of this paper was to review the current literature on the oral health status of individuals with craniofacial anomalies, concentrating on children with cleft lip and/or palate (CLP). CLP children are at high risk for developing caries and periodontal disease, have poor oral hygiene, and often have unmet dental needs. Recommendations for pediatric dentists caring for children with craniofacial anomalies include providing parent education, dietary counseling, oral hygiene instructions for the parent and child and implementing other preventive measures. PMID- 23756301 TI - Comparison of mineral trioxide aggregate and diluted formocresol in pulpotomized human primary molars: 42-month follow-up and survival analysis. AB - PURPOSE: The purpose of this study was to test the hypothesis that there is no significant difference in the clinical and radiographic outcomes of diluted formocresol (DFC) compared to gray mineral trioxide aggregate (GMTA) pulpotomy in human primary molars. METHODS: A total of 152 children with 252 primary molars met selection criteria. Of those, 119 and 133 teeth were randomly assigned to the GMTA and DFC groups, respectively. Periapical radiographs, taken pre- and/or postoperatively and at each 6-month follow-up, were digitized and evaluated by three blinded and calibrated examiners. RESULTS: Over a 42-month period, a total of 865 clinical and radiographic evaluations were conducted. There was no significant difference in clinical success, with the cumulative proportion of GMTA-treated teeth surviving at 0.98 vs DFC-treated teeth at 0.95 (P>.05). Radiographic success, however, was significantly greater for GMTA vs DFC, with the cumulative proportion of GMTA-treated teeth surviving at 0.90 vs DFC-treated teeth at 0.47 (P<.001). Overall, DFC-treated teeth were 5.1 times more likely to fail than GMTA-treated teeth. Radiographic pathologies were observed more frequently in the DFC-treated teeth (P<.05). CONCLUSION: Gray mineral trioxide aggregate can be considered an acceptable replacement for diluted formocresol when used as a medicament for primary molar pulpotomies. PMID- 23756302 TI - Isolite vs cotton roll isolation in the placement of dental sealants. AB - PURPOSE: The purpose of this split-mouth, randomized, controlled trial was to evaluate the retention rates of sealants placed under Isolite vs cotton roll isolation. METHODS: A convenience sample of 29 patients, with a mean age of 9.8 years and a total of 96 teeth, was included in this study. Matched contralateral pairs of first and second molars were randomized to receive sealants with Isolite or cotton roll isolation. All sealants were performed by one standardized operator. Sealants were placed on first and second permanent molars that had a matched contralateral molar requiring a sealant as well. Photographs were taken of the sealants on the day of placement, and at 6-month and 12-month recalls. Photographs were viewed, and retention of the sealants was evaluated and scored by three calibrated pediatric dentists. The scores were analyzed via Mann-Whitney U and chi-square tests. RESULTS: There were no significant differences in the retention rates between sealants placed using Isolite isolation compared with cotton roll isolation. CONCLUSION: Isolite and cotton roll isolation both appear to be equally effective in creating a favorable environment for sealant placement by a single operator. PMID- 23756303 TI - Factors affecting age at first dental exam for Medicaid-enrolled children seen at Federally Qualified Health Centers. AB - PURPOSE: The purpose of this study was to estimate age at first dental visit (FDV) and identify variables predicting earlier visits for Medicaid-enrolled children at Iowa Federally Qualified Health Centers (FQHC). METHODS: Statewide Medicaid claims data were used to draw a random sample of children who received their FDV prior to six years old at a FQHC, were Medicaid-enrolled within the first two months of life, and remained continuously enrolled over the study period. Forty children from each of five FQHCs had their dental charts abstracted and merged with other Medicaid records and birth certificate data. The logarithmic age at FDV was regressed against several predictor variables. RESULTS: Mean and median ages for FDV were 25.6 and 23 months old, respectively. When controlling for other variables, there were differences in FDV age according to: mother's marital status (P=.04); whether the child had any medical well-child visits (MCVs) at a FQHC prior to the FDV (P<.001); and which FQHC the child visited. Only approximately 28 percent of these children, however, had any MCV at the FQHC. CONCLUSIONS: Medicaid-enrolled children who visited Federally Qualified Health Centers for their first dental visit were seen at an earlier age than previously recorded for such health centers (mean=four years old). Children who also received any medical well-child visits at FQHCs were more likely to have earlier FDVs. PMID- 23756304 TI - Evaluation of primary carious dentin after cavity sealing in deep lesions: a 10- to 13-month follow-up. AB - PURPOSE: This study's purpose was to describe the primary dentin reactions following restoration without complete removal of infected dentin. METHODS: Fragments of carious dentin from 43 teeth with acute deep lesions were removed at baseline and compared to samples of carious dentin removed 60 days later, using scanning electron microscopy (SEM) photographs. At the follow-up periods (60 days; 10-13 months), restorations were evaluated using US Public Health Service criteria and standardized radiographs. A postprocessing routine of radiographs was used to identify changes in radiographic density between periods. RESULTS: At baseline, SEM photographs showed disorganized tissue and bacterial invasion. After 60 days, the dentin exhibited a better organization and signs of remineralization. Differences in restoration characteristics were detected for cavosurface discoloration (P=.008), wear (P<.001), and surface texture (P<.001) after 10 to 13 months. Digital subtraction radiographs showed that mean gray levels of carious and sound dentin increased after 10 to 13 months (P<.001). Differences in mean gray levels were detected between carious and sound dentin only for the 60-day images (P=.03). CONCLUSIONS: Removal of infected dentin wasn't fundamental for caries arrestment. Carious dentin tended to reorganize in a short period when properly sealed, and the remineralization process continued for longer periods. Correct diagnosis of pulp vitality seems fundamental for the success of this protocol. PMID- 23756305 TI - A message from your president. By your pupils you'll be taught. PMID- 23756306 TI - Oral care and sensory over-responsivity in children with autism spectrum disorders. AB - PURPOSE: The purpose of this study was to investigate the relationship between sensory sensitivities and oral care difficulties in children with autism spectrum disorders (ASDs) or typical development (TD). METHODS: Participants included 396 parents of 2- to 18-year-old children with ASDs or TD who completed a questionnaire about oral care in the home and dental office. Descriptive and bivariate analyses were conducted to examine the association between sensory sensitivities and oral care variables. RESULTS: Both hypotheses were supported: (1) ASDs children vs. TD children were reported to have a significantly greater prevalence of sensory over-responsivity across all sensory domains; and (2) ASDs children characterized as "sensory over-responders" exhibited a significantly greater prevalence of oral care difficulty in the home and dental office vs. ASDs children who responded more typically to sensory stimuli ("sensory not over responders"). CONCLUSIONS: This study provides further evidence for the impact of sensory processing problems on oral care, both in the home and dental office. Methods to best serve children with autism spectrum disorders may include strategies that alter the sensory characteristics of the dental environment as well as interventions to reduce children's sensory sensitivities. PMID- 23756307 TI - Comparison of different obturation techniques for primary molars by digital radiography. AB - PURPOSE: The purpose of this study was to compare six methods of root canal filling in primary mandibular second molars via digital radiography. METHODS: A total of 239 canals were prepared and obturated with zinc-oxide eugenol paste. Obturation methods compared were: anesthetic syringe; NaviTip syringe; pressure syringe; tuberculin syringe; lentulo spiral; and packing with a plugger. The canals were evaluated in photostimulated phosphor radiographs for length of obturation, presence of voids, and number and sum of void sizes. The data were analyzed using chi-square, Kruskal-Wallis and Mann-Whitney tests. RESULTS: There were significant differences between all groups in the length of obturation (P>.01) and presence of voids (P<.001). The lentulo and tuberculin syringe groups, respectively, showed the best and worst results for length of obturation. Significant differences were also found in the number of voids (P<.001) and mean sum of void sizes in the coronal (P<.001) and middle third (P=.003). For the number and size of the voids, the NaviTip group showed the best results. CONCLUSION: Lentulo produced the best results in terms of length of obturation, while NaviTip syringe produced the best results in controlling paste extrusion from the apical foramen and having the smallest void size and lowest number of voids. PMID- 23756308 TI - An effective psychoeducational intervention for early childhood caries prevention: part I. AB - PURPOSE: The purpose was to compare whether mothers exposed to an autonomy supportive psychoeducational videotaped message, informed by the self determination theory (SDT), demonstrated greater changes in oral health knowledge and behavioral intentions as a preventive means for early childhood caries (ECC) than mothers exposed to a neutral message delivered by brochure. METHODS: Data were collected at baseline, one-, and six-month follow-ups from 415 12- to 49 month-old WIC-enrolled children and their mothers: 283 in the video intervention group and 132 in the brochure control group. Mothers completed questionnaires on maternal knowledge and behavioral intentions for oral health care. Chi-square, Wilcoxon rank-sum, and Mann-Whitney tests were used to analyze data (P<.05). RESULTS: Relative to their baseline scores, the intervention group showed a greater increase in knowledge than the control group, both at one-month (P=.002) and six-month follow-ups (P<.001). The video group also demonstrated a greater increase in behavioral intentions than controls, both at one-month (P<.05) and six-month follow-ups (P<.001). Knowledge and behavioral intention levels at six month follow-up did not differ significantly from those at one-month follow-up, indicating that intervention-based increases in these measures were maintained over time. CONCLUSIONS: Data provided evidence of the effectiveness of the autonomy-supportive psychoeducational intervention for ECC prevention relative to a neutral brochure. PMID- 23756309 TI - An effective psychoeducational intervention for early childhood caries prevention: part II. AB - PURPOSE: The purpose was to compare whether mothers exposed to an autonomy supportive psychoeducational videotaped message, informed by self-determination theory (SDT), demonstrated greater changes in behavior concerning their children's oral health than mothers exposed to a neutral message delivered by brochure. METHODS: Data were collected at baseline, one- and six-month follow-ups from 415 12- to 49-month-old WIC-enrolled children and their mothers: 283 in the video intervention group and 132 in the brochure control group. Mothers completed questionnaires regarding their child's dietary/oral hygiene habits. Chi-square, Wilcoxon Signed Rank, Mann-Whitney, and McNemar tests were used to analyze data (P<0.05). RESULTS: Significantly more positive changes were observed for dietary/oral hygiene behaviors among the intervention group mothers at one- and six-month follow-ups than for the controls. Significantly fewer mothers in the intervention group shared dining ware with their child at both one- (P=0.0046) and six-month follow-ups (P<0.0001); this practice was decreased only at six months for the control group mothers (P=0.05). Restricting consideration only to mothers who were not checking for white spot lesions at baseline, a significantly greater proportion of mothers in the intervention group performed this behavior at six-months (P=0.0044). CONCLUSIONS: Data provided evidence of the effectiveness of the SDT videotaped oral health message relative to a neutral brochure. PMID- 23756310 TI - Dental anxiety among Israeli children and adolescents in a dental clinic waiting room. AB - PURPOSE: The purpose of this study was to evaluate dental anxiety among children and adolescents using self-reported questionnaires. METHODS: One hundred thirty 7 to 18-year-old patients (mean age=11.37 +/- 2.84) who attended a clinic were asked to complete the Dental Anxiety Scale (DAS) and the Dental Fear Survey (DFS) in the waiting room. RESULTS: Females demonstrated higher dental anxiety than males. Higher anxiety was observed among patients who had their last dental visit over a year prior to the current visit and among patients who expected operative procedures. Extraction was the most anxiety-producing item. While in the dental chair, teeth cleaning produced significantly more anxiety than restoration. A significant correlation existed between the DAS and the DFS. CONCLUSIONS: Pediatric dentists can expect high dental anxiety among: females; patients who wait long periods between visits; and patients expecting operative procedures. Teeth cleaning should not be considered an absolutely non-anxiety producing procedure for the patient. PMID- 23756311 TI - Prevalence of supernumerary teeth based on panoramic radiographs revisited. AB - PURPOSE: The purposes of this study were to: (1) identify, within the literature, reports on the prevalence of supernumerary teeth that have used panoramic radiographs (PRs) as a diagnostic tool; and (2) reanalyze the prevalence data based on the current sensitivity figures for PRs in identifying supernumerary teeth. METHODS: A comprehensive literature search in three databases identified 16 potential studies, of which seven were included in the final analysis. Based on the recent sensitivity data for PRs in identifying supernumerary teeth, the equation "P=r/q" was derived to reanalyze the prevalence data. Multiple regression analysis and paired t test were employed for the statistical analysis. RESULTS: The prevalence figure ranged from 1.2 percent to three percent, and, subsequent to the application of the adjustment factor, it increased to range from 2.4 percent to six percent. The prevalence figures for males was significantly higher than for females (RR=1.37). Furthermore, due to insufficient studies, statistical analysis was unable to elicit ethnical differences in the prevalence figures. CONCLUSIONS: The prevalence of supernumerary teeth is higher than indicated in the published reports and ranges from 2.4 percent to six percent or possibly even higher. PMID- 23756312 TI - Parents' interpretation of instructions to control the dose of fluoridated toothpaste used with young children. AB - PURPOSE: The purpose of this study was to determine the average amounts of fluoridated toothpaste applied by parents to a child's toothbrush in response to instructions to limit the quantity to a "pea-sized" or "smear" amount. METHODS: Fifty parents of 12- to 71-month-old children participated in this study. They were presented with three toothbrushes and asked to apply the amount of toothpaste they use typically with their child-a smear or a pea-sized quantity. The results were compared to the recommended weights of 0.25 g (pea-sized) and 0.125 g (smear). RESULTS: The mean amount applied in response to a "smear" weighed 0.21 +/- 0.19 g, which differed from the recommended weight of 0.125 g (P=.002). The mean amount applied in response to a "pea" weighed 0.30 +/- 0.21 g, which was greater than but not statistically significantly different from the recommended weight of 0.25 g (P=.10). Parents applied, on average, 0.33 +/- 0.24 g of toothpaste when instructed to apply the amount they typically use with their child. CONCLUSIONS: Most parents use more fluoridated toothpaste than is recommended for young children and verbal instructions to limit the dose are ineffective. Education by demonstrating a smear and pea-sized amounts of fluoridated toothpaste is recommended. PMID- 23756313 TI - Infant feeding practices and risk of dental caries in Japan: the Osaka Maternal And Child Health Study. AB - PURPOSE: The purpose of this study was to prospectively investigate the association between infant feeding practices and the development of early childhood caries (ECC). METHODS: Subjects were 315 children. Information about the variables under study and potential confounding factors were obtained by questionnaire during pregnancy and when the children were two to nine, 16 to 24, 29 to 39, and 41 to 49 months old. Outcome data were collected at 41 to 50 months old. Children were classified as having ECC if one or more primary teeth had decayed or been filled. RESULTS: Compared with breast-feeding for six months or fewer, breast-feeding for 18 months or longer tended to be positively associated with a risk of ECC, and a U-shaped relationship was observed. Use of a bottle to drink sweetened liquids other than milk and the introduction of solid foods at six months old or later were positively associated with a risk of ECC. There was no significant association between bottle-feeding while falling asleep at night and the risk of ECC. CONCLUSION: Prolonged breast-feeding, bottle use for sweetened liquids other than milk, and the introduction of solid foods at six months old or later might be risk factors for the development of dental caries. PMID- 23756314 TI - Prevalence of vision problems in a hospital-based pediatric population with malocclusion. AB - PURPOSE: The purpose of this study was to evaluate the prevalence of vision defects (myopia, astigmatism, strabismus, and hyperopia) in Class I, Class II, and Class III malocclusions. METHODS: A total of 1,326 patients were screened to assess the prevalence of vision defects and malocclusion. All the patients classified as Class I, Class II, and Class III malocclusions were submitted to an ophthalmologic visit for the evaluation of vision problems. The occurrence rates of vision defects were calculated as percentages of the total sample. Differences in incidence rates of each vision defect by sex were analyzed by chi-square test. RESULTS: Myopia was the most common (22 percent), followed by astigmatism (~20 percent), hyperopia (~12 percent), and strabismus (~4 percent). The prevalence of myopia was higher in Class II malocclusions, while the prevalence of astigmatism and hyperopia was higher in Class I malocclusion. No significant difference in vision defects by sex was found. CONCLUSIONS: No significant difference in vision defects by sex was found. The prevalence of astigmatism and hyperopia was higher in patients with Class I malocclusion. The prevalence of myopia was higher in patients with Class II malocclusion. PMID- 23756315 TI - Effect of 1.23% acidulated phosphate fluoride foam on white spot lesions in orthodontic patients: a randomized trial. AB - PURPOSE: The decalcification of enamel is a serious clinical problem in orthodontic patients and is usually observed as white spot lesions surrounding brackets. This study's purpose was to evaluate the effect of professionally applied 1.23 percent fluoride foam on reducing the formation of white spot lesions (WSLs) in patients with fixed orthodontic appliances. METHODS: In a randomized, double-blind, placebo-controlled trial, 100 participants were randomly divided into two groups. The two groups received fluoride foam and placebo foam, respectively, every two months during the treatment. The examinations before bonding and after debonding were performed by one examiner and included the presence and severity of WSLs on incisors, canines, and premolars. RESULTS: The incidence of WSLs was approximately 13 percent in the fluoride foam group and 51 percent in the placebo group (P<.001). The mean increment of WSLs score was significantly lower in the fluoride foam group (0.71 +/- 2.80) than in the placebo group (4.36 +/- 5.41; P<.001). The preventive fraction was approximately 76 percent, and the number needed to treat was calculated as 2.6. CONCLUSIONS: Professional application of 1.23 percent fluoride foam during orthodontic treatment effectively reduced the development of white spot lesions. A prophylactic regimen based on the routine use of fluoride foam during orthodontic treatment is recommended. PMID- 23756316 TI - Prevalence and evaluation of environmental risk factors associated with cleft lip and palate in a central Indian population. AB - PURPOSE: Cleft lip and palate, the most common developmental deformity seen worldwide, may be either genetic or environmental in origin. Recent research clearly shows the inter-relationship between environmental risk factors and development of oral clefts. The purpose of this study was to determine the prevalence of cleft lip and palate in the Nagpur region of India and to evaluate environmental risk factors associated with the occurrence of this orofacial abnormality. METHODS: The parents of infants born with or without cleft lip and palate were subjected to questionnaires that elicited sociodemographic profiles and histories of maternal dietary, medical, and environmental risk factors as well family histories of cleft. A multifactorial comparison of environmental risk factors associated with this deformity was performed. RESULTS: The prevalence of cleft lip and palate and cleft palate was found to be 0.66% and 0.27%, respectively, in the Nagpur region. The results demonstrated a positive association between cleft lip and palate and the environmental risk factors of nutritional deficiency, anemia, and self-administered medications. CONCLUSION: Several environmental risk factors appear to play an important role in the development of cleft lip and palate in a Central Indian population of low socioeconomic status. PMID- 23756317 TI - An unusual association of extraoral sinus tract with unerupted permanent tooth. AB - Cases have been reported in the literature in which extraoral sinus tracts of dental origin have been diagnosed and successfully treated. Similarly, the presence of an intracoronal radiolucency in unerupted permanent teeth has been found in the dental literature. The association of one with the other, however, is a rare occurrence. The purpose of this case report was to describe the treatment of a 7-year-old child who presented with an extraoral draining sinus originating from a carious, developing tooth bud of the unerupted permanent mandibular left second molar. After a thorough clinical and radiographic examination, a conclusive diagnosis was determined and surgical treatment was performed. The patient responded well, and the cutaneous lesion healed uneventfully. PMID- 23756318 TI - Target-molecule-triggered rupture of aptamer-encapsulated polyelectrolyte microcapsules. AB - Polyelectrolyte microcapsules have great potential for serving as carriers for the delivery of their contents when triggered by an external stimulus. Aptamers are synthetic ssDNA or RNA that can bind to specific targets with high affinity and selectivity. Aptamers may retain these superior molecular recognition properties after encapsulation within polymer microcapsules. In this work, stable polyelectrolyte microcapsules with encapsulated aptamers were obtained by the layer-by-layer (LbL) method. Polyelectrolyte films were deposited onto a CaCO3 template that had been predoped with polystyrene sulfonate (PSS) and aptamer sequences (SA) that have an affinity for the dye sulforhodamine B (SRB). The PSS and aptamers are thought to serve as an internal scaffold supporting the microcapsule walls. These microcapsules would present target-molecule-triggered rupture properties. Microcapsule collapse was triggered by the binding of SRB to the encapsulated aptamer. The specificity of microcapsule collapse was investigated using a similar dye, tetramethylrosamine (TMR), which does not have affinity for SA. A high concentration of TMR did not lead to the collapse of the microcapsules. The effect of target binding on the microcapsules was confirmed by scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). These microcapsules may have potential applications in targeted delivery systems for the controlled release of drugs, pesticides, or other payloads. PMID- 23756319 TI - Linear morphea and leg length discrepancy: treatment with a leg-lengthening procedure. AB - A 15-year-old Colombian boy with a 10-year history of linear morphea presented to a pediatric orthopedic clinic with a leg length discrepancy. The morphea had been previously treated with methotrexate, oral and topical steroids, and topical vitamin D, but the lesion persisted, extending down the entire medial aspect of the left leg across the popliteal fossa. The patient had atrophy and growth retardation of the left leg, resulting in lower extremity bone and joint pain and a 3-cm limb length disparity at maturity. The patient preferred left tibial lengthening to improve the limb length disparity. PMID- 23756320 TI - The effect of acute exercise on pistol shooting performance of police officers. AB - Previous studies indicate that rifle shooting performance while standing is compromised when fatigued. Apprehension of suspects by police officers may involve foot pursuit and firing a weapon from a standing position. The purpose of the current study was to investigate pistol shooting performance in police officers under similar conditions of physical fatigue. Participants (mean age: 30.1 years; 4.4 years of experience as police officer) completed two shooting trials separated by an acute bout of exercise on a cycle ergometer to voluntary exhaustion. Each trial consisted of three rounds of five rapid-fire shots at a target, each round separated by a 15-s rest. Participants' backs were turned to the target between rounds. Despite physical exertion, with an average heart rate of 164 bpm, shooting accuracy (mean distance of the closest 4 shots from the center of the target) and precision (diameter of the tightest 4-shot grouping) remained unchanged on postexercise trials relative to preexercise trials. This suggests that automatic shooting reactions override the adverse consequences of fatiguing exercise on shooting performance. PMID- 23756321 TI - Anti-inflammatory and immunomodulatory activities of rifamycin SV. AB - There have been several reports showing convincing evidence for non-bactericidal activities of the rifamycin antibiotics. In particular, the parent compound rifamycin SV has been employed in a limited number of cases to treat rheumatoid arthritis. Moreover, rifamycin SV and its derivative rifaximin have been found to be effective in experimental animal models of gut inflammation. The efficacy of rifamycin SV and rifaximin in these settings has been attributed partially to indirect non-bactericidal activities. To better clarify the mechanisms by which these two antibiotics exert their non-bactericidal effects, their activities were compared in in vitro cellular models of immunomodulation and inflammation. Both antibiotics were found to inhibit cytokine and chemokine synthesis from lipopolysaccharide-activated THP-1 monocytes and macrophages. It was also demonstrated, for the first time, that rifamycin SV exerts anti-inflammatory activities in HT-29 colonic epithelial cells. Moreover, rifamycin SV is also very effective in downregulating secretion of inflammatory cytokines from human CD4 T cells. In general, both antibiotics show similar activities on all four cell types tested. However, rifamycin SV is less cytotoxic than rifaximin when tested in these cells. PMID- 23756322 TI - Evaluating amikacin dosage regimens in intensive care unit patients: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation. AB - The objectives of this study were to conduct a comparative pharmacokinetic/pharmacodynamic (PK/PD) evaluation using Monte Carlo simulation of conventional versus high-dose extended-interval dosage (HDED) regimens of amikacin (AMK) in intensive care unit (ICU) patients for an Acinetobacter baumannii infection model. The simulation was performed in five populations (a control population and four subpopulations of ICU patients). Using a specific AMK PK/PD model and Monte Carlo simulation, the following were generated: simulated AMK steady-state plasma level curves; PK/PD efficacy indexes [time during which the serum drug concentration remains above the minimum inhibitory concentration (MIC) for a dosing period (%T>MIC) and ratio of peak serum concentration to MIC (Cmax/MIC)]; evolution of bacterial growth curves; and adaptive resistance to treatment. A higher probability of bacterial resistance was observed with the HDED regimen compared with the conventional dosage regimen. A statistically significant increase in Cmax/MIC and a statistically significant reduction in %T>MIC with the HDED regimen were obtained. A multiple linear relationship between CFU values at 24h with Cmax/MIC and %T>MIC was obtained. In conclusion, with the infection model tested, the likelihood of resistance to treatment may be higher against pathogens with a high MIC with the HDED regimen, considering that in many ICU patients the %T>MIC may be limited. If a sufficient value of %T>MIC (>=60%) is not reached, even though the Cmax/MIC is high, the therapeutic efficacy of the treatment may not be guaranteed. This study indicates that different AMK dosing strategies could directly influence the efficacy results in ICU patients. PMID- 23756323 TI - Radiographic bone texture analysis is correlated with 3D microarchitecture in the femoral head, and improves the estimation of the femoral neck fracture risk when combined with bone mineral density. AB - PURPOSE: Femoral neck fracture is a major public health problem in elderly persons, representing the main source of osteoporosis-related mortality and morbidity. In this study, we aimed at comparing radiographic texture analysis with three-dimensional (3D) microarchitecture in human femurs, and at evaluating whether bone texture analysis improved the assessment of the femoral neck fracture risk other than that obtainable by bone mineral density (BMD). MATERIALS AND METHODS: Thirteen osteoporotic femoral heads from patients who fractured their femoral neck and twelve non-fractured femoral heads from osteoarthritic patients were studied using respectively (1) a new high-resolution digital X-ray device (BMATM, D3A Medical Systems) allowing for bone texture analysis with fractal parameter Hmean, and (2) a micro-computed tomograph (CT) for 3D microarchitecture. BMD was measured postoperatively by DXA in all patients in the contralateral femur. RESULTS: In these femoral heads, we found that fractal parameter Hmean was correlated with 3D microarchitecture parameters: bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular separation (Tb.Sp) and fractal dimension (FD) respectively (p<0.05). Then, fractal parameter Hmean was significantly lower in the femoral heads from the fractured group than from the non-fractured group (p<0.01). Finally, multiple regression analysis showed that combining bone texture analysis and total hip BMD significantly improved the estimation of the femoral neck fracture risk from adjusted r(2)=0.46 to adjusted r(2)=0.67 (p<0.05). CONCLUSION: Radiographic bone texture analysis was correlated with 3D microarchitecture parameters in the femoral head, provided accurate discrimination between the femoral heads from the fractured and non-fractured groups, and significantly improved the estimation of the femoral neck fracture risk when combined with BMD. PMID- 23756324 TI - Standard versus inverted digital luminescence radiography in detecting pulmonary nodules: a ROC analysis. AB - OBJECTIVE: Observer performance tests were conducted to compare the effect of presenting digital luminescence radiography (DLR) monitor images in positive mode ("bones black") or negative mode ("bones white") in the detectability of subtle lung nodules. METHODS: Five radiologists independently reviewed digital radiographs of 55 patients with either (a) a single, small (6-12 mm), non- calcified peripheral nodule confirmed by chest CT (n=47) or (b) normal finding (n=8) confirmed by chest CT, respectively. Mean size of pulmonary nodules was 8.3mm (range 6-12 mm, median 7 mm). Radiographs were displayed either in standard mode (bones white) or inverse intensity (bones black). A total of 550 observations resulted. For the evaluation ROC analysis was performed using a specialized computer algorithm. RESULTS: The standard presentation mode showed a sensitivity of 61.7% and a specificity of 72.5%, the inverse presentation mode a sensitivity of 68.1% and a specificity of 75.0%. ROC- analysis showed that the difference between the standard mode (Az- value 0.694) and the inverse mode (Az- value 0.810) was significant in favour of the inverse presentation mode (p=0.001). This finding was especially observed in more experienced radiologist (Az- values 0.716 vs. 0.909, P<0.001). CONCLUSION: Our study demonstrates a significant advantage of the inverse mode in the detection of small pulmonary nodules compared with the commonly used negative mode when interpreted by more experienced radiologists. ADVANCE IN KNOWLEDGE: Inverse intensity images ("bones black") may have some advantages in the detection of small pulmonary nodules in experienced readers when presented on a stand-alone display. PMID- 23756325 TI - Prostate cancer: current status, new developments and applications in radiotherapy. PMID- 23756326 TI - How to attain expertise in clinical communication? AB - Several factors complicate the attainment of expertise in clinical communication. Medical curricula and postgraduate training insufficiently provide the required learning conditions of deliberate practice to overcome these obstacles. In this paper we provide recommendations for learning objectives and teaching methods for the attainment of professional expertise in patient education. Firstly, we propose to use functional learning objectives derived from the goals and strategies of clinical communication. Secondly, we recommend using teaching and assessment methods which: (1) contain stimulating learning tasks with opportunities for immediate feedback, reflection and corrections, and (2) give ample opportunity for repetition, gradual refinements and practice in challenging situations. Video-on-the-job fits these requirements and can be used to improve the competency in patient education of residents and medical staff in clinical practice. However, video-on-the-job can only be successful if the working environment supports the teaching and learning of communication and if medical staff which supervises the residents, is motivated to improve their own communication and didactic skills. PMID- 23756327 TI - Association between foot type and lower extremity injuries: systematic literature review with meta-analysis. AB - STUDY DESIGN: Systematic literature review with meta-analysis. OBJECTIVES: To investigate the association between nonneutral foot types (high arch and flatfoot) and lower extremity and low back injuries, and to identify the most appropriate methods to use for foot classification. METHODS: A search of 5 electronic databases (PubMed, Embase, CINAHL, SPORTDiscus, and ProQuest Dissertations and Theses), Google Scholar, and the reference lists of included studies was conducted to identify relevant articles. The review included comparative cross-sectional, case-control, and prospective studies that reported qualitative/quantitative associations between foot types and lower extremity and back injuries. Quality of the selected studies was evaluated, and data synthesis for the level of association between foot types and injuries was conducted. A random-effects model was used to pool odds ratio (OR) and standardized mean difference (SMD) results for meta-analysis. RESULTS: Twenty-nine studies were included for meta-analysis. A significant association between nonneutral foot types and lower extremity injuries was determined (OR = 1.23; 95% confidence interval [CI]: 1.11, 1.37; P<.001). Foot posture index (OR = 2.58; 95% CI: 1.33, 5.02; P<.01) and visual/physical examination (OR = 1.17; 95% CI: 1.06, 1.28; P<.01) were 2 assessment methods using distinct foot-type categories that showed a significant association with lower extremity injuries. For foot-assessment methods using a continuous scale, measurements of lateral calcaneal pitch angle (SMD, 1.92; 95% CI: 1.44, 2.39; P<.00001), lateral talocalcaneal angle (SMD, 1.36; 95% CI: 0.93, 1.80; P<.00001), and navicular height (SMD, 0.34; 95% CI: 0.16, 0.52; P<.001) showed significant effect sizes in identifying high-arch foot, whereas the navicular drop test (SMD, 0.45; 95% CI: 0.03, 0.87; P<.05) and relaxed calcaneal stance position (SMD, 0.49; 95% CI: 0.01, 0.97; P<.05) displayed significant effect sizes in identifying flatfoot. Subgroup analyses revealed no significant associations for children with flatfoot, cross-sectional studies, or prospective studies on high arch. CONCLUSIONS: High-arch and flatfoot foot types are associated with lower extremity injuries, but the strength of this relationship is low. Although the foot posture index and visual/physical examination showed significance, they are qualitative measures. Radiographic and navicular height measurements can delineate high-arch foot effectively, with only anthropometric measures accurately classifying flatfoot. LEVEL OF EVIDENCE: Prognosis, level 2a. PMID- 23756328 TI - Acitretin-responsive ichthyosis in Chanarin-Dorfman syndrome with a novel mutation in the ABHD5/CGI-58 gene. AB - Chanarin-Dorfman syndrome (CDS) is a rare nonlysosomal neutral lipid storage disorder characterized by congenital ichthyosis, lipid vacuoles in leukocytes (Jordan's anomaly), and hepatomegaly. The authors herein report an 18-month-old boy with ichthyosis and hepatomegaly diagnosed with CDS and confirmed to have a novel c.506-3C>G mutation in the ABHD5/CGI-58 gene. Our case also illustrates that retinoids such as acitretin could be useful in the treatment of skin manifestations in CDS even in the presence of liver derangement. PMID- 23756329 TI - Assessment of the addition of prehospital continuous positive airway pressure (CPAP) to an urban emergency medical services (EMS) system in persons with severe respiratory distress. AB - BACKGROUND: The use of continuous positive airway pressure (CPAP) assisted ventilation in the emergency department(ED) has been well described. OBJECTIVES: The purpose of this study was to measure the efficacy of adding pre-hospital CPAP to an urban emergency medical service (EMS) respiratory distress protocol on persons with respiratory distress. METHODS: A historical cohort analysis of consecutive patients between 2005 and 2010. Groups were matched for severity of respiratory distress. Physiologic variables were the primary outcome obtained from first responders and upon triage in the ED. Additional outcomes included endotracheal intubation rate, hospital mortality, overall hospital length of stay(LOS), intensive care unit (ICU) admission, and ICU length of stay (ICU LOS). RESULTS: There were 410 consecutive patients with predetermined criteria for severe respiratory distress, 235 historical controls matched with 175 post implementation patients. Average age was 67 years, 54% being male. There were significant median differences in heart and respiratory rates favoring the historical cohort (p < 0.05). There were no significant differences in intubation rate, overall hospital LOS, ICU admission rate, ICU LOS, and hospital mortality (p > 0.05).Patients that were continued on noninvasive ventilatory assistance had a significantly improved rate of intubation and ICU LOS (p < 0.05). CONCLUSIONS: The addition of CPAP to our pre-hospital respiratory distress protocol did not improve physiologic variables.There were no differences in overall and ICU LOS between groups. Persons with apparent continued ventilatory assistance appeared to have improved rates of intubation and ICU LOS [corrected]. PMID- 23756330 TI - Perceived hole size, performance, and body movement during putting in children with and without probable developmental coordination disorder. AB - The purpose of this study was to examine the relationships between perceived hole size (perception), performance, and body movement (action) in golf putting for children with probable developmental coordination disorder (DCD) and typically developing children (TDC). Forty-eight children (24 probable DCD, 24 TDC) performed putting in easy and hard conditions. Body movement was measured during putting, performance was measured as the distance between ball and hole, and perceived hole size was recorded using a Microsoft Paint drawing exercise 1 m away from the hole. The present results revealed that perceived hole size was positively related to putting performance, body movement was negatively associated with putting performance, and that there were negative correlations between body movement and perceived hole size. While children with probable DCD tended to perceive the hole as smaller, perform worse, and show more body movement, TDC exhibited the opposite. These findings help characterize the relationships between perception, performance, and action in children with probable DCD and TDC during golf putting. PMID- 23756331 TI - Compressed sensing for reduction of noise and artefacts in direct PET image reconstruction. AB - AIM: Image reconstruction in positron emission tomography (PET) can be performed using either direct or iterative methods. Direct reconstruction methods need a short reconstruction time. However, for data containing few counts, they often result in poor visual images with high noise and reconstruction artefacts. Iterative reconstruction methods such as ordered subset expectation maximization (OSEM) can lead to overestimation of activity in cold regions distorting quantitative analysis. The present work investigates the possibilities to reduce noise and reconstruction artefacts of direct reconstruction methods using compressed sensing (CS). MATERIALS AND METHODS: Raw data are generated either using Monte Carlo simulations using GATE or are taken from PET measurements with a Siemens Inveon small-animal PET scanner. The fully sampled dataset was reconstructed using filtered backprojection (FBP) and reduced in Fourier space by multiplication with an incoherently undersampled sampling pattern, followed by an additional reconstruction with CS. Different sampling patterns are used and an average of the reconstructions is taken. The images are compared to the results of an OSEM reconstruction and quantified using signal-to-noise ratio (SNR). RESULTS: The application of the proposed CS post-processing technique clearly improves the image contrast. Dependent on the undersampling factor, noise and artefacts are reduced resulting in an SNR that is increased up to 3.4-fold. For short acquisition times with low count statistics the SNR of the CS reconstructed image exceeds the SNR of the OSEM reconstruction. CONCLUSION: Especially for low count data, the proposed CS-based post-processing method applied to FBP reconstructed PET images enhances the image quality significantly. PMID- 23756332 TI - Risk of arrhythmias in 52 755 long-distance cross-country skiers: a cohort study. AB - AIMS: We aimed to investigate the association of number of completed races and finishing time with risk of arrhythmias among participants of Vasaloppet, a 90 km cross-country skiing event. METHODS AND RESULTS: All the participants without cardiovascular disease who completed Vasaloppet during 1989-98 were followed through national registries until December 2005. Primary outcome was hospitalization for any arrhythmia and secondary outcomes were atrial fibrillation/flutter (AF), bradyarrhythmias, other supraventricular tachycardias (SVT), and ventricular tachycardia/ventricular fibrillation/cardiac arrest (VT/VF/CA). Among 52 755 participants, 919 experienced arrhythmia during follow up. Adjusting for age, education, and occupational status, those who completed the highest number of races during the period had higher risk of any arrhythmias [hazard ratio (HR)1.30; 95% CI 1.08-1.58; for >=5 vs. 1 completed race], AF (HR 1.29; 95% CI 1.04-1.61), and bradyarrhythmias (HR 2.10; 95% CI 1.28-3.47). Those who had the fastest relative finishing time also had higher risk of any arrhythmias (HR 1.30; 95% CI 1.04-1.62; for 100-160% vs. >240% of winning time), AF (1.20; 95% CI 0.93-1.55), and bradyarrhythmias (HR 1.85; 95% CI 0.97-3.54). SVT or VT/VF/CA was not associated with finishing time or number of completed races. CONCLUSIONS: Among male participants of a 90 km cross-country skiing event, a faster finishing time and a high number of completed races were associated with higher risk of arrhythmias. This was mainly driven by a higher incidence of AF and bradyarrhythmias. No association with SVT or VT/VF/CA was found. PMID- 23756333 TI - Mast cells in human carotid atherosclerotic plaques are associated with intraplaque microvessel density and the occurrence of future cardiovascular events. AB - AIMS: Human autopsy, animal, and cell culture studies together have merged in a concept suggesting participation of mast cells (MCs) in the generation of atherosclerotic plaques. More specifically, these studies have suggested MC induced intraplaque neovascularization as one mechanism by which MCs may render the plaques vulnerable. The present study was designed to assess the association between MC numbers and neovascularization in human atherosclerotic plaques, and to relate the abundance of plaque MCs to the occurrence of adverse cardiovascular events during the follow-up. METHODS AND RESULTS: Atherosclerotic plaques of 270 patients suffering from carotid artery stenosis were stained for the presence of MCs (MC tryptase). Furthermore, during a follow-up of 3 years, cardiovascular related endpoints were assessed in 253 patients. On average a high number of MCs were observed per plaque cross-section [median 108 (55-233) cells per section]. Plaques with high MC numbers revealed an unstable lipid-rich inflammatory phenotype and were associated with symptomatic patients. In addition, MC numbers were positively associated with microvessel density (r = 0.416, P < 0.001). Patients with high intraplaque MC numbers showed significantly more cardiovascular events during the follow-up (58/142 vs. 31/111 events, P = 0.029). In a multivariate analysis with correction for the main risk factors of cardiovascular diseases, MCs remained independently associated with adverse cardiovascular events (P = 0.025). CONCLUSION: Mast cells are highly prevalent in human carotid atherosclerotic lesions and associated with plaque microvessel density. Furthermore, intraplaque MC numbers associate with future cardiovascular events. PMID- 23756334 TI - Sympathetic overactivity due to sleep fragmentation is associated with elevated diurnal systolic blood pressure in healthy elderly subjects: the PROOF-SYNAPSE study. AB - AIMS: Sleep fragmentation is a landmark of sleep disorders, because microarousals are systematically associated with sympathetic surges (i.e., sympathetic arousals). However, the impact of sympathetic sleep fragmentation on blood pressure (BP) remains understudied. We assessed the relationships between 24 h ambulatory BP monitoring, the autonomic arousal index (AAI) derived from pulse transit time, and heart rate variability indices. We hypothesized that repeated sympathetic arousals during sleep are associated with elevated BP in a large population of elderly volunteers. METHODS AND RESULTS: Volunteer subjects (n = 780, 57.4% women) with a mean age of 68.7 years and free of known sleep disordered breathing, coronary heart diseases, and neurological disorders underwent polygraphy, 24 h ECG Holter monitoring, and 24 h ambulatory BP monitoring. Multivariate regressions showed that sleep fragmentation, expressed by AAI, was associated with elevated diurnal (P = 0.008) and 24 h (P = 0.005) systolic BP and higher risk for 24 h [odds ratio (OR): 1.70 (1.04-2.80), P = 0.036] systolic hypertension, independently of confounders such as sleep disordered breathing, body mass index, sex, diabetes, hypercholesterolaemia, and self-reported sleep duration and quality. Increased AAI was associated with higher nocturnal and diurnal low-frequency power (P < 0.001) and low-to-high frequency ratio (P < 0.001), suggesting nocturnal and diurnal sympathetic overactivity. CONCLUSION: In healthy elderly subjects, repetitive sympathetic arousals during sleep are associated with elevated systolic BP and higher risk of hypertension, after controlling for confounders. Sympathetic overactivity is the proposed underlying mechanism. CLINICAL TRIAL REGISTRATION: NCT00766584 and NCT00759304. PMID- 23756335 TI - Endothelial dysfunction in coronary heart disease is more than a systemic process. PMID- 23756337 TI - Current thoughts and developments in facial nerve reanimation. AB - PURPOSE OF REVIEW: To present the most current literature regarding the management of acute and chronic facial paralysis. This review will focus primarily on smile reanimation in the setting of acute and chronic facial paralysis. The management of the flaccid and the hypertonic face will be discussed. RECENT FINDINGS: Recent developments include advances in neural repair with fibrin glue and the use of cadaveric nerve grafts as interposition grafts. Advances in nerve substitutes have been shown to limit donor-site morbidity and provide similar outcomes to autografts. Techniques for muscle transfer continue to evolve to improve smile outcomes. SUMMARY: The goal of facial reanimation surgery is to restore meaningful facial movement. The goal should be to have quality-driven clinical practice guidelines to better facilitate patient care. This process must be initiated by facial reanimation surgeons deciding to use consistent outcome measures to report their results. Currently, it is impossible to make a direct comparison between different surgical techniques because of inconsistent methods of evaluation. Despite the lack of consistent quantitative evaluation, there have been many exciting advances in the field. PMID- 23756336 TI - Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in diabetes and associated with mortality and incident heart failure admission. AB - AIMS: Diabetes may promote myocardial extracellular matrix (ECM) expansion that increases vulnerability. We hypothesized that: (i) type 2 diabetes would be associated with quantitative cardiovascular magnetic resonance (CMR) measures of myocardial ECM expansion, i.e. extracellular volume fraction (ECV); (ii) medications blocking the renin-angiotensin-aldosterone system (RAAS) would be associated with lower ECV; and (iii) ECV in diabetic individuals would be associated with mortality and/or incident hospitalization for heart failure. METHODS AND RESULTS: We enrolled 1176 consecutive patients referred for CMR without amyloidosis and computed ECV from measures of the haematocrit and myocardial and blood T1 pre- and post-contrast. Linear regression modelled ECV; Cox regression modelled mortality and/or hospitalization for heart failure. Diabetic individuals (n = 231) had higher median ECV than those without diabetes (n = 945): 30.2% (IQR: 26.9-32.7) vs. 28.1% (IQR: 25.9-31.0), respectively, P < 0.001). Diabetes remained associated with higher ECV in models adjusting for demographics, comorbidities, and medications (P < 0.001). Renin-angiotensin aldosterone system blockade was associated with lower ECV (P = 0.028) in multivariable linear models. Over a median of 1.3 years (IQR: 0.8-1.9), 38 diabetic individuals had events (21 incident hospitalizations for heart failure; 24 deaths), and ECV was associated with these events (HR: 1.52, 95% CI: 1.21-1.89 per 3% ECV increase) in multivariable Cox regression models. CONCLUSION: Diabetes is associated with increased ECV. Extracellular volume fraction detects amelioration of ECM expansion associated with RAAS blockade, and is associated with mortality and/or incident hospitalization for heart failure in diabetic individuals. Extracellular matrix expansion may be an important intermediate phenotype in diabetic individuals that is detectable and treatable. PMID- 23756338 TI - Treatment strategies and outcomes in patients with infected aortic endografts. AB - OBJECTIVE: Endovascular abdominal (EVAR) and thoracic (TEVAR) endografts allow aneurysm repair in high-risk patients, but infectious complications may be devastating. We reviewed treatment and outcomes in patients with infected aortic endografts. METHODS: Twenty-four patients were treated between January 1997 and July 2012. End points were mortality, morbidity, graft-related complications, or reinfection. RESULTS: Twenty males and four females with median age of 70 years (range, 35-80 years) had 21 infected EVARs and 3 TEVARs. Index repairs performed at our institution included eight EVARs and two TEVARs (10/1300; 0.77%). There were 19 primary endograft infections, 4 graft-enteric fistulae, and 1 aortobronchial fistula. Median time from repair to presentation was 11 months (range, 1-102 months); symptoms were fever in 17, abdominal pain in 11, and psoas abscess in 3. An organism was identified in 19 patients (8 mono- and 11 polymicrobial); most commonly Staphylococcus in 12 and Streptococcus in 6. All but one patient had successful endograft explantation. Abdominal aortic reconstruction was in situ repair in 21 (15 rifampin-soaked, 2 femoral vein, and 4 cryopreserved) and axillobifemoral bypass in three critically ill patients. Infected TEVARs were treated with rifampin-soaked grafts using hypothermic circulatory arrest. Early mortality (30 days or in-hospital) was 4% (n = 1). Morbidity occurred in 16 (67%) patients (10 renal, 5 wound-related, 3 pulmonary, and 1 had a cardiac event). Median hospital stay was 14 days (range, 6-78 days). One patient treated with in situ rifampin-soaked graft had a reinfection with fatal anastomotic blowout on day 44. At 14 months median follow-up (range, 1-82 months), patient survival, graft-related complications, and reinfection rates were 79%, 13%, and 4%, respectively. CONCLUSIONS: Endograft explantation and in situ reconstruction to treat infections can be performed safely. Extra-anatomic bypass may be used in high-risk patients. Resection of all infected aortic wall is recommended to prevent anastomotic breakdown. Despite high early morbidity, the risk of long-term graft-related complications and reinfections is low. PMID- 23756339 TI - A 14-year experience with blunt thoracic aortic injury. AB - OBJECTIVE: This study reviewed the natural history of blunt thoracic aortic trauma (BTAT) over a 14-year period at our level 1 trauma center and compared open vs endovascular treatment. METHODS: All patients with BTAT presenting to a level 1 trauma center from 1998 to 2011 were included in a retrospective analysis. Multiple data points and short-term and midterm outcomes were ascertained through a retrospective record review. RESULTS: We identified 129 patients with BTAT. Of these, 32 (25%) were dead on arrival, 38 (29%) underwent a resuscitative thoracotomy and died, 33 (26%) underwent open repair, 14 (11%) underwent endovascular repair, 9 (7%) underwent simultaneous procedures, and 3 (2%) were managed nonoperatively. Mean Injury Severity Scores and Revised Trauma Scores were similar (P = .484, P = .551) between the open repair group (n = 36) and the endovascular repair group (n = 14). In the open repair group, there were 14 deaths (42%) <= 30 days of injury, 3 strokes (9%), 2 patients (6%) with paralysis, 2 myocardial infarctions (MIs; 6%), and 3 patients (9%) who required hemodialysis. In the endovascular group, there was 1 death (7%) <= 30 days of injury, 1 (7%) stroke, and 1 (7%) stent collapse. No paralysis, MI, or renal failure requiring hemodialysis was noted in the endovascular group. The average length of stay was 15 days for patients treated with endovascular repair vs 24 days for those treated with open repair (P = .003). CONCLUSIONS: The incidence of BTAT is low but the mortality associated with it is significant. During the 14 year period studied, there was a clear change in management preference from open repair to endovascular repair at our level 1 trauma center. Outcomes, including stroke, MI, renal failure, paralysis, length of stay, and death, appear to be reduced in the endovascular group. PMID- 23756340 TI - The H2A/H2B-like histone-fold domain proteins at the crossroad between chromatin and different DNA metabolisms. AB - Core histones are the building block of chromatin and among the most highly conserved proteins in eukaryotes. The related "deviant" histones share the histone-fold domain, and serve various roles in DNA metabolism. We provide here a structural and functional outlook of H2A/H2B-like deviant histones in transcription, replication and remodeling. PMID- 23756341 TI - Mfd as a central partner of transcription coupled repair. AB - Transcription-coupled repair (TCR) is one of the key of the nucleotide excision repair (NER) pathways required to preserve genome integrity. Although understanding TCR is still a major challenge, recent single-molecule experiments have brought new insights into the initial steps of TCR leading to new perspectives. PMID- 23756342 TI - Pause, play, repeat: CDKs push RNAP II's buttons. AB - Cyclin-dependent kinases (CDKs) play a central role in governing eukaryotic cell division. It is becoming clear that the transcription cycle of RNA polymerase II (RNAP II) is also regulated by CDKs; in metazoans, the cell cycle and transcriptional CDK networks even share an upstream activating kinase, which is itself a CDK. From recent chemical-genetic analyses we know that CDKs and their substrates control events both early in transcription (the transition from initiation to elongation) and late (3' end formation and transcription termination). Moreover, mutual dependence on CDK activity might couple the "beginning" and "end" of the cycle, to ensure the fidelity of mRNA maturation and the efficient recycling of RNAP II from sites of termination to the transcription start site (TSS). As is the case for CDKs involved in cell cycle regulation, different transcriptional CDKs act in defined sequence on multiple substrates. These phosphorylations are likely to influence gene expression by several mechanisms, including direct, allosteric effects on the transcription machinery, co-transcriptional recruitment of proteins needed for mRNA-capping, splicing and 3' end maturation, dependent on multisite phosphorylation of the RNAP II C terminal domain (CTD) and, perhaps, direct regulation of RNA-processing or histone-modifying machinery. Here we review these recent advances, and preview the emerging challenges for transcription-cycle research. PMID- 23756343 TI - R-loops in bacterial transcription: their causes and consequences. AB - Nascent untranslated transcripts in bacteria are prone to generating RNA-DNA hybrids (R-loops); Rho-dependent transcription termination acts to reduce their prevalence. Here we discuss the mechanisms of R-loop formation and growth inhibition in bacteria. PMID- 23756344 TI - Are joint injury, sport activity, physical activity, obesity, or occupational activities predictors for osteoarthritis? A systematic review. AB - STUDY DESIGN: Systematic review with meta-analysis. OBJECTIVES: To identify risk factors for osteoarthritis (OA) of the knee, hip, and ankle, including joint injury, sport, physical activity, overweight/obesity, and occupational activity, in all age groups. BACKGROUND: OA is a significant health problem worldwide, affecting up to 10% of men and 18% of women over 60 years of age. There has not been a comprehensive review examining modifiable physical risk factors associated with the onset of OA. This evidence is important to inform the physiotherapy management of individuals following onset of OA. METHODS: Twelve electronic databases were systematically reviewed. The studies selected met the following criteria: (1) original data; (2) joint injury, sport activity, physical activity, overweight/obesity, and/or occupational activity investigated as risk factors; (3) outcomes included OA (hip, knee, and/or ankle); and (4) analytic component of study design. The data extracted included study design, years of follow-up, study population, OA definition, risk factors, and results (effect estimates reported or calculated where available). The quality of evidence was assessed based on a modified version of the Downs and Black checklist. RESULTS: Joint injury, obesity, and occupational activity were associated with an increased risk of OA of the knee and hip. Sport and physical activity produced inconsistent findings. Joint injury was identified as a significant risk factor for knee OA (combined odds ratio = 3.8; 95% confidence interval: 2.0, 7.2) and hip OA (combined odds ratio = 5.0; 95% confidence interval: 1.4, 18.2), as was previous meniscectomy with or without anterior cruciate ligament injury for knee OA (combined odds ratio = 7.4; 95% confidence interval: 4.0, 13.7). There is a paucity of research examining risk factors associated with ankle OA; this review identified only 2 studies with this outcome. CONCLUSION: Joint injury, obesity, and occupational activity are associated with an increased risk of knee and hip OA. Some findings remain inconclusive, including levels of physical activity and sport specificity in individuals who do not suffer an injury. Early identification of individuals at risk for OA provides an opportunity for physiotherapy management or other interventions to modify risk-related behavior. There is a need in the literature for additional high-quality studies, such as prospective cohort studies, that minimize potential bias in examining the relationship between physical risk factors and OA. LEVEL OF EVIDENCE: Prognosis, level 2a-. PMID- 23756345 TI - Reaching behavior in preterm infants during the first year of life: a systematic review. AB - The aim of this systematic literature review was to examine and discuss studies that investigated reaching in preterm infants during the first year of life. Databases were searched using keywords such as reaching, grasping, preterm, and premature, in addition to specific terms from the Medical Subject Headings (MeSH) (motor skills, infant, movement, premature birth, hands) regardless of year of publication. One hundred thirty-five studies were identified, 9 of which were selected. The results showed that preterm infants adopt strategies (bimanual reaches and reaches with less rectilinear trajectories toward an object in motion, reaches with semi-open and open hand, reaches at lower speeds, with increased movement units, and variable postural muscle activity) compared with full-term infants. However, the results on how intrinsic factors (e.g., prematurity) and extrinsic factors (e.g., body position, physical properties of the object) influence early reaching are still limited. PMID- 23756346 TI - Effects of fish oil supplementation on learning and behaviour of children from Australian Indigenous remote community schools: a randomised controlled trial. AB - Omega-3 fatty acids are essential for brain function. We recruited 409 children aged 3-13 years (M=8.27, SD=2.17) for a randomised controlled trial supplementing with placebo or fish oil capsules (providing 750mg docosahexaenoic plus eicosapentaenoic acids, and 60mg gamma linolenic acid/school day) for 20 school weeks (Phase 1) followed by one-way crossover to fish oil (Phase 2). Children undertook assessments of reading, spelling and non-verbal cognitive development (Draw-A-Person) at baseline, 20 and 40 weeks. Teachers completed Conners Behaviour Rating Scales (CBRS). The treatment group showed improvements in Draw-A Person compared with the placebo during Phase 1 (p=0.029), with strongest effects in Indigenous 7-12 year olds (p=0.008). The placebo group showed significant within-group improvements after switching to treatment (p<0.001). There was no treatment effect for reading or spelling, and CBRS data were unable to be analysed. These findings may be understood in the context that sustained school attendance and nutrition interact to produce school-related achievement. PMID- 23756347 TI - Influence of corneal biomechanical properties on surgically induced astigmatism in cataract surgery. AB - PURPOSE: To perform an overall follow-up of the morphologic, optical, and biomechanical properties of the cornea to determine new parameters influencing the refractive outcomes of cataract surgery. DESIGN: Clinical study. METHODS: Patients scheduled for cataract surgery were assessed for surgically induced corneal astigmatism (SIA) and higher-order aberrations, (HOAs) using a Scheimpflug rotating camera (Pentacam) together with corneal imaging by optical coherence tomography (Spectralis) and biomechanical analysis by the Ocular Response Analyzer preoperatively and 1, 7, and 30 days postoperatively. The central and peripheral corneal thicknesses; incision width, length, and architecture; corneal hysteresis (CH); and corneal resistance factor (CRF) were computed to identify new parameters influencing corneal optical changes that determine the final refractive result. RESULTS: The study enrolled 40 patients (40 eyes). The SIA and HOAs were significantly lower after microincision surgery (<= 2.2 mm) than after small-incision surgery (2.75 mm) (both P<.01). The CRF was significantly reduced with a direct corneal incision compared with a constructed incision (P<.01). Multivariate analysis showed that SIA was correlated not only with incision width (P<.05) but also with preoperative CH (P<.01). Corneal 3rd order trefoil depended on incision width (P<.01). CONCLUSIONS: In addition to the well-known influence of incision size on SIA, CH also modulates optical changes. The biomechanical features of the cornea should be taken into account preoperatively to better predict the refractive outcomes of cataract surgery. PMID- 23756348 TI - Rapid clinical evaluation: an early warning cardiac surgical scoring system for hand-held digital devices. AB - OBJECTIVES: The purpose of this study was to develop a new scoring system for the prompt recognition of clinical deterioration and early treatment in postoperative cardiac surgical patients. METHODS: All consecutive adult patients undergoing cardiac surgery between 1st January 2007 and 31st December 2010 were included. The new score was calculated daily until intensive care unit (ICU) discharge. The score consists of 11 variables representing six different organ systems. Performance was assessed using receiver-operating characteristic (ROC) curves and calibration tests. RESULTS: A total of 5207 patients with a mean age of 67.2 +/- 10.9 years were admitted to the ICU after cardiac surgery. The operations performed covered the whole spectrum of cardiac surgery. ICU mortality was 5.9%. The mean length of ICU stay was 4.6 +/- 7.0 days. The new score had an excellent discrimination with areas under the ROC curves between 0.91 and 0.96. Calibration was also excellent reflected by observed/expected mortality ratios ranging between 1.0 and 1.26. CONCLUSIONS: The new score is a simple and reliable scoring system to assess organ dysfunction in cardiac intensive care patients. It is designed especially for personal digital assistants to simplify and accelerate the process of risk stratification in cardiac surgical ICUs. PMID- 23756350 TI - The effectiveness of postoperative physical therapy treatment in patients who have undergone arthroscopic partial meniscectomy: systematic review with meta analysis. AB - STUDY DESIGN: Systematic review with meta-analysis. OBJECTIVES: To evaluate the effectiveness of postoperative physical therapy treatment for patients who have undergone arthroscopic partial meniscectomy. BACKGROUND: There is no consensus on which treatment is best for patients post meniscectomy. METHODS: A search for articles published from 1950 to March 2013 was conducted in the MEDLINE, Embase, CINAHL, LILACS, SciELO, IBECS, Scopus, Web of Science, PEDro, Academic Search Premier, and Cochrane Central Register of Controlled Trials databases. The key words were physiotherapy, physical therapy modalities, exercise therapy, rehabilitation, knee, placebo, groups, tibial meniscus, meniscus, arthroscopy, meniscectomy, partial meniscectomy, randomized controlled trial, controlled clinical trial, randomized, systematic review, and meta-analysis. RESULTS: Eighteen randomized controlled trials were included in the review, 6 of which were included in the meta-analysis. Outpatient physical therapy plus a home exercise program, compared to a home program alone, improved function compared to a home program alone (mean difference, 10.3; 95% confidence interval: 1.3, 19.3; P = .02) and knee flexion range of motion (mean difference, 9.1; 95% confidence interval: 3.7, 14.5; P = .0009). Inpatient physical therapy alone compared to inpatient plus outpatient physical therapy reduced the likelihood of effusion (odds ratio = 0.25; 95% confidence interval: 0.10, 0.61; P = .003). CONCLUSION: Physical therapy associated with home exercises seems to be effective in improving patient-reported knee function and range of motion in patients post arthroscopic meniscectomy, although the included randomized controlled trials were classified from moderate to high risk of bias and should be interpreted with caution. LEVEL OF EVIDENCE: Therapy, level 1a-. PMID- 23756349 TI - More help than hindrance: nucleosomes aid transcriptional regulation. AB - A major challenge of modern human biology is to understand how a differentiated somatic cell integrates the response to external signals in the complex context of basic metabolic and tissue-specific gene expression programs. This requires exploring two interconnected basic processes: the signaling network and the global function of the key transcription factors on which signaling acts to modulate gene expression. An apparently simple model to study these questions has been steroid hormones action, since their intracellular receptors both initiate signaling and are the key transcription factors orchestrating the cellular response. We have used progesterone action in breast cancer cells to elucidate the intricacies of progesterone receptor (PR) signaling crosstalk with protein kinases, histone modifying enzymes and ATP-dependent chromatin remodeling complexes. ( 1) Recently we have described the cistrome of PR in these cells at different times after addition of hormone and its relationship to chromatin structure. ( 2) The role of chromatin in transcription factor binding to the genome is still debated, but the dominant view is that factors bind preferentially to nucleosome-depleted regions, usually identified as DNaseI hypersensitive sites (DHS). In contrast with this vision, we have shown that PR requires nucleosomes for optimal binding and function. In breast cancer cells treated with progestins we identified 25,000 PR binding sites (PRbs), the majority encompassing several copies of the hexanucleotide TGTYCY, highly abundant in the genome. We found that strong functional PRbs accumulate around progesterone-induced genes mainly in enhancers, are enriched in DHS but exhibit high nucleosome occupancy. Progestin stimulation results in remodeling of these nucleosomes with displacement of histones H1 and H2A/H2B dimers. Our results strongly suggest that nucleosomes play crucial role in PR binding and hormonal gene regulation. PMID- 23756351 TI - Methane emissions from MBT landfills. AB - Within the scope of an investigation for the German Federal Environment Agency ("Umweltbundesamt"), the basics for the estimation of the methane emissions from the landfilling of mechanically and biologically treated waste (MBT) were developed. For this purpose, topical research including monitoring results regarding the gas balance at MBT landfills was evaluated. For waste treated to the required German standards, a methane formation potential of approximately 18 24 m(3)CH(4)/t of total dry solids may be expected. Monitoring results from MBT landfills show that a three-phase model with differentiated half-lives describes the degradation kinetics in the best way. This is due to the fact that during the first years of disposal, the anaerobic degradation processes still proceed relatively intensively. In addition in the long term (decades), a residual gas production at a low level is still to be expected. Most of the soils used in recultivation layer systems at German landfills show a relatively high methane oxidation capacity up to 5 l CH(4)/(m(2)h). However, measurements at MBT disposal sites indicate that the majority of the landfill gas (in particular at non covered areas), leaves the landfill body via preferred gas emission zones (hot spots) without significant methane oxidation. Therefore, rather low methane oxidation factors are recommended for open and temporarily covered MBT landfills. Higher methane oxidation rates can be achieved when the soil/recultivation layer is adequately designed and operated. Based on the elaborated default values, the First Order Decay (FOD) model of the IPCC Guidelines for National Greenhouse Gas Inventories, 2006, was used to estimate the methane emissions from MBT landfills. Due to the calculation made by the authors emissions in the range of 60,000 135,000 t CO(2-eq.)/a for all German MBT landfills can be expected. This wide range shows the uncertainties when the here used procedure and the limited available data are applied. It is therefore necessary to generate more data in the future in order to calculate more precise methane emission rates from MBT landfills. This is important for the overall calculation of the climate gas production in Germany which is required once a year by the German Government. PMID- 23756352 TI - Hazardous waste incinerators under waste uncertainty: balancing and throughput maximization via heat recuperation. AB - Hazardous waste incinerators (HWIs) differ substantially from thermal power facilities, since instead of maximizing energy production with the minimum amount of fuel, they aim at maximizing throughput. Variations in quantity or composition of received waste loads may significantly diminish HWI throughput (the decisive profit factor), from its nominal design value. A novel formulation of combustion balance is presented, based on linear operators, which isolates the wastefeed vector from the invariant combustion stoichiometry kernel. Explicit expressions for the throughput are obtained, in terms of incinerator temperature, fluegas heat recuperation ratio and design parameters, for an arbitrary number of wastes, based on fundamental principles (mass and enthalpy balances). The impact of waste variations, of recuperation ratio and of furnace temperature is explicitly determined. It is shown that in the presence of waste uncertainty, the throughput may be a decreasing or increasing function of incinerator temperature and recuperation ratio, depending on the sign of a dimensionless parameter related only to the uncertain wastes. The dimensionless parameter is proposed as a sharp a' priori waste 'fingerprint', determining the necessary increase or decrease of manipulated variables (recuperation ratio, excess air, auxiliary fuel feed rate, auxiliary air flow) in order to balance the HWI and maximize throughput under uncertainty in received wastes. A 10-step procedure is proposed for direct application subject to process capacity constraints. The results may be useful for efficient HWI operation and for preparing hazardous waste blends. PMID- 23756353 TI - CD28 aptamers as powerful immune response modulators. AB - CD28 is one of the main costimulatory receptors responsible for the proper activation of T lymphocytes. We have isolated two aptamers that bind to the CD28 receptor. As a monomer, one of them interfered with the binding of CD28 to its ligand (B7), precluding the costimulatory signal, whereas the other one was inactive. However, dimerization of any of the anti-CD28 aptamers was sufficient to provide an artificial costimulatory signal. No antibody has featured a dual function (i.e., the ability to work as agonist and antagonist) to date. Two different agonistic structures were engineered for each anti-CD28 aptamer. One showed remarkably improved costimulatory properties, surpassing the agonistic effect of an anti-CD28 antibody. Moreover, we showed in vivo that the CD28 agonistic aptamer is capable of enhancing the cellular immune response against a lymphoma idiotype and of prolonging survival of mice which receive the aptamer together with an idiotype vaccine. The CD28 aptamers described in this work could be used to modulate the immune response either blocking the interaction with B7 or enhancing vaccine-induced immune responses in cancer immunotherapy.Molecular Therapy - Nucleic Acids (2013) 2, e98; doi:10.1038/mtna.2013.26; published online 11 June 2013. PMID- 23756354 TI - Anaesthesia and orphan disease: laparoscopic cholecystectomy with paroxysmal nocturnal haemoglobinuria and human mAb therapy. PMID- 23756355 TI - The clinical spectrum of RET proto-oncogene mutations in codon 790. AB - OBJECTIVE: Due to a strong genotype-phenotype correlation, the timing of prophylactic thyroidectomy in rearranged during transfection (RET) gene mutation carriers is usually dictated by genetic analysis. SUBJECTS AND METHODS: We report a nationwide retrospective study of the clinical data of 77 French patients from 19 families with a mutation in codon 790 of the RET proto-oncogene. RESULTS: The average age at diagnosis was 35.6 years +/- 20.5. Thirty-nine patients were women. Fifty-five patients underwent operations for the treatment of medullary thyroid carcinoma (MTC) at the mean age of 38 years (4-82 years). The mean follow up duration was 89 months. TNM staging was as follows: T0NxMx in 19, TxNxMx in 1, T1NxMx in 22, T1N1Mx in 8, T2N1Mx in 1 and T3N1Mx in four patients. In the T1/x Nx group, 96% were considered cured after surgery. In the N1 group (n=13), six patients had multifocal disease and five patients were cured. Age and gender were not significant predictors of remission. Twenty-two patients did not undergo an operation (age 1.5-78 years); among them, 11 patients had a mean basal calcitonin (CT) level of 9.8 pg/ml (2-24) after 53 months of follow-up. One patient had been operated on for phaeochromocytoma (PHEO), and their CT level remained normal for 262 months. CONCLUSIONS: This study confirms that RET 790 mutation is associated with a non-aggressive form of multiple endocrine neoplasia type 2, as 28% of the patients were followed up without thyroidectomy, 25% had been thyroidectomised with no tumour being detected and even patients with MTC had slow-evolving disease. Moreover, only one patient had PHEO, and no-one had primary hyperparathyroidism. PMID- 23756356 TI - Abdominal muscle activity during a standing long jump. AB - STUDY DESIGN: Experimental laboratory study. OBJECTIVES: To measure the activation patterns (onset and magnitude) of the abdominal muscles during a standing long jump using wire and surface electromyography. BACKGROUND: Activation patterns of the abdominal muscles, especially the deep muscles such as the transversus abdominis (TrA), have yet to be examined during full-body movements such as jumping. METHODS: Thirteen healthy men participated. Wire electrodes were inserted into the TrA with the guidance of ultrasonography, and surface electrodes were attached to the skin overlying the rectus abdominis (RA) and external oblique (EO). Electromyographic signals and video images were recorded while each subject performed a standing long jump. The jump task was divided into 3 phases: preparation, push-off, and float. For each muscle, activation onset relative to the onset of the RA and normalized muscle activation levels (percent maximum voluntary contraction) were analyzed during each phase. Comparisons between muscles and phases were assessed using 2-way analyses of variance. RESULTS: The onset times of the TrA and EO relative to the onset of the RA were -0.13 ? 0.17 seconds and -0.02 ? 0.07 seconds, respectively. Onset of TrA activation was earlier than that of the EO. The activation levels of all 3 muscles were significantly greater during the push-off phase than during the preparation and float phases. CONCLUSION: Consistent with previously published trunk-perturbation studies in healthy persons, the TrA was activated prior to the RA and EO. Additionally, the highest muscle activation levels were observed during the push-off phase. PMID- 23756357 TI - Phase entrainment strength scales with movement amplitude disparity. AB - In the current study, we examined whether coupling influences resulting from unintended afference-based phase entrainment are affected by movement amplitude as such or by the amplitude relation between the limbs. We assessed entrainment strength by studying how passive movements of the contralateral hand influenced unimanual coordination with a metronome. Results showed that amplitude as such did not affect entrainment strength, whereas the amplitude relation between the hands did. Larger amplitudes of the passive hand relative to the active hand resulted in stronger entrainment. This dependence on relative amplitude implies that entrainment strength is not only based on the intensity of afferent signals generated in the entraining limb but also on the susceptibility of the entrained limb to these signals. PMID- 23756358 TI - Coin state properties in quantum walks. AB - Recent experimental advances have measured individual coin components in discrete time quantum walks, which have not received the due attention in most theoretical studies on the theme. Here is presented a detailed investigation of the properties of M, the difference between square modulus of coin states of discrete quantum walks on a linear chain. Local expectation values are obtained in terms of real and imaginary parts of the Fourier transformed wave function. A simple expression is found for the average difference between coin states in terms of an angle theta gauging the coin operator and its initial state. These results are corroborated by numerical integration of dynamical equations in real space. The local dependence is characterized both by large and short period modulations. The richness of revealed patterns suggests that the amount of information stored and retrieved from quantum walks is significantly enhanced if M is taken into account. PMID- 23756359 TI - Quasi-monoenergetic laser-plasma acceleration of electrons to 2 GeV. AB - Laser-plasma accelerators of only a centimetre's length have produced nearly monoenergetic electron bunches with energy as high as 1 GeV. Scaling these compact accelerators to multi-gigaelectronvolt energy would open the prospect of building X-ray free-electron lasers and linear colliders hundreds of times smaller than conventional facilities, but the 1 GeV barrier has so far proven insurmountable. Here, by applying new petawatt laser technology, we produce electron bunches with a spectrum prominently peaked at 2 GeV with only a few per cent energy spread and unprecedented sub-milliradian divergence. Petawatt pulses inject ambient plasma electrons into the laser-driven accelerator at much lower density than was previously possible, thereby overcoming the principal physical barriers to multi-gigaelectronvolt acceleration: dephasing between laser-driven wake and accelerating electrons and laser pulse erosion. Simulations indicate that with improvements in the laser-pulse focus quality, acceleration to nearly 10 GeV should be possible with the available pulse energy. PMID- 23756360 TI - One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer. AB - PURPOSE: We report the long-term results of a randomised trial comparing tamoxifen with tamoxifen plus cyclophosphamide, methotrexate and fluorouracil (CMF) in postmenopausal high-risk breast cancer patients. In addition, we analyse the prognostic and predictive value of centrally assessed subtypes. METHODS: Postmenopausal patients with breast cancer and positive nodes, deep invasion or size exceeding 5 cm were randomly assigned to 1 year of tamoxifen, or cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2 and fluorouracil 600 mg/m2 intravenously on day 1 every 4 weeks for nine cycles plus tamoxifen (CMFT). Tissue microarrays were constructed retrospectively and oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and proliferation-related Ki-67 antigen (Ki67) status were assessed. RESULTS: From October 1982 through March 1990 we randomised 1445 patients and 969 (67%) were eligible for the biomarker analysis. At 10-years 936 women had suffered a disease free survival (DFS) event (tamoxifen, 495 events in 686 patients; CMFT, 441 events in 642 patients). The addition of CMF to tamoxifen significantly improved DFS (adjusted hazard ratio 0.82; 95% confidence interval (CI) 0.71-0.93; P = 0.003) but not overall survival (adjusted hazard ratio 0.95; 95% CI 0.85-1.08; P = 0.44). DFS was superior in Luminal A tumours (ER or PgR positive, HER2 negative and Ki67 <= 14%) when compared to Luminal B or non-luminal (ER and PgR negative) tumours. There was no statistical evidence of heterogeneity by subtype in the benefit from CMF (P(interaction) = 0.45). CONCLUSION: CMF added to 1 year of tamoxifen reduces the risk of a DFS event. The benefit from CMF was not significantly different in Luminal A and B subtypes. PMID- 23756361 TI - Subsequent mortality experience in five-year survivors of childhood, adolescent and young adult cancer in Scotland: a population based, retrospective cohort study. AB - AIM: To assess the risk of death in patients who survive at least 5 years after diagnosis of childhood, adolescent or young adult cancer. PATIENTS AND METHODS: This was a population-based retrospective cohort study using linked national cancer registry and mortality records in Scotland. The study population consisted of 5229 individuals who were diagnosed with cancer before the age of 25 years between 1981 and 2003, and who survived at least 5 years after the date of diagnosis of their primary cancer. Indirect standardisation was used to calculate mortality ratios standardised for age and sex and absolute excess risks (AERs) compared to the general Scottish population. RESULTS: During 58,358 person-years of follow-up, there were 359 deaths among the cohort of cancer survivors. The overall SMR was 6.1 (95% confidence interval (CI) 5.5-6.7) and AER 51 (45-58) per 10,000 person-years. Largely because of age- and sex-related differences in background mortality, SMRs were higher in patients diagnosed at 0-14 years (SMR 11.0, 95% CI 9.3-12.9) than 15-24 years (4.7, 4.1-5.3), and in females (9.2, 7.8 10.8) than males (4.8, 4.2-5.5). SMRs and AERs varied substantially by primary cancer and by underlying cause of death. In general, SMRs were little altered by standardisation for an area-based indicator of socio-economic deprivation. Adjusted for age and sex, the risk of death was significantly lower in five-year survivors diagnosed during 1998-2003 compared to those diagnosed during 1981-1985 (Relative hazard ratio, 0.54, 95% CI 0.36-0.81). CONCLUSION: Long-term survivors of cancer in childhood and young adulthood remain at higher risk of mortality than the general population, although the absolute risk of death is low and the excess risk has decreased over time. PMID- 23756362 TI - Sildenafil and furosemide associated ototoxicity: consideration of drug-drug interactions, synergy, and broader clinical relevance. AB - Drug-induced ototoxicity, particularly those involving phosphodiesterase type 5 (PDE-5) inhibitors, is considered to be rare and to our knowledge such an adverse effect has not been reported in Canada. Here we present a case of a 77-year old man initiated on a sildenfil regimen for the treatment of pulmonary hypertension, who developed sudden bilateral hearing loss after taking sildenafil, in the setting of high dose furosemide and diltiazem. We outline the likely interplay of patient characteristics, drug synergy and drug-drug interactions in the development of his ototoxicity. Importantly, given the extent and popularity of PDE-5 inhibitors for erectile dysfunction as well as a newer therapeutic option for pulmonary hypertension, clinicians should be aware of the risk for drug induced ototoxicity, particularly in the setting of concomitant loop diuretics and CYP3A4 inhibiting medications. PMID- 23756363 TI - LP or not LP, that is the question: gold standard or unnecessary procedure in subarachnoid haemorrhage? AB - OBJECTIVE: To measure the sensitivity of modern CT in patients presenting to the emergency department and evaluated for possible subarachnoid haemorrhage, with particular attention to those presenting within 12 h of ictus. DESIGN: Retrospective cohort study. SETTING: Large district general hospital emergency department seeing 73,500 new attendances per year. PARTICIPANTS: Patients presenting to the emergency department and screened for suspected subarachnoid haemorrhage. OUTCOME MEASURES: Subarachnoid haemorrhage was defined by either the presence of subarachnoid blood on CT, positive CSF spectrophotometry defined by national guidelines or aneurysm identified on subsequent angiography if either of the former were equivocal. RESULTS: 244 patients were screened for subarachnoid haemorrhage during the 24 months between March 2006 and April 2008 (mean age 48.5 years). The sensitivity of CT overall for subarachnoid haemorrhage was 93.8% (95% CI 84% to 98%) increasing to 95% (95% CI 82% to 99%) if performed within 12 h of ictus. CONCLUSIONS: While modern CT has a high sensitivity for the diagnosis of acute subarachnoid haemorrhage, particularly within 12 h of ictus, it is still not sufficient to act as the sole diagnostic tool, and patients with a negative CT will require further investigation with a lumbar puncture. PMID- 23756364 TI - Activation of selected ankle muscles during exercises performed on rigid and compliant balance platforms. AB - STUDY DESIGN: Experimental laboratory study. OBJECTIVE: To compare how the design of 2 balance platforms affects ankle musculature activation for various weight bearing exercises. BACKGROUND: Balance platforms are widely used in both training and rehabilitation, and a better understanding of how platform design and type of exercise modify the demands on the ankle musculature may be helpful in staging exercise progression. METHODS: Surface electromyography was used to measure the activation level of the fibularis longus, tibialis anterior, and medial gastrocnemius while performing 4 exercises on 2 different balance platforms (compliant and rigid). Twenty-four (12 females, 12 males) healthy, sedentary subjects participated in the study. Analysis of variance was used for statistical analysis. RESULTS: There was no significant interaction between balance platforms and exercises (P>.05), and the type of platform did not influence muscle activation for the 3 muscles monitored (P>.05). The highest activation level for the fibularis longus and medial gastrocnemius was obtained during single-leg stance, and for the tibialis anterior during the single-leg squat (P<.05). CONCLUSION: In this study, although the demands on the ankle musculature were similar for selected exercises performed on a compliant versus a rigid balance platform, muscle activation level varied based on the exercise. PMID- 23756366 TI - Non-volatile memory based on the ferroelectric photovoltaic effect. AB - The quest for a solid state universal memory with high-storage density, high read/write speed, random access and non-volatility has triggered intense research into new materials and novel device architectures. Though the non-volatile memory market is dominated by flash memory now, it has very low operation speed with ~10 MUs programming and ~10 ms erasing time. Furthermore, it can only withstand ~10(5) rewriting cycles, which prevents it from becoming the universal memory. Here we demonstrate that the significant photovoltaic effect of a ferroelectric material, such as BiFeO3 with a band gap in the visible range, can be used to sense the polarization direction non-destructively in a ferroelectric memory. A prototype 16-cell memory based on the cross-bar architecture has been prepared and tested, demonstrating the feasibility of this technique. PMID- 23756365 TI - Morphine induced exacerbation of sepsis is mediated by tempering endotoxin tolerance through modulation of miR-146a. AB - Development of tolerance to endotoxin prevents sustained hyper inflammation during systemic infections. Here we report for the first time that chronic morphine treatment tempers endotoxin tolerance resulting in persistent inflammation, septicemia and septic shock. Morphine was found to down-regulate endotoxin/LPS induced miR-146a and 155 in macrophages. However, only miR-146a over expression, but not miR-155 abrogates morphine mediated hyper-inflammation. Conversely, antagonizing miR-146a (but not miR-155) heightened the severity of morphine-mediated hyper-inflammation. These results suggest that miR-146a acts as a molecular switch controlling hyper-inflammation in clinical and/or recreational use of morphine. PMID- 23756367 TI - tert-Butyl 1,5-bis(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)-1,5-dioxopentan-2 ylcarbamate urea/thiourea derivatives as potent H+/K(+)-ATPase inhibitors. AB - Amino acids are known to possess variable efficacy against ulceration. Considering the good antiulcer activity of amino acids, a series of urea/thiourea derivatives of glutamic acid conjugated benzisothiazole analogue 3a-u with various substituents on aryl ring were synthesized, spectroscopically characterized and evaluated for in vitro H(+)/K(+)-ATPase inhibition. Majority of the compounds possessed potency compared to that of omeprazole, a reference drug. In particular, methoxy derivatives 3p-u were the most active compounds possessing a significant 15-fold increase for para substituent thus, contributing positively to gastric H(+)/K(+)-ATPase inhibition. PMID- 23756368 TI - Synthesis and structure-activity relationship of 2-arylamino-4-aryl-pyrimidines as potent PAK1 inhibitors. AB - 2-Arylamino-4-aryl-pyrimidines were found to be potent inhibitors of PAK1 kinase. The synthesis and SAR are described. The incorporation of a bromide at the 5 position of the pyrimidine core and in combination with a 1,2-dimethylpiperazine pendant domain yielded a lead compound with potent PAK1 inhibition and anti proliferative activity in various colon cancer cell lines. PMID- 23756369 TI - Structures and biosynthesis of 12-membered macrocyclic depsipeptides from Streptomyces sp. ML55. AB - Two novel depsipeptides (1-2) were isolated from Streptomyces sp. ML55 together with two known analogues (3-4). Their structures were elucidated using a combination of NMR experiments, as well as detailed MS/MS experiments. The biosynthetic pathway of isolated compounds was dissected by genome sequencing data analysis for a hybrid nonribosomal peptide synthetase (NRPS) and polyketide synthetase (PKS) assembly line. PMID- 23756371 TI - Response to "Logistic regression in signal detection: another piece added to the puzzle". PMID- 23756370 TI - Profiling serum bile acid glucuronides in humans: gender divergences, genetic determinants, and response to fenofibrate. AB - Glucuronidation, catalyzed by uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic bile acids (BAs). We aimed to (i) characterize the circulating BA-glucuronide (BA-G) pool composition in humans, (ii) determine how sex and UGT polymorphisms influence this composition, and (iii) analyze the effects of the lipid-lowering drug fenofibrate on the circulating BA-G profile in 300 volunteers and 5 cholestatic patients. Eleven BA-Gs were determined in pre- and postfenofibrate samples. Men exhibited higher BA-G concentrations, and various genotype/BA-G associations were discovered in relevant UGT genes. The chenodeoxycholic acid-3G (CDCA-3G) concentration was associated with the UGT2B7 802C>T polymorphism. Glucuronidation assays confirmed the predominant role of UGT2B7 and UGT1A4 in CDCA-3G formation. Fenofibrate exposure increased the serum levels of five BA-G species, including CDCA-3G, and upregulated expression of UGT1A4, but not UGT2B7, in hepatic cells. This study demonstrated that fenofibrate stimulates BA glucuronidation in humans and thus reduces BA toxicity in the liver. PMID- 23756372 TI - A forensic analysis of drug targets from 2000 through 2012. AB - Pharmaceutical innovation is often measured by counting the new drugs approved by regulators. It is a simple and useful metric, but it has shortcomings. One of them is that it says little about the drugs' innovativeness. Are they variations of older medicines or molecules targeting entirely novel modes of action? As prices escalate, and payers and patients demand value, we need a better picture. This article aims to provide it by analyzing the drugs approved by the US Food and Drug Administration between 2000 and 2012. It examines their modes of action, highlights key trends, and discusses their implications for our ability to generate innovation. PMID- 23756373 TI - New insights on vertebrate olivo-cerebellar climbing fibers from computerized morphological reconstructions. AB - Characterization of neuronal connectivity is essential to understanding the architecture of the animal nervous system. Specific labeling and imaging techniques can visualize axons and dendrites of single nerve cells. Two dimensional manual drawing has long been used to describe the morphology of labeled neuronal elements. However, quantitative morphometry, which is essential to understanding functional significance, cannot be readily extracted unless the detailed neuronal geometry is comprehensively reconstructed in three-dimensional space. We have recently applied an accurate and robust digital reconstruction system to cerebellar climbing fibers, which form highly dense and complex terminal arbors as one of the strongest presynaptic endings in the vertebrate nervous system. Resulting statistical analysis has shown how climbing fibers morphology is special in comparison to other axonal terminals. While thick primary branches may convey excitation quickly and faithfully to the far ends, thin tendril branches, which have a larger bouton density, form the majority of presynaptic outputs. This data set, now publicly available from NeuroMorpho.Org for further modeling and analysis, may constitute the first detailed and comprehensive digital reconstruction of the complete axonal terminal field with identified branch types and full accounting of boutons for any neuronal class in the vertebrate brain. PMID- 23756374 TI - Reduction in early mortality on antiretroviral therapy for adults in rural South Africa since change in CD4+ cell count eligibility criteria. AB - OBJECTIVE: To explore the impact of expanded eligibility criteria for antiretroviral therapy (ART) on median CD4+ cell count at ART initiation and early mortality on ART. METHODS: Analyses included all adults (>=16 years) initiated on first-line ART between August 2004 and July 2012. CD4+ cell count threshold 350 cells per microliter for all adults was implemented in August 2011. Early mortality was defined as any death within 91 days of ART initiation. Trends in baseline CD4+ cell count and early mortality were examined by year (August to July) of ART initiation. Competing risks analysis was used to examine early mortality. RESULTS: A total of 19,080 adults (67.6% female) initiated ART. Median CD4+ cell count at ART initiation was 110-120 cells per microliter over the first 6 years, increasing marginally to 145 cells per microliter in 2010-2011 and more significantly to 199 cells per microliter in 2011-2012. Overall, there were 875 deaths within 91 days of ART initiation; early mortality rate was 19.4 per 100 person-years [95% confidence interval (CI) 18.2 to 20.7]. After adjustment for sex, age, baseline CD4+ cell count, and concurrent tuberculosis (TB), there was a 46% decrease in early mortality for those who initiated ART in 2011-2012 compared with the reference period 2008-2009 (subhazard ratio, 0.54; 95% CI: 0.41 to 0.71). CONCLUSIONS: Since the expansion of eligibility criteria, there is evidence of earlier access to ART and a significant reduction in early mortality rate in this primary health care programme. These findings provide strong support for national ART policies and highlight the importance of earlier ART initiation for achieving reductions in HIV-related mortality. PMID- 23756375 TI - [Surface proteins of bacteria of the genus Bifidobacterium]. AB - Beneficial effects due to the presence of probiotic bacteria of the genus Bifidobacterium in the human intestinal tract are still an interesting object of study. So far activities have been confirmed of bifidobacteria in stimulation of the host immune system, stimulation of tumor cell apoptosis, improvement of bowel motility, alleviation of symptoms of lactose intolerance, cholesterol lowering capacity, prevention and treatment of diarrhea and irritable bowel syndrome, alleviation of allergy or atopic dermatitis, maintenance of homeostasis of the intestine, and stimulation of the development of normal intestinal microflora in infants. A multitude of therapeutic properties encourages researchers to investigate the possibility of using the potential of Bifidobacterium in the prevention and treatment of other conditions such as rheumatoid arthritis and depression. Although it is known that the beneficial effects are due to intestinal mucosal colonization by these bacteria, the cell components responsible for the colonization are still not determined. In addition to the beneficial effects of probiotic administration, there were also negative effects including sepsis. Therefore research has been directed to identify specific components of Bifidobacterium responsible for probiotic effects. Currently researchers are focused on identifying, isolating and evaluating the properties of surface proteins that are probably involved in the adhesion of bacterial cells to the intestinal epithelium, improving colonization. This paper is an overview of current knowledge on Bifidobacterium surface proteins. The ways of transport and anchoring proteins in Gram-positive bacterial cells, the assembly of cell wall, and a description of the genus Bifidobacterium are presented. PMID- 23756376 TI - [Role of tumor microenvironment in the formation and progression of skin melanoma]. AB - Melanoma develops from melanocytes localized mainly in skin, to a lesser extent in uvea and mucosal tissue. It is one of the most aggressive tumors, resistant to standard therapies. It is caused mainly by UV radiation. Approximately 10% of melanomas have a familial background. Transformation of melanocytes is driven mainly by mutations in genes coding for proteins regulating proliferation, cell growth, cell cycle, and death. Although genetic changes are indisputable causes of melanoma formation, the key role of the skin microenvironment is becoming more and more acknowledged. Normal cells of the skin, such as keratinocytes, fibroblasts, endothelial, and immune cells, alongside melanocytes constitute a special microenvironment in which disturbed homeostasis may facilitate melanoma development. The process of transformation is initiated by aberrant interaction of keratinocytes and melanocytes. Proliferation and invasive growth of the developing neoplasm may be further facilitated by myofibroblasts as well as macrophages residing within the tumor. They are able to stimulate angiogenesis and suppress the immune response. Macrophages may, additionally, create aggressive hybrid cells through fusion with melanoma cells. Indispensable in the process of metastasis are endothelial cells which co-form blood vessels, the main routes of tumor cells' seeding. All of the aforementioned processes take place in a tumor growth-promoting atmosphere of low oxygen tension in the skin, further decreasing during tumor growth. Probably the tumor growth-promoting microenvironment is one of the main factors responsible for melanoma aggressiveness. PMID- 23756377 TI - Noninvasive remote activation of the ventral midbrain by transcranial direct current stimulation of prefrontal cortex. AB - The midbrain lies deep within the brain and has an important role in reward, motivation, movement and the pathophysiology of various neuropsychiatric disorders such as Parkinson's disease, schizophrenia, depression and addiction. To date, the primary means of acting on this region has been with pharmacological interventions or implanted electrodes. Here we introduce a new noninvasive brain stimulation technique that exploits the highly interconnected nature of the midbrain and prefrontal cortex to stimulate deep brain regions. Using transcranial direct current stimulation (tDCS) of the prefrontal cortex, we were able to remotely activate the interconnected midbrain and cause increases in participants' appraisals of facial attractiveness. Participants with more enhanced prefrontal/midbrain connectivity following stimulation exhibited greater increases in attractiveness ratings. These results illustrate that noninvasive direct stimulation of prefrontal cortex can induce neural activity in the distally connected midbrain, which directly effects behavior. Furthermore, these results suggest that this tDCS protocol could provide a promising approach to modulate midbrain functions that are disrupted in neuropsychiatric disorders. PMID- 23756378 TI - Monozygotic twins affected with major depressive disorder have greater variance in methylation than their unaffected co-twin. AB - Our understanding of major depressive disorder (MDD) has focused on the influence of genetic variation and environmental risk factors. Growing evidence suggests the additional role of epigenetic mechanisms influencing susceptibility for complex traits. DNA sequence within discordant monozygotic twin (MZT) pairs is virtually identical; thus, they represent a powerful design for studying the contribution of epigenetic factors to disease liability. The aim of this study was to investigate whether specific methylation profiles in white blood cells could contribute to the aetiology of MDD. Participants were drawn from the Queensland Twin Registry and comprised 12 MZT pairs discordant for MDD and 12 MZT pairs concordant for no MDD and low neuroticism. Bisulphite treatment and genome wide interrogation of differentially methylated CpG sites using the Illumina Human Methylation 450 BeadChip were performed in WBC-derived DNA. No overall difference in mean global methylation between cases and their unaffected co-twins was found; however, the differences in females was significant (P=0.005). The difference in variance across all probes between affected and unaffected twins was highly significant (P<2.2 * 10-16), with 52.4% of probes having higher variance in cases (binomial P-value<2.2 * 10-16). No significant differences in methylation were observed between discordant MZT pairs and their matched concordant MZT (permutation minimum P=0.11) at any individual probe. Larger samples are likely to be needed to identify true associations between methylation differences at specific CpG sites. PMID- 23756380 TI - Musculoskeletal predictors of movement quality for the forward step-down test in asymptomatic women. AB - STUDY DESIGN: Cross-sectional. OBJECTIVE: To investigate the interrater reliability of movement-quality ratings for the forward step-down (FSD) test and to compare hip muscle strength and lower extremity joint range of motion and muscle flexibility among asymptomatic women with different levels of movement quality. BACKGROUND: The interrater reliability of the FSD test has not yet been investigated. Additionally, it is not known whether differences in musculoskeletal measures exist among individuals with different levels of movement quality during the FSD test. METHODS: Two physical therapists assessed movement quality during the FSD test in 26 asymptomatic women (mean +/- SD age, 22.7 +/- 0.9 years). Hip muscle strength and lower extremity joint range of motion and muscle flexibility were also assessed. The interrater reliability of the FSD test was estimated by using the kappa coefficient and percent agreement. Differences in musculoskeletal measures based on movement quality were assessed by independent t tests. RESULTS: The kappa coefficient and percent agreement for rating the quality of movement on the FSD test were 0.80 (95% confidence interval: 0.57, 1.00) and 85%, respectively. The subjects with moderate movement quality had significantly less strength of the hip abductors, less knee flexion range of motion measured in prone (quadriceps flexibility), and less hip adduction range of motion measured in sidelying (iliotibial band/tensor fascia latae flexibility) compared to those with good movement quality. CONCLUSION: There was good agreement for the rating of movement quality during the FSD test, and there were physical attributes that distinguished those with moderate from those with good quality of movement. PMID- 23756379 TI - AKAPs integrate genetic findings for autism spectrum disorders. AB - Autism spectrum disorders (ASDs) are highly heritable, and six genome-wide association studies (GWASs) of ASDs have been published to date. In this study, we have integrated the findings from these GWASs with other genetic data to identify enriched genetic networks that are associated with ASDs. We conducted bioinformatics and systematic literature analyses of 200 top-ranked ASD candidate genes from five published GWASs. The sixth GWAS was used for replication and validation of our findings. Further corroborating evidence was obtained through rare genetic variant studies, that is, exome sequencing and copy number variation (CNV) studies, and/or other genetic evidence, including candidate gene association, microRNA and gene expression, gene function and genetic animal studies. We found three signaling networks regulating steroidogenesis, neurite outgrowth and (glutamatergic) synaptic function to be enriched in the data. Most genes from the five GWASs were also implicated--independent of gene size--in ASDs by at least one other line of genomic evidence. Importantly, A-kinase anchor proteins (AKAPs) functionally integrate signaling cascades within and between these networks. The three identified protein networks provide an important contribution to increasing our understanding of the molecular basis of ASDs. In addition, our results point towards the AKAPs as promising targets for developing novel ASD treatments. PMID- 23756381 TI - Integrating DNA strand-displacement circuitry with DNA tile self-assembly. AB - DNA nanotechnology has emerged as a reliable and programmable way of controlling matter at the nanoscale through the specificity of Watson-Crick base pairing, allowing both complex self-assembled structures with nanometer precision and complex reaction networks implementing digital and analog behaviors. Here we show how two well-developed frameworks, DNA tile self-assembly and DNA strand displacement circuits, can be systematically integrated to provide programmable kinetic control of self-assembly. We demonstrate the triggered and catalytic isothermal self-assembly of DNA nanotubes over 10 MUm long from precursor DNA double-crossover tiles activated by an upstream DNA catalyst network. Integrating more sophisticated control circuits and tile systems could enable precise spatial and temporal organization of dynamic molecular structures. PMID- 23756382 TI - Trends in malpractice litigation in relation to the delivery of breast care in the National Health Service. AB - Malpractice litigation involving the delivery of breast care has been evaluated in the United States of America (USA) but is a relatively new area of study in the United Kingdom (UK). We sought to study and evaluate the emerging trends in litigation claims in relation to breast disease with the National Health Service Litigation Authority (NHSLA) over the last 15 years, up to December 2010. PMID- 23756383 TI - Role of FDG-PET/CT in evaluating surgical outcomes of operable breast cancer- usefulness for malignant grade of triple-negative breast cancer. AB - BACKGROUND: The aim of this study was to evaluate the significance of (18)F fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for speculating the malignant level and prognostic value of operable breast cancers. METHODS: Of 578 consecutive patients with primary invasive breast cancer who underwent curative surgery between 2005 and 2010, 311 patients (53.8%) who received FDG-PET/CT before initial therapy were examined. RESULTS: Receiver operating characteristics (ROC) curve analysis showed the cutoff value of the maximum standardized uptake value (SUVmax) to predict cancer recurrence was 3.8 in all patients and 8.6 in patients with the triple-negative subtype, respectively. In all patients, 3-year DFS rates were 98.8% for patients with a tumor of SUVmax <= 3.8 and 91.6% for patients with a tumor of SUVmax > 3.8 (p < 0.001). High value of SUVmax was significantly associated with large tumor size (p < 0.001), lymph node metastasis (p = 0.040), high nuclear grade (p < 0.001), lymphovascular invasion (p = 0.032), negative hormone receptor status (p < 0.001), and positive HER2 status (p = 0.014). Based on the results of multivariate Cox analysis in all patients, high SUVmax (p = 0.001) and negative hormone receptor status (p = 0.005) were significantly associated with poor prognosis. In patients with triple-negative subtype, 3-year DFS rates were 90.9% for patients with a tumor of SUVmax <= 8.6 and 42.9% for patients with a tumor of SUVmax > 8.6 (p = 0.002), and high SUVmax was the only significant independent prognostic factor (p = 0.047). CONCLUSION: FDG-PET/CT is useful for predicting malignant behavior and prognosis in patients with operable breast cancer, especially the triple-negative subtype. PMID- 23756384 TI - Adiponectin and metabolic syndrome: pathway on the relationship. PMID- 23756385 TI - Maternal early-pregnancy vitamin D status in relation to linear growth at the age of 5-6 years: results of the ABCD cohort. AB - BACKGROUND/OBJECTIVES: Low vitamin D status during pregnancy may be associated with infant skeletal growth. However, evidence on the longer-term effect is limited. This study aims to assess the association between maternal vitamin D status in early pregnancy and markers of linear growth (height, leg length and relative leg length) of the child at age 5-6 years. SUBJECTS/METHODS: A subsample of data from the Amsterdam Born Children and Development (ABCD) study was used. Ethnic Dutch pregnant women and their children (n=1208) were included. Maternal serum vitamin D level was determined at first antenatal visit (median 13 weeks, interquartile range: 12-14). We investigated the association of maternal vitamin D, corrected for season, with height, leg length and relative leg length at age 5 6 years. RESULTS: Linear regression analyses showed no significant association between maternal vitamin D levels (nmol/l) and height (cm) (B=-0.006; P=0.205), leg length (cm) (B=-0.002, P=0.540) or relative leg length (%) (B=0.001; P=0.579). Adjustment for potential confounders (parental heights, maternal educational level, alcohol use during pregnancy, child sex, child age at measurement and child screen time) did not change these results. CONCLUSIONS: Maternal vitamin D level was not associated with early linear growth in children. Other factors, such as parental height, appear to be more important. PMID- 23756386 TI - Relationship of obesity and high urinary enterolignan concentrations in 6806 children and adults: analysis of National Health and Nutrition Examination Survey data. AB - The gut microbial environment (bacteria and metabolites) may have a role in obesity. Urinary enterolignan concentrations can provide a marker of interindividual differences in microbial environments. Analysis was conducted on 6806 individuals from 2003 to 2008 National Health and Nutrition Examination Survey data, and weight status, waist circumference groups and high- vs low enterolignan concentration was evaluated using multinomial logistic regression, adjusted for personal and dietary factors. High-enterolignan concentrations were defined as the 90th percentile value and greater. High-enterodiol concentration was associated with 18% and 42% lower likelihood of being overweight and obese, respectively, and 48% lower likelihood of having high-risk waist circumference among adults. High-enterolactone concentration was associated with 24% and 64% lower likelihood of being overweight and obese, respectively. Age and sex were not modifiers of these associations. These results from a large human study population provide additional evidence supporting the microbiome-obesity relationship. PMID- 23756388 TI - Membrane estrogen receptors - is it an alternative way of estrogen action? AB - The functions of estrogens are relatively well known, however the molecular mechanism of their action is not clear. The classical pathway of estrogen action is dependent on ERalpha and ERbeta which act as transcription factors. The effects of this pathway occur within hours or days. In addition, so-called, non classical mechanism of steroid action dependent on membrane estrogen receptors (mER) was described. In this mechanism the effects of estrogen action are observed in a much shorter time. Here we review the structure and cellular localization of mER, molecular basis of non-classical mER action, physiological role of mER as well as implications of mER action for cancer biology. Finally, some concerns about the new estrogen receptor - GPER and candidates for estrogen receptors - ER-X and ERx, are briefly discussed. It seems that mER is a complex containing signal proteins (signalosome), as IGF receptor, EGF receptor, Ras protein, adaptor protein Shc, non-receptor kinase c-Src and PI-3K, what rationalizes production of second messengers. Some features of membrane receptors are almost identical if compared to nuclear receptors. Probably, membrane and nuclear estrogen receptors are not separate units, but rather the components of a complex mechanism in which they both cooperate with each other. We conclude that the image of the estrogen receptor as a simple transcription factor is a far reaching simplification. A better understanding of the mechanisms of estrogen action will help us to design more effective drugs affecting signal pathways depending on both membrane and nuclear receptors. PMID- 23756387 TI - Association between whole-blood polyunsaturated fatty acids in pregnant women and early fetal weight. AB - BACKGROUND/OBJECTIVES: Studies suggest that intake of marine n-3 polyunsaturated fatty acids (n-3 PUFA) in pregnancy have an impact on birth weight, but only few have investigated the effect on early fetal growth. The objective of the study was to investigate the association between levels of PUFA in maternal blood in gestational week 24 and biometric measures and estimated fetal weight in gestational week 20. SUBJECTS/METHODS: In the COPSAC2010 cohort, whole-blood fatty acid composition (a biomarker of PUFA intake) from 583 women in week 24 was analyzed by gas chromatography. Biometric data (head circumference, abdominal circumference and femur length) were collected by ultra sound in week 20 and fetal weight was estimated. Associations between whole-blood PUFA (docosahexaenoic acid (DHA), total n-3 PUFA, n-6/n-3 PUFA, total n-6 PUFA) and fetal weight and biometrics measures were analyzed by multivariable-adjusted linear regression analyses. RESULTS: There was a wide range in maternal blood DHA, which varied from 1.8 to 6.9% depending on socioeconomic status, smoking and body mass index. After adjusting for these variables, no association was observed between any of the assessed PUFA components and the circumference of head or abdomen or fetal weight. However, an inverse association was established between DHA and total n-3 PUFA and femur length (P<0.02). CONCLUSION: Maternal whole blood PUFA composition, specifically her n-3 PUFA status, in gestational week 24 was not associated with overall early fetal weight gain, but this study indicates that it may decrease the length of femur. PMID- 23756389 TI - The impact of physical activity and nutrition on inflammatory bowel disease: the potential role of cross talk between adipose tissue and skeletal muscle. AB - Crohn's disease and ulcerative colitis are both chronic inflammatory bowel diseases (IBDs) characterized by a cyclical nature, which alternates between active and quiescent states, ultimately impairing a patients' quality of life. The etiology of IBD is not known but it likely involves a combination of genetic predisposition and environmental risk factors. Physical exercise has been suggested to provide protection against the onset of IBD, but there are inconsistencies in the findings of the published literature. Current research recommends exercise to help counteract some IBD-specific complications and preliminary studies suggest that physical activity may be beneficial in reducing the symptoms of IBD. Obesity is becoming more prevalent in patients diagnosed with IBD and may be associated with higher disease activity. There is evidence that adipokines are involved in the inflammatory and metabolic pathways. Hypertrophy of the mesenteric white adipose tissue has been long recognized as a characteristic feature of Crohn's disease; however its importance is unknown. Recent data suggest that dysregulation of adipokine secretion by white adipose tissue is involved in the pathogenesis of Crohn's disease. Skeletal muscle was shown to produce biologically active myokines, which could be a important contributor to the beneficial effects of exercise. There is mounting evidence for the bi-directional endocrine cross talk between adipose tissue and skeletal muscle. The objective of the present review is to explore the role of exercise and its impact on IBD. Also, we discuss how current discoveries regarding the importance of adipokines and myokines and their cross talk expand our view of the pathological changes and the therapeutic options for IBD. PMID- 23756390 TI - Nonsteroidal anti-inflammatory drugs (NSAID) sparing effects of glucosamine hydrochloride through N-glycosylation inhibition; strategy to rescue stomach from NSAID damage. AB - Gastrointestinal or cardiovascular complications limit nonsteroidal anti inflammatory drugs (NSAID) prescription. Glucosamine hydrochloride (GS-HCl) alternatively chosen, but debates still exist in its clinical efficiency. COX-2 instability through inhibiting COX-2 N-glycosylation of GS-HCl raised the possibility of NSAID sparing effect. Study was done to determine whether combination treatment of glucosamine and NSAID contributes to gastric safety through NSAID sparing effect. IEC-6 cells were stimulated with TNF-alpha and compared the expressions of inflammatory mediators after indomethacin alone or combination of indomethacin and GS-HCl by Western blotting and RT-PCR. C57BL/6 mice injected with type II collagen to induce arthritis were treated with indomethacin alone or combination of reduced dose of indomethacin and GS-HCl after 3 weeks. TNF-alpha increased the expression of COX-2, iNOS and inflammatory cytokines, but GS-HCl significantly attenuated TNF-alpha-induced COX-2 expression. Decreased COX-2 after GS-HCl was caused by N-glycosylation inhibition as much as tunicamycin. Combination of reduced dose of indomethacin and GS-HCl significantly reduced the expressions of ICAM-1, VCAM-1, IL-8, IL-1beta, MMP-2, MMP-7, MMP-9, and MMP-11 mRNA as well as NF-kappaB activation better than high dose indomethacin alone. These NSAID sparing effect of GS-HCl was further proven in collagen-induced arthritis model. Combination of GS-HCl and 2.5 mg/kg indomethacin showed significant protection from gastric damages as well as efficacious anti-arthritic effect. Taken together, COX-2 N-glycosylation inhibition by GS-HCl led to indomethacin sparing effects, based on which combination of GS-HCl and reduced dose of NSAID can provide the strategy to secure stomach from NSAID-induced gastric damage as well as excellent anti arthritic effects. PMID- 23756391 TI - Pro-resolution, protective and anti-nociceptive effects of a cannabis extract in the rat gastrointestinal tract. AB - Cannabis is widely used for treating a number of gastrointestinal ailments, but its use is associated with several adverse effects, particularly when the route of administration is via smoking. In the present study, we tested the effects (in rats) of a simple extract of medicinal cannabis (called "MFF") for its ability to promote resolution of colitis, to prevent gastric damage induced by naproxen, and to reduce gastric distention-induced visceral pain. Intracolonic, but not oral administration of MFF dose-dependently reduced the severity of hapten-induced colitis, an effect not reduced by pretreatment with antagonists of CB1 or CB2 receptors. Significant improvement of symptoms (diarrhea, weight loss) and healing of ulcerated tissue was evident with MFF treatment at doses that did not produce detectable urinary levels of 9-Delta-tetrahydrocannabinol (THC). MFF increased colonic hydrogen sulfide synthesis in healthy rats, but not in rats with colitis, and had no effect on colonic prostaglandin E2 synthesis. Orally, but not systemically administered MFF dose-dependently reduced the severity of naproxen-induced gastric damage, and a CB1 antagonist reversed this effect. MFF prevented gastric distention-induced visceral pain via a CB2-dependent mechanism. These results demonstrate that a simple extract of medicinal cannabis can significantly enhance resolution of inflammation and injury, as well as prevent injury, in the gastrointestinal tract. Interestingly, different cannabinoid receptors were involved in some of the effects. MFF may serve as the basis for a simple preparation of cannabis that would produce beneficial effects in the GI tract with reduced systemic toxicity. PMID- 23756392 TI - Influence of tianeptine on melatonin homeostasis and psychosomatic symptoms in patients with irritable bowel syndrome. AB - Selective serotonin reuptake inhibitors (SSRIs) exert beneficial effect on gastrointestinal tract (GIT), but its mechanism has not been recognized. One of the hypothesis assumes, that fluoxetine increases indirectly melatonin production. For this reason it can be hypothesized, that administration of drugs of opposite effect, for example tianepine (selective serotonin reuptake enhancer (SSRE), can reduce melatonin production resulting in harmful effects as regards GIT. The aim of the study was to confirm or reject this hypothesis. The study included 100 patients, aged 21-58 years, with irritable bowel syndrome (IBS). Basing on the Rome III Criteria patients with constipation-predominant (IBS-C, n=50) and with diarrhoea-predominant (IBS-D, n=50) and 25 health volunteers (control group C) were distinguished. Visual Analog Scale (VAS) and Hamilton Depression Rating Scale (HDRS) were used to determine the severity of somatic and psychic symptoms. The concentration of 6-sultatoxymelatonin (6-HMS) in the urine was measured by ELISA method. In both groups the patients were administrated tianeptine 12.5 mg three times daily or placebo for 8 weeks. After 8 weeks of tianeptine therapy no significant changes were found in urinary 6-HMS excretion both in IBS-C group (9.9+/-3.2 versus 11.5+/-3.5 MUg/24 h) and in IBS-D group (11.8+/-3.3 versus 12.2+/-3.5 MUg/24 h). Eight-week tianeptine therapy resulted in significant decrease of somatic and psychic symptoms in both investigated groups. The improvement in the quality of life indices was obtained in 76.5% of IBS-C and in 63.3% of IBS-D patients. CONCLUSIONS: tianeptine does not impair melatonin homeostasis in patients with IB, diminishes IBS symptoms and improves the patients' quality of life. PMID- 23756393 TI - Experimental methods of abdominal aortic aneurysm creation in swine as a large animal model. AB - Animal models of abdominal aortic aneurysms (AAA) enable preclinical studies on new therapeutic approaches and help to understand pathophysiology of the disease. The aim of this study was to demonstrate the effectiveness of selected methods of experimental induction of abdominal aortic aneurysm in swine and to adapt the EMG examination (electromyography) to record the vessel wall changes. The animals were divided into 3 groups comprising 4 individuals in whom AAA was surgically induced. In the first group the AAA was induced by mechanical stretching of the aortic wall and injection of 500 IU elastase under pressure. The second group received elastase and 6000 IU of collagenase. In the third group 0.5 M CaCl2 solution was introduced additionally. Enlargement of abdominal aorta was monitored for 4 weeks. The first group did not show any aorta dilatation. In the second group the aortic lumen was dilated on average by 71+/-3.5% (P<=0.001) as shown at autopsy and by 76.6+/-9.3% as measured by the ultrasound method. In the third group aorta was dilatated by 104.2+/-11.3% as obtained by ultrasound and 72+/-3% at post-mortem examination. Myoelectric activity of VSMC (vascular smooth muscle cell) was demonstrated and it was characterized by the presence of three types of waves closely related to the pressure changes in the vessel lumen. We conclude that collagen fibers damage plays a significant role in the AAA development in swine. The inflammatory process in the vessel's wall also contributes to AAA development. However, myoelectrical activity of VSMC does not significantly change despite histologically confirmed loss of muscular layer. PMID- 23756394 TI - Adiponectin and leptin receptors expression in Barrett's esophagus and normal squamous epithelium in relation to central obesity status. AB - Esophageal adenocarcinoma incidence is rapidly increasing which may be due to the growing incidence of Barrett's esophagus (BE) and obesity. The mechanisms linking obesity and progression of Barrett's carcinogenesis is poorly understood. The aim of the study was to evaluate the expression of adipokines receptors in BE and in normal squamous epithelium in the same patients in correlation with obesity parameters. METHODS: Expression of adiponectin receptors 1 and 2 protein (AdipoR1, AdipoR2) as well as leptin receptor protein (ObR) in biopsies from 27 BE and normal squamous epithelium (N) in the same patients as well as in obese and normal controls were assessed with Western-blot analysis. These correlations were confirmed with the quantitative RT-PCR (qRT-PCR). AdipoR1 and ObR protein levels were similar in BE mucosa and squamous epithelium in the same patients in Western-blot analysis (2303 vs. 2448 OB units; 106927 vs. 103390, respectively; p>0.05). RT-PCR analysis confirmed this observation for AdipoR1, R2 and ObR genes expression (0.11+/-0.08 vs. 0.19+/-0.24, p=0.78; 0.24+/-0.36 vs. 0.33+/-0.49, p=0.5375; 0.71+/-0.8 vs. 1.33+/-2.95, p=1.0; respectively). Using linear correlation analysis we found the positive correlation between AdipoR1 expression in Barrett's epithelium compared to squamous epithelium in the same patients (N) (r=0.5; p=0.008) and between ObR expression in BE and N (r=0.8; p<0.001). The AdipoR1 and ObR protein levels were significantly higher in BE patients compared to controls and obese controls (2303 vs. 895 vs. 1674 and OD units, p<0.05). CONCLUSIONS: in opposite to the prior hypothesis adiponectin and leptin receptors activation in BE may be not caused by obesity. PMID- 23756395 TI - Comparison between the effects of lisinopril and losartan on the cougn reflex in anesthetized and awake rabbits. AB - The aim of the present study was to analyze differences in cough induction between losartan and lisinopril in both anaesthetized and awake rabbits, i.e., under conditions in which the influences of higher brain areas on the cough reflex are strongly reduced or abolished. Losartan (500 MUg/kg), lisinopril (100 MUg/kg) and NaCl 0.9% saline solution (vehicle) were administered by intravenous injections. Animals were randomly assigned to the different experimental treatments. The cough reflex was induced by chemical (citric acid) and/or mechanical stimulation of the tracheobronchial tree. In anaesthetized rabbits, losartan and lisinopril caused similar hypotensive effects. Lisinopril, but not losartan, increased the cough response induced by both mechanical and chemical stimulation due to increases in the cough number, i.e. the number of coughs induced by each stimulation challenge. In awake animals, only lisinopril significantly increased the cough number. The results support the notion that cough potentiation induced by losartan, and possibly other sartans, is lower than that induced by most angiotensin-converting enzyme inhibitors despite the reduction or complete absence of higher brain functions. In this connection, the comparison between present results and our previous findings on ramipril and zofenopril shows that losartan and zofenopril display similar cough-inducing potency, much lower than that of lisinopril and ramipril. PMID- 23756396 TI - Multiplexed immunoassays for simultaneous quantification of cardiovascular biomarkers in the model of H(G)-nitro-L-arginine methylester (L-NAME) hypertensive rat. AB - The multimarker approach using Luminex technology represents a new tool for studying the pathogenesis of cardiovascular disease. Although many cardiac biomarkers in heart failure have been well established, the role and significance of their measurement in hypertensive patients is still questionable. The aim of our study was to evaluate the relationship of selected biomarkers in L-NAME induced hypertension to the left ventricular remodeling in the two different periods of hypertension development. Four groups of 3-month-old male Wistar rats were investigated: (1) control 4 (placebo for 4 weeks), (2) control 7 (placebo for 7 weeks), (3) L-NAME 4 (40 mg/kg/day for 4 weeks), and (4) L-NAME 7 (40 mg/kg/day for 7 weeks). BNP, cTnI, TNF-alpha, and VEGF were measured using Rat CVD Panel 1 Kit (Milliplex(r) MAP). Cardiac troponin T was determined using Elecsys(r) Troponin T high sensitive immunoassay (Roche, Switzerland). Although the systolic blood pressure increases about 50% in L-NAME-induced hypertension in rat, both hypertrophy and fibrosis were expressed only slightly in this experiment. The levels of BNP, TNF-alpha, or VEGF did not differ significantly among groups. However, cardiac troponin T measured by high sensitive ELISA was significantly (P<0.05) increased in L-NAME 4 (0.229 MUg/l versus 0.034 MUg/l) and L-NAME-7 groups (0.366 MUg/l versus 0.06 MUg/l) in comparison with the controls. We conclude that the slightly increased cTnT levels could indicate ischemic damage of L-NAME-hypertensive heart. Importantly, to our best knowledge, this is the first study indicating that CVD rat panel may be a useful methodological tool in experimental cardiology. PMID- 23756397 TI - The role of serotonergic 5-HT1A receptors in central cardiovascular regulation in haemorrhagic shock in rats. AB - The bleeding and haemorrhage is strictly related with accidents and many medical procedures. In some conditions it leads to hypovolaemia and further to hypovolaemic shock. Under conditions of haemorrhagic shock, heart rate and blood pressure critically collapse. Reversing the sympathoinhibitory phase of hypovolaemia could be crucial for clinical management of injured patients after haemorrhage. Systemic administration of 5-HT1A agonists seams to produce resuscitating effects. The aim of this study was to investigate the participation of central serotonin and, in particular, 5-HT1A receptors in cardiovascular regulation in haemorrhagic shock in rats. Intracerebroventricular (i.c.v.) administration of serotonin (5-HT) increased the heart rate (HR), mean arterial pressure (MAP) and implicated that all haemorrhaged animals survived for the whole observation time (2 hours). Similar, although significantly more minor, effects were achieved after selective 5-HT1A activation. Moreover, the i.c.v. administration of selective 5-HT1A antagonist before i.c.v. 5-HT injection partially inhibited 5-HT induced changes. The results of the present work indicate that 5-HT plays an important role in the reversal of the haemorrhagic shock in rats. These effects are at least partially dependent on activation of 5 HT1A receptors. PMID- 23756398 TI - Modulation of metabolic and cardiac dysfunctions by swimming in overweight rats on a high cholesterol and fructose diet: possible role of adiponectin. AB - Western diet rich in cholesterol and sucrose with decreased physical activity cause overweight and metabolic syndrome. The aim of the present study was to investigate the effect of swimming on the cardiac adiponectin mRNA expression in high cholesterol and fructose fed rats. Forty Sprague-Dawley male rats divided into 2 equal groups. First group - control, that was fed with chow diet for 15 weeks. Second group was fed with high cholesterol and fructose diet (HCFD) for 15 weeks. Ten rats from both groups performed swimming during the last 4 weeks. After 15 weeks serum glucose, insulin, lipogram, leptin, resistin, adiponectin, and cardiac enzymes (lactate dehydrogenase and creatine kinase - MB) levels were measured. HOMA-IR index was calculated, evaluation of cardiac adiponectin gene expression using RT-PCR and cardiac histopathological examination were studied. Left ventricular developed pressure (LVDP), dp/dtmax and -dp/dtmax were measured by isolated Langendorff-perfused heart. Swimming exercise in rats fed HCFD resulted in improvement of the glucose homeostasis and lipogram with decreased leptin, resistin and HOMA-IR index with elevation in serum adiponectin. Also, there was an over-expression of down-expressed cardiac adiponectin gene. Also, ventricular functions were ameliorated by swimming exercise training. Swimming exercise partially improved the ventricular function that could be possibly explained through increased the cardiac expression of adiponectin. PMID- 23756399 TI - The role of oxidative stress in acetylcholine-induced relaxation of endothelium denuded arteries. AB - Nitric oxide (NO) is produced in the endothelium in response to vasorelaxants, such as acetylcholine, and acts on vascular smooth muscle cells to induce vasorelaxation. Previously, we found that the smooth muscle of endothelium denuded arteries expresses functional NO synthase. We hypothesized that the destruction of arterial anatomical integrity induced by denuding arteries of their endothelial layers causes the vessels to become insensitive to vasodilators as a consequence of oxidative stress. In this study, we examined whether the acetylcholine-induced vasorelaxation observed in deendothelialized arteries is mediated by NO and/or affected by oxidative stress. For functional relaxation studies, the isolated thoracic aorta and pulmonary artery of male Wistar rats were used. Vessel superoxide production was assessed in preserved and endothelium denuded arteries by the lucigenin chemiluminescence method. In all arteries with intact endothelia, acetylcholine evoked vasorelaxation; this effect was inhibited in endothelium-denuded rings. Pretreatment of denuded rings with the free-radical scavenger tempol improved acetylcholine-induced relaxation. This effect was inhibited by the coadministration of 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1 one (ODQ), an inhibitor of guanylate cyclase, or N(G)-nitro-L-arginine methylester (L-NAME), an inhibitor of NO synthase. The chemiluminescent assay revealed that endothelial denudation of both vessel types increased the production of superoxide radicals which has been decreased after tempol administration. Our results show that non-endothelial NO could represent an additional source of physiologically active NO and that the insensitivity of endothelium-denuded vessels to vasodilators could be a consequence of oxidative stress. These findings question the concept that endothelial cells play an obligatory role in vasorelaxation. PMID- 23756400 TI - Effect of shiitake (Lentinus edodes) extract on antioxidant and inflammatory response to prolonged eccentric exercise. AB - The shiitake (Lentinus edodes) extract is purported to have potent antioxidant, anti-inflammatory and regenerative properties due to presence of many bioactive compounds such as ergothioneine. This study was designed to assess the antioxidant and anti-inflammatory activity of shiitake extract in healthy men exposed to exercise-induced skeletal muscles damage. Subjects ingested shiitake mushroom extract (700 mg, two times per day) or placebo for 10 days prior to two separate exercise trials (crossover study). The exercise session involved 90 min run at 65% VO2max (0% gradient) and 15-min eccentric phase at 65% VO2max (-10% gradient). Subjects experienced creatine kinase (peak 461+/-206 IU/L) and leukocytes (peak 9.82 x 103/MUL) elevations indicating muscle damage and inflammation. Exercise altered plasma IL-6 (peak 5.29+/-0.78 pg/mL), IL-10 (peak 24.75+/-6.22 pg/mL) and IL-1beta (peak 0.54+/-0.09 pg/mL) levels but did not affect tumour necrosis factor alpha (TNF-alpha) level relative to baseline. Shiitake extract did not demonstrate any effect on immune cells number and inflammatory mediators level, with the exception of IL-10. Thiol redox status (GSHtotal-2GSSG/GSSG) and niric oxide (NO) concentration increased after shiitake extract whereas H2O2 and 8-isoprostanes did not change. In conclusion, shiitake mushroom extract had no effect on markers of inflammation following prolonged eccentric exercise but demonstrated an antioxidant activity through the regulation of nitric oxide concentration and thiol redox status. PMID- 23756401 TI - Mitoxantrone ability to induce premature senescence in human dental pulp stem cells and human dermal fibroblasts. AB - In this study we assessed the effects of the frequently used chemotherapeutic agent mitoxantrone (MTX) on dental pulp stem cells (DPSCs) and compared it with the response of human dermal fibroblasts (HDFs). DPSCs are valuable source of mesenchymal stem cells which may be extremely useful in a number of clinical applications. It is evident that both normal and tumor cells are being affected during therapy and characterization of these cells under genotoxic stress contributes to the evaluation of their safety usage. In the experiment cells were exposed to doses 5-150 nmol/l MTX. Proliferation of cells was detected by Z2 counter and viability by Vi-Cell XR using Trypan blue exclusion staining. Cell cycle analysis was determinated by flow cytometry, induction of apoptosis by monitoring the activities of caspases. The expression of key proteins was detected by Western blotting. Senescence was analyzed by activity of beta galactosidase and by detection of persisting DSBs-associated gammaH2AX foci. Exposure of both cell types to lower concentrations of MTX resulted in premature senescence (SIPS), which was accompanied with typical morphological changes, increased activity of senescence-associated beta-galactosidase, persisting DSBs associated gammaH2AX foci and cell cycle arrest in G2 phase. MTX provokes the activation of p53-p21(WAF1/Cip1) pathway in both cell types and activates cell cycle inhibitor p16(INK4a) in HDFs, but not in DPSCs. Higher concentrations of MTX induced caspase-mediated apoptosis. CONCLUSIONS: MTX induces apoptosis or SIPS in both cell types in dependency on MTX doses. Both pathways prevent the proliferation of cells with damaged DNA. PMID- 23756402 TI - Younger patients report greater improvement in self-reported function after knee joint replacement. AB - STUDY DESIGN: Retrospective chart review. OBJECTIVES: To evaluate and compare the relationship between patients' age and the change in Oxford Knee Score from preoperative to postoperative assessments, and to investigate whether there is a relationship between preoperative Oxford Knee Score results and the indication for total knee replacement surgery, and if age affects this relationship. BACKGROUND: An increasing number of younger patients receive knee joint replacements, yet it is unknown how this cohort functions after surgery. This warrants investigation into the potential age-related differences in joint function following surgery. The Oxford Knee Score has been validated as a clinical tool but has yet to be accepted in the decision-making process regarding the need for, or appropriateness of, total knee replacement. METHODS: In a retrospective chart review, 240 patients completed the Oxford Knee Score questionnaire to evaluate chronic pain and/or dysfunction associated with the knee. RESULTS: The largest improvement with joint replacement was observed to occur in the youngest patient group (50-59 years old). Moreover, the Oxford Knee Score was shown to be the strongest predictor (odds ratio = 0.61) for the indicated intervention when compared to other predictors. The youngest patient group reported a significantly (P<.03) higher Oxford Knee Score result when indicated for surgery, compared to the oldest patient group (80-89 years old). CONCLUSION: The results provide insight into how age influences self-perceived joint function before and after joint replacement surgery, and into the clinical decision to provide the surgical option to younger patients. Moreover, the observed relationship between the Oxford Knee Score and the indicated treatment supports the use of the questionnaire as a preoperative tool in considering treatment options for patients with knee osteoarthritis. LEVEL OF EVIDENCE: Prognosis, level 2b. PMID- 23756403 TI - Subclavian crush syndrome AND subcutaneous ICD in primary prevention patients. PMID- 23756404 TI - A1C as a diabetes diagnosis method: experience in a coronary ICU. AB - AIMS: The laboratory diagnosis of diabetes mellitus is traditionally established by measurements of fasting blood glucose, random blood glucose with associated symptoms, and through the oral glucose tolerance test. A single measurement of glycated hemoglobin (A1C) eliminates practical difficulties of the above mentioned methods. The optimal cut-off values of A1C for the screening of diabetic patients in the context of acute coronary syndrome are being investigated. The aim of this study was to establish a cut-off value for A1C in order to more accurately identify diabetic patients in a group of patients admitted for acute coronary syndrome. METHODS: A prospective study was conducted with 149 patients consecutively admitted for acute coronary syndrome. The diagnosis of diabetes mellitus was established based on a history of the disease or through serial measurements of fasting blood glucose levels on admission and the patients were grouped into diabetic and nondiabetic. A1C values of the two groups were statistically compared to define the optimal cut-off value. RESULTS: Fifty-five (36.91%) patients were diabetic, whereas 94 (63.09%) constituted the nondiabetic group. The cut-off value for A1C with the greatest accuracy to distinguish between the two groups was 6.7%, with sensitivity of 85.45%, specificity of 91.89%, and 88.04% diagnostic accuracy. CONCLUSION: The value of 6.7% for A1C showed good accuracy for the diagnosis of diabetes mellitus in acute coronary syndrome. PMID- 23756405 TI - Brugada syndrome ECG pattern and fever: too warm is bad. AB - We describe a case of Brugada syndrome disclosed by fever and with non significant alterations after a flecainide test. PMID- 23756406 TI - Age-adjusted level of circulating elastin as a cardiovascular risk factor in medical check-up individuals. AB - AIMS: The level of circulating soluble elastin (CSE) is reported to increase proportionally with the degree of clinical atherosclerosis; however, its diagnostic use is limited because CSE also increases with age. We aimed to investigate whether alterations in CSE concentrations are implicated in potential cardiovascular dysfunctions (indicated by standard physiological parameters) in medical check-up individuals, taking age into consideration. METHODS: In a total of 531 individuals (age 20-89 years), CSE levels were correlated most significantly with age. The groups of male and female individuals were each further divided into two subgroups: those with higher and those with lower CSE levels than the reference values determined by polynomial regression. RESULTS: Male participants with lower CSE levels (n = 128) than the age-adjusted reference baseline levels showed higher serum glucose (P < 0.008), uric acid (P < 0.008) and triglyceride (P < 0.02) levels than those with higher CSE levels (n = 126). However, most of the parameters tested in female participants with lower CSE levels (n = 140) were statistically comparable to those with higher CSE levels (n = 137). The ratio of CSE level to the age-adjusted reference level was calculated in each of the male participants, and declines in the ratio were significantly correlated with increases of serum glucose, uric acid and triglyceride levels (P < 0.005, P < 0.02 and P < 0.006, respectively). CONCLUSION: The decrease in age adjusted CSE levels is a potential indicator of eventual cardiovascular dysfunction in medical check-up individuals, as predicted by the risk factors dyslipidemia, hyperuricemia or diabetes. PMID- 23756407 TI - A life-threatening manifestation of tachycardia-induced cardiomyopathy. AB - A 74-year-old man was referred to hospital for sustained dyspnea. The patient was normotensive (110/70 mmHg) with clinical evidence of congestive heart failure. ECG showed atrial flutter (145 bpm). Transthoracic echocardiography demonstrated a mildly dilated left ventricle with severe systolic dysfunction and a big irregular mobile mass, a mildly dilated right ventricle with moderate systolic dysfunction and a large mass protruding into the cavity. The patient was treated surgically for high embolic and sudden death risk after coronarography, which showed a single stenosis (70%) of the left anterior descending coronary. Myocardial biopsy demonstrated interstitial and endocardial fibrosis, no inflammatory pattern. After 6 months of follow-up echocardiography was normal. PMID- 23756408 TI - Cephalic vein with a supraclavicular course: rare, but do not forget it exists! PMID- 23756409 TI - Effect of guidance during cardiac catheterization on emotional, cognitive and behavioral outcomes. AB - AIMS: Percutaneous coronary intervention (PCI) may be perceived as a frightening experience. Some psychological factors are known correlates of recovery and rehabilitation of cardiac patients. Our objective was to investigate the emotional, cognitive and behavioral effects of patient guidance during their cardiac catheterization. METHODS: We performed a randomized trial comparing a patient group that was instructed while watching the monitor screen during their PCI (study group) and another group that was not (controls). Replies to questionnaires measuring emotional, cognitive and behavioral variables known to be associated with cardiac patients' health status, rehabilitation and quality of life were collected 1 day and 1 month after the procedure. RESULTS: The study group included 57 patients and the control group included 51 patients. Most patients (~87%) were men at the mean age of 60. They were well matched for reasons for referral to PCI. The study group reported less pain, a more positive affect, greater self-efficacy and stronger intentions to change health-related behaviors than the control group. At 1 month following the procedure, the study group evaluated their general health as significantly better, and reported a less negative affect, less cardiac anxiety, greater functional self-efficacy and more positive outcome expectancies regarding diet, and quitting smoking than the controls. CONCLUSION: A simple adjustment in the standard PCI protocol can become a highly beneficial psychological intervention for enhancing patient outcomes. PMID- 23756410 TI - Percutaneous coronary intervention in nonagenarian: a meta-analysis of observational studies. AB - BACKGROUND: Developed countries are facing a sustained increase in life expectancy. Along with all social and cultural implications of increase lifespan, very elderly patients are undergoing percutaneous coronary intervention (PCI) with increasing frequency. However, there is limited evidence to guide clinicians in evaluating pros and cons of PCI in this very frail patient population. We, thus, aimed to perform a systematic review and meta-analysis of clinical studies reporting on PCI with stenting in nonagenarians. METHODS: Studies reporting on five or more nonagenarians undergoing PCI were systematically searched in PubMed (last updated on November 2011). Baseline and clinical characteristics, in hospital and long-term outcomes were systematically appraised. End points of interest were in-hospital and long-term follow-up incidence of death and Major Adverse Cardiac Events (MACE; i.e. the composite of death from all causes, myocardial infarction or repeat revascularization). Events were pooled with a random-effect model, generating summary estimates of incidence rates [95% confidence intervals (CI)]. RESULTS: A total of 10 studies were included, reporting on a total of 575 nonagenarians undergoing PCI with stenting who represented 1.99% (1.34-2.5) of those undergoing revascularization in the cath lab in a mean period of 5 (3-7) years. Twenty-three percent (13-45) of patients presented with STEMI (ST Segment Elevation Myocardial Infarction), 10% (7-12) with cardiogenic shock and in 78% (64-88) of cases a multivessel disease was diagnosed. Meta-analytic pooling of event rates showed an in-hospital death risk of 12.61% (9.71-15.50) with MACE in 16.41% (13.36-19.47). After a follow-up ranging from 6 to 29 months (median 12), the risk of long-term death was 31.00% (17.10-45.52), with MACE in 37.00% (19.56-55.95; all CI 95%). CONCLUSION: Our meta-analysis, pooling the largest cohort ever of nonagenarians undergoing PCI with stents, confirms the feasibility of percutaneous coronary stenting even in this very frail patient subset, despite the expected severe event attrition during follow-up. Thus, nonagenarians with an acceptable risk profile, recent clinical instability and/or disabling symptoms should not be denied the possibility of percutaneous coronary revascularization. PMID- 23756411 TI - Radiotherapy and implanted cardioverter defibrillators: novel techniques make it feasible. PMID- 23756412 TI - A strange pneumonia. PMID- 23756413 TI - Inoue balloon valvuloplasty for rheumatic tricuspid valve stenosis: an excellent technique with some intrinsic difficulties. PMID- 23756414 TI - Cryoballoon ablation as index procedure for paroxysmal atrial fibrillation: long term results from a single center early experience. AB - AIMS: Cryoballoon ablation (CRAB) as a modality for pulmonary vein isolation (PVI) is increasingly being accepted. We aim to study the long-term durability of CRAB in atrial fibrillation. METHODS: The first 51 consecutive patients with documented paroxysmal atrial fibrillation(PAF) who underwent CRAB at our institute were considered. Forty patients formed the study group. Successful PVI was achieved in all the patients. Patients were evaluated with Holter ECG recordings at 1, 3, 6 and 12 months and subsequent follow-up was biannual and based on the clinical status and physician discretion whether symptoms occurred. For the study purpose, a baseline ECG, a 24-h Holter and clinical evaluation were performed in all patients at final follow-up. RESULTS: A large 28-mm cryoballoon (CB) was used in 38 patients (95%), and the small 23-mm CB in the remaining two individuals (2%). The freedom from atrial fibrillation off-antiarrhythmic drug treatment (AAD) after a single procedure at a mean follow-up of 36.6 +/- 4 months was 57.5% (23/40). Transient right phrenic nerve palsy was the most common complication. CONCLUSION: Single balloon size CRAB provides a durable atrial fibrillation-free-AAD-free survival in drug-resistant PAF patients over long-term follow-up with a success rate of 57.5% with a single procedure. PMID- 23756415 TI - Cardiac magnetic resonance for the assessment of myocardial viability: from pathophysiology to clinical practice. AB - Cardiac magnetic resonance (CMR) is commonly applied for the assessment of myocardial viability in patients with ischemic ventricular dysfunction, and it holds potential advantages over more traditional imaging modalities, including single-photon emission computed tomography (SPECT) and dobutamine stress echocardiography (DSE). CMR-based techniques for viability assessment include the evaluation of transmural extent of the scar using late gadolinium enhancement (LGE) images, the evaluation of end-diastolic wall thickness from resting cine images and the study of inotropic reserve during low-dose dobutamine infusion. During the past decade, the diffusion of the use of CMR for viability assessment confirmed the clinical strengths of this modality and, at the same time, helped to use old techniques with an increased level of awareness. With LGE CMR, both viable and nonviable dysfunctional myocardium can be visualized in a single image, allowing a direct quantification of the amount of regional viability, with a significant impact on the estimation of chance for recovery. As well, studies with CMR applied in the setting of ischemic heart disease allowed a better understanding of the best way to apply and interpret other tests for viability evaluation. For instance, it has been demonstrated that the transmural extension of the scar may influence the level of concordance between SPECT and DSE in assessing myocardial viability. The transmural extent of scar on LGE CMR also correlates with the timing of postrevascularization recovery of systolic function, with significant impact on the diagnostic accuracy of any applied imaging modality. PMID- 23756416 TI - Aortoaxillary bypass during cardiac operation. AB - AIMS: The aim of the present study was to analyze our experience in the use of the aortoaxillary bypass during cardiac operation in a limited series of patients with proximal atherosclerotic lesion of the subclavian artery combined with cardiac disease amenable to surgical treatment. METHODS: Of 1953 consecutive patients who underwent cardiac operation at our unit between April 2009 and July 2012, nine (0.5%; four women and five men; mean age 69.0 +/- 6.2 years) suffered from symptomatic occlusive disease of the subclavian artery, and underwent concomitant aortoaxillary bypass. A ring-reinforced polytetrafluoroethylene vascular graft was anastomosed to the proximal segment of the axillary artery, introduced into the pleural cavity through the first or the second intercostal space, and anastomosed to the ascending aorta. All perioperative data were collected prospectively. RESULTS: Seven (77.8%) left and two (22.2%) right aortoaxillary bypasses were achieved. Ten concomitant cardiac operations were performed. There were no early postoperative complications related to the subclavian artery revascularization. At a mean follow-up of 27.3 +/- 15.5 months, both the symptoms of the subclavian artery disease and those of the heart disease improved. High-resolution computed tomography angiography confirmed an excellent patency of the aortoaxillary bypass in all the patients but one. CONCLUSION: Concomitant aortoaxillary bypass and cardiac operation may be an option to keep in mind for patients with coexisting subclavian artery occlusion and heart disease, after the evidence that the combined operation does not increase the risk. Attention should be paid to the course of the bypass graft toward the axillary artery. PMID- 23756417 TI - The effect of rear-seat overloading in a car crash: pathological and kinematics evidences. AB - Seat belts have been shown to decrease the incidence of lethal lesions to the head, chest, and abdomen. Since the introduction of seat belts, it is reported that the incidence of traumatic lesions in these body parts is reduced. In the meantime, the characteristic lesions to the chest and abdomen caused by the use of seat belts are described (J Trauma. 2007;62(6):1473-1480).Reported is a peculiar case of an oblique front-to-rear car collision, in which overloading of the rear seat with packages pushed forward the passenger front seat in an abnormal way, causing fatal thoracic and abdominal lesions.The authors underline that the seat belt protection device is defeated if front seats are damaged by heavy unanchored bags on the rear seat or on the rear parcel shelf of a motor vehicle. PMID- 23756418 TI - One-pot aqueous synthesis of sub-10 nm responsive nanogels. AB - A strategy involving free radical copolymerization of a difunctional oligomer and a small-molecule crosslinker to give sub-10 nm nanogels is proposed. These nanogels can adapt to surrounding temperatures and regulate the release of a preloaded model anticancer drug 5-fluorouracil. PMID- 23756420 TI - Oral health care provision systems in the black sea countries part 14: the Republic of Macedonia. AB - This paper gives an overview of the development of health insurance and some aspects of the oral health care in the Republic of Macedonia since it became independent in 1991. First, it describes the provision of oral health care and treatments funded by the public health care system. The dental educational system and available epidemiological data are then described. Generally, few data are available about the dental workforce in recent years, especially regarding dental epidemiology. There are various specialisations in dentistry recognised in Macedonia, as well as three subspecialisations: implantology, maxillofacial and reconstructive prosthodontics, and prosthodontics for children. One aspect of particular interest is that there are many dental faculties in Macedonia and many dentists, relative to the population and the country's requirements. PMID- 23756419 TI - Comparative cross-linking and mass spectrometry of an intact F-type ATPase suggest a role for phosphorylation. AB - F-type ATPases are highly conserved enzymes used primarily for the synthesis of ATP. Here we apply mass spectrometry to the F1FO-ATPase, isolated from spinach chloroplasts, and uncover multiple modifications in soluble and membrane subunits. Mass spectra of the intact ATPase define a stable lipid 'plug' in the FO complex and reveal the stoichiometry of nucleotide binding in the F1 head. Comparing complexes formed in solution from an untreated ATPase with one incubated with a phosphatase reveals that the dephosphorylated enzyme has reduced nucleotide occupancy and decreased stability. By contrasting chemical cross linking of untreated and dephosphorylated forms we show that cross-links are retained between the head and base, but are significantly reduced in the head, stators and stalk. Conformational changes at the catalytic interface, evidenced by changes in cross-linking, provide a rationale for reduced nucleotide occupancy and highlight a role for phosphorylation in regulating nucleotide binding and stability of the chloroplast ATPase. PMID- 23756421 TI - Panoramic radiography for screening postmenopausal osteoporosis in India: a pilot study. AB - AIM: The overall aim of this pilot study was to establish the role of dental practitioners in identifying patients at risk of osteoporosis from panoramic radiographs. METHODS: The pilot study evaluated 32 randomly selected postmenopausal women with no known secondary cause of bone loss. A panoramic radiograph of each patient was taken and qualitative and quantitative radiomorphometric indices were determined. Bone mineral densities of the mandible and lumbar vertebrae were measured by dual energy x-ray absorptiometry. Using World Health Organization criteria, patients were divided into normal, osteopoenic and osteoporotic categories. The relationship of qualitative and quantitative indices with bone mineral densities of the mandible and lumbar area was analysed statistically. RESULTS: Significant positive correlation (Pearson coefficient) was observed between bone mineral densities of the mandible and bone mineral densities of lumbar vertebrae. There was significant (P<0.05) association between the mandibular cortical index (MCI) and osteoporosis (chi-square test), incidence of osteoporosis increased from group C1 to C2 to C3. Strong positive correlation (Pearson coefficient) was observed between all quantitative indices and bone mineral densities of lumbar vertebrae. Intra-observer and inter-observer reproducibility for the quantitative indices was poor (paired and unpaired t tests, respectively). However, it was excellent for the mandibular cortical index (kappa coefficient). CONCLUSIONS: The mandibular cortical index, a qualitative index based on morphological changes in the inferior cortex observed on panoramic radiograph, is useful tool for the screening of postmenopausal osteoporotic patients. Quantitative indices (mental index, inferior and superior panoramic mandibular indices, antegonion index and gonion index), although well correlated with skeletal bone loss, were not useful because of their poor reproducibility. A study with a larger sample is needed to confirm the results from this pilot. PMID- 23756422 TI - Knowledge of, attitude towards, and prevalence of tobacco use among dental students in Himachal Pradesh State, India. AB - AIM: The aim of the study was to assess the prevalence of tobacco use and knowledge of and attitude towards cessation counselling among dental students in Himachal Pradesh State, India. METHOD: The present study was conducted with the 219 third-year Bachelor of Dental Surgery (BDS) students in the five dental colleges of Himachal Pradesh during the month of March 2012. The Global Health Professional Students Survey (GHPSS) questionnaire, developed by the World Health Organization (WHO), the US Centers for Disease Control and Prevention (CDC) and the Canadian Public Health Association, was used in this study. The data were evaluated using statistical software and statistically tested with the chi-square test. RESULTS: The response was 210 (96%). Lifetime prevalence was 15% for smoking and 2% for tobacco use other than for smoking. Eighteen (9%) students were current smokers and four (2%) were tobacco users other than for smoking. Male students were significantly (P<0.001) more likely than female students to be current cigarette smokers. Approximately 14 (47%) of sometime smokers had smoked on school property and two (50%) of the sometime users of other tobacco products had used those products on school property. As for attitudes, 169 (85%) felt that health professionals serve as role models for their patients and the public. Only 17 (8.5%) of surveyed students had received formal instruction in smoking cessation approaches during their training and 167 (84.3%) thought that health professionals should receive specific training on cessation techniques. CONCLUSION: Although the current prevalence of tobacco use among third-year dental students in Himachal Pradesh is low, it still needs to be addressed by providing them with the necessary skills and support to quit smoking successfully and to provide counselling. PMID- 23756423 TI - The effect of erbium, chromium:yttrium-scandium-gallium-garnet (Er,Cr:YSGG) laser therapy on pain during cavity preparation in paediatric dental patients: a pilot study. AB - INTRODUCTION: Standard treatment for caries removal and cavity preparation for restorations using mechanical means is often accompanied by fear and pain for the patient. Although the pain may be reduced by local anaesthesia, fear of the needle, noise, and the vibration of mechanical preparation remain a cause of discomfort. Erbium, chromium:yttriumscandium- gallium-garnet (Er,Cr:YSGG) laser irradiation indicates that pain perception may be reduced relative to that caused by mechanical preparation. AIM: The aim of this pilot clinical study was to perform a preliminary evaluation of pain perception during cavity preparation comparing the mechanical removal and Er,Cr:YSGG laser removal of caries from enamel and dentine. METHODS: The study sample was ten children aged 7 to 12 years. Half of the preparations were completed by the laser alone and the other half were mechanically prepared. All cavities were restored with light-cured composite resin following the application of acid etch and a bonding agent. The time spent on cavity preparation and the behaviour of the patients during cavity preparation were recorded. Children were instructed to rate their pain on a visual analogue scale. In addition, the patients were asked to decide which was the more uncomfortable form of treatment and the preferred treatment for future caries therapy. RESULTS: Children showed considerably more body and head movement with the conventional mechanical preparation. The subjects rated the perception of pain lower when the laser technique was used. CONCLUSION: In the small number of children studied, the application of the Er,Cr:YSGG laser system was a more comfortable alternative or adjunctive method to conventional mechanical cavity preparation. A far larger study is necessary to confirm this finding. PMID- 23756424 TI - Psychiatric morbidity among patients with oral submucous fibrosis: a controlled study. AB - AIM: The study aimed to evaluate the association between oral submucous fibrosis (OSF) and psychiatric morbidity in a controlled manner. METHODS: Matched patients were divided into three groups: Those with areca nut chewing habits with OSF (Group 1; n=50); those with areca nut chewing habits without OSF (Group 2; n=50); those without areca habits and with dental problems other than OSF (Group 3; n=50). The Mini International Neuropsychiatric Interview was used to assess psychiatric morbidity. Dependence to areca products was also assessed. RESULTS: Sixteen (32%) Group 1 patients had psychiatric morbidity compared to one (2%) in Group 2 and two (4%) in Group 3 (P<0.001). Further, psychiatric morbidity was significantly higher among patients with advanced stages of OSF. In Groups 1 and 2, 49 (98%) and 47 (94%) patients, respectively, had dependence on areca products. CONCLUSION: This study has suggested the association of substantial psychiatric morbidity among patients with OSF. In addition to mandatory psychiatric management of these patients, future research should be targeted at a prospective evaluation of a cause and effect relationship as well as at psychiatric interventions. PMID- 23756425 TI - A clinico-biochemical evaluation of the role of a herbal (Ayurvedic) immunomodulator in chronic periodontal disease: a pilot study. AB - BACKGROUND: Host modulation is fast gaining popularity as a preferred therapeutic modality for periodontal disease. Recent research in the medical field into herbal immunomodulators such as Septilin(r) has spurred an interest in evaluating its efficacy in periodontitis for the first time. AIM: The aim of the study was to assess the immunomodulatory effects of the herbal immunomodulator Septilin(r) (Himalaya Drug Company, Bangalore, India) when used as an adjunct to scaling and root planing in chronic periodontal disease. METHODS: Forty systemically healthy patients aged between 25 and 55 years of age and with chronic periodontitis were randomly divided into two groups. The test group was administered Septilin(r) tablets for two weeks following scaling and root planing whereas the control group was treated by scaling and root planing alone. Changes in gingival index (GI), gingival bleeding index (GBI), serum C-reactive protein (CRP) levels and salivary tumour necrosis factor-alpha (TNF-alpha) levels were assessed at day 0, at two weeks, and at three and six months. RESULTS: The GI and GBI showed a statistically significant reduction at two weeks, three months and six months (P<0.001) in both groups. Salivary TNF-alpha level reduction was significant in the test group only (P<0.001). No significant change was found in serum CRP levels in both groups (P>0.05). CONCLUSION: In this pilot evaluation, Septilin(r) was found to be a safe and effective immunomodulator as an adjunct to routine periodontal therapy. Further long-term studies to test Septilin(r) on larger sections of the population are recommended. PMID- 23756426 TI - Estimation and comparison of salivary immunoglobulin A levels in tobacco chewers, tobacco smokers and normal subjects. AB - AIMS: To estimate the salivary immunoglobulin A (IgA) levels in tobacco chewers, tobacco smokers and normal subjects and to compare the salivary IgA levels among tobacco chewers and tobacco smokers. METHODS: The study group consisted of 80 subjects (tobacco users), 40 tobacco chewers and 40 tobacco smokers. Unstimulated whole saliva was collected from all tobacco users and 40 healthy age- and gender matched non-tobacco users as control group. The study and control groups were divided into four subgroups based on age range. Salivary IgA levels were estimated by single radial immunodiffusion assay (SRID). All data were analysed using statistical software and to compare the results in three groups, single factor analysis of variance was applied. RESULTS: The mean salivary IgA level in control group was 16.76 +/- 1.37 mg/dl (SD); in tobacco chewers it was 7.89 +/- 0.61 mg/dl (SD) and in tobacco smokers it was 6.55 +/- 0.99 mg/dl (SD). The salivary IgA levels were decreased in tobacco chewers and tobacco smokers compared with the controls. Among the tobacco users, tobacco smokers had much reduced salivary IgA levels compared to tobacco chewers. All of these results were highly significant (P<0.001). CONCLUSIONS: The present study showed that tobacco chewers and tobacco smokers had decreased salivary IgA levels and among tobacco users, tobacco smokers had much reduced salivary IgA levels compared to tobacco chewers in unstimulated whole saliva. PMID- 23756427 TI - Oral mini pulse therapy: report of a case and review of the literature. AB - Oral lichen planus (OLP) is a chronic mucocutaneous disease with an unknown aetiology, affecting 0.5-2% of the population and with a predilection for females in fourth to fifth decade of life. Most oral lichen planus lesions are asymptomatic but the atrophic and erosive forms of OLP can cause symptoms ranging from spontaneous soreness to severe pain interfering with eating, speech and swallowing. Various drugs have been used for the treatment of OLP including corticosteroids and other immunomodulators. However, no therapy is considered as the single most effective and without side effects in the management of this enigmatic disease. This paper presents a case of successful management of extensive, symptomatic atrophic OLP with a novel treatment protocol: oral mini pulse therapy with betamethasone. In spite of using long-term systemic corticosteroids, side effects were minimal and clinically uneventful. Further controlled trials with this therapy may provide a definitive mode of treatment for severe OLP cases. PMID- 23756428 TI - Western blots versus selected reaction monitoring assays: time to turn the tables? PMID- 23756429 TI - Serum miR-483-5p and miR-195 are predictive of recurrence risk in adrenocortical cancer patients. AB - Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Local and distant recurrences occur in a subset of tumors classified as 'aggressive' ACC (aACC), as opposed to 'non-aggressive' ACC (naACC). In this study, we investigated whether tissue and serum microRNAs (miRNAs) are predictive of ACC prognosis. Tissue miRNA expression profiles were determined using microarrays in a test series of six adrenocortical adenomas (ACAs), six naACCs, and six aACCs. Eight miRNAs were selected for further validation by quantitative RT-PCR (ten ACAs, nine naACCs, nine aACCs, and three normal adrenals). Serum levels of five miRNAs were measured in samples from 56 subjects (19 healthy controls (HC), 14 ACA, nine naACC, and 14 aACC patients). MiR-195 and miR-335 levels were significantly decreased in both tumor and serum samples of ACC patients relative to ACA patients or HC. MiR-139-5p and miR-376a levels were significantly increased in aACC compared with naACC patients in tumor samples only. Tissue miR 483-5p was markedly upregulated in a majority of ACC compared with ACA patients or HC, but most importantly, serum miR-483-5p was detected only in aACC patients. High circulating levels of miR-483-5p or low circulating levels of miR-195 were associated with both shorter recurrence-free survival (P=0.0004 and P=0.0014 respectively) and shorter overall survival (P=0.0005 and P=0.0086 respectively). In conclusion, this study reports for the first time that circulating miR-483-5p and miR-195 are promising noninvasive biomarkers with a highly specific prognostic value for the clinical outcome of ACC patients. PMID- 23756430 TI - The NF1 gene: a frequent mutational target in sporadic pheochromocytomas and beyond. AB - Patients suffering from the neurofibromatosis type 1 syndrome, which is caused by germline mutations in the NF1 gene, have a tiny but not negligible risk of developing pheochromocytomas. It is, therefore, of interest that the NF1 gene has recently been revealed to carry somatic, inactivating mutations in a total of 35 (21.7%) of 161 sporadic pheochromocytomas in two independent tumor series. A majority of the tumors in both studies displayed loss of heterozygosity at the NF1 locus and a low NF1 mRNA expression. In view of previous findings that many sporadic pheochromocytomas cluster with neurofibromatosis type 1 syndrome associated pheochromocytomas instead of forming clusters of their own, NF1 inactivation appears to be an important step in the pathogenesis of a large number of sporadic pheochromocytomas. A literature and public mutation database review has revealed that pheochromocytomas are among those human neoplasms in which somatic NF1 alterations are most frequent. PMID- 23756431 TI - Effects of repeated anodal tDCS coupled with cognitive training for patients with severe traumatic brain injury: a pilot randomized controlled trial. AB - OBJECTIVE: To determine whether cumulative anodal transcranial direct current stimulation (A-tDCS) of the left dorsolateral prefrontal cortex (DLPFC) could enhance rehabilitation of memory and attention in patients with traumatic brain injury (TBI). SETTING: Inpatient and outpatient neurorehabilitation unit. PARTICIPANTS: Twenty-three adult patients, 4- to 92- months post severe TBI. DESIGN: Participants were randomly allocated to 2 groups. The experimental group received A-tDCS (10 minutes; 1 mA; in the DLPFC), followed by rehabilitative cognitive training, daily for 15 days. Controls received A-tDCS for 25 seconds (sham condition) with the same rehabilitation. MAIN MEASURES: Battery of memory and attention tests, which included visual and auditory modalities. Participants were tested twice before beginning rehabilitation (to control for spontaneous recovery), after rehabilitation completion, and 4 months later. RESULTS: Tests scores in both groups were similar at 3 weeks before and immediately before treatment. After treatment, the experimental group exhibited larger effect sizes in 6 of 8 cognitive outcome measures, but they were not significantly different from controls. At follow-up, differences remained insignificant. CONCLUSION: In contrast to previous studies, our study did not provide sufficient evidence to support the efficacy of repeated A-tDCS for enhancing rehabilitation of memory and attention in patients after severe TBI. PMID- 23756432 TI - The Rehabilitation Institute of Chicago Military Traumatic Brain Injury Screening Instrument: determination of sensitivity, specificity, and predictive value. AB - BACKGROUND: Traumatic brain injury (TBI) is referred to as the signature injury of the wars in Iraq and Afghanistan. Given the prevalence of TBI in military personnel, there is a need for validated instruments tailored to accurately screen for TBI in this population. METHODS: Three hundred service members or veterans underwent a novel screen and a comprehensive diagnostic assessment to identify the occurrence of TBI and/or the presence of posttraumatic stress disorder. Negative predictive value, positive predictive value, sensitivity, and specificity were calculated. RESULTS: This screening tool for TBI yielded sensitivity of 96%, specificity of 64%, negative predictive value of 95%, and positive predictive value of 69%. CONCLUSION: The Rehabilitation Institute of Chicago Military Traumatic Brain Injury Screening Instrument has a high negative predictive value and high sensitivity for TBI. This tool identifies individuals likely to have sustained a TBI. Moreover, it detects those who are likely not to have sustained such an injury and can be reassured in this regard. Because such distinction can be made with a high degree of accuracy in rapid and cost effective fashion, it represents an important contribution to the armamentarium of TBI screening tools. PMID- 23756433 TI - Trends in the epidemiology of disability related to traumatic brain injury in the US Army and Marine Corps: 2005 to 2010. AB - BACKGROUND: Traumatic brain injury (TBI) has been recognized as a major public health issue for several decades. Despite technological advancements in protective equipment and medical care available during recent military conflicts, TBI is the most common neurological condition among Soldiers and Marines evaluated for discharge from service. This study describes the demographic, service-related, and disability characteristics of Soldiers and Marines referred for combat-related TBI disability evaluation. METHODS: Cross-sectional analysis of Soldiers and Marines evaluated for combat-related disability between October 1, 2004 and September 30, 2010 was performed. Traumatic brain injury cases were identified using the Veterans Affairs Schedule for Rating Disabilities code for TBI and compared with other combat-related disabilities. RESULTS: Combat-related TBI disability rates have significantly increased in both the Army and the Marine Corps since 2005. Significantly more unfitting conditions are present on average in combat-related TBI cases than in other combat-related disability cases. Combat related TBI disability cases are more likely to be medically retired than other types of combat-related disability. CONCLUSIONS: Because veterans with combat related TBI disabilities are likely to require chronic care for TBI-associated medical conditions, disability evaluation policy and programs must ensure that combat-related TBI disabilities are accurately identified and compensated, and the potential long-term care needs are addressed. PMID- 23756434 TI - Cancer prehabilitation: an opportunity to decrease treatment-related morbidity, increase cancer treatment options, and improve physical and psychological health outcomes. AB - Cancer prehabilitation, a process on the continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment, includes physical and psychological assessments that establish a baseline functional level, identifies impairments, and provides targeted interventions that improve a patient's health to reduce the incidence and the severity of current and future impairments. There is a growing body of scientific evidence that supports preparing newly diagnosed cancer patients for and optimizing their health before starting acute treatments. This is the first review of cancer prehabilitation, and the purpose was to describe early studies in the noncancer population and then the historical focus in cancer patients on aerobic conditioning and building strength and stamina through an appropriate exercise regimen. More recent research shows that opportunities exist to use other unimodal or multimodal prehabilitation interventions to decrease morbidity, improve physical and psychological health outcomes, increase the number of potential treatment options, decrease hospital readmissions, and reduce both direct and indirect healthcare costs attributed to cancer. Future research may demonstrate increased compliance with acute cancer treatment protocols and, therefore, improved survival outcomes. New studies suggest that a multimodal approach that incorporates both physical and psychological prehabilitation interventions may be more effective than a unimodal approach that addresses just one or the other. In an impairment-driven cancer rehabilitation model, identifying current and anticipating future impairments are the critical first steps in improving healthcare outcomes and decreasing costs. More research is urgently needed to evaluate the most effective prehabilitation interventions, and combinations thereof, for survivors of all types of cancer. PMID- 23756435 TI - A biomechanical perspective on physical therapy management of knee osteoarthritis. AB - SYNOPSIS: Altered knee joint biomechanics and excessive joint loading have long been considered as important contributors to the development and progression of knee osteoarthritis. Therefore, a better understanding of how various treatment options influence the loading environment of the knee joint could have practical implications for devising more effective physical therapy management strategies. The aim of this clinical commentary was to review the pertinent biomechanical evidence supporting the use of treatment options intended to provide protection against excessive joint loading while offering symptomatic relief and functional improvements for better long-term management of patients with knee osteoarthritis. The biomechanical and clinical evidence regarding the effectiveness of knee joint offloading strategies, including contralateral cane use, laterally wedged shoe insoles, variable-stiffness shoes, valgus knee bracing, and gait-modification strategies, within the context of effective disease management is discussed. In addition, the potential role of therapeutic exercise and neuromuscular training to improve the mechanical environment of the knee joint is considered. Management strategies for treatment of joint instability and patellofemoral compartment disease are also mentioned. Based on the evidence presented as part of this clinical commentary, it is argued that special considerations for the role of knee joint biomechanics and excessive joint loading are necessary in designing effective short- and long-term management strategies for treatment of patients with knee osteoarthritis. LEVEL OF EVIDENCE: Therapy, level 5. PMID- 23756436 TI - Rate and predictors of carotid artery intima media thickness progression in antiretroviral-naive HIV-infected and uninfected adults: a 48-week matched prospective cohort study. AB - BACKGROUND: Carotid intima media thickness (CIMT) progresses faster in HIV infected adults on antiretroviral therapy (ART) than the general population. It is unclear if the rate of progression is similarly faster in ART-naive, HIV infected adults. METHODS: This was a 48-week prospective cohort study to compare change in CIMT and inflammation markers in ART-naive, HIV-infected adults in no immediate need of ART (HIV-positive/ART-naive) and age/sex/body mass index (BMI) matched controls (HIV-negative). RESULTS: A total of 85 HIV-positive/ART-naive and 45 HIV-negative participants were enrolled. In the HIV-positive/ART-naive group, median baseline CD4+ T-cell count and HIV-1 RNA were 535 cells/mm3 and 6,916 copies/ml. Baseline common carotid artery (CCA) and bulb CIMTs were similar between groups. Changes in CIMT to 48 weeks at both sites were not different within- or between-groups (median [IQR] change in HIV-positive/ART-naive versus HIV-negative CCA CIMT -0.0071 mm [-0.0267-0.0233] versus 0.0113 mm [-0.0117 0.0306]; P = 0.19 between-groups; and bulb CIMT 0.0017 mm [-0.0367-0.06167] versus 0.01 mm [-0.0383-0.0625]; P = 0.54). After adjustment for cardiovascular disease (CVD) risk factors, change in CCA CIMT was greater in HIV-negative participants (-0.0046 versus 0.0177 mm for HIV-positive/ART-naive versus HIV negative; P = 0.01). In HIV-positive/ART-naive, interleukin (IL)-6, soluble tumour necrosis factor-alpha receptor (sTNFR)-II, vascular cell adhesion molecule 1 and intercellular adhesion molecule (ICAM)-1 were higher at both time points and D-dimer was higher at week 48 (P < 0.01 for all). IL-6, sTNFR-I and D-dimer increased over 48 weeks in HIV-positive/ART-naive participants (P < 0.01 for all). In HIV-positive/ART-naive participants, independent predictors of greater change in CCA CIMT were higher BMI (P = 0.05) and family history of CVD (P < 0.01) and of greater change in bulb CIMT were higher sTNFR-I (P = 0.03) and higher diastolic blood pressure (P < 0.01). CONCLUSIONS: In ART-naive HIV infected adults at low risk of HIV disease progression and low cardiovascular risk, CIMT progression rate was similar to matched controls. In addition to traditional CVD risk factors, higher levels of sTNFR-I predicted greater bulb CIMT changes. PMID- 23756437 TI - Severe forms of Baraitser-Winter syndrome are caused by ACTB mutations rather than ACTG1 mutations. AB - ACTB and ACTG1 mutations have recently been reported to cause Baraitser-Winter syndrome (BRWS) - a rare condition characterized by ptosis, colobomata, neuronal migration disorder, distinct facial anomalies and intellectual disability. One of the patients carrying an ACTB mutation was previously diagnosed with Fryns Aftimos syndrome (FAS), which is a rare and severe, multiple congenital anomaly (MCA) syndrome whose symptoms partially overlap with that of BRWS. However, several patients with Fryns-Aftimos were considered not to fit into the ACTB and ACTG1 spectrum because of their severe impairment and additional malformations. We report on three patients who had been diagnosed with FAS. All three patients carry a mutation in the ACTB gene. On the basis of the ACTB mutations and analysis of the clinical findings, we reclassify the diagnosis of these patients as severe BRWS. We suggest that mutations in ACTB cause a distinctly more severe phenotype than ACTG1 mutations, despite the structural similarity of beta- and gamma-actins and their overlapping expression pattern. We expand the spectrum of BRWS and confirm that FAS is not a separate entity but an early and severe manifestation of BRWS. PMID- 23756438 TI - Complete mtDNA genomes of Filipino ethnolinguistic groups: a melting pot of recent and ancient lineages in the Asia-Pacific region. AB - The Philippines is a strategic point in the Asia-Pacific region for the study of human diversity, history and origins, as it is a cross-road for human migrations and consequently exhibits enormous ethnolinguistic diversity. Following on a previous in-depth study of Y-chromosome variation, here we provide new insights into the maternal genetic history of Filipino ethnolinguistic groups by surveying complete mitochondrial DNA (mtDNA) genomes from a total of 14 groups (11 groups in this study and 3 groups previously published) including previously published mtDNA hypervariable segment (HVS) data from Filipino regional center groups. Comparison of HVS data indicate genetic differences between ethnolinguistic and regional center groups. The complete mtDNA genomes of 14 ethnolinguistic groups reveal genetic aspects consistent with the Y-chromosome, namely: diversity and heterogeneity of groups, no support for a simple dichotomy between Negrito and non-Negrito groups, and different genetic affinities with Asia-Pacific groups that are both ancient and recent. Although some mtDNA haplogroups can be associated with the Austronesian expansion, there are others that associate with South Asia, Near Oceania and Australia that are consistent with a southern migration route for ethnolinguistic group ancestors into the Asia-Pacific, with a timeline that overlaps with the initial colonization of the Asia-Pacific region, the initial colonization of the Philippines and a possible separate post colonization migration into the Philippine archipelago. PMID- 23756439 TI - CACP syndrome: identification of five novel mutations and of the first case of UPD in the largest European cohort. AB - Camptodactyly-Arthropathy-Coxa vara-Pericarditis (CACP) syndrome is a rare autosomal recessive disorder caused by mutations in PRG4 gene that encodes for proteoglycan 4, a mucin-like glycoprotein that is the major lubricant for joints and tendon surfaces. The molecular studies reported so far have described the identification of 15 mutations associated with this syndrome and the majority of them were found in families of Arabian origin. Here we report the molecular investigation of the largest European cohort that comprises 13 patients, and allowed the identification of 5 novel mutations and of the first case of CACP syndrome resulting from uniparental disomy of chromosome 1. PMID- 23756440 TI - Targeted next-generation sequencing as a comprehensive test for patients with and female carriers of DMD/BMD: a multi-population diagnostic study. AB - Duchenne and Becker muscular dystrophies (DMD/BMD) are the most commonly inherited neuromuscular disease. However, accurate and convenient molecular diagnosis cannot be achieved easily because of the enormous size of the dystrophin gene and complex causative mutation spectrum. Such traditional methods as multiplex ligation-dependent probe amplification plus Sanger sequencing require multiple steps to fulfill the diagnosis of DMD/BMD. Here, we introduce a new single-step method for the genetic analysis of DMD patients and female carriers in real clinical settings and demonstrate the validation of its accuracy. A total of 89 patients, 18 female carriers and 245 non-DMD patients were evaluated using our targeted NGS approaches. Compared with traditional methods, our new method yielded 99.99% specificity and 98.96% sensitivity for copy number variations detection and 100% accuracy for the identification of single-nucleotide variation mutations. Additionally, this method is able to detect partial deletions/duplications, thus offering precise personal DMD gene information for gene therapy. We detected novel partial deletions of exons in nine samples for which the breakpoints were located within exonic regions. The results proved that our new method is suitable for routine clinical practice, with shorter turnaround time, higher accuracy, and better insight into comprehensive genetic information (detailed breakpoints) for ensuing gene therapy. PMID- 23756441 TI - Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits. AB - Williams Beuren syndrome (WBS) is a multisystemic disorder caused by a hemizygous deletion of 1.5 Mb on chromosome 7q11.23 spanning 28 genes. A few patients with larger and smaller WBS deletion have been reported. They show clinical features that vary between isolated SVAS to the full spectrum of WBS phenotype, associated with epilepsy or autism spectrum behavior. Here we describe four patients with atypical WBS 7q11.23 deletions. Two carry ~3.5 Mb larger deletion towards the telomere that includes Huntingtin-interacting protein 1 (HIP1) and tyrosine 3 monooxygenase/tryptophan 5-monooxigenase activation protein gamma (YWHAG) genes. Other two carry a shorter deletion of ~1.2 Mb at centromeric side that excludes the distal WBS genes BAZ1B and FZD9. Along with previously reported cases, genotype-phenotype correlation in the patients described here further suggests that haploinsufficiency of HIP1 and YWHAG might cause the severe neurological and neuropsychological deficits including epilepsy and autistic traits, and that the preservation of BAZ1B and FZD9 genes may be related to mild facial features and moderate neuropsychological deficits. This report highlights the importance to characterize additional patients with 7q11.23 atypical deletions comparing neuropsychological and clinical features between these individuals to shed light on the pathogenic role of genes within and flanking the WBS region. PMID- 23756442 TI - Clarifying assent in pediatric research. AB - Assent is a relatively young term in research ethics, but became an often mentioned ethical requirement in current pediatric research guidelines. Also, the European Society of Human Genetics considers assent an important condition for the inclusion of children in biobanks. However, although many emphasize the importance of assent, few explain how they understand the concept and few have elaborated on the underlying grounds. In this paper, we will discuss the different underlying ethical principles of assent. In the first category, assent appears to be derived from informed consent. This understanding is grounded in respect for autonomy and protection against harm. We conclude that this interpretation of assent is not of added value as a majority of children cannot be considered competent to make autonomous decisions. In addition, other safeguards are more appropriate to protect children against harm. The grounds from the second category can be classified as engagement grounds. These grounds do justice to the specifics of childhood and are of added value. Furthermore, we argue that it follows that both the content and the process of assent should be adjusted to the individual child. This can be referred to as personalized assent. Personalized assent is an appeal to the moral responsibility and integrity of the researcher. PMID- 23756443 TI - Clinical utility gene card for: tuberous sclerosis complex (TSC1, TSC2). PMID- 23756444 TI - Mutations in the C-terminus of CDKL5: proceed with caution. AB - Mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene have been described in girls with Rett-like features and early-onset epileptic encephalopathy including infantile spasms. Milder phenotypes have been associated with sequence variations in the 3'-end of the CDKL5 gene. Identification of novel CDKL5 transcripts coding isoforms characterized by an altered C-terminal region strongly questions the eventual pathogenicity of sequence variations located in the 3'-end of the gene. We investigated a group of 30 female patients with a clinically heterogeneous phenotype ranging from nonspecific intellectual disability to a severe neonatal encephalopathy and identified two heterozygous CDKL5 missense mutations, the previously reported p.Val999Met and the novel mutation p.Pro944Thr. However, these mutations have also been detected in their healthy father. Considering our results and all data from the literature, we suggest that genetic variations beyond the codon 938 in human CDKL5115 protein may have minor or no significance. It is probable that screening of exons 19-21 of the CDKL5 gene is not useful in practical molecular diagnosis of atypical Rett syndrome. PMID- 23756445 TI - AP1S2 is mutated in X-linked Dandy-Walker malformation with intellectual disability, basal ganglia disease and seizures (Pettigrew syndrome). AB - MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy-Walker malformation and inconstant choreoathetosis. Four individuals had iron deposition in the basal ganglia seen on MRI or at autopsy. The mutation causing Pettigrew has remained elusive since the initial description of the condition. We report the identification of a mutation in the X-linked AP1S2 gene in the original Pettigrew syndrome family using X-chromosome exome sequencing. We report additional phenotype details for several of the affected individuals, allowing us to further refine the phenotype corresponding to this X-linked intellectual disability syndrome. The AP1S2 c.426+1 G>T mutation segregates with the disease in the Pettigrew syndrome family and results in loss of 46 amino acids in the clathrin adaptor complex small chain domain that spans most of the AP1S2 protein sequence. The mutation reported here in AP1S2 is the first mutation that is not predicted to cause a premature termination of the coding sequence or absence of the AP1S2 protein. Although most of the families affected by a mutation in AP1S2 were initially described as having different disorders assigned to at least three different OMIM numbers (MIM 300629, 300630 and 304340), our analysis of the phenotype shows that they are all the same syndrome with recognition complicated by highly variable expressivity that is seen within as well as between families and is probably not explained by differences in mutation severity. PMID- 23756447 TI - Solution-based circuits enable rapid and multiplexed pathogen detection. AB - Electronic readout of markers of disease provides compelling simplicity, sensitivity and specificity in the detection of small panels of biomarkers in clinical samples; however, the most important emerging tests for disease, such as infectious disease speciation and antibiotic-resistance profiling, will need to interrogate samples for many dozens of biomarkers. Electronic readout of large panels of markers has been hampered by the difficulty of addressing large arrays of electrode-based sensors on inexpensive platforms. Here we report a new concept -solution-based circuits formed on chip--that makes highly multiplexed electrochemical sensing feasible on passive chips. The solution-based circuits switch the information-carrying signal readout channels and eliminate all measurable crosstalk from adjacent, biomolecule-specific microsensors. We build chips that feature this advance and prove that they analyse unpurified samples successfully, and accurately classify pathogens at clinically relevant concentrations. We also show that signature molecules can be accurately read 2 minutes after sample introduction. PMID- 23756446 TI - Greasing the synaptic vesicle cycle by membrane lipids. AB - Neurotransmission is based on the exocytic release of neurotransmitters from synaptic vesicles (SVs) at nerve terminals and the subsequent retrieval of SV membranes. Evidence from genetic analysis of model organisms, high-resolution imaging, and biochemical studies indicate that, in addition to the well-studied function of exo-endocytic protein networks, membrane lipids and their derivatives play a key role in SV cycling. These include structural lipids such as cholesterol and sphingolipids as well as phosphoinositides (PIs), which interact with select components of the exocytic and endocytic machineries, thereby coupling both limbs of the SV cycle. Here we provide an overview of the function of lipids in SV cycling and discuss potential models of how lipids and lipid protein interactions may regulate presynaptic function. PMID- 23756448 TI - A novel planarization method based on photoinduced confined chemical etching. AB - A photoinduced confined chemical etching system based on TiO2 nanotube arrays is developed for the planarization of the copper surface, which is proved to be a prospective stress-free chemical planarization method for metals and semiconductors. PMID- 23756449 TI - Intra-arterial tissue plasminogen activator for an ischemic stroke in a 21-year old Hispanic woman with elevated beta human chorionic gonadotropin and complex clinical history. AB - The following case report discusses a 21-year-old Hispanic woman who was brought to the emergency room for evaluation because of experiencing acute left-sided hemiparesis with anosognosia. Upon further assessment, the patient was found to have a positive blood test for methamphetamines, positive human chorionic gonadotropin for pregnancy, and a history of patent foramen ovale. Neurological examination of the patient revealed left hemiparesis, dysarthria, and homonymous hemianopsia of the left side with a National Institutes of Health Stroke Scale of 12. Given the patient's assessment and positive radiological findings of a clot located within the right M1 segmental branch of the middle cerebral artery territory through the use of computed tomography angiography, deployment of intra arterial thrombolytics within 6 hours of symptom onset was utilized. The patient's clinical course was complicated by brain swelling requiring intubation. Return of neurological function was assessed with noninvasive and invasive neurological evaluation, which showed full cognitive and physical return of the functional baseline level at discharge. PMID- 23756450 TI - Estimated versus actual weight when dosing rt-PA in acute ischemic stroke: is there a difference? AB - INTRODUCTION: Intravenous (IV) recombinant tissue plasminogen activator (rt-PA) is the standard of care for patients exhibiting signs of acute ischemic stroke. IV rt-PA uses weight-based dosing, and often an estimated weight is used. The clinical effects of using estimated weight in dosing IV rt-PA remain unclear. The goal of this descriptive study was to determine if there was a significant difference in estimated versus actual weight dosing of rt-PA. METHODS: A retrospective chart review was performed to compare estimated versus actual patient weight. The sample consisted of patients from the hospital database who received IV rt-PA during June 2009-June 2010. Patients were included if they presented to the emergency department with stroke symptoms, received IV rt-PA, and had documented estimated and actual weights. Recorded (prescribed) dosing of IV rt-PA was compared with the suggested dosing using the admission weight. The differences between the weights and doses were calculated, analyzed, and categorized as being underdosed or overdosed. RESULTS: Twenty-six charts met the inclusion criteria. Using descriptive statistics and tests of difference, the mean estimated weight was 79.9 kg (+/-3.92 kg) and the mean actual weight was 78.5 kg (+/-3.86 kg); four patients had an estimated weight discrepancy of >=5 kg. Six had correct estimated dosing; however, all of these patients were greater than 100 kg and received the maximum dose of 90 mg. Eleven patients' estimated weights were underestimated, resulting in underdosing of IV rt-PA. Nine estimated weights were overestimated, leading to overdosing of the medication, but none of the dosing overages exceeded 10%. No statistical significance was found between the two groups' estimated weights or dosing errors, t(26) = 0.69, p = .79. DISCUSSION: Results from this study found documented estimated weights were not significantly different from actual weights and the precision of estimated weight were similar to weights obtained using a scale. Despite these results, methods for obtaining actual weights in the emergency department for high-risk patients should be explored. PMID- 23756451 TI - Epigenetic regulation of spinal CXCR2 signaling in incisional hypersensitivity in mice. AB - BACKGROUND: The regulation of gene expression in nociceptive pathways contributes to the induction and maintenance of pain sensitization. Histone acetylation is a key epigenetic mechanism controlling chromatin structure and gene expression. Chemokine CC motif receptor 2 (CXCR2) is a proinflammatory receptor implicated in neuropathic and inflammatory pain and is known to be regulated by histone acetylation in some settings. The authors sought to investigate the role of histone acetylation on spinal CXCR2 signaling after incision. METHODS: Groups of 5-8 mice underwent hind paw incision. Suberoylanilide hydroxamic acid and anacardic acid were used to inhibit histone deacetylase and histone acetyltransferase, respectively. Behavioral measures of thermal and mechanical sensitization as well as hyperalgesic priming were used. Both message RNA quantification and chromatin immunoprecipitation analysis were used to study the regulation of CXCR2 and ligand expression. Finally, the selective CXCR2 antagonist SB225002 was administered intrathecally to reveal the function of spinal CXCR2 receptors after hind paw incision. RESULTS: Suberoylanilide hydroxamic acid significantly exacerbated mechanical sensitization after incision. Conversely, anacardic acid reduced incisional sensitization and also attenuated incision-induced hyperalgesic priming. Overall, acetylated histone H3 at lysine 9 was increased in spinal cord tissues after incision, and enhanced association of acetylated histone H3 at lysine 9 with the promoter regions of CXCR2 and keratinocyte-derived chemokine (CXCL1) was observed as well. Blocking CXCR2 reversed mechanical hypersensitivity after hind paw incision. CONCLUSIONS: Histone modification is an important epigenetic mechanism regulating incision induced nociceptive sensitization. The spinal CXCR2 signaling pathway is one epigenetically regulated pathway controlling early and latent sensitization after incision. PMID- 23756452 TI - Fentanyl utility function: a risk-benefit composite of pain relief and breathing responses. AB - INTRODUCTION: Integrating opioid risk and benefit into a single function may give a useful single measure of the opioid's positive and negative effects. An explorative study on the effects of fentanyl on antinociception and respiratory depression was performed to construct fentanyl risk-benefit (utility) functions. METHODS: Twelve volunteers received a 3.5-MUg/kg fentanyl intravenous injection on 2 separate study days. On one occasion, ventilation at a clamped increased carbon dioxide concentration was measured and on another the pain tolerance to electrical stimulation. In both sessions, arterial plasma samples were obtained. The data were analyzed with a population pharmacokinetic-pharmacodynamic model. A simulation study was performed, using the model parameter estimates and their variances, in which simulated subjects received 3.5 MUg/kg of fentanyl. The resultant distributions were used to calculate the utility functions, defined as the probability of at least 50% analgesia (an increase in pain tolerance by >=50%) minus the probability of at least 50% respiratory depression (a reduction in ventilation by >=50%). Utility functions were constructed in concentration and time domains. RESULTS: Fentanyl produced significant respiratory depression and analgesia. The pharmacokinetic and pharmacodynamic models adequately described the data. The constructed utility functions were negative at effect-site concentrations of greater than 0.5 ng/ml in the first 90 min after the 3.5 MUg/kg bolus infusion. CONCLUSIONS: Utility functions based on fentanyl's experimental effects on respiration and pain relief were successfully constructed. These functions are useful in multiple effect comparisons among experimental drugs. Further studies are required to assess whether this risk-benefit analysis is valuable in clinical practice. PMID- 23756453 TI - Does goal-directed fluid therapy affect postoperative orthostatic intolerance?: A randomized trial. AB - BACKGROUND: Early mobilization is important for postoperative recovery but is limited by orthostatic intolerance (OI) with a prevalence of 50% 6 h after major surgery. The pathophysiology of postoperative OI is assumed to include hypovolemia besides dysregulation of vasomotor tone. Stroke volume-guided fluid therapy, so-called goal-directed therapy (GDT), corrects functional hypovolemia, and the authors hypothesized that GDT reduces the prevalence of OI after major surgery and assessed this in a prospective, double-blinded trial. METHODS: Forty two patients scheduled for open radical prostatectomy were randomized into standard fluid therapy (control group) or GDT groups. Both groups received a fixed-volume crystalloid regimen supplemented with 1:1 replacement of blood loss with colloid, and in addition, the GDT group received colloid to obtain a maximal stroke volume (esophageal Doppler). The primary outcome was the prevalence of OI assessed with a standardized mobilization protocol before and 6 h after surgery. Hemodynamic and hormonal orthostatic responses were evaluated. RESULTS: Twelve (57%) versus 15 (71%) patients in the control and GDT groups (P = 0.33), respectively, demonstrated OI after surgery, group difference 14% (CI, -18 to 45%). Patients in the GDT group received more colloid during surgery (1,758 vs. 1,057 ml; P = 0.001) and reached a higher stroke volume (102 vs. 89 ml; P = 0.04). OI patients had an increased length of hospital stay (3 vs. 2 days; P = 0.02) and impaired hemodynamic and norepinephrine responses on mobilization. CONCLUSION: GDT did not reduce the prevalence of OI, and patients with OI demonstrated impaired cardiovascular and hormonal responses to mobilization. PMID- 23756454 TI - Development and validation of an intraoperative predictive model for unplanned postoperative intensive care. AB - BACKGROUND: The allocation of intensive care unit (ICU) beds for postoperative patients is a challenging daily task that could be assisted by the real-time detection of ICU needs. The goal of this study was to develop and validate an intraoperative predictive model for unplanned postoperative ICU use. METHODS: With the use of anesthesia information management system, postanesthesia care unit, and scheduling data, a data set was derived from adult in-patient noncardiac surgeries. Unplanned ICU admissions were identified (4,847 of 71,996; 6.7%), and a logistic regression model was developed for predicting unplanned ICU admission. The model performance was tested using bootstrap validation and compared with the Surgical Apgar Score using area under the curve for the receiver operating characteristic. RESULTS: The logistic regression model included 16 variables: age, American Society of Anesthesiologists physical status, emergency case, surgical service, and 12 intraoperative variables. The area under the curve was 0.905 (95% CI, 0.900-0.909). The bootstrap validation model area under the curves were 0.513 at booking, 0.688 at 3 h before case end, 0.738 at 2 h, 0.791 at 1 h, and 0.809 at case end. The Surgical Apgar Score area under the curve was 0.692. Unplanned ICU admissions had more ICU-free days than planned ICU admissions (5 vs. 4; P < 0.001) and similar mortality (5.6 vs. 6.0%; P = 0.248). CONCLUSIONS: The authors have developed and internally validated an intraoperative predictive model for unplanned postoperative ICU use. Incorporation of this model into a real-time data sniffer may improve the process of allocating ICU beds for postoperative patients. PMID- 23756456 TI - Cancer prognosis: can anesthesia play a role? PMID- 23756457 TI - Effectiveness of dry needling for upper-quarter myofascial pain: a systematic review and meta-analysis. AB - STUDY DESIGN: Systematic review and meta-analysis. BACKGROUND: Myofascial pain syndrome (MPS) is associated with hyperalgesic zones in muscle called myofascial trigger points. When palpated, active myofascial trigger points cause local or referred symptoms, including pain. Dry needling involves inserting an acupuncture like needle into a myofascial trigger point, with the goal of reducing pain and restoring range of motion. OBJECTIVE: To explore the evidence regarding the effectiveness of dry needling to reduce pain in patients with MPS of the upper quarter. METHODS: An electronic literature search was performed using the key word dry needling. Articles identified with the search were screened for the following inclusion criteria: human subjects, randomized controlled trial (RCT), dry needling intervention group, and MPS involving the upper quarter. The RCTs that met these criteria were assessed and scored for internal validity using the MacDermid Quality Checklist. Four separate meta-analyses were performed: (1) dry needling compared to sham or control immediately after treatment, (2) dry needling compared to sham or control at 4 weeks, (3) dry needling compared to other treatments immediately after treatment, and (4) dry needling compared to other treatments at 4 weeks. RESULTS: The initial search yielded 246 articles. Twelve RCTs were ultimately selected. The methodological quality scores ranged from 23 to 40 points, with a mean of 34 points (scale range, 0-48; best possible score, 48). The findings of 3 studies that compared dry needling to sham or placebo treatment provided evidence that dry needling can immediately decrease pain in patients with upper-quarter MPS, with an overall effect favoring dry needling. The findings of 2 studies that compared dry needling to sham or placebo treatment provided evidence that dry needling can decrease pain after 4 weeks in patients with upper-quarter MPS, although a wide confidence interval for the overall effect limits the impact of the effect. Findings of studies that compared dry needling to other treatments were highly heterogeneous, most likely due to variance in the comparison treatments. There was evidence from 2 studies that lidocaine injection may be more effective in reducing pain than dry needling at 4 weeks. CONCLUSION: Based on the best current available evidence (grade A), we recommend dry needling, compared to sham or placebo, for decreasing pain immediately after treatment and at 4 weeks in patients with upper-quarter MPS. Due to the small number of high-quality RCTs published to date, additional well designed studies are needed to support this recommendation. LEVEL OF EVIDENCE: Therapy, level 1a-. PMID- 23756458 TI - Mortality due to viral hepatitis in the Global Burden of Disease Study 2010: new evidence of an urgent global public health priority demanding action. AB - The recently published Global Burden of Disease Study 2010 (GBD 2010) contains accurate, contemporary estimates of human morbidity and mortality, with substantial changes in the patterns of illness observed over the last two decades. One of the most significant alterations to these estimates has been the recognition that viral hepatitis is a leading cause of human mortality, with an estimated 1.29 million deaths worldwide in 2010. The global community must act to address emerging health priorities identified by GBD 2010, including the need to provide treatment and care to people living with viral hepatitis, especially in resource-poor settings. PMID- 23756459 TI - Connective tissue ulcers. AB - Connective tissue disorders (CTD), which are often also termed collagen vascular diseases, include a number of related inflammatory conditions. Some of these diseases include rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis (scleroderma), localized scleroderma (morphea variants localized to the skin), Sjogren's syndrome, dermatomyositis, polymyositis, and mixed connective tissue disease. In addition to the systemic manifestations of these diseases, there are a number of cutaneous features that make these conditions recognizable on physical exam. Lower extremity ulcers and digital ulcers are an infrequent but disabling complication of long-standing connective tissue disease. The exact frequency with which these ulcers occur is not known, and the cause of the ulcerations is often multifactorial. Moreover, a challenging component of CTD ulcerations is that there are still no established guidelines for their diagnosis and treatment. The morbidity associated with these ulcerations and their underlying conditions is very substantial. Indeed, these less common but intractable ulcers represent a major medical and economic problem for patients, physicians and nurses, and even well organized multidisciplinary wound healing centers. PMID- 23756460 TI - Quantum nuclear dynamics in the photophysics of diamondoids. AB - The unusual electronic properties of diamondoids, the nanoscale relatives of diamond, make them attractive for applications ranging from drug delivery to field emission displays. Identifying the fundamental origin of these properties has proven highly challenging, with even the most advanced quantum many-body calculations unable to reproduce measurements of a quantity as ubiquitous as the optical gap. Here, by combining first-principles calculations and Importance Sampling Monte Carlo methods, we show that the quantum dynamics of carbon nuclei is key to understanding the electronic and optical properties of diamondoids. Quantum nuclear effects dramatically modify the absorption lineshapes and renormalize the optical gaps. These findings allow us to formulate a complete theory of optical absorption in diamondoids, and establish the universal role of quantum nuclear dynamics in nanodiamond across the length scales. PMID- 23756461 TI - Direct interaction of FtsZ and MreB is required for septum synthesis and cell division in Escherichia coli. AB - How bacteria coordinate cell growth with division is not well understood. Bacterial cell elongation is controlled by actin-MreB while cell division is governed by tubulin-FtsZ. A ring-like structure containing FtsZ (the Z ring) at mid-cell attracts other cell division proteins to form the divisome, an essential protein assembly required for septum synthesis and cell separation. The Z ring exists at mid-cell during a major part of the cell cycle without contracting. Here, we show that MreB and FtsZ of Escherichia coli interact directly and that this interaction is required for Z ring contraction. We further show that the MreB-FtsZ interaction is required for transfer of cell-wall biosynthetic enzymes from the lateral to the mature divisome, allowing cells to synthesise the septum. Our observations show that bacterial cell division is coupled to cell elongation via a direct and essential interaction between FtsZ and MreB. PMID- 23756462 TI - Exonuclease hDIS3L2 specifies an exosome-independent 3'-5' degradation pathway of human cytoplasmic mRNA. AB - Turnover of mRNA in the cytoplasm of human cells is thought to be redundantly conducted by the monomeric 5'-3' exoribonuclease hXRN1 and the 3'-5' exoribonucleolytic RNA exosome complex. However, in addition to the exosome associated 3'-5' exonucleases hDIS3 and hDIS3L, the human genome encodes another RNase II/R domain protein-hDIS3L2. Here, we show that hDIS3L2 is an exosome independent cytoplasmic mRNA 3'-5' exonuclease, which exhibits processive activity on structured RNA substrates in vitro. hDIS3L2 associates with hXRN1 in an RNA-dependent manner and can, like hXRN1, be found on polysomes. The impact of hDIS3L2 on cytoplasmic RNA metabolism is revealed by an increase in levels of cytoplasmic RNA processing bodies (P-bodies) upon hDIS3L2 depletion, which also increases half-lives of investigated mRNAs. Consistently, RNA sequencing (RNA seq) analyses demonstrate that depletion of hDIS3L2, like downregulation of hXRN1 and hDIS3L, causes changed levels of multiple mRNAs. We suggest that hDIS3L2 is a key exosome-independent effector of cytoplasmic mRNA metabolism. PMID- 23756464 TI - A DIStinctively novel exoribonuclease that really likes U. AB - Regulated degradation plays a major role in determining the levels of both non coding (miRNA) and coding (mRNA) transcripts. Thus, insights into the factors and pathways that influence this process have broad, interdisciplinary implications. New findings by Malecki et al (2013), Lubas et al (2013), and Chang et al (2013) identify the protein Dis3L2 as a major player in the 3'-5' exonucleolytic decay of transcripts. Furthermore, they demonstrate a strong connection between terminal uridylation of the RNA substrate and enzymatic activity. PMID- 23756463 TI - Getting to the heart of the matter: long non-coding RNAs in cardiac development and disease. AB - Cardiogenesis in mammals requires exquisite control of gene expression and faulty regulation of transcriptional programs underpins congenital heart disease (CHD), the most common defect among live births. Similarly, many adult cardiac diseases involve transcriptional changes and sometimes have a developmental basis. Long non-coding RNAs (lncRNAs) are a novel class of transcripts that regulate cellular processes by controlling gene expression; however, detailed insights into their biological and mechanistic functions are only beginning to emerge. Here, we discuss recent findings suggesting that lncRNAs are important factors in regulation of mammalian cardiogenesis and in the pathogenesis of CHD as well as adult cardiac disease. We also outline potential methodological and conceptual considerations for future studies of lncRNAs in the heart and other contexts. PMID- 23756465 TI - CRISPRs extending their reach: prokaryotic RNAi protein Cas9 recruited for gene regulation. AB - A Cas protein from the CRISPR defence system against foreign DNA, also functions in endogenous gene regulation. Sampson et al (2013) have revealed that in pathogenic Francisella bacteria, the Cas9 protein guided by small RNAs represses the mRNA of a lipoprotein. This novel mechanism of post-transcriptional regulation enables the infecting bacteria to evade the TLR2-based innate immune response of its host. Thus, reminiscent of eukaryotic RNAi where some proteins facilitate both genome defence and gene regulation, a central prokaryotic RNAi protein not only destroys invading DNA but also controls mRNA expression. PMID- 23756466 TI - Optical detection of epigenetic marks: sensitive quantification and direct imaging of individual hydroxymethylcytosine bases. AB - Herein we report the specific labelling of the epigenetic modification 5 hydroxymethyl-cytosine along genomic DNA molecules with a fluorescent reporter molecule. Enzymatic glucosylation followed by a click chemistry reaction enables single molecule detection as well as global quantification of 5hmC in genomic DNA. PMID- 23756467 TI - Application of chiral N-tert-butylsulfinyl vinyl aziridines in Rh(I) catalyzed 1,4-addition of aryl boronic acids to cyclic enones. AB - Chiral N-tert-butylsulfinyl vinyl aziridine ligands prepared from a readily available (R)-tert-butanesulfinamide have been applied in the rhodium-catalyzed asymmetric 1,4-addition of aryl boronic acids to cyclic enones, which gives high yields and excellent enantioselectivities. PMID- 23756468 TI - Radiation-induced strengthening and absorption of dislocation loops in ferritic Fe-Cr alloys: the role of Cr segregation. AB - The understanding of radiation-induced strengthening in ferritic FeCr-based steels remains an essential issue in the assessment of materials for fusion and fission reactors. Both early and recent experimental works on Fe-Cr alloys reveal Cr segregation on radiation-induced nanostructural features (mainly dislocation loops), whose impact on the modification of the mechanical response of the material might be key for explaining quantitatively the radiation-induced strengthening in these alloys. In this work, we use molecular dynamics to study systematically the interaction of dislocations with 1/2<111> and <100> loops in all possible orientations, both enriched by Cr atoms and undecorated, for different temperatures, loop sizes and dislocation velocities. The configurations of the enriched loops have been obtained using a non-rigid lattice Monte Carlo method. The study reveals that Cr segregation influences the interaction mechanisms with both 1/2<111> and <100> loops. The overall effect of Cr enrichment is to penalize the mobility of intrinsically glissile 1/2<111> loops, modifying the reaction mechanisms as a result. The following three most important effects associated with Cr enrichment have been revealed: (i) absence of dynamic drag; (ii) suppression of complete absorption; (iii) enhanced strength of small dislocation loops (2 nm and smaller). Overall the effect of the Cr enrichment is therefore to increase the unpinning stress, so experimentally 'invisible' nanostructural features may also contribute to radiation-induced strengthening. The reasons for the modification of the mechanisms are explained and the impact of the loading conditions is discussed. PMID- 23756469 TI - Biomimetic total syntheses of spirobacillenes A and B. AB - The first total syntheses of spirobacillenes A and B were achieved concisely. The key transformation leading to spirobacillene A features a biomimetic intramolecular phenol-enol oxidative coupling reaction, and that leading to spirobacillene B highlights a bio-inspired intramolecular indole-ketone enolate oxidative coupling reaction. PMID- 23756470 TI - Comparison of fate profiles of PAHs in soil, sediments and mangrove leaves after oil spills by QSAR and QSPR. AB - First order removal rates for 15 polyaromatic hydrocarbons (PAHs) in soil, sediments and mangrove leaves were compared in relation to the parameters used in fate transport analyses (i.e., octanol-water partition coefficient, organic carbon-water partition coefficient, solubility, diffusivity in water, HOMO-LUMO gap, molecular size, molecular aspect ratio). The quantitative structure activity relationships (QSAR) and quantitative structure property relationships (QSPR) showed that the rate of disappearance of PAHs is correlated with their diffusivities in water as well as molecular volumes in different media. Strong correlations for the rate of disappearance of PAHs in sediments could not be obtained in relation to most of the parameters evaluated. The analyses showed that the QSAR and QSPR correlations developed for removal rates of PAHs in soils would not be adequate for sediments and plant tissues. PMID- 23756471 TI - Electronic and magnetic properties of pristine and transition metal doped ZnTe nanowires. AB - We have carried out density functional theory based calculations for understanding the structural, electronic and magnetic properties of pristine and transition metal (TM) doped ZnTe nanowires. Pristine ZnTe nanowires (NWs) turn out to be semiconducting in nature, with the band gap varying with the diameter of the NWs. In Mn-doped ZnTe NWs, the Mn atoms retain a magnetic moment of 5 MUB each and couple anti-ferromagnetically. A half metallic ferromagnetic state, although energetically not favorable, is observed arising from a strong hybridization between the d-states of Mn atoms and p-states of Te atoms. Further studies of V- and Sc-doped ZnTe NWs reveal the systems to be anti-ferromagnetic. PMID- 23756472 TI - Juvenile myoclonic epilepsy. PMID- 23756473 TI - Epidemiology of juvenile myoclonic epilepsy. AB - Juvenile myoclonic epilepsy (JME) is a widely recognized presumed genetic, electroclinical idiopathic generalized epilepsy syndrome. The prevalence of JME in large cohorts has been estimated to be 5% to 10% of all epilepsies and around 18% of idiopathic generalized epilepsies but may be lower in some settings. There is a marked female predominance. However, some of the basic epidemiology of JME is not well known, possibly because the syndrome is not sharply defined. A questionnaire study about the diagnostic criteria for JME suggests that diagnosis of JME can be made with the history of myoclonus plus a single generalized tonic clonic seizure plus generalized fast spike-waves or polyspike-waves on the EEG. However, until these diagnostic criteria are fully accepted, the detailed epidemiology of JME will remain imprecise. PMID- 23756474 TI - Lifetime prognosis of juvenile myoclonic epilepsy. AB - Juvenile myoclonic epilepsy (JME) is among the most common types of genetic epilepsies, displaying a good prognosis when treated with appropriate drugs, but with a well-known tendency to relapse after withdrawal. The majority of patients with JME have continuing seizures after a follow-up of two decades. However, 17% are able to discontinue medication and remain seizure-free thereafter. Clinicians should remember that there is a small but still considerable subgroup of JME patients whose seizures are difficult to treat before informing patients with newly-diagnosed JME about their "benign" prognosis. This resistant course is not fully explained, though there are many suggested factors. The dominating myoclonic seizures disappear or diminish in severity in the fourth decade of life. Despite the favorable seizure outcome in most of the cases, 3/4 of patients with JME have at least one major unfavorable social outcome. The possible subsyndromes of JME, its genetic background, and its pathophysiological and neuroimaging correlates should be further investigated. PMID- 23756475 TI - The history of juvenile myoclonic epilepsy. AB - Juvenile myoclonic epilepsy (JME) has been the subject of intensive research over the past 25years. It was discovered stepwise in Switzerland and France in the 19th century, adequately described in Germany and Uruguay in the 1950s, and rediscovered in North America in the early 1980s. Juvenile myoclonic epilepsy represents the most common idiopathic epilepsy syndrome. As a tribute to the primary author of the first extensive and detailed clinical description of JME, it is also called the Janz syndrome. Juvenile myoclonic epilepsy is an archetypical epileptic syndrome, with a fairly homogenous presentation and a still largely unknown etiology. Its clinical spectrum now includes cognitive and psychiatric symptoms as significant copathologies, and the elucidation of its probably multiple genetic mechanisms is an ongoing process. Juvenile myoclonic epilepsy may not qualify as a "benign" epilepsy, but seizures in most patients can be managed adequately and patients will not suffer severe limitations in their lifetime expectations. PMID- 23756476 TI - Chronodependency and provocative factors in juvenile myoclonic epilepsy. AB - In juvenile myoclonic epilepsy (JME), occurrence of seizures and epileptiform EEG discharges is influenced by internal and external factors. The most important internal factor is the chronodependency: the occurrence of myoclonic jerks in the early morning is one of the hallmarks of JME. Approximately two-thirds of the patients with JME report that seizures are provoked by a variety of general factors like stress, fatigue, fever, and sleep and more specific precipitants like flashing sunlight, music, reading, thinking, and excess alcohol. The prevalence rate of photosensitivity (photoparoxysmal EEG response) in patients with JME ranges from 8 to 90%; it is seen more often in females and adolescents and depends on drug use. Since both JME and photosensitivity are connected with generalized types of epilepsy and myoclonus, the two traits are comorbid for that reason. Epileptiform EEG discharges can be provoked by other activation methods: sleep, hyperventilation, and specific cognitive tasks. Attention seems to have a non-specific, inhibitory effect of the epileptiform discharges. Hyperventilation can induce absence seizures in patients with JME, while cognitive tasks are efficient in precipitating myoclonic seizures. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really? PMID- 23756477 TI - Neurophysiology of juvenile myoclonic epilepsy. AB - Juvenile myclonic epilepsy (JME) can be firmly diagnosed by a careful interview of the patient focusing on the seizures and by the EEG with the help, if necessary, of long-term video-EEG monitoring using sleep and/or sleep deprivation. Background activity is normal. The interictal EEG shows diffuse or generalized spike-wave (SW) and polyspike-wave (PSW) discharges. In some patients, non-specific changes or misleading features such as focal changes are found. Changes are mostly seen at sleep onset and at awakening. Provoked awakenings are more likely to activate interictal paroxysmal abnormalities than spontaneous awakenings. The presence of a photoparoxysmal response with or without myoclonic jerks (MJ) is common (30% of the cases). Myoclonic jerks are associated with a discharge of fast, irregular, generalized PSWs that predominate anteriorly. Myoclonic jerks appear to be associated with rhythmic EEG (spike) potentials at around 20Hz. These frequencies are in the range of movement-related fast sensorimotor cortex physiological rhythms. The application of jerk-locked averaging technique has provided findings consistent with a cortical origin of MJ. Paired TMS (transcranial magnetic stimulation) studies showed a defective intracortical inhibition, due to impaired GABA-A mediated mechanisms. In this review, we present the EEG characteristics of JME with particular emphasis on the pathophysiology of MJ and on the role of sleep deprivation on interictal and ictal changes. PMID- 23756478 TI - Juvenile myoclonic epilepsy--neuroimaging findings. AB - Juvenile myoclonic epilepsy (JME) has been classified as a syndrome of idiopathic generalized epilepsy and is characterized by specific types of seizures, showing a lack of pathology using magnetic resonance imaging (MRI) and computed tomography scanning. However, JME is associated with a particular personality profile, and behavioral and neuropsychological studies have suggested the possible involvement of frontal lobe dysfunction. The development of highly sensitive neuroimaging techniques has provided a means of elucidating the underlying mechanisms of JME. Positron emission tomography demonstrated metabolic and neurotransmitter changes in the dorsolateral prefrontal cortex reflecting the particular cognitive and behavioral profile of JME patients. (1)H-magnetic resonance spectroscopy has shown evidence of thalamic dysfunction, which appears to be progressive. Such techniques provide evidence of multi-focal disease mechanisms, suggesting that JME is a frontal lobe variant of a multi-regional, thalamocortical 'network' epilepsy, rather than a generalized epilepsy syndrome. Quantitative MRI revealed significant abnormalities of cortical gray matter in medial frontal areas close to the supplementary motor area and diffusion abnormalities with increased functional coupling between the motor and prefrontal cognitive systems. This altered structural connectivity of the supplementary motor area provides an explanatory framework for the particular imaging findings, seizure type, and seizure-provoking mechanisms in JME. PMID- 23756479 TI - What is special about the adolescent (JME) brain? AB - Juvenile myoclonic epilepsy (JME) involves cortico-thalamo-cortical networks. Thalamic, frontal gray matter, connectivity, and neurotransmitter disturbances have been demonstrated by structural/functional imaging studies. Few patients with JME show mutations in genes coding ion channels or GABAA (gamma-aminobutyric acid) receptor subunits. Recent research points to EFHC1 gene mutations leading to microdysgenesis and possible aberrant circuitry. Imaging studies have shown massive structural/functional changes of normally developing adolescent brain structures maturing at strikingly different rates and times. Gray matter (GM) volume diminishes in cortical areas (frontal and parietal) and deep structures (anterior thalamus, putamen, and caudate). Diffusion tensor imaging (DTI) findings support continued microstructural change in WM (white matter) during late adolescence with robust developmental changes in thalamocortical connectivity. The GABAA receptor distribution and specific receptor subunits' expression patterns change with age from neonate to adolescent/adult, contributing to age-related changes in brain excitability. Hormonal influence on brain structure development during adolescence is presented. Possible implications of brain changes during adolescence on the course of JME are discussed. PMID- 23756480 TI - The quest for juvenile myoclonic epilepsy genes. AB - Introduced into a specific population, a juvenile myoclonic epilepsy (JME) mutation generates linkage disequilibrium (LD). Linkage disequilibrium is strongest when the JME mutation is of recent origin, still "hitchhiking" alleles surrounding it, as a haplotype into the next thousands of generations. Recombinations decay LD over tens of thousands of generations causing JME alleles to produce smaller genetic displacements, requiring other genes or environment to produce an epilepsy phenotype. Family-based linkage analysis captures rare epilepsy alleles and their "hitchhiking" haplotypes, transmitted as Mendelian traits, supporting the common disease/multiple rare allele model. Genome-wide association studies identify JME alleles whose linkage disequilibrium has decayed through thousands of generations and are sorting out the common disease/common allele versus rare allele models. Five Mendelian JME genes have been identified, namely, CACNB4, CASR, GABRa1, GABRD, and Myoclonin1/EFHC1. Three SNP alleles in BRD2, Cx-36, and ME2 and microdeletions in 15q13.3, 15q11.2, and 16p13.11 also contribute risk to JME. PMID- 23756481 TI - Juvenile myoclonic epilepsy as a possible neurodevelopmental disease: role of EFHC1 or Myoclonin1. AB - Juvenile Myoclonic Epilepsy (JME) accounts for almost 12% of all epilepsies and is one of the most frequent forms of genetic generalized epilepsies. Genetic studies have revealed that mutations in EFHC1 (EF-hand containing one) account for 3 to 9% of all cases around the world. This gene encodes a protein that is not an ion channel, and several studies have tried to find its cellular role. In this article, we review the various functions that have been proposed for this protein. Interestingly, all of them could affect brain development at different steps, suggesting that the developmental assembly of neural circuits may play a prominent role in JME. PMID- 23756482 TI - Re-evaluation of myoclonin1 immunosignals in neuron, mitotic spindle, and midbody -nonspecific? AB - Mutations in EFHC1 gene cause juvenile myoclonic epilepsy (JME). We previously showed that myoclonin1 protein encoded by EFHC1 is expressed in prenatal choroid plexus and postnatal ependymal cell cilia but may not be in neurons. However, another group reported that myoclonin1 is expressed in neurons and at mitotic spindle, and that the suppression of EFHC1 by RNAi caused disruption of mitotic spindle structure, impaired M-phase progression, and an increase of apoptosis. We re-investigated their results by using the same polyclonal antibody that they used, and found that the signals in neurons remained in Efhc1-deficient mouse, suggesting that the signals in neurons were nonspecific. Furthermore, Efhc1 (-/-) mouse did not show any abnormalities such as disruption of mitotic spindle structure, impaired M-phase progression, and an increase of apoptosis. Further investigations are required to clarify these discrepancies. PMID- 23756483 TI - Genome wide association studies (GWAS) and common forms of human epilepsy. AB - Several GWAS focused on common forms of epilepsy are underway. Currently, only one locus has been published that reached genome wide statistical significance. Two other loci that also reach genome wide statistical significance have been reported as preliminary data and are awaiting publication. Several additional loci identified in these studies fall just short of statistical significance, and it is hoped that future large scale meta-analyses will confirm these early findings and identify new loci that influence common forms of human epilepsy. Next generation DNA sequencing (NGS) studies are also underway and in the future will identify rare DNA variations of large effect that also contribute to the final epilepsy phenotypes under study. Finally, these studies have the potential to identify biomarkers of antiepileptic drug (AED) response as epilepsy patient GWAS and NGS data are stratified based on AED efficacy and tolerability. PMID- 23756484 TI - The unexpected role of copy number variations in juvenile myoclonic epilepsy. AB - Structural genomic variants or copy number variants (CNVs) comprise submicroscopic deletions and duplications of chromosomal material, including both rearrangements at genomic hotspots as well as duplications and deletions with unique breakpoints. Copy number variants have increasingly been recognized in the Idiopathic/Genetic Generalized Epilepsies (IGE/GGE) including juvenile myoclonic epilepsy (JME). Microdeletions at 15q13.3, 15q11.2, and 16p13.11 are genetic risk factors that can be identified in 3% of patients with IGE including JME. These microdeletions, however, also represent genetic risk factors to a broad range of other neurodevelopmental disorders. Additionally, 6% of patients with GGE carry other, potentially pathogenic structural genomic variants. While family studies largely support the channelopathy concept of the idiopathic epilepsies, the results of studies investigating copy number variations suggest that JME genetically overlaps with a broad range of other neurodevelopmental disorders. In addition, the particular genetic properties of structural genomic variations as rare genetic variants highlight the complexity of the genetic architecture of human disease. PMID- 23756485 TI - Photoparoxysmal EEG response and genetic dissection of juvenile myoclonic epilepsy. AB - Heritable EEG traits are often associated with epilepsy, and photoparoxysmal EEG response (PPR) is the most notable example of this observation in JME. Such EEG traits may be a subclinical expression of the defective mechanism that leads to epilepsy. Therefore, these traits can be used to map epilepsy genes by dissecting the complex epilepsy phenotype in endophenotypic sections that on their own have a presumed monogenic cause. Two characteristics make PPR particularly interesting as a useful endophenotype for epilepsy gene mapping. First, it shows an increased comorbidity with some but not all forms of epilepsy. Second, its mode of inheritance is compatible with a monogenic cause, which promises relative straightforward gene identification through positional cloning. Here, we summarize the current state of affairs. PMID- 23756486 TI - Neuropsychology and behavior in juvenile myoclonic epilepsy. AB - Following decades of neglect, there has been an increasing interest in the behavioral aspects of juvenile myoclonic epilepsy (JME) in the recent literature. A number of authors have investigated psychiatric comorbidity, cognitive profiles, and related behavioral features associated with JME. Although these findings are not entirely uniform, most studies suggest an increased incidence in psychiatric comorbidity and specific cognitive deficits that explain some of the clinical observations of poor compliance and other unhealthy behaviors in people suffering from JME. Neuropsychological profiles in JME are suggestive of subtle frontal dysfunctions, and some of the observations have been linked with sophisticated structural and functional imaging findings. Taken together, there is evidence that JME is associated with dysfunctions in networks linking motor and cognitive neuronal centers. Interestingly, there is evidence from family studies that the behavioral abnormalities in JME are genetically determined, suggesting an underlying developmental disorder. PMID- 23756487 TI - Juvenile myoclonic epilepsy: psychiatric comorbidity and impact on outcome. AB - Juvenile myoclonic epilepsy (JME) is a well-defined age-related idiopathic epilepsy syndrome. Past studies have emphasized the difficulties in the treatment of patients with JME, which have been attributed to some specific psychiatric, psychological, and psychosocial characteristics. These aspects have aroused a significant amount of interest in the last two decades. In this article, the available studies that investigated the prevalence of psychiatric disorders (PDs) in JME and its impact on seizure outcome were reviewed in order to provide an update to clinicians about these two important aspects associated with this common epilepsy syndrome. The review disclosed a high prevalence of PDs in patients with JME, particularly mood, anxiety, and personality disorders. In addition, most recent studies have also observed that overall prevalence of PDs in JME has not shown statistically significant differences when compared with TLE, an epilepsy syndrome where the psychiatric aspects are most frequently studied. Taken together, data regarding the prevalence of PDs and their possible consequences on seizure outcome on JME indicate that special attention should be directed to psychological disturbances and psychiatric symptoms in this epilepsy syndrome. The early recognition and treatment of psychiatric symptoms, as well as psychological disturbances and psychosocial difficulties, should be considered fundamental to JME prognosis. PMID- 23756488 TI - Clinical aspects of juvenile myoclonic epilepsy. AB - Juvenile myoclonic epilepsy (JME) is a recognizable, frequent epileptic syndrome. The most typical ictal phenomenon is bilateral myoclonia without loss of consciousness (M), with most patients also presenting with generalized tonic clonic seizures (GTCSs) and some with absence seizures (ASs). The most striking features of JME are its onset around the time of puberty and the fact that seizure episodes occur after awakening from a sleep period or in the evening relaxation period and are facilitated by sleep deprivation and sudden arousal. Photic sensitivity is common in the EEG laboratory but uncommon or unrecognized in daily life. The clinical features of JME make it easy to diagnose. In recent years, awareness of JME has increased, and patients are often accurately diagnosed clinically before confirmation by EEG. The typical circumstance at diagnosis is a first GTCS episode, and one learns during the interview that the patient has had M in the morning for some time before the GTCS episode. There are only few differential diagnoses: the adolescent-onset progressive myoclonus epilepsies, or other forms of idiopathic generalized epilepsies of adolescence. With JME being so common, we propose that a first GTCS episode in a teenager should be considered as revealing JME until proven otherwise. PMID- 23756489 TI - Management of juvenile myoclonic epilepsy. AB - Juvenile myoclonic epilepsy (JME) is a common form of epilepsy and a fairly lifelong disorder that may significantly lower a patient's expectations and potential for a full life. Luckily, it is also a highly treatable disorder, and up to 85% of patients with JME will enjoy satisfactory seizure control. Among anticonvulsants, valproate still stands out as the most efficacious drug, but may be poorly tolerated by some, and is considered unsafe for the fetuses of pregnant women. Alternatives have emerged in recent years, especially levetiracetam, but also topiramate, zonisamide or lamotrigine. In some cases, combination therapy may be useful or even required. One should not forget the potential aggravation induced not only by some commonly used anticonvulsants, especially carbamazepine and oxcarbazepine, but also, in some patients, by lamotrigine. In special settings, older drugs like benzodiazepines and barbiturates may be useful. But the management of JME should also include intervention in lifestyle, with strict avoidance of sleep deprivation and the management of copathologies, including the cognitive and psychiatric problems that are often encountered. With adequate management, there will only remain a small proportion of patients with uncontrolled epilepsy and all of its related problems. Juvenile myoclonic epilepsy is a condition in which the clinician has a fair chance of significantly helping the patient with medication and counseling. PMID- 23756491 TI - Sixfold enhancement of photocurrent by surface charge controlled high density quantum dot coating. AB - A wet-chemical method for increasing the number of quantum dots (QDs) per unit surface area of TiO2 was developed. High density QD surface coating was induced by a surface charge controlled SILAR method, which led to a sixfold increase in photocurrent density from 2.15 mA cm(-2) to 15.03 mA cm(-2) in a QD-sensitized solar cell based on a Hg-doped PbS sensitized 2.4 MUm-thick TiO2 film. PMID- 23756490 TI - Consensus on diagnosis and management of JME: From founder's observations to current trends. AB - An international workshop on juvenile myoclonic epilepsy (JME) was conducted in Avignon, France in May 2011. During that workshop, a group of 45 experts on JME, together with one of the founding fathers of the syndrome of JME ("Janz syndrome"), Prof. Dr. Dieter Janz from Berlin, reached a consensus on diagnostic criteria and management of JME. The international experts on JME proposed two sets of criteria, which will be helpful for both clinical and scientific purposes. Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities with or without concomitant myoclonic jerks, and a greater time window for age at onset (6-25years). For both sets of criteria, patients should have a clear history of myoclonic jerks predominantly occurring after awakening and an EEG with generalized epileptiform discharges supporting a diagnosis of idiopathic generalized epilepsy. Patients with JME require special management because their epilepsy starts in the vulnerable period of adolescence and, accordingly, they have lifestyle issues that typically increase the likelihood of seizures (sleep deprivation, exposure to stroboscopic flashes in discos, alcohol intake, etc.) with poor adherence to antiepileptic drugs (AEDs). Results of an inventory of the different clinical management strategies are given. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really? PMID- 23756492 TI - Properties of liquid iron along the melting line up to Earth-core pressures. AB - We report a molecular dynamics study of the transport coefficients and the infinite frequency shear modulus of liquid iron at high temperatures and high pressures. We observe a simultaneous rise of both the shear viscosity and the diffusion coefficient along the melting line and estimate whether liquid iron can vitrify under Earth-core conditions. We show that in the conditions of the model studied in our work iron demonstrates a moderate increase of viscosity along the melting line. It is also demonstrated that at the limit of high temperatures and high pressures the liquid iron behaves similarly to the soft sphere system with exponent n ~ 4.6. PMID- 23756493 TI - A supramolecular DNA self-assembly based on beta-cyclodextrin-adamantane complexation as a bioorthogonal sticky end motif. AB - We propose linear end-to-end assemblies of short DNA duplexes based on beta cyclodextrin-adamantane complexation. The assembled duplexes exhibited increased Tm values compared with those of the corresponding natural hybrids. Competition experiments with external guest molecules showed a substantial decrease in Tm of the terminal modified duplexes, suggesting the viability of inter-duplex complexation. PMID- 23756494 TI - Phantoms for quality control procedures in digital breast tomosynthesis: dose assessment. AB - The recent introduction of digital breast tomosynthesis into clinical practice requires quality control procedures. In this study we have investigated whether the assessment of the average glandular dose for modelled standard breasts can be performed using a combination of polymethyl methacrylate (PMMA) and polyethylene (PE) slabs that matches standard breast thicknesses. For this purpose the energies absorbed per unit area of the image receptor when imaging standard breasts and PMMA-PE slabs have been matched taking account of both primary and scattered photons. To achieve this a two-step approach was used. Firstly, the behaviour of the scatter-to-primary ratio (SPR) of PMMA-PE phantoms and standard breasts was investigated using Monte Carlo simulations for various conditions. For imaging without an anti-scatter grid, it was found that the values of standard breast and phantom SPR were significantly different and it follows that these differences are relevant when matching the absorbed energy. In the second part, a set of PMMA-PE combinations is proposed which, for dosimetric purposes, can be used to simulate standard breasts in the thickness range 20 to 100 mm. The dosimetric error when using these PMMA-PE slabs was found to be below 6% for thicknesses up to 7 cm and increases to 10% for 10 cm thickness. PMID- 23756495 TI - Copper-catalyzed annulation of amidines for quinazoline synthesis. AB - An efficient Cu-catalyzed synthesis of quinazolines via the C-N bond formation reactions between N-H bonds of amidines and C(sp(3))-H bonds adjacent to sulfur or nitrogen atoms in the commonly used solvents, such as DMSO, DMF, DMA, NMP or TMEDA, followed by intramolecular C-C bond formation reactions was developed for the first time. PMID- 23756496 TI - Longitudinal analysis of resourcefulness, family strain, and depressive symptoms in grandmother caregivers. AB - BACKGROUND: Grandmothers living with grandchildren face stressors that may increase depressive symptoms, but cognitive-behavioral strategies, such as resourcefulness, may reduce the effects of stressors on mental health. PURPOSE: This analysis examined the contemporaneous and longitudinal relationships among intra-family strain, resourcefulness, and depressive symptoms in 240 grandmothers, classified by caregiving status to grandchildren. METHODS: Grandmothers raising grandchildren, grandmothers living in multigenerational homes, and non-caregivers to grandchildren reported on intra-family strain, resourcefulness, and depressive symptoms using mailed questionnaires at three time points over 5 years. Structural equation modeling was used to evaluate the mediating effects of resourcefulness and the relationships between variables. DISCUSSION: Grandmother caregiver status had significant effects on depressive symptoms and intra-family strain but not on resourcefulness. At all waves, higher resourcefulness was associated with fewer depressive symptoms, which reduced appraisals of intra-family strain. CONCLUSIONS: Interventions focused on strengthening resourcefulness could reduce depressive symptoms over time. PMID- 23756497 TI - Performance assessment of a 2D array of plastic scintillation detectors for IMRT quality assurance. AB - The purposes of this work are to assess the performance of a 2D plastic scintillation detectors array prototype for quality assurance in intensity modulated radiation therapy (IMRT) and to determine its sensitivity and specificity to positioning errors of one multileaf collimator (MLC) leaf and one MLC leaf bank by applying the principles of signal detection theory. Ten treatment plans (step-and-shoot delivery) and one volumetric modulated arc therapy plan were measured and compared to calculations from two treatment planning systems (TPSs) and to radiochromic films. The averages gamma passing rates per beam found for the step-and-shoot plans were 95.8% for the criteria (3%, 2 mm), 97.8% for the criteria (4%, 2 mm), and 98.1% for the criteria (3%, 3 mm) when measurements were compared to TPS calculations. The receiver operating characteristic curves for the one leaf errors and one leaf bank errors were determined from simulations (theoretical upper limits) and measurements. This work concludes that arrays of plastic scintillation detectors could be used for IMRT quality assurance in clinics. The use of signal detection theory could improve the quality of dosimetric verifications in radiation therapy by providing optimal discrimination criteria for the detection of different classes of errors. PMID- 23756498 TI - Iridovirus infection in terrestrial isopods from Sicily (Italy). AB - During our researches on systematics and ecology of terrestrial isopods, carried out in western Sicily, some specimens showing a blue-purple coloration were collected; they belonged to four species: Armadillidium decorum Brandt, 1833, Trichoniscus panormidensis Montesanto et al., 2011, Philoscia affinis Verhoeff, 1908, Porcellio siculoccidentalis Viglianisi et al., 1992. We hypothesized that such coloration could be due, as reported in literature, to characteristic paracrystalline arrays of virions inside the tissues of blue colored specimens. Ultrastructural observations by transmission electron microscopy, on tissues of A. decorum, showed the presence of electron-dense viral particles, with a diameter of nearly 0.12MUm. Dual-axis tomography, performed on specimens of A. decorum, evidenced an icosahedral structure of viral particles matching with that of Isopod Iridescent Virus (IIV). Molecular analysis, on 254bp portion of the major capsid protein (MCP) gene, allowed to place the virus into IIV-31 group, already known for other oniscidean species. The symptoms of infected individuals and the course of the disease were followed in laboratory, indicating similarities with other studies on Isopod Iridoviruses. Moreover, some notes on reproduction of infected ovigerous females are reported. Our data support unequivocal and direct evidences for the first case of IIV infection in terrestrial isopods reported in Italy. PMID- 23756499 TI - Varying kVp as a means of reducing CT breast dose to pediatric patients. AB - We investigated the possibility of reducing radiation dose to the breast tissue of pediatric females by using multiple tube voltages within a single CT examination. The peak kilovoltage (kVp) was adjusted when the x-ray beam was directly exposing the representative breast tissue of a 5-year-old, 10-year-old, and an adult female anthropomorphic phantom; this strategy was called kVp splitting and was emulated by using a different kVp over the anterior and posterior tube angles. Dose savings from kVp splitting were calculated relative to using a fixed kVp over all tube angles and the results indicated savings in all three phantoms when using 80 kVp over the posterior tube angles regardless of the anterior kVp. Monte Carlo (MC) simulations with and without kVp splitting were performed to estimate absorbed breast dose in voxelized models constructed from the CT images of pediatric female patients; 80 kVp was used over the posterior tube angles. The MC simulations revealed breast dose savings of between 9.8% and 33% from using kVp splitting compared to simulations using a fixed kVp protocol with the anterior technique. Before this strategy could be implemented clinically, the development of suitable image reconstruction algorithms and the image quality of scans with kVp splitting would need further study. PMID- 23756500 TI - The French-Canadian data set of Demirjian for dental age estimation: a systematic review and meta-analysis. AB - BACKGROUND: Estimation of age of an individual can be performed by evaluating the pattern of dental development. A dataset for age estimation based on the dental maturity of a French-Canadian population was published over 35 years ago and has become the most widely accepted dataset. The applicability of this dataset has been tested on different population groups. AIM: To estimate the observed differences between Chronological age (CA) and Dental age (DA) when the French Canadian dataset was used to estimate the age of different population groups. MATERIALS AND METHODS: A systematic search of literature for papers utilizing the French Canadian dataset for age estimation was performed. All language articles from PubMed, Embase and Cochrane databases were electronically searched for terms 'Demirjian' and 'Dental age' published between January 1973 and December 2011. A hand search of articles was also conducted. RESULTS: A total of 274 studies were identified from which 34 studies were included for qualitative analysis and 12 studies were included for quantitative assessment and meta-analysis. When synthesizing the estimation results from different population groups, on average, the Demirjian dataset overestimated the age of females by 0.65 years (-0.10 years to +2.82 years) and males by 0.60 years (-0.23 years to +3.04 years). CONCLUSION: The French Canadian dataset overestimates the age of the subjects by more than six months and hence this dataset should be used only with considerable caution when estimating age of group of subjects of any global population. PMID- 23756501 TI - Death due to an unrecognized groin abscess in a drug addict: a retrospective study. AB - Intravenous drug injection persists despite health risks and medical complications. Venous thrombosis, septic thrombophlebitis, artery necrosis, arterio-venous fistula, mycotic aneurysm, dissecting hematoma, pseudoaneurysm formation, and soft tissues infections (i.e. abscesses, cellulitis, infected ulcers), are some of the major clinical consequences lives threatening. The aim of this work is to present this unusual autoptic case of a drug addict man died for an unrecognized groin abscess referred to the Institute of Legal Medicine, University of Chieti, causing femoral vein's erosion, and to analyse the most common patterns of vascular lesions among drug addicts. It could be stimulated a new scientific debate because groin injections and their vascular complications increase over years; while soft tissue infections may hide vascular lesions' diagnosis. So physicians should have a high index of suspicion for serious vascular problems, among intravenous drug users (IDUs): prevention for avoiding groin injection and a proper treatment are necessary. PMID- 23756502 TI - Deletion of amelogenin Y-locus in forensics: literature revision and description of a novel method for sex confirmation. AB - Today, the molecular technique routinely for sex determination in forensics is based the detection of length variations in the X-Y homologous amelogenin gene (AMELX and AMELY). In humans, the amelogenin gene is a single-copy gene located on Xp22.1-Xp22.3 and Yp11.2; the simultaneous detection of the X and Y alleles using polymerase chain reaction (PCR) can lead to gender determination. Several studies have shown that normal males may be typed as females with this test: AMELY deletions may result in no product of amplification and normal males being typed as female as a result of the test (negative male). Considering the consequences of the result obtained using only the amelogenin marker, and the related potential difficulties in interpreting the results, the gender misinterpretation may be troublesome in clinical practice and in forensic casework. In this article, beginning with a review of the incidence of gender testing failures among different populations, and with the different strategies proposed in the literature in case of doubt regarding the presence of deleted AMEL in the DNA profile, we propose a method for the identification of samples with deleted AMEL that can be applied, as an additional assay, in case of doubt regarding PCR results of sex determination. PMID- 23756503 TI - The changing face of the 'royal disease'--medicolegal aspects of haemophilia. AB - Haemophilia represents a group of heritable disorders caused by deficiencies in plasma proteins that are involved in coagulation. The case of a two-year-old boy with an established diagnosis of haemophilia B is reported to demonstrate a rare cause of unexpected death. He had a recent history of epistaxis and was found unexpectedly dead. At autopsy the posterior pharynx was obstructed by blood clot with aspirated blood within the distal airways of the lungs, and melena throughout both small and large intestines. His death was due to haemorrhage and airway obstruction complicating epistaxis. The profile of individuals with haemophilia has been changing in recent years with less deaths from haemorrhage due to improved clinical management. As the life expectancy of these patients is increasing, forensic examiners will now have to consider not only possible haemorrhagic causes of death but will also have to determine the significance of more long standing infectious processes related to human immunodeficiency virus (HIV) and hepatitis C from contaminated transfusions, in addition to evaluating the role of the more usual diseases related to age. PMID- 23756504 TI - Fatal aortobronchial fistula. AB - Aortobronchial fistula is a rare condition characterized by the development of a communication between the aorta and a branch of the bronchial tree that results from processes that arise within the aorta, in the tissues of the mediastinum, or in the adjacent thoracic organs. Three cases are reported to demonstrate characteristic features. Case 1: An 82-year-old woman was found collapsed with blood clot in her mouth. At autopsy an atherosclerotic thoracic aortic aneurysm was found which had eroded into the underlying left main bronchus with filling of the larynx, trachea and main bronchi with fluid blood. There was no evidence of dissection. Case 2: A 30-year-old woman collapsed and died. At autopsy, coarctation of the thoracic aorta was found with a saccular aneurysm distal to this which was joined to the left main bronchus by a mass of necrotic tissue. The bronchus contained a cast of blood; blood was also present within the trachea and within the distal airways of the left lung. Case 3: A six-year-old girl collapsed with massive airway haemorrhage following bronchoscopy. At autopsy coarctation of the thoracic aorta was identified with a saccular aneurysm distal to this. A transverse tear of the thinned aneurysm wall communicated with a mass of necrotic friable tissue that extended through the wall of the left main bronchus. Distal airways were filled with fluid blood. All three deaths were due to haemorrhage from aortobronchial fistulas. The pathogenesis of aortobronchial fistulas involves a variety of mechanical, infective and neoplastic processes. Many cases will not be diagnosed until autopsy examination is performed. PMID- 23756505 TI - Dental orthopantomogram biometrics system for human identification. AB - Fingerprinting is the most widely accepted method of identification of people. But in cases of disfigured, decomposed, burnt or fragmented bodies, it is of limited value. Teeth and dental restorations on the other hand are extremely resistant to destruction by fire. They retain a number of their original characteristics, which are often unique and hence offer a possibility of rather accurate and legally acceptable identification of such remains. This study was undertaken to evaluate the utility of orthopantomography for human identification and propose a coding system for orthopantomogram (OPG), which can be utilized as an identification tool in forensic sciences. PMID- 23756506 TI - An approach to peer review in forensic pathology. AB - Peer review in forensic pathology has been a long time in evolution but may provide a very useful mechanism to check for, and to correct, errors, in addition to establishing an important educative vehicle for pathologists. A process is reported that has been established at our institution that involves both informal peer review in the mortuary and formal auditing of a set number of cases. Every autopsy case is discussed at a daily meeting of pathologists before a provisional cause of death is released. In addition, one in ten cases including all homicides, deaths in custody, suspicious and paediatric cases, and randomly selected additional cases undergo formal auditing by a second pathologist. Finally, administrative staff check the completed report. This formalized process, in a jurisdiction where autopsies are usually performed by only one pathologist, has been extremely useful in standardizing autopsy reports and in enabling pathologists to discuss cases and associated issues on a regular basis. PMID- 23756507 TI - Evaluation of sexual assaults in Turkey. AB - INTRODUCTION: Sex crimes remain an important problem all over the world. Very few studies about sexual offenses in Turkey have been published. Sexual assault is a serious social problem that constitutes serious health conditions affecting the lives of involved individuals. In this study, we aimed to investigate socio demographic features of victims, assailant-victim relationships and sexual assault findings. MATERIAL AND METHODS: A total of 324 sexual assault victims presenting to and examined in the Department of Forensic Medicine, Kahramanmaras Sutcu Imam University Medical Faculty, between January 2007 and December 2010 were included in the study. The victims completed a survey at face to face interviews. RESULTS: Of 324 victims, 268 (82.7%) were female and 56 (17.3%) were male. The mean age of the victims was 16.78 +/- 7.16 years. In all cases, types of the assaults were as following; vaginal penetration in 160 (49.4%), anal penetration in 117 (36.1%), oral penetration with penis in 7 (2.2%) and in the form of kissing, fondling, touching the sex organ and rubbing the sex organ in 60 (18.5%) cases. Of all the assaults, 149 (46%) were found to take place in the assailants' homes and 49 (15.1%) in the victims' homes. Of 139 cases, 85 (26.3%) had genital injury alone and 54 (16.7%) had anal injury. CONCLUSION: On the contrary to the previous studies, this study revealed that sexual assaults occurred mostly in the assailants' homes and that the incidence of anal trauma was higher. PMID- 23756508 TI - Using the Excess Heat Factor (EHF) to predict the risk of heat related deaths. AB - Extremes of climate are not uncommon in Australia and heatwaves are not infrequent. Periods of high ambient temperature may result in clusters of heat related deaths, which may place strain on forensic facilities. This paper describes the formulation of the Excess Heat Factor using meteorological data to provide a means of predicting death resulting from periods of extreme heat stress. The 2009 South Australian heatwave had the highest ranked Excess Heat Factor in Adelaide's records. There were 58 heat related deaths, with the bulk of the heat related deaths following the peak Excess Heat Factor value (144 degrees C(2)). The 2008 heatwave had a lower peak Excess Heat Factor value (36 degrees C(2)); there was only one heat related death, which followed the peak in the Excess Heat Factor. It is proposed that calculation of the Excess Heat Factor from meteorological data could provide a means to predict and identify heat related deaths resulting from extreme weather conditions. PMID- 23756509 TI - Estimating ages by third molars: stages of development in Brazilian young adults. AB - The purpose of this study was to estimate age through the analysis of third molar stages of development in Brazilian young adults. A cross-sectional study was conducted by analyzing 659 panoramic X-rays. Two techniques were used to establish the stages: Modified Scoring (MST) and Demirjian (DT). Regression formulas were calculated. Statistical analyses were conducted by t, Kappa tests, and simple and multiple linear regressions (5% level of significance). Out of the participants, 40.7% were female and 59.3% were male, with ages from 15-22 years. The Kappa test showed good results for intra-observer (0.84 for MST and 0.95 for DT) and inter-observer examination (0.81 for MST and 0.92 for DT). Differences were found in the stages of tooth formation between male and female, but differences were not observed between the left and right sides. We found that both DT and MST underestimated the ages in about 6 months, depending on the used classification and number of teeth. These methods are appropriate for assessing the ages of young Brazilians, although the DT showed better reproducibility. PMID- 23756510 TI - A comparative study of topological and sex differences in fingerprint ridge density in Argentinian and Spanish population samples. AB - Although several studies have recently assessed sex differences in fingerprint ridge density and its variability in human populations from different origins, such a study has not been carried out yet in the Amerindian population. The goal of this study was to determine the topological and sexual differences in fingerprint ridge density (RD) in native subjects from two samples of northwestern Argentina (Jujuy province) living at different altitudes. The results were compared with those obtained from a Spanish population sample. The study was based on data from all 10 fingerprints of 393 adult Argentinian men and women, 193 from the Puna-Quebrada region (more than 2500 m above sea level) and 200 from Ramal (500 m above sea level). Ridge density was assessed for three different areas (radial, ulnar and proximal) for all 10 fingers of each subject. In both samples, significant differences between areas were obtained, so radial RD > ulnar RD > proximal RD. No significant differences were found between samples in males, while females from both samples significantly differed in the radial and proximal areas. Females have higher RD, so narrower ridges, than men, in all areas and all fingers. Application of Bayes' theorem allowed us to obtain a ridge density threshold for discrimination of sexes in Argentinian samples and the threshold for discrimination of populations between Argentinian and Spanish samples. These results can be useful for forensic use. PMID- 23756511 TI - Age estimation by measuring open apices of lower erupted teeth in 12-16 years olds by radiographic evaluation. AB - The purpose of this study was to estimate chronological age from panoramic radiographs by measuring open apices of seven right or left mandibular teeth in children of South Indian origin. A total of 101 male and female patients aged between 12 and 16 years were selected. The panoramic radiographs of the patient were indirectly digitised. The variables N0, x3, x4, x5, x6, x7 and s were measured using a computer-aided drafting program. Statistical analysis was performed to derive a regression equation for estimation of age. Two variables x3 and x7 contributed significantly to the fit, yielding the following linear regression formula: Age = 16.025-9.445 (x7) + 1.620 (x3). Statistical analysis indicated that the regression equation explained 97.5% of total variance (R(2) = 0.975). The median of the residuals was -0.0348 years with an interquartile range (IQR) of 0.2520 years. The derived regression equations from these variables can serve as an invaluable tool in estimating the age of children between 12 and 16 years of South Indian origin. PMID- 23756512 TI - Estimation of stature using anthropometry of feet and footprints in a Western Australian population. AB - The aim of the study is to develop accurate stature estimation models for a contemporary Western Australian population from measurements of the feet and footprints. The sample comprises 200 adults (90 males, 110 females). A stature measurement, three linear measurements from each foot and bilateral footprints were collected from each subject. Seven linear measurements were then extracted from each print. Prior to data collection, a precision test was conducted to determine the repeatability of measurement acquisition. The primary data were then analysed using a range of parametric statistical tests. Results show that all foot and footprint measurements were significantly (P < 0.01-0.001) correlated with stature and estimation models were formulated with a prediction accuracy of +/- 4.673 cm to +/- 6.926 cm. Left foot length was the most accurate single variable in the simple linear regressions (males: +/- 5.065 cm; females: +/- 4.777 cm). This study provides viable alternatives for estimating stature in a Western Australian population that are equivalent to established standards developed from foot bones. PMID- 23756513 TI - Analysis of obstetrics and gynecology professional liability claims in Catalonia, Spain (1986-2010). AB - OBJECTIVE: To identify relevant factors involved in obstetrics and gynecology (OG) professional liability claims to help archive better management of risks. STUDY DESIGN: Analysis of 885 OG claims opened between 1986 and 2010, with the identification of the most common events leading to a claim, the economical and juridical characteristics of the claims, as well as the relevant trends over the study period. RESULTS: Most claims related to obstetrics. Labor, delivery and its complications accounted for 33.1% of the claims; 12.77% related specifically to cesarean. Oncological diseases, fetus death during labor and delivery, neurologically impaired infant and histerectomy-related problems were the most frequently claimed events. Most cases ended up without an indemnity payment and 37.7% of closed files were solved by an out-of-court procedure. Average payment was higher for the obstetric procedures than for those concerning gynecology cases. The proportion of claims relating to obstetrics increased during the study period, as well as the average payment. CONCLUSION: OG is at high-risk for malpractice claims, but compensation awards are not frequent. However, particular events, such as retained foreign objects, tubal ligation, ultrasound diagnosis or neurologically impaired newborns, deserve special attention regarding medico legal issues. PMID- 23756514 TI - Heterogeneity of existing research relating to sexual violence, sexual assault and rape precludes meta-analysis of injury data. AB - In order for medical practitioners to adequately explain to the court the findings of their clinical examinations of victims of sexual violence, they must have access to research data which will place their findings in to context. Unfortunately, existing research has reported a very wide range of injury prevalence data. This papers aims to provide an explanation for this wide variation in results and, furthermore, this paper aims to establish if it is possible to carry out a meta-analysis of existing research data, pertaining to the prevalence of injury after sexual assault. It is suggested that pooling of individual study results may allow statistically robust determination of the true prevalence of injury in victims of sexual violence. It is concluded that heterogeneity in research methodology, between existing research studies, is responsible for the broad range of reported prevalence rates. Finally, this heterogeneity is seen to preclude robust meta-analysis. PMID- 23756515 TI - Are teeth useful in estimating stature? AB - Estimating stature is an important step in reconstructive identification of skeletonized and dismembered human remains. While numerous body parts such as the skull and long bones have been used for the purpose, the dentition has seldom been applied. The present study has ventured to ascertain the usefulness of tooth crown measurements in stature prediction. Buccolingual and mesiodistal dimensions of all teeth (except third molars) and stature measurements were obtained from 95 living adults (47 females, 48 males). Correlation analysis revealed that 21 of the 56 tooth crown variables had a low albeit statistically significant correlation to stature (p < 0.05); correlation matrix computed for the crown variables showed significant inter-correlations between most teeth (problem of multi-collinearity). Therefore, instead of regular least square regression analysis, ridge regression was performed for the dentition, which revealed a moderate but statistically significant correlation to stature (R = 0.68; p < 0.0001). The ridge regression equation derived had a standard error of estimate (SEE) of 8.09 cm. The multiple correlation for tooth dimensions is lower to, and the SEE larger than, most other body parts. The moderate correlation is probably due to early completion of growth of tooth crowns vis-a-vis other parameters such as long bones that mature later and have a higher stature-correlation. This indicates that the dentition may be used only as a supplement to more robust indicators of stature. PMID- 23756517 TI - Estimation of sex from index and ring finger in a North Indian population. AB - Estimation of sex is an important parameter in the examination of unknown dismembered and commingled remains. The present study explores the possibility of estimation of sex from length of index and ring finger and the index and ring finger ratio in 140 individuals (70 boys and 70 girls) from North India. Index finger length (IFL) and ring finger length (RFL) of the participants were measured following standard procedures and landmarks. Sex differentiation in the present study was based on sectioning point analysis. The 'sectioning point' for the IFL, RFL and the index and the ring finger ratio was estimated from the average of the mean of male and female values. Binary logistic regression (BLR) analysis was employed to derive a predicting equation for estimation of sex. The results of the present study indicate that significant sex differences exist in the IFL and RFL and index and ring finger ratio. Among finger lengths, RFL is a better predictor of sex than IFL. It is further concluded that the index and ring finger length is of limited utility in estimation of sex in forensic casework and should be employed only in cases when no other means of sexing are available. The study suggests that the index and ring finger ratio should not be employed in estimation of sex in forensic casework due to considerable overlap in male and female values. PMID- 23756516 TI - Age differences among victims of sexual assault: a comparison between children, adolescents and adults. AB - The present study describes the characteristics and ascertains risk factors of victims of sexual assault according to three age groups: children, adolescents and adults. Data were retrospectively obtained from a database of forensic medical examination records of sexual assault victims in Bizkaia within a two year period (2009-2010). Descriptive statistics and uni- and multivariate analyzes were used. Sexual assaults with evidence of physical injury in the examination were significantly associated with the victims' age group and with sexual assaults with penetration. They are inversely associated with vulnerable victims and assaults committed by a known offender. Sexual assaults with penetration are related significantly to older age groups and they are negatively associated with sexual assault committed at the victim's place of residence. PMID- 23756518 TI - Review of forensically important entomological specimens collected from human cadavers in Malaysia (2005-2010). AB - Forensic entomological specimens collected from human decedents during crime scene investigations in Malaysia in the past 6 years (2005-2010) are reviewed. A total of 80 cases were recorded and 93 specimens were collected. From these specimens, 10 species of cyclorrphagic flies were identified, consisting of Chrysomya rufifacies (Macquart) -38 specimens (40.86%), Chrysomya megacephala (Fabricius) -36 specimens (38.70%), Chrysomya villeneuvi (Patton) -2 specimens (2.15%), Chrysomya nigripes (Aubertin) -2 specimens (2.15%), Chrysomya pinguis (Walker) -1 specimen (1.08%), Hermetia illucens (Linnaeus) -1 specimen (1.08%), Hemipyrellia liguriens (Wiedemann) -5 specimens (5.37%), Synthesiomyia nudiseta (Wulp) -1 specimen (1.08%), Megaselia scalaris (Loew)-1 specimen (1.08%) and Sarcophaga ruficornis (Fabricius) -4 specimens (4.30%). In two specimens (2.15%), the maggots were not identifiable. Ch. megacephala and Ch. rufifacies were the commonest species found in human decedents from three different ecological habitats. S. nudiseta is an uncommon species found only on human cadavers from indoors. A total of 75 cases (93.75%) had a single fly infestation and 5 cases (6.25%) had double fly infestation. In conclusion, although large numbers of fly species were found on human decedents, the predominant species are still those of Chrysomya. PMID- 23756519 TI - Estimation of stature using lower limb measurements in Sudanese Arabs. AB - OBJECTIVES: The estimation of stature from body parts is one of the most vital parts of personal identification in medico-legal autopsies, especially when mutilated and amputated limbs or body parts are found. The aim of this study was to assess the reliability and accuracy of using lower limb measurements for stature estimations. MATERIAL AND METHODS: The stature, tibial length, bimalleolar breadth, foot length and foot breadth of 160 right-handed Sudanese Arab subjects, 80 men and 80 women (25-30 years old), were measured. The reliability of measurement acquisition was tested prior to the primary data collection. The data were analysed using basic univariate analysis and linear and multiple regression analyses. RESULTS: The results showed acceptable standards of measurement errors and reliability. Sex differences were significant for all of the measurements. There was a positive correlation coefficient between lower-limb dimensions and stature (P-value < 0.01). The best predictors were tibial length and foot length. The stature prediction accuracy ranged from +/- 2.75-5.40 cm, which is comparable to the established skeletal standards for the lower limbs. CONCLUSION: This study provides new forensic standards for stature estimation using the lower limb measurements of Sudanese Arabs. PMID- 23756520 TI - The effect of weather conditions on burnt bone fragmentation. AB - This research assesses how weather conditions, such as temperature and rainfall, affect the fragmentation of burnt bone. The recovery of human remains from fatal fire scenes is often hampered by the fragmentary nature of the material, and through understanding how weather factors affect this fragmentation, it may be possible to adjust recovery timelines and protocols to maximise the quantity and quality of condition of the material recovered. These data are also valuable as a baseline for expected fragmentation, and expected differences in fragmentation, under different weather conditions. Sus scrofa (domestic pig) limbs were burned in a series of wood fires spaced over a period of eight months, from winter through fall, in a warm summer continental climate (Koppen-Geiger classification Dfb). Bone fragments were sorted by size and the proportional weights of each size category were compared to isolate any differences in fragmentation. Results suggest that in freezing conditions with remains recovery occurring the day after the fire, increased fragmentation is observed in younger remains but not in older remains. In older remains fragmentation is highest when temperatures fluctuate around 0 degrees C. It was observed that when remains recovery is delayed, fluctuating temperatures have a larger impact on fragmentation in the short term and freezing conditions are more significant in the longer term. Wet weather conditions increase levels of fragmentation. PMID- 23756521 TI - Age and sex estimation by metric measurements and fusion of hyoid bone in a Turkish population. AB - The hyoid bone is of great importance in forensic medicine practice and it has been studied for various forensic purposes; however, there have been few studies dealing with age and sex estimation using the hyoid bone. Using discriminant function analysis this study attempts to determine the utility of metric measurements and non-metric variations of the hyoid bone in terms of estimation of sex and age in a Turkish population and to find out differences with other populations by comparison of obtained results with the literature. For this purpose, the hyoid bones of 85 cadavers of known sex and age were extracted and 33 measurements were made with a computer program following photography with a camera. In addition to these measurements, the degree of fusion of the greater cornua to the hyoid corpus was examined. Out of 33 measurements, 18 showed significant sex-related differences. There was a sharp rise in hyoid bone fusion in both males and females after the age of 60 years. However, no marked sex related differences were observed regarding fusion. The unstandardised canonical discriminant function was estimated based on three variables, and the correct classification ratio was 77.4% for males and 81.3% for females. The obtained findings suggest that measurements of hyoid bone can be used for sex estimation in the Turkish population. PMID- 23756522 TI - Multiple stabbing in sex-related homicides. AB - It is possible that sexually driven homicides are the consequence of sexual deviation, but more often than not the main cause of such homicides stems from a non-paraphilic person's emotional component. It is known that homicides which involve multiple stabbing are very often the result of the assailant's highly expressed affect. This study tries to establish whether such homicides are essentially related to the sexual motives of the murderer. This paper is conducted through a retrospective autopsy study that includes 766 cases of homicides. These were reviewed and analysed according to the motive of the homicide, as well as by method, age, and gender of the victim, and the relationship between the victim and the assailant. The motives of homicides are classified as non-sexual and sexual, including homicides related to rape, jealousy, amorous affairs outside of an established relationship, deviant sexual behaviour of psychiatric patients, paraphilia, and disturbed emotional relationships between the victim and the assailant. Cases include both hetero- and homosexual relationships. Multiple stabbing occurs significantly more frequently in sex-related homicides (>= 3 stab wounds) than in other homicide types. When the criteria for multiple stabbing are changed (>= 4, 5, or 25 stab wounds), the percentage of sex-related homicides rises in every group in relation to the increased number of wounds. Sensitivity and specificity are represented by ROC curves for 3, 5 and 7 stab wounds. The correlation coefficients between multiple stabbing and sex-related homicides regarding gender are all near 0.9. For female victims, all homicides committed by 25 and more stab wounds were found to be sex-related. Statistically, jealousy was the most frequent motive for sex related multiple stabbing homicides. Regardless of age, homicides involving multiple stabbings should be considered sex-related, especially when the victim is female. PMID- 23756523 TI - Alias: lying to the police and pathological criminal behavior. AB - The use of aliases has been shown to be associated with antisocial behavior, but the empirical research on this topic is modest. The current study employs a multiple analytical approach to explore the association between aliases and career criminality in two large samples of adult offenders. We hypothesized that the use of aliases would not only be strongly associated with arrest history but this singular behavior would accurately classify a large proportion of habitual criminals. Results show that alias usage is robustly associated with career arrests net the effects of arrest onset, age, and sex in negative binomial regression models and was an excellent classifier (AUC = .82) of habitual criminality. Implications of the findings for forensic and criminal justice practitioners are offered. PMID- 23756524 TI - Safeguarding forensic DNA reference samples with nullomer barcodes. AB - Unintended transfer of biological material containing DNA is a concern to all laboratories conducting PCR analysis. While forensic laboratories have protocols in place to reduce the possibility of contaminating casework samples, there is no way to detect when a reference sample is mislabeled as evidence, or contaminates a forensic sample. Thus there is public concern regarding the safeguarding of DNA submitted to crime labs. We demonstrate a method of introducing an internal amplification control to reference samples, in the form of a nullomer barcode which is based upon sequences absent or rare from publically accessible DNA databases. The detection of this barcode would indicate that the source of analyzed DNA was from a reference sample provided by an individual, and not from an evidence sample. We demonstrate that the nullomers can be added directly to collection devices (FTA paper) to allow tagging during the process of sample collection. We show that such nullomer oligonucleotides can be added to existing forensic typing and quantification kits, without affecting genotyping or quantification results. Finally, we show that even when diluted a million-fold and spilled on a knife, the nullomer tags can be clearly detected. These tags support the National Research Council of the National Academy recommendation that "Quality control procedures should be designed to identify mistakes, fraud, and bias" in forensic science (National Academy of Sciences, 2009). PMID- 23756525 TI - Delta-storage pool disease as a mimic of abusive head trauma in a 7-month-old baby: a case report. AB - A seven-month-old baby was admitted to a hospital emergency department after collapsing suddenly while staying with his nanny. The baby displayed classic symptoms of shaken baby syndrome, including subdural haemorrhage, cytotoxic cerebral oedema, and bilateral retinal hemorrhages. Child protection services were informed, but both the parents and the nanny denied any involvement. In the subsequent weeks, the baby developed three other episodes of new subdural bleeding and a medico-legal investigation was started into the origin of the repeated subdural bleeding. Eventually, platelet aggregation tests and electron microscopy diagnosed a delta-storage pool disease; that is, a haemostatic disorder involving dense granules of the platelets. Initial minor blunt trauma may have resulted in subdural bleeding, while subsequent retinal haemorrhage could have been facilitated by the underlying haemostatic disorder. Delta-storage pool disease should be considered as a possible mimic of abusive head trauma similar to other rare conditions such as Menkes disease and type 1 glutaric aciduria. PMID- 23756526 TI - Population data for DXS6800, DXS101 and DXS8377 loci from Buenos Aires (Argentina). AB - The X-chromosomal short tandem repeats (X-STRs) DXS6800, DXS101 and DXS8377 were analysed in a population sample from Buenos Aires (Argentina) using a polymerase chain reaction (PCR) multiplex approach with fluorescent detection. We present allele frequencies for these loci in a population comprising 113 women and 99 men. The Hardy-Weinberg equilibrium (HWE) was tested in the female sample and no significant deviations were observed. The homogeneity of allele frequencies of men and women was compared by the Fisher's exact test and showed similar distributions. Linkage disequilibrium (LD) tests were performed in males for all pairs of loci and no significant associations were detected. Parameters of forensic interest were also estimated. PMID- 23756527 TI - Patterned genital injury in cases of rape--a case-control study. AB - A pattern of genital injury that separates trauma seen in sexual assault cases from trauma seen following consensual sexual intercourse has been a matter of debate. This study aimed at clarifying the question by eliminating as many confounders as possible in a prospective, case-control setup. A total of 98 controls and 39 cases were examined using the naked eye, the colposcope and toluidine blue dye followed by colposcopy. The overall frequency of having at least one lesion was strikingly similar in the two groups, but cases had significantly more abrasions, a trend towards more haematomas and a higher frequency of multiple lesions. Cases had a higher frequency of lesions in locations other than the 6 o'clock position. Our data suggests that cases have larger, more complex lesions. In conclusion, this study has confirmed the existence of different patterns of genital lesions. Background data for detection of genital lesions using the three most commonly used techniques is provided. These results will aid in the interpretation of findings seen when examining sexual assault victims. PMID- 23756528 TI - Age estimation by pulp/tooth ratio in lateral and central incisors by peri-apical X-ray. AB - Since 2004, several papers on the analysis of the apposition of secondary dentine have been published. The aim of this paper was to study a sample of peri-apical X ray images of upper and lower incisors, both lateral and medial, to examine the application of pulp/tooth area ratio as an indicator of age. A sample of 116 individuals, 62 men and 54 women, aged between 18 and 74 years, was studied. Data were fitted with age as a linear function of the pulp/tooth ratio of incisors. The total variance explained by the regression equation ranged from 51.3% of age, when lower lateral incisors were used as explanatory variable, to 81.6% when upper lateral incisors were used. The accuracy of the corresponding regression model yielded ME = 8.44 and 5.34 years, respectively. These results show that, although incisors are less reliable than canines or lower premolars, they can be used to estimate age-at-death when the latter are absent. PMID- 23756529 TI - An unusual case of smothering by a medical nebulizer. AB - The following report describes an unusual case of smothering by a medical nebulizer of a psychiatric in-patient and discusses the manner of death. A 43 year-old man, with previous medical history of paranoia was hospitalized at a psychiatric department because of a suicide attempt. He was found dead by the medical staff in the seclusion room. The patient is known suffering from asthma attacks treated by Ventoline((r)) spray. Autopsy findings showed a ventoline's nebulizer impacting within the pharynx and in the upper part of oesophagus. These findings were compatible with a death by smothering. Smothering is an uncommon cause of suicide and is particularly observed in psychiatric patient. Suicidal death is established by the study of the circumstances and autopsy finding. This paper highlights the importance of a closer psychiatric in-patient residing in seclusion room. PMID- 23756530 TI - Lack of efficacy during the switch from brand to generic allopurinol. AB - We report for the first time the lack of therapeutic effects after the switch from a brand formulation of allopurinol to a generic one. A 56-year-old man, with a 5 years history of well-treated gout arthropathy with allopurinol (Zyloric((r)) 300 mg/die), developed acute gout arthropathy after the switch from the brand formulation of allopurinol to a generic one. Clinical evaluation and laboratory findings confirmed the diagnosis of acute gout arthropathy. Generic formulation of the drug was dismissed and Zyloric((r)) was administered with an improvement of both clinical symptoms and laboratory findings. In conclusion, even if generic formulations are considered to have the same effects in comparison to the brand one, more data are necessaries in order to well define their effectiveness and rationale use. PMID- 23756531 TI - A forensic autopsy case of death in a patient with pseudoxanthoma elasticum- dermatopathologic findings as a clue of the cause of death. AB - Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder, characterized by papular skin lesions and cutaneous laxity caused by fragmentation and mineralization of elastic fibers. Although vascular and retinal aspects of this disease and their associated complications are well characterized, few authors have focused on the increased incidence of epilepsy in patients with PXE. A 28 year-old Korean male was found dead in his work place with bloody-foamy discharge from his mouth and nostrils. He reportedly had a convulsive episode 5 days prior to his death in the work place. The skin showed generalized laxity and many creases with maculopapular pigmentations. A histopathologic examination of the skin revealed Pseudoxanthoma elasticum. Based on the histopathological findings and medical history, death was postulated to be due to 'an internal cause, possibly related to a seizure attack'. Our findings suggest that histopathologic examinations of any lesions found during the forensic autopsy should be encouraged. PMID- 23756532 TI - ECG changes in a case of attempted partial hanging. AB - This is a case of attempted partial hanging that behaved like a cerebrovascular accident. The serial electrocardiograms (ECGs) showed the characteristic ST and T wave changes, QT prolongation and U waves later reverting to normal over a period of one month. PMID- 23756533 TI - Temporal evolution in peritoneal hemorrhage as depicted by postmortem CT. AB - BACKGROUND: Computed Tomography (CT) is now utilized as an effective tool for postmortem diagnoses. However, reports on the temporal evolution in imaging findings of these postmortem CT is limited. CASE PRESENTATION: One night, a 66 year old male following drinking at a bar on his way home slept in the road. He was ran over by a taxi at 01:28 and immediately transferred to a nearby hospital. During his transfer to the hospital, he lost consciousness and fell into a state of cardiopulmonary arrest, and died despite resuscitation attempts. CT images were taken at 02:30. Following this, CT images were re-taken 54 h after death, just prior to a medicolegal autopsy. RESULT & DISCUSSION: Small amount of intra abdominal hemorrhage was found during the initial CT examination. However, the extent of intra-abdominal bleeding observed during the second CT examination performed 54 h later had substantially increased. During the autopsy, the amount of intra-abdominal hemorrhage was 1700 mL. Injury to the mesentery, liver and pancreas was also observed. Additional major injuries discovered during the autopsy were, skin abrasions and lacerations of the scalp, subarachnoid hemorrhage, fractures of the ribs, right humerus, and pelvic bones. The deceased postmortem blood alcohol level was 2.4 mg/mL. The cause of death was determined as exanguination due to systemic injury. The mechanism of the postmortem increase in the intra-abdominal hemorrhage remained unknown. However, the amount of bleeding found during autopsies may not be the same as that at the time of death. As a result, the criteria for the diagnosis of the cause of death in autopsies should be carefully reconsidered. In addition, accompanying CT imaging at the time of death and possible postmortem changes should be carefully considered in postmortem CT imaging, so that there will not be incorrect assignment of the causes of death. PMID- 23756534 TI - Features and motivation of a fatal attack by a juvenile white shark, Carcharodon carcharias, on a young male surfer in New Caledonia (South Pacific). AB - We present the case of a non provoked fatal shark attack on a 19-year old male surfer in New Caledonia. Several severe bites removed the right arm and all flesh from the right thigh, provoking a quick hypovolemic shock that was fatal. The information provided by a witness and the analysis of a partial bite on the right calf allowed us to identify a 2.7 m TL (est. length) white shark as responsible for this attack. The features of the attack are consistent with a young predator motivated by hunger and the development of its predatory skills. PMID- 23756535 TI - A suicidal poisoning due to tramadol. A metabolic approach to death investigation. AB - Tramadol is a synthetic opioid, widely used for post-surgical and chronic pain. Lethal overdose due only to tramadol is not common; more often the poisoning is due to tramadol in combination with other substances. Reported is a suicidal case of lethal tramadol poisoning in a 48-year-old woman. Tramadol and its metabolites O-desmethyltramadol (M1), N-desmethyltramadol (M2), N,N-didesmethyltramadol (M3), N,O-didesmethyltramadol (M5) were detected by GC/MS in biological fluids (femoral blood, bile, urine, gastric content) and viscera (brain, lung, liver and kidney). The tramadol concentration in femoral blood was 61.83 mcg/ml which is approximately 30 times higher than that believed to be lethal. According with other Authors, a preferential formation of M1 over M2 (M1/M2 ratio >1) is indicative of acute death, while M1/M2 ratio <1 suggests that death occurred after a longer time lapse from ingestion. PMID- 23756536 TI - Letter to the editor: Response to "Assessing the presence of female DNA on post coital penile swabs: relevance to the investigation of sexual assault" published in the October 2012 edition of the Journal of Forensic and Legal Medicine. PMID- 23756537 TI - The role of MDR1 C3435T gene polymorphism on gingival hyperplasia in Turkish renal transplant patients treated with cyclosporine in the absence of calcium channel blockers. AB - OBJECTIVE: To investigate the occurrence of MDR1 C3435T gene polymorphisms in the Turkish renal transplant patients treated with cyclosporine (CsA), and correlate these findings with prevalence and degree of gingival hyperplasia (GH). METHODS: Before to renal transplantation, dental treatment and oral hygiene education of 300 renal disease patients was completed. Peripheral blood samples were collected from 154 renal transplant recipients on CsA treatment without calcium channel blockers. MDR1 C3435T gene polymorphism and GH were analyzed at posttransplant month 6. RESULTS: No difference was detected among groups for age, posttransplant period, creatine levels, serum concentration of CsA, or plaque and bleeding indices (P > .05). Out of all transplanted patients, 42.8% were found to have the heterozygote genotype. This was reduced to 37.5% when individuals with GH were taken into account. However, when degree of GH was analyzed, those with severe GH were found to have the heterozygote genotype significantly more often (P < .05). CONCLUSIONS: The MDR1 gene polymorphism is not associated with GH frequency, but may be associated with GH severity. PMID- 23756538 TI - A semi-automated tool for treatment plan-quality evaluation and clinical trial quality assurance. AB - The goal of this work is to develop a plan-quality evaluation program for clinical routine and multi-institutional clinical trials so that the overall evaluation efficiency is improved. In multi-institutional clinical trials evaluating the plan quality is a time-consuming and labor-intensive process. In this note, we present a semi-automated plan-quality evaluation program which combines MIMVista, Java/MATLAB, and extensible markup language (XML). More specifically, MIMVista is used for data visualization; Java and its powerful function library are implemented for calculating dosimetry parameters; and to improve the clarity of the index definitions, XML is applied. The accuracy and the efficiency of the program were evaluated by comparing the results of the program with the manually recorded results in two RTOG trials. A slight difference of about 0.2% in volume or 0.6 Gy in dose between the semi-automated program and manual recording was observed. According to the criteria of indices, there are minimal differences between the two methods. The evaluation time is reduced from 10-20 min to 2 min by applying the semi-automated plan-quality evaluation program. PMID- 23756540 TI - Immunohistochemical characterization of axonal sprouting in mice. AB - PURPOSE: Transgenic manipulation of mouse physiology facilitates the preclinical study of genetic risk factors, neural plasticity, and reactive processes accompanying Alzheimer's disease. Alternatively, entorhinal cortex lesions (ECLs) model pathophysiological denervation and axonal sprouting in rat. Given reports of anatomical differences between the mouse and rat hippocampus, application of the ECL paradigm to transgenic mice first requires comprehensive characterization of axonal sprouting in the wild-type. METHODS: Adult male C57BL/6 mice sustained unilateral transections of the perforant pathway. Subjects were sacrificed at 1, 4, 10, 18, and 28 days postlesion, and hippocampal sections were stained for AChE, the postsynaptic terminal marker drebrin, and the presynaptic terminal proteins SNAP-25, GAP-43, synapsin, and synaptophysin. To examine synaptic turnover and reinnervation, ipsilateral-to-contralateral staining densities were determined within the dentate molecular layer, and shrinkage-corrected ratios were compared to 28 day-yoked sham cases. RESULTS: At 28 days postlesion, ipsilateral terminal marker densities exhibited significant depression. In contrast, qualitative analyses at earlier time points suggested altered AChE staining patterns and increased SNAP-25 and synapsin immunoreactivity in the inner molecular layer (IML) of the dentate gyrus. CONCLUSIONS: C57BL/6 mice exhibit synaptic reorganization following perforant path transections. The IML may provide a key target for evaluation and intervention in ECL mouse models. PMID- 23756541 TI - Towards physiological ankle movements with the ActiGait implantable drop foot stimulator in chronic stroke. AB - PURPOSE: Functional electrical stimulation represents an alternative to conventional and passive ankle foot orthosis (AFO) for the treatment of stroke related drop foot. We evaluated the implantable 4-channel stimulator ActiGait, which selectively and directly stimulates the peroneal nerve. In addition, it bypasses the need for surface electrodes and cables. METHODS: Walking speed (10 meter gait test, [m/s]) and walking endurance (6-minute gait test [m/6min]) of 5 patients were tested prior to, as well as 6 and 12 weeks after, the implantation of the ActiGait implantable drop foot stimulator system. In addition, ankle joint angles were assessed during specific phases of the gait cycle, i.e. initiation angle (IA) at the first contact of the foot to the floor, initial plantar flexion (IPF), dorsiflexion (DF) and final plantar flexion (FPF) in [ degrees ] during stance phase. The ankle joint angles were measured at baseline and 12 weeks after ActiGait implantation. RESULTS: At the first follow-up, patients' gait speed was found to have increased (0.55; 0.77 m/s) as had walking endurance (211; 260 m). Improvement in gait speed (0.55; 0.77 m/s) and endurance (214; 248 m) was still present after 12 weeks. In addition, gait analysis after 12 weeks revealed a nearly normal physiological initiation angle (113 degrees vs 122 degrees ) and an increase in the initial plantar flexion (7 degrees vs. 0 degrees ). The initiation angle (IA) represents a well-suited parameter for adequate pre positioning of the foot at the beginning of the stance phase and is necessary to prevent stumbling and falling. Furthermore, IA is identical to the maximum achieved dorsiflexion during the swing phase of gait. Thus, analysis of the IA of subjects walking with the implantable drop foot stimulator systems ActiGait is particularly useful in showing that the implantable system restores the IA towards physiological ankle movements. CONCLUSION: The ActiGait system increased gait speed, walking endurance and the physiology of important ankle joint kinematics. This is most likely a result of ankle dorsiflexion by active peroneal stimulation during the swing phase of gait and optimized prepositioning (IA) of the foot at the beginning of stance phase. The ActiGait system represents a therapeutic option for the treatment of patients suffering drop foot due to a cerebrovascular insult. PMID- 23756542 TI - Analyses of the NAC transcription factor gene family in Gossypium raimondii Ulbr.: chromosomal location, structure, phylogeny, and expression patterns. AB - NAC domain proteins are plant-specific transcription factors known to play diverse roles in various plant developmental processes. In the present study, we performed the first comprehensive study of the NAC gene family in Gossypium raimondii Ulbr., incorporating phylogenetic, chromosomal location, gene structure, conserved motif, and expression profiling analyses. We identified 145 NAC transcription factor (NAC-TF) genes that were phylogenetically clustered into 18 distinct subfamilies. Of these, 127 NAC-TF genes were distributed across the 13 chromosomes, 80 (55%) were preferentially retained duplicates located in both duplicated regions and six were located in triplicated chromosomal regions. The majority of NAC-TF genes showed temporal-, spatial-, and tissue-specific expression patterns based on transcriptomic and qRT-PCR analyses. However, the expression patterns of several duplicate genes were partially redundant, suggesting the occurrence of sub-functionalization during their evolution. Based on their genomic organization, we concluded that genomic duplications contributed significantly to the expansion of the NAC-TF gene family in G. raimondii. Comprehensive analysis of their expression profiles could provide novel insights into the functional divergence among members of the NAC gene family in G. raimondii. PMID- 23756543 TI - Optical characterization of Prodan aggregates in water medium. AB - The fluorescent probe Prodan (2-dimethylamino-6-propionylnaphthalene) has been widely used in biological systems, mainly due to the high sensitivity of its emission spectrum to the medium polarity. Though mostly used as a membrane probe, in lipid dispersions Prodan partitions in water, mainly in the presence of gel phase bilayers. Here, optical properties of Prodan in aqueous medium are experimentally studied using absorption and emission spectroscopies, and compared with those of the probe in cyclohexane, where it is supposed to be very soluble. In parallel, theoretical calculations of the absorption spectrum of a monomer and aggregated Prodan in water were performed. Moreover, to understand Prodan-water and Prodan-Prodan interactions, solvation free energies of Prodan in water and in liquid Prodan were calculated. A light scattering profile underneath the optical absorption spectrum of Prodan in water clearly indicates the presence of aggregates at very low Prodan concentrations (0.9 MUM). Experimental evidence of Prodan aggregation is theoretically supported by solvation free energy calculations, which demonstrate that Prodan molecules interact preferentially with other Prodan molecules than with water molecules. Theoretical calculations for electronic transition energies of monomers and aggregated Prodan in water show that a Prodan optical absorption band at 358 nm is related to the monomeric form of Prodan. This band saturates as Prodan concentration increases, indicating that aggregated Prodan prevails at higher concentrations. The relative increase in Prodan aggregated population is monitored by the increase in an absorption band at higher energies, at around 250 nm, and by the disappearance of a band at around 280 nm. Surprisingly, it was observed that the fluorescent emission spectrum of Prodan is not sensitive to probe aggregation up to around 15 MUM. Hence, Prodan aggregation in water medium, even at very low concentrations, must be considered when using this fluorescent probe in biological systems, having in mind that its fluorescence spectrum is rather insensitive to aggregation. PMID- 23756544 TI - Usefulness of local postoperative care after laser dacryocystorhinostomy. AB - INTRODUCTION AND OBJECTIVES: Epiphora caused by nasolacrimal drainage system obstruction is the main indication for dacryocystorhinostomy (DCR). So are chronic conjunctivitis and dacryocystitis from the same origin. Nasal endoscopy and the introduction of laser assisted DCR have facilitated the performance of the technique. However, it requires complex and expensive equipment, so there are still supporters of the traditional external procedure. The aim of this work was to study the effectiveness and usefulness of local postoperative care in laser DCR final result. MATERIAL AND METHODS: We studied a group of 96 patients diagnosed with epiphora secondary to stenosis-occlusion of the nasolacrimal duct. Of these, 32 patients underwent surgery in both eyes, making a total of 128 cases. The surgery was performed in a private setting between January 1999 and December 2008. The 128 cases were divided into 2 groups: 59 cases in which between 4 and 6 postoperative cures were given in the 2 months following the surgery, and another group of 69 cases in which a single cure was given approximately 7 days after surgery. The final assessment of the outcome of the intervention was done in all cases between 24-30 months after surgery. RESULTS: In 27 cases out of 128 (79% success), there was a restenosis of tear drainage. No statistically significant differences were found between the 2 groups. CONCLUSIONS: In the sample of patients that were intervened using laser assisted DCR, implementation of postoperative cure was irrelevant in the success of the intervention. PMID- 23756546 TI - Comparison of twelve-lead electrocardiogram using a glove-based recording system with standard methodology. AB - We tested the clinically relevant diagnostic accuracy of a new electrocardiographic (ECG) recording system incorporating all 10 ECG electrodes in a single-size glove worn on the patient's left arm and placed on the chest. The PhysioGlove (PG) was designed to allow fast, reproducible, electrode placement with only minimal training. The American College of Cardiology/American Heart Association ECG recording guidelines and others have repeatedly highlighted the unacceptable progressive deterioration in ECG accuracy mainly resulting from a performer's lack of proficiency and diligence, leading to frequent electrode misplacement. We studied 428 consenting adult patients with a broad spectrum of anthropomorphic characteristics and ECG and cardiovascular pathologic entities. The chest girth was measured to ascertain the single-size PG clinical diagnostic accuracy in >=90% of this patient population. For each patient, a PG and standard cable electrocardiogram were consecutively recorded and interpreted by experienced electrocardiographers. The study included 3 phases: phase 1, run-in (n = 120); phase 2, comparative diagnostic accuracy (n = 208); and phase 3, randomized, blinded, diagnostic accuracy (n = 100). Of the entire study population (n = 428), 92% fit the chest girth range of 85 to 118 cm (34 to 47 in.), representing the reference standard clinical diagnostic PG chest girth range. The phase 2 PG diagnostic accuracy was 91.3% for entire chest girth range and 95.7% for the 89.4% of patients with a chest girth within the reference range. The mean PG diagnostic accuracy in phase 3 was 93% (95% confidence interval 89% to 95%). In conclusion, compared with standard-cable electrocardiograms, the PG demonstrated excellent diagnostic accuracy (93% to 95.7%) in >=90% of a typical western adult patient population. The PG's ease of use and minimal training requirements offer a promising tool to markedly improve ECG clinical diagnostic accuracy in most adult western patients. PMID- 23756547 TI - A meta-analysis of mortality and major adverse cardiovascular and cerebrovascular events following transcatheter aortic valve implantation versus surgical aortic valve replacement for severe aortic stenosis. AB - The purpose of this meta-analysis was to compare postprocedural mortality and major adverse cardiovascular and cerebrovascular events between transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) for severe aortic stenosis. Seventeen studies (n = 4,659) comparing TAVI (n = 2,267) and SAVR (n = 2,392) were included. End points were baseline logistic European System for Cardiac Operative Risk Evaluation score, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, transient ischemic attack, and major bleeding events. Mean differences or risk ratios with 95% confidence intervals were computed, and p values <0.05 were considered significant. The population was matched for risk between the 2 groups on the basis of logistic European System for Cardiac Operative Risk Evaluation score for all outcomes except 30-day all-cause mortality, which had a high-risk population in the TAVI group (p = 0.02). There was no significant difference found in all cause mortality at 30 days (p = 0.97) and at an average of 85 weeks (p = 0.07). There was no significant difference in cardiovascular mortality (p = 0.54) as well as the incidence of myocardial infarction (p = 0.59), stroke (p = 0.36), and transient ischemic attack (p = 0.85) at averages of 86, 72, 66, and 89 weeks, respectively. Compared with patients who underwent TAVI, those who underwent SAVR had a significantly higher frequency of major bleeding events (p <0.0001) at mean follow-up of 66 weeks. In conclusion, TAVI has similar cardiovascular and all cause mortality to SAVR at early and long-term follow-up. TAVI is superior to SAVR for major bleeding complications and noninferior to SAVR for postprocedural myocardial infarctions and cerebrovascular events. TAVI is a safe alternative to SAVR in selected high-risk elderly patients with severe aortic stenosis. PMID- 23756548 TI - Incomplete revascularization is associated with greater risk of long-term mortality after stenting in the era of first generation drug-eluting stents. AB - The association between incomplete revascularization (IR) and long-term mortality after stenting in the era of drug-eluting stents is not well understood. In the present study, we test the hypothesis that IR is associated with a greater risk of long-term (5-year) mortality after stenting for multivessel coronary disease. Using data from the Percutaneous Coronary Intervention Reporting System of New York State, 21,767 patients with multivessel disease who underwent stenting during October 2003 to December 2005 were identified. Complete revascularization (CR) was achieved in 6,844 patients (31.4%), and 14,923 patients (68.6%) were incompletely revascularized. The CR and IR patients were propensity matched on a 1:1 ratio on the number of diseased vessels, the presence of total occlusion, type of stents, and the probability of achieving CR estimated using a logistic model with established risk factors as independent variables. Patients were followed for vital status until December 31, 2008 using the National Death Index. Differences in survival between the matched CR and IR patients were compared. Among the 6,511 pairs of propensity-matched patients, the 5-year survival rate for IR was lower compared with CR (79.3% vs 81.4%, p = 0.004), and the risk of death during follow-up was 16% greater for IR compared with CR (hazard ratio 1.16, 95% confidence interval 1.06 to 1.27, p = 0.001). In addition, subgroup analyses demonstrated that the association between IR and long-term mortality was not dependent on major patient risk factors. In conclusion, IR is associated with an increased risk of long-term mortality after stenting for multivessel disease in the era of drug-eluting stents. PMID- 23756551 TI - Report of the first Asia-Pacific Forum on antiviral treatment of influenza, Asia Pacific Alliance for the Control of Influenza, Bangkok, 14 June 2012. AB - On 14 June 2012, the Asia-Pacific Alliance for the Control of Influenza (APACI) convened the first Antiviral Forum jointly with the Influenza Foundation of Thailand and the Thailand Department of Disease Control. The goals of the meeting were to improve pandemic planning in the region from lessons learned during the 2009 pandemic, particularly with regard to the safety and efficacy of antiviral use; gain a better understanding of the therapeutic use of antivirals in seasonal influenza; review and analyse the official influenza control policies of Asia Pacific countries and evidence gaps to support policy development; and to establish collaborative relationships to promote best practices in the use of antivirals for the treatment of influenza. The urgent need for education highlighting the importance of influenza and the benefits of antiviral drug use in the Asia-Pacific region was identified. PMID- 23756553 TI - Electrophoresis of a soft sphere in a necked cylindrical nanopore. AB - The influence of boundary shape on electrophoresis is modeled by considering a soft spherical particle comprising a positively charged rigid core and an uncharged membrane layer on the axis of a necked cylindrical pore with its throat positively charged. The presence of the throat makes the associated flow and electric fields nonuniform, yielding several interesting behaviors. In general, the reduction in the cross-section area of the pore intensifies the local electric field and, therefore, accelerates the particle. It also makes the ionic distribution nonuniform, and the electric field induced accelerates the particle. The maximum mobility occurs at the center of a throat, and the higher the charge density of the throat the larger the ratio of maximum mobility/mobility far away from the throat. This result is informative for the design of separation devices having variable cross sectional area. PMID- 23756555 TI - CO2 multicyclic capture of pretreated/doped CaO in the Ca-looping process. Theory and experiments. AB - We study in this paper the conversion of CaO-based CO2 sorbents when subjected to repeated carbonation-calcination cycles with a focus on thermally pretreated/doped sorbents. Analytical equations are derived to describe the evolution of conversion with the cycle number from a unifying model based on the balance between surface area loss due to sintering in the looping-calcination stage and surface area regeneration as a consequence of solid-state diffusion during the looping-carbonation stage. Multicyclic CaO conversion is governed by the evolution of surface area loss/regeneration that strongly depends on the initial state of the pore skeleton. In the case of thermally pretreated sorbents, the initial pore skeleton is highly sintered and regeneration is relevant, whereas for nonpretreated sorbents the initial pore skeleton is soft and regeneration is negligible. Experimental results are obtained for sorbents subjected to a preheating controlled rate thermal analysis (CRTA) program. By applying this preheating program in a CO2 enriched atmosphere, CaO can be subjected to a rapid carbonation followed by a slow rate controlled decarbonation, which yields a highly sintered skeleton displaying a small conversion in the first cycle and self-reactivation in the next ones. Conversely, carbonation of the sorbent at a slow controlled rate enhances CO2 solid-state diffusion, which gives rise, after a quick decarbonation, to a highly porous skeleton. In this case, CaO conversion in the first cycle is very large but it decays abruptly in subsequent cycles. Data for CaO conversion retrieved from the literature and from further experimental measurements performed in our work are analyzed as influenced by a variety of experimental variables such as preheating temperature program, preheating exposition time, atmosphere composition, presence of additives, and carbonation-calcination conditions. Conversion data are well fitted by the proposed model equations, which are of help for a quantitative interpretation of the effect of experimental conditions on the multicyclic sorbent performance as a function of sintering/regeneration parameters inferred from the fittings and allow foreseeing the critical conditions to promote reactivation. The peculiar behavior of some pretreated sorbents, showing a maximum conversion in a small number of cycles, is explained in light of the model. PMID- 23756556 TI - Orthogonality in discrete self-assembly--survey of current concepts. AB - Over years, mathematicians, biologists and chemists have capitalised on the highly useful concept of orthogonality for developing sophisticated complex systems. The use of orthogonal pairs ensures that any modification made on one pair does not propagate any effect onto the other. While the concept equally pertains to dynamic supramolecular interactions, interference-free self-assembly built on multiple orthogonal interactions is still limited and the underlying notions are not yet firmly established. Herein, we identify, classify and evaluate dynamic interactions in various orthogonal settings in order to distill out general recommendations for reliable dynamic orthogonality. Our classification has to exclude templating, allosteric and/or cooperative effects as the latter are specific for individual cases only. PMID- 23756557 TI - Long-term follow-up of cultured epidermal autograft in a patient with recessive dystrophic epidermolysis bullosa. PMID- 23756558 TI - Neutron imaging of ion transport in mesoporous carbon materials. AB - Neutron imaging is presented as a tool for quantifying the diffusion of ions inside porous materials, such as carbon electrodes used in the desalination process via capacitive deionization and in electrochemical energy-storage devices. Monolithic mesoporous carbon electrodes of ~10 nm pore size were synthesized based on a soft-template method. The electrodes were used with an aqueous solution of gadolinium nitrate in an electrochemical flow-through cell designed for neutron imaging studies. Sequences of neutron images were obtained under various conditions of applied potential between the electrodes. The images revealed information on the direction and magnitude of ion transport within the electrodes. From the time-dependent concentration profiles inside the electrodes, the average value of the effective diffusion coefficient for gadolinium ions was estimated to be 2.09 +/- 0.17 * 10(-11) m(2) s(-1) at 0 V and 1.42 +/- 0.06 * 10( 10) m(2) s(-1) at 1.2 V. The values of the effective diffusion coefficient obtained from neutron imaging experiments can be used to evaluate model predictions of the ion transport rate in capacitive deionization and electrochemical energy-storage devices. PMID- 23756560 TI - Significance of two skin biopsy performances with consecutive deeper sections in the differential diagnosis between cutaneous polyarteritis nodosa and livedo vasculopathy. PMID- 23756559 TI - Functional evaluation of circulating hematopoietic progenitors in Noonan syndrome. AB - Noonan syndrome (NS) is an autosomal dominant disorder, characterized by short stature, multiple dysmorphisms and congenital heart defects. A myeloproliferative disorder (NS/MPD), resembling juvenile myelomonocytic leukemia (JMML), is occasionally diagnosed in infants with NS. In the present study, we performed a functional evaluation of the circulating hematopoietic progenitors in a series of NS, NS/MPD and JMML patients. The different functional patterns were compared with the aim to identify a possible NS subgroup worthy of stringent hematological follow-up for an increased risk of MPD development. We studied 27 NS and 5 JMML patients fulfilling EWOG-MDS criteria. The more frequent molecular defects observed in NS were mutations in the PTPN11 and SOS genes. The absolute count of monocytes, circulating CD34+ hematopoietic progenitors, their apoptotic rate and the number of circulating CFU-GMs cultured in the presence of decreasing concentrations or in the absence of granulocyte-macrophage colony-stimulating factor (GM-CSF) were evaluated. All JMML patients showed monocytosis>1,000/ul. Ten out of the 27 NS patients showed monocytosis>1,000/ul, which included the 3 NS/MPD patients. In JMML patients, circulating CD34+ cells were significantly increased (median, 109.8/ul; range, 44-232) with a low rate of apoptosis (median, 2.1%; range, 0.4-12.1%), and circulating CFU-GMs were hyper-responsive to GM-CSF. NS/MPD patients showed the same flow cytometric pattern as the JMML patients (median, CD34+ cells/ul, 205.7; range, 58-1374; median apoptotic rate, 1.4%; range, 0.2-2.4%) and their circulating CFU-GMs were hyper-responsive to GM-CSF. These functional alterations appeared 10 months before the typical clinical manifestations in 1 NS/MPD patient. In NS, the CD34+ absolute cell count and circulating CFU-GMs showed a normal pattern (median CD34+ cells/ul, 4.9; range, 1.3-17.5), whereas the CD34+ cell apoptotic rate was significantly decreased in comparison with the controls (median, 8.6%; range, 0-27.7% vs. median, 17.6%; range, 2.8-49.6%), suggesting an increased CD34+ cell survival. The functional evaluation of circulating hematopoietic progenitors showed specific patterns in NS and NS/MPD. These tests are a reliable integrative tool that, together with clinical data and other hematological parameters, could help detect NS patients with a high risk for a myeloproliferative evolution. PMID- 23756561 TI - Onychophagia and onychotillomania: prevalence, clinical picture and comorbidities. AB - Onychophagia is defined as chronic nail biting behaviour, which usually starts during childhood. Onychotillomania results from recurrent picking and manicuring of the fingernails and/or toenails, leading to visual shortening and/or estraction of nails. The aim of this study was to assess the prevalence of onychophagia and onychotillomania in young adults, and the comorbidity of these conditions with anxiety disorders and obsessive compulsive disorders (OCD), as well as to determine factors related to these behaviours. A total of 339 individuals were interviewed with a structured questionnaire. Onychophagia was present in 46.9% of participants (including 19.2% active and 27.7% past nail biters), and an additional 3 people (0.9%) had onychotillomania. The majority of subjects (92.2%) described nail biting as an automatic behaviour. Tension before nail biting was reported by 65.7% of nail biters, and feelings of pleasure after nail biting by 42%. Among the participants with lifetime onychophagia, 22.5% met criteria of anxiety disorder and 3.1% of OCD, while in the group without onychophagia at least one anxiety disorder was diagnosed in 26.2% and OCD in 5.0%. We did not find any correlation between nail biting and other anxiety disorders or OCD. In conclusion, no single condition was associated with nail biting or influenced such behaviour; multiple psychological factors were involved. PMID- 23756562 TI - Overexpression of TOB1 confers radioprotection to bronchial epithelial cells through the MAPK/ERK pathway. AB - The aim of this study was to investigate the effects and mechanisms of antiproliferative transducer of erbB2, 1 (TOB1) on the radiosensitivity of the normal human bronchial epithelial cell line HBE. After exposure to different doses of irradiation or a certain dose for different time intervals, the expression of TOB1 mRNA and protein in HBE cells was determined by semi quantitative RT-PCR and western blot analysis. Liposome-induced recombinant plasmid transfection and G418 selection were performed to establish a stably transfected TOB1-overexpressing HBE cell line. A clonogenic assay was used to determine the radiosensitivity of the HBE cells with different TOB1 expression statuses. The cell cycle distribution was detected by flow cytometry. The ionizing radiation (IR)-induced gamma-H2AX foci formation was detected by immunofluorescence assay. The related mechanism was explored by western blot analysis. TOB1 expression in the HBE cells was not induced by IR, neither dose dependently nor time-dependently. Compared to the parental or 'mock' transfected HBE cells, the radiosensitivity of HBE cells overexpressing TOB1 was significantly decreased (P<0.05). Exogenous TOB1 prevented HBE cells from apoptosis after IR, in contrast to the control cells (P<0.05), and significantly decreased the IR-induced gamma-H2AX foci formation. After IR, the expression of DNA damage repair proteins such as XRCC1, MRE11, FEN1 and ATM was increased in the TOB1-overexpressing HBE cells when compared with the expression levels in the control cells. HBE/TOB1 cells presented a much higher phosphorylated ERK1/2 and phosphorylated p53 when compared with the levels in the control cell lines when receiving 6 Gy of X-rays. Notably, the increased expression of phosphorylated p53 in HBE/TOB1 cells after IR was sufficiently blocked by U0126, a specific inhibitor of MEK1/2. Different from its functions in several lung cancer cell lines, TOB1 demonstrated a radioprotective function in the immortalized normal human bronchial epithelial cell line HBE via the MAPK/ERK signaling pathway. PMID- 23756563 TI - Effect of bulky substituents on the self-assembly and mixing behavior of arylene ethynylene macrocycles at the solid/liquid interface. AB - In this work we provide a systematic scanning tunneling microscopy (STM) study on the self-assembling and mixing behavior of Arylene Ethynylene Macrocycles (AEMs) containing 1,4-phenylene, 1,4-naphthylene or 9,10-anthrylene substituents at the solid/liquid interface. The effect of bulky substituents on the self-assembly structure was investigated and we found that 1,4-phenylene ethynylene macrocycle (AEM-B) and 1,4-naphthylene ethynylene macrocycle (AEM-N) form four and three different patterns at the 1,2,4-trichloride benzene (TCB)/graphite interface, respectively, and a significant concentration effect was observed for both molecules. 9,10-anthrylene ethynylene macrocycle (AEM-A) only forms a filled honeycomb structure at relatively high concentrations. The effect of bulky substituents was attributed to the steric hindrance, which hinders full interdigitation of alkoxy chains. The mixing behavior of binary mixtures of arylene ethynylene macrocycles was also investigated at the TCB/HOPG interface. The results demonstrate that the steric hindrance brought by the bulky groups does not enable sufficient recognition between identical molecules at the interface and random mixing was observed for binary mixtures of AEM-B and AEM-N. The mixing behavior of AEMs could also be predicted by the parameter called the 2D isomorphism coefficient. PMID- 23756564 TI - Long-chain SFA at the sn-1, 3 positions of TAG reduce body fat deposition in C57BL/6 mice. AB - The present study aimed to determine the effect of positional distribution of long-chain SFA in TAG, especially at the sn-1, 3 positions, on fat deposition using the C57BL/6 mouse model. Throughout the 15 weeks of the study, mice were fed with diets fortified with palm olein (POo), chemically interesterified POo (IPOo) and soyabean oil (SOY). Mice receiving the SOY-enriched diet gained significantly higher amounts of subcutaneous fat (P= 0.011) and total fat (P= 0.013) compared with the POo group, despite similar body mass gain being recorded. During normalisation with food consumption to obtain the fat:feed ratio, mice fed with the POo-enriched diet exhibited significantly lower visceral (P= 0.044), subcutaneous (P= 0.006) and total (P= 0.003) fat:feed than those fed with the SOY-enriched diet. It is noteworthy that mice fed with the IPOo-enriched diet gained 14.3 % more fat per food consumed when compared with the POo group (P= 0.013), despite their identical total fatty acid compositions. This was mainly attributed to the higher content of long-chain SFA at the sn-1, 3 positions of TAG in POo, which results in delayed absorption after deacylation as evidenced by the higher amounts of long-chain SFA excreted in the faeces of mice fed with the POo-enriched diet. Negative correlations were found between the subcutaneous, visceral as well as total fat accretion per food consumption and the total SFA content at the sn-1, 3 positions, while no relationships were found for MUFA and PUFA. The present results show that the positional distribution of long-chain SFA exerts a more profound effect on body fat accretion than the total SFA content. PMID- 23756565 TI - CtBP1 is involved in epithelial-mesenchymal transition and is a potential therapeutic target for hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a highly invasive type of cancer. Metastasis is the leading cause of mortality of advanced HCC patients. In the metastasis cascade, cancer cells undergo epithelial-mesenchymal transition resulting in the loss of cell-to-cell adhesion, migration and invasion into the stroma. Loss of E cadherin expression is a key molecular event in epithelial-mesenchymal transition through several regulatory mechanisms including epigenetic modification, regulation by inhibitory transcriptional factors and deletion of chromosome 16q24 locus. C-terminal binding protein 1 (CtBP1) functions as a corepressor binding to several transcriptional factors and suppresses E-cadherin expression. We found that CtBP1 was upregulated in HCC when compared with paired normal liver tissues and was inversely correlated with E-cadherin expression in HCC by immunohistochemical assay using tissue array. Western blot analysis confirmed the results of the immunohistochemical assays. When CtBP1 was knocked down by siRNA in HepG2 cells (a human HCC cell line), E-cadherin was upregulated and the invasive ability of HepG2 cells was inhibited. In addition, following CtBP1 knockdown, the cell viability was decreased along with increased apoptosis rather than cell cycle arrest. These data suggest a pivotal role of CtBP1 in EMT of HCC, and its potential as a therapeutic target in human disease.